PMID- 29754298 TI - Characterization of extracellular polysaccharide/protein contents during the adsorption of Cd(II) by Synechocystis sp. PCC6803. AB - Cyanobacteria have been proven to be cheaper and more effective for the removal of metallic elements in aqueous solutions. In this study, the living cyanobacteria Synechocystis sp. PCC6803 was used to adsorb Cd(II) and its extracellular polymeric substances (EPS) were investigated in the adsorption process. The initial stage of adsorption of Cd(II) was a rapid process, and then increase slowly accompanied with the increases of biomass. The final adsorption percentage could achieve 86% when the Cd(II) concentration was 0.5 mg/L. It proved that Synechocystis sp. PCC6803 has a good adsorption capacity for heavy metal ions. EPS was extracted to investigate the secretion of which was dynamic and the maximum extracellular polysaccharides and proteins were 134.2 and 100.9 mg/g, respectively. Furthermore, the real-time PCR (RT-PCR) results of genes (slr0977 and exoD) involved in EPS synthesis and secretion indicated that the EPS production was firstly increased and then decreased slightly. Transmission electron microscope (TEM) observation revealed that heavy metal ions were absorbed into EPS layer. Fourier transform infrared spectrum (FT-IR) analysis showed that EPS was rich in functional groups which could combine with heavy metal ions, such as -OH and -NH groups. All the results obtained show that the secretion of EPS by cyanobacteria was one of the ways to resist heavy metal stress. And it shows a trend of rising first and then decreasing, the change regulation of which was consistent with adsorptive behavior. PMID- 29754299 TI - High-throughput NIR spectroscopic (NIRS) detection of microplastics in soil. AB - The increasing pollution of terrestrial and aquatic ecosystems with plastic debris leads to the accumulation of microscopic plastic particles of still unknown amount. To monitor the degree of contamination, analytical methods are urgently needed, which help to quantify microplastics (MP). Currently, time costly purified materials enriched on filters are investigated both by micro infrared spectroscopy and/or micro-Raman. Although yielding precise results, these techniques are time consuming, and are restricted to the analysis of a small part of the sample in the order of few micrograms. To overcome these problems, we tested a macroscopic dimensioned near-infrared (NIR) process spectroscopic method in combination with chemometrics. For calibration, artificial MP/ soil mixtures containing defined ratios of polyethylene, polyethylene terephthalate, polypropylene, and polystyrene with diameters < 125 MUm were prepared and measured by a process FT-NIR spectrometer equipped with a fiber-optic reflection probe. The resulting spectra were processed by chemometric models including support vector machine regression (SVR), and partial least squares discriminant analysis (PLS-DA). Validation of models by MP mixtures, MP free soils, and real-world samples, e.g., fermenter residue, suggests a reliable detection and a possible classification of MP at levels above 0.5 to 1.0 mass% depending on the polymer. The benefit of the combined NIRS chemometric approach lies in the rapid assessment whether soil contains MP, without any chemical pretreatment. The method can be used with larger sample volumes and even allows for an online prediction and thus meets the demand of a high-throughput method. PMID- 29754300 TI - Green synthesis of palm oil mill effluent-based graphenic adsorbent for the treatment of dye-contaminated wastewater. AB - Textile wastewater contains methylene blue (MB), a major coloring agent in textile industry. Activated carbon (AC) is the most widely used adsorbent in removing dyes from industrial wastewater. However, high production cost of AC is the major obstacle for its wide application in dye wastewater treatment. In this study, a sustainable approach in synthesizing graphenic adsorbent from palm oil mill effluent (POME), a potential carbonaceous source, has been explored. This new development in adsorption technique is considered as green synthesis as it does not require any binder during the synthesis process, and at the same time, it helps to solve the bottleneck of palm oil industry as POME is the main cause contributed to Malaysia's water pollution problem. The synthesized GSC was characterized through XRD, FESEM, and EDX. The adsorption performance of the synthesized GSC was evaluated by adsorption of MB. The effect of initial concentration of synthetic MB solution (1-20 mg/L) and weight of GSC (5-20 g) were investigated. A remarkable change in color of synthetic MB solution from blue to crystal clear was observed at the end of adsorption study. High efficiency of the synthesized GSC for dye-contaminated wastewater treatment is concluded. PMID- 29754301 TI - Immobilization of soil cadmium using combined amendments of illite/smectite clay with bone chars. AB - The widespread use of cadmium (Cd)-containing organic fertilizers is a source of heavy metal inputs to agricultural soils in suburban areas. Therefore, the research and development of new materials and technologies for the remediation of Cd-contaminated soil is of great significance and has the potential to guarantee the safety of agricultural products and the protection of human health. We performed pot experiments to determine the potential of combined amendments of illite/smectite (I/S) clay with bone chars for the remediation of Cd-contaminated agricultural soils in a suburban area of Beijing, China. The results showed that both diethylene triamine pentaacetic acid (DTPA)-extractable Cd in soil and the Cd in Brassica chinensis were significantly decreased by the application of 1, 2, or 5% combined amendments with various I/S and bone char (BC) ratios. The higher proportions of BC used in the combined amendments resulted in a better immobilization of soil Cd. The application of the 5% amendment that combined I/S with either pig or cattle BC resulted in the best immobilization. All of the combined amendments, regardless of the composition and ratio of the components, had no negative effects on the growth of B. chinensis. Therefore, it was concluded that combined amendments of I/S and BC have a good potential for remediating Cd-contaminated soils. PMID- 29754302 TI - Comparative study on treatment of kitchen wastewater using a mixed microalgal culture and an aerobic bacterial culture: kinetic evaluation and FAME analysis. AB - Microalgae-based treatment systems have been successfully used for the polishing of domestic wastewater. Research is underway in studying the suitability of using these systems as main treatment units. This study focuses on comparing the performances of a mixed microalgal culture and an aerobic bacterial culture, based on the kinetic evaluation, in removing organic carbon from a kitchen wastewater. The two systems were operated at six different solid retention times (SRTs)-2, 4, 6, 8, 10, and 12 days in continuous mode. The influent and effluent samples were analyzed for chemical oxygen demand (COD), total organic carbon (TOC), total nitrogen (TN), phosphates, and surfactants. Steady-state kinetics (k, Ks, Y, and kd) for organic carbon removal were obtained by fitting experimental data in linearized Michaelis-Menten and Monod equations. The mixed microalgal system showed similar or better performance in COD and TN removal (88 and 85%, respectively) when compared with the COD and TN removal by the aerobic bacterial system (89 and 48%). A maximum lipid yield of 40% (w/w of dry biomass) was observed in the microalgal system. Saturated fatty acids accounted for 50% of the total observed FAME species. The study indicates that the mixed microalgal culture is capable of treating kitchen wastewater and has the potential to replace aerobic bacteria in biological treatment systems in certain cases. PMID- 29754303 TI - Preparation and Cr(VI) removal performance of corncob activated carbon. AB - Corncob activated carbon (CCAC) was prepared by a H3PO4 activation method. The optimum conditions for the preparation of CCAC were determined by orthogonal experiments. The effects of pH, reaction time, CCAC dosage, and hexavalent chromium (Cr(VI)) concentrations on Cr(VI) removal by CCAC were studied. Corn straw activated carbon (CSAC) was also prepared using the optimum preparation conditions determined for CCAC. The properties of samples were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), Brunauer Emmett-Teller (BET) analysis, scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). The results showed that the optimum preparation conditions for CCAC were as follows: a mass of corncob of 10 g; a mass ratio of corncob to H3PO4 of 1:2; a 5% H3BO3 content of 10 mL; an impregnation time of 45 min; a carbonization temperature of 500 degrees C. The optimum conditions for the removal of Cr(VI) were as follows: pH < 9; temperature, 308 K; rotation speed, 150 r min-1; reaction time, 60 min; CCAC dosage, 1 g L-1. The Cr(VI) removal rate was above 98%, and the maximum adsorption capacity of CCAC was 9.985 mg g-1. The concentration of residual Cr(VI) in water was less than 0.05 mg L-1. FTIR showed that the surfaces of the samples had more oxygen-containing functional groups, which promoted the adsorption. XRD showed that CCAC and CSAC had similar peaks and that these peaks promoted the adsorption of Cr(VI). BET indicated that the number of pores in the samples followed the order CCAC > CSAC > CAC. SEM showed that the CCAC surface had a more porous structure, which enhanced adsorption. EDS showed that the C contents of CCAC and CSAC were much higher than that of CAC. Cr(VI) adsorption on CCAC followed quasi-second-order kinetics and was in accordance with a Langmuir adsorption isotherm, with monolayer adsorption. The adsorption reaction was endothermic, where higher temperatures increased the degree of spontaneous reaction. PMID- 29754304 TI - Impact of high-deductible insurance on adjuvant hormonal therapy use in breast cancer. AB - OBJECTIVE: High-deductible health plans (HDHPs) have become the predominant commercial health insurance arrangement in the US. HDHPs require substantial out of-pocket (OOP) costs for most services but often exempt medications from high cost sharing. We examined effects of HDHPs on OOP costs and utilization of adjuvant hormonal therapy (AHT), which are fundamental care for patients with breast cancer. METHODS: This controlled quasi-experimental study used claims data (2003-2012) from a large national health insurer. We included 986 women with incident early-stage breast cancer, age 25-64 years, insured by employers that mandated a transition from low-deductible (<= $500/year) to high-deductible (>= $1000/year) coverage, and 3479 propensity score-matched controls whose employers offered only low-deductible plans. We examined AHT utilization and OOP costs per person-year before and after the HDHP switch. RESULTS: At baseline, the OOP costs for AHT were $40.41 and $36.55 per person-year among the HDHP and control groups. After the HDHP switch, the OOP costs for AHT were $91.76 and $72.98 per person year among the HDHP and control groups, respectively. AHT OOP costs increased among HDHP members relative to controls but the change was not significant (relative change 13.72% [95% CI - 9.25, 36.70%]). AHT use among HDHP members did not change compared to controls (relative change of 2.73% [95% CI - 14.01, 19.48%]); the change in aromatase inhibitor use was - 11.94% (95% CI - 32.76, 8.88%) and the change in tamoxifen use was 20.65% (95% CI - 8.01, 49.32%). CONCLUSION: We did not detect significant changes in AHT use after the HDHP switch. Findings might be related to modest increases in overall AHT OOP costs, the availability of low-cost generic tamoxifen, and patient awareness that AHT can prolong life and health. Minimizing OOP cost increases for essential medications might represent a feasible approach for maintaining medication adherence among HDHP members with incident breast cancer. PMID- 29754305 TI - Changes to taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2018). AB - This article lists the changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses in February 2018. A total of 451 species, 69 genera, 11 subfamilies, 9 families and one new order were added to the taxonomy. The current totals at each taxonomic level now stand at 9 orders, 131 families, 46 subfamilies, 803 genera and 4853 species. A change was made to the International Code of Virus Classification and Nomenclature to allow the use of the names of people in taxon names under appropriate circumstances. An updated Master Species List incorporating the approved changes was released in March 2018 ( https://talk.ictvonline.org/taxonomy/ ). PMID- 29754306 TI - Genome sequence of a novel partitivirus identified from the oomycete Pythium nunn. AB - The mycoparasitic oomycete Pythium nunn isolate UZ415 contains two double stranded RNAs (dsRNAs) of different sizes. The 1707-nt dsRNA1 and the 1475-nt dsRNA2 potentially encode an RNA-dependent RNA polymerase (RdRp) and a coat protein (CP), respectively, with sequence similarity to the RdRp and CP of gammapartitiviruses (< 57% and < 36%). Phylogenetic analysis of the deduced RdRp amino acid sequences indicated that the virus identified from P. nunn is classifiable as a distinct member of the genus Ganmmapartitivirus in the family Partitiviridae. This virus isolate is hereby named Pythium nunn virus 1 (PnV1). PMID- 29754307 TI - Effects of Cocaine Self-Administration and Its Extinction on the Rat Brain Cannabinoid CB1 and CB2 Receptors. AB - The aim of this study was to evaluate changes in the expression of cannabinoid type 1 (CB1) and 2 (CB2) receptor proteins in several brain regions in rats undergoing cocaine self-administration and extinction training. We used a triad yoked procedure to distinguish between the motivational and pharmacological effects of cocaine. Using immunohistochemistry, we observed a significant decrease in CB1 receptor expression in the prefrontal cortex, dorsal striatum, and the basolateral and basomedial amygdala following cocaine (0.5 mg/kg/infusion) self-administration. Increased CB1 receptor expression in the ventral tegmental area in rats with previous cocaine exposure was also found. Following cocaine abstinence after 10 days of extinction training, we detected increases in the expression of CB1 receptors in the substantia nigra in both cocaine groups and in the subregions of the amygdala for only the yoked cocaine controls, while any method of cocaine exposure resulted in a decrease in CB2 receptor expression in the prefrontal cortex (p < 0.01), nucleus accumbens (p < 0.01), and medial globus pallidus (p < 0.01). Our findings further support the idea that the eCB system and CB1 receptors are involved in cocaine-reinforced behaviors. Moreover, we detected a cocaine-evoked adaptation in CB2 receptors in the amygdala, prefrontal cortex, and globus pallidus. PMID- 29754309 TI - Hypothesis: early renal replacement therapy increases mortality in critically ill patients with acute on chronic renal failure. A post hoc analysis of the AKIKI trial. PMID- 29754310 TI - The ten pitfalls of lactate clearance in sepsis. PMID- 29754308 TI - A state of the art review on optimal practices to prevent, recognize, and manage complications associated with intravascular devices in the critically ill. AB - Intravascular catheters are inserted into almost all critically ill patients. This review provides up-to-date insight into available knowledge on epidemiology and diagnosis of complications of central vein and arterial catheters in ICU. It discusses the optimal therapy of catheter-related infections and thrombosis. Prevention of complications is a multidisciplinary task that combines both improvement of the process of care and introduction of new technologies. We emphasize the main component of the prevention strategies that should be used in critical care and propose areas of future investigation in this field. PMID- 29754311 TI - Impact of combined antibiotic treatment on multidrug-resistant bacteria emergence after postoperative intra-abdominal infections : Discussion on the DURAPOP randomised clinical trial. PMID- 29754313 TI - Prediabetes and subsequent pancreatic fat accumulation. PMID- 29754312 TI - Cloning, purification and biochemical characterisation of a GH35 beta-1,3/beta 1,6-galactosidase from the mucin-degrading gut bacterium Akkermansia muciniphila. AB - A putative GH35 beta-galactosidase gene from the mucin-degrading bacterium Akkermansia muciniphila was successfully cloned and further investigated. The recombinant enzyme with the molecular mass of 74 kDa was purified to homogeneity and biochemically characterised. The optimum temperature of the enzyme was 42 degrees C, and the optimum pH was determined to be pH 3.5. The addition of sodium dodecyl sulphate (SDS) reduced the enzyme's activity significantly. The addition of Mg2+-ions decreased the activity of the beta-galactosidase, whereas other metal ions or EDTA showed no inhibitory effect. The enzyme catalysed the hydrolysis of beta1,3- and beta1,6- linked galactose residues from various substrates, whereas only negligible amounts of beta1,4-galactose were hydrolysed. The present study describes the first functional characterisation of a beta galactosidase from this human gut symbiont. PMID- 29754314 TI - Response to the letter by Dr. Tomoyuki Kawada regarding our manuscript: Independent association between prediabetes and future pancreatic fat accumulation: a 5-year Japanese cohort study. PMID- 29754315 TI - Three New Indole Alkaloids from Tabernaemontana divaricata. AB - Three new monoterpene indole alkaloids, 3alpha-hydroxymethyl-ibogamine (1), 3alpha-acetatemethoxyl-ibogamine (2), 16alpha-hydroxyl-ibogamine (3) together with six known alkaloids were isolated from the branches and leaves of Tabernaemontana divaricata (Apocynaceae). The structures of these alkaloids were determined by spectroscopic analyses. All isolated compounds showed no significant cytotoxicity against SGC-7901 gastric cancer, HeLa, and A-549 lung cancer cell lines (IC50 > 20 uM). PMID- 29754316 TI - Compromised mechanical homeostasis in arterial aging and associated cardiovascular consequences. AB - Aging leads to central artery stiffening and associated hemodynamic sequelae. Because healthy arteries exhibit differential geometry, composition, and mechanical behaviors along the central vasculature, we sought to determine whether wall structure and mechanical function differ across five vascular regions-the ascending and descending thoracic aorta, suprarenal and infrarenal abdominal aorta, and common carotid artery-in 20 versus 100-week-old male wild type mice. Notwithstanding generally consistent changes across these regions, including a marked thickening of the arterial wall, diminished in vivo axial stretch, and loss of elastic energy storage capacity, the degree of changes tended to be slightly greater in abdominal than in thoracic or carotid vessels. Likely due to the long half-life of vascular elastin, most mechanical changes in the arterial wall resulted largely from a distributed increase in collagen, including thicker fibers in the media, and localized increases in glycosaminoglycans. Changes within the central arteries associated with significant increases in central pulse pressure and adverse changes in the left ventricle, including increased cardiac mass and decreased diastolic function. Given the similar half-life of vascular elastin in mice and humans but very different life-spans, there are important differences in the aging of central vessels across these species. Nevertheless, the common finding of aberrant matrix remodeling contributing to a compromised mechanical homeostasis suggests that studies of central artery aging in the mouse can provide insight into mechanisms and treatment strategies for the many adverse effects of vascular aging in humans. PMID- 29754317 TI - Prediction of brain deformations and risk of traumatic brain injury due to closed head impact: quantitative analysis of the effects of boundary conditions and brain tissue constitutive model. AB - In this study, we investigate the effects of modelling choices for the brain skull interface (layers of tissues between the brain and skull that determine boundary conditions for the brain) and the constitutive model of brain parenchyma on the brain responses under violent impact as predicted using computational biomechanics model. We used the head/brain model from Total HUman Model for Safety (THUMS)-extensively validated finite element model of the human body that has been applied in numerous injury biomechanics studies. The computations were conducted using a well-established nonlinear explicit dynamics finite element code LS-DYNA. We employed four approaches for modelling the brain-skull interface and four constitutive models for the brain tissue in the numerical simulations of the experiments on post-mortem human subjects exposed to violent impacts reported in the literature. The brain-skull interface models included direct representation of the brain meninges and cerebrospinal fluid, outer brain surface rigidly attached to the skull, frictionless sliding contact between the brain and skull, and a layer of spring-type cohesive elements between the brain and skull. We considered Ogden hyperviscoelastic, Mooney-Rivlin hyperviscoelastic, neo Hookean hyperviscoelastic and linear viscoelastic constitutive models of the brain tissue. Our study indicates that the predicted deformations within the brain and related brain injury criteria are strongly affected by both the approach of modelling the brain-skull interface and the constitutive model of the brain parenchyma tissues. The results suggest that accurate prediction of deformations within the brain and risk of brain injury due to violent impact using computational biomechanics models may require representation of the meninges and subarachnoidal space with cerebrospinal fluid in the model and application of hyperviscoelastic (preferably Ogden-type) constitutive model for the brain tissue. PMID- 29754318 TI - Four new species of Metschnikowia and the transfer of seven Candida species to Metschnikowia and Clavispora as new combinations. AB - From comparisons of ITS1-5.8S-ITS2 and gene sequences for nuclear D1/D2 LSU rRNA, nuclear SSU (18S) rRNA, translation elongation factor 1-alpha (EF1-alpha) and RNA polymerase II subunit 2 (RPB2), the following four new ascosporogenous yeast species were resolved and are described as Metschnikowia anglica (NRRL Y-7298T [type strain], CBS 15342, MycoBank MB 823167), Metschnikowia leonuri (NRRL Y 6546T, CBS 15341, MB 823166), Metschnikowia peoriensis (NRRL Y-5942T, CBS 15345, MB 823164) and Metschnikowia rubicola (NRRL Y-6064T, CBS 15344, MB 823165). The following six species of Candida are members of the Metschnikowia clade and are proposed for transfer to Metschnikowia as new combinations: Candida chrysomelidarum (NRRL Y-27749T, CBS 9904, MB 823223), Candida gelsemii (NRRL Y 48212T, CBS 10509, MB 823192), Candida kofuensis (NRRL Y-27226T, CBS 8058, MB 823195), Candida picachoensis (NRRL Y-27607T, CBS 9804, MB 823197), Candida pimensis (NRRL Y-27619T, CBS 9805, MB 823205) and Candida rancensis (NRRL Y 48702T, CBS 8174, MB 823224). Candida fructus (NRRL Y-17072T, CBS 6380, MB 823206) is transferred to Clavispora as a new combination, and Candida musae is shown to be a synonym of C. fructus. Apparent multiple alleles for ITS, D1/D2, EF1-alpha and RPB2 were detected in strains of some species. PMID- 29754319 TI - Responses of rainbow trout intestinal epithelial cells to different kinds of nutritional deprivation. AB - In order to develop an in vitro system to study the cell biology of starvation in the fish intestine, rainbow trout intestinal epithelial cells were subjected to three kinds of nutrient deprivation and evaluated for 7 days. The RTgutGC cell line was grown into monolayers in Leibovitz's basal medium supplemented with fetal bovine serum (L15/FBS) and then subjected to deprivation of serum (L15); of serum, amino acids, and vitamin (L15/ex); and of all nutrients (L15/salts). After 7 days of nutrient deprivation, the cells remained attached to the plastic surface as monolayers but changes were seen in shape, with the cells becoming more polygonal, actin and alpha-tubulin cytoskeleton organization, and in tight junction protein-1 (ZO-1) localization. Two barrier functions, transepithelial electrical resistance (TEER) and Lucifer Yellow (LY) retention, were impaired by nutrient deprivation. In L15/FBS, cells rapidly healed a gap or wound in the monolayer. In L15 and L15/ex, some cells moved into the gap, but after 7 days, the wound remained unhealed, whereas in L15/salts, cells did not even migrate into the gap. Upon nutrient replenishment (L15/FBS) after 7 days in L15, L15/ex, or L15/salts, cells proliferated again and healed a wound. After 7 days of nutrient deprivation, monolayers were successfully passaged with trypsin and cells in L15/FBS grew to again form monolayers. Therefore, rainbow trout intestinal epithelial cells survived starvation, but barrier and wound healing functions were impaired. PMID- 29754320 TI - Pathophysiology and Genetics of Bronchiectasis Unrelated to Cystic Fibrosis. AB - Bronchiectasis is characterized by deregulated inflammatory response and recurrent bacterial infection resulting in progressive lung damage and an irreversible dilatation of bronchi and bronchioles. Generally accepted model of the development of bronchiectasis is the "vicious cycle hypothesis" that proposes compromising of the mucociliary clearance by an initial event, which leads to the infection of the respiratory tract followed by further impairment of mucociliary function, bacterial proliferation, and more inflammation. Bronchiectasis is a very common symptom in patients with cystic fibrosis (CF), while bronchiectasis unrelated to CF is heterogeneous pathology of unknown cause with a large number of potential contributory factors and poorly understood pathogenesis. It is presumed that bronchiectasis unrelated to CF is a multifactorial condition predisposed by genetic factors. Different molecules have been implicated in the onset and development of idiopathic bronchiectasis, as well as modulation of the disease severity and response to therapy. Most of these molecules are involved in the processes that contribute to the homeostasis of the lung tissue, especially mucociliary clearance, protease-antiprotease balance, and immunomodulation. Evaluation of the studies performed towards investigation of the role these molecules play in bronchiectasis identifies genetic variants that may be of potential importance for clinical management of the disease, and also of interest for future research efforts. This review focuses on the molecules with major roles in lung homeostasis and their involvement in bronchiectasis unrelated to CF. PMID- 29754322 TI - Continuity of Learning in Discontinuous Conditions: Children Experience of Transition in Irreversible Time. AB - In this theoretical paper, I propose that in certain conditions children's subjective continuity (irreversible time) of experience could be sustained by objective discontinuity in reference to instruments like the clock that is used to sequentialize time in school. I suggest that it happens through intervals-as transitions (c.f., breaks in school) that Min (2018; this special issue) undermines for epistemological reasons but insisted upon by Bergson. I use Bergson to epistemologically reframe Min's (2018) interesting suggestions -that I partially use- with respect to irreversible time. Yet, my epistemological and theoretical suggestion contrasts with both authors' perspective, for instance Bergson's critic of objective discontinuity as contaminating subjective experience while paradoxically tackling intervals that are constructed in discontinuous conditions. In this regard, I use Bergson's as well as He Min's conceptual contradictions with respect to subjective and objective time as zones for theoretical development enabling the extension of their approach. I mainly use ethnographic examples I made and secondarily from McLaren's (1999) analysis of the intersection of school, family and community rituals to illustrate my epistemological and theoretical propositions. PMID- 29754323 TI - The Effects of Exenatide and Metformin on Endothelial Function in Newly Diagnosed Type 2 Diabetes Mellitus Patients: A Case-Control Study. AB - INTRODUCTION: Exenatide is a new antidiabetic glucagon-like peptide-1 receptor agonist. In addition to its hypoglycemic effect, exenatide may have a potential protective benefit on vascular endothelial function. This study attempted to compare the effects of exenatide and traditional antidiabetic drug metformin treatment on endothelial function in overweight patients with type 2 diabetes. METHODS: Ninety overweight patients with newly diagnosed type 2 diabetes were recruited; 45 patients received exenatide (Exe) treatment and 45 patients received metformin (Met) treatment for 12 weeks. The control groups included 37 overweight and 24 non-overweight individuals. The parameters of glucose and lipid metabolism and endothelial function were measured before and after treatment. Vascular endothelial dysfunction was measured by reactive hyperemia index. RESULTS: Newly diagnosed patients with type 2 diabetes had more serious vascular endothelial dysfunction than both overweight and normal-weight control groups. The levels of body mass index, glucose, HbA1c, homeostasis model assessment insulin resistance, and homeostasis model assessment beta-cell function were improved significantly by both exenatide and metformin treatment. Both exenatide and metformin treatment can improve vascular endothelial function (Exe group: 1.67 +/- 0.52 vs 1.98 +/- 0.67, P < 0.05; Met group: 1.68 +/- 0.29 vs 1.82 +/- 0.24, P < 0.05). Exenatide treatment was no less effective than metformin in improving endothelial function (0.31 +/- 0.70 vs 0.13 +/- 0.24, P > 0.05). CONCLUSIONS: Newly diagnosed patients with type 2 diabetes may have vascular endothelial dysfunction. Both exenatide and metformin treatment can improve vascular endothelial dysfunction, and exenatide was no less effective than metformin treatment. PMID- 29754321 TI - Chronic low back pain: a mini-review on pharmacological management and pathophysiological insights from clinical and pre-clinical data. AB - Globally, low back pain (LBP) is one of the most common health problems affecting humans. The lifetime prevalence of non-specific LBP is approximately 84%, with the chronic prevalence at about 23%. Chronic LBP in humans is defined as LBP that persists for more than 12 weeks without a significant pain improvement. Although there are numerous evidence-based guidelines on the management of acute LBP, this is not the case for chronic LBP, which is regarded as particularly difficult to treat. Research aimed at discovering new drug treatments for alleviation of chronic mechanical LBP is lacking due to the paucity of knowledge on the pathobiology of this condition, despite its high morbidity in the affected adult population. For a debilitating condition such as chronic LBP, it is necessary to assess the sustained effects of pharmacotherapy of various agents spanning months to years. Although many rodent models of mechanical LBP have been developed to mimic the human condition, some of the major shortcomings of many of these models are (1) the presence of a concurrent neuropathic component that develops secondary to posterior intervertebral disc puncture, (2) severe model phenotype, and/or (3) use of behavioural endpoints that have yet to be validated for pain. Hence, there is a great, unmet need for research aimed at discovering new biological targets in rodent models of chronic mechanical LBP for use in drug discovery programs as a means to potentially produce new highly effective and well-tolerated analgesic agents to improve relief of chronic LBP. On a cautionary note, it must be borne in mind that because humans and rats display orthograde and pronograde postures, respectively, the different mechanical forces on their spines add to the difficulty in translation of promising rodent data to humans. PMID- 29754324 TI - Cost-utility analysis of an intervention designed to reduce the critical handling error of insufficient inspiratory effort. AB - OBJECTIVES: Up to 70-80% of patients use inhalers incorrectly. Dry-powder inhalers (DPIs) require forceful inhalation for optimal delivery, and approximately 40% of Global Initiative for Asthma (GINA)-defined Step-3+ patients inhale corticosteroid and long-acting beta-agonist through DPIs. The CRITIKAL study (Price et al. in J Allergy Clin Immunol Pract 5:1071-e9-1081-e9, 2017) found a statistically significant association between 'insufficient inspiratory effort' error and increased risk of uncontrolled asthma and hospitalisation requiring exacerbations. This paper explores the cost-effectiveness of an error targeted intervention. METHODS: A probabilistic Markov cost-utility model simulated patients transitioning between controlled and uncontrolled health states over one year. Odds ratios (ORs, from the CRITIKAL study) of a patient having uncontrolled asthma conditional on making the error were applied to baseline transition probabilities sourced from the literature, both indirectly via an adjustment formula (Zhang et al. in JAMA 280:1690-1691, 1998) and directly by assuming OR approximates relative risk (RR). The analysis explored complete/partial eradication of the error when the intervention was priced to match comparators, as well as impact of indirect costs based on lost/reduced productivity. RESULTS: The intervention dominated both DPI comparators over one year, with direct cost savings of L45/L86 with 0.0053/0.0102 additional quality adjusted life years (QALYs), and had the highest probability of being cost effective at a L20,000/QALY threshold. Key factors driving variance were weekly utilities per state and RR of moving to an uncontrolled state. CONCLUSION: The analysis demonstrated the economic and societal costs of 'insufficient inspiratory effort' and potential economic benefits of introducing an effective intervention to reduce/eradicate this error. Further research should assess the economic impact of other handling errors. PMID- 29754325 TI - Genome-wide association study dissects yield components associated with low phosphorus stress tolerance in maize. AB - KEY MESSAGE: Phosphorus deficiency in soil is a worldwide constraint threatening maize production. Through a genome-wide association study, we identified molecular markers and associated candidate genes and molecular pathways for low phosphorus stress tolerance. Phosphorus deficiency in soils will severely affect maize (Zea mays L.) growth and development, thus decreasing the final yield. Deciphering the genetic basis of yield-related traits can benefit our understanding of maize tolerance to low-phosphorus stress. However, considering that yield-related traits should be evaluated under field condition with large populations rather than under hydroponic condition at a single-plant level, searching for appropriate field experimental sites and target traits for low phosphorus stress tolerance is still very challenging. In this study, a genome wide association analysis using two natural populations was performed to detect candidate genes in response to low-phosphorus stress at two experimental sites representative of different climate and soil types. In total, 259 candidate genes were identified and these candidate genes are mainly involved in four major pathways: transcriptional regulation, reactive oxygen scavenging, hormone regulation, and remodeling of cell wall. Among these candidate genes, 98 showed differential expression by transcriptome data. Based on a haplotype analysis of grain number under phosphorus deficiency condition, the positive haplotypes with favorable alleles across five loci increased grain number by 42% than those without favorable alleles. For further verifying the feasibility of genomic selection for improving maize low-phosphorus tolerance, we also validated the predictive ability of five genomic selection methods and suggested that moderate density SNPs were sufficient to make accurate predictions for low-phosphorus tolerance traits. All these results will facilitate elucidating genetic basis of maize tolerance to low-phosphorus stress and improving marker-assisted selection efficiency in breeding process. PMID- 29754326 TI - Acid phosphatase gene GmHAD1 linked to low phosphorus tolerance in soybean, through fine mapping. AB - KEY MESSAGE: Map-based cloning identified GmHAD1, a gene which encodes a HAD-like acid phosphatase, associated with soybean tolerance to low phosphorus stress. Phosphorus (P) deficiency in soils is a major limiting factor for crop growth worldwide. Plants may adapt to low phosphorus (LP) conditions via changes to root morphology, including the number, length, orientation, and branching of the principal root classes. To elucidate the genetic mechanisms for LP tolerance in soybean, quantitative trait loci (QTL) related to root morphology responses to LP were identified via hydroponic experiments. In total, we identified 14 major loci associated with these traits in a RIL population. The log-likelihood scores ranged from 2.81 to 7.43, explaining 4.23-13.98% of phenotypic variance. A major locus on chromosome 08, named qP8-2, was co-localized with an important P efficiency QTL (qPE8), containing phosphatase genes GmACP1 and GmACP2. Another major locus on chromosome 10 named qP10-2 explained 4.80-13.98% of the total phenotypic variance in root morphology. The qP10-2 contains GmHAD1, a gene which encodes an acid phosphatase. In the transgenic soybean hairy roots, GmHAD1 overexpression increased P efficiency by 8.4-16.5% relative to the control. Transgenic Arabidopsis plants had higher biomass than wild-type plants across both short- and long-term P reduction. These results suggest that GmHAD1, an acid phosphatase gene, improved the utilization of organic phosphate by soybean and Arabidopsis plants. PMID- 29754327 TI - The many faces of IgG4-related disease: report of a case with inaugural recurrent aortic aneurism ruptures and literature review. AB - Vascular involvement in IgG4-related disease (IgG4-RD), is a well-recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. Being a newly recognized disease, its diagnosis and workup still represents a challenge in clinical practice. A 47-year-old-man with two aortic aneurysms ruptures, one at abdominal and the other at thoracic level, was referred to our rheumatology department. The initial analysis of the surgical specimen obtained 3 years earlier revealed a nonspecific aortitis. Re-evaluation of the biopsy with immunohistology now demonstrated the presence of IgG4 deposits. Evidence-based recommendations regarding diagnosis, treatment and follow-up of IgG4-related large-vessel involvement are lacking. In this particular case, histopathology were crucial. The authors review and discuss vascular involvement in IgG4-RD and respective treatment options. PMID- 29754328 TI - HBsAg-negative and anti-HBc-positive in eosinophilic granulomatosis with polyangiitis: a retrospective pilot study. AB - We examined whether resolved hepatitis B virus (HBV) infection was associated with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and affected AAV activity at diagnosis and prognosis during the follow-up. We reviewed the electronic medical records of 153 AAV patients, and included 91 hepatitis B surface antigen (HBsAg)-negative patients having results of both antibody to hepatitis B core antigen (anti-HBc) and surface antigen (anti-HBs). We collected clinical and laboratory data, Birmingham vasculitis activity score (BVAS) and five factor scores (FFS) at diagnosis and relapse rates during the follow-up. We divided patients into the two groups according to the presence of anti-HBc and compared variables between them in patients with AAV or those with each variant. The mean age and follow-up duration were 59.8 +/- 15.2-year-old and 48.0 +/- 47.5 months. Fifty patients (54.9%) had anti-HBc, and 61 patients (67.0%) had anti-HBs. Only thirty-six (39.6%) patients had ever experienced relapse after remission. There were no remarkable differences between HBsAg negative AAV patients with and without anti-HBc. However, in eosinophilic granulomatosis with polyangiitis (EGPA) patients, patients with HBs-negative/anti HBc-positive (resolved HBV infection) showed the higher initial mean BVAS and FFS (2009) than those without. Patients having anti-HBc exhibited significantly increased risk of relapse of EGPA than those having not (RR 16.0). Also, EGPA patients with HBs-negative/anti-HBc-positive showed meaningfully lower cumulative relapse-free survival rates than those without during the follow-up duration (p = 0.043). In conclusion, resolved HBV infection may importantly influence vasculitis activity at diagnosis and subsequently relapse after remission in EGPA patients. PMID- 29754329 TI - Efficacy and safety of sofosbuvir plus daclatasvir with or without ribavirin: large real-life results of patients with chronic hepatitis C genotype 4. AB - BACKGROUND AND AIM: Clinical studies evaluating the efficacy of daclatasvir (DCV) for treatment of chronic hepatitis C virus (HCV) genotype 4 (GT4) infection are scarce. This study aims to evaluate the efficacy and safety of DCV plus sofosbuvir (SOF) with or without ribavirin (RBV) for treatment of Egyptian patients infected with HCV GT4. METHODS: Between April 2016 and March of 2017, a large cohort of 946 patients with chronic HCV GT4 was enrolled for completing the treatment. Patients were classified into two groups: group 1 (easy to treat) was treated with a dual therapy of SOF/DCV daily for 12 weeks and group 2 (difficult to treat) was treated with a triple therapy of SOF/DCV/RBV daily for 12 weeks. Efficacy and safety of the treatments were estimated, and baseline characters associated with sustained virological response at 12 weeks post-treatment (SVR12) were investigated. RESULTS: Among the patient's cohort, SVR12 was achieved by 94% (891/946) in the overall patients, by 95% (718/758) in the easy-to-treat group, and by 92% (173/188) in the difficult-to-treat group. The most common adverse events recorded were fatigue, headache, nausea, asthenia, and gastrointestinal troubles. No patient discontinued treatment due to severe adverse events. CONCLUSION: The findings from the present study suggested that SOF/DCV (with or without RBV) regimen exhibited high effectiveness, was well tolerated in the treatment of chronic HCV GT 4, and revealed itself as a better option for patients with advanced liver disease, making the eradication of HCV a more realistic target to achieve. PMID- 29754330 TI - Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky. AB - PURPOSE OF REVIEW: Ankylosing spondylitis (AS) was historically seen as a predominantly male disease. However, more recent data showed a more homogenous sex prevalence. Unfortunately, in many studies in axial spondyloarthritis (axSpA), the number of women included is low and the analyses are often not stratified for gender distribution. The purpose of this review is to aggregate the existing data on gender differences in axSpA in order to increase the awareness that female axSpA patients are still under-recognized. RECENT FINDINGS: Several studies considering gender differences revealed that female axSpA patients had different disease manifestations due to different immunological, hormonal, and genetic responses. For instance, allelic frequencies of the AHNK gene and tissue non-specific alkaline phosphatase (TNAP) haplotypes differed between men and women with ankylosing spondylitis (AS). In addition, different levels of tumor necrosis factor (TNF), interleukins IL-6, IL-17, and IL-18, were found between the two sexes. Furthermore, female patients show a higher diagnostic delay compared to males. Several studies indicate a higher frequency of extra-articular manifestations (EAM) in female axSpA patients, such as enthesitis, psoriasis, and inflammatory bowel disease (IBD), whereas acute anterior uveitis is more prevalent in male patients. Male AS patients more frequently show a higher Bath Ankylosing Spondylitis Radiology Index (BASRI) scores and modified Stoke Ankylosing Spondylitis Spine Scores (mSASSS) than females, which indicates that males have higher radiological damage and radiographic progression. However, disease activity (BASDAI) and quality of life (AsQol) scores are significantly higher in women, and more importantly, they have significantly lower response rates to treatment with TNF inhibitors (TNFi) and a significantly lower drug adherence. Despite the fact that men with axial SpA have a worse radiologic prognosis, women have a high disease burden, in part because they have a longer delay in diagnosis, higher disease activity, and significantly less responsiveness to treatment with TNFi. PMID- 29754331 TI - Cellular stress responses to chronic heat shock and shell damage in temperate Mya truncata. AB - Acclimation, via phenotypic flexibility, is a potential means for a fast response to climate change. Understanding the molecular mechanisms underpinning phenotypic flexibility can provide a fine-scale cellular understanding of how organisms acclimate. In the last 30 years, Mya truncata populations around the UK have faced an average increase in sea surface temperature of 0.7 degrees C and further warming of between 1.5 and 4 degrees C, in all marine regions adjacent to the UK, is predicted by the end of the century. Hence, data are required on the ability of M. truncata to acclimate to physiological stresses, and most notably, chronic increases in temperature. Animals in the present study were exposed to chronic heat-stress for 2 months prior to shell damage and subsequently, only 3, out of 20 damaged individuals, were able to repair their shells within 2 weeks. Differentially expressed genes (between control and damaged animals) were functionally enriched with processes relating to cellular stress, the immune response and biomineralisation. Comparative transcriptomics highlighted genes, and more broadly molecular mechanisms, that are likely to be pivotal in this lack of acclimation. This study demonstrates that discovery-led transcriptomic profiling of animals during stress-response experiments can shed light on the complexity of biological processes and changes within organisms that can be more difficult to detect at higher levels of biological organisation. PMID- 29754333 TI - ? PMID- 29754334 TI - ? PMID- 29754332 TI - Differential correlations between changes to glutathione redox state, protein ubiquitination, and stress-inducible HSPA chaperone expression after different types of oxidative stress. AB - In primary bovine fibroblasts with an hspa1b/luciferase transgene, we examined the intensity of heat-shock response (HSR) following four types of oxidative stress or heat stress (HS), and its putative relationship with changes to different cell parameters, including reactive oxygen species (ROS), the redox status of the key molecules glutathione (GSH), NADP(H) NAD(H), and the post translational protein modifications carbonylation, S-glutathionylation, and ubiquitination. We determined the sub-lethal condition generating the maximal luciferase activity and inducible HSPA protein level for treatments with hydrogen peroxide (H2O2), UVA-induced oxygen photo-activation, the superoxide-generating agent menadione (MN), and diamide (DA), an electrophilic and sulfhydryl reagent. The level of HSR induced by oxidative stress was the highest after DA and MN, followed by UVA and H2O2 treatments, and was not correlated to the level of ROS production nor to the extent of protein S-glutathionylation or carbonylation observed immediately after stress. We found a correlation following oxidative treatments between HSR and the level of GSH/GSSG immediately after stress, and the increase in protein ubiquitination during the recovery period. Conversely, HS treatment, which led to the highest HSR level, did not generate ROS nor modified or depended on GSH redox state. Furthermore, the level of protein ubiquitination was maximum immediately after HS and lower than after MN and DA treatments thereafter. In these cells, heat-induced HSR was therefore clearly different from oxidative stress-induced HSR, in which conversely early redox changes of the major cellular thiol predicted the level of HSR and polyubiquinated proteins. PMID- 29754335 TI - ? PMID- 29754336 TI - ? PMID- 29754337 TI - ? PMID- 29754338 TI - ? PMID- 29754339 TI - [A ghastly find in a suitcase]. PMID- 29754340 TI - [Acute anal fissure]. PMID- 29754341 TI - [Malaria compact - Up-to-date background for general practitioners]. PMID- 29754343 TI - ? PMID- 29754342 TI - [Fit for travel in older adults]. PMID- 29754344 TI - ? PMID- 29754345 TI - ? PMID- 29754347 TI - ? PMID- 29754346 TI - ? PMID- 29754348 TI - ? PMID- 29754349 TI - ? PMID- 29754351 TI - ? PMID- 29754350 TI - ? PMID- 29754352 TI - ? PMID- 29754354 TI - ? PMID- 29754353 TI - ? PMID- 29754355 TI - ? PMID- 29754357 TI - ? PMID- 29754356 TI - ? PMID- 29754358 TI - ? PMID- 29754359 TI - ? PMID- 29754360 TI - ? PMID- 29754361 TI - ? PMID- 29754362 TI - ? PMID- 29754364 TI - ? PMID- 29754363 TI - ? PMID- 29754365 TI - ? PMID- 29754367 TI - ? PMID- 29754366 TI - ? PMID- 29754368 TI - ? PMID- 29754369 TI - ? PMID- 29754370 TI - ? PMID- 29754371 TI - ? PMID- 29754373 TI - ? PMID- 29754372 TI - ? PMID- 29754374 TI - ? PMID- 29754376 TI - ? PMID- 29754378 TI - ? PMID- 29754377 TI - ? PMID- 29754379 TI - ? PMID- 29754380 TI - [Nail diseases]. PMID- 29754381 TI - Non-tuberculous Mycobacterial Infections in Thoracic Transplant Candidates and Recipients. AB - PURPOSE OF REVIEW: To review and discuss the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of non-tuberculous mycobacteria (NTM) in thoracic transplantation. RECENT FINDINGS: Non-tuberculous mycobacteria are ubiquitous but are an uncommon cause of disease after solid organ transplantation. The incidence of infection is higher in thoracic transplant recipients than in abdominal transplant recipients, with most cases seen after lung transplantation. It is associated with increased morbidity and, occasionally, mortality. Infection in the pre-transplant setting can occur in lung transplant candidates, often posing a dilemma regarding transplant listing. Disease manifestations are diverse, and pulmonary disease is the most common. Diagnosis requires a high index of suspicion. Treatment requires a multiple-drug combination and is limited by drug-drug interactions and tolerability. Mycobacterium abscessus is a challenge in lung transplant recipients, due to its intrinsic resistance and propensity to relapse even after prolonged therapy. Mycobacterium chimaera is an emerging pathogen associated with contamination of heater-cooler units and is described to cause disease months after cardiothoracic surgery. NTM infections in thoracic organ transplant recipients are uncommon but are associated with substantial morbidity and mortality. Data from larger multicenter studies is needed to better define the epidemiology of NTM in thoracic transplantation, best treatment options, and the management of infected transplant candidates. PMID- 29754382 TI - 3D/2D model-to-image registration by imitation learning for cardiac procedures. AB - PURPOSE: In cardiac interventions, such as cardiac resynchronization therapy (CRT), image guidance can be enhanced by involving preoperative models. Multimodality 3D/2D registration for image guidance, however, remains a significant research challenge for fundamentally different image data, i.e., MR to X-ray. Registration methods must account for differences in intensity, contrast levels, resolution, dimensionality, field of view. Furthermore, same anatomical structures may not be visible in both modalities. Current approaches have focused on developing modality-specific solutions for individual clinical use cases, by introducing constraints, or identifying cross-modality information manually. Machine learning approaches have the potential to create more general registration platforms. However, training image to image methods would require large multimodal datasets and ground truth for each target application. METHODS: This paper proposes a model-to-image registration approach instead, because it is common in image-guided interventions to create anatomical models for diagnosis, planning or guidance prior to procedures. An imitation learning-based method, trained on 702 datasets, is used to register preoperative models to intraoperative X-ray images. RESULTS: Accuracy is demonstrated on cardiac models and artificial X-rays generated from CTs. The registration error was [Formula: see text] on 1000 test cases, superior to that of manual ([Formula: see text]) and gradient-based ([Formula: see text]) registration. High robustness is shown in 19 clinical CRT cases. CONCLUSION: Besides the proposed methods feasibility in a clinical environment, evaluation has shown good accuracy and high robustness indicating that it could be applied in image-guided interventions. PMID- 29754383 TI - Alteration of Bone Mineral Density Differs Between Genders in Obese Subjects After Laparoscopic Sleeve Gastrectomy: Bone Morphogenetic Protein 4 May Count. AB - OBJECTIVE: Laparoscopic sleeve gastrectomy (LSG) has proven to be successful in weight reduction but with potential loss of bone mass. Previous studies indicated that bone morphogenetic protein 4 (BMP4) plays an important role in both bone formation and glucose-lipid metabolism. This study aimed to investigate the changes in bone mineral density (BMD), bone metabolic parameters, and serum BMP4 levels in obese Chinese subjects after LSG. METHODS: Seventy-one obese patients (34 males, age 31.70 +/- 9.61 years and 37 females, age 32.80 +/- 11.45 years) were enrolled. BMD (at the right hip, femoral neck, and lumbar spine 1-4 (L1-L4)) was measured by dual-energy X-ray absorptiometry, bone metabolic markers, and routine anthropometric/laboratory biochemical parameters at baseline, 3, 6, and 12 months after LSG (abbreviated as 3, 6, and 12 M post-LSG, respectively) were recorded. Serum BMP4 levels were measured by enzyme-linked immunosorbent assay. RESULTS: LSG led to dramatic weight loss with improved glucose-lipid metabolism in all patients. In females, BMD was significantly decreased at the right hip at all time points studied and at the femoral neck at 6 and 12 M post-LSG (P < 0.05 or P < 0.01). In males, BMD was not significantly changed (all P > 0.05). Intriguingly, serum BMP4 levels were reduced slightly at 3 M post-LSG (P = 0.463) and were significantly at 6 M post-LSG (from 75.51 +/- 16.54 to 65.40 +/- 10.51 pg/mL, P = 0.048) in females, but unchanged in males (all P > 0.05). Vitamin D and 25-hydroxy vitamin D were increased in males at 12 M post-LSG (all P < 0.05). Osteocalcin was increased in males at all time points studied and in females at 3 and 6 M post-LSG (all P < 0.05). Type I collagen was increased in males at 3 and 6 M post-LSG and in females at all the time points studied (all P < 0.05). CONCLUSIONS: The effect of LSG on BMD differs between genders, decreasing significantly in females while remaining unchanged in males. Moreover, decreased BMP4 levels may partly account for the diminished BMD in obese Chinese female patients after LSG. PMID- 29754384 TI - Magnesium Sulfate Reduced Opioid Consumption in Obese Patients Undergoing Sleeve Gastrectomy: a Prospective, Randomized Clinical Trial. AB - OBJECTIVE: The purpose of the study was to investigate the effect of magnesium sulfate on pain management for pain after sleeve gastrectomy operation. DESIGN: A prospective, randomized, placebo-controlled clinical study. SETTING: University hospital. PARTICIPANTS: Eighty patients undergoing sleeve gastrectomy. MEASUREMENTS AND MAIN RESULTS: Visual analog scale for the evaluation of pain, sedation score, mean arterial pressure, heart rate, and total analgesic consumption was recorded. Serum magnesium levels were determined before the operation, at the end of the operation, and at 24 h. There were no significant differences between the groups with respect to demographics, and sedation scores. Cumulative morphine consumption and pain scores were found to be higher in the control group than the magnesium group. CONCLUSION: Perioperative use of magnesium sulfate reduced postoperative pain and opioid consumption in obese patients undergoing sleeve gastrectomy operations. PMID- 29754385 TI - Four-Year Evolution of a Thrombophylaxis Protocol in an Enhanced Recovery After Surgery (ERAS) Program: Recent Results in 485 Patients. AB - "Enhanced recovery after surgery" (ERAS) protocols may reduce morbidity, length of hospital stay (LOS), and costs. During the 4-year evolution of a bariatric ERAS protocol, we found that administration of thrombophylaxis selectively to high-risk morbidly obese patients (assessed postoperatively by Caprini score >= 3) undergoing omega loop gastric bypass ("mini" gastric bypass) or sleeve gastrectomy resulted in safe outcomes. Both procedures proved equally effective with this protocol. The vast majority of rapidly mobilized, low-risk patients did not appear to require antithrombotic heparin. Similar to other reported ERAS outcomes, our recent year's results in 485 patients included a mean LOS of 1.08 +/- 0.64 days (range 1-14), with 460 (95.0%) discharged on day 1 and 99.6% by day 2. There were 13 30-day complications (2.7%), two reinterventions (0.4%), and no hemorrhages. PMID- 29754386 TI - Nutritional Deficiencies in Chinese Patients Undergoing Gastric Bypass and Sleeve Gastrectomy: Prevalence and Predictors. AB - BACKGROUND: Nutritional deficiencies have been reported in bariatric surgery patients with inconsistent results. However, scarce data exist for Chinese patients. We aimed to assess nutritional deficiencies in Chinese patients undergoing Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), and to identify predictors of postoperative nutritional status. METHODS: A retrospective review of a prospectively collected database was conducted in the patients undergoing RYGB and SG in our hospital between June 2013 and January 2017. Anthropometric data and nutritional data were collected before surgery, at 6 and 12 months postoperatively. RESULTS: This study enrolled 269 patients (120 RYGB, 149 SG). Nutritional deficiencies were common in Chinese bariatric candidates, with vitamin D deficiency the most serious (78.8%), followed by vitamin B1 (39.2%), vitamin B6 (28.0%), folate (26.8%), vitamin C (18.0%) albumin (13.4%), transferrin (11.6%), and phosphorus (11.5%). Despite postoperative routine multivitamin and calcium supplements, nutritional deficiencies were still obvious for RYGB and SG patients. The prevalence of hemoglobin and vitamin B12 deficiencies increased remarkably in the RYGB group; the levels of hemoglobin, globin, vitamin B12, and ferritin decreased significantly (P < 0.05). Preoperative hemoglobin, vitamin B12, and ferritin levels were independently associated with postoperative decrease, respectively. Deficiencies of vitamin D, vitamin B1, vitamin B6, vitamin C, and albumin before surgery were predictors for deficiencies 1 year after surgery, respectively. CONCLUSION: Nutritional deficiencies are common in Chinese bariatric surgery candidates. Similar deficiencies were also seen after RYGB and SG. Routine evaluation and related corrections of preoperative nutritional abnormity could contribute to postoperative nutrient balance. PMID- 29754388 TI - Consumption of Probiotic Lactobacillus fermentum MTCC: 5898-Fermented Milk Attenuates Dyslipidemia, Oxidative Stress, and Inflammation in Male Rats Fed on Cholesterol-Enriched Diet. AB - There is a growing and alarming prevalence that increased serum cholesterol is closely related to increased cardiovascular disease risk. Probiotic consumption could be a safe and natural strategy to combat. Therefore, we sought to examine the cholesterol-lowering potential of co-supplementation of probiotic bacteria Lactobacillus fermentum MTCC: 5898-fermented buffalo milk (2.5% fat) in rats fed cholesterol-enriched diet. Male Wistar rats were divided into three groups on the basis of feed, viz. group 1, fed standard diet (SD); group 2, fed cholesterol enriched diet (CED); and group 3, fed cholesterol-enriched diet along with L. fermentum MTCC: 5898-fermented milk (CED+LF) for 90 days. At the endpoint, significantly higher levels of serum total cholesterol, low-density lipoprotein cholesterol, triacylglycerols, very low density lipoprotein cholesterol, atherogenic index, coronary artery risk index, hepatic lipids, lipid peroxidation, and mRNA expression of inflammatory cytokines (TNF-alpha and IL-6) in the liver while significantly lower levels of serum high-density lipoprotein cholesterol and anti-oxidative enzyme activities, catalase, superoxide dismutase, and glutathione peroxidase in the liver and kidney were observed in the CED group compared to the SD group. Compared to the CED group, these adverse physiological alterations were found significantly improved in the CED+LF group. Hence, this study proposes that L. fermentum MTCC: 5898 is a potential probiotic bacteria that can be consumed to tackle hypercholesterolemia. Graphical Abstract ?. PMID- 29754387 TI - Low Genetic Diversity and Low Gene Flow Corresponded to a Weak Genetic Structure of Ruddy-Breasted Crake (Porzana fusca) in China. AB - The Ruddy-breasted Crake (Porzana fusca) is an extremely poorly known species. Although it is not listed as globally endangered, in recent years, with the interference of climate change and human activities, its habitat is rapidly disappearing and its populations have been shrinking. There are two different life history traits for Ruddy-breasted Crake in China, i.e., non-migratory population in the south and migratory population in the north of China. In this study, mitochondrial control sequences and microsatellite datasets of 88 individuals sampled from 8 sites were applied to analyze their genetic diversity, genetic differentiation, and genetic structure. Our results indicated that low genetic diversity and genetic differentiation exit in most populations. The neutrality test suggested significantly negative Fu's Fs value, which, in combination with detection of the mismatch distribution, indicated that population expansion occurred in the interglacier approximately 98,000 years ago, and the time of the most recent common ancestor (TMRCA) was estimated to about 202,705 years ago. Gene flow analysis implied that the gene flow was low, but gene exchange was frequent among adjacent populations. Both phylogenetic and STRUCTURE analyses implied weak genetic structure. In general, the genetic diversity, gene flow, and genetic structure of Ruddy-breasted Crake were low. PMID- 29754389 TI - Cost-effectiveness of forced air warming during sedation in the cardiac catheterisation laboratory. AB - AIM: The aim of this study was to determine the cost-effectiveness of forced air warming (FAW) during sedation in a cardiac catheterisation laboratory. BACKGROUND: Forced air warming improves thermal comfort in comparison with standard care. It is not known whether the extra costs required for FAW are good value. DESIGN: Cost-effectiveness analysis alongside a randomized controlled trial conducted in 2016-2017. METHODS: A cost-effectiveness analysis was undertaken using Monte Carlo simulations from input distributions to estimate costs and effects associated with using FAW to reduce risk of thermal discomfort for patients receiving sedation in a cardiac catheterisation laboratory. A range of willingness to pay threshold values were tested with results plotted on a cost effectiveness acceptability curve. Costs were calculated in Australian currency ($AUD). RESULTS: Estimated total costs were $5.21 (SD 3.26) higher per patient for FAW in comparison to standard care. Estimated probability of success (rating of thermal comfort) was 0.16 (0.06) higher for FAW. Forced air warming becomes more likely to result in a net benefit than standard care at a willingness to pay threshold of $34. CONCLUSION: Forced air warming could be considered cost effective for procedures performed with sedation in a cardiac catheterisation laboratory if the extra cost of an incremental gain in thermal comfort is less than the decision maker's willingness to pay for it. Therefore, those responsible for decision-making regarding use of FAW in the cardiac catheterisation laboratory can use results of our model to decide if it represents good value for their organisation. PMID- 29754390 TI - The importance of contextual, relational and cognitive factors for novice nurses' emotional state and affective commitment to the profession. A multilevel study. AB - AIM: This study explored the effects of contextual, relational and cognitive factors derived from novice nurses' work experiences on emotions and affective commitment to the profession. BACKGROUND: With an increasing demand for well trained nurses, it is imperative to investigate which work-related factors most affect their commitment to develop effective strategies to improve work conditions, work satisfaction and emotional attachment. DESIGN: A repeated measures within subjects design. METHODS: From September 2013-September 2014 eighteen novice nurses described work-related experiences in unstructured diaries and scored their emotional state and affective commitment on a scale. The themes that emerged from the 18 diaries (with 580 diary entries) were quantified as contextual, relational and cognitive factors. Contextual factors refer to complexity of care and existential events; relational factors to experiences with patients, support from colleagues, supervisors and physicians; cognitive factors to nurses' perceived competence. RESULTS: The first multilevel regression analysis, based on the 18 diaries with 580 entries, showed that complexity of care, lack of support and lack of competence were negatively related to novice nurses' affective commitment, whereas received support was positively related. The next multilevel regression analyses showed that all contextual, relational and cognitive factors were either related to negative or positive emotions. CONCLUSION: To retain novice nurses in the profession, it is important to provide support and feedback. This enables novice nurses to deal with the complexity of care and feelings of incompetence and to develop a professional commitment. PMID- 29754391 TI - Clinical, dermoscopic, histological and molecular analysis of BAP1-inactivated melanocytic naevus/tumour in two familial cases of BAP1 syndrome. PMID- 29754392 TI - FTO, m6 Am , and the hypothesis of reversible epitranscriptomic mRNA modifications. AB - The fate of mRNA is regulated by epitranscriptomic nucleotide modifications, the most abundant of which is N6 -methyladenosine (m6 A). Although the pattern and distribution of m6 A in mRNA is mediated by specific methyltransferases, a recent hypothesis is that specific demethylases or 'erasers' allow m6 A to be dynamically reversed by signaling pathways. In this Review, we discuss the data in support and against this model. New insights into the function of fat mass and obesity-associated protein (FTO), the original enzyme thought to be an m6 A eraser, reveal that its physiologic target is not m6 A, but instead is N6 ,2'-O dimethyladenosine (m6 Am ). Another m6 A demethylase, ALKBH5, appears to have functions limited to sperm development in normal mice. Overall, the majority of the data suggest that m6 A is generally not reversible, although m6 A may be susceptible to demethylation in pathophysiological states such as cancer. PMID- 29754393 TI - Predicting stress urinary incontinence during pregnancy: combination of pelvic floor ultrasound parameters and clinical factors. AB - INTRODUCTION: The aim of this study was to develop and validate a predictive tool that combines pelvic floor ultrasound parameters and clinical factors for stress urinary incontinence during pregnancy. MATERIAL AND METHODS: A total of 535 women in the first or second trimester of pregnancy were included for an interview and transperineal ultrasound assessment from two hospitals. Imaging data sets were analyzed offline to assess for bladder neck vertical position, urethra angles (alpha, beta and gamma angles), hiatal area and bladder neck funneling. All significant continuous variables at univariable analysis were analyzed by receiver operating characteristics. Three multivariable logistic models were built on clinical factors, and combined with ultrasound parameters. The final predictive model with best performance and fewest variables was selected to establish a nomogram. Internal and external validation of the nomogram was performed by both discrimination represented by C-index and calibration measured by Hosmer-Lemeshow test. A decision curve analysis was conducted to determine the clinical utility of the nomogram. RESULTS: After excluding 14 women with invalid data, 521 women were analyzed. beta angle, gamma angle and hiatal area had limited predictive value for stress urinary incontinence during pregnancy, with area under curves of 0.558-0.648. The final predictive model included body mass index gain since pregnancy, constipation, previous delivery mode, beta angle at rest, and bladder neck funneling. The nomogram based on the final model showed good discrimination with a C-index of 0.789 and satisfactory calibration (p = 0.828), both of which were supported by external validation. Decision curve analysis showed that the nomogram was clinically useful. CONCLUSIONS: The nomogram incorporating both the pelvic floor ultrasound parameters and clinical factors has been validated to show good discrimination and calibration, and could be an important tool for stress urinary incontinence risk prediction at an early stage of pregnancy. PMID- 29754394 TI - Anesthesia for subcutaneous implantable cardioverter-defibrillator implantation: Perspectives from the clinical experience of a U.S. panel of physicians. AB - BACKGROUND AND OBJECTIVE: Worldwide adoption of the subcutaneous implantable cardioverter-defibrillator (S-ICD) for preventing sudden cardiac death continues to increase, as longer-term evidence demonstrating the safety and efficacy of the S-ICD expands. As a relatively new technology, comprehensive anesthesia guidance for the management of patients undergoing S-ICD placement is lacking. This article presents advantages and disadvantages of different periprocedural sedation and anesthesia options for S-ICD implants including general anesthesia, monitored anesthesia care, regional anesthesia, and nonanesthesia personnel administered sedation and analgesia. METHODS: Guidance, for approaches to anesthesia care during S-ICD implantation, is presented based upon literature review and consensus of a panel of high-volume S-ICD implanters, a regional anesthesiologist, and a cardiothoracic anesthesiologist with significant S-ICD experience. The panel developed suggested actions for perioperative sedation, anesthesia, surgical practices, and a decision algorithm for S-ICD implantation. CONCLUSIONS: While S-ICD implantation currently requires higher sedation than transvenous ICD systems, the panel consensus is that general anesthesia is not required or is obligatory for the majority of patients for the experienced S-ICD implanter. The focus of the implanting physician and the anesthesia services should be to maximize patient comfort and take into consideration patient specific comorbidities, with a low threshold to consult the anesthesiology team. PMID- 29754395 TI - Nurses' needs for care robots in integrated nursing care services. AB - AIMS: To determine the need for care robots among nurses and to suggest how robotic care should be prioritized in integrated nursing care services. BACKGROUND: Korea is expected to be a super-aged society by 2030. To solve care issues with elderly inpatient caused by informal caregivers, the government introduced "integrated nursing care services"; these are comprehensive care systems staffed by professionally trained nurses. To assist them, a care robot development project has been launched. DESIGN: The study applied a cross sectional survey. METHODS: In 2016, we conducted a multicentre survey involving 302 Registered Nurses in five hospitals including three tertiary and two secondary hospitals in Korea. The questionnaire consisted of general characteristics of nurses and their views on and extents of agreement about issues associated with robotic care. RESULTS: Trial centre nurses and those with >=10 years of experience reported positively on the prospects for robotic care. The top-three desired primary roles for care robots were "measuring/monitoring", "mobility/activity" and "safety care". "Reduction in workload", especially in terms of "other nursing services" which were categorized as nonvalue-added nursing activities, was the most valued feature. The nurses approved of the aid by care robots but were concerned about device malfunction and interruption of rapport with patients. CONCLUSION: Care robots are expected to be effective in integrated nursing care services, particularly in "measuring/monitoring". Such robots should decrease nurses' workload and minimize nonvalue-added nursing activities efficiently. No matter how excellent care robots are, they must cooperate with and be controlled by nurses. PMID- 29754396 TI - The upper pouch in oesophageal atresia shows proportional growth during late foetal life. PMID- 29754397 TI - Blink reflex recovery cycle to differentiate progressive supranuclear palsy from corticobasal syndrome. AB - BACKGROUND AND PURPOSE: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) may share similar clinical findings and tests to distinguish between the two disorders could be useful. We evaluated the blink reflex and R2 blink reflex recovery cycle (R2BRRC), determining diagnostic sensitivity, specificity and positive and negative predictive value of R2BRRC in differentiating patients with PSP from those with CBS. METHODS: This was a prospective data collection study investigating blink reflex and R2BRRC at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in 12 patients with PSP, eight patients with CBS and 10 controls. RESULTS: Patients with PSP have earlier recruitment of R2BRRC as compared with patients with CBS (ISI: 100 ms, P = 0.002; 150 ms, P < 0.001; 200 ms, P < 0.001; 300 ms, P = 0.02) and controls (ISI: 100 ms, P < 0.001; 150 ms, P < 0.001; 200 ms, P < 0.001; 300 ms, P = 0.004). The presence of an early recovery of the R2 differentiated PSP from CBS with a specificity and sensitivity of 87.5% and 91.7%, respectively. CONCLUSIONS: The R2BRRC curve might be considered to be a useful tool in differentiating patients with PSP from those with CBS. PMID- 29754398 TI - Development and course of chronic pain over 4 years in the general population: The HUNT pain study. AB - BACKGROUND: Epidemiological studies of chronic pain frequently report high prevalence estimates. However, there is little information about the development and natural course of chronic pain. METHODS: We followed a random sample of participants from a population-based study (HUNT 3) with annual measures over 4 years. RESULTS: Among those without chronic pain at baseline, the probability of developing moderate to severe chronic pain (cumulative incidence) during the first year was 5%, a pain status that was maintained among 38% at the second follow-up. The probability of developing chronic pain diminished substantially for those who maintained a status of no chronic pain over several years. Subjects with moderate to severe chronic pain at baseline had an 8% probability of recovery into no chronic pain, a status that was maintained for 52% on the second follow-up. The probability of recovery diminished substantially as a status of chronic pain was prolonged for several years. Pain severity, widespread pain, pain catastrophizing, depression and sleep were significant predictors of future moderate to severe chronic pain, both among subjects with and without chronic pain at baseline. CONCLUSION: These findings suggest that the prognosis is fairly good after a new onset of chronic pain. When the pain has lasted for several years, the prognosis becomes poor. The same social and psychological factors predict new onset and the prognosis of chronic pain. SIGNIFICANCE: The development and recovery of chronic pain is highly dependent on previous pain. The prognosis of chronic pain may be predicted well when considering its duration in combination with other clinical, social and psychological factors. Targeting modifiable prognostic factors may be particularly important for newly developed chronic pain. PMID- 29754399 TI - A mixed-method systematic review of the effectiveness and acceptability of preoperative psychological preparation programmes to reduce paediatric preoperative anxiety in elective surgery. AB - AIM: To explore the effectiveness of preoperative psychological preparation programmes aimed to reduce paediatric preoperative anxiety and the potential factors that could have an impact on parent and children's acceptance of such interventions. BACKGROUND: Various preoperative psychological preparation programmes are available to address paediatric preoperative anxiety. No mixed method review has been conducted to explore the effectiveness and acceptability of these programmes. DESIGN: A mixed-method systematic review. DATA SOURCES: Seven bibliographic databases were searched from inception to September 2016, complemented by hand searching of key journals, the reference lists of relevant reviews, search for grey literature and the contacting of associated experts. REVIEW METHODS: The review process was conducted based on the framework developed by the Evidence for Policy and Practice Information and Co-ordinating Centre. A narrative summary and a thematic synthesis were developed to synthesize the quantitative and qualitative data respectively, followed by a third synthesis to combine the previous syntheses. RESULTS: Nineteen controlled trials and eleven qualitative studies were included for data synthesis. The controlled trials reveal that educational multimedia applications and web-based programmes may reduce paediatric preoperative anxiety, while the effectiveness of therapeutic play and books remains uncertain. Qualitative studies showed parent-child dyads seek different levels of information. CONCLUSIONS: Providing matched information provision to each parent and child, actively involving children and their parents and teaching them coping skills, may be the essential hallmarks of a successful preoperative psychological preparation. Further research is necessary to confirm the effectiveness of therapeutic play and books. PMID- 29754401 TI - Treatment of localized-stage follicular lymphoma. AB - Follicular lymphoma (FL) is the most common indolent lymphoma, and it most frequently presents in an advanced stage. Therapeutic considerations for advanced stage are different from those of localized-stage FL, in which radiotherapy (RT) is generally recommended. However, the available evidence suffers from shortcomings that are relatively specific to this clinical entity due to its rarity and long survival with all available treatment modalities, including that most of the existing evidence originated at a time when diagnostic classifications, staging procedures and radiotherapeutic standards were different from those available today and when anti-CD20 monoclonal antibodies were not available. Available treatment modalities include observation, systemic therapy only, RT only and RT in combination with systemic therapy. We review the evidence available with each of them and the data from present-day clinical practice studies as well as briefly discuss what diagnostic and therapeutic developments may take place in the next few years. PMID- 29754400 TI - The international prevalence and variability of nonadherence to the nonpharmacologic treatment regimen after heart transplantation: Findings from the cross-sectional BRIGHT study. AB - INTRODUCTION: Heart transplant (HTx) recipients need to follow a complex therapeutic regimen. We assessed the international prevalence and variability in nonadherence to six nonpharmacologic treatment components (physical activity, sun protection, diet, alcohol use, nonsmoking, and outpatient follow-up visits). METHODS: We used self-report data of 1397 adult HTx recipients from the 36-HTx center, 11-country, 4-continent, cross-sectional BRIGHT study (ClinicalTrials.gov ID: NCT01608477). The nonadherence definitions used were as follows: Physical activity: <3 times/wk 20 minutes' vigorous activity, <5 times/wk 30 minutes' moderate activity, or <5 times/wk a combination of either intensity; Sun protection: not "always" applying any sun protection; Diet: not "often" or "always" following recommended diet(s); Alcohol use: >1 alcoholic drink/d (women) or >2 drinks/d (men); Smoking: current smokers or stopped <1 year before; Follow up visits: missing >=1 of the last 5 outpatient follow-up visits. Overall prevalence figures were adjusted to avoid over- or underrepresentation of countries. Between-country variability was assessed within each treatment component via chi-square testing. RESULTS: The adjusted study-wide nonadherence prevalence figures were as follows: 47.8% for physical activity (95% CI [45.2 50.5]), 39.9% for sun protection (95% CI [37.3-42.5]), 38.2% for diet recommendations (95% CI [35.1-41.3]), 22.9% for alcohol consumption (95% CI [20.8 25.1]), 7.4% for smoking cessation (95% CI [6.1-8.7]), and 5.7% for follow-up visits (95% CI [4.6-6.9]). Significant variability was observed between countries in all treatment components except follow-up visits. CONCLUSION: Nonadherence to the post-HTx nonpharmacologic treatment regimen is prevalent and shows significant variability internationally, suggesting a need for tailored adherence enhancing interventions. PMID- 29754402 TI - Impact of mean arterial pressure on sublingual microcirculation during cardiopulmonary bypass-Secondary outcome from a randomized clinical trial. AB - OBJECTIVE: In this substudy of a randomized, clinical trial, we explored the sublingual microcirculation during cardiac surgery at 2 different levels of blood pressure. We hypothesized that a higher map during CPB would cause higher MFI. METHODS: Thirty-six cardiac surgery patients undergoing CABG were included and randomized to either low (40-50 mm Hg) or high (70-80 mm Hg) MAP during CPB. SDF video images were recorded from the sublingual mucosa. Recordings were analyzed in a blinded fashion to quantify microcirculatory variables. RESULTS: MAP during CPB in the low target group was 45.0 mm Hg (SD: 5.3) vs 67.2 mm Hg (SD: 8.9) in the high target group. We found no significant difference between the 2 groups in MFI during CPB evaluated for AV: 2.91 vs 2.90 (P = .82). For sm AV (<20 MUm), the corresponding values were 2.87 and 2.85 in the low and high target groups, respectively (P = .82). CONCLUSIONS: We found no significant difference in sublingual microcirculatory flow expressed as MFI according to 2 different levels of MAP during CPB. PMID- 29754403 TI - 'One size does not fit all': Perspectives on diversity in community aged care. AB - OBJECTIVES: Typically, older people are viewed via a single health condition, yet health outcomes are likely impacted by the intersection of many individual characteristics. Promoting inclusive health care is underpinned by reducing bias, respectful communication and supporting individual needs and preferences. This study explores perspectives of community aged care workers on diversity training and implementing training into practice. METHODS: Ninety community aged care workers were telephone-interviewed three months after a one-day diversity training workshop. Interviews were audio-recorded, transcribed verbatim and analysed thematically. RESULTS: Five themes emerged: 'raising awareness'; 'reserving judgement'; 'confidence and empowerment to embed diversity into practice'; 'communicating effectively'; and 'thinking about change ... but'. CONCLUSIONS: Diversity concepts were positively received, but applying diversity principles into practice is more difficult. Recommendations to promote inclusive health care included raising awareness of bias, communicating with inclusive language and embedding diversity concepts into community aged care practice by addressing individual, organisational and wider system constraints. PMID- 29754404 TI - The Asian corn borer Ostrinia furnacalis feeding increases the direct and indirect defence of mid-whorl stage commercial maize in the field. AB - The Asian corn borer (Ostrinia furnacalis Guenee) is a destructive pest of maize (Zea mays L.). Despite large-scale commercial maize production, little is known about the defensive responses of field-grown commercial maize to O. furnacalis herbivory, and how these responses result in direct and indirect defence against this pest. To elucidate the maize transcriptome response to O. furnacalis feeding, leaves of maize hybrid Jingke968 were infested with O. furnacalis for 0, 2, 4, 12 and 24 h. Ostrinia furnacalis feeding elicited stronger and more rapid changes in the defence-related gene expression (i.e. after 2 h), and more differentially expressed genes (DEGs) were up-regulated than down-regulated at all times post-induction (i.e. 2, 4, 12 and 24 h) in the O. furnacalis pre infested maize plants. KEGG pathway analysis indicated that the DEGs in the O. furnacalis pre-infested maize are involved in benzoxazinoids, phytohormones, volatiles, and other metabolic pathways related to maize resistance to herbivores. In addition, the maize leaves previously infested by O. furnacalis for 24 h showed an obvious inhibition of the subsequent O. furnacalis performance, and maize volatiles induced by O. furnacalis feeding for 24 and 48 h attracted the parasitic wasp, Macrocentrus cingulum Brischke. The increased direct and indirect defences induced by O. furnacalis feeding were correlated with O. furnacalis-induced phytohormones, benzoxazinoids, and volatiles. Together, our findings provide new insights into how commercial maize orchestrates its transcriptome and metabolome to directly and indirectly defend against O. furnacalis at the mid-whorl stage in the field. PMID- 29754405 TI - GhL1L1 affects cell fate specification by regulating GhPIN1-mediated auxin distribution. AB - Auxin is as an efficient initiator and regulator of cell fate during somatic embryogenesis (SE), but the molecular mechanisms and regulating networks of this process are not well understood. In this report, we analysed SE process induced by Leafy cotyledon1-like 1 (GhL1L1), a NF-YB subfamily gene specifically expressed in embryonic tissues in cotton. We also identified the target gene of GhL1L1, and its role in auxin distribution and cell fate specification during embryonic development was analysed. Overexpression of GhL1L1 accelerated embryonic cell formation, associated with an increased concentration of IAA in embryogenic calluses (ECs) and in the shoot apical meristem, corresponding to altered expression of the auxin transport gene GhPIN1. By contrast, GhL1L1 deficient explants showed retarded embryonic cell formation, and the concentration of IAA was decreased in GhL1L1-deficient ECs. Disruption of auxin distribution accelerated the specification of embryonic cell fate together with regulation of GhPIN1. Furthermore, we showed that PHOSPHATASE 2AA2 (GhPP2AA2) was activated by GhL1L1 through targeting the G-box of its promoter, hence regulating the activity of GhPIN1 protein. Our results indicate that GhL1L1 functions as a key regulator in auxin distribution to regulate cell fate specification in cotton and contribute to the understanding of the complex process of SE in plant species. PMID- 29754407 TI - Composition and Chemical Variability of Enantia polycarpa Engl. & Diels Leaf Essential Oil from Cote d'Ivoire. AB - The composition of Enantia polycarpa Engl. & Diels leaf essential oil has been investigated for the first time using a combination of chromatographic and spectroscopic techniques. The compositions of 52 leaf essential oil samples have been subjected to statistical analysis, hierarchical cluster analysis (HCA) and principal component analysis (PCA). Four groups were differentiated, of which the compositions were dominated by beta-elemene and germacrene B (Group III, 22/52 samples); germacrene D (Group I, 16/52 samples); beta-cubebene (Group IV, 8/52 samples) and by germacrene B and germacrene D (Group II, 6/52 samples). A special attention was brought to the quantification of the thermolabile components, germacrene A, germacrene B and germacrene C, as well as that of their rearranged compounds, beta-elemene, gamma-elemene and delta-elemene. 13 C-NMR data of beta cubebene have been provided. PMID- 29754406 TI - Targeting TWIST1 through loss of function inhibits tumorigenicity of human glioblastoma. AB - TWIST1 (TW) is a bHLH transcription factor (TF) and master regulator of the epithelial-to-mesenchymal transition (EMT). In vitro, TW promotes mesenchymal change, invasion, and self-renewal in glioblastoma (GBM) cells. However, the potential therapeutic relevance of TW has not been established through loss-of function studies in human GBM cell xenograft models. The effects of TW loss of function (gene editing and knockdown) on inhibition of tumorigenicity of U87MG and GBM4 glioma stem cells were tested in orthotopic xenograft models and conditional knockdown in established flank xenograft tumors. RNAseq and the analysis of tumors investigated putative TW-associated mechanisms. Multiple bioinformatic tools revealed significant alteration of ECM, membrane receptors, signaling transduction kinases, and cytoskeleton dynamics leading to identification of PI3K/AKT signaling. We experimentally show alteration of AKT activity and periostin (POSTN) expression in vivo and/or in vitro. For the first time, we show that effect of TW knockout inhibits AKT activity in U87MG cells in vivo independent of PTEN mutation. The clinical relevance of TW and candidate mechanisms was established by analysis of the TCGA and ENCODE databases. TW expression was associated with decreased patient survival and LASSO regression analysis identified POSTN as one of top targets of TW in human GBM. While we previously demonstrated the role of TW in promoting EMT and invasion of glioma cells, these studies provide direct experimental evidence supporting protumorigenic role of TW independent of invasion in vivo and the therapeutic relevance of targeting TW in human GBM. Further, the role of TW driving POSTN expression and AKT signaling suggests actionable targets, which could be leveraged to mitigate the oncogenic effects of TW in GBM. PMID- 29754408 TI - The impact of early psychosocial intervention on self-efficacy of care recipient/carer dyads living with early-stage dementia-A mixed-methods study. AB - AIM: To evaluate the effect of a targeted community-based psychosocial intervention on self-efficacy outcomes for care recipient/carer dyads living with early-stage dementia. BACKGROUND: There is increasing interest in the role of self-efficacy and self-management structures in determining positive outcomes for people with dementia. The assumption is that care recipient/carer dyads who receive early support to identify and adjust to dementia-related changes will cope better in the long term. DESIGN: An explanatory sequential mixed-method design was employed. Primarily quantitative with qualitative data providing a supportive secondary role to expand on and illuminate the quantitative findings. METHODS: Eighty-eight dyads were recruited and allocated on a regional basis to an intervention or control group. Intervention group dyads received the Early Diagnosis Dyadic Intervention. Control group dyads received two information manuals. Quantitative data were collected at three time points. Qualitative data were collected via evaluation questionnaires and semistructured interviews. RESULTS: Intervention structure, content, and delivery were acceptable to the dyads but few quantitative self-efficacy findings reached statistical significance. Improvements in self-efficacy were evident in the postintervention evaluation qualitative responses where dyads expressed greater confidence in identifying and accessing community support. CONCLUSION: There is an urgent need for effective psychosocial interventions to help reduce the impact of dementia symptoms on patients, carers, and society. This study makes an important contribution to our understanding of the capacity of psychosocial interventions to improve self-efficacy outcomes for care recipient/carer dyads with early-stage dementia while also illustrating the challenges associated with measuring self efficacy in the early stages of the condition. PMID- 29754409 TI - Comparison of transvaginal ultrasound and saline contrast sonohysterography in evaluation of cesarean scar defect: a prospective cohort study. AB - INTRODUCTION: The aim of this study was to investigate the prevalence of post cesarean isthmocele and to measure agreement between transvaginal ultrasonography and saline contrast sonohysterography in assessment of isthmocele. MATERIAL AND METHODS: A prospective observational cohort study was carried out at Tampere University Hospital, Finland. Non-pregnant women delivered by cesarean section (n = 371) were examined with transvaginal ultrasonography (TVUS) and sonohysterography (SHG) six months after cesarean section. The main outcome measure was the prevalence of isthmocele using TVUS and SHG. Secondary outcome measures were characteristics of isthmocele. RESULTS: In all, 371 women were included. The prevalence of isthmocele was 22.4% based on TVUS and 45.6% based on SHG. Sensitivity and specificity for TVUS was 49.1 and 100%, respectively, when compared with SHG. Therefore, half of the defects (50.9%) diagnosed with SHG remained undiagnosed with TVUS. Bland-Altman analysis showed an underestimation of 1.1 mm (range 0.00-7.90) for TVUS compared with SHG, with 95% limits of agreement from -1.9 to 4.1 mm. CONCLUSIONS: This methodological study provides confirmatory data that TVUS and SHG are not in good agreement in the isthmocele diagnostics and the use of only TVUS may lead to an underestimation of the prevalence of isthmocele. Thus, SHG should be considered as a method of choice in diagnostics of isthmocele. PMID- 29754410 TI - Hi-tech restoration by two-steps biocleaning process of Triumph of Death fresco at the Camposanto Monumental Cemetery (Pisa, Italy). AB - AIMS: In this work, the 'hi-tech' complex biocleaning and restoration of the 14th century fresco Triumph of Death (5.6 * 15.0 m) at the Camposanto Monumental Cemetery (Pisa, Italy) is reported. Since 2000, the restoration based on the biological cleaning of noble medieval frescoes, has been successfully utilized in this site. METHODS AND RESULTS: The novelty of this study is the two-steps biocleaning process using Pseudomonas stutzeri A29 viable cells, previously applied for recovering other valuable frescoes. In this case, after the fresco detachment from the asbestos-cement support (eternity), both the animal glue and the residues of calcium caseinate were biologically removed respectively from the front and from the back of the fresco in 3 h as indicated by GC-MS and PY/GC-MS analyses. The data obtained during the monitoring of the biorestoration process confirmed that the adopted procedure does not leave residual cells on the fresco surfaces as showed by plate count method, ATP determination and also SEM observation. In addition, to avoid the risk of condensation phenomena after the relocation of the restored fresco sections onto the original walls, the use of a new support has been set up together with the design of a control system that allows a continuous monitoring of environmental parameters for prevention and conservation purposes. CONCLUSIONS: This large-scale biorestoration work clearly shows and confirms that this biotechnology is highly efficient, safe, noninvasive, risk-free and very competitive compared to the traditional cleaning methods, offering an unusual 'resurrection' of the degraded artworks also in very complicated and delicate conditions such as the Triumph of Death fresco, defined for its dimension and artistic importance the 'Pisa's Sistina frescoes'. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings can be of significant importance for other future new restoration activities and they are crucial for determining preservation strategies in this field. PMID- 29754411 TI - A case study of nurse practitioner care compared with general practitioner care for children with respiratory tract infections. AB - AIM: To compare quality of care provided by nurse practitioners (NP) with care provided by general practitioners (GP) for children with respiratory tract infections (RTI) in the Netherlands. BACKGROUND: Nurse practitioners increasingly manage acute conditions in general practice, with opportunities for more protocolled care. Studies on quality of NPs' care for children with RTIs are limited to the US healthcare system and do not take into account baseline differences in illness severity. DESIGN: Retrospective observational cohort study. METHODS: Data were extracted from electronic healthcare records of children 0-6 years presenting with RTI between January-December 2013. Primary outcomes were antibiotic prescriptions and early return visits. Generalized estimating equations were used to correct for potential confounders. RESULTS: A total of 899 RTI consultations were assessed (168 seen by NP; 731 by GP). Baseline characteristics differed between these groups. Overall antibiotic prescription and early return visit rates were 21% and 24%, respectively. Adjusted odds ratio for antibiotic prescription after NP vs. GP delivered care was 1.40 (95% confidence interval 0.89-2.22) and for early return visits 1.53 (95% confidence interval 1.01-2.31). Important confounder for antibiotic prescription was illness severity. Presence of wheezing was a confounder for return visits. Complication and referral rates did not differ. CONCLUSION: Antibiotic prescription, complication and referral rates for paediatric RTI consultations did not differ significantly between NP and GP consultations, after correction for potential confounders. General practitioners, however, see more severely ill children and have a lower return visit rate. A randomised controlled study is needed to determine whether NP care quality is truly noninferior. PMID- 29754412 TI - Affective neuroscience of self-generated thought. AB - Despite increasing scientific interest in self-generated thought-mental content largely independent of the immediate environment-there has yet to be any comprehensive synthesis of the subjective experience and neural correlates of affect in these forms of thinking. Here, we aim to develop an integrated affective neuroscience encompassing many forms of self-generated thought-normal and pathological, moderate and excessive, in waking and in sleep. In synthesizing existing literature on this topic, we reveal consistent findings pertaining to the prevalence, valence, and variability of emotion in self-generated thought, and highlight how these factors might interact with self-generated thought to influence general well-being. We integrate these psychological findings with recent neuroimaging research, bringing attention to the neural correlates of affect in self-generated thought. We show that affect in self-generated thought is prevalent, positively biased, highly variable (both within and across individuals), and consistently recruits many brain areas implicated in emotional processing, including the orbitofrontal cortex, amygdala, insula, and medial prefrontal cortex. Many factors modulate these typical psychological and neural patterns, however; the emerging affective neuroscience of self-generated thought must endeavor to link brain function and subjective experience in both everyday self-generated thought as well as its dysfunctions in mental illness. PMID- 29754413 TI - First description of a right hemicolectomy with complete mesocolic excision in a paediatic patient - a video vignette. PMID- 29754414 TI - Functional diversification of the kinesin-14 family in land plants. AB - In most eukaryotes, cytoplasmic dynein serves as the primary cytoskeletal motor for minus-end-directed processes along microtubules. However, land plants lack dynein, having instead a large number of kinesin-14s, which suggests that kinesin 14s may have evolved to fill the cellular niche left by dynein. In addition, land plants do not have centrosomes, but contain specialized microtubule-based structures called phragmoplasts that facilitate the formation of new cell walls following cell division. This Review aims to compile the evidence for functional diversification of kinesin-14s in land plants. Known functions include spindle morphogenesis, microtubule-based trafficking, nuclear migration, chloroplast distribution, and phragmoplast expansion. Plant kinesin-14s have also evolved direct roles in chromosome segregation in maize and novel biochemical features such as actin transport and processive motility in the homodimeric state. PMID- 29754416 TI - Attitudes to Brexit: A survey of nursing and midwifery students. PMID- 29754415 TI - Biological hydropersulfides and related polysulfides - a new concept and perspective in redox biology. AB - The chemical biology of thiols (RSH, e.g., cysteine and cysteine-containing proteins/peptides) has been a topic of extreme interest for many decades due to their reported roles in protein structure/folding, redox signaling, metal ligation, cellular protection, and enzymology. While many of the studies on thiol/sulfur biochemistry have focused on thiols, relatively ignored have been hydropersulfides (RSSH) and higher order polysulfur species (RSSn H, RSSn R, n > 1). Recent and provocative work has alluded to the prevalence and likely physiological importance of RSSH and related RSSn H. RSSH of cysteine (Cys-SSH) has been found to be prevalent in mammalian systems along with Cys-SSH-containing proteins. The RSSH functionality has not been examined to the extent of other biologically relevant sulfur derivatives (e.g., sulfenic acids, disulfides, etc.), whose roles in cell signaling are strongly indicated. The recent finding of Cys-SSH biosynthesis and translational incorporation into proteins is an unequivocal indication of its fundamental importance and necessitates a more profound look into the physiology of RSSH. In this Review, we discuss the currently reported chemical biology of RSSH (and related species) as a prelude to discussing their possible physiological roles. PMID- 29754417 TI - Teaching paediatric basic life support in medical schools using peer teaching or video demonstration: A prospective randomised trial. AB - AIM: The outcome of children with an out-of-hospital cardiac arrest is still poor, but bystander cardiopulmonary resuscitation can increase survival and minimise severe neurological sequelae. While teaching basic life support is standardised in emergency medicine classes, paediatric basic life support (PBLS) in neonates and toddlers is under-represented in paediatric curricula during university education. The appropriate mixture of E-learning and peer teaching lessons remains controversial in teaching paediatric basic skills. However, an increasing number of medical schools and paediatric classes switch their curricula to much cheaper and less tutor-dependent E-learning modules. We hypothesise that a peer teaching lesson is superior to a PBLS video demonstration with co-extensive contents and improves knowledge, skills and adherence to resuscitation guidelines. METHODS: Eighty-eight medical students were randomly assigned to a video PBLS lesson (n = 44) or a peer teaching group (n = 44). An objective structured clinical examination was performed immediately after the class and at the end of the semester. RESULTS: Students taught by a peer teacher performed significantly better immediately after the initial course and at the end of the semester when compared to the video-trained group (P = 0.008 and P = 0.003, respectively). In addition, a borderline regression analysis also revealed a better resuscitation performance of students instructed in the peer teaching group. CONCLUSIONS: In our setting, peer teaching is superior and more sustainable than a co-extensive video demonstration alone when teaching PBLS to medical students. However, additional studies with combinations of different teaching methods are necessary to evaluate long-term outcomes. PMID- 29754418 TI - Comprehensive outcomes after lung retransplantation: A single-center review. AB - INTRODUCTION: Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. METHODS: We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n = 38). We analyzed the postoperative course, graft function, renal function, microbiology, donor-specific antibodies (DSA), quality of life, and survival compared to a control cohort of primary transplant recipients matched for age and era. RESULTS: Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 92%). The postoperative course was more complex after retransplant than primary (ventilation time, 8 vs 2 days, P < .01; ICU stay 14 vs 4 days, P < 0.01), and peak lung function was lower (FEV1 2.2L vs 3L, P < .01). Quality of life scores were comparable, as were renal function, microbiology, and donor-specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (P = .39). CONCLUSIONS: Lung retransplantation is associated with a more complex postoperative course and lower peak lung function, but the long-term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure. PMID- 29754420 TI - The predictive value of the heart rate variability-derived Analgesia Nociception Index in children anaesthetized with sevoflurane: An observational pilot study. AB - BACKGROUND: The heart rate variability (HRV)-derived Analgesia Nociception Index (ANITM) is a continuous noninvasive tool to assess the nociception/antinociception balance in unconscious patients. It has been shown to be superior to haemodynamic variables in detecting insufficient antinociception in children, while little is known about its predictive value. METHODS: The primary objective of this prospective observational pilot study in paediatric surgical patients under sevoflurane anaesthesia was to compare the predictive value of the ANI and heart rate to help decide to give additional opioids. The paediatric anaesthesiologist in charge was blinded to ANI values. RESULTS: In patients with an ANI value <50 (indicating insufficient antinociception) at the moment of decision, ANI values dropped from +/-55 (indicating sufficient antinociception) to +/-35, starting 60 s before decision. Within 120 s after administration of fentanyl (1 MUg/kg), ANI values returned to +/-60. This phenomenon was only observed in the ANI values derived from HRV data averaged over 2 min. Heart rate remained unchanged. In patients with ANI values >=50 at the time of decision, opioid administration had no effect on ANI or heart rate. The same accounts for morphine for postoperative analgesia and fentanyl in case of intraoperative movement. CONCLUSIONS: This study provides evidence of a better predictive value of the ANI in detecting insufficient antinociception in paediatric surgical patients than heart rate. The same accounts for depicting re establishment of sufficient antinociception after opioid drug administration. SIGNIFICANCE: In paediatric surgical patients anaesthetized with sevoflurane, the heart rate variability-derived Analgesia Nociception Index (ANI) appears to be a better predictor of insufficient antinociception than heart rate. The ANI also appears to depict re-establishment of sufficient antinociception better than heart rate. PMID- 29754419 TI - Integration of T-cell receptor, Notch and cytokine signals programs mouse gammadelta T-cell effector differentiation. AB - gammadelta T-cells perform a wide range of tissue- and disease-specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-gamma (IFNgamma) and interleukin-17 (IL-17) producing gammadelta T-cells remain unknown. Here, we define the cues involved in the functional programming of gammadelta T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 gammadeltaTCR-transduced Rag2-/- T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNgamma versus IL-17 producing gammadelta T-cell subsets, with Notch and weak TCR ligands optimally enabling development of gammadelta17 cells in the presence of IL-1beta, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of gammadelta17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNgamma and IL-17 producing gammadelta T-cell subsets. PMID- 29754421 TI - Dynamical mechanisms of Arctic amplification. AB - The Arctic has become a hot spot of climate change, but the nonlinear interactions between regional and global scales in the coupled climate system responsible for Arctic amplification are not well understood and insufficiently described in climate models. Here, we compare reanalysis data with model simulations for low and high Arctic sea ice conditions to identify model biases with respect to atmospheric Arctic-mid-latitude linkages. We show that an appropriate description of Arctic sea ice forcing is able to reproduce the observed winter cooling in mid-latitudes as result of improved tropospheric stratospheric planetary wave propagation triggering a negative phase of the Arctic Oscillation/North Atlantic Oscillation in late winter. PMID- 29754423 TI - Imaging Mass Spectrometry for Characterization of Atrial Fibrillation Subtypes. AB - PURPOSE: Atrial fibrillation (AF) is a cardiac arrhythmia characterized by a rapid and irregular heart rhythm. AF types, paroxysmal (PX), persistent (PE), and long-lasting persistent (LSP), require differences in clinical management. Unfortunately, a significant proportion of AF patients are clinically misclassified. Therefore, the aim of this study is to prove that MALDI-Imaging (IMS) is valuable as a diagnostic aid in AF subtypes' assessment. EXPERIMENTAL DESIGN: Patients are clinically classified according to the guidelines of the European Society of Cardiology. FFPE tissue specimens from PE, PX, and LSP subtypes are analyzed by MALDI-IMS and evaluated by multi-statistical testing. Proteins are subsequently identified using LC-MS/MS and findings are confirmed by immunohistochemistry and through the determination of potential fibrosis via histopathology. RESULT: Determined that characteristic peptide signatures and peptide values facilitate to distinguish between PE, PX, and LSP arterial fibrillation subtypes. In particular, peptide values from alpha 1 type I collagen (CO1A1) are identified that are significantly higher in LSP and PE tissues but not in PX myocardial AF tissue. These findings are confirmed by immunohistochemistry and through the determination of potential fibrosis via histopathology. CONCLUSION AND RELEVANCE: These results represent an improvement in AF risk stratification by using MALDI-IMS as a promising approach for AF tissue assessment. PMID- 29754422 TI - ZEB1-mediated vasculogenic mimicry formation associates with epithelial mesenchymal transition and cancer stem cell phenotypes in prostate cancer. AB - The zinc finger E-box-binding homeobox 1 (ZEB1) induced the epithelial mesenchymal transition (EMT) and altered ZEB1 expression could lead to aggressive and cancer stem cell (CSC) phenotypes in various cancers. Tissue specimens from 96 prostate cancer patients were collected for immunohistochemistry and CD34/periodic acid-Schiff double staining. Prostate cancer cells were subjected to ZEB1 knockdown or overexpression and assessment of the effects on vasculogenic mimicry formation in vitro and in vivo. The underlying molecular events of ZEB1 induced vasculogenic mimicry formation in prostate cancer were then explored. The data showed that the presence of VM and high ZEB1 expression was associated with higher Gleason score, TNM stage, and lymph node and distant metastases as well as with the expression of vimentin and CD133 in prostate cancer tissues. Furthermore, ZEB1 was required for VM formation and altered expression of EMT related and CSC-associated proteins in prostate cancer cells in vitro and in vivo. ZEB1 also facilitated tumour cell migration, invasion and clonogenicity. In addition, the effects of ZEB1 in prostate cancer cells were mediated by Src signalling; that is PP2, a specific inhibitor of the Src signalling, dose dependently reduced the p-Src527 level but not p-Src416 level, while ZEB1 knockdown also down-regulated the level of p-Src527 in PC3 and DU-145 cells. PP2 treatment also significantly reduced the expression of VE-cadherin, vimentin and CD133 in these prostate cancer cells. Src signalling mediated the effects of ZEB1 on VM formation and gene expression. PMID- 29754424 TI - Cry1Ac production is costly for native plants attacked by non-Cry1Ac-targeted herbivores in the field. AB - Plants are the primary producers in most terrestrial ecosystems and have complex defense systems to protect their produce. Defense-deficient, high-yielding agricultural monocultures attract abundant nonhuman consumers, but are alternatively defended through pesticide application and genetic engineering to produce insecticidal proteins such as Cry1Ac (Bacillus thuringiensis). These approaches alter the balance between yield protection and maximization but have been poorly contextualized to known yield-defense trade-offs in wild plants. The native plant Nicotiana attenuata was used to compare yield benefits of plants transformed to be defenseless to those with a full suite of naturally evolved defenses, or additionally transformed to ectopically produce Cry1Ac. An insecticide treatment allowed us to examine yield under different herbivore loads in N. attenuata's native habitat. Cry1Ac, herbivore damage, and growth parameters were monitored throughout the season. Biomass and reproductive correlates were measured at season end. Non-Cry1Ac-targeted herbivores dominated on noninsecticide-treated plants, and increased the yield drag of Cry1Ac-producing plants in comparison with endogenously defended or undefended plants. Insecticide sprayed Cry1Ac-producing plants lagged less in stalk height, shoot biomass, and flower production. In direct comparison with the endogenous defenses of a native plant, Cry1Ac production did not provide yield benefits for plants under observed herbivore loads in a field study. PMID- 29754425 TI - Effects of oestradiol for luteal phase support in fresh embryo transfer cycles: A retrospective cohort study. AB - OBJECTIVE: Any benefit of oestradiol supplementation with progesterone for luteal support after fresh embryo transfer in in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycles remains controversial. In this study, we further addressed this question in cycles using gonadotropin-releasing hormone (GnRH) agonist for ovarian stimulation. DESIGN: A retrospective cohort study in a tertiary teaching and research hospital. PATIENT(S): A total of 1602 patients were given oestradiol valerate (E) in addition to progesterone (P) as luteal support. One thousand six hundred and two patients receiving progesterone alone were selected as the control group. MAIN OUTCOME MEASURE(S): Live birth rate. Secondary measures included clinical pregnancy rate, miscarriage rate and premature birth rate. RESULT(S): Clinical pregnancy and live birth rates were similar for the P alone vs the P+E group. In cycles with oestradiol (E2) levels less than 5000 pmol/L on the day of hCG trigger, E supplementation resulted in a significantly higher live birth rate (23.44% vs 32.92%, OR = 1.60 [95% CI 1.05 to 2.46]). In cycles with oestradiol levels 5000 to 10 000 pmol/L on the day of hCG trigger, E supplementation did not increase the live birth rate (34.43% vs 35.42%, OR = 0.90 [95% CI 0.80 to 1.01]). In cycles with oestradiol levels over 10 000 pmol/L on the day of hCG trigger, the live birth rate was significantly lower (36.83% vs 31.37%, OR = 0.78 [95% CI 0.62 to 0.99]) and the premature birth rate was significantly higher (19.66% vs 28.73%,OR = 1.65 [95% CI 1.05 to 2.59]) in the E supplementation group. CONCLUSION(S): Any benefit of oestradiol supplementation for luteal phase support appears to correlate with the serum oestradiol level on the day of hCG trigger. Oestradiol supplementation is beneficial for improving live birth rate in cycles with oestradiol levels less than 5000 pmol/L, but is not recommended in cycles with oestradiol levels over 10 000 pmol/L. PMID- 29754426 TI - Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta-analysis. AB - : Essentials Cancer patients are at risk for venous thromboembolism (VTE). The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear. In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy. Highest VTE rates were observed in patients with bladder and esophageal cancer. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo-radiotherapy remains unclear. Objectives This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment. Methods MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009-2016) and the International Society of Thrombosis and Haemostasis (2003-2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms. Results Twenty-eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty-five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two-thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between-study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer. Conclusions This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between-study variation, which deserves further evaluation in prospective studies. PMID- 29754427 TI - Pain and development of identity in adolescents who frequently use over-the counter analgesics: A qualitative study. AB - AIMS AND OBJECTIVES: This study aims to describe conditions that may influence the development of identity in adolescents frequently using over-the-counter analgesics. BACKGROUND: Frequent self-medication with analgesics among adolescents is associated with several physical pain points, low self-esteem and low ambitions for the future. Continuous use of over-the-counter analgesics can keep adolescents from learning healthier coping strategies. DESIGN: Qualitative individual interviews with adolescents and their mothers were conducted and transcribed. Furthermore, they were analysed as dyads. SETTING AND PARTICIPANTS: Students aged 14-16 years in 9th and 10th grades in 10 Norwegian junior high schools self-reporting at least weekly use of analgesics were asked to participate. Those who wanted to take part took a consent letter to their parents, also inviting the parent to participate. RESULTS: Six girls, two boys and their mothers were included. The teenagers were highly dependent on their mothers. They had often been bullied, lacked good relationships with peers, avoided conflicts and strived to be accepted. Their mothers felt solely responsible for their upbringing and showed great concern for all the pain experienced by their child. A close relationship between mother and child influenced how the adolescent managed their pain, including their use of over-the counter analgesics. Three main themes were identified in the stories of mother and child: "Vulnerable adolescents," "Mother knows best" and "Pain is a shared project." CONCLUSIONS: Pain among adolescents may be amplified by a difficult family situation and insecure relationships with peers. Strategies within the family may sustain pain as a shared project keeping the adolescent and main caregiver close together, and this might be hampering identity development. To help adolescents with pain and high consumption of over-the-counter analgesics, the adolescents' relationship with parents must be considered in designing an intervention. Guidance on pain assessment, pain management, including appropriate use of over-the-counter analgesics, should be included. PMID- 29754428 TI - Tapering off long-term opioid therapy in chronic non-cancer pain patients: A randomized clinical trial. AB - BACKGROUND: The indications for initiating long-term opioid treatment (L-TOT) for chronic non-cancer pain (CNCP) are often unclear and associated with problematic use. This study aimed at evaluating the efficacy of stabilizing opioid therapy followed by a sequential opioid tapering off program in CNCP patients. METHODS: A randomized clinical trial with a medications stabilization period (Phase 1) was followed by an opioid tapering off program (Phase 2). In Phase 2, patients were randomized to Control Group (stable treatment) or Taper off Group (sequential opioid dose reduction) and assessed at baseline, after stabilization and up to 6 months. Primary outcomes: measures of cognitive function; secondary outcomes: pain, sleep, rest, quality of life, depression, anxiety, opioid misuse and opioid withdrawal symptoms. RESULTS: In all, 274 patients were screened; 75 were included, out of which 40 dropped out before Phase 2. Those who succeeded Phase 1 (n = 35) had weak/moderate improvements of psychomotor function (p = 0.020), sleeping hours (p = 0.031), opioid withdrawal symptoms (p = 0.019), measures of quality of life (p <= 0.043) and opioid misuse scores (p = 0.003). In Phase 2, patients in Taper off Group (n = 15) experienced stable pain intensity and felt significantly more rested at third assessment than the Control Group (n = 20). CONCLUSIONS: The opioid tapering off program was not successful due to the vast number of dropouts. Phase 1 was associated with weak to moderate improvements on psychomotor function, sleeping, opioid withdrawal symptoms, quality of life and reduced risk of opioid misuse. In the intervention group of Phase 2, pain intensity was stable and patients felt more rested. SIGNIFICANCE: This trial showed that sequential tapering off L-TOT in CNCP patients may be an unfeasible approach. However, improvements after opioid treatment stabilization were achieved and stable pain intensity in those tapered off may encourage the development of more refined programs. PMID- 29754429 TI - Structural characterizations of human periostin dimerization and cysteinylation. AB - Human periostin plays a multifaceted role in remodeling the extracellular matrix milieu by interacting with other proteins and itself in both a heterophilic and homophilic manner. However, the structural mechanism for its extensive interactions has remained elusive. Here, we report the crystal structures of human periostin (EMI-Fas1I-IV ) and its Cys60Ala mutant. In combination with multi-angle light-scattering analysis and biochemical assays, the crystal structures reveal that periostin mainly exists as a dimer in solution and its homophilic interaction is mainly mediated by the EMI domain. Furthermore, Cys60 undergoes cysteinylation as confirmed by mass spectroscopy, and this site hardly affects the homophilic interaction. Also, the structures yield insights into how periostin forms heterophilic interactions with other proteins under physiological or pathological conditions. PMID- 29754430 TI - Position of human blood group O(H) and phenotype-determining enzymes in growth and infectious disease. AB - The human ABO(H) blood group phenotypes arise from the evolutionarily oldest genetic system found in primate populations. While the blood group antigen A is considered the ancestral primordial structure, under the selective pressure of life-threatening diseases blood group O(H) came to dominate as the most frequently occurring blood group worldwide. Non-O(H) phenotypes demonstrate impaired formation of adaptive and innate immunoglobulin specificities due to clonal selection and phenotype formation in plasma proteins. Compared with individuals with blood group O(H), blood group A individuals not only have a significantly higher risk of developing certain types of cancer but also exhibit high susceptibility to malaria tropica or infection by Plasmodium falciparum. The phenotype-determining blood group A glycotransferase(s), which affect the levels of anti-A/Tn cross-reactive immunoglobulins in phenotypic glycosidic accommodation, might also mediate adhesion and entry of the parasite to host cells via trans-species O-GalNAc glycosylation of abundantly expressed serine residues that arise throughout the parasite's life cycle, while excluding the possibility of antibody formation against the resulting hybrid Tn antigen. In contrast, human blood group O(H), lacking this enzyme, is indicated to confer a survival advantage regarding the overall risk of developing cancer, and individuals with this blood group rarely develop life-threatening infections involving evolutionarily selective malaria strains. PMID- 29754432 TI - BIM determines the number of merocytic dendritic cells, a cell type that breaks immune tolerance. AB - In contrast to conventional dendritic cells (cDC), when merocytic dendritic cells (mcDC) present antigens derived from apoptotic bodies, T-cell anergy is reversed rather than induced, a process that promotes autoimmunity. Interestingly, mcDC are present in higher proportion in type 1 diabetes-prone NOD mice than in autoimmune-resistant B6 and BALB/c mice, and the Insulin-dependent diabetes (Idd)13 locus is linked to mcDC proportion. Therefore, mcDC are notably associated with susceptibility to autoimmune diabetes. To identify which gene determines the proportion and absolute number of mcDC, we undertook a candidate gene approach by selecting relevant candidates within the Idd13 locus. We find that neither beta2m nor Sirpa appear to influence the proportion of mcDC. Instead, we show that Bim effectively modulates mcDC number in a hematopoietic intrinsic manner. We also demonstrate that Bim-deficiency does not impact other cDC subsets and appears to play a specific role in determining the proportion and absolute number of mcDC by promoting their survival. Together, these data demonstrate that Bim specifically modulates the number of mcDC. Identifying factors that facilitate apoptosis of mcDC by increasing BIM activity in a cell type-specific manner may help prevent autoimmunity. PMID- 29754431 TI - Expanding severe acute respiratory infection (SARI) surveillance beyond influenza: The process and data from 1 year of implementation in Vietnam. AB - BACKGROUND: In 2016, as a component of the Global Health Security Agenda, the Vietnam Ministry of Health expanded its existing influenza sentinel surveillance for severe acute respiratory infections (SARI) to include testing for 7 additional viral respiratory pathogens. This article describes the steps taken to implement expanded SARI surveillance in Vietnam and reports data from 1 year of expanded surveillance. METHODS: The process of expanding the suite of pathogens for routine testing by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) included laboratory trainings, procurement/distribution of reagents, and strengthening and aligning SARI surveillance epidemiology practices at sentinel sites and regional institutes (RI). RESULTS: Surveillance data showed that of 4003 specimens tested by the RI laboratories, 20.2% (n = 810) were positive for influenza virus. Of the 3193 influenza-negative specimens, 41.8% (n = 1337) were positive for at least 1 non-influenza respiratory virus, of which 16.2% (n = 518), 13.4% (n = 428), and 9.6% (n = 308) tested positive for respiratory syncytial virus, rhinovirus, and adenovirus, respectively. CONCLUSIONS: The Government of Vietnam has demonstrated that expanding respiratory viral surveillance by strengthening and building upon an influenza platform is feasible, efficient, and practical. PMID- 29754433 TI - Unsung heroes, flying blind-A metasynthesis of parents' experiences of caring for children with special health-care needs at home. AB - AIMS AND OBJECTIVES: To aggregate, synthesise and interpret qualitative research studies of parents' experiences of caring for a child with special health-care needs at home. BACKGROUND: Advances in the field of medical and nursing science have ensured better survival rates for children with chronic illnesses. Many of these children have significant special health-care needs. Today parents assume a caregiver role, undertaking tasks previously provided by nurses in hospitals. As the complexity of care delivered by parents continues to develop, synthesised knowledge can provide an evidence base that will support and guide nurses when caring for these families. DESIGN: Metasynthesis. METHODS: Based upon a systematic search protocol, a structured literature search, covering the years 2003-2016, was conducted in five electronic databases. Ten studies were included and appraised using the Critical Appraisal Skills Program assessment tool. A metasummary and a metasynthesis were undertaken guided by the metasynthesis methodology as described by Sandelowski and Barroso (Handbook for synthesizing qualitative research. New York, NY: Springer, 2007). RESULTS: The results were interpreted and integrated under the overarching theme "unsung heroes, flying blind," supported by eight elucidating categories that illustrate aspects of the parents' life world. CONCLUSIONS: The enormous burden of care can weaken the parents' will to carry on and result in a decreased ability to provide care. This can have an impact on the parents' health, family functioning and the sick child's potential health outcomes. Nurses are in a unique position to help these families and should be better prepared for the role. RELEVANCE TO CLINICAL PRACTICE: Knowledge of how parents of children with special health-care needs experience their daily lives can promote trust in nurses and guide them in their efforts to support families with children living with chronic illness. PMID- 29754434 TI - Ontogeny of Gonadotropin-Inhibitory Hormone (GnIH) in the cichlid fish Cichlasoma dimerus. AB - RFamide peptides are expressed in the early stages of development in most vertebrates. Gonadotropin-inhibitory hormone (GnIH) belongs to the RFamide family, and its role in reproduction has been widely studied in adult vertebrates, ranging from fish to mammals. As only three reports evaluated GnIH during development, the aim of this study was to characterise the ontogeny of GnIH in a fish model, Cichlasoma dimerus. We detected the presence of two GnIH immunoreactive (GnIH-ir) cell clusters with spatial and temporal differences. One cluster was observed by 3 days post-hatching (dph) in the nucleus olfacto retinalis (NOR) and the other in the nucleus posterioris periventricularis by 14 dph. The number of GnIH-ir neurons increased in both nuclei, whereas their size increased only in the NOR from hatchling to juvenile stages. These changes occurred from the moment larvae started feeding exogenously and during development and differentiation of gonadal primordia. We showed by double-label immunofluorescence that only GnIH-ir neurons in the NOR co-expressed GnRH3 associated peptide. In addition, GnIH-ir fibre density increased in all brain regions from 5 dph. GnIH-ir fibres were also detected in the retina, optic tract and optic tectum, suggesting that GnIH acts as a neuromodulator of photoreception and the integration of different sensory modalities. Also, there were GnIH-ir fibres in the pituitary from 14 dph, which were in close association with somatotropes. Moreover, GnIH-ir fibres were observed in the saccus vasculosus from 30 dph, suggesting a potential role of GnIH in the modulation of its function. Finally, we found that gnih was expressed from 1 dph, and that the pattern of variation of its transcript levels was in accordance with that of cell number. Present results are the starting point for the study of new GnIH roles during development. This article is protected by copyright. All rights reserved. PMID- 29754435 TI - Questionnaire-based evaluation of sexual life after laparoscopic surgery for endometriosis: a systematic review of prospective studies. AB - INTRODUCTION: Endometriosis is a benign disease that affects women of reproductive age. Laparoscopic excision of endometriotic implants is considered one of the most effective therapeutic options. The disease and its treatment can have a major impact on psychosexual well-being but this is often overlooked as most studies focus on pain instead of sexuality in a holistic approach. The aim of this study was to review the current literature regarding the effect of laparoscopic surgery for endometriosis on quality of sexual life (QoSL). MATERIAL AND METHODS: Following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses" guidelines we conducted a systematic review that involved searching PubMed and Embase databases for prospective studies evaluating the effect of laparoscopic surgery for endometriosis on QoSL, using validated questionnaires. RESULTS: Of 357 papers, 17 were selected for full text evaluation. Twelve studies using seven different questionnaires fulfilled the inclusion criteria. All studies reported improvements in QoSL following laparoscopic surgery for endometriosis. A meta-analysis could not be performed due to substantial heterogeneity among the included studies arising from differences in questionnaires, follow-up duration, stages of endometriosis, use of hormonal treatment, and missing data. CONCLUSIONS: Laparoscopic excision of endometriosis can improve QoSL. However, there is a need for randomized controlled trials based on a new validated questionnaire regarding specifically QoSL in association with endometriosis. As sexual functioning is a complex phenomenon driven by multiple physical, psychological and social factors, QoSL should be holistically evaluated by a team of different healthcare providers, implementing treatment programs that are individualized to each woman. PMID- 29754436 TI - Unresolved questions associated with the management of ventricular preexcitation syndrome. AB - BACKGROUND: Many recent recommendations concern the management of preexcitation syndrome. In clinical practice, they are sometimes difficult to use. The purpose of the authors was to discuss the main problems associated with this management. Three problems are encountered: (1) the reality of the absence of symptoms or the interpretation of atypical symptoms, (2) the electrocardiographic diagnosis of preexcitation syndrome that can be missed, and (3) the exact electrophysiological protocol and its interpretation used for the evaluation of the prognosis. Because of significant progress largely related to the development of curative treatment, it seems easy to propose ablation in many patients despite the related risks of invasive studies and to minimize the invasive risk by only performing ablation for patients with at-risk pathways. However, there is a low risk of spontaneous events in truly asymptomatic patients and the indication of accessory pathway ablation should be discussed case by case. PMID- 29754438 TI - Targeting transcriptional control of soluble guanylyl cyclase via NOTCH for prevention of cardiovascular disease. AB - Soluble guanylyl cyclase (sGC) is an effector enzyme of nitric oxide (NO). Recent work has unravelled how levels of this enzyme are controlled, and highlighted a role in vascular disease. We provide a timely summary of available knowledge on transcriptional regulation of sGC, including influences from the NOTCH signalling pathway and genetic variants. It is speculated that hypertension-induced repression of sGC starts a vicious circle that can be initiated by periods of stress, diet or genetic factors, and a key tenet is that reduction in sGC further raises blood pressure. The idea that dysregulation of sGC contributes to syndromes caused by defective NOTCH signalling is advanced, and we discuss drug repositioning for vascular disease prevention. The advantage of targeting sGC expression rather than activity is also considered. It is argued that transcriptional inputs on sGC arise from interactions with other cells, the extracellular matrix and microRNAs (miRNAs), and concluded that the promise of sGC as a target for prevention of cardiovascular disease has increased in recent time. PMID- 29754437 TI - Reduced fibre size, capillary supply and mitochondrial activity in constitutional thinness' skeletal muscle. AB - AIM: Constitutional thinness (CT) is a rare condition of natural low body weight, with no psychological issues, no marker of undernutrition and a resistance to weight gain. This study evaluated the skeletal muscle phenotype of CT women by comparison with a normal BMI control group. METHODS: Ten CT women (BMI < 17.5 kg/m2 ) and 10 female controls (BMI: 18.5-25 kg/m2 ) underwent metabolic and hormonal assessment along with muscle biopsies to analyse the skeletal muscular fibres pattern, capillarity, enzymes activities and transcriptomics. RESULTS: Constitutional thinness displayed similar energy balance metabolic and hormonal profile to controls. Constitutional thinness presented with lower mean area of all the skeletal muscular fibres (-24%, P = .01) and percentage of slow-twitch type I fibres (-25%, P = .02, respectively). Significant downregulation of the mRNA expression of several mitochondrial-related genes and triglycerides metabolism was found along with low cytochrome c oxidase (COX) activity and capillary network in type I fibres. Pre- and post-mitochondrial respiratory chain enzymes levels were found similar to controls. Transcriptomics also revealed downregulation of cytoskeletal-related genes. CONCLUSION: Diminished type I fibres, decreased mitochondrial and metabolic activity suggested by these results are discordant with normal resting metabolic rate of CT subjects. Downregulated genes related to cytoskeletal proteins and myocyte differentiation could account for CT's resistance to weight gain. PMID- 29754439 TI - Exploring psychological mechanisms of clinical response to an internet-delivered psychological pain management program. AB - BACKGROUND: The evidence for Internet-delivered pain management programs for chronic pain is growing, but there is little empirical understanding of how they effect change. Understanding mechanisms of clinical response to these programs could inform their effective development and delivery. METHODS: A large sample (n = 396) from a previous randomized controlled trial of a validated internet delivered psychological pain management program, the Pain Course, was used to examine the influence of three potential psychological mechanisms (pain acceptance, pain self-efficacy, fear of movement/re-injury) on treatment-related change in disability, depression, anxiety and average pain. Analyses involved generalized estimating equation models for clinical outcomes that adjusted for co occurring change in psychological variables. This was paired with cross-lagged analysis to assess for evidence of causality. Analyses involved two time points, pre-treatment and post-treatment. RESULTS: Changes in pain-acceptance were strongly associated with changes in three (depression, anxiety and average pain) of the four clinical outcomes. Changes in self-efficacy were also strongly associated with two (anxiety and average pain) clinical outcomes. These findings suggest that participants were unlikely to improve in these clinical outcomes without also experiencing increases in their pain self-efficacy and pain acceptance. However, there was no clear evidence from cross-lagged analyses to currently support these psychological variables as direct mechanisms of clinical improvements. There was only statistical evidence to suggest higher levels of self-efficacy moderated improvements in depression. CONCLUSIONS: The findings suggest that, while clinical improvements are closely associated with improvements in pain acceptance and self-efficacy, these psychological variables may not drive the treatment effects observed. SIGNIFICANCE: This study employed robust statistical techniques to assess the psychological mechanisms of an established internet-delivered pain management program. While clinical improvements (e.g. depression, anxiety, pain) were closely associated with improvements in psychological variables (e.g. pain self-efficacy and pain acceptance), these variables do not appear to be treatment mechanisms. PMID- 29754440 TI - Indications and interpretation of esophageal function testing. AB - Esophageal symptoms are common, and can arise from mucosal, motor, functional, and neoplastic processes, among others. Judicious use of diagnostic testing can help define the etiology of symptoms and can direct management. Endoscopy, esophageal high-resolution manometry (HRM), ambulatory pH or pH-impedance manometry, and barium radiography are commonly used for esophageal function testing; functional lumen imaging probe is an emerging option. Recent consensus guidelines have provided direction in using test findings toward defining mechanisms of esophageal symptoms. The Chicago Classification describes hierarchical steps in diagnosing esophageal motility disorders. The Lyon Consensus characterizes conclusive evidence on esophageal testing for a diagnosis of gastroesophageal reflux disease (GERD), and establishes a motor classification of GERD. Taking these recent advances into consideration, our discussion focuses primarily on the indications, technique, equipment, and interpretation of esophageal HRM and ambulatory reflux monitoring in the evaluation of esophageal symptoms, and describes indications for alternative esophageal tests. PMID- 29754442 TI - Psychosocial impact of diabetes. PMID- 29754441 TI - Schistosomicidal Activity of Dihydrobenzofuran Neolignans. AB - We have evaluated the antischistosomal activity of synthetic dihydrobenzofuran neolignans (DBNs) derived from (+/-)-trans-dehydrodicoumaric acid dimethyl ester (1) and (+/-)-trans-dehydrodiferulic acid dimethyl ester (2) against adult Schistosoma mansoni worms in vitro. Compound 4 ((+/-)-trans-4-O acetyldehydrodiferulic acid dimethyl ester) displayed the most promising activity; at 200 MUm, it kills 100 +/- 0% of worms after 24 h, which resembles the result achieved with praziquantel (positive control) at 1.56 MUm. The hydrogenation of the double bond between C7' and C8', the introduction of an additional methyl group at C3', and a double bond between C7 and C8 decreased the schistosomicidal activity of DBNs. On the other hand, the presence of the acetoxy group at C4 played an interesting role in this activity. These results demonstrated the interesting schistosomicidal potential of DBNs, which could be further exploited. PMID- 29754443 TI - Group benefits in joint perceptual tasks-a review. AB - In daily life, humans often perform perceptual tasks together to reach a shared goal. In these situations, individuals may collaborate (e.g., by distributing task demands) to perform the task better than when the task is performed alone (i.e., attain a group benefit). In this review, we identify the factors influencing if, and to what extent, a group benefit is attained and provide a framework of measures to assess group benefits in perceptual tasks. In particular, we integrate findings from two frequently investigated joint perceptual tasks: visuospatial tasks and decision-making tasks. For both task types, we find that an exchange of information between coactors is critical to improve joint performance. Yet, the type of exchanged information and how coactors collaborate differs between tasks. In visuospatial tasks, coactors exchange information about the performed actions to distribute task demands. In perceptual decision-making tasks, coactors exchange their confidence on their individual perceptual judgments to negotiate a joint decision. We argue that these differences can be explained by the task structure: coactors distribute task demands if a joint task allows for a spatial division and stimuli can be accurately processed by one individual. Otherwise, they perform the task individually and then integrate their individual judgments. PMID- 29754444 TI - Peptidome Analysis Reveals Novel Serum Biomarkers for Children with Autism Spectrum Disorder in China. AB - PURPOSE: Autism spectrum disorder (ASD) is a neurological and developmental disorder that begins early in childhood and lasts throughout one's life. Early diagnosis is essential for ASD since early treatment can enable children with ASD to make significant gains in language and social skills, but remains challenging since there are currently no specific biomarkers of ASD. This study is aimed to identify serum biomarkers for ASD. EXPERIMENTAL DESIGN: Serum of Han Chinese children with ASD (n = 68) and age-matched healthy controls (n = 80) is analyzed using magnetic bead-based separation combined with mass spectrum. RESULTS: Eight potential ASD serum biomarker peaks (m/z: 3886.69, 7775.12, 2381.71, 6638.63, 3319.17, 894.34, 4968.59, and 5910.53) with higher expression in ASD group are further identified as peptide regions of plasma serine protease inhibitor precursor (SERPINA5), platelet factor 4 (PF4), fatty acid binding protein 1(FABP1), apolipoprotein C-I precursor (APOC1), alpha-fetoprotein precursor (AFP), carboxypeptidase B2 (CPB2), trace amine-associated receptor 6 (TAAR6), and isoform1 of fibrinogen alpha chain precursor (FGA). The expression of identified proteins is validated by enzyme-linked immunosorbent assay (ELISA). CONCLUSIONS AND MEDICAL RELEVANCE: These findings reveal the exceptional disease etiology of ASD from a serum proteomic perspective, and the identified proteins might be potential biomarkers for ASD diagnosis. PMID- 29754445 TI - Engineering the unicellular alga Phaeodactylum tricornutum for high-value plant triterpenoid production. AB - Plant triterpenoids constitute a diverse class of organic compounds that play a major role in development, plant defence and environmental interaction. Several triterpenes have demonstrated potential as pharmaceuticals. One example is betulin, which has shown promise as a pharmaceutical precursor for the treatment of certain cancers and HIV. Major challenges for triterpenoid commercialization include their low production levels and their cost-effective purification from the complex mixtures present in their natural hosts. Therefore, attempts to produce these compounds in industrially relevant microbial systems such as bacteria and yeasts have attracted great interest. Here, we report the production of the triterpenes betulin and its precursor lupeol in the photosynthetic diatom Phaeodactylum tricornutum, a unicellular eukaryotic alga. This was achieved by introducing three plant enzymes in the microalga: a Lotus japonicus oxidosqualene cyclase and a Medicago truncatula cytochrome P450 along with its native reductase. The introduction of the L. japonicus oxidosqualene cyclase perturbed the mRNA expression levels of the native mevalonate and sterol biosynthesis pathway. The best performing strains were selected and grown in a 550-L pilot scale photobioreactor facility. To our knowledge, this is the most extensive pathway engineering undertaken in a diatom and the first time that a sapogenin has been artificially produced in a microalga, demonstrating the feasibility of the photo-bio-production of more complex high-value, metabolites in microalgae. PMID- 29754446 TI - Creating healthier graduates, campuses and communities: Why Australia needs to invest in health promoting universities. AB - ISSUE: Higher education is an important and influential setting for embedding health promotion principles and practice. Universities have a responsibility to their communities and more broadly as leaders in society. PROJECT: Settings-based health promotion is an effective method for increasing healthy environments and an organisational culture that supports health. "Healthy Universities" and the Okanagan Charter aim to embed health within the university structure through committed policies and programs. Collaboration across Australia can support this sector-wide adoption. CONCLUSIONS: Leadership is required from Australian universities to invest in health promotion. This is the time for higher education in Australia to consider its role in shaping the health of its local and global communities. PMID- 29754447 TI - Gain-of-function mutations in beet DODA2 identify key residues for betalain pigment evolution. AB - The key enzymatic step in betalain biosynthesis involves conversion of l-3,4 dihydroxyphenylalanine (l-DOPA) to betalamic acid. One class of enzymes capable of this is 3,4-dihydroxyphenylalanine 4,5-dioxygenase (DODA). In betalain producing species, multiple paralogs of this gene are maintained. This study demonstrates which paralogs function in the betalain pathway and determines the residue changes required to evolve a betalain-nonfunctional DODA into a betalain functional DODA. Functionalities of two pairs of DODAs were tested by expression in beets, Arabidopsis and yeast, and gene silencing was performed by virus induced gene silencing. Site-directed mutagenesis identified amino acid residues essential for betalamic acid production. Beta vulgaris and Mirabilis jalapa both possess a DODA1 lineage that functions in the betalain pathway and at least one other lineage, DODA2, that does not. Site-directed mutagenesis resulted in betalain biosynthesis by a previously nonfunctional DODA, revealing key residues required for evolution of the betalain pathway. Divergent functionality of DODA paralogs, one clade involved in betalain biosynthesis but others not, is present in various Caryophyllales species. A minimum of seven amino acid residue changes conferred betalain enzymatic activity to a betalain-nonfunctional DODA paralog, providing insight into the evolution of the betalain pigment pathway in plants. PMID- 29754448 TI - Periodontal infection with Porphyromonas gingivalis induces preterm birth and lower birth weight in rats. AB - Preterm birth (PTB), accompanied by low birth weight (LBW) or not, is a syndrome with tremendous risk factors and long-term health consequences for children. In recent decades, overwhelming studies have shown that periodontitis contributes to prematurity and LBW. This study was conducted to determine the link between maternal periodontitis and the pathogenesis of PTB and/or LBW through a rat infection model induced by Porphyromonas gingivalis, an important periodontopathic bacterium. The murine model was established by surgically ligating the left mandibular first molars and inoculating with P. gingivalis, and then all female rats initiated mating 6 weeks post infection. The gestational day and birth weight were recorded, and blood, amniotic fluid, and placental specimens were collected. Rats with a PTB and LBW newborns were observed in the P. gingivalis-infected group. Additionally, P. gingivalis infection significantly increased the maternal serum levels of interferon-gamma and interleukin-1beta, whereas no significant difference in the cytokine response was observed in the amniotic fluid. Moreover, with the translocation of P. gingivalis to placentas, remarkable changes in gestational tissues were found, followed by significantly enhanced expression of Toll-like receptor 2 (TLR2) as well as Fas and Fas ligand (FasL). These results support the concept that severe cases of periodontitis caused by P. gingivalis infection may be indicative of rats being more susceptible to PTB/LBW, probably through the activation of the TLR2 and Fas/FasL pathways within the placental tissues. This study gave us new insight into how maternal periodontopathogens might be linked to placental damage and premature pathogenesis. PMID- 29754449 TI - Transcranial alternating current stimulation modulates auditory temporal resolution in elderly people. AB - Recent research provides evidence for a functional role of brain oscillations for perception. For example, auditory temporal resolution seems to be linked to individual gamma frequency of auditory cortex. Individual gamma frequency not only correlates with performance in between-channel gap detection tasks but can be modulated via auditory transcranial alternating current stimulation. Modulation of individual gamma frequency is accompanied by an improvement in gap detection performance. Aging changes electrophysiological frequency components and sensory processing mechanisms. Therefore, we conducted a study to investigate the link between individual gamma frequency and gap detection performance in elderly people using auditory transcranial alternating current stimulation. In a within-subject design, twelve participants were electrically stimulated with two individualized transcranial alternating current stimulation frequencies: 3 Hz above their individual gamma frequency (experimental condition) and 4 Hz below their individual gamma frequency (control condition), while they were performing a between-channel gap detection task. As expected, individual gamma frequencies correlated significantly with gap detection performance at baseline and in the experimental condition, transcranial alternating current stimulation modulated gap detection performance. In the control condition, stimulation did not modulate gap detection performance. In addition, in elderly, the effect of transcranial alternating current stimulation on auditory temporal resolution seems to be dependent on endogenous frequencies in auditory cortex: Elderlies with slower individual gamma frequencies and lower auditory temporal resolution profit from auditory transcranial alternating current stimulation and show increased gap detection performance during stimulation. Our results strongly suggest individualized transcranial alternating current stimulation protocols for successful modulation of performance. PMID- 29754450 TI - Challenges of recruiting adolescents for appearance-related research in a specialist tertiary hospital. PMID- 29754451 TI - Maternal exercise, season and sex modify the daily fetal heart rate rhythm. AB - AIM: The knowledge on biological rhythms is rapidly expanding. We aimed to define the longitudinal development of the daily (24-hour) fetal heart rate rhythm in an unrestricted, out-of-hospital setting and to examine the effects of maternal physical activity, season and fetal sex. METHODS: We recruited 48 women with low risk singleton pregnancies. Using a portable monitor for continuous fetal electrocardiography, fetal heart rate recordings were obtained around gestational weeks 24, 28, 32 and 36. Daily rhythms in fetal heart rate and fetal heart rate variation were detected by cosinor analysis; developmental trends were calculated by population-mean cosinor and multilevel analysis. RESULTS: For the fetal heart rate and fetal heart rate variation, a significant daily rhythm was present in 122/123 (99.2%) and 116/121 (95.9%) of the individual recordings respectively. The rhythms were best described by combining cosine waves with periods of 24 and 8 hours. With increasing gestational age, the magnitude of the fetal heart rate rhythm increased, and the peak of the fetal heart rate variation rhythm shifted from a mean of 14:25 (24 weeks) to 20:52 (36 weeks). With advancing gestation, the rhythm-adjusted mean value of the fetal heart rate decreased linearly in females (P < .001) and nonlinearly in males (quadratic function, P = .001). At 32 and 36 weeks, interindividual rhythm diversity was found in male fetuses during higher maternal physical activity and during the summer season. CONCLUSION: The dynamic development of the daily fetal heart rate rhythm during the second half of pregnancy is modified by fetal sex, maternal physical activity and season. PMID- 29754452 TI - Part 1. Current prescribing trends of antibiotics by dentists in Australia from 2013 to 2016. AB - BACKGROUND: Literature has shown dentists tend to overprescribe antibiotics and do not always prescribe in accordance with recommended guidelines. Unnecessary prescribing is one major factor that contributes to the development of antibiotic resistance. The aim of the present study was to assess the antibacterial prescribing patterns of dentists in Australia from 2013 to 2016. METHODS: Data on dental antibacterial prescriptions dispensed under the Pharmaceutical Benefits Scheme (PBS) from 2013 to 2016 was accessed and prescribing trends analysed. The prescribing rates were standardized to the dose and population. RESULTS: There was a slight decrease in the dispensed use of most antibacterials from 2013 to 2016, but there was a significant increase in the dispensed use of amoxicillin/clavulanic acid of 11.2%. Amoxicillin was the most commonly dispensed antibiotic, accounting for approximately 65% of all antibacterials from 2013 to 2016, while phenoxymethylpenicillin accounted for only 1.4% of prescriptions in 2016. There were low but significant quantities of dispensed antibiotic prescriptions that do not fit with current guidelines. CONCLUSIONS: The data suggest that dentists in Australia are prescribing some antibiotics inappropriately and there is a preference for moderate- to broad-spectrum agents. The current PBS dental schedule is inconsistent with prescribing guidelines and may contribute to inappropriate prescribing. PMID- 29754453 TI - Dipeptidyl peptidase 4 inhibitor anagliptin ameliorates hypercholesterolemia in hypercholesterolemic mice through inhibition of intestinal cholesterol transport. AB - AIMS/INTRODUCTION: Recent data showed that dipeptidyl peptidase 4 (DPP-4) inhibitors exert a lipid-lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non-diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol-lowering action. MATERIALS AND METHODS: Male apolipoprotein E (ApoE) deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14 C-labeled cholesterol (14 C-Chol). In additional experiments, effects of exendin-4 in mice and of anagliptin in DPP-4-deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice. RESULTS: The serum total and non-high-density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE-deficient mice. The cholesterol-lowering effect was predominantly observed in the chylomicron fraction. The plasma 14 C-Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14 C-Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP-4 activity, and exendin-4 had no effect on the 14 C-Chol transport in ApoE-deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport-related microsomal triglyceride transfer protein, acyl coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin. CONCLUSIONS: These findings suggest that anagliptin might exert a cholesterol-lowering action through DPP-4-dependent and glucagon-like peptide 1 independent suppression of intestinal cholesterol transport. PMID- 29754454 TI - Heparinoid suppresses Der p-induced IL-1beta production by inhibiting ERK and p38 MAPK pathways in keratinocytes. AB - Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro-inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen-induced interleukin (IL)-1beta release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase-1 release, suggesting that heparinoid did not affect HDM allergen-induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro IL-1beta, but also suppressed IL-1beta messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal-regulated kinase and p38 pathways, which are required for IL 1beta expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL-1beta mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte-mediated skin inflammation. PMID- 29754455 TI - Technical Note: Using dual step wedge and 2D scintillator to achieve highly precise and robust proton range quality assurance. AB - PURPOSE: The purpose of this study was to develop a fast method for proton range quality assurance (QA) using a dual step wedge and two-dimensional (2D) scintillator and to evaluate the robustness, sensitivity, and long-term reproducibility of this method. METHODS: An in-house customized dual step wedge and a 2D scintillator were developed to measure proton ranges. Proton beams with homogenous fluence were delivered through wedge, and the images captured by the scintillator were used to calculate the proton ranges by a simple trigonometric method. The range measurements of 97 energies, comprising all clinically available synchrotron energies at our facility (ranges varying from 4 to 32 cm) were repeated ten times in all four gantry rooms for range baseline values. They were then used for evaluating room-to-room range consistencies. The robustness to setup uncertainty was evaluated by measuring ranges with +/-2 mm setup deviations in the x, y, and z directions. The long-term reproducibility was evaluated by 1 month of daily range measurements by this method. RESULTS: Ranges of all 97 energies were measured in less than 10 minutes including setup time. The reproducibility in a single day and daily over 1 month is within 0.1 and 0.15 mm, respectively. The method was very robust to setup uncertainty, with measured range consistencies within 0.15 mm for +/-2 mm couch shifts. The method was also sensitive enough for validating range consistencies among gantry rooms and for detecting small range variations. CONCLUSIONS: The new method of using a dual step wedge and scintillator for proton range QA was efficient, highly reproducible, and robust. This method of proton range QA was highly feasible and appealing from a workflow point of view. PMID- 29754456 TI - Pentraxin levels in non-eosinophilic versus eosinophilic asthma. AB - BACKGROUND: Innate immunity has been thought to be involved in asthma pathogenesis. Pentraxins, acting as soluble pattern recognition molecules, play an important role in humoral innate immunity. Asthma is a heterogeneous inflammatory disease of airways and can be classified as eosinophilic or non eosinophilic asthma. OBJECTIVE: To investigate whether pentraxin levels differ in subjects with eosinophilic versus non-eosinophilic asthma. Furthermore, to access the predictive performance of pentraxin levels for discriminating asthma inflammatory phenotypes. METHODS: A total of 80 asthmatic patients and 24 healthy control subjects underwent sputum induction at study inclusion. Differential leucocyte counts were performed on selected sputum. Plasma C-reactive protein (CRP), serum amyloid P (SAP), pentraxin 3 (PTX3), and sputum SAP, PTX3, IL-8 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Subjects with non-eosinophilic asthma had significantly increased pentraxin levels compared with those with eosinophilic asthma and healthy controls, with median (interquartile range) plasma CRP levels of 0.86 (0.28-2.07), 0.26 (0.14-0.85), and 0.15 (0.09-0.45)mg/L (P < .001), respectively, plasma SAP levels of 33.69 (19.79-58.39), 19.76 (16.11-30.58), and 20.06 (15.68-31.11)mg/L (P = .003), respectively, and sputum PTX3 levels of 4.9 (1.35-18.72), 0.87 (0.30-2.07), and 1.08 (0.31-4.32)ng/mL (P < .001), respectively. Conversely, sputum SAP concentrations of eosinophilic asthmatics (median, 21.49 ng/mL; IQR, 6.86-38.79 ng/mL) were significantly higher than those of non-eosinophilic patients (median, 8.15 ng/mL; IQR, 2.82-18.01 ng/mL) and healthy controls (median, 8.79 ng/mL; IQR, 2.00-16.18 ng/mL). Asthma patients with high plasma CRP (P = .004), SAP (P = .005) and sputum PTX3 levels (P < 0.001) also had significantly lower sputum eosinophil percentages. Sputum PTX3 levels had the best power (11.18-fold, P < .001) to predict non-eosinophilic airway inflammation in asthma patients. CONCLUSION AND CLINICAL RELEVANCE: Pentraxin levels differed significantly between patients with non-eosinophilic asthma and those with eosinophilic asthma. Furthermore, elevated pentraxin expressions may predict non-eosinophilic airway inflammation in asthmatic patients. PMID- 29754457 TI - Cardioprotective role of IGF-1 in the hypertrophied myocardium of the spontaneously hypertensive rats: A key effect on NHE-1 activity. AB - AIM: Myocardial Na+ /H+ exchanger-1 (NHE-1) hyperactivity and oxidative stress are interrelated phenomena playing pivotal roles in the development of pathological cardiac hypertrophy and heart failure. Exercise training is effective to convert pathological into physiological hypertrophy in the spontaneously hypertensive rats (SHR), and IGF-1-key humoral mediator of exercise training-inhibits myocardial NHE-1, at least in normotensive rats. Therefore, we hypothesize that IGF-1 by hampering NHE-1 hyperactivity and oxidative stress should exert a cardioprotective effect in the SHR. METHODS: NHE-1 activity [proton efflux ( RESULTS: IGF-1 significantly decreased NHE-1 activity ( CONCLUSION: IGF-1 exerts a cardioprotective role on the hypertrophied hearts of the SHR, in which the inhibition of NHE-1 hyperactivity, as well as the positive inotropic and antioxidant effects, emerges as key players. PMID- 29754458 TI - Integrating Point-of-care Testing Into a Community Emergency Department: A Mixed methods Evaluation. AB - OBJECTIVE: Point-of-care testing (POCT) is a commonly used technology that hastens the time to laboratory results in emergency departments (ED). We evaluated an ED-based POCT program on ED length of stay (LOS) and time to care, coupled with qualitative interviews of local ED stakeholders. METHODS: We conducted a mixed-methods study (2012-2016) to examine the impact of POCT in a single, community ED. The quantiative analysis involved an observational before after study comparing time to laboratory test result (POC troponin or POC chemistry) and ED LOS after implementation of POCT, using a propensity-weighted interrupted time series analysis (ITSA). A complementary qualitative analysis involved five semistructured interviews with staff using grounded theory on the benefits and challenges to ED POCT. RESULTS: A total of 47,399 ED visits were included in the study (24,705 in the preintervention period and 22,694 in the postintervention period). After POCT implementation, overall laboratory testing increased marginally from 61% to 62%. Central laboratory troponin and chemistry declined by > 50% and was replaced by POCT. Prior to POCT implementation, time to troponin and chemistry had declined steadily due to other improvements in laboratory efficiency. After POCT implementation, there was an immediate 20 minute further decline (p < 0.001) in both time to troponin and time to chemistry results using the propensity-weighted comparisons. However, the declining trend observed prior to POCT implementation did not continue at the same rate after implementation. Similarly, prior to POCT implementation, ED LOS declined due to other quality improvements. After POCT implementation, LOS continued declined at a similar rate. Because of this prior trend, the ITSA did not show a significant decline in LOS attributable to POCT. Common benefits of POCT perceived by staff in qualitative interviews included improved quality of care (64%) and reductions in time to test results (44%). Common challenges included concerns over POCT accuracy (32%) and technical barriers (29%). CONCLUSION: In the study ED, implementation of POCT was associated with a reduction in time to test result for both troponin and chemistry. Local staff felt that faster time to test result improved quality of care; however, concerns were raised with POCT accuracy. PMID- 29754459 TI - Metabolism, obesity and the metabolic syndrome. PMID- 29754460 TI - Prognostic evaluation of the elastic properties of the ascending aorta in dilated cardiomyopathy. AB - BACKGROUND: Nowadays there is an increased interest in the role of aortic stiffness in the pathophysiology of heart failure (HF), as it is a major determinant of left ventricular (LV) performance. We aimed at assessing the predictive value of the aortic stiffness parameters, measured by echocardiography, in patients affected by nonischaemic dilated cardiomyopathy (DCM) regarding three end-points: death, HF rehospitalization, combined death or HF rehospitalization in a long-term follow-up. MATERIALS AND METHODS: A total of 202 patients affected by nonischaemic DCM underwent an outpatient examination by echocardiography and blood pressure check at the brachial artery, in order to calculate aortic elastic properties (ie, compliance, distensibility, stiffness index, Peterson's elastic modulus, M-mode strain). ROC curves, Kaplan-Meier curves and multivariable Cox regressions (correcting for age, LV ejection fraction (LVEF), atrial fibrillation, cardiac resynchronization therapy (CRT)) were run to assess the predictive ability of aortic elastic properties against the 3 end-points. RESULTS: Mean follow-up was 9.83 +/- 2.80 years. 24.8% of patients died, while 34.7% were rehospitalized for HF cause and 44.6% experienced the combined end-point. LVEF did not correlate with aortic elastic properties. ROC curves and Kaplan-Meier curves were elaborated. Aortic stiffness did not predict death in our cohort. Otherwise, all aortic elastic properties predicted HF rehospitalization and combined death or HF rehospitalization, after correcting for age, LVEF, atrial fibrillation, CRT. CONCLUSIONS: Elastic properties of the ascending aorta measured by echocardiography in patients with nonischaemic DCM predict long-term HF rehospitalization and combined death or HF rehospitalization, also after correcting for the confounding factors. PMID- 29754462 TI - Predictors of outcome of prematurely born infants with pulmonary interstitial emphysema. AB - AIM: To determine how oxygenation, ventilation efficiency and tidal volume requirements changed with the development of pulmonary interstitial emphysema (PIE) and whether in affected patients a composite gas exchange index predicted death or bronchopulmonary dysplasia (BPD). METHODS: Infants who developed PIE from 2010 to 2016 were identified. The oxygenation index (OI), ventilation efficiency index (VEI), ventilation to perfusion ratio and inspiratory tidal volume were calculated before radiological evidence of PIE (pre-PIE) and at the worst PIE radiographic appearance (PIE-worst). RESULTS: Thirty infants, median (IQR) gestational age of 24.6 (24.3-26.7) weeks were assessed. Their age at pre PIE was 11 (6-19) days and 23 (13-42) days at PIE-worst. Compared to pre-PIE, at PIE-worst, the OI was higher [14.5 (10.7-19.2) vs 4.8 (3.1-6.1), respectively, p < 0.001], VEI was lower [0.01 (0.01-0.11) vs 0.16 (0.13-0.19), respectively, p < 0.001], ventilation to perfusion ratio was lower [0.15 (0.11-0.40) vs 0.26 (0.20 0.37), p = 0.033] and tidal volume was higher [9.9 (7.2-13.1) vs 6.4 (5.5-6.8) mL/kg, p = 0.007]. An OI >11.4 at PIE-worst predicted death or BPD with 80% sensitivity and 100% specificity. CONCLUSION: Development of PIE was associated with poorer oxygenation and ventilation efficiency despite increased tidal volumes. The OI at PIE-worst predicted death or BPD. PMID- 29754461 TI - Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin-actin transfer. AB - Formins accelerate actin polymerization, assumed to occur through flexible Formin Homology 1 (FH1) domain-mediated transfer of profilin-actin to the barbed end. To study FH1 properties and address sequence effects, including varying length/distribution of profilin-binding proline-rich motifs, we performed all atom simulations of a set of representative FH1 domains of formins: mouse mDia1 and mDia2, budding yeast Bni1 and Bnr1, and fission yeast Cdc12, For3, and Fus1. We find FH1 has flexible regions between high-propensity polyproline helix regions. A coarse-grained model retaining sequence specificity, assuming rigid polyproline segments, describes their size. Multiple bound profilins or profilin actin complexes expand mDia1-FH1, which may be important in cells. Simulations of the barbed end bound to Bni1-FH1-FH2 dimer show that the leading FH1 can better transfer profilin or profilin-actin, with decreasing probability as the distance from FH2 increases. PMID- 29754463 TI - Intestinal failure: the evolving demographic and patient outcomes on home parenteral nutrition. AB - AIM: We performed this study to examine and understand the evolving demographics and changing outcomes of intestinal failure (IF) and its implications for healthcare delivery. METHOD: We conducted a retrospective analysis of outcome data of children on home parenteral nutrition (HPN), over a 15-year period. RESULTS: A total of 31 patients received HPN: 15 for short bowel syndrome (SBS), eight neuromuscular disease (NMD) and eight for other causes. The HPN prevalence increased from 1.54 per million children in 2000 to 21.5 in 2016. The outcomes over last 5 years were better than those of previous 10 years. The rate of catheter-related bloodstream infection (CRBSI) had fallen from 4 to 1.3 and IF liver disease (IFALD) from 20% to 7.7%. The aetiology changed over years from SBS being the main cause to NMD contributing 43% to the total in 2016. This was especially relevant as NMD was associated with greater numbers of IFALD (38% vs 6.7%), CRBSI (1.51 vs 0.64/1000 PN days) and mortality. CONCLUSION: The outcome of long-term parenteral nutrition (PN) has improved. The increasing number of patients with NMD, coupled with their higher burden of care, results in an increasing health care burden, and the planning of intestinal rehabilitation services needs to reflect this. PMID- 29754464 TI - Clapping in time parallels literacy and calls upon overlapping neural mechanisms in early readers. AB - The auditory system is extremely precise in processing the temporal information of perceptual events and using these cues to coordinate action. Synchronizing movement to a steady beat relies on this bidirectional connection between sensory and motor systems, and activates many of the auditory and cognitive processes used when reading. Here, we use Interactive Metronome, a clinical intervention technology requiring an individual to clap her hands in time with a steady beat, to investigate whether the links between literacy and synchronization skills, previously established in older children, are also evident in children who are learning to read. We tested 64 typically developing children (ages 5-7 years) on their synchronization abilities, neurophysiological responses to speech in noise, and literacy skills. We found that children who have lower variability in synchronizing have higher phase consistency, higher stability, and more accurate envelope encoding-all neurophysiological response components linked to language skills. Moreover, performing the same task with visual feedback reveals links with literacy skills, notably processing speed, phonological processing, word reading, spelling, morphology, and syntax. These results suggest that rhythm skills and literacy call on overlapping neural mechanisms, supporting the idea that rhythm training may boost literacy in part by engaging sensory-motor systems. PMID- 29754465 TI - PbrmiR397a regulates lignification during stone cell development in pear fruit. AB - Lignified stone cells substantially reduce fruit quality. Therefore, it is desirable to inhibit stone cell development using genetic technologies. However, the molecular mechanisms regulating lignification are poorly understood in fruit stone cells. In this study, we have shown that microRNA (miR) miR397a regulates fruit cell lignification by inhibiting laccase (LAC) genes that encode key lignin biosynthesis enzymes. Transient overexpression of PbrmiR397a, which is the miR397a of Chinese pear (Pyrus bretschneideri), and simultaneous silencing of three LAC genes reduced the lignin content and stone cell number in pear fruit. A single nucleotide polymorphism (SNP) identified in the promoter of the PbrmiR397a gene was found to associate with low levels of fruit lignin, after analysis of the genome sequences of sixty pear varieties. This SNP created a TCA element that responded to salicylic acid to induce gene expression as confirmed using a cell based assay system. Furthermore, stable overexpression of PbrmiR397a in transgenic tobacco plants reduced the expression of target LAC genes and decreased the content of lignin but did not change the ratio of syringyl- and guaiacyl-lignin monomers. Consistent with reduction in lignin content, the transgenic plants showed fewer numbers of vessel elements and thinner secondary walls in the remaining elements compared to wild-type control plants. This study has advanced our understanding of the regulation of lignin biosynthesis and provided useful molecular genetic information for improving pear fruit quality. PMID- 29754466 TI - Temporal trends in paediatric bacterial meningitis in a tropical Australian region: 1992-2014. AB - AIM: The epidemiology of community-acquired bacterial meningitis has changed following the introduction of routine immunisation against common causative organisms. Indigenous children living in the Northern Territory, Australia, have high rates of bacterial infections. This study describes changes in the epidemiology of childhood bacterial meningitis and the distribution of the burden of disease in the Top End. METHODS: A retrospective review of cases derived from hospital medical records and laboratory data was performed. Inclusion criteria were children aged 3 months to 14 years of age, admitted to Royal Darwin Hospital between 1992 and 2014 and diagnosed with bacterial meningitis. Annual incidence of bacterial meningitis and the distribution of causative pathogens are described. Demographic data, investigations, treatment and outcomes were compared between Indigenous and non-Indigenous children. RESULTS: There were 137 cases of childhood bacterial meningitis identified over the 23-year period. The incidence reduced from 21 per 100 000 children per year for 1992-2002 to 11 per 100 000 per year for 2003-2014 (P = 0.0025). Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis were the most common causative organisms, with a reduction in cases for each pathogen observed across the study period. Indigenous children were over-represented (104/137, 76%). Case fatality rate was 8% (11/137); 91% of fatal cases presented to a remote facility. CONCLUSIONS: The incidence of childhood bacterial meningitis has declined in the Northern Territory of Australia, but Indigenous children are disproportionately affected. Routine immunisation is beneficial for all, although further efforts to 'Close the Gap' between health outcomes in Indigenous and non-Indigenous Australians is required. PMID- 29754467 TI - Teaching treatment planning for protons with educational open-source software: experience with FoCa and matRad. AB - Open-source, MATLAB-based treatment planning systems FoCa and matRAD were used in a pilot project for training prospective medical physicists and postgraduate physics students in treatment planning and beam modeling techniques for proton therapy. In the four exercises designed, students learnt how proton pencil beams are modeled and how dose is calculated in three-dimensional voxelized geometries, how pencil beam scanning plans (PBS) are constructed, the rationale behind the choice of spot spacing in patient plans, and the dosimetric differences between photon IMRT and proton PBS plans. Sixty students of two courses participated in the pilot project, with over 90% of satisfactory rating from student surveys. The pilot experience will certainly be continued. PMID- 29754468 TI - Bleeding score in type 1 von Willebrand disease patients using the condensed MCMDM-1 vWD validated questionnaire. AB - BACKGROUND: Assessment of the severity of bleeding symptom has led to the evolution of bleeding assessment tools which are now validated. AIMS: To administer the condensed molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease VWD (MCMDM-1 vWD) questionnaire to the Omani type 1 vWD patients and correlate it with the laboratory parameters. METHODS: Patients and controls were personally interviewed and the condensed MCMDM-1 vWD questionnaire administered by a single investigator. Bleeding score (BS) was calculated, based on the presence or absence of the bleeding symptoms according to a standard validated questionnaire in both the patients and the controls. RESULTS: The median age of the patient cohort was 27 (range, 7-49) years with 60.87% of females. The median time to administer condensed MCMDM-1 BS questionnaire was 11 minutes (interquartile range-IQR;7,16). Overall, bleeding from the oral cavity was the most predominant symptom (63%). The median BS was 5 (IQR;1,8) although individual scores ranged between 0 and 29. However, there was no statistically significant difference in BS between genders (males: median 4; IQR 1,6 and females: median 5, IQR 1,10) (P > .05, Kruskal-Wallis test) The Spearman's correlation value of BS was weak with FVIII:C levels and von Willebrand Ristocetin co-factor activity; very weak with von Willebrand Antigen level, and moderate with vonWillebrand Collagen Binding activity being -0.29, 0.28, -0.14 and -0.43, respectively. CONCLUSION: The BS reflects the severity of bleeding among the vWD patients. Although the BS was abnormal, it did not correlate significantly with the surrogate laboratory parameters [P > .05]. PMID- 29754469 TI - miRNA-103a-3p Promotes Human Gastric Cancer Cell Proliferation by Targeting and Suppressing ATF7 in vitro. AB - Studies have revealed that miR-103a-3p contributes to tumor growth in several human cancers, and high miR-103a-3p expression is associated with poor prognosis in advanced gastric cancer (GC) patients. Moreover, bioinformatics analysis has shown that miR-103a-3p is upregulated in The Cancer Genome Atlas (TCGA) stomach cancer cohort. These results suggest that miR-103a-3p may function as an oncogene in GC. The present study aimed to investigate the role of miR-103a-3p in human GC. miR-103a-3p expression levels were increased in 33 clinical GC specimens compared with adjacent nontumor stomach tissues. Gain- and loss-of-function studies were performed to identify the correlation between miR-103a-3p and tumorigenesis in human GC. Inhibiting miR-103a-3p suppressed GC cell proliferation and blocked the S-G2/M transition in MKN-45/SGC-7901 cells, whereas miR-103a-3p overexpression improved GC cell proliferation and promoted the S-G2/M transition in vitro. Bioinformatics and dual-luciferase reporter assays confirmed that ATF7 is a direct target of miR-103a-3p. Analysis of the TCGA stomach cancer cohort further revealed that miR-103a-3p expression was inversely correlated with ATF7 expression. Notably, silencing ATF7 showed similar cellular and molecular effects as miR-103a-3p overexpression, namely, increased GC cell proliferation, improved CDK2 expression and decreased P27 expression. ATF7 overexpression eliminated the effects of miR-103a-3p expression. These findings indicate that miR-103a-3p promotes the proliferation of GC cell by targeting and suppressing ATF7 in vitro. PMID- 29754470 TI - Current Challenges of Streptococcus Infection and Effective Molecular, Cellular, and Environmental Control Methods in Aquaculture. AB - Several bacterial etiological agents of streptococcal disease have been associated with fish mortality and serious global economic loss. Bacterial identification based on biochemical, molecular, and phenotypic methods has been routinely used, along with assessment of morphological analyses. Among these, the molecular method of 16S rRNA sequencing is reliable, but presently, advanced genomics are preferred over other traditional identification methodologies. This review highlights the geographical variation in strains, their relatedness, as well as the complexity of diagnosis, pathogenesis, and various control methods of streptococcal infections. Several limitations, from diagnosis to control, have been reported, which make prevention and containment of streptococcal disease difficult. In this review, we discuss the challenges in diagnosis, pathogenesis, and control methods and suggest appropriate molecular (comparative genomics), cellular, and environmental solutions from among the best available possibilities. PMID- 29754471 TI - LncRNA H19/miR-29b-3p/PGRN Axis Promoted Epithelial-Mesenchymal Transition of Colorectal Cancer Cells by Acting on Wnt Signaling. AB - This investigation was aimed at working out the combined role of lncRNA H19, miR 29b and Wnt signaling in the development of colorectal cancer (CRC). In the aggregate, 185 CRC tissues and corresponding para-carcinoma tissues were gathered. The human CRC cell lines (i.e. HT29, HCT116, SW480 and SW620) and normal colorectal mucosa cell line (NCM460) were also purchased. Si-H19, si-NC, miR-29b-3p mimics, miR-29b-3p inhibitor, si-PGRN and negative control (NC) were, respectively, transfected into the CRC cells. Lucif-erase reporter plasmids were prepared to evaluate the transduction activity of Wnt/beta-catenin signaling pathway, and dual-luciferase reporter gene assay was arranged to confirm the targeted relationship between H19 and miR-29b-3p, as well as between miR-29b-3p and PGRN. Finally, the proliferative and invasive capacities of CRC cells were appraised through transwell, MTT and scratch assays. As a result, over-expressed H19 and down-expressed miR-29b-3p displayed close associations with the CRC patients' poor prognosis (P < 0.05). Besides, transfection with si-H19, miR-29b 3p mimic or si-PGRN were correlated with elevated E-cadherin expression, decreased snail and vimentin expressions, as well as less-motivated cell proliferation and cell metastasis (P < 0.05). Moreover, H19 was verified to directly target miR-29b-3p based on the luciferase reporter gene assay (P < 0.05), and miR-29b-3p also bound to PGRN in a direct manner (P < 0.05). Finally, addition of LiCl (Wnt/beta-catenin pathway activator) or XAV93920 (Wnt/beta catenin pathway inhibitor) would cause remarkably altered E-cadherin, c-Myc, vimentin and snail expressions, as well as significantly changed transcriptional activity of beta-catenin/Tcf reporter plasmid (P < 0.05). In conclusion, the lncRNA H19/miR-29b-3p/PGRN/Wnt axis counted a great deal for seeking appropriate diagnostic biomarkers and treatment targets for CRC. PMID- 29754472 TI - Confirmation of Drought Tolerance of Ectopically Expressed AtABF3 Gene in Soybean. AB - Soybean transgenic plants with ectopically expressed AtABF3 were produced by Agrobacterium-mediated transformation and investigated the effects of AtABF3 expression on drought and salt tolerance. Stable Agrobacterium-mediated soybean transformation was carried based on the half-seed method (Paz et al. 2006). The integration of the transgene was confirmed from the genomic DNA of transformed soybean plants using PCR and the copy number of transgene was determined by Southern blotting using leaf samples from T2 seedlings. In addition to genomic integration, the expression of the transgenes was analyzed by RT-PCR and most of the transgenic lines expressed the transgenes introduced. The chosen two transgenic lines (line #2 and #9) for further experiment showed the substantial drought stress tolerance by surviving even at the end of the 20-day of drought treatment. And the positive relationship between the levels of AtABF3 gene expression and drought-tolerance was confirmed by qRT-PCR and drought tolerance test. The stronger drought tolerance of transgenic lines seemed to be resulted from physiological changes. Transgenic lines #2 and #9 showed ion leakage at a significantly lower level (P < 0.01) than non-transgenic (NT) control. In addition, the chlorophyll contents of the leaves of transgenic lines were significantly higher (P < 0.01). The results indicated that their enhanced drought tolerance was due to the prevention of cell membrane damage and maintenance of chlorophyll content. Water loss by transpiration also slowly proceeded in transgenic plants. In microscopic observation, higher stomata closure was confirmed in transgenic lines. Especially, line #9 had 56% of completely closed stomata whereas only 16% were completely open. In subsequent salt tolerance test, the apparently enhanced salt tolerance of transgenic lines was measured in ion leakage rate and chlorophyll contents. Finally, the agronomic characteristics of ectopically expressed AtABF3 transgenic plants (T2) compared to NT plants under regular watering (every 4 days) or low rate of watering condition (every 10 days) was investigated. When watered regularly, the plant height of drought-tolerant line (#9) was shorter than NT plants. However, under the drought condition, total seed weight of line #9 was significantly higher than in NT plants (P < 0.01). Moreover, the pods of NT plants showed severe withering, and most of the pods failed to set normal seeds. All the evidences in the study clearly suggested that overexpression of the AtABF3 gene conferred drought and salt tolerance in major crop soybean, especially under the growth condition of low watering. PMID- 29754473 TI - Actin Dysfunction Induces Cell Cycle Delay at G2/M with Sustained ERK and RSK Activation in IMR-90 Normal Human Fibroblasts. AB - The actin cytoskeleton plays a key role in the entry of mitosis as well as in cytokinesis. In a previous study, we showed that actin disruption delays mitotic entry at G2/M by sustained activation of extracellular signal-related kinase 1/2 (ERK1/2) in primary cells but not in transformed cancer cell lines. Here, we examined the mechanism of cell cycle delay at G2/M by actin dysfunction in IMR-90 normal human fibroblasts. We observed that de-polymerization of actin with cytochalasin D (CD) constitutively activated ribosomal S6 kinase (RSK) and induced inhibitory phosphorylation of Cdc2 (Tyr 15) in IMR-90 cells. In the presence of an actin defect in IMR-90 cells, activating phosphorylation of Wee1 kinase (Ser 642) and inhibitory phosphorylation of Cdc25C (Ser 216) was also maintained. However, when kinase-dead RSK (DN-RSK) was over-expressed, we observed sustained activation of ERK1/2, but no delay in the G2/M transition, demonstrating that RSK functions downstream of ERK in cell cycle delay by actin dysfunction. In DN-RSK overexpressing IMR-90 cells treated with CD, phosphorylation of Cdc25C (Ser 216) was blocked and phosphorylation of Cdc2 (Tyr 15) was decreased, but the phosphorylation of Wee1 (Ser 642) was maintained, demonstrating that RSK directly controls phosphorylation of Cdc25C (Ser 216), but not the activity of Wee1. These results strongly suggest that actin dysfunction in primary cells activates ERK1/2 to inhibit Cdc2, delaying the cell cycle at G2/M by activating downstream RSK, which phosphorylates and blocks Cdc25C, and by directly activating Wee1. PMID- 29754474 TI - Oxymatrine Causes Hepatotoxicity by Promoting the Phosphorylation of JNK and Induction of Endoplasmic Reticulum Stress Mediated by ROS in LO2 Cells. AB - Oxymatrine (OMT) often used in treatment for chronic hepatitis B virus infection in clinic. However, OMT-induced liver injury has been reported. In this study, we aim to investigate the possible mechanism of OMT-induced hepatotoxicity in human normal liver cells (L02). Exposed cells to OMT, the cell viability was decreased and apoptosis rate increased, the intracellular markers of oxidative stress were changed. Simultaneously, OMT altered apoptotic related proteins levels, including Bcl-2, Bax and pro-caspase-8/-9/-3. In addition, OMT enhanced the protein levels of endoplasmic reticulum (ER) stress makers (GRP78/Bip, CHOP, and cleaved-Caspase 4) and phosphorylation of c-Jun N-terminal kinase (p-JNK), as well as the mRNA levels of GRP78/Bip, CHOP, caspase-4, and ER stress sensors (IREI, ATF6, and PERK). Pre-treatment with Z-VAD-fmk, JNK inhibitor SP600125 and N-acetyl-l cysteine (NAC), a ROS scavenger, partly improved the survival rates and restored OMT-induced cellular damage, and reduced caspase-3 cleavage. SP600125 or NAC reduced OMT-induced p-JNK and NAC significantly lowered caspase-4. Furthermore, 4 PBA, the ER stress inhibitor, weakened inhibitory effect of OMT on cells, on the contrary, TM worsen. 4-PBA also reduced the levels of p-JNK and cleaved-caspase-3 proteins. Therefore, OMT-induced injury in L02 cells was related to ROS mediated p-JNK and ER stress induction. Antioxidant, by inhibition of p-JNK or ER stress, may be a feasible method to alleviate OMT-induced liver injury. PMID- 29754477 TI - Melioidosis: a neglected tropical disease PMID- 29754475 TI - Regulator of G-Protein Signaling 4 (RGS4) Controls Morphine Reward by Glutamate Receptor Activation in the Nucleus Accumbens of Mouse Brain. AB - Crosstalk between G-protein signaling and glutamatergic transmission within the brain reward circuits is critical for long-term emotional effects (depression and anxiety), cravings, and negative withdrawal symptoms associated with opioid addiction. A previous study showed that Regulator of G-protein signaling 4 (RGS4) may be implicated in opiate action in the nucleus accumbens (NAc). However, the mechanism of the NAc-specific RGS4 actions that induce the behavioral responses to opiates remains largely unknown. The present study used a short hairpin RNA (shRNA)-mediated knock-down of RGS4 in the NAc of the mouse brain to investigate the relationship between the activation of ionotropic glutamate receptors and RGS4 in the NAc during morphine reward. Additionally, the shRNA-mediated RGS4 knock-down was implemented in NAc/striatal primary-cultured neurons to investigate the role that striatal neurons have in the morphine-induced activation of ionotropic glutamate receptors. The results of this study show that the NAc-specific knockdown of RGS4 significantly increased the behaviors associated with morphine and did so by phosphorylation of the GluR1 (Ser831) and NR2A (Tyr1325) glutamate receptors in the NAc. Furthermore, the knock-down of RGS4 enhanced the phosphorylation of the GluR1 and NR2A glutamate receptors in the primary NAc/striatal neurons during spontaneous morphine withdrawal. These findings show a novel molecular mechanism of RGS4 in glutamatergic transmission that underlies the negative symptoms associated with morphine administration. PMID- 29754478 TI - Methicillin resistant Staphylococcus aureus contamination of phlebotomy tourniquets and faucets AB - Introduction: Methicillin resistant Staphylococcus aureus (MRSA) is transmitted through direct contact or fomites. The most important means of nosocomial spread is by hospital personnel. However, fomites are being increasingly recognized as sources of nosocomial infection. Objectives: Our aim was to describe the MRSA contamination rate of phlebotomy tourniquets and faucets in a tertiary care hospital and to compare the contamination of plastic tourniquets with that of fabric tourniquets. Method: A cross-sectional study was carried out in the general wards of a tertiary care hospital in the Colombo District. Two hundred tourniquets were collected and 100 faucets were swabbed and cultured on CHROMagarTM MRSA medium (CHROMagar Microbiology). Contamination rates of 50 plastic tourniquets and 50 fabric tourniquets were compared. Results: MRSA grew in 26% of tourniquets. Majority were plastic tubes. MRSA contamination of tourniquets did not significantly differ by ward (p>0.4). MRSA was found on 26% of faucets. Contamination rate was highest in the common wards for dermatology, dental, rheumatology, and neurology (55.6%), followed by gynaecology (45.2%), cardiology (33.3%), surgery (18.8%), psychiatry (11.1%), and medicine (5.6%). There was a significant difference in rates of contamination of faucets in the different wards (p<0.01). There was no significant difference in the colony count per surface area of the two types of tourniquets after a single use. Conclusions: MRSA contamination rates of tourniquets and faucets were high. Single-use plastic tourniquets were much less contaminated with MRSA than reused tourniquets. PMID- 29754476 TI - Targeting Super-Enhancers for Disease Treatment and Diagnosis. AB - The transcriptional regulation of genes determines the fate of animal cell differentiation and subsequent organ development. With the recent progress in genome-wide technologies, the genomic landscapes of enhancers have been broadly explored in mammalian genomes, which led to the discovery of novel specific subsets of enhancers, termed super-enhancers. Super-enhancers are large clusters of enhancers covering the long region of regulatory DNA and are densely occupied by transcription factors, active histone marks, and co-activators. Accumulating evidence points to the critical role that super-enhancers play in cell type specific development and differentiation, as well as in the development of various diseases. Here, I provide a comprehensive description of the optimal approach for identifying functional units of super-enhancers and their unique chromatin features in normal development and in diseases, including cancers. I also review the recent updated knowledge on novel approaches of targeting super enhancers for the treatment of specific diseases, such as small-molecule inhibitors and potential gene therapy. This review will provide perspectives on using super-enhancers as biomarkers to develop novel disease diagnostic tools and establish new directions in clinical therapeutic strategies. PMID- 29754479 TI - Pre-operative ultrasonographic prediction of hamstring autograft size for anterior cruciate ligament reconstruction surgery AB - Objectives: To evaluate the feasibility of ultrasonographic examination in predicting 4-strand semitendinosus and gracilis tendon (4S-STG) autograft size preoperatively in anterior cruciate ligament reconstruction and to evaluate the use of anthropometric measurement to predict the 4-strand semitendinosus and gracilis tendons (4S-STG) autograft size pre-operatively in anterior cruciate ligament reconstruction. Method: Twenty-seven patients were included in this study conducted from 1st January to 31st December 2013. All patients were skeletally mature and scheduled to undergo primary anterior cruciate ligament reconstruction using 4S-STG autograft. Ultrasonographic examination of semitendinosus and gracilis tendons to measure the cross sectional area was conducted and anthropometric data (weight, height, leg length and thigh circumference) was measured one day prior to surgery. True autograft diameters were measured intraoperatively using closed-hole sizing block in 0.5 mm incremental size. Results: There is a statistically significant correlation between the measured combined cross sectional area (semitendinosus and gracilis tendons) and 4S-STG autograft diameter (p = 0.023). An adequate autograft size (at least 7 mm) can be obtained when the combined cross sectional area is at least 15 mm2. There was no correlation with the anthropometric data except for thigh circumference (p = 0.037). Autograft size of at least 7 mm can be obtained when the thigh circumference is at least 41 mm. Conclusions: Both combined cross sectional area (semitendinosus and gracilis tendons) and thigh circumference can be used to predict an adequate 4S-STG autograft size. PMID- 29754480 TI - Pycnogenol(r) supplementation in minimal cognitive dysfunction. AB - BACKGROUND: Impairments in cognitive function are difficult to evaluate and measure. In most cases, subjects do not perceive any alteration in their own status, particularly in case of mild cognitive impairment. In case of minimal alterations of cognitive function, no real treatment exists at the moment. Functional and/or temporary alterations in the cerebral microcirculation may be involved in cognitive impairment, and some aspects of MCI may be theoretically caused by perfusional problems. Metabolic problems and sleep disturbances can also be associated to cognitive impairment. Pycnogenol(r) (Horphag) is a natural compound extracted from the bark of French maritime pine, and it is a highly standardized supplement. The aim of this registry was to evaluate the effects of supplementation with Pycnogenol(r) over a two-month-period in otherwise healthy individuals with minimal cognitive impairment and initial cognitive dysfunction selected on the basis of their MMSE score. METHODS: Eighty-seven healthy subjects with a MMSE score ranging from 18 to 23 (mild impairment) were included. Their BMI was <26 kg/m2, and no metabolic disorders were present. Participants were divided into two groups: one group was treated with standard management (SM) only (N.=44), whereas the other group received Pycnogenol(r) supplementation (150 mg/day) in addition to SM (N.=43). RESULTS: In the Pycnogenol(r) group MMSE score at inclusion was on average 21.64+/-1.5; after 8 weeks of supplementation, the average MMSE score increased significantly to 25.64+/-1.4 (P<0.05). In controls, the initial MMSE score was 22.43+/-1.2, comparable to the supplement group; however, in these subjects it did not show significant improvement after 8 weeks (average after treatment: 23.00+/-1.3). The median increase was 18% with Pycnogenol(r) vs. 2.48% in the SM group (P<0.05). CONCLUSIONS: Pycnogenol(r) has shown a large number of positive effects in subjects with initial cognitive impairment, due to its effects on oxidative stress levels. The safety and tolerability of Pycnogenol(r) are good, and thus the supplementation regimen should be tested in larger studies with a longer follow-up. PMID- 29754481 TI - Self-Aligned Functionalization Approach to Order Neuronal Networks at the Single Cell Level. AB - Despite significant progress, our knowledge of the functioning of the central nervous system still remains scarce to date. A better understanding of its behavior, in either normal or diseased conditions, goes through an increased knowledge of basic mechanisms involved in neuronal function, including at the single-cell level. This has motivated significant efforts for the development of miniaturized sensing devices to monitor neuronal activity with high spatial and signal resolution. One of the main challenges remaining to be addressed in this domain is, however, the ability to create in vitro spatially ordered neuronal networks at low density with a precise control of the cell location to ensure proper monitoring of the activity of a defined set of neurons. Here, we present a novel self-aligned chemical functionalization method, based on a repellant surface with patterned attractive areas, which permits the elaboration of low density neuronal network down to individual cells with a high control of the soma location and axonal growth. This approach is compatible with complementary metal oxide-semiconductor line technology at a wafer scale and allows performing the cell culture on packaged chip outside microelectronics facilities. Rat cortical neurons were cultured on such patterned surfaces for over one month and displayed a very high degree of organization in large networks. Indeed, more than 90% of the network nodes were settled by a soma and 100% of the connecting lines were occupied by a neurite, with a very good selectivity (low parasitic cell connections). After optimization, networks composed of 75% of unicellular nodes were obtained, together with a control at the micron scale of the location of the somas. Finally, we demonstrated that the dendritic neuronal growth was guided by the surface functionalization, even when micrometer scale topologies were encountered and we succeeded to control the extension growth along one dimensional-aligned nanostructures with sub-micrometrical scale precision. This novel approach now opens the way for precise monitoring of neuronal network activity at the single-cell level. PMID- 29754482 TI - Effect of Anisotropy of Cellulose Nanocrystal Suspensions on Stratification, Domain Structure Formation, and Structural Colors. AB - Outstanding optical and mechanical properties can be obtained from hierarchical assemblies of nanoparticles. Herein, the formation of helically ordered, chiral nematic films obtained from aqueous suspensions of cellulose nanocrystals (CNCs) were studied as a function of the initial suspension state. Specifically, nanoparticle organization and the structural colors displayed by the resultant dry films were investigated as a function of the anisotropic volume fraction (AVF), which depended on the initial CNC concentration and equilibration time. The development of structural color and the extent of macroscopic stratification were studied by optical and scanning electron microscopy as well as UV-vis spectroscopy. Overall, suspensions above the critical threshold required for formation of liquid crystals resulted in CNC films assembled with longer ranged order, more homogeneous pitches along the cross sections, and narrower specific absorption bands. This effect was more pronounced for the suspensions that were closer to equilibrium prior to drying. Thus, we show that high AVF and more extensive phase separation in CNC suspensions resulted in large, long-range ordered chiral nematic domains in dried films. Additionally, the average CNC aspect ratio and size distribution in the two separated phases were measured and correlated to the formation of structured domains in the dried assemblies. PMID- 29754483 TI - Distribution of Phthalate Metabolites between Paired Maternal-Fetal Samples. AB - Phthalic acid esters (PAEs) are readily metabolized to phthalate metabolites (mPAEs) in the human body. The occurrence of mPAEs in adult human samples is well documented; however, the maternal-fetal transmission of mPAEs has seldom been studied. In this study, 78 paired maternal-fetal samples, including maternal urine (MU), maternal serum (MS), cord serum (CS), and amniotic fluid (AF), were collected from pregnant women in Tianjin, China. Seven mPAEs were detected in MS, CS, and AF, whereas all 11 investigated mPAEs were found in MU. The median concentration of ?mPAEs was the highest in MU (128 ng/mL, with a range of 20.2 973 ng/mL), and proceeded in the order of CS (44.9, 13.9-315 ng/mL), MS (24.6, 3.75-156 ng/mL), and AF (10.4, 7.69-79.8 ng/mL). The values of ?mPAEs and several individual mPAEs were significantly correlated between MU and MS, with generally higher concentrations in MU, which indicated that urinary mPAEs is a good indicator of PAEs' exposure in adults. Notably, the median CS:MS ratios of ?mPAEs (1.58) were higher than 1, indicating that fetuses were exposed to mPAEs before birth. Significant correlations were also observed between MS and CS, which suggested that mPAEs in MS provide an indication of the fetal exposure. This study presents the first systematic analysis of the distribution and transmission of various mPAEs between mothers and fetuses. PMID- 29754484 TI - Dynamics of Phospholipid Membranes beyond Thermal Undulations. AB - We investigated the molecular dynamics of unilamellar liposomes by neutron spin echo spectroscopy. We report the first experimental evidence of a short-range motion at the length scale of the size of the headgroup of a lipid. The associated mean squared displacement shows a t0.26 dependence in the pico- to nanosecond region that indicates another process beyond the predictions of the Zilman-Granek (ZG) model ( t0.66) and translational diffusion ( t1). A comparison with theory shows that the observed low exponent is associated with a non Gaussian transient trapping of lipid molecules in a local area and supports the continuous time random walk model. The analysis of the mean squared displacement leads to the important conclusion that the friction at the interface between water and liposomes plays a minor role. Center of mass diffusion of liposomes and transient trapping of lipids define the range in which the ZG model can be applied to analyze membrane fluctuations. PMID- 29754485 TI - Supersaturable Self-Emulsifying Drug Delivery System of Krill Oil with Improved Oral Absorption and Hypotriglyceridemic Function. AB - This study aimed to develop a supersaturable self-emulsifying drug delivery system (S-SEDDS) of krill oil (KO), a rich source of docosahexaenoic acid and eicosapentaenoic acid (EPA), to improve its hypotriglyceridemic function. S-SEDDS of KO (KO/S-SEDDS) was prepared by the addition of lysolecithin, glycerin, and hydroxypropyl methylcellulose (HPMC). Self-emulsifying drug delivery system of KO (KO/SEDDS) and KO with HPMC (KO/HPMC) were also prepared for comparison purposes. The physicochemical and pharmacokinetic properties of KO samples were characterized, and the hypotriglyceridemic function of KO/S-SEDDS was evaluated. Micronized droplets in KO/SEDDS and KO/S-SEDDS with a mean diameter of ca. 270 nm could be observed in comparison to KO and KO/HPMC. Both KO/HPMC and KO/S-SEDDS tended to enhance the dissolution behavior of KO, and the S-SEDDS formulation improved the dissolution behavior of KO as a result of micronized droplets and the addition of HPMC. KO/S-SEDDS (60 mg of EPA/kg) improved the oral absorption of KO based on the pharmacokinetic profiling of EPA, and repeated oral administration of KO/S-SEDDS (250 mg of KO kg-1 day-1) for 7 days had a potent hypotriglyceridemic effect on rats with corn-oil-induced hypertriglyceridemia compared to orally administered KO. On the basis of these findings, the S-SEDDS approach might be an efficacious dosage option to enhance the nutraceutical properties of KO. PMID- 29754486 TI - Nanoparticle Wettability Influences Nanoparticle-Phospholipid Interactions. AB - We explored the influence of nanoparticle (NP) surface charge and hydrophobicity on NP-biomolecule interactions by measuring the composition of adsorbed phospholipids on four NPs, namely, positively charged CeO2 and ZnO and negatively charged BaSO4 and silica-coated CeO2, after exposure to bronchoalveolar lavage fluid (BALf) obtained from rats, and to a mixture of neutral dipalmitoyl phosphatidylcholine (DPPC) and negatively charged dipalmitoyl phosphatidic acid (DPPA). The resulting NP-lipid interactions were examined by cryogenic transmission electron microscopy (cryo-TEM) and atomic force microscopy (AFM). Our data show that the amount of adsorbed lipids on NPs after incubation in BALf and the DPPC/DPPA mixture was higher in CeO2 than in the other NPs, qualitatively consistent with their relative hydrophobicity. The relative concentrations of specific adsorbed phospholipids on NP surfaces were different from their relative concentrations in the BALf. Sphingomyelin was not detected in the extracted lipids from the NPs despite its >20% concentration in the BALf. AFM showed that the more hydrophobic CeO2 NPs tended to be located inside lipid vesicles, whereas less hydrophobic BaSO4 NPs appeared to be outside. In addition, cryo-TEM analysis showed that CeO2 NPs were associated with the formation of multilamellar lipid bilayers, whereas BaSO4 NPs with unilamellar lipid bilayers. These data suggest that the NP surface hydrophobicity predominantly controls the amounts and types of lipids adsorbed, as well as the nature of their interaction with phospholipids. PMID- 29754487 TI - Aqueous Photolysis of Benzobicyclon Hydrolysate. AB - Benzobicyclon [3-(2-chloro-4-(methylsulfonyl)benzoyl)-2 phenylthiobicyclo[3.2.1]oct-2-en-4-one] is a pro-herbicide used against resistant weeds in California rice fields. Persistence of its active product, benzobicyclon hydrolysate, is of concern. As an acidic herbicide, the neutral species photolyzed faster than the more predominant anionic species ( t1/2 = 1 and 320 h, respectively; natural sunlight), from a >10-fold difference in the quantum yield. Dissolved organic matter in natural waters reduced direct photolysis and increased indirect photolysis compared to high-purity water. Light attenuation appears significant in rice field water and can slow photolysis. These results, used in the pesticides in flooded applications model with other experimental properties, indicate that a floodwater hold time of 20 days could be sufficient for dissipation of the majority of initial aqueous benzobicyclon hydrolysate prior to release. However, soil recalcitrance of both compounds will keep aqueous benzobicyclon hydrolysate levels constant months after benzobicyclon application. PMID- 29754488 TI - Near-Ideal Xylene Selectivity in Adaptive Molecular Pillar[ n]arene Crystals. AB - The energy-efficient separation of alkylaromatic compounds is a major industrial sustainability challenge. The use of selectively porous extended frameworks, such as zeolites or metal-organic frameworks, is one solution to this problem. Here, we studied a flexible molecular material, perethylated pillar[ n]arene crystals ( n = 5, 6), which can be used to separate C8 alkylaromatic compounds. Pillar[6]arene is shown to separate para-xylene from its structural isomers, meta xylene and ortho-xylene, with 90% specificity in the solid state. Selectivity is an intrinsic property of the pillar[6]arene host, with the flexible pillar[6]arene cavities adapting during adsorption thus enabling preferential adsorption of para-xylene in the solid state. The flexibility of pillar[6]arene as a solid sorbent is rationalized using molecular conformer searches and crystal structure prediction (CSP) combined with comprehensive characterization by X-ray diffraction and 13C solid-state NMR spectroscopy. The CSP study, which takes into account the structural variability of pillar[6]arene, breaks new ground in its own right and showcases the feasibility of applying CSP methods to understand and ultimately to predict the behavior of soft, adaptive molecular crystals. PMID- 29754489 TI - Realistic Atomistic Structure of Amorphous Silicon from Machine-Learning-Driven Molecular Dynamics. AB - Amorphous silicon ( a-Si) is a widely studied noncrystalline material, and yet the subtle details of its atomistic structure are still unclear. Here, we show that accurate structural models of a-Si can be obtained using a machine-learning based interatomic potential. Our best a-Si network is obtained by simulated cooling from the melt at a rate of 1011 K/s (that is, on the 10 ns time scale), contains less than 2% defects, and agrees with experiments regarding excess energies, diffraction data, and 29Si NMR chemical shifts. We show that this level of quality is impossible to achieve with faster quench simulations. We then generate a 4096-atom system that correctly reproduces the magnitude of the first sharp diffraction peak (FSDP) in the structure factor, achieving the closest agreement with experiments to date. Our study demonstrates the broader impact of machine-learning potentials for elucidating structures and properties of technologically important amorphous materials. PMID- 29754490 TI - On the Adsorption of DNA Origami Nanostructures in Nanohole Arrays. AB - DNA origami nanostructures are versatile substrates for the controlled arrangement of molecular capture sites with nanometer precision and thus have many promising applications in single-molecule bioanalysis. Here, we investigate the adsorption of DNA origami nanostructures in nanohole arrays which represent an important class of biosensors and may benefit from the incorporation of DNA origami-based molecular probes. Nanoholes with well-defined diameter that enable the adsorption of single DNA origami triangles are fabricated in Au films on Si wafers by nanosphere lithography. The efficiency of directed DNA origami adsorption on the exposed SiO2 areas at the bottoms of the nanoholes is evaluated in dependence of various parameters, i.e., Mg2+ and DNA origami concentrations, buffer strength, adsorption time, and nanohole diameter. We observe that the buffer strength has a surprisingly strong effect on DNA origami adsorption in the nanoholes and that multiple DNA origami triangles with 120 nm edge length can adsorb in nanoholes as small as 120 nm in diameter. We attribute the latter observation to the low lateral mobility of once adsorbed DNA origami on the SiO2 surface, in combination with parasitic adsorption to the Au film. Although parasitic adsorption can be suppressed by modifying the Au film with a hydrophobic self-assembled monolayer, the limited surface mobility of the adsorbed DNA origami still leads to poor localization accuracy in the nanoholes and results in many DNA origami crossing the boundary to the Au film even under optimized conditions. We discuss possible ways to minimize this effect by varying the composition of the adsorption buffer, employing different fabrication conditions, or using other substrate materials for nanohole array fabrication. PMID- 29754491 TI - Decarboxylative Trifluoromethylation of Aliphatic Carboxylic Acids. AB - Herein we disclose an efficient method for the conversion of carboxylic acids to trifluoromethyl groups via the combination of photoredox and copper catalysis. This transformation tolerates a wide range of functionality including heterocycles, olefins, alcohols, and strained ring systems. To demonstrate the broad potential of this new methodology for late-stage functionalization, we successfully converted a diverse array of carboxylic acid-bearing natural products and medicinal agents to the corresponding trifluoromethyl analogues. PMID- 29754492 TI - Comparison of In-Solution, FASP, and S-Trap Based Digestion Methods for Bottom-Up Proteomic Studies. AB - Bottom-up proteomic strategies rely on efficient digestion of proteins into peptides for mass spectrometry analysis. In-solution and filter-based strategies are commonly used for proteomic analysis. In recent years, filter-aided sample preparation (FASP) has become the dominant filter-based method due to its ability to remove SDS prior to mass spectrometry analysis. However, the time-consuming nature of FASP protocols have led to the development of new filter-based strategies. Suspension traps (S-Traps) were recently reported as an alternative to FASP and in-solution strategies as they allow for high concentrations of SDS in a fraction of the time of a typical FASP protocol. In this study, we compare the yields from in-solution, FASP, and S-Trap based digestions of proteins extracted in SDS and urea-based lysis buffers. We performed label-free quantification to analyze the differences in the portions of the proteome identified using each method. Overall, our results show that each digestion method had a high degree of reproducibility within the method type. However, S Traps outperformed FASP and in-solution digestions by providing the most efficient digestion with the greatest number of unique protein identifications. This is the first work to provide a direct quantitative comparison of two filter based digestion methods and a traditional in-solution approach to provide information regarding the most efficient proteomic preparation. PMID- 29754494 TI - Stimuli-Sensitive and -Responsive Polymer Biomaterials. PMID- 29754495 TI - Evaluation of anterior intermeniscal ligament in discoid lateral meniscus cases and presenting the accompanying meniscal pathologies with MRI. AB - BACKGROUND: Although several studies were conducted to put forth the biomechanical function of anterior intermeniscal ligament (AIML) on the stability of meniscal structures, there are few data on the etiology of the early degeneration of discoid type compared to the normal shaped ones. PURPOSE: To determine the AIML subtypes and accompanying meniscal pathologies in discoid lateral menisci (DLM) on knee MRI exams. MATERIAL AND METHODS: Knee MRI exams of 171 individuals with DLM were reviewed. DLMs and AIMLs were typed according to Watanabe's classification and Nelson-Laprade classification, respectively. Medial and lateral menisci were evaluated for tear and menisco-capsular pathology. Pearson's correlation test was used for statistical analysis. RESULTS: DLM was type I in 83 (48.5%) individuals and type II in 88 (51.5%) individuals. AIML was absent in 90 (52.6%) participants; type I AIML was seen in 38 out 81 (22.2%), type II in 31 out of 81(18.1%), and type III in 12 out of 81 (7%). Meniscal pathology was observed in 56 (32.7%) individuals as follows: menisco-capsular strain/separation in 25 (14.6%); medial meniscal tear in 22 (12.8%); and lateral meniscal tear in nine (5.2%); Of these 56 cases, 26 (46%) had no AIML, 15 cases (27%) had type I, nine cases (16%) had type II, and six cases (11%) had type III AIML. CONCLUSION: No statistically significant correlation was found between the type of DLM and type of AIML ( P = 0.855), between the type of DLM and meniscal pathology ( P = 0.791), or between the type of AIML and meniscal pathology ( P = 0.282). PMID- 29754493 TI - Exploration of Near-Infrared-Emissive Colloidal Multinary Lead Halide Perovskite Nanocrystals Using an Automated Microfluidic Platform. AB - Hybrid organic-inorganic and fully inorganic lead halide perovskite nanocrystals (NCs) have recently emerged as versatile solution-processable light-emitting and light-harvesting optoelectronic materials. A particularly difficult challenge lies in warranting the practical utility of such semiconductor NCs in the red and infrared spectral regions. In this context, all three archetypal A-site monocationic perovskites-CH3NH3PbI3, CH(NH2)2PbI3, and CsPbI3-suffer from either chemical or thermodynamic instabilities in their bulk form. A promising approach toward the mitigation of these challenges lies in the formation of multinary compositions (mixed cation and mixed anion). In the case of multinary colloidal NCs, such as quinary Cs xFA1- xPb(Br1- yI y)3 NCs, the outcome of the synthesis is defined by a complex interplay between the bulk thermodynamics of the solid solutions, crystal surface energies, energetics, dynamics of capping ligands, and the multiple effects of the reagents in solution. Accordingly, the rational synthesis of such NCs is a formidable challenge. Herein, we show that droplet based microfluidics can successfully tackle this problem and synthesize Cs xFA1- xPbI3 and Cs xFA1- xPb(Br1- yI y)3 NCs in both a time- and cost-efficient manner. Rapid in situ photoluminescence and absorption measurements allow for thorough parametric screening, thereby permitting precise optical engineering of these NCs. In this showcase study, we fine-tune the photoluminescence maxima of such multinary NCs between 700 and 800 nm, minimize their emission line widths (to below 40 nm), and maximize their photoluminescence quantum efficiencies (up to 89%) and phase/chemical stabilities. Detailed structural analysis revealed that the Cs xFA1- xPb(Br1- yI y)3 NCs adopt a cubic perovskite structure of FAPbI3, with iodide anions partially substituted by bromide ions. Most importantly, we demonstrate the excellent transference of reaction parameters from microfluidics to a conventional flask-based environment, thereby enabling up-scaling and further implementation in optoelectronic devices. As an example, Cs xFA1- xPb(Br1 yI y)3 NCs with an emission maximum at 735 nm were integrated into light emitting diodes, exhibiting a high external quantum efficiency of 5.9% and a very narrow electroluminescence spectral bandwidth of 27 nm. PMID- 29754496 TI - Detection of loco-regional recurrence in malignant head and neck tumors: a comparison of CT, MRI, and FDG PET-CT. AB - Background The early and accurate detection of local or regional recurrence of head and neck tumor is critically important. Purpose To compare the diagnostic accuracy of contrast-enhanced computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI), and fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT, alone and in combination, in detecting the locoregional recurrence of malignant head and neck tumor. Material and Methods A total of 93 patients with loco-regional recurrence of malignant head and neck tumors underwent CT, MRI, and PET-CT within 30 days before surgery. CT, MRI, and PET-CT for each patient were retrospectively reviewed to determine the presence of recurrent tumors in the primary site on a patient-by-patient basis and that of regional lymph nodes on a level-by-level basis. The diagnostic accuracy of CT, MRI, and PET-CT, alone and combined, were accessed with the postoperative histopathological findings or with 12-month follow-up results as the standard of reference. Results The sensitivity/specificity/and accuracy of CT, MRI, and PET CT for the detection of primary site recurrence was 89.9/85.7/89.3%, 94.9/85.7/93.6%, and 97.5/92.9/96.8%, respectively. The sensitivity/specificity/accuracy of CT, MRI, and PET-CT for the detection of nodal recurrence was 66.3/99.4/92.4%, 74.7/99.4/94.2%, and 85.5/94.9/93.0%, respectively. MRI + PET-CT achieved the best performance in the receiver operating characteristics curve analysis (Az value = 0.958 for primary site recurrence and 0.929 for nodal recurrence). Conclusion MRI + PET-CT offered the highest diagnostic performance in the detection of loco-regional recurrence of malignant head and neck tumor, compared with CT, MRI, PET-CT, and other combinations including CT. PMID- 29754497 TI - The Compensatory ADHD Behaviors Scale (CABS): Development and Initial Validation. AB - Several measures are available that assess inattention, hyperactivity/impulsivity, and executive functioning deficits. Treatments for adults with attention-deficit/hyperactivity disorder (ADHD) and skill-based academic interventions focus on improving compensatory strategies to ameliorate functional impairment; however, no measure exists that examines the compensatory behaviors adults utilize to compensate for the functional deficits associated with inattention and hyperactivity/impulsivity. The current study aimed to determine the psychometric properties of the Compensatory ADHD Behaviors Scale (CABS). Five-hundred participants ( Mage = 36.83, SD = 11.57) completed measures of ADHD symptomatology, executive functioning, functional impairment, mood disorder symptoms, and the CABS. Analyses revealed that scales assessing both use and effectiveness of compensatory behaviors subscales had similar factor structures, reflecting present- and future-oriented behaviors. The present-, but not future-oriented, behaviors significantly related to ADHD symptomatology, executive dysfunction, and functional impairment; effectiveness of present oriented compensatory behaviors demonstrated incremental validity in predicting impairment. Compensatory strategies may be a useful variable to measure when examining functional impairment associated with inattention and hyperactivity/impulsivity. The current study provides preliminary evidence of the ability of CABS to validly measure various strategies associated with (clinical and subclinical) ADHD symptomatology, executive functioning, and overall impairment. PMID- 29754499 TI - Re: Field testing of ICHD-3 beta criteria of periictal headache in patients with focal epilepsy - a prospective diary study. PMID- 29754498 TI - Axonal Guidance Signaling Pathway Is Suppressed in Human Nasal Polyps. AB - Background Dysfunctional innervation might contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP), but the state of the axonal outgrowth signaling in CRSwNP is unknown. The purpose of this study was to explore the axonal outgrowth pathway-related protein expression in CRSwNP. Methods Institutional review board approved study in which tissue proteomes were compared between control and CRSwNP patients (n = 10/group) using an aptamer based proteomic array and confirmed by whole transcriptomic analysis. Results Compared with controls, proteins associated with axonal guidance signaling pathway such as beta-nerve growth factor, semaphorin 3A, Ras-related C3 botulinum toxin substrate 1, Bcl-2, protein kinase C delta type, and Fyn were significantly decreased in patients with CRSwNP (fold change [FC] = -1.17, P = .002; FC = 1.09, P < .001; FC = -1.33, P < .001; FC = -1.31, P < .001; FC = -1.31, P = .004; and FC = -1.20, P = 0.012, respectively). In contrast, reticulon-4 receptor, an inhibitory factor, was significantly increased in patients with CRSwNP (FC = 1.25, P < .001). Furthermore, neuronal growth-associated proteins such as ciliary neurotrophic factor receptor subunit alpha, neuronal growth regulator 1, neuronal cell adhesion molecule, neural cell adhesion molecule L1, platelet-derived growth factor subunit A, and netrin-4 were all significantly decreased in patients with CRSwNP (FC = -1.25, P < .001; FC = -1.27, P = .002; FC = -1.65, P = .013; FC = 4.20, P < .001; FC = -1.28, P < .001; and FC = -2.31, P < .001, respectively). In contrast, tissue eosinophil count ( P < .001) and allergic inflammation factors such as IgE, periostin, and galectin-10 were all significantly increased in patients with CRSwNP (FC = 12.28, P < .001; FC = 3.95, P < .001; and FC = 2.44, P < .001, respectively). Furthermore, the log FC of the studied proteins expression significantly and positively correlated with log FC of their mRNA expression ( P < .001, r = .88). Conclusions Axonal guidance signaling and neural growth factors pathways proteins are significantly suppressed in eosinophilic CRSwNP. PMID- 29754500 TI - Rare primary headaches in Italian tertiary Headache Centres: Three year nationwide retrospective data from the RegistRare Network. AB - Background Rare primary headaches are mainly included in Chapters 3, Trigeminal autonomic cephalalgias, and 4, Other primary headache disorders, Part One of the International Classification of Headache Disorders 3rd edition. Epidemiological data are scarce, mostly emerging from case series or small studies, with the exception of cluster headache. In order to overcome the knowledge gap about rare primary headaches, the RegistRare Network was launched in 2017 to promote research in the field. Methods A retrospective cohort study including patients who, from April 30, 2014 to May 1, 2017, visited seven Italian tertiary Headache Centres, was undertaken to estimate in that clinical setting prevalence and incidence of headaches included in Chapters 3 and 4, Part One of the International Classification of Headache Disorders 3rd edition. Prevalent headache is defined as a headache recorded within the study timeframe, regardless of when the diagnosis was made. Incident headache is defined as a headache diagnosed for the first time in the patient during the study period. Results Twenty thousand and eighty-three patients visited the participating centres, and 822 (4.1%) prevalent cases, of which 461 (2.3%) were incident cases, were registered. Headaches listed in Chapter 3 affected 668 patients, representing 81.3% of the total number of prevalent cases. Headaches listed in Chapter 4 affected 154 patients and represent 18.7% of the total number of prevalent cases. Cluster headaches represent the most frequently diagnosed rare headaches (70.4%). For 13 entities out of 20, no cases were registered in more than 50% (n >= 4) of the centres, and for 14 entities more than 50% of diagnoses were incident. Conclusions This large, multicentre study gives the first wide-ranging snapshot of the burden in clinical practice of rare headaches and confirms that cooperative networks are necessary to study rare headaches, as their prevalence is often very low. The launch of a disease registry by the RegistRare Network will favour research in this neglected population of headache patients. Trial registration NCT03416114. PMID- 29754502 TI - Much, if not all, of the cortical damage in MS can be attributed to the microglial cell - Commentary. PMID- 29754501 TI - Naturalistic language sampling to characterize the language abilities of 3-year olds with autism spectrum disorder. AB - Characterization of language in naturalistic settings in autism spectrum disorder has been lacking, particularly at young ages, but such information is important for parents, teachers, and clinicians to better support language development in real-world settings. Factors contributing to this lack of clarity include conflicting definitions of language abilities, use of non-naturalistic standardized assessments, and restricted samples. The current study examined one of the largest datasets of naturalistic language samples in toddlers with autism spectrum disorder, and language delay and typically developing contrast groups at age 3. A range of indices including length of phrase, grammatical markings, and social use of language was assayed during a naturalistic observation of a parent child play session. In contrast to historical estimates, results indicated only 3.7% of children with autism spectrum disorder used no words, and 34% were minimally verbal. Children with autism spectrum disorder and language delay exhibited similar usage of grammatical markings, although both were reduced compared to typically developing children. The greatest difference between autism spectrum disorder and language delay groups was the quantity of social language. Overall, findings highlight a range of language deficits in autism spectrum disorder, but also illustrate that the most severe level of impairments is not as common in naturalistic settings as previously estimated by standardized assessments. PMID- 29754503 TI - Hesperidin Suppresses Renin-Angiotensin System Mediated NOX2 Over-Expression and Sympathoexcitation in 2K-1C Hypertensive Rats. AB - Hesperidin, a flavonoid derived from citrus fruits, possesses several beneficial effects including anti-oxidation and anti-inflammation. The aim of this study was to investigate the effects of hesperidin on the renin-angiotensin system (RAS) cascade that mediated oxidative stress and sympathoexcitation in two-kidney, one clipped (2K-1C) hypertensive rats. 2K-1C hypertension was induced in male Sprague Dawley rats. Hypertensive rats were treated with hesperidin at 20[Formula: see text]mg/kg or 40[Formula: see text]mg/kg or losartan at 10[Formula: see text]mg/kg beginning at three weeks after surgery and then continued for four weeks ([Formula: see text]/group). Hesperidin reduced blood pressure in a dose dependent manner in hypertensive rats compared to untreated rats ([Formula: see text]). Increased plasma angiotensin converting enzyme (ACE) activity and angiotensin II levels, as well as, upregulated AT1 receptor protein expression in aortic tissues were attenuated in hypertensive rats treated with hesperidin. Hesperidin suppressed oxidative stress markers and NADPH oxidase over-expression, and restored plasma nitric oxide metabolites in 2K-1C rats. This was associated with improvement of the vascular response to acetylcholine in isolated mesenteric vascular beds and aortic rings from 2K-1C rats treated with hesperidin ([Formula: see text]). Enhancement of nerve-mediated vasoconstriction related to high plasma noradrenaline in the 2K-1C group was alleviated by hesperidin treatment ([Formula: see text]). Furthermore, losartan exhibited antihypertensive effects by suppressing the RAS cascade and oxidative stress and improved vascular dysfunction observed in 2K-1C rats ([Formula: see text]). Based on these results, it can be presumed that hesperidin is an antihypertensive agent. Its antihypertensive action might be associated with reducing RAS cascade-induced NOX2 over-expression and sympathoexcitation in 2K-1C hypertensive rats. PMID- 29754504 TI - Hominis placenta Suppresses Acute Lung Inflammation by Activating Nrf2. AB - Hominis placenta (HP), a dried human placenta, has been known to target liver, lung, or kidney meridians, improving the functions associated with these meridians in traditional Chinese or Asian medicine (TCM). Since recent studies implicate an HP extract in suppressing inflammation, we investigated whether an aqueous HP extract can ameliorate inflammation that occurred in the lungs. When administered with a single intratracheal lipopolysaccharide (LPS), C57BL/6 mice developed an acute neutrophilic lung inflammation along with an increased expression of pro-inflammatory cytokine genes. However, this was diminished by the administration HP extract via an intraperitoneal route 2 h after LPS treatment. Western blot and semi-quantitative RT-PCR analyses revealed that while suppressing the activity of a proinflammatory factor NF-[Formula: see text]B marginally, the HP extract strongly activated an anti-inflammatory factor Nrf2, with concomitant expression of Nrf2-dependent genes. Mechanistically, the HP extract suppressed the ubiquitin-mediated degradation of Nrf2, functioning similarly to a 26S proteasome inhibitor, MG132. Collectively, these results suggest that the HP extract suppresses inflammation in mouse lungs, which is in part related to the HP extract perturbing the ubiquitin-dependent degradation of Nrf2 and thus increasing the function of Nrf2. PMID- 29754505 TI - 1,[Formula: see text]2,[Formula: see text]3,[Formula: see text]4,[Formula: see text]6-Penta-O-Galloyl-beta-D-Glucose from Galla rhois Ameliorates Renal Tubular Injury and Microvascular Inflammation in Acute Kidney Injury Rats. AB - Renal ischemia-reperfusion injury (IRI), an important cause of acute kidney injury (AKI), causes increased renal tubular injury and microvascular inflammation. 1,[Formula: see text]2,[Formula: see text]3,[Formula: see text]4,[Formula: see text]6-penta-O-galloyl-[Formula: see text]-D-glucose (PGG) from Galla rhois has anticancer, anti-oxidation and angiogenesis effects. We examined protective effects of PGG on IRI-induced acute AKI. Clamping both renal arteries for 45[Formula: see text]min induced isechemia and then reperfusion. Treatment with PGG (10[Formula: see text]mg/kg/day and 50[Formula: see text]mg/kg/day for four days) significantly ameliorated urine volume, urine osmolality, creatinine clearance (Ccr) and blood urea nitrogen (BUN). In addition, PGG increased aquaporine 1/2/3, Na[Formula: see text]-K[Formula: see text]-ATPase and urea transporter (UT-B) and decreased ICAM-1, MCP-1, and HMGB-1 expression. In this histopathologic study, PGG improved glomerular and tubular damage. Immunohistochemistry results showed that PGG increased aquaporine 1/2, and Na[Formula: see text]-K[Formula: see text] ATPase and decreased ICAM-1 expression. These findings suggest that PGG ameliorates tubular injury including tubular dysfunction and microvascular inflammation in IRI-induced AKI rats. PMID- 29754507 TI - [When did the teaching of Semmelweis appear in schoolbooks? A forgotten pupil of Semmelweis: Mihaly Szabadfoldi (1820?-1867)]. PMID- 29754506 TI - Hirsutella sinensis Inhibits Lewis Lung Cancer via Tumor Microenvironment Effector T Cells in Mice. AB - Hirsutella sinensis fungus (HSF) is an artificial substitute of the well-known medicine Cordyceps sinensis with similar beneficial effects in humans. We previously found that HSF can regulate immune function and inhibit tumor growth; however, the mechanisms involved in these effects were still unclear. Accordingly, in this study, we investigated the effects of HSF on immune cell subsets in the tumor microenvironment in mice. The results showed that HSF inhibited Lewis lung cancer growth, alleviated abnormalities in routine blood tests, and enhanced tumor-infiltrating T cells, particularly the proportion of effector CD8[Formula: see text] T cells. In addition, HSF also ameliorated the immune-suppressive microenvironment and decreased the proportions of regulatory T cell and myeloid-derived suppressor cell populations. To confirm the effects of HSF on promotion of effector CD8[Formula: see text] T-cell production, we further evaluated changes in postoperative metastasis following treatment with HSF. Indeed, orthotopic lung metastasis was significantly suppressed, and survival times were increased in HSF-treated mice. Taken together, our findings suggested that HSF inhibited Lewis lung cancer by enhancing the population of effective CD8[Formula: see text] T cells. PMID- 29754509 TI - [New and traditional directions in the biology and management of childhood acute lymphoblastic leukemia]. AB - Owing to clinical trials and improvement over the past few decades, the majority of children with acute lymphoblastic leukemia (ALL) survive by first-line chemotherapy and combat with the problems of returning to community. However, many patients may have severe acute or late therapeutic side effects, and the survival rate in some groups (e.g., patients with MLL rearrangements, hypodiploidy, IKZF1 mutation or early precursor T cell phenotype) is far behind the average. Innovative strategies in medical attendance provide better clinical outcomes for them: complete gene diagnostics, molecularly targeted anticancer treatment, immuno-oncology and immune cell therapy. The number of genes with identified alterations in leukemic lymphoblasts is over thirty and their pathobiologic role is only partly clear. There are known patient groups where the use of specific drugs is based on gene expression profiling (e.g., tyrosine kinase inhibitors in Philadelphia-like B-cell ALL). The continuous assessment of minimal residual disease became a routine due to the determination of a leukemia associated immunophenotype by flow cytometry or a sensitive molecular marker by molecular genetics at diagnosis. Epitopes of cluster differentiation antigens on blast surface (primarily CD19, CD20 and CD22 on malignant B cells) can be attacked by monoclonal antibodies. Moreover, antitumor immunity can be strengthened utilizing either cell surface markers (bispecific T cell engagers, chimeric antigen receptor T cell therapy) or tumor-specific immune cells (immune checkpoint inhibitors). This review gives an insight into current knowledge in these innovative therapeutic directions. Orv Hetil. 2018; 159(20): 786-797. PMID- 29754510 TI - [Incidence of type 2 diabetes among oral cancer patients in Hungary]. AB - INTRODUCTION: Data proves that Hungary has a leading role in the statistics of oral cancer and patients living with type 2 diabetes. AIM: Our aim was to understand the statistical correlation between oral cancer and metabolic disorder (diabetes mellitus and impaired fasting glucose) due to the valuable data from the Semmelweis University. METHOD: We analyzed the data of 835 patients diagnosed with malignant oral cancer and 587 tumor-free control patients. We investigated the incidence and location of oral cancer among patients living with diabetes, and compared these datasets with our previous data from 14 years earlier. RESULTS: We found that in oral cancer patients, 26.1% had diabetes and 20.8% had impaired fasting glucose; in the control group these ratios were 10.8% and 11.1%. This difference is significant (p<0.05). 14 years ago in the tumor group 14.6%, in the control group 5.6% had diabetes, while 9.7% and 5.5% had impaired fasting glucose. Lip cancer had the biggest incidence. CONCLUSIONS: The rise of type 2 diabetes in the tumor group was significant. This could be a burden for the health care system. We want to highlight the importance of interdisciplinary cooperation between health care professionals. Orv Hetil. 2018; 159(20): 803-807. PMID- 29754511 TI - [New international consensus statement about the definition, classification, ethiology, diagnostics and therapy of dry eye (TFOS DEWS II)]. AB - Ten years have passed since the publication of the DEWS Report that summarized the information based on scientific literature concerning dry eye disease. Hundreds of papers have been published since then and time has come for a new summary. Organized by the Tear Film & Ocular Surface Society, 12 working groups summerized former and recent data. The DEWS II Report was created. The authors of the present publication summarize the most important changes in definition, classification, diagnostics, and therapy concerning dry eye disease. They also disclose the relevant changes on which the non-ophthalmologist specialists have to be informed. The DEWS II Report published by TFOS consists of 11 chapters. Completely new chapters deal with the role of sensation/pain and iatrogenic dry eyes. Orv Hetil. 2018; 159(20): 775-785. PMID- 29754512 TI - [Stroke prevention in the elderly: effectiveness and safety of edoxaban in elderly patients according to the results of the ENGAGE AF study]. AB - Atrial fibrillation is the most common clinically relevant arrhythmia frequently causing systemic thromboembolic events. Traditionally vitamin K antagonists had been used for decades to prevent these events. The emerging of the new direct anticoagulants has revolutionized this treatment and a gradual growth and extensive spread of usage is expected. The latest one approved in Hungary, edoxaban, is a factor Xa inhibitor. Once-daily administration and favourable safety profile are major benefits of this drug. In a large clinical study with a high number of patients it proved to be at least as effective as warfarin in the prevention of stroke and systemic embolization while causing significantly less major bleedings. As the incidence of atrial fibrillation increases with age, the observation that, compared with the other direct oral anticoagulants, the administration of edoxaban in the elderly has a favourable net clinical benefit (in the rate of prevented thromboembolic events and the number of caused bleedings) may have a great importance. Orv Hetil. 2018; 159(20): 798-802. PMID- 29754513 TI - Value-Based Treatment of Common Pediatric Fractures by Primary Care. PMID- 29754514 TI - What sources of bereavement support are perceived helpful by bereaved people and why? Empirical evidence for the compassionate communities approach. AB - AIMS: To determine who provides bereavement support in the community, what sources are perceived to be the most or least helpful and for what reason, and to identify the empirical elements for optimal support in developing any future compassionate communities approach in palliative care. DESIGN: A population-based cross-sectional investigation of bereavement experiences. Sources of support (informal, community and professional) were categorised according to the Public Health Model of Bereavement Support; most helpful reasons were categorised using the Social Provisions Scale, and least helpful were analysed using inductive content analysis. SETTING AND PARTICIPANTS: Bereaved people were recruited from databases of funeral providers in Australia via an anonymous postal survey (2013 2014). RESULTS: In total, 678 bereaved people responded to the survey. The most frequently used sources of support were in the informal category such as family, friends and funeral providers. While the professional category sources were the least used, they had the highest proportions of perceived unhelpfulness whereas the lowest proportions of unhelpfulness were in the informal category. The functional types of helpful support were Attachment, Reliable Alliance, Social Integration and Guidance. The five themes for least helpful support were: Insensitivity, Absence of Anticipated Support, Poor Advice, Lack of Empathy and Systemic Hindrance. CONCLUSION: A public health approach, as exemplified by compassionate communities policies and practices, should be adopted to support the majority of bereaved people as much of this support is already provided in informal and other community settings by a range of people already involved in the everyday lives of those recently bereaved. This study has provided further support for the need to strengthen the compassionate communities approach, not only for end of life care for dying patients but also along the continuum of bereavement support. PMID- 29754515 TI - Spontaneous direct carotid-cavernous sinus fistula secondary to a persistent primitive trigeminal artery treated by trans-venous coil embolisation. AB - A healthy 51-year-old female presented with a spontaneous direct carotid cavernous sinus fistula associated with a persistent primitive trigeminal artery. She had no history of connective tissue or cerebrovascular disorders or significant head trauma. This is a rare lesion with only 18 previously reported cases. It had similar clinical presentation and imaging appearance to a high-flow direct carotid-cavernous fistula and was uncovered after successful trans-venous coil embolisation of the fistula. It therefore needs to be considered in cases of direct carotid-cavernous fistula without history of trauma. Knowledge of types of persistent primitive trigeminal artery is also important for their critical treatment implications. PMID- 29754517 TI - Diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients. AB - INTRODUCTION: Thalassemia is among the most common genetic diseases. Patients with severe forms of the disease are transfusion-dependent, leading to iron overload. A condition which can eventually develop in the iron-loaded heart is iron overload cardiomyopathy, a debilitating disease that accounts for the majority of deaths in thalassemia patients. Areas covered: This review article provides a comprehensive summary of the diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients, with discussion covering current weak points and potential improvements of the relevant diagnostic and therapeutic strategies. Expert commentary: Current limitations of various diagnostic techniques for iron overload cardiomyopathy include suboptimal accuracy, untimely detection, or inadequate accessibility, and novel modalities are required to overcome these shortcomings. Treatment should address key pathophysiologic mechanisms of iron overload cardiomyopathy, which include cardiac iron mishandling and iron-induced oxidative injury. Apart from the promotion of iron removal by chelators, prevention of cardiac iron deposition and attenuation of oxidative damage should also be rigorously investigated on a cell to-bedside basis. PMID- 29754516 TI - Acute retinal hemorrhage after Pipeline embolization device placement for treatment of ophthalmic segment aneurysm: A case report. AB - Introduction Ophthalmic segment aneurysms may present with visual symptoms due to direct compression of the optic nerve. Treatment of these aneurysms with the Pipeline embolization device (PED) often results in visual improvement. Flow diversion, however, has also been associated with occlusion of the ophthalmic artery and visual deficits in a small subset of cases. Case report A 49-year-old Caucasian female presented with subarachnoid hemorrhage due to a ruptured anterior communicating artery aneurysm. On follow-up imaging, the patient was found to have a right asymptomatic ophthalmic segment aneurysm. Due to the irregular shape of the aneurysm and history of aneurysmal subarachnoid hemorrhage, the decision was made to treat the aneurysm with a PED. Postoperatively, the patient complained of floaters in the right eye. Detailed ophthalmologic examination showed retinal hemorrhage and cotton-wool spots on the macula. Such complication after PED placement has never been reported in the literature. Conclusion Visual complications after PED placement for treatment of ophthalmic segment aneurysms are rare. It is thought that even in cases where the ophthalmic artery occludes, patients remain asymptomatic due to the rich collateral supply from the external carotid artery branches. Here we report a patient who developed an acute retinal hemorrhage after PED placement. PMID- 29754518 TI - Cost of treating peripheral neuropathic pain with pregabalin or gabapentin at therapeutic doses in routine practice. AB - AIM: To analyze the cost of peripheral neuropathic pain (PNP) treatment with pregabalin or gabapentin at therapeutic doses in routine clinical practice. METHODS: Analysis of a retrospective, observational study of electronic medical records of patients treated for PNP with therapeutic doses of pregabalin or gabapentin, with 2 years' follow-up, considering PNP type, comorbidities, concomitant analgesia and resource use. RESULTS: The weighted total average cost/patient was lower for pregabalin than gabapentin (?2464 [2197-2730] vs ?3142 [2670-3614]; p = 0.014) due to significantly lower both healthcare and non healthcare costs. This is explained by a significantly lower use of concomitant analgesia, fewer primary care visits and fewer days of sick leave. CONCLUSION: At therapeutic doses, pregabalin was found to have lower healthcare and non healthcare costs than gabapentin in routine practice. PMID- 29754519 TI - The role of imaging in early diagnosis and prevention of joint damage in inflammatory arthritis. AB - INTRODUCTION: Inflammatory arthritis is characterized by chronic inflammation in the synovium, associated with degradation of cartilage and erosion of juxta articular bone. The bone loss and joint destruction mediated by aberrant immunological responses resulting in proinflammatory cytokine release and various immune cell activation are known as osteoimmunology. Areas covered: A structured literature search including Medline and PubMed, Cochrane meta-analyses and abstracts of international congresses was performed to review joint damage in inflammatory arthritis in terms of pathogenesis, novel imaging assessment, and prevention. Expert commentary: Deeper understanding of the integration of the skeletal and immune as well as inflammatory system is paving the way to prevent bone loss and bone destruction in inflammatory arthritis. With the availability of various imaging modalities such as ultrasound, magnetic resonance imaging (MRI) and high-resolution peripheral quantitative computed tomography (HR-pQCT), we are now able to detect early joint damage, early diagnosis of inflammatory arthritis, monitor the progression or even ascertain whether the inflammatory process is effectively suppressed to allow repair of joint damage by novel therapeutic agents. PMID- 29754520 TI - Much, if not all, of the cortical damage in MS can be attributed to the microglial cell - Yes. PMID- 29754521 TI - Development of a scoring tool (BLARt score) to predict functional outcome in lower limb amputees. AB - PURPOSE: To develop a valid preoperative scoring tool that predicts the probability of walking with a prosthetic limb after major lower limb amputation. METHODS: A retrospective review of 338 patients who had undergone lower limb amputation was conducted to identify characteristics that affected the success of rehabilitation with a prosthetic limb. These data were used to devise an assessment tool (the BLARt score), which was then tested and validated in 199 patients planned to undergo lower limb amputation in two UK regional centers. Functional rehabilitation outcomes were recorded at 12 months after surgery using the SIGAM mobility grading. RESULTS: No patient with a BLARt score >=13 achieved good functional outcome (defined as independent mobility, SIGAM grade E or F) and only 6 patients with a BLARt score >=17 achieved any functional outcome (defined as any ability to walk unaided, SIGAM grade C or greater). CONCLUSIONS: In the patient cohorts studied, the BLARt assessment tool was a strong predictor of whether or not patients would be able to walk with a prosthetic limb after surgery. It is simple to administer and could be useful in clinical practice to inform expectations for patients and clinicians. Implications for rehabilitation Patients undergoing lower limb amputation face major physical and psychological challenges after surgery that have a considerable impact on rehabilitation and their ability to walk independently. Many amputees are unable to walk with a prosthetic limb, but there are no validated tools to predict this before surgery. The BLARt is a potentially valuable measure that can predict the likelihood of being unable to walk after amputation. It is simple to use and could be useful to inform patients' and clinicians' expectations before surgery. PMID- 29754522 TI - Clinical measurement of the dart throwing motion of the wrist: variability, accuracy and correction. AB - Despite being functionally important, the dart throwing motion is difficult to assess accurately through goniometry. The objectives of this study were to describe a method for reliably quantifying the dart throwing motion using goniometric measurements within a healthy population. Wrist kinematics of 24 healthy participants were assessed using goniometry and optical motion tracking. Three wrist angles were measured at the starting and ending points of the motion: flexion-extension, radial-ulnar deviation and dart throwing motion angle. The orientation of the dart throwing motion plane relative to the flexion-extension axis ranged between 28 degrees and 57 degrees among the tested population. Plane orientations derived from optical motion capture differed from those calculated through goniometry by 25 degrees . An equation to correct the estimation of the plane from goniometry measurements was derived. This was applied and differences in the orientation of the plane were reduced to non significant levels, enabling the dart throwing motion to be measured using goniometry alone. PMID- 29754523 TI - Sites of fractures in explanted NeuFlex(r) silicone metacarpophalangeal joint prostheses. AB - Single-piece silicone implants dominate metacarpophalangeal joint arthroplasty. The NeuFlex(r) implant was introduced to improve on the clinical performance of other silicone implants by having a pre-flexed hinge. By visually examining a cohort of 30 explanted NeuFlex(r) metacarpophalangeal joint prostheses we sought to identify the failure modes of these implants. Seven were not fractured, 11 had fractured across the hinge, nine had fractured at the junction of the distal stem and the hinge, and three showed fractures at both the hinge and at the junction of the distal stem and the hinge. These data may prove helpful in identifying how the performance of single-piece silicone implant designs can be improved. PMID- 29754524 TI - Glomus tumour of the wrist involving the ulnar artery. PMID- 29754525 TI - Factors affecting surgical outcomes of digital glomus tumour: a multicentre study. AB - : This was a retrospective, multicentre study using data from four medical institutions of 72 patients of histologically confirmed digital glomus tumour removed by surgical excision. Mean follow-up period was 5.4 years. We investigated clinical outcomes and analysed the relationship between primary glomus tumour size, radiographic bony erosion, anatomic location, surgical approach, and surgical method as risk factors for recurrence. Complications and recurrence rate according to surgical approach and surgical method were compared. At final follow-up, recurrence was observed in five (6.9%) patients. Postoperative complications were observed in nine (12.5%), with two patients having numbness of fingertips, and seven having nail deformities. In a group with pulp lesions for which a direct approach was used and in a surgical loupe group, recurrence rates were high, however, this was not statistically significant. A nail-sparing approach and microscopic excision did not lower the incidence of nail deformities. No risk factors that significantly predicted recurrence were found. LEVEL OF EVIDENCE: IV. PMID- 29754526 TI - Recurrent Pityriasis Rubra Pilaris: A Case Report. AB - Pityriasis rubra pilaris (PRP) is an uncommon papulosquamous dermatosis characterized by follicular, erythematous, hyperkeratotic papules coalescing to salmon-coloured plaques with islands of sparing. The disease tends to be self limited and resolves spontaneously after a few years. In some cases, the disease is persistent. However, recurrence of this disease has rarely been described. An 8-year-old male was diagnosed with type III (classic juvenile) PRP. He was treated with acitretin, and his skin was clear after 6 months. He remained disease free for 6 years. At 14 years old, he was diagnosed again with type III PRP. His cutaneous manifestations were highly similar to his initial presentation. He was treated with acitretin and methotrexate concurrently and achieved skin clearance. Recurrence of type III PRP is possible although rarely described in the literature. Acitretin +/- methotrexate therapy is effective at achieving skin clearance. PMID- 29754527 TI - Recurrent and Fixed Neutrophilic Dermatosis Associated With Dasatinib. AB - BACKGROUND: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). Skin rashes are common, occurring in about a quarter of patients treated, and are generally mild. The commonest rash is a keratosis pilaris-like eruption. A neutrophilic dermatosis has rarely been reported. OBJECTIVE: We report a patient whose CML was successfully treated with dasatinib and who several years later developed episodes of a neutrophilic dermatosis recurring at the same sites. CONCLUSION: This report extends the clinical spectrum of neutrophilic dermatoses to include dasatinib-induced recurrent and fixed erythematous plaques. PMID- 29754528 TI - Canadian Patients' Preferences in Topical Psoriasis Care: Insights From the PROPEL Surveys. AB - BACKGROUND: Patients with psoriasis of all severities employ topical treatment, either alone or in combination. Promoting Patient Engagement at the Leading Edge of Topical Psoriasis Treatment (PROPEL) surveyed Canadian dermatologists and their patients about their attitudes toward topical care. OBJECTIVES: To identify gaps between patients and dermatologists regarding the burden of psoriasis, the burden of treatment, and priorities for topical care to Canadian patients with psoriasis. METHODS: Two parallel surveys explored patient attitudes toward psoriasis and their experience with topical care, as expressed by patients or as perceived by their dermatologists. A third survey, addressed to patients, included additional questions regarding treatment adherence to current topical treatment regimens. RESULTS: PROPEL dermatologists underestimated the burden associated with psoriatic itch. Otherwise, they were well aligned with patients' views, including their preference for maintaining topical care of their psoriasis over other treatment modalities, the nature of good psoriasis control, and desirable features of topical medications. Despite holding generally positive views of topical therapy, many patients self-identified as poorly adherent. CONCLUSIONS: Long-term adherence to psoriasis topical care remains a challenge. Formulations with improved acceptability might help patients maintain good adherence. PMID- 29754529 TI - Much, if not all, of the cortical damage in MS can be attributed to the microglial cell - No. PMID- 29754530 TI - Compression with 23 mmHg or 35 mmHg stockings after saphenous catheter foam sclerotherapy and phlebectomy of varicose veins: A randomized controlled study. AB - Objectives To compare two different medical compression stockings after varicose vein treatment. Patients and methods A randomized single-blind controlled study on two compression regimes after saphenous catheter foam sclerotherapy + phlebectomy was performed. After pads and 5 mmHg contention sock, 23 mmHg (group A, Struva 23(r)) or 35 mmHg (group B, Struva 35(r)) medical compression stocking was applied 24 h/day for seven days; subsequently 21-23 mmHg medical compression stocking in daytime. Symptoms, compliance, skin findings, and bioimpedance spectroscopy parameters were assessed. Results A total of 94 patients (48 and 49 limbs in groups A and B, respectively) were enrolled. Three (T3) and seven (T7) days post-operatively, most symptoms were significantly milder in group B, especially pain and heaviness at T7 and at day 40 (T40). Ambulation, medical compression stocking stability/tolerability and skin healing were significantly better in group B, with p = 0.046, 0.021/0.060, and 0.010, respectively, at T7. Bioimpedance parameters increased at T7 and decreased at T40 in both groups; leg reactance and limb L-Dex improved in group B at T7 and T40, respectively (p = 0.039 and 0.012). Conclusions Compression with 23 and 35 mmHg medical compression stocking after catheter foam sclerotherapy + phlebectomy was effective and well tolerated at immediate/short term. Compression with 35 mmHg medical compression stocking provided less adverse post-operative symptoms and better tissue healing. Bioimpedance results confirmed a slightly better edema improvement with 35 mmHg medical compression stocking. PMID- 29754531 TI - The role of subconcussive impacts on sway velocities in Division I men's lacrosse players. AB - Head impacts resulting in a concussion negatively affect the vestibular system, but little is known about the effect of subconcussive impacts on this system. This study's objective was to determine if subconcussive head impacts sustained over one competitive lacrosse season, effect sway velocity. Healthy Division I male lacrosse players (n = 33; aged 19.52 +/- 1.20 years) wore instrumented helmets to track head impact exposures. At the beginning and end of the season the players completed an instrumented Balance Error Scoring System assessment to assess sway velocity. Score differentials were correlated to the head impact exposure data collected via instrumented helmets when averaged within participant. Paired samples t-tests revealed a post-season increase in sway velocity on the double leg stance, firm surface (p = 0.002, d = 0.59); tandem stance, firm surface (p = 0.033, d = 0.39) and double leg, foam surface (p = 0.014, d = 0.45) A significant correlation was found between change in tandem stance, firm surface sway velocities and linear acceleration (p < 0.001, r = 0.65). It appears subconcussive impacts may result in tandem stance balance deficits. Repetitive head impacts may negatively affect sway velocity, even in the absence of a diagnosed concussion injury. PMID- 29754532 TI - More care out of hospital? A qualitative exploration of the factors influencing the development of the district nursing workforce in England. AB - : Objectives Many countries seek to improve care for people with chronic conditions and increase delivery of care outside of hospitals, including in the home. Despite these policy objectives in the United Kingdom, the home visiting nursing service workforce, known as district nursing, is declining. This study aimed to investigate the factors influencing the development of district nursing workforces in a metropolitan area of England. Methods A qualitative study in a metropolitan area of three million residents in diverse socio-economic communities using semi-structured interviews with a purposive sample of senior nurses in provider and commissioning organizations. Thematic analysis was framed by theories of workforce development. FINDINGS: All participants reported that the context for the district nursing service was one of major reorganizations in the face of wider National Health Service changes and financial pressures. The analysis identified five themes that can be seen to impact the ways in which the district nursing workforce was developed. These were: the challenge of recruitment and retention, a changing case-mix of patients and the requirement for different clinical skills, the growth of specialist home visiting nursing services and its impact on generalist nursing, the capacity of the district nursing service to meet growing demand, and the influence of the short-term service commissioning process on the need for long-term workforce development. Conclusion There is an apparent paradox between health policies which promote more care within and closer to home and the reported decline in district nursing services. Using the lens of workforce development theory, an explanatory framework was offered with factors such as the nature of the nursing labour market, human resource practices, career advancement opportunities as well as the contractual context and the economic environment. PMID- 29754533 TI - The validation of a swimming turn wall-contact-time measurement system: a touchpad application reliability study. AB - The effectiveness of the swimming turn is highly influential to overall performance in competitive swimming. The push-off or wall contact, within the turn phase, is directly involved in determining the speed the swimmer leaves the wall. Therefore, it is paramount to develop reliable methods to measure the wall contact-time during the turn phase for training and research purposes. The aim of this study was to determine the concurrent validity and reliability of the Pool Pad App to measure wall-contact-time during the freestyle and backstroke tumble turn. The wall-contact-times of nine elite and sub-elite participants were recorded during their regular training sessions. Concurrent validity statistics included the standardised typical error estimate, linear analysis and effect sizes while the intraclass correlating coefficient (ICC) was used for the reliability statistics. The standardised typical error estimate resulted in a moderate Cohen's d effect size with an R2 value of 0.80 and the ICC between the Pool Pad and 2D video footage was 0.89. Despite these measurement differences, the results from this concurrent validity and reliability analyses demonstrated that the Pool Pad is suitable for measuring wall-contact-time during the freestyle and backstroke tumble turn within a training environment. PMID- 29754534 TI - Attitudes of cystic fibrosis patients and their parents towards direct-to consumer genetic testing for carrier status. AB - BACKGROUND: An increasing number of direct-to-consumer (DTC) genetic testing companies have started offering tests for carrier status of autosomal recessive disorders. MATERIALS & METHODS: A written questionnaire was administered to 47 patients and 65 parents of children with Cystic Fibrosis (CF), a common severe autosomal recessive disorder, to assess their views about the offer of DTC carrier tests. All participants were recruited from a CF patient registry in Belgium. RESULTS & CONCLUSION: We found that very few patients and parents were aware of the offer of DTC genetic testing for carrier status, and were generally skeptical. A strong preference for the healthcare system over commercial companies as the provider of the test was observed. However, many participants believe people should have a right to access DTC genetic tests provided by commercial companies. PMID- 29754535 TI - The birth and potential death of IL28B genotyping for hepatitis C therapy. PMID- 29754536 TI - Pharmacogenetics and analgesic effects of antidepressants in chronic pain management. AB - Antidepressants are widely administered to chronic pain patients, but there is large interindividual variability in their efficacy and adverse effect rates that may be attributed to genetic factors. Studies have attempted to determine the impact of genetic polymorphisms in enzymes and transporters that are involved in antidepressant pharmacokinetics, for example, cytochrome P450 and P-gp. The impacts of genetic polymorphisms in the targets of antidepressants, such as the serotonin receptor or transporter, the noradrenaline transporter and the COMT and monoamine oxydase enzymes, have also been described. This manuscript discusses the current knowledge of the influence of genetic factors on the plasma concentrations, efficacy and adverse effects of the major antidepressants used in pain management. PMID- 29754537 TI - Translating next-generation sequencing from clinical trials to clinical practice for the treatment of advanced cancers. AB - Next-generation sequencing (NGS) is being applied in oncology care to identify specific molecular aberrations of patient's tumors. The use of NGS now allows for sequencing entire human genomes within a reasonable cost and practical time frames for treatment decision making. Further delineation of epigenetics, transcriptomics, metagenomics and NGS at the level of circulating tumor DNA reveal ever increasing complexity to understand these interactions and the roles they play in cancer. With the improvement in understanding the study of proteomics, it has become clear that NGS has room for innovation to someday include sequencing of proteins. Early embarkation of NGS incorporated into clinical trials has begun. Here, we review the feasibility and practicality of translating NGS from clinical trials to clinical practice. PMID- 29754538 TI - Detecting resistance in EGFR-mutated non-small-cell lung cancer after clonal selection through targeted therapy. AB - Tumor heterogeneity plays an important role in the development of treatment resistance, especially in the current era of targeted therapies. Although tumor heterogeneity is a widely recognized phenomenon, it is at present unclear how this knowledge should be incorporated into daily clinical practice. In this report, we describe an innovative nuclear imaging method that may play a role in detecting tumor heterogeneity in the future. PMID- 29754539 TI - CYP450 pharmacogenomics: a cardiology perspective. PMID- 29754540 TI - Fast and frugal trees: translating population-based pharmacogenomics to medication prioritization. AB - AIM: Fast and frugal decision trees (FFTs) can simplify clinical decision making by providing a heuristic approach to contextual guidance. We wanted to use FFTs for pharmacogenomic knowledge translation at point-of-care. MATERIALS & METHODS: The Pharmacogenomics for Every Nation Initiative (PGENI), an international nonprofit organization, collects data on regional polymorphisms as a predictor of metabolism for individual drugs and dosages. We advanced FFTs to work with PGENI pharmacogenomic data to produce medication recommendations that are accurate, transparent and straightforward to automate. RESULTS: By streamlining medication selection processes in the PGENI workflow, information technology applications can now be deployed. CONCLUSION: We developed a decision tree approach that can translate pharmacogenomic data to provide up-to-date recommended care for populations based on their medication-specific markers. PMID- 29754541 TI - PARP inhibitors: the journey from research hypothesis to clinical approval. AB - Cancer puts an increasing burden on our healthcare system and is a major cause of death. Therefore, novel approaches are required to improve cancer treatment. Cancer cells have several hallmarks that could be therapeutically targeted. Importantly, every tumor has a different combination of aberrations affecting the different hallmarks. This review focuses on targeting one of these hallmarks, the DNA damage response (DDR). DDR defects can not only cause cancer, but they can also be exploited therapeutically. This plays an important role even in 'classical' (DNA damaging) chemotherapy and radiotherapy, but more precise targeting of specific defects is expected to increase treatment efficacy and decrease normal tissue toxicity. Poly-(ADP-ribose) polymerase (PARP) inhibitors are the first clinical example of such synthetic lethality in tumors having specific DDR defects. They are currently under investigation as DDR-targeting anticancer drugs and they progress quickly in clinical trials. PMID- 29754542 TI - Meta-analysis reveals a specific association of the PNPLA3 I148M polymorphism with ALT level in adolescents. AB - AIM: To evaluate potential link between the PNPLA3 rs738409 polymorphism and alanine aminotransferase (ALT) levels through an evidence-based study. MATERIALS & METHODS: Electronic literature databases, including PubMed, Embase and the Institute for Scientific Information, were searched for relevant studies. Pooling standardized mean differences for quantitative variables and summary odds ratios (OR) were respectively calculated using per-allele comparison. RESULTS: Although a genotype-phenotype association was inconsistent in adults, this genetic effect was stable in adolescents. There was an approximate increase of 23% in ALT value, and 1.99-fold higher ALT elevation per risk allele increase with low heterogeneity. CONCLUSION: The PNPLA3 rs738409 polymorphism can have a differentiated influence on ALT level. Our meta-analysis provides reference data for the adjustment of diverse susceptibility due to the rs738409 polymorphism when evaluating liver injury in various populations. PMID- 29754543 TI - Organizational profile: PHG Foundation. AB - The PHG Foundation is an independent, nonprofit think tank dedicated to making science work for health. Originally founded to imagine a future where genomics would underpin the practice of both medicine and public health, the Foundation's focus is now on preparing for the future of personalized medicine, including forms of personalized disease prevention and early detection. A panoply of rapidly emerging scientific applications and technologies could be used alongside genomics to enable a fundamental shift toward increasingly effective and sustainable, person-centered health and care. Developing policy to anticipate and accelerate the uptake of such innovations into clinical and public health practice is more important than ever, and supporting the work of the All Party Parliamentary Group on Personalised Medicine is part of this effort. PMID- 29754544 TI - Designing expanded carrier screening panels: results of a qualitative study with European geneticists. AB - AIM: To explore the views of clinical and molecular geneticists on the inclusion of disorders and specific pathogenic mutations into expanded carrier screening (ECS) tests for reproductive purposes. MATERIALS & METHODS: In-depth semistructured interviews were conducted with 16 European geneticists between April and September 2014. RESULTS: All participants supported carrier screening for severe, childhood-onset autosomal recessive disorders with known natural history. Some participants were also in favor of screening for late-onset and X linked disorders. Regarding selection of specific pathogenic mutations, our participants argued that ECS should include highly penetrant pathogenic mutations with known genotype-phenotype associations. CONCLUSION: This study highlights main challenges surrounding the development of ECS panels and offers suggestions for future research in this rapidly advancing field. PMID- 29754545 TI - Ethical and legal considerations for pediatric biobank consent: current and future perspectives. AB - Innovations in laboratory and information technologies continue to drive the expansion of pediatric biorepository research, with collections of biosamples and data continuing to grow in scale and scope. In this review, we examine the trajectory of recent developments in ethical and legal scholarship on consent to pediatric biorepository research. We focus, in particular, on issues that are likely to grow in importance in coming years, either because significant controversies remain or because they represent trends that are likely to continue into the future. Of particular interest is the evolving conception of consent as a process, the trend toward increased participant engagement and other challenges likely to raise thorny new issues in this field in the decade ahead. PMID- 29754546 TI - The Googlization of health research: from disruptive innovation to disruptive ethics. AB - Consumer-oriented mobile technologies offer new ways of capturing multidimensional health data, and are increasingly seen as facilitators of medical research. This has opened the way for large consumer tech companies, like Apple, Google, Amazon and Facebook, to enter the space of health research, offering new methods for collecting, storing and analyzing health data. While these developments are often portrayed as 'disrupting' research in beneficial ways, they also raise many ethical issues. These can be organized into three clusters: questions concerning the quality of research; privacy/informed consent; and new power asymmetries based on access to data and control over technological infrastructures. I argue that this last cluster, insofar as it may affect future research agendas, deserves more critical attention. PMID- 29754547 TI - Young adults' attitudes toward pediatric whole-genome sequencing. AB - AIM: To characterize the views of young adults toward integrating whole-genome sequencing (WGS) into standard pediatric care, particularly when used as a supplement to newborn screening. MATERIALS & METHODS: This mixed methods descriptive study assessed the perspectives of a diverse group of 18- and 19-year olds (n = 145) in the USA using an informational video and online survey. RESULTS: Young adults typically recommended disclosing WGS results to both parents and children during childhood. In the qualitative analysis, most participants emphasized the anticipated health benefits of pediatric WGS, while a minority discussed possible negative emotional and developmental impacts. CONCLUSION: Differing preferences for pediatric WGS emphasize the importance that clinicians adopt responsive approaches when providing WGS and disclosing results to families. PMID- 29754548 TI - Personalized medicine and blood disorders. AB - Personalized medicine has been using genomics approaches to elucidate the etiology of a disease as well as to personalize the management for patients of a particular disease based on that individual's genetic features. It benefits patients across a multitude of therapeutic areas and advancements are particularly evident in hematology/oncology. The importance of genomics discoveries and development in nonmalignant blood disorders generally goes unrecognized, but it becomes critical now due to the global disease burden and a high mortality. This paper focuses on the exploration of personalized medicine applications in hemoglobin diseases, and thrombotic and bleeding disorders. It discusses the challenges which slow down the implementation as well. The available data suggest that the ability to understand the clinical features of a patient's genetic profile and the knowledge of disease mechanisms are the keys to facilitate new diagnosis, new therapies, new prescriptions and better healthcare. PMID- 29754549 TI - Case with triple-negative breast cancer shows overexpression of both cFOS and TGF beta1 in node-positive tissue. AB - We present herein a case report style article on a rare advanced triple-negative breast cancer (TNBC) patient with 6-month disease-free interval, and 10-month overall survival. Our results demonstrate that the poor clinical outcome of this patient was associated with pronounced, more than fivefold higher, overexpression of both cFOS and TGF-beta1 proteins in its metastatic nodal tissue extracts, when compared with the values of the two non-TNBC controls (with 'zero' disease-free interval and overall survival). This original observation suggests, for the first time, that both the cFOS and TGF-beta1 may be considered as a pair of biomarkers for an early assessment of poor prognosis for TNBC patients. The possible clinical implication of this observation is discussed. PMID- 29754550 TI - BACE1 levels are increased in plasma of Alzheimer's disease patients compared with matched cognitively healthy controls. AB - AIM: BACE1 is the secretase that acts in Abeta production in Alzheimer's disease (AD). MATERIALS & METHODS: We investigated mRNA expression in total blood and the levels of plasma protein BACE1 in AD patients compared with cognitively healthy subjects. Probable AD (n = 47) and non-AD control group (n = 32) were evaluated for mRNA expression for BACE1 using reverse transcription-qPCR. A subsample of n = 21 AD and n = 20 non-AD had plasma BACE1 levels analyzed, using ELISA. RESULTS: No differences were found on BACE1 mRNA between groups. However, higher levels of BACE1 were detected in plasma of AD patients. DISCUSSION: Blood-based diagnostic tools are desired to improve AD diagnosis. BACE1 plasma levels could provide an additional diagnostic tool for AD in association with neuropsychological tests. PMID- 29754551 TI - Update: looking beyond the 100,000 Genome Project. PMID- 29754552 TI - Highly personalized reports for personalized drug selection by expert systems as clinical decision support. PMID- 29754553 TI - Strategies for integrating personalized medicine into healthcare practice. AB - AIM: Research and innovation in personalized medicine are surging, however, its adoption into clinical practice is comparatively slow. We identify common challenges to the clinical adoption of personalized medicine and provide strategies for addressing these challenges. METHODS: Our team developed a list of common challenges through a series of group discussions, surveys and interviews, and convened a national summit to discuss solutions for overcoming these challenges. We used a framework approach for thematic analysis. RESULTS: We categorized challenges into five areas of need: education and awareness; patient empowerment; value recognition; infrastructure and information management; and ensuring access to care. We then developed strategies to address these challenges. CONCLUSION: In order for healthcare to transition into personalized medicine, it is necessary for stakeholders to build momentum by implementing a progression of strategies. PMID- 29754554 TI - Genomic medicine practice among physicians in Taiwan. AB - AIM: To examine genomic medicine (GM) practice and associated factors (i.e., attitudes, intention, self-efficacy, previous training in genomics, and demographic characteristics) among Taiwanese physicians. METHODS: A survey was distributed to physicians attending an internal training workshop at a large medical center in Taiwan. Data were analyzed using structural equation modeling. RESULTS: A total of 137 physicians comprised our final sample; less than a third of them had practiced GM. Yet, participants overall had positive intention, favorable attitudes, and high self-efficacy in GM practice. Moreover, intention, attitudes, self-efficacy, educational level, and continuing education in GM were positively and significantly associated with participants' GM practice. CONCLUSION: Offering continuing education for Taiwanese physicians is needed to enhance their practice in GM. PMID- 29754555 TI - Noncoding RNA for personalized prostate cancer treatment: utilizing the 'dark matters' of the genome. AB - Prostate cancer is the most commonly diagnosed cancer in men in western countries, with significant health impact. Clinically, it is complicated with the lack of biomarkers and effective treatments for aggressive disease, particularly castration-resistant prostate cancer. Although we have gained much insight into the biology of prostate cancer through studying protein-coding genes, they represent only a small fraction of our genome. Therefore, it is essential for us to investigate noncoding RNAs, which comprise the majority of our transcriptome, in order to achieve a better understanding of prostate cancer and move toward personalized medicine. In this article, we will address recent advancements in our knowledge of noncoding RNAs, and discuss the clinical potentials and challenges of different types of noncoding RNAs in prostate cancer. PMID- 29754556 TI - Responses to Crizotinib therapy in five patients with non-small-cell lung cancer who tested FISH negative and Ventana immunohistochemistry positive for ALK fusions. AB - AIM: Although immunohistochemistry (IHC) and reverse transcription-PCR can detect ALK rearrangements, the ALK break-apart FISH assay is currently considered the standard method. MATERIALS & METHODS: Five patients with advanced non-small-cell lung cancer, who had an ALK-negative FISH result that was later confirmed as positive by the Ventana IHC assay, were studied. Four had previously received chemotherapy or radiotherapy. All five were subsequently treated with Crizoitinib 250 mg twice daily. RESULTS & CONCLUSION: Four patients had a partial response to Crizotinib and one had stable disease. IHC is an efficient technique for diagnosing ALK rearrangements in patients with non-small-cell lung cancer, and may serve as an alternative to FISH in clinical practice. PMID- 29754557 TI - Dysregulation of miRNA-146a contributes to the development of lupus nephritis via targeting of TRAF6. AB - AIM: The objective of this study was to identify the association between genotypes of miR-146a rs2910164 and expression of TRAF6 as well as the risk of lupus nephritis (LN). RESULTS: A total of 567 systemic lupus erythematosus patients both with and without LN were included in the study. The luciferase activity of cells that carried miR-146a mimics was much lower than control and the miR-146a mRNA expression with the GG SNP was significantly overexpressed compared with that in GC and CC groups. Expressions of TRAF6 mRNA and protein with GG were markedly lower than those in GC and CC groups. Mesangial cells treated with miR-146a inhibitors displayed higher expression of TRAF6 mRNA and protein compared with scramble control, miR-146a mimics and TRAF6 siRNA groups. CONCLUSION: Rs2910164 is associated with the risk of LN and could function as a therapeutic target of the disease. PMID- 29754558 TI - Beyond the Genetic Information Nondiscrimination Act: ethical and economic implications of the exclusion of disability, long-term care and life insurance. AB - The Genetic Information Nondiscrimination Act (GINA) was intended to protect individuals in the USA from discrimination based on their genetic data, but does not apply to life, long-term care or disability insurance. Patient advocates and ethicists have argued that GINA does not go far enough. Others express concerns for the viability of insurance companies if millions of potential customers know more than professional actuaries. Here we discuss the exclusion of certain insurance types from GINA. We explore the ethical and economic implications of this distinction, and potential paths forward. We suggest that because long-term care and disability insurance can be essential for well-being, there is no good reason to place them in a class with life insurance and therefore beyond GINA's reach. PMID- 29754559 TI - Precision medicine in circadian rhythm sleep-wake disorders: current state and future perspectives. AB - In circadian rhythm sleep-wake disorders precision medicine is less developed than in other medical disciplines mainly because homeostatic sleep and circadian timing have a very complex phenotype with multiple genetic regulation mechanisms. However, biomarkers, phenotyping and psychosocial characteristics are increasingly used. Devices for polysomnography, actigraphy and sleep-tracking applications in mobile phones and other consumer devices with eHealth technologies are increasingly used. Also sleep-related questionnaires and the assessment of co-morbidities influencing sleep in circadian rhythm sleep-wake disorders are major contributors to precision sleep medicine. To further strengthen the (pharmaco-)genetic and biomarker pillar, technology needs to be evolved further. Routinely measuring treatment results using patient-reported outcome measures and clinical neurophysiological instruments will boost precision sleep medicine. PMID- 29754560 TI - Door to needle time and functional outcome for mild ischemic stroke over telestroke. AB - Introduction Faster intravenous alteplase (tPA) administration from time of symptom onset is associated with better functional outcome. Lack of recognition of mild ischemic stroke (MIS) might result in delay in treatment with tPA. We hypothesise that patients with MIS have a longer door to needle (DTN) time when compared to patients with severe stroke symptoms. Methods Data on all patients who received tPA at spoke hospitals through the Medical University of South Carolina (MUSC) telestroke network were analysed. Collected data included baseline characteristics, stroke severity on presentation measured by the National Institute of Health Stroke Scale (NIHSS), the rate of symptomatic intracerebral haemorrhage, discharge location, and discharge functional outcome measured by the modified Rankin scale. Results and Discussion Of the 454 patients treated with tPA through the MUSC telestroke network in the period from January 2013 to April 2017, 98 (22%) had MIS defined as NIHSS <= 5 on presentation; the remaining 356 (78%) patients were found to have severe stroke defined as NIHSS > 5 on presentation. Patients presenting with MIS were found to have a delay in receiving intravenous tPA by ~10 min ( p = 0.007) and approximately 15% of them had poor functional outcome at discharge. Patients with a MIS on presentation have significantly more prolonged DTN time. Nearly 15% of low severity strokes had poor outcome even after receiving tPA. PMID- 29754561 TI - An economic cost analysis of an expanding, multi-state behavioural telehealth intervention. AB - Introduction In this paper the economic costs associated with a growing, multi state telepsychiatry intervention serving rural American Indian/Alaska Native populations were compared to costs of travelling to provide/receive in-person treatment. Methods Telepsychiatry costs were calculated using administrative, information-technology, equipment and technology components, and were compared to travel cost models. Both a patient travel and a psychiatrist travel model were estimated utilising ArcGIS software and unit costs gathered from literature and government sources. Cost structure and sensitivity analysis was also calculated by varying modeling parameters and assumptions. Results and Discussion It is estimated that per-session costs were $93.90, $183.34, and $268.23 for telemedicine, provider-travel, and patient-travel, respectively. Restricting the analysis to satellite locations with a larger number of visits reduced telemedicine per-patient encounter costs (50 or more visits: $83.52; 100 or more visits: $80.41; and 150 or more visits: $76.25). The estimated cost efficiencies of telemedicine were more evident for highly rural communities. Finally, we found that a multi-state centre was cheaper than each state operating independently. Conclusions Consistent with previous research, this study provides additional evidence of the economic efficiency associated with telemedicine interventions for rural American Indian/Alaska Native populations. Our results suggest that there are economies of scale in providing behavioural telemedicine and that bigger, multi-state telemedicine centres have lower overall costs compared to smaller, state-level centres. Additionally, results suggest that telemedicine structures with a higher number of per-satellite patient encounters have lower costs, and telemedicine centres delivering care to highly rural populations produce greater economic benefits. PMID- 29754563 TI - New synthetic 3D culture systems to unlock the future of organoids in research and therapy. PMID- 29754562 TI - Cardiology electronic consultation (e-consult) use by primary care providers at VA medical centres in New England. AB - Introduction E-consultations (e-consults) were implemented at VA medical centers to improve access to specialty care. Cardiology e-consults are among the most commonly requested, but little is known about how primary care providers (PCPs) use cardiology e-consults to access specialty care. Methods This is a retrospective analysis of 750 patients' medical charts with cardiology e-consults requested by medical providers (October 2013-September 2015) in the VA New England Healthcare System. We described the patients and referring provider characteristics, and e-consult questions. We reviewed cardiologists' responses and examined their recommendations. Results Among the 424 e-consults requested from PCPs, 92.7% were used to request answers to clinical questions, while 7.3% were used for administrative purposes. Among the 393 e-consults with clinical questions, 60 e-consults were regarding preoperative management; these questions most commonly addressed general risk assessment ( n = 44), anti-coagulation/anti platelet management ( n = 33), and EKG interpretation ( n = 20). Cardiologists provided answers for the majority (89.6%) of clinical questions. Among the e consults in which cardiologists did not provide answers or clinical guidance ( n = 41), the reasons included missing or insufficient clinical information ( n = 18), medical complexity ( n = 6), and deferment to the patient's non-VA primary cardiologist ( n = 7). Cardiologists recommended that the patients be seen as face-to-face consults for 7.9% of e-consults. Discussion Primary care providers are the most frequent requesters of cardiology e-consults, using them primarily to obtain input on clinical questions. Cardiologists did not provide answers for one in ten, owing principally to insufficient available clinical information. Educating PCPs and standardizing the template for requesting e-consultation may help to reduce the number of unanswered e-consults. PMID- 29754564 TI - From genomes to genomic medicine: enabling personalized and precision medicine in the Middle East. PMID- 29754565 TI - IL-27 genetic variation and susceptibility of dilated cardiomyopathy in Chinese Han population. AB - AIM: Accumulating data showed that IL-27 polymorphisms are linked to the susceptibility of some autoimmune diseases. We assessed whether there was an association between two single nucleotide polymorphisms (SNPs) of IL-27 gene and dilated cardiomyopathy (DCM). MATERIALS & METHODS: Two SNPs (rs153109 and rs17855750) of IL-27 gene were genotyped by PCR-restriction fragment length polymorphism in 261 DCM patients and 303 unrelated healthy subjects in Chinese Han population. RESULTS: Compared with controls, our results showed that SNP rs153109 displayed significant associations with DCM in Chinese Han population, whereas no differences in genotype or allele frequencies were found between DCM patients and controls at SNP rs17855750. CONCLUSION: Our study showed that, for the first time, the association of the IL-27 gene SNP with the patients with DCM. PMID- 29754566 TI - Current ethical and legal issues in health-related direct-to-consumer genetic testing. AB - A variety of health-related genetic testing is currently advertized directly to consumers. This article provides a timely overview of direct-to-consumer genetic testing (DTC GT) and salient ethical issues, as well as an analysis of the impact of the recently adopted regulation on in vitro diagnostic medical devices on DTC GT. DTC GT companies currently employ new testing approaches, report on a wide spectrum of conditions and target new groups of consumers. Such activities raise ethical issues including the questionable analytic and clinical validity of tests, the adequacy of informed consent, potentially misleading advertizing, testing in children, research uses and commercialization of genomic data. The recently adopted regulation on in vitro diagnostic medical devices may limit the offers of predisposition DTC GT in the EU market. PMID- 29754567 TI - Primary care physician experiences with integrated pharmacogenomic testing in a community health system. AB - AIM: To explore primary care physicians' views of the utility and delivery of direct access to pharmacogenomics (PGx) testing in a community health system. METHODS: This descriptive study assessed the perspectives of 15 healthcare providers utilizing qualitative individual interviews. RESULTS: Three main themes emerged: perceived value and utility of PGx testing; challenges to implementation in practice; and provider as well as patient needs. CONCLUSION: While providers in this study viewed benefits of PGx testing as avoiding side effects, titrating doses more quickly, improving shared decision-making and providing psychological reassurance, challenges will need to be addressed such as privacy concerns, cost, insurance coverage and understanding the complexity of PGx test results. PMID- 29754568 TI - Toward dynamical systems medicine: personalized and preventive strategies. PMID- 29754570 TI - Cardiovascular risk factors in a child population: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: The main aim of the present study was to investigate the clustering of risk factors for cardiovascular diseases and metabolic syndrome in a large, healthy representative Norwegian child population. METHODS: From a population of 2817, parents of 2297 children agreed to participate. Values of waist circumference (WC), total cholesterol (TC), high-density lipoprotein (HDL), systolic blood pressure (sysBP), haemoglobin-A1c (HbA1c) and Andersen aerobic fitness test were used to test clustering of cardiometabolic risk factors in this sample. Expected distributions of probability for zero to five risk factors are, respectively, 23.7%, 39.6%, 26.4%, 8.8%, 1.5% and 0.1%. A cardiometabolic risk score from zero to five for each individual was derived by adding the number of variables in the least desirable quartile (highest for WC, sysBP, TC and HbA1c; lowest for aerobic fitness and HDL). RESULTS: A risk ratio of 5.8 (95% confidence interval 0.7-46.9) was found for five risk factors, though the small sample size rendered the results non-significant. An explorative analysis combining children with four and five risk factors did not reveal any significant clustering either. CONCLUSIONS: No clustering of risk factors was found among Norwegian children aged 6-12 years. PMID- 29754569 TI - Toward personalized medicine in Bardet-Biedl syndrome. AB - Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet-Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. Owing to their structure and function, cilia provide an attractive therapeutic target and genetic therapies are being explored in ciliopathy treatment. Promising avenues include gene therapy, gene editing techniques and splice-correcting and read through therapies. Targeted drug design has been successful in the treatment of genetic disease and research is underway in the discovery of known and novel drugs to treat Bardet-Biedl syndrome. PMID- 29754571 TI - Reference intervals for serum lipids and prevalence of dyslipidaemia in 6-12-year old children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: Elevated serum lipid concentrations in childhood are thought to be risk factors for the development of cardiovascular disease later in life. The present study aims to provide age- and gender-related reference intervals for total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol in healthy school children. We also investigated the prevalence of dyslipidaemia using the published criteria for these biomarkers. METHODS: Venous blood and anthropometric data were collected from 1340 children in the HOPP study, aged between 6 and 12 years. Age- and gender-related reference intervals (2.5th and 97.5th percentiles) were established according to the IFCC recommendations, using the software RefVal 4.10. RESULTS: Gender differences were observed for total cholesterol and non-HDL cholesterol, but not for HDL cholesterol. Age differences were observed for total cholesterol. The reference intervals were in the range of 3.1-5.9 mmol/L for total cholesterol, 1.0-2.4 mmol/L for HDL cholesterol and 1.4-4.2 mmol/L for non-HDL cholesterol. Dyslipidaemia prevalence was as follows: increased TC 9.6%, decreased HDL 1.6%, and increased non-HDL 5.6%. CONCLUSIONS: Age- and gender-related reference intervals in a Norwegian population are similar to those reported in other countries. The prevalence of dyslipidaemia among Norwegian children is significant, emphasising the importance of appropriate reference intervals in clinical practice. PMID- 29754572 TI - Factors affecting running performance in 6-12-year-olds: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: The purpose of this study was to examine factors affecting running performance in children. METHOD: A cross-sectional study exploring the relationships between height, weight, waist circumference, muscle mass, body fat percentage, relevant biomarkers, and the Andersen intermittent running test in 2272 children aged 6 to 12 years. Parental education level was used as a non physiological explanatory variable. RESULTS: Mean values (SD) and percentiles are presented as reference values. Height (beta = 6.4, p < .0001), high values of haemoglobin (beta = 18, p = .013) and low percentage of body fat (beta = -7.5, p < .0001) showed an association with results from the running test. In addition, high parental education level showed a positive association with the running test. CONCLUSION: Boys display better running performance than girls at all age ages, except 7 years old, probably because of additional muscle mass and less fatty tissue. Height and increased level of haemoglobin positively affected running performance. Lower body fat percentage and high parental education level correlated with better running performance. PMID- 29754573 TI - Waist circumference in 6-12-year-old children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: With overweight and obesity increasing worldwide, it has become ever more important to monitor the development and distribution of adiposity in children. This study investigated how the measurements of waist circumference (WC) and waist-to-height ratio (WHtR) in children 6-12 years old relate to earlier studies. METHODS: In 2015, 2271 children (boys, n = 1150) were measured for height, weight, and WC. Parental education level was used as a measure of socioeconomic status. RESULTS: A significant increase in WC with age was revealed for both sexes ( p < .0001). Boys at 10 and 12 years had a larger WC than girls; otherwise no difference between sexes was found. The WHtR decreased with age for girls ( p < .0001); 14% of the sample displayed a WHtR >= 0.50. Comparison with earlier studies showed a higher WC and WHtR despite no change in weight and body mass index. CONCLUSION: WC and WHtR are recommended as tools for identifying central obesity in children. The results indicate increased WC in 6-12-year-old children compared with earlier findings. PMID- 29754574 TI - Anthropometric measures as fitness indicators in primary school children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: As children's fitness continues to decline, frequent and systematic monitoring of fitness is important. Easy-to-use and low-cost methods with acceptable accuracy are essential in screening situations. This study aimed to investigate how the measurements of body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR) relate to selected measurements of fitness in children. METHODS: A total of 1731 children from grades 1 to 6 were selected who had a complete set of height, body mass, running performance, handgrip strength and muscle mass measurements. A composite fitness score was established from the sum of sex- and age-specific z-scores for the variables running performance, handgrip strength and muscle mass. This fitness z-score was compared to z-scores and quartiles of BMI, WC and WHtR using analysis of variance, linear regression and receiver operator characteristic analysis. RESULTS: The regression analysis showed that z-scores for BMI, WC and WHtR all were linearly related to the composite fitness score, with WHtR having the highest R2 at 0.80. The correct classification of fit and unfit was relatively high for all three measurements. WHtR had the best prediction of fitness of the three with an area under the curve of 0.92 ( p < 0.001). CONCLUSIONS: BMI, WC and WHtR were all found to be feasible measurements, but WHtR had a higher precision in its classification into fit and unfit in this population. PMID- 29754575 TI - Handgrip strength in 6-12-year-old children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: The aim of the study was to describe the natural course of handgrip strength development in primary school children and to establish a reference material to be used in future screening studies. In addition, the study aims to investigate a possible association between handgrip strength and cardiovascular risk factors. METHODS: Anthropometric measures along with results for handgrip strength, endurance tests, blood pressure and cholesterol were measured on 2272 children of both sexes. An ROC analysis was used to estimate the suitability of handgrip strength as a predictor for known cardiometabolic risk factors. RESULTS: A reference material for handgrip strength is presented for boys and girls aged 6 12 years. The results indicate that handgrip strength is unsuitable as a predictor for cardiometabolic risk factors in children. CONCLUSIONS: The results may be used as reference values for handgrip strength in 6-12-year-old children of both sexes. Handgrip strength may not be used as a screening tool for cardiometabolic risk factors in pre-pubertal children. PMID- 29754576 TI - Objectively assessed moderate-to-vigorous physical activity levels among primary school children in Norway: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: The objective was to investigate moderate-to-vigorous physical activity levels (MVPA) of primary school children at baseline of the Health Oriented Pedagogical Project (HOPP), Norway. METHODS: Data on 2123 children aged 6-12 years were included for analysis (75% participation rate). Average minutes per day in MVPA was objectively measured using accelerometry based on seven-day averages. The sample was analysed for age-, sex-, socioeconomic-, and season related patterns. A linear regression investigated the moderating effect of these factors as well as body mass index and waist circumference. RESULTS: Some 86.5% of the sample had at least 60 min/day MVPA, averaging 90.7 min/day. The main differences in daily averages were between age groups 61/2-9 and 10-12 ( p < .05). Boys (95.8 min/day, 95% CI: 94.1-97.5) were more active than girls (85.6 min/day, 95% CI: 83.9-87.2) in all age groups ( p < .0001). MVPA was lower by 3.5 min ( p < .0001) per additional year of age in the linear regression (R2 = 0.176) and was reduced by 20 min less per day in MVPA in the winter months compared with the summer months ( p < .0001). CONCLUSIONS: Physical activity levels are already in decline from 6-7 years old and are likely to continue to decline into adolescence. Interventions must therefore focus on primary school children. PMID- 29754577 TI - Development of weight and height in Norwegian children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: High prevalence of overweight and obesity increases the disease burden with higher risk for an expanding set of chronic diseases, including cardiovascular disease, diabetes mellitus, chronic kidney disease, certain types of cancers and an array of musculoskeletal disorders. Over the last decades, trends in children's weight have changed worldwide. METHODS: Anthropometric measurements of height and weight and calculations of body mass index (BMI) were recorded for 2297 children, aged 6-12 years. RESULTS: Percentiles for weight and height are presented, as well as overweight and obesity cut-off points according to International Obesity Task Force guidelines for each age group. Children's BMI is higher compared to older studies; however, a levelling-off of weight is evident, as 14-15% of the children are overweight in the present study. Children within the 90th and 97.5th percentiles display a higher annual increase in weight/height ratio compared to other percentiles. Parental level of education shows association with children's BMI. CONCLUSIONS: A levelling-off of weight gain among children is evident; however, overweight children tend to gain more weight than normal-weight children. PMID- 29754578 TI - Quality of life in primary school children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: The primary aim of the present study was to evaluate the association between parents' level of education, measurements of physical attributes, and quality of life in a general sample of primary school children. METHODS: The children's and the parents' versions of the Inventory of Life Quality in Children and Adolescents (ILC) were used to measure health-related quality of life (QOL) in 2140 school children (response rate 93%) and 1639 parents (response rate 71%) recruited from nine primary schools in Norway. A set of physical characteristics were also measured in the children: body mass index (BMI), waist circumference, average daily minutes of physical activity, aerobic fitness, and handgrip strength. RESULTS: The regression analysis showed stronger relationships between the covariates and QOL for the parents' assessments than for the children's. Parents' level of education was significantly related to children's QOL, with the strongest association for parental QOL assessment. Among the physical variables, aerobic fitness ( B = 0.01, p > .001 in both samples), and handgrip strength in the parents' sample ( B = 0.21, p < .05) were significantly related to the children's QOL. CONCLUSIONS: The present study replicated the well-known finding that parents' sociodemographic status is important for children's QOL. Our new contribution is to show that the physiological variables aerobic fitness and muscular strength also contributed significantly to explain variance in QOL. This opens up interesting perspectives on how to improve QOL among children through more emphasis on physical activity and physical fitness in schools. PMID- 29754579 TI - Peer relationships and quality of life in 11-12-year-old children: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: Social interactions play an important role in our everyday life. Studies on children's quality of life (QoL) show that peer relations are associated with both positive and negative outcomes. Popularity defines the degree to which a child is liked by his or her peers, whereas reciprocal friendship occurs when two children mutually nominate each other as friends. The overall aim was to examine associations between peer relations and children's QoL. METHODS: Baseline data were from the Health Oriented Pedagogical Project (HOPP). From a sample of 2297, 691 children aged 11-12 years participated. QoL was measured using the Norwegian version of the Inventory of Life Quality in Children and Adolescents (ILC). Popularity and friendship variables were based on number of nominations and represent quantitative features of peer relationships. RESULTS: Both popularity and reciprocal friendship had a positive association with children's QoL. Number of nominations (both for popularity and reciprocal friendship) played a significant role for the above-mentioned associations. Consequently, popularity (beta = 0.18) and reciprocal friendship (beta = 0.25) were associated with children's QoL with 95% CIs of 0.12-0.27 and 0.17-0.31, respectively. CONCLUSIONS: Findings from the current study contribute to contemporary research focused on children's QoL. Being able to rank reciprocal friendships, as well as recognizing that having more than one reciprocal friendship increases QoL, is important and could be beneficial for developing programs that promote high QoL, hence preventing possible maladjustments in a long-term perspective. PMID- 29754580 TI - The effects of a school-based physical activity intervention programme on children's executive control: The Health Oriented Pedagogical Project (HOPP). AB - AIMS: To assess the effects of a large school-based physical activity intervention on children's ability to resist distractions and maintain focus, known as executive control. METHODS: A quasi-experimental design with seven intervention and two control primary schools. The Health Oriented Pedagogical Project (HOPP) intervention consisted of 45 min of physical activity a day during school time for 6-8 months in addition to the regular weekly physical education lessons. A total of 1173 children, spanning from second grade (age 7 years) to sixth grade (age 12 years) were included in the analysis. Main outcome measures were executive control was measured at baseline and 1 year after using a modified Eriksen flanker task for the younger children (second and third grades) and a computerised Stroop task for the older children (fourth, fifth, and sixth grades). RESULTS: Both the intervention and control group showed improvements in executive control after 1 year. However, the children in the intervention group did not improve their performance more than those in the control group. CONCLUSIONS: No positive effect of the physical activity intervention programme on children's task performance was found, suggesting that the intervention did not affect children's executive control. PMID- 29754581 TI - The clinical characteristics and therapy response of patients with acquired pure red cell aplasia. AB - OBJECTIVE: To summarize the clinical characteristics of acquired pure red cell aplasia (PRCA) patients diagnosed in our hospital in the last 10 years. METHOD: The clinical features, immune state and treatment response of acquired PRCA patients diagnosed in our hospital from January 2007 to January 2017 were retrospectively analyzed. RESULTS: The results showed that thymoma (13.21%) and parvovirus B19 (11.32%) were the most common causes for secondary PRCA. Ferritin (Fer) levels and erythropoietin (EPO) levels were increased in PRCA patients. The total CR and PR rate of immunosuppressive therapy in our studies was 68.29% and 12.20%, respectively. Patients with EPO level >400 U/L and Fer level >200 ng/ml had significantly lower CR rate than others. The patients with EPO level >400 U/L also had longer hemoglobin recovery time than patients with EPO level <=400 U/L. Patients treated with corticosteroids (CS) + cyclosporine A (CsA) had lower relapse rate compared to the CS group (29.17% vs. 80.00%, P < .05). CONCLUSION: Our data showed that patients with PRCA had high EPO and Fer levels. Thymoma and viral infections are the most common causes for secondary PRCA. The CS+ CsA group had lower relapse rate than CS group although response rate was similar. Increased EPO and Fer levels might be the negative factors for prognosis of acquired PRCA. PMID- 29754582 TI - Altered lung biology of healthy never smokers following acute inhalation of E cigarettes. AB - BACKGROUND: Little is known about health risks associated with electronic cigarette (EC) use although EC are rising in popularity and have been advocated as a means to quit smoking cigarettes. METHODS: Ten never-smokers, without exposure history to tobacco products or EC, were assessed at baseline with questionnaire, chest X-ray, lung function, plasma levels of endothelial microparticles (EMP), and bronchoscopy to obtain small airway epithelium (SAE) and alveolar macrophages (AM). One week later, subjects inhaled 10 puffs of "Blu" brand EC, waited 30 min, then another 10 puff; n = 7 were randomized to EC with nicotine and n = 3 to EC without nicotine to assess biological responses in healthy, naive individuals. RESULTS: Two hr. post-EC exposure, subjects were again assessed as at baseline. No significant changes in clinical parameters were observed. Biological changes were observed compared to baseline, including altered transcriptomes of SAE and AM for all subjects and elevated plasma EMP levels following inhalation of EC with nicotine. CONCLUSIONS: This study provides in vivo human data demonstrating that acute inhalation of EC aerosols dysregulates normal human lung homeostasis in a limited cohort of healthy naive individuals. These observations have implications to new EC users, nonsmokers exposed to secondhand EC aerosols and cigarette smokers using EC to quit smoking. TRIAL REGISTRATION: ClinicalTrials.gov NCT01776398 (registered 10/12/12), NCT02188511 (registered 7/2/14). PMID- 29754583 TI - Validity evidence for the Hamburg multiple mini-interview. AB - BACKGROUND: Multiple mini-interviews (MMI) become increasingly popular for the selection of medical students. In this work, we examine the validity evidence for the Hamburg MMI. METHODS: We conducted three follow-up studies for the 2014 cohort of applicants to medical school over the course of two years. We calculated Spearman's rank correlation (rho) between MMI results and (1) emotional intelligence measured by the Trait Emotional Intelligence Questionnaire (TEIQue-SF) and the Situational Test of Emotion Management (STEM), (2) supervisors' and practice team members' evaluations of psychosocial competencies and suitability for the medical profession after a one-week 1:1 teaching in a general practice (GP) and (3) objective structured clinical examination (OSCE) scores. RESULTS: There were no significant correlations between MMI results and the TEIQue-SF (rho = .07, p > .05) or the STEM (rho = .05, p > .05). MMI results could significantly predict GP evaluations of psychosocial competencies (rho = .32, p < .05) and suitability for the medical profession (rho = .42, p < .01) as well as OSCE scores (rho = .23, p < .05). The MMI remained a significant predictor of these outcomes in a robust regression model including gender and age as control variables. CONCLUSIONS: Our findings suggest that MMIs can measure competencies that are relevant in a practical context. However, these competencies do not seem to be related to emotional intelligence as measured by self-report or situational judgement test. PMID- 29754584 TI - Analysing the role of complexity in explaining the fortunes of technology programmes: empirical application of the NASSS framework. AB - BACKGROUND: Failures and partial successes are common in technology-supported innovation programmes in health and social care. Complexity theory can help explain why. Phenomena may be simple (straightforward, predictable, few components), complicated (multiple interacting components or issues) or complex (dynamic, unpredictable, not easily disaggregated into constituent components). The recently published NASSS framework applies this taxonomy to explain Non adoption or Abandonment of technology by individuals and difficulties achieving Scale-up, Spread and Sustainability. This paper reports the first empirical application of the NASSS framework. METHODS: Six technology-supported programmes were studied using ethnography and action research for up to 3 years across 20 health and care organisations and 10 national-level bodies. They comprised video outpatient consultations, GPS tracking technology for cognitive impairment, pendant alarm services, remote biomarker monitoring for heart failure, care organising software and integrated case management via data warehousing. Data were collected at three levels: micro (individual technology users), meso (organisational processes and systems) and macro (national policy and wider context). Data analysis and synthesis were guided by socio-technical theories and organised around the seven NASSS domains: (1) the condition or illness, (2) the technology, (3) the value proposition, (4) the adopter system (professional staff, patients and lay carers), (5) the organisation(s), (6) the wider (institutional and societal) system and (7) interaction and mutual adaptation among all these domains over time. RESULTS: The study generated more than 400 h of ethnographic observation, 165 semi-structured interviews and 200 documents. The six case studies raised multiple challenges across all seven domains. Complexity was a common feature of all programmes. In particular, individuals' health and care needs were often complex and hence unpredictable and 'off algorithm'. Programmes in which multiple domains were complicated proved difficult, slow and expensive to implement. Those in which multiple domains were complex did not become mainstreamed (or, if mainstreamed, did not deliver key intended outputs). CONCLUSION: The NASSS framework helped explain the successes, failures and changing fortunes of this diverse sample of technology-supported programmes. Since failure is often linked to complexity across multiple NASSS domains, further research should systematically address ways to reduce complexity and/or manage programme implementation to take account of it. PMID- 29754585 TI - Significance and implications of FDA approval of pembrolizumab for biomarker defined disease. AB - The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval. PMID- 29754587 TI - Impact of calorie labelling in worksite cafeterias: a stepped wedge randomised controlled pilot trial. AB - BACKGROUND: For working adults, about one-third of energy is consumed in the workplace making this an important context in which to reduce energy intake to tackle obesity. The aims of the current study were first, to identify barriers to the feasibility and acceptability of implementing calorie labelling in preparation for a larger trial, and second, to estimate the potential impact of calorie labelling on energy purchased in worksite cafeterias. METHODS: Six worksite cafeterias were randomised to the intervention starting at one of six fortnightly periods, using a stepped wedge design. The trial was conducted between August and December 2016, across 17 study weeks. The intervention comprised labelling all cafeteria products for which such information was available with their calorie content (e.g. "250 Calories") displayed in the same font style and size as for price. A post-intervention survey with cafeteria patrons and interviews with managers and caterers were used to assess the feasibility and acceptability of the intervention. Intervention impact was assessed using generalised linear mixed modelling. The primary outcome was the total energy (kcal) purchased from intervention items in each cafeteria each day. RESULTS: Recruitment and retention of worksite cafeterias proved feasible, with post-intervention feedback suggesting high levels of intervention acceptability. Several barriers to intervention implementation were identified, including chefs' discretion at implementing recipes and the manual recording of sales data. There was no overall effect of the intervention: -0.4% (95%CI -3.8 to 2.9, p = .803). One site showed a statistically significant effect of the intervention, with an estimated 6.6% reduction (95%CI -12.9 to - 0.3, p = .044) in energy purchased in the day following the introduction of calorie labelling, an effect that diminished over time. The remaining five sites did not show robust changes in energy purchased when calorie labelling was introduced. CONCLUSIONS: A calorie labelling intervention was acceptable to both cafeteria operators and customers. The predicted effect of labelling to reduce energy purchased was only evident at one out of six sites studied. Before progressing to a full trial, the calorie labelling intervention needs to be optimised, and a number of operational issues resolved. TRIAL REGISTRATION: ISRCTN52923504 ; Registered: 22/09/2016; retrospectively registered. PMID- 29754586 TI - Do avian blood parasites influence hypoxia physiology in a high elevation environment? AB - BACKGROUND: Montane birds which engage in elevational movements have evolved to cope with fluctuations in environmental hypoxia, through changes in physiological parameters associated with blood oxygen-carrying capacity such as haemoglobin concentration (Hb) and haematocrit (Hct). In particular, elevational migrants which winter at low elevations, encounter varying intensities of avian haemosporidian parasites as they traverse heterogeneous environments. Whilst high intensity parasite infections lead to anaemia, one can expect that the ability to cope with haemosporidian infections should be a key trait for elevational migrants that must be balanced against reducing the oxygen-carrying capacity of blood in response to high elevation. In this study, we explored the links between environmental hypoxia, migration, and disease ecology by examining natural variation in infections status and intensity of avian haemoporidians across a suite of Himalayan birds with different migratory strategies while controlling for host phylogeny. RESULTS: We found predictably large variation in haemoglobin levels across the elevational gradient and this pattern was strongly influenced by season and whether birds are elevational migrants. The overall malaria infection intensity declined with elevation whereas Hb and Hct decreased with increase in parasite intensity, suggesting an important role of malaria parasites on hypoxia stressed birds in high elevation environments. CONCLUSIONS: Our results provide a key insight into how physiological measures and sub-clinical infections might affect dynamics of high-elevation bird populations. We suggest a potential impact of avian elevational migration on disease dynamics and exposure to high intensity infections with disease spread in the face of climate change, which will exacerbate hypoxic stress and negative effects of chronic avian malaria infection on survival and reproductive success in wild birds. Future work on chronic parasite infections must consider parasite intensity, rather than relying on infection status alone. PMID- 29754588 TI - Evaluating seroprevalence to circumsporozoite protein to estimate exposure to three species of Plasmodium in the Brazilian Amazon. AB - BACKGROUND: Brazil has seen a great decline in malaria and the country is moving towards elimination. However, for eventual elimination, the control program needs efficient tools in order to monitor malaria exposure and transmission. In this study, we aimed to evaluate whether seroprevalence to the circumsporozoite protein (CSP) is a good tool for monitoring the exposure to and/or evaluating the burden and distribution of Plasmodium species in the Brazilian Amazon. METHODS: Cross-sectional surveys were conducted in a rural area of Porto Velho, Rondonia state. Parasite infection was detected by microscopy and polymerase chain reaction. Antibodies to the sporozoite CSP repeats of Plasmodium vivax, P. falciparum, and P. malariae (PvCS, PfCS, and PmCS) were detected using the enzyme linked immunosorbent assay technique. Human leukocyte antigen (HLA)-DRB1 and DQB1 genes were typed using Luminex(r) xMAP(r) technology. RESULTS: The prevalence of immunoglobulin G against P. vivax CSP peptide (62%) was higher than P. falciparum (49%) and P. malariae (46%) CSP peptide. Most of the studied individuals had antibodies to at least one of the three peptides (72%), 34% had antibodies to all three peptides and 28% were non-responders. Although the majority of the population was not infected at the time of the survey, 74.3% of parasite-negative individuals had antibodies to at least one of the CSPs. Importantly, among individuals carrying the haplotypes DRB1*04~DQB1*03, there was a significantly higher frequency of PfCS responders, and DRB1*16~DQB1*03 haplotype for PvCS and PfCS responders. In contrast, HLA-DRB1*01 and HLA-DQB1*05 allelic groups were associated with a lack of antibodies to P. vivax and P. falciparum CSP repeats, and the haplotype DRB1*01~DQB1*05 was also associated with non-responders, including non-responders to P. malariae. CONCLUSIONS: Our results show that in low transmission settings, naturally acquired antibody responses against the CSP repeats of P. vivax, P. falciparum, and P. malariae in a single cross-sectional study may not represent a valuable marker for monitoring recent malaria exposure, especially in an area with a high prevalence of P. vivax. Furthermore, HLA class II molecules play an important role in antibody response and require further study with a larger sample size. It will be of interest to consider HLA analysis when using serosurveillance to monitor malaria exposure among genetically diverse populations. PMID- 29754589 TI - Orbital T-cell lymphoma in youngest recorded patient - early diagnosis, management, and successful outcome: a case report and review of the literature. AB - BACKGROUND: Primary orbital peripheral T-cell lymphoma, not otherwise specified is an exceedingly rare disorder with a very poor outcome, and to the best of our knowledge only a few cases have been reported in the English literature. We present the youngest reported case describing the successful outcome after management with a thorough review of the English literature of all the reported cases of primary peripheral T-cell lymphoma, not otherwise specified. CASE PRESENTATION: Our patient is a 3-year-old Syrian boy who presented with gradual progressive orbital swelling. A physical examination showed a left orbital dystopia and a superior medial displacement of the globe. Extraocular motility was limited in upward elevation of his left eye. A computed tomography scan and magnetic resonance imaging of his orbit showed a mass involving the lateral and inferior walls of his left orbit and extending intraconally. A diagnosis of peripheral T-cell lymphoma, not otherwise specified was made by careful histopathological examination and Berlin-Frankfurt-Munster protocol was initiated. A 6-month follow up with orbital magnetic resonance imaging showed no sign of orbital or brain involvement. CONCLUSIONS: Through this report we emphasize two takeaway lessons: (1) always have a high level of suspicion of this entity regardless of the age of the patient; and (2) careful histopathological examination is very important for prompt confirmation of the diagnosis and early commencement of proper treatment. PMID- 29754590 TI - Cerebral amyloid angiopathy mimicking central nervous system metastases: a case report. AB - BACKGROUND: This case describes an unusual presentation of an intracranial hemorrhage first thought to be metastatic disease on computed tomography and magnetic resonance imaging. The healthcare team completed an exhaustive search for a primary malignancy that was negative. Final diagnosis on brain biopsy showed intercranial hemorrhage secondary to cerebral amyloid angiopathy. With an increasing number of elderly patients and the rising cost of health care, this case can serve as a reminder to clinicians about their own responsibilities in limiting the cost of health care. CASE PRESENTATION: This is a case report about a 72-year-old white woman with an intracranial hemorrhage secondary to cerebral amyloid angiopathy. The brain lesions on computed tomography/magnetic resonance imaging mimicked a metastatic process until a brain biopsy could give a definitive diagnosis that was completely unexpected. Cerebral amyloid angiopathy is a rare cause of intracerebral hemorrhage and this diagnosis is important to consider in older patients on anticoagulation. CONCLUSIONS: Cerebral amyloid angiopathy is a rare diagnosis but should be considered in elderly patients on anticoagulation presenting with imaging findings consistent with intracerebral hemorrhage. While metastatic disease is a more common cause of intracerebral hemorrhage, cerebral amyloid angiopathy should remain in the differential diagnosis. This case report serves as a teaching point to clinicians in cases involving an older patient on anticoagulation. PMID- 29754591 TI - Clinical implications of the proposed ICD-11 PTSD diagnostic criteria. AB - BACKGROUND: Projected changes to post-traumatic stress disorder (PTSD) diagnostic criteria in the upcoming International Classification of Diseases (ICD)-11 may affect the prevalence and severity of identified cases. This study examined differences in rates, severity, and overlap of diagnoses using ICD-10 and ICD-11 PTSD diagnostic criteria during consecutive assessments of recent survivors of traumatic events. METHODS: The study sample comprised 3863 survivors of traumatic events, evaluated in 11 longitudinal studies of PTSD. ICD-10 and ICD-11 diagnostic rules were applied to the Clinician-Administered PTSD Scale (CAPS) to derive ICD-10 and ICD-11 diagnoses at different time intervals between trauma occurrence and 15 months. RESULTS: The ICD-11 criteria identified fewer cases than the ICD-10 across assessment intervals (range -47.09% to -57.14%). Over 97% of ICD-11 PTSD cases met concurrent ICD-10 PTSD criteria. PTSD symptom severity of individuals identified by the ICD-11 criteria (CAPS total scores) was 31.38 36.49% higher than those identified by ICD-10 criteria alone. The latter, however, had CAPS scores indicative of moderate PTSD. ICD-11 was associated with similar or higher rates of comorbid mood and anxiety disorders. Individuals identified by either ICD-10 or ICD-11 shortly after traumatic events had similar longitudinal course. CONCLUSIONS: This study indicates that significantly fewer individuals would be diagnosed with PTSD using the proposed ICD-11 criteria. Though ICD-11 criteria identify more severe cases, those meeting ICD-10 but not ICD-11 criteria remain in the moderate range of PTSD symptoms. Use of ICD-11 criteria will have critical implications for case identification in clinical practice, national reporting, and research. PMID- 29754592 TI - General practitioners' views on the influence of cost on the prescribing of asthma preventer medicines: a qualitative study. AB - Objective Out-of-pocket costs strongly affect patient adherence with medicines. For asthma, guidelines recommend that most patients should be prescribed regular low-dose inhaled corticosteroids (ICS) alone, but in Australia most are prescribed combination ICS-long-acting beta2-agonists (LABA), which cost more to patients and government. The present qualitative study among general practitioners (GPs) explored the acceptability, and likely effect on prescribing, of lower patient copayments for ICS alone.Methods Semistructured telephone interviews were conducted with 15 GPs from the greater Sydney area; the interviews were transcribed and thematically analysed.Results GPs reported that their main criteria for selecting medicines were appropriateness and effectiveness. They did not usually discuss costs with patients, had low awareness of out-of-pocket costs and considered that these were seldom prohibitive for asthma patients. GPs strongly believed that patient care should not be compromised to reduce cost to government. They favoured ICS-LABA combinations over ICS alone because they perceived that ICS-LABA combinations enhanced adherence and reduced costs for patients. GPs did not consider that lower patient copayments for ICS alone would affect their prescribing.Conclusion The results suggest that financial incentives, such as lower patient copayments, would be unlikely to encourage GPs to preferentially prescribe ICS alone, unless accompanied by other strategies, including evidence for clinical effectiveness. GPs should be encouraged to discuss cost barriers to treatment with patients when considering treatment choices.What is known about the topic? Australian guidelines recommend that most patients with asthma should be treated with low dose ICS alone to minimise symptom burden and risk of flare ups. However, most patients in Australian general practice are instead prescribed combination ICS LABA preventers, which are indicated if asthma remains uncontrolled despite treatment with ICS alone. It is not known whether GPs are aware that the combination preventers have a higher patient copayment and a higher cost to government.What does this paper add? This qualitative study found that GPs favoured combination ICS-LABA inhalers over ICS alone because they perceived ICS LABA combinations to have greater effectiveness and promote patient adherence. This aligned with GPs' views that their primary responsibility was patient care rather than generating cost savings for government. However, it emerged that GPs rarely discussed medicine costs with patients, had low knowledge of medicine costs to patients and the health system and reported that patients rarely volunteered cost concerns. GPs believed that lower patient copayments for asthma preventer medicines would have little effect on their prescribing practices.What are the implications for practitioners? This study suggests that, when considering asthma treatment choices, GPs should empathically explore with the patient whether cost-related medication underuse is an issue, and should be aware of the option of lower out-of-pocket costs with guideline-recommended ICS alone treatment. Policy makers must be aware that differential patient copayments for ICS preventer medicines are unlikely to act as an incentive for GPs to preferentially prescribe ICS alone preventers, unless the position of these preventers in guidelines and evidence for their clinical effectiveness are also reiterated. PMID- 29754593 TI - Comparison of health literacy in privately insured and public hospital orthopaedic patients. AB - Objective The aim of the present study was to quantify and compare patient health literacy between privately insured and public orthopaedic patients.Methods As part of the present cross-sectional study, elective postoperative orthopaedic patients across two sites were recruited and asked to complete a questionnaire at the first postoperative out-patient review. Patients were divided into three groups: (1) a public group (Public); (2) a private group (Private-pre); and (3) a private group that completed the questionnaire immediately after the out-patient review (Private-post). The questionnaire consisted of six questions regarding surgical management, expected recovery time and postoperative instructions. Patients were further asked to grade their satisfaction regarding information received throughout their management.Results In all, 150 patients completed the questionnaire, 50 in each of the three groups. Patients in the Public, Private pre and Private-post groups answered a mean 2.74, 3.24 and 4.70 of 6 questions correctly respectively. The Private-pre group was 1.46-fold more likely to demonstrate correct health literacy than the Public group, whereas the Private post group was 2.44-fold more likely to demonstrate improved health literacy than the Private-pre group. Patient satisfaction with information received was not associated with health literacy.Conclusion Limited health literacy in orthopaedic patients continues to be an area of concern. Both private and public orthopaedic patients demonstrated poor health literacy, but private patients demonstrated significant improvement after the out-patient review.What is known about the topic? Limited health literacy is a growing public health issue worldwide, with previous literature demonstrating a prevalence of low health literacy of 26% and marginal health literacy of 20% among all patient populations. Of concern, limited health literacy has been shown to result in a range of adverse health outcomes, including increased mortality and chronic disease morbidity. It has also been associated with an increased rate of hospitalisation and use of healthcare resources. Previous work in the orthopaedic trauma setting has found poor levels of health literacy and poor understanding of diagnosis, management and prognosis in the Australian public health system. Promisingly, it has been shown that simple, targeted interventions can improve patient health literacy.What does this paper add? This study further highlights that health literacy exhibited by orthopaedic patients is poor, particularly among patients in the public healthcare system. The present study is the first to have demonstrated that health literacy is poor among patients in both the public and private healthcare systems, despite these patients having distinctly different demographics. Promisingly, the present study shows that, unlike public orthopaedic out-patient review, private orthopaedic out-patient review appears to be effective in increasing patient health literacy regarding their orthopaedic condition and its management.What are the implications for practitioners? Health literacy is essential for patients to effectively communicate with doctors and achieve good health outcomes. Healthcare professionals need to be aware that a large proportion of patients have poor health literacy and difficulty understanding health-related information, particularly pertaining to that surrounding diagnosis, management and prognosis. This study highlights the need for healthcare professionals to ensure that they communicate with patients at an appropriate level to ensure patient understanding during the pre-, peri- and postoperative stages of management. Further, healthcare professionals should be aware that there is potential to improve patient health literacy at routine out patient review, provided that this opportunity is used as an educational resource. PMID- 29754594 TI - Review of medication errors that are new or likely to occur more frequently with electronic medication management systems. AB - Objective. The aim of the present study was to identify and quantify medication errors reportedly related to electronic medication management systems (eMMS) and those considered likely to occur more frequently with eMMS. This included developing a new classification system relevant to eMMS errors.Methods. Eight Victorian hospitals with eMMS participated in a retrospective audit of reported medication incidents from their incident reporting databases between May and July 2014. Site-appointed project officers submitted deidentified incidents they deemed new or likely to occur more frequently due to eMMS, together with the Incident Severity Rating (ISR). The authors reviewed and classified incidents.Results. There were 5826 medication-related incidents reported. In total, 93 (47 prescribing errors, 46 administration errors) were identified as new or potentially related to eMMS. Only one ISR2 (moderate) and no ISR1 (severe or death) errors were reported, so harm to patients in this 3-month period was minimal. The most commonly reported error types were 'human factors' and 'unfamiliarity or training' (70%) and 'cross-encounter or hybrid system errors' (22%).Conclusions. Although the results suggest that the errors reported were of low severity, organisations must remain vigilant to the risk of new errors and avoid the assumption that eMMS is the panacea to all medication error issues.What is known about the topic? eMMS have been shown to reduce some types of medication errors, but it has been reported that some new medication errors have been identified and some are likely to occur more frequently with eMMS. There are few published Australian studies that have reported on medication error types that are likely to occur more frequently with eMMS in more than one organisation and that include administration and prescribing errors.What does this paper add? This paper includes a new simple classification system for eMMS that is useful and outlines the most commonly reported incident types and can inform organisations and vendors on possible eMMS improvements. The paper suggests a new classification system for eMMS medication errors.What are the implications for practitioners? The results of the present study will highlight to organisations the need for ongoing review of system design, refinement of workflow issues, staff education and training and reporting and monitoring of errors. PMID- 29754596 TI - Sharing solutions for a reasoned and evidence-based response: chemsex/party and play among gay and bisexual men. AB - This Special Issue of Sexual Health examines research and healthcare practice relating to sexualised drug use among gay, bisexual and other men who have sex with men (GBMSM), colloquially known as 'chemsex' or 'party and play' (PnP). It draws together evidence relating to the epidemiology, sociology and psychology of chemsex, as well as the policy, community and clinical interventions that are required to ensure men have access to high-quality health care that meets their needs and reduces harm. Findings and discussions within the Issue emphasise the need to sensitively, non-judgementally and meaningfully engage with gay men about their engagement in chemsex in order to help improve their sexual health and wider wellbeing. PMID- 29754597 TI - Re-Wired: treatment and peer support for men who have sex with men who use methamphetamine. AB - : Background This paper examines a methamphetamine treatment and peer support program for gay men and other men who have sex with men (MSM) who use methamphetamine. Australian MSM use illicit drugs including methamphetamine at significantly higher rates than the broader community.1,2 Methamphetamine rates are higher again amongst HIV positive MSM. Methamphetamine in the MSM community is associated with sexual activity and may be associated with psychosocial harms including risk of the transmission of HIV and sexually transmissible infections.3,4,7,8 Methods: This paper presents the formal evaluation of Re Wired, Australia's first structured methamphetamine treatment and support program for MSM, consisting of a free, six week therapeutic group and Re-Wired 2.0, a follow up peer support group. Data collection included baseline and post intervention administration of the Kessler Scale of Psychological Distress (K10) and the Drug Use Disorders Identification Test (DUDIT), the Personal Wellbeing Index (PWI) and the Readiness to Change Questionnaire (RCQ). This was complemented with qualitative session feedback and a small number of post intervention participant interviews. RESULTS: Program evaluation demonstrated modest improvements in participant psychological distress, personal well-being and stage of change and reductions in methamphetamine use post intervention. Qualitative data revealed benefits of a specialised harm reduction intervention for this population through addressing fear of discrimination and stigma. CONCLUSIONS: The presented harm reduction program for MSM who use methamphetamine demonstrates the potential for a specialist peer-based approach to reduce harm in this vulnerable population. This approach may be suitable for adaptation with MSM populations in similar high-income settings. PMID- 29754599 TI - Recent advances in assessing xenobiotics migrating from packaging material - A review. AB - Migration of potentially toxic xenobiotics and their transformation products from packaging materials needs continuous monitoring efforts. This task requires utilizing both instrumental and biological methods as more and more novel materials reach market every year to serve consumers and reduce production costs. Unfortunately, these materials very often sneak past our legal regulations on their composition and emission of contaminants due to contact with the materials or products stored. For these reasons, more and more novel, holistic and multi tier approaches must be elaborated to uncompromisingly assure safety of these materials to living creatures. In the work presented, a review of methods enabling performing studies on extraction, leaching, qualitative and quantitative determination of xenobiotics and their combined effect on certain biological endpoints is given. Additionally, a basic approach guiding end-users and scientists to elaborate such studies is presented in the form of a basic scheme, and advantages and disadvantages of these methods are summarized. PMID- 29754600 TI - A highly selective colorimetric and ratiometric fluorescent probe for instantaneous sensing of Hg2+ in water, soil and seafood and its application on test strips. AB - A new simple and efficient oligothiophene-based colorimetric and ratiometric fluorescent probe has been developed for highly sensitive and fast detection of Hg2+ in water, soil and seafood. The probe 5-(1,3-dithiolan-2-yl)-2,2':5',2" terthiophene 3 TS can selectively detect Hg2+ via the Hg2+-promoted deprotection reaction of thioacetals, which caused a remarkable color change from colorless to yellow and a strong fluorescence enhancement with emission color varying from blue to yellow, enabling naked-eye detection of Hg2+. The probe shows high sensitivity with the detection limit down to 1.03 * 10-8 M. Visual color changes of 3 TS were observed on filter paper and TLC testing strips when they were impregnated on testing strips and immersed in Hg2+ solution. Moreover, the probe 3 TS has been successfully used to rapidly detect trace amounts of hazardous Hg2+ ions in tap, distilled, river and lake water, cropland soil, fish, shrimp and kelp samples with acceptable results and good recoveries. PMID- 29754601 TI - Preparation of carbon quantum dots from cigarette filters and its application for fluorescence detection of Sudan I. AB - Carbon quantum dots (CQDs) with quantum yield of 14% were successfully synthesized via a simple, low-cost, and green hydrothermal treatment using cigarette filters as carbon source for the first time. The obtained CQDs showed a strong emission at the wavelength of 465 nm, with an optimum excitation of 365 nm.Sudan I with maximum absorption wavelength at 477 nm could selectively quench the fluorescence of CQDs. Based on this principle, a fluorescence probe was developed for Sudan I determination. Furthermore, the quenching mechanism of the CQDs was elucidated. A linear relationship was found in the range of 2.40-104.0 MUmol/L Sudan I with the detection limit (3sigma/k) of 0.95 MUmol/L. Satisfactory results were achieved when the method was submitted to the determination of Sudan I in food samples. PMID- 29754602 TI - Retracted: Imprinted ZnO nanostructure-based electrochemical sensing of calcitonin: A clinical marker for medullary thyroid carcinoma. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor following concerns raised by various readers. The article reports different electron micrographs for different sample preparations, but some images are of different areas from the same sample. Figure 4E is a magnified section of Figure 4C, and the images are identical as demonstrated by overlapping the images and adjusting for magnification scale. The article reports EDX spectra in Figure 5C and Figure 5D for samples that are reported as different. An overlay of the spectra indicate they are identical in magnitude and in the random fluctuations of noise except in the specific zones where the signal was expected to vary. These problems with the data presented cast doubt on all the data, and accordingly also the conclusions based on that data, in this publication. As such this article represents a severe abuse of the scientific publishing system. The scientific community takes a very strong view on this matter and apologies are offered to readers of the journal that this was not detected during the submission process. PMID- 29754603 TI - Highly sensitive impedimetric biosensor for Hg2+ detection based on manganese porphyrin-decorated DNA network for precipitation polymerization. AB - In this work, a highly sensitive impedimetric biosensor was developed for mercuric ion (Hg2+) detection. The biosensor design was based on Hg2+-triggered exonuclease III (Exo III) cleavage for target recycling and DNAzyme-mediated catalytic for precipitation polymerization. Hg2+ induced thymine-thymine (T-T) mismatches were used to trigger the Exo III-catalyzed target recycling and produce free single-stranded DNA (defined as M). The outputted M then assisted the in formation of a DNA network on electrode surface to efficiently immobilize the porphyrin manganese (MnTmPyP). The formed MnTMPyP-double-stranded DNA (MnTmPyP-dsDNA) complex exhibited peroxidase-like activity capable of catalyzing a 3,3-diaminobenzidine (DAB) oxidation reaction, which produced an insoluble precipitate on the electrode surface. This reaction significantly enhanced the resistance signal for the quantitative determination of Hg2+. Under optimal conditions, the impedimetric biosensor exhibited a wide dynamic working range of 0.005 nM-100 nM with a detection limit of 1.47 pM. This platform also demonstrated good reproducibility and selectivity, offering a promising avenue for the detection of other molecules. PMID- 29754605 TI - Development and application of vortex-assisted membrane extraction based on metal organic framework mixed-matrix membrane for the analysis of estrogens in human urine. AB - A vortex-assisted membrane extraction (VA-ME) method based on several metal organic framework mixed-matrix membranes (MOF-MMMs) was firstly developed and applied for the analysis of four estrogens in human urine. The MOF-MMMs, with high MOF loading (~67 wt%), were prepared using a facile approach by embedding the MOFs in a polyvinylidene difluoride matrix. The method was suitable for a wide variety of MOF materials, and the incorporated MOFs retained their unique properties. Being model analytes, the estrogens became adsorbed on the MOFs in the vortex-stirred sample solutions and were subsequently desorbed in methanol and analyzed using high-performance liquid chromatography with fluorescence detection. The performance and durability of MIL-53(Al)-MMM was particularly noteworthy and was therefore selected to extract estrone, 17beta-estradiol, estriol, and ethinylestradiol from the urine of children and postmenopausal women. Various extraction conditions were optimized, and the analytical method showed good linearity in the range of 0.02-200 ng mL-1, recoveries ranging from 80.4% to 102.7% (RSD<=11.4%), and low limits of detection (0.005-1 ng mL-1). VA ME is a simple, accurate, and cost-effective pretreatment method, and its advantages such as good adsorption performance, simple operation, and straightforward removal and separation from solution highlight its broad utility for aqueous sample pretreatment. PMID- 29754604 TI - Electrochemiluminescence immunoassay based on site-specific labeling using a histidine-binding iridium(III) solvento complex. AB - Histidine bound bis-cyclometalated iridium (III) complexes were found to be luminescent in previous studies. This work demonstrates that the luminophores could be excited electrochemically and the electrogenerated chemiluminescence was observed in both homogeneous solutions and on the surface of magnetic beads. The findings laid a foundation for novel ECL immunoassay methodology featuring site specific labeling of antibodies and on-site formation of signal-generating units. Taking use of the findings and the unique advantages of the site-specific labeling approach, a sandwich immunoassay for a clinically important biomarker was conceptually proved. The limit of detection of <1 ng/mL procalcitonin in human plasma could be achieved from the unoptimized assay. PMID- 29754606 TI - A comparison study of nanofiber, microfiber, and new composite nano/microfiber polymers used as sorbents for on-line solid phase extraction in chromatography system. AB - Three different approaches has been used to obtain nano/micro fibers and their diversity and extraction properties were examined. The effect of their structure on stability in an ultra-high-performance liquid chromatography (UHPLC) system during on-line SPE procedure was monitored. Five types of various nano/micro fiber polymers were used as sorbents: polyamide 6 nanofibers, polyvinylidene difluoride nanofibers, polyethylene microfibers, and two new polycaprolactone microfiber/nanofiber and polycaprolactone microfibers/polyvinylidene difluoride nanofibers composite polymers. The fiber polymers were filled in a cartridge directly connected to the UHPLC system and tested. For each polymer, the optimal conditions of the on-line extraction were found and potential applicability on real samples was tested. The determination of ochratoxin A (OTA) in beer matrix was chosen as a case study. Relevant factors such as the mechanical and chemical stability of the nano/microfibers, filling the cartridges, fiber reusability and the possibility and the repeatability of all processes were involved in the proposed study. A new nano/micro composite sorbent consisting of polycaprolactone microfibers/polyvinylidene difluoride nanofibers was chosen as the most suitable sorbent for the on-line extraction of OTA from a beer matrix. The tested validation parameters had the value of intra-day precision lower than 1.48%, linearity in the range from 0.5 to 100 MUg L-1 with r2 >= 0.9999 for standard and matrix calibration curve, and recovery in the range 99.1-103.9% at five concentration levels. Long-term precision evaluated for 31 analyses over the period of three months did not exceed 2.9% RSD. It confirmed the column reusability and perfect stability of nano/micro composite sorbent in the presence of organic solvents and after repeated injection of a complex beer matrix. PMID- 29754607 TI - Exploring the potential of needle trap microextraction combined with chromatographic and statistical data to discriminate different types of cancer based on urinary volatomic biosignature. AB - The worldwide high cancer incidence and mortality demands for more effective and specific diagnostic strategies. In this study, we evaluated the efficiency of an innovative methodology, Needle Trap Microextraction (NTME), combined with gas chromatography-mass spectrometry (GC-MS), for the establishment of the urinary volatomic biosignature from breast (BC), and colon (CC) cancer patients as well as healthy individuals (CTL). To achieve this, 40 mL of the headspace of acidified urine (4 mL, 20% NaCl, pH = 2), equilibrated at 50 degrees C during 40 min, were loaded through the DVB/Car1000/CarX sorbent inside the NTD, and subjected to a GC-MS analysis. This allowed the identification of 130 VOMs from different chemical families that were further processed using discriminant analysis through the partial least squares method (PLS-DA). Several pathways are over activated in cancer patients, being phenylalanine pathway in BC and limonene and pinene degradation pathway in CC the most relevant. Butanoate metabolism is also highly activated in both cancers, as well as tyrosine metabolism in a lesser extension. In BC the xenobiotics metabolism by cytochrome P450 and fatty acid biosynthesis are also differentially activated. Different clusters corresponding to the groups recruited allowed to define sets of volatile organic metabolites (VOMs fingerprints) that exhibit high classification rates, sensitivity and specificity in the discrimination of the selected cancers. As far as we are aware, this is the first time that NTME is used for isolation urinary volatile metabolites, being the obtained results very promising. PMID- 29754608 TI - Multiplex polymerase chain reaction in combination with gel electrophoresis inductively coupled plasma mass spectrometry: A powerful tool for the determination of gene copy number variations and gene expression changes. AB - During the last few years multiplex real-time or quantitative polymerase chain reaction PCR (qPCR) has become the method of choice for multiplex gene expression changes and gene copy number variations (CNVs) analysis. However, such determinations require the use of different fluorescent labels for the different amplified sequences, which increases significantly the costs of the analysis and limits the applicability of the technique for simultaneous amplification of many targets of interest in a single reaction. In this regard, the use of the coupling between gel electrophoresis (GE) separation with inductively coupled plasma mass spectrometry (ICP-MS) detection allows the label-free determination of multiplex PCR-amplified sequences (amplicons) by monitoring the P present in the DNA backbone. The quantitative dimension is obtained since under optimal and controlled multiplex PCR conditions the peak areas of the separated amplicons are directly proportional to the amount of DNA template in the original sample. Moreover, the calibration of the GE-ICP-MS system with a DNA ladder permits direct estimation of the size (bp) of the PCR products. The suitability of the proposed multiplex strategy has been evaluated addressing two different situations: determination of CNVs and gene expression changes in human ovarian cancer cells. In the first case, the results obtained for the simultaneous quantitation of CNVs of four genes (HER2, CCNE1, GSTM1, ACTB) on DNA obtained from OVCAR-3 cells were in accordance with the literature data, and also with the results obtained by conventional simplex qPCR. In the second case, multiplex gene expression changes of BAX, ERCC1 and CTR1 genes, using ACTB as constitutive gene, on A2780cis respect to A2780 cells, resistant and sensitive to cisplatin, respectively, provided the same information as single reaction reverse transcription (RT)-qPCR. PMID- 29754609 TI - A rapid and sensitive method for the analysis of lignin phenols in environmental samples using ultra-high performance liquid chromatography-electrospray ionization-tandem mass spectrometry with multiple reaction monitoring. AB - A novel ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry method was developed to enable the analysis of ultra-low levels of lignin phenols (<100 fmol) in environmental samples. The method included a sample clean-up with a polymer sorbent based solid-phase extraction and reversed-phase chromatography that allowed separation of all lignin phenols with minimal interference from co-eluting matrix components. The application of 13C-labeled surrogate standards effectively compensated for variability associated with sample preparation and ion suppression. The method was fully validated and compared to gas chromatography-electron impact ionization-tandem mass spectrometry for Suwannee River humic acid standard reference material and extracted riverine dissolved organic matter. The comparison demonstrated the robustness and suitability of the method for ultra-low lignin phenol concentrations and high matrix interference. The simple and fast sample preparation coupled to analysis without derivatization makes it feasible for routine and high-volume analyses. PMID- 29754610 TI - Thread spray mass spectrometry for direct analysis of capsaicinoids in pepper products. AB - Thread spray ambient ionization uses single threads as a medium for sampling and ionization. This approach was demonstrated through the detection of various capsaicinoids from the interior of pepper fruits without destruction of the sample. Pepper residues present on the thread were analyzed by the application of DC voltage and solvent to cause field-induced charged droplet generation. Capsaicinoids extracted from the sample are contained in the electrosprayed droplets and transported to the mass spectrometer for characterization. The thread spray mass spectrometry method was optimized using commercially available materials like 100% cotton, cotton:polyester (35/65), 100% polyester, and nylon fabrics and subsequently applied for in-situ analysis of six different pepper fruits and pepper spray residues on fabrics. The results indicated that the special physico-chemical characteristics of threads allowed a rapid and convenient sampling and ionization of pepper products for analysis by mass spectrometry. The total capsaicinoid ion yields for the various pepper products correlated very well with that reported in Scoville Heat Units, suggesting that quantitative assessment of pungency levels may be achieved via the direct sample analysis without prior separation. PMID- 29754611 TI - Highly sensitive and visual detection of guanosine 3'-diphosphate-5' di(tri)phosphate (ppGpp) in bacteria based on copper ions-mediated 4 mercaptobenzoic acid modified gold nanoparticles. AB - Guanosine 3'-diphosphate-5'-di(tri)phosphate (ppGpp) plays a crucial role in the gene expression, metabolism, growth, and other significant processes of microorganisms. In this work, a facile sensitive and visual strategy for the detection of ppGpp has been established by developing a colorimetric probe of copper ions (Cu2+)-mediated 4-mercaptobenzoic acid (4-MBA) modified gold nanoparticles (AuNPs). The sensing process was characterized by transmission electron microscopy (TEM), zeta potential, dynamic light scattering (DLS) and UV vis spectroscopy. The strategy not only achieves desirable performance over a wide concentration range (0.05-10 MUM), but also exhibits excellent selectivity over other nucleotides and biomolecules. In addition, the results could be visualized by the naked eye. We have demonstrated the determination of ppGpp in Bacillus subtilis lysate samples. PMID- 29754613 TI - Epidemiology and Disparities in Care: The Impact of Socioeconomic Status, Gender, and Race on the Presentation, Management, and Outcomes of Patients Undergoing Ventral Hernia Repair. AB - More research is needed with regards to gender, race, and socioeconomic status on ventral hernia presentation, management, and outcomes. The role of culture and geography in hernia-related health care remains unknown. Currently existing nationwide registries have thus far yielded at best a modest overview of disparities in hernia care. The significant variation in care relative to gender, race, and socioeconomic status suggests that there is room for improvement in providing consistent care for patients with hernias. PMID- 29754612 TI - Development of extremely stable dual functionalized gold nanoparticles for effective colorimetric detection of clenbuterol and ractopamine in human urine samples. AB - New glutamic acid (Glu) and polyethylenimine (PE) functionalized ultra-stable gold nanoparticles (PE-Glu-AuNPs) were developed via a simple NaBH4 reduction method. The low toxicity and biocompatibility of PE-Glu-AuNPs were confirmed via an MTT assay in Raw 264.7 cells. Excitingly, PE-Glu-AuNPs were found to be extremely stable at room temperature up to six months and were utilized in an effective colorimetric naked eye assay of clenbuterol (CLB) and ractopamine (RCT) at pH 5. It was found that the selective assay of CLB and RCT is not affected by any other interferences (such as alanine, phenylalanine, NaCl, CaCl2, threonine, cysteine, glycine, glucose, urea and salbutamol). Furthermore, the detection of these beta-agonists can be visually accomplished through change color from wine red to purple blue. Notably, the aggregation induced detection of CLB and RCT was well confirmed through transmission electron microscopy (TEM) and dynamic light scattering (DLS) studies. DLS investigations, clearly showed, that in the presence of CLB and RCT, the initial size of PE-Glu-AuNPs (12.8 +/- 8.6 nm) was changed to 84.8 +/- 52.3 and 79.5 +/- 47.8 nm, respectively, via aggregation. Furthermore, the colorimetric assays of CLB and RCT with PE-Glu-AuNPs were effective starting from CLB and RCT concentrations of 200 nM and 400 nM, respectively, and could be visualized using the naked eyes. Remarkably, UV-vis titrations of PE-Glu-AuNPs with CLB and RCT could be used to well estimate their sub nanomolar detection limits (LODs) via standard deviation and linear fittings. The contribution of surface functional groups that support the analyte recognition was confirmed by fourier-transform infrared spectroscopy (FTIR) analysis. Moreover, the CLB and RCT assays with PE-Glu-AuNPs were supported by examination of human urine samples. PMID- 29754614 TI - Quality Measures in Hernia Surgery. AB - With growing pressures to formulate easily interpreted quality metrics, potential pitfalls exist that deleteriously affect the ultimate outcome of patients. This article defines what quality means in hernia surgery, how it is measured, who measures it, and how it is reported. Key governmental organizations responsible are highlighted. Although striving for high quality seems relatively straightforward, it is a challenge to account for all variables. Most definitions of quality are based on products and derived from minimum standards. This transition to basing it on health care delivery is ongoing, challenging, and incredibly important for the future of patients. PMID- 29754615 TI - Establishing a Hernia Program. AB - Hernia repair is one of the most common operations performed by surgeons; however, there is neither consistency in practice nor broadly accepted guidelines to advise best practices. Hernia Programs can help shape guidelines through voluntary participation, inclusion, continuous quality improvement, education, and research by all stakeholders involved in hernia surgery at the institution. Once established, a Hernia Program can improve the delivery of care and outcomes of hernia patients, leading to added value for the institution and health care system. PMID- 29754616 TI - Updates in Mesh and Biomaterials. AB - Prior publications of the Surgical Clinics of North America have highlighted the technical challenges of abdominal wall reconstruction. This article provides an update on synthetic, biologic, and biosynthetic mesh research since the 2013 Surgical Clinics of North America hernia publication and highlights the future of mesh research. This update features research that has been conducted since the prior publication to guide surgeons to choose the best and most appropriate mesh for their patients. PMID- 29754617 TI - Role of Prophylactic Mesh Placement for Laparotomy and Stoma Creation. AB - Incisional and parastomal hernias are a cause of significant morbidity and have a substantial effect on quality of life and economic costs for patients and hospital systems. Although many aspects of abdominal hernias are understood, prevention is a feature that is still being realized. This article reviews the current literature and determines the utility of prophylactic mesh placement in prevention of incisional and parastomal hernias. PMID- 29754618 TI - Preoperative Planning and Patient Optimization. AB - This article reviews the literature that supports routine expectations for smoking cessation; weight loss; diabetic, nutritional, or metabolic optimization; and decolonization techniques before ventral hernia repair. These methods diminish postoperative complications. In an era of value-centric care, an upfront investment in patient optimization can improve the quality of the repair by reducing wound morbidity and hernia recurrence, naturally translating to a reduction in cost. The adoption of these practices and further study aimed at identifying other effective optimization techniques are encouraged. PMID- 29754619 TI - Enhanced Recovery After Surgery Protocols: Rationale and Components. AB - Enhanced recovery after surgery (ERAS) protocols are spreading throughout various fields in surgery. ERAS protocols involve the implementation of evidence-based elements of care that are applied throughout the entire perioperative period to facilitate optimal recovery for the patient. ERAS protocols have been associated with improvements in quality of care, patient-reported and operative outcomes, and patient safety as well as reductions in cost. Thus, ERAS protocols have led to an overall improvement in health care value for the patient and the health care system. PMID- 29754620 TI - Incisional Hernia Repair: Open Retromuscular Approaches. AB - In this article, we discuss concepts, surgical techniques and published literature about the most common abdominal wall reconstructive techniques performed with retromuscular mesh placement through an open approach. PMID- 29754622 TI - Umbilical Hernia Repair: Overview of Approaches and Review of Literature. AB - Umbilical hernias are ubiquitous, and surgery is indicated in symptomatic patients. Umbilical hernia defects can range from small (<1 cm) to very large/complex hernias, and treatment options should be tailored to the clinical situation. Open, laparoscopic, and robotic options exist for repair, with each having its advantages and disadvantages. In general, mesh should be used for repair, because it has been shown to decrease recurrence rates, even in small hernias. Although outcomes are generally favorable after umbilical hernia repairs, some patients have chronic complaints that are mostly related to recurrences. PMID- 29754621 TI - Incisional Hernia Repair: Minimally Invasive Approaches. AB - A common surgical procedure, ventral hernia repair has long been a vexing problem, with no clear standard for repair and significant postoperative morbidity. Laparoscopic repair has the clear advantage of lower postoperative morbidity. However, application of laparoscopic ventral hernia repair is often limited by patient factors and hernia morphology. Long-term complications of intraperitoneal mesh and recurrence are concerning. Robotic-assisted surgery is the latest advance in minimally invasive hernia repair, combining the advantages of open repair with complete abdominal wall reconstruction and restoration of functional anatomy with the wound morbidity and decreased recovery time of laparoscopy. PMID- 29754623 TI - Surgical Management of Parastomal Hernias. AB - Parastomal hernias are a common complication after ostomy formation that can require surgical repair when they become symptomatic. Operative planning and a thorough understanding of the anatomy of the abdominal wall are important. Simple fascial repair is associated with an unacceptably high recurrence rate and should be used as a temporary measure only. Stoma relocation has a high recurrence rate. Prophylactic mesh can and should be used. At this time, the use of mesh is considered the standard of care in the repair of parastomal hernias. PMID- 29754624 TI - Flank and Lumbar Hernia Repair. AB - Flank and lumbar hernias are challenging because of their rarity and anatomic location. Several challenges exist when approaching these specific abdominal wall defects, including location, innervation of the lateral abdominal wall musculature, and their proximity to bony landmarks. These hernias are confined by the costal margin, spine, and pelvic brim, which makes closure of the defect, including mesh placement, difficult. This article discusses the anatomy of lumbar and flank hernias, the various etiologies for these hernias, and the procedural steps for open and robotic preperitoneal approaches. The available clinical evidence regarding outcomes for various repair techniques is also reviewed. PMID- 29754625 TI - Inguinal Hernia: Mastering the Anatomy. AB - The success of an inguinal hernia repair is defined by the permanence of the operation while creating the fewest complications at minimal cost and allowing patients an early return to activity. This success relies and depends on the surgeon's knowledge and understanding of groin anatomy and physiology. This article reviews relevant anatomy to inguinal hernia repair and technical steps to open tissue and mesh repairs as well as minimally invasive approaches. PMID- 29754626 TI - Inguinal Hernia: Four Open Approaches. AB - Open inguinal hernia approaches are varied. The best studied approaches are reviewed herein. The common factor among them is the imperative anatomy knowledge of the surgeon. This knowledge is key to improved outcomes. A tailored approach is best to determine which open technique, if any, is most appropriate for the patient. Although the anterior mesh approach is the most commonly applied, there is support in using the posterior approach or a tissue repair for subsets of patients, such as women. PMID- 29754627 TI - Minimally Invasive Approaches to Inguinal Hernias. AB - Both the transabdominal preperitoneal approach and the total extraperitoneal approach to inguinal hernias provide an effective means of repairing inguinal hernias. The robotic platform can be used and may help to decrease immediate postoperative pain; however, as this is a fairly new technique, more research will help further determine long-term outcomes. In all methods of fixation, we ensure adequate fixation medially with tacks placed on the Cooper ligament. Awareness of the nerves and vessels helps to guide dissection as well as prevent inadvertent injury during mesh fixation. PMID- 29754628 TI - Approach to the Patient with Chronic Groin Pain. AB - Chronic postoperative inguinal pain has become a primary outcome parameter after elective inguinal hernia repair with significant consequences affecting patient productivity, employment, and quality of life. A systematic and thorough preoperative evaluation is important to identify the etiologies and types of pain. Owing to the complex nature of chronic pain, a multimodal and multidisciplinary treatment approach is recommended. Patients with chronic pain refractory to conservative measures may be considered for surgical intervention. Triple neurectomy remains the most definitive and accepted remedial operation performed and provides effective relief in the majority of patients. PMID- 29754629 TI - Foreword. PMID- 29754630 TI - Preface. PMID- 29754631 TI - Diagnosis of Cushing's Syndrome in the Modern Era. AB - Four challenges complicate the evaluation for Cushing syndrome. These challenges include increasing global prevalence of obesity and diabetes; increasing use of exogenous glucocorticoids, which cause a Cushing syndrome phenotype; the confusion caused by nonpathologic hypercortisolism not associated with Cushing syndrome, which may present with symptoms consistent with Cushing syndrome; and difficulty identifying pathologic hypercortisolism when it is extremely mild or cyclic or in renal failure, incidental adrenal masses, and pregnancy. Careful choice of screening tests, consideration of confounding conditions, and repeated testing when the results are ambiguous improve the accuracy of diagnosis. PMID- 29754633 TI - Morbidity of Cushing's Syndrome and Impact of Treatment. AB - Cortisol excess in Cushing's syndrome is associated with metabolic, cardiovascular, and cognitive alterations, only partially reversible after resolution of hypercortisolism. Elevated cardiovascular risk may persist after eucortisolism has been achieved. Fractures and low bone mineral density are also described in Cushing's syndrome in remission. Hypercortisolism may induce irreversible structural and functional changes in the brain, leading to neuropsychiatric disorders in the active phase of the disease, which persist. Sustained deterioration of the cardiovascular system, bone remodeling, and cognitive function along with neuropsychological impairment are associated with high morbidity and poor quality of life before and after remission. PMID- 29754634 TI - Mortality in Patients with Endogenous Cushing's Syndrome. AB - Cushing's syndrome is associated with increased morbidity and mortality. Cardiovascular events, sepsis, and thromboembolism are the leading causes of mortality. Patient's with Cushing's due to a pituitary adenoma and those with Cushing's due to benign adrenal adenoma have relatively good survival outcomes often mirroring that of the general population. Persistent or recurrent disease is associated with high mortality risk. Ectopic Cushing's syndrome and Cushing's due to adrenocortical carcinoma confer the highest mortality risk among Cushing's etiologies. Prompt diagnosis and treatment, and specific monitoring for and treatment of associated comorbidities are essential to decrease the burden of mortality from Cushing's. PMID- 29754635 TI - Prognostic Factors of Long-Term Remission After Surgical Treatment of Cushing's Disease. AB - Transsphenoidal surgery is the main treatment of patients with adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Although biochemical remission occurs in most patients undergoing operations at specialized centers, the recurrence risk is significant. Visualization of microadenomas on preoperative imaging and confirmation of ACTH-positive adenomas have been associated with higher remission rates. Low cortisol levels in the first 2 weeks postoperatively have been associated with durable remission; however, recurrence cannot be excluded by any cortisol threshold. The decision to perform a pituitary reoperation is based on this parameter; the protocols are institution specific. Patients with Cushing's disease warrant lifelong endocrinologic surveillance. PMID- 29754632 TI - Genetics of Cushing's Syndrome. AB - The knowledge on the molecular and genetic causes of Cushing's syndrome (CS) has greatly increased in the recent years. Somatic mutations leading to overactive 3',5'-cyclic adenosine monophosphate/protein kinase A and wingless-type MMTV integration site family/beta-catenin pathways are the main molecular mechanisms underlying adrenocortical tumorigenesis. Corticotropinomas are characterized by resistance to glucocorticoid negative feedback, impaired cell cycle control and overexpression of pathways sustaining ACTH secretion. Recognizing the genetic defects behind corticotroph and adrenocortical tumorigenesis proves crucial for tailoring the clinical management of CS patients and for designing strategies for genetic counseling and clinical screening to be applied in routine medical practice. PMID- 29754636 TI - Outcomes of Pituitary Radiation for Cushing's Disease. AB - Achievement of biochemical remission with preservation of normal pituitary function is the goal of treatment for Cushing's disease. For patients with persistent or recurrent Cushing's disease after transsphenoidal resection, radiation therapy may be a safe and effective treatment. Stereotactic radiosurgery is favored over conventional fractionated external beam radiation. Hormonal recurrence rates range from 0% to 36% at 8 years after treatment. Tumor control rates are high. New pituitary hormone deficiency is the most common adverse effect after stereotactic radiosurgery and external beam radiation. The effects of radiation planning optimization and use of adjuvant medication on endocrine remission rates warrant investigation. PMID- 29754637 TI - New Molecular Targets for Treatment of Cushing's Disease. AB - Despite the best outcomes from trans-sphenoidal surgery, approximately one-third of patients with Cushing's disease will need medical therapy. Current treatments have drawbacks and there is a clear clinical need for new therapies. Recent understanding of molecular pathways leading to excess ACTH secretion has identified key components that may be targeted with the aim to provide novel effective treatment for this devastating disease. These include testicular orphan nuclear receptor 4, heat shock protein 90, and epidermal growth factor receptor. Based on data from preclinical studies, clinical trials are seeking to assess whether targeting these novel pathways can translate into patient benefit. PMID- 29754638 TI - Recent Advances on Subclinical Hypercortisolism. AB - During the last 20 years, a significant body of literature has accumulated regarding subclinical hypercortisolism in patients with adrenal incidentalomas. Retrospective studies have indicated these patients have an increase in cardiovascular events and mortality. Current recommendations for patients with adrenal incidentalomas include an overnight low-dose dexamethasone suppression test and a thorough evaluation of cardiovascular and metabolic risk factors. Further hormonal testing and close monitoring are necessary in patients with incomplete suppression. Unilateral adrenalectomy may be beneficial in cases with abnormal suppression and comorbidities related to hypercortisolemia. Prospective studies are need for a better risk stratification and tailored therapy. PMID- 29754639 TI - Adrenal Surgery for Cushing's Syndrome: An Update. AB - Recent advances in the molecular pathogenesis and the natural history of Cushing's syndrome have improved the understanding of the management of this disease. The long-term efficacy of several cortisol-lowering medical treatments is currently under evaluation. However, adrenalectomy is a safe option for the treatment of patients affected by Cushing's syndrome. Unilateral adrenalectomy is the gold standard for treatment of adrenocortical adenomas associated with hypercortisolism. Bilateral adrenalectomy has been widely used in the past as definitive treatment of bilateral macronodular hyperplasia and persistent or recurrent Cushing's disease. The indication and the potential applications of this technique have been recently critically analyzed. PMID- 29754640 TI - Adrenocortical Carcinoma with Hypercortisolism. AB - Adrenocortical carcinoma (ACC) is a rare and aggressive tumor. ACC may be associated with different syndromes of hormone excess, most frequently Cushing's syndrome with or without hypersecretion of androgens. Recent data suggest that cortisol excess is a negative prognostic factor in advanced and localized ACC. Surgery with radical intent, when feasible, is the most effective treatment for ACC with hypercortisolism. Mitotane is the medical treatment of choice, both postoperatively and in inoperable or metastatic cases. Because of its slow onset of action, combination with other antisecretory agents (ie, metyrapone) is helpful to achieve more rapid and effective control of hypercortisolism. PMID- 29754641 TI - The Ectopic Adrenocorticotropic Hormone Syndrome: Rarely Easy, Always Challenging. AB - Despite modern imaging techniques, differentiating ectopic adrenocorticotropic hormone (ACTH) syndrome from pituitary-dependent Cushing's syndrome, Cushing's disease, is especially difficult when well-differentiated carcinoids are the source of ACTH secretion, particularly pulmonary carcinoid tumors. ACTH-secreting pulmonary carcinoids, like the corticotroph adenomas causing Cushing's disease, are often small and difficult to detect, and patients present with a gradual onset of the classical signs and symptoms of Cushing's syndrome, indistinguishable from the presentation of Cushing's disease. Hence, the differential diagnosis relies on a combination of clinical assessment, dynamic biochemical tests, inferior petrosal sinus sampling, and multimodal imaging, each with its own caveats and pitfalls. PMID- 29754642 TI - Medical Therapy for Cushing's Syndrome in the Twenty-first Century. AB - Medical therapy has a useful adjunctive role in many patients with Cushing's syndrome. Patients with pituitary corticotroph adenomas who have received radiation therapy to the sella require medical therapy until the effects of radiation therapy occur. In addition, patients with Cushing's syndrome who cannot undergo surgery promptly, including those who are acutely ill and cannot safely undergo tumor resection, may benefit from medical therapy as a bridge to surgery. Other possible candidates for medical therapy are those with unresectable tumors or those whose tumor location remains unknown despite adequate diagnostic evaluation. PMID- 29754643 TI - Pregnancy in Patients with Cushing's Syndrome. AB - Progress in diagnosis and treatment of endocrine diseases has made pregnancy possible for women with endocrinopathies, including Cushing's syndrome (CS). The risk of maternal-fetal complications in patients who are not biochemically controlled, however, is substantial. Therefore, the surgical and/or medical control of hypercortisolism is mandatory prior to conceiving. A diagnosis of de novo CS during gestation is difficult due to changes in the hypothalamic pituitary-adrenal axis during pregnancy, which may lead to some clinical features suggestive of CS along with abnormal laboratory tests. This review presents the diagnosis and management of CS during pregnancy. PMID- 29754645 TI - Cushing's Syndrome 2018: Best Practices and Looking Ahead. PMID- 29754644 TI - Cushing's Syndrome in Pediatrics: An Update. AB - Cushing syndrome (CS) is a multisystem disorder resulting from the prolonged exposure to excess glucocorticoids. In children, CS most commonly results from the exogenous administration of steroids and the typical presentation is height deceleration concomitant with weight gain. Endogenous and ectopic causes are rare. CS in children may be associated with distinct germline and somatic mutations. Clinical practice guidelines are available assist clinicians. Patients should be referred to multidisciplinary centers of excellence with experience in endocrinology and surgery. Early detection and treatment is essential to reduce associated acute and long-term morbidity and potential death. PMID- 29754646 TI - Effect of carvedilol vs metoprolol succinate on mortality in heart failure with reduced ejection fraction. AB - BACKGROUND: Beta blocker therapy is indicated in all patients with heart failure with reduced ejection fraction (HFrEF) as per current guidelines. The relative benefit of carvedilol to metoprolol succinate remains unknown. This study aimed to compare survival benefit of carvedilol to metoprolol succinate. METHODS: The VA's databases were queried to identify 114,745 patients diagnosed with HFrEF from 2007 to 2015 who were prescribed carvedilol and metoprolol succinate. The study estimated the survival probability and hazard ratio by comparing the carvedilol and metoprolol patients using propensity score matching with replacement techniques on observed covariates. Sub-group analyses were performed separately for men, women, elderly, duration of therapy of more than 3 months, and diabetic patients. RESULTS: A total of 43,941 metoprolol patients were matched with as many carvedilol patients. The adjusted hazard ratio of mortality for metoprolol succinate compared to carvedilol was 1.069 (95% CI: 1.046-1.092, P value: < .001). At six years, the survival probability was higher in the carvedilol group compared to the metoprolol succinate group (55.6% vs 49.2%, P value < .001). The sub-group analyses show that the results hold true separately for male, over or under 65 years old, therapy duration more than three months and non-diabetic patients. CONCLUSION: Patients with HFrEF taking carvedilol had improved survival as compared to metoprolol succinate. The data supports the need for furthering testing to determine optimal choice of beta blockers in patients with heart failure with reduced ejection fraction. PMID- 29754647 TI - Effects of a 12-week mHealth program on peak VO2 and physical activity patterns after completing cardiac rehabilitation: A randomized controlled trial. AB - BACKGROUND: Site-based cardiac rehabilitation (CR) provides supervised exercise, education and motivation for patients. Graduates of CR have improved exercise tolerance. However, when participation in CR ceases, adherence to regular physical activity often declines, consequently leading to worsening risk factors and clinical events. Therefore, the purpose of this pilot study was to evaluate if a mHealth program could sustain the fitness and physical activity levels gained during CR. METHODS AND RESULTS: A 12-week mHealth program was implemented using physical activity trackers and health coaching. Twenty-five patients were randomized into mHealth or usual care after completing CR. The combination of a 4.7+/-13.8% increase in the mHealth and a 8.5+/-11.5% decrease in the usual care group resulted in a difference between groups (P<=.05) for absolute peak VO2. Usual care decreased the amount of moderate-low physical activity minutes per week (117+/-78 vs 50+/-53; P<.05) as well as moderate-high (111+/-87 vs 65+/-64; P<.05). mHealth increased moderate-high physical activity (138+/-113 vs 159+/ 156; NS). The divergent changes between mHealth and usual care in moderate-high physical activity minutes/week resulted in a difference between groups (21+/-103 vs - 46+/-36; P<.05). CONCLUSIONS: A 12-week mHealth program of physical activity trackers and health coaching following CR graduation can sustain the gains in peak VO2 and physical activity achieved by site-based CR. PMID- 29754648 TI - The cVAD registry for percutaneous temporary hemodynamic support: A prospective registry of Impella mechanical circulatory support use in high-risk PCI, cardiogenic shock, and decompensated heart failure. AB - : Management of patients requiring temporary, mechanical hemodynamic support during high- risk percutaneous coronary intervention (PCI) or in cardiogenic shock is rapidly evolving. With the availability of the Impella 2.5, CP, 5.0, LD, and RP percutaneous mechanical circulatory support devices, there is a need for continued surveillance of outcomes. Three factors underline the importance of a registry for these populations. First, large randomized trials of hemodynamic support, involving cardiogenic shock, are challenging to conduct. Second, there is increasing interest in the use of registries to provide "real-world" experience and to allow the flexibility to evaluate individual patient uses and outcomes. Third, current, large databases have not captured the specific impact of mechanical support treatment of cardiogenic shock. The predecessor to the catheter-based ventricular assist devices registry, known as USpella, began in 2009 with paper data acquisition but beginning in 2011 transferred to electronic data capture, enrolling 3,339 patients through 2016. Throughout, registry data have been used to assess the outcomes of Impella therapy, leading to 8 publications and 4 Food and Drug Administration premarket approvals covering multiple indications and Impella devices. Going forward, the registry will continue to assess not only in-hospital outcomes but long-term follow-up to 1 year. In addition, data management will be enhanced to assess quality and clinical experiences. The registry will also provide a mechanism for postmarketing surveillance. This manuscript reviews the ongoing catheter-based ventricular assist devices registry design, management, and contributions of the registry data. The upgraded registry will provide a more robust opportunity to assess acute and late outcomes of current and future device use worldwide. CONDENSED ABSTRACT: The current catheter-based ventricular assist devices registry is an international database documenting outcomes with temporary Impella hemodynamic support. The registry has supported 8 publications and 4 Food and Drug Administration premarket approvals since its inception in 2009. The current registry is more robust containing outcomes up to 1 year postprocedure. PMID- 29754649 TI - Telemedicine cardiovascular risk reduction in veterans: The CITIES trial. AB - BACKGROUND: Comprehensive programs addressing tailored patient self-management and pharmacotherapy may reduce barriers to cardiovascular disease (CVD) risk reduction. METHODS: This is a 2-arm (clinical pharmacist specialist-delivered, telehealth intervention and education control) randomized controlled trial including Veterans with poorly controlled hypertension and/or hypercholesterolemia. Primary outcome was Framingham CVD risk score at 6 and 12 months, with systolic blood pressure; diastolic blood pressure; total cholesterol; low-density lipoprotein; high-density lipoprotein; body mass index; and, for those with diabetes, HbA1c as secondary outcomes. RESULTS: Among 428 Veterans, 50% were African American, 85% were men, and 33% had limited health literacy. Relative to the education control group, the clinical pharmacist specialist-delivered intervention did not show a reduction in CVD risk score at 6 months (-1.8, 95% CI -3.9 to 0.3; P = .10) or 12 months (-0.3, 95% CI -2.4 to 1.7; P = .74). No differences were seen in systolic blood pressure, diastolic blood pressure, or low-density lipoprotein at 6 or 12 months. We did observe a significant decline in total cholesterol at 6 months (-7.0, 95% CI -13.4 to -0.6; P = .03) in the intervention relative to education control group. Among patients in the intervention group, 34% received at least 5 of the 12 planned intervention calls and were considered "compliers." A sensitivity analysis of the "complier average causal effect" of intervention compared to control showed a mean difference in CVD risk score reduction of 5.7 (95% CI -12.0 to 0.7) at 6 months and -1.7 (95% CI -7.6 to 4.8) at 12 months. CONCLUSIONS: Despite increased access to pharmacist resources, we did not observe significant improvements in CVD risk for patients randomized to the intervention compared to education control over 12 months. However, the intervention may have positive impact among those who actively participate, particularly in the short term. PMID- 29754650 TI - Shared decision-making tool for thromboprophylaxis in atrial fibrillation - A feasibility study. AB - BACKGROUND: Appropriate thromboprophylaxis for patients with atrial fibrillation or atrial flutter (AF) remains a national challenge. METHODS: We hypothesized that a shared decision-making interaction facilitated by an Atrial Fibrillation Shared Decision Making Tool (AFSDM) would improve patient knowledge about atrial fibrillation, and the risks and benefits of various treatment options for stroke prevention; increase satisfaction with the decision-making process; improve the therapeutic alliance between patient and the clinical care team; and increase medication adherence. Using a pre- and post-visit study design, we enrolled 76 patients and completed 2 office visits and 1-month telephone follow-up for 65 patients being seen in our Arrhythmia Clinic over the 1-year period (July 2016 through June 2017). Our primary outcome measure was change in decisional conflict between the first and second clinical visit. RESULTS: Decisional conflict decreased from an average of 31 to 9. Mean change was 22.3 (95% CI, 25.7 - 37.1), corresponding to an effect size of 0.94 standard deviations. Satisfaction with decision increased from 4.0 to 4.5, measures of therapeutic alliance with the care team (Kim Alliance scale) increased from 100.1 to 103.1, and satisfaction with provider increased from 4.2 to 4.5 (P < .0001 for all measures). AF knowledge assessment scores increased from 8.4 to 9.1, and knowledge about personal stroke and bleeding risk increased from 1 to 1.5 (P < .0001). Finally, medication adherence improved as reflected by an increase in the Morisky Medication Adherence scale from 5.9 to 6.4 (P < .0001). CONCLUSIONS: A shared decision-making interaction, facilitated by an AFSDM can significantly improve multiple measures of decision-making quality, leading to improved medication adherence and patient satisfaction. PMID- 29754651 TI - Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF). AB - BACKGROUND: Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. METHODS: This 52-week, multicenter, open label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. CONCLUSIONS: Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183). PMID- 29754652 TI - Risk of cardiovascular events and incident atrial fibrillation in patients without prior atrial fibrillation: Implications for expanding the indications for anticoagulation. AB - BACKGROUND: There is growing interest in the role for non-vitamin K antagonist oral anticoagulants (NOACs) in patients without atrial fibrillation (AF). We aimed to provide a comprehensive assessment of the risks of ischemic stroke, myocardial infarction (MI), AF, and major bleeding in patients without previously diagnosed AF. METHODS: Using a large US administrative database, we identified 6,495,875 patients >=50 years between January 1, 2011, and September 30, 2016, who were not diagnosed with AF and were not treated with oral anticoagulants or nonaspirin antiplatelet agents. We assessed the risks by age, sex, the number of risk factors, and the combination of risk factors. We also calculated the number needed to treat or harm based on the untreated risks in our data set and relative risks of NOAC treatment derived from a recent clinical trial. RESULTS: The event rates were 0.67%/y for ischemic stroke or MI, 0.96%/y for AF, and 0.52%/y for major bleeding. Among patients who had a stroke during follow-up, 84% were not diagnosed with AF at any time, and only 5% were diagnosed with AF before the stroke. Patients who had low number needed to treat for cardiovascular risk reduction (ie, potentially benefiting the most from the addition of NOACs) also had low number needed to harm for major bleeding (ie, facing serious harm). CONCLUSIONS: Patients without diagnosed AF but with certain risk factors were at a particularly high cardiovascular risk and may require new prevention approaches. In addition to the ongoing trials, future trials in other high-risk populations, for example, diabetes and chronic kidney disease, may be warranted. PMID- 29754653 TI - Trends in the incidence and outcomes of patients with aortic stenosis hospitalization. AB - BACKGROUND: Although the burden of aortic stenosis (AS) on our health care system is expected to rise, little is known regarding its epidemiology at the population level. Our primary objective was to evaluate trends in AS hospitalization, treatment and outcomes. METHODS: We performed a population-based observational study including 37,970 patients newly hospitalized with AS from 2004 and 2013 in Ontario, Canada. We calculated age- and sex-standardized rate of AS hospitalization through direct standardization. The independent association between year of the hospitalization, and 30-day and 1-year mortality rate was evaluated using logistic regression models to account for temporal changes in patient characteristics. RESULTS: The overall age- and sex-standardized AS hospitalization rate increased slightly from 36 per 100,000 in 2004 to 39 per 100,000 in 2013. A substantial increase was seen in patients >=85years, where hospitalization rates increased 29% from 400 to 516 per 100,000 from 2004 to 2013 (P<.001). In this study period, 36.2% of patients received aortic valve interventions within 30days of hospitalization. Among treated patients, an improving mortality trend was observed in which the adjusted odds ratio (OR) was significantly lower in 2013 as compared to 2004 (OR 0.55 for 30-day mortality, 0.74 for 1-year morality). In contrast, no significant temporal change in mortality was seen among patients without aortic valve intervention. CONCLUSION: AS hospitalizations in the elderly increased significantly beyond that was expected from population growth. Many AS patients did not receive aortic valve intervention after hospitalization. Mortality among the treated patients improved significantly over time. PMID- 29754654 TI - Dual antiplatelet therapy for perioperative myocardial infarction following CABG surgery. AB - OBJECTIVES: Perioperative myocardial infarction (MI) after coronary artery bypass graft surgery (CABG) has been associated with adverse outcome. Whether perioperative MI should be treated with dual antiplatelet therapy (DAPT) is unknown. We compared the effect of DAPT versus aspirin alone on short-term outcomes among patients with perioperative MI following CABG. METHODS: We used data from 3 clinical trials that enrolled patients undergoing isolated CABG: PREVENT IV (2002-2003), MEND-CABG II (2004-2005), and RED-CABG (2009-2010) (n = 9117). Perioperative MI was defined as CK-MB >5 times the upper limit of normal within 24 h of surgery (n = 2052). DAPT was defined as DAPT given after surgery and prior to discharge. A Cox regression model was used to assess the association between DAPT and 30-day nonfatal MI, stroke, or mortality after adjustment for baseline covariates. RESULTS: DAPT (n = 527) and aspirin alone (n = 1525) cohorts were similar in baseline comorbidities. Off pump bypass was used in 5.2% (n = 106) of patients. There was no difference in the 30-day composite of death, MI or stroke between patients receiving DAPT versus aspirin alone, nor in any of the individual components. There were fewer all-cause re-hospitalizations at 30 days following surgery among patients in the DAPT group (adjusted HR 0.71, CI 0.52 0.97, P = .033). CONCLUSION: One-quarter of CABG patients who had perioperative MI were treated with DAPT. DAPT was not associated with a difference in MI, stroke, or mortality at 30 days, but was associated with fewer re hospitalizations. Further studies are needed to determine the optimal antiplatelet regimen following perioperative MI. What is already known about this subject? Perioperative myocardial infarction portends poor outcome but optimal management is currently unclear. While dual antiplatelet therapy is standard of care for acute coronary syndrome, its role in perioperative myocardial infarction is unknown. What does this study add? Dual antiplatelet therapy use during perioperative myocardial infarction was not associated with a difference in myocardial infarction, stroke or mortality at 30 days. It was, however, associated with fewer re-hospitalizations at 30 days. How might this impact on clinical practice? Dual antiplatelet therapy may be a potential treatment option for perioperative myocardial infarction after CABG surgery. Further studies are needed to better understand treatment for this disease process. PMID- 29754655 TI - Characteristics and long term outcomes of patients with acute coronary syndromes due to culprit left main coronary artery disease treated with percutaneous coronary intervention. AB - BACKGROUND: Patients with acute coronary syndrome (ACS) due to unprotected culprit left main coronary artery disease (LMCAD) treated with percutaneous coronary intervention (PCI) are rare, high-risk, and not represented in trials. Data regarding long term outcome after PCI are limited. METHODS: Between January 2000 and December 2014, there were 8,794 patients hospitalized with unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI) or ST-elevation myocardial infarction (STEMI) treated with PCI at our institution; of these, 83 (0.94%) patients were identified as having culprit LMCAD ACS. RESULTS: Of the 83 patients with unprotected LMCAD ACS, 40 patients presented with STEMI and 43 patients presented with UA/NSTEMI. As compared to LM UA/NSTEMI, LM STEMI patients were younger and had less hypertension, with a trend towards greater frequency of cardiogenic shock. Distal LM involvement was common in both groups and did not differ by ACS type. In-hospital mortality was 33% in LM STEMI and 9% in LM UA/NSTEMI (P = .009). Over median follow up of 6.3 years, long term survival rates in both groups were similar (46% for STEMI vs 51% for UA/NSTEMI; P = .50 by log-rank). CONCLUSIONS: Unprotected culprit LMCAD ACS necessitating PCI is uncommon, occurring in <1% of cases, but is associated with reduced survival, with long term follow-up noting continued and similar risk of death regardless of index ACS type. PMID- 29754656 TI - The prognostic value of heart rate recovery in patients with coronary artery disease: A systematic review and meta-analysis. AB - BACKGROUND: Routine outpatient care of patients with coronary artery disease (CAD) lacks a simple measure of physical fitness and risk of mortality. Heart rate recovery (HRR) is noninvasive and easily obtainable in outpatient settings. Prior studies have suggested that delayed postexercise HRR in the first minutes is associated with mortality in several types of populations. However, a comprehensive overview of the prognostic value of delayed HRR for time to mortality specifically in CAD patients is not available. The purpose of the current meta-analysis is to evaluate the prognostic value of delayed HRR in CAD patients. METHODS: We conducted a systematic search in OVID MEDLINE and OVID EMBASE to identify studies reporting on HRR and risk of incident cardiovascular events or mortality in CAD patients. Hazard ratios for delayed versus nondelayed HRR were pooled using random-effects meta-analysis. RESULTS: Four studies were included, comprising 2,428 CAD patients. The study quality of the included studies was rated moderate (n = 2) to high (n = 2). Delayed HRR was defined by <=12 to <=21 beat/min in the recovery period. During follow-up (range 2.0-9.8 years), 151 patients died (6.2% [range 2.5%-19.5%]). Only data on mortality could be pooled. Heterogeneity was limited (I2 = 32%; P = .23); pooled unadjusted hazard ratio for mortality, based on 3 studies, was 5.8 (95% CI 3.2-10.4). CONCLUSIONS: In CAD patients, delayed HRR is significantly associated with all cause mortality. As exercise testing is performed routinely in CAD patients, HRR can be considered in monitoring exercise; still, further research must investigate the addition of HRR in current risk scores. PMID- 29754657 TI - Baseline characteristics and temporal differences in Acarbose Cardiovascular Evaluation (ACE) trial participants. PMID- 29754658 TI - Angiotensin receptor-neprilysin inhibitor therapy in heart failure: An end that justifies the means. PMID- 29754659 TI - IABP and cardiogenic shock: A heartbreaking story. PMID- 29754660 TI - Predictors of intra-aortic balloon pump hemodynamic failure in non-acute myocardial infarction cardiogenic shock. AB - OBJECTIVES: To characterize patient profile and hemodynamic profile of those undergoing intra-aortic balloon pump (IABP) for cardiogenic shock and define predictors of hemodynamic failure of IABP support. BACKGROUND: Clinical characteristics of IABP support in cardiogenic shock not related to acute myocardial infarction (AMI) remain poorly characterized. METHODS: We retrospectively studied a cohort of 74 patients from 2010 to 2015 who underwent IABP insertion for cardiogenic shock complicating acute decompensated heart failure not due to AMI. RESULTS: In the overall cohort, which consisted primarily of patients with chronic systolic heart failure (89%), IABP significantly augmented cardiac index and lowered systemic vascular resistance (P<.05). Despite this improvement, 28% of these patients died (24%) or require urgent escalation in mechanical circulatory support (MCS) (4%). Multivariable regression revealed that baseline left ventricular cardiac power index (LVCPI), a measure of LV power output derived from cardiac index and mean arterial pressure (P=.01), and history of ischemic cardiomyopathy (P=.003) were significantly associated with the composite adverse-event endpoint of death or urgent MCS escalation. An IABP Failure risk score using baseline LVCPI <0.28 W/m2 and ischemic history predicted 28-day adverse events with excellent discrimination. CONCLUSION: Despite hemodynamic improvements with IABP support, patients with non-AMI cardiogenic shock still suffer poor outcomes. Patients with ischemic cardiomyopathy and low LVPCI fared significantly worse. These patients may warrant closer observation or earlier consideration of more advanced hemodynamic support. PMID- 29754661 TI - Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial: Study Rationale and Design. AB - The Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA,NCT00911508)(1) trial is testing the hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art pharmacologic therapy. This international 140-center clinical trial was designed to randomize 2200 patients to a strategy of catheter ablation versus state-of-the art rate or rhythm control drug therapy. Inclusion criteria include: 1) age> 65, or <=65 with>= 1 risk factor for stroke, 2) documented AF warranting treatment, and 3) eligibility for both catheter ablation and>= 2 anti-arrhythmic or>= 2 rate control drugs. Patients were followed every 3 to 6 months (median 4 years) and underwent repeat trans-telephonic monitoring, Holter monitoring, and CT/MR in a subgroup of patient studies to assess the impact of treatment on AF recurrence and atrial structure. With 1100 patients in each treatment arm, CABANA is projected to have 90% power for detecting a 30% relative reduction in the primary composite endpoint of total mortality, disabling stroke, serious bleeding, or cardiac arrest. Secondary endpoints include total mortality; mortality or cardiovascular hospitalization; a combination of mortality, stroke, hospitalization for heart failure or acute coronary artery events; cardiovascular death alone; and heart failure death, as well as AF recurrence, quality of life, and cost effectiveness. At a time when AF incidence is rising rapidly, CABANA will provide critical evidence with which to guide therapy and shape health care policy related to AF for years to come. PMID- 29754662 TI - Rationale and design of a trial to personalize risk assessment in familial coronary artery disease. AB - BACKGROUND: The lifetime risk of coronary artery disease (CAD) is doubled in people with a family history of premature disease, yet this risk is not captured in most 5- or 10-year risk assessment algorithms. Coronary artery calcium scoring (CCS) is a marker of subclinical CAD risk, which has been shown in observational studies to provide prognostic information that is incremental to clinical assessment; is relatively inexpensive; and is performed with a small radiation dose. However, the use of CCS in guiding prevention is not strongly supported by guidelines. Showing definitive evidence of the efficacy and cost-effectiveness of CCS is therefore of importance. STUDY DESIGN: The proposed randomized controlled trial of the use of CCS will be targeted to 40- to 70-year-old first-degree relatives of patients with CAD onset <60 years old or second-degree relatives of patients with onset <50 years old. Control patients will undergo standard risk scoring and be blinded to CCS results. In the intervention group, primary prevention in patients undergoing CCS will be informed by this score. At 3 years, effectiveness will be assessed on change in plaque volume at computed tomography coronary angiography, the extent of which has been strongly linked to outcome. SUMMARY: The CAUGHT-CAD trial will provide evidence to inform the guidelines regarding the place of CCS in decision making regarding primary prevention of patients with a family history of premature disease. PMID- 29754663 TI - The prognostic value of the relationship between right atrial and pulmonary capillary wedge pressure in diverse cardiovascular conditions. AB - BACKGROUND: Physical examination of jugular venous pressure is used to estimate right atrial (RA) pressure and infer left-sided filling pressure to assist volume management. Previous studies in advanced heart failure patients showed about 75% concordance between RA and pulmonary capillary wedge (PCW) pressures. We sought to determine the relationship between mean RA and mean PCW pressure and assess the clinical significance in a broad population of patients undergoing invasive right heart catheterization (RHC). METHODS: We examined 4135 RHC cases at a single academic medical center from February 2007 to December 2014, analyzing baseline variables, hemodynamic data, and in-hospital mortality. RESULTS: The overall Pearson correlation for mean RA and PCW pressures was 0.68 with 70% concordance between dichotomized pressures (RA >=10 and PCW >=22 mmHg). Results were similar in subgroups with heart failure (r=0.67, 72%), STEMI/NSTEMI (r=0.60, 69%), unstable angina (r=0.78, 69%), stable/no angina (r=0.72, 67%), and valvular disease (r=0.61, 72%; Chi-square P=.15). Mean RA pressure was independently associated with in-hospital mortality in multivariate analysis (OR 1.12 [95% CI 1.081-1.157] per 1 mmHg increase, P<.001). The RA/PCW ratio was not independently associated with in-hospital mortality. Mean RA pressure was also weakly associated with worse renal function (rho=-0.16, P<.001). CONCLUSION: In patients undergoing right catheterization for diverse indications, the mean RA and PCW pressures correlated moderately well, but there was discordance in a sizable minority, in whom assessment of left-sided filling pressures using estimated jugular venous pressure may be misleading. Elevated right atrial pressure is a marker for in-hospital mortality. PMID- 29754664 TI - Investigation of Motivational Interviewing and Prevention Consults to Achieve Cardiovascular Targets (IMPACT) trial. AB - BACKGROUND: Patients undergoing cardiovascular (CV) procedures often have suboptimal CV risk factor control and may benefit from strategies targeting healthy lifestyle behaviors and education. Implementation of prevention strategies may be particularly effective at this point of heightened motivation. METHODS: A prospective, randomized, pilot study was conducted in 400 patients undergoing a nonurgent CV procedure (cardiac catheterization +/- revascularization) to evaluate the impact of different prevention strategies. Patients were randomized in a 1:1:1 fashion to usual care (UC; group A, n = 134), in-hospital CV prevention consult (PC; group B, n = 130), or PC plus behavioral intervention program (telephone-based motivational interviewing and optional tailored text messages) (group C, n = 133). The primary end point was the Delta change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to 6 month. RESULTS: The mean age was 64.6 +/- 10.8 years, 23.7% were female, and 31.5% were nonwhite. After 6 months, the absolute difference in non-HDL-C for all participants was -19.8 mg/dL (95% CI -24.1 to -15.6, P < .001). There were no between-group differences in the primary end point for the combined PC groups (B and C) versus UC, with a Delta adjusted between group difference of -5.5 mg/dL (95% CI -13.1 to 2.1, P = .16). Patients in the PC groups were more likely to be on high-intensity statins at 6 months (52.9% vs 38.1%, P = .01). After excluding participants with baseline non-HDL-C <100 mg/dL (initial exclusion criterion), Delta non-HDL-C and Delta low-density lipoprotein cholesterol were improved in the PC groups compared to UC (non-HDL-C -8.13 mg/dL [-16.00 to -0.27], P = .04; low-density lipoprotein cholesterol -7.87mg/dL [-15.10 to -0.64], P = .03). CONCLUSIONS: Although non-HDL-C reduction at 6 months following a nonurgent CV procedure was not significant in the overall cohort, an increased uptake in high potency statins may translate into improved long-term health outcomes and cost reductions. PMID- 29754665 TI - Transcatheter closure of patent foramen ovale following cryptogenic stroke: An updated meta-analysis of randomized controlled trials. AB - BACKGROUND: Transcatheter closure of patent foramen ovale (PFO) after cryptogenic stroke has long been a contentious issue. Herein, we pool aggregate data examining safety and efficacy of transcatheter closure of PFO compared with medical therapy following initial cryptogenic stroke. METHODS: We searched for randomized clinical trials (RCT) that compared device closure with medical management and reported on subsequent stroke and adverse events. Stroke was considered as the primary efficacy endpoint, whereas bleeding and atrial fibrillation were considered primary safety endpoints. Data were pooled by the random effects model and I2 was used to assess heterogeneity. RESULTS: A total of 5 RCT investigating 3630 patients met inclusion criteria. Pooled analysis revealed that device closure compared to medical management was associated with a significant reduction in stroke (RR=0.3, 95% CI=0.02-0.57). There was, however, a significant increase in atrial arrhythmias with device therapy (RR=4.8, 95% CI=2.2-10.7). We found no increase in bleeding (RR=0.80, 95% CI=0.5-1.4), death (RR=0.76, 95% CI=0.3-1.99) or "any adverse events" (RR=1.02, 95% CI=0.85-1.23) with device therapy. Sub-group analysis revealed that device closure significantly reduced the incidence of the composite primary endpoint among patients who had moderate to large shunt sizes (RR=0.22, 95% CI=0.02-0.42). CONCLUSIONS: Transcatheter closure is associated with a significant reduction in the risk of stroke compared to medical management at the expense of an increased risk of atrial arrhythmias. PMID- 29754666 TI - A genotype-directed comparative effectiveness trial of Bucindolol and metoprolol succinate for prevention of symptomatic atrial fibrillation/atrial flutter in patients with heart failure: Rationale and design of the GENETIC-AF trial. AB - BACKGROUND: Few therapies are available for the safe and effective treatment of atrial fibrillation (AF) in patients with heart failure. Bucindolol is a non selective beta-blocker with mild vasodilator activity previously found to have accentuated antiarrhythmic effects and increased efficacy for preventing heart failure events in patients homozygous for the major allele of the ADRB1 Arg389Gly polymorphism (ADRB1 Arg389Arg genotype). The safety and efficacy of bucindolol for the prevention of AF or atrial flutter (AFL) in these patients has not been proven in randomized trials. METHODS/DESIGN: The Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Metoprolol Succinate for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure (GENETIC-AF) trial is a multicenter, randomized, double-blinded "seamless" phase 2B/3 trial of bucindolol hydrochloride versus metoprolol succinate, for the prevention of symptomatic AF/AFL in patients with reduced ejection fraction heart failure (HFrEF). Patients with pre-existing HFrEF and recent history of symptomatic AF are eligible for enrollment and genotype screening, and if they are ADRB1 Arg389Arg, eligible for randomization. A total of approximately 200 patients will comprise the phase 2B component and if pre-trial assumptions are met, 620 patients will be randomized at approximately 135 sites to form the Phase 3 population. The primary endpoint is the time to recurrence of symptomatic AF/AFL or mortality over a 24-week follow-up period, and the trial will continue until 330 primary endpoints have occurred. CONCLUSIONS: GENETIC-AF is the first randomized trial of pharmacogenetic guided rhythm control, and will test the safety and efficacy of bucindolol compared with metoprolol succinate for the prevention of recurrent symptomatic AF/AFL in patients with HFrEF and an ADRB1 Arg389Arg genotype. (ClinicalTrials.govNCT01970501). PMID- 29754667 TI - Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants? AB - The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. PMID- 29754668 TI - Resource utilization and outcome among patients with selective versus nonselective troponin testing. AB - OBJECTIVE: In patients with suspected acute coronary syndrome (ACS), troponin testing is effective for diagnosis and prognosis. Troponin testing has now expanded to include patients without suspected ACS. This nonselective troponin testing has unknown consequences for resource utilization and outcome. Therefore, we examined selective versus nonselective troponin testing with respect to patient characteristics, resource utilization, and outcome. METHODS: This retrospective 1-year study included all patients with troponin testing at a U.S. emergency department. Testing was classified as selective (ACS) or nonselective (non-ACS) based on admission ICD-9 codes. Troponin upper reference limit (URL) was >=99th percentile. RESULTS: Among 47,053 patients, troponin was measured in 9109 (19%) of whom 5764 were hospitalized. Admission diagnosis was non-ACS in 4427 (77%) and ACS in 1337 (23%). Non-ACS patients were older, 71+/-17 versus 65+/-16 years, with longer hospital stay, 77 versus 32 h, and greater 1-year mortality 22% versus 6.7%; P<.001. In patients with troponin >=URL, revascularization was performed in 64 (4.7%) of non-ACS versus 213 (48%) of ACS; P<.001. In patients with troponin =URL, 1-year mortality was 35% in non-ACS versus 13% in ACS; P<.001. Death was non-cardiac in >80% of the non-ACS population CONCLUSIONS: Contemporary troponin testing is frequently nonselective. The non-ACS and ACS populations differ significantly regarding clinical characteristics, revascularization rates, and outcomes. Troponin elevation is a powerful predictor of 1-year mortality in non-ACS, this association reveals an opportunity for risk stratification and targeted therapy. KEY QUESTIONS: In patients with suspected acute coronary syndrome (ACS), troponin testing is effective for diagnosis and prognosis. However, troponin testing has now expanded to include patients without suspected ACS. This nonselective troponin testing has unknown consequences for hospital resource utilization and patient outcome. Our findings demonstrate contemporary troponin testing is largely nonselective (77% of testing was performed in patients without acute coronary syndrome). In comparison to patients with acute coronary syndrome, those with non-acute coronary syndrome are older, with longer hospital stay, lower revascularization rates, and greater 1-year mortality. Troponin elevation identifies a high-risk population in both acute coronary syndrome and non-acute coronary syndrome populations, yet effective treatment for the latter is lacking. PMID- 29754669 TI - Comparison of Fractional FLow Reserve And Intravascular ultrasound-guided Intervention Strategy for Clinical OUtcomes in Patients with InteRmediate Stenosis (FLAVOUR): Rationale and design of a randomized clinical trial. AB - BACKGROUND: Coronary angiography has limitations in defining the ischemia-causing stenotic lesion, especially in cases with intermediate coronary stenosis. Fractional flow reserve (FFR) is a current standard method to define the presence of ischemia, and intravascular ultrasound (IVUS) is the most commonly used invasive imaging tool that can provide the lesion geometry and can provide the information on plaque vulnerability. The primary aim of this study is to compare the safety and efficacy of FFR-guided and IVUS-guided percutaneous coronary intervention (PCI) strategies in patients with intermediate coronary stenosis. TRIAL DESIGN: Comparison of Fractional FLow Reserve And Intravascular ultrasound guided Intervention Strategy for Clinical OUtcomes in Patients with InteRmediate Stenosis (FLAVOUR) trial is an international, multicenter, prospective, randomized clinical trial. A total of 1,700 consecutive patients with intermediate stenosis (40%-70% by visual estimation) in a major epicardial coronary artery will be randomized 1:1 to receive either FFR-guided or IVUS guided PCI strategy. Patients will be treated with PCI according to the predefined criteria for revascularization; FFR <= 0.80 in the FFR-guided group and Minimal Lumen Area (MLA) <=3 mm2 (or 3 mm270%) in the IVUS-guided group. The primary end point is the patient-oriented composite outcome, which is a composite of all-cause death, myocardial infarction, and any repeat revascularization at 24months after randomization. We will test noninferiority of current standard FFR-guided PCI strategy compared with IVUS-guided decision for PCI and stent optimization strategy. CONCLUSION: The FLAVOUR trial will compare the safety and efficacy of FFR- and IVUS-guided PCI strategies in patients with intermediate coronary stenosis. This study will provide an insight on optimal evaluation and treatment strategy for patients with intermediate coronary stenosis. PMID- 29754670 TI - Knowledge to action: Rationale and design of the Patient-Centered Care Transitions in Heart Failure (PACT-HF) stepped wedge cluster randomized trial. AB - INTRODUCTION: Heart Failure (HF) is a common cause of hospitalization in older adults. The transition from hospital to home is high-risk, and gaps in transitional care can increase the risk of re-hospitalization and death. Combining health care services supported by meta-analyses, we designed the PACT HF transitional care model. METHODS: Adopting an integrated Knowledge Translation (iKT) approach in which decision-makers and clinicians are partners in research, we implement and test the effectiveness of PACT-HF among patients hospitalized for HF. We use a pragmatic stepped wedge cluster randomized trial design to introduce the complex health service intervention to 10 large hospitals in a randomized sequence until all hospitals initiate the intervention. The goal is for all patients hospitalized with HF to receive self-care education, multidisciplinary care, and early follow-up with their health care providers; and in addition, for high-risk patients to receive post-discharge nurse-led home visits and outpatient care in Heart Function clinics. This requires integration of care across hospitals, home care agencies, and outpatient clinics in our publicly funded health care system. While hospitals are the unit of recruitment and analysis, patients (estimated sample size of 3200) are the unit of analysis. Primary outcomes are hierarchically ordered as time to composite all-cause readmissions / emergency department (ED) visits / death at 3 months and time to composite all-cause readmissions / ED visits at 30 days. In a nested study of 8 hospitals, we measure the patient-centered outcomes of Discharge Preparedness, Care Transitions Quality, and Quality Adjusted Life Years (QALY); and the 6-month health care resource use and costs. We obtain all clinical and cost outcomes via linkages to provincial administrative databases. CONCLUSIONS: This protocol describes the implementation and testing of a transitional care model comprising health care services informed by high-level evidence. The study adopts an iKT and pragmatic approach, uses a robust study design, links clinical trial data with outcomes held in administrative databases, and includes patient-reported outcomes. Findings will have implications on clinical practice, health care policy, and Knowledge Translation (KT) research methodology. PMID- 29754671 TI - Rationale and design for the Vascular Outcomes study of ASA along with rivaroxaban in endovascular or surgical limb revascularization for peripheral artery disease (VOYAGER PAD). AB - BACKGROUND: Patients with peripheral artery disease (PAD) undergoing a lower extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial. STUDY DESIGN: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months. CONCLUSIONS: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization. PMID- 29754672 TI - Trends and outcomes of cardiac transplantation from donors dying of drug intoxication. AB - BACKGROUND: Deaths from drug intoxication have increased in the United States but outcomes of recipients of orthotopic heart transplantation (OHT) from these donors are not well characterized. METHODS: We performed a retrospective analysis of the United Network for Organ Sharing's STAR database between January 2000 and March 2014 and assessed mortality and retransplantation using adjusted Cox models by mechanism of donor death. RESULTS: Of the 31,660 OHTs from 2000 to 2014, 1233 (3.9%) were from drug intoxication. These donors were more likely to be female, white, with greater tobacco use and higher BMI compared to donors who died of other mechanisms. Drug intoxication accounted for 1.1% of OHT donors in 2000 and 6.2% in March 2014. No significant difference was observed in 10-year mortality (adjusted hazard ratio [HR], 95% confidence interval [CI]: 0.99, 0.87-1.13), 10 year retransplantation (adjusted HR 0.84, 0.49-1.41) or 1-year and 3-year rehospitalization with other mechanisms of death compared to drug intoxication. CONCLUSION: There has been a large increase in OHT donors who die of drug intoxication in the United States. OHT outcomes from these donors are similar to those dying from other mechanisms. These data have important implications for donor selection in context of the ongoing opioid epidemic. PMID- 29754673 TI - Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial. AB - BACKGROUND: Despite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). METHODS: HF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF <=35% between April 2003 and February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to prevalent digoxin status at baseline. The association between digoxin therapy and outcomes was assessed using Cox proportional hazard and inverse-probability weighted (IPW) regression models adjusted for demographics, medical history, medications, laboratory values, quality of life, and exercise parameters. RESULTS: The prevalence of digoxin therapy decreased from 52% during the first 6 months of enrollment to 35% at the end of the HF-ACTION trial (P <0.0001). Study participants were 59+/- 13 years of age, 72% were male, and approximately half had an ischemic etiology of HF. Patients receiving digoxin at baseline tended to be younger and were more likely to report New York Heart Association functional class III/IV symptoms (rather than class II) compared to those not receiving digoxin. Patients taking digoxin had worse baseline exercise capacity as measured by peak VO2 and 6-min walk test and greater impairments in health status as reflected by the Kansas City Cardiomyopathy Questionnaire. The association between digoxin and the risk of death or hospitalization differed depending on whether Cox proportional hazard (Hazard Ratio 1.03, 95% Confidence Interval 0.92 1.16; P = .62) or IPW regression models (HR 1.08, 95% CI 1.00-1.17; P = .057) were used to adjust for potential confounders. CONCLUSION: Although digoxin use was associated with high-risk clinical features, the association between digoxin therapy and outcomes was dependent on the statistical methods used for multivariable adjustment. Clinical equipoise exists and additional prospective research is required to clarify the role of digoxin in contemporary clinical practice including its effects on functional capacity, quality of life, and long term outcomes. PMID- 29754675 TI - ? PMID- 29754676 TI - ? PMID- 29754674 TI - Erratum to "Automatic segmentation of odour maps in the mouse olfactory bulb using regularized non-negative matrix factorization" [NeuroImage 98 (2014) 279 288]. PMID- 29754677 TI - [Racial discrimination in the care environment]. AB - Based on interviews carried out with people from overseas working in Parisian hospitals and observations made of women from Central and North Africa working in care facilities for elderly or disabled people, this article discusses the issue of racial discrimination. We focus on the way discrimination develops, its manifestations in the care sector and the way in which it is handled. PMID- 29754678 TI - [When the healthcare user displays racist behaviour]. AB - The staff working in health and medical-social services are a reflection of French society. Many of the employees of these services are migrants, from French overseas departments, whose descendants are particularly high in number in the Ile-de-France region. Users of the services, from the 'white' majority group can display racist attitudes. PMID- 29754679 TI - [Cultural diversity, tensions and solidarities within the nursing teams]. AB - Cultural and ethnic diversities present in the hospital as well as within the nursing teams impact on the way of working. Observing them from the point of view of the caregivers based on experiences of team guidance and training highlights issues related to the way the hospital teams experience these differences. These differences also have an effect conveyed through tensions, conflicts or solidarity. The place and the role of the managers are an important lever for supporting their teams, notably with regard to racism which can sometimes be expressed in the social relations present in the workplace. PMID- 29754680 TI - [Racism, between representations of the 'other' and nursing practices]. AB - The care environment, renowned for being humanistic and egalitarian, has long remained impenetrable to sociological studies. Surveys, however, reveal another side, where prejudices, unequal treatment and racism in care are expressed. Medicine is itself built on racial categories which still pervade epidemiology and genetics. PMID- 29754681 TI - [Everyday racism in initial training]. AB - Student nurses and nursing assistants are, during their training, both in placement practice and the training institute, exposed to racist behaviour and remarks. The teaching teams have an ethical duty to encourage discussion around this issue during initial training. PMID- 29754682 TI - [Prejudices and racism, nursing home teams share their experience]. AB - Many nursing homes look after residents from the majority population and employ staff from minority ethnic groups. This situation in these homes can generate a certain number of tensions resulting from racial discrimination. Employees share their experience. PMID- 29754683 TI - [Hospital and prison care in Ivory Coast]. AB - A state registered nurse for 23 years, Charles Ble Aziz discusses the nursing role in general hospitals in Ivory Coast, in particular at Aboisso regional general hospital where he works on the surgical ward. He also presents his initiative to establish a nursing consultation in a prison. PMID- 29754684 TI - [Personal care and support after death]. AB - As part of the palliative care provided to patients, personal care after death is a sign of the team's respect for the deceased person and marks the end of the care process. Beyond their professionalism, caregivers are confronted with their own humanity during this last act of care which marks the support for the deceased person and his or her family and friends in the first stages of their grief. PMID- 29754685 TI - [The nurse in the organisation of medical assistance on board a ship]. AB - Nursing practice on a ship involves certain risks and constraints inherent to the facilities themselves and the maritime environment. The response in the case of a medical incident at sea is guided by an organisation adapted to these constraints, overseen by a specific regulatory body. Different entities, players and resources may be involved depending on the diverse situations encountered. PMID- 29754686 TI - ? PMID- 29754687 TI - ? PMID- 29754688 TI - ? PMID- 29754689 TI - ? PMID- 29754692 TI - Heat and community sport guidelines. PMID- 29754690 TI - ? PMID- 29754693 TI - Preoperative 6-Minute Walk Distance Is Associated With Postoperative Cognitive Dysfunction. AB - BACKGROUND: Postoperative cognitive dysfunction (POCD) is a neurologic dysfunction that occurs after surgery. POCD persists for a long period, ranging from weeks to months, and affects a patient's quality of life. A 6-minute walk distance (6MWD) has been used to predict postoperative complications after several operations. The present study investigated whether there was an independent association of a low preoperative 6MWD with POCD in patients who underwent cardiac operations. METHODS: The study included 181 patients who underwent a cardiac operation. The 6MWD was performed prospectively on admission for the operation. POCD was defined as a decrease of 2 points or more in a patient's Mini-Mental State Examination score. POCD developed in 51 (28%) of these patients. Patients were categorized into a POCD or a non-POCD group, and the perioperative variables were compared between the groups. Multivariable logistic regression analysis was performed to identify risk factors for the development of POCD. RESULTS: The patients were a mean age of 71.4 years. The POCD group showed a significantly lower 6MWD (median, 400 m) than the non-POCD group (median, 450 m). The 6MWD, intensive care unit length of stay, age, and Mini-Mental State Examination score were identified as independent risk factors for POCD by multivariable analysis. The odds ratio for each increase of 50 m in the 6MWD was 0.807 for POCD. CONCLUSIONS: The 6MWD is useful in identifying patients with a higher chance of developing POCD after a cardiac operation. PMID- 29754694 TI - Risk factors for bad outcomes in incisional hernia repair: Lessons learned from the National Registry of Incisional Hernia (EVEREG). AB - INTRODUCTION: Registries are powerful tools for identifying factors predicting bad results. Our objective was to analyse data from the Spanish Registry of Incisional Hernia (EVEREG) to detect risk situations for the development of complications and recurrences. METHODS: We have analysed data of the cohort of hernias registered during the period from July 2012 to June 2014. We have compared the data between complicated and non-complicated patients in the short and long term follow-up. Data compared were: patient demographics, comorbid condition, hernia defect characteristics and surgical technique to determine which of them may be predictors of poor outcomes. RESULTS: During the period of study, we collected data from 1,336 hernias (43.7% males; 56.3% females) with a mean age of 63.6 years (SD 12.4) and BMI of 30.4 (SD 5.4). In the multivariate analysis, factors associated with complications were: age >70 years, previous neoplasm, diameter greater than 10cm, previous repair and bowel resection. Factors related with recurrences were: parastomal hernia, previous repair, emergency repair, postoperative complications and reoperation. A separation of components was the only protective factor for this type of analysis (OR 0.438; CI 0.27-0.71; p=0.0001). CONCLUSIONS: Risk factors for the development of complications and recurrences must be considered for promoting preoperative patient prehabilitation, planning the surgical technique and referring patients to specialized abdominal wall units. PMID- 29754695 TI - Splitters or lumpers: The 2017 WHO Classification of Head and Neck Tumours. PMID- 29754696 TI - Follicle stimulating hormone receptor protein is expressed in ovine uterus during the estrous cycle and utero-placenta during early pregnancy: An immunohistochemical study. AB - Follicle stimulating hormone (FSH) is a well characterized gonadotropin that controls primarily development and functions of ovarian follicles in mammalian species. FSH binds to a specific G protein-coupled receptor (FSHR) belonging to the glycoprotein hormone receptor family that plays an essential role in reproduction. Although the primary location of FSHR is in the gonads (mainly in ovarian follicles), FSHR protein and/or mRNA have also been detected in extragonadal female reproductive tissues including embryo, placenta, endometrium, cervix, ovarian cancer tissues, and/or endometriotic lesions in several species. To determine the pattern of FSHR expression in the uterus and placenta, uterine tissues were collected at the early, mid- and/or late luteal phases of the estrous cycle from non-treated or FSH-treated ewes, and utero-placental tissues were collected during early pregnancy followed by immunohistochemistry and image generation. FSHR was immunolocalized to several uterine and utero-placental compartments including luminal epithelium, endometrial glands and surrounding stroma, myometrium, and endothelium and vascular smooth muscle cells in endometrium, myometrium and mesometrium. Intensity of staining and distribution of FSHR in selected compartments differed and seems to depend on the stage of the estrous cycle or pregnancy, and FSH-treatment. These novel data demonstrate differential expression of FSHR protein indicating that FSH plays a specific role in regulation of uterine and utero-placenta functions in sheep. PMID- 29754697 TI - Corrigendum to "Angelica sinensis polysaccharide protects against acetaminophen induced acute liver injury and cell death by suppressing oxidative stress and hepatic apoptosis in vivo and in vitro" [Int. J. Biol. Macromol. 111 (May 2018) 1133-1139]. PMID- 29754698 TI - [What is the treatment duration after a venous thromboembolic event?] PMID- 29754699 TI - Systematic review of the incremental costs of interventions that increase immunization coverage. AB - Achieving and maintaining high vaccination coverage requires investments, but the costs and effectiveness of interventions to increase coverage remain poorly characterized. We conducted a systematic review of the literature to identify peer-reviewed studies published in English that reported interventions aimed at increasing immunization coverage and the associated costs and effectiveness of the interventions. We found limited information in the literature, with many studies reporting effectiveness estimates, but not providing cost information. Using the available data, we developed a cost function to support future programmatic decisions about investments in interventions to increase immunization coverage for relatively low and high-income countries. The cost function estimates the non-vaccine cost per dose of interventions to increase absolute immunization coverage by one percent, through either campaigns or routine immunization. The cost per dose per percent increase in absolute coverage increased with higher baseline coverage, demonstrating increasing incremental costs required to reach higher coverage levels. Future studies should evaluate the performance of the cost function and add to the database of available evidence to better characterize heterogeneity in costs and generalizability of the cost function. PMID- 29754700 TI - HPV single-dose vaccination: Impact potential, evidence base and further evaluation. PMID- 29754701 TI - Impact of routine rotavirus vaccination on all-cause and rotavirus hospitalizations during the first four years following vaccine introduction in Rwanda. AB - BACKGROUND: Rwanda introduced pentavalent rotavirus vaccine into its national immunization program in 2012. To determine the long-term impact of rotavirus vaccine on disease burden in a high burden setting, we examined trends in rotavirus and all-cause diarrhea hospitalizations in the first four years following rotavirus vaccine introduction. METHODS: We used data from an active surveillance system, from a review of pediatric ward registries, and from the Health Management Information System to describe trends in rotavirus and all cause diarrhea hospitalizations from January 2009 through December 2016. Percent reductions were calculated to compare the number of all-cause and rotavirus diarrhea hospitalizations pre- and post-rotavirus vaccine introduction. RESULTS: The proportion of diarrhea hospitalizations due to rotavirus declined by 25-44% among all children <5 years of age during 2013-2015 with a shift in rotavirus hospitalizations to older age groups. The proportion of total hospitalizations due to diarrhea among children <5 years of age decreased from 19% pre-vaccine introduction to 12-13% post-vaccine introduction. In the national hospital discharge data, substantial decreases were observed in all-cause diarrhea hospitalizations among children <5 years of age in 2013 and 2014 but these gains lessened in 2015-2016. DISCUSSION: Continued monitoring of long-term trends in all-cause diarrhea and rotavirus hospitalizations is important to ensure that the impact of the vaccination program is sustained over time and to better understand the changing age dynamics of diarrhea and rotavirus hospitalizations in the post vaccine introduction era. PMID- 29754703 TI - Progression of a series of patients with relapsing-remitting multiple sclerosis treated for 7 years with natalizumab using the "no evidence of disease activity" parameter. AB - INTRODUCTION: The safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions. OBJECTIVE: To determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the "no evidence of disease activity" (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters. PATIENTS AND METHODS: We performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions. RESULTS: The study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti-JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy. CONCLUSIONS: Natalizumab is highly effective as measured by the NEDA long-term remission parameter. PMID- 29754702 TI - Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound. AB - Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (tau, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although tau ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics. PMID- 29754704 TI - Genetic Advances in Post-traumatic Stress Disorder. AB - Post-traumatic stress disorder, or PTSD, is a condition that affects a subgroup of individuals that have suffered a previous traumatic event capable of generating changes at a psychological and behavioural level. These changes affect the personal, family, and social environment of those who suffer from this condition. Different genes have been identified as risk markers for development of this disorder. The population heterogeneity and individual differences (genetic and environmental) of each subject have made it difficult to identify valid markers in previous studies. For this reason, studies of Gene x Environment (G*E) have gathered importance in the last two decades, with the aim of identifying of the phenotypes of a particular disease. These studies have included genes such as SLC64A, FKBP5, and ADCYAP1R1, among others. Little is known about the interaction between the genes, pathways, and the molecular and neural circuitry that underlie PTSD. However their identification and association with stimuli and specific environments that stimulate the development of PTSD makes it focus of interest for identify genomic variations in this disorder. In turn, the epigenetic modifications that regulate the expression of genes involved in the hypothalamic-pituitary-adrenal (HPA) axis and the amygdala- hippocampal medial prefrontal cortex circuits play a role in the identification of biomarkers and endophenotypes in PTSD. In this review, the advances in genetic and epigenetic that have occurred in the genomic era in PTSD are presented. PMID- 29754705 TI - Inflammatory Markers in the Staging of Bipolar Disorder: A Systematic Review of the Literature. AB - BACKGROUND: Previous studies suggest that inflammatory molecules play an important role in the pathophysiology of Bipolar Disorder (BD). The evidence suggests that BD may present a progressive course. Therefore there are theories that postulate the relationship between progression and stages of the disease with distinct peripheral biomarkers. OBJECTIVE: The aim of this study was to carry out a systematic review of the literature of studies about the association between peripheral inflammatory markers and clinical variables related with staging in BD patients. METHODS: We conducted a systematic review using electronic databases: PubMed, SciELO, LiLACS and PsycINFO. Keywords were divided into inflammatory markers and, BD and staging. Studies involving euthymic BD patients, studies evaluating peripheral biomarkers and studies correlating these with clinical variables related to neuroprogression or stage of BD were included. RESULTS: We present and discuss the methods and findings of ten articles. The inflammatory markers were measured with different techniques and show some contradictories results. The TNF superfamily and inflammatory cytokines may have a relationship with the neuroprogression of the disease. CONCLUSIONS: This study suggests that TNF and ILs could play a role in neuroprogression. However, longitudinal studies are needed to clarify the relationship between factors associated with neuroprogression. PMID- 29754706 TI - Ethics Committees and Mental Health. AB - Although research processes are covered by the objectivity of science, they are still influenced by the interests of those who conduct them. This is why high level committees have been tasked with defining the scope of the studies and performing a thorough assessment of them, since these imply great dilemmas. This premise leads to the emergence of Ethics Committees, where liaison psychiatry has an important place due to its communication abilities and knowledge of the human behavior. This paper attempts to provide some observations to take into account when discussing the link between ethics and mental health. In this work, the authors approach the question of ethics committees and the importance that psychiatrist performance has within them. This is done through a review of relevant papers on the subject. A detailed description on research ethics is provided in terms of justification, purpose and duties. Likewise, emphasis is placed on each of the areas in which psychiatrists are involved and bear great responsibilities in the medical decision-making process. Similarly, this description also includes the moment in which participants give their informed consent when taking part in medical research. Finally, we conclude that there are several questions regarding the relevance given to these committees in the methodological and ethical assessment of research projects. This in turn implies greater effort in the search for a culture of quality which highlights the emphasis on research subjects. PMID- 29754707 TI - Legalization of Marijuana for Medical Use in Mexico. Open File. PMID- 29754708 TI - Mental health as a public health policy. PMID- 29754709 TI - Evaluation of the stigma towards people with a diagnosis of Schizophrenia using a Knowledge Scale. AB - INTRODUCTION: Social stigma is the assigning of negative stereotypes to people with schizophrenia. Different measurement tools have been used to evaluate this, including knowledge scales. The aim of this study was to evaluate the public stigma by measuring this knowledge and relate the degree of information with variables that have shown to influence on stigma presented by the affected population. METHODS: The sample was composed of 399 people and the inclusion criterion was being between 18 and 65 years of age. The "Questionnaire of knowledge on schizophrenia" was applied, as well as a questionnaire to collect sociodemographic information. Participants were recruited in places with large crowds. The following analyses were performed: multiple correlations, non parametric bivariate and hierarchical clusters. RESULTS: The questionnaire had two dimensions: "Beliefs on the knowledge of schizophrenia" and "Attitudes towards schizophrenia". There are significant differences between them, and the contact with people with SMI. In the analysis of clusters, there was difference in the two groups according to the combination of the two dimensions of the tools. CONCLUSIONS: It is highlighted that none of the dimensions measures true knowledge, and the questionnaire has an attitudinal dimension. More than contact itself, it is the type of interaction of a relevant variable at the level of stigma that questions the traditional hypothesis of contact. Further research is required on the characteristics of the tool and the aspects of the contact associated to a lower level of stigma in the population. PMID- 29754710 TI - Attributional Biases in Psychiatric Patients, a Religious, and a Control Group in the Assessment of a Hallucinatory Experience: The "White Christmas Test". AB - The aim of this study was to evaluate the auditory hallucinatory experience in a clinical sample of patients with psychiatric symptoms (e.g. Schizophrenia), a religious group (eg. Christians) and a "control" group (with no mental disorder and non-religious). The sample consisted of individuals of both sexes. The patient sample was recruited in two psychiatric hospitals of Buenos Aires City, the religious from an evangelical cult, and people with no religious beliefs or previous psychiatric symptoms (control group). The Hallucinatory Experiences Questionnaire and the Oxford-Liverpool Inventory Feelings and Experiences were the measurement tools used. The White Christmas Test was also administered in order to assess the degree of vivid imagery hearing based on a version of signal detection paradigm in which the subjects think that they hear a song in the background of white noise. The results showed that patients showed greater attributional bias (compared with evangelicals and the control group), but the religious group also tended to show greater bias (although less) than the control group. In addition, patients tended to show greater schizotypal and hallucinatory experiences compared with the evangelicals and the control group, but surprisingly, the control group showed higher negative schizotypy than the religious group, which indicates that religious practices could help reduce the negative effects of schizotypy. PMID- 29754711 TI - Changes in Resting EEG in Colombian Ex-combatants ith Antisocial Personality Disorder. AB - INTRODUCTION: Although the social and economic consequences of Colombian internal conflicts mainly affected the civilian population, they also had other implications. The ex-combatants, the other side of the conflict, have been the subject of many studies that question their personality structures and antisocial features. Results suggest that ex-combatants usually have characteristics of an antisocial personality disorder (ASPD) that is related with their behaviour. METHODS: Quantitative EEG (qEEG) was used to evaluate differences in cortical activity patterns between an ex-combatants group and a control group. The Psychopathy Checklist-Revised (PCL-R) was used to assess the presence of ASPD in the ex-combatants group, as well as the Diagnostic Interview for Genetic Studies (DIGS) for other mental disorders classified in the DCI-10. RESULTS: There are significant differences in psychopathy levels between groups, as well as in alpha 2 and beta waves, especially in left temporal and frontal areas for alpha-2 waves and left temporal-central regions for beta waves. CONCLUSIONS: qEEG measurements allow spectral resting potential to be differentiated between groups that are related with features typically involved in antisocial personality disorder, and to correlate them with patterns in the questionnaires and clinical interview. PMID- 29754712 TI - To What Extent do Clinical Practice Guidelines Respond to the Needs and Preferences of Patients Diagnosed with Obsessive-Compulsive Disorder? AB - INTRODUCTION: The number of Clinical Practice Guidelines (CPG) to help in making clinical decisions is increasing. However, there is currently a lack of CPG for Obsessive-Compulsive Disorder that take into account the requirements and expectations of the patients. OBJECTIVE: The aim of the present study was to determine whether recommendations of the NICE guideline, "Obsessive-compulsive disorder: core interventions in the treatment of obsessive-compulsive disorder and body dysmorphic disorder" agrees with the needs and preferences of patients diagnosed with OCD in the mental health service. MATERIAL AND METHOD: Two focal groups were formed with a total of 12 participants. They were asked about the impact of the disorder in their lives, their experiences with the mental health services, their satisfaction with treatments, and about their psychological resources. Preferences and needs were compared with the recommendations of the guidelines, and to facilitate their analysis, they were classified into four topics: information, accessibility, treatments, and therapeutic relationship. RESULTS: The results showed a high agreement between recommendations and patients preferences, particularly as regards high-intensity psychological interventions. Some discrepancies included the lack of prior low-intensity psychological interventions in mental health service, and the difficulty of rapid access the professionals. CONCLUSIONS: There is significant concordance between recommendations and patients preferences and demands, which are only partially responded to by the health services. PMID- 29754713 TI - Endoscopic Partial Arytenoidectomy for Bilateral Vocal Fold Paralysis: Medially Based Mucosal Flap Technique. AB - PURPOSE: Endoscopic partial arytenoidectomy (EPA) is one of the static operations for treatment of bilateral vocal fold paralysis (BVFP). Improvement in airway may cause voice loss and aspiration. The author reports his experience on EPA using medially based mucosal flap to enlarge posterior glottis without removing any part of membranous vocal fold. MATERIALS AND METHODS: Sixty-four consecutive patients with BVFP underwent EPA. Pre- and postoperative evaluations included Voice Handicap Index-30, aerodynamic and acoustic analysis, flow volume loops, perceptual evaluation of pre- and postoperative voice using grade, roughness, breathiness, asthenia, strain (GRBAS) scale, speech intensity, breathing ability evaluation, and functional outcome swallowing scale. RESULTS: Nine patients had preoperative tracheotomy and one patient required postoperative tracheotomy. All tracheotomized patients were decannulated 1 month after surgery. Fifty-six patients (88%) did not report dyspnea in their daily activities and were considered satisfied with their postoperative airway; eight patients required revision: seven total arytenoidectomy and one posterior cricoid split with costal cartilage grafting. All Voice Handicap Index-30 results and all acoustic results (except fundamental frequency) increased significantly after surgery (P < 0.05). All aerodynamic analysis results (except mean airflow rate) decreased significantly after EPA (P < 0.05). Mean airflow rate increased significantly after EPA (P < 0.05). All flow volume loop parameters increased significantly after EPA (P < 0.05). Perceptual comparison of pre- and postoperative voice revealed similar grade and roughness (P > 0.05); however, increased breathiness (P < 0.05) was observed. Mean speech intensity decreased from 67 dB to 61 dB (P < 0.05). Postoperative breathing ability was significantly better. Pre- and postoperative functional outcome swallowing scales were not significantly different (P > 0.05). CONCLUSIONS: EPA is a very successful static surgical option for BVFP. It results in comfortable airway with mild voice handicap. Postoperatively, it does not increase aspiration significantly. Endoscopic total arytenoidectomy is reserved for revision of failures. PMID- 29754714 TI - Membrane Potential Distinctly Modulates Mobility and Signaling of IL-2 and IL-15 Receptors in T Cells. AB - The high electric field across the plasma membrane might influence the conformation and behavior of transmembrane proteins that have uneven charge distributions in or near their transmembrane regions. Membrane depolarization of T cells occurs in the tumor microenvironment and in inflamed tissues because of K+ release from necrotic cells and hypoxia affecting the expression of K+ channels. However, little attention has been given to the effect of membrane potential (MP) changes on membrane receptor function. Therefore, we studied the influence of membrane de- and hyperpolarization on the biophysical properties and signaling of interleukin-2 (IL-2) and interleukin-15 (IL-15) receptors, which play important roles in T cell function. We investigated the mobility, clustering, and signaling of these receptors and major histocompatibility complex (MHC) I/II glycoproteins forming coclusters in lipid rafts of T cells. Depolarization by high K+ buffer or K+ channel blockers resulted in a decrease in the mobility of IL-2Ralpha and MHC glycoproteins, as shown by fluorescence correlation spectroscopy, whereas hyperpolarization by the K+ ionophore valinomycin increased their mobility. Contrary to this, the mobility of IL 15Ralpha decreased upon both de- and hyperpolarization. These changes in protein mobility are not due to an alteration of membrane fluidity, as evidenced by fluorescence anisotropy measurements. Forster resonance energy transfer measurements showed that most homo- or heteroassociations of IL-2R, IL-15R, and MHC I did not change considerably, either. MP changes modulated signaling by the two cytokines in distinct ways: depolarization caused a significant increase in the IL-2-induced phosphorylation of signal transducer and activator of transcription 5, whereas hyperpolarization evoked a decrease only in the IL-15 induced signal. Our data imply that the MP may be an important modulator of interleukin receptor signaling and dynamics. Enhanced IL-2 signaling in depolarized Treg cells highly expressing IL-2R may contribute to suppression of antitumor immune surveillance. PMID- 29754716 TI - Sex disparity persists in the prevention of cardiovascular disease in women on statin therapy compared to that in men. AB - BACKGROUND AND AIMS: The aim of this study was to assess whether women differ from men with regard to lowering lipid levels, achieving target of optimal lipid levels, and analyzing evidence-based dose and intensity of statin prescription in primary care patients. METHODS AND RESULTS: A multicenter cross-sectional survey was conducted among 1046 patients with dyslipidemia (554 women) who were receiving statin therapy from the Primary Health Care of Andalucia (Spain). A random sample was obtained using data from the electronic health record system. The primary outcomes were the prescription of statin therapy (intensity and dose), lowering lipid levels, and achieving target of optimal lipid levels. Women were less likely to be treated with a more potent statin than men (9.2% vs. 14.4%, p = 0.009), and they received lower doses (45 +/- 59 mg/day vs. 56 +/- 71 mg/day, p = 0.004) than men. Total cholesterol and LDL-C levels were higher in women than in men (5.7 +/- 1.3 mmol/l vs. 5.2 +/- 1.2 mmol/l, p < 0.0001 and 3.5 +/- 1.2 mmol/l vs. 3.1 +/- 1.0 mmol/l, p < 0.0001, respectively). Compliance with established goals for total cholesterol (47.7% vs. 31.3%, p < 0.0001) and LDL-C (39.7% vs. 25.4%, p < 0.0001) was superior in men than in women. In multivariate analysis, adjusted for age, the variables male gender and CVD were associated with a higher compliance with total cholesterol and LDL-C target levels, and the variable diabetes mellitus 2 was associated with a lower compliance with HDL-C and triglycerides target levels. CONCLUSIONS: Women were less likely to be prescribed high-intensity statin to achieve total cholesterol and LDL-C target levels, and mean doses of statin were lower in women than in men. Dyslipidemia is less closely controlled in women than in men. PMID- 29754717 TI - Diagnosis of asthma-COPD overlap: Is it possible a global definition? PMID- 29754715 TI - Assembly Kinetics of Vimentin Tetramers to Unit-Length Filaments: A Stopped-Flow Study. AB - Intermediate filaments (IFs) are principal components of the cytoskeleton, a dynamic integrated system of structural proteins that provides the functional architecture of metazoan cells. They are major contributors to the elasticity of cells and tissues due to their high mechanical stability and intrinsic flexibility. The basic building block for the assembly of IFs is a rod-like, 60 nm-long tetrameric complex made from two antiparallel, half-staggered coiled coils. In low ionic strength, tetramers form stable complexes that rapidly assemble into filaments upon raising the ionic strength. The first assembly products, "frozen" by instantaneous chemical fixation and viewed by electron microscopy, are 60-nm-long "unit-length" filaments (ULFs) that apparently form by lateral in-register association of tetramers. ULFs are the active elements of IF growth, undergoing longitudinal end-to-end annealing with one another and with growing filaments. Originally, we have employed quantitative time-lapse atomic force and electron microscopy to analyze the kinetics of vimentin-filament assembly starting from a few seconds to several hours. To obtain detailed quantitative insight into the productive reactions that drive ULF formation, we now introduce a "stopped-flow" approach in combination with static light scattering measurements. Thereby, we determine the basic rate constants for lateral assembly of tetramers to ULFs. Processing of the recorded data by a global fitting procedure enables us to describe the hierarchical steps of IF formation. Specifically, we propose that tetramers are consumed within milliseconds to yield octamers that are obligatory intermediates toward ULF formation. Although the interaction of tetramers is diffusion controlled, it is strongly driven by their geometry to mediate effective subunit targeting. Importantly, our model conclusively reflects the previously described occurrence of polymorphic ULF and mature filaments in terms of their number of tetramers per cross section. PMID- 29754718 TI - Predicting outcomes in bronchiectasis. PMID- 29754719 TI - Pulmonary function and respiratory muscle strength after arthrodesis of the spine in patients who have adolescent idiopathic scoliosis. PMID- 29754720 TI - Symptoms irregularity and increased risk of COPD acute exacerbations. PMID- 29754721 TI - Tuberculosis and gender - Factors influencing the risk of tuberculosis among men and women by age group. PMID- 29754722 TI - Lung cancer in pregnancy - Report of a case treated with crizotinib. PMID- 29754723 TI - Who Should Decide? Residence Capacity Evaluation of a Cognitively-Impaired Older Adult Requesting an "Unsafe" Discharge to Home. PMID- 29754724 TI - [Sharing experience in venous thromboembolism management]. PMID- 29754725 TI - [Time in therapeutic range (TTR) and follow-up of patients on vitamin K antagonist: A cohort analysis]. AB - INTRODUCTION: Despite the increasing utilization of direct oral anticoagulant (DOAC) prescriptions, vitamin K antagonists (VKAs) remain the treatment of choice for treating and preventing thromboembolic events. The morbidity and mortality of VKAs are partly due to the difficulty of keeping the patient within the therapeutic range. For patients treated by VKA, time in therapeutic range (TTR) is a quality parameter of treatment, widely used in clinical trials but rarely by prescribers. It is well established that its use correlates with the risk of hemorrhage, thrombosis or mortality. We studied this parameter in a cohort of patients to evaluate the quality of their therapeutic follow-up and tried to identify risk factors for low TTR. METHODS: The study was made in collaboration with LaboSud Oc Biologie for a duration of 4 months. It included 3387 patients representing 2,4029 INR. We calculated the patients' TTR. The laboratory transmitted to us the sex and age of each patient and the VKA molecule used, the therapeutic range and the specialty of the prescriber. We then analyzed the odds ratio associated with these different factors. RESULTS: The mean TTR was 68%, close to the TTR recommended by scientific societies. Patient's sex was the only statistically correlated factor, with a worse equilibrium in females taking VKAs (OR=1.22, 95% CI: 1.06-1.39, P=0.00552). Many factors usually correlated with poor equilibrium under VKA have not been studied due to lack of information. CONCLUSION: Given the context of economic restriction and the TTR of our cohort close to the recommended 70%, there would be no benefit in terms of safety to prefer DOAC for the patients involved in this study. Regular monitoring of the individual patient's as well as the cohort's TTR should optimize the management of patients receiving VKAs. PMID- 29754726 TI - [Doppler ultrasonography of the renal artery: Guidelines and predictive factors for the presence of a tight stenosis. Retrospective analysis of 450 consecutive examinations]. AB - : Duplex ultrasonography screening for renal artery stenosis has been the object of guidelines published by four societies designed to optimize the cost effectiveness of the examination. OBJECTIVES: To determine how well guideline indications for ultrasonography matched with requests and results in our university hospital; to determine whether compliance with guidelines was predictive of renal artery stenosis; to identify guidelines predictive of presence of stenosis; and to determine whether other predictive factors can be recognized. MATERIAL AND METHODS: Requests and results of 450 Duplex ultrasonography examinations of the renal arteries performed from January 1st 2014 to December 31st 2015 were compared with published guidelines. RESULTS: At least one guideline indication was identified for 212 of the 450 examinations performed (47.1%). Among these examinations, renal artery stenosis>=70% was identified in 18 patients (8.0%). No case of stenosis was identified during examinations performed outside guideline indications. Factors predictive of stenosis were: compliance with guidelines (OR=21.86 [2.88; 165.8]). Predictive guidelines were: resistant hypertension in spite of appropriate treatment (OR=3.85, [1.44; 10.33], P=0.011), accelerated hypertension (OR=7.30, [1.40; 37.99], P=0.049), sudden unexplained pulmonary edema (OR=7.30, [1.40; 37.99], P=0.049), unexplained renal insufficiency (OR=3.58, [1.37; 9.37], P=0.011), unexplained renal hypotrophy (OR=16.69, [4.38; 63.69], P<0.001), renal asymmetry (OR=4.32, [1.45; 12.85], P<0.016). No other factor was predictive of renal stenosis. These examinations had therapeutic consequences in only 50% of patients. CONCLUSION: This study confirms the relevance of published guidelines. The diagnostic-effectiveness of Duplex ultrasonography examinations to search for renal artery stenosis depends upon compliance with these guidelines. PMID- 29754727 TI - [Identifying barriers to screening for abdominal aortic aneurysm in general practice: Qualitative study of 14 general practitioners in Paris]. AB - INTRODUCTION: Abdominal aortic aneurysm (AAA) is a silent pathology with often fatal consequences in case of rupture. AAA screening, recommended in France and many other countries, has shown its effectiveness in reducing specific mortality. However, AAA screening rate remains insufficient. OBJECTIVE: To identify barriers to AAA screening in general practice. MATERIAL AND METHOD: Qualitative study carried out during 2016 among general practitioners based in Paris. RESULTS: Fourteen physicians were included. Most of the barriers were related to the physician: unawareness about AAA and screening recommendations, considering AAA as a secondary question not discussed with the patient, abdominal aorta not included in cardiovascular assessment, no search for a familial history of AAA, AAA considered a question for the specialist, lack of time, lack of training, numerous screenings to propose, oversight. Some barriers are related to the patient: unawareness of the pathology and family history of AAA, refusal, questioning the pertinence of the doctor's comments, failure to respect the care pathway. Others are related to AAA: source of anxiety, low prevalence, rarity of complications. The remaining barriers are related to screening: cost-benefit and risk-benefit ratios, sonographer unavailability, constraint for the patient, overmedicalization. CONCLUSION: Information and training of general practitioners about AAA must be strengthened in order to optimize AAA screening and reduce specific mortality. PMID- 29754728 TI - [Thrombosis and cancer: Awareness of private practitioners and patients in Poitou Charentes, a French region]. AB - OBJECTIVE: The purpose of this study was to enhance awareness among healthcare professionals about the application of guidelines relating to the management of venous thromboembolism (VTE) in cancer patients. METHODS: This collective approach involved: the Regional Health Agency (ARS), the Unions of Representatives of Healthcare Professionals (URPS), the Observatory of Drugs, the Medical Devices and Therapeutic Innovation agency (OMEDIT), the regional Oncology Network and specialist physicians. Performance indicators were defined to evaluate the actions performed. RESULTS: Multidisciplinary information meetings were organized. A standardized patient's folder was proposed in all healthcare institutions dealing with cancer, as a link between healthcare professionals and patients. Information brochures were prepared for healthcare professionals and patients. Web-based surveys were taken among healthcare professionals to evaluate changes in their knowledge and practices before and after the first actions taken. CONCLUSION: This collective approach improved the awareness of health professionals about care practices for VTE in cancer patients. PMID- 29754729 TI - [Femoral pseudoaneurysms in drug addicts: About 4 cases]. AB - PURPOSE: To describe the therapeutic management of false aneurysms of the femoral artery in drug addicts. PATIENTS AND METHODS: We report the cases of four drug addicts with pseudoaneurysms of the femoral artery. RESULTS: All patients were male with a mean age of 36 years. Emergency surgical treatment involved removal of the pseudoaneurysm followed by a venous graft (n=3) or patch (n=1). The post operative period was uneventful for three patients. One patient required early revision with a second venous bypass after bleeding from the first then later a second revision for resection of infected tissue and sartorius muscle plasty to cover the groin area. Late outcome was favorable for all patients after an average 12-month follow-up. CONCLUSION: No consensus has been reached concerning the appropriate treatment for false aneurysms of the femoral artery in drug addicts. Analyses of larger series with longer follow-ups are needed to elucidate the best emergency surgical methods capable of reducing the risk of rupture. PMID- 29754730 TI - [Direct oral anticoagulants (DOACS): A necessary focus]. AB - In 2008, we decided to enter the era of direct oral anticoagulants (DOACS). Was that the right decision to make? The answer will depend on how well we meet the conditions of proper use. This means avoiding underdosing and overdosing as well as understanding how DOACS were validated so that our prescriptions fulfill their role in the management of thrombotic disease. PMID- 29754731 TI - [Type A intramural hematoma of aorta: An undervalued clinical entity]. AB - Intramural hematoma of the ascending aorta occurs after rupture of the vasa vasorum. Previously considered as a first step of acute aortic dissection, it was later defined as a separate entity that may or may not lead to arterial dissection. The debate about the most appropriate treatment for a 69-year-old patient with intramural hematoma of the ascending aorta, led to this extensive review of the literature demonstrating that intramural hematoma type A is a life threatening condition requiring urgent surgical support. PMID- 29754732 TI - [Hypertension in black patients]. PMID- 29754733 TI - Assessing the Benefits of Preoperative Thoracic Epidural Placement for Lung Transplantation. AB - OBJECTIVE: The authors investigated the effect of preoperative thoracic epidural (PreTE) catheter placement versus not placing a preoperative thoracic epidural catheter (NoPreTE) on the duration of postoperative ventilation time, time to become coherent (measured as time to become Confusion Assessment Method-intensive care unit [ICU] negative), opioid consumption, ICU length of stay (LOS), and hospital LOS. DESIGN: Retrospective cohort design. SETTING: Single institution, university hospital. PARTICIPANTS: Patients undergoing lung transplantation. COMPARISON GROUPS: PreTE group was defined as patients who received a thoracic epidural preoperatively. NoPreTE group was defined as patients who either received a thoracic epidural postoperatively or who did not receive a thoracic epidural postoperatively. MEASUREMENTS AND MAIN RESULTS: Fifty-six patients for the PreTE and 99 for NoPreTE groups were included in the study. After a excluding patients with postoperative ventilation times greater than 96 hours, preoperative thoracic epidural was associated with shorter time on the ventilator (19.1 hours v 30.6 hours; p < 0.001), time to become coherent (26.4 hours v 37.6 hours; p = 0.008), ICU LOS (6.4 days v 12.4 days; p = 0.018), and hospital LOS (15.9 days v 23.5 days; p = 0.04) compared to patients who did not receive a preoperative epidural. After controlling for single versus double lung transplantation and duration of cardiopulmonary bypass (CPB), differences in time to become coherent, ICU LOS, and hospital LOS became nonsignificant. Opioid consumption was significantly higher in those patients who did not receive a preoperative epidural. Despite a high rate of anticoagulation for CPB (89.5%), no neurologic complications or epidural hematomas were observed. CONCLUSION: For those lung transplant patients ventilated for less than 96 hours postoperatively, preoperative thoracic epidural placement is associated with shorter postoperative ventilator time and reduced opioid consumption. Time to become coherent postoperatively, ICU LOS, and hospital LOS also improved in this cohort, though the significance decreased after adjusting for possible confounders. A larger prospective study is necessary to confirm if timing of thoracic epidural placement alters time to become coherent postoperatively and ICU LOS. PMID- 29754734 TI - History of Cardiac Anesthesia in India. PMID- 29754735 TI - Using stable isotope analysis to assess trophic relationships between Atlantic bluefin tuna (Thunnus thynnus) and striped dolphin (Stenella coeruleoalba) in the Strait of Gibraltar. AB - Stable isotope analysis (delta13C and delta15N from liver and muscle) was used to assess trophic relationships between Atlantic bluefin tuna (ABFT) (Thunnus thynnus) and striped dolphin (SC) (Stenella coeruleoalba) in the Strait of Gibraltar (SoG). delta15N values from ABFT muscle and liver tissues were significantly different from those of dolphin samples, but no for delta13C values. Diet estimation by MixSIAR models from muscle and liver revealed that ABFT fed mainly on squids (Todaropsis eblanae and Illex coindetii). The shrimp Pasiphaea sp. was estimated to be the most important prey-species in the diet of SC. Trophic positions estimated from muscle and liver isotopic data suggested that ABFT occupy a higher trophic level than SC. Estimations of isotopic niche, as measured by the standard ellipse area, indicated that ABFT show a broader trophic niche than SC; furthermore, SEAc did not show trophic overlap between both predators. The results of this study suggest that resource partitioning occurs between ABFT and SC in the SoG ecosystem. PMID- 29754736 TI - Unrevealing variation of microbial communities and correlation with environmental variables in a full culture-cycle of Undaria pinnatifida. AB - Bacteria are the most abundant organisms in natural environment and dominant drivers of multiple geochemical functions. Drawing a global picture of microbial community structure and understanding their ecological status remain a grand challenge. As a typical artificial process, aquaculture provides a large amount of foods and creates great economic benefits for human beings. However, few studies are aimed at the microbial community in the aquaculture environment of aquatic plants. We analyzed microbial communities from 21 water samples in a coastal aquaculture area during the whole cultural process of Undaria pinnatifida by using high-throughout sequencing of 16S rRNA gene. The progression of U. pinnatifida aquaculture can be divided into three stages, named Seeding, Growth, and Maturity, respectively. Microbial community structures in water of the aquaculture area were significantly changed during the progression of U. pinnatifida aquaculture. The relative abundance of Flavobacteriia and Thaumarchaeota classes increased in Growth stage, and beta-proteobacteria and Acidimirobiia classes decreased with the growth of U. pinnatifida. Meanwhile, environmental factors shaping the microbial community structures were uncovered during the U. pinnatifida aquaculture by using canonical correspondence analysis and Mantel test, in which temperature, dissolved oxygen, pH and nitrogen could be the major influencing factors. In addition, the microbial functions based on KEGG pathways were predicted from the microbial community compositions by PICRUSt. The comparison of predicted functions suggested that Environmental Information Processing and Genetic Information Processing were the functional categories with the most obvious shift in abundance among different stages of U. pinnatifida aquaculture. The findings of this study allowed us to better understand the microbial community in coastal aquaculture systems and the impact of seaweed cultivation on coastal ecosystems. PMID- 29754738 TI - Psychological follow-up care of neurofibromatosis type 2 patients and their relatives. AB - Neurofibromatosis type 2 (NF2) confronts patients and their relatives with the dual issue of a progressive disease and disability. Deafness creates a brutal rupture in the patients' course of life, and other disabilities often follow in addition, that further deteriorates their quality of life. Hearing rehabilitation, via a cochlear implant and auditory brainstem implant, attempts to reduce the feeling of isolation and suffering due to communication impairment. A NF2-specific quality of life questionnaire not only helps to evaluate the impact of the disease but it is also useful therapy proposals (treatment, auditory implants). This may contribute to improve the quality of care for patients and their families. Within the multidisciplinary NF2 team, the psychologist offers constant listening of patients, and their suffering at each stage of the disease, that takes into account the life context in which the disease occurs, thus playing a major role in the patient care offered. PMID- 29754737 TI - Biomechanical characterization of the native porcine aortic root. AB - A thorough understanding of the well-functioning, native aortic root is pivotal in an era, where valve sparing surgical techniques are developed and used with increasing frequency. The objective of this study was to characterize the local structural stiffness of the native aortic root, to create a baseline for understanding how different surgical interventions affect the dynamics of the aortic root. In this acute porcine study (N = 10), two dedicated force transducers were implanted to quantify the forces acting on both the annular plane and on the sinotubular junction (STJ). To assess the changes in geometry, eleven sonomicrometry crystals were implanted within the aortic root. The combination of force and length measurements yields the radial structural stiffness for each segment of the aortic root. The least compliant segment at the annular plane was the right-left interleaflet triangle with a stiffness modulus of 1.1 N mm-1 (SD0.4). At the sinotubular junction the same segment (right-left) was most compliant, compared with the two other segments, however not statistically significant different. The elastic energy storage was derived from the aortic root pressure volume relationship; the mean elastic energy storage was 826 uJ (SD529). In conclusion, the aortic root has been characterized in terms of both segmental forces, segmental change in length and elastic energy storage. This study is the first to assess the radial structural stiffness of different segments of the aortic root. The presented data is reference for further studies regarding the impact of surgical interventions on the aortic root. PMID- 29754739 TI - High-field intraoperative MRI in glioma surgery: A prospective study with volumetric analysis of extent of resection and functional outcome. AB - BACKGROUND: High-field intraoperative MRI (IoMRI) is a useful tool to improve the extent of glioma resection (EOR). OBJECTIVE: To compare the interest of 1.5T IoMRI in glioma surgery between enhancing and non-enhancing tumors, based on volumetric analysis. METHODS: A prospective single-center study included consecutive adult patients undergoing glioma surgery with IoMRI. Volumetric evaluation was based on FLAIR hypersignal after gadolinium injection in non enhancing tumors and T1 hypersignal after gadolinium injection in enhancing tumors. Endpoints comprised: residual tumor volume (RTV), EOR, workflow and clinical outcome on Karnofsky performance score (KPS). RESULTS: Fifty-three surgeries were performed from July 2014 to January 2016. Thirty-four patients underwent one IoMRI, and 19 two IoMRIs. In non-enhancing tumors, intraoperative RTV on 1st IoMRI T2/FLAIR was higher than in enhancing tumors on T1 sequences (7.25cm3 vs. 0.74cm3, respectively; P=0.008), whereas the RTV on 2nd IoMRIs and final RTV were no longer significantly different. After IoMRI, 72% of patients underwent additional resection. In non-enhancing tumors, EOR increased from 77.3% on 1st IoMRI to 97.4% on last MRI (P<0.001). Taking all tumors together, final RTV values were: median=0cm3, mean=3.9cm3. Mean final EOR was 94%. In 25% of patients, KPS was reduced during early postoperative course; at 3 and 6 months postoperatively, median KPS was 90. CONCLUSION: Intraoperative MRI guidance significantly enhanced the extent of glioma resection, especially for non- or minimally enhancing tumors, while preserving patient autonomy. PMID- 29754742 TI - Mesopithecus pentelicus from the Turolian locality of Kryopigi (Kassandra, Chalkidiki, Greece). AB - New material of the Mio-Pliocene colobine Mesopithecus from the Turolian locality of Kryopigi (Greece) is described here. It includes a complete skull with the atlas attached and other dental and postcranial elements representing at least five individuals (four males and one female). The material is compared with Mesopithecus delsoni, Mesopithecus pentelicus, Mesopithecus monspessulanus and intermediate forms from more than a dozen Turolian localities of the Greco Iranian province. These comparisons support the attribution of the Kryopigi material to M. pentelicus. The chronostratigraphic distribution of Mesopithecus species and intermediate forms suggests that the Kryopigi fauna could be dated as younger than the Perivolaki locality with M. delsoni/pentelicus (7.1-7.3 Ma, MN12) and older than the Dytiko localities with M. aff. pentelicus, M. cf. pentelicus and M. cf. monspessulanus (?middle MN13). The dimensions of the atlas are within the distribution of extant colobines. The skull shows bite-marks, probably caused by the hyaena Adcrocuta eximia. PMID- 29754740 TI - Detection of endometrial cancer cells in the fallopian tube lumen is associated with adverse prognostic factors and reduced survival. AB - OBJECTIVE: Stage is a critical determinant of prognosis and treatment for endometrial cancer (EC) patients. Women who have had a tubal ligation for sterilization have improved EC survival, secondary to lower stage at presentation, suggesting that transtubal spread may represent an important route of metastasis. We evaluated detection of intraluminal tumor cells (ILTCs) in relation to tumor characteristics and survival. METHODS: One pathologist retrospectively evaluated hematoxylin and eosin sections of routinely collected fallopian tubes for ILTCs from 295 EC patients, masked to outcome. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between demographic (age, race) and clinical [FIGO 2009 stage, lymphovascular space invasion (LVSI), histological subtype] characteristics and ILTCs. Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations between ILTCs and recurrence-free survival (RFS) and EC-specific survival, overall and stratified by histological subtype or stage. RESULTS: In univariable logistic regression models, age (55-64 vs. >=65: OR = 3.41, 95% CI = 1.48-7.84), stage (stage IV vs. stage I OR = 14.58, 95% CI = 5.27-40.35), LVSI (OR = 2.93, 95% CI = 1.42-6.04), and histological subtype (serous vs. low-grade endometrioid OR = 3.21, 95% CI = 1.08-9.58), were associated with ILTCs. Only age and stage remained significantly associated with ILTCs in adjusted models. ILTCs were significantly associated with lower EC specific survival among women with serous EC or stage I disease; however, adjustment for age, stage, and histology attenuated these associations. CONCLUSION: Our findings suggest that ILTCs are associated with adverse EC prognostic features and reduced survival in cases of early stage or serous histology. PMID- 29754743 TI - The effect of ontogeny on estimates of KNM-WT 15000's adult body size. AB - The Homo erectus specimen KNM-WT 15000 has played a critical role in our understanding of body size evolution. New interpretations suggest that KNM-WT 15000 had a younger age-at-death and a more rapid ontogenetic trajectory than previously suggested. Recent fossil discoveries and new interpretations suggest a wide range of body size and shape variation in H. erectus. Based on these new insights, we argue that KNM-WT 15000's adult stature and body mass could have been much smaller than has been traditionally presented in the literature. Using chimpanzee and modern human growth trajectories, we bracketed the range of possibilities for KNM-WT 15000's adult body size between 160.0 and 177.7 cm (5'3" 5'10") for stature and 60.0 and 82.7 kg (132-182 lbs.) for body mass. These estimates put KNM-WT 15000 near the mean rather than among the largest known H. erectus specimens. PMID- 29754744 TI - Reevaluation of 'endocostal ossifications' on the Kebara 2 Neanderthal ribs. PMID- 29754745 TI - The unusually diverse mortality patterns in the Pacific region during the 1918-21 influenza pandemic: reflections at the pandemic's centenary. AB - The 1918-21 influenza pandemic was the most lethal natural event in recent history. In the Pacific region, the pandemic's effects varied greatly across different populations and settings. In this region, the pandemic's lethal effects extended over 3 years, from November, 1918, in New Zealand to as late as July, 1921, in New Caledonia. Although a single virus strain probably affected all the islands, mortality varied from less than 0.1% in Tasmania, to 22% in Western Samoa. The varied expressions of the pandemic across the islands reflected the nature and timing of past influenza epidemics, degrees of social isolation, ethnicity and sex-related effects, and the likelihood of exposures to pathogenic respiratory bacteria during influenza illnesses. The high case-fatality rate associated with this pandemic seems unlikely to recur in future influenza pandemics; however, understanding the critical determinants of the mass mortality associated with the 1918-21 pandemic is essential to prepare for future pandemics. PMID- 29754746 TI - Cytokine Gene Polymorphism Profiles in Kidney Transplant Patients - Association of +1188A/C RS3212227 SNP in the IL12B Gene Prevents Delayed Graft Function. AB - BACKGROUND AND AIMS: Transplantation is the best treatment option for end stage kidney disease. The most common early complications in post-transplant period are acute rejection (AR) of the graft and delayed graft function (DGF). The underlying mechanisms in these events are heterogeneous and at least in part involve cytokine genes which regulate immune response to allograft. We have investigated whether functional single nucleotide polymorphisms (SNP) in the genes encoding IFN-gamma (IFNG), TNF (TNFA), IL-10 (IL10) and p40 subunit of IL 12/IL-23 (IL12B) could predict risk of AR and DGF in kidney allograft recipients. METHODS: Our study involved 152 kidney transplant recipients on standard immunosuppressive regimen which included calcineurin inhibitors, mycophenolic acid derivatives and corticosteroids. Genotyping of IFNG, TNFA, IL10 and IL12B was performed using commercial TaqMan assays. RESULTS: We found association between the carriers of AA genotype of IL12B +1188A/C polymorphism (rs3212227) and a lower rate of DGF (p = 0.037, OR = 0.45, 95% CI = 0.21-0.96), implying protective role of A allele in the pathogenesis of DGF in kidney transplant recipients, whereas no such association was observed with AR. None of the analyzed SNPs in TNFA (-308G/A), IFNG (+874T/A), IL10 (-1082G/A, -819T/C, 592C/A) were associated with AR or DGF in our patients. CONCLUSIONS: Our study shows a preliminary evidence that the AA genotype of rs3212227 SNP in the IL12B gene might be associated with a lower risk for DGF after kidney transplantation. In the future, additional well-designed large studies are required for the validation of our results. PMID- 29754747 TI - Sexual dimorphism in predisposition to Alzheimer's disease. AB - Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and rate of symptom progression, but the mechanisms underlying this sexual divergence are unknown. Although some have suggested this difference in risk is a reflection of the known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities toward the disease. Although a number of potential risk factors have been hypothesized to mediate these differences, none have been definitively verified. In this review, we first summarize the epidemiologic studies of prevalence and incidence of AD among the sexes. Next, we discuss the most likely risk factors to date that interact with biological sex, including (1) genetic factors, (2) sex hormones (3) deviations in brain structure, (4) inflammation and microglia, and (5) and psychosocial stress responses. Overall, though differences in life span are likely to account for part of the divide between the sexes in AD prevalence, the abundance of preclinical and clinical evidence presented here suggests an increase in intrinsic AD risk for women. Therefore, future studies focusing on the underlying biological mechanisms for this phenomenon are needed to better understand AD pathogenesis in both sexes, with the eventual goal of sex-specific prevention and treatment strategies. PMID- 29754748 TI - Retrospective analysis of postoperative interventions in mandibular fractures: a shift towards outpatient day surgery care. AB - The management of fractured mandibles typically involves admission and operation at the time of presentation. While this should involve only a short stay in hospital these patients are surgically stable, and so priority is often given to more urgent cases. We retrospectively evaluated the postoperative medical requirements of patients who were operated on at Fiona Stanley Hospital, Perth, Western Australia between 1 January 2015 and 31 December 2016. Patients were excluded if they had had multiple facial fractures, multiple injuries, had fractures that were comminuted or in edentulous mandibles, and those who had been in hospital for preoperative medical investigations and care. We also excluded fractures in children aged 16 years and under. The results showed that of a total of 173 patients, 12 had had medical consultations during their hospital stay, and only four had required intervention. The mean (range) preoperative time was 37 (1 - 46) hours and that from operation to discharge 21.5 (2 - 93) hours. While traditional management involves emergency admission and open reduction and internal fixation as soon as possible, delays of up to five days were not associated with appreciably worse outcomes. This, together with the negligible requirements for medical management perioperatively, provides a strong argument for a selected group to be treated as outpatients. PMID- 29754749 TI - Comparison of Oral and Axillary Temperatures in Intubated Pediatric Patients. AB - PURPOSE: Accurate body temperature measurement is essential in providing timely care to critically ill patients. Current practice within the Pediatric ICU (PICU) at a Midwestern academic medical center is to obtain axillary temperatures in endotracheally intubated patients. According to research, axillary temperatures have greater variance than other forms of temperature measurement. Research in adult patients show that oral temperature measurement in endotracheally intubated patients is acceptable as the heated gases from the ventilator has no significant effect on measured temperatures. This study sought to determine if the same is true in pediatrics. DESIGN AND METHODS: Oral and axillary temperatures of endotracheally intubated pediatric patients were obtained during unit prescribed vital assessment intervals. Patients were divided into neonate, infant, and children age groups with 25 sets of temperatures obtained for each group. Descriptive statistics and Bland-Altman plot interpretation were performed to determine confidence intervals for each age group. RESULTS: Bland-Altman plot analysis of oral and axillary routes of temperature measurement showed a high positive correlation within all age groups studied. The infant age group showed lower correlation in comparison to neonates and children. The infant age group also had an outlier of data sets with lower oral temperatures as compared to the axilla. CONCLUSIONS: Oral temperature measurement is a viable alternative to axillary temperature measurement in endotracheally intubated pediatric patients. Correction factors for age groups were calculated for prediction of axillary temperature based on measured oral temperature. PRACTICAL IMPLICATIONS: This study serves as evidence for practice change within the studied unit. PMID- 29754750 TI - Cocaine Place Conditioning Strengthens Location-Specific Hippocampal Coupling to the Nucleus Accumbens. AB - Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings provide in vivo evidence suggesting that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts. PMID- 29754751 TI - Pauses in Cholinergic Interneuron Activity Are Driven by Excitatory Input and Delayed Rectification, with Dopamine Modulation. AB - Cholinergic interneurons (ChIs) of the striatum pause their firing in response to salient stimuli and conditioned stimuli after learning. Several different mechanisms for pause generation have been proposed, but a unifying basis has not previously emerged. Here, using in vivo and ex vivo recordings in rat and mouse brain and a computational model, we show that ChI pauses are driven by withdrawal of excitatory inputs to striatum and result from a delayed rectifier potassium current (IKr) in concert with local neuromodulation. The IKr is sensitive to Kv7.2/7.3 blocker XE-991 and enables ChIs to report changes in input, to pause on excitatory input recession, and to scale pauses with input strength, in keeping with pause acquisition during learning. We also show that although dopamine can hyperpolarize ChIs directly, its augmentation of pauses is best explained by strengthening excitatory inputs. These findings provide a basis to understand pause generation in striatal ChIs. VIDEO ABSTRACT. PMID- 29754752 TI - Hippocampal 5-HT Input Regulates Memory Formation and Schaffer Collateral Excitation. AB - The efficacy and duration of memory storage is regulated by neuromodulatory transmitter actions. While the modulatory transmitter serotonin (5-HT) plays an important role in implicit forms of memory in the invertebrate Aplysia, its function in explicit memory mediated by the mammalian hippocampus is less clear. Specifically, the consequences elicited by the spatio-temporal gradient of endogenous 5-HT release are not known. Here we applied optogenetic techniques in mice to gain insight into this fundamental biological process. We find that activation of serotonergic terminals in the hippocampal CA1 region both potentiates excitatory transmission at CA3-to-CA1 synapses and enhances spatial memory. Conversely, optogenetic silencing of CA1 5-HT terminals inhibits spatial memory. We furthermore find that synaptic potentiation is mediated by 5-HT4 receptors and that systemic modulation of 5-HT4 receptor function can bidirectionally impact memory formation. Collectively, these data reveal powerful modulatory influence of serotonergic synaptic input on hippocampal function and memory formation. PMID- 29754753 TI - A Genetically Encoded Biosensor Reveals Location Bias of Opioid Drug Action. AB - Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. Here, we show that drugs differ in the subcellular location at which they activate ORs. We develop a genetically encoded biosensor that directly detects ligand-induced activation of ORs and uncover a real-time map of the spatiotemporal organization of OR activation in living neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by additionally driving OR activation in the somatic Golgi apparatus and Golgi elements extending throughout the dendritic arbor. These results establish an approach to probe the cellular basis of neuromodulation and reveal that drugs distort the spatiotemporal landscape of neuronal OR activation. PMID- 29754755 TI - Patients Should Define Value in Health Care: A Conceptual Framework. AB - The main tenet of value-based health care is delivering high-quality care that is centered on the patient, improving health, and minimizing cost. Collaborative decision-making frameworks have been developed to help facilitate delivering care based on patient preferences (patient-centered care). The current value-based health care model, however, focuses on improving population health and overlooks the individuality of patients and their preferences for care. We highlight the importance of eliciting patient preferences in collaborative decision making and describe a conceptual framework that incorporates individual patients' preferences when defining value. PMID- 29754754 TI - Excitatory and Inhibitory Neurons Utilize Different Ca2+ Sensors and Sources to Regulate Spontaneous Release. AB - Spontaneous neurotransmitter release (mini) is an important form of Ca2+ dependent synaptic transmission that occurs in the absence of action potentials. A molecular understanding of this process requires an identification of the underlying Ca2+ sensors. Here, we address the roles of the relatively low- and high-affinity Ca2+ sensors, synapotagmin-1 (syt1) and Doc2alpha/beta, respectively. We found that both syt1 and Doc2 regulate minis, but, surprisingly, their relative contributions depend on whether release was from excitatory or inhibitory neurons. Doc2alpha promoted glutamatergic minis, while Doc2beta and syt1 both regulated GABAergic minis. We identified Ca2+ ligand mutations in Doc2 that either disrupted or constitutively activated the regulation of minis. Finally, Ca2+ entry via voltage-gated Ca2+ channels triggered miniature GABA release by activating syt1, but had no effect on Doc2-driven minis. This work reveals an unexpected divergence in the regulation of spontaneous excitatory and inhibitory transmission in terms of both Ca2+ sensors and sources. PMID- 29754756 TI - Reverse Thenar Perforator Flap for Large Palmar and Digital Defects. AB - Reconstruction of large, full-thickness palmar and digital defects is challenging. The glabrous skin of the palm provides excellent color and texture match for palmar hand and digital defects. The reverse thenar perforator flap, which was previously infrequently used, provides a method for primary closure of large glabrous palmar skin defects. Because of the origin of the source vessels, the reverse thenar perforator flap is a good choice for larger radial-sided palmar and finger defects. This flap provides good aesthetic results for both the donor and the recipient. PMID- 29754757 TI - [How does vaping products work]. AB - To maximize the chances of replacing smoking with vaping, it is necessary to know the different types of existing devices, their characteristics and their most important settings as well as their influence on sensations. To support a user it is also important to understand the nature of the inhaled and exhaled vapor, as well as the possible mistakes that can lead to a less enjoyable experience. Highlighting e-liquids formulations and emissions can help understanding how a minimum of 95 % risk reduction compared to tobacco smoking is achieved and the influence of compounds on the user's experience. At last, a proper care, especially to refill the device and to change the resistance is the key to an effective use over time. PMID- 29754758 TI - Novel valosin-containing protein mutations associated with multisystem proteinopathy. AB - Over fifty missense mutations in the gene coding for valosin-containing protein (VCP) are associated with a unique autosomal dominant adult-onset progressive disease associated with combinations of proximo-distal inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We report the clinical, histological, and molecular findings in four new patients/families carrying novel VCP mutations: c.474 G > A (p.M158I); c.478 G > C (p.A160P); c.383G > C (p.G128A); and c.382G > T (p.G128C). Clinical features included myopathy, PDB, ALS and Parkinson's disease though frontotemporal dementia was not an associated feature in these families. One of the patients was noted to have severe manifestations of PDB and was suspected of having neoplasia. There were wide inter- and intra-familial variations making genotype-phenotype correlations difficult between the novel mutations and frequency or age of onset of IBM, PDB, FTD, ALS and Parkinson's disease. Increasing awareness of the full spectrum of clinical presentations will improve diagnosis of VCP-related diseases and thus proactively manage or prevent associated clinical features such as PDB. PMID- 29754759 TI - Exercise to improve diabetic peripheral neuropathy: An additional option? PMID- 29754760 TI - The role of SCUBE1 in the development of late stent thrombosis presenting with ST elevation myocardial infarction. AB - INTRODUCTION AND AIM: There is an important link between platelets and inflammation, thrombosis, and vascular and tissue repair mechanisms. SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) may function as a novel platelet-endothelial adhesion molecule and play pathological roles in cardiovascular biology. Stent thrombosis (ST) following percutaneous coronary intervention is an uncommon and potentially catastrophic event that can manifest as myocardial infarction and sudden death. High platelet reactivity is a risk factor for thrombotic events, including late ST. For this reason, in the current study, we researched the role of SCUBE1 in the development of late coronary ST. METHODS: We included 40 patients admitted to our hospital with a diagnosis of ST elevation myocardial infarction (STEMI) and signs of late ST on a coronary angiogram. For the control group, we recruited 50 healthy gender- and age-matched individuals who were seen for health check-ups. We also randomly included 100 patients with a diagnosis of STEMI without ST. RESULTS: There were no significant differences between the groups in terms of baseline and demographic characteristics. The mean SCUBE1 level in patients with STEMI with late ST at admission and the STEMI without ST group was significantly higher than in the control group (p<0.01). The mean SCUBE1 level in the STEMI with late ST group was significantly higher than in the STEMI without ST group (p=0.03). In multivariate regression analysis, serum SCUBE1 (odds ratio [OR]: 1.022; 95% confidence interval [CI]: 1.011-1.033, p<0.001) remained an independent predictor for the presence of late ST. In addition, receiver operating characteristic curve analysis was used to determine the optimal SCUBE1 cut-off value for predicting late ST. The area under the curve was 0.972 (95% CI 0.95-0.98). The SCUBE1 cut off value was 59.2 ng/ml, with a sensitivity of 95.4% and specificity of 82.9%. CONCLUSION: The present work is the first clinical study to demonstrate that serum SCUBE1 levels are significantly higher in patients with late ST and serum SCUBE1 was an independent predictor for the presence of late ST in our study population. PMID- 29754761 TI - Sexual abuse and psychosis: The security of research findings. PMID- 29754762 TI - Developmental delay in communication among toddlers and its relationship to caregiving behavior among violence-exposed, posttraumatically stressed mothers. AB - OBJECTIVES: This study aimed to understand if maternal interpersonal violence related posttraumatic stress disorder (IPV-PTSD) is associated with delayed language development among very young children ("toddlers"). METHODS: Data were collected from 61 mothers and toddlers (ages 12-42 months, mean age = 25.6 months SD = 8.70). Child expressive and receptive language development was assessed by the Ages and Stages Questionnaire (ASQ) communication subscale (ASQCS) that measures language acquisition. Observed maternal caregiving behavior was coded from videos of 10-min free-play interactions via the CARE-Index. Correlations, Mann-Whitney tests, and multiple linear regression were performed. RESULTS: There was no significant association between maternal IPV-PTSD severity and the ASQCS. Maternal IPV-PTSD severity was associated with continuous maternal behavior variables (i.e. sensitive and controlling behavior on the CARE-Index) across the entire sample and regardless of child gender. Maternal sensitivity was positively and significantly associated with the ASQCS. Controlling behavior was negatively and significantly associated with the ASQCS. CONCLUSIONS: Results are consistent with the literature that while maternal IPV-PTSD severity is not associated with child language delays, the quality of maternal interactive behavior is associated both with child language development and with maternal IPV-PTSD severity. Further study is needed to understand if the level of child language development contributes to intergenerational risk or resilience for relational violence and/or victimization. PMID- 29754763 TI - Importance and clinical implications of new methods for grading aortic valve regurgitation in patients supported with a continuous-flow left ventricular assist devices. PMID- 29754764 TI - Monitoring of early humoral immunity to identify lung recipients at risk for development of serious infections: A multicenter prospective study. AB - BACKGROUND: Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. METHODS: We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. RESULTS: We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as <5 mg/dl) were a risk factor for serious bacterial infection (adjusted odds ratio [OR] 3.96; 95% confidence interval [CI] 1.39 to 11.26; p = 0.0099). At Day 7 after transplantation, IgG hypogammaglobulinemia (defined as IgG <600 mg/dl) was associated with a higher risk of CMV disease (after adjustment for CMV mismatch: OR 8.15; 95% CI 1.27 to 52.55; p = 0.028) and fungal infection (adjusted OR 8.03, 95% CI 1.51 to 42.72; p = 0.015). Higher BAFF levels before transplantation were associated with a higher rate of development of serious bacterial infection and acute cellular rejection. CONCLUSION: Early monitoring of specific humoral immunity parameters proved useful for the identification of lung recipients who are at risk of serious infections. PMID- 29754765 TI - Effect of hydrodynamic mixing conditions on wet oxidation reactions in a stirred vessel reactor. AB - The aim of this study was to investigate the impact of mixing intensity and mixing flow patterns on solid waste degradation, and production of valuable intermediate by-products such as acetic acid. Total suspended solids generally decreased, soluble chemical oxygen demand, dissolved organic carbon, and acetic acid concentration generally increased with the progress of the reaction and increase in the mixing intensity. The results showed that axial-radial flow pattern (using pitch blade impeller) and medium impeller speed (500 rpm) resulted in a higher degree of solid degradation and production of acetic acid. PMID- 29754768 TI - Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy. AB - Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive. PMID- 29754767 TI - Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory. AB - Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population. PMID- 29754770 TI - Skewing effect of sulprostone on dendritic cell maturation compared with dinoprostone. AB - BACKGROUND: Dendritic cells (DCs) are the most efficient antigen-presenting cells and act at the center of the immune system owing to their ability to control both immune tolerance and immunity. In cancer immunotherapy, DCs play a key role in the regulation of the immune response against tumors and can be generated ex vivo with different cytokine cocktails. METHODS: We evaluated the feasibility of dinoprostone (PGE2) replacement with the molecular analog sulprostone, in our good manufacturing practice (GMP) protocol for the generation of DC-based cancer vaccine. We characterized the phenotype and the function of DCs matured in the presence of sulprostone as a potential substitute of dinoprostone in the pro inflammatory maturation cocktail consisting of tumor necrosis factor alpha (TNF alpha), interleukin-1 beta (IL-1beta) and IL-6. RESULTS: We found that sulprostone invariably reduces the recovery, but does not significantly modify the viability and the purity of DCs. The presence of sulprostone in the maturation cocktail increases the adhesion of single cells and of clusters of DCs to the flask, making them more similar to their immature counterpart in terms of adhesion and spreading proprieties. Moreover, we observed that sulprostone impairs the expression of co-stimulatory molecules and the spontaneous as well as the directed migration capacity of DCs. DISCUSSION: These findings underscore that the synthetic analog sulprostone strongly reduces the functional quality of DCs, thus cannot replace dinoprostone in the maturation cocktail of monocyte derived DCs. PMID- 29754769 TI - A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole Genome-Sequencing Studies. AB - Analysis of de novo mutations (DNMs) from sequencing data of nuclear families has identified risk genes for many complex diseases, including multiple neurodevelopmental and psychiatric disorders. Most of these efforts have focused on mutations in protein-coding sequences. Evidence from genome-wide association studies (GWASs) strongly suggests that variants important to human diseases often lie in non-coding regions. Extending DNM-based approaches to non-coding sequences is challenging, however, because the functional significance of non-coding mutations is difficult to predict. We propose a statistical framework for analyzing DNMs from whole-genome sequencing (WGS) data. This method, TADA Annotations (TADA-A), is a major advance of the TADA method we developed earlier for DNM analysis in coding regions. TADA-A is able to incorporate many functional annotations such as conservation and enhancer marks, to learn from data which annotations are informative of pathogenic mutations, and to combine both coding and non-coding mutations at the gene level to detect risk genes. It also supports meta-analysis of multiple DNM studies, while adjusting for study-specific technical effects. We applied TADA-A to WGS data of ~300 autism-affected family trios across five studies and discovered several autism risk genes. The software is freely available for all research uses. PMID- 29754772 TI - Verbal-spatial and visuospatial coding of power-space interactions. AB - A power-space interaction, which denotes the phenomenon that people responded faster to powerful words when they are placed higher in a visual field and faster to powerless words when they are placed lower in a visual field, has been repeatedly found. The dominant explanation of this power-space interaction is that it results from a tight correspondence between the representation of power and visual space (i.e., a visuospatial coding account). In the present study, we demonstrated that the interaction between power and space could be also based on a verbal-spatial coding in absence of any vertical spatial information. Additionally, the verbal-spatial coding was dominant in driving the power-space interaction when verbal space was contrasted with the visual space. PMID- 29754771 TI - Epstein-Barr virus-specific cytokine-induced killer cells for treatment of Epstein-Barr virus-related malignant lymphoma. AB - BACKGROUND: Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus specific cellular immunity may be applied in this context. METHODS: CIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-gamma, anti-CD3, interleukin (IL) 2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities. RESULTS: Pre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity. DISCUSSION: The transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD. PMID- 29754773 TI - Genome editing in plants: Advancing crop transformation and overview of tools. AB - Genome manipulation technology is one of emerging field which brings real revolution in genetic engineering and biotechnology. Targeted editing of genomes pave path to address a wide range of goals not only to improve quality and productivity of crops but also permit to investigate the fundamental roots of biological systems. These goals includes creation of plants with valued compositional properties and with characters that confer resistance to numerous biotic and abiotic stresses. Numerous novel genome editing systems have been introduced during the past few years; these comprise zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9). Genome editing technique is consistent for improving average yield to achieve the growing demands of the world's existing food famine and to launch a feasible and environmentally safe agriculture scheme, to more specific, productive, cost effective and eco-friendly. These exciting novel methods, concisely reviewed herein, have verified themselves as efficient and reliable tools for the genetic improvement of plants. PMID- 29754774 TI - Evaluation of Intraplaque Neovascularization Using Superb Microvascular Imaging and Contrast-Enhanced Ultrasonography. AB - BACKGROUND: Several studies have shown a linkage between intraplaque neovascularization (IPN) and plaque instability. Although contrast-enhanced ultrasonography (CEUS) may help visualize IPN in the carotid artery, its benefits are limited in Japan, where there is no health insurance coverage for contrast agents in medical imaging. Superb microvascular imaging (SMI), however, enables the depiction of low-velocity blood flow. The current study compares the diagnostic accuracy of SMI and CEUS in the evaluation of IPN. METHODS: The SMI and CEUS video images were transferred to a workstation and then analyzed to determine whether intraplaque blood flow signals were detected with SMI and whether plaques were contrast-enhanced with carotid artery CEUS. The images generated were independently interpreted by 2 radiologic technologists and 1 neurologist. RESULTS: Intraplaque enhancement was observed in 19 patients using CEUS while intraplaque blood flow signals were observed in 12 patients using SMI. A 100% specificity was recorded for SMI (all 12 patients with SMI-detected intraplaque blood flow showed contrast-enhanced plaques), while its sensitivity was 63% (8 of the 15 patients with no SMI-detected intraplaque blood flow showed contrast-enhanced plaques on CEUS). CONCLUSIONS: The results of this study show that patients with SMI-detected blood flow will tend to have plaque enhancement using CEUS. This suggests that SMI, as a simpler, safer, and noninvasive technique, can facilitate the visualization of carotid artery IPN without the use of a contrast agent, as well as in the clinical evaluation of plaque instability. PMID- 29754766 TI - Estimation of Genetic Correlation via Linkage Disequilibrium Score Regression and Genomic Restricted Maximum Likelihood. AB - Genetic correlation is a key population parameter that describes the shared genetic architecture of complex traits and diseases. It can be estimated by current state-of-art methods, i.e., linkage disequilibrium score regression (LDSC) and genomic restricted maximum likelihood (GREML). The massively reduced computing burden of LDSC compared to GREML makes it an attractive tool, although the accuracy (i.e., magnitude of standard errors) of LDSC estimates has not been thoroughly studied. In simulation, we show that the accuracy of GREML is generally higher than that of LDSC. When there is genetic heterogeneity between the actual sample and reference data from which LD scores are estimated, the accuracy of LDSC decreases further. In real data analyses estimating the genetic correlation between schizophrenia (SCZ) and body mass index, we show that GREML estimates based on ~150,000 individuals give a higher accuracy than LDSC estimates based on ~400,000 individuals (from combined meta-data). A GREML genomic partitioning analysis reveals that the genetic correlation between SCZ and height is significantly negative for regulatory regions, which whole genome or LDSC approach has less power to detect. We conclude that LDSC estimates should be carefully interpreted as there can be uncertainty about homogeneity among combined meta-datasets. We suggest that any interesting findings from massive LDSC analysis for a large number of complex traits should be followed up, where possible, with more detailed analyses with GREML methods, even if sample sizes are lesser. PMID- 29754776 TI - Immunoscore for (colorectal) cancer precision medicine. PMID- 29754778 TI - Long-acting inhaled bronchodilators for cystic fibrosis. PMID- 29754775 TI - In Situ Gene Therapy via AAV-CRISPR-Cas9-Mediated Targeted Gene Regulation. AB - Development of efficacious in vivo delivery platforms for CRISPR-Cas9-based epigenome engineering will be critical to enable the ability to target human diseases without permanent modification of the genome. Toward this, we utilized split-Cas9 systems to develop a modular adeno-associated viral (AAV) vector platform for CRISPR-Cas9 delivery to enable the full spectrum of targeted in situ gene regulation functionalities, demonstrating robust transcriptional repression (up to 80%) and activation (up to 6-fold) of target genes in cell culture and mice. We also applied our platform for targeted in vivo gene-repression-mediated gene therapy for retinitis pigmentosa. Specifically, we engineered targeted repression of Nrl, a master regulator of rod photoreceptor determination, and demonstrated Nrl knockdown mediates in situ reprogramming of rod cells into cone like cells that are resistant to retinitis pigmentosa-specific mutations, with concomitant prevention of secondary cone loss. Furthermore, we benchmarked our results from Nrl knockdown with those from in vivo Nrl knockout via gene editing. Taken together, our AAV-CRISPR-Cas9 platform for in vivo epigenome engineering enables a robust approach to target disease in a genomically scarless and potentially reversible manner. PMID- 29754779 TI - A Linc1405/Eomes Complex Promotes Cardiac Mesoderm Specification and Cardiogenesis. AB - Large intergenic non-coding RNAs (lincRNAs) play widespread roles in epigenetic regulation during multiple differentiation processes, but little is known about their mode of action in cardiac differentiation. Here, we identified the key roles of a lincRNA, termed linc1405, in modulating the core network of cardiac differentiation by functionally interacting with Eomes. Chromatin- and RNA immunoprecipitation assays showed that exon 2 of linc1405 physically mediates a complex consisting of Eomes, trithorax group (TrxG) subunit WDR5, and histone acetyltransferase GCN5 binding at the enhancer region of Mesp1 gene and activates its expression during cardiac mesoderm specification of embryonic stem cells. Importantly, linc1405 co-localizes with Eomes, WDR5, and GCN5 at the primitive streak, and linc1405 depletion impairs heart development and function in vivo. In summary, linc1405 mediates a Eomes/WDR5/GCN5 complex that contributes to cardiogenesis, highlighting the critical roles of lincRNA-based complexes in the epigenetic regulation of cardiogenesis in vitro and in vivo. PMID- 29754780 TI - Single-Cell Transcriptomics Meets Lineage Tracing. AB - Reconstructing lineage relationships between cells within a tissue or organism is a long-standing aim in biology. Traditionally, lineage tracing has been achieved through the (genetic) labeling of a cell followed by the tracking of its offspring. Currently, lineage trajectories can also be predicted using single cell transcriptomics. Although single-cell transcriptomics provides detailed phenotypic information, the predicted lineage trajectories do not necessarily reflect genetic relationships. Recently, techniques have been developed that unite these strategies. In this Review, we discuss transcriptome-based lineage trajectory prediction algorithms, single-cell genetic lineage tracing, and the promising combination of these techniques for stem cell and cancer research. PMID- 29754781 TI - Social engagement and the elderly in rural Indonesia. AB - Rural areas in Indonesia are older relative to urban areas. This paper questions how levels of social engagement vary across among the elderly in rural Indonesia. A sample of 2750 respondents aged 60 and over was drawn from 10 purposely selected relatively "old" villages. Our three measures of social engagement are: participation in income-generating activities, in communal activities, and in care work. While there are notable village-level differences in patterns of social engagement, the majority of our respondents are actively engaged in productive activities in their old age until they can no longer be so. A negative educational gradient in the likelihood of work participation suggests that needs for income security is a driver of the elderly's work participation. The notion of promoting active ageing, as typically understood in the Western and/or urban contexts, is of secondary importance to health care provision and managing old age disability in these ageing rural communities. PMID- 29754782 TI - Selection bias in population-representative studies? A commentary on Deaton and Cartwright. PMID- 29754783 TI - Therapeutic spaces of care farming: Transformative or ameliorating? AB - Since Wil Gesler's earliest articulation (Gesler, 1992; Gesler, 1996) key thinkers in the field of therapeutic landscapes have sought to emphasise the embodied, contextual and wholly relational nature of the relationship that exists between people and place. However, the extant research has tended to focus on the relational healing experience as this occurs 'in the moment' and with reference to a specific location or site of healing, with less attention being paid to what happens to people when they return to their ordinary or everyday places. In this paper, we reflect on findings from visual ethnographic work (including photography and film) that explored the therapeutic landscape experiences of people with intellectual disabilities engaged in care farming interventions for health and wellbeing. The study also recruited farm staff and family members or carers to take part, and comprised 20 participants in total. Having identified a gap in our understanding, consideration is given to wider impact that engaging in these sorts of activities had on the everyday lives of the participants in this study. We argue that this study has identified two types of therapeutic journey that broadly fit the experiences of study participants. The first type of journey denotes landscape experiences that are transformative. Here the therapeutic power of the care farm landscape resides in the ability of activities conducted on care farms to influence other aspects of participants' lives in ways that promote wellbeing. By contrast, there is another type of journey where the therapeutic power of the care farm resides in its ability to ameliorate challenging or harmful life situations, thus offering people a temporary site of respite or refuge. We conclude that these findings denote an important development for this sub-field of health geography, not only because they draw attention to the transformative power of the therapeutic encounter, but also the broader socio spatial environments in which people live and ways in which these can limit that power. PMID- 29754784 TI - The use of an online thoracic surgery curriculum: A win-win situation. PMID- 29754777 TI - International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. AB - BACKGROUND: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer. METHODS: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance. FINDINGS: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0.97 for colon tumour; r=0.97 for invasive margin; p<0.0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0.20, 95% CI 0.10-0.38; p<0.0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0.0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0.33, 95% CI 0.21-0.52; p<0.0001), including in Cox multivariable analysis (p<0.0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system. INTERPRETATION: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer. FUNDING: French National Institute of Health and Medical Research, the LabEx Immuno oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer. PMID- 29754786 TI - A picture or a thousand words: Routine timed barium esophagram after myotomy. PMID- 29754785 TI - Prognostic factors including lymphovascular invasion on survival for resected non small cell lung cancer. AB - OBJECTIVES: The aim of this study was to report on the influence of tumor lymphovascular invasion on overall survival and in patients with resected non small cell lung cancer and identify prognostic factors for survival. METHODS: This is a retrospective observational study of a consecutive series of patients who had surgical resection of non-small cell lung cancer in a single institution. The study covers a 3-year period. Overall survival was estimated by Kaplan-Meier method and multivariate Cox regression analysis was used to evaluate the relationship of lymphovascular invasion and other clinicopathologic variables. A multivariate regression was used to assess the relationship between tumor lymphovascular invasion and other clinical and pathologic characteristics. RESULTS: A total of 524 patients were identified and included in the study. Two hundred twenty-five patients (43%) had tumors with lymphovascular invasion. Patients with tumor lymphovascular invasion had a lower overall survival (P < .0001). Tumor lymphovascular invasion was independently associated with visceral pleural involvement (P < .0001). In a multivariable model, lymphovascular invasion (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.63-4.09; P < .0001), parietal pleural invasion (HR, 45.4; 95% CI, 2.08-990; P = .015), advanced age (HR, 1.028; 95% CI, 1.009-1.048; P = .004), and N2 lymph node involvement (HR, 1.837; 95% CI, 1.257-2.690; P = .002) were independent prognostic factors for lower overall survival. CONCLUSIONS: Lymphovascular invasion is associated with a worse overall survival in patients with resected non-small cell lung cancer regardless of tumor stage. Parietal pleural involvement, N2 nodal disease, and advanced age independently predict poor overall survival. PMID- 29754787 TI - All about the coronaries. PMID- 29754789 TI - It is not just about surgery versus stereotactic ablative radiotherapy, it is about curing as many patients with lung cancer as possible. PMID- 29754788 TI - Just buckle up. PMID- 29754790 TI - Aortic clamping strategy and postoperative stroke. AB - OBJECTIVE: The effect of aortic clamping strategy on short-term stroke during proximal graft construction for coronary artery bypass grafting (CABG) remains undefined. The aim of this study was to test the hypothesis that partial occluding clamp (POC) technique does not increase incidence of postoperative stroke compared with single clamp (SC) technique for performing proximal coronary anastomoses. METHODS: We identified 52,611 patients who underwent on-pump CABG in the Society of Thoracic Surgeons Adult Cardiac Surgery Database from July 1, 2014 to March 31, 2015. Propensity scores for POC were calculated on the basis of validated Society of Thoracic Surgeons predicted risk of postoperative stroke scores and used to adjust for intergroup differences to derive 17,819 matched pairs for analysis. RESULTS: Despite a similar number of total bypass grafts between matched SC versus POC groups, myocardial ischemic times were shorter (74.1 +/- 29.2 minutes vs 57.0 +/- 23.3 minutes; P < .0001) as were cardiopulmonary bypass times (95.0 +/- 35.0 minutes vs 89.7 +/- 34.4 minutes; P < .0001) for the POC group. Postoperative stroke rates were similar between SC versus POC (0.9% vs 1.1%; risk ratio, 1.1; 95% confidence interval, 0.9-1.4; P = .3) as were mortality rates (1.3% vs 1.3%; risk ratio, 1.0; 95% confidence interval, 0.8-1.2; P = .9). CONCLUSIONS: Aortic clamping strategy for constructing proximal anastomoses in CABG procedures does not affect short-term incidence of postoperative stroke or mortality. The use of POC incurred shorter myocardial ischemic and perfusion times compared with the SC technique with similar total number of bypass grafts. PMID- 29754791 TI - Still young at heart.... PMID- 29754792 TI - Living by numbers. PMID- 29754793 TI - How low can you go? PMID- 29754794 TI - Predicting outcomes in esophageal cancer: No such thing as a crystal ball. PMID- 29754795 TI - Low-quality lower lobes-discard, repair, or only use the good rest? PMID- 29754796 TI - Guardians of the Gut: Pretransplant IgA levels and seromucous infections. PMID- 29754797 TI - The invisible hands conducting minimally invasive mitral valve surgery. PMID- 29754798 TI - The Wheat sprouts new life. PMID- 29754799 TI - Extracting cancer mortality statistics from death certificates: A hybrid machine learning and rule-based approach for common and rare cancers. AB - OBJECTIVE: Death certificates are an invaluable source of cancer mortality statistics. However, this value can only be realised if accurate, quantitative data can be extracted from certificates-an aim hampered by both the volume and variable quality of certificates written in natural language. This paper proposes an automatic classification system for identifying all cancer related causes of death from death certificates. METHODS: Detailed features, including terms, n grams and SNOMED CT concepts were extracted from a collection of 447,336 death certificates. The features were used as input to two different classification sub systems: a machine learning sub-system using Support Vector Machines (SVMs) and a rule-based sub-system. A fusion sub-system then combines the results from SVMs and rules into a single final classification. A held-out test set was used to evaluate the effectiveness of the classifiers according to precision, recall and F-measure. RESULTS: The system was highly effective at determining the type of cancers for both common cancers (F-measure of 0.85) and rare cancers (F-measure of 0.7). In general, rules performed superior to SVMs; however, the fusion method that combined the two was the most effective. CONCLUSION: The system proposed in this study provides automatic identification and characterisation of cancers from large collections of free-text death certificates. This allows organisations such as Cancer Registries to monitor and report on cancer mortality in a timely and accurate manner. In addition, the methods and findings are generally applicable beyond cancer classification and to other sources of medical text besides death certificates. PMID- 29754801 TI - Ingestion of Food Particles Regulates the Mechanosensing Misshapen-Yorkie Pathway in Drosophila Intestinal Growth. AB - The intestinal epithelium has a high cell turnover rate and is an excellent system to study stem cell-mediated adaptive growth. In the Drosophila midgut, the Ste20 kinase Misshapen, which is distally related to Hippo, has a niche function to restrict intestinal stem cell activity. We show here that, under low growth conditions, Misshapen is localized near the cytoplasmic membrane, is phosphorylated at the threonine 194 by the upstream kinase Tao, and is more active toward Warts, which in turn inhibits Yorkie. Ingestion of yeast particles causes a midgut distention and a reduction of Misshapen membrane association and activity. Moreover, Misshapen phosphorylation is regulated by the stiffness of cell culture substrate, changing of actin cytoskeleton, and ingestion of inert particles. These results together suggest that dynamic membrane association and Tao phosphorylation of Misshapen are steps that link the mechanosensing of intestinal stretching after food particle ingestion to control adaptive growth. PMID- 29754800 TI - PCYT1A Regulates Phosphatidylcholine Homeostasis from the Inner Nuclear Membrane in Response to Membrane Stored Curvature Elastic Stress. AB - Cell and organelle membranes consist of a complex mixture of phospholipids (PLs) that determine their size, shape, and function. Phosphatidylcholine (PC) is the most abundant phospholipid in eukaryotic membranes, yet how cells sense and regulate its levels in vivo remains unclear. Here we show that PCYT1A, the rate limiting enzyme of PC synthesis, is intranuclear and re-locates to the nuclear membrane in response to the need for membrane PL synthesis in yeast, fly, and mammalian cells. By aligning imaging with lipidomic analysis and data-driven modeling, we demonstrate that yeast PCYT1A membrane association correlates with membrane stored curvature elastic stress estimates. Furthermore, this process occurs inside the nucleus, although nuclear localization signal mutants can compensate for the loss of endogenous PCYT1A in yeast and in fly photoreceptors. These data suggest an ancient mechanism by which nucleoplasmic PCYT1A senses surface PL packing defects on the inner nuclear membrane to control PC homeostasis. PMID- 29754802 TI - Intracellular Calcium Mobilization Is Required for Sonic Hedgehog Signaling. AB - Graded Shh signaling across fields of precursor cells coordinates patterns of gene expression, differentiation, and morphogenetic behavior as precursors form complex structures, such as the nervous system, the limbs, and craniofacial skeleton. Here we discover that intracellular calcium mobilization, a process tightly controlled and readily modulated, regulates the level of Shh-dependent gene expression in responding cells and affects the development of all Shh dependent cell types in the zebrafish embryo. Reduced expression or modified activity of ryanodine receptor (RyR) intracellular calcium release channels shifted the allocation of Shh-dependent cell fates in the somitic muscle and neural tube. Mosaic analysis revealed that RyR-mediated calcium mobilization is required specifically in Shh ligand-receiving cells. This work reveals that RyR channels participate in intercellular signal transduction events. As modulation of RyR activity modifies tissue patterning, we hypothesize that alterations in intracellular calcium mobilization contribute to both birth defects and evolutionary modifications of morphology. PMID- 29754803 TI - A Combinatorial Lipid Code Shapes the Electrostatic Landscape of Plant Endomembranes. AB - Membrane surface charge is critical for the transient, yet specific recruitment of proteins with polybasic regions to certain organelles. In eukaryotes, the plasma membrane (PM) is the most electronegative compartment of the cell, which specifies its identity. As such, membrane electrostatics is a central parameter in signaling, intracellular trafficking, and polarity. Here, we explore which are the lipids that control membrane electrostatics using plants as a model. We show that phosphatidylinositol-4-phosphate (PI4P), phosphatidic acidic (PA), and phosphatidylserine (PS) are separately required to generate the electrostatic signature of the plant PM. In addition, we reveal the existence of an electrostatic territory that is organized as a gradient along the endocytic pathway and is controlled by PS/PI4P combination. Altogether, we propose that combinatorial lipid composition of the cytosolic leaflet of organelles not only defines the electrostatic territory but also distinguishes different functional compartments within this territory by specifying their varying surface charges. PMID- 29754805 TI - Emergence of livestock-associated methicillin-resistant Staphylococcus aureus: Should it be a concern? PMID- 29754807 TI - Combined Venoarterial Extracorporeal Membrane Oxygenation and Impella for Diffuse Coronary Spasm After Surgical Myocardial Revascularization. PMID- 29754806 TI - Machine learning in cardiac CT: Basic concepts and contemporary data. AB - Propelled by the synergy of the groundbreaking advancements in the ability to analyze high-dimensional datasets and the increasing availability of imaging and clinical data, machine learning (ML) is poised to transform the practice of cardiovascular medicine. Owing to the growing body of literature validating both the diagnostic performance as well as the prognostic implications of anatomic and physiologic findings, coronary computed tomography angiography (CCTA) is now a well-established non-invasive modality for the assessment of cardiovascular disease. ML has been increasingly utilized to optimize performance as well as extract data from CCTA as well as non-contrast enhanced cardiac CT scans. The purpose of this review is to describe the contemporary state of ML based algorithms applied to cardiac CT, as well as to provide clinicians with an understanding of its benefits and associated limitations. PMID- 29754808 TI - Long-term Event Reduction After Left Atrial Appendage Closure. Results of the Iberian Registry II. AB - INTRODUCTION AND OBJECTIVES: Many patients with nonvalvular atrial fibrillation are still left without protection due to a contraindication for anticoagulants. This study aimed to establish the occurrence of stroke and major bleeding events in patients with nonvalvular atrial fibrillation and left atrial appendage closure with long-term follow-up and to explore the factors associated with higher long-term mortality. METHODS: Analysis of a multicenter single cohort prospectively recruited from 2009 to 2015. Thromboembolic and bleeding events were compared with those expected from CHA2DS2-VASc and HAS-BLED scores. Multivariate analysis examined variables associated with mortality during follow up. RESULTS: A total of 598 patients (1093 patient-years) with a contraindication for anticoagulants were recruited (median 75.4 years). The success rate of left atrial appendage closure device implantation was 95.8%. Thirty patients (5%) experienced periprocedural complications. The rate of events (per 100 patient years) during follow-up (mean 22.9 months; median 16.1 months) was as follows: death 7.0%; ischemic stroke 1.6% (vs 8.5% expected according to CHA2DS2-VASc; P < .001); intracranial hemorrhage 0.8%; gastrointestinal bleeding 3.2%; severe bleeding 3.9% (vs 6.3% expected by HAS-BLED, P = .002). These results were improved in the subgroup of 176 patients with follow-up > 24 months (mean follow up 46.6 months, 683 patient-years) for severe bleeding 2.6% (vs 6.3% expected by HAS-BLED, P < .033). The factors significantly associated with higher mortality were age (HR, 1.1), intracranial hemorrhage (HR, 6.8), and stroke during follow up (HR, 2.7). CONCLUSIONS: Left atrial appendage closure significantly reduced the incidence of stroke and bleeding events and the benefit was maintained. Intracranial hemorrhage, age and stroke were associated with higher mortality. PMID- 29754804 TI - Diabetes mellitus and cardiovascular risk: Update of the recommendations of the Diabetes and Cardiovascular Disease working group of the Spanish Diabetes Society (SED, 2018). AB - This document is an update to the clinical practice recommendations for the management of cardiovascular risk factors in diabetes mellitus. The consensus is made by members of the Cardiovascular Risk Group of the Spanish Diabetes Society. We have proposed and updated interventions on lifestyle, pharmacological treatment indicated to achieve therapeutic objectives according to the levels of HbA1c, degree of obesity, hypertension, hyperlipidemia, heart failure, platelet antiagregation, renal insufficiency, and diabetes in the elderly, as well as new biomarkers of interest in the evaluation of cardiovascular risk in individuals with diabetes mellitus. The work is an update of the interventions and therapeutic objectives in addition, it is noted the need for the inclusion of specialists in Endocrinology, Metabolism and Nutrition in Cardiac Rehabilitation Units for the control and monitoring of this population. PMID- 29754809 TI - Enucleation, Vaporization, and Resection: How To Choose the Best Surgical Treatment Option for a Patient with Male Lower Urinary Tract Symptoms. AB - Transurethral resection of the prostate remains the reference technique for patients with a prostate <100ml. Endoscopic enucleation is a safe and effective alternative, while photoselective vaporization of the prostate appears to be the treatment of choice for patients on anticoagulation medication. PMID- 29754810 TI - Saving the World with Satire: A Response to Chapron et al. PMID- 29754811 TI - Integrated Exposure Therapy and Exercise Reduces Fear of Falling and Avoidance in Older Adults: A Randomized Pilot Study. AB - OBJECTIVES: To evaluate the safety and acceptability of a novel 8-week intervention integrating exercise, exposure therapy, cognitive restructuring, and a home safety evaluation, conducted by a physical therapist, in reducing fear of falling and activity avoidance. To collect preliminary evidence of efficacy. DESIGN: Randomized pilot study comparing the intervention to time- and attention equivalent fall prevention education. SETTING: Participants' homes. PARTICIPANTS: 42 older adults with disproportionate fear of falling (high fear, low to moderate objective fall risk). MEASUREMENTS: Falls Efficacy Scale-International, modified Activity Card Sort, satisfaction, falls. RESULTS: Relative to education, the intervention reduced fear of falling (d = 1.23) and activity avoidance (d = 1.02) at 8 weeks, but effects eroded over a 6-month follow-up period. The intervention did not increase falls, and participants rated the exercise, exposure therapy, and non-specific elements as most helpful. CONCLUSIONS: An integration of exercise and exposure therapy may help older adults with disproportionate fear of falling, but modifications to the intervention or its duration may be needed to maintain participants' gains. PMID- 29754812 TI - A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation. AB - OBJECTIVES: This study sought to confirm a subgroup analysis of the prior FIX-HF 5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. BACKGROUND: CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. METHODS: A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration <130 ms, and ejection fraction >=25% and <=45% were randomized to continued medical therapy (control, n = 86) or CCM (treatment, n = 74, unblinded) for 24 weeks. Peak Vo2 (primary endpoint), Minnesota Living With Heart Failure questionnaire, NYHA functional class, and 6 min hall walk were measured at baseline and at 12 and 24 weeks. Bayesian repeated measures linear modeling was used for the primary endpoint analysis with 30% borrowing from the FIX-HF-5 subgroup. Safety was assessed by the percentage of patients free of device-related adverse events with a pre-specified lower bound of 70%. RESULTS: The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p < 0.001), NYHA functional class (p < 0.001), and 6-min hall walk (p = 0.02) were all better in the treatment versus control group. There were 7 device-related events, yielding a lower bound of 80% of patients free of events, satisfying the primary safety endpoint. The composite of cardiovascular death and HF hospitalizations was reduced from 10.8% to 2.9% (p = 0.048). CONCLUSIONS: CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172). PMID- 29754814 TI - LlamaTags: A Versatile Tool to Image Transcription Factor Dynamics in Live Embryos. AB - Embryonic cell fates are defined by transcription factors that are rapidly deployed, yet attempts to visualize these factors in vivo often fail because of slow fluorescent protein maturation. Here, we pioneer a protein tag, LlamaTag, which circumvents this maturation limit by binding mature fluorescent proteins, making it possible to visualize transcription factor concentration dynamics in live embryos. Implementing this approach in the fruit fly Drosophila melanogaster, we discovered stochastic bursts in the concentration of transcription factors that are correlated with bursts in transcription. We further used LlamaTags to show that the concentration of protein in a given nucleus heavily depends on transcription of that gene in neighboring nuclei; we speculate that this inter-nuclear signaling is an important mechanism for coordinating gene expression to delineate straight and sharp boundaries of gene expression. Thus, LlamaTags now make it possible to visualize the flow of information along the central dogma in live embryos. PMID- 29754815 TI - An Acquired Vulnerability of Drug-Resistant Melanoma with Therapeutic Potential. AB - BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here. PMID- 29754813 TI - Structure of an Ancient Respiratory System. AB - Hydrogen gas-evolving membrane-bound hydrogenase (MBH) and quinone-reducing complex I are homologous respiratory complexes with a common ancestor, but a structural basis for their evolutionary relationship is lacking. Here, we report the cryo-EM structure of a 14-subunit MBH from the hyperthermophile Pyrococcus furiosus. MBH contains a membrane-anchored hydrogenase module that is highly similar structurally to the quinone-binding Q-module of complex I while its membrane-embedded ion-translocation module can be divided into a H+- and a Na+ translocating unit. The H+-translocating unit is rotated 180 degrees in-membrane with respect to its counterpart in complex I, leading to distinctive architectures for the two respiratory systems despite their largely conserved proton-pumping mechanisms. The Na+-translocating unit, absent in complex I, resembles that found in the Mrp H+/Na+ antiporter and enables hydrogen gas evolution by MBH to establish a Na+ gradient for ATP synthesis near 100 degrees C. MBH also provides insights into Mrp structure and evolution of MBH-based respiratory enzymes. PMID- 29754816 TI - The Cohesin Ring Uses Its Hinge to Organize DNA Using Non-topological as well as Topological Mechanisms. AB - As predicted by the notion that sister chromatid cohesion is mediated by entrapment of sister DNAs inside cohesin rings, there is perfect correlation between co-entrapment of circular minichromosomes and sister chromatid cohesion. In most cells where cohesin loads without conferring cohesion, it does so by entrapment of individual DNAs. However, cohesin with a hinge domain whose positively charged lumen is neutralized loads and moves along chromatin despite failing to entrap DNAs. Thus, cohesin engages chromatin in non-topological, as well as topological, manners. Since hinge mutations, but not Smc-kleisin fusions, abolish entrapment, DNAs may enter cohesin rings through hinge opening. Mutation of three highly conserved lysine residues inside the Smc1 moiety of Smc1/3 hinges abolishes all loading without affecting cohesin's recruitment to CEN loading sites or its ability to hydrolyze ATP. We suggest that loading and translocation are mediated by conformational changes in cohesin's hinge driven by cycles of ATP hydrolysis. PMID- 29754817 TI - Vitamin D Switches BAF Complexes to Protect beta Cells. AB - A primary cause of disease progression in type 2 diabetes (T2D) is beta cell dysfunction due to inflammatory stress and insulin resistance. However, preventing beta cell exhaustion under diabetic conditions is a major therapeutic challenge. Here, we identify the vitamin D receptor (VDR) as a key modulator of inflammation and beta cell survival. Alternative recognition of an acetylated lysine in VDR by bromodomain proteins BRD7 and BRD9 directs association to PBAF and BAF chromatin remodeling complexes, respectively. Mechanistically, ligand promotes VDR association with PBAF to effect genome-wide changes in chromatin accessibility and enhancer landscape, resulting in an anti-inflammatory response. Importantly, pharmacological inhibition of BRD9 promotes PBAF-VDR association to restore beta cell function and ameliorate hyperglycemia in murine T2D models. These studies reveal an unrecognized VDR-dependent transcriptional program underpinning beta cell survival and identifies the VDR:PBAF/BAF association as a potential therapeutic target for T2D. PMID- 29754818 TI - Dynamic Architecture of DNA Repair Complexes and the Synaptonemal Complex at Sites of Meiotic Recombination. AB - Meiotic double-strand breaks (DSBs) are generated and repaired in a highly regulated manner to ensure formation of crossovers (COs) while also enabling efficient non-CO repair to restore genome integrity. We use structured illumination microscopy to investigate the dynamic architecture of DSB repair complexes at meiotic recombination sites in relationship to the synaptonemal complex (SC). DSBs resected at both ends are converted into inter-homolog repair intermediates harboring two populations of BLM helicase and RPA, flanking a single population of MutSgamma. These intermediates accumulate until late pachytene, when repair proteins disappear from non-CO sites and CO-designated sites become enveloped by SC-central region proteins, acquire a second MutSgamma population, and lose RPA. These and other data suggest that the SC may protect CO intermediates from being dismantled inappropriately and promote CO maturation by generating a transient CO-specific repair compartment, thereby enabling differential timing and outcome of repair at CO and non-CO sites. PMID- 29754819 TI - Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection. AB - The nervous system, the immune system, and microbial pathogens interact closely at barrier tissues. Here, we find that a bacterial pathogen, Streptococcus pyogenes, hijacks pain and neuronal regulation of the immune response to promote bacterial survival. Necrotizing fasciitis is a life-threatening soft tissue infection in which "pain is out of proportion" to early physical manifestations. We find that S. pyogenes, the leading cause of necrotizing fasciitis, secretes streptolysin S (SLS) to directly activate nociceptor neurons and produce pain during infection. Nociceptors, in turn, release the neuropeptide calcitonin gene related peptide (CGRP) into infected tissues, which inhibits the recruitment of neutrophils and opsonophagocytic killing of S. pyogenes. Botulinum neurotoxin A and CGRP antagonism block neuron-mediated suppression of host defense, thereby preventing and treating S. pyogenes necrotizing infection. We conclude that targeting the peripheral nervous system and blocking neuro-immune communication is a promising strategy to treat highly invasive bacterial infections. VIDEO ABSTRACT. PMID- 29754820 TI - Interfaces of Malignant and Immunologic Clonal Dynamics in Ovarian Cancer. AB - High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion. PMID- 29754821 TI - A Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization. AB - Diverse biological systems utilize fluctuations ("noise") in gene expression to drive lineage-commitment decisions. However, once a commitment is made, noise becomes detrimental to reliable function, and the mechanisms enabling post commitment noise suppression are unclear. Here, we find that architectural constraints on noise suppression are overcome to stabilize fate commitment. Using single-molecule and time-lapse imaging, we find that-after a noise-driven event human immunodeficiency virus (HIV) strongly attenuates expression noise through a non-transcriptional negative-feedback circuit. Feedback is established through a serial cascade of post-transcriptional splicing, whereby proteins generated from spliced mRNAs auto-deplete their own precursor unspliced mRNAs. Strikingly, this auto-depletion circuitry minimizes noise to stabilize HIV's commitment decision, and a noise-suppression molecule promotes stabilization. This feedback mechanism for noise suppression suggests a functional role for delayed splicing in other systems and may represent a generalizable architecture of diverse homeostatic signaling circuits. PMID- 29754822 TI - A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation. AB - Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to the generation and deposition of N-terminal exon1 fragments of the protein in intracellular aggregates. We combined electron tomography and quantitative fluorescence microscopy to analyze the structural and material properties of huntingtin exon1 assemblies in mammalian cells, in yeast, and in vitro. We found that huntingtin exon1 proteins can form reversible liquid like assemblies, a process driven by huntingtin's polyQ tract and proline-rich region. In cells and in vitro, the liquid-like assemblies converted to solid-like assemblies with a fibrillar structure. Intracellular phase transitions of polyglutamine proteins could play a role in initiating irreversible pathological aggregation. PMID- 29754824 TI - CnoX Is a Chaperedoxin: A Holdase that Protects Its Substrates from Irreversible Oxidation. AB - Bleach (HOCl) is a powerful oxidant that kills bacteria in part by causing protein aggregation. It inactivates ATP-dependent chaperones, rendering cellular proteins mostly dependent on holdases. Here we identified Escherichia coli CnoX (YbbN) as a folding factor that, when activated by bleach via chlorination, functions as an efficient holdase, protecting the substrates of the major folding systems GroEL/ES and DnaK/J/GrpE. Remarkably, CnoX uniquely combines this function with the ability to prevent the irreversible oxidation of its substrates. This dual activity makes CnoX the founding member of a family of proteins, the "chaperedoxins." Because CnoX displays a thioredoxin fold and a tetratricopeptide (TPR) domain, two structural motifs conserved in all organisms, this investigation sets the stage for the discovery of additional chaperedoxins in bacteria and eukaryotes that could cooperate with proteins from both the Hsp60 and Hsp70 families. PMID- 29754823 TI - Polepsilon Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis. AB - DNA polymerase epsilon (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polepsilon processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polepsilon complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4-/- mouse and POLE1 mutant human cells, Polepsilon hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4-/-p53+/- mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention. PMID- 29754825 TI - Structure of Human NatA and Its Regulation by the Huntingtin Interacting Protein HYPK. AB - Co-translational N-terminal protein acetylation regulates many protein functions including degradation, folding, interprotein interactions, and targeting. Human NatA (hNatA), one of six conserved metazoan N-terminal acetyltransferases, contains Naa10 catalytic and Naa15 auxiliary subunits, and associates with the intrinsically disordered Huntingtin yeast two-hybrid protein K (HYPK). We report on the crystal structures of hNatA and hNatA/HYPK, and associated biochemical and enzymatic analyses. We demonstrate that hNatA contains unique features: a stabilizing inositol hexaphosphate (IP6) molecule and a metazoan-specific Naa15 domain that mediates high-affinity HYPK binding. We find that HYPK harbors intrinsic hNatA-specific inhibitory activity through a bipartite structure: a ubiquitin-associated domain that binds a hNaa15 metazoan-specific region and an N terminal loop-helix region that distorts the hNaa10 active site. We show that HYPK binding blocks hNaa50 targeting to hNatA, likely limiting Naa50 ribosome localization in vivo. These studies provide a model for metazoan NAT activity and HYPK regulation of N-terminal acetylation. PMID- 29754827 TI - Atomic Structural Models of Fibrin Oligomers. AB - The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with gamma-gamma crosslinking, A:a and B:b knob-hole bonds, and alphaC regions-all important structural determinants not resolved crystallographically. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic parameters of fibrin oligomers. Atomic structures of protofibrils provide a basis to understand mechanisms of early stages of fibrin polymerization. PMID- 29754826 TI - Atomic Resolution Cryo-EM Structure of beta-Galactosidase. AB - The advent of direct electron detectors has enabled the routine use of single particle cryo-electron microscopy (EM) approaches to determine structures of a variety of protein complexes at near-atomic resolution. Here, we report the development of methods to account for local variations in defocus and beam induced drift, and the implementation of a data-driven dose compensation scheme that significantly improves the extraction of high-resolution information recorded during exposure of the specimen to the electron beam. These advances enable determination of a cryo-EM density map for beta-galactosidase bound to the inhibitor phenylethyl beta-D-thiogalactopyranoside where the ordered regions are resolved at a level of detail seen in X-ray maps at ~ 1.5 A resolution. Using this density map in conjunction with constrained molecular dynamics simulations provides a measure of the local flexibility of the non-covalently bound inhibitor and offers further opportunities for structure-guided inhibitor design. PMID- 29754829 TI - Randomization to 6-month Mediterranean diet compared with a low-fat diet leads to improvement in Dietary Inflammatory Index scores in patients with coronary heart disease: the AUSMED Heart Trial. AB - A higher dietary inflammatory index (DII(r)) score is associated with inflammation and incidence of coronary heart disease (CHD). We hypothesized that a Mediterranean diet (MedDiet) intervention would reduce DII score. We assessed dietary data from a randomized controlled trial comparing 6-month MedDiet versus low-fat diet intervention, in patients with CHD. We aimed to determine the DII scores of the prescribed diets' model meal plans, followed by whether dietary intervention led to lower (i.e., more anti-inflammatory) DII scores and consequently lower high sensitivity C-reactive protein (hs-CRP) and interleukin-6 (hs-IL-6). DII scores were calculated from 7-day food diaries. The MedDiet meal plan had a markedly lower DII score than the low-fat diet meal plan (-4.55 vs. 0.33, respectively). In 56 participants who completed the trial (84% male, mean age 62 +/- 9 years), the MedDiet group significantly reduced DII scores at 6 months (n = 27; -0.40 +/- 3.14 to -1.74 +/- 2.81, P = .008) and the low-fat diet group did not change (n = 29; -0.17 +/- 2.27 to 0.05 +/- 1.89, P = .65). There was a significant post-intervention adjusted difference in DII score between groups (compared to low-fat, MedDiet decreased by -1.69 DII points; P = .004). When compared to the low-fat diet, the MedDiet non-significantly reduced hs-IL-6 (-0.32 pg/mL, P = .29) and increased hs-CRP (+0.09 mg/L, P = .84). These findings demonstrated that MedDiet intervention significantly reduced DII scores compared to a low-fat diet. However, in this small cohort of patients with CHD this did not translate to a significant improvement in measured inflammatory markers. The effect of improvement in DII with MedDiet should be tested in larger intervention trials and observational cohorts. PMID- 29754828 TI - Prehabilitation and functional recovery for colorectal cancer patients. AB - Cancer and its treatments are associated with functional decline that has impactful consequences on quality of life, and care continuum. Thus, optimizing perioperative functional capacity has been identified as a research and clinical priority in cancer care. The process of enhancing physical fitness before an operation to enable the patient to withstand the stress of surgery has been termed prehabilitation. Main elements are preoperative exercise, nutrition therapy, and anxiety-reduction techniques. Given the growing body of evidence on prehabilitation efficacy, this narrative review will summarize the rational underlying preoperative interventions, and propose a structured clinical pathway aimed at optimizing preoperative functional capacity. PMID- 29754831 TI - A response to: "Sleep and circadian rhythms in severely brain-injured patients - A comment". PMID- 29754830 TI - Amyotrophic lateral sclerosis - Time for beta testing? PMID- 29754832 TI - Ondansetron in Pregnancy and the Risk of Congenital Malformations: A Systematic Review. AB - OBJECTIVE: Ondansetron, not approved for use in pregnancy, is increasingly being prescribed for nausea and vomiting in pregnancy and hyperemesis gravidarum. A number of recent lawsuits have highlighted the possibility that ondansetron may cause congenital malformations. The aim of this study was to systematically review epidemiological evidence on the potential association of prenatal exposure to ondansetron and congenital malformations. METHODS: Systematic searches in Medline and Embase were performed in June 2017 using controlled vocabulary and key words, and references of search results were reviewed. Full papers (RCTs, cohort, and case-control studies) were eligible for inclusion if they reported fetal outcomes of prenatal ondansetron exposure in humans. Excluded were: case reports, studies involving pre-medication with ondansetron prior to CS, animal studies, and foreign languages studies. RESULTS: Ten epidemiologic studies were included: five large retrospective cohort studies, two prospective observational studies, two population-based case-controls. and a retrospective case series. Sample sizes ranged from 17 to 1 501 434 infants exposed to ondansetron. A case control study identified an association between prenatal exposure to ondansetron and cleft palate, and one cohort study found an increased risk of cardiovascular defects. These findings were not reproduced in the other studies. CONCLUSION: While further investigation of the literature is needed, our results highlight the paucity of evidence linking prenatal exposure to ondansetron to an increased risk of congenital malformations. There is a need for additional epidemiologic studies to confirm whether ondansetron represents a safe and effective alternative treatment for nausea and vomiting in pregnancy and hyperemesis gravidarum. PMID- 29754833 TI - Discovery of benzimidazole derivatives as orally active renin inhibitors: Optimization of 3,5-disubstituted piperidine to improve pharmacokinetic profile. AB - We previously identified 2-tert-butyl-4-[(3-methoxypropyl)amino]-N-(2 methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidine-5 carboxamide 3 as a potent renin inhibitor. Since 3 showed unacceptably low bioavailability (BA) in rats, structural modification, using SBDD and focused on physicochemical properties was conducted to improve its PK profile while maintaining renin inhibitory activity. Conversion of the amino group attached at the 4-position of pyrimidine to methylene group improved PK profile and decreased renin inhibitory activity. New central cores with carbon side chains were explored to improve potency. We had designed a series of 5-membered azoles and fused heterocycles that interacted with the lipophilic S3 pocket. In the course of modification, renin inhibitory activity was enhanced by the formation of an additional hydrogen bonding with the hydroxyl group of Thr77. Consequently, a series of novel benzimidazole derivatives were discovered as potent and orally bioavailable renin inhibitors. Among those, compound 13 exhibited more than five fold of plasma renin inhibition than aliskiren in cynomolgus monkeys at dose ratio. PMID- 29754835 TI - Identification and expression analysis of long noncoding RNAs in embryogenesis and larval metamorphosis of Ciona savignyi. AB - Long noncoding RNAs (lncRNAs) play important roles in diverse developmental and pathological processes through chromatin reprogramming, cis regulation and posttranscriptional modification. They have been extensively studied in both vertebrates and invertebrates. However, the information of lncRNAs in urochordate is still lacking. In this study, we used the RNA-Seq data from three developmental stages (18, 21 and 42 hours post fertilization, hpf) of embryos and larvae in Ciona savignyi to identify candidate lncRNAs and analyze their expression profiles. A total of 29,944 unigenes were predicted as lncRNAs, five of which had hits with lncRNAs in NONCODE database. The acquired lncRNAs had an average length of 466 nt. The peaks of length, GC content and minimum free energy of the lncRNAs were significantly lower than that of the message RNAs (mRNAs). The average expression levels of lncRNAs were also lower than those of mRNAs. Among the three developmental stages, highly expressed lncRNAs concentrated in 18 hpf embryos. While, for those lncRNAs specifically up-regulated in 21 hpf embryos, their co-expressed mRNAs were enriched in GO terms of membrane, indicating these lncRNAs are involved in the regulation of luminal membrane biogenesis, and extracellular matrix secretion through membrane localized proteins during Ciona notochord tubulogenesis. The lncRNAs in 42 hpf larvae were distinct from those in 18 and 21 hpf embryos. This result is associated with the fact that swimming larvae are transiting into metamorphic juveniles at this stage, indicating lncRNAs are involved in the regulation of larval metamorphosis. Overall, our study identified a large number of lncRNAs in C. savignyi and revealed their expression characteristics and dynamics during Ciona embryogenesis and larval metamorphosis. The results will help to further understand the function of lncRNAs in chordate development and the evolution of lncRNAs. PMID- 29754834 TI - Site-specific incorporation of quadricyclane into a protein and photocleavage of the quadricyclane ligation adduct. AB - The quadricyclane (QC) ligation is a bioorthogonal reaction between a quadricyclane moiety and a nickel bis(dithiolene) derivative. Here we show that a QC amino acid can be incorporated into a protein site-specifically using the pyrrolysine-based genetic code expansion platform, and subsequently used for ligation chemistry. Additionally, we exploited the photolability of the QC ligation product to render the adduct cleavable with a handheld UV lamp. We further developed a protein purification method that involves QC ligation of biotin to a protein of interest, capture on streptavidin resin, and finally release using only UV light. The QC ligation thus brings novel chemical manipulations to the realm of bioorthogonal chemistry. PMID- 29754836 TI - Misoprostol for small bowel ulcers in patients with obscure bleeding taking aspirin and non-steroidal anti-inflammatory drugs (MASTERS): a randomised, double blind, placebo-controlled, phase 3 trial. AB - BACKGROUND: The incidence of obscure gastrointestinal bleeding, which originates from the small bowel and is mainly associated with the use of aspirin and non steroidal anti-inflammatory drugs (NSAIDs), is rising. We assessed the efficacy and safety of misoprostol for the treatment of small bowel ulcers and erosions in patients taking low-dose aspirin or NSAIDs with obscure gastrointestinal bleeding. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients (aged >=18 years) with small bowel ulcers who were taking low-dose aspirin, NSAIDs, or both for a minimum of 4 weeks, at University Hospital Crosshouse (Kilmarnock, UK). Eligible patients had evidence of obscure gastrointestinal bleeding (iron deficiency anaemia, a decrease in haemoglobin concentration of >=20 * 103 mg/L, or positive faecal occult blood test) and normal upper endoscopy and colonoscopy. Patients were randomly assigned (1:1) using an interactive voice response system to receive 200 MUg oral misoprostol or placebo four times daily for 8 weeks. Patients, investigators, and assessors were masked to treatment allocation. The primary endpoint was the complete healing of small bowel ulcers and erosions, assessed by video capsule endoscopy after 8 weeks of treatment. Primary analysis was by modified intention to treat, which included all randomised patients who received at least one dose of study treatment. Safety was assessed in the same population. The trial is registered with ClinicalTrials.gov, number NCT02202967. FINDINGS: Between Jan 7, 2016, and Oct 11, 2017, we randomly allocated 104 eligible patients: 52 to receive misoprostol and 52 to receive placebo. Two patients allocated to misoprostol were later found to meet one of the exclusion criteria, thus 50 randomly assigned patients in the misoprostol group and 52 patients in the placebo group received at least one dose of study treatment. Complete healing of small bowel ulcers and erosions was noted at week 8 in 27 (54%) of 50 patients in the misoprostol group and nine (17%) of 52 patients in the placebo group (percentage difference 36.7%, 95% CI 19.5-53.9; p=0.0002). Adverse events occurred in 23 (46%) of 50 patients in the misoprostol group and 22 (42%) of 52 patients in the placebo group. The most common adverse events were abdominal pain (ten [20%] in the misoprostol group vs 13 [25%] in the placebo group), nausea or vomiting (nine [18%] vs seven [13%]), and diarrhoea (11 [22%] vs six [12%]). Four (8%) of 50 patients in the misoprostol group had severe adverse events, compared with none in the placebo group. No serious adverse events were reported. INTERPRETATION: Misoprostol is effective for the treatment of small bowel ulcers and erosions in patients using low-dose aspirin and NSAIDs. Misoprostol might represent a pharmacological treatment option for lesions causing obscure gastrointestinal bleeding that is associated with aspirin and NSAIDs, but its use should be balanced against the risk of side-effects. FUNDING: National Health Service (NHS) Greater Glasgow and Clyde and NHS Ayrshire and Arran. PMID- 29754837 TI - Effects of exercise on gait and motor imagery in people with Parkinson disease and freezing of gait. AB - INTRODUCTION: Exercise improves gait in Parkinson disease (PD), but whether exercise differentially affects people with PD with (freezers) and without freezing of gait (non-freezers) remains unclear. This study examines exercise's effects on gait performance, neural correlates related to these effects, and potential neural activation differences between freezers and non-freezers during motor imagery (MI) of gait. METHODS: Thirty-seven participants from a larger exercise intervention completed behavioral assessments and functional magnetic resonance imaging (fMRI) scans before and after a 12-week exercise intervention. Gait performance was characterized using gait velocity and stride length, and a region of interest (ROI) fMRI analysis examined task-based blood oxygen-level dependent (BOLD) signal changes of the somatomotor network (SMN) during MI of forward (IMG-FWD) and backward (IMG-BWD) gait. RESULTS: Velocity (F(1,34) = 55.04, p < 0.001) and stride length (F(1,34) = 77.58, p < 0.001) were significantly lower for backward versus forward walking in all participants. The ROI analysis showed freezers had lower BOLD signal compared to non-freezers in the cerebellum (F(1,32) = 7.01, p = 0.01), primary motor (left: F(1,32) = 7.09, p = 0.01; right: F(1,32) = 7.45, p = 0.01), and primary sensory (left: F(1,32) = 9.59, p = 0.004; right: F(1,32) = 8.18, p = 0.007) cortices during IMG-BWD only. The evidence suggests the exercise intervention did not affect gait or BOLD signal during MI. CONCLUSION: While all participants had significantly slower and shorter backward velocity and stride length, respectively, the exercise intervention had no effect. Similarly, BOLD signal during MI did not change with exercise; however, freezers had significantly lower BOLD signal during IMG-BWD compared to non-freezers. This suggests potential decreased recruitment of the SMN during MI of gait in freezers. PMID- 29754838 TI - [BCG infection following intravesicular immunotherapy for bladder cancer]. AB - BACKGROUND: Bacille of Calmette et Guerin (BCG) immunotherapy is the most effective treatment for non-muscle-invasive bladder cancer. Yet, potentially severe localized or systemic mycobacterial infections can happen. STATE OF KNOWLEDGE: In a patient who underwent BCG instillation for bladder cancer, the diagnosis of BCG infection is usually suggested by more than 3 days of high-grade fever and systemic and/or local symptoms with no other plausible alternative diagnosis. BCG infection can be localized (usually to the genitourinary tract, the bones or blood vessels) or systemic (mainly with pulmonary and hepatic involvements). The presence of granuloma in tissue biopsies (other than from the genitourinary tract) supports the diagnosis. The advent of polymerase chain reaction has recently improved the sensitivity of microbiological investigations. The management of BCG infection is not well established but relies on broad spectrum antimycobacterial therapy (with the exclusion of pyrazinamide), glucocorticoids (in the context of general symptoms refractory to antimicrobial therapy alone) and occasionally surgery. CONCLUSION: BCG infection is a rare but not exceptional complication of BCG immunotherapy with heterogeneous clinical presentation. Prospective studies are warranted in order to improve treatment outcomes. PMID- 29754839 TI - [Retrospective study of 25 cases of pulmonary mucormycosis in acute leukaemia]. AB - INTRODUCTION: In acute leukaemia (AL), the occurrence of pulmonary mucormycosis (PM), the incidence of which is increasing, as a result of chemotherapy induced marrow aplasia, remains a life threatening complication. METHODS: Analysis of clinical, biological and thoracic CT characteristics of patients with PM developing during the treatment of AL between 2000 and 2015. Day 0 (D0) was defined as the day with first CT evidence of PM. RESULTS: Among 1193 patients, 25 cases of PM were recorded during 2099 episodes of bone marrow aplasia. At time of diagnosis of PM, 24/25 patients had been neutropenic for a median of 12 days. None of the patients had diabetes mellitus. On initial CT (D0), the lesion was solitary in 20/25 cases and a reversed halo sign (RHS) was observed in 23/25 cases. From D1 to D7, D8 to D15 and after D15, RHS was seen in 100 %, 75 % and 27 % of cases, respectively. A tissue biopsy was positive in 17/18 cases. The detection of circulating Mucorales DNA in serum was positive in 23/24 patients and in 97/188 serum specimens between D-9 and D9. Bronchoalveolar lavage contributed to diagnosis in only 3/21 cases. The antifungal treatment was mainly based on liposomal amphotericin B combined with, or followed by, posaconazole. A pulmonary surgical resection was performed in 9/25 cases. At 3 months, 76 % of patients were alive and median overall survival was 14 months. CONCLUSION: In AL, early use of CT could improve the prognosis of PM. The presence of a RHS on CT suggests PM and is an indication for prompt antifungal treatment. PMID- 29754840 TI - [Respiratory physiotherapy in acute viral bronchiolitis in the newborn. Pro/con arguments]. AB - This article reports an exchange of unbiased arguments between Mr Guy Postiaux speaking in favour of respiratory physiotherapy in acute viral bronchiolitis in the newborn and Prof. Jean-Christoph Dubus arguing against. A review of the literature suggests that traditional methods of physiotherapy should be abandoned because they are not validated and because they have harmful side effects. The latest Cochrane revue (2016) suggests the use of slow expiration techniques that have some validated elements and cause no harmful side effects. Large multicentre studies should be undertaken to confirm or refute the results of the five studies in the Cochrane review. Their analysis would allow extraction of objective evidence for the efficacy of slow expiration techniques on the relief of bronchopulmonary obstruction and the reduction of the degree of severity in the short and medium term. Studies of the effect of ambulatory respiratory physiotherapy for bronchiolitis of a moderate degree not requiring hospitalisation are not available. An evaluation is needed which is based on the pathophysiology of multifactorial bronchial obstruction and on the physical signs, of which auscultation is the cornerstone. PMID- 29754841 TI - [Risks associated with the use of non-steroidal anti-inflammatory drugs during pneumonia]. AB - INTRODUCTION: Outpatient treatment of community-acquired pneumonia (CAP) patients with non-steroidal anti-inflammatory drugs (NSAIDs) is frequent, although this is not based on clinical recommendations and there is no scientific evidence supporting better symptom relief in comparison to acetaminophen. STATE OF THE ART: Experimental data suggest that NSAIDs alter the intrinsic functions of neutrophils, limit their locoregional recruitment, alter bacterial clearance and delay the resolution of inflammatory processes during acute bacterial pulmonary challenge. In hospitalized children and adults with CAP, observational data suggest a strong and independent association between the outpatient exposure to NSAIDs and the occurrence of pleuropulmonary complications (pleural empyema, excavation, and abscess). In the only study taking into account possible protopathic bias, the association still persists. Other markers of morbidity have been described, including delay in hospital management, prolonged antibiotic therapy, and higher transfer rate to an intensive care unit. PERSPECTIVES: Data describing the role of self-medication and the biological mechanisms involved are needed. CONCLUSIONS: Intake of NSAIDs during outpatient treatment of CAP is probably the second modifiable factor of morbidity after inadequate antibiotic therapy. In light of existing data in children and adults, health authorities should urgently reassess the risk-benefit ratio of NSAIDS in CAP. PMID- 29754842 TI - [Lungs and fungi: level of evidence and doubts]. PMID- 29754843 TI - Revision of failed hemiarthroplasty for painful glenoid arthrosis to anatomic total shoulder arthroplasty. AB - BACKGROUND: The impending burden of revision shoulder arthroplasty has increased interest in outcomes of revision procedures. Painful glenoid arthrosis following hemiarthroplasty is a common cause of reoperation, and conversion to anatomic total shoulder arthroplasty is one option. METHODS: We identified patients who underwent revision of painful hemiarthroplasty to total shoulder arthroplasty over a 15-year period in a single tertiary-care health system. Presurgical and operative data were analyzed for 28 patients who met the inclusion and exclusion criteria. Patients were contacted at a minimum of 2 years' follow-up after revision surgery for functional outcome scores, reoperations, and implant survival. RESULTS: The 2- and 5-year implant survival rates were 93% and 86%, respectively. Functional outcomes were obtained from 21 patients with surviving implants. The mean American Shoulder and Elbow Surgeons score, visual analog scale score for pain, and Single Assessment Numerical Evaluation score were 78 +/ 20, 2.3 +/- 2.6, and 71 +/- 24, respectively. The mean Short Form 12 mental and physical scores were 49 +/- 10 and 43 +/- 9, respectively. Of the patients, 17 (81%) were either satisfied or very satisfied with their outcome. Complications were seen in 10 patients (36%), and 6 patients (21%) required reoperation. CONCLUSIONS: Anatomic total shoulder arthroplasty following hemiarthroplasty can achieve successful outcomes and implant survival rates. Given our poor understanding of reverse shoulder arthroplasty longevity, this procedure should remain an option for patients with glenoid arthrosis and an intact rotator cuff. PMID- 29754844 TI - Quantitative magnetic resonance imaging analysis of the cross-sectional areas of the anconeus epitrochlearis muscle, cubital tunnel, and ulnar nerve with the elbow in extension in patients with and without ulnar neuropathy. AB - BACKGROUND: The purpose of this study was to assess the cross-sectional area of the anconeus epitrochlearis muscle (AEM), cubital tunnel, and ulnar nerve with the elbow in extension in patients with and without ulnar neuropathy. METHODS: We performed a retrospective, level IV review of elbow magnetic resonance imaging (MRI) studies. Elbow MRI studies of 32 patients with an AEM (26 men and 6 women, aged 18-60 years), 32 randomly selected patients without an AEM (aged 16-71 years), and 32 patients with clinical ulnar neuritis (22 men and 10 women, aged 24-76 years) were reviewed. We evaluated the ulnar nerve cross-sectional area proximal to, within, and distal to the cubital tunnel; AEM cross-sectional area; and cubital tunnel cross-sectional area. RESULTS: We found no significant difference in the nerve caliber between patients with and without an AEM. No correlation was found between the AEM cross-sectional area and ulnar nerve cross sectional area within the cubital tunnel (r = 0.14). The mean cubital tunnel cross-sectional area was larger in patients with an AEM. Only 4 of the 32 patients with an AEM had findings of ulnar neuritis on MRI. Of the 32 patients with a clinical diagnosis of ulnar neuritis, only 2 had an AEM. CONCLUSIONS: With the elbow in extension, the presence or cross-sectional area of an AEM does not correlate with the area of the ulnar nerve or cubital tunnel. Only a small number of individuals with MRI evidence of an AEM had clinical evidence of ulnar neuropathy. Likewise, MRI evidence of an AEM was found in only a small number of individuals with clinical evidence of ulnar neuropathy. PMID- 29754845 TI - Do magnetic resonance imaging and computed tomography provide equivalent measures of rotator cuff muscle size in glenohumeral osteoarthritis? AB - BACKGROUND: Rotator cuff muscle volume is associated with outcomes after cuff repair and total shoulder arthroplasty. Muscle area on select magnetic resonance imaging (MRI) slices has been shown to be a surrogate for muscle volume. The purpose of this study was to determine whether computed tomography (CT) provides an equivalent measurement of cuff muscle area to a previously validated MRI measurement. METHODS: We included 30 patients before they were undergoing total shoulder arthroplasty with both preoperative CT and MRI scans performed within 30 days of one another at 1 institution using a consistent protocol. We reoriented CT sagittal and MRI sagittal T1 series orthogonal to the scapular plane. On both CT and MRI scans, we measured the area of the supraspinatus, infraspinatus-teres minor, and subscapularis on 2 standardized slices as previously described. We calculated intraclass correlation coefficients and mean differences. RESULTS: For the 30 subjects included, when MRI and CT were compared, the mean intraclass correlation coefficients were 0.989 (95% confidence interval [CI], 0.976-0.995) for the supraspinatus, 0.978 (95% CI, 0.954-0.989) for the infraspinatus-teres minor, and 0.977 (95% CI, 0.952-0.989) for the subscapularis. The mean differences were 0.2 cm2 (95% CI, 0.0-0.4 cm2) for the supraspinatus (P = .052), 0.8 cm2 (95% CI, 0.1-1.4 cm2) for the infraspinatus-teres minor (P = .029), and 0.3 cm2 (95% CI, -1.2 to 0.5 cm2) for the subscapularis (P = .407). CONCLUSION: CT provides nearly equivalent measures of cuff muscle area to an MRI technique with previously validated reliability and accuracy. While CT underestimates the infraspinatus area as compared with MRI, the difference is less than 1 cm2 and thus likely clinically insignificant. PMID- 29754846 TI - Can Gentamicin-collagen Sponges Prevent Seroma Formation Following Mastectomy? AB - BACKGROUND: The aim of this study was to investigate whether gentamicin-collagen (GC) sponges can lower the incidence of seroma and surgical site infections following breast cancer surgery. PATIENTS AND METHODS: A retrospective cohort study was performed. Two consecutive cohorts of patients who underwent a mastectomy with or without an axillary lymph node dissection were compared. The first cohort was treated conventionally (n = 38), the second cohort received GC sponges (n = 39). Endpoints were the incidence of clinical significant seroma (CSS) and surgical site infections (SSI), the mean number of aspirations, and the mean aspirated volume. RESULTS: GC sponges lowered the CSS incidence from 73.7% to 38.5% (P = .002). The mean number of aspirations and the mean aspirated volume were not affected. SSI incidence was 15.8% in the conventional cohort compared with 7.7% in the GC cohort (P = .23). CONCLUSION: Application of GC sponges significantly lowered the incidence of CSS. The incidence of SSI was halved, although this was not significant. PMID- 29754847 TI - Feasibility of Classification of Triple Negative Breast Cancer by Immunohistochemical Surrogate Markers. AB - INTRODUCTION: Recently, Burstein et al identified 4 stable molecular subtypes of triple negative breast cancer (TNBC) by mRNA profiling: luminal androgen receptor (LAR), mesenchymal (MES), basal-like immune-activated (BLIA), and basal-like immune-suppressive (BLIS) types. The purpose of this study was to assess the feasibility of immunohistochemistry (IHC) surrogate panel in classifying the TNBC molecular subtypes using a large cohort of TNBC retrieved from a single institution. MATERIALS AND METHODS: IHC for androgen receptor [AR], claudin-3, E cadherin, cytokeratin 5/6 [CK5/6], epidermal growth factor receptor [EGFR], indoleamine 2,3-dioxygenase 1 [IDO1], and Forkhead box C1 [FOXC1] were performed using the tissue microarray constructed from 200 TNBC samples. RESULTS: The 200 TNBCs were classified as LAR (AR+, n = 22; 11.0%), MES (claudin 3- and/or E cadherin-, n = 23; 11.5%), basal-like (CK5/6+ and/or EGFR+, n = 85; 42.5%), mixed (n = 60; 30%), and unclassifiable type (n = 10; 5%). LAR type was associated with older patient age, apocrine histologic features, low density of stromal tumor infiltrating lymphocytes (TIL), and low Ki-67 labeling index. MES type was associated with tumor cell discohesiveness and metaplastic features. Basal-like type was associated with younger patient age, high histologic grade, high stromal TIL density, and high Ki-67 labeling index. Basal-like TNBCs were further classified as BLIA (IDO1+ and FOXC1-, n = 27) or BLIS type (IDO1- and FOXC1+, n = 11). BLIS type was associated with large tumor size and low stromal TIL density, which had the worst prognostic outcome among 4 subtypes. CONCLUSION: The IHC surrogate panel may define TNBC subtypes with distinct clinicopathologic characteristics and prognostic significance. PMID- 29754848 TI - Transnasal Lidocaine for Treating Headache in the Emergency Department. PMID- 29754849 TI - Combination Therapies: Quantifying the Effects of Transarterial Embolization on Microwave Ablation Zones. AB - PURPOSE: To quantify the effect of transarterial embolization on microwave (MW) ablations in an in vivo porcine liver model. MATERIALS AND METHODS: Hepatic arteriography and cone-beam computed tomography (CT) scans were performed in 6 female domestic swine. Two lobes were embolized to an endpoint of substasis with 100-300-MUm microspheres. MW ablations (65 W, 5 min) were created in embolized (n = 15) and nonembolized (n = 12) liver by using a 2.45-GHz system and single antenna. Cone-beam CT scans were obtained to monitor the ablations, document gas formation, and characterize arterial flow. Ablation zones were excised and sectioned. A mixed-effects model was used to compare ablation zone diameter, length, area, and circularity. RESULTS: Combined transarterial embolization and MW ablation zones had significantly greater area (mean +/- standard deviation, 11.8 cm2 +/- 2.5), length (4.8 cm +/- 0.5), and diameter (3.1 cm +/- 0.6) compared with MW only (7.1 cm2 +/- 1.9, 3.7 cm +/- 0.6, and 2.4 cm +/- 0.3, respectively; P = .0085, P = .0077, and P = .0267, respectively). Ablation zone circularity was similar between groups (P = .9291). The larger size of the combined ablation zones was predominantly the result of an increase in size of the peripheral noncharred zone of coagulation (1.3 cm +/- 0.4 vs 0.8 cm +/- 0.2; P = .0104). Cone-beam CT scans demonstrated greater gas formation during combined ablations (1.8 cm vs 1.1 cm, respectively). Mean maximum temperatures 1 cm from the MW antennas were 86.6 degrees C and 68.7 degrees C for the combined embolization/ablation and MW-only groups, respectively. CONCLUSIONS: Combining transarterial embolization and MW ablation increased ablation zone diameter and area by approximately 27% and 66%, respectively, in an in vivo non-tumor-bearing porcine liver model. This is largely the result of an increase in the size of the peripheral ablation zone, which is most susceptible to local blood flow. PMID- 29754850 TI - Biologic Drug Effect and Particulate Embolization of Drug-Eluting Stents versus Drug-Coated Balloons in Healthy Swine Femoropopliteal Arteries. AB - PURPOSE: To compare the drug effect in treated vessels and downstream effects in distal skeletal muscle of drug-coated balloons (DCBs) and drug-eluting stents (DESs) in a healthy preclinical swine model. MATERIALS AND METHODS: Four groups of treated iliofemoral arteries (percutaneous transluminal angioplasty [PTA]+DES, DCB+DES, DCB+bare metal stent [BMS], and DCB alone) of 12 healthy swine were assessed, with euthanasia at 30 days. Biological drug effect was evaluated using smooth muscle cell (SMC) loss score according to both depth and circumference as well as a neointimal fibrin and medial proteoglycan scores which were compared between the 4 groups. Vascular and skeletal muscle changes in regions downstream from the treated site were also assessed histologically for evidence of emboli. RESULTS: DESs showed greater medial SMC loss in the treated arteries irrespective of preceding DCB or PTA treatment in terms of depth (DCB+DES vs PTA+DES vs DCB+BMS vs DCB alone; median, 4.0 mm vs 3.8 mm vs 3.0 mm vs 2.2 mm; P = .009) and circumference (4.0 mm vs 3.5 mm vs 2.0 mm vs 1.2 mm, respectively; P = .007). Sections of skeletal muscles downstream from the treated arteries showed arteriolar changes of fibrinoid necrosis consistent with paclitaxel effect exclusively in the DCB groups (DCB+BMS, 26.9% of sections; DCB+DES, 14.3%; DCB alone, 19.2%; PTA+DES, 0%; P = .02). CONCLUSIONS: In the treated arteries, irrespective of preceding DCB treatment or PTA, DES treatment showed maximum drug effects vs DCB alone or in combination with BMS placement, and there was no detrimental toxic effect in DCB-treated iliofemoral arteries before DES treatment compared with PTA before DES treatment. Downstream vascular changes were exclusively seen in groups treated with DCBs. PMID- 29754851 TI - Treatment of Hepatocellular Carcinoma with Tumor Thrombus with the Use of Iodine 125 Seed Strand Implantation and Transarterial Chemoembolization: A Propensity Score Analysis. AB - PURPOSE: To evaluate the safety and efficacy of iodine-125 (125I) seed strand implantation in combination with transarterial chemoembolization for the treatment of hepatitis B-related unresectable hepatocellular carcinoma (HCC) with portal vein invasion. MATERIALS AND METHODS: From January 2013 to June 2016, 76 HCC patients with type II tumor thrombus were included in this single-center retrospective study. Twenty patients underwent 125I seed strand implantation combined with transarterial chemoembolization (group A; n = 20), while 56 patients underwent transarterial chemoembolization alone (group B; n = 56). The procedure-related and radiation complications were assessed. Overall survivals were compared by propensity-score analysis. RESULTS: The technique was successfully performed in all patients. The mean intended dose (r = 10 mm; z = 0; 240 days) was 62.6 +/- 1.8 Gy. No grade 3 or 4 adverse events related to the procedure occurred in either group. After propensity-score-matching analysis, 19 patients were selected into each group, respectively. In the propensity-matching cohort, the median overall survival time was significantly longer in group A than in the group B (19 pairs; 28.0 +/- 2.4 vs 8.7 +/- 0.4 mo; P = .001). Treatment strategy, arterioportal shunt, and number of transarterial chemoembolization sessions were significant predictors of favorable overall survival time. CONCLUSIONS: 125I seed strand implantation combined with transarterial chemoembolization is a safe and effective treatment for HCC patients with portal vein invasion. PMID- 29754853 TI - Early Implementation of Malnutrition Clinical Quality Metrics to Identify Institutional Performance Improvement Needs. PMID- 29754854 TI - Indirect adaptive fuzzy fault-tolerant tracking control for MIMO nonlinear systems with actuator and sensor failures. AB - In this paper, an active fuzzy fault tolerant tracking control (AFFTTC) scheme is developed for a class of multi-input multi-output (MIMO) unknown nonlinear systems in the presence of unknown actuator faults, sensor failures and external disturbance. The developed control scheme deals with four kinds of faults for both sensors and actuators. The bias, drift, and loss of accuracy additive faults are considered along with the loss of effectiveness multiplicative fault. A fuzzy adaptive controller based on back-stepping design is developed to deal with actuator failures and unknown system dynamics. However, an additional robust control term is added to deal with sensor faults, approximation errors, and external disturbances. Lyapunov theory is used to prove the stability of the closed loop system. Numerical simulations on a quadrotor are presented to show the effectiveness of the proposed approach. PMID- 29754855 TI - Sampled-data-based vibration control for structural systems with finite-time state constraint and sensor outage. AB - The problem of sampled-data-based vibration control for structural systems with finite-time state constraint and sensor outage is investigated in this paper. The objective of designing controllers is to guarantee the stability and anti disturbance performance of the closed-loop systems while some sensor outages happen. Firstly, based on matrix transformation, the state-space model of structural systems with sensor outages and uncertainties appearing in the mass, damping and stiffness matrices is established. Secondly, by considering most of those earthquakes or strong winds happen in a very short time, and it is often the peak values make the structures damaged, the finite-time stability analysis method is introduced to constrain the state responses in a given time interval, and the H-infinity stability is adopted in the controller design to make sure that the closed-loop system has a prescribed level of disturbance attenuation performance during the whole control process. Furthermore, all stabilization conditions are expressed in the forms of linear matrix inequalities (LMIs), whose feasibility can be easily checked by using the LMI Toolbox. Finally, numerical examples are given to demonstrate the effectiveness of the proposed theorems. PMID- 29754852 TI - Predictors of Survival after Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases. AB - PURPOSE: To identify clinical parameters that are prognostic for improved overall survival (OS) after yttrium-90 radioembolization (RE) in patients with liver metastases from colorectal cancer (CRC). MATERIALS AND METHODS: A total of 131 patients who underwent RE for liver metastases from CRC, treated at 2 academic centers, were reviewed. Twenty-one baseline pretreatment clinical factors were analyzed in relation to OS by the Kaplan-Meier method along with log-rank tests and univariate and multivariate Cox regression analyses. RESULTS: The median OS from first RE procedure was 10.7 months (95% confidence interval [CI], 9.4-12.7 months). Several pretreatment factors, including lower carcinoembryonic antigen (CEA; <=20 ng/mL), lower aspartate transaminase (AST; <=40 IU/L), neutrophil lymphocyte ratio (NLR) <5, and absence of extrahepatic disease at baseline were associated with significantly improved OS after RE, compared with high CEA (>20 ng/mL), high AST (>40 IU/L), NLR >=5, and extrahepatic metastases (P values of <.001, <.001, .0001, and .04, respectively). On multivariate analysis, higher CEA, higher AST, NLR >=5, extrahepatic disease, and larger volume of liver metastases remained independently associated with risk of death (hazard ratios of 1.63, 2.06, 2.22, 1.48, and 1.02, respectively). CONCLUSIONS: The prognosis of patients with metastases from CRC is impacted by a complex set of clinical parameters. This analysis of pretreatment factors identified lower AST, lower CEA, lower NLR, and lower tumor burden (intra- or extrahepatic) to be independently associated with higher survival after hepatic RE. Optimal selection of patients with CRC liver metastases may improve survival rates after administration of yttrium-90. PMID- 29754856 TI - Three-dimensional dental and craniofacial manifestations in patients with late diagnosis of mucopolysaccharidosis type II: report of 2 cases. AB - The objective of this study was to report the clinical evaluation results and 3 dimensional (3-D) dental and craniofacial characteristics observed in 2 male patients with mucopolysaccharidosis type II. The patients were evaluated clinically (soft tissue evaluation, evaluation of occlusion, periodontal and dental examinations) and by using craniofacial computed tomography, with evaluation of 3-D images in ITK-Snap v. 2.2 (Penn Image Computing and Science Laboratory, Philadelphia, PA; http://www.itksnap.org/) and 3-D Slicer (http://www.slicer.org/) software. Mandibular 3-D volumetric label maps were built from computed tomography scans of both patients and compared through superimposition on a healthy patient's mandibular images. Clinically, the patients presented the following oral manifestations: macroglossia, total open bite and generalized diastemas, and absence of caries. Patient 1 showed dental calculus and bleeding at the gingival margin. Patient 2 showed bleeding at the gingival margin, a permanent maxillary left central incisor missing as a result of trauma, and impacted permanent mandibular left and right second molars. 3-D images showed wide arches, prominent antegonial notches, a narrow mandibular body in the region of the antegonial notches, bilateral severe condylar hypoplasia, and enlarged coronoid processes. 3-D imaging and superimpositions revealed oral and skeletal displacements, contributing to the identification of changes in the course of mucopolysaccharidosis type II in patients with a late diagnosis. PMID- 29754858 TI - For the love of Piltdown Man. PMID- 29754857 TI - Comparison of normal saline versus Lactated Ringer's solution for fluid resuscitation in patients with mild acute pancreatitis, A randomized controlled trial. AB - BACKGROUND/OBJECTIVES: Aggressive fluid resuscitation is recommended for initial management of acute pancreatitis. However, there are few studies which focus on types of fluid therapy. METHODS: We performed a randomized controlled trial in patients with acute pancreatitis. The patients were randomized into two groups. Each group received Normal Saline solution (NSS) or Lactated Ringer's solution (LRS) through a goal-directed fluid resuscitation protocol. Systemic inflammatory response syndrome (SIRS) at 24 and 48 h, mortality, presence of local complications and inflammatory markers were measured. RESULTS: Forty-seven patients were included. Twenty-four patients (51%) received NSS and 23 patients received LRS. There was significant reduction in SIRS after 24 h among subjects who resuscitated with LRS compared with NSS (4.2% in NSS, 26.1% in LRS, P = 0.02). However, SIRS reduction at 48 h was not different between groups (33.4% in NSS, 26.1% in LRS, P = 0.88). Mortality was not different between NSS and LRS (4.2% in NSS, 0% in LRS, P = 1.00). CRP, ESR and procalcitonin increased at 24 h and 48 h after admission with no difference between the two groups. Local complications were 29.2% in NSS and 21.7% in LRS (P = 0.74). The median length of hospital stay was not significantly different in the two groups (5.5 days in NSS, 6 days in LRS, P = 0.915). CONCLUSIONS: Lactated Ringer's solution was superior to NSS in SIRS reduction in acute pancreatitis only in the first 24 h. But SIRS at 48 h and mortality were not different between LRS and NSS. PMID- 29754859 TI - Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at two Swedish centres 2005 2014. AB - BACKGROUND AND PURPOSE: Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). MATERIAL AND METHODS: mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005-2014 were retrospectively included. Median follow-up (mFU) was 63 months. RESULTS: A majority had clear cell histology, 1-3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6-5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1-3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2-0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months. CONCLUSIONS: OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis. PMID- 29754860 TI - Norovirus, glycans and attachment. PMID- 29754861 TI - Mid-Cavity Variant Takotsubo Cardiomyopathy-Magnetic Resonance Imaging Findings. PMID- 29754862 TI - The Use of a Fitbit Device for Assessing Physical Activity and Sedentary Behavior in Preschoolers. AB - OBJECTIVE: To determine the accuracy of the Fitbit Flex (FF) activity monitor for assessing preschoolers' physical activity (PA) and sedentary behavior (SED) in free-living conditions. STUDY DESIGN: This is a cross-sectional study of 27 preschoolers (41% girls; age, 4.9 years) who each wore the FF and ActiGraph GT3X+ (AG) simultaneously for 24 hours. Raw data from each device were temporally matched and summarized into estimates of SED, moderate-to-vigorous PA, and total PA after removing sleep and nonwear time periods. Equivalence testing was performed to compare the 90% CIs of the estimates from the FF with the respective equivalence zone (+/-15% of the mean estimates) from the AG. RESULTS: The FF yielded equivalent estimates of SED (mean difference, 42-71 minutes/day) and total PA (mean difference, 42-70 minutes/day), but lower moderate-to-vigorous PA (mean difference, 29-67 minutes/day) than the AG, on average. The FF showed strong correlations and relatively low mean absolute percent errors (MAPEs) in relation to the AG for SED (r = 0.87; MAPE = 9.1%) and total PA (r = 0.71; MAPE = 14.3%), but a moderate correlation and high MAPE for moderate-to-vigorous PA (r = 0.59; MAPE = 70.1%). CONCLUSIONS: The FF activity monitor accurately estimated the amount of time spent in SED and overall PA in preschool-aged children, but with an underestimation of moderate-to-vigorous PA. Our findings support the use of the FF as a feasible and a relatively accurate PA monitoring tool in clinical and research settings. PMID- 29754864 TI - Adherence to Polyethylene Glycol Treatment in Children with Functional Constipation Is Associated with Parental Illness Perceptions, Satisfaction with Treatment, and Perceived Treatment Convenience. AB - OBJECTIVES: To assess treatment adherence in children with functional constipation and to evaluate the association with parental beliefs about medication, illness perceptions, treatment satisfaction, and satisfaction with information about medication. STUDY DESIGN: A cross-sectional survey was administered among parents of children with functional constipation treated with polyethylene glycol. Adherence was measured via the Medication Adherence Report Scale (MARS-5, score 5-25), with greater scores indicating better adherence (scores >=23 were defined as adherent). Beliefs about medication, illness perceptions, satisfaction with treatment, and satisfaction with information about treatment were measured with the Beliefs about Medication Questionnaire, the Brief Illness Perception Questionnaire, the Treatment Satisfaction Questionnaire for Medication (TSQM), and the Satisfaction with Information about Medication Questionnaire. Associations between the questionnaire scores and adherence (MARS 5 score as a continuous variable) were analyzed with regression analyses. RESULTS: In total, 43 of 115 included children (37%) were adherent (MARS-5 >=23). Spearman rank correlation test revealed a statistically significant correlation between TSQM-convenience, TSQM-satisfaction, Brief Illness Perception Questionnaire question 8 (emotions), and the MARS-5 score (rs 0.342, P = .000; rs 0.258, P = .006; rs -0.192, P = .044), which suggests that parental perceived treatment convenience, satisfaction with treatment, and illness perceptions may affect adherence in children with functional constipation. In the hierarchical multivariate regression model, 22% of the variability of the MARS-5 score could be explained by the selected predictors. The TSQM-convenience score contributed the most to the model (beta: 0.384, P = .000). CONCLUSIONS: Parents reported low adherence rates in their children with functional constipation. Treatment inconvenience, dissatisfaction with treatment, and the emotional impact of functional constipation may negatively influence treatment adherence. PMID- 29754865 TI - Incidence Trends and Risk Factor Variation in Severe Intraventricular Hemorrhage across a Population Based Cohort. AB - OBJECTIVE: To quantify the current burden of severe intraventricular hemorrhage (IVH), describe time trends in severe IVH, identify IVH-associated risk factors, and determine the contribution of mediating factors. STUDY DESIGN: The retrospective cohort included infants 220/7-316/7 weeks of gestation without severe congenital anomalies, born at hospitals in the California Perinatal Quality Care Collaborative between 2005 and 2015. The primary study outcome was severe (grade III or IV) IVH. RESULTS: Of 44 028 infants, 3371 (7.7%) had severe IVH. The incidence of severe IVH decreased significantly across California from 9.7% in 2005 to 5.9% in 2015. After stratification by gestational age, antenatal steroid exposure was the only factor associated with a decreased odds of severe IVH for all gestational age subgroups. Other factors, including delivery room intubation, were associated with an increased odds of severe IVH, though significance varied by gestational age. Factors analyzed in the mediation analysis accounted for 45.6% (95% CI 38.7%-71.8%) of the reduction in severe IVH, with increased antenatal steroid administration and decreased delivery room intubation mediating a significant proportion of this decrease, 19.4% (95% CI 13.9%-27.5%) and 27.3% (95% CI 20.3%-39.2%), respectively. The unaccounted proportion varied by gestational age. CONCLUSIONS: The incidence of severe IVH decreased across California, associated with changes in antenatal steroid exposure and delivery room intubation. Maternal, patient, and delivery room factors accounted for less than one-half of the decrease in severe IVH. Study of other factors, specifically neonatal intensive care unit and hospital-level factors, may provide new insights into policies to reduce severe IVH. PMID- 29754863 TI - Relationships of Anxiety and Depression with Cardiovascular Health in Youth with Normal Weight to Severe Obesity. AB - OBJECTIVE: To evaluate the relationships of depression and anxiety symptoms with cardiovascular disease (CVD) risk factors and measures of vascular health in youth. STUDY DESIGN: Participants (n = 202) were 8- to 18-year-olds from a cross sectional study evaluating cardiovascular health across a wide range of body mass index values (normal weight to severe obesity). CVD risk measurement included blood pressure, fasting lipids, glucose, insulin, carotid artery intima-media thickness, compliance and distensibility, brachial artery flow-mediated dilation, carotid-radial artery pulse wave velocity, body fat percentage, and a metabolic syndrome cluster score. Anxiety and depression symptoms were self-reported on the Screen for Child Anxiety Related Disorders and Center for Epidemiological Studies Depression Scale for Children. Two sets of adjustment variables were used in evaluation of differences between those with and without anxiety or depression symptomatology for the CVD risk factor and vascular outcomes. The first set included adjustment for Tanner stage, sex, and race; the second was additionally adjusted for percent body fat. RESULTS: Anxiety was not significantly associated with CVD risk factors or vascular health in either model. Depression was associated with high-density lipoprotein cholesterol, triglycerides, and metabolic syndrome cluster score; these relationships were attenuated when accounting for percent body fat. CONCLUSIONS: When accounting for body fat, we found no clear relationship of self-reported depression or anxiety symptoms with CVD risk factors or vascular health in youth. PMID- 29754866 TI - Outpatient Pharmacotherapy for Neonatal Abstinence Syndrome. AB - OBJECTIVE: To determine differences in lengths of stay, length of therapy, emergency department (ED) utilization, and hospital readmissions between infants with neonatal abstinence syndrome (NAS) treated exclusively with inpatient pharmacotherapy compared with those discharged on outpatient pharmacotherapy. STUDY DESIGN: This retrospective cohort study of infants enrolled in the Tennessee Medicaid program used administrative and vital records data from 2009 to 2011. Medical record review was used to confirm cases of NAS and classify treatment type. Negative binomial regression was used to compare length of therapy and ordinal regression was used to determine frequency of ED visits and hospital readmissions. RESULTS: Among a cohort of 736 patients with confirmed NAS, 72.3% were treated with pharmacotherapy of which approximately one-half (45.5%) were discharged home on outpatient medications. For infants discharged on outpatient pharmacotherapy, initial hospital length of stay was shorter (11 vs 23 days; P < .001) and length of therapy was longer (60 vs 19 days; adjusted incidence rate ratio [aIRR] 2.84, 95%CI 2.31-3.52). After adjusting for potential confounders, infants discharged on outpatient pharmacotherapy had a greater number of ED visits within 6 months of discharge (adjusted odds ratio [aOR] 1.52, 95% CI 1.06-2.17) compared with those treated as inpatients alone. CONCLUSIONS: Outpatient pharmacotherapy for NAS was associated with higher length of therapy and higher rates of ED utilization when compared with infants treated exclusively as inpatients. Future research should focus on improving the efficiency of NAS management while minimizing postdischarge complications. PMID- 29754867 TI - Assessing Ethics Knowledge: Development of a Test of Ethics Knowledge in Neonatology. AB - OBJECTIVE: To develop and validate the Test of Ethics Knowledge in Neonatology (TEK-Neo) with good internal consistency reliability, item performance, and construct validity that reliably assesses interprofessional staff and trainee knowledge of neonatal ethics. STUDY DESIGN: We adapted a published test of ethics knowledge for use in neonatology. The novel instrument had 46 true/false questions distributed among 7 domains of neonatal ethics: ethical principles, professionalism, genetic testing, beginning of life/viability, end of life, informed permission/decision making, and research ethics. Content and correct answers were derived from published statements and guidelines. We administered the voluntary, anonymous test via e-mailed link to 103 participants, including medical students, neonatology fellows, neonatologists, neonatology nurses, and pediatric ethicists. After item reduction, we examined psychometric properties of the resulting 36-item test and assessed overall sample performance. RESULTS: The overall response rate was 27% (103 of 380). The test demonstrated good internal reliability (Cronbach alpha = 0.66), with a mean score of 28.5 +/- 3.4 out of the maximum 36. Participants with formal ethics training performed better than those without (30.3 +/- 2.9 vs 28.1 +/- 3.5; P = .01). Performance improved significantly with higher levels of medical/ethical training among the 5 groups: medical students, 25.9 +/- 3.7; neonatal nurses/practitioners, 27.7 +/- 2.7; neonatologists, 28.8 +/- 3.7; neonatology fellows, 29.8 +/- 2.9; and clinical ethicists, 33.0 +/- 1.9 (P < .0001). CONCLUSIONS: The TEK-Neo reliably assesses knowledge of neonatal ethics among interprofessional staff and trainees in neonatology. This novel tool discriminates between learners with different levels of expertise and can be used interprofessionally to assess individual and group performance, track milestone progression, and address curricular gaps in neonatal ethics. PMID- 29754869 TI - Adolescent Health, Confidentiality in Healthcare, and Communication with Parents. PMID- 29754868 TI - Attitudes Surrounding the Management of Neonates with Severe Necrotizing Enterocolitis. AB - OBJECTIVES: To assess providers' recommendations as to comfort care versus medical and surgical management in clinical scenarios of newborns with severe bowel loss and to assess how a variety of factors influence providers' decision making. STUDY DESIGN: We conducted a survey of pediatric surgeons and neonatologists via the American Pediatric Surgical Association and American Academy of Pediatrics Section of Neonatal-Perinatal Medicine. We examined how respondents' recommendations were affected by a variety of patient and provider factors. RESULTS: There were 288 neonatologists and 316 pediatric surgeons who responded. Irrespective of remaining bowel length, comfort care was recommended by 73% of providers for a premature infant with necrotizing enterocolitis and 54% for a full-term infant with midgut volvulus. The presence of comorbidities and earlier gestational age increased the proportion of providers recommending comfort care. Neonatologists were more likely to recommend comfort care than surgeons across all scenarios (OR, 1.45-2.00; P < .05), and this difference was more pronounced with infants born closer to term. In making these recommendations, neonatologists placed more importance on neurodevelopmental outcomes (P < .001), and surgeons emphasized experience with long-term quality of life (P < .001). CONCLUSION: Despite a contemporary survival of >90% in infants with intestinal failure, a majority of providers still recommend comfort care in infants with massive bowel loss. Significant differences were identified in clinical decision making between surgeons and neonatologists. These data reinforce the need for targeted education on long-term outcomes in intestinal failure to neonatal and surgical providers. PMID- 29754870 TI - Decreased operator X-ray exposure by optimized fluoroscopy during radiofrequency ablation of common atrial flutter. AB - PURPOSE: To evaluate operator and patient irradiation during radiofrequency ablation (RFA) of common atrial flutter (AF) using three different fluoroscopy settings. MATERIAL AND METHOD: A total of 38 patients who underwent RFA of AF with three different fluoroscopy settings (low dose, standard dose and collimated field) were included. Twelve patients (11 men, 1 woman; mean age, 67+/-12 [SD]years) were included in the low dose group (3.75 frames per second), 13 patients (13 men; mean age, 66+/-8 [SD]years) were included in the standard dose group (7.5 frames per second) and 13 patients (13 men; mean age, 71+/-12 [SD]years) were included in the collimated field group (7.5 frames per second). Operator and patient exposure were compared between groups. RESULT: No differences in procedure time and radiation exposure were found between the three groups. In the low dose group, mean operator X-ray exposures of eye-lens (4.7+/ 2.9 [SD]MUSv/h; range: 0.9-10.5MUSv/h), whole body (1.6+/-1.2 [SD]MUSv/h; range 0.5-3.6MUSv/h) and hand skin (11.1+/-10.8 [SD] MUSv/h; range 2.4-35.4MUSv/h) were significantly lower than those in the standard dose group (P<0.001). Significant patient dose reduction was found between low dose group (0.7+/-0.4 [SD]Gy/h; range: 0.3-0.9Gy/h) and standard (1.7+/-0.5 [SD]Gy/h; range: 0.8 to 3.9Gy/h) and collimated (1.8+/-0.5 [SD]Gy/h; range: 0.7-3.0Gy/h) groups (P<0.01). CONCLUSION: The use of a low dose setting (3.75 f/s) during fluoroscopy dramatically reduces operator's irradiation during RFA of AF by a mean of 90%. PMID- 29754871 TI - Dynamic contrast-enhanced MR imaging of the rectum: Correlations between single section and whole-tumor histogram analyses. AB - PURPOSE: To evaluate the interobserver and intermethod correlations of histogram metrics of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters acquired by multiple readers using the single-section and whole-tumor volume methods. MATERIALS AND METHODS: Four DCE parameters (Ktrans, Kep, Ve , Vp) were evaluated in 45 patients (31 men and 14 women; mean age, 61+/-11 years [range, 29-83 years]) with locally advanced rectal cancer using pre chemoradiotherapy (CRT) MRI. Ten histogram metrics were extracted using two methods of lesion selection performed by three radiologists: the whole-tumor volume method for the whole tumor on axial section-by-section images and the single-section method for the entire area of the tumor on one axial image. The interobserver and intermethod correlations were evaluated using the intraclass correlation coefficients (ICCs). RESULTS: The ICCs showed excellent interobserver and intermethod correlations in most of histogram metrics of the DCE parameters. The ICCs among the three readers were > 0.7 (P<0.001) for all histogram metrics, except for the minimum and maximum. The intermethod correlations for most of the histogram metrics were excellent for each radiologist, regardless of the differences in the radiologists' experience. CONCLUSION: The interobserver and intermethod correlations for most of the histogram metrics of the DCE parameters are excellent in rectal cancer. Therefore, the single-section method may be a potential alternative to the whole-tumor volume method using pre-CRT MRI, despite the fact that the high agreement between the two methods cannot be extrapolated to post-CRT MRI. PMID- 29754872 TI - Editorial overview: Neurotechnologies. PMID- 29754873 TI - Elaboration and validation of the method for the quantification of the emetic toxin of Bacillus cereus as described in EN-ISO 18465 - Microbiology of the food chain - Quantitative determination of emetic toxin (cereulide) using LC-MS/MS. AB - A method for the quantification of the Bacillus cereus emetic toxin (cereulide) was developed and validated. The method principle is based on LC-MS as this is the most sensitive and specific method for cereulide. Therefore the study design is different from the microbiological methods validated under this mandate. As the method had to be developed a two stage validation study approach was used. The first stage (pre-study) focussed on the method applicability and the experience of the laboratories with the method. Based on the outcome of the pre study and comments received during voting at CEN and ISO level a final method was agreed to be used for the second stage the (final) validation of the method. In the final (validation) study samples of cooked rice (both artificially contaminated with cereulide or contaminated with B. cereus for production of cereulide in the rice) and 6 other food matrices (fried rice dish, cream pastry with chocolate, hotdog sausage, mini pancakes, vanilla custard and infant formula) were used. All these samples were spiked by the participating laboratories using standard solutions of cereulide supplied by the organising laboratory. The results of the study indicate that the method is fit for purpose. Repeatability values were obtained of 0.6 MUg/kg at low level spike (ca. 5 MUg/kg) and 7 to 9.6 MUg/kg at high level spike (ca. 75 MUg/kg). Reproducibility at low spike level ranged from 0.6 to 0.9 MUg/kg and from 8.7 to 14.5 MUg/kg at high spike level. Recovery from the spiked samples ranged between 96.5% for mini pancakes to 99.3% for fries rice dish. PMID- 29754874 TI - Preoperative Screening for Obstructive Sleep Apnea and Outcomes in PACU. AB - PURPOSE: Practice guidelines from the perianesthesia community suggest that preoperative identification of patients with obstructive sleep apnea (OSA) and standardized longer observation in postanesthesia care unit (PACU) promotes safety after general anesthesia. The purpose of this study was to determine if longer monitoring of patients with OSA in the PACU improves patient outcomes after general anesthesia. DESIGN: Evidence-based best practices literature review. METHODS: PACU patient charts were retrospectively analyzed for the presence of OSA diagnosis and screening scores. Information was compared with the postoperative oxygen saturation in PACU and nursing respiratory assessment documentation. FINDINGS: Most patients (96.5%) did not experience oxygen desaturation regardless of OSA diagnosis or STOP (snore, tired, observed, pressure) score. There was no evidence extracted from this sample that suggested patients with OSA experienced a higher incidence of respiratory symptoms while in the PACU. CONCLUSIONS: This study did not affirm that patients with OSA experienced a higher incidence of oxygen desaturation or respiratory symptoms despite receiving additional monitoring in PACU. PMID- 29754875 TI - Spike persistence and normalization in benign epilepsy with centrotemporal spikes - Implications for management. AB - PURPOSE: This study was performed 1) to determine the timing of spike normalization in patients with benign epilepsy with centrotemporal spikes (BECTS); 2) to identify relationships between age of seizure onset, age of spike normalization, years of spike persistence and treatment; and 3) to assess final outcomes between groups of patients with or without spikes at the time of medication tapering. METHODS: Retrospective analysis of BECTS patients confirmed by clinical data, including age of onset, seizure semiology and serial electroencephalography (EEG) from diagnosis to remission. Age at spike normalization, years of spike persistence, and time of treatment onset to spike normalization were assessed. Final seizure and EEG outcome were compared between the groups with or without spikes at the time of AED tapering. RESULTS: One hundred and thirty-four patients were included. Mean age at seizure onset was 7.52 +/- 2.11 years. Mean age at spike normalization was 11.89 +/- 2.11 (range: 6.3-16.8) years. Mean time of treatment onset to spike normalization was 4.11 +/- 2.13 (range: 0.24-10.08) years. Younger age of seizure onset was correlated with longer duration of spike persistence (r = -0.41, p < 0.001). In treated patients, spikes persisted for 4.1 +/- 1.95 years, compared with 2.9 +/- 1.97 years in untreated patients. No patients had recurrent seizures after AED was discontinued, regardless of the presence/absence of spikes at time of AED tapering. CONCLUSION: Years of spike persistence was longer in early onset BECTS patients. Treatment with AEDs did not shorten years of spike persistence. Persistence of spikes at time of treatment withdrawal was not associated with seizure recurrence. PMID- 29754877 TI - A novel technique to measure severity of pediatric pectus excavatum using white light scanning. AB - BACKGROUND/PURPOSE: Computed tomography (CT) derived Haller Index (HI) remains the standard for quantifying severity in patient with pectus excavatum (PE). Optical scanning described in literature reports optimistic results and new indices that correlate with HI. This study assessed the feasibility of a handheld White Light Scanner (WLS) to obtain 3D measurements and indices of PE deformity. METHODS: From April 2015-April 2017, WLS scanning was conducted by orthotists during clinical visits. Included were children with PE up to 18 years. Analysis assessed correlation of a WLS-derived severity index, Hebal-Malas Index (HMI), with physician measured PE Depth (PED), and CT-derived HI. RESULTS: Of 195 participants, 185(94%) patients with PE were scanned and 127(69%) had complete WLS data. For 88 patients undergoing monitoring, HMI correlated with PED (r = 0.42, p = 0.004). For 39 patients with pre-operative CT, HMI demonstrated strong correlation with HI (r = 0.87, p<0.0001). CONCLUSIONS: WLS demonstrated high feasibility of scanning PE. WLS-derived HMI best correlates with HI for patients with severe pectus deformity. Our current data is suggestive that WLS is best applied for severe deformities and yet to be established for milder deformities. Future yearly WLS will provide data on deformity progression and surgical therapy. LEVEL OF EVIDENCE: IV. TYPE OF STUDY: Diagnostic Study. PMID- 29754876 TI - Bone morphogenetic protein 4 antagonizes hair cell regeneration in the avian auditory epithelium. AB - Permanent hearing loss is often a result of damage to cochlear hair cells, which mammals are unable to regenerate. Non-mammalian vertebrates such as birds replace damaged hair cells and restore hearing function, but mechanisms controlling regeneration are not understood. The secreted protein bone morphogenetic protein 4 (BMP4) regulates inner ear morphogenesis and hair cell development. To investigate mechanisms controlling hair cell regeneration in birds, we examined expression and function of BMP4 in the auditory epithelia (basilar papillae) of chickens of either sex after hair cell destruction by ototoxic antibiotics. In mature basilar papillae, BMP4 mRNA is highly expressed in hair cells, but not in hair cell progenitors (supporting cells). Supporting cells transcribe genes encoding receptors for BMP4 (BMPR1A, BMPR1B, and BMPR2) and effectors of BMP4 signaling (ID transcription factors). Following hair cell destruction, BMP4 transcripts are lost from the sensory epithelium. Using organotypic cultures, we demonstrate that treatments with BMP4 during hair cell destruction prevent supporting cells from upregulating expression of the pro-hair cell transcription factor ATOH1, entering the cell cycle, and fully transdifferentiating into hair cells, but they do not induce cell death. By contrast, noggin, a BMP4 inhibitor, increases numbers of regenerated hair cells. These findings demonstrate that BMP4 antagonizes hair cell regeneration in the chicken basilar papilla, at least in part by preventing accumulation of ATOH1 in hair cell precursors. PMID- 29754878 TI - Extracorporeal Membrane Oxygenation (ECMO) Risk Stratification in Newborns with Congenital Diaphragmatic Hernia (CDH). AB - BACKGROUND: A means for early postnatal stratification of ECMO risk in CDH newborns could be used to comparatively assess the utilization and outcomes of ECMO use between centers. While multiple CDH mortality risk calculators are available, no validated tool exists specifically for prediction of ECMO use. The purpose of this study was to derive and validate an ECMO risk stratification model. METHODS: The study population was obtained from CDH Study Group registry for the period between 2007 and 2016. Only centers offering ECMO were included. The cohort was restricted to ECMO candidates and then divided into derivation and validation sets. Using all relevant perinatal predictors in the registry, univariate analysis was performed for the composite outcome of ECMO use or death without ECMO use. The model was derived using the derivation cohort with multivariable logistic regression and automatic stepwise forward selection (P < 0.05 for qualifying variables), and a c-statistic was obtained. The model was then tested on the validation cohort. Sample reuse validation and bootstrap validation were performed. The validated model was then tested for accuracy on CDH subgroups. RESULTS: There were 1992 patients in the derivation cohort. Four significant variables were identified in the final ECMO risk model: 1-min and 5 min Apgar scores and highest and lowest post-ductal partial pressure of CO2 during the first 24 h of life. The model c-statistic was 0.824 which was confirmed with cross-validation and bootstrap optimism correction. The validation cohort c-statistic was 0.823 (N = 993). The model had good discrimination for left and right CDH, inborn and outborn patients, patients born before and after 2011, and high and low volume centers. The model performed significantly better for postnatally diagnosed patients. CONCLUSIONS: This study represents proof-of concept that a risk model can accurately estimate the probability of ECMO use in CDH newborns. This stratification could assist centers as a metric for assessment of ECMO usage and outcomes. Refinement and prospective validation of this model should be carried out prior to clinical application. LEVEL OF EVIDENCE: 3. PMID- 29754879 TI - Congenital pyloric atresia - nine new cases: Single-center experience of the long term follow-up and the lessons learnt over a decade. AB - BACKGROUND: Congenital pyloric atresia (CPA) is a rare anomaly with an incidence of 1 in 100,000 live births. Depending on the type of anomaly patients can either present in the neonatal period or later in life with subtle nonspecific signs and symptoms. We present our institute's experience in handling these cases over the last decade and highlight lessons learnt. MATERIALS AND METHODS: We retrospectively reviewed records of patients diagnosed with CPA and managed at our centre between Jan 2006 to June 2016. We looked into the period of gestation, birth weight, gender, age at onset of symptoms, age at presentation to the hospital, symptoms, investigations, associated anomalies, management and outcomes and follow up periods. RESULTS: Nine patients were operated during the ten year period of study (6 males and 3 females). The median age at onset of symptoms was 06 months (01 day-36 months) and the median age of reporting to the hospital was 07 months (01 day-44 months) with a mean delay of 5 months between onset of symptoms and reporting to hospital. Six patients (67%) had associated anomalies including one with posterior urethral valve which has been reported for the first time in literature. Four out of five (80%) late presenters underwent an upper gastrointestinal endoscopy for diagnostic confirmation. All patients were operated upon and Type 1 CPA was seen in five patients (56%), Type 2 in two patients (33%) and Type 3 in one patient (11%). The overall survival was 89% as one patient with associated Epidermolysis Bullosa expired after 4 months due to fulminant sepsis. Three patients were lost to follow up and amongst the remaining five; the median follow up period is 36 months. CONCLUSION: CPA is a rare entity that may present late with subtle signs like failure to thrive and nonbilious vomit. A high index of suspicion is mandated in these cases and an Upper Gastrointestinal Endoscopy will help in early diagnosis and avoid further unnecessary investigations. A feeding jejunostomy may benefit malnourished sick children before definitive surgery. LEVEL OF EVIDENCE: Level 3, Type of study: Retrospective study. PMID- 29754880 TI - Prognostic value of mitral annular systolic plane excursion and tricuspid annular plane systolic excursion in cats with hypertrophic cardiomyopathy. AB - INTRODUCTION: Hypertrophic cardiomyopathy (HCM) has a variable prognosis; left atrial size, presence of clinical signs and left ventricular systolic function have been shown to predict outcomes. Mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) assess longitudinal ventricular systolic function and are decreased in cats with HCM. The aim of the study was to ascertain whether MAPSE and TAPSE have prognostic value in HCM and if cats with pleural effusion have lower MAPSE and TAPSE than cats with pulmonary oedema. ANIMALS: One hundred eighty-four client-owned cats diagnosed with HCM. METHODS: This is a retrospective study. Echocardiography was used to diagnose HCM (end-diastolic left ventricular wall thickness >= 6 mm) and to measure MAPSE and TAPSE. Survival information was obtained. RESULTS: No multivariable model including MAPSE or TAPSE could be generated in this population. Cats with pleural effusion +/- pulmonary oedema had lower MAPSE measured at the interventricular septum (MAPSE IVS) and TAPSE, compared with cats with pulmonary oedema only. MAPSE IVS was the only factor predicting pleural effusion on multivariable regression model. CONCLUSIONS: Lower MAPSE and TAPSE were not independently associated with outcomes on multivariable analysis. Cats with pleural effusion +/- pulmonary oedema had lower TAPSE and MAPSE IVS than cats with pulmonary oedema, and MAPSE IVS was the only predictive factor associated with the development of pleural effusion in this population. PMID- 29754881 TI - Appraising forensic anthropology in the Philippines: Current status and future directions. AB - The increasing significance of forensic anthropology in the 21st century, yet unequitable worldwide distribution of expertise, necessitates a stocktaking of the discipline on a local scale. The purpose of this work is to appraise the current state of forensic anthropology in the Philippines and provide the rationale for its further development within the country. Recent efforts in research, education, and legislation that seek to boost Philippine forensic anthropology specifically and forensic sciences generally are highlighted. Furthermore, this work hopes to serve as a springboard for future students, scholars, and practitioners seeking to advance the field in the Philippines. PMID- 29754882 TI - Activation of AMPK for a Break in Hepatic Lipid Accumulation and Circulating Cholesterol. PMID- 29754883 TI - The Promising Role of New Generation HDACis in Anti-Cancer Therapies. PMID- 29754885 TI - Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. AB - Langerhans cell histiocytosis (LCH) is an inflammatory neoplasia of myeloid precursor cells driven by mutations in the mitogen-activated protein kinase pathway. When disease involves the skin, LCH most commonly presents as a seborrheic dermatitis or eczematous eruption on the scalp and trunk. Evaluation for involvement of other organ systems is essential, because 9 of 10 patients presenting with cutaneous disease also have multisystem involvement. Clinical manifestations range from isolated disease with spontaneous resolution to life threatening multisystem disease. Prognosis depends on involvement of risk organs (liver, spleen, and bone marrow) at diagnosis, particularly on presence of organ dysfunction, and response to initial therapy. Systemic treatment incorporating steroids and cytostatic drugs for at least one year has improved prognosis of multisystem LCH and represents the current standard of care. PMID- 29754887 TI - In the blink of an eye. PMID- 29754884 TI - Circulating Salivary miRNA hsa-miR-221 as Clinically Validated Diagnostic Marker for Hand, Foot, and Mouth Disease in Pediatric Patients. AB - Enhancements in the diagnostic capabilities using host biomarkers are currently much needed where sensitivity and specificity issues plague the diagnosis of Hand, Foot and Mouth Disease (HFMD) in pediatrics clinical samples. We investigated miRNome profiles of HFMD saliva samples against healthy children and developed miRNA-based diagnosis models. Our 6-miRNA scoring model predicted HFMD with an overall accuracy of 85.11% in the training set and 92.86% in the blinded test set of Singapore cohort. Blinded evaluation of the model in Taiwan HFMD cases resulted in 77.08% accuracy with the 6-miRNA model and 68.75% with the 4 miRNA model. The strongest predictor of HFMD in all of the panels, hsa-miR-221 was found to be consistently and significantly downregulated in all of our HFMD cohorts. This is the first study to prove that HFMD infection could be diagnosed by circulating miRNAs in patient's saliva. Moreover, this study also serves as a stepping stone towards the future development of other infectious disease diagnosis workflows using novel biomarkers. PMID- 29754886 TI - Langerhans cell histiocytosis in children: Diagnosis, differential diagnosis, treatment, sequelae, and standardized follow-up. AB - A definitive diagnosis of Langerhans cell histiocytosis (LCH) requires a combination of clinical presentation, histology, and immunohistochemistry. The inflammatory infiltrate contains various proportions of LCH cells, the disease hallmark, which are round and have characteristic "coffee-bean" cleaved nuclei and eosinophilic cytoplasm. Positive immunohistochemistry staining for CD1a and CD207 (langerin) are required for a definitive diagnosis. Isolated cutaneous disease should only be treated when symptomatic, because spontaneous resolution is common. Topical steroids are first-line treatment for localized disease of skin and bone. For multifocal single-system or multisystem disease, systemic treatment with steroids and vinblastine for 12 months is the standard first-line regimen. Current research is seeking more effective regimens because recurrence rates, which increase the risk of sequelae, are still high (30-50%) in patients with multisystem disease. An active area of research is the use of targeted therapy directed at the mitogen-activated protein kinase pathway. Adequate follow up to monitor for disease progression, relapse, and sequelae is recommended in all patients. PMID- 29754888 TI - Topical 2% tofacitinib for children with alopecia areata, alopecia totalis, and alopecia universalis. PMID- 29754889 TI - The multidisciplinary tumor board for the management of cutaneous neoplasms: A national survey of academic medical centers. PMID- 29754890 TI - Instagram and the dermatologist: An ethical analysis. PMID- 29754891 TI - Should medical students follow up on skin biopsy results? When education conflicts with patient privacy. PMID- 29754892 TI - Safety concerns regarding use of topical brimonidine for hemostasis. PMID- 29754893 TI - Variants in ZNF804A and DTNBP1 assessed for cognitive impairment in schizophrenia using a multiplex family-based approach. PMID- 29754894 TI - Lethal area 50 percent (LA50) or standardized mortality ratio (SMR): Which one is more conclusive? AB - BACKGROUND: Burn injuries impose a considerable burden on healthcare systems. It is among the top ten causes of mortality and a major cause of disability. This study aimed to calculate and compare the lethal area fifty percent (LA50) and standardized mortality ratio (SMR) in patients with burns. METHODS: This is a five-year cross-sectional study. The study population consisted of 3284 patients with acute burns who were admitted to the Burn Department of Imam Reza Hospital in Mashhad, Iran, from 2010 to 2015. LA50 and SMR were calculated. SPSS 16 was used for logistic regression analysis. RESULTS: The mean percentage of burn total body surface area (TBSA%) was 37.0 (25.5), and deceased patients with burns had a significantly higher burn TBSA% than alive discharged patients (70.3 (24.2) vs. 28.1 (17.1), p<0.001). The most common cause of burn was fire (71.7%). The total case fatality rate was 21.2%. However, this index was more than double in females than in males (31.9% vs. 14.3%, p<0.001). The SMR, based on the abbreviated burn severity index (ABSI), increased from 61% to 80% during the 5-year period. LA50 for total admitted patients was 63.8% (95% confidence interval [CI]=60.4-67.7). LA50 for scalds was the highest (72.1%) compared to those of other types of mechanisms of burn injuries. TBSA, age, and gender were found to be mutually independent predictors of death. CONCLUSION: The trend of LA50 in these five years declined by 12%, whereas the SMR was below 100%. Improvement in burn management quality in high-risk groups including the elderly, females, and patients with extensive burns may improve LA50 in burn units. However, LA50 alone is not a conclusive index for the performance of a burn department, and it should be interpreted alongside with SMR. PMID- 29754895 TI - Drug consumption rooms: Comparing times, spaces and actors in issues of social acceptability in French public debate. AB - BACKGROUND: In October 2016, the first French drug consumption room (DCR) opened in Paris. We propose to examine the process through which this issue has been framed as a matter of public concern, after being ignored for almost 20 years. Our analysis of the controversy on DCRs investigates how public conversations on harm reduction evolve according to the time period (from the 1990s to the present), scale of discourse (local vs. national), and involved actors (politicians, professionals, local residents, and drug users). METHODOLOGY: Our methodology includes analyses of media content: we reviewed 1735 articles published between 1990 and 2017. Our theoretical approach is in line with the sociology "des epreuves" derived from pragmatic sociology and controversy analysis. This approach goes beyond interactionism by attempting to place situations back into broader sociological realities. We also pay special attention to governance, a political lens that focuses on local aspects of negotiations and on the implication of a variety of actors. RESULTS: While the current debate on DCRs in France draws on constraints and resources already present in the harm reduction debate of the 1980s, it also repositions itself by avoiding moral argumentation and featuring less confrontation in the professional sphere. Today, we can see that the center of this tense debate has shifted from the professional sphere to the political and residential spheres. Most often, residents advance concerns that are not directly related to drug users themselves, but that derive from their apprehension of living in a displaced and stranded neighborhood. The public conversation leaves little room for drug users, even though they are the primary stakeholders of harm reduction and play a crucial role in DCR advocacy. CONCLUSION: Our work reveals that the controversy about DCR is the product of complex interactions between different kinds of actors harm reduction professionals, political actors at the local and national levels, local residents, and drug users. Comparing different instances of public debate reveals the specific limitations and potentials for change in French drug policy. PMID- 29754897 TI - Correction to Lancet Diabetes Endocrinol 2018; 6:627-36. PMID- 29754896 TI - Haemodialysis Catheter in the Aortic Arch. PMID- 29754899 TI - Dynamic Fluctuations in Subcellular Localization of the Hippo Pathway Effector Yorkie In Vivo. AB - The Hippo pathway is an evolutionarily conserved signaling network that integrates diverse cues to control organ size and cell fate. The central downstream pathway protein in Drosophila is the transcriptional co-activator Yorkie (YAP and TAZ in humans), which regulates gene expression with the Scalloped/TEA domain family member (TEAD) transcription factors [1-8]. A central regulatory step in the Hippo pathway is phosphorylation of Yorkie by the NDR family kinase Warts, which promotes Yorkie cytoplasmic localization by stimulating association with 14-3-3 proteins [9-12]. Numerous reports have purported a static model of Hippo signaling whereby, upon Hippo activation, Yorkie/YAP/TAZ become cytoplasmic and therefore inactive, and upon Hippo repression, Yorkie/YAP/TAZ transit to the nucleus and are active. However, we have little appreciation for the dynamics of Yorkie/YAP/TAZ subcellular localization because most studies have been performed in fixed cells and tissues. To address this, we used live multiphoton microscopy to investigate the dynamics of an endogenously tagged Yorkie-Venus protein in growing epithelial organs. We found that the majority of Yorkie rapidly traffics between the cytoplasm and nucleus, rather than being statically localized in either compartment. In addition, discrete cell populations within the same organ display different rates of Yorkie nucleo-cytoplasmic shuttling. By assessing Yorkie dynamics in warts mutant tissue, we found that the Hippo pathway regulates Yorkie subcellular distribution by regulating its rate of nuclear import. Furthermore, Yorkie's localization fluctuates dramatically throughout the cell cycle, being predominantly cytoplasmic during interphase and, unexpectedly, chromatin enriched during mitosis. Yorkie's association with mitotic chromatin is Scalloped dependent, suggesting a potential role in mitotic bookmarking. PMID- 29754900 TI - Burst Firing in Bee Gustatory Neurons Prevents Adaptation. AB - Animals detect changes in the environment using modality-specific, peripheral sensory neurons. The insect gustatory system encodes tastant identity and concentration through the independent firing of gustatory receptor neurons (GRNs) that spike rapidly at stimulus onset and quickly adapt. Here, we show the first evidence that concentrated sugar evokes a temporally structured burst pattern of spiking involving two GRNs within the gustatory sensilla of bumblebees. Bursts of spikes resulted when a sucrose-activated GRN was inhibited by another GRN at a frequency of ~22 Hz during the first 1 s of stimulation. Pharmacological blockade of gap junctions abolished bursting, indicating that bee GRNs have electrical synapses that produce a temporal pattern of spikes when one GRN is activated by a sugar ligand. Bursting permitted bee GRNs to maintain a high rate of spiking and to exhibit the slowest rate of adaptation of any insect species. Feeding bout duration correlated with coherent bursting; only sugar concentrations that produced bursting evoked the bumblebee's feeding reflex. Volume of solution imbibed was a direct function of time in contact with food. We propose that gap junctions among GRNs enable a sustained rate of GRN spiking that is necessary to drive continuous feeding by the bee proboscis. PMID- 29754901 TI - nocte Is Required for Integrating Light and Temperature Inputs in Circadian Clock Neurons of Drosophila. AB - Circadian clocks organize biological processes to occur at optimized times of day and thereby contribute to overall fitness. While the regular daily changes of environmental light and temperature synchronize circadian clocks, extreme external conditions can bypass the temporal constraints dictated by the clock. Despite advanced knowledge about how the daily light-dark changes synchronize the clock, relatively little is known with regard to how the daily temperature changes influence daily timing and how temperature and light signals are integrated. In Drosophila, a network of ~150 brain clock neurons exhibit 24-hr oscillations of clock gene expression to regulate daily activity and sleep. We show here that a temperature input pathway from peripheral sensory organs, which depends on the gene nocte, targets specific subsets of these clock neurons to synchronize molecular and behavioral rhythms to temperature cycles. Strikingly, while nocte1 mutant flies synchronize normally to light-dark cycles at constant temperatures, the combined presence of light-dark and temperature cycles inhibits synchronization. nocte1 flies exhibit altered siesta sleep, suggesting that the sleep-regulating clock neurons are an important target for nocte-dependent temperature input, which dominates a parallel light input into these cells. In conclusion, we reveal a nocte-dependent temperature input pathway to central clock neurons and show that this pathway and its target neurons are important for the integration of sensory light and temperature information in order to temporally regulate activity and sleep during daily light and temperature cycles. PMID- 29754898 TI - Replay of Episodic Memories in the Rat. AB - Vivid episodic memories in people have been characterized as the replay of multiple unique events in sequential order [1-3]. The hippocampus plays a critical role in episodic memories in both people and rodents [2, 4-6]. Although rats remember multiple unique episodes [7, 8], it is currently unknown if animals "replay" episodic memories. Therefore, we developed an animal model of episodic memory replay. Here, we show that rats can remember a trial-unique stream of multiple episodes and the order in which these events occurred by engaging hippocampal-dependent episodic memory replay. We document that rats rely on episodic memory replay to remember the order of events rather than relying on non episodic memories. Replay of episodic memories survives a long retention-interval challenge and interference from the memory of other events, which documents that replay is part of long-term episodic memory. The chemogenetic activating drug clozapine N-oxide (CNO), but not vehicle, reversibly impairs episodic memory replay in rats previously injected bilaterally in the hippocampus with a recombinant viral vector containing an inhibitory designer receptor exclusively activated by a designer drug (DREADD; AAV8-hSyn-hM4Di-mCherry). By contrast, two non-episodic memory assessments are unaffected by CNO, showing selectivity of this hippocampal-dependent impairment. Our approach provides an animal model of episodic memory replay, a process by which the rat searches its representations in episodic memory in sequential order to find information. Our findings using rats suggest that the ability to replay a stream of episodic memories is quite old in the evolutionary timescale. PMID- 29754902 TI - Host Energy Source Is Important for Disease Tolerance to Malaria. AB - Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3-6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7-9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival; treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance. PMID- 29754903 TI - Gigantism Precedes Filter Feeding in Baleen Whale Evolution. AB - Baleen whales (Mysticeti) are the largest animals on Earth, thanks to their ability to filter huge volumes of small prey from seawater. Mysticetes appeared during the Late Eocene, but evidence of their early evolution remains both sparse and controversial [1, 2], with several models competing to explain the origin of baleen-based bulk feeding [3-6]. Here, we describe a virtually complete skull of Llanocetus denticrenatus, the second-oldest (ca. 34 Ma) mysticete known. The new material represents the same individual as the type and only specimen, a fragmentary mandible. Phylogenetic analysis groups Llanocetus with the oldest mysticete, Mystacodon selenensis [2], into the basal family Llanocetidae. Llanocetus is gigantic (body length ~8 m) compared to other early mysticetes [7 9]. The broad rostrum has sharp, widely spaced teeth with marked dental abrasion and attrition, suggesting biting and occlusal shearing. As in extant mysticetes, the palate bears many sulci, commonly interpreted as osteological correlates of baleen [3]. Unexpectedly, these sulci converge on the upper alveoli, suggesting a peri-dental blood supply to well-developed gums, rather than to inter-alveolar racks of baleen. We interpret Llanocetus as a raptorial or suction feeder, revealing that whales evolved gigantism well before the emergence of filter feeding. Rather than driving the origin of mysticetes, baleen and filtering most likely only arose after an initial phase of suction-assisted raptorial feeding [2, 4, 5]. This scenario differs strikingly from that proposed for odontocetes, whose defining adaptation-echolocation-was present even in their earliest representatives [10]. PMID- 29754904 TI - Feedforward Inhibition Conveys Time-Varying Stimulus Information in a Collision Detection Circuit. AB - Feedforward inhibition is ubiquitous as a motif in the organization of neuronal circuits. During sensory information processing, it is traditionally thought to sharpen the responses and temporal tuning of feedforward excitation onto principal neurons. As it often exhibits complex time-varying activation properties, feedforward inhibition could also convey information used by single neurons to implement dendritic computations on sensory stimulus variables. We investigated this possibility in a collision-detecting neuron of the locust optic lobe that receives both feedforward excitation and inhibition. We identified a small population of neurons mediating feedforward inhibition, with wide visual receptive fields and whose responses depend both on the size and speed of moving stimuli. By studying responses to simulated objects approaching on a collision course, we determined that they jointly encode the angular size of expansion of the stimulus. Feedforward excitation, on the other hand, encodes a function of the angular velocity of expansion and the targeted collision-detecting neuron combines these two variables non-linearly in its firing output. Thus, feedforward inhibition actively contributes to the detailed firing-rate time course of this collision-detecting neuron, a feature critical to the appropriate execution of escape behaviors. These results suggest that feedforward inhibition could similarly convey time-varying stimulus information in other neuronal circuits. PMID- 29754906 TI - Search for information in nursing. Sources and resources. PMID- 29754905 TI - The Post-anaphase SUMO Pathway Ensures the Maintenance of Centromeric Cohesion through Meiosis I-II Transition in Mammalian Oocytes. AB - The production of haploid gametes requires the maintenance of centromeric cohesion between sister chromatids through the transition between two successive meiotic divisions, meiosis I and meiosis II. One mechanism for the cohesion maintenance is shugoshin-dependent protection of centromeric cohesin at anaphase I onset [1-3]. However, how centromeric cohesion is maintained during late anaphase I and telophase I, when centromeric shugoshin is undetectable [1-3], remains largely unexplored. Here we show that the centromeric small ubiquitin related modifier (SUMO) pathway is critical for the maintenance of centromeric cohesion during post-anaphase-I periods in mouse oocytes. SUMO2/3 and E3 ligase PIAS are enriched near centromeres during late anaphase I and telophase I. Specific perturbation of the centromeric SUMO pathway results in precocious loss of centromeric cohesin at telophase I, although shugoshin-dependent centromeric protection at anaphase I onset remains largely intact. Prevention of the SUMO perturbation during post-anaphase-I periods restores the maintenance of centromeric cohesion through the meiosis I-II transition. Thus, the post-anaphase I centromeric SUMO pathway ensures continuous maintenance of centromeric cohesion through the meiosis I-II transition. PMID- 29754907 TI - Measures of left atrial function predict incident atrial fibrillation in STEMI patients treated with primary percutaneous coronary intervention. AB - RATIONALE: Atrial fibrillation (AF) is the most common arrhythmia following acute myocardial infarction (AMI). Maximal left atrial (LA) volume is the only echocardiographic atrial parameter employed clinically to assess risk of AF development. OBJECTIVE: This study sought to determine the prognostic value of left atrial functional measures such as left atrial emptying fraction (LAEF) and left atrial expansion index (LAi) in predicting incident AF in the post-STEMI setting. METHODS AND RESULTS: STEMI patients treated with primary percutaneous coronary intervention (pPCI) at Gentofte Hospital, Denmark were prospectively enrolled from September 2006 to December 2008 and had an echocardiogram performed a median 2 days (interquartile-range: 1-3 days) following pPCI. LA maximal volume, LA minimal volume, LAEF and LAi were measured from echocardiograms of 373 patients using the area-length method. End point was incident AF. Median follow up time was 5.6 years (interquartile-range: 5.0-6.1 years), 24 patients (6%) developed incident AF, and follow-up was 100%. In multivariable Cox regression, LAEF and LAi but not maximal LA volume remained independent predictors of AF. Results were similar in competing risk analysis treating all-cause mortality as a competing risk. LAEF and LAi, but not maximal LA volume, added incremental prognostic information in predicting incident AF when added to the CHARGE-AF risk score and the CHA2DS2-VASc score. CONCLUSION: LAEF and LAi independently predicted incident AF following STEMI and added incremental prognostic information in addition to established predictors of AF. Maximal LA volume was not an independent predictor of incident AF after multivariable adjustment. PMID- 29754908 TI - An operational definition of SHATS (Systemic Hemodynamic Atherosclerotic Syndrome): Role of arterial stiffness and blood pressure variability in elderly hypertensive subjects. AB - BACKGROUND: CV risk exponentially increases as the number of damaged organs increases The Systemic Hemodynamic Atherosclerotic Syndrome (SHATS) represents a novel conceptualization of the CV continuum focusing on simultaneous multi-organ alteration. This is the first study operationally defining SHATS and aimed at identifying its determinants. METHODS: Left Ventricular Hypertrophy (echocardiography), Common Carotid Artery plaque and increased thickness (ultrasound), and Chronic Kidney Disease (estimated Glomerular Filtration Rate) indexed selective target organ damage. SHATS was operationally defined as their simultaneous presence in a patient. PWV was measured by Sphygmocor(r) and BP variability by 24 h ABPM. RESULTS: SHATS affected 19.9% of the 367 studied subjects. Subjects with SHATS had a similar prevalence in diabetes mellitus, but a greater prevalence of very stiff artery (84.9 vs 64.3%, p < 0.01) and use of antihypertensive medications. In the presence of similar office BP, SHATS was associated with higher 24 h SBP and lower 24 h DBP (a greater pulsatile pressure!), reduced nighttime SBP fall, and a twofold greater prevalence of reverse dipper status (48.2 vs 20.2%, p < 0.001). BMI (positive correlation) and DBP (negative correlation) were the only traditional CV risk factors significantly associated with the odds of having SHATS. Very stiff artery and BP variability were significant independent determinants of SHATS, with highly predictive accuracy. CONCLUSION: SHATS, the simultaneous damage of multiple target organs, may easily operationally defined. Very stiff artery and BP variability represent key factors for SHATS. The present results support the hypothesis of SHATS as a systemic condition, needing further characterization. PMID- 29754909 TI - Serum PCSK9 levels predict the occurrence of acute coronary syndromes in patients with severe carotid artery stenosis. AB - BACKGROUND: The pharmacological inhibition of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) has shown to dramatically impact on low-density lipoprotein-cholesterol (LDL-C) levels and associated cardiovascular (CV) diseases. However, the potential use of PCSK9 serum levels as a CV risk biomarker remains to be clarified. METHODS: 189 patients with severe carotid artery atherosclerosis undergoing carotid endarterectomy (CEA) and whose clinical records and serum sample aliquots for PCSK9 level measurement were available both directly before CEA and at 24-month follow-up were included in the present pilot study. The study endpoint was to determine whether PCSK9 serum levels prior to CEA would predict the occurrence of acute coronary syndromes (ACS) at 24-month follow-up. RESULTS: PCSK9 serum levels were significantly accurate in predicting ACS at 24-month follow-up, as assessed by ROC curve analysis (AUC: 0.719 [95% CI 0.649-0.781]). According to the cut-off point indicated by Youden's index, PCSK9 values >431.3 ng/mL were correlated with a higher risk of ACS occurrence (Log Rank test, p = 0.0003). At Cox regression analysis, the predictive ability of high serum PCSK9 was confirmed also after adjustment for age, gender, baseline statin treatment and active smoking, dyslipidemia, and chronic coronary artery disease (HR 17.04 [95% CI 3.34-86.81]; p = 0.001). CONCLUSIONS: High serum PCSK9 levels predict ACS occurrence at 24-month follow-up after CEA in patients with severe carotid artery stenosis. Larger clinical studies are needed to evaluate whether PCSK9 serum levels could be used towards predicting the risk of ACS in patients with advanced carotid atherosclerosis. PMID- 29754910 TI - Lifestyle advice and interventions for cardiovascular risk reduction: A systematic review of guidelines. AB - BACKGROUND: Lifestyle factors are important in preventing cardiovascular disease (CVD) development. We aimed to systematically review guidelines on primary prevention of CVD and their recommendations on lifestyle advice or intervention, in order to guide primary prevention programs. METHODS: Publications in MEDLINE, CINAHL over 7 years since May 3, 2009 were identified. G-I-N International Guideline Library, National Guidelines Clearinghouse, National Library for Health Guideline finder, Canadian Medical Association InfoBase were searched. On the February 8, 2017, we updated the search from Websites of organizations responsible for guidelines development. STUDY SELECTION: 2 reviewers screened the titles and abstracts to identify Guidelines from Western countries containing recommendations for lifestyle advice and interventions in primary prevention of CVD. DATA EXTRACTION: 2 reviewers independently assessed rigor of guideline development using the AGREEII instrument, and one extracted recommendations. RESULTS: Of the 7 guidelines identified, 6 showed good rigor of development (range 45-86%). The guidelines were consistent in recommendations for smoking cessation, limiting saturated fat and salt intake, avoiding transaturated-fat and sugar, with particular emphasis on sugar-sweetened beverages. Guidelines generally agreed on recommendations for physical activity levels and diets rich in fruit, vegetables, fish and wholegrains. Guidelines differed on recommendations for specific dietary patterns and alcohol consumption. Recommendations on psychological factors and sleep are currently limited. CONCLUSIONS: Current guidelines agree on the importance of lifestyle in the prevention of CVD with consensus on most factors including physical activity, smoking cessation and diet, which should be actively integrated in cardiovascular risk reduction programs aiming to improve clinical outcomes. PMID- 29754911 TI - PCSK-9: Entering a new era of cardiovascular risk prediction. PMID- 29754912 TI - Search of multiple markers of organ damage for better cardiovascular risk stratification in hypertension: Role of "SHATS" syndrome in the clinical practice. PMID- 29754913 TI - Lifestyle and cardiovascular disease: Barefooting through the guidelines. PMID- 29754914 TI - Extreme influenza epidemics and out-of-hospital cardiac arrest. AB - INTRODUCTION: There is compelling evidence for an association between influenza epidemics and major adverse cardiovascular events. However, the role of extreme influenza epidemics as a trigger of out-of-hospital cardiac arrest (OHCA) is unclear. Thus, we evaluated the potential association between extreme influenza epidemics and incidence of OHCA. METHODS: We used a quasi-experimental design with time-series analysis of national registry data for cases of OHCA from all 47 prefectures of Japan during influenza seasons between 2005 and 2014. A Poisson regression time-series model with a distributed lag non-linear model was used to estimate prefecture-specific effects of influenza epidemics on OHCA. A multivariate meta-analysis was conducted for nationally pooled estimates. RESULTS: In total, 481,516 OHCAs of presumed cardiac origin were reported during the study period. The minimum morbidity percentile (MMP) was estimated as the 0th percentile for influenza incidence. The overall cumulative relative risk versus the MMP was 1.25 (95% confidence interval, 1.16-1.34) for extreme influenza epidemics (at the 99th percentile of influenza incidence). The effect of extreme influenza epidemics was significant for lag periods of 1.5-7.1 and 17.9-21 days. Multivariate random-effects meta-analysis indicated significant spatial heterogeneity among prefectures (Cochran Q test, p = 0.011; I2 = 23.2%). CONCLUSION: Extreme influenza epidemics are associated with higher risk of OHCA. Our findings suggest that several weeks' prevention for extreme influenza infections should be implemented to reduce the risk of OHCA. PMID- 29754915 TI - Virus infection as a trigger for sudden cardiac arrest. PMID- 29754917 TI - Assessing device landing zone calcification before TAVI - It's not that easy. PMID- 29754916 TI - Accuracy of device landing zone calcium volume measurement with contrast-enhanced multidetector computed tomography. AB - BACKGROUND: The extent of aortic valve calcification is an important determinant of procedural success in transcatheter aortic valve implantation (TAVI). We sought to validate device landing zone calcium volume (DLZ-CV) measurements on contrast-enhanced multidetector computed tomography (MDCT) with non-contrast enhanced scans as reference. METHODS: We determined DLZ-CV in 141 patients undergoing transfemoral TAVI. Non-contrast-enhanced images were analyzed using a threshold of 130 HU as reference (DLZ-CV130). For contrast-enhanced scans, we applied various thresholds including 450 HU (DLZ-CV450), 850 HU (DLZ-CV850), mean aortic attenuation (AttenAo) + 2 SD (DLZ-CV2SD), AttenAo + 4 SD (DLZ-CV4SD), AttenAo + 4 SD + 5 mm3 volume filter (DLZ-CV4SD+), and based on visual estimation (DLZ-CVvis). We compared DLZ-CV values between patients with versus without paravalvular leak (PVL), and between patients with versus without post-dilatation stratified by the type of prosthesis. RESULTS: All DLZ-CV measurements on contrast-enhanced scans significantly differed from DLZ-CV130 (p < 0.001 for all comparisons). The best approximation to DLZ-CV130 was achieved with DLZ-CV4SD+ (508 mm3 [332-772]; Pearson correlation: R = 0.87, p < 0.001; Bland-Altman: mean difference 1339 mm3 [limits of agreement 79;2600]). Moreover, DLZ-CV4SD+ allowed for discrimination of PVL >=1 degrees or the need for post-dilatation in patients receiving self-expanding prostheses. Procedural outcome using balloon expandable prostheses was independent of DLZ-CV. CONCLUSION: Measurement of DLZ CV using contrast-enhanced scans with unadjusted thresholds results in incorrect estimation of the calcium volume. The use of a scan-specific individual HU threshold including a volume filter (DLZ-CV4SD+) provides the best approximation to the reference and allows for discrimination of PVL >= 1 degrees in patients receiving the Acurate neo prosthesis. PMID- 29754918 TI - Can we do better next time? Contemporary procedural insights derived from a post mortem series of left main coronary stent implants. PMID- 29754919 TI - Balloon-expandable stents for recoarctation of the aorta in small children. Two centre experience. AB - BACKGROUND: In young patients with native aortic coarctation (CoA), the management of choice is surgery. However, in re-coarctation (re-CoA) surgery is associated with increased morbidity and even mortality. Some children with native CoA present relative contraindications for surgery. METHODS: From 2006 to 2017, thirty-four patients (male n = 20; 59%) from two centres with re-CoA (31) and native CoA (3) were managed by stent implantation with premounted balloon expandable stents. Inclusion criteria were age < 3 years and >1 month, weight < 16 kg. Median age was 6,5 months (min. 1; max. 34 months), median weight 6,2 kg (min. 3,7; max. 16 kg). Thirteen patients (38%) had Re-CoA and hypoplastic left heart syndrome (HLHS). In three patients (9%) the native CoA was stented due to contraindications for surgical treatment. RESULTS: All procedures were successful. The median peak invasive systolic pressure gradient declined from 31 mm Hg (max. 118; min. 4) to 0 mm Hg (max. 32; min.-7) (p < 0.001). The median minimal diameter of the narrowed segment of aorta increased from 3 mm (max. 6,9; min. 1,0) to 7 mm (max. 11,5; min. 3,5) (p < 0.001). There were no serious complications. The median follow-up time was 12,5 months (max. 88; min. 0 month). During this time ten patients (29%) required re-dilatation and two of them re stenting. CONCLUSION: Percutaneous stent implantation for Re-CoA and in selected patients for native CoA can be performed successfully in very young patients with a good immediate hemodynamical result. However, repeated stent angioplasties and further on interventional 'opening' of the stent is necessary to augment the aorta to adult size. PMID- 29754920 TI - Stents in treatment of aortic coarctation and recoarctation in small children. PMID- 29754921 TI - Global longitudinal strain corrected by RR-interval is a superior echocardiographic predictor of outcome in patients with atrial fibrillation. AB - BACKGROUND: Echocardiographic assessment of systolic and diastolic function during atrial fibrillation (AF) is challenging. This study evaluates the prognostic value of strain in patients with AF and suggests a novel approach on how to take into account the varying heart cycle lengths in AF. METHODS: Echocardiograms from 204 patients with AF during examination were analyzed offline. Patients with known heart failure (HF) were excluded. Peak global longitudinal strain (GLS) was averaged from 18 myocardial segments. To adjust for the varying heart cycle lengths, we indexed GLS with the square root of the RR interval, (GLS/?(RR)). The composite endpoint included incident HF, stroke, myocardial infarction and all-cause mortality. RESULTS: During a median follow-up of 2.4 years, 82 patients (40%) reached the composite endpoint. Decreasing GLS/?(RR) was significantly associated with the composite endpoint, and the risk of reaching the endpoint increased significantly per 1%/sec1/2 decrease in strain (HR 1.13, 95% CI 1.07-1.20, p < 0.001). GLS/?(RR) remained an independent predictor even after adjustment for various risk factors and conventional echocardiography (LVEF and E/e') (HR 1.10, 95% CI: 1.02-1.19, p = 0.017). In contrast, GLS did not remain a significant predictor after adjusting for the same variables (p = 0.07), neither did LVEF (p = 0.11). CONCLUSION: Decreasing GLS/?(RR) was significantly associated with increased risk of an adverse outcome and remained an independent predictor after multivariable adjustment. Indexing GLS with the square root of the RR-interval can counteract the variable cycle length in AF patients and GLS/?(RR) offers a more convincing risk-stratification assessment in AF patients compared with GLS. PMID- 29754922 TI - Cardiac resynchronization therapy in the ageing population - With or without an implantable defibrillator? AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective treatment option for systolic heart failure, but the benefit of an additional implantable cardioverter-defibrillator (ICD) in elderly patients is not well established. The aim of our study was to evaluate the impact of an additional ICD on survival in elderly CRT recipients. METHODS: Patients aged >=75 years with an indication for CRT and primary preventive ICD therapy, which underwent implantation of either a CRT-pacemaker (CRT-P) or CRT-defibrillator (CRT-D) were included in the study. Patient characteristics, procedural and follow-up data, and subsequent all-cause mortality were analyzed. RESULTS: A total of 775 consecutive patients underwent CRT implantation, whereof 177 patients fulfilled the inclusion criteria. Of these, 80 patients with CRT-P and 97 with CRT-D formed the two study groups. Patients in the CRT-P group were significantly older (82.6 +/- 4.5 vs. 77.8 +/- 1.9 years, p < 0.001) and more often female (44 vs. 25%; p < 0.001), had a better left ventricular ejection fraction (29.5 +/- 5.7 vs. 27.4 +/- 6.0%; p = 0.019) and narrower QRS-complex (150 +/- 19 vs. 158 +/- 18 ms; p = 0.025). During a mean follow-up of 26 +/- 19 months, 62 (35%) study patients died, 28 (35%) in the CRT P and 34 (35%) in the CRT-D group (p = 0.994). The Kaplan-Meier analysis of survival probability showed no significant difference between the two groups (p = 0.562). CONCLUSION: In our study, an additional ICD had no impact on survival in elderly patients undergoing implantation of a CRT device. Randomized controlled trials have to confirm this finding. PMID- 29754923 TI - Enhanced late sodium current underlies pro-arrhythmic intracellular sodium and calcium dysregulation in murine sodium channelopathy. AB - BACKGROUND: Long QT syndrome mutations in the SCN5A gene are associated with an enhanced late sodium current (INa,L) which may lead to pro-arrhythmic action potential prolongation and intracellular calcium dysregulation. We here investigated the dynamic relation between INa,L, intracellular sodium ([Na+]i) and calcium ([Ca2+]i) homeostasis and pro-arrhythmic events in the setting of a SCN5A mutation. METHODS AND RESULTS: Wild-type (WT) and Scn5a1798insD/+ (MUT) mice (age 3-5 months) carrying the murine homolog of the SCN5A-1795insD mutation on two distinct genetic backgrounds (FVB/N and 129P2) were studied. [Na+]i, [Ca2+]i and Ca2+ transient amplitude were significantly increased in 129P2-MUT myocytes as compared to WT, but not in FVB/N-MUT. Accordingly, INa,L wassignificantly more enhanced in 129P2-MUT than in FVB/N-MUT myocytes, consistent with a dose-dependent correlation. Quantitative RT-PCR analysis revealed intrinsic differences in mRNA expression levels of the sodium/potassium pump, the sodium/hydrogen exchanger, and sodium-calcium exchanger between the two mouse strains. The rate of increase in [Na+]i, [Ca2+]i and Ca2+ transient amplitude following the application of the Na+/K+-ATPase inhibitor ouabain was significantly greater in 129P2-MUT than in 129P2-WT myocytes and was normalized by the INa,L inhibitor ranolazine. Furthermore, ranolazine decreased the incidence of pro-arrhythmic calcium after-transients elicited in 129P2-MUT myocytes. CONCLUSIONS: In this study we established a causal link between the magnitude of INa,L, extent of Na+ and Ca2+ dysregulation, and incidence of pro arrhythmic events in murine Scn5a1798insD/+ myocytes. Furthermore, our findings provide mechanistic insight into the anti-arrhythmic potential of pharmacological inhibition of INa,L in patients with LQT3 syndrome. PMID- 29754924 TI - Evaluation of left ventricular systolic function during atrial fibrillation: Is it reliable? PMID- 29754925 TI - Too old to shock?: Questioning added benefit of ICD in elderly CRT patients. PMID- 29754926 TI - Another step towards a mechanism-based, subtype-specific therapy in long QT syndrome. PMID- 29754928 TI - Pathological mechanisms of left main stent failure. AB - BACKGROUND: Despite the increasing use of left main (LM) percutaneous coronary intervention (LM-PCI), there have been no pathological studies devoted to understanding the causes of LM stent failure. We aimed to systematically determine the pathological mechanisms of LM stent failure. METHODS AND RESULTS: From the CVPath Stent registry, a total of 46 lesions were identified to have LM PCI. Pathologic stent failure (PSF) was defined as stent thrombosis, restenosis and in-stent chronic total occlusion (CTO). Failed and patent LM stented lesions were pathologically assessed to determine predictors of PSF. Malapposition and uncovered struts were numerically greater in the LM ostium, body, and bifurcation while neointimal thickness was relatively greater in bifurcation and proximal circumflex. In this study cohort, half of the lesions (n = 23) showed PSF. Stent thrombosis (ST, n = 18) was the major mode of PSF followed by in-stent CTO (n = 4) and restenosis (n = 1). Failed lesions showed significantly greater prevalence of malapposition >20% of struts/section (65% vs. 13%, P < 0.01), stent struts crossing an ostial side branch >30% of the circumference (48% vs. 13%, P < 0.01) and uncovered struts >30% (57% vs. 18%, P = 0.03). In multivariate analysis, the prevalence of malapposition >20% was the strongest risk factor for PSF (Odds ratio 8.0, 95% confidence interval 1.8-45.4, P < 0.01) followed by struts crossing an ostial side branch >30% (Odds ratio 4.2, 95% confidence interval 0.8 24.7, P = 0.09). CONCLUSION: Our data demonstrate the main pathological predictors for LM stent failure are malapposition and struts crossing an ostial side branch and suggest that imaging-guided PCI may be important. PMID- 29754927 TI - Incremental prognostic value of left atrial function indices in the prediction of incident atrial fibrillation in patients with ST-elevation myocardial infarction. PMID- 29754929 TI - One-size-fits-all peak VO2, a dream or a nightmare. PMID- 29754930 TI - New assessment of endothelial function measured by short time flow-mediated vasodilation: Comparison with conventional flow-mediated vasodilation measurement. AB - BACKGROUND: Measurement of flow-mediated vasodilation (FMD) is an established method for assessing endothelial function. Measurement of FMD is useful for showing the relationship between atherosclerosis and endothelial function, mechanisms of endothelial dysfunction, and clinical implications including effects of interventions and cardiovascular events. To shorten and simplify the measurement of FMD, we have developed a novel technique named short time FMD (stFMD). We investigated the validity of stFMD for assessment of endothelial function compared with conventional FMD. METHODS AND RESULTS: We evaluated stFMD and conventional FMD in 82 subjects including patients with atherosclerotic risk factors and cardiovascular disease (66 men and 16 women, 57 +/- 16 years). Both stFMD and conventional FMD were significantly correlated with age, systolic blood pressure, diastolic blood pressure and baseline brachial artery diameter. In addition, stFMD was significantly correlated with conventional FMD (r = 0.76, P < 0.001). Bland-Altman plot analysis showed good agreement b etween stFMD and conventional FMD. Moreover, stFMD in the at risk group and that in the cardiovascular disease group were significantly lower than that in the no risk group (4.6 +/- 2.3% and 4.4 +/- 2.2% vs. 7.3 +/- 1.9%, P < 0.001, respectively). Optimal cutoff value of stFMD for diagnosing atherosclerosis was 7.0% (sensitivity of 71.0% and specificity of 85.0%). CONCLUSIONS: These findings suggest that measurement of stFMD, a novel and simple method, is useful for assessing endothelial function. Measurement of stFMD may be suitable for screening of atherosclerosis when repeated measurements of vascular function are required and when performing a clinical trial using a large population. CLINICAL TRIAL REGISTRATION INFORMATION: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000025458. PMID- 29754931 TI - Percutaneous left atrial appendage closure with complex anatomy by using the staged 'kissing-Watchman' technology with double devices. AB - BACKGROUND: Left atrial appendage closure (LAAC) is an efficient alternative of oral anticoagulation to prevent stroke in patients with non-valvular atrial fibrillation (NVAF). Due to complexities of LAA anatomy, a complete closure may not always be obtained with a single device. The aim of this study was to evaluate the feasibility and safety of the staged 'kissing-Watchman' technology to occlude the LAA with complex anatomy. METHODS: In our center, among 300 cases underwent LAAC with Watchman device from February 2012 to December 2016, 7 complex LAAs were implanted double devices using the staged 'kissing-Watchman' technology. The anatomic morphology, procedure characteristics and safety were analyzed. RESULTS: Of the 7 LAAs, the anatomic morphology includes 6 cauliflowers and 1 chicken wings, each has 2 big lobes and a large common ostium. In the two staged LAAC procedures, there were no differences in X-ray exposure time, but the total procedure time (p = 0.0634), contrast volume (p = 0.0802) and X-ray dose (p = 0.0803) in the first procedure showed a tendency over the second. All the procedures were successful, except for one case with a 2 mm of peri-device leakage, there were no severe complications or major adverse events including device dislocation, thrombosis, obvious peri-device leakage (>=5 mm), pericardial effusion/tamponade, stroke/transient ischemic attack/systemic embolism, death and major bleeding during the 7-day perioperative period and the 6-month follow-up. CONCLUSIONS: The staged 'kissing-Watchman' technology is feasible and safe, which might provide a strategy to occlude the LAA with complex anatomy when an incomplete closure is inevitable with a single device. PMID- 29754932 TI - Mild hypothermia inhibits the Notch 3 and Notch 4 activation and seizure after stroke in the rat model. AB - Ischemic brain injury is an important cause for seizure. Mild hypothermia of the brain or the whole body is an effective way to remit the post-stroke seizure. Our previous study revealed an implication of Notch 1 and 2 in the post-stroke seizure. This study further investigated the involvement of Notch 3 and 4 in post stroke seizure and the effect of mild hypothermia on these two factors. A global cerebral ischemia (GCI) model was conducted in Sprague Dawley rats. Seizure activity was evaluated by the frequency of seizure attacks, seizure severity scores, and seizure discharges. Seizures were frequently occurred in the first and the second 24 h after GCI, however active whole-body cooling (mild hypothermia) and DAPT (Notch inhibitor) injection into the hippocampus, alone or in combination, alleviated seizure activity after GCI. Immunohistochemistry and Western blot assays revealed the up-regulation of Notch intracellular domain (NICD) 3 and 4 in the cerebral cortex and hippocampus following GCI, but mild hypothermia and DAPT inhibited the up-regulation of NICD 3 and 4. NF-kappaB, PPARalpha, PPARgamma, cyclin D1, Sox2 and Pax6 are associated with the pathogenesis of diverse type of seizures. GCI induced NF-kappaB, cyclin D1, and Pax6 activity, but suppressed PPARgamma. These effects of GCI were abolished by both mild hypothermia and DAPT treatment. This indicated the implication of Notch signaling in the effects of GCI. Collectively, mild hypothermia inhibits Notch 3 and Notch 4 activation and seizure after stroke in the rat model. This study adds to the further understanding of the pathogenesis of post-stroke seizures and the protective mechanism of mild hypothermia. PMID- 29754935 TI - A middle-aged woman with microscopic hematuria detected at a medical check-up. PMID- 29754933 TI - Sleep duration and sleep quality in people with and without intellectual disability: A meta-analysis. AB - This study provides the first meta-analysis of the purported differences in sleep time and sleep quality between people with and without intellectual disabilities. Twenty-one papers were identified that compared sleep time and/or sleep quality in people with and without intellectual disabilities. The meta-analysis of sleep time revealed that people with an intellectual disability slept for 18 min less, on average, than people without an intellectual disability. This significant difference was limited to those studies that tested groups of people with an identified genetic syndrome or developmental disorder. The analysis of sleep quality also concluded that people with intellectual disabilities experienced poorer sleep: In 93% of comparisons between groups, sleep was found to be of poorer quality in the group of people with intellectual disabilities. There were no differences found between studies that measured sleep objectively and those that used diary or questionnaire measures. Notably, most samples were drawn from populations of people with specified genetic syndromes or developmental disorders, rather than intellectual disability of heterogeneous origin. Similarly, most studies investigated sleep in children, although there was no evidence that the differences between the groups reduced during adulthood. Most studies used highly-regarded objective measures of sleep, such as polysomnography or actigraphy, although methodological flaws were evident in the identification of samples and the measurement of intellectual disability. PMID- 29754936 TI - Painful lesions on the arms of a teenage wrestler. PMID- 29754937 TI - Young woman with dyspnea and upper abdominal pain. PMID- 29754934 TI - Comprehensive Genomic Profiling of Metastatic Tumors in a Phase 2 Biomarker Study of Everolimus in Advanced Renal Cell Carcinoma. AB - INTRODUCTION: Genomic events leading to activation of mechanistic target of rapamycin (mTOR) are common in renal cell carcinoma (RCC). Everolimus is an allosteric mTOR inhibitor with efficacy in metastatic RCC. We characterized the genomic profile of RCC tumors from metastatic sites and assessed whether particular alterations correlate with clinical response to everolimus. PATIENTS AND METHODS: An open-label, single-arm phase 2 biomarker study of everolimus 10 mg daily was conducted in metastatic RCC patients. Needle biopsy or metastasectomy was performed on metastatic tumors before everolimus initiation. Next-generation sequencing was performed using a targeted hybrid capture panel detecting alterations within exons and key introns of >= 300 cancer-associated genes. Disease assessments were obtained every 8 weeks using standard radiographic modalities and evaluated by Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Objective response was seen in 1 (4.2%) of 24 patients. Two patients (8.3%) had stable disease lasting > 6 months. Median (90% confidence interval) overall and progression-free survival were 20.1 (8.6, NA) and 3.8 (2.4, 5.4) months, respectively. Next-generation sequencing was successful on 18 pretreatment specimens and 3 on-treatment specimens. Alterations in the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway were identified in 8 (44%) of 18 pretreatment samples. An mTOR E2419D mutation was identified in the patient who experienced partial response. Alterations in VHL, PBRM1, SETD2, KDM5C, and ATM were common in the RCC metastases before initiation of everolimus. CONCLUSION: Nearly half of heavily pretreated RCC metastases may harbor mutations in components of the PI3K-AKT-mTOR pathway. Commonly mutated genes in primary RCC were also altered at a high frequency in RCC metastases. PMID- 29754938 TI - Shortness of breath after thoracentesis: Did we do something wrong? PMID- 29754939 TI - Incremental risk of long-term mortality with increased burden of comorbidity in hospitalized patients with pneumonia. AB - BACKGROUND: Patients hospitalized for pneumonia often have concurrent comorbid conditions (CCs). The influence of CCs on the risk of subsequent death is not fully understood. METHODS: We examined adults hospitalized for pneumonia between 1996 through 2015 at Mayo Clinic for the presence of 20 priori selected CCs. We estimated cumulative all-cause mortality by number of CCs using multivariable Cox regression model. RESULTS: Study comprised of 9580 adults (age 70 +/- 17.0 years, men 53%, whites 88%) with median number of CCs 3 (interquartile 1-4), and overall deaths 6032 (62.9%) during 50,934 person-years of follow up (118.5 deaths/1000 person-years). After adjustment, any single comorbid condition was associated with 9% greater risk of death (95% confidence interval 1.08-1.11, P < 0.0001). When study cohort was stratified according to number of comorbidities (none, 1, 2, 3, 4, 5, and >=6 CCs), the risk of death increased as the number of CCs increased (33 for no CCs vs 252 deaths for >=6 CCs per 1000 person-years). CONCLUSIONS: Long-term mortality after hospitalization for pneumonia increases as the burden of comorbidities increases. Therefore, a simple comorbidity count help improve prognostic accuracy in identifying patients at increased risk of death following an episode of pneumonia. PMID- 29754940 TI - Radioguided hepatic resection with 18F-DOPA in a patient with metastatic medullary thyroid carcinoma. AB - INTRODUCTION: Medullary carcinoma accounts for 1-2% of all thyroid malignancies. 13-20% of patients present with distant metastasis, with 45% of the cases affecting the liver. CLINICAL CASE: A 50-year-old woman, diagnosed with medullary thyroid carcinoma, was treated with total thyroidectomy and a modified neck dissection in 1999. Two lymph node recurrences in the neck were treated with surgical resection; during surveillance, she developed elevated calcitonin levels, the recurrence site was identified with 18F-DOPA PET/CT in the liver. Metabolic activity was not associated with a visible lesion in CT, MRI nor ultrasound. Radioguided surgery with 18F-DOPA allowed an anatomic resection of segments IVb and V. DISCUSSION: In patients with medullary carcinoma and elevated calcitonin during surveillance, 18F-DOPA PET/CT is an option to evaluate the site of recurrence. Radioguided resection was feasible in this patient, whose hepatic recurrence was not visible with any other imaging method. CONCLUSION: Radioguided hepatic resection with 18F-DOPA in metastatic medullary thyroid carcinoma is feasible when the recurrence site is not anatomically identified by any other imaging studies. PMID- 29754941 TI - Different uptake of 123I-MIBG in the two main liver lobes: A persistant unsolved mistery. AB - PURPOSE: After radiopharmaceutical injection, a heightened 123I-MIBG concentration is frequently observed in the left hepatic lobe compared to the right one, but the reason of this finding remains unknown. Our aim was to retrospectively analyze the different 123I-MIBG uptake pattern between the two hepatic lobes and correlate our results with some epidemiological/clinical features. MATERIAL AND METHODS: Ninety-four 123I-MIBG scintigraphies from 71 patients were selected. Regions of interest were drawn in the right and left lobes using transverse tomographic sections and left to right activity ratios (L/R ratio) were calculated at 6 and 24h after radiotracer administration. RESULTS: Twenty-seven examinations were positive for hypermetabolic lesions while the remaining 67 were negative. In all cases mean early and delayed L/R ratios were greater than 1.00; average early L/R ratio was 1.37 and delayed L/R ratio 1.52. The delayed L/R ratio was significantly higher than the early one. There was no difference in the L/R ratios with regard to age, gender, primary disease and result of scintigraphy. CONCLUSIONS: 123I-MIBG uptake was higher in left hepatic lobe compared to right and this ratio did not correlate with any epidemiological or clinical feature. The reason of this metabolic is not yet explained and some biomolecular hypotheses could be tested in 3D dynamic in vitro models. PMID- 29754943 TI - Reply. PMID- 29754942 TI - Dead space analysis at different levels of positive end-expiratory pressure in acute respiratory distress syndrome patients. AB - PURPOSE: To analyze the effects of positive end-expiratory pressure (PEEP) on Bohr's dead space (VDBohr/VT) in patients with acute respiratory distress syndrome (ARDS). MATERIAL AND METHODS: Fourteen ARDS patients under lung protective ventilation settings were submitted to 4 different levels of PEEP (0, 6, 10, 16 cmH2O). Respiratory mechanics, hemodynamics and volumetric capnography were recorded at each protocol step. RESULTS: Two groups of patients responded differently to PEEP when comparing baseline with 16-PEEP: those in which driving pressure increased > 15% (?P?15%, n = 7, p = .016) and those in which the change was <=15% (?P<=15%, n = 7, p = .700). VDBohr/VT was higher in ?P<=15% than in ?P<=15% patients at baseline ventilation [0.58 (0.49-0.60) vs 0.46 (0.43-0.46) p = .018], at 0-PEEP [0.50 (0.47-0.54) vs 0.41 (0.40-0.43) p = .012], at 6-PEEP [0.55 (0.49-0.57) vs 0.44 (0.42-0.45) p = .008], at 10-PEEP [0.59 (0.51-0.59) vs 0.45 (0.44-0.46) p = .006] and at 16-PEEP [0.61 (0.56-0.65) vs 0.47 (0.45-0.48) p = .001]. We found a good correlation between ?P and VDBohr/VT only in the ?P?15% group (r = 0.74, p < .001). CONCLUSIONS: Increases in PEEP result in higher VDBohr/VT only when associated with an increase in driving pressure. PMID- 29754944 TI - The effectiveness of enteral nutrition as stress ulcer prophylaxis remains uncertain. PMID- 29754947 TI - Corrigendum to "Transposon-associated lincosamide resistance lnu(C) gene identified in Brachyspira hyodysenteriae ST83" [Vet. Microbiol. 214 (2018) 51 55]. PMID- 29754945 TI - Decision analysis defining optimal management of clinical stage 1 high-risk nonseminomatous germ cell testicular cancer with lymphovascular invasion. AB - BACKGROUND: Risk of recurrent disease for men with clinical stage 1 high-risk nonseminomatous germ cell testicular cancer (CS1 NSGCT) with lymphovascular invasion (LVI) after orchiectomy is 50% and current treatment options (surveillance [S], retroperitoneal lymph node dissection [RPLND], or 1 cycle of BEP [BEP *1]) are associated with a 99% disease specific survival, therefore practice patterns vary. We performed a decision analysis using updated data of long-term complications for men with CS1 NSGCT with LVI to quantify and assess relative treatment values. METHODS: Decision analysis included previously defined utilities (via standard gamble) for posttreatment states of living from 0 (death from disease) to 1 (alive in perfect health) and updated morbidity probabilities. We quantified the values of S, RPLND, and BEP *1 via the rollback method. Sensitivity analyses including a range of orchiectomy cure rates and utility values were performed. RESULTS: Estimated probabilities favoring treatment with RPLND (0.97) or BEP *1 (0.97) were equivalent and superior to surveillance (0.88). Sensitivity analysis of orchiectomy cure rates (50%-100%) failed to find a cure rate that favored S over BEP *1 or RPLND. Varying utility values for cure after S from 0.92 (previously defined utility) to 1 (perfect health), failed to find a viable utility state favoring S over BEP *1 or RPLND. An orchiectomy cure rate of >=82% would be required for S to equal treatment of either type. CONCLUSIONS: We demonstrate that for surveillance to be superior to treatment with BEP *1 or RPLND, the orchiectomy cure rate must be at least 82%, which is not expected in a patient population with high-risk CS1 NSGCT. PMID- 29754946 TI - Comparison of interfacial behavior and silver extraction kinetics with various types calix[4]arene derivatives at heterogeneous liquid-liquid interfaces. AB - Various p-tert-octylcalix[4]arene derivatives as hydrophobic extractants have been prepared to investigate Ag(I) extraction efficiency in a batch-wise process in nitric acid media. The influence of the functional groups of the hydrophobic extractants on the interfacial behavior and Ag(I) extraction efficiency in nitric acid media has been investigated using the drop-volume method. Fitting of the interfacial tension isotherms to the Gibbs and Szyszkowski equations has provided parameters characterizing the interfacial activity of the extractants, in particular the Gibbs free energy of adsorption at the interface, the interface excess on saturation (Ginfinity) and the average area per the adsorbed extractant molecule (Amin). The amido-type p-tert-octylcalix[4]arene derivatives have strong interfacial activity and fast extraction rates. The interface excess at saturation (Ginfinity) increased with the type of functional groups in the following order: methyl ketonic < phenyl ketonic < dibenzyl amido < diethyl amido < quinolyl < pyridyl. The relationship between the interfacial activity and the dependence of the Ag(I) extraction efficiency on the different functional groups is discussed. The interfacial behavior of the extractants affected both the solvent extraction equilibrium and the kinetics and the overall results are consistent with a mass transfer mechanism at the heterogeneous liquid-liquid interfaces. PMID- 29754948 TI - The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core. AB - This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties). PMID- 29754949 TI - Interpretation of Dual-Energy X-Ray Absorptiometry-Derived Body Composition Change in Athletes: A Review and Recommendations for Best Practice. AB - Dual-energy X-ray absorptiometry (DXA) is a medical imaging device which has become the method of choice for the measurement of body composition in athletes. The objectives of this review were to evaluate published longitudinal DXA body composition studies in athletic populations for interpretation of "meaningful" change, and to propose a best practice measurement protocol. An online search of PubMed and CINAHL via EBSCO Host and Web of Science enabled the identification of studies published until November 2016. Those that met the inclusion criteria were reviewed independently by 2 authors according to their methodological quality and interpretation of body composition change. Twenty-five studies published between 1996 and November 2016 were reviewed (male athletes: 13, female athletes: 3, mixed: 9) and sample sizes ranged from n = 1 to 212. The same number of eligible studies was published between 2013 and 2016, as over the 16 yr prior (between 1996 and 2012). Seven did not include precision error, and fewer than half provided athlete-specific precision error. There were shortfalls in the sample sizes on which precision estimates were based and inconsistencies in the level of pre-scan standardization, with some reporting full standardization protocols and others reporting only single (e.g., overnight fast) or no control measures. There is a need for standardized practice and reporting in athletic populations for the longitudinal measurement of body composition using DXA. Based on this review and those of others, plus the official position of the International Society for Clinical Densitometry, our recommendations and protocol are proposed as a guide to support best practice. PMID- 29754950 TI - Oral health-related quality of life in primary Sjogren's syndrome. AB - OBJECTIVE: To assess health-related quality of life (HRQoL) and oral health related quality of life, and correlate them with unstimulated whole salivary flow (UWSF) and oral sicca symptoms in patients with primary Sjogren's syndrome (PSS). METHODS: We included 60 patients with PSS and 60 healthy controls matched according to gender and age (+/-3 years). We measured the UWSF and scored the European League Against Rheumatism (EULAR) Sjogren's Syndrome Patient Reported Index (ESSPRI). We assessed the short version of the SF-36 as a generic measurement of HRQoL and the Xerostomia Quality of Life Scale (XeQoLS) questionnaire to evaluate oral quality of life. We evaluated oral symptoms using an 8-item Visual Analogue Scale (VAS) questionnaire. RESULTS: We observed a poorer HRQoL (lower scores in SF-36) and oral quality of life (higher scores in XeQoLS), as well as a greater severity of symptoms in the VAS questionnaire upon comparing patients vs. controls. The XeQoL correlated with the UWSF (tau = -0.24, P = .008), the ESSPRI (tau =0.45, P = .0001), VAS 1-2 and VAS 5-8 and the SF-36 score (tau = -0.28, P = .002). CONCLUSIONS: Patients with PSS had a poorer HRQoL and oral quality of life than controls. UWSF contributes to the oral quality of life which, in turn, has an impact on HRQoL. Symptomatic treatment of xerostomia as well as the prevention of infections, decay and tooth loss would help to improve the oral quality of life in these patients. PMID- 29754951 TI - Mitochondrial Translation Efficiency Controls Cytoplasmic Protein Homeostasis. AB - Cellular proteostasis is maintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response. In striking contrast, increased accuracy extended lifespan, improved cytosolic aggregate clearance, and suppressed a normally stress-induced, Msn2/4-dependent interorganellar proteostasis transcription program (IPTP) that regulates genes important for mitochondrial proteostasis. Collectively, the data demonstrate that cytosolic protein homeostasis and nuclear stress signaling are controlled by mitochondrial translation efficiency in an inter-connected organelle quality control network that determines cellular lifespan. PMID- 29754952 TI - Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes. AB - Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism. Men with prediabetes were randomized to eTRF (6-hr feeding period, with dinner before 3 p.m.) or a control schedule (12-hr feeding period) for 5 weeks and later crossed over to the other schedule. eTRF improved insulin sensitivity, beta cell responsiveness, blood pressure, oxidative stress, and appetite. We demonstrate for the first time in humans that eTRF improves some aspects of cardiometabolic health and that IF's effects are not solely due to weight loss. PMID- 29754955 TI - Structural Insights into Subunits Assembly and the Oxyester Splicing Mechanism of Neq pol Split Intein. AB - Split inteins are expressed as two separated subunits (N-intein and C-intein) fused to the corresponding exteins. The specific association of both intein subunits precedes protein splicing, which results in excision of the intein subunits and in ligation, by a peptide bond, of the concomitant exteins. Catalytically active intein precursors are typically too reactive for crystallization or even isolation. Neq pol is the trans-intein of the B-type DNA polymerase I split gene from hyperthermophile Nanoarchaeum equitans. We have determined the crystal structures of both the isolated NeqN and the complex of NeqN and NeqC subunits carrying the wild-type sequences, including the essential catalytic residues Ser1 and Thr+1, in addition to seven and three residues of the N- and C-exteins, respectively. These structures provide detailed information on the unique oxyester chemistry of the splicing mechanism of Neq pol and of the extensive rearrangements that occur in NeqN during the association step. PMID- 29754954 TI - The Polycomb-Dependent Epigenome Controls beta Cell Dysfunction, Dedifferentiation, and Diabetes. AB - To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin state signatures that track beta cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes. beta cell-specific Polycomb (Eed/PRC2) loss of function in mice triggers diabetes-mimicking transcriptional signatures and highly penetrant, hyperglycemia-independent dedifferentiation, indicating that PRC2 dysregulation contributes to disease. The work provides novel resources for exploring beta cell transcriptional regulation and identifies PRC2 as necessary for long-term maintenance of beta cell identity. Importantly, the data suggest a two-hit (chromatin and hyperglycemia) model for loss of beta cell identity in diabetes. PMID- 29754956 TI - Measuring Endoplasmic Reticulum Signal Sequences Translocation Efficiency Using the Xbp1 Arrest Peptide. AB - Secretory proteins translocate across the mammalian ER membrane co translationally via the ribosome-sec61 translocation machinery. Signal sequences within the polypeptide, which guide this event, are diverse in their hydrophobicity, charge, length, and amino acid composition. Despite the known sequence diversity in the ER signals, it is generally assumed that they have a dominant role in determining co-translational targeting and translocation process. We have analyzed co-translational events experienced by secretory proteins carrying efficient versus inefficient signal sequencing, using an assay based on Xbp1 peptide-mediated translational arrest. With this method we were able to measure the functional efficiency of ER signal sequences. We show that an efficient signal sequence experiences a two-phase event whereby the nascent chain is pulled from the ribosome during its translocation, thus resuming translation and yielding full-length products. Conversely, the inefficient signal sequence experiences a single weaker pulling event, suggesting inadequate engagement by the translocation machinery of these marginally hydrophobic signal sequences. PMID- 29754957 TI - Pharmacological Inhibition of the Ubiquitin Ligase RNF5 Rescues F508del-CFTR in Cystic Fibrosis Airway Epithelia. AB - In cystic fibrosis (CF), deletion of phenylalanine 508 (F508del) in the CFTR channel is associated with misfolding and premature degradation of the mutant protein. Among the known proteins associated with F508del-CFTR processing, the ubiquitin ligase RNF5/RMA1 is particularly interesting. We previously demonstrated that genetic suppression of RNF5 in vivo leads to an attenuation of intestinal pathological phenotypes in CF mice, validating the relevance of RNF5 as a drug target for CF. Here, we used a computational approach, based on ligand docking and virtual screening, to discover inh-02, a drug-like small molecule that inhibits RNF5. In in vitro experiments, treatment with inh-02 modulated ATG4B and paxillin, both known RNF5 targets. In immortalized and primary bronchial epithelial cells derived from CF patients homozygous for the F508del mutation, long-term incubation with inh-02 caused significant F508del-CFTR rescue. This work validates RNF5 as a drug target for CF, providing evidence to support its druggability. PMID- 29754958 TI - Automated Deep Learning-Based System to Identify Endothelial Cells Derived from Induced Pluripotent Stem Cells. AB - Deep learning technology is rapidly advancing and is now used to solve complex problems. Here, we used deep learning in convolutional neural networks to establish an automated method to identify endothelial cells derived from induced pluripotent stem cells (iPSCs), without the need for immunostaining or lineage tracing. Networks were trained to predict whether phase-contrast images contain endothelial cells based on morphology only. Predictions were validated by comparison to immunofluorescence staining for CD31, a marker of endothelial cells. Method parameters were then automatically and iteratively optimized to increase prediction accuracy. We found that prediction accuracy was correlated with network depth and pixel size of images to be analyzed. Finally, K-fold cross validation confirmed that optimized convolutional neural networks can identify endothelial cells with high performance, based only on morphology. PMID- 29754953 TI - Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity. AB - Kidney cancer, one of the ten most prevalent malignancies in the world, has exhibited increased incidence over the last decade. The most common subtype is "clear cell" renal cell carcinoma (ccRCC), which features consistent metabolic abnormalities, such as highly elevated glycogen and lipid deposition. By integrating metabolomics, genomic, and transcriptomic data, we determined that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors, which are otherwise genetically heterogeneous. Notably, the expression of key urea cycle enzymes, including arginase 2 (ARG2) and argininosuccinate synthase 1 (ASS1), is strongly repressed in ccRCC. Reduced ARG2 activity promotes ccRCC tumor growth through at least two distinct mechanisms: conserving the critical biosynthetic cofactor pyridoxal phosphate and avoiding toxic polyamine accumulation. Pharmacological approaches to restore urea cycle enzyme expression would greatly expand treatment strategies for ccRCC patients, where current therapies only benefit a subset of those afflicted with renal cancer. PMID- 29754959 TI - Human Induced Pluripotent Stem Cell-Derived Cardiac Cell Sheets Expressing Genetically Encoded Voltage Indicator for Pharmacological and Arrhythmia Studies. AB - Fulfilling the potential of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes for studying conduction and arrhythmogenesis requires development of multicellular models and methods for long-term repeated tissue phenotyping. We generated confluent hiPSC-derived cardiac cell sheets (hiPSC-CCSs), expressing the genetically encoded voltage indicator ArcLight. ArcLight-based optical mapping allowed generation of activation and action-potential duration (APD) maps, which were validated by mapping the same hiPSC-CCSs with the voltage sensitive dye, Di-4-ANBDQBS. ArcLight mapping allowed long-term assessment of electrical remodeling in the hiPSC-CCSs and evaluation of drug-induced conduction slowing (carbenoxolone, lidocaine, and quinidine) and APD prolongation (quinidine and dofetilide). The latter studies also enabled step-by-step depiction of drug induced arrhythmogenesis ("torsades de pointes in the culture dish") and its prevention by MgSO4 and rapid pacing. Phase-mapping analysis allowed biophysical characterization of spiral waves induced in the hiPSC-CCSs and their termination by electrical cardioversion and overdrive pacing. In conclusion, ArcLight mapping of hiPSC-CCSs provides a powerful tool for drug testing and arrhythmia investigation. PMID- 29754960 TI - High-Level Precise Knockin of iPSCs by Simultaneous Reprogramming and Genome Editing of Human Peripheral Blood Mononuclear Cells. AB - We have developed an improved episomal vector system for efficient generation of integration-free induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells. More recently, we reported that the use of an optimized CRISPR Cas9 system together with a double-cut donor increases homology-directed repair mediated precise gene knockin efficiency by 5- to 10-fold. Here, we report the integration of blood cell reprogramming and genome editing in a single step. We found that expression of Cas9 and KLF4 using a single vector significantly increases genome editing efficiency, and addition of SV40LT further enhances knockin efficiency. After these optimizations, genome editing efficiency of up to 40% in the bulk iPSC population can be achieved without any selection. Most of the edited cells show characteristics of iPSCs and genome integrity. Our improved approach, which integrates reprogramming and genome editing, should expedite both basic research and clinical applications of precision and regenerative medicine. PMID- 29754962 TI - Influence of margin histology on development of pancreatic fistula following pancreatoduodenectomy. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is a potentially debilitating complication following pancreatoduodenectomy (PD). There are limited data correlating pancreatic parenchymal histopathologic features specifically fat and fibrosis content with development of POPF after PD. METHODS: Patients who underwent PD (January 2010-May 2015) with archived pathologic slides were included. Each pancreatic neck transection margin was histologically graded for fat and fibrosis, scored from 0 to 4, and grader was blinded to clinical outcomes. Main pancreatic duct diameter and duct wall thickness were microscopically measured. Patients were dichotomized into high and low categories with respect to pancreatic fat and fibrosis and primary outcome of POPF. RESULTS: Of 301 patients, 24 developed POPF (8.0%). One hundred ten patients (36.5%) had low fat (score <2), and 149 (49.5%) had low fibrosis (score <2), and average duct diameter was 3.9 +/- 1.3 mm. Patients with low fibrosis had a higher rate of POPF (12.8% versus 3.3%, P = 0.005). Low fibrosis (odds ratio [OR] 4.29, 95% confidence interval [CI] 1.56-11.7, P = 0.005), nonpancreatic adenocarcinoma pathology (OR 3.25, 95% CI 1.25-8.43, P = 0.02), and increased body mass index (BMI) (OR 1.11, 95% CI 1.03-1.12, P = 0.007) were associated with POPF development on univariate analysis. Low fibrosis and increased BMI remained independently associated on multivariate analysis. High fat content was frequently concurrently identified in specimens with high fibrosis (67.8%). Surgeon-described gland consistency did not correlate with histopathologic findings (Spearman's rank correlation coefficients of -0.144 and 0.304, respectively) or to incidence of POPF. No patient who underwent preoperative chemotherapy developed POPF (n = 30, 10%). CONCLUSIONS: Low pancreatic neck fibrosis content and increased patient BMI are associated with increased rates of POPF following PD, while pancreatic fat content does not appear to influence this outcome. Pancreatic neck fat and fibrosis often coexist in the same specimen. The association between preoperative chemotherapy and low POPF rates needs further examination. Frozen section analysis of pancreatic neck margin for fibrosis content may be more accurate than surgeon assessment in identifying patients at risk for POPF. These assessments can potentially guide therapeutic interventions, including selective prophylactic drain placement and use of postoperative somatostatin analog therapy. PMID- 29754961 TI - Hematopoietic Stem Cells but Not Multipotent Progenitors Drive Erythropoiesis during Chronic Erythroid Stress in EPO Transgenic Mice. AB - The hematopoietic stem cell (HSC) compartment consists of a small pool of cells capable of replenishing all blood cells. Although it is established that the hematopoietic system is assembled as a hierarchical organization under steady state conditions, emerging evidence suggests that distinct differentiation pathways may exist in response to acute stress. However, it remains unclear how different hematopoietic stem and progenitor cell subpopulations behave under sustained chronic stress. Here, by using adult transgenic mice overexpressing erythropoietin (EPO; Tg6) and a combination of in vivo, in vitro, and deep sequencing approaches, we found that HSCs respond differentially to chronic erythroid stress compared with their closely related multipotent progenitors (MPPs). Specifically, HSCs exhibit a vastly committed erythroid progenitor profile with enhanced cell division, while MPPs display erythroid and myeloid cell signatures and an accumulation of uncommitted cells. Thus, our results identify HSCs as master regulators of chronic stress erythropoiesis, potentially circumventing the hierarchical differentiation-detour. PMID- 29754963 TI - Predictors of a drainable suppurative adenitis among children presenting with cervical adenopathy. AB - OBJECTIVES: We sought to identify predictors for a drainable suppurative adenitis [DSA] among patients presenting with acute cervical lymphadenitis. METHODS: A retrospective cross sectional study of all patients admitted to an urban pediatric tertiary care emergency department over a 15 year period. Otherwise healthy patients who underwent imaging for an evaluation of cervical lymphadenitis were included. Cases were identified using a text-search module followed by manual review. We excluded immunocompromised patients and those with lymphadenopathy felt to be not directly infected (i.e. reactive) or that was not acute (symptom duration >28 days). Data collected included: age, gender, duration of symptoms, highest recorded temperature, physical exam findings, laboratory and imaging results, and surgical findings. A DSA was defined as >1.5 cm in diameter on imaging. We performed binary logistic regression to determine independent clinical predictors of a DSA. RESULTS: Three hundred sixty-one patients met inclusion criteria. Three hundred six patients (85%) had a CT scan, 55 (15%) had an ultrasound and 33 (9%) had both. DSA was identified in 71 (20%) patients. Clinical features independently associated with a DSA included absence of clinical pharyngitis, WBC >15,000/mm3, age <=3 years, anterior cervical chain location, largest palpable diameter on exam >3 cm and prior antibiotic treatment of >24 h. The presence of fever, skin erythema, or fluctuance on examination, was not found to be predictive of DSA. CONCLUSIONS: We identified independent predictors of DSA among children presenting with cervical adenitis. Risk can be stratified into risk groups based on these clinical features. PMID- 29754964 TI - Ketamine exposure demographics and outcomes over 16 years as reported to US poison centers. AB - BACKGROUND: This study sought to examine ketamine exposures reported to US poison centers over the past 16 years and identify trends in exposures and outcomes. METHODS: A retrospective review was performed of all cases involving ketamine exposures reported to US poison centers and entered into the National Poison Data System from 2000 to 2015. Cases were divided into those involving ketamine alone and those involving ketamine and other agents. Data collected included: age, sex, form of ketamine used, reason for exposure, and outcome. RESULTS: A total of 3109 cases were evaluated. 1595 (51%) reported ketamine to be the only substance exposure, while 1514 (49%) involved multiple substances with ketamine. For single agent exposures, more involved males (67%) between the ages of 16-25 years (49%). Single agent ketamine exposures peaked between 2000 and 2002, fell consistently until 2008; then rebounded to previous peak levels through 2015. Intentional exposures (65% of all cases) were the most common reason for single agent ketamine exposures. 53% of ketamine-only cases resulted in minor effects, with two deaths. In contrast, ketamine exposures with multiple agents resulted in outcomes judged as moderate or worse in 62% of cases, including 20 deaths. CONCLUSION: Single-agent ketamine exposures reported to US poison centers have rebounded to historical peaks in recent years. More deaths and serious outcomes were reported in ketamine exposures involving multiple substances. PMID- 29754965 TI - Gender-based outcome differences for emergency department presentation ofnon STEMI acute coronary syndrome. AB - BACKGROUND: It is known that women generally have worse mortality outcomes than men with regards to ST-segment elevation myocardial infarction. However, less is known about contemporary gender differences in non-STEMI acute coronary syndrome, particularly those presenting to emergency departments within a regionalized system of care with standardized protocols. METHODS: Retrospective registry data from 2010 to 2016 were examined from the North Texas Mission: Lifeline system of care, representing 33 hospitals around the Dallas Texas metropolitan area. We explored gender-based differences using multivariate logistic regression model, controlling for patient's age, baseline condition, and hospital factors. RESULTS: There were 16,861 patients who presented directly to emergency departments with NSTEMI, and 6513 (38.6%) were women. At baseline, women were older (68.04 vs. 63.7 years, p < 0.001) and presented with history of prior cardiovascular disease more often than men. Women had higher unadjusted in-hospital mortality rates than men (4.8% vs. 3.9%, p < 0.001), which persisted after controlling for patient age, comorbidities, and hospital factors. Women also had 23 min longer ED lengths of stay (p < 0.001) and were much less likely to receive an early invasive strategy (diagnostic coronary angiography within 24 h of arrival) than men (47.0% vs 54.4%, p < 0.001). CONCLUSION: Emergency department NSTEMI protocols should consider potential gender disparities that exist for women. Overall, women had worse outcomes, which persist even in an urban system of care with standardized protocols. PMID- 29754966 TI - TLR4 gene polymorphisms rs11536889 is associated with intracranial aneurysm susceptibility. AB - Intracranial aneurysm (IA) is a common lesion which often present asymptomatic until the time of rupture and result in subarachnoid hemorrhage (SAH). The pathogenesis of IA formation is complex and is influenced by both genetic and environmental risk factors. For exploring the detailed molecular and cellular mechanisms involved in the pathogenesis of IA, recent studies indicated inflammatory pathways and their genetic variants may as potential biomarkers. In this study, functionally relevant polymorphisms in the toll-like receptor 4 (TLR4) were screened in 330 IA patients and 313 controls from a Han Chinese population. Eight single nucleotide gene polymorphisms (SNPs) genotyped by the Improved Multiple Ligase Detection Reaction (iMLDR) method. Our results indicated that the presence of the minor allele (C) of the TLR4 SNP rs11536889 was associated with a decreased risk of IA (C vs. G, OR = 0.731; 95% CI 0.567-0.943; P = 0.017). This association was also present at the genotype level in a codominant model (GC vs. GG, OR = 0.447; 95% CI 0.226-0.884; P = 0.020) and a recessive model (CC vs. GG + GC, OR = 0.489; 95% CI 0.250-0.955; P = 0.035). In summary, we firstly found that the TLR4 SNP rs11536889 was significantly associated with the susceptibility of IA. Our results indicated TLR4 SNP rs11536889 may be a marker for IA risk, though the exact functional roles of TLR4 SNP rs11536889 in IA formation are still not very clear. PMID- 29754967 TI - White matter microstructural alterations in clinically isolated syndrome and multiple sclerosis. AB - This study aims to determine whether and how diffusion alteration occurs in the earliest stage of multiple sclerosis (MS) and the differences in diffusion metrics between CIS and MS by using the tract-based spatial statistics (TBSS) method based on diffusion tensor imaging (DTI). Thirty-six CIS patients (mean age +/- SD: 34.0 years +/- 12.6), 36 relapsing-remitting multiple sclerosis (RRMS) patients (mean age +/- SD: 35.0 years +/- 9.4) and 36 age- and gender-matched normal controls (NCs) were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (lambda1) and radial diffusivity (lambda23). In the CIS patients, TBSS analyses revealed diffusion alterations in a few white matter (WM) regions including the anterior thalamic radiation, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, body and splenium of the corpus callosum, internal capsule, external capsule, and cerebral peduncle. MS patients showed more widespread diffusion changes (decreased FA, increased lambda1, lambda23 and MD) than CIS. Exploratory analyses also revealed the possible associations between WM diffusion metrics and clinical variables (Expanded Disability Status Scale and disease duration) in the patients. This study provided imaging evidence for DTI abnormalities in CIS and MS and suggested that DTI can improve our knowledge of the path physiology of CIS and MS and clinical progression. PMID- 29754968 TI - Recurrent pseudoprogression in isocitrate dehydrogenase 1 mutant glioblastoma. AB - In a subset of glioblastoma (GBM) patients, the differentiation between tumor progression and tumor pseudoprogression (PsP) is challenging. This case describes a male patient suffering from isocitrate dehydrogenase 1 (IDH1) mutant GBM who demonstrated an increasing contrast-enhancing (CE) lesion on a cranial magnetic resonance imaging (cMRI) scan 8 months after radiochemotherapy. In accordance with the response assessment in neuro-oncology (RANO) criteria, the cMRI lesion was classified as recurrent tumor, although 18F-fluoroethyl-L-tyrosine positron emission tomography (18F-FET-PET) did not indicate vital tumor tissue. The patient underwent re-surgery but histopathology only revealed reactive and necrotic tissue, consistent with PsP. Nine weeks after complete resection of the CE lesion, a new lesion emerged that later regressed in the follow-up cMRI scans, thereby retrospectively establishing the diagnosis of recurrent PsP. PMID- 29754969 TI - Pathways to DRG-based hospital payment systems in Japan, Korea, and Thailand. AB - Countries in Asia are working towards achieving universal health coverage while ensuring improved quality of care. One element is controlling hospital costs through payment reforms. In this paper we review experiences in using Diagnosis Related Groups (DRG) based hospital payments in three Asian countries and ask if there is an "Asian way to DRGs". We focus first on technical issues and follow with a discussion of implementation challenges and policy questions. We reviewed the literature and worked as an expert team to investigate existing documentation from Japan, Republic of Korea, and Thailand. We reviewed the design of case-based payment systems, their experience with implementation, evidence about impact on service delivery, and lessons drawn for the Asian region. We found that countries must first establish adequate infrastructure, human resource capacity and information management systems. Capping of volumes and prices is sometimes essential along with a high degree of hospital autonomy. Rather than introduce a complete classification system in one stroke, these countries have phased in DRGs, in some cases with hospitals volunteering to participate as a first step (Korea), and in others using a blend of different units for hospital payment, including length of stay, and fee-for-service (Japan). Case-based payment systems are not a panacea. Their value is dependent on their design and implementation and the capacity of the health system. PMID- 29754971 TI - Stenotrophomonas maltophilia. AB - This infographic describes the key regulated traits of Stenotrophomonas maltophilia, important for beneficial plant interactions, and also its increasing incidence as a nosocomial and community-acquired infection. Stenotrophomonas maltophilia is a cosmopolitan and ubiquitous bacterium found in a range of environmental habitats, including extreme ones, although in nature it is mainly associated with plants. S. maltophilia fulfils important ecosystem functions in the sulfur and nitrogen cycles, in degradation of complex compounds and pollutants, and in promoti on of plant growth and health. Stenotrophomonas can also colonize extreme man-made niches in hospitals, space shuttles, and clean rooms. S. maltophilia has emerged as a global opportunistic human pathogen, which does not usually infect healthy hosts but is associated with high morbidity and mortality in severely immunocompromised and debilitated individuals. S. maltophilia can also be recovered from polymicrobial infections, most notably from the respiratory tract of cystic fibrosis patients. Close relatives of S. maltophilia, for example, S. rhizophila, provide a harmless alternative for biotechnological applications without human health risks. PMID- 29754970 TI - Cessation of breastfeeding in association with oxytocin administration and type of birth. A prospective cohort study. AB - BACKGROUND: Some studies have suggested an association between synthetic oxytocin administration and type of birth with the initiation and consolidation of breastfeeding. AIM: This study aimed to test whether oxytocin administration and type of birth are associated with cessation of exclusive breastfeeding at different periods. A second objective was to investigate whether the administered oxytocin dose is associated with cessation of exclusive breastfeeding. METHODS: We conducted a prospective cohort study (n=529) in a tertiary hospital. Only full term singleton pregnancies were included. Four groups were established based on the type of birth (vaginal or cesarean) and the intrapartum administration of oxytocin. Follow-up was performed to evaluate the consolidation of exclusive breastfeeding at 1, 3 and 6months. FINDINGS: During follow-up, the proportion of exclusive breastfeeding decreased in all groups. After adjusting for confounding variables, the group with cesarean birth without oxytocin (planned cesarean birth) had the highest risk of cessation of exclusive breastfeeding (odds ratio [95% confidence interval], 2.51 [1.53-4.12]). No association was found between the oxytocin dose administered during birth and puerperium period and the cessation of exclusive breastfeeding. CONCLUSION: Planned cesarean birth without oxytocin is associated with the cessation of exclusive breastfeeding at 1, 3 and 6months of life. It would be desirable to limit elective cesarean births to essentials as well as to give maximum support to encourage breastfeeding in this group of women. The dose of oxytocin given during birth and puerperium period is not associated with cessation of exclusive breastfeeding. PMID- 29754972 TI - Acquisition of tolerance to egg allergy in a child with repeated egg-induced acute pancreatitis. PMID- 29754973 TI - Generalized urticaria caused by ingestion of sweet potato cake. PMID- 29754974 TI - Implication of fraction of exhaled nitric oxide and blood eosinophil count in severe asthma. AB - BACKGROUND: Severe asthma is a complex disease with heterogeneous features and involves type 2 airway inflammation, including eosinophil accumulation. Surrogate biomarkers, fraction of exhaled nitric oxide (FeNO) and blood eosinophil count (b EOS), may predict eosinophilic airway inflammation. Here we investigated clinical characteristics of severe asthma phenotype using a combined analysis of FeNO and b-EOS. METHODS: This retrospective study examined clinical data of patients with severe asthma (N = 107; median age, 64 years) treated at Saitama Medical University Hospital from 2009 to 2016. Thresholds of FeNO and b-EOS for sputum eosinophil ratio >=2% were determined using receiver operating characteristic curve (ROC) analysis. Clinical characteristics were analyzed after classifying patients into four subgroups according to these thresholds. RESULTS: Of 39 induced sputum samples examined, ROC area under the curve for predicting sputum eosinophilia was 82.0% (p = 0.001) for b-EOS and 77.0% (p = 0.006) for FeNO at optimal cut-off values of >=300/MUL and >=25 ppb, respectively. The number of sensitized allergens was higher in the high FeNO/low b-EOS and high FeNO/high b EOS subgroups (p < 0.05). The prevalence of chronic sinusitis was higher in the low FeNO/high b-EOS and high FeNO/high b-EOS subgroups (p = 0.04). The high FeNO/high b-EOS subgroup included the largest proportion (approximately 40%) of patients experiencing frequent severe exacerbations. Both low FeNO/low b-EOS and high FeNO/low b-EOS subgroups showed less severe exacerbations. CONCLUSIONS: Combined evaluation of FeNO and b-EOS can identify patients with frequent exacerbations and stratify the appropriate therapy for type 2 inflammation predominant severe asthma. PMID- 29754975 TI - Endoscopic endonasal double flap technique for reconstruction of large anterior skull base defects: technical note. AB - INTRODUCTION: One of the main concerns in endoscopic endonasal approaches to the skull base has been the high incidence and morbidity associated with cerebrospinal fluid leaks. The introduction and routine use of vascularized flaps allowed a marked decrease in this complication followed by a great expansion in the indications and techniques used in endoscopic endonasal approaches, extending to defects from huge tumours and previously inaccessible areas of the skull base. OBJECTIVE: Describe the technique of performing endoscopic double flap multi layered reconstruction of the anterior skull base without craniotomy. METHODS: Step by step description of the endoscopic double flap technique (nasoseptal and pericranial vascularized flaps and fascia lata free graft) as used and illustrated in two patients with an olfactory groove meningioma who underwent an endoscopic approach. RESULTS: Both patients achieved a gross total resection: subsequent reconstruction of the anterior skull base was performed with the nasoseptal and pericranial flaps onlay and a fascia lata free graft inlay. Both patients showed an excellent recovery, no signs of cerebrospinal fluid leak, meningitis, flap necrosis, chronic meningeal or sinonasal inflammation or cerebral herniation having developed. CONCLUSION: This endoscopic double flap technique we have described is a viable, versatile and safe option for anterior skull base reconstructions, decreasing the incidence of complications in endoscopic endonasal approaches. PMID- 29754976 TI - Histopathological changes in parotid gland following submandibular gland failure: an experimental animal study. AB - INTRODUCTION: Submandibular glands are exposed to many effects due to diseases and therapeutic interventions. A study evaluating the effect of submandibular gland dysfunction on the parotid gland has not been presented in the literature. OBJECTIVE: The aim of this study was to evaluate the histopathological changes in the parotid gland following submandibular gland failure. METHODS: Three groups of seven randomly selected female New Zealand rabbits weighing 2500-3000g were studied. Unilateral and bilateral submandibular glands were removed in Groups 1 and 2, respectively. No procedure was performed in Group III, the control group. The parotid glands were removed 30 days later. Histological parameters were evaluated and graded between 0 (none) and 3 (severe). Differences between groups were compared using the Mann-Whitney U test. RESULTS: Mean mucus accumulation in acinar cells was 2.57+/-0.53 and 1.71+/-0.75 in Groups 1 and 2, respectively (p<0.05). This value was 0.57+/-0.53 in Group 3, which was significantly lower than in Groups 1 and 2 (p<0.05). Mean dilatation of the intercalated ducts' lumen was 1.28+/-0.48 and 1.57+/-0.53 in Groups 1 and 2, respectively (p>0.05). This value was 0.28+/-0.48 in Group 3, which was significantly lower than in Groups 1 and 2 (p<0.05). Mean mucus accumulation in the intercalated ducts' lumen was 2.00+/-0.81 and 1.00+/-0.57 in Groups 2 and 3, respectively (p<0.05). CONCLUSION: The findings of this study indicate that only 1 month after submandibular gland failure, the parotid glands exhibit significant changes. PMID- 29754977 TI - Use of the long-term quality of life assessment in the decision to indicate surgery in patients with chronic rhinosinusitis. AB - INTRODUCTION: Quality-of-life questionnaires have been used to support decision making in patients with chronic rhinosinusitis in the past decade. The choice of treatment in practice, however, also considers the patient's decision. OBJECTIVE: To assess the long-term quality of life of patients with chronic rhinosinusitis who decided to avoid surgery. METHODS: This is a prospective longitudinal study with a group of patients with chronic rhinosinusitis, with and without indication for surgery, with application of the questionnaire SNOT-22 in two periods: between 2011 and 2012 and between June and August 2016, via email. RESULTS: Data were collected from 42 patients, of which 13 presented indications for surgery and 29 were not indicated for surgery. The average quality of life score was 42.1 (+/-16.4) in the group with an indication for surgery and 40.6 (+/-23.4) in the group without this indication, p=0.84. All the patients were assessed by a single doctor with blinding in relation to the initial score. No differences were detected between the groups. The impact of the chronic rhinosinusitis was reduced even among the patients with the indication for surgery. Both groups scored over 40. CONCLUSION: This study can help predict the impact of the chronic rhinosinusitis over time and better adjust expectations with non-surgical treatment. PMID- 29754979 TI - Microbial contamination of liposomal amphotericin B nebuliser devices in lung transplant patients. PMID- 29754978 TI - Risk stratification using a novel liver functional reserve score of combination prothrombin time-international normalized ratio to albumin ratio and albumin in patients with hepatocellular carcinoma. AB - BACKGROUND: Liver function in patients with hepatocellular carcinoma is generally graded according to the Child-Pugh system; however, some variables in the Child Pugh grade are subjective. We developed a novel, objective score called the prothrombin time-international normalized ratio to albumin ratio. The aim of this study was to evaluate the prognostic value of this new score in patients with hepatocellular carcinoma after hepatic resection. METHODS: The study comprised 199 patients who underwent elective hepatic resection for hepatocellular carcinoma between January 2003 and December 2014. We investigated retrospectively the relation between prothrombin time-international normalized ratio to albumin ratio, disease-free survival, and overall survival and compared the value of liver functional reserve between prothrombin time-international normalized ratio to albumin ratio and Child-Pugh grade. RESULTS: The optimal cut-off level of the prothrombin time-international normalized ratio to albumin ratio was 0.288. In multivariate analysis, the independent and significant predictors of cancer recurrence consisted of hepatitis C virus infection (P = .043), preoperative retention rate of indocyanine green at 15 minutes >=15% (P = .039), the presence of multiple tumors (P = .001) or microvascular invasion (P < .001), and prothrombin time-international normalized ratio to albumin ratio >=0.288 (P = .022). The independent predictors of poor overall survival were microvascular invasion (P = .001) and prothrombin time-international normalized ratio to albumin ratio >=0.288 (P = .001). In patients with a high prothrombin time international normalized ratio to albumin ratio, pathologic liver cirrhosis (P < .001), postoperative ascites (P = .039), and postoperative liver failure (P = .040) were greater than for their counterparts. CONCLUSION: The prothrombin time international normalized ratio to albumin ratio may reflect liver function and may be a novel indicator of poor long-term outcome in patients with hepatocellular carcinoma after hepatic resection. PMID- 29754980 TI - Implant Survival and Patient-Reported Outcomes After Total Hip Arthroplasty in Young Patients. AB - BACKGROUND: Younger patients are undergoing total hip arthroplasty (THA) for various conditions that affect the hip joint. This study evaluates the implant survival and long-term patient-reported outcomes of THA in patients aged 35 years or younger. METHODS: Data were collected through a retrospective chart review, and follow-up surveys were conducted to determine implant survival and patient reported outcomes. Kaplan-Meier survival analysis was performed to evaluate implant survival, and the hip disability and osteoarthritis outcome score (HOOS) was used to describe patient-reported outcomes. Descriptive statistics were used to summarize baseline and follow-up data, and univariate and multivariate analyses were used to compare implant survival and patient-reported outcomes. RESULTS: This study included 400 patients (548 THAs). The average age at the time of surgery was 27 (range: 8-35) years, and the mean time to follow-up was 14 (range: 2-29.7) years. The 10- and 20-year implant survival was 87% and 61%, respectively. Implant survival differed based on primary diagnosis (P = .05), and it was significantly better in patients aged 25 years or older at the time of surgery, male patients, and patients with ceramic-on-ceramic or ceramic-on plastic implants (P < .05). Mean HOOS scores at follow-up were 86 for pain, 84 for symptoms, 86 for ADLs, and 77 for sports. All HOOS scores were significantly worse after revision THA (P < .01). CONCLUSION: Young patients have good implant survival and favorable long-term outcomes after THA. There are several predictors of implant survival and patient-reported outcomes after THA in young patients. PMID- 29754981 TI - Dialysis Patients Undergoing Total Knee Arthroplasty Have Significantly Increased Odds of Perioperative Adverse Events Independent of Demographic and Comorbidity Factors. AB - BACKGROUND: The prevalence of dialysis-dependent patients is growing, and an increasing number of these patients are being considered for total knee arthroplasty (TKA). Studies assessing the preoperative risk associated with TKA in this population are limited to institutional cohorts with small sample sizes or national inpatient databases that lack follow-up data. METHODS: The 2006-2015 National Surgical Quality Improvement Program databases were queried for adult patients undergoing elective TKA. Differences in 30-day any/severe/minor adverse event, need for reoperation, readmission, and mortality were compared for dialysis-dependent and nondialysis TKA patients using risk-adjusted logistic regression. To account for the smaller number of dialysis patients and variations in study populations, coarsened exact matching was used. The proportion of adverse events that occurred before vs after discharge was also assessed. RESULTS: In total, 250 dialysis-dependent patients and 163,560 nondialysis patients met inclusion criteria. After controlling for patient demographics (age, sex, body mass index, functional status) and overall health (American Society of Anesthesiologists class), matched analysis revealed dialysis-dependent patients to be significantly more likely to experience any adverse event (odds ratio = 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), severe adverse event (odds ratio = 2.49; 95% CI, 1.61-3.84; P < .001), reoperation (odds ratio = 2.38; 95% CI, 1.19-4.75; P = .014), readmission (odds ratio = 2.32; 95% CI, 1.47-3.66; P = .001), and mortality (odds ratio = 6.71; 95% CI, 2.99-22.50; P = .002). The majority of adverse outcomes occurred postdischarge. CONCLUSION: Independent of patient demographics and overall health (American Society of Anesthesiologists), patients undergoing dialysis before TKA are significantly more likely to experience 30-day adverse outcomes than matched nondialysis cohorts. Preoperative evaluation of bone health status and management of medical treatment are warranted in this fragile population. Cautious surgical planning, patient counseling, and heightened surveillance are necessitated throughout their perioperative period and postoperative recovery plans may need to be different from nondialysis counterparts. Furthermore, hospitals and physicians must take these increased risks into account when working on bundle payment reimbursement strategies and resource allocation. LEVEL OF EVIDENCE: 3. PMID- 29754982 TI - Computed Tomography Techniques Help Understand Wear Patterns in Retrieved Total Knee Arthroplasty. AB - BACKGROUND: Suboptimal total knee arthroplasty (TKA) position of both femoral and tibial components is thought to be linked with poor clinical outcomes, polyethylene wear and the "unexplained" painful knee arthroplasty. The aim of this study was to better understand the effect of implant orientation on knee implant performance. METHODS: We analyzed 30 retrieved contemporary TKA implants. Implant positioning measurements in the coronal plane were made prior to revision using a diagnostic algorithm, based on 3D computed tomography (CT) images. Each retrieved polyethylene component was imaged using a micro-CT scanner and a high resolution computational 3D model of each component was digitally reconstructed. The difference in thickness between medial and lateral components was calculated. Statistical analysis was performed to investigate the association between component positioning and damage patterns. RESULTS: We found a significant correlation between both the tibiofemoral and femoral angles and difference in thickness between polyethylene compartments: varus angulations were strongly associated with thinner medial compartments, whilst valgus angulations were associated with thinner lateral compartments. Moreover, suboptimal tibiofemoral orientations and tibial component angulations were associated to greater differences in thickness between polyethylene compartments. CONCLUSION: Our study is the first to compare accurate 3D CT measurements of prerevision TKA positioning in the coronal plane with postrevision retrieval analysis from innovative, accurate and highly reliable micro-CT-based method. Our results demonstrate the impact of component positioning on polyethylene damage and helps understanding of the in vivo performance of these implants. LEVEL OF EVIDENCE: III. PMID- 29754983 TI - Cognitive impairment in intensive care unit patients: A pilot mixed-methods feasibility study exploring incidence and experiences for recovering patients. AB - BACKGROUND: Despite improvements in survival after critical illness and intensive care unit (ICU) treatment, some recovering patients still face ongoing challenges. There are few investigations exploring the incidence, risk factors, and trajectory for cognitive impairment (CI) in former ICU patients in Australia. OBJECTIVES: To test the feasibility of a study protocol designed to ascertain the incidence and impact of CI during recovery from a critical illness. METHODS: We conducted a mixed-methods longitudinal single-centre pilot study. Participants were adult patients mechanically ventilated for >=48 h. Cognitive function was assessed during hospitalisation and at 1 week, 2 months, and 6 months after hospital discharge, using the Montreal Cognitive Assessment instrument. Factors potentially affecting cognitive function were also collected, including demographic and clinical variables and fatigue, frailty, and muscle strength. Semistructured interviews were conducted to further explore participants' experiences during recovery. RESULTS: We screened 2068 patients (10% met the inclusion criteria). Participants (n = 20) were mostly male with a mean age 61.9 years and a median of 4 days of mechanical ventilation. Data collection was complete for 14 and 11 participants at 2 months and 6 months, respectively. Pre illness patients were not cognitively impaired; one patient had delirium in ICU. The proportion of patients with CI ranged from 80% (17/18) while in hospital to 35% (5/14) at 6 months. Participants were challenged by fatigue and sleep disruption during recovery but were not particularly concerned about CI. CONCLUSIONS: Recruitment in ICU was challenging as few patients received prolonged mechanical ventilation. The protocol was feasible, but some attrition was noted. A significant proportion of patients had mild CI, largely confined to recall, and language cognitive domains; quantitative findings were supported by interview findings. Further investigations are required to ascertain the most appropriate inclusion criteria to enable identification of those at highest risk of CI. PMID- 29754984 TI - Donor lymphocyte infusion in myeloid disorders. AB - A number of modalities including both pharmaceutical and cell-based treatments have long been tested and developed to prevent and treat relapses after allogeneic stem cell transplantation (allo-HSCT). The ability of donor T cells to recognize antigenic structures on leukemic cell surfaces and destroy them is a well-known fact. Based on this fact, the idea of using donor T cells to contribute to the development of adoptive immunotherapy has emerged. Donor lymphocytes are easy to obtain and donor lymphocyte infusions (DLI) have a simple rational while this treatment modality is an effective example of cellular therapy. The group of chronic myeloid leukemia patients who are more likely to benefit from DLI include: a) patients in the chronic phase of hematologic relapse and b) patients with molecular/cytogenetic relapse. DLI appear to be an appropriate treatment option to be used in combination with conventional chemotherapy or hypomethylating agents in the treatment of post-allo-HSCT relapse for acute myeloid leukemia and myelodysplastic syndrome, if:) the burden of tumor is low b) the relapse is at a molecular level rather than an overt hematologic relapse c) the patient has favorable cytogenetic characteristics d) time interval between transplantation and relapse is relatively longer (>5 months) e) response could be obtained after salvage therapies. In the event that minimal residual disease (MRD) or increasing mixed chimerism is detected, prompt administration of DLI for prophylactic purposes without waiting for a manifest relapse, was found to be effective in inducing a full donor chimerism and overcoming MRD and eventually preventing a manifest relapse. PMID- 29754985 TI - Response: scoring of mosaic embryos after preimplantation genetic testing - the rollercoaster ride between fear, hope and embryo wastage. PMID- 29754986 TI - The microbiome of Haemaphysalis lemuris (Acari: Ixodidae), a possible vector of pathogens of endangered lemur species in Madagascar. AB - Lemurs are primate species that are endemic to Madagascar. At present, about 90% of lemur species are endangered, and 5 species are among the 25 most endangered primates worldwide. Health status is a major factor impacting the viability of wild populations of many endangered species including lemurs. Given this context, we analyzed the microbiome of 24 specimens of Haemaphysalis lemuris, the most common tick parasitizing lemurs in their native habitats. Ticks were collected from 6 lemur species and microbiomes analyzed using next-generation sequencing. Our results show that the H. lemuris microbiome is highly diverse, including over 500 taxa, 267 of which were identified to genus level. Analysis of the microbiome also shows that there is a distinct "host" (lemur species) component when explaining the differences among and between microbial communities of H. lemuris. This "host" component seems to overwhelm any "locality" (geographic origin of the sample) component. In addition to the microbiome data, targeted PCR was used to test for the presence of three pathogens recently detected in the blood of wild lemurs: Borrelia sp., Candidatus Neoehrlichia sp., and Babesia sp. Overall, the presence of DNA of Rickettsia spp., Bartonella spp., Francisella spp., and a Babesia sp., in H. lemuris, is consistent with the hypothesis that these ectoparasites may act as vector for these pathogens. Further studies assessing vector competence are needed to confirm this hypothesis. PMID- 29754987 TI - A statewide effort to reduce high-dose opioid prescribing through coordinated care organizations. AB - BACKGROUND: Oregon's Medicaid program is delivered through 16 Coordinated Care Organizations (CCOs) participating in a statewide performance improvement program to reduce high-dose opioid prescribing. CCOs were allowed flexibility to develop their own dose targets and any policies, trainings, guidelines, and/or materials to meet these targets. In this study, we characterize CCO strategies to reduce high-dose opioid prescribing across the 16 CCOs. METHODS: We reviewed relevant CCO documents and conducted semi-structured interviews with CCO administrators to acquire opioid-related policies, practices, timelines and contextual factors. We applied a systematic coding procedure to develop a comprehensive description of each CCO's strategy. We used administrative data from the state to summarize contextual utilization data for each CCO. RESULTS: Most CCOs selected a target daily morphine milligram equivalent (MME) dose of 90 mg. Sixteen issued quantity limits related to dose, eight restricted specific drug formulations (short-acting or long-acting), and 11 allowed for time-limited taper plan periods for patients over threshold. Many CCOs also employed provider trainings, feedback reports, and/or onsite technical assistance. Other innovations included incentive measures, electronic health record alerts, and toolkits with materials on local alternative therapy resources and strategies for patient communication. CCOs leveraging collaborations with regional partners appeared to mount a greater intensity of interventions than independently operating CCOs. CONCLUSIONS: CCOs developed a diversity of interventions to confront high-risk opioid prescribing within their organization. As healthcare systems mount interventions to reduce risky opioid prescribing, it is critical to carefully describe these activities and examine their impact on process and health outcomes. PMID- 29754988 TI - Bioremediation of petroleum-contaminated soil using aged refuse from landfills. AB - This study explored the effects and mechanisms of petroleum-contaminated soil bioremediation using aged refuse (AR) from landfills. Three treatments of petroleum-contaminated soil (47.28 mg.g-1) amended with AR, sterilized aged refuse (SAR) and petroleum-contaminated soil only (as a control) were tested. During 98 days of incubation, changes in soil physicochemical properties, residual total petroleum hydrocarbon (TPH), biodegradation kinetics, enzyme activities and the microbial community were investigated. The results demonstrated that AR was an effective soil conditioner and biostimulation agent that could comprehensively improve the quality of petroleum-contaminated soil and promote microbial growth, with an 74.64% TPH removal rate, 22.36 day half-life for SAR treatment, compared with the control (half-life: 138.63 days; TPH removal rate: 22.40%). In addition, the petroleum-degrading bacteria isolation results demonstrated that AR was also a petroleum-degrading microbial agent containing abundant microorganisms. AR addition significantly improved both the biotic and abiotic conditions of petroleum-contaminated soil without other additives. The cooperation of conditioner addition, biostimulation and bioaugmentation in AR treatment led to better bioremediation effects (half-life: 13.86 days; TPH removal rate: 89.83%). In conclusion, AR amendment is a cost-effective, easy-to use method facilitating in situ large-scale application while simultaneously recycling huge amounts of AR from landfills. PMID- 29754989 TI - The Brain Health Registry: An internet-based platform for recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies. AB - INTRODUCTION: Recruitment, assessment, and longitudinal monitoring of participants for neuroscience studies and clinical trials limit the development of new treatments. Widespread Internet use allows data capture from participants in an unsupervised setting. The Brain Health Registry, a website and online registry, collects data from participants and their study partners. METHODS: The Brain Health Registry obtains self and study partner report questionnaires and neuropsychological data, including the Cogstate Brief Battery, Lumos Labs Neurocognitive Performance Test, and MemTrax Memory Test. Participants provide informed consent before participation. RESULTS: Baseline and longitudinal data were obtained from nearly 57,000 and 28,000 participants, respectively. Over 18,800 participants were referred to, and nearly 1800 were enrolled in, clinical Alzheimer's disease and aging studies, including five observational studies and seven intervention trials. DISCUSSION: Online assessments of participants and study partners provide useful information at relatively low cost for neuroscience studies and clinical trials and may ultimately be used in routine clinical practice. PMID- 29754991 TI - Prolonged exposure to job strain and long-term mental disorders. PMID- 29754990 TI - The role of job strain in understanding midlife common mental disorder: a national birth cohort study. AB - BACKGROUND: Long-standing concerns exist about reverse causation and residual confounding in the prospective association between job strain and risk of future common mental disorders. We aimed to address these concerns through analysis of data collected in the UK National Child Development Study, a large British cohort study. METHODS: Data from the National Child Development Study (n=6870) were analysed by use of multivariate logistic regression to investigate the prospective association between job strain variables at age 45 years and risk of future common mental disorders at age 50 years, controlling for lifetime psychiatric history and a range of other possible confounding variables across the lifecourse. Population attributable fractions were calculated to estimate the public health effect of job strain on midlife mental health. FINDINGS: In the final model, adjusted for all measured confounders, high job demands (odds ratio 1.70, 95% CI 1.25-2.32; p=0.0008), low job control (1.89, 1.29-2.77; p=0.0010), and high job strain (2.22, 1.59-3.09; p<0.0001) remained significant independent predictors of future onset of common mental disorder. If causality is assumed, our findings suggest that 14% of new cases of common mental disorder could have been prevented through elimination of high job strain (population attributable fraction 0.14, 0.06-0.20). INTERPRETATION: High job strain appears to independently affect the risk of future common mental disorders in midlife. These findings suggest that modifiable work-related risk factors might be an important target in efforts to reduce the prevalence of common mental disorders. FUNDING: iCare Foundation and Mental Health Branch, NSW Health. PMID- 29754993 TI - Topography-Guided LASIK versus Small Incision Lenticule Extraction: Long-term Refractive and Quality of Vision Outcomes. PMID- 29754992 TI - The utility of routine clinical 12-lead ECG in assessing eligibility for subcutaneous implantable cardioverter defibrillator. AB - INTRODUCTION: The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a life-saving device. Recording of a specialized 3-lead electrocardiogram (ECG) is required for S-ICD eligibility assessment. The goals of this study were: (1) evaluate the effect of ECG filtering on S-ICD eligibility, and (2) simplify S-ICD eligibility assessment by development of an S-ICD ineligibility prediction tool, which utilizes the widely available routine 12-lead ECG. METHODS AND RESULTS: Prospective cross-sectional study participants [n = 68; 54% male; 94% white, with wide ranges of age (18-81 y), body mass index (19-53), QRS duration (66-150 ms), and left ventricular ejection fraction (37-77%)] underwent 12-lead supine, 3-lead supine and standing ECG recording. All 3-lead ECG recordings were assessed using the standard S-ICD pre-implantation ECG morphology screening. Backward, stepwise, logistic regression was used to build a model for 12-lead prediction of S-ICD eligibility. Select electrocardiogram waves and complexes: QRS, R-, S, and T amplitudes on all 12 leads, averaged QT interval, QRS duration, and R/T ratio in the lead with the largest T wave (R/Tmax) were included as predictors. The effect of ECG filtering on ECG morphology was evaluated. A total of 9 participants (13%) failed S-ICD screening prior to filtering. Filtering at 3-40 Hz, similar to the S ICD default, reduced S-ICD ineligibility to 4%. A regression model that included RII, SII-aVL, TI, II, aVL, aVF, V3-V6, and R/Tmax perfectly predicted S-ICD eligibility, with an Area Under the Receiver Operating Characteristic Curve of 1.0. CONCLUSION: Routine clinical 12-lead ECG can be used to predict S-ICD eligibility. ECG filtering may improve S-ICD eligibility. PMID- 29754994 TI - Corrigendum to "The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer" [Canc. Lett. 423 (2018) 36-46]. PMID- 29754995 TI - Additive Benefit of Radiomics Over Size Alone in the Distinction Between Benign Lesions and Luminal A Cancers on a Large Clinical Breast MRI Dataset. AB - RATIONALE AND OBJECTIVES: The objective of this study was to demonstrate improvement in distinguishing between benign lesions and luminal A breast cancers in a large clinical breast magnetic resonance imaging database by using quantitative radiomics over maximum linear size alone. MATERIALS AND METHODS: In this retrospective study, 212 benign lesions and 296 luminal A breast cancers were automatically segmented from dynamic contrast-enhanced breast magnetic resonance images. Thirty-eight radiomic features were extracted. Tenfold cross validation was performed to assess the ability to distinguish between lesions and cancers using maximum linear size alone and lesion signatures obtained with stepwise feature selection and a linear discriminant analysis classifier including and excluding size features. Area under the receiver operating characteristic curve (AUC) was used as the figure of merit. RESULTS: For maximum linear size alone, AUC and 95% confidence interval was 0.797 (0.754, 0.835) compared to 0.846 (0.808, 0.875) (P = .005) and 0.848 (0.811, 0.880) (P = .003) for lesion signature feature selection protocols including and excluding size features, respectively. The irregularity feature was chosen in 9 of 10 folds and in all folds when size features were included and excluded, respectively. AUC for the radiomic signature using feature selection from all features was statistically equivalent to using feature selection from all features excluding size features, within an equivalence margin of 2%. CONCLUSIONS: Inclusion of multiple radiomic features, automatically extracted from magnetic resonance images, in a lesion signature significantly improved the ability to distinguish between benign lesions and luminal A breast cancers, compared to using maximum linear size alone. The radiomic feature of irregularity appears to play an important but not a solitary role within the context of feature selection and computer-aided diagnosis. PMID- 29754997 TI - Patient-Friendly Summary of the ACR Appropriateness Criteria: Monitoring Response to Neoadjuvant Systemic Therapy for Breast Cancer. PMID- 29754996 TI - DCE-MRI in Human Gliomas: A Surrogate for Assessment of Invasive Hypoxia Marker HIF-1Alpha Based on MRI-Neuronavigation Stereotactic Biopsies. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to correlate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters with data from a specific marker of hypoxia, hypoxia-inducible factor 1alpha (HIF-1alpha), in human gliomas on a point-to-point basis by using coregistered magnetic resonance imaging and frameless stereotactic biopsies. MATERIALS AND METHODS: Thirty-four patients with treatment-naive gliomas underwent DCE, axial T1-weighted, T2 weighted, T2-weighted fluid acquisition of inversion recovery, and three dimensional T1-weighted brain volume with gadolinium contrast enhancement sequences on a 3.0-T magnetic resonance scanner before stereotactic surgery. Quantitative perfusion indices such as endothelial transfer constant, fractional extravascular extracellular space volume, fractional plasma volume, and reflux rate were measured at corresponding stereotactic biopsy sites. Each sample was considered an independent measurement, and its histology grade was diagnosed. HIF 1alpha expression was quantified from the point-to-point biopsy tissues. Analyses of receiver operating characteristic curves were done for HIF-1alpha to discriminate different grades of glioma. To look for correlations between immunohistochemical parameters and DCE indices, Spearman's correlation coefficient was used. RESULTS: Seventy biopsy samples from 34 subjects were included in the analysis. Mean immunoreactivity scores of HIF-1alpha were 2.75 +/ 1.11 for grade II (n = 24), 6.20 +/- 2.33 for grade III (n = 20), and 10.46 +/- 2.42 for grade IV (n = 26). HIF-1alpha showed very good-to-excellent accuracy in discriminating grade II from III, III from IV, and II from IV (area under the curve = 0.838, 0.862, and 0.994, respectively). Endothelial transfer constant and fractional extravascular extracellular space volume showed a significantly positive correlation with HIF-1alpha expression (r = 0.686, P < .001; r = 0.549, P < .001, respectively). CONCLUSION: Our study demonstrated HIF-1alpha to be a significant predictor of different grades of gliomas with high sensitivity and specificity. DCE-MRI is a useful, noninvasive imaging tool for quantitative evaluation of HIF-1alpha, and its parameters may be used as a surrogate for HIF 1alpha expression. PMID- 29754998 TI - Changing Culture. PMID- 29754999 TI - Preoccupied With Work. PMID- 29755000 TI - Democracy and Burnout: The ACR's Special Role. PMID- 29755001 TI - Understanding Why Patients No-Show: Observations of 2.9 Million Outpatient Imaging Visits Over 16 Years. AB - PURPOSE: To understand why patients "no-show" for imaging appointments, and to provide new insights for improving resource utilization. MATERIALS AND METHODS: We conducted a retrospective analysis of nearly 2.9 million outpatient examinations in our radiology information system from 2000 to 2015 at our multihospital academic institution. No-show visits were identified by the "reason code" entry "NOSHOW" in our radiology information system. We restricted data to radiography, CT, mammography, MRI, ultrasound, and nuclear medicine examinations that included all studied variables. These variables included modality, patient age, appointment time, day of week, and scheduling lead time. Multivariate logistic regression was used to identify factors associated with no-show visits. RESULTS: Out of 2,893,626 patient visits that met our inclusion criteria, there were 94,096 no-shows during the 16-year period. Rates of no-show visits varied from 3.36% in 2000 to 2.26% in 2015. The effect size for no-shows was strongest for modality and scheduling lead time. Mammography had the highest modality no show visit rate of 6.99% (odds ratio [OR] 5.38, P < .001) compared with the lowest modality rate of 1.25% in radiography. Scheduling lead time greater than 6 months was associated with more no-show visits than scheduling within 1 week (OR 3.18, P < .001). Patients 60 years and older were less likely to miss imaging appointments than patients under 40 (OR 0.70, P < .001). Mondays and Saturdays had significantly higher rates of no-show than Sundays (OR 1.52 and 1.51, P < .001). CONCLUSION: Modality type and scheduling lead time were the most predictive factors of no-show. This may be used to guide new interventions such as targeted reminders and flexible scheduling. PMID- 29755002 TI - Radiology Report Readability: An Opportunity to Improve Patient Communication. PMID- 29755003 TI - Populations under siege and in prison require investment from Syria's national tuberculosis programme. PMID- 29755004 TI - I know why you voted for Trump: (Over)inferring motives based on choice. AB - People often speculate about why others make the choices they do. This paper investigates how such inferences are formed as a function of what is chosen. Specifically, when observers encounter someone else's choice (e.g., of political candidate), they use the chosen option's attribute values (e.g., a candidate's specific stance on a policy issue) to infer the importance of that attribute (e.g., the policy issue) to the decision-maker. Consequently, when a chosen option has an attribute whose value is extreme (e.g., an extreme policy stance), observers infer-sometimes incorrectly-that this attribute disproportionately motivated the decision-maker's choice. Seven studies demonstrate how observers use an attribute's value to infer its weight-the value-weight heuristic-and identify the role of perceived diagnosticity: more extreme attribute values give observers the subjective sense that they know more about a decision-maker's preferences, and in turn, increase the attribute's perceived importance. The paper explores how this heuristic can produce erroneous inferences and influence broader beliefs about decision-makers. PMID- 29755005 TI - Assessing the Financial Benefits of Faster Development Times: The Case of Single source Versus Multi-vendor Outsourced Biopharmaceutical Manufacturing. AB - PURPOSE: The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns. METHODS: Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case. FINDINGS: The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million). IMPLICATIONS: For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees. PMID- 29755006 TI - Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI RADS (Vesical Imaging-Reporting And Data System). AB - CONTEXT: Management of bladder cancer (BC) is primarily driven by stage, grade, and biological potential. Knowledge of each is derived using clinical, histopathological, and radiological investigations. This multimodal approach reduces the risk of error from one particular test, but may present a staging dilemma when results conflict. Multiparametric magnetic resonance imaging (mpMRI) may improve patient care through imaging of the bladder with better resolution of the tissue planes than computed tomography and without radiation exposure. OBJECTIVE: To define a standardized approach to imaging and reporting mpMRI for BC, by developing a VI-RADS score. EVIDENCE ACQUISITION: We created VI-RADS (Vesical Imaging-Reporting And Data System) through consensus using existing literature. EVIDENCE SYNTHESIS: We describe standard imaging protocols and reporting criteria (including size, location, multiplicity, and morphology) for bladder mpMRI. We propose a five-point VI-RADS score, derived using T2-weighted MRI, diffusion-weighted imaging, and dynamic contrast enhancement, which suggests the risks of muscle invasion. We include sample images used to understand VI RADS. CONCLUSIONS: We hope that VI-RADS will standardize reporting, facilitate comparisons between patients, and in future years, will be tested and refined if necessary. While we do not advocate mpMRI for all patients with BC, this imaging may compliment pathology or reduce radiation-based imaging. Bladder mpMRI may be most useful in patients with non-muscle-invasive cancers, in expediting radical treatment or for determining response to bladder-sparing approaches. PATIENT SUMMARY: Magnetic resonance imaging (MRI) scans for bladder cancer are becoming more common and may provide accurate information that helps improve patient care. Here, we describe a standardized reporting criterion for bladder MRI. This should improve communication between doctors and allow better comparisons between patients. PMID- 29755007 TI - Structure of the alimentary tract in the Atlantic mudskipper Periophthalmus barbarus (Gobiidae: Oxudercinae): anatomical, histological and ultrastructural studies. AB - The alimentary tract of oxudercine gobies is characterized by a lack of an anatomically distinct stomach, owing to which they are classified as stomachless. Since the environment, food requirements, and feeding habits have a significant impact on the anatomy of the alimentary tract of fish, it was assumed that predominantly carnivorous, semi-terrestrial mudskippers would have a stomach. In order to verify this hypothesis, anatomical, histological, histochemical and ultrastructural analysis of the alimentary tract of the Atlantic mudskipper Periophthalmus barbarus was performed. The results revealed that despite a lack of clear anatomical distinction within the alimentary tract, there were four well distinguished sections visible at the histological level: oesophagus, stomach, intestine, and rectum. The division was enhanced by the presence of a pyloric sphincter and an ileorectal valve. The stomach contained tubular glands composed of oxynticopeptic cells. Gland cells had pepsinogen granules and a well-developed tubulovesicular network of smooth membranes, which indicates the secretion of gastric juice. The presence of neutral mucus in the apical region of surface epithelial cells as protection against hydrochloric acid as well as the presence of active pepsin also confirm gastric function. However, low pepsin activity seems to implies low protein digestion. The results of this study indicate that the Atlantic mudskipper P. barbarus has a functional stomach. PMID- 29755008 TI - COVERING THE COVER. PMID- 29755009 TI - Toward a new ultrasound-based imaging method for the diagnosis of acute pancreatitis: A preliminary study suggesting that it may be feasible. PMID- 29755010 TI - Immunosuppressive therapy and the risk of hepatitis B reactivation: Consensus report. AB - This consensus report includes expert opinions and recommendations regarding the screening, and if necessary, the follow-up, prophylaxis, and treatment of hepatitis B before the treatment in patients who will undergo immunosuppressive therapy due to an emergency risk of hepatitis B reactivation. To increase awareness regarding the risk of hepatitis B reactivation in immunosuppressive patients, academicians from several university health research and training centers across Turkey came together and discussed the importance of the subject, current status, and issues in accordance with the current literature data and presented solutions. PMID- 29755011 TI - Autophagy and liver cancer. AB - Autophagy is a key biological phenomenon conserved from yeast to mammals. Under basal conditions, activation of autophagy leads to the protein degradation as well as damaged organelles for maintaining cellular homeostasis. Deregulation of autophagy has been identified as a key mechanism contributing to the pathogenesis and progression of several liver diseases, including hepatocellular carcinoma (HCC), one of the most common and mortal types of cancer. Currently used treatment strategies in patients with HCC result in variable success rates. Therefore, novel early diagnosis and treatment techniques should be developed. Manipulation of autophagy may improve responses of cancer cell to treatments and provide novel targeted therapy options for HCC. In this review, we summarized how our understanding of autophagy-cell death connection may have an impact on HCC therapy. PMID- 29755012 TI - Association of a single nucleotide polymorphism in the TLR2 gene (rs3804099), but not in the TLR4 gene (rs4986790), with Helicobacter pylori infection and peptic ulcer. AB - BACKGROUND/AIMS: Toll-like receptors (TLRs), particularly TLR2 and TLR4, take part in elicitation of immune responses against Helicobacter pylori (H. pylori). This study aimed to investigate the relationship between single nucleotide polymorphisms (SNP) rs3804099 in the TLR2 gene and rs4986790 in the TLR4 gene with H. pylori infection and peptic ulcer (PU). MATERIALS AND METHODS: Blood specimens were obtained from 350 individuals, including 100 H. pylori-infected patients with PU, 125 H. pylori-infected asymptomatic subjects (AS), and 125 non infected healthy subjects (NHS). The DNA was extracted, and the SNPs were determined using ARMS-PCR method. RESULTS: The frequency of CT genotype at TLR2 SNP rs3804099 in both the PU and AS groups was significantly higher than in the NHS group (p<0.05). In total H. pylori-infected individuals (PU+AS), the frequency of the CT genotype at rs3804099 was also significantly higher than in the NHS group (p<0.005). The frequency of the CC genotype at rs3804099 in PU+AS was markedly lower than in the NHS group (p=0.066). PU patients carried CT genotype more frequently than total healthy individuals (AS+NHS) (p<0.03). The distribution of the TT genotype was lower, whereas the frequency of the CT genotype was higher in AS individuals infected with CagA+ strains than those infected with CagA- strains (p<0.03). No significant differences were found among the PU, AS, and NHS groups regarding the genetic differences at rs4986790 in the TLR4 gene. CONCLUSION: These results provide evidence regarding the association of the rs3804099 in the TLR2 gene with H. pylori infection and PU. The rs3804099 may affect vulnerability to H. pylori infection, particularly to CagA+ strains of bacteria. PMID- 29755013 TI - Screening for latent tuberculosis infection in patients with inflammatory bowel disease: Can interferon-gamma release assays replace the tuberculin skin test? AB - BACKGROUND/AIMS: Screening for latent tuberculosis infection is mandatory before starting anti-tumor necrosis factor therapy. New assays based on interferon-gamma (IFN-gamma) release have recently become available and may be more accurate. The aim of this study was to compare QuantiFERON-TB and tuberculin skin test in screening for latent infection in patients with inflammatory bowel disease. MATERIALS AND METHODS: We prospectively screened 138 patients with inflammatory bowel disease for latent tuberculosis infection with chest X-ray, tuberculin skin test, and a third-generation QuantiFERON-TB test. The association of the results in both tests with immunosuppression or inflammatory activity was determined by logistic regression. RESULTS: The tuberculin skin test and QuantiFERON-TB were positive in 21.7% and 24.6% of the patients, respectively. Overall, 71% patients were receiving immunosuppressants. Concordance between the two tests was moderate (kappa=0.59; 95% confidence interval (CI), 0.43-0.75) and was higher in immunosuppressant-naive patients (kappa=0.75; 95% CI, 0.52-0.97) than in immunosuppressed patients (kappa=0.51; 95% CI, 0.30-0.72). In both the tests, disease activity and receiving immunosuppression were not associated with the test results. Nevertheless, QuantiFERON-TB was negatively influenced with two or more immunosuppressive drugs. CONCLUSION: Concordance between the two tests was moderate, and it appears lower with immunosuppression. QuantiFERON-TB alone may be appropriate in immunosuppressant-naive patients. Both tests should be considered in immunosuppressed patients. PMID- 29755015 TI - Assessing the outcome of patients with liver cirrhosis during hospital stay: A comparison of lymphocyte/monocyte ratio with MELD and Child-Pugh scores. AB - BACKGROUND/AIMS: Developing an easy and reliable score for evaluating the prognosis of patients with liver cirrhosis has always been challenging for hepatologists. This study aimed to assess the lymphocyte-to-monocyte ratio (LMR) in comparison with the Model for End-Stage Liver Disease (MELD) and Child-Pugh (CP) scores for determining the outcomes in these patients during hospital stay. MATERIALS AND METHODS: Receiver operator characteristic (ROC) curve was used to assess the efficacy of three parameters (LMR and MELD and CP scores) in determining the outcomes in 182 patients with cirrhosis. The cutoff values were calculated using Youden index, and the area under the curves (AUCs) was also compared. The associations of these scores between the survived and nonsurvived group was studied. The predictors of patient survival were determined using logistic regression analysis. RESULTS: The mean values for LMR and MELD and CP scores were 6.23, 11.62, and 9.32, respectively. MELD and CP were positively correlated with each other. LMR was negatively correlated to both MELD and CP scores (p=0.04). Pairwise comparison showed that the difference between the AUCs of MELD and LMR was not statistically significant (0.958 vs. 0.807; p > 0.05). With the LMR cutoff value of > 3.31 (sensitivity, 80%; specificity, 74.83%), patients were segregated into low and high LMR groups. MELD and CP scores were significantly higher in the low LMR group than in the high LMR group (p=0.000). Patients in the low LMR group showed decreased survival than those in the high LMR group (p=0.000). The nonsurvived group had lower LMR and higher MELD and CP scores than those of the survived group (p=0.000). Logistic regression model showed MELD (p=0.000), CP score (p=0.010), 1/LMR (p=0.004), alanine aminotransferase (ALT) level (p=0.010), and international normalized ratio (INR; p=0.043) as predictors of outcome of these patients. CONCLUSION: LMR can be used to determine the outcome of patients during hospital stay, because it is easy to calculate and can be interpreted with efficacy nearly equal to those of MELD and CP scores. PMID- 29755016 TI - Prevalence of advanced colorectal neoplasm is higher in liver transplant recipients. AB - BACKGROUND/AIMS: Patients with liver transplantation are at increased risk of developing new malignancy because of the prolonged immunosuppression after transplantation. The aims of this study were to investigate whether advanced colorectal neoplasms occurs more in liver transplant recipients compared to healthy individuals and to evaluate the effect of immunosuppression on advanced colorectal neoplasia. MATERIALS AND METHODS: This was a retrospective, single centered, case-control study. We reviewed 348 liver transplant patients who had undergone a colonoscopy after liver transplantation from 1991 to 2012. Healthy controls from asymptomatic individuals who had undergone colonoscopy for screening purposes were randomly selected and reviewed. RESULTS: Advanced colorectal neoplasms were identified in 17 of the 348 patients (4.9%). The risk of advanced colorectal neoplasia was 3.6 times greater in liver transplant patients (odds ratio [OR] 3.578; 95% confidence interval [CI] 1.578-8.115; p=0.001). The risk of developing colon cancer was 8.4 times higher in transplant patients (OR 8.416; 95% CI 1.808-39.172; p=0.001). CONCLUSION: Liver transplant recipients were at a high risk of colorectal cancer. Therefore, colonoscopy surveillance after liver transplantation is recommended. Immunosuppressive therapy could facilitate carcinogenesis. PMID- 29755014 TI - Diagnosis of cirrhosis in patients with chronic hepatitis C genotype 4: Role of ABCB11 genotype polymorphism and plasma bile acid levels. AB - BACKGROUND/AIMS: Chronic hepatitis C (CHC)-related mortality generally results from cirrhosis and subsequent complications. We aimed to investigate the potential role of plasma bile acid levels and ABCB11 1331T > C (V444A, rs2287622) (ATP-binding cassette subfamily B, member 11) gene polymorphism in fibrosis prediction in CHC genotype 4 patients. MATERIALS AND METHODS: This case control study included 85 healthy control and the following 225 subjects: 170 adult patients infected with hepatitis C virus (HCV) and categorized into three groups according to liver biopsy; no fibrosis group (F0) (n=33), early fibrosis group (F1-F2) (n=61), and advanced fibrosis group (F3-F4) (n=76). Fasting bile acid levels, hepatitis C virus (HCV) genotyping, and ABCB11 1331T > C gene polymorphism were assessed. RESULTS: The frequency of the variant homozygote genotype CC in advanced fibrosis was significantly higher than that in early fibrosis (48.7% vs. 36.1%) (odd ratio, OR =2.58; 95% confidence interval, CI=1.07 6.20; p=0.03). C allele was significantly represented in advanced fibrosis (65.8%) compared with that in early fibrosis (51.6%) (OR=1.80, 95% CI=1.10-2.93, p=0.01). A significant elevation of plasma bile acid levels in advanced fibrosis was observed compared with those in early fibrosis (p<=0.001). Receiver operating characteristic curve for plasma bile acid levels at cutoff value of 75.5 MUmol/L had a 59% specificity and 97.4% sensitivity as a predictor of advanced hepatic fibrosis (AUROC=0.78%). CONCLUSION: We concluded that Egyptian patients having chronic hepatitis C genotype 4 with CC genotype of ABCB11 SNP 1331T > C and high plasma bile acid levels at cutoff value of 75.5 MUmol/L were associated with advanced hepatic fibrosis. PMID- 29755017 TI - Endoscopic papillectomy of benign ampullary lesions: Outcomes from a multicenter study. AB - BACKGROUND/AIMS: Endoscopic papillectomy (EP) has emerged as an alternative to surgery in the management of ampullary lesions. The aim of this study is to evaluate feasibility, efficacy, safety, outcome, and impact of EP in the management of benign ampullary lesions. MATERIALS AND METHODS: This is a multicenter, retrospective study of 44 patients who had EP of benign ampullary lesions. RESULTS: Over the 11-year period, 44 (55.7%) of 79 patients underwent EP for benign ampullary lesions. Complete resection was achieved in 40 patients (91%). An underlying adenocarcinoma was the only risk factor for incomplete resection. Twenty-eight lesions (63.6%) were resected en-bloc and 16 lesions (36.4%) were resected in piecemeal fashion. Post-papillectomy histopathologic diagnoses were tubular adenoma in 14 patients (32%), invasive adenocarcinoma in 9 patients (20.5%), tubullovillous adenoma in 7 patients (16%), tubullovillous adenoma with carcinoma limited to the mucosal layer in 5 patients (11.3%), adenoma with high-grade dysplasia in 4 patients (9%), neuroendocrine tumor in 1 patient (2.3%), ganglioneuroma in 1 patient (2.3%), hamartomatous polyp in 1 patient (2.3%), adenofibroma in 1 patients (2.3%), and Brunner gland hyperplasia in 1 patient (2.3%). Seven (15.9%) procedure-related complications occurred: 3 (6.8%) bleeding, 2 (4.5%) pancreatitis, 1 (2.3%) abdominal pain, and 1 (2.3%) stent migration to the pancreatic duct. Seven patients (17%) had recurrence. CONCLUSION: Endoscopic papillectomy is a safe and effective method and can be considered as a first-line approach in patients with benign ampullary lesions with intent for cure. It also allows for correct histological diagnosis and staging. PMID- 29755018 TI - Ambulatory colonoscopy under sedoanalgesia in adult patients with and without irritable bowel syndrome: A prospective, cross-sectional, and double-blind comparison. AB - BACKGROUND/AIMS: It is unclear whether patients with irritable bowel syndrome (IBS) require a high dose of sedatives during colonoscopy. In this study, we investigated the pre-procedural anxiety levels, sedative consumption, procedure times, complications, and patient's satisfaction between patients with IBS and controls for ambulatory colonoscopy under sedation. MATERIALS AND METHODS: Rome III criteria were used in the diagnosis of IBS. Anxiety levels were measured using Spielberger's State-Trait Anxiety Inventory (STAI) and Beck Anxiety Inventory (BAI). Patients received a fixed dose of midazolam (0.02 mg/kg), fentanyl (1 MUg/kg), ketamine (0.3 mg/kg), and incremental doses of propofol under sedation protocol. Demographic data, heart rate, blood pressure, and oxygen saturation were measured. Procedure times, recovery and discharge times, drug doses used, complications associated with the sedation, and patient's satisfaction scores were also recorded. RESULTS: The mean Trait (p=0.015), State (p=0.029), Beck anxiety scores (p=0.018), the incidence of disruptive movements (p=0.044), and the amount of propofol (p=0. 024) used were significantly higher in patients with IBS. There was a decline in mean systolic blood pressure at the 6th minute in patients with IBS (p=0.026). No association was found between the sedative requirement and the anxiety scores. CONCLUSION: Patients with IBS who underwent elective colonoscopy procedures expressed higher pre-procedural anxiety scores, required more propofol consumption, and experienced more disruptive movements compared with controls. On the contrary, the increased propofol consumption was not associated with the increased pre-procedural anxiety scores. PMID- 29755019 TI - The importance of acoustic radiation force impulse (ARFI) elastography in the diagnosis and clinical course of acute pancreatitis. AB - BACKGROUND/AIMS: Acute pancreatitis (AP) is characterized by acute inflammation of the pancreas and it has a highly variable clinical course. The aim of our study was to evaluate the value of acoustic radiation force impulse (ARFI) elastography in the diagnosis and clinical course of AP. MATERIALS AND METHODS: Consecutive patients with a diagnosis of AP (patients group) and healthy subject (control group) were prospectively enrolled to the study. Demographic features and clinical, laboratory, and radiological data were recorded. Virtual Touch Tissue Quantification (VTQ) was used to implement ARFI elastography. The tissue elasticity is proportional to the square of the wave velocity (SWV). RESULTS: A total of 108 patients (age, 57+/-1.8 y) and 79 healthy subjects (age, 53.6+/-1.81 y) were included in the study. There were 100 (92.5%) edematous and 8 (7.4%) necrotizing AP. The mean SWV was significantly higher in the patient group than in the control group (2.43+/-0.08 vs. 1.27+/-0.025 m/s, p < 0.001). There was not significant difference between patient and control group regarding age and gender. SWV cutoff value of 1.63 m/s was associated with 100% sensitivity and 98% specificity for the diagnosis of AP. There was not significant difference between patients with and without complications and patients with edematous and necrotizing AP regarding mean SWV value. There was also not significant correlation between mean SWV value and age, mean length of hospital stay, and mean amylase level. CONCLUSION: ARFI elastography may be a feasible method for the diagnosis of AP, but it has no value for the prediction of clinical course of AP. PMID- 29755020 TI - Dynamic thiol/disulphide homeostasis in acute pancreatitis. AB - BACKGROUND/AIMS: The dynamic thiol/disulfide homeostasis plays pivotal roles in many physiological mechanisms in an organism. We aimed to investigate whether dynamic thiol/disulfide homeostasis changes among patients with acute pancreatitis. MATERIALS AND METHODS: This prospective trial contained 45 patients with acute pancreatitis and 45 sex-and age-matched healthy volunteers as control group. Thiol/disulfide homeostasis parameters were measured by a novel and automated assay, and detected results were compared between the two groups. RESULTS: Disulfide/total thiol percent ratio and disulfide/native thiol percent ratios were significantly higher in acute pancreatitis group; besides the native thiol, total thiol levels and native thiol/total thiol percent ratios were significantly lower (for all p < 0.001). CONCLUSION: The thiol/disulfide homeostasis is impaired in acute pancreatitis with a shift toward the oxidative status, and this deficiency might be a pathogenic factor in acute pancreatitis. The correction of this thiol/disulfide imbalance may be a new target in the management of acute pancreatitis. PMID- 29755021 TI - A single-center experience of post-transplant lymphoproliferative disorder (PTLD) cases after pediatric liver transplantation: Incidence, outcomes, and association with food allergy. AB - BACKGROUND/AIMS: We evaluated our 16-year single-center experience of pediatric post-transplant lymphoproliferative disorder (PTLD) cases who underwent liver transplantation between 2001 and 2017. MATERIALS AND METHODS: Of the 236 pediatric patients who underwent liver transplantation between 2001 and 2017, the clinical and laboratory data of eight patients diagnosed with PTLD were reviewed. The pre-transplant Epstein-Barr virus (EBV) status of 172 patients was also recorded. RESULTS: The total incidence of PTLD was 3.4%. The incidence of PTLD was 10% in pre-transplant EBV immunoglobulin G (IgG)-seronegative patients and 0.8% in pre-transplant EBV IgG-seropositive patients. The mean age of the patients at liver transplantation was 2.71+/-3.21 years, and four patients were aged below 1 year at the time of transplantation. PTLD was diagnosed at 21.81+/ 18.1 months after transplantation. The primary site of involvement was variable among patients: peripheral and mediastinal lymph nodes, stomach and intestine, transplanted graft, bone marrow, and nasopharynx. The eosinophil count varied greatly among patients, with a mean value of 524.62+/-679/mm3. Three patients had a food allergy and were administered an elimination diet at the time of PTLD diagnosis. Six patients had PTLD of B-cell origin. One patient died due to neutropenic sepsis during chemotherapy, whereas seven patients were followed up in full remission for 7.75+/-4 years. CONCLUSION: PTLD is a life-threatening complication of solid-organ transplantation with a heterogeneous clinical spectrum. Food allergy had a close association with PTLD. A close follow-up of patients with risk factors and an early diagnosis with appropriate treatment may lead to a better outcome. PMID- 29755022 TI - Adult multicentric burkitt lymphoma with bowel obstruction due to intussusception. AB - Primary malignant tumors of the small intestine are very rare, accounting for 2% 3% of all gastrointestinal malignancies. Lymphoma constitutes about 15%-20% of all small intestine neoplasms and 20%-30% of all primary gastrointestinal lymphomas. The ileum is the most common site for gastrointestinal lymphomas. Because the symptoms and physical findings are non-specific, the preoperative diagnosis is usually difficult. In this case report, we describe the highly unusual case of sporadic Burkitt lymphoma with complete intestinal obstruction due to intussusception of the proximal jejunum and discuss the treatment options. PMID- 29755024 TI - Closure of non-healing perianal Crohn's disease with surgery and vacuum-assisted closure (VAC) system. PMID- 29755023 TI - An unusual cause of gastrointestinal bleeding and intestinal obstruction. PMID- 29755025 TI - Can elongation of the ileum by epiploic appendagitis result in acute abdomen? PMID- 29755026 TI - Endoscopic sleeve gastroplasty for obesity: A multicenter study of 248 patients with 24 months follow-up. PMID- 29755027 TI - Endometriosis: A concise practical guide to current diagnosis and treatment AB - This book addresses the management of endometriosis from a holistic approach, including theoretical principles, conservative treatment of the condition, diagnostic and surgical procedures, as well as the outcome of research. Endometriosis and its treatment are complex issues. We believe that a combination of treatment modalities is needed in order to effectively address the pain, infertility, and other difficulties associated with endometriosis. In addition to theory and scientific principles, minimally invasive surgical procedures for the treatment of endometriosis are described in a stepwise manner. Separate sections of the books are devoted to specific conditions, urological procedures, and general surgical procedures because the condition is ideally treated on an interdisciplinary basis. Areas of overlap with other specialties are also addressed. PMID- 29755028 TI - The opinions and thoughts of women who underwent hysterosalpingography for the first time: Letter to the editor PMID- 29755030 TI - Detrimental effect of Hypericum perforatum on ovarian functions. AB - OBJECTIVE: Hypericum perforatum (HP) is widely used for depression and distress treatment as an over-the-counter plant in any age. This study investigated the safety of HP on ovarian functions and infertility. MATERIAL AND METHODS: HP given to the rats in two different doses (100 and 300 mg/kg/day) with drinking water for four weeks. Half of the treatment groups have been sacrificed at the end of four weeks intervention, remained have been sacrificed after additional waiting period for four weeks to see reversibility if there is. At the end of experiment, under the anesthesia with Ketamine and Xylasine (50 mg/kg and 5 mg/kg, respectively), blood samples and both ovarian tissues were obtained. RESULTS: Although, primordial follicles number were not affected with the dose of 100 mg/kg, significantly decreased 28.6% when the dose tripled. Primary follicles number stayed the same, but secondary and tertiary follicles numbers were significantly decreased dose dependently and four weeks later of the intervention, they were still significantly remained low. Anti Mullarian Hormone level was not significant amongst the group. CONCLUSION: HP treatment did not change serum level of Anti Mullarian Hormone, this because of primary follicle number has not decreased. On the other hand, the other follicles count dose dependently decreased and full recovery was not gained four weeks later. Especially HPs detrimental effect on primordial follicles takes the attention, if any woman use HP can face with ovarian failure as well. PMID- 29755029 TI - A double-blind, placebo-controlled trial of Fennel (Foeniculum vulgare) on menopausal symptoms: A high placebo response AB - Objective: The present study aimed to evaluate the effects of oral fennel on menopausal symptoms. Material and Methods: This double-blind, randomized, placebo controlled trial was conducted on 50 postmenopausal women in Mashhad (Iran). Patients were randomly divided into two groups of fennel (n=25) and placebo (n=25). Measurements were performed at baseline and after three months using the Menopause-Specific Quality of Life questionnaire. Results: Both placebo and treatment groups revealed significant improvements in the hot flush score (p<0.001 for fennel and p<0.01 for placebo), night sweats (p=0.007 for fennel and p<0.01 for placebo), sweating (p=0.002 for fennel and p<0.01 for placebo), symptoms of anxiety (p=0.05 for fennel and p=0.001 for placebo), feeling depressed (p<0.01 for fennel and p=0.006 for placebo), and impatience with other people (p<0.01 for fennel and p=0.003 for placebo). There were no significant differences in any menopausal symptoms between the fennel and placebo groups, except for coughing and sneezing when urinating (p=0.03). Conclusion: The failure to indicate a significant effect may have been caused by a high placebo response. It is suggested that future trials should include a placebo run-in phase or design a sequential, parallel study with larger sample sizes to mitigate the placebo effect. PMID- 29755031 TI - What is your diagnosis? PMID- 29755032 TI - Effects of mature cystic teratoma on reproductive health and malignant transformation: A retrospective analysis of 80 cases. AB - OBJECTIVE: Examining the cases of mature cystic teratoma (MCT) that are diagnosed and treated in our clinic regarding their association with fertility; and detecting the rate of malignant degeneration and the types of malignancies. MATERIAL AND METHODS: Patients, operated due to adnexal mass between April 2012 and August 2017 and diagnosed with MCT, were retrospectively examined. Mean age of the 80 cases, which met the criteria, was 30.60+/-10.5. 9 were suffering from infertility, according to hospital records. 67% of these (6 cases) were accompanied by endometriosis and MCT was bilateral in 55.5% of them (5 cases). Malignant degeneration was present in 6.25% of the cases (5 cases), all were monodermal tumors. Malignant degeneration was more common among the cases with adnexal masses larger in diameter (9.1+/-2.9 cm) and with postmenopausal age. Tumor markers were in normal range for the patients that developed malignancy. Malignant degeneration was not present among the infertile patients with endometriosis. RESULTS: Although MCTs do not seem to affect the ovarian reserve negatively, the complaint of infertility is prominent in case of concurrent presence of endometriosis. During assessment, concurrent endometriosis should be considered. Imaging findings, large adnexal masses and postmenopausal period are important for the assessment of MCT concerning malignant degeneration. It should not be overlooked: tumor markers may be normal. CONCLUSION: MCTs can be present concurrent with endometriomas. In such cases the complaints of infertility are more distinct. In MCT malign degeneration, mass diameter, complex mass internal structure and postmenopausal status are important factors. PMID- 29755033 TI - Impact of a History of Hypertension in Pregnancy on Later Diagnosis of Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation/flutter (AF) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders (HPDs) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without. METHODS AND RESULTS: A nested case-control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57+/-8 (mean+/ SD) years, (controls 56+/-8 years), 32+/-8 years (controls 31+/-8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPDs, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21 6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92-5.23). CONCLUSIONS: Women with AF are more likely to have had a HPD, a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF, studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed. PMID- 29755034 TI - Association Between Gestational Hypertension and Risk of Cardiovascular Disease Among 617 589 Norwegian Women. AB - BACKGROUND: Preeclampsia and gestational hypertension (GH) are the most common hypertensive pregnancy disorders. Preeclampsia has been linked to increased risk of cardiovascular disease (CVD), but a similar association for GH has not been established. We aimed to determine the association between GH and subsequent CVD, and explore the additional role of small-for-gestational-age infants, preterm delivery, and parity. METHODS AND RESULTS: Data from the Medical Birth Registry of Norway were linked to the Cardiovascular Disease in Norway project and the Norwegian Cause of Death Registry. Hazard ratios and 95% confidence intervals were computed using Cox proportional hazard regression, comparing women with and without GH during their first and/or second pregnancy. We included all women with a first delivery from 1980 through 2009 (n=617 589) and followed them for a median of 14.3 (quartile 1-quartile 3: 6.9-21.5) years. Women with GH in the first pregnancy had 1.8-fold (95% confidence interval, 1.7-2.0) higher risk of subsequent CVD compared with women without any hypertensive pregnancy disorder. When GH occurred in combination with small-for-gestational-age infants and/or preterm delivery, the hazard ratio was 2.6 (95% confidence interval, 2.3-3.0). When women with GH were compared with women with preeclampsia, the risk of CVD was comparable when the pregnancy complications occurred in either the first or second pregnancy but was significantly higher for preeclampsia without complications when the disorder occurred in both pregnancies. CONCLUSIONS: GH was associated with increased risk of subsequent CVD, and the highest risk was observed when GH was combined with small-for-gestational-age infants and/or preterm delivery. PMID- 29755035 TI - Cardiovascular Sequels of Hypertension in Pregnancy. PMID- 29755038 TI - Hypertensive Disorders in Pregnancy and the Risk of Cardiovascular Disease: A Need for Postpartum Strategies for the Primary Prevention. PMID- 29755037 TI - Do Young Women Need Treatment for Hypertension After Pregnancy Complications? PMID- 29755036 TI - Pregnancy-Related Risk Factors Are Associated With a Significant Burden of Treated Hypertension Within 10 Years of Delivery: Findings From a Population Based Norwegian Cohort. AB - BACKGROUND: The association between pregnancy complications and women's later cardiovascular disease has, primarily, been evaluated in studies lacking information on important covariates. This report evaluates the prospective associations between pregnancy-related risk factors (preeclampsia/eclampsia, gestational hypertension, pregestational and gestational diabetes mellitus, preterm delivery, and fetal growth restriction) and pharmacologically treated hypertension within 10 years after pregnancy, while adjusting for a wide range of covariates. METHODS AND RESULTS: Prepregnancy normotensive women participating in the MoBa (Norwegian Mother and Child Cohort Study) from January 2004 through July 2009 were linked to the Norwegian Prescription Database to identify women with pharmacologically treated hypertension beyond the postpartum period of 3 months. The burden of hypertension associated with pregnancy-related risk factors was evaluated using an attributable fraction method. A total of 1480 women developed pharmacologically treated hypertension within the follow-up among 60 027 women (rate of hypertension, 3.6/1000 person-years). The proportion of hypertension associated with a history of preeclampsia/eclampsia, gestational hypertension, preterm delivery, and pregestational or gestational diabetes mellitus was 28.6% (95% confidence interval, 25.5%-31.6%) on the basis of multivariable analyses adjusting for numerous covariates. The proportion was similar for women with a healthy prepregnancy body mass index (18.5-24.9 kg/m2; attributable fraction (AF)% 25.9%; 95% confidence interval, 21.3%-30.3%), but considerably higher for nulliparous women at baseline within the first 5 years of follow-up. Small-for gestational age, however, did not increase subsequent hypertension risk in multivariable analyses. CONCLUSIONS: A structured postpartum follow-up of high risk women identified through pregnancy-related risk factors would facilitate personalized preventive strategies to postpone or avoid onset of premature cardiovascular events. PMID- 29755039 TI - Antibiotics are the main cause of life threatening allergic reactions during surgery. PMID- 29755040 TI - Health Policy Affects Health Outcomes: Community Determinants of Health. PMID- 29755041 TI - Building Resilience after Disasters through the Youth Leadership Program: The Importance of Community and Academic Partnerships on Youth Outcomes. PMID- 29755042 TI - The Church Bridge Project: An Academic-Community Perspective of a Church-Based Weight Management Pilot Intervention among Young Adult African Americans. PMID- 29755043 TI - Domestic Violence and Pregnancy: A Community-Based Participatory Research Coalition Approach to Identifying Needs and Informing Policy. PMID- 29755044 TI - School-Based Interprofessional Asthma Self-Management Education Program for Middle School Students: A Feasibility Trial. PMID- 29755045 TI - Building Resilience after Disasters through the Youth Leadership Program: The Importance of Community and Academic Partnerships on Youth Outcomes. AB - BACKGROUND: The Youth Leadership Program (YLP) was created as a school community university partnership after the devastating effects of Hurricane Katrina. The YLP goal was to support youth and improve by engaging them in disaster recovery initiatives. OBJECTIVES: The purpose of the study was to describe the development of the St. Bernard Parish YLP and evaluate if the program was associated with increasing self-efficacy and decreasing trauma symptoms. Specifically, this study explored how a mental health intervention related to hurricane recovery influenced students' perceived ability to achieve goals, fostering post-disaster self-efficacy. METHODS: The YLP began in 2006, with two major initiatives; data were analyzed before and after YLP activities. Students completed disaster screenings annually, with measures of trauma symptoms and self-efficacy. RESULTS: Findings from this study showed that students who participated in the YLP, compared with peers who did not participate, scored significantly higher on self efficacy. In addition, an interaction effect revealed that gains in self-efficacy also resulted in reduced trauma symptoms for both groups of students. CONCLUSIONS: The YLP demonstrated how disaster response interventions supporting resilience-based leadership and empowerment influenced students' perceived ability to achieve goals fostering post-disaster resilience. Successful initiatives, such as the YLP, emphasize the importance of parallel and interactive individual, family and community support processes to enhance the recovery experience for both individuals and communities. PMID- 29755046 TI - The Church Bridge Project: An Academic-Community Perspective of a Church-Based Weight Management Pilot Intervention among Young Adult African Americans. AB - BACKGROUND: Churches are effective community partners and settings to address weight management among African Americans. There is limited information on the use of churches to reach young adult populations and church collaborations with primary care clinics. OBJECTIVES: The Church Bridge Project represents a community-academic partnership that presents the recruitment process of a church based weight management intervention and describes baseline data of participants recruited from churches and primary care providers. We also discuss research contributions, challenges and limitations, study applicability, and practice implications from an academic and community perspective. METHODS: Church leaders were involved in the entire research process. The theory-driven intervention included 12 diabetes prevention program-adapted education and motivational interviewing (MI)-guided sessions. Participants were recruited through primary care providers and church leaders. Demographics, medical and weight history, stage of change for weight loss, social support, and self-efficacy for diet and physical activity, weight, and girth circumferences were measured. Baseline descriptive data were analyzed. RESULTS: Of 64 potential participants, 42 (65.6%) were enrolled in the study and 16 (25.0%) completed baseline data collection. No participants were recruited through primary care providers. Recruited participants were similar to the target population except for being all obese and mostly female. The mean +/- SD age of participants was 34.31 +/- 8.86 years with most reporting having more than a high school education (n = 14 [87.5%]), individual yearly income of less than $59,000 (n = 12 [75.0%]), and been married or living with a partner (n = 9 [56.3%]). Most reported a history of hypertension and an immediate family history of diabetes and hypertension. Most participants were classified as class III obesity. CONCLUSIONS: Young adults and primary care providers are difficult to engage in church-based interventions. Church leaders were comfortable with a collaborate model for decision making, but not an empower model. Churches remain a successful method to reach African Americans; however, more research is needed to motivate young adults to participate in health intervention research. PMID- 29755047 TI - Domestic Violence and Pregnancy: A CBPR Coalition Approach to Identifying Needs and Informing Policy. AB - BACKGROUND: Community engagement-the collaborative process of addressing issues that impact the well-being of a community-is a strategic effort to address community issues. The Gulf States Health Policy Center (GS-HPC) formed the Hattiesburg Area Health Coalition (HAHC) in November 2014 for the purpose of addressing policies impacting the health of Forrest and Lamar counties in Mississippi. OBJECTIVES: To chronicle the community-based participatory research (CBPR) process used by HAHC's identification of infant and maternal health as a policy area, domestic violence in pregnancy as a priority area within infant and maternal health, and a community action plan (CAP) regarding this priority area. METHODS: HAHC reviewed data and identified infant and maternal health as a priority area. They then conducted a policy scan of local prenatal health care to determine the policy area of domestic violence in pregnancy. RESULTS: HAHC developed a CAP identifying three goals with regard to domestic violence and pregnancy that together informed policy. Changes included the development of materials specific to resources available in the area. The materials and recommended changes will first be implemented by Southeast Mississippi Rural Health Initiative (SeMRHI) through a screening question for all pregnant patients, and the adoption of policies for providing information and referrals. CONCLUSIONS: The lack of community-level data was a challenge to HAHC in identifying focus and priority areas, but this was overcome by shared leadership and community engagement. After completion of the CAP, 100% of expecting mothers receiving prenatal care in the area will be screened for domestic violence. PMID- 29755048 TI - School-Based Interprofessional Asthma Self-Management Education Program for Middle School Students: A Feasibility Trial. AB - BACKGROUND: Asthma is the most common chronic disease among school-aged children under 18 years of age and is a major cause of morbidity, loss of school days, and increased hospitalizations. Asthma disproportionately affects low-income, minority youth in Alabama. The benefits of improving asthma control and self management have significance for improving health, preventing disease, and reducing health disparities by addressing social, behavioral, environmental, economic, and medical determinants of health. OBJECTIVES: This collaborative community partnership between the Mobile County Public School System, University of South Alabama (USA), and USA Children's and Women's Hospital involved nursing students, respiratory therapy students, and medical residents from three colleges and the hospital. The research question was whether a school-based asthma self management education program presented by an interprofessional team was feasible for teens with asthma in a medically underserved area (MUA). METHODS: Middle school students with a diagnosis of asthma participated in this institutional review board-approved study. Asthma assessments, one-on-one coaching, and group education were done over five sessions, using Power Breathing for teens curriculum. Instruments were the Childhood Asthma Control Test (ACT), the Asthma Responsibility Questionnaire (ARQ), the Self-Efficacy Scale, the Pediatric Asthma Quality of Life Questionnaire (PAQLQ), peak flow monitoring, and spirometry. RESULTS: Eighteen students with moderate to severe persistent asthma completed the program with reduced asthma symptoms and increased asthma control, medication knowledge/skills, self-efficacy, and asthma responsibility. CONCLUSIONS: Adolescents with asthma need education in medication management, spacer use, peak flow, trigger avoidance, and coaching to take on the responsibility of asthma care. This multidimensional, interprofessional approach can strengthen asthma self-management in a middle school medically underserved community population. PMID- 29755050 TI - Beyond the Manuscript: Developing a Productive Workgroup Within a Community Coalition: Transtheoretical Model Processes, Stages of Change, and Lessons Learned. PMID- 29755049 TI - Developing a Productive Workgroup Within a Community Coalition: Transtheoretical Model Processes, Stages of Change, and Lessons Learned. AB - BACKGROUND: Addressing complex problems such as health disparities requires collaboration among individuals and agencies. Yet, methods by which productive and cohesive community-based volunteer workgroups are developed and activated to improve health outcomes are often not discussed. OBJECTIVE: Using the transtheoretical model (TTM) as a framework, we discuss effective processes for developing an action-oriented community-based workgroup committed to producing evidence-based information relevant to health policy. METHODS: Workgroup members answered open-ended survey questions and participated in focused coalition-wide discussions to identify factors that facilitated movement of the embedded workgroup from precontemplation to committed action. Frequency and content of e mail exchanges and workgroup meetings were also considered.Results and Lessons Learned: Activating the group's process of social support or helping relationships was essential throughout the stages of change to promote cohesion and trust. Consciousness raising (awareness), and dramatic relief (emotional arousal) were particularly critical for initial movement from precontemplation to contemplation to preparation. Using group time to promote member's self reevaluation (how work is relevant) and self-liberation (commitment) prevented attrition and facilitated effort. As the workgroup enacted planned activities, stimulus control and reinforcement management processes facilitated movement through the action and maintenance stages of change. CONCLUSIONS: By attending to both individual and organizational processes of change, we effectively created an action-oriented multidisciplinary workgroup focused on obtaining evidence to guide local and regional health policy decisions and improve health outcomes for under-resourced patients. PMID- 29755051 TI - Investing in Gulfport: Development of an Academic-Community Partnership to Address Health Disparities. AB - BACKGROUND: Invest Health, a collaboration between the Robert Wood Johnson Foundation and The Reinvestment Fund, selected 50 midsized cities to participate in a health initiative that encourages cross-sector alliances to think creatively about mechanisms that address barriers to reducing health disparities among low income populations. Gulfport, Mississippi, was 1 of 50 teams chosen to participate. OBJECTIVE: To develop an academic-community partnership among the University of Southern Mississippi, Coastal Family Health Center (CFHC), Mercy Housing and Human Development (MHHD), the Mississippi State Department of Health Office of Health Disparity Elimination, and Gulfport residents to create the Healthy Gulfport Initiative, and, ultimately, the Gulf Coast Healthy Communities Collaborative (GCHCC). METHODS: A Gulfport City team was developed per Invest Health guidelines and included five individuals who represented the public sector, community development, and an academic or health-related anchor institution in the community. Several data sources were used to develop city-wide priority health outcomes. A priority neighborhood experiencing health disparities related to the priority health outcomes was identified. A community-engaged needs assessment was conducted in the priority neighborhood. Residents were engaged in prioritizing the health, education, and activity needs of their community via a participatory nominal group process and survey data collection. RESULTS: Residents in the priority neighborhood lack access to health care and healthy food options owing to transportation difficulties and proximity to resources. CONCLUSIONS: The GCHCC will be established to act as a "backbone organization," so that a common agenda can be created with an emphasis on potential for collective impact. PMID- 29755052 TI - Lessons Learned from Data Collection as Health Screening in Underserved Farmworker Communities. AB - BACKGROUND: Girasoles is an academic-community partnership investigating heat related illness (HRI) among farm-workers. An unexpected outcome is health screening and intervention for participants without access to health care. OBJECTIVES: We present a case of renal failure in a farmworker, detected during data collection, to illustrate how academic-community collaboration can result in clinical benefits for study participants. METHODS: Girasoles is examining physiologic responses to heat stress, associated vulnerability factors, and HRI symptoms. Data include blood pressure, fasting and non-fasting blood glucose, blood creatinine, blood urea nitrogen, and urine dipsticks. Participants with out of-range findings are referred to local health care providers. RESULTS: During two summers, health screenings of 192 workers resulted in 71 referrals (37%) for conditions to be rechecked and treated. One of these referrals involved chronic renal failure requiring extensive follow-up by research team members. CONCLUSIONS: The case of renal failure illustrates the value of collaborative research as a health intervention with vulnerable populations. PMID- 29755054 TI - Cervical Cancer Screening among Underscreened and Unscreened Brazilian Women: Training Community Health Workers to be Agents of Change. AB - BACKGROUND: Despite the availability of cervical cancer screening programs in Brazil, some women do not participate in these programs owing to structural and/or interpersonal/intrapersonal barriers, resulting in high cervical cancer incidence and mortality. Integrating community health workers (CHWs) into the delivery of cervical cancer screening interventions is potentially a feasible strategy to address these barriers. OBJECTIVES: This study aimed to implement and evaluate a CHW training to deliver a brief intervention to promote cervical cancer screening among underscreened and unscreened women in Brazil. METHODS: The curriculum addressed cervical cancer and screening, behavioral intervention strategies, and protection of human subjects in research. Pretest and post-test questionnaires assessed changes in CHW objective and perceived knowledge as well as perceived skills and confidence (N = 15). RESULTS: There was a significant increase in objective and perceived knowledge about cervical cancer, behavior change strategies, and protection of human subjects in research between pretest and post-test, but not in self-perception about skills and confidence to motivate women to engage in cervical cancer screening. CONCLUSIONS: Improvements in CHW knowledge about cervical cancer screening and behavior change represents a step forward toward successful interventions, but adaptations are needed to boost their self-confidence and perceived skills with regard to their ability to promote behavior change at the community level. PMID- 29755053 TI - State Licensing Regulations on Screen Time in Childcare Centers: An Impetus for Participatory Action Research. AB - BACKGROUND: New licensing regulations require Louisiana early care and education centers (ECEs) to limit children's screen time and increase physical activity. A community- academic partnership involving academic, community, government, and ECE stakeholders launched two initiatives: (1) an evaluation of the implementation of licensing regulations at the local level and (2) a statewide effort to develop technical assistance for ECE directors. OBJECTIVES: To describe the methods and lessons learned and to establish recommendations based on this ongoing participatory action research. METHODS: A case study approach was used to identify the lessons learned and recommendations thus far, based on partners' perspectives and ECE directors' participation. LESSONS LEARNED: Recommendations include to share power and funding among stakeholders, to engage directors as partners to overcome recruitment challenges, and to start with the end in mind to ensure meaningful community engagement. CONCLUSIONS: This participatory action approach is leading to innovative, feasible strategies to increase children's physical activity. PMID- 29755055 TI - A Multigenerational Strategy to Transform Health Education into Community Action. AB - BACKGROUND: The National Institute for Minority Health and Health Disparities funded Centers of Excellence to address health disparities through research, education and professional training, and community engagement. This article summarizes a decade of multigenerational educational programing embedded in the Community Engagement Core (CEC) of the National Institute for Minority Health and Health Disparities-funded Center for Healthy Communities-Center of Excellence at the University of South Alabama. OBJECTIVES: Our objective is to demonstrate how community-based participatory research (CBPR) initiated the multigenerational approach, uniting the community health education and the educational pipeline programs, and transformed a traditional professional symposium into a mechanism to increase community participation and action. METHODS: Community engagement and education adhered to CBPR principles and methods. A 3-year planning process before full funding of the Center of Excellence allowed the CHC to develop community partnerships and implement pilot projects that would assure community access and participation in COE programs. Program innovation was rooted in community suggestions and community priorities. The annual Regional Health Disparities Symposium (RHDS) was literally transformed through community engagement. CONCLUSIONS: Education programs for adults and youth achieved their goals independently, the STARS AND STRIPES (Student Training for Academic Reinforcement in the Sciences and Special Training to Raise Interest and Prepare for Entry into the Sciences) pipeline program has a success rate of 88% for participants' admission to colleges and universities. CHA-led events have documented an outreach to more than 6,500 community members and the COE has funded eight CHA-led projects directly addressing community action plans developed through CBPR methods during the history of the RHDS. But the real story has emerged from transformative multigenerational interaction via CBPR. PMID- 29755056 TI - Therapeutic Recreation in the Public Schools: A Community Partnership. AB - BACKGROUND: In 2002, the University of Southern Mississippi's Therapeutic Recreation Program and the Hattiesburg (MS) Public School District's Department of Exceptional Children and Health Services formed a partnership that has lasted (off and on) for 15 years. METHODS: The partnership was formed based on a shared mission of education and training, and grew in depth based on reciprocated respect and support. RESULTS: Early collaborative efforts included simple programming efforts that provided health and educational benefits for the students with disabilities in the public schools and training for the future professionals in therapeutic recreation at the university. As the program progressed, more complex programs were designed to teach students with disabilities to build the capacity for pursuing and maintaining personal health. CONCLUSIONS: Planned programming efforts for the near future focus on collecting data to support the development of an extracurricular athletic program for students with disabilities. PMID- 29755058 TI - When the Eyes Are Shut: The Strange Case of Girolamo Cardano's Idolum in Somniorum Synesiorum Libri IIII (1562). AB - In his treatise on dreams Somniorum Synesiorum Libri IIII, published in 1562, the Italian Renaissance philosopher and physician Girolamo Cardano distinguishes between idola and visiones (or visa). Historians have discussed the reasons for such a distinction without taking into account Cardano's original theory of sense perception. In this article I shall argue that, in order to interpret the meaning of idola and visiones in Cardano's theory of dreams, one should bear in mind his view that hearing is superior to sight and that while idola are essentially based on sound, visiones depend on images. PMID- 29755057 TI - Processes and Outcomes of a Community-Based Participatory Research-Driven Health Needs Assessment: A Tool for Moving Health Disparity Reporting to Evidence-Based Action. AB - BACKGROUND: The community-based participatory research (CBPR)-driven health needs assessment was a tool used to inform community-led, -implemented, and -sustained research and prevention strategies. METHODS: The Morehouse School of Medicine Prevention Research Center (MSM PRC) research and prevention initiatives are implemented in direct response to priorities identified through this process and tool. Led by a community-majority coalition board, the assessment coupled state and city secondary data with primary survey data collected by and from community residents. RESULTS: Hypertension, diabetes, obesity, and sexually transmitted infections were most frequently cited individual and community health priorities. Lack of social and family cohesion, limited or no opportunities to exercise, poor nutrition and lack of awareness and knowledge about diseases, and insufficient access to affordable health care were cited determinants of health priorities. CONCLUSIONS: The CBPR-driven community health needs assessment (CHNA) informed and established a data-driven community engaged research agenda, policy, systems and environmental change approaches, community-led grants and job creation leveraging neighborhood contexts and strengths. PMID- 29755059 TI - Pierre Bayle and the Secularization of Conscience. AB - I argue that Pierre Bayle was the first modern author to re-secularize the concept of moral conscience after it had been tied to Christian theology for centuries. Bayle's first moral writings espoused a traditional, theological conception of conscience which was unfit to support his theory of toleration. Over three decades of reflection, Bayle gradually rendered conscience completely independent of theology, and therefore made it suitable as a foundation of a theory of universal toleration. We witness in Bayle's moral writings not only the emergence of the modern, secular conscience, but also the process of secularization. PMID- 29755060 TI - Volney and the French Revolution. AB - This article examines Volney right before and after 1789. Placed together in their intellectual historical context, his works in this period - Travels in Syria and Egypt (1787), Considerations (1788), and The Ruins (1791) - offer a valuable guide into the workings of the "Enlightenment narrative" of "European" and "Oriental" history at the critical juncture of the age of revolutions. The image of Volney as a progressive stadial historian and optimist revolutionary hereby cedes its place to that of Volney the worried republican indulged in the heroic attempt to find a way to build a free and stable polity. PMID- 29755061 TI - "Writers Who Have Rendered Women Objects of Pity": Mary Wollstonecraft's Literary Criticism in the Analytical Review and A Vindication of the Rights of Woman. AB - This article details the variety of critical strategies in Mary Wollstonecraft's A Vindication of the Rights of Woman, finding strong connections with her writing as a reviewer for the Analytical Review, the literary review published by the reformer and Dissenter Joseph Johnson. In Rights of Woman, Wollstonecraft employed textual analyses and an evolving set of theoretical positions that had been introduced in the course of her career at the Analytical Review. By elucidating the importance of the reviews and the specificity of Wollstonecraft's procedures, this article contributes to a growing consensus that Rights of Woman initiated feminist literary criticism. PMID- 29755062 TI - Family, Gender, and Progress: Sophie de Grouchy and Her Exclusion in the Publication of Condorcet's Sketch of Human Progress. AB - I examine some of the evidence for collaboration between Condorcet and Sophie de Grouchy on the writing of the Sketch of Human Progress, but also uncover the ways in which the publication and reception of that text worked to exclude a woman who was a philosopher in her own right from a work she clearly contributed to. I show that at least one passage that was added in the 1795 edition makes the work philosophically more interesting. PMID- 29755063 TI - Marx and the Kabbalah: Aaron Shemuel Lieberman's Materialist Interpretation of Jewish History. AB - This essay addresses the reception of Karl Marx's writings among Russian Jewish revolutionaries in the 1870s. It explores the way Aaron Shemuel Lieberman (1843 1880), known as "the father of Jewish socialism," interpreted Marx through a kabbalistic prism. It argues that Jews were attracted to Marx in part because of the overlaps between historical materialism and certain strands of the kabbalistic tradition. It also sheds light on the early reception of Marx and the way his theory of revolution was reinterpreted to reflect the unique socio economic conditions of the Russian Empire. PMID- 29755064 TI - John Robert Seeley, Natural Religion, and the Victorian Conflict between Science and Religion. AB - This essay examines the publishing and reception of J. R. Seeley's Natural Religion (1882), a book that sought to bring about a reconciliation between science and religion. While Natural Religion has long been overlooked, it is argued that its reception gives us insight into changing views about the relationship between science and religion in the late Victorian period. The essay also explores how the reception of the book was conditioned by its bibliographic lineage as it was signed not by Seeley, but "by the Author of Ecce Homo." PMID- 29755067 TI - [Prognostic Significance of Mode of Nodal Involvement in Pulmonary pN1 Squamous Cell Carcinoma]. AB - According to the tumor, node, metastasis (TNM) classification of the Union for International Cancer Control (UICC) and the International Association for the Study of Lung Cancer (IASLC), N factor is defined by the anatomic extent of the metastatic lymph nodes, but is not related to the metastatic pattern. N1 is defined as "metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension". Lymph node involvement is one of the most important prognosistic factors in non small cell lung cancer patients. Squamous cell carcinoma (SCC) arises in the central airway and directly invades adjacent lymph nodes more frequently compared to the other histologic types. We retrospectively evaluated the prognostic impact of lymph node involvement patterns in pulmonary pN1 squamous cell carcinoma (SCC) patients. The clinical records of 23 patients with pN1 SCC who underwent complete resection and systematic lymph node dissection at our institute were retrospectively reviewed. We classified the patient into 2 N1 groups based on the nodal involvement pattern:metastatic N1 nodes involved directly by the main tumor (direct group) and metastatic N1 nodes not directly involved by the main tumor (separate group). The direct group consisted of 10 patients, and the separate group comprised 13 patients. There were no significant difference in the gender, tumor size, surgical procedure, and number of metastatic lymph nodes. Overall survival and disease-free survival curves were plotted using the Kaplan-Meier method, and the statistical differences between both groups was determined by the log-rank test. P values <0.05 were considered statistically significant. The direct group had a much better 5-year overall survival rate of 100.0% compared with 55.9% for the separate group (p=0.037). The N factors in TNM classification are defined only by anatomical location. However, our results suggest that the mode of nodal involvement in pulmonary pN1 SCC might be a prognostic factor. Accordingly, it is likely that biological behaviors are different between direct metastasis and separate metastasis. Since there are some limitations in this study:its retrospective design and small sample size, the clinical implication of direct extension to N1 lymph nodes needs to be confirmed by a large scale prospective study in the future. PMID- 29755068 TI - [Tuberculous Pleurisy Diagnosed by Thoracoscopic Lung Biopsy]. AB - A 44-year-old woman was referred to our hospital with pleural effusion and unknown fever. Mycobacterium tuberculosis was not detected by culture of pleural effusion and sputum and gastric fluid. Pleural fluid was serous and exudative, and cytological examination showed no malignant cells. Computed tomography revealed a little pleural thickening of the right middle lobe and massive pleural effusion. As acute pleurisy was suspected based on the findings of imaging studies, thoracoscopy was performed under general anesthesia. Many yellowish white, small nodules were seen on the parietal pleura, and white small nodule were seen on the visceral pleura of the right middle lobe. Mycobacterium tuberculosis was not detected by culture and polymerase chain reaction for Mycobacterium tuberculosis( TB-PCR) of parietal pleura and pleural effusion, but was detected by only culture and TB-PCR of visceral pleura, yielding a diagnosis of tuberculous pleurisy. Her symptoms improved and the right pleural effusion decreased with isoniazid (INH), rifampicin (RFP), ethambutol (EB) and pyrazinamide(PZA) treatment. PMID- 29755069 TI - [Plication for Diaphragmatic Eventration by Complete Video-assisted Thoracoscopic]. AB - A 61-year-old woman was admitted to our hospital with progressive dyspnea on exertion. Chest X-rays and computed tomography (CT) showed elevation of the left diaphragm and atelectasis of the left lung. Eventration of the diaphragm was performed. The redundant diaphragm was plicated with vertical mattress sutures and reinforced by the suturing of the remnant diaphragm to the diaphragm near to the chest wall. During the thoracoscopic procedures, thoracoscopic examination from a small part of the resected diaphragm was conducted simultaneously to ensure safety and avoid damage to intra-abdominal organs. After plication, dyspnea on exertion was resolved and the patient was discharged on the 9th post operative day. PMID- 29755070 TI - [Hemothorax due to Idiopathic Rupture of Pulmonary Artery with Defect of Tunica Media]. AB - A 47-years-old man with hemodynamic shock was refered to our hospital by an ambulance. Chest computed tomography(CT)showed left hemothorax and the extravasation of contrast media in his left lung. Emergency operation was done. A lot of intrathoracic hematoma and pulsating bleeding from the lung was found, and lingular segmentectomy was performed. Pathologically, the rupture of pulmonary artery of 2.2 mm in diameter was found without the finding of imflammation nor degeneration due to any basal diseases. Around the lesion, some artery of 0.3~3.0 mm in diameter showed defect of tunica media. This vascular anomaly was considered to lead his hemothorax. PMID- 29755071 TI - [Salvage Surgery after Radical Chemotherapy for N3 Non-small Cell Lung Cancer]. AB - A 49-year-old man was admitted to our hospital for an abnormal chest shadow. Computed tomography showed a pulmonary nodular shadow in the right upper lobe and swelling of the right hilar, mediastinal and supraclavicular lymph nodes. A positron emission tomography(PET) scan showed fluorodeoxyglucose accumulation in the tumor and swollen lymph nodes. He was diagnosed with stage cT1aN3M0 (IIIB) pulmonary adenocarcinoma and was treated with a combination of cisplatin and paclitaxel. After 6 cycles of chemotherapy, serum carcinoembryonic antigen (CEA) level was markedly decreased. A PET scan showed fluorodeoxyglucose accumulation only in the primary site. He was diagnosed with stage ycT1aN0M0(IA) disease, and the salvage surgery was scheduled. As chemotherapy had resulted in severe fibrosis of the lung hilum, he underwent a partial resection. After partial resection of the right upper lobe, he has been alive without recurrence for 8 years. PMID- 29755072 TI - [Primary Pulmonary Vein Stenosis Developed after Bidirectional Glenn Procedure;Report of Two Cases]. AB - We experienced 2 cases of primary pulmonary vein stenosis(PVS),which developed after a bidirectional Glenn procedure was performed for complex heart defects with normal pulmonary venous return. Although the patients successfully underwent primary sutureless repair for left PVS, restenosis of the affected pulmonary veins occurred several months after surgery in both patients. Stent implantation followed by balloon angioplasty was performed for stent stenosis in 1 patient without effect. However, the patient later underwent a successful fenestrated Fontan procedure. Catheter intervention was contraindicated in the 2nd patient due to almost complete obstruction of the left pulmonary veins with upstream hypoplasia. To improve the results of PVS treatment, earlier diagnosis by quantitative lung perfusion scintigraphy, magnetic resonance imaging, and close echocardiographic observation together with earlier, aggressive treatment combining surgery and catheter interventions are recommended. PMID- 29755073 TI - [Beating Mitral Valve Replacement for Functional Mitral Regurgitation after Cardiac Resynchronization Therapy;Report of a Case]. AB - A 72-year-old man was admitted to our hospital because of dyspnea. He had a history of cardiac resynchronization therapy for congestive heart failure due to dilated cardiomyopathy 6 months previously. Echocardiography revealed severe functional mitral regurgitation which had been mild 6 months before. Because medical treatment was ineffective, on-pump beating mitral valve replacement using a bioprosthesis was performed to prevent reperfusion injury. The patient was easily weaned from cardiopulmonary bypass with low-dose inotropic support and scheduled intra-aortic balloon pump. Then, he was discharged in a good condition on the 37th postoperative day. Beating mitral valve replacement seems to be a good surgical option for patients with poor left ventricular function. PMID- 29755074 TI - [Structural Deterioration of a Bovine Pericardial Valve in a Tricuspid Position 14 Years Postoperatively;Report of a Case]. AB - Although nonstructural dysfunction of a bioprosthesis caused by pannus formation or native valve attachment has been well described, structural valve deterioration( SVD) caused by calcification or tear of a bioprosthesis, especially a bovine pericardial valve, is very rare in the tricuspid position. We report a case of redo tricuspid valve surgery for SVD 14 years after tricuspid valve replacement( TVR) using a Carpentier-Edwards Perimount (CEP) pericardial valve. A 71-year-old woman was referred to our hospital because of exertional dyspnea and pre-syncope. She had undergone mitral valve replacement with a St. Jude Medical mechanical valve and TVR with a CEP pericardial valve 14 years previously. Transthoracic echocardiography revealed tricuspid valve stenosis with a mean trans-tricuspid valve pressure gradient (TVPG) of 7.3 mmHg. Redo TVR using a CEP Magna Mitral Ease valve was performed under cardiac arrest. Severe calcification was observed on the ventricular side of the leaflets of the explanted valve. The mean TVPG decreased to 3.2 mmHg after surgery, and the patient's postoperative course was uneventful. PMID- 29755075 TI - [Huge Left Thrombosis after Mitral Valvuloplasty and Maze Procedure;Report of a Case]. AB - Generally, anticoagulation therapy is not essential for patients who maintain sinus rhythm after mitral valvuloplasty. A 66-year-old woman who had undergone mitral valvuloplasty and maze procedure for treatment of mitral valve regurgitation and atrial fibrillation 4 years ago was diagnosed as having left atrial thrombosis despite maintenance of sinus rhythm on electrocardiography. Echocardiography showed narrow mitral valvular area(1.5 cm2), loss of A wave and a huge left atrium. Repeat surgery was performed to replace the mitral valve and to remove the thrombus. The thrombus attached to the posterior wall of the left atrium with a wide basis, and was unrelated to the ablation line of maze procedure. Careful follow-up and anticoagulation therapy should be considered for patients who have a large left atrium and/or rheumatic mitral valve after valvuloplasty even though sinus rhythm is maintained. PMID- 29755076 TI - [Constrictive Pericarditis with Intractable Ascites after Aortic Valve Replacement;Report of a Case]. AB - We report a 68-year-old man, who developed refractory ascites of unknown cause after aortic valve replacement. He was diagnosed with constrictive pericarditis because of "dip-and-plateau" waveform findings via cardiac catheterization and operated with cardiopulmonary bypass. Following waffle procedure, we incised pericardium for decompression, so that pericardial mobility and diastolic dysfunction was improved. Postoperative computed tomography (CT) image also showed decrease of ascites fluid. We concluded that pericardiotomy is an established surgical procedure and is excellent indication to constrictive pericarditis. PMID- 29755077 TI - [Left Atrial Myxoma with Ossification;Report of a Case]. AB - A 69-year-old female with left atrial tumor was refered to our hospital for surgical treatment. The tumor was attached to the interatrial septum and resected completely. Histopathological analysis confirmed a myxoma with ossification(mature bone). These findings may support the hypothesis that the undifferentiated mesenchymal cells are the origin of cardiac myxoma. PMID- 29755078 TI - [Re-expansion Pulmonary Edema after Surgery for Spontaneous Tension Hemopneumothorax;Report of a Case]. AB - A 23-year-old man was admitted to our hospital because of chest pain and dyspnea. X-ray and computed tomography showed left tension hemopneumothorax. After the emergent surgery, re-expansion pulmonary edema (RPE) occurred. Non-invasive positive pressure ventilation (NPPV) was applied to control RPE and RPE was successfully recovered. NPPV may be useful in managing RPE. PMID- 29755079 TI - [Micronodular Thymoma with Lymphoid Stroma;Report of a Case]. AB - We report a surgical case of micronodular thymoma with lymphoid stroma (MNT), which is a rare type of thymoma. A 66-year-old man was referred to our hospital for further examination and treatment of a nodule in the mediastinum. Computed tomography(CT) showed a 20-mm nodule in the anterior mediastinum, and positron emission tomography-CT showed slight uptake in the same region. Thymoma was suspected and videoassisted thymectomy was performed. Histopathological findings showed spindleshaped tumor cells forming storiform, with the background of lymphoid stroma, and the tumor was diagnosed as MNT. The long-term outcome after resection of MNT currently remains unclear, and accumulation of further cases is required. PMID- 29755080 TI - [Atypical Pulmonary Carcinoid Tumor with Elevated Serum ProGRP;Report of a Case]. AB - We report a case of an atypical pulmonary carcinoid with high serum ProGRP. A 78 year-old man was found to have an abnormal shadow by a chest X-ray. Chest computed tomography (CT) revealed a solitary pulmonary nodule in the right middle lobe, which was homogeneous, well demarcated, and round. The level of serum ProGRP was elevated to 104.6 pg/ml (normal<81 pg/ml). The nodule was suspected to be a pulmonary carcinoid tumor, and a right middle lobectomy with mediastinal lymph node dissection was performed. Histopathological diagnosis was an atypical pulmonary carcinoid. Pro-GRP decreased to be normal level 5 month after operation. PMID- 29755081 TI - [Assessment of Surgical Treatment for Chronic Pulmonary Aspergillosis]. AB - OBJECTIVES: The purpose of this study is to assess retrospectively our treatment strategy for chronic pulmonary aspergillosis(CPA). PATIENTS AND METHOD: From 2002 to 2015, 11 patients underwent pulmonary resection for CPA in our hospital. Six patients were diagnosed simple pulmonary aspergilloma (SPA) and 5 were chronic progressive pulmonary aspergillosis(CPPA). Clinical characteristics, preoperative treatment, postoperative treatment, surgical procedure, postoperative complication, recurrence, and prognosis were retrospectively reviewed. RESULTS: Two patients of SPA and 5 of CPPA were treated with antifungal agents preoperatively. Two patients required wedge resection and 4 required lobectomy in SPA. Five patients required lobectomy in CPPA. All patients were treated with antifungal agents postoperatively. One patient presented recurrent disease in both SPA and CPPA. All patients has been alive. CONCLUSION: Surgical resection of CPA leads good results in selected patients. The treatment with surgery with perioperative antifungal treatment is thought to be important based on our experience. PMID- 29755082 TI - [Pulmonary Pleomorphic Carcinoma Relapsed after Surgery Surviving Long-term by Chemotherapy and Nivolumab]. AB - A 60'-year-old man was referred to our hospital because of nodular shadow found at mass screening. We diagnosed the tumor as non-small cell lung cancer by transbronchial biopsy. Chest computed tomography showed a tumor shadow of 3 cm in diameter with cavity. Right middle lobectomy was performed and the pathological diagnosis was pleomorphic carcinoma of the lung. The tumor recurrence was found at 10 months after surgery, and was treated with cisplatin, docetaxel plus bevacizumab for 6 cycles. A complete remission was achieved, but regrowth at 5 months after chemotherapy was noted. The patient was treated with nivolumab following carboplatin, gemcitabine plus bevacizumab 3 cycles. A good partial response is continuing 2 years and 5 months after confirming recurrence. PMID- 29755083 TI - [Growth Process of Cystic Lung Cancer Followed with Computed Tomography Findings Over 5 Years]. AB - An estimated 2~16% of primary lung cancers form cavities with cases that form thin-walled cavities being comparatively rare. We treated a patient with squamous cell carcinoma of the lung with a small cystic shadow that showed no changes for 3 years. The cyst then suddenly grew larger, after which the cyst wall thickened over time and a thin-walled cavity was seen. Here we report this important case showing the development process of lung cancer that formed a thin-walled cavity, together with a discussion of the literature. PMID- 29755084 TI - [Further Surgery for Mitral Stenosis 12-years after Mitral Valve Repair;Report of a Case]. AB - A rare case of mitral stenosis after mitral valve repair for non-rheumatic mitral regurgitation is presented. An 81-year-old woman who had undergone mitral valve repair using an annuloplasty ring 12 years earlier, was referred to our hospital because of dyspnea during exertion. As echocardiography revealed severe mitral stenosis, and redo surgery was carried out. During the surgery, fibrous tissue covered the annuloplasty ring and extended onto both leaflets of the mitral valve, which narrowed its orifice, by rendering the leaflets stiff and immobile. It was not possible to remove the fibrous tissue covering the mitral valve without damaging the leaflets. Hence, the annuloplasty ring and both leaflets were excised. The mitral valve was replaced with a 27 mm Magna Mitral Ease, and subsequently, postoperative course was uneventful. PMID- 29755085 TI - [Subdural Hematoma after Open Heart Surgery for Infective Endocarditis Presenting with Pre-operative Intracranial Hemorrhage Infarction;Report of a Case]. AB - A 47-year-old woman with a history of radiation enteritis and implantation of a central venous port was admitted to our intensive care unit(ICU) suffering from high fever. She was diagnosed with active infective endocarditis due to catheter related blood stream infection. Although echocardiography showed a large vegetation on the mitral valve, surgical therapy was postponed for 5 weeks because of intracranial hemorrhage infarction. On the 3rd day after mitral valve repair, she developed consciousness disturbance and computed tomography(CT) revealed acute subdural hematoma of the posterior cranial fossa. Fortunately, she fully recovered from the neurological complication without surgical intervention. PMID- 29755086 TI - [Total Arch Replacement with Concomitant Thoracic Endovascular Aortic Repair Via the Ascending Aorta for Extended Thoracic Aneurysm;Report of a Case]. AB - The patient was a 66 year-old male. Computed tomography (CT) angiography showed a huge aneurysm(120 mm) in the aortic arch and chronic type B aortic dissection(45 mm) in the descending aorta. Echocardiography showed patent ductus arteriosus( PDA). Because of pulmonary hypertension due to PDA, it was considered unacceptable to put him under general anesthesia twice. We performed thoracic endovascular aortic repair (TEVAR) via the ascending aorta and total arch replacement (TAR) simultaneously to prevent paraplegia. After establishment of cardiopulmonary bypass( CPB), a stent graft was inserted via the ascending aorta to cover the dissection site of descending aorta, the aorta was opened under circulatory arrest, and PDA was suture closed. Another stent graft whose two proximal rows of Z-stent was removed, was inserted to descending aorta via the ascending aorta landing on the previous stent graft. The proximal end of this stent graft was anastomosed to the distal end of the prosthetic arch graft and arch branches were reconstructed as usual. The postoperative course was uneventful. PMID- 29755087 TI - [Successful Echo-guided Deployment of Stent Graft for Intraoperative Retrograde Aortic Dissection and Rupture;Report of a Case]. AB - We report a case of chronic dissecting thoracoabdominal aneurysm with intraoperative retrograde aortic dissection and rupture at proximal descending aorta, which was successfully treated by echoguided stent-graft insertion. An 82 year old male underwent thoracoabdominal aortic replacement for dilatation of infra-diaphragmatic aorta. Under F-F bypass, his thoracoabdominal aorta was replaced by a Dacron graft with 4-branches. After he weaned from F-F bypass, we found massive bleeding from proximal descending aorta. Trans-esophageal echocardiography (TEE) showed aortic dissection from the clamp site to the distal anastomotic site of the former total arch replacement. We temporary got hemostasis by suture and surgical glue, and anastomosed a 10 mm-graft to the thoracoabdominal main graft as conduit, then inserted and deployed 2 pieces of stent-graft. Direct echo and TEE contributed to the accurate positioning of them. Bleeding was completely controlled. He well recovered without paraplegia. Post operative computed tomography (CT) showed good positioning and dilatation of the stentgraft and the perfect reverse remodeling of thoracic aorta. PMID- 29755088 TI - [Hybrid Repair of Distal Arch Aortic Aneurysm:Total Aortic Arch Repair with the Lupiae Vascular Graft and Thoracic Endovascular Aortic Repair;Report of Two Cases]. AB - Surgical treatment for distal arch aortic aneurysm is generally invasive, and there is no definitive approach for it. We report 2 cases of men who was admitted for the treatment of aortic aneurysm. First case is a 78-year-old man. Two saccular aneurysm were observed on distal aortic arch and descending aorta by contrast-enhanced computed tomography. Two staged-repair was performed with using the Lupiae vascular graft and thoracic endovascular aortic repair(TEVAR). The postoperative course was uneventful, and he was discharged on day 21 after 1st operation. Second case is a 68-yearold man. Dessecting aneurysm was observed on distal aortic arch and descending aorta 3 months after incidence of type B aortic dissection. Two staged-repair was performed with using the Lupiae vascular graft and TEVAR. However, additional TEVAR was performed for enlargement of descending aorta half a year after 1st operation. Two staged-repair using Lupiae vascular graft and TEVAR was useful for alleviating a burden of a patient and avoiding paraplegia. PMID- 29755089 TI - [Surgical Repair of Kommerell's Diverticulum with Right Sided Aortic Arch;Report of a Case]. AB - A 54-year-old woman was referred for assessment of dysphagia and extrinsic compression of the esophagus detected by upper gastrointestinal endoscopy. Computed tomography revealed the rightsided aortic arch with mirror image branching and Kommerell's diverticulum. To relieve the esophageal compression, surgical intervention was indicated. Descending aortic replacement with a Dacron graft was performed through right thoracotomy under partial cardiopulmonary bypass. The patient was discharged without any complication, and her dysphagia disappeared. PMID- 29755090 TI - [Successful Surgical Repair of the Aortic Annular Infective Endocarditis with Subvalvular Abscess;Report of a Case]. AB - A 49-year-old female was admitted to our hospital with a history of fever for 2 weeks and consciousness disorder.Transthoracic echocardiography demonstrated aortic regurgitation with a mobile fibrous band adhering to the right cusp. Infective endocarditis was diagnosed by positive blood culture and echocardiographic findings. Emergent aortic valve surgery was performed because of uncontrollable infection. A destroyed aortic annulus and subvalvular abscess was found during the operation. Removal of abscess tissue and annuloplasty with self-pericardium were successfully performed. PMID- 29755091 TI - [Coil Embolization of Bronchial Artery Aneurysm;Report of a Case]. AB - An 82-year-old male was admitted due to mild chest discomfort. Enhanced computed tomography showed a large bronchial artery aneurysm(BAA) of 26*27 mm at the left hilus. To avoid the rupture of BAA, coil embolization alone was performed. There has been no enlargement of BAA for these 4 years. In general, coil embolization only should be indicated in a patient with BAA with a stalk because of thoracic endovascular aortic repair (TEVAR) being off-label and low cost performance. TEVAR would be considered as a last resort only in case of enlarging BAA even after coil embolization. PMID- 29755092 TI - [Two-stage Surgery for Uterine Intravenous Leiomyomatosis with Right Ventricular Extension;Report of a Case]. AB - Intravenous leiomyomatosis is a rare neoplastic condition characterized by the benign intravascular proliferation of smooth muscle cells originating from either the uterine venous wall or a uterine leiomyoma. In the present report, we describe the case of a 36-year-old woman, who was referred to our institution due to abdominal pain. Computed tomography indicated the presence of a giant intravenous leiomyoma originating from the uterus and extending to the right ventricle with complex pathways. The patient was successfully treated by tumor resection under circulatory arrest in two-stage operations in conjunction with gonadotrophin-releasing hormone agonists therapy. She continued to recover and did not exhibit any recurrence at the 8-month follow-up. PMID- 29755093 TI - [Concomitant Atrial Septal Defect Closure and Repair of Pectus Excavatum in a 50 year-old Patient;Report of a Case]. AB - We report a case of atrial septal defect (ASD) with severe pectus excavatum. A 50 year-old female had a stroke due to paradoxical embolism from deep vein thrombosis thorough ASD. Her preoperative computed tomography(CT) revealed a severe pectus excavatum (Haller CT index 28.6). The patient underwent ASD closure and repair of the pectus excavatum concomitantly. Median full sternotomy was performed for ASD closure. And we adopted sterno-costal elevation for pectus excavatum repair. Cartilages of the 3rd to the 7th rib were segmentally resected and the remainders were re-sutured to the sternum. The operation was performed uneventfully. The postoperative echocardiogram revealed no residual shunt. And the deformity of the anterior chest wall was remarkably lessen. PMID- 29755094 TI - [Giant Intrathoracic Goiter Requiring Emergency Airway Management;Report of a Case]. AB - An 81-year-old woman with acute respiratory distress was referred to our hospital. Computed tomography showed a large mass in the upper mediastinum with severe tracheal stenosis. Endotracheal intubation was performed under the preparation of extracorporeal membrane oxygenation and high-frequency jet ventilation, and the tumor was completely removed. The pathologic diagnosis was a goiter. Post-operatively, respiratory distress disappeared. No tumor recurrences have been noted for more than 2 years after surgery. PMID- 29755095 TI - [Mediastinal Bronchial Artery Aneurysm Associated with Bronchiectasis;Report of a Case]. AB - The patient was a 66-year-old man who had treated with bronchiectasis. He was admitted to our hospital because of hemoptysis. A chest plain computed tomography (CT) showed bronchiectasis in the left lower lobe and nodular lesion in the mediastinum. Chest contrast CT revealed a left bronchial artery aneurysm, and hyperplastic left bronchial arteries dilating and winding toward the left lower lobe. We performed selective angiography of the bronchial artery, revealing an aneurysm, and we performed 3 times of bronchial arterial embolization( BAE). He was performed surgery at 7th day following BAE. After postoperative empyema treatment, he was discharged on the 124th postoperative day. PMID- 29755096 TI - [Role of Surgery in Multimodality Treatment for Non-small Cell Lung Cancer;Current Status and Future Perspectives]. AB - Recent improvement of outcomes for resected non-small cell lung cancer (NSCLC) has been contributed not only by increased detection of early-stage disease and improvement of preoperative diagnosis/perioperative management but also by improvement of multimodality treatment. The introduction of newly developed systemic therapies including molecular targeted agents and immune checkpoint inhibitors dramatically changed clinical outcomes of advanced NSCLC. Accordingly, the role of surgery during the multimodality treatment will be changed more than ever. In this article, we overviewed the current status of the multimodality treatment for clinical stageIII (N2)disease and postoperative adjuvant therapy and discussed the role of surgery during these situations. We also discussed the future perspectives of the role of surgery during the multimodality treatment for advanced NSCLC. PMID- 29755097 TI - [Expectation for Surgery in Multi-modality Treatment in Non-small Cell Lung Cancer]. AB - Clinical N2-stageIIIA non-small cell lung cancer(NSCLC) is known to be quite heterogeneous. Many clinical trials proved the effect of postoperative adjuvant chemotherapy for locally advanced NSCLC, which is recommended as grade C1 by Clinical Guideline for Lung Cancer, however, induction treatment for clinical N2 stageIIIA remains still controversial. We showed retrospective data of concurrent chemoradiotherapy using S-1 and cisplatin followed by surgery, which may provide a better prognosis for locally advanced NSCLC patients. In addition, we summarized the findings of prospective clinical trials for treatment of clinical N2-stageIIIA NSCLC patients. PMID- 29755098 TI - [Present Status and Future Issues of Multidisciplinary Treatment of Lung Cancer from the Viewpoint of a Respiratory Surgeon]. AB - With the advent of molecular targeted therapeutic agents and immunity checkpoint inhibitors, lung cancer drug therapy has advanced. We cannot expect to improve the performance of surgical treatment without drug therapy. The problem of improving the performance of surgical treatment for lung cancer is:1 the role of surgery in multidisciplinary treatment for c-stageIII N2 lung cancer, 2 post operative adjuvant therapy, 3 multidisciplinary treatment of post-operative recurrence, 4 salvage surgery, and 5 sublobar resection in high risk cases. We will describe each of these with reference to our own experiences and literature considerations. PMID- 29755099 TI - [The Role of Video-assisted Thoracic Surgery in Multimodality Therapy]. AB - Minimally invasive surgery is being widely performed for the management of lung cancers owing to rapid technological advances in surgical devices and techniques. In recent times, because chemotherapy and radiotherapy have both become less invasive treatment strategies, therapeutic opportunities for the use of multimodality therapy have been increasing. Minimally invasive surgery is an important component that requires additional improvements to derive the complete benefit of multimodality therapy. We have been actively performing video-assisted thoracic surgery(VATS) for the management of advanced lung cancers, as well as early lung cancers to reduce surgical stress in our patients, thereby enhancing the scope of multimodality therapy. Although some reports have demonstrated the efficacy of VATS for the management of early lung cancers, only a limited number of reports have discussed the advantage of VATS for the management of advanced lung cancers. In this report, we reviewed patients with advanced lung cancer (pathological stageII or III) in whom complete resection was performed between January 2011 and December 2016, and we examined the role of VATS as a component of multimodality therapy. PMID- 29755100 TI - [Induction Chemoradiotherapy for Locally Advanced Non-small Cell Lung Cancer]. AB - The management of locally advanced non-small cell lung cancer (LA-NSCLC) is still controversial, because of complicated patient status and poor prognosis. The purpose of this study was to evaluate the treatment results for induction chemoradiotherapy (iCRT) followed by surgery for LA-NSCLC. From 1999 to 2016, 157 patients were surgically treated after iCRT in our hospital, and their median follow-up was 43 months. Overall survival( OS) was 66.8%, and relapse-free survival( RFS) was 52.0%. The poor prognostic factor in OS by multivariate analysis was lower-lobe origin, incomplete radiotherapy, reoperation, and RFS was lower-lobe origin. The result of our hospital was feasible compared with definitive CRT. The definitive CRT is mainstream for treatment of LA-NSCLC and adjuvant anti-programmed death ligand 1 antibody will influence the treatment strategy, however there are some patients who can get benefit only by iCRT followed by surgery. iCRT followed by surgery is one of the feasible treatment for LA-NSCLC. PMID- 29755101 TI - [Outcome of Surgical Treatment of Locally Advanced Lung Cancer after Induction Chemoradiotherapy]. AB - OBJECTIVE: The outcome of surgical treatment of non-small-cell lung cancer after induction chemoradiotherapy was investigated. SUBJECTS: The subjects were 74 patients with non-small-cell lung cancer who received induction chemoradiotherapy( ICRT) between 1998 and 2016. ICRT was administered to pT3 lung cancer invading the chest wall(20 patients), pT4 lung cancer invading the adjacent organ(22 patients), and cN2 lung cancer(32 patients). cN2 was confirmed by mediastinoscopy(13 patients) and endobronchial ultrasound-guided transbronchial needle aspiration(EBUS-TBNA)(19 patients). RESULTS: Sixty-eight and 6 patients were male and female, respectively, and the mean age was 59.6 years old. The histologic type was adenocarcinoma in 43 patients, squamous cell carcinoma in 24, adenosquamous carcinoma in 5, and others in 2. In chemotherapy, 2 or more anticancer drugs including platinum agent were administered. The radiation dosage was 36 Gy in 1 patient, 40 Gy in 43, 50 Gy in 28, and 60 Gy in 2. The effect of ICRT was complete response( CR) in 1 patient, partial response( PR) in 40, and stable disease (SD) in 33 (CR+PR:55.4%). The surgical procedure was lobectomy in 60 patients, pneumonectomy in 10, bilobectomy in 3, and segmentectomy in 1. Tracheobronchoplasty was performed in 9 patients, and combined resection of the vertebral body, left atrium, carina, superior vena cava, aorta, and brachiocephalic subclavian artery was performed in 7, 5, 4, 3, 3, and 3 patients, respectively. Regarding postoperative complications, empyema developed in 5 patients, acute respiratory distress syndrome(ARDS)in 3, pneumonia in 3, tracheobronchial dehiscence in 2, postoperative hemorrhage in 1, atrial fibrillation in 1, and others in 5. Postoperative complication rate was 27.0%, and operative death occurred due to postoperative hemorrhage in 1 patient. Complete resection was achieved in 69 patients(93.2%). Regarding the histological effect of ICRT, Ef.1/2/3 = 32/28/14(Ef.2-3:56.7%), and down stage was achieved in 24 patients (32.4%). The 5-year survival rate of all 74 patients was 51.0%, median survival time (MST)was 62.7 months, and the recurrence-free survival rate was 47.3%. Recurrence occurred in 28 patients (40.6%)with complete resection and the recurrence was distant metastasis in 20 of them. Regarding the outcome by the effect of ICRT, the 5-year survival rates of patients who achieved CR+PR/SD, Ef.2 3/Ef.0-1, and down stage/non-down stage were 66.0%/34.3%(p=0.009), 73.2%/20.1%(p=0.001), and 83.7%/44.0%(p=0.02), respectively, showing that the outcomes of patients who achieved CR/PR, Ef.2-3, and down stage were significantly favorable. CONCLUSION: The morbidity and mortality rates of patients who underwent surgery after ICRT were 27 and 1.4%, respectively. More than half of the patients achieved CR-PR and Ef.2-3, 1/3 of the cases were down staged, and the outcomes of these patients were significantly favorable. Surgery after ICRT may improve the treatment outcome of patients with locally advanced lung cancer. PMID- 29755102 TI - [Multimodality Therapy for Lung Cancer with Chest Wall Invasion]. AB - The standard therapy for patients with T3N0-1M0 non-small cell lung cancer (NSCLC) involving the chest wall is considered initial resection and adjuvant chemotherapy. However, the compliance of adjuvant therapy is relatively low, and the prognosis for those patients has not been satisfactory. We therefore advocated a new strategy of induction chemoradiotherapy followed by surgery and conducted a prospective, multi-institutional phaseII trial with the aim of improving the survival. The mature results of this trial showed the treatment strategy to be safe and effective with a high rate of pathologic response. We also reviewed surgical cases in our hospital retrospectively. Induction therapy was administered for a half of patients with NSCLC involving the chest wall, and a pathologic complete response (Ef.3) was obtained in 23% of those cases with an excellent prognosis. We therefore conclude that induction therapy, especially chemoradiotherapy, would increase the possibility of cure for NSCLC patients with chest wall invasion. PMID- 29755103 TI - [When Should We Perform Surgery for N2 Lung Cancer?;Induction Chemoradiotherapy or Surgery for Local Recurrence or Residual Tumor after Definitive Chemoradiotherapy]. AB - BACKGROUND: Standard treatment for locally advanced clinical N2 lung cancer is definitive chemoradiotherapy, and induction chemoradiotherapy(IND-CRT) followed by surgery is an option. Most of them recurs remotely within a few years after initial therapy. Patients who received salvage surgery(SAL) after definitive chemoradiotherapy had no remote relapse for some period after definitive chemoradiotherapy, thus the outcome of SAL may be better than those of IND-CRT, but the operative risks of both procedures seem to be high. OBJECTIVE: To compare the prognosis and risk of SAL and IND-CRT. METHOD: From January 2001 through December 2015, 39 patients with clinical N2 primary lung cancer underwent surgery after chemoradiotherapy. Twenty-six patients received IND-CRT, and 13 underwent SAL. Perioperative factors, overall survival rates at 5 years, lung-cancer specific mortality, relapse-free survival rates, and the rates of perioperative complications were compared between the groups. RESULT: The median follow up period was 41.0 months(5~120 months). Twelve patients were women, and 27 were men. The average age was 60.2 years. The patients comprised 1.7% of the 2,330 anatomical resections performed during the same period. The radiation dose was 46.4 Gy who received IND-CRT and 61.4 Gy in those who received SAL(p<0.001). In patients who received IND-CRT, median period from the end of the initial treatment to surgery was 1.2 months in IND-CRT and 17.2 months in SAL. Lobectomy was performed in 37 patients, pneumonectomy in 2 patients. In patients who received IND-CRT, an average operation time was 236 minutes, mean bleeding volume was 135 g. In patients who underwent SAL, they were 236 minutes and 188 g(p=0.998, p=0.365). There was no perioperative and in-hospital death in either group. Postoperative complications developed in 5 of INDCRT(19.2%)and 3 in SAL(23.1%). The 5-year overall survival rate of all cases was 60.4%(IND-CRT 53.9, SAL 81.8%;p=0.737). The lung cancer-specific survival rate at 5 years was 60.4% overall, 57.5% in IND-CRT, and 90.0% in SAL(p=0.176). The 5-year relapse-free survival rate was 52.7% overall, 37.6% in IND-CRT, 57.7% in SAL(p=0.175). Although the differences were not statistically significant, SAL tended to have better outcomes. CONCLUSION: SAL did not differ significantly from IND-CRT with respect to postoperative complications or surgical invasiveness in patients with clinical N2 lung cancer and had good outcomes. SAL and IND-CRT seem to be a sufficiently meaningful treatment but should be performed by surgeons with sufficient knowledge and experience. PMID- 29755104 TI - [Multidisciplinary Approach to Recurrence after Resection of Primary Lung Cancer]. AB - BACKGROUND: The standard approach for treating recurrence after complete resection of primary non-small cell lung cancer has been controversial. We present here a multidisciplinary strategy for postoperative recurrence in patients with primary lung cancer. PATIENTS AND METHODS: Over the last 7 years, we examined the disease-free survival and overall survival of 70 patients who underwent multidisciplinary treatment for recurrence after surgical resection of primary lung cancer. RESULTS: The median overall survival was 32.3 months after surgery and 17.4 months after recurrence developed, indicating significantly better prognoses in females and in patients with adenocarcinoma, stage I disease, driver mutation positivity, a longer postoperative disease-free period, and never smokers. Eight patients survived more than 5 years after recurrence;of these patients, all had adenocarcinomas, 7 had oligometastases and/or tumor dormancy, and 5 received multiple-drug regimens. CONCLUSION: Multidisciplinary treatment for recurrence after resection of primary lung cancer was effective for patients receiving various drug regimens. In patients with oligometastases, disease control was achieved by a combination of local treatments targeting each involved organ. In patients with tumor dormancy, follow-up or a drug holiday was important to maintain the patient's quality of life. PMID- 29755105 TI - Current and Potential Future Seasonal Trends of Indoor Dwelling Temperature and Likely Health Risks in Rural Southern Africa. AB - Climate change has resulted in rising temperature trends which have been associated with changes in temperature extremes globally. Attendees of Conference of the Parties (COP) 21 agreed to strive to limit the rise in global average temperatures to below 2 degrees C compared to industrial conditions, the target being 1.5 degrees C. However, current research suggests that the African region will be subjected to more intense heat extremes over a shorter time period, with projections predicting increases of 4-6 degrees C for the period 2071-2100, in annual average maximum temperatures for southern Africa. Increased temperatures may exacerbate existing chronic ill health conditions such as cardiovascular disease, respiratory disease, cerebrovascular disease, and diabetes-related conditions. Exposure to extreme temperatures has also been associated with mortality. This study aimed to consider the relationship between temperatures in indoor and outdoor environments in a rural residential setting in a current climate and warmer predicted future climate. Temperature and humidity measurements were collected hourly in 406 homes in summer and spring and at two hour intervals in 98 homes in winter. Ambient temperature, humidity and windspeed were obtained from the nearest weather station. Regression models were used to identify predictors of indoor apparent temperature (AT) and to estimate future indoor AT using projected ambient temperatures. Ambient temperatures will increase by a mean of 4.6 degrees C for the period 2088-2099. Warming in winter was projected to be greater than warming in summer and spring. The number of days during which indoor AT will be categorized as potentially harmful will increase in the future. Understanding current and future heat-related health effects is key in developing an effective surveillance system. The observations of this study can be used to inform the development and implementation of policies and practices around heat and health especially in rural areas of South Africa. PMID- 29755106 TI - A Rare Case of Adult-Onset Rectosigmoid Hypoganglionosis. AB - BACKGROUND Intestinal hypoganglionosis is very rare and accounts for 3% to 5% of all classified congenital intestinal innervation disorders. Isolated hypoganglionosis of the colon is a particularly rare form of the disease, and differential diagnosis includes association with Hirschsprung's disease and chronic intestinal pseudo-obstruction (CIPO) related to visceral myopathies. Most cases are diagnosed at an early age or in childhood with only a few cases reported in adults. CASE REPORT We report a case of isolated hypoganglionosis of the rectum and sigmoid presenting as an emergency with acute intestinal obstruction in a 20-year-old male patient. A history of chronic constipation was reported since childhood, but this condition had never been investigated. A preoperative CT scan showed a megasigmoid and megarectum. A Hartmann's procedure was performed. The patient made a slow recovery and was discharged on the 12th postoperative day in good condition. Histology showed features consistent with isolated hypoganglionosis, and a full thickness rectal biopsies taken 2 months later confirmed the diagnosis. CONCLUSIONS Isolated hypoganglionosis in an adult is very rare, and a high index of suspicion is warranted in young patients with a history of chronic constipation to avoid delayed presentation as an emergency. PMID- 29755107 TI - KAI1/CD82 Genetically Engineered Endothelial Progenitor Cells Inhibit Metastasis of Human Nasopharyngeal Carcinoma in a Mouse Model. AB - BACKGROUND Endothelial progenitor cells (EPCs) are regarded as promising targeted vectors for delivering therapeutic genes or agents in cancer therapy. The purpose of this study was to investigate the role of intravenously administered KAI1/CD82 genetically transduced EPCs in the tumorigenesis and metastasis of nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS EPCs were isolated from human umbilical cord blood, expanded in culture, and stably transduced with lentiviral vectors expressing KAI1/CD82. The KAI1/CD82 EPCs were injected intravenously into nude mice bearing human NPC xenografts. Tumor growth and the incidence of liver and lung metastases were observed. Expression of KAI1/CD82 was determined by immunofluorescent staining. RESULTS The NPC model was successfully established. Tumor growth was not suppressed when mice were injected with KAI1/CD82 EPCs (KAI1/CD82 EPCs group) compared with when non-transduced EPCs was present (EPCs group) or the control (1.485+/-0.234, 1.388+/-0.204, and 1.487+/-0.223g, respectively; P>0.05). However, the incidence of lung metastasis was significantly reduced in the KAI1/CD82+ EPCs group compared with the EPCs group and the control group (10%, 55% and 45%, respectively; P=0.005), and there was a significant decrease in the number of metastatic foci on the lung surface (17.50+/-3.54, 34.27+/-5.35, and 38.44+/-9.63 respectively; P=0.007). Moreover, KAI1/CD82 was expressed in lung metastatic foci of the KAI1/CD82 EPCs group, but not in the EPCs group and control group. CONCLUSIONS EPCs can be used as a delivery vehicle for suppressor genes KAI1/CD82 to NPC, and the migration of KAI1/CD82 genetically engineered EPCs can inhibit NPC lung metastasis in a mouse model. PMID- 29755108 TI - [Physical activity questionnaires: a systematic review and analysis of their psychometric properties in Spanish population over 60 years old]. AB - BACKGROUND: Questionnaires for estimating physical activity are measurement tools widely used by health professionals. Therefore, it is important to know their characteristics and quality. This systematic review aimed at identifying and analyzing de psychometric properties of the existing physical activity questionnaires validated in Spanish people older than 60 years of age, as well as to inform about the methodological quality of the studies performed concerning their validity and/or reliability. METHODS: A systematic review of the available scientific literature regarding studies focused on the validity and/or reliability of questionnaires used for estimating the prevalence of physical activity among Spanish populations over 60 years old. The Qualitative Attributes and Measurement Properties of Physical Activity Questionnaires checklist (QAPAQ), was used to evaluate the sample characteristics, the psychometric properties, the validity, the test-retest reliability and the methodological quality of each study identified. RESULTS: A total of 8 questionnaires were found and analyzed, highlighting in means of validity the short Spanish version (VREM) of the Minnesota Leisure Time Physical Activity Questionnaire (construct validity 95.5% with Kappa = 0.93) as well as in reliability (ICC=0.96), along with the Modified Baecke (ICC = 0,92-0,96). Four questionnaires met more than 80% of the criteria proposed by the QAPAQ. The YPAS was the questionnaire which reached the higher score. CONCLUSIONS: When estimating the amount of physical activity performed by Spanish people older than 60 years of age by means of questionnaires, it is advisable to use (in this order) the YPAS, VREM and Modified Baecke. PMID- 29755110 TI - Endostatin gene therapy delivered by attenuated Salmonella typhimurium in murine tumor models. AB - Salmonella typhimurium (hereafter S. typhimurium), as Gram-negative facultative anaerobic bacteria, are good candidates for cancer therapy and delivering therapeutic antitumor agents. However, it is necessary to reduce the virulence of such bacteria and enhance their tumor-targeting ability, and their immunostimulatory ability to induce tumor cell apoptosis. In this study, we constructed a S. typhimurium mutant named S634 harboring aroA mutation and additional mutations involved in modifications of lipid A. Upon intraperitoneal infection in mice, the aroA-deficient strain S634 showed greatly attenuated virulence and preferential accumulation within tumor tissue. We next investigated the ability of S636, the asd mutant derivative of S634, to deliver the anti angiogenic agent "endostatin" (S636/pES) and to inhibit tumor growth in mouse CT26 colon carcinoma and B16F10 melanoma models. S636/pES-treated tumor-bearing mice showed suppressed tumor growth and prolonged survival, compared to mice treated with either the bacteria carrying empty plasmids or PBS intraperitoneally. Immunohistochemical studies demonstrated that, when tumor bearing mice were infected with S636/pES, Salmonella colonization and endostatin expression were accompanied by the increase of apoptosis level and suppression of tumor angiogenesis within tumor tissues. Our findings showed that endostatin gene therapy delivered by attenuated S. typhimurium displays therapeutic antitumor effects in murine tumor models. PMID- 29755109 TI - Regulated intratumoral expression of IL-12 using a RheoSwitch Therapeutic System(r) (RTS(r)) gene switch as gene therapy for the treatment of glioma. AB - The purpose of this study was to determine if localized delivery of IL-12 encoded by a replication-incompetent adenoviral vector engineered to express IL-12 via a RheoSwitch Therapeutic System(r) (RTS(r)) gene switch (Ad-RTS-IL-12) administered intratumorally which is inducibly controlled by the oral activator veledimex is an effective approach for glioma therapy. Mice bearing 5-10-day-old intracranial GL-261 gliomas were intratumorally administered Ad-RTS-mIL-12 in which IL-12 protein expression is tightly controlled by the activator ligand, veledimex. Local tumor viral vector levels concomitant with veledimex levels, IL-12-mRNA expression, local and systemic cytokine expression, tumor and systemic flow cytometry and overall survival were studied. Ad-RTS-mIL-12+veledimex elicited a dose-related increase in tumor IL-12 mRNA and IL-12 protein and discontinuation of veledimex resulted in a return to baseline levels. These changes correlated with local immune and antitumor responses. Veledimex crossed the blood-brain barrier in both orthotopic GL-261 mice and cynomolgus monkeys. We have demonstrated that this therapy induced localized controlled production of IL-12 which correlates with an increase in tumor-infiltrating lymphocytes (TILs) leading to the desired biologic response of tumor growth inhibition and regression. At day 85 (study termination), 65% of the animals that received veledimex at 10 or 30 mg/m2/day were alive and tumor free. In contrast, the median survival for the other groups were: vehicle 23 days, bevacizumab 20 days, temozolomide 33 days and anti-PD-1 37 days. These findings suggest that the controlled intratumoral production of IL-12 induces local immune cell infiltration and improved survival in glioma, thereby demonstrating that this novel regulated immunotherapeutic approach may be an effective form of therapy for glioma. PMID- 29755111 TI - Genomic landscape and prognostic analysis of mantle cell lymphoma. AB - To gain insight into the molecular pathogenesis of patients with mantle cell lymphoma (MCL), next-generation whole-exome sequencing of 16 MCL patients was performed. We identified recurrent mutations in genes that are well known to be functionally relevant in MCL, including ATM (37.5%), TP53 (31.3%), WHSC1 (31.3%), CCND1 (18.8%), NOTCH2 (6.3%), and CDKN2A (6.3%). We also identified somatic mutations in genes for which a functional role in MCL has not been previously suspected. These genes included CCDC15, APC, CDH1, S1PR1, ATRX, BRCA2, CASP8, and NOTCH3. Further, we investigated the prognostic factors associated with MCL from clinical, pathological, and genetic mutations. Mutations of TP53 (P = 0.021) was a significant prognostic factor with shorter overall survival (OS). Although there was no statistical difference, the median survival time of patients with WHSC1 mutations was shorter than those without mutations (P = 0.070). Mutations in ATM and CCND1 had no prognostic value (P = 0.552, 0.566). When adjusted for MCL International Prognostic Index (MIPI) or combined MCL-International Prognostic Index (MIPI-c), TP53 and WHSC1 mutations were the most important prognostic factors in MCL (P < 0.05). Our data provide an unbiased view of the landscape of mutations in MCL and commend that all patients benefit from mutations of TP53 and WHSC1 at diagnosis, in addition to MIPI and MIPI-c score. PMID- 29755113 TI - Comment on "How the evolution of multicellularity set the stage for cancer". PMID- 29755112 TI - Tumour buds determine prognosis in resected pancreatic ductal adenocarcinoma. AB - BACKGROUND: The prognostic effect of tumour budding was retrospectively analysed in a cohort of 173 patients with resected pancreatic ductal adenocarcinomas (PDACs) of the prospective clinical multicentre CONKO-001 trial. METHODS: Haematoxylin and eosin (H&E)-stained whole tissue slides were evaluated. In two independent approaches, the mean number of tumour buds was analysed according to the consensus criteria in colorectal cancer, in one 0.785 mm2 field of view and additionally in 10 high-power fields (HPF) (HPF = 0.238 mm2). RESULTS: Tumour budding was significantly associated with a higher tumour grade (p < 0.001) but not with distant or lymph node metastasis. Regardless of the quantification approach, an increased number of tumour buds was significantly associated with reduced disease-free survival (DFS) and overall survival (OS) (10 HPF approach DFS: HR = 1.056 (95% CI 1.022-1.092), p = 0.001; OS: HR = 1.052 (95% CI 1.018 1.087), p = 0.002; consensus method DFS: HR = 1.037 (95% CI 1.017-1.058), p < 0.001; OS: HR = 1.040 (95% CI 1.019-1.061), p < 0.001). Recently published cut offs for tumour budding in colorectal cancer were prognostic in PDAC as well. CONCLUSIONS: Tumour budding is prognostic in the CONKO-001 clinical cohort of patients. Further standardisation and validation in additional clinical cohorts are necessary. PMID- 29755114 TI - AZ304, a novel dual BRAF inhibitor, exerts anti-tumour effects in colorectal cancer independently of BRAF genetic status. AB - BACKGROUND: BRAF mutation is associated with poor clinical outcome of patients with malignant tumours, and mediates resistance to chemotherapy and targeted therapy. This study aimed to determine whether V600E mutant and wild type BRAF colorectal cancers exhibit distinct sensitivities to the dual BRAF inhibitor AZ304. METHODS: Kinase activity was assessed by the AlphaScreen assay. Then, MTT assay, EdU assay, colony-formation assay and Western blot were performed to evaluate the anti-tumour effects of AZ304 in vitro. In vivo efficacy was investigated by xenograft analysis and immunohistochemistry. RESULTS: AZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC50 values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of human cancer cell lines with different BRAF and RAS genetic statuses. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. In addition, the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independently of BRAF mutational status. CONCLUSIONS: The BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo. PMID- 29755116 TI - Health-related quality of life after treatment for bladder cancer in England. AB - BACKGROUND: Little is known about quality of life after bladder cancer treatment. This common cancer is managed using treatments that can affect urinary, sexual and bowel function. METHODS: To understand quality of life and inform future care, the Department of Health (England) surveyed adults surviving bladder cancer 1-5 years after diagnosis. Questions related to disease status, co-existing conditions, generic health (EQ-5D), cancer-generic (Social Difficulties Inventory) and cancer-specific outcomes (Functional Assessment of Cancer Therapy Bladder). RESULTS: In total, 673 (54%) patients responded; including 500 (74%) men and 539 (80%) with co-existing conditions. Most respondents received endoscopic treatment (60%), while 92 (14%) and 99 (15%) received radical cystectomy or radiotherapy, respectively. Questionnaire completion rates varied (51-97%). Treatment groups reported >=1 problem using EQ-5D generic domains (59 74%). Usual activities was the most common concern. Urinary frequency was common after endoscopy (34-37%) and radiotherapy (44-50%). Certain populations were more likely to report generic, cancer-generic and cancer-specific problems; notably those with co-existing long-term conditions and those treated with radiotherapy. CONCLUSION: The study demonstrates the importance of assessing patient-reported outcomes in this population. There is a need for larger, more in-depth studies to fully understand the challenges patients with bladder cancer face. PMID- 29755117 TI - Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study. AB - BACKGROUND: To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixed-dose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours. METHODS: A total of 36 patients with advanced solid tumours received intravenous SHR-1210 at 60 mg, 200 mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The concentration of SHR-1210 was detected for pharmacokinetics, and receptor occupancy on circulating T lymphocytes was assessed for pharmacodynamics. RESULTS: No dose-limiting toxicities were observed. Maximum administered dose was not reached. Most adverse events were grade 1 or 2. Treatment-related severe adverse events were found in two patients. No treatment-related death was reported. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. In responders, the median follow-up time was 16.0 months (range 8.3-19.5), and the median duration of response was not reached (range 2.7-17.5+ months). The half-life of SHR-1210 was 2.94 d, 5.61 d and 11.0 d for 3 dose levels, respectively. CONCLUSIONS: Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration. PMID- 29755115 TI - Endothelial Akt1 loss promotes prostate cancer metastasis via beta-catenin regulated tight-junction protein turnover. AB - BACKGROUND: Cancer research, in general, is focused on targeting tumour cells to limit tumour growth. These studies, however, do not account for the specific effects of chemotherapy on tumour endothelium, in turn, affecting metastasis. METHODS: We determined how endothelial deletion of Akt1 promotes prostate cancer cell invasion in vitro and metastasis to the lungs in vivo in endothelial specific Akt1 knockdown mice. RESULTS: Here we show that metastatic human PC3 and DU145 prostate cancer cells invade through Akt1-deficient human lung endothelial cell (HLEC) monolayer with higher efficiency compared to control HLEC. Although the endothelial Akt1 loss in mice had no significant effect on RM1 tumour xenograft growth in vivo, it promoted metastasis to the lungs compared to the wild-type mice. Mechanistically, Akt1-deficient endothelial cells exhibited increased phosphorylation and nuclear translocation of phosphorylated beta catenin, and reduced expression of tight-junction proteins claudin-5, ZO-1 and ZO 2. Pharmacological inhibition of beta-catenin nuclear translocation using compounds ICG001 and IWR-1 restored HLEC tight-junction integrity and inhibited prostate cancer cell transendothelial migration in vitro and lung metastasis in vivo. CONCLUSIONS: Here we show for the first time that endothelial-specific loss of Akt1 promotes cancer metastasis in vivo involving beta-catenin pathway. PMID- 29755118 TI - Tumour mutation status and melanoma recurrence following a negative sentinel lymph node biopsy. AB - BACKGROUND: A proportion of patients develop recurrence following a tumour negative sentinel lymph node biopsy (SLNB). This study aimed to explore whether melanoma patients with BRAF or NRAS mutant tumours have an increased risk of developing disease recurrence following a negative SLNB compared to patients with wild-type tumours. METHODS: Prospective cohort study of melanoma patients at three tertiary referral centres in Melbourne, who underwent SLNB. Clinical, pathological and molecular characteristics and recurrence data were prospectively recorded. Multivariate Cox proportional hazards regression models estimated the adjusted hazard ratio (aHR) and corresponding 95% confidence interval (CI) for the association between mutation status and development of recurrence following a negative-SLNB. RESULTS: Overall, 344/477 (72.1%) patients had a negative SLNB. Of these, 54 (15.7%) developed subsequent recurrence. The risk of disease recurrence following a negative SLNB was increased for patients with either a BRAF or NRAS mutant tumour compared to wild-type tumours (aHR 1.92, 95% CI: 1.02-3.60, p = 0.04). CONCLUSION: Melanoma patients with BRAF or NRAS mutant tumours had an increased risk compared to patients with BRAF/NRAS wild-type tumours of developing disease recurrence following a tumour-negative SLNB. The findings also confirm the importance of continued surveillance to monitor for disease recurrence among SLNB-negative patients. PMID- 29755119 TI - Predictive potential of tumour-stroma ratio on benefit from adjuvant bevacizumab in high-risk stage II and stage III colon cancer. AB - BACKGROUND: The tumour-stroma ratio (TSR) has proven to be an independent prognostic factor in colon cancer. METHODS: Haematoxylin eosin tissue slides of patients from the AVANT trial were microscopically scored for TSR and categorised as stroma -low or stroma -high. Scores were correlated to the primary and secondary endpoint disease-free survival (DFS) and overall survival (OS). RESULTS: Patients with stroma-high tumours (N = 339, 28%) had a significantly shorter DFS (p < 0.001) compared to stroma-low tumours (N = 824, 68%). In the bevacizumab-FOLFOX-4 arm, DFS was significantly shorter compared to FOLFOX-4 in stroma-low tumours, with a hazard ratio (HR) of 1.94 (95% CI 1.24-3.04; p = 0.004). In stroma-high tumours a trend for better DFS was seen in bevacizumab FOLFOX-4 vs. FOLFOX-4 (HR 0.61 (95% CI 0.35-1.07; p = 0.08)). For bevacizumab XELOX vs. FOLFOX-4, this was not seen (stroma-low HR 1.07 (95% CI 0.64-1.77; p = 0.80); stroma-high HR 0.78 (95% CI 0.47-1.30; p = 0.35)). OS showed the same pattern for bevacizumab-FOLFOX-4 vs. FOLFOX-4 with a HR of 2.53 (95% CI 1.36 4.71; p = 0.003) for stroma-low and HR 0.50 (95% CI 0.22-1.14; p = 0.10) for stroma-high tumours. For bevacizumab-XELOX vs. FOLFOX-4, HR 1.13 (95% CI 0.55 2.31; p = 0.74) for stroma-low tumours and HR 0.74 (95% CI 0.37-1.51; p = 0.41) for stroma-high tumours. CONCLUSIONS: This exploratory analysis suggests a significantly shorter DFS and OS in stroma-low tumours with addition of bevacizumab to intravenous oxaliplatin-based chemotherapy, contrary to stroma high tumours, where a beneficial trend is observed. PMID- 29755121 TI - Assessment of contrast sensitivity by Spaeth Richman Contrast Sensitivity Test and Pelli Robson Chart Test in patients with varying severity of glaucoma. AB - PURPOSE: This study was designed to assess the efficacy, reliability and repeatability of SPARCS (Spaeth Richman Contrast Sensitivity Test) as compared to the conventional Pelli Robson Chart Test for the assessment of contrast sensitivity in patients with glaucoma. MATERIALS AND METHODS: We evaluated 135 eyes of 135 patients who were age and sex matched into three groups (controls, disc suspects and glaucoma) of 45 patients each. The glaucoma subgroup was further divided into subgroups of mild, moderate and severe based on the visual field damage. RESULTS: There was a strong positive correlation between Pelli Robson scores and SPARCS scores (S = 0.807, P < 0.001). Intraclass correlation coefficient (ICC) for Pelli Robson Test was 0.952 and 0.988 for SPARCS. The coefficient of repeatability (COR) for mean SPARCS was 5.65%, while COR of Pelli Robson Test was 12.44%. SPARCS was found to have better repeatability than Pelli Robson Test based on COR values. Pelli Robson score had a sensitivity of 80% and a specificity of 65.6% for detecting glaucoma patients as compared to 84.4% and 70%, respectively, for SPARCS scores. CONCLUSION: SPARCS is a better alternative to conventional Pelli Robson Chart Test for assessment of contrast sensitivity in patients with glaucoma. Being independent of the effects of literacy and educational status, it offers a universal way to measure contrast sensitivity. It can also be reliably used in patients with varying severity of glaucoma. PMID- 29755123 TI - Carcinosarcoma of the esophagus with rapid morphological change. PMID- 29755120 TI - Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study. AB - BACKGROUND: In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. METHODS: The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. RESULTS: Patients <18 months (18 m) showed a better outcome in all stages as compared to older patients (5-year OS in localised stages: <18 m: 0.95 +/- 0.04, >18 m: 0.67 +/- 0.14, p = 0.011; metastatic: <18 m: 0.76 +/- 0.15, >18 m: 0.28 +/- 0.09, p = 0.084). The genomic 'background', but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. CONCLUSIONS: This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA. PMID- 29755122 TI - Eponymous women in ophthalmology: syndromes with prominent eye manifestations named after female physicians. PMID- 29755124 TI - Response to Zorzi et al. PMID- 29755125 TI - Clinical narrative: autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is an inflammatory liver disease that is characterized by circulating autoantibodies, hypergammaglobulinemia, and a lymphoplasmocytic infiltration with interface hepatitis on liver biopsy. Treatment with corticosteroids and other immunosuppressive agents is effective and early diagnosis can result in near-normal life expectancy. Untreated patients, however, can progress to cirrhosis and liver failure. The clinical presentation is heterogeneous and may pose diagnostic and therapeutic dilemmas. This case-based review will address the diagnosis and management of this disease, in addition to difficult but commonly encountered clinical scenarios. PMID- 29755126 TI - NRP-1 interacts with GIPC1 and alpha6/beta4-integrins to increase YAP1/?Np63alpha dependent epidermal cancer stem cell survival. AB - We have identified an epidermal cancer stem (ECS) cell population that drives formation of rapidly growing and highly invasive and vascularized tumors. VEGF-A and neuropilin-1 (NRP-1) are highly expressed in ECS cell tumors and VEGF-A/NRP-1 interaction is required for ECS cell survival and tumor vascularization. We now identify a novel signaling cascade that is triggered by VEGF-A/NRP-1. We show that NRP-1 forms a complex with GIPC1 and alpha6/beta4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/?Np63alpha to enhance ECS cell survival, invasion, and angiogenesis. Loss of NRP-1, GIPC1, alpha6/beta4 integrins, YAP1, or ?Np63alpha reduces these responses. Moreover, restoration of constituently active YAP1 or ?Np63alpha in NRP-1 null cells restores the ECS cell phenotype. Tumor xenograft experiments show that NRP-1 knockout ECS cells form small tumors characterized by reduced vascularization as compared to wild-type cells. The NRP-1 knockout tumors display signaling changes consistent with a role for the proposed signaling cascade. These studies suggest that VEGF-A interacts with NRP-1 and GIPC1 to regulate alpha6/beta4-integrin, FAK, Src, PI3K/PDK1, LATS1 signaling to increase YAP1/?Np63alpha accumulation to drive ECS cell survival, angiogenesis, and tumor formation. PMID- 29755128 TI - Circulating-free tumour DNA and the promise of disease phenotyping in hepatocellular carcinoma. PMID- 29755127 TI - A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR 574-5p-ZEB1 axis in triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients. PMID- 29755129 TI - Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12. AB - The TP53-MDM2-AR-AKT signalling network plays a critical role in the development and progression of prostate cancer. However, the molecular mechanisms regulating this signalling network are not completely defined. By conducting transcriptome analysis, denaturing immunoprecipitations and immunopathology, we demonstrate that the TP53-MDM2-AR-AKT cross-talk is regulated by the deubiquitinating enzyme USP12 in prostate cancer. Our findings explain why USP12 is one of the 12 most commonly overexpressed cancer-associated genes located near an amplified super enhancer. We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer. Consequently, USP12 levels are predictive not only of cancer development but also of patient's therapy resistance, relapse and survival. Therefore, our findings suggest that USP12 could serve as a promising therapeutic target in currently incurable castrate-resistant prostate cancer. PMID- 29755130 TI - Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. AB - Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy. PMID- 29755132 TI - Why rely on friends instead of family? The role of exchanges and civic engagement in a rural sub-Saharan African context. AB - Social science research has shown there is a nearly universal norm of seeking assistance from family members in times of need. However, when do individuals prefer to rely on friends, rather than family members, when they need support? This question has not been carefully addressed. To fill this gap in the literature we examine why rural Malawians - who typically have strong bonds with kin - might prefer to rely on friends instead of family if a crisis were to occur. Using the 2008 and 2010 waves of the Malawi Longitudinal Study of Families and Health (MLSFH), we consider how financial and non-financial exchanges with kin, and civic engagement, are associated with the composition of individuals' support networks. We find the decision to request a friend's help during a crisis is consistently associated with participation in civic-oriented activities, expanding our understanding of the determinants of different risk-pooling strategies. PMID- 29755133 TI - ASSESSMENT OF THE KNOWLEDGE AND PRACTICES OF EXCLUSIVE BREASTFEEDING AMONGST THE BREASTFEEDING MOTHERS IN ADJUMANI DISTRICT, WEST NILE. AB - Background: Despite national policy guidelines advocating exclusive breastfeeding for the first six months of life to promote and accelerate child survival, the proportion of women exclusively breastfeeding for the first six months has remained small. Objective: To describe the knowledge and practices of mothers regarding exclusive breastfeeding in a semi-urban Ugandan population. Design: A descriptive cross-sectional study. Setting: Semi-urban Ugandan population in four parishes in Adjumani District, the West Nile region of Uganda. Subjects: The breastfeeding mothers with infants aged 3-12 months. Results: Of the 385 breastfeeding mothers surveyed, 62.6% (241/385) and 53.5% (206/385) knew the exact meaning and the recommended duration of exclusive breastfeeding respectively. Nearly 68.6% (264/385) initiated breastfeeding within one hour after delivery and only 42.1% (162/385) exclusively breastfed their babies in the first six months of life. For the mothers who initiated non-breast milk feeds before the first six months of birth, most stated the following reasons: 'advice from the home', 'did not know the appropriate time', baby got thirsty and baby was crying at the sight of food'. Conclusion: This study revealed low levels of knowledge and practice of the recommended duration of exclusive breastfeeding among the breastfeeding mothers. Continuous breastfeeding awareness campaigns are needed to improve knowledge and practice of exclusive breastfeeding among breastfeeding mothers. PMID- 29755131 TI - KMT2C mediates the estrogen dependence of breast cancer through regulation of ERalpha enhancer function. AB - Estrogen receptor alpha (ERalpha) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERalpha require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERalpha control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERalpha activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERalpha enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen driven proliferation, it conversely promotes tumor outgrowth under hormone depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERalpha, displaying ongoing sensitivity to ERalpha antagonists. We conclude that KMT2C is a key regulator of ERalpha activity whose loss uncouples breast cancer proliferation from hormone abundance. PMID- 29755134 TI - Social relations and life satisfaction: the role of friends. AB - Social capital is defined as the individual's pool of social resources found in his/her personal network. A recent study on Italians living as couples has shown that friendship relationships, beyond those within an individual's family, are an important source of support. Here, we used data from Aspects of Daily Life, the Italian National Statistical Institute's 2012 multipurpose survey, to analyze the relation between friendship ties and life satisfaction. Our results show that friendship, in terms of intensity (measured by the frequency with which individuals see their friends) and quality (measured by the satisfaction with friendship relationships), is positively associated to life satisfaction. PMID- 29755135 TI - Electromagnetic Field and Radio Frequency Circuit Co-Simulation for Magnetic Resonance Imaging Dual-Tuned Radio Frequency Coils. AB - Electromagnetic (EM) field simulation plays a key role in the design of magnetic resonance imaging radio frequency (RF) coils. However, the values of the components in tuning and matching circuits often need to be iterated repeatedly in the conventional simulation method in order to achieve optimal scattering parameters. This leads to a time-consuming optimization to tune and match RF coils, particularly dual-tuned coils that are comprised of multiple lumped elements. A method combining EM field simulation and circuit simulation was employed in this paper, which can dramatically improve simulation efficiency for the optimization of the values of the lumped elements and corresponding EM field distribution. A systematical theoretical analysis of the co-simulation method was presented. To validate the accuracy and efficiency of the co-simulation method, a comparison study was conducted between the conventional simulation and the proposed co-simulation approaches. PMID- 29755136 TI - Ring faults and ring dikes around the Orientale basin on the Moon. AB - The Orientale basin is the youngest and best-preserved multiring impact basin on the Moon, having experienced only modest modification by subsequent impacts and volcanism. Orientale is often treated as the type example of a multiring basin, with three prominent rings outside of the inner depression: the Inner Rook Montes, the Outer Rook Montes, and the Cordillera. Here we use gravity data from NASA's Gravity Recovery and Interior Laboratory (GRAIL) mission to reveal the subsurface structure of Orientale and its ring system. Gradients of the gravity data reveal a continuous ring dike intruded into the Outer Rook along the plane of the fault associated with the ring scarp. The volume of this ring dike is ~18 times greater than the volume of all extrusive mare deposits associated with the basin. The gravity gradient signature of the Cordillera ring indicates an offset along the fault across a shallow density interface, interpreted to be the base of the low-density ejecta blanket. Both gravity gradients and crustal thickness models indicate that the edge of the central cavity is shifted inward relative to the equivalent Inner Rook ring at the surface. Models of the deep basin structure show inflections along the crust-mantle interface at both the Outer Rook and Cordillera rings, indicating that the basin ring faults extend from the surface to at least the base of the crust. Fault dips range from 13-22 degrees for the Cordillera fault in the northeastern quadrant, to 90 degrees for the Outer Rook in the northwestern quadrant. The fault dips for both outer rings are lowest in the northeast, possibly due to the effects of either the direction of projectile motion or regional gradients in pre-impact crustal thickness. Similar ring dikes and ring faults are observed around the majority of lunar basins. PMID- 29755137 TI - Legal Marriage, Unequal Recognition, and Mental Health among Same-Sex Couples. AB - The authors examined whether the perception of unequal relationship recognition, a novel, couple-level minority stressor, has negative consequences for mental health among same-sex couples. Data came from a dyadic study of 100 (N = 200) same-sex couples in the U.S. Being in a legal marriage was associated with lower perceived unequal recognition and better mental health; being in a registered domestic partnership or civil union - not also legally married - was associated with greater perceived unequal recognition and worse mental health. Actor Partner Interdependence Models tested associations between legal relationship status, unequal relationship recognition, and mental health (nonspecific psychological distress, depressive symptomatology, and problematic drinking), net controls (age, gender, race/ethnicity, education, and income). Unequal recognition was consistently associated with worse mental health, independent of legal relationship status. Legal changes affecting relationship recognition should not be seen as simple remedies for addressing the mental health effects of institutionalized discrimination. PMID- 29755138 TI - Modulation of Surface-Initiated ATRP by Confinement: Mechanism and Applications. AB - The mechanism of surface-initiated atom transfer polymerization (SI-ATRP) of methacrylates in confined volumes is systematically investigated by finely tuning the distance between a grafting surface and an inert plane by means of nanosized patterns and micrometer thick foils. The polymers were synthesized from monolayers of photocleavable initiators, which allow the analysis of detached brushes by size-exclusion chromatography (SEC). Compared to brushes synthesized under "open" polymerization mixtures, nearly a 4-fold increase in brush molar mass was recorded when SI-ATRP was performed within highly confined reaction volumes. Correlating the SI-ATRP of methyl methacrylate (MMA), with and without "sacrificial" initiator, to that of lauryl methacrylate (LMA) and analyzing the brush growth rates within differently confined volumes, we demonstrate faster grafting kinetics with increasing confinement due to the progressive hindering of CuII-based deactivators from the brush propagating front. This effect is especially noticeable when viscous polymerization mixtures are generated and enables the synthesis of several hundred nanometer thick brushes within relatively short polymerization times. The faster rates of confined SI-ATRP can be additionally used to fabricate, in one pot, precisely structured brush gradients, when volume confinement is continuously varied across a single substrate by spatially tuning the vertical distance between the grafting and the confining surfaces. PMID- 29755139 TI - Thermomechanical Properties and Glass Dynamics of Polymer-Tethered Colloidal Particles and Films. AB - Polymer-tethered colloidal particles (aka "particle brush materials") have attracted interest as a platform for innovative material technologies and as a model system to elucidate glass formation in complex structured media. In this contribution, Brillouin light scattering is used to sequentially evaluate the role of brush architecture on the dynamical properties of brush particles in both the individual and assembled (film) state. In the former state, the analysis reveals that brush-brush interactions as well as global chain relaxation sensitively depend on grafting density; i.e., more polymer-like behavior is observed in sparse brush systems. This is interpreted to be a consequence of more extensive chain entanglement. In contrast, the local relaxation of films does not depend on grafting density. The results highlight that relaxation processes in particle brush-based materials span a wider range of time and length scales as compared to linear chain polymers. Differentiation between relaxation on local and global scale is necessary to reveal the influence of molecular structure and connectivity on the aging behavior of these complex systems. PMID- 29755140 TI - Resilience in carbonate production despite three coral bleaching events in 5 years on an inshore patch reef in the Florida Keys. AB - The persistence of coral reef frameworks requires that calcium carbonate (CaCO3) production by corals and other calcifiers outpaces CaCO3 loss via physical, chemical, and biological erosion. Coral bleaching causes declines in CaCO3 production, but this varies with bleaching severity and the species impacted. We conducted census-based CaCO3 budget surveys using the established ReefBudget approach at Cheeca Rocks, an inshore patch reef in the Florida Keys, annually from 2012 to 2016. This site experienced warm-water bleaching in 2011, 2014, and 2015. In 2017, we obtained cores of the dominant calcifying coral at this site, Orbicella faveolata, to understand how calcification rates were impacted by bleaching and how they affected the reef-wide CaCO3 budget. Bleaching depressed O. faveolata growth and the decline of this one species led to an overestimation of mean (+/- std. error) reef-wide CaCO3 production by + 0.68 (+/- 0.167) to + 1.11 (+/- 0.236) kg m-2 year-1 when using the static ReefBudget coral growth inputs. During non-bleaching years, the ReefBudget inputs slightly underestimated gross production by - 0.10 (+/- 0.022) to - 0.43 (+/- 0.100) kg m-2 year-1. Carbonate production declined after the first year of back-to-back bleaching in 2014, but then increased after 2015 to values greater than the initial surveys in 2012. Cheeca Rocks is an outlier in the Caribbean and Florida Keys in terms of coral cover, carbonate production, and abundance of O. faveolata, which is threatened under the Endangered Species Act. Given the resilience of this site to repeated bleaching events, it may deserve special management attention. PMID- 29755141 TI - HUMAN DECISIONS AND MACHINE PREDICTIONS. AB - Can machine learning improve human decision making? Bail decisions provide a good test case. Millions of times each year, judges make jail-or-release decisions that hinge on a prediction of what a defendant would do if released. The concreteness of the prediction task combined with the volume of data available makes this a promising machine-learning application. Yet comparing the algorithm to judges proves complicated. First, the available data are generated by prior judge decisions. We only observe crime outcomes for released defendants, not for those judges detained. This makes it hard to evaluate counterfactual decision rules based on algorithmic predictions. Second, judges may have a broader set of preferences than the variable the algorithm predicts; for instance, judges may care specifically about violent crimes or about racial inequities. We deal with these problems using different econometric strategies, such as quasi-random assignment of cases to judges. Even accounting for these concerns, our results suggest potentially large welfare gains: one policy simulation shows crime reductions up to 24.7% with no change in jailing rates, or jailing rate reductions up to 41.9% with no increase in crime rates. Moreover, all categories of crime, including violent crimes, show reductions; and these gains can be achieved while simultaneously reducing racial disparities. These results suggest that while machine learning can be valuable, realizing this value requires integrating these tools into an economic framework: being clear about the link between predictions and decisions; specifying the scope of payoff functions; and constructing unbiased decision counterfactuals. JEL Codes: C10 (Econometric and statistical methods and methodology), C55 (Large datasets: Modeling and analysis), K40 (Legal procedure, the legal system, and illegal behavior). PMID- 29755142 TI - THE LOCAL INFLUENCE OF PIONEER INVESTIGATORS ON TECHNOLOGY ADOPTION: EVIDENCE FROM NEW CANCER DRUGS. AB - Local opinion leaders may play a key role in easing information frictions associated with technology adoption. This paper analyzes the influence of physician investigators who lead clinical trials for new cancer drugs. By comparing diffusion patterns across 21 new cancer drugs, we separate correlated regional demand for new technology from information spillovers. Patients in the lead investigator's region are initially 36% more likely to receive the new drug, but utilization converges within four years. We also find that superstar physician authors, measured by trial role or citation history, have broader influence than less prominent authors. PMID- 29755143 TI - Likely Transiting Exocomets Detected By Kepler. AB - We present the first good evidence for exocomet transits of a host star in continuum light in data from the Kepler mission. The Kepler star in question, KIC 3542116, is of spectral type F2V and is quite bright at Kp = 10. The transits have a distinct asymmetric shape with a steeper ingress and slower egress that can be ascribed to objects with a trailing dust tail passing over the stellar disk. There are three deeper transits with depths of ? 0.1% that last for about a day, and three that are several times more shallow and of shorter duration. The transits were found via an exhaustive visual search of the entire Kepler photometric data set, which we describe in some detail. We review the methods we use to validate the Kepler data showing the comet transits, and rule out instrumental artefacts as sources of the signals. We fit the transits with a simple dust-tail model, and find that a transverse comet speed of ~35-50 km s-1 and a minimum amount of dust present in the tail of ~ 1016 g are required to explain the larger transits. For a dust replenishment time of ~10 days, and a comet lifetime of only ~300 days, this implies a total cometary mass of ? 3 * 1017 g, or about the mass of Halley's comet. We also discuss the number of comets and orbital geometry that would be necessary to explain the six transits detected over the four years of Kepler prime-field observations. Finally, we also report the discovery of a single comet-shaped transit in KIC 11084727 with very similar transit and host-star properties. PMID- 29755145 TI - Remote C-H Functionalization via Selective Hydrogen Atom Transfer. AB - The selective functionalization of remote C-H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis. This radical mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways. As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C-H functionalization. This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena. PMID- 29755144 TI - The FIELDS Instrument Suite for Solar Probe Plus: Measuring the Coronal Plasma and Magnetic Field, Plasma Waves and Turbulence, and Radio Signatures of Solar Transients. AB - NASA's Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products. PMID- 29755147 TI - Kinetic and thermodynamic studies of chlorinated organic compound degradation by siderite-activated peroxide and persulfate. AB - The efficacy of two oxidant systems, iron-activated hydrogen peroxide (H2O2) and iron-activated hydrogen peroxide coupled with persulfate (S2O82-), was investigated for treatment of two chlorinated organic compounds, trichloroethene (TCE) and 1,2-dichloroethane (DCA). Batch tests were conducted at multiple temperatures (10-50 degrees C) to investigate degradation kinetics and reaction thermodynamics. The influence of an inorganic salt, dihydrogen phosphate ion (H2PO4-), on oxidative degradation was also examined. The degradation of TCE was promoted in both systems, with greater degradation observed for higher temperatures. The inhibition effect of H2PO4- on the degradation of TCE increased with increasing temperature for the iron-activated H2O2 system but decreased for the iron-activated hydrogen peroxide-persulfate system. DCA degradation was limited in the iron-activated hydrogen peroxide system. Conversely, significant DCA degradation (87% in 48 hours at 20 degrees C) occurred in the iron-activated hydrogen peroxide-persulfate system, indicating the crucial role of sulfate radical (SO4-.) from persulfate on the oxidative degradation of DCA. The activation energy values varied from 37.7 to 72.9 kJ/mol, depending on the different reactants. Overall, the binary hydrogen peroxide-persulfate oxidant system exhibited better performance than hydrogen peroxide alone for TCE and DCA degradation. PMID- 29755146 TI - Stigma Consciousness Modulates Cortisol Reactivity to Social Stress in Women. AB - The aim of the current study was to examine whether stigma consciousness shapes cortisol responses to social stress among women in the lab. Undergraduate women (N = 45) completed background measures and then participated in a public speaking task, with assessments of cortisol prior to the stressor as well as 20- and 40 minutes post stressor onset. Results from multilevel models revealed that women higher in stigma consciousness evidenced blunted cortisol reactivity following social stress across the study session compared to women lower in stigma consciousness. This interaction was robust to adjustment for a number of covariates, including demographic (e.g., age), physiological (e.g., menstrual cycle) and psychological (e.g., depressive symptomatology) factors. Potential explanations for observed cortisol patterns are discussed, including hypo reactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated anticipatory stress. To conclude, implications for health disparities research are considered. PMID- 29755148 TI - Modified Well-Field Configurations for Improved Performance of Contaminant Elution and Tracer Tests. AB - Contaminant elution and tracer (CET) tests are one method for characterizing the impact of mass transfer, transformation, and other attenuation processes on contaminant transport and mass removal for subsurface systems. The purpose of the work reported herein is to explore specific well-field configurations for improving CET tests by reducing the influence of preferential flow and surrounding-plume effects. Three injection-extraction well configurations were tested for different domain conditions using a three-dimensional numerical model. The three configurations were the traditional configuration with a single pair of injection-extraction wells, modified configuration I with one extraction well located between two injection wells, and modified configuration II with two pairs of injection-extraction couplets (one nested within the other). Elution curves for resident contaminant and breakthrough curves from simulated tracer tests were examined for specific landmarks such as the presence and extent of steady-state (relatively high concentrations) and asymptotic (asymptotic decrease to low concentrations) phases, as well as distinct changes in slope. Temporal-moment analysis of the breakthrough curves was conducted to evaluate mass recovery. Effective diffusion coefficients were obtained by fitting selected functions to the elution curves. Based on simulation results for a homogeneous domain, full isolation of the inner extraction well from the surrounding plume was obtained for the modified configuration II, whereas the extraction wells are impacted by the surrounding plume for the other two configurations. Therefore, configuration II was used for additional simulations conducted with layered and heterogeneous domains. Tracer-test simulations for homogeneous and layered domains indicate 100% mass recovery for the inner extraction well. For the heterogeneous domain, decreasing the distance between the inner injection-extraction well couplet and adjusting the pumping-rate distribution between the two extraction wells increased the mass recovery from 69% to 99%. PMID- 29755150 TI - Biodegradation of Ammonium Ions and Formate During Ammonium Formate Metabolism by Yarrowia lipolytica and Pichia guilliermondii in a Batch Reactor. AB - The use of microorganisms for the biodegradation of pollutants is increasingly being studied. But at high concentrations, these pollutants become rather inhibitors for the metabolism of microorganisms. In this study, the biodegradation of ammonium formate at various concentrations (1.59-7.94 mM) by Yarrowia Lipolytica and Pichia guilliermondii isolated from the rubber effluent is studied by following the variation of ammonium ions and formate. A fitting of eight models of substrate inhibition was performed and the parameters were determined by nonlinear regression using MATLAB 8.5 (c). The R2 and the RSME allow to choose the best model. The results show that ammonium ions (3.17 mM ammonium formate) are used as substrate; no inhibition is observed. But beyond this concentration, the inhibition effect begins to be observed with the specific rates of ammonium biodegradation which decrease. Formate monitoring reveals that is used as the main source of energy and does not inhibit the growth of yeasts. The models of Luong and Webb seem to be more appropriate for predicting the observed phenomena of inhibition. For Yarrowia lipolytica, R2 = 0.958 and 0.998 with RSME = 0.005342 and 0.003433, for Pichia guillermondii, R2 = 0.999 and 0.992 with RSME = 0.0005121 and 0.001212. PMID- 29755149 TI - Influence of Integrated Membrane Treatment on the Phytotoxicity of Wastewater from the Coke Industry. AB - In this paper, coke wastewater that had passed through biological and integrated membrane processes (filtration on sand bed-reverse osmosis) was chosen to assess the phytotoxicity of selected industrial wastewater with regard to the test plant Vicia faba. An innovative research technique in vitro test was conducted in a large scale phytothrone chamber on two matrices: cotton and Murashige and Skoog Basal Medium (MSBM). The toxicity of wastewater was evaluated for samples: (1) treated in the treatment plant by biological processes, (2) filtrated through a sand bed and filtrated (3) reverse osmosis (RO) membrane. The results showed that there is a noticeable correlation between increasing concentrations of wastewater and seed germination of the test plant. Although the wastewater collected from the coke plant was treated biologically, it showed very high levels of germination inhibition (90-98% for cotton matrix and 92-100% for MSBM matrix) and strong toxic effects. The wastewater collected from the coke plant showed a significantly greater phytotoxic effect compared with those obtained from the effluent treated on a sand bed and in RO. However, wastewater, even after treatment on a sand bed (reduction of COD-39%, TN-46%, TOC-42%, TC-47%, SS-50%, 16PAHs-53%), was still toxic and germination inhibition was in the range of 24 48% for the cotton matrix and 14-54% for the MSBM matrix. The toxicity of wastewater treated in the membrane process was the lowest (reduction of COD-85%, TN-95%, TOC-85%, TC-86%, SS-98%, 16PAHs-67%). The germination inhibition was in the range of 4-10% for the cotton matrix and 2-12% for the MSBM matrix. These samples are classified as non-toxic or slightly toxic to the model plant. The present study highlights the necessity of monitoring not only the basic physical and chemical indicators (including the level of toxic substances as PAHs), but also their effect on the test organisms in wastewater samples. PMID- 29755151 TI - Shape Covariation (or the Lack Thereof) Between Vertebrae and Other Skeletal Traits in Felids: The Whole is Not Always Greater than the Sum of Parts. AB - Within carnivorans, cats show comparatively little disparity in overall morphology, with species differing mainly in body size. However, detailed shape analyses of individual osteological structures, such as limbs or skulls, have shown that felids display significant morphological differences that correlate with their observed ecological and behavioural ranges. Recently, these shape analyses have been extended to the felid axial skeleton. Results demonstrate a functionally-partitioned vertebral column, with regions varying greatly in level of correlation between shape and ecology. Moreover, a clear distinction is evident between a phylogenetically-constrained neck region and a selection responsive posterior spine. Here, we test whether this regionalisation of function reflected in vertebral column shape is also translated into varying levels of phenotypic integration between this structure and most other skeletal elements. We accomplish this comparison by performing pairwise tests of integration between vertebral and other osteological units, quantified with 3D geometric morphometric data and analysed both with and without phylogenetic correction. To our knowledge, this is the first study to test for integration across a comprehensive sample of whole-skeleton elements. Our results show that, prior to corrections, strong covariation is present between vertebrae across the vertebral column and all other elements, with the exception of the femur. However, most of these significant correlations disappear after correcting for phylogeny, which is a significant influence on cranial and limb morphology of felids and other carnivorans. Our results thus suggest that the vertebral column of cats displays relative independence from other skeletal elements and may represent several distinct evolutionary morphological modules. PMID- 29755152 TI - Eco-Evolutionary Processes Generating Diversity Among Bottlenose Dolphin, Tursiops truncatus, Populations off Baja California, Mexico. AB - For highly mobile species that nevertheless show fine-scale patterns of population genetic structure, the relevant evolutionary mechanisms determining structure remain poorly understood. The bottlenose dolphin (Tursiops truncatus) is one such species, exhibiting complex patterns of genetic structure associated with local habitat dependence in various geographic regions. Here we studied bottlenose dolphin populations in the Gulf of California and Pacific Ocean off Baja California where habitat is highly structured to test associations between ecology, habitat dependence and genetic differentiation. We investigated population structure at a fine geographic scale using both stable isotope analysis (to assess feeding ecology) and molecular genetic markers (to assess population structure). Our results show that there are at least two factors affecting population structure for both genetics and feeding ecology (as indicated by stable isotope profiles). On the one hand there is a signal for the differentiation of individuals by ecotype, one foraging more offshore than the other. At the same time, there is differentiation between the Gulf of California and the west coast of Baja California, meaning that for example, nearshore ecotypes were both genetically and isotopically differentiated either side of the peninsula. We discuss these data in the context of similar studies showing fine scale population structure for delphinid species in coastal waters, and consider possible evolutionary mechanisms. PMID- 29755153 TI - Church and Family Support Networks and Depressive Symptoms among African Americans: Findings from the National Survey of American Life. PMID- 29755154 TI - Expectancies, working alliance, and outcome in transdiagnostic and single diagnosis treatment for anxiety disorders: An investigation of mediation. AB - Patients' outcome expectancies and the working alliance are two psychotherapy process variables that researchers have found to be associated with treatment outcome, irrespective of treatment approach and problem area. Despite this, little is known about the mechanisms accounting for this association, and whether contextual factors (e.g., psychotherapy type) impact the strength of these relationships. The primary aim of this study was to examine whether patient-rated working alliance quality mediates the relationship between outcome expectancies and pre- to post-treatment change in anxiety symptoms using data from a recent randomized clinical trial comparing a transdiagnostic treatment (the Unified Protocol [UP]; Barlow et al., 2011a; Barlow, Sauer-Zavala, et al., in press) to single diagnosis protocols (SDPs) for patients with a principal heterogeneous anxiety disorder (n = 179). The second aim was to explore whether cognitive behavioral treatment condition (UP versus SDP) moderated this indirect relationship. Results from mediation and moderated mediation models indicated that, when collapsing across the two treatment conditions, the relationship between expectancies and outcome was partially mediated by the working alliance (B = .037, SE = .05, 95% CI [.005, .096]). Interestingly, within-condition analyses showed that this conditional indirect effect was only present for SDP patients, whereas in the UP condition, working alliance did not account for the association between expectancies and outcome. These findings suggest that outcome expectancies and working alliance quality may interact to influence treatment outcomes, and that the nature and strength of the relationships among these constructs may differ as a function of the specific cognitive-behavioral treatment approach utilized. PMID- 29755155 TI - Paternal Multiple Partner Fertility and Environmental Chaos Among Unmarried Nonresident Fathers. AB - This study examined the association between paternal multiple partner fertility (MPF; having children with two or more partners) and indicators of environmental chaos (partnership instability, residential instability, work stability, material hardship, and perceived social support) among unmarried, non-resident fathers. Survey data from the Fragile Families and Child Wellbeing Study (N = 873) were used to compare unmarried non-resident fathers who experienced MPF to those who had children with one partner. Results show that paternal MPF is associated with most indicators of environmental chaos (greater partnership instability, residential instability, work instability, material hardship), but not social support. Results suggest that fathers who experience MPF face challenges beyond those of other non-resident fathers. Policies and interventions should address aspects of instability and hardship that are unique to paternal MPF in order to encourage fathers' positive contributions to children and families. Directions for future research are discussed. PMID- 29755156 TI - Residential Segregation of European and Non-European Migrants in Sweden: 1990 2012. AB - In this paper, we analyse how a migrant population that is both expanding and changing in composition has affected the composition of Swedish neighbourhoods at different scales. The analysis is based on Swedish geocoded individual-level register data for the years 1990, 1997, 2005, and 2012. This allows us to compute and analyse the demographic composition of neighbourhoods that range in size from encompassing the nearest 100 individuals to the nearest 409,600 individuals. First, the results confirm earlier findings that migrants, especially those from non-European countries, face high levels of segregation in Sweden. Second, large increases in the non-European populations in combination with high levels of segregation have increased the proportion of non-European migrants living in neighbourhoods that already have high proportions of non-European migrants. Third, in contrast to what has been the established image of segregation trends in Sweden, and in an apparent contrast to the finding that non-European migrants increasingly live in migrant-dense neighbourhoods, our results show that segregation, when defined as an uneven distribution of different populations across residential contexts, is not increasing. On the contrary, for both European migrants from 1990 and non-European migrants from 1997, there is a downward trend in unevenness as measured by the dissimilarity index at all scale levels. However, if segregation is measured as differences in the neighbourhood concentration of migrants, segregation has increased. PMID- 29755157 TI - The Measurement of Ethnic Segregation in the Netherlands: Differences Between Administrative and Individualized Neighbourhoods. AB - The debate on residential segregation often focuses on the concentration of migrant groups in specific neighbourhoods and its presumed effects on, e.g. personal life chances and social inclusion. However, cross-regional and international comparisons of segregation are hampered by differences in the size and delineation of the spatial units that are used for its measurement: the Modifiable Areal Unit Problem. This paper therefore measures segregation for scalable 'individualized neighbourhoods', defined by a predefined number of closest neighbours instead of by administrative or statistical boundaries. This approach allows for measuring segregation levels and patterns across different spatial scales, ranging from the micro-scale (50 neighbours) to larger spatial areas (51,200 neighbours). Using population register data from the Netherlands, we study the segregation of four different migrant origin groups across individualized neighbourhoods at eleven spatial scales. Outcomes are compared to those found using administrative neighbourhoods. We are especially interested in how levels and patterns of segregation change with an increase in scale level. Our findings indicate that segregation levels and patterns are different across various spatial scales, and the most relevant spatial scale is also group specific. Measuring segregation while using scalable individualized neighbourhoods seems an appropriate way to deal with both the multiscalar nature of segregation and the large within-district variety associated with it. PMID- 29755158 TI - A Comparative Study of Segregation Patterns in Belgium, Denmark, the Netherlands and Sweden: Neighbourhood Concentration and Representation of Non-European Migrants. AB - In this paper, we use geo-coded, individual-level register data on four European countries to compute comparative measures of segregation that are independent of existing geographical sub-divisions. The focus is on non-European migrants, for whom aggregates of egocentric neighbourhoods (with different population counts) are used to assess small-scale, medium-scale, and large-scale segregation patterns. At the smallest scale level, corresponding to neighbourhoods with 200 persons, patterns of over- and under-representation are strikingly similar. At larger-scale levels, Belgium stands out as having relatively strong over- and under-representation. More than 55% of the Belgian population lives in large scale neighbourhoods with moderate under- or over-representation of non-European migrants. In the other countries, the corresponding figures are between 30 and 40%. Possible explanations for the variation across countries are differences in housing policies and refugee placement policies. Sweden has the largest and Denmark the smallest non-European migrant population, in relative terms. Thus, in both migrant-dense and native-born-dense areas, Swedish neighbourhoods have a higher concentration and Denmark a lower concentration of non-European migrants than the other countries. For large-scale, migrant-dense neighbourhoods, however, levels of concentration are similar in Belgium, the Netherlands, and Sweden. Thus, to the extent that such concentrations contribute to spatial inequalities, these countries are facing similar policy challenges. PMID- 29755160 TI - Induction of Metamorphosis Causes Differences in Sex-Specific Allocation Patterns in Axolotls (Ambystoma mexicanum) that Have Different Growth Histories. AB - We tested the hypothesis that salamanders growing at different rates would have allocation patterns that differ among male and female metamorphic and larval salamanders. We raised individual axolotls, Ambystoma mexicanum, on four food regimes: constant high growth (throughout the experiment), constant low growth (restricted throughout the experiment), high growth switched to low growth (ad libitum switched after 140 d to restricted), and low growth switched to high growth (restricted switched after 140 d to ad libitum). Because axolotls are obligate paedomorphs, we exposed half of the salamanders to thyroid hormone to induce metamorphosis. We assayed growth and dissected and weighed gonads and fat bodies. Salamanders that were switched from restricted to ad libitum food regime delayed metamorphosis. In all treatment groups, females had larger gonads than males and males had larger fat bodies than females. The association between storage and reproduction differed between larvae and metamorphs and depended on sex. PMID- 29755159 TI - Kuhnian revolutions in neuroscience: the role of tool development. AB - The terms "paradigm" and "paradigm shift" originated in "The Structure of Scientific Revolutions" by Thomas Kuhn. A paradigm can be defined as the generally accepted concepts and practices of a field, and a paradigm shift its replacement in a scientific revolution. A paradigm shift results from a crisis caused by anomalies in a paradigm that reduce its usefulness to a field. Claims of paradigm shifts and revolutions are made frequently in the neurosciences. In this article I will consider neuroscience paradigms, and the claim that new tools and techniques rather than crises have driven paradigm shifts. I will argue that tool development has played a minor role in neuroscience revolutions. PMID- 29755161 TI - Microfluidic Droplet Consistency Monitoring and Cell Detection via Laser Excitation. AB - Microfluidic droplets formed in emulsions are used in a variety of analytical techniques and hold great potential for future scientific and commercial applications. Our experiments merge quantitative quality engineering methods into the microdroplet field. We present a unique microdroplet generation and consistency monitoring system with laser optics excitation and detection. Our setup analyzes each droplet with sub-millisecond signal resolution and single photon accuracy, and is compatible with process control methods. To demonstrate the consistency of microdroplet generation over time, we measure and examine the mean frequency of aqueous plug-shaped droplet (microplug) formation in oil phase, as well as the mean length of plugs, and the interval between consecutive droplets. We also demonstrate the detection of cancer cells encapsulated within aqueous microdroplets in continuous oil phase flow. Two-channel optical monitoring allows for the simultaneous and independent inspection of both microdroplet generation and identification of green fluorescent protein-labelled cancer cells within the droplets. Increased accuracy and consistency are central to many established and developing microfluidic technologies. A systematic, quantitative approach as demonstrated with our experiments may be essential in the development of advanced microfluidic concepts that require exacting reproducibility and would greatly benefit from incorporated automated measurement techniques for process control. PMID- 29755162 TI - Bayesian regression model for recurrent event data with event-varying covariate effects and event effect. AB - In the course of hypertension, cardiovascular disease events (e.g., stroke, heart failure) occur frequently and recurrently. The scientific interest in such study may lie in the estimation of treatment effect while accounting for the correlation among event times. The correlation among recurrent event times come from two sources: subject-specific heterogeneity (e.g., varied lifestyles, genetic variations, and other unmeasurable effects) and event dependence (i.e., event incidences may change the risk of future recurrent events). Moreover, event incidences may change the disease progression so that there may exist event varying covariate effects (the covariate effects may change after each event) and event effect (the effect of prior events on the future events). In this article, we propose a Bayesian regression model that not only accommodates correlation among recurrent events from both sources, but also explicitly characterizes the event-varying covariate effects and event effect. This model is especially useful in quantifying how the incidences of events change the effects of covariates and risk of future events. We compare the proposed model with several commonly used recurrent event models and apply our model to the motivating lipid-lowering trial (LLT) component of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (ALLHAT-LLT). PMID- 29755163 TI - Design verification of a compact system for detecting tissue perfusion using bimodal diffuse optical technologies. AB - It is essential to monitor tissue perfusion during and after reconstructive surgery, as restricted blood flow can result in graft failures. Current clinical procedures are insufficient to monitor tissue perfusion, as they are intermittent and often subjective. To address this unmet clinical need, a compact, low-cost, multimodal diffuse correlation spectroscopy and diffuse reflectance spectroscopy system was developed. We verified system performance via tissue phantoms and experimental protocols for rigorous bench testing. Quantitative data analysis methods were employed and tested to enable the extraction of tissue perfusion parameters. This design verification study assures data integrity in future in vivo studies. PMID- 29755164 TI - Mass Measurements of Focal Adhesions in Single Cells Using High Resolution Surface Plasmon Resonance Microscopy. AB - Surface plasmon resonance microscopy (SPRM) is a powerful label-free imaging technique with spatial resolution approaching the optical diffraction limit. The high sensitivity of SPRM to small changes in index of refraction at an interface allows imaging of dynamic protein structures within a cell. Visualization of subcellular features, such as focal adhesions (FAs), can be performed on live cells using a high numerical aperture objective lens with a digital light projector to precisely position the incident angle of the excitation light. Within the cell-substrate region of the SPRM image, punctate regions of high contrast are putatively identified as the cellular FAs. Optical parameter analysis is achieved by application of the Fresnel model to the SPRM data and resulting refractive index measurements are used to calculate protein density and mass. FAs are known to be regions of high protein density that reside at the cell substratum interface. Comparing SPRM with fluorescence images of antibody stained for vinculin, a component in FAs, reveals similar measurements of FA size. In addition, a positive correlation between FA size and protein density is revealed by SPRM. Comparing SPRM images for two cell types reveals a distinct difference in the protein density and mass of their respective FAs. Application of SPRM to quantify mass can greatly aid monitoring basic processes that control FA mass and growth and contribute to accurate models that describe cell-extracellular interactions. PMID- 29755165 TI - Open Access to the Evidence: Helpful Hints to Save Valuable Time and Resources in the Quest to Provide Evidence-Informed Physiotherapy Interventions. PMID- 29755166 TI - Knowledge, Attitudes, and Practice of In-Patient Physiotherapists in Ontario Regarding Patients Who Are Super-Morbidly Obese. AB - Purpose: This article describes the knowledge, attitudes, and practice of in patient physiotherapists in Ontario regarding the treatment of patients who are super-morbidly obese (SMO; i.e., those whose BMI is >50). Method: A 62-item questionnaire was developed to assess demographics, sources of knowledge, current practice, and attitudes such as confidence, willingness, and the perceived effectiveness of treatment. It was distributed electronically using FluidSurveys. All physiotherapists working in a clinical role with adults in an in-patient setting in Ontario were eligible to participate. Results: A total of 276 physiotherapists completed the survey. Most of them had learned about the treatment from non-structured sources such as clinical experience. More than half (52%) of the participants disagreed that their place of employment was well prepared to facilitate the treatment of patients who are SMO. The majority of respondents were confident in treating these patients, were willing to treat them (82%), and believed that physiotherapy would improve at least one health outcome (96%) for them; however, 46% were reluctant to treat for fear of personal injury. Participants most commonly felt limited by lack of equipment and lack of staff to assist. Conclusions: Physiotherapists have positive attitudes toward treating patients who are SMO, and increased equipment and staff to assist, as well as appropriate education, may decrease the fear of injury for physiotherapists while treating these patients and improve health outcomes for them. PMID- 29755167 TI - Interrater Reliability of the Observable Movement Quality Scale for Children. AB - Purpose: The authors investigated the interrater reliability, the standard deviation of the random measurement error, and the limits of agreement (LoA) of the Observable Movement Quality (OMQ) scale in children. Movement quality is important in the recognition of motor problems, and the OMQ scale, a questionnaire used by paediatric physical therapists, has been developed for use with an age-specific motor test to observe movement quality and score relative to what is expected for a child's age. Method: Paediatric physical therapists (n=28; 2 men, 26 women) observed video-recorded assessments of age-related motor tests in children (n=9) aged 6 months to 6 years and filled in the OMQ scale (possible score range 15-75 points). For our analyses, we used linear mixed models without fixed effects. Results: The interrater reliability was moderate (intra-class correlation coefficient [ICC2,1]: 0.67, 95% CI: 0.47, 0.88); neither work setting nor work experience exerted any influence on it. The standard deviation of the random measurement error was 5.7, and the LoA was 31.5. Item agreement was good (proportion of observed agreement [Po] total 0.82-0.99). Conclusion: The OMQ scale showed moderate interrater reliability when being used by therapists who were unfamiliar with the questionnaire and who had received only 2 hours of training. Feedback from the participants suggested a need for more comprehensive training in using the OMQ scale in clinical practice. PMID- 29755168 TI - Amount and Content of Sensorimotor Therapy Delivered in Three Stroke Rehabilitation Units in Quebec, Canada. AB - Purpose: This study creates a baseline clinical portrait of sensorimotor rehabilitation in three stroke rehabilitation units (SRUs) as a first step in implementing a multi-centre clinical research platform. Method: Participants in this cross-sectional, descriptive study were the patients and rehabilitation teams in these SRUs. Prospective (recording of therapy time and content and a Web based questionnaire) and retrospective (chart audit) methods were combined to characterize the practice of the rehabilitation professionals. Results: The 24- to 39-bed SRUs admitted 100-240 inpatients in the year audited. The mean combined duration of individual occupational and physical therapy was 6.3-7.5 hours/week/patient. When evening hours and the contributions of other professionals as well as group therapy and self-practice were included, the total amount of therapy was 13.0 (SD 3) hours/patient/week. Chart audit and questionnaire data revealed the Berg Balance Scale was the most often used outcome measure (98%-100%), and other outcome measure use varied. Clinicians favoured task-oriented therapy (35%-100%), and constraint-induced movement therapy (0%-15%), electrical stimulation of the tibialis anterior (0%-15%), and body weight-supported treadmill training (0%-1%) were less often used. Conclusions: This study is the first to provide objective data on therapy time and content of stroke rehabilitation in Quebec SRUs. PMID- 29755169 TI - Interrater Reliability of Three Versions of the Chedoke Arm and Hand Activity Inventory. AB - Purpose: The purpose of this study was to estimate the interrater reliability of three shortened versions of the Chedoke Arm and Hand Activity Inventory (CAHAI-7, CAHAI-8, CAHAI-9) when used with persons with acquired brain injury (ABI). The CAHAI is an assessment of upper limb function with high reliability in the stroke and ABI populations. In the stroke population, three shortened versions of the measure have established reliability. Clinicians report time constraints as a barrier to using standardized assessments; thus, establishing the reliability of the shortened versions of the CAHAI in the ABI population may increase the use of this measure. Method: This was an observational, parameter estimation study. The participants were recruited from an in-patient ABI rehabilitation programme. The administration of the CAHAI to six persons with ABI was video recorded, and the video recordings were assessed by six clinicians to estimate interrater reliability. A Latin square design was used to balance the order in which the raters evaluated the videos. A repeated-measures analysis of variance was performed, and the variance components were used to calculate an intra-class correlation coefficient (ICC) and standard error of measurement (SEM) with 95% confidence limits (CLs) for each of the shortened versions. Results: Interrater reliability was high for all three versions: CAHAI-7, ICC=0.96 (95% CL: 0.89, 0.99; SEM 2.65); CAHAI-8, ICC=0.96 (95% CL: 0.90, 0.99; SEM 2.72); and CAHAI-9, ICC=0.95 (95% CL: 0.85, 0.99; SEM 3.49). Conclusions: These results suggest that the three shortened versions of the CAHAI demonstrate high reliability in the ABI population. These versions may be particularly useful when time constraints or patient tolerance are an issue. PMID- 29755170 TI - Patient Education Provided by Physiotherapists for Patients with Chronic Obstructive Pulmonary Disease: Results of a Scoping Review. AB - Purpose: Physiotherapists have been acknowledged as playing a vital role in the care of people living with chronic obstructive pulmonary disease (COPD), and this care includes providing patient education (PE). Yet very little is known about the issues critical to providing this PE. The purpose of this scoping review was to identify and map out the current knowledge about the content, processes, and overall effectiveness of the PE provided by physiotherapists for people living with COPD. Method: Using the guidelines developed by Arksey and O'Malley in 2005 and by Levac in 2010, key databases were searched. A total of 447 articles were identified and screened for the following inclusion criteria: adults living with COPD, published in English or French between 1995 and 2015, and describing the PE provided by physiotherapists. Fourteen studies matched these criteria. Results: In the majority of studies, both physiotherapists and nurses provided PE to patients. Common PE topics included energy conservation, exacerbations, and breathlessness. None of the studies included measures for evaluating the effectiveness of the PE. Conclusions: Even though physiotherapists routinely provide PE to people living with COPD, this PE varies substantially. The heterogeneity of the studies and lack of measures of effectiveness prevented them from providing any evidence-based recommendations for physiotherapists. PMID- 29755171 TI - Long-Term Resolution of Severe Ankle Contractures Using Botulinum Toxin, Serial Casting, Splinting, and Motor Retraining. AB - Purpose: Serial casting for ankle contractures is traditionally performed in prone, a position that patients may not easily tolerate. Also, although serial casting is effective in correcting contracture, its effect dissipates quickly. This case report describes a procedure for performing casting for ankle contractures in a supine or sitting position. It also describes a process that enables the effect of serial casting to be maintained long term. Client Description: The client was an adult who had suffered traumatic brain injury and severe bilateral ankle contractures. Intervention: He received botulinum toxin and serial casting for his bilateral ankle contractures, one ankle at 8 months and the other at 13 months after the injury. He then underwent a programme of splinting and motor training. Measures and Outcome: The client gained more than 40 degrees dorsiflexion for both ankles after receiving botulinum toxin injections and serial casting. The improvement in ankle range enabled him to progress to walking practice. Ankle splinting was gradually reduced. On discharge at 25 months post-injury, the ankle joint range was maintained. Implications: The use of botulinum toxin and serial casting, followed by an intensive programme of splinting and motor training, may be an option to consider for effective long term resolution of severe contractures after acquired brain injury. PMID- 29755172 TI - Retrospective Review of Student Research Projects in a Canadian Master of Science in Physical Therapy Programme and the Perceived Impact on Advisors' Research Capacity, Education, Clinical Practice, Knowledge Translation, and Health Policy. AB - Purpose: This study's aim was to characterize the nature of students' research conducted for a Master of Science in Physical Therapy (MScPT) degree programme at a Canadian university and evaluate the lead advisors' perspectives of its impact on their research capacity, education, clinical practice, knowledge translation, and health policy. Methods: We conducted a quantitative, cross-sectional, retrospective review of research reports from 2003 to 2014 to characterize the MScPT students' research and a quantitative, cross-sectional e-survey of lead research advisors to evaluate the impact of this research. Results: Data were abstracted from reports of 201 research projects completed between 2003 and 2014. Projects were conducted primarily in university-affiliated hospitals (41.6%) or the university's physical therapy department (41.1%), and the majority (52.5%) had a clinical focus. Of the 95 lead advisors of 201 projects, 59 advisors (response rate 62.1%) of 119 projects completed the survey questionnaire. The respondents most frequently identified clinical practice (45.1%) and advisors' research capacity (31.4%) as areas positively affected by the students' research. Conclusions: The MScPT students' research projects facilitate the conduct of extensive research internally and across affiliated hospitals. This research appears to advance not only clinical practice but also the ability of lead advisors to undertake research. PMID- 29755173 TI - Patients' Perspectives on and Experiences of Home Exercise Programmes Delivered with a Mobile Application. AB - Purpose: We explored patients' perspectives on home exercise programmes (HEPs) and their experiences using a mobile application designed to facilitate home exercise. Method: Data were generated using qualitative, semi-structured, face-to face interviews with 10 participants who were receiving outpatient physiotherapy. Results: Establishing a therapeutic partnership between physiotherapists and patients enabled therapists to customize the HEPs to the patients' lifestyles and preferences. Analysis suggests that using the mobile application improved participants' ability to integrate the HEP into their daily life and was overwhelmingly preferred to traditional paper handouts. Conclusions: The results suggest that efforts to engage patients in HEPs need to take their daily lives into account. To move in this direction, sample exercise prescription questions are offered. Mobile applications do not replace the clinical encounter, but they can be an effective tool and an extension of delivering personalized HEPs in an existing therapeutic partnership. PMID- 29755174 TI - Clinical Diagnostic Tests versus Medial Branch Blocks for Adults with Persisting Cervical Zygapophyseal Joint Pain: A Systematic Review and Meta-Analysis. AB - Purpose: A systematic review and meta-analysis were performed to identify clinical tests for diagnosing cervical zygapophyseal joint pain (CZP) and to determine their diagnostic accuracy. Method: A search strategy was carried out to find relevant evidence published in CINAHL, Embase, MEDLINE, and PEDro from 1980 to January 1, 2015, pertaining to the clinical diagnosis of CZP. Quality assessment was completed using the Quality Assessment of Diagnostic Accuracy Studies-2. Results were analyzed to pool sensitivity and specificity and clarify diagnostic value. Results: Seven articles (n=463) were included for data synthesis and review. Intersegmental mobility tests were found to have the highest diagnostic accuracy, with pooled sensitivity of 0.91 (95% CI: 0.85, 0.94) and specificity of 0.74 (95% CI: 0.65, 0.81). The pooled sensitivity for mechanical sensitivity (palpation) was 0.88 (95% CI: 0.78, 0.95), and specificity was 0.61 (95% CI: 0.50, 0.71). Conclusion: Limited studies are available that discuss the clinical diagnosis of CZP, and significant heterogeneity is present in the available data. In this review, intersegmental mobility tests were found to be the most accurate. Clustering of tests, agreement on a reference standard, and further exploration of CZP referral patterns are recommended. PMID- 29755176 TI - What Does Cochrane Say about ... the Rehabilitation of Ankle Injuries? PMID- 29755175 TI - Integrating Physiotherapists into Primary Health Care Organizations: The Physiotherapists' Perspective. AB - Purpose: This study's purpose was to gain insight into physiotherapists' perspectives on the perceived barriers and facilitators of integrating physiotherapists into primary health care (PHC) teams. Method: A qualitative descriptive approach consisting of semi-structured face-to-face or telephone interviews was used. Interviews were audio recorded, transcribed verbatim, and checked by the interviewers to ensure trustworthiness. Data were analyzed using Braun and Clarke's six steps to thematic analysis. Results: Eight participants were interviewed, representing physiotherapists from diverse demographics and geographical regions in Ontario. Common themes discussed were the orientation process, their experiences of integrating the physiotherapist's role into the organization, programme development compared with one-to-one care, the characteristics of the physiotherapist and the interdisciplinary team, and the resources available in the organization. Our key findings of influential factors for integration were (1) the diversity and novelty of new physiotherapists' role, (2) team members' understanding of the physiotherapists' role, and (3) physiotherapists' actions and values regarding PHC. Conclusions: The integration process is affected by factors ranging from individual to system levels. The integration of physiotherapists into PHC would be enhanced by a greater understanding of the role of physiotherapy in PHC by physiotherapists, other health care professionals, and system planners. PMID- 29755177 TI - Rheological and thermal properties of suspensions of microcapsules containing phase change materials. AB - The thermal and rheological properties of suspensions of microencapsulated phase change materials (MPCM) in glycerol were investigated. When the microcapsule concentration is raised, the heat storage capacity of the suspensions becomes higher and a slight decline in the thermal conductivity of the suspensions is observed. The temperature-dependent shear-thinning behaviour of the suspensions was found to be strongly affected by non-encapsulated phase change materials (PCM). Accordingly, the rheological properties of the MPCM suspensions could be described by the Cross model below the PCM melting point while a power law model best described the data above the PCM melting point. The MPCM suspensions are interesting for energy storage and heat transfer applications. However, the non encapsulated PCM contributes to the agglomeration of the microcapsules, which can lead to higher pumping consumption and clogging of piping systems. PMID- 29755178 TI - Experiential wellbeing data from the American Time Use Survey: Comparisons with other methods and analytic illustrations with age and income. AB - There has been a recent upsurge of interest in self-reported measures of wellbeing by official statisticians and by researchers in the social sciences. This paper considers data from a wellbeing supplement to the American Time Use Survey (ATUS), which parsed the previous day into episodes. Respondents provided ratings of five experiential wellbeing adjectives (happiness, stress, tiredness, sadness, and pain) for each of three randomly selected episodes. Because the ATUS Well-being module has not received very much attention, in this paper we provide the reader with details about the features of these data and our approach to analyzing the data (e.g., weighting considerations), and then illustrate the applicability of these data to current issues. Specifically, we examine the association of age and income with all of the experiential wellbeing adjective in the ATUS. Results from the ATUS wellbeing module were broadly consistent with earlier findings on age, but did not confirm all earlier findings between income and wellbeing. We conclude that the ATUS, with its measurement of time use, specific activities, and hedonic experience in a nationally representative survey, offers a unique opportunity to incorporate time use into the burgeoning field of wellbeing research. PMID- 29755180 TI - The roles of history: age and prior exploitation in aquatic container habitats have immediate and carry-over effects on mosquito life history. AB - Per-capita resource availability in aquatic habitats is influenced directly by consumer density via resource competition and indirectly via delayed resource competition when temporally non-overlapping cohorts of larvae exploit the same resources. In detritus-based systems, resources are likely to be influenced by the age of the aquatic habitat, as detritus changes in quality over time and may be replenished by new inputs.For aquatic insects that exploit detritus-based habitats, feeding conditions experienced during immature stages can influence fitness directly via effects on development and survivorship, but also indirectly by influencing adult traits such as fecundity and longevity.Larval habitat age and prior resource exploitation were manipulated in a field experiment using the container mosquito Aedes triseriatus.It was found that A. triseriatus from older habitats had greater larval survival, faster development and greater adult longevity. Exploitation of larval habitats by a prior cohort of larvae had a significant negative effect on subsequent cohorts of larvae by delaying development.It is suggested that extended conditioning of detritus probably resulted in conversion of recalcitrant resources to more available forms which improved the quality of the habitat.In a parallel study, evidence was found of carry-over effects of habitat age and prior exploitation on adult longevity for A. triseriatus and Aedes japonicus collected from unmanipulated aquatic habitats.These results indicate the importance of detritus dynamics and the discontinuous nature of resource competition in these mosquito-dominated aquatic systems. PMID- 29755179 TI - Multiple mortality events in bats: a global review. AB - Despite conservation concerns for many species of bats, factors causing mortality in bats have not been reviewed since 1970. Here we review and qualitatively describe trends in the occurrence and apparent causes of multiple mortality events (MMEs) in bats around the world.We compiled a database of MMEs, defined as cases in which >= 10 dead bats were counted or estimated at a specific location within a maximum timescale of a year, and more typically within a few days or a season. We tabulated 1180 MMEs within nine categories.Prior to the year 2000, intentional killing by humans caused the greatest proportion of MMEs in bats. In North America and Europe, people typically killed bats because they were perceived as nuisances. Intentional killing occurred in South America for vampire bat control, in Asia and Australia for fruit depredation control, and in Africa and Asia for human food. Biotic factors, accidents, and natural abiotic factors were also important historically. Chemical contaminants were confirmed causes of MMEs in North America, Europe, and on islands. Viral and bacterial diseases ranked low as causes of MMEs in bats.Two factors led to a major shift in causes of MMEs in bats at around the year 2000: the global increase of industrial wind power facilities and the outbreak of white-nose syndrome in North America. Collisions with wind turbines and white-nose syndrome are now the leading causes of reported MMEs in bats.Collectively, over half of all reported MMEs were of anthropogenic origin. The documented occurrence of MMEs in bats due to abiotic factors such as intense storms, flooding, heat waves, and drought is likely to increase in the future with climate change. Coupled with the chronic threats of roosting and foraging habitat loss, increasing mortality through MMEs is unlikely to be compensated for, given the need for high survival in the dynamics of bat populations. PMID- 29755182 TI - Star product on complex sphere [Formula: see text]. AB - We construct a [Formula: see text]-equivariant local star product on the complex sphere [Formula: see text] as a non-Levi conjugacy class [Formula: see text]. PMID- 29755181 TI - The pervasive role of social learning in primate lifetime development. AB - In recent decades, an accelerating research effort has exploited a substantial diversity of methodologies to garner mounting evidence for social learning and culture in many species of primate. As in humans, the evidence suggests that the juvenile phases of non-human primates' lives represent a period of particular intensity in adaptive learning from others, yet the relevant research remains scattered in the literature. Accordingly, we here offer what we believe to be the first substantial collation and review of this body of work and its implications for the lifetime behavioral ecology of primates. We divide our analysis into three main phases: a first phase of learning focused on primary attachment figures, typically the mother; a second phase of selective learning from a widening array of group members, including some with expertise that the primary figures may lack; and a third phase following later dispersal, when a migrant individual encounters new ecological and social circumstances about which the existing residents possess expertise that can be learned from. Collating a diversity of discoveries about this lifetime process leads us to conclude that social learning pervades primate ontogenetic development, importantly shaping locally adaptive knowledge and skills that span multiple aspects of the behavioral repertoire. PMID- 29755183 TI - Regularized Laplacian determinants of self-similar fractals. AB - We study the spectral zeta functions of the Laplacian on fractal sets which are locally self-similar fractafolds, in the sense of Strichartz. These functions are known to meromorphically extend to the entire complex plane, and the locations of their poles, sometimes referred to as complex dimensions, are of special interest. We give examples of locally self-similar sets such that their complex dimensions are not on the imaginary axis, which allows us to interpret their Laplacian determinant as the regularized product of their eigenvalues. We then investigate a connection between the logarithm of the determinant of the discrete graph Laplacian and the regularized one. PMID- 29755184 TI - Financial and Emotional Support in Close Personal Ties among Central Asian Migrant Women in Russia. AB - This study advances research on the role of personal networks as sources of financial and emotional support in immigrants' close personal ties beyond the immediate family. Because resource scarcity experienced by members of immigrant communities is likely to disrupt normatively expected reciprocal support, we explored multi-level predictors of exchange processes with personal network members that involve (1) only receiving support, (2) only providing support, and (3) reciprocal support exchanges. We focus on an understudied case of Central Asian migrant women in the Russian Federation using a sample of 607 women from three ethnic groups-Kyrgyz, Tajik, Uzbek-who were surveyed in two large Russian cities-Nizhny Novgorod and Kazan. The survey collected information on respondents' demographic, socioeconomic, and migration-related characteristics, as well as characteristics of up to five individuals with whom they had a close relationship. Multi-level multinomial regression analyses were used to account for the nested nature of the data. Our results revealed that closer social relationships (siblings and friends) and greater levels of resources (income and regularized legal status) at both ego and alter levels were positively related to providing, receiving, and reciprocally exchanging financial and emotional support. Egos were more likely to provide financial assistance to transnational alters, whereas they were more likely to engage in mutual exchanges of emotional support with their network members from other countries. Personal network size and density showed no relationship with support exchanges. These findings provide a nuanced picture of close personal ties as conduits for financial and emotional support in migrant communities in a major, yet understudied, migrant-receiving context. PMID- 29755185 TI - Recidivism in a Sample of Serious Adolescent Offenders. AB - Objectives: A broad research literature in criminology documents key aspects of how criminal offending develops and changes over the life span. We contribute to this literature by showcasing methods that are useful for studying medium-term patterns of subsequent criminal justice system involvement among a sample of serious adolescent offenders making the transition to early adulthood. Methods: Our approach relies on 7 years of post-enrollment follow-up from the Pathways to Desistance Study. Each person in the study was adjudicated delinquent for or convicted of one or more relatively serious offenses during adolescence. Their local jurisdiction juvenile court petition records and their adult FBI arrest records were systematically searched. Results: We estimate in-sample 7-year recidivism rates in the 75% to 80% range. Our analysis also provides recidivism rate estimates among different demographic groups within the sample. Extrapolated long-term recidivism rates are estimated to be on the order of 79% to 89%. Conclusions: The Pathways data suggest that recidivism rates of serious adolescent offenders are high and quite comparable to the rates estimated on other samples of serious offenders in the extant literature. Our analysis also reveals a pattern of heightened recidivism risk during the earliest months and years of the follow-up period followed by a steep decline. PMID- 29755186 TI - In vitro study of matrix metalloproteinases 1, 2, 9, 13 and serum amyloid A mRNAs expression in equine fibroblast-like synoviocytes treated with doxycycline. AB - Application of synthetic matrix metalloproteinases (MMPs) inhibitors, such as doxycycline is one of the possible therapeutic options for osteoarthritis. However, little is known about the protective mechanism of doxycycline in equine models on MMPs inhibitors as well as on serum amyloid A (SAA) gene expression. This study investigated the effects of doxycycline on mRNA expression of MMP-1, MMP-2, MMP-9, MMP-13, and SAA of equine fibroblast-like synoviocytes (FLSs). The FLSs were established from synovial fluids of clinically normal metacarpophalangeal joints of 6 skeletally mature horses. The cells were treated with either 10 or 100 MUg/mL of doxycycline for 48 h. The mRNA expression of MMP 1, MMP-2, MMP-9, MMP-13, and SAA were assessed using real-time polymerase chain reaction (PCR). Treatment with doxycycline resulted in significantly decreased mRNA expression of MMP-1 in FLSs at both concentrations (P = 0.001). No significant differences were detected among groups for MMP-2, MMP-9, and MMP-13 (P > 0.05). Only a tendency towards a decrease in mRNA expression level of SAA in the presence of doxycycline could be detected. Doxycycline inhibits MMP-1 gene expression at the transcript level. These findings indicate that doxycycline can protect the articular environment through inhibition of MMP-1 at transcript level. PMID- 29755187 TI - Using a computer simulation model to examine the impact of biosecurity measures during a facility-level outbreak of equine influenza. AB - On-farm biosecurity measures are an important part of a control plan to minimize the introduction and spread of infectious diseases, such as equine influenza, in an equine facility. It can be challenging, however, to evaluate the efficacy of biosecurity measures under field conditions. We used an agent-based computer simulation model to describe the impact of: i) preventive vaccination; ii) reduced horse-to-horse contact; and iii) a combination of vaccination and reduced contact during an outbreak of equine influenza in a simulated horse facility. The model demonstrated that the most effective intervention was a combination of a high proportion of recently vaccinated horses and a substantial reduction in horse-to-horse contact once equine influenza had been identified in the facility. This study highlights the importance of compliance when implementing biosecurity measures, such as facility-level infection control practices, on horse farms. PMID- 29755188 TI - Comparison between cerebrospinal fluid and serum lactate concentrations in neurologic dogs with and without structural intracranial disease. AB - The objectives of this study were to investigate the relationship between cerebrospinal fluid lactate and serum concentrations in dogs with clinical signs of central nervous system disease and to establish if cerebrospinal fluid lactate (CSF) concentrations are higher in dogs with structural intracranial disease (Group Pos-MRI) compared to dogs that have clinical signs of intracranial disease but no structural brain disease (Group Neg-MRI) based on magnetic resonance imaging (MRI) findings. Using a prospective study canine blood and cerebrospinal fluid were collected in 24 dogs with neurological signs after undergoing brain MRI. Dogs were divided in 2 groups. No significant difference between serum lactate (1.57 +/- 0.9 mmol/L) and CSF lactate concentration (1.34 +/- 0.3 mmol/L) was detected. There was a direct correlation between CSF and serum lactate concentration (R = 0.731; P = 0.01). No significant difference was found in CSF lactate concentration between the 2 groups of dogs (P = 0.13). PMID- 29755189 TI - Roles of the crp and sipB genes of Salmonella enterica serovar Typhimurium in protective efficacy and immune responses to vaccination in mice. AB - Salmonella enterica serovar Typhimurium has a wide host range and is capable of causing infections ranging from severe gastroenteritis to systemic infection in humans. To determine if attenuated S. Typhimurium strains can serve as safe and effective oral vaccines to prevent typhoid fever, the biologic characteristics of crp and sipB deletion mutants were evaluated. Previous studies had found that the crp and sipB genes are related to Salmonella pathogenicity. In this study, cytotoxicity, protective efficacy, and immune responses of the host were analyzed. Our previous data had shown a significance decrease in virulence for the crp and sipB mutants compared with a wild-type strain. The current study confirmed this finding in HeLa cells and showed that the crp mutant was significantly less cytotoxic (P < 0.05) than the sipB mutant. Mice vaccinated with the crp mutant showed significantly better protection after challenge with the wild-type strain (P < 0.05) and significantly greater responses in serum IgG (P < 0.01) and secretory IgA (P < 0.05) compared with the mice vaccinated with the sipB mutant (P < 0.05). Our results indicate that the crp mutant has the potential to be a vaccine candidate and is safe in mice. PMID- 29755190 TI - Venous blood gases, plasma biochemistry, and hematology of wild-caught common chameleons (Chamaeleo chamaeleon). AB - The purpose of this study was to determine a wide range of selected hematologic, venous blood gases, and plasma biochemistry analytes in common chameleons (Chamaeleo chamaeleon). Blood samples were collected from the ventral tail vein of 41 common chameleons to determine reference intervals for 30 different blood analytes. The calcium-to-phosphorus ratio, packed cell volume (PCV), refractometric total solids (TS), blood cell counts, and differentials were also determined. The microscopic evaluation of blood smears revealed inclusion bodies in monocytes in 7 of the samples. Females showed significantly higher values of plasma proteins and calcium and cholesterol concentrations and males showed significantly higher values of aspartate aminotransferase (AST) and gamma glutamyl transferase (GGT) plasma concentrations. Significant differences were found between similar analytes determined by different testing methodologies in the PCV/hematocrit, electrolytes (sodium, potassium), and plasma proteins [TS, total protein (TP) and albumin]. Blood analytes determined in this study can provide baseline data that may be useful when evaluating the health status of common chameleons, taking into consideration the potential effects of gender and the type of analyzer used. PMID- 29755191 TI - 26S proteasome and insulin-like growth factor-1 in serum of dogs suffering from malignant tumors. AB - Studies in humans have shown that the ubiquitin-proteasome pathway and the insulin-like growth factor axis are involved in carcinogenesis, thus, components of these systems might be useful as prognostic markers and constitute potential therapeutic targets. In veterinary medicine, only a few studies exist on this topic. Here, serum concentrations of 26S proteasome (26SP) and insulin-like growth factor-1 (IGF-1) were measured by canine enzyme-linked immunosorbent assay (ELISA) in 43 dogs suffering from malignant tumors and 21 clinically normal dogs (control group). Relationships with tumor size, survival time, body condition score (BCS), and tumor entity were assessed. The median 26SP concentration in the tumor group was non-significantly higher than in the control group. However, dogs with mammary carcinomas displayed significantly increased 26SP levels compared to the control group and dogs with tumor size less than 5 cm showed significantly increased 26SP concentrations compared to dogs with larger tumors and control dogs. 26SP concentrations were not correlated to survival time or BCS. No significant difference in IGF-1 levels was found between the tumor group and the control group; however, IGF-1 concentrations displayed a larger range of values in the tumor group. Dogs with tumors greater than 5 cm showed significantly higher IGF-1 levels than dogs with smaller tumors. The IGF-1 concentrations were positively correlated to survival time, but no correlation with BCS was found. Consequently, serum 26SP concentrations seem to be increased in some dogs suffering from malignant tumors, especially in dogs with mammary carcinoma and smaller tumors. Increased serum IGF-1 concentrations could be an indication of large tumors and a poor prognosis. PMID- 29755192 TI - Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. AB - The aim of this study was to determine the efficacy and pharmacokinetics of bupivacaine in combination with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. Sixteen healthy adult cats (3.3 +/- 0.6 kg) were included in a prospective, randomized, masked clinical trial after obtaining owners' consent. Anesthetic protocol included buprenorphine-propofol-isoflurane. Meloxicam [0.2 mg/kg body weight (BW)] was administered subcutaneously before surgery. Cats were randomly divided into 2 groups to receive 1 of 2 treatments. Intraperitoneal bupivacaine 0.25% (2 mg/kg BW) was administered with epinephrine (BE group; 2 MUg/kg BW) or dexmedetomidine (BD group; 1 MUg/kg BW) before ovariohysterectomy (n = 8/group). A catheter was placed in the jugular vein for blood sampling. Blood samples were collected for up to 8 h after bupivacaine was administered. Plasma concentrations and pharmacokinetics of bupivacaine were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) and non-compartmental model, respectively. Pain was evaluated using the UNESP-Botucatu multidimensional composite pain scale (MCPS), the Glasgow composite feline pain scale (GPS), and a dynamic visual analog scale up to 8 h after extubation. Rescue analgesia was provided with buprenorphine if MCPS was >= 6. Repeated measures linear models were used for analysis of pain and sedation scores (P < 0.05). Maximum bupivacaine plasma concentrations (Cmax) for BE and BD were 1155 +/- 168 ng/mL and 1678 +/- 364 ng/mL (P = 0.29) at 67 +/- 13 min (Tmax) and 123 +/- 59 min (P = 0.17), respectively. Pharmacokinetic parameters and pain scores were not different between treatments (P > 0.05). One cat in the BE group received rescue analgesia (P = 0.30). Intraperitoneal bupivacaine with epinephrine or dexmedetomidine produced concentrations below toxic levels and similar analgesic effects. It is therefore safe to administer these drug combinations in cats undergoing ovariohysterectomy. PMID- 29755193 TI - H9N2 avian influenza virus retained low pathogenicity after serial passage in chickens. AB - The H9N2 strains of avian influenza viruses (AIVs) circulate worldwide in poultry and cause sporadic infection in humans. To better understand the evolution of these viruses while circulating in poultry, an H9N2 chicken isolate was passaged 19 times in chickens via aerosol inoculation. Whole-genome sequencing showed that the viruses from the initial stock and those after the 8th and 19th passages (P0, P8, and P19) all had the same monobasic cleavage site in the hemagglutinin (HA), typical for viruses of low pathogenicity. However, at position 226 of the HA protein the ratio of glutamine (which favors avian-type receptor binding) to leucine (which favors mammalian-type receptor binding) decreased from 54:46 in P0, to 87:13 in P8, and then 0:100 in P19. In chickens exposed to aerosols of P0, P8, or P19, replication of the viruses was similar and mainly limited to the respiratory tract. None of the infected chickens showed any clinical signs. Over the 19 passages the viruses maintained relatively stable infectivity but gradually lost lethality to chicken embryos. According to the hemagglutination inactivation assay, P8 was slightly and P19 significantly (P < 0.05) less thermostable than P0. Collectively, after 19 passages in chickens the H9N2 AIVs retained low pathogenicity with a positive selection of L226 in the HA. These findings suggest that H9N2 viruses might acquire mammalian specificity after asymptomatic circulation in avian species. PMID- 29755195 TI - Evaluation of the efficacy of a novel porcine circovirus type 2 synthetic peptide vaccine. AB - A novel porcine circovirus type 2 (PCV2) peptide vaccine comprised of a consensus capsid (Cap) protein domain encoded by open reading frame 2 was developed to control PCV2 infection. The efficacy of the vaccine was evaluated against a commercial baculovirus-expressed recombinant PCV2 subunit vaccine based on the Cap protein. The amino acid sequence of this Cap protein was designed based on the alignment of amino acid sequences from different isolates from Europe, North America, and Asia. The vaccine was evaluated in either phosphate-buffered saline or adjuvanted with aluminum hydroxide, cobalt oxide, or liposome. Overall the PCV2 peptide vaccine was less efficacious against PCV2 challenge compared with the commercial PCV2 vaccine. The peptide vaccine was the most efficacious when liposome was used as an adjuvant, significantly (P < 0.05) reducing viremia while increasing the levels of neutralizing antibodies and interferon-gamma secreting cells. This suggests, in the presence of liposome, the peptide vaccine was able to elicit both humoral and cellular immune responses. PMID- 29755194 TI - Time course of Salmonella shedding and antibody response in naturally infected pigs during grower-finisher stage. AB - A longitudinal trial was conducted to determine the course of Salmonella shedding and antibody response in naturally infected grower-finisher pigs. Ten-week-old pigs (n = 45) were transferred from a farm with history of salmonellosis and housed at a research facility. Weekly fecal samples (weeks 1 to 11) as well as tissue samples at slaughter were cultured for Salmonella. Serum samples were tested for presence of Salmonella antibody by enzyme-linked immunosorbent assay (ELISA). Data were analyzed using a multilevel mixed-effects logistic regression model. Over 10 wk, 91% and 9% of pigs shed Salmonella <= 4 and > 5 times, respectively. The estimated median of Salmonella shedding duration was 3 to 4 wk but some pigs shed Salmonella for up to 8 wk. Salmonella shedding increased 1 wk post-arrival but followed a decreasing pattern afterwards up to week 11 (P < 0.05). Salmonella isolates (n = 29), which were recovered from 18 pigs at different occasions, were S. Typhimurium (28%), S. Livingstone (21%), S. Infantis (14%), S. Montevideo (7%), S. Benfica (3%), S. Amsterdam (3%), S. Senftenberg (17%), and S. I:Rough-O (7%). Of 11 pigs from which the first and last isolates were serotyped, 10 pigs were reinfected with a different serotype. At slaughter, Salmonella was isolated from 7 pigs, of which 5 (71%) had not tested positive for at least 7 wk prior to slaughter. Antibody response peaked 4 wk after the peak of Salmonella infection; Salmonella shedding reduced as antibody response elevated (P < 0.05). These findings indicate that pigs may shed Salmonella into the mid point of the grower-finisher stage and may be reinfected with different serotypes. PMID- 29755196 TI - Effect of a commercially available fish-based dog food enriched with nutraceuticals on hip and elbow dysplasia in growing Labrador retrievers. AB - The aim of this study was to evaluate the prevalence of hip and elbow dysplasia in a group of growing Labrador retrievers fed a fish-based diet enriched with nutraceuticals with chondroprotective properties. The puppies ranged from 3 to 12 mo of age and were divided into 2 groups, each fed a different diet. The control diet consisted of a high quality, chicken-based dog food, while the test diet was a fish-based dog food, enriched with nutraceuticals. Hip and elbow joints were radiographed and scored at 6 and 12 mo of age. Overall, 42 dogs completed the study. At 12 mo of age, no differences were found between the groups in the prevalence of hip and elbow dysplasia, although dogs fed the fish-based food enriched with nutraceuticals had a less severe grade of osteoarthritis at 12 mo. It was concluded that the fish-based diet with nutraceuticals did have beneficial effects on the development of severe osteoarthritis. PMID- 29755197 TI - Peak vertical force in a stabilized canine cranial cruciate deficient stifle model: A one-year follow-up. AB - This study aimed to describe the peak vertical force (PVF) over a 1-year period in a stabilized canine cranial cruciate deficient stifle model. Our hypothesis was that PVF would be restored to Baseline (intact) at the end of the follow-up. Fifteen (> 20 kg) mixed-breed dogs were included in this study. Cranial cruciate ligament was transected on Day (D) 0 followed by lateral suture stabilization at D28. Peak vertical force was acquired at D-1, D14, D26, D91, D210 and D357. When compared to Baseline, the PVF was significantly decreased at D14, D26, and D91. Values at D210 and D357 were not statistically different to Baseline. This study suggests a return to normal baseline peak vertical force in a canine cranial cruciate deficient stifle model when lateral suture stabilization has been performed 28 days after surgical transection. PMID- 29755198 TI - Modeling and inference for infectious disease dynamics: a likelihood-based approach. AB - Likelihood-based statistical inference has been considered in most scientific fields involving stochastic modeling. This includes infectious disease dynamics, where scientific understanding can help capture biological processes in so-called mechanistic models and their likelihood functions. However, when the likelihood of such mechanistic models lacks a closed-form expression, computational burdens are substantial. In this context, algorithmic advances have facilitated likelihood maximization, promoting the study of novel data-motivated mechanistic models over the last decade. Reviewing these models is the focus of this paper. In particular, we highlight statistical aspects of these models like overdispersion, which is key in the interface between nonlinear infectious disease modeling and data analysis. We also point out potential directions for further model exploration. PMID- 29755200 TI - Capture and Purification of Polyphenols Using Functionalized Hydrophobic Resins. AB - Adsorption can be an effective way of purifying polyphenols from complex mixtures. However, polyphenols may be present in small concentrations, making it difficult to selectively adsorb them onto standard hydrophobic resins and obtain appreciable adsorption. In this work, nonfunctionalized hydrophobic resins (Amberlite XAD-7HP, XAD-16) are compared with functionalized resins with imidazole (Biotage RENSA PX) and pyridine (RENSA PY) in terms of capacity and selectivity toward p-coumaric acid, trans-resveratrol, and naringenin. The obtained results indicate that, due to hydrogen bonding, the functionalized resins provide more capacity (e.g., 80 mg.g-1 vs 11.3 mg.g-1 for trans resveratrol) and up to five times more selectivity than standard resins. Despite such strong affinity, at low pH, the isotherm slope can decrease up to four times when compared to the XAD resins for the same ethanol content, making desorption easier. The included isotherm data is enough to model any chromatography dynamic simulation for the studied compounds. PMID- 29755201 TI - A Constraint Optimization Approach to Causal Discovery from Subsampled Time Series Data. AB - We consider causal structure estimation from time series data in which measurements are obtained at a coarser timescale than the causal timescale of the underlying system. Previous work has shown that such subsampling can lead to significant errors about the system's causal structure if not properly taken into account. In this paper, we first consider the search for system timescale causal structures that correspond to a given measurement timescale structure. We provide a constraint satisfaction procedure whose computational performance is several orders of magnitude better than previous approaches. We then consider finite sample data as input, and propose the first constraint optimization approach for recovering system timescale causal structure. This algorithm optimally recovers from possible conflicts due to statistical errors. We then apply the method to real-world data, investigate the robustness and scalability of our method, consider further approaches to reduce underdetermination in the output, and perform an extensive comparison between different solvers on this inference problem. Overall, these advances build towards a full understanding of non parametric estimation of system timescale causal structures from sub-sampled time series data. PMID- 29755199 TI - The Impact of Well-Field Configuration on Contaminant Mass Removal and Plume Persistence for Homogeneous versus Layered Systems. AB - A three-dimensional numerical model was used to simulate the impact of different well-field configurations on pump-and-treat mass removal efficiency for large groundwater contaminant plumes residing in homogeneous and layered domains. Four well-field configurations were tested, Longitudinal, Distributed, Downgradient, and natural gradient (with no extraction wells). The reductions in contaminant mass discharge (CMDR) as a function of mass removal (MR) were characterized to assess remediation efficiency. Systems whose CDMR-MR profiles are below the 1:1 relationship curve are associated with more efficient well-field configurations. For simulations conducted with the homogeneous domain, the CMDR-MR curves shift leftward, from convex-downward profiles for natural gradient and Longitudinal to first-order behaviour for Distributed, and further leftward to a sigmoidal profile for the Downgradient well-field configuration. These results reveal the maximum potential impacts of well-field configuration on mass-removal behaviour, which is attributed to mass-transfer constraints associated with regions of low flow. In contrast, for the simulations conducted with the layered domain, the CMDR-MR relationships for the different well-field configurations exhibit convex upward profiles. The nonideal mass-removal behaviour in this case is influenced by both well-field configuration and back diffusion associated with low permeability units. PMID- 29755202 TI - Modeling Temporal Interaction Dynamics in Organizational Settings. AB - Most workplace phenomena take place in dynamic social settings and emerge over time, and scholars have repeatedly called for more research into the temporal dynamics of organizational behavior. One reason for this persistent research gap could be that organizational scholars are not aware of the methodological advances that are available today for modeling temporal interactions and detecting behavioral patterns that emerge over time. To facilitate such awareness, this Methods Corner contribution provides a hands-on tutorial for capturing and quantifying temporal behavioral patterns and for leveraging rich interaction data in organizational settings. We provide an overview of different approaches and methodologies for examining temporal interaction patterns, along with detailed information about the type of data that needs to be gathered in order to apply each method as well as the analytical steps (and available software options) involved in each method. Specifically, we discuss and illustrate lag sequential analysis, pattern analysis, statistical discourse analysis, and visualization methods for identifying temporal patterns in interaction data. We also provide key takeaways for integrating these methods more firmly in the field of organizational research and for moving interaction analytical research forward. PMID- 29755203 TI - Hybrid Masculinity and Young Men's Circumscribed Engagement in Contraceptive Management. AB - This research explores how gender shapes contraceptive management through in depth interviews with 40 men and women of color ages 15 to 24, a life stage when the risk of unintended pregnancy is high in the United States. Although past research focuses on men's contraception-avoidant behaviors, little sociological work has explored ways men engage in contraception outside of condoms, such as contraceptive pills. Research often highlights how women manage these methods alone. Our research identifies how young men of color do help manage these methods through their engagement in contraceptive decision-making and use. Men accomplish this without limiting their partners' ability to prevent pregnancy. This is despite structural barriers such as poverty and gang-related violence that disproportionately affect low-income young men of color and often shape their reproductive goals. However, men's engagement is still circumscribed so that women take on a disproportionate burden of pregnancy prevention, reifying gender boundaries. We identify this as a form of hybrid masculinity, because men's behaviors are seemingly egalitarian but also sustain women's individualized risk of unintended pregnancy. This research points to the complexity of how race, class, and gender intersect to create an engaged but limited place for men in contraceptive management among marginalized youth. PMID- 29755204 TI - Cryopreservation studies of an artificial co-culture between the cobalamin requiring green alga Lobomonas rostrata and the bacterium Mesorhizobium loti. AB - Algal-bacterial co-cultures, rather than cultures of algae alone, are regarded as having the potential to enhance productivity and stability in industrial algal cultivation. As with other inocula in biotechnology, to avoid loss of production strains, it is important to develop preservation methods for the long-term storage of these cultures, and one of the most commonly used approaches is cryopreservation. However, whilst there are many reports of cryopreserved xenic algal cultures, little work has been reported on the intentional preservation of both algae and beneficial bacteria in xenic cultures. Instead, studies have focused on the development of methods to conserve the algal strain(s) present, or to avoid overgrowth of bacteria in xenic isolates during the post-thaw recovery phase. Here, we have established a co-cryopreservation method for the long-term storage of both partners in a unialgal-bacterial co-culture. This is an artificial model mutualism between the alga Lobomonas rostrata and the bacterium Mesorhizobium loti, which provides vitamin B12 (cobalamin) to the alga in return for photosynthate. Using a Planer Kryo 360 controlled-rate cooler, post-thaw viability (PTV) values of 72% were obtained for the co-culture, compared to 91% for the axenic alga. The cultures were successfully revived after 6 months storage in liquid nitrogen, and continued to exhibit mutualism. Furthermore, the alga could be cryopreserved with non-symbiotic bacteria, without bacterial overgrowth occurring. It was also possible to use less controllable passive freezer chambers to cryopreserve the co-cultures, although the PTV was lower. Finally, we demonstrated that an optimised cryopreservation method may be used to prevent the overgrowth potential of non-symbiotic, adventitious bacteria in both axenic and co-cultures of L. rostrata after thawing. PMID- 29755206 TI - Epilithic Chamaesiphon (Synechococcales, Cyanobacteria) species in mountain streams of the Alps-interspecific differences in photo-physiological traits. AB - Many alpine streams inhabit conspicuous epilithic biofilms on pebbles and rocks that are formed by members of the cyanobacterial genus Chamaesiphon (Synechococcales). In the Austrian Alps, some Chamaesiphon species can even overgrow up to 70% of the surface of river rocks, and hence they must play an important but still unstudied ecological role in the organic matter flux. Since photo-biological traits have not been investigated so far, photosynthetic features, pigments, and UV-sunscreen compounds were studied in three Chamaesiphon morphospecies (C. geitleri, C. polonicus, C. starmachii). These species form conspicuously differently colored spots on cobbles and boulders in the alpine streams. While C. polonicus typically forms red crusts on flat pebble conglomerate, C. geitleri and C. starmachii are characterized by dark brown and black biofilms in the field, respectively. Photosynthesis-irradiance (PE) curves indicate that all three Chamaesiphon species have different light requirements for photosynthesis, with C. starmachii and C. polonicus preferring high and low photon fluence rates, respectively, while C. geitleri takes a position in between. This low-light requirement of C. polonicus is also reflected in ca. ten times lower chlorophyll a, zeaxanthin, and beta-carotene concentrations, as well as in a lack of the UV-sunscreen scytonemin. All Chamaesiphon morphospecies exhibit the mycosporine-like amino acid porphyra-334. The physiological and biochemical data indicate strong intraspecific differences in photosynthetic activity and pigment patterns, which explain well the distinct preferences of the three studied Chamaesiphon morphospecies for sun-exposed or shaded habitats. PMID- 29755205 TI - Enumerating viable phytoplankton using a culture-based Most Probable Number assay following ultraviolet-C treatment. AB - Ballast water management systems (BWMS) must be tested to assess their compliance with standards for the discharge of organisms, for example in the >= 10- and < 50 MUm size category, which is dominated by phytoplankton. Assessment of BWMS performance with the vital stains fluorescein diacetate + 5-chlorofluorescein diacetate, required by regulations in the USA, is problematic in the case of ultraviolet-C (UVC) radiation. This is because UVC targets nucleotides-and thus reproduction, hence viability-rather than membrane integrity, which is assayed by the stains. The Serial Dilution Culture-Most Probable Number (SDC-MPN) method, long used to enumerate fragile phytoplankton from natural communities, is appropriate for counting viable phytoplankton. We developed QA/QC "best practice" criteria for its application as a robust and repeatable assay of viable cells in cultures of phytoplankton before and after experimental treatment, then constructed dose-response curves for UVC-induced loss of viable cells in 12 species of phytoplankton from seven divisions. Sensitivity to UVC, expressed as the dose required to reduce viability by 99%-the criterion for type approval of treatment systems-varied more than 10-fold and was not correlated with cell size. The form of the dose-response curves varied between taxa, with most having a threshold dose below which there was no reduction in viability. Analysis of the patterns of growth indicates that if recovery from treatment occurred, it was complete in 1 or 2 days in > 80% of cases, long before the assays were terminated. We conclude that the SDC-MPN assay as described is robust and adaptable for use on natural phytoplankton. PMID- 29755209 TI - The influence of abiotic factors on the bloom-forming alga Ulva flexuosa (Ulvaceae, Chlorophyta): possibilities for the control of the green tides in freshwater ecosystems. AB - Ulva species are characterised by the capacity to achieve rapid biomass increase, which results in the formation of "green tides", particularly in nutrient-rich seawaters. Over the last decade, formation of large-scale Ulva mats has been increasingly observed in freshwater systems in Central Europe. Mass development of Ulva in freshwater ecosystems presents a growing burden in spite of its economic benefits. This study explores the formation dynamics of Ulva flexuosa mats with respect to habitat conditions, using the examples of a number of water systems located in Poland. Elevated water temperature, pH and high concentration of sulphates are among the most important factors affecting biometric parameters of Ulva blooms. An evident disparity was observed between lotic water ecosystems and lentic water ecosystems, which differed in terms of chemical characteristics of the habitat and mat structure properties. In flowing water, U. flexuosa displays a definitely higher potential for blooms. On the other hand, mass occurrence of U. flexuosa in freshwaters is caused by the inflow of fecund waters, especially following intense precipitation in summertime, as well as by periodic increases in salinity, pH and sulphate levels. The study suggests that potential U. flexuosa blooms in landlocked ecosystems may be controlled by means of reducing the inflow of particularly sulphate-rich waters. PMID- 29755208 TI - Biorefinery of the macroalgae Ulva lactuca: extraction of proteins and carbohydrates by mild disintegration. AB - The effect of osmotic shock, enzymatic incubation, pulsed electric field, and high shear homogenization on the release of water-soluble proteins and carbohydrates from the green alga Ulva lactuca was investigated in this screening study. For osmotic shock, both temperature and incubation time had a significant influence on the release with an optimum at 30 degrees C for 24 h of incubation. For enzymatic incubation, pectinase demonstrated being the most promising enzyme for both protein and carbohydrate release. Pulsed electric field treatment was most optimal at an electric field strength of 7.5 kV cm-1 with 0.05 ms pulses and a specific energy input relative to the released protein as low as 6.6 kWh kgprot 1. Regarding literature, this study reported the highest protein (~ 39%) and carbohydrate (~ 51%) yields of the four technologies using high shear homogenization. Additionally, an energy reduction up to 86% was achieved by applying a novel two-phase (macrostructure size reduction and cell disintegration) technique. PMID- 29755207 TI - Effect of the epiphytic bacterium Bacillus sp. WPySW2 on the metabolism of Pyropia haitanensis. AB - A variety of different symbiotic microbial communities are harbored on the surface of seaweeds, the interactions of which depend upon nutritional exchanges between the microbes and the hosts. Metabolomic profiling is able to provide a comprehensive and unbiased snapshot of the metabolites associated with seaweed microbe interactions. In this study, the relationships between phycosphere bacteria and the red alga Pyropia haitanensis were investigated on a metabolomic basis using gas chromatography-mass spectrometry, and the pathways of the interactions between the seaweed and its associated phycospheric microbes were revealed. Bacillus sp. WPySW2, one bacterial species isolated from the phycosphere of Pyropia species, had a significant influence on the metabolomic profile of the algae. Some of the intracellular metabolites such as phenylalanine, leucine, isoleucine, valine, proline, tyrosine, threonine, octadecanoic acid, hexadecanoic acid, and citric acid were downregulated in the thalli of P. haitanensis when it was co-cultured with Bacillus sp. WPySW2, while several special metabolites including melibiose, serine, glycerol-3-phosphate, galactosylglycerol, and alanine were upregulated. The results demonstrated that P. haitanensis grew better when it was co-cultured with Bacillus sp. WPySW2 at 20 degrees C. In conclusion, several main intracellular metabolites were downregulated and upregulated, which might have facilitated bacterial colonization. PMID- 29755210 TI - Deep Learning for Classification of Normal Swallows in Adults. AB - Cervical auscultation is a method for assessing swallowing performance. However, its ability to serve as a classification tool for a practical clinical assessment method is not fully understood. In this study, we utilized neural network classification methods in the form of Deep Belief networks in order to classify swallows. We specifically utilized swallows that did not result in clinically significant aspiration and classified them on whether they originated from healthy subjects or unhealthy patients. Dual-axis swallowing vibrations from 1946 discrete swallows were recorded from 55 healthy and 53 unhealthy subjects. The Fourier transforms of both signals were used as inputs to the networks of various sizes. We found that single and multi-layer Deep Belief networks perform nearly identically when analyzing only a single vibration signal. However, multi-layered Deep Belief networks demonstrated approximately a 5% to 10% greater accuracy and sensitivity when both signals were analyzed concurrently, indicating that higher order relationships between these vibrations are important for classification and assessment. PMID- 29755211 TI - Microfluidic Diatomite Analytical Devices for Illicit Drug Sensing with ppb-Level Sensitivity. AB - The escalating research interests in porous media microfluidics, such as microfluidic paper-based analytical devices, have fostered a new spectrum of biomedical devices for point-of-care (POC) diagnosis and biosensing. In this paper, we report microfluidic diatomite analytical devices (MUDADs), which consist of highly porous photonic crystal biosilica channels, as an innovative lab-on-a-chip platform to detect illicit drugs. The MUDADs in this work are fabricated by spin-coating and tape-stripping diatomaceous earth on regular glass slides with cross section of 400*30um2. As the most unique feature, our MUDADs can simultaneously perform on-chip chromatography to separate small molecules from complex biofluidic samples and acquire the surface-enhanced Raman scattering spectra of the target chemicals with high specificity. Owing to the ultra-small dimension of the diatomite microfluidic channels and the photonic crystal effect from the fossilized diatom frustules, we demonstrate unprecedented sensitivity down to part-per-billion (ppb) level when detecting pyrene (1ppb) from mixed sample with Raman dye and cocaine (10 ppb) from human plasma. This pioneering work proves the exclusive advantage of MUDADs as emerging microfluidic devices for chemical and biomedical sensing, especially for POC drug screening. PMID- 29755212 TI - Multiple neural control and stabilization. AB - In this paper, we present a multiple neural control and stabilization strategy for nonlinear and unstable systems. This control strategy method is efficient especially when the system presents different behaviors or different equilibrium points and when we hope to drive the whole process to a desired state ensuring stabilization. The considered control strategy has been applied on a nonlinear unstable system possessing two equilibrium points. It has been shown that the use of the multiple neural control and stabilization strategy increases further the stability domain of the system further than when we use a single neural control strategy. PMID- 29755213 TI - Stereotype Content: Warmth and Competence Endure. AB - Two dimensions persist in social cognition, whether people are making sense of individuals or groups. The Stereotype Content Model terms the basic dimensions perceived warmth (trustworthiness, friendliness) and competence (capability, assertiveness). Measured reliably and validly, these Big Two dimensions converge across methods: survey, cultural, laboratory, and biobehavioral approaches. Generality across place, levels, and time further support the framework. Parallel pairs have emerged repeatedly over the history of psychology and in current theories. The SCM proposes and tests a comprehensive causal theory: perceived social structure (cooperation, status) -> stereotypes (warmth, competence) -> emotional prejudices (pride, pity, contempt, envy) -> discrimination (active and passive help and harm). The SCM uncovers systematic content and dynamics of stereotypes, with practical implications. PMID- 29755214 TI - Ecophysiological and morphological comparison of two populations of Chlainomonas sp. (Chlorophyta) causing red snow on ice-covered lakes in the High Tatras and Austrian Alps. AB - Based on analyses of multiple molecular markers (18S rDNA, ITS1, ITS2 rDNA, rbcL), an alga that causes red snow on the melting ice cover of a high-alpine lake in the High Tatras (Slovakia) was shown to be identical with Chlainomonas sp. growing in a similar habitat in the Tyrolean Alps (Austria). Both populations consisted mostly of smooth-walled quadriflagellates. They occurred in slush, and shared similar photosynthetic performances (photoinhibition above 1300 umol photons m-2 s-1), very high levels of polyunsaturated fatty acids (PUFA, 64% and 74% respectively) and abundant astaxanthin accumulation, comparable to the red spores of Chlamydomonas nivalis (Bauer) Wille. Physiological differences between the Slovak and Austrian populations included higher levels of alpha-tocopherol and a 13Z-isomer of astaxanthin in the former. High accumulation of secondary pigments in the Slovak population probably reflected harsher environmental conditions, since the collection was made later in the growing season when cells were exposed to higher irradiance at the surface. Using a polyphasic approach, we compared Chlainomonas sp. with Chlamydomonas nivalis. The latter causes 'conventional' red snow, and shows high photophysiological plasticity, with high efficiency under low irradiance and no photoinhibition up to 2000 umol photons m 2 s-1. Its PUFA content was significantly lower (50%). An annual cycle of lake-to snow colonization by Chlainomonas sp. from slush layers deeper in the ice cover is proposed. Our results point to an ecologically highly specialized cryoflora species, whose global distribution is likely to be more widespread than previously assumed. PMID- 29755215 TI - Resonance Signaling and Yoga. PMID- 29755216 TI - Yoga for Heart Failure: A Review and Future Research. AB - Background: Complementary and alternative medicine is a rapidly growing area of biomedical inquiry. Yoga has emerged in the forefront of holistic medical care due to its long history of linking physical, mental, and spiritual well-being. Research in yoga therapy (YT) has associated improved cardiovascular and quality of life (QoL) outcomes for the special needs of heart failure (HF) patients. Aim: The aim of this study is to review yoga intervention studies on HF patients, discuss proposed mechanisms, and examine yoga's effect on physiological systems that have potential benefits for HF patients. Second, to recommend future research directions to find the most effective delivery methods of yoga to medically stable HF patients. Methods: The authors conducted a systematic review of the medical literature for RCTs involving HF patients as participants in yoga interventions and for studies utilizing mechanistic theories of stretch and new technologies. We examined physical intensity, mechanistic theories, and the use of the latest technologies. Conclusions: Based on the review, there is a need to further explore yoga mechanisms and research options for the delivery of YT. Software apps as exergames developed for use at home and community activity centers may minimize health disparities and increase QoL for HF patients. PMID- 29755217 TI - Immediate Effects of Yoga Breathing with Intermittent Breath Holding on Response Inhibition among Healthy Volunteers. AB - Background: There is very little evidence available on the effects of yoga-based breathing practices on response inhibition. The current study used stop-signal paradigm to assess the effects of yoga breathing with intermittent breath holding (YBH) on response inhibition among healthy volunteers. Materials and Methods: Thirty-six healthy volunteers (17 males + 19 females), with mean age of 20.31 +/- 3.48 years from a university, were recruited in a within-subject repeated measures (RM) design. The recordings for stop signal task were performed on three different days for baseline, post-YBH, and post yogic breath awareness (YBA) sessions. Stop-signal reaction time (SSRT), mean reaction time to go stimuli (go RT), and the probability of responding on-stop signal trials (p [r/s]) were analyzed for 36 volunteers using RM analysis of variance. Results: SSRT reduced significantly in both YBH (218.33 +/- 38.38) and YBA (213.15 +/- 37.29) groups when compared to baseline (231.98 +/- 29.54). No significant changes were observed in go RT and p (r/s). Further, the changes in SSRT were not significantly different among YBH and YBA groups. Conclusion: Both YBH and YBA groups were found to enhance response inhibition in the stop-signal paradigm. YBH could be further evaluated in clinical settings for conditions where response inhibition is altered. PMID- 29755218 TI - Effects of Yoga Training on Body Composition and Oxidant-Antioxidant Status among Healthy Male. AB - Background: The stressful condition may cause oxidative stress, which is responsible for various diseases. Aims: The present study was designed to find out whether yoga has impact on the reduction of oxidative stress. Methods: For the present study, 95 (n = 95) healthy male volunteers within the age group of 18 24 years were included, 35 (n = 35) volunteers were excluded. The remaining 60 (n = 60) volunteers were randomly divided into two groups: (a) Yoga Group (n = 30) and (b) Control Group (n = 30). Yoga training was given for 60 min per day, 6 days per week for 12 weeks in the yoga group, with no yoga training in control group. Assessment of body composition and oxidant-antioxidant status were performed in both the groups at baseline, before yoga training (0 week) and after (12 weeks) of the training. Results: Significant reduction (P < 0.001) in the percentage of body fat and malondialdehyde; significant elevation (P < 0.001) in superoxide dismutase, catalase, reduced glutathione and ascorbic acid levels were noted in the yoga group after 12 weeks when compared to baseline data (0 week). However, there was no significant difference in height, weight, body mass index, body surface area and lean body mass among the yoga group after 12 weeks when compared to baseline data. These changes might be due to yoga training. Conclusions: Regular yoga practice reduces body fat and oxidative stress. Yoga training may be helpful to reduce the chance of occurrence of various diseases and helps to maintain normal healthy lifestyle. PMID- 29755219 TI - Effect of Yogic Breathing on Accommodate Braille Version of Six-letter Cancellation Test in Students with Visual Impairment. AB - Context: Attentional processes tend to be less well developed in the visually impaired, who require special training to develop them fully. Yogic breathing which alters the patterns of respiration has been shown to enhance attention skills. Letter cancellation tests are well-established tools to measure attention and attention span. Here, a modified Braille version of the six-letter cancellation test (SLCT) was used for students with visual impairment (VI). Aim: This study aimed to assess the immediate effects of Bhramari Pranayama (BhPr) and breath awareness (BA) on students with VI. Methods: This study was a self-as control study held on 2 consecutive days, on 19 participants (8 males, 11 females), with a mean age of 15.89 +/- 1.59 years, randomized into two groups. On the 1st day, Group 1 performed 10 min breath awareness and Group 2 performed Bhramari; on the 2nd day, practices were reversed. Assessments used a SLCT specially adapted for the visually impaired before and after each session. Results: The Braille letter cancellation test was successfully taken by 19 students. Scores significantly improved after both techniques for each student following practices on both days (P < 0.001). BhPr may have more effect on attention performance than BA as wrong scores significantly increased following BA (P < 0.05), but the increase in the score after Bhramari was not significant. Conclusions: Despite the small sample size improvement in attentional processes by both yoga breathing techniques was robust. Attentional skills were definitely enhanced. Long-term practice should be studied. PMID- 29755220 TI - Effect of Mula Bandha Yoga in Mild Grade Pelvic Organ Prolapse: A Randomized Controlled Trial. AB - Background: Pelvic organ prolapse is the growing health issue related to women of the reproductive and postmenopausal age group in India and across the globe. Treatment option for pelvic organ prolapse includes both surgical and non surgical intervention. The development of pelvic organ prolapse is an indication for major surgery among 20% of all women. Nevertheless, the recurrence of pelvic organ prolapse is detected among 58% of the patient after surgery. This highlights the need for preventive measures for reducing the impact of pelvic organ prolapse. Aims and Objective: To study the effect of 3 months yoga therapy in female patients suffering from mild pelvic organ prolapse. Material and Methods: 50 Participants were allocated into two groups (25 in each group) by generating Random allocation sequence. Women aged 20-60 with symptomatic mild pelvic organ prolapse in the yoga group were offered Mulabandha yoga therapy along with other conventional treatment modalities, while the control group was only on conventional treatment. All participants gave written informed consent. An assessment was done by improvement in chief complaints and Pelvic Floor Distress Inventory-20 (PFDI-20) & Pelvic floor impact Questionnaire-7 (PFIQ-7) at baseline and at the end of 4, 8 & 12 weeks. Results At the end of 12 weeks, Post study comparison between the two groups showed a significant improvement in chief complaints like perennial pain, P/V discharge, Perineal muscle laxity and Feeling of something coming out P/V (P < 0.001). Participants in the yoga group improved by (on average) 5.7 (95% confidence interval 3.1 to 14.7) points more on the PFDI 20 than did participants in the control group (P = 0.1) and a mean score of PFIQ 7 was also improved significantly. Conclusions: Although Mulabandha (Root Lock) yoga therapy led to a significantly greater improvement in PFDI-20 & PFIQ-7 scores the difference between the groups was below the presumed level of clinical relevance (15 points). More studies are needed to identify factors related to the success of Mulabandha (Root Lock) yoga therapy and to investigate long-term effects. PMID- 29755221 TI - Effect of 6 Months of Meditation on Blood Sugar, Glycosylated Hemoglobin, and Insulin Levels in Patients of Coronary Artery Disease. AB - Background and Objectives: Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. It has been recognized that stress, diabetes, and hypertension are important in etiology and progression of CAD. This study is to evaluate the role of meditation in improving biochemical parameters such as blood glucose, glycosylated hemoglobin, and serum insulin levels in known CAD patients. Material and Methods: Sixty CAD patients are divided into two groups of which one group did meditation and other did not. Blood glucose, glycosylated hemoglobin, and fasting serum insulin levels were measured before and at the end of 6 months of study in both the groups. Results: At the end of the study, significant decrease was seen in patients who practiced meditation as compared to other group. Conclusion: Meditation may modulate the physiological response to stress through neurohumoral activation, which may be a novel therapeutic target for the treatment of CAD. PMID- 29755222 TI - Yoga as a Therapeutic Intervention for the Management of Type 2 Diabetes Mellitus. AB - Purpose: This study aimed to investigate the effects of 12 weeks yogic intervention on blood sugar and lipid profile in elder women with Type 2 diabetes mellitus (T2DM). Subjects and Methods: Twenty elderly (age range 55-70 years) T2DM women were divided into two groups, namely, yogic intervention group (YIG: n = 10, age 64.70 +/- 4.03, body mass index [BMI] 24.26 +/- 3.40) and control group (CG: n = 10, age 64.40 +/- 4.79, BMI 24.28 +/- 2.36). YIG underwent yoga practice (Asanas, Kriyas, Pranayamas) for 12 weeks (3 sessions/week), while the CG continued their usual routine activities. Standing height, body weight, BMI, blood sugar, and lipid profile were measured before commencement and after 6 and 12 weeks of yogic intervention in both groups. Results: There was a significant (P < 0.01) decrease in fasting plasma glucose, postprandial blood sugar, total cholesterol, triglycerides, low-density lipoprotein, and very low density lipoprotein, with a significant (P < 0.01) increase in high-density lipoprotein level from its initial value in YIG, while showing insignificant result in CG. Conclusion: It can be said that yogic intervention may have the beneficial effects on blood sugar and lipid profile in elderly women with T2DM. PMID- 29755223 TI - Study to Evaluate the Changes in Polycystic Ovarian Morphology after Naturopathic and Yogic Interventions. AB - Background: Polycystic ovarian syndrome (PCOS) is one of the commonest endocrine disorders in women, with a prevalence ranging from 2.2% to 26% in India. Patients with PCOS face challenges including irregular menstrual cycles, hirsutism, acne, acanthosis nigricans, obesity and infertility. 9.13% of South Indian adolescent girls are estimated to suffer from PCOS. The efficacy of Yoga & Naturopathy (Y&N) in the management of polycystic ovarian syndrome requires to be investigated. Aims: The aim of the present study is to observe the morphological changes in polycystic ovaries of patients following 12 weeks of Y&N intervention. Settings and Design: The study was conducted at the Government Yoga and Naturopathy Medical College and Hospital, Chennai, India. The study was a single blinded prospective, pre-post clinical trial. Methods and Material: Fifty PCOS patients of age between 18 and 35 years who satisfied the Rotterdam criteria were recruited for the study. According to their immediate participation in the study they were either allocated to the intervention group (n=25) or in the wait listed control group (n=25). The intervention group underwent Y&N therapy for 12 weeks. Change in polycystic ovarian morphology, anthropometric measurements and frequency of menstrual cycle were studied before and after the intervention. Results: Significant improvement was observed in the ovarian morphology (P<0.001) and the anthropometric measurements (P<0.001) between the two groups. Conclusions: The findings of the study indicate that Y&N interventions are efficient in bringing about beneficial changes in polycystic ovarian morphology. We speculate that a longer intervention might be required to regulate the frequency of menstrual cycle. PMID- 29755224 TI - No Differences in Energy Cost of a Predetermined Exercise among Young Overweight/Obese and Undernourished Individuals. AB - Background: Physical activity is an integral part of one's daily life. Obese (Ob) and undernourished (UN) persons are known to underperform physically as compared to normal weight (N) individuals. In this study, we have measured the energy spent to perform a prefixed exercise on treadmill walking and basal heart rate and blood pressure. Body mass index (BMI) and body fat of participating individuals were assessed. Fasting blood sugar and lipid profile were also evaluated. Materials and Methods: Eighty-three young individuals (male: 41; female: 42) of medical faculty, Universiti Sultan Zainal Abidin, who volunteered for the study, were recruited. The mean age of the individuals was 19.8 +/- 0 years (P < 1.08). The individuals were grouped as N, UN/underweight, and overweight (Ow)/Ob based on BMI. Results: The results of the study revealed that there were no differences in the energy spent on performing the predetermined treadmill walking of 20 min duration among the three groups (a mean of 78 and 70 calories in all male and female subgroups, respectively). The distance covered by the males was 1.6 km while the females covered 1.4 km on treadmill walking in 20 min time. Basal blood pressure and heart rate and fasting blood sugar did not reveal any significant difference among the groups. However, total cholesterol and triglyceride levels were marginally higher in the Ow/Ob groups of male and female individuals as compared to other groups. Conclusion: Since the study individuals were very young and competitive by nature and possibly had no major metabolic disturbances, the differences in physical activity performances were not obvious. Possibly, such differences would become apparent only at later stages of life as age advances or when the intensity and duration of exercise are set at higher levels. PMID- 29755225 TI - Classification of Electrophotonic Images of Yogic Practice of Mudra through Neural Networks. AB - Background: Mudras signify a gesture with hands, eyes, and the body. Different configurations of the joining of fingertips are also termed mudra and are used by yoga practitioners for energy manipulation and for therapeutic applications. Electrophotonic imaging (EPI) captures the coronal discharge around the fingers as a result of electron capture from the ten fingers. The coronal discharge around each fingertip is studied to understand the effect of mudra on EPI parameters. Methods: The participants were from Swami Vivekananda Yoga Anusandhana Samsthana and Sushrutha Ayurvedic Medical College, in Bengaluru, India. There were 29 volunteers in the mudra group and 32 in the control group. There were two designs: one was a pre-post design with control the other was pre post with repeated measures with 18 individuals practicing mudra for 3 days. The duration of intervention for the pre-post design was 10 min on the 1st day, 15 min on the 2nd day, and 20 min on the 3rd day. A neural network classifier was used for classifying mudra and control samples. Results: The EPI parameters, normalized area and average intensity, passed the test of normality Shapiro-Wilk. The Cohen's d, effect size was 0.988 and 0.974 for the mudra and control groups, respectively. Neural network-based analysis showed the classification accuracy of the post-intervention samples for mudra and control varied from 85% to 100% while the classification accuracy varied from 55% to 70% for the pre-intervention samples. The result of the mudra intervention showed statistically significant changes in the mean values on the 3rd day compared to the 1st day. Conclusions: The effect size of the variations in mudra was more than that of the control group. Mudra practice of a longer duration showed statistically significant change in the EPI parameter, average intensity in comparison to the practice on the 1st day. PMID- 29755226 TI - Bioenergy and its Implication for Yoga Therapy. AB - Electro photonic imaging (EPI) is being researched relative to its application for yoga therapy. Three parameters of interest in EPI measurements are as follows: Communication energy (C), integral or normalized area (IA), and Entropy (E). It is important to note that C indicates the total energy of communication for the organ system; IA is an indication of total amount of energy that is available for the organ system while entropy is an indication of the amount of coherence of the energy. Coherence and entropy are inversely related; this means less the entropy, more the coherence and vice versa. Illustrative cases of successful therapy with yoga practices in a wide variety of abnormal conditions are examined, and in every case, entropy is shown to decrease for the affected organ system while communication energy stays within stable range. Relative to the electromagnetic (Rubik) and living matrix (Oschman) models, it is suggested that the regulation of energy, its coherence in the biological system and interaction with life processes provide the basis for model building and design of health-promoting procedures. Further, this approach is examined relative to yoga theory, traditional medicine systems, and scientific developments in the field of gene expression and neuroplasticity and a generalized model that we call Unified System of Medicine is proposed. This model has direct implications on methods used to control the environmental factors to get robust results from EPI application for therapeutic purposes. Implications for furthering research in yoga therapy using EPI and implications of EPI as a translational technology between traditional medicine systems and modern medicine is discussed. PMID- 29755228 TI - Effect of 1-Week Yoga-Based Residential Program on Cardiovascular Variables of Hypertensive Patients: A Comparative Study. AB - Introduction: Hypertension (HTN) is an important public health concern and a leading cause of morbidity and mortality worldwide. Yoga is a form of mind-body medicine shown to be effective in controlling blood pressure (BP) and reduces cardiac risk factors in HTN. Integrated approach of Yoga therapy (IAYT) is a residential yoga-based lifestyle intervention proven to be beneficial in several health conditions. Aim: To study the efficacy of 1 week of residential IAYT intervention on cardiovascular parameters in hypertensive patients. Methodology: Twenty hypertensive individuals (7 females) within age range between 30 and 60 years (average; 46.62 +/- 9.9 years), who underwent 1 week of IAYT treatment for HTN, were compared with age- gender-matched non-IAYT group (5 females; average age; 47.08 +/- 9.69 years) in terms of systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), cardiac output (CO), stroke volume (SV), baroreflex sensitivity (BRS), and total peripheral vascular resistance (TPVR), IAYT program consisted of sessions of asanas, breathing practices, meditation and relaxation techniques, low salt, low-calorie diet, devotional session, and counseling. Individuals in non-IAYT group followed their normal routine. All the variables were assessed before and after one week. Data were analyzed using SPSS version 16. RM-ANOVA was applied to assess within group and between group changes after intervention. Results: There was a significant improvement in SBP (P = 0.004), DBP (P = 0.008), MAP (0.03), BRS (P < 0.001), and TPVR (P = 0.007) in IAYT, group whereas in control group, we did not find significant difference in any of the variables. Between-group comparison showed a significant improvement in SBP (P = 0.038), BRS (P = 0.034), and TPVR (P = 0.015) in IAYT group as compared to non IAYT group. Conclusion: One-week IAYT intervention showed an improvement in baroreflex sensitivity, systolic BP, and total peripheral vascular resistance in hypertensive patients. However, further randomized control trials need to be performed to confirm the present findings. PMID- 29755227 TI - Effect of Yoga in the Treatment of Eating Disorders: A Single-blinded Randomized Controlled Trial with 6-Months Follow-up. AB - Aim of the Study: The aim of this study is to examine the effect of yoga treatment of eating disorders (EDs). Methods: Adult females meeting the Diagnostic and Statistical Manual-IV criteria for bulimia nervosa or ED not otherwise specified (n = 30) were randomized to 11-week yoga intervention group (2 * 90 min/week) or a control group. Outcome measures, the Eating Disorder Examination (EDE)-Interview and Eating Disorders Inventory-2 (EDI-2) scores, were administered at baseline, posttest, and at 6-month follow-up. There was a dropout rate of 30% (posttest) and 37% (6-month follow-up). Results: The intervention group showed reductions in EDE global score (P < 0.01), the EDE subscale restraint (P < 0.05), and eating concern (P < 0.01) compared to the control group. The differences between the groups increased at 6-month follow-up. There were no differences between the groups in the EDI-2 score. Conclusion: The results indicate that yoga could be effective in the treatment of ED. PMID- 29755229 TI - Ossification of posterior longitudinal ligament and cervical spondylosis: Same cause - Same treatment. PMID- 29755230 TI - Scoliosis conservative treatment: A review of literature. AB - Background: Scoliosis is defined as lateral curvature of the spine which is also associated with a change in the curves in sagittal plane and vertebral rotation. Various types of conservative treatment approaches have been recommended for the patients with scoliosis. The aim of this review article was to introduce the various methods of conservative treatment which can be used for the patients with scoliosis. Methods: A search was done in some databases including PubMed, ISI Web of knowledge, Google scholar, Ebsco, Embasco, and Scopus. Some keywords such as conservative treatment, orthosis, brace, exercise, and physical therapy were used in combination with scoliosis. As the aim of this paper was to introduce the conservative methods, no quality assessment was done in this review study. Results: Forty papers were found on various conservative treatments approaches which have been used for the patients with scoliosis, in which most of the papers focused on different designs of braces. There were a few studies on other interventions such as wedge, functional electrical stimulation, and yoga. Conclusion: Various treatment approaches have been used to treat scoliosis based on conservative approach. It is suggested that the efficiency of various methods be evaluated based on available literature. PMID- 29755231 TI - Charcot spinal arthropathy. AB - Charcot spinal arthropathy (CSA) is a rare progressive disorder of vertebral joint degeneration that occurs in the setting of any condition characterized by decreased afferent innervation with loss of deep pain and proprioceptive sensation in the vertebral column. While surgical circumferential arthrodesis remains the most effective treatment modality, it is associated with multiple complications, including hardware construct failure. This manuscript represents an up-to-date narrative review of the treatment of CSA, its associated complications, and complication prevention. PMID- 29755233 TI - Cervical lift-up laminoplasty with titanium basket plates after resection of intradural tumor. AB - Background: Performing cervical laminoplasty after wide laminectomy may be technically demanding. The unique technique of cervical lift-up laminoplasty using titanium basket plates was applied for the reconstruction of cervical laminae after wide laminectomy for the resection of intradural tumors. Materials and Methods: This technical study included 14 cases that could be followed periodically for at least 6 months after surgery. Participants were 8 male and 6 female, with a mean age of 41.6 years (range, 13-71 years). Tumors were intramedullary in 11 cases and extramedullary in 3 cases. After resection of intradural tumors, custom-designed titanium baskets were fitted to expand the spinal canal. Combining baskets of different sizes are also possible for each side at one level. A mixture of hydroxyapatite granules and collagen was packed into the basket. The reconstructed posterior laminae were secured using titanium mini plates. The fascia of the paravertebral muscles was sutured to the spino ligamentous complex to further stabilize the posterior elements of the cervical spine. Results: No wounds or implant problems requiring revision surgery were recognized. Imaging analysis demonstrated no significant change in C2-C7 angle cervical range of motion between before and after surgery, suggesting sequential spinal stability at the base of the laminae. Conclusions: This technical note suggests that cervical lift-up laminoplasty with titanium basket plates appears practical and useful as a procedure to reconstruct cervical laminae after wide laminectomy. PMID- 29755232 TI - Augmentation of fenestrated pedicle screws with cement in patients with osteoporotic spine. AB - Background: Backing out and failure of pedicle screws in patients with osteoporosis is becoming a big problem due to wide use of these screws nowadays. Purpose: The aim of this study is to evaluate the purchase of fenestrated pedicle screws augmented with cement in patients with osteoporosis. Study Design: This was retrospective observational study. Patients and Methods: From May 2015 to January 2016, 25 patients with a poor bone stock condition underwent posterior fixation by fenestrated pedicle screws and cement augmentation. Assessment of pain improvement was done by visual analogue score (VAS) score while the long term clinical outcome was assessed using Oswestry low back disability questionnaire (Oswestry disability index [ODI]). Implant stability was evaluated by plain radiography. Complications were evaluated in all cases. Results: All patients were followed up clinically and radiographically for a mean age of 24.84 months. There was a significant reduction in pain and improvement of the quality of life as detected using VAS scores and ODI questionnaire consecutively (P < 0.001). No radiological loosening or backing out of screws was observed. Cement leakage occurred in five cases. Conclusion: Augmentation of fenestrated screws with cement provided effective and lasting purchase in patients with osteoporosis. The only clinical complication strictly related to this technique was cement leakage. PMID- 29755234 TI - The substantiation of the elastic-viscoplastic model of the human spine for modeling the correction process of kyphoscoliotic deformation. AB - Purpose: The relevance of the problem is caused by an increase in the number of spine-related diseases among children, including scoliosis. Currently, there are no methodologies for the treatment of scoliosis, which ensure an unambiguous positive result. The purpose of the article is to justify the spinal model as an elastic viscoplastic body for further mathematical modeling of the process of spine correction and search for its optimal conditions. Methodology: The leading approach to the study of this problem is the development of techniques for the surgical treatment of deformities of the vertebral column with the aid of an external fixation device for the spine, providing for a rigid connection of the elements of the apparatus with each other and with the spine. The rigid connection between the elements of the external fixation device increases the degree of static indeterminacy of the design, which leads to the occurrence of additional dangerous stresses in the details of the apparatus and in the vertebrae. The control actions in such devices do not provide an adequate result for the process of correction of the vertebral column. Results: The main result is the substantiation of the spine model as an elastic viscoplastic body. This will allow more detailed consideration of the medical and biological features of the spine and the physical and mechanical properties of human bone and soft tissues. The proposed model will allow developing an adaptive design of the device, taking into account specific features of the organism and more effectively managing the correction process. Value: The materials of the article can be useful for scientists, doctors and specialists in conducting scientific research on the problem of spine deformation correction and the development of appropriate technical means. PMID- 29755235 TI - Unusual cause of high cervical myelopathy-C1 arch stenosis. AB - Introduction: High cervical myelopathy can be rarely caused by the developmental anomalies of atlas. Patients with C1 arch stenosis can present in early childhood or later in life. In symptomatic patients, posterior decompression at atlas is mandatory. We report the first clinical series of 20 patients of C1 arch stenosis in the English literature. Materials and Methods: This is retrospective case series having a cohort of 20 patients with congenital C1 arch stenosis. Results: There were 12 pediatric (age <18 years) and 8 adult patients. Mean age was 22.85 years. Syndromic association was seen in four patients. Following decompressive surgery, these patients noticed a symptomatic improvement. Conclusions: Isolated C1 arch stenosis is a surgically curable rare cause of high cervical myelopathy and responds well to surgery. PMID- 29755236 TI - Posterior identification and exposure of the V3 segment of the vertebral artery. AB - Objective: The purpose of this study was to define the anatomy of the V3 segment of the vertebral artery (VA) from the posterior approach. Methods: Ten formalin fixed cadavers were carefully dissected bilaterally using landmark features to identify and safely expose the VA from the posterior. Measurements regarding morphometric characteristics of landmark features and feasible resection quantifications were obtained and analyzed. The C2 pars was resected completely in all cadavers, averaging 15.03 +/- 1.06 mm in thickness. Results: The average diameter of the VA at the midline of C2 on the right side was 4.66 +/- 0.51 mm compared to the left 5.2 +/- 0.49 mm (P = 0.002). The distance of the VA from the midline increased from caudal to rostral. The distance between the VA to the lateral edge of the dura in the middle of the window of approach was 9.67 +/- 0.81 mm. The rostral-caudal length of the window of approach was 21.94 +/- 1.60 mm. The percentage of C2 body removal was 28.04% +/- 6.09% through each side (249.55 +/- 55.5/898.2 +/- 146.17 mm2). While carefully exposing the VA, a posterior approach can be feasible in cases of injury during C1-C2 instrumentation or during resection of tumors of the C2 pars with or without extension into the C2 body. Discussion: The posterior approach for a C2 partial corpectomy can also be used as an adjunct to anterior approaches when necessary to widen the extent of bone resection. Conclusion: Exposure of the V3 segment of the vertebral artery was defined as well as the extent of C2 corpectomy through the posterior approach. PMID- 29755237 TI - The expandable transforaminal lumbar interbody fusion - Two years follow-up. AB - Study Design: This was a retrospective, observational study. Objectives: We hypothesize that the expandable transforaminal lumbar interbody fusion (TLIF) cage achieves satisfactory clinical outcomes while allowing for safe placement, improvement, and maintenance of foraminal and disc dimensions at 24 months postsurgery with low risk of cage migration, subsidence, and nerve injury. Methods: TLIF with expandable cages was performed in 54 patients (62 levels) over a 24-month-period using open midline or minimally invasive surgery techniques with placement of Globus Caliber, Rise, or Altera expandable cages. All patients underwent clinical and radiological assessment at 6 weeks, 6 months, 1, and 2 years postoperatively. Clinical outcome was measured by Oswestry disability index (ODI), visual analog pain score for both back and leg (visual analog scores [VASs]). Radiological assessment was done by X-ray standing lateral position. Results: There were significant clinical improvements in ODI, VAS leg, and VAS back at all postoperative time points. Disc height, foraminal height, focal Cobb angle, and global Cobb angle were significantly increased and maintained at all time points for 24 months (P < 0.001). Dural tear occurred in one patient (1.9%). There were neither intra- or postoperative neurological complications nor cage subsidence nor migration. Conclusions: These preliminary results indicate that the use of an expandable interbody cage achieves good clinical outcomes by improving and maintaining foraminal dimensions and disc height with minimal complication rate. PMID- 29755239 TI - Type III odontoid fractures: A subgroup analysis of complex, high-energy fractures treated with external immobilization. AB - Study Design: Retrospective cohort study. Objective: Type III odontoid fractures are classically treated nonoperatively, yet, the current literature on Type III odontoid fractures includes fractures of multiple etiologies and fracture morphologies. We hypothesize that a subgroup of complex, Type III fractures caused by high-energy mechanisms are more likely to fail nonoperative treatment. Materials and Methods: Acute Type III odontoid fractures were identified at a single institution from 2008 to 2015. Fractures were categorized as high- or low energy fracture with high-energy fractures defined as those with lateral mass comminution (>50%) or secondary fracture lines into the pars interarticularis or vertebral body. Patients were treated in either a hard collar orthosis or halo vest and were followed for fracture union and stability. Results: One hundred and twenty-five Type III odontoid fractures were identified with 51% classified as complex fractures. Thirty-three patients met the inclusion and exclusion criteria including 15 patients treated in a halo vest and 18 in a hard collar orthosis. Mean follow-up was 32 (+/-44) weeks. Seven patients demonstrated progressive displacement of either 2 mm of translation or 5 degrees of angulation and underwent delayed surgical stabilization. Two additional patients required delayed surgery for nonunion and myelopathy. Initial fracture displacement and angulation were not correlative with final outcome. No statistical advantage of halo vest versus hard collar orthosis was observed. Conclusions: Complex Type III odontoid fractures are distinctly different from low-energy injuries. In the current study, 21% of patients were unsuccessfully treated nonoperatively with external immobilization and required surgery. For complex Type III fractures, we recommend initial conservative treatment, while maintaining close monitoring throughout patient recovery and fracture union. PMID- 29755240 TI - Comparison of thermal spread with the use of an ultrasonic osteotomy device: Sonopet ultrasonic aspirator versus misonix bonescalpel in spinal surgery. AB - Background: The development of high speed rotating burrs has greatly advanced spinal surgery in recent years. However, they produce unwanted frictional heat and temperature elevation during the burring process. We compare the misonix bone scalpel (MBS) and the Sonopet ultrasonic aspirator to assess which would be the safer device in terms of the risk of thermal injury following laminectomy. Methods: We describe an experimental nonrandomized study comparing two ultrasonic osteotomy devices. We use the device tip temperature and temperature of inner cortex of the lamina, following laminectomy, as the primary outcome. Our secondary outcome is to assess which device is associated with a lower risk of osteonecrosis and potential thermal injury to surrounding dura and nerves. Results: The average device tip temperature for the Sonopet ultrasonic aspirator following the process of laminectomy was 36.8 with a maximum temperature of 41.8 degrees C. The average device tip temperature for the MBS following laminectomy was 48.6 with a maximum temperature of 85.3 degrees C. Conclusion: Our results have demonstrated the safety of the Sonopet ultrasonic aspirator with the Nakagawa serrated knife with temperatures below the threshold for osteonecrosis and thermal neural injury. However, the MBS has shown to occasionally reach high temperatures above the threshold of potential thermal injury to surrounding nerves and dura for a very short period of time. We advise to withdraw and re insert the ultrasonic tip repeatedly to re-establish adequate cooling and lubrication. Further studies should be carried out using cadaveric bone at body temperature to simulate more accurate results. PMID- 29755238 TI - Cervical sagittal balance parameters after single-level anterior cervical discectomy and fusion: Correlations with clinical and functional outcomes. AB - Background: Normal sagittal cervical alignment has been associated with improved outcome after anterior cervical discectomy and fusion (ACDF). Objective: The aim of this study is to identify alterations of cervical sagittal balance parameters after single-level ACDF and assess correlations with postoperative functionality. Methods: A retrospective chart review was performed between January 2010 and January 2014 to identify adult patients with no previous cervical spine surgery who underwent ACDF at any one level between C2 and C7 for the single-level degenerative disease. Tumor, infection, and trauma cases were excluded from the study. For the included cases, the following data were recorded preoperatively and 6 months-1 year after surgery: sagittal balance-marker measurements of the C1 C2 angle, C2-C7 angle, C7 slope, segmental angle at the operated level, and sagittal vertical axis (SVA) distance between C2 and C7, as well as the neck disability index and visual analog scale of pain. Results: The present study included 47 patients (average age: 51.2 years; range: 28-86 years). A moderate negative correlation between a smaller C2-C7 angle and the presence of right arm pain before treatment was found (P = 0.0281). Postoperatively, functionality scores significantly improved in all patients. C1-C2 angle increased with statistical significance (P = 0.0255). C2-C7 angle, segmental angle, C7 slope, and SVA C2-C7 distance did not change with statistical significance after surgery. C7 slope significantly correlated with overall cervical sagittal balance (P < 0.05). Conclusions: Single-level ACDF significantly increases upper cervical lordosis (C1-C2) without significantly changing lower cervical lordosis (C2-C7). The C7 slope is a significant marker of overall cervical sagittal alignment (P < 0.05). PMID- 29755241 TI - Preoperative manual on-table-traction for the reduction of thoracolumbar burst fractures: A technical note. AB - Thoracolumbar burst fractures can frequently be treated either conservatively or surgically. Surgery is generally preferred when safe early mobilization with a reconstructed sagittal alignment is wanted without any external restraint. Various dedicated instruments are available on the market to perform reduction and distraction maneuvers on the spine intraoperatively to restore normal sagittal alignment after a fracture. The authors describe a simple but effective technique of proper patient positioning and preoperative on-table-traction that can effectively aid in the restoration of alignment and performance of surgery even with the most basic instrumentation. PMID- 29755243 TI - Strong convergence and bounded perturbation resilience of a modified proximal gradient algorithm. AB - The proximal gradient algorithm is an appealing approach in finding solutions of non-smooth composite optimization problems, which may only has weak convergence in the infinite-dimensional setting. In this paper, we introduce a modified proximal gradient algorithm with outer perturbations in Hilbert space and prove that the algorithm converges strongly to a solution of the composite optimization problem. We also discuss the bounded perturbation resilience of the basic algorithm of this iterative scheme and illustrate it with an application. PMID- 29755244 TI - Genuine modified Bernstein-Durrmeyer operators. AB - The present paper deals with genuine Bernstein-Durrmeyer operators which preserve some certain functions. The rate of convergence of new operators via a Peetre [Formula: see text]-functional and corresponding modulus of smoothness, quantitative Voronovskaya type theorem and Gruss-Voronovskaya type theorem in quantitative mean are discussed. Finally, the graphic for new operators with special cases and for some values of n is also presented. PMID- 29755242 TI - Spinal schistosomiasis: Cases in Egyptian population. AB - Background: Spinal cord involvement by schistosomiasis is considered to be rare. Clinical presentation of spinal schistosomiasis ranges from radicular pain to myelopathy causing flaccid paraplegia, bladder incontinence, and dysesthesia. We reported six cases with spinal schistosomiasis. Methodology: We did a retrospective analysis of the records in our department from March 1995 to March 2015, and we found that six cases of proved spinal schistosomiasis were documented, with follow-up period more than a year, aiming to find an assumption for a guideline for this ambiguous issue. Results: We found five cases from six were males and average age group was 26 years old (14-43). All had motor deficit (100%) which was variable, only two (33.33%) had dense weakness (G0) at time of presentation, three (50%) patients had sphincter disturbance also, and 50% of the patients presented with back pain as initial symptom. Only one of six patients had a positive history of the infestation. All patients went through surgical intervention, which was decompression laminectomy then biopsy or excision. Total excision was feasible only in two cases (33.33%), which had a well-defined lesion in imaging, while in others, lesion was ill defined and adherent, so biopsy was done. Steroids up to 2-month duration were used in all patients (100%) and praziquantel in repeated cycles after surgical excision or biopsy was used in all patients (100%). Conclusion: History of travelling to endemic areas should raise the suspicion which may be the cornerstone of diagnosis, particularly in conus/epiconus intramedullary lesions. Surgical excision and spinal canal decompression are the best line of treatment in cases of schistosomiasis even if this excision was not total but to confirm and exclude other forms of pathology. Steroids and oral Praziquantel in repeated cycles are the best medication regimen in case of myelitis and in postoperative treatment. PMID- 29755245 TI - A new smoothing modified three-term conjugate gradient method for [Formula: see text]-norm minimization problem. AB - We consider a kind of nonsmooth optimization problems with [Formula: see text] norm minimization, which has many applications in compressed sensing, signal reconstruction, and the related engineering problems. Using smoothing approximate techniques, this kind of nonsmooth optimization problem can be transformed into a general unconstrained optimization problem, which can be solved by the proposed smoothing modified three-term conjugate gradient method. The smoothing modified three-term conjugate gradient method is based on Polak-Ribiere-Polyak conjugate gradient method. For the Polak-Ribiere-Polyak conjugate gradient method has good numerical properties, the proposed method possesses the sufficient descent property without any line searches, and it is also proved to be globally convergent. Finally, the numerical experiments show the efficiency of the proposed method. PMID- 29755246 TI - Towards Optimal Connectivity on Multi-layered Networks. AB - Networks are prevalent in many high impact domains. Moreover, cross-domain interactions are frequently observed in many applications, which naturally form the dependencies between different networks. Such kind of highly coupled network systems are referred to as multi-layered networks, and have been used to characterize various complex systems, including critical infrastructure networks, cyber-physical systems, collaboration platforms, biological systems and many more. Different from single-layered networks where the functionality of their nodes is mainly affected by within-layer connections, multi-layered networks are more vulnerable to disturbance as the impact can be amplified through cross-layer dependencies, leading to the cascade failure to the entire system. To manipulate the connectivity in multi-layered networks, some recent methods have been proposed based on two-layered networks with specific types of connectivity measures. In this paper, we address the above challenges in multiple dimensions. First, we propose a family of connectivity measures (SUBLINE) that unifies a wide range of classic network connectivity measures. Third, we reveal that the connectivity measures in SUBLINE family enjoy diminishing returns property, which guarantees a near-optimal solution with linear complexity for the connectivity optimization problem. Finally, we evaluate our proposed algorithm on real data sets to demonstrate its effectiveness and efficiency. PMID- 29755247 TI - The Impact of Financial Hardship on Single Parents: An Exploration of the Journey From Social Distress to Seeking Help. AB - Single parent families are at high risk of financial hardship which may impact on psychological wellbeing. This study explored the impact of financial hardship on wellbeing on 15 single parents. Semi-structured interviews were conducted and analysed using constructivist thematic analysis. Participants described food and fuel poverty, and the need to make sacrifices to ensure that children's basic needs were met. In some cases, participants went without food and struggled to pay bills. Isolation, anxiety, depression, paranoia, and suicidal thoughts were described. However, participants reported that psychological services not able to take the needs of single parents in to account. Support for single parents must acknowledge the impact of social circumstances and give more consideration economic drivers of distress. PMID- 29755248 TI - Maternal and Paternal Predictors of Child Depressive Symptoms: An Actor-Partner Interdependence Framework. AB - Family members are theorized to influence each other via transactional or systems related processes; however, the literature is limited given its focus on mother child relationships and the utilization of statistical approaches that do not model interdependence within family members. The current study evaluated associations between self-reported parental affect, parenting behavior, and child depressive symptoms among 103 mother-father-child triads. Children ranged in age from 8 to 12 years. Higher maternal negative affect was associated with greater maternal and paternal harsh/negative parenting behavior. While maternal negative affect was directly associated with child depressive symptoms, paternal negative affect was indirectly associated with child depressive symptoms via paternal harsh/negative behavior. In a separate model, maternal positive affect was indirectly associated with child depressive symptoms via maternal supportive/positive behavior. These results highlight the importance of simultaneously modeling maternal and paternal characteristics as predictors of child depressive symptoms. PMID- 29755249 TI - The Feasibility, Appropriateness, Meaningfulness, and Effectiveness of Parenting and Family Support Programs Delivered in the Criminal Justice System: A Systematic Review. AB - Children whose parents are involved in the criminal justice system (CJS) are at increased risk of developing social, emotional, and behavioural difficulties and are more likely than their peers to become involved in the CJS themselves. Parenting behaviour and parent-child relationships have the potential to affect children's outcomes with positive parenting practices having the potential to moderate some of the negative outcomes associated with parental involvement in the CJS. However, many parents in the CJS may lack appropriate role models to support the development of positive parenting beliefs and practices. Parenting programs offer an opportunity for parents to enhance their parenting knowledge and behaviours and improve relationships with children. Quantitative and qualitative evidence pertaining to the implementation and effectiveness of parenting programs delivered in the CJS was included. Five databases were searched and a total of 1145 articles were identified of which 29 met the review inclusion criteria. Overall, programs were found to significantly improve parenting attitudes; however, evidence of wider effects is limited. Additionally, the findings indicate that parenting programs can be meaningful for parents. Despite this, a number of challenges for implementation were found including the transient nature of the prison population and a lack of parent-child contact. Based on these findings, recommendations for the future development and delivery of programs are discussed. PMID- 29755250 TI - Guiding Young Children's Digital Media Use: SES-Differences in Mediation Concerns and Competence. AB - Previous research about parents' mediation of their young children's (digital) media use has predominantly focused on the different types, determinants, and effectiveness of parental mediation strategies. Although research on parents' perceived mediation concerns and competences is scarce, it is known that, compared to mothers and high-educated parents, fathers and low-educated parents experience greater insecurity (i.e., higher concern and lower competence) when applying media mediation. Based on Bourdieu's theory of social capital it may be expected that-in addition to educational level-marital status and family income predict parents' perceived mediation concerns and competences: Family demographics may predict parents' media proficiency and adoption of new media technologies and these media ecological factors may, in turn, affect perceived concerns and competences. To test this assumption, survey data were collected among 1029 parents of children between the ages of 1 to 9 years. We found that parents' basic media proficiency was lower in low income, low educated, and single-parent families, whereas parents' advanced media proficiency was only lower in low educated and single-parent families. As expected, parents' ease of active co-use was positively associated with parents' basic proficiency, ease of restrictive mediation by basic and advanced proficiency, and ease of imposing technical restrictions by advanced media proficiency. Parents' perceived mediation concerns were, however, unrelated to parents' media proficiency. Also, as expected, low educated parents were less inclined to adopt new media technologies. Adoption of new media was negatively related to perceived mediation concerns, yet did not predict parents' perceived competence. PMID- 29755251 TI - Associations between Psychopathology in Mothers, Fathers and Their Children: A Structural Modeling Approach. AB - This study investigated associations between parental and child psychopathology with parenting stress as a possible mediator, in order to get more insight in mothers' and fathers' roles in the development of psychopathology in children. Parents of 272 clinically referred (aged 6-20, 66% boys) reported about their own and their child's behavioral problems, and about parenting stress. Data were analyzed using Structural Equation Modeling. Outcomes of path models demonstrated that mothers' higher internalizing and externalizing problems were associated with respectively children's higher internalizing and externalizing problems. Fathers' higher externalizing problems were associated with both children's higher internalizing and externalizing problems, but fathers' internalizing problems were only associated with children's lower externalizing problems. Parenting stress fully mediated the relation between mothers' and children's externalizing problems, and partly mediated the relation between mothers' and children's internalizing problems. For fathers, parenting stress partly mediated the relation between fathers' internalizing problems and children's externalizing problems. Findings indicate that for mothers, the association between parental and child psychopathology is specific, whereas for fathers it is non-specific. Furthermore, results suggest that reducing parenting stress may decrease child problem behavior. Longitudinal studies are needed in order to gain more insight in the direction and underlying mechanisms of the relation between parental and child psychopathology, including parental stress. PMID- 29755252 TI - A Digital Endocranial Cast of the Early Paleocene (Puercan) 'Archaic' Mammal Onychodectes tisonensis (Eutheria: Taeniodonta). AB - Eutherian mammals-placentals and their closest extinct relatives-underwent a major radiation following the end-Cretaceous extinction, during which they evolved disparate anatomy and established new terrestrial ecosystems. Much about the timing, pace, and causes of this radiation remain unclear, in large part because we still know very little about the anatomy, phylogenetic relationships, and biology of the so-called 'archaic' eutherians that prospered during the ~10 million years after the extinction. We describe the first digital endocranial cast of a taeniodont, a bizarre group of eutherians that flourished in the early Paleogene, reconstructed from a computed tomography (CT) scan of a late Puercan (65.4 million year old) specimen of Onychodectes tisonensis that recovered most of the forebrain and midbrain and portions of the inner ear. Notable features of the endocast include long, broad olfactory bulbs, dorsally-positioned rhinal fissures, and a lissencephalic cerebrum. Comparison with other taxa shows that Onychodectes possessed some of the largest olfactory bulbs (relative to cerebral size) of any known mammal. Statistical analysis of modern mammals shows that relative olfactory bulb dimensions are not strongly correlated with body size or fossorial digging for shelter, but relative bulb width is significantly greater in taxa that habitually dig to forage for food. The anatomical description and statistical results allow us to present an ecological model for Onychodectes and similar taeniodonts, in which they are animals of simple behavior that rely on a strong sense of smell to locate buried food before extracting and processing it with their specialized skeletal anatomy. PMID- 29755253 TI - Minimal Frame Operator Norms Via Minimal Theta Functions. AB - We investigate sharp frame bounds of Gabor frames with chirped Gaussians and rectangular lattices or, equivalently, the case of the standard Gaussian and general lattices. We prove that for even redundancy and standard Gaussian window the hexagonal lattice minimizes the upper frame bound using a result by Montgomery on minimal theta functions. PMID- 29755254 TI - Characterization of crosstalk in stereoscopic display devices. AB - Many different types of stereoscopic display devices are used for commercial and research applications. Stereoscopic displays offer the potential to improve performance in detection tasks for medical imaging diagnostic systems. Due to the variety of stereoscopic display technologies, it remains unclear how these compare with each other for detection and estimation tasks. Different stereo devices have different performance trade-offs due to their display characteristics. Among them, crosstalk is known to affect observer perception of 3D content and might affect detection performance. We measured and report the detailed luminance output and crosstalk characteristics for three different types of stereoscopic display devices. We recorded the effect of other issues on recorded luminance profiles such as viewing angle, use of different eye wear, and screen location. Our results show that the crosstalk signature for viewing 3D content can vary considerably when using different types of 3D glasses for active stereo displays. We also show that significant differences are present in crosstalk signatures when varying the viewing angle from 0 degrees to 20 degrees for a stereo mirror 3D display device. Our detailed characterization can help emulate the effect of crosstalk in conducting computational observer image quality assessment evaluations that minimize costly and time-consuming human reader studies. PMID- 29755255 TI - On the depths and shapes of the freshest kilometer-scale simple craters on the lunar maria: A new crater shape model. AB - Recent work on the shapes of small, simple impact craters on the Moon has shown that the parabolic ideal does not well represent the vast majority of these craters. They are hyperbolic in shape and usually resemble a cone more than a parabola. A parabolic shape also does not fit the most commonly held archetype for simple craters in general (Linne), which is also hyperbolic. In addition, Linne itself may not be the best model for fresh simple craters, in terms of cross-sectional shape, although shape data to compare it to have heretofore been lacking. Here, the "free shadowfront method" for determining the shapes of simple craters is used to measure 64 fresh simple craters on five lunar maria to test both assumptions. Laser altimetry cross sections, available for many of the craters measured herein, are used to complement and spot-check the shadow measurement results, and thereby demonstrate the efficacy of the free shadowfront method. A new shape model is established, and two craters that better fit this model than Linne are identified. These are located at 24.45 degrees N/328.12 degrees E and 31.35 degrees N/296.46 degrees E and have diameters of 1.40 and 2.73 km, respectively. An apparent dichotomy between fresh simple craters smaller than 2.5 km and those larger than this is observed. Flat floors are found to be ubiquitous among the larger craters, but rare and small in extent in smaller ones. A slide in one crater which appears to be an incipient flat floor suggests a major mode of formation for these flat floors. PMID- 29755257 TI - Evaluating the genus Cespitularia MilneEdwards & Haime, 1850 with descriptions of new genera of the family Xeniidae (Octocorallia, Alcyonacea). AB - Several species of the family Xeniidae, previously assigned to the genus Cespitularia Milne Edwards & Haime, 1850 are revised. Based on the problematical identity and status of the type of this genus, it became apparent that the literature has introduced misperceptions concerning its diagnosis. A consequent examination of the type colonies of Cespitularia coerulea May, 1898 has led to the establishment of the new genus Conglomeratuscleragen. n. and similarly to the assignment of Cespitularia simplex Thomson & Dean, 1931 to the new genus, Caementabundagen. n. Both new genera are described and depicted and both feature unique sclerite morphology, further highlighting the importance of sclerite microstructure for generic position among Xeniidae. Freshly collected material was subjected to molecular phylogenetic analysis, whose results substantiated the taxonomic assignment of the new genera, as well as the synonymies of several others. PMID- 29755256 TI - Alliance across group treatment for veterans with posttraumatic stress disorder: The role of interpersonal trauma and treatment type. AB - Objective: Examine initial levels and pattern of change of alliance in group treatment for posttraumatic stress disorder (PTSD) for veterans. Method: One hundred and seventy-eight male veterans with PTSD were recruited for this study. Participants were randomly assigned to either group cognitive behavioral therapy (GCBT) or to group present-centered therapy (GPCT). Alliance with fellow group members was assessed every other session throughout the group (total of seven assessments). Hierarchical linear modeling was used to determine whether treatment condition or index trauma type (interpersonal or non-interpersonal) impacted initial levels of alliance or change in alliance over time. Results: Alliance increased significantly throughout treatment in both conditions. The presence of an interpersonal index event, compared to a non-interpersonal index event, did not significantly impact either initial levels of alliance or change in alliance over time. Participants in the GCBT condition experienced significantly greater growth in alliance over time compared to those in the GPCT condition (p > .05), but did not have significantly different initial alliance ratings. Conclusions: The components and focus of the GCBT treatment may have facilitated more rapid bonding among members. Interpersonal traumatic experience did not negatively impact group alliance. PMID- 29755258 TI - A new, alpine species of Lissodesmus Chamberlin, 1920 from Tasmania, Australia (Diplopoda, Polydesmida, Dalodesmidae). AB - Lissodesmus nivalissp. n. is described from 1450-1550 m elevation on the treeless, alpine Ben Lomond plateau in northeast Tasmania, Australia. The new species is distinguished from all other Tasmanian and Victorian Lissodesmus species by a unique combination of gonopod telopodite features: solenomere without a pre-apical process, tibiotarsus Y-shaped, femoral process L-shaped with forked tips, prefemoral process with a long comb of teeth below an irregularly dentate apical margin, and a roughened "shoulder process" near the base of the prefemoral process. PMID- 29755259 TI - Descriptions of two new species of Platygaster Latreille that attack gall midges (Diptera, Cecidomyiidae) with notes on their biology (Hymenoptera, Platygastridae). AB - Platygaster ingeniosus Matsuo & Yamagishi, sp. n. and P. urniphila Matsuo & Yamagishi, sp. n. (Hymenoptera: Platygastridae) are described from Japan. The former species is an egg-larval solitary parasitoid of Masakimyia pustulae Yukawa and Sunose (Diptera: Cecidomyiidae). The latter species is an egg-larval gregarious parasitoid of Rhopalomyia longitubifex (Shinji) (Diptera: Cecidomyiidae). PMID- 29755261 TI - Spider assemblages associated with different crop stages of irrigated rice agroecosystems from eastern Uruguay. AB - The rice crop and associated ecosystems constitute a rich mosaic of habitats that preserve a rich biological diversity. Spiders are an abundant and successful group of natural predators that are considered efficient in the biocontrol of the major insect pests in agroecosystems. Spider diversity in different stages of the rice crop growth from eastern Uruguay was analysed. Field study was developed on six rice farms with rotation system with pasture, installed during intercropping stage as cover crop. Six rice crops distributed in three locations were sampled with pitfall and entomological vaccum suction machine. Sixteen families, representing six guilds, were collected. Lycosidae, Linyphiidae, Anyphaenidae and Tetragnathidae were the most abundant families (26%, 25%, 20% and 12%, respectively) and comprised more than 80% of total abundance. Other hunters (29%), sheet web weavers (25%) and ground hunters (24%) were the most abundant guilds. Species composition along different crop stages was significantly different according to the ANOSIM test. The results showed higher spider abundance and diversity along the crop and intercrop stages. This study represents the first contribution to the knowledge of spider diversity associated with rice agroecosystem in the country. PMID- 29755260 TI - Characterization of the complete mitochondrial DNA of Theretra japonica and its phylogenetic position within the Sphingidae (Lepidoptera, Sphingidae). AB - In the present study, the complete mitogenome of Theretra japonica was sequenced and compared with other sequenced mitogenomes of Sphingidae species. The mitogenome of T. japonica, containing 37 genes (13 protein-coding genes, 22 tRNA genes, and two rRNA genes) and a region rich in adenine and thymine (AT-rich region), is a circular molecule with 15,399 base pairs (bp) in length. The order and orientation of the genes in the mitogenome are similar to those of other sequenced mitogenomes of Sphingidae species. All 13 protein-coding genes (PCGs) are initiated by ATN codons except for the cytochrome C oxidase subunit 1 gene (cox1) which is initiated by the codon CGA as observed in other lepidopteran insects. Cytochrome C oxidase subunit 2 gene (cox2) has the incomplete termination codon T and NADH dehydrogenase subunit 1 gene (nad1) terminates with TAG while the remainder terminates with TAA. Additionally, the codon distributions of the 13 PCGs revealed that Ile and Leu2 are the most frequently used codon families and codons CGG, CGC, CCG, CAG, and AGG are absent. The 431 bp AT-rich region includes the motif ATAGA followed by a 23 bp poly-T stretch, short tandem repeats (STRs) of TC and TA, two copies of a 28 bp repeat 'ATTAAATTAATAAATTAA TATATTAATA' and a poly-A element. Phylogenetic analyses within Sphingidae confirmed that T. japonica belongs to the Macroglossinae and showed that the phylogenetic relationship of T. japonica is closer to Ampelophaga rubiginosa than Daphnis nerii. Phylogenetic analyses within Theretra demonstrate that T. japonica, T. jugurtha, T. suffusa, and T. capensis are clustered into one clade. PMID- 29755262 TI - Eight new Arthrinium species from China. AB - The genus Arthrinium includes important plant pathogens, endophytes and saprobes with a wide host range and geographic distribution. In this paper, 74 Arthrinium strains isolated from various substrates such as bamboo leaves, tea plants, soil and air from karst caves in China were examined using a multi-locus phylogeny based on a combined dataset of ITS rDNA, TEF1 and TUB2, in conjunction with morphological characters, host association and ecological distribution. Eight new species were described based on their distinct phylogenetic relationships and morphological characters. Our results indicated a high species diversity of Arthrinium with wide host ranges, amongst which, Poaceae and Cyperaceae were the major host plant families of Arthrinium species. PMID- 29755263 TI - Changing patterns in orbital pathology. PMID- 29755264 TI - An update on mesenchymal tumours of the orbit with an emphasis on the value of molecular/cytogenetic testing. AB - Mesenchymal tumours of the orbit are uncommon. Beyond childhood primary sarcomas are extremely rare and the literature is limited to case reports and short case series. However there is a diverse assortment of benign and malignant soft tissue tumours that may involve the orbit. Techniques to identify tumour specific cytogenetic or molecular genetic abnormalities often resulting in over- expressed proteins are becoming an increasingly important ancillary technique for these tumours. This review focuses on 3 specific areas: 1. Orbital mesenchymal tumours where cytogenetics are important to reach the correct diagnosis. The majority of these are chromosomal translocations that often result in a fusion gene and protein product; 2. Orbital mesenchymal tumours where cytogenetics are important to identify patients who will do well versus those with a poorer prognosis. This is turn helps with therapeutic options. In some tumours e.g. synovial sarcoma the chromosomal translocations can occur with 2 different regions resulting in different fusion products that carry a different prognosis. Alternatively whilst the majority of alveolar rhadomyosarcomas are fusion positive a minority are fusion negative with a better prognosis; 3. Orbital mesenchymal tumours where the identification of specific cytogenetic abnormalities has resulted in overexpression of specfic proteins which are diagnostically useful biomarkers for immunohistochemistry. PMID- 29755265 TI - Pleomorphic adenoma of the lacrimal gland: A review with updates on malignant transformation and molecular genetics. AB - Pleomorphic adenoma (benign mixed tumor) is the most common epithelial neoplasm of the lacrimal gland. It is usually a slow growing, well-circumscribed, mass that is identical to its salivary gland counterpart. Patients generally have an excellent prognosis for vision and long-term survival after complete surgical excision. There is a tendency to reoccur, especially if there is an incomplete excision, and rarely, malignant transformation to carcinoma ex pleomorphic adenoma can occur, which has a much poorer prognosis. The molecular genetics of lacrimal gland pleomorphic adenomas have only recently been studies, but appear to display similar genetic aberration found in the salivary gland counterparts. PMID- 29755266 TI - Orbital pathology - Iatrogenic findings and artefacts. AB - The relationship between the ophthalmologist and ophthalmic pathologist is particularly important in orbital disease, as diagnosis is heavily dependent on correlation with clinical context. If the patient has previously had treatment to the orbit or an adjacent area, whether for the same or a different condition, tissue changes may occur which affect the histological appearance of any specimen taken. This article is an overview of therapeutic interventions which may cause either orbital pathology or an altered appearance of the tissue, either of which can pose a diagnostic challenge. The problem of artefact is also addressed as another factor which may alter the appearance of a specimen. It is hoped that the information provided in this brief review will help clinicians better evaluate what information may be relevant when submitting a specimen. PMID- 29755267 TI - Cognitive biases in orbital mass lesions - Lessons learned. AB - Purpose: A patient's presentation and clinical diagnosis can at times be clouded by their past medical history. Clinicians' anchoring bias towards initial information, such as a history of cancer, may lead them astray when creating a differential diagnosis for a patient who presents with new signs and symptoms of a mass lesion, assuming metastatic disease without seeking tissue confirmation. Methods: The presentation, workup, diagnosis, and treatment of two patients who presented with orbital masses in the context of a primary prostate cancer are presented in this report. Results: In both cases, prostate cancer metastasis to the orbit was top on the differential. Ultimately, histopathological examination of biopsies taken from the orbital masses revealed orbital lymphoma in both patients. Conclusion: With mounting rates of patients who have survived a previous cancer, multiple primary cancers within one patient are becoming increasingly common. While prostate cancer metastasis to the orbit is a relatively rare event, orbital lymphoma is a more common diagnosis in orbital masses. Therefore, when patients present with orbital masses in the context of prostate cancer, the conclusion should not immediately be metastasis and a tissue diagnosis should be sought; especially given that the treatment of these entities is different. PMID- 29755268 TI - Cytogenetic results of choroidal nevus growth into melanoma in 55 consecutive cases. AB - Purpose: To investigate the cytogenetic results of choroidal nevus with photographically-documented transformation into choroidal melanoma. Methods: Retrospective analysis of 55 consecutive patients who underwent fine needle aspiration biopsy (FNAB) for DNA isolation and whole genome array based assay for chromosomes 3, 6, and 8 analysis prior to plaque radiotherapy. Tumors with abnormalities in chromosomes 3 and 8 were considered high-risk for metastasis. Results: At diagnosis of choroidal nevus the mean patient age was 57 years (median 57, range 10-83 years). All patients were Caucasian and 36 (65%) were female. At the time of nevus diagnosis, the mean tumor basal diameter was 7.4 mm (median 6.5, range 1.5-18.0 mm) and tumor thickness was 2.2 mm (median 2.2, range 0.5-3.9 mm). The mean interval between diagnosis of choroidal nevus and transformation into choroidal melanoma was 58 months (median 42, range 3-238 months). At the time of melanoma diagnosis, the mean tumor basal diameter was 9.7 mm (median 9.0, range 5.0-19.0) and tumor thickness was 3.5 mm (median 3.4, range 1.3-8.1). Cytogenetic analysis of FNAB-isolated melanoma revealed 25 patients (45%) with high-risk and 30 (55%) with low-risk cytogenetic findings. The rate of tumor growth into melanoma was inversely related to high-risk cytogenetic profile (p = 0.03) as those with fast transformation <= 1 year showed high-risk in 80% compared to those with slow transformation > 1 year whoshowed high-risk profile in only 38%. Fast transformation into melanoma conferred a relative risk (RR) of 2.116 for high-risk cytogenetic profile, compared to slow transformation. Conclusions: Choroidal nevus with rapid transformation into melanoma within 1 year is significantly more likely to demonstrate high-risk cytogenetic profile, at risk for metastatic disease, compared to those with slow transformation. PMID- 29755269 TI - Inflammatory myofibroblastic tumor of the orbit: A clinico-pathological study of 25 cases. AB - Background: Inflammatory myofibroblastic tumor (IMT) is a rare entity characterized by the presence of myofibroblasts and inflammatory cells within a fibrous stroma, which typically occurs in children or young adults. The IMT is considered generally a benign lesion, although about 20% of cases may experience recurrence, and most rarely develop metastasis. Herein, we present the largest series of primary orbital IMT ever reported. Patients and methods: The clinical records of 25 patients, collected between the 1995 and 2015, with biopsy-proven diagnosis of orbital IMT were retrospectively reviewed to determine demographic, clinical, radiologic and pathological features, management, and outcome. Results: The study included 13 females and 12 male patients, age ranged from 5 to 76 years. Disease onset was in all cases unilateral (25/25), with posterior location (10/25) or extending anterior to posterior (7/25). The most common signs and symptoms were: proptosis (19/25), ptosis (18/25), diplopia (10/25), periocular swelling (9/25), pain (8/25), redness (7/25). All patients underwent to incisional biopsy which included total or subtotal tumor resection avoiding arming of the adjacent structure, followed by systemic steroid therapy (22/25) or radiotherapy (3/25). The disease recurred in 6 (24%) patients who responded to the subsequent therapy. No one developed metastasis or died because of the disease. Conclusion: IMT is a distinct entity which may occur in the orbit primarily. It should be considered in differential diagnosis in all orbital masses, particularly with onset of acute or subcronic inflammation. Surgical biopsy associated to a partial debulcking of the tumor, avoiding to damage adjacent vital structure may contribute to improve the outcome. Steroid therapy, seems to be the suitable as first line medical therapy, although, as reported in literature, not all cases respond to this treatment regimen. Radiotherapy, may be considered as an alternative therapy. Recurrences occurred in 24% of patients and may be treated with additional surgical resection and a new course of steroid or radiotherapy. No specific pathological features which may correlate with the prognosis have been found in this series. PMID- 29755270 TI - Histiocytic lesions of the orbit: A study of 9 cases. AB - Purpose: To describe the clinical presentation, treatment, and outcome of patients with histiocytic lesions of the orbit. Methods: Retrospective study of 9 patients treated and followed up between October 2001 and January 2018. Results: Eight patients in our series were males and one patient was female. The mean age at presentation was 16.8 years (range, 1 to 42 years). All patients had unilateral disease. The most common presenting complaint was upper eyelid swelling in 8 of 9. All patients underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI). Eight of 9 patients demonstrated orbital bone erosion with adjacent soft tissue mass. Destruction of the orbital roof and contrast enhancement of dura were detected in 3 cases. All cases underwent orbitotomy and subtotal tumor excision with additional bone curettage (4 cases) and intraorbital steroid (40 mg triamcinolone acetonide) injection (3 cases). Adjuvant systemic chemotherapy consisting of vinblastine and prednisone was administered in 3 cases with dural involvement. External radiotherapy (1000 cGy) was applied in one case because of widespread disease. Histopathologic diagnoses were eosinophilic granuloma (7 cases), necrotic xanthogranuloma (1 case), and Langerhans cell sarcoma (1 case). The mean follow-up period after diagnosis was 19.7 months (range, 1-96 months). There was no systemic or multifocal bone involvement in eosinophilic granuloma cases at initial presentation and follow up. None of these patients developed diabetes insipidus or neurologic symptoms. The patient with Langerhans cell sarcoma died from systemic disease 1 month after diagnosis of the orbital tumor. The patient with necrotic xanthogranuloma did not develop any malignancy at 9 months follow-up. Conclusions: Eosinophilic granuloma was the most frequently encountered orbital histiocytic lesion in our series. Eosiophilic granuloma usually responded well to subtotal tumor excision, bone curettage, and intraorbital corticosteroid injections. Systemic chemotherapy was used in cases with full thickness bone destruction and adjacent dural enhancement in an effort to prevent the development of central nervous system disease. PMID- 29755271 TI - Clinical, radiological and histopathological characteristics of surgically removed orbital hematic cysts: A case series. AB - Background: Hematic cyst is a rare orbital condition that has a wide range of clinical presentation and is characterized pathologically by lack of endothelial lining. Purpose: To correlate clinical and radiological features of hematic cysts, to tissue diagnosis, and investigate the possible etiology behind this condition, its relation to trauma and other interesting histopathological findings. Methods: Retrospective case series at King Khaled Eye Specialist Hospital (KKESH) and King Abdulaziz University Hospital (KAUH) of all orbital lesions with tissue findings supporting the clinical and/or radiological diagnosis of hematic cyst. Results: A series of 13 cases was studied, 8 males and 5 females. Age ranged from 2 to 84 years with a median of 54. Most cases presented with proptosis (76.9%) and limitation of eye movements (69.2%). History of trauma was confirmed in only 2/13. The clinical diagnosis of hematic cyst was made prior to surgery in 38.4%. Magnetic Resonance Imaging (MRI) confirmed the presence of blood in the orbit in 7/7. Surgical intervention was the mainstay of treatment. Histopathologically, these lesions demonstrated variable constituents including blood break-down products (hemosiderin), macrophages, mononuclear inflammatory cells, hemorrhage, absent endothelial lining, reactive fibrosis and capsule-like formation. Cholesterol clefts with typical granulomas and multinucleated giant cells were present in 2 cases. A clue to an underlying vascular lesion was found histopathologically in 30.8%. None of the patients developed recurrence or long-term complications with an average follow up period of 1 year. Conclusion: Hematic cyst is a challenging clinical diagnosis that can be aided by radiological examination and histopathological confirmation. Trauma does not seem to play a major role while presence of a pre-existing vascular lesion with spontaneous hemorrhage may be an etiologic factor. Associated cholesterol granuloma is an interesting controversial finding. Surgical intervention is curative with possible persisting motility disturbance and/or the eye deviation and worse prognosis in post-traumatic cases. PMID- 29755272 TI - Langerhans cell histiocytosis in an 18-month-old child presenting as periorbital cellulitis. AB - Langerhans cell histiocytosis (LCH) is a rare multi-system disease. It presents infrequently as a childhood orbital tumor, and can mimic more common inflammatory orbital disease processes. We report the clinical, histopathological, and electron microscopic findings of orbital LCH in an 18-month-old child, along with a review of the recent literature regarding molecular pathogenetic analysis of LCH. The child presented with a two-week history of progressive left periorbital edema and redness. He was initially diagnosed and treated empirically for bacterial periorbital cellulitis, but subsequently underwent ophthalmological consultation after he failed to improve. Histopathological examination of an orbital biopsy specimen revealed numerous Langerhans-type cells, which stain positive for CD1A and CD207 (langerin). Electron microscopic examination demonstrated characteristic Birbeck granules within the Langerhans-type cells. Three year follow-up did not demonstrate recurrence or disease progression. PMID- 29755273 TI - Orbital progressive transformation of germinal centers as part of the spectrum of IgG4-related ophthalmic disease: Clinicopathologic features of three cases. AB - Progressive transformation of germinal centers (PTGC) is a form of follicular hyperplasia recently associated with immunoglobulin G4-related disease (IgG4-RD), but the ophthalmic manifestations of this combination are poorly described. In this retrospective case series, we present three cases of IgG4-related orbital disease (IgG4-ROD) showing varying degrees of PTGC involving the orbit and lacrimal gland. Three adult women presented with ill-defined lacrimal gland enlargement. Histologic sections showed variable fibrosis and large, irregular lymphoid follicles with prominent mantle zones penetrating the germinal centers, highlighted by Bcl-2 and/or IgD immunostains. The interfollicular areas contained a mixture of plasma cells, scattered histiocytes and eosinophils. Mixed T and B cells were present, and no signs of monoclonality were identified. All cases showed more than 100 IgG4 positive cells per high power field. Epstein-Barr virus in situ hybridization performed in one case was negative. The serum IgG4 level was tested in one case and showed elevation above the normal range. After 2-10 months of follow-up, the patients showed either near-complete resolution or no remaining signs of ophthalmic disease. Increasing awareness of these PTGC in extra-nodal locations, including the orbit, may provide a better understanding of the histologic spectrum of this disease. PMID- 29755274 TI - NUT carcinoma of the sinonasal tract infiltrating the orbit in a man with birdshot chorioretinitis. AB - A 48-year-old man with a history of birdshot chorioretinitis presented with blurry vision, retro-bulbar pain and sinusitis. Though visual acuity was unaffected, he had left optic disc oedema and mild restriction of left eye abduction. His symptoms progressed quickly, with diplopia in primary gaze, epistaxis from his left nostril, and a left relative afferent pupillary defect (RAPD). On computed tomography, there was a mass in the nasal cavity that extended through the left cribriform plate and lamina papyracea and posteriorly into the optic canal. Pathological examination of biopsy specimens revealed sheets of undifferentiated cells with extensive areas of necrosis and islands of squamous differentiation. The tumour cells expressed monokeratin, p63, CD34, and p16. Molecular testing indicated rearrangement of the NUTM1 (15q14) locus and fusion of the NUTM1 and BRD4 (19p13.12) loci, confirming the diagnosis of NUT carcinoma of the sinonasal tract. This is the first reported case of NUT carcinoma in a patient with birdshot chorioretinitis. The onset of chorioretinitis may have been the earliest sign of the effects of the BRD4-NUTM1 fusion protein, resulting in expression of HLA-A29. There is evidence that bromodomain and extra terminal (BET) family proteins play a role in inflammatory marker expression. PMID- 29755275 TI - Isolated superior oblique muscle extranodal marginal zone B cell lymphoma: case report. AB - We describe a rare case of isolated extraocular muscle ocular adnexal lymphoma of a middle-aged female who presented with redness in the left eye associated with progressive proptosis over one year. Magnetic resonance imaging of the orbit indicated isolated enlargement of the left superior oblique (SO) muscle with an apparent diffusion coefficient (ADC) of (0.77 +/- 0.11 * 10-3 mm2/s). Histopathology with immunohistochemical staining of the incisional biopsy from the SO muscle belly confirmed the diagnosis of extranodal marginal zone B cell lymphoma. PMID- 29755277 TI - Orbital immature teratoma: A rare entity with diagnostic challenges. AB - Childhood orbital teratomas are congenital lesions that presents most often at birth with progressive, severe unilateral proptosis. Due to the rarity of such tumors, the diagnosis is often missed with delay in the patient's management. We are presenting a unique case of an immature right orbital teratoma with extensive growth in a full-term newly born baby boy. In this case report, we provide description of the clinical findings, initial misdiagnosis and the eventual management with review of similar reported cases. PMID- 29755276 TI - Primary mesenchymal chondrosarcoma of the orbit: Histopathological report of 3 pediatric cases. AB - Mesenchymal chondrosarcoma (MCS) is an unusual tumor mainly found in the skeleton. Around third of the cases occur in extra-skeletal sites with the orbit being the third most common site in these cases. In previous reviews of the orbital cases, it has been concluded that orbital MCS tends to occur in women in the second or third decades of life. However, 8 cases of orbital MCS have been reported so far in the pediatric age group (age less than 18 years-old) one of which has been considered congenital MCS in a 5-days old newborn girl. We describe 3 additional pediatric cases with primary orbital MCS and they were all males. Our cases presented with proptosis and calcific orbital masses on imaging studies. Histopathological examination of the excised masses shared the typical presence of undifferentiated mesenchymal cells and immature areas of cartilage. The diagnosis of MCS was further confirmed by immunohistochemical staining. Brief review of the literature in relation to this diagnosis in the orbit is also presented. PMID- 29755278 TI - Orbital tumor associated with a microphthalmic eye and colobomatous cleft: Pilocytic astrocytoma (glioma) or massive retinal gliosis. AB - A 11-year-old boy with congenital microphthalmos of the right eye presented with gradual protrusion of his ocular prosthesis. MRI showed an orbital mass adjacent to the microphthalmic eye. After removal of the eye and the orbital soft tissue mass a gliotic mass, resembling a pilocytic astrocytoma WHO grade 1 (glioma) was diagnosed. Through a colobomatous cleft in the eye the tumour spread in the orbit. There were no clinical signs of neurofibromatosis 1. This case showed a very rare association between a microphthalmic and colobomatous eye and pilocytic astrocytoma, grade 1. However a far advanced and infiltrative massive retinal gliosis cannot be definitively excluded as differential diagnosis. PMID- 29755279 TI - Bilateral orbital isolated (solitary) neurofibroma in the absence of neurofibromatosis - A case report. AB - Isolated neurofibroma is a slowly progressive tumor rarely found in the orbit accounting for less than 1% of the space occupying lesions of the orbit. It usually presents in the 2nd to 5th decades of life with proptosis, swelling, visual changes, ptosis, diplopia or pain. Almost all cases reported are unilateral. We report a 23-year-old female with no systemic features or family history of neurofibromatosis who presented with right upper eyelid swelling. Radiological studies revealed bilateral identical masses in the superior orbits. The patient underwent surgical excision of the lesion on the right side and it was proved to be neurofibroma. She did not have a recurrence with a follow up period of 2 years but developed sensory deficit. This is the fifth reported case of bilateral isolated neurofibroma. PMID- 29755280 TI - Blastomyces species and orbital apex syndrome: Unsuspected co-infection. AB - Blastomyces species are thermally dimorphic fungi existing as yeast in tissue. We report an initially immunocompetent patient with orbital apex syndrome (OAS) whose presentation suggested giant cell arteritis. Subsequently, metastatic carcinoma was entertained as a cause of OAS until bronchoscopy yielded Blastomyces species. The patient rapidly succumbed with multiorgan failure despite Amphotericin B administration. At post-mortem, Blastomyces co-infection with fungal hyphae in keeping with Aspergillus species was found in cavernous sinus and in infarcted optic nerve. To the best of our knowledge, co-infection with these two organisms in this clinical setting has not been reported. PMID- 29755281 TI - Optic nerve choristoma. PMID- 29755282 TI - Another bilingual advantage? Perception of talker-voice information. AB - A bilingual advantage has been found in both cognitive and social tasks. In the current study, we examine whether there is a bilingual advantage in how children process information about who is talking (talker-voice information). Younger and older groups of monolingual and bilingual children completed the following talker voice tasks with bilingual speakers: a discrimination task in English and German (an unfamiliar language), and a talker-voice learning task in which they learned to identify the voices of three unfamiliar speakers in English. Results revealed effects of age and bilingual status. Across the tasks, older children performed better than younger children and bilingual children performed better than monolingual children. Improved talker-voice processing by the bilingual children suggests that a bilingual advantage exists in a social aspect of speech perception, where the focus is not on processing the linguistic information in the signal, but instead on processing information about who is talking. PMID- 29755283 TI - Degree of bilingualism modifies executive control in Hispanic children in the USA. AB - Past studies examining the cognitive function of bilingual school-aged children have pointed to enhancements in areas of executive control relative to age matched monolingual children. The majority of these studies has tested children from a middle-class background and compared performance of bilinguals as a discrete group against monolinguals. The objective of the present study was to determine if cognitive enhancement from bilingualism is sensitive to the child's degree of bilingualism in a sample of eight- and nine-year old Spanish-English bilingual children of low socioeconomic status. The results showed that the more balanced the children were in their language skills, the better they performed on non-verbal tasks of cognitive function. These results support an additive view of bilingualism, where more balanced proficiency in two languages is associated with more enhanced cognitive function, regardless of socioeconomic background. PMID- 29755284 TI - The Value of MRI in Distinguishing Subtypes of Lipomatous Extremity Tumors Needs Reassessment in the Era of MDM2 and CDK4 Testing. AB - Introduction: Extremity lipomas and well-differentiated liposarcomas (WDLs) are difficult to distinguish on MR imaging. We sought to evaluate the accuracy of MRI interpretation using MDM2 amplification, via fluorescence in-situ hybridization (FISH), as the gold standard for pathologic diagnosis. Furthermore, we aimed to investigate the utility of a diagnostic formula proposed in the literature. Methods: We retrospectively collected 49 patients with lipomas or WDLs utilizing MDM2 for pathologic diagnosis. Four expert readers interpreted each patient's MRI independently and provided a diagnosis. Additionally, a formula based on imaging characteristics (i.e. tumor depth, diameter, presence of septa, and internal cystic change) was used to predict the pathologic diagnosis. The accuracy and reliability of imaging-based diagnoses were then analyzed in comparison to the MDM2 pathologic diagnoses. Results: The accuracy of MRI readers was 73.5% (95% CI 61-86%) with substantial interobserver agreement (kappa=0.7022). The formula had an accuracy of 71%, which was not significantly different from the readers (p=0.71). The formula and expert observers had similar sensitivity (83% versus 83%) and specificity (64.5% versus 67.7%; p=0.659) for detecting WDLs. Conclusion: The accuracy of both our readers and the formula suggests that MRI remains unreliable for distinguishing between lipoma and WDLs. PMID- 29755285 TI - Probabilistic seismic hazard assessment of southern part of Ghana. AB - This paper presents a seismic hazard map for the southern part of Ghana prepared using the probabilistic approach, and seismic hazard assessment results for six cities. The seismic hazard map was prepared for 10% probability of exceedance for peak ground acceleration in 50 years. The input parameters used for the computations of hazard were obtained using data from a catalogue that was compiled and homogenised to moment magnitude (Mw). The catalogue covered a period of over a century (1615-2009). The hazard assessment is based on the Poisson model for earthquake occurrence, and hence, dependent events were identified and removed from the catalogue. The following attenuation relations were adopted and used in this study-Allen (for south and eastern Australia), Silva et al. (for Central and eastern North America), Campbell and Bozorgnia (for worldwide active shallow-crust regions) and Chiou and Youngs (for worldwide active-shallow-crust regions). Logic-tree formalism was used to account for possible uncertainties associated with the attenuation relationships. OpenQuake software package was used for the hazard calculation. The highest level of seismic hazard is found in the Accra and Tema seismic zones, with estimated peak ground acceleration close to 0.2 g. The level of the seismic hazard in the southern part of Ghana diminishes with distance away from the Accra/Tema region to a value of 0.05 g at a distance of about 140 km. PMID- 29755286 TI - Characterisation of ground motion recording stations in the Groningen gas field. AB - The seismic hazard and risk analysis for the onshore Groningen gas field requires information about local soil properties, in particular shear-wave velocity (VS). A fieldwork campaign was conducted at 18 surface accelerograph stations of the monitoring network. The subsurface in the region consists of unconsolidated sediments and is heterogeneous in composition and properties. A range of different methods was applied to acquire in situ VS values to a target depth of at least 30 m. The techniques include seismic cone penetration tests (SCPT) with varying source offsets, multichannel analysis of surface waves (MASW) on Rayleigh waves with different processing approaches, microtremor array, cross-hole tomography and suspension P-S logging. The offset SCPT, cross-hole tomography and common midpoint cross-correlation (CMPcc) processing of MASW data all revealed lateral variations on length scales of several to tens of metres in this geological setting. SCPTs resulted in very detailed VS profiles with depth, but represent point measurements in a heterogeneous environment. The MASW results represent VS information on a larger spatial scale and smooth some of the heterogeneity encountered at the sites. The combination of MASW and SCPT proved to be a powerful and cost-effective approach in determining representative VS profiles at the accelerograph station sites. The measured VS profiles correspond well with the modelled profiles and they significantly enhance the ground motion model derivation. The similarity between the theoretical transfer function from the VS profile and the observed amplification from vertical array stations is also excellent. PMID- 29755287 TI - Project description and crowdfunding success: an exploratory study. AB - Existing research on antecedent of funding success mainly focuses on basic project properties such as funding goal, duration, and project category. In this study, we view the process by which project owners raise funds from backers as a persuasion process through project descriptions. Guided by the unimodel theory of persuasion, this study identifies three exemplary antecedents (length, readability, and tone) from the content of project descriptions and two antecedents (past experience and past expertise) from the trustworthy cue of project descriptions. We then investigate their impacts on funding success. Using data collected from Kickstarter, a popular crowdfunding platform, we find that these antecedents are significantly associated with funding success. Empirical results show that the proposed model that incorporated these antecedents can achieve an accuracy of 73 % (70 % in F-measure). The result represents an improvement of roughly 14 percentage points over the baseline model based on informed guessing and 4 percentage points improvement over the mainstream model based on basic project properties (or 44 % improvement of mainstream's performance over informed guessing). The proposed model also has superior true positive and true negative rates. We also investigate the timeliness of project data and find that old project data is gradually becoming less relevant and losing predictive power to newly created projects. Overall, this study provides evidence that antecedents identified from project descriptions have incremental predictive power and can help project owners evaluate and improve the likelihood of funding success. PMID- 29755288 TI - Roles of Perilipins in Diseases and Cancers. AB - Perilipins, an ancient family of lipid droplet-associated proteins, are embedded in a phospho-lipid monolayer of intracellular lipid droplets. The core of lipid droplets is composed of neutral fat, which mainly includes triglyceride and cholesterol ester. Perilipins are closely related to the function of lipid droplets, and they mediate lipid metabolism and storage. Therefore, perilipins play an important role in the development of obesity, diabetes, cancer, hepatic diseases, atherosclerosis, and carcinoma, which are caused by abnormal lipid metabolism. Accumulation of lipid droplets is a common phenomenon in tumor cells. Available data on the pathophysiology of perilipins and the relationship of perilipins with endocrine metabolic diseases and cancers are summarized in this mini-review. The research progress on this family offers novel insights into the therapeutic strategies for these diseases. PMID- 29755290 TI - Retromer Dysfunction and Neurodegenerative Disease. AB - In recent years, genomic, animal and cell biology studies have implicated deficiencies in retromer-mediated trafficking of proteins in an increasing number of neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's Disease (PD) and Frontotemporal Lobar Degener-ation (FTLD). The retromer complex, which is highly conserved across all eukaryotes, regulates the sorting of transmembrane proteins out of endo-somes to the cell surface or to the trans Golgi network. Within retromer, cargo selection and binding are performed by a trimer of the Vps26, Vps29 and Vps35 proteins, named the "Cargo-Selective Complex (CSC)". Sorting of cargo into tubules for distribution to the trans-Golgi network or the cell sur-face is achieved through the dimeric sorting nexin (SNX) component of retromer and accessory proteins such as the WASH complex which medi ates the formation of discrete endosomal tubules enabling the sorting of cargo into distinct pathways through production of filamentous actin patch-es. In the present article, we review the molecular structure and function of the retromer and summarize the evidence linking retromer dysfunction to neurodegenerative disease. PMID- 29755291 TI - Transcription Factor Co-expression Networks of Adipose RNA-Seq Data Reveal Regulatory Mechanisms of Obesity. AB - Background: Transcription Factors (TFs) control actuation of genes in the genome and are key mediators of complex processes such as obesity. Master Regulators (MRs) are the genes at the top of a regulation hierarchy which regulate other genes. Objective: To elucidate clusters of highly co-expressed TFs (modules), involved pathways, highly inter-connected TFs (hub-TFs) and MRs leading to obesity and leanness, using porcine model for human obesity. Methods: We identified 817 expressed TFs in RNA-Sequencing dataset representing extreme degrees of obesity (DO; lean, obese). We built a single Weighted Transcription Factor Co-expression Network (WTFCN) and TF sub-networks (based on the DO). Hub TFs and MRs (using iRegulon) were identi-fied in biologically relevant WTFCNs modules. Results: Single WTFCN detected the Red module significantly associated with DO (P < 0.03). This module was enriched for regulation processes in the immune system, e.g.: Immune system process (Padj = 2.50E-06) and metabolic lifestyle disorders, e.g. Circadian rhythm - mammal pathway (Padj = 2.33E-11). Detected MR, hub-TF SPI1 was involved in obesity, immunity and osteoporosis. Within the obese sub-network, the Red module suggested possible associations with immunity, e.g. TGF-beta signaling pathway (Padj = 1.73E-02) and osteoporosis, e.g. Osteoclast differentiation (Padj = 1.94E-02). Within the lean sub-network, the Magenta module displayed associations with type 2 diabetes, obesity and os teoporosis e.g. Notch signaling pathway (Padj = 2.40E-03), osteoporosis e.g. hub TF VDR (a prime candidate gene for osteoporosis). Conclusion: Our results provide insights into the regulatory network of TFs and biologically relevant hub TFs in obesity. PMID- 29755289 TI - Decoding the Emerging Patterns Exhibited in Non-coding RNAs Characteristic of Lung Cancer with Regard to their Clinical Significance. AB - Lung cancer continues to be the leading topic concerning global mortality rate caused by can-cer; it needs to be further investigated to reduce these dramatic unfavorable statistic data. Non-coding RNAs (ncRNAs) have been shown to be important cellular regulatory factors and the alteration of their expression levels has become correlated to extensive number of pathologies. Specifically, their expres-sion profiles are correlated with development and progression of lung cancer, generating great interest for further investigation. This review focuses on the complex role of non-coding RNAs, namely miR-NAs, piwi-interacting RNAs, small nucleolar RNAs, long non-coding RNAs and circular RNAs in the process of developing novel biomarkers for diagnostic and prognostic factors that can then be utilized for personalized therapies toward this devastating disease. To support the concept of personalized medi-cine, we will focus on the roles of miRNAs in lung cancer tumorigenesis, their use as diagnostic and prognostic biomarkers and their application for patient therapy. PMID- 29755292 TI - Decoding Common Features of Neurodegenerative Disorders: From Differentially Expressed Genes to Pathways. AB - Background: Neurodegeneration is a progressive/irreversible loss of neurons, building blocks of our nervous system. Their degeneration gradually collapses the entire structural and functional system manifesting in myriads of clinical disorders categorized as Neurodegenerative Disorders (NDs) such as Alzheimer's Disease, (AD), Parkinson's Disease (PD), Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). NDs are characterized by a puzzling interplay of molecular and cellular defects affecting subset of neuronal populations in specific affected brain areas. Objective: In present study, comparative in silico analysis was performed by utilizing gene expression datasets of AD, PD, FTD and ALS to identify potential common features to gain insights into complex molecular pathophysiology of the selected NDs. Methods: Gene expression data of four disorders were subjected to the identification of Differential Gene Expression (DEG) and their mapping on biological processes, KEGG pathways and molecular functions. Detailed comparative analysis was performed to highlight the common grounds of these dis-orders at various stages. Results: Astoundingly, 106 DEGs were found to be common across all disorders. Alongwith in total 100 GO terms and 7 KEGG pathways were found to be significantly enriched across all disorders. EGFR, CDC42 and CREBBP have been identified as the significantly interacting nodes in gene-gene in-teraction and in Protein-Protein Interaction (PPI) network as well. Furthermore, interaction of common DEGs targets with miRNA's has been scrutinized. Conclusion: The complex molecular underpinnings of these disorders are currently elusive. Despite heterogeneous clinical and pathological expressions, common features have been recognized in many NDs which provide evidence of their convergence. PMID- 29755293 TI - Role of Sequence Variations in AhR Gene Towards Modulating Smoking Induced Lung Cancer Susceptibility in North Indian Population: A Multiple Interaction Analysis. AB - Background: AhR, a ubiquitously expressed ligand-activated transcription factor, upon its encounter with the foreign ligands activates the transcriptional machinery of genes encoding for bio-transformation enzymes like CYP1A1 hence, mediating the metabolism of Poly aromatic hydrocarbons and nitrosamines which account for the maximally found carcinogen in cigarette smoke. Polymorphic variants of AhR play a significant role and are held responsible for disposing the individuals with greater chances of acquiring lung cancer. Objective: To study the role of AhR variants (rs2282885, rs10250822, rs7811989, rs2066853) in affect-ing lung cancer susceptibility. Methods: 297 cases and 320 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used. To analyze high order in teractions Multifactor Dimensionality Reduction and Classification and regression tree was used. Results: Subjects carrying the variant genotype for AhR rs7811989 showed a two-fold risk (p=0.007) and a marginal risk was also seen in case of individuals carrying either single or double copy of suscep-tible allele for rs102550822 (p=0.02). Whereas the variant allele for rs2066853 showcased a strong pro-tective effect (p=0.003). SQCC individuals with mutant genotype of rs2066853 also exhibited a protec-tive effect towards lung cancer (OR=0.30, p=0.0013). The association of rs7811989 mutant genotype and rs10250822 mutant genotype was evident especially in smokers as compared to non-smokers. AhR rs2066853 showed a decreased risk in smokers with mutant genotype (p=0.002). MDR approach gave the best interaction model of AhR rs2066853 and smoking (CVC=10/10, prediction error=0.42). Conclusion: AhR polymorphic variations can significantly contribute towards lung cancer predisposi-tion. PMID- 29755294 TI - Inhibition of the PI3K but not the MEK/ERK pathway sensitizes human glioma cells to alkylating drugs. AB - Background: Intrinsic chemoresistance of glioblastoma (GBM) is frequently owed to activation of the PI3K and MEK/ERK pathways. These signaling cascades are tightly interconnected however the quantitative contribution of both to intrinsic resistance is still not clear. Here, we aimed at determining the activation status of these pathways in human GBM biopsies and cells and investigating the quantitative impact of both pathways to chemoresistance. Methods: Receptor tyrosine kinase (RTK) pathways in temozolomide (TMZ) treatment naive or TMZ resistant human GBM biopsies and GBM cells were investigated by proteome profiling and immunoblotting of a subset of proteins. Resistance to drugs and RTK pathway inhibitors was assessed by MTT assays. Apoptotic rates were determined by Annexin V staining and DNA damage with comet assays and immunoblotting. Results: We analyzed activation of RTK pathways by proteome profiling of tumor samples of patients which were diagnosed a secondary GBM and underwent surgery and patients which underwent a second surgery after TMZ treatment due to recurrence of the tumor. We observed substantial activation of the PI3K and MEK/ERK pathways in both groups. However, AKT and CREB phosphorylation was reduced in biopsies of resistant tumors while ERK phosphorylation remained unchanged. Subsequent proteome profiling revealed that multiple RTKs and downstream targets are also activated in three GBM cell lines. We then systematically describe a mechanism of resistance of GBM cell lines and human primary GBM cells to the alkylating drugs TMZ and cisplatin. No specific inhibitor of the upstream RTKs sensitized cells to drug treatment. In contrast, we were able to restore sensitivity to TMZ and cisplatin by inhibiting PI3K in all cell lines and in human primary GBM cells. Interestingly, an opposite effect was observed when we inhibited the MEK/ERK signaling cascade with two different inhibitors. Conclusions: Temozolomide treatment naive and TMZ resistant GBM biopsies show a distinct activation pattern of the MEK/ERK and PI3K signaling cascades indicating a role of these pathways in resistance development. Both pathways are also activated in GBM cell lines, however, only the PI3K pathway seems to play a crucial role in resistance to alkylating agents and might serve as drug target for chemosensitization. PMID- 29755295 TI - Patterns of Emotional Availability between Mothers and Young Children: Associations with Risk Factors for Borderline Personality Disorder. AB - Emotional availability (EA) characterizes a warm, close relationship between caregiver and child. We compared patterns (clusters) of EA on risk factors, including those for borderline personality disorder (BPD). We sampled 70 children aged 4 to 7 years from low-socioeconomic backgrounds, 51% of whose mothers had BPD. We coded filmed interactions for EA: mothers' sensitivity, structuring, non intrusiveness, non-hostility, and children's responsiveness to, and involvement of, mothers. We additionally coded children's over-responsiveness and over involvement. Using person-centered analyses, we identified four clusters: high functioning, low-functioning, asynchronous (mothers above average on two of four dimensions, children below) and below average. Mothers in the low-functioning cluster had lower income, less social support, more of the borderline feature of negative relationships and more depression than did mothers in the high functioning cluster. The children in the low-functioning group had more risk factors for BPD (physical abuse, neglect, and separation from, or loss of caregivers, and negative narrative representations of the mother-child relationship in their stories) than did children in the high-functioning group. The asynchronous group included older girls who were over-responsive and over involving with their mothers in an apparent role reversal. Interventions targeting emotional availability may provide a buffer for children facing cumulative risks and help prevent psychopathology. PMID- 29755296 TI - PTSD and Problem Drinking in Relation to Seeking Mental Health and Substance Use Treatment Among Sexual Assault Survivors. AB - This study seeks to understand the effects of the co-occurrence of PTSD and problem drinking on formal help-seeking among sexual assault survivors over time. Data comes from a diverse sample of 1,863 women in a large Midwestern city who participated in a three-year study on women's experiences with sexual assault. Generalized Estimating Equations (GEE) were used to estimate the parameters of generalized linear models to assess the effects of PTSD and problem drinking on survivor mental health help-seeking and substance use treatment-seeking over time. In our models, having more PTSD, more education, and receiving a reaction of tangible support increased the odds of survivors seeking mental health treatment, which replicates past findings. This is the first study of women sexual assault survivors to find a unique effect of both PTSD and problem drinking on substance use treatment- seeking. The findings suggest survivors with co-occurring PTSD and problem drinking are less likely to seek substance use treatment over time. Future directions are discussed for research on survivors with co-occurring symptoms. PMID- 29755297 TI - Estimating inverse-probability weights for longitudinal data with dropout or truncation: The xtrccipw command. AB - Individuals may drop out of a longitudinal study, rendering their outcomes unobserved but still well defined. However, they may also undergo truncation (for example, death), beyond which their outcomes are no longer meaningful. Kurland and Heagerty (2005, Biostatistics 6: 241-258) developed a method to conduct regression conditioning on nontruncation, that is, regression conditioning on continuation (RCC), for longitudinal outcomes that are monotonically missing at random (for example, because of dropout). This method first estimates the probability of dropout among continuing individuals to construct inverse probability weights (IPWs), then fits generalized estimating equations (GEE) with these IPWs. In this article, we present the xtrccipw command, which can both estimate the IPWs required by RCC and then use these IPWs in a GEE estimator by calling the glm command from within xtrccipw. In the absence of truncation, the xtrccipw command can also be used to run a weighted GEE analysis. We demonstrate the xtrccipw command by analyzing an example dataset and the original Kurland and Heagerty (2005) data. We also use xtrccipw to illustrate some empirical properties of RCC through a simulation study. PMID- 29755298 TI - Addressing Female Genital Mutilation/Cutting (FGM/C) in the Era of Clitoral Reconstruction: Plastic Surgery. AB - Purpose of the Review: The aim of this review is to give an overview of the recent evidence on clitoral reconstruction and other relevant reconstructive plastic surgery measures after female genital mutilation/cutting (FGM/C). Recent Findings: Recent publications present refinements and modifications of the surgical technique of clitoral reconstruction along with reconstruction of the labia majora and clitoral hood. Novel approaches with reposition of the clitoral nerve, anchoring of the labia majora, fat grafting, and full thickness mucosa grafts have been introduced. The current evidence on outcomes of clitoral reconstruction shows potential benefits. However, there is a risk of postoperative complications and a negative outcome. Experts in the field advocate for a multidisciplinary approach including psychosexual counseling and health education with or without subsequent clitoral reconstructive surgery. Summary: The evolution of reconstructive treatment for women with FGM/C is expanding, however at a slow rate. The scarcity of evidence on clitoral reconstruction halters availability of clinical guidelines and consensus regarding best practice. Clitoral reconstruction should be provided by multidisciplinary referral centers in a research setting with long-term follow-up on outcomes of postoperative morbidity and possible benefits. PMID- 29755299 TI - In Vivo 6-([18F]Fluoroacetamido)-1-hexanoicanilide PET Imaging of Altered Histone Deacetylase Activity in Chemotherapy-Induced Neurotoxicity. AB - Background: Histone deacetylases (HDACs) regulate gene expression by changing histone deacetylation status. Neurotoxicity is one of the major side effects of cisplatin, which reacts with deoxyribonucleic acid (DNA) and has excellent antitumor effects. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor with neuroprotective effects against cisplatin-induced neurotoxicity. Purpose: We investigated how cisplatin with and without SAHA pretreatment affects HDAC expression/activity in the brain by using 6-([18F]fluoroacetamido)-1 hexanoicanilide ([18F]FAHA) as a positron emission tomography (PET) imaging agent for HDAC IIa. Materials and Methods: [18F]FAHA and [18F]fluoro-2-deoxy-2-D glucose ([18F]FDG) PET studies were done in 24 mice on 2 consecutive days and again 1 week later. The mice were divided into three groups according to drug administration between the first and second imaging sessions (Group A: cisplatin 2 mg/kg, twice; Group B: cisplatin 4 mg/kg, twice; Group C: cisplatin 4 mg/kg, twice, and SAHA 300 mg/kg pretreatment, 4 times). Results: The Ki value of [18F]FAHA was increased and the percentage of injected dose/tissue g (% ID/g) of [18F]FDG was decreased in the brains of animals in Groups A and B. The Ki value of [18F]FAHA and % ID/g of [18F]FDG were not significantly different in Group C. Conclusions: [18F]FAHA PET clearly showed increased HDAC activity suggestive of cisplatin neurotoxicity in vivo, which was blocked by SAHA pretreatment. PMID- 29755300 TI - The Effect of Gel Microstructure on Simulated Gastric Digestion of Protein Gels. AB - The objective of this study was to analyse the impact of the gel structure obtained by different heat-induced temperatures on the in vitro gastric digestibility at pH 2. To achieve this, gels were prepared from soy protein, pea protein, albumin from chicken egg white and whey protein isolate at varying temperatures (90, 120 and 140 degrees C) for 30 min. Gels were characterised prior to digestion via microstructure and SDS-PAGE analysis. Subsequently, the gastric digestion process was followed via the protein hydrolysis and HPSEC analysis up to 180 min. Peptides of different sizes (<5 kDa) were gradually formed during the digestion. Our results showed that gels induced at 140 degrees C were digested faster. The protein source and gelation temperature had great influence on the in vitro gastric protein digestibility. PMID- 29755301 TI - Fluid Gels: a New Feedstock for High Viscosity Jetting. AB - Suspensions of gel particles which are pourable or spoonable at room temperature can be created by shearing a gelling biopolymer through its gelation (thermal or ion mediated) rather than allowing quiescent cooling - thus the term 'fluid gel' may be used to describe the resulting material. As agar gelation is thermoreversible this type of fluid gel is able to be heated again to melt agar gel particles to varying degrees then re-form a network quiescently upon cooling, whose strength depends on the temperature of re-heating, determining the amount of agar solubilised and subsequently able to partake in re-gelation. Using this principle, for the first time fluid gels have been applied to a high viscosity 3D printing process wherein the printing temperature (at the nozzle) is controllable. This allows the use of ambient temperature feedstocks and by altering the nozzle temperature, the internal nature (presence or absence of gel particles) and gel strength of printed droplets differs. If the nozzle prints at different temperatures for each layer a structure with modulated texture could be created. PMID- 29755302 TI - The Theory of Planned Behavior and E-cig Use: Impulsive Personality, E-cig Attitudes, and E-cig Use. AB - The current paper applied the Theory of Planned Behavior (TPB; Ajzen & Fishbein, 1988) to understand how impulsive personality traits and attitudes concerning e cig use relate to the likelihood of electronic cigarette (e-cig) use. Seven hundred and fourteen participants (Mean age = 34.04, SD = 10.89, 48.6% female) completed cross-sectional measures of e-cig use attitudes (CEAC) and the Short UPPS-P Impulsive Behavior Scale. A structural path analysis suggested that urgency and deficits in conscientiousness were significantly related to e-cig attitudes (CFI = 0.99, TLI = 0.99, RMSEA = 0.02; urgency: beta = 0.32, p = .001; deficits in conscientiousness: beta = -0.48, p < .001). E-cig attitude scores were significantly higher for e-cig users than non-users, beta = 0.85, p < .001. There was no significant direct path from impulsive personality traits to e-cig use. Findings provide initial support for a model in which impulsive traits are related to e-cig use through positive e-cig attitudes. PMID- 29755304 TI - On the natural diversity of phenylacylated-flavonoid and their in planta function under conditions of stress. AB - Plants contain light signaling systems and undergo metabolic perturbation and reprogramming under light stress in order to adapt to environmental changes. Flavonoids are one of the largest classes of natural phytochemical compounds having several biological functions conferring stress defense to plants and health benefits in animal diets. A recent study of phenylacylated-flavonoids (also called hydroxycinnamoylated-flavonoids) of natural accessions of Arabidopsis suggested that phenylacylation of flavonoids relates to selection under different natural light conditions. Phenylacylated-flavonoids which are decorated with hydroxycinnamoyl units, namely cinnamoyl, 4-coumaroyl, caffeoyl, feruloyl and sinapoyl moieties, are widely distributed in the plant kingdom. Currently, more than 400 phenylacylated flavonoids have been reported. Phenylacylation renders enhanced phytochemical functions such as ultraviolet absorbance and antioxidant activity, although, the physiological role of phenylacylation of flavonoids in plants is largely unknown. In this review, we provide an overview of the occurrence and natural diversity of phenylacylated flavonoids as well as postulating their biological functions both in planta and with respect to biological activity following their consumption. PMID- 29755303 TI - How to prove the existence of metabolons? AB - Sequential enzymes in biosynthetic pathways are organized in metabolons. It is challenging to provide experimental evidence for the existence of metabolons as biosynthetic pathways are composed of highly dynamic protein-protein interactions. Many different methods are being applied, each with strengths and weaknesses. We will present and evaluate several techniques that have been applied in providing evidence for the orchestration of the biosynthetic pathways of cyanogenic glucosides and glucosinolates in metabolons. These evolutionarily related pathways have ER-localized cytochromes P450 that are proposed to function as anchoring site for assembly of the enzymes into metabolons. Additionally, we have included commonly used techniques, even though they have not been used (yet) on these two pathways. In the review, special attention will be given to less exploited fluorescence-based methods such as FCS and FLIM. Ultimately, understanding the orchestration of biosynthetic pathways may contribute to successful engineering in heterologous hosts. PMID- 29755306 TI - Sensitive Capacitive-type Hydrogen Sensor Based on Ni Thin Film in Different Hydrogen Concentrations. AB - Background: Hydrogen sensors are micro/nano-structure that are used to locate hydrogen leaks. They are considered to have fast response/recovery time and long lifetime as compared to conventional gas sensors. In this paper, fabrication of sensitive capacitive-type hydrogen gas sensor based on Ni thin film has been investigated. The C-V curves of the sensor in different hydrogen concentrations have been reported. Method: Dry oxidation was done in thermal chemical vapor deposition furnace (TCVD). For oxidation time of 5 min, the oxide thickness was 15 nm and for oxidation time 10 min, it was 20 nm. The Ni thin film as a catalytic metal was deposited on the oxide film using electron gun deposition. Two MOS sensors were compared with different oxide film thickness and different hydrogen concentrations. Results: The highest response of the two MOS sensors with 15 nm and 20 nm oxide film thickness in 4% hydrogen concentration was 87.5% and 65.4% respectively. The fast response times for MOS sensors with 15 nm and 20 nm oxide film thickness in 4% hydrogen concentration was 8 s and 21 s, respectively. Conclusion: By increasing the hydrogen concentration from 1% to 4%, the response time for MOS sensor (20nm oxide thickness), was decreased from 28s to 21s. The recovery time was inversely increased from 237s to 360s. The experimental results showed that the MOS sensor based on Ni thin film had a quick response and a high sensitivity. PMID- 29755305 TI - A Cross-Sectional Survey Study to Assess Prevalence and Attitudes Regarding Research Misconduct among Investigators in the Middle East. AB - Background: Recent studies from Western countries indicate significant levels of questionable research practices, but similar data from low and middle-income countries are limited. Our aims were to assess the prevalence of and attitudes regarding research misconduct among researchers in several universities in the Middle East and to identify factors that might account for our findings. Methods: We distributed an anonymous questionnaire to a convenience sample of investigators at several universities in Egypt, Lebanon, and Bahrain. Participants were asked to a) self-report their extent of research misconducts, as well as their knowledge of colleagues engaging in similar research misconducts and b) provide their extent of agreement with certain attitudes about research misconduct. We used descriptive, bivariate, and multivariate logistic regression statistics to analyze the data. Results: Data from 278 participants showed a high prevalence of misconduct, as 59.4% of our respondents self-reported to committing at least one misbehaviors and 74.5% reported having knowledge of any misbehaviors among any of their colleagues. The most common type of self-report misconduct was "circumventing research ethics regulations" (50.5%) followed by "fabrication and falsification" (28.6%). A significant predictor of misconduct included a lack of "prior ethics training". Conclusion: Scientific misconduct represents a significant issue in several universities in the Middle East. The demonstration that a lack of "prior ethics training" was a significant predictor of misconduct should lead to educational initiatives in research integrity. Further studies are needed to confirm whether our results can be generalized to other universities in the Middle East. PMID- 29755307 TI - Adopting Quaternion Wavelet Transform to Fuse Multi-Modal Medical Images. AB - Medical image fusion plays an important role in clinical applications such as image-guided surgery, image-guided radiotherapy, noninvasive diagnosis, and treatment planning. In this paper, we propose a novel multi-modal medical image fusion method based on simplified pulse-coupled neural network and quaternion wavelet transform. The proposed fusion algorithm is capable of combining not only pairs of computed tomography (CT) and magnetic resonance (MR) images, but also pairs of CT and proton-density-weighted MR images, and multi-spectral MR images such as T1 and T2. Experiments on six pairs of multi-modal medical images are conducted to compare the proposed scheme with four existing methods. The performances of various methods are investigated using mutual information metrics and comprehensive fusion performance characterization (total fusion performance, fusion loss, and modified fusion artifacts criteria). The experimental results show that the proposed algorithm not only extracts more important visual information from source images, but also effectively avoids introducing artificial information into fused medical images. It significantly outperforms existing medical image fusion methods in terms of subjective performance and objective evaluation metrics. PMID- 29755308 TI - Stereoselective Synthesis of 3,3'-Bisindolines by Organocatalytic Michael Additions of Fluorooxindole Enolates to Isatylidene Malononitriles in Aqueous Solution. AB - A highly diastereoselective organocatalytic reaction for the synthesis of fluorinated 3,3'-bisindolines exhibiting adjacent tetrasubstituted carbon stereocenters is described. A broad variety of heterochiral bisindolines was prepared in 91-99% yield using 3-fluorooxindoles and isatylidene malononitriles in the presence of catalytic amounts of triethylamine in water or aqueous solution. The reaction can be upscaled without compromising yield and diastereoselectivity and the general usefulness of this method was demonstrated with various Michael acceptors and extended to aldol and Mannich reactions. PMID- 29755310 TI - [Formula: see text]-optimality in copula models. AB - Optimum experimental design theory has recently been extended for parameter estimation in copula models. The use of these models allows one to gain in flexibility by considering the model parameter set split into marginal and dependence parameters. However, this separation also leads to the natural issue of estimating only a subset of all model parameters. In this work, we treat this problem with the application of the [Formula: see text]-optimality to copula models. First, we provide an extension of the corresponding equivalence theory. Then, we analyze a wide range of flexible copula models to highlight the usefulness of [Formula: see text]-optimality in many possible scenarios. Finally, we discuss how the usage of the introduced design criterion also relates to the more general issue of copula selection and optimal design for model discrimination. PMID- 29755309 TI - Targeted Delivery of CRISPR/Cas9-Mediated Cancer Gene Therapy via Liposome Templated Hydrogel Nanoparticles. AB - Due to its simplicity, versatility, and high efficiency, the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology has emerged as one of the most promising approaches for treatment of a variety of genetic diseases, including human cancers. However, further translation of CRISPR/Cas9 for cancer gene therapy requires development of safe approaches for efficient, highly specific delivery of both Cas9 and single guide RNA to tumors. Here, novel core shell nanostructure, liposome-templated hydrogel nanoparticles (LHNPs) that are optimized for efficient codelivery of Cas9 protein and nucleic acids is reported. It is demonstrated that, when coupled with the minicircle DNA technology, LHNPs deliver CRISPR/Cas9 with efficiency greater than commercial agent Lipofectamine 2000 in cell culture and can be engineered for targeted inhibition of genes in tumors, including tumors the brain. When CRISPR/Cas9 targeting a model therapeutic gene, polo-like kinase 1 (PLK1), is delivered, LHNPs effectively inhibit tumor growth and improve tumor-bearing mouse survival. The results suggest LHNPs as versatile CRISPR/Cas9-delivery tool that can be adapted for experimentally studying the biology of cancer as well as for clinically translating cancer gene therapy. PMID- 29755311 TI - Interactive Sonification Exploring Emergent Behavior Applying Models for Biological Information and Listening. AB - Sonification is an open-ended design task to construct sound informing a listener of data. Understanding application context is critical for shaping design requirements for data translation into sound. Sonification requires methodology to maintain reproducibility when data sources exhibit non-linear properties of self-organization and emergent behavior. This research formalizes interactive sonification in an extensible model to support reproducibility when data exhibits emergent behavior. In the absence of sonification theory, extensibility demonstrates relevant methods across case studies. The interactive sonification framework foregrounds three factors: reproducible system implementation for generating sonification; interactive mechanisms enhancing a listener's multisensory observations; and reproducible data from models that characterize emergent behavior. Supramodal attention research suggests interactive exploration with auditory feedback can generate context for recognizing irregular patterns and transient dynamics. The sonification framework provides circular causality as a signal pathway for modeling a listener interacting with emergent behavior. The extensible sonification model adopts a data acquisition pathway to formalize functional symmetry across three subsystems: Experimental Data Source, Sound Generation, and Guided Exploration. To differentiate time criticality and dimensionality of emerging dynamics, tuning functions are applied between subsystems to maintain scale and symmetry of concurrent processes and temporal dynamics. Tuning functions accommodate sonification design strategies that yield order parameter values to render emerging patterns discoverable as well as rehearsable, to reproduce desired instances for clinical listeners. Case studies are implemented with two computational models, Chua's circuit and Swarm Chemistry social agent simulation, generating data in real-time that exhibits emergent behavior. Heuristic Listening is introduced as an informal model of a listener's clinical attention to data sonification through multisensory interaction in a context of structured inquiry. Three methods are introduced to assess the proposed sonification framework: Listening Scenario classification, data flow Attunement, and Sonification Design Patterns to classify sound control. Case study implementations are assessed against these methods comparing levels of abstraction between experimental data and sound generation. Outcomes demonstrate the framework performance as a reference model for representing experimental implementations, also for identifying common sonification structures having different experimental implementations, identifying common functions implemented in different subsystems, and comparing impact of affordances across multiple implementations of listening scenarios. PMID- 29755312 TI - Integrated fMRI Preprocessing Framework Using Extended Kalman Filter for Estimation of Slice-Wise Motion. AB - Functional MRI acquisition is sensitive to subjects' motion that cannot be fully constrained. Therefore, signal corrections have to be applied a posteriori in order to mitigate the complex interactions between changing tissue localization and magnetic fields, gradients and readouts. To circumvent current preprocessing strategies limitations, we developed an integrated method that correct motion and spatial low-frequency intensity fluctuations at the level of each slice in order to better fit the acquisition processes. The registration of single or multiple simultaneously acquired slices is achieved online by an Iterated Extended Kalman Filter, favoring the robust estimation of continuous motion, while an intensity bias field is non-parametrically fitted. The proposed extraction of gray-matter BOLD activity from the acquisition space to an anatomical group template space, taking into account distortions, better preserves fine-scale patterns of activity. Importantly, the proposed unified framework generalizes to high resolution multi-slice techniques. When tested on simulated and real data the latter shows a reduction of motion explained variance and signal variability when compared to the conventional preprocessing approach. These improvements provide more stable patterns of activity, facilitating investigation of cerebral information representation in healthy and/or clinical populations where motion is known to impact fine-scale data. PMID- 29755313 TI - Individualized Functional Parcellation of the Human Amygdala Using a Semi supervised Clustering Method: A 7T Resting State fMRI Study. AB - The amygdala plays an important role in emotional functions and its dysfunction is considered to be associated with multiple psychiatric disorders in humans. Cytoarchitectonic mapping has demonstrated that the human amygdala complex comprises several subregions. However, it's difficult to delineate boundaries of these subregions in vivo even if using state of the art high resolution structural MRI. Previous attempts to parcellate this small structure using unsupervised clustering methods based on resting state fMRI data suffered from the low spatial resolution of typical fMRI data, and it remains challenging for the unsupervised methods to define subregions of the amygdala in vivo. In this study, we developed a novel brain parcellation method to segment the human amygdala into spatially contiguous subregions based on 7T high resolution fMRI data. The parcellation was implemented using a semi-supervised spectral clustering (SSC) algorithm at an individual subject level. Under guidance of prior information derived from the Julich cytoarchitectonic atlas, our method clustered voxels of the amygdala into subregions according to similarity measures of their functional signals. As a result, three distinct amygdala subregions can be obtained in each hemisphere for every individual subject. Compared with the cytoarchitectonic atlas, our method achieved better performance in terms of subregional functional homogeneity. Validation experiments have also demonstrated that the amygdala subregions obtained by our method have distinctive, lateralized functional connectivity (FC) patterns. Our study has demonstrated that the semi supervised brain parcellation method is a powerful tool for exploring amygdala subregional functions. PMID- 29755315 TI - Does Post-task Declarative Learning Have an Influence on Early Motor Memory Consolidation Over Day? An fMRI Study. AB - Previous studies demonstrated the influence of the post-learning period on procedural motor memory consolidation. In an early period after the acquisition, motor skills are vulnerable to modifications during wakefulness. Indeed, specific interventions such as world-list learning within this early phase of motor memory consolidation seem to enhance motor performance as an indicator for successful consolidation. This finding highlights the idea that manipulations of procedural and declarative memory systems during the early phase of memory consolidation over wakefulness may influence off-line consolidation. Using functional magnetic resonance imaging (fMRI) during initial motor sequence learning and motor sequence recall, we indirectly assess the influence of a secondary task taken place in the early phase of memory consolidation. All participants were scanned using fMRI during the learning phase of a serial reaction time task (SRTT) at 8 a.m. Afterwards, they were randomly assigned to one of five conditions. One group performed a declarative verbal, one a declarative nonverbal learning task. Two groups worked on attention tasks. A control group passed a resting condition. Participants stayed awake the whole day and performed the SRTT in the MRI scanner 12 h later at 8 p.m. At the behavioral level, the analysis of the reaction times failed to show a significant group difference. The primary analysis assessing fMRI data based on the contrast (sequence - random) between learning and retrieval also did not show any significant group differences. Therefore, our main analysis do not support the hypothesis that a secondary task influences the retrieval of the SRTT. In a more liberal fMRI analysis, we compared only the sequence blocks of the SRTT from learning to recall. BOLD signal decreased in the ipsilateral cerebellum and the supplementary motor area solely in the verbal learning group. Although our primary analysis failed to show significant changes between our groups, results of the secondary analysis could be an indication for a beneficial effect of the verbal declarative task in the early post-learning phase. A nonverbal learning task did not affect the activation within the motor network. Further studies are needed to replicate this finding and to assess the usefulness of this manipulation. PMID- 29755314 TI - Non-invasive Investigation of Human Hippocampal Rhythms Using Magnetoencephalography: A Review. AB - Hippocampal rhythms are believed to support crucial cognitive processes including memory, navigation, and language. Due to the location of the hippocampus deep in the brain, studying hippocampal rhythms using non-invasive magnetoencephalography (MEG) recordings has generally been assumed to be methodologically challenging. However, with the advent of whole-head MEG systems in the 1990s and development of advanced source localization techniques, simulation and empirical studies have provided evidence that human hippocampal signals can be sensed by MEG and reliably reconstructed by source localization algorithms. This paper systematically reviews simulation studies and empirical evidence of the current capacities and limitations of MEG "deep source imaging" of the human hippocampus. Overall, these studies confirm that MEG provides a unique avenue to investigate human hippocampal rhythms in cognition, and can bridge the gap between animal studies and human hippocampal research, as well as elucidate the functional role and the behavioral correlates of human hippocampal oscillations. PMID- 29755316 TI - Single Ethanol Withdrawal Regulates Extrasynaptic delta-GABAA Receptors Via PKCdelta Activation. AB - Alcohol (ethanol, EtOH) is one of the most widely abused drugs with profound effects on brain function and behavior. GABAA receptors (GABAARs) are one of the major targets for EtOH in the brain. Temporary plastic changes in GABAARs after withdrawal from a single EtOH exposure occur both in vivo and in vitro, which may be the basis for chronic EtOH addiction, tolerance and withdrawal symptoms. Extrasynaptic delta-GABAAR endocytosis is implicated in EtOH-induced GABAAR plasticity, but the mechanisms by which the relative abundance and localization of specific GABAARs are altered by EtOH exposure and withdrawal remain unclear. In this study, we investigated the mechanisms underlying rapid regulation of extrasynaptic delta-GABAAR by a single EtOH withdrawal in cultured rat hippocampal neurons. Thirty-minutes EtOH (60 mM) exposure increased extrasynaptic tonic current (Itonic) amplitude without affecting synaptic GABAAR function in neurons. In contrast, at 30 min after withdrawal, Itonic amplitude and responsiveness to acute EtOH were both reduced. Similar results occurred in neurons with okadaic acid (OA) or phorbol 12,13-dibutyrate (PDBu) exposure. Protein kinase C (PKC) inhibition prevented the reduction of Itonic amplitude and the tolerance to acute EtOH, as well as the reduction of GABAAR-delta subunit abundance induced by a single EtOH withdrawal. Moreover, EtOH withdrawal selectively increased PKCdelta level, whereas PKCdelta inhibition specifically rescued the EtOH-induced alterations in GABAAR-delta subunit level and delta GABAAR function. Together, we provided strong evidence for the important roles of PKCdelta in the rapid regulation of extrasynaptic delta-GABAAR induced by a single EtOH withdrawal. PMID- 29755317 TI - Microglial Phagocytosis and Its Regulation: A Therapeutic Target in Parkinson's Disease? AB - The role of phagocytosis in the neuroprotective function of microglia has been appreciated for a long time, but only more recently a dysregulation of this process has been recognized in Parkinson's disease (PD). Indeed, microglia play several critical roles in central nervous system (CNS), such as clearance of dying neurons and pathogens as well as immunomodulation, and to fulfill these complex tasks they engage distinct phenotypes. Regulation of phenotypic plasticity and phagocytosis in microglia can be impaired by defects in molecular machinery regulating critical homeostatic mechanisms, including autophagy. Here, we briefly summarize current knowledge on molecular mechanisms of microglia phagocytosis, and the neuro-pathological role of microglia in PD. Then we focus more in detail on the possible functional role of microglial phagocytosis in the pathogenesis and progression of PD. Evidence in support of either a beneficial or deleterious role of phagocytosis in dopaminergic degeneration is reported. Altered expression of target-recognizing receptors and lysosomal receptor CD68, as well as the emerging determinant role of alpha-synuclein (alpha-SYN) in phagocytic function is discussed. We finally discuss the rationale to consider phagocytic processes as a therapeutic target to prevent or slow down dopaminergic degeneration. PMID- 29755319 TI - AMBRA1-Mediated Mitophagy Counteracts Oxidative Stress and Apoptosis Induced by Neurotoxicity in Human Neuroblastoma SH-SY5Y Cells. AB - Therapeutic strategies are needed to protect dopaminergic neurons in Parkinson's disease (PD) patients. Oxidative stress caused by dopamine may play an important role in PD pathogenesis. Selective autophagy of mitochondria (mitophagy), mainly regulated by PINK1 and PARKIN, plays an important role in the maintenance of cell homeostasis. Mutations in those genes cause accumulation of damaged mitochondria, leading to nigral degeneration and early-onset PD. AMBRA1ActA is a fusion protein specifically expressed at the mitochondria, and whose expression has been shown to induce a powerful mitophagy in mammalian cells. Most importantly, the pro autophagy factor AMBRA1 is sufficient to restore mitophagy in fibroblasts of PD patients carrying PINK1 and PARKIN mutations. In this study, we investigated the potential neuroprotective effect of AMBRA1-induced mitophagy against 6 hydroxydopamine (6-OHDA)- and rotenone-induced cell death in human neuroblastoma SH-SY5Y cells. We demonstrated that AMBRA1ActA overexpression was sufficient to induce mitochondrial clearance in SH-SY5Y cells. We found that apoptosis induced by 6-OHDA and rotenone was reversed by AMBRA1-induced mitophagy. Finally, transfection of SH-SY5Y cells with a vector encoding AMBRA1ActA significantly reduced 6-OHDA and rotenone-induced generation of reactive oxygen species (ROS). Altogether, our results indicate that AMBRA1ActA is able to induce mitophagy in SH-SY5Y cells in order to suppress oxidative stress and apoptosis induced by both 6-OHDA and rotenone. These results strongly suggest that AMBRA1 may have promising neuroprotective properties with an important role in limiting ROS induced dopaminergic cell death, and the utmost potential to prevent PD or other neurodegenerative diseases associated with mitochondrial oxidative stress. PMID- 29755318 TI - Arc 3' UTR Splicing Leads to Dual and Antagonistic Effects in Fine-Tuning Arc Expression Upon BDNF Signaling. AB - Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis-Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3' UTR. These include two conserved introns which distinctively modulate Arc mRNA stability by targeting it for destruction via the nonsense mediated decay pathway. Here, we further investigated how splicing of the Arc mRNA 3' UTR region contributes to modulate Arc expression in cultured neurons. Unexpectedly, upon induction with brain derived neurotrophic factor, translational efficiency of a luciferase reporter construct harboring Arc 3' UTR is significantly upregulated and this effect is dependent on splicing of Arc introns. We find that, eIF2alpha dephosphorylation, mTOR, ERK, PKC, and PKA activity are key to this process. Additionally, CREB-dependent transcription is required to couple Arc 3' UTR splicing to its translational upregulation, suggesting the involvement of de novo transcribed trans-acting factors. Overall, splicing of Arc 3' UTR exerts a dual and unique effect in fine-tuning Arc expression upon synaptic signaling: while inducing mRNA decay to limit the time window of Arc expression, it also elicits translation of the decaying mRNA. This antagonistic effect likely contributes to the achievement of a confined yet efficient burst of Arc protein expression, facilitating its role as an effector of synapse-specific plasticity. PMID- 29755320 TI - Mechanically Gated Ion Channels in Mammalian Hair Cells. AB - Hair cells in the inner ear convert mechanical stimuli provided by sound waves and head movements into electrical signal. Several mechanically evoked ionic currents with different properties have been recorded in hair cells. The search for the proteins that form the underlying ion channels is still in progress. The mechanoelectrical transduction (MET) channel near the tips of stereociliary in hair cells, which is responsible for sensory transduction, has been studied most extensively. Several components of the sensory mechanotransduction machinery in stereocilia have been identified, including the multi-transmembrane proteins tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5, transmembrane inner ear (TMIE) and transmembrane channel-like proteins 1 and 2 (TMC1/2). However, there remains considerable uncertainty regarding the molecules that form the channel pore. In addition to the sensory MET channel, hair cells express the mechanically gated ion channel PIEZO2, which is localized near the base of stereocilia and not essential for sensory transduction. The function of PIEZO2 in hair cells is not entirely clear but it might have a role in damage sensing and repair processes. Additional stretch-activated channels of unknown molecular identity and function have been found to localize at the basolateral membrane of hair cells. Here, we review current knowledge regarding the different mechanically gated ion channels in hair cells and discuss open questions concerning their molecular composition and function. PMID- 29755321 TI - Voltage Gated Calcium Channel Activation by Backpropagating Action Potentials Downregulates NMDAR Function. AB - The majority of excitatory synapses are located on dendritic spines of cortical glutamatergic neurons. In spines, compartmentalized Ca2+ signals transduce electrical activity into specific long-term biochemical and structural changes. Action potentials (APs) propagate back into the dendritic tree and activate voltage gated Ca2+ channels (VGCCs). For spines, this global mode of spine Ca2+ signaling is a direct biochemical feedback of suprathreshold neuronal activity. We previously demonstrated that backpropagating action potentials (bAPs) result in long-term enhancement of spine VGCCs. This activity-dependent VGCC plasticity results in a large interspine variability of VGCC Ca2+ influx. Here, we investigate how spine VGCCs affect glutamatergic synaptic transmission. We combined electrophysiology, two-photon Ca2+ imaging and two-photon glutamate uncaging in acute brain slices from rats. T- and R-type VGCCs were the dominant depolarization-associated Ca2+conductances in dendritic spines of excitatory layer 2 neurons and do not affect synaptic excitatory postsynaptic potentials (EPSPs) measured at the soma. Using two-photon glutamate uncaging, we compared the properties of glutamatergic synapses of single spines that express different levels of VGCCs. While VGCCs contributed to EPSP mediated Ca2+ influx, the amount of EPSP mediated Ca2+ influx is not determined by spine VGCC expression. On a longer timescale, the activation of VGCCs by bAP bursts results in downregulation of spine NMDAR function. PMID- 29755322 TI - Microglial Activation After Systemic Stimulation With Lipopolysaccharide and Escherichia coli. AB - Background: Microglial activation after systemic infection has been suggested to mediate sepsis-associated delirium. A systematic review of animal studies suggested distinct differences between microglial activation after systemic challenge with live bacteria and lipopolysaccharide (LPS). Here, we describe a mouse model of microglial activation after systemic challenge with live Escherichia coli (E. coli) and compare results with systemic challenge with LPS. Methods: Sixty mice were intraperitoneally injected with E. coli (1 * 104 colony forming units) and sacrificed at 12, 20, 48, and 72 h after inoculation. For 48 and 72 h time points, mice were treated with ceftriaxone. Thirty mice were intraperitoneally injected with LPS (5 mg/kg) and sacrificed 3 and 48 h after inoculation; 48 control mice were intraperitoneally injected with isotonic saline. Microglial response was monitored by immunohistochemical staining with Iba-1 antibody and flow cytometry; and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. Results: Mice infected with live E. coli showed microglial activation 72 h post-inoculation, with increased cell number in cortex (p = 0.0002), hippocampus (p = 0.003), and thalamus (p = 0.0001), but not in the caudate nucleus/putamen (p = 0.33), as compared to controls. At 72 h, flow cytometry of microglia from E. coli infected mice showed increased cell size (p = 0.03) and CD45 expression (p = 0.03), but no increase in CD11b expression, and no differences in brain mRNA expression of inflammatory mediators as compared to controls. In mice with systemic LPS stimulation, microglial cells were morphologically activated at the 48 h time point with increased cell numbers in cortex (p = 0.002), hippocampus (p = 0.0003), thalamus (p = 0.007), and caudate nucleus/putamen (p < 0.0001), as compared to controls. At 48 h, flow cytometry of microglia from LPS stimulated mice showed increased cell size (p = 0.03), CD45 (p = 0.03), and CD11b (p = 0.04) expression. Brain mRNA expression of TNF-alpha (p = 0.02), IL-1beta (p = 0.02), and MCP-1 (p = 0.03) were increased as compared to controls. Interpretation: Systemic challenge with live E. coli causes a neuro inflammatory response, but this response occurs at a later time point and is less vigorous as compared to LPS stimulation.The E. coli model mimics the clinical situation of infection associated delirium more closely than stimulation with supra-natural LPS. PMID- 29755323 TI - Environmental Enrichment Prevents Transcriptional Disturbances Induced by Alpha Synuclein Overexpression. AB - Onset and progression of neurodegenerative disorders, including synucleinopathies such as Parkinson's disease, have been associated with various environmental factors. A highly compelling association from a therapeutic point of view has been found between a physically active lifestyle and a significantly reduced risk for Parkinson's disease. Mimicking such conditions in animal models by promoting physical activity, social interactions, and novel surroundings yields in a so called enriched environment known to enhance adult neurogenesis, increase synaptic plasticity, and decelerate neuronal loss. Yet, the genes that connect beneficial environmental cues to the genome and delay disease-related symptoms have remained largely unclear. To identify such mediator genes, we used a 2 * 2 factorial design opposing genotype and environment. Specifically, we compared wildtype to transgenic mice overexpressing human SNCA, a key gene in synucleinopathies encoding alpha-synuclein, and housed them in a standard and enriched environment from weaning to 12 months of age before profiling their hippocampal transcriptome using RNA-sequencing. Under standard environmental conditions, differentially expressed genes were overrepresented for calcium ion binding, membrane, synapse, and other Gene Ontology terms previously linked to alpha-synuclein biology. Upregulated genes were significantly enriched for genes attributed to astrocytes, microglia, and oligodendrocytes. These disturbances in gene activity were accompanied by reduced levels of several presynaptic proteins and the immediate early genes EGR1 and NURR1. Intriguingly, housing transgenic animals in the enriched environment prevented most of these perturbations in gene activity. In addition, a sustained activation specifically in transgenic animals housed in enriched conditions was observed for several immediate early genes including Egr1, Nr4a2/Nurr1, Arc, and Homer1a. These findings suggest a compensatory mechanism through an enriched environment-activated immediate early gene network that prevented most disturbances induced by alpha-synuclein overexpression. This regulatory framework might harbor attractive targets for novel therapeutic approaches that mimic beneficial environmental stimuli. PMID- 29755325 TI - Robust Cell Detection for Large-Scale 3D Microscopy Using GPU-Accelerated Iterative Voting. AB - High-throughput imaging techniques, such as Knife-Edge Scanning Microscopy (KESM),are capable of acquiring three-dimensional whole-organ images at sub micrometer resolution. These images are challenging to segment since they can exceed several terabytes (TB) in size, requiring extremely fast and fully automated algorithms. Staining techniques are limited to contrast agents that can be applied to large samples and imaged in a single pass. This requires maximizing the number of structures labeled in a single channel, resulting in images that are densely packed with spatial features. In this paper, we propose a three dimensional approach for locating cells based on iterative voting. Due to the computational complexity of this algorithm, a highly efficient GPU implementation is required to make it practical on large data sets. The proposed algorithm has a limited number of input parameters and is highly parallel. PMID- 29755324 TI - Effect of Chronic Oxidative Stress on Neuroinflammatory Response Mediated by CD4+T Cells in Neurodegenerative Diseases. AB - In a state of oxidative stress, there is an increase of reactive species, which induce an altered intracellular signaling, leading to dysregulation of the inflammatory response. The inability of the antioxidant defense systems to modulate the proinflammatory response is key to the onset and progression of neurodegenerative diseases. The aim of this work is to review the effect of the state of oxidative stress on the loss of regulation of the inflammatory response on the microglia and astrocytes, the induction of different CD4+T cell populations in neuroinflammation, as well as its role in some neurodegenerative diseases. For this purpose, an intentional search of original articles, short communications, and reviews, was carried out in the following databases: PubMed, Scopus, and Google Scholar. The articles reviewed included the period from 1997 to 2017. With the evidence obtained, we conclude that the loss of redox balance induces alterations in the differentiation and number of CD4+T cell subpopulations, leading to an increase in Th1 and Th17 response. This contributes to the development of neuroinflammation as well as loss of the regulation of the inflammatory response in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), and Multiple Sclerosis (MS). In contrast, regulatory T cells (Tregs) and Th2 modulate the inflammatory response of effect of T cells, microglia, and astrocytes. In this respect, it has been found that the mobilization of T cells with anti-inflammatory characteristics toward damaged regions of the CNS can provide neuroprotection and become a therapeutic strategy to control inflammatory processes in neurodegeneration. PMID- 29755326 TI - Transient Hypothyroidism During Lactation Arrests Myelination in the Anterior Commissure of Rats. A Magnetic Resonance Image and Electron Microscope Study. AB - Thyroid hormone deficiency at early postnatal ages affects the cytoarchitecture and function of neocortical and telencephalic limbic areas, leading to impaired associative memory and in a wide spectrum of neurological and mental diseases. Neocortical areas project interhemispheric axons mostly through the corpus callosum and to a lesser extent through the anterior commissure (AC), while limbic areas mostly project through the AC and hippocampal commissures. Functional magnetic resonance data from children with late diagnosed congenital hypothyroidism and abnormal verbal memory processing, suggest altered ipsilateral and contralateral telencephalic connections. Gestational hypothyroidism affects AC development but the possible effect of transient and chronic postnatal hypothyroidism, as occurs in late diagnosed neonates with congenital hypothyroidism and in children growing up in iodine deficient areas, still remains unknown. We studied AC development using in vivo magnetic resonance imaging and electron microscopy in hypothyroid and control male rats. Four groups of methimazole (MMI) treated rats were studied. One group was MMI-treated from postnatal day (P) 0 to P21; some of these rats were also treated with L-thyroxine (T4) from P15 to P21, as a model for early transient hypothyroidism. Other rats were MMI-treated from P0 to P150 and from embryonic day (E) 10 to P170, as a chronic hypothyroidism group. The results were compared with age paired control rats. The normalized T2 signal using magnetic resonance image was higher in MMI treated rats and correlated with the number and percentage of myelinated axons. Using electron microscopy, we observed decreased myelinated axon number and density in transient and chronic hypothyroid rats at P150, unmyelinated axon number increased slightly in chronic hypothyroid rats. In MMI-treated rats, the myelinated axon g-ratio and conduction velocity was similar to control rats, but with a decrease in conduction delays. These data show that early postnatal transient and chronic hypothyroidism alters AC maturation that may affect the transfer of information through the AC. The alterations cannot be recovered after delayed T4-treatment. Our data support the neurocognitive delay found in late T4 treated children with congenital hypothyroidism. PMID- 29755327 TI - Simultaneity and Temporal Order Judgments Are Coded Differently and Change With Age: An Event-Related Potential Study. AB - Multisensory integration is required for a number of daily living tasks where the inability to accurately identify simultaneity and temporality of multisensory events results in errors in judgment leading to poor decision-making and dangerous behavior. Previously, our lab discovered that older adults exhibited impaired timing of audiovisual events, particularly when making temporal order judgments (TOJs). Simultaneity judgments (SJs), however, were preserved across the lifespan. Here, we investigate the difference between the TOJ and SJ tasks in younger and older adults to assess neural processing differences between these two tasks and across the lifespan. Event-related potentials (ERPs) were studied to determine between-task and between-age differences. Results revealed task specific differences in perceiving simultaneity and temporal order, suggesting that each task may be subserved via different neural mechanisms. Here, auditory N1 and visual P1 ERP amplitudes confirmed that unisensory processing of audiovisual stimuli did not differ between the two tasks within both younger and older groups, indicating that performance differences between tasks arise either from multisensory integration or higher-level decision-making. Compared to younger adults, older adults showed a sustained higher auditory N1 ERP amplitude response across SOAs, suggestive of broader response properties from an extended temporal binding window. Our work provides compelling evidence that different neural mechanisms subserve the SJ and TOJ tasks and that simultaneity and temporal order perception are coded differently and change with age. PMID- 29755329 TI - Assessment of Appetitive Behavior in Honey Bee Dance Followers. AB - Honey bees transfer different informational components of the discovered feeding source to their nestmates during the waggle dance. To decode the multicomponent information of this complex behavior, dance followers have to attend to the most relevant signal elements while filtering out less relevant ones. To achieve that, dance followers should present improved abilities to acquire information compared with those bees not engaged in this behavior. Through proboscis extension response assays, sensory and cognitive abilities were tested in follower and non follower bees. Individuals were captured within the hive, immediately after following waggle runs or a bit further from the dancer. Both behavioral categories present low and similar spontaneous odor responses (SORs). However, followers exhibit differences in responsiveness to sucrose and odor discrimination: followers showed increased gustatory responsiveness and, after olfactory differential conditioning, better memory retention than non-followers. Thus, the abilities of the dance followers related to appetitive behavior would allow them to improve the acquisition of the dance surrounding information. PMID- 29755328 TI - Evidence for a Resting State Network Abnormality in Adults Who Stutter. AB - Neural network-based investigations of stuttering have begun to provide a possible integrative account for the large number of brain-based anomalies associated with stuttering. Here we used resting-state EEG to investigate functional brain networks in adults who stutter (AWS). Participants were 19 AWS and 52 age-, and gender-matched normally fluent speakers. EEGs were recorded and connectivity matrices were generated by LORETA in the theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-20 Hz), and beta2 (20-30 Hz) bands. Small-world propensity (SWP), shortest path, and clustering coefficients were computed for weighted graphs. Minimum spanning tree analysis was also performed and measures were compared by non-parametric permutation test. The results show that small-world topology was evident in the functional networks of all participants. Three graph indices (diameter, clustering coefficient, and shortest path) exhibited significant differences between groups in the theta band and one [maximum betweenness centrality (BC)] measure was significantly different between groups in the beta2 band. AWS show higher BC than control in right temporal and inferior frontal areas and lower BC in the right primary motor cortex. Abnormal functional networks during rest state suggest an anomaly of DMN activity in AWS. Furthermore, functional segregation/integration deficits in the theta network are evident in AWS. These deficits reinforce the hypothesis that there is a neural basis for abnormal executive function in AWS. Increased beta2 BC in the right speech-motor related areas confirms previous evidence that right audio-speech areas are over-activated in AWS. Decreased beta2 BC in the right primary motor cortex is discussed in relation to abnormal neural mechanisms associated with time perception in AWS. PMID- 29755330 TI - The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. AB - Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue. PMID- 29755332 TI - Neurofeedback and the Neural Representation of Self: Lessons From Awake State and Sleep. AB - Neurofeedback has been around for half a century, but despite some promising results it is not yet widely appreciated. Recently, some of the concerns about neurofeedback have been addressed with functional magnetic resonance imaging and magnetoencephalography adding their contributions to the long history of neurofeedback with electroencephalography. Attempts to address other concerns related to methodological issues with new experiments and meta-analysis of earlier studies, have opened up new questions about its efficacy. A key concern about neurofeedback is the missing framework to explain how improvements in very different and apparently unrelated conditions are achieved. Recent advances in neuroscience begin to address this concern. A particularly promising approach is the analysis of resting state of fMRI data, which has revealed robust covariations in brain networks that maintain their integrity in sleep and even anesthesia. Aberrant activity in three brain wide networks (i.e., the default mode, central executive and salience networks) has been associated with a number of psychiatric disorders. Recent publications have also suggested that neurofeedback guides the restoration of "normal" activity in these three networks. Using very recent results from our analysis of whole night MEG sleep data together with key concepts from developmental psychology, cloaked in modern neuroscience terms, a theoretical framework is proposed for a neural representation of the self, located at the core of a double onion-like structure of the default mode network. This framework fits a number of old and recent neuroscientific findings, and unites the way attention and memory operate in awake state and during sleep. In the process, safeguards are uncovered, put in place by evolution, before any interference with the core representation of self can proceed. Within this framework, neurofeedback is seen as set of methods for restoration of aberrant activity in large scale networks. The framework also admits quantitative measures of improvements to be made by personalized neurofeedback protocols. Finally, viewed through the framework developed, neurofeedback's safe nature is revealed while raising some concerns for interventions that attempt to alter the neural self-representation bypassing the safeguards evolution has put in place. PMID- 29755333 TI - Top Mysteries of the Mind: Insights From the Default Space Model of Consciousness. AB - Aside from the nature of consciousness itself, there are still many unsolved problems in the neurosciences. Despite the vast and quickly growing body of work in this field, we still find ourselves perplexed at seemingly simple qualities of our mental being such as why we need to sleep. The neurosciences are at least beginning to take a hold on these mysteries and are working toward solving them. We hold a perspective that metastable consciousness models, specifically the Default Space Model (DSM), provide insights into these mysteries. In this perspective article, we explore some of these curious questions in order to elucidate the interesting points they bring up. The DSM is a dynamic, global theory of consciousness that involves the maintenance of an internal, 3D simulation of the external, physical world which is the foundation and structure of consciousness. This space is created and filled by multiple frequencies of membrane potential oscillations throughout the brain and body which are organized, synchronized and harmonized by the thalamus. The veracity of the DSM is highlighted here in its ability to further understanding of some of the most puzzling problems in neuroscience. PMID- 29755334 TI - Deep Learning Methods to Process fMRI Data and Their Application in the Diagnosis of Cognitive Impairment: A Brief Overview and Our Opinion. PMID- 29755335 TI - Corrigendum: Event- and Time-Driven Techniques Using Parallel CPU-GPU Co processing for Spiking Neural Networks. AB - [This corrects the article on p. 7 in vol. 11, PMID: 28223930.]. PMID- 29755331 TI - Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc. AB - Many psychiatric disorders, despite their specific characteristics, share deficits in the cognitive domain including executive functions, emotional control and memory. However, memory deficits have been in many cases undervalued compared with other characteristics. The expression of Immediate Early Genes (IEGs) such as, c-fos, Egr1 and arc are selectively and promptly upregulated in learning and memory among neuronal subpopulations in regions associated with these processes. Changes in expression in these genes have been observed in recognition, working and fear related memories across the brain. Despite the enormous amount of data supporting changes in their expression during learning and memory and the importance of those cognitive processes in psychiatric conditions, there are very few studies analyzing the direct implication of the IEGs in mental illnesses. In this review, we discuss the role of some of the most relevant IEGs in relation with memory processes affected in psychiatric conditions. PMID- 29755336 TI - A Subject-Specific Kinematic Model to Predict Human Motion in Exoskeleton Assisted Gait. AB - The relative motion between human and exoskeleton is a crucial factor that has remarkable consequences on the efficiency, reliability and safety of human-robot interaction. Unfortunately, its quantitative assessment has been largely overlooked in the literature. Here, we present a methodology that allows predicting the motion of the human joints from the knowledge of the angular motion of the exoskeleton frame. Our method combines a subject-specific skeletal model with a kinematic model of a lower limb exoskeleton (H2, Technaid), imposing specific kinematic constraints between them. To calibrate the model and validate its ability to predict the relative motion in a subject-specific way, we performed experiments on seven healthy subjects during treadmill walking tasks. We demonstrate a prediction accuracy lower than 3.5 degrees globally, and around 1.5 degrees at the hip level, which represent an improvement up to 66% compared to the traditional approach assuming no relative motion between the user and the exoskeleton. PMID- 29755337 TI - Influence of APOE and RNF219 on Behavioral and Cognitive Features of Female Patients Affected by Mild Cognitive Impairment or Alzheimer's Disease. AB - The risk for Alzheimer's disease (AD) is associated with the presence of the ??4 allele of Apolipoprotein E (APOE) gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-??4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-??4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients. PMID- 29755339 TI - Therapeutic Potential of a Prolyl Hydroxylase Inhibitor FG-4592 for Parkinson's Diseases in Vitro and in Vivo: Regulation of Redox Biology and Mitochondrial Function. AB - As the main transcription factor that regulates the cellular responses to hypoxia, Hypoxia-inducible factor-1alpha (HIF-1alpha) plays an important role in the pathogenesis of Parkinson's disease (PD). HIF-1alpha is normally degraded through ubiquitination after hydroxylation by prolyl hydroxylases (PHD). Emerging evidence has suggested that HIF PHD inhibitors (HIF-PHI) may have neuroprotective effects on PD through increasing HIF-1alpha levels. However, the therapeutic benefit of HIF-PHI for PD remains poorly explored due to the lack of proper clinical compounds and understanding of the underlying molecular mechanisms. In this study, we examined the therapeutic benefit of a new HIF-PHI, FG-4592, which is currently in phase 3 clinical trials to treat anemia in patients with chronic kidney diseases (CKD) in PD models. FG-4592 attenuates MPP+ -induced apoptosis and loss of tyrosine hydroxylase (TH) in SH-SY5Y cells. Pretreatment with FG-4592 mitigates MPP+-induced loss of mitochondrial membrane potential (MMP), mitochondrial oxygen consumption rate (OCR), production of reactive oxygen species (ROS) and ATP. Furthermore, FG-4592 counterbalances the oxidative stress through up-regulating nuclear factor erythroid 2 p45-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and superoxide dismutase 2 (SOD2). FG-4592 treatment also induces the expression of Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) through increasing the phosphorylation of AMP activated protein kinase (AMPK). In MPTP-treated mice, FG-4592 protects against MPTP-induced loss of TH-positive neurons of substantia nigra and attenuates behavioral impairments. Collectively, our study demonstrates that FG-4592 is a promising therapeutic strategy for PD through improving the mitochondrial function under oxidative stress. PMID- 29755340 TI - Glutamate Transporter GLT1 Expression in Alzheimer Disease and Dementia With Lewy Bodies. AB - Glutamate transporter solute carrier family 1, member 2 (GLT1/EAAT2), a major modulator of glutamate homeostasis in astrocytes, is assessed in post-mortem human brain samples of frontal cortex area 8 in advanced stages of Alzheimer disease (AD) and terminal stages of dementia with Lewy bodies (DLB) in order to gain understanding of astrogliopathy in diseases manifested by dementia. Glial fibrillary acidic protein (GFAP) mRNA expression is significantly increased in AD but not in DLB, whereas GLT1, vesicular glutamate transporter 1 (vGLUT1) and aldehyde dehydrogenase 1 family member 1 (ALDH1L1) are not modified in AD and DLB when compared with controls. GLT1 protein levels are not altered in AD and DLB but GFAP and ALDH1L1 are significantly increased in AD, and GFAP in DLB. As a result, a non-significant decrease in the ratio between GLT1 and GFAP, and between GLT1 and ALDH1L1, is found in both AD and DLB. Double-labeling immunofluorescence and confocal microscopy revealed no visible reduction of GLT1 immunoreactivity in relation to beta-amyloid plaques in AD. These data suggest a subtle imbalance between GLT1, and GFAP and ALDH1L1 expression, with limited consequences in glutamate transport. PMID- 29755338 TI - A Review of the Pedunculopontine Nucleus in Parkinson's Disease. AB - The pedunculopontine nucleus (PPN) is situated in the upper pons in the dorsolateral portion of the ponto-mesencephalic tegmentum. Its main mass is positioned at the trochlear nucleus level, and is part of the mesenphalic locomotor region (MLR) in the upper brainstem. The human PPN is divided into two subnuclei, the pars compacta (PPNc) and pars dissipatus (PPNd), and constitutes both cholinergic and non-cholinergic neurons with afferent and efferent projections to the cerebral cortex, thalamus, basal ganglia (BG), cerebellum, and spinal cord. The BG controls locomotion and posture via GABAergic output of the substantia nigra pars reticulate (SNr). In PD patients, GABAergic BG output levels are abnormally increased, and gait disturbances are produced via abnormal increases in SNr-induced inhibition of the MLR. Since the PPN is vastly connected with the BG and the brainstem, dysfunction within these systems lead to advanced symptomatic progression in Parkinson's disease (PD), including sleep and cognitive issues. To date, the best treatment is to perform deep brain stimulation (DBS) on PD patients as outcomes have shown positive effects in ameliorating the debilitating symptoms of this disease by treating pathological circuitries within the parkinsonian brain. It is therefore important to address the challenges and develop this procedure to improve the quality of life of PD patients. PMID- 29755341 TI - Plasma Biomarkers Differentiate Parkinson's Disease From Atypical Parkinsonism Syndromes. AB - Objective: Parkinson's disease (PD) has significant clinical overlaps with atypical parkinsonism syndromes (APS), which have a poorer treatment response and a more aggressive course than PD. We aimed to identify plasma biomarkers to differentiate PD from APS. Methods: Plasma samples (n = 204) were obtained from healthy controls and from patients with PD, dementia with Lewy bodies (DLB), multiple system atrophy, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), or frontotemporal dementia (FTD) with parkinsonism (FTD-P) or without parkinsonism. We measured plasma levels of alpha-synuclein, total tau, p Tau181, and amyloid beta 42 (Abeta42) by immunomagnetic reduction-based immunoassay. Results: Plasma alpha-synuclein level was significantly increased in patients with PD and APS when compared with controls and FTD without parkinsonism (p < 0.01). Total tau and p-Tau181 were significantly increased in all disease groups compared to controls, especially in patients with FTD (p < 0.01). A multivariate and receiver operating characteristic curve analysis revealed that a cut-off value for Abeta42 multiplied by p-Tau181 for discriminating patients with FTD from patients with PD and APS was 92.66 (pg/ml)2, with an area under the curve (AUC) of 0.932. An alpha-synuclein cut-off of 0.1977 pg/ml could separate FTD-P from FTD without parkinsonism (AUC 0.947). In patients with predominant parkinsonism, an alpha-synuclein cut-off of 1.388 pg/ml differentiated patients with PD from those with APS (AUC 0.87). Conclusion: Our results suggest that integrated plasma biomarkers improve the differential diagnosis of PD from APS (PSP, CBD, DLB, and FTD-P). PMID- 29755342 TI - Mitochondria, Estrogen and Female Brain Aging. AB - Mitochondria play an essential role in the generation of steroid hormones including the female sex hormones. These hormones are, in turn, able to modulate mitochondrial activities. Mitochondria possess crucial roles in cell maintenance, survival and well-being, because they are the main source of energy as well as of reactive oxygen species (ROS) within the cell. The impairment of these important organelles is one of the central features of aging. In women's health, estrogen plays an important role during adulthood not only in the estrous cycle, but also in the brain via neuroprotective, neurotrophic and antioxidant modes of action. The hypestrogenic state in the peri- as well as in the prolonged postmenopause might increase the vulnerability of elderly women to brain degeneration and age related pathologies. However, the underlying mechanisms that affect these processes are not well elucidated. Understanding the relationship between estrogen and mitochondria might therefore provide better insights into the female aging process. Thus, in this review, we first describe mitochondrial dysfunction in the aging brain. Second, we discuss the estrogen-dependent actions on the mitochondrial activity, including recent evidence of the estrogen-brain-derived neurotrophic factor and estrogen-sirtuin 3 (SIRT3) pathways, as well as their potential implications during female aging. PMID- 29755343 TI - Bilirubin Oxidation Products and Cerebral Vasoconstriction. AB - Key evidence in support of the hypothesis that bilirubin oxidation products (BOXes) contribute to the vasoconstriction associated with subarachnoid hemorrhage (SAH) are the (1) presence of BOXes in cerebral spinal fluid from SAH patients and (2) ability of one or more BOXes to elicit vasoconstriction. We critically evaluate this key evidence, detail where gaps remain, and describe recent approaches that will address these gaps. PMID- 29755345 TI - Analogous beta-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice. AB - The analogous beta-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer's disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor alpha, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), gamma-aminobutyric acid (gamma-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases. PMID- 29755346 TI - A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Effects of Loki zupa in Patients With Chronic Asthma. AB - The purpose of this study was to evaluate the efficacy and safety of Uyghur medical formula Loki zupa in patients with chronic asthma. Adult patients with chronic asthma randomly received placebo or Loki zupa as add-on to inhaled corticosteroids (ICS) maintenance treatment. Loki zupa or mimics was administered orally 10 ml per time, three times a day for 8 weeks. The primary endpoints were asthma control test (ACT) score and peak expiratory flow (PEF). The secondary endpoints were acute exacerbation rate, lung function, night waking days, and symptom-free days in the near 2 weeks, Asthma Quality of Life Questionnaire (AQLQ) score and some inflammatory cytokines in peripheral blood. A total of 240 adult patients with chronic asthma were enrolled, and 218 patients were randomized to placebo (n = 109) or Loki zupa (n = 109) in addition to ICS for 8 weeks. Treatment with Loki zupa resulted in significant improvement in ACT score compared to the placebo group (p = 0.002). Furthermore, oral taken of Loki zupa increased the PEF obviously (p = 0.026). Loki zupa treatment did not improve the forced expiratory volume in 1 s (FEV1, p = 0.131) and FEV1/FVC compared to the placebo treatment (p = 0.805). The placebo group had higher rates of acute exacerbations than the Loki zupa group (6.3% vs. 0, p = 0.027). Subjects randomized to Loki zupa had increased daytime symptom-free days within 2 weeks than placebo (p = 0.016). However, Loki zupa had no effect on night waking days in the near 2 weeks (p = 0.369) and AQLQ score (p = 0.113). No significant effect was found on inflammatory cytokines (IL-2, IL-4, IL-5, IL-10, IL-13, IL-17, IL 33, IFN-gamma, and TGF-beta) between the two groups (p > 0.05). No adverse events and severe asthma exacerbations were recorded in the two groups (p > 0.05). Loki zupa add-on to standard ICS produced clinically significant improvements in ACT score, PEF, daytime symptom-free days and acute exacerbation in patients with chronic asthma. Clinical trial: This study is registered at http://www.chictr.org.cn/ with identifier number ChiCTR-IPR-16008106. PMID- 29755344 TI - Endophytic Fungi-Alternative Sources of Cytotoxic Compounds: A Review. AB - Cancer is a major cause of death worldwide, with an increasing number of cases being reported annually. The elevated rate of mortality necessitates a global challenge to explore newer sources of anticancer drugs. Recent advancements in cancer treatment involve the discovery and development of new and improved chemotherapeutics derived from natural or synthetic sources. Natural sources offer the potential of finding new structural classes with unique bioactivities for cancer therapy. Endophytic fungi represent a rich source of bioactive metabolites that can be manipulated to produce desirable novel analogs for chemotherapy. This review offers a current and integrative account of clinically used anticancer drugs such as taxol, podophyllotoxin, camptothecin, and vinca alkaloids in terms of their mechanism of action, isolation from endophytic fungi and their characterization, yield obtained, and fungal strain improvement strategies. It also covers recent literature on endophytic fungal metabolites from terrestrial, mangrove, and marine sources as potential anticancer agents and emphasizes the findings for cytotoxic bioactive compounds tested against specific cancer cell lines. PMID- 29755347 TI - Honokiol, a Polyphenol Natural Compound, Attenuates Cisplatin-Induced Acute Cytotoxicity in Renal Epithelial Cells Through Cellular Oxidative Stress and Cytoskeleton Modulations. AB - Cisplatin is a potent anti-cancer drug that has been widely used in the treatment of various cancers; however, cisplatin administration results in severe nephrotoxicity and impedes its clinical applications. In this study, we showed that honokiol, a polyphenol constituent extracted from Magnolia officinalis exhibited a short-term protective effect against cisplatin-induced damages in renal epithelial cells in vitro. The protective effects of honokiol were resulted from the combination of (1) reduced cellular oxidative stress ranging from 53 to 32% reduction during a 24-h incubation, (2) the maintenance of cellular antioxidant capacity and (3) the stabilization of cytoskeletal structure of the kidney epithelial cells. By promoting the polymerization of actin (1.6-fold increase) and tubulin (1.8-fold increase) cytoskeleton, honokiol not only maintained epithelial cell morphology, but also stabilized cellular localizations of tight junction protein Occludin and adhesion junction protein E-Cadherin. With stabilized junction protein complexes and structural polymerized cytoskeleton network, honokiol preserved epithelial cell polarity and morphology and thus reduced cisplatin-induced cell disruption and damages. Our data demonstrated for the first time that honokiol could counteract with cisplatin-induced damages in renal epithelial cells in vitro, future in vivo studies would further validate the potential clinical application of honokiol in cisplatin-based cancer treatments with reduced nephrotoxicity. PMID- 29755348 TI - The Fibrin Cleavage Product Bbeta15-42 Channels Endothelial and Tubular Regeneration in the Post-acute Course During Murine Renal Ischemia Reperfusion Injury. AB - Early and adequate restoration of endothelial and tubular renal function is a substantial step during regeneration after ischemia reperfusion (IR) injury, occurring, e.g., in kidney transplantation, renal surgery, and sepsis. While tubular epithelial cell injury has long been of central importance, recent perception includes the renal vascular endothelium. In this regard, the fibrin cleavage product fibrinopeptide Bbeta15-42 mitigate IR injury by stabilizing interendothelial junctions through its affinity to VE-cadherin. Therefore, this study focused on the effect of Bbeta15-42 on post-acute physiological renal regeneration. For this, adult male C57BL/6 mice were exposed to a 30 min bilateral renal ischemia and reperfusion for 24 h or 48 h. Animals were randomized in a non-operative control group, two operative groups each treated with i.v. administration of either saline or Bbeta15-42 (2.4 mg/kg) immediately prior to reperfusion. Endothelial activation and inflammatory response was attenuated in renal tissue homogenates by single application of Bbeta15-42. Meanwhile, Bbeta15-42 did not affect acute kidney injury markers. Regarding the angiogenetic players VEGF-A, Angiopoietin-1, Angiopoietin-2, however, we observed significant higher expressions at mRNA and trend to higher protein level in Bbeta15-42 treated mice, compared to saline treated mice after 48 h of IR, thus pointing toward an increased angiogenetic activity. Similar dynamics were observed for the intermediate filament vimentin, the cytoprotective protein klotho, stathmin and the proliferation cellular nuclear antigen, which were significantly up-regulated at the same points in time. These results suggest a beneficial effect of anatomical contiguously located endothelial cells on tubular regeneration through stabilization of endothelial integrity. Therefore, it seems that Bbeta15-42 represents a novel pharmacological approach in the targeted therapy of acute renal failure in everyday clinical practice. PMID- 29755349 TI - Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile. AB - Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects. PMID- 29755350 TI - Extracts From Hypericum hircinum subsp. majus Exert Antifungal Activity Against a Panel of Sensitive and Drug-Resistant Clinical Strains. AB - During the last two decades incidences of fungal infections dramatically increased and the often accompanying failure of available antifungal therapies represents a substantial clinical problem. The urgent need for novel antimycotics called particular attention to the study of natural products. The genus Hypericum includes many species that are used in the traditional medicine to treat pathological states like inflammations and infections caused by fungi. However, despite the diffused use of Hypericum-based products the antifungal potential of the genus is still poorly investigated. In this study five Hypericum species autochthonous of Central and Eastern Europe were evaluated regarding their polyphenolic content, their toxicological safety and their antifungal potential against a broad panel of clinical fungal isolates. LC-MS analysis led to the identification and quantification of 52 compounds, revealing that Hypericum extracts are rich sources of flavonols, benzoates and cinnamates, and of flavan-3 ols. An in-depth screen of the biological activity of crude extracts clearly unveiled H. hircinum subsp. majus as a promising candidate species for the search of novel antifungals. H. hircinum is diffused in the Mediterranean basin from Spain to Turkey where it is traditionally used to prepare a herbal tea indicated for the treatment of respiratory tract disorders, several of which are caused by fungi. Noteworthy, the infusion of H. hircinum subsp. majus excreted broad antifungal activity against Penicillium, Aspergillus and non-albicans Candida isolates comprising strains both sensitive and resistant to fluconazole. Additionally, it showed no cytotoxicity on human cells and the chemical characterization of the H. hircinum subsp. majus infusion revealed high amounts of the metabolite hyperoside. These results scientifically support the traditional use of H. hircinum extracts for the treatment of respiratory tract infections and suggest the presence of exploitable antifungal principles for further investigations aimed at developing novel antifungal therapies. PMID- 29755351 TI - Gastrodin Attenuates Bilateral Common Carotid Artery Occlusion-Induced Cognitive Deficits via Regulating Abeta-Related Proteins and Reducing Autophagy and Apoptosis in Rats. AB - Gastrodin (GAS), an active constituent extracted from Gastrodia elata Blume, is used to treat ischemic stroke, epilepsy, dizziness, and dementia for centuries in China. This study examined its effects on vascular dementia (VD) and the underlying molecular mechanisms. VD was established by ligation of bilateral common carotid artery occlusion (BCCAO). A total of 7 days after BCCAO surgery, GAS (15, 30, and 60 mg/kg) was orally administered for 28 consecutive days to evaluate therapeutic effects. Cognitive function was tested by the Morris water maze. The neuronal morphological changes were examined via Hematoxylin-Eosin staining. Flow cytometry was used for evaluating apoptosis in the hippocampi. The target protein expression was examined by Western blot. The results showed that BCCAO induced cognitive impairment, hippocampus CA1 and CA3 pyramidal neuron damage, beta-amyloid (Abeta) deposition, excessive autophagy, and apoptosis. GAS treatment significantly improved BCCAO-induced cognitive deficits and hippocampus neuron damage. Molecular analysis revealed that GAS exerted the protective effect via reducing the levels of Abeta1-40/42, APP, and beta-site APP-cleaving enzyme 1 expression, and increasing Abeta-related protein, a disintegrin and metalloprotease 10, and insulin degrading enzyme expression. Meanwhile, GAS inhibited excessive autophagy via decreasing Beclin-1, LC3-II, and p62 levels. Furthermore, GAS inhibited apoptosis through the downregulation of Bax and upregulation of Bcl-2. Moreover, P38 MAPK signaling pathway was involved in the process. Our findings demonstrate that GAS was effective in the treatment of BCCAO-induced VD via targeting Abeta-related protein formation and inhibiting autophagy and apoptosis of hippocampus neurons. PMID- 29755352 TI - The Problem of Benzodiazepine Use and Its Extent in the Driver Population: A Population-Based Registry Study. AB - Background: Benzodiazepines are driving-impairing medicines (DIM). This study presents current consumption of dispensed benzodiazepines in the Spanish general population, with a focus in pattern of use and concomitant medicines consumed with. Methods: A population-based registry study was carried out to assess the year-2016 granted benzodiazepines dispensation in Castile and Leon. Weighting was performed to obtain the adjusted benzodiazepine consumption for licensed drivers according to age and gender using our national drivers' license census data. Results: Benzodiazepines were used by 15.38% of the general population and 10.97% of drivers. Nearly 2% of the population and more than 1% of drivers took these medicines every day. The amount consumed (until 3 or more benzodiazepines per day) and concomitant use of other DIM were also higher. Women were the most frequent consumers, and anxiolytic use was usual. Consumption increases with age, but there were differences between men and women drivers from 60 years old. Conclusions: The current use of benzodiazepines must serve to awareness of the healthcare personnel, patients, and authorities on their risks, above all on the road safety. PMID- 29755353 TI - Importance of Toxicokinetics to Assess the Utility of Zebrafish Larvae as Model for Psychoactive Drug Screening Using Meta-Chlorophenylpiperazine (mCPP) as Example. AB - The number of new psychoactive substances (NPS) increases rapidly, harming society and fuelling the need for alternative testing strategies. These should allow the ever-increasing number of drugs to be tested more effectively for their toxicity and psychoactive effects. One proposed strategy is to complement rodent models with zebrafish (Danio rerio) larvae. Yet, our understanding of the toxicokinetics in this model, owing to the waterborne drug exposure and the distinct physiology of the fish, is incomplete. We here explore the toxicokinetics and behavioral effects of an NPS, meta-chlorophenylpiperazine (mCPP), in zebrafish larvae. Uptake kinetics of mCPP, supported by toxicokinetic modeling, strongly suggested the existence of active transport processes. Internal distribution showed a dominant accumulation in the eye, implying that in zebrafish, like in mammals, melanin could serve as a binding site for basic drugs. We confirmed this by demonstrating significantly lower drug accumulation in two types of hypo-pigmented fish. Comparison of the elimination kinetics between mCPP and previously characterized cocaine demonstrated that drug affinities to melanin in zebrafish vary depending on the structure of the test compound. As expected from mCPP-elicited responses in rodents and humans, zebrafish larvae displayed hypoactive behavior. However, significant differences were seen between zebrafish and rodents with regard to the concentration dependency of the behavioral response and the comparability of tissue levels, corroborating the need to consider the organism-internal distribution of the chemical to allow appropriate dose modeling while evaluating effects and concordance between zebrafish and mammals. Our results highlight commonalities and differences of mammalian versus the fish model in need of further exploration. PMID- 29755354 TI - Genome Analysis of Multidrug-Resistant Shewanella algae Isolated From Human Soft Tissue Sample. PMID- 29755355 TI - Bio-Inspired Protein-Based Nanoformulations for Cancer Theranostics. AB - Over the past decade, more interests have been aroused in engineering protein based nanoformulations for cancer treatment. This excitement originates from the success of FDA approved Abraxane (Albumin-based paclitaxel nanoparticles) in 2005. The new generation of biocompatible endogenous protein-based nanoformulations is currently constructed through delivering cancer therapeutic and diagnostic agents simultaneously, as named potential theranostics. Protein nanoformulations are commonly incorporated with dyes, contrast agents, drug payloads or inorganic nanoclusters, serving as imaging-guided combinatorial cancer therapeutics. Employing the nature identity of proteins, the theranostics, escape the clearance by reticuloendothelial cells and have a long blood circulation time. The nanoscale sizet allows them to be penetrated deeply into tumor tissues. In addition, stimuli release and targeted molecules are incorporated to improve the delivery efficiency. The ongoing advancement of protein-based nanoformulations for cancer theranostics in recent 5 years is reviewed in this paper. Fine-designed nanoformulations based on albumin, ferritin, gelatin, and transferrin are highlighted from the literature. Finally, the current challenges are identified in translating protein-based nanoformulations from laboratory to clinical trials. PMID- 29755356 TI - Anti-Parkinson Potential of Silymarin: Mechanistic Insight and Therapeutic Standing. AB - Parkinson's disease (PD) involves aggregation of alpha-synuclein and progressive loss of dopaminergic neurons. Pathogenesis of PD may also be related to one's genetic background. PD is most common among geriatric population and approximately 1-2% of population suffers over age 65 years. Currently no successful therapies are in practice for the management of PD and available therapies tend to decrease the symptoms of PD only. Furthermore, these are associated with diverse range of adverse effects profile. The neuroprotective effects of polyphenols are widely studied and documented. Among phytochemicals, silymarin is one of the most widely used flavonoids because of its extensive therapeutic properties and has been indicated in pathological conditions of prostate, CNS, lungs, skin, liver, and pancreas. Silymarin is a mixture of flavonolignans (silybin, isosilybin, and silychristin), small amount of flavonoids (taxifolin), fatty acids, and other polyphenolic compounds extracted from the dried fruit of Silybum marianum and is clinically used for hepatoprotective effects since ancient times. Neuroprotective effects of silymarin have been studied in various models of neurological disorders such as Alzheimer's disease, PD, and cerebral ischemia. The aim of the present study is to provide a comprehensive review of the recent literature exploring the effects of silymarin administration on the progression of PD. Reducing oxidative stress, inflammatory cytokines, altering cellular apoptosis machinery, and estrogen receptor machinery are mechanisms that are responsible for neuroprotection by silymarin, as discussed in this review. Additionally, because of poor aqueous solubility, the bioavailability of silymarin is low and only 23-47% of silymarin reaches systemic circulation after oral administration. Our primary focus is on the chemical basis of the pharmacology of silymarin in the treatment of PD and its mechanisms and possible therapeutic/clinical status while addressing the bioavailability limitation. PMID- 29755357 TI - N-Glycosylation of Lipocalin 2 Is Not Required for Secretion or Exosome Targeting. AB - Lipocalin 2 (LCN2) is a highly conserved secreted adipokine acting as a serum transport protein for small hydrophobic molecules such as fatty acids and steroids. In addition, LCN2 limits bacterial growth by sequestering iron containing siderophores and further protects against intestinal inflammation and tumorigenesis associated with alterations in the microbiota. Human LCN2 contains one N-glycosylation site conserved in other species. It was postulated that this post-translational modification could facilitate protein folding, protects from proteolysis, is required for proper trafficking from the Golgi apparatus to the cell surface, and might be relevant for effective secretion. We here show that the homologous nucleoside antibiotic tunicamycin blocks N-linked glycosylation but not secretion of LCN2 in primary murine hepatocytes, derivatives thereof, human lung carcinoma cell line A549, and human prostate cancer cell line PC-3. Moreover, both the glycosylated and the non-glycosylated LCN2 variants are equally targeted to exosomes, demonstrating that this post-translational modification is not necessary for proper trafficking of LCN2 into these membranous extracellular vesicles. Furthermore, a hydrophobic cluster analysis revealed that the N-glycosylation site is embedded in a highly hydrophobic evolutionarily conserved surrounding. In sum, our data indicate that the N glycosylation of LCN2 is not required for proper secretion and exosome cargo recruitment in different cell types, but might be relevant to increase overall solubility. PMID- 29755359 TI - Commentary: Trunk Muscle Activity during Drop Jump Performance in Adolescent Athletes with Back Pain. PMID- 29755358 TI - Therapeutic Angiogenesis of Chinese Herbal Medicines in Ischemic Heart Disease: A Review. AB - Ischemic heart disease (IHD) is one of the primary causes of death around the world. Therapeutic angiogenesis is a promising innovative approach for treating IHD, improving cardiac function by promoting blood perfusion to the ischemic myocardium. This treatment is especially important for targeting patients that are unable to undergo angioplasty or bypass surgery. Chinese herbal medicines have been used for more than 2,500 years and they play an important role alongside contemporary medicines in China. Growing evidence in animal models show Chinese herbal medicines can provide therapeutic effect on IHD by targeting angiogenesis. Identifying the mechanism in which Chinese herbal medicines can promote angiogenesis in IHD is a major topic in the field of traditional Chinese medicine, and has the potential for advancing therapeutic treatment. This review summarizes the progression of research and highlights potential pro-angiogenic mechanisms of Chinese herbal medicines in IHD. In addition, an outline of the limitations of Chinese herbal medicines and challenges they face will be presented. PMID- 29755360 TI - Healthy Lung Vessel Morphology Derived From Thoracic Computed Tomography. AB - Knowledge of the lung vessel morphology in healthy subjects is necessary to improve our understanding about the functional network of the lung and to recognize pathologic deviations beyond the normal inter-subject variation. Established values of normal lung morphology have been derived from necropsy material of only very few subjects. In order to determine morphologic readouts from a large number of healthy subjects, computed tomography pulmonary angiography (CTPA) datasets, negative for pulmonary embolism, and other thoracic pathologies, were analyzed using a fully-automatic, in-house developed artery/vein separation algorithm. The number, volume, and tortuosity of the vessels in a diameter range between 2 and 10 mm were determined. Visual inspection of all datasets was used to exclude subjects with poor image quality or inadequate artery/vein separation from the analysis. Validation of the algorithm was performed manually by a radiologist on randomly selected subjects. In 123 subjects (men/women: 55/68), aged 59 +/- 17 years, the median overlap between visual inspection and fully-automatic segmentation was 94.6% (69.2 99.9%). The median number of vessel segments in the ranges of 8-10, 6-8, 4-6, and 2-4 mm diameter was 9, 34, 134, and 797, respectively. Number of vessel segments divided by the subject's lung volume was 206 vessels/L with arteries and veins contributing almost equally. In women this vessel density was about 15% higher than in men. Median arterial and venous volumes were 1.52 and 1.54% of the lung volume, respectively. Tortuosity was best described with the sum-of-angles metric and was 142.1 rad/m (138.3-144.5 rad/m). In conclusion, our fully-automatic artery/vein separation algorithm provided reliable measures of pulmonary arteries and veins with respect to age and gender. There was a large variation between subjects in all readouts. No relevant dependence on age, gender, or vessel type was observed. These data may provide reference values for morphometric analysis of lung vessels. PMID- 29755361 TI - The Contribution of Different Components in QiShenYiQi Pills(r) to Its Potential to Modulate Energy Metabolism in Protection of Ischemic Myocardial Injury. AB - Ischemic heart diseases remain a challenge for clinicians. QiShenYiQi pills(r) (QSYQ) has been reported to be curative during coronary heart diseases with modulation of energy metabolism as one of the underlying mechanisms. In this study, we detected the effect of QSYQ and its components on rat myocardial structure, mitochondrial respiratory chain complexes activity and energy metabolism, and heart function after 30 min of cardiac ischemia, with focusing on the contribution of each component to its potential to regulate energy metabolism. Results showed that treatment with QSYQ and all its five components protected myocardial structure from damage by ischemia. QSYQ also attenuated release of myocardial cTnI, and restored the production of ATP after cardiac ischemia. AS-IV and Rb1, but not Rg1, R1, and DLA, had similar effect as QSYQ in regulation of energy metabolism. These results indicate that QSYQ may prevent ischemia-induced cardiac injury via regulation of energy metabolism, to which each of its components contributes differently. PMID- 29755362 TI - The Interplay of Rogue and Clustered Ryanodine Receptors Regulates Ca2+ Waves in Cardiac Myocytes. AB - Ca2+ waves in cardiac myocytes can lead to arrhythmias owing to delayed after depolarisations. Based on Ca2+ regulation from the junctional sarcoplasmic reticulum (JSR), a mathematical model was developed to investigate the interplay of clustered and rogue RyRs on Ca2+ waves. The model successfully reproduces Ca2+ waves in cardiac myocytes, which are in agreement with experimental results. A new wave propagation mode of "spark-diffusion-quark-spark" is put forward. It is found that rogue RyRs greatly increase the initiation of Ca2+ sparks, further contribute to the formation and propagation of Ca2+ waves when the free Ca2+ concentration in JSR lumen ([Ca2+]lumen) is higher than a threshold value of 0.7 mM. Computational results show an exponential increase in the velocity of Ca2+ waves with [Ca2+]lumen. In addition, more CRUs of rogue RyRs and Ca2+ release from rogue RyRs result in higher velocity and amplitude of Ca2+ waves. Distance between CRUs significantly affects the velocity of Ca2+ waves, but not the amplitude. This work could improve understanding the mechanism of Ca2+ waves in cardiac myocytes. PMID- 29755363 TI - An Evidence-Based Approach for Choosing Post-exercise Recovery Techniques to Reduce Markers of Muscle Damage, Soreness, Fatigue, and Inflammation: A Systematic Review With Meta-Analysis. AB - Introduction: The aim of the present work was to perform a meta-analysis evaluating the impact of recovery techniques on delayed onset muscle soreness (DOMS), perceived fatigue, muscle damage, and inflammatory markers after physical exercise. Method: Three databases including PubMed, Embase, and Web-of-Science were searched using the following terms: ("recovery" or "active recovery" or "cooling" or "massage" or "compression garment" or "electrostimulation" or "stretching" or "immersion" or "cryotherapy") and ("DOMS" or "perceived fatigue" or "CK" or "CRP" or "IL-6") and ("after exercise" or "post-exercise") for randomized controlled trials, crossover trials, and repeated-measure studies. Overall, 99 studies were included. Results: Active recovery, massage, compression garments, immersion, contrast water therapy, and cryotherapy induced a small to large decrease (-2.26 < g < -0.40) in the magnitude of DOMS, while there was no change for the other methods. Massage was found to be the most powerful technique for recovering from DOMS and fatigue. In terms of muscle damage and inflammatory markers, we observed an overall moderate decrease in creatine kinase [SMD (95% CI) = -0.37 (-0.58 to -0.16), I2 = 40.15%] and overall small decreases in interleukin-6 [SMD (95% CI) = -0.36 (-0.60 to -0.12), I2 = 0%] and C-reactive protein [SMD (95% CI) = -0.38 (-0.59 to-0.14), I2 = 39%]. The most powerful techniques for reducing inflammation were massage and cold exposure. Conclusion: Massage seems to be the most effective method for reducing DOMS and perceived fatigue. Perceived fatigue can be effectively managed using compression techniques, such as compression garments, massage, or water immersion. PMID- 29755364 TI - Early Effects of a Low Fat, Fructose-Rich Diet on Liver Metabolism, Insulin Signaling, and Oxidative Stress in Young and Adult Rats. AB - The increase in the use of refined food, which is rich in fructose, is of particular concern in children and adolescents, since the total caloric intake and the prevalence of metabolic syndrome are increasing continuously in these populations. Nevertheless, the effects of high fructose diet have been mostly investigated in adults, by focusing on the effect of a long-term fructose intake. Notably, some reports evidenced that even short-term fructose intake exerts detrimental effects on metabolism. Therefore, the aim of this study was to compare the metabolic changes induced by the fructose-rich diet in rats of different age, i.e., young (30 days old) and adult (90 days old) rats. The fructose-rich diet increased whole body lipid content in adult, but not in young rats. The analysis of liver markers of inflammation suggests that different mechanisms depending on the age might be activated after the fructose-rich diet. In fact, a pro-inflammatory gene-expression analysis showed just a minor activation of macrophages in young rats compared to adult rats, while other markers of low-grade metabolic inflammation (TNF-alpha, myeloperoxidase, lipocalin, haptoglobin) significantly increased. Inflammation was associated with oxidative damage to hepatic lipids in young and adult rats, while increased levels of hepatic nitrotyrosine and ceramides were detected only in young rats. Interestingly, fructose-induced hepatic insulin resistance was evident in young but not in adult rats, while whole body insulin sensitivity decreased both in fructose-fed young and adult rats. Taken together, the present data indicate that young rats do not increase their body lipids but are exposed to metabolic perturbations, such as hepatic insulin resistance and hepatic oxidative stress, in line with the finding that increased fructose intake may be an important predictor of metabolic risk in young people, independently of weight status. These results indicate the need of corrective nutritional interventions for young people and adults as well for the prevention of fructose-induced metabolic alterations. PMID- 29755365 TI - The Relation Between Capillary Transit Times and Hemoglobin Saturation Heterogeneity. Part 1: Theoretical Models. AB - Capillary dysfunction impairs oxygen supply to parenchymal cells and often occurs in Alzheimer's disease, diabetes and aging. Disturbed capillary flow patterns have been shown to limit the efficacy of oxygen extraction and can be quantified using capillary transit time heterogeneity (CTH). However, the transit time of red blood cells (RBCs) through the microvasculature is not a direct measure of their capacity for oxygen delivery. Here we examine the relation between CTH and capillary outflow saturation heterogeneity (COSH), which is the heterogeneity of blood oxygen content at the venous end of capillaries. Models for the evolution of hemoglobin saturation heterogeneity (HSH) in capillary networks were developed and validated using a computational model with moving RBCs. Two representative situations were selected: a Krogh cylinder geometry with heterogeneous hemoglobin saturation (HS) at the inflow, and a parallel array of four capillaries. The heterogeneity of HS after converging capillary bifurcations was found to exponentially decrease with a time scale of 0.15-0.21 s due to diffusive interaction between RBCs. Similarly, the HS difference between parallel capillaries also drops exponentially with a time scale of 0.12-0.19 s. These decay times are substantially smaller than measured RBC transit times and only weakly depend on the distance between microvessels. This work shows that diffusive interaction strongly reduces COSH on a small spatial scale. Therefore, we conclude that CTH influences COSH yet does not determine it. The second part of this study will focus on simulations in microvascular networks from the rodent cerebral cortex. Actual estimates of COSH and CTH will then be given. PMID- 29755366 TI - Normal Values of Corrected Heart-Rate Variability in 10-Second Electrocardiograms for All Ages. AB - Purpose: Heart-rate variability (HRV) measured on standard 10-s electrocardiograms (ECGs) has been associated with increased risk of cardiac and all-cause mortality, but age- and sex-dependent normal values have not been established. Since heart rate strongly affects HRV, its effect should be taken into account. We determined a comprehensive set of normal values of heart-rate corrected HRV derived from 10-s ECGs for both children and adults, covering both sexes. Methods: Five population studies in the Netherlands (Pediatric Normal ECG Study, Leiden University Einthoven Science Project, Prevention of Renal and Vascular End-stage Disease Study, Utrecht Health Project, Rotterdam Study) provided 10-s, 12-lead ECGs. ECGs were stored digitally and analyzed by well validated analysis software. We included cardiologically healthy participants, 42% being men. Their ages ranged from 11 days to 91 years. After quality control, 13,943 ECGs were available. Heart-rate correction formulas were derived using an exponential model. Two time-domain HRV markers were analyzed: the corrected standard deviation of the normal-to-normal RR intervals (SDNNc) and corrected root mean square of successive RR-interval differences (RMSSDc). Results: There was a considerable age effect. For both SDNNc and RMSSDc, the median and the lower limit of normal decreased steadily from birth until old age. The upper limit of normal decreased until the age of 60, but increased markedly after that age. Differences of the median were minimal between men and women. Conclusion: We report the first comprehensive set of normal values for heart-rate corrected 10-s HRV, which can be of value in clinical practice and in further research. PMID- 29755367 TI - The Transcription Factor Hif-1 Enhances the Radio-Resistance of Mouse MSCs. AB - Mesenchymal stromal cells (MSCs) are multipotent progenitors supporting bone marrow hematopoiesis. MSCs have an efficient DNA damage response (DDR) and are consequently relatively radio-resistant cells. Therefore, MSCs are key to hematopoietic reconstitution following total body irradiation (TBI) and bone marrow transplantation (BMT). The bone marrow niche is hypoxic and via the heterodimeric transcription factor Hypoxia-inducible factor-1 (Hif-1), hypoxia enhances the DDR. Using gene knock-down, we have previously shown that the Hif 1alpha subunit of Hif-1 is involved in mouse MSC radio-resistance, however its exact mechanism of action remains unknown. In order to dissect the involvement of Hif-1alpha in the DDR, we used CRISPR/Cas9 technology to generate a stable mutant of the mouse MSC cell line MS5 lacking Hif-1alpha expression. Herein, we show that it is the whole Hif-1 transcription factor, and not only the Hif-1alpha subunit, that modulates the DDR of mouse MSCs. This effect is dependent upon the presence of a Hif-1alpha protein capable of binding to both DNA and its heterodimeric partner Arnt (Hif-1beta). Detailed transcriptomic and proteomic analysis of Hif1a KO MS5 cells leads us to conclude that Hif-1alpha may be acting indirectly on the DNA repair process. These findings have important implications for the modulation of MSC radio-resistance in the context of BMT and cancer. PMID- 29755368 TI - Saliva Proteomics Analysis Offers Insights on Type 1 Diabetes Pathology in a Pediatric Population. AB - The composition of the salivary proteome is affected by pathological conditions. We analyzed by high resolution mass spectrometry approaches saliva samples collected from children and adolescents with type 1 diabetes and healthy controls. The list of more than 2000 high confidence protein identifications constitutes a comprehensive characterization of the salivary proteome. Patients with good glycemic regulation and healthy individuals have comparable proteomic profiles. In contrast, a significant number of differentially expressed proteins were identified in the saliva of patients with poor glycemic regulation compared to patients with good glycemic control and healthy children. These proteins are involved in biological processes relevant to diabetic pathology such as endothelial damage and inflammation. Moreover, a putative preventive therapeutic approach was identified based on bioinformatic analysis of the deregulated salivary proteins. Thus, thorough characterization of saliva proteins in diabetic pediatric patients established a connection between molecular changes and disease pathology. This proteomic and bioinformatic approach highlights the potential of salivary diagnostics in diabetes pathology and opens the way for preventive treatment of the disease. PMID- 29755369 TI - Pheromone Binding Protein EhipPBP1 Is Highly Enriched in the Male Antennae of the Seabuckthorn Carpenterworm and Is Binding to Sex Pheromone Components. AB - The seabuckthorn carpenterworm moth Eogystia hippophaecolus is a major threat to seabuckthorn plantations, causing considerable ecological and economic losses in China. Transcriptomic analysis of E. hippophaecolus previously identified 137 olfactory proteins, including three pheromone-binding proteins (PBPs). We investigated the function of E. hippophaecolus PBP1 by studying its mRNA and protein expression profiles and its binding ability with different compounds. The highest levels of expression were in the antennae, particularly in males, with much lower levels of expression in the legs and external genitals. Recombinant PBP1 showed strong binding to sex-pheromone components, suggesting that antennal EhipPBP1 is involved in binding sex-pheromone components during pheromone communication. PMID- 29755370 TI - Effects of Ethanol on Sensory Inputs to the Medial Giant Interneurons of Crayfish. AB - Crayfish are capable of two rapid, escape reflexes that are mediated by two pairs of giant interneurons, the lateral giants (LG) and the medial giants (MG), which respond to threats presented to the abdomen or head and thorax, respectively. The LG has been the focus of study for many decades and the role of GABAergic inhibition on the escape circuit is well-described. More recently, we demonstrated that the LG circuit is sensitive to the acute effects of ethanol and this sensitivity is likely mediated by interactions between ethanol and the GABAergic system. The MG neurons, however, which receive multi-modal sensory inputs and are located in the brain, have been less studied despite their established importance during many naturally occurring behaviors. Using a combination of electrophysiological and neuropharmacological techniques, we report here that the MG neurons are sensitive to ethanol and experience an increase in amplitudes of post-synaptic potentials following ethanol exposure. Moreover, they are affected by GABAergic mechanisms: the facilitatory effect of acute EtOH can be suppressed by pretreatment with a GABA receptor agonist whereas the inhibitory effects resulting from a GABA agonist can be occluded by ethanol exposure. Together, our findings suggest intriguing neurocellular interactions between alcohol and the crayfish GABAergic system. These results enable further exploration of potentially conserved neurochemical mechanisms underlying the interactions between alcohol and neural circuitry that controls complex behaviors. PMID- 29755371 TI - Voltage-Activated Ion Channels in Non-excitable Cells-A Viewpoint Regarding Their Physiological Justification. PMID- 29755372 TI - Use of Laser Assisted Optical Rotational Cell Analyzer (LoRRca MaxSis) in the Diagnosis of RBC Membrane Disorders, Enzyme Defects, and Congenital Dyserythropoietic Anemias: A Monocentric Study on 202 Patients. AB - Chronic hemolytic anemias are a group of heterogeneous diseases mainly due to abnormalities of red cell (RBC) membrane and metabolism. The more common RBC membrane disorders, classified on the basis of blood smear morphology, are hereditary spherocytosis (HS), elliptocytosis, and hereditary stomatocytoses (HSt). Among RBC enzymopathies, the most frequent is pyruvate kinase (PK) deficiency, followed by glucose-6-phosphate isomerase, pyrimidine 5' nucleotidase P5'N, and other rare enzymes defects. Because of the rarity and heterogeneity of these diseases, diagnosis may be often challenging despite the availability of a variety of laboratory tests. The ektacytometer laser-assisted optical rotational cell analyser (LoRRca MaxSis), able to assess the RBC deformability in osmotic gradient conditions (Osmoscan analysis), is a useful diagnostic tool for RBC membrane disorders and in particular for the identification of hereditary stomatocytosis. Few data are so far available in other hemolytic anemias. We evaluated the diagnostic power of LoRRca MaxSis in a large series of 140 patients affected by RBC membrane disorders, 37 by enzymopathies, and 16 by congenital diserythropoietic anemia type II. Moreover, nine patients with paroxysmal nocturnal hemoglobinuria (PNH) were also investigated. All the hereditary spherocytoses, regardless the biochemical defect, showed altered Osmoscan curves, with a decreased Elongation Index (EI) max and right shifted Omin; hereditary elliptocytosis (HE) displayed a trapezoidal curve and decreased EImax. Dehydrated hereditary stomatocytosis (DHSt) caused by PIEZO1 mutations was characterized by left-shifted curve, whereas KCNN4 mutations were associated with a normal curve. Congenital diserythropoietic anemia type II and RBC enzymopathies had Osmoscan curve within the normal range except for glucosephosphate isomerase (GPI) deficient cases who displayed an enlarged curve associated with significantly increased Ohyper, offering a new diagnostic tool for this rare enzyme defect. The Osmoscan analysis performed by LoRRca MaxSis represents a useful and feasible first step screening test for specialized centers involved in the diagnosis of hemolytic anemias. However, the results should be interpreted by caution because different factors (i.e., splenectomy or coexistent diseases) may interfere with the analysis; additional tests or molecular investigations are therefore needed to confirm the diagnosis. PMID- 29755373 TI - Bidirectional Causal Connectivity in the Cortico-Limbic-Cerebellar Circuit Related to Structural Alterations in First-Episode, Drug-Naive Somatization Disorder. AB - Background: Anatomical and functional deficits in the cortico-limbic-cerebellar circuit are involved in the neurobiology of somatization disorder (SD). The present study was performed to examine causal connectivity of the cortico-limbic cerebellar circuit related to structural deficits in first-episode, drug-naive patients with SD at rest. Methods: A total of 25 first-episode, drug-naive patients with SD and 28 healthy controls underwent structural and resting-state functional magnetic resonance imaging. Voxel-based morphometry and Granger causality analysis (GCA) were used to analyze the data. Results: Results showed that patients with SD exhibited decreased gray matter volume (GMV) in the right cerebellum Crus I, and increased GMV in the left anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), and left angular gyrus. Causal connectivity of the cortico-limbic-cerebellar circuit was partly affected by structural alterations in the patients. Patients with SD showed bidirectional cortico-limbic connectivity abnormalities and bidirectional cortico-cerebellar and limbic cerebellar connectivity abnormalities. The mean GMV of the right MFG was negatively correlated with the scores of the somatization subscale of the symptom checklist-90 and persistent error response of the Wisconsin Card Sorting Test (WCST) in the patients. A negative correlation was observed between increased driving connectivity from the right MFG to the right fusiform gyrus/cerebellum IV, V and the scores of the Eysenck Personality Questionnaire extraversion subscale. The mean GMV of the left ACC was negatively correlated with the WCST number of errors and persistent error response. Negative correlation was found between the causal effect from the left ACC to the right middle temporal gyrus and the scores of WCST number of categories achieved. Conclusions: Our findings show the partial effects of structural alterations on the cortico-limbic cerebellar circuit in first-episode, drug-naive patients with SD. Correlations are observed between anatomical alterations or causal effects and clinical variables in patients with SD, and bear clinical significance. The present study emphasizes the importance of the cortico-limbic-cerebellar circuit in the neurobiology of SD. PMID- 29755374 TI - Altered Amygdala Resting-State Functional Connectivity and Hemispheric Asymmetry in Patients With Social Anxiety Disorder. AB - Background: The amygdala plays a key role in emotional hyperreactivity in response to social threat in patients with social anxiety disorder (SAD). We investigated resting-state functional connectivity (rs-FCN) of the left and right amygdala with various brain regions and functional lateralization in patients with SAD. Methods: A total of 36 patients with SAD and 42 matched healthy controls underwent functional magnetic resonance imaging (fMRI) at rest. Using the left and right amygdala as seed regions, we compared the strength of the rs FCN in the patient and control groups. Furthermore, we investigated group differences in the hemispheric asymmetry of the functional connectivity maps of the left and right amygdala. Results: Compared with healthy controls, the rs-FCN between the left amygdala and the dorsolateral prefrontal cortex was reduced in patients with SAD, whereas left amygdala connectivity with the fusiform gyrus, anterior insula, supramarginal gyrus, and precuneus was increased or positively deflected in the patient group. Additionally, the strength rs-FCN between the left amygdala and anterior insula was positively associated with the severity of the fear of negative evaluation in patients with SAD (r = 0.338, p = 0.044). The rs-FCN between the right amygdala and medial frontal gyrus was decreased in patients with SAD compared with healthy controls, whereas connectivity with the parahippocampal gyrus was greater in the patient group than in the control group. The hemispheric asymmetry patterns in the anterior insula, intraparietal sulcus (IPS), and inferior frontal gyrus of the patient group were opposite those of the control group, and functional lateralization of the connectivity between the amygdala and the IPS was associated with the severity of social anxiety symptoms (r = 0.365, p = 0.037). Conclusion: Our findings suggest that in addition to impaired fronto-amygdala communication, the functional lateralization of amygdala function plays a central role in the pathophysiology of SAD. PMID- 29755376 TI - Relation Between Mathematical Performance, Math Anxiety, and Affective Priming in Children With and Without Developmental Dyscalculia. AB - Many children show negative emotions related to mathematics and some even develop mathematics anxiety. The present study focused on the relation between negative emotions and arithmetical performance in children with and without developmental dyscalculia (DD) using an affective priming task. Previous findings suggested that arithmetic performance is influenced if an affective prime precedes the presentation of an arithmetic problem. In children with DD specifically, responses to arithmetic operations are supposed to be facilitated by both negative and mathematics-related primes (=negative math priming effect).We investigated mathematical performance, math anxiety, and the domain-general abilities of 172 primary school children (76 with DD and 96 controls). All participants also underwent an affective priming task which consisted of the decision whether a simple arithmetic operation (addition or subtraction) that was preceded by a prime (positive/negative/neutral or mathematics-related) was true or false. Our findings did not reveal a negative math priming effect in children with DD. Furthermore, when considering accuracy levels, gender, or math anxiety, the negative math priming effect could not be replicated. However, children with DD showed more math anxiety when explicitly assessed by a specific math anxiety interview and showed lower mathematical performance compared to controls. Moreover, math anxiety was equally present in boys and girls, even in the earliest stages of schooling, and interfered negatively with performance. In conclusion, mathematics is often associated with negative emotions that can be manifested in specific math anxiety, particularly in children with DD. Importantly, present findings suggest that in the assessed age group, it is more reliable to judge math anxiety and investigate its effects on mathematical performance explicitly by adequate questionnaires than by an affective math priming task. PMID- 29755377 TI - Precision, Reliability, and Effect Size of Slope Variance in Latent Growth Curve Models: Implications for Statistical Power Analysis. AB - Latent Growth Curve Models (LGCM) have become a standard technique to model change over time. Prediction and explanation of inter-individual differences in change are major goals in lifespan research. The major determinants of statistical power to detect individual differences in change are the magnitude of true inter-individual differences in linear change (LGCM slope variance), design precision, alpha level, and sample size. Here, we show that design precision can be expressed as the inverse of effective error. Effective error is determined by instrument reliability and the temporal arrangement of measurement occasions. However, it also depends on another central LGCM component, the variance of the latent intercept and its covariance with the latent slope. We derive a new reliability index for LGCM slope variance-effective curve reliability (ECR)-by scaling slope variance against effective error. ECR is interpretable as a standardized effect size index. We demonstrate how effective error, ECR, and statistical power for a likelihood ratio test of zero slope variance formally relate to each other and how they function as indices of statistical power. We also provide a computational approach to derive ECR for arbitrary intercept-slope covariance. With practical use cases, we argue for the complementary utility of the proposed indices of a study's sensitivity to detect slope variance when making a priori longitudinal design decisions or communicating study designs. PMID- 29755375 TI - Influence of CRHR1 Polymorphisms and Childhood Abuse on Suicide Attempts in Affective Disorders: A GxE Approach. AB - Background: Previous studies have shown that the hypothalamus-pituitary-adrenal axis (HPA-axis) is closely involved in the development of affective disorders. Given that early life events are also linked to dysregulation of the same system, there might be an association between childhood adversities and suicidal behavior in affective disorders, moderated by HPA-axis genes. We aimed to investigate a potential association between childhood trauma and previous suicide attempts in affective disorder patients, moderated by variants of the corticotropin-releasing hormone receptor 1 (CRHR1) gene. Methods: The current pilot study is part of an ongoing study on suicidal behavior in affective disorders (VieSAD). Two hundred fifty eight Caucasian affective disorder patients were assessed at the Department of Psychiatry and Psychotherapy of the Medical University Vienna and the Karl Landsteiner University for Health and Science. An assemblage of psychiatric interviews was performed (e.g., SCAN, HAMD, SBQ-R, CTQ) and DNA samples of peripheral blood cells were genotyped with TaqMan(r) SNP Genotyping Assays (rs7209436, rs4792887, rs110402, rs242924, and rs242939). Results: Neither genetic, nor haplotypic associations between CRHR1 polymorphisms and previous suicide attempts could be established for the present sample. Using a binary logistic regression model, significant gene-environment-interactions were found for the single nucleotide polymorphisms (SNPs) rs7209436 and rs110402, reflecting the impact of childhood trauma and CRHR1 polymorphisms on previous suicide attempts. Limitations: A larger sample size will be required to ultimately elucidate the link between childhood trauma and the HPA axis in suicidal behavior. Conclusion: This pilot study presents promising gene-environment interaction findings in affective disorder patients with a history of suicide attempts. PMID- 29755379 TI - Behavioral Patterns of Children Involved in Bullying Episodes. AB - This study applied a systematic observation strategy to identify coercive behavioral patterns in school environments. The aim was to describe stability and change in the behavioral patterns of children identified as victims of bullying. To this end, the following specific objectives were defined: (1) to identify episodes of bullying based on the frequency of negative behaviors received and power imbalances between bully and victim; (2) to describe stability and behavioral changes in student victims based on their social and academic conduct and the aggression they receive from peers and teachers; and (3) to describe the functional mechanisms responsible for the process of social organization (i.e., the Social Effectiveness, Social Responsiveness, and Social Reciprocity Indexes). The sample consisted of nine children identified as victims, nine classified as bullies, and nine matched controls, all elementary school students from the study developed at the National Autonomous University of Mexico files. A multidimensional/idiographic/follow-up observational design was used. Observational data describes asymmetry between victims and bullies based on microanalyses of the reciprocity of their behavioral exchanges. In addition, the behavioral patterns of victimized children were identified in relation to their academic activity and social relationships with peers. A model of coercive reciprocity accurately describes the asymmetry found among bullies, victims, and controls. A reduction in victimization was found to be related to: (1) responsiveness to the initiation of social interactions by peers and teachers; and (2) the time allocated to academic behavior during the study. PMID- 29755378 TI - The Architectonic Experience of Body and Space in Augmented Interiors. AB - The environment shapes our experience of space in constant interaction with the body. Architectonic interiors amplify the perception of space through the bodily senses; an effect also known as embodiment. The interaction of the bodily senses with the space surrounding the body can be tested experimentally through the manipulation of multisensory stimulation and measured via a range of behaviors related to bodily self-consciousness. Many studies have used Virtual Reality to show that visuotactile conflicts mediated via a virtual body or avatar can disrupt the unified subjective experience of the body and self. In the full-body illusion paradigm, participants feel as if the avatar was their body (ownership, self-identification) and they shift their center of awareness toward the position of the avatar (self-location). However, the influence of non-bodily spatial cues around the body on embodiment remains unclear, and data about the impact of architectonic space on human perception and self-conscious states are sparse. We placed participants into a Virtual Reality arena, where large and narrow virtual interiors were displayed with and without an avatar. We then applied synchronous or asynchronous visuotactile strokes to the back of the participants and avatar, or, to the front wall of the void interiors. During conditions of illusory self identification with the avatar, participants reported sensations of containment, drift, and touch with the architectonic environment. The absence of the avatar suppressed such feelings, yet, in the large space, we found an effect of continuity between the physical and the virtual interior depending on the full body illusion. We discuss subjective feelings evoked by architecture and compare the full-body illusion in augmented interiors to architectonic embodiment. A relevant outcome of this study is the potential to dissociate the egocentric, first-person view from the physical point of view through augmented architectonic space. PMID- 29755381 TI - The Relationships of Self-Esteem, Future Time Perspective, Positive Affect, Social Support, and Career Decision: A Longitudinal Multilevel Study. AB - This study aimed, first, to determine whether the intra-individual variability in positive affect was related to the intra-individual variability in career decision-making self-efficacy, and career choice anxiety. The second objective was to examine whether social support moderates the relationship between affect and these outcome variables. The third objective was to find out how career decision-making self-efficacy and career choice anxiety change according to self esteem and future time perspective. We conducted a study using the daily diary method in which participants were asked to rate their affect or attitudes for 21 consecutive days. In total, 128 university students participated in this study. The main results were as follows. First, positive affect was associated positively with career decision-making self-efficacy and negatively with career choice anxiety. Second, social support had a synergy effect with positive affect to influence career choice anxiety. Third, self-esteem was related positively to career decision-making self-efficacy and negatively to career choice anxiety. We discuss theoretical and practical implications. PMID- 29755382 TI - Effect of the Symbolic Meaning of Speed on the Perceived Duration of Children and Adults. AB - The present study investigated how the symbolic meaning of speed affects time perception in children and adults. We employed a time reproduction task in which participants were asked to reproduce temporal intervals previously presented. In Experiment 1, 45 primary school children and 22 university students performed a time reproduction task with cars (meaning of fastness) and trucks (meaning of slowness) presented for 11 and 21 s in static and moving conditions. Results showed that young children under-reproduced the duration more than the older children and adults, especially when the stimulus presented was a car. Moreover, participants under-reproduced moving stimuli compared to static one. In Experiment 2, we tested 289 participants who were divided into nine different age groups according to their school class: five from primary school, three from Junior High, and one from the university. Participants performed a time reproduction task with a motorbike (meaning of fastness) or a bicycle (meaning of slowness) under static and moving conditions for 11, 21, and 36 s. The results confirmed the effects of symbolic meaning of speed on children's time perception and showed that vehicles that evoked the idea of fastness were under-reproduced compared to stimuli evoking the idea of slowness. PMID- 29755380 TI - Effects of Physical Exercise on Cognitive Functioning and Wellbeing: Biological and Psychological Benefits. AB - Much evidence shows that physical exercise (PE) is a strong gene modulator that induces structural and functional changes in the brain, determining enormous benefit on both cognitive functioning and wellbeing. PE is also a protective factor for neurodegeneration. However, it is unclear if such protection is granted through modifications to the biological mechanisms underlying neurodegeneration or through better compensation against attacks. This concise review addresses the biological and psychological positive effects of PE describing the results obtained on brain plasticity and epigenetic mechanisms in animal and human studies, in order to clarify how to maximize the positive effects of PE while avoiding negative consequences, as in the case of exercise addiction. PMID- 29755384 TI - Weibo or WeChat? Assessing Preference for Social Networking Sites and Role of Personality Traits and Psychological Factors. AB - Research trying to understand individual difference in the use of different social networking sites (SNSs) is minimal. In the present study, we collected data from 714 college students in China (273 males) to assess how personality traits and psychological factors relate to excessive use of WeChat and Weibo. We found that excessive use of Weibo and WeChat correlated positively with neuroticism, loneliness, and external locus of control and negatively with agreeableness, social support, and social interaction. Furthermore, people that scored high on loneliness, lack of social support, and poor social interaction skills excessively used Weibo more than WeChat. These results entail that by fulfilling different needs, WeChat and Weibo attract different kinds of people; significant lesson for future development of SNSs. PMID- 29755385 TI - Sex, Age, and Emotional Valence: Revealing Possible Biases in the 'Reading the Mind in the Eyes' Task. AB - The 'Reading the Mind in the Eyes' test (RMET) assesses a specific socio cognitive ability, i.e., the ability to identify mental states from gaze. The development of this ability in a lifespan perspective is of special interest. Whereas former investigations were limited mainly to childhood and adolescence, the focus has been shifted towards aging, and psychiatric and neurodegenerative diseases recently. Although the RMET is frequently applied in developmental psychology and clinical settings, stimulus characteristics have never been investigated with respect to potential effects on test performance. Here, we analyzed the RMET stimulus set with a special focus on interrelations between sex, age and emotional valence. Forty-three persons rated age and emotional valence of the RMET picture set. Differences in emotional valence and age ratings between male and female items were analyzed. The linear relation between age and emotional valence was tested over all items, and separately for male and female items. Male items were rated older and more negative than female stimuli. Regarding male RMET items, age predicted emotional valence: older age was associated with negative emotions. Contrary, age and valence were not linearly related in female pictures. All ratings were independent of rater characteristics. Our results demonstrate a strong confound between sex, age, and emotional valence in the RMET. Male items presented a greater variability in age ratings compared to female items. Age and emotional valence were negatively associated among male items, but no significant association was found among female stimuli. As personal attributes impact social information processing, our results may add a new perspective on the interpretation of previous findings on interindividual differences in RMET accuracy, particularly in the field of developmental psychology, and age-associated neuropsychiatric diseases. A revision of the RMET might be afforded to overcome confounds identified here. PMID- 29755383 TI - Seeing More Than Human: Autism and Anthropomorphic Theory of Mind. AB - Theory of mind (ToM) is defined as the process of taking another's perspective. Anthropomorphism can be seen as the extension of ToM to non-human entities. This review examines the literature concerning ToM and anthropomorphism in relation to individuals with Autism Spectrum Disorder (ASD), specifically addressing the questions of how and why those on the spectrum both show an increased interest for anthropomorphism and may even show improved ToM abilities when judging the mental states of anthropomorphic characters. This review highlights that while individuals with ASD traditionally show deficits on a wide range of ToM tests, such as recognizing facial emotions, such ToM deficits may be ameliorated if the stimuli presented is cartoon or animal-like rather than in human form. Individuals with ASD show a greater interest in anthropomorphic characters and process the features of these characters using methods typically reserved for human stimuli. Personal accounts of individuals with ASD also suggest they may identify more closely with animals than other humans. It is shown how the social motivations hypothesized to underlie the anthropomorphizing of non-human targets may lead those on the spectrum to seek social connections and therefore gain ToM experience and expertise amongst unlikely sources. PMID- 29755386 TI - Bridge Over an Aging Population: Examining Longitudinal Relations Among Human Resource Management, Social Support, and Employee Outcomes Among Bridge Workers. AB - This two-wave complete panel study aims to examine human resource management (HRM) bundles of practices in relation to social support [i.e., leader-member exchange (LMX), coworker exchange (CWX)] and employee outcomes (i.e., work engagement, employability, and health), within a context of workers aged 65+. Based upon the social exchange theory and the Job Demands-Resources (JD-R) framework, it was hypothesized that HRM bundles at Time 1 would increase bridge workers' outcomes at Time 2, and that this relationship would be mediated by perceptions of LMX and CWX at Time 2. Using a longitudinal design, hypotheses were tested in a unique sample of Dutch bridge employees (N = 228). Results of several structural equation modeling analyses revealed no significant associations between HRM bundles, and social support, moreover, no significant associations were found in relation to employee outcomes. However, the results of the best-fitting final model revealed the importance of the impact of social support on employee (65+) outcomes over time. PMID- 29755387 TI - Population Size and the Rate of Language Evolution: A Test Across Indo-European, Austronesian, and Bantu Languages. AB - What role does speaker population size play in shaping rates of language evolution? There has been little consensus on the expected relationship between rates and patterns of language change and speaker population size, with some predicting faster rates of change in smaller populations, and others expecting greater change in larger populations. The growth of comparative databases has allowed population size effects to be investigated across a wide range of language groups, with mixed results. One recent study of a group of Polynesian languages revealed greater rates of word gain in larger populations and greater rates of word loss in smaller populations. However, that test was restricted to 20 closely related languages from small Oceanic islands. Here, we test if this pattern is a general feature of language evolution across a larger and more diverse sample of languages from both continental and island populations. We analyzed comparative language data for 153 pairs of closely-related sister languages from three of the world's largest language families: Austronesian, Indo European, and Niger-Congo. We find some evidence that rates of word loss are significantly greater in smaller languages for the Indo-European comparisons, but we find no significant patterns in the other two language families. These results suggest either that the influence of population size on rates and patterns of language evolution is not universal, or that it is sufficiently weak that it may be overwhelmed by other influences in some cases. Further investigation, for a greater number of language comparisons and a wider range of language features, may determine which of these explanations holds true. PMID- 29755388 TI - Structural Equation Modeling With Many Variables: A Systematic Review of Issues and Developments. AB - Survey data in social, behavioral, and health sciences often contain many variables (p). Structural equation modeling (SEM) is commonly used to analyze such data. With a sufficient number of participants (N), SEM enables researchers to easily set up and reliably test hypothetical relationships among theoretical constructs as well as those between the constructs and their observed indicators. However, SEM analyses with small N or large p have been shown to be problematic. This article reviews issues and solutions for SEM with small N, especially when p is large. The topics addressed include methods for parameter estimation, test statistics for overall model evaluation, and reliable standard errors for evaluating the significance of parameter estimates. Previous recommendations on required sample size N are also examined together with more recent developments. In particular, the requirement for N with conventional methods can be a lot more than expected, whereas new advances and developments can reduce the requirement for N substantially. The issues and developments for SEM with many variables described in this article not only let applied researchers be aware of the cutting edge methodology for SEM with big data as characterized by a large p but also highlight the challenges that methodologists need to face in further investigation. PMID- 29755389 TI - Evidence for Sequential Performance Effects in Professional Darts. AB - Objectives: The study of sequential effects in aiming tasks might shed light on the organization of repetitive motor performances over time. To date, investigations of such effects in sports have been limited and yielded mixed results. Given the relatively short time intervals between successive attempts, and the absence of defensive interventions, dart throwing provides a potentially fruitful testing ground for examining the presence of sequential performance effects in the motor domain. Methods and Results: A total of 80 competitive darts matches of 10 of the world's best players were scored from publicly available video footage in terms of sequences of hits and misses of triple 20. In darts, throws are organized in legs, i.e., a rapid succession of three throws by the same player, allowing us to investigate various transitions in performance (throw 1 -> 2, 2 -> 3, and 3 -> 1). The resulting binary sequences were analyzed statistically in terms of independence and stationarity. Across players significant statistical evidence was found for sequential dependence from the first throw in a leg to the second throw, but not for the other transitions. As regards to stationarity, a significant decline in performance was observed in the course of the match. Conclusions: In professional darts, evidence can be found for both sequential dependence as well as for non-stationarity, implying that performance does not, or at least not always, constitute a stationary random independent process. More research is needed on the motor control mechanisms underlying the observed carry-over effects within triplets as well as the possible causes of non-stationarity. PMID- 29755390 TI - Influence of Music on the Behaviors of Crowd in Urban Open Public Spaces. AB - Sound environment plays an important role in urban open spaces, yet studies on the effects of perception of the sound environment on crowd behaviors have been limited. The aim of this study, therefore, is to explore how music, which is considered an important soundscape element, affects crowd behaviors in urban open spaces. On-site observations were performed at a 100 m * 70 m urban leisure square in Harbin, China. Typical music was used to study the effects of perception of the sound environment on crowd behaviors; then, these behaviors were classified into movement (passing by and walking around) and non-movement behaviors (sitting). The results show that the path of passing by in an urban leisure square with music was more centralized than without music. Without music, 8.3% of people passing by walked near the edge of the square, whereas with music, this percentage was zero. In terms of the speed of passing by behavior, no significant difference was observed with the presence or absence of background music. Regarding the effect of music on walking around behavior in the square, the mean area and perimeter when background music was played were smaller than without background music. The mean speed of those exhibiting walking around behavior with background music in the square was 0.296 m/s slower than when no background music was played. For those exhibiting sitting behavior, when background music was not present, crowd density showed no variation based on the distance from the sound source. When music was present, it was observed that as the distance from the sound source increased, crowd density of those sitting behavior decreased accordingly. PMID- 29755391 TI - Odor Learning and Its Experience-Dependent Modulation in the South American Native Bumblebee Bombus atratus (Hymenoptera: Apidae). AB - Learning about olfactory stimuli is essential in bumblebees' life since it is involved in orientation, recognition of nest sites, foraging efficiency and food yield for the colony as a whole. To evaluate associative learning abilities in bees under controlled environmental conditions, the proboscis extension response (PER) assay is a well-established method used in honey bees, stingless bees and successfully adapted to bumblebees of the genus Bombus. However, studies on the learning capacity of Bombus atratus (Hymenoptera: Apidae), one of the most abundant native species in South America, are non-existent. In this study, we examined the cognitive abilities of worker bees of this species, carrying out an olfactory PER conditioning experiment. Bumblebees were able to learn a pure odor when it was presented in paired association with sugared reward, but not when odor and reward were presented in an unpaired manner. Furthermore, if the bees were preexposed to the conditioned odor, the results differed depending on the presence of the scent either as a volatile in the rearing environment or diluted in the food. A decrement in learning performance results from the non-reinforced pre-exposure to the to-be-conditioned odor, showing a latent inhibition phenomenon. However, if the conditioned odor has been previously offered diluted in sugared reward, the food odor acts as a stimulus that improves the learning performance during PER conditioning. The native bumblebee B. atratus is thus a new hymenopteran species capable of being trained under controlled experimental conditions. Since it is an insect increasingly reared for pollination service, this knowledge could be useful in its management in crops. PMID- 29755392 TI - Psychometric Properties of the Chinese Version of the Brief Borderline Symptom List in Undergraduate Students and Clinical Patients. AB - The brief version of the Borderline Symptom List (BSL-23) is a self-rated scale developed from the initial 95-item version of Borderline Symptom List (BSL-95). The current study aimed to evaluate the psychometric properties of the Chinese version of the BSL-23. A total of 570 undergraduate students and 323 clinical patients completed the BSL-23, the borderline subscale of the Personality Diagnostic Questionnaire (PDQ-4+), the Center for Epidemiologic Studies Depression Scale (CES-D), the Barratt Impulsiveness Scale, 11th version (BIS-11), the Childhood Trauma Questionnaire (CTQ) and the Attachment Style Questionnaire (ASQ). A Confirmatory Factor Analysis (CFA) was conducted to test the one-factor structure of the BSL-23. Cronbach's alpha, Omega coefficient, Split-Half coefficient, Mean Inter-Item Correlation (MIC) and test-retest reliability were also measured. The correlations between the BSL-23 and other psychological variables were used to assess criterion-related validity and convergent validity. Participants who scored >= 5 on the borderline subscale of the PDQ-4+ were placed into the borderline personality disorder (BPD) screening-positive group, while the others were placed into the screening-negative group. Independent sample t tests were performed to examine the differences in BSL-23 scores between the BPD screening-positive group and the BPD screening-negative group. The CFA results supported the one-factor structure of the BSL-23 in both samples. The internal consistency was high both in the undergraduate sample (Cronbach's alpha = 0.93, Omega = 0.95, Split-Half coefficient = 0.89, MIC = 0.38) and the clinical sample (Cronbach's alpha = 0.97, Omega = 0.97, Split-Half coefficient = 0.96, MIC = 0.56). The test-retest reliability within 2 weeks was 0.62. The BSL-23 displayed moderate to high correlations with the PDQ-4+-Borderline subscale, the CES-D, the BIS-11, the CTQ and the ASQ (r = 0.35 - 0.70). In addition, the BSL-23 discriminated between the BPD screening-positive and the BPD screening-negative participants, and also between the patient sample and undergraduate sample. In conclusion, the Chinese version of the BSL-23 has satisfactory psychometric properties to assess BPD symptoms. PMID- 29755393 TI - Language Lateralization and Auditory Attention Impairment in Young Adults at Ultra-High Risk for Psychosis: A Dichotic Listening Study. AB - Objectives: Impaired attention and language functions are common in psychosis, but have been less explored in subjects with ultra-high risk for psychosis (UHR). The aim of the study was to investigate differences in language lateralization and auditory attention in UHR subjects compared to healthy controls with a dichotic listening paradigm. In addition, symptoms from The Structural Interview for Prodromal Syndromes (SIPS) were explored in relation to performance on dichotic listening. Methods: The UHR subjects (n = 46, female = 28, mean age = 17.9) were compared to a group of healthy controls (n = 40, female = 20, mean age = 16.8). A split-plot repeated measures analysis of covariance was conducted with group as between-subjects factor and attention conditions (non-forced, forced right, forced-left) and side (right ear, left ear) as repeated measures factors (2*3*2 design) using gender, age and handedness as covariates. SIPS symptoms were subjected to Spearman's r correlations with laterality indexes and attentional gain in each ear. Results: There was a statistically significant three-way interaction of group (UHR, healthy controls) * forced condition (non-forced, forced-right, forced-left) * side (right ear, left ear), p = 0.048. The effect was due to an interaction between group * side in the forced-left condition. There were no significant differences between UHR subjects and healthy controls in the non-forced condition. Right ear gain correlated with "Perceptual abnormalities/Hallucinations" (P4), r = 0.486, p = 0.001. Conclusion: UHR subjects demonstrated impairment in top-down attentional mechanisms, but showed no language lateralization abnormalities. Impairment in top-down attentional mechanisms are frequently reported from dichotic listening studies in patients with schizophrenia. Higher levels of perceptual abnormalities and hallucinatory experiences were associated with enhanced report from the right ear in the forced right condition. PMID- 29755394 TI - A Pathway to Psychological Difficulty: Perceived Chronic Social Adversity and Its Symptomatic Reactions. AB - In this paper, we attempt to predict and explain psychological maladjustment or difficulty. Specifically, we discuss the concept of perceived chronic social adversity, and we expect that such perceived chronic social adversity may potentially lead to chronic stress responses. Accordingly, we propose the symptomatic reactions of perceived chronic social adversity. We put forward a set of hypotheses regarding the relationships between perceived chronic social adversity and those chronic stress responses, and we further hypothesize a mediating role of individualized negative essentialism brought by perceived chronical social adversity. Resilience and individual differences in the ability to cope with perceived adversity are discussed. Future research and prevention need to pay more attention to effects of subjective personal experiences on psychological difficulty, focusing on the importance of exploring daily social experiences in improving cognitive construction processes and developing appropriate preventions. PMID- 29755395 TI - Early-Onset Creutzfeldt-Jakob Disease Mimicking Immune-Mediated Encephalitis. AB - Objectives: The objective of this study is to explore the clinical, radiological, and pathological manifestations of a rare subtype of prion disease and their implication for differential diagnosis in case of an early onset neuropsychiatric deterioration. Methods: We discuss a patients' clinical history, as well as the string of investigations and symptomatological evolution that finally led to a pathological diagnosis. Results: Our patient had the extremely rare VV1 type sporadic Creutzfeldt-Jakob disease (sCJD). We explain the differential diagnosis of progressive encephalomyelitis with rigidity and myoclonus and its implications for treatment. Conclusion: sCJD, especially the VV1 subtype, can present at an early age with an insidious psychiatric onset. Classical findings of prion disease-14-3-3 protein, PSWC on electroencephalography, and magnetic resonance imaging patterns-are not always present. The presence of neural autoantibodies does not always implicate pathogenicity in the presence of other neurological/neurodegenerative conditions. PMID- 29755396 TI - Overlapping Autoimmune Syndromes in Patients With Glial Fibrillary Acidic Protein Antibodies. AB - Background: Glial fibrillary acidic protein (GFAP) astrocytopathy, an autoimmune central nervous system disorder with a specific GFAP-IgG, often coexists with other antibodies. Objective: The aim of this article was to study overlapping syndromes in autoimmune GFAP astrocytopathy. Methods: Antibody was detected by indirect immunofluorescence assay. Patient data were analyzed retrospectively. Results: Thirty patients with positive GFAP-IgG were included, of whom 10 were defined as overlapping syndrome. Four patients with positive aquaporin-4 (AQP4) IgG, two with N-methyl-d-aspartate receptor-IgG, three with unknown neuronal antibodies, and one with double AQP4 and myelin oligodendrocyte glycoprotein-IgG were identified. GFAP-IgG and other specific antibodies occurred simultaneously at the initial attack in eight patients. The main symptoms included fever, headache, ataxia, psychosis, hypersomnia, dyskinesia, dementia, seizure, myelitis, and optical symptoms. Brain magnetic resonance imaging in four patients revealed characteristic radial enhancing patterns in the white matter. Cortical abnormalities were found in four patients. Other brain abnormalities occurred in the hypothalamus, midbrain, pons, medulla, cerebellum, and meninges. Six patients exhibited lesions in the spinal cord. In a subgroup study, patients with overlapping syndrome were younger at onset than those with non-overlapping syndrome. Conclusion: Overlapping antibodies are common in GFAP astrocytopathy. PMID- 29755397 TI - Stress-Axis Regulation by Vitamin D3 in Multiple Sclerosis. AB - Introduction: Multiple sclerosis (MS) has been associated with both a poor vitamin D status and hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis. Since nuclear receptor ligands may regulate each other, we explored the association of vitamin D3 supplements with circadian cortisol levels in a double blind and placebo-controlled supplementation study. Methods: Female patients with relapsing-remitting MS received vitamin D3 supplements (4,000 IU/day; n = 22) or placebo (n = 19) during 16 weeks. Salivary cortisol levels, repeatedly measured during the day, and serum 25(OH)D levels were assessed before (T0) and after (T1) this treatment period. Results: Median 25(OH)D levels at T1 were 139.9 (interquartile range 123.5-161.2) and 74.5 nmol/L (58.6-88.1) in the vitamin D3 and placebo group, respectively (p < 0.001). Comparisons within and between groups showed no differences in area under the curve (AUC) and slope of the cortisol day curve. Although the AUC of the cortisol awakening response (CAR, sampling each 15 min the first hour after awakening) showed a reduction over time in the vitamin D3 group [39.16 nmol/L (27.41-42.07) at T0 to 33.37 nmol/L (26.75 38.08) at T1] compared to the placebo group [33.90 nmol/L (25.92-44.61) at T0 to 35.00 nmol/L (25.46-49.23) at T1; p = 0.044], there was no significant difference in AUC of CAR at T1 corrected for baseline AUC of CAR (p = 0.066). Conclusion: Suppression of HPA-axis activity by vitamin D3 supplements in non-depressed MS patients may be best reflected by CAR as primary outcome measure. Further studies should address this interaction and its potential implications for the disease course of MS. Registration: This study was registered on ClinicalTrials.gov (NCT02096133) and EudraCT (2014-000728-97). PMID- 29755398 TI - Deconvolution of Human Brain Cell Type Transcriptomes Unraveled Microglia Specific Potential Biomarkers. AB - Microglial cells form a context-dependent network of brain immunoeffector cells. Despite their indispensable roles, unresolved questions exist around biomarker discovery relevant to their cellular localization, self-renewing potential, and brain developmental dynamics. To resolve the existent gap in the annotation of candidate biomarkers, we conducted a meta-analysis of brain cells using available high-throughput data sets for deciphering microglia-specific expression profiles. We have identified 3,290 significant genes specific to microglia and further selected the top 20 dysregulated genes on the basis of p-value and log2FC. To this list, we added 7 known microglia-specific markers making the candidate list comprising 27 genes for further downstream analyses. Next, we established a connectome of these potential markers with their putative protein partners, which demonstrated strong associations of upregulated genes like Dedicator of cytokinesis 2 (DOCK2) with early/mature microglial markers such as Sphingosine kinase 1 (SPHK1), CD68, and CD45. To elucidate their respective brain anatomical location, we deconvoluted the BrainSpan Atlas expression data. This analysis showed high expression of the majority of candidate genes in microglia-dense regions (Amygdala, Hippocampus, Striatum) in the postnatal brain. Furthermore, to decipher their localized expression across brain ages, we constructed a developmental dynamics map (DDM) comprising extensive gene expression profiles throughout prenatal to postnatal stages, which resulted in the discovery of novel microglia-specific gene signatures. One of the interesting readout from DDM is that all the microglia-dense regions exhibit dynamic regulation of few genes at 37 post conception week (pcw), the transition period between pre- and postnatal stages. To validate these findings and correlate them as potential biomarkers, we analyzed the expression of corresponding proteins in hESC-derived human microglia precursors. The cultured microglial precursors showed expression of Pentraxin 3 (PTX3) and SPHK1 as well as several known markers like CD68, Allograft inflammatory factor 1 (AIF1/IBA1). In summary, this study has furnished critical insights into microglia dynamics across human brain ages and cataloged potential transcriptomic fingerprints that can be further exploited for designing novel neurotherapeutics. PMID- 29755399 TI - Leg Prosthesis With Somatosensory Feedback Reduces Phantom Limb Pain and Increases Functionality. AB - Phantom limb pain (PLP) develops in most patients with lower limb amputation. Changes in the peripheral and central nervous system (CNS) are hypothesized to contribute to PLP. Based on ideas to modify neural reorganization within the CNS, the aim of the study was to test, whether prostheses with somatosensory feedback might help to reduce PLP, and increase the functionality of movement with a prosthesis. We therefore equipped the prostheses of 14 lower leg amputees with a simple to use feedback system that provides electrocutaneous feedback to patients' thigh whenever the foot and toes of the prosthesis touch the ground. Two weeks of training with such a feedback prosthesis reduced PLP, increased the functional use of the prosthesis, and increased patients' satisfaction with prosthesis use. We found a significant overall reduction of PLP during the course of the training period. Most patients reported lower PLP intensities at the end of the day while before training they have usually experienced maximal PLP intensities. Furthermore, patients also reported larger walking distances and more stable walking and better posture control while walking on and across a bumpy or soft ground. After training, the majority of participants (9/14) preferred such a feedback system over no feedback. This study extends former observations of a similar training procedure with arm amputees who used a similar feedback training to improve the functionality of an arm prosthesis in manipulating and grasping objects. PMID- 29755401 TI - Impulsivity in Parkinson's Disease Is Associated With Alterations in Affective and Sensorimotor Striatal Networks. AB - A subset of patients with Parkinson's disease (PD) experiences problems with impulse control, characterized by a loss of voluntary control over impulses, drives, or temptations regarding excessive hedonic behavior. The present study aimed to better understand the neural basis of such impulse control disorders (ICDs) in PD. We collected resting-state functional connectivity and structural MRI data from 21 PD patients with ICDs and 30 patients without such disorders. To assess impulsivity, all patients completed the Barratt Impulsiveness Scale and performed an information-gathering task. MRI results demonstrated substantial differences in neural characteristics between PD patients with and without ICDs. Results showed that impulsivity was linked to alterations in affective basal ganglia circuitries. Specifically, reduced frontal-striatal connectivity and GPe volume were associated with more impulsivity. We suggest that these changes affect decision making and result in a preference for risky or inappropriate actions. Results further showed that impulsivity was linked to alterations in sensorimotor striatal networks. Enhanced connectivity within this network and larger putamen volume were associated with more impulsivity. We propose that these changes affect sensorimotor processing such that patients have a greater propensity to act. Our findings suggest that the two mechanisms jointly contribute to impulsive behaviors in PD. PMID- 29755400 TI - Intermittent Hypoxia Is Associated With High Hypoxia Inducible Factor-1alpha but Not High Vascular Endothelial Growth Factor Cell Expression in Tumors of Cutaneous Melanoma Patients. AB - Epidemiological associations linking between obstructive sleep apnea and poorer solid malignant tumor outcomes have recently emerged. Putative pathways proposed to explain that these associations have included enhanced hypoxia inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) cell expression in the tumor and altered immune functions via intermittent hypoxia (IH). Here, we examined relationships between HIF-1alpha and VEGF expression and nocturnal IH in cutaneous melanoma (CM) tumor samples. Prospectively recruited patients with CM tumor samples were included and underwent overnight polygraphy. General clinical features, apnea-hypopnea index (AHI), desaturation index (DI4%), and CM characteristics were recorded. Histochemical assessments of VEGF and HIF-1alpha were performed, and the percentage of positive cells (0, <25, 25-50, 51-75, >75%) was blindly tabulated for VEGF expression, and as 0, 0-5.9, 6.0-10.0, >10.0% for HIF-1alpha expression, respectively. Cases with HIF-1alpha expression >6% (high expression) were compared with those <6%, and VEGF expression >75% of cells was compared with those with <75%. 376 patients were included. High expression of VEGF and HIF-1alpha were seen in 88.8 and 4.2% of samples, respectively. High expression of VEGF was only associated with increasing age. However, high expression of HIF-1alpha was significantly associated with age, Breslow index, AHI, and DI4%. Logistic regression showed that DI4% [OR 1.03 (95% CI: 1.01-1.06)] and Breslow index [OR 1.28 (95% CI: 1.18-1.46)], but not AHI, remained independently associated with the presence of high HIF-1alpha expression. Thus, IH emerges as an independent risk factor for higher HIF-1alpha expression in CM tumors and is inferentially linked to worse clinical CM prognostic indicators. PMID- 29755403 TI - Has the Time Come to Stratify and Score SUDEP Risk to Inform People With Epilepsy of Their Changes in Safety? AB - Recent publication of the American Academy of Neurology SUDEP guidance highlighted the importance to American clinicians of making people with epilepsy aware of SUDEP risk. It is the first guideline to do this in the United States. It follows precedent set out in the UK by National Institute of Clinical Excellence in 2004. While a significant achievement, the lack of clarity of how to deliver this guidance in an enduring and person-centered manner, raises concerns on how its long-term effectiveness in risk mitigation. Shared decision making with an emphasis on delivering person-centered communication to foster self-management strategies is increasingly recognized as the ideal model of patient-clinician communication in chronic diseases such as epilepsy. The tension between delivering evidence-based risk information, yet, tailoring it to the individual is complex. It needs to incorporate the potential for change not only in seizure factors but also other health and social factors. Safety advice needs to be dynamic and situation sensitive as opposed to a "one off" discussion. As a significant minority of people with epilepsy have drug-resistant seizures, the importance of keeping the advice contextual at different intervals of the person's life cannot be overstated as many of them are managed in primary care. We present some exploratory work, which identifies the need to improve communication at a primary care level and to review risks regularly. Regular reviews using a structured risk factor checklist as a screening tool could identify, sooner, people who's health issues are worsening and justify referrals to specialists. PMID- 29755402 TI - Default Mode Network Oscillatory Coupling Is Increased Following Concussion. AB - Concussion is a common form of mild traumatic brain injury. Despite the descriptor "mild," a single injury can leave long-lasting and sustained alterations to brain function, including changes to localized activity and large scale interregional communication. Cognitive complaints are thought to arise from such functional deficits. We investigated the impact of injury on neurophysiological and functionally specialized resting networks, known as intrinsic connectivity networks (ICNs), using magnetoencephalography. We assessed neurophysiological connectivity in 40 males, 20 with concussion and 20 without. Regions-of-interest that comprise nodes of ICNs were defined, and their time courses derived using a beamformer approach. Pairwise fluctuations and covariations in band-limited amplitude envelopes were computed reflecting measures of functional connectivity. Intra-network connectivity was compared between groups using permutation testing and correlated with symptoms. We observed increased resting spectral connectivity in the default mode network (DMN) and motor networks (MOTs) in our concussion group when compared with controls, across alpha through gamma ranges. Moreover, these differences were not explained by power spectrum density within the ICNs. Furthermore, this increased coupling was significantly associated with symptoms in the DMN and MOTs-but once accounting for comorbidities (including, depression, anxiety, and ADHD) only the DMN continued to be associated with symptoms. The DMN plays a critical role in shifting between cognitive tasks. These data suggest even a single concussion can perturb the intrinsic coupling of this functionally specialized network in the brain, and may explain persistent and wide-ranging symptomatology. PMID- 29755404 TI - Cognitive Rehabilitation in Bilateral Vestibular Patients: A Computational Perspective. AB - There is evidence that vestibular sensory processing affects, and is affected by, higher cognitive processes. This is highly relevant from a clinical perspective, where there is evidence for cognitive impairments in patients with peripheral vestibular deficits. The vestibular system performs complex probabilistic computations, and we claim that understanding these is important for investigating interactions between vestibular processing and cognition. Furthermore, this will aid our understanding of patients' self-motion perception and will provide useful information for clinical interventions. We propose that cognitive training is a promising way to alleviate the debilitating symptoms of patients with complete bilateral vestibular loss (BVP), who often fail to show improvement when relying solely on conventional treatment methods. We present a probabilistic model capable of processing vestibular sensory data during both passive and active self-motion. Crucially, in our model, knowledge from multiple sources, including higher-level cognition, can be used to predict head motion. This is the entry point for cognitive interventions. Despite the loss of sensory input, the processing circuitry in BVP patients is still intact, and they can still perceive self-motion when the movement is self-generated. We provide computer simulations illustrating self-motion perception of BVP patients. Cognitive training may lead to more accurate and confident predictions, which result in decreased weighting of sensory input, and thus improved self-motion perception. Using our model, we show the possible impact of cognitive interventions to help vestibular rehabilitation in patients with BVP. PMID- 29755405 TI - Dual Paraneoplastic Endocrine Syndromes Heralding Onset of Extrapulmonary Small Cell Carcinoma: A Case Report and Narrative Review. AB - Objective: Extrapulmonary small cell carcinoma (EPSCC) is rare and frequent metastases at presentation can complicate efforts to identify a site of origin. In particular, SCC comprises <1% of prostate cancers and has been implicated in castration resistance. Methods: Clinical, laboratory, imaging, and pathology data are presented. Results: A 56-year-old man with locally advanced prostate adenocarcinoma on androgen deprivation therapy presented with a clogged nephrostomy tube. Laboratory results included calcium 13.8 mg/dL (8.5-10.5 mg/dL), albumin 3.6 g/dL (3.5-5 mg/dL), and potassium 2.8 mmol/L (3.5-5.2 mmol/L). Hypercalcemia investigation revealed intact PTH 19 pg/mL (16-87 pg/mL), 25-OH vitamin D 15.7 ng/mL (>30 ng/mL), and PTH-related peptide (PTHrP) 63.4 pmol/L (<2.3 pmol/L). Workup for hypokalemia yielded aldosterone 5.3 ng/dL (<31 ng/dL), renin 0.6 ng/mL/h (0.5-4 ng/mL/h), and 6:00 a.m. cortisol 82 ug/dL (6.7 22.6 ug/dL) with ACTH 147 pg/mL (no ref. range). High-dose Dexamethasone suppression testing suggested ACTH-dependent ectopic hypercortisolism. Contrast enhanced CT findings included masses in the liver and right renal pelvis, a heterogeneous enlarged mass in the region of the prostate invading the bladder, bilateral adrenal thickening, and lytic lesions in the pelvis and spine. Liver biopsy identified epithelioid malignancy with Ki proliferation index 98% and immunohistochemical staining positive for synaptophysin and neuron-specific enolase, compatible with high-grade small cell carcinoma. Staining for ACTH was negative; no stain for CRH was available. Two weeks after chemotherapy, 6:00 a.m. cortisol normalized and CT scans showed universal improvement. Conclusion: Extensive literature details paraneoplastic syndromes associated with SCC, but we report the first case of EPSCC diagnosed due to onset of dual paraneoplastic syndromes. PMID- 29755408 TI - Editorial: Updates and New Concepts in Regulation of Proinflammatory Gene Expression by Steroid Hormones. PMID- 29755407 TI - Circulating and Adipose Tissue mRNA Levels of Zinc-alpha2-Glycoprotein, Leptin, High-Molecular-Weight Adiponectin, and Tumor Necrosis Factor-Alpha in Colorectal Cancer Patients With or Without Obesity. AB - Objectives: To explore zinc-alpha2-glycoprotein (ZAG), leptin, high-molecular weight adiponectin (HMW-ADPN), and tumor necrosis factor-alpha (TNF-alpha) levels in serum and subcutaneous and visceral white adipose tissue (sWAT and vWAT) among normal weight (NW) and overweight/obese (OW/OB) patients with colorectal cancer (CRC). Methods: A total of 76 Chinese CRC patients (42 NW + CRC, 34 OW/OB + CRC) and 40 healthy controls were recruited. Serum levels of the adipokines of interest were measured by an enzyme-linked immunosorbent assay method, and their mRNA levels in sWAT and vWAT were determined by reverse transcription quantitative PCR methods. Results: Serum ZAG levels in the NW + CRC group were significantly increased by 11.7% compared with the healthy controls. Serum leptin levels in the OW/OB + CRC group were found to be increased by 57.7%, while HMW ADPN levels were decreased by 23.5% when compared with the NW + CRC group of CRC patients. Additionally, ZAG mRNA levels in sWAT were significantly reduced by 78.8% in OB + CRC in comparison with NW + CRC patients. ZAG mRNA levels were negatively associated with body mass index (BMI) in sWAT but positively correlated with BMI in vWAT. TNF-alpha mRNA levels in vWAT of OB + CRC patients were significantly increased by 2.8-fold when compared with NW + CRC patients. In particular, CRC was independently associated with serum ZAG levels. The risk of CRC in participants with high tertile serum ZAG levels was 5.84-fold higher than in those with low tertile ZAG levels after adjusting for age, gender, and other confounders [odds ratio (OR) = 6.84, 95% confidence interval (CI) 1.70-27.54, P = 0.03]. The CRC risk in participants with high tertile leptin levels was only 10.7% of those with low tertile leptin levels (OR = 0.11, 95% CI 0.01-0.89, P = 0.04). The area under the receiver operating characteristic (ROC) curve of ZAG was 0.66 (95% CI 0.54-0.77, P < 0.05). At the cutoff value of 1.42 ug/mL serum ZAG, the sensitivity and specificity for differentiating patients with CRC from controls were 62.2 and 69.2%, respectively. Conclusion: Serum ZAG levels were significantly increased in CRC patients. Subjects with higher circulating ZAG and lower leptin levels were more likely to have CRC than those with lower ZAG and higher leptin levels. Serum ZAG might be a potential diagnostic biomarker for CRC in the Chinese population. PMID- 29755406 TI - The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis. AB - Kisspeptin-GPR54 signaling in the hypothalamus is required for reproduction and fertility in mammals. Kiss1 neurons are key regulators of gonadotropin-releasing hormone (GnRH) release and modulation of the hypothalamic-pituitary-gonadal (HPG) axis. Arcuate Kiss1 neurons project to GnRH nerve terminals in the median eminence, orchestrating the pulsatile secretion of luteinizing hormone (LH) through the intricate interaction between GnRH pulse frequency and the pituitary gonadotrophs. Arcuate Kiss1 neurons, also known as KNDy neurons in rodents and ruminants because of their co-expression of neurokinin B and dynorphin represent an ideal hub to receive afferent inputs from other brain regions in response to physiological and environmental changes, which can regulate the HPG axis. This review will focus on studies performed primarily in rodent and ruminant species to explore potential afferent inputs to Kiss1 neurons with emphasis on the arcuate region but also considering the rostral periventricular region of the third ventricle (RP3V). Specifically, we will discuss how these inputs can be modulated by hormonal, metabolic, and environmental factors to control gonadotropin secretion and fertility. We also summarize the methods and techniques that can be used to study functional inputs into Kiss1 neurons. PMID- 29755409 TI - Glial Cells Missing 1 Regulates Equine Chorionic Gonadotrophin Beta Subunit via Binding to the Proximal Promoter. AB - Equine chorionic gonadotrophin (eCG) is a placental glycoprotein critical for early equine pregnancy and used therapeutically in a number of species to support reproductive activity. The factors in trophoblast that transcriptionally regulate eCGbeta-subunit (LHB), the gene which confers the hormones specificity for the receptor, are not known. The aim of this study was to determine if glial cells missing 1 regulates LHB promoter activity. Here, studies of the LHB proximal promoter identified four binding sites for glial cells missing 1 (GCM1) and western blot analysis confirmed GCM1 was expressed in equine chorionic girdle (ChG) and surrounding tissues. Luciferase assays demonstrated endogenous activity of the LHB promoter in BeWo choriocarcinoma cells with greatest activity by a proximal 335 bp promoter fragment. Transactivation studies in COS7 cells using an equine GCM1 expression vector showed GCM1 could transactivate the proximal 335 bp LHB promoter. Chromatin immunoprecipitation using primary ChG trophoblast cells showed GCM1 to preferentially bind to the most proximal GCM1-binding site over site 2. Mutation of site 1 but not site 2 resulted in a loss of endogenous promoter activity in BeWo cells and failure of GCM1 to transactivate the promoter in COS-7 cells. Together, these data show that GCM1 binds to site 1 in the LHB promoter but also requires the upstream segment of the LHB promoter between -119 bp and -335 bp of the translation start codon for activity. GCM1 binding partners, ETV1, ETV7, HOXA13, and PITX1, were found to be differentially expressed in the ChG between days 27 and 34 and are excellent candidates for this role. In conclusion, GCM1 was demonstrated to drive the LHB promoter, through direct binding to a predicted GCM1-binding site, with requirement for another factor(s) to bind the proximal promoter to exert this function. Based on these findings, we hypothesize that ETV7 and HOXA13 act in concert with GCM1 to initiate LHB transcription between days 30 and 31, with ETV1 partnering with GCM1 to maintain transcription. PMID- 29755412 TI - Association Between Progesterone Elevation on the Day of Human Chronic Gonadotropin Trigger and Pregnancy Outcomes After Fresh Embryo Transfer in In Vitro Fertilization/Intracytoplasmic Sperm Injection Cycles. AB - Progesterone elevation (PE) during the late follicular phase of controlled ovarian stimulation in fresh embryo transfer in vitro fertilization (IVF)/intracytoplasmic sperm injection cycles has been claimed to be associated with decreased pregnancy rates. However, the evidence is not unequivocal, and clinicians still have questions about the clinical validity of measuring P levels during the follicular phase of stimulated cycles. We reviewed the existing literature aimed at answering four relevant clinical questions, namely (i) Is gonadotropin type associated with PE during the follicular phase of stimulated cycles? (ii) Is PE on the day of human chorionic gonadotropin (hCG) associated with negative fresh embryo transfer IVF/intracytoplasmic sperm injection (ICSI) cycles outcomes in all patient subgroups? (iii) Which P thresholds are best to identify patients at risk of implantation failure due to PE in a fresh embryo transfer? and (iv) Should a freeze all policy be adopted in all the cycles with PE on the day of hCG? The existing evidence indicates that late follicular phase progesterone rise in gonadotropin releasing analog cycles is mainly caused by the supraphysiological stimulation of granulosa cells with exogenous follicle stimulating hormone. Yet, the type of gonadotropin used for stimulation seems to play no significant role on progesterone levels at the end of stimulation. Furthermore, PE is not a universal phenomenon with evidence indicating that its detrimental consequences on pregnancy outcomes do not affect all patient populations equally. Patients with high ovarian response to control ovarian stimulation are more prone to exhibit PE at the late follicular phase. However, in studies showing an overall detrimental effect of PE on pregnancy rates, the adverse effect of PE on endometrial receptivity seems to be offset, at least in part, by the availability of good quality embryo for transfer in women with a high ovarian response. Given the limitations of the currently available assays to measure progesterone at low ranges, caution should be applied to adopt specific cutoff values above which the effect of progesterone rise could be considered detrimental and to recommend "freeze-all" based solely on pre-defined cutoff points. PMID- 29755410 TI - Mitochondrial Chaperones in the Brain: Safeguarding Brain Health and Metabolism? AB - The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases. PMID- 29755413 TI - Seminal Plasma Activity to Improve Implantation in In Vitro Fertilization-How Can It Be Used in Daily Practice? PMID- 29755411 TI - Time-of-Day Effects on Metabolic and Clock-Related Adjustments to Cold. AB - Background: Daily cyclic changes in environmental conditions are key signals for anticipatory and adaptive adjustments of most living species, including mammals. Lower ambient temperature stimulates the thermogenic activity of brown adipose tissue (BAT) and skeletal muscle. Given that the molecular components of the endogenous biological clock interact with thermal and metabolic mechanisms directly involved in the defense of body temperature, the present study evaluated the differential homeostatic responses to a cold stimulus at distinct time windows of the light/dark-cycle. Methods: Male Wistar rats were subjected to a single episode of 3 h cold ambient temperature (4 degrees C) at one of 6 time points starting at Zeitgeber Times 3, 7, 11, 15, 19, and 23. Metabolic rate, core body temperature, locomotor activity (LA), feeding, and drinking behaviors were recorded during control and cold conditions at each time-point. Immediately after the stimulus, rats were euthanized and both the soleus and BAT were collected for real-time PCR. Results: During the light phase (i.e., inactive phase), cold exposure resulted in a slight hyperthermia (p < 0.001). Light phase cold exposure also increased metabolic rate and LA (p < 0.001). In addition, the prevalence of fat oxidative metabolism was attenuated during the inactive phase (p < 0.001). These metabolic changes were accompanied by time-of-day and tissue-specific changes in core clock gene expression, such as DBP (p < 0.0001) and REV-ERBalpha (p < 0.01) in the BAT and CLOCK (p < 0.05), PER2 (p < 0.05), CRY1 (p < 0.05), CRY2 (p < 0.01), and REV-ERBalpha (p < 0.05) in the soleus skeletal muscle. Moreover, genes involved in substrate oxidation and thermogenesis were affected in a time-of-day and tissue-specific manner by cold exposure. Conclusion: The time-of-day modulation of substrate mobilization and oxidation during cold exposure provides a clear example of the circadian modulation of physiological and metabolic responses. Interestingly, after cold exposure, time-of-day mostly affected circadian clock gene expression in the soleus muscle, despite comparable changes in LA over the light-dark-cycle. The current findings add further evidence for tissue-specific actions of the internal clock in different peripheral organs such as skeletal muscle and BAT. PMID- 29755414 TI - Non-Synonymous Single-Nucleotide Polymorphisms and Physical Activity Interactions on Adiposity Parameters in Malaysian Adolescents. AB - Background: Several non-synonymous single-nucleotide polymorphisms (nsSNPs) have been shown to be associated with obesity. Little is known about their associations and interactions with physical activity (PA) in relation to adiposity parameters among adolescents in Malaysia. Methods: We examined whether (a) PA and (b) selected nsSNPs are associated with adiposity parameters and whether PA interacts with these nsSNPs on these outcomes in adolescents from the Malaysian Health and Adolescents Longitudinal Research Team study (n = 1,151). Body mass indices, waist-hip ratio, and percentage body fat (% BF) were obtained. PA was assessed using Physical Activity Questionnaire for Older Children (PAQ-C). Five nsSNPs were included: beta-3 adrenergic receptor (ADRB3) rs4994, FABP2 rs1799883, GHRL rs696217, MC3R rs3827103, and vitamin D receptor rs2228570, individually and as combined genetic risk score (GRS). Associations and interactions between nsSNPs and PAQ-C scores were examined using generalized linear model. Results: PAQ-C scores were associated with % BF (beta = -0.44 [95% confidence interval -0.72, -0.16], p = 0.002). The CC genotype of ADRB3 rs4994 (beta = -0.16 [-0.28, -0.05], corrected p = 0.01) and AA genotype of MC3R rs3827103 (beta = -0.06 [-0.12, -0.00], p = 0.02) were significantly associated with % BF compared to TT and GG genotypes, respectively. Significant interactions with PA were found between ADRB3 rs4994 (beta = -0.05 [-0.10, -0.01], p = 0.02) and combined GRS (beta = -0.03 [-0.04, -0.01], p = 0.01) for % BF. Conclusion: Higher PA score was associated with reduced % BF in Malaysian adolescents. Of the nsSNPs, ADRB3 rs4994 and MC3R rs3827103 were associated with % BF. Significant interactions with PA were found for ADRB3 rs4994 and combined GRS on % BF but not on measurements of weight or circumferences. Targeting body fat represent prospects for molecular studies and lifestyle intervention in this population. PMID- 29755415 TI - Mitochondrial Dynamics in Type 2 Diabetes and Cancer. AB - Mitochondria are bioenergetic, biosynthetic, and signaling organelles that control various aspects of cellular and organism homeostasis. Quality control mechanisms are in place to ensure maximal mitochondrial function and metabolic homeostasis at the cellular level. Dysregulation of these pathways is a common theme in human disease. In this mini-review, we discuss how alterations of the mitochondrial network influences mitochondrial function, focusing on the molecular regulators of mitochondrial dynamics (organelle's shape and localization). We highlight similarities and critical differences in the mitochondrial network of cancer and type 2 diabetes, which may be relevant for treatment of these diseases. PMID- 29755416 TI - Complete Genomic Analysis of a Salmonella enterica Serovar Typhimurium Isolate Cultured From Ready-to-Eat Pork in China Carrying One Large Plasmid Containing mcr-1. AB - One mcr-1-carrying ST34-type Salmonella Typhimurium WW012 was cultured from 3,200 ready-to-eat (RTE) pork samples in 2014 in China. Broth dilution method was applied to obtain the antimicrobial susceptibility of Salmonella Typhimurium WW012. Broth matting assays were carried out to detect transferability of this phenotype and whole-genome sequencing was performed to analyze its genomic characteristic. Thirty out of 3,200 RTE samples were positive for Salmonella and the three most frequent serotypes were identified as S. Derby (n = 8), S. Typhimurium (n = 6), and S. Enteritidis (n = 6). One S. Typhimurium isolate (S. Typhimurium WW012) cultured from RTE prepared pork was found to contain the mcr-1 gene. S. Typhimurium WW012 expressed a level of high resistance to seven different antimicrobial compounds in addition to colistin (MIC = 8 mg/L). A single plasmid, pWW012 (151,609-bp) was identified and found to be of an IncHI2/HI2A type that encoded a mcr-1 gene along with six additional antimicrobial resistance genes. Plasmid pWW012 contained an IS30-mcr-1-orf-orf IS30 composite transposon that can be successfully transferred to Escherichia coli J53. When assessed further, the latter demonstrated considerable similarity to three plasmids pHYEC7-mcr-1, pSCC4, and pHNSHP45-2, respectively. Furthermore, plasmid pWW012 also contained a multidrug resistance (MDR) genetic structure IS26 aadA2-cmlA2-aadA1-IS406-sul3-IS26-dfrA12-aadA2-IS26, which showed high similarity to two plasmids, pHNLDF400 and pHNSHP45-2, respectively. Moreover, genes mapping to the chromosome (4,991,167-bp) were found to carry 28 mutations, related to two component regulatory systems (pmrAB, phoPQ) leading to modifications of lipid A component of the lipopolysaccharide structure. Additionally, one mutation (D87N) in the quinolone resistance determining region (QRDR) gene of gyrA was identified in this mcr-1 harboring S. Typhimurium. In addition, various virulence factors and heavy metal resistance-encoding genes were also identified on the genome of S. Typhimurium WW012. This is the first report of the complete nucleotide sequence of mcr-1-carrying MDR S. Typhimurium strain from RTE pork in China. PMID- 29755418 TI - Microbiome and Culture Based Analysis of Chronic Rhinosinusitis Compared to Healthy Sinus Mucosa. AB - The role of bacteria in chronic rhinosinusitis (CRS) is still not well understood. Whole microbiome analysis adds new aspects to our current understanding that is mainly based on isolated bacteria. It is still unclear how the results of microbiome analysis and the classical culture based approaches interrelate. To address this, middle meatus swabs and tissue samples were obtained during sinus surgery in 5 patients with CRS with nasal polyps (CRSwNP), 5 patients with diffuse CRS without nasal polyps (CRSsNP), 5 patients with unilateral purulent maxillary CRS (upm CRS) and 3 patients with healthy sinus mucosa. Swabs were cultured, and associated bacteria were identified. Additionally, parts of each tissue sample also underwent culture approaches, and in parallel DNA was extracted for 16S rRNA gene amplicon-based microbiome analysis. From tissue samples 4.2 +/- 1.2 distinct species per patient were cultured, from swabs 5.4 +/- 1.6. The most frequently cultured species from the swabs were Propionibacterium acnes, Staphylococcus epidermidis, Corynebacterium spp. and Staphylococcus aureus. The 16S-RNA gene analysis revealed no clear differentiation of the bacterial community of healthy compared to CRS samples of unilateral purulent maxillary CRS and CRSwNP. However, the bacterial community of CRSsNP differed significantly from the healthy controls. In the CRSsNP samples Flavobacterium, Pseudomonas, Pedobacter, Porphyromonas, Stenotrophomonas, and Brevundimonas were significantly enriched compared to the healthy controls. Species isolated from culture did not generally correspond with the most abundant genera in microbiome analysis. Only Fusobacteria, Parvimonas, and Prevotella found in 2 unilateral purulent maxillary CRS samples by the cultivation dependent approach were also found in the cultivation independent approach in high abundance, suggesting a classic infectious pathogenesis of odontogenic origin in these two specific cases. Alterations of the bacterial community might be a more crucial factor for the development of CRSsNP compared to CRSwNP. Further studies are needed to investigate the relation between bacterial community characteristics and the development of CRSsNP. PMID- 29755417 TI - An Integrated Response of Trichodesmium erythraeum IMS101 Growth and Photo Physiology to Iron, CO2, and Light Intensity. AB - We have assessed how varying CO2 (180, 380, and 720 MUatm) and growth light intensity (40 and 400 MUmol photons m-2 s-1) affected Trichodesmium erythraeum IMS101 growth and photophysiology over free iron (Fe') concentrations between 20 and 9,600 pM. We found significant iron dependencies of growth rate and the initial slope and maximal relative PSII electron transport rates (rPm). Under iron-limiting concentrations, high-light increased growth rates and rPm; possibly indicating a lower allocation of resources to iron-containing photosynthetic proteins. Higher CO2 increased growth rates across all iron concentrations, enabled growth to occur at lower Fe' concentrations, increased rPm and lowered the iron half saturation constants for growth (Km). We attribute these CO2 responses to the operation of the CCM and the ATP spent/saved for CO2 uptake and transport at low and high CO2, respectively. It seems reasonable to conclude that T. erythraeum IMS101 can exhibit a high degree of phenotypic plasticity in response to CO2, light intensity and iron-limitation. These results are important given predictions of increased dissolved CO2 and water column stratification (i.e., higher light exposures) over the coming decades. PMID- 29755420 TI - Characterization of Two Novel Bacteriophages Infecting Multidrug-Resistant (MDR) Acinetobacter baumannii and Evaluation of Their Therapeutic Efficacy in Vivo. AB - Acinetobacter baumannii is emerging as a challenging nosocomial pathogen due to its rapid evolution of antibiotic resistance. We report characterization of two novel bacteriophages, PBAB08 and PBAB25, infecting clinically isolated, multidrug resistant (MDR) A. baumannii strains. Both phages belonged to Myoviridae of Caudovirales as their morphology observed under an electron microscope. Their genomes were double stranded linear DNAs of 42,312 base pairs and 40,260 base pairs, respectively. The two phages were distinct from known Acinetobacter phages when whole genome sequences were compared. PBAB08 showed a 99% similarity with 57% sequence coverage to phage AB1 and PBAB25 showed a 97% similarity with 78% sequence coverage to phage IME_AB3. BLASTN significant alignment coverage of all other known phages were <30%. Seventy six and seventy genes encoding putative phage proteins were found in the genomes of PBAB08 and PBAB25, respectively. Their genomic organizations and sequence similarities were consistent with the modular theory of phage evolution. Therapeutic efficacy of a phage cocktail containing the two and other phages were evaluated in a mice model with nasal infection of MDR A. baumannii. Mice treated with the phage cocktail showed a 2.3 fold higher survival rate than those untreated in 7 days post infection. In addition, 1/100 reduction of the number of A. baumannii in the lung of the mice treated with the phage cocktail was observed. Also, inflammatory responses of mice which were injected with the phage cocktail by intraperitoneal, intranasal, or oral route was investigated. Increase in serum cytokine was minimal regardless of the injection route. A 20% increase in IgE production was seen in intraperitoneal injection route, but not in other routes. Thus, the cocktail containing the two newly isolated phages could serve as a potential candidate for therapeutic interventions to treat A. baummannii infections. PMID- 29755419 TI - The Fusarium graminearum Histone Acetyltransferases Are Important for Morphogenesis, DON Biosynthesis, and Pathogenicity. AB - Post-translational modifications of chromatin structure by histone acetyltransferase (HATs) play a central role in the regulation of gene expression and various biological processes in eukaryotes. Although HAT genes have been studied in many fungi, few of them have been functionally characterized. In this study, we identified and characterized four putative HATs (FgGCN5, FgRTT109, FgSAS2, FgSAS3) in the plant pathogenic ascomycete Fusarium graminearum, the causal agent of Fusarium head blight of wheat and barley. We replaced the genes and all mutant strains showed reduced growth of F. graminearum. The DeltaFgSAS3 and DeltaFgGCN5 mutant increased sensitivity to oxidative and osmotic stresses. Additionally, DeltaFgSAS3 showed reduced conidia sporulation and perithecium formation. Mutant DeltaFgGCN5 was unable to generate any conidia and lost its ability to form perithecia. Our data showed also that FgSAS3 and FgGCN5 are pathogenicity factors required for infecting wheat heads as well as tomato fruits. Importantly, almost no Deoxynivalenol (DON) was produced either in DeltaFgSAS3 or DeltaFgGCN5 mutants, which was consistent with a significant downregulation of TRI genes expression. Furthermore, we discovered for the first time that FgSAS3 is indispensable for the acetylation of histone site H3K4, while FgGCN5 is essential for the acetylation of H3K9, H3K18, and H3K27. H3K14 can be completely acetylated when FgSAS3 and FgGCN5 were both present. The RNA-seq analyses of the two mutant strains provide insight into their functions in development and metabolism. Results from this study clarify the functional divergence of HATs in F. graminearum, and may provide novel targeted strategies to control secondary metabolite expression and infections of F. graminearum. PMID- 29755421 TI - Fungal Biodiversity and Their Role in Soil Health. AB - Soil health, and the closely related terms of soil quality and fertility, is considered as one of the most important characteristics of soil ecosystems. The integrated approach to soil health assumes that soil is a living system and soil health results from the interaction between different processes and properties, with a strong effect on the activity of soil microbiota. All soils can be described using physical, chemical, and biological properties, but adaptation to environmental changes, driven by the processes of natural selection, are unique to the latter one. This mini review focuses on fungal biodiversity and its role in the health of managed soils as well as on the current methods used in soil mycobiome identification and utilization next generation sequencing (NGS) approaches. The authors separately focus on agriculture and horticulture as well as grassland and forest ecosystems. Moreover, this mini review describes the effect of land-use on the biodiversity and succession of fungi. In conclusion, the authors recommend a shift from cataloging fungal species in different soil ecosystems toward a more global analysis based on functions and interactions between organisms. PMID- 29755423 TI - Enzymatic Synthesis of Protein Hydrolysates From Animal Proteins: Exploring Microbial Peptidases. PMID- 29755422 TI - Porcine Endogenous Retrovirus (PERV) - Molecular Structure and Replication Strategy in the Context of Retroviral Infection Risk of Human Cells. AB - The xenotransplantation of porcine tissues may help overcome the shortage of human organs for transplantation. However, there are some concerns about recipient safety because the risk of porcine endogenous retrovirus (PERV) transmission to human cells remains unknown. Although, to date, no PERV infections have been noted in vivo, the possibility of such infections has been confirmed in vitro. Better understanding of the structure and replication cycle of PERVs is a prerequisite for determining the risk of infection and planning PERV-detection strategies. This review presents the current state of knowledge about the structure and replication cycle of PERVs in the context of retroviral infection risk. PMID- 29755424 TI - Genetic Adaptation to Growth Under Laboratory Conditions in Escherichia coli and Salmonella enterica. AB - Experimental evolution under controlled laboratory conditions is becoming increasingly important to address various evolutionary questions, including, for example, the dynamics and mechanisms of genetic adaptation to different growth and stress conditions. In such experiments, mutations typically appear that increase the fitness under the conditions tested (medium adaptation), but that are not necessarily of interest for the specific research question. Here, we have identified mutations that appeared during serial passage of E. coli and S. enterica in four different and commonly used laboratory media and measured the relative competitive fitness and maximum growth rate of 111 genetically re constituted strains, carrying different single and multiple mutations. Little overlap was found between the mutations that were selected in the two species and the different media, implying that adaptation occurs via different genetic pathways. Furthermore, we show that commonly occurring adaptive mutations can generate undesired genetic variation in a population and reduce the accuracy of competition experiments. However, by introducing media adaptation mutations with large effects into the parental strain that was used for the evolution experiment, the variation (standard deviation) was decreased 10-fold, and it was possible to measure fitness differences between two competitors as small as |s| < 0.001. PMID- 29755425 TI - Identification and Characterization of c-di-GMP Metabolic Enzymes of Leptospira interrogans and c-di-GMP Fluctuations After Thermal Shift and Infection. AB - Leptospirosis is a widespread zoonotic disease caused by pathogenic Leptospira species. The most common species, Leptospira interrogans, can transfer from contaminated soil or water to the human body. It is able to survive these changing environments through sensing and responding to the changes of environmental cues. Cyclic di-GMP (c-di-GMP) is a special secondary messenger in bacteria, which can respond to the environment and regulate diverse bacterial behaviors. The c-di-GMP levels in bacterial cells are regulated by diguanylatecyclases (DGC) and phosphodiesterases (PDE), which are responsible for synthesizing or hydrolyzing c-di-GMP, respectively. In this study, distribution and phylogenetics of c-di-GMP metabolic genes among 15 leptospiral species were systematically analyzed. Bioinformatics analysis revealed that leptospiral species contain a multitude of c-di-GMP metabolic genes. C-di-GMP metabolic genes in L. interrogans strain Lai 56601 were further analyzed and the results showed that these genes have very diverse expression patterns. Most of the putative DGCs and PDEs possess enzymatic activities, as determined by riboswitch-based dual fluorescence reporters in vivo or HPLC in vitro. Furtherer analysis of subdomains from GGDEF-containing proteins revealed that the ability to synthesize c-di-GMP was lost when the GAF domain from LA1483 and PAS domain from LA2932 were deleted, while deletion of the REC domain from LA2528 did not affect its ability to synthesize c-di-GMP. Furthermore, high temperatures generally resulted in low c di-GMP concentrations in L. interrogans and most of the c-di-GMP metabolic genes exhibited differential temperature regulation. Also, infection of murine J774A.1 cells resulted in reduced c-di-GMP levels, while no significant change of c-di GMP metabolic genes on transcriptional levels were observed during the infection of J774A.1 cells. Taken together, these results provide a basic platform for future studies of c-di-GMP signaling pathways in Leptospira. PMID- 29755426 TI - Comparative Genomics and Mutational Analysis Reveals a Novel XoxF-Utilizing Methylotroph in the Roseobacter Group Isolated From the Marine Environment. AB - The Roseobacter group comprises a significant group of marine bacteria which are involved in global carbon and sulfur cycles. Some members are methylotrophs, using one-carbon compounds as a carbon and energy source. It has recently been shown that methylotrophs generally require a rare earth element when using the methanol dehydrogenase enzyme XoxF for growth on methanol. Addition of lanthanum to methanol enrichments of coastal seawater facilitated the isolation of a novel methylotroph in the Roseobacter group: Marinibacterium anthonyi strain La 6. Mutation of xoxF5 revealed the essential nature of this gene during growth on methanol and ethanol. Physiological characterization demonstrated the metabolic versatility of this strain. Genome sequencing revealed that strain La 6 has the largest genome of all Roseobacter group members sequenced to date, at 7.18 Mbp. Multilocus sequence analysis (MLSA) showed that whilst it displays the highest core gene sequence similarity with subgroup 1 of the Roseobacter group, it shares very little of its pangenome, suggesting unique genetic adaptations. This research revealed that the addition of lanthanides to isolation procedures was key to cultivating novel XoxF-utilizing methylotrophs from the marine environment, whilst genome sequencing and MLSA provided insights into their potential genetic adaptations and relationship to the wider community. PMID- 29755428 TI - Culex quinquefasciatus (Diptera: Culicidae) From Florida Transmitted Zika Virus. AB - We report a laboratory colony of Culex quinquefasciatus mosquitoes were experimentally able to salivate Zika virus (ZIKV, Flaviviridae; Flavivirus) at 16 days post infection (dpi). ZIKV RNA was detected in bodies and in saliva deposited on filter paper cards with subsequent studies demonstrating the presence of live ZIKV in saliva. PMID- 29755427 TI - 16S rRNA Gene Sequencing for Deciphering the Colorectal Cancer Gut Microbiome: Current Protocols and Workflows. AB - The human gut holds the densest microbiome ecosystem essential in maintaining a healthy host physiology, whereby disruption of this ecosystem has been linked to the development of colorectal cancer (CRC). The advent of next-generation sequencing technologies such as the 16S rRNA gene sequencing has enabled characterization of the CRC gut microbiome architecture in an affordable and culture-free approach. Nevertheless, the lack of standardization in handling and storage of biospecimens, nucleic acid extraction, 16S rRNA gene primer selection, length, and depth of sequencing and bioinformatics analyses have contributed to discrepancies found in various published studies of this field. Accurate characterization of the CRC microbiome found in different stages of CRC has the potential to be developed into a screening tool in the clinical setting. This mini review aims to concisely compile all available CRC microbiome studies performed till end of 2016 and to suggest standardized protocols that are crucial in developing a gut microbiome screening panel for CRC. PMID- 29755429 TI - Cyanobacterial Community Composition and Bacteria-Bacteria Interactions Promote the Stable Occurrence of Particle-Associated Bacteria. AB - Within meso/eutrophic freshwater ecosystems the dominance of cyanobacterial blooms during summer months has substantial impacts on ecosystem function with the production of toxins and subsequent induction of hypoxia altering food web structures and biogeochemical cycles. Cyanobacterial aggregates are extensively colonized by heterotrophic bacteria that provide the cyanobacteria with key nutrients and contribute towards remineralisation of organic matter. Here we sampled from five sites within a shallow eutrophic pond over a 6 months period, relating changes in the abundance of particle-associated heterotrophic taxa to phytoplankton abundance, toxin gene copies and physiochemical properties. The abundance of a majority of particle-associated bacteria were stable, in that they persisted despite perturbation. Cyanobacterial species abundance more likely correlated with stable rather than unstable bacteria and unstable bacteria were associated with allochthonous (terrestrial) organic matter. The occurrence of the most stable bacteria was correlated with large numbers of other bacteria suggesting bacteria-bacteria interactions have implications for the stable occurrence of microorganisms on particles. Freshwater ecosystems are frequently inundated with fresh nutrients in the form of surface runoff and experience an increasing number of high temperature days. In addition to increasing the severity and longevity of cyanobacterial blooms, run-off changes the nature of the particle-associated community compromising stability. This disruption has the potential to drive changes in the carbon and nitrogen cycles and requires further attention. PMID- 29755430 TI - Distribution Patterns of Polyphosphate Metabolism Pathway and Its Relationships With Bacterial Durability and Virulence. AB - Inorganic polyphosphate (polyP) is a linear polymer of orthophosphate residues. It is reported to be present in all life forms. Experimental studies showed that polyP plays important roles in bacterial durability and virulence. Here we investigated the relationships of polyP with bacterial durability and virulence theoretically. Bacterial lifestyle, environmental persistence, virulence factors (VFs), and species evolution are all included in the analysis. The presence of seven genes involved in polyP metabolism (ppk1, ppk2, pap, surE, gppA, ppnK, and ppgK) and 2595 core VFs were verified in 944 bacterial reference proteomes for distribution patterns via HMMER. Proteome size and VFs were compared in terms of gain and loss of polyP pathway. Literature mining and phylogenetic analysis were recruited to support the study. Our analyzes revealed that the presence of polyP metabolism is positively correlated with bacterial proteome size and the number of virulence genes. A potential relationship of polyP in bacterial lifestyle and environmental durability is suggested. Evolutionary analysis shows that polyP genes are randomly lost along the phylogenetic tree. In sum, based on our theoretical analysis, we confirmed that bacteria with polyP metabolism are associated with high environmental durability and more VFs. PMID- 29755431 TI - Outer Membrane Vesicles: Current Status and Future Direction of These Novel Vaccine Adjuvants. AB - Adjuvants have been of great interest to vaccine formulation as immune stimulators. Prior to the recent research in the field of immune stimulation, conventional adjuvants utilized for aluminum-based vaccinations dominated the adjuvant market. However, these conventional adjuvants have demonstrated obvious defects, including poor protective efficiency and potential side effects, which hindered their widespread circulation. Outer membrane vesicles (OMVs) naturally exist in gram-negative bacteria and are capable of engaging innate and adaptive immunity and possess intrinsic adjuvant capacity. They have shown tremendous potential for adjuvant application and have recently been successfully applied in various vaccine platforms. Adjuvants could be highly effective with the introduction of OMVs, providing complete immunity and with the benefits of low toxicity; further, OMVs might also be designed as an advanced mucosal delivery vehicle for use as a vaccine carrier. In this review, we discuss adjuvant development, and provide an overview of novel OMV adjuvants and delivery vehicles. We also suggest future directions for adjuvant research. Overall, we believe that OMV adjuvants would find high value in vaccine formulation in the future. PMID- 29755432 TI - Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer. AB - Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues (n = 11), PDX-tissues (n = 22), PDX-derived cell lines (n = 13), and patient-derived tumor cell lines (n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in murine cells, in PDX tissues and early thereof-derived cell cultures. We conclude that further analysis is needed concerning their impact on results obtained from studies performed with PDX but also with murine tumor models. PMID- 29755433 TI - De Novo DNA Synthesis in Aedes aegypti Midgut Cells as a Complementary Strategy to Limit Dengue Viral Replication. AB - Aedes aegypti is the main vector of Dengue Virus, carrying the virus during the whole mosquito life post-infection. Few mosquito fitness costs have been associated to the virus infection, thereby allowing for a swift dissemination. In order to diminish the mosquito population, public health agency use persistent chemicals with environmental impact for disease control. Most countries barely use biological controls, if at all. With the purpose of developing novel Dengue control strategies, a detailed understanding of the unexplored virus-vector interactions is urgently needed. Damage induced (through tissue injury or bacterial invasion) DNA duplication (endoreplication) has been described in insects during epithelial cells renewal. Here, we delved into the mosquito midgut tissue ability to synthesize DNA de novo; postulating that Dengue virus infection could trigger a protective endoreplication mechanism in some mosquito cells. We hypothesized that the Aedes aegypti orthologue of the Drosophila melanogaster hindsight gene (not previously annotated in Aedes aegypti transcriptome/genome) is part of the Delta-Notch pathway. The activation of this transcriptional cascade leads to genomic DNA endoreplication. The amplification of the genomic copies of specific genes ultimately limits the viral spreading during infection. Conversely, inhibiting DNA synthesis capacity, hence endoreplication, leads to a higher viral replication. PMID- 29755434 TI - A Polyphasic and Taxogenomic Evaluation Uncovers Arcobacter cryaerophilus as a Species Complex That Embraces Four Genomovars. AB - The species Arcobacter cryaerophilus is found in many food products of animal origin and is the dominating species in wastewater. In addition, it is associated with cases of farm animal and human infectious diseases,. The species embraces two subgroups i.e., 1A (LMG 24291T = LMG 9904T) and 1B (LMG 10829) that can be differentiated by their 16S rRNA-RFLP pattern. However, some authors, on the basis of the shared intermediate levels of DNA-DNA hybridization, have suggested abandoning the subgroup classification. This contradiction indicates that the taxonomy of this species is not yet resolved. The objective of the present study was to perform a taxonomic evaluation of the diversity of A. cryaerophilus. Genomic information was used along with a Multilocus Phylogenetic Analysis (MLPA) and phenotypic characterization on a group of 52 temporally and geographically dispersed strains, coming from different types of samples and hosts from nine countries. The MLPA analysis showed that those strains formed four clusters (I IV). Values of Average Nucleotide Identity (ANI) and in silico DNA-DNA Hybridization (isDDH) obtained between 13 genomes representing strains of the four clusters were below the proposed cut-offs of 96 and 70%, respectively, confirming that each of the clusters represented a different genomic species. However, none of the evaluated phenotypic tests enabled their unequivocal differentiation into species. Therefore, the genomic delimited clusters should be considered genomovars of the species A. cryaerophilus. These genomovars could have different clinical importance, since only the cluster I included strains isolated from human specimens. The discovery of at least one stable distinctive phenotypic character would be needed to define each cluster or genomovar as a different species. Until then, we propose naming them "A. cryaerophilus gv. pseudocryaerophilus" (Cluster I = LMG 10229T), "A. cryaerophilus gv. crypticus" (Cluster II = LMG 9065T), "A. cryaerophilus gv. cryaerophilus" (Cluster III = LMG 24291T) and "A. cryaerophilus gv. occultus" (Cluster IV = LMG 29976T). PMID- 29755435 TI - Analysis of Phylogenetic Variation of Stenotrophomonas maltophilia Reveals Human Specific Branches. AB - Stenotrophomonas maltophilia is a non-fermenting Gram-negative bacterium that is ubiquitous in the environment. In humans, this opportunistic multi-drug-resistant pathogen is responsible for a plethora of healthcare-associated infections. Here, we utilized a whole genome sequencing (WGS)-based phylogenomic core single nucleotide polymorphism (SNP) approach to characterize S. maltophilia subgroups, their potential association with human infection, and to detect any possible transmission events. In total, 89 isolates (67 clinical and 22 environmental) from Germany were sequenced. Fully finished genomes of five strains were included in the dataset for the core SNP phylogenomic analysis. WGS data were compared with conventional genotyping results as well as with underlying disease, biofilm formation, protease activity, lipopolysaccharide (LPS) SDS-PAGE profiles, and serological specificity of an antibody raised against the surface-exposed O antigen of strain S. maltophilia K279a. The WGS-based phylogenies grouped the strains into 12 clades, out of which 6 contained exclusively human and 3 exclusively environmental isolates. Biofilm formation and proteolytic activity did correlate neither with the phylogenetic tree, nor with the origin of isolates. In contrast, the genomic classification correlated well with the reactivity of the strains against the K279a O-specific antibody, as well as in part with the LPS profiles. Three clusters of clinical strains had a maximum distance of 25 distinct SNP positions, pointing to possible transmission events or acquisition from the same source. In conclusion, these findings indicate the presence of specific subgroups of S. maltophilia strains adapted to the human host. PMID- 29755437 TI - Conditionally Rare Taxa Contribute but Do Not Account for Changes in Soil Prokaryotic Community Structure. AB - The rare biosphere is predicted to aid in maintaining functional redundancy as well as contributing to community turnover across many environments. Recent developments have partially confirmed these hypotheses, while also giving new insights into dormancy and activity among rare communities. However, less attention has been paid to the rare biosphere in soils. This study provides insight into the rare biosphere's contribution to soil microbial diversity through the study of 781 soil samples representing 24 edaphically diverse sites. Results show that Bray-Curtis dissimilarity for time-sensitive conditionally rare taxa (CRT) does not correlate with whole community dissimilarity, while dissimilarity for space-sensitive CRT only weakly correlate with whole community dissimilarity. This adds to current understanding of spatiotemporal filtering of rare taxa, showing that CRT do not account for community variance across tested soils, but are under the same selective pressure as the whole community. PMID- 29755436 TI - The Effect of Hydrostatic Pressure on Enrichments of Hydrocarbon Degrading Microbes From the Gulf of Mexico Following the Deepwater Horizon Oil Spill. AB - The Deepwater Horizon oil spill was one of the largest and deepest oil spills recorded. The wellhead was located at approximately 1500 m below the sea where low temperature and high pressure are key environmental characteristics. Using cells collected 4 months following the Deepwater Horizon oil spill at the Gulf of Mexico, we set up Macondo crude oil enrichments at wellhead temperature and different pressures to determine the effect of increasing depth/pressure to the in situ microbial community and their ability to degrade oil. We observed oil degradation under all pressure conditions tested [0.1, 15, and 30 megapascals (MPa)], although oil degradation profiles, cell numbers, and hydrocarbon degradation gene abundances indicated greatest activity at atmospheric pressure. Under all incubations the growth of psychrophilic bacteria was promoted. Bacteria closely related to Oleispira antarctica RB-8 dominated the communities at all pressures. At 30 MPa we observed a shift toward Photobacterium, a genus that includes piezophiles. Alphaproteobacterial members of the Sulfitobacter, previously associated with oil-degradation, were also highly abundant at 0.1 MPa. Our results suggest that pressure acts synergistically with low temperature to slow microbial growth and thus oil degradation in deep-sea environments. PMID- 29755438 TI - Caspase-3 Inhibition Attenuates the Cytopathic Effects of EV71 Infection. AB - Previous studies demonstrate that human enterovirus 71 (EV71), a primary causative agent for hand, foot, and mouth disease, activates caspase-3 through the non-structural viral 3C protein to induce host cell apoptosis; however, until now it was unclear how 3C activates caspase-3 and how caspase-3 activation affects viral production. Our results demonstrate that 3C binds caspase-8 and caspase-9 but does not directly bind caspase-3 to activate them, and that the proteolytic activity of 3C is required by the activation of caspase-8, caspase-9, and caspase-3. Inhibition of caspase-3 activity attenuates apoptosis in 3C transfected cells. Furthermore, caspase-3 inhibitor protects host cells from the cytopathic effect of EV71 infection and prevents cell cycle arrest, which is known to be favored for EV71 viral replication. Inhibition of caspase-3 activity decreases EV71 viral protein expression and viral production, but has no effect on viral entry, replication, even polyprotein translation. Therefore, caspase-3 is exploited functionally by EV71 to facilitate its production, which suggests a novel therapeutic approach for the treatment and prevention of hand, foot, and mouth disease. PMID- 29755439 TI - Dicer-Like Proteins Regulate Sexual Development via the Biogenesis of Perithecium Specific MicroRNAs in a Plant Pathogenic Fungus Fusarium graminearum. AB - Ascospores act as the primary inoculum of Fusarium graminearum, which causes the destructive disease Fusarium head blight (FHB), or scab. MicroRNAs (miRNAs) have been reported in the F. graminearum vegetative stage, and Fgdcl2 is involved in microRNA-like RNA (milRNA) biogenesis but has no major impact on vegetative growth, abiotic stress or pathogenesis. In the present study, we found that ascospore discharge was decreased in the Fgdcl1 deletion mutant, and completely blocked in the double-deletion mutant of Fgdcl1 and Fgdcl2. Besides, more immature asci were observed in the double-deletion mutant. Interestingly, the up regulated differentially expressed genes (DEGs) common to DeltaFgdcl1 and DeltaFgdcl1/2 were related to ion transmembrane transporter and membrane components. The combination of small RNA and transcriptome sequencing with bioinformatics analysis predicted 143 novel milRNAs in wild-type perithecia, and 138 of these milRNAs partly or absolutely depended on Fgdcl1, while only 5 novel milRNAs were still obtained in the Fgdcl1 and Fgdcl2 double-deletion mutant. Furthermore, 117 potential target genes were predicted. Overall, Fgdcl1 and Fgdcl2 genes were partly functionally redundant in ascospore discharge and perithecium-specific milRNA generation in F. graminearum, and these perithecium specific milRNAs play potential roles in sexual development. PMID- 29755440 TI - Biodegradable Plastic Mulch Films: Impacts on Soil Microbial Communities and Ecosystem Functions. AB - Agricultural plastic mulch films are widely used in specialty crop production systems because of their agronomic benefits. Biodegradable plastic mulches (BDMs) offer an environmentally sustainable alternative to conventional polyethylene (PE) mulch. Unlike PE films, which need to be removed after use, BDMs are tilled into soil where they are expected to biodegrade. However, there remains considerable uncertainty about long-term impacts of BDM incorporation on soil ecosystems. BDMs potentially influence soil microbial communities in two ways: first, as a surface barrier prior to soil incorporation, indirectly affecting soil microclimate and atmosphere (similar to PE films) and second, after soil incorporation, as a direct input of physical fragments, which add carbon, microorganisms, additives, and adherent chemicals. This review summarizes the current literature on impacts of plastic mulches on soil biological and biogeochemical processes, with a special emphasis on BDMs. The combined findings indicated that when used as a surface barrier, plastic mulches altered soil microbial community composition and functioning via microclimate modification, though the nature of these alterations varied between studies. In addition, BDM incorporation into soil can result in enhanced microbial activity and enrichment of fungal taxa. This suggests that despite the fact that total carbon input from BDMs is minuscule, a stimulatory effect on microbial activity may ultimately affect soil organic matter dynamics. To address the current knowledge gaps, long term studies and a better understanding of impacts of BDMs on nutrient biogeochemistry are needed. These are critical to evaluating BDMs as they relate to soil health and agroecosystem sustainability. PMID- 29755442 TI - The Algicidal Fungus Trametes versicolor F21a Eliminating Blue Algae via Genes Encoding Degradation Enzymes and Metabolic Pathways Revealed by Transcriptomic Analysis. AB - The molecular mechanism underlying the elimination of algal cells by fungal mycelia has not been fully understood. Here, we applied transcriptomic analysis to investigate the gene expression and regulation at time courses of Trametes versicolor F21a during the algicidal process. The obtained results showed that a total of 193, 332, 545, and 742 differentially expressed genes were identified at 0, 6, 12, and 30 h during the algicidal process, respectively. The gene ontology terms were enriched into glucan 1,4-alpha-glucosidase activity, hydrolase activity, lipase activity, and endopeptidase activity. The KEGG pathways were enriched in degradation and metabolism pathways including Glycolysis/Gluconeogenesis, Pyruvate metabolism, the Biosynthesis of amino acids, etc. The total expression levels of all Carbohydrate-Active enZYmes (CAZyme) genes for the saccharide metabolism were increased by two folds relative to the control. AA5, GH18, GH5, GH79, GH128, and PL8 were the top six significantly up regulated modules among 43 detected CAZyme modules. Four available homologous decomposition enzymes of other species could partially inhibit the growth of algal cells. The facts suggest that the algicidal mode of T. versicolor F21a might be associated with decomposition enzymes and several metabolic pathways. The obtained results provide a new candidate way to control algal bloom by application of decomposition enzymes in the future. PMID- 29755441 TI - A Genomic Outlook on Bioremediation: The Case of Arsenic Removal. AB - Microorganisms play a major role in biogeochemical cycles. As such they are attractive candidates for developing new or improving existing biotechnological applications, in order to deal with the accumulation and pollution of organic and inorganic compounds. Their ability to participate in bioremediation processes mainly depends on their capacity to metabolize toxic elements and catalyze reactions resulting in, for example, precipitation, biotransformation, dissolution, or sequestration. The contribution of genomics may be of prime importance to a thorough understanding of these metabolisms and the interactions of microorganisms with pollutants at the level of both single species and microbial communities. Such approaches should pave the way for the utilization of microorganisms to design new, efficient and environmentally sound remediation strategies, as exemplified by the case of arsenic contamination, which has been declared as a major risk for human health in various parts of the world. PMID- 29755443 TI - Genomic Organization and Expression of Iron Metabolism Genes in the Emerging Pathogenic Mold Scedosporium apiospermum. AB - The ubiquitous mold Scedosporium apiospermum is increasingly recognized as an emerging pathogen, especially among patients with underlying disorders such as immunodeficiency or cystic fibrosis (CF). Indeed, it ranks the second among the filamentous fungi colonizing the respiratory tract of CF patients. However, our knowledge about virulence factors of this fungus is still limited. The role of iron-uptake systems may be critical for establishment of Scedosporium infections, notably in the iron-rich environment of the CF lung. Two main strategies are employed by fungi to efficiently acquire iron from their host or from their ecological niche: siderophore production and reductive iron assimilation (RIA) systems. The aim of this study was to assess the existence of orthologous genes involved in iron metabolism in the recently sequenced genome of S. apiospermum. At first, a tBLASTn analysis using A. fumigatus iron-related proteins as query revealed orthologs of almost all relevant loci in the S. apiospermum genome. Whereas the genes putatively involved in RIA were randomly distributed, siderophore biosynthesis and transport genes were organized in two clusters, each containing a non-ribosomal peptide synthetase (NRPS) whose orthologs in A. fumigatus have been described to catalyze hydroxamate siderophore synthesis. Nevertheless, comparative genomic analysis of siderophore-related clusters showed greater similarity between S. apiospermum and phylogenetically close molds than with Aspergillus species. The expression level of these genes was then evaluated by exposing conidia to iron starvation and iron excess. The expression of several orthologs of A. fumigatus genes involved in siderophore-based iron uptake or RIA was significantly induced during iron starvation, and conversely repressed in iron excess conditions. Altogether, these results indicate that S. apiospermum possesses the genetic information required for efficient and competitive iron uptake. They also suggest an important role of the siderophore production system in iron uptake by S. apiospermum. PMID- 29755445 TI - Coral Bacterial-Core Abundance and Network Complexity as Proxies for Anthropogenic Pollution. AB - Acclimatization via changes in the stable (core) or the variable microbial diversity and/or abundance is an important element in the adaptation of coral species to environmental changes. Here, we explored the spatial-temporal dynamics, diversity and interactions of variable and core bacterial populations associated with the coral Mussismilia hispida and the surrounding water. This survey was performed on five reefs along a transect from the coast (Reef 1) to offshore (Reef 5), representing a gradient of influence of the river mouth, for almost 12 months (4 sampling times), in the dry and rainy seasons. A clear increasing gradient of organic-pollution proxies (nitrogen content and fecal coliforms) was observed from Reef 1 to Reef 5, during both seasons, and was highest at the Buranhem River mouth (Reef 1). Conversely, a clear inverse gradient of the network analysis of the whole bacterial communities also revealed more-complex network relationships at Reef 5. Our data also indicated a higher relative abundance of members of the bacterial core, dominated by Acinetobacter sp., at Reef 5, and higher diversity of site-stable bacterial populations, likely related to the higher abundance of total coliforms and N content (proxies of sewage or organic pollution) at Reef 1, during the rainy season. Thus, the less "polluted" areas may show a more-complex network and a high relative abundance of members of the bacterial core (almost 97% in some cases), resulting in a more homogeneous and well-established bacteriome among sites/samples, when the influence of the river is stronger (rainy seasons). PMID- 29755446 TI - Different Diversity and Distribution of Archaeal Community in the Aqueous and Oil Phases of Production Fluid From High-Temperature Petroleum Reservoirs. AB - To get a better knowledge on how archaeal communities differ between the oil and aqueous phases and whether environmental factors promote substantial differences on microbial distributions among production wells, we analyzed archaeal communities in oil and aqueous phases from four high-temperature petroleum reservoirs (55-65 degrees C) by using 16S rRNA gene based 454 pyrosequencing. Obvious dissimilarity of the archaeal composition between aqueous and oil phases in each independent production wells was observed, especially in production wells with higher water cut, and diversity in the oil phase was much higher than that in the corresponding aqueous phase. Statistical analysis further showed that archaeal communities in oil phases from different petroleum reservoirs tended to be more similar, but those in aqueous phases were the opposite. In the high temperature ecosystems, temperature as an environmental factor could have significantly affected archaeal distribution, and archaeal diversity raised with the increase of temperature (p < 0.05). Our results suggest that to get a comprehensive understanding of petroleum reservoirs microbial information both in aqueous and oil phases should be taken into consideration. The microscopic habitats of oil phase, technically the dispersed minuscule water droplets in the oil could be a better habitat that containing the indigenous microorganisms. PMID- 29755444 TI - Microfluidic PCR Amplification and MiSeq Amplicon Sequencing Techniques for High Throughput Detection and Genotyping of Human Pathogenic RNA Viruses in Human Feces, Sewage, and Oysters. AB - Detection and genotyping of pathogenic RNA viruses in human and environmental samples are useful for monitoring the circulation and prevalence of these pathogens, whereas a conventional PCR assay followed by Sanger sequencing is time consuming and laborious. The present study aimed to develop a high-throughput detection-and-genotyping tool for 11 human RNA viruses [Aichi virus; astrovirus; enterovirus; norovirus genogroup I (GI), GII, and GIV; hepatitis A virus; hepatitis E virus; rotavirus; sapovirus; and human parechovirus] using a microfluidic device and next-generation sequencer. Microfluidic nested PCR was carried out on a 48.48 Access Array chip, and the amplicons were recovered and used for MiSeq sequencing (Illumina, Tokyo, Japan); genotyping was conducted by homology searching and phylogenetic analysis of the obtained sequence reads. The detection limit of the 11 tested viruses ranged from 100 to 103 copies/MUL in cDNA sample, corresponding to 101-104 copies/mL-sewage, 105-108 copies/g-human feces, and 102-105 copies/g-digestive tissues of oyster. The developed assay was successfully applied for simultaneous detection and genotyping of RNA viruses to samples of human feces, sewage, and artificially contaminated oysters. Microfluidic nested PCR followed by MiSeq sequencing enables efficient tracking of the fate of multiple RNA viruses in various environments, which is essential for a better understanding of the circulation of human pathogenic RNA viruses in the human population. PMID- 29755447 TI - Stomatal Closure and SA-, JA/ET-Signaling Pathways Are Essential for Bacillus amyloliquefaciens FZB42 to Restrict Leaf Disease Caused by Phytophthora nicotianae in Nicotiana benthamiana. AB - Bacillus amyloliquefaciens FZB42 is a plant growth-promoting rhizobacterium that induces resistance to a broad spectrum of pathogens. This study analyzed the mechanism by which FZB42 restricts leaf disease caused by Phytophthora nicotianae in Nicotiana benthamiana. The oomycete foliar pathogen P. nicotianae is able to reopen stomata which had been closed by the plant innate immune response to initiate penetration and infection. Here, we showed that root colonization by B. amyloliquefaciens FZB42 restricted pathogen-mediated stomatal reopening in N. benthamiana. Abscisic acid (ABA) and salicylic acid (SA)-regulated pathways mediated FZB42-induced stomatal closure after pathogen infection. Moreover, the defense-related genes PR-1a, LOX, and ERF1, involved in the SA and jasmonic acid (JA)/ethylene (ET) signaling pathways, respectively, were overexpressed, and levels of the hormones SA, JA, and ET increased in the leaves of B. amyloliquefaciens FZB42-treated wild type plants. Disruption of one of these three pathways in N. benthamiana plants increased susceptibility to the pathogen. These suggest that SA- and JA/ET-dependent signaling pathways were important in plant defenses against the pathogen. Our data thus explain a biocontrol mechanism of soil rhizobacteria in a plant. PMID- 29755448 TI - Low-Light Anoxygenic Photosynthesis and Fe-S-Biogeochemistry in a Microbial Mat. AB - We report extremely low-light-adapted anoxygenic photosynthesis in a thick microbial mat in Magical Blue Hole, Abaco Island, The Bahamas. Sulfur cycling was reduced by iron oxides and organic carbon limitation. The mat grows below the halocline/oxycline at 30 m depth on the walls of the flooded sinkhole. In situ irradiance at the mat surface on a sunny December day was between 0.021 and 0.084 MUmol photons m-2 s-1, and UV light (<400 nm) was the most abundant part of the spectrum followed by green wavelengths (475-530 nm). We measured a light dependent carbon uptake rate of 14.5 nmol C cm-2 d-1. A 16S rRNA clone library of the green surface mat layer was dominated (74%) by a cluster (>97% sequence identity) of clones affiliated with Prosthecochloris, a genus within the green sulfur bacteria (GSB), which are obligate anoxygenic phototrophs. Typical photopigments of brown-colored GSB, bacteriochlorophyll e and (beta )isorenieratene, were abundant in mat samples and their absorption properties are well-adapted to harvest light in the available green and possibly even UV-A spectra. Sulfide from the water column (3-6 MUmol L-1) was the main source of sulfide to the mat as sulfate reduction rates in the mats were very low (undetectable-99.2 nmol cm-3 d-1). The anoxic water column was oligotrophic and low in dissolved organic carbon (175-228 MUmol L-1). High concentrations of pyrite (FeS2; 1-47 MUmol cm-3) together with low microbial process rates (sulfate reduction, CO2 fixation) indicate that the mats function as net sulfide sinks mainly by abiotic processes. We suggest that abundant Fe(III) (4.3-22.2 MUmol cm 3) is the major source of oxidizing power in the mat, and that abiotic Fe-S reactions play the main role in pyrite formation. Limitation of sulfate reduction by low organic carbon availability along with the presence of abundant sulfide scavenging iron oxides considerably slowed down sulfur cycling in these mats. PMID- 29755449 TI - Immunization Elicits Antigen-Specific Antibody Sequestration in Dorsal Root Ganglia Sensory Neurons. AB - The immune and nervous systems are two major organ systems responsible for host defense and memory. Both systems achieve memory and learning that can be retained, retrieved, and utilized for decades. Here, we report the surprising discovery that peripheral sensory neurons of the dorsal root ganglia (DRGs) of immunized mice contain antigen-specific antibodies. Using a combination of rigorous molecular genetic analyses, transgenic mice, and adoptive transfer experiments, we demonstrate that DRGs do not synthesize these antigen-specific antibodies, but rather sequester primarily IgG1 subtype antibodies. As revealed by RNA-seq and targeted quantitative PCR (qPCR), dorsal root ganglion (DRG) sensory neurons harvested from either naive or immunized mice lack enzymes (i.e., RAG1, RAG2, AID, or UNG) required for generating antibody diversity and, therefore, cannot make antibodies. Additionally, transgenic mice that express a reporter fluorescent protein under the control of Iggamma1 constant region fail to express Ighg1 transcripts in DRG sensory neurons. Furthermore, neural sequestration of antibodies occurs in mice rendered deficient in neuronal Rag2, but antibody sequestration is not observed in DRG sensory neurons isolated from mice that lack mature B cells [e.g., Rag1 knock out (KO) or MUMT mice]. Finally, adoptive transfer of Rag1-deficient bone marrow (BM) into wild-type (WT) mice or WT BM into Rag1 KO mice revealed that antibody sequestration was observed in DRG sensory neurons of chimeric mice with WT BM but not with Rag1-deficient BM. Together, these results indicate that DRG sensory neurons sequester and retain antigen-specific antibodies released by antibody-secreting plasma cells. Coupling this work with previous studies implicating DRG sensory neurons in regulating antigen trafficking during immunization raises the interesting possibility that the nervous system collaborates with the immune system to regulate antigen mediated responses. PMID- 29755450 TI - The Complexity of Fungal beta-Glucan in Health and Disease: Effects on the Mononuclear Phagocyte System. AB - beta-glucan, the most abundant fungal cell wall polysaccharide, has gained much attention from the scientific community in the last few decades for its fascinating but not yet fully understood immunobiology. Study of this molecule has been motivated by its importance as a pathogen-associated molecular pattern upon fungal infection as well as by its promising clinical utility as biological response modifier for the treatment of cancer and infectious diseases. Its immune effect is attributed to the ability to bind to different receptors expressed on the cell surface of phagocytic and cytotoxic innate immune cells, including monocytes, macrophages, neutrophils, and natural killer cells. The characteristics of the immune responses generated depend on the cell types and receptors involved. Size and biochemical composition of beta-glucans isolated from different sources affect their immunomodulatory properties. The variety of studies using crude extracts of fungal cell wall rather than purified beta glucans renders data difficult to interpret. A better understanding of the mechanisms of purified fungal beta-glucan recognition, downstream signaling pathways, and subsequent immune regulation activated, is, therefore, essential not only to develop new antifungal therapy but also to evaluate beta-glucan as a putative anti-infective and antitumor mediator. Here, we briefly review the complexity of interactions between fungal beta-glucans and mononuclear phagocytes during fungal infections. Furthermore, we discuss and present available studies suggesting how different fungal beta-glucans exhibit antitumor and antimicrobial activities by modulating the biologic responses of mononuclear phagocytes, which make them potential candidates as therapeutic agents. PMID- 29755451 TI - Autoantibody Signaling in Pemphigus Vulgaris: Development of an Integrated Model. AB - Pemphigus vulgaris (PV) is an autoimmune skin blistering disease effecting both cutaneous and mucosal epithelia. Blister formation in PV is known to result from the binding of autoantibodies (autoAbs) to keratinocyte antigens. The primary antigenic targets of pathogenic autoAbs are known to be desmoglein 3, and to a lesser extent, desmoglein 1, cadherin family proteins that partially comprise the desmosome, a protein structure responsible for maintaining cell adhesion, although additional autoAbs, whose role in blister formation is still unclear, are also known to be present in PV patients. Nevertheless, there remain large gaps in knowledge concerning the precise mechanisms through which autoAb binding induces blister formation. Consequently, the primary therapeutic interventions for PV focus on systemic immunosuppression, whose side effects represent a significant health risk to patients. In an effort to identify novel, disease specific therapeutic targets, a multitude of studies attempting to elucidate the pathogenic mechanisms downstream of autoAb binding, have led to significant advancements in the understanding of autoAb-mediated blister formation. Despite this enhanced characterization of disease processes, a satisfactory explanation of autoAb-induced acantholysis still does not exist. Here, we carefully review the literature investigating the pathogenic disease mechanisms in PV and, taking into account the full scope of results from these studies, provide a novel, comprehensive theory of blister formation in PV. PMID- 29755452 TI - Influenza Virus: A Master Tactician in Innate Immune Evasion and Novel Therapeutic Interventions. AB - Influenza is a contagion that has plagued mankind for many decades, and continues to pose concerns every year, with millions of infections globally. The frequent mutations and recombination of the influenza A virus (IAV) cast a looming threat that antigenically novel strains/subtypes will rise with unpredictable pathogenicity and fear of it evolving into a pandemic strain. There have been four major influenza pandemics, since the beginning of twentieth century, with the great 1918 pandemic being the most severe, killing more than 50 million people worldwide. The mechanisms of IAV infection, host immune responses, and how viruses evade from such defensive responses at the molecular and structural levels have been greatly investigated in the past 30 years. While this has advanced our understanding of virus-host interactions and human immunology, and has led to the development of several antiviral drugs, they have minimal impact on the clinical outcomes of infection. The heavy use of these drugs has also imposed selective pressure on IAV to evolve and develop resistance. Vaccination remains the cornerstone of public health efforts to protect against influenza; however, rapid mass-production of sufficient vaccines is unlikely to occur immediately after the beginning of a pandemic. This, therefore, requires novel therapeutic strategies against this continually emerging infectious virus with higher specificity and cross-reactivity against multiple strains/subtypes of IAVs. This review discusses essential virulence factors of IAVs that determine sustainable human-to-human transmission, the mechanisms of viral hijacking of host cells and subversion of host innate immune responses, and novel therapeutic interventions that demonstrate promising antiviral properties against IAV. This hopefully will promote discussions and investigations on novel avenues of prevention and treatment strategies of influenza, that are effective and cross protective against multiple strains/subtypes of IAV, in preparation for the advent of future IAVs and pandemics. PMID- 29755453 TI - CLEC10A Is a Specific Marker for Human CD1c+ Dendritic Cells and Enhances Their Toll-Like Receptor 7/8-Induced Cytokine Secretion. AB - Dendritic cells (DCs) are major players for the induction of immune responses. Apart from plasmacytoid DCs (pDCs), human DCs can be categorized into two types of conventional DCs: CD141+ DCs (cDC1) and CD1c+ DCs (cDC2). Defining uniquely expressed surface markers on human immune cells is not only important for the identification of DC subpopulations but also a prerequisite for harnessing the DC subset-specific potential in immunomodulatory approaches, such as antibody mediated antigen targeting. Although others identified CLEC9A as a specific endocytic receptor for CD141+ DCs, such a receptor for CD1c+ DCs has not been discovered, yet. By performing transcriptomic and flow cytometric analyses on human DC subpopulations from different lymphohematopoietic tissues, we identified CLEC10A (CD301, macrophage galactose-type C-type lectin) as a specific marker for human CD1c+ DCs. We further demonstrate that CLEC10A rapidly internalizes into human CD1c+ DCs upon binding of a monoclonal antibody directed against CLEC10A. The binding of a CLEC10A-specific bivalent ligand (the MUC-1 peptide glycosylated with N-acetylgalactosamine) is limited to CD1c+ DCs and enhances the cytokine secretion (namely TNFalpha, IL-8, and IL-10) induced by TLR 7/8 stimulation. Thus, CLEC10A represents not only a candidate to better define CD1c+ DCs-due to its high endocytic potential-CLEC10A also exhibits an interesting candidate receptor for future antigen-targeting approaches. PMID- 29755454 TI - The Use of the Humanized Mouse Model in Gene Therapy and Immunotherapy for HIV and Cancer. AB - HIV and cancer remain prevailing sources of morbidity and mortality worldwide. There are current efforts to discover novel therapeutic strategies for the treatment or cure of these diseases. Humanized mouse models provide the investigative tool to study the interaction between HIV or cancer and the human immune system in vivo. These humanized models consist of immunodeficient mice transplanted with human cells, tissues, or hematopoietic stem cells that result in reconstitution with a nearly full human immune system. In this review, we discuss preclinical studies evaluating therapeutic approaches in stem cell-based gene therapy and T cell-based immunotherapies for HIV and cancer using a humanized mouse model and some recent advances in using checkpoint inhibitors to improve antiviral or antitumor responses. PMID- 29755455 TI - RNAi-Based Identification of Gene-Specific Nuclear Cofactor Networks Regulating Interleukin-1 Target Genes. AB - The potent proinflammatory cytokine interleukin (IL)-1 triggers gene expression through the NF-kappaB signaling pathway. Here, we investigated the cofactor requirements of strongly regulated IL-1 target genes whose expression is impaired in p65 NF-kappaB-deficient murine embryonic fibroblasts. By two independent small hairpin (sh)RNA screens, we examined 170 genes annotated to encode nuclear cofactors for their role in Cxcl2 mRNA expression and identified 22 factors that modulated basal or IL-1-inducible Cxcl2 levels. The functions of 16 of these factors were validated for Cxcl2 and further analyzed for their role in regulation of 10 additional IL-1 target genes by RT-qPCR. These data reveal that each inducible gene has its own (quantitative) requirement of cofactors to maintain basal levels and to respond to IL-1. Twelve factors (Epc1, H2afz, Kdm2b, Kdm6a, Mbd3, Mta2, Phf21a, Ruvbl1, Sin3b, Suv420h1, Taf1, and Ube3a) have not been previously implicated in inflammatory cytokine functions. Bioinformatics analysis indicates that they are components of complex nuclear protein networks that regulate chromatin functions and gene transcription. Collectively, these data suggest that downstream from the essential NF-kappaB signal each cytokine inducible target gene has further subtle requirements for individual sets of nuclear cofactors that shape its transcriptional activation profile. PMID- 29755456 TI - Targeting Regulatory T Cells to Treat Patients With Systemic Lupus Erythematosus. AB - Regulatory T cells (Tregs) are central in integration and maintenance of immune homeostasis. Since breakdown of self-tolerance is a major culprit in the pathogenesis of systemic lupus erythematosus (SLE), restoration of the immune tolerance through the manipulation of Tregs can be exploited to treat patients with SLE. New information has revealed that Tregs besides their role in suppressing the immune response are important in tissue protection and regeneration. Expansion of Tregs with low-dose IL-2 represents an approach to control the autoimmune response. Moreover, control of Treg metabolism can be exploited to restore or improve their function. Here, we summarize the function and diversity of Tregs and recent strategies to improve their function in patients with SLE. PMID- 29755458 TI - Flexible Signaling of Myeloid C-Type Lectin Receptors in Immunity and Inflammation. AB - Myeloid C-type lectin receptors (CLRs) are important sensors of self and non-self that work in concert with other pattern recognition receptors (PRRs). CLRs have been previously classified based on their signaling motifs as activating or inhibitory receptors. However, specific features of the ligand binding process may result in distinct signaling through a single motif, resulting in the triggering of non-canonical pathways. In addition, CLR ligands are frequently exposed in complex structures that simultaneously bind different CLRs and other PRRs, which lead to integration of heterologous signaling among diverse receptors. Herein, we will review how sensing by myeloid CLRs and crosstalk with heterologous receptors is modulated by many factors affecting their signaling and resulting in differential outcomes for immunity and inflammation. Finding common features among those flexible responses initiated by diverse CLR-ligand partners will help to harness CLR function in immunity and inflammation. PMID- 29755459 TI - Type I Interferons, Autophagy and Host Metabolism in Leprosy. AB - For those with leprosy, the extent of host infection by Mycobacterium leprae and the progression of the disease depend on the ability of mycobacteria to shape a safe environment for its replication during early interaction with host cells. Thus, variations in key genes such as those in pattern recognition receptors (NOD2 and TLR1), autophagic flux (PARK2, LRRK2, and RIPK2), effector immune cytokines (TNF and IL12), and environmental factors, such as nutrition, have been described as critical determinants for infection and disease progression. While parkin-mediated autophagy is observed as being essential for mycobacterial clearance, leprosy patients present a prominent activation of the type I IFN pathway and its downstream genes, including OASL, CCL2, and IL10. Activation of this host response is related to a permissive phenotype through the suppression of IFN-gamma response and negative regulation of autophagy. Finally, modulation of host metabolism was observed during mycobacterial infection. Both changes in lipid and glucose homeostasis contribute to the persistence of mycobacteria in the host. M. leprae-infected cells have an increased glucose uptake, nicotinamide adenine dinucleotide phosphate generation by pentose phosphate pathways, and downregulation of mitochondrial activity. In this review, we discussed new pathways involved in the early mycobacteria-host interaction that regulate innate immune pathways or metabolism and could be new targets to host therapy strategies. PMID- 29755460 TI - Proteinase 3 Interferes With C1q-Mediated Clearance of Apoptotic Cells. AB - Proteinase 3 (PR3) is the autoantigen in granulomatosis with polyangiitis, an autoimmune necrotizing vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCAs). Moreover, PR3 is a serine protease whose membrane expression can potentiate inflammatory diseases such as ANCA-associated vasculitis and rheumatoid arthritis. During apoptosis, PR3 is co-externalized with phosphatidylserine (PS) and is known to modulate the clearance of apoptotic cells through a calreticulin (CRT)-dependent mechanism. The complement protein C1q is one mediator of efferocytosis, the clearance of altered self-cells, particularly apoptotic cells. Since PR3 and C1q are both involved in the clearance of apoptotic cells and immune response modulation and share certain common ligands (i.e., CRT and PS), we examined their possible interaction. We demonstrated that C1q binding was increased on apoptotic rat basophilic leukemia (RBL) cells that expressed PR3, and we demonstrated the direct interaction between purified C1q and PR3 molecules as shown by surface plasmon resonance. To better understand the functional consequence of this partnership, we tested C1q-dependent phagocytosis of the RBL cell line expressing PR3 and showed that PR3 impaired C1q enhancement of apoptotic cell uptake. These findings shed new light on the respective roles of C1q and PR3 in the elimination of apoptotic cells and suggest a novel potential axis to explore in autoimmune diseases characterized by a defect in apoptotic cell clearance and in the resolution of inflammation. PMID- 29755461 TI - Efficient Uptake of Recombinant Lipidated Survivin by Antigen-Presenting Cells Initiates Antigen Cross-Presentation and Antitumor Immunity. AB - Survivin is overexpressed in various types of human cancer, but rarely expressed in terminally differentiated adult tissues. Thus, survivin is a potential target antigen for a cancer vaccine. However, self-tumor-associated antigens are not highly immunogenic. Bacteria-derived lipoproteins can activate antigen-presenting cells through their toll-like receptors to enhance immune responses. In this context, lipidated survivin is an attractive candidate for cancer immunotherapy. In the present study, recombinant lipidated human survivin (LSur) was prepared from an Escherichia coli-based system. We investigated whether LSur is efficiently captured by antigen-presenting cells then facilitating effective induction of survivin cross-presentation and generation of immunity against cancer cells. Our results demonstrate that LSur, but not its non-lipidated counterpart, can activate mouse bone-marrow-derived-dendritic cells (BMDCs) to enhance cytokine (IL-6, TNF-alpha, and IL-12) secretion and costimulatory molecules (CD40, CD80, CD86, and MHC II) expression. However, the pathways involved in the capture of the recombinant lipidated antigen by antigen presenting cells have not yet been elucidated. To this end, we employ various endocytosis inhibitors to study the effect on LSur internalization. We show that the internalization of LSur is suppressed by the inhibition of various routes of endocytosis. These results suggest that endocytosis of LSur by BMDCs can be mediated by multiple mechanisms. Furthermore, LSur is trafficked to the early endosome after internalization by BMDCs. These features of LSur are advantageous for cross-presentation and the induction of antitumor immunity. We demonstrate that immunization of C57BL/6 mice with LSur under treatment with exogenous adjuvant-free formulation induce survivin-specific CD8+ T-cell responses and suppress tumor growth. The antitumor responses are mediated by CD8+ cells. Our findings indicate that LSur is a potential candidate for stimulating protective antitumor immunity. This study suggests that lipidated tumor antigens may be a promising approach for raising a robust antitumor response in cancer immunotherapy. PMID- 29755462 TI - Comparison of Phenotypic and Functional Characteristics Between Canine Non-B, Non T Natural Killer Lymphocytes and CD3+CD5dimCD21- Cytotoxic Large Granular Lymphocytes. AB - Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3 CD21-) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3+CD5dimCD21- lymphocytes are putative canine NK cells. Based on our previous reports, we hypothesized that phenotypic modulation could occur between these two populations during activation. In this study, we investigated the phenotypic and functional differences between CD3+CD5dimCD21- (cytotoxic large granular lymphocytes) and CD3-CD5-CD21- NK lymphocytes before and after culture of peripheral blood mononuclear cells isolated from normal dogs. The results of this study show that CD3+CD5dimCD21- lymphocytes can be differentiated into non-B, non T NK (CD3-CD5-CD21-TCRalphabeta-TCRgammadelta-GranzymeB+) lymphocytes through phenotypic modulation in response to cytokine stimulation. In vitro studies of purified CD3+CD5dimCD21- cells showed that CD3-CD5-CD21- cells are derived from CD3+CD5dimCD21- cells through phenotypic modulation. CD3+CD5dimCD21- cells share more NK cell functional characteristics compared with CD3-CD5-CD21- cells, including the expression of T-box transcription factors (Eomes, T-bet), the production of granzyme B and interferon-gamma, and the expression of NK cell related molecular receptors such as NKG2D and NKp30. In conclusion, the results of this study suggest that CD3+CD5dimCD21- and CD3-CD5-CD21- cells both contain a subset of putative NK cells, and the difference between the two populations may be due to the degree of maturation. PMID- 29755457 TI - Androgen-Induced Immunosuppression. AB - In addition to determining biological sex, sex hormones are known to influence health and disease via regulation of immune cell activities and modulation of target-organ susceptibility to immune-mediated damage. Systemic autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis are more prevalent in females, while cancer shows the opposite pattern. Sex hormones have been repeatedly suggested to play a part in these biases. In this review, we will discuss how androgens and the expression of functional androgen receptor affect immune cells and how this may dampen or alter immune response(s) and affect autoimmune disease incidences and progression. PMID- 29755464 TI - Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer. AB - Oncolytic viral therapy is a new promising strategy against cancer. Oncolytic viruses (OVs) can replicate in cancer cells but not in normal cells, leading to lysis of the tumor mass. Beside this primary effect, OVs can also stimulate the immune system. Tumors are an immuno-suppressive environment in which the immune system is silenced in order to avoid the immune response against cancer cells. The delivery of OVs into the tumor wakes up the immune system so that it can facilitate a strong and durable response against the tumor itself. Both innate and adaptive immune responses contribute to this process, producing an immune response against tumor antigens and facilitating immunological memory. However, viruses are recognized by the immune system as pathogens and the consequent anti viral response could represent a big hurdle for OVs. Finding a balance between anti-tumor and anti-viral immunity is, under this new light, a priority for researchers. In this review, we provide an overview of the various ways in which different components of the immune system can be allied with OVs. We have analyzed the different immune responses in order to highlight the new and promising perspectives leading to increased anti-tumor response and decreased immune reaction to the OVs. PMID- 29755463 TI - The Role of Optineurin in Antiviral Type I Interferon Production. AB - After a viral infection and the stimulation of some pattern-recognition receptors as the toll-like receptor 3 in the endosomes or the RIG-I-like receptors in the cytosol, activation of the IKK-related kinase TBK1 leads to the production of type I interferons (IFNs) after phosphorylation of the transcription factors IRF3 and IRF7. Recent findings indicate an involvement of K63-linked polyubiquitination and of the Golgi-localized protein optineurin (OPTN) in the activation of this crucial kinase involved in innate antiviral immunity. This review summarizes the sensing of viruses and the signaling leading to type I IFN production following TBK1 activation through its ubiquitination and the sensing of ubiquitin chains by OPTN at the Golgi apparatus. PMID- 29755465 TI - IRF3 Negatively Regulates Toll-Like Receptor-Mediated NF-kappaB Signaling by Targeting TRIF for Degradation in Teleost Fish. AB - NF-kappaB signaling is tightly regulated and essential to innate and adaptive immune responses, its regulatory mechanism remains unclear in various organisms, especially teleosts. In this study, we reported that IRF3 can negatively regulate TRIF-mediated NF-kappaB signaling pathway. Overexpression of IRF3 can inhibit TRIF-mediated NF-kappaB signaling pathway. However, knockdown of IRF3 had an opposite effect. IRF3 can promote the degradation of TRIF protein in mammal and fish cells, but this effect could be inhibited by MG132 treatment. Furthermore, we found that the inhibitory effect of IRF3 primary depended on its IRF association domain domain. IRF3 is crucial for the polyubiquitination and proteasomal degradation of TRIF. Our findings indicate that IRF3 negatively regulates TLR-mediated NF-kappaB signaling pathway by targeting TRIF for ubiquitination and degradation. This study provides a novel evidence on the negative regulation of innate immune signaling pathways in teleost fish and thus might provide new insights into the regulatory mechanisms in mammals. PMID- 29755467 TI - Silicosis and Silica-Induced Autoimmunity in the Diversity Outbred Mouse. AB - Epidemiological studies have confidently linked occupational crystalline silica exposure to autoimmunity, but pathogenic mechanisms and role of genetic predisposition remain poorly defined. Although studies of single inbred strains have yielded insights, understanding the relationships between lung pathology, silica-induced autoimmunity, and genetic predisposition will require examination of a broad spectrum of responses and susceptibilities. We defined the characteristics of silicosis and autoimmunity and their relationships using the genetically heterogeneous diversity outbred (DO) mouse population and determined the suitability of this model for investigating silica-induced autoimmunity. Clinically relevant lung and autoimmune phenotypes were assessed 12 weeks after a transoral dose of 0, 5, or 10 mg crystalline silica in large cohorts of DO mice. Data were further analyzed for correlations, hierarchical clustering, and sex effects. DO mice exhibited a wide range of responses to silica, including mild to severe silicosis and importantly silica-induced systemic autoimmunity. Strikingly, about half of PBS controls were anti-nuclear antibodies (ANA) positive, however, few had disease-associated specificities, whereas most ANAs in silica-exposed mice showed anti-ENA5 reactivity. Correlation and hierarchical clustering showed close association of silicosis, lung biomarkers, and anti-ENA5, while other autoimmune characteristics, such as ANA and glomerulonephritis, clustered separately. Silica-exposed males had more lung inflammation, bronchoalveolar lavage fluid cells, IL-6, and autoantibodies. DO mice are susceptible to both silicosis and silica-induced autoimmunity and show substantial individual variations reflecting their genetic diverseness and the importance of predisposition particularly for autoimmunity. This model provides a new tool for deciphering the relationship between silica exposure, genes, and disease. PMID- 29755468 TI - Approaches to Improve Chemically Defined Synthetic Peptide Vaccines. AB - Progress made in peptide-based vaccinations to induce T-cell-dependent immune responses against cancer has invigorated the search for optimal vaccine modalities. Design of new vaccine strategies intrinsically depends on the knowledge of antigen handling and optimal epitope presentation in both major histocompatibility complex class I and -II molecules by professional antigen presenting cells to induce robust CD8 and CD4 T-cell responses. Although there is a steady increase in the understanding of the underlying mechanisms that bridges innate and adaptive immunology, many questions remain to be answered. Moreover, we are in the early stage of exploiting this knowledge to clinical advantage. Several adaptations of peptide-based vaccines like peptide-adjuvant conjugates have been explored and showed beneficial outcomes in preclinical models; but in the clinical trials conducted so far, mixed results were obtained. A major limiting factor to unravel antigen handling mechanistically is the lack of tools to efficiently track peptide vaccines at the molecular and (sub)cellular level. In this mini-review, we will discuss options to develop molecular tools for improving, as well as studying, peptide-based vaccines. PMID- 29755469 TI - Urinary Peptides As a Novel Source of T Cell Allergen Epitopes. AB - Mouse allergy in both laboratory workers and in inner-city children is associated with allergic rhinitis and asthma, posing a serious public health concern. Urine is a major source of mouse allergens, as mice spray urine onto their surroundings, where the proteins dry up and become airborne on dust particles. Here, we tested whether oligopeptides that are abundant in mouse urine may contribute to mouse allergic T cell response. Over 1,300 distinct oligopeptides were detected by mass spectrometry analysis of the low molecular weight filtrate fraction of mouse urine (LoMo). Posttranslationally modified peptides were common, accounting for almost half of total peptides. A pool consisting of 225 unique oligopeptides of 13 residues or more in size identified within was tested for its capacity to elicit T cell reactivity in mouse allergic donors. Following 14-day in vitro stimulation of PBMCs, we detected responses in about 95% of donors tested, directed against 116 distinct peptides, predominantly associated with Th2 cytokines (IL-5). Peptides from non-urine related proteins such as epidermal growth factor, collagen, and Beta-globin accounted for the highest response (15.9, 9.1, and 8.1% of the total response, respectively). Peptides derived from major urinary proteins (MUPs), kidney androgen-regulated protein (KAP), and uromodulin were the main T cell targets from kidney or urine related sources. Further ex vivo analysis of enrichment of 4-1BB expressing cells demonstrated that LoMo pool-specific T cell reactivity can be detected directly ex vivo in mouse allergic but not in non-allergic donors. Further cytometric analysis of responding cells revealed a bone fide memory T cell phenotype and confirmed their Th2 polarization. Overall, these data suggest that mouse urine derived oligopeptides are a novel target for mouse allergy-associated T cell responses, which may contribute to immunopathological mechanisms in mouse allergy. PMID- 29755471 TI - Extracellular Vesicles Shed By Trypanosoma cruzi Potentiate Infection and Elicit Lipid Body Formation and PGE2 Production in Murine Macrophages. AB - During the onset of Trypanosoma cruzi infection, an effective immune response is necessary to control parasite replication and ensure host survival. Macrophages have a central role in innate immunity, acting as an important trypanocidal cell and triggering the adaptive immune response through antigen presentation and cytokine production. However, T. cruzi displays immune evasion mechanisms that allow infection and replication in macrophages, favoring its chronic persistence. One potential mechanism is the release of T. cruzi strain Y extracellular vesicle (EV Y), which participate in intracellular communication by carrying functional molecules that signal host cells and can modulate the immune response. The present work aimed to evaluate immune modulation by EV Y in C57BL/6 mice, a prototype resistant to infection by T. cruzi strain Y, and the effects of direct EV Y stimulation of macrophages in vitro. EV Y inoculation in mice prior to T. cruzi infection resulted in increased parasitemia, elevated cardiac parasitism, decreased plasma nitric oxide (NO), reduced NO production by spleen cells, and modulation of cytokine production, with a reduction in TNF-alpha in plasma and decreased production of TNF-alpha and IL-6 by spleen cells from infected animals. In vitro assays using bone marrow-derived macrophages showed that stimulation with EV Y prior to infection by T. cruzi increased the parasite internalization rate and release of infective trypomastigotes by these cells. In this same scenario, EV Y induced lipid body formation and prostaglandin E2 (PGE2) production by macrophages even in the absence of T. cruzi. In infected macrophages, EV Y decreased production of PGE2 and cytokines TNF-alpha and IL-6 24 h after infection. These results suggest that EV Y modulates the host response in favor of the parasite and indicates a role for lipid bodies and PGE2 in immune modulation exerted by EVs. PMID- 29755466 TI - Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today. AB - Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcepsilonRI and FgammaR signaling, IL-4, IL-10, and TGF beta1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area. PMID- 29755470 TI - CD36 Shunts Eicosanoid Metabolism to Repress CD14 Licensed Interleukin-1beta Release and Inflammation. AB - Interleukin (IL)-1beta is a potential target for treatment of several inflammatory diseases, including envenomation by the scorpion Tityus serrulatus. In this context, bioactive lipids such as prostaglandin (PG)E2 and leukotriene (LT)B4 modulate the production of IL-1beta by innate immune cells. Pattern recognition receptors (PRRs) that perceive T. serrulatus venom (TsV), and orchestrate LTB4, PGE2, and cyclic adenosine monophosphate (cAMP) production to regulate IL-1beta release are unknown. Furthermore, molecular mechanisms driving human cell responses to TsV remain uncharacterized. Here, we identified that both CD14 and CD36 control the synthesis of bioactive lipids, inflammatory cytokines, and mortality mediated by TsV. CD14 induces PGE2/cAMP/IL-1beta release and inflammation. By contrast, CD36 shunts eicosanoid metabolism toward production of LTB4, which represses the PGE2/cAMP/IL-1beta axis and mortality. Of importance, the molecular mechanisms observed in mice strongly correlate with those of human cell responses to TsV. Overall, this study provides major insights into molecular mechanisms connecting CD14 and CD36 with differential eicosanoid metabolism and inflammation mediated by IL-1beta. PMID- 29755473 TI - Differential Effect of Viable Versus Necrotic Neutrophils on Mycobacterium tuberculosis Growth and Cytokine Induction in Whole Blood. AB - Neutrophils exert both positive and negative influences on the host response to tuberculosis, but the mechanisms by which these differential effects are mediated are unknown. We studied the impact of live and dead neutrophils on the control of Mycobacterium tuberculosis using a whole blood bioluminescence-based assay, and assayed supernatant cytokine concentrations using LuminexTM technology and ELISA. CD15+ granulocyte depletion from blood prior to infection with M. tuberculosis lux impaired control of mycobacteria by 96 h, with a greater effect than depletion of CD4+, CD8+, or CD14+ cells (p < 0.001). Augmentation of blood with viable granulocytes significantly improved control of mycobacteria by 96 h (p = 0.001), but augmentation with necrotic granulocytes had the opposite effect (p = 0.01). Both augmentations decreased supernatant concentrations of tumor necrosis factor and interleukin (IL)-12 p40/p70, but necrotic granulocyte augmentation also increased concentrations of IL-10, G-CSF, GM-CSF, and CCL2. Necrotic neutrophil augmentation reduced phagocytosis of FITC-labeled M. bovis BCG by all phagocytes, whereas viable neutrophil augmentation specifically reduced early uptake by CD14+ cells. The immunosuppressive effect of dead neutrophils required necrotic debris rather than supernatant. We conclude that viable neutrophils enhance control of M. tuberculosis in blood, but necrotic neutrophils have the opposite effect-the latter associated with induction of IL-10, growth factors, and chemoattractants. Our findings suggest a mechanism by which necrotic neutrophils may exert detrimental effects on the host response in active tuberculosis. PMID- 29755476 TI - Transitional B Cells and TLR9 Responses Are Defective in Selective IgA Deficiency. AB - Selective IgA deficiency (IgAD) is the most common primary antibody deficiency in the western world with affected individuals suffering from an increased burden of autoimmunity, atopic diseases and infections. It has been shown that IgAD B cells can be induced with germinal center mimicking reactions to produce IgA. However, IgA is the most prevalent antibody in mucosal sites, where antigen-independent responses are important. Much interest has recently focused on the role of TLR9 in both naive and mature B cell differentiation into IgA secreting plasma cells. Here, we analyze the phenotype and function of T and B cells in individuals with IgAD following IgA-inducing CpG-TLR9 stimulations. The IgAD individuals had significantly lower numbers of transitional B cells (CD19+CD24hiCD38hi) and class switched memory B cells (CD20+CD27+IgD-) ex vivo. However, proportions of T cell populations ex vivo as well as in vitro induced T effector cells and T regulatory cells were comparable to healthy controls. After CpG stimulation, the transitional B cell defect was further enhanced, especially within its B regulatory subset expressing IL-10. Finally, CpG stimulation failed to induce IgA production in IgAD individuals. Collectively, our results demonstrate a defect of the TLR9 responses in IgAD that leads to B cell dysregulation and decreased IgA production. PMID- 29755472 TI - The Elusive Anti-Candida Vaccine: Lessons From the Past and Opportunities for the Future. AB - Candidemia is a bloodstream fungal infection caused by Candida species and is most commonly observed in hospitalized patients. Even with proper antifungal drug treatment, mortality rates remain high at 40-50%. Therefore, prophylactic or preemptive antifungal medications are currently recommended in order to prevent infections in high-risk patients. Moreover, the majority of women experience at least one episode of vulvovaginal candidiasis (VVC) throughout their lifetime and many of them suffer from recurrent VVC (RVVC) with frequent relapses for the rest of their lives. While there currently exists no definitive cure, the only available treatment for RVVC is again represented by antifungal drug therapy. However, due to the limited number of existing antifungal drugs, their associated side effects and the increasing occurrence of drug resistance, other approaches are greatly needed. An obvious prevention measure for candidemia or RVVC relapse would be to immunize at-risk patients with a vaccine effective against Candida infections. In spite of the advanced and proven techniques successfully applied to the development of antibacterial or antiviral vaccines, however, no antifungal vaccine is still available on the market. In this review, we first summarize various efforts to date in the development of anti-Candida vaccines, highlighting advantages and disadvantages of each strategy. We next unfold and discuss general hurdles encountered along these efforts, such as the existence of large genomic variation and phenotypic plasticity across Candida strains and species, and the difficulty in mounting protective immune responses in immunocompromised or immunosuppressed patients. Lastly, we review the concept of "trained immunity" and discuss how induction of this rapid and nonspecific immune response may potentially open new and alternative preventive strategies against opportunistic infections by Candida species and potentially other pathogens. PMID- 29755474 TI - Exercise Increases Insulin Sensitivity and Skeletal Muscle AMPK Expression in Systemic Lupus Erythematosus: A Randomized Controlled Trial. AB - : Systemic lupus erythematosus (SLE) patients may show increased insulin resistance (IR) when compared with their healthy peers. Exercise training has been shown to improve insulin sensitivity in other insulin-resistant populations, but it has never been tested in SLE. Therefore, the aim of the present study was to assess the efficacy of a moderate-intensity exercise training program on insulin sensitivity and potential underlying mechanisms in SLE patients with mild/inactive disease. A 12-week, randomized controlled trial was conducted. Nineteen SLE patients were randomly assigned into two groups: trained (SLE-TR, n = 9) and non-trained (SLE-NT, n = 10). Before and after 12 weeks of the exercise training program, patients underwent a meal test (MT), from which surrogates of insulin sensitivity and beta-cell function were determined. Muscle biopsies were performed after the MT for the assessment of total and membrane GLUT4 and proteins related to insulin signaling [Akt and AMP-activated protein kinase (AMPK)]. SLE-TR showed, when compared with SLE-NT, significant decreases in fasting insulin [-39 vs. +14%, p = 0.009, effect size (ES) = -1.0] and in the insulin response to MT (-23 vs. +21%, p = 0.007, ES = -1.1), homeostasis model assessment IR (-30 vs. +15%, p = 0.005, ES = -1.1), a tendency toward decreased proinsulin response to MT (-19 vs. +6%, p = 0.07, ES = -0.9) and increased glucagon response to MT (+3 vs. -3%, p = 0.09, ES = 0.6), and significant increases in the Matsuda index (+66 vs. -31%, p = 0.004, ES = 0.9) and fasting glucagon (+4 vs. -8%, p = 0.03, ES = 0.7). No significant differences between SLT TR and SLT-NT were observed in fasting glucose, glucose response to MT, and insulinogenic index (all p > 0.05). SLE-TR showed a significant increase in AMPK Thr 172 phosphorylation when compared to SLE-NT (+73 vs. -12%, p = 0.014, ES = 1.3), whereas no significant differences between groups were observed in Akt Ser 473 phosphorylation, total and membrane GLUT4 expression, and GLUT4 translocation (all p > 0.05). In conclusion, a 12-week moderate-intensity aerobic exercise training program improved insulin sensitivity in SLE patients with mild/inactive disease. This effect appears to be partially mediated by the increased insulin stimulated skeletal muscle AMPK phosphorylation. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01515163. PMID- 29755475 TI - Impact of a 3-Months Vegetarian Diet on the Gut Microbiota and Immune Repertoire. AB - The dietary pattern can influence the immune system directly, but may also modulate it indirectly by regulating the gut microbiota. Here, we investigated the effect of a 3-months lacto-ovo-vegetarian diet on the diversity of gut microbiota and the immune system in healthy omnivorous volunteers, using high throughput sequencing technologies. The short-term vegetarian diet did not have any major effect on the diversity of the immune system and the overall composition of the metagenome. The prevalence of bacterial genera/species with known beneficial effects on the intestine, including butyrate-producers and probiotic species and the balance of autoimmune-related variable genes/families were, however, altered in the short-term vegetarians. A number of bacterial species that are associated with the expression level of IgA, a key immunoglobulin class that protects the gastrointestinal mucosal system, were also identified. Furthermore, a lower diversity of T-cell repertoire and expression level of IgE, as well as a reduced abundance of inflammation-related genes in the gut microbiota were potentially associated with a control group with long-term vegetarians. Thus, the composition and duration of the diet may have an impact on the balance of pro-/anti-inflammatory factors in the gut microbiota and immune system. PMID- 29755477 TI - Glycan Shielding and Modulation of Hepatitis C Virus Neutralizing Antibodies. AB - Hepatitis C virus (HCV) envelope glycoprotein heterodimer, E1E2, plays an essential role in virus entry and assembly. Furthermore, due to their exposure at the surface of the virion, these proteins are the major targets of anti-HCV neutralizing antibodies. Their ectodomain are heavily glycosylated with up to 5 sites on E1 and up to 11 sites on E2 modified by N-linked glycans. Thus, one third of the molecular mass of E1E2 heterodimer corresponds to glycans. Despite the high sequence variability of E1 and E2, N-glycosylation sites of these proteins are generally conserved among the seven major HCV genotypes. N-glycans have been shown to be involved in E1E2 folding and modulate different functions of the envelope glycoproteins. Indeed, site-directed mutagenesis studies have shown that specific glycans are needed for virion assembly and infectivity. They can notably affect envelope protein entry functions by modulating their affinity for HCV receptors and their fusion activity. Importantly, glycans have also been shown to play a key role in immune evasion by masking antigenic sites targeted by neutralizing antibodies. It is well known that the high mutational rate of HCV polymerase facilitates the appearance of neutralization resistant mutants, and occurrence of mutations leading to glycan shifting is one of the mechanisms used by this virus to escape host humoral immune response. As a consequence of the importance of the glycan shield for HCV immune evasion, the deletion of N-glycans also leads to an increase in E1E2 immunogenicity and can induce a more potent antibody response against HCV. PMID- 29755479 TI - Lysophosphatidylcholine Promotes Phagosome Maturation and Regulates Inflammatory Mediator Production Through the Protein Kinase A-Phosphatidylinositol 3 Kinase p38 Mitogen-Activated Protein Kinase Signaling Pathway During Mycobacterium tuberculosis Infection in Mouse Macrophages. AB - Tuberculosis is caused by the infectious agent Mycobacterium tuberculosis (Mtb). Mtb has various survival strategies, including blockade of phagosome maturation and inhibition of antigen presentation. Lysophosphatidylcholine (LPC) is a major phospholipid component of oxidized low-density lipoprotein and is involved in various cellular responses, such as activation of second messengers and bactericidal activity in neutrophils. In this study, macrophages were infected with a low infectious dose of Mtb and treated with LPC to investigate the bactericidal activity of LPC against Mtb. In macrophages infected with Mtb strain, H37Ra or H37Rv, LPC suppressed bacterial growth; however, this effect was suppressed in bone marrow-derived macrophages (BMDMs) isolated from G2A (a G protein-coupled receptor involved in some LPC actions) knockout mice. LPC also promoted phagosome maturation via phosphatidylinositol 3 kinase (PI3K)-p38 mitogen-activated protein kinase (MAPK)-mediated reactive oxygen species production and intracellular Ca2+ release during Mtb infection. In addition, LPC induced increased levels of intracellular cyclic adenosine monophosphate (cAMP) and phosphorylated glycogen synthase kinase 3 beta (GSK3beta) in Mtb-infected macrophages. Protein kinase A (PKA)-induced phosphorylation of GSK3beta suppressed activation of NF-kappaB in LPC-treated macrophages during Mtb infection, leading to decreased secretion of pro-inflammatory cytokines and increased secretion of anti-inflammatory cytokines. These results suggest that LPC can effectively control Mtb growth by promoting phagosome maturation via cAMP induced activation of the PKA-PI3K-p38 MAPK pathway. Moreover, LPC can regulate excessive production of pro-inflammatory cytokines associated with bacterial infection of macrophages. PMID- 29755481 TI - "Phage Transplantation in Allotransplantation": Possible Treatment in Graft Versus-Host Disease? AB - Graft-versus-host disease, both acute and chronic (aGvHD, cGvHD) remains a major complication in patients undergoing hematopoietic cell transplantation (HCT) and a significant therapeutic challenge, as many patients do not respond adequately to presently available therapy. Increasing antimicrobial resistance has greatly revived interest in using bacterial viruses (phages) to combat antibiotic resistant bacteria. In recent years, evidence has accumulated indicating that phages also have anti-inflammatory and immunomodulatory activities. This article suggests how these anti-bacterial and immunomodulatory activities of phages may be translated into a novel treatment of acute GvHD. PMID- 29755480 TI - Molecular Determinants of Target Cell Recognition by Human gammadelta T Cells. AB - The unique capabilities of gamma-delta (gammadelta) T cells to recognize cells under stressed conditions, particularly infected or transformed cells, and killing them or regulating the immune response against them, paved the way to the development of promising therapeutic strategies for cancer and infectious diseases. From a mechanistic standpoint, numerous studies have unveiled a remarkable flexibility of gammadelta T cells in employing their T cell receptor and/or NK cell receptors for target cell recognition, even if the relevant ligands often remain uncertain. Here, we review the accumulated knowledge on the diverse mechanisms of target cell recognition by gammadelta T cells, focusing on human gammadelta T cells, to provide an integrated perspective of their therapeutic potential in cancer and infectious diseases. PMID- 29755482 TI - Silicon Improves Chilling Tolerance During Early Growth of Maize by Effects on Micronutrient Homeostasis and Hormonal Balances. AB - Low soil temperature in spring is a major constraint for the cultivation of tropical and subtropical crops in temperate climates, associated with inhibition of root growth and activity, affecting early growth and frequently plant performance and final yield. This study was initiated to investigate the physiological base of cold-protective effects induced by supplementation with silicon (Si), widely recommended as a stress-protective mineral nutrient. Maize was used as a cold-sensitive model plant, exposed to chilling stress and low root zone temperature (RZT) during early growth in a lab to field approach. In a pot experiment, 2-weeks exposure of maize seedlings to low RZT of 12-14 degrees C, induced leaf chlorosis and necrosis, inhibition of shoot and root growth and micronutrient limitation (particularly Zn and Mn). These phenotypes were mitigated by seed treatments with the respective micronutrients, but surprisingly, also by Si application. Both, silicon and micronutrient treatments were associated with increased activity of superoxide dismutase in shoot and roots (as a key enzyme for detoxification of reactive oxygen species, depending on Zn and Mn as cofactors), increased tissue concentrations of phenolics, proline, and antioxidants, but reduced levels of H2O2. These findings suggest that mitigation of oxidative stress is a major effect of Zn, Mn, and Si applied as cold stress protectants. In a soil-free culture system without external nutrient supply, Si significantly reduced large leaching losses of Zn and Mn from germinating seeds exposed to low-temperature stress. Silicon also increased the translocation of micronutrient seed reserves to the growing seedling, especially the Zn shoot translocation. In later stages of seedling development (10 days after sowing), cold stress reduced the root and shoot contents of important hormonal growth regulators (indole acetic acid, gibberellic acid, zeatin). Silicon restored the hormonal balances to a level comparable with non-stressed plants and stimulated the production of hormones involved in stress adaptation (abscisic, salicylic, and jasmonic acids). Beneficial effects of Si seed treatments on seedling establishment and the nutritional status of Zn and Mn were also measured for a field-grown silage maize, exposed to chilling stress by early sowing. This translated into increased final biomass yield. PMID- 29755483 TI - Multiple Origins and Nested Cycles of Hybridization Result in High Tetraploid Diversity in the Monocot Prospero. AB - Polyploidy is a major driving force in angiosperm evolution, but our understanding of establishment and early diversification processes following allo vs. auto-polyploidy is limited. An excellent system to address such questions is the monocot plant Prospero autumnale, as it comprises several genomically and chromosomally distinct diploid cytotypes and their auto- and allotetraploid derivatives. To infer origins and evolutionary trajectories of the tetraploids, we use genome size data, in situ hybridization with parental genomic DNAs and specific probes (satDNA, rDNAs), as well as molecular-phylogenetic analyses. Thus, we demonstrate that an astounding range of allotetraploid lineages has been formed recurrently by chromosomal re-patterning, interactions of chromosomally variable parental genomes and nested cycles of extensive hybridization, whereas autotetraploids have originated at least twice and are cytologically stable. During the recurrent formation and establishment across wide geographic areas hybridization in some populations could have inhibited lineage diversification and nascent speciation of such a hybrid swarm. However, cytotypes that became fixed in populations enhanced the potential for species diversification, possibly exploiting the extended allelic base, and fixed heterozygosity that polyploidy confers. The time required for polyploid cytotype fixation may in part reflect the lag phase reported for polyploids between their formation and species diversification. PMID- 29755484 TI - Responses of Aquatic Plants to Eutrophication in Rivers: A Revised Conceptual Model. AB - Compared to research on eutrophication in lakes, there has been significantly less work carried out on rivers despite the importance of the topic. However, over the last decade, there has been a surge of interest in the response of aquatic plants to eutrophication in rivers. This is an area of applied research and the work has been driven by the widespread nature of the impacts and the significant opportunities for system remediation. A conceptual model has been put forward to describe how aquatic plants respond to eutrophication. Since the model was created, there have been substantial increases in our understanding of a number of the underlying processes. For example, we now know the threshold nutrient concentrations at which nutrients no longer limit algal growth. We also now know that the physical habitat template of rivers is a primary selector of aquatic plant communities. As such, nutrient enrichment impacts on aquatic plant communities are strongly influenced, both directly and indirectly, by physical habitat. A new conceptual model is proposed that incorporates these findings. The application of the model to management, system remediation, target setting, and our understanding of multi-stressor systems is discussed. We also look to the future and the potential for new numerical models to guide management. PMID- 29755478 TI - The Contribution of Autoantibodies to Inflammatory Cardiovascular Pathology. AB - Chronic inflammation and resulting tissue damage underlie the vast majority of acquired cardiovascular disease (CVD), a general term encompassing a widely diverse array of conditions. Both innate and adaptive immune mechanisms contribute to chronic inflammation in CVD. Although maladies, such as atherosclerosis and cardiac fibrosis, are commonly conceptualized as disorders of inflammation, the cellular and molecular mechanisms that promote inflammation during the natural history of these diseases in human patients are not fully defined. Autoantibodies (AAbs) with specificity to self-derived epitopes accompany many forms of CVD in humans. Both adaptive/induced iAAbs (generated following cognate antigen encounter) and also autoantigen-reactive natural antibodies (produced independently of infection and in the absence of T cell help) have been demonstrated to modulate the natural history of multiple forms of CVD including atherosclerosis (atherosclerotic cardiovascular disease), dilated cardiomyopathy, and valvular heart disease. Despite the breadth of experimental evidence for the role of AAbs in CVD, there is a lack of consensus regarding their specific functions, primarily due to disparate conclusions reached, even when similar approaches and experimental models are used. In this review, we seek to summarize the current understanding of AAb function in CVD through critical assessment of the clinical and experimental evidence in this field. We additionally highlight the difficulty in translating observations made in animal models to human physiology and disease and provide a summary of unresolved questions that are critical to address in future studies. PMID- 29755485 TI - A Role of U12 Intron in Proper Pre-mRNA Splicing of Plant Cap Binding Protein 20 Genes. AB - The nuclear cap-binding complex (CBC) is composed of two cap-binding proteins: CBP20 and CBP80. The CBP20 gene structure is highly conserved across land plant species. All studied CBP20 genes contain eight exons and seven introns, with the fourth intron belonging to the U12 class. This highly conserved U12 intron always divides the plant CBP20 gene into two parts: one part encodes the core domain containing the RNA binding domain (RBD), and the second part encodes the tail domain with a nuclear localization signal (NLS). In this study, we investigate the importance of the U12 intron in the Arabidopsis thaliana CBP20 gene by moving it to different intron locations of the gene. Relocation of the U12 intron resulted in a significant decrease in the U12 intron splicing efficiency and the accumulation of wrongly processed transcripts. These results suggest that moving the U12 intron to any other position of the A. thaliana CBP20 gene disturbs splicing, leading to substantial downregulation of the level of properly spliced mRNA and CBP20 protein. Moreover, the replacement of the U12 intron with a U2 intron leads to undesired alternative splicing events, indicating that the proper localization of the U12 intron in the CBP20 gene secures correct CBP20 pre-mRNA maturation and CBP20 protein levels in a plant. Surprisingly, our results also show that the efficiency of U12 splicing depends on intron length. In conclusion, our study emphasizes the importance of proper U12 intron localization in plant CBP20 genes for correct pre-mRNA processing. PMID- 29755486 TI - Organelle Genome Inheritance in Deparia Ferns (Athyriaceae, Aspleniineae, Polypodiales). AB - Organelle genomes of land plants are predominately inherited maternally but in some cases can also be transmitted paternally or biparentally. Compared to seed plants (>83% genera of angiosperms and >12% genera of gymnosperms), plastid genome (plastome) inheritance has only been investigated in fewer than 2% of fern genera, and mitochondrial genome (mitogenome) from only one fern genus. We developed a new and efficient method to examine plastome and mitogenome inheritance in a fern species-Deparia lancea (Athyriaceae, Aspleniineae, Polypodiales), and found that plastid and mitochondrial DNAs were transmitted from only the maternal parentage to a next generation. To further examine whether both organelle genomes have the same manner of inheritance in other Deparia ferns, we sequenced both plastid and mitochondrial DNA regions of inter-species hybrids, and performed phylogenetic analyses to identify the origins of organellar DNA. Evidence from our experiments and phylogenetic analyses support that both organelle genomes in Deparia are uniparentally and maternally inherited. Most importantly, our study provides the first report of mitogenome inheritance in eupolypod ferns, and the second one among all ferns. PMID- 29755487 TI - Enhancing EPA Content in an Arctic Diatom: A Factorial Design Study to Evaluate Interactive Effects of Growth Factors. AB - Microalgae with a high content of the omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are of great demand for microalgae-based technologies. An Arctic strain of the diatom Attheya septentrionalis was shown in previous experiments to increase its EPA content from 3.0 to 4.6% of dry weight (DW) in the nutrient-replete exponential phase and nutrient-depleted stationary phase, respectively. In the present study, a factorial-design experiment was used, to investigate this effect in more detail and in combination with varying salinities and irradiances. A mathematical model revealed that both growth phase and salinity, alone and in combination, influenced the EPA content significantly. Maximum EPA values of 7.1% DW were obtained at a salinity of 22 and after 5 days in stationary phase, and might be related to a decreased silica content, an accumulation of storage lipids containing EPA, or both. However, growth rates were lower for low salinity (0.54 and 0.57 d-1) than high salinity (0.77 and 0.98 d-1) cultures. PMID- 29755489 TI - Optimizing Production in the New Generation of Apricot Cultivars: Self incompatibility, S-RNase Allele Identification, and Incompatibility Group Assignment. AB - Apricot (Prunus armeniaca L.) is a species of the Rosaceae that was originated in Central Asia, from where it entered Europe through Armenia. The release of an increasing number of new cultivars from different breeding programs is resulting in an important renewal of plant material worldwide. Although most traditional apricot cultivars in Europe are self-compatible, the use of self-incompatible cultivars as parental genotypes for breeding purposes is leading to the introduction of a number of new cultivars that behave as self-incompatible. As a consequence, there is an increasing need to interplant those new cultivars with cross-compatible cultivars to ensure fruit set in commercial orchards. However, the pollination requirements of many of these new cultivars are unknown. In this work, we analyze the pollination requirements of a group of 92 apricot cultivars, including traditional and newly-released cultivars from different breeding programs and countries. Self-compatibility was established by the observation of pollen tube behavior in self-pollinated flowers under the microscope. Incompatibility relationships between cultivars were established by the identification of S-alleles by PCR analysis. The self-(in)compatibility of 68 cultivars and the S-RNase genotype of 74 cultivars are reported herein for the first time. Approximately half of the cultivars (47) behaved as self-compatible and the other 45 as self-incompatible. Identification of S-alleles in self incompatible cultivars allowed allocating them in 11 incompatibility groups, six of them reported here for the first time. The determination of pollination requirements and the incompatibility relationships between cultivars is highly valuable for the appropriate selection of apricot cultivars in commercial orchards and of parental genotypes in breeding programs. The approach described can be transferred to other woody perennial crops with similar problems. PMID- 29755488 TI - Medicago truncatula SOC1 Genes Are Up-regulated by Environmental Cues That Promote Flowering. AB - Like Arabidopsis thaliana, the flowering of the legume Medicago truncatula is promoted by long day (LD) photoperiod and vernalization. However, there are differences in the molecular mechanisms involved, with orthologs of two key Arabidopsis thaliana regulators, FLOWERING LOCUS C (FLC) and CONSTANS (CO), being absent or not having a role in flowering time function in Medicago. In Arabidopsis, the MADS-box transcription factor gene, SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (AtSOC1), plays a key role in integrating the photoperiodic and vernalization pathways. In this study, we set out to investigate whether the Medicago SOC1 genes play a role in regulating flowering time. Three Medicago SOC1 genes were identified and characterized (MtSOC1a-MtSOC1c). All three MtSOC1 genes, when heterologously expressed, were able to promote earlier flowering of the late-flowering Arabidopsis soc1-2 mutant. The three MtSOC1 genes have different patterns of expression. However, consistent with a potential role in flowering time regulation, all three MtSOC1 genes are expressed in the shoot apex and are up-regulated in the shoot apex of plants in response to LD photoperiods and vernalization. The up-regulation of MtSOC1 genes was reduced in Medicago fta1 1 mutants, indicating that they are downstream of MtFTa1. Insertion mutant alleles of Medicago soc1b do not flower late, suggestive of functional redundancy among Medicago SOC1 genes in promoting flowering. PMID- 29755490 TI - Quantitative Tandem Affinity Purification, an Effective Tool to Investigate Protein Complex Composition in Plant Hormone Signaling: Strigolactones in the Spotlight. AB - Phytohormones tightly regulate plant growth by integrating changing environmental and developmental cues. Although the key players have been identified in many plant hormonal pathways, the molecular mechanisms and mode of action of perception and signaling remain incompletely resolved. Characterization of protein partners of known signaling components provides insight into the formed protein complexes, but, unless quantification is involved, does not deliver much, if any, information about the dynamics of the induced or disrupted protein complexes. Therefore, in proteomics research, the discovery of what actually triggers, regulates or interrupts the composition of protein complexes is gaining importance. Here, tandem affinity purification coupled to mass spectrometry (TAP MS) is combined with label-free quantification (LFQ) to a highly valuable tool to detect physiologically relevant, dynamic protein-protein interactions in Arabidopsis thaliana cell cultures. To demonstrate its potential, we focus on the signaling pathway of one of the most recently discovered phytohormones, strigolactones. PMID- 29755491 TI - Roles of Soybean Plasma Membrane Intrinsic Protein GmPIP2;9 in Drought Tolerance and Seed Development. AB - Aquaporins play an essential role in water uptake and transport in vascular plants. The soybean genome contains a total of 22 plasma membrane intrinsic protein (PIP) genes. To identify candidate PIPs important for soybean yield and stress tolerance, we studied the transcript levels of all 22 soybean PIPs. We found that a GmPIP2 subfamily member, GmPIP2;9, was predominately expressed in roots and developing seeds. Here, we show that GmPIP2;9 localized to the plasma membrane and had high water channel activity when expressed in Xenopus oocytes. Using transgenic soybean plants expressing a native GmPIP2;9 promoter driving a GUS-reporter gene, it was found high GUS expression in the roots, in particular, in the endoderm, pericycle, and vascular tissues of the roots of transgenic plants. In addition, GmPIP2;9 was also highly expressed in developing pods. GmPIP2;9 expression significantly increased in short term of polyethylene glycol (PEG)-mediated drought stress treatment. GmPIP2;9 overexpression increased tolerance to drought stress in both solution cultures and soil plots. Drought stress in combination with GmPIP2;9 overexpression increased net CO2 assimilation of photosynthesis, stomata conductance, and transpiration rate, suggesting that GmPIP2;9-overexpressing transgenic plants were less stressed than wild-type (WT) plants. Furthermore, field experiments showed that GmPIP2;9-overexpressing plants had significantly more pod numbers and larger seed sizes than WT plants. In summary, the study demonstrated that GmPIP2;9 has water transport activity. Its relative high expression levels in roots and developing pods are in agreement with the phenotypes of GmPIP2;9-overexpressing plants in drought stress tolerance and seed development. PMID- 29755492 TI - Common Features Between the Proteomes of Floral and Extrafloral Nectar From the Castor Plant (Ricinus Communis) and the Proteomes of Exudates From Carnivorous Plants. AB - Label-free quantitative proteome analysis of extrafloral (EFN) and floral nectar (FN) from castor (Ricinus communis) plants resulted in the identification of 72 and 37 proteins, respectively. Thirty proteins were differentially accumulated between EFN and FN, and 24 of these were more abundant in the EFN. In addition to proteins involved in maintaining the nectar pathogen free such as chitinases and glucan 1,3-beta-glucosidase, both proteomes share an array of peptidases, lipases, carbohydrases, and nucleases. A total of 39 of the identified proteins, comprising different classes of hydrolases, were found to have biochemical matching partners in the exudates of at least five genera of carnivorous plants, indicating the EFN and FN possess a potential to digest biological material from microbial, animal or plant origin equivalent to the exudates of carnivorous plants. PMID- 29755493 TI - Dynamic Modeling of Indole Glucosinolate Hydrolysis and Its Impact on Auxin Signaling. AB - Plants release chemicals to deter attackers. Arabidopsis thaliana relies on multiple defense compounds, including indol-3-ylmethyl glucosinolate (I3G), which upon hydrolysis initiated by myrosinase enzymes releases a multitude of bioactive compounds, among others, indole-3-acetonitrile and indole-3-acetoisothiocyanate. The highly unstable isothiocyanate rapidly reacts with other molecules. One of the products, indole-3-carbinol, was reported to inhibit auxin signaling through binding to the TIR1 auxin receptor. On the contrary, the nitrile product of I3G hydrolysis can be converted by nitrilase enzymes to form the primary auxin molecule, indole-3-acetic acid, which activates TIR1. This suggests that auxin signaling is subject to both antagonistic and protagonistic effects of I3G hydrolysis upon attack. We hypothesize that I3G hydrolysis and auxin signaling form an incoherent feedforward loop and we build a mathematical model to examine the regulatory network dynamics. We use molecular docking to investigate the possible antagonistic properties of different I3G hydrolysis products by competitive binding to the TIR1 receptor. Our simulations reveal an uncoupling of auxin concentration and signaling, and we determine that enzyme activity and antagonist binding affinity are key parameters for this uncoupling. The molecular docking predicts that several I3G hydrolysis products strongly antagonize auxin signaling. By comparing a tissue disrupting attack - e.g., by chewing insects or necrotrophic pathogens that causes rapid release of I3G hydrolysis products - to sustained cell-autonomous I3G hydrolysis, e.g., upon infection by biotrophic pathogens, we find that each scenario gives rise to distinct auxin signaling dynamics. This suggests that plants have different defense versus growth strategies depending on the nature of the attack. PMID- 29755494 TI - Transcription Factor SmWRKY1 Positively Promotes the Biosynthesis of Tanshinones in Salvia miltiorrhiza. AB - Tanshinones, one group of bioactive diterpenes, were widely used in the treatment of cardiovascular diseases. WRKYs play important roles in plant metabolism, but their regulation mechanism in Salvia miltiorrhiza remains elusive. In this study, one WRKY transcription factor SmWRKY1 was isolated and functionally characterized from S. miltiorrhiza. Multiple sequence alignment and phylogenetic tree analysis showed SmWRKY1 shared high homology with other plant WRKYs such as CrWRKY1. SmWRKY1 was found predominantly expressed in leaves and stems, and was responsive to salicylic acid (SA), methyl jasmonate (MeJA), and nitric oxide (NO) treatment. Subcellular localization analysis found that SmWRKY1 was localized in the nucleus. Over-expression of SmWRKY1 significantly elevated the transcripts of genes coding for enzymes in the MEP pathway especially 1-deoxy-D-xylulose-5 phosphate synthase (SmDXS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (SmDXR), resulted in over fivefold increase in tanshinones production in transgenic lines (up to 13.7 mg/g DW) compared with the control lines. A dual luciferase (Dual-LUC) assay showed that SmWRKY1 can positively regulate SmDXR expression by binding to its promoter. Our work revealed that SmWRKY1 participated in the regulation of tanshinones biosynthesis and acted as a positive regulator through activating SmDXR in the MEP pathway, thus provided a new insight to further explore the regulation mechanism of tanshinones biosynthesis. PMID- 29755495 TI - Iron Retention in Root Hemicelluloses Causes Genotypic Variability in the Tolerance to Iron Deficiency-Induced Chlorosis in Maize. AB - Antagonistic interactions of phosphorus (P) hamper iron (Fe) acquisition by plants and can cause Fe deficiency-induced chlorosis. To determine the physiological processes underlying adverse Fe-P interactions, the maize lines B73 and Mo17, which differ in chlorosis susceptibility, were grown hydroponically at different Fe:P ratios. In the presence of P, Mo17 became more chlorotic than B73. The higher sensitivity of Mo17 to Fe deficiency was not related to Fe-P interactions in leaves but to lower Fe translocation to shoots, which coincided with a larger pool of Fe being fixed in the root apoplast of P-supplied Mo17 plants. Fractionating cell wall components from roots showed that most of the cell wall-contained P accumulated in pectin, whereas most of the Fe was bound to root hemicelluloses, revealing that co-precipitation of Fe and P in the apoplast was not responsible for Fe inactivation in roots. A negative correlation between chlorophyll index and hemicellulose-bound Fe in 85 inbred lines of the intermated maize B73 * Mo17 (IBM) population indicated that apoplastic Fe retention contributes to genotypic differences in chlorosis susceptibility of maize grown under low Fe supplies. Our study indicates that Fe retention in the hemicellulose fraction of roots is an important determinant in the tolerance to Fe deficiency induced chlorosis of graminaceous plant species with low phytosiderophore release, like maize. PMID- 29755496 TI - Banana21: From Gene Discovery to Deregulated Golden Bananas. AB - Uganda is a tropical country with a population in excess of 30 million, >80% of whom live in rural areas. Bananas (Musa spp.) are the staple food of Uganda with the East African Highland banana, a cooking banana, the primary starch source. Unfortunately, these bananas are low in pro-vitamin A (PVA) and iron and, as a result, banana-based diets are low in these micronutrients which results in very high levels of inadequate nutrition. This inadequate nutrition manifests as high levels of vitamin A deficiency, iron deficiency anemia, and stunting in children. A project known as Banana21 commenced in 2005 to alleviate micronutrient deficiencies in Uganda and surrounding countries through the generation of farmer and consumer-acceptable edible bananas with significantly increased fruit levels of PVA and iron. A genetic modification approach was adopted since bananas are recalcitrant to conventional breeding. In this review, we focus on the PVA biofortification component of the Banana21 project and describe the proof-of concept studies conducted in Australia, the transfer of the technology to our Ugandan collaborators, and the successful implementation of the strategy into the field in Uganda. The many challenges encountered and the potential future obstacles to the practical exploitation of PVA-enhanced bananas in Uganda are discussed. PMID- 29755497 TI - Lycopene Is Enriched in Tomato Fruit by CRISPR/Cas9-Mediated Multiplex Genome Editing. AB - Numerous studies have been focusing on breeding tomato plants with enhanced lycopene accumulation, considering its positive effects of fruits on the visual and functional properties. In this study, we used a bidirectional strategy: promoting the biosynthesis of lycopene, while inhibiting the conversion from lycopene to beta- and alpha-carotene. The accumulation of lycopene was promoted by knocking down some genes associated with the carotenoid metabolic pathway. Finally, five genes were selected to be edited in genome by CRISPR/Cas9 system using Agrobacterium tumefaciens-mediated transformation. Our findings indicated that CRISPR/Cas9 is a site-specific genome editing technology that allows highly efficient target mutagenesis in multiple genes of interest. Surprisingly, the lycopene content in tomato fruit subjected to genome editing was successfully increased to about 5.1-fold. The homozygous mutations were stably transmitted to subsequent generations. Taken together, our results suggest that CRISPR/Cas9 system can be used for significantly improving lycopene content in tomato fruit with advantages such as high efficiency, rare off-target mutations, and stable heredity. PMID- 29755498 TI - Rice Premature Leaf Senescence 2, Encoding a Glycosyltransferase (GT), Is Involved in Leaf Senescence. AB - Premature leaf senescence (PLS), which has a significant impact on yield, is caused by various underlying mechanisms. Glycosyltransferases, which function in glycosyl transfer from activated nucleotides to aglycones, are involved in diverse biological processes, but their roles in rice leaf senescence remain elusive. Here, we isolated and characterized a leaf senescence-related gene from the Premature Leaf Senescent mutant (pls2). The mutant phenotype began with leaf yellowing at tillering and resulted in PLS during the reproductive stage. Leaf senescence was associated with an increase in hydrogen peroxide (H2O2) content accompanied with pronounced decreases in net photosynthetic rate, stomatal conductance, and transpiration rate. Map-based cloning revealed that a mutation in LOC_Os03g15840 (PLS2), a putative glycosyltransferase- encoding gene, was responsible for the defective phenotype. PLS2 expression was detected in all tissues surveyed, but predominantly in leaf mesophyll cells. Subcellular localization of the PLS2 was in the endoplasmic reticulum. The pls2 mutant accumulated higher levels of sucrose together with decreased expression of sucrose metabolizing genes compared with wild type. These data suggested that the PLS2 allele is essential for normal leaf senescence and its mutation resulted in PLS. PMID- 29755499 TI - Genetic Dissection of Maize Embryonic Callus Regenerative Capacity Using Multi Locus Genome-Wide Association Studies. AB - The regenerative capacity of the embryonic callus, a complex quantitative trait, is one of the main limiting factors for maize transformation. This trait was decomposed into five traits, namely, green callus rate (GCR), callus differentiating rate (CDR), callus plantlet number (CPN), callus rooting rate (CRR), and callus browning rate (CBR). To dissect the genetic foundation of maize transformation, in this study multi-locus genome-wide association studies (GWAS) for the five traits were performed in a population of 144 inbred lines genotyped with 43,427 SNPs. Using the phenotypic values in three environments and best linear unbiased prediction (BLUP) values, as a result, a total of 127, 56, 160, and 130 significant quantitative trait nucleotides (QTNs) were identified by mrMLM, FASTmrEMMA, ISIS EM-BLASSO, and pLARmEB, respectively. Of these QTNs, 63 QTNs were commonly detected, including 15 across multiple environments and 58 across multiple methods. Allele distribution analysis showed that the proportion of superior alleles for 36 QTNs was <50% in 31 elite inbred lines. Meanwhile, these superior alleles had obviously additive effect on the regenerative capacity. This indicates that the regenerative capacity-related traits can be improved by proper integration of the superior alleles using marker-assisted selection. Moreover, a total of 40 candidate genes were found based on these common QTNs. Some annotated genes were previously reported to relate with auxin transport, cell fate, seed germination, or embryo development, especially, GRMZM2G108933 (WOX2) was found to promote maize transgenic embryonic callus regeneration. These identified candidate genes will contribute to a further understanding of the genetic foundation of maize embryonic callus regeneration. PMID- 29755500 TI - Haplotype-Based Genotyping in Polyploids. AB - Accurate identification of polymorphisms from sequence data is crucial to unlocking the potential of high throughput sequencing for genomics. Single nucleotide polymorphisms (SNPs) are difficult to accurately identify in polyploid crops due to the duplicative nature of polyploid genomes leading to low confidence in the true alignment of short reads. Implementing a haplotype-based method in contrasting subgenome-specific sequences leads to higher accuracy of SNP identification in polyploids. To test this method, a large-scale 48K SNP array (Axiom Arachis2) was developed for Arachis hypogaea (peanut), an allotetraploid, in which 1,674 haplotype-based SNPs were included. Results of the array show that 74% of the haplotype-based SNP markers could be validated, which is considerably higher than previous methods used for peanut. The haplotype method has been implemented in a standalone program, HAPLOSWEEP, which takes as input bam files and a vcf file and identifies haplotype-based markers. Haplotype discovery can be made within single reads or span paired reads, and can leverage long read technology by targeting any length of haplotype. Haplotype-based genotyping is applicable in all allopolyploid genomes and provides confidence in marker identification and in silico-based genotyping for polyploid genomics. PMID- 29755501 TI - Enhanced Conjugation of Auxin by GH3 Enzymes Leads to Poor Adventitious Rooting in Carnation Stem Cuttings. AB - Commercial carnation (Dianthus caryophyllus) cultivars are vegetatively propagated from axillary stem cuttings through adventitious rooting; a process which is affected by complex interactions between nutrient and hormone levels and is strongly genotype-dependent. To deepen our understanding of the regulatory events controlling this process, we performed a comparative study of adventitious root (AR) formation in two carnation cultivars with contrasting rooting performance, "2101-02 MFR" and "2003 R 8", as well as in the reference cultivar "Master". We provided molecular evidence that localized auxin response in the stem cutting base was required for efficient adventitious rooting in this species, which was dynamically established by polar auxin transport from the leaves. In turn, the bad-rooting behavior of the "2003 R 8" cultivar was correlated with enhanced synthesis of indole-3-acetic acid conjugated to aspartic acid by GH3 proteins in the stem cutting base. Treatment of stem cuttings with a competitive inhibitor of GH3 enzyme activity significantly improved rooting of "2003 R 8". Our results allowed us to propose a working model where endogenous auxin homeostasis regulated by GH3 proteins accounts for the cultivar dependency of AR formation in carnation stem cuttings. PMID- 29755502 TI - Functional Conservation and Divergence of Soybean GmSTOP1 Members in Proton and Aluminum Tolerance. AB - Proton (H+) and aluminum (Al) rhizotoxicity are two major factors limiting crop production in acid soils. Orthologs of the zinc-finger transcription factor, Sensitive To Proton Rhizotoxicity1 (STOP1), have been found to play an essential role in the tolerance to both stresses by regulating the transcription of multiple H+ and Al tolerant genes. In the present study, color three GmSTOP1 homologs were identified in the soybean genome. All three GmSTOP1 exhibited similar properties as reflected by the harboring of four potential zinc finger domains, localizing in the nucleus, and having transactivation activity. Expression profiling showed that H+ stress slightly modulated transcription of all three GmSTOP1s, while Al significantly up-regulated GmSTOP1-1 and GmSTOP1-3 in root apexes and GmSTOP1-3 in basal root regions. Furthermore, complementation assays in an Arabidopsis Atstop1 mutant line overexpressing these GmSTOP1s demonstrated that all three GmSTOP1s largely reverse the H+ sensitivity of the Atstop1 mutant and restore the expression of genes involved in H+ tolerance. In contrast, only GmSTOP1-1 and GmSTOP1-3 could partially recover Al tolerance in the Atstop1 mutant. These results suggest that the function of three GmSTOP1s is evolutionarily conserved in H+ tolerance, but not in Al tolerance. PMID- 29755503 TI - Genome-Wide Association Analysis of Age-Dependent Egg Weights in Chickens. AB - Egg weight (EW) is an economically-important trait and displays a consecutive increase with the hen's age. Because extremely large eggs cause a range of problems in the poultry industry, we performed a genome-wide association study (GWAS) in order to identify genomic variations that are associated with EW. We utilized the Affymetrix 600 K high density SNP array in a population of 1,078 hens at seven time points from day at first egg to 80 weeks age (EW80). Results reveal that a 90 Kb genomic region (169.42 Mb ~ 169.51 Mb) in GGA1 is significantly associated with EW36 and is also potentially associated with egg weight at 28, 56, and 66 week of age. The leading SNP could account for 3.66% of the phenotypic variation, while two promising genes (DLEU7 and MIR15A) can be mapped to this narrow significant region and may affect EW in a pleiotropic manner. In addition, one gene (CECR2 on GGA1) and two genes (MEIS1 and SPRED2 on GGA3), which involved in the processes of embryogenesis and organogenesis, were also considered to be candidates related to first egg weight (FEW) and EW56, respectively. Findings in our study could provide worthy theoretical basis to generate eggs of ideal size based on marker assisted breeding selection. PMID- 29755504 TI - Molecular Identification of Shark Meat From Local Markets in Southern Brazil Based on DNA Barcoding: Evidence for Mislabeling and Trade of Endangered Species. AB - Elasmobranchs, the group of cartilaginous fishes that include sharks and rays, are especially vulnerable to overfishing due to low fecundity and late sexual maturation. A significant number of elasmobranch species are currently overexploited or threatened by fisheries activities. Additionally, several recent reports have indicated that there has been a reduction in regional elasmobranch population sizes. Brazil is an important player in elasmobranch fisheries and one of the largest importers of shark meat. However, carcasses entering the shark meat market have usually had their fins and head removed, which poses a challenge to reliable species identification based on the morphology of captured individuals. This is further complicated by the fact that the internal Brazilian market trades several different elasmobranch species under a common popular name: "cacao." The use of such imprecise nomenclature, even among governmental agencies, is problematic for both controlling the negative effects of shark consumption and informing the consumer about the origins of the product. In this study, we used DNA barcoding (mtDNA, COI gene) to identify, at the species level, "cacao" samples available in local markets from Southern Brazil. We collected 63 samples traded as "cacao," which we found to correspond to 20 different species. These included two teleost species: Xiphias gladius (n = 1) and Genidens barbus (n = 6), and 18 species from seven elasmobranch orders (Carcharhiniformes, n = 42; Squaliformes, n = 3; Squatiniformes, n = 2; Rhinopristiformes, n = 4; Myliobatiformes, n = 3; Rajiformes, n = 1; and Torpediniformes, n = 1). The most common species in our sample were Prionace glauca (n = 15) and Sphyrna lewini (n = 14), while all other species were represented by four samples or less. Considering IUCN criteria, 47% of the elasmobranch species found are threatened at the global level, while 53% are threatened and 47% are critically endangered in Brazil. These results underline that labeling the meat of any shark species as "cacao" is problematic for monitoring catch allocations from the fishing industry and discourages consumer engagement in conservationist practices through informed decision-making. PMID- 29755505 TI - Integrative Analysis Identifies Genetic Variants Associated With Autoimmune Diseases Affecting Putative MicroRNA Binding Sites. AB - Genome-wide and fine mapping studies have shown that more than 90% of genetic variants associated with autoimmune diseases (AID) are located in non-coding regions of the human genome and especially in regulatory sequences, including microRNAs (miRNA) target sites. MiRNAs are small endogenous noncoding RNAs that modulate gene expression at the post-transcriptional level. Single nucleotide polymorphisms (SNPs) located within the 3' untranslated region of their target mRNAs (miRSNP) can alter miRNA binding sites. Yet, little is known about their effect on regulation by miRNA and the consequences for AID. Conversely, it is well known that two or more AID may share part of their genetic background. Here, we hypothesized that miRSNPs could be associated with more than one AID. To identify miRSNPs associated with AID, we integrated results from three different prediction tools (Polymirts, miRSNP, and miRSNPscore) using a naive Bayes classifier approach to identify miRSNPs predicted to affect binding sites of miRNAs. Further, to detect miRSNPs associated with two or more AID, we integrated predictions with summary statistics from 12 AID studies. In addition, to prioritize miRSNPs, miRNAs and AID-associated target genes, we used public expression quantitative trait locus (eQTL) data and mRNA-seq and small RNA-seq data. We identified 34 miRNSPs associated with at least two AID. Furthermore, we found 86 miRNAs predicted to target 18 of the associated gene's mRNAs. Our integrative approach revealed new insights into miRNAs and AID associated target genes. Thus, it helped to prioritize AID noncoding risk SNPs that might be involved in the causal mechanisms, providing valuable information for further functional studies. PMID- 29755506 TI - Genome-Wide Association Study for Susceptibility to and Recoverability From Mastitis in Danish Holstein Cows. AB - Because mastitis is very frequent and unavoidable, adding recovery information into the analysis for genetic evaluation of mastitis is of great interest from economical and animal welfare point of view. Here we have performed genome-wide association studies (GWAS) to identify associated single nucleotide polymorphisms (SNPs) and investigate the genetic background not only for susceptibility to - but also for recoverability from mastitis. Somatic cell count records from 993 Danish Holstein cows genotyped for a total of 39378 autosomal SNP markers were used for the association analysis. Single SNP regression analysis was performed using the statistical software package DMU. Substitution effect of each SNP was tested with a t-test and a genome-wide significance level of P-value < 10-4 was used to declare significant SNP-trait association. A number of significant SNP variants were identified for both traits. Many of the SNP variants associated either with susceptibility to - or recoverability from mastitis were located in or very near to genes that have been reported for their role in the immune system. Genes involved in lymphocyte developments (e.g., MAST3 and STAB2) and genes involved in macrophage recruitment and regulation of inflammations (PDGFD and PTX3) were suggested as possible causal genes for susceptibility to - and recoverability from mastitis, respectively. However, this is the first GWAS study for recoverability from mastitis and our results need to be validated. The findings in the current study are, therefore, a starting point for further investigations in identifying causal genetic variants or chromosomal regions for both susceptibility to - and recoverability from mastitis. PMID- 29755507 TI - Computational Protein Phenotype Characterization of IL10RA Mutations Causative to Early Onset Inflammatory Bowel Disease (IBD). AB - The deleterious amino acid substitution mutations in IL-10 receptor alpha gene are most frequently reported in several autoimmune diseases including early onset inflammatory bowel disease (IBD). Despite the important role of IL-10 RA in maintaining immune homeostasis, the specific structural and functional implications of these mutations on protein phenotype, stability, ligand binding and post translational characteristics is not well explored. Therefore, this study performed the multidimensional computational analysis of IL10RA missense variations causative to pediatric or early onset inflammatory bowel disease (<5 years of age). Our computational algorithmic screening identified the deleterious nature of p. W45G, p. Y57C, p. W69G, p.T84I, p.Y91C, p.R101W, p.R117C, and p.R117H, IBD causative IL10-RA mutations. The sensitivity and specificity analysis of different computational methods showed that CADD outperform SIFT, PolyPhen 2.0, FATHMM, LRT, MetaLR, MetaSVM, PROVEAN and Condel in predicting the pathogenicity of IL10RA mutations. Our three-dimensional protein modeling assays showed that the point mutations cause major drifts in the structural plasticity of IL10 RA molecule and negatively influence its stability. Findings from molecular docking analysis have shown that these point mutations decrease the binding affinity of IL10RA toward IL10 and may likely to disturb the IL10 signaling pathway. This study provides an easy frame work for phenotypic characterization of mutant IL10RA molecule in terms of structure, flexibility and stability aspects. Our approach may also add a new dimension to conventional functional biology assays in quickly studying IL10 RA mutations and also for designing and developing inhibitors for mutant IL10RA molecule. PMID- 29755508 TI - Spatiotemporal variability and contribution of different aerosol types to the Aerosol Optical Depth over the Eastern Mediterranean. AB - This study characterizes the spatiotemporal variability and relative contribution of different types of aerosols to the Aerosol Optical Depth (AOD) over the Eastern Mediterranean as derived from MODIS Terra (3/2000-12/2012) and Aqua (7/2002-12/2012) satellite instruments. For this purpose, a 0.1 degrees * 0.1 degrees gridded MODIS dataset was compiled and validated against sunphotometric observations from the AErosol RObotic NETwork (AERONET). The high spatial resolution and long temporal coverage of the dataset allows for the determination of local hot spots like megacities, medium sized cities, industrial zones, and power plant complexes, seasonal variabilities, and decadal averages. The average AOD at 550 nm (AOD550) for the entire region is ~ 0.22 +/- 0.19 with maximum values in summer and seasonal variabilities that can be attributed to precipitation, photochemical production of secondary organic aerosols, transport of pollution and smoke from biomass burning in Central and Eastern Europe, and transport of dust from the Sahara Desert and the Middle East. The MODIS data were analyzed together with data from other satellite sensors, reanalysis projects and a chemistry-aerosol-transport model using an optimized algorithm tailored for the region and capable of estimating the contribution of different aerosol types to the total AOD550. The spatial and temporal variability of anthropogenic, dust and fine mode natural aerosols over land and anthropogenic, dust and marine aerosols over the sea is examined. The relative contribution of the different aerosol types to the total AOD550 exhibits a low/high seasonal variability over land/sea areas, respectively. Overall, anthropogenic aerosols, dust and fine mode natural aerosols account for ~ 51 %, ~ 34 % and ~ 15 % of the total AOD550 over land, while, anthropogenic aerosols, dust and marine aerosols account ~ 40 %, ~ 34 % and ~ 26 % of the total AOD550 over the sea, based on MODIS Terra and Aqua observations. PMID- 29755509 TI - Synthesis, Structural Characterization, and Antibacterial Activity of Novel Erbium(III) Complex Containing Antimony. AB - The novel 3D edta-linked heterometallic complex [Sb2Er(edta)2(H2O)4]NO3.4H2O (H4edta = ethylenediaminetetraacetic acid) was synthesized and characterized by elemental analyses, single-crystal X-ray diffraction, powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and thermal analysis. The complex crystallizes in the monoclinic system with space group Pm. In the complex, each erbium(III) ion is connected with antimony(III) ions bridging by four carboxylic oxygen atoms, and in each [Sb(edta)]- anion, the antimony(III) ion is hexacoordinated by two nitrogen atoms and four oxygen atoms from the edta4 ions, together with a lone electron pair at the equatorial position. The erbium(III) ion is octacoordinated by four oxygen atoms from four different edta4 ions and four oxygen atoms from the coordinated water molecules. The carboxylate bridges between antimony and erbium atoms form a planar array, parallel to the (1 0 0) plane. There is an obvious weak interaction between antimony atom and oxygen atom of the carboxyl group from the adjacent layer. The degradation of the complex proceeds in several steps and the water molecules and ligands are successively emitted, and the residues of the thermal decomposition are antimonous oxide and erbium(III) oxide. The complex was evaluated for its antimicrobial activities by agar diffusion method, and it has good activities against the test bacterial organisms. PMID- 29755510 TI - Assessment of Multivariate Neural Time Series by Phase Synchrony Clustering in a Time-Frequency-Topography Representation. AB - Most EEG phase synchrony measures are of bivariate nature. Those that are multivariate focus on producing global indices of the synchronization state of the system. Thus, better descriptions of spatial and temporal local interactions are still in demand. A framework for characterization of phase synchrony relationships between multivariate neural time series is presented, applied either in a single epoch or over an intertrial assessment, relying on a proposed clustering algorithm, termed Multivariate Time Series Clustering by Phase Synchrony, which generates fuzzy clusters for each multivalued time sample and thereupon obtains hard clusters according to a circular variance threshold; such cluster modes are then depicted in Time-Frequency-Topography representations of synchrony state beyond mere global indices. EEG signals from P300 Speller sessions of four subjects were analyzed, obtaining useful insights of synchrony patterns related to the ERP and even revealing steady-state artifacts at 7.6 Hz. Further, contrast maps of Levenshtein Distance highlight synchrony differences between ERP and no-ERP epochs, mainly at delta and theta bands. The framework, which is not limited to one synchrony measure, allows observing dynamics of phase changes and interactions among channels and can be applied to analyze other cognitive states rather than ERP versus no ERP. PMID- 29755511 TI - Examination Stress Results in Attentional Bias and Altered Neural Reactivity in Test-Anxious Individuals. AB - Examination stress occurs so frequently in the lives of students. The neural mechanisms of attentional bias induced by examination stress in test-anxious individuals remain unclear. Accordingly, we investigated the attentional bias toward test-related threatening words in selected high and low test-anxious participants under the stress of final examinations by using an event-related potential (ERP) technique. A classic dot-probe paradigm was adopted with a test related/test-unrelated threatening word and a neutral word pair as cues. Results showed attention bias and enhanced N200 amplitude toward test-related threat in high test-anxious individuals, whereas avoidance of test-related threat and decreased N200 amplitude were shown in low test-anxious individuals. Additionally, ERP data revealed the relatively enhanced LPP amplitude in low test anxious participants compared with that in high test-anxious participants. No attentional bias toward test-unrelated threat was found. In conclusion, examination stress resulted in attentional bias and functional perturbations of a brain circuitry that reacted rapidly to test-related threat in high test-anxious individuals. PMID- 29755512 TI - Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences. AB - Alzheimer's disease (AD) is the most common type of dementia, mainly encompassing cognitive decline in subjects aged >=65 years. Further, AD is characterized by selective synaptic and neuronal degeneration, vascular dysfunction, and two histopathological features: extracellular amyloid plaques composed of amyloid beta peptide (Abeta) and neurofibrillary tangles formed by hyperphosphorylated tau protein. Dementia and AD are chronic neurodegenerative conditions with a complex physiopathology involving both genetic and environmental factors. Recent clinical studies have shown that proton pump inhibitors (PPIs) are associated with risk of dementia, including AD. However, a recent case-control study reported decreased risk of dementia. PPIs are a widely indicated class of drugs for gastric acid-related disorders, although most older adult users are not treated for the correct indication. Although neurological side effects secondary to PPIs are rare, several preclinical reports indicate that PPIs might increase Abeta levels, interact with tau protein, and affect the neuronal microenvironment through several mechanisms. Considering the controversy between PPI use and dementia risk, as well as both cognitive and neuroprotective effects, the aim of this review is to examine the relationship between PPI use and brain effects from a neurobiological and clinical perspective. PMID- 29755513 TI - Motor Imagery during Action Observation of Locomotor Tasks Improves Rehabilitation Outcome in Older Adults after Total Hip Arthroplasty. AB - This study aimed at determining whether the combination of action observation and motor imagery (AO + MI) of locomotor tasks could positively affect rehabilitation outcome after hip replacement surgery. Of initially 405 screened participants, 21 were randomly split into intervention group (N = 10; mean age = 64 y; AO + MI of locomotor tasks: 30 min/day in the hospital, then 3*/week in their homes for two months) and control group (N = 11, mean age = 63 y, active controls). The functional outcomes (Timed Up and Go, TUG; Four Step Square Test, FSST; and single- and dual-task gait and postural control) were measured before (PRE) and 2 months after surgery (POST). Significant interactions indicated better rehabilitation outcome for the intervention group as compared to the control group: at POST, the intervention group revealed faster TUG (p = 0.042), FSST (p = 0.004), and dual-task fast-paced gait speed (p = 0.022), reduced swing-time variability (p = 0.005), and enhanced cognitive performance during dual tasks while walking or balancing (p < 0.05). In contrast, no changes were observed for body sway parameters (p >= 0.229). These results demonstrate that AO + MI is efficient to improve motor-cognitive performance after hip surgery. Moreover, only parameters associated with locomotor activities improved whereas balance skills that were not part of the AO + MI intervention were not affected, demonstrating the specificity of training intervention. Overall, utilizing AO + MI during rehabilitation is advised, especially when physical practice is limited. PMID- 29755515 TI - Anticorrelations between Active Brain Regions: An Agent-Based Model Simulation Study. AB - Anticorrelations among brain areas observed in fMRI acquisitions under resting state are not endowed with a well-defined set of characters. Some evidence points to a possible physiological role for them, and simulation models showed that it is appropriate to explore such an issue. A large-scale brain representation was considered, implementing an agent-based brain-inspired model (ABBM) incorporating the SER (susceptible-excited-refractory) cyclic mechanism of state change. The experimental data used for validation included 30 selected functional images of healthy controls from the 1000 Functional Connectomes Classic collection. To study how different fractions of positive and negative connectivities could modulate the model efficiency, the correlation coefficient was systematically used to check the goodness-of-fit of empirical data by simulations under different combinations of parameters. The results show that a small fraction of positive connectivity is necessary to match at best the empirical data. Similarly, a goodness-of-fit improvement was observed upon addition of negative links to an initial pattern of only-positive connections, indicating a significant information intrinsic to negative links. As a general conclusion, anticorrelations showed that it is crucial to improve the performance of our simulation and, since these cannot be assimilated to noise, should be always considered in order to refine any brain functional model. PMID- 29755514 TI - Motor Improvement of Skilled Forelimb Use Induced by Treatment with Growth Hormone and Rehabilitation Is Dependent on the Onset of the Treatment after Cortical Ablation. AB - We previously demonstrated that the administration of GH immediately after severe motor cortex injury, in rats, followed by rehabilitation, improved the functionality of the affected limb and reexpressed nestin in the contralateral motor cortex. Here, we analyze whether these GH effects depend on a time window after the injury and on the reexpression of nestin and actin. Injured animals were treated with GH (0.15 mg/kg/day) or vehicle, at days 7, 14, and 35 after cortical ablation. Rehabilitation was applied at short and long term (LTR) after the lesion and then sacrificed. Nestin and actin were analyzed by immunoblotting in the contralateral motor cortex. Giving GH at days 7 or 35 after the lesion, but not 14 days after it, led to a remarkable improvement in the functionality of the affected paw. Contralateral nestin and actin reexpression was clearly higher in GH-treated animals, probably because compensatory brain plasticity was established. GH and immediate rehabilitation are key for repairing brain injuries, with the exception of a critical time period: GH treatment starting 14 days after the lesion. Our data also indicate that there is not a clear plateau in the recovery from a brain injury in agreement with our data in human patients. PMID- 29755517 TI - Antibacterial and Antioxidant Compounds from the Flower Extracts of Vernonia amygdalina. AB - Vernonia amygdalina is traditionally used in Ethiopia to treat various diseases. This prompted us to isolate bioactive compounds from the flowers of this plant. The CHCl3 extract after silica gel column chromatography has led to the isolation of two compounds identified as tricosane (1) and vernolide (2), while the acetone extract furnished isorhamnetin (3) and luteolin (4). The acetone extract and isorhamnetin significantly scavenged the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical by 91.6 and 94%, respectively. It was also shown that the acetone extract and isorhamnetin inhibited lipid peroxidation by 74 and 80%, respectively. The extracts and isolated compounds were also evaluated for their antibacterial activity with the CHCl3 extract and vernolide showing strong activity against S. aureus with an inhibition zone of 21 and 19 mm, respectively. On the other hand, the acetone extract and isorhamnetin were active against all bacterial pathogens tested. The work presented herein has demonstrated that vernolide and isorhamnetin had antibacterial activity. The antioxidant activity displayed by the flowers of V. amygdalina is accounted to the presence of isorhamnetin. Therefore, the biological activities displayed by the extracts and isolated compounds from this plant corroborate the traditional uses of this plant by the local people against various diseases. PMID- 29755518 TI - Double Barrel Nasal Trumpets to Prevent Upper Airway Obstruction after Nasal and Non-Nasal Surgery. AB - Objectives: During anesthesia emergence, patients are extubated and the upper airway can become vulnerable to obstruction. Nasal trumpets can help prevent obstruction. However, we have found no manuscript describing how to place nasal trumpets after nasal surgery (septoplasties or septorhinoplasties), likely because (1) the lack of space with nasal splints in place and (2) surgeons may fear that removing the trumpets could displace the splints. The objective of this manuscript is to describe how to place nasal trumpets even with nasal splints in place. Materials and Methods: The authors describe techniques (Double Barrel Technique and Modified Double Barrel Technique) that were developed over three years ago and have been used in patients with obstructive sleep apnea (OSA) and other patients who had collapsible or narrow upper airways (i.e., morbidly obese patients). Results: The technique described in the manuscript provides a method for placing one long and one short nasal trumpet in a manner that helps prevent postoperative upper airway obstruction. The modified version describes a method for placing nasal trumpets even when there are nasal splints in place. Over one hundred patients have had nasal trumpets placed without postoperative oxygen desaturations. Conclusions: The Double Barrel Technique allows for a safe emergence from anesthesia in patients predisposed to upper airway obstruction (such as in obstructive sleep apnea and morbidly obese patients). To our knowledge, the Modified Double Barrel Technique is the first description for the use of nasal trumpets in patients who had nasal surgery and who have nasal splints in place. PMID- 29755516 TI - Synaptic Paths to Neurodegeneration: The Emerging Role of TDP-43 and FUS in Synaptic Functions. AB - TAR DNA-binding protein-43 KDa (TDP-43) and fused in sarcoma (FUS) as the defining pathological hallmarks for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coupled with ALS-FTD-causing mutations in both genes, indicate that their dysfunctions damage the motor system and cognition. On the molecular level, TDP-43 and FUS participate in the biogenesis and metabolism of coding and noncoding RNAs as well as in the transport and translation of mRNAs as part of cytoplasmic mRNA-ribonucleoprotein (mRNP) granules. Intriguingly, many of the RNA targets of TDP-43 and FUS are involved in synaptic transmission and plasticity, indicating that synaptic dysfunction could be an early event contributing to motor and cognitive deficits in ALS and FTD. Furthermore, the ability of the low-complexity prion-like domains of TDP-43 and FUS to form liquid droplets suggests a potential mechanism for mRNP assembly and conversion. This review will discuss the role of TDP-43 and FUS in RNA metabolism, with an emphasis on the involvement of this process in synaptic function and neuroprotection. This will be followed by a discussion of the potential phase separation mechanism for forming RNP granules and pathological inclusions. PMID- 29755520 TI - Efficacy, Safety, and Quality of Treatment Satisfaction of Premixed Human and Analogue Insulin Regimens in a Large Cohort of Type 2 Diabetic Patients: PROGENS BENEFIT Observational Study. AB - Diabetes is a lifelong course disease, so insulin treatment has to be effective and safe, and patients should be satisfied with it. We aimed to compare efficacy, safety, and quality of treatment satisfaction of human and premixed analogue insulin among 3264 patients (53.58% women) with type 2 diabetes mellitus (T2DM) in a real-life environment. 2493 patients (62.77%) had been assigned to group I where before the inclusion into the study the treatment regimen has been changed from analogue to human premixed insulin and 771 patients (37.23%) to group II where the treatment with insulin analogue remained unchanged. At the end of the study, there was a reduction of HbA1c observed in both of the groups; however, Delta HbA1c was significantly higher in group 1 (-0.599 versus -0.406; P < 0.001 at visit 3 versus visit 1). The number of hypoglycemic episodes during the study observation was insignificantly reduced in both groups. Diabetes treatment satisfaction measured with DTSQ increased at the end of the study and was significantly better in group I compared to group II (P < 0.001). This observational study proved that both human and premixed analogue insulin are effective and safe, and patients are satisfied with the treatment. PMID- 29755519 TI - Simulated Cholinergic Reinnervation of beta (INS-1) Cells: Antidiabetic Utility of Heterotypic Pseudoislets Containing beta Cell and Cholinergic Cell. AB - Cholinergic neurons can functionally support pancreatic islets in controlling blood sugar levels. However, in islet transplantation, the level of cholinergic reinnervation is significantly lower compared to orthotopic pancreatic islets. This abnormal reinnervation affects the survival and function of islet grafts. In this study, the cholinergic reinnervation of beta cells was simulated by 2D and 3D coculture of INS-1 and NG108-15 cells. In 2D culture conditions, 20 mM glucose induced a 1.24-fold increase (p < 0.0001) in insulin secretion from the coculture group, while in the 3D culture condition, a 1.78-fold increase (p < 0.0001) in insulin secretion from heterotypic pseudoislet group was observed. Glucose stimulated insulin secretion (GSIS) from 2D INS-1 cells showed minimal changes when compared to 3D structures. E-cadherin expressed in INS-1 and NG108-15 cells was the key adhesion molecule for the formation of heterotypic pseudoislets. NG108-15 cells hardly affected the proliferation of INS-1 cells in vitro. Heterotypic pseudoislet transplantation recipient mice reverted to normoglycemic levels faster and had a greater blood glucose clearance compared to INS-1 pseudoislet recipient mice. In conclusion, cholinergic cells can promote insulin secreting cells to function better in vitro and in vivo and E-cadherin plays an important role in the formation of heterotypic pseudoislets. PMID- 29755521 TI - Cataract as Early Ocular Complication in Children and Adolescents with Type 1 Diabetes Mellitus. AB - Cataract is a rare manifestation of ocular complication at an early phase of T1DM in the pediatric population. The pathophysiological mechanism of early diabetic cataract has not been fully understood; however, there are many theories about the possible etiology including osmotic damage, polyol pathway, and oxidative stress. The prevalence of early diabetic cataract in the population varies between 0.7 and 3.4% of children and adolescents with T1DM. The occurrence of diabetic cataract in most pediatric patients is the first sign of T1DM or occurs within 6 months of diagnosis of T1DM. Today, there are many experimental therapies for the treatment of diabetic cataract, but cataract surgery continues to be a gold standard in the treatment of diabetic cataract. Since the cataract is the leading cause of visual impairment in patients with T1DM, diabetic cataract requires an initial screening as well as continuous surveillance as a measure of prevention and this should be included in the guidelines of pediatric diabetes societies. PMID- 29755522 TI - In Situ Preservation Fraction of Parathyroid Gland in Thyroidectomy: A Cohort Retrospective Study. AB - Background and Objectives: Parathyroid failure is the most common symptom after thyroidectomy. To prevent it, a gland was preserved in situ or an ischemic one was autotransplanted. This study explored the relationship between in situ preservation of the parathyroid gland and gland failure. Methods: Consecutive patients who underwent initial total thyroidectomy were enrolled retrospectively in a prospectively maintained database. Patients were divided into groups by parathyroid gland remaining in situ fraction (PGRIF) (PGRIF = number of in situ glands/(total number of identified glands - number of glands in specimen). Patients were graded by tertiles and followed at least one year after surgery. Results: 559 patients were included. PGRIF is significantly inversely associated with transient hypoparathyroidism, protracted hypoparathyroidism, and postoperative hypocalcemia. PGRIF was identified as an independent risk factor for transient hypoparathyroidism, protracted hypoparathyroidism, and postoperative hypocalcemia (OR = 0.177, 0.190, and 0.330, resp.). Autotransplantation of parathyroid gland would not affect the calcium level in the long term. Conclusion: In situ preservation of parathyroid gland is crucial for parathyroid function. Less preserved is the independent risk factor for postoperative hypoparathyroidism and hypocalcemia, resulting in a worse function of parathyroid gland in the long term. PMID- 29755523 TI - Hypophyseal Involvement in Immunoglobulin G4-Related Disease: A Retrospective Study from a Single Tertiary Center. AB - This study aims to outline the clinical features and outcomes of IgG4-related hypophysitis (IgG4-RH) patients in a tertiary medical center. We reviewed clinical manifestations and imaging and pituitary function tests at baseline, as well as during follow-up. Ten patients were included. The mean age at diagnosis of IgG4-RH was 48.4 (16.0-64.0) years. An average of 3 (0-9) extrapituitary organs were involved. Five patients had panhypopituitarism, three had only posterior hypopituitarism, one had only anterior hypopituitarism, and one had a normal pituitary function. One patient in our study had pituitary mass biopsy, lacking IgG4-positive cells despite lymphocyte infiltration forming an inflammatory pseudotumor. Five patients with a clinical course of IgG4-RH less than nine months and a whole course of IgG4-RD less than two years were managed with glucocorticoids, while three patients with a longer history were administered glucocorticoids plus immunosuppressive agents. One patient went through surgical excision, and one patient was lost to follow-up. All patients showed a prompt response clinically, but only three patients had normalized serum IgG4 levels. Two patients who took medications for less than six months relapsed. Conclusions. IgG4-RD is a broad disease, and all physicians involved have to be aware of the possibility of pituitary dysfunction. Younger patients should be expected. The histopathological feature of pituitary gland biopsy could be atypical. For patients with a longer history, the combination of GC and immunosuppressive agents is favorable. Early and adequate courses of treatment are crucial for the management of IgG4-RH. With GC and/or immunosuppressant treatment, however, pituitary function or diabetes insipidus did not improve considerably. PMID- 29755525 TI - Quality of Life, Depression, and Anxiety in Patients with Uveal Melanoma: A Review. AB - The aim is to summarize current knowledge on both QoL and depressive/anxious symptoms in patients with UM, including studies on the effect on QoL and psychological status of genetic testing related to the risk of metastatic disease. A review from the last 25 years by using the databases "PsycInfo," "Medline," and "Science Direct" was performed. As a total result, eighteen papers were retrieved. Eight studies (44.4%) used a prospective design methodology: two were retrospective observations (11.1%), three were cross-sectional observational studies (16.6%), and three (16.6%) were naturalistic follow-up studies. One trial was conducted with a case-control design (5.5%), and one was a methodological paper (5.5%). The number of subjects included in the studies ranged widely, between 7 and 842 (mean: 152.1 +/- 201.3), for a total of 2587 patients, 1306 males (50.5%) and 1281 females (49.5%). The mean age of subject enrolled was 61.3 +/- 4.1 years. Twenty-six different scales, questionnaires, or interviews were utilized. No significant differences in QoL between radiotherapy and enucleation emerged. Genetic testing did not significantly affect QoL or psychological status. PMID- 29755526 TI - Salivary Levels of Hemoglobin for Screening Periodontal Disease: A Systematic Review. AB - Periodontal disease is a common inflammatory disease. It affects about 20-50% of global population in both developed and developing countries. Early detection of slight changes of periodontal tissue plays an important role in prevention of onset and progression of periodontal disease. Hence, there is a need of a screening test to assess periodontal tissue for health check-ups. Salivary levels hemoglobin (Hb) has been proposed to assess the conditions of the inflammation of gingiva. The aim of this systematic review was to evaluate and summarize critically the current evidences for Hb as periodontal screening test. We performed a literature search of report published using PubMed databases. A total of 55 articles were retrieved and 16 were selected. Our review focuses on corelation coefficient with periodontal clinical parameters or sensitivity and specificity. As a result, fourteen studies calculated sensitivity and specificity of Hb. Six studies measured salivary levels hemoglobin at laboratory: three studies used polyclonal antibody reactions and other studies used colorimetric tests. Eight studies used paper strip method: 4 studies used monoclonal antibody reaction and 4 studies used colorimetric tests. Youden's indexes by antibody reaction were better than those of colorimetric methods. Evidences are described above and further studies are necessary to set the cut off values stratified by gender, age and number of remaining teeth. PMID- 29755527 TI - Dentigerous Cystic Changes in the Follicles Associated with Radiographically Normal Impacted Mandibular Third Molars. AB - Objective: To assess the incidence of dentigerous cystic changes in the follicles of radiographically normal impacted mandibular third molars. Methods: One hundred and thirteen follicles obtained after surgical removal of impacted mandibular third molars with radiolucency of less than 2.5 mm in the radiograph were sent for histopathologic evaluation to evaluate pathologic changes. Results: The incidence of dentigerous cystic changes observed was 15.9%, that is, 18 out of 113 patients (51 males and 62 females), with the maximum incidence of cystic changes seen in the follicular space size of 0.5 mm. The mean age of the patients included was 27.8 +/- 8.1. The most common indication for extraction among the patients in this study was recurrent pericoronitis (95%). There were no statistically significant differences in occurrence of cystic changes based on age, gender, angulation, relation to ramus, depth, side of impaction, and follicle size (P > 0.05). Conclusion: Dental follicles obtained from surgically removed impacted mandibular third molars should be submitted for histopathologic examination irrespective of the radiographic size of the follicle. PMID- 29755524 TI - A Clinical Roadmap to Investigate the Genetic Basis of Pediatric Pheochromocytoma: Which Genes Should Physicians Think About? AB - Pheochromocytoma is very rare at a pediatric age, and when it is present, the probability of a causative genetic mutation is high. Due to high costs of genetic surveys and an increasing number of genes associated with pheochromocytoma, a sequential genetic analysis driven by clinical and biochemical phenotypes is advised. The published literature regarding the genetic landscape of pediatric pheochromocytoma is scarce, which may hinder the establishment of genotype phenotype correlations and the selection of appropriate genetic testing at this population. In the present review, we focus on the clinical phenotypes of pediatric patients with pheochromocytoma in an attempt to contribute to an optimized genetic testing in this clinical context. We describe epidemiological data on the prevalence of pheochromocytoma susceptibility genes, including new genes that are expanding the genetic etiology of this neuroendocrine tumor in pediatric patients. The clinical phenotypes associated with a higher pretest probability for hereditary pheochromocytoma are presented, focusing on differences between pediatric and adult patients. We also describe new syndromes, as well as rates of malignancy and multifocal disease associated with these syndromes and pheochromocytoma susceptibility genes published more recently. Finally, we discuss new tools for genetic screening of patients with pheochromocytoma, with an emphasis on its applicability in a pediatric population. PMID- 29755528 TI - Hypogammaglobulinemia Observed One Year after Rituximab Treatment for Idiopathic Thrombocytopenic Purpura. AB - We present the case of a 19-year-old female with severe hypogammaglobulinemia after having had treatment with rituximab for idiopathic thrombocytopenic purpura requiring intravenous immunoglobulins. She was admitted with the diagnosis of left-sided pneumonia with parapneumonic effusion. The patient was treated with piperacillin/tazobactam after having a poor response to co-amoxiclav. The patient had been tested for immunoglobulin levels, and the levels were very low. She has a history of ITP for which she received steroids. She also received rituximab for the same on four separate occasions, and the last one was about 1 year ago. PMID- 29755529 TI - Intramuscular (Infiltrating) Lipoma of the Floor of the Mouth. AB - Lipoma is a very common soft tissue neoplasm, but only infrequently found in the oral region. Intramuscular lipoma (IML) is a relatively common variant of lipoma. The most common site for IML is the large muscles of the extremities, and it is quite rare in the oral cavity. A case of IML affecting the floor of the mouth/tongue of a 42-year-old female is described. The patient presented with a 4 cm diameter yellow mass in the right side of the sublingual area. Axial and coronal magnetic resonance imaging demonstrated its infiltrating nature that can be distinguished from the ordinary well-encapsulated lesion. The lesion was excised with adequate surgical margins. Histopathologically, the lesion was composed of mature adipose tissue that infiltrated the muscle in a diffuse manner. No lipoblasts, atypical cells, or high mitotic index were found. There was no evidence of recurrence two years postoperatively. Review of the literature yielded that IML occurring in the sublingual region is extremely rare. PMID- 29755530 TI - The Effect of Age on the Regenerative Potential of Human Eyelid Adipose-Derived Stem Cells. AB - Human eyelid adipose-derived stem cells (HEASCs) are a new source of autologous mesenchymal stem cells, which are derived from neuroectoderm and potentially applied in the tissue regeneration and cell therapies. Based on the prevalence of blepharoplasty in Asia and the availability of HEASCs, we investigated the effect of donor age on their characteristics and regenerative potential of HEASCs in vitro. The HEASCs were isolated from patients of three groups: (1) <20 years (n = 4), (2) >20 years, <45 years (n = 5), and (3) >55 years (n = 4). For each group, the proliferative capacity, colony-forming ability, surface markers, differentiation ability, wound healing function, and secreted protein were contrastively evaluated and quantified for statistical analysis. It was found that HEASCs were successfully isolated and cultured by an explant culture method. The proliferative rates, osteogenic and chondrogenic differentiation potentials, wound healing ability, and the expression of TGF-beta1 and fibronectin protein of HEASCs significantly decreased as age increased. However, the expression of CD90 antigen and the adipogenic differentiation showed an age-related increase in HEASCs. As many degenerative diseases increase in prevalence with age, the age related changes of the HEASCs proliferation potential, differentiation capacity, and wound healing ability should be taken into account whenever they are intended for use in research or cytotherapy. PMID- 29755532 TI - Transcutaneous Bilirubin Measurements Can Be Used to Measure Bilirubin Levels during Phototherapy. AB - Objective: To determine whether transcutaneous bilirubin measurements (TcB) before and during phototherapy taken from covered skin during phototherapy correlate with total serum bilirubin (TSB) levels. Study Design: In this prospective observational study, healthy term newborns who required TSB measurements were included. TcB measurements were taken from the forehead before starting and during phototherapy using the BiliChek device. Before starting phototherapy, part of the forehead was covered. Blood for TSB measurement was collected within 5 minutes of TcB measurements. Correlations and mean differences between TcB and TSB before and during phototherapy were calculated. Result: Paired TSB and TcB measurements before and during phototherapy in 151 newborns were performed. The mean gestational age was 38.8 weeks and birth weight was 3.1 kg; 53% were male. Before starting phototherapy, TSB and TcB were 183.8 +/- 41.6 and 190.5 +/- 43 MUmol/l, respectively. During phototherapy, TSB and TcB were 191.8 +/- 39.4 and 187.8 +/- 45.3 MUmol/l, respectively. Linear regression analysis showed a significant correlation between TcB and TSB before starting phototherapy and during phototherapy (r: 0.85; p < 0.001 and r: 80.0; p < 0.001), respectively. Before starting phototherapy, the mean difference between TSB and TcB was 6.2 +/- 23.2 MUmol/l, with a 95% CI of -39.3 to 51.7 MUmol. During phototherapy, the mean difference was -2.8 +/- 23.5 MUmol/l, with a 95% CI of 48.9 to 43.3 MUmol/l. Conclusion: TcB measurements from covered skin in jaundiced term infants during phototherapy correlate with TSB and can be used to monitor bilirubin levels during phototherapy. PMID- 29755531 TI - Adjunctive Platelet-Rich Plasma (PRP) in Infrabony Regenerative Treatment: A Systematic Review and RCT's Meta-Analysis. AB - Background and Objective: The purpose of this study was to highlight the clinical performance of platelet-rich plasma (PRP) used as an adjunctive tool for regeneration in infrabony periodontal defects using different biomaterials or performing different surgical flap approaches. Comparative evaluation of main clinical outcomes as probing pocket depth reduction, clinical attachment gain, and recession reduction with and without the use of PRP has been analysed. Materials and Methods: According to the focused question, an electronic and hand searching has been performed up to December 2016. From a batch of 73 articles, the selection strategy and Jadad quality assessment led us to include 15 studies for the meta-analysis. Results: Despite the high heterogeneity found and the lack of complete data regarding the selected clinical outcomes, a comparative analysis has been possible by the categorization of used biomaterials and surgical flap approaches. This method led us to observe the best performance of grafts with the use of adjunctive PRP in CAL gain and PPD reduction. No difference has been outlined with a specific surgical flap. Conclusions: Although PRP is considered a cheap and patient's derived growth factor, the not conclusive data reported would suggest that its use in addition to bone substitutes could be of some clinical benefit in the regenerative treatment of infrabony defects. Clinical Relevance: This systematic review was intended to sort out the huge controversial debate in the field about the possible use of PRP in regenerative surgery in infrabony defect. The clinical relevance of using blood-borne growth factors to conventional procedures is effective as these could determine a better performance and outcomes despite the surgical approach adopted and limit the use of additional biomaterials for the blood clot stabilization. PMID- 29755533 TI - New onset colitis in an adult patient with chronic granulomatous disease treated with hematopoietic stem cell transplantation: a diagnostic dilemma. AB - Background: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency characterized by recurrent life-threatening bacterial and fungal infections, granuloma formation and intestinal disease. This disease is caused by defects in NADPH oxidase, which result in the inability of phagocytes (neutrophils, monocytes and macrophages) to destroy certain microbes. The only established curative therapy for CGD is hematopoietic stem cell transplantation. Case presentation: A 23-year-old Caucasian male with X-linked chronic granulomatous disease underwent a reduced-intensity conditioning, matched unrelated donor peripheral blood stem cell transplant, after which he was started on tacrolimus and mycophenolate for graft-versus-host disease prophylaxis. Seven months later, he was admitted to hospital for nutritional support secondary to odynophagia and anorexia. Upper endoscopy revealed ulcers in his esophagus, and he was initially treated with acyclovir due to the risk of CMV infection until biopsies came back negative for viral colitis. Following a sigmoidoscopy that showed nonspecific colitis, he was started on mesalamine. Although pathology showed a pattern of widespread inflammatory changes initially suggestive of CGD colitis, a peripheral blood chimerism study showed 100% donor alleles suggesting CGD remission. Since this patient's colitis was refractory to other immunomodulators, and due to its severity, the patient underwent a partial colectomy 1 year after his HSCT and will likely require the removal of the remaining large bowel. Conclusions: This case demonstrates a unique presentation of colitis in a post-transplant CGD patient. Since CGD colitis could be excluded due to the patient's recent successful hematopoietic stem cell transplantation, a broad differential diagnosis is required for determining the etiology of this new onset colitis in this patient with pre-existing chronic granulomatous disease. This case delineates the need for interdisciplinary care and describes a severe case of colitis after hematopoietic stem cell transplantation. PMID- 29755534 TI - Nano Packaged Tamoxifen and Curcumin; Effective Formulation against Sensitive and Resistant MCF-7 Cells. AB - Tamoxifen is routinely used for treatment of Estrogen-positive breast carcinoma. Approximately, 50% of patients with metastatic cancer will develop resistance to Tamoxifen. In this research, Tamoxifen was combined with the anti-cancer compound Curcumin. Diblocknanopolymer was used to package the new formulation of Curcumin and Tamoxifen. Anti-cancer efficacy of the obtained compound was evaluated in Tamoxifen-sensitive (TS). MCF-7, Tamoxifen-resistant (TR) MCF-7 cancer cells and Fibroblast cells. MTT assay was used to evaluate anti-proliferation and toxicity. Flow cytometry and Annexin-V-FLUOS were used to assay anti-proliferation and induction of apoptosis respectively. Our results indicate that the obtained nano compound is less toxic to normal cells compared to Tamoxifen alone, and has higher anti-proliferation and pro-apoptotic activity on TS-MCF-7 and TR-MCF-7. The nanopolymer reduces the Tamoxifen toxicity in normal cells and counters the developed resistance to the drug in cancer cells. PMID- 29755535 TI - Optimization and Characterization of Aspirin Encapsulated Nano-liposomes. AB - Resistance to aspirin and its cytotoxicity significantly limits its therapeutic applications. Nano-liposomal encapsulation of aspirin can reduce its cytotoxicity. In this study, aspirin encapsulating nano-liposomes (AS-NL) was prepared and its performance in drug delivery and also cytotoxicity was evaluated. The effects of two independent variables including number of freeze/thawing cycles and concentration of aspirin on encapsulation efficiency was investigated using response surface methodology (RSM). A drug profile release was obtained by AS-NL. The concentration of cholesterol as effective for liposome stability and sodium lauryl sulfate (SLS) as a drug release facilitator was also optimized using RSM. The maximum aspirin encapsulation efficiency (41.44%) and drug release (33.92%) was obtained for 0.514 mg cholesterol and 0.007 mg SLS used for liposome formulation. The morphology and size of AS-NLs were characterized using transmission electron microscopy (TEM) and dynamic light scattering (DLS). The stability of AS-NL was evaluated by measuring the size change of nano liposomes during 21 days using DLS analysis. The stability of AS-NL during this period was acceptable. The cytotoxicity test of AS-NL by MTT test reveals the cytotoxicity of aspirin can be reduced by using liposome encapsulation. PMID- 29755536 TI - Preclinical Study of Ibuprofen Loaded Transnasal Mucoadhesive Microemulsion for Neuroprotective Effect in MPTP Mice Model. AB - Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), showed very promising neuroprotection action, but it suffers from high first pass metabolism and limited ability to cross blood brain barrier. Severe gastric toxicity following oral administration further limits its utility. Hence, the aim of this study was to investigate whether ibuprofen loaded mucoadhesive microemulsion (MMEI) could enhance the brain uptake and could also protect the dopaminergic neurons from MPTP-mediated neural inflammation. In this work, ibuprofen loaded polycarbophil based mucoadhesive microemulsion (MMEI) was developed by using response surface methodology (RSM). Male C57BL/6 mice were intranasally given 2.86 mg ibuprofen/kg/day for 2 consecutive weeks, which were pre-treated with four MPTP injections (20 mg/kg of body weight) at 2 h interval by intraperitoneal route and immunohistochemistry was performed. Globule size of optimal MMEI was 46.73 nm +/- 3.11 with PdI value as 0.201 +/- 0.19. Histological observation showed that optimal MMEI was biocompatible and suitable for nasal application. The result showed very significant effect (p < 0.05) of all three independent variables on the responses of the developed MMEI. Noticeable improvement in motor performance with spontaneous behavior was observed. TH neurons count in substantia nigra with the density of striatal dopaminergic nerve terminals after MMEI administration. Results of this study confirmed neuroprotection action of ibuprofen through intranasal MMEI against MPTP induced inflammation in dopaminergic nerves in animal model and hence, MMEI can be useful for prevention and management of Parkinson disease (PD). PMID- 29755537 TI - Preparation and Characterization of Nanoparticle beta-Cyclodextrin:Geraniol Inclusion Complexes. AB - The aim of the present study was to formulate beta-cyclodextrin (beta-CD) nanoparticles loaded with geraniol (GR) essential oil (EO) with appropriate physicochemical properties. Complexation of GR with beta-CD was optimized by evaluation of four formulations, using the co-precipitation method, and the encapsulation efficiency (EE), loading, size, particle size distribution (PDI) and zeta potential were investigated. Further characterization was performed with nuclear magnetic resonance spectroscopy (1H NMR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and infra-red (IR) spectroscopy analysis. Results showed that the physicochemical properties of the nanoparticles were affected by GR content in formulations that yielded nanoscale size particles ranging from 111 to 258 nm. The highest encapsulation efficiency (79.4 +/- 5.4%) was obtained when the molar ratio of EO to beta-CD was 0.44: 0.13 with negative zeta potential (-21.1 +/- 0.5 mV). The 1H-NMR spectrum confirmed the formation structure of the EO and beta-CD nanoparticle complex. Complexation with geraniol resulted in changes of IR profile, NMR chemical shifts, DSC properties, and SEM of beta-cyclodextrin. Inclusion complex of essential oil with beta-cyclodextrin was considered as promising bioactive materials for designing functional food. PMID- 29755538 TI - Synergistic Effect of ZnO Nanoparticles and Carbon Nanotube and Polymeric Film on Electrochemical Oxidation of Acyclovir. AB - A simple and selective carbon paste electrode has been developed for the electrochemical determination of acyclovir (ACV). This electrode was designed by incorporation of multi-walled carbon nanotubes (MWCNTs) and ZnO nanoparticles into the carbon paste matrix, and then poly (o-aminophenol; OAP) film were subsequently electropolymerized on it. The surface structure of nanoparticles were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Surface morphology and electrochemical properties of the prepared nanocomposite modified electrode were investigated by SEM and cyclic voltammetry (CV). The calibration graph was linear over the concentration range 0.089 to 7.96 ug mL-1 for ACV determination with a detection limit of 0.067 ug mL 1. The proposed electrode was successfully applied for ACV determination in pharmaceutical formulations with satisfactory results. PMID- 29755539 TI - The importance of alpha-CT and Salt bridges in the Formation of Insulin and its Receptor Complex by Computational Simulation. AB - Insulin hormone is an important part of the endocrine system. It contains two polypeptide chains and plays a pivotal role in regulating carbohydrate metabolism. Insulin receptors (IR) located on cell surface interacts with insulin to control the intake of glucose. Although several studies have tried to clarify the interaction between insulin and its receptor, the mechanism of this interaction remains elusive because of the receptor's structural complexity and structural changes during the interaction. In this work, we tried to fractionate the interactions. Therefore, sequential docking method utilization of HADDOCK was used to achieve the mentioned goal, so the following processes were done: the first, two pdb files of IR i.e., 3LOH and 3W11 were concatenated using modeller. The second, flexible regions of IR were predicted by HingeProt. Output files resulting from HingeProt were uploaded into HADDOCK. Our results predict new salt bridges in the complex and emphasize on the role of salt bridges to maintain an inverted V structure of IR. Having an inverted V structure leads to activate intracellular signaling pathway. In addition to presence salt bridges to form a convenient structure of IR, the importance of alpha-chain of carboxyl terminal (alpha-CT) to interact with insulin was surveyed and also foretokened new insulin/IR contacts, particularly at site 2 (rigid parts 2 and 3). Finally, several conformational changes in residues Asn711-Val715 of alpha-CT were occurred, we suggest that alpha-CT is a suitable situation relative to insulin due to these conformational alterations. PMID- 29755540 TI - Synthesis of Some Benzofuran Derivatives Containing Pyrimidine Moiety as Potent Antimicrobial Agents. AB - In this investigation, the synthesis of 2-substituted pyrimidines by the reaction of benzofuran chalcones (3a-d) with urea, thiourea and guanidine hydrochloride was reported. The structures of title compounds (4a-d), (5a-d) and (6a-d) were established on the basis of analytical and spectral data. The synthesized compounds were screened for antimicrobial activity and molecular docking studies. Some of the compounds displayed excellent antimicrobial activity. The molecular docking analysis revealed that compounds 5a and 5c with the lowest binding energy in comparison to others suggesting its potential as best inhibitor of GluN-6-P. Consequently, it is confirmed from the above analysis that the compounds 5a and 5c might serve as a useful backbone scaffold for rational design, adaptation and investigation of more active analogs as potential broad spectrum antimicrobial agents. PMID- 29755541 TI - Design, Synthesis and Biological Evaluation of Novel Peptide-Like Analogues as Selective COX-2 Inhibitors. AB - A new series of peptide-like derivatives containing different aromatic amino acids and possessing pharmacophores of COX-2 inhibitors as SO2Me or N3 attached to the para position of an end phenyl ring was synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. The synthetic reactions were based on the solid phase peptide synthesis method using Wang resin. One of the analogues, i.e., compound 2d, as the representative of these series was recognized as the most effective and the highest selective COX-2 inhibitor with IC50 value of 0.08 MUM and COX-2 selectivity index of 351.2, among the other synthesized compounds. Molecular docking study was operated to determine possible binding models of compound 2d to COX-2 enzyme. The study showed that the p-azido phenyl fragment of 2d occupied inside the secondary COX-2 binding site (Arg513, and His90). The structure-activity relationships acquired disclosed that compound 2d with 4-(azido phenyl) group as pharmacophore and histidine as amino acid gives the essential geometry to provide inhibition of the COX-2 enzyme with high selectivity. Compound 2d can be a good candidate for the development of new hits of COX-2 inhibitors. PMID- 29755542 TI - Design, Synthesis and Antitubercular Evaluation of Novel Series of Pyrazinecarboxamide Metal Complexes. AB - The interest in the synthesis of metallic complexes of different drugs to make them more efficient in biological environment of the human body is seen for the last few decades. Wide range of metal complexes are already used in clinical practice which encourages additional research for innovating new metal based drugs, such as metal-mediated antibiotics, anti-parasitic, antiviral, antibacterial, and anticancer compounds. Tuberculosis has been known as one of the most disastrous disease putting burden on health system worldwide. Though the therapeutic agents to combat the disease are well practiced, emergence of multi drug resistant strains makes the treatment strategies more difficult. The following work aims to synthesize copper, ferrous, ferric, cobalt and manganese complexes of renowned anti tuberculosis drug, pyrazinamide (PZ). These compounds were tested for anti-tuberculosis using five multidrug resistant strain of Mycobacterium tuberculosis. For this purpose BACTEC MGIT 960 system was used. The drug PZ was also screened with the synthesized complexes. The two complexes of cobalt and manganese proved potent among all of the compounds tested. PMID- 29755543 TI - Prediction of Lipophilicity and Pharmacokinetics of Chloroacetamides by Chemometric Approach. AB - In this study, the existence of biological potential of selected N-(substituted phenyl)-2-chloroacetamides was examined none empirically, as was the possibility of applying simple experimental technique in predicting essential properties which affect the biological activity of the compounds. By applying the Lipinski and Ghose's rules, it has been revealed that the examined chloroacetamides fulfill the theoretical requirements for bioactive compounds. In addition, lipophilicity was determined by applying the reversed-phase thin-layer chromatography (RPTLC18F254s) in the mixtures of water and two organic modifiers separately (methanol and acetone) and by using relevant software packages. The chromatographic retention parameters, RM0 and m, as the presumed criteria for the lipophilicity of the examined chloroacetamides were correlated by linear regression analysis, and the relevant chemometric methods (Cluster Analysis and Principal Component Analysis) with the standard measure of lipophilicity, log P, and with the selected pharmacokinetic predictors. Thus good correlations in both water-modifier systems (average correlation coefficients, r , 0.947 and 0.931) were obtained. The chemometric methods, as well as the classical correlation methods gave similar results which demonstrated that the chromatographic retention parameters, RM0 and m, can successfully describe the lipophilicity and the pharmacokinetics of the N-(substituted phenyl)-2-chloroacetamides in the first steps of preclinical research. PMID- 29755544 TI - Physicochemical, Stress Degradation Evaluation and Pharmacokinetic Study of AZGH101; a New Synthesized COX2 Inhibitor after I.V. and Oral Administration in Male and Female Rats. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) act mainly via inhibition of prostaglandins synthesis by inhibition of cyclooxygenase (COX) isoenzymes (COX-1 and COX-2). Selective COX-2 inhibitors which are also known as coxibs provide the main therapeutic effects of NSAIDs. Zarghi et al. reported 6-benzoyl-2-(4 (methylsulfonyl) phenyl) quinoline-4-carboxylic acid (AZGH101) as a novel derivative of ketoprofen with improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with ketoprofen. In this study, the log P and stability of AZGH101 were evaluated and the pharmacokinetic characteristics of this compound were investigated following intravenous (10 mg/kg), and oral administration (20 mg/kg), to Wistar rats. As the data demonstrated, the AZGH101was classified as lipid soluble compound and had suitable stability according to forced degradation protocol ICH guideline for new drug substance. This derivative absorbs, distributes, and eliminates similar in both sexes. The AUC 0-infinity, absolute bioavailability, Cl, and Vd were not different in both sexes. According to the obtained data, the AZGH101 does not have a sex dependent pharmacokinetic in Wistar rats. PMID- 29755545 TI - Exposure Assessment for Some Pesticides through Rice Consumption in Iran Using a Multiresidue Analysis by GC-MS. AB - In communities which consume rice as main food, importance of risk assessment for contaminants is always taken into consideration by health authorities. The present study is an attempt for monitoring of 56 pesticides from different chemical groups in rice samples collected from local markets in Tehran and estimation of daily intake of interested pesticides through this monitoring. A valid method based on spiked calibration curves and QuEChERS sample preparation was developed for determination of pesticides residue in rice by GC/MS. The analytical results of the proposed method were in good agreement with the proficiency test (FAPAS 0969). One-hundred-thirty-five rice samples were analyzed and 11 pesticide residues were found in 10.4% of the samples. Of which 5.2% were contaminated with unregulated pesticides. None of the samples, which were contaminated with regulated pesticides, had contamination higher than maximum residue limit. The mean estimated dose (ED) was calculated with respect of mean of contamination and mean daily consumption of rice. ED of the found pesticides is much lower than the related ADIs. PMID- 29755546 TI - Occurrence of Ochratoxin A in Grape Juice of Iran. AB - Ochratoxin A (OTA) is one of the most important mycotoxins that contaminate a broad range of agricultural and food products. In this study, the occurrence of OTA in available brands of grape juice in Iran purchased from retail outlets or producer were determined for the first time using high-performance liquid chromatography (HPLC) with immunoaffinity columns(IAC) as the clean-up step. The average recoveries for OTA in grape juice ranged from 54.2 to 86.6% with the coefficient of variation lower than 17.3% in lowest spiked level (0.5 ug/L). The estimated LOD and LOQ of OTA were 0.04 ug/L and 0.125 ug/L, respectively. In our study, 70 samples of grape juice evaluated for OTA content. The results showed that in 39 out of 70 samples (55.7%) OTA levels were above the LOQ with the maximum level of 2.6 ug/L and the mean contamination was 0.5 ug/L. Although the mean contamination of OTA in analyzing samples was lower than the MRL set by EU, the high incidence of contamination in these products is worried. Considering the importance of OTA in public health, control of pre- and post-harvest, storage and grape juice manufacturing process, such as HACCP, GAP, and GMP recommended preventive measures are required. PMID- 29755547 TI - Lipocalin2 Protects Human Embryonic Kidney Cells against Cisplatin-Induced Genotoxicity. AB - Cisplatin is one of the most useful chemotherapeutics which performs its cytotoxic effect via accumulation of platinum resulting in oxidative stress, and destruction of cell DNA. This could probably cause secondary cancers in healthy tissues. Lipocalin2 (Lcn2) is a protein which its expression is increased in oxidative stresses. Therefore, the present study was performed to evaluate the protective effects of Lcn2 up-regulation on cisplatin genotoxicity. In order to up-regulate Lcn2 expression, HEK293 cells were transfected with pcDNA3.1-Lcn2 vector. Afterwards, stable cells consistently expressing Lcn2 were selected via screening with G418 antibiotic. Next, overexpression of Lcn2 was evaluated by RT PCR and ELISA, comparing to the control non-transfected cells. Then, in order to evaluate the cytoprotective effects of Lcn2 overexpression, transfected and non transfected cells were subjected to cisplatin treatment followed by MTT and alkaline Comet assays. RT-PCR and ELISA assays confirmed up-regulation of Lcn2 by the stable cells. MTT assay of the Lcn2 over-expressing cells showed higher IC50 values comparing to the non-transfected cells. Furthermore, the Comet assay confirmed Lcn2 protective effects on the cisplatin (1 ug/mL) induced genotoxicity. In the present study, for the first time, we showed the protective effect of Lcn2 on cisplatin induced genotoxicity. Therefore, one of the probable mechanisms of Lcn2 cytoprotctive effects under oxidative stress conditions could be due to the prevention of genotoxicity. However, further evaluations in this regard must be considered. PMID- 29755548 TI - Ameliorative Effect of Beraprost Sodium on Celecoxib Induced Cardiotoxicity in Rats. AB - Selective COX-2 inhibitors are most widely used analgesic and anti-inflammatory drugs; however, its maximal use is highly associated with various serious abnormal cardiovascular events. Beraprost sodium (BPS), prostacyclin analogue has been shown to vasodilatory, antiplatelates, anti-inflmmatory, and antioxidant activity. The objective of the present study was to evaluate the effect of BPS on celecoxib cardiotoxicity in rats. Toxicity was induced in male Albino rats (250 280 g) by celecoxib (100 mg/kg/day). BPS (30 MUg/kg/day) was administered alone and in combination with celecoxib for 14 days and various biochemicals, hemodynamic, left ventricular, biochemical, and histopathological parameters were studied. Cardiotoxicity of celecoxib was revealed by a significant increase in serum lactate dehydrogenase (LDH), troponin-T (Tn-T), tumor necrosis factor-alpha (TNF- alpha), creatine kinase-MB (CK-MB) and systolic blood pressure (SBP), left ventricular end diastolic pressure (LVEDP), LV (dp/dt)max, and LV (dp/dt)min as well as tissue thiobarbituric acid reactive substance (TBARS) and a significant decrease in tissue reduced glutathione (GSH). However, treatment with BPS reversed these alteration in LDH, Tn-T, TNF-alpha, CK-MB, SBP, LVEDP, LV (dp/dt)max, LV (dp/dt)min, TBARS and GSH levels. The histopathological study in cardiac left ventricle revealed protection of myocardium as manifested reduction of fibrosis by abolition of collagen deposition when celecoxib was combined with beraprost sodium. It could be concluded that beraprost sodium may prove a useful adjunct in patients being prescribed celecoxib. PMID- 29755549 TI - Evaluation of Diabetogenic Mechanism of High Fat Diet in Combination with Arsenic Exposure in Male Mice. AB - Obesity is a main reason of type 2 diabetes and also chronic exposure to arsenic (As) can produce diabetic symptoms. In previous studies, the association between high-fat diet and arsenic in the incidence of diabetes was found, but the role of beta cells activity, liver mitochondrial oxidative stress, and hepatic enzymes (leptin, adiponectin and beta amylase) was unclear. Thus, present study was conducted to evaluate the diabetogenic mechanism of arsenic followed by concomitant administration of high-fat diet (HFD) in male mice. In this experimental study, the mice consumed with HFD or low-fat diet (LFD) while exposed to As 25 or 50 ppm in drinking water for 20 weeks. At the end of experiments, hyperglycemia, insulin resistance variables, lipid profile, hepatic enzymes, liver mitochondrial oxidative stress, islet insulin secretion, liver, and pancreas histopathology were evaluated in all mice by their own methods. Control HFD fed mice showed a significant increase in FBG, OGTT, HOMA-IR, ITT, lipid profile, leptin, beta-amylase, liver mitochondrial oxidative stress, hepatic enzymes and decreased FPI, HOMA-beta, adiponectin, and islet insulin secretion or content. However, exposure to HFD concomitant with Arsenic revealed an impressive reduction in FBG, FPI, HOMA-IR, HOMA-beta, ITT, lipid profile, and islet insulin secretion or content. This exposure enhanced OGTT, leptin, adiponectin, liver mitochondrial oxidative stress, and hepatic enzymes. In conclusion, HFD and arsenic concomitant administration induced impairment of OGTT and islet insulin secretion or content through the mitochondrial oxidative stress. PMID- 29755550 TI - The Effects of Buthotus schach Scorpion Venom on Electrophysiological Properties of Magnocellular Neurons of Rat Supraoptic Nucleus. AB - Bothutous Schach (BS) scorpion venom consists of several polypeptides that could modulate ion channels. In this study, the effects of BS crude venom on passive and active electrophysiological properties of rat neurons in supraoptic nucleus (SON) of hypothalamus was investigated using whole-cell patch clamp technique. The results showed that bath application of BS venom produced significant change in passive properties of SON neurons, namely a decrease in resting membrane potential and an increase in input resistance of the cells. Also, significant change in active properties of SON neurons was shown after bath application of BS venom; including a decrease in the number of evoked action potential along with an increase in half width and decay time of action potential and a significant decrease in after-hyperpolarization amplitude. Finally, a decreased latency to the first spike accompanied by a lower current threshold to elicit the first spike was shown compared with the values before venom application. These effects are possibly through blocking different ion channels including potassium channels. Further experiments using different fractions of the venom is required to specify venom effects on various ion channels. PMID- 29755551 TI - Antidepressant-like Effect of a Chalcone Compound, DHIPC and Its Possible Mechanism. AB - DHIPC (2,4-dichloro-2'-hydroxyl-4',6'-diisoprenyloxychalcone) is a new chalcone compound. In this study, its antidepressant-like activity of compound DHIPC was evaluated by the forced swimming test and the tail suspension test in mice. The results showed that DHIPC significantly reduced the immobility time for 2 h after treatment through the oral administration at dose of 10, 20, and 30 mg/kg in the forced swimming test and the tail suspension test, indicating a significant antidepressant-like effect. The maximal effect was obtained at 30 mg/kg, which is similar to the positive control fluoxetine. The main monoamine neurotransmitters and their metabolites in rat brain were also simultaneously determined. It was found that DHIPC significantly increased the concentrations of the main neurotransmitters serotonin and noradrenalin, and also significantly increased 5 hydroxyindoleacetic acid contents in hippocampus, hypothalamus, and cortex in brain part. So, the probable mechanism of action of DHIPC is thought to be related to increase in serotonin and noradrenalin in the brain. PMID- 29755553 TI - Neuroprotective Effect of Paroxetine on Memory Deficit Induced by Cerebral Ischemia after Transient Bilateral Occlusion of Common Carotid Arteries in Rat. AB - Memory deficit is the most visible symptom of cerebral ischemia. The hippocampus is sensitive against cerebral ischemia. Oxidative stress and inflammation are involved in the pathological process after cerebral ischemic injury. Paroxetine has anti-oxidative and anti-inflammatory effects. In this study, the effect of paroxetine on memory deficit after cerebral ischemia was investigated. Cerebral ischemia/reperfusion (I/R) injury model was established using the bilateral occlusion of common carotid artery method. Paroxetine (10 mg/kg) was intraperitoneally injected into rats, 24 h before surgery or once a day for 7 days after surgery. Learning and memory were evaluated using the Morris water maze task, then the brain tissue was fixed and hippocampal CA1 pyramidal cells damage was analyzed using the Nissl staining method. In the ischemia group the escape latency time (ELT) and the swimming path length (SPL) were significantly increased and the time spent in target quadrant (TSTQ) was significantly decreased compared with the control group. The ELT and the SPL were significantly shortened and the TSTQ was significantly increased compared with the ischemia group after Pre- or post-ischemic administration of paroxetine. The percentage of viable pyramidal cells in the ischemia group was significantly decreased compared with the control group. The percentage of viable cells was significantly increased following pre-or post-ischemic administration of paroxetine compared with the ischemia group. Memory deficit due to I/R was improved and the percentage of viable cells in CA1 region was increased after administration of paroxetine. Therefore, paroxetine may have a neuroprotective effect against cerebral ischemia. PMID- 29755552 TI - Efficacy of Alpha Glucosidase Inhibitor from Marine Actinobacterium in the Control of Postprandial Hyperglycaemia in Streptozotocin (STZ) Induced Diabetic Male Albino Wister Rats. AB - The current study was carried out to evaluate the in-vitro and in-vivo efficiency of alpha glucosidase inhibitor of marine actinobacteria in the control of postprandial hyperglycaemia. Soil samples were collected from salterns, coastal area in Kothapatnam, Ongole, Andhra Pradesh, India. Among the actinobacterial isolates tested for yeastalpha-glucosidase inhibitory activity, only three isolates showed prominent inhibition. The patient isolate was selected and identified as Streptomyces coelicoflavus SRBVIT13 using 16S r-RNA gene sequencing. In in-vitro studies, the chloroform extract of Streptomyces coelicoflavus SRBVIT13 showed significant enzyme inhibitory activity against yeast and mammalian alpha-glucosidaseenzymes. In animal studies, the oral ingestion of chloroform extract (600 mg/kg) of S. coelicoflavus SRBVIT13 in maltose and sucrose loaded diabetic rats, showed significant regulation of postprandial blood glucose by 82.25% and a 77.25% reduction, respectively. The lead compound from S. coelicoflavusSRBVIT13 was isolated, purified, characterized, and identified by stranded analytical techniques as 2-t-butyl-5 chloromethyl-3-methyl-4-oxoimidazolidine-1-carboxylic acid, t-butyl ester. The results obtained in the present study are promising and the bioactive compound from S. coelicoflavusSRBVIT13 may be considered as a potential agent in regulating the postprandial hyperglycaemia. PMID- 29755554 TI - Evaluation of Antioxidant and Anti-Melanogenic Activity of Different Extracts of Aerial Parts of N. Sintenisii in Murine Melanoma B16F10 Cells. AB - Nepeta (Lamiaceae) is an important genus with beneficial medicinal properties. N. sintenisii Bornm. has been used in folk medicine of Iran to cure various diseases. We investigated the anti-melanogenesis effects of n-hexane, MeOH, CH2Cl2, n-BuOH, EtOAc, and H2O extracts isolated from the plant in B16 melanoma cells. Various assays including cytotoxicity, mushroom tyrosinase inhibition, inhibition of cellular tyrosinase, melanin content, the amount of reactive oxygen species and western blotting were done to assess the plant activities on melanogenesis inhibition. All extracts of N. sintenisii could significantly reduce both tyrosinase activity and the cellular melanin content. Reactive oxygen species were also significantly decreased following the treatment of cell with n BuOH and EtOAc extracts with no cytotoxicity. The plant significantly decreased the amount of microphthalmia-associated transcription factor proteins. Collectively, N. sintenisii inhibited melanin synthesis and tyrosinase activity in B16 melanoma cells with no cytotoxic effects. Hence, it might merit further investigations for elucidation of anti-hyperpigmentation agents. PMID- 29755555 TI - The Ethanolic Extract of Eysenhardtia polystachya (Ort.) Sarg. Bark and Its Fractions Delay the Progression of Rheumatoid Arthritis and Show Antinociceptive Activity in Murine Models. AB - Eysenhardtia polystachya is widely used in folk medicine as an anti-rheumatic and analgesic agent, but no systematic study of its effects on several markers associated with rheumatoid arthritis and its ethnomedical use as analgesic agent has been performed. We evaluated the anti-arthritic and antinociceptive properties of an ethanolic extract of E. polystachya (EE) bark and its rich flavonoids fractions in murine models. The EE was administered orally at doses of 25, 50, 100, and 200 mg/kg/day, and its fractions at 25 mg/kg/day in all animal models. Anti-arthritic activity was evaluated using a complete Freund's adjuvant (CFA)-induced rheumatoid arthritis model in rats. The severity of arthritis was evaluated by changes in paw oedema, body weight, arthritic index, radiological scores, histological assessment of synovial joints, erythrocyte sedimentation rate, haematocrit, haemoglobin, serum rheumatoid factor, serum C-reactive protein and serum levels of the pro-inflammatory cytokines IL-1beta, IL-6, TNF-alpha, IL 18, IFN-gamma, GM-CSF, and anti-inflammatory cytokines IL-4, IL-10, IL-13. Antinociceptive activity was evaluated using an acetic acid-induced abdominal contraction test and a hot-plate test in mice. EE and its rich-flavonoids fractions inhibited secondary inflammatory reactions, diminished the specific histopathological alterations in the joint capsule and reduced the serum concentrations of the pro-inflammatory cytokines IL-6, TNF-alpha, and GM-CSF in arthritic rats. EE also reduced the number of writhes produced by acetic acid and increased the response time on the hot plate for mice. Our findings support the use of Eysenhardtia polystachya bark for the treatment of rheumatoid arthritis and pain management. PMID- 29755556 TI - Defensive Properties of Ginsenoside Re against UV-B-Induced Oxidative Stress through Up-Regulating Glutathione and Superoxide Dismutase in HaCaT Keratinocytes. AB - Ginseng is now used worldwide as a traditional Oriental medicine. Ginsenosides, also known as ginseng saponins, are responsible for most pharmacological efficacies of ginseng. This work aimed to assess the novel skin anti-photoaging potential of ginsenoside Re (Re), a protopanaxatriol-type ginsenoside, by analyzing reactive oxygen species (ROS), pro-matrix metalloproteinase-2 (proMMP 2) and -9 (proMMP-9), total glutathione (GSH), superoxide dismutase (SOD), and cellular viability in UV-B-irradiated HaCaT keratinocytes. When HaCaT cells were pretreated with Re prior to UV-B irradiation, Re significantly suppressed the UV B-induced ROS elevation. It was also able to attenuate the UV-B-induced proMMP-2 and -9 elevations at both activity and protein levels. Re was capable of overcoming the UV-B-reduced total GSH content and SOD activity in concentration dependent ways. Under the experimental conditions used, Re could interfere with cellular viabilities in neither non-irradiated nor UV-B-irradiated keratinocytes. PMID- 29755557 TI - Evaluation of Silibinin Effects on the Viability of HepG2 (Human hepatocellular liver carcinoma) and HUVEC (Human Umbilical Vein Endothelial) Cell Lines. AB - Human hepatocellular carcinoma is one of the most common recurrent malignancies since there is no effective therapy for it. Silibinin, a widely used drug and supplement for various liver disorders, demonstrated anti-cancer effects on human hepatocellular carcinoma, human prostate adenocarcinoma cells, human breast carcinoma cells, human ectocervical carcinoma cells, and human colon cancer cells. Considering the anti-hepatotoxic activity of silibinin and its strong preventive and anti-cancer efficacy against various epithelial cancers, we investigated the efficacy of silibinin against human HCC and HUVEC cell lines. Silibinin effects on the growth and mode of cell death of these two cell lines are presented in this paper. HepG2 and HUVEC cells were incubated with different doses of silibinin (12.5, 25, 50, 100, 150 and 200 MUg/mL) at 24, 48, and 72 h. Cytotoxicity was assessed using MTT and Trypan blue assays. Mode of cell death induced by silibinin was investigated using LDH assay and acridine orange/PI double dye staining. The results showed that silibinin has dose-dependent inhibitory effect on the viability of HepG2 and HUVEC cells. However, Silibinin causes a more continuous dose-dependent cytotoxicity in HepG2 cells compared to the HUVEC cells in which some degrees of resistance is apparent at the beginning. The mode of cell death looks also different in these two cell lines with HepG2 cells being more in favor of apoptosis while necrosis is more evident for the HUVEC cells. PMID- 29755558 TI - Antiparasitic Activity and Essential Oil Chemical Analysis of the Piper Tuberculatum Jacq Fruit. AB - With the increase of neglected diseases such as leishmaniasis and Chagas disease, there was a need for the search for new therapeutic alternatives that reduce the harm caused by medicine available for treatment. Thus, this study was performed to investigate the antiparasitic activity of the essential oil from the fruits of Piper tuberculatum Jacq, against lines of Leishmania braziliensis (MHOM/CO/88/UA301), Leishmania infantum (MHOM/ES/92/BCN83) and Trypanosoma cruzi (LC-B5 clone). Before running protocols, an analysis of the chemical composition of essential oil was conducted, which presented monoterpenes and sesquiterpenes. As major constituents, beta-pinene and alpha-pinene were identified. Regarding to antiparasitic activity, the essential oil had an EC50 values of 133.97 ug/mL and 143.59 ug/mL against variations promastigotes of L. infantum and L. braziliensis, respectively. As for trypanocidal activity, the oil showed EC50 value of 140.31 ug/mL against epimastigote form of T. cruzi. Moreover, it showed moderate cytotoxicity in fibroblasts with LC50 value of 204.71 ug/mL. The observed effect may be related to the presence of terpenes contained in the essential oil, since it has its antiparasitic activity proven in the literature. PMID- 29755559 TI - Inhibitory Effect of Viola odorata Extract on Tumor Growth and Metastasis in 4T1 Breast Cancer Model. AB - Viola odorata as a medical herb is used in liver disorders and relieving cancer pain. In the present study, the cytotoxic, antioxidant, and anti-metastatic properties of Viola odorata hydro-alcoholic extract (VOE) were investigated in 4T1 breast cancer model. After treatment of 4T1 breast cancer cells with VOE, cell viability was measured by MTT assay. The implanted mice were treated with different concentration of VOE (50, 150 and 250 mg/kg) for 21 days. Levels of lactate dehydrogenase (LDH), gamma -glutamyl transferase (GGT), alkaline phosphatase (ALP), carcinoembryonic antigen (CEA) and cancer antigen 15-3(CA15-3) in serum, and also catalase (CAT) and superoxide dismutase (SOD) activities in tumor tissue were measured. Metastatic rate was investigated in liver, spleen and lung tissues. VOE decreased cell viability of 4T1 cells, significantly. VOE significantly inhibited the cell proliferation, but not vasculature in the tumors that revealed by immunohistochemical analysis for Ki-67 and CD31 expression, respectively. VOE increased the Bax/Bcl-2 ratio in VOE250-treated group compared to control group. Serum analysis showed that treatment with 250 mg/kg of VOE significantly reduced LDH (not ALP and GGT) levels compared to controls. No linear correlation was found between the values of CEA and CA15-3 with tumor size. The rate of CAT activity was increased in VOE250-treated rats whereas, CAT and SOD activities were reduced in VOE50 group. VOE250 significantly decreased the metastatic rate in liver and lung compared to the other doses of VOE. Consequently, Viola odorata has cytotoxic effects on 4T1 cells and affects antioxidant activity and metastasis in breast cancer. PMID- 29755560 TI - Anti-hypercholesterolemic Effect of Berbamine Isolated from Rhizoma Coptidis in Hypercholesterolemic Zebrafish Induced by High-Cholesterol Diet. AB - The anti-hypercholesterolemic effect of berbamine (BBM) isolated from Rhizoma Coptidis (RC) was investigated in hypercholesterolemic zebrafish model induced by high-cholesterol (HC) diet. Zebrafish embryo assay revealed no significant difference in morphology and cell death with the treatment of BBM less than 20 MUg/mL. In zebrafish larvae, the fluorescently labeled cholesterol in caudal artery was reduced dose-dependently after BBM treatment. For adult zebrafish, administration of 0.2% BBM exhibited a significant decrease in plasma total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL c) levels by 37%, 38% and 28%, respectively, along with a fall in lipid content in liver. Further investigation suggested that the mRNA expression of 3-hydroxy-3 methylglutaryl-coenzyme A reductase (HMGCR) and microsomal triglyceride transfer protein (MTP) in liver were down-regulated and the transcription levels of liver gene low-density lipoprotein receptor (LDLR) and cytochrome P450 polypeptide 1a of subfamily A of family 7 (CYP7A1a) were significantly up-regulated with BBM treatment. Histological study showed that BBM can alleviate hepatic steatosis induced by HC diet. These data suggested that BBM has anti-hypercholesterolemic and hepatoprotective effects. The mechanism probably related to the up-regulation of cholesterol transport and bile acid synthesis as well as inhibition of cholesterol synthesis and lipoprotein assembly or secretion. PMID- 29755561 TI - Crude Methanol Extract of Echinophora Platyloba Induces Apoptosis and Cell Cycle Arrest at S-Phase in Human Breast Cancer Cells. AB - The aim of the present study was to determine cytotoxic activity of crude methanolic extract of Echinophora platyloba on breast cancer MDA-MB-231 cell line. The free radical scavenging effects of methanolic extract of E. platyloba were tested using DPPH method. Crude methanolic extract exhibited potential antioxidant activity with an IC50 value of 234.28 +/- 21.63 MUg/mL when compared to the standard BHT with an IC50 value of the 19.5 +/- 0.8 MUg/mL. In addition, the in-vitro cytotoxic activity of this extract was studied against MDA-MB-231 and MCF-10a cells by MTT assay for 12, 24 and 36 h. Our data showed 534.6 +/- 7.2 MUg/mL of extract following 24 h of incubation was the most cytotoxic dose against MDA-MB-231 cells in comparison with other doses. This extract could induce apoptosis and promote cell-cycle arrest at S-phase in MDA-MB-231 cells after 24 h of incubation, as compared to the control group (p < 0.001) and could significantly up-regulate the expression of bax and p27 genes at the level of 2.8 and 2.2 folds, respectively. While, a significant amount of down-regulation was observed for bcl-2 gene expression, which was observed to be 0.4 fold. The present results prove the anticancer capacity of crude methanolic extract of E. platyloba to inhibit limit cell proliferation, and inducing cell cycle arrest and apoptosis. PMID- 29755562 TI - Investigation of beta-Sitosterol and Prangol Extracted from Achillea Tenoifolia Along with Whole Root Extract on Isolated Rat Pancreatic Islets. AB - The genus Achillea (Asteraceae) consisting of important medicinal species, growing wildly in Iran, of which A. tenuifolia is found in Iran-o-Turan regions. Regarding the traditional use of Achillea species for treatment of diabetes and also lack of information on phyto-constituents of A. tenuifolia underground parts, in this study anti-diabetic activity of the plant have been reported. In order to find the main active components, underground parts of the plant were extracted with water and fractioned by hexane, ethyl acetate, and methanol and the separation of the main compounds were carried out via medium pressure liquid chromatography (MPLC). Also, anti-diabetic effects of the extract were investigated on rat pancreatic islets. The root extract of the plant as well as the compound beta-sitosterol showed moderate alpha-amylase inhibitory activity, however prangol did not suppress the enzyme activity. The results of islet cells' bio-function assays revealed that the herb root extract was able to increase the secretion of insulin in high concentration (10 mg/mL) and improved the cell viability with no toxicity in all doses. Furthermore, the herbal extract could reduce the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO). The plant extract also significantly decreased the enzyme activity for both caspase-3 and -9 and increased the antioxidant capacity of the isolated cells. Taking together, preparations or extracts from the underground parts of the plant are good candidates for further anti-diabetic investigation and clinical trials. PMID- 29755563 TI - Anti-mutagenic and Anti-oxidant Potencies of Cetraria Aculeata (Schreb.) Fr., Cladonia Chlorophaea (Florke ex Sommerf.) Spreng. and Cetrelia olivetorum (Nyl.) W.L. Culb. & C.F. Culb.). AB - In this study, the mutagenic and anti-mutagenic effects of methanol extract of three lichen species (Cetraria aculeata, Cladonia chlorophaea and Cetrelia olivetorum) were investigated by using E. coli-WP2, Ames-Salmonella (TA1535 and TA1537) and sister chromatid exchange (SCE) test systems. The results obtained from bacterial test systems demonstrated that methanol extracts of three lichen species have strong anti-mutagenic potencies on TA1535, TA1537 strains and to a lesser extent on E. coli-WP2 strain. The anti-oxidant level of human lymphocytes cells was determined in order to clarify the mechanism underlying the anti mutagenic effects of these lichen species. Co-treatments of 5, 10 and 20 ug/mL concentrations of these three lichen species with AFB decreased the frequencies of SCE and the level of MDA and increased the amount of SOD, GSH and GPx which decreased by aflatoxin. The findings of this work have clearly demonstrated that Cetraria aculeata, Cladonia chlorophaea and Cetrelia olivetorum have significant anti-mutagenic effects which are thought to be partly due to the anti-oxidant activities and the interaction capability of lichen extracts with mutagen agents (Sodium azide, acridin, N-methyl-N'-nitro-N-nitrosoguanidine and aflatoxin B1). PMID- 29755564 TI - A New Taraxastane Triterpene from Euphorbia Denticulata with Cytotoxic Activity Against Prostate Cancer Cells. AB - In this research, aerial parts of Euphorbia denticulata Lam were collected from Sanandaj city in Kurdistan province at the West of Iran. It was extracted by maceration using acetone as solvent. The isolation of compounds were carried out with repeated column chromatography using silica gel and normal preparative HPLC using YMC-Pack-Sil column and hexane: ethyl acetate as mobile phase. The structures of isolated compounds were elucidated by extensive 1 and 2D-NMR as well as HRESI-MS spectra and the cytotoxicity was done against DU-145 human prostate cancer cell line using standard MTT assay. It afforded a new 12 taraxastane derivative and two known cycloartane triterpenes including: taraxast 12-ene-3beta,20,21(alpha)-triol (1), cycloartane-3beta,25-diol (2), and cycloartane-3beta,24,25-triol (3). They exhibited cytotoxic effects, with IC50 values of 12.2 +/- 2.9, 27.5 +/- 4.9, and 18.3 +/- 1.4 uM, respectively. PMID- 29755565 TI - In-Vitro Anti-Proliferative and Pro-Apoptotic Properties of Sutureja Khuzestanica on Human Breast Cancer Cell Line (MCF-7) and Its Synergic Effects with Anticancer Drug Vincristine. AB - Satureja khuzestanica Jamzad (Marzeh Khuzestani in Persian) is an endemic plant that is widely distributed in the southern part of Iran. Despite the number of papers published on this plant, no one has focused on its anticancer effects. Therefore, the present study was designed to investigate the selective cytotoxic and anti-proliferative properties of satureja khuzestanica total extract (SKE). MCF-7 human breast cancer cells were used in this study. Cytotoxicity of the extract was determined using MTT and neutral red assaysafter 24 h treatment period. Biochemical markers of apoptosis (caspase-3, Bax, Bcl-2) and cell proliferation (cyclin D1) were evaluated by immunoblotting. Vincristine was used to evaluate the synergic effect of extract with an anticancer drug. The data showed that treatment of cells with SKE (150 and 200 ug/mL for 24 h) significantly reduced cell viability, activated caspase 3 and increased Bax/Bcl2 ratio. In addition, cyclin D1 expression was significantly decreased in the SKE treated cells. In addition, concomitant treatment of the MCF-7 cells with SKE and vincristine produced a potent anti-proliferative and pro-apoptotic effect compared to extract or drug alone. In conclusion, satureja extract has a potential anti-cancer property against human breast cancer cells and its combination with chemotherapeutic agent vincristine may induce cell death effectively and be a potent modality to treat this type of cancer. PMID- 29755566 TI - Anti-Diabetic Effects of Amygdalus Lycioides Spach in Streptozocin-Induced Diabetic Rats. AB - Diabetes mellitus is a group of metabolic disorders characterized by elevated blood sugar and abnormalities in insulin secretion and action. There are many anti-diabetic plants, which might supply useful sources for developing new medicines that can be used in treatment of diabetes mellitus. The primary objective of the present investigation is to evaluate the anti-diabetic properties of the aerial parts of Amygdalus lycioides in streptozocin-induced diabetic rats. Sixty rats were divided into 6 groups: streptozocin-induced diabetic control, insulin-treated diabetic group, and four Amygdalus lycioides treated diabetic groups (125, 250, 500, and 1000 mg/kg/day). After 2 weeks of plant extract administration, the effects of extracts on blood glucose, body weight, BUN, creatinine, total cholesterol, LDL, HDL, triglyceride, total protein, Na, K, and plasma enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) were analyzed. The pancreas of rats was also stained for stereological studies. Phytochemical evaluation of this extract showed the presence of flavonoids and tannins compounds. Glucose serum levels and glucose tolerance test showed a decrease in treatment with Amygdalus lycioides (1000 mg/kg). Serum total cholesterol, LDL, triglyceride, creatinine and alkaline phosphatase levels were decreased significantly by the extract but aspartate aminotransferase found to be increased after treatment. The total number and numerical density of beta cells increased in the Amygdalus lycioides group (1000 mg/kg). It seems that Amygdalus lycioides may act as a potential drug to treat diabetes and its complications. However, more investigations should be done to more clarify these results. PMID- 29755567 TI - Volatile Constituents from Different Parts of Three Lamiacea Herbs from Iran. AB - The essential oils obtained by hydrodistillation from the stem, leaf and flower of Phlomis aucheri Boiss., which is endemic to Iran, stem, leaf and root of Teucrium polium L. and solvent free microwave extraction oil from leaf of Ajuga chamaecistus Ging. Subsp chamaecistus were analyzed by GC and GC/MS. Germacrene D (11.10%, 28.31% and 21. 06%) was the main constituent in the stem, leaf, and flower oils of P. aucheri, respectively. The other main component in the stem oil of the plant was (E) - anethole (24.58%) and in the flower oil was beta- caryophyllene (15.93%). All three oils were rich in regard to sesquiterpenes. The main components in the stem, leaf and root of T. polium were alpha- muurolol (25.02%, 20.03% and 19.53%), alpha- cadinol (15.72%, 8.11% and 13.01%) and beta cayophyllene (10.86%, 10.11% and 10.64%) respectively. All three oils were rich in regard to sesquiterpenes. The major components in the leaf oil of A.chamaecistus were (z)-beta-ocimene (12.11%) and germacrene D (10.11%). The oil of the plant was rich in regard to both monoterpens and sesquiter penes. PMID- 29755568 TI - Exosomes Secreted by Normoxic and Hypoxic Cardiosphere-derived Cells Have Anti apoptotic Effect. AB - Cardiosphere-derived cells (CDCs) have emerged as one of the most promising stem cell types for cardiac protection and repair. Exosomes are required for the regenerative effects of human CDCs and mimic the cardioprotective benefits of CDCs such as anti-apoptotic effect in animal myocardial infarction (MI) models. Here we aimed to investigate the anti-apoptotic effect of the hypoxic and normoxic human CDCs-derived exosomes on induced apoptosis in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). In this study, CDCs were cultured under normoxic (18% O2) and hypoxic (1% O2) conditions and CDC-exosomes were isolated from conditioned media by differential ultracentrifugation. Cobalt chloride as hypoxia-mimetic agents at a high concentration was used to induce apoptosis in hESC-CMs. The caspase-3/7 activity was determined in apoptosis-induced hESC-CMs. The results indicated that the caspase-positive hESC-CMs were significantly decreased from 30.63 +/- 1.44% (normalized against untreated cardiomyocytes) to 1.65 +/- 0.1 and 1.1 +/- 1.09 in the presence of normoxic exosomes (N-exo) at concentration of 25 and 50 MUg/mL, respectively. Furthermore, hypoxic exosomes (H exo) at concentration of 25 and 50 MUg/mL led to 8.75 and 12.86 % reduction in caspase-positive cells, respectively. The anti-apoptotic activity of N-exo at the concentrations of 25 and 50 MUg/mL was significantly higher than H-exo. These results could provide insights into optimal preparation of CDCs which would greatly influence the anti-apoptotic effect of CDC-exosomes. Totally, CDC secreted exosomes have the potential to increase the survival of cardiomyocytes by inhibiting apoptosis. Therefore, CDC-exosomes can be developed as therapeutic strategy in ischemic cardiac disease. PMID- 29755569 TI - Synthesis of Silica-coated Iron Oxide Nanoparticles: Preventing Aggregation without Using Additives or Seed Pretreatment. AB - The Stober process is frequently used to prepare silica-coated iron oxide nanoparticles. This is usually achieved by seeding a reaction mixture consisting of water, ethanol and a catalyst with iron oxide particles and adding a silica precursor. The hydrolysis and condensation of precursor monomers results in the deposition of a silica layer on iron oxide particles. However, this process is accompanied by an increase in the ionic strength of the medium which promotes the rapid aggregation of iron oxide particles. A number of methods have been developed to prevent seed aggregation during the coating process. The majority of these methods include a pretreatment step in which the surface of iron oxide particles is modified in a manner that increases their stability in aqueous solutions. Here we suggest that by decreasing the initial concentration of the catalyst for a short period to minimize nucleation by reducing precursor hydrolysis rate and then gradually increasing the concentration to the optimum level to allow silica formation to proceed normally it may be possible to prevent aggregation without surface modification. The properties of the resulting nanoparticles as analyzed by transmission electron microscopy and magnetometry as well as their efficiency at extracting genomic DNA from different bacterial strains compared to that of a commercial extraction kit are also reported. PMID- 29755570 TI - Identification of a Novel Tumor-Binding Peptide for Lung Cancer Through in-vitro Panning. AB - Tumor-targeted therapies are playing growing roles in cancer research. The exploitation of these powerful therapeutic modalities largely depends on the discovery of tumor-targeting ligands. Phage display has proven a promising high throughput screening tool for the identification of novel specific peptides with high binding affinity to cancer cells. In the present study, we describe the use of phage display to isolate peptide ligands binding specifically to human lung cancer cells. Towards this goal, we screened a phage display library of 7-mer random peptides in-vitro on non-small cell lung carcinoma (A549) as the target cell. Following selection rounds, there was a highly considerable enrichment of lung cancer-binding phages and a significant increase - 170 fold - of the phage recovery efficiency. After three rounds of in-vitro panning, a group of peptides with different frequencies were obtained. The binding efficiency and selectivity of these peptides for target and control cells were studied. The results of cellular binding assay and cell ELISA (enzyme-linked immunosorbent assay) revealed that LCP1 (Lung Cancer Peptide1) with the displayed sequence AWRTHTP is the most effective peptide in binding to lung cancer cells compared with normal lung epithelial cells and different non-lung tumor cells. In conclusion, our findings suggest that LCP1 may represent a novel peptide that binds specifically to lung cancer cells and further studies can pave the way for its application as a potential targeting moiety in the targeted delivery of diagnostic and therapeutic agents into lung malignant cells. PMID- 29755571 TI - Plasma Oxytocin Level and Sexual Dysfunction in Depressed Women Treated by Either Fluoxetine or Citalopram: a Pilot Clinical Trial. AB - Sexual dysfunction is a common cause of selective serotonin reuptake inhibitor (SSRI) withdrawal. Various studies indicate that decreased oxytocin is involved as a mechanism of delayed ejaculation induced by SSRIs. The aim of the present pilot study was to evaluate and compare sexual dysfunction and oxytocin levels in women being treated with either fluoxetine or citalopram. Thirty-nine women with the diagnosis of major depressive disorder were enrolled in the study. A baseline blood sample was collected and each participant was given either fluoxetine 20 mg/d or citalopram 20 mg/d. After 1 month, a second blood sample was collected and sexual dysfunction was evaluated via the Female Sexual Function Index (FSFI) questionnaire. Twenty-three women completed the study (12 and 11 in the fluoxetine and citalopram groups, respectively). After 1 month, the FSFI scores were 22.8 +/- 7.8 and 22.5 +/- 4.8 in the fluoxetine and citalopram groups, respectively. The oxytocin levels were 187.8 +/- 38.8 pg/mL and 214.6 +/- 23.1 pg/mL in the fluoxetine and citalopram groups, respectively. Statistical analysis did not reveal any difference in the FSFI score between the two groups after 1 month (p = 0.89). However, the oxytocin levels were significantly lower in the fluoxetine group than in the citalopram group (p = 0.05). We also observed a positive relationship between the FSFI score and oxytocin level at 1 month after starting fluoxetine or citalopram (r = 0.43, p = 0.04).A positive relationship between the oxytocin level and FSFI score supports the hypothesis that the oxytocin level plays a role in sexual dysfunction induced by SSRIs. PMID- 29755572 TI - Introducing Potential Key Proteins and Pathways in Human Laryngeal Cancer: A System Biology Approach. AB - The most common malignant neoplasm of the head and neck region is laryngeal cancer which presents a significant international health problem. The present study aims to screen potential proteins related to laryngeal cancer by network analysis to further understanding disease pathogenesis and biomarker discovery. Differentially expressed proteins were extracted from literatures of laryngeal cancer that compare proteome profiling of patient>s tissue with healthy controls. The PPI network analyzed for up and down regulated proteins with Cytoscape Version 3.4. After PPI construction, topological properties of the two networks have been analyzed. Besides, by using MCODE. the Gene Ontology (GO) analysis, the related modules and pathways were examined. Our study screened 275 differentially changed proteins, including 136 up- and 139 down-regulated proteins. For each network, it has been considered 20 key proteins as hub and 20 as bottleneck. A number of 26 hub-bottleneck nodes is introduced for the two networks. A total of 11 modules including 6 downregulated and 5 upregulated network modules were obtained. The most significant GO function in the significant upregulated module was the RNA processing, and the most significant one in the downregulated module with highest score was the respiratory electron transport chain. Among 275 investigated proteins, 12 crucial proteins are determined that 4 of them can be introduce as a possible biomarker panel including YWHAZ, PPP2R1A, HSP90AA1, and CALM3 for human laryngeal cancer. PMID- 29755573 TI - Thymus and activation-regulated chemokine (TARC)/CCL17 and IgE are associated with elderly asthmatics. AB - Background: The pathogenesis of asthma, which is an allergic lung disease, is associated with a variety of allergens such as house dust mite, pollen, and mould, IgE containing serum IgE and allergen-specific-IgE, and inflammatory cytokines including thymus and activation-regulated chemokine (TARC)/CCL17. Because aging is an essential factor in the pathogenesis of asthma, we examined biomarkers related to asthmatic subjects depending on age. Results: Physiological indices such as FEV1(forced expiratory capacity in 1 s), FEV1 (% predicted), and FEV1/FVC(forced vital capacity) (%) in asthmatic subjects were lower than those in normal subjects. Total IgE, Der p1 specific IgE, and Der f1 specific IgE were elevated in serum of asthmatics relative to normal individuals. Regulated on activation, normal T cell expressed and secreted (RANTES)/CCL5 in serum and interleukin 6 (IL-6), interleukin 8 (IL-8), monocyte chemoattractant protein (MCP)-1/CCL2, RANTES, and macrophage inflammatory protein (MIP)-1alpha/CCL3 in bronchoalveolar lavage fluid (BALF) of asthmatic subjects were higher than in normal individuals. Upon classification of experimental groups depending on age, physiological indices and Der p1-specific IgE (class) were decreased in middle aged adult and elderly adult groups relative to the young adult group. TARC levels in serum were strongly elevated in the elderly adult group relative to the young adult and the middle aged adult groups. TARC in serum was related to total IgE in serum in the elderly adult group. Conclusions: Taken together, although TARC in serum and BALF is not different between normal and asthmatic individuals, TARC increases in serum of elderly asthmatic subjects. The level of TARC has a positive effect on the level of IgE in the elderly adult group. These findings may help us better understand the relationship of pathogenesis of allergic diseases and aging. PMID- 29755575 TI - Waist-hip ratio related genetic loci are associated with risk of impaired fasting glucose in Chinese children: a case control study. AB - Background: The meta-analyses of genome-wide association studies identified several waist-hip ratio (WHR) related loci in individuals of European ancestry. Since the pattern of fat distribution and the relationship between fat distribution and glucose metabolism disturbance in Chinese are different from those in Europeans, the present study aimed to explore the individual and cumulative effects of WHR-related loci on glycemic phenotypes in Chinese children. Methods: A total of 2030 children were recruited from two independent studies. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Logistic regression and linear regression model were used to examine the association of 11 SNPs and genetic risk score (GRS) with impaired fasting glucose (IFG) and fasting plasma glucose (FPG), respectively. Results: Three SNPs (rs6795735, rs984222 and rs1011731) were nominally associated with IFG (all P < 0.05). Each WHR-increasing (C) allele of rs6795735 (ADAMTS9) was associated with a 40.1% increased risk of IFG (OR = 1.401, 95% CI = 1.131 1.735, P = 0.002), which remained significant after Bonferroni correction. We observed no association of both weighted and unweighted GRS with FPG and IFG (all P > 0.05). Conclusions: We identified individual effects of rs6795735 (ADAMTS9), rs984222 (TBX15-WARS2), and rs1011731 (DNM3-PIGC) on glycemic phenotypes in Chinese children for the first time. The study suggests that genetic predisposition to central obesity is associated with impaired fasting glucose, providing more evidence for the pathogenesis of diabetes. PMID- 29755576 TI - Cold-pressed minke whale oil reduces circulating LDL/VLDL-cholesterol, lipid oxidation and atherogenesis in apolipoprotein E-deficient mice fed a Western-type diet for 13 weeks. AB - Background: Long-chain n3-polyunsaturated fatty acids (LC n3-PUFA) are well known for their anti-inflammatory activity and their impact on cardiovascular disease. Cold-pressed whale oil (CWO) has half the amount of LC n3-PUFA compared to cod liver oil (CLO). Still, there has been observed more pronounced beneficial effects on cardiovascular disease markers from intake of CWO compared to intake of CLO in human intervention studies. Extracts from CWO deprived of fatty acids have also been shown to display antioxidative and anti-inflammatory effects in vitro. The aim of this study was to investigate whether intake of a high-fat Western-type diet (WD) supplemented with CWO would prevent the development of atherosclerotic lesions in apolipoprotein E-deficient (ApoE-/-) mice. Methods: Seventy female ApoE-/- mice were fed a WD containing 1% CWO, CLO or corn oil (CO). Atherosclerotic lesion formation, body and tissue weights, hepatic gene expression together with serum levels of LDL/VLDL-cholesterol, ox-LDL, total antioxidant status and various serum cardiovascular disease/proinflammatory markers were evaluated. Statistical analyses were performed using SPSS, and Shapiro-Wilk's test was performed to determine the distribution of the variables. Statistical difference was assessed using One-Way ANOVA with Tukeys' post hoc test or Kruskal-Wallis test. The hepatic relative gene expression was analysed with REST 2009 (V2.0.13). Results: Mice fed CWO had less atherosclerotic lesions in the aortic arch compared to mice fed CO. Levels of LDL/VLDL-cholesterol and ox LDL-cholesterol were also markedly reduced whereas total antioxidant levels were enhanced in mice fed CWO compared to CO-fed mice. In addition, CWO-fed mice gained less weight and several hepatic genes involved in the cholesterol metabolism were up-regulated compared to CO-fed mice. Conclusion: In the present study mice fed a WD supplemented with 1% CWO had reduced formation of atherosclerotic lesions in the aortic arch, reduced serum LDL/VLDL-cholesterol and ox-LDL-cholesterol, increased serum total antioxidant status and reduced body weight compared to mice fed a WD supplemented with 1% CO. PMID- 29755574 TI - Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. AB - Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are essential amino acids with protein anabolic properties, which have been studied in a number of muscle wasting disorders for more than 50 years. However, until today, there is no consensus regarding their therapeutic effectiveness. In the article is demonstrated that the crucial roles in BCAA metabolism play: (i) skeletal muscle as the initial site of BCAA catabolism accompanied with the release of alanine and glutamine to the blood; (ii) activity of branched-chain keto acid dehydrogenase (BCKD); and (iii) amination of branched-chain keto acids (BCKAs) to BCAAs. Enhanced consumption of BCAA for ammonia detoxification to glutamine in muscles is the cause of decreased BCAA levels in liver cirrhosis and urea cycle disorders. Increased BCKD activity is responsible for enhanced oxidation of BCAA in chronic renal failure, trauma, burn, sepsis, cancer, phenylbutyrate-treated subjects, and during exercise. Decreased BCKD activity is the main cause of increased BCAA levels and BCKAs in maple syrup urine disease, and plays a role in increased BCAA levels in diabetes type 2 and obesity. Increased BCAA concentrations during brief starvation and type 1 diabetes are explained by amination of BCKAs in visceral tissues and decreased uptake of BCAA by muscles. The studies indicate beneficial effects of BCAAs and BCKAs in therapy of chronic renal failure. New therapeutic strategies should be developed to enhance effectiveness and avoid adverse effects of BCAA on ammonia production in subjects with liver cirrhosis and urea cycle disorders. Further studies are needed to elucidate the effects of BCAA supplementation in burn, trauma, sepsis, cancer and exercise. Whether increased BCAA levels only markers are or also contribute to insulin resistance should be known before the decision is taken regarding their suitability in obese subjects and patients with type 2 diabetes. It is concluded that alterations in BCAA metabolism have been found common in a number of disease states and careful studies are needed to elucidate their therapeutic effectiveness in most indications. PMID- 29755577 TI - The association between parental depression and adolescent's Internet addiction in South Korea. AB - Background: A number of risk factors for Internet addiction among adolescents have been identified to be associated with their behavior, familial, and parental factors. However, few studies have focused on the relationship between parental mental health and Internet addiction among adolescents. Therefore, we investigated the association between parental mental health and children's Internet addiction by controlling for several risk factors. Methods: This study used panel data collected by the Korea Welfare Panel Study in 2012 and 2015. We focused primarily on the association between Internet addiction which was assessed by the Internet Addiction Scale (IAS) and parental depression which was measured with the 11-item version of the Center for Epidemiologic Studies Depression Scale. To analyze the association between parental depression and log transformed IAS, we conducted multiple regression analysis after adjusting for covariates. Results: Among 587 children, depressed mothers and fathers comprised 4.75 and 4.19%, respectively. The mean IAS score of the adolescents was 23.62 +/- 4.38. Only maternal depression (beta = 0.0960, p = 0.0033) showed higher IAS among children compared to nonmaternal depression. Strongly positive associations between parental depression and children's Internet addiction were observed for high maternal education level, adolescents' gender, and adolescent's academic performance. Conclusions: Maternal depression is related to children's Internet addiction; particularly, mothers who had graduated from the university level or above, male children, and children's normal or better academic performance show the strongest relationship with children's Internet addiction. PMID- 29755578 TI - A systematic review and meta-analysis of gender difference in epidemiology of HIV, hepatitis B, and hepatitis C infections in people with severe mental illness. AB - Background: People with severe mental disorders (SMDs) are associated with increased risk of infectious disease including human immunodeficiency virus infection (HIV) and hepatitis viruses, such as hepatitis B virus (HBV), hepatitis C virus (HCV), and other types of hepatitis viruses because of high-risk behaviors compared to the general population. The prevalence of HIV in people with SMDs is higher in females than in males. Unlike HIV, the prevalence of HBV and HCV is higher in males than in females. This study aimed to carry out a systematic review and meta-analysis to determine the prevalence and estimated gender difference in the risk of HIV, HBV, and HCV in people with SMD. Methods: Literature search was performed using the electronic databases PubMed, EMBASE, and Scopus. Publications were screened according to predefined inclusion criteria. A qualitative and quantitative analysis was undertaken for this systematic review. Eighteen materials published from 1993 to 2017 were included in the qualitative and quantitative analysis. Random-effect model was used to calculate weighted prevalence, odds ratio (OR), and corresponding 95% confidence interval (CI). Results: 12,290 citations were identified and 18 articles including 11,175 participants were included. The results of our meta-analysis show that the prevalence of HIV, HBV, and HCV in people with SMD was 7.59% (95% CI 4.82-11.75), 15.63% (95% CI 7.19-30.69), and 7.21% (95% CI 4.44-11.50), respectively. The prevalence of HIV was higher in women (8.25%) than men (7.04%), but the prevalence of HBV and HCV was higher in men than women (18.91% versus 12.02% and 9.16% versus 5.43% for HBV and HCV in men versus women, respectively). A meta-analysis of included studies demonstrated a significantly increased risk of HBV (OR 1.72; 95% CI 1.17-2.53) and HCV (OR 2.01; 95% CI 1.16-3.20) infections in men compared to women in people with SMD. However, no significant association was observed between gender and HIV. The funnel plot and Egger's regression tests provided no evidence of substantial publication bias in the prevalence and gender difference in association for HIV, HBV, and HCV in people with SMD. Conclusions: In our review, the prevalence of HIV, HBV, and HCV was high. The prevalence of HBV is significantly higher than HIV and HCV. There was a significantly increased risk of HBV and HCV infections in men compared to women. No significant association was observed between gender and HIV. People with SMDs warrant greater emphasis in efforts to identify and treat HIV, HBV and HCV. PMID- 29755580 TI - Finding local genome rearrangements. AB - Background: The double cut and join (DCJ) model of genome rearrangement is well studied due to its mathematical simplicity and power to account for the many events that transform gene order. These studies have mostly been devoted to the understanding of minimum length scenarios transforming one genome into another. In this paper we search instead for rearrangement scenarios that minimize the number of rearrangements whose breakpoints are unlikely due to some biological criteria. One such criterion has recently become accessible due to the advent of the Hi-C experiment, facilitating the study of 3D spacial distance between breakpoint regions. Results: We establish a link between the minimum number of unlikely rearrangements required by a scenario and the problem of finding a maximum edge-disjoint cycle packing on a certain transformed version of the adjacency graph. This link leads to a 3/2-approximation as well as an exact integer linear programming formulation for our problem, which we prove to be NP complete. We also present experimental results on fruit flies, showing that Hi-C data is informative when used as a criterion for rearrangements. Conclusions: A new variant of the weighted DCJ distance problem is addressed that ignores scenario length in its objective function. A solution to this problem provides a lower bound on the number of unlikely moves necessary when transforming one gene order into another. This lower bound aids in the study of rearrangement scenarios with respect to chromatin structure, and could eventually be used in the design of a fixed parameter algorithm with a more general objective function. PMID- 29755579 TI - Exploring PTSD in emergency operators of a major University Hospital in Italy: a preliminary report on the role of gender, age, and education. AB - Background: Emergency services personnel face frequent exposure to potentially traumatic events, with the potential for chronic symptomatic distress. The DSM-5 recently recognized a particular risk for post-traumatic stress disorder (PTSD) among first responders (criterion A4) but data are still scarce on prevalence rates and correlates. Objective: The aim of the present study was to explore the possible role of age, gender, and education training in a sample of emergency personnel diagnosed with DSM-5 PTSD. Methods: The Trauma and Loss Spectrum-Self Report (TALS-SR) and the Work and Social Adjustment Scale (WSAS) were administered to 42 between nurses and health care assistants, employed at the emergency room of a major University Hospital (Pisa) in Italy. Results: 21.4% of the sample reported DSM-5 PTSD with significantly higher scores in the TALS-SR domain exploring the acute reaction to trauma and losses among health care assistants, older, and non-graduated subjects. A significant correlation between the number of the TALS-SR symptoms endorsed, corresponding to DSM-5 PTSD diagnostic criteria emerged in health care assistants. Conclusions: Despite further studies are needed in larger samples, our data suggest a high risk for PTSD and post-traumatic stress spectrum symptoms in nurses and health care workers operating in an emergency department, particularly among health care assistants, women, older, and non-graduated operators. PMID- 29755581 TI - Gender differences and risk factors for smoking among patients with various psychiatric disorders in Saudi Arabia: a cross-sectional study. AB - Background: The higher prevalence of smoking among psychiatric patients is well established. However, gender-specific associations have rarely been the focus of studies among patients with various psychiatric disorders. The aim of this study was to estimate the gender-specific prevalence of current smoking by psychiatric patients and its association with various psychiatric disorders and the use of psychotropic medications. Methods: A cross-sectional observational study was performed between July 2012 and June 2014. Patients were recruited from six hospitals located in the five regions of Saudi Arabia. Results: Of the 1193 patients, 402 (33.7%) were current smokers. The incidence of current smoking was much higher among males than females (58.3% versus 6.7%, p < 0.001). In one or both genders, current smoking was associated with marital status, education, family income, residence, obesity, physical activity, substance abuse, inpatient status, previous psychiatric hospitalization, and age at onset of psychiatric illness. In both gender, smoking was higher in patients who had a secondary psychiatric disorder (66.7% versus 37.5%, respectively), those who had a primary psychotic disorder (63.7% versus 12.3%), and those taking antipsychotic medication (64.1% versus 8.3%) but lower in patients who had a primary depressive disorder (40.3% versus 4.3%), those who had a primary anxiety disorder (45.8% versus 0.0%), and those taking antidepressant medications (53.7% versus 3.6%). In a multivariate analysis adjusted for demographic/clinical characteristics and psychiatric disorders, current smoking was independently associated with primary psychotic disorders in females (OR = 3.47, 1.45-8.27, p = 0.005) but not in males. In a multivariate analysis adjusted for demographic/clinical characteristics and psychotropic medications, current smoking was independently associated with antipsychotic medication use in males (OR = 1.79, 1.10-2.93, p = 0.020). Current smoking was strongly associated with substance abuse in both univariate and multivariate analyses. Conclusion: The prevalence of current smoking is high with marked gender difference in a large sample of mixed psychiatric patients in Saudi Arabia. Smoking-cessation programs may be urgently needed for these vulnerable patients. PMID- 29755582 TI - RSM based optimization of nutritional conditions for cellulase mediated Saccharification by Bacillus cereus. AB - Background: Cellulases are enzyme which have potential applications in various industries. Researchers are looking for potential cellulolytic bacterial strains for industrial exploitation. In this investigation, cellulase production of Bacillus cereus was explored while attacking poplar twigs. The bacterium was isolated from the gut of freshwater fish, Labeo rohita and identified by 16S rRNA gene sequencing technology. Various nutritional conditions were screened and optimized through response surface methodology. Initially, Plackett-Burman design was used for screening purpose and optimization was conducted through Box-Bhenken design. Results: The maximum cellulase production occurred at 0.5% yeast extract, 0.09% MgSO4, 0.04% peptone, 2% poplar waste biomass, initial medium pH of 9.0, and inoculum size of 2% v/v at 37 degrees C with agitation speed of 120 rpm for 24 h of submerged fermentation. The proposed model for optimization of cellulase production was found highly significant. The indigenously produced cellulase enzyme was employed for saccharification purpose at 50 degrees C for various time periods. Maximum total sugars of 31.42 mg/ml were released after 6 h of incubation at 50 degrees C.The efficiency of this enzyme was compared with commercial cellulase enzyme revealing significant findings. Conclusion: These results suggested potential utilization of this strain in biofuel industry. PMID- 29755583 TI - Relationship between Asymmetry of Gait and Muscle Torque in Patients after Unilateral Transfemoral Amputation. AB - Many studies have shown that unilateral transfemoral amputation involves asymmetric gait. Transfemoral amputation leads to muscle atrophy in a tight stump resulting in asymmetry in muscle torque between the amputated and intact limb. This research is aimed at verifying if a relationship between torque values of hip joint flexors and extensors and gait asymmetry in patients with TFA exists. Fourteen adult subjects with unilateral TFA took part in the experiment. Gait symmetry was evaluated based on the ground reaction force (GRF). Measurements of muscle torque of hip flexors and extensors were taken with a Biodex System. All measurements were taken under isokinetic (60 degrees /s and 120 degrees /s) and isometric conditions. The symmetry index of vertical GRF components was from 7.5 to 11.5%, and anterio-posterior GRF from 6.2 to 9.3%. The symmetry index for muscle torque was from 24.3 to 44% for flexors, from 39 to 50.5% for extensors, and from 28.6 to 50% in the flexor/extensor ratio. Gait asymmetry correlated with muscle torque in hip joint extensors. Therapy which enhances muscle torque may be an effective form of patient therapy. The patient needs to undergo evaluation of their muscle strength and have the therapy programme adjusted to their level of muscle torque deficit. PMID- 29755584 TI - Development and Validation of an Age-Specific Lower Extremity Finite Element Model for Simulating Pedestrian Accidents. AB - The objective of the present study is to develop an age-specific lower extremity finite element model for pedestrian accident simulation. Finite element (FE) models have been used as a versatile tool to simulate and understand the pedestrian injury mechanisms and assess injury risk during crashes. However, current computational models only represent certain ages in the population, the age spectrum of the pedestrian victims is very large, and the geometry of anatomical structures and material property of the lower extremities changes with age for adults, which could affect the injury tolerance, especially in at-risk populations such as the elderly. The effects of age on the material mechanical property of bone and soft tissues of the lower extremities as well as the geometry of the long bone were studied. Then an existing 50th percentile male pedestrian lower extremity model was rebuilt to depict lower extremity morphology for 30- to 70-year-old (YO) individuals. A series of PMHS tests were simulated to validate the biofidelity and stability of the created age-specific models and evaluate the lower extremity response. The development of age-specific lower extremity models will lead to an improved understanding of the pedestrian lower extremity injury mechanisms and injury risk prediction for the whole population in vehicle-pedestrian collision accidents. PMID- 29755585 TI - A Study of the Effect of the Front-End Styling of Sport Utility Vehicles on Pedestrian Head Injuries. AB - Background: The number of sport utility vehicles (SUVs) on China market is continuously increasing. It is necessary to investigate the relationships between the front-end styling features of SUVs and head injuries at the styling design stage for improving the pedestrian protection performance and product development efficiency. Methods: Styling feature parameters were extracted from the SUV side contour line. And simplified finite element models were established based on the 78 SUV side contour lines. Pedestrian headform impact simulations were performed and validated. The head injury criterion of 15 ms (HIC15) at four wrap-around distances was obtained. A multiple linear regression analysis method was employed to describe the relationships between the styling feature parameters and the HIC15 at each impact point. Results: The relationship between the selected styling features and the HIC15 showed reasonable correlations, and the regression models and the selected independent variables showed statistical significance. Conclusions: The regression equations obtained by multiple linear regression can be used to assess the performance of SUV styling in protecting pedestrians' heads and provide styling designers with technical guidance regarding their artistic creations. PMID- 29755587 TI - A novel close-circulating vapor stripping-vapor permeation technique for boosting biobutanol production and recovery. AB - Background: Butanol derived from renewable resources by microbial fermentation is considered as one of not only valuable platform chemicals but alternative advanced biofuels. However, due to low butanol concentration in fermentation broth, butanol production is restricted by high energy consumption for product recovery. For in situ butanol recovery techniques, such as gas stripping and pervaporation, the common problem is their low efficiency in harvesting and concentrating butanol. Therefore, there is a necessity to develop an advanced butanol recovery technique for cost-effective biobutanol production. Results: A close-circulating vapor stripping-vapor permeation (VSVP) process was developed with temperature-difference control for single-stage butanol recovery. In the best scenario, the highest butanol separation factor of 142.7 reported to date could be achieved with commonly used polydimethylsiloxane membrane, when temperatures of feed solution and membrane surroundings were 70 and 0 degrees C, respectively. Additionally, more ABE (31.2 vs. 17.7 g/L) were produced in the integrated VSVP process, with a higher butanol yield (0.21 vs. 0.17 g/g) due to the mitigation of butanol inhibition. The integrated VSVP process generated a highly concentrated permeate containing 212.7 g/L butanol (339.3 g/L ABE), with the reduced energy consumption of 19.6 kJ/g-butanol. Conclusions: Therefore, the present study demonstrated a well-designed energy-efficient technique named by vapor stripping-vapor permeation for single-stage butanol removal. The butanol separation factor was multiplied by the temperature-difference control strategy which could double butanol recovery performance. This advanced VSVP process can completely eliminate membrane fouling risk for fermentative butanol separation, which is superior to other techniques. PMID- 29755586 TI - Ethanol production potential from AFEXTM and steam-exploded sugarcane residues for sugarcane biorefineries. AB - Background: Expanding biofuel markets are challenged by the need to meet future biofuel demands and mitigate greenhouse gas emissions, while using domestically available feedstock sustainably. In the context of the sugar industry, exploiting under-utilized cane leaf matter (CLM) in addition to surplus sugarcane bagasse as supplementary feedstock for second-generation ethanol production has the potential to improve bioenergy yields per unit land. In this study, the ethanol yields and processing bottlenecks of ammonia fibre expansion (AFEXTM) and steam explosion (StEx) as adopted technologies for pretreating sugarcane bagasse and CLM were experimentally measured and compared for the first time. Results: Ethanol yields between 249 and 256 kg Mg-1 raw dry biomass (RDM) were obtained with AFEXTM-pretreated sugarcane bagasse and CLM after high solids loading enzymatic hydrolysis and fermentation. In contrast, StEx-pretreated sugarcane bagasse and CLM resulted in substantially lower ethanol yields that ranged between 162 and 203 kg Mg-1 RDM. The ethanol yields from StEx-treated sugarcane residues were limited by the aggregated effect of sugar degradation during pretreatment, enzyme inhibition during enzymatic hydrolysis and microbial inhibition of S. cerevisiae 424A (LNH-ST) during fermentation. However, relatively high enzyme dosages (> 20 mg g-1 glucan) were required irrespective of pretreatment method to reach 75% carbohydrate conversion, even when optimal combinations of Cellic(r) CTec3, Cellic(r) HTec3 and Pectinex Ultra-SP were used. Ethanol yields per hectare sugarcane cultivation area were estimated at 4496 and 3416 L ha-1 for biorefineries using AFEXTM- or StEx-treated sugarcane residues, respectively. Conclusions: AFEXTM proved to be a more effective pretreatment method for sugarcane residues relative to StEx due to the higher fermentable sugar recovery and enzymatic hydrolysate fermentability after high solids loading enzymatic hydrolysis and fermentation by S. cerevisiae 424A (LNH-ST). The identification of auxiliary enzyme activities, adequate process integration and the use of robust xylose-fermenting ethanologens were identified as opportunities to further improve ethanol yields from AFEXTM- and StEx-treated sugarcane residues. PMID- 29755588 TI - Enhanced biological fixation of methane for microbial lipid production by recombinant Methylomicrobium buryatense. AB - Background: Due to the success of shale gas development in the US, the production cost of natural gas has been reduced significantly, which in turn has made methane (CH4), the major component of natural gas, a potential alternative substrate for bioconversion processes compared with other high-price raw material sources or edible feedstocks. Therefore, exploring effective ways to use CH4 for the production of biofuels is attractive. Biological fixation of CH4 by methanotrophic bacteria capable of using CH4 as their sole carbon and energy source has obtained great attention for biofuel production from this resource. Results: In this study, a fast-growing and lipid-rich methanotroph, Methylomicrobium buryatense 5GB1 and its glycogen-knock-out mutant (AP18) were investigated for the production of lipids derived from intracellular membranes, which are key precursors for the production of green diesel. The effects of culture conditions on cell growth and lipid production were investigated in high cell density cultivation with continuous feeding of CH4 and O2. The highest dry cell weight observed was 21.4 g/L and the maximum lipid productivity observed was 45.4 mg/L/h obtained in batch cultures, which corresponds to a 2-fold enhancement in cell density and 3-fold improvement in lipid production, compared with previous reported data from cultures of 5GB1. A 90% enhancement of lipid content was achieved by limiting the biosynthesis of glycogen in strain AP18. Increased CH4/O2 uptake and CO2 evaluation rates were observed in AP18 cultures suggesting that more carbon substrate and energy are needed for AP18 growth while producing lipids. The lipid produced by M. buryatense was estimated to have a cetane number of 75, which is 50% higher than biofuel standards requested by US and EU. Conclusions: Cell growth and lipid production were significantly influenced by culture conditions for both 5GB1 and AP18. Enhanced lipid production in terms of titer, productivity, and content was achieved under high cell density culture conditions by blocking glycogen accumulation as a carbon sink in the strain AP18. Differences observed in CH4/O2 gas uptake and CO2 evolution rates as well as cell growth and glycogen accumulation between 5GB1 and AP18 suggest changes in the metabolic network between these strains. This bioconversion process provides a promising opportunity to transform CH4 into biofuel molecules and encourages further investigation to elucidate the remarkable CH4 biofixation mechanism used by these bacteria. PMID- 29755589 TI - Engineering and systems-level analysis of Pseudomonas chlororaphis for production of phenazine-1-carboxamide using glycerol as the cost-effective carbon source. AB - Background: Glycerol, an inevitable byproduct of biodiesel, has become an attractive feedstock for the production of value-added chemicals due to its availability and low price. Pseudomonas chlororaphis HT66 can use glycerol to synthesize phenazine-1-carboxamide (PCN), a phenazine derivative, which is strongly antagonistic to fungal phytopathogens. A systematic understanding of underlying mechanisms for the PCN overproduction will be important for the further improvement and industrialization. Results: We constructed a PCN overproducing strain (HT66LSP) through knocking out three negative regulatory genes, lon, parS, and prsA in HT66. The strain HT66LSP produced 4.10 g/L of PCN with a yield of 0.23 (g/g) from glycerol, which was of the highest titer and the yield obtained among PCN-producing strains. We studied gene expression, metabolomics, and dynamic 13C tracer in HT66 and HT66LSP. In response to the phenotype changes, the transcript levels of phz biosynthetic genes, which are responsible for PCN biosynthesis, were all upregulated in HT66LSP. Central carbon was rerouted to the shikimate pathway, which was shown by the modulation of specific genes involved in the lower glycolysis, the TCA cycle, and the shikimate pathway, as well as changes in abundances of intracellular metabolites and flux distribution to increase the precursor availability for PCN biosynthesis. Moreover, dynamic 13C-labeling experiments revealed that the presence of metabolite channeling of 3-phosphoglyceric acid to phosphoenolpyruvate and shikimate to trans-2,3-dihydro-3-hydroxyanthranilic acid in HT66LSP could enable high-yielding synthesis of PCN. Conclusions: The integrated analysis of gene expression, metabolomics, and dynamic 13C tracer enabled us to gain a more in depth insight into complex mechanisms for the PCN overproduction. This study provides important basis for further engineering P. chlororaphis for high PCN production and efficient glycerol conversion. PMID- 29755590 TI - Wide-pulse, high-frequency, low-intensity neuromuscular electrical stimulation has potential for targeted strengthening of an intrinsic foot muscle: a feasibility study. AB - Background: Strengthening the intrinsic foot muscles is a poorly understood and largely overlooked area. In this study, we explore the feasibility of strengthening m. abductor hallucis (AH) with a specific paradigm of neuromuscular electrical stimulation; one which is low-intensity in nature and designed to interleave physiologically-relevant low frequency stimulation with high frequencies to enhance effective current delivery to spinal motoneurones, and enable a proportion of force produced by the target muscle to be generated from a central origin. We use standard neurophysiological measurements to evaluate the acute (~ 30 min) peripheral and central adaptations in healthy individuals. Methods: The AH in the dominant foot of nine healthy participants was stimulated with 24 * 15 s trains of square wave (1 ms), constant current (150% of motor threshold), alternating (20 Hz-100 Hz) neuromuscular electrical stimulation interspersed with 45 s rest. Prior to the intervention, peripheral variables were evoked from the AH compound muscle action potential (Mwave) and corresponding twitch force in response to supramaximal (130%) medial plantar nerve stimulation. Central variables were evoked from the motor evoked potential (MEP) in response to suprathreshold (150%) transcranial magnetic stimulation of the motor cortex corresponding to the AH pathway. Follow-up testing occurred immediately, and 30 min after the intervention. In addition, the force-time-integrals (FTI) from the 1st and 24th WPHF trains were analysed as an index of muscle fatigue. All variables except FTI (T-test) were entered for statistical analysis using a single factor repeated measures ANOVA with alpha set at 0.05. Results: FTI was significantly lower at the end of the electrical intervention compared to that evoked by the first train (p < 0.01). Only significant peripheral nervous system adaptations were observed, consistent with the onset of low-frequency fatigue in the muscle. In most of these variables, the effects persisted for 30 min after the intervention. Conclusions: An acute session of wide-pulse, high-frequency, low-intensity electrical stimulation delivered directly to abductor hallucis in healthy feet induces muscle fatigue via adaptations at the peripheral level of the neuromuscular system. Our findings would appear to represent the first step in muscle adaptation to training; therefore, there is potential for using WPHF for intrinsic foot muscle strengthening. PMID- 29755592 TI - Six new subterranean freshwater gastropod species from northern Albania and some new records from Albania and Kosovo (Mollusca, Gastropoda, Moitessieriidae and Hydrobiidae). AB - During a field trip to the western part of the Balkan Peninsula in 2016, investigations of several caves and karstic springs revealed six new gastropod species living in subterranean waters and resulted in some note-worthy faunistic records. Five of the new species are assigned to the genus Paladilhiopsis Pavlovic, 1913, namely P. prekalensissp. n., P. lozekisp. n., P. szekeresisp. n., P. wohlberedtisp. n., P. falniowskiisp. n. and one to the genus Plagigeyeria Tomlin, 1930, namely P. steffekisp. n. New Albania and Kosovo distribution records are given for Iglica illyrica Schutt, 1975, Plagigeyeria zetaprotogona Schutt, 1960, Vinodolia matjasici (Bole, 1961), and the first georeferenced record is given for Saxurinator schlickumi Schutt, 1960. The most important environmental factors influencing habitat selection of these subterranean freshwater gastropods are briefly discussed. PMID- 29755591 TI - Improved insulin sensitivity and lower postprandial triglyceride concentrations after cold-pressed turnip rapeseed oil compared to cream in patients with metabolic syndrome. AB - Background: The aim of this study was to compare acute effects of turnip rapeseed oil rich with mono- and polyunsaturated fatty acids and cream on postprandial triglyceride levels and post-glucose load measures of insulin sensitivity in population of men with metabolic syndrome. Methods: This open-label balanced crossover study included 37 men with metabolic syndrome. They underwent an oral glucose-fat tolerance test where they ingested 75 g of glucose with either 240 mL of cream or 84 mL of turnip rapeseed oil depending on the study arm. Hourly postprandial blood samples were drawn up to 5 h after this oral glucose-fat tolerance test to determine the changes in triglyceride concentrations and to measure insulin sensitivity. Changes in insulin sensitivity were calculated with different insulin sensitivity indices (OGIS, Stumvoll, Gutt and McAuley scores) derived from measured insulin and glucose concentrations. The oral glucose-fat tolerance test was preceded by a period during which the participants consumed a daily portion of either 35 mL of turnip rapeseed oil or 37.5 g of butter depending on the study arm in addition to their habitual diets. Both dietary periods lasted from 6 to 8 weeks. After an 8-week wash-out period the subjects crossed over to the other study arm and underwent the same process with the other fat adjunct. Results: The area under the curve for hourly triglyceride concentrations was 16% smaller after turnip rapeseed oil than after cream (13.86 [interquartile range 8.54] vs. 16.41 [9.09] mmol/l, p < 0.001). The insulin sensitivity markers of OGIS (324 [38.97] vs. 377 [68.38] p < 0.001), Stumvoll score (0.079 [0.029] vs. 0.085 [0.029], p = 0.038) and Gutt score (67.0 +/- 2.78 vs. 78.8 +/- 4.97 p = 0.001) were higher after turnip rapeseed oil period than after butter period. There was a non-significant change in the McAuley score. Conclusion: Dietary turnip rapeseed oil improved postprandially measured insulin sensitivity and triglyceride concentrations compared to cream and butter. This provides a possible efficient dietary mean to treat cardiovascular risk factors.Trial registration ClinicalTrials.gov NCT01119690 (05-06-2010). PMID- 29755593 TI - Effect of stem cell transplantation of premature ovarian failure in animal models and patients: A meta-analysis and case report. AB - Stem cell transplantation has been considered a promising therapeutic approach for premature ovarian failure (POF). However, to date, no quantitative data analysis of stem cell therapy for POF has been performed. Therefore, the present study performed a meta-analysis to assess the efficacy of stem cell transplantation in improving ovarian function in animal models of POF. In addition, a case report of a patient with POF subjected to stem cell treatment was included to demonstrate that stem cell therapy also contributes to the recovery of ovarian function in patients. Published studies were identified by a systematic review of the PubMed, Embase, and Cochrane's library databases, and references cited in associated reviews were also considered. Data regarding follicle-stimulating hormone (FSH), estradiol (E2), ovarian weight, follicle count, the number of pregnancies and other parameters, including delivery route and cell type, were extracted. Pooled analysis, sensitivity analyses, subgroup analyses and meta-regression were performed. In the case of POF, transvaginal ultrasound (TVS), abdominal ultrasound (TAS) and color Doppler flow imaging (CDFI) were performed to observe the endometrial morphology and blood flow signals in the patient. Overall, pooled results from 16 pre-clinical studies demonstrated that stem cell-based therapy significantly improved FSH levels [standardized mean difference (SMD)=-1.330; 95% confidence interval (CI), -(2.095 0.565); P=0.001], E2 levels (SMD=2.334; 95% CI, 1.350-3.319; P<0.001), ovarian weight (SMD=1.310; 95% CI, 0.157-2.463; P=0.026), follicle count (SMD=1.871; 95% CI, 1.226-2.516; P<0.001), and the number of pregnancies (risk ratio=1.715, 95% CI, 1.213-2.424; P=0.002). The results of TVS and TAS demonstrated improved ovarian size and endometrial thickness in the patient with POF after MSC treatment. Of note, a rich blood flow signal in the endometrium was observed on CDFI. It appeared that stem cell-based therapy may be an effective method for the resumption of ovarian function in a patient and in animal models of POF; however, large-scale and high-quality future studies are required to confirm the present findings due to heterogeneity. PMID- 29755594 TI - Perineural invasion in early-stage cervical cancer and its relevance following surgery. AB - Perineural invasion (PNI) is the neoplastic invasion of nerves by cancer cells, a process that has attracted attention as a novel prognostic factor for cancer. The present study aimed to investigate the prognostic value of PNI in patients with early-stage cervical cancer (International Federation of Gynecology and Obstetrics stage IA2-IIA). A total of 210 patients who underwent radical hysterectomy and pelvic lymphadenectomy between 2007 and 2012 were included in the current study, of whom 8.57% (18/210) exhibited PNI. Patients with PNI were more likely to exhibit adverse histopathological features, such as increased tumor size, depth of stromal invasion, parametrial invasion, lymphovascular space invasion and lymph nodes metastases (all P<0.05). Patients with PNI exhibited shorter disease-free and overall survival (P=0.002 and P=0.017, respectively). However, PNI was not identified as an independent risk factor for either recurrence or death by multivariate analysis. Furthermore, 88.9% (16/18) of patients with PNI received adjuvant therapy following surgery. PNI was significantly associated with well-established indicators for adjuvant therapy. In conclusion, PNI was associated with multiple high-risk factors and its presence was indicative of a poor outcome in patients with early-stage cervical cancer, which may influence management decisions regarding adjuvant therapy. PMID- 29755595 TI - Long non-coding RNA LSINCT5 promotes ovarian cancer cell proliferation, migration and invasion by disrupting the CXCL12/CXCR4 signalling axis. AB - Long stress-induced noncoding transcript 5 (LSINCT5) is a member of the LSINCT family, members of which are expressed during stress-induced cell formation and have also been reported to promote cancer progression. In the present study, the association between LSINCT5 expression and clinical significance was investigated and the biological function of LSINCT5 in epithelial ovarian cancer (EOC) was explored. LSINCT5 expression was examined in EOC tissues by reverse transcription quantitative polymerase chain reaction and its association with clinicopathological factors was analysed. Cell proliferation, migration and invasion tests were performed to observe the role of LSINCT5 in human ovarian cancer cell lines in vitro. The negative control (NC) and siLSINCT5 SKOV3 cells were treated with chemokine ligand 12 (CXCL12) and their proliferation, migration and invasion activities were examined. LSINCT5 was overexpressed in EOC compared with normal ovarian tissue. LSINCT5 expression was significantly associated with the International Federation of Gynecologists and Obstetricians cancer stage and the presence of lymphatic metastases. Silencing LSINCT5 significantly reduced the expression of chemokine receptor 4 (CXCR4) and inhibited SKOV3 cell proliferation, migration and invasion, however the CXCL12 expression level had no significant change. When NC and siLSINCT5-SKOV3 cells were treated with CXCL12, the proliferation and invasion ability were significantly enhanced. The migration ability of the siLSINCT5-SKOV3 cells was also significantly enhanced. The present study indicated that LSINCT5 serves an important role in ovarian cancer metastasis by regulating the CXCL12/CXCR4 signalling axis, suggesting that this pathway may be a potential target for the treatment of patients with EOC. PMID- 29755597 TI - 5-Fluorouracil may enrich cancer stem cells in canine mammary tumor cells in vitro. AB - Mammary gland carcinomas are the most common neoplasms in women and unsterilized female dogs. Owing to the existence of cancer stem cells (CSCs), chemotherapy is not able to cure these types of diseases completely. A number of studies have demonstrated that CSCs are resistant to chemotherapeutic drugs, but whether canine mammary tumor cells that have acquired resistance to 5-fluorouracil (5-FU) exhibited properties of CSCs remains unknown. The aim of the present study was to investigate whether 5-fluorouracil-resistant canine mammary tumor cells exhibited properties of CSCs. CSCs were analyzed using western blot assays, ultra-low attachment sphere cultures, flow cytometry and migration (wound healing and Transwell) assays. The results indicated that, compared with parental cells, proteins associated with the Wnt/beta-catenin signaling pathway and aldehyde dehydrogenase 1 were overexpressed, the number and size of spheres in the 5-FU resistant cells were increased, the ratio of CD44+/CD24-/low cells was increased and the migratory ability was improved in vitro compared with the 5-FU susceptible cells. In conclusion, stimulation with chemotherapeutic drugs including 5-FU is a good method for increasing the proportion of canine mammary tumor stem cells in vitro, which may provide further understanding of chemotherapeutic methods and CSCs. PMID- 29755596 TI - Phytochemicals: Current strategies for treating breast cancer. AB - Females with early-stage metastatic, estrogen-dependent breast cancer are generally treated with surgery, radiation and chemotherapy, or with more targeted approaches such as aromatase inhibitors (anastrozole or letrozole) or anti estrogens (tamoxifen). Despite widespread successful usage of these agents for the treatment of breast cancer, resistance, tumor relapse and metastasis remain the principal causes of mortality for patients with breast cancer. While numerous groups have made major contributions toward an improved understanding of resistance mechanisms, the currently insufficient grasp of the most critical pathways involved in resistance is evident in the inability to adequately treat and drastically improve patient outcomes in females with hormone-refractory breast cancer, including triple negative breast cancer. Therefore, further investigation of novel therapeutic approaches is paramount to reveal previously unconsidered agents that could be utilized to treat metastatic disease. Numerous naturally occurring phytochemicals have recently gained interest as potential therapeutic breast cancer agents appear to directly affect estrogen-dependent and estrogen-independent breast cancer cell proliferation, potentially via affecting breast cancer stem cell populations. While numerous natural compounds have exhibited promise, they are limited by their bioavailability. Therefore, to effectively treat future hormone-refractory breast tumors, it is critical to adequately refine and formulate these agents for effective therapeutic use and delivery. Herein, the literature on the current state of phytochemicals is reviewed, including their limitations and potential as targeted therapies for breast cancer. PMID- 29755598 TI - Efficacy of an SMS-Based Smoking Intervention Using Message Self-Authorship: A Pilot Study. AB - Introduction: Text-message-based interventions hold great potential for intervention and are increasingly feasible, given advances in information technology. Aims: This pilot randomized controlled trial (RCT) aims to compare the efficacy of self-versus expert-authored content delivered via text-messaging for smoking cessation. Methods: Sixty-two participants aged 25-66 attended laboratory sessions pre- and post-30 days of text-messaging intervention. Participants were randomised to one of two experimental conditions - self authorship (SA) only and SA with implementation intentions (SA+ii) - or active control. Participants composed 30-60 brief motivational cessation messages for use during their cessation attempt. SA+ii participants were further instructed to anticipate obstacles and form simple if-then plans to overcome them. Experimental groups received their self-authored texts during the intervention phase, whereas control participants received expert-authored messages. Results: Overall, smoking decreased as measured by change in exhaled carbon monoxide (CO), F(1,59) = 4.43, p = 0.04. The SA+ii group showed slightly greater CO reduction (M = 3.63, SD = 5.39) than control (M = 0.03, SD = 5.80; t(40) = 2.08, p = 0.04). SA alone (M = 1.97, SD = 9.30) was not more effective than control. Conclusions: SA does not appear to increase efficacy. However, this pilot supports prior research, indicating that text-based interventions can increase smoking cessation success and may decrease psychological symptoms of withdrawal. Much research is needed to identify ways to bolster intervention efficacy. PMID- 29755599 TI - Nuclear Lamin Protein C Is Linked to Lineage-Specific, Whole-Cell Mechanical Properties. AB - INTRODUCTION: Lamin proteins confer nuclear integrity and relay external mechanical cues that drive changes in gene expression. However, the influence these lamins have on whole-cell mechanical properties is unknown. We hypothesized that protein expression of lamins A, B1, and C would depend on the integrity of the actin cytoskeleton and correlate with cellular elasticity and viscoelasticity. METHODS: To test these hypotheses, we examined the protein expression of lamins A, B1, and C across five different cell lines with varied mechanical properties. Additionally, we treated representative "soft/stiff" cell types with cytochalasin D and LMNA siRNA to determine the effect of a more compliant whole-cell phenotype on lamin A, B1 and C protein expression. RESULTS: A positive, linear correlation existed between lamin C protein expression and average cell moduli/apparent viscosity. Though moderate correlations existed between lamin A/B1 protein expression and whole-cell mechanical properties, they were statistically insignificant. Inhibition of actin polymerization, via cytochalasin D treatment, resulted in reduced cell elasticity, viscoelasticity, and lamin A and C protein expression in "stiff" MG-63 cells. In "soft" HEK-293T cells, this treatment reduced cell elasticity and viscoelasticity but did not affect lamin B1 or C protein expression. Additionally, LMNA siRNA treatment of MG 63 cells decreased whole-cell elasticity and viscoelasticity. CONCLUSION: These findings suggest that lamin C protein expression is strongly associated with whole-cell mechanical properties and could potentially serve as a biomarker for mechanophenotype. PMID- 29755600 TI - Cardiovascular Disease Risk Factors: Hypertension, Diabetes Mellitus and Obesity among Tabuk Citizens in Saudi Arabia. AB - Background: Cardiovascular Disease (CVD) is considered as the main cause of death worldwide. Identifying the links among CVDs risk factors can help decrease CVD related deaths. Aim: To assess the prevalence of risk factors for CVD and their relationships among the Tabuk City population in Saudi Arabia. Methods: A cross sectional design was used; 432 participants in the Tabuk region were included in this study. Results: The prevalence of diabetes mellitus (DM) was 5.6%, the prevalence of hypertension (HTN) was 11.1% and obesity and overweight together were 69.9%. Mean Body Mass Index (BMI), HTN, and DM increased with age. There was a correlation between BMI with HTN (r=.200, p<.001), BMI and DM (r=.149, p<.001) and DM and HTN (r=.366, p<.001). Conclusion: Public awareness may help in reducing the prevalence of CVD. PMID- 29755601 TI - A Practical Approach to the Percutaneous Treatment of Iatrogenic Aorto-coronary Dissection. AB - Catheter-induced aortic dissection during coronary angiography and Percutaneous Coronary Intervention (PCI) is a relatively infrequent, but potentially life threatening complication. Patients who suffer this complication may require emergency aortic surgery. More recently, reports of treating the ostium of the dissected coronary artery have emerged as an alternative therapeutic option. In this article we describe two cases of extensive guide catheter induced dissection and their successful treatment using PCI and provide a concise overview of the available literature. PMID- 29755602 TI - Evaluation and Comparison of Total Antioxidant Capacity of Saliva Between Patients with Recurrent Aphthous Stomatitis and Healthy Subjects. AB - Background & Objectives: Recurrent Aphthous Stomatitis (RAS) is one of the most common chronic ulcerative lesions of the oral mucosa and its development may be associated with oxidative stress. The aim of this study was to evaluate salivary Total Antioxidant Capacity (TAC) in patients with minor RAS. Materials & Methods: In this case-control study, 27 patients with minor RAS and 28 age- and sex matched controls without RAS were enrolled. TAC was measured in unstimulated saliva for patients (during active lesion phase and after healing) and controls by immunologic assay. Data were analyzed by SPSS 18 using paired and unpaired t tests (P<0.05). Results: Salivary TAC levels of patients presented a significant increase from active lesion phase (0.26+/-0.16) to healing time (0.43+/-0.41); (P=0.034). There was no significant difference in the level of salivary TAC between patients during active lesion phase and controls (0.24+/-0.13); (P=0.641). Conclusion: Increasing level of salivary TAC may be involved in remission of RAS lesions, suggesting its evaluation in future studies. PMID- 29755603 TI - Bacterial CRISPR Regions: General Features and their Potential for Epidemiological Molecular Typing Studies. AB - Introduction: CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) loci as novel and applicable regions in prokaryotic genomes have gained great attraction in the post genomics era. Methods: These unique regions are diverse in number and sequence composition in different pathogenic bacteria and thereby can be a suitable candidate for molecular epidemiology and genotyping studies. Results:Furthermore, the arrayed structure of CRISPR loci (several unique repeats spaced with the variable sequence) and associated cas genes act as an active prokaryotic immune system against viral replication and conjugative elements. This property can be used as a tool for RNA editing in bioengineering studies. Conclusion: The aim of this review was to survey some details about the history, nature, and potential applications of CRISPR arrays in both genetic engineering and bacterial genotyping studies. PMID- 29755604 TI - Probiotics Strains Modulate Gut Microbiota and Lipid Metabolism in Mule Ducks. AB - Background: Livestock production should respond to societal, environmental and economic changes. Since 2006 and the ban on antibiotics as growth factors in European Union, the use of probiotics has become widespread and has demonstrated the effect of intestinal microbiota on the performance of farm animals. Objective: The aim of this study was to investigate the effect of supplementation with Lactobacillus salivarius (as a probiotics strain or combined with other strains) on zootechnical performance, metabolic and immune gene expression and intestinal microbiota diversity in mule ducks using high-throughput sequencing and real-time PCR. Method: The mule ducks were reared for 79 days and overfed for 12 days with or without probiotics. Samples were collected at 14 (starting period) and 91 days (end of overfeeding period), 3 hours post feeding. Results: Irrespective of digestive content, age, level of feed intake or supplementation with probiotics, Firmicutes, Proteobacteria and Bacteroidetes were the dominant phyla in the bacterial community in mule ducks. At 14 days, both the ileal and cecal samples were dominated by Firmicutes (in particular the Clostridiales order). Overfeeding induced a shift between Clostridiales and Lactobacillales in the ileal samples whereas in the cecal samples, the relative abundance of Firmicutes decreased. Overfeeding also induced hepatic over-expression of Fatty Acid Synthase (FAS) and of the lipid transporter gene Fatty Acid Binding Protein 4 (FABP4). This increase in lipid metabolism genes is associated with a decrease in inflammatory response. Conclusion: Finally, probiotic supplementation had only a slight impact on gene expression and microbiota diversity, both at 14 days and after overfeeding. PMID- 29755606 TI - Chronic Osteomyelitis - Bacterial Flora, Antibiotic Sensitivity and Treatment Challenges. AB - Background: Chronic osteomyelitis is a catastrophic sequel of delayed diagnosis of acute osteomyelitis. Objectives: The objectives of the study were to determine bacterial flora and antibiotic sensitivity, and to evaluate the outcome of an aggressive surgical approach to chronic osteomyelitis. Methods: This is a single surgeon, prospective cohort study on 30 consecutive patients with clinically and radiologically diagnosed chronic osteomyelitis presented to a hospital. We prospectively recorded demographic, clinical, radiological features, treatment protocol, microbiologic results of culture and sensitivity. The main treatment outcome measures were clinical signs of eradication of infection. Results: Microbiologic results showed that Gram-negative and mixed flora accounts for more than half of chronic osteomyelitis cases while Staphylococcus aureus was a dominating single pathogen (39%). We detected a high resistance rate to common antibiotics, e.g. 83% of S. aureus isolates were resistant to oxacillin (MRSA). The mean duration of bone infection was 4.2 years (3 months to 30 years) and the mean number of operations was 1.5 (1-5) . The mean follow-up was 15 months (12-18 months). Infection was eradicated in 95% (21 out of 22) treated by a single procedure and in all patients (n=8) by double procedure. Conclusion: Presented the high rate of MRSA strains is alarming and calls for updating of the antibiotic therapy guidelines in the country. Good results in treatment of chronic osteomyelitis can be achieved by a single-stage protocol including radical debridement combined with systemic and topical antibiotic. PMID- 29755605 TI - The Prevalence of Osteopenia and Osteoporosis Among Malaysian Type 2 Diabetic Patients Using Quantitative Ultrasound Densitometer. AB - Background: Type 2 Diabetes Mellitus (T2DM) and osteoporosis are both chronic conditions and the relationship between them is complex. Objective: The aims of this study were to assess the prevalence of Low Bone Mineral density (LBMD, i.e., osteopenia and osteoporosis), as well as, the difference and associations between Quantitative Ultrasound Scan (QUS) parameters with socio-demographic data and clinical related data among T2DM in Penang, Malaysia. Method: An observational, cross-sectional study with a convenient sample of 450 T2DM patients were recruited from the outpatient diabetes clinic at Hospital Pulau Pinang (HPP) to measure Bone Mineral Density (BMD) at the heel bone using QUS. In addition, a self-reported structured questionnaire about the socio-demographic data and osteoporosis risk factors were collected. Moreover, the study included the retrospective collection of clinical data from patients' medical records. Results: The mean value of T-score for normal BMD, osteopenic and osteoporotic patients' were (-0.41+/-0.44), (-1.65+/-0.39) and (-2.76+/-0.27), respectively. According to QUS measurements, more than three quarters of T2DM patients (82%) were at high risk of abnormal BMD. The results showed that QUS scores were significantly associated with age, gender, menopausal duration, educational level and diabetic related data. Moreover, the QUS parameters and T-scores demonstrated significant negative correlation with age, menopausal duration, diabetic duration and glycaemic control, as well as, a positive correlation with body mass index and waist to hip ratio. The current study revealed that none of the cardiovascular disease risk factors appear to influence the prevalence of low BMD among T2DM Malaysian patients. Conclusion: The study findings revealed that the assessment of T2DM patients' bone health and related factor are essential and future educational programs are crucial to improve osteoporosis management. PMID- 29755607 TI - Risk Factors for the Development of Nerve Palsy Following Primary Total Hip Arthroplasty. AB - Background: Nerve palsy following total hip arthroplasty (THA) is a complication that worsens the functional prognosis. The present study analyzed the risk factors of nerve palsy following THA. Methods: The subjects of this study included 6,123 cases in which primary THA was performed under spinal anesthesia with cementless implants used in the posterolateral approach. Results: Fourteen cases (0.22%) developed nerve palsy following THA, all of which involved palsy of the entire peroneal nerve region. The diagnoses included osteoarthritis due to subluxation (n=6), complete hip dislocation (n=3), osteonecrosis of the femoral head (n=2), primary osteoarthritis (n=1), osteoarthritis due to trauma (n=1), and multiple osteochondromatosis (n=1). Recovery from nerve palsy was confirmed in 10 cases; the longest recovery period was three years. A univariate analysis revealed significant differences in the osteoarthritis due to subluxation, osteonecrosis of the femoral head, complete hip dislocation, body weight and body mass index. However, none of the factors remained significant in multivariate analysis. Peroneal (ischiadic) nerve palsy following THA occurred in patients with osteonecrosis of the femoral head, complete hip dislocation, low body weight and a low body mass index. However, there were no cases of nerve palsy after the introduction of THA combined with shortening osteotomy of the femur for complete hip dislocation. patients. Conclusion: It is necessary to pay attention to direct pressure in cases of lower body weight and lower BMI because compression of the sciatic nerve during surgery and compression of the fibular head are considered to be risk factors. PMID- 29755609 TI - Towards an EU measure of child deprivation. AB - This paper proposes a new measure of child material and social deprivation (MSD) in the European Union (EU) which includes age appropriate child-specific information available from the thematic deprivation modules included in the 2009 and 2014 waves of the "EU Statistics on Income and Living Conditions" (EU-SILC). It summarises the main results of the in-depth analysis of these two datasets, identifies an optimal set of robust children MSD items and recommends a child specific MSD indicator for use by EU countries and the European Commission in their regular social monitoring. In doing this, the paper replicates and expands on the methodological framework outlined in Guio et al. (2012, 2016), particularly by including additional advanced reliability tests. PMID- 29755608 TI - Evaluating Pictures of Nature and Soft Music on Anxiety and Well-Being During Elective Surgery. AB - Background: Patients going through surgery being awake often have a sense of anxiety and need support to relax. Objective: The aim of this study was to investigate whether looking at pictures of natural scenery could reduce anxiety and pain and increase relaxation and well-being being awake during the elective surgery. Methods: This three-arm, randomized intervention study consisted of one group viewing pictures of natural scenery, one group listening to soft instrumental music, and one control group without distraction, all adult patients (n=174). The State Trait Anxiety Inventory short form and a visual analogue scale on well-being were used as well as sedation treatment if necessary. Results: No differences related to anxiety after surgery were found among the three groups. When controlling for the effect of sedative treatment, however, patients without sedation had a lower degree of anxiety postoperatively (p=0.014). Younger patients had a higher degree of anxiety and lower degree of postoperative relaxation and well-being. Conclusion: Viewing pictures of natural scenery while being awake during elective surgery is as relaxing as listening to soft instrumental music. Offering nature scenery pictures for patients to view could be relaxing during the elective surgery. PMID- 29755610 TI - The Living Conditions of Children with Shared Residence - the Swedish Example. AB - Among children with separated parents, shared residence - i.e., joint physical custody where the child is sharing his or her time equally between two custodial parents' homes - is increasing in many Western countries and is particularly common in Sweden. The overall level of living among children in Sweden is high; however, the potential structural differences between children in various post separation family arrangements have not been sufficiently studied. Potential risks for children with shared residence relate to the daily hassles and stress when having two homes. This study aims at investigating the living conditions of children with shared residence compared with children living with two custodial parents in the same household and those living with one custodial parent, respectively. Swedish national survey data collected from children aged 10-18 years (n ~ 5000) and their parents were used. The outcomes were grouped into: Economic and material conditions, Social relations with parents and peers, Health and health behaviors, Working conditions and safety in school and in the neighborhood, and Culture and leisure time activities. Results from a series of linear probability models showed that most outcomes were similar for children with shared residence and those living with two custodial parents in the same household, while several outcomes were worse for children living with one parent. However, few differences due to living arrangements were found regarding school conditions. This study highlights the inequalities in the living conditions of Swedish children, with those living with one parent having fewer resources compared with other children. PMID- 29755613 TI - A Summary of a Cochrane Review: Acupuncture or acupressure for induction of labour. PMID- 29755612 TI - Determination of Care Burden of Caregivers of Patients with Multiple Sclerosis in Turkey. AB - The aim of this study was to determine the care burden of caregivers of patients with multiple sclerosis in Turkey. This descriptive study was conducted with 92 caregivers. To collect data, information form and Zarit Caregiver Burden Interview (ZCBI) were used. Most of the caregivers (65.2%) were females and 71.7% of them were married. The average age of caregivers was 38 and above. The mean ZCBI score of caregivers was 25.44 +/- 9.50. The ZCBI score was significantly higher in caregivers providing care for more than six years (28.09 +/- 10.16). Additionally, the ZCBI score was significantly higher in caregivers providing care 3-4 hours per day (32.23 +/- 8.37) and providing physical care (29.28 +/- 5.18). PMID- 29755611 TI - Morphological Biomarker Differentiating MCI Converters from Nonconverters: Longitudinal Evidence Based on Hemispheric Asymmetry. AB - Identifying subjects with mild cognitive impairment (MCI) who may probably progress to Alzheimer's disease (AD) is important for better understanding the disease mechanisms and facilitating early treatments. In addition to the direct volumetric and thickness measurement based on high-resolution magnetic resonance imaging (MRI), hemispheric asymmetry could be a potential index to detect morphological variations in MCI patients with a high risk of conversion to AD. The present study collected a set of longitudinal MRI data from 53 MCI converters and nonconverters and investigated the asymmetry differences between groups. Asymmetry variation was observed in the medial temporal lobe, especially in the entorhinal cortex, between converters and nonconverters 3 years before the former developed AD. The proposed asymmetry analysis was observed to be sensitive to detect morphological changes between groups as compared to the methods of voxel based morphometry (VBM) and thickness measurement. Hemispheric asymmetry in specific brain regions as a neuroimaging biomarker can provide helpful information for prediction of MCI conversion. PMID- 29755614 TI - Implant treatment in ultra-aged society. AB - Implant therapy is gaining presence as a prosthodontic treatment option. However, the graying of the population has led to an increase in the number of older adults requiring special consideration in implant treatment because of their systemic health problems. Additionally, with the growth of the elderly population in need of long-term care, a greater number of older adults who have received implant treatment are receiving long-term care, raising various issues that need to be addressed. In the present review article, we describe the significance of implant treatment in older adults, issues when performing implant treatment in geriatric patients, and measures to be taken when implant patients have lapsed into a state of requiring long-term care. In addition, in view of population aging, we propose an approach for applying implant treatment to older adults. This approach includes using an appropriate type of implant system depending on the remaining life expectancy and the patient's general condition, performing less invasive surgery, providing treatment using prosthetic appliances that are easy to manage and can be modified, and ensuring oral health management by providing an Implant Card to patients when the treatment is completed. PMID- 29755615 TI - Candida is a protractive factor of chronic oral ulcers among usual outpatients. AB - Although many oral ulcers have similar clinical appearances, their etiologies can range from reactive to neoplastic to oral manifestations of dermatological diseases. In patients with an HIV infection, fungal diseases may cause ulceration in the oral cavity; however, there have been few studies of oral ulcerative lesions associated with Candida in patients without an HIV infection. Nevertheless, we encountered chronic oral ulcer associated with Candida among our frequent outpatients without an HIV infection. The present article reviews the causes of oral ulcers, focusing on Candida as a protractive factor for chronic oral ulcers, and it is recommended that Candida involvement be considered in diagnosis of a certain chronic oral ulcer, that remains of unknown origin even if some examinations have been performed. PMID- 29755616 TI - Histological and immunological characteristics of the junctional epithelium. AB - The continuity of epithelial tissue is collapsed by tooth eruption. The junctional epithelium (JE) is attached to the tooth surface by hemidesmosomes, which constitutes the front-line defense against periodontal bacterial infection. JE constitutively expresses intercellular adhesion molecule-1 (ICAM-1), and neutrophils and lymphocytes penetrate into JE via interaction between ICAM-1 and LFA-1 expressed on the surface of these migrating cells. JE also expresses cytokines and chemokines. These functions of JE are maintained even in germ-free condition. Therefore, the constitutive expression of adhesion molecules, cytokines, and chemokines might be used not only for anti-pathogenic defense but also for maintaining the physiological homeostasis of JE. In this review, we have mainly focused on the structural and functional features of JE, and discussed the function of intraepithelial lymphocytes in JE as a front-line anti-microbial defense barrier and regulator of JE hemostasis. PMID- 29755619 TI - Molecularly-targeted therapy for the oral cancer stem cells. AB - Human cancer tissues are heterogeneous in nature and become differentiated during expansion of cancer stem cells (CSCs). CSCs initiate tumorigenesis, and are involved in tumor recurrence and metastasis. Furthermore, data show that CSCs are highly resistant to anticancer drugs. Cetuximab, a specific anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is used in cancer treatment. Although development of resistance to cetuximab is well recognized, the underlying mechanisms remain unclear. Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR)/ErbB2, has antiproliferative effects and is used to treat patients with ErbB2-positive metastatic breast cancer. In this review, cetuximab and lapatinib-resistant oral squamous cell carcinoma (OSCC) cells proliferation and migration signal transduction passway is discussed by introducing our research. PMID- 29755618 TI - Wear of resin composites: Current insights into underlying mechanisms, evaluation methods and influential factors. AB - The application of resin composites in dentistry has become increasingly widespread due to the increased aesthetic demands of patients, improvements in the formulation of resin composites, and the ability of these materials to bond to tooth structures, together with concerns about dental amalgam fillings. As resistance to wear is an important factor in determining the clinical success of resin composite restoratives, this review article defines what constitutes wear and describes the major underlying phenomena involved in this process. Insights are further included on both in vivo and in vitro tests used to determine the wear resistance of resin composite and the relationships between these tests. The discussion focuses on factors that contribute to the wear of resin composite. Finally, future perspectives are included on both clinical and laboratory tests and on the development of resin composite restorations. PMID- 29755617 TI - Regulation of defensive function on gingival epithelial cells can prevent periodontal disease. AB - Periodontal disease is a bacterial biofilm-associated inflammatory disease that has been implicated in many systemic diseases. A new preventive method for periodontal disease needs to be developed in order to promote the health of the elderly in a super-aged society. The gingival epithelium plays an important role as a mechanical barrier against bacterial invasion and a part of the innate immune response to infectious inflammation in periodontal tissue. The disorganization of cell-cell interactions and subsequent inflammation contribute to the initiation of periodontal disease. These make us consider that regulation of host defensive functions, epithelial barrier and neutrophil activity, may become novel preventive methods for periodontal inflammation. Based on this concept, we have found that several agents regulate the barrier function of gingival epithelial cells and suppress the accumulation of neutrophils in the gingival epithelium. We herein introduce the actions of irsogladine maleate, azithromycin, amphotericin B, and Houttuynia cordata (dokudami in Japanese), which is commonly used in traditional medicine, on the epithelial barrier and neutrophil migration in gingival epithelial cells in vivo and in vitro, in order to provide support for the clinical application of these agents to the prevention of periodontal inflammation. PMID- 29755620 TI - Human Genomic Loci Important in Common Infectious Diseases: Role of High Throughput Sequencing and Genome-Wide Association Studies. AB - HIV/AIDS, tuberculosis (TB), and malaria are 3 major global public health threats that undermine development in many resource-poor settings. Recently, the notion that positive selection during epidemics or longer periods of exposure to common infectious diseases may have had a major effect in modifying the constitution of the human genome is being interrogated at a large scale in many populations around the world. This positive selection from infectious diseases increases power to detect associations in genome-wide association studies (GWASs). High throughput sequencing (HTS) has transformed both the management of infectious diseases and continues to enable large-scale functional characterization of host resistance/susceptibility alleles and loci; a paradigm shift from single candidate gene studies. Application of genome sequencing technologies and genomics has enabled us to interrogate the host-pathogen interface for improving human health. Human populations are constantly locked in evolutionary arms races with pathogens; therefore, identification of common infectious disease-associated genomic variants/markers is important in therapeutic, vaccine development, and screening susceptible individuals in a population. This review describes a range of host-pathogen genomic loci that have been associated with disease susceptibility and resistant patterns in the era of HTS. We further highlight potential opportunities for these genetic markers. PMID- 29755621 TI - The Influence of Expectation on Nondeceptive Placebo and Nocebo Effects. AB - Nondeceptive placebo has demonstrated its efficiency in clinical practice. Although the underlying mechanisms are still unclear, nondeceptive placebo effect and nondeceptive nocebo effect may be mediated by expectation. To examine the extent to which expectation influences these effects, the present study compared nondeceptive placebo and nocebo effects with different expectation levels. Seventy-two healthy female participants underwent a standard conditioning procedure to establish placebo and nocebo effects. Sequentially, participants were randomized to one of the four experimental groups-baseline (BL), no expectation intervention (NoEI), expectation increasing (EI), and expectation decreasing (ED) groups, to receive either no intervention or interventions through different verbal suggestions that modulated their expectation. Placebo and nocebo effects were established in all four groups after the conditioning phase. However, after disclosing the placebo and nocebo, the analgesic and the hyperalgesic effects only persisted in the EI group, when compared with the BL group. Our results provide evidence highlighting the critical role of increased expectation in nondeceptive placebo and nocebo effects. The finding suggests that open-label placebo or nocebo per se might be insufficient to induce strong analgesic or hyperalgesic response and sheds insights into administrating open label placebo and avoiding open-label nocebo in clinical practice. PMID- 29755622 TI - Serum Triamcinolone Levels following Cervical Interlaminar Epidural Injection. AB - Background: Cervical interlaminar epidural steroid injections (ESIs) are commonly performed procedures to treat painful cervical radiculopathy, but little is known about the systemic absorption and serum levels of steroids following injection. The primary objective of this study was to investigate the pharmacokinetics of fluoroscopy-guided cervical epidural-administered triamcinolone acetonide in a cohort of patients with cervical radicular pain seeking treatment in a pain medicine clinic. Methods: The study cohort included eight patients undergoing a fluoroscopically guided C7-T1 interlaminar ESI at a pain medicine specialty clinic. Blood was collected prior to the ESI and on days 1, 2, 4, 6, 8, 14, 21, 28, 35, and 42 following the injection. The sample extract was analyzed by tandem mass spectrometry. Results: The terminal elimination half-life of cervical epidural-administered triamcinolone in a noncompartmental analysis was 219 hours. In the noncompartmental analysis, peak triamcinolone concentrations of 5.4 ng/mL were detected within 22.1 hours after administration. Conclusions: The pharmacokinetics of cervical epidural-administered triamcinolone is consistent with our previous study of lumbar ESI, demonstrating that the elimination half life is longer than that which has been reported following intravenous triamcinolone. The elimination half-life was shorter following cervical ESI than that which has been reported following lumbar ESI. PMID- 29755623 TI - Main Considerations of Cardiogenic Shock and Its Predictors: Systematic Review. AB - The mortality rate of post-infarction cardiogenic shock (CS) was 80.0-90.0%. Recent studies show a significant reduction of hospital mortality to approximately 50.0%. CS is defined as systemic tissue hypoperfusion resulting from systolic and/or diastolic heart dysfunction, the main cause of which is acute myocardial infarction (AMI). The main predictors are biological markers such as troponin, CKMB and lactate. A systematic literature review and meta analysis is performed in order to present and correlate the main literary findings on CS and its evolution with possible changes in biomarkers such as troponin, lactate and CKMB. After criteria of literary search with the use of the mesh terms: cardiogenic shock; acute myocardial infarction; biomarkers; troponin; CKMB; lactate; clinical trials and use of the bouleanos "and" between the mesh terms and "or" among the historical findings. In the main databases such as Pubmed, Medline, Bireme, EBSCO, Scielo, etc., a total of 96 papers that were submitted to the eligibility analysis were collated and, after that, 41 studies were selected, following the rules of systematic review - PRISMA (Transparent reporting of systematic reviews and meta-analyzes-http://www.prisma statement.org/). Some risk factors for its development in AMI are advanced age, female gender, anterior wall infarction, diabetes mellitus, systemic arterial hypertension, previous history of infarction and angina. The CS associated with AMI depends on its extent and its complications, being the main ones: mitral regurgitation, rupture of the interventricular septum and rupture of the free wall of the left ventricule. The diagnosis is based on the clinical manifestations, such as mental confusion, oliguria, hypotension, tachycardia, fine pulse, sweating, and cold extremities; in hemodynamic aspects: systolic blood pressure was < 90.0 mm Hg or 30 mm Hg below baseline, pulmonary capillary pressure was > 18.0 mm Hg and cardiac index was < 2.2 L/min/m2. Laboratory and imaging exams should be requested to evaluate the possible etiology of CS, its systemic repercussions and comorbidities. The treatment aims at the rapid reestablishment of the blood flow in the affected artery, to improve the patient's prognosis. The biomarkers dosage in the daily clinical practice of the different cardiological centers can facilitate the diagnosis and the conduction of the dubious cases and the best evaluation of the degree of myocardial suffering after CS. PMID- 29755625 TI - Minimal Invasive Technique in Atrial Septal Defect Surgery. AB - Background: Median sternotomy with minimal skin incision (MSWMSI) and modified anterior mini-thoracotomy (MAMT) approach that both are innovative techniques modified from previous documented techniques are important alternative to conventional median sternotomy in atrial septal defect (ASD) repair. Our aim is to explain the details of two performed techniques in our center and explain the results. Methods: Totally 54 children with ASD (20 female and 34 male) were operated with two different techniques i.e. MAMT and MSWMSI in Imam Ali heart surgery center between May 2010 and May 2013. Intra and postoperative variables such as cardiopulmonary bypass time and aortic cross-clamp time, intensive care unit stay time, length of incision, postoperative hematoma and seroma, dehiscence mortality, exploration for postoperative bleeding, neurologic complication, infection and amount of blood transfusion were recorded. Results: Mean cardiopulmonary bypass time was 30 +/- 11 min, and mean aortic cross-clamp time was 7 +/- 2 min. The mean amount of blood transfusion was 150 +/- 39 mL, and the mean chest tube drainage after surgery was 140 +/- 57 mL. Superficial skin infection occurred in three patients. Subcutaneous hematoma and seroma were founded in six patients. In 50 cases the defect was secundum type, in two patients it was sinus venosus type, and in two with associated perimembranous ventricular septal defect repair. Conclusion: Both approaches are safe and may be the surgical techniques of choice for secundum ASD repair in all age groups; and we can also utilize these techniques for more complicated kinds of surgery, for instance, sinus venosus type ASD with or without partial anomalous defect. PMID- 29755624 TI - Clinical Significance of Skin Autofluorescence in Patients With Type 2 Diabetes Mellitus With Chronic Heart Failure. AB - Background: Recent clinical studies have shown that skin autofluorescence (AF) levels are significantly associated with diabetic complications. In contrast, data regarding the relationships between skin AF and chronic heart failure (CHF) are limited. The aim of this study was to clarify the clinical significance of skin AF in patients with type 2 diabetes mellitus (DM) with CHF. Methods: This cross-sectional study enrolled 257 outpatients with type 2 DM with CHF who were treated medically (96 men and 161 women; mean age, 79 +/- 7 years). Associations between skin AF and various clinical parameters were examined. Results: Incidence of skin AF in patients with a history of hospitalization due to HF was significantly higher than in those without a history of hospitalization due to HF (3.0 +/- 0.5 AU vs. 2.7 +/- 0.5 AU, respectively, P < 0.001). Significant positive correlations were found between skin AF and various clinical parameters, such as E/e' as a maker of left ventricular diastolic function (r = 0.30, P < 0.001), high-sensitivity cardiac troponin T levels as a marker of myocardial injury (r = 0.45, P < 0.001), reactive oxygen metabolite levels as an oxidative stress marker (r = 0.31, P < 0.001), and cardio-ankle vascular index as a marker of arterial function (r = 0.38, P < 0.001). Furthermore, multiple regression analyses showed that these clinical parameters (E/e' (beta = 0.25, P < 0.001)), high-sensitivity cardiac troponin T levels (beta = 0.30, P < 0.001), cardio-ankle vascular index (beta = 0.21, P < 0.001), reactive oxygen metabolite levels (beta = 0.15, P < 0.01), and a history of hospitalization due to HF (beta = 0.23, P < 0.001) were independent variables when skin AF was used as a subordinate factor. Conclusion: The findings of this study showed that skin AF may be a determining factor for prognosis in patients with type 2 DM with CHF. Further investigations in a large prospective study, including intervention therapies, are required to validate the results of this study. PMID- 29755626 TI - The Impact of Admission Serum Creatinine on Major Adverse Clinical Events in ST Segment Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention. AB - Background: Impaired renal function has been shown in previous studies to be an independent predictor of cardiovascular adverse events amongst patients admitted for percutaneous coronary intervention (PCI) following ST-segment elevation myocardial infarction (STEMI). This study investigates the impact of admission serum creatinine (SCr) on major cardiovascular outcomes among STEMI patients undergoing PCI. Methods: A retrospective study of patients admitted for PCI following STEMI was conducted using the National Cardiovascular Database Action Registry (NCDR) at Cleveland Clinic Akron General (CCAG) Hospital. The primary outcome was a composite of major clinical events: cardiogenic shock, atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, bleeding and mechanical ventilation. SCr was an independent and continuous variable. Results: A total of 656 patients included in the study with the diagnosis of STEMI who subsequently underwent primary PCI. Patients with eGFR < 60 mL/min/1.73 m2 on admission had an increased incidence of cardiogenic shock (P = 0.001), bleeding (P < 0.001), heart failure (P < 0.0005) and higher mortality rates (P = 0.0005). Furthermore, in the setting of STEMI, elevated SCr was also associated with an increased risk of developing major adverse events like cardiogenic shock (P = 0.05), bleeding (P = 0.05), and heart failure (P = 0.005). Conclusions: In the setting of STEMI, elevated SCr and eGFR < 60 mL/min/1.73 m2 was associated with an increased risk of developing major adverse events including cardiogenic shock, bleeding and heart failure. PMID- 29755628 TI - Eptifibatide Bolus Dose During Elective Percutaneous Coronary Intervention. AB - Background: Eptifibatide is a platelet glycoprotein IIb/IIIa receptor antagonist used for the prevention of cardiac ischemic complications of percutaneous coronary intervention (PCI). Eptifibatide has been used with bolus dose only or bolus plus infusion in patients undergoing PCI which have shown less complications, but the risk of bleeding has been increased. We aimed to compare the outcome and bleeding rate of bolus dose alone or plus infusion in elective PCI. Methods: In this quasi-experimental study, we compared the outcome of elective PCI following single bolus dose intracoronary (41 patients) or bolus plus intravenous infusion (19 patients) of eptifibatide. In-hospital and follow up major adverse cardiac events (MACEs) and bleeding rate were recorded and evaluated between groups. Results: Both groups were comparable regarding baseline findings. Bolus only compared to bolus plus infusion group had lower in-hospital (19.5% vs. 31.6%) and follow-up MACE (15.4% vs. 17.6%), lower bleeding in hospital (14.6% vs. 21.1%) and follow-up (2.4% vs. 5.3%) as well as lower mortality rate in hospital (4.9% vs. 15.8%), but higher follow-up mortality (10.3% vs. 0), but the difference was not significant. Conclusions: We observed no significant difference regarding bleeding or MACE between intracoronary bolus infusion and bolus plus intravenous infusion of eptifibatide. It seems intracoronary bolus infusion of eptifibatide due to use of lower doses is a better choice in elective PCI to prevent post-PCI MACE. PMID- 29755629 TI - Interventricular Vessel of the Heart. AB - The communication from right to left through the interventricular septum of the heart became identified by the anatomical study for 4 years. One thousand nine hundred years ago, Galen stated that blood seeps through the perforations in the interventricular septum of the heart. However, William Harvey, working 400 years ago, failed to find any. The interventricular vessel is a slit between the fibers of the muscle feasible to be patent by relaxing and widening of the helical heart at the right atrial filling phase at the end of the diastole. The case exhibited the flow of venous blood passing from right to left through the interventricular vessel at the right atrial filling phase concordant to the fourth heart sound. The earliest left ventricular activation closed the interventricular sphincter surrounding the interventricular vessel in the middle of the left muscular part of the interventricular septum. The fourth heart sound is common at the atrial filling phase in hypertrophy of systemic hypertension and in ischemic heart disease. It is necessary to explore vigorously the unknown etiology of the fourth heart sound (S4). PMID- 29755627 TI - Molecular Diagnosis of Bacterial Definite Infective Endocarditis by Real-Time Polymerase Chain Reaction. AB - Infective endocarditis (IE) can be diagnosed using the Duke criteria, which cannot be conclusive especially when the results of blood cultures are negative. This study aimed at using real-time polymerase chain reaction (PCR) technique to isolate bacteria present in whole blood samples of patients with definitive IE on the basis of the method designed in this study. This laboratory and test study was conducted on 20 whole blood samples taken from patients with definitive IE. Real-time PCR of the 16s rRNA was utilized to directly analyze whole blood samples to diagnose bacterial IE. Of 20 whole blood samples with definitive IE, only one blood culture (5%) was positive and the isolated bacterium belonged to Streptococci viridans group. Also, 13 whole blood samples were positive using real-time PCR technique. The isolated bacteria were Enterococcus faecalis with seven (35%) cases, Streptococcus gallolyticus with two (10%) cases, Streptococcus mutans with one (5%) case, Streptococcus sanguinis with one (5%) case, Streptococcus salivarius with one (5%) case, and Staphylococcus aureus with one (5%) case. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) using real-time PCR technique were 65%, 100%, 100%, and 74%, respectively. The developed real-time PCR method allows us to detect bacteria in whole blood samples and is much more sensitive than culturing method. It also permits the differentiation of the main group of bacteria within a few hours for IE. PMID- 29755630 TI - Echocardiographic Features in Bartonella Endocarditis: A Case Series. AB - Bartonella spp. are emerging pathogens that are reported as the cause of blood culture-negative endocarditis ( BCNE). However, echocardiographic features and assessment of this endocarditis remains unclear. Four patients with B. henselae endocarditis were identified. All patients had underlying cardiac conditions: rheumatic heart disease in three, congenital heart disease in one. Evidence of vegetations was found on the aortic valve in all patients with large, highly mobile vegetations and severely destroyed valves demonstrated by the transthoracic echocardiogram leading to severe aortic regurgitation and heart failure. The vegetations were found on both the aortic and the mitral valve in two patients. All patients had negative blood cultures and underwent urgent valves replacement due to heart failure with good clinical outcome. The diagnosis of B. henselae endocarditis is based mainly on clinical suspicion in BCNE, specific serologic testing and polymerase chain reaction (PCR) detection on excised valve tissue. PMID- 29755631 TI - Anomalous Coronary Artery From the Opposite Sinus (ACAOS): Technical Challenges During Percutaneous Coronary Intervention. AB - Anomalies of the coronary arteries are reported in 1-2% of patients among diagnostic angiogram. Ectopic origin of right coronary artery (RCA) from opposite sinus is one of the most common and they are mainly benign, but at times may be malignant. We report a case of a 69-year-old male who underwent early invasive percutaneous coronary intervention for non-ST-segment elevation myocardial infarction (NSTEMI) where RCA arising from left sinus at the root of left main artery was culprit and various technical challenges were encountered while intervening in form of cannulation to tracking of hardwares. RCA was cannulated with floating wire technique using hockey stick guide catheter and revascularized by deployment of 3.5 * 38 mm Promus Premier Everolimus eluting stent (Boston Scientific, USA). To the best of our knowledge, this is the first ever report of ectopic RCA being revascularized by using hockey stick catheter. PMID- 29755632 TI - Is There Always a Need for Permanent Pacemaker Replacement After Device Infection? A Tale of Two Patients. AB - There has been an increase in number of cardiac implantable electronic devices (CIEDs) implantation and with this we have witnessed increased rates of CIED infection mainly in elderly population. It is important to assess conditions that may not reliably improve with cardiac pacing or those who lack adequate beneficial effect from permanent pacing before contemplating implantation or reimplantation of these devices. Sometimes, the initial cardiac pathology may revert obviating the need for reimplantation as in the two cases that we have discussed below. This reduces the chance of further infection of CIED, and decreases mortality and morbidity due to recurrent CIED infection and decreases cost of care. PMID- 29755633 TI - Coronary Artery Thromboses, Stent Thrombosis and Antiphospholipid Antibody Syndrome: Case Report. AB - The antiphospholipid antibody syndrome (APS) is defined by a state of hypercoagulability secondary to an autoimmune disorder. There are evidences that approximately 2.8-5.5% of cases of acute myocardial infarction (AMI) in young individuals are secondary to APS. In this case report, three coronary artery thromboses occurring within a short period are described. Initially, there was an ST-segment elevation (STEMI) in the presence of coronary artery disease (CAD), with the vessel being treated with stent implantation. Thereafter, a subacute stent thrombosis occurred (high thrombotic load in almost all coronary arteries), which was treated with implantation of two stents. Subsequently, there was a new infarction owing to a new thrombosis in the native coronary artery. The treatment of APS in patients who developed thrombotic events is full anticoagulation from the initial stages maintained throughout life. The standard anticoagulant therapy is administration of vitamin K antagonists, such as warfarin. PMID- 29755634 TI - Mitroflow Aortic Bioprosthesis Failure in Type B Aortic Dissection: Preventive Left Main Stenting in Transapical Transcatheter Aortic Valve Implantation Strategy. AB - Mitroflow aortic prosthesis dysfunction in case of complex vascular disease is considered a challenging scenario. Because of the high risk for surgical reoperation and the presence of chronic aortic dissection originated from a calcified Kommerel diverticulum, we considered to perform a transapical valve-in valve transcatheter aortic valve implantation (TAVI) procedure. Myocardial ischemia is a dreadful complication reported in valve-in-valve TAVI procedures, mainly in patients with degenerated Mitroflow aortic bioprostheses. Because of the narrow shape of Valsalva sinuses and the short distance between Mitroflow annulus and left coronary ostium, to overcome the risk of possible Mitroflow leaflets displacement during TAVI expansion thus overlapping coronary ostia, we performed a preventive angioplasty. Then, we implanted a bare metal stent on the left main protruding in the aortic root. At 3 years follow-up the patient was in good clinical conditions. PMID- 29755635 TI - Microfluidic platform for probing cancer cells migration property under periodic mechanical confinement. AB - Cancer cell migration and invasion, which are involved in tumour metastasis, are hard to predict and control. Numerous studies have demonstrated that physical cues influence cancer cell migration and affect tumour metastasis. In this study, we proposed the use of a microchannel chip equipped with a number of vertical constrictions to produce periodic compression forces on cells passing through narrow channels. The chip with repeated vertical confinement was applied on adherent MHCC-97L liver cancer cells and suspended OCI-AML leukaemia cells to determine the migration ability of these cancer cells. Given the stimulation of the periodic mechanical confinement on-chip, the migration ability of cancer cells was promoted. Moreover, the migration speed increased as the stimulation was enhanced. Both AFM nanoindentation and optical stretching tests on cancer cells were performed to measure their mechanical property. After confinement stimulation, the cancer cells possessed higher deformability and lower stiffness than non-stimulating cells. The confinement stimulation altered the cell cytoskeleton, which governs the migration speed. This phenomenon was determined through gene expression analysis. The proposed on-chip cell migration assays will help characterise the migration property of cancer cells and benefit the development of new therapeutic strategies for metastasis. PMID- 29755636 TI - Microfluidic chip for non-invasive analysis of tumor cells interaction with anti cancer drug doxorubicin by AFM and Raman spectroscopy. AB - Raman spectroscopy has been playing an increasingly significant role for cell classification. Here, we introduce a novel microfluidic chip for non-invasive Raman cell natural fingerprint collection. Traditional Raman spectroscopy measurement of the cells grown in a Polydimethylsiloxane (PDMS) based microfluidic device suffers from the background noise from the substrate materials of PDMS when intended to apply as an in vitro cell assay. To overcome this disadvantage, the current device is designed with a middle layer of PDMS layer sandwiched by two MgF2 slides which minimize the PDMS background signal in Raman measurement. Three cancer cell lines, including a human lung cancer cell A549, and human breast cancer cell lines MDA-MB-231 and MDA-MB-231/BRMS1, were cultured in this microdevice separately for a period of three days to evaluate the biocompatibility of the microfluidic system. In addition, atomic force microscopy (AFM) was used to measure the Young's modulus and adhesion force of cancer cells at single cell level. The AFM results indicated that our microchannel environment did not seem to alter the cell biomechanical properties. The biochemical responses of cancer cells exposed to anti-cancer drug doxorubicin (DOX) up to 24 h were assessed by Raman spectroscopy. Principal component analysis over the Raman spectra indicated that cancer cells untreated and treated with DOX can be distinguished. This PDMS microfluidic device offers a non invasive and reusable tool for in vitro Raman measurement of living cells, and can be potentially applied for anti-cancer drug screening. PMID- 29755637 TI - Elastic Modulus and Thermal Conductivity of Thiolene/TiO2 Nanocomposites. AB - Metal oxide based polymer nanocomposites find diverse applications as functional materials, and in particular thiol-ene/TiO2 nanocomposites are promising candidates for dental restorative materials. The important mechanical and thermal properties of the nanocomposites, however, are still not well understood. In this study, the elastic modulus and thermal conductivity of thiol-ene/TiO2 nanocomposite thin films with varying weight fractions of TiO2 nanoparticles are investigated by using Brillouin light scattering spectroscopy and 3omega measurements, respectively. As the TiO2 weight fraction increases from 0 to 90%, the effective elastic longitudinal modulus of the films increases from 6.2 to 37.5 GPa, and the effective thermal conductivity from 0.04 to 0.76 W/m K. The former increase could be attributed to the covalent cross-linking of the nanocomposite constituents. The latter one could be ascribed to the addition of high thermal conductivity TiO2 nanoparticles and the formation of possible conductive channels at high TiO2 weight fractions. The linear dependence of the thermal conductivity on the sound velocity, reported for amorphous polymers, is not observed in the present nanocomposite system. PMID- 29755638 TI - Locally Adaptive Smoothing with Markov Random Fields and Shrinkage Priors. AB - We present a locally adaptive nonparametric curve fitting method that operates within a fully Bayesian framework. This method uses shrinkage priors to induce sparsity in order-k differences in the latent trend function, providing a combination of local adaptation and global control. Using a scale mixture of normals representation of shrinkage priors, we make explicit connections between our method and kth order Gaussian Markov random field smoothing. We call the resulting processes shrinkage prior Markov random fields (SPMRFs). We use Hamiltonian Monte Carlo to approximate the posterior distribution of model parameters because this method provides superior performance in the presence of the high dimensionality and strong parameter correlations exhibited by our models. We compare the performance of three prior formulations using simulated data and find the horseshoe prior provides the best compromise between bias and precision. We apply SPMRF models to two benchmark data examples frequently used to test nonparametric methods. We find that this method is flexible enough to accommodate a variety of data generating models and offers the adaptive properties and computational tractability to make it a useful addition to the Bayesian nonparametric toolbox. PMID- 29755639 TI - Pilot Experiment: The Effect of Added Flavorants on the Taste and Pleasantness of Mixtures of Glycerol and Propylene Glycol. AB - Introduction: The US Food and Drug Administration banned most "sweet" flavorants for use in cigarettes due to the concern that sweet flavors appeal to young, beginning smokers. However, many of the same flavors, including fruity and confection-associated aromas (e.g. vanilla) are still used in e-cigarettes. Sweet flavors may have a number of effects, including enhancement of the taste of other ingredients. The current work focused on the impact of model flavorants on the taste of a mixture of propylene glycol and vegetable glycerine, solvents used in most e-cigarettes and related products. Methods: A device delivered mixtures of propylene glycol and vegetable glycerine into the mouth in parallel with puffs of clean air (control) or odorized air. Aromas included two "fruity" esters ("pineapple" and "banana"), two confection-associated aromas ("vanilla" and "caramel/malty"), menthol (not a "sweet" aroma, but commonly used in e cigarettes), and a "burnt" aroma not expected enhance flavor. Twenty young adults, aged 18-25, rated the sweetness, bitterness, and pleasantness of all stimuli (within-subjects design). Results: Both fruity aromas significantly enhanced sweetness, both confection-associated aromas significantly enhanced pleasantness, and the caramel/malty aroma significantly reduced bitterness. Menthol and the "burnt" aroma had no measurable effects on the taste of solvent mixtures. Conclusion: Some flavorants modulated the taste of solvents commonly used in e-cigarettes in ways consistent with an enhanced sensory profile. Implications: If similar effects occur in actual products, improved flavor profiles could facilitate continued use, particularly in non-smokers experimenting with e-cigarettes and related products. PMID- 29755640 TI - Melatonin and tumeric ameliorate aging-induced changes: implication of immunoglobulins, cytokines, DJ-1/NRF2 and apoptosis regulation. AB - Aging is associated with several biological, physiological, cellular and histological changes. In the present study, we investigated the effect of aging on different signaling pathways, including antioxidant system, apoptosis and immune status. Several natural products were used to ameliorate and block aging related changes. Melatonin and turmeric have been known to ameliorate and decrease aging-related changes. However, the exact mechanism(s) of their action is not fully understood. In the present study, we tried to uncover the regulatory mechanism(s) by which melatonin and turmeric work against aging. We found that aging differentially regulated blood serum immunoglobulins; increased IgA and decreased IgE. Furthermore, all the serum cytokines investigated (TNF-alpha, IFN gamma, IL-6 and IL-8) were highly increased by aging. In addition, the antioxidant upstream regulators; DJ-1 and NRF2 were markedly repressed with aging in thymus tissues. We also found that aging induced apoptosis promoting genes p53 and Bax mRNA in thymus tissues. Finally, we found clear histological changes in thymus and spleen tissues. Administration of either melatonin or tumeric clearly ameliorated and blocked to some extinct the effect of aging. Altogether, aging was associated with downregulation of antioxidant regulators; DJ-1 and NRF2, promoted apoptosis and induced changes in the immune status. Furthermore, melatonin and tumeric markedly reversed the action of aging through activating DJ 1/NRF2 signaling pathway and inhibiting p53/Bax apoptotic pathway. PMID- 29755641 TI - Ischemic preconditioning attenuates acute lung injury after partial liver transplantation. AB - Pulmonary complications frequently occur after liver transplantation and are often life-threatening. Thus, we investigated whether hepatic ischemic preconditioning (IP) attenuates acute lung injury (ALI) after small-for-size liver transplantation. Rat livers were explanted after 9-min ischemia plus 5-min reperfusion, reduced to 50% of original size ex vivo, and implanted into recipients with approximately twice the donor body weight, resulting in quarter size liver grafts (QSG). After QSG transplantation, hepatic Toll-like receptor 4 (TLR4) and tumor necrosis factor-alpha (TNFalpha ) expression increased markedly and high mobility group box-1 (HMGB1), an endogenous damage-associated molecular pattern molecule (DAMP), was released from QSG into the blood. IP blunted TLR4 and TNFalpha expression and HMGB1 release from QSG. In the lungs of QSG recipients without IP treatment, nuclear factor-kappaB (NF-kappaB) activation and intercellular adhesion molecule (ICAM)-1 expression increased; alveolar septal walls thickened with increased cellularity as neutrophils, monocytes/macrophage and T lymphocytes infiltrated into alveolar septa and alveolar spaces; and pulmonary cleaved caspase-8 and -3 and TUNEL-positive cells increased. In contrast, in the lungs of recipients of ischemic-preconditioned QSG, NF-kappaB activation and ICAM-1 expression were blunted; leukocyte infiltration was decreased; and alveolar septal wall thickening, caspase activation, and cell apoptosis were attenuated. IP did not increase heat-shock proteins in the lungs of QSG recipients. In conclusion, toxic cytokine and HMGB1 released from failing small-for-size grafts leads to pulmonary adhesion molecule expression, leukocyte infiltration and injury. IP prevents DAMP release and toxic cytokine formation in small-for-size grafts, thereby attenuating ALI. PMID- 29755642 TI - An improved method for increasing the efficiency of gene transfection and transduction. AB - Transfection and transduction using lentivirus has gained attention in biomedical research. To date, how to reach the maximum transfection and viral transduction efficiency is still challenging. Here we compared the transfection and viral transduction efficiency using commercially available transfection reagents including FuGENE 6, Lipofectamine 2000 and Lipofectamine 3000 in different cell lines and primary cultured cells. Enhanced green fluorescent protein (EGFP) was clearly seen in Eppendorf tubes from harvested cells using Lipofectamine 3000 without using a microscope and UV activation. Strong expression of EGFP was observed in HEK293 cells, mouse primary cortical neurons and human umbilical vein endothelial cells (HUVECs) using confocal microscopy. Western blot showed the strongest EGFP expression using cell lysates from Lipofectamine 3000 transfected HEK293 cells and transduced HUVECs compared with Lipofectamine 2000 or FuGENE 6 reagents. Using Cx43 shRNA lentivirus combined with Lipofectamine 3000 transfection reagent, we can achieve about 90% Cx43 knockdown efficacy in HUVECs. Therefore, our results suggest that a much higher transfection and viral transduction efficiency can be attained by using Lipofectamine 3000 transfection reagent. PMID- 29755643 TI - Tumor associated macrophages deliver iron to tumor cells via Lcn2. AB - Cancer cells exhibit an increasing iron demand associated with the tumor progression. But the mechanism of iron accumulation in the tumor microenvironment is still unclear. Tumor associated macrophages (TAMs) in the tumor microenvironment may act as extra iron source. However, evidence is still lacking in TAMs as iron donors. In the present study, we found that iron concentration was significantly increased at tumor metastatic stage, which could be attributed to up-regulated expression of lipocalin2 (Lcn2). TAMs in the microenvironment secreted Lcn2. Moreover, TAMs increased intracellular iron concentration in tumor cells via Lcn2 as transporter, which could be restored by Lcn2 antibody neutralization. In conclusion, TAMs increased intracellular iron concentration of the tumor cells via Lcn2 which acted as an iron transporter. Targeting Lcn2 secretion in TAMs to "starve cancer cells" could act as alternative option for tumor therapy. PMID- 29755644 TI - Potential implication of SGK1-dependent activity change in BV-2 microglial cells. AB - It has recently been established that microglial activation is involved in the pathophysiology of various neurological and psychiatric disorders such as amyotrophic lateral sclerosis and schizophrenia. The pathological molecular machineries underlying microglial activation and its accelerating molecules have been precisely described in the diseased central nervous system (CNS). However, to date, the details of physiological mechanism, which represses microglial activation, are still to be elucidated. Our latest report demonstrated that serum and glucocorticoid-inducible kinases (SGK1 and SGK3) were expressed in multiple microglial cell lines, and their inhibitor enhanced the toxic effect of lipopolysaccharide on microglial production of inflammatory substances such as TNFalpha and iNOS. In the present report, we prepared SGK1-lacked microglial cell line (BV-2) and demonstrated that deficiency of SGK1 in microglia induced its toxic conversion, in which it took amoeboid morphology characteristic of reactive microglia, increased CD68 expression, quickened its proliferation, and showed higher susceptibility to ATP and subsequent cell death. Our data indicate that SGK1 plays pivotal roles in inhibiting its pathological activation, and suggest its potential function as a therapeutic target for the treatment of various disorders related to the inflammation in the CNS. PMID- 29755645 TI - Hepatic steatosis in chronic hepatitis B: a study of metabolic and genetic factors. AB - Hepatic steatosis is a common finding in liver biopsy and may co-exist with chronic hepatitis B (CHB) infection. The aims of this study were to determine the prevalence of steatosis in CHB patients among Filipinos; determine the factors related to the presence of steatosis among individuals with and without CHB infection; and to investigate the possible association between steatosis and polymorphism in interleukin 28B (IL28B) gene. The presence of steatosis was correlated with clinical, biochemical and histological parameters. Peripheral blood samples of CHB patients with steatosis, CHB patients without steatosis and normal controls were genotyped for IL28B rs8099917 T>G using the TaqMan assay. Of the 46 CHB patients, 41% (19/46) had steatosis. Body mass index (BMI), fasting blood sugar (FBS), lipid profile and alanine transaminase levels were observed to be significantly different between CHB patients with steatosis and normal controls. The serum FBS of CHB patients with steatosis was significantly higher than patients without steatosis. High density lipoprotein cholesterol of patients without steatosis was significantly higher than patients with steatosis. Although not statistically significant, BMI, triglycerides, low density lipoprotein cholesterol and histology activity index in CHB patients with steatosis were found to be higher than those without steatosis. There was no significant association between the stage of fibrosis and severity of steatosis. In conclusion, the prevalence of hepatic steatosis among Filipino patients with CHB is 41%. Steatosis in CHB patients was associated with metabolic factors such as diabetes and dyslipidemia. IL28B rs8099917 T>G polymorphism is not associated with steatosis. PMID- 29755646 TI - A Qualitative Exploration of the Meaning and Understanding of Male Partner Involvement in Pregnancy-Related Care among men in rural South Africa. AB - Male partner involvement (MPI) during antenatal care has been promoted as an effective intervention to improve maternal and newborn health outcomes. Although MPI is commonly defined as men attending antenatal clinic visits with their female partner, few men attend antenatal clinic visits in rural communities in the province of Mpumalanga, South Africa. The study aimed to qualitatively explore the meaning and understanding of MPI as perceived by men visiting primary health care clinics in rural communities in Mpumalanga. Six focus groups discussions (n = 53) were conducted, digitally recorded, simultaneously transcribed, and translated verbatim into English. Data were analyzed using thematic content analysis. Perceptions of male roles during and after pregnancy differed among men. Male involvement was understood as giving instrumental support to female partners through financial help, helping out with physical tasks, and providing emotional support. Accompanying female partners to the clinic was also viewed as partner support, including behaviors such as holding a spot for her in the clinic queues. Community attitudes, traditional beliefs, and negative experiences in health facilities were barriers for MPI. This study provides support for concerted efforts to work with both men and women within the cultural context to explore the important roles of all members of the family in working together to provide the best possible health outcomes for mother and infant. In particular, future interventions should focus on making antenatal care services more responsive to male partners, and improving male partner accessibility in health care facilities. PMID- 29755647 TI - Autologous tumor cells/bacillus Calmette-Guerin/formalin-based novel breast cancer vaccine induces an immune antitumor response. AB - Autologous cancer cell vaccines represent a multivalent patient-specific treatment. Studies have demonstrated that these immunotherapies should be combined with immunomodulators to improve results. We tested in breast cancer the antitumor effects of a 200 ug autologous tumor cells homogenate combined with 0.0625 mg of bacillus Calmette-Guerin (BCG), and 0.02% formalin. We used a 4T1 murine model of BALB/c receiving four weekly injections of either this vaccine or control treatments. The control treatments were either Phosphate Buffer Saline, BCG treated with formalin, or the tumor cells homogenate plus BCG alone. We found that mice treated with the vaccine had the lowest tumor growth rate and mitosis percentage. The vaccinated group also showed a marked increase in infiltration of antitumor cells (natural killer, CD8 + T and CD4+ Th1 cells), as well as a decrease of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Additionally, we also observed a possible activation of the immune memory response as indicated by plasma cell tumor infiltration. Our results demonstrate that our proposed breast cancer vaccine induces a potent antitumor effect in 4T1 tumor-bearing mice. Its effectiveness, low cost and simple preparation method, makes it a promising treatment candidate for personalized breast cancer immunotherapy. PMID- 29755648 TI - SAAV2152 is a single-stranded DNA binding protein: the third SSB in Staphylococcus aureus. AB - Single-stranded DNA-binding proteins (SSBs) play crucial roles in DNA replication, repair, and recombination. Unlike E. coli, which contains only one type of SSB (EcSSB), some bacteria have two paralogous SSBs, namely, SsbA and SsbB. In this study, we found the third SSB-like protein in Staphylococcus aureus, SAAV2152, which was designated as SaSsbC. SaSsbC is a protein of 131 amino acids and shares 38%, 36%, and 33% sequence identity to SaSsbB, SaSsbA, and EcSSB, respectively. Gene map analysis showed that unlike the E. coli ssb gene, which is adjacent to uvrA gene, the S. aureus ssb gene SAAV2152 is flanked by the putative SceD, the putative YwpF, and fabZ genes. A homology model showed that SaSsbC consists of the classic oligonucleotide/oligosaccharide-binding fold at the N-terminus. At the C-terminus, SaSsbC did not exhibit sequence similarity to that of EcSSB. Electrophoretic mobility shift analysis showed that SaSsbC formed a single complex with ssDNA of different lengths. Mutational analysis revealed that Tyr36, Tyr47, Phe53, and Tyr81 in SaSsbC are at positions that structurally correspond to the important residues of EcSSB for binding to ssDNA and are also critical for SaSsbC to bind ssDNA. Unlike EcSSB, which can stimulate EcPriA, SaSsbC did not affect the activity of SaPriA. In addition, SaSsbA inhibitor 9 methyl-2,3,7-trihydroxy-6-fluorone (NSC5426) could inhibit the ssDNA-binding activity of SaSsbC with IC50 of 78 MUM. In conclusion, this study has identified and characterized SAAV2152 as a kind of SSB, and further research can directly focus on determining its actual physiological role in S. aureus. PMID- 29755649 TI - Evaluation of the primitive fraction by functional in vitro assays at the RNA and DNA level represents a novel tool for complementing molecular monitoring in chronic myeloid leukemia. AB - Quantification of BCR-ABL1 mRNA levels in peripheral blood of chronic myeloid leukemia patients is a strong indicator of response to tyrosine-kinase inhibitors (TKI) treatment. However, additional prognostic markers are needed in order to better classify patients. The hypothesis of leukemic stem cells (LSCs) heterogeneity and persistence, suggests that their functional evaluation could be of clinical interest. In this work, we assessed the primitive and progenitor fractions in patients at diagnosis and during TKI treatment using functional in vitro assays, defining a "functional leukemic burden" (FLB). We observed that the FLB was reduced in vivo in both fractions upon treatment. However, different FLB levels were observed among patients according to their response to treatment, suggesting that quantification of the FLB could complement early molecular monitoring. Given that FLB assessment is limited by BCR-ABL1 mRNA expression levels, we developed a novel detection method of primitive cells at the DNA level, using patient-specific primers and direct nested PCR in colonies obtained from functional in vitro assays. We believe that this method could be useful in the context of discontinuation trials, given that it is unknown whether the persistent leukemic clone represents LSCs, able to resume the leukemia upon TKI removal. PMID- 29755650 TI - Preclinical comparison of proteasome and ubiquitin E1 enzyme inhibitors in cutaneous squamous cell carcinoma: the identification of mechanisms of differential sensitivity. AB - Proteasome inhibitors have distinct properties and the biochemical consequences of suppressing ubiquitin E1 enzymes and the proteasome differ. We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines. The effects of both a pulse of treatment and more extended incubation were investigated. This is relevant to directly-delivered therapy (topical treatment/intratumoral injection) where the time of exposure can be controlled and a short exposure may better reflect systemically-delivered inhibitor pharmacokinetics. These agents can selectively kill cSCC cells but there are variations in the pattern of cSCC cell line sensitivity/resistance. Variations in the responses to proteasome inhibitors are associated with differences in the specificity of the inhibitors for the three proteolytic activities of the proteasome. There is greater selectivity for killing cSCC cells compared to normal keratinocytes with a pulse of proteasome inhibitor treatment than with a more extended exposure. We provide evidence that c-MYC-dependent NOXA upregulation confers susceptibility to a short incubation with proteasome inhibitors by priming cSCC cells for rapid BAK-dependent death. We observed that bortezomib-resistant cSCC cells can be sensitive to MLN7243-induced death. Low expression of the ubiquitin E1 UBA1/UBE1 participates in conferring susceptibility to MLN7243 by increasing sensitivity to MLN7243-mediated attenuation of ubiquitination. This study supports further investigation of the potential of proteasome and ubiquitin E1 inhibition for cSCC therapy. Direct delivery of inhibitors could facilitate adequate exposure of skin cancers. PMID- 29755652 TI - Correlation of MDR1 gene polymorphism with propofol combined with remifentanil anesthesia in pediatric tonsillectomy. AB - The motive of this study was to investigate the interaction between polymorphisms in the MDR1 gene and anesthetic effects following pediatric tonsillectomy. In total, 240 children undergoing tonsillectomy with preoperative propofol remifentanil anesthesia were selected. Genomic DNA was extracted from the peripheral blood of children after operation, and the MDR1 gene polymorphisms of 2677 G>T/A, 1236 C>T and 3435 C>T were detected by direct sequencing. We tested mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate at several time-points: T0 (5 mins after the repose), T1 (0 min after tracheal intubation), T2 (5 mins after the tracheal intubation), T3 (0 min after the tonsillectomy), T4 (0 min after removal of the mouth-gag) and T5 (5 min after the extubation). The visual analog scale, the face, legs, activity, cry, and consolability pain assessment, and the Ramsay sedation score were recorded after the patients regained consciousness. Adverse reactions were also recorded. The time of induction, respiration recovery, eye-opening, and extubation of children with the CC genotype were found to be shorter compared to the CT + TT genotype of MDR1 1236C > T (all P <.05). The mean arterial pressure, diastolic blood pressure, systolic blood pressure, and heart rate were significantly reduced at T5 in children with the CC genotype (all P <.05). The visual analog scale at 1, 2, 4, and 8 hours post-operation, and the Ramsay sedation score at 5, 10, and 30 min after the extubation were decreased, while the face, legs, activity, cry, and consolability pain assessment score increased (all P <0.05). There was no statistically significant difference in the adverse reaction of MDR1 mutations (P> 0.05). It could be concluded that anesthetic effect following pediatric tonsillectomy in patients with the MDR1 1236C > T CC genotype was stronger than in those carrying the CT + TT genotype. PMID- 29755651 TI - The clinical impact of using complex molecular profiling strategies in routine oncology practice. AB - Molecular profiling and functional assessment of signalling pathways of advanced solid tumours are becoming increasingly available. However, their clinical utility in guiding patients' treatment remains unknown. Here, we assessed whether molecular profiling helps physicians in therapeutic decision making by analysing the molecular profiles of 1057 advanced cancer patient samples after failing at least one standard of care treatment using a combination of next-generation sequencing (NGS), immunohistochemistry (IHC) and other specific tests. The resulting information was interpreted and personalized treatments for each patient were suggested. Our data showed that NGS alone provided the oncologist with useful information in 10-50% of cases (depending on cancer type), whereas the addition of IHC/other tests increased extensively the usefulness of the information provided. Using internet surveys, we investigated how therapy recommendations influenced treatment choice of the oncologist. For patients who were still alive after the provision of the molecular information (76.8%), 60.4% of their oncologists followed report recommendations. Most treatment decisions (93.4%) were made based on the combination of NGS and IHC/other tests, and an approved drug- rather than clinical trial enrolment- was the main treatment choice. Most common reasons given by physicians to explain the non-adherence to recommendations were drug availability and cost, which remain barriers to personalised precision medicine. Finally, we observed that 27% of patients treated with the suggested therapies had an overall survival > 12 months. Our study demonstrates that the combination of NGS and IHC/other tests provides the most useful information in aiding treatment decisions by oncologists in routine clinical practice. PMID- 29755654 TI - MYCN acts as a direct co-regulator of p53 in MYCN amplified neuroblastoma. AB - The MYC oncogenes and p53 have opposing yet interrelated roles in normal development and tumorigenesis. How MYCN expression alters the biology and clinical responsiveness of pediatric neuroblastoma remains poorly defined. Neuroblastoma is p53 wild type at diagnosis and repression of p53 signaling is required for tumorigenesis. Here, we tested the hypothesis that MYCN amplification alters p53 transcriptional activity in neuroblastoma. Interestingly, we found that MYCN directly binds to the tetrameric form of p53 at its C-terminal domain, and this interaction is independent of MYCN/MAX heterodimer formation. Chromatin analysis of MYCN and p53 targets reveals dramatic changes in binding, as well as co-localization of the MYCN-p53 complex at p53-REs and E-boxes of genes critical to DNA damage responses and cell cycle progression. RNA sequencing studies show that MYCN-p53 co-localization significantly modulated the expression of p53 target genes. Furthermore, MYCN-p53 interaction leads to regulation of alternative p53 targets not regulated in the presence of low MYCN levels. These novel targets include a number of genes involved in lipid metabolism, DNA repair, and apoptosis. Taken together, our findings demonstrate a novel oncogenic role of MYCN as a transcriptional co regulator of p53 in high-risk MYCN amplified neuroblastoma. Targeting this novel oncogenic function of MYCN may enhance p53-mediated responses and sensitize MYCN amplified tumors to chemotherapy. PMID- 29755653 TI - TumorNext-Lynch-MMR: a comprehensive next generation sequencing assay for the detection of germline and somatic mutations in genes associated with mismatch repair deficiency and Lynch syndrome. AB - The current algorithm for Lynch syndrome diagnosis is highly complex with multiple steps which can result in an extended time to diagnosis while depleting precious tumor specimens. Here we describe the analytical validation of a custom probe-based NGS tumor panel, TumorNext-Lynch-MMR, which generates a comprehensive genetic profile of both germline and somatic mutations that can accelerate and streamline the time to diagnosis and preserve specimen. TumorNext-Lynch-MMR can detect single nucleotide variants, small insertions and deletions in 39 genes that are frequently mutated in Lynch syndrome and colorectal cancer. Moreover, the panel provides microsatellite instability status and detects loss of heterozygosity in the five Lynch genes; MSH2, MSH6, MLH1, PMS2 and EPCAM. Clinical cases are described that highlight the assays ability to differentiate between somatic and germline mutations, precisely classify variants and resolve discordant cases. PMID- 29755655 TI - Dose-finding study of intensive weekly alternating schedule of docetaxel, 5 fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer. AB - Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. Methods: Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m2/d 1-2, 8-9, 15-16, 22-23, with 100 mg/m2/d increase for dose level; DTX 50 mg/m2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m2 d 8, 22, every 4 weeks. Intra- and inter patients dose-escalation was planned. Results: Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m2/d and 80 mg/m2, respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. Conclusions: First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy. PMID- 29755656 TI - Single-walled and multi-walled carbon nanotubes induce sequence-specific epigenetic alterations in 16 HBE cells. AB - Recent studies have identified carbon nanotube (CNT)-induced epigenetic changes as one of the key players in patho-physiological response. In the present study, we investigated whether CNT exposure is associated with epigenetic changes in human bronchial epithelial cells (16 HBE), in vitro. We focused on global DNA methylation, methylation of LINE-1 elements and promoter sequence of twelve functionally important genes (SKI, DNMT1, HDAC4, NPAT, ATM, BCL2L11, MAP3K10, PIK3R2, MYO1C, TCF3, FGFR 1 and AGRN). Additionally, we studied the influence of CNT exposure on miRNA expression. Using a LC-MS/MS method and pyrosequencing for LINE-1, we observed no significant changes in global DNA methylation (%) between the concentrations of multi-walled and single-walled CNT (MWCNT and SWCNT, respectively). Significant changes in sequence-specific methylation was observed in at least one CpG site for DNMT1 (SWCNT), HDAC4 (MWCNT), NPAT/ATM (MWCNT and SWCNT), MAP3K10 (MWCNT), PIK3R2 (MWCNT and SWCNT) and MYO1C (SWCNT). While changes in DNA methylation of the genes were relatively small, these changes were associated with changes in RNA expression, especially for MWCNT. However, the study did not reveal any significant alteration in the miRNA expression, associated with MWCNT and SWCNT exposure. Based on our results, mainly MWCNT influence DNA methylation and expression of the studied genes and could have significant impact on several critical cellular processes. PMID- 29755657 TI - Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression through JAK-STAT3 signaling pathway in FLS. AB - We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor alpha (IL-6Ralpha), gp130, receptor activator of nuclear factor kappaB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Ralpha; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Ralpha increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Ralpha-gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug. PMID- 29755658 TI - Combined linkage and association analysis of classical Hodgkin lymphoma. AB - The heritability of classical Hodgkin lymphoma (cHL) has yet to be fully deciphered. We report a family with five members diagnosed with nodular sclerosis cHL. Genetic analysis of the family provided evidence of linkage at chromosomes 2q35-37, 3p14-22 and 21q22, with logarithm of odds score >2. We excluded the possibility of common genetic variation influencing cHL risk at regions of linkage, by analysing GWAS data from 2,201 cHL cases and 12,460 controls. Whole exome sequencing of affected family members identified the shared missense mutations p.(Arg76Gln) in FAM107A and p.(Thr220Ala) in SLC26A6 at 3p21 as being predicted to impact on protein function. FAM107A expression was shown to be low or absent in lymphoblastoid cell lines and SLC26A6 expression lower in lymphoblastoid cell lines derived from p.(Thr220Ala) mutation carriers. Expression of FAM107A and SLC26A6 was low or absent in Hodgkin Reed-Sternberg (HRS) cell lines and in HRS cells in Hodgkin lymphoma tissue. No sequence variants were detected in KLHDC8B, a gene previously suggested as a cause of familial cHL linked to 3p21. Our findings provide evidence for candidate gene susceptibility to familial cHL. PMID- 29755659 TI - The clinicopathological significance of monocarboxylate transporters in testicular germ cell tumors. AB - Background: Metabolic reprogramming is one of the hallmarks of cancer. The hyperglycolytic phenotype is often associated with the overexpression of metabolism-associated proteins, such as monocarboxylate transporters (MCTs). MCTs are little explored in germ cell tumors (GCTs), thus, the opportunity to understand the relevance of these metabolic markers and their chaperone CD147 in this type of tumor arises. The main aim of this study was to evaluate the expression of MCT1, MCT2, MCT4 and CD147 in testicular GCT samples and the clinicopathological significance of these metabolism related proteins. Results: MCT1, MCT4 and CD147 were associated with higher stages, higher M and N stages and histological type, while MCT4 was also associated with higher risk stratification, presence of vascular invasion, and lower overall and event free survival. MCT4 silencing in JEG-3 had no significant effect in cell viability, proliferation and death, as well as extracellular levels of glucose and lactate. However, MCT4-silenced cells showed an increase in migration and invasion. Conclusion: The proteins herein studied, with the exception of MCT2, were associated with characteristics of worse prognosis, lower global and event free survival of patients with GCTs. Also, in vitro MCT4 silencing stimulated cell migration and invasion. Materials and Methods: Immunohistochemical expression was evaluated on samples from 149 adult patients with testicular GCT, arranged in Tissue Microarrays (TMAs), and associated with the clinicopathological data. Also, MCT4 silencing studies using siRNA were performed in JEG-3 cells. PMID- 29755660 TI - Measuring glucocorticoid receptor expression in vivo with PET. AB - The glucocorticoid receptor (GR) is an emerging drug target for several common and deadly solid tumors like breast and prostate cancer, and clinical trials studying the antitumor effects of GR antagonists are beginning. Since GR expression can be variable in tumor cells, and virtually all normal mammalian tissues express some GR, we hypothesized that an imaging tool capable of detecting GR positive tumors and/or measuring GR occupancy by drug in tumor and normal tissues could improve the precision application of anti-GR therapies in the clinic. To this end, we developed a fluorine-18 labeled corticosteroid termed GR02 that potently binds the endogenous ligand binding pocket on full length GR. Binding of 18F-GR02 was suppressed in many normal tissues by co-treatment with mifepristone, a GR antagonist in human use, and was elevated in many normal tissues among mice lacking circulating corticosteroids due to adrenalectomy. 18F GR02 also accumulated in GR positive subcutaneous and subrenal capsule prostate cancer models, and uptake in tumors was competed by mifepristone. Combined with a straightforward and high yielding radiosynthesis, these data establish the foundation for near-term clinical translation of 18F-GR02. PMID- 29755661 TI - Identification of copy number alterations in colon cancer from analysis of amplicon-based next generation sequencing data. AB - The objective of this study was to determine the feasibility to detect copy number alterations in colon cancer samples using Next Generation Sequencing data and to elucidate the association between copy number alterations in specific genes and the development of cancer in different colon segments. We report the successful detection of somatic changes in gene copy number in 37 colon cancer patients by analysis of sequencing data through Amplicon CNA Algorithm. Overall, we have found a total of 748 significant copy number alterations in 230 significant genes, of which 143 showed CN losses and 87 showed CN gains. Validation of results was performed on 20 representative genes by quantitative qPCR and/or immunostaining. By this analysis, we have identified 4 genes that were subjected to copy number alterations in tumors arising in all colon segments (defined "common genes") and the presence of copy number alterations in 14 genes that were significantly associated to one specific site (defined "site-associated genes"). Finally, copy number alterations in ASXL1, TSC1 and IL7R turned out to be clinically relevant since the loss of TSC1 and IL7R was associated with advanced stages and/or reduced survival whereas copy number gain of ASXL1 was associated with good prognosis. PMID- 29755662 TI - Hotspot KRAS exon 2 mutations in CD166 positive colorectal cancer and colorectal adenoma cells. AB - Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer deaths worldwide. Recent studies have shown that cancer stem cells (CSCs) are an important cause of tumor recurrence and metastasis. We hypothesized that CSCs marker CD166-positive CRC and colorectal adenoma (CAD) cells consist of more hotspot mutations than CD166-negative CRC and colorectal adenoma cells. To verify this, formalin fixed paraffin embedded tissue specimens from 42 patients each with CRC and CAD were recruited and CD166 immunohistochemical (IHC) staining followed by macrodissection was performed. DNA extracted was used for quantitative polymerase chain reaction detection on a somatic mutation array. Results showed that the immunoreactivity of CD166 protein had significant difference among CRC, CAD, and normal colorectal epithelial tissues (NCET) (P < 0.0001, Kruskal-Wallis test). Moreover, nucleotide changes were found in APC, KRAS, P53, PIK3CA, FBXW7 and SRC genes. Among those genes, KRAS exon 2 mutations were validated in another cohort of 70 CRC and 72 CAD specimens. Results showed that the difference in percentage of KRAS exon 2 mutations between CD166 positive and CD166 negative CRC specimens was significant (P < 0.05, chi-square test). Long term follow-up of the CRC patients showed that CD166-positive KRAS exon 2 mutations was useful in discriminating CRC patients with worse outcome. This study has provided evidence that KRAS exon 2 mutations are concentrated in CD166-positive cancer cells, with prognostic significance in CRC, and those mutations are also detected in CAD. PMID- 29755663 TI - The ongoing challenge of large anal cancers: prospective long term outcomes of intensity-modulated radiation therapy with concurrent chemotherapy. AB - Purpose: Patterns of failure and long term outcomes were prospectively evaluated following tumor factors-stratified radiation dose for anal/perianal cancer. Methods: Between 2008-2013, patients with anal/perianal squamous cell carcinoma were accrued to an institutional REB-approved prospective study. All patients were treated with image-guided intensity-modulated radiation therapy (IG-IMRT). Radiation dose selection (27-36 Gy for elective target, and 45-63 Gy for gross target) was based on tumor clinico-pathologic features. Chemotherapy regimen was 5-fluorouracil/mitomycin-C (weeks 1&5). Local [LF], regional failure [RF], distant metastasis [DM], overall- [OS], disease-free [DFS], colostomy-free survival [CFS] and late toxicity were analyzed. Results: Overall, 101 patients were evaluated; median follow-up: 56.5 months; 49.5% male; 34.7% T3/4-category, and 35.6% N+. Median radiation dose was 63 Gy. The most common acute grade >=3 toxicities were skin (41.6%) and hematological (30.7%). Five-year OS, DFS, CFS, LF, RF, DM rates were 83.4%, 75.7%, 74.7, 13.9%, 4.6% and 5% respectively. Five year LF for patients with T1-2 and T3-4 disease were 0% and 39.2% respectively. All LF (n = 14, after 63 Gy, in tumors >=5 cm) were in the high dose volume except one marginal to the high dose volume. All RF (n = 4) were within elective dose volume except one within the high dose volume. On multivariable analysis, T3/4-category predicted for poor DFS, CFS and OS. The overall late grade >=3 toxicity was 36.2% (mainly anal [20%]). Conclusions: Individualized radiation dose selection using IG-IMRT resulted in good long term outcomes. However, central failures remain a problem for locally advanced tumors even with high dose radiation (63 Gy/7weeks). PMID- 29755664 TI - Identification of core aberrantly expressed microRNAs in serous ovarian carcinoma. AB - MicroRNAs (miRNAs) have recently demonstrated great potential and enormous promise in the diagnosis, prognosis and therapy of various types of cancer. In this study, we performed a comprehensive miRNA expression analysis in the omental metastasis of serous ovarian carcinoma (SOC) using small RNA sequencing. Two hundred and fifty-one aberrantly expressed miRNAs were identified, which clearly separated malignant omentum from normal omentum. Furthermore, miRNA profiles in primary chemo-sensitive and chemo-resistant/refractory SOC were determined using publicly available data. Comparing miRNA expression profiles in omental metastases and primary chemo-sensitive and chemo-resistant/refractory tumors, a set of 70 miRNAs that were aberrantly expressed in both primary and metastatic SOC has been identified for the first time. These core aberrantly expressed miRNAs may play crucial roles in the tumorigenesis, growth, and metastasis of SOC. Therefore, they can serve as potential diagnostic biomarkers and as therapeutic targets for miRNA-mediated therapy. Kaplan-Meier overall survival analysis using The Cancer Genome Atlas data demonstrated that 10 miRNAs (hsa-miR 135, 150, -340, 625, 1908, 3187, -96, -196b, -449c, and -1275) were associated with survival of patients with SOC, which may serve as potential prognostic biomarkers. PMID- 29755665 TI - Increased level and fragmentation of plasma circulating cell-free DNA are diagnostic and prognostic markers for renal cell carcinoma. AB - Background: Reliable biomarkers for renal cell carcinoma (RCC) have yet to be found. Circulating cell-free DNA (cfDNA) is an emerging resource for the diagnosis and prognosis of various cancers. This study aims to identify novel blood biomarkers for RCC. Materials And Methods: Plasma cfDNA was extracted from RCC patients (n = 92) and healthy controls (n = 41). Levels of cfDNA were determined using quantitative real-time PCR of ACTB as the target gene, and cfDNA fragment size was measured using a microfluidics-based platform. Diagnostic potential was assessed using receiver operating characteristic (ROC) and logistic regression analysis, and prognostic potential was evaluated using log-rank test. Results: Median levels of cfDNA from RCC patients were significantly higher than those from healthy controls (3803 vs 2242 copies/ml, p < 0.001). Median fragment sizes of cfDNA in RCC patients were shorter than those in healthy controls (170 vs 171 bp, p = 0.052). To evaluate level of cfDNA as a diagnostic tool for RCC, ROC curve analysis revealed a sensitivity of 63.0% and a specificity of 78.1%. Multivariate analysis indicated that age, gender and the level of cfDNA were significantly associated with the presence of RCC (p < 0.001, p = 0.013, p < 0.001, respectively). Additionally, shorter cfDNA fragment size was negatively associated with progression-free survival (p = 0.006). Conclusions: Our study demonstrates the diagnostic and prognostic potential of plasma cfDNA as a biomarker for RCC. PMID- 29755666 TI - Impact of lenalidomide maintenance on the immune environment of multiple myeloma patients with low tumor burden after autologous stem cell transplantation. AB - Lenalidomide is a potent anti-myeloma drug with immunomodulatory properties. It is increasingly used in a low-dose maintenance setting to prolong remission duration after standard treatment. Data on the in vivo effects of lenalidomide are scarce and sometimes different from the well-described in vitro effects. We therefore evaluated the numerical, phenotypical and functional impact of lenalidomide maintenance on several immune cell types in a cohort of seventeen homogeneously treated myeloma patients achieving a low residual myeloma burden after a bortezomib based-induction followed by autologous stem cell transplantation. Lenalidomide maintenance: 1) increased the fraction of naive CD8+ T cells and several memory T-cell subsets, 2) reduced the numbers of terminal effector CD8+ T cells, 3) resulted in a higher expression of co stimulatory molecules on resting T cells and of the inhibitory checkpoint molecules LAG-3 on CD4+ T cells and TIM-3 on CD4+ and CD8+ T cells, 4) reduced the number of TIGIT+ CD8+ T cells, 5) increased the number of regulatory T cells with a phenotype associated with strong suppressive capacity. Purified CD8+ T cells showed increased and more polyfunctional recall viral responses. However, PBMC responses were not enhanced during lenalidomide maintenance and CD4+ T-cell responses specific for the myeloma-associated antigen MAGE-C1 even tended to become lower. We conclude that lenalidomide maintenance after autologous stem cell transplantation has complex pleotropic effects on the immune environment. Immune interventions such as anti-myeloma vaccination should include measures to tackle an expanded inhibitory Treg compartment. PMID- 29755667 TI - A set of cancer stem cell homing peptides associating with the glycan moieties of glycosphingolipids. AB - Cancer stem cells (CSCs) are currently believed to be involved in tumor metastasis and relapse. And treatments against CSCs are well concerned issues. Peptides targeting to mouse and human CSCs were screened from an M13 phage display library. The first subset of cancer stem cell homing peptides (CSC HPs), CSC HP-1 to -12, were screened with mouse EMT6 breast cancer stem cells. Among them, CSC HP-1, CSC HP-3, CSC HP-8, CSC HP-9, and CSC HP-10 can bind to mouse CT26 colon CSCs; CSC HP-1, CSC HP-2, CSC HP-3, and CSC HP-8 can bind to mouse Hepa1-6 liver CSCs; as well as CSC HP-1, CSC HP-2, CSC HP-3, CSC HP-8, CSC HP-9, CSC HP-10, and CSC HP-11 can bind to human PANC-1 pancreatic CSCs. The second subset of cancer stem cell homing peptides, CSC HP-hP1 to -hP3, were screened with human PANC-1 pancreatic CSCs. Both CSC HP-hP1 and CSC HP-hP2 were demonstrated able to bind mouse EMT6, CT26 and Hepa1-6 CSCs as well as human colorectal HT29 and lung H1650 CSCs. CSC HP-1 and CSC HP-hP1 could strongly associate with the Globo 4 and Lewis Y glycan epitopes coupled on a microarray chip or Globo 4 and Globo H conjugated on bovine serum albumin. CSC HP-10, CSC HP 11 and CSC HP-hP2 could associate with the disialylated saccharide Neu5Ac-alpha 2,6-Gal-beta-1,3-(Neu5Ac-alpha-2,6)-GalNAc coupled on a microarray chip. These results indicate that the CSC HPs may target to the known stem cell glycan markers GbH and Lewis Y as well as the disialylated saccharide. PMID- 29755668 TI - Mutant p53 tunes the NRF2-dependent antioxidant response to support survival of cancer cells. AB - NRF2 (NFE2L2) is one of the main regulators of the antioxidant response of the cell. Here we show that in cancer cells NRF2 targets are selectively upregulated or repressed through a mutant p53-dependent mechanism. Mechanistically, mutant p53 interacts with NRF2, increases its nuclear presence and resides with NRF2 on selected ARE containing gene promoters activating the transcription of a specific set of genes while leading to the transcriptional repression of others. We show that thioredoxin (TXN) is a mutant p53-activated NRF2 target with pro-survival and pro-migratory functions in breast cancer cells under oxidative stress, while heme oxygenase 1 (HMOX1) is a mutant p53-repressed target displaying opposite effects. A gene signature of NRF2 targets activated by mutant p53 shows a significant association with bad overall prognosis and with mutant p53 status in breast cancer patients. Concomitant inhibition of thioredoxin system with Auranofin and of mutant p53 with APR-246 synergizes in killing cancer cells expressing p53 gain-of-function mutants. PMID- 29755669 TI - A stitch in time saves nine: external quality assessment rounds demonstrate improved quality of biomarker analysis in lung cancer. AB - Biomarker analysis has become routine practice in the treatment of non-small cell lung cancer (NSCLC). To ensure high quality testing, participation to external quality assessment (EQA) schemes is essential. This article provides a longitudinal overview of the EQA performance for EGFR, ALK, and ROS1 analyses in NSCLC between 2012 and 2015. The four scheme years were organized by the European Society of Pathology according to the ISO 17043 standard. Participants were asked to analyze the provided tissue using their routine procedures. Analysis scores improved for individual laboratories upon participation to more EQA schemes, except for ROS1 immunohistochemistry (IHC). For EGFR analysis, scheme error rates were 18.8%, 14.1% and 7.5% in 2013, 2014 and 2015 respectively. For ALK testing, error rates decreased between 2012 and 2015 by 5.2%, 3.2% and 11.8% for the fluorescence in situ hybridization (FISH), FISH digital, and IHC subschemes, respectively. In contrast, for ROS1 error rates increased between 2014 and 2015 for FISH and IHC by 3.2% and 9.3%. Technical failures decreased over the years for all three markers. Results show that EQA contributes to an ameliorated performance for most predictive biomarkers in NSCLC. Room for improvement is still present, especially for ROS1 analysis. PMID- 29755670 TI - Systemic inflammatory status predict the outcome of k-RAS WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope peptide anticancer vaccine. AB - TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56dimCD16brightNKs (p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS (p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value (p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients. PMID- 29755671 TI - Should reporting of peri-neural invasion and extra prostatic extension be mandatory in prostate cancer biopsies? correlation with outcome in biopsy cases treated conservatively. AB - The identification of perineural invasion (PNI) and extraprostatic extension (ECE) in prostate cancer (PC) biopsies is time consuming and can be difficult. Although this is required information in many datasets, there is little evidence on their effect on outcome in patients treated conservatively. Cases of PC were identified from three cancer registries in the UK from men with clinically localized prostate cancer diagnosed by needle biopsy from 1990-2003. The endpoint was prostate cancer death (DOD). Patients treated radically within 6 months, those with objective evidence of metastases or who had prior hormone therapy were excluded. Follow-up was through cancer registries up until 2012. Deaths were divided into those from PC and those from other causes, according to WHO criteria. 988 biopsy cases (6522 biopsy cores) were centrally reviewed by three uropathologists and assigned a Gleason score and Grade Group (GG). The presence of both PNI and ECE was recorded. Of 988 patients, PNI was present in 288 (DOD = 75) and ECE in 23 (DOD = 5). On univariable analysis PNI was highly significantly associated with DOD (hazard ratio [HR] 2.28, 95% CI: 1.68, 3.1, log-rank test p value = 4.8 * 10-8), but ECE was not (log-rank test p-value = 0.334). On multivariable analysis with GG, serum PSA (per 10%), clinical stage and extent of disease (per 10%), PNI lost significance (HR 1.16, 95% CI: 0.83, 1.63, likelihood ratio test p-value = 0.371). The utility of routinely examining prostate biopsies for ECE and PNI is doubtful as it is not independently associated with higher grade, stage or prognosis. PMID- 29755672 TI - Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma. AB - The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Matrigel(r), and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic Membrane (CAM) and Matrigel(r) plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients. PMID- 29755673 TI - Role of epigenetic factors in the selection of the alternative splicing isoforms of human KRAS in colorectal cancer cell lines. AB - Mutation-driven activation of KRAS is crucial to cancer development. The human gene yields four mRNA splicing isoforms, 4A and 4B being translated to protein. Their different properties and oncogenic potential have been studied, but the mechanisms deciding the ratio 4A/4B are not known. To address this issue, the expression of the four KRAS isoforms was determined in 9 human colorectal cancer cell lines. HCT116 and SW48 were further selected because they present the highest difference in the ratio 4A/4B (twice as much in HCT116 than in SW48). Chromatin structure was analysed at the exon 4A, characteristic of isoform 4A, at its intronic borders and at the two flanking exons. The low nucleosome occupancy at exon 4A in both cell lines may result in a fast transcriptional rate, which would explain the general lower abundance of isoform 4A, also found in cells and tissues by other authors, but due to its similarity between both cell lines, chromatin structure does not influence alternative splicing. DNA methylation downstream exon 4A significantly differs in HCT116 and SW48 cells, but the CCCTC binding factor, which affects the processivity of RNA polymerase and the alternative splicing, does not bind the differentially methylated sequences. Quantitative epigenetic analysis at mononucleosomal level revealed significant differences between both cell lines in H3K4me3, H3K27me3, H3K36me3, H3K9ac, H3K27ac and H4K20me1, and the inhibition of some histone-modifying enzymes alters the ratio 4A/4B. It can be concluded that the epigenetic modification of histones has an influence on the selection of isoforms 4A and 4B. PMID- 29755674 TI - Infusion of bone marrow derived multipotent mesenchymal stromal cells for the treatment of steroid-refractory acute graft-versus-host disease: a multicenter prospective study. AB - The prognosis of steroid-refractory acute graft-versus-host disease (aGVHD) remains poor and better treatments are urgently needed. Multipotent mesenchymal stromal cell (MSC)-based therapy emerged as a promising approach but response rates were highly variable across studies. We conducted a multicenter prospective study assessing the efficacy of 1-2 infusion(s) of cryopreserved, third-party donor bone marrow-derived MSCs for treating grade II-IV steroid-refractory or dependent aGVHD in a series of 33 patients. MSCs were produced centrally and distributed to 8 hospitals throughout Belgium to be infused in 2 consecutive cohorts of patients receiving 1-2 or 3-4 * 106 MSCs/kg per dose, respectively. All patients received MSCs as the first rescue therapy after corticosteroids, with the exception for one patient who received prior treatment with mycophenolate mofetil (that was still ongoing by the time of MSC therapy). In these conditions, MSC therapy resulted in at least a partial response in 13 patients (40.6%) at day 30 and in 15 patients (46%) within 90 days after first MSC infusion. The corresponding complete response rates were 21.6% (7 patients) and 30% (10 patients), respectively. Only 5 patients achieved a sustained complete response, lasting for at least 1 month. The 1-year overall survival was 18.2% (95% CI: 8.82-37.5%). Higher response and survival rates were observed among patients receiving 3-4 * 106 MSCs/kg for first infusion, as compared with patients receiving 1-2 * 106 MSCs/ kg. Response and survival with MSC therapy for SR/SD-aGVHD remains to be optimized. PMID- 29755675 TI - High incidence of other primary malignancies in patients with synchronous multiple gastric cancers "a multi-center retrospective cohort study". AB - This study evaluated the relationship between synchronous multiple gastric cancer and other primary malignancies. During 2002-2013, 1094 consecutive surgically treated gastric cancer patients were enrolled. Preoperatively, we performed total colonoscopy and whole-body computed tomography. When malignancies in other organs were suspected, detailed organ-specific examinations were performed. Synchronous multiple gastric cancer occurred in 102 patients (9.3%)which was frequently observed in patients with preoperative other primary malignancies (p < 0.001). Preoperative other primary malignancy was an independent risk factor for synchronous multiple gastric cancer (p = 0.001; hazard ratio: 2.145, 95% confidence interval: 1.354-3.399) and an independent prognostic factor of overall survival in patients undergoing gastrectomy with curative intent (p = 0.021; hazard ratio: 1.481, 95% confidence interval: 1.060-2.070). Thus, patients with preoperative other primary malignancies have a high risk of synchronous multiple gastric cancer. Careful preoperative examination is recommended to improve survival. PMID- 29755677 TI - Sex-specific differences in the occurrence of Fusobacterium nucleatum subspecies and Fusobacterium periodonticum in the oral cavity. AB - The periodontitis-associated species Fusobacterium nucleatum (FN) has been implicated in several extra-oral diseases, including preterm birth and colorectal cancer. Due to its genetic and phenotypic heterogeneity, FN is classified in four subspecies which may differ in their disease potential. Here we compared the prevalence of FN subspecies and the close relative F. periodonticum (FP) via 16S rRNA gene analysis in saliva from 100 healthy individuals (60 females, and 40 males) from eleven countries spanning five continents. By focusing on the most abundant sequence types (i.e. analysis of approximately ten clone sequences each) the average number of FN/FP subspecies per individual differed significantly between females and males, i.e. 2.93 versus 2.5, respectively (P = 0.043). FN subsp. fusiforme/vincentii was significantly more prevalent in females vs males, with 2.85 vs. 1.68 sequence reads per individual, respectively (P = 0.012). A significant age-related difference was observed in females but not in males, i.e. 2.6 subspecies on average in females <= 30 years vs. 3.2 in females > 30 (P = 0.0076). Given the link between FN and systemic disorders our findings highlight the need for microbial studies at the subspecies level to further characterize the role of periodontal pathogens in diseases that affect females and males differently, e.g. colorectal cancer. PMID- 29755676 TI - Genetic heterogeneity and actionable mutations in HER2-positive primary breast cancers and their brain metastases. AB - Brain metastases constitute a challenge in the management of patients with HER2 positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes FGFR2, PIK3CA and ATR, homozygous deletion in CDKN2A and amplification in KRAS. Shifts in clonal composition and the acquisition of additional mutations in the progression from primary HER2-positive breast cancer to brain metastases following anti-HER2 therapy were investigated in additional five patients. Likely pathogenic mutations private to or enriched in the brain lesions affected cancer and clinically actionable genes, including ATR, BRAF, FGFR2, MAP2K4, PIK3CA, RAF1 and TP53. Changes in clonal composition and the acquisition of additional mutations in brain metastases may affect potentially actionable genes in HER2-positive breast cancers. Our observations have potential clinical implications, given that treatment decisions for patients with brain metastatic disease are still mainly based on biomarkers assessed in the primary tumor. PMID- 29755678 TI - Functional invadopodia formed in glioblastoma stem cells are important regulators of tumor angiogenesis. AB - Glioblastoma (GBM) represents the most common and lethal brain tumor. High vascularization, necrosis and invasiveness are hallmarks of GBM aggressiveness with recent data suggesting the important role of glioblastoma stem cells (GSCs) in these processes. It is now well established that cancer cells employ specialized structures termed invadosomes to potentiate invasion. However, the role of these structures in GBM dissemination remains poorly investigated. In this study, we showed that GBM-isolated GSCs form invadopodia-like protrusions endowed with degradative action. Interestingly, their formation depends on extracellular matrix (ECM) sensing via the CD44 receptor. We also found that GSCs invasive migration occurring during tubes assembly is promoted through invadopodia-mediated-ECM remodeling and LIM kinases signaling. Moreover, our study demonstrates that GSCs are highly adaptable cells that are able not only to restore damaged endothelial-derived tubes but also to generate in cooperation with normal endothelial cells (ECs) intact vascular channels. Taken together, our data provide new insights in GBM microvasculature and suggest that GSCs targeting in combination with anti-VEGF therapy may block tumor progression. PMID- 29755679 TI - microRNA profiles in urine by next-generation sequencing can stratify bladder cancer subtypes. AB - Bladder cancer (BC) is the most frequent malignancy of the urinary tract with a high incidence in men and smokers. Currently, there are no non-invasive markers useful for BC diagnosis and subtypes classification that could overcome invasive procedures such as cystoscopy. Dysregulated miRNA profiles have been associated with numerous cancers, including BC. Cell-free miRNAs are abundantly present in a variety of biofluids including urine and make them promising candidates in cancer biomarker discovery. In the present study, the identification of miRNA fingerprints associated with different BC status was performed by next-generation sequencing on urine samples from 66 BC and 48 controls. Three signatures based on dysregulated miRNAs have been identified by regression models, assessing the power to discriminate different BC subtypes. Altered miRNAs according to invasiveness and grade were validated by qPCR on 112 cases and 65 controls (among which 46 cases and 16 controls were an independent group of subjects while the rest were replica samples). The area under the curve (AUC) computed including three miRNAs (miR-30a-5p, let-7c-5p and miR-486-5p) altered in all BC subtypes showed a significantly increased accuracy in the discrimination of cases and controls (AUC model = 0.70; p-value = 0.01). In conclusions, the non-invasive detection in urine of a selected number of miRNAs altered in different BC subtypes could lead to an accurate early diagnosis of cancer and stratification of patients. PMID- 29755680 TI - COP9 signalosome subunit 5 regulates cancer metastasis by deubiquitinating SNAIL. AB - Cancer metastasis is a major cause of mortality in cancer patients. The transcription factor SNAIL plays an important role in cancer metastasis and progression, and its expression is tightly regulated by the ubiquitin-proteasome system through the balance between ubiquitin ligases and deubiquitinating enzymes. While several ubiquitin ligases of SNAIL have been identified, it is not yet clear regarding deubiquitinating enzyme. In this study, we identified COP9 signalosome subunit 5 (COPS5) as a deubiquitinating enzyme of SNAIL by using siRNA library screening. COPS5 downregulation significantly reduced the expression of SNAIL and impaired the metastatic potential of lung cancer cells both in vitro and in vivo. Importantly, we demonstrated that COPS5 binds to SNAIL and stabilizes its expression by deubiquitination. Furthermore, we observed the positive correlation between COPS5 and SNAIL expression in the clinical tissue samples of lung adenocarcinomas by using tissue microarray analysis. These findings provide strong evidence that COPS5 can be a new therapeutic target for cancer metastasis as a deubiquitinating enzyme of SNAIL. PMID- 29755682 TI - Evaluation of the impact of S-adenosylmethionine-dependent methyltransferase inhibitor, 3-deazaneplanocin A, on tissue injury and cognitive function in mice. AB - Cancer patients display cognitive impairment due, at least partly, to the treatments. Additionally, chemotherapeutic treatments can lead to organ injury, limiting their use, and are likely to have negative impacts on patients' quality of life. The aim of this study was to investigate the toxicity of 3 Deazaneplanocin A (DZNep) on several tissues and organs, as well as on cognitive functions. DZNep is an inhibitor of S-adenosylmethionine-dependent methyltransferase (in particular of the histone methyltransferase EZH2) which showed antitumoral functions in preclinical trials but whose effects on behavior and on organs (side effects) are not known. Chronic injections of DZNep were performed intraperitoneally in male NMRI mice (2 mg/kg; i.p.; three times per week) during 8 weeks. A follow-up of body weight was assessed during all experiments. Histological analysis were performed on several organs. EZH2 expression and H3K27me3 were assayed by western-blot. Several behavioral tests were performed during treatment and 2 weeks after. A particular focus was made on spontaneous locomotor activity, cognitive functions (spontaneous alternation and recognition memory), and anxiety- and depression-related behavior. Hematological modifications were also assessed. Chronic DZNep treatment transiently reduced animal growth. It had no effect on most organs but provoked a reversible splenomegaly, and persistent testis reduction and erythropoiesis. DZNep administration did not alter animal behavior. In conclusion, this study is encouraging for the use of DZNep for cancer treatment. Indeed, it has no effect on animal behavior, conferring an advantageous safety, and induces irreversible side effects limited on testis which are unfortunately found in most chemotherapy treatments. PMID- 29755681 TI - Dendritic cell activation enhances anti-PD-1 mediated immunotherapy against glioblastoma. AB - Introduction: The glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade. Results: We show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response. Conclusions: This study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB. Methods: Using a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD 1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed. PMID- 29755683 TI - Increased mucosal expression of miR-215 precedes the development of neoplasia in patients with long-standing ulcerative colitis. AB - Identification of biological markers predicting the onset of neoplasia in patients with long-standing ulcerative colitis (UC) could allow for risk stratification in this population. In this study, we retrospectively identified subjects with chronic UC who developed colon neoplasia (n = 16) matched to UC patients who never developed neoplasia. RNA was extracted from archived colonic biopsies obtained at an interval of 1-2 years prior and 3-5 years prior to the onset of neoplasia. miRNA expression was assessed using Nanostring arrays in 12 subjects, and significantly up-regulated miRNAs were evaluated by real time pcr in the entire cohort of patients. Expression of miR-215 was also assessed in UC associated colon cancers and compared to p53 expression. By array analysis, there were 17 significantly down-regulated and 7 significantly up-regulated miRNAs in subjects who later developed neoplasia. miR-215 was significantly up-regulated both 1-2 years prior to the onset of neoplasia (3.5-fold, p < 0.001) and 3-5 years prior to the onset of neoplasia (5.4-fold, p = 0.007). miR-215 expression was also increased in UC-associated colon cancers (5.3-fold, p = 0.03) and adjacent non-dysplastic UC tissue (6.2-fold, p = 0.02). p53 was expressed in 20% of patients prior to the onset of neoplasia and in 67% of UC-associated colon cancers, although was not correlated with miR-215 expression. Our data demonstrates that expression of miR-215 can discriminate patients who progressed to neoplasia from non-progressors as early as 5 years prior to the diagnosis of neoplasia, supporting that this and perhaps other miRNAs could serve as predictive biomarkers to risk stratify patients with chronic UC. PMID- 29755684 TI - Large deletion at the CDC73 gene locus and search for predictive markers of the presence of a CDC73 genetic lesion. AB - The Hyperparathyroidism with Jaw-Tumours syndrome is caused by mutations of the CDC73 gene: it has been suggested that early onset of the disease and high Ca2+ levels may predict the presence of a CDC73 mutation. We searched for large deletions at the CDC73 locus in patients with: HPT-JT (nr 2), atypical adenoma (nr 7) or sporadic parathyroid carcinoma (nr 11) with a specific MLPA and qRT-PCR assays applied on DNA extracted from whole blood. A Medline search in database for all the papers reporting a CDC73 gene mutation, clinical/histological diagnosis, age at onset, Ca2+, PTH levels for familial/sporadic cases was conducted with the aim to possibly identify biochemical/clinical markers predictive, in first diagnosis, of the presence of a CDC73 gene mutation. A novel genomic deletion of the first 10 exons of the CDC73 gene was found in a 3 generation HPT-JT family, confirmed by SNP array analysis. A classification tree built on the published data, showed the highest probability of having a CDC73 mutation in subjects with age at the onset < 41.5 years (44/47 subjects, 93.6%, had the mutation). Whereas the lowest probability was found in subjects with age at the onset >= 41.5 years and Ca2+ levels <13.96 mg/dL (7/20 subjects, 35.0%, had the mutation, odds ratio = 27.1, p < 0.001). We report a novel large genomic CDC73 gene deletion identified in an Italian HPT-JT family. Age at onset < 41.5 ys and Ca2+ > 13.96 mg/dL are predictive for the presence of a CDC73 genetic lesion. PMID- 29755685 TI - Selected PET radiomic features remain the same. AB - Purpose: We investigated whether PET radiomic features are affected by differences in the scanner, scan protocol, and lesion location using 18F-FDG PET/CT and PET/MR scans. Results: SUV, TMR, skewness, kurtosis, entropy, and homogeneity strongly correlated between PET/CT and PET/MR images. SUVs were significantly higher on PET/MR0-2 min and PET/MR0-10 min than on PET/CT in gynecological cancer (p = 0.008 and 0.008, respectively), whereas no significant difference was observed between PET/CT, PET/MR0-2 min, and PET/MR0-10 min images in oral cavity/oropharyngeal cancer. TMRs on PET/CT, PET/MR0-2 min, and PET/MR0 10 min increased in this order in gynecological cancer and oral cavity/oropharyngeal cancer. In contrast to conventional and histogram indices, 4 textural features (entropy, homogeneity, SRE, and LRE) were not significantly different between PET/CT, PET/MR0-2 min, and PET/MR0-10 min images. Conclusions: 18F-FDG PET radiomic features strongly correlated between PET/CT and PET/MR images. Dixon-based attenuation correction on PET/MR images underestimated tumor tracer uptake more significantly in oral cavity/oropharyngeal cancer than in gynecological cancer. 18F-FDG PET textural features were affected less by differences in the scanner and scan protocol than conventional and histogram features, possibly due to the resampling process using a medium bin width. Methods: Eight patients with gynecological cancer and 7 with oral cavity/oropharyngeal cancer underwent a whole-body 18F-FDG PET/CT scan and regional PET/MR scan in one day. PET/MR scans were performed for 10 minutes in the list mode, and PET/CT and 0-2 min and 0-10 min PET/MR images were reconstructed. The standardized uptake value (SUV), tumor-to-muscle SUV ratio (TMR), skewness, kurtosis, entropy, homogeneity, short-run emphasis (SRE), and long-run emphasis (LRE) were compared between PET/CT, PET/MR0-2 min, and PET/MR0 10 min images. PMID- 29755686 TI - Transcriptome based individualized therapy of refractory pediatric sarcomas: feasibility, tolerability and efficacy. AB - Survival rates of pediatric sarcoma patients stagnated during the last two decades, especially in adolescents and young adults (AYAs). Targeted therapies offer new options in refractory cases. Gene expression profiling provides a robust method to characterize the transcriptome of each patient's tumor and guide the choice of therapy. Twenty patients with refractory pediatric sarcomas (age 8 35 years) were assessed with array profiling: ten had Ewing sarcoma, five osteosarcoma, and five soft tissue sarcoma. Overexpressed genes and deregulated pathways were identified as actionable targets and an individualized combination of targeted therapies was recommended. Disease status, survival, adverse events (AEs), and quality of life (QOL) were assessed in patients receiving targeted therapy (TT) and compared to patients without targeted therapy (non TT). Actionable targets were identified in all analyzed biopsies. Targeted therapy was administered in nine patients, while eleven received no targeted therapy. No significant difference in risk factors between these two groups was detected. Overall survival (OS) and progression free survival (PFS) were significantly higher in the TT group (OS: P=0.0014, PFS: P=0.0011). Median OS was 8.83 versus 4.93 months and median PFS was 6.17 versus 1.6 months in TT versus non TT group, respectively. QOL did not differ at baseline as well as at four week intervals between the two groups. TT patients had less grade 1 AEs (P=0.009). The frequency of grade 2-4 AEs did not differ. Overall, expression based targeted therapy is a feasible and likely beneficial approach in patients with refractory pediatric sarcomas that warrants further study. PMID- 29755687 TI - Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience. AB - International guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-EGFR agents for metastatic colorectal cancer (CRC) patients. Daily, new data emerges on the theranostic and prognostic role of molecular biomarkers; this is a strong incentive for a validated, sensitive, and broadly available molecular screening test. Next-generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. We report here our 2 years of clinical practice using NGS results to guide therapeutic decisions. The Ion Torrent AmpliSeq colon/lung cancer panel, which allows mutation detection in 22 cancer related genes, was prospectively used in clinical practice (BELAC ISO 15189 accredited method). The DNA of 741 formalin-fixed paraffin-embedded CRC tissues, including primary tumors and metastasis, was obtained from 14 different Belgian institutions and subjected to targeted NGS. Of the tumors tested, 98% (727) were successfully sequenced and 89% (650) harbored at least one mutation. KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively. These mutation frequencies were consistent with those reported in public databases. Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%). The median turnaround time between reception of the sample in the laboratory and report release was 8 calendar days. Overall, the AmpliSeq colon/lung cancer panel was successfully applied in daily practice and provided reliable clinically relevant information for CRC patients. PMID- 29755688 TI - Four immunohistochemical assays to measure the PD-L1 expression in malignant pleural mesothelioma. AB - Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway are expected to be a novel therapy for combating future increases in numbers of malignant pleural mesothelioma (MPM) patients. However, the PD-L1 expression, which is a predictor of the response to ICIs, is unclear in MPM. We studied the PD-L1 expression using four immunohistochemical assays (SP142, SP263, 28-8 and 22C3) in 32 MPM patients. The PD-L1 expression in tumor cells and immune cells was evaluated to clarify the rate of PD-L1 expression and the concordance among the four assays in MPM. The positivity rate of PD-L1 expression was 53.1% for SP142, 28.1% for SP263, 53.1% for 28-8, and 56.3% for 22C3. Nine cases were positive and 10 were negative for all assays. Discordance among the four assays was found in 13 cases. The concordance rates between SP142 and 22C3 and between 28-8 and 22C3 were the highest (84.4%). The concordance rates between SP263 and the other three assays were low (71.9% to 75.0%). The PD-L1 expression in MPM was almost equivalent for three of the assays. Given the cut-off values set in our study, these findings suggested that these assays, except for SP263, can be used for accurate PD-L1 immunostaining in MPM. PMID- 29755689 TI - A subgroup of pleural mesothelioma expresses ALK protein and may be targetable by combined rapamycin and crizotinib therapy. AB - Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. Targeting aberrantly overexpressed kinases to cure MPM is a promising therapeutic strategy. Here, we examined ALK, MET and mTOR as potential therapeutic targets and determined the combinatorial efficacy of ALK and mTOR targeting on tumor cell growth in vivo. First, ALK overexpression, rearrangement and mutation were studied in primary MPM by qRT PCR, FISH, immunohistochemistry and sequence analysis; mTOR and MET expression by qRT-PCR and immunohistochemistry. Overexpression of full-length ALK transcripts was observed in 25 (19.5%) of 128 primary MPM, of which ten expressed ALK protein. ALK overexpression was not associated with gene rearrangement, amplification or kinase-domain mutation. mTOR protein was detected in 28.7% MPM, co-expressed with ALK or MET in 5% and 15% MPM, respectively. The ALK/MET inhibitor crizotinib enhanced the anti-tumor effect of the mTOR-inhibitor rapamycin in a patient-derived MPM xenograft with co-activated ALK/mTOR: combined therapy achieved tumor shrinkage in 4/5 tumors and growth stagnation in one tumor. Treatment effects on proliferation, apoptosis, autophagy and pathway signaling were assessed using Ki-67 immunohistochemistry, TUNEL assay, LC3B immunofluorescence, and immunoblotting. Co-treatment significantly suppressed cell proliferation and induced autophagy and caspase-independent, necrotic cell death. Rapamycin/crizotinib simultaneously inhibited mTORC1 (evidenced by S6 kinase and RPS6 dephosphorylation) and ALK signaling (ALK, AKT, STAT3 dephosphorylation), and crizotinib suppressed the adverse AKT activation induced by rapamycin. In conclusion, co-treatment with rapamycin and crizotinib is effective in suppressing MPM tumor growth and should be further explored as a therapeutic alternative in mesothelioma. PMID- 29755690 TI - Prognostic value of LINE-1 methylation level in 321 patients with primary liver cancer including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. AB - Background: The methylation level of long interspersed nucleotide element-1 (LINE 1) is a good surrogate marker of the global DNA methylation level. The relationship between LINE-1 methylation level and prognosis in primary liver cancer (PLC) patients remains unclear. Results: LINE-1 methylation levels were significantly lower in HCC and cHCC-CC tissues, but not in ICC tissues, than those in noncancerous liver parenchyma (HCC: p < 0.0001; cHCC-CC: p < 0.001; and ICC: p = 0.053). HCC cases with hypomethylated LINE-1 had significantly shorter relapse-free survival (RFS) (log-rank, p = 0.008); however, this was not observed for the cHCC-CC or ICC cases. Multivariate Cox regression analysis revealed a significantly higher HCC recurrence rate in the group with hypomethylated LINE-1 (hazard ratio, 1.62; 95% confidence interval, 1.06-2.58; p = 0.025). Conclusions: The genome-wide DNA hypomethylation status estimated via LINE-1 methylation levels might be indicative of poor RFS in patients with HCC but not ICC or cHCC CC. Methods: We evaluated the level of LINE-1 methylation in 321 cases of curatively resected PLC {231 hepatocellular carcinoma (HCC), 19 combined hepatocellular and cholangiocarcinoma (cHCC-CC) and 71 intrahepatic cholangiocarcinoma (ICC)} via pyrosequencing of formalin-fixed paraffin-embedded (FFPE) tissues and examined its prognostic value. PMID- 29755691 TI - Coffee consumption is not associated with ovarian cancer risk: a dose-response meta-analysis of prospective cohort studies. AB - Background: Coffee consumption has been associated with numerous cancers, but evidence on ovarian cancer risk is controversial. Therefore, we performed a meta analysis on prospective cohort studies in order to review the evidence on coffee consumption and risk of ovarian cancer. Methods: Studies were identified through searching the PubMed and MEDLINE databases up to March 2017. Risk estimates were retrieved from the studies, and dose-response analysis was modelled by using restricted cubic splines. Additionally, a stratified analysis by menopausal status was performed. Results: A total of 8 studies were eligible for the dose response meta-analysis. Studies included in the analysis comprised 787,076 participants and 3,541 ovarian cancer cases. The results showed that coffee intake was not associated with ovarian cancer risk (RR = 1.06, 95% CI: 0.89, 1.26). Stratified and subgroup analysis showed consisted results. Conclusions: This comprehensive meta-analysis did not find evidence of an association between the consumption of coffee and risk of ovarian cancer. PMID- 29755692 TI - Defunctioning ileostomy reduces leakage rate in rectal cancer surgery - systematic review and meta-analysis. AB - Objectives: The role of a defunctioning ileostomy in every anterior rectal resection with total mesorectal excision (TME) is still controversial. In this study, we aimed to review the current literature to determine the impact of ileostomy creation on postoperative outcomes in patients undergoing anterior rectal resection with TME. Methods: MEDLINE, Embase and Cochrane Library were searched for eligible studies. We analyzed data up to October 2017. Eligible studies had to compare patients with vs. without a defunctioning ileostomy in rectal cancer surgery and comprise data on anastomotic leakage in both groups. The primary outcome was anastomotic leakage. Secondary outcomes included the complication rate, mortality, reoperation rate, length of hospital stay and 30 day readmission. Results: Initial search yielded 1,966 articles. Thorough evaluation resulted in 13 eligible articles which were analyzed. Leakage rate (RR = 0.43, 95% CI 0.28-0.67) and the number of reoperations (RR = 0.62, 95% CI 0.40 0.94) were significantly lower in the defunctioning stoma group. Morbidity was significantly higher in the stoma group (RR = 1.32, 95% CI 1.05-1.65). Analysis of mortality, length of hospital stay and readmission rate did not show any significant differences. Conclusion: A defunctioning ileostomy may decrease the anastomotic leakage rate, additionally significantly reducing the risk of reoperations but it may also increase the overall complication rate. The presence of the protective stoma has no effect on mortality, length of hospital stay and readmission rate. PMID- 29755693 TI - Exosomes in melanoma: a role in tumor progression, metastasis and impaired immune system activity. AB - Exosomes (Exo) are small vesicles produced by melanoma cells and the accessory cells of the tumor microenvironment. They emerge via both classical and direct pathways and actively participate in tumor colonisation of distant tissues. The proteins, nucleic acids, cytokines and growth factors engulfed by Exo are transferred to recipient cells, where they drive numerous functions required for the tumor escape from immune system control and tumor progression. By positively or negatively modulating immune cell properties, Exo provoke immune suppression and, in turn, defective dendritic cell (DC) functions. Together, these effects limit the cytotoxicity of T-cells and expand both T-regulatory and myeloid derived suppressor populations. They also hinder perforin and granzyme production by natural killer cells. Finally, Exo also control the organotropism of melanoma cells. The distinct phenotypic properties of Exo can be exploited both for diagnostic purposes and in the early identification of melanoma patients likely to respond to immunotherapy. The potential therapeutic application of Exo derived from DCs has been demonstrated in vaccination trials, which showed an increase in anti-melanoma activity with respect to circulating tumor cells. However, additional studies are required before Exo can be effectively used in diagnostic and therapeutic applications in melanoma. PMID- 29755694 TI - The versatile nature of miR-9/9* in human cancer. AB - miR-9 and miR-9* (miR-9/9*) were first shown to be expressed in the nervous system and to function as versatile regulators of neurogenesis. The variable expression levels of miR-9/9* in human cancer prompted researchers to investigate whether these small RNAs may also have an important role in the deregulation of physiological and biochemical networks in human disease. In this review, we present a comprehensive overview of the involvement of miR-9/9* in various human malignancies focusing on their opposing roles in supporting or suppressing tumor development and metastasis. Importantly, it is shown that the capacity of miR 9/9* to impact tumor formation is independent from their influence on the metastatic potential of tumor cells. Moreover, data suggest that miR-9/9* may increase malignancy of one cancer cell population at the expense of another. The functional versatility of miR-9/9* emphasizes the complexity of studying miRNA function and the importance to perform functional studies of both miRNA strands in a relevant cellular context. The possible application of miR-9/9* as targets for miRNA-based therapies is discussed, emphasizing the need to obtain a better understanding of the functional properties of these miRNAs and to develop safe delivery methods to target specific cell populations. PMID- 29755695 TI - Hypertension in malignancy-an underappreciated problem. AB - Hypertension is one of the most common comorbidities in cancer patients with malignancy, in particular, in the elderly. On the other hand, hypertension is a long-term consequence of antineoplastic treatment, including both chemotherapy and targeted agents. Several chemotherapeutics and targeted drugs may be responsible for development or worsening of the hypertension. The most common side effect of anti-VEGF (vascular endothelial growth factor) treatment is hypertension. However, pathogenesis of hypertension in patients receiving this therapy appears to be associated with multiple pathways and is not yet fully understood. Development of hypertension was associated with improved antitumor efficacy in patients treated with anti-antiangiogenic drugs in some but not in all studies. Drugs used commonly as adjuvants such as steroids, erythropoietin stimulating agents etc, may also cause rise in blood pressure or exacerbate preexisiting hypertension. Hypotensive therapy is crucial to manage hypertension during certain antineoplastic treatment. The choice and dose of antihypertensive drugs depend upon the presence of organ dysfunction, comorbidities, and/or adverse effects. In addition, severity of the hypertension and the urgency of blood pressure control should also be taken into consideration. As there are no specific guidelines on the hypertension treatment in cancer patients we should follow the available guidelines to obtain the best possible outcomes and pay the attention to the individualization of the therapy according to the actual situation. PMID- 29755696 TI - The use of long non-coding RNAs as prognostic biomarkers and therapeutic targets in prostate cancer. AB - Prostate cancer is the most common cancer in men and the second leading cause of cancer-related deaths. The most used biomarker to detect prostate cancer is Prostate Specific Antigen (PSA), whose levels are measured in serum. However, it has been recently established that molecular markers of cancer should not be based solely on genes and proteins but should also reflect other genomic traits; long non-coding RNAs (lncRNAs) serve this purpose. lncRNAs are transcripts of >200 bases that do not encode proteins and that have been shown to display abnormal expression profiles in different types of cancer. Experimental studies have highlighted lncRNAs as potential biomarkers for prognoses and treatments in patients with different types of cancer, including prostate cancer, where the PCA3 lncRNA is currently used as a diagnostic tool and management strategy. With the development of genomic technologies, particularly next-generation sequencing (NGS), several other lncRNAs have been linked to prostate cancer and are currently under validation for their medical use. In this review, we will discuss different strategies for the discovery of novel lncRNAs that can be evaluated as prognostic biomarkers, the clinical impact of these lncRNAs and how lncRNAs can be used as potential therapeutic targets. PMID- 29755699 TI - Sequential immunotherapy in a patient with primary refractory Hodgkin lymphoma and novel mutations. AB - Primary resistant Hodgkin lymphoma is an aggressive disease with few treatment options and short survival. Neoplastic cells of classical Hodgkin lymphoma are heavily dependent on microenvironmental stimuli, regularly express PD-L1, and a relevant proportion of relapsed patients is sensitive to blocking of the PD1/PD L1 axis. However, response duration is limited and further treatment options are unknown but urgently needed. We report a case of a patient without relevant response to five subsequent chemotherapy regimens who immediately and dramatically responded to an anti-PD1 mab. During the following two years she responded to the anti-CTLA-4 mab ipilimumab, the Jak2 inhibitor ruxolitinib, and a combination of lenalidomide plus cyclophosphamide given in subsequent relapses. A thorough genomic analysis demonstrated seven genomic alterations with six of them not previously described in this disease (i.e. BRIP1 G212fs*62, KRAS L19F, KDM5A R1239W, MYC A59T, ARIDA1A E1683fs*15 and TP53 277Y). Three alterations were considered actionable and one of them drugable. The number of mutations increased over time and the BRIP1 mutation was found to be a germline mutation. PMID- 29755700 TI - Temporal variations in patterns of Escherichia coli strain diversity and antimicrobial resistance in the migrant Egyptian vulture. AB - Aims: Multiple antimicrobial resistance in Escherichia coli of wild vertebrates is a global concern with scarce assessments on the subject from developing countries that have high human-wild species interactions. We studied the ecology of E. coli in a wintering population of Egyptian Vultures in India to understand temporal changes in both E. coli strains and patterns of antimicrobial resistance. Methods and Results: We ribotyped E. coli strains and assessed antimicrobial resistance from wintering vultures at a highly synanthropic carcass dump in north-west India. Both E. coli occurence (90.32%) and resistance to multiple antimicrobials (71.43%) were very high. Clear temporal patterns were apparent. Diversity of strains changed and homogenized at the end of the Vultures' wintering period, while the resistance pattern showed significantly difference inter-annually, as well as between arrival and departing individuals within a wintering cycle. Significance of study: The carcass dump environment altered both E. coli strains and multiple antimicrobial resistance in migratory Egyptian Vultures within a season. Long-distance migratory species could therefore disseminate resistant E. coli strains across broad geographical scales rendering regional mitigation strategies to control multiple antimicrobial resistance in bacteria ineffective. PMID- 29755697 TI - Natural killer cells as a therapeutic tool for infectious diseases - current status and future perspectives. AB - Natural Killer (NK) cells are involved in the host immune response against infections due to viral, bacterial and fungal pathogens, all of which are a significant cause of morbidity and mortality in immunocompromised patients. Since the recovery of the immune system has a major impact on the outcome of an infectious complication, there is major interest in strengthening the host response in immunocompromised patients, either by using cytokines or growth factors or by adoptive cellular therapies transfusing immune cells such as granulocytes or pathogen-specific T-cells. To date, relatively little is known about the potential of adoptively transferring NK cells in immunocompromised patients with infectious complications, although the anti-cancer property of NK cells is already being investigated in the clinical setting. This review will focus on the antimicrobial properties of NK cells and the current standing and future perspectives of generating and using NK cells as immunotherapy in patients with infectious complications, an approach which is promising and might have an important clinical impact in the future. PMID- 29755698 TI - Epigenetic control of macrophage polarization: implications for targeting tumor associated macrophages. AB - The progression of cancer is a result of not only the growth of the malignant cells but also the behavior of other components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are key components of the TME that influence tumor growth and disease progression. TAMs can either inhibit or support tumor growth depending on their polarization to classically-activated macrophages (M1s) or alternatively-activated macrophages (M2s), respectively. Epigenetic regulation plays a significant role in determining this polarization and manipulating the epigenetic regulation in macrophages would provide a means for selectively targeting M2s thereby eliminating tumor-supporting TAMs while sparing tumor-inhibiting M1 TAMs. Many pharmacologic modulators of epigenetic enzymes are currently used clinically and could be repurposed for treating tumors with high TAM infiltrate. While much research involving epigenetic enzymes and their modulators has been performed in M1s, significantly less is known about the epigenetic regulation of M2s. This review highlights the field's current knowledge of key epigenetic enzymes and their pharmacologic modulators known to influence macrophage polarization. PMID- 29755701 TI - Role of Cytokines as Molecular Marker of Dengue Severity. AB - Objective: Dengue infection is a rapidly spreading vector-borne disease and is endemic in the Indian subcontinent. It has varied manifestations ranging from subclinical infection to severe fatal shock syndrome. This study aimed to estimate cytokine level in dengue patients and correlate them with dengue severity. Methods: Cases of dengue fever diagnosed in the department of medicine of our institute from July 2015 to November 2016 were included in the study. The clinical features, biochemical, hematological and radiological parameters along with cytokine levels (Interferon-gamma, Interleukin-6, and Tumour Necrosis Factor alpha) were recorded in all patients. Results: Out of 80 confirmed cases of dengue included in the study, 50 had nonsevere dengue (Group 1), and 30 patients had severe dengue (Group 2). The median level of serum TNF-alpha in group 2 (62.5 pg/mL) was significantly higher than the median level in group 1 (20 pg/mL), (p=0.043). Similarly, the median level of serum IFN-gamma in group 2 (10.25 pg/mL) was significantly higher than the median level in group 1 (8.5 pg/mL), (p=0.002). The median level of IL-6 was also higher in group 2 (29 pg/ml) as compared group 1(14.2 pg/ml), but this result was not significant (p>0.05). Conclusion: Some cytokines may play a role in the pathogenesis of severe manifestations of dengue. PMID- 29755702 TI - Human T-cell Leukemia Virus Type I Associated with an Increased Risk of Primary Malignant Neoplasm. PMID- 29755703 TI - Gut Colonization with Carbapenem-resistant Enterobacteriaceae Adversely Impacts the Outcome in Patients with Hematological Malignancies: Results of A Prospective Surveillance Study. AB - Background: Gut colonisation with carbapenem-resistant enterobacteriaceae (CRE) is a risk factor for CRE bacteremia and patients with haematological malignancies (HM) are at the highest risk of mortality. Methods: We conducted a prospective surveillance study of gut colonisation with CRE and its impact on the outcome of 225 consecutive patients of HM over 28 months. Results: The median age of the cohort was 46 years, the majority with acute leukaemia. 48 (21%) patients were colonised with CRE on admission (CAD). Another 46 patients were colonised with CRE in the hospital (CIH). The risk factors for CAD and CIH were a diagnosis of acute leukaemia and duration of hospital stay respectively. CRE accounted for 77% of infection-related mortality (IRM). The incidence of CRE bacteremia in CRE positive patients was 18% (17/94), and mortality in those with CRE bacteremia was 100%. IRM was 35.3% in CIH group compared to 10.5% in the CAD group (p=0.0001). IRM was highest in those with acute myeloid leukaemia (AML) and CIH (54.9% p=0.0001). On multivariate analysis, CIH was the most important risk factor for IRM (HR-7.2). Conclusion: Our data demonstrate that a substantial proportion of patients with HM are colonised with CRE without prior hospitalisation, but those with nosocomial colonisation have the highest risk of mortality, particularly in those with AML. PMID- 29755704 TI - Breastfeeding in Patients with Chronic Myeloid Leukaemia: Case Series with Measurements of Drug Concentrations in Maternal Milk and Literature Review. AB - Breastfeeding in patients with chronic myeloid leukaemia (CML) during tyrosine kinase inhibitors (TKIs) therapy is not recommended but interruption of TKI treatment may cause the loss of remission. We studied the 3 cases of pregnancy and breastfeeding in women with CML and observed that stopping treatment without major molecular response may end in haematological relapse. The concentrations of nilotinib and imatinib in maternal milk were measured and nilotinib distribution in human breast milk was demonstrated for the first time. The estimated maximal doses of imatinib and nilotinib which an infant may ingest with the maternal milk were less than the therapeutical doses. However, the unknown impact of the low dose chronic exposure to these TKIs in infants imposes the limitations on their use during breastfeeding. Breastfeeding without TKI treatment may be safe with molecular monitoring, but preferably in those patients with CML who have durable deep molecular response. PMID- 29755705 TI - Appropriate Duration of Intravenous Treatment of Candidemia and Timing of Step Down to Oral Therapy in Non-neutropenic Patients. AB - In this review, we have analyzed the available literature pertaining to the total duration of intravenous (IV) therapy and the appropriate timing of step down to oral therapy in the management of candidemia. Overview of the guidelines and literature seem to indicate that a minimum of 14 days of antifungal therapy is required in the treatment of candidemia without deeply seated infection. However, this was never based on evidence. Furthermore, step down to oral therapy seems to be dependent on the clinical stability criteria of the patient with candidemia after 4 to 7 days of IV therapy. Further studies are required to evaluate the appropriate total duration of IV therapy, appropriate timing of step down to oral therapy and to validate the clinical criteria that would allow the switch to happen. PMID- 29755706 TI - Infectious Risks and Complications in Adult Leukemic Patients Receiving Blinatumomab. AB - Background: Blinatumomab is an anti-CD19 immunotherapy approved for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) with significantly increased survival rate. While blinatumomab showed lower rates of infection, neutropenia and mucosal barrier injury versus chemotherapy, its infection risks are not well described. Methods: All patients who received blinatumomab for >= seven days at an academic cancer center from May 2015 to April 2017 were included. Patient characteristics pertinent to infectious risks and complications were examined. Results: Twenty patients with refractory (25%), relapsed (70%), or remitted (5%) B-ALL who received a total of 35 cycles were included. Ten of the 35 cycles were interrupted, none of which were due to infections. Twenty-six infections (n) were observed with lower respiratory (9), gastrointestinal (6) and bacteremia (5) being most common. Compared to patients without nodular, possible mold pneumonia (n=16), patients with nodular pneumonia (n=4) had significantly lower baseline absolute neutrophil count (ANC) (2319 v. 208/MUL, p=0.011). There were no differences in baseline characteristics including ANC between bacteremic and non-bacteremic patients. One patient was discharged with no antibacterial prophylaxis since ANC recovered to >500cells/MUL, but developed Pseudomonal bacteremia within a week with ANC ~100cells/MUL. Conclusion: Despite blinatumomab's relatively modest myelosuppression and the lack of mucotoxicity, host factors (e.g., duration and degree of neutropenia/lymphopenia) play a key role and should be considered when choosing anti-microbial prophylaxis. In relapsed/refractory disease, the ANC should be monitored closely post blinatumomab since neutropenia can unexpectedly develop after treatment which may be compounded by the underlying disease and recent chemotherapy effects. PMID- 29755707 TI - Decolonization of Intestinal Carriage of MDR/XDR Gram-Negative Bacteria with Oral Colistin in Patients with Hematological Malignancies: Results of a Randomized Controlled Trial. AB - Background: Intestinal colonization by MDR/XDR gram-negative bacteria leads to an increased risk of subsequent bloodstream infections (BSI) in patients receiving chemotherapy as a treatment for hematologic malignancies. Objectives: The objective of this study was to evaluate the efficacy of oral colistin in eradicating the intestinal carriage of MDR/XDR Gram-negative bacteria in patients with hematological malignancies. Methods: In a tertiary hematology center, adult patients with intestinal colonization by MDR/XDR Gram-negative bacteria were included in a randomized controlled trial (RCT) during a period from November 2016 to October 2017. Patients were treated with oral colistin for 14 days or observed with the primary outcome set as decolonization on day 21 post-treatment. Secondary outcomes included treatment safety and changes in MICs of isolated microorganisms. ClinicalTrials.gov Identifier: NCT02966457. Results: Short-time positive effect (61.3% vs 32.3%; OR 3.32; 95% CI 1.17-9.44; p=0.0241) was demonstrated on the day 14 of colistin treatment, without any statistical difference on day 21 post-treatment. The incidence of BSI in decolonization group was lower in the first 30 days after the intervention (3.2% vs. 12.9%), but overall in the 90-day observation period, it did not show any advantages comparing to control group (log-rank test; p=0.4721). No serious adverse effects or increase in resistance to colistin was observed. Conclusions: This study suggests that in hematological patients the strategy of selective intestinal decolonization by colistin may be beneficial to decrease the rate of MDR/XDR Gram negative intestinal colonization and the risk of BSI in the short-term period, having no long-term sustainable effects. PMID- 29755708 TI - Growth and Endocrine Function in Tunisian Thalassemia Major Patients. AB - beta-thalassemia major (beta-TM) is among the most common hereditary disorders imposing high expenses on health-care system worldwide. The patient's survival is dependent on lifetime blood transfusion which leads to iron overload and its toxicity in various organs including endocrine glands. This article provides an overview of endocrine disorders in beta-TM patients. This single center investigation enrolled 28 beta-TM patients (16 males, 12 females) regularly transfused with packed red cell since early years of life. For each patient were determined: age, sex, number of transfusions received, history of splenectomy and anthropometric parameters. All patients underwent an evaluation of hormonal status including growth, gonadal, thyroid, adrenal cortex, and parathyroid glands. Dual-energy X-ray absorptiometry was used to diagnose low bone mass. Assessment of iron overload status was performed by measuring the serum ferritin concentration and the results of magnetic resonance imaging T2*. Growth retardation was found in 16 of the 28 studied patients (57 %). Thirteen among them had delayed puberty. Spontaneous puberty was achieved in 16 cases. Growth hormone (GH) deficiency was found in 10 cases (35 %). Seventeen among the studied patients (60 %) developed disorders of glucose homeostasis. Subclinical hypothyroidism was found in six patients (21 %). Intensive chelation therapy had allowed the reversibility of this complication in five cases. Adrenal Insufficiency was observed in 9 cases (32%). Hypoparathyroidism has occurred in one case. Ten of the 28 studied patients had low bone mass (35%). Twenty-three of the 28 studied patients (82%) had at least one endocrine complication. PMID- 29755710 TI - Laboratory Biomarkers to Facilitate Differential Diagnosis between Measles and Kawasaki Disease in a Pediatric Emergency Room: A Retrospective Study. AB - This retrospective study was conducted to analyze clinical and laboratoristic parameters to individuate specific differences and facilitate differential diagnosis between Measles and Kawasaki Disease (KD) at first evaluation in an emergency room. We found similar clinical features as duration of fever and number of KD criteria (p > 0.5) but significant differences in white blood cell count, neutrophils, CRP and LDH levels (p < 0.001). LDH value >= 800 mg/dl had sensibility of 89% and specificity of 90% for Measles while CRP >= 3 mg/dl had sensibility 89% and specificity of 85% for KD. The combined use of CRP, LDH and AST showed accuracy of 86.67%. PMID- 29755709 TI - Perioperative Management of Sickle Cell Disease. AB - Over 30 million people worldwide have sickle cell disease (SCD). Emergent and non emergent surgical procedures in SCD have been associated with relatively increased risks of peri-operative mortality, vaso-occlusive (painful) crisis, acute chest syndrome, post-operative infections, congestive heart failure, cerebrovascular accident and acute kidney injury. Pre-operative assessment must include a careful review of the patient's known crisis triggers, baseline hematologic profile, usual transfusion requirements, pre-existing organ dysfunction and opioid use. Use of preoperative blood transfusions should be selective and decisions individualized based on the baseline hemoglobin, surgical procedure and anticipated volume of blood loss. Intra- and post-operative management should focus on minimizing hypoxia, hypothermia, acidosis, and intravascular volume depletion. Pre- and post-operative incentive spirometry use should be encouraged. PMID- 29755711 TI - Parasitic Hypereosinophilia in Childhood: a Diagnostic Challenge. AB - Severe hypereosinophilia (HE) in children is rare, and its etiological diagnosis is challenging. We describe a case of a 30-month-old boy, living in a rural area, who was admitted to our Clinic with a 7-day history of fever and severe hypereosinophilia. A comprehensive diagnostic workup could not identify the cause of this condition. On day 6, the rapidly increasing eosinophil count (maximum value of 56,000/mm3), the risk of developing hypereosinophilic syndrome, and the patient's history prompted us to undertake an empiric treatment with albendazole. The eosinophil count progressively decreased following treatment. On day 13, clinical condition and hematological data were satisfactory, therefore the treatment was discontinued, and the patient was discharged. Three months later, anti-nematode IgG antibodies were detected in patient serum, thus establishing the etiological diagnosis. In conclusion, an empiric anthelmintic treatment seems to be justified when parasitic hypereosinophilia is strongly suspected, and other causes have been excluded. PMID- 29755713 TI - A Mobile Multimedia Reminiscence Therapy Application to Reduce Behavioral and Psychological Symptoms in Persons with Alzheimer's. AB - The goal of this project is to develop a novel and innovative mobile solution to address behavioral and psychological symptoms of dementia (BPSD) that occur in individuals with Alzheimer's. BPSD can include agitation, restlessness, aggression, apathy, obsessive-compulsive and repetitive behaviors, hallucinations, delusions, paranoia, and wandering. Alzheimer's currently affects 5.4 million adults in the United States and that number is projected to increase to 14 million by 2050. Almost 90% of all affected with AD experience BPSD, resulting in increased healthcare costs, heavier burden on caregivers, poor patient outcomes, early nursing home placement, long-term hospitalizations, and misuse of medications. Pharmacological support may have undesirable side effects such as sedation. Nonpharmacological interventions are alternative solutions that have shown to be effective without undesirable side effects. Music therapy has been found to lower BPSD symptoms significantly. Our study is based on combination of the reminiscence and the music therapies where past memorable events are recalled using prompts such as photos, videos, and music. We are proposing a mobile multimedia solution, a technical version of the combined reminiscence, and music therapies to prevent the occurrence of BPSD, especially for the rural population who have reduced access to dementia care services. PMID- 29755714 TI - Identification of Cerebral Artery Stenosis Using Bilateral Photoplethysmography. AB - Cerebral artery stenosis is currently diagnosed by transcranial Doppler (TCD), computed tomographic angiography (CTA), or magnetic resonance angiography (MRA). CTA exposes a patient to radiation, while CTA and MRA are invasive and side effects were related to contrast medium use. This study aims to provide a technique that can simply discriminate between people with normal blood vessels and those with cerebral artery stenosis using photoplethysmography (PPG), which is noninvasive and inexpensive. Moreover, the measurement takes only 120 seconds and is conducted on the fingers. The technique projects the light of a specific wavelength and analyzes the pulse waves which are generated when the blood passes through the blood vessels according to one's heartbeat using the transmitted light. Normalization was performed after dividing the extracted pulse waveform into windows, and maximum positive and negative amplitudes (MPA, MNA) were extracted from the detected pulse waves as features. The extracted features were used to identify normal subjects and those with cerebral artery stenosis using a linear discriminant analysis. The study results showed that the recognition rate using MPA was 92.2%, MNA was 90.6%, and combined MPA + MNA was 90.6%. The technique proposed is expected to detect early stage asymptomatic cerebral artery stenosis and help prevent ischemic stroke. PMID- 29755715 TI - A Deep Belief Network and Dempster-Shafer-Based Multiclassifier for the Pathology Stage of Prostate Cancer. AB - Object: Pathologic prediction of prostate cancer can be made by predicting the patient's prostate metastasis prior to surgery based on biopsy information. Because biopsy variables associated with pathology have uncertainty regarding individual patient differences, a method for classification according to these variables is needed. Method: We propose a deep belief network and Dempster-Shafer (DBN-DS-) based multiclassifier for the pathologic prediction of prostate cancer. The DBN-DS learns prostate-specific antigen (PSA), Gleason score, and clinical T stage variable information using three DBNs. Uncertainty regarding the predicted output was removed from the DBN and combined with information from DS to make a correct decision. Result: The new method was validated on pathology data from 6342 patients with prostate cancer. The pathology stages consisted of organ-confined disease (OCD; 3892 patients) and non-organ-confined disease (NOCD; 2453 patients). The results showed that the accuracy of the proposed DBN-DS was 81.27%, which is higher than the 64.14% of the Partin table. Conclusion: The proposed DBN-DS is more effective than other methods in predicting pathology stage. The performance is high because of the linear combination using the results of pathology-related features. The proposed method may be effective in decision support for prostate cancer treatment. PMID- 29755712 TI - Lymphoproliferative Syndromes Associated with Human Herpesvirus-6A and Human Herpesvirus-6B. AB - Human herpesvirus 6A and 6B (HHV-6A and HHV-6B) have been noted since their discovery for their T-lymphotropism. Although it has proven difficult to determine the extent to which HHV-6A and HHV-6B are involved in the pathogenesis of many diseases, evidence suggests that primary infection and reactivation of both viruses may induce or contribute to the progression of several lymphoproliferative disorders, ranging from benign to malignant and including infectious mononucleosis-like illness, drug induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS), and nodular sclerosis Hodgkin's lymphoma. Herein, we discuss the conditions associated with the lymphoproliferative capacity of HHV-6, as well as the potential mechanisms behind them. Continued exploration on this topic may add to our understanding of the interactions between HHV-6 and the immune system and may open the doors to more accurate diagnosis and treatment of certain lymphoproliferative disorders. PMID- 29755717 TI - patternize: An R package for quantifying colour pattern variation. AB - The use of image data to quantify, study and compare variation in the colors and patterns of organisms requires the alignment of images to establish homology, followed by color-based segmentation of images. Here we describe an R package for image alignment and segmentation that has applications to quantify color patterns in a wide range of organisms. patternize is an R package that quantifies variation in color patterns obtained from image data. patternize first defines homology between pattern positions across specimens either through manually placed homologous landmarks or automated image registration. Pattern identification is performed by categorizing the distribution of colors using an RGB threshold, k-means clustering or watershed transformation.We demonstrate that patternize can be used for quantification of the color patterns in a variety of organisms by analyzing image data for butterflies, guppies, spiders and salamanders. Image data can be compared between sets of specimens, visualized as heatmaps and analyzed using principal component analysis (PCA). patternize has potential applications for fine scale quantification of color pattern phenotypes in population comparisons, genetic association studies and investigating the basis of color pattern variation across a wide range of organisms. PMID- 29755716 TI - Automatic Semantic Segmentation of Brain Gliomas from MRI Images Using a Deep Cascaded Neural Network. AB - Brain tumors can appear anywhere in the brain and have vastly different sizes and morphology. Additionally, these tumors are often diffused and poorly contrasted. Consequently, the segmentation of brain tumor and intratumor subregions using magnetic resonance imaging (MRI) data with minimal human interventions remains a challenging task. In this paper, we present a novel fully automatic segmentation method from MRI data containing in vivo brain gliomas. This approach can not only localize the entire tumor region but can also accurately segment the intratumor structure. The proposed work was based on a cascaded deep learning convolutional neural network consisting of two subnetworks: (1) a tumor localization network (TLN) and (2) an intratumor classification network (ITCN). The TLN, a fully convolutional network (FCN) in conjunction with the transfer learning technology, was used to first process MRI data. The goal of the first subnetwork was to define the tumor region from an MRI slice. Then, the ITCN was used to label the defined tumor region into multiple subregions. Particularly, ITCN exploited a convolutional neural network (CNN) with deeper architecture and smaller kernel. The proposed approach was validated on multimodal brain tumor segmentation (BRATS 2015) datasets, which contain 220 high-grade glioma (HGG) and 54 low-grade glioma (LGG) cases. Dice similarity coefficient (DSC), positive predictive value (PPV), and sensitivity were used as evaluation metrics. Our experimental results indicated that our method could obtain the promising segmentation results and had a faster segmentation speed. More specifically, the proposed method obtained comparable and overall better DSC values (0.89, 0.77, and 0.80) on the combined (HGG + LGG) testing set, as compared to other methods reported in the literature. Additionally, the proposed approach was able to complete a segmentation task at a rate of 1.54 seconds per slice. PMID- 29755718 TI - Categorisation of Colour Terms Using New Validation Tools: A Case Study and Implications. AB - This article elaborates on the results of a field experiment conducted among speakers of the Chakali language, spoken in northern Ghana. In the original study, the Color-aid Corporation Chart was used to perform the focal task in which consultants were asked to point at a single colour tile on the chart. However, data from the focal task could not be analysed since the Color-aid tiles had not yet been converted into numerical values set forth by the Commission internationale de l'eclairage (CIE). In this study, the full set of 314 Color-aid tiles were measured for chromaticity and converted into the CIE values at the Daylight Laboratory of the Norwegian University of Science and Technology. This article presents the conversion methodology and makes the results of the measurements, which are available in the Online Appendix. We argue that some visual-perception terms cannot be reliably ascribed to colour categories established by the Color-aid Corporation. This suggests that the ideophonic expressions in the dataset do not denote 'colours', as categorised in the Color aid system, as it was impossible to average the consultants' data into a CIE chromaticity diagram, illustrate the phenomena on the Natural Colour System (NCS) Circle and Triangle diagrams, and conduct a statistical analysis. One of the implications of this study is that a line between a visual-perception term and a colour term could be systematically established using a method with predefined categorical thresholds. PMID- 29755719 TI - Periodic Fluctuation of Perceived Duration. AB - In recent years, several studies have reported that the allocation of spatial attention fluctuates periodically. This periodic attention was revealed by measuring behavioral performance as a function of cue-to-target interval in the Posner cueing paradigm. Previous studies reported behavioral oscillations using target detection tasks. Whether the influence of periodic attention extends to cognitively demanding tasks remains unclear. To assess this, we examined the effects of periodic attention on the perception of duration. In the experiment, participants performed a temporal bisection task while a cue was presented with various cue-to-target intervals. Perceived duration fluctuated rhythmically as a function of cue-to-target interval at a group level but not at an individual level when the target was presented on the same side as the attentional cue. The results indicate that the perception of duration is influenced by periodic attention. In other words, periodic attention can influence the performance of cognitively demanding tasks such as the perception of duration. PMID- 29755721 TI - Effects of Congruent and Incongruent Stimulus Colour on Flavour Discriminations. AB - In addition to gustatory, olfactory and somatosensory input, visual information plays a role in our experience of food and drink. We asked whether colour in this context has an effect at the perceptual level via multisensory integration or if higher level cognitive factors are involved. Using an articulatory suppression task, comparable to Stevenson and Oaten, cognitive processes should be interrupted during a flavour discriminatory task, so that any residual colour effects would be traceable to low-level integration. Subjects judged in a three alternative forced-choice paradigm the presence of a different flavour (triangle test). On each trial, they tasted three liquids from identical glasses, with one of them containing a different flavour. The substances were congruent in colour and flavour, incongruent or uncoloured. Subjects who performed the articulatory suppression task responded faster and made fewer errors. The findings suggest a role for higher level cognitive processing in the effect of colour on flavour judgements. PMID- 29755720 TI - Development of Asymmetric Vection for Radial Expansion or Contraction Motion: Comparison Between School-Age Children and Adults. AB - Vection is illusory self-motion elicited by visual stimuli and is more easily induced by radial contraction than expansion flow in adults. The asymmetric feature of vection was reexamined with 18 younger (age: 6-8 years) and 19 older children (age: 9-11 years) and 20 adults. In each experimental trial, participants observed either radial expansion or contraction flow; the latency, cumulative duration, and saturation of vection were measured. The results indicated that the latency for contraction was significantly shorter than that for expansion in all age-groups. In addition, the latency and saturation were significantly shorter and greater, respectively, in the younger or older children compared with the adults, regardless of the flow pattern. These results indicate that the asymmetry in vection for expansion or contraction flow emerges by school age, and that school-age children experience significantly more rapid and stronger vection than adults. PMID- 29755722 TI - Implicit and Explicit Evaluation of Visual Symmetry as a Function of Art Expertise. AB - In perception, humans typically prefer symmetrical over asymmetrical patterns. Yet, little is known about differences in symmetry preferences depending on individuals' different past histories of actively reflecting upon pictures and patterns. To address this question, we tested the generality of the symmetry preference for different levels of individual art expertise. The preference for symmetrical versus asymmetrical abstract patterns was measured implicitly, by an Implicit Association Test (IAT), and explicitly, by a rating scale asking participants to evaluate pattern beauty. Participants were art history and psychology students. Art expertise was measured using a questionnaire. In the IAT, art expertise did not alter the preference for symmetrical over asymmetrical patterns. In contrast, the explicit rating scale showed that with higher art expertise, the ratings for the beauty of asymmetrical patterns significantly increased, but, again, participants preferred symmetrical over asymmetrical patterns. The results are discussed in light of different theories on the origins of symmetry preference. Evolutionary adaptation might play a role in symmetry preferences for art experts similarly to nonexperts, but experts tend to emphasize the beauty of asymmetrical depictions, eventually considering different criteria, when asked explicitly to indicate their preferences. PMID- 29755723 TI - A Novel Method of Color Appearance Simulation Using Achromatic Point Locus With Lightness Dependence. AB - The purpose of the present study is to propose a simple algorithm for color appearance simulation under a color illuminant. Achromatic point is a chromaticity of rays that appear neither red nor green, neither blue nor yellow under a given illuminant condition. Saturation and hue of surface colors are evaluated with respect to the achromatic point of the same lightness, while the achromatic point under a colored illuminant depends on the lightness tested. We previously found that this achromatic point locus can be simply approximated as a line with a parallel offset from the lightness axis of CIE LAB space normalized to daylight. We propose a model that applies shifts in the lightness direction after applying hue/saturation shifts using the cone-response (von Kries) transformation under an iso-lightness constraint, such that achromatic points would be aligned with the lightness axis in the CIE LAB space under daylight normalization. We tested this algorithm, which incorporates evaluation of color appearance in different lightness levels, using #theDress image. Resemblance between our simulation and subjective color-matching results implies that human color vision possibly processes shifts in color and lightness independently, as a previous study reported. Changes in the chromaticity distribution of the images were compared with conventional models, and the proposed model preserved relative color difference better, especially at the lower lightness levels. The better performance in lower lightness levels would be advantageous in displays with wider dynamic range in luminance. This implies that the proposed model is effective in simulating color appearance of images with nonnegligible lightness and color differences. PMID- 29755724 TI - Assessment of #TheDress With Traditional Color Vision Tests: Perception Differences Are Associated With Blueness. AB - Based on known color vision theories, there is no complete explanation for the perceptual dichotomy of #TheDress in which most people see either white-and-gold (WG) or blue-and-black (BK). We determined whether some standard color vision tests (i.e., color naming, color matching, anomaloscope settings, unique white settings, and color preferences), as well as chronotypes, could provide information on the color perceptions of #TheDress. Fifty-two young observers were tested. Fifteen of the observers (29%) reported the colors as BK, 21 (40%) as WG, and 16 (31%) reported a different combination of colors. Observers who perceived WG required significantly more blue in their unique white settings than those who perceived BK. The BK, blue-and-gold, and WG observer groups had significantly different color preferences for the light cyan chip. Moreland equation anomaloscope matching showed a significant difference between WG and BK observers. In addition, #TheDress color perception categories, color preference outcomes, and unique white settings had a common association. For both the bright and dark regions of #TheDress, the color matching chromaticities formed a continuum, approximately following the daylight chromaticity locus. Color matching to the bright region of #TheDress showed two nearly distinct clusters (WG vs. BK) along the daylight chromaticity locus and there was a clear cutoff for reporting WG versus BK. All results showing a significant difference involved blue percepts, possibly due to interpretations of the illuminant interactions with the dress material. This suggests that variations in attributing blueness to the #TheDress image may be significant variables determining color perception of #TheDress. PMID- 29755725 TI - The Effect of Romantic Relationships on the Evaluation of the Attractiveness of One's Own Face. AB - The present study sought to explore the effect of romantic relationships on the attractiveness evaluation of one's own face using two experiments with the probability evaluation and the subjective rating method. Experiment 1 and Experiment 2 enrolled couples and single individuals as participants, respectively. The results of the two experiments indicated that the participants evaluated their own face as significantly more attractive than did others of the same sex. More importantly, the romantic relationship enhanced the positive bias in the evaluation of self-face attractiveness, that is, couple participants showed a stronger positive bias than did single individuals. It was also found that a person in a romantic relationship was prone to overestimating the attractiveness of his or her lover's face, from the perspective of both probability evaluation and rating score. However, the abovementioned overestimation did not surpass the evaluations of the exaggeratedly attractive face. The present results supported the observer hypothesis, demonstrating the romantic relationship to be an important influential factor of facial attractiveness. Our findings have important implications for the research of self face evaluation. PMID- 29755726 TI - Trueperella pyogenes and Brucella abortus Coinfection in a Dog and a Cat on a Dairy Farm in Egypt with Recurrent Cases of Mastitis and Abortion. AB - Trueperella pyogenes was isolated from a dog and a cat with a mixed infection with Brucella abortus. Both lived on a dairy cattle farm with a history of regular cases of abortion and mastitis. Identification of the bacteria was done by means of MALDI-TOF MS, loop-mediated isothermal amplification (LAMP) based on cpn60, partial 16S rRNA sequencing, and growth on Loeffler Serum Medium. Isolation of Trueperella pyogenes on the dairy farm highlights its neglected role in reproduction failure and draws attention to its effects in the dairy industry in Egypt. Diagnosis and control of abortion in Egypt should include Trueperella pyogenes as one of possible causes of abortion. PMID- 29755727 TI - Antimicrobial Resistance Profile of E. coli Isolated from Raw Cow Milk and Fresh Fruit Juice in Mekelle, Tigray, Ethiopia. AB - Aim: Foodborne illnesses represent a public health problem in developed and developing countries. They cause great suffering and are transmitted directly or indirectly between animals and humans and circulate in the global environment. E. coli are among them, causing a major public health problem. The aim of this study was therefore to study the antimicrobial resistance profile of E. coli from raw cow milk and fruit juice. Materials and Methods: A cross-sectional study was conducted from October 2016 to June 2017 on 258 samples collected from milk shops (n = 86), dairy farms (n = 86), and fruit juice (n = 86) in different subcities of Mekelle. Bacteriological procedures were used for isolation of E. coli in the collected samples and for identification of the antimicrobial resistance profile. Result: The overall mean viable bacterial count and standard deviation of samples from milk shop, fruit juice, and dairy milk were found to be 8.86 +/- 107, 7.2 +/ 107, and 8.65 +/- 107 CFU/ml and 33.87 +/- 106, 6.68 +/- 106, and 22.0 +/- 106, respectively. Of the samples tested, 39 from milk shops (45.35%), 20 from fruit juice (23.26%), and 24 from dairy farms (27.91%) were found to be positive for E. coli. The isolated E. coli were highly resistant to ampicillin (70%), sulfamethoxazole-trimethoprim (60%), clindamycin (80%), erythromycin (60%), chloramphenicol (50%), and kanamycin (50%) and were found to be susceptible to some antibiotics like gentamicin (100%), norfloxacin (100%), tetracycline (60%), polymyxin B (90%), and ciprofloxacin (90%). Conclusion: The current study supports the finding that raw milk and fruit juice can be regarded as critical source of pathogenic E. coli. This supports the need for strict monitoring and the implementation of effective hygienic and biosecurity measures in the whole food chain of these products as well as a prudent use of antimicrobials. PMID- 29755728 TI - Combination of Multifocal Electroretinogram and Spectral-Domain OCT Can Increase Diagnostic Efficacy of Parkinson's Disease. AB - Background: The retinal changes have been identified in morphology and function in Parkinson's disease (PD). However, the controversial results suggest that it is incredible that only using a single method for testing retinal change to evaluate Parkinson's disease. The aim of this study was to assess retinal changes and increase the diagnostic efficacy of Parkinson's disease with a combination of multifocal electroretinogram (mf-ERG) and spectral domain optical coherence tomography (SD-OCT) examinations. Method: Fifty-three PD patients and forty-one healthy controls were enrolled. Subjects were assessed for retinal function using mf-ERG and retinal structure using SD-OCT. Results: The PD patients had a significantly decreased amplitude density of P1 and a delayed implicit time of P1 in some regions. The macular retinal thickness, macular volume, and average RNFL thickness were decreased in PD. The AUC of a single parameter of either retinal function or structure was low. Both of them were higher in diagnostic value to discriminate PD patients. Conclusion: The amplitude density of P1 combined with macular volume can get a high diagnostic efficacy to discriminate between participants with or without PD. It indicates that a combination of mf-ERG and SD OCT provides a good clinical biomarker for diagnosis of PD. PMID- 29755729 TI - Deep Brain Stimulation in Parkinson's Disease. PMID- 29755730 TI - Having concomitant asthma phenotypes is common and independently relates to poor lung function in NHANES 2007-2012. AB - Background: Evidence for distinct asthma phenotypes and their overlap is becoming increasingly relevant to identify personalized and targeted therapeutic strategies. In this study, we aimed to describe the overlap of five commonly reported asthma phenotypes in US adults with current asthma and assess its association with asthma outcomes. Methods: Data from the National Health and Nutrition Examination Surveys (NHANES) 2007-2012 were used (n = 30,442). Adults with current asthma were selected. Asthma phenotypes were: B-Eos-high [if blood eosinophils (B-Eos) >= 300/mm3]; FeNO-high (FeNO >= 35 ppb); B-Eos&FeNO-low (B Eos < 150/mm3 and FeNO < 20 ppb); asthma with obesity (AwObesity) (BMI >= 30 kg/m2); and asthma with concurrent COPD. Data were weighted for the US population and analyses were stratified by age (< 40 and >= 40 years old). Results: Of the 18,619 adults included, 1059 (5.6% [95% CI 5.1-5.9]) had current asthma. A substantial overlap was observed both in subjects aged < 40 years (44%) and >= 40 years (54%). The more prevalent specific overlaps in both age groups were AwObesity associated with either B-Eos-high (15 and 12%, respectively) or B Eos&FeNO-low asthma (13 and 11%, respectively). About 14% of the current asthma patients were "non-classified". Regardless of phenotype classification, having concomitant phenotypes was significantly associated with (adjusted OR, 95% CI) >= 2 controller medications (2.03, 1.16-3.57), and FEV1 < LLN (3.21, 1.74-5.94), adjusted for confounding variables. Conclusions: A prevalent overlap of commonly reported asthma phenotypes was observed among asthma patients from the general population, with implications for objective asthma outcomes. A broader approach may be required to better characterize asthma patients and prevent poor asthma outcomes. PMID- 29755731 TI - Recent advances in intravenous anesthesia and anesthetics. AB - Anesthesiology, as a field, has made promising advances in the discovery of novel, safe, effective, and efficient methods to deliver care. This review explores refinement in the technology of soft drug development, unique anesthetic delivery systems, and recent drug and device failures. PMID- 29755734 TI - Highly sticky surfaces made by electrospun polymer nanofibers. AB - We report on a comprehensive study of the unique adhesive properties of mats of polymethylmethacrylate (PMMA) nanofibers produced by electrospinning. Fibers are deposited on glass, with varying of the diameter and the relative orientation of the polymer filaments (random vs. aligned configuration). While no significant variation is observed in the static contact angle (~130 degrees ) of deposited water drops upon changing the average fiber diameter up to the micrometer scale, fibers are found to exhibit unequalled water adhesion. Placed vertically, they can hold up water drops as large as 60 MUL, more than twice the values typically obtained with hairy surfaces prepared by different methods. For aligned fibers with anisotropic wetting behavior, the maximum volume measured in the direction perpendicular to the fibers goes up to 90 MUL. This work suggests new routes to tailor the wetting behavior on extended areas by nanofiber coatings, with possible applications in adsorbing and catalytic surfaces, microfluidic devices, and filtration technologies. PMID- 29755735 TI - Microbiome-Immune Interactions and Liver Disease. PMID- 29755732 TI - Recent advances in understanding oogenesis: interactions with the cytoskeleton, microtubule organization, and meiotic spindle assembly in oocytes. AB - Maternal control of development begins with production of the oocyte during oogenesis. All of the factors necessary to complete oocyte maturation, meiosis, fertilization, and early development are produced in the transcriptionally active early oocyte. Active transcription of the maternal genome is a mechanism to ensure that the oocyte and development of the early embryo begin with all of the factors needed for successful embryonic development. To achieve the maximum maternal store, only one functional cell is produced from the meiotic divisions that produce the oocyte. The oocyte receives the bulk of the maternal cytoplasm and thus is significantly larger than its sister cells, the tiny polar bodies, which receive a copy of the maternal genome but essentially none of the maternal cytoplasm. This asymmetric division is accomplished by an enormous cell that is depleted of centrosomes in early oogenesis; thus, meiotic divisions in oocytes are distinct from those of mitotic cells. Therefore, these cells must partition the chromosomes faithfully to ensure euploidy by using mechanisms that do not rely on a conventional centrosome-based mitotic spindle. Several mechanisms that contribute to assembly and maintenance of the meiotic spindle in oocytes have been identified; however, none is fully understood. In recent years, there have been many exciting and significant advances in oogenesis, contributed by studies using a myriad of systems. Regrettably, I cannot adequately cover all of the important advances here and so I apologize to those whose beautiful work has not been included. This review focuses on a few of the most recent studies, conducted by several groups, using invertebrate and vertebrate systems, that have provided mechanistic insight into how microtubule assembly and meiotic spindle morphogenesis are controlled in the absence of centrosomes. PMID- 29755736 TI - Surgical specialty and preoperative medical consultation based on commercial health insurance claims. AB - Background: Surgical patients are sometimes referred for preoperative evaluations by consultants in other medical specialties, although consultations are unnecessary for many patients, particularly for healthy patients undergoing low risk surgeries. Surgical specialty has been shown to predict usage of preoperative consultations. However, evidence is generally limited regarding factors associated with preoperative consultations. This study evaluates surgical specialty and other predictors of preoperative consultations. Methods: This retrospective cohort study analyzed surgery claims of 7400 privately insured patients in Washington, United States, from eight surgical specialties. We estimated log-Poisson generalized estimating equation models that regress whether a patient received a consultation on surgical specialty and covariates accounting for the data's hierarchical structure with patients nesting within surgeons, and surgeons nesting within provider organizations. Covariates include age, gender, Deyo comorbidity index, surgical risk, and geographic factors. Results: Overall, 485 (6.6%) patients had a preoperative consultation. The incidence of preoperative consultation varied significantly by surgical specialty. Orthopedics, neurosurgery, and ophthalmology had 3.9 (95% CI 2.4, 6.5), 2.3 (95% CI 1.1, 4.5), and 2.3 (95% CI 1.1, 4.6) times greater adjusted likelihoods of preoperative consultation than general surgery, respectively. The adjusted likelihoods of consultation for gynecology, urology, otolaryngology, and vascular surgery were not statistically different from general surgery. The following covariates were associated with greater likelihood of preoperative consultation: greater age, higher surgical risk, having one or more comorbidities vs. none, and small rural towns vs. urban areas. More than 75% of all consultations were provided to patients with a Deyo comorbidity index of 0 or 1. Low surgical risk patients had 0.3 (95% CI 0.3, 0.5) times the likelihood of preoperative consultation of intermediate and high-risk patients overall. Conclusions: The likelihood of preoperative consultation varied fourfold (an absolute 9% points) across surgical specialties. Most consultations were provided to patients with low comorbidity and with low or intermediate surgical risk. To improve usage of preoperative consultations as an evidence-based practice, future research should determine how the health outcomes effects of preoperative consultations vary depending on comorbidity burden and surgical risk. PMID- 29755733 TI - Recent advancements in the management of retinoblastoma and uveal melanoma. AB - Retinoblastoma and uveal melanoma are the most common intraocular malignancies observed in pediatric and adult populations, respectively. For retinoblastoma, intra-arterial chemotherapy has dramatically improved treatment outcomes and eye salvage rates compared with traditional salvage rates of systemic chemotherapy and external beam radiation therapy. Intravitreal injections of chemotherapy have also demonstrated excellent efficacy for vitreous seeds. Uveal melanoma, on the other hand, is treated predominantly with iodine-125 plaque brachytherapy or with proton beam therapy. Major strides in uveal melanoma genomics have been made since the early 2000s, allowing ocular oncologists to better understand the metastatic risks of the tumor on the basis of specific genetic signatures. Loss of-function mutations of the BAP1 gene are associated with the highest metastatic risk, whereas gain-of-function mutations of SF3B1 and EIF1AX often confer a better prognosis. Expression of a cancer-testis antigen called PRAME (preferentially expressed antigen in melanoma) has been shown to increase metastatic risks in both low-risk and high-risk melanomas. New therapeutic approaches, including molecular therapies and nanoparticle phototherapy, are currently being investigated as alternative treatment modalities for uveal melanoma. PMID- 29755737 TI - Inactivation of Pure Bacterial Biofilms by Impaction of Aerosolized Consumer Products Containing Nanoparticulate Metals. AB - The ability of nanotechnology-enabled consumer sprays to inactivate bacteria has direct health implications. This research investigated the ability of six nanosilver-based consumer sprays to inactivate bacteria. We determined the minimal inhibitory concentrations (MICs) of the products by an agar dilution method, collected particles released from sprays onto bacterial films using impactors, and determined metal concentrations in the products using ICPMS. Also, the size of silver nanoparticles in the products' suspensions was determined using single particle (sp)ICPMS. Two of the six nanoproducts inhibited growth of Escherichia coli and Bacillus atrophaeus bacteria (MICs of 40,000 and 160,000 ppm). Collection of particles aerosolized from these two products onto films of the same bacteria inhibited bacterial growth; however, the mass concentration deposited onto bacterial films was lower than the MICs. Furthermore, these two nanoproducts had the lowest silver concentrations compared to the other four nanosilver products. Yet, they had the smallest nanosilver particles: mean size of ~20 to 30 nm vs. ~45 nm for the other products. Their suspensions were more acidic (pH ~3-5) and had higher concentrations of zinc and magnesium compared to other products. This research illustrates that some consumer nanoproducts have antibacterial potential and may affect our microbiota. Yet, the inactivation potential cannot solely be presumed based on the nanosilver presence and concentration in the product; the final nanoproduct's form, including its matrix, must be considered. As nanomaterials are increasingly incorporated into consumer goods, this research highlights the need to investigate final-form consumer nanoproducts and their potential to affect our microbial environment. PMID- 29755738 TI - Environmental fate of nanopesticides: durability, sorption and photodegradation of nanoformulated clothianidin. AB - A lot of research efforts are currently dedicated to the development of nano enabled agrochemicals. Knowledge about their environmental behaviour is however scarce, which impedes the assessment of the new risk and benefits relative to currently used agrochemicals. With the aim to advance our understanding of the fate of nanopesticides in the environment and support the development of robust exposure assessment procedures, the main objectives of the study were to (i) investigate the extent to which three nanoformulations can affect the photodegradation and sorption of the insecticide clothianidin, and (ii) evaluate various approaches to estimate durability, a key parameter for the exposure assessment of nanopesticides. The nanoformulations increased the photodegradation half-life in water by a maximum of 21% relative to the conventional formulation. Sorption to soil was investigated by two methods and over time, and results show that sorption was increased by up to 51% and 10%, relative to unformulated clothianidin and the commercial formulation, respectively. Our results generally indicate that nanoformulations may have a greater impact on the fate of pesticide active ingredients than commercial formulations. It is important to note however that differences in fate parameters were generally very moderate, including in realistic worst-case conditions (high pesticide concentration and ionic strength). Our results collectively suggest that clothianidin was rapidly released from the nanocarrier systems and that the durability of the three nanoformulations would be short in water as well as in soil environments (including under realistic soil to solution ratio). The durability of nanoformulations after their application in the environment is an essential parameter that needs to be characterised for the development as well as for the evaluation of nano-enabled agrochemicals. This study illustrates how performances of nano-enabled products can be critically benchmarked against existing products to support an objective assessment of new environmental risks and benefits. In this context, the fate of the nanocarrier system is of great interest and should be the topic of further research. PMID- 29755740 TI - X-ray lasers for structure and dynamics in biology. AB - Recent advances in the application of X-ray lasers to structural biology are providing time-resolved high-resolution imaging of many processes, from enzyme kinetics to the riboswitch in action, drug action, and light-sensitive proteins. PMID- 29755739 TI - Abdominal obesity and metabolic syndrome: exercise as medicine? AB - Background: Metabolic syndrome is defined as a cluster of at least three out of five clinical risk factors: abdominal (visceral) obesity, hypertension, elevated serum triglycerides, low serum high-density lipoprotein (HDL) and insulin resistance. It is estimated to affect over 20% of the global adult population. Abdominal (visceral) obesity is thought to be the predominant risk factor for metabolic syndrome and as predictions estimate that 50% of adults will be classified as obese by 2030 it is likely that metabolic syndrome will be a significant problem for health services and a drain on health economies.Evidence shows that regular and consistent exercise reduces abdominal obesity and results in favourable changes in body composition. It has therefore been suggested that exercise is a medicine in its own right and should be prescribed as such. Purpose of this review: This review provides a summary of the current evidence on the pathophysiology of dysfunctional adipose tissue (adiposopathy). It describes the relationship of adiposopathy to metabolic syndrome and how exercise may mediate these processes, and evaluates current evidence on the clinical efficacy of exercise in the management of abdominal obesity. The review also discusses the type and dose of exercise needed for optimal improvements in health status in relation to the available evidence and considers the difficulty in achieving adherence to exercise programmes. Conclusion: There is moderate evidence supporting the use of programmes of exercise to reverse metabolic syndrome although at present the optimal dose and type of exercise is unknown. The main challenge for health care professionals is how to motivate individuals to participate and adherence to programmes of exercise used prophylactically and as a treatment for metabolic syndrome. PMID- 29755741 TI - Sample manipulation and data assembly for robust microcrystal synchrotron crystallography. AB - With the recent developments in microcrystal handling, synchrotron microdiffraction beamline instrumentation and data analysis, microcrystal crystallo-graphy with crystal sizes of less than 10 um is appealing at synchrotrons. However, challenges remain in sample manipulation and data assembly for robust microcrystal synchrotron crystallography. Here, the development of micro-sized polyimide well-mounts for the manipulation of microcrystals of a few micrometres in size and the implementation of a robust data-analysis method for the assembly of rotational microdiffraction data sets from many microcrystals are described. The method demonstrates that microcrystals may be routinely utilized for the acquisition and assembly of complete data sets from synchrotron microdiffraction beamlines. PMID- 29755742 TI - Multiple-scale structures: from Faraday waves to soft-matter quasicrystals. AB - For many years, quasicrystals were observed only as solid-state metallic alloys, yet current research is now actively exploring their formation in a variety of soft materials, including systems of macromolecules, nanoparticles and colloids. Much effort is being invested in understanding the thermodynamic properties of these soft-matter quasicrystals in order to predict and possibly control the structures that form, and hopefully to shed light on the broader yet unresolved general questions of quasicrystal formation and stability. Moreover, the ability to control the self-assembly of soft quasicrystals may contribute to the development of novel photonics or other applications based on self-assembled metamaterials. Here a path is followed, leading to quantitative stability predictions, that starts with a model developed two decades ago to treat the formation of multiple-scale quasiperiodic Faraday waves (standing wave patterns in vibrating fluid surfaces) and which was later mapped onto systems of soft particles, interacting via multiple-scale pair potentials. The article reviews, and substantially expands, the quantitative predictions of these models, while correcting a few discrepancies in earlier calculations, and presents new analytical methods for treating the models. In so doing, a number of new stable quasicrystalline structures are found with octagonal, octadecagonal and higher order symmetries, some of which may, it is hoped, be observed in future experiments. PMID- 29755743 TI - Epoxide hydrolysis as a model system for understanding flux through a branched reaction scheme. AB - The epoxide hydrolase StEH1 catalyzes the hydrolysis of trans-methylstyrene oxide to 1-phenyl-propane-1,2-diol. The (S,S)-epoxide is exclusively transformed into the (1R,2S)-diol, while hydrolysis of the (R,R)-epoxide results in a mixture of product enantiomers. In order to understand the differences in the stereoconfigurations of the products, the reactions were studied kinetically during both the pre-steady-state and steady-state phases. A number of closely related StEH1 variants were analyzed in parallel, and the results were rationalized by structure-activity analysis using the available crystal structures of all tested enzyme variants. Finally, empirical valence-bond simulations were performed in order to provide additional insight into the observed kinetic behaviour and ratios of the diol product enantiomers. These combined data allow us to present a model for the flux through the catalyzed reactions. With the (R,R)-epoxide, ring opening may occur at either C atom and with similar energy barriers for hydrolysis, resulting in a mixture of diol enantiomer products. However, with the (S,S)-epoxide, although either epoxide C atom may react to form the covalent enzyme intermediate, only the pro-(R,S) alkylenzyme is amenable to subsequent hydrolysis. Previously contradictory observations from kinetics experiments as well as product ratios can therefore now be explained for this biocatalytically relevant enzyme. PMID- 29755744 TI - Enzyme catalysis captured using multiple structures from one crystal at varying temperatures. AB - High-resolution crystal structures of enzymes in relevant redox states have transformed our understanding of enzyme catalysis. Recent developments have demonstrated that X-rays can be used, via the generation of solvated electrons, to drive reactions in crystals at cryogenic temperatures (100 K) to generate 'structural movies' of enzyme reactions. However, a serious limitation at these temperatures is that protein conformational motion can be significantly supressed. Here, the recently developed MSOX (multiple serial structures from one crystal) approach has been applied to nitrite-bound copper nitrite reductase at room temperature and at 190 K, close to the glass transition. During both series of multiple structures, nitrite was initially observed in a 'top-hat' geometry, which was rapidly transformed to a 'side-on' configuration before conversion to side-on NO, followed by dissociation of NO and substitution by water to reform the resting state. Density functional theory calculations indicate that the top hat orientation corresponds to the oxidized type 2 copper site, while the side-on orientation is consistent with the reduced state. It is demonstrated that substrate-to-product conversion within the crystal occurs at a lower radiation dose at 190 K, allowing more of the enzyme catalytic cycle to be captured at high resolution than in the previous 100 K experiment. At room temperature the reaction was very rapid, but it remained possible to generate and characterize several structural states. These experiments open up the possibility of obtaining MSOX structural movies at multiple temperatures (MSOX-VT), providing an unparallelled level of structural information during catalysis for redox enzymes. PMID- 29755745 TI - Exploitation of knowledge databases in the synthesis of zinc(II) malonates with photo-sensitive and photo-insensitive N,N'-containing linkers. AB - Photoinitiated solid-state reactions are known to affect the physical properties of coordination polymers, such as fluorescence and sorption behaviour, and also afford extraordinary architectures (e.g. three-periodic structures with polyorganic ligands). However, the construction of novel photo-sensitive coordination polymers requires an understanding of the factors which govern the mutual disposition of reactive fragments. A series of zinc(II) malonate complexes with 1,2-bis(pyridin-4-yl)ethylene and its photo-insensitive analogues has been synthesized for the purpose of systematic analysis of their underlying nets and mutual disposition of N-donor ligands. The application of a big data-set analysis for the prediction of a variety of possible complex compositions, coordination environments and networks for a four-component system has been demonstrated for the first time. Seven of the nine compounds possess one of the highly probable topologies for their underlying nets; in addition, two novel closely related four coordinated networks were obtained. Complexes containing 1,2-bis(pyridin-4 yl)ethylene and 1,2-bis(pyridin-4-yl)ethane form isoreticular compounds more readily than those with 4,4'-bipyridine and 1,2-bis(pyridin-4-yl)ethylene. The effects of the precursor, either zinc(II) nitrate or zinc(II) acetate, on the composition and dimensionality of the resulting architecture are discussed. For three of the four novel complexes containing 1,2-bis(pyridin-4-yl)ethylene, the single-crystal-to-single-crystal [2 + 2] cycloaddition reactions were carried out. UV irradiation of these crystals afforded either the 0D->1D or the 3D->3D transformations, with and without network changes. One of the two 3D->3D transformations was accompanied by solvent (H2O) cleavage. PMID- 29755746 TI - Polymorphism of terthio-phene with surface confinement. AB - The origin of unknown polymorphic phases within thin films is still not well understood. This work reports on crystals of the molecule terthio-phene which were grown by thermal gradient crystallization using glass-plate substrates. The crystalline domains displayed a plate-like morphology with an extended lateral size of about 100 um, but a thickness of only a few um. Specular X-ray diffraction patterns confirmed the presence of a new polymorph of terthio-phene. Crystal structure solution from a single crystal peeled from the film revealed a structure with an extremely large unit-cell volume containing 42 independent molecules. In contrast to the previously determined crystal structure of terthio phene, a herringbone packing motif was observed where the terminal ends of the molecules are arranged within one plane (i.e. the molecular packing conforms to the flat substrate surface). This type of molecular packing is obtained by 180 degrees flipped molecules combined with partially random (disordered) occupation. A densely packed interface between terthio-phene crystallites and the substrate surface is obtained, this confirms that the new packing motif has adapted to the flat substrate surface. PMID- 29755747 TI - Structural studies of crystalline forms of triamterene with carboxylic acid, GRAS and API molecules. AB - Pharmaceutical salt solvates (dimethyl sulfoxide, DMSO) of the drug triamterene with the coformers acetic, succinic, adipic, pimelic, azelaic and nicotinic acid and ibuprofen are prepared by liquid-assisted grinding and solvent-evaporative crystallization. The modified DeltapKa rule as proposed by Cruz-Cabeza [(2012 ?). CrystEngComm, 14, 6362-6365] is in close agreement with the results of this study. All adducts were characterized by X-ray diffraction and thermal analytical techniques, including single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermal gravimetric analysis. Hydrogen bonded motifs combined to form a variety of extended tapes and sheets. Analysis of the crystal structures showed that all adducts existed as salt solvates and contained the amino-pyridinium-carboxyl-ate heterodimer, except for the solvate containing triamterene, ibuprofen and DMSO, as a result of the presence of a strong and stable hemitriamterenium duplex. A search of the Cambridge Structural Database (CSD 5.36, Version 1.18) to determine the frequency of occurrence of the putative supramolecular synthons found in this study showed good agreement with previous work. PMID- 29755748 TI - Molecular dynamics study of tridymite. AB - Structural changes in tridymite have been investigated by molecular dynamics simulation. Two thermal processes were carried out, one cooling from the high temperature hexagonal structure of tridymite (HP-tridymite) and the other heating from the low-temperature monoclinic structure of tridymite (MX1-tridymite). The former process showed that HP, LHP (low-temperature hexagonal structure), OC (orthorhombic structure with C2221 symmetry) and OP (orthorhombic structure with P212121 symmetry)-like structures appeared in sequence. In contrast, the latter process showed that MX1, OP, OC, LHP and HP-like structures appeared in sequence. Detailed analysis of the calculated structures showed that the configuration underwent stepwise changes associated with several characteristic modes. First, the structure of HP-tridymite determined from diffraction experiments was identified as a time-averaged structure in a similar manner to beta-cristobalite, thus indicating the important role of floppy modes of oxygen atoms at high temperature - one of the common features observed in silica crystals and glass. Secondly, the main structural changes were ascribed to a combination of distortion of the six-membered rings in the layers and misalignment between layers. We suggest that the slowing down of floppy oxygen movement invokes the multistage emergence of structures with lower symmetry on cooling. This study therefore not only reproduces the sequence of the main polymorphic transitions in tridymite, except for the appearance of the monoclinic phase, but also explains the microscopic dynamic structural changes in detail. PMID- 29755750 TI - Ionic scattering factors of atoms that compose biological molecules. AB - Ionic scattering factors of atoms that compose biological molecules have been computed by the multi-configuration Dirac-Fock method. These ions are chemically unstable and their scattering factors had not been reported except for O-. Yet these factors are required for the estimation of partial charges in protein molecules and nucleic acids. The electron scattering factors of these ions are particularly important as the electron scattering curves vary considerably between neutral and charged atoms in the spatial-resolution range explored in structural biology. The calculated X-ray and electron scattering factors have then been parameterized for the major scattering curve models used in X-ray and electron protein crystallography and single-particle cryo-EM. The X-ray and electron scattering factors and the fitting parameters are presented for future reference. PMID- 29755749 TI - pi-pi-Induced aggregation and single-crystal fluorescence anisotropy of 5,6,10b tri-aza-acephenanthrylene. AB - The structural origin of absorption and fluorescence anisotropy of the single crystal of the pi-conjugated heterocyclic system 5,6,10b-tri-aza-acephenan thrylene, TAAP, is presented in this study. X-ray analysis shows that the crystal framework in the space group P [Formula: see text] is formed by centrosymmetric dimers of face-to-face mutually oriented TAAP molecules joined by pi-pi non covalent interactions. The conformation of the TAAP molecule is stabilized by intramolecular C-H?N(sp2), N(sp2)H?pi(CN), and C-H?O(sp2) hydrogen bonds. The presence of weak pi-pi interactions is confirmed by quantum theory of atoms in molecules (QTAIM) and non-covalent interaction (NCI) analysis. The analysis of the optical spectra of TAAP in solution and in the solid state does not allow the specification of the aggregation type. DFT calculations for the dimer in the gas phase indicate that the lowest singlet excitation is forbidden by symmetry, suggesting H-type aggregation, even though the overall absorption spectrum is bathochromically shifted as for the J-type. The experimental determination of the permanent dipole moment of a TAAP molecule in 1,4-dioxane solution indicates the presence of the monomer form. The calculated absorption and emission spectra of the crystal in a simple approximation are consistent with the experimentally determined orientation of the absorption and emission transition dipole moments in TAAP single crystals. The electrostatic interaction between monomers with a permanent dipole moment (ca 4 D each) could result in the unusual spectroscopic JH-aggregate behaviour of the TAAP dimer. PMID- 29755751 TI - Heterogeneous local order in self-assembled nanoparticle films revealed by X-ray cross-correlations. AB - We report on the self-assembly of gold nanoparticles coated with a soft poly(ethylene glycol) shell studied by X-ray cross-correlation analysis. Depending on the initial concentration of gold nanoparticles used, structurally heterogeneous films were formed. The films feature hot spots of dominating four- and sixfold local order with patch sizes of a few micrometres, containing 104-105 particles. The amplitude of the order parameters suggested that a minimum sample amount was necessary to form well ordered local structures. Furthermore, the increasing variation in order parameters with sample thickness demonstrated a high degree of structural heterogeneity. This wealth of information cannot be obtained by the conventional microscopy techniques that are commonly used to study nanocrystal superstructures, as illustrated by complementary scanning electron microscopy measurements. PMID- 29755752 TI - Decoupling anion-ordering and spin-Peierls transitions in a strongly one dimensional organic conductor with a chessboard structure, (o-Me2TTF)2NO3. AB - A mixed-valence conducting cation radical salt of the unsymmetrically substituted o-Me2TTF donor molecule (TTF is tetrathiafulvalene) was obtained upon electrocrystallization in the presence of the non-centrosymmetric NO3- anion. It crystallizes at room temperature in the monoclinic P21/c space group, with the anion disordered on an inversion centre. The donor molecules are stacked along the a axis. A 90 degrees rotation of the longest molecular axis of o-Me2TTF generates a chessboard-like structure, preventing lateral S?S contacts between stacks and providing a strongly one-dimensional electronic system, as confirmed by overlap interaction energies and band structure calculations. A strong dimerization within the stacks explains the semi-conducting behaviour of the salt, with sigmaroom temp = 3-5 S cm-1 and Eactivated = 0.12-0.14 eV. An X-ray diffuse scattering survey of reciprocal space, combined with full structure resolutions at low temperatures (250, 85 and 20 K), evidenced the succession of two structural transitions: a ferroelastic one with an anion-ordering (AO) process and the establishment of a (0, 1/2, 1/2) superstructure below 124 (+/-3) K, also visible via resistivity thermal dependence, followed by a stack tetramerization with the establishment of a (1/2, 1/2, 1/2) superstructure below 90 (+/-5) K. The latter ground state is driven by a spin-Peierls (SP) instability, as demonstrated by the temperature dependence of the magnetic susceptibility. Surprisingly, these two kinds of instability appear to be fully decoupled here, at variance with other tetra-methyl-tetra-thia-fulvalene (TMTTF) or tetramethyl-tetra-selena-fulvalene (TMTSF) salts with such non-centrosymmetric counter-ions. PMID- 29755753 TI - Mental disorders among workers in the healthcare industry: 2014 national health insurance data. AB - Background: Numerous studies have shown that healthcare professionals are exposed to psychological distress. However, since most of these studies assessed psychological distress using self-reporting questionnaires, the magnitude of the problem is largely unknown. We evaluated the risks of mood disorders, anxiety disorders, sleep disorders, and any psychiatric disorders in workers in healthcare industry using Korea National Health Insurance (NHI) claims data from 2014, which are based on actual diagnoses instead of self-evaluation. Methods: We used Korea 2014 NHI claims data and classified employees as workers in the healthcare industry, based on companies in the NHI database that were registered with hospitals, clinics, public healthcare, and other medical services. To estimate the standardized prevalence of the selected mental health disorders, we calculated the prevalence of diseases in each age group and sex using the age distribution of the Korea population. To compare the risk of selected mental disorders among workers in the healthcare industry with those in other industries, we considered age, sex, and income quartile characteristics and conducted propensity scored matching. Results: In the matching study, workers in healthcare industry had higher odds ratios for mood disorders (1.13, 95% CI: 1.11 1.15), anxiety disorders (1.15, 95% CI: 1.13-1.17), sleep disorders (2.21, 95% CI: 2.18-2.24), and any psychiatric disorders (1.44, 95% CI: 1.43-1.46) than the reference group did. Among workers in healthcare industry, females had higher prevalence of psychiatric disorders than males, but the odds ratios for psychiatric disorders, compared to the reference group, were higher in male workers in healthcare industry than in females. Conclusions: The prevalence of mood disorders, anxiety disorders, sleep disorders, and all psychiatric disorders for workers in the healthcare industry was higher than that of other Korean workers. The strikingly high prevalence of sleep disorders could be related to the frequent night-shifts in these professions. The high prevalence of mental health problems among workers in healthcare industry is alarming and requires prompt action to protect the health of the "protectors." PMID- 29755754 TI - Chlamydia pneumoniae-induced tumour necrosis factor alpha responses are lower in children with asthma compared with non-asthma. AB - Introduction: Chlamydia pneumoniae respiratory tract infection has been implicated in the pathogenesis of reactive airway disease and asthma. Innate cytokine responses that are protective of infection with intracellular pathogens may be impaired in patients with asthma. Tumour necrosis factor alpha (TNF-alpha) is a cytokine related to functions of monocytes and may inhibit C. pneumoniae infection. We investigated TNF-alpha responses in C. pneumoniae-infected peripheral blood mononuclear cells (PBMCs) in patients with asthma and non asthma, and whether ciprofloxacin, azithromycin or doxycycline affects TNF-alpha responses. Methods: PBMC (1.5*106) from paediatric patients with asthma (n=19) and non-asthmatic controls (n=6) were infected or mock infected for 1 hour with or without C. pneumoniae AR-39 at a multiplicity of infection=0.1, and cultured+ciprofloxacin, azithromycin or doxycycline (0.1 ug/mL) for 48 hours. TNF alpha levels were measured in supernatants by ELISA. Results: When PBMC from patients with asthma were infected with C. pneumoniae, levels of TNF-alpha were significantly lower than in subjects without asthma (48 hours) (5.5+/-5.6, 38.4+/ 53.7; p=0.0113). However, baseline responses (no infection with C. pneumoniae) were similar in asthma and non-asthma (1.0+/-1.7, 1.1+/-1.2; p=0.89). When PBMC frompatiens with asthma were infected with C. pneumoniae+ciprofloxacin, azithromycin or doxycycline, TNF-alpha levels increased (25%-45%); this affect was not observed in PBMC from patients without asthma. Conclusions: We identified differences in the quantity of TNF-alpha produced by C. pneumoniae-infected PBMC in asthma compared with non-asthma. PMID- 29755755 TI - Lung volumes identify an at-risk group in persons with prolonged secondhand tobacco smoke exposure but without overt airflow obstruction. AB - Introduction: Exposure to secondhand smoke (SHS) is associated with occult obstructive lung disease as evident by abnormal airflow indices representing small airway disease despite having preserved spirometry (normal forced expiratory volume in 1 s-to-forced vital capacity ratio, FEV1/FVC). The significance of lung volumes that reflect air trapping in the presence of preserved spirometry is unclear. Methods: To investigate whether lung volumes representing air trapping could determine susceptibility to respiratory morbidity in people with SHS exposure but without spirometric chronic obstructive pulmonary disease, we examined a cohort of 256 subjects with prolonged occupational SHS exposure and preserved spirometry. We elicited symptom prevalence by structured questionnaires, examined functional capacity (maximum oxygen uptake, VO2max) by exercise testing, and estimated associations of those outcomes with air trapping (plethysmography-measured residual volume-to-total lung capacity ratio, RV/TLC), and progressive air trapping with exertion (increase in fraction of tidal breathing that is flow limited on expiration during exercise (per cent of expiratory flow limitation, %EFL)). Results: RV/TLC was within the predicted normal limits, but was highly variable spanning 22%+/-13% and 16%+/-8% across the increments of FEV1/FVC and FEV1, respectively. Respiratory complaints were prevalent (50.4%) with the most common symptom being >=2 episodes of cough per year (44.5%). Higher RV/TLC was associated with higher OR of reporting respiratory symptoms (n=256; r2=0.03; p=0.011) and lower VO2max (n=179; r2=0.47; p=0.013), and %EFL was negatively associated with VO2max (n=32; r2=0.40; p=0.017). Conclusions: In those at risk for obstruction due to SHS exposure but with preserved spirometry, higher RV/TLC identifies a subgroup with increased respiratory symptoms and lower exercise capacity. PMID- 29755756 TI - Treatment choice, medication adherence and glycemic efficacy in people with type 2 diabetes: a UK clinical practice database study. AB - Objective: Using primary care data obtained from the UK Clinical Practice Research Datalink, this retrospective cohort study examined the relationships between medication adherence and clinical outcomes in patients with type 2 diabetes. Research design and methods: Data were extracted for patients treated between 2008 and 2016, and stratified by oral antihyperglycemic agent (OHA) line of therapy (mono, dual or triple therapy). Patients were monitored for up to 365 days; associations between medication possession ratio (MPR) and outcomes at 1 year (glycated hemoglobin A1c (HbA1c), weight and hypoglycemia incidence) were assessed using linear regression modeling and descriptive analyses. Results: In total, 33 849 patients were included in the study (n=23 925 OHA monotherapy; n=8406 OHA dual therapy; n=1518 OHA triple therapy). One-year change in HbA1c was greater among adherent (-0.90 to -1.14%; -9.8 to -12.5 mmol/mol) compared with non-adherent patients (-0.49 to -0.69%; -5.4 to -7.5 mmol/mol). On average, adherent patients had higher hypoglycemia event rates than non-adherent patients (rate ratios of 1.24, 1.10 and 2.06 for OHA mono, dual and triple therapy cohorts, respectively) and experienced greater weight change from baseline. A 10% improvement in MPR was associated with -0.09% (-1.0 mmol/mol), -0.09% (-1.0 mmol/mol) and -0.21% (-2.3 mmol/mol) changes in HbA1c for OHA mono, dual and triple therapy cohorts, respectively. Conclusions: For patients with type 2 diabetes, increasing medication adherence can bring about meaningful improvements in HbA1c control as the requirement for treatment escalation increases. Regimens associated with weight loss and the avoidance of hypoglycemia were generally associated with better medication adherence and improved glycemic control. PMID- 29755757 TI - Need to improve awareness and treatment compliance in high-risk patients for diabetic complications in Nepal. AB - Objective/introduction: It is known that knowledge, awareness, and practice influence diabetic control. We compared factors pertaining to healthy lifestyle (exercising, avoiding smoking), self-help (attending appointments, following treatment regimens), and diabetic awareness in high-risk patients for diabetic complications, specifically, those on insulin versus non-insulin treatment, and also those with a longer diabetic duration (>=5 years) versus a shorter duration. Methods: 200 consecutive patients with type 2 diabetes (52.0+/-11.6 years) attending diabetic clinic at a referral hospital in Nepal were recruited. A structured questionnaire explored non-clinical parameters including age, gender, diabetic duration, awareness about diabetes control, self-help, and lifestyle. Clinical data were also measured: HbA1c, fasting blood sugar (FBS), blood pressure, and treatment type (insulin, diet/tablet). Results: A significantly higher proportion of patients on insulin (vs non-insulin) or with diabetic duration >=5 years (vs <5 years) self-reported not doing regular exercise, forgetting to take medicine, and not knowing whether their diabetes was controlled (p<=0.005). HbA1c/FBS levels were significantly higher for patients on insulin or with a longer diabetic duration (p<=0.001). 92% of those on insulin (vs 31% on non-insulin) and 91% with diabetic duration >=5 years (vs 28% of <5 years) self-reported to seeking medical help due to episodes of uncontrolled blood sugar in the last year (p<0.001). Conclusion: Poor self-help/lifestyle and reduced knowledge/awareness about diabetic control was found in patients on insulin or with longer diabetic duration. This is a worrying finding as these patients are already at high risk for developing diabetic complications. The findings highlight need for targeting this more vulnerable group and provide more support/diabetic educational tools. PMID- 29755759 TI - Neutron activation analysis with a Monte Carlo simulation for kidney stones. AB - Mechanistic questions regarding kidney stone formation have led researchers to look for the presence of trace elements. Neutron activation analysis is able to identify elements at parts-per-million concentrations. Four different types of kidney stones were irradiated with thermal neutrons to produce radioisotopes. Gamma spectroscopy of samples at different counting times was used to reduce identification errors by correlating results with the half-life of identified elements. For more precise identification, Monte Carlo simulation was used to cross-check the identification process. The simulation showed promising results that could lead to fast and accurate identification of trace elements as the simulation code is improved. Sodium (Na), potassium (K), calcium (Ca), bromine (Br), samarium (Sm), zinc (Zn), cadmium (Cd), ytterbium (Yb), gold (Au), cobalt (Co), and manganese (Mn) were identified as being present in the stones, by both the experimentally measured gamma spectrum and the simulation. Among these, Ca, Br, and Zn were found to be of potential clinical relevance via a literature review. Concentrations of the elements were compared to those noted in the literature. For uric acid stones, a correlation with the literature was found for Zn and Ca. A negative correlation was found between Zn and Br for non-uric acid stones. More samples are needed to test for statistical significance. PMID- 29755758 TI - Autoantibodies in chronic hepatitis C virus infection: impact on clinical outcomes and extrahepatic manifestations. AB - Goals: To examine the role that autoantibodies (auto-abs) play in chronic hepatitis C virus (HCV) regarding demographics, presence of extrahepatic manifestations and long-term outcomes in a large US cohort. Background: Auto-abs have been reported to be prevalent in patients with chronic HCV infection, but data on the natural history of these patients are limited. Study: The study included 1556 consecutive patients with HCV without concurrent HIV and/or HBV who had testing for antinuclear antibody (ANA), antimitochondrial antibody (AMA), antismooth muscle antibody (ASMA) and/or antiliver kidney microsomal antibody (LKM). Primary outcomes included development of cirrhosis, hepatic decompensations, hepatocellular carcinoma (HCC), mortality and/or sustained virological response (SVR) to antiviral therapy. Results: A total of 388 patients tested positive for any auto-ab (ANA 21.8%, ASMA 13.3%, AMA 2.2% and LKM 1.2%). Patients who tested positive versus negative were more likely to be women (29.3% vs 20.9%, p<0.001) and less likely to achieve SVR with most treated patients receiving interferon-based therapies (37.2% vs 47.1%, p=0.031). There was no difference between groups for baseline laboratory data, disease state or rate of extrahepatic manifestations (42.8% vs 45.0%, p=0.44). Kaplan-Meier analysis revealed no statistically significant difference between groups for the 10-year development of cirrhosis, hepatic decompensations, HCC nor survival. Furthermore, auto-ab positivity was only found to be a predictor for a lower rate of SVR on multivariate analysis (adjusted OR=1.61, 95 % CI 1.00 to 2.58, p=0.048). Conclusions: In our cohort, auto-ab positivity was common, especially in women, and predicted a lower rate of SVR but otherwise had no impact on the natural history of chronic HCV or presence of extrahepatic manifestations. PMID- 29755760 TI - Impact of measles supplementary immunisation activities on utilisation of maternal and child health services in low-income and middle-income countries. AB - Background: Measles supplementary immunisation activities (SIAs) are an integral component of measles elimination in low-income and middle-income countries (LMICs). Despite their success in increasing vaccination coverage, there are concerns about their negative consequences on routine services. Few studies have conducted quantitative assessments of SIA impact on utilisation of health services. Methods: We analysed the impact of SIAs on utilisation of selected maternal and child health services using Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 28 LMICs, where at least one SIA occurred over 2000-2014. Logistic regressions were conducted to investigate the association between SIAs and utilisation of the following services: facility delivery, postnatal care and outpatient sick child care (for fever, diarrhoea, cough). Results: SIAs do not appear to significantly impact utilisation of maternal and child services. We find a reduction in care-seeking for treatment of child cough (OR 0.67; 95% CI 0.48 to 0.95); and a few significant effects at the country level, suggesting the need for further investigation of the idiosyncratic effects of SIAs in each country. Conclusion: The paper contributes to the debate on vertical versus horizontal programmes to ensure universal access to vaccination. Measles SIAs do not seem to affect care-seeking for critical conditions. PMID- 29755761 TI - Distinctive features of gastrointestinal stromal tumors arising from the colon and rectum. AB - Background: Colon and rectal gastrointestinal stromal tumors (GISTs) are rare and poorly characterized. Because the majority of treatment guidelines for GISTs are extrapolated from tumors of gastric and small bowel origin, our aim was to better characterize the unique clinicopathologic features and prognostic factors of colon and rectal GISTs to guide clinical care. Methods: The National Cancer Data Base (NCDB) was queried from 2006 to 2013 for cases of GISTs in the stomach, colon, and rectum. Patient demographics, clinical characteristics, and survival were compared. Results: A total of 11,302 gastric GISTs were compared to 398 colon and 393 rectal GISTs. After propensity matching, compared to gastric GISTs, rectal GISTs had improved overall survival (HR =0.695, P=0.0264), while colon GISTs had worse overall survival (HR =1.6, P=0.0005). Surgical treatment for rectal GISTs was more likely to be local excision compared to colonic GISTs (51.1% vs. 8.4%, P<0.0001). Colon and gastric GISTs were less likely to receive systemic therapy compared to rectal GISTs (34.2% vs. 34.0% vs. 55.2%, P<0.0001). Adjuvant systemic therapy conveyed a survival advantage to rectal GISTs (HR =0.47, P=0.042) but not colon GISTs. There was a negative impact of adjuvant therapy on survival for colon GISTs <5 cm (HR =3.41, P=0.032). Conclusions: Patients with rectal GISTs live longer than those with colon and gastric GISTs, and adjuvant therapy prolongs their survival. Many patients with colon GISTs are treated with adjuvant therapy despite a detrimental effect on survival. Tumor biology of colon and rectal GISTs needs to be better studied to tailor treatment. PMID- 29755762 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in ovarian and gastrointestinal peritoneal carcinomatosis: results from a 7-year experience. AB - Background: An increasing promising evidence and increasing long-term oncologic outcomes support the use of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as locoregional treatment for peritoneal carcinosis (PC) especially from ovarian and gastrointestinal tumors, but also for others cancers. Methods: A prospective monocentric study was performed in Papa Giovanni XXIII Hospital, Bergamo (Italy). Patients and tumor characteristics were analyzed. Overall survival (OS), disease free survival (DFS) and morbidity were analyzed with Kaplan-Meier curves and log-rank testing. Results: A total of 150 patients undergone CRS + HIPEC were analyzed from January 2011 to June 2017. The principal origins of PC were: gastric cancer (GC) (n=40), colon cancer (n=31), appendiceal cancer (AC) (n=18), ovarian cancer (OC) (n=49), others (n=12). Major morbidity [>=3 Common Terminology Criteria for Adverse Events (CTCAE)] and perioperative mortality rates were 38% and 2.7% respectively. Re-operation rate was 15.3%. Median OS is 9, 35, 47, 51, 82 months (29% 3-year OS; 27% 5-year OS; 48% 5-year OS; 40% 5-year OS; 67% 5-year OS respectively) in GC, colorectal cancer (CRC), OC, others tumors and AC respectively. Median DFS is 4, 14, 17, 19, 82 months (32% 3-year DFS; 22% 5-year DFS; 29% 5-year DFS; 11% 5-year DFS; 67% 5 year DFS respectively) in GC, CRC, others tumors, OC and AC respectively. Conclusions: A therapeutic approach that combined CRS + HIPEC could achieve long term survival in selected groups of patients with PC from gastrointestinal, gynecological and others tumors with acceptable morbidity and mortality. A good expertise and a high volume of patients are necessary to manage PC and to further improve results. PMID- 29755763 TI - Prognostic factors and hazard ratios in colorectal cancer patients over 80 years of age: a retrospective, 20-year, single institution review. AB - Background: An aging population and a high incidence of colorectal cancer (CRC) in patients over the age of 80 make it important to understand survival times, hazard ratios and prognostic factors in this group. A better understanding of these factors will help clinicians determine appropriate therapeutic strategies for such patients, including when more aggressive treatment strategies may be preferred to palliative treatment. Methods: A retrospective analysis of 619 CRC patients of >=80 years of age from 1991-2010 at Baylor Scott & White Hospital in Temple, Texas. Twelve variables were analyzed through statistical analysis as potential prognostic factors for survival. Univariate and multivariate Cox proportional hazard models were used to determine hazard ratios. The elderly population was further stratified by age subgroup (80-84, 85-89, >=90). Results: Median survival time was 53.6, 30.0, and 11.3 months for age groups of 80-84, 85 89, and >=90, respectively. Median survival time for stage 0/I, II, III, and IV patients was 72.4, 53.5, 28.0, and 5.9 months, respectively. Patients not receiving surgery had significantly higher mortality (hazard ratio 2.605; 95% CI, 1.826-3.694). For stage III CRC patients, those not receiving chemotherapy had significantly higher mortality (hazard ratio 1.808; 95% CI, 1.018-1.827). Conclusions: Our study provides evidence to support the benefits of surgery and chemotherapy (for stage III) patients over 80, potentially contributing to improved clinical decisions in treating elderly CRC patients. Such patients are sometimes undertreated due to their underrepresentation in clinical trials. Additional prospective studies with a higher proportion of patients over 80 are needed. PMID- 29755765 TI - Travel distance and use of salvage palliative chemotherapy in patients with metastatic colorectal cancer. AB - Background: Salvage palliative chemotherapy in metastatic colorectal cancer has been associated with significant improvement in survival. However, not all patients receive all available therapies. Travel burden can affect patient access and use of future therapy. The present study aims to determine relationship between travel distance (TD) and salvage palliative chemotherapy in patients with metastatic colorectal cancer. Method: A patient cohort diagnosed with metastatic colorectal cancer during 2006-2010 in the province of Saskatchewan, Canada was studied. Logistic regression analyses were performed to assess relationship between travel distance and subsequent line therapies. Results: The median age of 264 eligible patients was 62 years [interquartile range (IQR): 53-72]. The patients who received salvage systemic therapy had a median distance to travel of 60.0 km (IQR: 4.7-144) compared with 88.1 km (IQR: 4.8-189) if they did not receive second- or third-line therapy (P=0.06). In multivariate analysis distance to the cancer center <100 km, odds ratio (OR) 1.69 (95% CI: 1.003-2.84), no metastasectomy, OR 1.89 (95% CI: 1.03-3.46), and absence of comorbid illness as per Charlson comorbid index, OR 1.45 (95% CI: 1.19-1.77) were correlated with the use of second- and subsequent line therapies. Conclusions: Our result revealed that travel distance to the cancer center greater than 100 km was associated less frequent use of second or subsequent line therapies in patients with metastatic colorectal cancer. PMID- 29755764 TI - Tumor location impact in stage II and III colon cancer: epidemiological and outcome evaluation. AB - Background: We aimed to describe clinico-pathological characteristics and differences between right-sided (RCC) and left-sided colon cancer (LCC) in Tunisian population. We also analyzed outcome to determine whether location is of prognostic significance. Methods: Clinico-pathological characteristics and Kaplan Meier survival were compared between two groups of LCC [150] and RCC [53] patients with stage II and III adenocarcinoma treated with curative intent between 2003-2014. Results: RCC patients were significantly more likely to be female, (56.6% vs. 39.3%, P=0.029) and to have undifferentiated tumor (87.1% vs. 8.4%, P=0.014), then LCC. After a median follow up of 49 months, 5-year overall survival (OS) was significantly worse in RCC vs. LCC [42% vs. 78%; hazard ratio (HR) =2.07; 95% CI: 1.05-4.09; P=0.03], no difference in relapse free survival (RFS) was observed. Median time to relapse was significantly shorter in RCC (15 months) vs. LCC (24 months), P=0.005. Tumor location significantly impacted survival in stage III, 5-year OS was 45% in RCC, and 63% in LCC, (HR =2.28; 95% CI: 1.01-5.24; P=0.04), there was no impact of tumor location in stage II, (HR =1.94; 95% CI: 0.54-6.93; P=0.29). Conclusions: Prognostic impact of tumor location should be considered as a stratification factor in the future clinical trials. PMID- 29755766 TI - Percutaneous irreversible electroporation with systemic treatment for locally advanced pancreatic adenocarcinoma. AB - Background: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. Methods: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. Results: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in patient stay was 1 day (range, 1-5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. Conclusions: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials. PMID- 29755767 TI - Utilization of neoadjuvant intensity-modulated radiation therapy and proton beam therapy for esophageal cancer in the United States. AB - Background: Randomized esophageal cancer (EC) trials have utilized two- or three dimensional conformal radiotherapy (3DCRT). Advanced radiotherapy (RT) techniques [(ARTs): intensity-modulated radiotherapy (IMRT) and proton beam therapy (PBT)] may have benefits, but are relatively unproven. This is the first study to date evaluating utilization of ARTs versus 3DCRT in the trimodality setting in the United States. Methods: The National Cancer Data Base (NCDB) was queried (2004 2013) for newly-diagnosed cT1b-T4bN0/N+M0 EC receiving neoadjuvant CRT followed by esophagectomy. The primary objective was to assess temporal trends, with multivariable logistic regression analysis assessing factors predictive of receiving ARTs. Secondarily, Kaplan-Meier analysis evaluated overall survival (OS), Cox proportional hazards modeling determined variables associated with OS, and postoperative complications were compared between cohorts. Results: Altogether, 3,138 patients met criteria; 1,398 (45%) received 3DCRT, and 1,740 (55%) received ARTs (99% IMRT, 1% PBT). Temporally, utilization of ARTs is steadily rising in the United States, from 20% in 2004 to 69% in 2013, corresponding with a progressive decrease in utilization of 3DCRT. ARTs were more often delivered with advancing age, squamous cell histology, N2+ disease, and at academic centers (P<0.05 for all). Centers in the Southwest were more likely to use ARTs, and those in the Midwest least likely (P<0.05 for both). As expected, there were no OS differences (P=0.8477); there were also no differences in postoperative events (P>0.05 for all). Treatment at an academic center independently correlated with improved OS (P<0.001). Conclusions: Utilization of ARTs (IMRT in the vast majority) is steadily rising in the United States; 3DCRT is now used in a minority of patients. This has implications for payers and insurance coverage. ART use is impacted by not only age and disease factors, but also regional and facility differences. Treatment at an academic facility independently correlated with higher survival, which has implications for patient counseling. PMID- 29755768 TI - Detecting promoter methylation pattern of apoptotic genes Apaf1 and Caspase8 in gastric carcinoma patients undergoing chemotherapy. AB - Background: DNA methylation patterns in cells dysregulation CpG island methylation of genes involved in cancer leads to increased levels of the cancer. Restoration of the apoptotic route in tumor cells of stomach in order for placing Casp8 and Apaf1 genes is a proper approach for new treatments of gastric cancer. The objective of the present study was to investigate the relationship between the pattern of methylation promoter in apoptotic genes of Casp8 and Apaf1 and gastric carcinoma in patients receiving chemotherapy. Methods: Genomic DNA was extracted from 30 samples of FFPE tumor, normal tissues and blood samples. Hyper methylation analysis of Casp8 and Apaf1 genes was conducted using MSP method; the results were analyzed through electrophoresis on agarose gel and software spss20. Results: In this study, methylation rate of Apaf1 gene with (P>0.05) was not significant but methylation rate of Casp8 gene with (P<0.05) was significant. In addition, there was a significant relationship between Apaf1 gene methylation in blood with stage (P<0.05), Apaf1 gene methylation in tissue with stage (P<0.05) and grade (P<0.01) and between Casp8 gene methylation in blood with age (P<0.001) of patients but no significant relationship was seen for other factors. Conclusions: Our results suggest that epigenetic mechanisms play an important role in the pathogenesis of gastric cancer and can be utilized as prognostic biomarkers for it. Also no significant difference between Casp8 and Apaf1 promoter hypermethylation in blood and tissue samples indicated that methylation status of blood sample can be early and non-invasive diagnostic marker in gastric cancer. PMID- 29755769 TI - An assessment of candidate genes to assist prognosis in gastric cancer. AB - Background: Gastric cancer (GC) is the fourth commonest cancer worldwide, with the second highest mortality rate. Its poor mortality is linked to delayed presentation. There is a drive towards non-invasive biomarker screening and monitoring of many different types of cancer, although with limited success so far. We aimed to determine if any genes from a 32-gene panel could be used to determine GC prognosis. Methods: We carried out a retrospective study on the expression of 32 genes, selected for their proven or potential links to GC, on historic formalin fixed paraffin-embedded (FFPE) GC specimens from our unit. Gene expression was measured using quantitative nuclease protection assays (qNPA) technology. Following statistical analysis of the results, immunohistochemical staining for eight genes, both discriminating and non-discriminating, was conducted in seven age and sex matched non-metastatic: metastatic GC pairings. The stained samples were reviewed by two blinded consultant histopathologists. Results: Multivariate Cox analysis of the gene expression data revealed metastatic status, age, sex and five genes appeared to influence GC survival. Genes negatively influencing survival included BCAS1, P53 and HSP90AA1 (relative risks 2.20, 3.73 and 7.53 respectively). Genes conveying survival benefit included CASP3 and TERT (relative risks 0.10 and 0.24 respectively). Immunohistochemical staining of seven age and sex matched non-metastatic: metastatic pairs revealed no association between gene expression and protein expression. Conclusions: Our study found several genes whose expression may affect GC prognosis. However, immunohistochemical analysis revealed no association between gene expression and protein expression. It remains to be determined whether gene expression or protein expression are reliable means of assessing GC prognosis. PMID- 29755770 TI - Safety and initial efficacy of radiation segmentectomy for the treatment of hepatic metastases. AB - Background: Hepatic metastatectomy and ablation are associated with prolonged survival, but not all lesions are anatomically amenable to these therapies. We evaluated safety and initial efficacy of segmental ablative transarterial radioembolization, or radiation segmentectomy (RS), as a treatment for hepatic metastases. Methods: A single institution retrospective analysis was performed of patients with hepatic metastases, determined unamenable to resection by a multidisciplinary tumor board, treated with RS from 2015-2017. Safety parameters evaluated were pre and post procedure liver chemistry, MELD score, ALBI grade, platelet count, and adverse events using both Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 and Clavien Dindo (CD) classifications. Initial efficacy was evaluated using RECIST, mRECIST, and PERCIST criteria. Results: Ten patients underwent between 1-3 RS treatments. There was no clinical treatment toxicity or significant post-treatment change in liver chemistry, MELD, or ALBI score. One patient had a CTCAE Grade 1/CD Grade 1 adverse event. All patients showed partial or complete imaging response at initial assessment (1-3 months). Seven patients demonstrated disease control at a mean of 7.1 months post treatment. Three patients developed out of field disease progression. One RS was technically unsuccessful. Conclusions: Early evaluation of segmental radioembolization suggests a safe treatment option for select patients with hepatic metastases. Initial efficacy as definitive radiotherapy with minimal toxicity is promising in anatomic locations unamenable to resection or alternative means of ablation. PMID- 29755771 TI - Preoperative survival calculator for resectable hepatocellular carcinoma. AB - Background: Estimation of preoperative overall survival (OS) of hepatocellular carcinoma (HCC) may guide surgical decision-making. Methods: OS was analyzed using the National Cancer Data Base from 1998-2012. Patients with HCC who underwent wedge resection, lobectomy or extended lobectomy were selected. Patients who had metastatic disease or previous treatment prior to surgery were excluded. Data was randomly allocated to model building (nb =4,364) and validation cohorts (nv =1,091). Multivariable regression analyses of the nb were used to construct prediction models and optimized using nv. Results: HCC patients (n=5,455) who underwent curative resection had a median OS of 36 months (95% CI, 34-38 months) with 1- and 3-year OS of 73% (95% CI, 72-74%) and 50% (95% CI, 49 51%), respectively. The patient median age was 65, 66% of patients were male, median tumor size was 60 mm; clinical stage 1 =25%, stage 2 =30% and stage 3 =45%. Alpha fetoprotein (AFP) was elevated in 63% of patients. Factors significant in the prediction model included degree of resection, age, race, tumor size, grade, and histologic subtype. Conclusions: A preoperative OS calculator was developed to assist in the treatment evaluation and OS prediction of HCC patients. PMID- 29755772 TI - Histological and immunohistochemical study of hepatoblastoma: correlation with tumour behaviour and survival. AB - Background: Hepatoblastoma (HB) has different histological subtypes, with varying prognosis. Though the survival has drastically improved, subsets of patients are not responsive to therapy. Therefore, it becomes important to determine the factors which affect the behaviour of the tumour. This study was aimed to look at the histopathological subtypes and compare with immunohistochemical (IHC) expression of CK19, beta-catenin and EpCAM and survival. Methods: This study included 55 cases of HB. IHC expression of CK19, beta-catenin and EpCAM were correlated with histological subtypes, tumour behaviour, response to chemotherapy and survival. Results: Most common epithelial subtype was fetal (43.2%) and mixed epithelial (54.8%) in pre- and post-chemotherapy groups respectively. Microvascular invasion (MVI) was present in 14/33 resected tumours. CK19 expression was seen in 54.2% and 72.2% of embryonal subtype, nuclear beta-catenin expression in 48.7% and 57.1% and EpCAM in 100% and 82.1% of tumours in pre- and post-chemotherapy groups, respectively. Fetal subtype had a lesser chance of MVI, recurrence, metastasis and death. Beta-catenin expression was associated with lower event free survival (EFS) and EpCAM with >=50% viable tumour following chemotherapy (P=0.04). Age at diagnosis <=2 years, male sex, alpha-fetoprotein <10,000 IU/mL following chemotherapy, solitary tumour (P=0.001), size <=5 cm, pretreatment extent of disease (PRETEXT) I&II, mitosis <=2/10 high power fields (hpf), viable tumour <50% (P=0.04) and absent nuclear expression of beta-catenin, predicted a higher EFS rate. Conclusions: Beta-catenin expression is associated with lower EFS and EpCAM expression with tumour viability. Multifocality and viable tumour >=50% were significant factors predicting lower EFS. These factors should be included in the prognostication of HBs. PMID- 29755773 TI - Early experience with cytoreduction and hyperthermic intraperitoneal chemotherapy at a newly developed center for peritoneal malignancy. AB - Background: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has improved outcomes for patients with peritoneal carcinomatosis (PC). We present our experience from a newly developed peritoneal surface malignancy program. Methods: An IRB approved retrospective review was performed for the first 50 patients treated with CRS/HIPEC with clinicopathologic data described. Results: Patients treated with CRS/HIPEC were Caucasian (64%), female (66%) with a median age of 53 years (range, 11-73 years). Primary pathology included: appendix (40%, n=20), ovary (20%, n=10), colon (14%, n=7), desmoplastic small round cell tumor (14%, n=7) or other (12%, n=6). The median peritoneal cancer index (PCI) score was 15.5 (range, 1-39) and 92% underwent complete cytoreduction (CCR 0/1). Median hospital length of stay was 9.0 days (range, 6-35 days). Eight patients (16%) suffered major morbidity with 2 (4%) 30-day mortalities. Conclusions: Short-term outcomes observed after CRS/HIPEC in a newly developed center for PC are consistent with published higher volume center experiences. PMID- 29755774 TI - Racial/ethnic disparities in gallbladder cancer receipt of treatments. AB - Background: Gallbladder cancer is a rare malignancy, yet it has a dismal prognosis. Overall survival has improved in all races/ethnicities except Hispanics and blacks. Despite improvements in gallbladder cancer management, it is not clear whether racial/ethnic disparities in stage at diagnosis and treatments exist that could potentially be the source of survival disparities. The purpose of this study was to examine race/ethnicity-specific trends in the stage of disease and receipt of treatments among adult gallbladder cancer patients in the US. Methods: Using the 2000-2013 Surveillance, Epidemiology, and End Results (SEER) 18 registries in the US. Race/ethnicity-specific cancer stage at diagnosis and treatments received among adults with gallbladder cancer were evaluated. Differences in gallbladder cancer stage at presentation, treatment modalities and number of lymph nodes (LN) removed among each race/ethnicity were evaluated using multivariate logistic regression models. Results: A total of 7,507 patients with gallbladder cancer were included. There were no racial/ethnic disparities in stage at diagnosis. With regard to disparities in treatments, blacks were significantly less likely to receive curative surgery compared to whites [adjusted odds ratio (AOR) 0.67, 95% CI: 0.56-0.80; P<0.001]. No racial/ethnic disparities in radiation therapy were observed. In patients undergoing curative surgery, Hispanics were significantly less likely to have optimal LN clearance compared to whites (AOR 0.59, 95% CI: 0.47-0.74; P<0.001). After stratification into 2-time periods (2000 to 2006 and 2007 to 2013), racial/ethnic disparities in treatments seemed to be more pronounced over time. Conclusions: Among US adults with gallbladder cancer, no racial/ethnic disparities in stage at diagnosis were observed. However, blacks, and Hispanics were less likely to receive curative surgery, and optimal LN clearance than Whites, which are consistent with the lack of survival improvements in those groups and they should be target groups for future studies to address treatment disparities. PMID- 29755775 TI - Rectal and anal canal neuroendocrine tumours. AB - Neuroendocrine tumors (NETs) are rare, representing 0.5% of all newly diagnosed malignancies. Rectal and anal canal (AC) NETs account for less than 1% of all rectal and AC cancers. Review our institutional experience on NET of the rectum and AC, with emphasis on demographic, histological and treatment features and oncologic outcomes. The study group was identified from the Portuguese Regional South Oncological Registry. From 2000 to 2014, 22 patients with rectal or AC NETs were treated at our institution. Medical records were retrospectively reviewed. There were 12 males (54.5%) and 10 females (45.5%) and the median age at diagnosis was 59.5 years. The majority had rectal NET (81.8%). All 4 patients with AC NETs had neuroendocrine carcinoid (NEC) tumors. Of the patients with rectal NETs, 3 had NEC and 15 had NET, mainly G1. Different approaches to treatment were made according to histological and staging features. After an average follow-up of 39.1 months, 16 patients were alive and only one with evidence of disease. The median time to progression was 12.4 months and the liver was the most frequent site of metastasis. The European and North American Neuroendocrine Societies offer guidelines for the treatment of rectal NETs. However, for AC NETs there are only small series and not prospective studies due to their rarity, hence the importance to report institutional experience. Our practice demonstrated that primary excisional treatment, regardless the histology, provides a favorable prognosis and long survival. PMID- 29755776 TI - Gastrointestinal stromal tumors in the imatinib era: 15 years' experience of a tertiary center. AB - Gastrointestinal stromal tumors (GISTs) were associated with a disease free survival rate of disease of 50% at 5 years, but the actual natural history since the advent of imatinib is poorly described. Our objective was to evaluate the evolution in the treatment and prognosis of patients with GISTs since the start of imatinib. Retrospective analysis of GISTs diagnosed between January 2000 and June 2015 in a Portuguese large volume center. We included 131 patients, 55% female, with a mean age of 64+/-14 years, followed for a median of 30 months; 64% of cases had gastric involvement; 92% of the tumors were c-Kit positive; 95% of patients were operated. Imatinib was initiated in 25% of patients, as adjuvant therapy in 69%; 75% reported adverse effects, and 16% developed resistance. The recurrence rate was 4%, and was associated with age at diagnosis (P=0.037), tumor size (P=0.028), presence of metastases (P=0.019) and high-risk lesions (P=0.036). Survival at 1, 3 and 5 years was 87%, 71% and 61%, respectively. One year's mortality was significantly associated with tumor size (P=0.021), stage IV at diagnosis (P=0.003), non-complete resection (P=0.002) and palliation with imatinib (P=0.035). Similar associations were observed at the 3 and 5 years. In the imatinib era there is an increased long-term survival in comparison with previous epidemiological data, and reduced recurrence rates. In more advanced cases survival remains limited in the short term. PMID- 29755778 TI - Second-line therapy in advanced upper gastrointestinal cancers: current status and new prospects. AB - The prognosis of patients with advanced upper gastrointestinal cancers (UGC) remains poor. Current available systemic armamentarium is limited, and little progress has been made over the last decades. Main achievements have been obtained in first-line setting, however an increasingly proportion of patients are considered for second-line therapy, although data from randomized trials are scarce or even lacking. In this comprehensive review we examine the literature to summarize the efficacy and limitations of second-line systemic options in patients with advanced UGC, with a glimpse into the innovations. PMID- 29755780 TI - Appendiceal diverticulosis: a harbinger of underlying primary appendiceal adenocarcinoma? AB - Diagnosis of primary appendiceal adenocarcinoma (PAA) is hindered by its rarity and largely asymptomatic nature. Appendiceal diverticulosis (AD) is equally rare. We report an unusual case of PAA presenting with perforated appendiceal diverticulitis, and discuss a review of the literature about its association, and its surgical and pathological implications. A middle-aged man was admitted with right iliac fossa (RIF) pain and a corresponding tender abdominal mass for 5 days. Computerised tomography (CT) scan demonstrated a thickened appendix with 3 cm abscess at its base. During laparoscopic appendicectomy, the appendiceal phlegmon was adhered to the surrounding bowel. Histology showed a perforated diverticulum near the appendiceal tip, and a primary appendiceal well differentiated adenocarcinoma located proximal to it with clear margins. Up to 48% of ADs are associated with appendiceal neoplasms, but its coexistence with PAA is reported in fewer than ten instances worldwide. Obstructing appendiceal tumours, by raising intraluminal pressure, can predispose to AD formation. Intestinal-type PAA is often managed like its colorectal counterpart, although controversies about management of PAA in a perforated AD remain. Recognition of the association of AD and PAA is critical to ensure meticulous oncological resection and histological examination. PMID- 29755781 TI - Prolonged survival of metastatic hepatocellular carcinoma: a case report. AB - Management of hepatocellular carcinoma (HCC) generally follows EASL-EORTC clinical practise guideline. We report a case of a 50-year-old man who had multinodular HCC with lung metastases, whose management had deviated from the standard guideline but still survive 5 years after initial diagnosis. PMID- 29755779 TI - Immune checkpoint inhibitors in gastrointestinal malignancies. AB - Gastrointestinal (GIT) tumors are extremely fatal and lethal tumors with limited therapeutic options. Antitumor immunity is new line of research in management of solid tumors. Immune check points are negative regulators of immune system and control the immune response. These checkpoints are exploited by cancer cells. Cancer cells causes early activation of checkpoints and suppress the immune response, and therefore have unchecked growth and metastasis of malignant cells. Immune checkpoint inhibitors (ICIs), downregulates these checkpoints and activate the proliferation of cytotoxic T cells which helps in lysis of tumor cells. ICIs have shown the promising results in management of melanoma, non-small cell lung cancer and renal cell carcinoma. Encouraged by their recent success in solid tumors many clinical trials are ongoing to evaluate their efficacy in GIT tumors. In this article we will try to explain rationale for use of ICIs in GIT tumors. We will summarize the ongoing research, preliminary results and future aspects of ICIs in GIT malignancies. PMID- 29755777 TI - Management of locally advanced rectal cancer in the elderly: a critical review and algorithm. AB - Colorectal cancer incidence and death rates have been declining over the past 10 years. However, it remains the second leading cause of death in men ages 60-79 and the third leading cause of death in men over 80 and in women over 60 years old. However, there is little data specific to the treatment of the elder patient, since few of these patients are included in trials. With the advent of improved therapies, there are many alternative options available. Still, no definitive consensus or guidelines have been defined for this particular patient population. The goal of this study is to review the literature on the management of rectal cancer in the elderly and to propose treatment algorithms to help the oncology team in treatment decision-making. PMID- 29755783 TI - Erratum to updated survival outcomes and analysis of long-term survivors from the MORE study on safety and efficacy of radioembolization in patients with unresectable colorectal cancer liver metastases. AB - [This corrects the article DOI: 10.21037/jgo.2017.03.10.]. PMID- 29755782 TI - FOLFIRINOX treatment leading to pathologic complete response of a locally advanced pancreatic cancer. AB - Pancreatic cancer (PC) is a lethal disease with a poor prognosis. It is typically asymptomatic and therefore most often diagnosed at an advanced stage. A primary unresectable PC can become resectable in case of tumor regression turning palliative into neoadjuvant therapy. We present a 67-year old female patient who was diagnosed with a locally advanced adenocarcinoma of the pancreatic head. After receiving palliative intended chemotherapy with the FOLFIRINOX regimen, staging computed tomography revealed local resectability of the pancreatic head tumor. The patient underwent an uneventful total pancreatectomy. Pathohistological investigation revealed a pathologic complete response (pCR). pCR after FOLFIRINOX treatment in primary unresectable PC is extremely rare. It might enable surgical resection and can increase the survival rate. PMID- 29755784 TI - Butin Attenuates Brain Edema in a Rat Model of Intracerebral Hemorrhage by Anti Inflammatory Pathway. AB - Background: This study evaluates the effect of butin against brain edema in intracerebral hemorrhage (ICH). Methodology: ICH was induced by injecting bacterial collagenase in the brain and all the animals were separated into four groups such as control group, ICH group treated with vehicle, Butin 25 and 50 mg/kg group receives butin (25 and 50 mg/kg, i.p.)60 min after the induction of ICH in all animals. One day after neurological score, hemorrhagic injury and expressions of protein responsible for apoptosis and inflammatory cytokines were assessed in the brain tissue of ICH rats. Result: Neurological scoring significantly increased and hemorrhagic lesion volume decreased in butin treated group of rats compared to ICH group. However, treatment with butin significantly decreases the ratio of Bax/Bcl-2 and protein expression of Cleaved caspase-3 than ICH group in dose dependent manner. Level of inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and interlukin-6 (IL-6) in the brain tissues were significantly decreased in the butin treated group than ICH group. In addition butin attenuates the altered signaling pathway of NF-kappaB in the brain tissues of ICH rats. Conclusion: Our study concludes that butin attenuates the altered behavior and neuronal condition in ICH rats by reducing apoptosis and inflammatory response. PMID- 29755785 TI - Extracellular Pectinase from a Novel Bacterium Chryseobacterium indologenes Strain SD and Its Application in Fruit Juice Clarification. AB - Pectinase is one of the important enzymes of industrial sectors. Presently, most of the pectinases are of plant origin but there are only a few reports on bacterial pectinases. The aim of the present study was to isolate a novel and potential pectinase producing bacterium as well as optimization of its various parameters for maximum enzyme production. A total of forty bacterial isolates were isolated from vegetable dump waste soil using standard plate count methods. Primary screening was done by hydrolysis of pectin. Pectinase activity was determined by measuring the increase in reducing sugar formed by the enzymatic hydrolysis of pectin. Among the bacterial isolates, the isolate K6 exhibited higher pectinase activity in broth medium and was selected for further studies. The selected bacterial isolate K6 was identified as Chryseobacterium indologenes strain SD. The isolate was found to produce maximum pectinase at 37 degrees C with pH 7.5 upon incubation for 72 hours, while cultured in production medium containing citrus pectin and yeast extract as C and N sources, respectively. During enzyme-substrate reaction phase, the enzyme exhibited its best activity at pH of 8.0 and temperature of 40 degrees C using citrus pectin as substrate. The pectinase of the isolate showed potentiality on different types of fruit juice clarification. PMID- 29755786 TI - Laparoscopic-Assisted Transgastric ERCP: A Single-Institution Experience. AB - Background: Laparoscopic-assisted transgastric endoscopic retrograde cholangiopancreatography (LAERCP) is used for treatment in patients after Roux-en Y gastric bypass (RYGB), where transoral access to the biliary tree is not possible. We describe our technique and experience with this procedure. Methods: Electronic medical record search was performed from September 2012 to January 2016, identifying patients who underwent LAERCP per operative records. Charts were reviewed for demographic, clinical, and outcomes data. Results: Sixteen patients were identified. Average time since bypass was 6.9 years, and length of stay was 3.7 days. Five patients underwent simultaneous cholecystectomy. Eleven patients, or 43%, had cholecystectomy more than 2 years previously. ERCP with sphincterotomy was completed in 15 of 16 patients (94%). Our technique involves access to the bypassed stomach via a laparoscopically placed 15 mm port. We observed one major complication of post-ERCP necrotizing pancreatitis. No minor complications nor mortalities were seen in our series. Conclusion: Biliary obstruction can occur many years after RYGB and cholecystectomy. Our findings suggest that RYGB patients may be at a higher risk of primary CBD stone formation. LAERCP is a reliable option for common bile duct (CBD) clearance; our technique of LAERCP is technically simple and associated with low complication rate, making it appealing to surgeons not trained in advanced laparoscopy. PMID- 29755787 TI - New Possibilities in Life with Type 2 Diabetes: Experiences from Participating in a Guided Self-Determination Programme in General Practice. AB - Research suggests that guided self-determination programmes can support self management of diabetes by empowering self-determined goal setting and competence building. As most research in this area has focused on people with type 1 diabetes, knowledge is lacking on how adults with type 2 diabetes mellitus experience participation in such programmes. This study reports the modelling phase of a complex intervention design that explored the experiences of adults with type 2 diabetes who participated in a nurse-led guided self-determination programme in general practice and examines how the programme affected patients' motivation to self-manage diabetes. The qualitative design with semistructured interviews included 9 adults with type 2 diabetes who participated in the programme. Qualitative content analysis was used to analyse the data. The findings indicate that the participants experienced new life possibilities after participating in the programme, which seemed to have a positive influence on their motivation for self-management. Through reflections about how to live with diabetes, the participants reinterpreted their life with diabetes by gradually developing a closer relationship with the disease, moving towards acceptance. The fact that dialogue with the nurses was seen to be on an equal footing helped support the participants to become more self-determined. PMID- 29755788 TI - Factors Associated with Participation in Pulmonary Tuberculosis Screening Using Chest X-Ray among Diabetes Mellitus Type II Patients in Denpasar, Bali, Indonesia. AB - Diabetes mellitus (DM) increases the risk of developing pulmonary tuberculosis (TB) disease. Therefore, pulmonary TB screening among DM patients is essential. This study aimed to identify factors associated with participation of DM type II patients in pulmonary TB screening using chest X-ray. This was a cross-sectional analytic study and was part of TB-DM screening study in Denpasar, Bali, Indonesia. The sample consisted of 365 DM type II patients selected by quota sampling among DM type II patients joining the screening program from January until March 2016 in 11 public health centres in Denpasar. Data were collected via structured interviews. The contributing factors were determined by modified Poisson regression test for cross-sectional data. From the findings, less than half (45.48%) of DM type II patients participated in chest X-ray examination for TB. Factors associated with participation in pulmonary TB screening were having a higher educational level [APR = 1.34, 95% CI (1.07-1.67)], having family member who developed pulmonary TB disease [APR = 1.47, 95% CI (1.12-1.93)], the travel time to referral hospital for screening being <= 15 minutes [APR = 1.6, 95% CI (1.26-2.03)], having health insurance [APR = 2.69, 95% CI (1.10-6.56)], and receiving good support from health provider [APR = 1.35, 95% CI (1.06-1.70)]. Therefore, training for health provider on providing counselling, involvement of family members in screening process, and improving the health insurance coverage and referral system are worth considering. PMID- 29755789 TI - Relationship of Meteorological and Air Pollution Parameters with Pneumonia in Elderly Patients. AB - Background and Purpose: In this study, we aimed to evaluate the relationship between pneumonia and meteorological parameters (temperature, humidity, precipitation, airborne particles, sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide (NO2), nitrite oxide (NO), and nitric oxide (NOX)) in patients with the diagnosis of pneumonia in the emergency department. Methods: Our study was performed retrospectively with patients over 65 years of age who were diagnosed with pneumonia. The meteorological variables in the days of diagnosing pneumonia were compared with the meteorological variables in the days without diagnosis of pneumonia. The sociodemographic characteristics, complete blood count of the patients, and meteorological parameters (temperature, humidity, precipitation, airborne particles, SO2, CO, NO2, NO, and NOX) were investigated. Results: When the temperature was high and low, the number of days consulted due to pneumonia was related to low air temperature (p < 0.05). During the periods when PM 10, NO, NO2, NOX, and CO levels were high, the number of days referred for pneumonia was increased (p < 0.05). Conclusion: As a result, climatic (temperature, humidity, pressure levels, rain, etc.) and environmental factors (airborne particles, CO, NO, and NOX) were found to be effective in the number of patients admitted to the hospital due to pneumonia. PMID- 29755790 TI - The Effect of a Textured Insole on Symmetry of Turning. AB - Turning while walking is a common daily activity. Individuals with unilateral impairment frequently perform turns asymmetrically. The purpose of the study was to investigate the effect of a discomfort-inducing textured insole on symmetry of turning. Nine healthy individuals performed turns to the right while walking with no insole, immediately after the insole was inserted in the right shoe, and after walking for six minutes with the insole. The duration of turning, displacements of pelvic markers, and perceived level of discomfort were evaluated. Utilizing the insole was associated with the increased level of perceived discomfort (p < 0.05). Moreover, using the insole was linked to changes in the displacement of two pelvic markers and larger asymmetry index while turning immediately after the insole was inserted in the right shoe as compared to no insole condition (p < 0.05). The duration of right turning increased immediately after the insole was inserted (p < 0.05) and after walking with the insole for six minutes. The results indicate that the textured insole creates asymmetry of turning in healthy individuals. The outcome provides a background for future studies focused on using a textured insole to minimize the asymmetry of turning commonly seen in individuals with unilateral impairment. PMID- 29755791 TI - Local Treatment of Metastatic Prostate Cancer: What is the Evidence So Far? AB - Background: Advances in technological, laboratorial, and imaging studies and new treatments available in the last decades significantly improved prostate cancer survival rates. However, this did not occur in metastatic prostate cancer (mPCa) at diagnosis which, in young and fit patients, will become invariably resistant to the established treatments. Progression will lead to an impairment in patients' quality of life and disease-related death. Methods: The authors intend to perform a literature review of the advantages of primary treatment of mPCa. Articles were retrieved and filtered for relevance from PubMed, SciELO, and ScienceDirect until March 2017. Results: Primary treatment is currently indicated only in cases of nonmetastatic PCa. Nonetheless, there might be some benefits in doing local treatment in mPCa in order to control local disease, prevent new metastasis, and improve the efficacy of chemotherapy and hormonotherapy with similar complications rate when compared to locally confined cancer. Independent factors that have a negative influence are age above 70 years, cT4 stage or high grade disease, PSA >= 20 ng/ml, and pelvic lymphadenopathies. The presence of 3 or more of these factors conditions CSS and OS is the same between patients who performed local treatment and those who did not. Metastasis degree and location number can also influence outcome. Meanwhile, patients with visceral metastases have worse results. Conclusions: There is growing evidence supporting local treatment in cases of metastatic prostate cancer at diagnosis in the context of a multimodal approach. However, it should be kept in mind that most of the existing studies are retrospective and it would be important to make consistent prospective studies with well-defined patient selection criteria in order to sustain the existing data and understand the main indications to select patients and perform primary treatment in mPCa. PMID- 29755792 TI - Sofosbuvir Plus Daclatasvir in Treatment of Chronic Hepatitis C Genotype 4 Infection in a Cohort of Egyptian Patients: An Experiment the Size of Egyptian Village. AB - Background and Aims: As indicated by the World Health Organization (WHO), Egypt is positioned as the country with the world's highest prevalence of Hepatitis C virus (HCV). HCV is transmitted through unexamined blood transfusions, different employments of syringes, and poor cleansing, as per the WHO. Our study aimed at screening and management of chronic hepatitis C genotype 4 infected patients in Bardeen village, Sharkeya Governorate, Egypt, with Sofosbuvir plus Daclatasvir, as well as estimating the safety and efficacy of that regimen. Methods: Screening of adult patients in Bardeen village was done from March 2016 till November 2016 using hepatitis C virus antibodies by third-generation ELISA testing. Positive results were confirmed by PCR. Patients eligible for treatment received Sofosbuvir 400 mg and Daclatasvir 60 mg daily for 12 weeks and were assessed for sustained virologic response at 12 weeks following the end of treatment (SVR 12). Results: Out of 2047 subjects screened for hepatitis C virus, 249 (12.2%) showed positive results. 221 out of those 249 subjects (88.7%) had detectable RNA by PCR. Treatment of eligible patients (183 patients) with Sofosbuvir plus Daclatasvir for 12 weeks resulted in 96% achievement of sustained virologic response at week 12. Adverse events were tolerable. Conclusion: Sofosbuvir plus Daclatasvir regimen is safe and effective for treatment of chronic hepatitis C Genotype 4 infected patients with minimal adverse events. HCV eradication program implemented in Egypt can be a model for other countries with HCV and limited resources. The availability of generic drugs in Egypt will help much in eradication of the virus. PMID- 29755793 TI - Timing of Frontal Plane Trunk Lean, Not Magnitude, Mediates Frontal Plane Knee Joint Loading in Patients with Moderate Medial Knee Osteoarthritis. AB - The purpose of this study was to examine the influence of trunk lean and contralateral hip abductor strength on the peak knee adduction moment (KAM) and rate of loading in persons with moderate medial knee osteoarthritis. Thirty-one males (17 with osteoarthritis, 14 controls) underwent 3-dimensional motion analysis, strength testing of hip abductors, and knee range of motion (ROM) measures, as well as completing the knee osteoarthritis outcome score (KOOS). No differences were found between groups or limbs for gait cycle duration, but the osteoarthritis group had longer double-limb support during weight acceptance (p < 0.001) and delayed frontal plane trunk motion towards the stance limb (p < 0.01). This was reflected by a lower rate of loading for the osteoarthritis group compared to controls (p < 0.001), whereas no differences were found for peak KAM. Trunk angle, contralateral hip abductor strength, and BMI explained the rate of loading at the involved knee (p < 0.001), an association not found for the contralateral knee or control knees. Prolonged trunk lean over the stance limb may help lower peak KAM values. Rate of frontal plane knee joint loading may partly be mediated by the contralateral limb's abductor strength, accentuating the importance of bilateral lower limb strength for persons with knee osteoarthritis. PMID- 29755794 TI - Time of Anderson-Fabry Disease Detection and Cardiovascular Presentation. AB - Background: Anderson-Fabry disease is an X-linked inherited disease, which manifests in a different manner depending on gender and genotype. Making a working diagnosis of Anderson-Fabry disease is difficult because of several reasons: (a) that it is a multiorgan disease with wide variety of phenotypes, (b) different timelines of presentation, (c) gender differences, and (d) possible coexistence with other comorbidities. Late-onset/cardiac type of presentation with minimal involvement of other organs can additionally make diagnosis difficult. Aim: To describe different cardiac manifestations at different time points in the course of the disease: (1) 72-year-old female (echocardiography detection), heterozygote, significant left and mild right ventricular hypertrophy; (2) 62-year-old male (echocardiography detection), hemizygote, left ventricular hypertrophy, implanted cardiac pacemaker, a performed percutaneous coronary intervention after myocardial infarction, degenerative medium degree aortic valve stenosis; (3) 45-year-old female (asymptomatic/family screening), heterozygote, thickened mitral papillary muscle, mild left ventricular hypertrophy, first degree diastolic dysfunction; and (4) 75-year-old female (symptomatic/family screening), heterozygote, cardiomyopathy with reduced left ventricular ejection fraction after heart surgery (mitral valve annuloplasty and plastic repair of the tricuspid valve). Conclusion: All patients have Anderson Fabry disease but with different clinical presentations depending on the gender, the type of mutation, and the time of detection. All these features can make the patients' profiles unique and delay the time of detection. PMID- 29755796 TI - Transorbital Craniocerebral Penetration by a Sharp Object with an Intact Globe. AB - Traumatic eye injuries are common in children and are mostly superficial. Vigilance must always be practiced when examining these children to avoid missing any hidden serious injuries that may result in devastating complications. We describe the acute and definitive management of a child treated 17 h after transorbital craniocerebral penetration by a sharp object. Despite the rarity of these types of injury, a good outcome can be achieved if they are promptly recognized and managed. PMID- 29755795 TI - Double Bolus Alteplase Therapy during Cardiopulmonary Resuscitation for Cardiac Arrest due to Massive Pulmonary Embolism Guided by Focused Bedside Echocardiography. AB - Massive pulmonary embolism (PE) frequently leads to cardiac arrest (CA) which carries an extremely high mortality rate. Although available, randomized trials have not shown survival benefits from thrombolytic use. Thrombolytics however have been used successfully during resuscitation in clinical practice in multiple case reports and in retrospective studies. Recent resuscitation guidelines recommend using alteplase for PE related CA; however they do not offer a standardized treatment regimen. The most consistently applied approach is an intravenous bolus of 50 mg tissue plasminogen activator (t-PA) early during cardiopulmonary resuscitation (CPR). There is no consensus on the subsequent dosing. We present a case in which two 50 mg boluses of t-PA were administered 20 minutes apart during CPR due to persistent hemodynamic compromise guided by bedside echocardiogram. The patient had an excellent outcome with normalization of cardiac function and no neurologic sequela. This case demonstrates the benefit of utilizing bedside echocardiography to guide administration of a second bolus of alteplase when there is persistent hemodynamic compromise despite achieving return of spontaneous circulation after the initial bolus, and there is evidence of persistent right ventricle dysfunction. Future trials are warranted to help establish guidelines for thrombolytic use in cardiac arrest to maximize safety and efficacy. PMID- 29755797 TI - A Rare and Lethal Complication: Cerebral Edema in the Adult Patient with Diabetic Ketoacidosis. AB - Commonly seen in the emergency department, diabetic ketoacidosis is a potentially lethal sequela of uncontrolled diabetes mellitus. In the adult population, a rare complication of diabetic ketoacidosis is cerebral edema. This case report discusses a 26-year-old male with new onset diabetes mellitus who developed cerebral edema leading to death. PMID- 29755798 TI - Bradycardia after Tube Thoracostomy for Spontaneous Pneumothorax. AB - We present the case of an elderly patient who became bradycardic after chest tube insertion for spontaneous pneumothorax. Arrhythmia is a rare complication of tube thoracostomy. Unlike other reported cases of chest tube induced arrhythmias, the bradycardia in our patient responded to resuscitative measures without removal or repositioning of the tube. Our patient, who had COPD, presented with shortness of breath due to spontaneous pneumothorax. Moments after tube insertion, patient developed severe bradycardia that responded to Atropine. In patients requiring chest tube insertion, it is important to be prepared to provide cardiopulmonary resuscitative therapy in case the patient develops a life-threatening arrhythmia. PMID- 29755799 TI - Spontaneous Regression of Metastatic Papillary Thyroid Cancer in a Lymph Node. AB - Spontaneous regression of cancer is defined as disappearance of cancer in the absence of specific therapy. In thyroid cancer patients with biochemically incomplete response to initial treatments, spontaneous decline in thyroglobulin levels without any cancer treatment is a well-known phenomenon; however, spontaneous regression of persistent or recurrent structural disease has not been reported. We here present a case of papillary thyroid cancer in a 58-year-old female who underwent total thyroidectomy and two radioiodine ablations. She had persistently elevated thyroglobulin levels. Six years after her initial treatments, she had biopsy-proven cervical lymph node metastasis. The patient opted not to undergo any further treatment. Over the course of the next 10 years, without any additional treatment, the lymph node disappeared and her thyroglobulin levels decreased to almost undetectable ranges, implying near complete regression. Our case illustrates that metastatic papillary thyroid cancer in lymph nodes can regress spontaneously. PMID- 29755800 TI - Hypothermia in Multiple Sclerosis: Beyond the Hypothalamus? A Case Report and Review of the Literature. AB - Hypothermia is a rare and poorly understood complication of Multiple Sclerosis (MS). We report on a 66-year-old patient currently with Secondary Progressive MS (SP-MS) who developed unexplained hypothermia associated with multiple hospitalisations and we review the literature on this topic. In our case, magnetic resonance imaging (MRI) of the brain failed to highlight hypothalamic disease, but spinal MRI identified a number of spinal cord lesions. Given the incidence and clinical significance of spinal involvement in MS and the hypothermic disturbances observed in high Spinal Cord Injury (SCI), we hypothesise that upper spinal cord pathology, along with hypothalamic and brainstem dysfunctions, can contribute to hypothermia. PMID- 29755801 TI - Central Hypoventilation: A Rare Complication of Wallenberg Syndrome. AB - Central alveolar hypoventilation disorders denote conditions resulting from underlying neurologic disorders affecting the sensors, the central controller, or the integration of those signals leading to insufficient ventilation and reduction in partial pressures of oxygen. We report a patient who presented with a left lateral medullary ischemic stroke after aneurysm repair who subsequently developed a rare complication of CAH. Increased awareness of this condition's clinical manifestations is crucial to make an accurate diagnosis and understand its complications and prognosis. PMID- 29755802 TI - Cytomegalovirus Colitis Masquerading as Apple-Core Lesion after Systemic Chemotherapy in a Patient with Relapsed Acute Myeloid Leukemia. AB - We report the case of a 71-year-old male with relapsed acute myeloid leukemia who developed cytomegalovirus (CMV) colitis presenting as an apple-core lesion during induction chemotherapy. CMV infection occurs rarely during induction chemotherapy for acute myeloid leukemia. CMV infection is usually observed in patients with acquired immune deficiency syndrome (AIDS) and in those on immunosuppressive agents following bone marrow transplant. Although rare, CMV colitis should be considered in patients who are critically ill after systemic chemotherapy as it can cause significant morbidity and mortality. PMID- 29755803 TI - Acute Mastoiditis Complicated with Concomitant Bezold's Abscess and Lateral Sinus Thrombosis. AB - Bezold's abscess is a very rare extracranial complication of acute mastoiditis. Lateral sinus thrombosis is another intracranial complication of acute mastoiditis that can occur, but there are only few reports of concomitant ispilateral Bezold's abscess and lateral sinus thrombosis with favorable outcome. We diagnosed and treated successfully a 14-year-old girl suffering from Streptococcus pneumoniae acute mastoiditis complicated with Bezold's abscess and lateral sinus thrombosis. Surgical treatment included myringotomy, cortical mastoidectomy, and Bezold's abscess incision and drainage. During the course of treatment, we concluded that lateral sinus thrombosis was not caused from mastoiditis by direct spread but from pressure on internal jugular vein caused from Bezold's abscess. PMID- 29755804 TI - SAPHO Syndrome Masquerading as Metastatic Breast Cancer. AB - SAPHO syndrome is a rare clinical entity composed of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO). We describe a case of SAPHO syndrome masquerading as metastatic breast cancer in a patient with localized breast cancer who presented with cord compression. There was no pathologic evidence of metastatic cancer; however, a bone scan indicated osseous involvement. After multidisciplinary review of images and with additional findings of pustulosis and acne, a clinical diagnosis of SAPHO was made. PMID- 29755805 TI - Analysis of Bacterial Diversity in Different Heavy Oil Wells of a Reservoir in South Oman with Alkaline pH. AB - The identification of potential hydrocarbon utilizing bacteria is an essential requirement in microbial enhanced oil recovery (MEOR). Molecular approaches like proteomic and genomic characterization of the isolates are replacing the traditional method of identification with systemic classification. Genotypic profiling of the isolates includes fingerprint or pattern-based technique and sequence-based technique. Understanding community structure and dynamics is essential for studying diversity profiles and is challenging in the case of microbial analysis. The present study aims to understand the bacterial community composition from different heavy oil contaminated soil samples collected from geographically related oil well areas in Oman and to identify spore-forming hydrocarbon utilizing cultivable bacteria. V4 region of 16S rDNA gene was the target for Ion PGMTM. A total of 825081 raw sequences were obtained from Ion torrent from all the 10 soil samples. The species richness and evenness were found to be moderate in all the samples with four main phyla, Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria, the most abundant being Firmicutes. Bacillus sp. ubiquitously dominated in all samples followed by Paenibacillus, which was followed by Brevibacillus, Planococcus, and Flavobacterium. Principal Coordinate Analysis (PCoA) and UPGMA dendrogram clustered the 10 soil samples into four main groups. Weighted UniFrac significance test determined that there was significant difference in the communities present in soil samples examined. It can be concluded that the microbial community was different in all the 10 soil samples with Bacillus and Paenibacillus sp. as predominating genus. The 16S rDNA sequencing of cultivable spore-forming bacteria identified the hydrocarbon utilizing bacteria as Bacillus and Paenibacillus sp. and the nucleotide sequences were submitted to NCBI GenBank under accession numbers KP119097-KP119115. Bacillus and Paenibacillus sp., which were relatively abundant in the oil fields, can be recommended to be chosen as candidates for hydrocarbon utilization study. PMID- 29755806 TI - Massive Hemoptysis: Danger is Real, Promptness is Essential. PMID- 29755807 TI - Assessing the Prevalence and Incidence of Asthma and Chronic Obstructive Pulmonary Disease in the Eastern Mediterranean Region. AB - OBJECTIVES: This study conducted in 2016 aimed to assess the prevalence and incidence of asthma and chronic obstructive pulmonary disease (COPD) in the Eastern Mediterranean Region (EMR). MATERIAL AND METHODS: A meta-analysis to evaluate the published research relating to asthma and COPD was conducted using data from 23 EMR Office (EMRO) countries and searching using the web of science, PubMed, SciVerse Scopus, Google scholar, and MEDLINE databases. The keywords entered were all EMRO countries (Afghanistan, Bahrain, Djibouti, Egypt, Islamic republic Iran, Iraq, Jordan, Kuwait, Lebanon, Libyan Arab Jamahiriya, Morocco, Oman, Pakistan, Palestine, Qatar, Saudi Arab, Somalia, Sudan, Syrian Arab Republic, Tunisia, the United Arab Emirates, Yemen republic, and Cyprus) and asthma OR chronic obstructive pulmonary disease (COPD) OR (chronic bronchitis). Our definition of asthma and COPD was according to the World Health Organization (WHO). RESULTS: A total of 92 published articles were identified. The pooled prevalence of asthma and COPD was 9.38 (confidence interval [CI]: 9.20-9.55) and 5.39 (CI: 5.17-5.62), respectively. There were no articles about COPD and asthma in Bahrain and Djibouti; no articles about asthma in Jordan and Libyan Arab Jamahiriya; and no articles about COPD in Afghanistan, Iraq, Oman, Palestine, Somalia, Sudan, and Yemen republic. The highest prevalence of asthma was observed in Kuwait, and the highest prevalence of COPD was observed in Pakistan. CONCLUSION: The EMRO countries have inadequate research and data in the areas of asthma and COPD. More efforts and relevant studies must be conducted to understand the countrywide prevalence and real burden of these diseases. PMID- 29755808 TI - The Role of Duration of Hyperbaric Oxygen Therapy on Lung Injury: An Experimental Study Lung Injury and Hyperbaric Oxygen Therapy. AB - OBJECTIVES: We aim to histopathologically analyze the effect of hyperbaric oxygen (HBO) therapy in the lung tissue. MATERIAL AND METHODS: A total of 21 rabbits were divided into three groups, with each containing seven rabbits. Group 1 was the control group. Group 2 underwent HBO of 3 atmosphere absolute (ATA) for 90 min/day for 7 days. In group 3, HBO at 3 ATA was administered 90 min/day for 28 days. Oxygen saturation (SpO2) was determined by pulse oximetry before and after administration of HBO. Rabbits were sacrificed, and the apex of the right lung was excised. RESULTS: SpO2 was 98-100% in all rabbits before HBO administration. After the procedure, the mean SpO2 was 92% and 83% in groups 2 and 3, respectively. As expected, histopathologic examination in group 1 was normal. In group 2, congestion in the lung vessels, mononuclear cell infiltration in the bronchial mucosa, interstitial edema, and alveolar dilation were evident. Histopathologic examination in group 3 indicated diffuse alveolar edema, peribronchial mononuclear cell infiltration, thickening of the alveolar and vessel wall, and intraalveolar hemorrhage. CONCLUSION: There is a strict relationship between duration of HBO administration and severity of lung injury. PMID- 29755809 TI - A 12-week, Randomized, Parallel-group, Phase III Study Comparing the Efficacy of Once-daily Budesonide/formoterol Turbuhaler (160/4.5 MUg/d) with Twice-daily Budesonide (400 MUg/d) During the Step-down Period in Well-controlled Asthma. AB - OBJECTIVES: Budesonide/formoterol fumarate (BUD/FF) is recommended in the stepwise management of uncontrolled asthma, but data on a once-daily dose of this medication in a step-down period are lacking. We aimed to compare BUD/FF and BUD in terms of the changes in asthma control scores and lung functions. MATERIAL AND METHODS: This 12-week, randomized, parallel-group, single-center, open-label study was conducted in well-controlled asthmatic patients receiving twice-daily BUD/FF (160/4.5 MUg 2 inhalations) randomized into once-daily BUD/FF (160/4.5 MUg 1 inhalation) or twice-daily BUD (200 MUg 2 inhalations). RESULTS: At week 12, the medians of Asthma Control Test (ACT) were 23 (interquartile range [IQR]: 22 24) in the BUD/FF group and 23 (IQR: 22-24.5) in the BUD group, while the medians of Asthma Control Questionnaire (ACQ) were 0.43 (IQR: 0.29-0.82) in the BUD/FF group and 0.57 (IQR: 0.43-0.93) in the BUD group. No statistically significant difference was observed in either ACT (p=0.673) or ACQ (p=0.295) between the treatments. The ACT scores significantly decreased from baseline to week 12 in both treatments. Peak expiratory flow (PEF) and forced expiratory volume in 1 second (FEV1) also had no statistically significant differences between treatments. PEF in the BUD/FF group and FEV1 in both treatments significantly decreased from baseline to week 12. CONCLUSION: Compared to twice-daily BUD, once daily BUD/FF provides equivalent asthma control scores and lung function during the step-down period after switching from twice-daily doses of BUD/FF in well controlled asthma. PMID- 29755810 TI - Evaluation of Traffic Accident Risk in In-City Bus Drivers: The Use of Berlin Questionnaire. AB - OBJECTIVES: Traffic accidents associated with high mortality rate may produce serious problems especially in highways. Obstructive sleep apnea (OSA) has been associated with a high risk for traffic accidents due to excessive daytime sleepiness even in in-city drivers. In the present study, it was aimed to evaluate the rate of OSA symptoms and to identify risk factors associated with traffic accidents in in-city bus drivers. MATERIAL AND METHODS: A self administered questionnaire including demographic and anthropometric features, sleep and work schedules, Berlin questionnaire, Epworth sleepiness score (ESS), and history of traffic accidents was used. RESULTS: The questionnaire was conducted for 1400 male bus drivers (mean age, 38.0+/-6.4 y, body mass index, 27.8+/-3.9 kg/m2). A total of 1058 (75.6%) drivers had one or more accidents while driving bus. According to the Berlin questionnaire, 176 (12.6%) drivers were found to have high OSA risk and the accident rate was 83.0% in high-risk group, whereas 74.5% of low-risk drivers had accidents (p=0.043). The drivers with a history of traffic accident were older (p=0.030), had higher ESS (p=0.019), and were more in the high-risk OSA group according to the Berlin questionnaire (p=0.015). In multivariate linear regression analysis, traffic accident was associated with only Berlin questionnaire (p=0.015). CONCLUSION: The present results support that city bus drivers with high OSA risk according to Berlin questionnaire have increased accident rates. Therefore, we suggest using Berlin questionnaire for screening sleep apnea not only in highway drivers but also in in-city bus drivers. PMID- 29755811 TI - Occupational Risk Factors and the Relationship of Smoking with Anxiety and Depression. AB - OBJECTIVES: The aim of the present study was to evaluate the relation of smoking with anxiety and depression in workers who were exposed to occupational risk factors. For this purpose, working time, smoking status, nicotine dependence, and respiratory functions of the workers who were exposed to physical and/or chemical harmful substances were evaluated and the presence of anxiety/depression was investigated. MATERIAL AND METHODS: Male workers who were exposed to occupational risk factors such as solvents, heavy metals, and dust and visited the outpatient clinic for occupational diseases within a one-year period were included. Pulmonary Function Test and Fagerstrom Test for Nicotine Dependence were performed. Anxiety and depression statuses of the workers were assessed using the Hospital Anxiety and Depression Scale. RESULTS: The mean age of 665 male workers was 45 y (range, 38-48 y), and they were most commonly exposed to solvents (45.9%), followed by heavy metal fume/dust (20.9%). Of the workers, 252 (37.9%) had anxiety, 294 (44.2%) had depression, and 171 (25.7%) had both. More than half of the workers in each occupation/exposure group were smokers. Respiratory complaints were present in 34% of the workers. According to the regression analysis, the presence of respiratory system complaints was found to be a significant risk factor for anxiety, depression, and anxiety plus depression. CONCLUSION: In conclusion, smoking and anxiety/depression were found to be the conditions affecting more than half of the workers with occupational exposure. PMID- 29755812 TI - Is Bilateral Staged Muscle-Sparing Thoracotomy Performed within 1 Week for Lung Hydatid Cysts Safe for Pediatric Patients? AB - OBJECTIVES: Median sternotomy or staged thoracotomies are generally the preferred surgical treatment options for bilateral lung hydatid cysts. According to literature, it is usually recommended to wait from 3 weeks to 3 months between bilateral staged thoracotomies. The aim of this study is to compare postoperative complications, hospitalization days and morbidity and mortality ratios between unilateral thoracotomy and bilateral staged thoracotomy groups and to evaluate the safety of performing bilateral staged thoracotomy within 1 week for lung hydatid cysts in pediatric patients. MATERIAL AND METHODS: In total, 112 patients under the age of 16 years who underwent surgery between 2000 and 2016 because of pulmonary hydatid cysts were included in this study. The patients were classified into two groups as Group 1 (unilateral muscle-sparing thoracotomy) and Group 2 (bilateral staged muscle-sparing thoracotomy applied within 1 week). RESULTS: There were 91 patients in Group 1 and 21 patients in Group 2. No statistically significant differences were detected when both groups were compared by age, gender, perforation rates, follow-up period and postoperative complications. CONCLUSION: To prevent hydatid cysts complications, the elapsed time between two thoracotomies should be not only long enough to evaluate the postoperative complications but also relatively short to prevent possible complications that may develop in the other lung. In our opinion, a patient follow-up of 3-7 days between thoracotomies is sufficient for the assessment of patients' clinical status and possible complications. PMID- 29755814 TI - Massive Hemoptysis from a Pulmonary Artery Pseudoaneurysm during Cardiac Surgery. AB - Massive hemoptysis is a life-threatening condition usually related to a pathology of the bronchial arteries. Pulmonary artery pseudoaneurysms represent a relatively rare cause of severe airway bleeding, but are associated with a mortality rate of over 50%. A case of massive intraoperative hemoptysis treated with temporary occlusion of the right pulmonary artery and delayed endovascular occlusion of the feeding segmental artery is described. PMID- 29755813 TI - Silicosis in Turkey: Is it an Endless Nightmare or is There Still Hope? AB - Silicosis is an ancient but still life-threatening occupational lung disease because of its incurable nature. Although its risks are known in many occupational settings and effective control strategies are well established, new cases, even epidemics, continue to occur in different sectors of Turkey. Before taking action, defining the magnitude of the problem is essential. In this concise review, we aimed to present the current situation of silicosis in Turkey. According to the data available to date, silicosis continues to be a major health problem in different sectors. Sandblasting seems to have the highest risk for the development of silicosis. Disease onset at early age and history of short exposure duration may indicate intense silica exposure. After denim sandblasters, dental technicians seem to be the new and recently recognized high-risk occupation group as per the increasing reports. Because of the lack of a definite treatment of silicosis, prevention of the disease should be the main target. Better occupational disease registry systems would be useful to assess the magnitude of the problem. In addition to implementing the necessary regulations, a close inspection of the workplaces for potential risks is essential. Other social and economic factors related with the occurrence of disease, such as unregistered employment rate and unlicensed and uninsured work, should also be considered. Finally, optimal healthcare and better living conditions for patients with silicosis should be ensured. PMID- 29755815 TI - Late Endobronchial Pulmonary Metastasis in a Patient with Breast Cancer. AB - The lung is a common location for malignant metastases. However, endobronchial metastases from nonpulmonary neoplasms are rare. Metastatic breast cancer usually occurs in 2-3 years of the disease course. A 65-year-old woman visited our hospital for the evaluation of dry cough. The patient had a history of breast cancer, which was treated with modified radical mastectomy and axillary dissection 10 years ago; she was then treated with aromatase inhibitor for 5 years. Chest X-ray revealed right hilum enlargement. Thorax computed tomography revealed a 35-mm diameter mass that was localized in the right hilum. Fiberoptic bronchoscopy was performed, and an endobronchial lesion was observed in the right main lobe carina. Pathological evaluation revealed that the mass was a metastasis of the invasive ductal carcinoma of the breast. Weekly paklitaxel chemotherapy was initiated because of the symptomatic disease. We reported the case of a patient with breast cancer who had an endobronchial metastasis. Her disease-free interval was 10 years. This case indicates that a long-term follow-up of breast cancer is necessary, and biopsies must be performed to make a final diagnosis when any suspicious hilum enlargement is observed. PMID- 29755816 TI - Does Dry Eye Affect Repeatability of Corneal Topography Measurements? AB - Objectives: The purpose of this study was to assess the repeatability of corneal topography measurements in dry eye patients and healthy controls. Materials and Methods: Participants underwent consecutive corneal topography measurements (Sirius; Costruzione Strumenti Oftalmici, Florence, Italy). Two images with acquisition quality higher than 90% were accepted. The following parameters were evaluated: minimum and central corneal thickness, aqueous depth, apex curvature, anterior chamber volume, horizontal anterior chamber diameter, iridocorneal angle, cornea volume, and average simulated keratometry. Repeatability was assessed by calculating intra-class correlation coefficient. Results: Thirty three patients with dry eye syndrome and 40 healthy controls were enrolled to the study. The groups were similar in terms of age (39 [18-65] vs. 30.5 [18-65] years, p=0.198) and gender (M/F: 4/29 vs. 8/32, p=0.366). Intra-class correlation coefficients among all topography parameters within both groups showed excellent repeatability (>0.90). Conclusion: The anterior segment measurements provided by the Sirius corneal topography system were highly repeatable for dry eye patients and are sufficiently reliable for clinical practice and research. PMID- 29755817 TI - Comparison of Electrocoagulation and Conventional Medical Drops for Treatment of Conjunctivochalasis: Short-Term Results. AB - Objectives: To compare the effectiveness of electrocoagulation and conventional medical drops for treatment of conjunctivochalasis using anterior segment-optical coherence tomography (AS-OCT). Materials and Methods: Forty eyes of 20 patients with bilateral conjunctivochalasis were included in this prospective study. Twenty eyes of 10 patients were assigned to Group 1 and underwent electrocoagulation. The other 20 eyes of 10 patients were assigned to Group 2 and received conventional medical treatment consisting of non-steroidal antiinflammatory drop (topical 0.5% ketorolac tromethamine) 4 times a day and artificial tears (0.15% sodium hyaluronate) 6 times a day for 4 weeks. Before and 4 weeks after treatment, all patients were evaluated by slit-lamp biomicroscopy, tear film break-up time (TBUT) test, and ocular surface disease index (OSDI) questionnaire. Tear meniscus height (TMH), tear meniscus area (TMA), and conjunctivochalasis area (CCA) were measured with AS-OCT. Results: In Group 1, posttreatment values of TMH, TMA, and TBUT were significantly higher (p<0.001, p=0.006, and p<0.001, respectively), while CCA and OSDI scores were significantly lower than pretreatment values (p<0.001 for both values). In Group 2, only OSDI decreased significantly between pretreatment and posttreatment values (p<0.001). The other parameters did not change significantly after treatment (p>0.05 for all values). Conclusion: Electrocoagulation is an effective modality for treatment of conjunctivochalasis. PMID- 29755818 TI - Retinal Angiomatous Proliferation: Multimodal Imaging Characteristics and Follow up with Eye-Tracked Spectral Domain Optical Coherence Tomography of Precursor Lesions. AB - Objectives: To present the multimodal imaging characteristics of precursor retinal angiomatous proliferation (RAP) lesions and follow-up results with eye tracked spectral-domain optical coherence tomography (SD-OCT). Materials and Methods: Six eyes of 6 patients aged 77.5+/-5.9 years diagnosed with precursor RAP lesion were included in this prospective observational case series. Best corrected visual acuity (BCVA) measurement and complete ophthalmologic examination were performed for all subjects, as well as fundus photography (FP), fundus autofluorescence (FAF), SD-OCT, fluorescein angiography (FA), indocyanine green angiography (ICGA), optical coherence tomography angiography (OCTA), and their long-term follow-up results are presented. Results: The mean BCVA was 0.8+/ 0.16 (0.6-1) Snellen and the mean follow-up was 26.3+/-14.8 months. Images of the precursor RAP lesions demonstrated no specific findings on FP and FAF, showed focal hypofluorescent foci with no leakage on FA and IGA, and appeared as extrafoveal small, round, well-defined, hyperreflective foci typically located in the outer retinal layers on SD-OCT B-scans with high sampling density. OCTA demonstrated the precursor lesions as the deep capillary plexus abnormalities in 3 eyes. Two eyes progressed to stage 1 RAP during the follow-up period. Conclusion: This study defined the diagnostic characteristics and clinical course of precursor RAP lesions. Our findings highlight the importance of B-scans with high sampling density for the diagnosis of precursor lesions and using eye tracking mode SD-OCT during follow-up. PMID- 29755819 TI - Vitreoretinal Interface Characteristics in Eyes with Idiopathic Macular Holes: Qualitative and Quantitative Analysis. AB - Objectives: To determine the qualitative and quantitative vitreoretinal interface characteristics with spectral domain optical coherence tomography (SD-OCT) in eyes with macular hole (MH) and investigate their relation with best corrected visual acuity (BCVA) and MH duration. Materials and Methods: Sixty-one eyes of 46 consecutive patients diagnosed with idiopathic MH were included in the study. The mean age of the patients was 66.7+/-7.5 (51-79) years. Complete ophthalmologic examination and SD-OCT examination were performed in all eyes and MH stages were determined according to SD-OCT findings. Qualitative characteristics of the vitreoretinal interface were investigated, including vitreomacular traction, vitreopapillary traction, maculopapillary traction, vitreoschisis, intraretinal cyst, presence of epiretinal membrane, and the integrity of the photoreceptor inner segment-outer segment junction (IS/OS) and external limiting membrane (ELM). In addition, MH diameter, MH base diameter (MHBD), ELM defect diameter, IS/OS defect diameter, and MH height were quantitatively measured and the MH index was calculated. Results: Out of 61 eyes, 9.8% were classified as stage 1a, 19.7% as stage 1b, 18% as stage 2, 23% as stage 3, and 29.5% as stage 4. Mean BCVA was 0.28+/-0.24 (1 mps-1.0) Snellen and MH duration was 10.08+/-18.6 (1-108) months. The most common interface characteristics associated with MH were determined as intraretinal cyst (91.8%), IS/OS defect (78.7%) and ELM defect (63.9%). Duration and stage of MH were inversely proportional to BCVA but directly proportional to the presence and diameter of IS/OS and ELM defects. BCVA was significantly lower in eyes with IS/OS and ELM defects (p<0.0001; p<0.0001 Mann-Whitney U test). Conclusion: We determined that the most important factors affecting BCVA in cases with idiopathic MH were MH stage, MH duration, MHBD, and the presence and diameter of IS/OS and ELM defects, which suggests that these parameters should be considered while making decisions about prognosis and treatment. PMID- 29755820 TI - Surgical Outcomes of Idiopathic Epiretinal Membrane: the Gulhane Experience. AB - Objectives: We aimed to report our experiences and outcomes of vitreoretinal surgery in idiopathic epiretinal membrane. Materials and Methods: We retrospectively reviewed patients who underwent vitreoretinal surgery for idiopathic epiretinal membrane between January 2012 and 2014. The patients' pre- and postoperative visual acuity, slit-lamp examination findings, and optical coherence tomography (OCT) images were evaluated. Results: Forty-five eyes of 45 patients (36% male, 64% female) were included (mean age, 69+/-8.2 years). Mean postoperative follow-up time was 7+/-4 (1-12) months. The mean preoperative logMAR best corrected visual acuity was 0.58+/-0.32 and postoperatively 0.40+/ 0.31, 0.33+/-0.33, 0.28+/-0.34 respectively at 3, 6, and 12 months. All OCT parameters showed statistically significant anatomical improvement at 1, 3, 6, and 12 months. Correlation analysis showed that central macular thickness (r=0.69, p<0.05) and central macular volume (r=0.69, p<0.05) were the only parameters that had strong positive correlations with visual improvement. Conclusion: Epiretinal membrane causes heterogeneous anatomical changes in the macula for every patient. Therefore, a correlation between visual gain and changes in central macular thickness could not yet be demonstrated. We believe that central macular volume may be a better parameter for following these patients. PMID- 29755821 TI - Is There a Relationship Between Use of Anti-Vascular Endothelial Growth Factor Agents and Atrophic Changes in Age-Related Macular Degeneration Patients? AB - Choroidal neovascularization due to age-related macular degeneration (AMD) is currently treated successfully with anti-vascular endothelial growth factor (VEGF) intravitreal agents. Emerging evidence suggests that anti-VEGF treatment may potentially increase development of geographic atrophy. However, there is not yet direct proof of a causal relationship between geographic atrophy and use of anti-VEGF agents in neovaskuler AMD. The aim of this review is to discuss the evidence concerning the association between anti-VEGF therapy and progression of geographic atrophy. PMID- 29755822 TI - Descemet Membrane Endothelial Keratoplasty with Irregular-Edged Graft: A Salvage Method for Large Radial Graft Tears. AB - Large radial tears of donor Descemet membrane (DM) during the preparation of Descemet membrane endothelial keratoplasty (DMEK) grafts can make the trephination stage impossible because of small graft diameter. This results in irregular-edged grafts. In this study, we report two pseudophakic bullous keratopathy patients who underwent DMEK surgery with irregular-edged Descemet membrane (DM) grafts. Main outcome measures were preoperative and postoperative 1 , 3-, and 6-month best corrected visual acuity (BCVA), endothelial cell density (ECD) and central corneal thickness (CCT). Intraoperative and early postoperative complications were also evaluated. Both irregular-edged grafts were successfully implanted into the anterior chamber, unfolded, and attached to the posterior corneal stroma. Patients' BCVA at 6 months was 1.0 (Snellen equivalent: 20/20) and 0.6 (Snellen equivalent: 20/32) respectively. Decrease in ECD at the last visit was 27% and 25%. CCT decreased from 723 MUm and 850 MUm to 530 MUm and 523 MUm, respectively. No intraoperative complications occurred except for the large radial Descemet membrane graft tears that developed during donor DM stripping. None of the cases needed a rebubbling procedure postoperatively. We have demonstrated that irregular-edged DM grafts can be successfully implanted for DMEK surgery with good clinical outcomes. PMID- 29755823 TI - Optic Nerve Avulsion and Retinal Detachment After Penetrating Ocular Trauma: Case Report. AB - Optic nerve avulsion is a rare pathology with poor prognosis usually seen after blunt trauma. The optic nerve is separated from the sclera by indirect forces due to the relatively weak structure of the lamina cribrosa area. Here we describe an 11-year-old boy who experienced optic nerve avulsion and retinal detachment after penetrating ocular trauma. PMID- 29755824 TI - Olfactory Neuroblastoma: A Rare Cause of External Ophthalmoplegia, Proptosis and Compressive Optic Neuropathy. AB - Olfactory neuroblastoma (ONB), which is a neuroectodermal tumor of the nasal cavity, is a rare and locally aggressive malignancy that may invade the orbit via local destruction. In this study, we report a patient with proptosis, external ophthalmoplegia, and compressive optic neuropathy caused by ONB. A detailed clinical examination including ocular imaging and histopathological studies were performed. The 62-year-old female patient presented to our clinic with complaints of proptosis and visual deterioration in the left eye. Her complaints started 2 months prior to admission. Visual acuity in the left eye was counting fingers from 2 meters. There was relative afferent pupillary defect. She had 6 mm of proptosis and limitation of motility. Fundus examination was normal in the right eye, but there was a hyperemic disc, and increased vascular tortuosity and dilation of the retinal veins in the left eye. Computerized tomography and magnetic resonance imaging of the brain and orbits demonstrated a large heterogeneous mass in the left superior nasal cavity with extensions into the ethmoidal sinuses as well as into the left orbit, compressing the medial rectus muscle and optic nerve. Endoscopic biopsy of the lesion was consistent with an ONB (Hyams' grade III). Orbital invasion may occur in patients with ONB. Therefore, it is important to be aware of this malignancy because some patients present with ophthalmic signs such as external ophthalmoplegia, proptosis, or compressive optic neuropathy. PMID- 29755825 TI - Bilateral Asymmetric Rhegmatogenous Retinal Detachment in a Patient with Stickler Syndrome. AB - Here we present the long-term anatomical and visual outcomes of bilateral asymmetric rhegmatogenous retinal detachment repair in a patient with Stickler syndrome. A 17-year-old girl presented with decreased visual acuity in both eyes for more than one year. Her best-corrected visual acuity (BCVA) was 0.1 in the right eye and 0.05 in the left eye. Slit-lamp anterior segment examination revealed subcapsular cataract in both eyes. Fundus examination showed bilateral rhegmatogenous retinal detachment, chronic retinal detachment accompanied by multiple retinal holes, tears and membranous fibrillary vitreous in the peripheral retina. Grade C2 proliferative vitreoretinopathy was observed in the left eye. Scleral buckling surgery was performed initially for both eyes. After the primary surgical procedure, retinal reattachment was achieved in the right eye and the left eye underwent phacoemulsification, intraocular lens implantation, pars plana vitrectomy (PPV), and silicone oil injection. After these surgical procedures retinal reattachment was achieved in the left eye. Silicone oil removal was performed six months after PPV surgery. After surgical treatment, BCVA was 0.6 in the right eye at the end of the 3.5-year follow-up period. After silicone oil removal, BCVA reached 0.2 in the left eye after 36 months of follow-up and retinal reattachment was achieved in both eyes. Scleral buckling surgery and PPV are effective and confidential methods for the treatment of chronic retinal detachment cases in Stickler syndrome. PMID- 29755826 TI - Pharmacovigilance via Baseline Regularization with Large-Scale Longitudinal Observational Data. AB - Several prominent public health hazards [29] that occurred at the beginning of this century due to adverse drug events (ADEs) have raised international awareness of governments and industries about pharmacovigilance (PhV) [6,7], the science and activities to monitor and prevent adverse events caused by pharmaceutical products after they are introduced to the market. A major data source for PhV is large-scale longitudinal observational databases (LODs) [6] such as electronic health records (EHRs) and medical insurance claim databases. Inspired by the Self-Controlled Case Series (SCCS) model [27], arguably the leading method for ADE discovery from LODs, we propose baseline regularization, a regularized generalized linear model that leverages the diverse health profiles available in LODs across different individuals at different times. We apply the proposed method as well as SCCS to the Marshfield Clinic EHR. Experimental results suggest that the proposed method outperforms SCCS under various settings in identifying benchmark ADEs from the Observational Medical Outcomes Partnership ground truth [26]. PMID- 29755827 TI - Stereoselective Synthesis of Isoxazolidines via Copper-Catalyzed Alkene Diamination. AB - A convenient copper-catalyzed intramolecular/intermolecular alkene diamination reaction to synthesize 3-aminomethyl-functionalized isoxazolidines under mild reaction conditions and with generally high levels of diastereoselectivity was achieved. This reaction demonstrates that previously underutilized unsaturated carbamates are good [Cu]-catalyzed diamination substrates. Sulfonamides, anilines, benzamide, morpholine, and piperidine can serve as the external amine source. This relatively broad amine range is attributed to the mild reaction conditions. Reduction of the N-O bond could also be achieved, revealing the corresponding 3,4-diamino-1-alcohols efficiently. PMID- 29755828 TI - Chemoselective Hydrogenation of Aldehydes under Mild, Base-Free Conditions: Manganese Outperforms Rhenium. AB - Several hydride Mn(I) and Re(I) PNP pincer complexes were applied as catalysts for the homogeneous chemoselective hydrogenation of aldehydes. Among these, [Mn(PNP-iPr)(CO)2(H)] was found to be one of the most efficient base metal catalysts for this process and represents a rare example which permits the selective hydrogenation of aldehydes in the presence of ketones and other reducible functionalities, such as C=C double bonds, esters, or nitriles. The reaction proceeds at room temperature under base-free conditions with catalyst loadings between 0.1 and 0.05 mol% and a hydrogen pressure of 50 bar (reaching TONs of up to 2000). A mechanism which involves an outer-sphere hydride transfer and reversible PNP ligand deprotonation/protonation is proposed. Analogous isoelectronic and isostructural Re(I) complexes were only poorly active. PMID- 29755829 TI - Cobalt-Doped Black TiO2 Nanotube Array as a Stable Anode for Oxygen Evolution and Electrochemical Wastewater Treatment. AB - TiO2 has long been recognized as a stable and reusable photocatalyst for water splitting and pollution control. However, it is an inefficient anode material in the absence of photoactivation due to its low electron conductivity. To overcome this limitation, a series of conductive TiO2 nanotube array electrodes have been developed. Even though nanotube arrays are effective for electrochemical oxidation initially, deactivation is often observed within a few hours. To overcome the problem of deactivation, we have synthesized cobalt-doped Black-TiO2 nanotube array (Co-Black NTA) electrodes that are stable for more than 200 h of continuous operation in a NaClO4 electrolyte at 10 mA cm-2. Using X-ray photoelectron spectroscopy, X-ray absorption spectroscopy, electron paramagnetic resonance spectroscopy, and DFT simulations, we are able to show that bulk oxygen vacancies (Ov) are the primary source of the enhanced conductivity of Co-Black. Cobalt doping both creates and stabilizes surficial oxygen vacancies, Ov, and thus prevents surface passivation. The Co-Black electrodes outperform dimensionally stable IrO2 anodes (DSA) in the electrolytic oxidation of organic rich wastewater. Increasing the loading of Co leads to the formation of a CoO x film on top of Co-Black electrode. The CoO x /Co-Black composite electrode was found to have a lower OER overpotential (352 mV) in comparison to a DSA IrO2 (434 mV) electrode and a stability that is greater than 200 h in a 1.0 M KOH electrolyte at a current density of 10 mA cm-2. PMID- 29755830 TI - Effects of Substrate and Polymer Encapsulation on CO2 Electroreduction by Immobilized Indium(III) Protoporphyrin. AB - Heterogenization of molecular catalysts for CO2 electroreduction has attracted significant research activity, due to the combined advantages of homogeneous and heterogeneous catalysts. In this work, we demonstrate the strong influence of the nature of the substrate on the selectivity and reactivity of electrocatalytic CO2 reduction, as well as on the stability of the studied immobilized indium(III) protoporphyrin IX, for electrosynthesis of formic acid. Additionally, we investigate strategies to improve the CO2 reduction by tuning the chemical functionality of the substrate surface by means of electrochemical and plasma treatment and by catalyst encapsulation in polymer membranes. We point out several underlying factors that affect the performance of electrocatalytic CO2 reduction. The insights gained here allow one to optimize heterogenized molecular systems for enhanced CO2 electroreduction without modification of the catalyst itself. PMID- 29755831 TI - Insight, Motivation and Outcome in Drug Treatment for Offenders: A Review of the Recent Literature. AB - Researchers in addiction and psychotherapy have long agreed that insight into problem severity and motivation for treatment are important client factors in successful treatment. For offenders these factors are linked to recidivism and relapse rates post-treatment. Authors in both fields agree that the combination of insight and motivation are key to positive treatment outcomes. However, this literature review found little effort to measure these factors in substance abuse literature with offenders. Articles identified contained the terms 'motivation;' 'insight;' and 'drug treatment' were paired with the term 'offenders' in varying combinations to identify articles meeting study criteria. Inductive analysis revealed that the majority of the articles did not measure insight and motivation, nor did they measure outcomes. Only seven of the 16 articles included measures of insight and motivation. Of these, only one study measured outcome as well. In addition, qualitative aspects of insight and motivation were not accounted for by assessments used. Recommendations for future research include measuring insight and motivation as well as treatment outcome, and tailoring treatment for this population accordingly, so as to better predict recidivism rates post-treatment. PMID- 29755832 TI - Collaborative Phenotype Inference from Comorbid Substance Use Disorders and Genotypes. AB - Data in large-scale genetic studies of complex human diseases, such as substance use disorders, are often incomplete. Despite great progress in genotype imputation, e.g., the IMPUTE2 method, considerably less progress has been made in inferring phenotypes. We designed a novel approach to integrate individuals' comorbid conditions with their genotype data to infer missing (unreported) diagnostic criteria of a disorder. The premise of our approach derives from correlations among symptoms and the shared biological bases of concurrent disorders such as co-dependence on cocaine and opioids. We describe a matrix completion method to construct a bi-linear model based on the interactions of genotypes and known symptoms of related disorders to infer unknown values of another set of symptoms or phenotypes. An efficient stochastic and parallel algorithm based on the linearized alternating direction method of multipliers was developed to solve the proposed optimization problem. Empirical evaluation of the approach in comparison with other advanced data matrix completion methods via a case study shows that it both significantly improves imputation accuracy and provides greater computational efficiency. PMID- 29755833 TI - Risk Factors for Umbilical Cord Prolapse at the Time of Artificial Rupture of Membranes. AB - Objective The aim of the study was to examine the association between cervical exam at the time of artificial rupture of membranes (AROM) and cord prolapse. Study Design We conducted a retrospective cohort study using the data from the Consortium on Safe Labor. We included women with cephalic presentation and singleton pregnancies at >= 23 weeks' gestation who underwent AROM during the course of labor. Multivariable logistic regression was used to calculate the adjusted odds ratio (aOR) with 95% confidence interval (95% CI), controlling for prespecified covariates. Results Of 57,204 women who underwent AROM, cord prolapse occurred in 113 (0.2%). Compared with dilation 6 to 10 cm + station >= 0 at the time of AROM, <6 cm + any station and 6-10 cm + station <= -3 were associated with increased risks of cord prolapse (<6 cm + station <= -3 [aOR, 2.29; 95% CI, 1.02-5.40]; <6 cm + station -2.5 to -0.5 [aOR, 2.34; 95% CI, 1.23 4.97]; <6 cm + station >= 0 [aOR, 3.31; 95% CI, 1.39-8.09]; and 6-10 cm + station <= -3 [aOR, 5.47; 95% CI, 1.35-17.48]). Conclusion Cervical dilation < 6 cm with any station and 6 to 10 cm with station <= -3 were associated with a higher risk of cord prolapse. PMID- 29755834 TI - Sample Complexity of the Boolean Multireference Alignment Problem. AB - The Boolean multireference alignment problem consists in recovering a Boolean signal from multiple shifted and noisy observations. In this paper we obtain an expression for the error exponent of the maximum A posteriori decoder. This expression is used to characterize the number of measurements needed for signal recovery in the low SNR regime, in terms of higher order autocorrelations of the signal. The characterization is explicit for various signal dimensions, such as prime and even dimensions. PMID- 29755835 TI - Trisomy 6 as the sole stemline abnormality in a patient with acute monocytic leukemia: a case report. AB - It is rare for trisomy 6 to occur as the sole autosomal anomaly in hematological malignancies, but this finding has been reported to be associated with a hypoplastic bone marrow. We report the case of a 75-year-old male with acute monocytic leukemia, in which trisomy 6 was detected as the sole stemline abnormality. We also summarize the 26 published cases of acute myeloid leukemia involving isolated trisomy 6. PMID- 29755836 TI - Vitamin D deficiency and degree of coronary artery luminal stenosis in women undergoing coronary angiography: a prospective observational study. AB - BACKGROUND AND AIMS: Low serum 25-OH D levels are associated with increased cardiovascular morbidity and mortality. Recent studies have linked 25-OH D deficiency with the presence of CAD. Women, especially post-menopausal, tend to suffer from accelerated atherosclerosis, along with vitamin D deficiency. In the present study we sought to investigate whether there is a direct association of coronary artery luminal stenosis with 25-OH D deficiency in women. PATIENTS AND METHODS: We enrolled women aged >40 who were scheduled to undergo elective coronary angiography between 3/2011 and 10/2016 in a prospective observational study. RESULTS: We included a total of 105 women. Patients had hypertension (73%), hyperlipidemia (54%), diabetes (29%), smoking (31%), family history of CAD (62%), and known CAD (21%). Median 25-OH D levels were 15.8 ng/mL (range, 3.9 79). Patients had left-anterior descending (31%), left circumflex (22%), and right coronary artery disease (26%); 27% had 2-vessel and 11% had 3-vessel disease. There was a significant inverse correlation between 25-OH D levels and the degree of maximum luminal stenosis. The burden of CAD increased across categories of worsening 25-OH D deficiency. CONCLUSIONS: Vitamin D deficiency is associated with the degree of luminal stenosis and burden of CAD in women undergoing coronary angiography. Future studies should investigate if the repletion of 25-OH D impacts the progression of CAD and cardiovascular mortality. PMID- 29755837 TI - Chagasic cardiomyopathy and Pompe disease: case report. AB - BACKGROUND: Pompe disease is a lysosomal storage disease with an autosomal recessive inheritance characterized by an insufficient activity of the acid alpha glucosidase enzyme. The incidence varies from 1:40000 to 1:200000 live births and cardiac involvement in adults is rare. Chagas disease is an infection caused by the protozoan Trypanosoma cruzi, in which one-third of the cases progress to the chronic form, and may lead to cardiac involvement, usually from the fifth decade of life onwards. We report a case of a patient with Chagas and Pompe diseases who had early cardiac involvement and rapid evolution to heart failure. CASE REPORT: A 43-year-old male patient with a history of ischemic stroke at 28 years with gait ataxia sequelae. A few years after the episode, he experienced gait impairment and difficulty climbing stairs, attributed to stroke. A family screening for Pompe disease was carried out years later, and thus the diagnosis was made. As for Chagas disease, the investigation was performed because the patient lives in an endemic area. The cardiovascular physical examination did not show significant changes. The electrocardiogram showed sinus rhythm with left bundle branch block and first-degree atrioventricular block; the transthoracic echocardiogram demonstrated left ventricular systolic dysfunction; the Holter monitoring showed several episodes of ventricular tachycardia. The patient is undergoing optimized treatment for heart failure and enzyme replacement therapy for Pompe disease. CONCLUSION: Cardiomyopathy with early onset and with rapid evolution suggests overlap of the two diseases. PMID- 29755839 TI - Standardization of deep partial-thickness scald burns in C57BL/6 mice. AB - Mouse burn models are used to understand the wound healing process and having a reproducible model is important. The different protocols used by researchers can lead to differences in depth of partial-thickness burn wounds. Additionally, standardizing a protocol for mouse burns in the laboratory for one strain may result in substantially different results in other strains. In our current study we describe the model development of a deep partial-thickness burn in C57BL/6 mice using hot water scalding as the source of thermal injury. As part of our model development we designed a template with specifications to allow for even contact of bare mouse skin (2*3 cm) with hot water while protecting the rest of the mouse. Burn depth was evaluated with H&E, Masson's trichrome, and TUNEL staining. Final results were validated with pathology analysis. A water temperature of 54 degrees C with a scalding time of 20 seconds produced consistent deep partial-thickness burns with available equipment described. Other than temperature and time, factors such as template materials and cooling steps after the burn could affect the uniformity of the burns. These findings are useful to burn research by providing some key parameters essential for researchers to simplify the development of their own mouse burn models. PMID- 29755838 TI - Application of laser scanning confocal microscopy in the soft tissue exquisite structure for 3D scan. AB - Three-dimensional (3D) printing is a new developing technology for printing individualized materials swiftly and precisely in the field of biological medicine (especially tissue-engineered materials). Prior to printing, it is necessary to scan the structure of the natural biological tissue, then construct the 3D printing digital model through optimizing the scanned data. By searching the literatures, magazines at home and abroad, this article reviewed the current status, main processes and matters needing attention of confocal laser scanning microscope (LSCM) in the application of soft tissue fine structure 3D scanning, empathizing the significance of LSCM in this field. PMID- 29755840 TI - Treatment of mallet finger deformity with a modified palmaris longus tendon graft through a bone tunnel. AB - OBJECTIVE: To investigate the clinical effect of treating mallet finger deformity using a modified palmaris longus tendon graft through a bone tunnel. METHODS: Altogether, 21 patients with mallet finger deformity (16 men, 5 women; average age 31 years, range 19-47 years) were treated with a modified palmaris longus tendon graft through a bone tunnel during 18 months (2014-2016). Four index fingers, seven middle fingers, eight ring fingers, and two little fingers were treated for four cutting injuries, eleven finger sprains, four crush injuries, and two twist injuries (7 open and 14 closed injuries). Duration from injury to surgery was 9 h to 13 weeks. Three patients underwent surgery after 6 weeks of unsuccessful conservative treatment. No tendon was attached to the extensor tendon insertion in 16 patients, and 5 had residual tendon of <0.2 cm attached. All patients had distal segment flexion deformity and dorsiflexion disorder. Surgery comprised transverse penetration and vertical drilling of the base of the distal phalanx (2.0 and 2.5 mm diameter drills). Equal shallow semitendinosus pieces of the palmaris longus tendon (4 cm) were obtained from the sagittal end and were passed through a dorsal bone hole, emerging from a transverse bone hole. The two bundles were sutured to the main tendon. Tension was adjusted, and the broken ends were sutured. The distal interphalangeal joints were fixed in hyperextension. RESULTS: All patients were followed for 7-16 months (average 6.0 +/- 0.3 months) postoperatively. All 21 patients had grade A wound healing, with no complications (e.g., necrotic wound, recurrence, joint stiffness). The mallet finger deformity was corrected with good appearance, no obvious abnormalities, and satisfactory flexion and extension. Two patients had a superficial wound infection. Each recovered after symptomatic treatment. One patient had a mild result, with limited extension. There were no recurrences. Results were evaluated according to Patel et al.'s system, which revealed 15 excellent and 5 good results (combined 95.23% rate), with 1 mild result (limited extension). Patients were satisfied with the appearance and function of the affected fingers, and the desired surgical end result was achieved. CONCLUSION: Use of this modified surgery for treating mallet finger deformity, especially with no or little tendon attached at the extensor tendon insertion, results in nearly anatomical reconstruction of the extensor tendon insertion. Its advantages include simple surgery, reliable fixation, fewer complications, and clinical efficacy. PMID- 29755841 TI - Quantitative PET of liver functions. AB - Improved understanding of liver physiology and pathophysiology is urgently needed to assist the choice of new and upcoming therapeutic modalities for patients with liver diseases. In this review, we focus on functional PET of the liver: 1) Dynamic PET with 2-deoxy-2-[18F]fluoro-D-galactose (18F-FDGal) provides quantitative images of the hepatic metabolic clearance Kmet (mL blood/min/mL liver tissue) of regional and whole-liver hepatic metabolic function. Standard uptake-value (SUV) from a static liver 18F-FDGal PET/CT scan can replace Kmet and is currently used clinically. 2) Dynamic liver PET/CT in humans with 11C palmitate and with the conjugated bile acid tracer [N-methyl-11C]cholylsarcosine (11C-CSar) can distinguish between individual intrahepatic transport steps in hepatic lipid metabolism and in hepatic transport of bile acid from blood to bile, respectively, showing diagnostic potential for individual patients. 3) Standard compartment analysis of dynamic PET data can lead to physiological inconsistencies, such as a unidirectional hepatic clearance of tracer from blood (K1; mL blood/min/mL liver tissue) greater than the hepatic blood perfusion. We developed a new microvascular compartment model with more physiology, by including tracer uptake into the hepatocytes from the blood flowing through the sinusoids, backflux from hepatocytes into the sinusoidal blood, and re-uptake along the sinusoidal path. Dynamic PET data include information on liver physiology which cannot be extracted using a standard compartment model. In conclusion, SUV of non-invasive static PET with 18F-FDGal provides a clinically useful measurement of regional and whole-liver hepatic metabolic function. Secondly, assessment of individual intrahepatic transport steps is a notable feature of dynamic liver PET. PMID- 29755842 TI - Lipopolysaccharide endotoxemia induces amyloid-beta and p-tau formation in the rat brain. AB - Amyloid beta (Abeta) plaques are not specific to Alzheimer's disease and occur with aging and neurodegenerative disorders. Soluble brain Abeta may be neuroprotective and increases in response to neuroinflammation. Sepsis is associated with neurocognitive compromise. The objective was to determine, in a rat endotoxemia model of sepsis, whether neuroinflammation and soluble Abeta production are associated with Abeta plaque and hyperphosphorylated tau deposition in the brain. Male Sprague Dawley rats received a single intraperitoneal injection of 10 mg/kg of lipopolysaccharide endotoxin (LPS). Brain and blood levels of IL-1beta, IL-6, and TNFalpha and cortical microglial density were measured in LPS-injected and control animals. Soluble brain Abeta and p-tau were compared and Abeta plaques were quantified and characterized. Brain uptake of [18F]flutemetamol was measured by phosphor imaging. LPS endotoxemia resulted in elevations of cytokines in blood and brain. Microglial density was increased in LPS-treated rats relative to controls. LPS resulted in increased soluble Abeta and in p-tau levels in whole brain. Progressive increases in morphologically-diffuse Abeta plaques occurred throughout the interval of observation (to 7-9 days post LPS). LPS endotoxemia resulted in increased [18F]flutemetamol in the cortex and increased cortex: white matter ratios of activity. In conclusion, LPS endotoxemia causes neuroinflammation, increased soluble Abeta and Abeta diffuse plaques in the brain. Abeta PET tracers may inform this neuropathology. Increased p-tau in the brain of LPS treated animals suggests that downstream consequences of Abeta plaque formation may occur. Further mechanistic and neurocognitive studies to understand the causes and consequences of LPS-induced neuropathology are warranted. PMID- 29755843 TI - FDG PET-CT SUVmax and IASLC/ATS/ERS histologic classification: a new profile of lung adenocarcinoma with prognostic value. AB - Quantitative analysis of glucose consumption measured by maximum standardized uptake value (SUVmax) in lung adenocarcinoma (LA) remains in discussion and metabolic information provided by FDG-PET is not included in cancer staging. The first aim of this work was to evaluate the correlation between SUVmax and different histologic subtypes of LA. The second aim was to establish the correlation between SUVmax and TNM, genetic mutations and prognostic. Glucose consumption of primary tumor was quantified using SUVmax in 112 patients with histologically-confirmed LA. Specimens were classified according to the IASLC/ATS/ERS into in situ -AIS-, minimally invasive -MIA-, invasive (lepidic, papillary, acinar, solid and micropapillary) and invasive mucinous adenocarcinoma. Tumors were grouped according to three histological grades; low grade: AIS, MIA, intermediate-grade: lepidic, acinar, papillary and high-grade: micropapillary, solid and mucinous. Comparisons between SUVmax and histologic subtypes were performed with Kruskal-Wallis followed by a Dunn's test. Overall (OS) and disease-free survival (DFS) were calculated. SUVmax was histologically dependent (P<0.001): AIS 0.5+/-0.1, MIA 1.1+/-0.9 lepidic 3.3+/-3.1, acinar 8.6+/ 6.7, papillary 3.9+/-5.1, micropapillary 4.9+/-3.4, solid 10.4+/-5.4 and invasive mucinous 2.7+/-1.2. SUVmax was associated with TNM stage in stage IA and IB. SUVmax was significantly lower in patients with K-RAS and EGFR mutation. Low SUVmax was associated with low-grade histology and with a higher OS and DSF compared to high SUVmax (intermediate and high-grade histology). SUVmax on FDG PET is a powerful information in the presurgical evaluation of LA patients. It provides prognostic data and should be considered in the staging algorithm of patients with LA. PMID- 29755844 TI - Standard OSEM vs. regularized PET image reconstruction: qualitative and quantitative comparison using phantom data and various clinical radiopharmaceuticals. AB - We investigated the block sequential regularized expectation maximization (BSREM) algorithm. ACR phantom measurements with different count statistics and 60 PET/CT research scans from the GE Discovery 600 and 690 scanners were reconstructed using BSREM and the standard-of-care OSEM algorithm. Hot concentration recovery and cold contrast recovery were measured from the phantom data. Two experienced nuclear medicine physicians reviewed the clinical images blindly. Liver SNR liver and SUVmax of the smallest lesion detected in each patient were also measured. The relationship between the maximum and mean hot concentration recovery remained monotonic below 1.5 maximum concentration recovery. The mean cold contrast recovery remained stable even for decreasing statistics with a highest absolute difference of 4% in air and 2% in bone for each reconstruction method. The D600 images resulted in an average 30% higher SNR than the D690 data for BSREM; there was no difference in SNR results between the two scanners with OSEM. The small lesion SUVmax values on the BSREM images with beta of 250, 350 and 450, respectively were on average 80%, 60% and 43% (D690) and 42%, 29%, and 21% (D600) higher than in the case of OSEM. In conclusion, BSREM can outperform OSEM in terms of contrast recovery and organ uniformity over a range of PET tracers, but a task dependent regularization strength parameter (beta) selection may be necessary. To avoid image noise and artifacts, our results suggest that using higher beta values (at least 350) may be appropriate, especially if the data has low count statistics. PMID- 29755845 TI - Determination of binding affinity of molecular imaging agents for steroid hormone receptors in breast cancer. AB - 16alpha-[18F]Fluoro-17beta-estradiol ([18F]FES) and 21-[18F]-Fluoro 16alpha,17alpha-[(R)-(1'-alpha-furylmethylidene)dioxyl]-19-norpregn-4-ene-3,20 dione ([18F]FFNP) are being investigated as imaging biomarkers for breast cancer patients. Quantitative positron emission tomography (PET) reflects both total receptor content and binding affinity. To study factors that may alter radiopharmaceutical binding and impact PET accuracy, assays that can separate receptor amount from binding affinity are needed. The study purpose was to quantify the binding parameters of [18F]FES and [18F]FFNP in breast cancer. Estrogen receptor-alpha (ER) and progesterone receptor (PR) positive breast cancer cell lines (MCF-7 and T47D) were used to measure [18F]FES and [18F]FFNP binding parameters via saturation and competitive binding curves. The equilibrium dissociation constant (Kd) and total receptor density (Bmax) were determined using nonlinear regression of the saturation binding curves. Half-maximal inhibitory concentration (IC50) was determined using nonlinear regression of the competitive binding curves. Linear correlation between increasing cell number and tracer uptake was observed for both [18F]FES and [18F]FFNP (R2=0.99 and 0.91, respectively). Using [18F]FES, the Kd for ER in MCF-7 cells was 0.13+/-0.02 nM with a Bmax of 1901+/-89.3 fmol/mg protein and IC50 of 0.085 nM (95% CI: 0.069 0.104 nM). Using [18F]FFNP, the Kd for PR in T47D cells was 0.41+/-0.05 nM with a Bmax of 1984+/-75.6 fmol/mg protein and IC50 of 2.6 nM (95% CI: 2.0-3.4 nM). The ligand binding function of ER and PR can be quantified using [18F]FES and [18F]FFNP and are comparable to previous studies using tritiated radioligands. [18F]FES and [18F]FFNP can be used in cell-based assays to quantify receptor radioligand binding affinity, which cannot be obtained from a single PET examination. PMID- 29755848 TI - CT dose modulation using automatic exposure control in whole-body PET/CT: effects of scout imaging direction and arm positioning. AB - Automatic exposure control (AEC) modulates tube current and consequently X-ray exposure in CT. We investigated the behavior of AEC systems in whole-body PET/CT. CT images of a whole-body phantom were acquired using AEC on two scanners from different manufactures. The effects of scout imaging direction and arm positioning on dose modulation were evaluated. Image noise was assessed in the chest and upper abdomen. On one scanner, AEC using two scout images in the posteroanterior (PA) and lateral (Lat) directions provided relatively constant image noise along the z-axis with the arms at the sides. Raising the arms increased tube current in the head and neck and decreased it in the body trunk. Image noise increased in the upper abdomen, suggesting excessive reduction in radiation exposure. AEC using the PA scout alone strikingly increased tube current and reduced image noise in the shoulder. Raising the arms did not substantially influence dose modulation and decreased noise in the abdomen. On the other scanner, AEC using the PA scout alone or Lat scout alone resulted in similar dose modulation. Raising the arms increased tube current in the head and neck and decreased it in the trunk. Image noise was higher in the upper abdomen than in the middle and lower chest, and was not influenced by arm positioning. CT dose modulation using AEC may vary greatly depending on scout direction. Raising the arms tended to decrease radiation exposure; however, the effect depends on scout direction and the AEC system. PMID- 29755846 TI - Repeatability of FDG PET/CT metrics assessed in free breathing and deep inspiration breath hold in lung cancer patients. AB - We measured the repeatability of FDG PET/CT uptake metrics when acquiring scans in free breathing (FB) conditions compared with deep inspiration breath hold (DIBH) for locally advanced lung cancer. Twenty patients were enrolled in this prospective study. Two FDG PET/CT scans per patient were conducted few days apart and in two breathing conditions (FB and DIBH). This resulted in four scans per patient. Up to four FDG PET avid lesions per patient were contoured. The following FDG metrics were measured in all lesions and in all four scans: Standardized uptake value (SUV)peak, SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), based on an isocontur of 50% of SUVmax. FDG PET avid volumes were delineated by a nuclear medicine physician. The gross tumor volumes (GTV) were contoured on the corresponding CT scans. Nineteen patients were available for analysis. Test-retest standard deviations of FDG uptake metrics in FB and DIBH were: SUVpeak FB/DIBH: 16.2%/16.5%; SUVmax: 18.2%/22.1%; SUVmean: 18.3%/22.1%; TLG: 32.4%/40.5%. DIBH compared to FB resulted in higher values with mean differences in SUVmax of 12.6%, SUVpeak 4.4% and SUVmean 11.9%. MTV, TLG and GTV were all significantly smaller on day 1 in DIBH compared to FB. However, the differences between metrics under FB and DIBH were in all cases smaller than 1 SD of the day to day repeatability. FDG acquisition in DIBH does not have a clinically relevant impact on the uptake metrics and does not improve the test-retest repeatability of FDG uptake metrics in lung cancer patients. PMID- 29755847 TI - 18F-FDG PET/CT findings in hepatosplenic Gamma-Delta T-cell lymphoma: case reports and review of the literature. AB - Hepatosplenic Gamma Delta T cell lymphoma (gammadeltaHSTL) is a rare, highly aggressive, and rapidly lethal T cell lymphoma which manifests 18F-FDG PET/CT findings that can mimic benign conditions. Patients with gammadeltaHSTL present with unexplained symptoms of a hematologic malignancy like the B symptoms of lymphoma including weight loss, fevers, and night sweats, as well as, splenomegaly and hepatomegaly. Thrombocytopenia, anemia, or neutropenia are also common due to spleen, liver and bone marrow involvement. The peripheral blood, however, typically does not show abnormal T cells. The clinical and 18F-FDG PET/CT findings are presented for 3 patients with gammadeltaHSTL. Patients with gammadeltaHSTL may have a normal 18F-FDG PET/CT or an 18F-FDG PET/CT with any combination of the three findings: splenomegaly with intense FDG uptake; hepatomegaly with increased FDG uptake; and diffuse, increased FDG uptake in the bone marrow. Importantly, lymphadenopathy is usually absent, and most patients show morphologically normal lymph nodes with normal FDG uptake. Due to the aggressive nature of the disease, gammadeltaHSTL is a critical diagnosis to consider in patients who present with clinical signs of suspected hematologic malignancy and variable 18F-FDG PET/CT findings. The absence of lymphadenopathy and normal FDG uptake in lymph nodes are typical pertinent negative findings that differentiate gammadeltaHSTL from other lymphomas. A bone or liver biopsy is frequently necessary to establish the diagnosis and should be recommended. PMID- 29755849 TI - Accreditation in India: Pathways and Mechanisms. AB - Continuing medical education (CME) is a valuable mechanism to update physicians' knowledge with ever-increasing plethora of contemporary advances within medical fraternity. Over time, scope of CME has seen change from simple clinical updates to comprehensive continuing professional development (CPD), which is accomplished with help of accredited CME programmes. The Medical Council of India, in 2011, made a mandatory resolution for doctors to attend minimum of 30 hours of CME/5 years to ensure recertification. Authorised accreditation councils and licensing authorities award CME credits for maintenance of physicians' licensures. To date, in India, only 9 of 26 State Medical Councils have made re-registration mandatory. Although CME events benefit healthcare professionals by improving their proficiency and awareness, costs even to attend such interventions may be prohibitive. Despite financial help being received through grants and sponsorships, ethics of industry-sponsored CME remains a matter of debate. However, over past 10 years, pharmaceutical companies have started going beyond basic product information in order to focus on building physicians' knowledge in various therapeutic areas. Though CME credit system and criteria for re-licensure for medical practice in India are evolving at a rapid pace, there is a need for harmonisation and robust implementation across all states in India. PMID- 29755850 TI - Three-Dimensional Printing and Cell Therapy for Wound Repair. AB - Significance: Skin tissue damage is a major challenge and a burden on healthcare systems, from burns and other trauma to diabetes and vascular disease. Although the biological complexities are relatively well understood, appropriate repair mechanisms are scarce. Three-dimensional bioprinting is a layer-based approach to regenerative medicine, whereby cells and cell-based materials can be dispensed in fine spatial arrangements to mimic native tissue. Recent Advances: Various bioprinting techniques have been employed in wound repair-based skin tissue engineering, from laser-induced forward transfer to extrusion-based methods, and with the investigation of the benefits and shortcomings of each, with emphasis on biological compatibility and cell proliferation, migration, and vitality. Critical issues: Development of appropriate biological inks and the vascularization of newly developed tissues remain a challenge within the field of skin tissue engineering. Future Directions: Progress within bioprinting requires close interactions between material scientists, tissue engineers, and clinicians. Microvascularization, integration of multiple cell types, and skin appendages will be essential for creation of complex skin tissue constructs. PMID- 29755851 TI - A Comparison of Three Methods for the Analysis of Skin Flap Viability: Reliability and Validity. AB - Objective: Technological advances have provided new alternatives to the analysis of skin flap viability in animal models; however, the interrater validity and reliability of these techniques have yet to be analyzed. The present study aimed to evaluate the interrater validity and reliability of three different methods: weight of paper template (WPT), paper template area (PTA), and photographic analysis. Approach: Sixteen male Wistar rats had their cranially based dorsal skin flap elevated. On the seventh postoperative day, the viable tissue area and the necrotic area of the skin flap were recorded using the paper template method and photo image. The evaluation of the percentage of viable tissue was performed using three methods, simultaneously and independently by two raters. The analysis of interrater reliability and viability was performed using the intraclass correlation coefficient and Bland Altman Plot Analysis was used to visualize the presence or absence of systematic bias in the evaluations of data validity. Results: The results showed that interrater reliability for WPT, measurement of PTA, and photographic analysis were 0.995, 0.990, and 0.982, respectively. For data validity, a correlation >0.90 was observed for all comparisons made between the three methods. In addition, Bland Altman Plot Analysis showed agreement between the comparisons of the methods and the presence of systematic bias was not observed. Innovation: Digital methods are an excellent choice for assessing skin flap viability; moreover, they make data use and storage easier. Conclusion: Independently from the method used, the interrater reliability and validity proved to be excellent for the analysis of skin flaps' viability. PMID- 29755852 TI - High-Frequency Generator in Wound Healing of Marjolin's Ulcer After Carcinoma Resection. AB - Marjolin's ulcers (MU) are skin malignancies that form over burn injuries. These very aggressive ulcers can result in functional and wound healing impairment, and require a well thought out treatment plan. Physiotherapy offers resources to help promote recovery of these patients, as described in this case report, in which the patient with a history of burn in the lower limbs evolved to malignancy 32 years later. This patient underwent tumor resection of the left foot, with recurrence and lymphadenectomy. Physical therapy included the application of high frequency generator (HFG) for wound healing and exercises for functional recovery. The treatment lasted for many months and resulted in the improvement of the surgical wound areas, pain, swelling, sensitivity, strength muscle, and gait. It was observed that the use of HFG can be a tool in the tissue repair of surgical wound after the resection of MU; however, further studies need to be carried out to suit parameters and ensure safety of cancer patients. PMID- 29755853 TI - Reg3beta from cardiomyocytes regulated macrophage migration, proliferation and functional skewing in experimental autoimmune myocarditis. AB - Macrophages play critical roles in inflammatory initiation, development, resolution and cardiac regeneration of myocarditis. However, Reg3beta, as a member of regenerating family of proteins, contributes to dedifferentiation of injury cardiomyocytes as well as cardiac function remodeling. It remains unclear whether Reg3beta was associated with macrophages reprogramming during autoimmune myocarditis. Our results showed that Reg3beta could effectively recruit macrophages, promoted their proliferation and phagocytosis, and facilitated their polarized into M2 macrophages. Macrophage, especially M1 phenotype contributed to Reg3beta production by cardiomyocytes. Our data also indicated that Reg3beta was involved in self-protection mechanism following cardiac injury or stress. This suggests that Reg3beta might be a critically protective factor of myocardium. PMID- 29755854 TI - Neuroanatomical autonomic substrates of brainstem-gut circuitry identified using transsynaptic tract-tracing with pseudorabies virus recombinants. AB - To investigate autonomic substrates of brainstem-gut circuitry identified using trans-synaptic tracing with pseudorabies virus (PRV)-152, a strain that expresses enhanced green fluorescent protein, and PRV-614, a strain that expresses enhanced red fluorescent protein, injecting into the rat rectum wall. 3-7 days after PRV 152 injection, spinal cord and brainstem were removed and sectioned, and processed for PRV-152 visualization using immunofluorescence labeling against PRV 152. 6 days after PRV-614 injection, brainstem was sectioned and the neurochemical phenotype of PRV-614-positive neurons was identified using double immunocytochemical labeling against PRV-614 and TPH. We observed that the largest number of PRV-152- or PRV-614-positive neurons was located in the gigantocellular reticular nucleus (Gi), lateral paragigantocellular (LPGi), rostral ventrolateral reticular nucleus (RVL), solitary tract nucleus (Sol), locus coeruleus (LC), raphe magnus nucleus (RMg), subcoeruleus nucleus (SubCD). Double-labeled PRV 614/tryptophan hydroxylase (TPH) neurons were concentrated in the RMg, LPGi and Sol. These brainstem neurons are candidates for relaying autonomic command signals to the gut. The autonomic substrate of brainstem-gut circuitry likely plays an important role in mediating different aspects of stress behaviors. PMID- 29755857 TI - New directions in building a scientific social network: Experiences in the Supercourse project and application to Central Asia. AB - Introduction: Networking leaders in the field of public health and medicine is very important for improving health locally and globally, especially in times of disaster. Methods: Fishing can best be defined as using an internet search engine to find the name and email address of the person or organization that is being sought. Results: With over 500 hours of work, the group compiled a list of nearly 2,000 email addresses of Ministers of Health, deans of the 1,800 medical schools and schools of public health, and heads of medical and public health societies. PMID- 29755855 TI - Association of HSP90B1 genetic polymorphisms with efficacy of glucocorticoids and improvement of HRQoL in systemic lupus erythematosus patients from Anhui Province. AB - Objective: The aim of this study was to investigate the associations between HSP90B1 gene polymorphisms and the efficacy of glucocorticoids (GCs) and the improvement of health-related quality of life (HRQoL) in Anhui patients with systemic lupus erythematosus (SLE). Method: A total of 305 patients with SLE were recruited to the study. These patients were treated with GCs for 12 weeks and classified into two groups (sensitivity and insensitivity) according to the response to GCs measured by the scores on SLE disease activity index (SLEDAI). The HRQoL of SLE patients were evaluated by 36-item Short Form Health Survey (SF 36) at baseline and 12 weeks respectively. HapMap database and Haploview software were used to select HSP90B1 gene tag single nucleotide polymorphisms (SNPs). Benjamini & Hochberg (BH) method based on false discovery rate (FDR) was used for multiple testing correction. Results: A total of 291 patients were included in final data analysis with 14 patients excluded due to loss to follow-up. Among these patients, 160 patients were sensitive to GCs and 131 patients were insensitive to GCs. Twelve tag SNPs of HSP90B1 gene were selected. The rs12426382 polymorphism was associated with the efficacy of GCs (dominant model: crude OR=0.514, 95% CI=0.321-0.824, P=0.006; adjusted OR=0.513, 95% CI=0.317-0.831, P=0.007). After BH correction, there was no association between rs12426382 polymorphism and efficacy of GCs (PBH =0.084). In haplotype analysis, the haplotype CCCGAACATCCC (OR=2.273, 95% CI=1.248-4.139, P=0.006) and CTGGGACGTTC (OR=0.436, 95% CI=0.208-0.916, P=0.025) showed significant associations with the efficacy of GCs. After corrected by BH method, CCCGAACATCCC was still associated with the efficacy of GCs (PBH =0.048). The rs3794241, rs1165681, rs2722188, rs3794240 and rs10861147 polymorphisms were associated with the improvement of HRQoL among SLE patients (P < 0.05). But no association existed after the correction of BH method (P > 0.05). Conclusions: The results of this study demonstrated that HSP90B1 genetic polymorphisms might be associated with the efficacy of GCs, but not associated with the improvement of HRQoL in Anhui population with SLE. PMID- 29755856 TI - The guiding role of bone metabolism test in osteoporosis treatment. AB - Osteoporosis (OP) and osteoporotic fractures are becoming a serious health care issue in the world. Calcium and vitamin D are the basic treatment for osteoporosis. Nonetheless, they do not effectively reduce the incidences of fracture. Currently approved treatments for osteoporosis include selective estrogen receptor modulators (SERMs), bisphosphonates, denosumab, teriparatide, calcitonin and others. However, the appearance of some adverse effects including atypical fracture and breast cancer has limited long-term treatments above mentioned. Therefore, treatment decision should be made on an individual basis, taking into account the relative benefits and risks in different patients. Bone metabolism test helps to assess the patient's condition, which may ultimately lead to therapeutic options and better clinical outcomes. PMID- 29755859 TI - The Central Asian Journal of Global Health: A Supercourse Journal. PMID- 29755860 TI - Is the Supercourse useful for Latin America? AB - BACKGROUND: The success of the Supercourse showed that the effort was needed in Latin America. But would a Spanish language version be better for the region? METHODS: Google Analytics was used to determine website usage. A custom evaluation form was created to get user feedback on the usefulness of both the English language and Spanish language Supercouse lectures. RESULTS: Over a year's span from June 2009 to June 2010 there were 257,403 unique visits and 448,939 page views. The overall average rating of lectures was 4.87 with the Spanish language lectures getting even higher ratings. CONCLUSION: Supercourse lectures in Spanish were a great success in Latin America. This success shows the need for this information and similar success could be found in Central Asia. PMID- 29755861 TI - Modernization and growth in Kazakhstan. PMID- 29755862 TI - Missing Millions and Measuring Progress towards the Millennium Development Goals with a focus on Central Asia States. AB - Background: In developing countries, population estimates and assessments of progress towards the Millennium Development Goals are based increasingly on household surveys. It is not recognised that they are inappropriate for obtaining information about the poorest of the poor. This is because they, typically, omit by design: those not in households because they are homeless; those who are in institutions; and mobile, nomadic or pastoralist populations. In addition, in practice, because they are difficult to reach, household surveys will typically under-represent: those in fragile, disjointed or multiple occupancy households; those in urban slums; and may omit certain areas of a country deemed to pose a security risk. Those six sub-groups constitute a pretty comprehensive ostensive definition of the 'poorest of the poor'. Methods: This paper documents these omissions in general, drawing on worldwide literature about the theory and practice of implementing censuses and household surveys; and shows how substantial proportions are missing from both censuses and the sample frames of surveys. Results: This paper suggests that between 300 and 350 million will effectively be missed worldwide from the sampling frames of such surveys and from most censuses. The impact on the health MDGs is illustrated for the five republics of the former Soviet Union making up Central Asia: Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan. Conclusions: It is impossible to assess progress towards or away from the MDGS in both the Central Asian Republics and worldwide. It is urgent to find solutions to the problem of the 'missing' poor population sub-groups. PMID- 29755858 TI - Effects of Amyloid Beta Peptide on Neurovascular Cells. AB - Alzheimer's disease (AD) is a chronic neurodegenerative disorder, which is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in specific regions of the brain, accompanied by impairment of the neurons, and progressive deterioration of cognition and memory of affected individuals. Although the cause and progression of AD are still not well understood, the amyloid hypothesis is dominant and widely accepted. According to this hypothesis, an increased deposition of amyloid-beta peptide (Abeta) in the brain is the main cause of the AD's onset and progression. There is increasing body of evidence that blood-brain barrier (BBB) dysfunction plays an important role in the development of AD, and may even precede neuron degeneration in AD brain. In the early stage of AD, microvasculature deficiencies, inflammatory reactions, surrounding the cerebral vasculature and endothelial dysfunctions are commonly observed. Continuous neurovascular degeneration and accumulation of Abeta on blood vessels resulting in cerebral amyloid angiopathy is associated with further progression of the disease and cognitive decline. However, little is known about molecular mechanisms that underlie Abeta induced damage of neurovascular cells. In this regards, this review is aimed to address how Abeta impacts the cerebral endothelium. Understanding the cellular pathways triggered by Abeta leading to alterations in cerebral endothelial cells structure and functions would provide insights into the mechanism of BBB dysfunction and inflammatory processes in Alzheimer's, and may offer new approaches for prevention and treatment strategies for AD. PMID- 29755863 TI - Public Health Challenges and Priorities for Kazakhstan. AB - The Republic of Kazakhstan is one of the largest and fastest growing post-Soviet economies in Central Asia. Despite recent improvements in health care in response to Kazakhstan 2030 and other state-mandated policy reforms, Kazakhstan still lags behind other members of the Commonwealth of Independent States of the European Region on key indicators of health and economic development. Although cardiovascular diseases are the leading cause of mortality among adults, HIV/AIDS, tuberculosis, and blood-borne infectious diseases are of increasing public health concern. Recent data suggest that while Kazakhstan has improved on some measures of population health status, many environmental and public health challenges remain. These include the need to improve public health infrastructure, address the social determinants of health, and implement better health impact assessments to inform health policies and public health practice. In addition, more than three decades after the Declaration of Alma-Ata, which was adopted at the International Conference on Primary Health Care convened in Kazakhstan in 1978, facilitating population-wide lifestyle and behavioral change to reduce risk factors for chronic and communicable diseases, as well as injuries, remains a high priority for emerging health care reforms and the new public health. This paper reviews the current public health challenges in Kazakhstan and describes five priorities for building public health capacity that are now being developed and undertaken at the Kazakhstan School of Public Health to strengthen population health in the country and the Central Asian Region. PMID- 29755864 TI - The Case of NRENs in Central Asia. AB - National Research and Education Network organizations (NRENs) provide advanced information and communication technology (ICT) services for the academic community of their country. Their focus is often on providing affordable high speed bandwidth amongst their members and to other research networks, but NRENs also provide other advanced services such as electronic repositories, educational environments and supercomputing facilities. Higher Education and Research institutions have to play an active role in the transformation to the "Knowledge Society". A recent (2010) report of the International Telecommunication Union has identified NRENs as important vehicles in reaching the goals of the World Summit of the Information Society. It is also demonstrated that the Central Asian countries score very low in the Networked Readiness Indices of the World Economic Forum, including areas where strong NRENs could improve the status quo. NRENs therefore have a role that is also important for the nation itself and therefore claims for government support are legitimate. About 62% of the countries of the world already have an NREN and there are four characteristics that are common to these NRENs. In nearly all of the cases the NREN is a not-for-profit organization that not only serves the academic community, but is also owned by the same community. Four out of five Central Asian countries have an active NREN and these NRENs all participate in the EC funded CAREN project that aims to set up a sustainable regional network for the academic communities in the participating countries. Today, the Central Asian Research and Education Network (CAREN) is upgrading the ancient Silk Road to a 21st-century high-speed internet highway for research and educational institutions through the region. Operational since July 2010, CAREN currently interconnects scientists and students from Kazakhstan, Kyrgyzstan, Tajikistan, and Turkmenistan. PMID- 29755865 TI - The HUPO Human Proteome Project (HPP), a Global Health Research Collaboration. AB - The global Human Proteome Project (HPP) was announced by the Human Proteome Organization (HUPO) at the 2010 World Congress of Proteomics in Sydney, Australia, and launched at the 2011 World Congress of Proteomics in Geneva, Switzerland, with analogies to the highly successful Human Genome Project. Extensive progress was reported at the September 2012 World Congress in Boston, USA. The HPP is designed to map the entire human proteome using available and emerging technologies. The HPP aims to create a molecular and biological foundation for improving health globally through better understanding of disease processes, more accurate diagnoses, and targets for more effective therapies and preventive interventions against many diseases. There are opportunities for individual investigators everywhere to access advanced datasets and to join HPP research teams. PMID- 29755866 TI - Keeping Up with the Times. PMID- 29755867 TI - Speman(r), A Proprietary Ayurvedic Formulation, Reverses Cyclophosphamide-Induced Oligospermia In Rats. AB - Background: This investigation was aimed to evaluate the effect of Speman(r), a well known ayurvedic proprietary preparation, in an experimental model of cyclophosphamide-(CP) induced oligospermia in rats. Materials and Methods: Thirty male rats were randomized in to five, equally-sized groups. Rats in group 1 served as a normal control; group 2 served as an untreated positive control; groups 3, 4, 5 received Speman(r) granules at doses of 300, 600, and 900mg/kg body weight p.o. respectively, once daily for 13 days. On day four, one hour after the respective treatment, oligospermia was induced by administering a single dose of CP (100mg/kg body weight p.o.) to all the groups except group1. At the end of the study period the rats were euthanised and accessory reproductive organs were weighed and subjected to histopathological examination. The semen samples were subject to enumeration of sperms. Weight of the reproductive organs, histopathological examination of the tissues, and sperm count were the parameters studied to understand the effect of Speman(r) on rats with CP-induced oligospermia. Results: Changes that occurred due to the administration of CP at a dose of 100 mg/kg body weight were dose dependently reversed with Speman(r) at a dose of 300, 600, and 900 mg/kg body weight. There was a statistically significant increase in sperm count and the weight of the seminal vesicle, epididymis, and prostate. Conclusion: Findings of this investigation indicate that Speman(r) dose dependently reversed the CP-induced derangement of various parameters pertaining to the reproductive system. This could explain the total beneficial actions of Speman(r) reported in several other clinical trials. PMID- 29755868 TI - Lifestyle intervention as a treatment for obesity among school-age-children in Celaya, Guanajuato: An experimental study. AB - Introduction: Obesity is a risk factor in chronic diseases, and its frequency among children in Mexico is increasing. Objective: To determine the effect of lifestyle intervention as a treatment for obesity in school-age-children from Celaya, Mexico. Methodology: For this experimental study, four schools were randomly selected. Children and parents participated voluntarily and signed consent forms. Two schools were chosen as the experimental group and the other two formed the control group. Age, gender, weight, height, BMI and blood pressure were recorded for each participant. Intervention: Children and parents were asked to walk in their schools for 30 minutes a day Monday through Friday and to attend 8 instructional sessions over a period of four months dedicated to the selection and preparation of meals. Statistical Analysis: The OR and 95% CI were calculated to determine the effect of the intervention; a Z-test for two proportions for overweight and obesity in the control and experimental groups were carried out for comparison. Results: 157 children were included in the experimental group and 144 in the control group. To compare the proportions of the overweight and the obese between the groups, a Z-test = -0.36 (p-value 0.72) were obtained showing no effect of the intervention in lifestyle; OR =1.09, 95% CI (0.67, 1.77). It was adjusted according to the attendance to the sessions resulting in an OR = 2.00, 95% CI (0.69, 5.77), demonstrating that not attending the sessions was a confounder. Conclusions: Intervention in lifestyle should be measured over a longer period of time in order to determine what effects it may have on changes in body mass index. PMID- 29755869 TI - The State of Cardiovascular Disease in the Kyrgyz Republic. PMID- 29755870 TI - The Impact of Global Institutions on National Health HIV/AIDS Policy Making in Developing Countries. AB - This article explores the relationship of global institutions such as the International Monetary Fund, World Trade Organization, World Bank, and individual developing countries in social health policy making in terms of HIV and AIDS. We examine the role of IGOs and NGOs in regarding to HIV/AIDS issues then analyse the TRIPs agreement as a tool for developing countries to negotiate with International organisations in global health policy decisions. PMID- 29755872 TI - Precision of Disability Estimates for Southeast Asians in the American Community Survey 2008-2010 Microdata. AB - Detailed social data about the United States (US) population were collected as part of the US decennial Census until 2000. Since then, the American Community Survey (ACS) has replaced the long form previously administered in decennial years. The ACS uses a sample rather than the entire US population, and therefore only estimates can be created from the data. This investigation computes disability estimates, standard error, margin of error, and a more comprehensive "range of uncertainty" measure for non-Latino-whites (NLW) and four Southeast Asian groups. Findings reveal that disability estimates for Southeast Asians have a much higher degree of imprecision than for NLW. Within Southeast Asian groups, Vietnamese have the highest level of certainty, followed by the Hmong. Cambodian and Laotian disability estimates contain high levels of uncertainty. Difficulties with self-care and vision contain the highest level of uncertainty relative to ambulatory, cognitive, independent living, and hearing difficulties. PMID- 29755871 TI - BRCA1 and BRCA2 Gene Mutations Screening In Sporadic Breast Cancer Patients In Kazakhstan. AB - Background: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Kazakhstan women. Aim: To evaluate the role of BRCA1/2 mutations in Kazakhstan women presenting with sporadic breast cancer. Methods: We investigated the distribution and nature of polymorphisms in BRCA1 and BRCA2 entire coding regions in 156 Kazakhstan sporadic breast cancer cases and 112 age-matched controls using automatic direct sequencing. Results: We identified 22 distinct variants, including 16 missense mutations and 6 polymorphisms in BRCA1/2 genes. In BRCA1, 9 missense mutations and 3 synonymous polymorphisms were observed. In BRCA2, 7 missense mutations and 3 polymorphisms were detected. There was a higher prevalence of observed mutations in Caucasian breast cancer cases compared to Asian cases (p<0.05); higher frequencies of sequence variants were observed in Asian controls. No recurrent or founder mutations were observed in BRCA1/2 genes. There were no statistically significant differences in age at diagnosis, tumor histology, size of tumor, and lymph node involvement between women with breast cancer with or without the BRCA sequence alterations. Conclusions: Considering the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of BRCA1/2 mutations and reliable genetic counseling for Kazakhstan sporadic breast cancer patients. Evaluation of common polymorphisms and mutations and breast cancer risk in families with genetic predisposition to breast cancer is ongoing in another current investigation. PMID- 29755873 TI - Editorial: BRCA1 and BRCA2 gene mutations screening in sporadic breast cancer patients in Kazakhstan. PMID- 29755874 TI - Cardiovascular risk factors in young male adults: impact of physical activity and parental education. AB - Background: This study was conducted to assess whether choices of physical activity, smoking status, and parental education and income were correlated with the health status of young adult males which are important for preventive health policy. Methods: 491 18-29-year old males from lower socioeconomical districts in Turkey participated in this study. Information about demographic characteristics, parental education, household income, smoking status, and physical activity was obtained by means of a standardized questionnaire. BMI and metabolic parameters (serum lipid profile) were assessed. Results: Mean total cholesterol, LDL, HDL and triglyceride levels were in the normal range. The physically active group displayed a better lipid profile. No relationship was found between parental education and serum lipids. Smoking was slightly correlated with household income (r=103, p=0.022). Conclusion: Young adult males who participate in relatively high levels of physical activity are at lower CHD risk than less active ones. The present study also showed that lower socioecnomic status does not always correlate with higher levels of cardiovascular risk factors. In conclusion, data supports that while family history cannot be changed, HDL levels can be modulated by lifestyle factors as in other populations and that with the determined benefits of increasing physical activity and thus, HDL levels, policy reform in schools to promote physical activity are warranted. PMID- 29755875 TI - The Central Asian Supercourse to Increase Scientific Productivity. PMID- 29755876 TI - Use of Public Health Promotion Items to Improve Health in Saudi Arabia. PMID- 29755878 TI - Adolescent abortions: Situational analysis based on official statistics conducted in Kazakhstan during the last 5 years (2007-2011). AB - In recent decades, adolescent pregnancy has become an important health issue in a great number of both developed and developing countries. We have investigated the official statistics database of the National Ministry of the Health (MoH) and their #13 Statutory Form (SF) and found the total number of abortions between 2007-2011 in Kazakhstan decreased by 28%. The total number of adolescent (up to 15 plus 15-18 years old) abortions decreased by 52.7%. Contrary to this decrease in the total number of adolescent abortions, spontaneous abortions have increased from 23.2% to 45.0%,. We found a tendency towards a decrease in the number of adolescents with the first pregnancy among adolescents 15-18 who had abortion between 2007-2011, from 51.3% to 35.8%. This clearly reflects the success of prevention activities among adolescents who have already had an abortion or child labor. During the analyzed period, there were two lethal outcomes from abortionsamong girls15-18 years old. There are some limitations in the assessment levels and dynamic changes of abortions among adolescents due to the division of age in the official statistical database. PMID- 29755877 TI - Alcohol Use, Risk Taking, Leisure Activities and Health Care Use Among Young People in Northern Vietnam. AB - Alcohol consumption is associated with a wide range of health and social consequences. It is also associated with a number of risk taking behaviours. These include illicit drug use and unsafe sex. Alcohol consumption appears to be increasing in Vietnam. The purpose of this paper is to examine the patterns of alcohol consumption and its relationship with a number of other risk taking behaviours amongst young people. Information was also obtained concerning leisure activities and use of health care. The paper also sets out to examine possible gender differences in relation to alcohol consumption and risk behaviour and to propose the development and implementation of alcohol monitoring and prevention programs in Vietnam. The study involved a cross-sectional, community survey using a standardised interview. This was conducted during face-to-face interviews with 1,408 young people aged 10-19 years. Respondents were recruited randomly through the lists of the households from 12 selected communes in three areas in Northern Vietnam. The findings presented here were part of a larger health risk behaviour survey. Levels of alcohol use were low. Overall, 16.5% of participants were experienced drinkers, and only 4% of them were current drinkers. Males were significantly more likely than females to report drinking. This study also showed that rates of alcohol consumption were associated with age, education, geographical area, gender, tobacco smoking, involvement in violence, watching television, computer use and playing computer games, wearing safety helmets and use of health services. Alcohol consumption tended to increase with age for both males and females. Alcohol and its effects on young people are clearly a growing public health issue in Vietnam. Because of this, more detailed behavioral research should be conducted into the relationship between alcohol consumption and other risky behaviours amongst young people. It is also recommended that alcohol harm reduction policies should be implemented and integrated into measures to reduce levels of other health problems such as HIV/AIDS and non communicable diseases. Such policies should ideally be evidence-based and evaluated. PMID- 29755879 TI - TB case detection in Tajikistan - analysis of existing obstacles. AB - Background: Tajikistan National TB Control Program. Objective: (1) To identify the main obstacles to increasing TB Detection in Tajikistan. (2) To identify interventions that improve TB detection. Methods: Review of the available original research data, health normative base, health systems performance and national economic data, following WHO framework for detection of TB cases, which is based on three scenarios of why incident cases of TB may not be notified. Results: Data analysis revealed that some aspects of TB case detection are more problematic than others and that there are gaps in the knowledge of specific obstacles to TB case detection. The phenomenon of "initial default" in Tajikistan has been documented; however, it needs to be studied further. The laboratory services detect infectious TB cases effectively; however, referrals of appropriate suspects for TB diagnosis may lag behind. The knowledge about TB in the general population has improved. Yet, the problem of TB related stigma persists, thus being an obstacle for effective TB detection. High economic cost of health services driven by under-the-table payments was identified as another barrier for access to health services. Conclusion: Health system strengthening should become a primary intervention to improve case detection in Tajikistan. More research on reasons contributing to the failure to register TB cases, as well as factors underlying stigma is needed. PMID- 29755880 TI - Developing a Supercourse Help Desk for India. PMID- 29755881 TI - Total and high-molecular-weight adiponectin levels in relation to insulin resistance among overweight/obese adults. AB - Objective: To determine whether baseline levels or intervention-associated changes in total and high molecular weight (HMW) adiponectin levels were associated with insulin resistance after six months of behavioral treatment for weight loss. Design: An ancillary study to a behavioral weight loss trial; the intervention was delivered in group sessions. Methods: Participants included 143 overweight/obese adults with a mean BMI of 33.7 kg/m2. The sample was 88% female, 67% white, and 44.2 +/- 8.5 years old. Circulating adiponectin levels (total and HMW) and the homeostasis model assessment (HOMA) of insulin resistance were measured and evaluated. Results: At baseline, there was significant inverse associations between total adiponectin and HOMA (p < 0.001) and between HMW adiponectin and HOMA (p < 0.001) independent of weight. At 6-mo, there was a 17% improvement in HOMA, 8% increase in total adiponectin, 17% increase in HMW adiponectin levels, and 8.72% weight loss (p's for all< 0.001). There was also a significant inverse association between changes in total adiponectin and HOMA (p = 0.04) that was independent of baseline weight and weight loss. In contrast, the association between changes in HMW adiponectin and HOMA was attenuated after adjustment for weight loss. Conclusions: An increased level of total adiponectin was associated with improved insulin sensitivity, regardless of baseline weight and weight loss. However, baseline total and HMW adiponectin levels were more strongly associated with HOMA than changes in these measures at six months. HMW adiponectin level was not related more closely to insulin resistance than total adiponectin level. PMID- 29755882 TI - Concurrent Brucellosis and Q Fever Infection: a Case Control Study in Bamyan Province, Afghanistan. AB - Background: More than 500,000 people are affected by brucellosis each year while the incidence of Q fever is poorly recorded. Consistent outbreaks of brucellosis have been reported in Afghanistan, affecting social and economic life. This study aimed to determine the means of propagation of brucellosis and Q-fever and establish appropriate control measures for both. Methods and Materials: An outbreak of 1,317 cases of brucellosis and Q fever was investigated from May 2011 to the end of 2012 in Bamyan province of Afghanistan. A total of 100 cases were selected by random sampling with equal number of neighbor controls. Data were collected through structured questionnaire. Results: The average age was 30 years +/-14 years. Of those sampled, 62% were female, 38% were male, and resided in three districts: Punjab, Yakawlang and Waras. Using multivariate analysis, being a housewife (OR=7.36), being within proximity of kitchens to barns (OR= 2.98), drinking un-boiled milk (OR= 5.26), butchering (OR= 3.53) and purchasing new animals in the last six months (OR= 3.53) were significantly associated with contraction of brucellosis and Q fever. Conclusion: Health educators should focus on families dealing with animals, especially on females. Pasturing, healthy milking, dunging, and slaughtering practices, along with use of safe dairy products should be the focus of preventive measures. PMID- 29755883 TI - Prevalence of Risk Factors for Non-Communicable Diseases in the Adult Population of Urban Areas in Kabul City, Afghanistan. AB - Background: Non-Communicable diseases (NCDs) are a major global problem. This study aims to estimate the prevalence of common risk factors for NCDs among the adult population in urban areas of Kabul city, Afghanistan. Methods and Materials: This study was conducted from December 2011 through March 2012 and involved a survey of 1169 respondents, aged 40 years and above. Multistage cluster sampling was used for participant selection, followed by random sampling of the participants. The World Health Organization STEPwise approachfor Surveillance (STEPS) was modified and used for this study. Results: The overall prevalence of smoking was 5.1% (14.7% men versus 0.3% women) and using mouth snuff was 24.4% in men and 1.3% in women. The prevalence of obesity and hypertension were 19.1% and 45.2 % in men and 37.3% and 46.5% in women. Prevalence of diabetes was 16.1% in men and 12% in women. The overall prevalence of obesity, hypertension and diabetes mellitus was 31.2%, 46% and 13.3%, respectively. On average, subjects consumed 3.37 servings of fruit and 2.96 servings of leafy vegetables per week. Mean walking and sitting hours per week (as proxies for physical activity) were 19.4 and 20.5, respectively. A multivariate model demonstrated that age was a significant risk factor for obesity (OR=1.86), diabetes (OR=2/09) and hypertension (OR=4.1). Obesity was significantly associated with sex (OR=1.65). Conclusion: These results highlight the need for interventions to reduce and prevent risk factors of non-communicable diseases in urban areas of Kabul City, Afghanistan. PMID- 29755885 TI - Emerging Infectious Diseases, Antimicrobial Resistance and Millennium Development Goals: Resolving the Challenges through One Health. AB - Most emerging infectious diseases are zoonoses, which could severely hamper reaching the targets of millennium development goals (MDG). Five out of the total eight MDG's are strongly associated with the Emerging Infectious Diseases (EIDs). Recent emergence and dissemination of drug-resistant pathogens has accelerated and prevent reaching the targets of MDG, with shrinking of therapeutic arsenal, mostly due to antimicrobial resistance (AMR). World Health Organization (WHO has identified AMR as 1 of the 3 greatest threats to global health. Until now, methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) have been observed in hospital-acquired infections. In India, within a span of three years, New Delhi metallo-beta-lactamase prevalence has risen from three percent in hospitals to twenty- fifty percent and is found to be colistin resistant as well. Routine use of antimicrobials in animal husbandry accounts for more than 50% in tonnage of all antimicrobial production to promote growth and prophylaxis. This has consequences to human health and environmental contamination with a profound impact on the environmental microbiome, resulting in resistance. Antibiotic development is now considered a global health crisis. The average time required to receive regulatory approval is 7.2 years. Moreover, the clinical approval success is only 16%. To overcome resistance in antimicrobials, intersectoral partnerships among medical, veterinary, and environmental disciplines, with specific epidemiological, diagnostic, and therapeutic approaches are needed. Joint efforts under "One Health", beyond individual professional boundaries are required to stop antimicrobial resistance against zoonoses (EID) and reach the MDG. PMID- 29755884 TI - Prevalence of obesity among Bangladeshi pregnant women at their first trimester of pregnancy. AB - BACKGROUND: Paradoxically, the escalating global epidemic of maternal obesity coexists with malnutrion in many areas of Bangladesh. This proves a major challenge to obstetric practice from preconception to postpartum due to related comorbid conditions including: maternal death or severe morbidity, gestational diabetes and hypertension, increased risk of early and recurrent miscarriage, pre eclampsia, thromboembolism, post-caesarean wound infection, postpartum haemorrhage, and low breastfeeding rates. A dramatic increase in birth defects and other pregnancy-induced disorders related to maternal obesity has added millions of dollars to health care costs leading great economical loss to the country. OBJECTIVE: The study was designed to determine the prevalence of obesity among Bangladeshi pregnant women in their 1st trimester of pregnancy. STUDY DESIGN: 426 pregnant women presenting to the antenatal care until of Azimpur maternity hospital of Dhaka, Bangladesh were randomly selected for this cross sectional study to determine their weight status using body mass index (BMI, kg/m2). RESULT: 90 (21.2%) pregnant women were reported as obese with pregnancy BMI of >30 kg/m2. 171 (40.1%) and 140 (32.8%) pregnant women were reported as overweight and healthy with pregnancy BMI of 25-29.9 kg/m2 and 18.5-24.9 kg/ m2, respectively. Statistical analysis revealed obesity and overweight status were found to be significantly associated with age; women aged 31 or above were more likely to be obese (OR=2.5; 95% CI 1.53-3.96) and overweight (OR=3.3; 95% CI 2.15 4.99). CONCLUSION: This study provides evidence of increasing trends in obesity among Bangladeshi pregnant women, which poses possible health risks both for mother and child. The findings of this study may act as baseline data for monitoring the effectiveness of national programs for the prevention and control of maternal obesity. PMID- 29755887 TI - Current Impact, Future Prospects and Implications of Mobile Healthcare in India. AB - India has a diverse geographical landscape and predominately rural population. Telemedicine is identified as one of the technological pillars to support healthcare services in this region, but is associated with high cost and complex infrastructure, thus restricting its wider use. Mobile-based healthcare (m Health) services may provide a practical, promising alternative approach to support healthcare facilities. India has a high mobile user base, both in cities and in rural regions. The appropriate identification of mobile data transmission technology for healthcare services is vital to optimally use the available technology. In this article, we review current telecommunication systemsin India, specifically the evolving consensus on the need for CDMA (Code Division Multiple Access - a wireless technology used by leading international and national operators. This technology is deployed in 800MHz band making it economically viable and far reaching with high quality of services) to continue its operations in India along with mobile healthcare services. We also discuss how healthcare services may be extended using m-Health technologies, given the availability of telecommunications and related services. PMID- 29755886 TI - A 24-hour dietary recall for assessing the intake pattern of choline among Bangladeshi pregnant women at their third trimester of pregnancy. AB - Maternal choline intake during the third trimester of human pregnancy can modify systemic and local epigenetic marks in fetal-derived tissues, promoting better pregnancy outcomes, increased immunity, as well as improved mental and physical work capacity with proper memory and cognitive development. 103 pregnant women presenting to the antenatal care of Azimpur Maternity Hospital of Dhaka, Bangladesh in their third trimester of pregnancy were randomly selected for this cross sectional study exploring dietary intake patterns of choline. A dietary recall form was administered to estimate frequency and amount of food consumption of foods for the previous 24 hours. Most women reported diets that delivered less than the recommended choline intake (mean +/- SD; 189.5 +/- 98.2) providing only 42.72% of total RDA value. The results of this study may indicate that dietary choline among pregnant, Bangladeshi women may not be adequate to meet the needs of both, the mother and fetus. Further studies are warranted to determine clinical implications. PMID- 29755888 TI - Screening of Gestational Diabetes and Hypertension Among Antenatal Women in Rural West India. AB - Background: Hypertension and gestational diabetes are among the leading causes of maternal and perinatal mortality, especially in rural areas of developing countries with meager health facilities. With early diagnosis and timely treatment, these adverse events can be decreased. The primary aim of this study was to implement a screening program for gestational diabetes and hypertension, and to assess risk factors associated with these conditions among antenatal women in the rural area of the Gujarat province in India. Methods: A cross-sectional study was conducted at one of the rural areas of Gujarat province in India. Following a random cluster sampling procedure, the village of Davas was selected. A multistage random sampling method was utilized, resulting in a sample of 346 antenatal women. Screening guidelines from the American Diabetes Association were followed for gestational diabetes screening. Results: The majority of antenatal mothers (55.50%) were between 21-25 years of age. 242 antenatal women were multigravida, and among them, 85.96% had institutional delivery at their last pregnancy. Of the total 346 women, 17.60% were prehypertensive. The prevalence of systolic hypertension was 1.40%, diastolic hypertension was 0.90%, and gestational diabetes was 1.73%. Conclusion: Socioeconomically upper class, a family history of hypertension, and BMI >= 25 were strong risk factors for hypertension during pregnancy and gestational diabetes. Health education should be made readily available to antenatal mothers by paramedical workers regarding symptoms of hypertension and gestational diabetes mellitus for early self identification. PMID- 29755889 TI - Why Does Kazakhstan Need New Scientific Journals? PMID- 29755890 TI - Satisfaction with surgical correction of stress urinary incontinence in women: A pilot study in Almaty, Kazakhstan. PMID- 29755891 TI - A New Paradigm of Primary Health Care in Kazakhstan: Personalized, Community based, Standardized, and Technology-driven. AB - This paper discusses the need for change from Kazakhstan's current disease centric healthcare paradigm to a new primary health and wellness-centric health care paradigm, technology-driven and based on personal relationships within a social context. While many different papers have been published about the importance of prevention and primary health care, few have focused on healthcare transition in Kazakhstan or other countries in Central Asia. The WHO's historic 1978 Alma-Ata Declaration signed in Kazakhstan promoted the centrality of primary care to the provision of effective, efficient, and equitable health services. Modern technologies such as the Internet, social media, and portable medical devices democratize medicine, providing great opportunities to rethink the Alma Ata Declaration and reinvent primary health care on an entirely new platform that is knowledge-based and technology-assisted. The new paradigm suggested for the future development of health in Central Asian region emphasizes personal relationships and encourages sustainable solutions created by communities. This paper also introduces HealthCity, a new project in Kazakhstan aiming at introducing private, community-based and standardized primary healthcare that is driven by SmartHealth innovative technology. PMID- 29755892 TI - Regional control of regulatory immune cells in the intestine. AB - Purpose of review: The intestine contains the largest compartment of immune regulatory cells which include T regulatory cells and IL-10 producing macrophages. These cell populations serve to restrain unnecessary immune responses of the intestine, which may lead to the pathogenesis of Crohn's disease or food allergy. Recent findings: This review discusses the recent findings pertaining to the functional regulation of these cells which may provide insight into novel therapies. Both T regulatory cells and macrophages are regulated in microbiota-dependent and microbiota-independent manners, i.e., dietary antigens. Often, this is specific to regional specialization and environment in small intestine vs. colon. Summary: These immune regulatory cells are largely regulated by microbiota in the colon, whereas in the small intestine, the microbiota has less affect, as seen in germ-free mice studies. Targeting these cells in their specific compartments may direct future treatment modalities for inflammatory bowel disease as ulcerative colitis and Crohn's are vastly different diseases. PMID- 29755894 TI - Divalent Cation Removal by Donnan Dialysis for Improved Reverse Electrodialysis. AB - Divalent cations in feedwater can cause significant decreases in efficiencies for membrane processes, such as reverse electrodialysis (RED). In RED, power is harvested from the mixing of river and seawater, and the obtainable voltage is reduced and the resistance is increased if divalent cations are present. The power density of the RED process can be improved by removing divalent cations from the fresh water. Here, we study divalent cation removal from fresh water using seawater as draw solution in a Donnan dialysis (DD) process. In this way, a membrane system with neither chemicals nor electrodes but only natural salinity gradients can be used to exchange divalent cations. For DD, the permselectivity of the cation exchange membrane is found to be crucial as it determines the ability to block salt leakage (also referred to as co-ion transport). Operating DD using a membrane stack achieved a 76% reduction in the divalent cation content in natural fresh water with residence times of just a few seconds. DD pretreated fresh water was then used in a RED process, which showed improved gross and net power densities of 9.0 and 6.3%, respectively. This improvement is caused by a lower fresh water resistance (at similar open circuit voltages), due to exchange of divalent for monovalent cations. PMID- 29755895 TI - Role of Thermography in the Diagnosis of Chronic Sinusitis. AB - Introduction Thermography is a form of radiography that images the skin surface temperature. Thermograms are pictorial representations of thermal maps of the entire body's outer surface. Thermography was applied as an attempt to evaluate its usefulness in the diagnosis of chronic sinusitis (CS). Hence, this study was done to determine the diagnostic value of thermography for patients suffering from CS. Methodology Patients attending the Department of Otorhinolaryngology and Head and Neck Surgery over a two years' duration with symptoms suggestive of CS were included in this diagnostic evaluation study. X-ray paranasal sinuses (PNS) and nose, thermography of head and neck, and computed tomography (CT) of PNS and nose (axial and coronal sections) were performed on them. The thermograms and X ray sinuses obtained were compared with the computed tomography of PNS findings. Results The study population consisted of 167 patients (75 males and 92 females) and the mean age of the study population was 38.6 years. The sensitivity and specificity of thermography of the head and neck in diagnosing frontal, ethmoidal, maxillary, and sphenoidal sinusitis were 92.59% and 68.58%, 100% and 66.32%, 70.06% and 85.88%, 99.18% and 0%, respectively. Whereas the sensitivity and specificity of the X-ray PNS and nose in diagnosing frontal, ethmoidal, maxillary, and sphenoidal sinusitis were 92.59% and 77.88%, 73.61% and 81.05%, 89.19% and 98.92%, 74.44% and 99.18%, respectively. Conclusion Thermography is better than X-rays in diagnosing frontal and ethmoidal sinusitis and as good as X ray PNS and nose in diagnosing maxillary sinusitis. Thermography failed to pick up sphenoidal sinusitis. The advantages of thermography are that it is a radiation-free, non-invasive, and cost-effective method for diagnosing CS. PMID- 29755893 TI - Policing the intestinal epithelial barrier: Innate immune functions of intraepithelial lymphocytes. AB - Purpose of review: This review will explore the contribution of IELs to mucosal innate immunity and highlight the similarities in IEL functional responses to bacteria, viruses and protozoan parasite invasion. Recent findings: IELs rapidly respond to microbial invasion by activating host defense responses, including the production of mucus and antimicrobial peptides to prevent microbes from reaching the epithelial surface. During active infection, IELs promote epithelial cytolysis, cytokine and chemokine production to limit pathogen invasion, replication and dissemination. Commensal-induced priming of IEL effector function or continuous surveillance of the epithelium may be important contributing factors to the rapidity of response. Summary: Impaired microbial recognition, dysregulated innate immune signaling or microbial dysbiosis may limit the protective function of IELs and increase susceptibility to disease. Further understanding of the mechanisms regulating IEL surveillance and sentinel function may provide insight into the development of more effective targeted therapies designed to reinforce the mucosal barrier. PMID- 29755896 TI - Bouveret's Syndrome: Literature Review. AB - It was in 1896 that Bouveret's syndrome acquired its name after the French physician Leon Bouveret, who published two case reports in Revue de Medecin. Bouveret's syndrome describes gastric outlet obstruction secondary to an impacted gallstone. The gallstone reaches the small bowel through a bilioenteric fistula as a consequence of chronic inflammation and adherence between the biliary system and the bowels which increase the intraluminal pressure and leads to secondary wall ischemia and wall perforation with gallstone passage into the bowel. Bouveret's syndrome's prevalence is highest among elderly women. Despite the rarity of Bouveret's syndrome, it can cause notable morbidity and mortality rates. We underwent a review of literature about Bouveret syndrome to increase awareness of its occurrence and potentially life-threatening complications. PMID- 29755897 TI - Improving Door to Groin Puncture Time for Mechanical Thrombectomy via Iterative Quality Protocol Interventions. AB - INTRODUCTION: Delays in door to groin puncture time (DGPT) for patients with ischemic stroke caused by acute large vessel occlusions (LVO) are associated with worse clinical outcomes. We present the results of a quality improvement protocol for endovascular stroke treatment at the University of California, San Diego (UCSD) that aimed to minimize DGPT. MATERIALS AND METHODS: Our stroke team implemented a series of quality improvement measures to decrease DGPT, with a target of 90 minutes or less. Sixty-three patients treated at our center were retrospectively divided into three groups based on the date of their intervention as a proxy for the implementation of process improvement protocols: 23 patients treated from July to December 2015, 24 patients treated from January to July 2016, and 16 patients treated from July 2016 to December 2016. Multivariate log linear and logistic regression analyses were used to assess the predictors of prolonged DGPT and compliance with target DGPT (<90 min), respectively. RESULTS: Date of intervention-a proxy for the implementation of process improvement protocols-was predictive of compliance with target DGPT. Patients treated from July 2016 to December 2016-after the full implementation of process improvements were 3.2 times more likely to meet or exceed the target DGPT compared to patients treated from July 2015 to December 2015 (p=0.011). When adjusting for potential confounders in a multivariate analysis, patients in the final cohort were associated with shorter DGPT (Exp(B)=0.61, p=0.013) and remained significantly more likely to achieve the DGPT goal (OR=14.2, p=0.007). CONCLUSION: An iterative quality improvement process can significantly improve DGPT. This analysis demonstrates the utility of a formal quality improvement system at an academic comprehensive stroke center. PMID- 29755898 TI - An Unusual Presentation of Kikuchi-Fujimoto Disease with Recurrent Subdural Effusion. AB - A 24-year-old man complained of a right temporal headache for four weeks. The patient denied any trauma or previous anticoagulation use. He also reported tender right facial swelling. His physical exam was unrevealing except for right cranial nerve (CN) VI palsy, right parotid enlargement, and cervical adenopathy. Laboratory findings were significant for mild leukopenia at 3300 cells/uL. The computed tomography (CT) scan obtained showed a chronic left subdural effusion with a 4 mm midline shift and confirmed right parotid enlargement and cervical lymphadenopathy. Surgical burr hole evacuation was done and the fluid was sent for wound culture analysis. The infectious diseases service recommended initiating antibiotics, which were later stopped due to cerebrospinal fluid (CSF) cultures with no growth of any organisms. His CN VI palsy resolved during admission. The patient was discharged with follow-up for biopsy. The patient was lost to follow-up. The patient presented to the emergency department (ED) three months later, with a left-sided frontal headache. A repeat CT scan showed a new, right-sided fluid collection outside the brain parenchyma. Burr hole evacuation was done again and purulent fluid was drained. Antibiotics were held this time, but anti-tuberculous therapy was initiated empirically. The otolaryngology service was consulted and a lymph node biopsy was performed. The pathology showed histiocytic necrotizing lymphadenitis. A dural biopsy was done as well and was consistent with histiocytic necrotizing lymphadenitis involving the dura. Cultures from the subdural fluid did not grow any organism. The patient remained neurologically intact. He improved after surgery was done to drain the fluid and was managed by analgesics. The cultures from the extra-parenchymal fluid collection remained negative for pathogens and tuberculous mycobacteria. The patient was discharged with rheumatology clinic follow-up. He saw the rheumatologist six weeks after the discharge. During his clinic visit, the patient reported no recurrence of headaches, fevers, rash, or joint pain. Our patient had a rare presentation of Kikuchi-Fujimoto disease, in which he had a subdural fluid collection resulting in neurological complications that required surgical intervention. PMID- 29755899 TI - Correlations between Health Insurance Status and Risk Factors for Cardiovascular Disease in the Elderly Asian American Population. AB - Background Asian Americans are often seen as a model minority; however, the group faces significant cultural, language, and financial barriers to adequate health care access. Assessing health insurance's impact on cardiovascular disease risk factors among older Asian Americans may provide support for further research and intervention development focused on improving insurance enrollment. The authors sought to examine the associations between elevated blood pressure and body mass index and insurance coverage. Methods Individuals attended health fairs held by a student-led organization in Southern California between 2008 and 2011. Age and insurance status were obtained through participant questionnaires. Participants' blood pressure and body mass index were measured. Analyses identified health and insurance associations. Results In total, 53.8% of respondents were 60 years or older. Of these, 30.9% had an elevated blood pressure and 36.6% had an elevated body mass index. Of respondents 60 years or older, 52.0% had health insurance. Both elevated blood pressure (p = 0.04) and body mass index (p = 0.03) were significantly associated with lacking insurance. Conclusions Insured participants were less likely to have elevated blood pressure and body mass index measurements, supporting a positive correlation between having insurance and less risk factors for cardiovascular disease. These findings provide incentives for further research into the importance of health insurance in preventative health care. PMID- 29755900 TI - Fahr's Disease: A Differential to Be Considered for Various Neuropsychiatric Presentations. AB - Fahr's disease, also known as familial idiopathic basal ganglia calcification, is a neurodegenerative disorder affecting cerebral microvessels, mainly the basal ganglia, and presenting with diverse neuropsychiatric manifestations. It is considered to be mainly hereditary, with autosomal dominant inheritance. In light of its various presentations and incomplete penetrance, Fahr's disease is known to be underestimated and underdiagnosed. Here, an early-onset case of Fahr's disease is presented mainly with pure psychiatric symptoms. Given the diversity of the presenting symptoms, and variations in the age of onset, further investigation of organic etiologies in patients presenting with neuropsychiatric symptoms, family members of patients with Fahr's disease, and patients with unexplained cerebral calcification is recommended. PMID- 29755901 TI - Emerging Cellular Therapies for Glioblastoma Multiforme. AB - Glioblastoma multiforme (GBM) is the most common type of malignant primary brain cancer in adults. It is composed of highly malignant cells that display metastatic and angiogenic characteristics, making it resistant to current first line chemotherapy with temozolomide, an alkylating agent. Despite many years of research, GBM remains poorly responsive to multiple available therapies, giving GBM patients, who receive the conventional combination of chemoradiotherapies and surgical resection, a dismal prognosis. There is growing evidence that the conventional systemic chemotherapeutic agents for GBM are ineffective in improving the disease progression. We aim to explore the emerging cellular therapies which may play a significant role in treating GBM. PMID- 29755902 TI - Efficacy and Safety of Wheat Grass in Thalassemic Children on Regular Blood Transfusion. AB - BACKGROUND: In thalassemia, mutations either in alpha or beta chain synthesis results in low hemoglobin (Hb). Wheatgrass has been used for many years for health purposes. Some reports suggest the beneficial effect of wheatgrass on transfusion requirements. Folic acid is also known to play an important role in several biochemical reactions. In some patients with thalassemia, the supplementation of folic acid is useful. OBJECTIVE: To evaluate the efficacy and safety of wheatgrass in children with thalassemia receiving chronic blood transfusions. MATERIAL AND METHODS: In this randomized prospective study, 69 children with thalassemia were divided into the wheatgrass group and the control group (no wheatgrass). Both groups received a regular blood transfusion and folic acid. The treatment duration was 18 months. Anthropometric parameters, number of transfusions, and amount of blood transfused were compared within and between the groups at the end of the therapy. Clinical examinations, laboratory investigations, and ultrasounds for liver and spleen span were performed at the baseline and then every six months till 18 months. Adverse effects (if any) were noted on every visit. Quality of life (QOL) was evaluated before and at the end of the study using a questionnaire. RESULTS: Sixty-nine (study group (n=45; mean age 6.35 +/- 2.65 yrs); control group (n=24; 4.86 +/- 2.77 yrs)) patients were enrolled, of which 12 from the study group and three from the control group did not complete the study. The difference in liver size within the wheatgrass group was significant (P <0.021) only at 18 months but not in the control group at any time point. The difference in spleen size was significant within the wheatgrass group (P<0.005) as well as the control group (P<0.001) at 18 months only. The difference in serum ferritin levels was not significant between the two groups. The increase in serum ferritin levels at the end of the study was significant in the control group when compared to the baseline (P<0.01). There was no difference in the average number of transfusions or in the blood transfusion requirement between the two groups. The difference in the QOL at the start and end was significant in the wheatgrass group (P<0.05). CONCLUSION: Wheatgrass appears to play a promising role in children with thalassemia receiving chronic blood transfusions. PMID- 29755903 TI - Subungual Amelanotic Melanoma Masquerading as Onychomycosis. AB - Subungual amelanotic melanoma is rare. In addition, amelanotic melanoma can mimic non-melanocytic tumors. A 67-year-old woman had a four-year history of dystrophy of the left fourth fingernail. Periodic acid-Schiff staining of the nail plate demonstrated fungal hyphae, establishing a diagnosis of tinea unguium. The nail plate subsequently detached and the underlying nail bed showed a red, friable mass that was biopsied and confirmed a diagnosis of melanoma. In conclusion, additional morphologic change of a persistent nail dystrophy-even with a biopsy confirmed diagnosis of onychomycosis-may require consideration for repeat evaluation, including a biopsy, to exclude the possibility of a subungual malignant tumor. PMID- 29755904 TI - Radiation-induced Cavernous Malformation as a Late Sequelae of Stereotactic Radiosurgery for Epilepsy. AB - Stereotactic radiosurgery (SRS) is a promising treatment for medically intractable mesial temporal lobe epilepsy. SRS for epilepsy has had an acceptable safety profile with reports of radiation-induced vascular malformations confined to central nervous system pathologies with prominent angiogenesis - namely, primary brain tumors, metastases, and arteriovenous malformations. Theoretical risks for radiation-induced lesions following radiosurgery for epilepsy have yet to be established. Of 13 patients treated in a pilot trial for medial temporal lobe epilepsy, one developed multiple delayed radiation-induced cavernous malformations following radiosurgery. This patient received a prescription dose of 20 Gy delivered to the amygdala, anterior hippocampus, and parahippocampal gyrus. Eight years following treatment, computed tomography imaging demonstrated an evolving hyperdensity in the mesial temporal lobe. Magnetic resonance imaging confirmed multiple T2 hypointense lesions with a mixed-signal intensity core in the left parahippocampal gyrus and anterior temporal lobe. The patient was initially managed conservatively. However, recurrent hemorrhage ultimately caused an acute deterioration in mental status, aphasia, and hemiparesis, necessitating surgical resection. Pathology confirmed radiation-induced cavernous malformations. This represents the first case of a radiation-induced vascular lesion as a long-term sequela of radiosurgery for epilepsy and illustrates the potential for this complication even when low doses are used in patients without angiogenic lesions. Optimal timing and indications for surgical resection of radiation-induced cavernous malformations prior to the development of neurologic symptoms warrant further refinement. Long-term vigilance and clinical monitoring are required. PMID- 29755905 TI - A Case of Neurotrophic Keratopathy Concomitant to Brain Metastasis. AB - We report a case of a 63-year-old Caucasian female referred to the cornea service of Clinica Oculistica with a neurotrophic corneal ulcer, decreased corneal sensitivity, absent corneal reflex, and decreased lacrimation. The medical record review was relevant for mastectomy and adjuvant therapy for breast cancer complicated by pontocerebellar angle metastasis. Eye patching and application of antibiotic and vitamin ointments were prescribed at first, without a significant improvement. Thus, treatment with autologous serum was started. In about two weeks, the cornea recovered and visual acuity improved with a residual corneal scarring. Finally, we should mention that, in our case, the main cause of the neurotrophic corneal ulcer could be identified in the previous trigeminal damage at the pontocerebellar angle and trigeminal ganglion. Sensory nerves play an important regulatory role via neuro-mediators on corneal wound healing, as denervation may interfere with cellular metabolism and inhibit mitosis, leading to an epithelial defect even with no direct damage. PMID- 29755906 TI - Rare Forms of Castleman Disease Mimicking Malignancy: Mesenteric and Pancreatic Involvement. AB - Castleman disease is a lymphoproliferative disorder with unknown etiology and pathogenesis. While the disease may involve all parts of the body, the mediastinum appears to be the most common part of involvement. In this study, we present two cases of Castleman disease with different localizations that mimicked malignancy. A 62-year-old female patient presented with jaundice. Laboratory analysis indicated aspartate aminotransferase: 250 U/L, total bilirubin: 4 mg/dl, and carbohydrate antigen (CA) 19-9: 900 U/ml. Computerized tomography (CT) of the abdomen showed a mass originating from the pancreas head which resulted in a biliary tract obstruction. A positron emission tomography-computed tomography (PET/CT) showed that the only site of involvement was the pancreas head. A decision was made to perform pancreaticoduodenectomy. During intra-abdominal exploration, lymphadenopathies were identified in the surroundings of the retropancreatic portal vein and the hepatic artery. Histopathological investigation of the dissected lymph nodes demonstrated findings consistent with granulomatous plasma-cell-rich Castleman disease. A 55-year-old female patient presented with abdominal pain, nausea, and vomiting. Computerized tomography of the abdomen showed an abdominal mass of 7 cm, originating from the mesenterium, with high-contrast uptake in the mesenterium in the lower abdominal quadrant. The mesenteric mass was resected along with segmentary small intestine resection. Histopathological investigation of the mass showed a giant granulomatous structure that consisted of plasma cells consistent with Castleman disease. Castleman disease should be kept in mind during differential diagnosis of locally advanced lymph nodes observed during preoperative investigations and intraoperative exploration. PMID- 29755907 TI - The 100 Most Influential Papers and Recent Trends in the Field of Gastrointestinal Stromal Tumours: A Bibliometric Analysis. AB - Background Bibliometric analysis is a statistical tool used to examine the exponential growth in medical research. Many analogous analyses have been conducted, but none existed for gastrointestinal stromal tumors (GISTs). Hence, we conducted a citation analysis of the hundred most cited and recently published articles on this topic. Methods Scopus was chosen as the primary database, through which the top 100 and recent publications were ranked according to the citation count and were then analysed. Results The 100 most cited articles were published between 1992 and 2013, among which the greatest number of articles were published in the years 2002 (n = 15) and 2006 (n = 11). Amidst the 24 countries from which the articles originated, the United States of America (n = 76) topped the list. The Journal of Clinical Oncology (n = 15) and the American Journal of Clinical Pathology (n = 10) contributed majority of the top articles. Harvard Medical School alone produced 44 of the top 100. Articles from 2013 to date showed the same trend as that of top 100 articles regarding origin and institutions. Conclusion Basic science and genetics of GISTs are established, and new drugs are being studied for medicinal therapy. Surgical management and diagnostics of these tumors, however, are yet to be studied as extensively. PMID- 29755909 TI - Malrotation of the Gut in Adults: An Often Forgotten Entity. AB - Malrotation of the gut is a common paediatric condition that usually presents in the first month of life. However, presentation in adults is rare, and as a diagnostic dilemma quite often surprises the surgeon intraoperatively. If this condition is not timely recognized, it may result in disastrous consequences, such as gangrene of the small gut. We present the case of a 21-year-old male who presented to the emergency room with recurrent episodes of colicky abdominal pain and bilious vomiting. Contrast-enhanced computerized tomography (CT) revealed malrotation of the gut. The patient was planned for Ladd's procedure. Malrotation in adults may present in an acute way due to midgut volvulus or may have a chronic indolent course with recurrent vomiting and abdominal pain. In patients with acute obstruction, this differential should be kept in mind, especially if the patient has no previous abdominal surgery or evidence of tuberculosis. Contrast-enhanced CT is the investigation of choice and reveals typical findings, like whirlpool sign, corkscrew sign, or reversed relation of superior mesenteric artery and vein. The treatment is surgical as failure to do so may result in intestinal gangrene. The procedure of choice is Ladd's procedure. Every patient, even if asymptomatic, warrants this procedure as it is impossible to predict the timing of catastrophic complications. PMID- 29755908 TI - Gastric Volvulus: A Rare Entity Case Report and Literature Review. AB - Gastric volvulus is a rare entity defined as an abnormal rotation of the stomach around itself. It is a diagnosis of exclusion; the clinical index of suspicion is always low and is mostly diagnosed on imaging or on the surgery table. When it occurs, it is an emergency due to the risk of strangulation and consequent gangrene of the stomach. Mesentero-axial (MA) gastric volvuli constitute one third of all cases. Here, we are present an interesting case of acute MA gastric volvulus diagnosed with imaging and treated subsequently. PMID- 29755910 TI - Coronary Artery Fistula Causing Acute Myocardial Infarction and Right Ventricle Thrombus. AB - Coronary artery fistula (CAF) is a rare congenital anomaly, which is most commonly asymptomatic. In symptomatic cases, aneurysms can occur with complications of thromboembolic events. This report describes a rare case of CAF presenting with complications of inferior acute myocardial infarction and thrombus formation in the right ventricle. PMID- 29755911 TI - Posterior Fontanelle Encephalomeningocele in a Neonate: A Case Report. AB - Encephalomeningoceles are subtypes of neural tube defects (NTD). We present the case of a one-day-old neonate who was found to have a posterior fontanelle encephalomeningocele that was only discovered after birth. The unique presentation of this case and the surgical management is also considered. PMID- 29755912 TI - Scrotal Rejuvenation. AB - Genital rejuvenation is applicable not only to women (vaginal rejuvenation) but also to men (scrotal rejuvenation). There is an increased awareness, reflected by the number of published medical papers, of vaginal rejuvenation; however, rejuvenation of the scrotum has not received similar attention in the medical literature. Scrotal rejuvenation includes treatment of hair-associated scrotal changes (alopecia and hypertrichosis), morphology-associated scrotal changes (wrinkling and laxity), and vascular-associated scrotal changes (angiokeratomas). Rejuvenation of the scrotum potentially may utilize medical therapy, such as topical minoxidil and oral finasteride, for scrotal alopecia and conservative modalities, such as depilatories and electrolysis, for scrotal hypertrichosis. Lasers and energy-based devices may be efficacious for scrotal hypertrichosis and scrotal angiokeratomas. Surgical intervention is the mainstay of therapy for scrotal laxity; however, absorbable suspension sutures are postulated as a potential intervention to provide an adequate scrotal lift. Hair transplantation for scrotal alopecia and injection of botulinum toxin into the dartos muscle for scrotal wrinkling are hypothesized as possible treatments for these conditions. The interest in scrotal rejuvenation is likely to increase as men and their physicians become aware of both the conditions of the scrotum that may warrant rejuvenation and the potential treatments of the scrotum for these individuals. PMID- 29755913 TI - Concurrent Chemoradiation Affects the Clinical Outcome of Small Bowel Complications Following Pelvic Irradiation: Prospective Observational Study from a Regional Cancer Center. AB - Background To appraise the spectrum of small bowel complications following pelvic irradiation and to assess the clinical outcome and factors associated with adverse clinical outcome in these patients. Methods This descriptive clinical study was done for three years in a tertiary care center in South India. Patients managed for post-irradiation small bowel complications, irrespective of the indication for radiotherapy, were studied. Patients with associated non gastrointestinal radiation toxicity, radiation proctitis, and radiation colitis were excluded. The parameters assessed were the range of small bowel complications, a comparison of operative and non-operative management, morbidity and mortality, the severity of complications in relation to the dose of radiotherapy, and various factors influencing the clinical outcome. Results A total of 50 patients were studied. Stricture and perforation peritonitis were the most common presentation (n=25; 50%). A majority of the patients (n=37; 74%) presented after six months following radiotherapy. Post-operative mortality was 16% (n=5). Age, body mass index (BMI), previous surgery, operative intervention, primary or adjuvant radiotherapy, concurrent chemoradiotherapy (CCRT), and various radiation protocols were not associated with adverse clinical outcomes with respect to overall mortality, the requirement of surgery, and operative mortality. However patients who were operated and those who received CCRT had a significantly longer mean intensive care unit (ICU) stay (3.51 days vs. 0.68 days; p = 0.0001) as well as overall mean hospital stay (14.87 days vs. 5.58 days; p = 0.001) and an insignificant mortality rate (16% vs. 15%; p = 0.4085). Conclusion The present study observed that the patients who were operated and those who received CCRT had significantly longer hospitalization and relatively higher mortality. Considering the fact that many of the patients who develop post irradiation complications may not report back to the same center, the incidence of small bowel complications could be higher in reality, which ascertains the necessity for more precision in the radiation technique and operative care in developing countries. PMID- 29755915 TI - Unusual Long Survival with a Giant Invasive Pheochromocytoma of an Incompatible Patient. AB - Pheochromocytomas (PHEOs) are rare neuroendocrine tumors and about 2-13% of PHEOs are malignant. Predicting malignancy in PHEO cases with invasion but without metastasis is still controversial in the literature. This study presents an unusual long survival with a giant invasive PHEO in an incompatible patient and a review of the literature. In 1989, a 23-year-old female patient was operated for a giant adrenal mass with a pathological final diagnosis of PHEO. Information to the patient's family was provided about the short life span of the patient in the postoperative period because the tumor could not be totally resected. The patient started using regular antihypertensive drugs only after 1994. In 1994, 3700 mBq 131-I-metaiodobenzylguanidine (MIBG) treatment was given. Since then, no specific treatment was administered for PHEO due to patient incompatibility. She was diagnosed with type 2 diabetes mellitus at the age of 40 years and had a cerebrovascular accident due to hypertension at the age of 42. New abdominal computed tomography (CT) showed a right-sided 75 x 37 mm irregular and heterogeneous mass lesion extending inferiorly from the diaphragmatic crus level located in the right adrenal locus compatible with local recurrence. There was no I-123-MIBG uptake. She refused to have advanced workup and further treatment options. Malignant PHEOs reduce overall survival as a consequence of excessive catecholamine release, large tumor burden, and malignancy-related complications. Currently, the treatment of a malignant PHEO still has difficulties for both patients and doctors. Main treatment options for malignant PHEOs are primarily surgical excision. The effect of radionuclide therapy on survival time still remains to be determined. Efforts should be made to identify clinical, biochemical, and pathological criteria for malignancy and to develop new therapies in these patients with malignancy. The clinical course of malignant PHEOs is remarkably variable. Disease-specific survival rate changes from 58 to 88.1% at five years in the literature. Recent discoveries have enhanced new options for treatment, from radionuclide therapy and targeted molecular therapy to immunotherapy. A multidisciplinary approach is needed to individualize treatment in patients with malignant and invasive PHEO. PMID- 29755914 TI - Supracondylar Humeral Fractures: An Audit of the Frequency of Bi-columnar Fixation and Intra-articular Wire Placement. AB - Introduction For supracondylar humeral (SCH) fractures, biomechanical studies suggest the most stable wire configuration achieves bi-columnar fixation. Achieving medial column fixation using lateral-entry-only wires may require an intracapsular entry point. The aim of this study was to identify the rate of bi columnar fixation achieved in our department when treating SCH fractures with percutaneous wire fixation. A secondary aim was to identify the rate of placement of an intra-articular wire. Further aims were to examine if failure to achieve bi columnar fixation was associated with an increased loss of fixation and whether the placement of an intra-articular wire resulted in any cases of deep infection or septic arthritis. Material and methods All Gartland type 3 supracondylar humeral fractures, June 2014 to December 2016, were retrospectively identified. Intra-operative films were reviewed to determine bi-columnar fixation and the presence/absence of an intra-articular wire. Loss of reduction requiring revision and post-operative infections were determined from the electronic patient record. Results Of 49 supracondylar fractures identified, 42 were fixed with lateral entry only wires (24 with two wires and 18 with three wires), and seven were fixed with medial/lateral cross wires (four with one lateral wire, two with two wires, and one with three wires). Bi-columnar fixation was achieved in 41/49 cases (84%). All cases where bi-columnar fixation was not achieved were fixed with lateral-entry-only wires. One out of 49 fractures (2%) required the revision of fixation at 10 days due to loss of reduction. In this case, the initial fixation was with two lateral-entry-only wires, without bi-columnar fixation. An intra-articular wire was present in 44 out of 49 cases (90%). One out of 49 cases (2%) had a superficial wound infection. There were no cases of deep infection or septic arthritis. Conclusion In our department, the rate of bi-columnar fixation was high and, in this group, no cases required revision fixation. One of eight cases judged to not have bi-columnar fixation initially, required revision due to loss of fixation. We contend that bi-columnar fixation generally achieves a stable wire configuration even using lateral-entry-only wires for SCH fractures. The rate of intra-articular wire placement was high; however, infection rates were low with no cases of septic arthritis. PMID- 29755916 TI - A Case of Sinonasal Undifferentiated Carcinoma with Brain Metastases. AB - Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive neoplasm arising in the nasal cavity and paranasal sinuses. We report a unique case of an 80-year old man who presented with a locally advanced SNUC involving the ethmoid, sphenoid, and maxillary sinuses and bilateral lymph nodes, clinical T4N2M0. Given his age and the initial extent of his primary tumour, he was treated with neoadjuvant chemotherapy followed by chemoradiation with a split course of 50 Gray (Gy) in 40 fractions delivered twice a day. Four months after his treatments, he developed a recurrence at the left lower eyelid and left frontal sinus, intrabdominal metastases, and a left cerebellar metastasis. A single fraction of 22 Gy was delivered to the cerebellar lesion using stereotactic radiosurgery. He survived 17 months from the initial presentation. We review the available literature regarding treatment of brain metastases and use of hyperfractionated radiotherapy in this rare head and neck cancer. PMID- 29755917 TI - Sharing is Caring: Minimizing the Disruption with Palliative Care. AB - There is an upward trend incidence of multiple chronic life-limiting conditions with a well-documented associated impact on patients and their caregivers. When patients approach the end of life, they are often faced with a challenging multidimensional burden while navigating a complex health care system. Patients and families/caregivers are faced with daily decisions, often with little or no frame of reference or medical knowledge. The "what, how, when, and where" puzzle during this challenging time can be overwhelming for patients and their families, and when clinicians do not contemplate this associated workload's impact on patients and caregivers' capacity for self-care, patients and caregivers scramble to find compensatory solutions, often putting their health care at lower priority. This consequently warrants the underlying importance of palliative care and integrating it into the patients' health care plans earlier. There is increasing evidence from recent trials that supported implementing national policies regarding the early integration of palliative care and its role in improving the quality of life, increasing survival, and supporting patients' and caregivers' values when making decisions about their health care while possibly minimizing the burden of illness. The mission of palliative care is to assess, anticipate, and alleviate the challenges and suffering for patients and their caregivers by providing well-constructed approaches to disease-related physical treatments as well as psychological, financial, and spiritual aspects. Communication among all participants (the patient, family/caregivers, and all involved health care professionals) ought to be timely, thorough, and patient centric. Palliative medicine arguably represents an example of shared decision making (SDM)-facilitating a patient-centered, informed decision-making through an empathic conversation that is supported by clinicians' expertise and the best available evidence that takes patients values and preferences into consideration. Palliative care teams often consider the burden placed on patients and their caregivers, thus treatment plans would be assessed and introduced into the patients' lives with reflection on the related workload and the potential capacity to take on those plans. Such an approach to pause-and-examine, understand-and-discuss, and assess-and-alleviate might provide a possible example of a health care system that is minimally disruptive to patients and their families. This is an opportunity to replace the information-filled encounter with a more constructive engagement and empowerment to all major stakeholders to participate-an axiom integral to palliative care. Using the best available evidence in caring for patients while enacting SDM, palliative care, primary care, and other subspecialty clinicians need to consider the significant workload and burden that comes with health care and thus explore pathways to minimize the disruption in patients and caregivers' lives. As we collaborate to end cancer and all other mobdeities, we a need a concurrent movement to transform this disease centered, payer-driven health care era to a rather patient-entered, thoughtful, and minimally disruptive one will benefit patients and physicians alike. PMID- 29755919 TI - Molecular phylogenetic species in Alternaria pathogens infecting pistachio and wild relatives. AB - Many important pathogens of crops worldwide are members of section Alternaria within the genus Alternaria. Representative species in this section such as Alternaria alternata, Alternaria tenuissima, and Alternaria arborescens show high variability, intermediate characters and plasticity in morphological features, which makes species identification difficult. The aim of this study was to characterize Alternaria species associated with pistachio and wild relatives in Turkey using molecular phylogenetics. One hundred isolates of Alternaria spp. from pistachio and wild relatives from Turkey were investigated. In addition, standard morphological reference isolates and Alternaria blight pathogens of pistachio from USA were included. Sequence data from major allergen a1, ATPase, endopolygalacturanase, and anonymous regions OPA1.3 and SCAR2 were obtained. Gene trees were estimated based on maximum parsimony, maximum-likelihood, and bayesian inference methods. Species tree estimation was performed based on Yule speciation and strict molecular clock assumption. Among the collection of Alternaria spp. from Turkey, only one A. arborescens isolate and three isolates which were morphologically A. alternata/A. arborescens intermediate types, but, phylogenetically close to A. arborescens were discovered. While A. alternata and A. tenuissima formed one phylogenetic species, A. alternata/tenuissima were phylogenetically distinct from A. arborescens. Furthermore, a TaqI restriction site in the endopolygalacturanase gene was explored as a novel diagnosis for identification of A. alternata/tenuissima and A. arborescens. All these molecular phylogenetic approaches allow to distinguish morphologically similar Alternaria pathogens and molecular phylogenies of Alternaria pathogens from pistachio and wild relatives in Turkey are described for the first time. PMID- 29755918 TI - CoQ10 a super-vitamin: review on application and biosynthesis. AB - Coenzyme Q10 (CoQ) or ubiquinone is found in the biological system which is synthesized by the conjugation of benzoquinone ring with isoprenoid chain of variable length. Coenzyme Q10 supplementation energizes the body and increases body energy production in the form of ATP and helps to treat various human diseases such as cardiomyopathy, muscular dystrophy, periodontal disease, etc. Reports of these potential therapeutic advantages of CoQ10 have resulted in its high market demand, which focus the researchers to work on this molecule and develop better bioprocess methods for commercial level production. At the moment, chemical synthesis, semi-synthetic method as well as bio-production utilizing microbes as biofactory are in use for the synthesis of CoQ10. Chemical synthesis involves use of cheap and easily available precursor molecules such as isoprenol, chloromethylquinone, vinylalane, and solanesol. Chemical synthesis methods due to the use of various solvents and chemicals are less feasible, which limits its application. The microbial production of CoQ10 has added advantages of being produced in optically pure form with high yield using inexpensive medium composition. Several bacteria, e.g., Agrobacterium, Paracoccus, Rhodobacterium, and yeast such as Candida, Rhodotorula are the potent ubiquinone producer. Some alternative biosynthetic pathway for designing of CoQ10 production coupled with metabolic engineering might help to increase CoQ10 production. The most common practiced strategy for strain development for commercial CoQ10 production is through natural isolation and chemical mutagenesis. Here, we have reviewed the chemical, semi-synthetic as well as microbial CoQ10 production in detail. PMID- 29755920 TI - Patterns of chemical diversity in the marine ascidian Phallusia spp.: anti-tumor activity and metabolic pathway inhibiting steroid biosynthesis. AB - The complex nature of marine biodiversity is partially responsible for the lack of studies in Indian ascidian species, which often target a small number of novel biomolecules. We performed untargeted metabolomics using gas chromatography-mass spectrometry (GC-MS) in two invasive ascidian species to investigate the inter specific chemical diversity of Phallusia nigra and P. arabica in search of drug like properties and metabolic pathways. The chemical profiling of individual ascidian species was obtained using GC-MS, and the metabolites were determined by searching in NIST library and literature data. The principal component analysis of GC-MS mass spectral variables showed a clear discrimination of these two ascidian species based on the chemical composition and taxonomy. The metabolites, lipids, macrolides, and steroids contributed strongly to the discrimination of these two species. Results of this study confirmed that GC-MS-based chemical profiling could be utilized as a tool for chemotaxonomic classification of ascidian species. The extract of P. nigra showed promising anti-tumor activity against HT29 colon cancer 35 uM and MCF7-breast cancer (34.76 uM) cells compared to P. arabica. Of the more than 70 metabolites measured, 18 metabolites that mapped various pathways linked to three metabolic pathways being impacted and altered in steroid biosynthesis, primary bile acid biosynthesis, and steroid hormone biosynthesis were observed to have changed significantly (p > 0.004, FDR < 0.01). Also, higher expression of this pathway was associated with more significant cytotoxicity in breast and colon carcinoma cells. PMID- 29755921 TI - A Comprehensive Review of Tourette Syndrome and Complementary Alternative Medicine. AB - Purpose of Review: Tourette syndrome (TS) is a neuropsychiatric condition defined by both motor and phonic tics over a period of at least 1 year with the onset before 18 years of age. The purpose of this article is to review the use of complementary alternative medicine (CAM) in children and adults with Tourette syndrome with emphasis on recent research. Recent Findings: Most patients do not tell their physician about the use of CAM unless if specifically asked. Of the studies reviewed, description of the treatment and the frequency of use were most often reported. Few studies examine the role or effectiveness of CAM in the treatment of TS specifically. Summary: Practitioners should be aware of current research regarding various CAM modalities used for TS patients, including efficacy, potential adverse effects, and interactions with medications. Robust data about the use of CAM, efficacy, and potential side effects is lacking and requires further research to clarify optimal use. PMID- 29755922 TI - The Approach to Antibodies After Heart Transplantation. AB - a Purpose of review: This review summarizes recent data about antibodies after cardiac transplantation; what testing modalities are available and how frequently to employ them; as well as when treatment is necessary. b Recent findings: Technologies available for antibody detection have progressed over the past couple decades. New and preformed antibodies are associated with worse outcomes in transplant recipients. c Summary: The frequency of screening for post transplant antibodies and for antibody-mediated rejection (AMR) should be based on risk stratification. The presence of antibodies alone post-transplant does not constitute a diagnosis of AMR. Treatment of post-transplant antibodies and AMR should be made in conjunction with consideration of AMR grade and graft dysfunction. Future directions will involve improved detection methods and further understanding of non-HLA antibodies and de novo antibodies in the post transplant population. Additionally, aggressive efforts are currently underway to provide more therapeutic options. PMID- 29755923 TI - Epigenetic Alterations Impact on Antipsychotic Treatment in Elderly Patients. AB - Purpose of the review: Antipsychotics are commonly prescribed for the treatment of psychosis as well as behavioral and psychological symptoms of dementia (BPSD) in elderly patients. However, elderly patients often experience decreased antipsychotic efficacy and increased side effects, though the mechanisms underlying these changes with age are not clear. Recent findings: Although aging can affect drug metabolism and clearance through changes in renal and hepatic function, additional pharmacokinetic and pharmacodynamic changes due to aging induced epigenetic alterations also impact processes important for antipsychotic function. Epigenetic mechanisms account for some of the altered efficacy and increased side effects seen in elderly patients. Summary: Both clinical and animal studies from our group and others have demonstrated a plausible epigenetic mechanism involving histone modifications that can adversely affect the efficacy of antipsychotics and increase their side effects in elderly patients. Hopefully, further investigation of this mechanism will benefit elderly patients who need treatment for psychosis and BPSD. PMID- 29755924 TI - Dual-nozzle microfluidic droplet generator. AB - The droplet-generating microfluidics has become an important technique for a variety of applications ranging from single cell analysis to nanoparticle synthesis. Although there are a large number of methods for generating and experimenting with droplets on microfluidic devices, the dispensing of droplets from these microfluidic devices is a challenge due to aggregation and merging of droplets at the interface of microfluidic devices. Here, we present a microfluidic dual-nozzle device for the generation and dispensing of uniform sized droplets. The first nozzle of the microfluidic device is used for the generation of the droplets, while the second nozzle can accelerate the droplets and increase the spacing between them, allowing for facile dispensing of droplets. Computational fluid dynamic simulations were conducted to optimize the design parameters of the microfluidic device. PMID- 29755925 TI - Recent developments of nano-structured materials as the catalysts for oxygen reduction reaction. AB - Developments of high efficient materials for electrocatalyst are significant topics of numerous researches since a few decades. Recent global interests related with energy conversion and storage lead to the expansion of efforts to find cost-effective catalysts that can substitute conventional catalytic materials. Especially, in the field of fuel cell, novel materials for oxygen reduction reaction (ORR) have been noticed to overcome disadvantages of conventional platinum-based catalysts. Various approaching methods have been attempted to achieve low cost and high electrochemical activity comparable with Pt-based catalysts, including reducing Pt consumption by the formation of hybrid materials, Pt-based alloys, and not-Pt metal or carbon based materials. To enhance catalytic performance and stability, numerous methods such as structural modifications and complex formations with other functional materials are proposed, and they are basically based on well-defined and well-ordered catalytic active sites by exquisite control at nanoscale. In this review, we highlight the development of nano-structured catalytic materials for ORR based on recent findings, and discuss about an outlook for the direction of future researches. PMID- 29755926 TI - Challenges in paper-based fluorogenic optical sensing with smartphones. AB - Application of optically superior, tunable fluorescent nanotechnologies have long been demonstrated throughout many chemical and biological sensing applications. Combined with microfluidics technologies, i.e. on lab-on-a-chip platforms, such fluorescent nanotechnologies have often enabled extreme sensitivity, sometimes down to single molecule level. Within recent years there has been a peak interest in translating fluorescent nanotechnology onto paper-based platforms for chemical and biological sensing, as a simple, low-cost, disposable alternative to conventional silicone-based microfluidic substrates. On the other hand, smartphone integration as an optical detection system as well as user interface and data processing component has been widely attempted, serving as a gateway to on-board quantitative processing, enhanced mobility, and interconnectivity with informational networks. Smartphone sensing can be integrated to these paper-based fluorogenic assays towards demonstrating extreme sensitivity as well as ease-of use and low-cost. However, with these emerging technologies there are always technical limitations that must be addressed; for example, paper's autofluorescence that perturbs fluorogenic sensing; smartphone flash's limitations in fluorescent excitation; smartphone camera's limitations in detecting narrow-band fluorescent emission, etc. In this review, physical optical setups, digital enhancement algorithms, and various fluorescent measurement techniques are discussed and pinpointed as areas of opportunities to further improve paper-based fluorogenic optical sensing with smartphones. PMID- 29755927 TI - Deep data analysis via physically constrained linear unmixing: universal framework, domain examples, and a community-wide platform. AB - Many spectral responses in materials science, physics, and chemistry experiments can be characterized as resulting from the superposition of a number of more basic individual spectra. In this context, unmixing is defined as the problem of determining the individual spectra, given measurements of multiple spectra that are spatially resolved across samples, as well as the determination of the corresponding abundance maps indicating the local weighting of each individual spectrum. Matrix factorization is a popular linear unmixing technique that considers that the mixture model between the individual spectra and the spatial maps is linear. Here, we present a tutorial paper targeted at domain scientists to introduce linear unmixing techniques, to facilitate greater understanding of spectroscopic imaging data. We detail a matrix factorization framework that can incorporate different domain information through various parameters of the matrix factorization method. We demonstrate many domain-specific examples to explain the expressivity of the matrix factorization framework and show how the appropriate use of domain-specific constraints such as non-negativity and sum-to-one abundance result in physically meaningful spectral decompositions that are more readily interpretable. Our aim is not only to explain the off-the-shelf available tools, but to add additional constraints when ready-made algorithms are unavailable for the task. All examples use the scalable open source implementation from https://github.com/ramkikannan/nmflibrary that can run from small laptops to supercomputers, creating a user-wide platform for rapid dissemination and adoption across scientific disciplines. PMID- 29755928 TI - The Effects of Social Support on Strenuous Physical Exercise. AB - In humans, socio-environmental cues play an important role in determining adaptive psychophysiological states and behaviours. In sport and exercise, cues to cohesive groups and close, supportive relationships are ubiquitous, possibly because of their effects on neurobiological mechanisms underlying physical performance. Clinical research has shown that the presence of supportive others can lead to reductions in perceptions of pain, while research from sport and exercise science has shown that pain and physical fatigue occupy ranges on a single spectrum of physical discomfort, which works to regulate outputs during strenuous physical exertion. Given the similar neurobiological underpinnings of pain and fatigue, the involvement of both in the self-regulation of strenuous physical outputs, and the effects of social support on perceptions of pain and neurophysiological stress responses more generally, we hypothesised that perceptions of social support affect outputs during strenuous physical exercise by altering activity in self-regulatory mechanisms involved in perceptions of pain and fatigue. We used a between-subjects experimental design to test this hypothesis, varying participants' social support and measuring physical outputs and perceptions of physical discomfort and exertion during a series of maximum effort cycling bouts. Analyses showed that participants in the social support condition produced greater initial outputs and steeper declines over time, compared to controls. This effect was moderated by participant neuroticism; an important predictor of how individuals react to social support. We discuss these findings in terms of proposed causal mechanisms linking supportive, cohesive social environments with self-regulation and physical performance. PMID- 29755930 TI - Parents' attitudes towards topical fluoride and vaccines for children: Are these distinct or overlapping phenomena? AB - Despite attention paid to parental refusal of child vaccines, the phenomenon of topical fluoride refusal is poorly understood. We examine the extent to which parent attitudes and Internet use regarding topical fluoride treatment and vaccines may overlap and, in turn, uniquely or distinctly correlate with fluoride and vaccine refusal for the child. In 2017, we analyzed data collected from 2011 to 12 for 361 children from three Washington state dental clinics. The instrument included analogous measures of topical fluoride and vaccine safety concerns, perceived severity of preventable cavities/disease, and Internet use for fluoride/vaccine information; and measures of non-fluoridated toothpaste use, attitudes towards dental x-rays and amalgam and composite fillings. We assessed dental chart-based topical fluoride refusal occurring in 2009 or 2010 and parent reported vaccine refusal. All analogous fluoride and vaccine items were substantively correlated. However, in a series of adjusted models, none of these items were significantly associated with fluoride refusal. Multiple fluoride and vaccine items were associated with vaccine refusal in unadjusted models; but only vaccine safety concerns, perceived severity of a preventable cavity, and Internet use for vaccine information remained significant in adjusted models. Although there is concordance between the two refusal behaviors as well as analogous attitudes and Internet use, these findings challenge the idea that fluoride refusal should be addressed with interventions focusing on vaccine refusal. Further research is required on the factors underlying refusal of preventive dental care. PMID- 29755931 TI - Social determinants of self-rated health among Japanese mothers of children with disabilities. AB - Caregivers of children with disability are more likely to be affected by social determinants that lead to poor health. Additionally, a previous study revealed that although mothers of a single child with disability wanted to have another child, various obstacles including social, cultural, economic, and biological factors existed and some had to give up on having another child. Since the mental health and well-being of these mothers were poorer than those of mothers with multiple children with and without disabilities, such family composition may also affect maternal health. This study aimed to investigate and compare the social determinants of self-rated health of mothers only having children with disabilities and those having multiple children with and without disabilities. Through parents' associations of children with disabilities throughout Japan, 2311 self-administrated questionnaires were distributed to mothers of such children from January to March 2016. Out of the 1133 responses (return rate 49%), 1012 (43.8%) mothers of children with disabilities under 20 years of age were used for this study. Logistic regression showed that poor financial situation was most strongly related to poor self-rated health among all mothers. Other factors related to poor self-rated health were a lack of existence of child without disability, social isolation, low health consciousness, child's sex (girl), and severity of disability (mild/moderate). However, these relationships differ based on the existence of a child without disability. Investigating how socioeconomic and cultural conditions relate to family composition including child birth, and how they determine health is needed in the future. PMID- 29755929 TI - High PINCH1 Expression in Human Laryngeal Carcinoma Associates with Poor Prognosis. AB - Focal adhesion signaling to actin cytoskeleton is critically implicated in cell migration and cancer invasion and metastasis. Actin-binding proteins cofilin and N-WASP regulate actin filament turnover, and focal adhesion proteins parvins and PINCH mediate integrin signaling to the actin cytoskeleton. Altered expression of these proteins has been implicated in human cancer. This study addresses their expression and prognostic significance in human laryngeal carcinoma. Protein expressions of cofilin, N-WASP, alpha-parvin, beta-parvin, and PINCH1 were examined by immunohistochemistry in 72 human laryngeal squamous cell carcinomas. Correlations with clinicopathological data and survival were evaluated. All proteins examined were overexpressed in human laryngeal carcinomas compared to adjacent nonneoplastic epithelium. High expression of PINCH1 was associated significantly with high grade, lymph node-positive, and advanced stage disease. Moreover, high PINCH1 expression significantly associated with poor overall and disease-free survival and high cytoplasmic PINCH1 expression was shown by multivariate analysis to independently predict poor overall survival. In conclusion, we provide novel evidence that focal adhesion signaling to actin cytoskeleton is implicated in human laryngeal carcinogenesis and PINCH1 has prognostic significance in the disease. PMID- 29755932 TI - Family food purchases of high- and low-calorie foods in full-service supermarkets and other food retailers by Black women in an urban US setting. AB - Public health interventions to increase supermarket access assume that shopping in supermarkets is associated with healthier food purchases compared to other store types. To test this assumption, we compared purchasing patterns by store type for certain higher-calorie, less healthy foods (HCF) and lower-calorie, healthier foods (LCF) in a sample of 35 black women household shoppers in Philadelphia, PA. Data analyzed were from 450 food shopping receipts collected by these shoppers over four-week periods in 2012. We compared the likelihood of purchasing the HCF (sugar-sweetened beverages, sweet/salty snacks, and grain based snacks) and LCF (low-fat dairy, fruits, and vegetables) at full-service supermarkets and six other types of food retailers, using generalized estimating equations. Thirty-seven percent of participants had household incomes at or below the poverty line, and 54% had a BMI >30. Participants shopped primarily at full service supermarkets (55%) or discount/limited assortment supermarkets (22%), making an average of 11 shopping trips over a 4-week period and spending mean (SD) of $350 ($222). Of full-service supermarket receipts, 64% included at least one HCF item and 58% at least one LCF. Most trips including HCF (58%) and LCF (60%) expenditures were to full-service or discount/limited assortment supermarkets rather than smaller stores. Spending a greater percent of total dollars in full-service supermarkets was associated with spending more on HCF (p = 0.03) but not LCF items (p = 0.26). These findings in black women suggest a need for more attention to supermarket interventions that change retailing practices and/or consumer shopping behaviors related to foods in the HCF categories examined. PMID- 29755933 TI - Increasing overweight and obesity erodes engagement in one's neighborhood by women, but not men. AB - Obesity is socially stigmatized in the U.S., especially for women. Significant research has focused on the role that the social and built environments of neighborhoods play in shaping obesity. However, the role of obesity in shaping neighborhood social structure has been largely overlooked. We test the hypothesis that large body size inhibits an individual's engagement in his or her neighborhood. Our study objectives are to assess if (1) body size (body mass index) interacts with gender to predict engagement in one's neighborhood (neighborhood engagement) and (2) if bonding social capital interacts with gender to predict neighborhood engagement independent of body size. We used data collected from the cross-sectional 2011 Phoenix Area Social Survey (PASS), which systematically sampled residents across four neighborhood types (core urban, urban fringe, suburban, retirement) across the Phoenix Metopolitian Area. Survey data was analyzed using logistic regression for 804 participants, including 35% for whom missing data was computed using multiple imputation. We found that as body size increases, women-but not men-have reduced engagement in their neighborhood, independent of bonding social capital and other key covariates (objective 1). We did not observe the interaction between gender and bonding social capital associated with neighborhood engagement (objective 2). Prior scholarship suggests obesity clusters in neighborhoods due to processes of social, economic, and environmental disadvantage. This finding suggests bi directionality: obesity could, in turn, undermine neighborhood engagement through the mechanism of weight stigma and discrimination. PMID- 29755934 TI - Physical activity levels of adults with various physical disabilities. AB - This study examined the physical activity (PA) levels of people with specific disabilities, using health care registration data. Data of 321,656 adults (83%) from the Dutch Public Health Monitor 2012 were used to assess adherence to the World Health Organization (WHO) PA guidelines (%) and the time (min/week) spent on moderate-to-vigorous-intensity and vigorous-intensity PA. Specific physical and sensory (i.e. vision and hearing) disabilities were identified by means of two health claims registries that include reimbursement of functional aids and long-term care. Generalized estimated equations were used to determine the association of PA with disabilities, adjusted for confounders (model 1) and additionally for self-reported activity limitations (model 2). Adults with disabilities had lower levels of WHO PA guidelines adherence (range: -49.8% to 11.9%, p < 0.01) and of moderate-to-vigorous-intensity PA (range: -691 to -200 min/week, p < 0.01) than adults without physical and sensory disabilities. Adults with physical disabilities had the lowest levels. The difference in levels of vigorous-intensity PA between adults with and without physical and sensory disabilities ranged from -12 to 8 min/week Only adults receiving long-term care due to physical disabilities had significantly lower vigorous-intensity PA levels (-12 min/week, p < 0.01). After adjustment for self-reported activity limitations, the difference in PA levels between adults with and without physical and sensory disabilities attenuated, especially among those with physical disabilities, but PA levels were still lower for adults with physical disabilities (-34.5% to -9.8% and -466 to -172 min/week, p < 0.01, respectively). Regardless of self-reported activity limitations, adults with objectively measured disabilities, especially those with physical disabilities, had lower PA levels compared to adults without physical and sensory disabilities. PMID- 29755935 TI - Aspergillus endocarditis of the mitral valve with ventricular myocardial invasion, cerebral vasculitis, and intracranial mycotic aneurysm formation in a patient with hemophagocytic lymphohistiocytosis. AB - Aspergillus endocarditis is a rare infection and reported mainly in immunocompromised hosts. We report a case of mitral valve aspergillus endocarditis with ventricular myocardial invasion, cerebral vasculitis and intracranial fungal aneurysm formation in a patient with hemophagocytic lymphohistiocytosis (HLH). This case illustrates the importance of prompt investigation and treatment of masses seen on an echocardiogram for rare infections such as Aspergillus endocarditis in immunocompromised patients. PMID- 29755936 TI - Phase-encoded single-voxel magnetic resonance spectroscopy for suppressing outer volume signals at 7 Tesla. AB - BACKGROUND: Due to imperfect slice profiles, unwanted signals from outside the selected voxel may significantly contaminate metabolite signals acquired using in vivo magnetic resonance spectroscopy (MRS). The use of outer volume suppression may exceed the SAR threshold, especially at high field. OBJECTIVE: We propose using phase-encoding gradients after radiofrequency (RF) excitation to spatially encode unwanted signals originating from outside of the selected single voxel. METHODS: Phase-encoding gradients were added to a standard single voxel point resolved spectroscopy (PRESS) sequence which selects a 2 * 2 * 2 cm3 voxel. Subsequent spatial Fourier transform was used to encode outer volume signals. Phantom and in vivo experiments were performed using both phase-encoded PRESS and standard PRESS at 7 Tesla. Quantification was performed using fitting software developed in-house. RESULTS: Both phantom and in vivo studies showed that spectra from the phase-encoded PRESS sequence were relatively immune from contamination by oil signals and have more accurate quantification results than spectra from standard PRESS spectra of the same voxel. CONCLUSION: The proposed phase-encoded single-voxel PRESS method can significantly suppress outer volume signals that may appear in the spectra of standard PRESS without increasing RF power deposition. PMID- 29755938 TI - Successful elimination of recurrent ventricular tachycardia by epicardial ablation over coronary artery supplying postinfarction aneurysm. PMID- 29755937 TI - Rapid scanning wide-field clutter elimination in epi-optoacoustic imaging using comb LOVIT. AB - Epi-style optoacoustic (OA) imaging provides flexibility by integrating the irradiation optics and ultrasound receiver, yet clutter generated by optical absorption near the probe obscures deep OA sources. Localised vibration tagging (LOVIT) retrieves OA signal from images that are acquired with and without a preceding ultrasonic pushing beam: Radiation force leads to a phase shift of signals coming from the focal area resulting in their visibility in a difference image, whereas clutter from outside the pushing beam is eliminated. Disadvantages of a single-focus approach are residual clutter from inside the pushing beam above the focus, and time-intensive scanning of the focus to retrieve a large field-of-view. To speed up acquisition, we propose to create multiple foci in parallel, forming comb-shaped ARF patterns. By subtracting OA images obtained with interleaved combs, this technique moreover results in greatly improved clutter reduction in phantoms mimicking optical, acoustic and elastic properties of breast tissue. PMID- 29755939 TI - An original management of focal atrial tachycardia originating from a giant left atrial appendage. PMID- 29755940 TI - Isolated Wolff-Parkinson-White syndrome in identical twins. PMID- 29755941 TI - Surgical patch venoplasty after unsuccessful percutaneous balloon venoplasty for pacemaker lead-related superior vena cava stenosis. PMID- 29755942 TI - Electrical isolation of the right pulmonary veins requiring ablation from the right atrial septum. PMID- 29755943 TI - Holt-Oram syndrome in two families diagnosed with left ventricular noncompaction and conduction disease. PMID- 29755944 TI - Intra-atrial reentrant tachycardia originating from the pulmonary vein cuff anastomosis in a lung transplantation patient: Ultra-high-density 3-dimensional mapping. PMID- 29755945 TI - Atrial flutter following ethanol infusion in the vein of Marshall. PMID- 29755946 TI - Iatrogenic atrial septal defect with right-to-left shunt following atrial fibrillation ablation in a patient with arrhythmogenic right ventricular cardiomyopathy. PMID- 29755947 TI - Pitfalls of pacemaker detection of ventricular high-rate events. PMID- 29755948 TI - Two cases of acute pneumococcal purulent arthritis. AB - We present two adult cases of pneumococcal severe arthritis one case with, and other case without pericarditis those occurred in one season. Both cases eventually recovered, and the isolated S. pneumoniae strains were serotype 12F and penicillin susceptible. The patients were not elderly and had no medical history including pneumonia and vaccination. Although S. pneumoniae is a relatively rare causative pathogen of arthritis and/or pericarditis recently, a greater number of cases may be expected as a result of serotype conversion due to the increased use of pneumococcal conjugate vaccines in Japan. PMID- 29755949 TI - Tetanus - A Rare But Real Threat. AB - Tetanus is a potentially fatal disease of the nervous system arising from toxins produced by Clostridium tetani, an anaerobic bacterium found in soil [1]. Characterized by muscular rigidity, spasms and autonomic dysregulation its identification and, importantly, its prevention remain critical to the welfare of at risk patients. We present the case of a twenty two year old woman who presented to hospital with trismus and generalized muscle spasms three days following a dog bite to the right hand. Here, we discuss the presentation of generalized tetanus and the use of neurophysiology to facilitate its diagnosis. PMID- 29755950 TI - MATLAB algorithm to implement soil water data assimilation with the Ensemble Kalman Filter using HYDRUS. AB - Data assimilation is becoming a promising technique in hydrologic modelling to update not only model states but also to infer model parameters, specifically to infer soil hydraulic properties in Richard-equation-based soil water models. The Ensemble Kalman Filter method is one of the most widely employed method among the different data assimilation alternatives. In this study the complete Matlab(c) code used to study soil data assimilation efficiency under different soil and climatic conditions is shown. The code shows the method how data assimilation through EnKF was implemented. Richards equation was solved by the used of Hydrus 1D software which was run from Matlab. *MATLAB routines are released to be used/modified without restrictions for other researchers*Data assimilation Ensemble Kalman Filter method code.*Soil water Richard equation flow solved by Hydrus-1D. PMID- 29755951 TI - Method of determining loosely bound compounds of heavy metals in the soil. AB - Method of determination of heavy metals loosely bound compounds in the soil was developed using three separate extractions. The group of loosely bound compounds of metals includes exchangeable, complexed, and specifically adsorbed forms. This method is available, rapid and not expensive. Extraction takes less than 24 h. Sample procedure preparation is simple, and the analysis consists of only three steps, which can be performed simultaneously. The parallel extraction gives reliable and reproducible results and provides a relatively complete idea of the metals mobility in the soil, their availability to plants, migratory capacity, and transformation. *Method is suitable for a wide range of heavy metals and soil types. From the obtained data, the content of loosely bound compounds of heavy metals and the coefficients of metals mobility in the soil can be calculated.*Method is suitable for estimation the microelement supply of uncontaminated soils. The content of elements in the 1 N CH3COONH4 extract characterizes the actual pool of elements, and their content in the 1 N HCl extract defines their potential pool in the soil.*The coefficient of mobility (Km) is calculated to assess the contamination of soil with heavy metals. Estimation criteria of Km for Haplic Chernozem were developed. PMID- 29755952 TI - A simple and fast method for fixation of cultured cell lines that preserves cellular structures containing gamma-tubulin. AB - When using fluorescence microscope techniques to study cells, it is essential that the cell structure and contents are preserved after preparation of the samples, and that the preparation method employed does not create artefacts that can be perceived as cellular structure/components. gamma-Tubulin forms filaments that in some cases are immunostained with an anti-gamma-tubulin antibody, but this immunostaining is not reproducible [[1], [2]]. In addition, the C terminal region of gamma-tubulin (green fluorescence protein tagged [GFP]-gamma-tubulin334 -449) forms cytosolic GFP-labeled structures, which can easily be imaged in live cells but are not preserved in fixed cells [[1], [3]]. The purpose of this study was to identify a fixation technique that preserves cellular constituents containing gamma-tubulin. *This protocol describes a method that preserves gamma tubulin-containing structures in fixed cells.*The technique entails two-step fixation. A pre-fixation step using paraformaldehyde is followed by a final fixation and permeabilization step performed at -80 degrees C.*In comparison with other methodology for fixation [[4], [5], [6]], the technique presented here uses a short pre-fixation step with a mixture of paraformaldehyde and sucrose followed by a short fixation/permeabilization step with a mixture of methanol and acetone at -80 degrees C. PMID- 29755953 TI - First-Line Treatment in EGFR Mutant Non-Small Cell Lung Cancer: Is There a Best Option? AB - First generation or second generation EGFR tyrosine kinase inhibitors are currently the standard of care for the first-line management of non-small cell lung cancer (NSCLC) patients with activating mutations within the kinase domain of the epidermal growth factor receptor gene (1, 2). Resistance to targeted therapy can develop after 9-11 months (3-8). Third generation inhibitors were developed to target the EGFR T790M clone, which is the most common dominant second site resistance mutation after first or second generation inhibitors. Osimertinib received full FDA approval for the second-line treatment of advanced NSCLC based on a phase III study comparing the compound to chemotherapy. Recent data demonstrates an important impact for osimertinib in the front-line space based on results comparing the compound to first-generation erlotinib or gefitinib therapy. PMID- 29755955 TI - Editorial: Immunotherapy for Tumor in the Brain: Insights From-and For-Other Tumor Sites. PMID- 29755954 TI - Immune Response Generated With the Administration of Autologous Dendritic Cells Pulsed With an Allogenic Tumoral Cell-Lines Lysate in Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma. AB - Background and objective: Diffuse intrinsic pontine glioma (DIPG) is a lethal brainstem tumor in children. Dendritic cells (DCs) have T-cell stimulatory capacity and, therefore, potential antitumor activity for disease control. DCs vaccines have been shown to reactivate tumor-specific T cells in both clinical and preclinical settings. We designed a phase Ib immunotherapy (IT) clinical trial with the use of autologous dendritic cells (ADCs) pulsed with an allogeneic tumors cell-lines lysate in patients with newly diagnosed DIPG after irradiation (radiation therapy). Methods: Nine patients with newly diagnosed DIPG met enrollment criteria. Autologous dendritic cell vaccines (ADCV) were prepared from monocytes obtained by leukapheresis. Five ADCV doses were administered intradermally during induction phase. In the absence of tumor progression, patients received three boosts of tumor lysate every 3 months during the maintenance phase. Results: Vaccine fabrication was feasible in all patients included in the study. Non-specific KLH (9/9 patients) and specific (8/9 patients) antitumor response was identified by immunologic studies in peripheral blood mononuclear cells (PBMC). Immunological responses were also confirmed in the T lymphocytes isolated from the cerebrospinal fluid (CSF) of two patients. Vaccine administration resulted safe in all patients treated with this schema. Conclusion: These preliminary results demonstrate that ADCV preparation is feasible, safe, and generate a DIPG-specific immune response detected in PBMC and CSF. This strategy shows a promising backbone for future schemas of combination IT. PMID- 29755956 TI - Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a collection of hematologic malignancies with specific driver mutations that direct the pathology of the disease. The understanding of the origin and function of these mutations at early stages of transformation is critical to understand the etiology of the disease and for the design of effective therapies. The chromosome inversion inv(16) is thought to arise as a founding mutation in a hematopoietic stem cell (HSC) to produce preleukemic HSCs (preL-HSCs) with myeloid bias and differentiation block, and predisposed to AML. Studies in mice and human AML cells have established that inv(16) AML follows a clonal evolution model, in which preL-HSCs expressing the fusion protein CBFbeta-SMMHC persist asymptomatic in the bone marrow. The emerging leukemia-initiating cells (LICs) are composed by the inv(16) and a heterogeneous set of mutations. In this review, we will discuss the current understanding of inv(16) preleukemia development, and the function of CBFbeta SMMHC related to preleukemia progression and LIC activity. We also discuss important open mechanistic questions in the etiology of inv(16) AML. PMID- 29755958 TI - Gut Microbiota Contributes to Resistance Against Pneumococcal Pneumonia in Immunodeficient Rag-/- Mice. AB - Streptococcus pneumoniae causes infection-related mortality worldwide. Immunocompromised individuals, including young children, the elderly, and those with immunodeficiency, are especially vulnerable, yet little is known regarding S. pneumoniae-related pathogenesis and protection in immunocompromised hosts. Recently, strong interest has emerged in the gut microbiota's impact on lung diseases, or the "gut-lung axis." However, the mechanisms of gut microbiota protection against gut-distal lung diseases like pneumonia remain unclear. We investigated the role of the gut commensal, segmented filamentous bacteria (SFB), against pneumococcal pneumonia in immunocompetent and immunocompromised mouse models. For the latter, we chose the Rag-/- model, with adaptive immune deficiency. Immunocompetent adaptive protection against S. pneumoniae infection is based on antibodies against pneumococcal capsular polysaccharides, prototypical T cell independent-II (TI-II) antigens. Although SFB colonization enhanced TI-II antibodies in C57BL/6 mice, our data suggest that SFB did not further protect these immunocompetent animals. Indeed, basal B cell activity in hosts without SFB is sufficient for essential protection against S. pneumoniae. However, in immunocompromised Rag-/- mice, we demonstrate a gut-lung axis of communication, as SFB influenced lung protection by regulating innate immunity. Neutrophil resolution is crucial to recovery, since an unchecked neutrophil response causes severe tissue damage. We found no early neutrophil recruitment differences between hosts with or without SFB; however, we observed a significant drop in lung neutrophils in the resolution phase of S. pneumoniae infection, which corresponded with lower CD47 expression, a molecule that inhibits phagocytosis of apoptotic cells, in SFB-colonized Rag-/- mice. SFB promoted a shift in lung neutrophil phenotype from inflammatory neutrophils expressing high levels of CD18 and low levels of CD62L, to pro-resolution neutrophils with low CD18 and high CD62L. Blocking CD47 in SFB(-) mice increased pro-resolution neutrophils, suggesting CD47 down-regulation may be one neutrophil-modulating mechanism SFB utilizes. The SFB-induced lung neutrophil phenotype remained similar with heat-inactivated S. pneumoniae treatment, indicating these SFB induced changes in neutrophil phenotype during the resolution phase are not simply secondary to better bacterial clearance in SFB(+) than SFB(-) mice. Together, these data demonstrate that the gut commensal SFB may provide much needed protection in immunocompromised hosts in part by promoting neutrophil resolution post lung infection. PMID- 29755961 TI - Correlation and Interchangeability of Venous and Capillary Blood Gases in Non Critically Ill Neonates. AB - Background: Venous blood gas (VBG) is frequently used in the neonatal unit as alternative for capillary blood gas (CBG). However, studies reporting correlation are conflicting and data on interchangeability in neonates are lacking. Objective: We investigated the correlation and interchangeability of the components between VBG and CBG in infants admitted to the neonatal intensive care unit. Methods: In a prospective study in the neonatal unit in Leiden University Medical Center (Netherlands), simultaneously VBG and CBG were withdrawn in neonates when both venous puncture and intravenous access as blood gas monitoring was indicated. From each blood gas analysis, a Pearson correlation, intraclass correlation, and Bland-Altman analysis was performed. Clinically acceptable difference for each blood gas value was defined up-front by means of an absolute difference: pH +/- 0.05; partial pressure of carbon dioxide (pCO2) (+/-0.67 kPa = 5 mmHg); partial pressure of oxygen (pO2) (+/-0.67 kPa = 5 mmHg); base excess +/- 3 mmol/l; and bicarbonate (HCO3-) +/- 3 mmol/l. Results: In 93 patients [median gestational age 31 (IQR 29-34) weeks], 193 paired samples of VBG and CBG were collected. The Pearson correlation between VBG and CBG was very strong for pH (r = 0.79; P < 0.001), BE (r = 0.90; P < 0.001) and bicarbonate (r = 0.87; P < 0.001); strong for pCO2 (r = 0.68; P < 0.001); and moderate for pO2 (r = 0.31; P < 0.001). The percentage of the interchangeability within our acceptable absolute difference for pH was 88%, pCO2 72%, pO2 55%, BE 90%, and bicarbonate 94%. Conclusion: VBG and CBG in neonates are well correlated and mostly interchangeable, except for pO2. PMID- 29755959 TI - PvdQ Quorum Quenching Acylase Attenuates Pseudomonas aeruginosa Virulence in a Mouse Model of Pulmonary Infection. AB - Pseudomonas aeruginosa is the predominant pathogen in pulmonary infections associated with cystic fibrosis. Quorum sensing (QS) systems regulate the production of virulence factors and play an important role in the establishment of successful P. aeruginosa infections. Inhibition of the QS system (termed quorum quenching) renders the bacteria avirulent thus serving as an alternative approach in the development of novel antibiotics. Quorum quenching in Gram negative bacteria can be achieved by preventing the accumulation of N-acyl homoserine lactone (AHL) signaling molecule via enzymatic degradation. Previous work by us has shown that PvdQ acylase hydrolyzes AHL signaling molecules irreversibly, thereby inhibiting QS in P. aeruginosa in vitro and in a Caenorhabditis elegans model of P. aeruginosa infection. The aim of the present study is to assess the therapeutic efficacy of intranasally instilled PvdQ acylase in a mouse model of pulmonary P. aeruginosa infection. First, we evaluated the deposition pattern of intranasally administered fluorochrome-tagged PvdQ (PvdQ-VT) in mice at different stages of pulmonary infection by in vivo imaging studies. Following intranasal instillation, PvdQ-VT could be traced in all lung lobes with 42 +/- 7.5% of the delivered dose being deposited at 0 h post bacterial-infection, and 34 +/- 5.2% at 72 h post bacterial-infection. We then treated mice with PvdQ during lethal P. aeruginosa pulmonary infection and that resulted in a 5-fold reduction of lung bacterial load and a prolonged survival of the infected animals with the median survival time of 57 hin comparison to 42 h for the PBS-treated group. In a sublethal P. aeruginosa pulmonary infection, PvdQ treatment resulted in less lung inflammation as well as decrease of CXCL2 and TNF alpha levels at 24 h post-bacterial-infection by 15 and 20%, respectively. In conclusion, our study has shown therapeutic efficacy of PvdQ acylase as a quorum quenching agent during P. aeruginosa infection. PMID- 29755962 TI - Acceptability of Bedside Resuscitation With Intact Umbilical Cord to Clinicians and Patients' Families in the United States. AB - Background: While delayed umbilical cord clamping in preterm infants has shown to improve long-term neurological outcomes, infants who are thought to need resuscitation do not receive delayed cord clamping even though they may benefit the most. A mobile resuscitation platform allows infants to be resuscitated at the mother's bedside with the cord intact. The newborn is supplied with placental blood during the resuscitation in view of the mother. The objective of the study is to assess the usability and acceptability of mobile resuscitation platform, LifeStart trolley, among the infants' parents and perinatal providers. Methods: A resuscitation platform was present during every delivery that required advanced neonatal providers for high-risk deliveries. Perinatal providers and parents of the infants were given a questionnaire shortly after the delivery. Results: 60 neonatal subjects were placed on the trolley. The majority of deliveries were high risk for meconium-stained amniotic fluid (43%), and non-reassuring fetal heart rate (45%). About 50% of neonatal providers felt that there were some concerns regarding access to the baby. No parents were uncomfortable with the bedside neonatal interventions, and most parents perceived that communication was improved because of the proximity to the care team. Conclusion: Bedside resuscitation with umbilical cord intact through the use of a mobile resuscitation trolley is feasible, safe, and effective, but about half of the perinatal providers expressed concerns. Logistical issues such as improved space management and/or delivery setup should be considered in centers planning to perform neonatal resuscitation with an intact cord. PMID- 29755960 TI - Long Sun-Exposures Influencing High Sub-Cutaneous Synthesis of Vitamin-D3 may be Associated with Exacerbation of Symptoms in Allergic-Asthma. AB - Objectives: Does excessive sun-exposure, non-use of sunscreen and/or high doses of vitamin-D3 supplements provoke exacerbation of asthma? Design: Clinical examinations, retrospective records-access and questionnaire surveys were distributed to a convenience sample of allergic-asthma patient (n=183). Setting: Patients (19-89 years) attending the outpatient respiratory clinics at Maidstone Hospital were enrolled. Results: 90.3% of patients (total IgE levels >=75 kU/L ; n=103) exposed to direct sunlight of >= 15 minutes per day continuously for 6-7 days presented with wheeze (chi2(1) = 7.46; p< 0.05) compared to only 9.7% patients of similar atopy-status, presenting with wheeze if exposed to sunlight of < 15 minutes per day for 6-7 days. 68.9% patients (with IgE levels >= 75 kU/L ; n=103), non-users of sunscreen (SPF 30 and above), exposed to direct sunlight of >= 15 minutes per day continuously for 6-7 days developed a wheeze, compared to fewer users of sunscreen (9.7%, n=103), exposed to the same duration of sunlight who developed asthma symptoms (p< 0.05). Vitamin-D3 supplementation in asthma-patients with clinical signs of hypovitaminosis-D (n=21), produced symptoms of morning chest-tightness (76.2%), allergic rhinitis (61.9%) and wheeze (100%), 2 weeks after initiation of treatment. Conclusions: Our results advocate direct sunlight exposure < 15 minutes per day and use of sunscreen as a novel approach to preventing atopic-asthma symptoms in allergic-asthma patients.. Activated vitamin-D3 is well-recognised to shift the immune-balance towards Th2 predominance, favouring allergic asthma. These results suggest that limiting subcutaneous synthesis of vitamin-D3 in asthma patients and re-addressing dosage of vitamin-D3 supplementation is necessary may contribute to prevent exacerbation of symptoms. PMID- 29755957 TI - Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR Mycobacterium tuberculosis Strains. AB - Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health. PMID- 29755963 TI - Environmental Toxin Screening Using Human-Derived 3D Bioengineered Liver and Cardiac Organoids. AB - Introduction: Environmental toxins, such as lead and other heavy metals, pesticides, and other compounds, represent a significant health concern within the USA and around the world. Even in the twenty-first century, a plethora of cities and towns in the U.S. have suffered from exposures to lead in drinking water or other heavy metals in food or the earth, while there is a high possibility of further places to suffer such exposures in the near future. Methods: We employed bioengineered 3D human liver and cardiac organoids to screen a panel of environmental toxins (lead, mercury, thallium, and glyphosate), and charted the response of the organoids to these compounds. Liver and cardiac organoids were exposed to lead (10 uM-10 mM), mercury (200 nM-200 uM), thallium (10 nM-10 uM), or glyphosate (25 uM-25 mM) for a duration of 48 h. The impacts of toxin exposure were then assessed by LIVE/DEAD viability and cytotoxicity staining, measuring ATP activity and determining IC50 values, and determining changes in cardiac organoid beating activity. Results: As expected, all of the toxins induced toxicity in the organoids. Both ATP and LIVE/DEAD assays showed toxicity in both liver and cardiac organoids. In particular, thallium was the most toxic, with IC50 values of 13.5 and 1.35 uM in liver and cardiac organoids, respectively. Conversely, glyphosate was the least toxic of the four compounds, with IC50 values of 10.53 and 10.85 mM in liver and cardiac organoids, respectively. Additionally, toxins had a negative influence on cardiac organoid beating activity as well. Thallium resulting in the most significant decreases in beating rate, followed by mercury, then glyphosate, and finally, lead. These results suggest that the 3D organoids have significant utility to be deployed in additional toxicity screening applications, and future development of treatments to mitigate exposures. Conclusion: 3D organoids have significant utility to be deployed in additional toxicity screening applications, such as future development of treatments to mitigate exposures, drug screening, and environmental toxin detection. PMID- 29755964 TI - Cross-Jurisdictional Resource Sharing in Local Health Departments: Implications for Services, Quality, and Cost. AB - Background: Forty one percent of local health departments in the U.S. serve jurisdictions with populations of 25,000 or less. Researchers, policymakers, and advocates have long questioned how to strengthen public health systems in smaller municipalities. Cross-jurisdictional sharing may increase quality of service, access to resources, and efficiency of resource use. Objective: To characterize perceived strengths and challenges of independent and comprehensive sharing approaches, and to assess cost, quality, and breadth of services provided by independent and sharing health departments in Connecticut (CT) and Massachusetts (MA). Methods: We interviewed local health directors or their designees from 15 comprehensive resource-sharing jurisdictions and 54 single-municipality jurisdictions in CT and MA using a semi-structured interview. Quantitative data were drawn from closed-ended questions in the semi-structured interviews; municipal demographic data were drawn from the American Community Survey and other public sources. Qualitative data were drawn from open-ended questions in the semi-structured interviews. Results: The findings from this multistate study highlight advantages and disadvantages of two common public health service delivery models - independent and shared. Shared service jurisdictions provided more community health programs and services, and invested significantly more ($120 per thousand (1K) population vs. $69.5/1K population) on healthy food access activities. Sharing departments had more indicators of higher quality food safety inspections (FSIs), and there was a non-linear relationship between cost per FSI and number of FSI. Minimum cost per FSI was reached above the total number of FSI conducted by all but four of the jurisdictions sampled. Independent jurisdictions perceived their governing bodies to have greater understanding of the roles and responsibilities of local public health, while shared service jurisdictions had fewer staff per 1,000 population. Implications: There are trade offs with sharing and remaining independent. Independent health departments serving small jurisdictions have limited resources but strong local knowledge. Multi-municipality departments have more resources but require more time and investment in governance and decision-making. When making decisions about the right service delivery model for a given municipality, careful consideration should be given to local culture and values. Some economies of scale may be achieved through resource sharing for municipalities <25,000 population. PMID- 29755965 TI - The Development of Long-Term Adverse Health Effects in Oil Spill Cleanup Workers of the Deepwater Horizon Offshore Drilling Rig Disaster. AB - Background: The purpose of this study was to assess the long-term adverse health effects of the 2010 Deepwater Horizon Gulf oil spill exposure in workers who participated in its cleanup work. Methods: Medical charts of both the oil spill exposed and unexposed subjects were reviewed. The changes in the white blood cells, platelets, hemoglobin, hematocrit, blood urea nitrogen, creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT) levels, as well as their pulmonary and cardiac functions were evaluated. Results: Medical records from 88 subjects (oil spill cleanup workers, n = 44 and unexposed, n = 44) were reviewed during initial and 7 years follow up visits after the disaster occurred. Compared with the unexposed subjects, oil spill exposed subjects had significantly reduced platelet counts (*103/uL) at their initial (254.1 +/- 46.7 versus 289.7 +/- 63.7, P = 0.000) and follow-up (242.9 +/- 55.6 versus 278.4 +/- 67.6, P = 0.000) visits compared with the unexposed subjects (254.6 +/- 51.9 versus 289.7 +/- 63.7, P = 0.008). The hemoglobin and hematocrit levels were increased significantly both at their initial and follow-up visits in the oil spill exposed subjects compared to the unexposed subjects. Similarly, the oil spill exposed subjects had significantly increased ALP, AST, and ALT levels at their initial and follow-up visits compared with those of the unexposed subjects. Illness symptoms that were reported during their initial visit still persisted at their 7-year follow-up visit. Notably, at their 7-year follow-up visit, most of the oil spill exposed subjects had also developed chronic rhinosinusitis and reactive airway dysfunction syndrome as new symptoms that were not reported during their initial visit. Additionally, more abnormalities in pulmonary and cardiac functions were also seen in the oil spill exposed subjects. Conclusion: This long-term follow-up study demonstrates that those people involved in the oil spill cleanup operations experiences persistent alterations or worsening of their hematological, hepatic, pulmonary, and cardiac functions. In addition, these subjects experienced prolonged or worsening illness symptoms even 7 years after their exposure to the oil spill. PMID- 29755966 TI - N/S Co-doped Carbon Derived From Cotton as High Performance Anode Materials for Lithium Ion Batteries. AB - Highly porous carbon with large surface areas is prepared using cotton as carbon sources which derived from discard cotton balls. Subsequently, the sulfur nitrogen co-doped carbon was obtained by heat treatment the carbon in presence of thiourea and evaluated as Lithium-ion batteries anode. Benefiting from the S, N co-doping, the obtained S, N co-doped carbon exhibits excellent electrochemical performance. As a result, the as-prepared S, N co-doped carbon can deliver a high reversible capacity of 1,101.1 mA h g-1 after 150 cycles at 0.2 A g-1, and a high capacity of 531.2 mA h g-1 can be observed even after 5,000 cycles at 10.0 A g-1. Moreover, excellently rate capability also can be observed, a high capacity of 689 mA h g-1 can be obtained at 5.0 A g-1. This superior lithium storage performance of S, N co-doped carbon make it as a promising low-cost and sustainable anode for high performance lithium ion batteries. PMID- 29755967 TI - Metal-Mediated Halogen Exchange in Aryl and Vinyl Halides: A Review. AB - Halogenated arenes and alkenes are of prime importance in many areas of science, especially in the pharmaceutical, agrochemical, and chemical industries. While the simplest ones are commercially available, some of them are still hardly accessible depending on their substitution patterns and the nature of the halogen atom. Reactions enabling the selective and efficient replacement of the halogen atom of an aryl or alkenyl halide by another one, lighter, or heavier, are therefore of major importance since they can be used for example to turn a less reactive aryl/alkenyl chloride into the more reactive iodinated derivatives or, in a reversed sense, to block an undesired reactivity, for late-stage modifications or for the introduction of a radionuclide. If some halogen exchange reactions are possible with activated substrates, they usually require catalysis with metal complexes. Remarkably efficient processes have been developed for metal-mediated halogen exchange in aryl and vinyl halides: they are overviewed, in a comprehensive manner, in this review article. PMID- 29755968 TI - Exploring the Interaction Mechanism Between Cyclopeptide DC3 and Androgen Receptor Using Molecular Dynamics Simulations and Free Energy Calculations. AB - Androgen receptor (AR) is a key target in the discovery of anti-PCa (Prostate Cancer) drugs. Recently, a novel cyclopeptide Diffusa Cyclotide-3 (DC3), isolated from Hedyotisdiffusa, has been experimentally demonstrated to inhibit the survival and growth of LNCap cells, which typically express T877A-mutated AR, the most frequently detected point mutation of AR in castration-resistant prostate cancer (CRPC). But the interaction mechanism between DC3 and AR is not clear. Here in this study we aim to explore the possible binding mode of DC3 to T877A mutated AR from molecular perspective. Firstly, homology modeling was employed to construct the three-dimensional structure of the cyclopeptide DC3 using 2kux.1.A as the template. Then molecular docking, molecular dynamics (MD) simulations, and molecular mechanics/generalized Born surface area (MM-GBSA) methods were performed to determine the bind site and explore the detailed interaction mechanism of DC3-AR complex. The obtained results suggested that the site formed by H11, loop888-893, and H12 (site 2) was the most possible position of DC3 binding to AR. Besides, hydrogen bonds, hydrophobic, and electrostatic interactions play dominant roles in the recognition and combination of DC3-AR complex. The essential residues dominant in each interaction were specifically revealed. This work facilitates our understanding of the interaction mechanism of DC3 binding to AR at the molecular level and contributes to the rational cyclopeptide drug design for prostate cancer. PMID- 29755969 TI - Evaluation of Fluorine-18-Labeled alpha1(I)-N-Telopeptide Analogs as Substrate Based Radiotracers for PET Imaging of Melanoma-Associated Lysyl Oxidase. AB - Accumulating evidence suggests an unequivocal role of lysyl oxidases as key players of tumor progression and metastasis, which renders this enzyme family highly attractive for targeted non-invasive functional imaging of tumors. Considering their function in matrix remodeling, malignant melanoma appears as particularly interesting neoplasia in this respect. For the development of radiotracers that enable PET imaging of the melanoma-associated lysyl oxidase activity, substrates derived from the type I collagen alpha1 N-telopeptide were labeled with fluorine-18 using N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) as prosthetic reagent. With regards to potential crosslinking to tumor-associated collagen in vivo, their interaction with triple-helical type I collagen was studied by SPR. A mouse model of human melanoma was established on the basis of the A375 cell line, for which the expression of the oncologically relevant lysyl oxidase isoforms LOX and LOXL2 was demonstrated in Western blot and immunohistochemical experiments. The radiopharmacological profiles of the peptidic radiotracers were evaluated in normal rats and A375 melanoma-bearing mice by ex vivo metabolite analysis, whole-body biodistribution studies and dynamic PET imaging. Out of three 18F-labeled telopeptide analogs, the one with the most favorable substrate properties has shown favorable tumor uptake and tumor-to-muscle ratio. Lysyl oxidase-mediated tumor uptake was proven by pharmacological inhibition using beta-aminopropionitrile and by employing negative-control analogs of impeded or abolished targeting capability. The latter were obtained by substituting the lysine residue by ornithine and norleucine, respectively. Comparing the tumor uptake of the lysine-containing peptide with that of the non-functional analogs indicate the feasibility of lysyl oxidase imaging in melanoma using substrate-based radiotracers. PMID- 29755970 TI - How to Achieve Better Results Using PASS-Based Virtual Screening: Case Study for Kinase Inhibitors. AB - Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI) library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of "active" and "inactive" compounds included in the training sets. PASS (Prediction of Activity Spectra for Substances), which is based on a modified Naive Bayes algorithm, was applied since it had been shown to be robust and to provide good predictions of many biological activities based on just the structural formula of a compound even if the information in the training set is incomplete. We used different subsets of kinase inhibitors for this case study because many data are currently available on this important class of drug-like molecules. Based on the subsets of kinase inhibitors extracted from the ChEMBL 20 database we performed the PASS training, and then applied the model to ChEMBL 23 compounds not yet present in ChEMBL 20 to identify novel kinase inhibitors. As one may expect, the best prediction accuracy was obtained if only the experimentally confirmed active and inactive compounds for distinct kinases in the training procedure were used. However, for some kinases, reasonable results were obtained even if we used merged training sets, in which we designated as inactives the compounds not tested against the particular kinase. Thus, depending on the availability of data for a particular biological activity, one may choose the first or the second approach for creating ligand-based computational tools to achieve the best possible results in virtual screening. PMID- 29755971 TI - Impact of Increasing Levels of Oxygen Consumption on the Evolution of Color, Phenolic, and Volatile Compounds of Nebbiolo Wines. AB - Since the end of the last century, many works have been carried out to verify the effect of controlled oxygen intake on the chemical and organoleptic characteristics of red wines. In spite of the large number of studies on this subject, oxygen remains a cutting-edge research topic in oenology. Oxygen consumption leads to complex and not univocal changes in wine composition, sometimes positive such as color stabilization, softening of mouthfeel, increase of aroma complexity. However, the variability of these effects, which depend both on the oxygenation conditions and the composition of the wine, require more efforts in this research field to effectively manage wine oxygen exposure. The present study is focused on the evolution of the chemical composition of four different Nebbiolo wines, each of them added with 4 different doses of oxygen (7, 14, 21, and 28 mg/L total intake) during the first month of storage. In this perspective, the evolution over time of wine color and polyphenols was studied. Acetaldehyde, glyceraldehyde and glyoxylic acid were quantified by HPLC. These compounds can play a role in wine aging creating condensed colored and stable products involving anthocyanins with or without tannins. Moreover, some volatile aldehydes correlated with oxidized olfactory notes, including methional and (E)-2 alkenals, have been quantified by GC-MS. Overall, during storage a decrease of color intensity, total and free anthocyanins and an increase in polymeric pigments (in particular the contribution to the red color of pigments not bleachable by SO2 or dTAT%) and some minor aldehydes was observed. Nevertheless, the differences in color parameters between the samples with different doses of oxygen were modest. These evidences were in contrast with an evident and detectable increase of free acetaldehyde content at increasing doses of oxygen measured after 60 days of storage. The effect of oxygen on color and production of SO2 non-bleachable pigments during aging varies with wine composition, with Nebbiolo wines appearing not very reactive in this respect, probably due to their low content in anthocyanins and high content in tannins. PMID- 29755972 TI - Lignocellulosic Biomass Transformations via Greener Oxidative Pretreatment Processes: Access to Energy and Value-Added Chemicals. AB - Anthropogenic climate change, principally induced by the large volume of carbon dioxide emission from the global economy driven by fossil fuels, has been observed and scientifically proven as a major threat to civilization. Meanwhile, fossil fuel depletion has been identified as a future challenge. Lignocellulosic biomass in the form of organic residues appears to be the most promising option as renewable feedstock for the generation of energy and platform chemicals. As of today, relatively little bioenergy comes from lignocellulosic biomass as compared to feedstock such as starch and sugarcane, primarily due to high cost of production involving pretreatment steps required to fragment biomass components via disruption of the natural recalcitrant structure of these rigid polymers; low efficiency of enzymatic hydrolysis of refractory feedstock presents a major challenge. The valorization of lignin and cellulose into energy products or chemical products is contingent on the effectiveness of selective depolymerization of the pretreatment regime which typically involve harsh pyrolytic and solvothermal processes assisted by corrosive acids or alkaline reagents. These unselective methods decompose lignin into many products that may not be energetically or chemically valuable, or even biologically inhibitory. Exploring milder, selective and greener processes, therefore, has become a critical subject of study for the valorization of these materials in the last decade. Efficient alternative activation processes such as microwave- and ultrasound irradiation are being explored as replacements for pyrolysis and hydrothermolysis, while milder options such as advanced oxidative and catalytic processes should be considered as choices to harsher acid and alkaline processes. Herein, we critically abridge the research on chemical oxidative techniques for the pretreatment of lignocellulosics with the explicit aim to rationalize the objectives of the biomass pretreatment step and the problems associated with the conventional processes. The mechanisms of reaction pathways, selectivity and efficiency of end-products obtained using greener processes such as ozonolysis, photocatalysis, oxidative catalysis, electrochemical oxidation, and Fenton or Fenton-like reactions, as applied to depolymerization of lignocellulosic biomass are summarized with deliberation on future prospects of biorefineries with greener pretreatment processes in the context of the life cycle assessment. PMID- 29755973 TI - Identification of Loop D Domain Amino Acids in the Human Aquaporin-1 Channel Involved in Activation of the Ionic Conductance and Inhibition by AqB011. AB - Aquaporins are integral proteins that facilitate the transmembrane transport of water and small solutes. In addition to enabling water flux, mammalian Aquaporin 1 (AQP1) channels activated by cyclic GMP can carry non-selective monovalent cation currents, selectively blocked by arylsulfonamide compounds AqB007 (IC50 170 MUM) and AqB011 (IC50 14 MUM). In silico models suggested that ligand docking might involve the cytoplasmic loop D (between AQP1 transmembrane domains 4 and 5), but the predicted site of interaction remained to be tested. Work here shows that mutagenesis of two conserved arginine residues in loop D slowed the activation of the AQP1 ion conductance and impaired the sensitivity of the channel to block by AqB011. Substitution of residues in loop D with proline showed effects on ion conductance amplitude that varied with position, suggesting that the structural conformation of loop D is important for AQP1 channel gating. Human AQP1 wild type, AQP1 mutant channels with alanines substituted for two arginines (R159A+R160A), and mutants with proline substituted for single residues threonine (T157P), aspartate (D158P), arginine (R159P, R160P), or glycine (G165P) were expressed in Xenopus laevis oocytes. Conductance responses were analyzed by two-electrode voltage clamp. Optical osmotic swelling assays and confocal microscopy were used to confirm mutant and wild type AQP1-expressing oocytes were expressed in the plasma membrane. After application of membrane-permeable cGMP, R159A+R160A channels had a significantly slower rate of activation as compared with wild type, consistent with impaired gating. AQP1 R159A+R160A channels showed no significant block by AqB011 at 50 MUM, in contrast to the wild type channel which was blocked effectively. T157P, D158P, and R160P mutations had impaired activation compared to wild type; R159P showed no significant effect; and G165P appeared to augment the conductance amplitude. These findings provide evidence for the role of the loop D as a gating domain for AQP1 ion channels, and identify the likely site of interaction of AqB011 in the proximal loop D sequence. PMID- 29755974 TI - A Curriculum-Based Approach to Teaching Biosafety Through eLearning. AB - Anyone working in biosafety capacity enhancement faces the challenge of ensuring that the impact of a capacity enhancing activity continues and becomes sustainable beyond the depletion of funding. Many training efforts face the limitation of one-off events: they only reach those people present at the time. It becomes incumbent upon the trainees to pass on the training to colleagues as best they can, whilst the demand for the training never appears to diminish. However, beyond the initial effort to establish the basic content, repeating capacity enhancement events in different locations is usually not economically feasible. Also, the lack of infrastructure and other resources needed to support a robust training programme hinder operationalizing a "train-the-trainer" approach to biosafety training. One way to address these challenges is through the use of eLearning modules that can be delivered online, globally, continuously, at low cost, and on an as-needed basis to multiple audiences. Once the modules are developed and peer-reviewed, they can be maintained on a remote server and made available to various audiences through a password-protected portal that delivers the programme content, administers preliminary and final exams, and provides the administrative infrastructure to register users and track their progress through the modules. Crucial to the implementation of such an eLearning programme is an approach in which the modules are intentionally developed together as a cohesive curriculum. Once developed, such a curriculum can be released as a stand-alone programme for the training of governmental risk assessors and regulators or used as accredited components in post-graduate degree programmes in biosafety, at minimal cost to the government or university. Examples from the portfolio of eLearning modules developed by the International Centre for Genetic Engineering and Biotechnology (ICGEB) are provided to demonstrate these key features. PMID- 29755975 TI - Policy-Led Comparative Environmental Risk Assessment of Genetically Modified Crops: Testing for Increased Risk Rather Than Profiling Phenotypes Leads to Predictable and Transparent Decision-Making. AB - We describe two contrasting methods of comparative environmental risk assessment for genetically modified (GM) crops. Both are science-based, in the sense that they use science to help make decisions, but they differ in the relationship between science and policy. Policy-led comparative risk assessment begins by defining what would be regarded as unacceptable changes when the use a particular GM crop replaces an accepted use of another crop. Hypotheses that these changes will not occur are tested using existing or new data, and corroboration or falsification of the hypotheses is used to inform decision-making. Science-led comparative risk assessment, on the other hand, tends to test null hypotheses of no difference between a GM crop and a comparator. The variables that are compared may have little or no relevance to any previously stated policy objective and hence decision-making tends to be ad hoc in response to possibly spurious statistical significance. We argue that policy-led comparative risk assessment is the far more effective method. With this in mind, we caution that phenotypic profiling of GM crops, particularly with omics methods, is potentially detrimental to risk assessment. PMID- 29755976 TI - A General Safety Assessment for Purified Food Ingredients Derived From Biotechnology Crops: Case Study of Brazilian Sugar and Beverages Produced From Insect-Protected Sugarcane. AB - Insect-protected sugarcane that expresses Cry1Ab has been developed in Brazil. Analysis of trade information has shown that effectively all the sugarcane derived Brazilian exports are raw or refined sugar and ethanol. The fact that raw and refined sugar are highly purified food ingredients, with no detectable transgenic protein, provides an interesting case study of a generalized safety assessment approach. In this study, both the theoretical protein intakes and safety assessments of Cry1Ab, Cry1Ac, NPTII, and Bar proteins used in insect protected biotechnology crops were examined. The potential consumption of these proteins was examined using local market research data of average added sugar intakes in eight diverse and representative Brazilian raw and refined sugar export markets (Brazil, Canada, China, Indonesia, India, Japan, Russia, and the USA). The average sugar intakes, which ranged from 5.1 g of added sugar/person/day (India) to 126 g sugar/p/day (USA) were used to calculated possible human exposure. The theoretical protein intake estimates were carried out in the "Worst-case" scenario, assumed that 1 MUg of newly-expressed protein is detected/g of raw or refined sugar; and the "Reasonable-case" scenario assumed 1 ng protein/g sugar. The "Worst-case" scenario was based on results of detailed studies of sugarcane processing in Brazil that showed that refined sugar contains less than 1 MUg of total plant protein /g refined sugar. The "Reasonable-case" scenario was based on assumption that the expression levels in stalk of newly expressed proteins were less than 0.1% of total stalk protein. Using these calculated protein intake values from the consumption of sugar, along with the accepted NOAEL levels of the four representative proteins we concluded that safety margins for the "Worst-case" scenario ranged from 6.9 * 105 to 5.9 * 107 and for the "Reasonable-case" scenario ranged from 6.9 * 108 to 5.9 * 1010. These safety margins are very high due to the extremely low possible exposures and the high NOAELs for these non-toxic proteins. This generalized approach to the safety assessment of highly purified food ingredients like sugar illustrates that sugar processed from Brazilian GM varieties are safe for consumption in representative markets globally. PMID- 29755978 TI - Development of an Effective Chain Elongation Process From Acidified Food Waste and Ethanol Into n-Caproate. AB - Introduction: Medium chain fatty acids (MCFAs), such as n-caproate, are potential valuable platform chemicals. MCFAs can be produced from low-grade organic residues by anaerobic reactor microbiomes through two subsequent biological processes: hydrolysis combined with acidogenesis and chain elongation. Continuous chain elongation with organic residues becomes effective when the targeted MCFA(s) are produced at high concentrations and rates, while excessive ethanol oxidation and base consumption are limited. The objective of this study was to develop an effective continuous chain elongation process with hydrolyzed and acidified food waste and additional ethanol. Results: We fed acidified food waste (AFW) and ethanol to an anaerobic reactor while operating the reactor at long (4 d) and at short (1 d) hydraulic retention time (HRT). At long HRT, n-caproate was continuously produced (5.5 g/L/d) at an average concentration of 23.4 g/L. The highest n-caproate concentration was 25.7 g/L which is the highest reported n caproate concentration in a chain elongation process to date. Compared to short HRT (7.1 g/L n-caproate at 5.6 g/L/d), long HRT resulted in 6.2 times less excessive ethanol oxidation. This led to a two times lower ethanol consumption and a two times lower base consumption per produced MCFA at long HRT compared to short HRT. Conclusions: Chain elongation from AFW and ethanol is more effective at long HRT than at short HRT not only because it results in a higher concentration of MCFAs but also because it leads to a more efficient use of ethanol and base. The HRT did not influence the n-caproate production rate. The obtained n-caproate concentration is more than twice as high as the maximum solubility of n-caproic acid in water which is beneficial for its separation from the fermentation broth. This study does not only set the record on the highest n caproate concentration observed in a chain elongation process to date, it notably demonstrates that such high concentrations can be obtained from AFW under practical circumstances in a continuous process. PMID- 29755977 TI - Wearable Technology for Chronic Wound Monitoring: Current Dressings, Advancements, and Future Prospects. AB - Chronic non-healing wounds challenge tissue regeneration and impair infection regulation for patients afflicted with this condition. Next generation wound care technology capable of in situ physiological surveillance which can diagnose wound parameters, treat various chronic wound symptoms, and reduce infection at the wound noninvasively with the use of a closed loop therapeutic system would provide patients with an improved standard of care and an accelerated wound repair mechanism. The indicating biomarkers specific to chronic wounds include blood pressure, temperature, oxygen, pH, lactate, glucose, interleukin-6 (IL-6), and infection status. A wound monitoring device would help decrease prolonged hospitalization, multiple doctors' visits, and the expensive lab testing associated with the diagnosis and treatment of chronic wounds. A device capable of monitoring the wound status and stimulating the healing process is highly desirable. In this review, we discuss the impaired physiological states of chronic wounds and explain the current treatment methods. Specifically, we focus on improvements in materials, platforms, fabrication methods for wearable devices, and quantitative analysis of various biomarkers vital to wound healing progress. PMID- 29755981 TI - Diagnostic Test Accuracy of Serum Anti-PLA2R Autoantibodies and Glomerular PLA2R Antigen for Diagnosing Idiopathic Membranous Nephropathy: An Updated Meta Analysis. AB - Background: M-type phospholipase A2 receptor (PLA2R) is known as a major antigen on podocytes, which is involved with the pathogenesis of idiopathic membranous nephropathy (iMN). Many studies have shown that serum anti-PLA2R autoantibodies (sPLA2R) are prevalent in patients with iMN but are rarely detected in secondary membranous nephropathy (SMN) or other glomerulonephritis. The anti-PLA2R is considered as a promising serum biomarker in iMN but reports about its diagnostic value are variable and inconsistent. Objective: To evaluate the diagnostic test accuracy (DTA) of anti-PLA2R and glomerular PLA2R antigen (gPLA2R) for diagnosing iMN. Method: MEDLINE, EMBASE, WEB OF SCIENCE, and COCHRANE LIBRARY were searched from 2009 January to February 2018. Heterogeneity was evaluated by Q test and I2. Source of heterogeneity was explored by subgroup analysis and meta-regression. Meta-analysis was executed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Results: Totally, 35 studies were retrieved under the pre-set study eligibility criteria. Twenty-eight studies were included to evaluate the DTA of anti-PLA2R for differentiating iMN from non-iMN. They indicated a pooled sensitivity of 65% (63-67%), specificity of 97% (97-98%), positive likelihood ratio of 15.65 (9.95-24.62), and negative likelihood ratio of 0.37 (0.32-0.42) with a diagnostic OR (sDOR) of 50.41 (31.56 to 80.52) and AUC of 0.9393. No threshold effect was detected. The heterogeneity analysis for sDOR showed that I2 = 50.3% and Cochran-Q = 54.29, df = 27 (p = 0.0014). Heterogeneity was significant. Meta-regression revealed that sample size might be the potential source of heterogeneity. Subgroup analysis demonstrated that method type and ratio of patients with nephrotic-range proteinuria at baseline might be the source of heterogeneity. Sixteen studies reported the diagnostic value of glomerular PLA2R antigen for differentiating iMN from non iMN. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, sDOR, and AUC were 79% (76-81%), 90% (88-92%), 8.17 (5.60 11.93), 0.25 (0.19-0.33), 39.37 (22.18-60.13), and 0.9278. Heterogeneity analysis showed that Cochran-Q = 35.36; df = 15 (p = 0.002), and I2 for sDOR was 57.6%. Conclusion: sPLA2R and gPLA2R demonstrated a good diagnostic accuracy in differentiating iMN and non-iMN. PMID- 29755983 TI - Commentary: Theileria Parasites Secrete a Prolyl Isomerase to Maintain Host Leukocyte Transformation. PMID- 29755980 TI - Importance of Validating Antibodies and Small Compound Inhibitors Using Genetic Knockout Studies-T Cell Receptor-Induced CYLD Phosphorylation by IKKepsilon/TBK1 as a Case Study. AB - CYLD is a deubiquitinating enzyme that plays a crucial role in immunity and inflammation as a negative regulator of NF-kappaB transcription factor and JNK kinase signaling. Defects in either of these pathways contribute to the progression of numerous inflammatory and autoimmune disorders. Therefore, we set out to unravel molecular mechanisms that control CYLD activity in the context of T cell receptor (TCR) signaling. More specifically, we focused on CYLD phosphorylation at Ser418, which can be detected upon immunoblotting of cell extracts with phospho(Ser418)-CYLD specific antibodies. Jurkat T cells stimulated with either anti-CD3/anti-CD28 or PMA/Ionomycin (to mimic TCR signaling) were used as a model system. The role of specific kinases was analyzed using pharmacological as well as genetic approaches. Our initial data indicated that CYLD is directly phosphorylated by the noncanonical IkappaB kinases (IKKs) IKKepsilon and TANK Binding Kinase 1 (TBK1) at Ser418 upon TCR stimulation. Treatment with MRT67307, a small compound inhibitor for IKKepsilon and TBK1, inhibited TCR-induced CYLD phosphorylation. However, the phospho(Ser418)-CYLD immunoreactive band was still present in CRISPR/Cas9 generated IKKepsilon/TBK1 double knockout cell lines, where it could still be prevented by MRT67307, indicating that the initially observed inhibitory effect of MRT67307 on TCR induced CYLD phosphorylation is IKKepsilon/TBK1-independent. Most surprisingly, the phospho(Ser418)-CYLD immunoreactive band was still detectable upon immunoblotting of cell extracts obtained from CYLD deficient cells. These data demonstrate the non-specificity of MRT67307 and phospho(Ser418)-CYLD specific antibodies, implying that previously published results based on these tools may also have led to wrong conclusions. We therefore advise to use genetic knockout studies or alternative approaches for a better validation of antibodies and small compound inhibitors. Interestingly, immunoprecipitation with the phospho(Ser418) CYLD antibody, followed by immunoblotting with anti-CYLD, revealed that CYLD is phosphorylated by IKKepsilon/TBK1 at Ser418 upon T cell stimulation, but that its direct detection with the phospho(Ser418)-CYLD-specific antibody in a western blot is masked by another inducible protein of the same size that is recognized by the same antibody. PMID- 29755982 TI - Clinical Genetics in Interstitial Lung Disease. AB - Interstitial lung disease (ILD) comprises a heterogeneous group of diffuse parenchymal lung processes with overlapping clinical, radiographic, and histopathologic features. Among the most common and deadly ILDs are idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP). As the name implies, the cause of IPF remains elusive, but a variety of genetic and infectious risk factors have been identified. CHP results from chronic inhalation of an organic antigen, usually of avian or mold origin, and may occur in patients with a genetic predisposition. While IPF is treated with anti-fibrotic compounds, CHP is generally treated by suppression of the immune system and elimination of the causative antigen. Despite advances in our understanding of IPF and CHP, there exists substantial variability in the diagnosis and treatment of these disease processes. Furthermore, IPF and CHP natural history and treatment response remain far from uniform, leaving it unclear which patients derive the most benefit from disease-specific therapy. While clinical prediction models have improved our understanding of outcome risk in patients with various forms of ILD, recent advances in genomic technology provides a valuable opportunity to begin understanding the basis for outcome variability. Such advances will ultimately allow for the incorporation of genomic markers into risk stratification and clinical decision-making. In this piece, we highlight recent advances in our understanding of the genomic factors that influence susceptibility and outcome risk among patients with IPF and CHP. Genomic modalities used to identify these genomic markers include genome-wide association studies, analyses of gene expression, drug-gene interaction testing, telomere length determination, telomerase mutation analysis, and studies of the lung microbiome. We then identify gaps in knowledge that should be addressed to help facilitate the incorporation of these genomic technologies into ILD clinical practice. PMID- 29755984 TI - Kampo Medicines for Frailty in Locomotor Disease. AB - Frailty is a syndrome that includes broad problems of senility and consists of three domains: physical, psychological, and social. Kampo medicine is used for intervention in cases of hypofunction in a mental or physical state. Kampo treatment, using Hojin formulations such as Hachimijiogan and Gosyajinkigan, is useful in patients with "jinkyo," or kidney hypofunction. Ketsu includes both blood and its metabolic products that circulate throughout the body. Oketsu is a disturbance of ketsu and is considered to be a microcirculation disorder. Anti oketsu formulations, such as Keishibukuryogan and Jidabokuippo, are useful in the treatment of trauma patients who are experiencing swelling and pain. "Ki" is the universal energy that exists in the world. Hoki formulations, such as Rikkunshito and Hochuekkito, are useful in patients with poor appetites for reinforcing vital energy. Juzentaihoto and Ninjinyoeito are useful in patients with hypofunction of ki and ketsu, which are accompanying symptoms of coldness or cutaneous dryness. Thus, Kampo medicines can be used as a superior approach for the management of frailty. PMID- 29755979 TI - Design and validation of diffusion MRI models of white matter. AB - Diffusion MRI is arguably the method of choice for characterizing white matter microstructure in vivo. Over the typical duration of diffusion encoding, the displacement of water molecules is conveniently on a length scale similar to that of the underlying cellular structures. Moreover, water molecules in white matter are largely compartmentalized which enables biologically-inspired compartmental diffusion models to characterize and quantify the true biological microstructure. A plethora of white matter models have been proposed. However, overparameterization and mathematical fitting complications encourage the introduction of simplifying assumptions that vary between different approaches. These choices impact the quantitative estimation of model parameters with potential detriments to their biological accuracy and promised specificity. First, we review biophysical white matter models in use and recapitulate their underlying assumptions and realms of applicability. Second, we present up-to-date efforts to validate parameters estimated from biophysical models. Simulations and dedicated phantoms are useful in assessing the performance of models when the ground truth is known. However, the biggest challenge remains the validation of the "biological accuracy" of estimated parameters. Complementary techniques such as microscopy of fixed tissue specimens have facilitated direct comparisons of estimates of white matter fiber orientation and densities. However, validation of compartmental diffusivities remains challenging, and complementary MRI-based techniques such as alternative diffusion encodings, compartment-specific contrast agents and metabolites have been used to validate diffusion models. Finally, white matter injury and disease pose additional challenges to modeling, which are also discussed. This review aims to provide an overview of the current state of models and their validation and to stimulate further research in the field to solve the remaining open questions and converge towards consensus. PMID- 29755985 TI - Single-Ring Intermediates Are Essential for Some Chaperonins. AB - Chaperonins are macromolecular complexes found throughout all kingdoms of life that assist unfolded proteins reach a biologically active state. Historically, chaperonins have been classified into two groups based on sequence, subunit structure, and the requirement for a co-chaperonin. Here, we present a brief review of chaperonins that can form double- and single-ring conformational intermediates in their protein-folding catalytic pathway. To date, the bacteriophage encoded chaperonins phi-EL and OBP, human mitochondrial chaperonin and most recently, the bacterial groEL/ES systems, have been reported to form single-ring intermediates as part of their normal protein-folding activity. These double-ring chaperonins separate into single-ring intermediates that have the ability to independently fold a protein. We discuss the structural and functional features along with the biological relevance of single-ring intermediates in cellular protein folding. Of special interest are the phi-EL and OBP chaperonins which demonstrate features of both group I and II chaperonins in addition to their ability to function via single-ring intermediates. PMID- 29755987 TI - Low Pathogenic Avian Influenza Exposure Risk Assessment in Australian Commercial Chicken Farms. AB - This study investigated the pathways of exposure to low pathogenic avian influenza (LPAI) virus among Australian commercial chicken farms and estimated the likelihood of this exposure occurring using scenario trees and a stochastic modeling approach following the World Organization for Animal Health methodology for risk assessment. Input values for the models were sourced from scientific literature and an on-farm survey conducted during 2015 and 2016 among Australian commercial chicken farms located in New South Wales and Queensland. Outputs from the models revealed that the probability of a first LPAI virus exposure to a chicken in an Australian commercial chicken farms from one wild bird at any point in time is extremely low. A comparative assessment revealed that across the five farm types (non-free-range meat chicken, free-range meat chicken, cage layer, barn layer, and free range layer farms), free-range layer farms had the highest probability of exposure (7.5 * 10-4; 5% and 95%, 5.7 * 10-4-0.001). The results indicate that the presence of a large number of wild birds on farm is required for exposure to occur across all farm types. The median probability of direct exposure was highest in free-range farm types (5.6 * 10-4 and 1.6 * 10-4 for free range layer and free-range meat chicken farms, respectively) and indirect exposure was highest in non-free-range farm types (2.7 * 10-4, 2.0 * 10-4, and 1.9 * 10-4 for non-free-range meat chicken, cage layer, and barn layer farms, respectively). The probability of exposure was found to be lowest in summer for all farm types. Sensitivity analysis revealed that the proportion of waterfowl among wild birds on the farm, the presence of waterfowl in the range and feed storage areas, and the prevalence of LPAI in wild birds are the most influential parameters for the probability of Australian commercial chicken farms being exposed to avian influenza (AI) virus. These results highlight the importance of ensuring good biosecurity on farms to minimize the risk of exposure to AI virus and the importance of continuous surveillance of LPAI prevalence including subtypes in wild bird populations. PMID- 29755988 TI - Bite Forces and Their Measurement in Dogs and Cats. AB - Bite force is generated by the interaction of the masticatory muscles, the mandibles and maxillae, the temporomandibular joints (TMJs), and the teeth. Several methods to measure bite forces in dogs and cats have been described. Direct in vivo measurement of a bite in dogs has been done; however, bite forces were highly variable due to animal volition, situation, or specific measurement technique. Bite force has been measured in vivo from anesthetized dogs by electrical stimulation of jaw adductor muscles, but this may not be reflective of volitional bite force during natural activity. In vitro bite forces have been estimated by calculation of the force produced using mechanical equations representing the jaw adductor muscles and of the mandible and skull structure Bite force can be estimated in silico using finite element analysis (FEA) of the computed model of the anatomical structures. FEA can estimate bite force in extinct species; however, estimates may be lower than the measurements in live animals and would have to be validated specifically in domestic dogs and cats to be reliable. The main factors affecting the bite forces in dogs and cats are body weight and the skull's morphology and size. Other factors such as oral pain, TMJ disorders, masticatory muscle atrophy, and malocclusion may also affect bite force. Knowledge of bite forces in dogs and cats is essential for various clinical and research fields such as the development of implants, materials, and surgical techniques as well as for forensic medicine. This paper is a summary of current knowledge of bite forces in dogs and cats, including the effect of measurement methods and of other factors. PMID- 29755986 TI - Implications of Cellular Aging in Cardiac Reprogramming. AB - Aging is characterized by a chronic functional decline of organ systems which leads to tissue dysfunction over time, representing a risk factor for diseases development, including cardiovascular. The aging process occurring in the cardiovascular system involves heart and vessels at molecular and cellular level, with subsequent structural modifications and functional impairment. Several modifications involved in the aging process can be ascribed to cellular senescence, a biological response that limits the proliferation of damaged cells. In physiological conditions, the mechanism of cellular senescence is involved in regulation of tissue homeostasis, remodeling, and repair. However, in some conditions senescence-driven tissue repair may fail, leading to the tissue accumulation of senescent cells which in turn may contribute to tumor promotion, aging, and age-related diseases. Cellular reprogramming processes can reverse several age-associated cell features, such as telomere length, DNA methylation, histone modifications and cell-cycle arrest. As such, induced Pluripotent Stem Cells (iPSCs) can provide models of progeroid and physiologically aged cells to gain insight into the pathogenesis of such conditions, to drive the development of new therapies for premature aging and to further explore the possibility of rejuvenating aged cells. An emerging picture is that the tissue remodeling role of cellular senescence could also be crucial for the outcomes of in vivo reprogramming processes. Experimental evidence has demonstrated that, on one hand, senescence represents a cell-autonomous barrier for a cell candidate to reprogramming, but, on the other hand, it may positively sustain the reprogramming capability of surrounding cells to generate fully proficient tissues. This review fits into this conceptual framework by highlighting the most prominent concepts that characterize aging and reprogramming and discusses how the aging tissue might provide a favorable microenvironment for in vivo cardiac reprogramming. PMID- 29755989 TI - Assessing Biosecurity Risks for the Introduction and Spread of Diseases Among Commercial Sheep Properties in New South Wales, Australia, Using Foot-and-Mouth Disease as a Case Study. AB - Sheep production systems are a major industry in Australia, with a gross value of roughly $4.66 billion; 87.3% of which is attributable to export markets. Exotic diseases such as foot-and-mouth disease (FMD) are a potential threat to the viability of Australia's export market. Previous outbreaks of FMD in developed countries, and challenges in the management of onshore biosecurity, signify the importance of on-farm biosecurity in controlling disease transmission. This study aims to investigate the risk of disease introduction and spread among New South Wales (NSW) sheep properties using FMD as a case study and draw recommendation for the industry. Exposure and partial consequence assessments, using scenario trees and Monte Carlo stochastic modeling, were conducted to identify pathways of introduction and spread and calculate the probabilities of these pathways occurring. Input parameters were estimated from the data obtained during qualitative interviews with producers and scientific literature. According to the reported practices of sheep producers and assuming each pathway was carrying the FMD virus, the exposure assessment estimates the median (5-95%) probability of FMD exposure of sheep on a naive property to be 0.619 (0.541-0.698), 0.151 (0.085 0.239), 0.235 (0.153-0.324), and 0.710 (0.619-0.791) for introduction through new stock, wildlife, carriers (humans, dogs, and vehicles), and neighbors, respectively. The spread assessment estimated the median probability of FMD spreading from an infected sheep property to neighboring enterprises to be 0.603 (0.504-0.698). A similar probability was estimated for spread via wildlife (0.523; 0.404-0.638); and a lower spread probability was estimated for carriers (0.315; 0.171-0.527), sheep movement (0.285; 0.161-0.462), and dead stock (0.168; 0.070-0.312). The sensitivity analysis revealed that the introduction of an FMD infected sheep was more influential for exposure via new stock than isolation practices. Sharing adjacent boundaries was found to be the most influential factor for exposure and spread between neighboring enterprises, and to a lesser extent, hygiene practices were found to have the most influence on exposure and spread through carriers. To minimize the potential risk of FMD introduction and spread between sheep properties, maintenance of boundary fences, identification of infected animals before introduction to the property, and hygiene and disinfection practices should be improved. PMID- 29755991 TI - Drying Rate and Product Quality Evaluation of Roselle (Hibiscus sabdariffa L.) Calyces Extract Dried with Foaming Agent under Different Temperatures. AB - The utilisation of roselle (Hibiscus sabdariffa L.) calyx as a source of anthocyanins has been explored through intensive investigations. Due to its perishable property, the transformation of roselle calyces into dried extract without reducing their quality is highly challenging. The aim of this work was to study the effect of air temperatures and relative humidity on the kinetics and product quality during drying of roselle extract foamed with ovalbumin and glycerol monostearate (GMS). The results showed that foam mat drying increased the drying rate significantly and retained the antioxidant activity and colour of roselle calyces extract. Shorter drying time was achieved when higher air temperature and/or lower relative humidity was used. Foam mat drying produced dried brilliant red roselle calyces extract with better antioxidant activity and colour qualities when compared with nonfoam mat drying. The results showed the potential for retaining the roselle calyces extract quality under suggested drying conditions. PMID- 29755992 TI - The First Euro-Asian Congress of Pharmacoepidemiology: A Real Instance for a Multidisciplinary Approach. PMID- 29755990 TI - Left Right Patterning, Evolution and Cardiac Development. AB - Many aspects of heart development are determined by the left right axis and as a result several congenital diseases have their origins in aberrant left-right patterning. Establishment of this axis occurs early in embryogenesis before formation of the linear heart tube yet impacts upon much later morphogenetic events. In this review I discuss the differing mechanisms by which left-right polarity is achieved in the mouse and chick embryos and comment on the evolution of this system. I then discus three major classes of cardiovascular defect associated with aberrant left-right patterning seen in mouse mutants and human disease. I describe phenotypes associated with the determination of atrial identity and venous connections, looping morphogenesis of the heart tube and finally the asymmetric remodelling of the embryonic branchial arch arterial system to form the leftward looped arch of aorta and associated great arteries. Where appropriate, I consider left right patterning defects from an evolutionary perspective, demonstrating how developmental processes have been modified in species over time and illustrating how comparative embryology can aide in our understanding of congenital heart disease. PMID- 29755993 TI - The Role of Hydroxychloroquine as a Steroid-sparing Agent in the Treatment of Immune Thrombocytopenia: A Review of the Literature. AB - Immune Thrombocytopenia (ITP) is an autoimmune disease in which platelet destruction causes thrombocytopenia. Due to the known steroid toxicities, alternative agents have been evaluated for the treatment of these patients. We aimed to review the literature and find evidences regarding the potential benefits of hydroxychloroquine (HCQ) as a steroid-sparing agent in the treatment of ITP. We searched English language articles within Web of Science, PubMed, and Scopus. Cohorts, clinical trials, case reports, conference papers, and letters were included. We excluded papers which either focused on administration of HCQ for non-ITP conditions or studies on other treatment modalities for ITP. In total, 54 ITP cases with either primary or systemic lupus erythematosus (SLE) associated ITP were included in four studies (SLE-associated ITP; n = 23). All patients have received corticosteroids previously and >90% received other agents with HCQ concomitantly. Overall response was achieved in more than 60% of patients. Sustained response in 18 (33.3%) patients was associated with no treatment or HCQ alone. One of the studies reported a significantly better response in patients with definite SLE compared to those with positive antinuclear antibody and no definite SLE. Similarly, another study found a nonsignificant trend toward better long-term response in patients with definite SLE compared to incomplete SLE. The included articles reported the efficacy of the HCQ with acceptable safety. Available data regarding the use of HCQ for this indication are spare and more studies are needed in ITP with different severity. It seems that HCQ can be considered as an option in the treatment of SLE associated ITP, and although promising, currently, the place of HCQ in the treatment of ITP continues to evolve. PMID- 29755994 TI - Therapeutic Effects of Low-dose Bismuth Subcitrate on Symptoms and Health-related Quality of Life in Adult Patients with Irritable Bowel Syndrome: A Clinical Trial. AB - Objective: Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract that causes abdominal pain or discomfort and alters bowel with no organic abnormalities. Treatment options for IBS have increased in number in the past decade, and clinicians should not be limited to use only conventional treatments to cure it. This article is a placebo-controlled clinical trial to assess the therapeutic effects of low-dose bismuth subcitrate on symptoms and the health-related quality of life in adult patients with IBS. Methods: This clinical trial was done during July 2015 to January 2016 in Isfahan, Iran. For each of three subtypes (IBS-constipation dominant, IBS-diarrhea dominant [IBS-D], and IBS mixed), we included patients with IBS aged 18-70 years, diagnosed according to the Rome III criteria. In this study, 129 eligible patients were enrolled, of which 119 continued on the protocol to the end of study. They were allocated in placebo group (Group A) and intervention group (Group B). The medication for Group B was mebeverine and bismuth subcitrate and for Group A was mebeverine and placebo of bismuth subcitrate. Initially, the patients of both groups completed IBS-related questionnaires (IBS-quality of life, IBS-severity scoring system), then given drugs for a 4-week period (1st on-drug period). Then, both groups were given only mebeverine hydrochloride 200 mg capsule for another 4 weeks (off-drug period). At last, Group A and Group B were given medication (2nd on-drug period), the same as 1st on-drug period. Findings: With respect to quality of life, the trend of IBS-QOL score changed significantly during the study period in both the intervention and placebo groups; however, no significant differences were observed between the two groups (P < 0.005). In subgroups analysis, quality of life significantly improved in IBS-D during the study from the first measurement to the end of study (P = 0.004). The trends of changes in the severity of pain during the study between the intervention and control group were significantly different (P = 0.018). Conclusion: According to our study, IBS-D patients' symptoms improved significantly with bismuth therapy. We found that adding low dose bismuth to mebeverine in nonresponsive IBS patients in conventional treatment could be helpful. PMID- 29755995 TI - Assessing Medical Prescription Forms as a Communication Tool in Trans-European Health Care. AB - Objective: The objective of the study was to compare the medical prescription forms in European Union (EU) countries, evaluating their convergence toward the implementation of cross-border care, as proposed by the existing EU health-care directives. It also aims to assess how the existing EU prescription models fulfill higher standards of medication prescribing quality and patient safety. Methods: Prescription forms from all EU countries were purposively collected. The prescription fields and other content elements were qualitatively and quantitatively analyzed. Forms were statistically compared with each other and a theoretical EU cross-border prescription form, using hierarchical cluster analysis and nonparametric testing. Findings: None of the EU countries' prescriptions include all the elements required by the cross-border legislation (CBL), with most countries having seven or less mandatory elements. Cluster analysis revealed that countries with similar prescription forms are geographically nearer. Important elements from the EU directive to assure patient safety are also absent such as the International Classification of Diseases, the patient's ID according to the European Health Insurance Card, and the patient's contact. However, Western and Nordic countries showed higher standardization when compared to the CBL and model. Conclusion: Political action is still needed to harmonize medical prescription forms between countries, serving the common goal of trans-European health care and to increase EU patients' safety using medications and other prescribed treatments. PMID- 29755996 TI - Evaluation of Clinical Pharmacy Services in the Intensive Care Unit of a Tertiary University Hospital in the Northwest of Iran. AB - Objective: Current literature indicates that the presence of clinical pharmacists in hospitals results in improved patient care, rational drug therapy, and treatment costs. This study assessed the clinical pharmacy services in the intensive care unit (ICU) of a tertiary hospital at Tabriz University of Medical Sciences, Iran. Methods: During a 9-month cross-sectional study (2014-2015), the clinical pharmacy interventions in 27 sessions and educational activities for patients and health-care professionals were randomly assessed based on the Australian guideline and standard of practice for clinical pharmacy. The interventions of clinical pharmacist were evaluated in terms of their clinical importance. Findings: In this study, a total of 832 interventions on 242 patients were performed by the clinical pharmacist, and approximately 93.6% of the interventions were approved by the attending physician. Most interventions concerned adding a new medication to a drug regimen or switching to a needed new medication. Each patient received an average of three interventions. The clinical pharmacist provided drug information to employees and medical staff in 108 of the total 832 interventions (13%). Medical residents who were surveyed indicated that the quality of education, research, and patient care was improved by the attendance of a clinical pharmacist. Conclusion: The results of this study show that the collaboration of a clinical pharmacist with the medical staff of an ICU can improve pharmacotherapy approach and increase the quality of education. PMID- 29755997 TI - Bispectral Index in Poisoning Cases with Multi-drug Ingestion: A Predictable Role for Early Endotracheal Intubation. AB - Objective: Bispectral index (BIS) is one of the several methods used to monitor the depth of anesthesia. Poisoning with ingestion of different drugs is one of the most common poisonings that have different clinical signs from drowsiness to coma. This study was performed to compare the BIS index number in poisoned patients with multi drugs ingestion with or without the need for endotracheal intubation. Methods: This cross-sectional study was performed on poisoned patients with ingestion of different drugs referring to Clinical Toxicology Department of Noor University Hospital, Isfahan, Iran. The clinical signs and symptoms and the vital signs at the admission time were measured, and the required therapies were given. The endotracheal intubation was done for patients who had the indication of intubation. BIS was monitored and compared for all patients with or without a need for intubation on the admission time and time of endotracheal intubation. Obtained data were analyzed by SPSS software. Findings: At the admission time, the mean (standard error [SE]) BIS index value for poisoned patients who needed endotracheal intubation was 66.47 +/- 2.57 in comparison with 85.21 +/- 1.47 for patients who did not need intubation (P < 0.001). The results of receiver operating characteristic curve (mean +/- SE) showed the discrimination was excellent for BIS (0.899 +/- 0.04; 95% confidence interval: 0.81-0.98) (P < 0.0001). BIS <79.5 had the sensitivity 88% and specificity 87% for endotracheal intubation. Conclusion: BIS is an appropriate index for prediction of the need to intubation in poisoned patients with ingestion of different drugs. PMID- 29755998 TI - Application of a Pharmacokinetic Model of Metformin Clearance in a Population with Acute Myeloid Leukemia. AB - Objective: We aimed to estimate the metformin-associated lactic acidosis (MALA) risk by assessing retrospectively the renal clearance variability and applying a pharmacokinetic (PK) model of metformin clearance in a population diagnosed with acute myeloid leukemia (AML) and diabetes mellitus (DM). Methods: All adults with preexisting DM and newly diagnosed AML at Roswell Park Cancer Institute were reviewed (January 2003-December 2010, n = 78). Creatinine clearance (CrCl) and total body weight distributions were used in a two-compartment PK model adapted for multiple dosing and modified to account for actual intra- and inter individual variability. Based on this renal function variability evidence, 1000 PK profiles were simulated for multiple metformin regimens with the resultant PK profiles being assessed for safe CrCl thresholds. Findings: Metformin 500 mg up to three times daily was safe for all simulated profiles with CrCl >=25 mL/min. Furthermore, the estimated overall MALA risk was below 10%, remaining under 5% for 500 mg given once daily. CrCl >=65.25 mL/min was safe for administration in any of the tested regimens (500 mg or 850 mg up to three times daily or 1000 mg up to twice daily). Conclusion: PK simulation-guided prescribing can maximize metformin's beneficial effects on cancer outcomes while minimizing MALA risk. PMID- 29755999 TI - Prescribing Pattern and Prescription-writing Quality of Antineoplastic Agents in the Capital City of a Middle-income Developing Country. AB - Objective: Cancer is a global health concern with growing incidence worldwide. Chemotherapy is the main treatment modality in many malignancies. This study aimed at evaluation of antineoplastic prescribing pattern and prescription writing quality in the capital city of Iran. Methods: All dispensed chemotherapy prescriptions by four main authorized pharmacies in Tehran during 1 month were targeted. Prescriptions with no antineoplastic medications or written by specialties other than oncology-related fields were excluded from the study. From the total 10,944 eligible prescriptions, 2736 (25%) prescriptions were selected randomly for data extraction. Findings: Total 5784 antineoplastic medications were written by 239 physicians; most of them were adult hematologist-oncologist (69.0%) and male (86.6%). Each prescription contained an average of 1.8 (+/-0.9) antineoplastic medications. The most widely prescribed antineoplastic agents were cyclophosphamide (16.2%), fluorouracil (15.2%), doxorubicin (12.8%), and oxaliplatin (11.0%). The quality of prescription writing was poor; diagnosis, drug dosing, treatment schedule, and instructions were mostly absent. Sixty percent of drugs were written in brand names. Conclusion: The prescribing writing quality was poor and patients were at great risk of medication errors. Prompt action including policies and educational strategies should be taken to assure effective and safe patient treatment with antineoplastic medications. PMID- 29756001 TI - Experiences with Deriva: An Asset Management Platform for Accelerating eScience. AB - The pace of discovery in eScience is increasingly dependent on a scientist's ability to acquire, curate, integrate, analyze, and share large and diverse collections of data. It is all too common for investigators to spend inordinate amounts of time developing ad hoc procedures to manage their data. In previous work, we presented Deriva, a Scientific Asset Management System, designed to accelerate data driven discovery. In this paper, we report on the use of Deriva in a number of substantial and diverse eScience applications. We describe the lessons we have learned, both from the perspective of the Deriva technology, as well as the ability and willingness of scientists to incorporate Scientific Asset Management into their daily workflows. PMID- 29756000 TI - Bullous Fixed Drug Eruption Following Ibuprofen Ingestion. AB - Fixed drug eruption (FDE) is a drug reaction involving skin and less commonly mucosal membranes. The common manifestation is localized well-demarcated patches or plaques appeared following receiving of a culprit drug. When re-exposure occurs, the rashes will appear at areas involved in previous episodes. Limited reports on bullous FDE due to ibuprofen have been documented before. Herein, we described an elderly man who experienced multifocal lesions in his oral mucosa, penis, and multiple sites of skin following ibuprofen ingestion confirmed as FDE by pathological studies. The culprit drug had been discontinued. Systemic and topical glucocorticoids as well as supportive care had been instituted. The patient's outcome was favorable and his lesions had been recovered within the next weeks. Patient's follow-up showed that he had received ibuprofen again sometime later resulting in anal mucosal lesion and similar penile involvement. In routine clinical practice, mucocutaneous adverse drug reactions should be considered. A high index of suspicion, the detailed medication history, the course of the symptoms, and distributing pattern of the lesions are essential clues for the diagnosis. However, judicious and prompt pathological studies can help to differentiate multifocal bullous FDE from major skin drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis. PMID- 29756002 TI - ERMrest: A Collaborative Data Catalog with Fine Grain Access Control. AB - Creating and maintaining an accurate description of data assets and the relationships between assets is a critical aspect of making data findable, accessible, interoperable, and reusable (FAIR). Typically, such metadata are created and maintained in a data catalog by a curator as part of data publication. However, allowing metadata to be created and maintained by data producers as the data is generated rather then waiting for publication can have significant advantages in terms of productivity and repeatability. The responsibilities for metadata management need not fall on any one individual, but rather may be delegated to appropriate members of a collaboration, enabling participants to edit or maintain specific attributes, to describe relationships between data elements, or to correct errors. To support such collaborative data editing, we have created ERMrest, a relational data service for the Web that enables the creation, evolution and navigation of complex models used to describe and structure diverse file or relational data objects. A key capability of ERMrest is its ability to control operations down to the level of individual data elements, i.e. fine-grained access control, so that many different modes of data oriented collaboration can be supported. In this paper we introduce ERMrest and describe its fine-grained access control capabilities that support collaborative editing. ERMrest is in daily use in many data driven collaborations and we describe a sample policy that is based on a common biocuration pattern. PMID- 29756005 TI - Peripheral Lymph Node Excisional Biopsy: Yield, Relevance, and Outcomes in a Remote Surgical Setup. AB - Objective: To study the patient profile for symptomatic peripheral lymphadenopathy in terms of histopathological findings and demography and evaluate the yield, relevance, and outcomes of peripheral lymph node biopsy (PLNB) as a diagnostic step in a remote setup in the absence of less invasive options like fine-needle aspiration cytology (FNAC) or ultrasonogram- (USG-) guided FNAC. Methods: A retrospective review of patients undergoing PLNB between 1 May 2011 and 30 April 2013 was done. Demographics, histopathological reports, and outcomes were studied. Results: Of 132 patients, 51 (38.63%) were male and 81 (61.36%) were female. There were 48 (36.3%) patients in the age group less than 16 years, and 84 (63.6%) were beyond 16 years. The commonest site of biopsy was the neck in 114 (86.36%) patients. The histopathological diagnosis was tuberculosis (TB) in 60 (45.45%) patients, reactive lymphadenitis in 29 (21.9%), nonspecific granuloma in 18 (13.6%), lymphoma in 7 (5.3%), acute lymphadenitis in 7 (5.3%), metastatic secondary in 3 (2.2%), and other benign causes in 8 (6.06%). Conclusions: PLNB is a procedure with good diagnostic yield in evaluation of peripheral lymphadenopathy. Its relevance is appreciable in a remote setup where less invasive options are unavailable. Its simplicity and lack of mortality/significant morbidity make it a valid option in rural surgical practice. PMID- 29756003 TI - Onset and Remission of Psychosis in Parkinson's Disease: Pharmacologic and Motoric Markers. AB - Background: Psychosis is among the most disabling complications of Parkinson's disease (PD). The chronicity of PD psychosis remains understudied and the relative importance of dopaminergic therapy versus the disease process itself in engendering psychosis remains unclear. Objectives: To examine pharmacologic and motoric correlates of PD psychosis onset and remission in a longitudinally monitored PD cohort. Methods: We analyzed data from 165 participants enrolled in a longitudinal PD study through the Morris K. Udall Parkinson's Disease Research Center of Excellence at Johns Hopkins University. Evaluations included formal psychiatric assessment and were conducted at two-year intervals. Regression with generalized estimated equations (GEE) was used to produce unadjusted and adjusted estimates for time-varying longitudinal associations between psychosis and putative risk factors. Results: Sixty-two participants (37.6%) were diagnosed with psychosis during at least one evaluation. Of forty-nine participants with psychosis followed over multiple evaluations, 13 (26.5%) demonstrated remission despite significant Hoehn & Yahr stage increase (p=0.009); two of these cases later relapsed. Multivariable regression with GEE identified dementia diagnosis, akinesia-rigidity, anticholinergic usage, and levodopa-carbidopa dose to be significantly associated with psychosis, while disease duration was not. A sub analysis of 30 incident psychosis cases suggested that dopamine agonist dose was lowered after psychosis onset with a compensatory increase in levodopa-carbidopa dosage. Conclusions: Our findings suggest that in the context of standard therapy, PD-related psychotic disorder can remit at a frequency of approximately 27%. Additionally, akinetic-rigid motor impairment was more strongly associated with psychosis than disease duration, independent of cognitive impairment and medications. PMID- 29756004 TI - Galectin-3 and incident cognitive impairment in REGARDS, a cohort of blacks and whites. AB - Introduction: The relationship between serum galectin-3 and incident cognitive impairment was analyzed in the Reasons for Geographic and Racial Differences in Stroke study. Methods: Baseline galectin-3 was measured in 455 cases of incident cognitive impairment and 546 controls. Galectin-3 was divided into quartiles based on the weighted distribution in the control group, and the first quartile was the referent. Results: There was an increasing odds of cognitive impairment across quartiles of galectin-3 (odds ratios, 1.00 [0.68-1.46], 1.45 [1.01-2.10], and 1.58 [1.10-2.27] relative to the quartile 1; P trend = .003) in an unadjusted model, which persisted after adjusting for age, sex, and race (P = .004). Adjustment for cardiovascular risk factors greatly attenuated this association (odds ratios, 0.97 [0.60-1.57], 1.52 [0.94-2.46], and 1.27 [0.76-2.12]; P = .15). The association differed by diabetes status (P interaction, .007). Among nondiabetics (293 cases, 411 controls), those with galectin-3 in the fourth compared with first quartile had an odds ratio of 1.6 (0.95-2.99; P trend, .02). In diabetics, the odds ratio was 0.23 (0.04-1.33). Discussion: Serum galectin-3 was associated with increased risk of incident cognitive impairment in a large cohort study of blacks and whites but only in nondiabetics. PMID- 29756006 TI - Theoretical model and characteristics of mitochondrial thermogenesis. AB - Based on the first law of thermodynamics and the thermal diffusion equation, the deduced theoretical model of mitochondrial thermogenesis satisfies the Laplace equation and is a special case of the thermal diffusion equation. The model settles the long-standing question of the ability to increase cellular temperature by endogenous thermogenesis and explains the thermogenic characteristics of brown adipocytes. The model and calculations also suggest that the number of free available protons is the major limiting factor for endogenous thermogenesis and its speed. PMID- 29756007 TI - Mapping disulfide bonds from sub-micrograms of purified proteins or micrograms of complex protein mixtures. AB - Disulfide bonds are vital for protein functions, but locating the linkage sites has been a challenge in protein chemistry, especially when the quantity of a sample is small or the complexity is high. In 2015, our laboratory developed a sensitive and efficient method for mapping protein disulfide bonds from simple or complex samples (Lu et al. in Nat Methods 12:329, 2015). This method is based on liquid chromatography-mass spectrometry (LC-MS) and a powerful data analysis software tool named pLink. To facilitate application of this method, we present step-by-step disulfide mapping protocols for three types of samples-purified proteins in solution, proteins in SDS-PAGE gels, and complex protein mixtures in solution. The minimum amount of protein required for this method can be as low as several hundred nanograms for purified proteins, or tens of micrograms for a mixture of hundreds of proteins. The entire workflow-from sample preparation to LC-MS and data analysis-is described in great detail. We believe that this protocol can be easily implemented in any laboratory with access to a fast scanning, high-resolution, and accurate-mass LC-MS system. PMID- 29756008 TI - Fabrication and modification of implantable optrode arrays for in vivo optogenetic applications. AB - Graphical Abstract: Abstract: Recent advances in optogenetics have established a precisely timed and cell-specific methodology for understanding the functions of brain circuits and the mechanisms underlying neuropsychiatric disorders. However, the fabrication of optrodes, a key functional element in optogenetics, remains a great challenge. Here, we report reliable and efficient fabrication strategies for chronically implantable optrode arrays. To improve the performance of the fabricated optrode arrays, surfaces of the recording sites were modified using optimized electrochemical processes. We have also demonstrated the feasibility of using the fabricated optrode arrays to detect seizures in multiple brain regions and inhibit ictal propagation in vivo. Furthermore, the results of the histology study imply that the electrodeposition of composite conducting polymers notably alleviated the inflammatory response and improved neuronal survival at the implant/neural-tissue interface. In summary, we provide reliable and efficient strategies for the fabrication and modification of customized optrode arrays that can fulfill the requirements of in vivo optogenetic applications. PMID- 29756009 TI - Molecular architecture of mouse and human pancreatic zymogen granules: protein components and their copy numbers. AB - A molecular model of pancreatic zymogen granule (ZG) is critical for understanding its functions. We have extensively characterized the composition and membrane topology of rat ZG proteins. In this study, we report the development of targeted proteomics approaches to quantify representative mouse and human ZG proteins using LC-SRM and heavy isotope-labeled synthetic peptides. The absolute quantities of mouse Rab3D and VAMP8 were determined as 1242 +/- 218 and 2039 +/- 151 (mean +/- SEM) copies per ZG. The size distribution and the averaged diameter of ZGs 750 +/- 23 nm (mean +/- SEM) were determined by atomic force microscopy. The absolute quantification of Rab3D was then validated using semi-quantitative Western blotting with purified GST-Rab3D proteins as an internal standard. To extend our proteomics analysis to human pancreas, ZGs were purified using human acini obtained from pancreatic islet transplantation center. One hundred and eighty human ZG proteins were identified for the first time including both the membrane and the content proteins. Furthermore, the copy number per ZG of human Rab3D and VAMP8 were determined to be 1182 +/- 45 and 485 +/- 15 (mean +/- SEM). The comprehensive proteomic analyses of mouse and human pancreatic ZGs have the potential to identify species-specific ZG proteins. The determination of protein copy numbers on pancreatic ZGs represents a significant advance towards building a quantitative molecular model of a prototypical secretory vesicle using targeted proteomics approaches. The identification of human ZG proteins lays a foundation for subsequent studies of altered ZG compositions and secretion in pancreatic diseases. PMID- 29756011 TI - Transoral incisional fundoplication for reflux after peroral endoscopic myotomy: a crucial addition to our arsenal. AB - Introduction: Increased esophageal acid exposure is seen in a large percentage of patients with achalasia who undergo peroral endoscopic myotomy (POEM). Endoscopic transoral fundoplication (TIF) is a novel endoscopic technique for the management of patients with chronic gastroesophageal reflux (GERD). We present the first case series evaluating the role of TIF post-POEM. Methods: Consecutive patients 18 years or older from our academic institution who underwent a POEM procedure and subsequently underwent TIF for symptomatic reflux or regurgitation between December 2014 and June 2017 were included. The primary outcome was discontinuation of proton-pump inhibitor (PPI) use and healing of esophagitis (when initially present) on post-procedure esophagogastroduodenoscopy (EGD). Technical success was defined as successful completion of the endoscopic fundoplication. Adverse events (AEs) were recorded for all patients. Results : Five patients were included (60 % male, average age 55 +/- 14 years). Technical success was achieved in 100 % of patients. Discontinuation of PPI use was achieved in 5/5 patients (100 %). Three patients had esophagitis pre-procedure and all were noted to have resolution of inflammation on post-procedure EGD. No adverse events were noted. Mean follow-up time was 27 months (range 5 - 34 months). Conclusion: TIF post-POEM appears feasible, safe, and efficacious in improving symptoms and esophagitis, decreasing long-term risks of acid exposure, and decreasing risks of long-term PPI use in patients post-POEM in this small cohort of patients. Larger studies are needed to confirm these initial findings. PMID- 29756010 TI - Mitochondrial protein sulfenation during aging in the rat brain. AB - There is accumulating evidence that cysteine sulfenation (cys-SOH) in proteins plays an important role in cellular response to oxidative stress. The purpose of the present study was to identify mitochondrial proteins that undergo changes in cys-SOH during aging. Studies were conducted in rats when they were 5 or 30 months of age. Following blocking of free protein thiols with N-ethylmaleimide, protein sulfenic acids were reduced by arsenite to free thiol groups that were subsequently labeled with biotin-maleimide. Samples were then comparatively analyzed by two-dimensional Western blots, and proteins showing changes in sulfenation were selectively identified by mass spectrometry peptide sequencing. As a result, five proteins were identified. Proteins showing an age-related decrease in sulfenation include pyruvate carboxylase and pyruvate dehydrogenase; while those showing an age-related increase in sulfenation include aconitase, mitofilin, and tubulin (alpha-1). Results of the present study provide a general picture of mitochondrial protein sulfenation in brain oxidative stress and implicate the involvement of protein sulfenation in overall decline of mitochondrial function during brain aging. PMID- 29756012 TI - Needle fracture during endoscopic ultrasound-guided fine needle aspiration using a needle with a side hole. AB - Background and study aims Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is widely performed to obtain pathological evidence from several parts of the body. Major complications of EUS-FNA are bleeding, pancreatitis, and abdominal pain. Needle fracture is a rare complication of EUS-FNA and only a few relevant reports are available. Here, we report a case of needle fracture during EUS-FNA using a needle with a side hole. A 61-year-old man underwent EUS-FNA of the uncinate process of the pancreas to confirm malignancy. A 20-gauge needle with a side hole was used to puncture the mass from the first part of the duodenum. The needle fracture occurred at the side hole during the third passage, and the fragment remained in the pancreas. Fortunately, the patient did not exhibit any symptoms due to the needle fragment. This case indicates that repeated puncture using the same needle with a side hole might increase risk of needle fracture during EUS-FNA. It is important to inform clinicians about the potential risk of needle fracture, particularly given the increasing number of EUS-FNAs being performed. PMID- 29756013 TI - Colonic stent versus emergency surgery as treatment of malignant colonic obstruction in the palliative setting: a systematic review and meta-analysis. AB - Background and study aims : Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer death worldwide. Malignant colonic obstruction (MCO) due to CRC occurs in 8 % to 29 % of patients.The aim of this study was to perform a systematic review and meta-analysis of RCTs comparing colonic SEMS versus emergency surgery (ES) for MCO in palliative patients. This was the first systematic review that included only randomized controlled trials in the palliative setting. Methods : A literature search was performed according to the PRISMA method using online databases with no restriction regarding idiom or year of publication. Data were extracted by two authors according to a predefined data extraction form. Primary outcomes were: mean survival, 30-day adverse events, 30-day mortality and length of hospital stay. Stoma formation, length of stay on intensive care unit (ICU), technical success and clinical success were recorded for secondary outcomes. Technical success (TS) was defined as successful stent placement across the stricture and its deployment. Clinical success (CS) was defined as adequate bowel decompression within 48 h of stent insertion without need for re-intervention. Results : We analyzed data from four RCT studies totaling 125 patients. The 30-day mortality was 6.3 % for SEMS treated patients and 6.4 % for ES-treated patients, with no difference between groups (RD: - 0.00, 95 % CI [-0.10, 0.10], I 2 : 0 %). Mean survival was 279 days for SEMS and 244 days for ES, with no significant difference between groups (RD: 20.14, 95 % CI: [-42.92, 83.21], I 2 : 44 %). Clinical success was 96 % in the ES group and 86.1 % in the SEMS group (RD: - 0.13, 95 % CI [-0.23, - 0.02], I 2 : 51 %). Permanent stoma rate was 84 % in the ES group and 14.3 % in the SEMS group (RR: 0.19, 95 % CI: [0.11, 0.33], I 2 : 28 %). Length of hospital stay was shorter in SEMS group (RD: - 5.16, 95 % CI: [-6.71, - 3.61], I 2 : 56 %). There was no significant difference between groups regarding adverse events (RD 0.18, 95 % CI: [-0.19, 0.54;]) neither regarding ICU stay. (RD: - 0.01, 95 % CI: [ 0.08, 0.05], I 2 : 7 %). The most common stent-related complication was perforation (42.8 % of all AE). Conclusion : Mortality, mean survival, length of stay in the ICU and early complications of both methods were similar. SEMS may be an alternative to surgery with the advantage of early hospital discharge and lower risk of permanent stoma. PMID- 29756014 TI - Hemodialysis is a strong risk factor for post-endoscopic sphincterotomy bleeding in patients with choledocholithiasis. AB - Background and study aims: Hemodialysis (HD) is considered one of the risk factors for post-endoscopic sphincterotomy (ES) bleeding. Therefore, we conducted a retrospective study to evaluate HD as a risk factor for post-ES bleeding in patients with choledocholithiasis. Patients and methods: We used the post-ES bleeding rate as the main outcome measure. To evaluate the influence of HD on the risk of post-ES bleeding, logistic regression and propensity score analyses were conducted. In addition, univariate analysis-based comparisons of various clinical parameters (as secondary outcome measures) were performed between the patients in the HD and non-HD groups that experienced post-ES bleeding. Results: A total of 1518 patients were enrolled. In the multivariate analysis, a platelet count of < 50,000, anticoagulant therapy, bleeding during ES, and HD were found to be significantly associated with post-ES bleeding (odds ratio [OR]: 35.30, 95 % confidence interval [CI]: 3.81 - 328.00; OR: 4.39, 95 % CI: 1.53 - 12.60; OR: 4.28, 95 % CI: 2.30 - 7.97; and OR: 13.30, 95 % CI: 5.78 - 30.80, respectively). Propensity score matching created 28 matched pairs. Propensity score analysis showed that the risk difference between the groups was 0.214 (95 % CI: 0.022 - 0.407). In a comparison between the patients in the HD and non-HD groups that suffered post-ES bleeding, it was found that the post-ES bleeding was significantly more severe in the HD group (p = 0.033), and massive blood transfusions and long periods of hospitalization were more frequently required in the HD group (p = 0.008 and p < 0.001, respectively). Conclusion: HD is an independent risk factor for post-ES bleeding and makes post-ES bleeding more serious. PMID- 29756015 TI - Difference in real-time magnetic image analysis of colonic looping patterns between males and females undergoing diagnostic colonoscopy. PMID- 29756016 TI - Prophylactic clip closure may reduce the risk of delayed bleeding after colorectal endoscopic submucosal dissection. AB - Background and study aims : Endoscopic submucosal dissection (ESD) has a high en bloc resection rate and is widely performed for large superficial colorectal tumors, but delayed bleeding remains one of the most common complications of colorectal ESD. The aim of the present study was to evaluate the clinical efficacy of prophylactic clip closure of mucosal defects for the prevention of delayed bleeding after colorectal ESD. Patients and methods : We enrolled consecutive patients with colorectal lesions between January 2012 and May 2017 in this retrospective study. In the early part of this period, post-ESD mucosal defects were not closed (non-closure group); however, from January 2014, post-ESD mucosal defects were prophylactically closed with clips when possible (closure group). The main outcome measured was delayed bleeding. Variables were analyzed using the chi-squared test, Fisher's exact test, or Student's t-test. Results : Of 156 lesions analyzed, 61 were in the non-closure group and 95 in the closure group. Overall, delayed bleeding occurred in 5 cases (3.2 %). The delayed bleeding rate was 0 % (0/95) in the closure group and 8.2 % (5/61) in the non closure group ( P = 0.008). The mean procedure time for closure was 10.4 +/- 4.6 min (range 3 - 26 min). Conclusions : We demonstrated that prophylactic clip closure of mucosal defects might reduce the risk of delayed bleeding after colorectal ESD. PMID- 29756017 TI - Endocytoscopic findings of colorectal neuroendocrine tumors (with video). AB - Background and study aims Gastrointestinal neuroendocrine tumors (NET) are generally submucosal in location. Because these tumors are covered with normal mucosa, biopsy is necessary to confirm histological diagnosis before treatment. We explored the diagnostic capabilities of the endocytoscope, which can perform ultra-high magnification in vivo, for staining and diagnosing submucosal tumors in situ. PMID- 29756018 TI - A structured light laser probe for gastrointestinal polyp size measurement: a preliminary comparative study. AB - Background and study aims: Polyp size measurement is an important diagnostic step during gastrointestinal endoscopy, and is mainly performed by visual inspection. However, lack of depth perception and objective reference points are acknowledged factors contributing to measurement errors in polyp size. In this paper, we describe the proof-of-concept of a polyp measurement device based on structured light technology for future endoscopes. Patients and methods: Measurement accuracy, time, user confidence, and satisfaction were evaluated for polyp size assessment by (a) visual inspection, (b) open biopsy forceps of known size, (c) ruled snare, and (d) structured light probe, for a total of 392 independent polyp measurements in ex vivo porcine stomachs. Results: Visual assessment resulted in a median estimation error of 2.2 mm, IQR = 2.6 mm. The proposed probe can reduce the error to 1.5 mm, IQR = 1.67 mm ( P = 0.002, 95 %CI) and its performance was found to be statistically similar to using forceps for reference ( P = 0.81, 95 %CI) or ruled snare ( P = 0.99, 95 %CI), while not occluding the tool channel. Timing performance with the probe was measured to be on average 54.75 seconds per polyp. This was significantly slower than visual assessment (20.7 seconds per polyp, P = 0.005, 95 %CI) but not significantly different from using a snare (68.5 seconds per polyp, P = 0.73, 95 %CI). However, the probe's timing performance was partly due to lens cleaning problems in our preliminary design. Reported average satisfaction on a 0 - 10 range was highest for the proposed probe (7.92), visual assessment (7.01), and reference forceps (7.82), while significantly lower for snare users with a score of 4.42 ( P = 0.035, 95 %CI). Conclusions: The common practice of visual assessment of polyp size was found to be significantly less accurate than tool-based assessment, but easy to carry out. The proposed technology offers an accuracy on par with using a reference tool or ruled snare with the same satisfaction levels of visual assessment and without occluding the tool channel. Further study will improve the design to reduce the operating time by integrating the probe within the scope tip. PMID- 29756019 TI - Size of colorectal polyps determines time taken to remove them endoscopically. AB - Background an study aims: Polypectomy and endoscopic mucosal resection (EMR) are effective and safe ways of removing polyps from the colon at endoscopy. Guidelines exist for advising the time allocation for diagnostic endoscopy but not for polypectomy and EMR. The aim of this study was to identify if time allocated for polypectomy and EMR at planned therapeutic lists in our endoscopy unit is sufficient for procedures to be carried out. We also wanted to identify factors that might be associated with procedures taking longer than the allocated time and to identify factors that might predict duration of these procedures. Patients and methods: A retrospective case study of planned 100 lower gastrointestinal EMR and polypectomy procedures at colonoscopy and sigmoidoscopy was performed and analyzed with quantitative analysis. Results: The mean actual procedural time (APT) for 100 procedures was 52 minutes and the mean allocated time (AT) was 43.05 minutes. Hence the mean APT was 9 minutes longer than the mean AT. Factors that were significantly associated with procedures taking longer than the allocated time were patient age ( P = 0.029) and polyp size ( P = 0.005). Factors that significant changed the actual procedure time were patient age ( P = 0.018), morphology ( P = 0.002) and polyp size ( P < 0.001). Procedures involving flat and lateral spreading tumor (LST) type polyps took longer than the protruding ones. On multivariate analysis, polyp size was the only factor that associated with actual procedure time. Number of polyps, quality of bowel preparation, and distance of polyp from insertion did significantly change procedure duration. Conclusion: Factors that significantly contribute to duration of polypectomy and EMR at lower gastrointestinal endoscopy include patient age and polyp size and morphology on univariate analysis, with polyp size being the factor with a significant association on multivariate analysis. We recommend that endoscopy units take these factors into consideration locally when allocating time for these procedures to be safe and effective. PMID- 29756020 TI - Multicenter prospective evaluation of the express view reading mode for small bowel capsule endoscopy studies. AB - Background: Reducing the reading time of capsule endoscopy films is of high priority for gastroenterologists. We report a prospective multicenter evaluation of an "express view" reading mode (Intromedic capsule system). Methods: Eighty three patients with obscure gastrointestinal bleeding were prospectively included in 10 centers. All patients underwent small-bowel capsule endoscopy (Intromedic, Seoul, Republic of Korea). Films were read in standard mode, then a second reading was performed in express view mode at a second center. For each lesion, the precise location, nature, and relevance were collected. A consensus reading and review were done by three experts, and considered to be the gold standard. Results: The mean reading time of capsule films was 39.7 minutes (11 - 180 minutes) and 19.7 minutes (4 - 40 minutes) by standard and express view mode, respectively ( P < 1 * 10 - 4 ). The consensus review identified a significant lesion in 44/83 patients (53.0 %). Standard reading and express view reading had a 93.3 % and 82.2 % sensitivity, respectively (NS). Consensus review identified 70 significant images from which standard reading and express view reading detected 58 (82.9 %) and 55 (78.6 %), respectively. The informatics algorithm detected 66/70 images (94.3 %) thus missing four small-bowel angiodysplasia. Conclusion: The express view algorithm allows an important shortening of Intromedic capsule film reading time with a high sensitivity. PMID- 29756021 TI - Full-thickness resection with an over-the-scope device: possible translocation of adenoma tissue in a case of an incomplete resection at the appendix. AB - Background and study aims Clip-assisted endoscopic full-thickness resection has great potential for treatment of difficult-to-resect colorectal neoplasia. Here, we report on endoscopic full-thickness resection at the appendiceal orifice with the appendix in situ requiring emergency surgery due to acute appendicitis. Final histopathology showed appendicitis and residual serrated adenoma within the appendiceal stump, but unexpectedly, also a displaced adenoma fragment at the serosal surface of the cecum. Given the transmural placement of the clip prior to snare resection, translocation of neoplastic tissue to the extra luminal site in cases of incomplete adenoma/carcinoma resection could be a concern. PMID- 29756022 TI - Endoscopic submucosal dissection of early gastric cancer via inverted overtube in a patient with situs inversus totalis: a case report. AB - Background and study aims A 72-year-old man with complete situs inversus presented with early gastric cancer on the lesser curvature wall of the antrum of the stomach. Endoscopic submucosal dissection (ESD) was selected as a treatment. When the patient was positioned in the left decubitus position, the lesion was hidden by blood and gastric fluid because it was located on the gravitational side. Therefore, we decided to perform ESD with the patient in the right lateral decubitus position and use an inverted overtube, which provided a good endoscopic view without the need to rearrange the endoscopist, assistants, or endoscopic system. ESD was safe and feasible using the inverted overtube. PMID- 29756023 TI - Endoscopic polymer injection and endoluminal plication in treatment of gastroesophageal reflux disease: evaluation of long-term results. AB - Background and study aims: Us of proton pump inhibitors (PPIs) has made endoscopic treatment of gastroesophageal reflux disease (GERD) more efficient, with reduction in morbidity and complications. However, some patients persist with symptoms despite medical treatment and some are not compliant with it or cannot afford it for financial reasons, and thus they require non-pharmacological therapeutic options such as surgical fundoplication. Surgery may be effective in the short term, but there is related morbidity and concern about its long-term efficacy. The possibility of minimally invasive endoluminal surgeries has resulted in interest in and development of newly endoscopic devices. Good short term results with surgical fundoplication lack of studies of is with long follow up justify our interest in this study. The aim of this study was to investigate the efficacy of endoscopic polymer injection and endoluminal full-thickness plication in the long-term control of GERD. Patients and methods: Forty-seven patients with GERD who underwent an endoscopic procedure were followed up for 60 months and evaluated for total response (RT), partial response (RP) and no response (SR) to endoscopic treatment with reintroduction of PPIs. Results: Twenty-one patients received polymer injection (G0) and 26 endoluminal plication (G1). The number of patients with no response to endoscopic treatment with reintroduction of PPIs increased in time for both techniques (G0 P = 0.006; G1 P < 0.001). There was symptomatic improvement up to 12 months, with progressive loss of this trending up to 60 months in G0 and G1 ( P < 0.001). Health-related quality of life score (GERD-HRQL) demonstrated TR in G0 and G1 at 1, 3, 6 and 12 months. The 60-month analysis showed an increased number of patients with SR in both groups. The quality of life assessment (SF-36) showed benefit in G0 up to 3 months. G0 showed a higher rate of complications. There were no deaths. There was healing of esophagitis at 3 months in 45 % of patients in G0 and 40 % in G1. There was no improvement in manometric or pH findings. Conclusion : Endoscopic therapies were ineffective in controlling GERD in the long term. PMID- 29756024 TI - Preparation and preclinical evaluation of a 68Ga-labelled c(RGDfK) conjugate comprising the bifunctional chelator NODIA-Me. AB - Background: We recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three, five-membered azaheterocyclic arms for the development of 68Ga- and 64Cu-based radiopharmaceuticals. Here, a 68Ga labelled conjugate comprising the bifunctional chelator NODIA-Me in combination with the alphavbeta3-targeting peptide c(RGDfK) has been synthesized and characterized. The primary aim was to evaluate further the potential of our NODIA Me chelating system for the development of 68Ga-labelled radiotracers. Results: The BFC NODIA-Me was conjugated to c(RGDfK) by standard peptide chemistry to obtain the final bioconjugate NODIA-Me-c(RGDfK) 3 in 72% yield. Labelling with [68Ga]GaCl3 was accomplished in a fully automated, cGMP compliant process to give [68Ga]3 in high radiochemical yield (98%) and moderate specific activity (~ 8 MBq nmol- 1). Incorporation of the Ga-NODIA-Me chelate to c(RGDfK) 2 had only minimal influence on the affinity to integrin alphavbeta3 (IC50 values [natGa]3 = 205.1 +/- 1.4 nM, c(RGDfK) 2 = 159.5 +/- 1.3 nM) as determined in competitive cell binding experiments in U-87 MG cell line. In small-animal PET imaging and ex vivo biodistribution studies, the radiotracer [68Ga]3 showed low uptake in non-target organs and specific tumor uptake in U-87 MG tumors. Conclusion: The results suggest that the bifunctional chelator NODIA-Me is an interesting alternative to existing ligands for the development of 68Ga-labelled radiopharmaceuticals. PMID- 29756025 TI - A 'Plug and Play' Platform for the Production of Diverse Monoterpene Hydrocarbon Scaffolds in Escherichia coli. AB - The terpenoids constitute one of the largest and most diverse classes of natural compounds with applications as pharmaceuticals, flavorings and fragrances, pesticides and biofuels. Synthetic biology is ideally placed to create new routes to this chemical diversity and facilitation of new compound discovery. The C10 monoterpenoids display a huge structural diversity produced from a single substrate, geranyl diphosphate, by a family of monoterpene cyclases and synthases (mTC/S). Here we employ a library of mTC/S in a single 'plug and play' platform system for the production of over 30 different monoterpenoids in Escherichia coli by fermentation on glucose. These products include several compounds never before produced in engineered microbes demonstrating the power of this approach to rapidly create routes to structural diversity. PMID- 29756028 TI - Sharpening of Hierarchical Visual Feature Representations of Blurred Images. AB - The robustness of the visual system lies in its ability to perceive degraded images. This is achieved through interacting bottom-up, recurrent, and top-down pathways that process the visual input in concordance with stored prior information. The interaction mechanism by which they integrate visual input and prior information is still enigmatic. We present a new approach using deep neural network (DNN) representation to reveal the effects of such integration on degraded visual inputs. We transformed measured human brain activity resulting from viewing blurred images to the hierarchical representation space derived from a feedforward DNN. Transformed representations were found to veer toward the original nonblurred image and away from the blurred stimulus image. This indicated deblurring or sharpening in the neural representation, and possibly in our perception. We anticipate these results will help unravel the interplay mechanism between bottom-up, recurrent, and top-down pathways, leading to more comprehensive models of vision. PMID- 29756029 TI - Circadian Behavioral Responses to Light and Optic Chiasm-Evoked Glutamatergic EPSCs in the Suprachiasmatic Nucleus of ipRGC Conditional vGlut2 Knock-Out Mice. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) innervate the hypothalamic suprachiasmatic nucleus (SCN), a circadian oscillator that functions as a biological clock. ipRGCs use vesicular glutamate transporter 2 (vGlut2) to package glutamate into synaptic vesicles and light-evoked resetting of the SCN circadian clock is widely attributed to ipRGC glutamatergic neurotransmission. Pituitary adenylate cyclase-activating polypeptide (PACAP) is also packaged into vesicles in ipRGCs and PACAP may be coreleased with glutamate in the SCN. vGlut2 has been conditionally deleted in ipRGCs in mice [conditional knock-outs (cKOs)] and their aberrant photoentrainment and residual attenuated light responses have been ascribed to ipRGC PACAP release. However, there is no direct evidence that all ipRGC glutamatergic neurotransmission is eliminated in vGlut2 cKOs. Here, we examined two lines of ipRGC vGlut2 cKO mice for SCN-mediated behavioral responses under several lighting conditions and for ipRGC glutamatergic neurotransmission in the SCN. Circadian behavioral responses varied from a very limited response to light to near normal photoentrainment. After collecting behavioral data, hypothalamic slices were prepared and evoked EPSCs (eEPSCs) were recorded from SCN neurons by stimulating the optic chiasm. In cKOs, glutamatergic eEPSCs were recorded and all eEPSC parameters examined (stimulus threshold, amplitude, rise time or time-to-peak and stimulus strength to evoke a maximal response) were similar to controls. We conclude that a variable number but functionally significant percentage of ipRGCs in two vGlut2 cKO mouse lines continue to release glutamate. Thus, the residual SCN-mediated light responses in these cKO mouse lines cannot be attributed solely to ipRGC PACAP release. PMID- 29756026 TI - Analysis of Gut Microbiome and Diet Modification in Patients with Crohn's Disease. AB - Objective: The human intestine harbors trillions of commensal microbes that live in homeostasis with the host immune system. Changes in the composition and complexity of gut microbial communities are seen in inflammatory bowel disease (IBD), indicating disruption in host-microbe interactions. Multiple factors including diet and inflammatory conditions alter the microbial complexity. The goal of this study was to develop an optimized methodology for fecal sample processing and to detect changes in the gut microbiota of patients with Crohn's disease receiving specialized diets. Design: Fecal samples were obtained from patients with Crohn's disease in a pilot diet crossover trial comparing the effects of a specific carbohydrate diet (SCD) versus a low residue diet (LRD) on the composition and complexity of the gut microbiota and resolution of IBD symptoms. The gut microbiota composition was assessed using a high-density DNA microarray PhyloChip. Results: DNA extraction from fecal samples using a column based method provided consistent results. The complexity of the gut microbiome was lower in IBD patients compared to healthy controls. An increased abundance of Bacteroides fragilis (B. fragilis) was observed in fecal samples from IBD positive patients. The temporal response of gut microbiome to the SCD resulted in an increased microbial diversity while the LRD diet was associated with reduced diversity of the microbial communities. Conclusion: Changes in the composition and complexity of the gut microbiome were identified in response to specialized carbohydrate diet. The SCD was associated with restructuring of the gut microbial communities. PMID- 29756027 TI - Translatome Regulation in Neuronal Injury and Axon Regrowth. AB - Transcriptional events leading to outgrowth of neuronal axons have been intensively studied, but the role of translational regulation in this process is not well understood. Here, we use translatome analyses by ribosome pull-down and protein synthesis characterization by metabolic isotopic labeling to study nerve injury and axon outgrowth proteomes in rodent dorsal root ganglia (DRGs) and sensory neurons. We identify over 1600 gene products that are primarily translationally regulated in DRG neurons after nerve injury, many of which contain a 5'UTR cytosine-enriched regulator of translation (CERT) motif, implicating the translation initiation factor Eif4e in the injury response. We further identified approximately 200 proteins that undergo robust de novo synthesis in the initial stages of axon growth. ApoE is one of the highly synthesized proteins in neurons, and its receptor binding inhibition or knockout affects axon outgrowth. These findings provide a resource for future analyses of the role of translational regulation in neuronal injury responses and axon extension. PMID- 29756031 TI - Significance of Eosinophils in Promoting Pancreatic malignancy. AB - Background: Several reports indicate that eosinophils are induced in chronic pancreatitis including patients with pancreatic malignancy. However, significance of eosinophilic pancreatitis (EP) is poorly understood and unexplored. Aim: Accumulation and degranulation of eosinophils promote pancreatic fibrosis and malignancy. Method: Human pancreatic tissue biopsy samples including chronic pancreatitis (n=3), malignant (n=4), non-malignant (n=3), and normal (n=3) were used for H&E, anti-MBP staining, anti-tryptase staining, anti-IgE staining and Mason's trichrome staining. Results: We show induced eosinophils and degranulated eosinophils indicated by the presence of anti-MBP stained extracellular granules in the malignant pancreatic (pancreatic cancer) and non-malignant human pancreatic tissues. A comparable number of eosinophils were observed in non malignant and malignant pancreatic tissue sections, but the sections differed in degranulated eosinophils and the presence of extracellular granules. Additionally, induced mast cells and tissue-specific IgE positive cells were also detected in the tissue sections of malignant pancreatitis patients compared to non-malignant human pancreatic patients. Tissue-specific IgE induction is critical for the degranulation of eosinophils and mast cells that may lead to increased accumulation of collagen in malignant compared to non-malignant human pancreatic tissue samples. We show a large number of anti-tryptase stained extracellular granules in the tissue sections of malignant pancreatic cancer patients. Both IgE and eosinophil major basic proteins (MBP) are reported for the activation and degranulation of mast cells in tissues. Conclusion: Taken together, our investigation concludes that eosinophils and mast cells accumulation and degranulation are critical in promoting pancreatitis pathogenesis that may lead to the development of pancreatic fibrosis and malignancy. PMID- 29756030 TI - 3d Tissue Engineered In Vitro Models Of Cancer In Bone. AB - Biological models are necessary tools for gaining insight into underlying mechanisms governing complex pathologies such as cancer in the bone. Models range from in vitro tissue culture systems to in vivo models and can be used with corresponding epidemiological and clinical data to understand disease etiology, progression, driver mutations, and signaling pathways. In bone cancer, as with many other cancers, in vivo models are often too complex to study specific cell cell interactions or protein roles, and 2D models are often too simple to accurately represent disease processes. Consequently, researchers have increasingly turned to 3D in vitro tissue engineered models as a useful compromise. In this review, tissue engineered 3D models of bone and cancer are described in depth and compared to 2D models. Biomaterials and cell types used are described, and future directions in the field of tissue engineered bone cancer models are proposed. PMID- 29756032 TI - Spin- and valley-polarized one-way Klein tunneling in photonic topological insulators. AB - Recent advances in condensed matter physics have shown that the spin degree of freedom of electrons can be efficiently exploited in the emergent field of spintronics, offering unique opportunities for efficient data transfer, computing, and storage (1-3). These concepts have been inspiring analogous approaches in photonics, where the manipulation of an artificially engineered pseudospin degree of freedom can be enabled by synthetic gauge fields acting on light (4-6). The ability to control these degrees of freedom significantly expands the landscape of available optical responses, which may revolutionize optical computing and the basic means of controlling light in photonic devices across the entire electromagnetic spectrum. We demonstrate a new class of photonic systems, described by effective Hamiltonians in which competing synthetic gauge fields, engineered in pseudospin, chirality/sublattice, and valley subspaces, result in bandgap opening at one of the valleys, whereas the other valley exhibits Dirac-like conical dispersion. We show that this effective response has marked implications on photon transport, among which are as follows: (i) a robust pseudospin- and valley-polarized one-way Klein tunneling and (ii) topological edge states that coexist within the Dirac continuum for opposite valley and pseudospin polarizations. These phenomena offer new ways to control light in photonics, in particular, for on-chip optical isolation, filtering, and wave-division multiplexing by selective action on their pseudospin and valley degrees of freedom. PMID- 29756033 TI - High-flux soft x-ray harmonic generation from ionization-shaped few-cycle laser pulses. AB - Laser-driven high-harmonic generation provides the only demonstrated route to generating stable, tabletop attosecond x-ray pulses but has low flux compared to other x-ray technologies. We show that high-harmonic generation can produce higher photon energies and flux by using higher laser intensities than are typical, strongly ionizing the medium and creating plasma that reshapes the driving laser field. We obtain high harmonics capable of supporting attosecond pulses up to photon energies of 600 eV and a photon flux inside the water window (284 to 540 eV) 10 times higher than previous attosecond sources. We demonstrate that operating in this regime is key for attosecond pulse generation in the x-ray range and will become increasingly important as harmonic generation moves to fields that drive even longer wavelengths. PMID- 29756034 TI - Toward tailoring Majorana bound states in artificially constructed magnetic atom chains on elemental superconductors. AB - Realizing Majorana bound states (MBS) in condensed matter systems is a key challenge on the way toward topological quantum computing. As a promising platform, one-dimensional magnetic chains on conventional superconductors were theoretically predicted to host MBS at the chain ends. We demonstrate a novel approach to design of model-type atomic-scale systems for studying MBS using single-atom manipulation techniques. Our artificially constructed atomic Fe chains on a Re surface exhibit spin spiral states and a remarkable enhancement of the local density of states at zero energy being strongly localized at the chain ends. Moreover, the zero-energy modes at the chain ends are shown to emerge and become stabilized with increasing chain length. Tight-binding model calculations based on parameters obtained from ab initio calculations corroborate that the system resides in the topological phase. Our work opens new pathways to design MBS in atomic-scale hybrid structures as a basis for fault-tolerant topological quantum computing. PMID- 29756035 TI - The ultrafast dynamics and conductivity of photoexcited graphene at different Fermi energies. AB - For many of the envisioned optoelectronic applications of graphene, it is crucial to understand the subpicosecond carrier dynamics immediately following photoexcitation and the effect of photoexcitation on the electrical conductivity the photoconductivity. Whereas these topics have been studied using various ultrafast experiments and theoretical approaches, controversial and incomplete explanations concerning the sign of the photoconductivity, the occurrence and significance of the creation of additional electron-hole pairs, and, in particular, how the relevant processes depend on Fermi energy have been put forward. We present a unified and intuitive physical picture of the ultrafast carrier dynamics and the photoconductivity, combining optical pump-terahertz probe measurements on a gate-tunable graphene device, with numerical calculations using the Boltzmann equation. We distinguish two types of ultrafast photo-induced carrier heating processes: At low (equilibrium) Fermi energy (EF ? 0.1 eV for our experiments), broadening of the carrier distribution involves interband transitions (interband heating). At higher Fermi energy (EF ? 0.15 eV), broadening of the carrier distribution involves intraband transitions (intraband heating). Under certain conditions, additional electron-hole pairs can be created [carrier multiplication (CM)] for low EF, and hot carriers (hot-CM) for higher EF. The resultant photoconductivity is positive (negative) for low (high) EF, which in our physical picture, is explained using solely electronic effects: It follows from the effect of the heated carrier distributions on the screening of impurities, consistent with the DC conductivity being mostly due to impurity scattering. The importance of these insights is highlighted by a discussion of the implications for graphene photodetector applications. PMID- 29756036 TI - Tuning peptide self-assembly by an in-tether chiral center. AB - The self-assembly of peptides into ordered nanostructures is important for understanding both peptide molecular interactions and nanotechnological applications. However, because of the complexity and various self-assembling pathways of peptide molecules, design of self-assembling helical peptides with high controllability and tunability is challenging. We report a new self assembling mode that uses in-tether chiral center-induced helical peptides as a platform for tunable peptide self-assembly with good controllability. It was found that self-assembling behavior was governed by in-tether substitutional groups, where chirality determined the formation of helical structures and aromaticity provided the driving force for self-assembly. Both factors were essential for peptide self-assembly to occur. Experiments and theoretical calculations indicate long-range crystal-like packing in the self-assembly, which was stabilized by a synergy of interpeptide pi-pi and pi-sulfur interactions and hydrogen bond networks. In addition, the self-assembled peptide nanomaterials were demonstrated to be promising candidate materials for applications in biocompatible electrochemical supercapacitors. PMID- 29756037 TI - Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT. AB - LeuT, a prokaryotic member of the neurotransmitter:sodium symporter (NSS) family, is an established structural model for mammalian NSS counterparts. We investigate the substrate translocation mechanism of LeuT by measuring the solution-phase structural dynamics of the transporter in distinct functional states by hydrogen/deuterium exchange mass spectrometry (HDX-MS). Our HDX-MS data pinpoint LeuT segments involved in substrate transport and reveal for the first time a comprehensive and detailed view of the dynamics associated with transition of the transporter between outward- and inward-facing configurations in a Na+- and K+ dependent manner. The results suggest that partial unwinding of transmembrane helices 1/5/6/7 drives LeuT from a substrate-bound, outward-facing occluded conformation toward an inward-facing open state. These hitherto unknown, large scale conformational changes in functionally important transmembrane segments, observed for LeuT in detergent-solubilized form and when embedded in a native like phospholipid bilayer, could be of physiological relevance for the translocation process. PMID- 29756039 TI - Artificial 3D hierarchical and isotropic porous polymeric materials. AB - Hierarchical porous materials that replicate complex living structures are attractive for a wide variety of applications, ranging from storage and catalysis to biological and artificial systems. However, the preparation of structures with a high level of complexity and long-range order at the mesoscale and microscale is challenging. We report a simple, nonextractive, and nonreactive method used to prepare three-dimensional porous materials that mimic biological systems such as marine skeletons and honeycombs. This method exploits the concurrent occurrence of the self-assembly of block copolymers in solution and macrophase separation by nucleation and growth. We obtained a long-range order of micrometer-sized compartments. These compartments are interconnected by ordered cylindrical nanochannels. The new approach is demonstrated using polystyrene-b-poly(t-butyl acrylate), which can be further explored for a broad range of applications, such as air purification filters for viruses and pollution particle removal or growth of bioinspired materials for bone regeneration. PMID- 29756038 TI - Phase behaviors of colloidal analogs of bent-core liquid crystals. AB - Bent-core liquid crystal (LC) molecules are known to form mesophases with fascinating polar order and supramolecular chirality despite the achiral nature of the mesogens. The assembly of colloidal particles with geometrical similarity to bent-core molecular mesogens not only provides new insights into the physical behaviors of atoms or molecules but also leads to new materials with broad applications. Despite tremendous progress in colloidal synthesis and assembly, there has been a lack of colloidal model systems of bent-core molecular mesogens for LC property discovery and application development. This article describes a systematic study on the phase behaviors of colloidal analogs of bent-core LC mesogens in both experiments and simulations. We demonstrated that bent rods with controlled bending angle (alpha) and aspect ratio (L/D, with L and D as the length and diameter of each rod arm, respectively) can spontaneously assemble into several typical banana phases including smectic A, smectic C, synclinic tilted antiferroelectric-like smectic, and twist smectic phases, resembling bent core LC molecules. The formation and transition of these phases were found to be strongly dependent on the geometric parameters of rods. Phase diagrams were developed to illustrate the existence and stability range of all the LC phases in alpha and L/D space. This work opens the door to the development of novel complex types of molecular or colloidal self-organization and new functional materials with electro-optical or nonlinear optical properties. PMID- 29756041 TI - A novel method of identifying motor primitives using wavelet decomposition. AB - This study reports a new technique for extracting muscle synergies using continuous wavelet transform. The method allows to quantify coincident activation of muscle groups caused by the physiological processes of fixed duration, thus enabling the extraction of wavelet modules of arbitrary groups of muscles. Hierarchical clustering and identification of the repeating wavelet modules across subjects and across movements, was used to identify consistent muscle synergies. Results indicate that the most frequently repeated wavelet modules comprised combinations of two muscles that are not traditional agonists and span different joints. We have also found that these wavelet modules were flexibly combined across different movement directions in a pattern resembling directional tuning. This method is extendable to multiple frequency domains and signal modalities. PMID- 29756040 TI - Experimental two-dimensional quantum walk on a photonic chip. AB - Quantum walks, in virtue of the coherent superposition and quantum interference, have exponential superiority over their classical counterpart in applications of quantum searching and quantum simulation. The quantum-enhanced power is highly related to the state space of quantum walks, which can be expanded by enlarging the photon number and/or the dimensions of the evolution network, but the former is considerably challenging due to probabilistic generation of single photons and multiplicative loss. We demonstrate a two-dimensional continuous-time quantum walk by using the external geometry of photonic waveguide arrays, rather than the inner degree of freedoms of photons. Using femtosecond laser direct writing, we construct a large-scale three-dimensional structure that forms a two-dimensional lattice with up to 49 * 49 nodes on a photonic chip. We demonstrate spatial two dimensional quantum walks using heralded single photons and single photon-level imaging. We analyze the quantum transport properties via observing the ballistic evolution pattern and the variance profile, which agree well with simulation results. We further reveal the transient nature that is the unique feature for quantum walks of beyond one dimension. An architecture that allows a quantum walk to freely evolve in all directions and at a large scale, combining with defect and disorder control, may bring up powerful and versatile quantum walk machines for classically intractable problems. PMID- 29756042 TI - Skeletal Muscle Metrics on Clinical 18F-FDG PET/CT Predict Health Outcomes in Patients with Sarcoma. AB - The aim of this study was to determine the association of measures of skeletal muscle determined from 18F-FDG PET/CT with health outcomes in patients with soft tissue sarcoma. 14 patients (8 women and 6 men; mean age 66.5 years) with sarcoma had PET/CT examinations. On CTs of the abdomen and pelvis, skeletal muscle was segmented, and cross-sectional muscle area, muscle volume, and muscle attenuation were determined. Within the segmented muscle, intramuscular fat area, volume, and density were derived. On PET images, the standardized uptake value (SUV) of muscle was determined. Regression analyses were conducted to determine the association between the imaging measures and health outcomes including overall survival (OS), local recurrence-free survival (LRFS), distant cancer recurrence (DCR), and major surgical complications (MSC). The association between imaging metrics and pre-therapy levels of serum C-reactive protein (CRP), creatinine, hemoglobin, and albumin was determined. Decreased volumetric muscle CT attenuation was associated with increased DCR. Increased PET SUV of muscle was associated with decreased OS and LRFS. Lower muscle SUV was associated with lower serum hemoglobin and albumin. Muscle measurements obtained on routine 18F-FDG PET/CT are associated with outcomes and serum hemoglobin and albumin in patients with sarcoma. PMID- 29756043 TI - Surgical Management of Nephrolithiasis in the Bottlenose Dolphin: Collaborations Between the Urologist and Veterinarian. AB - Background: Cohorts of bottlenose (Tursiops truncatus) dolphins are at significant risk for nephrolithiasis development. However, effective surgical treatment has been limited due to absence of literature and also familiarity by both veterinarians and urologists. Recently a joint veterinarian and urology team were called to treat local bottlenose dolphins in San Diego, CA, and they performed several cases. The fund of knowledge from these cases is presented for future providers who may be asked to surgically treat these animals. Case Presentation: Two surgical kidney stone cases were performed by a joint veterinarian and physician team. An effective ureteroscopic stone removal was performed on a 39-year-old female bottlenose dolphin with 9.7 mm distal ureteral calculus. The second case involved laparoscopic ureterolithotomy on a 31-year-old male bottlenose dolphin with a 6-mm right distal ureteral calculus that previously failed retrograde ureteroscopic removal. The stone was not effectively removed laparoscopically as well due to failure to progress associated with operative machinery malfunction. The dolphin was ultimately euthanized. Conclusion: Despite suboptimal outcome in one case, extremely valuable lessons were learned during both cases. We present our surgical experiences, as well as pertinent anatomical differences, in these animals with the hope that this discussion will facilitate future surgical kidney stone treatment of dolphins. PMID- 29756045 TI - A Knowledge-Based Assessment of Dermatological Care for Transgender Women. AB - Dermatologic care plays an important role in the transitioning process for transgender women, with changes occurring to the skin from hormone therapy (HT) and gender affirming procedures. We sought to identify knowledge gaps in a group of transgender women pertaining to both skin and hair changes during the transitioning process. The study was conducted as a cross-sectional survey. Our results demonstrate potential gaps in knowledge that transgender women have regarding HT and gender affirming procedures. PMID- 29756046 TI - Hormonal Treatment of Transgender Women with Oral Estradiol. AB - Purpose: Maintaining cross-sex hormone levels in the normal physiologic range for the desired gender is the cornerstone of transgender hormonal therapy, but there are limited data on how to achieve this. We investigated the effectiveness of oral estradiol therapy in achieving this goal. Methods: We analyzed data on all transgender females seen in our clinic since 2008 treated with oral estradiol. We looked at the success of achieving serum levels of testosterone and 17-beta estradiol in the normal range on various doses of estradiol (with and without antiandrogens spironolactone and finasteride). Results: There was a positive correlation between estradiol dose and 17-beta estradiol, but testosterone suppression was less well correlated. Over 70% achieved treatment goals (adequate 17-beta estradiol levels and testosterone suppression) on 4 mg daily or more. Nearly a third of patients did not achieve adequate treatment goals on 6 or even 8 mg daily of estradiol. Spironolactone, but not finasteride, use was associated with impairment of obtaining desired 17-beta estradiol levels. Spironolactone did not enhance testosterone suppression, and finasteride was associated with higher testosterone levels. Conclusions: Oral estradiol was effective in achieving desired serum levels of 17-beta estradiol, but there was wide individual variability in the amount required. Oral estradiol alone was not infrequently unable to achieve adequate testosterone suppression. Spironolactone did not aid testosterone suppression and seemed to impair achievement of goal serum 17-beta estradiol levels. Testosterone levels were higher with finasteride use. We recommend that transgender women receiving estradiol therapy have hormone levels monitored so that therapy can be individualized. PMID- 29756044 TI - Gender Dysphoria in Adults: An Overview and Primer for Psychiatrists. AB - Regardless of their area of specialization, adult psychiatrists are likely to encounter gender-variant patients; however, medical school curricula and psychiatric residency training programs devote little attention to their care. This article aims to assist adult psychiatrists who are not gender specialists in the delivery of respectful, clinically competent, and culturally attuned care to gender-variant patients, including those who identify as transgender or transsexual or meet criteria for the diagnosis of Gender Dysphoria (GD) as defined by The Diagnostic and Statistical Manual of Mental Disorders (5th edition). The article will also be helpful for other mental health professionals. The following areas are addressed: evolution of diagnostic nosology, epidemiology, gender development, and mental health assessment, differential diagnosis, treatment, and referral for gender-affirming somatic treatments of adults with GD. PMID- 29756047 TI - Complete Mitochondrial Genomes of Baikal Oilfishes (Perciformes: Cottoidei), Earth's Deepest-Swimming Freshwater Fishes. AB - Sculpins are predominantly benthic sit-and-wait predators that inhabit marine and freshwaters of the Northern Hemisphere. In striking contrast to riverine relatives, sculpins endemic to Lake Baikal have diversified in both form and function, with multiple taxa having adaptations for pelagic and bathyal niches within the world's deepest lake. Baikal Oilfishes (Comephorus spp.) represent a highly apomorphic taxon with unique skeletal morphology, soft anatomy, and reproductive ecology. Selection for novel behavior and life history may be evident in genes responsible for organismal energy balance, including those encoding subunits of the electron transport chain. Complete mitochondrial genomes were sequenced for the Big Baikal Oilfish (Comephorus baicalensis) and Little Baikal Oilfish (Comephorus dybowskii). Mitochondrial genomes encode genes essential for electron transport, and data provided here will complement ongoing investigations of genome-to-phenome maps for teleost respiration and metabolism. Phylogenetic analyses including oilfish mitogenomes and all publicly available cottoid representative sequences are largely concordant with previous studies. PMID- 29756048 TI - Alcohol Upregulation of CYP2A5: Role of Reactive Oxygen Species. AB - Hepatic cytochrome P450 (CYP) 2E1 and CYP2A5 activate many important drugs and hepatotoxins. CYP2E1 is induced by alcohol, but whether CYP2A5 is upregulated by alcohol is not known. This article reviews recent studies on the induction of CYP2A5 by alcohol and the mechanism and role of reactive oxygen species (ROS) in this upregulation. Chronic feeding of ethanol to wild type mice increased CYP2A5 catalytic activity and protein and mRNA levels. This induction was blunted in CYP2E1 knockout mice and by a CYP2E1 inhibitor, but was restored in CYP2E1 knockin mice, suggesting a role for CYP2E1 in the induction of CYP2A5 by alcohol. Since CYP2E1 actively generates ROS, the possible role of ROS in the induction of CYP2A5 by alcohol was determined. ROS production was elevated by ethanol treatment. The antioxidants N-acetyl cysteine and vitamin C lowered the alcohol induced elevation of ROS and blunted the alcohol-mediated induction of CYP2A5. These results suggest that ROS play a novel role in the crosstalk between CYP2E1 and CYP2A5. Alcohol treatment activated nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor which up-regulates expression of CYP2A5. The antioxidants blocked the activation of Nrf2. The alcohol-induced elevation of CYP2A5, but not CYP2E1, was lower in Nrf2 knockout mice. We propose that increased generation of ROS from the alcohol-induced CYP2E1 activates Nrf2, which subsequently up-regulates the expression of CYP2A5. Thus, a novel consequence of the alcohol-mediated induction of CYP2E1 and increase in ROS is the activation of redox-sensitive transcription factors, such as Nrf2, and expression of CYP2A5. Further perspectives on this alcohol-CYP2E1-ROS-Nrf2-CYP2A5 pathway are presented. PMID- 29756050 TI - Effects of Arginine Vasopressin on Migration and Respiratory Burst Activity in Human Leukocytes. AB - Arginine vasopressin can bind to high-affinity vasopressin V1a receptors in human leukocytes. This study aims to investigate the effects of arginine vasopressin on migration and chemotaxis of neutrophils and oxygen free radical release by human leukocytes. Neutrophils and monocytes were obtained from peripheral blood samples of ten healthy volunteers. Leukocyte migration was microscopically assessed in a modified 48-blind well microchemotaxis chamber, and respiratory burst activity was estimated using 2',7'-dichlorofluorescin diacetate in descending concentrations of arginine vasopressin. Arginine vasopressin stimulates migration of monocytes and neutrophils depending on concentration and on interaction with other chemoattractants. The strongest chemotactic responses of monocytes to arginine vasopressin were observed in the micro and nanomolar range and in the nanomolar range for neutrophils (p<0.001). Pre-incubation of leukocytes with arginine vasopressin decreased migration of leukocytes in a dose-dependent manner. Arginine vasopressin did not stimulate release of oxygen free radicals by neutrophils. Arginine vasopressin stimulates in a dose-dependent manner the migration of monocytes and neutrophils. However, pre-incubation of leukocytes with arginine vasopressin decreased the migratory response of monocytes and neutrophils to other chemoattractants. These findings may be of importance in the treatment regimen of patients with septic shock. PMID- 29756049 TI - Cost-Effectiveness of Treatments for Genotype 1 Hepatitis C Virus Infection in non-VA and VA Populations. AB - Background: Chronic hepatitis C viral (HCV) infection affects millions of Americans. Healthcare systems face complex choices between multiple highly efficacious, costly treatments. This study assessed the cost-effectiveness of HCV treatments for chronic, genotype 1 HCV monoinfected, treatment-naive individuals in the Department of Veterans Affairs (VA) and general U.S. healthcare systems. Methods: We conducted a decision-analytic Markov model-based cost-effectiveness analysis, employing appropriate payer perspectives and time horizons, and discounting benefits and costs at 3% annually. Interventions included: Sofosbuvir/ledipasvir (SOF-LDV); ombitasvir/paritaprevir/ritonavir/dasabuvir (3D); sofosbuvir/simeprevir (SOF-SMV); sofosbuvir/pegylated interferon/ribavirin (SOF-RBV-PEG); boceprevir/pegylated interferon/ribavirin (BOC-RBV-PEG); and pegylated interferon/ribavirin (PEG-RBV). Outcomes were sustained virologic response (SVR), advanced liver disease, costs, quality adjusted life years (QALYs), and incremental cost-effectiveness. Results: SOF-LDV and 3D achieve higher SVR rates compared to older regimens and reduce advanced liver disease (>20% relative to no treatment), increasing QALYs by over 2 years per person. For the non-VA population, at current prices ($5,040 per week for SOF-LDV and $4,796 per week for 3D), SOF-LDV's lifetime cost ($293,370) is $18,000 lower than 3D's because of its shorter treatment duration in subgroups. SOF-LDV costs $17,100 per QALY gained relative to no treatment. 3D costs $208,000 per QALY gained relative to SOF-LDV. Both dominate other treatments and are even more cost-effective for the VA, though VA aggregate treatment costs still exceed $4 billion at SOF-LDV prices of $3,308 per week. Drug prices strongly determine relative cost effectiveness for SOF-LDV and 3D; With sufficient price reductions (approximately 20-30% depending on the health system), 3D could be cost-effective relative to SOF-LDV. Limitations include the lack of long-term head-to-head regimen effectiveness trials. Conclusions: New HCV treatments are cost-effective in multiple healthcare systems if trial-estimated efficacy is achieved in practice, though, at current prices, total expenditures could present substantial challenges. PMID- 29756051 TI - Penile Calciphylaxis in a Patient with End-stage Renal Disease: A Case Report and Review of the Literature. AB - Penile calciphylaxis is a rare cause of penile gangrene that presents in patients with end-stage renal disease. The rates of comorbidity and mortality of penile calciphylaxis are extremely high. Unlike other penile gangrene, such as Fournier's gangrene, the benefit of aggressive surgical therapy is controversial. Here we present a case of penile calciphylaxis in a 43-year-old man with end stage renal disease on hemodialysis. He received total penectomy but died due to multisystem complications 2 weeks after surgery. We review the literature on the management options and outcomes in patients with penile calciphylaxis. PMID- 29756052 TI - Serum CA72-4 as a Biomarker in the Diagnosis of Colorectal Cancer: A Meta analysis. AB - : The purpose of this meta-analysis was to investigate the serum CA72-4 as a biomarker in the diagnosis of colorectal cancer by pooling the open published data. METHODS: An electronic search of databases Pubmed, Medline, Web of Science, Cochrane Embase CBM, and CNKI were performed by two reviewers (Han Yanqing, Dong Cheng) independently to identify the studies relevant to serum CA72-4 as a biomarker in the diagnosis of colorectal cancer. The patient number of true positive(tp), false positive(fp), false negative(fn) and true negative(tn) were extracted from each included study. The diagnostic performance of serum CA72-4 as a biomarker in the diagnosis of colorectal cancer was assessed by pooled sensitivity, specificity and hierarchical summary receiver operating characteristic curve (HSROC). All the data was pooled by MetaDiSc 1.4 and Stata/SE 11.0 statistical software. Results A total of 22 studies with 2474 colorectal patients and 1576 controls were included in the present study and meta analysis. The combined diagnostic sensitivity and specificity were 0.50 (95%CI:0.48-0.52) and 0.86 (95%CI:0.84-0.88) for serum CA72-4 as a biomarker in the diagnosis of colorectal cancer. The pooled positive and negative likelihood ratio were 3.41(95%CI:2.57-4.53) and 0.62(0.55-0.71). The pooled area under the ROC curve (AUC) was 0.73. Deeks'funnel plot and Egger's line regression test (p=0.49) showed no significant publication bias in the present meta-analysis. Conclusion Due toits low diagnostic sensitivity, the diagnostic performance of serum CA72-4 as a biomarker for colorectal cancer screening is limited. PMID- 29756053 TI - Association Between Uric Acid and Metabolic Syndrome in Elderly Women. AB - Objective: To investigate the relationship between uric acid and metabolic syndrome (MetS) in elderly women. Methods: A total of 468 women aged >=60 years participating in a health examination were enrolled. The association between uric acid and MetS and its individual variables was evaluated by univariate and multivariate logistic regression models. Results: A dose-response relationship was observed for the prevalence of MetS and uric acid quartiles. Subjects in the second, third and fourth quartile of uric acid had a 2.23-fold, 2.25-fold and 4.41-fold increased risk, respectively, of MetS than those in the first uric acid quartile (p for trend <0.001). Furthermore, each 1 mg/dl increment of serum uric acid level had a 1.38-fold increased risk of MetS (OR 1.38; 95% CI, 1.14-1.69; p=0.001). Conclusions: Our present study demonstrated that elevated uric acid was positively associated with the prevalence of MetS in elderly women. Further random control trials are needed to elucidate the effectiveness of treatment of hyperuricaemia in reducing the incidence of MetS in elderly women. PMID- 29756054 TI - Distinct Expression and Prognostic Value of MS4A in Gastric Cancer. AB - Gastric cancer has high malignancy and early metastasis, which lead to poor survival rate. In this study, we assessed the expressions and prognostic values of MS4A family, a newly recently discovered family, by two online dataset, GEPIA and Kaplan Meier-plotter. From these results eight members, MS4A2, MS4A6, MS4A7, MS4A8, MS4A14, MS4A15, TMEM176A and TMEM176B showed positive expression in gastric cancer or normal tissues, and these genes were screened for further analysis of prognostic values. We observed that low mRNA expressions of MS4A2, MS4A7, MS4A14, MS4A15, TMEM176A and TMEM176B were correlated with better overall survival (OS) in all gastric cancer patients, while high mRNA expression of MS4A6 was observed to be associated with good prognosis. MS4A8's high mRNA level was correlated to better OS in diffuse gastric cancer patients. Further, we estimated prognostic values of MS4A family in gastric cancer patients with different clinic pathological features, including clinical stages, differentiation level, lymph node status and HER2 status. Our results indicate that these eight MS4A members can estimate prognosis in patients with different pathological groups. In conclusion, MS4A family members are potential biomarkers, and may contribute to tumor progression in gastric cancer. PMID- 29756055 TI - The Right Author in the Right Journal at the Right Time: future perspectives. PMID- 29756056 TI - Spring recoil and supraglottic airway devices: lessons from the law of conservation of energy. PMID- 29756057 TI - Clinical application of limiting laryngeal mask airway cuff pressures utilizing inflating syringe intrinsic recoil. AB - Background: Overinflation of the laryngeal mask airway (LMA) cuff may cause many of the complications associated with the use of the LMA. There is no clinically acceptable (cost effective and practical) method to ensure cuff pressure is maintained below the manufacturer's recommended maximum value of 60 cm H2O (44 mmHg). We studied the use of the intrinsic recoil of the LMA inflating syringe as an effective and practical way to limit cuff pressures at or below the manufacturer's recommended values. Methods: We enrolled 332 patients into three separate groups: LMAs inserted and inflated per standard practice at the institution with only manual palpation of the pilot balloon; LMA cuff pressures measured by a pressure transducer and reduced to < 60 cm H2O (44 mmHg); and LMA intra-cuff pressure managed by the intrinsic recoil of the syringe. Results: There were no statistically significant differences between the pressure transducer group and the syringe recoil group for initial cuff pressure or cuff pressure 1 hour after surgery. Both the syringe recoil group and pressure transducer group were less likely than the standard practice group to have sore throat and dysphagia 1 hour after surgery. These differences remained 24 hours after surgery. Conclusions: Syringe recoil provides an efficient and reproducible method similar to manometry in preventing overinflation of the LMA cuff and decreasing the incidence of postoperative laryngopharyngeal complications. PMID- 29756058 TI - Pupillary dilation reflex and pupillary pain index evaluation during general anaesthesia: a pilot study. AB - Background: Pupillary response by pupillary dilatation reflex (PDR) is a robust reflex, even measurable during general anaesthesia. However, the ability of infrared pupillometry to detect PDR differences obtained by intraoperative opioid administration in anaesthesized patients remains largely unknown. We analyzed the performance of automated infrared pupillometry in detecting differences in pupillary dilatation reflex response by a inbuilt standardized nociceptive stimulation program in patients under general anesthesia with a standardized propofol/fentanyl scheme. Methods: In this single center, interventional cohort study 38 patients (24-74 years) were enrolled. Patients were anesthetized with propofol until loss of consciousness. Two dynamic pupil measurements were performed in each patient (before opioid administration and after opioid steady state). Automated infrared pupillometry was used to determine PDR during nociceptive stimulations (10-60 mA) applied by a inbuilt pupillary pain index protocol (PPI) to the skin area innervated by the median nerve. Increasing stimulations by protocol are device specific and automatically performed until pupil dilation of > 13%. Pupil characteristics, blood pressure, heart rate values were collected. Results: After opioid administration, patients needed a higher stimulation intensity (45.26 mA vs 30.79 mA, p = 0.00001). PPI score showed a reduction after analgesic treatment (5.21 vs 7.68, p = 0.000001), resulting in a 32.16% score reduction. Conclusions: PDR via automated increased tetanic stimulation may reflect opioid effect under general anaesthesia. Further research is required to detect possible confounding factors such as medication interaction and optimization of individualized opioid dosage. PMID- 29756059 TI - Pre-selection of primary intubation technique is associated with a low incidence of difficult intubation in patients with a BMI of 35 kg/m2 or higher. AB - Background: The incidence of difficult intubation (DI) in obese patients may reach a two-digit figure. No studies have assessed the effect of primary use of special intubation devices on lowering the incidence of DI. We assessed the effect of primary selection of special intubation techniques on the incidence of DI in patients with a BMI of 35 kg/m2 or higher. Patients and methods: Data from 546 patients with a BMI of 35 kg/m2 or higher who underwent bariatric surgery at Wolfson Medical Center from 2010 through 2014 was retrospectively extracted and analyzed for demographics, predictors of DI and intubation techniques employed. Difficult intubation was defined as the presence of at least one of the followings: laryngoscopy grade 3 or 4, need for >1 laryngoscopy or intubation attempt, need for changing the blade size, failed direct laryngoscopy (DL), difficult or failed videolaryngoscopy (VL-Glidescope), difficult or failed awake fiberoptic intubation (AFOI) and using VL or awake AFOI as rescue airway techniques. Primary intubation techniques were direct DL, VL and AFOI. We correlated the predictors of DI with the actual incidence of DI and with the choice of intubation technique employed. Results: The overall incidence of DI was 1.6% (1.5% with DL vs. 2.2 with VL + AFOI, p = 0.61). With logistic regression analysis, age was the only significant predictor of DI. Predictors of DI that affected the selection of VL or AFOI as primary intubation tools were Mallampati class 3 or 4, limited neck movement, age, male gender, body mass index and obstructive sleep apnea syndrome. Conclusion: The lower incidence of DI in our study group may stem from the primary use of special intubation devices, based on the presence of predictors of DI. PMID- 29756060 TI - Factors associated with acute and chronic pain after inguinal herniorraphy. AB - Objectives: The aim of this study was to analyse the relationship between types of anaesthesia, patients' demographic variables, preoperative emotional states and the prevalence of postoperative pain. Method: In this randomized prospective study, postoperative pain was assessed in 100 patients, who were ASA (American Society of Anaesthesiologist) I-II and between 18-65 years old, undergoing inguinal herniorrhaphy with either general or spinal anaesthesia. In addition, postoperative pain compared with patients' demographic properties and psychological conditions in each group was also considered. Acute pain was evaluated at 1, 2, 4, 6, 12 and 24th hours with the Numerical Rating Scale (NRS) and chronic neuropathic pain was at 1, 2 and 3rd months with Douleur Neuropathique 4 Questions (DN4). All patients were treated with the same analgesics after operation. Results: Group spinal anaesthesia had lower acute pain at 1 and 2nd hours but they felt more severe pain at the 24th hour. Also patients' anxieties were correlated with acute and chronic postoperative pain. Ten patients complained about postoperative chronic pain after 3 months and there was no significant difference between groups. Conclusion: Spinal anaesthesia decreased acute pain intensity at the first postoperative hours. Patients with anxiety felt high pain levels and they had an increased chronic pain prevalence. PMID- 29756061 TI - Anaesthesiology trainees and their needs: a Romanian perspective. Results from a European survey. AB - Anaesthesiology training is going through continuous transformations worldwide. Recent data from a European Survey on anaesthesiology postgraduate trainees and their concerns have been published for the first time, following an initiative by the European Society of Anaesthesiology. Among the responders of this survey, 10.8% were represented by Romanian trainees. The main needs of the Romanian anaesthesiology trainees who completed the questionnaire were, in descending order educational contents/EDAIC, technical skills, exchange programmes, residency workload, residency costs and autonomy transition. Another observation coming from the analysed data is that Romanian anaesthesiologists in training are highly concerned and interested in the field of intensive care medicine. The results also pinpoint to the high costs associated with continuous medical education, leading to a high incentive for workforce migration. PMID- 29756062 TI - Effect of preoperative gabapentin and acetaminophen on opioid consumption in video-assisted thoracoscopic surgery: a retrospective study. AB - Background: Patients undergoing video-assisted thoracoscopic surgery (VATS) are particularly vulnerable to opioid-induced sedation and hypoventilation. Accordingly, reducing opioid consumption in these patients is a primary goal of multimodal analgesic regimens. Although administration of preoperative gabapentin and acetaminophen has been shown to decrease postoperative opioid consumption in other surgeries, this approach has not been studied in VATS lobectomy. Our objective was to examine the impact of the addition of preoperative gabapentin and acetaminophen to a VATS lobectomy multimodal analgesic plan on postoperative opioid consumption, nausea/vomiting, and sedation. Methods: With IRB approval, we performed a retrospective chart review of patients who underwent VATS lobectomy at a single center between 2015 and 2016 to identify those that received preoperative gabapentin and acetaminophen and those that received neither. Opioid consumption in the first 24 hours postoperatively was converted to oral morphine equivalents (OMEQs). Postoperative sedation was evaluated using Aldrete scores and the percentage of patients requiring antiemetics in the first 24 hours was also examined. Results: There were 133 patients who were opioid naive: 31 received preoperative gabapentin and acetaminophen and 102 received neither. Median 24 hour postoperative opioid consumption was lower but not statistically significant in the gabapentin and acetaminophen group vs. neither (36 mg vs. 45 mg, p = 0.08). Notably, there was a change in the distribution of opioid consumption, with no patients in the gabapentin and acetaminophen group requiring more than 200 mg OMEQ in the first 24 hours postoperatively. No significant difference in postoperative nausea/vomiting or sedation was observed. Conclusions: The addition of preoperative gabapentin and acetaminophen to a VATS lobectomy multimodal analgesic regimen reduces the incidence of high dose postoperative opioid consumption without observed negative side effects. PMID- 29756063 TI - The Carrico index is the parameter that guides the requirement of oxygen in the postoperative period in patients undergoing head and neck surgery under general anaesthesia: a cross-sectional study. AB - Background & aims: Altered lung function and consequent decrease in oxygenation has been linked to the duration of anaesthesia. This necessitates oxygen monitoring and supplementation in the perioperative period. But, evidence is lacking regarding the parameter that guides best the oxygen supplementation in the postoperative period and the parameter that correlates best with the duration of anaesthesia. Methods: Adult patients scheduled for head & neck surgery under general anaesthesia were recruited. Two radial arterial blood samples one at pre induction and the other at one hour after extubation were obtained. Primary outcome measures were partial pressure of oxygen (PaO2), saturation (SpO2), arterial oxygen content (CaO2) and Carrico index (PaO2/FiO2) and their relation with duration of anaesthesia. Results: Data from 112 patients showed a hypoxaemia incidence of 11.6%. We observed a drop in the mean CaO2 and haemoglobin concentration but a rise in the mean PaO2 at recovery. The mean PaO2/FiO2 deteriorated by 225.65 +/- 72.46 (95% CI 367.66, 83.64, p = 0.000) at recovery and there was a significant correlation (r = 0.2, p = 0.03) between duration of anaesthesia and decrease in PaO2/FiO2 at recovery with a regression coefficient of 0.27 (95% CI 0.02, 0.50). Conclusions: The Carrico index was proven to be the best parameter which needs to be monitored perioperatively to detect the alteration in the gaseous exchange in patients undergoing general anaesthesia for head and neck surgery. There is a positive correlation between the decrease in the Carrico index and the duration of anaesthesia especially when it is prolonged beyond 150 minutes. PMID- 29756064 TI - Neuromuscular monitoring: an update. AB - This review makes an advocacy for neuromuscular blockade monitoring during anaesthesia care, by: (i) describing the fundamental principles of the methods currently available, at the same time emphasizing quantitative recording measurements; (ii) describing the different ways in which muscles respond to the effect of neuromuscular blockade and their use in clinical practice; (iii) presenting results of different studies on timing and agents of neuromuscular block reversal, including a recommendation for sugammadex use and experimental results with calabadion and (iv) in the end emphasizing the need for implementing neuromuscular monitoring as a practice that should be used every time a neuromuscular block is required. PMID- 29756065 TI - The effects of mechanical ventilation on the quality of sleep of hospitalised patients in the Intensive Care Unit. AB - Aim: To examine the effects of mechanical ventilation on the quality of sleep in patients in the intensive care unit (ICU) using recent and relevant literature. Methods: To verify the examined objective, the results of the analysis of available original scientific works have been used including defined inclusion/exclusion criteria and search strategy. Appropriate works found were analysed further. The applied methodology was in line with the general principles of Evidence-Based Medicine. The following literary databases were used: CINAHL, Medline and gray literature: Google Scholar. Results: A total of 91 trials were found. Eleven of these relevant to the follow-up analysis were selected: all trials were carried out under real ICU conditions and the total of 192 patients were included in the review. There is an agreement within all trials that sleep in patients requiring mechanical ventilation is disturbed. Most reviewed trials have shown that mechanical ventilation is probably not the main factor causing sleep disturbances, but an appropriate ventilation strategy can significantly help to improve its quality by reducing the frequency of the patient-ventilator asynchrony. Conclusion: Based on the analysis, it appears that an appropriate ventilation mode setting can have a beneficial effect on the quality of sleep in ICU patients. PMID- 29756067 TI - Concurrent intraoperative uterine rupture and placenta accreta. Do preoperative chronic hypertension, preterm premature rupture of membranes, chorioamnionitis, and placental abruption provide warning to this rare occurrence? AB - Uterine and placental pathology can be a major cause of morbidity and mortality in the parturient and infant. When presenting alone, placental abruption, uterine rupture, or placenta accreta can result in significant peripartum hemorrhage, requiring aggressive surgical and anesthetic management; however, the presence of multiple concurrent uterine and placental pathologies can result in significant morbidity and mortality. We present the anesthetic management of a parturient who underwent an urgent cesarean delivery for non-reassuring fetal tracing in the setting of chronic hypertension, preterm premature rupture of membranes, and chorioamnionitis who was subsequently found to have placental abruption, uterine rupture, and placenta accreta. PMID- 29756066 TI - Postanaesthetic shivering - from pathophysiology to prevention. AB - Postoperative shivering is a common complication of anaesthesia. Shivering is believed to increase oxygen consumption, increase the risk of hypoxemia, induce lactic acidosis, and catecholamine release. Therefore, it might increase the postoperative complications especially in high-risk patients. Moreover, shivering is one of the leading causes of discomfort for postsurgical patients. Shivering is usually triggered by hypothermia. However, it occurs even in normothermic patients during the perioperative period. The aetiology of shivering has been understood insufficiently. Another potential mechanism is pain and acute opioid withdrawal (especially with the use of short-acting narcotics). Besides that shivering is poorly understood, the gold standard for the treatment and prevention has not been defined yet. Perioperative hypothermia prevention is the first method to avoid shivering. Many therapeutic strategies for treating shivering exist and most are empiric. Unfortunately, the overall quality of the antishivering guidelines is low. Two main strategies are available: pharmacological and non-pharmacological antishivering methods. The combination of forced-air warming devices and intravenous meperidine is the most validated method. We also analysed different medications but final conclusion about the optimal antishivering medication is difficult to be drawn due to the lack of high quality evidence. Nevertheless, control of PS is possible and clinically effective with simple pharmacological interventions combined with non pharmacological methods. However, to be consistent with the most up-to-date, evidence-based practice, future antishivering treatment protocols should optimize methodological rigor and transparency. PMID- 29756068 TI - Patient Satisfaction and Treatment Adherence for Urban Adolescents and Young Adults with Pelvic Inflammatory Disease. AB - Objectives: Urban adolescents with pelvic inflammatory disease (PID) often seek care in emergency departments (ED). This study examines the effect of the ED patient experience - wait time (WT) and length of stay (LOS) - on satisfaction and medication adherence among urban adolescents with PID. Methods: Adolescents with PID were enrolled in an urban teaching hospital ED. Chart data were matched with 2-week interview queries about satisfaction and medication adherence. Chi square and logistic regression analyses evaluated the relationships between WT, LOS, provider type, satisfaction, and medication adherence. Results: Of 83 participants, 96% report satisfaction with care, but only 45% report medication adherence. Mean WT was 55 minutes and mean LOS 200 minutes. Patients with higher LOS were less adherent with medication; this relationship became non-significant after adjustments. Patients seen by trainees had much longer LOS, but no differences in satisfaction or medication adherence. Conclusions: Urban adolescents with PID report satisfaction with ED care despite prolonged LOS and medication adherence is poor. Optimization of ED workflows may improve outcomes in young women with PID. PMID- 29756069 TI - Implementation of depression and anxiety screening in patients undergoing radiotherapy. AB - Anxiety and depression are disabling, underdiagnosed issues that affect the management of oncology patients. Until recently, there has been no standard protocol for screening and treating these ailments at our cancer centre. The purpose of this institutional review board-approved study was to analyse the implementation of a screening tool in our clinical workflow with the aim of screening over 90% of patients and increasing referrals to mental health services by 50%. PMID- 29756070 TI - Reducing severe hypoglycaemia in hospitalised patients with diabetes: Early outcomes of standardised reporting and management. AB - Background: Severe hypoglycaemic events (HGEs) in hospitalised patients are associated with poor outcomes and prolonged hospitalization. Systematic, coordinated care is required for acute management and prevention of HGEs; however, studies evaluating quality control efforts are scarce. Objective: To investigate the effectiveness of system-based interventions to improve management response to HGEs. Methods: System-based interventions were designed and implemented following a root cause analysis of HGE in adult patients with diabetes from two general medical wards with the highest incidence of HGE. Interventions included electronic medical record programming for a standardised order set for basal-bolus insulin regimen and hypoglycemia protocol, automated dextrose order, automated MD notification, and recommendation for endocrine consultation after two critical HGEs. The Pyxis MedStation was programmed to alert nurses to recheck blood glucose 15 min after the treatment. A card with the HGE management protocol was attached to each provider's ID badge and educational seminars were given to all providers. Main outcomes and measures: Primary outcomes were to evaluate median time from HGE (glucose <50 mg/dL) to euglycemia (>100 mg/dL), and time from HGE to follow-up finger-stick (FS) testing preintervention and postintervention. Secondary outcomes were cumulative incidence of HGEs, recurrent hypoglycemia, rate of physician notification and use of standardised treatments among adults with diabetes on the two general medical wards. Results: Among hospitalised adults with diabetes and HGE, median time from HGE to euglycemia declined from 225+/-46 min preintervention to 87+/-26 min postintervention (p=0.03). Median time from HGE to next FS testing also declined (76+/-14 min to 28+/-10 min, p<0.001). Standardised treatment administration for HGE improved significantly from 34% (12/35) to 97% (36/37); physician notification rate improved significantly from 51% (18/35) to 78% (29/37).Among hospitalised adults with diabetes, incidence of HGE decreased from 12% (35/295) over 3 months (preintervention period) to 6% (37/610) over 6 months (postintervention period) (p<0.001), while recurrent HGE did not show significant differences (37% (13/35) to 24% (9/37), p=0.09). Conclusions: System-based interventions had a clinically important impact on decreasing time from HGE to euglycemia and to next FS testing. This hypoglycemia bundle of care may be applied and tested in other community hospitals to improve patient safety. PMID- 29756071 TI - Improving the quality of physical health monitoring in CAMHS for children and adolescents prescribed medication for ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterised by a persistent, pervasive pattern of inattention, impulsivity and hyperactivity. Stimulant medication such as methylphenidate has an established evidence base in the treatment of children and adolescents with ADHD. However, it is also associated with a risk of side effects which may include decreased appetite, increased blood pressure and possible reduced growth. Monitoring physical health in children and adolescents prescribed medication for ADHD is a key clinical responsibility and includes a number of parameters as outlined in the National Institute for Health and Care Excellence Guidelines. Ascertaining the centiles of physical observations is essential to put these into developmental context and accurately inform treatment decisions. This quality improvement project aimed to improve physical health monitoring in children and adolescents prescribed stimulant medication for ADHD within a large specialist urban inner-city Child and Adolescent Mental Health Service (CAMHS) in South London and Maudsley NHS Foundation Trust. Baseline data were obtained to establish the quality of physical monitoring including blood pressure, height, weight and centiles. Targeted interventions included the development of a novel web-based application designed to calculate and record centiles. We report an improvement in total proportion compliance with physical health monitoring from 24% to 75%. The frequency of recording baseline blood pressure centiles increased from 0% to 62%; recording baseline height centiles increased from 37% to 81% and recording baseline weight centiles increased from 37% to 81%. Improvement in the delivery of high-quality care was achieved and sustained through close collaboration with clinicians involved in the treatment pathway in order to elicit and respond effectively to feedback for improvement and codevelop interventions which were highly effective within the clinical system. We believe this model to be replicable in other CAMHS services and ADHD clinics to improve the delivery of high-quality clinical care. PMID- 29756073 TI - Purpuric Eruption: Sign of Infected Bypass Graft. PMID- 29756072 TI - Managing antibiotics wisely: a quality improvement programme in a tertiary neonatal unit in the UK. AB - Microbial resistance to antibiotics is a serious global health problem compounded by antibiotic overuse and limited investment in new antibiotic research. Inappropriate perinatal antibiotic exposure is increasingly linked to lifelong adverse outcomes through its impact on the developing microbiome. Antibiotic stewardship may be the only effective preventative strategy currently available. As the first tertiary neonatal unit in the UK to collaborate in an international quality improvement programme (QIP) with Vermont Oxford Network (VON), we present the results of our antibiotic stewardship initiative. The QIP was officially launched in January 2016 and aimed to reduce antibiotic usage rate (AUR) by 20% of baseline by 31st December 2016 without compromising patient safety. A multidisciplinary team of professionals and parent representatives shared good practices and improvement strategies through international webinars and local meetings, devised uniform data collection methodology and implemented a number of carefully selected 'Plan-Do-Study-Act' cycles. Run charts were used to present data and, where appropriate, statistical analysis undertaken to compare outcomes. The QIP resulted in a sustained reduction in AUR from a baseline median of 347 to 198 per 1000 patient-days (a reduction of 43%). The proportion of culture negative sepsis screens where antibiotics were stopped within 36-48 hours increased consistently from a baseline of 32.5% to 91%. The antibiotic days per patient at discharge reduced from a median of 3 to 2 days, and there was a reduction in practice variation. Our annual mortality and necrotising enterocolitis rates for the VON cohort (<30 weeks or <1500 g) were the best ever recorded, 5.5% and 1.4%, respectively. Audits confirmed a high level of staff and family awareness of the QIP. The QIP achieved a sustained reduction in antibiotic use without compromising patient safety. Our challenge is to sustain this improvement safely. PMID- 29756074 TI - Discovery of small molecules through pharmacophore modeling, docking and molecular dynamics simulation against Plasmodium vivax Vivapain-3 (VP-3). AB - Vivapain-3(VP-3) protein is a family of cysteine rich proteases of malaria parasite is extensively reported to participate in a range of wide cellular processes including survival. VP-3 of plasmodium recognized as an attractive drug target in vector-borne diseases like malaria. In the present study we robust a homology model of VP-3 protein and generated the pharmacophore based models adapted to screen the best drug like compounds from PubChem database. Our results finds the fourteen best lead molecules were mapped with core pharmacophore features of VP-3 and top hits were further evaluated by molecular dynamics simulation and docking studies. Based on the molecular dynamics simulation and docking results and binding vicinity of ligand molecules, top five i.e., CID 74427945, CID 74427946, CID 360883, CID193721 and CID 51416859 showed the best docking scores with good molecular interactions against VP-3. Furthermore in silico ADMET and in vitro assays clearly exhibited that out of five three CID74427946, CID74427945 and CID360883 ligand molecules showed the best promising inhibition against VP-3. The present study believed to provide significant information of potential ligand inhibitors against VP-3 to design and develop the next generation malaria therapeutics through computational approach. PMID- 29756075 TI - Alterations in amino acid metabolism during growth by Staphylococcus aureus following exposure to H2O2 - A multifactorial approach. AB - Temperature and pH are known to vary in a wound site due to the immune response and subsequent healing processes. This study used a multifactorial design to examine the cellular responses of Staphylococcus aureus to hydrogen peroxide (0 100 mM) when bacteria were grown in temperatures of 37 +/- 2 degrees C and pH 7 +/- 1, conditions potentially encountered in wound sites. A centroid sample was included in the design which represented the mid-point values of all three environmental parameters (37 degrees C, pH 7, 50 mM H2O2). Cytoplasmic extracts and corresponding medium supernatants were analysed for amino acid composition by gas chromatography. Exposures of S. aureus to H2O2 during the inoculation process resulted in extended lag phases lasting well after the peroxide had been neutralised by the bacterium's antioxidant systems, after which the bacteria eventually resumed growth at equivalent rates to the controls. Even though the subsequent growth rates appeared normal, the cells exhibited a variant metabolic regime at the mid-exponential phase of growth as a result of the initial exposure to peroxide. The alterations in metabolism were reflected by the differential amino acid profiles measured in the cytoplasmic extracts (P < 0.0001). The data indicated that the metabolic responses to H2O2 challenge were uniquely different depending on the variations of temperature and pH. The uptake patterns of amino acids from the media also altered depending on prevailing environmental conditions. From these results, it was proposed that a specific reproducible homeostasis could be induced under a specific set of defined environmental conditions. It was also evident that early toxic insults on the bacterial culture could have lasting impacts on cellular homeostasis after successive generations, even after the offending chemical had been removed and initial cell integrity restored. It was concluded that metabolic homeostasis would be continually adjusting and responding to changing environmental conditions to deploy defensive proteins as well as optimising processes for survival. The powerful ability to continually and rapidly adapt to the environment may represent the key feature supporting the virulence of S. aureus as an opportunistic pathogen invading the wound site. PMID- 29756077 TI - Persistent macular puckering following excision of causative orbital tumor. AB - Purpose: To describe the clinical course of a patient with a retrobulbar orbital tumor causing myopic shift and macular pucker. Observation: Following complete surgical removal of a retrobulbar orbital cavernous hemangioma, the myopic shift improved but the macular pucker persisted even 3 years after orbital surgery, with no sign of tumor recurrence. Conclusion and importance: Chorioretinal folds secondary to chronic mechanical force from an orbital tumor may persist long after the tumor is removed. This case may assist ophthalmologists in their discussions with, and counseling of, patients regarding visual prognosis following excision of orbital tumors that are causing retinal changes. PMID- 29756076 TI - Gap junctional communication is involved in differentiation of osteoclasts from bone marrow and peripheral blood monocytes. AB - Aims: The aim of the study was to compare the influence of gap junctional communication (GJC) in osteoclastogenesis from bone marrow (BM) and peripheral blood (PB) monocytes. These widely used sources differ in purity, since BM cultures contain a significant number of stromal cells. We studied whether stimulation of GJC in BM monocyte/stromal cell cultures differs from the effect in pure PB monocyte cultures. We compared the differentiation also in acidosis, which is a known inducer of bone resorption. Main methods: Human BM and PB monocytes were isolated from BM aspirates or whole blood samples. The cells were cultured on human bone slices with osteoclastogenic growth factors and a GJC modulator, antiarrhythmic peptide AAP10, at physiological and acidic pH. Key findings: Both BM and PB monocytes differentiated into osteoclasts. Acidosis increased resorption in both cultures but stimulated cell fusion only in BM cultures, which demonstrates the role of stromal cells in osteoclastogenesis. At physiological pH, AAP10 increased the number of multinuclear cells and bone resorption in both BM and PB cultures indicating that GJC is involved in differentiation in both of these osteoclastogenesis assays. Interestingly, in PB cultures at pH 6.5 the stimulation of GJC with AAP10 inhibited both osteoclastogenesis and bone resorption suggesting a different role of GJC in BM and PB monocytes at stressed environment. Significance: The study is conducted with primary human tissue samples and adds new knowledge on factors affecting osteoclastogenesis from different monocyte sources. PMID- 29756079 TI - Structural and Electrophysiologic Outcomes in a Patient with Retinal Metallosis. PMID- 29756078 TI - Engineering "Endothelialized" Microfluidics for Investigating Vascular and Hematologic Processes Using Non-Traditional Fabrication Techniques. AB - Investigating the complex interplay between blood cells and the endothelium is crucial in understanding the pathophysiology of many diseases. Observation of the in vivo vasculature is difficult due to the complexities of vessel geometry, limited visualization capability, as well as variability and complexity inherent to biologic systems. Therefore, in vitro systems serve as ideal tools to study these cellular interactions. Microfluidic technologies are an ideal tool for recapitulating the vasculature in vivo as they can be used to fabricate fluidic channels on the size scale capillaries using gas permeable, biologically inert, and optically transparent substrates. Microfluidic channels can be vascularized by coating the inner surface of the microchannels with a confluent monolayer of endothelial cells, representing a reductionist, tightly controlled, in vitro model of the microvasculature. In this review, we present advances in the field of "endothelialized" microfluidics, focusing specifically on non-traditional fabrication and endothelialization techniques. We then summarize the various applications of endothelialized microfluidics, and speculate on the future directions of the field, including the exciting applications to personalized medicine. PMID- 29756081 TI - Favourable Prognosis when Lung-Cancer Patients with Superior Vena Cava Obstruction (SVCO) are Referred Promptly to EBUS-TBNA Prior to Medical or Surgical Management. AB - Background: Primary care patients with superior vena cava obstruction (SVCO) syndrome are usually referred to emergency departments for urgent medical management (high-dose corticosteroids to reduce inflammation), pre-biopsy radiotherapy and/or stent placements to restore patency to the vessel. Biopsy, diagnosis and staging of the mediastinal mass is often postponed until resolution of SVCO symptoms. However, lung cancers metastasise rapidly and delays can influence the eventual outcome of patients. An additional merit in treating SVCO symptoms post-biopsy is that high-dose corticosteroids and pre-biopsy radiotherapy will degrade the quality of biopsy specimens, complicating diagnosis and subsequent management. Aims: To determine if direct referrals of SVCO patients from primary care to the respiratory department for Endobronchial ultrasound (EBUS)-transbronchial needle-aspiration (TBNA) resulted in better outcomes. Methods: Direct referrals to the respiratory department from primary care physicians were sought. A total of 8 patients with symptoms of SVCO were rapidly diagnosed via EBUS-TBNA and ROSE, radiotherapy and specific chemotherapy was initiated following communication with oncology colleagues. High-dose corticosteroids were administered post-EBUS. Results: Rapid resolution of symptoms for SVCO were noted, without need for surgical intervention. In particular, one patient with small-cell lung cancer (the most aggressive type of lung cancer) remains well and cancer-free 14 months from diagnosis. Discussion: EBUS-TBNA is a safe modality for biopsy in SVCO as there is no risk of further compression of the vessel. We need a paradigm shift in referral and a guideline of SVCO patients in primary care, an urgent biopsy is important in mediastinal cancers which have high metastatic potentials. PMID- 29756080 TI - De Novo Mutations and Rare Variants Occurring in NMDA Receptors. AB - A significant number of variants/mutations in the N-methyl-D-aspartate glutamatergic receptor (NMDAR) gene family (GRIN) have been identified along with stunning advances in the technologies of next generation of whole-exome sequencing. Mutations in human GRIN genes are distributed throughout the entire gene, from amino terminal domain to C-terminal domain, in patients with various neuropsychiatric disorders, including autism spectrum disorders, epilepsy, intellectual disability, attention deficit hyperactivity disorder, and schizophrenia. Analyzing the currently available human genetic variations illustrates the genetic variation intolerance to missense mutations differs significantly among domains within the GRIN genes. Functional analyses of these mutations and their pharmacological profiles provide the first opportunity to understand the molecular mechanism and targeted therapeutic strategies for these neurological and psychiatric disorders, as well as unfold novel clues to channel function. PMID- 29756083 TI - Drugs to Treat Alcohol Dependence-A Perspective. AB - Despite increased awareness, prevention campaigns, and tighter laws and regulations, alcohol consumption caused an average of 88,000 deaths per year and a burden of $249 billion to the U.S economy in 2010. Only three FDA-approved drugs, disulfiram, naltrexone and acamprosate are available for the treatment of alcohol use disorder. These drugs are only effective modestly and patient compliance is a serious issue because of several adverse side effects, necessitating the developments of newer drugs. The current research drug development efforts remains in the identification new alcohol targets and elucidating the molecular mechanism of its action is needed for effective intervention. In addition, current treatment could be improved by testing the existing medications for comorbid conditions using the patient's genetic background information. PMID- 29756082 TI - Altered Cortical GABA in Female Veterans with Suicidal Behavior: Sex Differences and Clinical Correlates. AB - Background: Suicide is a public health concern in the civilian and veteran populations. Stressful life events are precipitating factors for suicide. The neurochemical underpinnings of the association between stress/trauma and suicide risk are unclear, especially in regards to sex differences. We hypothesized that gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter may be a neurochemical candidate that is critical in the association between stress and suicide risk in veterans. Methods: Proton magnetic resonance spectroscopy (1H MRS) at 3.0 Tesla was used to measure in vivo neurochemistry in the anterior cingulate cortex (ACC; predominantly the dorsal ACC) of 81 veterans (16 females), including 57 (11 females) who endorsed past suicidal ideation (SI) and/or suicide attempt (SA) and 24 (5 females) with no history of SI and/or SA. Suicidal behavior (SB) was defined as the presence of SI and/or SA. Results: We observed no significant differences in GABA/ Creatine+phosphocreatine (Cr+PCr) between veterans with SB (SB+) and without SB (SB-). However, the female SB+ group showed significantly reduced GABA/Cr+PCr vs. the female SB- group. We observed a trend level significant negative correlation between GABA/Cr+PCr and the defensive avoidance (DA) subscale on the Trauma Symptom Inventory (TSI) in the SB+ group. In contrast, the SB- group exhibited a positive relationship between the two variables. Furthermore, we found significant negative correlations between GABA/Cr+PCr and Hamilton Rating Scale for Depression (HAM-D) scores as well as between GABA/Cr+PCr and several subscales of the TSI in female veterans. Conclusions: This study suggests that reduced GABA/Cr+ PCr ratio in the ACC, which may be related to altered inhibitory capacity, may underlie suicide risk in female veterans. Further, the negative association between GABA/Cr+PCr and stress symptomatology and depression scores suggests that MRS studies may shed light on intermediate phenotypes of SB. PMID- 29756084 TI - Reconsidering the International Association for the Study of Pain definition of pain. AB - Introduction: The definition of pain promulgated by the International Association for the Study of Pain (IASP) is widely accepted as a pragmatic characterisation of that human experience. Although the Notes that accompany it characterise pain as "always subjective," the IASP definition itself fails to sufficiently integrate phenomenological aspects of pain. Methods: This essay reviews the historical development of the IASP definition, and the commentaries and suggested modifications to it over almost 40 years. Common factors of pain experience identified in phenomenological studies are described, together with theoretical insights from philosophy and biology. Results: A fuller understanding of the pain experience and of the clinical care of those experiencing pain is achievable through greater attention to the phenomenology of pain, the social "intersubjective space" in which pain occurs, and the limitations of language. Conclusion: Based on these results, a revised definition of pain is offered: Pain is a mutually recognizable somatic experience that reflects a person's apprehension of threat to their bodily or existential integrity. PMID- 29756085 TI - Neuropathic pain in leprosy: symptom profile characterization and comparison with neuropathic pain of other etiologies. AB - Introduction: Previous studies reported a high prevalence of neuropathic pain in leprosy, being especially present in "pharmacologically cured" patients. The presence of neuropathic pain in leprosy poses a supplementary burden in patient's quality of life, daily activities, and mood. Objectives: The aim of this study was to assess whether neuropathic pain in leprosy has similar symptom profile as neuropathic pain of other etiologies and to retrospectively assess the efficacy of neuropathic pain medications regularly prescribed to leprosy. Methods: Leprosy and nonleprosy patients had their neuropathic pain characterized by the neuropathic pain symptom inventory (NPSI, ranges from 0 to 100, with 100 being the maximal neuropathic pain intensity) in a first visit. In a second visit, leprosy patients who had significant pain and received pharmacological treatment in the first evaluation were reassessed (NPSI) and had their pain profile and treatment response further characterized, including information on drugs prescribed for neuropathic pain and their respective pain relief. Results: The pain characteristics based on NPSI did not significantly differ between leprosy and nonleprosy neuropathic pain patients in visit 1 after correction for multiple analyses, and cluster analyses confirmed these findings (ie, no discrimination between leprosy and nonleprosy groups; Pearson chi2 = 0.072, P = 0.788). The assessment of pain relief response and the drugs taken by each patient, linear regression analysis showed that amitriptyline, when effective, had the highest percentage of analgesic relief. Conclusions: Neuropathic pain in leprosy is as heterogeneous as neuropathic pain of other etiologies, further supporting the concept that neuropathic pain is a transetiological entity. Neuropathic pain in leprosy may respond to drugs usually used to control pain of neuropathic profile in general, and amitriptiline may constitute a potential candidate drug for future formal clinical trials aimed at controlling neuropathic pain in leprosy. PMID- 29756086 TI - Postoperative opioids, endocrine changes, and immunosuppression. AB - Opioids are among most effective drugs for managing acute postoperative pain. This article discusses the potential effects of perioperative opioids on endocrine and immune function. PMID- 29756088 TI - Situating pain in a more helpful place. AB - Milton Cohen et al. proposed a revision of the IASP definition of pain of 1979. This commentary summarizes, why this redefinition is necessary, appropriate, and timely. PMID- 29756089 TI - The International Association for the Study of Pain definition of pain: as valid in 2018 as in 1979, but in need of regularly updated footnotes. AB - Milton Cohen, John Quintner, and Simon van Rysewyk proposed a revision of the IASP definition of pain of 1979. This commentary summarizes, why this proposal is useful for guiding assessment of pain, but not its definition. PMID- 29756087 TI - From acute to persistent low back pain: a longitudinal investigation of somatosensory changes using quantitative sensory testing-an exploratory study. AB - Introduction: Chronic low back pain (LBP) is commonly associated with generalised pain hypersensitivity. It is suggested that such somatosensory alterations are important determinants for the transition to persistent pain from an acute episode of LBP. Although cross-sectional research investigating somatosensory function in the acute stage is developing, no longitudinal studies designed to evaluate temporal changes have been published. Objectives: This exploratory study aimed to investigate the temporal development of somatosensory changes from the acute stage of LBP to up to 4 months from onset. Methods: Twenty-five people with acute LBP (<3 weeks' duration) and 48 pain-free controls were prospectively assessed at baseline using quantitative sensory testing with the assessor blinded to group allocation, and again at 2 and 4 months. Psychological variables were concurrently assessed. People with acute LBP were classified based on their average pain severity over the previous week at 4 months as recovered (<=1/10 numeric rating scale) or persistent (>=2/10 numeric rating scale) LBP. Results: In the persistent LBP group, (1) there was a significant decrease in pressure pain threshold between 2 and 4 months (P < 0.013), and at 4 months, pressure pain threshold was significantly different from the recovered LBP group (P < 0.001); (2) a trend towards increased temporal summation was found at 2 months and 4 months, at which point it exceeded 2 SDs beyond the pain-free control reference value. Pain-related psychological variables were significantly higher in those with persistent LBP compared with the recovered LBP group at all time points (P < 0.05). Conclusion: Changes in mechanical pain sensitivity occurring in the subacute stage warrant further longitudinal evaluation to better understand the role of somatosensory changes in the development of persistent LBP. Pain-related cognitions at baseline distinguished persistent from the recovered LBP groups, emphasizing the importance of concurrent evaluation of psychological contributors in acute LBP. PMID- 29756090 TI - Capsaicin 8% patch reversibly reduces A-delta fiber evoked potential amplitudes. AB - Introduction: The capsaicin 8% patch is a treatment option in patients with localized peripheral neuropathic pain. Better understanding of its mechanisms of action and knowledge on predictive biomarkers for a treatment response is warranted. Objectives: To use electrically evoked pain-related potentials for investigation of A-delta fiber conduction after capsaicin 8% patch treatment. Methods: We studied 11 healthy controls at the dorsal hand and the foot and 12 patients with neuropathic pain at the area affected by neuropathic pain before and 2 hours after application of a capsaicin 8% patch (Qutenza). Patients were additionally phenotyped using quantitative sensory testing and skin biopsy. Results: Peak-to-peak N1-P1 amplitudes (PPA) were reduced after Qutenza application by a median of 60% in 6/11 controls and by 33% in patients with neuropathic pain compared with baseline; they were increased in 3 controls that did not develop capsaicin-induced pain. Patients with elevated cold detection thresholds more often had reduced PPA after Qutenza than those with normal cold detection threshold. Patients with reduced PPA after capsaicin application and with capsaicin-induced pain were more likely to achieve pain reduction on Qutenza. Conclusion: The capsaicin 8% patch induces a reduction in A-delta PPA in healthy persons and in patients with neuropathic pain adding to the mechanistic understanding of its effect. PMID- 29756091 TI - Embedding the IASP pain curriculum into a 3-year pre-licensure physical therapy program: redesigning pain education for future clinicians. AB - Supplemental Digital Content is Available in the Text. This article describes the process and evaluation of embedding the IASP Pain Curriculum for Physical Therapy into a 3-year Doctor of Physiotherapy Program in Australia. PMID- 29756092 TI - Arts, Science, Engineering and Medicine Collaborate to Educate Public on Bioenergetics. AB - Mitochondrial dysfunction has correlated with a rise in energy deficiency disorders (EDD). The EDDs include mitochondrial disorders, obesity, metabolic disorders, cardiovascular and neurodegenerative disorders. Many individuals in our communities are at high risk of developing these disorders, yet are unaware of it. Our goal was to increase public awareness of mitochondrial health, whilst providing students with an innovative educational experience. We designed a 'Bioenergetics exhibition' by introducing Arts into traditional STEM (Science, Technology, Engineering & Mathematics) disciplines to create a new STEAM-(Health) initiative. Results indicated ~120,000 guests visited the exhibition, including many school-aged children, teachers and families. Comparative analysis of random first-time vs. repeat visitor surveys demonstrated a statistically significant (8.25% at p-value = 0.006) increase in knowledge of mitochondrial disease and bioenergetics. Our findings clearly support the power of the STEAM-H initiative in creatively communicating the complex science to a broader community. PMID- 29756094 TI - The 2017 National Psoriasis Foundation Research Symposium. PMID- 29756095 TI - Comparison of Cortical and Subcortical Measurements in Normal Older Adults across Databases and Software Packages. AB - This work explores the feasibility of combining anatomical MRI data across two public repositories namely, the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Progressive Parkinson's Markers Initiative (PPMI). We compared cortical thickness and subcortical volumes in cognitively normal older adults between datasets with distinct imaging parameters to assess if they would provide equivalent information. Three distinct datasets were identified. Major differences in data were scanner manufacturer and the use of magnetization inversion to enhance tissue contrast. Equivalent datasets, i.e., those providing similar volumetric measurements in cognitively normal controls, were identified in ADNI and PPMI. These were datasets obtained on the Siemens scanner with TI = 900 ms. Our secondary goal was to assess the agreement between subcortical volumes that are obtained with different software packages. Three subcortical measurement applications (FSL, FreeSurfer, and a recent multi-atlas approach) were compared. Our results show significant agreement in the measurements of caudate, putamen, pallidum, and hippocampus across the packages and poor agreement between measurements of accumbens and amygdala. This is likely due to their smaller size and lack of gray matter-white matter tissue contrast for accurate segmentation. This work provides a segue to combine imaging data from ADNI and PPMI to increase statistical power as well as to interrogate common mechanisms in disparate pathologies such as Alzheimer's and Parkinson's diseases. It lays the foundation for comparison of anatomical data acquired with disparate imaging parameters and analyzed with disparate software tools. Furthermore, our work partly explains the variability in the results of studies using different software packages. PMID- 29756096 TI - An overlooked complication of the inguinal hernia repair: Dysejaculation. AB - The objective of this study was to investigate the rate of post-herniorrhaphy dysejaculation in the current literature. A comprehensive search of PubMed, Medline, Google Scholar, and Google databases was performed using the keywords "groin hernia and chronic pain," "inguinal hernia and chronic pain," "dysejaculation," and "ejaculatory pain." The eligible studies were evaluated in terms of ejaculatory pain and surgical technique used. Ten studies with 122 patients were eligible for the analysis. The rate of ejaculatory pain for a total of 5521 patients was found to be 2.2%. The incidence of postoperative ejaculatory pain was found to be 2.1% following laparoscopic techniques and 1.1 % following open repair. Open techniques were not related to the increased frequency of dysejaculation. Sufficient data could not be obtained from the studies for the ejaculatory pain, and thus, no statistical evaluation was performed. Dysejaculation is a common cause of postoperative morbidity after inguinal hernia repair. Attention to technical details of the primary operation may reduce the incidence of dysejaculation. PMID- 29756097 TI - Evaluation of stressors in intensive care units. AB - Objective: Physical and psychological stressors adversely affect the treatment and length of stay of patients in intensive care units. In this study, we aimed to describe environmental and psychological stressors affecting intensive care unit patients and to determine their priorities. Material and Methods: In this study, the 40-item Intensive Care Unit Environmental Stressor Scale was administered to patients in the General Surgery Intensive Care Unit and the Anesthesiology and Reanimation Intensive Care Unit. The patients' age, gender, marital status, educational status, cause of hospitalization, and intensive care unit length of stay were questioned and recorded. Acute Physiology And Chronic Health Evaluation II scores were determined for intensive care unit patients. Results: A total of 98 patients, 80 in the General Surgery Intensive Care Unit and 18 in the Anesthesiology and Reanimation Intensive Care Unit, were included in the study between May 1, 2015 and October 31, 2015. Fifty-six of the patients were male (57.1%) and 42 were female (42.9%). The mean age of the patients was 55.1+/-15.1 years. The mean intensive care unit length of stay was 3.4+/-1.6 days. The median Acute Physiology And Chronic Health Evaluation II score of the patients was 6 (0 to 17). The patients were most affected by thirst (mean 2.44). The second most stressful stress factor was the presence of tubes in the mouth and nose (mean 2.25). The least stressful factor for the patients was the presence of nurses constantly performing activities around the bed. Although 51% of the patients were postoperative, pain was ranked 5th among stress factors. Conclusion: The environmental and psychological factors affecting intensive care unit patients varied according to age, sex, and educational and surgical status. These factors had adverse effects on the patients. The elimination or modification of these factors would contribute positively to the treatment of intensive care unit patients and shorten their length of stay in the intensive care unit. PMID- 29756098 TI - Objectively structured verbal examination to assess surgical clerkship education: An evaluation of students' perception. AB - Objective: The objectivity and reliability of examining methods are controversial. We subjected fourth-year medical students to a specially designed verbal exam which we called objectively structured verbal examination. We aimed to evaluate feedback from students about objectively structured verbal examination as an assessment instrument for gauging their surgical knowledge. Material and Methods: Objectively structured verbal examination modules were developed according to the learning goals of the surgical clerkship. Upon finishing surgery rotation, the students were subjected to objectively structured verbal examination as part of their final evaluation. The students' perception of objectively structured verbal examination was assessed by their responses to a questionnaire. Results: Forty-two of 58 students returned filled questionnaires. Objectively structured verbal examination was accepted by 72% of the students as an objective tool, and 86% of them found it enabled unbiased evaluation. Overall, most students expressed positive feedback regarding objectively structured verbal examination. Conclusion: The feedback received from students showed that objectively structured verbal examination is a reliable and objective method to assess their knowledge. This feedback reflects that objectively structured verbal examination merits further development and enhancement. PMID- 29756093 TI - Lineage Plasticity in Cancer Progression and Treatment. AB - Historically, it has been widely presumed that differentiated cells are determined during development and become irreversibly committed to their designated fates. In certain circumstances, however, differentiated cells can display plasticity by changing their identity, either by dedifferentiation to a progenitor-like state or by transdifferentiation to an alternative differentiated cell type. Such cellular plasticity can be triggered by physiological or oncogenic stress, or it can be experimentally induced through cellular reprogramming. Notably, physiological stresses that promote plasticity, such as severe tissue damage, inflammation, or senescence, also represent hallmarks of cancer. Furthermore, key drivers of cellular plasticity include major oncogenic and tumor suppressor pathways and can be exacerbated by drug treatment. Thus, plasticity may help cancer cells evade detection and treatment. We propose that cancer can be considered as a disease of excess plasticity, a notion that has important implications for intervention and treatment. PMID- 29756099 TI - Can volumetric measurement be used in the selection of treatment for inguinoscrotal hernias? AB - Objective: Inguinoscrotal hernias are often qualified subjectively as big, giant, scrotal, etc. In order to classify this type of hernia, objective criteria are needed. For this purpose, we aimed to introduce a scrotal volume measurement based classification system and propose a corresponding surgical plan (open or laparoscopic surgery, anterior or posterior repair) based on volumetric data. Material and Methods: Between October 2012 and October 2013, 30 consecutive male patients with a mean age of 59.5 years (range: 36 to 82 years) presenting with unilateral ISH were included in this retrospective study. Physical measurements in the upright position and computerized tomography measurements using the Valsalva maneuver were obtained from all patients. Results: Of the 30 patients, 26 patients had scrotal volumes less than 1000 mL, two patients had SVs between 1001 and 2000 mL, one patient had an SV between 2001 and 3000 mL, and one patient had an SV greater than 3000 mL. Laparoscopic total extraperitoneal repair was performed in patients with scrotal volumes inferior to 1000 mL. In three patients with scrotal volumes between 1000 and 3000 mL, an open posterior approach was used. In one patient with a scrotal volume superior to 3000 mL, no surgical intervention was performed due to the patient's cardiac comorbidity. Conclusion: By establishing a common language among surgeons, we believe that the volumetric measurement-based scrotal hernia classification system proposed in this study will lead to further studies on the subject. PMID- 29756100 TI - Randomized prospective comparison of long-term results of onlay and sublay mesh repair techniques for incisional hernia. AB - Objective: Incisional hernia is a significant problem after laparotomy, and there is still no consensus on an ideal treatment method. The aim of this study was to compare the results of onlay and sublay mesh repair techniques. Material and Methods: In this randomized prospective trial, 100 patients were divided into two groups: onlay and sublay groups. Recurrences were evaluated by performing a physical examination. Results: The median follow-up was 37.1 (26.6 to 46.5) months. In the onlay group, the mean operation time was significantly shorter. However, in terms of postoperative pain and wound complications, the sublay group had significantly better results. The recurrence rates were found to be similar in both groups (6% in the onlay group and 2% in the sublay group). Conclusion: In the treatment of incisional hernia, sublay mesh repair is superior to onlay mesh repair in terms of postoperative pain and wound complications. Both techniques have similar recurrence rates. PMID- 29756101 TI - A short term analysis of surgical management of umbilical and paraumbilical hernia. AB - Objective: Umbilical hernia and paraumbilical hernia are ventral herniae that occur in infants and adults. According to current evidence, mesh repair is the treatment of choice to avoid recurrence. The aim of this study is to analyze the surgical methods, the types of meshes used, and their benefits. Material and Methods: A retrospective analysis of patients diagnosed with umbilical hernia and paraumbilical hernia was performed. The patients' consent was obtained retrospectively. The various surgical techniques and different meshes used were analyzed. Forty-three patients were selected for the study. Of these, 23 patients underwent open mesh repair, 12 patients underwent laparoscopic intraperitoneal onlay mesh repair repair, and eight patients underwent open intraperitoneal onlay mesh repair repair. The duration of the surgery, mesh used, number of days of hospital stay, type of anesthesia, and postoperative complications were analyzed. Results: Of the 43 patients, the patients who underwent open intraperitoneal onlay mesh repair had shorter postoperative hospital stays compared to other methods (median=1 day; range=1 to 2 days). The duration of surgery was longer for laparoscopic intraperitoneal onlay mesh repair and open mesh repair compared to the open intraperitoneal onlay mesh repair technique (p<0.05). Conclusion: The open intraperitoneal onlay mesh repair technique had advantages over the other methods for small-defect umbilical hernia and paraumbilical hernia. The duration of surgery was long for laparoscopic intraperitoneal onlay mesh repair compared to open mesh repair and the open intraperitoneal onlay mesh repair technique. Postoperative complications were insignificant for all three methods. Another advantage of the open intraperitoneal onlay mesh repair technique was a shorter postoperative hospital stay. PMID- 29756102 TI - Management of iatrogenic injuries due to endoscopic sphincterotomy: Surgical or conservative approaches. AB - Objective: The best therapeutic approach for endoscopic retrograde cholangiopancreatography-related perforations remains controversial; while some authors suggest routine conservative management, others advocate mandatory surgical exploration. We aimed to evaluate our clinical experience of perforations during endoscopic sphincterotomy. Material and Methods: A retrospective chart review from January 2010 to October 2015 identified 20 patients with endoscopic retrograde cholangiopancreatography-related perforations. Data collection included demographics, time to diagnosis, type of perforation, treatment strategy, surgical procedure, complications, hospital stay, and outcome. All patients were classified into two groups on the basis of radiological and operative findings. Results: Only five patients underwent surgical treatment, whereas 15 patients were managed conservatively. The mean time to diagnosis was 7.8 hrs (range: 1 to 36 hrs). In patients who underwent surgical treatment, the types of perforations included type I and III in one patient each and type II in three patients. Surgical procedures included laparoscopic and open cholecystectomy with t-tube drainage in two patients each and primary repair of duodenal injury with hepaticojejunostomy in one patient. Among conservatively managed patients, eight, four, and three had type II, type III, and type IV injuries, respectively. Of these 15 patients, 60% (n=9) underwent percutaneous procedures. The mean length of hospital stay was similar for conservatively and surgically treated patients (12 vs. 12.4 days, respectively, p=0.790). One patient (5%) with type I injury died of multiorgan deficiency. Conclusion: With close close clinical follow-up, medical treatment can be beneficial for most patients, and surgical procedures should be reserved for patients with type I (definite) and type II/III injuries; in patients with these clinical parameters, conservative management will likely be unsuccessful. PMID- 29756104 TI - Treatment of phytobezoars: Tailoring management to diverse presentations. AB - Objective: A minimally invasive approach is feasible and successful for the treatment of phytobezoars. We would like to draw attention to the overconsumption of Sorbus domestica and discuss the management options of patients presenting with different symptoms due to phytobezoars. Material and Methods: Data from patients diagnosed with phytobezoars in the Department of General Surgery from 2010 to 2016 were prospectively collected and evaluated. Results: Twenty patients diagnosed with phytobezoars were included in the study. The etiology of phytobezoar was Sorbus domestica seeds in 12 patients, watermelon seeds in two patients, Japanese persimmon seeds in one patient, and unidentified in five patients. Fourteen patients underwent surgery, while the remaining patients were treated conservatively. Minimally invasive surgery was used in all but two cases, where the surgery was converted to laparotomy. Two patients developed postoperative morbidity. There was no mortality. Conclusion: The treatment modality should be selected for each patient according to the presenting symptoms and characteristics of phytobezoar. In cases where surgery is performed, a minimally invasive approach is feasible and successful for the treatment of ileus. PMID- 29756103 TI - Factors affecting successful colonoscopy procedures: Single-center experience. AB - Objective: Colonoscopy is a gold standard procedure for several colon pathologies. Successful colonoscopy means demonstration of the ileocecal valve and determination of colon polyps. Here we aimed to evaluate our colonoscopy success and results. Material and Methods: This retrospective descriptive study was performed in Istanbul Eren hospital endoscopy unit between 2012 and 2015. Colonoscopy results and patient demographics were obtained from the hospital database. All colonoscopy procedures were performed under general anesthesia and after full bowel preparation. Results: In all, 870 patients were included to the study. We reached to the cecum in 850 (97.8%) patients. We were unable to reach the cecum in patients who were old and obese and those with previous lower abdominal operations. Angulation, inability to move forward, and tortuous colon were the reasons for inability to reach the cecum. Total 203 polyp samplings were performed in 139 patients. We performed 1, 2, and 3 polypectomies in 97, 28, and 10 patients, respectively. There were 29 (3.3%) colorectal cancers in our series. There was no mortality or morbidity in our study. Conclusion: General anesthesia and full bowel preparation may be the reason for increased success of colonoscopy. Increased experience and patient-endoscopist cooperation increased the rate of cecum access and polyp resection and decreased the complication rate. PMID- 29756105 TI - Non-operative management of abdominal gunshot injuries: Is it safe in all cases? AB - Objective: In line with advances in diagnostic methods and expectation of a decrease in the number of negative laparotomies, selective non-operative management of abdominal gunshot wounds has been increasingly used over the last three decades. We aim to detect the possibility of treatment without surgery and present our experience in selected cases referred from Syria to a hospital at the Turkish-Syrian border. Material and Methods: Between February 2012 and June 2014, patients admitted with abdominal gunshot wounds were analyzed. Computed tomography was performed for all patients on admission. Patients who were hemodynamically stable and did not have symptoms of peritonitis at the time of presentation were included in the study. The primary outcome parameters were mortality and morbidity. Successful selective non-operative management (Group 1) and unsuccessful selective non-operative management (Group 2) groups were compared in terms of complications, blood transfusion, injury site, injury severity score (ISS), and hospital stay. Results: Of 158 truncal injury patients, 18 were considered feasible for selective non-operative management. Of these, 14 (78%) patients were treated without surgery. Other Four patients were operated upon progressively increasing abdominal pain and tenderness during follow-up. On diagnostic exploration, all of these cases had intestinal perforations. No mortality was observed in selective non-operative management. There was no statistically significant difference between Group 1 and Group 2, in terms of length of hospital stay (96 and 127 h, respectively). Also, there was no difference between groups in terms of blood transfusion necessity, injury site, complication rate, and injury severity score (p>0.05). Conclusion: Decision making on patient selection for selective non-operative management is critical to ensure favorable outcomes. It is not possible to predict the success of selective non-operative management in advance. Cautious clinical examination and close monitoring of these patients is vital; however, emergency laparotomy should be performed in case of change in vital signs and positive symptoms concerning peritonitis. PMID- 29756106 TI - A new surgical approach for pilonidal sinus disease: "de-epithelialization technique''. AB - Objective: In the treatment of pilonidal sinus disease different approaches are used such as conservative treatment and fasciocutaneous rotation flap. The aim of this study was to evaluate the efficacy of "de-epithelialization technique" as a new approach in pilonidal sinus disease treatment. Material and Methods: Forty pilonidal sinus disease patients treated with de-epithelialization method were evaluated retrospectively. Patient age, gender, body mass index, wound healing time, visual analog scale scores, operation times, hospital stay duration, drain removal time, cosmetic satisfaction rates, complications, and recurrence rates were evaluated. Results: The numbers of male and female patients in this study were 39 and 1, respectively. The median age of the patients was 25 years and the mean BMI was 26.6. The mean operating time was 43 min, and all patients were discharged 5 h after the operation. Wound healing time varied from 10 to 20 days. Median follow-up period was 9 months (4-17 months). One patient with high body mass index suffered from partial wound separation. No other complications such as infections and fluid collections (hematoma and seromas) were observed. Maximum cosmetic satisfaction rate was 90% (n=36), and no patient had a recurrence during the follow-up period. Conclusion: "De-epithelialization" may be considered as a complementary and/or alternative approach to other surgical techniques such as primary closure, rhomboid excision, and Limberg flap in the treatment of pilonidal sinus disease, with acceptable cosmesis and recurrence rates. PMID- 29756107 TI - Analysis of 89 patients who underwent tube thoracostomy performed by general surgeons. AB - Objective: Death due to thoracic trauma accounts for 20% of all trauma deaths. The aim of this study was to discuss the approach applied by general surgeons to thoracic trauma in our center. Material and Methods: A total of 89 patients (82 male, 7 female; mean age: 26.8 years; range: 7 to 77 years) with thoracic trauma who were admitted to the emergency department and underwent thoracostomy performed by general surgeons between January 2008 and December 2013 were retrospectively analyzed. Results: Penetrating trauma was found in 61 patients (68%); this was the most common cause of thoracic trauma. Pneumothorax, the most common clinical sign, was found in 57 patients (64%). Abdominal pathologies, the most common concomitant extra-thoracic pathologies, were found in 17 patients (19%). Fifteen patients (17%) underwent laparotomy due to intra-abdominal organ injuries. Splenic trauma and diaphragmatic injury were detected in five patients. Complications were seen in two patients (2.2%): one had an air leak and one had persistent pneumothorax. Three patients with multi-trauma died in the early period due to additional pathologies. No mortality was seen in any patient due to thoracic trauma. Conclusion: All general surgeons should be highly familiar with approaches to thoracic trauma, and necessary interventions should be performed in emergency situations. It is also essential to correctly identify patients who require timely and appropriate referral to a tertiary center to reduce the rates of mortality and morbidity. PMID- 29756108 TI - Thoracoscopic vagal-sparing esophagectomy and colonic interposition for caustic stricture. AB - Minimally invasive esophagectomy is an increasing trend in surgery. Thoracoscopic esophagectomy is applicable and an alternative procedure to conventional esophagectomy in patients especially with end-stage benign diseases like caustic stricture. A 33-year-old female patient was admitted to the department of general surgery with dysphagia. The patient was suffering from caustic stricture due to ingestion of hydrochloric acid. A totally thoracoscopic and laparoscopic vagal sparing esophagectomy and colonic interposition was performed. As a more physiologic alternative, vagal-sparing esophagectomy is the ideal operation for these patients. PMID- 29756109 TI - First experience with a new technique: Portable gamma camera usage for sentinel lymph node identification in a patient with breast cancer. AB - The newest development in sentinel lymph node imaging is portable gamma probe imaging. In this case report, results of all SLN detection methods were analyzed. The patient was imaged using a large field-of-view gamma camera with additional blue dye administration and intraoperative localization of sentinel lymph node using both gamma probe and portable gamma camera was performed. In this case report, the value of additional portable gamma camera imaging was analyzed. PMID- 29756110 TI - Agenesis of the isthmus of the thyroid gland. AB - The thyroid is an endocrine gland composed of two lobes connected by the isthmus tissue. Thyroid isthmus agenesis is a rare condition, and only a few cases have been reported in the literature. Here, we discuss the case of a 56-year-old female patient in whom agenesis of the thyroid isthmus was discovered incidentally during surgery for a multinodular goitre. When agenesis of the isthmus is found, associated thyroid lobe agenesis and the presence of ectopic thyroid tissue must be considered. In addition, associated autoimmune thyroid nodule, thyroiditis, primary thyroid carcinoma, metastasis, and amyloidosis must be considered in the differential diagnosis. Preoperative awareness of potential agenesis of the isthmus and its associated thyroid anomalies in patients with planned thyroid surgery will significantly contribute to safety during surgical procedures and result in fewer surgery-related complications. PMID- 29756111 TI - Glomus tumor of the stomach. AB - Glomus tumor is a rare benign mesenchymal neoplasm derived from the glomus body, an arteriovenous shunt mainly located in dermis and subcutis. The most common localization of this tumor is extremities, especially nailbed. Glomus tumor in the gastrointestinal system is a rare condition. Here we report a gastric glomus tumor to raise awareness of this tumor and show the difficulties in the diagnosis. PMID- 29756112 TI - Idiopathic weight loss due to an entero-enteric fistula from a gossypiboma retained for 27 years. AB - Gossypiboma refers to a mass formed around surgical instruments or materials left in the body postoperatively. The occurrence of gossypibomas remains an important problem, despite improvements in surgical procedures and operating room facilities. The clinical presentation of gossypiboma can vary depending on the host response. This report describes a case of abdominal gossypiboma after splenectomy. A 48-year-old man who had undergone splenectomy 27 years ago was admitted to our clinic suffering from non-specific symptoms for 2 weeks. He was cachectic, but laboratory test results were normal. Abdominal ultrasonography and computed tomography revealed a mass in the left hypochondrium. An entero-enteric fistula and an encapsulated foreign body (surgical compress) were detected during an exploratory laparotomy, and the foreign body was removed. Preventing gossypibomas is very important because of their potential to create medico-legal problems and increase mortality and morbidity. Therefore, forgotten surgical material should be considered in all patients with a surgical history, and surgery should be performed carefully. PMID- 29756113 TI - Primary splenic angiosarcoma diagnosed after splenectomy for spontaneous rupture. AB - Primary splenic angiosarcoma is a rare abnormality and has a bad prognosis. It has unknown pathogenesis. This abnormality is usually presented by splenic rupture. Surgery is the most promising treatm Surgery is the most accepted and accurate method for diagnosis and treatment. Surgery before rupture increases the life expectancy. A 65-year-old woman who presented to the emergency room with abdominal pain, abdominal distension, and anemia was found to have a splenic mass and massive ascites. After getting a hemorrhagic sample from the abdomen, the patient was operated with splenic rupture prediagnosis. The spleen material was reported as splenic angiosarcoma. The staging 18F-FDG-Positron Emission Tomography-Computed Tomography did not show any metastasis. Five months later, paclitaxel treatment was initiated upon liver and bone metastasis, and the treatment still continues. Splenic angiosarcoma has a place among splenic parenchymal lesions. The splenectomy material names the diagnosis. Pathologic examination of splenectomy material is revealed certain diagnosis. PMID- 29756114 TI - Is erythema nodosum coexisting with lesions of the breast a suggestive sign for idiopathic granulomatous mastitis? AB - Coexistence of idiopathic granulomatous mastitis and erythema nodosum is very unusual. In this paper, we present a patient with idiopathic granulomatous mastitis accompanied by erythema nodosum to highlight the diagnostic importance of erythema nodosum and its relationship with treatment response of breast lesion. A 39-year-old female with a breast lesion and erythema nodosum was started on treatment with corticosteroids before the results of her histopathological evaluation were obtained. The response to treatment was very quick. Erythema nodosum totally disappeared and the breast lesion regressed noticeably within a week. We think that erythema nodosum associated with a breast lesion may be a sign suggestive of idiopathic granulomatous mastitis and can be used for the evaluation of the response to corticosteroid treatment. More case reports are needed to justify the use of erythema nodosum as a sign suggestive of idiopathic granulomatous mastitis. PMID- 29756115 TI - Severe decrease in SpO2 and methemoglobinemia following subareolar isosulfan blue administration and clinical relevance. AB - The level of axillary lymph node involvement in breast cancer is a critical decision factor for adjuvant therapy and the most important indicator of prognosis and survival. Sentinel lymph node biopsy is a minimally invasive technique with low morbidity in axillary staging of breast cancer. Radiocolloid substances (Technetium-99m) and/or blue dyes such as methylene blue or isosulfan blue are used during sentinel lymph node biopsy. Isosulfan blue stain is frequently used in sentinel lymph node biopsy and rarely causes complications. The present case report presents a severe decrease in SpO2 due to methemoglobinemia following isosulfan blue administration as well as skin and urine signs and inconsistency with clinical picture in a 67-year-old, 77 kg, ASA II female case who underwent sentinel lymph node biopsy under general anesthesia. PMID- 29756116 TI - Intraabdominal gossypiboma: Report of two cases. AB - Gossypiboma which cause medico-legal implications is a heritage of previous surgery. In this study, we present two cases of gossypiboma mimicking intraabdominal malignancy. Case 1: A 28-year-old woman presented with an epigastric mass measuring 10 cm in diameter and a history of open cholecystectomy performed three years ago. Radiological exams revealed a cystic mass at the lesser sac and suggested serous cystadenocarcinoma. Case 2: A 36-year-old female patient with a history of two caesarean sections had a mass in the left lower quadrant. Radiological imaging showed tumoral mass near the left ovary. The exact diagnosis of gossypiboma were achieved by laparotomy and pathological examination in both cases. Gossypibomas usually present with nonspecific symptoms and appear many years after surgery. Therefore, its preoperative diagnosis is very difficult. High degree of suspicion is essential and it should be considered in the differential diagnosis of intraabdominal masses in patients who have previously undergone surgery. PMID- 29756117 TI - Endoscopic repair of rectal perforation due to colonoscopy with a clamp method. AB - Colon perforation during colonoscopy is a rare complication that usually requires surgical intervention. Traditionally, primary repair by laparoscopy, laparotomy, resection, and anastomosis is performed for such perforations. More recently developed minimally invasive endoscopic instruments have also been used in the repair of these perforations; this is becoming increasingly common. An endoscopic over-the-scope clip clamp was used in a 59-year-old male patient who suffered a rectum perforation in connection with a diagnostic colonoscopy. He was referred to our clinic. A colonoscopy was performed in our clinic to assess the rectal perforation caused by a diagnostic colonoscopy 2 h after the initial colonoscopy, with the concurrent therapeutic purpose of repairing the perforation using an endoscopic clamping method. Oral feeding was started 24 h after the procedure. After three days, the patient was discharged. An endoscopic clamping method in appropriate cases can be a safe and appropriate alternative therapy in the management of colonoscopic perforations. PMID- 29756118 TI - Management of gastrointestinal adverse events induced by immune-checkpoint inhibitors. PMID- 29756119 TI - Customization of therapy for gastroesophageal adenocarcinoma patients. AB - Gastroesophageal adenocarcinomas (GEACs) remain a global health problem. These are most often diagnosed at advanced stage and the estimated 5-year relative survival rate is about 5%. Although cure is not possible for patients with advanced GEAC, systemic therapy (chemotherapy or biochemotherapy) can palliate symptoms, improve survival and provide a better quality of life. One of the most promising options for some patients with advanced stage GEAC is immunotherapy, which can result in durable responses. Numerous phase III trials evaluating targeted therapies in different lines are ongoing and it is hoped that better biomarkers will emerge to identify patients who can benefit from targeted agents and immunotherapy in the future. Surgery remains as the corner stone for localized GEAC and adjunctive therapies can increase the survival rates by about 10%. The high toxicity and low completion rates of adjuvant therapy led to the strategies of preoperative treatment. With the results of ongoing pre-operative therapy trials we will be able to determine the optimal adjunctive approach for resectable GEAC. PMID- 29756120 TI - Quantitative image analysis for evaluation of tumor response in clinical oncology. AB - The objective, accurate, and standardized evaluation of tumor response to treatment is an indispensable procedure in clinical oncology. Compared to manual measurement, computer-assisted linear measurement can significantly improve the accuracy and reproducibility of tumor burden quantification. For irregular-shaped and infiltrating or diffuse tumors, which are difficult to quantify by linear measurement, computer-assisted volumetric measurement may provide a more objective and sensitive quantification to evaluate tumor response to treatment than linear measurement does. In the evaluation of tumor response to novel oncologic treatments such as targeted therapy, changes in overall tumor size do not necessarily reflect tumor response to therapy due to the presence of internal necrosis or hemorrhages. This leads to a new generation of imaging biomarkers to evaluate tumor response by using texture analysis methods, also called radiomics. Computer-assisted texture analysis technology offers a more comprehensive and in depth imaging biomarker to evaluate tumor response. The application of computer assisted quantitative imaging analysis techniques not only reduces the inaccuracy and improves the reliability in tumor burden quantification, but facilitates the development of more comprehensive and intelligent approaches to evaluate treatment response, and hence promotes precision imaging in the evaluation of tumor response in clinical oncology. This article summarizes the state-of-the-art technical developments and clinical applications of quantitative imaging analysis in evaluation of tumor response in clinical oncology. PMID- 29756122 TI - Very low-protein diet to postpone renal failure: Pathophysiology and clinical applications in chronic kidney disease. AB - The uremic syndrome is a metabolic disorder characterized by the impairment of renal handling of several solutes, the resulting accumulation of toxic products and the activation of some adaptive but detrimental mechanisms which all together contribute to the progression of renal damage. In moderate to advanced renal failure, the dietary manipulation of nutrients improves metabolic abnormalities and may contribute to delay the time of dialysis initiation. This commentary focuses on the physiopathological rationale and the clinical application of the very low-protein diet supplemented with ketoanalogs for the management of chronic kidney disease. PMID- 29756123 TI - The quality of total mesorectal excision specimen: A review of its macroscopic assessment and prognostic significance. AB - As a surgical procedure which could significantly lower the recurrence rate of cancers, total mesorectal excision (TME) has been the gold standard for middle and lower rectal cancer treatment. However, previous studies have shown that the procedure did not achieve the ideal theoretical local recurrence rates of rectal cancers. Some researchers pointed out it was very likely that not all so-called TME treatments completely removed the mesorectum, implying that some of these TME surgical treatments failed to meet oncological quality standards. Therefore, a suitable assessment tool for the surgical quality of TME is necessary. The notion of "macroscopic assessment of mesorectal excision (MAME)" was put forward by some researchers as a better assessment tool for the surgical quality of TME and has been confirmed by a series of studies. Besides providing rapid and accurate surgical quality feedbacks for surgeons, MAME also effectively assesses the prognosis of patients with rectal cancer. However, as a new assessment tool used for TME surgical quality, MAME has an only limited influence on the current guidelines and is yet to be widely applied in most countries. The aims of this review are to provide a detailed introduction to MAME for clinical practice and to summarize the current prognostic significance of MAME. PMID- 29756121 TI - Critically dysregulated signaling pathways and clinical utility of the pathway biomarkers in lymphoid malignancies. AB - Accumulating evidence confirmed that many dysregulated signaling pathways and aberrant genetic alterations contribute to the oncogenesis and heterogeneity of lymphoid malignancies. Therapeutically targeting dysregulating signaling pathways and their hidden oncogenic biomarkers are becoming available, but did not show desired therapeutic effect in current clinical practice. It is meaningful to further understand the underlying mechanisms of the dysregulated signaling pathways and to address the potential utility of pathway-related biomarkers. To precisely identify the dysregulation of signaling pathways and the "driver" oncogenic biomarkers, as well as to develop reliable and reproducible risk stratification based on biomarkers will be challenging. Nevertheless, pathway based targeted therapy will raise the hope to improve the outcomes of the patients with lymphoid malignancies, especially with aggressive types, and the efficient utility of pathway-related biomarkers in diagnosis, prognosis, prediction of lymphoid malignancies may also be able to power precision medicine. PMID- 29756124 TI - Functional promoter rs189037 variant of ATM is associated with decrease in lung diffusing capacity after irradiation for non-small-cell lung cancer. AB - Objective: Single-nucleotide polymorphisms (SNPs) in the ataxia telangiectasia mutated gene ATM have been linked with pneumonitis after radiotherapy for lung cancer but have not been evaluated in terms of pulmonary function impairment. Here we investigated potential associations between SNPs in ATM and changes in diffusing capacity of the lung for carbon monoxide (DLCO) in patients with non small-cell lung cancer (NSCLC) after radiotherapy. Methods: From November 1998 through June 2009, 448 consecutive patients with inoperable primary NSCLC underwent definitive (>=60 Gy) radiotherapy, with or without chemotherapy. After excluding patients with a history of thoracic surgery, radiation, or lung cancer; without DNA samples available for analysis; or without pulmonary function testing within the 12 months before and the 12 months after radiotherapy, 100 patients were identified who are the subjects of this study. We genotyped two SNPs of ATM previously found to be associated with radiation-induced pneumonitis (rs189037 and rs228590) and evaluated potential correlations between these SNPs and impairment (decreases) in DLCO by using logistic regression analysis. Results: Univariate and multivariate analyses showed that the AA genotype of ATM rs189037 was associated with decreased DLCO after definitive radiotherapy than the GG/AG genotypes [univariate coefficient, -0.122; 95% confidence interval (CI), -0.236 to -0.008; P = 0.037; and multivariate coefficient, -0.102; 95% CI, -0.198 to 0.005; P = 0.038]. No such correlations were found for rs228590 (univariate coefficient, -0.096; 95% CI, -0.208 to 0.017; P = 0.096). Conclusions: The AA genotype of ATM rs189037 was associated with higher risk of lung injury than were the GG/AG genotypes in patients with NSCLC treated with radiotherapy. This finding should be validated prospectively with other patient populations. PMID- 29756125 TI - Distributed query-aware quantization for high-dimensional similarity searches. AB - The concept of similarity is used as the basis for many data exploration and data mining tasks. Nearest Neighbor (NN) queries identify the most similar items, or in terms of distance the closest points to a query point. Similarity is traditionally characterized using a distance function between multi-dimensional feature vectors. However, when the data is high-dimensional, traditional distance functions fail to significantly distinguish between the closest and furthest points, as few dissimilar dimensions dominate the distance function. Localized similarity functions, i.e. functions that only consider dimensions close to the query, quantize each dimension independently and only compute similarity for the dimensions where the query and the points fall into the same bin. These quantizations are query-agnostic. There is potential to improve accuracy when a query-dependent quantization is used. In this paper we propose a Query dependent Equi-Depth (QED) on-the-fly quantization method to improve high-dimensional similarity searches. The quantization is done for each dimension at query time and localized scores are generated for the closest p fraction of the points while a constant penalty is applied for the rest of the points. QED not only improves the quality of the distance metric, but also improves query time performance by filtering out non relevant data. We propose a distributed indexing and query algorithm to efficiently compute QED. Our experimental results show improvements in classification accuracy as well as query performance up to one order of magnitude faster than Manhattan-based sequential scan NN queries over datasets with hundreds of dimensions. PMID- 29756126 TI - Acupuncture/Moxibustion RCT for Distal Sensory Peripheral Neuropathy in HIV/AIDS: Rationale, Design, Methods, Procedure and Logistics. AB - Distal sensory peripheral neuropathy is a common neurological complication experienced by people living with the human immunodeficiency virus (HIV). Traditional Chinese medicine (TCM) may offer effective interventions in the management of its symptoms. To improve the quality and transparency of reporting acupuncture clinical trials, the Consolidated Standards of Reporting Trials (CONSORT) guidelines were developed in 1996 and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) recommendations were introduced in 2001. Incorporating international guidelines, this paper describes the development of a RCT including rationale, design, methods, procedures and logistics for a pilot study aimed at evaluating acupuncture and moxibustion for neuropathy associated with HIV. Using STRICTA guidelines as a template, aspects of clinical research design are explored to further optimise future studies of TCM. PMID- 29756127 TI - Image Segmentation and Modeling of the Pediatric Tricuspid Valve in Hypoplastic Left Heart Syndrome. AB - Hypoplastic left heart syndrome (HLHS) is a single-ventricle congenital heart disease that is fatal if left unpalliated. In HLHS patients, the tricuspid valve is the only functioning atrioventricular valve, and its competence is therefore critical. This work demonstrates the first automated strategy for segmentation, modeling, and morphometry of the tricuspid valve in transthoracic 3D echocardiographic (3DE) images of pediatric patients with HLHS. After initial landmark placement, the automated segmentation step uses multi-atlas label fusion and the modeling approach uses deformable modeling with medial axis representation to produce patient-specific models of the tricuspid valve that can be comprehensively and quantitatively assessed. In a group of 16 pediatric patients, valve segmentation and modeling attains an accuracy (mean boundary displacement) of 0.8 +/- 0.2 mm relative to manual tracing and shows consistency in annular and leaflet measurements. In the future, such image-based tools have the potential to improve understanding and evaluation of tricuspid valve morphology in HLHS and guide strategies for patient care. PMID- 29756129 TI - Deep Multi-Task Multi-Channel Learning for Joint Classification and Regression of Brain Status. AB - Jointly identifying brain diseases and predicting clinical scores have attracted increasing attention in the domain of computer-aided diagnosis using magnetic resonance imaging (MRI) data, since these two tasks are highly correlated. Although several joint learning models have been developed, most existing methods focus on using human-engineered features extracted from MRI data. Due to the possible heterogeneous property between human-engineered features and subsequent classification/regression models, those methods may lead to sub-optimal learning performance. In this paper, we propose a deep multi-task multi-channel learning (DM2L) framework for simultaneous classification and regression for brain disease diagnosis, using MRI data and personal information (i.e., age, gender, and education level) of subjects. Specifically, we first identify discriminative anatomical landmarks from MR images in a data-driven manner, and then extract multiple image patches around these detected landmarks. A deep multi-task multi channel convolutional neural network is then developed for joint disease classification and clinical score regression. We train our model on a large multi center cohort (i.e., ADNI-1) and test it on an independent cohort (i.e., ADNI-2). Experimental results demonstrate that DM2L is superior to the state-of-the-art approaches in brain diasease diagnosis. PMID- 29756130 TI - Lifelong-RL: Lifelong Relaxation Labeling for Separating Entities and Aspects in Opinion Targets. AB - It is well-known that opinions have targets. Extracting such targets is an important problem of opinion mining because without knowing the target of an opinion, the opinion is of limited use. So far many algorithms have been proposed to extract opinion targets. However, an opinion target can be an entity or an aspect (part or attribute) of an entity. An opinion about an entity is an opinion about the entity as a whole, while an opinion about an aspect is just an opinion about that specific attribute or aspect of an entity. Thus, opinion targets should be separated into entities and aspects before use because they represent very different things about opinions. This paper proposes a novel algorithm, called Lifelong-RL, to solve the problem based on lifelong machine learning and relaxation labeling. Extensive experiments show that the proposed algorithm Lifelong-RL outperforms baseline methods markedly. PMID- 29756131 TI - Editorial: The importance of faculty and student international exchange programs. PMID- 29756132 TI - Comparison between five CAD/CAM systems for fit of zirconia copings. AB - OBJECTIVE: The aim of this in-vitro study was to investigate the marginal and internal fit of zirconia copings fabricated by five CAD/CAM (computer-aided design/computer-assisted manufacture) systems. METHOD AND MATERIALS: A typodont mandibular right first molar was prepared according to ideal parameters for a zirconia crown, scanned digitally, and 100 identical resin dies fabricated by 3D printing. Samples were randomly divided into five groups and sent to CAD/CAM systems for zirconia copings (A, Ceramill-Motion 2, Amann Girrbach; B, Weiland, Ivoclar Vivadent; C, Cerec, Ivoclar Vivadent; D, Prettau Zirconia, Zirkonzahn; E, Cad4dent). CAD of the copings included standardized cement space of 30 um and CAM was carried out. Copings were tried/adjusted on the respective dies and embedded under a standardized load of 20 N in self-curing resin. Samples were sectioned mesiodistally into two halves. Marginal and internal gap values were measured with a digital microscope at 50 to 200 * magnification at nine sites. RESULTS: The lowest and highest mean gap values of 46.93 +/- 13.50 and 101.65 +/- 35.56 MUm were found for Group A and Group D, respectively. ANOVA showed a statistically significant difference between the mean values of all the groups (P = .000). Multiple comparisons with post hoc Tukey test indicated a statistically significant difference (P < .05) between: Group A and all groups except B; B with D; C with A; D with A; and B and E with A. Mean buccal/lingual gap value was found to be 51.54 +/- 58.54 MUm. Of the nine sites, the least gap resulted at the buccal axial wall and the greatest at the central groove. The overall mean gap recorded for the copings was 72.43 +/- 57.56 MUm. CONCLUSION: Marginal and internal adaptations of CAD/CAM zirconia copings is influenced by manufacturing technique, and variations exist for different systems. Measurement sites showed different levels. CAD/CAM systems investigated showed a clinically acceptable level of gap values (< 120 um). PMID- 29756128 TI - Diabetic Retinopathy: Focus on Minority Populations. AB - Diabetic retinopathy is a major cause of blindness in the United States. With rise of the epidemic of obesity and diabetes in the USA and around the globe, serious and common diabetic complications are evolving as a major public health problem, particularly among minority populations. These populations are disproportionately affected by diabetes and 2-3 times more likely to develop visually significant complications. In this highly illustrated review article, we discuss the diabetic epidemic, highlighting the biology and the pathophysiologic mechanisms of this disorder on the anatomy of the eye. We also discuss the risk factors and the implications for minority populations. For the health care providers, we provide cutting edge information and imminently relevant information to help evaluate, manage, and know when to refer their patients to a specialist in ophthalmology to quell the tide of the epidemic. PMID- 29756133 TI - Biology of teeth and implants: Host factors - pathology, regeneration, and the role of stem cells. AB - In chronic periodontitis and peri-implantitis, cells of the innate and adaptive immune systems are involved directly in the lesions within the tissues of the patient. Absence of a periodontal ligament around implants does not prevent a biologic process similar to that of periodontitis from affecting osseointegration. Our first focus is on factors in the biology of individuals that are responsible for the susceptibility of such individuals to chronic periodontitis and to peri-implantitis. Genetic factors are of significant importance in susceptibility to these diseases. Genetic factors of the host affect the composition of the oral microbiome in the same manner that they influence other microbiomes, such as those of the intestines and of the lungs. Our second focus is on the central role of stem cells in tissue regeneration, in the functioning of innate and adaptive immune systems, and in metabolism of bone. Epithelial cell rests of Malassez (ERM) are stem cells of epithelial origin that maintain the periodontal ligament as well as the cementum and alveolar bone associated with the ligament. The tissue niche within which ERM are found extends into the supracrestal areas of collagen fiber-containing tissues of the gingivae above the bony alveolar crest. Maintenance and regeneration of all periodontal tissues involves the activity of a variety of stem cells. The success of dental implants indicates that important groups of stem cells in the periodontium are active to enable that biologic success. Successful replantation of avulsed teeth and auto-transplantation of teeth is comparable to placing dental implants, and so must also involve periodontal stem cells. Biology of teeth and biology of implants represents the biology of the various stem cells that inhabit specialized niches within the periodontal tissues. Diverse biologic processes must function together successfully to maintain periodontal health. Osseointegration of dental implants does not involve formation of cementum or collagen fibers inserted into cementum - indicating that some stem cells are not active around dental implants or their niches are not available. Investigation of these similarities and differences between teeth and implants will help to develop a better understanding of the biology and physiologic functioning of the periodontium. PMID- 29756134 TI - Synchronized-pressing fabrication of cost-efficient crystalline perovskite solar cells via intermediate engineering. AB - A cost-effective fabrication method that can produce a remarkable enhancement in the device efficiency along with a reduction in the fabrication cost is one of the crucial requirements for the commercialization of perovskite-based solar cells. Here, we report a low-cost, printable, and highly effective synchronized pressing annealing (SPA) method for inverted planar perovskite solar cells. In this method, two films are combined face-to-face for annealing, and separated as in a roll-to-roll process. Consequently, the SPA method provides two homogeneous highly crystalline MAPbI3 films with monolithic millimeter-scale crystalline grains by intermediate-induced crystallization engineering. The grains present a tendency of oriented growth along the <110> direction, parallel to the substrate, which leads to efficient charge transport. The IPSCs fabricated by the SPA method demonstrate a high efficiency of ~17% with significantly enhanced photocurrents and fill factors. Moreover, the characteristics of both top and bottom devices are very similar, with nearly identical J-V curves and photoresponse spectra. As the SPA method is compatible with the printing technology for mass production, and as it can produce twin devices of high quality via one fabrication process, it can provide a remarkable reduction in the fabrication cost. PMID- 29756135 TI - Microbial small molecules - weapons of plant subversion. AB - Covering: up to 2018 Plants live in close association with a myriad of microbes that are generally harmless. However, the minority of microbes that are pathogens can severely impact crop quality and yield, thereby endangering food security. By contrast, beneficial microbes provide plants with important services, such as enhanced nutrient uptake and protection against pests and diseases. Like pathogens, beneficial microbes can modulate host immunity to efficiently colonize the nutrient-rich niches within and around the roots and aerial tissues of a plant, a phenomenon mirroring the establishment of commensal microbes in the human gut. Numerous ingenious mechanisms have been described by which pathogenic and beneficial microbes in the plant microbiome communicate with their host, including the delivery of immune-suppressive effector proteins and the production of phytohormones, toxins and other bioactive molecules. Plants signal to their associated microbes via exudation of photosynthetically fixed carbon sources, quorum-sensing mimicry molecules and selective secondary metabolites such as strigolactones and flavonoids. Molecular communication thus forms an integral part of the establishment of both beneficial and pathogenic plant-microbe relations. Here, we review the current knowledge on microbe-derived small molecules that can act as signalling compounds to stimulate plant growth and health by beneficial microbes on the one hand, but also as weapons for plant invasion by pathogens on the other. As an exemplary case, we used comparative genomics to assess the small molecule biosynthetic capabilities of the Pseudomonas genus; a genus rich in both plant pathogenic and beneficial microbes. We highlight the biosynthetic potential of individual microbial genomes and the population at large, providing evidence for the hypothesis that the distinction between detrimental and beneficial microbes is increasingly fading. Knowledge on the biosynthesis and molecular activity of microbial small molecules will aid in the development of successful biological agents boosting crop resiliency in a sustainable manner and could also provide scientific routes to pathogen inhibition or eradication. PMID- 29756136 TI - A triphenylamine-functionalized luminescent sensor for efficient p-nitroaniline detection. AB - The combination of pi-conjugated fluorophores within a hybrid system gives rise to a triphenylamine-functionalized material [Zn(bpba)(NO3)] (1) (Hbpba = 4-(bis(4 (pyridin-4-yl)phenyl)amino)benzoic acid). Compound 1 features a 2D + 2D -> 2D parallel polycatenation structure with 63-hcb net. Photophysical studies revealed that the title phase showed superior sensitivity towards p-nitroaniline (p-NA) with a low detection limit (down to ~0.10 ppm). Specifically, following a new detection route, vapor-sensing experiments using a saturated ethanol solution of nitroaromatic isomers have been established for the first time. Highly sensitive and selective detection of p-NA by the proposed material with a rapid response time (t = 30 s, QE > 90.0%) as compared to that via the control isomers (t = 60s, QE < 6.0%) demonstrates an attractive feasible route and a promising luminescent sensor for nitroaromatic detection. PMID- 29756137 TI - ROS-responsive mesoporous silica nanoparticles for MR imaging-guided photodynamically maneuvered chemotherapy. AB - Mesoporous silica nanoparticles (MSNs) with stimuli-responsive gatekeepers have been extensively investigated for controlled drug delivery at the target sites. Herein, we developed reactive oxygen species (ROS)-responsive MSNs (R-MSNs), consisting of a gadolinium (Gd)-DOTA complex as the ROS-responsive gatekeeper and polyethylene glycol (PEG)-conjugated chlorin e6 as the ROS generator, for magnetic resonance (MR) imaging-guided photodynamic chemotherapy. Doxorubicin (DOX), chosen as an anticancer drug, was physically encapsulated into DOTA conjugated MSNs, followed by chemical crosslinking via the addition of GdCl3. DOX R-MSNs could effectively maintain their structural integrity in a physiological environment for 7 days and show an enhanced in vitro T1-MR imaging signal for the Gd-DOTA complex. Upon 660 nm laser irradiation, the release rate of DOX from DOX R-MSNs remarkably increased along with the disintegration of the gatekeeper, whereas DOX release was significantly retarded without irradiation. When DOX-R MSNs were intravenously injected into tumor-bearing mice, they were effectively accumulated in tumor tissue, which was demonstrated using MR imaging. In addition, tumor growth was significantly suppressed by DOX-R-MSNs, allowing for site-specific release of DOX in a photodynamically maneuvered manner. Overall, these results suggest that R-MSNs have potential as drug carriers for MR imaging guided photodynamic chemotherapy. PMID- 29756139 TI - Optical guiding-based cell focusing for Raman flow cell cytometer. AB - We report the use of an optical guiding arrangement generated in a microfluidic channel to produce a stream of single cells in a line for single-cell Raman spectroscopic analysis. The optical guiding arrangement consisted of dual-line optical tweezers, generated using a 1064 nm laser, aligned in the shape of a '' symbol. By controlling the laser power in the tweezers and the flow rate in the microfluidic channel, a single line flow of cells could be produced in the tail of the guiding arrangement, where the 514.5 nm Raman excitation beam was also located. Furthermore, by resonantly exciting the Raman spectrum, a good-quality Raman spectrum could be recorded from the flowing single cells as they passed through the Raman excitation focal spot without the need to trap the cells. As a proof of concept, it was shown that red blood cells (RBCs) could be guided to the tail of the optical guide and the Raman spectra of the resonantly excited cells could be recorded in a continuous manner without trapping the cells at a cell flow rate of ~500 cells per h. From the recorded spectra, we were able to distinguish between RBCs containing hemoglobin in the normal form (normal-RBCs) and the met form (met-RBCs) from a mixture of RBCs comprising met-RBCs and normal RBCs in a ratio of 1 : 9. PMID- 29756138 TI - Carboxymethyl pachyman (CMP) reduces intestinal mucositis and regulates the intestinal microflora in 5-fluorouracil-treated CT26 tumour-bearing mice. AB - The compound 5-fluorouracil (5-FU) is the first choice chemotherapeutic agent for the treatment of colorectal cancer (CRC), but intestinal mucositis is a primary limiting factor in anticancer therapy. There is currently no broadly effective targeted treatment to cure this side effect. Carboxymethylated pachyman (CMP) is a polysaccharide that is modified from the structure of pachyman isolated from Poria cocos (Chinese name: Fu Ling). Meanwhile, recent studies have shown that CMP exhibits immune regulatory, anti-inflammatory and antioxidant activities. Therefore, the purpose of this study was to evaluate the intestinal protective effect of CMP in 5-FU-treated CT26 tumour-bearing mice and to further explore its underlying mechanism(s) of action. Initially, a CT26 colon carcinoma xenograft mice model was established. The colon length, colon tissue injury, intestinal flora, short-chain fatty acids (SCFAs) and indicators linked to inflammation, antioxidation and apoptosis were then measured. Our results showed that CMP in combination with 5-FU reversed intestinal shortening (p < 0.01) and alleviated 5 FU-induced colon injury (p < 0.001) via suppression of ROS production; increasing the levels of CAT, GSH-Px and GSH; decreasing expression of NF-kappaB, p-p38 and Bax; and elevating the levels of Nrf2 and Bcl-2. More importantly, CMP had a significant impact and counteracted the intestinal microflora disorders produced by 5-FU by increasing the proportion of Bacteroidetes, lactobacilli, and butyric acid-producing and acetic acid-producing bacteria and restoring the intestinal flora diversity. Overall, this work suggested that CMP could regulate the ecological balance of the intestinal flora and reduce colon injuries induced by 5 FU in CT26 tumour-bearing mice, and the mechanism involved may be associated with the regulation of the NF-kappaB, Nrf2-ARE and MAPK/P38 pathways. PMID- 29756140 TI - Synthesis of unsymmetrical multi-aroyl derivatives of ferrocene using palladium catalysed oxidative C-H aroylation. AB - A palladium catalysed methodology for mono-selective oxidative aroylation of ferrocene has been achieved. 10 mol% of Pd(OAc)2 was used as the catalyst for this radical aroylation reaction using O-methyl-oxime as the directing group. tert-Butyl hydroperoxide was used as an oxidant and both aldehydes and alcohols were used as acyl-equivalents. The protocol has been extended to aryl, heteroaryl and sterically hindered aroylating agents. Acidic-hydrolysis with 6(N) HCl of the directing group resulted in unsymmetrically substituted ketone derivatives of ferrocene, which have not been achieved otherwise. PMID- 29756141 TI - Near-unity thermally activated delayed fluorescence efficiency in three- and four coordinate Au(i) complexes with diphosphine ligands. AB - The synthesis and photoluminescence properties of three-coordinate Au(i) complexes with rigid diphosphine ligands LMe {1,2-bis[bis(2 methylphenyl)phosphino]benzene}, LEt {1,2-bis[bis(2 ethylphenyl)phosphino]benzene}, and LiPr {1,2-bis[bis(2 isopropylphenyl)phosphino]benzene} are investigated. The LMe and LEt ligands afford two types of complexes: dinuclear complexes [MU-LMe(AuCl)2] (1d) and [MU LEt(AuCl)2] (2d) with an Au(i)-Au(i) bond and mononuclear three-coordinate Au(i) complexes LMeAuCl (1) and LEtAuCl (2). On the other hand, the bulkiest ligand, LiPr, affords three-coordinate Au(i) complexes, LiPrAuCl (3) and LiPrAuI (4), but no dinuclear complexes. X-ray analysis suggests that both 3 and 4 possess a highly distorted trigonal planar geometry. Moreover, luminescence data reveal that at room temperature, 3 and 4 exhibit yellow-green thermally activated delayed fluorescence in the crystalline state with maximum emission wavelengths at 558 and 549 nm, respectively. The emission yields are close to unity. Quantum chemical calculations suggest that the emission of 4 originates from the (sigma + X) -> pi* excited state that possesses strong intraligand charge-transfer character. The luminescent properties of four-coordinate Au(i) complex (5) possessing a tetrahedral geometry are discussed on the basis of the emission spectra and decay times measured in a temperature range of 309-77 K. PMID- 29756142 TI - Corannulene: a molecular bowl of carbon with multifaceted properties and diverse applications. AB - Unlike typical polycyclic aromatic hydrocarbons, such as coronene, which are flat and planar, corannulene is a molecular bowl of carbon. It can be imagined as the cap region of fullerene C60 or an end of a single-walled carbon nanotube. This structural distinction manifests itself in unique properties. For example, corannulene exhibits bowl-flipping dynamics, electron accepting capability, and formation of a ball-in-socket type of interaction with C60. These varied properties allow for application of corannulene in a myriad of disciplines ranging from organic electronics and sensing to energy storage and self-assembly. In this feature article, our goal is to discuss the major synthetic developments in corannulene chemistry which allow the scientific community access to this beautiful molecule in a practical fashion, the unique properties of the corannulene nucleus that sets it apart from the planar polynuclear aromatic hydrocarbons, and lastly its applications in the arena of materials chemistry. PMID- 29756143 TI - Potential use of MCR-ALS for the identification of coeliac-related biochemical changes in hyperspectral Raman maps from pediatric intestinal biopsies. AB - Raman hyperspectral imaging is an emerging practice in biological and biomedical research for label free analysis of tissues and cells. Using this method, both spatial distribution and spectral information of analyzed samples can be obtained. The current study reports the first Raman microspectroscopic characterisation of colon tissues from patients with Coeliac Disease (CD). The aim was to assess if Raman imaging coupled with hyperspectral multivariate image analysis is capable of detecting the alterations in the biochemical composition of intestinal tissues associated with CD. The analytical approach was based on a multi-step methodology: duodenal biopsies from healthy and coeliac patients were measured and processed with Multivariate Curve Resolution Alternating Least Squares (MCR-ALS). Based on the distribution maps and the pure spectra of the image constituents obtained from MCR-ALS, interesting biochemical differences between healthy and coeliac patients has been derived. Noticeably, a reduced distribution of complex lipids in the pericryptic space, and a different distribution and abundance of proteins rich in beta-sheet structures was found in CD patients. The output of the MCR-ALS analysis was then used as a starting point for two clustering algorithms (k-means clustering and hierarchical clustering methods). Both methods converged with similar results providing precise segmentation over multiple Raman images of studied tissues. PMID- 29756144 TI - Evaluation of a cooling/heating-assisted microextraction instrument using a needle trap device packed with aminosilica/graphene oxide nanocomposites, covalently attached to cotton. AB - A low-cost and reliable cooling/heating-assisted microextraction (CHaME) instrument was designed and fabricated for use in different modes of microextraction methods. The CHaME setup is able to cool down the sorbent and simultaneously heat the sample in a wide temperature range. Consequently, it can create a large thermal gap between the sorbent and the sample matrix, to promote the release of analytes from the sample tissue and enhance their effective trapping on the microextraction phase. The primary versions of the instrument have previously been evaluated, coupled with different modes of solid- and liquid phase microextraction strategies. Compared with conventional microextraction systems, it is able to extract volatile organic compounds from complicated solid matrices more effectively, rapidly and without any need for a sample preparation step. In this research, the final and compact version of the CHaME instrument was fabricated and employed in a cooling/heating-assisted needle trap device (CHaME NTD) for microextraction of polycyclic aromatic hydrocarbons (PAHs) in contaminated soil samples, prior to GC-FID determination. An aminosilica/graphene oxide nanocomposite was synthesized, covalently attached to cotton (Am Si/GO/Cot), packed inside a needle, and applied as an effective sorbent for trapping of the analytes. The influence of experimental parameters on the extraction efficiency of the TC-NTD-GC-FID strategy was evaluated and optimized. Under the optimal conditions, linear dynamic ranges (LDRs), limits of detection (LODs), and relative standard deviations (RSDs) for the PAHs were 0.001-2.0 MUg g 1, 5-38 pg g-1, and 6.2-9.8% (n = 6), respectively. The CHaME-NTD-GC-FID procedure was compared with the traditional NTD-GC-FID method. Additionally, the Am-Si/GO/Cot nanocomposite sorbent was compared with the most frequently used commercial sorbents. The results demonstrated the remarkable performance of the CHaME-NTD procedure and the Am-Si/GO/Cot composite sorbent. The developed setup was also used for the extraction and determination of PAHs in contaminated soil samples, through the CHaME-NTD-GC-FID procedure. PMID- 29756145 TI - Well-defined styryl and biphenyl calcium complexes from dilithio compounds and calcium iodide: synthesis, structure and reactivity toward nitrous oxide. AB - Efficient synthesis and structure elucidation of carbon-calcium sigma-bonded compounds are of remarkable interest and importance in organometallic chemistry of the heavier s-block metals. In this paper, we report that styryl and biphenyl calcium complexes with well-defined structures can be facilely obtained via metathesis reaction between their corresponding dilithio compound and calcium iodide. Single-crystal X-ray structural analysis of these calcium complexes revealed their unique iodide-bridged or dicalcium-bridged structures. Their reactivity toward nitrous oxide was disclosed. PMID- 29756146 TI - Effect of geometrical constraints on human pluripotent stem cell nuclei in pluripotency and differentiation. AB - Mechanical stimuli and geometrical constraints transmitted across the cytoskeleton to the nucleus affect the nuclear morphology and cell function. Human pluripotent stem cells (hPSCs) represent an effective tool for evaluating transitions in nuclear deformability from the pluripotent to differentiated stage, and for deciphering the underlying mechanisms. We report the first study that investigates the nuclear deformability induced by geometrical constraints of hPSCs both in the pluripotent stage and during early germ layer specification. We specifically developed micro-structured surfaces coupled with high-content imaging analysis algorithms to quantitatively characterize nuclear deformability. Our results show that hPSCs possess high nuclear deformability, which does not alter pluripotency. We observed nuclear deformability transition along early germ layer specification: during early ectoderm differentiation nuclear deformability is strongly reduced, during early endoderm differentiation nuclei keep a deformed shape and during early mesoderm specification they show an intermediate behaviour. Different mRNA expressions between hPSCs differentiated on flat and micro-structured surfaces have been observed along early mesoderm and early endoderm specification. In order to better understand the mechanisms of the nuclear deformability transition observed during early ectoderm differentiation, we also employed cytoskeletal and nuclear protein inhibitors to evaluate their role in determining the nuclear shape. Actin and nesprin are essential for maintaining deformed nuclei, while lamin A/C and intermediate filaments confer rigidity to the nucleus. This study suggests that nuclear deformability is highly regulated during differentiation. PMID- 29756147 TI - Direct coating of a g-C3N4 layer onto one-dimensional TiO2 nanocluster/nanorod films for photoactive applications. AB - We report the coating of metal-free graphitic carbon nitride (g-C3N4) onto titanium dioxide (TiO2) nanorods via a thermal evaporation method. Prior to g C3N4 coating, TiO2 nanoclusters were grown on TiO2 nanorods to enhance the surface area by dipping in a TiCl3 solution for 12, 24 and 36 h. The prepared films were analyzed to assess the improvement in absorbance and reduction in recombination losses. Nanoclustered TiO2 grown for 24 h and then coated with a g C3N4 film (i.e., TC_24h_CN) had the highest photocurrent of 235 and 290 MUA, respectively, when measured by transient photocurrent and linear sweep voltammetry techniques. The enhanced performance resulted from a reduced recombination of electron-hole pairs. The TC_24h_CN film displayed an excellent photoresponse over 15 h of exposure to visible light and hence could potentially be used in water purification device technology. PMID- 29756148 TI - Understanding the viral load during the synthesis and after rebinding of virus imprinted particles via real-time quantitative PCR. AB - In the present study, virus imprinted particles have been synthesized for recognizing and specifically binding viruses. These materials may be used for biomimetic sensing schemes and for selective removal of virus particles. Virus imprinting procedures require careful optimization of the synthesis route for obtaining selective and efficiently binding imprinted materials. A remaining limitation has been a facile method for the quantification of the viral load during the imprinting process. Herein, human adenovirus (AdV) was selected as a model virus facilitating the development and application of a rapid virus quantification method based on a molecular biological approach. A real-time quantitative polymerase chain reaction, a.k.a., the qPCR method was developed for monitoring the AdV viral load during the synthesis of AdV imprinted particles, and subsequent rebinding studies. The developed analytical strategy allows the direct, rapid, and sensitive quantification of human adenovirus type 5 concentrations during synthesis and application of AdV imprinted polymers (AdV MIPs) with a broad dynamic range suitable for both application scenarios. In addition, it was demonstrated by gel electrophoresis analysis that viruses indeed bind to the beads even after several washing steps. PMID- 29756149 TI - A new ether-based electrolyte for lithium sulfur batteries using a S@pPAN cathode. AB - A new electrolyte composed of 4 M LiFSI in dibutyl ether (DBE) is proposed for Li S batteries. Dissolution of lithium polysulfides is definitely inhibited by DBE. More impressively, the electrolyte ensures a high Coulombic efficiency for Li deposition/stripping (~99.2%) without dendrite growth. Enhanced cycling stability is demonstrated when coupled with a sulfurized poly(acrylonitrile) (S@pPAN) cathode. This electrolyte offers new insight into electrolyte design for high performance Li-S batteries. PMID- 29756150 TI - Rechargeable aqueous zinc-iodine batteries: pore confining mechanism and flexible device application. AB - Here we report a flexible and rechargeable aqueous Zn-iodine battery with an iodine/carbon cloth cathode. Combined experimental and computational studies suggest that the battery undergoes a reversible reaction of Zn + I2 <-> ZnI2 with suppressed I3- formation by confining iodine species in porous carbon. PMID- 29756152 TI - A quasi-solid-state and self-powered biosupercapacitor based on flexible nanoporous gold electrodes. AB - A quasi-solid-state and flexible biofuel cell using a hydrogel electrolyte preloaded with sugar as a fuel is described. The device can function as a self powered biosupercapacitor delivering pulses for over 600 cycles, with a power density over 10 times higher than that from the biofuel cell alone. PMID- 29756151 TI - A simple architecture with self-assembled monolayers to build immunosensors for detecting the pancreatic cancer biomarker CA19-9. AB - The challenge of the early diagnosis of pancreatic cancer in routine clinical practice requires low-cost means of detection, and this may be achieved with immunosensors based on electrical or electrochemical principles. In this paper, we report a potentially low-cost immunosensor built with interdigitated gold electrodes coated with a self-assembled monolayer and a layer of anti-CA19-9 antibodies, which is capable of detecting the pancreatic cancer biomarker CA19-9 using electrical impedance spectroscopy. Due to specific, irreversible adsorption of CA19-9 onto its corresponding antibody, according to data from polarization modulated infrared reflection absorption spectroscopy (PM-IRRAS), the immunosensor is highly sensitive and selective. It could detect CA19-9 in commercial samples with a limit of detection of 0.68 U mL-1, in addition to distinguishing between blood serum samples from patients with different concentrations of CA19-9. Furthermore, by treating the capacitance data with information visualization methods, we were able to verify the selectivity and robustness of the immunosensor with regard to false positives, as the samples containing higher CA19-9 concentrations, including those from tumor cells, could be distinguished from those with possible interferents. PMID- 29756153 TI - A metal-organic framework based on a custom-designed diisophthalate ligand exhibiting excellent hydrostability and highly selective adsorption of C2H2 and CO2 over CH4. AB - The ligand truncation strategy provides facile access to a wide variety of linkers for the construction of MOFs bearing diverse structures and intriguing properties. In this work, we employed this strategy to design and prepare a novel bent diisophthalate ligand, and used it to successfully construct a copper-based MOF ZJNU-51 with the formula of [Cu2L(H2O)2].5DMF (H4L = 5,5'-(triphenylamine 4,4'-diyl) diisophthalic acid), which was thoroughly characterized by various techniques including FTIR, TGA, PXRD and single-crystal X-ray diffraction. ZJNU 51 is a two-fold interpenetrated network in which the single network consists of dicopper paddlewheel units connected by the organic ligands and contains open channels as well as six distinct types of metal-organic cages. Furthermore, gas adsorption properties with respect to C2H2, CO2, and CH4 were systematically investigated, demonstrating that ZJNU-51 is a highly promising material for C2H2/CH4 and CO2/CH4 separations. Specifically, the IAST adsorption selectivity at 298 K and 1 atm reaches 35.6 and 5.4 for the equimolar C2H2/CH4 and CO2/CH4 gas mixtures, respectively. More significantly, as revealed by PXRD and N2 adsorption measurements, ZJNU-51 exhibits excellent chemical stability, which lays a good foundation for its practical application. PMID- 29756154 TI - A novel porphyrin-based near-infrared fluorescent probe for hypochlorite detection and its application in vitro and in vivo. AB - Reactive oxygen species (ROS), especially HOCl/ClO-, have been demonstrated to play essential roles in both physiological and pathological processes, and an abnormal level of HOCl/ClO- is related to some diseases. In this work, a very fast responsive (within 30 seconds) porphyrin-based fluorescent probe, TPP-TCF, for ClO- with a NIR emissive wavelength was prepared. This probe exhibited excellent selectivity towards ClO- and would not be interfered with by other ROS and typical nucleophiles. The limit of detection (LOD) for ClO- was evaluated to be 0.29 MUM, indicating high sensitivity towards ClO-. In further bioimaging experiments, TPP-TCF displayed low-cytotoxicity and good cell penetrability for recognizing exogenous ClO- in HeLa cells. Moreover, this probe was successfully applied in imaging endogenous ClO- in living animals. PMID- 29756155 TI - Half-metallicity in a honeycomb-kagome-lattice Mg3C2 monolayer with carrier doping. AB - To obtain high-performance spintronic devices with high integration density, two dimensional (2D) half-metallic materials are highly desired. Herein, we proposed a stable 2D material, i.e., the Mg3C2 monolayer, with a honeycomb-kagome lattice based on the particle-swarm optimization algorithm and first-principles calculations. This monolayer is an anti-ferromagnetic (AFM) semiconductor in its ground state. We have also demonstrated that a transition from an AFM semiconductor to a ferromagnetic half-metal in this 2D material can be induced by carrier (electron or hole) doping. The half-metallicity arises from the 2pz orbitals of the carbon (C) atoms for the electron-doped system and from the C 2px and 2py orbitals in the case of hole doping. Our findings highlight a new promising material with controllable magnetic and electronic properties towards 2D spintronic applications. PMID- 29756156 TI - Calcite crystallization in the cement system: morphological diversity, growth mechanism and shape evolution. AB - Carbonation plays an indispensable role in engineering construction, embracing mineralization, CO2 sequestration and low pH induced corrosion, but the essential mechanism of carbonation occurring in calcium silicate hydrate or portlandite can hardly be interpreted. Observation on how carbonation proceeds at the nano scale is thus critical for a better understanding of its dynamics. Here, using electron microscopy combined with first-principles calculation, a new view on carbonation in the cement system is revealed, considering morphological diversity, growth mechanism and shape evolution. Two types of crystalline forms of calcium carbonate (i.e. cubic and spindle) under room conditions were observed and determined to be calcite, both experimentally and theoretically. The mechanism of morphological evolution of calcite in a cement system was demonstrated based on the theory of aqueous chemistry. The [Ca2+] to [CO3] ratio was the principle cause for the diversity in crystal morphology instead of the types of reactants (i.e. portlandite or calcium silicate hydrates). Excess calcium species in the solution could selectively adsorb on surfaces, resulting in an inhibitive effect on the growth of specific crystal faces, (1 0 4)calcite and (2 1 1[combining macron])calcite in this case. Furthermore, a relationship between relative ionic concentration and the length to diameter ratio was established to predict the shape transformation. This work makes it possible to explore the chemical nature of carbonation from a nano scope rather than being confined to the macroscopic carbonation of concrete. PMID- 29756157 TI - Influence of Itch and Pain on Sleep Quality in Patients with Hidradenitis Suppurativa. AB - There is a lack of data evaluating the influence of hidradenitis suppurativa related subjective symptoms on sleep quality. The aim of this study was to assess the influence of itch and pain on sleep quality in 108 patients with hidradenitis suppurativa compared with 50 controls. The Athens Insomnia Scale (AIS) and Pittsburgh Sleep Quality Index (PSQI) were used to evaluate a spectrum of sleep disturbances. Mean +/- standard deviation AIS and PSQI scores among patients with hidradenitis suppurativa vs. controls were assessed as 5.4 +/- 4.3 vs. 5.5 +/- 3.4 and 6.5 +/- 3.6 vs. 3.1 +/- 1.9 points, respectively. The presence of both itch and pain had a significant impact on the frequency of insomnia. Pain was a crucial factor responsible for poor sleep quality among patients with hidradenitis suppurativa; its presence significantly affected subjective sleep quality, sleep duration and daytime dysfunction. Itch and pain have an important impact on insomnia and sleep quality in patients with hidradenitis suppurativa. PMID- 29756158 TI - Preferences of older patients regarding hip fracture rehabilitation service configuration: A feasibility discrete choice experiment. AB - OBJECTIVE: As part of a wider feasibility study, the feasibility of gaining older patients' views for hip fracture rehabilitation services was tested using a discrete choice experiment in a UK context. DESIGN: Discrete choice experiment is a method used for eliciting individuals' preferences about goods and services. SUBJECTS/PATIENTS: The discrete choice experiment was administered to 41 participants who had experienced hip fracture (mean age 79.3 years; standard deviation (SD) 7.5 years), recruited from a larger feasibility study exploring a new multidisciplinary rehabilitation for hip fracture. METHODS: Attributes and levels for this discrete choice experiment were identified from a systematic review and focus groups. The questionnaire was administered at the 3-month follow up. RESULTS: Participants indicated a significant preference for a fully qualified physiotherapist or occupational therapist to deliver the rehabilitation sessions (beta = 0.605, 95% confidence interval (95% CI) 0.462-0.879), and for their rehabilitation session to last less than 90 min (beta = -0.192, 95% CI 0.381 to -0.051). CONCLUSION: The design of the discrete choice experiment using attributes associated with service configuration could have the potential to inform service implementation, and assist rehabilitation service design that incorporates the preferences of patients. PMID- 29756159 TI - Survival and Associated Risk Factors for Mortality Among Infants with Critical Congenital Heart Disease in a Developing Country. AB - Critical congenital heart disease (CCHD) is associated with significant morbidity and mortality. However, data on survival of CCHD and the risk factors associated with its mortality are limited. This study examined CCHD survival and the risk factors for CCHD mortality. Using a retrospective cohort study of infants born with CCHD from 2006 to 2015, survival over 10 years was estimated using Kaplan Meier analysis, and the risk factors for mortality were analyzed using multivariate Cox proportional hazards regression. A total of 491 CCHD cases were included in the study, with an overall mortality rate of 34.8% (95% confidence interval [CI] 30.6-39.2). The intervention/surgical mortality rate was 9.8% <= 30 days and 11.5% > 30 days after surgery, and 17% died before surgery or intervention. The median age at death was 2.7 months [first quartile: 1 month, third quartile: 7.3 months]. The CCHD survival rate was 90.4% (95% CI 89-91.8%) at 1 month, 69.3% (95% CI 67.2-71.4%) at 1 year, 63.4% (95% CI 61.1-65.7%) at 5 years, and 61.4% (95% CI 58.9-63.9%) at 10 years. Weight of < 2 kg at diagnosis, associated syndromes, poor pre-operative condition, and non-duct-dependent CCHD were independent risk factors for poor survival, with hazard ratios of 2.61, 2.10, 2.22, and 1.70, respectively. CCHD is associated with a high mortality rate. Low weight, poor pre-operative condition, associated syndromes, and non duct-dependent CCHD are significant risk factors affecting the survival of infants with CCHD. PMID- 29756160 TI - Fetal and Postnatal Echocardiographic Diagnosis of Ebstein Anomaly of the Mitral Valve. AB - Ebstein anomaly of mitral valve (MV) is an extremely rare congenital heart disease. In the current report, we present a case of Ebstein of MV that was diagnosed prenatally. Fetal echocardiogram showed that the posterior leaflet of MV was tethered to the lateral wall of left ventricle (LV) with downward displacement into LV cavity. Postnatal transthoracic and transesophageal echocardiograms confirmed the diagnosis with apical displacement of the level of coaptation MV into the LV cavity. To the best of our knowledge, fetal diagnosis of Ebstein anomaly of MV has not yet been reported in the medical literature. PMID- 29756161 TI - Risk Factors for Failure of Systemic-to-Pulmonary Artery Shunts in Biventricular Circulation. AB - Systemic-to-pulmonary artery shunt placement is an established palliative procedure for congenital heart disease, but it is associated with high morbidity and mortality. Data of all patients with biventricular circulation who underwent systemic-to-pulmonary artery shunt implantation between 2000 and 2016 were reviewed. Endpoints of the study were shunt failure and shunt-related mortality. Shunt failure was defined as any shunt dysfunction requiring intervention or reoperation. Shunt-related mortality was defined as death due to shunt dysfunction. A total of 217 shunts (central shunt, n = 131, Blalock-Taussig shunt, n = 86) were implanted in 178 patients. The median age of the patients was 98 days [1 day to 1.2 years]. Corrective surgery was performed at a median time of 0.6 years [3 months to 7 years] after shunt placement. Shunt failure was diagnosed in 21 patients (9.6%) at a median time of 14.6 days [0 days to 2 years]. Causes of shunt failure were stenosis (n = 11; 5%) and thrombosis (n = 10; 4.6%). The rate of freedom from shunt failure was 89.9 +/- 2.6% at 1 year, the rate of shunt-related mortality was 3% (n = 5), and the rate of freedom from shunt-related mortality at 1 year was 97.5 +/- 1%. Platelet transfusion was required in 43 patients (20%), all for postoperative thrombocytopenia. Perioperative platelet transfusion (p = 0.03) and shunt size of 3 mm (p = 0.03) were identified as risk factors for shunt failure. Shunt size of 3 mm was also identified as a risk factor for shunt-related mortality. The ideal shunt size in patients with biventricular circulation requiring a systemic-to-pulmonary artery shunt is 3.5 mm or larger. Platelet transfusion increases the risk of shunt failure and should be avoided. Type of shunt and diagnosis have no influence on morbidity or mortality after shunt placement. PMID- 29756162 TI - Retrospective analysis of mepivacaine, prilocaine and chloroprocaine for low-dose spinal anaesthesia in outpatient perianal procedures. AB - PURPOSE: Perianal procedures are carried out in an outpatient setting regularly. The purpose of this retrospective analysis was to investigate the impact of different local anaesthetics (LA) for spinal anaesthesia (SPA) on operating room (OR) efficiency (perioperative process times, turnaround times) and postoperative recovery. This study aims on the determination of the optimal LA for low-dose SPA in the specific setting of a high-volume day-surgery centre. METHODS: Anaesthesia records of all patients undergoing perianal outpatient surgery under saddle-block SPA at the Mannheim University Medical Centre from 2008 until 2017 were analysed. Patients were categorized as having received prilocaine, mepivacaine or chloroprocaine. RESULTS: Two thousand seven hundred forty-six patients were included. Postoperative recovery was faster for chloroprocaine 1% compared with both other LAs. Preoperative processes but not process times in the OR were shorter for chloroprocaine. In contrary, turnaround times were significantly prolonged when chloroprocaine had been used, leading to reduction of OR efficiency. CONCLUSION: Low-dose SPA provides reliable blocks for perianal surgery. Considerations on the choice of LA for SPA must include not only the recovery profile, but also the impact on OR efficiency. Due to shorter turnaround times and a manageable prolonged duration of stay, prilocaine is the preferable LA for low-dose SPA in perianal outpatient surgery at a high-volume day-surgery centre. PMID- 29756163 TI - Diagnostic utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG PET) in asymptomatic subjects at increased risk for Alzheimer's disease. AB - PURPOSE: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer's disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) epsilon4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. METHODS: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. RESULTS: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE epsilon4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. CONCLUSION: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE epsilon4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications. PMID- 29756165 TI - Study on the dose modification factor of strut adjusted volume implant (SAVI) with a 169Yb source using MCNP4C. AB - The SAVI has gained widespread use for accelerated partial breast irradiation (APBI) brachytherapy. Treatments with SAVI produce inherent heterogeneities including variable backscatter due to proximity to the tissue-air interface and variable cavity contents, causing inaccuracy in the dose calculation. In this study, a model of SAVI with sources of 169Yb developed recently was defined and simulations with MCNP4C code of Monte Carlo were performed through different scenarios to assess the effects of these heterogeneities on the dose distribution. The results showed that the dose delivered to target volume may be lower than the planned dose by up to 9-16%. Therefore, the therapy with169Yb must be viewed with caution and a correction factor must be applied in treatment planning systems. It was also observed that the presence of air cavity changed the relative dose 1% for a symmetric plan compared to a water cavity and up to 5% for an asymmetric plan. It was indicated that the dose modification factor (DMF) did not differ in any significant way to that of the symmetric plan. The effect of the composition on the DMF was negligible because the natures of water and breast tissue were approximately similar. All the obtained results indicated that should 169Yb sources be used with SAVI applications, some amendments of treatment planning systems would be employed. PMID- 29756164 TI - Methods for the determination of skeletal muscle blood flow: development, strengths and limitations. AB - Since the first measurements of limb blood flow at rest and during nerve stimulation were conducted in the late 1800s, a number of methods have been developed for the determination of limb and skeletal muscle blood flow in humans. The methods, which have been applied in the study of aspects such as blood flow regulation, oxygen uptake and metabolism, differ in terms of strengths and degree of limitations but most have advantages for specific settings. The purpose of this review is to describe the origin and the basic principles of the methods, important aspects and requirements of the procedures. One of the earliest methods, venous occlusion plethysmography, is a noninvasive method which still is extensively used and which provides similar values as other more direct blood flow methods such as ultrasound Doppler. The constant infusion thermodilution method remains the most appropriate for the determination of blood flow during maximal exercise. For resting blood flow and light-to-moderate exercise, the non invasive ultrasound Doppler methodology, if handled by a skilled operator, is recommendable. Positron emission tomography with radiolabeled water is an advanced method which requires highly sophisticated equipment and allows for the determination of muscle-specific blood flow, regional blood flows and estimate of blood flow heterogeneity within a muscle. Finally, the contrast-enhanced ultrasound method holds promise for assessment of muscle-specific blood flow, but the interpretation of the data obtained remains uncertain. Currently lacking is high-resolution methods for continuous visualization and monitoring of the skeletal muscle microcirculation in humans. PMID- 29756167 TI - Sex Differences in Gene and Protein Expression After Intracerebral Hemorrhage in Mice. AB - Sex dimorphism has been demonstrated after experimental intracerebral hemorrhage (ICH). Decreased mortality and improved neurobehavioral outcomes occur in female compared to male mice after intrastriatal autologous blood or collagenase injection. Sex-specific differences in post-ICH gene and protein expression may provide mechanistic insight into this phenomenon. Ten- to 12-week-old C57BL/6 male (M) and female in high estrous state (HE-F) underwent left intrastriatal collagenase injection. We assessed neurobehavioral outcomes over the first 30 days, hematoma volume and cerebral edema evolution over the first 24 h, and transcriptomic gene and protein expression at pre-selected time points during the acute phase of injury. Genome-wide expression profiling was performed with Affymetrix GeneChip Mouse Genome 2.0 Probes, and proteomics analyses were performed using mass spectroscopy. Sex does not affect hemorrhage evolution, but female sex is associated with improved neurobehavioral recovery after ICH. A total of 7037 probes qualified for our filtering criteria, representing 5382 mapped genes and 256 unmapped genes. Female-unique pathways involved cell development, growth, and proliferation, while male-unique pathways involved molecular degradation. At 6 and 24 h post-ICH, differential expression was observed in 850 proteins vs baseline in males, 608 proteins vs baseline in females, and 1 protein in females vs males. Female sex is associated with improved neurobehavioral recovery, and differential gene and protein expression after intrastriatal collagenase injection. PMID- 29756166 TI - Dosimetric characterisation of the optically-stimulated luminescence dosimeter in cobalt-60 high dose rate brachytherapy system. AB - This study investigates the characteristics and application of the optically stimulated luminescence dosimeter (OSLD) in cobalt-60 high dose rate (HDR) brachytherapy, and compares the results with the dosage produced by the treatment planning system (TPS). The OSLD characteristics comprised linearity, reproducibility, angular dependence, depth dependence, signal depletion, bleaching rate and cumulative dose measurement. A phantom verification exercise was also conducted using the Farmer ionisation chamber and in vivo diodes. The OSLD signal indicated a supralinear response (R2 = 0.9998). It exhibited a depth independent trend after a steep dose gradient region. The signal depletion per readout was negligible (0.02%), with expected deviation for angular dependence due to off-axis sensitive volume, ranging from 1 to 16%. The residual signal of the OSLDs after 1 day bleached was within 1.5%. The accumulated and bleached OSLD signals had a standard deviation of +/- 0.78 and +/- 0.18 Gy, respectively. The TPS was found to underestimate the measured doses with deviations of 5% in OSLD, 17% in the Farmer ionisation chamber, and 7 and 8% for bladder and rectal diode probes. Discrepancies can be due to the positional uncertainty in the high-dose gradient. This demonstrates a slight displacement of the organ at risk near the steep dose gradient region will result in a large dose uncertainty. This justifies the importance of in vivo measurements in cobalt-60 HDR brachytherapy. PMID- 29756168 TI - Transsplenic splenoportography and portal venous interventions in pediatric patients. AB - BACKGROUND: Data regarding transsplenic portal venous access for diagnostic imaging and endovascular intervention in children are limited, possibly due to concerns regarding high bleeding risks and resultant underutilization. OBJECTIVE: To investigate the safety and utility of transsplenic splenoportography and portal venous interventions in children. MATERIALS AND METHODS: A retrospective review was performed of all pediatric patients undergoing percutaneous transsplenic portal venous access and intervention at two large tertiary pediatric institutions between January 2012 and April 2017 was performed. Parameters assessed included procedural indications, procedural and relevant prior imaging, technical details of the procedures, laboratory values and clinical follow-up. RESULTS: Transsplenic portal venous access was achieved in all patients. Diagnostic transsplenic splenoportography was performed in 22 patients and was 100% successful at providing the desired anatomical and functional information. Four transsplenic portal venous interventions were performed with 100% success: meso-Rex shunt angioplasty, snare targeted transjugular intrahepatic portosystemic shunt (TIPS) creation through cavernous transformation, pharmacomechanical thrombectomy for acute thrombosis, and transplant portal vein angioplasty. Intraperitoneal bleeding occurred in 2/26 (7.7%) and one case required transfusion (3.8%). No cases of hemorrhage were observed when transsplenic access size was 4 Fr or smaller. CONCLUSION: Transsplenic splenoportography in children is safe and effective when noninvasive imaging methods have yielded incomplete information. Additionally, a transsplenic approach has advantages for complex portal interventions. Bleeding risks are proportional to tract access size and may be mitigated by tract embolization. PMID- 29756169 TI - Vitellogenin transcytosis in follicular cells of the honeybee Apis mellifera and the wasp Polistes simillimus. AB - Vitellogenin receptor (VgR) is a low-density lipoprotein receptor responsible for the mediated endocytosis of vitellogenin (Vg) during egg formation in insects. The maturing oocyte is enveloped by a follicular epithelium, which has large intercellular spaces during Vg accumulation (patency). However, Vg has been reported in the cytoplasm of follicular cells, indicating that there may be a transcellular route for its transport. This study verified the presence of VgR in the follicular cells of the ovaries of the honeybee Apis mellifera and the wasp Polistes simillimus in order to evaluate if Vg is transported via transcytosis in these insects. Antibodies specific for vitellogenin receptor (anti-VgR), vitellogenin (anti-Vg), and clathrin (anti-Clt) were used for immunolocalization. The results showed the presence of VgR on the apical and basal plasma membranes of follicular cells of the vitellogenic follicles in both species, indicating that VgR may have been transported from the basal to the apical cell domain, followed by its release into the perivitelline space, evidenced by the presence of apical plasma membrane projections containing VgR. Co-localization proved that Vg bind to VgR and that the transport of this protein is mediated by clathrin. These data suggest that, in these social insects, Vg is transported via clathrin mediated VgR transcytosis in follicular cells. PMID- 29756170 TI - Further characteristics of Arcanobacterium pinnipediorum DSM 28752T and Arcanobacterium wilhelmae DSM 102162T, two novel species of genus Arcanobacterium. AB - The newly described type strains Arcanobacterium pinnipediorum DSM 28752T and Arcanobacterium wilhelmae DSM 102162T, initially isolated from an anal swab of a harbor seal (Sammra et al. Int J Syst Evol Microbiol 65:4539-4543, 2015) and the genital tract of a rhinoceros (Sammra et al. Int J Syst Evol Microbiol 67:2093 2097, 2017), could be further characterized by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and Fourier transform infrared (FT-IR) spectroscopy and by sequencing the genomic targets 16S-23S rDNA intergenic spacer region (ISR) and the genes rpoB, gap, and tuf. The two strains investigated in the present study were isolated together with several other bacterial species indicating that the pathogenic importance of both species remained unclear. However, the detection of specific spectra by MALDI-TOF MS and by FT-IR spectroscopy and the presented genotypic approaches might help to identify A. pinnipediorum and A. wilhelmae in the future and might elucidate the role these two species play in infections of animals. PMID- 29756172 TI - Relationship between erosive tooth wear and beverage consumption among a group of schoolchildren in Mexico City. AB - OBJECTIVE: To assess the association between erosive tooth wear (ETW) and consumption of different kinds of beverages in a group of schoolchildren 11-14 years old in Mexico City. METHODS: Cross-sectional study in a sample of students (n = 512) in Mexico City. The Basic Erosive Wear Examination (BEWE) was used to quantify ETW. Beverage consumption (BC) was determined using a frequency questionnaire; beverages included pure water, natural fruit juices, milk, hot beverages, and soft drinks. Ordinal logistic regression model was used to evaluate the association between the presence of ETW and BC. RESULTS: In total, 45.7% of the schoolchildren showed an initial loss of surface texture (BEWE = 1) and 18.2% a distinct defect involving loss of dental tissue (BEWE >= 2) in at least one tooth. For each glass (350 ml) of milk/week, the odds of not having erosive wear (BEWE = 0) versus having an initial loss of surface texture (BEWE = 1) or of having an initial loss of surface texture versus the presence of a defect involving the loss of dental tissue (BEWE >= 2) decreased 4% (OR = 0.96, 95% CI 0.93-0.99, p = 0.008); for each portion of sweet carbonated beverage consumed (350 ml), the odds increased 3% (OR = 1.03, 95% CI 1.001-1.07, p = 0.046). CONCLUSION: The intake of milk and milk-based products could be a dietary means of helping prevent ETW, especially if their consumption could replace sweet carbonated drink consumption. CLINICAL RELEVANCE: Knowing the impact of beverage consumption on ETW helps to provide suitable recommendations for the prevention and control of ETW in order to promote tooth longevity. PMID- 29756171 TI - Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival. AB - We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death. PMID- 29756175 TI - Zinc Supplementation Ameliorates Diabetic Cataract Through Modulation of Crystallin Proteins and Polyol Pathway in Experimental Rats. AB - Non-enzymatic glycation of lens proteins and elevated polyol pathway in the eye lens have been the characteristic features of a diabetic condition. We have previously reported the benefits of zinc supplementation in reducing hyperglycemia and associated metabolic abnormalities and oxidative stress in diabetic rats. The current study explored whether zinc supplementation protects against cataractogenesis through modulation of glycation of lens proteins, elevated polyol pathway, oxidative stress, and proportion of different heat shock proteins in the eye lens of diabetic rats. Streptozotocin-induced diabetic rats were fed with a zinc-enriched diet (5 and 10 times of normal) for 6 weeks. Supplemental zinc alleviated the progression and maturation of diabetes-induced cataract. Zinc was also effective in preventing the reduced content of total and imbalanced proportion of soluble proteins in the lens. Supplemental zinc also alleviated cross-linked glycation and concomitant expression of the receptor of glycated products and oxidative stress indicators in the eye lens. Zinc supplementation further induced the concentration of heat shock protein in the eye lens of diabetic rats, specifically alpha-crystallin. Zinc supplementation counteracted the elevated activity and expression of polyol pathway enzymes and molecules in the lens. The results of this animal study endorsed the advantage of zinc supplementation in exerting the antiglycating influence and downregulating polyol pathway enzymes to defer cataractogenesis in diabetic rats. PMID- 29756173 TI - Prediction of changes due to mandibular autorotation following miniplate-anchored intrusion of maxillary posterior teeth in open bite cases. AB - BACKGROUND: Prediction of the treatment outcome of various orthodontic procedures is an essential part of treatment planning. Using skeletal anchorage for intrusion of posterior teeth is a relatively novel procedure for the treatment of anterior open bite in long-faced subjects. METHODS: Data were analyzed from lateral cephalometric radiographs of a cohort of 28 open bite adult subjects treated with intrusion of the maxillary posterior segment with zygomatic miniplate anchorage. Mean ratios and regression equations were calculated for selected variables before and after intrusion. RESULTS: Relative to molar intrusion, there was approximately 100% vertical change of the hard and soft tissue mention and 80% horizontal change of the hard and soft tissue pogonion. The overbite deepened two folds with 60% increase in overjet. The lower lip moved forward about 80% of the molar intrusion. Hard tissue pogonion and mention showed the strongest correlations with molar intrusion. There was a general agreement between regression equations and mean ratios at 3 mm molar intrusion. CONCLUSIONS: This study attempted to provide the clinician with a tool to predict the changes in key treatment variables following skeletally anchored maxillary molar intrusion and autorotation of the mandible. PMID- 29756176 TI - Response: Similar effect of quercetin on CYP2E1 and CYP2C9 activities in humans? PMID- 29756174 TI - Phenotypic detection of clinical isolates of Haemophilus influenzae with altered penicillin-binding protein 3. AB - The aims of this study were to determine the correlation of mutations in the ftsI gene (coding for PBP3) of Haemophilus influenzae with aminopenicillin resistance and to evaluate the 2017 European Committee for Antibiotic Susceptibility Testing (EUCAST) guidelines for clinical categorization of ampicillin, amoxicillin, and amoxicillin-clavulanate for strains with mutated PBP3 conferring resistance (rPBP3). A panel of 91 H. influenzae isolates was genetically characterized by sequencing of the fstI gene. For all the studied isolates, a screening with benzylpenicillin 1U (BP1) was carried out and minimum inhibitory concentrations (MICs) of ampicillin, amoxicillin, and amoxicillin-clavulanate were tested and interpreted according to EUCAST recommendations. ftsI sequence analysis revealed a total of 14 different amino acid substitutions in PBP3. The substitution patterns most commonly observed were [D350N, M377I, A502V, N526K] among the bla positive rPBP3 strains (37.5%) and [D350N, A502T, N526K] among the bla-negative rPBP3 strains (24.5%). Screening with BP1 was able to correctly categorize 100% of the bla-negative sPBP3 strains, 100% of the bla-positive strains, and 92% of the bla-negative rPBP3 ones. Only 29% of the bla-negative rPBP3 strains evaluated displayed ampicillin MICs above the current EUCAST resistant breakpoint defined at 1 MUg/ml. The PBP3 substitution patterns of the strains evaluated are similar to the ones observed in previous Spanish and European studies. Although the screening with BP1 proved to be adequate in the detection of bla-negative rPBP3 strains, these cannot be reliably identified by current 2018 EUCAST breakpoints for ampicillin. PMID- 29756177 TI - Interspecific germ cell transplantation: a new light in the conservation of valuable Balkan trout genetic resources? AB - Interspecific transplantation of germ cells from the brown trout Salmo trutta m. fario and the European grayling Thymallus thymallus into rainbow trout Oncorhynchus mykiss recipients was carried out in order to improve current practices in conservation of genetic resources of endangered salmonid species in the Balkan Peninsula. Current conservation methods mainly include in situ efforts such as the maintenance of purebred individuals in isolated streams and restocking with purebred fingerlings; however, additional ex situ strategies such as surrogate production are needed. Steps required for transplantation such as isolation of high number of viable germ cells and fluorescent labeling of germ cells which are to be transplanted have been optimized. Isolated and labeled brown trout and grayling germ cells were intraperitoneally transplanted into 3 to 5 days post hatch rainbow trout larvae. Survival of the injected larvae was comparable to the controls. Sixty days after transplantation, fluorescently labeled donor cells were detected within the recipient gonads indicating successful incorporation of germ cells (brown trout spermatogonia and oogonia 27%; grayling spermatogonia-28%; grayling oogonia-23%). PCR amplification of donor mtDNA CR fragments within the recipient gonads additionally corroborated the success of incorporation. Overall, the transplantation method demonstrated in this study presents the first step and a possible onset of the application of the germ cell transplantation technology in conservation and revitalization of genetic resources of endangered and endemic species or populations of salmonid fish and thus give rise to new or improved management strategies for such species. PMID- 29756178 TI - Hippocampal deep brain stimulation: persistent seizure control after bilateral extra-cranial electrode fracture. AB - Hippocampal deep brain stimulation (DBS) can provide an effective alternative for intractable temporal lobe epilepsy. In this case report, we describe a peculiar outcome after a post-traumatic wire-disconnection of a bilateral hippocampal DBS device. The patient presented a postoperative long-term significant reduction in seizure frequency even with an absent electric stimulation. This case gives the possibility to consider alternatives in epilepsy surgery, based on stimulation interference (lesional or electrical disturbing) in the epileptogenic zone. PMID- 29756180 TI - Anodal tDCS of the swallowing motor cortex for treatment of dysphagia in multiple sclerosis: a pilot open-label study. AB - Swallowing difficulties are a common symptom of multiple sclerosis (MS). The early detection and treatment of dysphagia is critical to prevent complications, including poor nutrition, dehydration, and lung infections. Recently, transcranial direct current stimulation (tDCS) has been proven to be effective in ameliorating swallowing problems in stroke patients. In this pilot study, we aimed to assess safety and efficacy of transcranial direct current stimulation (tDCS) in the treatment of dysphagia in MS patients. We screened 30 patients by using the 10-item DYsphagia in MUltiple Sclerosis (DYMUS) questionnaire, and patients at risk for dysphagia underwent a clinical and fiberoptic endoscopic evaluation of swallowing (FEES). Six patients who presented with mild to moderate dysphagia underwent the experimental procedures. These consisted of 5 sessions of anodal tDCS applied in consecutive days over the right swallowing motor cortex. Patients were followed-up at 1 week, 1 month and 3 months after treatment, and changes in the Dysphagia Outcome and Severity Scale (DOSS) score between baseline and post-tDCS were assessed. Our results showed that in all patients, the tDCS treatment determined a mild but significant clinical benefit (one-point improvement in the DOSS score) lasting up to 1 month. In conclusion, our preliminary results show that anodal tDCS has therapeutic potential in the treatment of swallowing problems in patients suffering with MS. However, future double-blind, randomized, and sham-controlled studies are needed to confirm the present findings. PMID- 29756179 TI - Basal vitamin D levels and disease activity in multiple sclerosis patients treated with fingolimod. AB - BACKGROUND: Several studies have shown an association between 25-hydroxyvitamin D (25[OH]D) levels and multiple sclerosis (MS) susceptibility and/or level of disease activity in patients treated with first line drugs. AIMS: To investigate whether baseline 25[OH]D values could influence disease activity also during treatment with the second-line drug fingolimod (FTY). PATIENTS AND METHODS: We enrolled 176 MS patients who started FTY at the San Raffaele Hospital (OSR) MS center with available 25[OH]D measurement at the time of treatment start. We then prospectively followed them for 2 years with periodic clinical examinations and MRI scans. RESULTS: We found no linear correlation between baseline 25[OH]D levels and annualized relapse rate (ARR) or time to first relapse. However, we observed that patients with serum 25[OH]D >= 100 nmol/l showed a lower number of Gd+ and combined unique activity (CUA) lesions at baseline compared to patients with the lowest 25[OH]D levels (less than 50 nmol/l, p value < 0.05). Moreover, they showed fewer CUA lesions at 2-year follow-up also when accounting for baseline level of disease activity (p value < 0.05). CONCLUSIONS: In patients treated with FTY, those with the highest baseline 25(OH)D levels had a significantly lower number of active lesions at baseline; the same effect, even if weaker, was observed also at 2-year follow-up when adjusting for baseline disease activity. Given Vitamin D supplementation safety profile, also if a causal effect has not yet been shown, most of MS patients could probably benefit from 25[OH]D levels above those currently considered to be sufficient. PMID- 29756181 TI - Morphology-tunable tellurium nanomaterials produced by the tellurite-reducing bacterium Lysinibacillus sp. ZYM-1. AB - Although tellurite is highly toxic to organisms, elemental tellurium nanomaterials (TeNMs) have many uses. The microbe-mediated reduction of tellurite to Te(0) has been shown to be a green and cost-effective approach for turning waste into wealth. However, it is difficult to tune the morphology of biogenic nanomaterials. In this study, a series of experiments was conducted to investigate the factors influencing tellurite reduction by the tellurite-reducing bacterium Lysinibacillus sp. ZYM-1, including pH, tellurite concentration, temperature, and heavy metal ions. The optimal removal efficiency of tellurite was respectively achieved at pH 8, 0.5 mM tellurite, and 40 degrees C. All of the tested metal ions retarded the reduction of tellurite, especially Cd2+ and Co2+, which completely inhibited its reduction. Further characterization of the biogenic TeNMs indicated that their morphology could be tuned by the tellurite concentration, pH, temperature, and organic solvents used. Regular Te nanosheets were produced using 5 mM tellurite. The TeNMs were primarily synthesized in the cell membrane. Hexagonal Te nanoplates, nanorods, nanoflowers, and nanobranches were synthesized when combining membrane fractions with tellurite and NADH. The diverse morphologies are assumed to be induced by the synergy between the reduction kinetics and the protein structure. Therefore, this study confirmed that the bacterium can tune the morphology of TeNMs, broadening the potential application of biogenic TeNMs. PMID- 29756182 TI - Controlling risks of P water pollution by sorption on soils, pyritic material, granitic material, and different by-products: effects of pH and incubation time. AB - Batch experiments were used to test P sorbent potential of soil samples, pyritic and granitic materials, mussel shell, mussel shell ash, sawdust, and slate waste fines for different pH and incubation times. Maximum P sorption varied in a wide range of pH: < 4 for pyritic material, 4-6 for forest soil, > 5 for slate fines, > 6 for shell ash, and pH 6-8 for mussel shell. P sorption was rapid (< 24 h) for forest soil, shell ash, pyritic material, and fine shell. On the opposite side, it was clearly slower for vineyard soil, granitic material, slate fines, pine sawdust, and coarse shell, with increased P sorption even 1 month later. For any incubation time, P sorption was > 90% in shell ash, whereas forest soil, pyritic material, and fine shell showed sorption rates approaching 100% within 24 h of incubation. These results could be useful to manage and/or recycle the sorbents tested when focusing on P immobilization or removal, in circumstances where pH changes and where contact time may vary from hours to days, thus aiding to diminish P pollution and subsequent eutrophication risks, promoting conservation and sustainability. PMID- 29756183 TI - Effects of heavy metal species, concentrations, and speciation on pentachlorophenol sorption by river biofilms. AB - The sorption of trace organic pollutants at solid/liquid interfaces is one of the most important processes that influence their fate and behaviours in the aquatic environment. Sorption is affected by coexisting contaminants. The process and extent to which coexisting heavy metals affect the sorption of organochlorine pesticides (OCPs), especially acid radical anion heavy metals, are still unclear. Here, the effects of the species, concentrations, and speciation of the heavy metals Cu, Pb, and Cr, and the metalloid As on the sorption of pentachlorophenol (PCP), as a model OCP, by river biofilms were investigated through batch experiments. The results show that the presence of Cu, Pb, Cr, and As decreased the maximum sorption quantity of PCP onto the biofilms by 67.7, 9.2, 58.4, and 14.4%, respectively. The inhibitory effect of heavy metals on sorption decreased as the initial concentration ratios of heavy metals to PCP increased. In addition, the impact of heavy metals on PCP sorption was attributed to differences in heavy metal speciation. Cu and Pb commonly existed as divalent cations, but Cr and As existed as anionic acid radicals under the experimental conditions. The inhibitory effects of heavy metals on PCP sorption by biofilms were enhanced as the cation valence state increased, while the effects were weakened as the anionic acid radical valence state increased. Although all four heavy metals had inhibitory effects on PCP sorption by biofilms, there were distinct differences in the mechanisms causing these effects. PMID- 29756184 TI - Determinants of CO2 emissions in the MERCOSUR: the role of economic growth, and renewable and non-renewable energy. AB - The main objective of this study was to analyze the impact of energy consumption (divided into renewable and non-renewable sources) and income on CO2 emissions within the environmental Kuznets curve (EKC) model for the Southern Common Market (MERCOSUR). To do so, the annual panel data collected during the 1990-2014 periods was used. The CO2 variable, representing carbon dioxide emissions in metric tons per capita, was used as a proxy for the emission of pollutants. The annual data were obtained from the World Bank (World Development Indicators). The sample consisted of the five MERCOSUR member countries: Argentina, Brazil, Paraguay, Uruguay, and Venezuela, comprising a period of 25 consecutive years. The results showed that energy consumption from renewable sources had a negative impact on CO2 emissions, while the energy consumption from non-renewable sources had a positive impact. The positive impact of economic development on CO2 emissions was also seen. In addition, this study supports the validity of the EKC hypothesis for the MERCOSUR because GDP (real output) leads to environmental degradation while GDP2 reduces the level of gas emissions. PMID- 29756185 TI - Remediation of arsenic-contaminated paddy soil by iron-modified biochar. AB - Arsenic contamination in paddy soils has aroused global concern due to its threats to food security and human health. Biochar modified with different iron materials was prepared for arsenic (As) immobilization in contaminated soils. Soil incubation experiments were carried to investigate the effects of biochar modified with Fe-oxyhydroxy sulfate (Biochar-FeOS), FeCl3 (Biochar-FeCl3), and zero-valent iron (Biochar-Fe) on the pH, NaHCO3-extractable As concentrations, and the As fractions in soils. The scanning electron microscope and X-ray diffraction analysis demonstrated that iron was successfully loaded onto the surface or embedded into the pores of the biochar. Addition of Biochar-FeOS, Biochar-FeCl3, and Biochar-Fe had no significant effects on the soil pH but significantly decreased the contents of NaHCO3-extractable As in soils by 13.95 30.35%, 10.97-28.39%, and 17.98-35.18%, respectively. Biochar-FeOS, Biochar FeCl3, and Biochar-Fe treatments decreased the concentrations of non-specifically sorbed and specifically sorbed As fractions in soils, and increased the amorphous and poorly crystalline, hydrated Fe, Al oxide-bound, and residual As fractions. Compared with the other iron-modified biochars, Biochar-FeOS showed the most effective immobilization and has the potential for the remediation of As contaminated paddy soils. PMID- 29756186 TI - Polybrominated diphenyl ethers in cord blood and perinatal outcomes from Laizhou Wan Birth Cohort, China. AB - We explored whether polybrominated diphenyl ethers (PBDEs) exposed in cord blood could have any potential relationship with perinatal outcomes. Participants were pregnant females (n = 222) who were recruited from a prospective birth cohort (Laizhou Wan Birth Cohort, LWBC) between September 2010 and February 2012. We measured eight PBDE congeners (BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183) in cord serum and examined their relationship with perinatal outcomes. The median levels of BDE-28, BDE-47, BDE-85, BDE-99, BDE-100, BDE-153, BDE-154, and BDE-183 were 2.92, 3.93, 2.29, 7.03, 3.03, 3.14, 1.46, and 2.55 ng/g lipids, respectively. For each log unit increase in BDE-47, BDE-100, and ?4PBDEs, gestational age increased by 0.70 weeks (95% confidence interval [CI] 0.25, 1.15), 0.48 weeks (95% CI 0.03, 0.94), and 0.73 weeks (95% CI 0.12, 1.34), respectively. We also found that BDE-47 was positively associated with head circumference (beta = 0.42, 95% CI 0.00, 0.84). Given that our study area is one of the major brominated flame retardant production areas in China, and the cord PBDEs levels were relatively higher than those reported in most other Asian areas, more studies on the effects of in utero PBDE exposure on fetal growth and child development are warranted. PMID- 29756187 TI - The formation of unsaturated zones within cemented paste backfill mixtures effects on the release of copper, nickel, and zinc. AB - Flooding of cemented paste backfill (CPB) filled mine workings is, commonly, a slow process and could lead to the formation of unsaturated zones within the CPB fillings. This facilitates the oxidation of sulfide minerals and thereby increases the risk of trace metal leaching. Pyrrhotitic tailings from a gold mine (cyanidation tailing (CT)), containing elevated concentrations of nickel (Ni), copper (Cu), and zinc (Zn), were mixed with cement and/or fly ash (1-3 wt%) to form CT-CPB mixtures. Pyrrhotite oxidation progressed more extensively during unsaturated conditions, where acidity resulted in dissolution of the Ni, Cu, and Zn associated with amorphous Fe precipitates and/or cementitious phases. The establishment of acidic, unsaturated conditions in CT-CBP:s with low fractions (1 wt%) of binders increased the Cu release (to be higher than that from CT), owing to the dissolution of Cu-associated amorphous Fe precipitates. In CT-CPB:s with relatively high proportions of binder, acidity from pyrrhotite oxidation was buffered to a greater extent. At this stage, Zn leaching increased due the occurrence of fly ash-specific Zn species soluble in alkaline conditions. Irrespective of binder proportion and water saturation level, the Ni and Zn release were lower, compared to that in CT. Fractions of Ni, Zn, and Cu associated with acid-soluble phases or amorphous Fe precipitates, susceptible to remobilization under acidic conditions, increased in tandem with binder fractions. Pyrrhotite oxidation occurred irrespective of the water saturation level in the CPB mixtures. That, in turn, poses an environmental risk, whereas a substantial proportion of Ni, Cu, and Zn was associated with acid-soluble phases. PMID- 29756188 TI - Transcatheter aortic valve implantation: the optimal alternative to cardiac reoperation also from the patient's perspective. PMID- 29756189 TI - Percutaneous mitral valvuloplasty in the modern era. PMID- 29756190 TI - Patient-prosthesis mismatch after minimally invasive aortic valve replacement. PMID- 29756191 TI - Use of adipose-derived stromal cells in the treatment of chronic ischaemic heart disease: safety and feasibility study. PMID- 29756192 TI - Heart rate variability during and after chemotherapy with anthracycline in patients with breast cancer. PMID- 29756193 TI - Selected adipokines and thickness of the intima-media complex in patients with systemic lupus erythematosus. PMID- 29756194 TI - Efficacy and safety of prolonged mild therapeutic hypothermia treatment in patients after out-of-hospital cardiac arrest: preliminary data. PMID- 29756195 TI - Should the family witness cardiopulmonary resuscitation? Perceptions of health professionals in Poland. PMID- 29756196 TI - Endovascular treatment of thoracoabdominal aortic aneurysm in Loeys-Dietz syndrome. PMID- 29756197 TI - Late left atrioventricular disruption: an unusual complication of mitral valve replacement after endocarditis. PMID- 29756198 TI - Bioresorbable vascular scaffolds for a long diffuse coronary lesion: insights from optical coherence tomography at 25-month follow-up. PMID- 29756199 TI - Borderline bilateral renal artery stenosis assessed with high-resolution angiography, intravascular ultrasound, and renal fractional flow reserve in a patient with renovascular hypertension. PMID- 29756200 TI - Ablation of symptomatic ventricular tachycardia after surgical correction of ventricular septal defect in childhood: using high-density mapping, how precise is EnSite Precision? PMID- 29756201 TI - Venoarterial extracorporeal membrane oxygenation in massive pulmonary embolism. PMID- 29756202 TI - Scapular breadth is associated with forelimb-dominated suspensory behavior in Atelidae: Comments on Selby and Lovejoy (2017). PMID- 29756203 TI - The growing role of machine learning and artificial intelligence in developmental medicine. PMID- 29756204 TI - Distributions of ectomycorrhizal and foliar endophytic fungal communities associated with Pinus ponderosa along a spatially constrained elevation gradient. AB - PREMISE OF THE STUDY: Understanding distributions of plant-symbiotic fungi is important for projecting responses to environmental change. Many coniferous trees host ectomycorrhizal fungi (EM) in association with roots and foliar endophytic fungi (FE) in leaves. We examined how EM and FE associated with Pinus ponderosa each vary in abundance, diversity, and community structure over a spatially constrained elevation gradient that traverses four plant communities, 4 degrees C in mean annual temperature, and 15 cm in mean annual precipitation. METHODS: We sampled 63 individuals of Pinus ponderosa in 10 sites along a 635 m elevation gradient that encompassed a geographic distance of 9.8 km. We used standard methods to characterize each fungal group (amplified and sequenced EM from root tips; isolated and sequenced FE from leaves). KEY RESULTS: Abundance and diversity of EM were similar across sites, but community composition and distributions of the most common EM differed with elevation (i.e., with climate, soil chemistry, and plant communities). Abundance and composition of FE did not differ with elevation, but diversity peaked in mid-to-high elevations. CONCLUSIONS: Our results suggest relatively tight linkages between EM and climate, soil chemistry, and plant communities. That FE appear less linked with these factors may speak to limitations of a culture-based approach, but more likely reflects the small spatial scale encompassed by our study. Future work should consider comparable methods for characterizing these functional groups, and additional transects to understand relationships of EM and FE to environmental factors that are likely to shift as a function of climate change. PMID- 29756205 TI - Retrospective analysis of changes in response topographies of escape-maintained aggressive behavior during functional analyses. AB - We observed changes in the rates of response topographies during the demand condition of functional analyses for participants who demonstrated problem behavior maintained by escape. Over the course of the functional analysis for each participant, the number of topographies decreased from the first to the last session. Additionally, after the first session of the demand condition the rate of responding for one topography increased or remained at high levels while the rates of all other topographies decreased. The implications of these results when conducting functional analysis are discussed. PMID- 29756206 TI - Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. AB - The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade >=3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa. PMID- 29756207 TI - Quantification of tissue-engineered trachea performance with computational fluid dynamics. AB - OBJECTIVES/HYPOTHESIS: Current techniques for airway characterization include endoscopic or radiographic measurements that produce static, two-dimensional descriptions. As pathology can be multilevel, irregularly shaped, and dynamic, minimal luminal area (MLA) may not provide the most comprehensive description or diagnostic metric. Our aim was to examine the utilization of computational fluid dynamics (CFD) for the purpose of defining airway stenosis using an ovine model of tissue-engineered tracheal graft (TETG) implantation. STUDY DESIGN: Animal research model. METHODS: TETGs were implanted into sheep, and MLA was quantified with imaging and endoscopic measurements. Graft stenosis was managed with endoscopic dilation and stenting when indicated. Geometries of the TETG were reconstructed from three-dimensional fluoroscopic images. CFD simulations were used to calculate peak flow velocity (PFV) and peak wall shear stress (PWSS). These metrics were compared to values derived from a quantitative respiratory symptom score. RESULTS: Elevated PFV and PWSS derived from CFD modeling correlated with increased respiratory symptoms. Immediate pre- and postimplantation CFD metrics were similar, and implanted sheep were asymptomatic. Respiratory symptoms improved with stenting, which maintained graft architecture similar to dilation procedures. With stenting, baseline PFV (0.33 m/s) and PWSS (0.006 Pa) were sustained for the remainder of the study. MLA measurements collected via bronchoscopy were also correlated with respiratory symptoms. PFV and PWSS found via CFD were correlated (R2 = 0.92 and 0.99, respectively) with respiratory symptoms compared to MLA (R2 = 0.61). CONCLUSIONS: CFD is valid for informed interventions based on multilevel, complex airflow and airway characteristics. Furthermore, CFD may be used to evaluate TETG functionality. LEVEL OF EVIDENCE: NA. Laryngoscope, E272-E279, 2018. PMID- 29756209 TI - High-flow oxygen insufflation into the trachea during endolaryngeal surgery. PMID- 29756208 TI - Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression. AB - RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus with pyrosequencing technology detected RNF43 hotspot mutations in one (0.88%) of 113 colorectal polyp cases and in 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harbouring mutated RNF43 experienced a higher recurrence rate than those harbouring non-mutated RNF43. In addition, the growth of RNF43 wild-type colorectal cancer cell lines was significantly increased by RNF43 silencing. We generated Rnf43 knockout mice in a C57BL/6 N background by using the CRISPR-Cas9 system. Although intestinal organoids from Rnf43 knockout mice did not show continuous growth in the absence of R-spondin, an azoxymethane/dextran sodium sulphate mouse model demonstrated that tumours were markedly larger in Rnf43 knockout mice than in wild-type mice. These findings provide evidence that Wnt signalling activation by RNF43 mutations during the tumourigenic stage enhances tumour growth and promotes a high recurrence rate in colorectal cancer patients. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29756210 TI - Assessment of main factor causing sensory quality defects in chicken seasoning during storage. AB - BACKGROUND: Chicken seasoning is a widely consumed palatable seasoning made with chicken meat. Quality, and especially sensory quality, may determine the consumer choice of food. The same bag of chicken seasoning will be stored by the consumers over a long period of time when it is in use, so it is particularly important to be able to assess its sensory quality. However, the sensory quality defects of chicken seasoning during storage remain unknown. This study evaluated flavor changes in chicken seasoning during storage using sensory evaluation and gas chromatography-mass spectrometry (GC-MS). RESULTS: The sensory evaluation indicated a perceptible change in rancidity during storage. The GC-MS results showed increases in the content of aldehydes, heterocyclic compounds, ketones, and sulfur compounds associated with lipid oxidation. A random forest model was constructed to predict the storage time based on the data for volatile compounds related to lipid oxidation. The low average predicted error indicated a good correlation between lipid oxidation and storage time. CONCLUSION: These results suggest that lipid oxidation is the main factor behind sensory quality defects in chicken seasoning during storage. This can be used as the basis for further evaluation of sensory quality and the shelf life of chicken seasoning. (c) 2018 Society of Chemical Industry. PMID- 29756212 TI - Optimization of artemisinin extraction from Artemisia annua L. with supercritical carbon dioxide + ethanol using response surface methodology. AB - Malaria is a high priority life-threatening public health concern in developing countries, and therefore there is a growing interest to obtain artemisinin for the production of artemisinin-based combination therapy products. In this study, artemisinin was extracted from the Artemisia annua L. plant using supercritical carbon dioxide (SC-CO2 ) modified with ethanol. Response surface methodology based on central composite rotatable design was employed to investigate and optimize the extraction conditions of pressure (9.9-30 MPa), temperature (33-67 degrees C), and co-solvent (ethanol, 0-12.6 wt.%). Optimum SC-CO2 extraction conditions were found to be 30 MPa and 33 degrees C without ethanol. Under optimized conditions, the predicted artemisinin yield was 1.09% whereas the experimental value was 0.71 +/- 0.07%. Soxhlet extraction with hexane resulted in higher artemisinin yields and there was no significant difference in the purity of the extracts obtained with SC-CO2 and Soxhlet extractions. Results indicated that SC-CO2 and SC-CO2 +ethanol extraction is a promising alternative for the extraction of artemisinin to eliminate the use of organic solvents, such as hexane, and produce extracts that can be used for the production of antimalarial products. PMID- 29756211 TI - Appropriateness criteria predict outcomes for sinus surgery and may aid in future patient selection. AB - OBJECTIVES: Appropriateness criteria to determine surgical candidacy for chronic rhinosinusitis (CRS) have recently been described. This study stratified patients who underwent endoscopic sinus surgery (ESS) according to these new appropriateness criteria and evaluated postoperative improvements among appropriateness categories. METHODS: Adult patients with uncomplicated CRS electing ESS were prospectively enrolled in a multi-institutional cohort study between March 2011 and June 2015 to assess outcomes. Subsequently, appropriateness criteria that consider preoperative medical therapy, 22-item SinoNasal Outcome Test (SNOT-22) scores, and Lund-Mackay computed tomography scores were retrospectively applied. RESULTS: A total of 92.6% (436 of 471) were categorized as "appropriate" ESS candidates, 3.8% (18 of 471) as "uncertain," and 3.6% (17 of 471) as "inappropriate." Among uncertain patients, two-thirds (12 of 18) had identifiable reasons for undergoing ESS, most commonly oral corticosteroid intolerance (n = 6). Postoperative follow-up was available for 79% (n = 372). Clinically significant SNOT-22 improvements occurred in both appropriate and uncertain groups (all P < 0.050) but not among the inappropriate group. The inappropriate group reported less mean improvement in SNOT-22 total score compared to appropriate (P = 0.008) and uncertain (P = 0.006) groups. CONCLUSION: The vast majority of patients (~93%) who underwent ESS in a multi institutional research program were identified as appropriate candidates for surgical intervention, as defined by current appropriateness criteria. Valid considerations frequently exist for offering ESS to patients categorized as uncertain. Appropriate and uncertain candidates report similar, clinically significant SNOT-22 improvements following surgery. Patients classified as inappropriate reported significantly less improvement following ESS. Surgical appropriateness criteria may assist in predicting outcomes of ESS. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2448-2454, 2018. PMID- 29756213 TI - The influence of different soft-tissue grafting procedures at single implant placement on esthetics: A randomized controlled trial. AB - BACKGROUND: Soft-tissue grafting to thicken the soft tissue around dental implants was proposed to ameliorate the esthetic outcome. Traditionally, connective tissue is used as a grafting material, but a xenogeneic collagen matrix was introduced as an alternative to reduce patient morbidity. METHODS: A total of 60 patients randomly received either no graft (n = 20, NG group), a connective tissue graft (n = 20, CTG group), or a xenogeneic collagen matrix (n = 20, XCM group) when an implant was placed in a preserved alveolar ridge. Changes in mid-buccal mucosal level (MBML) at 1 (T1 ) and 12 (T12 ) months after final implant crown placement were compared to the pre-extraction level. Additionally, esthetics, marginal bone level, clinical peri-implant parameters, and patient satisfaction were assessed. RESULTS: At T12 , mean changes in MBML were -0.48 +/- 1.5 mm, -0.04 +/- 1.1 mm, and -0.17 +/- 1.3 mm in the NG, CTG, and XCM groups (P = 0.56), respectively. Regarding the other outcome variables, no significant intergroup differences were observed. CONCLUSIONS: Soft-tissue grafting at single implant placement in preserved alveolar ridges does not result in a better esthetic outcome or in better peri-implant health and should not be considered as a standard procedure. PMID- 29756214 TI - Unilateral periorbital swelling: a diagnostic dilemma. PMID- 29756215 TI - Attentional refreshing moderates the word frequency effect in immediate and delayed recall tasks. AB - Using an online sample experiment, the study described herein addresses the fervent debate about the relationships between working memory and long-term memory (LTM). We manipulated refreshing opportunities and LTM status of memoranda by varying, respectively, the type of span tasks (simple span with short or long lists versus complex span tasks) and the frequency of the memory words (low versus high). In accordance with the hypothesis that refreshing is involved particularly in complex rather than simple span tasks, the frequency effect in immediate recall tests was reduced in the former. Moreover, contrary to previous studies in which refreshing increases LTM effects in delayed recall tests, our data point in the opposite direction. However, the frequency effect was also reduced in the simple task with short lists, suggesting that refreshing might not be the only process underlying the reduction of frequency effect in delayed tests. Finally, no differences in delayed recall were found between the complex span task that affords refreshing opportunities and the other tasks, suggesting that another process than refreshing, probably consolidation, might be involved in delayed recall. PMID- 29756216 TI - Bioavailability of suppository acetaminophen in healthy and hospitalized ill dogs. AB - To determine the plasma pharmacokinetics of suppository acetaminophen (APAP) in healthy dogs and clinically ill dogs. This prospective study used six healthy client-owned and 20 clinically ill hospitalized dogs. The healthy dogs were randomized by coin flip to receive APAP orally or as a suppository in crossover study design. Blood samples were collected up to 10 hr after APAP dosing. The hospitalized dogs were administered APAP as a suppository, and blood collected at 2 and 6 hr after dosing. Plasma samples were analyzed by ultra-performance liquid chromatography with triple quadrupole mass spectrometry. In healthy dogs, oral APAP maximal concentration (CMAX =2.69 MUg/ml) was reached quickly (TMAX =1.04 hr) and eliminated rapidly (T1/2 = 1.81 hr). Suppository APAP was rapidly, but variably absorbed (CMAX =0.52 MUg/ml TMAX =0.67 hr) and eliminated (T1/2 = 3.21 hr). The relative (to oral) fraction of the suppository dose absorbed was 30% (range <1%-67%). In hospitalized ill dogs, the suppository APAP mean plasma concentration at 2 hr and 6 hr was 1.317 MUg/ml and 0.283 MUg/ml. Nonlinear mixed effects modeling did not identify significant covariates affecting variability and was similar to noncompartmental results. Results supported that oral and suppository acetaminophen in healthy and clinical dogs did not reach or sustain concentrations associated with efficacy. Further studies performed on different doses are needed. PMID- 29756217 TI - Comparative two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) of human milk to identify dysregulated proteins in breast cancer. AB - Breast cancer (BC) remains a major cause of mortality, and early detection is considered important for reducing BC-associated deaths. Early detection of BC is challenging in young women, due to the limitations of mammography on the dense breast tissue of young women. We recently reported results of a pilot proteomics study, using one-dimensional polyacrylamide gel electrophoresis (1D-PAGE) and mass spectrometry (MS) to investigate differences in milk proteins from women with and without BC. Here, we applied two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and MS to compare the protein pattern in milk from the breasts of a single woman who was diagnosed with BC in one breast 24 months after donating her milk. Statistically different gel spots were picked for protein digestion followed by nanoliquid chromatography tandem MS (nanoLC-MS/MS) analysis. The upregulated proteins in BC versus control are alpha-amylase, gelsolin isoform a precursor, alpha-2-glycoprotein 1 zinc isoform CRA_b partial, apoptosis-inducing factor 2 and vitronectin. Several proteins were downregulated in the milk of the breast later diagnosed with cancer as compared to the milk from the healthy breast, including different isoforms of albumin, cholesterol esterase, different isoforms of lactoferrin, different proteins from the casein family and different isoforms of lysozyme. Results warrant further studies to determine the usefulness of these milk proteins for assessing risk and detecting occult disease. MS data is available via ProteomeXchange with identifier PXD009860. PMID- 29756218 TI - Tyrosine absorption spectroscopy: Backbone protonation effects on the side chain electronic properties. AB - The UV-vis spectrum of Tyrosine and its response to different backbone protonation states have been studied by applying the Perturbed Matrix Method (PMM) in conjunction with molecular dynamics (MD) simulations. Herein, we theoretically reproduce the UV-vis absorption spectrum of aqueous solution of Tyrosine in its zwitterionic, anionic and cationic forms, as well as of aqua-p Cresol (i.e., the moiety that constitutes the side chain portion of Tyrosine). To achieve a better accuracy in the MD sampling, the Tyrosine Force Field (FF) parameters were derived de novo via quantum mechanical calculations. The UV-vis absorption spectra are computed considering the occurring electronic transitions in the vertical approximation for each of the chromophore configurations sampled by the classical MD simulations, thus including the effects of the chromophore semiclassical structural fluctuations. Finally, the explicit treatment of the perturbing effect of the embedding environment permits to fully model the inhomogeneous bandwidth of the electronic spectra. Comparison between our theoretical-computational results and experimental data shows that the used model captures the essential features of the spectroscopic process, thus allowing to perform further analysis on the strict relationship between the quantum properties of the chromophore and the different embedding environments. (c) 2018 Wiley Periodicals, Inc. PMID- 29756219 TI - Is topical epinephrine safe for hemostasis in endoscopic sinus surgery? PMID- 29756220 TI - Cutaneous manifestations of JAK2+ myeloproliferative neoplasms. PMID- 29756221 TI - Rapid growth rate is associated with poor prognosis in cutaneous squamous cell carcinoma. AB - BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) represents the most common form of skin cancer after basal cell carcinoma, and can be both locally invasive and metastatic to distant sites. Growth rate (GR) has been poorly evaluated in cSCC, despite clinical evidence suggesting that GR is an important risk factor in cSCC. AIM: To analyse the influence of GR in cSCC prognosis. METHODS: We retrospectively evaluated GR in a series of 90 cSCCs and tried to correlate GR with prognosis in cSCC. RESULTS: We demonstrated that tumours with a GR of > 4 mm/month exhibit a higher risk of nodal progression and a shorter progression time to lymph node metastasis in cSCC than those with GR of < 4 mm/month. As expected, GR correlated with tumour proliferation, as determined by Ki-67 expression. CONCLUSIONS: We consider a GR of 4 mm/month as the cutoff point that distinguishes between rapid- and slow-progressing tumours and, more importantly, to identify a subset of high-risk cSCCs. PMID- 29756222 TI - Disease-Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium. AB - Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field. PMID- 29756223 TI - Climate-related genetic variation in a threatened tree species, Pinus albicaulis. AB - PREMISE OF THE STUDY: With ongoing climate change, understanding of intraspecific adaptive variation is critical for conservation and restoration of plant species. Such information is especially scarce for threatened and endangered tree species, such as Pinus albicaulis Engelm. Therefore, our principal aims were to assess adaptive variation and characterize its relationship with climate of seed origin. METHODS: We grew seedlings from 49 P. albicaulis populations representative of the interior northwestern United States in two common garden field experiments under warm-dry conditions that mimic climatic conditions predicted in the current century for areas within the species' range. Differences among populations were assessed for growth and survival. We then used regression to describe clines of apparent adaptive variation in relation to climate variation among the populations' origins. KEY RESULTS: We detected genetic divergence for growth and survival among populations of P. albicaulis. These differences corresponded to distinct climatic clines. Populations originating from locations with lower spring precipitation exhibited greater survival in response to natural drought. Populations originating from increasingly milder climates exhibited greater height growth under relatively limited stress in early years and greater fitness after 12 yr. CONCLUSIONS: The results suggest that P. albicaulis exhibits adaptive variation for drought tolerance and growth in response to selection pressures associated with variation in moisture availability and temperature, respectively. Even so, clinal variation was relatively gentle. Thus, apparent differences in local adaptation to climate among populations appears to be relatively low. PMID- 29756225 TI - Pollen wall degradation in the Brassicaceae permits cell emergence after pollination. AB - PREMISE OF THE STUDY: Despite attempts to degrade the sporopollenin in pollen walls, this material has withstood a hundred years of experimental treatments and thousands of years of environmental attack in insects and soil. We present evidence that sporopollenin, nonetheless, locally degrades only minutes after pollination in Arabidopsis thaliana flowers, and describe here a two-part pollen germination mechanism in A. thaliana involving both chemical weakening of the exine wall and swelling of the underlying intine. METHODS: We explored naturally occurring components from pollen and stigma surfaces and found a tripartite mix of hydrogen peroxide, peroxidase and catalase enzymes (all at high levels at the pollination interface) to be experimentally sufficient to degrade the sporopollenin of some Brassicaceae family members. KEY RESULTS: At pollination, factors carried on the pollen surface may mix with factors on the stigma surface in a reaction that locally oxidizes the exine pollen wall. Hydrogen peroxide, catalases, and peroxidases are biologically present at the right time and place and, when mixed experimentally, are sufficient to degrade the walls of susceptible pollen. CONCLUSIONS: Our work on native biochemistry for breaching sporopollenin suggests new research directions in pollen aperture evolution and could aid efforts to analyze sporopollenin's composition, needed for application of this corrosion-resistant, but long-intractable material. PMID- 29756226 TI - Tuberculous granuloma developed 9 years after bacillus Calmette-Guerin vaccination in a patient with immunodeficiency. PMID- 29756227 TI - The genetic nomenclature of recessive cerebellar ataxias. AB - The recessive cerebellar ataxias are a large group of degenerative and metabolic disorders, the diagnostic management of which is difficult because of the enormous clinical and genetic heterogeneity. Because of several limitations, the current classification systems provide insufficient guidance for clinicians and researchers. Here, we propose a new nomenclature for the genetically confirmed recessive cerebellar ataxias according to the principles and criteria laid down by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders. We apply stringent criteria for considering an association between gene and phenotype to be established. The newly proposed list of recessively inherited cerebellar ataxias includes 62 disorders that were assigned an ATX prefix, followed by the gene name, because these typically present with ataxia as a predominant and/or consistent feature. An additional 30 disorders that often combine ataxia with a predominant or consistent other movement disorder received a double prefix (e.g., ATX/HSP). We also identified a group of 89 entities that usually present with complex nonataxia phenotypes, but may occasionally present with cerebellar ataxia. These are listed separately without the ATX prefix. This new, transparent and adaptable nomenclature of the recessive cerebellar ataxias will facilitate the clinical recognition of recessive ataxias, guide diagnostic testing in ataxia patients, and help in interpreting genetic findings. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756229 TI - Retiform hemangioendothelioma presenting as a pedunculated nodule on the site of an inguinal pyoderma chronica. PMID- 29756228 TI - Comparison of ultrasonographic findings of schwannomas and angioleiomyomas. AB - A subcutaneous tumor accompanied by tenderness has a myriad of differential diagnoses. Indeed, using physical findings alone to achieve a diagnosis is often challenging. In this study, we focused on schwannomas and angioleiomyomas, which usually develop as hard subcutaneous tumors and are often associated with tenderness. We aimed to determine significant differentiating features between the tumor types, using ultrasonography. We compared clinical findings and ultrasonographic imaging and calculated the statistical significance for each item. In total, we analyzed 11 schwannomas and 13 angioleiomyomas of the extremities, trunk and head. There was no significant difference in patient characteristics or clinical findings. Meanwhile, the mean maximum diameter (P = 0.002), localization (P = 0.04) and entering or exiting nerves (P = 0.01) were significantly different according to ultrasonography findings. Thus, ultrasonography provides excellent information for the initial assessment of a slow-growing, painful, subcutaneous soft tissue mass. According to our study, it is difficult to identify a single, differentiating feature between angioleiomyoma and schwannoma on ultrasonography, but including multiple findings during the work-up can facilitate differential diagnosis. PMID- 29756230 TI - The relationship between pulmonary artery wedge pressure and pulmonary blood volume derived from contrast echocardiography: A proof-of-concept study. AB - BACKGROUND: Pulmonary transit time (PTT) obtained from contrast echocardiography is a marker of global cardiopulmonary function. Pulmonary blood volume (PBV), derived from PTT, may be a noninvasive surrogate for left-sided filling pressures, such as pulmonary artery wedge pressure (PAWP). We sought to assess the relationship between PBV obtained from contrast echocardiography and PAWP. METHODS: Participants were adult survivors of childhood cancer that had contrast echocardiography performed nearly simultaneously with right-heart catheterization. PTT was derived from time-intensity curves of contrast passage through the right ventricle (RV) and left atrium (LA). PBV relative to overall stroke volume (rPBV) was estimated from the product of PTT and heart rate during RV-LA transit. PAWP was obtained during standard right-heart catheterization. The Spearman correlation coefficient was used to assess the relationship between rPBV and PAWP. RESULTS: The study population consisted of 7 individuals who had contrast echocardiography and right-heart catheterization within 3 hours of each other. There was a wide range of right atrial (1-17 mm Hg), mean pulmonary artery (18-42 mm Hg), and PAW pressures (4-26 mm Hg) as well as pulmonary vascular resistance (<1-6 Wood Units). We observed a statistically significant correlation between rPBV and PAWP (r = .85; P = .02). CONCLUSION: Relative PBV derived from contrast echocardiography correlates with PAWP. If validated in larger studies, rPBV could potentially be used as an alternative to invasively determine left sided filling pressure. PMID- 29756232 TI - Differences in emotion regulation difficulties among adults and adolescents across eating disorder diagnoses. AB - OBJECTIVE: Although much empirical attention has been devoted to emotion regulation (ER) in individuals with eating disorders, little is known about ER across a wide age range and among different ED subtypes. The current study sought to examine ER in a sample of eating disorder patients. METHOD: A total of 364 adults and adolescents with anorexia nervosa restricting subtype (AN-R), anorexia nervosa binge/purge subtype (AN-BP), or bulimia nervosa (BN) were assessed with the Difficulties in Emotion Regulation Scale (DERS). RESULTS: Older ages were associated with higher DERS total, nonacceptance, goals, and impulsivity scores. When controlling for age, patients with BN and AN-BP had higher overall DERS scores than those with AN, and there were some differences among diagnostic subtypes on specific facets of ER. CONCLUSIONS: These results indicate that treatments for emotion dysregulation may be applied across eating disorder diagnoses and ages, and inform how these strategies apply to different diagnostic groups. PMID- 29756231 TI - Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes. AB - BACKGROUND: Parkinsonisms are neurodegenerative disorders characterized pathologically by alpha-synuclein-positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau-positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown. OBJECTIVE: The current study investigated the pathological correlates of these susceptibility MRI measures. METHODS: In vivo MRIs (T1- and T2-weighted, and T2*) and pathology were obtained from 14 subjects enrolled in an NINDS PD Biomarker Program (PDBP). We assessed R2* and quantitative susceptibility mapping values in the SN, semiquantitative alpha-synuclein, tau, and iron values, as well as neuronal and glial counts. Data were analyzed using age-adjusted Spearman correlations. RESULTS: R2* was associated significantly with nigral alpha-synuclein (r = 0.746; P = 0.003). Quantitative susceptibility mapping correlated significantly with Perls' (r = 0.758; P = 0.003), but not with other pathological measurements. Neither measurement correlated with tau or glial cell counts (r <= 0.11; P >= 0.129). CONCLUSIONS: Susceptibility MRI measurements capture nigral pathologies associated with parkinsonian syndromes. Whereas quantitative susceptibility mapping is more sensitive to iron, R2* may reflect pathological aspects of the disorders beyond iron such as alpha-synuclein. They may be invaluable tools in diagnosing differential parkinsonian syndromes, and tracking in living patients the dynamic changes associated with the pathological progression of these disorders. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756235 TI - Long-term safety and efficacy of continuous acitretin monotherapy for three children with different severe hyperkeratotic disorders in China. AB - Long-term systemic treatment with acitretin for severe hyperkeratotic disorders is needed to maintain quality of life of afflicted patients, but treatment has been limited owing to its potential side-effects including skeletal malformations, particularly for children during their growth and development. A retrospective investigation was conducted with three children afflicted with a severe hyperkeratotic disorder, namely Darier's disease, bullous ichthyosiform erythroderma or lamellar ichthyosis, who were continuously maintained on 0.2-0.3 mg/kg per day acitretin for more than 12 years after an initial period at a larger acitretin dose to bring each disease under control. The patients had good responses to acitretin treatment, which was assessed for safety, skeletal abnormalities, growth retardation and other potential side-effects. Acitretin monotherapy was an effective treatment for these children, and maintenance doses were well tolerated with no skeletal or other observable side-effects during the course of the study. PMID- 29756233 TI - A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients. AB - Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n = 239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p < 0.001) and overall survival (p < 0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n = 114, p = 0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p <= 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29756234 TI - Inhaling xenon ameliorates l-dopa-induced dyskinesia in experimental parkinsonism. AB - Parkinson's disease motor symptoms are treated with levodopa, but long-term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N-methyl-d-aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa-induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold-standard rat and primate models of PD and levodopa-induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa-induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa-induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29756236 TI - An Ultrahigh Output Rechargeable Electrode of a Hydrophilic Radical Polymer/Nanocarbon Hybrid with an Exceptionally Large Current Density beyond 1 A cm-2. AB - Facile charge transport by a hydrophilic organic radical-substituted polymer and the 3D current collection by a self-assembled mesh of single-walled carbon nanotube bundles lead to the operation of an ultrahigh-output rechargeable electrode. Exceptionally large current density beyond 1 A cm-2 and high areal capacity around 3 mAh cm-2 are achieved, which are 101-2 times larger than those of the previously reported so-called "ultrafast electrodes." A sub-millimeter thick, flexible, highly safe organic redox polymer-based rechargeable device with an aqueous sodium chloride electrolyte is fabricated to demonstrate the superior performance. PMID- 29756237 TI - Biopolymers for Antitumor Implantable Drug Delivery Systems: Recent Advances and Future Outlook. AB - In spite of remarkable improvements in cancer treatments and survivorship, cancer still remains as one of the major causes of death worldwide. Although current standards of care provide encouraging results, they still cause severe systemic toxicity and also fail in preventing recurrence of the disease. In order to address these issues, biomaterial-based implantable drug delivery systems (DDSs) have emerged as promising therapeutic platforms, which allow local administration of drugs directly to the tumor site. Owing to the unique properties of biopolymers, they have been used in a variety of ways to institute biodegradable implantable DDSs that exert precise spatiotemporal control over the release of therapeutic drug. Here, the most recent advances in biopolymer-based DDSs for suppressing tumor growth and preventing tumor recurrence are reviewed. Novel emerging biopolymers as well as cutting-edge polymeric microdevices deployed as implantable antitumor DDSs are discussed. Finally, a review of a new therapeutic modality within the field, which is based on implantable biopolymeric DDSs, is given. PMID- 29756238 TI - Otopathologic evaluation of temporalis fascia grafts following successful tympanoplasty in humans. AB - OBJECTIVE: Temporalis fascia is a commonly used graft material in tympanoplasty; however, little is known about how the histological structure of fascia remodels postimplantation. Herein, we aim to quantify the pre- and postoperative microstructure of temporalis fascia and compare histological findings to the native tympanic membrane (TM). METHODS: Temporal bone specimens having undergone successful subtotal or total drum replacement using temporalis fascia were identified (n = 3). Surgically prepared preimplantation temporalis fascia (PreTF, n = 4) and normal TMs (n = 5) were used as controls. Multiple measurements of thickness of PreTF and of normal and fascia reconstructed TMs at the mesotympanum and hypotympanum were obtained. Collagen fiber patterns of normal and reconstructed TMs were histologically described. RESULTS: In cases of fascia tympanoplasty, the mean time of surgery to death was 16 years (range 8-28 years). All cases contained an aerated middle ear without residual perforation. There was no significant difference between the thickness of PreTF and fascia of reconstructed TMs (234.9 +/- 144.9 MUm vs. 162.9 +/- 71.9 MUm, P = 0.1). The lamina propria and total thicknesses of controls (59.8 +/- 39.3 MUm and 83.7 +/- 42.4 MUm, respectively) were thinner than the PreTF and fascia-reconstructed TMs, respectively, in all cases (P <= 0.001, P <= 0.001). Reconstructed TMs contained a thick, longitudinal fiber structure that was qualitatively similar to PreTF. CONCLUSION: Based on human temporal bone specimens, temporalis fascia does not significantly remodel, change thickness, or change fibrous structure following successful tympanoplasty. Results have implications for selection and surgical preparation of graft materials in TM reconstruction. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:E351-E358, 2018. PMID- 29756239 TI - Rational Design and Facile Synthesis of Boranophosphate Ionic Liquids as Hypergolic Rocket Fuels. AB - The design and synthesis of new hypergolic ionic liquids (HILs) as replacements for toxic hydrazine derivatives have been the focus of current academic research in the field of liquid bipropellant fuels. In most cases, however, the requirements of excellent ignition performances, good hydrolytic stabilities, and low synthetic costs are often contradictory, which makes the development of high performance HILs an enormous challenge. Here, we show how a fuel-rich boranophosphate ion was rationally designed and used to synthesize a series of high-performance HILs with excellent comprehensive properties. In the design strategy, we introduced the {BH3 } moiety into the boranophosphate ion for improving the self-ignition property, whereas the complexation of boron and phosphite was used to improve the hydrolytic activity of the borohydride species. As a result, these boranophosphate HILs exhibited wide liquid operating ranges (>220 degrees C), high densities (1.00-1.10 g cm-3 ), good hydrolytic stabilities, and short ignition delay times (2.3-9.7 milliseconds) with white fuming nitric acid (WFNA) as the oxidizer. More importantly, these boranophosphate HILs could be readily prepared in high yields from commercial phosphite esters, avoiding complex and time-consuming synthetic routes. This work offers an effective strategy of designing boranophosphate HILs towards safer and greener hypergolic fuels for liquid bipropellant applications. PMID- 29756240 TI - Vitamin D intake and survival and recurrence in head and neck cancer patients. AB - OBJECTIVES/HYPOTHESIS: With an unacceptably low 5-year survival rate and few identified modifiable factors that affect head and neck cancer (HNC) outcomes, HNC survival remains an important public health problem. Vitamin D has been shown to be associated with immune reactivity and improved outcomes for some cancer sites, but findings are mixed, and few studies have examined vitamin D in relation to HNC. This study aimed to assess the association between vitamin D intake and survival outcomes in HNC patients. STUDY DESIGN: Prospective cohort study. METHODS: This study utilized data on 434 HNC patients with valid pretreatment food frequency questionnaire data who participated in the University of Michigan Head and Neck Specialized Program of Research Excellence epidemiology project. Cox proportional hazard models were used to estimate the associations between total, dietary, and supplemental vitamin D intake and HNC outcomes, while adjusting for other known prognostic factors. RESULTS: After multivariable adjustment, we found a statistically significant inverse trend between total vitamin D intake and recurrence (Q4 vs. Q1 hazard ratio: 0.47, 95% confidence interval: 0.20-1.10, P trend = .048). We observed no association with dietary or supplemental intake separately, and no association was observed with all-cause or HNC-specific mortality. CONCLUSIONS: These findings suggest that HNC patients with lower levels of vitamin D intake are at higher risk of recurrence. If borne out in future studies, our results suggest that increased vitamin D intake through dietary intervention or the use of supplements may be a feasible intervention for prevention of recurrence in HNC patients. LEVEL OF EVIDENCE: 2b. Laryngoscope, E371-E376, 2018. PMID- 29756241 TI - Long-term outcomes and prognosis in submandibular gland malignant tumors: A multicenter study. AB - OBJECTIVES/HYPOTHESIS: Submandibular gland tumors (SMGTs) are rare and characterized by heterogeneity in histologic profiles. The aim of the present study was to retrieve data on submandibular gland (SMG) malignancies and identify factors influencing survival. STUDY DESIGN: Retrospective study. METHODS: A multicenter, retrospective study on patients who underwent primary surgery for SMGTs at three referral centers was performed. RESULTS: Among 204 patients with SMGTs, 50 (24.5%) with SMG malignancies were analyzed in detail. Definitive pT status was: 21 (42%) pT1, 14 (28%) pT2, 10 (20%) pT3, and five (10%) pT4. Nodal metastases and perineural spread were diagnosed in 15 (30%) and 25 (50%) patients, respectively. High-grade lesions were identified in 32 (64%) patients. Follow-up status, available for 49 (98%) patients, was as follows: 23 (47%) patients were alive without disease, 11 (22.5%) died of disease, five (10.2%) alive with disease, and 10 (20.4%) died of other causes. Five- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 66.4% and 57.1%, 76.6% and 72.1%, 69.1% and 62.4%, respectively. At univariate analysis, OS, DSS, and RFS were influenced by pT status, pN status, and perineural spread. OS and RFS were also affected by the presence of facial palsy and pain. RFS was negatively influenced by positive margins. Multivariate analysis confirmed that OS, DSS, and RFS were independently affected by perineural spread, whereas nodal involvement influenced only RFS. CONCLUSIONS: The malignancy rate of SMGTs is comparable to that reported for parotid tumors. Most patients presented with high-grade lesions. pT status, pN status, and perineural spread significantly affected prognosis. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 29756242 TI - Novel Materials for 3D Printing by Photopolymerization. AB - The field of 3D printing, also known as additive manufacturing (AM), is developing rapidly in both academic and industrial research environments. New materials and printing technologies, which enable rapid and multimaterial printing, have given rise to new applications and utilizations. However, the main bottleneck for achieving many more applications is the lack of materials with new physical properties. Here, some of the recent reports on novel materials in this field, such as ceramics, glass, shape-memory polymers, and electronics, are reviewed. Although new materials have been reported for all three main printing approaches-fused deposition modeling, binder jetting or laser sintering/melting, and photopolymerization-based approaches, apparently, most of the novel physicochemical properties are associated with materials printed by photopolymerization approaches. Furthermore, the high resolution that can be achieved using this type of 3D printing, together with the new properties, has resulted in new implementations such as microfluidic, biomedical devices, and soft robotics. Therefore, the focus here is on photopolymerization-based additive manufacturing including the recent development of new methods, novel monomers, and photoinitiators, which result in previously inaccessible applications such as complex ceramic structures, embedded electronics, and responsive 3D objects. PMID- 29756243 TI - Narrow band imaging for risk stratification of glottic cancer within leukoplakia. AB - BACKGROUND: This study investigates relevance of narrow band imaging (NBI) in stratifying risk of malignant transformation within leukoplakia. METHODS: We conducted a prospective analysis that included 62 patients with 91 changes of leukoplakia on vocal folds. The NBI was obtained before microsurgery. Categorization of the lesion as benign was made when vessels of surrounding epithelium were classified as type I, II, or IV according to Ni classification. If there were visualized intraepithelial papillary capillary loops of type V, the lesion was classified as malignant. Results were compared to the histopathological diagnosis. RESULTS: The NBI assessment classified 75 lesions (82.4%) as benign and 16 (17.6%) as malignant. Histopathological results revealed the diagnosis of no dysplastic changes or low grade dysplasia in 77 cases (84.6%). Another 14 cases (15.4%) occurred with high-grade dysplasia, carcinoma in situ, and invasive cancer. Sensitivity, specificity, and accuracy of NBI in predicting malignancy within leukoplakia were 100%, 97.4%, and 97.8%, respectively. The kappa index was 0.92 (95% confidence interval 81.1%-100%). CONCLUSION: The noninvasive procedure of an NBI endoscopy may be recommended as an accurate method in predicting the risk of malignant transformation within the vocal fold leukoplakia and, therefore, would be useful in the clinic for planning the patient's therapy. PMID- 29756244 TI - Helical intensity-modulated radiotherapy with concurrent chemotherapy for oropharyngeal squamous cell carcinoma: A prospective investigation of acute swallowing and toxicity patterns. AB - BACKGROUND: Conformal radiotherapy modalities may minimize treatment toxicities. The purpose of this study was to document the extent and timing of dysphagia and related toxicities during helical intensity-modulated radiotherapy (IMRT) with chemotherapy for oropharyngeal squamous cell carcinoma (SCC). METHODS: We conducted a prospective study of 76 patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy. Dysphagia and acute toxicity data were collected weekly during treatment and at 2, 4, and 12 weeks posttreatment using the Functional Oral Intake Scale, diet descriptors, and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. RESULTS: Patients experienced maximum incidence of grade 3 dysphagia (61%), mucositis (30%), and thick saliva (38%), with grade 2 xerostomia (87%) and dysgeusia (97%). Only 14.5% were nil-by-mouth. Symptoms peaked in week 7 and improved thereafter. Grade 3 dysphagia was twice as common for T3 to T4 tumors compared with T2. CONCLUSION: Results confirm that patients with oropharyngeal SCC undergoing helical IMRT with chemotherapy continue to experience incidences of acute toxicities comparable with other conformal techniques, and need supportive cares. PMID- 29756245 TI - Age-related differences in health-related quality of life among thyroid cancer survivors compared with a normative sample: Results from the PROFILES Registry. AB - BACKGROUND: The purpose of this study was to compare general health-related quality of life (HR-QOL) of thyroid cancer survivors with a normative sample stratified by age at diagnosis (adolescents and young adults 18-35 years; middle aged adults 36-64 years; elderly 65-84 years), and to compare general HR-QOL and disease-specific symptoms among adolescents and young adults, middle-aged adults, and elderly thyroid cancer survivors in an exploratory population-based cross sectional study. METHODS: All patients diagnosed with thyroid cancer between 1990 and 2008, who were registered in the Eindhoven Cancer Registry, received a survey. Our final sample included 293 thyroid cancer survivors. RESULTS: Compared with a normative sample, adolescents and young adult thyroid cancer survivors showed statistically significant and clinically meaningfully worse physical, role, cognitive, and social functioning, and more fatigue and financial problems. Adolescents and young adult thyroid cancer survivors scored statistically significant and clinically meaningfully better on physical functioning and interest in sex compared with the elderly and had less sympathetic and throat/mouth problems compared with middle-aged adults. CONCLUSION: Thyroid cancer seems to have a greater impact on younger than older thyroid cancer survivors and the lower HR-QOL in older compared to younger thyroid cancer survivors is probably caused mostly by their age and not the cancer. PMID- 29756246 TI - Ewing sarcoma of the head and neck: The Mayo Clinic experience. AB - BACKGROUND: Treatment options of Ewing sarcoma of the head and neck include surgery, radiotherapy (RT), and chemoradiotherapy. However, local control can be challenging. METHODS: We conducted a retrospective review of all patients with head and neck Ewing sarcoma treated from 1972 to 2015 at a single tertiary care hospital. RESULTS: Seventeen patients met criteria (median 21 years, range 5-58 years; 5 women). Mean follow-up was 10.4 years (range 2.2-39 years). Tumors occurred commonly in the cervical spine (5/17), the skull (3/17), and the paranasal sinuses (3/17). A total of 14 of 17 patients underwent surgical resection, 9 with gross total resection. After multimodality therapy, the 5-year overall survival (OS) and recurrence-free survival (RFS) was 87% and 75%, respectively. CONCLUSION: Combined multimodal treatment resulted in a 5-year OS and RFS of 87% and 75%, respectively. Aggressive surgical resection with adjuvant chemoradiotherapy should be considered. Although negative margin surgery is the goal, subtotal resection may be acceptable in the setting of adjuvant treatment. PMID- 29756247 TI - Fertility preservation in women with marrow failure syndromes prior to allogeneic stem cell transplantation. PMID- 29756248 TI - Oral proliferative verrucous leukoplakia: A challenge for clinical management. PMID- 29756249 TI - Value of CT added to ultrasonography for the diagnosis of lymph node metastasis in patients with thyroid cancer. AB - BACKGROUND: The benefit of CT for the diagnosis of lymph node metastasis in patients with thyroid cancer is still unclear. METHODS: Three hundred fifty-one patients with thyroid cancers from 7 hospitals were prospectively enrolled in order to compare diagnostic performance between a combination of ultrasound and CT (ultrasound/CT) and ultrasound alone for prediction of lymph node metastasis and to calculate patient-based benefits of CT added to ultrasound. RESULTS: Of 801 pathologically proven neck levels, ultrasound/CT showed higher sensitivities in both central and lateral compartments and improved accuracy in the lateral compartment compared to ultrasound alone. In the retropharyngeal/superior mediastinal compartment, although CT could detect lymph node metastasis an ultrasound could not. Patient-based benefit was demonstrated in 13.1% of patients (46/351), and was higher in patients with cancers >1 cm than cancers <=1 cm. CONCLUSION: In patients with thyroid cancer, CT improved surgical planning by enhancing the sensitivity for lymph node metastasis and by detecting lymph node metastasis that was overlooked with ultrasound alone. PMID- 29756250 TI - Esthesioneuroblastoma with distant metastases: Systematic review & meta-analysis. AB - BACKGROUND: The purpose of this study was to determine the clinical outcomes and review the management strategies for metastatic esthesioneuroblastoma. METHODS: We conducted a systematic review and meta-analysis. RESULTS: Forty-eight studies totaling 118 patients met inclusion criteria. Chemotherapy in combination with surgery and/or radiation exhibited the best overall survival when compared to monotherapy and no treatment (P < .001). However, most patients (66%) received either monotherapy or no therapy. The number and location of metastases among the 3 treatment groups did not significantly differ (P = .85). Treatment modality remained significantly associated with overall survival on multivariable analysis (P < .001). Platinum-based chemotherapy was most commonly utilized but did not provide a survival benefit when compared with all other regimens (P = .88). CONCLUSION: Distant metastases with esthesioneuroblastoma portend a poor prognosis. Chemotherapy in combination with surgery and/or radiation was associated with improved overall survival. Further research into the optimal systemic therapeutic regimen for patients with distant metastases is critical. PMID- 29756251 TI - Fixed Low-Dose Hydroxyurea for the Treatment of Adults with Sickle Cell Anemia in Nigeria. PMID- 29756252 TI - Oral Fumaderm(r) to treat cutaneous sarcoidosis. PMID- 29756253 TI - Prognostic stratification of patients with nasopharyngeal carcinoma based on tumor immune microenvironment. AB - BACKGROUND: Little is known about immune-related prognostic factors in patients with nasopharyngeal carcinoma (NPC). METHODS: We retrospectively reviewed 66 patients with NPC. Epstein-Barr virus (EBV) status, programmed cell death-ligand 1 (PD-L1) expression, and tumor-infiltrating lymphocyte (TIL) densities were analyzed, and a prognostic evaluation of these immune-related parameters was performed. RESULTS: The multivariate analyses demonstrated that CD8-positive TIL density but not PD-L1 expression on tumor cells or immune cells was a significant predictive factor for progression-free survival (PFS) and overall survival (OS). Subgroup analyses demonstrated that a positive PD-L1 expression on tumor cells in combination with a higher CD8-positive TIL density was significantly associated with favorable prognosis, whereas positive PD-L1 expression on tumor cells with lower CD8-positive TIL density was associated with worse prognosis. CONCLUSION: Our results suggest that PD-L1 expression on tumor cells in combination with CD8 positive TIL density could be a useful predictive biomarker for risk stratification in patients with NPC. PMID- 29756255 TI - Comparative optimism in older adults' future health expectations. AB - OBJECTIVES: Despite a common belief that health declines with age, many older adults remain optimistic about their future health. However, the longitudinal impact of personal and comparatively optimistic future health estimates (FHEs) is unclear. METHOD: Among 408 older adults (Mage = 70.32 years), this study identified the prevalence, source, and two-year stability of comparatively optimistic FHEs; examined demographic, psychosocial, and health correlates of comparative FHEs; and assessed the role of comparative FHEs in predicting eight year survival odds. RESULTS: Nearly half of participants were comparatively optimistic due to interpersonal pessimism more so than personal optimism. Regarding stability, comparative optimism declined over the two-year period. Being younger and having more perceived control, dispositional optimism, and recent positive emotions were associated with better FHEs for oneself and a similar other. Beyond effects of age, gender, relationship status, and dispositional optimism, optimistic personal FHEs predicted eight-year survival odds. CONCLUSIONS: Findings have implications for predicting survival and advancing the conceptual understanding of comparative FHEs. Statement of contribution What is already known on the subject? Previous research has demonstrated that older adults tend to believe diminished health accompanies increasing age. Despite this notion, older adults remain comparatively optimistic about their health. What does this study add? The longitudinal results of the current study indicated that nearly half of participants were categorized as comparative optimists, primarily due to interpersonal pessimism. The current study demonstrated that there is little distinction between personal FHEs and those for a similar other in terms of demographic, psychosocial, and health correlates. The current study identified factors that predicted eight-year survival among older adults, such as being female, younger, in a committed relationship, and better personal FHEs. PMID- 29756254 TI - Early outcomes in transoral vestibular thyroidectomy: Robotic versus endoscopic techniques. AB - BACKGROUND: The transoral thyroidectomy vestibular approach has been utilized via both robotic (TORTVA) and endoscopic (TOETVA) techniques to perform thyroidectomy. However, there have been no studies evaluating outcomes between these approaches. Here we describe our outcomes for thyroid lobectomy with TORTVA and TOETVA. METHODS: All cases of transoral vestibular approach thyroid lobectomy at Johns Hopkins Hospital were reviewed. Primary outcomes and demographic data were then compared between TORTVA and TOETVA. RESULTS: Twenty-seven cases were identified, 7 using the robotic approach and 20 using the endoscopic approach. The procedural success rate for the robotic and endoscopic cohorts was 5 of 7 (71%) and 19 of 20 (95%), respectively (P = .15). There were no persistent nerve injuries, mental, or recurrent in either cohort. Median operative time for TOETVA was 188 minutes versus 322 minutes for TORTVA (P = .001). CONCLUSION: Thyroid lobectomy can be safely performed via both techniques, although performed more quickly endoscopically, which is likely due in part to differences in the learning curves. PMID- 29756256 TI - Peptidylarginine deiminases and deiminated proteins at the epidermal barrier. AB - Deimination or citrullination is a post-translational modification catalysed by a family of calcium-dependent enzymes called peptidylarginine deiminases (PADs). It corresponds to the transformation of arginine residues within a peptide sequence into citrulline residues. Deimination induces a decreased net charge of targeted proteins; therefore, it alters their folding and changes intra- and intermolecular ionic interactions. Deimination is involved in several physiological processes (inflammation, gene regulation, etc.) and human diseases (rheumatoid arthritis, neurodegenerative diseases, cancer, etc.). Here, we describe the PADs expressed in the epidermis and their known substrates, focusing on their role in the epidermal barrier function. PMID- 29756257 TI - Stable Boron Dithiolene Radicals. AB - Whereas low-temperature (-78 degrees C) reaction of the lithium dithiolene radical 1. with boron bromide gives the dibromoboron dithiolene radical 2. , the parallel reaction of 1. with (C6 H11 )2 BCl (0 degrees C) affords the dicyclohexylboron dithiolene radical 3. . Radicals 2. and 3. were characterized by single-crystal X-ray diffraction, UV/Vis, and EPR spectroscopy. The nature of these radicals was also probed computationally. Under mild conditions, 3. undergoes unexpected thiourea-mediated B-C bond activation to give zwitterion 4, which may be regarded as an anionic dithiolene-modified carbene complex of the sulfenyl cation RS+ (R=cyclohexyl). PMID- 29756259 TI - Autonomic Dysfunction in Parkinson's Disease: The Hidden Game Changer? PMID- 29756258 TI - A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non-Hodgkin lymphoma. AB - Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre-diagnosis red blood cell (RBC) specimens in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T-NHL), B cell NHL (B-NHL) and three individual B-NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B-NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T-NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B-NHLs other than CLL/SLL and for VLCSFA and MUFA with T-NHL suggest an influence of fatty acid metabolism on lymphomagenesis. PMID- 29756261 TI - Study of the relationships between brachytherapy plan parameters in an attempt to verify total dwell time in vaginal cylinder applications. AB - PURPOSE: Source strength (Sk ), sizes of vaginal cylinder applicators (VCA), number of dwell positions (DPs), and the prescribed dose (D) are basic parameters in brachytherapy (BT) treatment planning contributing to total dwell time (TDT). This study was aimed at assessing the relationships between the specified variables in an attempt to verify the TDT in high-dose-rate (HDR) vaginal cylinder applications. METHODS: One hundred and twenty-one patients treated with Gynesource-Co60 (Bebig, Germany) using VCAs of diameters 20, 25, and 30 mm at University College Hospital, Nigeria, were enrolled in this study. Brachytherapy doses ranging from 3 to 7 Gy were always prescribed to points 5 mm away from the cylinder's surface. Treatment planning was undertaken on HDR-Basic treatment planning system (TPS) which utilizes source step size of 5 mm. Data on the stated parameters related to the first BT fractions of the patients were acquired. With the aid of EViews statistical software, two forms of mathematical models were thereafter developed. The resulting TDTs from the models were compared with the TPS values using Minitab statistical software. RESULTS: The relationships obtained for the increasing sizes of the VCA were TDT1(min)=2.22+3.17DSk;TDT1(min)=3.52+3.74DSk;TDT1(min)= 1.96+6.91DSkandTDT2(min)=0.50-0.03Sk+0.02D+0.55DPs;TDT2(min)=7.08 0.06Sk+0.02D+0.67DPs;TDT2(min)=7.02-0.11Sk+0.03D+1.25DPs The model-based TDTs correlate with the TPS-calculated values with r1 = 0.80 (P = 0.412) and r2 = 0.97 (P = 0.468). CONCLUSIONS: The findings of this study could suggest likely variations in the treatment time when certain changes occur in the related parameters. The increasing size of the vaginal cylinder has a positive influence on the brachytherapy treatment time. The latter model has been a useful tool in the verification of the dose delivery time at the first HDR brachytherapy center in Nigeria and West Africa. PMID- 29756260 TI - Membrane trafficking in morphogenesis and planar polarity. AB - Our understanding of how membrane trafficking pathways function to direct morphogenetic movements and the planar polarization of developing tissues is a new and emerging field. While a central focus of developmental biology has been on how protein asymmetries and cytoskeletal force generation direct cell shaping, the role of membrane trafficking in these processes has been less clear. Here, we review recent advances in Drosophila and vertebrate systems in our understanding of how trafficking events are coordinated with planar cytoskeletal function to drive lasting changes in cell and tissue topologies. We additionally explore the function of trafficking pathways in guiding the complex interactions that initiate and maintain core PCP (planar cell polarity) asymmetries and drive the generation of systematically oriented cellular projections during development. PMID- 29756262 TI - Reducing the standard serving size of alcoholic beverages prompts reductions in alcohol consumption. AB - AIMS: To test whether reducing the standard serving size of alcoholic beverages would reduce voluntary alcohol consumption in a laboratory (study 1) and a real world drinking environment (study 2). Additionally, we modelled the potential public health benefit of reducing the standard serving size of on-trade alcoholic beverages in the United Kingdom. DESIGN: Studies 1 and 2 were cluster-randomized experiments. In the additional study, we used the Sheffield Alcohol Policy Model to estimate the number of deaths and hospital admissions that would be averted per year in the United Kingdom if a policy that reduces alcohol serving sizes in the on-trade was introduced. SETTING: A semi-naturalistic laboratory (study 1), a bar in Liverpool, UK (study 2). PARTICIPANTS: Students and university staff members (study 1: n = 114, mean age = 24.8 years, 74.6% female), residents from local community (study 2: n = 164, mean age = 34.9 years, 57.3% female). INTERVENTIONS AND COMPARATORS: In study 1, participants were assigned randomly to receive standard or reduced serving sizes (by 25%) of alcohol during a laboratory drinking session. In study 2, customers at a bar were served alcohol in either standard or reduced serving sizes (by 28.6-33.3%). MEASUREMENTS: Outcome measures were units of alcohol consumed within 1 hour (study 1) and up to 3 hours (study 2). Serving size condition was the primary predictor. FINDINGS: In study 1, a 25% reduction in alcohol serving size led to a 20.7-22.3% reduction in alcohol consumption. In study 2, a 28.6-33.3% reduction in alcohol serving size led to a 32.4-39.6% reduction in alcohol consumption. Modelling results indicated that decreasing the serving size of on-trade alcoholic beverages by 25% could reduce the number of alcohol-related hospital admissions and deaths per year in the United Kingdom by 4.4-10.5% and 5.6-13.2%, respectively. CONCLUSIONS: Reducing the serving size of alcoholic beverages in the United Kingdom appears to lead to a reduction in alcohol consumption within a single drinking occasion. PMID- 29756263 TI - Biotransformation and Biological Interaction of Graphene and Graphene Oxide during Simulated Oral Ingestion. AB - The biotransformation and biological impact of few layer graphene (FLG) and graphene oxide (GO) are studied, following ingestion as exposure route. An in vitro digestion assay based on a standardized operating procedure (SOP) is exploited. The assay simulates the human ingestion of nanomaterials during their dynamic passage through the different environments of the gastrointestinal tract (salivary, gastric, intestinal). Physical-chemical changes of FLG and GO during digestion are assessed by Raman spectroscopy. Moreover, the effect of chronic exposure to digested nanomaterials on integrity and functionality of an in vitro model of intestinal barrier is also determined according to a second SOP. These results show a modulation of the aggregation state of FLG and GO nanoflakes after experiencing the complex environments of the different digestive compartments. In particular, chemical doping effects are observed due to FLG and GO interaction with digestive juice components. No structural changes/degradation of the nanomaterials are detected, suggesting that they are biopersistent when administered by oral route. Chronic exposure to digested graphene does not affect intestinal barrier integrity and is not associated with inflammation and cytotoxicity, though possible long-term adverse effects cannot be ruled out. PMID- 29756264 TI - Study design and early result of a phase I study of SABR for early-stage glottic cancer. AB - OBJECTIVE: Avoidance of organs at risk has become possible with advances in image guided volumetric-modulated arc therapy (VMAT) techniques. This study was designed to evaluate the safety and feasibility of stereotactic ablative radiotherapy (SABR) for early stage glottic cancer. This report presents the preliminary result of the first and second dose level. METHODS: Fraction size was increased from 3.5 gray (Gy) (total dose 59.5 Gy) to 9 Gy (total dose 45 Gy). Dose-limiting toxicities were defined as grade 3 or higher treatment-related toxicities. Voice outcome was assessed with electroglottography, and quality of life (QoL) was measured with the Head and Neck Cancer Inventory (HNCI). RESULTS: Seven patients received 59.5 Gy at 3.5 Gy per fraction as the first dose level, and five patients received 55 Gy at 5 Gy per fraction as the second dose level. None of the patients developed grade 3+ toxicity throughout a median follow-up of 17.5 months (range, 1.7-30.6 months). One patient in the second dose level recurred in the primary site at 4 months after radiotherapy (RT) and received total laryngectomy. The rest of participants were disease-free at locoregional and distant sites. Jitter, shimmer, mean phonation time, and noise-to-harmony ratio did not change significantly at 6 months after RT. HNCI scores between pretreatment and posttreatment were not significantly different (P = 0.221). CONCLUSION: This study revealed acceptable toxicity, voice outcome, and QoL in patients treated with hypofractionated VMAT of 3.5 Gy and 5 Gy per fraction. This phase I study is currently ongoing with a dose of 55 Gy in 11 fractions and 45 Gy in five fractions. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2560-2565, 2018. PMID- 29756265 TI - Web-based thyroid imaging reporting and data system: Malignancy risk of atypia of undetermined significance or follicular lesion of undetermined significance thyroid nodules calculated by a combination of ultrasonography features and biopsy results. AB - BACKGROUND: The purpose of this study was to construct a web-based predictive model using ultrasound characteristics and subcategorized biopsy results for thyroid nodules of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) to stratify the risk of malignancy. METHODS: Data included 672 thyroid nodules from 656 patients from a historical cohort. We analyzed ultrasound images of thyroid nodules and biopsy results according to nuclear atypia and architectural atypia. Multivariate logistic regression analysis was performed to predict whether nodules were diagnosed as malignant or benign. RESULTS: The ultrasound features, including spiculated margin, marked hypoechogenicity, calcifications, biopsy results, and cytologic atypia, showed significant differences between groups. A 13-point risk scoring system was developed, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the development and validation sets were 0.837 and 0.830, respectively (http://www.gap.kr/thyroidnodule_b3.php). CONCLUSION: We devised a web-based predictive model using the combined information of ultrasound characteristics and biopsy results for AUS/FLUS thyroid nodules to stratify the malignant risk. PMID- 29756267 TI - Evaluation of prototype of improved electron collimation system for Elekta linear accelerators. AB - PURPOSE: This study evaluated a new electron collimation system design for Elekta 6-20 MeV beams, which should reduce applicator weights by 25%-30%. Such reductions, as great as 3.9 kg for the largest applicator, should result in considerably easier handling by members of the radiotherapy team. METHODS: Prototype 10 * 10 and 20 * 20-cm2 applicators, used to measure weight, in-field flatness, and out-of-field leakage dose, were constructed according to the previously published design with two minor modifications: (a) rather than tungsten, lead was used for trimmer material; and (b) continuous trimmer outer edge bevel was approximated by three steps. Because of lead plate softness, a 0.32-cm aluminum plate replaced the equivalent lead thickness on the trimmer's downstream surface for structural support. Models of all applicators (6 * 6-25 * 25 cm2 ) with these modifications were inserted into a Monte Carlo (MC) model for dose calculations using 7, 13, and 20 MeV beams. Planar dose distributions were measured and calculated at 1- and 2-cm water depths to evaluate in-field beam flatness and out-of-field leakage dose. RESULTS: Prototype 10 * 10 and 20 * 20 cm2 applicator measurements agreed with calculated weights, in-field flatness, and out-of-field leakage doses for 7, 13, and 20 MeV beams. Also, MC dose calculations showed that all applicators (6 * 6-25 * 25 cm2 ) and 7, 13, and 20 MeV beams met our stringent in-field flatness specifications (+/-3% major axes; +/-4% diagonals) and IEC out-of-field leakage dose specifications. CONCLUSIONS: Our results validated the new electron collimating system design for Elekta 6-20 MeV electron beams, which could serve as basis for a new clinical electron collimating system with significantly reduced applicator weights. PMID- 29756268 TI - Does rotational thromboelastometry accurately predict coagulation status in patients with lupus anticoagulant? AB - INTRODUCTION: Rotational thromboelastometry (ROTEM) is increasingly used as a tool for monitoring coagulation status. However, ROTEM is susceptible to misinterpretation due to particular coagulation abnormalities. Here, we report the effects of lupus anticoagulant (LA) on ROTEM. METHODS: A prospective observational analysis was performed on 16 children with prior studies indicating the presence of LA or antiphospholipid antibodies. ROTEM analysis was performed, and samples were further analyzed by adding phospholipids (PL) to repeat ROTEM analysis if clotting time (CT) abnormalities were discovered with comparison to ROTEM using an equal volume of isotonic saline. Prothrombin time (PT), activated partial thromboplastin time (APTT), dilute Russell's viper venom test (DRVVT), hexagonal phase phospholipid neutralization test (StaClot LA), and factor II activity studies were additionally performed. RESULTS: Eighteen samples were analyzed by ROTEM. Prolonged CT on INTEM and EXTEM was observed for 11 samples. Samples with CT prolongation had high DRVVT ratios and prolonged APTT. Further, the addition of PL partially reversed this effect, demonstrating PL-dependent inhibition as the cause of CT prolongation. No factor II deficiencies were identified, excluding LA hypoprothrombinemia syndrome as a cause of these findings. CONCLUSION: Strongly positive LA can prolong the CT on ROTEM studies and lead to erroneous conclusions regarding coagulation status in this patient population. PMID- 29756266 TI - The analysis of false prolongation of the activated partial thromboplastin time (activator: silica): Interference of C-reactive protein. AB - BACKGROUND: To investigate the effect of C-reactive protein on the activated partial thromboplastin time (APTT) (different activators) in different detecting systems. METHODS: The C-reactive protein and coagulation test of 112 patients with the infectious disease were determined by automation protein analyzer IMMAG 800 and automation coagulation analyzer STA-R Evolution, respectively. The pooled plasma APTT with different concentrations of C-reactive protein was measured by different detecting system: STA-R Evolution (activator: silica, kaolin), Sysmex CS-2000i (activator: ellagic acid), and ACL TOP 700 (activator: colloidal silica). In addition, the self-made platelet lysate (phospholipid) was added to correct the APTT prolonged by C-reactive protein (150 mg/L) on STA-R Evolution (activator: silica) system. RESULTS: The good correlation between C-reactive protein and APTT was found on the STA-R Evolution (activator: silica) system. The APTT on the STA-R Evolution (activator: silica) system was prolonged by 24.6 second, along with increasing C-reactive protein concentration. And the APTT of plasma containing 150 mg/L C-reactive protein was shortened by 3.4-6.9 second when the plasma was mixed with self-made platelet lysate. However, the APTT was prolonged unobviously on other detecting systems including STA-R Evolution (activator: kaolin), Sysmex CS-2000i, and ACL TOP 700. CONCLUSION: C-reactive protein interferes with the detection of APTT, especially in STA-R Evolution (activator: silica) system. The increasing in C-reactive protein results in a false prolongation of the APTT (activator: silica), and it is most likely that C reactive protein interferes the coagulable factor binding of phospholipid. PMID- 29756269 TI - Genetic and clinical features of Chinese patients with mitochondrial ataxia identified by targeted next-generation sequencing. AB - AIM: To characterize the mutations in mitochondrial DNA (mtDNA) and mitochondrion related nuclear genes (nDNA), and clinical features in Chinese patients with mitochondrial ataxia. METHODS: Targeted next-generation sequencing (NGS) technology was performed to screen the whole mtDNA sequence and nDNA genes in a cohort of 33 unrelated ataxia patients. RESULTS: A total of 5 pedigrees were finally genetically diagnosed as mitochondrial ataxia, with 3 pathogenic mutations (m.8344A>G, m.9176T>C, and m.9185T>C), one likely pathogenic mutation (m.3995A>G) in mtDNA, and one pathogenic mutation (c.1159_1162dupAAGT, p.Ser388Terfs) in PDHA1. The prevalence of mitochondrial ataxia in our patient cohort is 15.2%. In addition, all 4 patients with mtDNA mutations experienced symptoms of ataxia with age at onset ranging from 12 to 39 years (21 +/- 12.2) and developed extrapyramidal symptoms during the disease course. One male patient with pyruvate dehydrogenase deficiency showed an acute intermittent ataxia phenotype. CONCLUSIONS: Our results implicate that mitochondrial ataxia might not be as rare in Chinese as previously assumed. This study firstly defines the mutations of mitochondrial ataxia in a Chinese population by targeted NGS, which broadens the clinical spectrum of mtDNA mutations and highlights the importance of screening mtDNA and nDNA mutations among undefined ataxia patients. PMID- 29756270 TI - Impact of suggestion on the human experimental model of cold hyperalgesia after topical application of high-concentration menthol [40%]. AB - BACKGROUND: Human experimental pain models in healthy subjects offer unique possibilities to study mechanisms of pain within a defined setting of expected pain symptoms, signs and mechanisms. Previous trials in healthy subjects demonstrated that topical application of 40% menthol is suitable to induce cold hyperalgesia. The objective of this study was to evaluate the impact of suggestion on this experimental human pain model. METHODS: The study was performed within a single-centre, randomized, placebo-controlled, double-blind, two-period crossover trial in a cohort of 16 healthy subjects. Subjects were tested twice after topical menthol application (40% dissolved in ethanol) and twice after ethanol (as placebo) application. In the style of a balanced placebo trial design, the subjects received during half of the testing the correct information about the applied substance (topical menthol or ethanol) and during half of the testing the incorrect information, leading to four tested conditions (treatment conditions: menthol-told-menthol and menthol-told-ethanol; placebo conditions: ethanol-told-menthol and ethanol-told-ethanol). RESULTS: Cold but not mechanical hyperalgesia was reliably induced by the model. The cold pain threshold decreased in both treatment conditions regardless whether true or false information was given. Minor suggestion effects were found in subjects with prior ethanol application. CONCLUSIONS: The menthol model is a reliable, nonsuggestible model to induce cold hyperalgesia. Mechanical hyperalgesia is not as reliable to induce. SIGNIFICANCE: Cold hyperalgesia may be investigated under unbiased and suggestion-free conditions using the menthol model of pain. PMID- 29756271 TI - Sustained response of graft-versus-host disease-associated angiomatosis treated with propranolol. PMID- 29756272 TI - Harnessing Human Decellularized Blood Vessel Matrices and Cellular Construct Implants to Promote Bone Healing in an Ex Vivo Organotypic Bone Defect Model. AB - Decellularized matrices offer a beneficial substitute for biomimetic scaffolds in tissue engineering. The current study examines the potential of decellularized placental vessel sleeves (PVS) as a periosteal protective sleeve to enhance bone regeneration in embryonic day 18 chick femurs contained within the PVS and cultured organotypically over a 10 day period. The femurs are inserted into decellularized biocompatibility-tested PVS and maintained in an organotypic culture for a period of 10 days. In femurs containing decellularized PVS, a significant increase in bone volume (p < 0.001) is evident, demonstrated by microcomputed tomography (uCT) compared to femurs without PVS. Histological and immunohistological analyses reveal extensive integration of decellularized PVS with the bone periosteum, and enhanced conservation of bone architecture within the PVS. In addition, the expressions of hypoxia inducible factor-1 alpha (HIF 1alpha), type II collagen (COL-II), and proteoglycans are observed, indicating a possible repair mechanism via a cartilaginous stage of the bone tissue within the sleeve. The use of decellularized matrices like PVS offers a promising therapeutic strategy in surgical tissue replacement, promoting biocompatibility and architecture of the tissue as well as a factor-rich niche environment with negligible immunogenicity. PMID- 29756273 TI - Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers. AB - Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro 1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3 yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non-haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long-term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance. PMID- 29756274 TI - NiTi loss on the dentinal walls and instrument deformation during root canal preparation. AB - The purpose of this study was to quantify the presence of nickel (Ni) and titanium (Ti) on dentin walls of prepared root canals using Endosequence (ES) and Wave One (WO) systems, the deformation, and fracture of these instruments. Thirty extracted human premolar teeth were selected and prepared with WO, ES, and manually (control group-CG). Each instrument was used in four root canals. The root canals were irrigated with 2.5% sodium hypochlorite solution. After preparation, roots were sectioned longitudinally and the apical third was analyzed by scanning electron microscopy with X-ray microanalysis (SEM-EDS). The percentage of Ni and Ti found on dentin walls was compared using Kruskal-Wallis test and post hoc Dunn. The instruments deformation and fracture was evaluate by SEM before and after use. Spiral distortion, fractures, and surface wear were compared using Mann-Whitney test. The level of significance was set at 5%. Ni and Ti were found on the dentin walls of the apical root canal for ES and WO systems (p > .05). No distortion in the spirals and no instrument fracture were observed. Regarding to surface wear, most of the instruments scored as moderate wear (p > .05). This study concluded the WO and ES presented Ni and Ti loss. In addition, the preparation of four root canals did not caused irreversible deformation in WO and ES instruments. PMID- 29756277 TI - Delays to diagnosis and treatment of lung cancer in Australia: healthcare professional perceptions of actual versus acceptable timeframes. AB - BACKGROUND: Streamlined referral to specialist care impacts lung cancer outcomes. AIM: To examine Australian healthcare professionals' (HCP) perceptions of the timeliness of pathways to diagnosis and treatment for people with lung cancer, compared against timeframe guidelines. METHODS: A 21-item survey of HCP evaluating patient waiting times to diagnosis and treatment of lung cancer was distributed through two Australian conferences, a national Multidisciplinary Team directory and email. Main outcome measures were HCP estimates of actual and acceptable waiting times in their practice and factors contributing to perceived delays. RESULTS: A total of 135 responses was obtained from HCP working in secondary healthcare who had recent clinical experience treating lung cancer patients. While 79% believed a diagnosis of lung cancer should be obtained within 14 days of first clinical suspicion, only 56% estimated that this occurred in their practice due mainly to delays in primary care. Most HCP (81%) estimated that patients receive treatment within 28 days of seeing a specialist, but 28% believed a wait of >14 days to treatment was a 'delay', generally due to resource limitations. In general, most HCP estimates of time spent in primary care were longer than those in the literature, while estimates for secondary care were shorter. CONCLUSIONS: Australian HCP treating lung cancer patients perceive a mismatch between acceptable and estimated waiting times to diagnosis and treatment of lung cancer due to patient, provider and system factors. If perceived delays are justified, it is unclear whether HCP overestimate times spent by patients in primary care or underestimate delays in secondary care. Variations in HCP expectations need to be addressed. PMID- 29756276 TI - A novel diagnostic algorithm for heparin-induced thrombocytopenia. AB - INTRODUCTION: While diagnostic algorithm using PF4-heparin enzyme-linked immunosorbent assay (ELISA) optical density (OD), and heparin neutralization assay (HNA), or 4T score have been proposed to replace serotonin-release assay (SRA) for heparin-induced thrombocytopenia (HIT), their performance against SRA is unclear. In this study, we proposed and validated the performance of a new algorithm combining PF4-heparin ELISA optical density (OD), HNA and 4T score against SRA for HIT diagnosis. METHODS: Heparin neutralization assays were performed on specimens submitted for HIT testing with positive PF4-heparin ELISA from December 2015 to September 2017, which were separated into a "training" and a "validation" data set. 4T scores were calculated for ELISA positive cases. RESULTS: A total of 123 consecutive unique patient samples had positive PF4 heparin ELISA with also HNA data, SRA data, and 4T scores available. Compared to SRA, a "laboratory criteria" (ELISA OD >= 1.4 and HNA >= 70%) had a sensitivity of 88% (14/16) and specificity of 91% (42/46), and a "combined criteria" (4T score = 8, or 4T score = 6 or 7 and ELISA OD >= 1.0, or 4T score = 4 or 5 and ELISA OD >= 2.0) had a sensitivity of 75% (12/16) and specificity of 98% (45/46) in the training data set. Laboratory and combined criteria had 90% (56/62) concordance rate. Importantly, for these concordant cases, the diagnostic specificity is 100% (46/46). Based on the data, a novel diagnostic algorithm combining these 2 criteria was proposed and validated prospectively. CONCLUSION: A novel algorithm has high diagnostic accuracy and potentially could eliminate the need for SRA testing in at least 90% patients with suspected HIT. PMID- 29756278 TI - Sleep-related motor and behavioral disorders: Recent advances and new entities. AB - Patients with sleep-related motor and behavioral disorders present to a variety of subspecialty clinics (neurology, sleep medicine, respiratory medicine, psychiatry). Diagnosing these disorders can be difficult, and sometimes they have a significant impact on quality of life. Alongside a number of common and well recognized conditions, several new disease entities have been described in recent years that present with abnormal nocturnal motor phenomena (such as ADCY5 associated disease and anti-IgLON5 disease). Our understanding of the neural basis and prognostic significance of other sleep-related disorders has also grown, particularly rapid eye movement sleep behavior disorder. This review (along with a collection of previously unpublished videos) is intended to aid in the recognition and treatment of these patients. The recent change in terminology from nocturnal frontal lobe epilepsy to sleep-related hypermotor epilepsy is also discussed. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756279 TI - A Designed Enzyme Promotes Selective Post-translational Acylation. AB - A computationally designed, allosterically regulated catalyst (CaM M144H) produced by substituting a single residue in calmodulin, a non-enzymatic protein, is capable of efficient and site selective post-translational acylation of lysines in peptides with highly diverse sequences. Calmodulin's binding partners are involved in regulating a large number of cellular processes; this new chemical-biology tool will help to identify them and provide structural insight into their interactions with calmodulin. PMID- 29756280 TI - Determination of phenolic compounds and antioxidant activities from peel, flesh, seed of guava (Psidium guajava L.). AB - White-flesh guava is widely planted in tropical or subtropical areas of Southeast Asia. Despite of folk statements on specific function, few researches are focused on the description of its plant secondary metabolites. In the present work, contents of total phenolics and flavonoids as well as antioxidant activity from different parts (peel, flesh, and seed) were determined. The constituents of ethanol extracts were characterized by HPLC-QTOF-MS. A total of 69 phenolic compounds as well as nine polar compounds were detected, with flavonoids, hydrolyzable tannins, phenolic acid derivatives, and benzophenones of the four predominant phenolic compounds. Moreover, the presence of other phenolics (lignan, phenylethanoid, stilbenoid, and dihydrochalcones) was revealed. Simultaneously, the polar compounds, such as triterpenoids, iridoid were identified. Benzophenones and triterpenoids were proved to be marked constitutes of peel and flesh, respectively. The existence of isoflavonoids, lignan, phenylethanoid were firstly reported for edible parts or by-products of guava. The results showed that white-flesh guavas, particularly peel parts, were superior resources of antioxidant compounds, with exploitation value. PMID- 29756275 TI - Nitric Oxide-Releasing Macromolecular Scaffolds for Antibacterial Applications. AB - Exogenous nitric oxide (NO) represents an attractive antibacterial agent because of its ability to both disperse and directly kill bacterial biofilms while avoiding resistance. Due to the challenges associated with administering gaseous NO, NO-releasing macromolecular scaffolds are developed to facilitate NO delivery. This progress report describes the rational design and application of NO-releasing macromolecular scaffolds as antibacterial therapeutics. Special consideration is given to the role of the physicochemical properties of the NO storage vehicles on antibacterial or anti-biofilm activity. PMID- 29756281 TI - Lightweight, Highly Permeable, Biocompatible, and Antiadhesive Composite Meshes for Intraperitoneal Repairs. AB - Ventral hernia is a public health issue and millions of meshes are used to repair abdominal wall defects every year. Polypropylene-based composite meshes represent an important class of materials for intraperitoneal repair, but the meshes generally give rise to infection, seroma, migration, and adhesion, leading to severe consequence or even reoperation. Here, a facile and versatile one-way fabrication of lightweight, highly permeable, and biocompatible composite meshes with superior antiadhesion properties is proposed by modifying polypropylene meshes with well-defined polydopamine nanocoating. The resulting composite meshes are found to significantly enhance the biocompatibility and antiadhesion effect in rat model. The scalable production and excellent biomedical properties of composite meshes make them a promising candidate for future-generation ventral hernia repair materials. PMID- 29756282 TI - Acute arthritis: predictive factors and current practice in the approach to diagnosis and management across two hospitals in Sydney. AB - BACKGROUND: Literature pertaining to the predictive factors for septic arthritis is limited. AIMS: The primary objective was to investigate the predictive factors for septic arthritis. The secondary objectives were to investigate the predictive factors for crystal arthritis and to explore current practices in the management of acute arthritis. METHODS: A retrospective analysis was undertaken. All patients with an acute arthritis who underwent a joint aspiration for diagnostic and management purposes were considered for inclusion. The outcome measures were patient demographics, findings on physical examination, findings on blood and synovial fluid analysis and management. RESULTS: Of the patients who presented with an acute arthritis, 24 of the 172 joint aspirations undertaken were positive for bacteria (13.95%). Of the 172 joint aspirations, 90 were positive for crystals (52.33%). Investigated variables associated with increased risk for the presence of bacteria on synovial fluid included features of sepsis (P < 0.001), joint-restricted range of motion (P = 0.048), elevated C-reactive protein (P < 0.001) and elevated total leukocyte count on synovial fluid (P < 0.001). Of the 24 joint aspirations that were positive for bacteria, 13 had associated positive blood cultures (54.17%). Of the 172 joint aspirations, antibiotics were administered in 96 cases (55.81%). Of these, antibiotics were administered prior to joint aspiration in 41 cases (42.71%). CONCLUSIONS: In our study, the most common cause of acute arthritis was crystal arthropathy. An accurate physical examination in conjunction with synovial fluid analysis is of particular importance in diagnosing septic arthritis. Blood cultures are not a reliable substitute for joint aspiration but should nevertheless be undertaken. PMID- 29756283 TI - Erythrocytes from patients with myeloproliferative neoplasms and splanchnic venous thrombosis show greater expression of Lu/BCAM. AB - INTRODUCTION: Lutheran/BCAM protein (Lu) on the surface of erythrocytes is key for their adhesion to the endothelium, and erythrocytes from individuals with JAK2V617F-mutated myeloproliferative neoplasms (MPN) have increased endothelial adhesion. Splanchnic vein thrombosis (SVT) is a devastating thrombotic complication of MPN, and frequently, the only diagnostic feature is the JAK2V617F mutation. We sought to examine whether erythrocytes from patients with JAK2V617F mutated SVT (MPN-SVT) exhibited increased Lu expression, thereby supporting a mechanistic contribution to the development of thrombosis. METHODS: We report the validation of a novel flow cytometry assay for Lu expression on erythrocytes. We examined the expression of Lu on erythrocytes from a cohort of MPN patients with and without SVT, and healthy controls. Samples were obtained from 20 normal individuals, 22 with MPN (both JAK2V617F-mutated and wild-type) and 8 with JAK2V617F-mutated MPN-SVT. RESULTS: Lu expression by erythrocytes from patients with MPN and MPN-SVT is significantly increased compared to erythrocytes from healthy individuals (P < .05), but there was no significant difference between patients with MPN-SVT and MPN. CONCLUSIONS: Patients with MPN have increased expression of the red cell Lu/BCAM adhesion molecule. Further work is required to determine the role of the increased Lu/BCAM adhesion to the endothelium in the development of thrombosis in MPN of all genotypes. PMID- 29756284 TI - Factors associated with ATXN2 CAG/CAA repeat intergenerational instability in Spinocerebellar ataxia type 2. AB - Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by the unstable expansion of a cytosine-adenine-guanine (CAG)/cytosine-adenine adenine (CAA) repeat in the ATXN2 gene, which normally encodes 22 glutamines (Q22). A large study was conducted to characterize the CAG/CAA repeat intergenerational instability in SCA2 families. Large normal alleles (Q24-31) were significantly more unstable upon maternal transmissions. In contrast, expanded alleles (Q32-750) were significantly more unstable during paternal transmissions, in correlation with repeat length. Significant correlations were found between the instability and the age at conception in paternal transmissions. In conclusion, intergenerational instability at ATXN2 locus is influenced by the sex, repeat length and age at conception of the transmitting parent. These results have profound implications for genetic counseling services. PMID- 29756285 TI - Evolution of a rapid onsite evaluation (ROSE) service for endobronchial ultrasound guided (EBUS) fine needle aspiration (FNA) cytology in a UK Hospital: A 7 year audit. AB - OBJECTIVE: Endobronchial ultrasound fine needle aspiration (EBUS FNA) is a well established procedure for the diagnosis and staging of lung cancer. We review our provision of this service at the Royal Devon and Exeter NHS Foundation Trust and the role of rapid onsite evaluation (ROSE) with the increasing demand for molecular markers in this era of personalized medicine. METHODS: A review of the changes in the Endoscopy clinic over the 7 years from the introduction of EBUS at the end of 2010 until 2017 was carried out. This included the availability of material obtained for diagnosis, accurate subtyping, and molecular testing. We also assessed the success of molecular genetics DNA techniques from EBUS material versus formalin fixed paraffin embedded tissue (FFPE). RESULTS: A total of 1218 EBUS cases with ROSE were reported between 2011 and 2017 Percentage diagnostic rates were calculated as 83, 82, 84, 92, 93, 94, and 92 for 2011, 2012, 2013, 2014, 2015, 2016, and 2017, respectively. Availability of material for immunocytochemistry ranged from 86 to 100% over the 7 years. Molecular testing was successfully performed for EGFR in 89-100% of requested cases and ALK testing in 87-100% of requested cases. EBUS sourced material gave on average twice the amount of DNA and fewer amplicon repeats per patient compared to FFPE material. CONCLUSION: ROSE at EBUS FNA provides access to suitable material for molecular testing with increased yields in the form of needle washings for EGFR with FFPE materials for ALK and PDL1 testing. PMID- 29756287 TI - Racial differences in the prevalence of oncogenic oral human papillomavirus infection types in the United States adult population. AB - BACKGROUND: The purpose of this study was to describe the prevalence of oral human papillomavirus (HPV) types according to race and to examine risk factors for oral HPV infection in United States adults. METHODS: Using 2009-2014 data from the National Health and Nutrition Examination Survey, 13 981 subjects were examined. Prevalence of oral HPV and individual oncogenic HPV types were described according to race. Multivariable logistic and linear regressions were used to examine the risk factors for infection and coinfection. RESULTS: Oncogenic and nononcogenic oral HPV infections were significantly more prevalent in black subjects. Infections with oral HPV types 16 and 51 were more prevalent in white subjects, whereas HPV types 35 and 58 were more prevalent in black subjects. CONCLUSION: We identified 4 oral HPV types that differ by race. Future research on HPV types (especially those that differ by race) may help elucidate their potential role in carcinogenesis and cancer disparities. PMID- 29756286 TI - Rapid and quantitative chemical exchange saturation transfer (CEST) imaging with magnetic resonance fingerprinting (MRF). AB - PURPOSE: To develop a fast magnetic resonance fingerprinting (MRF) method for quantitative chemical exchange saturation transfer (CEST) imaging. METHODS: We implemented a CEST-MRF method to quantify the chemical exchange rate and volume fraction of the Nalpha -amine protons of L-arginine (L-Arg) phantoms and the amide and semi-solid exchangeable protons of in vivo rat brain tissue. L-Arg phantoms were made with different concentrations (25-100 mM) and pH (pH 4-6). The MRF acquisition schedule varied the saturation power randomly for 30 iterations (phantom: 0-6 MUT; in vivo: 0-4 MUT) with a total acquisition time of <=2 min. The signal trajectories were pattern-matched to a large dictionary of signal trajectories simulated using the Bloch-McConnell equations for different combinations of exchange rate, exchangeable proton volume fraction, and water T1 and T2 relaxation times. RESULTS: The chemical exchange rates of the Nalpha amine protons of L-Arg were significantly (P < 0.0001) correlated with the rates measured with the quantitation of exchange using saturation power method. Similarly, the L-Arg concentrations determined using MRF were significantly (P < 0.0001) correlated with the known concentrations. The pH dependence of the exchange rate was well fit (R2 = 0.9186) by a base catalyzed exchange model. The amide proton exchange rate measured in rat brain cortex (34.8 +/- 11.7 Hz) was in good agreement with that measured previously with the water exchange spectroscopy method (28.6 +/- 7.4 Hz). The semi-solid proton volume fraction was elevated in white (12.2 +/- 1.7%) compared to gray (8.1 +/- 1.1%) matter brain regions in agreement with previous magnetization transfer studies. CONCLUSION: CEST-MRF provides a method for fast, quantitative CEST imaging. PMID- 29756288 TI - Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines. AB - OBJECTIVE: This systematic review provided a critical synthesis and a comprehensive overview of guidelines on the treatment of mixed states. METHOD: The MEDLINE/PubMed and EMBASE databases were systematically searched from inception to March 21st, 2018. International guidelines covering the treatment of mixed episodes, manic/hypomanic, or depressive episodes with mixed features were considered for inclusion. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. RESULTS: The final selection yielded six articles. Despite their heterogeneity, all guidelines agreed in interrupting an antidepressant monotherapy or adding mood-stabilizing medications. Olanzapine seemed to have the best evidence for acute mixed hypo/manic/depressive states and maintenance treatment. Aripiprazole and paliperidone were possible alternatives for acute hypo/manic mixed states. Lurasidone and ziprasidone were useful in acute mixed depression. Valproate was recommended for the prevention of new mixed episodes while lithium and quetiapine in preventing affective episodes of all polarities. Clozapine and electroconvulsive therapy were effective in refractory mixed episodes. The AGREE II overall assessment rate ranged between 42% and 92%, indicating different quality level of included guidelines. CONCLUSION: The unmet needs for the mixed symptoms treatment were associated with diagnostic issues and limitations of previous research, particularly for maintenance treatment. PMID- 29756289 TI - Supramolecularly Catalyzed Polymerization: From Consecutive Dimerization to Polymerization. AB - Herein, we propose a new method for promoting covalent polymerization by supramolecular catalysts. To this end, we employed cucurbit[8]uril (CB[8]) as a supramolecular catalyst, and successfully prepared polyelectrolytes in an aqueous solution by taking advantage of the CB[8]-enhanced photodimerization of Brooker merocyanine moieties. Interestingly, 10 mol % CB[8] is enough to effectively catalyze this polymerization, because CB[8] can be spontaneously replaced by terminal groups from photodimerized products. In addition, the molecular weights of the obtained polyelectrolytes can be varied by the irradiation time or the monomer. By combining supramolecular catalysis and polymer chemistry, this line of research may enrich the methodology of polymerization and open up new horizons for supramolecular polymer chemistry. PMID- 29756290 TI - A standardized, closed-loop system for monitoring pediatric tracheostomy-related adverse events. AB - OBJECTIVES/HYPOTHESIS: Advancement in neonatal and pediatric intensive care has increased the need for chronic-care interventions, including tracheostomy. It is well established that children with a tracheostomy are at a high risk for adverse events, many of which are preventable. Despite this, there is no standardized method of monitoring tracheostomy-related adverse events (TRAEs). Our objective was to describe and assess a standardized, closed-loop system for monitoring TRAEs. STUDY DESIGN: Prospective Study. METHODS: A specific tracheostomy-related category was established within the adverse event reporting system in January 2015. Monthly TRAE reports were supplied to the multidisciplinary tracheostomy team (MDT) with descriptions of event type, severity, and preventability. The MDT reviewed events and discussed necessary follow-up. The frequency of events was standardized by inpatient tracheostomy days (ITDs) using an automated monthly list. Adverse events were tracked using a control chart. Aggregated data were divided into biannual reports for analysis. RESULTS: Eighty-five TRAEs were reported between January 2015 and June 2017, averaging 5.75 per 1,000 ITDs. Most common events include unplanned decannulation (50%) and improper use of tracheostomy supplies (21%). The frequency of all preventable events has decreased by 76% since the second half of 2015. During this timeframe, minor events have decreased, moderate events have maintained a frequency of less than one per 1,000 ITDs, and only one severe event occurred. CONCLUSIONS: This standardized, closed-loop reporting method, modeled after other successful intensive care unit reporting systems, accurately tracks TRAEs. We have observed a decrease in preventable TRAEs without a negative impact on rates of severe events. Results suggest improved quality of care for patients with tracheostomy. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2419-2424, 2018. PMID- 29756291 TI - Mediation of time perspectives on inclinations to use alcohol and motivation to change relationship. AB - OBJECTIVES: Trajectories of change accompanying alcohol-specialized care can be affected by numerous variables. Massive urges to drink can substantially hamper personal motivation to change. However, time perspective could also play an indirect role in this association. This research explores whether time perspectives mediates the relationship between inclinations to use or not to use alcohol and patients' motivation to change. DESIGN: The sample included 150 outpatients in care for their problematic alcohol use. Models of mediation were planned. RESULTS: At the entry in care, three specific time perspectives, Past Negative, Present Fatalistic, and Future, acted as discrete mediators. CONCLUSIONS: These findings highlight underlying mechanisms connecting inclinations to use or to avoid the substance and the patient's motivation to change. Time perspective could also be an interesting intervention target in existing alcohol-specialized treatment programs. PMID- 29756292 TI - Primary intestinal-type adenocarcinoma of the oral tongue: Case report and review of histologic origin and oncologic management. AB - BACKGROUND: Primary intestinal-type adenocarcinoma (ITAC) of the oral tongue is an extremely uncommon malignancy with only 3 cases reported in the literature. This high-grade malignancy originates from metaplasia of minor salivary glands. METHODS: A 40-year-old man presented with a gradually enlarging midline oral tongue mass, odynophagia, and dysphagia. Management included a median lingual glossectomy, bilateral neck dissections, and adjuvant chemoradiation with 5 fluorouracil (5-FU). Additional chemotherapy with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) was given to mimic therapy in colonic adenocarcinomas. RESULTS: Thirteen months after surgery and adjuvant chemoradiotherapy, there is no evidence of locoregional or distant disease. His diet and speech have normalized after reconstruction without free tissue transfer. CONCLUSION: We report the fourth case of oral tongue ITAC, and present the first histologic evidence of metaplasia of oral cavity salivary epithelium. We also discuss adjuvant therapy recommendations given the lack of clarity for treatment of this rare disease. PMID- 29756293 TI - Spotting the elusive Siberian tiger: Complete response to ibrutinib in a patient with Waldenstrom Macroglobulinemia. PMID- 29756294 TI - Determination of brompheniramine enantiomers in rat plasma by cation-selective exhaustive injection and sweeping cyclodextrin modified electrokinetic chromatography method. AB - A method consisting of cation-selective exhaustive injection and sweeping (CSEI sweeping) as online preconcentration followed by a cyclodextrin modified electrokinetic chromatography (CDEKC) enantioseparation has been developed for the simultaneous determination of two brompheniramine enantiomers in rat plasma. In this method, analytes were electrokinetically injected at a voltage of 8 kV for 80 s in a fused-silica capillary. Prior to the injection, the capillary was rinsed with 50 mM phosphate buffer of pH 3.5, followed by a plug of a higher conductivity buffer (150 mM phosphate pH 3.5, 20 psi, 6 min) and a plug of water (0.5 psi, 5 s). Separation was carried out applying -20 kV in 50 mM phosphate buffer, pH 3.5, containing 10% v/v ACN and 30 mg/mL sulfated-beta-cyclodextrin (S beta-CD). Analytical signals were monitored at 210 nm. The detection sensitivity of brompheniramine enantiomers was enhanced by about 2400-fold compared to the normal injection mode (hydrodynamic injection for 3 s at 0.5 psi, with a BGE of 50 mM phosphate buffer containing 20 mg/mL S-beta-CD at pH 3.5), and LLOQ of two enantiomers were both 0.0100 MUg/mL. In addition, this method had fairly good repeatability and showed promising capabilities in the application of stereoselective pharmacokinetic investigations for brompheniramine enantiomers in rat. PMID- 29756295 TI - Treatment outcomes of patients with primary squamous cell carcinoma of the retromolar trigone. AB - OBJECTIVES/HYPOTHESIS: Squamous cell carcinoma of the retromolar trigone (RMT SCC) is a relatively uncommon primary site for oral cavity malignancy. However, given its proximity to the mandible and buccal mucosa, RMT SCC typically exhibits early invasion and generally presents at an advanced stage. Large-sample studies are needed to assess the epidemiology and clinical outcomes of this tumor. Our aim was to describe the determinants of survival in patients with RMT SCC. STUDY DESIGN: Retrospective cohort study. METHODS: Retrospective, population-based cohort study of patients in the Surveillance, Epidemiology, and End Results tumor registry who were diagnosed with RMT SCC from 1973 to 2012. Primary endpoints were overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 4,022 cases of RMT SCC were identified. The mean age at diagnosis was 65 years. Thirty-nine percent of cases presented with stage IV disease. The median OS by stages I to IV were 73.7, 52.4, 27.5, and 23.4 months, respectively (P < .05). Overall, 34.3% of patients underwent surgery, 23.5% received radiation therapy, and 34.1% had both surgical and radiation therapy. On multivariate analysis, advanced age, greater tumor size, and advanced stage were associated with worse OS and DSS (P < .05), surgery predicted improved OS and DSS (P < .05), and radiation therapy predicted improved OS only (P < .05). CONCLUSIONS: RMT SCC is an aggressive malignancy that portends a poor prognosis, though early-stage tumors (stages I and II) have significantly improved survival. Any surgical intervention independently predicted higher survival outcomes. There may be a role of dual modality approaches, particularly for larger tumors. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 29756297 TI - Retinal specializations and visual ecology in an animal with an extremely elaborate pupil shape: the little skate Leucoraja (Raja) erinacea Mitchell, 1825. AB - Investigating retinal specializations offers insights into eye functionality. Using retinal wholemount techniques, we investigated the distribution of retinal ganglion cells in the Little skate Leucoraja erinacea by (a) dye-backfilling into the optic nerve prior to retinal wholemounting; (b) Nissl-staining of retinal wholemounts. Retinas were examined for regional specializations (higher numbers) of ganglion cells that would indicate higher visual acuity in those areas. Total ganglion cell number were low compared to other elasmobranchs (backfilled: average 49,713 total ganglion cells, average peak cell density 1,315 ganglion cells mm-2 ; Nissl-stained: average 47,791 total ganglion cells, average peak cell density 1,319 ganglion cells mm-2 ). Ganglion cells fit into three size categories: small (5-20 um); medium (20-30 um); large: (>= 30 um), and they were not homogeneously distributed across the retina. There was a dorsally located horizontal visual streak with increased ganglion cell density; additionally, there were approximately three local maxima in ganglion cell distribution (potential areae centrales) within this streak in which densities were highest. Using computerized tomography (CT) and micro-CT, geometrical dimensions of the eye were obtained. Combined with ganglion cell distributions, spatial resolving power was determined to be between 1.21 and 1.37 cycles per degree. Additionally, photoreceptor sizes across different retinal areas varied; photoreceptors were longest within the horizontal visual streak. Variations in the locations of retinal specializations appear to be related to the animal's anatomy: shape of the head and eyes, position of eyes, location of tapetum, and shape of pupil, as well as the visual demands associated with lifestyle and habitat type. PMID- 29756296 TI - Effect of obesity on oxygen uptake and cardiovascular dynamics during whole-body and leg exercise in adult males and females. AB - Obesity has been associated with a slowing of VO2 dynamics in children and adolescents, but this problem has not been studied in adults. Cardiovascular mechanisms underlying this effect are not clear. In this study, 48 adults (18 males, 30 females) grouped according to body mass index (BMI) (lean < 25 kg.m-2 , overweight = 25-29.9 kg.m-2 , obese >=30 kg.m-2 ) provided a fasting blood sample, completed a maximal graded exercise test and six bouts of submaximal exercise on a cycle ergometer, and performed two protocols of calf exercise. Dynamic response characteristics of VO2 and leg vascular conductance (LVC) were assessed during cycling (80% ventilatory threshold) and calf exercise (30% MVC), respectively. Dynamic responses of cardiac output, mean arterial pressure and total systemic vascular conductance were also assessed during cycling based on measurements at 30 and 240 sec. The time constant of the second phase of the VO2 response was significantly greater in obese than lean subjects (39.4 (9.2) vs. 29.1 (7.6) sec); whereas dynamic responses of cardiac output and systemic vascular conductance were not affected by BMI. For calf exercise, the time constant of the second growth phase of LVC was slowed significantly in obese subjects (22.1 (12.7) sec) compared with lean and overweight subjects (11.6 (4.5) sec and 13.4 (6.7) sec). These data show that obesity slows dynamic responses of VO2 during cycling and the slower phase of vasodilation in contracting muscles of male and female adults. PMID- 29756298 TI - Primary whole-gland ablation for localized prostate cancer with high-intensity focused ultrasound: The important predictors of biochemical recurrence. AB - OBJECTIVES: To identify predictive factors of biochemical recurrence for patients undergoing high-intensity focused ultrasound treatment for localized prostate cancer. METHODS: We retrospectively identified patients receiving whole-gland prostate ablation with high-intensity focused ultrasound for localized prostate cancer from 2009 to 2015. All the patients received pre-high-intensity focused ultrasound radical transurethral resection of the prostate. We included perioperative parameters as follows: age, preoperative prostate volume, stage of operation, initial prostate-specific antigen, T stage, postoperative prostate specific antigen nadir, Gleason score, time to prostate-specific antigen nadir and the presence of prostate-specific antigen biochemical recurrence. Multivariable Cox regression and Kaplan-Meier analysis were used for investigating predictors of recurrence, and receiver operating characteristic analysis was used for the cut-off values of prostate-specific antigen nadir. RESULTS: Among 182 patients, 26.9% had prostate-specific antigen biochemical recurrence after high-intensity focused ultrasound during the median follow-up period of 32.21 months. Gleason score >=7 (Gleason score 7, hazard ratio 2.877, P = 0.027), stage >=T2b (T2b, hazard ratio 3.16, P = 0.027) and prostate-specific antigen nadir (hazard ratio 1.11, P < 0.001) were statistically significant, whereas there was no significance in prostate volume and initial prostate specific antigen. We posit that a cut-off level of prostate-specific antigen nadir 0.43 ng/mL might be considered as an independent predictive factor for prostate-specific antigen biochemical recurrence in high-intensity focused ultrasound patients in multivariate analysis (P < 0.001, hazard ratio 7.39, 95% confidence interval 3.56-15.37), and created a new nadir-related prediction model for biochemical recurrence prediction. CONCLUSIONS: Postoperative prostate specific antigen nadir of 0.43 ng/mL can be considered an important predictive factor for biochemical recurrence in primary whole-prostate gland high-intensity focused ultrasound treatment, and the nadir-related prediction model might provide a reference for early salvage treatment. Furthermore, Gleason score >=7, stage >=T2b might be associated with unfavorable outcomes, although prostate volume and higher initial prostate-specific antigen appear not to be associated with biochemical recurrence for the high-intensity focused ultrasound treatment. PMID- 29756299 TI - Dystrophic calcinosis cutis of the auricles after injury in Down's syndrome. PMID- 29756300 TI - A case of neutrophilic dermatoses including pyoderma gangrenosum as a continuous disease spectrum to SAPHO syndrome. PMID- 29756301 TI - Oligometastatic status as predictor of survival in metastatic human papillomavirus-positive oropharyngeal carcinoma. AB - BACKGROUND: Oligometastasis is a good prognostic indicator when compared to widely metastatic disease in malignancies of other organ systems. We hypothesized that oligometastasis in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) would be associated with better overall survival. METHODS: This is a retrospective review of all HPV-positive oropharyngeal SCC treated at one center with at least 1-year of follow-up. Patients were stratified into 2 cohorts: oligometastasis (1-2 metastases, confined to 1 organ system) or polymetastasis (>2 metastases or multiple organ involvement) with cohorts compared for time to distant metastasis and overall survival after metastasis. RESULTS: Thirty-eight of 506 patients (7.5%) developed metachronous distant metastasis; 12 developed oligometastasis and 26 developed polymetastasis. Median overall survival after oligometastasis was significantly longer than polymetastasis at 45 months (95% confidence interval [CI] 19 months - not reached) and 10 months (95% CI 5-24 months; P = .00028). CONCLUSION: Oligometastasis in metastatic HPV-positive oropharyngeal SCC portends a better prognosis than polymetastasis. PMID- 29756302 TI - Velopharyngeal dysfunction from intranasal substance abuse: Case series and review of literature. AB - OBJECTIVE: Intranasal substance abuse with cocaine or opioids can result in complications involving the midline nasal and oral structures. When the defect involves the velopharyngeal musculature, this leads to velopharyngeal dysfunction (VPD). This article aims to illustrate this clinical entity through a series of four patients and a review of the literature. METHODS: A series of four cases of VPD due to intranasal narcotic use and their management are discussed. A comprehensive search in PubMed was conducted for cases of VPD associated with intranasal drug use in the English-language literature. RESULTS: Four female patients presented with symptoms of VPD, including worsening nasal regurgitation, poor speech intelligibility, and hypernasal speech. One patient presented with nasopharyngeal stenosis. All patients admitted to intranasal cocaine, methamphetamine, and/or prescription narcotics use prior to the onset of symptoms. The diagnosis was confirmed with abnormal velopharyngeal musculature seen on nasopharyngoscopy. Both conservative and surgical treatment options were proposed. A literature review identified nine cases of VPD. Erosion of the velum was seen in all cases. Reported treatments included obturator prosthetic, local flap, and free flap. Ancillary investigations were not consistently pursued to rule out other etiologies to VPD. CONCLUSION: Intranasal illicit drug use can result in destructive changes leading to VPD. This is the largest case series to date of this difficult clinical problem. Management principles including options for conservative and surgical interventions are summarized. LEVEL OF EVIDENCE: 4. Laryngoscope, 2018. PMID- 29756303 TI - Cholesteric Liquid Crystal Shells as Enabling Material for Information-Rich Design and Architecture. AB - The responsive and dynamic character of liquid crystals (LCs), arising from their ability to self-organize into long-range ordered structures while maintaining fluidity, has given them a role as key enabling materials in the information technology that surrounds us today. Ongoing research hints at future LC-based technologies of entirely different types, for instance by taking advantage of the peculiar behavior of cholesteric liquid crystals (CLCs) subject to curvature. Spherical shells of CLC reflect light omnidirectionally with specific polarization and wavelength, tunable from the UV to the infrared (IR) range, with complex patterns arising when many of them are brought together. Here, these properties are analyzed and explained, and future application opportunities from an interdisciplinary standpoint are discussed. By incorporating arrangements of CLC shells in smart facades or vehicle coatings, or in objects of high value subject to counterfeiting, game-changing future uses might arise in fields spanning information security, design, and architecture. The focus here is on the challenges of a digitized and information-rich future society where humans increasingly rely on technology and share their space with autonomous vehicles, drones, and robots. PMID- 29756304 TI - Reply to: "Autonomic dysfunction in Parkinson's disease: The hidden game changer?" PMID- 29756305 TI - Did you "miss" me? A subtle case of intravascular large B-cell lymphoma. PMID- 29756306 TI - Mussel-Inspired Polydopamine Coating for Flexible Ternary Resistive Memory. AB - In recent years, numerous organic molecules and polymers carrying various functional groups were synthesized and used in fabrication of wearable electronic devices. Compared to previous materials that suffer from poisonousness, stiffness and complex film fabrication, we circumvent above matters by taking advantage of mussel-inspired polydopamine as our active material to realize resistive random access memories (RRAMs). Polydopamine thin films were grown on indium tin oxide glass catalyzed by Cu2 SO4 /H2 O2 and characterized by Fourier infrared spectroscopy (FT-IR), UV/Vis spectroscopy and scanning electron microscopy. The Al/Polydopamine film/ITO devices possess ternary memory behavior with good ternary device yield with two threshold voltages around 1.50 V and 3.50 V, long data retention over 104 s of continuous reading or 104 pulse reading. The two resistance switchings are attributed to defects functioning as charge traps and the formation of conductive filaments. A flexible device based on Al/polydopamine film/ITO/polyethylene terephthalate retains its ternary memory behavior after being bent with a bending radius of 1.54 cm and bending cycles up to 5000, demonstrating good compatibility and flexibility of polydopamine. PMID- 29756308 TI - Improving adolescents' periodontal health: evaluation of a mobile oral health App associated with conventional educational methods: a cluster randomized trial. AB - BACKGROUND: Adolescence is a decisive period in the construction of new conduits. OBJECTIVE: The influence of an App associated with conventional educational methods in adolescents' oral health. STUDY DESIGN: Randomized controlled trial including 291 participants (mean age = 16.1 years) in baseline. The study consisted of four phases. Interventions were evaluated through the knowledge score (KS) and oral indexes (OHI-S/GBI). KS was obtained through five affirmations about periodontal diseases applied in different moments (pre-test, post-test, and follow-up test). Phase I included pre-test and oral clinical examination. Sample was randomly divided into two groups: oral (OG) and video orientation (VG) and post-test (phase II). Phase III characterized the formation of groups: OG + App/OG without App/VG + App/VG without App. App consisted of reinforcement messages which was sent during 30 days. Phase IV comprised follow up test and clinical evaluation. RESULTS: There was no significant difference in KS between OG/VG. Overall, App improved KS (P < 0.001). VG + App showed a significant increase in KS in the follow-up test compared to the post-test (P = 0.046). There was a significant reduction in oral indexes for all methods. CONCLUSION: App was effective in increasing knowledge, especially associated with video. The different methods were equally effective for a better standard in oral hygiene. PMID- 29756309 TI - Infection hazards of xenotransplantation: Retrospect and prospect. PMID- 29756307 TI - Age-adjusted comorbidity and survival in locally advanced laryngeal cancer. AB - BACKGROUND: The purpose of this study was to quantify the relationship among age, pretreatment comorbidity, and survival outcomes in patients with locally advanced laryngeal cancer. METHODS: Baseline comorbidity data were collected and age adjusted Charlson Comorbidity Index (CCI) was calculated for each case. Kaplan Meier and Cox proportional hazards modeling were used to determine associations with survival. RESULTS: For 548 patients, with a median age of 59 years (range 31 91 years), 58% were treated with larynx preservation and the rest with total laryngectomy and adjuvant radiotherapy (RT). Two hundred thirty-eight patients (43%) had at least 1 comorbidity each. Cardiovascular diseases were the most common comorbidities (19%). The 5-year overall survival (OS) for patients with CCI <=3 (n = 442) were superior to CCI >3 (n = 106; 60% vs 41%; P < .0001), although the 5-year disease-specific survival (DSS) rates were not significantly different. The 5-year noncancer CSS was better for age-adjusted CCI <=3 (88% vs 67%; P < .0001). CONCLUSION: The age-adjusted CCI is a significant predictor of noncancer CSS and OS for patients with locally advanced laryngeal cancer but is not associated with DSS. PMID- 29756310 TI - Folate receptor-targeted 19 F MR molecular imaging and proliferation evaluation of lung cancer. AB - BACKGROUND: Folate receptors (FRs) hold great potential as important diagnostic and prognostic biological marker for cancer. PURPOSE: To assess the targeted capability of the FR-targeted perfluorocarbon (PFC) nanoparticles and to assess in vivo the relationship between FR expression and tumor proliferation with fluorine-19 (19 F) MR molecular imaging. STUDY TYPE: Prospective animal cancer model. ANIMAL MODEL: H460 (n = 14) and A549 (n = 14) nude mice subcutaneous tumor models. FIELD STRENGTH: 9.4T, 1 H and 19 F RARE sequences. ASSESSMENT: Intracellular uptake of the PFC nanoparticles was tested in H460 and A549 cell lines. 19 F MRI of H460 and A549 subcutaneous tumors was performed following intravenous injection of PFC nanoparticles. The concentration of PFC in tumors were compared. 3'-Deoxy-3'-18 F-fluorothymidine (18 F-FLT) positron emission tomography / computed tomography (PET/CT) imaging, Ki-67, and proliferating cell nuclear antigen (PCNA) staining were performed to confirm tumor proliferation. STATISTICAL TESTS: One-way or two-way analysis of variance. P < 0.05 was considered a significant difference. RESULTS: The diameter of the FR-targeted nanoparticles was 108.8 +/- 0.56 nm, and the zeta potential was -58.4 +/- 10.8 mV. H460 cells incubated with FR-targeted nanoparticles showed ~59.87 +/- 3.91% nanoparticles-labeled, which is significantly higher than the other groups (P < 0.001). The PFC concentration in H460 tumors after injection with FR-targeted nanoparticles was 4.64 +/- 1.21, 8.04 +/- 1.38, and 9.16 +/- 2.56 mmol/L at 8 hours, 24 hours, and 48 hours, respectively (P < 0.05 compared to others). The ratio of 18 F-FLT uptake for H460 and A549 tumors was 3.32 +/- 0.17 and 1.48 +/- 0.09 (P < 0.05), and there was more Ki-67 and PCNA in H460 tumor than A549. DATA CONCLUSION: 19 F MRI with FR-targeted PFC nanoparticles can be used in differentiating of FR-positive and FR-negative tumors, and further, in evaluation of the two cancer models proliferation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1617-1625. PMID- 29756311 TI - Seed-Surface Grafting Precipitation Polymerization for Preparing Microsized Optically Active Helical Polymer Core/Shell Particles and Their Application in Enantioselective Crystallization. AB - Core/shell particles constructed by polymer shell and silica core have constituted a significant category of advanced functional materials. However, constructing microsized optically active helical polymer core/shell particles still remains as a big academic challenge due to the lack of effective and universal preparation methods. In this study, a seed-surface grafting precipitation polymerization (SSGPP) strategy is developed for preparing microsized core/shell particles with SiO2 as core on which helically substituted polyacetylene is covalently bonded as shell. The resulting core/shell particles exhibit fascinating optical activity and efficiently induce enantioselective crystallization of racemic threonine. Taking advantage of the preparation strategy, novel achiral polymeric and hybrid core/shell particles are also expected. PMID- 29756312 TI - Cyclic Peptides for Efficient Detection of Collagen. AB - We report here a new class of collagen-binding peptides, cyclic collagen-mimetic peptides (cCMPs), that efficiently hybridize with the triple-helix-forming portions of collagen. cCMPs are composed of two parallel collagen-like (Xaa-Yaa Gly)n strands with both termini tethered by covalent linkages. Enzyme-linked immunosorbent assays and western blotting analysis showed that cCMPs exhibit more potent affinity toward collagen than reported collagen-binding peptides and can specifically detect different collagen polypeptides in a mixture of proteins. Collagen secreted from cultured cells was detected by confocal microscopy with fluorescein-labeled cCMP. The cCMP is also shown to detect sensitively folding intermediates in the endoplasmic reticulum, something that was difficult to visualize with conventional collagen detectors. Molecular-dynamics simulations suggested that a cCMP forms a more stably hybridized product than its single chain counterpart; this could explain why cCMP has higher affinity toward denatured collagen. These results indicate the usefulness of cCMPs as tools for detecting denatured collagen. PMID- 29756314 TI - Exploring attentional biases towards facial expressions of pain in men and women. AB - BACKGROUND: Interpersonal factors may help explain why men and women differ in their perception and expression of pain. Whilst the focus is often on the person in pain, how observers respond to those in pain is important. This study explored whether male-female differences exist in the way observers attend to expressions of pain in others. METHODS: Fifty-three adults (26 females) completed a visual dot-probe task, to measure selective attentional biases to facial expressions of pain and fear. Expression pairs (e.g. pain/neutral) were displayed by either the same male or female actor, and in two different viewing duration conditions: 150 and 1250 ms. Dot-probes appeared in either a congruent or incongruent location to the target expression. RESULTS: No evidence was found for sex-related attentional biases towards pain or fear. However, when examining congruency and incongruency indexes separately, differences emerged. The congruency index analysis indicated that in the 150-ms presentation condition, both men and women were slower during congruent female pain/neutral trials when compared to neutral/neutral trials, and relatively faster at responding during congruent male pain/neutral trials. CONCLUSIONS: There is utility in exploring the attentional processes involved in the decoding of pain-related expressions to understand the influence of sex and gender differences in pain. Although male-female differences were found, this was most clearly related to the actor. Our results point to an early attentional mechanism that orients attention away from female expressions of pain. Future consideration of sex- and gender-related contextual factors in attentional processing is warranted. SIGNIFICANCE: Sex-related factors seem to affect how observers view the pain of others. Our results point to an early attentional mechanism that orients the attention of observers away from female expressions of pain. PMID- 29756313 TI - Antagonistic activities of volatiles produced by two Bacillus strains against Monilinia fructicola in peach fruit. AB - BACKGROUND: Brown rot caused by Monilinia fructicola is one of most serious diseases of postharvest peach fruit. The objective of this study was to select effective antagonistic bacteria against Monilinia fructicola and evaluate the effects of these strains against brown rot. RESULTS: Four bacterial strains producing inhibitory volatile gas against Monilinia fructicola were isolated from the peach rhizosphere soil. The volatiles produced by 12a (Bacillus vallismortis) and 14b (Bacillus altitudinis) showed considerable antagonistic activities. Monilinia fructicola showed 80.3% and 68.4% mycelial growth inhibition and cell damage in the presence of strains 12a and 14b, respectively. The inhibition rate of brown rot in peach fruit fumigated with the culture solution of 12a or 14b reached 77.1% and 50.0%, respectively. The volatile compounds produced by 12a and 14b were identified according to gas chromatographic-mass spectrometric analysis. Among them, 6-methyl-2-heptanone and 2-pentylfuran completely inhibited mycelial growth at 100 uL L-1 concentration. Cedrol showed strong inhibitory activity against mycelial growth at 100 ug L-1 and isodecyl methacrylate inhibited growth at high concentration. The inhibition rate of the 50 uL L-1 artificial mixture of these four volatiles was 59.3% in vitro. CONCLUSION: These results indicate that the two antagonistic bacteria and some volatiles produced by them have potential value in controlling brown rot in harvested peach fruit. (c) 2018 Society of Chemical Industry. PMID- 29756315 TI - Silver Nanoflower Decorated Graphene Oxide Sponges for Highly Sensitive Variable Stiffness Stress Sensors. AB - Soft conductive materials should enable large deformation while keeping high electrical conductivity and elasticity. The graphene oxide (GO)-based sponge is a potential candidate to endow large deformation. However, it typically exhibits low conductivity and elasticity. Here, the highly conductive and elastic sponge composed of GO, flower-shaped silver nanoparticles (AgNFs), and polyimide (GO AgNF-PI sponge) are demonstrated. The average pore size and porosity are 114 um and 94.7%, respectively. Ag NFs have thin petals (8-20 nm) protruding out of the surface of a spherical bud (300-350 nm) significantly enhancing the specific surface area (2.83 m2 g-1 ). The electrical conductivity (0.306 S m-1 at 0% strain) of the GO-AgNF-PI sponge is increased by more than an order of magnitude with the addition of Ag NFs. A nearly perfect elasticity is obtained over a wide compressive strain range (0-90%). The strain-dependent, nonlinear variation of Young's modulus of the sponge provides a unique opportunity as a variable stiffness stress sensor that operates over a wide stress range (0-10 kPa) with a high maximum sensitivity (0.572 kPa-1 ). It allows grasping of a soft rose and a hard bottle, with the minimal object deformation, when attached on the finger of a robot gripper. PMID- 29756317 TI - Free energy landscapes of prototropic tautomerism in pyridoxal 5'-phosphate schiff bases at the active site of an enzyme in aqueous medium. AB - We have performed hybrid quantum-classical metadynamics simulations and quantum chemical calculations to investigate the free energy landscapes of intramolecular proton transfer and associated tautomeric equilibrium in pyridoxal 5 '-phosphate (PLP) Schiff Bases, namely the internal and external aldimines, at the active site of serine hydroxymethyltransferase (SHMT) enzyme in aqueous medium. It is important to determine the relative stability of the two tautomers (ketoenamine and enolimine) of the PLP aldimines to study the catalytic activity of the concerned enzyme. Both the internal PLP aldimine (PLP-LYS) and the external PLP aldimine (PLP-SER) of SHMT are found to have a higher stability for the ketoenamine tautomer over the enolimine form. The higher stability of the ketoenamine tautomer can be attributed to the more number of favorable interactions of the ketoenamine form with its surroundings at the active site of the enzyme. The ketoenamine is found to be stabilized by about 2.5 kcal/mol in the PLP-LYS internal aldimine, while this stabilization is about 6.7 kcal/mol for the PLP-SER external aldimine at the active site of the enzyme compared to the corresponding enolimine forms. The interactions faced by the PLP aldimines at the active site pocket determine the relative dominance of the tautomers and could possibly alter the tautomeric shift in different PLP dependent enzymes. (c) 2018 Wiley Periodicals, Inc. PMID- 29756318 TI - No evidence for considering wake-up and daytime unwitnessed strokes differently for thrombectomy. PMID- 29756316 TI - Fine particulate matter associated mortality burden of lung cancer in Hebei Province, China. AB - BACKGROUND: The association between fine particulate matter (PM2.5 ) and lung cancer (LC) mortality in China is limited. The Beijing-Tianjin-Hebei region is infamous for serious air pollution. Seven of the top 10 cities with the worst air quality are located in Hebei Province. Thus, we explored the effect of 10 years of PM2.5 on the LC mortality rate in Hebei Province. METHODS: We quantified associations between LC mortality and PM2.5 and estimated the LC mortality burden attributed to PM2.5 with predicted county level LC deaths in 2014. RESULTS: The 10-year PM2.5 LC mortality associations were non-linear, with thresholds of 63 MUg/m3 overall, 69 MUg/m3 for men, 68 MUg/m3 for women, 66 MUg/m3 for those aged 30-64 years, and 62 MUg/m3 for those aged >= 65 years. The relative risks for these groups were 1.09 (95% confidence interval [CI] 1.08-1.10), 1.06 (95% CI 1.03-1.10), 1.20 (95% CI 1.10-1.26), 1.07 (95% CI 1.05-1.11), and 1.10 (95% CI: 1.07-1.13), respectively. There were 2525 (95% CI 2265-2780) LC deaths attributed to 10-year PM2.5 in 2014, at fractions of 8.3% (95% CI 7.4-9.1%) overall, 5.7% (95% CI 2.8-9.4%) for men, 16.7% (95% CI: 8.3-21.6%) for women, 6.5% (95% CI 4.7 10.3%) for those aged 30-64 years, and 9.1% (95% CI 6.4-11.5%) for those aged >= 65 years. CONCLUSION: Our results suggest that a reduction in the PM2.5 exposure levels below thresholds would prevent a substantial number of LC deaths in Hebei Province. PMID- 29756319 TI - Thrombolysis on direct oral anticoagulants: the 'grey area'. PMID- 29756320 TI - Every physician should discourage cigarette smoking. PMID- 29756322 TI - European Medicines Agency: Approval of new glucose-lowering medicines for type 2 diabetes. PMID- 29756323 TI - Primary mediastinal histiocytic sarcoma presenting as pleural effusion. AB - Histiocytic sarcoma (HS) is a rare malignant neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. As HS may mimic non Hodgkin lymphoma (NHL) pathologically, before the era of immunohistochemistry, many previously reported cases were misdiagnosed NHL. Up to date, there are only a few reports delineating the cytological features in fine-needle aspiration or bronchoalveolar lavage, but not in the effusion fluid yet. Herein, we report the case of a 61-year-old male with a mediastinal tumor presenting with malignant pleural effusion. The effusion cytology showed atypical epithelioid (histiocytoid) cells, both in loose clusters and a dispersed pattern, with scanty admixed inflammatory infiltrate. Distinct from the benign histiocytes, these tumor cells exhibited evident cytological atypia, including irregular nuclear contours, significant nuclear pleomorphism, brisk mitotic figures, and apoptotic bodies in the Papanicolaou stain. With the Liu stain, most tumor cells showed abundant blue-gray cytoplasm, some with small cytoplasmic vacuoles and formation of pseudopods. Subsequent biopsies of the tumor nodules in the right lower lung and pleura showed diffuse sheets of neoplastic cells expressing CD4, CD45, CD68, and lysozyme by immunohistochemistry, confirming the diagnosis. Usually subtyping the lymphoma in the effusion fluid is not an important issue since most patients already have previously confirmed lymphoma. In rare situation, like our patient, the disease may present initially as a malignant effusion. Immunophenotyping using cell blocks and/or excisional specimens is mandatory for a definitive diagnosis. PMID- 29756324 TI - Prospective frequency correction using outer volume suppression-localized navigator for MR spectroscopy and spectroscopic imaging. AB - PURPOSE: New frequency correction methods are required to achieve the accurate measurement of frequency drifts in MRS and MRSI. We present a prospective frequency correction method with outer volume suppression (OVS)-based localization and selective water excitation for effective frequency correction with better SNR improvement compared to other techniques. METHODS: An OVS localized navigator was developed to prospectively correct frequency drifts during MRS and MRSI measurements. The performance of the navigator was tested on the human brain and a solution phantom for frequency drifts induced by head motion or gradient heating by a preceding DWI experiment at 3T. RESULTS: The OVS localized navigator could accurately track motion-induced frequency drifts with an RMS error of 0.5 Hz. The SNR of MRS signals was not affected by use of the OVS localized navigator when compared with and without the navigator (P > 0.05). The frequency drifts induced by DWI experiments were 5.1 +/- 0.3 Hz/min during MRSI measurements on humans, resulting in increased spectral linewidth, significant bias in metabolite concentrations, and significantly increased Cramer-Rao lower bounds (P < 0.05). After prospective frequency corrections, the quality of MRSI was recovered to the level of those without any DWI-induced frequency drifts, judged by the spectral linewidth, metabolite concentrations, and Cramer-Rao lower bounds. CONCLUSION: The OVS-localized navigator demonstrated effective prospective frequency corrections for large frequency drifts (5 Hz/min) without introducing any saturation-induced SNR loss. These benefits can be particularly beneficial for the acquisition of MRS signals with long T1 and/or short TR, and spectral editing. PMID- 29756325 TI - Effect of dietary alpha-ketoglutarate and allicin supplementation on the composition and diversity of the cecal microbial community in growing pigs. AB - BACKGROUND: The search for substitutes for antibiotics has recently become urgent. In our previous work, dietary alpha-ketoglutarate (AKG) combined with allicin improved growth performance and enhanced immunity in growing pigs, whereas the effects on them of intestinal microbiota were unclear. Here, we further investigate the effects of dietary AKG and allicin supplementation on the composition and diversity of intestinal microbiota in growing pigs. RESULTS: Treatment with a combination of AKG and allicin enhanced cecal bacteria richness and diversity, as evidenced by changes in Chao 1, ACE, Shannon, and Simpson values when compared to the control group and antibiotics group. At the phylum level, Bacteroidetes and Firmicutes were the two most abundant phyla. Treatment with a combination of AKG and allicin increased the numbers of Firmicutes and reduced the numbers of Bacteroidetes. Prevotella was the most abundant genus; it was increased by treatment with a combination of AKG and allicin. Furthermore, compared with the antibiotic group, the level of acetate was increased in the AKG group with or without allicin. Treatment with a combination of AKG and allicin increased the levels of cecal butyrate and total volatile fatty acids (VFA) when compared with the control group in growing pigs. CONCLUSION: Dietary 1.0% AKG combined with 0.5% allicin improved cecal microbial composition and diversity, which might further promote VFA metabolism in growing pigs. (c) 2018 Society of Chemical Industry. PMID- 29756326 TI - Gastrostomy tube placement among infants with hypoplastic left heart syndrome undergoing stage 1 palliation. AB - OBJECTIVE: Different feeding strategies have been suggested to improve growth and survival of infants with hypoplastic left heart syndrome following stage 1 palliation. The study objective was to assess hospital mortality following stage 1 palliation among infants with hypoplastic left heart syndrome who had two feeding modalities, gastrostomy tube vs no gastrostomy tube. DESIGN: Retrospective study design. SETTING: Multicenter pediatric heath information system database. PATIENT: About 4287 patients with hypoplastic left heart syndrome who underwent stage 1 Norwood procedure from 2004 through 2013. Infants who had gastrostomy tube with or without fundoplication procedure were identified and their clinical characteristics were compared. INTERVENTION: None. OUTCOMES MEASURES: The primary outcome was discharge hospital mortality following stage 1 palliation. RESULTS: About 1214 patients who underwent stage 1 palliation had gastrostomy tube placement prior to hospital discharge. About 881 only had this procedure, while 333 patients also underwent fundoplication. Infants who had a gastrostomy tube placement vs no gastrostomy procedure had longer hospital stay, but significantly lower hospital mortality (5% vs 19%, P < .001). Hospital mortality was lower in infants who had only gastrostomy vs gastrostomy with fundoplication procedure (4% vs 8%, P = .004). In the multivariable analysis, gastrostomy procedure was associated with a higher likelihood of survival to hospital discharge (HR: 0.06, CI [0.04, 0.1]), whereas additional fundoplication procedure increased the risk of mortality (HR: 2.77, CI [1.52, 5.04]). CONCLUSIONS: The gastrostomy procedure did not place infants with hypoplastic left heart syndrome at higher risk of mortality. These infants should be considered for gastrostomy tube placement if they had persistent difficulty in oral feeding following stage 1 palliation. PMID- 29756327 TI - Use of radioiodine-131 scan to measure influence of surgical discipline, practice, and volume on residual thyroid tissue after total thyroidectomy for differentiated thyroid carcinoma. AB - BACKGROUND: Our study's purpose is to determine the influence of surgical discipline, surgeon site, and volume on remnant thyroid tissue visualized on radioactive iodine-131 (I-131) scans after total thyroidectomy and I-131 ablation in patients with well-differentiated thyroid carcinomas. METHODS: We retrospectively reviewed all cases of patients who received I-131 therapeutic ablation and postablation radioactive I-131 scans at our center after thyroidectomy to calculate the fraction of administered dose multiplied by 1000 (UDR1000). RESULTS: The remnant thyroid tissue (ie, the UDR1000), between academic and community surgeons was 0.471 (+/-0.705) and 1.190 (+/-2.487), respectively (P = .001). The UDR1000 between otolaryngology-head and neck surgery and general surgery was 0.654 (+/-1.575) and 1.043 (+/-1.625), respectively (P = .159). The UDR1000 partitioned by patient frequencies of <10, 10 to 19, and >=20 patients yielded 1.255 (+/-2.554), 0.926 (+/-2.084), and 0.467 (+/-0.721), respectively (P = .003). CONCLUSION: Our study found statistically significant differences in residual thyroid tissue visualized on radioactive I-131 scans based on surgeon parameters. PMID- 29756329 TI - A patient with an unusual cyst of the inter-atrial septum and atrial sepal defect. AB - Hepatic and renal cysts are relatively common among healthy people, but there are few published reports of primary cysts of the atrial septum. Here, we report a case of an unusual cyst of the atrial septum accompanied by atrial septal defect (ASD) in a 42-year-old woman. Microscopic examination showed the deposition of calcium salts within the tissue mass and an organized thrombus surrounded by a fibrous capsule. The case was discussed with reference to the relevant published literature and compared to other documented types of atrial septal cysts. The final diagnostic conclusion was a primary atrial septal cyst. PMID- 29756330 TI - Postoperative prophylactic antibiotics for facial fractures: A systematic review and meta-analysis. AB - OBJECTIVE: Perioperative antibiotic prophylaxis in patients undergoing surgery for maxillofacial fractures is standard practice. However, the use of postoperative antibiotic prophylaxis remains controversial. This systematic review and meta-analysis sought to evaluate the effect of postoperative antibiotic therapy on the incidence of surgical site infection (SSI) in patients with maxillofacial fractures. METHODS: MEDLINE, Embase, and the Cochrane Library were searched from inception through October 2017. Randomized controlled trials (RCTs) and cohort studies evaluating the efficacy of pre-, peri-, and postoperative antibiotic prophylaxis in preventing SSI in maxillofacial fractures were included. Data were extracted from studies using a standardized data collection form, with two reviewers independently performing extraction and quality assessment for each study. Risk ratios (RRs) for SSI were pooled using a random-effects model. RESULTS: Among 2,150 potentially eligible citations, 13 studies met inclusion criteria and provided data to be included in a meta analysis. The addition of postoperative antibiotic prophylaxis to a standard preoperative and/or perioperative antibiotic regimen showed no significant difference in the risk of SSI (RR = 1.11 [95% CI: 0.86-1.44], P > .1). There were also no differences in the risk of SSI when restricting the analysis to mandibular fractures (eight studies, RR = 1.22 [95% CI: 0.92-1.62]) or open surgical techniques (eight studies, RR = 1.02 [95% CI: 0.62-1.67]). A sensitivity analysis did not find any significant differences in risk when restricting to RCTs (seven trials, RR = 1.00 [95% CI: 0.61-1.67]) or cohort studies (six studies, RR = 1.21 [95% CI: 0.89-1.63]). CONCLUSIONS: Our findings, along with the available evidence, does not support the routine use of postoperative antibiotic prophylaxis in patients with maxillofacial fractures. Avoiding the unnecessary use of antibiotic therapy in the postoperative period could have important implications for healthcare costs and patient outcomes. Laryngoscope, 2018. PMID- 29756328 TI - Serum-derived carcinoembryonic antigen (CEA) activates fibroblasts to induce a local re-modeling of the extracellular matrix that favors the engraftment of CEA expressing tumor cells. AB - Elevated levels of the carcinoembryonic antigen (CEA; CEACAM5) in the serum of colorectal cancer (CRC) patients represent a clinical biomarker that correlates with disease recurrence. However, a mechanistic role for soluble CEA (sCEA) in tumor progression and metastasis remains to be established. In our study, we report that sCEA acts as a paracrine factor, activating human fibroblasts by signaling through both the STAT3 and AKT1-mTORC1 pathways, promoting their transition to a cancer-associated fibroblast (CaF) phenotype. sCEA-activated fibroblasts express and secrete higher levels of fibronectin, including cellular EDA+ -fibronectin (Fn-EDA) that selectively promote the implantation and adherence of CEA-expressing cancer cells. Immunohistochemical analyses of liver tissues derived from CRC patients with elevated levels of sCEA reveal that the expression of cellular Fn-EDA co-registers with CEA-expressing liver metastases. Taken together, these findings indicate a direct role for sCEA as a human fibroblast activation factor, in priming target tissues for the engraftment of CEA-expressing cancer cells, through the differentiation of tissue-resident fibroblasts, resulting in a local change in composition of the extracellular matrix. PMID- 29756331 TI - Mammalian X Chromosome Dosage Compensation: Perspectives From the Germ Line. AB - Sex chromosomes are advantageous to mammals, allowing them to adopt a genetic rather than environmental sex determination system. However, sex chromosome evolution also carries a burden, because it results in an imbalance in gene dosage between females (XX) and males (XY). This imbalance is resolved by X dosage compensation, which comprises both X chromosome inactivation and X chromosome upregulation. X dosage compensation has been well characterized in the soma, but not in the germ line. Germ cells face a special challenge, because genome wide reprogramming erases epigenetic marks responsible for maintaining the X dosage compensated state. Here we explain how evolution has influenced the gene content and germ line specialization of the mammalian sex chromosomes. We discuss new research uncovering unusual X dosage compensation states in germ cells, which we postulate influence sexual dimorphisms in germ line development and cause infertility in individuals with sex chromosome aneuploidy. PMID- 29756332 TI - A Degradable and Recyclable Photothermal Conversion Polymer. AB - Decomposition and repolymerization of conjugated polymers offer great promise for developing recyclable photothermal conversion materials, which yet remain challenging. Herein, a crosslinked conjugated polymer based on a dynamic covalent bond of Schiff base is developed. This polymer possesses photothermal conversion efficiency as high as 90.4 %. Decomposition of the polymer under specialized conditions is corroborated by various characterizations. The kinetics study is also investigated to understand this degradation process. Furthermore, those decomposed species can be repolymerized back to conjugated polymers which possess the same photothermal conversion efficiency as the pristine polymer. Such a degradable and recyclable photothermal polymer is successfully used as a heat source for photothermal-electrical conversion to generate Seebeck voltage under either near infrared (NIR) irradiation or solar illumination. PMID- 29756333 TI - Safe Use of Epidural Corticosteroid Injections: Recommendations of the WIP Benelux Work Group. AB - BACKGROUND: Epidural corticosteroid injections are used frequently worldwide in the treatment of radicular pain. Concerns have arisen involving rare major neurologic injuries after this treatment. Recommendations to prevent these complications have been published, but local implementation is not always feasible due to local circumstances, necessitating local recommendations based on literature review. METHODS: A work group of 4 stakeholder pain societies in Belgium, The Netherlands, and Luxembourg (Benelux) has reviewed the literature involving neurological complications after epidural corticosteroid injections and possible safety measures to prevent these major neurologic injuries. RESULTS: Twenty-six considerations and recommendations were selected by the work group. These involve the use of imaging, injection equipment particulate and nonparticulate corticosteroids, epidural approach, and maximal volume to be injected. CONCLUSION: Raising awareness about possible neurological complications and adoption of safety measures recommended by the work group aim at reducing the risks for these devastating events. PMID- 29756334 TI - Effect of cell-phone radiofrequency on angiogenesis and cell invasion in human head and neck cancer cells. AB - BACKGROUND: Today, the cell phone is the most widespread technology globally. However, the outcome of cell-phone radiofrequency on head and neck cancer progression has not yet been explored. METHODS: The chorioallantoic membrane (CAM) and human head and neck cancer cell lines, FaDu and SCC25, were used to explore the outcome of cell-phone radiofrequency on angiogenesis, cell invasion, and colony formation of head and neck cancer cells, respectively. Western blot analysis was used to investigate the impact of the cell phone on the regulation of E-cadherin and Erk1/Erk2 genes. RESULTS: Our data revealed that cell-phone radiofrequency promotes angiogenesis of the CAM. In addition, the cell phone enhances cell invasion and colony formation of human head and neck cancer cells; this is accompanied by a downregulation of E-cadherin expression. More significantly, we found that the cell phone can activate Erk1/Erk2 in our experimental models. CONCLUSION: Our investigation reveals that cell-phone radiofrequency could enhance head and neck cancer by stimulating angiogenesis and cell invasion via Erk1/Erk2 activation. PMID- 29756335 TI - Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)S. AB - The objective of the current review was to update the previous evidence-based medicine review of treatments for restless legs syndrome published in 2008. All randomized, controlled trials (level I) with a high quality score published between January 2007 and January 2017 were reviewed. Forty new studies qualified for efficacy review. Pregabalin, gabapentin enacarbil, and oxycodone/naloxone, which did not appear in the previous review, have accrued data to be considered efficacious. Likewise, new data enable the modification of the level of efficacy for rotigotine from likely efficacious to efficacious. Intravenous ferric carboxymaltose and pneumatic compression devices are considered likely efficacious in idiopathic restless legs syndrome. Bupropion and clonidine were reviewed, but the lack of data determined a rating of insufficient evidence for efficacy. The following interventions continue to be considered efficacious as in 2008: levodopa, ropinirole, pramipexole, cabergoline, pergolide, and gabapentin. Bromocriptine, oxycodone, carbamazepine, and valproic acid are considered likely efficacious. Oral iron is nonefficacious in iron-sufficient subjects, but its benefit for patients with low peripheral iron status has not been adequately evaluated. Restless legs syndrome augmentation has been identified as a significant long-term treatment complication for pramipexole more than pregabalin and possibly for all dopaminergic agents more than alpha2delta ligands. Therefore, special monitoring for augmentation is required for all dopaminergic medications as well as tramadol. Other drugs also require special safety monitoring: cabergoline, pergolide, oxycodone, methadone, tramadol, carbamazepine, and valproic acid. Finally, we also highlighted gaps and needs for future clinical research and studies of restless legs syndrome. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756336 TI - Isolation and initial characterization of new betanodaviruses in shellfish. AB - Betanodaviruses cause the disease viral nervous necrosis (VNN) in finfish. Using a novel approach with two consecutive PCRs, detection semi-nested two-step RT-PCR (DSN-2 RT-PCR) and discriminative multiplex two-step RT-PCR (DMT-2 RT-PCR), we have identified the presence of a new type of betanodavirus in shellfish and called it Korean shellfish nervous necrosis virus (KSNNV). Partial nucleotide sequences of the T4 region in RNA2 fragment of KSNNVs were 73%-75% homologous to those of other reported genotypes and formed a new cluster of betanodavirus in phylogenetic tree analysis. Successful isolation of KSNNV was achieved in two of six shellfish samples containing high concentrations of virus using the blind passage method, and the typical shapes of betanodavirus were confirmed in KSNNV KOR1 by electron microscopy. In the experimental infection test, seven of 14 fish species showed susceptibility to KSNNV-KOR1 isolate but without clinical signs or death. Although the range of susceptible host species was not significantly different from the RGNNV type, the concentration of KSNNV in the brain of infected fish (102 -105 copies/mg brain) was much lower compared to that found in sevenband grouper (Epinephelus septemfasciatus Thunberg) sampled in the moribund stage with RGNNV infection (106 -107 copies/mg brain). However, histopathological analyses showed the presence of multiple vacuoles in brains of all KSNNV-infected fish at 14 days postinjection. In detection test, as a single or multiple type with the other genotype(s) (RGNNV or BFNNV), the prevalence of KSNNV was 8.4% and 8.7% in domestic (62 of 741 samples) and Chinese samples (12 of 138 samples), respectively, but not in finfish. We propose that KSNNVs obtained from shellfish be classified into a separate and new genotype of betanodavirus. PMID- 29756337 TI - Highly Efficient and Diastereoselective Construction of Trifluoromethyl Containing Spiro[pyrrolidin-3,2'-oxindole] by a Catalyst-free Mutually Activated [3+2] Cycloaddition Reaction. AB - A catalyst-free self-catalyzed [3+2] cycloaddition reaction of isatin-derived alpha-(trifluoromethyl)imines with vinylpyridines is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of a series of 5'-trifluoromethyl-spiro[pyrrolidin-3,2'-oxindoles] in excellent yields and diastereoselectivities. The reaction mechanism has been investigated by control experiments, DFT calculation of pKa values and the kinetic profiles, revealing that this reaction featured the mutual activation between isatin derived alpha-(trifluoromethyl)imines and vinylpyridine to generate the reactive species. PMID- 29756338 TI - Marsupialization of mandibular cystic ameloblastoma: Retrospective study of 7 years. AB - BACKGROUND: This retrospective study investigated the reduction rate and speed of shrinkage after marsupialization in mandibular cystic ameloblastoma and clarified whether marsupialization is appropriate for unicystic ameloblastoma and multicystic ameloblastoma. METHODS: Sixty-three patients with mandibular cystic ameloblastoma were initially treated with marsupialization. Premarsupialization and postmarsupialization panoramic radiographs were reviewed for reduction rate and speed of shrinkage, and then were evaluated with age, sex, tumor location, and tumor type. RESULTS: The overall recurrence rate was 4.5% (2/44). The average reduction rate after marsupialization was 65.6%. No significant difference was found between unicystic ameloblastoma and multicystic ameloblastoma in reduction rate. The speed of shrinkage of unicystic ameloblastoma was significantly faster than that of multicystic ameloblastoma (P < .05). Similarly, patients with multicystic ameloblastoma had longer marsupialization periods than those with unicystic ameloblastoma (P < .05). CONCLUSION: Marsupialization is effective in reducing tumor size for both unicystic ameloblastoma and multicystic ameloblastoma. Marsupialization plus second-stage curettage is recommended as the primary treatment for mandibular cystic ameloblastoma. PMID- 29756339 TI - 'No one to trust': the cultural embedding of atomism in financial markets. AB - The paper ethnographically explores the cultural embedding of atomistic indifference in online, global financial markets: arenas that have been digitally designed according to economic ideals and that demand an extreme form of relational and social dissociation from the partners to exchange and from those affected by the transactions. Its case-study is lay financial-trading in Israel, a country undergoing extensive neoliberalization. The study shows that dissociation is embedded in an economic culture marked by constant, multi-sited declarations that economic-Others are cold, uncaring and manipulative. It takes shape as traders convert the distrust towards Others into distrust towards portions of the Self that represent links to these Others, namely their own social-psychology and social concern. Acting atomistically and selfishly in the market thus entails considerable reflexive work. The paper contributes to an ongoing debate on the moral and cultural embeddedness of markets in general and of the expanding financial markets in particular. PMID- 29756340 TI - [Hg4 Te8 (Te2 )4 ]8- : A Heavy Metal Porphyrinoid Embedded in a Lamellar Structure. AB - The use of ionic liquids (Cn C1 Im)[BF4 ] with long alkyl chains (n=10, 12) in the ionothermal treatment of Na2 [HgTe2 ] led to lamellar crystal structures with molecular macrocyclic anions [Hg8 Te16 ]8- (1), the heaviest known topological relative of porphyrin. [Hg8 Te16 ]8- differs from porphyrin by the absence of an electronic pi-system, which prevents a "global" aromaticity. Quantum chemical studies reveal instead small ring currents in the pyrrole-type five-membered rings that indicate weak local (sigma) aromaticity. As a result of their lamellar nature, the compounds are promising candidates for the formation of sheets containing chalcogenidometalate anions. PMID- 29756341 TI - Identifying sagittal otoliths of Mediterranean Sea gobies: variability among phylogenetic lineages. AB - In this study, we describe and analyse the morphology of the sagitta, the largest otolith, of 25 species of Gobiidae inhabiting the Adriatic and north-western Mediterranean seas. Our goal was to test the usefulness and efficiency of sagittal otoliths for species identification. Our analysis of otolith contours was based on mathematical descriptors called wavelets, which are related to multi scale decompositions of contours. Two methods of classification were used: an iterative system based on 10 wavelets that searches the Analisi de Formes d'Otolits (AFORO) database and a discriminant method based only on the fifth wavelet. With the exception of paedomorphic species, the results showed that otolith anatomy and morphometry can be used as diagnostic characters distinguishing the three Mediterranean phylogenetic goby lineages (Pomatoschistus or sand-goby lineage, Aphia lineage and Gobius lineage). The main anatomical differences were related to overall shape (square to rhomboid), the development and shape of the postero-dorsal and antero-ventral lobes and the degree of convexity of dorsal and ventral margins. Iterative classifications and discriminant analysis of otolith contour provided very similar results. In both cases, more than 70% of specimens were correctly classified to species and more than 80% to genus. Iterations in the larger AFORO database (including 216 families of teleosts) attained a 100% correct classification at the family level. PMID- 29756342 TI - Safety of preoperative ibuprofen in pediatric tonsillectomy. AB - OBJECTIVE: Oral ibuprofen is believed to be safe and effective after pediatric adenotonsillectomy. There has been little study of its use as a preoperative analgesic. We attempt to document its safety in this setting. STUDY DESIGN: Individual case control study. METHODS: Children who underwent tonsillectomy or adenotonsillectomy from January 2013 to December 2015 did not receive preoperative ibuprofen. Those who underwent tonsillectomy or adenotonsillectomy from January 2016 to December 2017 received oral ibuprofen 7 mg/kg preoperatively. Pre- and postoperative records were reviewed. Intraoperative bleeding > 50 mL or early postoperative bleeding requiring surgical control were outcome measures. Delayed bleeding events were also recorded. RESULTS: A total of 217 children met inclusion criteria. Of those, 112 patients did not receive preoperative ibuprofen, and 105 patients did receive preoperative ibuprofen. Mean age was 8.7 years (range: 1-18) in the control/non-ibuprofen cohort and 8.3 years (range: 1-18) in the ibuprofen cohort. No child experienced significant intraoperative or early postoperative bleeding in the non-ibuprofen (95% confidence interval [CI] 0-0.027) or in the ibuprofen cohort (95% CI 0- 0.029). Delayed bleeding rates were similar in both groups. CONCLUSION: In this series, children treated with preoperative ibuprofen did not experience increased bleeding during or soon after tonsillectomy compared to controls. Pain control was not studied in these patients. These favorable safety data argue for a future prospective randomized study of preoperative ibuprofen's effectiveness in reducing pain and opioid requirement after pediatric tonsillectomy. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:2415-2418, 2018. PMID- 29756343 TI - Risk of bladder cancer by disease severity in relation to metabolic factors and smoking: A prospective pooled cohort study of 800,000 men and women. AB - Previous studies on metabolic factors and bladder cancer (BC) risk have shown inconsistent results and have commonly not investigated associations separately by sex, smoking, and tumor invasiveness. Among 811,633 participants in six European cohorts, we investigated sex-specific associations between body mass index (BMI), mid-blood pressure (BP, [systolic + diastolic]/2), plasma glucose, triglycerides, total cholesterol and risk of BC overall, non-muscle invasive BC (NMIBC) and muscle invasive BC (MIBC). Among men, we additionally assessed additive interactions between metabolic factors and smoking on BC risk. During follow-up, 2,983 men and 754 women were diagnosed with BC. Among men, triglycerides and BP were positively associated with BC risk overall (hazard ratio [HR] per standard deviation [SD]: 1.17 [95% confidence interval (CI) 1.06 1.27] and 1.09 [1.02-1.17], respectively), and among women, BMI was inversely associated with risk (HR: 0.90 [0.82-0.99]). The associations for BMI and BP differed between men and women (pinteraction <= 0.005). Among men, BMI, cholesterol and triglycerides were positively associated with risk for NMIBC (HRs: 1.09 [95% CI 1.01-1.18], 1.14 [1.02-1.25], and 1.30 [1.12-1.48] respectively), and BP was positively associated with MIBC (HR: 1.23 [1.02-1.49]). Among women, glucose was positively associated with MIBC (HR: 1.99 [1.04-3.81]). Apart from cholesterol, HRs for metabolic factors did not significantly differ between MIBC and NMIBC, and there were no interactions between smoking and metabolic factors on BC. Our study supports an involvement of metabolic aberrations in BC risk. Whilst some associations were significant only in certain sub-groups, there were generally no significant differences in associations by smoking or tumor invasiveness. PMID- 29756344 TI - Treatment with cyclosporin in auto-immune cytopenias in children: The experience from the French cohort OBS'CEREVANCE. PMID- 29756345 TI - Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition. AB - Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts (CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6, and also CYP2B6*4 carriers) received single-dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S-bupropion bioactivation, which may affect therapeutic outcomes. PMID- 29756346 TI - Evaluation and treatment of pulsatile tinnitus associated with sigmoid sinus wall anomalies. AB - OBJECTIVE: Describe clinical and radiographic features of sigmoid sinus wall anomalies (SSWA) associated with pulsatile tinnitus (PT) and determine factors predictive of response to surgery. METHODS: Preoperative diagnostic imaging and treatment response were reviewed after surgical repair of 40 ears among 38 consecutive patients presenting with PT associated with SSWA who underwent transtemporal sinus wall reconstruction. RESULTS: Twenty-three ears had isolated sigmoid sinus dehiscence, and 17 had diverticulum. The rates of transverse sinus stenosis (TSS) and empty sella, 66% and 32% respectively, were significantly higher than in historical controls (P = 0.02 and 0.001). Thirty-six out of 40 subjects (90%) had complete resolution of their PT following surgery, including all those with a diverticulum. For subjects with dehiscence alone without diverticulum, a favorable response to surgery was strongly associated with the presence of TSS (P = 0.01) and empty sella (P = 0.02). CONCLUSION: Sigmoid sinus diverticulum and dehiscence are a clinically important cause of PT. Women of childbearing age with an elevated body mass index (BMI) are commonly affected, and there is a high rate of associated TSS and empty sella. Transtemporal sinus wall reconstruction has a high rate of success in appropriately selected patients. Patients with isolated sinus wall dehiscence without diverticulum, TSS, or empty sella are less likely to respond to transtemporal sinus wall reconstruction. These data imply a multifactorial cause of PT in at least some patients with SSWA. LEVEL OF EVIDENCE: 4 Laryngoscope, 128:S1-S13, 2018. PMID- 29756348 TI - Is it currently possible to evaluate the risk posed by PERVs for clinical xenotransplantation? PMID- 29756347 TI - Pre-diagnostic urinary 15-F2t -isoprostane level and liver cancer risk: Results from the Shanghai Women's and Men's Health Studies. AB - Oxidative stress has been hypothesized to affect cancer development via various mechanisms, but the evidence from human is limited and inconclusive. 15-F2t isoprostane (15-F2t -IsoP) is an accurate marker of oxidative stress in humans. Recent studies showed that the evidence of urinary 15-F2t -IsoP level correlating cancer risk is conflicting. We conducted a case-control study nested within two population-based cohort studies. Pre-diagnosis urine samples, collected at cohort enrollment, from 363 incident liver cancer cases and 725 individually matched controls, were used to determine the level of 15-F2t -IsoP by enzyme-linked immunosorbent assay. Conditional logistic regression model was used to estimate the odds ratio to measure the association between the urinary 15-F2t -IsoP level and liver cancer risk. We found that higher pre-diagnostic urinary 15-F2t -IsoP level was associated with an increased liver cancer risk, with an adjusted OR in males (OR4th vs. 1st quartile = 8.84, 95% CI 2.74-28.60), which was significantly higher than those in females (OR4th vs. 1st quartile = 1.75, 95% CI 0.70-4.42). HBsAg carriers with higher 15-F2t -IsoP had a significantly increased liver cancer risk (ORfemale = 59.04, 95% CI 12.26, 284.30; ORmale = 92.55, 95% CI 34.83, 245.96) compared to non-carriers with lower 15-F2t -IsoP. High urinary 15-F2t -IsoP level was associated with high liver cancer risk, suggesting that 15-F2t -IsoP may be a promising biomarker for liver cancer risk. The result suggests that people with sero-positive HBsAg and higher level of 15 F2t -IsoP might be given a higher priority on future surveillance program of liver cancer. PMID- 29756350 TI - Selective parathyroid venous sampling in primary hyperparathyroidism: A systematic review and meta-analysis. AB - OBJECTIVE: Minimally invasive parathyroidectomy requires accurate preoperative localization techniques. There is considerable controversy about the effectiveness of selective parathyroid venous sampling (sPVS) in primary hyperparathyroidism (PHPT) patients. The aim of this meta-analysis is to examine the diagnostic accuracy of sPVS as a preoperative localization modality in PHPT. METHODS: Studies evaluating the diagnostic accuracy of sPVS for PHPT were electronically searched in the PubMed, EMBASE, Web of Science, and Cochrane Controlled Trials Register databases. Two independent authors reviewed the studies, and revised quality assessment of diagnostic accuracy study tool was used for the quality assessment. Study heterogeneity and pooled estimates were calculated. RESULTS: Two hundred and two unique studies were identified. Of those, 12 studies were included in the meta-analysis. Pooled sensitivity, specificity, and positive likelihood ratio (PLR) of sPVS were 74%, 41%, and 1.55, respectively. The area-under-the-receiver operating characteristic curve was 0.684, indicating an average discriminatory ability of sPVS. On comparison between sPVS and noninvasive imaging modalities, sensitivity, PLR, and positive posttest probability were significantly higher in sPVS compared to noninvasive imaging modalities. Interestingly, super-selective venous sampling had the highest sensitivity, accuracy, and positive posttest probability compared to other parathyroid venous sampling techniques. CONCLUSION: This is the first meta analysis to examine the accuracy of sPVS in PHPT. sPVS had higher pooled sensitivity when compared to noninvasive modalities in revision parathyroid surgery. However, the invasiveness of this technique does not favor its routine use for preoperative localization. Super-selective venous sampling was the most accurate among all other parathyroid venous sampling techniques. Laryngoscope, 2662-2667, 2018. PMID- 29756352 TI - Outcomes after cricotracheal resection for idiopathic subglottic stenosis. AB - OBJECTIVES: Idiopathic subglottic stenosis (iSGS) is a rare disease in which patients develop airway narrowing and dyspnea from relapsing subglottic and tracheal granulation and scar tissue that narrows the airway. Definitive management has involved surgical resection and reconstruction of the subglottis and trachea. However, treatment options remain highly variable at different institutions. Here, we present our outcomes and experience after cricotracheal resection (CTR) for iSGS at a high-volume tertiary care center. METHODS: A review of one surgeon's experience with a population of iSGS patients who underwent CTR between the years 1999 and 2017. The diagnosis of iSGS was one of exclusion and was based on history and microlaryngoscopy and bronchoscopy exams. Recurrence of subglottic stenosis was evaluated using Kaplan-Meier survival estimate analysis. RESULTS: Sixty-one patients met criteria for iSGS and underwent CTR. Our population was 97% female and had an average of 4.3 balloon dilations prior to CTR. Mean follow-up time after CTR was 7.14 years. Eight (13%) patients developed recurrence of subglottic stenosis after CTR. Mean and median time to recurrence after CTR was 12.5 years and 14.1 years, respectively. CONCLUSION: Cricotracheal resection is associated with a small, long-term recurrence rate of stenosis. It remains an important option for individuals with refractory iSGS. It may be reasonable to consider early CTR in the management of certain patients with iSGS. Further research should investigate risk factors that predispose patients to recurrence after CTR. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2268-2272, 2018. PMID- 29756351 TI - Cinnamaldehyde and related phenylpropanoids, natural repellents, and insecticides against Sitophilus zeamais (Motsch.). A chemical structure-bioactivity relationship. AB - BACKGROUND: The insecticidal and repellent effects on adult Sitophilus zeamais of 12 cinnamaldehyde-related compounds was evaluated by contact toxicity bioassays and a two-choice olfactometer. To determine non-toxicity in mammals, body weight, serum biochemical profiles, liver weight, physiological parameters, sperm motility, and histopathological data were obtained as complementary information in C57BL/6 mice treated with the best natural compound. RESULTS: Based on 24 h LC95 and LC50 values, alpha-methyl-cinnamaldehyde and cinnamaldehyde exhibited better insecticidal action than the other compounds. The best repellent effect was observed with alpha-bromo-cinnamaldehyde, which even repelled at the lowest concentration studied (0.28 umol L-1 ). The evaluation of a quantitative structure-activity relationship found a linear relationship between the LC50 values for adult weevil toxicity and dipolo with Q values (giving the difference between orbital electronegativity carbon 1 and orbital electronegativity carbon 3 of the molecule) in cinnamaldehyde-related compounds. The polar surface and Log P descriptors also revealed a linear relationship with the S. zeamais repellent effect for cinnamaldehyde analogues. Cinnamaldehyde did not show toxicity in the parameters evaluated in mice. CONCLUSION: From the phenylpropanoid components studied, the natural compound that had the best insecticidal and repellent action against S. zeamais was cinnamaldehyde. It presented no mammalian toxicity. (c) 2018 Society of Chemical Industry. PMID- 29756354 TI - Neural Correlates of Suicidality in Adolescents with Major Depression: Resting State Functional Connectivity of the Precuneus and Posterior Cingulate Cortex. AB - OBJECTIVE: Major depressive disorder (MDD) is associated with suicidal thoughts and behaviors ("suicidality"). Of the three components of Joiner's interpersonal theory of suicide, two involve negatively valenced, self-related beliefs: perceived burdensomeness and thwarted belongingness. However, the neurocircuitry underlying self-processing and suicidality has not been fully explored. This study examined the association between suicidality and the neurocircuitry of regions relevant to self-referential processing in adolescents with depression. METHOD: Fifty-eight adolescents underwent assessment and a resting-state fMRI scan. Resting-state functional connectivity (RSFC) analyses included two brain regions implicated in self-referential processing: precuneus and posterior cingulate cortex (PCC). Suicidality was measured using the Index of Depression and Anxiety Symptoms. While controlling for depression severity, we conducted whole-brain correlation analyses between suicidality and left and right precuneus and PCC connectivity maps. RESULTS: Suicidality was positively associated with RSFC between left precuneus and left primary motor and somatosensory cortices, and middle and superior frontal gyri. Suicidality was negatively associated with RSFC between left PCC and left cerebellum, lateral occipital cortex, and temporal occipital fusiform gyrus. CONCLUSIONS: Findings of hyperconnectivity stemming from the precuneus and hypoconnectivity from the PCC may reflect maladaptive self reflection and mentalization. However, additional investigation is warranted to further clarify these relationships. PMID- 29756353 TI - Effect of potassium sorbate (E-202) and the antifungal PgAFP protein on Aspergillus carbonarius growth and ochratoxin A production in raisin simulating media. AB - BACKGROUND: Ochratoxin A (OTA) is a mycotoxin produced by several species of Aspergillus and Penicillium fungi. The presence of OTA in raisins is mainly related to black Aspergillus spp. contamination. This toxin poses risks to human and animal health due to its high toxicity and carcinogenicity. New strategies to avoid the risk associated with OTA are therefore necessary. RESULTS: A comparison was made between the effects of the antifungal protein PgAFP and potassium sorbate (E-202) on the growth of Aspergillus carbonarius, biosynthetic- and stress-related gene expression and its OTA production at two water activity (aw ) levels, 0.95 and 0.93 aw . The results showed that PgAFP successfully controlled OTA production, whereas E-202, despite being able to reduce Aspergillus carbonarius growth, caused a significant increase in OTA production by the fungus. CONCLUSION: PgAFP protein, a biological compound with an antifungal activity, is safer to use than E-202 and may be proposed as a food preservative and a useful strategy to control ochratoxigenic A. carbonarius in raisins. (c) 2018 Society of Chemical Industry. PMID- 29756355 TI - Development and Validation of a High-Quality Composite Real-World Mortality Endpoint. AB - OBJECTIVE: To create a high-quality electronic health record (EHR)-derived mortality dataset for retrospective and prospective real-world evidence generation. DATA SOURCES/STUDY SETTING: Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). STUDY DESIGN: We developed a recent, linkable, high quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. PRINCIPAL FINDINGS: For advanced non-small-cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan-Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI-based estimates. CONCLUSIONS: For EHR derived data to yield reliable real-world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI. PMID- 29756356 TI - Neuroimaging abnormalities in individuals exhibiting Parkinson's disease risk markers. AB - BACKGROUND: The concept of prodromal Parkinson's disease (PD) involves variable combinations of nonmotor features and subtle motor abnormalities as a result of ongoing neurodegeneration in the brain stem including substantia nigra (SN) and abnormal findings upon transcranial sonography and nuclear imaging. Except for nuclear imaging, the predictive value of risk markers for the conversion to overt PD is low. OBJECTIVE: The objective of this study was to determine whether PD risk markers are associated with changes in brain structure and to what extent cognitive changes are risk markers for PD. METHODS: Diffusion-weighted imaging, voxel-based morphometry, and cortical thickness analysis was performed in 29 individuals with hyposmia and/or an increased SN hyperechogenicity (SN+) upon transcranial sonography and 28 controls without these 2 risk markers. Classical parkinsonian signs were an exclusion criterion. All of the participants underwent a neuropsychological test battery addressing executive functions, learning ability, and verbal fluency. RESULTS: In the PD risk group, diffusion-weighted imaging mean diffusivity was increased in 4 left hemisphere clusters (posterior thalamus, inferior longitudinal fasciculus, fornix, corticospinal tract). A negative relationship of mean diffusivity and smell function was present for the posterior thalamus and the corticospinal tract. There was a significant correlation of mean diffusivity values and SN+ in all clusters. Neither voxel based morphometry nor cortical thickness analysis revealed any group differences. No relevant group differences were observed for cognitive tests included. CONCLUSION: PD-free individuals with PD risk markers show microstructural changes of the white matter, including areas relevant for motor and limbic processes. In addition, our study provides for the first time a neuroanatomical correlate for SN hyperechogenicity. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756357 TI - A refined cavity construction algorithm for the conductor-like screening model. AB - A cavity construction algorithm based on the triangulation of an iso-surface is introduced as a new standard for dielectric continuum solvation calculations with the Conductor-like Screening Model COSMO. It overcomes deficiencies which have become apparent for the original COSMO standard cavity, especially in concave regions of the molecular shaped cavity. The new standard, called FINE Cavity, is described in this article with several application examples. The earlier COSMO cavity construction algorithms are described for comparison. (c) 2018 Wiley Periodicals, Inc. PMID- 29756358 TI - Echocardiographic parameters to identify sickle cell patients with cardio pathology. AB - BACKGROUND: Sickle cell disease (SCD) affects millions of people and causes chronic hemolytic anemia leading to vasculopathies such as pulmonary hypertension and abnormalities in cardiac function that increase complications and mortality. It is therefore crucial to identify cardiac abnormalities in SCD. We aimed to assess the prevalence of echocardiographic parameters in SCD to help identify cardiopulmonary risk. METHODS: Ninety-one patients (53% male), median age of 30, body surface area (BSA) of 1.79 m2 , hemoglobin of 8.8 g/dL, and creatinine of 0.7 mg/dL identified. We retrospectively measured laboratory and echocardiographic parameters in patients with SCD : left ventricular (LV) dimensions, LV ejection fraction (LVEF), LV Myocardial Performance Index (MPI), LV Mass Index (MI), Left Atrial Volume Index (LAVI), Tricuspid Regurgitation Velocity (TRV), tricuspid annular plane systolic excursion (TAPSE), right heart dimensions. RESULTS: Prevalence of left heart abnormalities was 32%: increased LV end-diastolic diameter (EDD), 78%: LV MPI, 21%: diastolic dysfunction, 38%: decreased LVEF, 24%: increased LVMI, and 47%: increased LAVI. Right heart abnormalities were 39%: TAPSE, 38%: increased TRV, and 59%: increased pulmonary systolic pressure (PASP). Multivariate logistic regression analysis was significant for increased LVMI and LAVI in those with hemoglobin <=8 g/dL (odds ratio (OR) 7.4, 95% confidence interval (CI) 2.23-24.6, P = .001) and (OR 3.32, 95% CI 1.18-9.33, P = .023). CONCLUSIONS: We confirmed increased prevalence of abnormal LVEDD, LVMI, diastolic function, LAVI, and PASP in SCD. In addition, we identified abnormal LV MPI (78%), TAPSE (29%). These parameters may be useful and readily accessible echocardiographic prognostic tools in this population. PMID- 29756359 TI - Editorial Comment from Dr Teishima and Dr Matsubara to Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. PMID- 29756360 TI - Acylation of Homoatomic Ge9 Cages and Subsequent Decarbonylation. AB - The direct acylation of Ge9 Zintl clusters by the reaction of K[Ge9 {Si(SiMe3 )3 }3 ] with acyl chlorides in hexane or toluene solutions is presented, leading to the neutral, carbonyl-derivatized products [{Si(SiMe3 )3 }3 Ge9 (CO)R'] (R'=Me, iPr, tBu, Ph, Bz, cyclopropylmethyl, phenethyl, 4-vinylphenyl). This reaction is applicable to a wide range of acyl chlorides and allows for diverse functionalization of Ge9 Zintl clusters. [{Si(SiMe3 )3 }3 Ge9 (CO)tBu] readily releases CO at ambient conditions under formation of [{Si(SiMe3 )3 }3 Ge9 tBu]. This temperature-dependent decarbonylation most likely proceeds via a radical Norrish-type I alpha-bond cleavage. Except for R'=tBu and Bz all obtained acyl derivatized Ge9 cluster compounds do not release CO even at elevated temperatures. All compounds were characterized by NMR spectroscopy. [{Si(SiMe3 )3 }3 Ge9 (CO)R'] (R'=tBu, Ph, Me, iPr) as well as [{Si(SiMe3 )3 }3 Ge9 tBu] were further structurally characterized by single crystal X-ray diffraction. PMID- 29756361 TI - Fingerprints of acacia aging treatments by barrels or chips based on volatile profile, sensorial properties, and multivariate analysis. AB - BACKGROUND: Despite the acceptance of the use of chips as an alternative enological practice to traditional barrels, there is substantial interest in looking for parameters that enable the aging technique to be identified. In the present study, the volatile compound composition and sensorial characteristics of wines aged with chips and barrels of acacia wood were monitored with the aim of finding fingerprints that could be used to discriminate between the two types of aging. RESULTS: Principal component analysis (PCA) calculated from chemical outputs permitted the two aging techniques to be distinguished. After 4 months of aging in barrels, concentrations of vanillin, ferulic acid, syringaldehyde, and furfural decreased considerably due to the higher oxidation produced by the acacia wood's porosity. This fact made it more difficult to discriminate between those wines aged in barrels for the longest times. On the other hand, PCA applied to sensorial data allowed a clear differentiation between wines aged in acacia barrels for longer periods and those macerated with chips, due to the notable presence of sensory attributes described as acacia wood, nutty, honeyed, and toasty. CONCLUSION: Chemical and sensorial data can be regarded as complementary methods to obtain fingerprints that enable differentiation between the two different aging techniques by means of acacia wood. (c) 2018 Society of Chemical Industry. PMID- 29756362 TI - A Trichromatic and White-Light-Emitting MOF Composite for Multi-Dimensional and Multi-Response Ratiometric Luminescent Sensing. AB - Present here is a new dual ratiometric luminescent probe D which is a trichromatic and white-light-emitting metal-organic framework (MOF) composite facilely obtained by incorporating red/green-emitting complex modules into a blue emitting MOF. Probe D exhibits remarkable capabilities of sensing different volatile organic solvents (VOSs) via 2D code recognition of the two VOS-dependent MOF ligand-to-module ratios of the emission-peak intensities. For specific VOSs, the resultant luminescent color changes from the starting white color are sharp enough to be visible to the naked eye. Remarkably, D can differentiate solution phase nitroaromatics and metal ions by recording the evolution of the two ratios during titration processes, enabling an unusual 3D code recognition using the titrant amount as the third dimension for the first time. D also can be used to detect dinoseb, Fe3+ and Al3+ ions quantitatively by analysis of the ratios with detection limits as low as 0.050, 0.41, and 0.12 ppm, respectively. Clearly, such a self-referencing trichromatic probe can maximize the output information and significantly enhance the detection selectivity and sensitivity via multi dimensional sensing, and has great potentials for practical applications. PMID- 29756364 TI - Free jejunal flap transfer with multiple vascular pedicles for safe and reliable pharyngoesophageal reconstruction. AB - BACKGROUND: In pharyngoesophageal reconstruction, we transferred a long jejunum flap containing multiple pedicles to achieve a 100% flap survival rate, and used the redundant mesentery to cover important tissues and fill in the dead space to reduce common postoperative complications, such as surgical site infections and fistula formation. METHODS: A total of 243 jejunal flap transfers with multiple vascular anastomoses were reviewed to examine flap survival and rates of early postoperative complications, such as surgical site infections and fistula formation, perioperative mortality, and donor site morbidity. RESULTS: All 243 jejunal flaps survived without any partial necrosis. The surgical site infections occurred in 15 cases (6.2%) and fistula formation in 9 cases (3.7%). The perioperative mortality rate was 0.4%. There were 7 cases (2.9%) with donor site morbidity. CONCLUSION: Although our procedure requires extra operating time for additional vessel anastomoses, it could be performed safely and reliably with a high success rate. PMID- 29756365 TI - Revised mechanism of carboxylation of ribulose-1,5-biphosphate by rubisco from large scale quantum chemical calculations. AB - Here, we describe a computational approach for studying enzymes that catalyze complex multi-step reactions and apply it to Ribulose 1,5-bisphosphate carboxylase-oxygenase (Rubisco), the enzyme that fixes atmospheric carbon dioxide within photosynthesis. In the 5-step carboxylase reaction, the substrate Ribulose 1,5-bisphosphate (RuBP) first binds Rubisco and undergoes enolization before binding the second substrate, CO2 . Hydration of the RuBP.CO2 complex is followed by C?C bond scission and stereospecific protonation. However, details of the roles and protonation states of active-site residues, and sources of protons and water, remain highly speculative. Large-scale computations on active-site models provide a means to better understand this complex chemical mechanism. The computational protocol comprises a combination of hybrid semi-empirical quantum mechanics and molecular mechanics within constrained molecular dynamics simulations, together with constrained gradient minimization calculations using density functional theory. Alternative pathways for hydration of the RuBP.CO2 complex and associated active-site protonation networks and proton and water sources were investigated. The main findings from analysis of the resulting energetics advocate major revision to existing mechanisms such that: hydration takes place anti to the CO2 ; both hydration and C?C bond scission require early protonation of CO2 in the RuBP.CO2 complex; C?C bond scission and stereospecific protonation reactions are concerted and, effectively, there is only one stable intermediate, the C3-gemdiolate complex. Our main conclusions for interpreting enzyme kinetic results are that the gemdiolate may represent the elusive Michaelis-Menten-like complex corresponding to the empirical Km (=Kc ) with turnover to product via bond scission concerted with stereospecific protonation consistent with the observed catalytic rate. (c) 2018 Wiley Periodicals, Inc. PMID- 29756363 TI - Treatment for T3 to T4a laryngeal cancer by open partial horizontal laryngectomies: Prognostic impact of different pathologic tumor subcategories. AB - BACKGROUND: The purpose of this retrospective study was to identify subcategories in cT3 to cT4a supraglottic/glottic cancers, describing their different spreading patterns, and local and locoregional recurrence modes. METHODS: Four hundred eighty-nine patients who underwent open partial horizontal laryngectomies (OPHLs) were retrospectively classified as: subcategory I (anterior pT3 with normal arytenoid mobility); subcategory II (posterior pT3 with impaired/absent mobility); subcategory III (anterior pT4 with normal mobility); and subcategory IV (posterior pT4 with impaired/absent mobility). RESULTS: Five-year overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), locoregional, local control, freedom from laryngectomy, and laryngectomy-free survival were significantly better in anterior tumors (subcategories I and III) when compared with the corresponding posterior ones (subcategories II and IV). CONCLUSION: Anterior cT3 tumors are manageable by OPHL, and this approach could also be proposed in the treatment of early anterior cT4aN0. Despite promising results, OPHLs should be considered under investigation in posterior cT3 tumors due to clinical and biological behavior similar to cT4a tumors. PMID- 29756367 TI - Oral cancer involving masticator space (T4b): Review of literature and future directions. AB - The oral cancer with masticator-space involvement is classified as T4b disease. The limited data suggest that the masticator space is a complex anatomic area and tumors with varying degrees of infiltration may have different oncologic outcomes. It is not advisable to group all T4b tumors as one and consider them for palliative-intent treatment. A group of patients with limited spread (infra notch) has potential for good outcome. These cancers can be considered for downstaging to T4a classification based on best available data and clinical considerations. The radical surgical resection remains the mainstay of curative intent treatment and the ability to achieve negative margins at the skull base remains the most important prognostic factor. The alternative approaches to either increase radicality of surgery or to downsize the tumor with neoadjuvant therapies have shown encouraging trends but larger, well designed, and prospective studies will be needed to make meaningful conclusions. It is important to rationalize and form common ground for further research. PMID- 29756368 TI - Re: Sexual Harassment. PMID- 29756369 TI - beta-Lactam allergy de-labelling. PMID- 29756366 TI - Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease. AB - Background Nigral degeneration patterns differ between PSP and PD. However, the relationship between nigral degeneration and midbrain atrophy in PSP remains unclear. Objective We analyzed differences and relationships between nigral degeneration and midbrain atrophy in PSP and PD. Methods Neuromelanin-sensitive MRI and midbrain volumetry were performed in 11 PSP patients, 24 PD patients, and 10 controls to measure the neuromelanin-sensitive SNpc area and midbrain volume. Results The neuromelanin-sensitive SNpc area and midbrain volume were significantly smaller in PSP patients compared with PD patients and controls. Motor deficits were inversely correlated with neuromelanin-sensitive SNpc area in PD, but not PSP patients. There was no significant correlation between neuromelanin-sensitive SNpc area and midbrain volume in either disease group. Midbrain volumetry discriminated PSP from PD. Diagnostic accuracy was improved when neuromelanin-sensitive MRI analysis was added. Conclusions Neuromelanin sensitive MRI and midbrain volumetry may reflect the clinical and pathological characteristics of PSP and PD. Combining neuromelanin-sensitive MRI and midbrain volumetry may be useful for differentiating PSP from PD. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756370 TI - Severe extensive ecchymotic oedema in the buttock. PMID- 29756349 TI - Integrating the DNA damage and protein stress responses during cancer development and treatment. AB - During evolution, cells have developed a wide spectrum of stress response modules to ensure homeostasis. The genome and proteome damage response pathways constitute the pillars of this interwoven 'defensive' network. Consequently, the deregulation of these pathways correlates with ageing and various pathophysiological states, including cancer. In the present review, we highlight: (1) the structure of the genome and proteome damage response pathways; (2) their functional crosstalk; and (3) the conditions under which they predispose to cancer. Within this context, we emphasize the role of oncogene-induced DNA damage as a driving force that shapes the cellular landscape for the emergence of the various hallmarks of cancer. We also discuss potential means to exploit key cancer-related alterations of the genome and proteome damage response pathways in order to develop novel efficient therapeutic modalities. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29756371 TI - Severe extensive ecchymotic oedema in the buttock. PMID- 29756372 TI - Adolescent injuries should not be ignored. PMID- 29756373 TI - Do feeding practices during transfusion influence the risk of developing necrotising enterocolitis in preterm infants? AB - Our evidence-based review set out to answer the clinical question 'In a preterm infant (patient) with anaemia of prematurity, do feeding practices (intervention) during blood transfusion reduce the risk of developing transfusion-associated necrotising enterocolitis (outcome)'? We found limited evidence that withholding feeding during red blood cell transfusion in preterm infants may reduce the risk of development of transfusion-associated necrotising enterocolitis. As clinical equipoise seemingly exists, it seems reasonable for individual units to make their own decisions regarding whether to withhold or continue enteral feeds during red blood cell transfusion until further evidence is available. The UK based Withholding Enteral Feeds Around Transfusion (WHEAT) trial, a nation-wide multi-centre 'opt-out' randomised controlled study, hopefully will definitively answer our clinical question. Further research in other areas of neonatal care, using this innovative study design, is needed and it is exciting to see such a study underway. PMID- 29756374 TI - An egg a day keeps starvation at bay. PMID- 29756375 TI - Chest physiotherapy is of no benefit for infants with bronchiolitis. PMID- 29756376 TI - Palatal Lesion in a 3-Year-Old Boy. PMID- 29756377 TI - Spinal muscular atrophy. PMID- 29756378 TI - Malodorous feet. PMID- 29756379 TI - Malodorous feet. PMID- 29756380 TI - Metabolic Inhibitors of O-GlcNAc Transferase That Act In Vivo Implicate Decreased O-GlcNAc Levels in Leptin-Mediated Nutrient Sensing. AB - O-Linked glycosylation of serine and threonine residues of nucleocytoplasmic proteins with N-acetylglucosamine (O-GlcNAc) residues is catalyzed by O-GlcNAc transferase (OGT). O-GlcNAc is conserved within mammals and is implicated in a wide range of physiological processes. Herein, we describe metabolic precursor inhibitors of OGT suitable for use both in cells and in vivo in mice. These 5 thiosugar analogues of N-acetylglucosamine are assimilated through a convergent metabolic pathway, most likely involving N-acetylglucosamine-6-phosphate de-N acetylase (NAGA), to generate a common OGT inhibitor within cells. We show that of these inhibitors, 2-deoxy-2-N-hexanamide-5-thio-d-glucopyranoside (5SGlcNHex) acts in vivo to induce dose- and time-dependent decreases in O-GlcNAc levels in various tissues. Decreased O-GlcNAc correlates, both in vitro within adipocytes and in vivo within mice, with lower levels of the transcription factor Sp1 and the satiety-inducing hormone leptin, thus revealing a link between decreased O GlcNAc levels and nutrient sensing in peripheral tissues of mammals. PMID- 29756381 TI - Myocardial multilayer strain does not provide additional value for detection of myocardial viability assessed by SPECT imaging over and beyond standard strain. AB - BACKGROUND: The aim of this study was to evaluate the value of multilayer strain analysis to the assessment of myocardial viability (MV) through the comparison of both speckle tracking echocardiography and single-photon emission computed tomography (SPECT) imaging. We also intended to determine which segmental longitudinal strain (LS) cutoff value would be optimal to discriminate viable myocardium. METHODS: We included 47 patients (average age: 61 +/- 11 years) referred to our cardiac imaging center for MV evaluation. All patients underwent transthoracic echocardiography with measures of LS, SPECT, and coronary angiography. RESULTS: In all, 799 segments were analyzed. We correlated myocardial tracer uptake by SPECT with sub-endocardial, sub-epicardial, and mid segmental LS values with r = .514 P < .0001, r = .501 P < .0001, and r = .520 P < .0001, respectively. The measurements of each layer strain (sub-endocardial, sub epicardial, and mid) had the same performance to predict MV viability as defined by SPECT with areas under curve of 0.819 [0.778-0.861, P < .0001], 0.809 [0.764 0.854, P < .0001], and 0.817 [0.773-0.860, P < .0001], respectively. The receiver operating characteristic analysis yielded a cutoff value of -6.5% for mid segmental LS with a sensitivity of 76% and specificity of 76% to predict segmental MV as defined by SPECT. CONCLUSIONS: Multilayer strain analysis does not evaluate MV with more accuracy than standard segmental LS analysis. PMID- 29756382 TI - Treatment delays in laryngeal squamous cell carcinoma: A national cancer database analysis. AB - OBJECTIVE: To characterize treatment delays in laryngeal cancer and associate delays with patient, tumor, and treatment factors and with overall survival. METHODS: We identified 33,819 adults with laryngeal squamous cell carcinoma (LSCC) in the National Cancer Database from 2004 to 2013. We calculated durations of diagnosis-to-treatment initiation, surgery-to-adjuvant treatment, radiotherapy duration, total treatment package, and diagnosis-to-treatment end intervals. Delays were associated with patient, tumor, and treatment characteristics via multivariable logistic regression and with overall survival by Cox proportional hazards regression. RESULTS: Median durations of diagnosis-to-treatment initiation, surgery-to-radiation initiation, radiation treatment, total treatment package, and diagnosis-to-treatment end were 28, 42, 48, 91, and 107 days in surgical patients; median durations of diagnosis-to-treatment initiation, radiation treatment, and diagnosis-to-treatment end were 33, 50, and 85 days in nonsurgical patients. Race and insurance status were linked to delays in most intervals. Academic and high-volume facilities had less delayed radiation treatment but increased delays in most other intervals. Delayed surgery-to radiation and total treatment package intervals were associated with overall survival in surgical patients (hazard ratio [HR] = 1.15 [1.03-1.29], P = 0.015; HR = 1.16 [1.02-1.31], P = 0.025). Diagnosis-to-treatment initiation and diagnosis-to-treatment end intervals were associated with overall survival in nonsurgical patients (HR = 1.08 [1.02-1.14], P = 0.007; HR = 1.09 [1.03-1.16], P = 0.003, respectively) but not in surgical patients (HR = 0.96 [0.87-1.06] P = 0.440; HR = 1.13 [0.99-1.29], P = 0.062). Radiation delays were associated with overall survival in surgical and nonsurgical patients (HR = 1.21 [1.09-1.36], P = 0.001; HR = 1.37 [1.30-1.44], P < 0.001). CONCLUSION: These durations can serve as national benchmarks. Delays could be considered quality indicators in LSCC. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2018. PMID- 29756383 TI - A novel affective-motivational-based Overground System for detecting spinal cord injury-associated thermal and mechanical hypersensitivity in rats. AB - BACKGROUND: Preclinical research for neuropathic pain has depended primarily on the use of behavioural nociceptive testing that is sensory-discriminatory-based and reflexive in nature. This can be particularly problematic in spinal cord injury (SCI)-associated neuropathic pain research where hyperreflexia may develop thus confounding interpretation of reflexive responses as pain symptoms. To address this, we have designed an affective-motivational-based Overground System that has interchangeable floors to allow examination of nociceptive behaviours in response to mechanical and cold stimuli prior to and following spinal cord injury. METHODS: The animals were pretrained for 3-4 weeks to cross three Overground System surfaces (cold, rough and neutral) at a consistent pace in order to obtain a food reward (Froot LoopsTM ). RESULTS: Following SCI, crossing times were significantly decreased due to more rapid crossing over the cold surface despite forgoing of the food reward, in contrast with the sham control animals. This was correlated with the development of cold hypersensitivity as assessed by standard acetone droplet testing. In response to the rough surface, slower paced crossings (increased time to cross) were observed post-SCI (also resulting in forgoing of the food reward), compared to pre-SCI times and sham control animals. This was correlated with the development of mechanical hypersensitivity as assessed by standard von Frey testing. CONCLUSIONS: Different responses in crossing behaviour for the cold and rough surfaces suggest a precise adaptive change in decision-making behaviour depending on the stimulus presented; thus, outcome measures may be easily tailored for different types of hypersensitivity symptoms. SIGNIFICANCE: We have designed an Overground System that is easy to establish and addresses a major concern in preclinical pain research by providing a cognitive- and motivational-based system for hypersensitivity detection. The affective-motivational-based Overground System allows examination of pain-like behaviours in response to cold (thermal) and rough (mechanical) stimulation prior to and following spinal cord injury. This system provides a more holistic and comprehensive assessment of nociceptive responses following SCI and helps overcome concerns of hyperreflexia confounding evoked behavioural outcome measures in SCI models. Further, the incorporation of cognitive and motivational components brings preclinical research closer to replicating the clinical experience of a patient's motivation to participate in rewarding lifestyle activities in relation to their pain. PMID- 29756384 TI - Performance of Metarhizium anisopliae-treated foam in combination with Phytoseiulus longipes Evans against Tetranychus evansi Baker & Pritchard (Acari: Tetranychidae). AB - BACKGROUND: Tetranychus evansi (Te) is an exotic pest of solanaceous crops in Africa. The predatory mite Phytoseiulus longipes (Pl) and the fungus Metarhizium anisopliae (Ma) are potential biocontrol agents of Te. The present study investigated the efficacy of fungus-treated foam placed above or below the third Te-infested tomato leaf. The persistence of fungus-treated foam and the performance of Pl with and without fungus-treated foam were evaluated. RESULTS: The fungus-treated foam was effective when Te infestation was below the third tomato leaf as no damage was recorded on any of the upper tomato leaves up to 30 days post-treatment. However, in the control treatments, the infestation increased considerably from 9 +/- 0.3% to 100 +/- 0% (mean +/- standard error) at 15 days post-treatment. The reuse of the fungus-treated foam at 15, 30 and 45 days post-treatment resulted in 19 +/- 1.4%, 25 +/- 1.2% and 54 +/- 2.1%, respectively, infestation by Te. The fungus-treated foam and Pl alone were efficient, but there was no benefit to combining them for use against Te. CONCLUSION: The fungus-treated foam is an effective method to optimise the use of Ma in screenhouse conditions. These two control agents could be integrated in an integrated pest management strategy for crop protection. However, these results need to be confirmed in large field trials. (c) 2018 Society of Chemical Industry. PMID- 29756385 TI - Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect. AB - Approximately 75% of cord blood transplant (CBT) recipients experience human herpes virus-6 (HHV-6) reactivation. Considering the immunomodulatory effects of HHV-6, we hypothesized that early HHV-6 reactivation may influence the risk of relapse of the underlying hematologic malignancy. In 152 CBT recipients with hematological malignancies, we determined the association between HHV-6 reactivation by day +28 and 2-year cumulative incidence of relapse. In univariate analysis, the absence of HHV-6 reactivation (n = 32) was associated with less relapse (26 [18-35]% vs. 7 [0-17]% in groups with vs. without HHV-6 reactivation, respectively; P = .03). This difference was due to a remarkably low relapse incidence among patients without HHV-6 reactivation. In multivariable analysis, the absence of HHV-6 reactivation was associated with less relapse (hazard ratio [95% confidence interval]: 0.2 [0.05-0.9], P = .03). This association was independent of patient-, disease-, and transplant-related characteristics known to influence the risk of relapse. Natural killer cell and T-cell reconstitution at day +28 were similar between patients with vs. without HHV-6 reactivation. Our results suggest that CB allografts not complicated by HHV-6 reactivation by day +28 have a powerful graft-versus-tumor effect. Knowledge about early HHV-6 reactivation may stratify patients at day +28 into low vs. high relapse risk groups. PMID- 29756386 TI - KRAS mutation and epithelial-macrophage interplay in pancreatic neoplastic transformation. AB - Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased (i) ductal to acinar gene expression ratios, (ii) epithelial cells proliferation and (iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a protumorigenic phenotype in macrophages. Altered macrophages decreased epithelial pigment epithelial derived factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) and in our human PDA specimens. Epithelium-macrophage cross-talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a protumorigenic phenotype in macrophages, in turn augmenting neoplastic growth. PMID- 29756388 TI - Semaglutide for type 2 diabetes mellitus: A systematic review and meta-analysis. AB - AIMS: To assess the efficacy and safety of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes. MATERIALS AND METHODS: We searched major electronic databases and grey literature sources for randomized controlled trials comparing semaglutide with placebo or other antidiabetic agents. Primary outcome was change from baseline in HbA1c. Secondary endpoints included change from baseline in body weight, blood pressure, heart rate and incidence of hypoglycaemia, gastrointestinal adverse effects, pancreatitis and diabetic retinopathy. RESULTS: A total of 6 placebo-controlled and 7 active-controlled studies with subcutaneous semaglutide were included. We identified only 1 trial with oral semaglutide. Compared with placebo, subcutaneous semaglutide 0.5 and 1 mg reduced HbA1c by 1.01% (95% CI, 0.56-1.47) and 1.38% (1.05-1.70), respectively. Both doses demonstrated superior glycaemic efficacy compared to other antidiabetic agents, including sitagliptin, exenatide, liraglutide, dulaglutide and insulin glargine. Semaglutide also had a beneficial effect on body weight (mean difference vs placebo -4.11 kg, 95% CI -4.85 to -3.37 for semaglutide 1 mg) and systolic blood pressure. We did not observe increased hypoglycaemia rates with semaglutide; nevertheless, we noted an increased incidence of nausea, vomiting and diarrhoea. Cases of pancreatitis were infrequent and the odds ratio for diabetic retinopathy compared with placebo was 1.32 (95% CI, 0.98-1.77). CONCLUSIONS: Semaglutide is a potent once-weekly GLP-1 RA, significantly reducing HbA1c, body weight and systolic blood pressure. However, it is associated with increased incidence of gastrointestinal adverse events. Results for pancreatitis and retinopathy require further assessment in post-approval pharmacovigilance studies. PMID- 29756389 TI - Pretreatment risk stratification of feeding tube use in patients treated with intensity-modulated radiotherapy for head and neck cancer. AB - BACKGROUND: The purpose of this study was to establish a risk stratification model for feeding tube use in patients who undergo intensity-modulated radiotherapy (IMRT) for head and neck cancers. METHODS: One hundred thirty-nine patients treated with definitive IMRT (+/- concurrent chemotherapy) for head and neck mucosal cancers were included in this study. Patients were recommended a prophylactic feeding tube and followed up by a dietician for at least 8 weeks postradiotherapy (post-RT). Potential prognostic factors were analyzed for risk and duration of feeding tube use for at least 25% of dietary requirements. RESULTS: Many variables had significant effects on risk and/or duration of feeding tube use in univariate analyses. Subsequent multivariable analysis showed that T classification >=3 and level 2 lymphadenopathy were the best independent significant predictors of higher risk and duration of feeding tube use, respectively, in oral cavity, pharyngeal, and supraglottic primaries. CONCLUSION: In patients treated with definitive IMRT, T classification >=3 and level 2 lymphadenopathy can potentially stratify patients into 4 risk groups for developing severe dysphagia requiring feeding tube use. PMID- 29756390 TI - FVIII p.Arg1800His mutation is associated with mild/moderate hemophilia A in Chinese population. PMID- 29756387 TI - ADAM-C score: New risk score for predicting diagnostic yield of transesophageal echocardiography after cerebral ischemia. AB - BACKGROUND AND AIM: The clinical utility of transesophageal echocardiography (TEE) after brain ischemia (BI) remains a matter of debate. We aimed to evaluate the clinical impact of TEE and to build a score that could help physicians to identify which patients should better benefit from TEE. METHODS: This prospective, multicenter, observational study included patients over 18 years old, hospitalized for BI. TEE findings were judged discriminant if the results showed important information leading to major changes in the management of patients. Most patients with patent foramen ovale were excluded. Variables independently associated with a discriminant TEE were used to build the prediction model. RESULTS: Of the entire population (1479 patients), 255 patients (17%) were classified in the discriminant TEE group. Five parameters were selected as predictors of a discriminant TEE. Accordingly, the ADAM-C score could be calculated as follows: Score = 4 (if age >=60) + 2 (if diabetes) + 2 (if aortic stenosis from any degrees) + 1 (if multi-territory stroke) + 2 (if history of coronary artery disease). At a threshold lower than 3, the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of detecting discriminant TEE were 88% (95% CI 85-90), 44% (95% CI 41-47), 21% (95% CI 19-27), and 95% (95% CI 94-97), respectively. CONCLUSION: A simple score based on clinical and transthoracic echocardiographic parameters can help physicians to identify patients who might not benefit from TEE. Indeed, a score lower than 3 has an interesting NPV of 95% (95% CI 94-97). PMID- 29756392 TI - Successful treatment of severe facial lymphedema by lymphovenous anastomosis. AB - BACKGROUND: Facial edema is a common complication after neck dissection and/or chemoradiotherapy for head and neck cancer. Edema subsides spontaneously in most cases but sometimes persists, in which case surgical intervention is required. We report a case of severe facial edema that showed significant improvement upon lymphovenous anastomosis (LVA). METHODS: A 66-year-old man with oral floor cancer developed progressive facial lymphedema after tumor resection, bilateral neck dissections, chemoradiotherapy, and fibular and rectus abdominis musculocutaneous flap transfer. His eyesight was completely disturbed due to severe eyelid edema. The LVAs were performed in the bilateral preauricular area. Surgical findings showed stagnation of the lymphatic fluids in dilated lymphatic vessels, which were drained to the superficial temporal veins by LVA. RESULTS: The edema subsided rapidly and the patient's eyesight returned as soon as 4 days postoperatively. CONCLUSION: Using LVA in the preauricular region can be a choice of surgical treatment for severe facial edema. PMID- 29756391 TI - Rho kinase and Na+ /H+ exchanger mediate endothelin-1-induced pulmonary arterial smooth muscle cell proliferation and migration. AB - Excessive production of endothelin-1 (ET-1) has been observed in almost all forms of pulmonary hypertension. ET-1, a highly potent vasoconstrictor, can also potentiate pulmonary arterial smooth muscle cell (PASMC) growth and migration, both of which contribute to the vascular remodeling that occurs during the development of pulmonary hypertension. Increasing evidence indicates that alkalinization of intracellular pH (pHi ), typically due to activation of Na+ /H+ exchange (NHE), is associated with enhanced PASMC proliferation and migration. We recently demonstrated that application of exogenous ET-1 increased NHE activity in murine PASMCs via a mechanism requiring Rho kinase (ROCK). However, whether ROCK and/or increased NHE activity mediate ET-1-induced migration and proliferation in PASMCs remains unknown. In this study, we used fluorescent microscopy in transiently cultured PASMCs from distal pulmonary arteries of the rat and the pH-sensitive dye, BCECF-AM, to measure changes in resting pHi and NHE activity induced by exposure to exogenous ET-1 (10-8 mol/L) for 24 h. Cell migration and proliferation in response to ET-1 were also measured using Transwell assays and BrdU incorporation, respectively. We found that application of exogenous ET-1 had no effect on NHE1 expression, but increased pHi , NHE activity, migration, and proliferation in rat PASMCs. Pharmacologic inhibition of NHE or ROCK prevented the ET-1-induced changes in cell function (proliferation and migration). Our results indicate that ET-1 modulates PASMC migration and proliferation via changes in pHi homeostasis through a pathway involving ROCK. PMID- 29756393 TI - Opioid prescribing practices in patients undergoing surgery for oral cavity cancer. AB - OBJECTIVES: Opioids have been overprescribed after general and orthopedic surgeries, but prescribing patterns have not been reported for head and neck surgery. The objectives of this retrospective review are to describe postoperative opioid prescriptions after oral cancer surgery and determine which patients receive higher amounts. METHODS: A single institution retrospective review was performed for 81 adults with oral cavity tumors undergoing surgery. Opioid prescriptions upon discharge were reported in daily oral morphine equivalents (OME). High opioids were defined as > 90 mg daily and > 200 mg total, commensurate with U.S. Center for Disease Control and Prevention and state guidelines. Multivariable logistic regression was performed to investigate factors associated with high opioids. RESULTS: The median number of doses dispensed was 30 (interquartile range [IQR] 30-45; range 3-120). The median daily dose was 30 mg (IQR 20-45 mg; range 15-240 mg). Five patients (6%) received higher than the recommended daily dose. The median total dispensed amount was 225 mg (IQR 150-250 mg; range 15-1200 mg). Fifty-one (63%) received greater than the recommended total dose. On multivariable logistic regression, advanced tumor stage (odds ratio [OR] 11.5; 95% confidence interval [CI] 1.2-109.4; P = 0.034) and inpatient pain scores (OR 1.3 per 1-unit increase; 95% CI 1.0-1.7; P = 0.039) were associated with receiving high total opioids after surgery. CONCLUSION: The majority of patients received greater than the recommended 200 mg total OME. Advanced stage and higher inpatient pain scores were associated with receiving more opioids for discharge. Consensus-driven analgesic plans are needed to reduce excess opioids after discharge following head and neck surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:2361-2366, 2018. PMID- 29756394 TI - Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first-line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. AB - OBJECTIVES: To examine the prognostic role of the pretreatment aspartate transaminase/alanine transaminase or De Ritis ratio in patients with metastatic renal cell carcinoma receiving first-line systemic tyrosine kinase inhibitor therapy. METHODS: We retrospectively searched the medical records of 579 patients with metastatic renal cell carcinoma who visited Samsung Medical Center, Seoul, Korea, from January 2001 through August 2016. After excluding 210 patients, we analyzed 360 patients who received first-line tyrosine kinase inhibitor therapy. Cancer-specific survival and overall survival were defined as the primary and secondary end-points, respectively. A multivariate Cox proportional hazards regression model was used to identify independent prognosticators of survival outcomes. RESULTS: The overall population was divided into two groups according to the pretreatment De Ritis ratio as an optimal cut-off value of 1.2, which was determined by a time-dependent receiver operating characteristic curve analysis. Patients with a higher pretreatment De Ritis ratio (>=1.2) had worse cancer specific survival and overall survival outcomes, compared with those with a lower De Ritis ratio (<1.2). Notably, a higher De Ritis ratio (>=1.2) was found to be an independent predictor of both cancer-specific survival (hazard ratio 1.61, 95% confidence interval 1.13-2.30) and overall survival outcomes (hazard ratio 1.69, 95% confidence interval 1.19-2.39), along with male sex, multiple metastasis (>=2), non-clear cell histology, advanced pT stage (>=3), previous metastasectomy and the Memorial Sloan Kettering Cancer Center risk classification. CONCLUSION: Our findings show that the pretreatment De Ritis ratio can provide valuable information about the survival outcomes of metastatic renal cell carcinoma patients receiving first-line tyrosine kinase inhibitor therapy. PMID- 29756395 TI - Hole Mobility Modulation in Single-Crystal Metal Phthalocyanines by Changing the Metal-pi/pi-pi Interactions. AB - Weak intermolecular interactions in organic semiconducting molecular crystals play an important role in determining molecular packing and electronic properties. Single crystals of metal-free and metal phthalocyanines were synthesized to investigate how the coordination of the central metal atom affects their molecular packing and resultant electronic properties. Single-crystal field effect transistors were made and showed a hole mobility order of ZnPc>MnPc>FePc>CoPc>CuPc>H2 Pc>NiPc. Density functional theory (DFT) and 1D polaron transport theory reach a good agreement in reproducing the experimentally measured trend for hole mobility. Additional detail analysis at the DFT level suggests the metal atom coordination into H2 Pc planes can tune the hole mobility via adjusting the intermolecular distances along the shortest axis with closest parallel pi stackings. PMID- 29756397 TI - Topical superoxide dismutase in posttreatment fibrosis in patients with head and neck cancer. AB - BACKGROUND: Topical superoxide dismutase (SOD) has been shown to decrease postradiation fibrosis in some cancers but has not demonstrated an effect in patients with head and neck cancer. The purpose of this study was to determine if topical SOD is an effective treatment for postradiation neck fibrosis. METHODS: This was a randomized prospective blinded clinical study of topical SOD versus placebo for the treatment of neck fibrosis. Measures of fibrosis grade and quality of life were obtained at baseline and after 3 months of treatment. RESULTS: Improvement in fibrosis score was comparable between the 2 study arms at 3 months. CONCLUSION: Both study groups showed improvement but the differences between groups was not statistically significant. Topical SOD likely has limited benefit for posttreatment neck fibrosis but this study confirms other published evidence of benefit from active physical therapy of posttreatment fibrosis in patients with head and neck cancer. PMID- 29756398 TI - Survival without adjuvant chemotherapy for selected patients with stage II and III nasopharyngeal carcinoma after concurrent chemoradiotherapy alone. AB - BACKGROUND: The role of adjuvant chemotherapy after concurrent chemoradiotherapy (CRT) for nasopharyngeal carcinoma (NPC) is controversial. We report our phase II prospective study of withholding adjuvant chemotherapy in a subgroup of patients with American Joint Committee on Cancer (AJCC) stage II and III NPC with low risk for metastasis. METHODS: Between April 1998 and December 2008, 263 patients with stage II (AJCC 1997 T2aN0, T1-T2aN1; AJCC 2010 T1N1) NPC or stage III (AJCC 1997 T1-T2aN2; AJCC 2010 T1N2) NPC were enrolled. Patients received standard concurrent CRT with cisplatin and 5-fluorouracil (5-FU) but without adjuvant chemotherapy. RESULTS: With a median follow-up of 107 months, the 5-year overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS) were 92.4%, 84.4%, and 90.7% for all patients; 94.1%, 85.9%, and 92.9% for patients with stage II NPC; and 90.9%, 83.2%, and 88.9% for patients with stage III NPC, respectively. CONCLUSION: It is safe to withhold adjuvant chemotherapy for selected patients with stage II and III NPC. PMID- 29756396 TI - Radiation therapy patient education using VERT: combination of technology with human care. AB - The Virtual Environment for Radiotherapy Training (VERT) system is a recently available tool for radiation therapy education. The majority of research regarding VERT-based education is focused on students, with a growing area of research being VERT's role in patient education. Because large differences in educational requirements exist between students and patients, focused resources and subsequent evaluations are necessary to provide solid justification for the unique benefits and challenges posed by VERT in a patient education context. This commentary article examines VERT's role in patient education, with a focus on salient visual features, VERT's ability to address some of the spatial challenges associated with RT patient education and how to combine technology with human care. PMID- 29756400 TI - pH changes in radicular dentine associated with calcium hydroxide and corticosteroid/antibiotic pastes. AB - The aim was to compare hydroxyl ion diffusion through dentine following placement of calcium hydroxide and Ledermix paste. Thirty-six teeth were divided into one control (n = 6) and three experimental (n = 10) groups - (i) Pulpdent paste; (ii) Pulpdent/Ledermix pastes; (iii) Ledermix paste and (iv) Saline. pH was measured in inner and outer dentine cavities over 12 months. Inner dentine time to maximum pH (Tmax ) was 1 week for Pulpdent and 2 weeks for Pulpdent/Ledermix. Pulpdent's outer dentine Tmax was 4 weeks and Pulpdent/Ledermix was 10 weeks. After day 1, Pulpdent pH was higher and this continued for 12 months. Pulpdent's outer dentine pH was higher than Ledermix and controls, but not significantly different from Pulpdent/Ledermix. Pulpdent/Ledermix had significantly higher pH than controls and Ledermix from day 5 until 10 months when Pulpdent/Ledermix outer dentine pH decreased and became similar. In all groups, pH reduced after 3 months. PMID- 29756399 TI - Distinct progression pattern of susceptibility MRI in the substantia nigra of Parkinson's patients. AB - BACKGROUND: Susceptibility MRI may capture Parkinson's disease-related pathology. This study delineated longitudinal changes in different substantia nigra regions. METHODS: Seventy-two PD patients and 62 controls were studied at both baseline and after 18 months with MRI. R2* and quantitative susceptibility mapping values from the substantia nigra pars compacta and substantia nigra pars reticulata were calculated. Mixed-effects models compared controls with PD or PD subgroups having different disease durations: early (<1 year), middle (<5 years, middle-stage PD), and late (>5 years, late-stage PD). Pearson's correlation assessed associations between imaging and clinical measures. RESULTS: At baseline, R2* and quantitative susceptibility mapping were higher in both the substantia nigra pars compacta and substantia nigra pars reticulata in all PD patients (group effect, P <= 0.003). Longitudinally, the substantia nigra pars compacta R2* showed a faster increase in PD compared with controls (time * group, P = 0.002), whereas quantitative susceptibility mapping did not (P = 0.668). The substantia nigra pars reticulata R2* and quantitative susceptibility mapping did not differ between PD and controls (time * group, P >= 0.084), although both decreased longitudinally (time effect, P <= 0.004). Baseline substantia nigra pars compacta R2* was higher in all PD subgroups (group, P <= 0.006), but showed a significantly faster increase only in later-stage PD (time * group, P < 0.0001) that correlated with changes in nonmotor symptoms (r = 0.746, P = 0.002). Baseline substantia nigra pars reticulata quantitative susceptibility mapping was higher in middle-stage PD and later-stage PD (group, P <= 0.002), but showed a longitudinal decrease (time * group, P = 0.004) only in later-stage PD that correlated with changes in motor signs (r = 0.837, P < 0.001). CONCLUSION: Susceptibility MRI revealed distinct patterns of PD progression in the substantia nigra pars compacta and substantia nigra pars reticulata. The different patterns are particularly clear in later stage patients. These findings may resolve past controversies and have implications in the pathophysiological processes during PD progression. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756402 TI - 'Friends that last a lifetime': the importance of emotions amongst volunteers working with refugees in Calais. AB - The European 'refugee crisis' has generated a broad movement of volunteers offering their time and skills to support refugees across the continent, in the absence of nation states. This article focuses on volunteers who helped in the informal refugee camp in Calais called the 'Jungle'. It looks at the importance of emotions as a motivating factor for taking on responsibilities that are usually carried out by humanitarian aid organizations. We argue that empathy is not only the initial motivator for action, but it also sustains the voluntary activity as volunteers make sense of their emotions through working in the camp. This type of volunteering has also created new spaces for sociability and community, as volunteers have formed strong emotional and relational bonds with each other and with the refugees. Finally, this article contributes to the growing body of literature that aims at repositioning emotions within the social sciences research to argue that they are an important analytical tool to understand social life and fieldwork. PMID- 29756401 TI - Alpha1 -adrenergic stimulation selectively enhances endothelium-mediated vasodilation in rat cremaster arteries. AB - We have systematically investigated how vascular smooth muscle alpha1 adrenoceptor activation impacts endothelium-mediated vasodilation in isolated, myogenically active, rat cremaster muscle 1A arteries. Cannulated cremaster arteries were pressurized intraluminally to 70 mmHg to induce myogenic tone, and exposed to vasoactive agents via bath superfusion at 34 degrees C. Smooth muscle membrane potential was measured via sharp microelectrode recordings in pressurized, myogenic arteries. The alpha1 -adrenergic agonist phenylephrine (25 100 nmol/L) produced further constriction of myogenic arteries, but did not alter the vasorelaxant responses to acetylcholine (0.3 MUmol/L), SKA-31 (an activator of endothelial Ca2+ -dependent K+ channels) (3 MUmol/L) or sodium nitroprusside (10 MUmol/L). Exposure to 0.25-1 MUmol/L phenylephrine or 1 MUmol/L norepinephrine generated more robust constrictions, and also enhanced the vasodilations evoked by acetylcholine and SKA-31, but not by sodium nitroprusside. In contrast, the thromboxane receptor agonist U46619 (250 nmol/L) dampened responses to all three vasodilators. Phenylephrine exposure depolarized myogenic arteries, and mimicking this effect with 4-aminopyridine (1 mmol/L) was sufficient to augment the SKA-31-evoked vasodilation. Inhibition of L-type Ca2+ channels by 1 MUmol/L nifedipine decreased myogenic tone, phenylephrine-induced constriction and prevented alpha1 -adrenergic enhancement of endothelium-evoked vasodilation; these latter deficits were overcome by exposure to 3 and 10 MUmol/L phenylephrine. Mechanistically, augmentation of ACh-evoked dilation by phenylephrine was dampened by eNOS inhibition and abolished by blockade of endothelial KCa channels. Collectively, these data suggest that increasing alpha1 -adrenoceptor activation beyond a threshold level augments endothelium-evoked vasodilation, likely by triggering transcellular signaling between smooth muscle and the endothelium. Physiologically, this negative feedback process may serve as a "brake" to limit the extent of vasoconstriction in the skeletal microcirculation evoked by the elevated sympathetic tone. PMID- 29756403 TI - Nasopharyngeal CCL5 in infants with severe bronchiolitis and risk of recurrent wheezing: A multi-center prospective cohort study. PMID- 29756404 TI - Nasal fibroscopy as a routine screening procedure of sinonasal adenocarcinoma of woodworkers: French longitudinal case study. AB - BACKGROUND: The purpose of this study was to assess the relevancy of flexible nasoendoscopy as a routine screening procedure of sinonasal adenocarcinoma among people occupationally exposed to wood dust. METHODS: This study included woodworkers, occupationally exposed to wood dust. Evaluations were scheduled at the time of inclusion (T0) and after a 2-year period (T1). A questionnaire was used for standardized data collection. The score was based on anatomic landmarks on each side that are parts of the olfactory clefts: the area of middle turbinate, the anterior part of the olfactory cleft, the top of the choanal arch, the spheno-ethmoidal recess, the posterior part of the olfactory cleft, and the middle part of the olfactory cleft. RESULTS: A total of 965 nasoendoscopies (T0+T1) were performed. Olfactory clefts were visualized in 72% of the cases. Nasoendoscopies revealed pathological findings in 33.6% of cases: polyps, thick nasal secretion aspect, mucous edema, retractile scars and synechia, crusts, mucous erythema, and growth. One case of carcinoma was confirmed. Adverse effects (epistaxis, blood mark on the endo-sheath, sneezing, or rhinorrhea) after the medical procedure occurred in 30% of cases without severe complications. CONCLUSION: Flexible nasoendoscopy offers meaningful efficacy and a promising safety profile, and, therefore, could become the new cornerstone of the routine screening procedure of sinonasal adenocarcinoma among woodworkers. PMID- 29756406 TI - Interspecific network centrality, host range and early-life development are associated with wildlife hosts of Rift Valley fever virus. AB - Rift Valley fever virus (RVFV) is responsible for a substantive disease burden in pastoralist communities and the agricultural sector in the African continent and Arabian Peninsula. Enzootic, epizootic and zoonotic RVFV transmission dynamics remain ill-defined, particularly due to a poor understanding of the role of mammalian hosts in the epidemiology and infection ecology of this arbovirus. Using a piecewise structural equation model, this study sought to identify associations between biological and ecological characteristics of mammalian species and documented RVFV infection to highlight species-level traits that may influence wildlife host status. Interspecific network centrality, size of species home range and reproductive life-history traits were all associated with being an RVFV host. The identification of these species-level characteristics may help to provide ecological context for the role of wildlife amplification hosts in the epidemiology of spillover to livestock and humans and may also help to identify specific points of vulnerability at the wildlife-livestock interface. PMID- 29756405 TI - Duplicated major histocompatibility complex class II genes in the tongue sole (Cynoglossus semilaevis). AB - The major histocompatibility complex (MHC) molecule plays an important role in the vertebrate immune system. However, we have a limited understanding of the MHC genomic structure in teleosts. Using gene cloning and family analysis, we isolate the MHC class II genes in the tongue sole (Cynoglossus semilaevis) and find that both class II A and class II B genes are duplicated (named Cyse-DAA and Cyse-DBA, Cyse-DAB and Cyse-DBB, respectively). The class II A genes consist of four exons with a highly conserved genomic structure, but each gene has unique and defining exon 2 and intron 2 sequences. The class II B genes have a conserved six-exon genomic structure, with intron 3 splitting the beta2 encoding region into two exons. Each class II B gene has unique variations in exon 2 and intron 1 sequences. The two class II A genes have similar expression patterns among tissues, with high levels in spleen and gill. Both class II B genes have similar patterns, with high expression in spleen, gill and intestine. The alleles of MHC class II have wide distribution and reliable inheritance in the families analysed. This indicates that the duplicated MHC genes are all classical class II genes. The class II gene duplication with divergent exon and intron sequences, but similar expression patterns in tongue sole provides new insights into MHC evolution. PMID- 29756407 TI - A prospective study for treatment of nasal valve collapse due to lateral wall insufficiency: Outcomes using a bioabsorbable implant. AB - OBJECTIVE: To examine 6-month outcomes for treatment of lateral nasal wall insufficiency with a bioabsorbable implant. STUDY DESIGN: Prospective, multicenter, nonrandomized, single-blinded study. METHODS: One hundred and one patients with severe-to-extreme class of Nasal Obstruction Symptom Evaluation (NOSE) scores were enrolled at 14 U.S. clinics (September 2016-March 2017). Patients were treated with a bioabsorbable implant designed to support lateral wall, with or without concurrent septoplasty and/or turbinate reduction procedure(s). NOSE scores and visual analog scale (VAS) were measured at baseline and month 1, 3, and 6 postoperatively. The Lateral Wall Insufficiency (LWI) score was determined by independent physicians observing the lateral wall motion video. RESULTS: Forty-three patients were treated with implant alone, whereas 58 had adjunctive procedures. Seventeen patients reported 19 adverse events, all of which resolved with no clinical sequelae. Patients showed significant reduction in NOSE scores at 1, 3, and 6 months postoperatively (79.5 +/- 13.5 preoperatively, 34.6 +/- 25.0 at 1 month, 32.0 +/- 28.4 at 3 months, and 30.6 +/- 25.8 at 6 months postoperatively; P < 0.01 for all). They also showed significant reduction in VAS scores postoperatively (71.9 +/- 18.8 preoperatively, 32.7 +/- 27.1 at 1 month, 30.1 +/- 28.3 at 3 months, and 30.7 +/- 29.6 at 6 months postoperatively; P < 0.01 for all). These results were similar in patients treated with the implant alone compared to those treated with the implant and adjunctive procedures. Consistent with patient-reported outcomes, postoperative LWI scores were demonstrably lower (1.83 +/- 0.10 and 1.30 +/- 0.11 pre- and postoperatively; P < 0.01). CONCLUSION: Stabilization of the lateral nasal wall with a bioabsorbable implant improves patients' nasal obstructive symptoms over 6 months. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2483-2489, 2018. PMID- 29756408 TI - [Ph3 C][B(C6 F5 )4 ]: A Highly Efficient Metal-Free Single-Component Initiator for the Helical-Sense-Selective Cationic Copolymerization of Chiral Aryl Isocyanides and Achiral Aryl Isocyanides. AB - Commercially available [Ph3 C][B(C6 F5 )4 ] served as a highly efficient metal free and single-component initiator not only for the carbocationic polymerization of polar and bulky aryl isocyanides with extremely high activity up to 1.2*107 g of polymer/(molcat. h), but also for the helical-sense-selective polymerization of chiral aryl isocyanides and copolymerization with achiral aryl isocyanides to afford high-molecular-weight functional poly(aryl isocyanide)s with good solubility as well as AIE characteristics and/or a single-handed helical conformation. PMID- 29756409 TI - Acute Kidney Injury during Parvovirus B19-Induced Transient Aplastic Crisis in Sickle Cell Disease. PMID- 29756410 TI - The feasibility and efficacy of preparing porcine Descemet's membrane endothelial keratoplasty (DMEK) grafts by two techniques: An ex-vivo investigation for future xeno-DMEK. AB - BACKGROUND: Descemet's membrane endothelial keratoplasty (DMEK) might be a promising technique for future xeno-corneal transplantation due to its ultrathin graft, extremely low rejection occurrence, suture-free graft fixation, and minimal immunosuppressive regime usage. The aim of this study is to explore the feasibility and efficacy of preparing porcine DMEK grafts by 2 techniques and investigate the graft ultrastructure. METHODS: Two mainstream techniques, mechanical stripping technique and liquid bubble technique, were modified to prepare the porcine DMEK grafts. In all, 40 corneas harvested from WZS-pigs (aged 10-12 months) were subjected to the techniques (20 corneas for each technique). The success rate, time consumption, and endothelial cell density (ECD) before and after preparation were recorded and compared between the 2 techniques. And the ultrastructure of the porcine DEMK graft was investigated by transmission electron microscope. In addition, 9 WZS-pigs with different ages were sacrificed to explore the correlation between the thickness of Descemet's membrane and porcine age. RESULTS: After modifying several technical details, the porcine DMEK grafts were successfully prepared by either mechanical stripping technique or liquid bubble technique, and the mark technique to distinguish the 2 sides of the graft was also explored. In all, 13 DMEK grafts (65%) were prepared successfully by the mechanical stripping technique, whereas 14 successful cases (70%) were prepared by the liquid bubble technique. The success rates between the 2 techniques showed no significant difference (P = .847). However, the mechanical stripping technique was significantly time-consuming when compared with the liquid bubble technique (P < .0001). The ECDs reduced significantly after preparation no matter what techniques were used (P < .0001), but the ECD after the liquid bubble preparation was significantly higher than the ECD after mechanical stripping (P = .032). The ECD reduction positively correlated to the time consumption for both mechanical stripping technique (P = .0014, R2 = 0.621) and liquid bubble technique (P = .013, R2 = 0.412). The ultrastructure showed the graft was comprised of stromal residuals, non-banded layer, and endothelial layer. Unlike human Descemet's membrane (DM), anterior banded layer was not observed. The thickness of porcine DM increased with the age, and a significant positive correlation between them was found (P < .0001, R2 = 0.949), and the predict equation was Y = 0.3764*X + 7.378 (Y indicates the thickness, whereas X indicates the age). CONCLUSIONS: Porcine DMEK grafts could be prepared either by mechanical stripping technique or liquid bubble technique, and the liquid bubble technique seems superior over the mechanical stripping technique regarding time consumption and ECD preservation. Although there are several technical barriers to overcome, xeno-DMEK might be a promising direction for future xeno-corneal transplantation. PMID- 29756412 TI - Adjuvant therapy in major salivary gland cancers: Analysis of 8580 patients in the National Cancer Database. AB - BACKGROUND: Evidence surrounding the effect of adjuvant treatment in salivary gland cancers is limited. The benefit of adding chemotherapy to adjuvant treatment is also of interest. We investigated the association of these treatments with survival and whether this differed by stage or the presence of adverse features. METHODS: A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the National Cancer Data Base (NCDB) was conducted. RESULTS: Treatment with adjuvant radiotherapy was associated with improved survival for both patients with early-stage (hazard ratio [HR] 0.744; P = .004) and late-stage (HR 0.688; P < .001) disease with adverse features. Further addition of chemotherapy to the adjuvant treatment of patients with late stage disease with adverse features was not associated with a survival benefit (HR 1.028; P = .705). CONCLUSION: Adjuvant radiotherapy is associated with improved survival for patients with adverse features, regardless of stage. The addition of chemotherapy to the adjuvant treatment of patients with late-stage disease with adverse features is not associated with improved outcomes. PMID- 29756411 TI - Hexarelin treatment preserves myocardial function and reduces cardiac fibrosis in a mouse model of acute myocardial infarction. AB - Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide. Growth hormone secretagogues (GHS) have been shown to improve cardiac function in models of IHD. This study determined whether hexarelin (HEX), a synthetic GHS, preserves cardiac function and morphology in a mouse model of myocardial infarction (MI). MI was induced by ligation of the left descending coronary artery in C57BL/6J mice followed by vehicle (VEH; n = 10) or HEX (0.3 mg/kg/day; n = 11) administration for 21 days. MI-injured and sham mice (treated with VEH; n = 6 or HEX; n = 5) underwent magnetic resonance imaging for measurement of left ventricular (LV) function, mass and infarct size at 24 h and 14 days post-MI. MI-HEX mice displayed a significant improvement (P < 0.05) in LV function compared with MI-VEH mice after 14 days treatment. A significant decrease in LV mass, interstitial collagen and collagen concentration was demonstrated with chronic HEX treatment (for 21 days), accompanied by a decrease in TGF-beta1 expression, myofibroblast differentiation and an increase in collagen-degrading MMP-13 expression levels. Furthermore, heart rate variability analysis demonstrated that HEX treatment shifted the balance of autonomic nervous activity toward a parasympathetic predominance and sympathetic downregulation. This was combined with a HEX-dependent decrease in troponin-I, IL-1beta and TNF alpha levels suggestive of amelioration of cardiomyocyte injury. These results demonstrate that GHS may preserve ventricular function, reduce inflammation and favorably remodel the process of fibrotic healing in a mouse model of MI and hold the potential for translational application to patients suffering from MI. PMID- 29756413 TI - The VEGFA -1154G/A polymorphism is associated with reduced risk of rheumatoid arthritis but not with systemic lupus erythematosus in Mexican women. AB - BACKGROUND: Levels of circulating vascular endothelial growth factor (VEGF) (a potent endothelial-cell-specific angiogenic factor) have been correlated with disease activity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, several single nucleotide polymorphisms (SNPs), including the VEGFA -2578C/A, have been associated with RA in some populations. By contrast, the role of different VEGFA SNPs in the susceptibility to SLE has received little attention. Thus, the present study aimed to determine whether the VEGFA -2578C/A, -1154G/A and -634G/C polymorphisms confer risk or were associated with reduced risk of RA or SLE in a Mexican population. METHODS: The present study included 903 women from Mexico: 405 were patients with RA, 282 had SLE and 216 were healthy individuals. The genotypes were obtained with TaqMan probes. RESULTS: The data obtained in the present study suggest that the VEGFA -2578C/A and -634G/C polymorphisms are not risk factors for RA or SLE; however, VEGFA 1154G/A was associated with reduced risk in women with RA (odds ratio = 0.6, pc = 0.0051) but not with SLE (odds ratio = 0.7, pc = 0.13). CONCLUSIONS: The present study is the first to document an association between VEGFA -1154G/A and reduced risk in women with RA but not with SLE. PMID- 29756414 TI - Arterial to end-tidal carbon dioxide tension difference (CO2 gap) as a prognostic marker for adverse outcomes in emergency department patients presenting with suspected sepsis. AB - OBJECTIVE: The arterial to end-tidal carbon dioxide tension difference (CO2 gap) correlates with physiologic dead space. The prognostic value of increased CO2 gap in trauma and respiratory distress patients is documented. Transpulmonary arteriovenous shunting is identified as a predictor of mortality in non-pulmonary sepsis. We set out to investigate the prognostic value of the CO2 gap in a pilot study of patients with suspected sepsis from non-respiratory causes. METHODS: Patients presenting to tertiary Australian ED with suspected sepsis (n = 215) underwent near-simultaneous end-tidal carbon dioxide and partial pressure of carbon dioxide measurements. We investigated the correlation of CO2 gap levels with the primary outcome of in-hospital mortality (IHM) and secondary outcomes of sepsis (DeltaSOFA >=2) and IHM and/or intensive care unit stay >=72 h (IHM/ICU72h) in patients with sepsis because of non-respiratory causes. RESULTS: Among patients included in the analysis (n = 165), the CO2 gap showed modest positive correlation with qSOFA (rho = 0.39) and weak positive correlation with SOFA scores (rho = 0.29) (both P < 0.01). The CO2 gap had modest predictive value for primary outcome (IHM), area under receiver operating curve (AUROC 0.85, 95% confidence interval [CI] 0.78-0.90) and IHM/ICU72h outcome (AUROC 0.80, 95% CI 0.73-0.86), but lower predictive value for sepsis outcome (AUROC 0.64, 95% CI 0.55-0.71) (all P < 0.001). We report modest test performance for primary outcome at CO2 gap >=5 and >=10 mmHg cut-offs. CONCLUSION: In this pilot study of patients with suspected sepsis from non-respiratory causes, an increased CO2 gap demonstrates value in risk stratification and needs to be further evaluated and compared to other existent biomarkers. PMID- 29756415 TI - The Expression of Androgen Receptor and Its Variants in Human Prostate Cancer Tissue according to Disease Status, and Its Prognostic Significance. AB - PURPOSE: To evaluate changes in the expression of androgen receptor (AR) and its variants (ARVs) in human prostate cancer (PCa) tissues according to disease status, and its prognostic significance following radical prostatectomy (RP). MATERIALS AND METHODS: A total of 282 PCa cases were evaluated, which included 252 localized PCa, 8 metastatic castration resistant prostate cancer (CRPC), and 22 benign prostatic hyperplasia (BPH) cases. Samples were collected from patients who underwent RP or transurethral resection and were stored in ethically approved tissue banks. Quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry were performed for AR and ARVs. Each tissue was confirmed as cancerous (greater than 80%) using hematoxylin and eosin staining. AR and ARVs expression was compared according to disease status. The biochemical recurrence free survival (BCRFS) rates in men with localized PCa was analyzed according to AR and ARV7 expression using the Kaplan-Meier curve. RESULTS: Only 58 of the 252 localized PCa were included in the analysis because of insufficient cancer tissue. AR and ARV7 mRNA expression was higher in the CRPC tissue than in the localized PCa tissue (p=0.025, p=0.002, respectively). In localized PCa tissue, high AR mRNA and protein level was associated with a low BCRFS rate (log ranked, p=0.019, p<0.001, respectively). CONCLUSIONS: Overall AR and ARV7 mRNA expression levels were increased in CRPC tissues compared to localized PCa and BPH tissues. High AR protein and mRNA expression in the tumor tissue may be considered a predictive factor of BCRFS following RP. PMID- 29756416 TI - Testosterone and Sarcopenia. AB - Aging affects metabolism, leading to physiological and functional impairments, and is also related to changes in body composition, including reduced skeletal muscle mass and increased body fat. These changes are correlated with the pathophysiology of sarcopenia, which is defined as age-related loss of skeletal muscle mass and strength. Low testosterone levels are associated with unfavorable body composition changes, and sex hormones decrease with aging. Androgen deficiency, along with lack of exercise and poor nutrition, may be among the modifiable contributors to sarcopenia. Testosterone treatment has been reported to have beneficial effects on muscle mass and function, but the results have been inconsistent. Here, we discuss the correlation between testosterone and muscle mass and function, the impact of testosterone on sarcopenia, and the probable mechanisms underlying these effects. PMID- 29756418 TI - Statins and Erectile Dysfunction. PMID- 29756419 TI - Growth Hormone and Aging: Updated Review. AB - Role of growth hormone (GH) in mammalian aging is actively explored in clinical, epidemiological, and experimental studies. The age-related decline in GH levels is variously interpreted as a symptom of neuroendocrine aging, as one of causes of altered body composition and other unwelcome symptoms of aging, or as a mechanism of natural protection from cancer and other chronic diseases. Absence of GH signals due to mutations affecting anterior pituitary development, GH secretion, or GH receptors produces an impressive extension of longevity in laboratory mice. Extension of healthspan in these animals and analysis of survival curves suggest that in the absence of GH, aging is slowed down or delayed. The corresponding endocrine syndromes in the human have no consistent impact on longevity, but are associated with remarkable protection from age related disease. Moreover, survival to extremely old age has been associated with reduced somatotropic (GH and insulin-like growth factor-1) signaling in women and men. In both humans and mice, elevation of GH levels into the supranormal (pathological) range is associated with increased disease risks and reduced life expectancy likely representing acceleration of aging. The widely advertised potential of GH as an anti-aging agent attracted much interest. However, results obtained thus far have been disappointing with few documented benefits and many troublesome side effects. Possible utility of GH in the treatment of sarcopenia and frailty remains to be explored. PMID- 29756417 TI - Dehydroepiandrosterone and Erectile Function: A Review. AB - To review the contemporary knowledge regarding the dehydroepiandrosterone and erectile function. Medline was reviewed for English-language journal articles spanning the time between January 1990 and December 2017, using the terms 'erectile function', 'dehydroepiandrosterone'. We used Journal Articles and review articles that found to be relevant to the purpose of this review. Criteria included all pertinent review articles, randomized controlled trials with tight methodological design, cohort studies and retrospective analyses. We also manually revised references from selected articles. Several interesting studies have addressed the age-related decline in dehydroepiandrosterone levels with many age-related phenomena or deterioration in various physiological functions. Particularly, aging; neurological functions including decreased well-being, cognition, and memory; increased depression, decreased bone mineral density, obesity, diabetes, increased cardiovascular morbidity, erectile dysfunction (ED), and decreased libido. Supporting this result, some trials of dehydroepiandrosterone supplementation in healthy, middle-aged, and elderly subjects have reported improvements in different aspects of well-being. Several studies had demonstrated that dehydroepiandrosterone level is declined as a part of aging. Large-scale well-designed prospective studies are warranted to better define indications and therapeutic implications of dehydroepiandrosterone in men with ED. PMID- 29756420 TI - Multiple arterial aneurysms: do not forget syphilitic etiology. PMID- 29756421 TI - Survey of cutaneous adverse reactions to targeted cancer therapies: value of dermatological advice. AB - BACKGROUND: Target-therapy offers a better efficacy for several cancers, with less toxic adverse effects, if compared with traditional chemotherapy. However cutaneous complications are increased in number and complexity. The severity of these reactions positively correlates with efficacy, and the management of these reactions is challenging. METHODS: This was a multicenter cross-sectional study on a consecutive series of adult patients with incident cutaneous reactions linked to targeted cancer therapies observed in five referral centers for cancer treatment in the province of Bergamo and Brescia in northern Italy. Each center was asked to collect data on the first 5 consecutive cases of severe adverse cutaneous events observed during a one-week surveillance period. RESULTS: From June to October 2012, 25 patients with cutaneous adverse reactions linked to targeted therapies were included in the study. The main prescribed drugs were cetuximab (52%) and erlotinib (20%) and the most common reactions were folliculitis/pustules (40%) and rash/erythema (40%). Hand-foot reaction syndrome was present in 8% of patients. A total of 30% of patients treated for a cutaneous reaction underwent a consultation by a dermatologist. In these patients the rate of oncologic therapy continuation without regimen modifications was higher (100%), while it was progressively lower in patients treated by oncologists (71%) or without any specific treatment (60%). CONCLUSIONS: Adverse reaction should be recognized by both dermatologists and oncologists and a multidisciplinary approach is mandatory. PMID- 29756423 TI - Persistent hyponatraemia following suspected krait envenomation in a 5 year old Sri Lankan child: a case report PMID- 29756424 TI - Incomplete Kawasaki Disease with coronary aneurysms in a young infant of 45 days presented as neonatal sepsis PMID- 29756422 TI - Gestational age and birth weight centiles of singleton babies delivered normally following spontaneous labor, in Southern Sri Lanka AB - Aims: To estimate the gestational age and birth weight centiles of babies delivered normally, without any obstetric intervention, in women with uncomplicated singleton pregnancies establishing spontaneous onset of labour. Method: Consecutive women with uncomplicated singleton pregnancies, attending the Academic Obstetrics and Gynecology Unit of the Teaching Hospital Mahamodara Galle, Sri Lanka, with confirmed dates and establishing spontaneous onset of labor and delivering vaginally between gestational age of 34 - 41 weeks, without any obstetric intervention , during the period September 2013 to February 2014 were studied. The gestational age at spontaneous onset of labor and vaginal delivery and the birth weights of the babies were recorded. Results: There were 3294 consecutive deliveries during this period, and of them 1602 (48.6%) met the inclusion criteria. Median gestational age at delivery was 275 days (range 238 291 days, IQR 269 to 280 days) and the median birth weight was 3000 g (range1700g - 4350g; IQR 2750-3250g). The 10th, 50th and 90th birth weight centiles of the babies delivered at a gestational age of 275 days were approximately 2570g, 3050g and 3550g respectively. Conclusions: The median gestational age among women with uncomplicated singleton pregnancies who established spontaneous onset of labor and delivered vaginally, without any obstetric intervention, was approximately five days shorter than the traditionally accepted 280 days. At a gestational age of 275 days, the mean birth weight was approximately 3038g and the 50th centile of the birth weight of the babies delivered was approximately 3050g. PMID- 29756425 TI - Long QT interval induced by clindamycin: a case report PMID- 29756426 TI - Nephrotic syndrome in a patient with visceral leishmaniasis: a case report PMID- 29756427 TI - Gaucher's disease Type I: a case report PMID- 29756428 TI - Trans-femoral lower limb transplantation in a Sri Lankan patient: a case report and surgical technique PMID- 29756429 TI - Bacterial osteomyelitis: microbiological, clinical, therapeutic, and evolutive characteristics of 344 episodes. AB - OBJECTIVE: Osteomyelitis is a difficult-to-cure infection, with high relapse rate despite adequate therapy. Large published osteomyelitis series in adults are rare. METHODS: A total of 344 adult osteomyelitis patients were studied and followed > 12 months after hospital discharge. Demographic, microbiological, clinical, therapeutic and outcome data were analyzed. RESULTS: Mean age was 52.5 +/- 18.3 years and 233 (67.7%) were male. Main osteomyelitis types were post surgical (31.1%), post-traumatic (26.2%) and hematogenous (23%). Tibia (24.1%) and femur (21.8%), and methicillin-susceptible S. aureus (29.6%) were the most commonly involved bone and bacteria, respectively. Median follow-up was 12.0 (IQR 0-48) months. Inflammatory markers were increased in 73.6%. Overall, patients were treated by IV and oral routes with one (IV: 44.5%, oral: 26.7%), two (IV: 30.1%, oral: 21.8%) or >= 2 (IV: 15.2%, oral: 6.1%) antibiotics. Median duration on IV/oral antimicrobials was 28.0 (IQR 24-28) and 19.5 (IQR 4-56) days, respectively. Anti-staphylococcal beta-lactams cloxacillin/cefazolin (19.2%) and ciprofloxacin (5.5%) were the most frequently used IV and orally, respectively. Overall 234 (68.0%) underwent surgery, 113 (32.8%) debridement, 97 (27.4%) debridement + muscle flap and 24 (7%) amputation. At the end of follow-up 208 patients (60.6%) did not have relapsed. Operated patients had significantly less relapses (p<0.0001). A total of 23 (6.7%) died, 11 (3.2%) by infectious complications and 48 (14%) were lost in the follow-up. CONCLUSIONS: Osteomyelitis is due to different causes complicating its therapy. Risk factors or causal microorganism could influence its treatment and outcome. Aggressive surgery along with adequate antimicrobial therapy are mandatory for cure. PMID- 29756431 TI - [Advances in acid resistant mechanism of acetic acid bacteria and related quorum sensing system]. AB - Acetic acid bacteria (AAB) are obligately aerobic Gram-negative bacteria. Known for their ability to oxidize ethanol to acetic acid and robust tolerance to acetic acid, AAB have been widely used in industrial vinegar fermentation. Besides the incomplete oxidative ability, investigation of their resistance mechanisms to acetic acid is intriguing and crucial for high titer vinegar production. In this review, we evaluated a variety of resistant pathways involved in carbohydrate metabolism, protein metabolism, lipid metabolism, and stress response based on genomics and proteomics investigations in AAB. Specifically, the discovery in modules related to quorum sensing (QS) system in Komagataeibacter species and the emerging genome data of AAB opens a new window to screen acid resistance regulatory networks, which may promote industrial strain breeding and fermentation optimizing. We reviewed the latest research progress of quorum sensing in acetic acid bacteria based on the brief introduction of genomic and proteomic studies. PMID- 29756432 TI - [Research progress in pneumolysin]. AB - Pneumolysin is a multifunctional virulence factor expressed by Streptococcus pneumoniae. Pneumolysin includes 4 domains and is a member of cholesterol dependent cytolysins. Pneumolysin has extensive cytotoxicity to a range of host cells. Furthermore, pneumolysin can activate complement classical pathway, and induce macrophages and monocytes to produce proinflammatory cytokines, mediate host immune responses. Consequently, pneumolysin is a potential candidate target for research and development of vaccines and drugs. In this review, the latest research progresses on the structure and function of pneumolysin, and related vaccines are discussed. PMID- 29756430 TI - [Evaluation of a PCR-multiplex technique for the rapid diagnosis of bacteriemia]. AB - OBJECTIVE: Rapid and safe diagnosis of bacteremia is a continuous challenge in clinical microbiology. In this work, we evaluated a multiple PCR system that identifies 23 common pathogens as well as the production of 3 resistance mechanisms potentially present in them. METHODS: During a period of 2 months the positive blood cultures were processed in the usual way for identification and determination of their antimicrobial sensitivity. At the same time were incorporated into FilmArray panels. RESULTS: The agreement between two methods for bacterial identification was 100%. The time of obtaining the results by the molecular technique did not exceed 1 hour 15 minutes and in 7 cases of the 21 studied (33%) a modification of the empirical therapy was carried out. CONCLUSIONS: The implementation of rapid techniques such as multiple PCR offers a fast, reliable and easy to perform diagnosis in the therapeutic management of sepsis. PMID- 29756433 TI - [Advances in quorum-sensing LuxR solos in bacteria]. AB - Quorum-sensing (QS) involved in the production of N-Acylhomoserine lactones (AHLs) is a universal way of communication of gram-negative bacteria. Complete AHL-QS system includes pairs of AHLs synthase belonging to LuxI family and cognate LuxR-family AHLs sensor-regulator. However, many gram-negative bacteria have evidenced the presence of AHL-QS related LuxR-type genes, which are unpaired to a cognate LuxI. These unpaired LuxRs have been called solos or orphans. LuxR solos are thought to be important for bacterial signal perception in eavesdropping, intra-species and inter-kingdom communication, which become research topic in the field of QS. Here, the finding, concept, protein structure, and main types of LuxR solos are illustrated. Furthermore, the function and important protein of LuxR solos associated with sensing AHLs or non-AHLs are reviewed. The prospect and significance of quorum sensing LuxR solos in bacteria are also discussed. PMID- 29756434 TI - [Micro-morphological variation pattern of Isaria cicadae]. AB - Objective: To reveal the morphological pattern of Isaria cicadae. Methods: We observed 17 morphological characters and measured 75 strains of 15 populations in I. cicadae. Statistical analysis system (SAS) 8.1 was used to analyze the morphological data, the morphological pattern was analyzed in 15 populations of I. cicadae, using the descriptive statistical analysis, nested analysis and Q cluster analysis. Results: Two types of asexual conidium (large and small conidium) were observed in I. cicadae. The gourd-shaped and bottle-shaped conidiogenous cells were observed in I. cicadae. Many chlamydospores of I. cicadae were easy to form in PDA medium. Many fusion hyphae were generated between hyphae, and some fusion hyphae between hypha and chlamydospore, the fusion hyphae between conidiogenous cells were also observed. The CV of 17 morphological characters was from 13.07 to 104.09% in I. cicadae, indicating an ample morphological diversity at the species level. The nested variation analysis of the 17 morphological characters indicated that about 11.29% of the variability was attributable to the differentiation among populations, the rest 15.27% of the variability was derived from individual strains, and the remaining 73.44% was resided in the observations in the same strain. Conclusion: The phenotypic variation within strain was the main morphological variation of I. cicadae. The morphological characters had no significant relationship with geographical origin in I. cicadae. PMID- 29756435 TI - [Characterization and molecular modification of beta-glucosidase from Citrobacter koser GXW-1]. AB - Objective: The aim of this study was to characterize beta-glucosidase from Citrobacter koser GXW-1 isolated from soil and to improve the enzyme by molecular modification. Mehods: A bacterial strain with beta-glucosidase activity was screened from the soil around Wuming sugar mill in Guangxi by esculin-ferric ammonium citrate selecting plate. The 16S rDNA of the strain was obtained and analyzed. By searching GenBank database, the genes encoding beta-glucosidase from the same genus Citrobacter were found. These sequences were aligned. Then, a gene encoding beta-glucosidase was amplified by PCR. The recombinant plasmid pQE-cbgl was constructed. The recombinant protein was purified with Ni-NTA. The enzyme properties of the recombinant protein CBGL were studied in detail. At last, the wild enzyme CBGL was reformed by error-prone PCR and site-directed random mutagenesis. Results: C. koser GXW-1 with beta-glucosidase activity was isolated from the soil. A gene encoding beta-glucosidase was cloned from the wild strain GXW-1. The properties of CBGL were identified. Its optimal pH and temperature were 6.0 and 45C. Its Km and Vmax value were (11.280+/-1.073) mmol/L and (0.1704+/-0.0073) MUmol/(mg.min), respectively. Its Ki values was (66.84+/-3.40) mmol/L. CBGL can hydrolyze alpha-pNPG, stevioside, daidzin and genistin. CBGL was modified by error-prone PCR and site directed random mutagenesis. A positive mutant W147F was obtained successfully. Its Vmax was 2.54 times that of the wild enzyme CBGL. Conclusion: CBGL not only can hydrolyze beta-glycosidic bond, but also can hydrolyze the alpha-glycosidic bond in alpha-pNPG. Furthermore, CBGL can hydrolyze stevioside, daidzin and genistin. These characteristics indicate that the beta-glucosidase CBGL has important applications in theoretical research and in industry. PMID- 29756436 TI - [Causes of succession of planktonic algae in Shennong bay of Three Gorges Reservoir in spring in 2014]. AB - Objective: Algal blooms occurred in some sections of Shennong bay after impounding of Three Gorges Reservoir. Methods: Related environmental and hydrodynamic factors were monitored during the period of algal blooming season in 2014 (March 20, April 13, May 23) in Shennong bay, Three Gorges Reservoir. To study succession of planktonic algae, water stable coefficient, euphotic depth and mixed layer depth were used to analyze stratification and hydrodynamic characteristics. Results: We identified 6 phyla, 38 species (genera) planktonic algae. The sensitive area of algal bloom was at SN05 (677.677*105 cells/L) and SN06 (716.761*105 cells/L), and the planktonic algae biomass during this period was significantly different (ANOVA, p<0.05). Moderate water temperature, adequate nutrients, weak stratification and poor mixing promoted the rapid growth and breakout of the diatom bloom with Cyclotella spp. as the dominant species in March. Further increase of water temperature, stronger stratification and decrease of dissolved silicate and mixing layer restricted the diatom growth. Chlorella spp. and Chlamydomonas spp. grew better in shallow mixed layer with rich nutrients and evident stratification. Then Chlorophycean bloom broke out with Chlorella spp. as the dominant species and Chlamydomonas spp. the next dominant species. High biomass maintained in April. In May, algal bloom gradually vanished due to sharp fluctuation of water level and increase of velocity. Monitored maximum water velocity was 0.1141 m/s at 2 m depth, exceeded an optimal flow rate perfect for growth of planktonic algae. Conclusion: Stratification and hydrodynamic characteristics had important effect on planktonic algae under the condition of adequate nutrients. Velocity became the main factor that inhibited the growth of algae in Shennong bay in pre-flood falling stage of the Three Gorges Reservoir. PMID- 29756437 TI - [Biological and epidemiological characteristics of the pathogen of hypertrophy sorosis scleroteniosis, Ciboria shiraiana]. AB - Objective: We studied the biological and the epidemiological characteristics of the pathogen of hypertrophy sorosis scleroteniosis, which is a devastating fungal disease of mulberry. Methods: We studied the asexual and sexual reproductive phase stages of C. shiraiana, including the infection ability of hyphal, dormancy of sclerotia, the structures, release, number and germination of ascospores from apothecia, as well as the phenology of sclerotial germination. Results: In C. shiraiana, hyphae had no infection ability toward the female flowers of mulberry. Sclerotia of C. shiraiana must undergo cold treatment above 6 weeks, then the dormancy-breaking sclerotia could germinate to apothecia. One to fifteen apothecia were germinated from one sclerotium, and the number of ascospores in a 1.5 cm diameter apothecia could contain up to (5.6-6.3)*107. Ascospore C. shiraiana had significantly higher germination rates in acid than in neutral and alkaline environments. From late January to middle April, sclerotia germinated to apothecia, and got the highest value in the middle of March. Conclusion: C. shiraiana is a formidable pathogen to cause epidemic disease and damage in mulberry. PMID- 29756438 TI - [Chemotaxis and characteristics of chemotactic genes in Novosphingobium strains]. AB - Objective: The present study aims to analyze the chemotaxis genes and proteins of several PAH-degrading Novosphingobium strains, and the chemotaxis of these strains toward aromatic compounds and intermediates. Methods: Based on genome comparative analysis, we identified the chemotaxis genes organization and proteins distribution. We used drop and swarm plate assays to detect the chemotaxis of these strains toward aromatic compounds and intermediates of TCA cycle. Results: We found that all these Novosphingobium strains showed chemotaxis, but the chemotatic ability varied. The completed genome sequenced strains N. pentaromativorans F2, N. pentaromativorans US6-1, N. pentaromativorans PP1Y, Novosphingobium sp. AP12, Novosphingobium sp. Rr 2-17, and Novosphingobium nitrogenifigens DSM 19370 contained MCP, CheW, CheA, CheB, CheR and CheY. Strain F2, US6-1 and PP1Y, shared a consistent order of chemotaxis genes in "che" cluster. The chemotatic system of these Novosphingobium strains belonged to the Fla chemotactic system. Conclusion: These strains all contained a complete chmotaxis pathway. Their chemotactic ability toward aromatic compounds and intermediates varied, and the chemotaxis of US6-1 was obvious. PMID- 29756439 TI - [Genome-wide prediction and analysis of the secretory proteins and ORFs signal peptide of ginkgo endophyte KM-1-2] AB - Objective: Endophytes are widespread in plants and build long-term mutually beneficial symbiotic relationship with the host. However, the mechanism of their interactions with the host needs further study. To explore the mechanism of endophytic bacterium ginkgo endophyte KM-1-2, we managed to forecast its secretory proteins based on its genome and explicit characteristics. Methods: Signal peptide analysis software SignalP, transmembrane helical structure analysis software TMHMM and Phobius, cells position software PSORT, subcellar localization software TargetP and GPI anchor site analysis software big-PI Predictor were used to predict the scope of all secreted proteins, which were defined as secretome. Results: Altogether 128 typical signal peptide secretory proteins were screened out of 5299 protein sequences in KM-1-2 genome, accounting for 2.4% of the whole genome. The shortest ORF encoding these proteins is 61 bp, the longest one is 2105 bp and the average is 373 bp. The length of the signal peptide guiding secretory protein was distributed between 15 to 37 aa, with the average length of 24 aa. Amino acid with the highest present frequency of signal peptide in proper order is alanine, leucine and valine. The type of signal peptide cleavage belongs to A-X-A which named SPI cleavage type. Among the total secretory proteins 66 pieces have functional description and 26 pieces were enzymes. These enzymes mainly include glycoside hydrolase, esterase transferase, REDOX enzyme and carbon oxygen lyase. Conclusion: The predicted secretory proteins of Streptomyces lavendulae KM-1-2 were achieved through bioinformatics analysis. These secretory proteins involved some enzymes and other unknown functions. This result laid the foundation for further study between endophyte and host. PMID- 29756440 TI - [The development of Agaricus bisporus wet bubble disease and the nuclear phase of pathogen]. AB - Objective: We studied the dynamic nuclear behavior of Hypomyces perniciosus on axenic culture and its disease progression after infection on different growth stages of Agaricus bisporus. Methods: Infection process was initiated by inoculating different stages of A. bisporus fruit body, and different depths of compost and casing soil with H. perniciosus. Disease progression was studied by observing symptoms on the fruit body using light microscopy and scanning electron microscopy. The nuclear behavior of H. perniciosus was determined by observation using fluorescence light microscopy after binding of DNA specific fluorochrome dye (DAPI:4, 6-Diamidino-2-phenylindole dihydrochloride) to the nuclei. Results: Inoculating H. perniciosus on different depths of compost and casing soil resulted in different disease rate as follows:on the surface of casing soil>in the center of casing soil>between the casing soil and the compost>in the center of compost. H. perniciosus can infect any stage of fruit body development, when young primordial (up to 3 mm) was infected, large, irregular and tumorous fungal masses were formed. H. perniciosus directly penetrated A. bisporus without the formation of appressorium-like structures. The germination of the conidia led to a necrotic brown lesion symptom on A. bisporus at the beginning stages of disease development. The mycelium of A. bisporus plasmolysed, hydropically degenerated, cytoplasmolysed, emptied of mycelium cytosol and eventual death as the disease advanced. H. perniciosus produced two types of conidia. Group I conidia had no septa, colorless and smooth containing one nucleus. Group II didymoconidium had septa, containing two nuclei, separated by septa. The first round of mitosis occurred in conidia with no nucleus in the germinal tube. Another kind of asexual spore for thicker cell wall wart convex chlamydospore, chlamydospore had two cells. The upper cell had two nuclear while the basal cell had one or two nuclear, when germinated, it produced one or two germinal tubes. The number of nuclear in the germinal tube was irregular, usually contained 0 to 2 nuclear. Conclusion: H. perniciosus can infect any part of the A. bisporus fruit body and can cause tremendous cytology changed. If we perform single spore isolation to do genetic analysis, one must isolate conidia with no septa. PMID- 29756441 TI - Multiresponsive Kinematics and Robotics of Surface-Patterned Polymer Film. AB - Soft robots, sensors, and energy harvesters require materials that are capable of converting external stimuli to visible deformations, especially when shape programmable deformations are desired. Herein, we develop a polymer film that can reversibly respond to humidity, heating, and acetone vapors with the generation of shape-programmable large deformations. Poly(vinylidene fluoride) film, capable of providing acetone responsiveness, is designed with microchannel patterns created on its one side by using templates, and the microchannels-patterned side is then treated with hygroscopic 3-aminopropyltriethoxysilane (APTES) to give humidity/heating-responsive elements. The APTES-modified microchannels lead to anisotropic flexural modulus and hygroscopicity in the film, resulting in the shape-programmed kinematics depending on the orientations of surface microchannels. As the microchannels align at oblique/right angles with respect to the long axis of the film strips, the coiling/curling motions can be generated in response to the stimuli, and the better motion performances are found in humidity and heating-driven systems. This material utilized in self-adaptive soft robots exhibits prominent toughness, powerful strength, and long endurance for converting humidity and heat to mechanical works including transportation of lightweight objects, automatic sensing cap, and mimicking crawling in nature. We thus believe that this material with shape-programmable multisensing capability might be suitable for soft machines and robotics. PMID- 29756442 TI - Modulation of the Cellular Uptake of DNA Origami through Control over Mass and Shape. AB - Designer nanoparticles with controlled shapes and sizes are increasingly popular vehicles for therapeutic delivery due to their enhanced cell-delivery performance. However, our ability to fashion nanoparticles has offered only limited control over these parameters. Structural DNA nanotechnology has an unparalleled ability to self-assemble three-dimensional nanostructures with near atomic resolution features, and thus, it offers an attractive platform for the systematic exploration of the parameter space relevant to nanoparticle uptake by living cells. In this study, we examined the cell uptake of a panel of 11 distinct DNA-origami shapes, with the largest dimension ranging from 50-400 nm, in 3 different cell lines. We found that larger particles with a greater compactness were preferentially internalized compared with elongated, high-aspect ratio particles. Uptake kinetics were also found to be more cell-type-dependent than shape-dependent, with specialized endocytosing dendritic cells failing to saturate over 12 h of study. The knowledge gained in the current study furthers our understanding of how particle shape affects cellular uptake and heralds the development of DNA nanotechnologies toward the improvement of current state-of the-art cell-delivery vehicles. PMID- 29756443 TI - Shellac Films as a Natural Dielectric Layer for Enhanced Electron Transport in Polymer Field-Effect Transistors. AB - Shellac, a natural polymer resin obtained from the secretions of lac bugs, was evaluated as a dielectric layer in organic field-effect transistors (OFETs) on the basis of donor (D)-acceptor (A)-type conjugated semiconducting copolymers. The measured dielectric constant and breakdown field of the shellac layer were ~3.4 and 3.0 MV/cm, respectively, comparable with those of a poly(4-vinylphenol) (PVP) film, a commonly used dielectric material. Bottom-gate/top-contact OFETs were fabricated with shellac or PVP as the dielectric layer and one of three different D-A-type semiconducting copolymers as the active layer: poly(cyclopentadithiophene- alt-benzothiadiazole) with p-type characteristics, poly(naphthalene-bis(dicarboximide)- alt-bithiophene) [P(NDI2OD-T2)] with n-type characteristics, and poly(dithienyl-diketopyrrolopyrrole- alt-thienothiophene) [P(DPP2T-TT)] with ambipolar characteristics. The electrical characteristics of the fabricated OFETs were then measured. For all active layers, OFETs with a shellac film as the dielectric layer exhibited a better mobility than those with PVP. For example, the mobility of the OFET with a shellac dielectric and n-type P(NDI2OD-T2) active layer was approximately 2 orders of magnitude greater than that of the corresponding OFET with a PVP insulating layer. When P(DPP2T-TT) served as the active layer, the OFET with shellac as the dielectric exhibited ambipolar characteristics, whereas the corresponding OFET with the PVP dielectric operated only in hole-accumulation mode. The total density of states was analyzed using technology computer-aided design simulations. The results revealed that compared with the OFETs with PVP as the dielectric, the OFETs with shellac as the dielectric had a lower trap-site density at the polymer semiconductor/dielectric interface and much fewer acceptor-like trap sites acting as electron traps. These results demonstrate that shellac is a suitable dielectric material for D-A-type semiconducting copolymer-based OFETs, and the use of shellac as a dielectric layer facilitates electron transport at the interface with D-A-type copolymer channels. PMID- 29756444 TI - Immobilization of an Amphiphilic Molecular Cobalt Catalyst on Carbon Black for Ligand-Assisted Water Oxidation. AB - We have prepared the amphiphilic molecular catalyst [CoIII(LOC18)(pyrr)2]ClO4 (1), where LOC18 is the deprotonated form of N, N'-[4,5-bis(octadecyloxy)-1,2 phenylene]dipicolinamide. Species 1 can be anchored onto a carbon black support to yield the assembly 1@CB, which can catalyze water oxidation at an affordable onset overpotential of 0.32 V, with a current density of 10 mA/cm2 at 0.37 V. Moreover, 1@CB displays TOF = 3850 h-1. A mechanism is proposed based on the experimental and density-functional-theory-calculated data. PMID- 29756445 TI - Multicapillary Gas Chromatography-Temperature Modulated Metal Oxide Semiconductor Sensors Array Detector for Monitoring of Volatile Organic Compounds in Closed Atmosphere Using Gaussian Apodization Factor Analysis. AB - A unique metal oxide semiconductor sensor (MOS) array detector with eight sensors was designed and fabricated in a PTFE chamber as an interface for coupling with multicapillary gas chromatography. This design consists of eight transfer lines with equal length between the multicapillary columns (MCC) and sensors. The deactivated capillary columns were passed through each transfer line and homemade flow splitter to distribute the same gas flow on each sensor. Using the eight ports flow splitter design helps us to equal the length of carrier gas path and flow for each sensor, minimizing the dead volume of the sensor's chamber and increasing chromatographic resolution. In addition to coupling of MCC to MOS array detector and other considerations in hardware design, modulation of MOS temperature was used to increase sensitivity and selectivity, and data analysis was enhanced with adapted Gaussian apodization factor analysis (GAFA) as a multivariate curve resolution algorithm. Continues air sampling and injecting system (CASI) design provides a fast and easily applied method for continues injection of air sample with no additional sample preparation. The analysis cycle time required for each run is less than 300 s. The high sample load and sharp injection with the fast separation by MCC decrease the peak widths and improve detection limits. This homemade customized instrument is an alternative to other time-consuming and expensive technologies for continuous monitoring of outgassing in air samples. PMID- 29756446 TI - Direct Observation of the Local Reaction Environment during the Electrochemical Reduction of CO2. AB - The electrochemical reduction of carbon dioxide is sensitive to electrolyte polarization, which causes gradients in pH and the concentration of carbon dioxide to form near the cathode surface. It is desirable to measure the concentration of reaction-relevant species in the immediate vicinity of the cathode because the intrinsic kinetics of carbon dioxide reduction depend on the composition of the local reaction environment. Meeting this objective has proven difficult because conventional analytical methods only sample products from the bulk electrolyte. In this study, we describe the use of differential electrochemical mass spectrometry to measure the concentration of carbon dioxide and reaction products in the immediate vicinity of the cathode surface. This capability is achieved by coating the electrocatalyst directly onto the pervaporation membrane used to transfer volatile species into the mass spectrometer, thereby enabling species to be sampled directly from the electrode electrolyte interface. This approach has been used to investigate hydrogen evolution and carbon dioxide reduction over Ag and Cu. We find that the measured CO2 reduction activity of Ag agrees well with what is measured by gas chromatography of the effluent from an H-cell operated with the same catalyst and electrolyte. A distinct advantage of our approach is that it enables observation of the depletion of carbon dioxide near the cathode surface due to reaction with hydroxyl anions evolved at the cathode surface, something that cannot be done using conventional analytical techniques. We also demonstrate that the influence of this relatively slow chemical reaction can be minimized by evaluating electrocatalytic activity during a rapid potential sweep, thereby enabling measurement of the intrinsic kinetics. For CO2 reduction over Cu, nine products can be observed simultaneously in real time. A notable finding is that the abundance of aldehydes relative to alcohols near the cathode surface is much higher than that observed in the bulk electrolyte. It is also observed that for increasingly cathodic potentials the relative abundance of ethanol increases at the expense of propionaldehyde. These findings suggest that acetaldehyde is a precursor to ethanol and propionaldehyde and that propionaldehyde is a precursor to n-propanol. PMID- 29756447 TI - Electrochemical Methodologies for the Detection of Pathogens. AB - Bacterial infections remain one of the principal causes of morbidity and mortality worldwide. The number of deaths due to infections is declining every year by only 1% with a forecast of 13 million deaths in 2050. Among the 1400 recognized human pathogens, the majority of infectious diseases is caused by just a few, about 20 pathogens only. While the development of vaccinations and novel antibacterial drugs and treatments are at the forefront of research, and strongly financially supported by policy makers, another manner to limit and control infectious outbreaks is targeting the development and implementation of early warning systems, which indicate qualitatively and quantitatively the presence of a pathogen. As toxin contaminated food and drink are a potential threat to human health and consequently have a significant socioeconomic impact worldwide, the detection of pathogenic bacteria remains not only a big scientific challenge but also a practical problem of enormous significance. Numerous analytical methods, including conventional culturing and staining techniques as well as molecular methods based on polymerase chain reaction amplification and immunological assays, have emerged over the years and are used to identify and quantify pathogenic agents. While being highly sensitive in most cases, these approaches are highly time, labor, and cost consuming, requiring trained personnel to perform the frequently complex assays. A great challenge in this field is therefore to develop rapid, sensitive, specific, and if possible miniaturized devices to validate the presence of pathogens in cost and time efficient manners. Electrochemical sensors are well accepted powerful tools for the detection of disease-related biomarkers and environmental and organic hazards. They have also found widespread interest in the last years for the detection of waterborne and foodborne pathogens due to their label free character and high sensitivity. This Review is focused on the current electrochemical-based microorganism recognition approaches and putting them into context of other sensing devices for pathogens such as culturing the microorganism on agar plates and the polymer chain reaction (PCR) method, able to identify the DNA of the microorganism. Recent breakthroughs will be highlighted, including the utilization of microfluidic devices and immunomagnetic separation for multiple pathogen analysis in a single device. We will conclude with some perspectives and outlooks to better understand shortcomings. Indeed, there is currently no adequate solution that allows the selective and sensitive binding to a specific microorganism, that is fast in detection and screening, cheap to implement, and able to be conceptualized for a wide range of biologically relevant targets. PMID- 29756448 TI - An Approach to Synthesize Chondroitin Sulfate-E (CS-E) Oligosaccharide Precursors. AB - An approach was developed to synthesize chondroitin sulfate-E (CS-E) oligosaccharides by adopting a postglycosylation-transformation strategy: different from all of the traditional approaches, the characteristic groups of CS E were introduced following the assembly of the oligosaccharides. The adjusted strategy rendered an easy chain elongation strategy. All of the elongation steps generated high yields with excellent glycosylation outcomes. An orthogonally protected disaccharide was used as the building block to provide flexibility for the group transformation and derivatization at the N-2 position of the GalNAc residue and the O-1,5 positions of the GlcA residue, thereby providing ready access for the further examination of the structure-activity relationship (SAR) of CS-E molecules. PMID- 29756449 TI - Quantification of Material Fluorescence and Light Scattering Cross Sections Using Ratiometric Bandwidth-Varied Polarized Resonance Synchronous Spectroscopy. AB - Presented herein is the ratiometric bandwidth-varied polarized resonance synchronous spectroscopy (BVPRS2) method for quantification of material optical activity spectra. These include the sample light absorption and scattering cross section spectrum, the scattering depolarization spectrum, and the fluorescence emission cross-section and depolarization spectrum in the wavelength region where the sample both absorbs and emits. This ratiometric BVPRS2 spectroscopic method is a self-contained technique capable of quantitatively decoupling material fluorescence and light scattering signal contribution to its ratiometric BVPRS2 spectra through the linear curve-fitting of the ratiometric BVPRS2 signal as a function of the wavelength bandwidth used in the PRS2 measurements. Example applications of this new spectroscopic method are demonstrated with materials that can be approximated as pure scatterers, simultaneous photon absorbers/emitters, simultaneous photon absorbers/scatterers, and finally simultaneous photon absorbers/scatterers/emitters. Because the only instruments needed for this ratiometric BVPRS2 technique are the conventional UV-vis spectrophotometer and spectrofluorometer, this work should open doors for routine decomposition of material UV-vis extinction spectrum into its absorption and scattering component spectra. The methodology and insights provided in this work should be of broad significance to all chemical research that involves photon/matter interactions. PMID- 29756450 TI - Two C-O Bond Formations on a Carbenic Carbon: Palladium-Catalyzed Coupling of N Tosylhydrazones and Benzo-1,2-quinones To Construct Benzodioxoles. AB - A novel and efficient method for the formation of two C-O bonds on a carbenic carbon is reported. This palladium-catalyzed coupling of N-tosylhydrazones and benzo-1,2-quinones were involved the process of carbonyl ylides generation, aromatization, and intramolecular nucleophilic addition, delivering various useful benzodioxoles in high yields. PMID- 29756451 TI - Cubic Sodium Cobalt Metaphosphate [NaCo(PO3)3] as a Cathode Material for Sodium Ion Batteries. AB - Cubic-framework sodium cobalt-based metaphosphate NaCo(PO3)3 was recently demonstrated to be an attractive Na+ cationic conductor. It can be potentially used in the next-generation rechargeable Na ion batteries. The crystal structure and electrical conductivity were studied and found to have a three-dimensional framework with interconnecting tunnels for Na+ migration ( J. Solid State Electrochem. , 2016 , 20 , 1241 ). This inspired us to study the electrochemical (de)intercalation behavior of Na+ in the NaCo(PO3)3 assuming a cubic Pa3 framework. Herein, synergizing experimental and computational tools, we present the first report on the electrochemical activity and Na+ diffusion pathway analysis of cubic NaCo(PO3)3 prepared via conventional solid-state route. The electrochemical analyses reveal NaCo(PO3)3 to be an active sodium insertion material with well-defined reversible Co3+/Co2+ redox activity centered at 3.3 V (vs Na/Na+). Involving a solid-solution redox mechanism, close to 0.7 Na+ per formula unit can be reversibly extracted. This experimental finding is augmented with bond valence site energy (BVSE) modeling to clarify Na+ migration in cubic NaCo(PO3)3. BVSE analyses suggest feasible Na+ migration with moderate energy barrier of 0.68 eV. Cubic NaCo(PO3)3 forms a 3.3 V sodium insertion material. PMID- 29756452 TI - gamma-Carboline Synthesis by Heterocyclization of TosMIC Derivatives. AB - A new method for the synthesis of gamma-carbolines by a heterocyclization that involves alpha-indol-2-ylmethyl TosMIC derivatives and different electrophiles has been developed. This methodology has been successfully applied to the synthesis of several highly substituted gamma-carbolines. PMID- 29756453 TI - Bacterial Membrane Depolarization-Linked Fuel Cell Potential Burst as Signal for Selective Detection of Alcohol. AB - The biosensing application of microbial fuel cell (MFC) is hampered by its long response time, poor selectivity, and technical difficulty in developing portable devices. Herein, a novel signal form for rapid detection of ethanol was generated in a photosynthetic MFC (PMFC). First, a dual chambered (100 mL each) PMFC was fabricated by using cyanobacteria-based anode and abiotic cathode, and its performance was examined for detection of alcohols. A graphene-based nanobiocomposite matrix was layered over graphite anode to support cyanobacterial biofilm growth and to facilitate electron transfer. Injection of alcohols into the anodic chamber caused a transient potential burst of the PMFC within 60 s (load 1000 Omega), and the magnitude of potential could be correlated to the ethanol concentrations in the range 0.001-20% with a limit of detection (LOD) of 0.13% ( R2 = 0.96). The device exhibited higher selectivity toward ethanol than methanol as discerned from the corresponding cell-alcohol interaction constant ( Ki) of 780 and 1250 mM. The concept was then translated to a paper-based PMFC (p PMFC) (size ~20 cm2) wherein, the cells were merely immobilized over the anode. The device with a shelf life of ~3 months detected ethanol within 10 s with a dynamic range of 0.005-10% and LOD of 0.02% ( R2 = 0.99). The fast response time was attributed to the higher wettability of ethanol on the immobilized cell surface as validated by the contact angle data. Alcohols degraded the cell membrane on the order of ethanol > methanol, enhanced the redox current of the membrane-bound electron carrier proteins, and pushed the anodic band gap toward more negative value. The consequence was the potential burst, the magnitude of which was correlated to the ethanol concentrations. This novel approach has a great application potential for selective, sensitive, rapid, and portable detection of ethanol. PMID- 29756454 TI - Short Communication: Discordance in Drug Resistance Mutations Between Blood Plasma and Semen or Rectal Secretions Among Newly Diagnosed HIV-1-Infected Thai Men Who Have Sex with Men. AB - Human immunodeficiency virus 1 (HIV-1) infection is most commonly transmitted by sexual contact across mucosal surfaces. Information on concordance in drug resistance profile between blood plasma and anogenital compartments in resource limited settings is limited. We aimed to determine discordances in genotypic drug resistance-associated mutations (DRAMs) between blood plasma and semen or rectal secretions among newly diagnosed, antiretroviral therapy (ART)-naive, HIV-1 infected Thai men who have sex with men (MSM). Blood plasma, semen, and rectal secretions of HIV-1-infected Thai MSM enrolled from the Test and Treat cohort were tested for genotypic mutations in the reverse transcriptase and protease genes. Seven participants with baseline DRAMs in blood plasma were included in this analysis. In anogenital samples, HIV-1 RNA could be fully amplified for DRAMs assessment in semen from three participants and in rectal secretions from four participants. DRAMs were identified in semen from two of three participants and in rectal secretions from four of four participants. Three participants had DRAMs in anogenital compartments that were not detected in blood plasma-one had DRAMs in semen that was not detected in blood plasma (I54FI) and two had DRAMs in rectal secretions that was not detected in blood plasma (I47IM; K70N, L74I, Y115F, M184V, K103N, V108I, and H221Y). Discordance in DRAMs between blood plasma and anogenital compartments is not uncommon among newly diagnosed, ART-naive, HIV 1-infected Thai MSM. Monitoring of drug-resistant virus in these vector compartments is warranted particularly as pre-exposure prophylaxis and treatment as prevention are increasingly used as the mainstay strategies to end the AIDS epidemic. PMID- 29756455 TI - Characterization of the Transmitted Virus in an Ongoing HIV-1 Epidemic Driven by Injecting Drug Use. AB - Understanding features of the HIV-1 transmission process has the potential to inform biological interventions for prevention. We have examined the transmitted virus in a cohort of people who inject drugs and who are at risk of HIV-1 infection through blood contamination when injecting in a group. This study focused on seven newly infected participants in St. Petersburg, Russia, who were in acute or early infection. We used end-point dilution polymerase chain reaction to amplify single viral genomes to assess the complexity of the transmitted virus. We also used deep sequencing to further assess the complexity of the virus. We interpret the results as indicating that a single viral variant was transmitted in each case, consistent with a model where the exposure to virus during transmission was limited. We also looked at phenotypic properties of the viral Env protein in isolates from acute and chronic infection. Although differences were noted, there was no consistent pattern that distinguished the transmitted variants. Similarly, despite the reduced genetic heterogeneity of the more recent subtype A HIV-1 epidemic in St. Petersburg, we did not see reduced variance in the neutralization properties compared to isolates from the more mature subtype C HIV-1 epidemic. Finally, in looking at members of injecting groups related to the acute HIV-1 infection/early subjects, we found examples of sequence linkage consistent with ongoing and rapid spread of HIV-1 in these groups. These studies emphasize the dynamic nature of this epidemic and reinforce the idea that improved prevention methods are needed. PMID- 29756456 TI - No Time to Delay! Fiebig Stages and Referral in Acute HIV infection: Seattle Primary Infection Program Experience. AB - There has been increasing recognition of the importance of diagnosing individuals during the earliest stages of human immunodeficiency virus (HIV) infection. Sera from individuals referred to a primary HIV infection research program were screened using the IgG-sensitive Vironostika HIV-1 Microelisa System, IgG/IgM sensitive GS HIV-1/HIV-2 Plus O antibody enzyme immunoassay (EIA), or Abbott ARCHITECT HIV antigen (Ag)/antibody (Ab) Combo assay and confirmed by the Bio-Rad Multispot and Western blot. A subset of participants was co-enrolled in a study designed to compare the ability of point-of-care tests to detect early infection. We calculated time within primary infection laboratory stages using actual observed transitions and with an expectation-maximization algorithm. Three hundred and sixty participants contributed data to this analysis. Of 123 persons referred with EIA-negative/RNA-positive test results (Fiebig stage I-II) or for concern for symptoms, 24 (20%) were still in stages I-II, and 99 (80%) were in stages III or later at their screening visit. Participants were estimated to spend a median of 13.5 days in stages I and II, 2.3 days in stage III, and 7.8 days in stage IV. OraQuick performed on oral fluids detected 53% of 17 participants in stage V. The durations of stages we observed are consistent with previous publications. Most persons referred for research no longer had acute infection at their first visit. Programs wishing to identify persons in the very earliest stages of infection need to expedite referrals or develop targeted screening programs. PMID- 29756458 TI - Evaluation of the effects of adding vibrotactile feedback to myoelectric prosthesis users on performance and visual attention in a dual-task paradigm. AB - OBJECTIVE: To evaluate the effects of adding vibrotactile feedback to myoelectric prosthesis users on the performance time and visual attention in a dual-task paradigm. DESIGN: A repeated-measures design with a counterbalanced order of two conditions. SETTING: Laboratory setting. SUBJECTS: Transradial amputees using a myoelectric prosthesis with normal or corrected eyesight ( N = 12, median age = 65 +/- 13 years). Exclusion criteria were orthopedic or neurologic problems. INTERVENTIONS: Subjects performed grasping tasks with their prosthesis, while controlling a virtual car on a road with their intact hand. The dual task was performed twice: with and without vibrotactile feedback. MAIN MEASURES: Performance time of each of the grasping tasks and gaze behavior, measured by the number of times the subjects shifted their gaze toward their hand, the relative time they applied their attention to the screen, and percentage of error in the secondary task. RESULTS: The mean performance time was significantly shorter ( P = 0.024) when using vibrotactile feedback (93.2 +/- 9.6 seconds) compared with the performance time measured when vibrotactile feedback was not available (107.8 +/- 20.3 seconds). No significant differences were found between the two conditions in the number of times the gaze shifted from the screen to the hand, in the time the subjects applied their attention to the screen, and in the time the virtual car was off-road, as a percentage of the total game time (51.4 +/- 15.7 and 50.2 +/- 19.5, respectively). CONCLUSION: Adding vibrotactile feedback improved performance time during grasping in a dual-task paradigm. Prosthesis users may use vibrotactile feedback to perform better during daily tasks, when multiple cognitive demands are present. PMID- 29756457 TI - Descriptive Analysis of Associated Factors for Urgent Versus Nonurgent Inpatient Spine Transfers to a Tertiary Care Hospital. AB - Patients with spine-associated symptoms are transferred regularly to higher levels of care for operative intervention. It is unclear what factors lead to the transfer of patients with spine pathology to level I care facilities, and which transfers are indicated. All patients with isolated spinal pathology who were transferred from 2011 to 2015 were reviewed. Patients were divided into urgent transfers, defined as anyone who required operative intervention, and nonurgent transfers. Two hundred twenty-seven patients were transferred for isolated spinal pathology over 51 months; 109 (48.0%) patients required urgent intervention and 118 (52.0%) patients required nonurgent care. No significant differences were found between groups in terms of private insurance, age, sex, race, or Charlson comorbidity index. The urgent group was less likely to have a traumatic chief complaint (57.8% vs 78.0%, P = .001). More than half of all spine patients who were transferred to a tertiary care center required minimal intervention. PMID- 29756459 TI - The effects of respiratory muscle training on peak cough flow in patients with Parkinson's disease: a randomized controlled study. AB - OBJECTIVE: To compare the effects of an inspiratory versus and expiratory muscle training program on voluntary and reflex peak cough flow in patients with Parkinson disease. DESIGN: A randomized controlled study. SETTING: Home-based training program. PARTICIPANTS: In all, 40 participants with diagnosis of Parkinson's disease were initially recruited in the study and randomly allocated to three study groups. Of them, 31 participants completed the study protocol (control group, n = 10; inspiratory training group, n = 11; and expiratory training group, n = 10) Intervention: The inspiratory and expiratory group performed a home-based inspiratory and expiratory muscle-training program, respectively (five sets of five repetitions). Both groups trained six times a week for two months using a progressively increased resistance. The control group performed expiratory muscle training using the same protocol and a fixed resistance. MAIN MEASURES: Spirometric indices, maximum inspiratory pressure, maximum expiratory pressure, and peak cough flow during voluntary and reflex cough were assessed before and at two months after training. RESULTS: The magnitude of increase in maximum expiratory pressure ( d = 1.40) and voluntary peak cough flow ( d = 0.89) was greater for the expiratory muscle-training group in comparison to the control group. Reflex peak cough flow had a moderate effect ( d = 0.27) in the expiratory group in comparison to the control group. Slow vital capacity ( d = 0.13) and forced vital capacity ( d = 0.02) had trivial effects in the expiratory versus the control group. CONCLUSIONS: Two months of expiratory muscle-training program was more beneficial than inspiratory muscle training program for improving maximum expiratory pressure and voluntary peak cough flow in patients with Parkinson's disease. PMID- 29756460 TI - Inhaled Fasudil Lacks Pulmonary Selectivity in Thromboxane-Induced Acute Pulmonary Hypertension in Newborn Lambs. AB - INTRODUCTION: Pulmonary hypertension (PH) is a potentially deadly disease for infants and adults with few existing medical interventions and no cure. In PH, increased blood pressure in the pulmonary artery eventually leads to heart failure. Fasudil, an antagonist of Rho-kinase, causes vasodilation leading to decreased systemic artery pressure and pulmonary artery pressure (PAP). This study compared the effects of fasudil administered as either an intravenous infusion or inhaled aerosol in newborn lambs. HYPOTHESIS: Inhaled aerosol delivery of fasudil will provide selective pulmonary vasodilation when compared with intravenous administration. METHODS: Newborn lambs (~11 days) were surgically instrumented and mechanically ventilated under anesthesia. A pulmonary artery catheter and ultrasonic flow probe were inserted to measure hemodynamics. Acute PH was pharmaceutically induced via continuous intravenous infusion of thromboxane. After achieving a 2- to 3-fold elevation of PAP, fasudil was administered either as intravenous infusion (2.5 mg/kg) or inhaled aerosol (100 mg of fasudil in 2 mL of saline). Changes in PAP, mean systemic arterial pressure (MABP), pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), cardiac output, and heart rate were assessed. In addition, plasma concentrations of fasudil were measured. RESULTS: Both routes of fasudil delivery produced significant decreases in PAP and PVR but also produced similar decreases in MABP and SVR. The Cmax for intravenous fasudil was greater than that for inhaled fasudil. CONCLUSIONS: These results suggest inhaled fasudil lacks pulmonary selectivity when compared with intravenous fasudil. PMID- 29756461 TI - Polyphenolic Content, Antioxidant and Antimicrobial Activities of Vernonia mespilifolia Less. Used in Folk Medicine in the Eastern Cape Province, South Africa. AB - Vernonia mespilifolia Less. is a shrub of the Asteraceae family used in the South African traditional medicine system for the management of weight loss, hypertension, and heartwater disease. There is a need for scientific evaluation to validate its ethnomedicinal usage. In vitro assays were conducted to evaluate the polyphenolic content, antioxidant and antimicrobial properties of different solvent extracts (acetone, aqueous, and ethanol) of the whole plant of Vernonia mespilifolia spectrophotometric and agar dilution techniques, respectively. The result revealed varying amounts of polyphenolics in the different solvent extracts corresponding to the antioxidant activities. Also, only the acetone and ethanol extracts inhibited the growth of the selected bacteria and fungi. These findings reveal that the extracts have strong bioactive compounds and hence support its ethnomedicinal application. PMID- 29756462 TI - LGI1 antibody encephalitis and psychosis. AB - OBJECTIVE:: To describe a case of leucine-rich, glioma inactivated 1 antibody encephalitis presenting with psychosis. METHODS:: Case report. RESULTS:: A young man with leucine-rich, glioma inactivated 1-antibody encephalitis initially presented with acute psychotic symptoms, short-term memory loss and faciobrachial dystonic seizures. Magnetic resonance imaging revealed hippocampal lesions. Electroencephalography revealed frontotemporal slowing of background activity. CONCLUSION:: Increased awareness of leucine-rich, glioma inactivated 1-antibody encephalitis may promote early recognition and treatment. PMID- 29756463 TI - Nanodrug delivery platform for glucocorticoid use in skeletal muscle injury. AB - Glucocorticoids are utilized for their anti-inflammatory properties in the skeletal muscle and arthritis. However, the major drawback of use of glucocorticoids is that it leads to senescence and toxicity. Therefore, based on the idea that decreasing particle size allows for increased surface area and bioavailability of the drug, in the present study, we hypothesized that nanodelivery of dexamethasone will offer increased efficacy and decreased toxicity. The dexamethasone-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared using nanoprecipitation method. The morphological characteristics of the nanoparticles were studied under scanning electron microscope. The particle size of nanoparticles was 217.5 +/- 19.99 nm with polydispersity index of 0.14 +/- 0.07. The nanoparticles encapsulation efficiency was 34.57% +/- 1.99% with in vitro drug release profile exhibiting a sustained release pattern over 10 days. We identified improved skeletal muscle myoblast performance with improved closure of the wound along with increased cell viability at 10 nmol/L nano-dexamethasone-PLGA. However, dexamethasone solution (1 MUmol/L) was injurious to cells because the migration efficiency was decreased. In addition, the use of dexamethasone nanoparticles decreased lipopolysaccharide-induced lactate dehydrogenase release compared with dexamethasone solution. Taken together, the present study clearly demonstrates that delivery of PLGA-dexamethasone nanoparticles to the skeletal muscle cells is beneficial for treating inflammation and skeletal muscle function. PMID- 29756464 TI - Glucose Acutely Reduces Cytosolic and Mitochondrial H2O2 in Rat Pancreatic Beta Cells. AB - AIMS: Whether H2O2 contributes to the glucose-dependent stimulation of insulin secretion (GSIS) by pancreatic beta cells is highly controversial. We used two H2O2-sensitive probes, roGFP2-Orp1 (reduction/oxidation-sensitive enhanced green fluorescent protein fused to oxidant receptor peroxidase 1) and HyPer (hydrogen peroxide sensor) with its pH-control SypHer, to test the acute effects of glucose, monomethyl succinate, leucine with glutamine, and alpha-ketoisocaproate on beta cell cytosolic and mitochondrial H2O2 concentrations. We then tested the effects of low H2O2 and menadione concentrations on insulin secretion. RESULTS: RoGFP2-Orp1 was more sensitive than HyPer to H2O2 (response at 2-5 vs. 10 MUM) and less pH-sensitive. Under control conditions, stimulation with glucose reduced mitochondrial roGFP2-Orp1 oxidation without affecting cytosolic roGFP2-Orp1 and HyPer fluorescence ratios, except for the pH-dependent effects on HyPer. However, stimulation with glucose decreased the oxidation of both cytosolic probes by 15 MUM exogenous H2O2. The glucose effects were not affected by overexpression of catalase, mitochondrial catalase, or superoxide dismutase 1 and 2. They followed the increase in NAD(P)H autofluorescence, were maximal at 5 mM glucose in the cytosol and 10 mM glucose in the mitochondria, and were partly mimicked by the other nutrients. Exogenous H2O2 (1-15 MUM) did not affect insulin secretion. By contrast, menadione (1-5 MUM) did not increase basal insulin secretion but reduced the stimulation of insulin secretion by 20 mM glucose. INNOVATION: Subcellular changes in beta cell H2O2 levels are better monitored with roGFP2 Orp1 than HyPer/SypHer. Nutrients acutely lower mitochondrial H2O2 levels in beta cells and promote degradation of exogenously supplied H2O2 in both cytosolic and mitochondrial compartments. CONCLUSION: The GSIS occurs independently of a detectable increase in beta cell cytosolic or mitochondrial H2O2 levels. Antioxid. Redox Signal. 00, 000-000. PMID- 29756465 TI - Hand-Use-at-Home Questionnaire: validity and reliability in children with neonatal brachial plexus palsy or unilateral cerebral palsy. AB - OBJECTIVE: To investigate construct validity and test-retest reliability of the parent-rated Hand-Use-at-Home questionnaire (HUH) in children with neonatal brachial plexus palsy or unilateral cerebral palsy. DESIGN AND SUBJECTS: For this cross-sectional study, children with neonatal brachial plexus palsy or unilateral cerebral palsy, aged 3-10 years, were eligible. MAIN MEASURES: The HUH, Pediatric Outcome Data Collection Instrument Upper Extremity Scale (neonatal brachial plexus palsy only), and Children's Hand-Use Experience Questionnaire (unilateral cerebral palsy only) were completed. The HUH was completed twice in subgroups of both diagnoses. Lesion-extent (indication of involved nerve rootlets in neonatal brachial plexus palsy as confirmed during clinical observation and/or nerve surgery) and Manual Ability Classification System levels (unilateral cerebral palsy) were obtained from the medical records. Spearman correlation coefficients between the HUH and all clinical variables, agreement, standard error of measurement, smallest detectable change and intra-class correlation were calculated. RESULTS: A total of 260 patients participated (neonatal brachial plexus palsy: 181), of which 56 completed the second HUH (neonatal brachial plexus palsy: 16). Median age was 6.9 years for children with neonatal brachial plexus palsy, 116 had C5-C6 lesions. Median age for children with unilateral cerebral palsy was 6.4 years, 33 had Manual Ability Classification System Level II. The HUH correlated moderately with lesion-extent ( rs =-0.5), Pediatric Outcome Data Collection Instrument Upper Extremity Scale ( rs = 0.6) and Children's Hand-Use Experience Questionnaire ( rs = 0.5) but weakly with Manual Ability Classification System levels ( rs = -0.4). Test-retest reliability was excellent (intra-class correlation2,1 = 0.89, standard error of measurement = 0.599 and smallest detectable change = 1.66 logits) and agreement was good (mean difference HUH1 - HUH2 = 0.06 logits). CONCLUSION: The HUH showed good construct validity and test-retest reliability in children with neonatal brachial plexus palsy or unilateral cerebral palsy. PMID- 29756466 TI - Simultaneous In Situ Monitoring of Trimethoxysilane Hydrolysis Reactions Using Raman, Infrared, and Nuclear Magnetic Resonance (NMR) Spectroscopy Aided by Chemometrics and Ab Initio Calculations. AB - Sol-gels are found in many different scientific fields and have very broad applications. They are often prepared by the hydrolysis and condensation of alkoxysilanes such as trimethoxysilanes, which are commonly used as precursors in the preparation of silsequioxanes via the sol-gel process. The reaction rates of such reactions are influenced by a wide range of experimental factors such as temperature, pH, catalyst, etc. In this study, we combined multiple in situ spectroscopic techniques to monitor the hydrolysis and partial condensation reactions of methyltrimethoxysilane and phenyltrimethoxysilane. A rich set of kinetics information on intermediate species of the hydrolysis reactions were obtained and used for kinetics modeling. Raman and nuclear magnetic resonance (NMR) spectroscopy provided the most information about hydrolysis and NMR provided the most information about condensation. A quantitative method based on Raman spectra to quantify the various transient intermediate hydrolysis products was developed using NMR as the primary method, which can be deployed in the field where it is impractical to carry out NMR measurements. PMID- 29756468 TI - Estimating Electroencephalograph Network Parameters Using Mutual Information. AB - Statistical parameters that measure strength, integration, and segregation of a multichannel electroencephalograph (EEG) network are evaluated using a similarity measure based on mutual information (MI) between the measured channel data. Compared with the unsigned linear correlation coefficient, MI is more robust to volume conduction and is applicable to nonlinear data. The statistical parameters estimated are node strength, average path length, and clustering coefficient. These parameters provide valuable insights into the brain network of the subject. MI is evaluated using a recently developed procedure based on the Gaussian copula. It is a computationally efficient procedure since estimation of MI is carried out analytically. This procedure is illustrated here for a 30-channel random noise and EEG network. The results are compared with those obtained using the linear correlation coefficient. The results show improvements by using MI to estimate the network properties. PMID- 29756467 TI - The language we use - the effect of writing mental health care plans in the first person. AB - OBJECTIVE: This study describes the impact of Motivational Aftercare Planning (MAP) - an intervention to increase consumer/clinician collaboration on the content of mental health recovery plans. The intervention focussed on enhancing existing discharge processes in psychiatric inpatient wards and supporting nursing staff in using motivational interviewing techniques to facilitate the completion of these plans. METHODS: We conducted a qualitative thematic content analysis of the recovery plans completed throughout the study ( n = 110). Chi squared tests were then used to compare the occurrence of themes and content identified in recovery plans pre and post the intervention ( n = 55). RESULTS: The thematic content of the recovery plans shifted in focus following the intervention, with a change from third to first person language. Those completed prior to the intervention generally mentioned: decreasing symptoms of mental illness; acceptance of the illness; achieving clinical stability; risk management and treatment compliance. The recovery plans completed after the intervention focussed on: general wellness; participate in meaningful activities; community life; social roles and connections with others. CONCLUSIONS: This study demonstrated that a simple time-limited, facilitated intervention resulted in a change of thematic content in recovery plans. The use of these plans and its effect on care planning will need further evaluation. PMID- 29756470 TI - Improving dementia literacy among Chinese Australians using YouTube. PMID- 29756471 TI - Medication Regimen Complexity Measured by MRCI: A Systematic Review to Identify Health Outcomes. AB - OBJECTIVE: To perform a systematic review to identify health outcomes related to medication regimen complexity as measured by the Medication Regimen Complexity Index (MRCI) instrument. DATA SOURCES: Cochrane Library, LILACS, PubMed, Scopus, EMBASE, Open Thesis, and Web of Science were searched from January 1, 2004, until April 02, 2018, using the following search terms: outcome assessment, drug therapy, and Medication Regimen Complexity Index and their synonyms in different combinations. STUDY SELECTION AND DATA EXTRACTION: Studies that used the MRCI instrument to measure medication regimen complexity and related it to clinical, humanistic, and/or economic outcomes were evaluated. Two reviewers independently carried out the analysis of the titles, abstracts, and complete texts according to the eligibility criteria, performed data extraction, and evaluated study quality. DATA SYNTHESIS: A total of 23 studies met the inclusion criteria; 18 health outcomes related to medication regimen complexity were found. The health outcomes most influenced by medication regimen complexity were hospital readmission, medication adherence, hospitalization, adverse drug events, and emergency sector visit. Only one study related medication regimen complexity with humanistic outcomes, and no study related medication regimen complexity to economic outcomes. Most of the studies were of good methodological quality. Relevance to Patient Care and Clinical Practice: Health care professionals should pay attention to medication regimen complexity of the patients because this may influence health outcomes. CONCLUSION: This study identified some health outcomes that may be influenced by medication regimen complexity: hospitalization, hospital readmission, and medication adherence were more prevalent, showing a significant association between MRCI increase and these health outcomes. PMID- 29756473 TI - Reticulon 3 regulates very low density lipoprotein secretion by controlling very low density lipoprotein transport vesicle biogenesis. AB - Secretion of very low density lipoprotein (VLDL) by the liver is an important physiological process; however, the rate of VLDL secretion is determined by its transport from the endoplasmic reticulum (ER) to the Golgi. This transport event is facilitated by a specialized ER-derived vesicle, the VLDL transport vesicle (VTV). We have reported earlier a detailed VTV proteome, which revealed that reticulon 3 (RTN3) is uniquely present in the VTV. Our immunoblotting and electron microscopic data demonstrate that RTN3 is enriched in the VTV; however, other ER-derived vesicles do not contain RTN3. Co-immunoprecipitation data coupled with confocal microscopic analyses strongly suggest that RTN3 interacts with VLDL core protein, apoB100, at the ER level. Our data show that either blocking of RTN3 using specific antibodies or RTN3 knockdown resulted in significant reduction in VTV biogenesis from hepatic ER membranes. Additionally, VLDL secretion from hepatocytes was significantly decreased when RTN3 was silenced by RTN3 siRNA. We conclude that RTN3 regulates VLDL secretion by controlling VTV-mediated ER-to-Golgi transport of nascent VLDL. PMID- 29756472 TI - Diabetes Control: Is Vinegar a Promising Candidate to Help Achieve Targets? AB - BACKGROUND: Renewed interest in vinegar as a glucose-lowering agent led to several small trials in the recent past. However, none of the trials could independently provide sufficient evidence. OBJECTIVES: Our review aimed to obtain reliable estimates of effects of vinegar on short-term and long-term blood glucose control. METHODS: Large bibliographic databases were searched from inception to date of search without language and publication date restrictions. All clinical trials evaluating effect of vinegar on diabetes mellitus patients were eligible. Two authors independently extracted data on fasting and 2-hour postprandial blood glucose, insulin, and HbA1c levels at the various time points. MS Excel, SAS(r) v9.3, and RevMan v5.3 were used for data analysis. RESULTS: Small significant reduction in mean HbA1c was observed after 8 to 12 weeks of vinegar administration: -0.39% (95% confidence interval = -0.59, -0.18; I2 = 0%). Other long-term outcomes favored vinegar but were not significant. Short-term outcomes showed significantly lower pooled mean difference in glucose levels at 30 minutes in the vinegar group. Readings at 60, 90, and 120 minutes were lower in the vinegar group but not statistically significant. Adverse effects profile also favored the vinegar group. CONCLUSIONS: It is worthwhile to carry out carefully planned large trails to determine the efficacy and effectiveness of vinegar as an adjunct treatment modality. PMID- 29756474 TI - Henna ( Lawsonia inermis) as an Inexpensive Method to Prevent Decubitus Ulcers in Critical Care Units: A Randomized Clinical Trial. AB - BACKGROUND: Henna has been used to combat various diseases and pathological conditions of the skin. This study aimed to determine the cooling and protecting effects of henna on prevention of decubitus ulcers in critical care units. METHOD: This is a randomized clinical trial. It was conducted on 80 patients hospitalized in intensive care units. Patients were randomly allocated into 2 groups of control and intervention (n = 40) by blocking method. For the intervention group, along with the standard prevention cares for decubitus ulcers, henna was applied with 15 cm extent on the patients' sacrum. RESULTS: At the end of the study, 1 patient in the intervention group (2.7% male) and 6 patients in the control group (14.29% male, 2.85% female) had developed decubitus ulcers; this difference was significant ( P = .001). CONCLUSION: For every patient at risk of developing decubitus ulcers, application of henna as a preventive measure is recommended. PMID- 29756475 TI - National Survey of Pediatric Care Providers: Assessing Time and Impact of Coding and Documentation in Physician Practice. AB - BACKGROUND: Documentation and billing/coding are essential to medical practice. Physicians spend significant time documenting to meet coding and medicolegal requirements, potentially reducing time for patient care and learning. We sought to assess time spent charting in pediatric practice and provider understanding and comfort level regarding billing/coding. METHODS: An anonymous web-based survey was emailed to members of American Academy of Pediatrics Section of Pediatric Trainees practicing in the United States. RESULTS: A total of 601 trainees responded to the survey. Thirty-seven percent of trainees spent more than half of patient encounter time documenting in outpatient settings while 62% ( P < .01) in inpatient settings. There was a positive correlation between trainees' apprehension about documentation and reporting increased stress due to documentation ( r = 0.32, P < 0.001). Sixty-two percent respondents had no prior training of billing/coding, and >70% feel necessity of including billing/coding in the medical curriculum ( P < 0.0001). CONCLUSIONS: Our study highlights increasing burden of documentation in practice. Majority of pediatric trainees feel the need to including billing/coding skills as a part of medical curriculum. PMID- 29756476 TI - Ginger Extract and [6]-Gingerol Inhibit Contraction of Rat Entire Small Intestine. AB - This study aims to investigate the effect of oral administration and the direct action of ginger extract or [6]-gingerol on small intestinal contractility. The direct effect of 10 minutes preincubation of ginger ethanolic extract (10, 100 and 300 MUg/mL) or [6]-gingerol (1, 30, and 100 MUM) on 0.01 to 30 MUM ACh induced contractions of all parts of the small intestine isolated from normal rats was investigated using the organ bath technique. For in vivo study, the rats were orally administered with extract (10, 20, and 100 mg/kg/d) or [6]-gingerol (2 mg/kg/d) for 7 days, followed by determining the contractile responses to ACh of rat isolated duodenum, jejunum, and ileum and their histology were assessed. Direct application of the extract or [6]-gingerol attenuated ACh-induced contractions in each small intestinal segment, Emax was reduced by 40% to 80%, while EC50 increased 3- to 8-fold from control. Similarly, in the in vivo study ACh-induced contractions were reduced in all parts of the small intestine isolated from rats orally treated with ginger extract (20 and 100 mg/kg/d) or [6] gingerol (2 mg/kg/d). Emax decreased 15% to 30%, while EC50 increased 1- to 3 fold compared to control. No discernable changes in the histology of intestinal segments were detectable. Thus, the results support the clinical application of ginger for disorders of gastrointestinal motility. PMID- 29756478 TI - Outcome of serious violent offenders with psychotic illness and cognitive disorder dealt with by the New South Wales criminal justice system. AB - BACKGROUND: The few studies of the recidivism by people with psychotic illness and cognitive disorder who are convicted of serious violent offences and sentenced by the courts. METHOD: Re-imprisonment data were obtained for 661 individuals convicted of serious non-lethal violent offences in the District Courts of New South Wales in the years 2006 and 2007. Rates of re-imprisonment of offenders known to psychotic illness or cognitive disorder (intellectual disability or acquired brain injury) was compared to those not known to have those conditions. A survival analysis was performed controlling for the effects of male sex, having a report by a mental health professional at the initial sentencing and receiving a custodial sentence for the initial offence. RESULTS: There was no significant difference in the overall likelihood of further imprisonment between those with psychotic disorder (53.7%), those with cognitive disorder (50.7%) or among those with neither condition (45.2%; chi2 = 2.22, p = 0.33). A Kaplan-Meier analysis found that people with a psychotic disorder were returned to custody earlier than those not known to have psychosis ( p = 0.002). People with psychosis spent a non-significantly greater time in custody (mean 477 days) than those with a cognitive disorder (mean 334 days) or among those with neither condition (mean 348 days) (Mann-Whitney Z-score = 1.5, eta2 = 0.003, p value = 0.13). For the entire sample of 661 offenders, those who received non custodial sentences for their initial offences had a lower likelihood of spending any time in custody in the follow-up period. CONCLUSION: The likelihood of returning to custody of sentenced violent offenders with psychotic illness or cognitive disorder is higher than that of released forensic patients in New South Wales followed up for a similar period. The results suggest an opportunity to improve the outcome of offenders with psychosis by better treatment and rehabilitation. PMID- 29756477 TI - Anti-Hyperglycemic and Anti-Inflammatory Activities of Polyphenolic-Rich Extract of Syzygium cumini Linn Leaves in Alloxan-Induced Diabetic Rats. AB - In this study, anti-hyperglycemic and anti-inflammatory activities of polyphenolic-rich extract of Syzygium cumini leaves in alloxan-induced diabetic rats were determined. Diabetes was induced by a single intraperitoneal injection of alloxan (150 mg/kg body weight) in female Wistar rats. The rats were orally administered with 400 mg/kg free phenol, 400 mg/kg bound phenol, and 5 mg/kg metformin, respectively. On the 14th day of oral administration, the animals were sacrificed, anti-hyperglycemic and anti-inflammatory were assessed. Fasting blood glucose and glycated hemoglobin levels; homeostasis model assessment-insulin resistance scores, lipid peroxidation concentration, glucose-6-phosphatase activity, and all concentrations of anti-inflammatory studied in alloxan-induced diabetic rats were significantly ( P < .05) reduced with the administration of polyphenolic-rich extract of Syzygium cumini leaves. Also there was significant ( P < .05) increase in glycogen and insulin concentrations, pancreatic beta-cell scores, antioxidant enzymes and hexokinase activities, as well as glucose transporter levels in diabetic animals administered with polyphenolic-rich extract of S cumini leaves. The results indicate that S cumini leaves possess anti-hyperglycemic and anti-inflammatory activities. PMID- 29756479 TI - Representation of people with intellectual disability in Australian mental health policy. PMID- 29756481 TI - Biofeedback interventions for individuals with cerebral palsy: a systematic review. AB - PURPOSE: The purpose of this study is to evaluate the quality of evidence of biofeedback interventions aimed at improving motor activities in people with Cerebral Palsy (CP). Second, to describe the relationship between intervention outcomes and biofeedback characteristics. METHODS: Eight databases were searched for rehabilitation interventions that provided external feedback and addressed motor activities. Two reviewers independently assessed and extracted data. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to evaluate quality of evidence for outcome measures related to two International Classification of Functioning, Disability and Health (ICF) chapters. RESULTS: Fifty-seven studies were included. There were 53 measures related Activities and Participation and 39 measures related to Body Functions. Strength of evidence was "Positive, Very-Low" due to the high proportion of non controlled studies and heterogeneity of measures. Overall, 79% of studies and 63% of measures showed improvement post-intervention. Counter to motor learning theory recommendations, most studies provided feedback consistently and concurrently throughout the intervention regardless of the individual's desire or progress. CONCLUSION: Heterogeneous interventions and poor study design limit the strength of biofeedback evidence. A thoughtful biofeedback paradigm and standardized outcome toolbox can strengthen the confidence in the effect of biofeedback interventions for improving motor rehabilitation for people with CP. Implications for Rehabilitation Biofeedback can improve motor outcomes for people with Cerebral Palsy. If given too frequently, biofeedback may prevent the client from learning autonomously. Use consistent and concurrent feedback to improve simple/specific motor activities. Use terminal feedback and client-directed feedback to improve more complex/general motor activities. PMID- 29756480 TI - Tracheoesophageal Prosthesis Use Is Associated With Improved Overall Quality of Life in Veterans With Laryngeal Cancer. AB - OBJECTIVES: Veterans have an increased risk of laryngeal cancer, yet their oncologic and functional outcomes remain understudied. We sought to determine the longitudinal impact of tracheoesophageal puncture and voice prosthesis on quality of-life measures in veterans following total laryngectomy (TL). METHODS: We performed a cross-sectional analysis of TL patients (n = 68) treated at the Michael E. DeBakey Veterans Affairs Medical Center using the Voice Handicap Index (VHI), MD Anderson Dysphagia Index (MDADI), and University of Washington Quality of Life Index (UW-QOL). RESULTS: Using tracheoesophageal (TE) speech was associated with significantly better VHI, MDADI, and UW-QOL scores compared to other forms of communication. The association between TE speech use on VHI, MDADI, and UQ-QOL persisted even when the analysis was limited to patients with >5-year follow-up and was maintained on multivariate analysis that accounted for a history of radiation and laryngectomy for recurrent laryngeal cancer. CONCLUSIONS: Using tracheoesophageal speech after total laryngectomy is associated with durable improvements in quality of life and functional outcomes in veterans. Tracheoesophageal voice restoration should be attempted whenever technically feasible in patients that meet the complex psychosocial and physical requirements to appropriately utilize TE speech. PMID- 29756482 TI - Physical contact between human vascular endothelial and smooth muscle cells modulates cytosolic and nuclear calcium homeostasis. AB - The interaction between vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) plays an important role in the modulation of vascular tone. There is, however, no information on whether direct physical communication regulates the intracellular calcium levels of human VECs (hVECs) and (or) human VSMCs (hVSMCs). Thus, the objective of the study is to verify whether co-culture of hVECs and hVSMCs modulates cytosolic ([Ca2+]c) and nuclear calcium ([Ca2+]n) levels via physical contact and (or) factors released by both cell types. Quantitative 3D confocal microscopy for [Ca2+]c and [Ca2+]n measurement was performed in cultured hVECs or hVSMCs or in co-culture of hVECs-hVSMCs. Our results show that: (1) physical contact between hVECs-hVECs or hVSMCs-hVSMCs does not affect [Ca2+]c and [Ca2+]n in these 2 cell types; (2) physical contact between hVECs and hVSMCs induces a significant increase only of [Ca2+]n of hVECs without affecting the level of [Ca2+]c and [Ca2+]n of hVSMCs; and (3) preconditioned culture medium of hVECs or hVSMCs does not affect [Ca2+]c and [Ca2+]n of both types of cells. We concluded that physical contact between hVECs and hVSMCs only modulates [Ca2+]n in hVECs. The increase of [Ca2+]n in hVECs may modulate nuclear functions that are calcium dependent. PMID- 29756483 TI - The GlideScope with modified Magill forceps facilitates nasogastric tube insertion in anesthetized patients: A randomized clinical study. AB - Objective Insertion of a nasogastric tube (NGT) in patients who have been intubated with an endotracheal tube while under general anesthesia can cause difficulties and lead to complications, including hemorrhage. A visualization aided modality was recently used to facilitate NGT insertion. Some studies have focused on the role of modified Magill forceps, which have angles similar to those of the GlideScope blade (Verathon, Bothell, WA, USA). Methods Seventy patients were divided into a control group (Group C) and an experimental group (GlideScope and modified Magill forceps, Group M). Results The total NGT insertion time was significantly shorter in Group M than C (71.3 +/- 22.6 vs. 96.7 +/- 57.5 s; mean difference, -25.3 s; 95% confidence interval [CI], 20.8 71.5). There were also significantly fewer mean insertion attempts in Group M than C (1.0 +/- 0.0 vs. 2.11 +/- 0.93). The success rate for the first attempt in Group C was 37.1%, while that in Group M was 100% (relative risk, 2.7; 95% CI, 1.7-4.1). Conclusion The use of the GlideScope with modified Magill forceps for insertion of an NGT in patients who are already intubated and under general anesthesia will shorten the insertion time and improve the success rate. PMID- 29756484 TI - Biomaterials Evaluation: Conceptual Refinements and Practical Reforms. AB - Regarding the widespread and ever-increasing applications of biomaterials in different medical fields, their accurate assessment is of great importance. Hence the safety and efficacy of biomaterials is confirmed only through the evaluation process, the way it is done has direct effects on public health. Although every biomaterial undergoes rigorous premarket evaluation, the regulatory agencies receive a considerable number of complications and adverse event reports annually. The main factors that challenge the process of biomaterials evaluation are dissimilar regulations, asynchrony of biomaterials evaluation and biomaterials development, inherent biases of postmarketing data, and cost and timing issues. Several pieces of evidence indicate that current medical device regulations need to be improved so that they can be used more effectively in the evaluation of biomaterials. This article provides suggested conceptual refinements and practical reforms to increase the efficiency and effectiveness of the existing regulations. The main focus of the article is on strategies for evaluating biomaterials in US, and then in EU. PMID- 29756485 TI - Associations between factors related to atopic disease and glaucoma in the National Health and Nutrition Examination Survey. AB - INTRODUCTION: Previous studies have suggested associations between glaucoma and serum sensitization to specific allergens. The purpose of this study was to examine associations between inciting factors for atopic disease, atopic diseases and symptoms, and glaucoma in the 2005-2006 National Health and Nutrition Examination Survey. METHODS: The study population included adult participants of National Health and Nutrition Examination Survey 2005-2006. Inciting factors for atopic disease included pet ownership, mildew/musty smell in home, cockroaches in home, use of water treatment devices, and crowded living conditions. Atopic diseases and symptoms included hay fever, eczema, any allergy, sneezing problems, and sinus infections. The outcome was glaucoma defined by the Rotterdam criteria. Covariates included age, gender, ethnicity, and allergy-related medication use. Logistic regression was used to examine associations between each exposure and glaucoma prevalence, controlling for all covariates. Statistical analyses were weighted by the National Health and Nutrition Examination Survey multistage sampling design. RESULTS: The weighted study population included 83,205,587 subjects, of whom 2,657,336 (3.2%) had glaucoma. After adjusting for covariates, factors associated with increased glaucoma included cat ownership (odds ratio =1.99, 95% confidence interval = 1.02-3.87) and mildew/musty smell in home (odds ratio = 1.95, 95% confidence interval = 0.99-3.84; borderline significance), while history of eczema was associated with decreased glaucoma (odds ratio = 0.27, 95% confidence interval = 0.02-0.99). CONCLUSION: In National Health and Nutrition Examination Survey, self-reported cat ownership is associated with increased glaucoma prevalence, while a mildew/musty smell in home may have a borderline association with increased glaucoma prevalence. These findings are possibly related to laboratory associations identified in the same population and further studies are needed to identify potential mechanisms to explain these associations. PMID- 29756486 TI - Osteonectin as a screening marker for pancreatic cancer: A prospective study. AB - Objective Osteonectin plays a central role in various processes during the development of pancreatic adenocarcinoma. This prospective pilot study was performed to determine the feasibility of serum osteonectin as a screening tool for pancreatic cancer. Methods Blood samples were collected from 15 consecutive patients with newly diagnosed pancreatic cancer and 30 matched healthy controls. Serum osteonectin was measured using an osteonectin enzyme-linked immunosorbent assay kit. The primary outcomes were the diagnostic performance of serum osteonectin and the threshold value for differentiation of patients from controls. Results The median/quartile range of serum osteonectin in patients and controls were 306.8/288.5 ng/mL and 67.5/39.8 ng/mL, respectively. Osteonectin concentrations significantly differed among the study groups. A plasma osteonectin concentration of >100.18 ng/mL as selected by the receiver operating characteristic curves demonstrated an estimated area under the curve of 86% for prediction of pancreatic cancer. Tumour size was a significant predictor of serum osteonectin. A statistically significant difference in serum osteonectin between T1/T2 and T3/T4 tumours was found. Post-hoc comparisons revealed statistically significant differences in the serum osteonectin among the control, T1/T2, and T3/T4 groups. Conclusion Osteonectin may be used as a screening tool for pancreatic cancer, although this must be validated in prospective studies. PMID- 29756487 TI - Evaluation of the relationship between loneliness and medication adherence in patients with diabetes mellitus: A cross-sectional study. AB - Objective The emotional status of patients with diabetes mellitus (DM) is important in the course of treatment. The present study aimed to determine the level of loneliness among patients with DM and to evaluate the relationship between the patients' level of loneliness and medication adherence. Method This cross-sectional study used a semi-structured questionnaire and the University of California, Los Angeles Loneliness Scale to collect data from 325 patients who were diagnosed with DM. Results We found that loneliness scores were significantly elevated in individuals with a low level of education, unmarried individuals, and students. Furthermore, these scores were elevated in patients diagnosed with type 1 DM, patients on insulin therapy, patients diagnosed with diabetic foot syndrome, patients who did not exercise regularly, and patients who reported being disturbed by reminders from their families or spouses to take their medications or they did not feel anything after such reminders. Conclusions Individuals with DM may encounter various problems in their daily lives. Evaluating the emotional status in these individuals, including loneliness and treatment adherence, is important in ensuring that their needs are being met. PMID- 29756488 TI - Structural Validity and Measurement Invariance of the Pearlin Mastery Scale in Spanish-Speaking Primary Care Patients. AB - The Pearlin Mastery (PM) Scale is frequently used in health research to assess individuals' personal mastery or the extent to which they believe they are in control of their own lives. It has been adapted from English into multiple languages including Spanish. However, no studies have assessed the psychometric properties of Spanish translations of the scale. This analysis evaluated structural validity and measurement invariance of the original Spanish translation of the PM Scale in two groups of Spanish-speaking individuals receiving primary care at community clinics in Florida. Confirmatory factor analysis (CFA) indicated that the 5-item version used in the literature yields a unidimensional factor structure as expected; however, multiple-group CFA revealed that the PM Scale items did not load equivalently on the factor across samples. This indicates that the Spanish version of the PM Scale may not measure mastery consistently across groups, possibly due to differences in respondents' semantic understanding of items or differences in the meaning of the construct itself. Findings suggest that researchers seeking to measure personal mastery in Spanish speaking participants from diverse cultural backgrounds should consider alternative approaches including the development of new instruments. PMID- 29756490 TI - Three new triterpenoid saponins from Albizia julibrissin. AB - Three new triterpenoid saponins, julibrosides A5-A7 (1-3), together with five known saponins (4-8), were isolated from the stem bark of Albizia julibrissin. Their structures were elucidated on the basis of extensive spectroscopic data analysis of MS, 1D and 2D NMR, and chemical methods. Compounds 7 and 8 were isolated from the genus Albizia for the first time. The new compounds showed no cytotoxicity and anti-inflammatory activity. PMID- 29756489 TI - Sevoflurane exerts brain-protective effects against sepsis-associated encephalopathy and memory impairment through caspase 3/9 and Bax/Bcl signaling pathway in a rat model of sepsis. AB - Objective We compared the effects of sevoflurane and isoflurane on systemic inflammation, sepsis-associated encephalopathy, and memory impairment in a rat sepsis model of cecal ligation and puncture (CLP)-induced polymicrobial peritonitis. Methods Twenty-four rats were assigned to sham, CLP, CLP + sevoflurane, and CLP + isoflurane groups. At 72 hours after CLP, the rats underwent behavior tests. Serum cytokines were evaluated. Brain tissue samples were collected for determination of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase; the wet/dry weight ratio; myeloperoxidase (MPO) and malondialdehyde (MDA); apoptotic gene release; and histologic examinations. Results The MPO level, wet/dry weight ratio, and histopathology scores were lower and the Bcl2a1 and Bcl2l2 expressions were upregulated in both the CLP + sevoflurane and CLP + isoflurane groups compared with the CLP group. The interleukin-6, interleukin-1beta, MDA, and caspase 3, 8, and 9 levels were lower; the GPX, SOD, Bax, Bcl2, and Bclx levels were higher; and non-associative and aversive memory were improved in the CLP + sevoflurane group compared with the CLP + isoflurane group. Conclusion Sevoflurane decreased apoptosis and oxidative injury and improved memory in this experimental rat model of CLP. Sevoflurane sedation may protect against brain injury and memory impairment in septic patients. PMID- 29756492 TI - Cementless total hip arthroplasty in young patients under the age of 30: a minimum 10-year follow-up. AB - PURPOSE: The purpose of this study was to evaluate the clinical and radiologic outcomes of young patients (under the age of 30) who received a total hip arthroplasty (THA) and in whom patients had been followed for more than 10 years. MATERIALS AND METHODS: This retrospective study was conducted for 51 hips (44 patients) that had undergone THA. The mean age for the index operation was 25.71 years, and the mean follow-up period was 13.7 years. Clinical outcomes were evaluated by Harris hip score (HHS), activity level, and complications. Radiographic evaluations were assessed according to osteolysis, loosening, and polyethylene wear. RESULTS: The average HHS improved from 67.47 pre-operatively to 97.42 at the final follow-up ( p < 0.001). The activity level changed from 1.92 pre-operatively to 1.33 at the final follow-up ( p < 0.001). Ten cases had undergone revision arthroplasty within the follow-up period, and the overall survival rate was 80.4% at the final follow-up with revision for any reason as the end point. Polyethylene liners were used in all revision cases ( p = 0.003). Patients with modular stem had a higher failure rate than patients with a fully porous coated stem ( p < 0.001). Furthermore, a small diameter head size was associated with a higher risk of revision surgery ( p = 0.003). Complications such as dislocations were found in three hips. CONCLUSION: Cementless THA yields encouraging clinical and radiological results in young and active patients under the age of 30. However, the bearing surface, type of stem, and head size influenced component durability and revision rate. PMID- 29756491 TI - Innovative Healthy Lifestyles School-Based Public-Private Partnerships Designed to Curb the Childhood Obesity Epidemic Globally: Lessons Learned From the Mondelez International Foundation. AB - Public-private partnerships (PPPs) have been recognized as central for addressing the childhood obesity epidemic. However, very few real-world examples have been published documenting the workings of effective PPPs. The objective of this article is to identify the factors that enabled the successful implementation of school-based PPPs focusing mainly on nutrition and physical activity in 7 countries located in Asia (China and India), Africa (South Africa), Europe (Germany, United Kingdom), and Latin America (Brazil and Mexico). We triaged qualitative data from (1) proceedings from 2 school-based healthy lifestyles program evaluation workshops in October 2013 and in May 2016; (2) Mondelez International Foundation (MIF) annual country reports and MIF project reports; and (3) interviews with key program leaders from each program. Extracted data were mapped into each of the 11 guiding principles for effective PPPs recently developed by a multisectoral public-private group of stakeholders in the United States. Three of the 7 countries met all, and the remaining 4 met between 4 and 7 of the guiding principles. Therefore, it is not surprising that there is strong evidence that all programs are having a positive impact on healthy lifestyles knowledge and practices in the target populations. This MIF-led initiative provides important lessons as to how to establish effective PPPs designed to tackle the childhood obesity epidemic globally. PMID- 29756493 TI - Association between urinary sodium excretion and coronary heart disease in hospitalized elderly patients in China. AB - Objective This study was performed to evaluate the association between urinary sodium excretion and coronary heart disease (CHD) in hospitalized elderly patients in China. Methods The 24-h urinary excretion specimens of 541 patients were collected, and the serum creatinine concentration and urinary sodium/potassium ratio were measured. Associations were explored by multivariate logistic regression analysis. Results The mean 24-h urinary sodium excretion was 200.4 mmol, corresponding to 11.7 g of salt intake. Both of these values were higher in men than in women. The salt intake of 80- to 89-year-old patients was significantly lower than that of 70- to 79-year-old patients. The 24-h urinary sodium excretion and spot urine Na/K ratios were significantly higher in overweight/obese and hypertensive patients. The 24-h urinary sodium excretion of men who smoked was significantly higher than that of women. The spot urine Na/K ratio was significantly higher in patients with cerebral thrombosis. The urinary Na/K ratio, smoking status, and hypertension were independent risk factors for CHD. Conclusions This cross-sectional survey suggests that the Na/K ratio may better represent salt loading than Na excretion alone in studying the association between sodium intake and CHD. There was no association between sodium and CHD prevalence. PMID- 29756494 TI - Lexical properties: Trademarks, dictionaries, and the sense of the generic. AB - The third edition of Webster's International Dictionary, first published in 1961, represented a novel approach to lexicography. It recorded the English language used in everyday life, incorporating colloquial terms that previous grammarians would have considered unfit for any responsible dictionary. Many were scandalized by the new lexicography. Trademark lawyers were not the most prominent of these critics, but the concerns they expressed are significant because they touched on the core structure of the trademark as a form of property in language. In the course of eavesdropping on everyday usage, Merriam-Webster's lexicographers picked up on the use of trademarks as common nouns: "thermos" as a generic noun for any vacuum flask, "cellophane" as a term for transparent wrapping, and so on. If Webster's Third were to be taken as sound evidence of the meaning of words, then the danger was that some of the most familiar marks in the USA would be judged "generic" in the legal sense, and would thereby cease to be proprietary. In this article, we explore the implications of this encounter between law and lexicographic technique. PMID- 29756495 TI - Historicizing transcultural psychiatry: people, epistemic objects, networks, and practices. AB - The history of transcultural psychiatry has recently attracted much historical attention, including a workshop in March 2016 in which an international panel of scholars met at the Maison de Sciences de l'Homme Paris-Nord (MSH-PN). Papers from this workshop are presented here. By conceiving of transcultural psychiatry as a dynamic social field that frames its knowledge claims around epistemic objects that are specific to the field, and by focusing on the ways that concepts within this field are used to organize intellectual work, several themes are explored that draw this field into the historiography of psychiatry. Attention is paid to the organization of networks and publications, and to important actors within the field who brought about significant developments in the colonial and post-colonial conceptions of mental illness. PMID- 29756496 TI - Bilateral total hip arthroplasty: one-stage versus two-stage procedure. AB - BACKGROUND: Despite several studies, controversy has prevailed over the rate of complications following 1-stage and 2-stage bilateral total hip arthroplasty (THA). In the current study, we compare the complications and functional outcomes of 1-stage and 2-stage procedures. METHODS: One hundred and eighty patients (ASA class I or II) with bilateral hip osteoarthritis were assigned randomly to two equal groups. The two groups were matched in terms of age and sex. All of the surgeries were performed via the Hardinge approach using uncemented implants. In 2-stage procedures, surgeries were performed with a 6-month to 1-year interval. All patients were evaluated 1 year postoperatively. RESULTS: The Harris Hip Score (HHS) averaged 84.1 and 82.6 in 1-stage and 2-stage groups, respectively ( p = 0.528). The hospital stay was significantly longer in the 2-stage group (9.8 days vs. 4.9 days). The cumulative haemoglobin drop and the number of transfused blood units were the same. One patient in each group developed symptomatic deep venous thrombosis which was managed successfully. There was no patient with perioperative death, pulmonary embolism, infection, dislocation, periprosthetic fracture or heterotrophic ossification. No patient required reoperation. Two patients in the 1-stage group developed unilateral temporary peroneal nerve palsy, which was resolved after 3-4 months. CONCLUSION: 1-stage bilateral THA can be used successfully for patients with bilateral hip disease without increasing the rate of complications. Functional and clinical outcomes are comparable and hospital stay is significantly shorter. PMID- 29756498 TI - Construct validity and inter-rater reliability of the Dutch activity measure for post-acute care "6-clicks" basic mobility form to assess the mobility of hospitalized patients. AB - To evaluate the construct validity and the inter-rater reliability of the Dutch Activity Measure for Post-Acute Care "6-clicks" Basic Mobility short form measuring the patient's mobility in Dutch hospital care. First, the "6-clicks" was translated by using a forward-backward translation protocol. Next, 64 patients were assessed by the physiotherapist to determine the validity while being admitted to the Internal Medicine wards of a university medical center. Six hypotheses were tested regarding the construct "mobility" which showed that: Better "6-clicks" scores were related to less restrictive pre-admission living situations (p = 0.011), less restrictive discharge locations (p = 0.001), more independence in activities of daily living (p = 0.001) and less physiotherapy visits (p < 0.001). A correlation was found between the "6-clicks" and length of stay (r= -0.408, p = 0.001), but not between the "6-clicks" and age (r= -0.180, p = 0.528). To determine the inter-rater reliability, an additional 50 patients were assessed by pairs of physiotherapists who independently scored the patients. Intraclass Correlation Coefficients of 0.920 (95%CI: 0.828-0.964) were found. The Kappa Coefficients for the individual items ranged from 0.649 (walking stairs) to 0.841 (sit-to-stand). The Dutch "6-clicks" shows a good construct validity and moderate-to-excellent inter-rater reliability when used to assess the mobility of hospitalized patients. Implications for Rehabilitation Even though various measurement tools have been developed, it appears the majority of physiotherapists working in a hospital currently do not use these tools as a standard part of their care. The Activity Measure for Post-Acute Care "6-clicks" Basic Mobility is the only tool which is designed to be short, easy to use within usual care and has been validated in the entire hospital population. This study shows that the Dutch version of the Activity Measure for Post-Acute Care "6 clicks" Basic Mobility form is a valid, easy to use, quick tool to assess the basic mobility of Dutch hospitalized patients. PMID- 29756497 TI - Relationship between muscular and bony anatomy in native hips: a theoretical background for approach-specific implant positioning. AB - INTRODUCTION: The aim of this study was to analyse the relationship between bony joint orientation and the distribution of hip musculature. METHODS: The bone anatomy of the hip (femoral antetorsion (AT), acetabular anteversion (AV), and combined anteversion (AV/AT)) and the muscle volume of the gluteal muscles and the tensor fasciae latae were analysed bilaterally using computed tomography data of 49 patients. Muscle force direction (MFD) was determined for each muscle. The total MFD of the hip musculature was calculated and then correlated with the bony anatomy. RESULTS: The mean AV, AT, and AV/AT were 21.9 degrees +/- 5.9 degrees , 7.22 degrees +/- 7.4 degrees , and 29.2 degrees +/- 9 degrees , respectively. We found the following mean muscle volumes: gluteus maximus: 780 +/- 227 cm3, gluteus medius: 322 +/- 82 cm3, gluteus minimus: 85 +/- 20 cm3, and tensor fasciae latae: 68 +/- 22 cm3. The mean MFD was 18.92 degrees +/- 1.29 degrees . We found a uniform distribution of the musculature that was not correlated with the bone anatomy. CONCLUSION: This study highlights the variability in native acetabular and femoral anatomy and that bone hip anatomy does not correlate with the distribution of hip musculature. Although native acetabular anteversion matches the suggested targets for cup insertion, native combined anteversion is not related to current implant insertion targets. Understanding native muscular anatomy and the alterations that occur with different surgical approaches can serve as an explanatory model for THAs that has become unstable despite the components being implanted within the safe zone. PMID- 29756499 TI - Machine Learning for Outcome Prediction in Electroencephalograph (EEG)-Monitored Children in the Intensive Care Unit. AB - The aim of this study was to evaluate the performance of models predicting in hospital mortality in critically ill children undergoing continuous electroencephalography (cEEG) in the intensive care unit (ICU). We evaluated the performance of machine learning algorithms for predicting mortality in a database of 414 critically ill children undergoing cEEG in the ICU. The area under the receiver operating characteristic curve (AUC) in the test subset was highest for stepwise selection/elimination models (AUC = 0.82) followed by least absolute shrinkage and selection operator (LASSO) and support vector machine with linear kernel (AUC = 0.79), and random forest (AUC = 0.71). The explanatory models had the poorest discriminative performance (AUC = 0.63 for the model without considering etiology and AUC = 0.45 for the model considering etiology). Using few variables and a relatively small number of patients, machine learning techniques added information to explanatory models for prediction of in-hospital mortality. PMID- 29756500 TI - siRNA: an alternative treatment for diabetes and associated conditions. AB - Diabetes is a condition that is not completely treatable but life of a diabetic patient can be smoothed by preventing or delaying the associate conditions like diabetic retinopathy, nephropathy, impaired wound healing process, etc. Apart from conventional methods to regulate diabetic condition, new techniques using siRNA have been emerged to prevent the associated conditions. This paper focuses on how siRNA used as a tool to silence the expression of genes which plays critical role in pathogenesis of these conditions. A marked improvement in wound healing process of diabetic patients has been observed with siRNA treatment by silencing of Keap1 gene. Glucagon plays critical role in glucose homoeostasis and increases blood glucose level during hypoglycaemia. Glucose homoeostasis is impaired in diabetic patient and suppressing the expression of glucagon secretion with siRNA is used to suppress the progress of diabetes. Similarly, silencing expression of several factors has demonstrated improvement of treatment of diabetic nephropathy, retinopathy and inflammation by the use of siRNA. PMID- 29756501 TI - Unrecoverable bi-products of drilling titanium alloy and tantalum metal implants: a pilot study. AB - BACKGROUND: Trabecular metal implants with a porous architecture that allows for the incorporation of bone into the implant during healing are gaining popularity in alloplastic revision procedures. The bi-products of drilling titanium alloy (Ti) and tantalum (Ta) implants have not been previously assessed. METHODS: Four holes were drilled in each of 2 spatially porous trabecular implants, one Ta and the other Ti alloy (Ti-6Al-7Nb), for this pilot in vitro study. The particles were flushed out with a continuous flow of saline. The particles' weight and the volume were then measured using a Radwag XA 110/2X (USA) laboratory balance. The total volume of the obtained metal fines was measured by titration using a 10 mm3 measurement system. RESULTS: A cobalt carbide bit was used since the holes could not be made with a standard bone drill. Each Ti and Ta implant lost 1.26 g and 2.48 g of mass, respectively. The volume of free particles recovered after each stage was 280 mm3 and 149 mm3, respectively. Approximately 0.6% of the total implant mass was not recovered after drilling (roughly 2% of the mass of the particles created by drilling), despite the use of 5 um filters. CONCLUSIONS: It is technically difficult to drill holes in Ti and Ta implants using standard surgical tools. The drilling process creates a considerable amount of metal particles, which cannot be recovered despite intensive flushing. This may have an adverse influence on the bio-functionality (survival) of the endoprosthesis and present deleterious systemic consequences. PMID- 29756502 TI - MRI prevalence and characteristics of supraacetabular fossae in patients with hip pain. AB - BACKGROUND: Supraacetabular fossae (SAF) are normal anatomic variants found at the 12 o'clock position of the acetabulum and can be mistaken for osteochondral defects. PURPOSE: Determine SAF prevalence on MRI of patients with hip pain. Characterise SAF by type, size, and location. Determine sensitivity of radiology reports and sensitivity of radiographs in SAF detection. METHODS: MRIs performed over 1 year in patients with hip/groin pain were analysed for SAF. Measurements of SAF in the coronal and sagittal planes and location using clockface notation were recorded. Radiology reports were reviewed to determine if SAF were identified and radiographs were assessed for presence of SAF. Mean characteristics of type 1 and 2 SAF were compared using Student's t-test. RESULTS: 214 hips (mean age 35.9 +/- 14.2 years; 66.8% female) were analysed. Twenty-seven hips (12.6%) had SAF. There were five type 1 SAF (mean age 16.8 +/- 2.2 years) and 23 type 2 SAF (mean age 33.0 +/- 16.3 years). Mean dimensions of type 1 and 2 SAF (coronal width * sagittal width * depth, in millimetres) were 7.1 * 6.5 * 3.4 and 6.1 * 5.9 * 2.8, respectively. Mean clockwise location in the coronal and sagittal planes (in minutes) was 1236 and 1212 for type 1 SAF and 1213 and 1207 for type 2 SAF. Radiology reports identified 7.1% of SAF identified on MRI. Plain radiographs demonstrated 67.9% of SAF identified on MRI. CONCLUSION: This study found a 12.6% prevalence of SAF in hips. Radiology reports had a 7.1% sensitivity in correctly identifying SAF on MRI. IRB: Pro00016584. PMID- 29756504 TI - Tuberculous peritonitis and pleurisy accompanied by pulmonary cryptococcosis: A case report. AB - Although the infectious diseases tuberculosis (TB) and cryptococcosis both cause formation of single or multiple nodules in immunodeficient hosts, cases of co infection of these diseases are rarely seen. We report a patient who was co infected with TB and cryptococcosis. A male patient with no clinical evidence of immunodeficiency presented with a 3-week history of abdominal distension accompanied by oedema of recurring lower extremities. The patient was diagnosed with tuberculous peritonitis and tuberculous pleurisy by an abdominal puncture biopsy. Several months after being treated for TB, the patient was diagnosed with Cryptococcus infection and received antifungal treatment. Computed tomographic and magnetic resonance imaging findings suggested that treatment was effective. This case illustrates the challenges encountered during assessment of neoplasms associated with TB and cryptococcosis. Differential diagnosis requires an abdominal puncture biopsy. Diagnosis of Cryptococcus infection also requires a positive cryptococcal culture and positive India ink staining analysis. Notably, our patient also showed no obvious symptoms of cryptococcosis after receiving anti-TB treatment. Accordingly, in this report, we discuss the possible pathogenic mechanisms that underlie the coincidence of both types of inflammatory lesions. We emphasize the need for a greater awareness of atypical presentations of TB accompanied by Cryptococcus infection. PMID- 29756503 TI - Social Relationships and Suicidal Ideation Among the Elderly Who Live Alone in Republic of Korea: A Logistic Model. AB - With population aging and change in family structure, the number of the elderly who live alone is rapidly increasing in Korea. The aim of this study was to explore the association between social relationships-especially newly formed formal social relationships (FSRs)-and suicidal ideation among Korean elderly who live alone. The elderly who live alone (N = 2509) from the 2014 Survey of Living Conditions and Welfare Needs of Older Koreans were analyzed using logistic regression. This study found that informal social relationships (ISRs) (eg, children, friends and neighbors) of the elderly who live alone had statistically significant association with suicidal ideation, whereas FSRs (eg, formal helper and social participation) did not have significant association with suicidal ideation. The findings of this study suggest that the Korean Government needs to strengthen public system for alleviating social isolation of the elderly living alone. Therefore, this study proposed 2 strategic approaches to maintain and strengthen ISRs and to develop different types of FSRs (eg, the measures to combine FSRs with ISRs, gatekeepers, etc). PMID- 29756505 TI - Novel Vector Construction Based on Alternative Adenovirus Types via Homologous Recombination. AB - Adenoviral vector (AdV) is one of the most used vectors in gene therapy clinical trials. However the therapeutic effect of AdV is limited due to preexisting immunity to the currently used human adenovirus type 5 and pre-decided vector tropism. It is highly demanded to develop novel AdVs originated from other types than adenovirus type 5. Here, we describe a method for direct cloning of adenovirus utilizing linear-linear homologous recombination, followed by rapid adenoviral genome modification via linear-circular homologous recombination. A plasmid bearing chosen adenoviral genome with the desired modification is generated in three weeks, from which a novel AdV can be reconstituted. PMID- 29756506 TI - Dislocation rate increases with bariatric surgery before total hip arthroplasty. AB - INTRODUCTION: Annually in the USA, 113,000 patients with refractory obesity undergo bariatric surgery (BS), and a subset does so in order to lower body mass index to become a more desirable total hip arthroplasty (THA) candidate. This study aims to evaluate THA risk with and without bariatric surgery. METHODS: 12,160 patients were identified in a claim-based review of the entire Medicare database with ICD-9 codes to identify patients in three groups. Patients who underwent BS prior to THA (Group I: 1,545 experimental group) and two control groups that did not undergo BS but had either a body mass index >40 (Group II: 6,918 bariatric control) or <25 (Group III: 3,697 normal weight control). Preoperative demographics/comorbidities and short-term medical (30 day) and long term surgical (90-day and 2-year) complications were evaluated. RESULTS: Group I had female predominance, youngest age, and highest incidence of: deficiency anaemia, cardiovascular disease, liver disease, diabetes, polysubstance abuse, psychiatric disorders and smoking. At 2 years, Group I had approximately twice the dislocation and revision risk compared to both Groups II and III; Groups I and II had over four times the risk of infection and wound complications compared to Group III. CONCLUSION: In the Medicare population, these patients continue to have complication rates similar to and sometimes greater than obese patients with no prior bariatric surgery. Greater dislocation risk is possibly due to ligamentous laxity related to decreased collagen/elastin and/or component malposition due to intraoperative visualisation challenges. PMID- 29756507 TI - Novel drug delivery systems for ocular therapy: With special reference to liposomal ocular delivery. AB - Delivery of drugs to eyes is a great challenge to researchers because of a number of barriers in the eye preventing the actual dose from reaching the site. A number of ophthalmic delivery systems have been developed in the past couple of years that are not only new but also safe and reliable and help to overcome all those barriers in the eye which are responsible for the very less bioavailability of drugs. In this review, we tried to focus on current research in ocular delivery of drug substances giving special emphasis to liposomal delivery system. A brief analysis of other novel ocular delivery systems, ocular physiology, and microbial sources of disease are also highlighted herein. We analyzed the various research findings for churning a general idea for novel ocular delivery system and its future use. The novel formulations may overcome the addressed problems of ophthalmic medication and comply with the quality assurance issues. The liposomal delivery is advantageous as they have the ability to entrap both hydrophobic and hydrophilic drugs and are suitable for delivery to both the anterior and posterior segment of the eye. Therefore, the use of this alternative approach is quite a necessity. PMID- 29756508 TI - Association between Abdominal Free Fluid and Postoperative Complications and Mortality in Patients with Small-Bowel Obstruction. AB - BACKGROUND AND AIMS: Small-bowel obstruction is a frequent cause of hospitalization. The condition is potentially life-threatening, causing many admission days and is a heavy burden socioeconomically. Patients with small-bowel obstruction may develop abdominal free fluid and the quality of this fluid may be predictive of worse outcomes. Our aim was to examine whether the presence of free fluid and its density, measured on computed tomography scans, was associated with severe complications and mortality postoperatively. MATERIALS AND METHODS: Patients admitted to the Department of Surgery, Zealand University Hospital with a diagnosis of small-bowel obstruction between January 2010 and December 2015 were included. Medical records were reviewed and preoperative computed tomography scans were examined. A radiologist blinded to the outcomes reviewed all Hounsfield unit values of the free fluid. The primary outcomes evaluated were odds ratios of the severity of complications and hazard ratios of 30- and 90-day mortality postoperatively. RESULTS: A total of 289 patients were included. Analyses revealed an adjusted odds ratio of 1.03 (95%confidence interval = 0.93 1.15) between the presence of free fluid and postoperative complications and an adjusted hazard ratio of 1.28 (95% confidence interval = 0.80-2.05, p = 0.30) of the 30-day mortality in this patient group. Furthermore, the analyses revealed an adjusted odds ratio of 1.22 (95% confidence interval 0.98-1.52) between the density of the free fluid > 20 Hounsfield unit and postoperative complications and an adjusted hazard ratio of 0.85 (95% confidence interval = 0.28-2.63, p = 0.78) of the 30-day mortality. CONCLUSION: No significant correlation was found between the presence of free fluid nor its density in regard to postoperative complications or mortality in patients with small-bowel obstruction. PMID- 29756509 TI - Hemispheric asymmetry in holistic processing of words. AB - Holistic processing has been regarded as a hallmark of face perception, indicating the automatic and obligatory tendency of the visual system to process all face parts as a perceptual unit rather than in isolation. Studies involving lateralized stimulus presentation suggest that the right hemisphere dominates holistic face processing. Holistic processing can also be shown with other categories such as words and thus it is not specific to faces or face-like expertize. Here, we used divided visual field presentation to investigate the possibly different contributions of the two hemispheres for holistic word processing. Observers performed same/different judgment on the cued parts of two sequentially presented words in the complete composite paradigm. Our data indicate a right hemisphere specialization for holistic word processing. Thus, these markers of expert object recognition are domain general. PMID- 29756510 TI - Oncoplastic Breast-Conserving Surgery in Iceland: A Population-Based Study. AB - BACKGROUND AND AIMS: In Iceland, oncoplastic breast-conservation surgery has been performed since 2008. The aim of this population-based study was to assess and compare the efficacy and patient satisfaction of standard breast-conservation surgery with oncoplastic breast-conservation surgery. MATERIALS AND METHODS: This is a population-based, retrospective, observational cohort study on all women undergoing breast-conservation surgery in Iceland from the 1 January 2008 to 31 December 2014. A multivariate logistic regression and linear regression were performed to assess differences in outcomes and a patient satisfaction questionnaire was used to assess certain patient-related outcome measures. RESULTS AND CONCLUSION: A total of 750 women underwent breast-conserving surgery, 665 had standard breast-conservation surgery and 85 oncoplastic breast conservation surgery. Oncoplastic breast-conservation surgery was associated with a significantly larger mean size (2.4 cm vs 1.7 cm, p < 0.001) and weight (181.8 g vs 63.4 g, p < 0.001) of breast specimen excised when compared to standard breast-conservation surgery. After correcting for confounding factors, there was no significant difference in surgical margin involvement (odds ratio = 0.97, confidence interval = 0.44-1.97), frequency of complications (odds ratio = 1.06, confidence interval = 0.46-2.18), frequency of reoperations (odds ratio = 0.98; confidence interval = 0.50-1.81), or time to first adjuvant therapy (-0.23 days for oncoplastic breast-conservation surgery, p = 0.95). Patient satisfaction was high in both groups, although not statistically different (96% in oncoplastic breast-conservation surgery group vs 89% in the standard breast-conservation surgery group, p = 0.84). Our results show that oncoplastic breast-conservation surgery is at least as safe as standard breast-conservation surgery in selected cases and may be preferable in ductal carcinoma in situ. PMID- 29756511 TI - Surface integrity of polyethylene liners following trunnionosis of a dual modular neck total hip implant. AB - BACKGROUND: There has been a trend in the evolution of total hip arthroplasty towards increased modularity; with this increase in modularity come some potentially harmful consequences. Modularity at the neck shaft junction has been linked to corrosion, adverse reaction to metal debris and pseudotumour formation. AIM: The aim of this retrieval study is to assess whether the surface integrity of the polyethylene (PE) liner is affected by metal wear debris in a single implant design series of THA revised for trunnionosis. METHODS: A retrieval analysis of thirty dual-taper modular neck hip prostheses was performed; the mean time from implantation to revision was 2.7 years (1.02-6.2). PE liners were analysed using a scanning electron microscope with an energy dispersive spectrometer to assess for metal particles embedded on the liner surface. Serum metal ion levels and inflammatory markers were also analysed. RESULTS: There were small numbers of metal particles present on the PE liners. The mean number of metal particles per liner was four and the particles varied in size from 0.5 um to 122 um mean 16 um. All patients had elevated metal ion levels: cobalt 6.02 ug/l, chromium 1.22 ug/l, titanium 3.11 ug/l. The cobalt:chromium ratio was 7.55:1. Inflammatory markers were also marginally raised (ESR 17; CRP 10). CONCLUSION: These results suggest that retention of PE liners may be reasonable when performing isolated revision of the femoral component in cases of failure at the modular neck stem junction, especially when the inner diameter of the liner is already optimised for head size and stability. PMID- 29756512 TI - Profile of Roche's Elecsys Troponin T Gen 5 STAT blood test (a high-sensitivity cardiac troponin assay) for diagnosing myocardial infarction in the emergency department. AB - INTRODUCTION: The Elecsys Troponin T Gen 5 STAT test (distributed in the United States (US) by Roche Diagnostics, Indianapolis, IN) is the first high-sensitivity cardiac troponin test approved for use by the FDA in the US (2017). Areas covered: The test offers clinicians the opportunity for more rapid decision making for diagnosing myocardial infarction (MI) in the emergency department (ED). The Troponin T Gen 5 STAT test (labeled as TNT-G5ST on the reagent pack) is similar to the Troponin T hs STAT (TNT-HSST) and Troponin T hs (TNT-HS) tests that have been available outside the US since 2009. Collectively, these tests can all be considered as high-sensitivity cardiac troponin T (hs-cTnT) assays. Expert commentary: Studies performed in the US and throughout the world using 0 and 3 h blood draws for hs-cTnT testing in patients with possible MI have reliably achieved a sensitivity of >94% and negative predictive value of >=99% for MI in the ED setting. PMID- 29756513 TI - Self-directed therapy programmes for arm rehabilitation after stroke: a systematic review. AB - AIM: To investigate the effectiveness of self-directed arm interventions in adult stroke survivors. METHODS: A systematic review of Medline, EMBASE, CINAHL, SCOPUS and IEEE Xplore up to February 2018 was carried out. Studies of stroke arm interventions were included where more than 50% of the time spent in therapy was initiated and carried out by the participant. Quality of the evidence was assessed using the Cochrane risk of bias tool. RESULTS: A total of 40 studies ( n = 1172 participants) were included (19 randomized controlled trials (RCTs) and 21 before-after studies). Studies were grouped according to no technology or the main additional technology used (no technology n = 5; interactive gaming n = 6; electrical stimulation n = 11; constraint-induced movement therapy n = 6; robotic and dynamic orthotic devices n = 8; mirror therapy n = 1; telerehabilitation n = 2; wearable devices n = 1). A beneficial effect on arm function was found for self-directed interventions using constraint-induced movement therapy ( n = 105; standardized mean difference (SMD) 0.39, 95% confidence interval (CI) -0.00 to 0.78) and electrical stimulation ( n = 94; SMD 0.50, 95% CI 0.08-0.91). Constraint-induced movement therapy and therapy programmes without technology improved independence in activities of daily living. Sensitivity analysis demonstrated arm function benefit for patients >12 months poststroke ( n = 145; SMD 0.52, 95% CI 0.21-0.82) but not at 0-3, 3-6 or 6-12 months. CONCLUSION: Self directed interventions can enhance arm recovery after stroke but the effect varies according to the approach used and timing. There were benefits identified from self-directed delivery of constraint-induced movement therapy, electrical stimulation and therapy programmes that increase practice without using additional technology. PMID- 29756514 TI - Ilex paraguariensis Extends Lifespan and Increases an Ability to Resist Environmental Stresses in Drosophila. AB - Aging is a complex process resulting in (1) a decline in body functions and capacity to withstand environmental stress and (2) an increased susceptibility to diseases including, but not limited to, cardiovascular disorders, diabetes, cancer, and dementia. Among a number of herbal products used to alleviate symptoms associated with aging is Ilex paraguariensis (IP). This product has been reported to have anticancer, anti-inflammatory, and antioxidant activities. However, its effect on an organisms' longevity has not been thoroughly studied to date. Here, we report that 10 mg/mL IP supplementation significantly extended the lifespan of Drosophila. Additionally, IP enhanced flies' ability to resist environmental stress as estimated using starvation, paraquat, and desiccation assays. Additional experiments revealed insignificant changes in weight gain, physical activity, and metabolic profiles such as levels of water, lipid, and protein in flies receiving IP supplementation. Rather, levels of messenger RNA for enzymes that scavenge reactive oxygen species (i.e., superoxide dismutases, catalase, and glutathione peroxidase) were found to be significantly altered despite subtle changes in their catalytic activities. We hope that our research demonstrating IP-induced lifespan extension and related biological mechanisms of this interesting phenomenon will encourage further studies, which may eventually determine whether IP has utility as a novel antiaging agent. PMID- 29756515 TI - Effects of polaprezinc on gastric mucosal damage and neurotransmitters in a rat model of chemotherapy-induced vomiting. AB - Objective To investigate the effects of polaprezinc (PZ) on cyclophosphamide (CTX)- or cisplatin (DDP)-induced gastric mucosal injury and on a rat model of neurotransmitter-mediated vomiting. Methods Sprague-Dawley rats were divided at random into Control, CTX, DDP, PZ+CTX, and PZ+DDP groups. After 20 days, brain tissues and sera were analyzed for the levels of dopamine (DA), 5 hydroxytryptamine (5-HT), and nuclear factor kappa B (NF-kappaB). Hematoxylin and eosin-stained sections of stomach, intestine, and brain tissues were examined using light microscopy. Results The levels of DA, 5-HT, and NF-kappaB in brain and serum samples of rats treated with CTX or DDP were significantly increased compared with those of rats in the Control group. There was a significant decrease in these values in the PZ group. Moreover, PZ reduced damage to brain tissue caused by CTX or DDP. Conclusions PZ decreased the levels of DA, 5-HT, and NF-kappaB in blood and brain tissues caused by CTX or DDP and reduced the chemotherapy-induced damage to the small intestine, stomach, and brain. These findings can be translated to the clinic to enhance the efficacy and safety of chemotherapy. PMID- 29756516 TI - Transplantation of a Peripheral Nerve with Neural Stem Cells Plus Lithium Chloride Injection Promote the Recovery of Rat Spinal Cord Injury. AB - Transplantation of neural stem cells (NSCs) holds great potential for the treatment of spinal cord injury (SCI). However, transplanted NSCs poorly survive in the SCI environment. We injected NSCs into tibial nerve and transplanted tibial nerve into a hemisected spinal cord and investigated the effects of lithium chloride (LiCl) on the survival of spinal neurons, axonal regeneration, and functional recovery. Our results show that most of the transplanted NSCs expressed glial fibrillary acidic protein, while there was no obvious expression of nestin, neuronal nuclei, or acetyltransferase found in NSCs. LiCl treatment produced less macrosialin (ED1) expression and axonal degeneration in tibial nerve after NSC injection. Our results also show that a regimen of LiCl treatment promoted NSC differentiation into NF200-positive neurons with neurite extension into the host spinal cord. The combination of tibial nerve transplantation with NSCs and LiCl injection resulted in more host motoneurons surviving in the spinal cord, more regenerated axons in tibial nerve, less glial scar area, and decreased ED1 expression. We conclude that lithium may have therapeutic potential in cell replacement strategies for central nervous system injury due to its ability to promote survival and neuronal generation of grafted NSCs and reduced host immune reaction. PMID- 29756517 TI - Local, Controlled Release In Vivo of Vascular Endothelial Growth Factor Within a Subcutaneous Scaffolded Islet Implant Reduces Early Islet Necrosis and Improves Performance of the Graft. AB - Islet transplantation remains the only alternative to daily insulin therapy for control of type 1 diabetes (T1D) in humans. To avoid the drawbacks of intrahepatic islet transplantation, we are developing a scaffolded islet implant to transplant islets into nonhepatic sites. The implant test bed, sized for mice, consists of a limited (2-mm) thickness, large-pore polymeric sponge scaffold perforated with peripheral cavities that contain islets suspended in a collagen hydrogel. A central cavity in the scaffold holds a 2-mm diameter alginate sphere for controlled release of the angiogenic cytokine vascular endothelial growth factor ( VEGF). Host microvessels readily penetrate the scaffold and collagen gel to vascularize the islets. Here, we evaluate the performance of the implant in a subcutaneous (SC) graft site. Implants incorporating 500 syngeneic islets reversed streptozotocin-induced diabetes in mice approximately 30 d after SC placement. Controlled release of a modest quantity (20 ng) of VEGF within the implant significantly reduced the time to normoglycemia compared to control implants lacking VEGF. Investigation of underlying causes for this effect revealed that inclusion of 20 ng of VEGF in the implants significantly reduced central necrosis of islets 24 h after grafting and increased implant vascularization (measured 12 d after grafting). Collectively, our results demonstrate (1) that the scaffolded islet implant design can reverse diabetes in SC sites in the absence of prevascularization of the graft site and (2) that relatively low quantities of VEGF, delivered by controlled release within the implant, can be a useful approach to limit islet stress after grafting. PMID- 29756518 TI - The Route by Which Intranasally Delivered Stem Cells Enter the Central Nervous System. AB - Intranasal administration is a promising route of delivery of stem cells to the central nervous system (CNS). Reports on this mode of stem cell delivery have not yet focused on the route across the cribriform plate by which cells move from the nasal cavity into the CNS. In the current experiments, human mesenchymal stem cells (MSCs) were isolated from Wharton's jelly of umbilical cords and were labeled with extremely bright quantum dots (QDs) in order to track the cells efficiently. At 2 h after intranasal delivery in immunodeficient mice, the labeled cells were found under the olfactory epithelium, crossing the cribriform plate adjacent to the fila olfactoria, and associated with the meninges of the olfactory bulb. At all times, the cells were separate from actual nerve tracts; this location is consistent with them being in the subarachnoid space (SAS) and its extensions through the cribriform plate into the nasal mucosa. In their location under the olfactory epithelium, they appear to be within an expansion of a potential space adjacent to the turbinate bone periosteum. Therefore, intranasally administered stem cells appear to cross the olfactory epithelium, enter a space adjacent to the periosteum of the turbinate bones, and then enter the SAS via its extensions adjacent to the fila olfactoria as they cross the cribriform plate. These observations should enhance understanding of the mode by which stem cells can reach the CNS from the nasal cavity and may guide future experiments on making intranasal delivery of stem cells efficient and reproducible. PMID- 29756520 TI - Sustainability of an Enhanced Recovery Program for Pancreaticoduodenectomy with Pancreaticogastrostomy. AB - BACKGROUND: Enhanced recovery program for pancreaticoduodenectomy have become standard care. Little is known about adherence rates and sustainability of the program, especially when pancreaticogastrostomy is used in reconstruction. The aim of this study was, therefore, to evaluate adherence rates and continued outcome, after implementation of an enhanced recovery program. METHODS: Consecutive patients undergoing pancreaticoduodenectomy at the Department of Surgery, Skane University Hospital, Lund, Sweden were followed, after implementation of enhanced recovery program, October 2012. In April 2015, some items in the enhanced recovery program were modified, namely earlier removal of nasogastric tubes and abdominal drain. The patients were analyzed in three groups, the implementation group (control) and two post-implementation groups; intermediate and modified group. Sustainability was assessed according to length of stay and adherence rate. RESULTS: In total, 160 patients were identified. The overall protocol adherence rate increased from 65% to 72%, p = 0.035. While the pre- and intraoperative protocol items were fulfilled to more than >90%, the postoperative were lower, but increasing over time; 48%, 50%, and 58%, p = 0.033. Postoperative complications and hospital length of stay did not change significantly. CONCLUSION: The positive outcome of an enhanced recovery program for pancreaticoduodenectomy was reasonably well sustained. Compliance with the protocol has increased, but strict adherence remains a challenge, especially with the postoperative items. PMID- 29756519 TI - Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson's Disease. AB - Parkinson's disease (PD) causes motor dysfunction and dopaminergic cell death. Drug treatments can effectively reduce symptoms but often cause unwanted side effects. Stem cell therapies using cell replacement or indirect beneficial secretomes have recently emerged as potential therapeutic strategies. Although various types of stem cells have been proposed as possible candidates, adipose derived stem cells (ADSCs) are easily obtainable, more abundant, less ethically disputed, and able to differentiate into multiple cell lineages. However, treatment of PD using adult stem cells is known to be less efficacious than neuron or embryonic stem cell transplantation. Therefore, improved therapies are urgently needed. n-Butylidenephthalide (BP), which is extracted from Angelica sinensis, has been shown to have anti-inflammatory and neuroprotective effects. Indeed, we previously demonstrated that BP treatment of ADSCs enhances the expression of neurogenesis and homing factors such as nuclear receptor related 1 protein, stromal-derived factor 1, and brain-derived neurotrophic factor. In the present study, we examined the ability of BP-pretreated ADSC transplantation to improve PD motor symptoms and protect dopamine neurons in a mouse model of PD. We evaluated the results using neuronal behavior tests such as beam walking, rotarod, and locomotor activity tests. ADSCs with or without BP pretreatment were transplanted into the striatum. Our findings demonstrated that ADSC transplantation improved motor abilities with varied efficacies and that BP stimulation improved the therapeutic effects of transplantation. Dopaminergic cell numbers returned to normal in ADSC-transplanted mice after 22 d. In summary, stimulating ADSCs with BP improved PD recovery efficiency. Thus, our results provide important new strategies to improve stem cell therapies for neurodegenerative diseases in future studies. PMID- 29756521 TI - Cost Analysis of Initial Treatment With Endovascular Revascularization, Open Surgery, or Primary Major Amputation in Patients With Peripheral Artery Disease. AB - PURPOSE: To compare the total initial treatment costs for open surgery, endovascular revascularization, and primary major amputation within a single payer healthcare system. METHODS: A multicenter, retrospective analysis was undertaken to evaluate 1138 patients with symptomatic peripheral artery disease (PAD) who underwent 1017 endovascular procedures, 86 open surgeries, and 35 major amputations between 2013 and 2016. A cost-mix analysis was performed on individual patient data generated for selected diagnosis-related groups. Mean costs are presented with the 95% confidence interval (CI). RESULTS: There was no intergroup difference in demographics or private health insurance status. However, the amputation group had a higher proportion of emergency procedures (68.6% vs 13.3% vs 27.9%, p<0.001) and critical limb ischemia (88.6% vs 35.9% vs 37.2%, p<0.001) compared with the endovascular therapy and open surgery groups, respectively. The endovascular revascularization group spent less time in hospital and used fewer intensive care unit (ICU) resources compared with the open surgery and major amputation groups (hospital length of stay: 3.4 vs 10.0 vs 20.2 days, p<0.01; ICU: 2.4 vs 22.6 vs 54.6 hours, p<0.01), respectively. While mean prosthetic and device costs were higher in the endovascular group [AUD$2770 vs AUD$1658 (open) and AUD$1219 (amputation), p<0.01], substantial disparities were observed in costs associated with longer operating theater times, length of stay, and ICU utilization, which resulted in significantly higher costs in the open and amputation groups. After adjusting for confounders, the AUD$18,396 (95% CI AUD$16,436 to AUD$20,356) mean cost per admission for the endovascular revascularization group was significantly less (p<0.001) than the open surgery (AUD$31,908, 95% CI AUD$28,285 to AUD$35,530) and major amputation groups (AUD$43,033, 95% CI AUD$37,706 to AUD$48,361). CONCLUSION: Endovascular revascularization procedures for PAD cost the health payer less compared with open surgery and primary amputation. While devices used to deliver contemporary endovascular therapy are more expensive, the reduction in bed days, ICU utilization, and related hospital resources results in a significantly lower mean total cost per admission for the initial treatment. PMID- 29756522 TI - Pre-Clinical Testing of Therapies for Traumatic Brain Injury. AB - Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients. PMID- 29756523 TI - The Effect of Health Education by Pharmacists on 10-Year Atherosclerotic Cardiovascular Disease Risk: A Cluster-Randomized Control Study in a Low Socioeconomic Status Javanese Population. AB - BACKGROUND: Evidence from previous studies demonstrates that lifestyle modification reduces the incidence and complications of atherosclerotic cardiovascular disease. The study aimed to investigate the effect of a lifestyle intervention provided by pharmacists on the 10-year atherosclerotic cardiovascular disease (ASCVD) risk and quality of life (QoL) in a low socioeconomic status Javanese population. METHODS: This research was a cluster randomized controlled study of 1-year duration, conducted in a lower social economic community in the Sleman District of Yogyakarta, Indonesia. The eligible subjects were dichotomized into 2 groups: 40 to 55 years (n = 61 vs 65) and 56 to 70 years (n = 21 vs 43) for intervention and control subjects, respectively. The ASCVD score and risk factors within the age-based groups were analyzed using T test/Mann-Whitney test for continuous data or chi-square test for categorical data. RESULTS: The intervention and control subjects had similar baseline characteristics ( P > .05), including the ASCVD risk with the low- and high-risk classification for younger and elder subjects, respectively. At final follow-up, the younger intervention subjects had lower 10-year ASCVD risk ( P = .001), higher high-density lipoprotein cholesterol ( P = .02), smoking status ( P = .001), persistence rate ( P = .03), and QoL value for the physical and social function domains ( P < .05) than the control subjects, whereas the elder intervention subjects only had better ASCVD risk score than controls ( P = .03). Smoking interacting with intervention was the most influential variable on ASCVD risk in logistic regression analysis. CONCLUSION: The study demonstrates that the health education by the pharmacists produce significant outcomes of the ASCVD risk, smoking status, and QoL of physical and social function particularly in the younger group. PMID- 29756526 TI - Individual differences in the production of disfluency: A latent variable analysis of memory ability and verbal intelligence. AB - Recent work has begun to focus on the role that individual differences in executive function and intelligence have on the production of fluent speech. However, isolating the underlying causes of different types of disfluency has been difficult given the speed and complexity of language production. In this study, we focused on the role of memory abilities and verbal intelligence, and we chose a task that relied heavily on memory for successful performance. Given the task demands, we hypothesised that a substantial proportion of disfluencies would be due to memory retrieval problems. We contrasted memory abilities with individual differences in verbal intelligence as previous work highlighted verbal intelligence as an important factor in disfluency production. A total of 78 participants memorised and repeated 40 syntactically complex sentences, which were recorded and coded for disfluencies. Model comparisons were carried out using hierarchical structural equation modelling. Results showed that repetitions were significantly related to verbal intelligence. Unfilled pauses and repairs, in contrast, were marginally ( p < .09) related to memory abilities. The relationship in all cases was negative. Conclusions explore the link between different types of disfluency and particular problems arising in the course of production, and how individual differences inform theoretical debates in language production. PMID- 29756525 TI - The effectiveness of physical exercise as an intervention to reduce depressive symptoms following traumatic brain injury: A meta-analysis and systematic review. AB - Alongside the obvious health benefits, physical exercise has been shown to have a modest anti-depressant effect for people in the general population. To the authors' knowledge, there are no current literature reviews or meta-analyses available exploring this effect for people with a traumatic brain injury (TBI). A systematic review of intervention studies utilising physical exercise and mood outcome measures for a TBI population was performed in November 2016. Baseline and outcome data were extracted for the nine studies which met the inclusion criteria. Effect sizes were calculated for the three controlled trials and six uncontrolled trials and entered into the meta-analysis. Consistent with research in non-brain injury populations, the current meta-analysis identified a small to medium effect size of physical exercise on reducing depressive symptoms in people with a TBI. This would support further rigorous trials to provide additional evidence for the efficacy of physical exercise interventions for people with TBI. Limitations of the current meta-analysis and clinical implications are discussed. PMID- 29756524 TI - Chest Pain, Atherosclerotic Cardiovascular Disease Risk, and Cardiology Referral in Primary Care. AB - BACKGROUND: The atherosclerotic cardiovascular disease (ASCVD) 10-year risk estimate is recommended by cardiologists for determining risk of a cardiac event. However, the majority of patients presenting to primary care with chest pain have noncardiac etiologies. Therefore, we determined if high versus low ASCVD risk was associated with primary care physicians' referral to cardiology in patients with and without chest pain. METHODS: Deidentified electronic health record (EHR) data was obtained from 5795 patients treated in academic primary care clinics from 2008 to 2015. Referral to cardiology was defined by an EHR code, chest pain was defined by ICD-9-CM code (786.5) and ASCVD was modeled as high versus low risk. Separate logistic regression models were computed to estimate the association between chest pain and referral to cardiology, ASCVD risk and referral, and both chest pain and ASCVD risk and referral with adjustment for potential confounding factors. RESULTS: More patients with (n = 95, 7.8%) versus without (n = 75, 2.0%) chest pain were referred to cardiology ( P < .0001). Separate unadjusted models revealed chest pain and high versus low ASCVD risk were significantly associated with referral (odds ratio [OR] = 4.20; 95% confidence interval [CI] 3.07-5.73 and OR = 1.41; 95% CI 1.04-1.91, respectively). After adjusting for ASCVD risk and confounders, chest pain but not high ASCVD risk remained significantly associated with referral (OR = 1.75; 95% CI 1.24-2.47 and OR = 1.15; 95% CI 0.72-1.82, respectively). CONCLUSIONS: In primary care patients presenting with chest pain, ASCVD risk scores are not associated with referral to cardiology. Overall, less than 8% of patients with chest pain were referred. While there is no evidence to indicate excessive referral to cardiology, we posit that implementing ASCVD risk tools in decision aids could contribute to referring those most in need of cardiology care. PMID- 29756527 TI - When Will Telemedicine Appear in the ICU? AB - As our population ages and the demand for high-level intensive care unit (ICU) services increase, the ICU physician supply continues to lag. In addition, hospitals, physician groups, and patients are demanding rapid access for the highest level of expertise in the care of critically ill patients. Telemedicine in the ICU combined with remote patient monitoring has been increasingly touted as a model of care to increase efficiencies and quality of care. Telemedicine in the ICU provides the potential to connect critically ill patients to sophisticated specialty care on a 24/7 basis, even for those hospitalized in rural locations where access to timely specialty consultations are uncommon. Research on the use of telemedicine in the ICU has suggested improved outcomes, such as reductions in mortality, reductions in length of stay, and greater adherence to evidence-based guidelines. Although the clinical footprint of telemedicine in ICU has grown over the past 20 years, there has been a relative slowing of implementation. This review examines the clinical evidence supporting the use of telemedicine in the ICU and discusses the impact on clinical efficacy and costs of care. Additionally, we review the current hurdles to more rapid adoption, including the significant financial investment, different models of care affecting the return on investment, and the varied cultural attitudes that impact the success and acceptance of care models using telemedicine in the ICU. PMID- 29756528 TI - Stuttering Frequency, Speech Rate, Speech Naturalness, and Speech Effort During the Production of Voluntary Stuttering. AB - PURPOSE: Voluntary stuttering techniques involve persons who stutter purposefully interjecting disfluencies into their speech. Little research has been conducted on the impact of these techniques on the speech pattern of persons who stutter. The present study examined whether changes in the frequency of voluntary stuttering accompanied changes in stuttering frequency, articulation rate, speech naturalness, and speech effort. METHOD: In total, 12 persons who stutter aged 16 34 years participated. Participants read four 300-syllable passages during a control condition, and three voluntary stuttering conditions that involved attempting to produce purposeful, tension-free repetitions of initial sounds or syllables of a word for two or more repetitions (i.e., bouncing). The three voluntary stuttering conditions included bouncing on 5%, 10%, and 15% of syllables read. Friedman tests and follow-up Wilcoxon signed ranks tests were conducted for the statistical analyses. RESULTS: Stuttering frequency, articulation rate, and speech naturalness were significantly different between the voluntary stuttering conditions. Speech effort did not differ between the voluntary stuttering conditions. Stuttering frequency was significantly lower during the three voluntary stuttering conditions compared to the control condition, and speech effort was significantly lower during two of the three voluntary stuttering conditions compared to the control condition. CONCLUSIONS: Due to changes in articulation rate across the voluntary stuttering conditions, it is difficult to conclude, as has been suggested previously, that voluntary stuttering is the reason for stuttering reductions found when using voluntary stuttering techniques. Additionally, future investigations should examine different types of voluntary stuttering over an extended period of time to determine their impact on stuttering frequency, speech rate, speech naturalness, and speech effort. PMID- 29756529 TI - Analytical and ecotoxicological studies on degradation of fluoxetine and fluvoxamine by potassium ferrate. AB - A large amount of pharmaceuticals are flushed to environment via sewage system. The compounds are persistent in environment and are very difficult to remove in drinking water treatment processes. Degradation of fluoxetine (FLU) and fluvoxamine (FLX) by ferrate(VI) were investigated. For the 10 mg/L of FLU and FLX, 35% and 50% of the compounds were degraded in the presence of 50 mg/L FeO42- within 10 minutes, respectively. After 10 minutes of the reaction, degradation of FLU and FLX is affected by formation of by-products which were likely more reactive with ferrate and competed in the reaction with FeO42-. In the case of FLU, the identified degradation by-products were hydrofluoxetine, N-methyl-3 phenyl-2-propen-1-amine, 4-(trifluoromethyl)phenol and 1-{[(1R,S)-1-Phenyl-2 propen-1-yl]oxy}-4-(trifluoromethyl)benzene. In the case of FLX, the degradation by-products were fluvoxamine acid and 5-methoxy-1-[4-(trifluoromethyl)phenyl]pent 2-en-1-imine. The results of the ecotoxicological study based on protozoa Spirostomum ambiguum have shown that 50 mg/L FeO42- reduced toxicity of 10 mg/L of FLU and FLX by around 50%. However, in the case of FLX, the results of the ecotoxicological study suggested formation of slightly more toxic compound(s) than FLX during reaction with FeO42-. Application of ferrate(VI) is a viable option for drinking water treatment process; however, caution is needed due to formation of by-products with unknown human health risk. PMID- 29756530 TI - Occurrence of Spontaneous Cortical Spreading Depression Is Increased by Blood Constituents and Impairs Neurological Recovery after Subdural Hematoma in Rats. AB - Acute subdural hemorrhage (ASDH) is common and associated with severe morbidity and mortality. To date, the role of spontaneous cortical spreading depression (sCSD) in exaggerating secondary injury after ASDH, is poorly understood. The present study contains two experimental groups: First, we investigated and characterized the occurrence of sCSD after subdural blood infusion (300 MUL) via tissue impedance (IMP) measurement in a rat model. Second, we compared the occurrence and influence of sCSD on lesion growth and neurological deficit in the presence and absence of whole blood constituents. In the first experimental group, three IMP traits could be distinguished after ASDH: no sCSD, recurrent sCSD, and constant elevated IMP (anoxic depolarization [AD]). In the second experimental group, sCSD occurred more often after autologous blood, compared with paraffin oil infusion. Lesion volume 7 days post-ASDH was 27.3 +/- 6.8 mm3 after blood and 3.4 +/- 2.1 mm3 after paraffin oil infusion. Subgroup analysis showed larger lesion size in animals with sCSD, than in those without. Further, occurrence of sCSD led to worse neurological outcomes in both groups. sCSD occurs early after ASDH and does not depend on the presence of whole blood constituents. However, numbers and degree of sCSD are more frequent and severe after autologous blood infusion, compared with an inert volume substance. The occurrence of sCSD leads to lesion growth and worse neurological outcome. Thus, our data advocate close monitoring and targeted treatment of sCSD after ASDH evacuation. PMID- 29756531 TI - The Ethics of End-of-Trial Obligations in a Pediatric Malaria Vaccine Trial: The Perspectives of Stakeholders From Ghana and Tanzania. AB - This study explores stakeholder experiences and perspectives on end-of-trial obligations at the close of a phase II/III Pediatric Malaria Vaccine Trial (PMVT) [GSK/PATH-MVI RTS, S) (NCT00866619]. We conducted 52 key informant interviews with major stakeholders of an international multicentre PMVT in Ghana and Tanzania. The responses fell into four main themes: (a) Communicating End-of Trial, (b) Maintaining Health Care Services, (c) Dissemination of Results, and (d) Post-Trial Access. Interviewee responses shared important practical experiences and insights that complement current thinking in the literature on research ethics guidance: (a) accompany end-of-trial communication with information on personal and family health care responsibilities, (b) establish public health indicators to measure the impact of research on a health care system, PMID- 29756532 TI - Caring for a Dying Partner: The Male Experience. AB - OBJECTIVE: Caring for someone close who is dying, such as a spouse, is an emotive experience; however, there is little research examining the phenomenon of caregiving for a spouse at the end of life and of men's experiences specifically. Existing literature suggests that men who are providing care are less likely to seek help than women, especially psychological and emotional support for themselves. The aim of the current study was to explore the lived experiences of men caring for a dying spouse or partner and their help-seeking for themselves during this time. METHODS: Eight semi-structured interviews were conducted with men caring for their partner, who was receiving palliative care. Interviews were transcribed verbatim and analyzed using interpretative phenomenological analysis. RESULTS: Three superordinate themes emerged from the data, "Illness Questions Everything," "Constructing the Caring Role," and "Help-Seeking at the Limit." The arrival of a terminal illness into a partnership is traumatic, and while it can deepen relationships, it can also create distance. The carer role has conflicting demands and carers need to make sense of their experience in order for the carer role to be constructed as a source of purpose or meaning. Finally, the idea of seeking help for oneself as a carer during this time is seen as "incompatible," unmanageable, and can only be considered if constructed as a "last resort." SIGNIFICANCE OF RESULTS: Men care too; however, they can feel confused by this role and unsure as to how this fits with their identity as a man. They make sense of this by identifying as a partner whose "duty" or "responsibility" is to provide care. Although this is an understandable stance, it puts them at risk of further emotional, psychological, and physiological difficulties if their own needs are not met. Men need to be supported during this time and their caring qualities need to be destigmatized and demystified so that they can feel more able to identify with the role and look after themselves while caring for their dying partner. PMID- 29756534 TI - Neurostimulant Prescribing Patterns in Children Admitted to the Intensive Care Unit after Traumatic Brain Injury. AB - Neurostimulant medications are commonly prescribed following traumatic brain injury (TBI) in adults; little is known about their use in children with TBI. Our objective was to analyze neurostimulant prescribing practices from 2005 to 2015 in children admitted to the intensive care unit (ICU) with TBI. We hypothesized that neurostimulant prescriptions have increased over time and are associated with older age and injury severity. A retrospective cohort study of patients age 1 month to 18 years with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge diagnosis code for TBI admitted to the ICU between 2005 and 2015 in 37 pediatric hospitals included in the Pediatric Health Information System was conducted. Variables examined include patient and injury characteristics and neurostimulant medication use. Descriptive statistics and multi-variable logistic regression testing were used to determine variables associated with neurostimulant prescription. Of 30,881 patients with TBI, most were male (64%) and age 0-4 years (43%). In patients with mechanism of injury reported (n = 21,998), TBI was most frequently due to falls (36%) and motor vehicle collisions (36%). One thousand sixty-four neurostimulants were prescribed to 878 (3%) patients with 41% of prescriptions for amantadine and 38% for methylphenidate. Neurostimulants were prescribed a median (interquartile range) of 17 (8-35) days post-injury and increased over the study decade (R2 = 0.806). In a multi-variable analysis, variables most strongly associated with receipt of a neurostimulant were age 14-18 years (odds ratio 5.8, 95% confidence interval [4.3,7.8]), motor vehicle collision (3.1, [2.4,4.2]), intracranial pressure (ICP) monitor (3.8, [3.1,4.5]), and mechanical ventilation (3.4, [2.7,4.3]). Use of neurostimulants following pediatric TBI is uncommon, has increased over time, and is associated with indicators of higher severity of illness. Knowledge of prescribing practices may assist in optimizing the design of efficacy and outcome studies that will inform clinical guidelines. PMID- 29756535 TI - Building the Case: Changing Consumer Perceptions of the Value of Expanded Community Pharmacist Services. AB - BACKGROUND: The role of the community pharmacist has traditionally been a medication dispenser; however, community pharmacists' responsibilities must expand to include more direct patient care services in order to transform primary care practice. OBJECTIVES: Use case-based scenarios to (1) determine factors that contribute to positive and negative consumer perceptions of expanded community pharmacist patient care roles, (2) identify facilitators and barriers that contribute to consumer perceptions of the value of expanded community pharmacist patient care services, and (3) develop a successful approach and strategies for increasing consumer advocacy for the value of expanded community pharmacist patient care services. METHODS: Two consumer focus groups used scenario-based guided discussions and Likert scale questionnaires to elicit consumer reactions, facilitators, and barriers to expanded community pharmacist services. RESULTS: Convenience, timeliness, and accessibility were common positive reactions across all 3 scenarios. Team approach to care and trust were viewed as major facilitators. Participant concerns included uncertainty about pharmacist training and qualifications, privacy, pharmacists' limited bandwidth to accept new tasks, and potential increased patient costs. Common barriers to service uptake included a lack of insurance payment and physician preference to provide the services. CONCLUSION: Consumer unfamiliarity with non-traditional community pharmacist services is likely an influencer of consumers' hesitancy to utilize such services; therefore, an opportunity exists to engage consumers and advocacy organizations in supporting expanded community pharmacist roles. This study can inform consumers, advocates, community pharmacists, primary care providers, and community-based organizations on methods to shape consumer perceptions on the value of community pharmacist expanded services. PMID- 29756536 TI - Intervention for a lexical reading and spelling difficulty in two Greek-speaking primary age children. AB - An intervention study was carried out with two nine-year-old Greek-speaking dyslexic children. Both children were slow in reading single words and text and had difficulty in spelling irregularly spelled words. One child was also poor in non-word reading. Intervention focused on spelling in a whole-word training using a flashcard technique that had previously been found to be effective with English speaking children. Post-intervention assessments conducted immediately at the end of the intervention, one month later and then five months later showed a significant improvement in spelling of treated words that was sustained over time. In addition, both children showed generalisation of improvement to untrained words and an increase in scores in a standardised spelling assessment. The findings support the effectiveness of theoretically based targeted intervention for literacy difficulties. PMID- 29756533 TI - Genetic Engineering of Mesenchymal Stem Cells for Differential Matrix Deposition on 3D Woven Scaffolds. AB - Tissue engineering approaches for the repair of osteochondral defects using biomaterial scaffolds and stem cells have remained challenging due to the inherent complexities of inducing cartilage-like matrix and bone-like matrix within the same local environment. Members of the transforming growth factor beta (TGFbeta) family have been extensively utilized in the engineering of skeletal tissues, but have distinct effects on chondrogenic and osteogenic differentiation of progenitor cells. The goal of this study was to develop a method to direct human bone marrow-derived mesenchymal stem cells (MSCs) to deposit either mineralized matrix or a cartilaginous matrix rich in glycosaminoglycan and type II collagen within the same biochemical environment. This differential induction was performed by culturing cells on engineered three-dimensionally woven poly(E caprolactone) (PCL) scaffolds in a chondrogenic environment for cartilage-like matrix production while inhibiting TGFbeta3 signaling through Mothers against DPP homolog 3 (SMAD3) knockdown, in combination with overexpressing RUNX2, to achieve mineralization. The highest levels of mineral deposition and alkaline phosphatase activity were observed on scaffolds with genetically engineered MSCs and exhibited a synergistic effect in response to SMAD3 knockdown and RUNX2 expression. Meanwhile, unmodified MSCs on PCL scaffolds exhibited accumulation of an extracellular matrix rich in glycosaminoglycan and type II collagen in the same biochemical environment. This ability to derive differential matrix deposition in a single culture condition opens new avenues for developing complex tissue replacements for chondral or osteochondral defects. PMID- 29756538 TI - Comparison between three in vitro methods to measure magnesium degradation and their suitability for predicting in vivo degradation. AB - A lot of research has been done in the field of magnesium-based implant material. This study is focused on finding an explanation for the large disparity in results from similar experiments in literature. The hypothesis is that many different measurement protocols are used to quantify magnesium degradation and this leads to inconsistent results. Cylindrical, pure magnesium samples were used for this study. The degradation took place in revised simulated body fluid at 37 degrees C. Hydrogen evolution was measured to quantify the degradation. Two commonly used experimental protocols were examined: static conditions and a fluid changing method. For static testing, the samples stayed in fluid. For the fluid changing method, the fluid was changed after 2 and 5 days of immersion. In addition, a new method with continuous fluid flow was established. After an initial phase, the results confirm that for all three methods, the degradation behavior differs strongly. The static condition results in a very slow degradation rate. The fluid change method leads to a similar behavior like the static condition except that the degradation was speeded up after the fluid changes. The continuous degradation is linear for a long period after the initial phase. In comparison with in vivo degradation behavior, the degradation process in continuous flow shows the best fitting. The accumulation of degradation products, especially the increasing pH value, has a strong inhibiting effect. This cannot be observed in vivo so that a constant experimental environment realizable by continuous flow is more suitable for magnesium-based implant material testing. PMID- 29756537 TI - Use of negative pressure wound therapy in a chronic leg wound with coexisting rheumatoid arthritis: a case study. AB - We present a case of a 69-year-old woman with rheumatoid arthritis. The patient's condition was managed with steroid therapy for more than 12 years. She had a coexisting infected chronic ulceration in the left leg, which was treated with negative pressure wound therapy for 52 days. Use of this therapy within the wound reduced exudate and the bacterial count, which dramatically accelerated the process of wound healing. PMID- 29756539 TI - Skin Regeneration with a Scaffold of Predefined Shape and Bioactive Peptide Hydrogels. AB - We developed a highly elastic customized scaffold for soft tissue regeneration and combined them with bioactive hydrogels with stem cell-inducing ability. This was done to mimic mechanical properties of native soft tissues and improve the viability of transplanted cells as well as efficiency of tissue regeneration. The proposed study was aimed at evaluating various characteristics of scaffolds and investigating their tissue-regenerating ability. Finger-shaped porous scaffolds were successfully fabricated by an indirect 3D printing of poly (L-lactide-co-E caprolactone) (PLCL), which provides high elasticity for soft tissue engineering. In addition, a self-assembling peptide hydrogel coupled with substance P (RARADADARARADADA/RARADADARARADADA-substance P, RADA16/RADA16-SP) was used to accelerate angiogenesis and recruit intrinsic mesenchymal stem cells (MSCs). This study included three kinds of groups: Group I = PLCL scaffold with human dermal fibroblasts (HDFs) (P+C), Group II = PLCL scaffold with HDFs and RADA16 (P+C+R), and Group III = PLCL scaffold with HDFs, RADA16, and RADA16-SP (P+C+R+S). The samples were implanted into immunodeficient mice subcutaneously and harvested at 1 and 4 weeks. Tissue regeneration was evaluated by histological analysis with hematoxylin and eosin (H&E) and Masson's trichrome (MT) staining. The images showed that a large number of cells were recruited into the scaffolds, and collagen was deposited in the constructs of the P+C+R+S group. Additionally, recruitment of MSCs, angiogenesis, and collagen were observed by immunofluorescence staining. The results show that the P+C+R+S group had more type I and type III collagen, which are formed in soft tissues, and were deposited on the scaffold compared with the other groups. Moreover, more blood vessels and MSCs were induced in the P+C+R+S group than in those of the P + C and P+C+R groups. Consequently, the results suggest that the construct of the customized porous PLCL scaffold and RADA16/RADA16-SP hydrogel could be a good treatment modality to treat skin defects. PMID- 29756540 TI - Immunological recovery in patients with pulmonary tuberculosis after intensive phase treatment. AB - Objectives This study aimed to examine the change and significance of immune parameters in patients with sputum smear-positive pulmonary tuberculosis (TB) after 2 months of intensive phase anti-TB treatment. Methods The immune parameters of 232 cases of sputum smear-positive pulmonary TB were detected before and after 2 months of intensive phase anti-TB treatment and compared with 50 cases from healthy volunteers (controls). The T lymphocyte cell population in peripheral blood was detected using flow cytometry. Serum levels of interleukin (IL)-1beta, soluble interleukin-2 receptor, IL-6, and tumour necrosis factor alpha were measured by ELISA. Results After 2 months of intensive phase anti-TB treatment, a reduction in the percentage of CD4+ T cells showed a significant restoration similar to that of controls. Moreover, after intensive anti-TB treatment, serum levels of IL-1beta, soluble interleukin-2 receptor, IL-6, and tumour necrosis factor-alpha were significantly decreased compared with before treatment. Additionally, serum levels of IL-1beta and IL-6 showed a diminished recovery compared with controls. Conclusions Our findings suggest immunological recovery in patients with pulmonary TB after intensive phase treatment. Therefore, serum cytokine levels are considered potential host biomarkers for monitoring the response of treatment for pulmonary TB. PMID- 29756541 TI - Does Reverse Triiodothyronine Testing Have Clinical Utility? An Analysis of Practice Variation Based on Order Data from a National Reference Laboratory. AB - BACKGROUND: Clinical laboratories are under pressure to increase value by improving test utilization. The clinical utility of reverse triiodothyronine (rT3) is controversial. A study was conducted to identify order patterns that might suggest inappropriate utilization of rT3. METHODS: All orders for thyroid tests placed over a period of one year at a national reference laboratory were reviewed. Order patterns by client (hospital) and by provider were analyzed. A Pareto analysis was conducted to determine the percentage of orders placed as a function of the percentage of providers. A systematic review of the indexed literature and an informal review of the web were conducted to identify indications for rT3 testing. RESULTS: There were 402,386 orders for 447,664 thyroid tests, including 91,767 orders for rT3. These orders were placed by 60,733 providers located at 1139 different organizations. Only 20% of providers who ordered thyroid tests placed an order for rT3. Of those who placed an order for rT3, 95% placed two orders or fewer for rT3. One hundred providers (0.1% of the 60,733 providers who placed orders for thyroid tests) accounted for 29.5% of the orders for rT3. Of the 100 providers, 60 with the highest order volumes for rT3 were classified as practitioners of functional medicine. A systematic review of Medline found little evidence to support the high volumes of orders for rT3. A survey of Web sites for functional medicine suggests that rT3 is useful for the diagnosis of rT3 dominance and can be used to direct triiodothyronine replacement therapy. CONCLUSIONS: There is wide practice variation in rT3 testing. A high proportion of tests are ordered by a relatively small proportion of providers. There is little evidence to support high volumes of rT3 testing placed by some practitioners. PMID- 29756542 TI - Campylobacteriosis in dogs and cats: a review. AB - Campylobacter species are commonly isolated from faecal samples collected from dogs and cats, with the most prevalent species being C. upsaliensis, C. helveticus, and C. jejuni. Although the majority of dogs and cats are subclinically infected, some will develop mild to moderate enteritis. Immature animals, animals from intensive housing backgrounds, and animals with concurrent disease are especially predisposed to infection and the development of clinical signs. Bacterial culture methods applied in diagnostic laboratories remain biased to C. jejuni and C. coli detection, but molecular methods to diagnose Campylobacter spp. infections in dogs and cats have become widely available and can aid rapid and accurate diagnosis. Multilocus sequence typing has also been developed for subtyping different strains and has been used in epidemiological investigations. In the majority of cases, clinical signs are self-limiting and antimicrobial treatment is not warranted. Campylobacter spp. isolated from dogs and cats have shown resistance to commonly used antimicrobials, so antimicrobial therapy should only be administered where this is justified. Contact with dogs and cats is a recognised risk factor for human campylobacteriosis, thus people living or working in close contact with cats and dogs should be made aware of the zoonotic organisms these animals can shed. PMID- 29756543 TI - Postdoctoral Opportunities for Nursing PhD Graduates: A Resource Guide. AB - Before completing a nursing PhD program, doctoral students are encouraged to seek out and apply for a position in one of many, often highly competitive postdoctoral programs. These programs include the more traditional National Institutes of Health (NIH) funded experiences, such as the T32, as well as the nontraditional institution funded positions, including the associate faculty role. Graduates often need guidance on which postdoctoral programs are available, the resources each program offers to promote development of the applicant's program of research, the disadvantages of each program, and what each program uses as benchmarks for success. This article summarizes both traditional and nontraditional postdoctoral positions including the T32, F32, F99/K00, T90/R90, research supplements, associate faculty, research associate, and hospital affiliated postdoctoral positions. This article updates previous papers describing postdoctoral opportunities and offers a starting place to aide PhD students planning their postgraduate activities in seeking and evaluating these positions. PMID- 29756544 TI - Influence of malnutrition on the development of the central nervous system of malnourished children. AB - INTRODUCTION: Protein-caloric malnutrition is a public health concern in certain areas of the Brazil. It can affect growth, the auditory nervous system development and, consequently, the cognition. This study compared the Brainstem Auditory Evoked Potential (BAEP) between malnourished and eutrophic children. METHODS: A total of 111 children, aged 0-60 months, were examined: 57 were malnourished, according to the World Health Organization criteria, and 54 were normo-nourished. All the subjects underwent otorhinolaryngological evaluations and had acoustic immittance and transient evoked otoacoustic emissions within the normal range. The BAEP responses to click and tone burst stimuli were recorded at intensities of 80, 60, 40, and 30 dBNA. RESULTS: We observed that latencies of I, III, and V waves and interpeaks III-V at 80 dBNA with click stimuli were significantly higher in all malnourished children when compared to those in the eutrophic children, as was the I-V interval in the 0- to 24-month group. The V wave latencies at those intensities were also significantly higher in malnourished children. CONCLUSIONS: Malnourished children presented changes in BAEP characterized by delayed wave latency and interpeak intervals when compared to eutrophic children, suggesting alterations in both peripheral and central auditory pathways development and maturation. PMID- 29756545 TI - In Vitro and In Vivo Correlation of Bone Morphogenetic Protein-2 Release Profiles from Complex Delivery Vehicles. AB - Local sustained delivery of bioactive molecules from biomaterials is a promising strategy to enhance bone regeneration. To optimize delivery vehicles for bone formation, the design characteristics are tailored with consequential effect on bone morphogenetic protein-2 (BMP-2) release and bone regeneration. Complying with the 3R principles (Replacement, Reduction, and Refinement), the growth factor release is often investigated in vitro using several buffers to mimic the in vivo physiological environment. However, this remains an unmet need. Therefore, this study investigates the in vitro-in vivo correlation (IVIVC) of BMP-2 release from complex delivery vehicles in several commonly used in vitro buffers: cell culture model, phosphate buffered saline, and a strong desorption buffer. The results from this study showed that the release environment affected the BMP-2 release profiles, creating distinct relationships between release versus time and differences in extent of release. According to the guidance set by the U.S. Food and Drug Administration (FDA), IVIVC resulted in level A internal predictability for individual composites. Since the IVIVC was influenced by the BMP-2 loading method and composite surface chemistry, the external predictive value of the IVIVCs was limited. These results show that the IVIVCs can be used for predicting the release of an individual composite. However, the models cannot be used for predicting in vivo release for different composite formulations since they lack external predictability. Potential confounding effects of drug type, delivery vehicle formulations, and application site should be added to the equation to develop one single IVIVC applicable for complex delivery vehicles. Altogether, these results imply that more sophisticated in vitro systems should be used in bone regeneration to accurately discriminate and predict in vivo BMP-2 release from different complex delivery vehicles. PMID- 29756546 TI - Sinomenine Induces G1-Phase Cell Cycle Arrest and Apoptosis in Malignant Glioma Cells Via Downregulation of Sirtuin 1 and Induction of p53 Acetylation. AB - Sinomenine, a bioactive alkaloid isolated from the traditional Chinese herb Sinomenium acutum, possesses antiinflammatory, antinociceptive, antifibrotic, and antitumorigenic properties. In this work, we sought to explore the biological effects of sinomenine on glioma cells. It was found that sinomenine caused a concentration-dependent inhibition of viability in both U87 and U251 glioma cells. Sinomenine at 16 MUmol/L caused 55% to 60% reduction in the proliferation of U87 and U251 cells. Moreover, sinomenine treatment induced a G0/G1 cell cycle arrest and apoptosis. Mechanistically, sinomenine promoted p53 expression and acetylation and reduced the expression of sirtuin 1. Ectopic expression of sirtuin 1 significantly prevented sinomenine-induced p53 acetylation and growth suppression in glioma cells. Moreover, sinomenine inhibited the growth of U87 xenograft tumors in vivo and raised the p53 protein expression. Collectively, sinomenine shows antiproliferative effects against glioma cells which is mediated through downregulation of sirtuin 1 and induction of p53 activity. PMID- 29756547 TI - Well-Being Correlates of Perceived Positivity Resonance: Evidence From Trait and Episode-Level Assessments. AB - Positivity resonance is a type of interpersonal connection characterized by shared positivity, mutual care and concern, and behavioral and biological synchrony. Perceived positivity resonance is hypothesized to be associated with well-being. In three studies ( N = 175, N = 120, N = 173), perceived positivity resonance was assessed at the trait level (Study 1) or the episode level, using the Day Reconstruction Method (Studies 2 and 3). Primary analyses reveal that perceived positivity resonance is associated with flourishing mental health, depressive symptoms, loneliness, and illness symptoms. These associations largely remain statistically significant when controlling for daily pleasant emotions or social interaction more generally. Ancillary analyses in Studies 2 and 3 support the construct validity of the episode-level assessment of perceived positivity resonance. The overall pattern of results is consistent with Positivity Resonance Theory. Discussion centers on avenues for future research and the need for behavioral interventions. PMID- 29756548 TI - Threat to the Group's Image Can Motivate High Identifiers to Take Action Against In-group Transgressions. AB - When transgressions are committed by a group, those highly identified with the group are often least likely to recognize the transgressions, feel collective guilt, and engage in action to address them. We hypothesized that especially among high identifiers, demonstrating that in-group transgressions threaten the group's image can induce normative conflict and thus collective guilt and action. In the first study, we demonstrate that high (vs. low) image threat increases normative conflict among high identifiers. In Study 2, we show that inducing normative conflict through image threat leads to increased collective guilt and collective action among high identifiers. In Study 3, we replicate this effect with the addition of a control condition to demonstrate increased normative conflict and collective guilt relative to both a low threat and baseline conditions. In Study 4, we again replicate these effects with a modified manipulation that more precisely manipulated image threat. Together, these studies indicate that image threat can be an effective motivator for high identifiers to address in-group transgressions. PMID- 29756549 TI - Family Functioning in Adolescents with Perinatal HIV Infection. AB - This study aimed to assess family functioning in adolescents with perinatal HIV infection receiving antiretroviral therapy compared with healthy controls. Correlations between self-reported and caregiver-reported family functions were also evaluated. A sample of 195 participants including 65 perinatally HIV infected adolescents and 130 healthy controls were enrolled. The total family functioning score in HIV-infected adolescents was significantly lower than that in healthy controls by self-report (105.86 vs 115.41; P <= .001). Caregivers of HIV-infected adolescents also reported lower scores of family functioning than those of controls (109.91 vs 114.98; P <= .001). Among the HIV-infected group, there was no or minimal correlation between the self-reported and caregiver reported total scores of family functioning. However, there were moderate correlations between self-reported and caregiver-reported family functioning total scores in the control group. Overall, HIV-infected adolescents reported lower family functioning than healthy controls. Improved functioning in the family may help with better adjustment in perinatally HIV-infected adolescents. PMID- 29756550 TI - Chronic Disease Self-Management Challenges among Rural Women Living with HIV/AIDS in Prakasam, Andhra Pradesh, India: A Qualitative Study. AB - Rural women living with HIV/AIDS (WLHA) in India experience challenges self managing HIV/AIDS in their rural communities. The purpose of this qualitative study was to explore factors influencing their care and antiretroviral treatment (ART) adherence. Themes that emerged from the qualitative focus groups among WLHA (N = 24) in rural Prakasam, Andhra Pradesh, India, included: (1) coming to know about HIV and other health conditions, (2) experiences being on ART, (3) challenges maintaining a nutritious diet, (4) factors affecting health care access and quality, and (5) seeking support for a better future. Chronic disease self-management in rural locales is challenging, given the number of barriers which rural women experience on a daily basis. These findings suggest a need for individual- and structural-level supports that will aid in assisting rural WLHA to self-manage HIV/AIDS as a chronic illness. PMID- 29756551 TI - Religion and HIV-Related Stigma among Nurses Who Work with People Living with HIV/AIDS in Puerto Rico. AB - HIV-related stigma among nurses can impact health care services for people with HIV/AIDS (PWHA). health care professionals' religious views can potentially foster stigmatizing attitudes. There is scarce scientific literature exploring the role of religion on HIV/AIDS stigma among nurses. This study aimed to explore the role of religion in the stigmatization of PWHA by nurses in Puerto Rico. We conducted an exploratory study using qualitative techniques. We conducted 40 in depth interviews with nurses who provided services to PWHA. Three main factors emerged in the analysis as contributors to HIV/AIDS stigmatization: (1) nurses' personal religious experiences, (2) religion as a rationale for HIV-related stigma, and (3) religious practices during health care delivery. The results show that religious beliefs play a role in how nurses understood HIV/AIDS and provided service. Results point toward the need for interventions that address personal religious beliefs while reducing HIV/AIDS stigma among nurses. PMID- 29756552 TI - Management of Traumatic Hip Fracture in the Palliative Care Unit. AB - We report on the case of an elderly patient in a palliative care unit who fell and sustained a hip fracture. Hip fractures are potentially terminal events for elderly patients with other life-limiting conditions. The case highlights the need for more evidence to determine the best approach to care for hip fractures in patients who are in the final weeks or months of life. PMID- 29756553 TI - Effects of Expanding Envelope Fluctuations on Consonant Perception in Hearing Impaired Listeners. AB - This study examined the perceptual consequences of three speech enhancement schemes based on multiband nonlinear expansion of temporal envelope fluctuations between 10 and 20 Hz: (a) "idealized" envelope expansion of the speech before the addition of stationary background noise, (b) envelope expansion of the noisy speech, and (c) envelope expansion of only those time-frequency segments of the noisy speech that exhibited signal-to-noise ratios (SNRs) above -10 dB. Linear processing was considered as a reference condition. The performance was evaluated by measuring consonant recognition and consonant confusions in normal-hearing and hearing-impaired listeners using consonant-vowel nonsense syllables presented in background noise. Envelope expansion of the noisy speech showed no significant effect on the overall consonant recognition performance relative to linear processing. In contrast, SNR-based envelope expansion of the noisy speech improved the overall consonant recognition performance equivalent to a 1- to 2-dB improvement in SNR, mainly by improving the recognition of some of the stop consonants. The effect of the SNR-based envelope expansion was similar to the effect of envelope-expanding the clean speech before the addition of noise. PMID- 29756555 TI - Nuances of integrating palliative care and end-stage liver disease PMID- 29756554 TI - Happy but overconfident: positive affect leads to inaccurate metacomprehension. AB - When learning from text, it is important that learners not only comprehend the information provided but also accurately monitor and judge their comprehension, which is known as metacomprehension accuracy. To investigate the role of a learner's affective state for text comprehension and metacomprehension accuracy, we conducted an experiment with N = 103 university students in whom we induced positive, negative, or neutral affect. Positive affect resulted in poorer text comprehension than neutral affect. Positive affect also led to overconfident predictions, whereas negative and neutral affect were both associated with quite accurate predictions. Independent of affect, postdictions were rather underconfident. The results suggest that positive affect bears processing disadvantages for achieving deep comprehension and adequate prediction accuracy. Given that postdictions were more accurate, practice tests might represent an effective instructional method to help learners in a positive affective state to accurately judge their text comprehension. PMID- 29756556 TI - Mapping the scope of occupational therapy practice in palliative care: A European Association for Palliative Care cross-sectional survey. AB - BACKGROUND: Occupational therapists play an integral role in the care of people with life-limiting illnesses. However, little is known about the scope of occupational therapy service provision in palliative care across Europe and factors influencing service delivery. AIM: This study aimed to map the scope of occupational therapy palliative care interventions across Europe and to explore occupational therapists' perceptions of opportunities and challenges when delivering and developing palliative care services. DESIGN: A 49-item online cross-sectional survey comprised of fixed and free text responses was securely hosted via the European Association for Palliative Care website. Survey design, content and recruitment processes were reviewed and formally approved by the European Association for Palliative Care Board of Directors. Descriptive statistics and thematic analysis were used to analyse data. Setting/respondents: Respondents were European occupational therapists whose caseload included palliative care recipients (full-time or part-time). RESULTS: In total, 237 valid responses were analysed. Findings demonstrated a consistency in occupational therapy practice in palliative care between European countries. Clinician time was prioritised towards indirect patient care, with limited involvement in service development, leadership and research. A need for undergraduate and postgraduate education was identified. Organisational expectations and understanding of the scope of the occupational therapy role constrain the delivery of services to support patients and carers. CONCLUSION: Further development of occupational therapy in palliative care, particularly capacity building in leadership and research activities, is warranted. There is a need for continuing education and awareness raising of the role of occupational therapy in palliative care. PMID- 29756557 TI - Barriers to end-of-life discussions among hematologists: A qualitative study. AB - BACKGROUND: Integrated palliative care is correlated with earlier end-of-life discussion and improved quality of life. Patients with haematological malignancies are far less likely to receive care from specialist palliative or hospice services compared to other cancers. AIM: The main goal of this study was to determine hematologists' barriers to end-of-life discussions when potentially fatal hematological malignancies recur. DESIGN: Qualitative grounded theory study using individual interviews. SETTING/PARTICIPANTS: Hematologists ( n = 10) from four hematology units were asked about their relationships with their patients and their attitudes toward prognosis and end-of-life discussions at the time of recurrence. RESULTS: As long as there are potential treatments, hematologists fear that end-of-life discussions may undermine their relationship and the patient's trust. Because of their own representations, hematologists have great difficulty opening up to their patients' end-of-life wishes. When prognosis is uncertain, negative outcome, that is, death, is not fully anticipated. Persistent hope silences the threat of death. CONCLUSION: This study reveals some of the barriers clinicians face in initiating early discussion about palliative care or patients' end-of-life care plan. These difficulties may explain why early palliative care is little integrated into the hematology care model. PMID- 29756558 TI - Social Integration and Domestic Violence Support in an Indigenous Community: Women's Recommendations of Formal Versus Informal Sources of Support. AB - Throughout North America, indigenous women experience higher rates of intimate partner violence and sexual violence than any other ethnic group, and so it is of particular importance to understand sources of support for Native American women. In this article, we use social network analysis to study the relationship between social integration and women's access to domestic violence support by examining the recommendations they would give to another woman in need. We ask two main questions: First, are less integrated women more likely to make no recommendation at all when compared with more socially integrated women? Second, are less integrated women more likely than more integrated women to nominate a formal source of support rather than an informal one? We use network data collected from interviews with 158 Canadian women residing in an indigenous community to measure their access to support. We find that, in general, less integrated women are less likely to make a recommendation than more integrated women. However, when they do make a recommendation, less integrated women are more likely to recommend a formal source of support than women who are more integrated. These results add to our understanding of how access to two types of domestic violence support is embedded in the larger set of social relations of an indigenous community. PMID- 29756559 TI - Help-Seeking Behaviors for Intimate Partner Violence Perpetration by Men Receiving Substance Use Treatment: A Mixed-Methods Secondary Analysis. AB - Despite the high prevalence of intimate partner violence (IPV) perpetration by men receiving substance use treatment, little is known about their help-seeking behaviors for IPV. A secondary analysis of a mixed-methods study of men receiving substance use treatment who perpetrated IPV examined the prevalence, characteristics, and barriers associated with IPV perpetration disclosure and help-seeking. In total, 170 men were interviewed using a structured questionnaire, and a subsample of 20 were interviewed in-depth about their experiences. Logistic regression determined variables associated with disclosure and help-seeking. Thematic analysis of the in-depth interviews explored barriers to disclosure and help-seeking. Only half the participants had told anyone about their IPV perpetration and about one quarter reported having sought any sort of support. Whereas participants were more likely to disclose their IPV perpetration to informal resources (such as friends or family), they tended to seek help from formal resources (such as health professionals or the police). A greater proportion of physical IPV perpetrators, who had disclosed, had been arrested or had police involvement for IPV, suggesting that their disclosure may not have been voluntary. The following themes emerged from the qualitative data about the barriers to disclosure and help-seeking for IPV perpetration: fear that their children would be taken into care by social services, shame and embarrassment, and a minimization or normalization of their behavior. In addition, many participants highlighted that they had never been previously asked about IPV during treatment for substance use and stressed the need for greater expertise in or knowledge of this topic from specialist services. Substance use treatment services should enquire about men's relationships and IPV perpetration to facilitate disclosure and provide support. Further research is necessary to determine the context of disclosure and help-seeking for IPV perpetration to increase the likelihood of identification. PMID- 29756561 TI - Advances in the treatment of explicit water molecules in docking and binding free energy calculations. AB - BACKGROUND: The inclusion of direct effects mediated by water during the ligand receptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. OBJECTIVE: In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. RESULTS: Here, we analyse software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. CONCLUSIONS: Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon. PMID- 29756560 TI - Sexual Coercion Perpetration and Victimization: Gender Similarities and Differences in Adolescence. AB - Sexual coercion is a worldwide health problem that endangers the well-being of those involved. In the same line of the most recent and comprehensive studies, this study sought to investigate the extent of sexual coercion, both perpetration and victimization, among male and female adolescents. Moreover, it jointly analyzed the predictive power of different variables that have been considered as useful to design preventive programs. For this purpose, a cross-sectional study, using proportional stratified cluster sampling, was performed and 1,242 Spanish adolescents (15-19 years old) were surveyed. Results show that both genders had reported committing and suffering sexual coercion. However, perpetration was reported more often by males: no significant gender difference was found in victimization. It was also concluded that need for control and power, normative beliefs about sexual coercion, hostile sexism, negative alcohol expectancies, and sociosexual orientation were significant predictors of perpetration for both genders. Concerning victimization, need for control and power and normative beliefs were found to be significant predictors for males and females, as were negative alcohol expectancies and sexual esteem, though only for males. According to these results, both genders can be both perpetrators and victims of sexual coercion in adolescence, but not to the same extent. Moreover, preventive programs should include activities related to perpetration and victimization, taking into account the effectiveness of their components to intervene with male and female adolescents. PMID- 29756562 TI - Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine. AB - Matrix metalloproteinases (MMPs) play a key role in remodelling of the extracellular matrix (ECM) and, at the same time, influence cell differentiation, migration, proliferation and survival. Their importance in variety of human diseases including cancer, rheumatoid arthritis, pulmonary emphysema and fibrotic disorders has been known for many years but special attention should be paid on the role of MMPs in the central nervous system (CNS) disorders. Till now, there are not many well documented physiological MMP target proteins in the brain and only some pathological ones. Numerous neurodegenerative diseases is a consequence or result in disturbed remodeling of brain ECM, therefore proper action of MMPs as well as control of their activity may play crucial roles in the development and the progress of these diseases. In present review we discuss the role of metalloproteinase inhibitors, from the well-known natural endogenous tissue inhibitors of metalloproteinases (TIMPs) through exogenous synthetic ones like (4 phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines, batimastat (BB-94) and FN-439. As the MMP-TIMP system has been well described in physiological development as well as in pathological conditions mainly in neoplasctic diseases, the knowledge about the enzymatic system in mammalian brain tissue remain still poorly understood in this context. Therefore, we focus on MMPs inhibition in the context of physiological function of adult brain as well as pathological conditions including neurodegenerative diseases, brain injuries and others. PMID- 29756563 TI - Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases. AB - Inflammation plays a crucial role in the development of many complex diseases and disorders including autoimmune diseases, metabolic syndrome, neurodegenerative diseases, and cardiovascular pathologies. Prostaglandins play a regulatory role in inflammation. Cyclooxygenases are the main mediators of inflammation by catalyzing the initial step of arachidonic acid metabolism and prostaglandin synthesis. The differential expression of the constitutive isoform COX-1 and the inducible isoform COX-2, and the finding that COX-1 is the major form expressed in the gastro-intestinal tract, lead to the search for COX-2-selective inhibitors as anti-inflammatory agents that might diminish the gastrointestinal side effects of traditional non-steroidal anti-inflamatory drugs (NSAIDs). COX-2 isoform is expressed predominantly in inflammatory cells and decidedly upregulated in chronic and acute inflammations, becoming a critical target for many pharmacological inhibitors. COX-2 selective inhibitors happen to show equivalent efficacy with that of conventional NSAIDs, but they have reduced gastrointestinal side effects. This review would elucidate the most recent findings on selective COX-2 inhibition and their relevance to human pathology, concretely in inflammatory pathologies characterized by a prolonged pro-inflammatory status, including autoimmune diseases, metabolic syndrome, obesity, atherosclerosis, neurodegenerative diseases, chronic obstructive pulmonary disease, arthritis, chronic inflammatory bowel disease and cardiovascular pathologies. PMID- 29756564 TI - Clinical and Pharmacologic Features of Monoclonal Antibodies and Checkpoint Blockade Therapy in Multiple Myeloma. AB - BACKGROUND: Survival of multiple myeloma patients has considerably improved in the last decades thanks to the introduction of many new drugs, including immunomodulatory agents, proteasome inhibitors and, more recently, monoclonal antibodies. METHODS: We analyzed the most recent literature focusing on the clinical and pharmacologic aspects of monoclonal antibody-based therapies in multiple myeloma, including monoclonal antibodies directed against plasma cell antigens, as well as checkpoint blockade therapy directed against immune inhibitory molecules, used as single agents or in combination therapy. RESULTS: Anti-CD38 monoclonal antibodies including daratumumab, isatuximab and MOR202 have shown outstanding results in relapsed and/or refractory multiple myeloma patients. The addition of daratumumab to bortezomib-dexamethasone or lenalidomide dexamethasone substantially improved patients' outcome in this patient population. The anti-SLAMF7 molecule elotuzumab in combination with lenalidomide dexamethasone showed to be superior to lenalidomide-dexamethasone alone, without adding meaningful toxicity. Checkpoint blockade therapy in combination with immunomodulatory agents produced objective responses in more than 50% of treated patients. However, this combination was also associated with an increase in toxicity and a thorough safety evaluation is currently ongoing. CONCLUSION: Monoclonal antibodies are reshaping the standard of care for multiple myeloma and ongoing trials will help physicians to optimize their use in order to further improve patients' outcome. PMID- 29756565 TI - Anti-TNF biosimilars in inflammatory bowel disease: searching the proper patient's profile? AB - Biosimilars of infliximab (CT-P13) are currently approved and available for the same indications as the originator. Some concerns about safety and immunogenicity have risen in the past because of lack of data in IBD. Since 2015, several cohort studies have been conducted in IBD showing that CT-P13 has comparable safety and efficacy profile to the originator, both in adult and pediatric population, either in naive patients, or even in those who switched from the originator to CT P13. This review aims to analyze the current literature data in order to define a clear patient profile, to identify those IBD patients who would benefit the most from the use of CT-P13. PMID- 29756566 TI - Flavonoids and Reduction of Cardiovascular Disease (CVD) in Chronic Obstructive Pulmonary Disease (COPD). AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases (CV) often coexist. COPD and CVD are complex diseases characterized by a strict interaction between environment and genetic. The mechanisms linking these two diseases are complex, multifactorial and not entirely understood, influencing the therapeutic approach. COPD is characterized by several comorbidities, it is hypothesizable that treatment of cardiovascular co-morbidities may reduce morbidity and mortality. Flavonoids are an important class of plant low molecular weight secondary metabolites (SMs). Convincing data from laboratory, epidemiological, and human clinical studies point to an important effects on CVD risk prevention. OBJECTIVE: This review aims to provide up-to-date information on the ability of Flavonoids to reduce the CVD risk. CONCLUSIONS: Current studies support the potential of Flavonoids to prevent the risk of CVD. Well-designed clinical studies are suggested to evaluate advantages and limits of Flavonoids for managing CVD comorbidity in COPD. PMID- 29756567 TI - Chronic Low Back Pain: Current Pharmacotherapeutic Therapies and a New Biological Approach. AB - The syndrome of chronic low back pain (CLBP) represents one of the leading causes of long-term disability worldwide. The prevalence of CLBP rises significantly in relation to increasing average of life expectancy. CLBP arises by chronification of acute low back pain. There are many factors that contribute to the emergency of CLBP; frequent etiopathogenetic factors include e.g. a functional blockage of intervertebral joints. The treatment of CLBP has a complex character. An important part of treatment consists of pharmacotherapy of pain, under which several groups of drugs are being used. The problem lies in the side effects of many of these traditionally used substances. Therefore, new and safer methods of treatments are being searched. Innovative option of pharmacology of CLBP represents injections containing collagen, which can be combined with the traditionally used drugs, thus helping to reduce their dosage and to increase the overall safety of therapy of CLBP. PMID- 29756568 TI - Aporphines and Alzheimer's disease: Towards a Medical Approach Facing the Future. AB - Alzheimer's disease (AD) is a neurodegenerative disease that is reducing progressively the part cognitive inside the Central Nervous System (CNS) and that affects the memories and emotions of the patients who endure this disease. Many drugs have been assessed in patients with different evolutionary grades of the disease, having diverse results, depending on the used compound. Some of them afford dependence and many others with side effects that affect the emotional part and the economic cost of the treatment. The natural products have diversified their therapeutic uses, and have been used in the treatment of AD in accordance with its easy medical administration and bioavailability. In this review, the use of aporphines in nature is showed for treating Alzheimer's disease, alkaloids isolated from natural and/or synthetic sources have been used principally as cholinesterase inhibitors (acetyl- and butyrylcholinesterase) as galantamine, for instance, though its use has been questioned for being slightly effective or marginal. The use of aporphines give the possibility of generating new treatments with nitrogenous chemical structures of diverse complexity and that are focused in this review comparatively and with real therapeutic scopes. PMID- 29756569 TI - Editorial: Therapeutic Advances and their Biomedical Perspectives - Part 2. PMID- 29756570 TI - An Introduction of the Guest Editors. PMID- 29756571 TI - The Mechanism of Dietary Protein Modulation of Bone Metabolism via Alterations in Members of the GH/IGF Axis. AB - Dietary protein intake as a critical regulatory factor of bone metabolism is a vital element to regulate nutritional status of mammals. Under the action of protease, dietary protein is digested into peptides and free amino acids (FAAs). Then, the metabolites are absorbed by enterocytes and metabolized in various organs of mammals. The dietary protein intake regulates bone metabolism generally via two aspects, dietary itself and signaling transduction. At the dietary level, different kinds of amino acids (AAs) of dietary protein may affect various protein metabolism of bone by regulating proteasome depending on proteolysis and protein synthesis. In addition, dietary protein from multiple sources such as animal, vegetal and healthcare products, presents distinct influences on bone metabolism via regulating calcium balance; At the cellular level, these products can regulate several biological functions via regulating signaling transduction. For example, the significant member of growth hormone/insulin-like growth factor (GH/IGF) axis can be regulated by dietary protein, which has an influence on bone metabolism through different approaches. This review mainly discusses the relationship between dietary protein and GH/IGF axis and illustrates the regulation of bone metabolism in mammals by dietary protein and its signaling transduction. PMID- 29756572 TI - How Can Xenosensors Act in Chemical Detoxification Metabolism? AB - There are some disparities between pharmacological and toxicological xenobiotic receptor (xenosensors) pathways. These variations include receptor models that indicate several toxic patterns. Such models have demanded some update from traditional medical receptor relations studied by pharmacologists. These may include the response time, the molecular level, and unclear directions of toxicological metabolism. Xenosensors activities were affected by many factors that include genetic elements, physiological status, xenobiotic complication, and species-specific variations. Thus, this review aims to highlight the most advanced features of xenosensors related to toxicant biotransformations and other patterns such as characteristics, recognition, and the relations between different xenosensors. PMID- 29756573 TI - Lactoferrin: Major Physiological Functions and Applications. AB - Lactoferrin (lactotransferrin; Lf) is an iron-binding glycoprotein and one of the most important bioactivators in milk and other external secretions. It has numerous biological roles, including the regulation of iron absorption and modulation of immune responses, and has anti-microbial, anti-viral, antioxidant, anti-cancer, and anti-inflammatory activities. Lf regulates the quantity of iron absorbed in the intestine via its role in iron transport and can also chelate iron, directly or indirectly. Notably, it has been used as an adjuvant therapy for some intestinal diseases. It is now used in nutraceuticalsupplemented infant formula and other food products. This article reviews the content, distribution, physiologic functions and current applications of Lf, and aims to shed light on future prospects for additional applications of Lf. PMID- 29756574 TI - Dietary Protein and Gut Microbiota Composition and Function. AB - Dietary protein and its metabolites, amino acids, are essential nutrients for humans and animals. Accumulated research has revealed that the gut microbiota mediate the crosstalk between protein metabolism and host immune response. Gut microbes are involved in the digestion, absorption, metabolism and transformation process of dietary protein in the gastrointestinal tract. Amino acids can be metabolized into numerous microbial metabolites, and these metabolites participate in various physiological functions related to host health and diseases. The components of dietary protein impact the gut microbiota composition and microbial metabolites. The source, concentration, and amino acid balance of dietary protein are primary factors which contribute to the composition, structure and function of gut microbes. A suitable ratio between protein and carbohydrate or even a low protein diet is recommended over a diet with protein in excess of requirements. Greater levels and undigested protein lead to an increase of pathogenic microorganism with associated higher risk of metabolic diseases. Herein, the crosstalk between dietary protein and gut microbiota composition and function is summarized, which will help to reveal the potential mechanism of gut microbes on the gastrointestinal tract health. PMID- 29756575 TI - Effects of Stress on the Mucus-microbial Interactions in the Gut. AB - Stress shows both direct- and indirect-effects on the functions of the gastrointestinal tract, in particular on the mucus physiology and the composition of microbiota. Mucus mainly consists of heavily glycosylated proteins called mucins, which are secreted by goblet cells. The gut mucus layer is a pivotal part of the intestinal protection and colonized by commensal microbes, essential for the development and health of the host. There is a symbiotic interaction between intestinal microbiota and the host cells. On the one hand, mucus provides nutrients for the growth and adhesion of microbes; on the other hand, mucin degrading bacteria generate energy sources for the host epithelium. However, the mucusmicrobial interaction has rarely been considered in the context of stress exposure. Therefore, this paper principally reviews the effects of stress on both mucus secretion and gut microbiota and is hoped to provide a new perspective for future study. PMID- 29756576 TI - Improving Feed Protein Utilization Rate in Cattle through Nutritional Approaches. AB - Cattle supply important amounts of nutritious products such as beef and milk for human consumption. However, cattle excrete large amounts of feces and urine with low utilization rate of dietary crude protein (CP). These not only negatively affect the global environment by emissions of ammonia (NH3) and nitrous oxide (N2O) and bleaching the soil and underground water, but also increase the feed cost. The low nitrogen (N) utilization rate of cattle could possibly result from the activity of rumen microorganisms degrading feed CP. Many studies indicate that it is possible to manipulate the N metabolism to improve the N utilization rate of cattle through nutritional approaches, such as dietary supplementation of rumen protected essential amino acids (EAA) including methionine (Met), lysine (Lys) and EAA analogs or feeding rations with relatively low N concentration. It is necessary to study the microbial synthesis of EAA in the rumen, the requirements of EAA of cattle under different feeding regimes, and to develop products which are more efficient and less costly to improve the N utilization rate of cattle. PMID- 29756577 TI - Molecular Targets and Natural Compounds in Drug Development for the Treatment of Inflammatory Pain. AB - This chapter explores therapeutic targets and the anti-inflammatory nature of some naturally- occurring compounds and the current or potential use of these compounds in the treatment of chronic inflammatory pain states. We will review the mechanisms of chronic inflammatory pain, the molecular targets of selected natural compounds in inhibiting inflammatory pain, and the traditional and current approaches to treating pain using these compounds. Previous research on experimental as well as clinical pain will be summarized from in vitro to animal and human models. Potential areas for further research will also be discussed. PMID- 29756578 TI - Endocrine Disrupting Chemical Induced "Pollution of Metabolic Pathways": A Case of Shifting Paradigms With Implications for Vascular Diseases. AB - The latter half of the twentieth century has witnessed a humongous spurt in the use of synthetic chemicals in a wide variety of industrial and agricultural applications leading to specific perturbations affecting every trophic level of the ecosystems due to unmitigated environmental contamination. Despite the incremental usefulness of endocrine disrupting chemicals (EDCs) such as pesticides and plasticizers, their statutory impact on environmental health is assuming worrisome proportions. The EDCs can disrupt physiological homeostasis resulting in developmental and reproductive abnormalities. Both preclinical animal experiments, as well as epidemiological studies, have correlated EDC exposure with metabolic disorders such as metabolic syndrome, type 2 diabetes as well as cardiovascular health. Here we briefly review the statutory impact of EDCs on metabolic disruption as well as their impact on environmental health. Finally, difficulties pertaining to the categorization of EDC induced metabolic diseases as risk factors for global disease burden have been addressed taking into account the complexity of such interactions. PMID- 29756579 TI - Recent changes in the management of patients with food allergy in a tertiary referral centre: A Dietitian's perspective. AB - It is has been suggested that the prevalence of food allergy has increased over the last few decades with estimates now suggesting between 3.9-8% of children are food allergic (Kattan, 2016). Studies also suggest that rates of food allergy resolution are slowing, meaning more children are remaining allergic for longer (Sicherer et al, 2014). The mainstay of food allergy management is dietary exclusion of known food allergen/s. Exclusion diets are frequently difficult for patients and their families to manage and the literature highlights that they impact negatively on quality of life (Valentine et al, 2011) . The Paediatric Allergy Dietitian is a crucial member of the allergy multi- disciplinary team and is ideally placed to offer practical advice, support and guidance to food allergic patients and their families (Mackenzie et al, 2015). In recent years strategies used to manage food allergic patients have changed. Rather than strict avoidance, management of dairy and egg allergy now focuses on early introduction of extensively heat treated or "baked" al-lergen, allowing increased dietary choice, improved quality of life and poten-tially promoting tolerance to milk and egg in the raw state (Anagnostou et al, 2015). Similarly, traditionally nut allergic patients were advised to avoid all nuts regardless of whether they had mono or poly sensitised. Now, nut aller-gic individuals are actively encouraged to introduce safe selected nuts into their diets. This article explores the evidence in both these areas of food allergy man-agement, changes in practice and discusses the crucial role of the allergy Dietitians in practical implementation. PMID- 29756580 TI - Subtypes of antiphospholipid antibodies in neurologic accidents: an observational study. AB - OBJECTIVE: Until now, concomitant neurological manifestations and positive antiphospholipid antibodies (APA(s)) have been investigated in different manners. The most important conflicts in this field are whether those manifestations are directly related to APA(s) or not and treatment strategies. METHOD: In this study, adopting a different manner, we selected patients with a recently defined neurological problem (according to study protocol) and positive APA without any other risk factor, to compare types, amounts, and titer of APAs. RESULTS: We recruited 100 patients. 89% of those who completed the study were persistent positive APA among them 16% LAC, 41% IgG aCL, 42% IgM aCL patient, 17% IgG beta2GP1, and 15% IgM beta2GP1 were reported. 10% of patients found to have concomitant lupus manifestations and 37% showed anti-DNA. It was found that IgG and IgM anti-cardiolipin are the most prevalent antibodies. Cerebral vascular accident (33%), retinal artery/vein occlusion (21%), and seizure (20%) were the most frequent presentations of the patients. In addition, IgG and IgM anti cardiolipin, lupus anticoagulant was 100% positive in multiple sclerosis (3% of patients). In addition, IgM anti-beta2-Glycoprotein-1 was 100% positive in optic neuritis (5% of patients) and significantly associated with this accident. It was also prevalent in Guillain-Barre Syndrome. Finally, in cerebrovascular accident, the most prevalent persistent positive antibody was IgM anti-cardiolipin antibody. CONCLUSION: In this study there was likely some association between subtypes of APA(s) and neurological accidents. However, the exact correlation between those symptoms and APA(s) needs more future investigations. PMID- 29756582 TI - Polypharmacology Approach Against Migraine with Aura and Brain Edema for the Development of an Efficient Inhibitor and its Analogues. AB - BACKGROUND: Polypharmacology is a design or use of pharmaceutical agents in which single drug is used to treat multiple diseases. Aquaporin proteins are identified to treat migraine with aura and brain edema. This study focuses on Aquaporin-1 and Aquaporin-4. AQP-1 is expressed in small afferent sensory nerve fibers. Over expression of peripheral nervous system causes migraine. METHODS: AQP-4 is an abundant channel water protein in brain that regulates water transport to prevent homeostasis. Over-expression of AQP-4 contributes to water imbalance in ischemic pathology resulting in cerebral edema. Purpose of this study is to identify a potent inhibitor for the treatment of migraine with aura and brain edema. RESULTS: As in the recent studies, no conventional methodologies have been focused through the approach of polypharmacology. Structures of AQP-1 and AQP- 4 proteins were retrieved from PDB (Protein Data Bank). PyRx software was used to perform molecular docking. CONCLUSION: Analogues of ligands were analyzed which contained significant similarities of associated proteins to get efficient inhibitor. Toxicity of lead compound was measured through admetSAR. A lead compound was predicted to treat these diseases. PMID- 29756583 TI - 4D-QSAR Studies Using a New Descriptor of the Klopman Index: Antibacterial Activities of Sulfone Derivatives Containing 1, 3, 4-Oxadiazole Moiety Based on MCET Model. AB - INTRODUCTION: In this paper, we have introduced a new atomic descriptor with Klopman index to determine the local reactive sites of the molecular systems during electrophilic, and nucleophilic attacks. This index, similar to other local reactivity descriptors but more advanced, has been used as a realistic descriptor to discover new aspects of molecular structure. METHODS: Nonlinear Least Squares (NLLS) methods to define the parameters maximizing the fit between the observed points and the computed simulation results were performed according to the Levenberg- Marquardt (LM) algorithm. We have attempted to demonstrate the structural properties of compounds that contribute not only basic pharmacophore (b-Pha) but also positive (Auxiliary Group- AG) or negative (Anti-Pharmacophore Shielding-APS) due to the new local atomic reactivity. RESULTS AND CONCLUSION: In the 4D-QSAR study, nonparametric regression analysis was used to determine the adjustable constants. Using the leave One Out Cross-Validation (LOO-CV), antibacterial activities (pEC50-MUM) were predicted as r2 loo-cv (q2) = 0.979, r2 pred (r2) = 0.911, respectively, for 27 training sets and 9 test set compounds. Also, the rm2 (overall) value, which indicates the closeness between the predicted and corresponding observed data, was calculated to be 0.957. The model obtained by the Molecular Conformer Electron Topological (MCET) method was compared with the q2 loo-cv and R2 non-cv values determined by the CoMFA and CoMSIA methods and more satisfactory results were obtained. PMID- 29756584 TI - 4D-QSAR Study of Some Pyrazole Pyridine Carboxylic Acid Derivatives By Electron Conformational-Genetic Algorithm Method. AB - INTRODUCTION: In the present work, pharmacophore identification and biological activity prediction for 86 pyrazole pyridine carboxylic acid derivatives were made using the electron conformational genetic algorithm approach which was introduced as a 4D-QSAR analysis by us in recent years. In the light of the data obtained from quantum chemical calculations at HF/6-311 G** level, the Electron Conformational Matrices of Congruity (ECMC) were constructed by EMRE software. Comparing the matrices, electron conformational submatrix of activity (ECSA, Pha) was revealed that are common for these compounds within a minimum tolerance. A parameter pool was generated considering the obtained pharmacophore. METHODS: To determine the theoretical biological activity of molecules and identify the best subset of variables affecting bioactivities, we used the nonlinear least square regression method and genetic algorithm. RESULTS: The results obtained in this study are in good agreement with the experimental data presented in the literature. The model for training and test sets attained by the optimum 12 parameters gave highly satisfactory results with R2 training= 0.889, q2=0.839 and SEtraining=0.066, q2 ext1 = 0.770, q2 ext2 = 0.750, q2 ext3=0.824, ccctr = 0.941, ccctest = 0.869 and cccall = 0.927. PMID- 29756585 TI - Animal Models Used for Testing Hydrogels in Cartilage Regeneration. AB - Local cartilage or osteochondral lesions are painful and harmful. Besides pain and limited function of joints, cartilage defect is considered as one of the leading extrinsic risk factors for osteoarthritis (OA). Thus, clinicians and scientists have paid great attention to regenerative therapeutic methods for the early treatment of cartilaginous defects. Regenerative medicine, showing great hope for regenerating cartilage tissue, relies on the combination of biodegradable scaffolds and particular biological factors, such as growth factors, genetic cues. Among all biomaterials, hydrogels have become a promising type of scaffolds for simultaneous cell growth and drug delivery in cartilage tissue engineering. A wide range of animal models have been applied in testing repair with hydrogels in cartilage defects. This review summarized the current animal models used to test hydrogels technologies for the regeneration of cartilage. Advantages and disadvantages in the establishment of the cartilage defect animal models among different species were emphasized, as well as the feasibility of replication of diseases in animals. PMID- 29756586 TI - The Review of Nanomaterials Inducing the Differentiation of Stem Cells into Chondrocyte Phenotypes in Cartilage Tissue Engineering. AB - Cartilage, as a nanostructured tissue, because of its awfully poor capacity for inherent regeneration and complete hierarchical structure, is severely difficult to regenerate after damages. Tissue engineering methods have provided a great contribution for cartilage repair. Nanomaterials have special superiority in regulating stem cell behaviors due to their special mechanical and biological properties and biomimetic characteristics. Therefore, they have been given great attention in tissue regeneration. Nanomaterials are divided into organic and inorganic nanomaterials. They provide the microenvironment to support differentiation of stem cells. Nanomaterials inducing stem cells to differentiate into chondrocyte phenotypes would be a benefit for cartilage tissue regeneration, then promoting the development of cartilage tissue engineering. In this review, we summarized the important roles of nanomaterials in chondrogenic differentiation of stem cells. PMID- 29756587 TI - Spontaneous Intracranial Hypotension as a Cause of Exacerbation in Huntington's Disease. PMID- 29756588 TI - Toward a Shared-Care Model of Relapsing-Remitting Multiple Sclerosis: Role of the Primary Care Practitioner. AB - : The objective of this study was to develop a shared-care model to enable primary-care physicians to participate more fully in meeting the complex, multidisciplinary healthcare needs of patients with multiple sclerosis (MS). DESIGN: The design consisted of development of consensus recommendations and a shared-care algorithm. PARTICIPANTS: A working group of 11 Canadian neurologists involved in the management of patients with MS were included in this study. MAIN MESSAGE: The clinical management of patients with multiple sclerosis is increasing in complexity as new disease-modifying therapies (DMTs) become available, and ongoing safety monitoring is required. A shared-care model that includes primary care physicians is needed. Primary care physicians can assist in the early detection of MS of individuals presenting with neurological symptoms. Additional key roles for family physicians are health promotion, symptom management, and safety and relapse monitoring of DMT-treated patients. General principles of health promotion include counseling MS patients on maintaining a healthy lifestyle; performing standard screening measures; and identifying and treating comorbidities. Of particular importance are depression and anxiety, which occur in >20% of MS patients. Standard work-ups and treatments are needed for common MS-related symptoms, such as fatigue, pain, bladder dysfunction, sexual dysfunction, spasticity, and sleep disorders. Ongoing safety monitoring is required for patients receiving specific DMTs. Multiple sclerosis medications are generally contraindicated during pregnancy, and patients should be counseled to practice effective contraception. CONCLUSIONS: Multiple sclerosis is a complex, disabling illness, which, similar to other chronic diseases, requires ongoing multidisciplinary care to meet the evolving needs of patients throughout the clinical course. Family physicians can play an invaluable role in maintaining general health, managing MS-related symptoms and comorbidities, monitoring for treatment-related adverse effects and MS relapses, and coordinating allied health services to ensure continuity of care to meet the complex and evolving needs of MS patients through the disease course. RESUME: Elaborer un modele de soins partages dans les cas de sclerose en plaques recurrente-remittente. Objectif: Elaborer un modele de soins partages afin de permettre aux medecins de premiere ligne de mieux repondre aux besoins complexes et multidisciplinaires de patients atteints de la sclerose en plaques (SP). Conception : Recommandations resultant d'un consensus et elaboration d'un algorithme en matiere de soins partages. PARTICIPANTS: Un groupe de travail forme de onze neurologues canadiens impliques dans la prise en charge de patients atteints de la SP. Message-cle : La prise en charge clinique de patients atteints de la SP est de plus en plus complexe dans la mesure ou des medicaments modificateurs de l'evolution de la maladie (MMSP) deviennent accessibles et ou un suivi permanent en matiere de securite est necessaire. Soulignons aussi qu'un modele de soins partages incluant les medecins de premiere ligne est necessaire. Ces professionnels peuvent permettre un depistage plus rapide de la SP chez des individus presentant des symptomes neurologiques. Ils peuvent aussi jouer un role de premier plan en matiere de promotion de la sante, de soulagement des symptomes et de suivi de patients traites avec des MMSP en ce qui a trait a leur securite et a de possibles rechutes. Parmi les principes generaux de promotion de la sante, on peut inclure les suivants : offrir aux patients atteints de la SP des conseils leur permettant de maintenir de saines habitudes de vie ; adopter des mesures de depistage standards ; identifier et traiter les comorbidites. A cet egard, l'anxiete et la depression sont d'une importance particuliere et sont frequemment signalees (> 20 %) chez les patients atteints de SP. Des demarches d'investigation et des traitements standards sont necessaires dans le cas des symptomes courants relies a la SP, par exemple de la fatigue, des douleurs, une dysfonction vesicale, des dysfonctions sexuelles, de la spasticite et des troubles du sommeil. On l'a dit, un suivi permanent s'impose dans le cas de patients beneficiant d'un traitement specifique avec des MMSP. Les medicaments associes a la SP sont generalement contre-indiques durant la grossesse de sorte qu'on devrait conseiller aux patients d'adopter des methodes de contraception efficaces. CONCLUSIONS: La SP est une maladie complexe et invalidante qui, a l'instar d'autres maladies chroniques, exige des soins multidisciplinaires continus afin de repondre, en lien avec un tableau clinique precis, aux besoins en constante evolution des patients. Les medecins de premiere ligne peuvent jouer un role irremplacable a plusieurs egards : dans le maintien d'une bonne sante ; le suivi et le soulagement des symptomes et des comorbidites relies a la SP ; le suivi des rechutes et des effets indesirables associes aux traitements. N'oublions pas non plus la coordination des services paramedicaux afin d'assurer, durant l'evolution de la SP, une continuite des soins repondant aux besoins complexes et en constante evolution des patients atteints de cette maladie. PMID- 29756589 TI - Effect of Combination Therapy with Neuroprotective and Vasoprotective Agents on Cerebral Ischemia. AB - : Because most tested drugs are active against only one of the damaging processes associated with stroke, other mechanisms may cause cellular death. Thus, a combination of protective agents targeting different pathophysiological mechanisms may obtain better effects than a single agent. The major objective of this study was to investigate the effect of combination therapy with vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) after controlled ischemic brain injury in rabbits. METHODS: Animals were randomly assigned to one of the following groups: sham group, saline-treated control group or NGF+VEGF treated group. Animals received an intracerebral microinjection of VEGF and NGF or saline at 5 or 8 hours after ischemia. The two specified time points of administration were greater than or equal to the existing therapeutic time window for monoterapy with VEGF or NGF alone (3 or 5 hours of ischemia). Infarct volume, water content, neurological deficits, neural cell apoptosis and the expression of caspase-3 and Bcl-2 were measured. RESULTS: Compared with saline-treated controls, the combination therapy of VEGF and NGF significantly reduced infarct volume, water content, neural cell apoptosis and the expression of caspase-3, up regulated the expression of Bcl-2 and improved functional recovery (both p<0.01) when administered 5 or 8 hours after ischemia. The earlier the administration the better the neuroprotection. CONCLUSIONS: These results showed that the combination therapy with VEGF and NGF provided neuroprotective effects. In addition, the time window of combination treatment should be at least 8 hours after ischemia, which was wider than monotherapy. RESUME: Les effets d'une polytherapie combinant agents neuro-protecteurs et agents vasoprotecteurs dans les cas d'ischemie cerebrale. Contexte:Etant donne que la plupart des medicaments prealablement testes tendent a n'agir contre seulement un des processus de dommage associes aux AVC, il est possible que d'autres processus entrainent une mort cellulaire. A cet effet, il se pourrait qu'une combinaison d'agents protecteurs ciblant divers mecanismes physiopathologiques permette d'obtenir de meilleurs resultats qu'un simple agent. Apres avoir suscite de facon controlee des lesions cerebrales ischemiques chez des lapins, l'objectif principal de la presente etude a donc ete de se pencher sur l'impact d'une polytherapie combinant la proteine dite " facteur de croissance de l'endothelium vasculaire " (ou " VEGF " en anglais) avec le " facteur de croissance des nerfs " (ou " NGF " en anglais). Methodes: Les animaux ont ete attribues au hasard a l'un des groupes suivants : ceux ayant recu un traitement fictif ; ceux, du groupe temoin, ayant beneficie d'un traitement a base de solution saline ; et finalement ceux ayant ete traites au moyen des VEGF et NGF. A noter que les lapins ont recu une micro injection intracerebrale de VEGF et de NGF ou de solution saline 5 heures ou 8 heures a la suite de leur AVC. Ces deux delais d'administration des VEGF et NGF sont equivalents ou superieurs aux delais actuels d'administration des VEGF ou NGF a titre de monotherapie (3 heures ou 5 heures a la suite d'un AVC). Tant le volume des infarctus, le contenu en eau, les deficits neurologiques ainsi causes, l'apoptose des neurones que l'expression des proteases caspase 3 et des proteines Bcl-2 ont ete mesures. Resultats: Si on la compare au traitement a base de solution saline administre au groupe temoin, la polytherapie a base de VEGF et de NGF, lorsqu'administree 5 heures ou 8 heures a la suite de l'AVC, a su reduire de facon notable le volume des infarctus, le contenu en eau, l'apoptose des neurones et l'expression des proteases caspase 3. Elle a egalement permis de reguler a la hausse l'expression des proteines Bcl-2 en plus d'entrainer une amelioration de la recuperation fonctionnelle (p < 0,01 pour ces deux aspects). Ainsi donc, plus tot l'on opte pour cette polytherapie, meilleure sera la neuroprotection encourue. CONCLUSIONS: Ces resultats demontrent que la polytherapie a base de VEGF et de NGF procure des effets neuroprotecteurs. Quant au delai d'administration de ce traitement combinatoire, il devrait etre d'au moins 8 heures a la suite d'un AVC, ce qui est plus eleve que la monotherapie. PMID- 29756590 TI - MRI and Tractography in Hypertrophic Olivary Degeneration. PMID- 29756591 TI - A Strategic View for Intraoperative Neuromonitoring in Canada 2017. PMID- 29756593 TI - Subacute Combined Degeneration from Nitrous Oxide Abuse in a Patient with Pernicious Anemia. PMID- 29756592 TI - Three-Year Follow-Up Study in Patients with Guillain-Barre Syndrome. AB - : A majority of patients with Guillain-Barre syndrome (GBS) have tendency of a good recovery. Our aim was to evaluate the outcome of the disease 1 and 3 years after GBS symptom onset. METHODS: During 2014, GBS was diagnosed in 82 patients in seven tertiary healthcare centers. Neurological follow-up was conducted in 57 (70%) patients after 1 year, and in 54 (66%) after 3 years. Functional disability was estimated according to the GBS disability scale (GDS), with a score of 0-3 indicating mild disability and a score of 4-6 indicating severe disability during acute phase, whereas a score >1 indicated poor recovery on follow-ups. Visual analog scale was used to assess sensory symptoms and musculoskelatal pain, and Krupp's Fatigue Severity Scale was used to asses fatigue. RESULTS: Poor functional outcome was found in 39% of GBS patients at year 1 and 30% at year 3. Paresthesias/dysesthesias were detected in 60% of patients after 1 year and 43% after 3 years. Musculoskeletal pain was present in 40% of patients at year 1 and 33% at year 3. Significant fatigue after 1 year was found in 21% of subjects and after 3 years in 7%. Parameters associated with poor functional outcome after 1 year were age >55 years (p=0.05), severe disability at admission (p1 indique une recuperation difficile au moment des suivis. L'echelle visuelle analogue (EVA) a aussi ete utilisee pour evaluer leurs symptomes sensoriels et leurs douleurs musculo-squelettiques. Enfin, l'echelle de gravite de la fatigue de Krupp a ete utilisee pour evaluer leur degre de fatigue. Resultats: La premiere annee, on a observe une pietre amelioration des capacites fonctionnelles chez 39% des patients atteints du SGB; pour la troisieme annee, cette proportion etait de 30%. Au bout d'un an, on a aussi detecte la presence de paresthesie/dysesthesie chez 60% des patients; pour la troisieme annee, cette proportion etait de 43%. Des douleurs musculo-squelettiques ont ete rapportees chez 40% des patients apres un an; deux ans plus tard, ce pourcentage chutait a 33%. Enfin, un etat de fatigue important a ete note chez 21% des patients au bout d'un an; ce pourcentage n'etait plus que de 7% au bout de trois ans. Les parametres associes a une pietre amelioration des capacites fonctionnelles au bout d'un an etaient l'age (>55 ans; p=0,05) ainsi qu'une incapacite severe au moment de leur admission (p<0,05) et de leur conge (p<0,01). Au bout de trois ans, une pietre amelioration des capacites fonctionnelles etait associee au sexe masculin (p<0,05) et a une incapacite severe au moment d'obtenir un conge (p=0,06). CONCLUSIONS: Un an et trois ans apres l'apparition des premiers symptomes du SGB, un nombre important de patients donnaient a voir des sequelles neurologiques, ce qui incluait une forme ou une autre d'incapacite fonctionnelle, des symptomes sensoriels, des douleurs et un etat de fatigue. PMID- 29756594 TI - From the Editor's desk....: April 2018. PMID- 29756596 TI - Hepatic encephalopathy: classification and treatment. PMID- 29756595 TI - 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. AB - BACKGROUND & AIMS: Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection at a lower dose than tenofovir disoproxil fumarate (TDF) through more efficient delivery of tenofovir to hepatocytes. In 48-week results from two ongoing, double blind, randomized phase III trials, TAF was non-inferior to TDF in efficacy with improved renal and bone safety. We report 96-week outcomes for both trials. METHODS: In two international trials, patients with chronic HBV infection were randomized 2:1 to receive 25 mg TAF or 300 mg TDF in a double-blinded fashion. One study enrolled HBeAg-positive patients and the other HBeAg-negative patients. We assessed efficacy in each study, and safety in the pooled population. RESULTS: At week 96, the differences in the rates of viral suppression were similar in HBeAg-positive patients receiving TAF and TDF (73% vs. 75%, respectively, adjusted difference -2.2% (95% CI -8.3 to 3.9%; p = 0.47), and in HBeAg-negative patients receiving TAF and TDF (90% vs. 91%, respectively, adjusted difference 0.6% (95% CI -7.0 to 5.8%; p = 0.84). In both studies the proportions of patients with alanine aminotransferase above the upper limit of normal at baseline, who had normal alanine aminotransferase at week 96 of treatment, were significantly higher in patients receiving TAF than in those receiving TDF. In the pooled safety population, patients receiving TAF had significantly smaller decreases in bone mineral density than those receiving TDF in the hip (mean % change -0.33% vs. -2.51%; p <0.001) and lumbar spine (mean % change -0.75% vs. -2.57%; p <0.001), as well as a significantly smaller median change in estimated glomerular filtration rate by Cockcroft-Gault method (-1.2 vs. -4.8 mg/dl; p <0.001). CONCLUSION: In patients with HBV infection, TAF remained as effective as TDF, with continued improved renal and bone safety, two years after the initiation of treatment. Clinicaltrials.gov number: NCT01940471 and NCT01940341. LAY SUMMARY: At week 96 of two ongoing studies comparing the efficacy and safety of tenofovir alafenamide (TAF) to tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B patients, TAF continues to be as effective as TDF with continued improved renal and bone safety. Registration: Clinicaltrials.gov number: NCT01940471 and NCT01940341. PMID- 29756599 TI - Contribution of Balkan Medical Journal to the development and dissemination of medical science in the Balkans PMID- 29756597 TI - [Curvibacter sp. strain HJ-1 induced the formation of aragonite under the condition of low Mg/Ca ratio]. AB - Objective: To study the effects of bacteria on the species and morphology of carbonate minerals. Methods: We conducted a series of cultural experiments in the medium with initial Mg/Ca ratio of 2 but without carbonate ion using Curvibacter sp. strain HJ-1 for 50 days. During the cultivation, bacterial density, precipitate quantities, calcium and magnesium concentration were determined. The morphologies of precipitated carbonates were observed using scanning electron microscopy, and mineral species of carbonate were determined by X-ray diffraction. Results: Strain HJ-1 could induce the precipitation of carbonate minerals, the quality of carbonate gradually increased with the incubation time. XRD patterns showed that the mineral precipitates consisted of high-Mg calcite and aragonite. The percentage of aragonite in the precipitates was up to 86%. The morphology of carbonate minerals was multiform, including rod-shaped, dumbbell shaped, spherical, tabular, as well as irregular and flake. Conclusion: The formation of aragonite under the condition of low Mg/Ca ratio has a close correlation with extracellular polysaccharide secreted by Curvibacter sp. strain HJ-1. PMID- 29756601 TI - Nanoscale thermal cross-talk effect on phase-change probe memory. AB - Phase-change probe memory is considered as one of the most promising means for next-generation mass storage devices. However, the achievable storage density of phase-change probe memory is drastically affected by the resulting thermal cross talk effect while previously lacking detailed study. Therefore, a three dimensional model that couples electrical, thermal, and phase-change processes of the Ge2Sb2Te5 media is developed, and subsequently deployed to assess the thermal cross-talk effect based on a Si/TiN/ Ge2Sb2Te5/diamond-like carbon (DLC) structure by appropriately tailoring the electro-thermal and geometrical properties of the storage media stack for a variety of external excitations. The modeling results show that the DLC capping with a thin thickness, a high electrical conductivity, and a low thermal conductivity is desired to minimize the thermal cross-talk, while the TiN underlayer has a slight impact on the thermal cross-talk. Combining the modeling findings with the previous film deposition experience, an optimized phase-change probe memory architecture is presented, and its capability of providing ultra-high recording density simultaneously with a sufficiently low thermal cross-talk is demonstrated. PMID- 29756602 TI - Exploring load, velocity, and surface disorder dependence of friction with one dimensional and two-dimensional models. AB - The effect of surface disorder, load, and velocity on friction between a single asperity contact and a model surface is explored with one-dimensional and two dimensional Prandtl-Tomlinson (PT) models. We show that there are fundamental physical differences between the predictions of one-dimensional and two dimensional models. The one-dimensional model estimates a monotonic increase in friction and energy dissipation with load, velocity, and surface disorder. However, a two-dimensional PT model, which is expected to approximate a tip sample system more realistically, reveals a non-monotonic trend, i.e. friction is inert to surface disorder and roughness in wearless friction regime. The two dimensional model discloses that the surface disorder starts to dominate the friction and energy dissipation when the tip and the sample interact predominantly deep into the repulsive regime. Our numerical calculations address that tracking the minimum energy path and the slip-stick motion are two competing effects that determine the load, velocity, and surface disorder dependence of friction. In the two-dimensional model, the single asperity can follow the minimum energy path in wearless regime; however, with increasing load and sliding velocity, the slip-stick movement dominates the dynamic motion and results in an increase in friction by impeding tracing the minimum energy path. Contrary to the two-dimensional model, when the one-dimensional PT model is employed, the single asperity cannot escape to the minimum energy minimum due to constraint motion and reveals only a trivial dependence of friction on load, velocity, and surface disorder. Our computational analyses clarify the physical differences between the predictions of the one-dimensional and two-dimensional models and open new avenues for disordered surfaces for low energy dissipation applications in wearless friction regime. PMID- 29756603 TI - Solid lipid nanoparticles release DNA upon endosomal acidification in human embryonic kidney cells. AB - Nanotechnology can produce materials with unique features compared to their bulk counterparts, which can be useful for medical applications (i.e. nanomedicine). Among the therapeutic agents used in nanomedicine, small molecules or biomacromolecules, such as proteins or genetic materials, can be designed for disease diagnostics and treatment. To transport these biomacromolecules to the target cells, nanomedicine requires nanocarriers. Solid lipid nanoparticles (SLNs) are among the promising nanocarriers available, because they can be made from biocompatible materials and present high stability (over one year). In addition, upon the binding genetic material, SLNs form SLNplexes. However, little is yet known about how cells process these SLNplexes-in particular, how internalization and endosome acidification affects the transfection mediated by SLNplexes. Therefore, we aim to investigate how these processes affect SLNplex transfection in HEK293T cells. We find that the SLNplex is mainly internalized by clathrin-mediated endocytosis, which is a fast and reliable pathway to transfection, leading to approximately 60% transfection efficiency. Interestingly, upon acidification (below pH 5.0), the SLN seems to release its DNA content, which can be an essential step for SLNplex transfection. The underlying mechanisms described in this work may help improve SLNplex formulations and transfection efficiency. Moreover, these advances can improve the field of nanomedical research and bring new ways to cure diseases. PMID- 29756605 TI - Corrigendum: Efficient visible-light photocatalytic degradation system assisted by conventional Pd catalysis. AB - This corrects the article DOI: 10.1038/srep09561. PMID- 29756606 TI - Corrigendum: Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model. AB - This corrects the article DOI: 10.1038/srep21868. PMID- 29756604 TI - Alkaloids, Nitric Oxide, and Nitrite Reductases: Evolutionary Coupling as Key Regulators of Cellular Bioenergetics with Special Relevance to the Human Microbiome. AB - Typical alkaloids expressed by prokaryotic and eukaryotic cells are small heterocyclic compounds containing weakly basic nitrogen groups that are critically important for mediating essential biological activities. The prototype opiate alkaloid morphine represents a low molecular mass heterocyclic compound that has been evolutionarily fashioned from a relatively restricted role as a secreted antimicrobial phytoalexin into a broad spectrum regulatory molecule. As an essential corollary, positive evolutionary pressure has driven the development of a cognate 6-transmembrane helical (TMH) domain MU3 opiate receptor that is exclusively responsive to morphine and related opiate alkaloids. A key aspect of "morphinergic" signaling mediated by MU3 opiate receptor activation is its functional coupling with regulatory pathways utilizing constitutive nitric oxide (NO) as a signaling molecule. Importantly, tonic and phasic intra-mitochondrial NO production exerts profound inhibitory effects on the rate of electron transport, H+ pumping, and O2 consumption. Given the pluripotent role of NO as a selective, temporally-defined chemical regulator of mitochondrial respiration and cellular bioenergetics, the expansion of prokaryotic denitrification systems into mitochondrial NO/nitrite cycling complexes represents a series of evolutionary modifications of existential proportions. Presently, our short review provides selective discussion of evolutionary development of morphine, opiate alkaloids, MU3 opiate receptors, and NO systems, within the perspectives of enhanced mitochondrial function, cellular bioenergetics, and the human microbiome. PMID- 29756600 TI - The development of neural stimulators: a review of preclinical safety and efficacy studies. AB - OBJECTIVE: Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. APPROACH: The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. MAIN RESULTS: Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess efficacy and, given an appropriate animal model, the safety of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to develop any specialist surgical tooling required. SIGNIFICANCE: The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator. PMID- 29756612 TI - Cancer of the head and neck: a set of indicators based on register and administrative data. AB - SUMMARY: Head and neck (H&N) tumours are a heterogeneous group of neoplasms with 5-year relative survival ranging from about 25% for the hypopharynx to 60% for the larynx in Europe. To improve survival rates, along with therapeutic improvements, it is important to standardise and optimise care received by patients with H&N tumours across different healthcare providers. To reach this goal, it is necessary to evaluate adherence to standards of received care at a population level. Published guidelines can serve as the basis to develop indicators, which can be computed from administrative health databases, measuring the adherence to specific recommendations at the individual level in unselected H&N cancer patients, identified from a population cancer register. We developed a set of indicators and calculated them in a cohort of 2007-2012 incident cases of H&N tumours in the cancer register of the Milan province (n = 1441 cases). The study cohort was mainly composed of men (77%) and patients older than 50 years (89%). Surgery was the most frequently employed treatment (66%). Ten percent of patients had no recorded treatment. Timing between cyto-histological assessment and first therapy for those having a recorded microscopic verification procedure was <= 60 days for 90.4% of patients undergoing surgery, 86.3% of those undergoing radiotherapy, and 90.7% of patients receiving chemotherapy. Eighty three percent of patients underwent cyto-histological assessment in the 180 days before the first treatment. Evaluation by a pain therapist, opioid therapy or hospitalisation for palliative therapy in the 90 days before death was performed in 51% of patients who eventually died of cancer. This is the first Italian study defining and calculating quality indicators to monitor adherence to standards of care received by H&N cancer patients at a population level. PMID- 29756613 TI - Neutrophil-to-lymphocyte ratio as a prognostic factor for pharyngocutaneous fistula after total laryngectomy. AB - SUMMARY: The role of systemic inflammatory response as a prognostic factor has been proposed in a variety of cancers. The purpose of this study was to investigate the prognostic value of the pretreatment neutrophil-to-lymphocyte ratio (NLR) in the incidence of pharyngocutaneous fistula (PCF) in patients who underwent total laryngectomy. We conducted a retrospective cohort analysis of 141 patients with squamous cell carcinoma of larynx who underwent total laryngectomy from 2009 to 2015. The incidence of PCF was 49.6%. A higher risk of 23% was observed among patients with NLR > 2.5 for the occurrence of PCF (p = 0.007). Patients with laryngeal squamous cell carcinoma who present elevated values in the ration > LR> (> 2.5) presented a higher risk of developing pharyngocutaneous fistula in the postoperative setting of total laryngectomy. PMID- 29756614 TI - Transoral glossoepiglottopexy in the treatment of adult obstructive sleep apnoea: a surgical approach. AB - SUMMARY: The treatment of obstructive sleep apnoea syndrome (OSAS) is still a matter of debate; among the different therapeutic alternatives, both surgical and conservative, treatment with continuous positive airway pressure (CPAP) is considered the "gold standard". The recent scientific literature reports that even if CPAP represents an effective solution for sleep apnoeas, 12% of patients do not benefit from its use. In most cases, primary collapse of the epiglottis is responsible for failure. We developed a surgical technique that provides a stable support to the epiglottis without influencing its function during swallowing while preserving laryngeal anatomy and physiology. The procedure we propose is based on that conceived by Monnier for children affected by laryngomalacia. We analysed a group of 20 patients who underwent glossoepiglottopexy between January 2015 and September 2016 and compared data (AHI, ODI, t90, ESS, EAT10, etc.) collected before and 6 months after surgery to demonstrate the safety and effectiveness of our glossoepiglottopexy (GEP). The results allow us to consider GEP as a valid choice to treat adults who suffer from sleep apnoeas. PMID- 29756615 TI - Correlation between musical aptitude and learning foreign languages: an epidemiological study in secondary school Italian students. AB - SUMMARY: The aim of this study was to assess if a correlation exists between language learning skills and musical aptitude through the analysis of scholarly outcomes concerning the study of foreign languages and music. We enrolled 502 students from a secondary Italian school (10-14 years old), attending both traditional courses (2 hours/week of music classes scheduled) and special courses (six hours). For statistical analysis, we considered grades in English, French and Music. Our results showed a significant correlation between grades in the two foreign languages and in music, both in the traditional courses and in special courses, and better results in French than for special courses. These results are discussed and interpreted through the literature about neuroanatomical and physiological mechanisms of foreign language learning and music perception. PMID- 29756616 TI - Treatment of cholesteatoma with intact ossicular chain: anatomic and functional results. AB - SUMMARY: In case of cholesteatoma with intact ossicular chain, the primary aims of surgery are complete removal of the cholesteatoma matrix and reconstruction of a dry and safe middle ear; if possible, ossicular chain continuity and therefore the preoperative hearing must be preserved. The aim of this retrospective study is to present the experience of the U.O.C. Otorinolaringoiatria Universitaria of University of Bari "Aldo Moro" in treatment of intact ossicular chain cholesteatoma with Bondy modified radical mastoidectomy (BMRM) and canal wall up tympanoplasty (CWUT). The study group was composed of 65 subjects affected by cholesteatoma with intact ossicular chain. Mean age was 40.7 years (range 6-79), with 42 males and 23 females. 30 patients were treated by a BMRM and 35 by CWUT, in 22 cases without mastoidectomy and in 13 cases with mastoidectomy. Mean follow up was 24.25 months. In the BMRM group, no cases of residual cholesteatoma located in the middle ear space were detected; at follow-up, 1 patient developed a retraction pocket (3.33%), 1 patient showed a small epidermal cysts of the tympanic membrane (3.33%) and 3 patients (10%) experienced otorrhoea. In CWUT, residual cholesteatoma was detected in 2 cases (5.7%); at follow-up, 3 patients presented recurrent cholesteatoma (8.57%; 2, 6 and 8 years after surgery), 3 cases a retraction pocket (8.57%) and one case otorrhoea (2.86%). Statistical analysis showed a significant higher number of residual cholesteatoma in CWUT (p 0.005) and differences in terms of long-term complications. No significant changes in hearing occurred post-operatively or at 1 year follow-up in either group. The current trend in our centre is to perform BMRM when indicated and CWUT preferably without mastoidectomy in case of mesotympanic cholesteatoma with normal OC. PMID- 29756617 TI - Is it possible to define the ideal lips? AB - SUMMARY: The lips are an essential component of the symmetry and aesthetics of the face. Cosmetic surgery to modify the lips has recently gained in popularity, but the results are in some cases disasterous. In this review, we describe the features of the ideal lips for an individual's face. The features of the ideal lips with respect to facial anatomy, important anatomical landmarks of the face, the facial proportions of the lips and ethnic and sexual differences are described. The projection and relative sizes of the upper and lower lips are as significant to lip aesthetics as the proportion of the lips to the rest of the facial structure. Robust, pouty lips are considered to be sexually attractive by both males and females. Horizontal thirds and the golden ratio describe the proportions that contribute to the beauty and attractiveness of the lips. In young Caucasians, the ideal ratio of the vertical height of the upper lip to that of the lower lip is 1:1.6. Blacks, genetically, have a greater lip volume. The shape and volume of a person's lips are of great importance in the perception of beauty by humans. The appearance of the lips in part determines the attractiveness of a person's face. In females, fuller lips in relation to facial width as well as greater vermilion height are considered to be attractive. PMID- 29756619 TI - Electrodeposited-film electrodes derived from a precursor dinitrosyl iron complex for electrocatalytic water splitting. AB - In artificial photosynthesis, water splitting plays an important role for the conversion and storage of renewable energy sources. Here, we report a study on the electrocatalytic properties of the electrodeposited-film electrodes derived from irreversible electro-reduction/-oxidation of a molecular dinitrosyl iron complex (DNIC) {Fe(NO)2}9 [(Me6tren)Fe(NO)2]+ (Me6tren = tris[2 (dimethylamino)ethyl]amine) for the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER) in alkaline solution, individually. For HER, the overpotential and Tafel slope for the electrodeposited-film cathode are lower than those of the equiv.-weight Pt/C electrode. The electrodeposited-film anode for the OER is stable for 139 h. Integration of the electrodeposited-film cathode and anode into a single electrode-pair device for electrocatalytic water splitting exhibits an onset voltage of 1.77 V, achieving a geometrical current density of 10 mA cm-2. PMID- 29756618 TI - Intraparotid facial nerve schwannoma: two case reports and a review of the literature. AB - SUMMARY: Schwannomas are rare benign tumours that arise from Schwann cells. The most known and studied is the intracranial vestibular schwannoma, even if it is not the most frequent. More often schwannomas arise from peripheral sensitive nerves, and the vagous is most involved among the cranial nerves. Intraparotid schwannomas account for just 10% of all facial involvement, so they are an extremely rare localisation. At present, there are less than 100 cases described in the literature. We performed a retrospective analysis of parotidectomy in two Italian hospitals and present two cases of intraparotid schwannoma and a review of the literature. In the first case, we performed a parotidectomy with a stripping of tumour from the nerve. In the other case, a hypoglossal-facial neurorrhaphy was performed. Follow-up was 24 months in the first (House-Brackmann II degree in temporal-ocular and III in facial-cervical branches) and 30 months in the second case (House-Brackmann III degree in both temporal-ocular and facial cervical branches). Preoperative diagnosis of facial nerve schwannoma is a challenge; however, it is extremely important since post-operative palsy is common and often higher grade. Unfortunately, schwannoma has similar radiologic finding as more common pleomorphic adenoma and often FNAC is not helpful. Due to its rarity and benign nature, there is debate in the literature on the need for surgical removal. Wait-and-see is a valid option, but may could give problems in secondary surgery. Stripping or near-total removal can be useful in cases of limited involvement of the nerve. Neurorrhaphy can provide good functional results when facial sacrifice is needed. PMID- 29756620 TI - Electrolyte-gated transistors based on phenyl-C61-butyric acid methyl ester (PCBM) films: bridging redox properties, charge carrier transport and device performance. AB - The n-type organic semiconductor phenyl-C61-butyric acid methyl ester (PCBM), a soluble fullerene derivative well investigated for organic solar cells and transistors, can undergo several successive reversible, diffusion-controlled, one electron reduction processes. We exploited such processes to shed light on the correlation between electron transfer properties, ionic and electronic transport as well as device performance in ionic liquid (IL)-gated transistors. Two ILs were considered, based on bis(trifluoromethylsulfonyl)imide [TFSI] as the anion and 1-ethyl-3-methylimidazolium [EMIM] or 1-butyl-1-methylpyrrolidinium [PYR14] as the cation. The aromatic structure of [EMIM] and its lower steric hindrance with respect to [PYR14] favor a 3D (bulk) electrochemical doping. As opposed to this, for [PYR14] the doping seems to be 2D (surface-confined). If the n-doping of the PCBM is pursued beyond the first electrochemical process, the transistor current vs. gate-source voltage plots in [PYR14][TFSI] feature a maximum that points to the presence of finite windows of high conductivity in IL-gated PCBM transistors. PMID- 29756621 TI - Electrochemical oxidation of ciprofloxacin in two different processes: the electron transfer process on the anode surface and the indirect oxidation process in bulk solutions. AB - Herein, the rotating disk electrode technique was used for the first time to investigate the effects of mass-transfer limitations and pH on the electrochemical oxidation of CPX, to determine the kinetics of CPX oxidation and to explore intrinsic mechanisms during the electron transfer process. Firstly, cyclic voltammetry revealed that an obvious irreversible CPX oxidation peak was observed within the potential window from 0.70 to 1.30 V at all pHs. Based on the Levich equation, the electrochemical oxidation of CPX in the electron transfer process was found to be controlled by both diffusion and kinetic processes when pH = 2, 5, 7 and 9; the diffusion coefficient of CPX at pH = 2 was calculated to be 1.5 * 10-7 cm2 s-1. Kinetic analysis indicated that the reaction on the electrode surface was adsorption-controlled compared to a diffusion process; the surface concentration of electroactive species was estimated to be 1.15 * 10-9 mol cm-2, the standard rate constant of the surface reaction was calculated to be 1.37 s-1, and CPX oxidation was validated to be a two-electron transfer process. Finally, a possible CPX oxidation pathway during the electron transfer process was proposed. The electrochemical degradation of CPX on a Ti-based anode was also conducted subsequently to investigate the electrochemical oxidation of CPX in the indirect oxidation process in bulk solutions. The effects of pH and current density were determined and compared to related literature results. The oxidation of CPX at different pHs is believed to be the result of a counterbalance between favorable and unfavorable factors, namely electromigration and side reactions of oxygen evolution, respectively. The effects of current density indicated a diffusion- and reaction-controlled process at low currents followed by a reaction controlled process at high currents. The results presented in this study provide better understanding of the electrochemical oxidation of CPX and would enable the development of new treatment methods based on electrochemistry. PMID- 29756622 TI - Photocatalytic acylarylation of unactivated alkenes with diaryliodonium salts toward indanones and related compounds. AB - A novel photocatalytic acylarylation of unactivated alkenes using diaryliodonium salts as the arylation reagent is described. The reaction produces a variety of 2 benzyl indanones, 3,4-dihydronaphthalen-1(2H)-ones, and 2,3-dihydroquinolin-4(1H) ones in promising yields with excellent diastereoselectivity under very mild conditions, which may be appealing for the synthesis of biologically active molecules. PMID- 29756623 TI - Metal organic frameworks as a catalyst for oxygen reduction: an unexpected outcome of a highly active Mn-MOF-based catalyst incorporated in activated carbon. AB - Owing to their unique chemistry and physical properties, metal-organic frameworks (MOFs) are an interesting class of materials which can be utilized for a wide array of applications. MOFs have been proposed to be used as catalysts for fuel cells, but their low intrinsic electronic conductivity hampered their utilization as is. In this work, we present the synthesis and application of MOF-based precious-metal-group-free (PGM-free) catalysts for oxygen reduction based on a unique metal-organic framework-carbon composite material. Benzene tricarboxylic acid-based MOFs were synthesized inside activated carbon (AC) with four different, first row transition metals: Mn, Fe, Co, and Cu. The MOFs@AC were analyzed electrochemically to measure their catalytic activity. Further physical and chemical characterization studies are performed to measure the material properties. The MOFs@AC are found to be conductive and active catalysts for the oxygen reduction reaction in an alkaline environment. Surprisingly, the Mn-MOF based@AC exhibits the best performance with an onset potential of 0.9 V vs. RHE and the almost four-electron mechanism, as opposed to most other known PGM-free catalysts, which show Fe and Co as the most active metals. PMID- 29756624 TI - Small bite-angle 2-phosphinophosphinine ligands enable rhodium-catalysed hydroboration of carbonyls. AB - Two Rh complexes of the 2-phosphinophosphinine ligand 2-PPh2-3-Me-6-SiMe3-C5H2P (1) were prepared: dinuclear trans-[{Rh(CO)(Cl)(MU-1)}2] (2) and chelating [Rh(1)(COD)][B(ArF)4] (3). Despite the widespread use of Rh catalysts for the hydroboration of alkenes, 3 is reported to be the first Rh catalyst for ketone and ketimine hydroboration, with high activity observed at 0.1 mol% loading. PMID- 29756625 TI - Salient space detection algorithm for signal extraction from contaminated and distorted spectrum. AB - An algorithm for signal extraction from a contaminated and distorted spectrum is proposed. First, this algorithm combines the salient space of the spectrum and the statistical characteristics of the noise to detect signal regions at different scales. Second, it extracts signals by subtracting the baseline from the spectrum in the signal regions. The baseline is fitted by segmented polynomial functions. This algorithm has been applied to simulated and experimental data, and the results show that this algorithm can accurately and automatically extract signals with varying widths from a contaminated spectrum. This method minimizes the influence of baseline distortion and exhibits good anti noise capability and high real-time performance. PMID- 29756626 TI - Metabolic glycan labeling-assisted discovery of cell-surface markers for primary neural stem and progenitor cells. AB - A chemical approach was developed for identifying cell-surface markers for primary neural stem cells (NSCs). Using an in vitro coculture system of primary NSCs combined with metabolic labeling of sialoglycans with bioorthogonal functional groups, we selectively enriched and identified a list of cell-surface sialoglycoproteins that were more abundantly expressed in neural stem and progenitor cells. PMID- 29756627 TI - Ruthenium-catalyzed C-H allylation of arenes with allylic amines. AB - The Ru-catalyzed pyridyl-directed C-H allylation of arenes with allylic amines has been developed. This reaction was carried out in the presence of 5 mol% of [Ru(p-cymene)Cl2]2 and 0.5 equiv. of AgOAc in CF3CH2OH at 75 degrees C, affording the allylated products of arenes in moderate to excellent yields. The method exhibits a wide scope of allylic amines and arenes and shows a good compatibility of functional groups. The pyrazolyl- and pyrimidyl-directed C-H allylation of arenes was also performed under the same conditions. PMID- 29756628 TI - A nanoporous MXene film enables flexible supercapacitors with high energy storage. AB - MXene films are attractive for use in advanced supercapacitor electrodes on account of their ultrahigh density and pseudocapacitive charge storage mechanism in sulfuric acid. However, the self-restacking of MXene nanosheets severely affects their rate capability and mass loading. Herein, a free-standing and flexible modified nanoporous MXene film is fabricated by incorporating Fe(OH)3 nanoparticles with diameters of 3-5 nm into MXene films and then dissolving the Fe(OH)3 nanoparticles, followed by low calcination at 200 degrees C, resulting in highly interconnected nanopore channels that promote efficient ion transport without compromising ultrahigh density. As a result, the modified nanoporous MXene film presents an attractive volumetric capacitance (1142 F cm-3 at 0.5 A g 1) and good rate capability (828 F cm-3 at 20 A g-1). Furthermore, it still displays a high volumetric capacitance of 749 F cm-3 and good flexibility even at a high mass loading of 11.2 mg cm-2. Therefore, this flexible and free-standing nanoporous MXene film is a promising electrode material for flexible, portable and compact storage devices. This study provides an efficient material design for flexible energy storage devices possessing high volumetric capacitance and good rate capability even at a high mass loading. PMID- 29756629 TI - Flexible h-BN foam sheets for multifunctional electronic packaging materials with ultrahigh thermostability. AB - Recently developed electronic packaging materials based on low dimensional materials such as carbon nanotubes, graphene, and hexagonal boron nitride (h-BN) exhibit advantageous electrical, thermal, and mechanical properties for protecting electronic devices as well as dissipating heat flux from highly integrated circuits or high power electronic devices. Their thermal transport is mainly achieved by precise control of the nanostructure for nano-fillers to form the thermally conductive pathway. However, due to the viscoelastic behaviors of host polymeric materials, their phase or structural stability is significantly reduced by enhanced molecular motion at high temperature, resulting in poor thermal transport and mechanical strength. Here, we introduce flexible and robust h-BN foam sheets with a three-dimensional network structure, which exhibit much enhanced thermostability at high temperature. Furthermore, the additional infiltration of Fe3O4 nanoparticles into those structures results in relatively high electromagnetic absorbing performance. The combination of thermostability and mechanical strength based on the h-BN foam sheets provides novel opportunities for multifunctional thermally conductive materials in coatings and films without severely compromising auxiliary characteristics such as mechanical strength and thermal stability. PMID- 29756631 TI - Patients with Acne Vulgaris Have a Distinct Gut Microbiota in Comparison with Healthy Controls. AB - Acne vulgaris has been postulated to have a gastrointestinal mechanism; however, little is known about gut microbiota dysfunction in this condition. The aim of this cross-sectional study was to investigate whether the gut microbiota is altered in acne. Faecal bacterial diversity was analysed in 43 patients with acne and 43 controls, using hypervariable tag sequencing of the V3-V4 region of the 16S rDNA gene. Distinct differences were found in microbial diversity between patients with acne and controls (Shannon diversity index (p = 0.009) and Simpson diversity index (p = 0.01)). At the phylum level, the abundance of Firmicutes was lower in the patient group, but that of Bacteroidiain was higher. The most significantly depleted taxa in acne were Clostridia, Clostridiales, Lachnospiraceae and Ruminococcaceae genera, which are potentially beneficial. In conclusion, patients with acne vulgaris have gut microbial dysbiosis; further study is needed to understand its role in the pathogenesis of acne. PMID- 29756630 TI - A biomimetic microfluidic model to study signalling between endothelial and vascular smooth muscle cells under hemodynamic conditions. AB - Cell signalling and mechanics influence vascular pathophysiology and there is an increasing demand for in vitro model systems that enable examination of signalling between vascular cells under hemodynamic conditions. Current 3D vessel wall constructs do not recapitulate the mechanical conditions of the native tissue nor do they allow examination of cell-cell interactions under relevant hemodynamic conditions. Here, we describe a 3D microfluidic chip model of arterial endothelial and smooth muscle cells where cellular organization, composition and interactions, as well as the mechanical environment of the arterial wall are mimicked. The hemodynamic EC-VSMC-signalling-on-a-chip consists of two parallel polydimethylsiloxane (PDMS) cell culture channels, separated by a flexible, porous PDMS membrane, mimicking the porosity of the internal elastic lamina. The hemodynamic EC-VSMC-signalling-on-a-chip allows co-culturing of human aortic endothelial cells (ECs) and human aortic vascular smooth muscle cells (VSMCs), separated by a porous membrane, which enables EC-VSMC interaction and signalling, crucial for the development and homeostasis of the vessel wall. The device allows real time cell imaging and control of hemodynamic conditions. The culture channels are surrounded on either side by vacuum channels to induce cyclic strain by applying cyclic suction, resulting in mechanical stretching and relaxation of the membrane in the cell culture channels. The blood flow is mimicked by creating a flow of medium at the EC side. Vascular cells remain viable during prolonged culturing, exhibit physiological morphology and organization and make cell-cell contact. During dynamic culturing of the device with a shear stress of 1-1.5 Pa and strain of 5-8%, VSMCs align perpendicular to the given strain in the direction of the flow and EC adopt a cobblestone morphology. To our knowledge, this is the first report on the development of a microfluidic device, which enables a co-culture of interacting ECs and VSMCs under hemodynamic conditions and presents a novel approach to systematically study the biological and mechanical components of the intimal-medial vascular unit. PMID- 29756632 TI - Effects of push-off ability and handcycle type on handcycling performance in able bodied participants. AB - OBJECTIVE: To assess the effects on handcycling performance and physiological responses, of: (i) making a closed chain by comparing handcycling in a recumbent bike with 2-feet footrest (closed chain) with handcycling with 1 footrest (partial closed chain) and without a footrest (no closed chain); (ii) equipment by comparing handcycling in a recumbent bike with a kneeling bike. METHODS: Ten able-bodied participants performed submaximal exercise and sprint tests, once in a knee-ling bike and 3 times on a recumbent: 2-feet support, 1-foot support and without foot support. Physical strain (submaximal oxygen uptake and heart rate), peak (POpeak) and mean power output (POmean) were measured. RESULTS: Significantly higher POpeak and POmean were found with 2-feet support (mean 415 W (standard deviation (SD) 163) and mean 281 W (SD 96)) and higher POmean with 1 foot support (mean 279 W (SD 104)) compared with no foot support (mean 332 W (SD 127) and mean 254 W (SD 101)), p < 0.05. No differences were found for physical strain. In the kneeling bike, POpeak and POmean were significantly higher (mean 628 W (SD 231) and 391 W (SD 121)) than in the recumbent (mean 415 W (SD 163) and 281 W (SD 96)), p = 0.001. CONCLUSION: The ability to make a closed chain has a significant positive effect on handcycling sprint performance; therefore, this ability may be a discriminating factor. Sprint performance was significantly higher in kneeling compared with recumbent handcycling. PMID- 29756634 TI - External validation of the 80+ score and comparison with three clinical scores identifying patients at least 75 years old at risk of unplanned readmission within 30 days after discharge. AB - AIM OF THE STUDY: A potentially avoidable readmission is an unplanned readmission occurring within 30 days of discharge. As 20% of hospitalised elderly patients are rehospitalised as an unplanned readmission, it is necessary to identify with a clinical score those patients who are at risk of readmission and need discharge interventions as a priority. The main objective of this study was to externally validate and compare the 80+ score with the three other scores predicting the risk of unplanned readmission. METHODS: We conducted a retrospective case-control study using a clinical data warehouse. The study included patients hospitalised between 1 September 2014 and 31 October 2015 in an 800-bed university hospital. We included patients aged 75 and over. Cases were readmitted at the emergency department within 30 days after the index discharge. Controls were not readmitted as an emergency within 30 days. Four clinical scores (80+ score, LACE index, HOSPITAL score, TRST) were externally validated. Discrimination of the scores was assessed by calculating the area under the receiver operating characteristic curves (AUC). Calibration was assessed with a Hosmer-Lemeshow chi2 test. RESULTS: We included 438 patients. For discrimination, the 80+ score, the LACE index, the HOSPITAL score and the TRST had AUCs of 0.506 (95% confidence interval [CI] 0.413 0.546), 0.534 (95% CI 0.459-0.591, 0.517 (95% CI 0.466-0.598) and 0.589 (95% CI 0.524-0.654), respectively. The Hosmer-Lemeshow chi2 tests had p-values of 0.44, 0.43, 0.11 and 0.49, respectively. CONCLUSION: In our study, the 80+ score was externally validated and showed less favourable discrimination than the three other scores in this population. PMID- 29756633 TI - Immunotherapy in head and neck cancer - scientific rationale, current treatment options and future directions. AB - Head and neck squamous cell carcinoma (HNSCC) is a frequent tumour arising from multiple anatomical subsites in the head and neck region. The treatment for early stage disease is generally single modality, either surgery or radiotherapy. The treatment for locally advanced tumours is multimodal. For recurrent/metastatic HNSCC palliative chemotherapy is standard of care. The prognosis is limited and novel treatment approaches are urgently needed. HNSCC evades immune responses through multiple resistance mechanisms. HNSCC is particularly characterised by an immunosuppressive environment which includes the release of immunosuppressive factors, activation, expansion of immune cells with inhibitory activity and decreased tumour immunogenicity. An in-depth understanding of these mechanisms led to rational design of immunotherapeutic approaches and clinical trials. Currently, only immune checkpoint inhibitors, namely monoclonal antibodies targeting the immune inhibitory receptor programmed cell death 1 (PD-1) and its ligand PD-L1 have proven clinical efficacy in randomised phase III trials. The PD 1 inhibitor nivolumab is the only drug approved for platinum-refractory recurrent/metastatic HNSCC. However, many more immunotherapeutic treatment options are currently under investigation. Ongoing trials are investigating immunotherapeutic approaches also in the curative setting and combination therapies using different immunotherapeutic approaches. This review article summarises current knowledge of the role of the immune system in the development and progression of HNSCC, and provides a comprehensive overview on the development of immunotherapeutic approaches. PMID- 29756635 TI - Trends in the use of mammography for early breast cancer detection in Switzerland: Swiss Health Surveys 2007 and 2012. AB - AIMS: Breast cancer is the most common cancer in women worldwide. We assessed changes in the use of breast cancer screening 2007-2012 in Switzerland, and associations with socioeconomic and health-related determinants. METHODS: We used the nationwide and representative data from the Swiss Health Surveys 2007 and 2012. We analysed the self-reported use of mammography in the last 12 months (proportion of population) among women aged 40-79 years, and opportunistic (without clinical symptoms, initiated by the woman or a physician) and programmatic screening mammography (as part of a systematic screening programme). We performed multivariate logistic regression analyses (presented as adjusted odds ratios, aORs). RESULTS: The use of any mammography in the last 12 months declined from 19.1% (95% confidence interval [CI] 17.7-20.5%) in 2007 to 11.7% (95% CI 10.7-12.6%) in 2012. This decline was more pronounced in regions with a long-standing or no cantonal breast cancer screening programme (aOR 0.5, 95% CI 0.4-0.6, and aOR 0.5, 95% CI 0.4-0.6, respectively), but remained relatively stable in regions with a recently introduced programme (aOR 0.9, 95% CI 0.6-1.3, p-value from test for interaction 0.01). Opportunistic screening dropped from 12.0% (95% CI 10.9-13.2%) in 2007 to 6.2% (95% CI 5.5-6.9%; p <0.001) in 2012, whereas the use of programmatic mammography remained stable at 3.1% (95% CI 2.6 3.7%). Use of any mammography was higher in women aged 50-69 years, residing in a region with a systematic screening programme in place, and women having a private hospital stay insurance, but was not associated with education level and non Swiss citizenship. CONCLUSIONS: Overall attendance of breast cancer screening is low in Switzerland and decreased between 2007 and 2012, despite expanding cantonal mammography screening programmes. Many factors may have contributed to this decline, including the ongoing scientific and public debates on the value of breast cancer screening. PMID- 29756636 TI - Recurrence of phonetic responding. AB - This study determined if previously reinforced academic responding recurred when alternative responses were differentially reinforced and subsequently placed on extinction, and whether the magnitude of resurgence was related to the rate of differential reinforcement for the alternative behavior. Three kindergarten students read Greek letters aloud as arbitrary consonant-vowel blends. Resurgence was reliably demonstrated within and across participants, and the magnitude of resurgence was related to the prior rate of differential reinforcement of alternative behavior. PMID- 29756637 TI - Withdrawal of immunosuppressant or biologic therapy for patients with quiescent Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is a chronic, relapsing and remitting disease of the gastrointestinal tract that can cause significant morbidity and disability. Current treatment guidelines recommend early intervention with immunosuppressant or biological therapy in high-risk patients with a severe disease phenotype at presentation. The feasibility of therapeutic de-escalation once remission is achieved is a commonly encountered question in clinical practice, driven by patient and clinician concerns regarding safety, adverse events, cost and national regulations. Withdrawal of immunosuppressant and biologic drugs in patients with quiescent CD may limit adverse events and reduce healthcare costs. Alternatively, stopping these drug therapies may result in negative outcomes such as disease relapse, drug desensitization, bowel damage and need for surgery. OBJECTIVES: To assess the feasibility and safety of discontinuing immunosuppressant or biologic drugs, administered alone or in combination, in patients with quiescent CD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and the Cochrane IBD Group Specialized Register from inception to 19 December 2017. We also searched the reference lists of potentially relevant manuscripts and conference proceedings to identify additional studies. SELECTION CRITERIA: Randomized controlled trials (RCTs) and prospective cohort studies that followed patients for a minimum duration of six months after drug discontinuation were considered for inclusion. The patient population of interest was adults (> 18 years) with CD (as defined by conventional clinical, endoscopic or histologic criteria) who had achieved remission while receiving immunosuppressant or biologic drugs administered alone or in combination. Patients then discontinued the drug regimen following a period of maintenance therapy of at least six months. The comparison was usual care (i.e. continuation of the drug regimen). DATA COLLECTION AND ANALYSIS: The primary outcome measure was the proportion of patients who relapsed following discontinuation of immunosuppressant or biologic drugs, administered alone or in combination. Secondary outcomes included: the proportion of patients who responded to the reintroduction of immunosuppressant or biologic drugs, given as monotherapy or combination therapy; the proportion of patients who required surgery following relapse; the proportion of patients who required hospitalization for CD following relapse; the proportion of patients who developed new CD-related complications (e.g. fistula, abscesses, strictures) following relapse; the proportion of patients with elevated biomarkers of inflammation (CRP, fecal calprotectin) in those who stop and those who continue therapy; the proportion of patients with anti-drug antibodies and low serum trough drug levels; time to relapse; and the proportion of patients with adverse events, serious adverse events and withdrawal due to adverse events. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (95% CI). Data were analyzed on an intention-to-treat basis where patients with missing outcome data were assumed to have relapsed. The overall quality of the evidence supporting the primary and secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: A total of six RCTs (326 patients) evaluating therapeutic discontinuation in patients with quiescent CD were eligible for inclusion. In four RCTs azathioprine monotherapy was discontinued, and in two RCTs azathioprine was discontinued from a combination therapy regimen consisting of azathioprine with infliximab. No studies of biologic monotherapy withdrawal were eligible for inclusion. The majority of studies received unclear or low risk of bias ratings, with the exception of three open-label RCTs, which were rated as high risk of bias for blinding. Four RCTs (215 participants) compared discontinuation to continuation of azathioprine monotherapy, while two studies (125 participants) compared discontinuation of azathioprine from a combination regimen to continuation of combination therapy. Continuation of azathioprine monotherapy was shown to be superior to withdrawal for risk of clinical relapse. Thirty-two per cent (36/111) of azathioprine withdrawal participants relapsed compared to 14% (14/104) of participants who continued with azathioprine therapy (RR 0.42, 95% CI 0.24 to 0.72, GRADE low quality evidence). However, it is uncertain if there are any between-group differences in new CD-related complications (RR 0.34, 95% CI 0.06 to 2.08, GRADE low quality evidence), adverse events (RR 0.88, 95% CI 0.67 to 1.17, GRADE low quality evidence), serious adverse events (RR 3.29, 95% CI 0.35 to 30.80, GRADE low quality evidence) or withdrawal due to adverse events (RR 2.59, 95% CI 0.35 to 19.04, GRADE low quality evidence). Common adverse events included infections, mild leukopenia, abdominal symptoms, arthralgias, headache and elevated liver enzymes. No differences between azathioprine withdrawal from combination therapy versus continuation of combination therapy were observed for clinical relapse. Among patients who continued combination therapy with azathioprine and infliximab, 48% (27/56) had a clinical relapse compared to 49% (27/55) of patients discontinued azathioprine but remained on infliximab (RR 1.02, 95% CI 0.68 to 1.52, P = 0.32; GRADE low quality evidence). The effects on adverse events (RR 1.11, 95% CI 0.44 to 2.81, GRADE low quality of evidence) or serious adverse events are uncertain (RR 1.00, 95% CI 0.21 to 4.66; GRADE very low quality of evidence). Common adverse events in the combination therapy studies included infections, liver test elevations, arthralgias and infusion reactions. AUTHORS' CONCLUSIONS: The effects of withdrawal of immunosuppressant therapy in people with quiescent Crohn's disease are uncertain. Low quality evidence suggests that continuing azathioprine monotherapy may be superior to withdrawal for avoiding clinical relapse, while very low quality evidence suggests that there may be no difference in clinical relapse rates between discontinuing azathioprine from a combination therapy regimen, compared to continuing combination therapy. It is unclear whether withdrawal of azathioprine, initially administered alone or in combination, impacts on the development of CD-related complications, adverse events, serious adverse events or withdrawal due to adverse events. Further high-quality research is needed in this area, particularly double-blind RCTs in which biologic therapy or an immunosuppressant other than azathioprine is withdrawn. PMID- 29756639 TI - The carboxylate-releasing phosphorus-mobilizing strategy can be proxied by foliar manganese concentration in a large set of chickpea germplasm under low phosphorus supply. AB - Root foraging and root physiology such as exudation of carboxylates into the rhizosphere are important strategies for plant phosphorus (P) acquisition. We used 100 chickpea (Cicer arietinum) genotypes with diverse genetic backgrounds to study the relative roles of root morphology and physiology in P acquisition. Plants were grown in pots in a low-P sterilized river sand supplied with 10 MUg P g-1 soil as FePO4 , a poorly soluble form of P. There was a large genotypic variation in root morphology (total root length, root surface area, mean root diameter, specific root length and root hair length), and root physiology (rhizosheath pH, carboxylates and acid phosphatase activity). Shoot P content was correlated with total root length, root surface area and total carboxylates per plant, particularly malonate. A positive correlation was found between mature leaf manganese (Mn) concentration and carboxylate amount in rhizosheath relative to root DW. This is the first study to demonstrate that the mature leaf Mn concentration can be used as an easily measurable proxy for the assessment of belowground carboxylate-releasing processes in a range of chickpea genotypes grown under low-P, and therefore offers an important breeding trait, with potential application in other crops. PMID- 29756640 TI - Aortic valve hemodynamics in atrial fibrillation: Should the highest Doppler signal be used to estimate severity of aortic stenosis? AB - Grading severity of AS in AF is complicated by varying stroke volumes associated with fluctuating maximum velocities and pressure gradients across the aortic valve. Current guidelines recommend averaging five continuous-wave peak velocity and mean gradient (MG) Doppler signals across the aortic valve when estimating severity of AS in AF. However, it is unknown when grading severity of AS how the average of multiple Doppler signals vs the highest Doppler signal in AF compares to the Doppler signals when the patient is in normal sinus rhythm. We present a series of patients with AS who had two echocardiograms performed within 2-4 months of each other, one when in normal sinus rhythm and one when in AF, and compare the aortic valve hemodynamics associated with the two rhythms. PMID- 29756642 TI - Reference values and correlates of right atrial volume in healthy adults by two dimensional echocardiography. AB - BACKGROUND: Right atrial (RA) volume is an important parameter in the evaluation of patients with pulmonary hypertension. Aim of this study was to define reference ranges for RA volume by two-dimensional echocardiography (2DE) in healthy adults. METHODS: A total of 596 healthy subjects [mean age 45.7 +/- 14.6 years, range 18-88 years; 60.1% women] underwent a transthoracic echocardiography. In addition, a meta-analysis was performed of published studies measuring RA volume in healthy subjects, using 2DE single plane area-length (A-L) and/or method of disks (MOD) at end-systole in apical four-chamber view. RESULTS: In our cohort, RA volume was higher in men than women but did not vary with age. Body surface area (BSA), stroke volume (SV), and tricuspid annular plane systolic excursion (TAPSE) were the only independent variables associated with RA volume (beta coefficient 0.569, 0.123, and 0.131, respectively; all P < .001). In the pooled analysis, normalized RA volume was 25.7 +/- 7.0 mL/m2 in men and 21.2 +/- 5.8 mL/m2 in women for A-L, 21.6 +/- 5.6 mL/m2 in men and 18.2 +/- 5.4 mL/m2 in women for MOD (all P values < .0001). The upper limit was about 36 mL/m2 in men and 31 mL/m2 in women for A-L and 31 mL/m2 in men and 27 mL/m2 in women for MOD. CONCLUSIONS: RA volume was found to be higher in men but not influenced by age. It was mainly correlated with larger BSA, indices of preload (SV) and RV longitudinal function (TAPSE). A statistically significant difference was found between A-L and MOD. PMID- 29756638 TI - Sex differences in diaphragmatic fatigue: the cardiovascular response to inspiratory resistance. AB - KEY POINTS: Diaphragmatic fatigue (DF) elicits a sympathetically mediated metaboreflex resulting in increased heart rate, blood pressure and limb vascular resistance. Women may be more resistant to DF compared to men, and therefore it was hypothesised that women would experience an attenuated inspiratory muscle metaboreflex during inspiratory pressure-threshold loading (PTL) performed to task failure. At the time of PTL task failure, the severity of DF was not different between sexes; however, inspiratory muscle endurance time was significantly longer in women than in men. For a given cumulative diaphragmatic force output, the severity of DF was less in women than in men. Women exhibited a blunted cardiovascular response to inspiratory resistance (i.e. metaboreflex) that may have implications for exercise tolerance. ABSTRACT: Diaphragmatic fatigue (DF) elicits reflexive increases in sympathetic vasomotor outflow (i.e. metaboreflex). There is some evidence suggesting women may be more resistant to DF compared to men, and therefore may experience an attenuated inspiratory muscle metaboreflex. To this end, we sought to examine the cardiovascular response to inspiratory resistance in healthy young men (n = 9, age = 24 +/- 3 years) and women (n = 9, age = 24 +/- 3 years). Subjects performed isocapnic inspiratory pressure-threshold loading (PTL, 60% maximal inspiratory mouth pressure) to task failure. Diaphragmatic fatigue was assessed by measuring transdiaphragmatic twitch pressure (Pdi,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial pressure (MAP) were measured beat-by-beat throughout PTL via photoplethysmography, and low-frequency systolic pressure (LFSBP ; a surrogate for sympathetic vasomotor tone) calculated from arterial waveforms using power spectrum analysis. At PTL task failure, the degree of DF was similar between sexes (~23% reduction in Pdi,tw ; P = 0.33). However, time to task failure was significantly longer in women than in men (27 +/- 11 vs. 16 +/- 11 min, respectively; P = 0.02). Women exhibited less of an increase in HR (13 +/- 8 vs. 19 +/- 12 bpm; P = 0.02) and MAP (10 +/- 8 vs. 14 +/- 9 mmHg; P = 0.01), and significantly lower LFSBP (23 +/- 11 vs. 34 +/- 8 mmHg2 ; P = 0.04) during PTL compared to men. An attenuation of the inspiratory muscle metaboreflex may influence limb and respiratory muscle haemodynamics with implications for exercise performance. PMID- 29756643 TI - Isolated premature restriction or closure of foramen ovale in fetuses: Echocardiographic characteristics and outcome. AB - BACKGROUND: Premature restriction or closure of foramen ovale (FO) in otherwise structurally normal hearts may be associated with right ventricular dilation, tricuspid regurgitation, pericardial effusion, heart failure, even poor perinatal outcomes. Data about these rare conditions are lacking. METHODS: We retrospectively reviewed the echocardiographic records of 9704 fetuses seen from 2010 to 2014 in Beijing Anzhen Hospital, a regional and national referral center, to ascertain the presence of restriction or closure of FO. We collected the fetal echocardiography and perinatal outcome data for this group of fetuses with restriction or closure of FO. RESULTS: In this large, single-institution cohort (n = 9704), 6707 fetuses seen between 23 and 37 weeks of gestation had normal heart structures; of these, 60 (0.89%) had restrictive FO (rFO) and 5 (0.07%) had closure of FO (cFO). Fetal echocardiographic images showed right atrial dilation in 48 (73.84%), right ventricular dilation in 38 (58.46%), tricuspid regurgitation in 19 (29.23%), and pericardial effusion in 10 (15.38%). Also in this group, 50 (83.3%) with rFO and 4 (80.0%) with cFO had follow-up data. No prenatal deaths occurred in either the rFO or the cFO group, but the neonatal mortality included 1 in the rFO group and 2 in the cFO group. CONCLUSION: Premature rFO/cFO are rare in fetuses with otherwise structurally normal hearts. The fetal echocardiographic characteristics include right atrial and ventricular dilated, tricuspid regurgitation, and pericardial effusion. Most fetuses had a good outcome, although there was an association between rFO, especially cFO, with neonatal morality and complications (prematurity, maternal preeclampsia and placental abruption, hydrops fetalis, and necrotizing enterocolitis with perforation). PMID- 29756641 TI - Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder. AB - BACKGROUND: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. OBJECTIVE: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. METHODS: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. RESULTS: MAPT-H2 variants were associated with PD (odds ratios: 0.62 0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. CONCLUSIONS: Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29756646 TI - Cholangiocarcinoma issue. PMID- 29756644 TI - Metabolic and gene expression hallmarks of seed germination uncovered by sodium butyrate in Medicago truncatula. AB - Because high-quality seeds are essential for successful crop production in challenging environments, understanding the molecular bases of seed vigour will lead to advances in seed technology. Histone deacetylase inhibitors, promoting histone hyperacetylation, are used as tools to explore aspects still uncovered of the abiotic stress response in plants. The aim of this work was to investigate novel signatures of seed germination in Medicago truncatula, using the histone deacetylase inhibitor sodium butyrate (NaB) as stress agent. NaB-treated and untreated seeds collected at 2 and 8 hr of imbibition and at the radicle protrusion stage underwent molecular phenotyping and nontargeted metabolome profiling. Quantitative enrichment analysis revealed the influence of NaB on seed nucleotide, amino acid, lipid, and carbohydrate metabolism. Up-regulation of antioxidant and polyamine biosynthesis genes occurred in response to NaB. DNA damage evidenced in NaB-treated seeds correlated with up-regulation of base excision repair genes. Changes in N1 -methyladenosine and N1 -methylguanine were associated with up-regulation of MtALKBH1 (alkylation repair homolog) gene. N2 ,N2 -dimethylguanosine and 5-methylcytidine, tRNA modifications involved in the post-transcriptional regulation of DNA damage response, were also accumulated in NaB-treated seeds at the radicle protrusion stage. The observed changes in seed metabolism can provide novel potential metabolic hallmarks of germination. PMID- 29756647 TI - Surgery for perihilar cholangiocarcinoma. PMID- 29756648 TI - Direct Percutaneous Endoscopic Jejunostomy: Procedural and Nutrition Outcomes in a Large Patient Cohort. AB - BACKGROUND: Direct percutaneous endoscopic jejunostomy (DPEJ) is used for enteral nutrition (EN) in patients with postoperative anastomotic leaks after esophagectomy/gastrectomy and at high risk for aspiration. We characterized the indications, technical success, procedural/nutrition outcomes, and adverse events in a large cohort of patients undergoing DPEJ insertion. METHODS: Patients undergoing DPEJ insertion between January 2009 and March 2015 were identified from an institutional endoscopy database. Demographic, procedural, and nutrition outcome data were collected from electronic medical records. Regression analyses were used to identify predictors of adverse events and procedural success. RESULTS: A total of 452 patients underwent 480 attempts at DPEJ insertion. Indications included preoperative or postoperative weight loss (64%), postoperative upper gastrointestinal (UGI) anastomotic leak (13%), aspiration prevention (10%), and other (13%). Of attempted procedures, 398 (83%) were successful. Feeding was initiated in 389 (98%) of patients; a median of 1775 calories was delivered daily. Median body mass index (BMI) at baseline was 22.9 (11.4-44.7) and did not change over follow-up. Median change in BMI after DPEJ was similar in groups that received EN with palliative and curative intent. Adverse events following 480 attempted DPEJ insertions included 13 (3%) immediate and 74 (15%) delayed, 13 (3%) of which were serious. Patients with head and neck cancer had more adverse events than those with esophageal cancer (P = .020). CONCLUSION: DPEJ is a successful and safe procedure that effectively provides access for EN support in malnourished patients and patients with postoperative UGI cancer. PMID- 29756649 TI - Measuring peripheral oxytocin and vasopressin in nonhuman primates. AB - Studying the neural and hormonal changes that modulate behavior is critical to understanding social relationships. Of particular interest is measuring oxytocin (OT) and arginine vasopressin (AVP) peripherally, and preferably, non-invasively, in nonhuman primates. Due to these peptides' neural origin and their stimulation of brain areas that influence social behavior, there has been debate whether peripheral measures in blood, urine, and saliva reflect central levels in the brain. This review elucidates the challenges of OT measurement and the solutions that provide valuable data on OT's role in social behavior. This review discusses the recent studies in rhesus macaques which indicate that exogenous OT delivered by nasal spray results in increased OT in cerebrospinal fluid, and it notes the new methodologies that can measure both endogenous and exogenous OT simultaneously, which thereby determine the source of measured OT in biological fluids. Next, this review highlights the utility of measuring urinary OT by summarizing the results of clearance rate studies in humans and marmosets, which characterize the timing that circulating OT enters urine and illustrate that endogenous releasers of OT also increase urinary OT. With the ability to reliably measure OT and AVP in urine and in blood, we can now study free-ranging captive, and non-captive primates to answer questions about the biology of social bonding that were not possible before. One procedural concern that this review also highlights is whether extraction of the peptides prior to assay is needed, as the values are higher in samples that have not been extracted. Studies indicate that extractions eliminate the interfering compounds that cause higher values. Across studies, to ensure the reliability of measuring OT for nonhuman primates, this review makes suggestions based on empirical evidence for how to correctly preserve samples and emphasizes the need to validate each assay for individual species. PMID- 29756650 TI - Stillbirth rates across three ape species in accredited American zoos. AB - Stillbirths, or births of infants that died in the womb, represent a failure of the materno-feto-placental unit to maintain a suitable fetal environment. Typical studies of nonhuman primate (NHP) stillbirth patterns are primarily descriptive and focus on macaques (genus Macaca). Thus, less is known about other NHP species and rarer still are studies that examine possible biological factors that influence stillbirth rates across taxa. To examine possible contributors to stillbirths in great apes, we analyzed 36 years (1980-2016) of historical data documenting births of zoo-housed chimpanzees (Pan troglodytes, N = 391), western lowland gorillas (Gorilla gorilla gorilla, N = 491), and orangutans (Pongo spp, N = 307) in accredited zoological parks in the United States. The average number of births for each of the 446 mothers was 2.7, resulting in a total of 1,189 births with 143 stillbirths (12%). Stillbirths represented 12% of chimpanzee births, 13% of gorilla births, and 10% of orangutan births. We used generalized linear mixed effects models to assess possible relationships between stillbirth likelihood and mother origin (wild- versus captive-born), age, and genus. Across taxa, older mothers were more likely to have a stillbirth (p = 0.004). While these results are likely influenced by both biological and management-related factors (e.g., selective captive breeding), they may be useful to population managers in evaluating pregnancy risks for great apes. Captive settings and archival studbook data such as these may provide a unique opportunity to further explore this topic. PMID- 29756652 TI - LASER treatment for women with high-grade vaginal intraepithelial neoplasia: A propensity-matched analysis on the efficacy of ablative versus excisional procedures. AB - OBJECTIVE: To investigate the long-term effectiveness of LASER treatment in women affected by high-grade vaginal intra-epithelial neoplasia. METHODS: Data of consecutive women treated for high-grade vaginal intra-epithelial neoplasia were retrieved. Efficacy and long-term effectiveness of ablative and excisional procedures were tested using a propensity-matched algorithm. Risk of recurrence over the time was assessed using Kaplan-Meier and Cox models. RESULTS: Overall, 204 patients met the inclusion criteria. LASER ablation and exicision were performed in 169 (82.8%) and 35 (17.2%) patients. A total of 41 (20%) patients developed high-grade vaginal intraepithelial neoplasia at a median follow-up of 65 (range, 6-120) months. We observed that only HPV persistence (HR: 2.37 [95%CI:1.03, 5.42]; P = 0.04) was associated with the risk of recurrence at multivariate analysis. Seven (3.4%) invasive cancers of the lower genital tract were observed in our population. Considering the efficacy of type of procedure (after we applied the propensity-matched analysis), we observed that type of procedure did not influence persistence of HPV infection (22.8% after excision and 15.7% after ablation; P = 0.424). Similarly, recurrence (17.1% vs. 18.6%; P = 1.00) and lower genital tract (2.8% vs. 1.4%; P = 1.00) rates were similar between groups. CONCLUSIONS: Women affected by high-grade vaginal intra epithelial neoplasia are at high risk of recurrence. LASER ablation seems to be equivalent to excision in term of long-term effectiveness. Lasers Surg. Med. 50:933-939, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29756653 TI - The effect of photodynamic therapy on pathogenic bacteria around peri-implant sulcus and in the cavity between abutment and implant after healing phase: A prospective clinical study. AB - OBJECTIVES: To compare levels of pathogens from peri-implant sulcus versus abutment screw cavities after photodynamic therapy. MATERIAL AND METHODS: Twenty patients were included. Photodynamic therapy (PDT) was applied both in sulcus and cavities after sampling following suprastructures loading, and repeated after 2 weeks. Two samples each containing four paper points were collected for each implant at baseline, 2 weeks, 3 months: (i) peri-implant sulcus and (ii) abutment screw cavities. Seventy-five percent ethanol was applied in another 20 patients as the control group in the same way. qPCR was used to quantify periodontal pathogens: Porphyromonas gingivalis, Fusobacterium nucleatum, Streptococcus mutans. RESULTS: PDT showed a better bacterial reduction than ethanol. P. g. and F. n. were most frequently detected, while less for S. m. P. gingivalis' proportion from both sites was significantly higher than the other two bacteria (P < 0.05), except for 2 weeks' peri-implant sulcus sample. Bacteria counts from abutment screw cavities were always less than those from peri-implant sulcus and was significantly lower for total bacteria at 3 months (P < 0.05). Total bacterial from abutment screw cavities significantly reduced at 3 months compared to baseline (P < 0.05). CONCLUSIONS: PDT appears to be effective in bacterial reduction compared to ethanol and can reduce P. gingivalis with short time intervals, as well as decreasing total bacteria counts within abutment screw cavities in the long run, suggesting PDT an effective way sterilizing inner surface of oral implant suprastrutures. Lasers Surg. Med. 50:433-439, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29756651 TI - Optical signature of nerve tissue-Exploratory ex vivo study comparing optical, histological, and molecular characteristics of different adipose and nerve tissues. AB - BACKGROUND: During several anesthesiological procedures, needles are inserted through the skin of a patient to target nerves. In most cases, the needle traverses several tissues-skin, subcutaneous adipose tissue, muscles, nerves, and blood vessels-to reach the target nerve. A clear identification of the target nerve can improve the success of the nerve block and reduce the rate of complications. This may be accomplished with diffuse reflectance spectroscopy (DRS) which can provide a quantitative measure of the tissue composition. The goal of the current study was to further explore the morphological, biological, chemical, and optical characteristics of the tissues encountered during needle insertion to improve future DRS classification algorithms. METHODS: To compare characteristics of nerve tissue (sciatic nerve) and adipose tissues, the following techniques were used: histology, DRS, absorption spectrophotometry, high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy, and solution 2D 13 C-1 H heteronuclear single-quantum coherence spectroscopy. Tissues from five human freshly frozen cadavers were examined. RESULTS: Histology clearly highlights a higher density of cellular nuclei, collagen, and cytoplasm in fascicular nerve tissue (IFAS). IFAS showed lower absorption of light around 1200 nm and 1750 nm, higher absorption around 1500 nm and 2000 nm, and a shift in the peak observed around 1000 nm. DRS measurements showed a higher water percentage and collagen concentration in IFAS and a lower fat percentage compared to all other tissues. The scattering parameter (b) was highest in IFAS. The HR-MAS NMR data showed three extra chemical peak shifts in IFAS tissue. CONCLUSION: Collagen, water, and cellular nuclei concentration are clearly different between nerve fascicular tissue and other adipose tissue and explain some of the differences observed in the optical absorption, DRS, and HR NMR spectra of these tissues. Some differences observed between fascicular nerve tissue and adipose tissues cannot yet be explained but may be helpful in improving the discriminatory capabilities of DRS in anesthesiology procedures. Lasers Surg. Med. 50:948-960, 2018. (c) 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID- 29756655 TI - Depression and its effects on the success of resin-based restorations. AB - AIMS: There are many factors that play into the success or failure of dental treatments, and mental health has been hypothesized to increase failure rates in treatment such as resin-based restorations. The goal of this work was to evaluate if composite resin dental restorations perform the same in individuals with depression in comparison to matched individuals without depression. METHODS AND RESULTS: A total of 6,026 individuals from the University of Pittsburgh Dental Registry and DNA Repository project were evaluated and 326 patients with depression were selected for this study. They were matched by age, sex, ethnicity, and smoking history with 326 subjects without depression. Rates of failure of resin-based restorations were determined in both groups. Chi-square was used for all comparisons with alpha set at 0.05. We found significantly higher failure rates of resin-based restorations in patients diagnosed with clinical depression (p < 0.00001, OR = 1.89, 95% C.I. 1.6 to 2.23). DISCUSSION: The significantly higher failure rates in patients with clinical depression suggests that clinical depression has an effect on the success of resin-based restorations. The results of this study suggest a need for more personalized dental care for patients, which includes taking into account their mental health and its subsequent effects on oral health and hygiene, and customized definitions of follow-up time intervals. PMID- 29756654 TI - Effect of reward type on object discrimination learning in socially monogamous coppery titi monkeys (Callicebus cupreus). AB - Highly valued food items are often used as rewards to reinforce an animal's behavior. For social species, social interaction is rewarding and can drive an individual's behavior as well. In the currently study, we wanted to compare the efficacy of a food reward and a social reward on object discrimination learning in socially monogamous titi monkeys. We hypothesized that titi monkeys would perform more accurately for a social reward (their pair mate) than for a food reward (a highly desired food item). Eleven adult titi monkeys were tested with a two-object visual discrimination task for both types of reward. The colors and shapes of the objects in the two-object discrimination task were counterbalanced across subjects. During each trial, subjects were shown two objects, and the trial ended when the subject touched the reinforced shape (S+) or after 5 min. A correct trial was defined as one when the subject touched S+ first. We found that 45.5% of subjects were able to learn the task with a social reward, and 83.3% were able to learn the task with a food reward. We found that subjects balked more often and had fewer correct trials for the social reward. Finally, subjects took longer to approach the shapes for a social reward, possibly indicating lower motivation to engage in the task when a social reward is used compared to a food reward. Although significantly fewer subjects met criteria of success with the social reward than with the food reward, our results show that titi monkeys can learn a visual discrimination task with either type of reward. PMID- 29756656 TI - Pathophysiology and treatment of achalasia in a muscle mechanical perspective. AB - This review provides a biomechanical perspective on the pathophysiology and treatment of achalasia. The esophagus is efficient in transporting ingested material to the stomach in healthy subjects. A fine balance exists between the peristaltic forces generated in the esophageal body (which herein is defined as the preload) and the resistance in the outlet, the esophago-gastric junction (which is defined as the afterload). Achalasia is a rare esophageal disease that progressively over many years challenges esophageal efficacy. Clinical features and current literature are interpreted using well-known muscle mechanics models and terms from cardiac mechanophysiology. The preload, afterload, length-tension, and strain softening concepts in particular are useful for understanding the remodeling induced by achalasia. The concepts are also useful in understanding the treatment that aim to reduce the lower esophageal sphincter pressure that does not relax sufficiently in achalasia. These treatments cover endoscopic or laparoscopic myotomy, pneumatic balloon dilation, and Botox injections. In addition to the intended reduction of the afterload for aboral transport of ingested materials, the treatments tend to induce gastroesophageal reflux in some patients because they obliterate an important component in the reflux barrier. PMID- 29756657 TI - Amplitude envelope correlations measure synchronous cortical oscillations in performing musicians. AB - A major question facing cognitive neuroscience is measurement of interbrain synchrony between individuals performing joint actions. We describe the application of a novel method for measuring musicians' interbrain synchrony: amplitude envelope correlations (AECs). Amplitude envelopes (AEs) reflect energy fluctuations in cortical oscillations over time; AE correlations measure the degree to which two envelope fluctuations are temporally correlated, such as cortical oscillations arising from two individuals performing a joint action. Wireless electroencephalography was recorded from two pianists performing a musical duet; an analysis pipeline is described for computing AEs of cortical oscillations at the duet performance frequency (number of tones produced per second) to test whether these oscillations reflect the temporal dynamics of partners' performances. The pianists' AE correlations were compared with correlations based on a distribution of AEs simulated from white noise signals using the same methods. The AE method was also applied to the temporal characteristics of the pianists' performances, to show that the observed pair's AEs reflect the temporal dynamics of their performance. AE correlations offer a promising approach for assessing interbrain correspondences in cortical activity associated with performing joint tasks. PMID- 29756658 TI - Loop Length Affects Syn-Anti Conformational Rearrangements in Parallel G Quadruplexes. AB - A G-quadruplex forming sequence from the MYC promoter region was modified with syn-favoring 8-bromo-2'-deoxyguanosine residues. Depending on the number and position of modifications in the intramolecular parallel G-quadruplex, substitutions with the bromoguanosine analogue at the 5'-tetrad induce conformational rearrangements with concerted all-anti to all-syn transitions for all residues of the modified G-quartet. No unfavorable steric interactions of the C8-substituents in the medium grooves are apparent in the high-resolution structure as determined for a tetrasubstituted MYC quadruplex that exclusively forms the all-syn isomer. In contrast, considerable steric clashes with 5' phosphate oxygen atoms for those analogues that follow a less flexible 1 nucleotide loop in the native all-anti conformation seem to constitute the major driving force for the tetrad inversion and allow for the rational design of appropriately substituted sequences. Correlations found between the population of species subjected to a tetrad flip and melting temperatures indicate that more effective conformational transitions are compromised by lower thermal stabilities of the modified parallel quadruplexes. PMID- 29756659 TI - Fragmentation pathways arising from protonation at different sites in aminoalkyl substituted 3-hydroxy-1,2,5-oxadiazoles (3-hydroxyfurazans). AB - RATIONALE: The gas-phase fragmentation chemistry of multifunctional cations is highly influenced by the site of protonation. Possible relationships between protonation site and fragmentation processes were studied using 4-aminoalkyl-3 hydroxyfurazans. For these heterocyclic amines, the starting points for competing fragmentation pathways varied with protonation at multiple sites in two tautomers. METHODS: Mass spectra were acquired using electrospray ionization (positive mode) coupled to triple quadrupole and ion trap mass spectrometers; precursor-product ion relationships were studied by collision-induced dissociation. Quantum mechanical computations were performed at the MP2/6 311++G(2d,p)//omegaB97X-D/6-311+G(d) level of theory. RESULTS: Prominent successive losses of NO and CO and competing losses of CH2 =NH or NH3 were observed as fragmentation processes. The lowest barrier computed for the initial step in a fragmentation pathway was associated with the [M + H]+ ion protonated at N5 in the heterocyclic ring, whereas an alternative ring cleavage leading to complementary product ions was initiated by protonation of the ring at N2. Side chain protonation led to loss of NH3 without cleavage of the 3-hydroxyfurazan ring. CONCLUSIONS: The product ions obtained by the competing fragmentation processes varied with the site of protonation. Interestingly, the most abundant product ions observed at low collision energies were formed by cleavage of protonated molecules possessing more internal energy than other isomers. PMID- 29756660 TI - Synthesis of Azo Dyes from Mesoionic Carbenes and Nitrous Oxide. AB - Covalent adducts of imidazole-based mesoionic carbenes and nitrous oxide (N2 O, "laughing gas") can be converted into azo dyes by reaction with arenes in the presence of AlCl3 or HCl. The azo coupling can be achieved with electron-rich aromatic compounds such as mesitylene, trimethoxybenzene, azulene, or dibenzo-18 crown-6. The latter coupling reaction allows for the easy preparation of a colorimetric sensor for potassium or sodium ions. As a putative intermediate of the reaction with acid, we were able to isolate and structurally characterize a rare diazohydroxide. Using imidazolium compounds with two N2 O groups, it was possible to prepare amine-substituted azo dyes or dyes with two azoarene groups attached to the heterocycle. A triazole-based mesoionic carbene was also found to form a stable covalent adduct with N2 O. The adduct could be used to prepare novel azo triazolium dyes in good yields. PMID- 29756661 TI - The Effect of the Active-Site Structure on the Activity of Copper Mordenite in the Aerobic and Anaerobic Conversion of Methane into Methanol. AB - Samples of the zeolite mordenite with different Si/Al ratios were used to synthesize materials with monomeric and oligomeric copper sites that are active in the direct conversion of methane into methanol. A comparison of two reactivation protocols with oxygen (aerobic oxidation) and water (anaerobic oxidation), respectively, revealed that such copper-oxo species possess different reactivity towards methane and water. We show for the first time that oligomeric copper species exhibit high activity under both aerobic and anaerobic activation conditions, whereas monomeric copper sites produce methanol only in aerobic processes. PMID- 29756663 TI - Coupling trapped ion mobility spectrometry to mass spectrometry: trapped ion mobility spectrometry-time-of-flight mass spectrometry versus trapped ion mobility spectrometry-Fourier transform ion cyclotron resonance mass spectrometry. AB - RATIONALE: There is a need for fast, post-ionization separation during the analysis of complex mixtures. In this study, we evaluate the use of a high resolution mobility analyzer with high-resolution and ultrahigh-resolution mass spectrometry for unsupervised molecular feature detection. Goals include the study of the reproducibility of trapped ion mobility spectrometry (TIMS) across platforms, applicability range, and potential challenges during routine analysis. METHODS: A TIMS analyzer was coupled to time-of-flight mass spectrometry (TOF MS) and Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) instruments for the analysis of singly charged species in the m/z 150-800 range of a complex mixture (Suwannee River Fulvic Acid Standard). Molecular features were detected using an unsupervised algorithm based on chemical formula and IMS profiles. RESULTS: TIMS-TOF MS and TIMS-FT-ICR MS analysis provided 4950 and 7760 m/z signals, 1430 and 3050 formulas using the general Cx Hy N0-3 O0-19 S0-1 composition, and 7600 and 22 350 [m/z; chemical formula; K; CCS] features, respectively. CONCLUSIONS: TIMS coupled to TOF MS and FT-ICR MS showed similar performance and high reproducibility. For the analysis of complex mixtures, both platforms were able to capture the major trends and characteristics; however, as the chemical complexity at the level of nominal mass increases with m/z (m/z >300 350), only TIMS-FT-ICR MS was able to report the lower abundance compositional trends. PMID- 29756662 TI - Existence of Diverse Modifications in Small-RNA Species Composed of 16-28 Nucleotides. AB - RNA contains diverse modifications that exert an important influence in a variety of cellular processes. So far, more than 150 modifications have been identified in various RNA species, mainly in ribosomal RNA (rRNA), transfer RNA (tRNA), and messenger RNA (mRNA). In contrast to rRNA, tRNA, and mRNA, the known modifications in small RNA species have been primarily limited to 2'-O-ribose methylation in plants and inosine in mammals. The methylation of small RNAs in mammals is still unclear. Current methods widely used in the characterization of small RNAs are mainly based on the strategy of nucleic acid hybridization and sequencing, which cannot characterize modifications in small RNAs. Herein, we have systematically investigated modifications in small RNAs composed of 16-28 nucleotides (nt) by establishing an effective isolation and neutral enzymatic digestion of small RNAs in combination with liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). This method allowed us to simultaneously detect 57 different types of nucleoside modification. By using this approach, we revealed 24 modifications in small RNAs comprising 16-28 nt from human cells. In addition, we found that the obesity-associated protein (FTO) may demethylate N6 -methyladenosine (m6 A) and N6 ,2'-O-dimethyladenosine (m6 Am) in small RNAs of 16-28 nt. Our study demonstrates the existence of diverse modifications in small RNAs composed of 16-28 nt, which may promote in-depth understanding of the regulatory roles of noncoding RNAs. PMID- 29756665 TI - Metabolomics as a clinical testing method for the diagnosis of vaginal dysbiosis. AB - Microbes play an important role in vaginal health, with lactobacilli a particularly abundant species. When dysbiosis occurs, the tools to determine whether it is a condition such as bacterial vaginosis, and whether it warrants antibiotic treatment, are currently suboptimal. We propose that standardization and implementation of an affordable metabolomics-based diagnostic technique could reduce instances of false positives, stress associated with misdiagnosis, and potentially save time and money. Basing diagnosis on the detection of pH elevated above 4.5 and specific polyamines could provide a better method to assist a physician determine whether treatment is warranted. PMID- 29756664 TI - Patient blood management: how is implementation going?: A report comparing the 2015 survey with the 2013 survey of PBM in England. AB - BACKGROUND: Patient blood management (PBM) is an evidence-based approach to optimising the care of patients who might need transfusion. In 2013, all NHS Trusts in England were surveyed about their readiness to implement PBM. National PBM recommendations were launched in 2014. AIMS: The aim of this study was to determine progress of PBM initiatives. METHODS/MATERIALS: A survey was constructed by staff in hospitals and NHS Blood and Transplant (NHSBT). An online questionnaire was sent to all NHS Trusts in England (N = 149) in November 2015. RESULTS: Improvements in 2015: Education/training in transfusion: 80-100% from 60 90% in 2013 Provision of information relating to consent for transfusion: 98% from 65% in 2013 (P = <0.001) The management of anaemia: elective general surgery management, 66% from 41% in 2013 (P = <0.001) Transfusion alternatives: Tranexamic use in surgery, 92% from 71% in 2013 (P = <0.001) Laboratory staff empowered to challenge transfusion requests, 95% from 65% in 2013 (P = 0.001) Further work required: Electronic systems to support requesting (e.g. mandatory recording of diagnosis: 47% from 48% in 2013 (P = 0.85), incorporation of standardised requesting codes: 27% from 33% in 2013 (P = 0.24) Appropriate use of components: in 2015, only 42% had a lower red cell transfusion thresholds policy in non-bleeding patients CONCLUSIONS: The results provided information to support the development of local and national work plans. It is hoped that the collaborative work across NHS Blood and Transplant (NHSBT), the National Blood Transfusion Committee (NBTC) and NHS Trusts will continue to drive the PBM agenda to support best practice in this field. PMID- 29756666 TI - Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia. AB - PROBLEM: The lymphatic vasculature controls leukocytes trafficking and limits the adaptive immune response. In previous models of preeclampsia (PE), defective immune function caused by disruption of lymphangiogenesis was shown to be involved in the disease pathophysiology. Especially, the dysfunction of regulatory T cells (Treg) at the maternal-fetal interface may be one of the causes of severe PE. In particular, activation of Tregs to obtain immune tolerance requires adequate antigen presentation through the lymphatic system. We hypothesized that impaired lymphangiogenesis and imbalanced Tregs at the maternal fetal interface are associated with the pathophysiology of severe PE. However, the current research addressing this hypothesis is limited. Therefore, to compare differences in lymphangiogenesis in severe PE and normal conditions, we aimed to examine the location of lymphatics at the maternal-fetal interface and to investigate the association between lymphangiogenesis and Tregs in severe PE. METHOD OF STUDY: We obtained entire uterus from normal pregnant mice. Placental and fetal membranes, including decidua, were obtained from 10 pregnant women with severe PE and 10 gestational age-matched controls. Immunohistochemistry for LYVE1 was used to localize the distribution of lymphatic vessels and CD4, CD25, and FOXP3 for Treg. RESULTS: LYVE1-positive vessels were present in the uterine wall of mice. LYVE1-positive lymphatic vessels were localized on the human decidua. Tubular lymphatics were abundant in the control decidua, but significantly reduced in severe PE. Furthermore, lymphatic vessel density correlated with the number of decidual Tregs. CONCLUSION: Abnormal decidual lymphangiogenesis is associated with reduced numbers of decidual Tregs in severe PE. PMID- 29756667 TI - Soluble Fgl2 restricts autoimmune hepatitis progression via suppressing Tc17 and conventional CD8+ T cell function. AB - BACKGROUND: Autoimmune hepatitis (AIH) is an inflammatory disease caused by an aberrant immune response to hepatic self-antigens in which regulatory T cells (Tregs) are critical for maintaining immunosupression. The soluble form of fibrinogen-like protein 2 (sFGL2), a novel effector molecule of Treg, is rarely investigated in AIH. In the present study, we dissected the role of sFGL2 in autoimmune hepatitis and its potential mechanism underlying AIH progression. METHODS: Plasma and intrahepatic sFGL2 levels, as well as Treg cells, were measured in both AIH patients and experimental autoimmune hepatitis (EAH) mice. Th1, Th2, Th17 and Treg-related cytokines were measured in the liver of EAH mice. Treg expression of sFgl2 and its effect on CD8+ T cell activity in EAH were assessed. The clinical relevance of sFGL2 in AIH-associated inflammation and fibrosis was evaluated. RESULTS: Th17 responses is predominant in robust AIH patients and EAH mice. In AIH patients and EAH mice, the frequency of plasma Tregs was reduced, whereas intrahepatic Tregs were increased significantly. The plasma sFGL2 level was significantly higher at active phases compared to those during remission and was correlated with AIH progression. Enhanced sFGL2 expression was found in Tregs and inhibited conventional CD8+ T cells and Tc17 cell in EAH mice ex vivo. CONCLUSIONS: The Th17 response dominates autoimmune hepatitis progression. The increase in intrahepatic and plasma sFGL2 by Tregs may restrict AIH progression by inhibiting conventional CD8+ T cells and Tc17 cell function. The high correlation between sFGL2 and disease severity may predict AIH outcome. PMID- 29756669 TI - A cross-cultural investigation of children's implicit attitudes toward White and Black racial outgroups. AB - Initial theory and research examining children's implicit racial attitudes suggest that an implicit preference favoring socially advantaged groups emerges early in childhood and remains stable across development (Dunham, Baron, & Banaji, 2008). In two studies, we examined the ubiquity of this theory by measuring non-Black minority and non-White majority children's implicit racial attitudes toward White and Black racial outgroups in two distinct cultural contexts. In Study 1, non-Black minority children in an urban North American community with a large Black population showed an implicit pro-White (versus Black) bias in early childhood. Contrary to previous findings, the magnitude of this bias was lower among older children. In Study 2, Malay (majority) and Chinese (minority) children and adults in the Southeast Asian country of Brunei, with limited contact with White or Black peers, showed an implicit pro-White (versus Black) bias in early childhood. However, the magnitude of bias was greater for adults. Together, these findings support initial theorizing about the early development of implicit intergroup cognition, but suggest that context may affect these biases across development to a greater extent than was previously thought. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=vgQP8e4MSCk&feature=youtu.be. PMID- 29756668 TI - Amelioration of Escherichia coli-induced endometritis with ascorbic acid in non pregnant mouse models. AB - PROBLEM: Infection-induced endometritis is associated with infertility. The outcome with oral antibiotics remains poor. This study therefore investigates the role of ascorbic acid in resolving endometritis. METHOD OF STUDY: Animals with established oestrus cycles were inoculated with Escherichia coli. Two days post inoculation, the animals were administered ascorbic acid (10, 100 and 1000 mg/kg) and amoxicillin (500 mg/kg) for 5 days. Other groups included water only and E. coli inoculated with no treatment. Body temperatures, weights and vaginal cytology were examined. On the sixth day, after anaesthesia, blood samples were obtained for haematological analysis. Uterine organs were weighed, ex-vivo functionality analysed and histopathological analysis performed. RESULTS: Ascorbic acid (AA) (100 and 1000 mg/kg) regularized the cycle of the endometritic animals comparable to amoxicillin. AA (1000 mg/kg) and amoxicillin, significantly decreased (P < .05) the endometritis-induced increase in uterine weights, restored the endometrial architecture and significantly (P < .05) normalized uterine contractions to control values. Improved haematological profiles were additionally observed on treatment with ascorbic acid (100 and 1000 mg/kg). CONCLUSION: AA compared favourably with amoxicillin in endometritis management, suggesting that AA can be used in the management of infection-induced endometritis, normal cycling and normal uterine function. PMID- 29756670 TI - The Influence of Post System Design and Material on the Biomechanical Behavior of Teeth with Little Remaining Coronal Structure. AB - PURPOSE: To evaluate the influence of different post systems on the biomechanical behavior of teeth with a severe loss of remaining coronal structure. MATERIALS AND METHODS: Fifty standardized bovine teeth (n = 10 per group) were restored with: cast post-and-core (CPC), prefabricated metallic post (PFM), parallel glass fiber post (P-FP), conical glass-fiber post (C-FP), or composite core (no post, CC). The survival rate during thermomechanical challenging (TC), the fracture strength (FS), and failure patterns (FP) were evaluated. Finite element models evaluated the stress distribution after the application of 100 N. RESULTS: All specimens survived TC. Similar FS was observed among post-containing groups. Groups P-FP and CC presented 100% repairable fractures. The von Mises analysis showed the maximum stresses into the root canal in groups restored with metallic posts. Glass-fiber posts and CC presented the maximum stresses at the load contact point. Glass-fiber groups showed lower stresses in the analysis of maximal contact pressure; CPC led to the highest values of contact pressure. The modified von Mises (mvM) stress in dentin did not show differences among groups. Moreover, mvM values did not reach the dentin fracture limit for any group. CONCLUSIONS: The type of intracanal post had a relevant influence on the biomechanical behavior of teeth with little remaining coronal structure. PMID- 29756671 TI - Wasabi 6-(methylsulfinyl)hexyl isothiocyanate induces apoptosis in human colorectal cancer cells through p53-independent mitochondrial dysfunction pathway. AB - 6-(Methylsulfinyl)hexyl isothiocyanate (6-MSITC), a major bioactive compound in Wasabi [Wasabia japonica (Miq.) Matsum.], has revealed the inhibitory effect on colon carcinogenesis in rat cancer model although the underlying mechanism is unclear. In this study, we used two types of human colorectal cancer cells (HCT116 p53+/+ and HCT116 p53-/- ) to investigate the anticancer activity and molecular mechanisms of 6-MSITC. Interestingly, 6-MSITC inhibited the cell proliferation in both types of cells with similar IC50 value although a light increase in the phosphorylation and accumulation of P53 protein was observed in HCT116 p53+/+ cells at 24 h after treatment. In addition, 6-MSITC increased the ratio of proapoptotic cells in both types of cells with the same fashion in a p53 independent manner. The data from mitochondrial analysis revealed that 6-MSITC enhanced the ratio of proapoptotic B-cell lymphoma-2-associated X protein/antiapoptotic myeloid cell leukemia 1, and sequentially caused mitochondrial membrane potential (DeltaPsim ) loss, cytochrome c release, and caspase-3 activation in both types of cells. Taken together, Wasabi 6-MSITC induced apoptosis of human colorectal cancer cells in p53-independent mitochondrial dysfunction pathway. These findings suggest that 6-MSITC might be a potential agent for colon cancer chemoprevention although with p53 mutation. (c) 2018 BioFactors, 2018. PMID- 29756672 TI - Successful conservative management of an intramural gastric abscess: a case report. PMID- 29756673 TI - Single organ testicular vasculitis: an unusual cause for unilateral scrotal pain and swelling. PMID- 29756674 TI - How to do a combined robotic anterior resection and liver resection: da Vinci Xi. PMID- 29756675 TI - Corrigendum: An Oxofluoride Catalyst Comprised of Transition Metals and a Metalloid for Application in Water Oxidation. PMID- 29756676 TI - Impact of serious mental illness on surgical patient outcomes. AB - BACKGROUND: People with comorbid mental illness have poorer health status and disparate access to healthcare. Several studies internationally have reported mixed findings regarding the association between mental illness and surgical patient outcomes. This study examines the surgical outcomes in people with decompensated serious mental illness (SMI) within the setting of the Australian universal healthcare system. METHODS: Retrospective cohort study involving elective overnight surgical patients aged 18 years and above who attended a large public tertiary referral hospital in Sydney, Australia, between 2010 and 2014. Patients were identified using ICD-10-AM diagnosis codes. Outcomes measure including in-hospital mortality, post-operative complications, morbidity, admission and time in intensive care, length and cost of hospitalization, discharge destination and 28-day re-admission rates were examined. RESULTS: Of 23 343 surgical patient admissions, 451 (2%) patients had decompensated comorbid SMI with a subset of 47 (0.2%) having a specific psychotic illness. Patients with SMI comorbidity had significantly higher in-hospital mortality (2% versus 0%), post operative complications (22% versus 8%), total comorbidity (7.6 versus 3.4 secondary codes), admissions (29% versus 9%) and time in intensive care (34.6 h versus 5.0 h), stay in hospital (12.2 days versus 4.6 days), admission costs ($24 162 versus $12 336), re-admission within 28 days (14% versus 10%) and discharges to another facility (11% versus 3%). CONCLUSION: Patients with comorbid SMI had significantly worse surgical outcomes and incur much higher costs compared with the general surgical population. These results strongly highlight that specific perioperative interventions are needed to proactively improve the identification, management and outcomes for these disadvantaged patients. PMID- 29756677 TI - Ectopic liver attached to a chronically inflamed gallbladder: a rare and surgically challenging combination. PMID- 29756678 TI - Current management of adhesive small bowel obstruction. AB - Small bowel obstruction is a common and significant surgical presentation. Approximately 30% of presentations will require surgery during admission. The great challenge of adhesive small bowel obstruction (ASBO) management is the early detection of silent intestinal ischaemia in patients initially deemed suitable for conservative therapy. Recent literature emphasizes the effectiveness of computed tomography enterography and water-soluble contrast studies in the management of ASBO. Low-volume undiluted water-soluble contrast has been shown to have both triage and therapeutic value in the management of ASBO. Their use has been demonstrated to reduce the need for surgery to below 20%. There has also been growing interest in clinicoradiological algorithms which aim to predict ischaemia early in the course of presentation. The aim of this review is to summarize the latest evidence and clarify previous uncertainties, specifically regarding the duration of conservative treatment, timing of contrast studies and the reliability of predictive algorithms. Based on this latest evidence, we have formulated a management protocol which aims to integrate these latest developments and formalize a strategy for best management in ASBO. PMID- 29756680 TI - Design of Single-Site Photocatalysts by Using Metal-Organic Frameworks as a Matrix. AB - Single-site photocatalysts generally display excellent photocatalytic activity and considerably high stability compared with homogeneous catalytic systems. A rational structural design of single-site photocatalysts with isolated, uniform, and spatially separated active sites in a given solid is of prime importance to achieve high photocatalytic activity. Intense attention has been focused on the design and fabrication of single-site photocatalysts by using porous materials as a platform. Metal-organic frameworks (MOFs) have great potential in the design and fabrication of single-site photocatalysts due to their remarkable porosity, ultrahigh surface area, extraordinary tailorability, and significant diversity. MOFs can provide an abundant number of binding sites to anchor active sites, which results in a significant enhancement in photocatalytic performance. In this focus review, the development of single-site MOF photocatalysts that perform important and challenging chemical redox reactions, such as photocatalytic H2 production, photocatalytic CO2 conversion, and organic transformations, is summarized thoroughly. Successful strategies for the construction of single-site MOF photocatalysts are summarized and major challenges in their practical applications are noted. PMID- 29756679 TI - Effect of Heat Processing on IgE Reactivity and Cross-Reactivity of Tropomyosin and Other Allergens of Asia-Pacific Mollusc Species: Identification of Novel Sydney Rock Oyster Tropomyosin Sac g 1. AB - SCOPE: Shellfish allergy is an increasing global health priority, frequently affecting adults. Molluscs are an important shellfish group causing food allergy but knowledge of their allergens and cross-reactivity is limited. Optimal diagnosis of mollusc allergy enabling accurate advice on food avoidance is difficult. Allergens of four frequently ingested Asia-Pacific molluscs are characterized: Sydney rock oyster (Saccostrea glomerata), blue mussel (Mytilus edulis), saucer scallop (Amusium balloti), and southern calamari (Sepioteuthis australis), examining cross-reactivity between species and with blue swimmer crab tropomyosin, Por p 1. METHODS AND RESULTS: IgE ELISA showed that cooking increased IgE reactivity of mollusc extracts and basophil activation confirmed biologically relevant IgE reactivity. Immunoblotting demonstrated strong IgE reactivity of several proteins including one corresponding to heat-stable tropomyosin in all species (37-40 kDa). IgE-reactive Sydney rock oyster proteins were identified by mass spectrometry, and the novel major oyster tropomyosin allergen was cloned, sequenced, and designated Sac g 1 by the IUIS. Oyster extracts showed highest IgE cross-reactivity with other molluscs, while mussel cross-reactivity was weakest. Inhibition immunoblotting demonstrated high cross reactivity between tropomyosins of mollusc and crustacean species. CONCLUSION: These findings inform novel approaches for reliable diagnosis and improved management of mollusc allergy. PMID- 29756682 TI - Design Strategy of Multi-electron Transfer Catalysts Based on a Bioinformatic Analysis of Oxygen Evolution and Reduction Enzymes. AB - Understanding the design strategy of photosynthetic and respiratory enzymes is important to develop efficient artificial catalysts for oxygen evolution and reduction reactions. Here, based on a bioinformatic analysis of cyanobacterial oxygen evolution and reduction enzymes (photosystem II: PS II and cytochrome c oxidase: COX, respectively), the gene encoding the catalytic D1 subunit of PS II was found to be expressed individually across 38 phylogenetically diverse strains, which is in contrast to the operon structure of the genes encoding major COX subunits. Selective synthesis of the D1 subunit minimizes the repair cost of PS II, which allows compensation for its instability by lowering the turnover number required to generate a net positive energy yield. The different bioenergetics observed between PS II and COX suggest that in addition to the catalytic activity rationalized by the Sabatier principle, stability factors have also provided a major influence on the design strategy of biological multi electron transfer enzymes. PMID- 29756681 TI - Neuronal IL-4Ralpha modulates neuronal apoptosis and cell viability during the acute phases of cerebral ischemia. AB - Ischemic stroke caused by an embolus or local thrombosis results in neural tissue damage (an infarct) in the territory of the occluded cerebral artery. Decades of studies have increased our understanding of the molecular events during cerebral infarction; however, translation of these discoveries to druggable targets for ischemic stroke treatment has been largely disappointing. Interleukin-4 (IL-4) is a multifunctional cytokine that exerts its cellular activities via the interleukin-4 receptor alpha (IL-4Ralpha). This cytokine receptor complex is associated with diverse immune and inflammatory responses. Recent studies have suggested a role of the cytokine IL-4 in long-term ischemic stroke recovery, involving immune cell activity. In contrast, the role of the receptor, IL-4Ralpha especially in the acute phase of infarction is unclear. In this study, we determined that IL-4Ralpha is expressed on neurons and that during the early phases of cerebral infarction (24 h) levels of this receptor are increased to regulate cellular apoptosis factors through activation of STAT6. In this context, we show a neuroprotective role for IL-4Ralpha in an in vivo surgical model of cerebral ischemia and in ex vivo brain slice explants, using both genetic knockout of this receptor and RNAi-mediated gene knockdown. IL-4Ralpha may therefore represent a novel target and pathway for therapeutic development in ischemic stroke. PMID- 29756683 TI - Non-operative management of isolated single abdominal stab wound: is it safe? AB - BACKGROUND: This is a retrospective review of prospectively collected data on our hospital, a Level 1 trauma centre, where stable patients with single abdominal stab wounds are considered for non-operative (conservative) management if they fulfil the criteria with the aid of computed tomography. The aim is to review our current approach in managing these patients. METHODS: Patients' data were obtained from January 2005 to June 2016. All injuries classed as assault or self harm by sharp object in Injury Severity Score body region 4 were included. Patients were excluded from this study if they had haemodynamic instability, peritonism, significant findings on computed tomography, intoxicated, sustained head injury, sedated and intubated or evisceration of bowel, impalement of the stabbed object, potential thoraco-abdominal injury and multiple stab wounds. The patients were divided into non-operative and delayed operative groups for analysis. RESULTS: One hundred and sixty-six of the 313 patients who presented with abdominal stab wounds matched our criteria. One hundred and sixty-three patients (98.2%) from the non-operative group were discharged without complications following period of observation, while three patients underwent operative intervention following trial of non-operative management. The mean length of stay for the successful non-operative group and the group which required delayed operative intervention were 2.8 and 6 days, respectively. No morbidity or mortality was recorded in either group. CONCLUSION: Our observational study showed that in a Level 1 trauma centre, patients with single anterior abdominal stab wound and normal vital signs can potentially be safely managed with non-operative approach provided that these patients are cooperative for close observation. PMID- 29756684 TI - A prospective "bottom up" study of the costs of faecal incontinence in ambulatory patients. AB - BACKGROUND AND AIM: The few studies that have examined direct costs of faecal incontinence are limited in that they employed retrospective databases, postal surveys, and focused upon institutionalised patients or post partum women. The aim of the current study was to identify the direct pre-treatment costs of faecal incontinence expended by a range of home dwelling patients and identify relationships between costs and severity of incontinence. METHODS: Consecutive patients attending an outpatient clinic for treatment of faecal incontinence were interviewed using a questionnaire, modeled on the Dowel Bryant Incontinence Cost Index. The information collected included costs of: (i) basic personal hygiene: pads, laundry, wipes, cleansers; (ii) medication: loperamide, creams and stool bulking agents; and (iii) diagnostic: medical attendance, anorectal physiology, colonoscopy. Costs were broken down into personal expenses, government costs, and costs to health funds. A St Mark's Faecal Incontinence Severity Score was recorded. RESULTS: A total of 100 consecutive patients consented (15 males, 85 females) mean age 70.8 (SD12) years. Mean St Mark's score was 12 (SD4.5). The median total patient cost was $437.72 AUD (range 0-2807) per annum. Government costs were $537AUD (range 135-1657), and health fund median $0 AUD (0-1628). Incontinence severity correlated with personal expense only median $283.75AUD (range 0-2350). The aged were more incontinent but costs did not increase in relation to age. CONCLUSION: Faecal incontinence results in a substantial financial burden for both patients and Government. Effective treatments which relieve the financial burden of faecal incontinence, are likely to be economically advantageous into the future for both patients and Government. PMID- 29756685 TI - Evaluation of right ventricular myocardial strains by speckle tracking echocardiography after percutaneous device closure of atrial septal defects in children. AB - OBJECTIVES: The aim of this study was to clarify the influence of the ASD closure by occluder device on right ventricular acute and long-term changes in longitudinal systolic strains, by evaluating right ventricular wall deformation in children using speckle tracking echocardiography (STE). METHODS AND MATERIALS: We enrolled 30 children with ASDs and 40 controls in our study. The Amplatzer atrial defect occluder was used to close the ASDs. Transthoracic echocardiographic examinations were performed at 3 points in time: the day before closure, 1 day after closure, and 3 months after closure. The dimensions of the right atrium (RA) and the right ventricle (RV) were measured in apical four chamber view. RV segmental longitudinal systolic strains (SLSs) and global longitudinal systolic strain (GLS) were obtained by two-dimensional STE. RESULTS: Before ASD closure, the RV SLSs and GLS were significantly higher than those of the controls. At 1 day after closure, the diameters of RA and RV decreased. All the RV SLSs and GLS decreased accordingly and were lower than the control values. At 3 months after closure, the apical free wall strain, all segments of septal strains, and GLS increased significantly compared with the values obtained at 1 day after closure. The diameters of the RA and RV decreased further as well. There were no significant differences in the strains compared with the control values, except for the free wall basal strain. CONCLUSIONS: Transcatheter device closure of ASDs improves RV strain indices and RV function recover to normal over 3 months. PMID- 29756686 TI - A rare case of mitral valve dissection and aortic-left ventricular tunnel associated with possible autoimmune vasculitis. AB - We report a very rare case of mitral valve dissection and aortic-left ventricular tunnel caused by possible autoimmune vasculitis. We suspected Behcet's disease in this patient. There was no obvious clinical evidence of infective endocarditis. Echocardiography is the diagnostic tool of choice to recognize valvular dysfunction, related pathology, and possible complications. The patient may require immunosuppressive therapy due to the high likelihood of recurrence in the perioperation period. PMID- 29756687 TI - Comparing the sniffing behavior of great apes. AB - The importance of smell in humans is well established but we know little about it in regard to our closest relatives, the great apes, as systematic studies on their olfactory behavior are still lacking. Olfaction has long been considered to be of lesser importance in hominids given their relatively smaller olfactory bulbs, fewer functional olfactory receptor genes than other species and absence of a functional vomeronasal organ. Therefore, the aim of this study was to evaluate the use of olfaction in hominids. In particular, we observed sniffing behavior in captive groups of four species (Sumatran orangutans, Pongo abelii; Western lowland gorillas, Gorilla gorilla gorilla; Western chimpanzees, Pan troglodytes verus; bonobos, Pan paniscus) and evaluated in which contexts sniffing was used. Our results show that all investigated species frequently used the sense of smell, and that the sniffing frequency varied with species, sex, age, and context. Most sniffing events were observed in gorillas in comparison to the three other species. Sniffing frequencies were also influenced by sex, with males sniffing slightly more often than females. Furthermore, our results revealed an effect of age, with younger individuals sniffing more often than older individuals. All species mainly sniffed in the non-social context (i.e., toward food and other environmental items) rather than in the social context (i.e., at conspecifics), suggesting that the evaluation of the environment and the nutritional value of food items is of major importance to all great ape species investigated here. In contrast to the other species and female chimpanzees, however, male chimpanzees most often used olfaction to inspect their conspecifics. Together, our study suggests that olfaction is likely to be more important in great apes than previously appreciated. PMID- 29756688 TI - Localized genital bullous pemphigoid. AB - Genital bullous pemphigoid (GBP) is a rare localized subset of bullous pemphigoid (BP). BP is characterized by autoantibodies against hemidesmosomes, which are involved in the structural integrity of the epidermis, and this results in subepidermal blistering. Typically, GBP affects women and children. We report an adult male who presented with a scrotal rash and blisters that developed into erosions. Only two previous cases in men have been reported. Immunofluoresence and histopathology confirmed the diagnosis of BP. The patient responded to mycophenolate mofetil and doxycycline. PMID- 29756689 TI - 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir. AB - Dolutegravir (DTG), an important active pharmaceutical ingredient (API) used in combination therapy for the treatment of HIV, has been synthesized in continuous flow. By adapting the reported GlaxoSmithKline process chemistry batch route for Cabotegravir, DTG was produced in 4.5 h in sequential flow operations from commercially available materials. Key features of the synthesis include rapid manufacturing time for pyridone formation, one-step direct amidation of a functionalized pyridone, and telescoping of multiple steps to avoid isolation of intermediates and enable for greater throughput. PMID- 29756691 TI - Cerebrovascular autoregulation impairments during cardiac surgery with cardiopulmonary bypass are related to postoperative cognitive deterioration: prospective observational study. AB - BACKGROUND: Post-operative cognitive dysfunction (POCD) occurs in approximately 33-83% of patients after cardiac surgery with cardiopulmonary bypass (CPB). Recent clinical data suggest that real-time, intraoperative monitoring of patient specific cerebrovascular autoregulation (CA) may help to prevent POCD by detecting individual critical limits for mean arterial pressure (MAP) outside which CA is impaired. Objectives of the study were to detect the episodes of impaired CA during cardiac surgery with CPB, and to investigate the association between CA impairment and POCD. METHODS: The observational study of non-invasive ultrasonic volumetric CA monitoring included 59 patients undergoing elective coronary artery bypass graft surgery with CPB. All patients underwent series of neuropsychological tests the day before and ten days after the surgery in order to evaluate cognitive function. RESULTS: 22 patients (37%) experienced POCD, 37 patients (63%) showed no cognitive deterioration. The duration of the single longest CA impairment event was found reliably associated with occurrence of POCD (p < 0.05). The critical duration of the single longest CA impairment event was 5.03 minutes (odds ratio 14.5; CI 3.9- 51.8) for studied population. CONCLUSIONS: Prospective clinical study showed that single longest CA impairment may result in post-operative deterioration of mental abilities. The duration of the single longest CA impairment event is the risk factor that is associated with POCD. PMID- 29756692 TI - The presence of elastic compression stockings reduces the fluid responsiveness of patients in the operating room. AB - BACKGROUND: The aim of this study was to investigate whether elastic compression stockings (ECS) can affect fluid responsiveness parameters before and during passive leg raising (PLR) maneuvers. METHODS: In the operating room (OR), we performed a prospective study including patients referred for cardiac surgery. Blood pressure (BP), DeltaPP, heart rate (HR), central venous pressure (CVP), stroke volume (SV) and aortic blood flow (ABF) (by esophageal doppler) were measured according to four conditions: supine position without ECS (baseline 1), lower limbs raised to an angle of 45 degrees (PLR 1), returned to the supine position with ECS (baseline 2), then a second PLR maneuver with ECS was performed (PLR 2). RESULTS: Twenty patients were included. BP, SV, ABF and CVP increased significantly. DeltaPP and HR decreased during PLR 1. At baseline 2, HR and DeltaPP decreased significantly compared to baseline 1. During PLR 2, increase of SV (4% [9]) and ABF (4% [9]), and the decrease of DeltaPP (-19% [104]) were significantly lower than those observed at PLR 1 (7% [21] P=0.05; 9% [8] P=0.02 and -66% [40] P=0.02, respectively). Eleven patients presented a DeltaPP>=13% at baseline 1. Only 1 patient still presented a DeltaPP>=13% with ECS at baseline 2. Only 3/9 patients with an increase of ABF >=10% and 2/11 patients with an increase of PP >=12% during the PLR 1 presented similar results during PLR 2. CONCLUSIONS: In the OR, ECS provoke a self-fluid loading increasing ABF, decreasing DeltaPP and PLR response. The presence of ECS should be considered when managing hemodynamic parameters of patients. PMID- 29756693 TI - Multi-parametric functional hemodynamic optimization improves postsurgical outcome after intermediate risk open gastrointestinal surgery, a randomized controlled trial. AB - BACKGROUND: Perioperative goal directed therapy (pGDT) using flow monitoring has been associated with improved outcomes. However, its protocols are often based on stroke volume only: as a target for fluid loading, inotropic support and vasopresors (via mathematical coupling of systemic vascular resistance). In this trial, we have tested the multi- parametric pGDT protocol based on esophageal Doppler variables (corrected flow time, peak velocity) in intermediate-to-high risk patients undergoing gastrointestinal surgery. METHODS: Intermediate-to-high risk patients undergoing gastrointestinal surgery were randomized to standard care (CONTROL) or multi-parametric pGDT (INTERVENTION). Postoperative complications and death rate as well as hospital length of stay were assessed as primary and secondary outcomes. RESULTS: Overall, 140 patients (INTERVENTION - 71 and CONTROL - 69) were included and randomized out of 197 eligible. Higher vasoactive/inotropic drugs use and lower fluid balance were observed in the INTERVENTION group leading to favorable hemodynamic profile. The pGDT intervention was associated with improved primary outcome (28 days mortality and morbidity defined as occurrence of any defined complication) - 20 patients (28.2%) vs. 32 (46.4%) in the CONTROL group (p=0.036); RR 0.61 (95% CI 0.39 0.95), p=0.03. No differences in mortality and hospital length of stay were observed between groups. CONCLUSIONS: In this monocentric trial the multi parametric pGDT protocol based on domain specific functional hemodynamic parameters was associated with lower rate of postoperative complications in intermediate-to-high risk patients undergoing scheduled gastrointestinal procedures. PMID- 29756694 TI - Effects of inhalation and intravenous anesthesia on intraoperative cardiopulmonary function and postoperative complications in patients undergoing thoracic surgery. AB - INTRODUCTION: There is a high incidence of postoperative cardiopulmonary complications after thoracic surgery with one lung ventilation (OLV), the effect of general anesthetics on intraoperative cardiopulmonary function and postoperative complications is still unclear. EVIDENCE ACQUISITION: We searched the Embase, PubMed, Cochrane Library, Springer, Wiley, CNKI, VIP and Wanfang databases for randomized controlled trials (RCTs) in which inhalation anesthesia and intravenous anesthesia were compared; intraoperative cardiopulmonary function and postoperative complications were assessed in patients undergoing thoracic surgery with intraoperative one-lung ventilation (OLV). EVIDENCE SYNTHESIS: Twenty-three RCTs with a total of 1349 patients were included. Compared with intravenous anesthesia, inhalation anesthesia significantly increased pulmonary shunt fraction (Qs/Qt) (mean: 5.72, 95% CI: 3.93 to 7.51, P<0.0001), and improved Cardiac Index (CI) (mean difference [MD]: 0.19, 95% CI: 0.10 to 0.28, P<0.0001), but decreased Oxygenation Index (OI) during OLV intraoperatively (MD: -27.37, 95% CI: -43.92 to -10.82, P=0.001). Inhalation anesthesia could reduce postoperative pulmonary complications (RR: 0.47, 95% CI: 0.33 to 0.66, P<0.0001), but did not reduce postoperative cardiac adverse events (P>0.05). CONCLUSIONS: Inhalation anesthesia can preserve intraoperative cardiac function and reduce postoperative pulmonary complications in patients undergoing thoracic surgery with OLV; although it decreases intraoperative pulmonary function, inhalation anesthesia may be superior to intravenous anesthesia in thoracic surgery. Publication bias existed in some included studies, and the sample size was not large enough in CI and cardiac adverse events. PMID- 29756690 TI - Preoperative predictive model for acute kidney injury after elective cardiac surgery: a prospective multicentre cohort study. AB - BACKGROUND: Predictive models of CS-AKI include emergency surgery and patients with haemodynamic instability. Our objective was to evaluate the performance of validated predictive models (Thakar and Demirjian) in elective cardiac surgery and to propose a better score in the case of poor performance. METHODS: A prospective, multicentre, observational study was designed. Data were collected from 942 patients undergoing cardiac surgery, after excluding emergency surgery and patients with an intraaortic balloon pump. The main outcome measure was CS AKI defined by the composite of requiring dialysis or doubling baseline creatinine values. RESULTS: Both models showed poor discrimination in elective surgery (Thakar's model, AUROC = 0.57, 95% CI = 0.50-0.64 and Demirjian's model, AUROC= 0.64, 95% CI = 0.58-0.71). We generated a new model whose significant independent predictors were: anaemia, age, hypertension, obesity, congestive heart failure, previous cardiac surgery and type of surgery. It classifies patients with scores 0-3 as low risk (< 5%), scores 4-7 as medium risk (up to 15%) and scores > 8 as high risk (>30%) of developing CS-AKI with a statistically significant correlation (p <0.001). Our model reflects acceptable discriminatory ability (AUC = 0.72, 95% CI = 0.66-0.78) which is significantly better than Thakar and Demirjian's models (p<0.01). CONCLUSIONS: We developed a new simple predictive model of CS-AKI in elective surgery based on available preoperative information. Our new model is easy to calculate and can be an effective tool for communicating risk to patients and guiding decision-making in the perioperative period. The study requires external validation. PMID- 29756695 TI - Stimulating versus non-stimulating catheter for lumbar plexus continuous infusion after total hip replacement. AB - BACKGROUND: This study was aimed to investigate whether stimulating catheters for continuous lumbar plexus block reduce local anesthetic consumption after hip arthroplasty if compared with traditional non-stimulating catheters. METHODS: Seventy-two ASA I-III, 18-82 year-old, undergoing primary hip replacement (THA) for osteoarthritis with spinal anesthesia were randomized into two groups: Stim group (stimulating catheter, n=36) and Nonstim group (non-stimulating catheter, n=36). After surgery, 15 ml of mepivacaine 1% were administered in both groups through the catheter. An electronic pump was connected to deliver ropivacaine 0.2% (3 ml/h, bolus 3 ml, lock out 15 min) for the first 72h. Patients were given ketorolac 30 mg i.v. every 8h, acetaminophen 1g i.v. every 8h and oxycodone 10 mg per os for rescue analgesia. Primary outcome was postoperative local anesthetic consumption. Numerical Rating Scale (NRS), complications, both quadriceps and obturator strength measurements, and opioid requirement were also registered. Mixed effect models (random intercept) were built for repeated measures over time. A difference between groups was considered statistically significant if p< 0.05. RESULTS: Local anesthetic consumption and NRS were comparable between groups. Patients in the Nonstim group required significant more rescue opioid analgesia compared with the Stim group during the first 36h (p = 0.002). Quadriceps and adductor muscle strength was equally preserved in the two groups. CONCLUSIONS: The study showed comparable local anesthetic consumption, pain scores and muscle strength preservation between the two groups. The stimulating catheter allowed a significant, although underpowered, reduction in opioid consumption. PMID- 29756696 TI - Preliminary experience with epidural and perineural catheter localization with pulsed wave Doppler ultrasonography. AB - BACKGROUND: Various methods for peripheral nerve and epidural catheter location assessment exist, with varying degrees of ease of use, utility, and accuracy. Pulsed wave Doppler (PWD) evaluates the presence of fluid flow and is possible modality to assess the location of a percutaneously inserted perineural catheter. METHODS: A retrospective chart review was conducted in which PWD ultrasonography was used to confirm the position of nerve catheters for regional anesthesia. Data was collected to assess 24-hour postoperative pain scores, opioid consumption, complications, and the incidence of catheter replacement. RESULTS: Eighty-six patients were included; average age was 58 years and a 27% incidence of chronic pain. These catheters were left in place based on the PWD images. Three catheters failed and a total of 16 catheters were repositioned. In the first 24 hours average pain scores ranges between 3.5 to 5.9 and median postoperative opioid consumption range was 11.3 mg to 60.8 mg. For epidural catheters, PWD changes were more obvious with air injection and there was only one episode of hemodynamic instability. CONCLUSIONS: Our preliminary experience with PWD ultrasonography suggests that they may offer the ability to selectively assess flow at different locations to identify the proper location of epidural and perineural catheters. Future randomized, controlled investigations are warranted to further evaluate the effectiveness and safety of this modality. PMID- 29756697 TI - Consents or waivers of responsibility? Parents' information in NICU. AB - BACKGROUND: Informing the patient is a base of modern medicine; nonetheless, a great discrepancy exists between hospitals on the way this information should be administered. This is particularly important when the patient are babies: the information should be given to their parents who should approve or disapprove the treatment. Aim of this study is to assess the adequacy of the information administered to the parents of babies admitted into the Neonatal Intensive Care Units. METHODS: We analyzed the consent forms of center-north Italy NICUs. To this aim, we assessed if the forms had acceptable length and other features; we then asked some volunteers to simulate an information process and to score the forms for their easiness, comprehensibility and explicability to others. RESULTS: Twenty-one NICUs accepted to participate. Only 7 out of 21 had an adequate information form; the other 14 could be described as "waiver of responsibility " (WOR), because they were too prolix and contained too many hypothetical procedures. The overall level of easiness, comprehensibility and explicability to others was suboptimal, being lower in those forms we defined WOR. CONCLUSIONS: The results are far to be optimal. More care should be devoted to the process of informing parents at the admission into the NICU: an information overload should be avoided and information should be tailored on the baby's state. Further analysis should be devoted to whether the use of WOR is routine in other countries. PMID- 29756699 TI - The limits of viability in preterm infants, a growing ethical dilemma. PMID- 29756698 TI - [Engineering of a flavonoid 3'-hydroxylase from tea plant (Camellia sinensis) for biosynthesis of B-3',4'-dihydroxylated flavones]. AB - Objective: A flavonoid 3'-hydroxylase from tea plant was engineered to synthesize B-3',4'-dihydroxylated flavones such as eriodictyol, dihydroquercetin and quercetin. Methods: Four articifical P450 constructs harboring both flavonoid 3' hydroxylase gene from Camellia sinensis (CsF3'H) and P450 reductase gene from Arabidopsis thaliana (ATR1 or ATR2) were introduced into Escherichia coli strains TOP10, DH5alpha and BL21, resultantly engineering strains S1 to S12. The plasmid pYES-Dest52-CsF3'H harboring CsF3'H gene was introduced into yeast Saccharomyces cerevisiae WAT11 designated as strain S13. The plasmid pES-HIS-CsF3H::AtFLS 9 AA was constructed through fusing flavanone 3-hydroxylase gene from Camellia sinensis (CsF3H) and flavonol synthase gene from Arabidopsis thaliana (AtFLS). Plasmid pES-URA-CsF3'H and pES-HIS-CsF3H::AtFLS 9 AA were then co-introduced into yeast S. cerevisiae WAT11 designated as strain S14. Results: Strain S6 generated highest bioconversion efficiency at 25C among all E. coli strains during 24 h fernentation. Supplemented with 1000 MUmol/L naringenin, dihydrokaempferol and kaempferol, the maximum amounts of eriodictyol, dihydroquercetin and quercetin produced by strain S13 were 734.32 MUmol/L, 446.07 MUmol/L and 594.64 MUmol/L respectively. Supplemented with 5 mmol/L naringenin, the maximum amounts of eriodictyol, kaempferol, quercetin, dihydroquercetin and dihydrokaempferol produced by strain S14 were 1412.16 MUmol/L, 490.25 MUmol/L, 445.75 MUmol/L, 66.75 MUmol/L and 73.50 MUmol/L during 36-48 h fermentaion respectively. Conclusion: CsF3'H was engineered for biosynthesis of B-3',4'-dihydroxylated flavone. PMID- 29756701 TI - Prevalence of Mycoplasma pneumoniae infection in pediatric patients with acute asthma exacerbation. AB - INTRODUCTION: Mycoplasma pneumoniae may be involved in refractory asthma exacerbation. OBJECTIVE: To determine the prevalence of Mycoplasma pneumoniae infection in patients with acute asthma exacerbation. Material and method. A prospective, crosssectional, observational, case-control study was carried out in patients older than 2 years old and younger than 12. Immunoglobulin M (IgM) antibodies were serologically determined for M. pneumoniae, using the NovaLisa(r) NovaTec kit for enzyme-linked immunosorbent assay (ELISA). Test results >= 11 NTU (NovaTec units) were regarded as positive. The statistical analysis was performed by means of the analysis of variance (ANOVA) and the chi2 test, with a significance level of p < 0.05. RESULTS: One hundred and eighty children were studied, of which 130 had asthma and 50 comprised the control group. Specific IgM was positive for 60 patients, that is 46.15% of the asthmatic children (p < 0.001). The severity of the exacerbation was directly related to IgM levels (p < 0.001). Hospitalization rate was 75%, and it was significantly associated to specific IgM levels (p < 0.001). CONCLUSION: Our data suggest that children with acute asthma show a high prevalence (46%) of Mycoplasma pneumoniae infection and that there is a close relation between severe acute asthma exacerbation and the presence of Mycoplasma pneumoniae infection. These findings might result in therapeutic implications centered in the use of specific antibiotics to fight this atypical organism. Key words: acute asthma, exacerbation, Mycoplasma pneumoniae. PMID- 29756700 TI - Use of ultrasonography as a noninvasive decisive tool to determine the accurate endotracheal tube size in anesthetized children. AB - BACKGROUND: It is hard to determine the appropriate size and correct tracheal position of endotracheal tube (ETT) in children. The aim of this study is to determine tracheal diameter in children by using ultrasonography technique as objective tool and compare it with commonly used aged based formulas for the ETT size estimation. PATIENTS AND METHODS: Patients undergoing elective surgery in a tertiary children's hospital were prospectively enrolled. The subglottic transverse tracheal diameter was determined by ultrasonography. An anesthesiologist who was blind to ultrasonographic examination, determined the tube size and performed intubation by evaluating the space between vocal cords with the help of a direct laryngoscopic view. Ultrasonographically measured tracheal diameter, tube diameters, leak/pressure controls, and results of age based tube size calculations were recorded. RESULTS: A total of 61 patients, mean age of 12 +/- 4.21 (2- 17) years and mean weight of 38 +/- 22.94 (10-106) kg were enrolled. The diameter of trachea measured by ultsonography was 13.0 (11.4-15.1). Outer diameter (mm) of the ETT determined by anesthesiologist was 8.42 +/- 1.43; calculated by Cole formula was 9.0 +/- 1,42; calculated by Khine formula was 7.67 +/- 1.46; calculated by Motoyama formula was 8.33 +/- 1.42. ETT cuff was inflated after ETT placement due to leak in 31 (47.7%) patients. Tube was replaced by a larger tube due to excessive leak in one patient. Poor intraclass correlation was found between ultrasonographically determined tracheal diameter and aged based tube diameter calculations (tracheal diameter vs Cole [0.273], Khine [0.207], and Motoyama [0.230]). CONCLUSION: Ultrasonographical determination of transverse tracheal diameter is a suitable method for determining the correct endotracheal tube size when compared with the age based formulas. PMID- 29756702 TI - Non-nutritive sweeteners: children and adolescent consumption and food sources. AB - : The availability of food and beverages with non-nutritive sweeteners (NNSs) has increased in recent years. OBJECTIVES: To estimate NNSs consumption among children and adolescents in the Autonomous City of Buenos Aires, the prevalence of a daily intake higher than acceptable, and the main food and beverages contributing to it. MATERIAL AND METHODS: Descriptive study about the information collected in the First Food and Nutritional/Nutrition Survey of Buenos Aires City, which was conducted in 2011 and included 2664 children and adolescents aged 2-18 years. Consumption was assessed by means of a 24- hour recall. NNSs content in food and beverages was obtained from nutrition facts labels. The total dietary intake for each NNSs and the adequacy to the acceptable daily intake (ADI) established by the Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO). RESULTS: Forty four percent of preschoolers, 53% of school children, and 51% of adolescents have had food with NNSs. No child was exposed to a consumption of aspartame, acesulfameK, and sucralose higher than the ADI. Saccharin consumption was higher than the ADI in 0.3% of preschoolers while cyclamate consumption was higher than the ADI in 0.9% of school children and 0.1% of adolescents, due to the consumption of concentrated juice, to be diluted with water. Beverages provided 67% of cyclamate, 91% of acesulfameK, and 96% of aspartame. Table-top sweeteners provided 30% of cyclamate and 32% of saccharin. CONCLUSION: Consumption of food and beverages with NNSs is usual among children and adolescents, mainly from beverages. Less than 1% of children are exposed to a consumption of cyclamate and saccharin higher than the ADI. PMID- 29756703 TI - Most commonly isolated viruses in asthma exacerbation and their correlation with eosinophil and total serum immunoglobulin E levels. AB - BACKGROUND: Asthma exacerbations are still a cause of hospitalization at the Emergency Department. The triggers of asthma exacerbations include allergens and infections -mostly viral-. The objective of this study was to establish the relationship between viruses detected during an asthma exacerbation and eosinophil and serum immunoglobulin E (IgE) levels in pediatric patients. POPULATION AND METHODS: Cross-sectional. analytical study. Children aged 5-15 years seen at the Pediatric Emergency Department with an asthma exacerbation in the period between March 2013 and February 2016 were included. Viral ribonucleic acid was extracted from nasopharyngeal aspirates using the CLART Pneumo Vir kit. Eosinophil levels were measured in peripheral blood and total IgE levels, in serum. Eosinophilia was defined as a count >= 0.4 x 103/ mm3 and high IgE. as a level >= 350 IU/L. The Pearson's correlation was carried out. A value of p <= 0.05 was considered significant. RESULTS: Out of 211 children with asthma exacerbation, a virus was isolated in 20%. The most commonly isolated viruses were rhinovirus. enterovirus, and respiratory syncytial virus. A correlation of 0.89 was established between eosinophil and total serum IgE levels in children with asthma exacerbation and rhinovirus, with a p value of 0.0001. CONCLUSIONS: Rhinovirus, enterovirus, and respiratory syncytial virus were the most common viruses in asthma exacerbations in children younger than 15 years. A correlation was established between eosinophil and IgE levels in the presence of rhinovirus. PMID- 29756705 TI - Ultrasound-guided vascular cannulation. Experience in critically-ill pediatric patients. AB - INTRODUCTION: Central vascular cannulation in children is a highly complex technique and poses many difficulties. Vascular ultrasound can make this procedure easier. OBJECTIVE: To describe the characteristics of ultrasound-guided vascular cannulation in critically-ill pediatric patients. POPULATION AND METHODS: Outcome measures prospectively recorded were vessels most frequently cannulated, their localization, the measurement of their diameter/depth, the success rate and complications developed, among others. RESULTS: One hundred and twenty four vascular punctures were performed in 86 pediatric patients. Vascular accesses were the femoral vein (39.7%), followed by the femoral artery (27.2%) and the internal jugular vein (14.7%). Femoral vessels were localized at a depth of 0.75 +/- 0.25 mm, with a mean diameter of 0.31 +/- 0.16 mm. The depth of jugular vein vessels was smaller (0.64 +/- 0.24 mm) and their overall diameter, larger (0.44 +/- 0.19 mm). The mean number of attempts in ultrasound-guided cannulations was 2.2 +/- 1.3. The success rate was 79% and was associated to a larger vessel diameter (0.39 +/- 0.20 mm vs. 0.28 +/- 0.13 mm, p= 0.01) and a lower number of attempts (1.90 +/- 1.16 vs. 3.45 +/- 1.77, p= 0.001). Complications were accidental puncture of another vessel (5.3%) and hematoma formation during puncture (2.3%). CONCLUSIONS: In the pediatric patients studied, ultrasound-guided vascular cannulation allowed vessel visualization and measurement of their depth and diameter; the success rate was high and it was associated to a low complication rate. PMID- 29756704 TI - Cerebrospinal fluid shunt-associated infections in pediatrics: Analysis of the epidemiology and mortality risk factors. AB - INTRODUCTION: Infections are the most common complications of ventricular cerebrospinal fluid shunts. The objective of this study was to describe the clinical, microbiological, and evolutionary characteristics of children with ventricular cerebrospinal fluid shunt-associated infections and analyze the risk factors for mortality. POPULATION AND METHODS: Descriptive, retrospective study carried out at Hospital "Prof. Dr. Juan P. Garrahan" in the Autonomous City of Buenos Aires. All patients hospitalized between January 1st, 2012 and December 31st, 2015 who were compatible with ventriculitis and had a positive cerebrospinal fluid culture were assessed. RESULTS: A total of 49 patients with 57 infections were included. Their median age was 62 months (interquartile range: 19-114). Males predominated: 34 (70%). A central nervous system tumor was the most common underlying disease: 20 (40%). Coagulase-negative Staphylococcus was isolated in 26 (46%); Staphylococcus aureus, in 13 (23%); Gram-negative bacilli, in 11 (19%); and other microorganism, in 7 (12%). Treatment consisted of removal of ventricular shunt plus antibiotic therapy for 55 (97%) infections. The mortality rate was 9%. The only statistically significant factors associated with mortality were positive blood cultures (p= 0.04), fever at the time of admission (p= 0.04), and septic shock (p= 0.0006). CONCLUSIONS: Coagulase-negative Staphylococcus was the most common microorganism. Valve removal plus antibiotic therapy was the most frequently instituted treatment. Fever at the time of admission, positive blood cultures, and septic shock were predictors of mortality. PMID- 29756706 TI - Ovarian masses in infant-juvenile age. AB - INTRODUCTION: The appropraite surgical treatment to pediatric patients with ovarian lesions are heterogeneous and ovarian preservation is desirable in children. The aim of this study is to the discuss findings related to a set of patients who were operated on for ovarian lesions. PATIENTS AND METHODS: A retrospective study carried out in 13 years on 56 patients under the age of 17. These patients were divided into 3 groups according to ovarian pathologic diagnosis: 25 with functional (cyts and torsion), 18 with epithelial ovarian lesions and 13 with germ cell tumours. These three groups were compared in terms of menarche, torsion, age, duration, size, pain, mass, vomiting, irregular menstruation, location and operation type. RESULTS: Follicle cysts, serous cyst adenomas and teratomas were the most common in these groups. The mean age of the patients was 12.18+/-4.84 years. The most common symptoms and signs were abdominal-pelvic pain (85.7%) and swelling(37.5%). Torsion was seen in 21 patients (37.5%), mean mass size was found to be 10.46+/-6.55 cm. A salpingo oophorectomy (SO) was performed in 38 patients and cyst excision (CE) was performed in 18 patients. In premenarcheal cases, torsion was seen more in menarcheal cases and in the functional lesion group. CE was performed more often in the functional and t SO was performed often in the epithelial and germ cells groups. CONCLUSION: Torsion and functional ovarian pathologies are thought to be common in premenstrual ages and malign lesions are very rare in all age groups so we recommend ovarian protective surgery should be preferred. PMID- 29756707 TI - Impact of the hyperchloremic component of metabolic acidosis on the patient's hydration status and the treatment of diabetic ketoacidosis. AB - INTRODUCTION: Diabetic ketoacidosis (DKA) is characterized by metabolic acidosis (MA) with a high anion gap (AG), although, occasionally, it can present with hyperchloremia. It has been postulated that the early presence of hyperchloremia could reflect a better hydration status; however, its prevalence and impact on DKA treatment remain unknown. determine the prevalence of the hyperchloremic component in MA prior to treatment and to assess whether it is associated with a better hydration status and a shorter recovery time from DKA compared to patients with high AG only. Patients and Methods. Patients hospitalized with DKA (between January 2014 and June 2016) were grouped according to whether they were admitted with MA with high AG only. or with hyperchloremia, and clinical and laboratory outcome measures and response to treatment were compared. RESULTS: Forty patients (17 males, median age: 14.5 years [2.4-18]) were included; 22 with hyperchloremic metabolic acidosis (prevalence of 55%) and 18 with metabolic acidosis with high AG only. The presence of hyperchloremia was not associated with a better hydration status (weight loss percentage in both groups: 4.9%; p= 0.81) nor with a faster treatment response (MA with a hyperchloremic component: 9.5 hours; MA with high AG only: 11 hours; p= 0.64). CONCLUSIONS: The prevalence of MA with a hyperchloremic component among children with DKA was 55% and was not associated with a better hydration status nor with a faster recovery from the metabolic decompensation. PMID- 29756708 TI - Hypercalcemia and hypophosphatemia among preterm infants receiving aggressive parenteral nutrition. AB - INTRODUCTION: Aggressive parenteral nutrition is the standard of care among very low-birth weight preterm infants. However, in recent studies, its impact on short term outcomes, has been evaluated. The objective was to compare the prevalence of hypercalcemia and hypophosphatemia among preterm infants receiving aggressive or standard parenteral nutrition. METHODS: Observational, retrospective study comparing a group of preterm infants weighing less than 1250 grams who received aggressive parenteral nutrition with a historical control group. The prevalence of hypercalcemia was estimated and its association with aggressive parenteral nutrition was searched adjusting by confounders. The mean phosphate level was estimated for the control group by linear regression and was compared to the value in the other group. RESULTS: Forty patients per group were included. The prevalence of hypercalcemia was higher in the group who received aggressive parenteral nutrition (87.5% versus 35%, p= 0.001). Aggressive parenteral nutrition was associated with hypercalcemia when adjusting by birth weight, intrauterine growth restriction, amino acid, and calorie intake (adjusted odds ratio: 21.8, 95% confidence interval [CI]: 3.7-128). The mean calcium level was different between both groups (p= 0.002). Infants who received aggressive parenteral nutrition had more sepsis without reaching statistical significance and the mean phosphate level was lower than that estimated for the control group (p= 0.04). The prevalence of hypophosphatemia in this group was 90% (95% CI: 76 97%). CONCLUSIONS: Our data show an association between hypercalcemia/hypophosphatemia and aggressive parenteral nutrition. It is recommended to frequently monitor calcium and phosphate levels since they might be associated with adverse clinical outcomes. PMID- 29756709 TI - Strategies of blind children to achieve cognitive development. A qualitative study. AB - INTRODUCTION: Studying the cogni t ive development of blind children is particularly interesting in itself and because it provides intervention guidelines. The etiology of blindness is heterogeneous but this does not hinder the possibility of establishing the characteristics typical of its development. If these children acquire language at approximately 2 years, it means the last stage of sensorimotor intelligence has been achieved. OBJECTIVE: To determine the strategies that blind infants and toddlers adopt during the sensorimotor period to achieve an adequate level of development. Population and method. The study was carried out in students from a public Special Education School of the Autonomous City of Buenos Aires. This was a qualitative study for the identification of coincidences to define strategies. Blind children aged 3 months to 3 years were observed. The analysis unit was each significant segment of the "directed play" sessions conducted in a Gesell chamber and guided by the stimulation therapist. RESULTS: Thirty-four children were included and 55 observations were made. Children's "modes of action" were categorized as significant features of a strategy. Four thematic focuses and four stages were identified and chronologically supported with acquisitions that were considered "organizers." The assessment showed that 71% of children achieved an adequate cognitive development for their age. CONCLUSION: Systematizing strategies will help to develop an instrument to detect delays and define intervention guidelines. PMID- 29756710 TI - MEFV gene mutations and clinical course in pediatric patients with Henoch Schonlein purpura. AB - OBJECTIVE: To determine the frequency of the MEFV gene mutations in pediatric patients diagnosed with HSP and to assess the effect of the MEFV gene mutations on their prognosis. Material and Methods. Ccross-sectional study; pediatric patients between 2-11 years diagnosed with HSP were included. These cases were investigated for 6 MEFV gene mutations (M694V, M680I, A744S, R202Q, K695R, E148Q). RESULTS: Eighty cases were included in the study of which 55% were male (n= 44). The mean age was 6.44 +/- 2.52 years. Disease recurrence occurred in 9 patients, invagination in 5 patients and convulsion in 1 patient during follow up. Approximately half of the patients received steroids. The MEFV gene mutations was not detected in 44 (55%) of the patients. There was a heterozygous mutation in 19 (22%). E148Q was found in 8 patients, M694V in 5 patients, A744S in 4 patients, and the R202Q heterozygous mutation in 2 patients. The M608I homozygous mutation was detected in 1 patient and the M694V homozygous mutation in 1 patient. The compound heterozygous MEFV gene mutations was found in 15 patients. The presence of the MEFV gene mutations was not correlated with the frequency of renal and gastrointestinal involvement and prognosis, the development of complications and the use of steroids. CONCLUSION: The presence of the MEFV gene mutations does not correlate with the clinical course and complication in Turkish pediatric patients with HSP. PMID- 29756711 TI - Smoke-Free Adolescents. Effectiveness of an educational intervention. Controlled, before and after study. PMID- 29756712 TI - Traumatic cataract surgery in pediatric patients. Experience in a site. AB - of this study was to determine the characteristics of patients younger than 14 years who underwent traumatic cataract surgery at the Unit of Pediatric Ophthalmology, Strabismus and Neuro-Ophthalmology "Dra. Ana Maria Illescas Putzeys" of Hospital de Ojos y Oidos "Dr. Rodolfo Robles V." A retrospective, descriptive, and observational study was carried out to review the medical records of patients who underwent cataract surgery between 2010 and 2015. A total of 54 children underwent traumatic cataract surgery; 75% were boys; 68% were in the 6-11-year-old age range. Blunt force trauma was observed in 57.4%. A visual acuity of 20/70 or better was achieved by 68.2% of patients. PMID- 29756714 TI - Developing child autonomy in pediatric healthcare: towards an ethical model. AB - The changes initiated by the new National Civil and Commercial Code in Argentina underline the pediatric task to empower children's and adolescents' developing autonomy. In this paper, we have framed a model describing autonomy in child healthcare. We carried out a literature review focusing on i) the concept of autonomy referring to the absolute value of the autonomous individual, and ii) the age-driven process of competent decisionmaking development. We summarized our findings developing a conceptual model that includes the child, the pediatrician and the parents. The pediatricianchild relationship is based on different forms of guidance and cooperation, resulting in varying levels of activity and passivity. Parental authority influences the extent of autonomy, based on the level of respect of the child's moral equality. Contextual, existential, conceptual, and socialethical conditions shall be considered when applying the model to facilitate dialogue between pediatricians, children, parents and other actors. PMID- 29756715 TI - An update on amniotic bands sequence. AB - Amniotic bands sequence is a congenital disorder characterized by craniofacial, body wall, and limb anomalies that may be associated with fetalplacental fibrous bands. Its prevalence has been reported to range from 0.19 to 8.1 per 10 000 births. Different theories have attempted to explain the etiology of amniotic band sequence; however, none has individually been able to support each and every defect observed, so it has been considered to be a multifactorial condition. The (pre- and post-natal) identification of anomalies suggestive of amniotic band sequence is useful for the diagnostic approach and implementation of timely therapeutic interventions favoring the release of the amniotic bands using fetoscopy with recovery of the involved distal limb perfusion, or else the possibility of performing a post-natal surgical repair. It is also helpful to provide genetic counseling. This article offers an update on the epidemiological aspects, etiological theories, risk factors, clinical characteristics, diagnosis (including antenatal diagnosis), genetic counseling, therapeutic approach, and prognosis of amniotic bands sequence. PMID- 29756713 TI - Prevalence of cow's milk protein allergy among children in a university community hospital. AB - INTRODUCTION: Cow's milk protein allergy (CMPA) is the most common food allergy in pediatrics. In Argentina, the prevalence of this disease has been evaluated in a few trials. OBJECTIVES: To estimate the prevalence of CMPA and describe its variation throughout a period of 11 years. POPULATION AND METHODS: A retrospective cohort study was carried out in live newborn infants enrolled in a health care program of a university community hospital. RESULTS: One hundred and sixteen cases of children with CMPA were identified. Cumulative prevalence was 0.8% (95% confidence interval [CI]: 0.65-0.95). A percent increase of 0.4% in 2004 to 1.2% in 2014 was observed in the number of cases per year. CONCLUSION: In 2014, CMPA prevalence was 1.2%, i.e. three times that of 2004. PMID- 29756716 TI - Dilated cardiomyopathy and severe heart failure. An update for pediatricians. AB - Dilated cardiomyopathy is the main cause of heart failure leading to heart transplant. Its prognosis is variable and depends on the etiology, the patient's age at onset, and the severity. The management of dilated cardiomyopathy is aimed at minimizing symptoms and preventing disease progression; it requires a comprehensive screening for comorbidities and the prevention of complications to improve the overall status of these children and mitigate their prognosis. Here we present a review oriented at the multidisciplinary management that pediatricians should consider when seeing these patients. PMID- 29756717 TI - [Cyanosis in 14-year-old patient. Methemoglobinemia: case report]. AB - The bluish coloration of skin and mucous membranes, called as cyanosis, could be explained by high reduced hemoglobin in the capillaries, or the presence of elevated methemoglobin concentration. It is important to think of methemoglobinemia as a differential diagnosis in a cyanotic patient who does not respond to oxygen administration once cardiorespiratory causes are discarded; since it requires other diagnostic methods and specific treatment. We described a case of cyanosis in a fourteen-year-old adolescent with probable congenital methemoglobinemia. We discussed their probable causes, clinic presentation, diagnosis and treatment. PMID- 29756718 TI - [Drug reaction with eosinophilia and systemic symptoms due to carbamazepine. Pediatric case]. AB - Severe skin reactions include Stevens-Johnson Syndrome, toxic epidermal necrolysis and Drug reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, which are uncommon in the pediatric population (incidence 1/1000- 10 000 children), but they have bad prognosis. Drug-sensitive Syndrome with eosinophilia and systemic symptoms consists in rash, hematological abnormalities, lymphadenopathy and organ involvement. We report the case of a 12-year-old male patient who developed this pathology after initiating anticonvulsant therapy with carbamazepine. We consider that it is important to be aware of this disease and to include it among the differential diagnoses in patients with similar conditions because this syndrome is life-threatening. PMID- 29756719 TI - [Pulmonary hypertension associated with the human immunodeficiency virus in children: treatment with sildenafil. A case report]. AB - Pulmonary hypertension associated with human immunodeficiency virus infection is an extremely rare disease in pediatrics; it requires a high clinical suspicion to reach a diagnosis. Its appearance poses an unfavorable prognostic, but early diagnosis and specific treatment can improve outcomes. We report the clinical case of a fifteen-year-old patient diagnosed with human immunodeficiency virus infection of vertical transmission, without antiretroviral treatment, with cough and progressive exertional dyspnea, associated with signs of right heart failure in which severe pulmonary hypertension was diagnosed. After discarding other causes, it was assumed pulmonary hypertension associated with human immunodeficiency virus infection. Treatment was performed with sildenafil with good response. PMID- 29756720 TI - A novel mutation of Dent's disease in an 11-year-old male with nephrolithiasis and nephrocalcinosis. AB - Dent's disease is a rare X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrolcalcinosis or nephrolithiasis, proximal tubular dysfunction and renal failure in adulthood. Females are carriers and usually mildly affected. Progression to endstage renal failure are at the 3rd-5th decades of life in 30-80% of affected males. In the absence of therapy targeting for the molecular defect, the current care of patients with Dent's disease is supportive, focusing on the prevention of nephrolithiasis and nephrocalcinosis. We present an 11-year-old child with nephrocalcinosis and nephrolithiasis caused by a new mutation at CLCN5 gene. PMID- 29756721 TI - [Pseudotumor cerebri associated with hypovitaminosis A, B6 and D. About two cases]. AB - Idiopathic endocranial hypertension is infrequently associated with hypovitaminosis A and D. The case of an 8-year-old female with 24-hour blurred vision and bilateral papilledema is presented. Nuclear magnetic resonance was normal. Opening pressure of cerebrospinal fluid: 260 mmH2O. She presented vitamin A and D deficiency and started replacement therapy. The second case corresponds to a 12-year-old male with fever and odynophagia of 3 days. History of glomerulonephritis and overweight. He had bipalpebral edema and papilledema. Computed tomography scan of the orbit: increase of fluid in the sheath of both optic nerves. Nuclear magnetic resonance: intrasellar arachnoidocele. Opening pressure of cerebrospinal fluid: 400 mmH2O. He presented vitamin D and B6 deficiency and started replacement treatment. The elevation of intracranial pressure triggers compensation mechanisms that, when they fail, can compromise life or cause serious neurological disabilities. Recognizing the cause for an accurate therapeutic approach is key to reduce the morbidity and mortality associated with this pathology. PMID- 29756722 TI - [Use of posaconazole in children: Experience in a tertiary pediatric hospital]. AB - There is limited information on the use of posaconazole in children. This retrospective and descriptive study was conducted to evaluate the clinical, microbiological characteristics and evolution of patients treated with posaconazole between August 2010 and March 2017. We included 16 children. Median age: 161 months (interquartile range -IQR- 69-173 m). All had underlying disease and a proven invasive fungal infection. The most frequent isolated were Mucor spp. and Aspergillus spp. The mean posaconazole dose was 600 mg/day (400-800 mg/day) and the median duration of treatment was 223 days (IQR 48-632). Ten patients had adverse effects, but only one required suspension of the antifungal treatment due to hydroelectrolytic disorders. PMID- 29756724 TI - Stevens-Johnson Syndrome associated with methotrexate treatment for acute lymphoblastic leukemia: a case report. AB - Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare mucocutaneous diseases which are associated with a prolonged course and potentially lethal outcome. They are mostly drug induced and mortality rates are very high. Although mostly skin is involved, multiple organ systems such as cardiovascular, pulmonary, gastrointestinal, and urinary systems may be affected. Here, we report a case of Stevens- Johnson Syndrome associated with methotrexate treatment who developed acute cardiac failure and gastrointestinal hemorrhage beside skin findings. He had been treated with intravenous immunglobulin and methylprednisolone succesfully and continued chemotherapy with methotrexate treatment again. PMID- 29756723 TI - [Pleuropulmonary blastoma: case report]. AB - Pleuropulmonary Blastoma corresponds to a malignant primary lung disorder, exclusive of pediatric age, infrequent and of aggressive characteristics. Age on diagnosis is 1 month-12 years. Rates per sex are equal. It can be found inside pleura or lungs. Respiratory distress associated or not with pneumothorax, chest pain and fever are classical clinical signs. These symptoms could be misdiagnosed as pneumonia. Radiologically, a large mass near the pleura at the base of the right lung without air bronchogram is its most common form. It has three histological types: type I (cystic), type II (mixed) and type III (solid). Its treatment requires tumor excision and multimodal chemotherapy. Pleuropulmonary Blastoma type I has good prognosis; type II and III variants have lower survival. We report a 2-year-old girl, pointing to the clinicalradiological diagnosis. PMID- 29756725 TI - [Tuberculosis by multiresistant Mycobacterium africanum. Pediatric clinical case]. AB - Tuberculosis, considered since 2003 by the World Health Organization a global health emergency, causes annual mortality of approximately 2 million people, mainly in developing countries. In the Spanish pediatric population, the incidence is 5 cases/100 000 children between 5 and 14 years and 13 cases/100 000 children between 0 and 4 years. The infection is transmitted through the respiratory tract by baciliferous patients. Children eliminate few bacilli in respiratory secretions and do not usually transmit the infection. In Spain, the resistance to isoniazid in the general population is 5%, being higher in the immigrant population, which is important to take into account for the treatment of cases. A case of tuberculosis due to Mycobacterium africanum multiresistant to treatment is presented, with satisfactory evolution after multiple therapy. PMID- 29756726 TI - [Neonatal facial palsy: identification of herpes simplex virus 1 in cerebrospinal fluid. Case report]. AB - Neonatal facial palsy is very uncommon and is generally diagnosed at birth. We present the first published case of neonatal facial palsy with identification of herpes simplex virus 1 in cerebrospinal fluid. A 35-day-old male was presented at the Emergency Department with mouth deviation to the left and impossibility of full closure of the right eye. There were no symptoms of infection or relevant medical history. Physical examination was compatible with peripheral facial palsy. Studies performed at admission were normal (blood count, biochemical analysis and coagulation blood tests and cerebrospinal fluid analysis). The patient was admitted on oral prednisolone and intravenous aciclovir. Cranial magnetic resonance was normal. Polymerase chain reaction test for herpes simplex virus 1 in cerebrospinal fluid was reported positive after 48 hours of admission. Patient followed good evolution and received prednisolone for 7 days and acyclovir for 21 days. At discharge, neurological examination was normal. PMID- 29756728 TI - [Hydatid disease in children of Buenos Aires Province]. AB - Hydatidosis is a parasitic zoonosis caused by Echinococcus granulosus. It is endemic in Argentina and in the province of Buenos Aires, especially to the south of the Rio Salado basin. During 2014 and 2016, the Department of Rural Zoonoses was notified of 479 cases of hydatidosis, with 12.1% confirmed in children under 18 years of age. Fifty-nine percent corresponded to males and the group of 13 to 17 years was the most prevalent one (47%). Sixty-four percent had liver involvement, 22% pulmonary involvement, 5% hepatopulmonary involvement, 5% splenic involvement and 4% cerebral involvement. Thirtythree percent of the cases were asymptomatic. Sixty percent resided in urban areas and of these 20% did not present an epidemiological link. This is a disease of mandatory reporting and there are provincial and national programs that contemplate free actions tending to control it, but despite this, it continues to be a difficult problem to solve. PMID- 29756727 TI - [Laryngeal papillomatosis: A rare cause of dysphonia in the child. Case series]. AB - Juvenile laryngeal papillomatosis is an uncommon disease caused by human papilloma virus, mainly types 6 and 11. It is the most common benign laryngeal tumor in children. This condition should be suspected in any children with persistent and progressive dysphonia with or without stridor and respiratory distress. Flexible laryngoscopy under local anesthesia allows to visualize the typical wart-like lesions. The diagnosis is confirmed by pathological anatomy. Existing treatment is palliative and consists mainly of the surgical excision of the papillomas to maintain the airway without obstruction and to improve the quality of the voice, but it has a high rate of relapse. We present 20 patients with juvenile laryngeal papillomatosis. We describe the clinical manifestations, the diagnostic methods and the treatment of this pathology. PMID- 29756729 TI - [Mycobacterium tuberculosis PhoP system]. AB - PhoPR is an important two-component regulatory system in Mycobacterium tuberculosis. PhoP is essential for virulence as a response regulator involved in cell wall lipid biosynthesis and regulation of gene expression. In this review, the structure, function and vaccine application of PhoP were summarized, as well as some questions that need to be solved. PMID- 29756730 TI - Visual System Assessment in Infants, Children, and Young Adults by Pediatricians AB - Appropriate visual assessments help identify children who may benefit from early interventions to correct or improve vision. Examination of the eyes and visual system should begin in the nursery and continue throughout both childhood and adolescence during routine well-child visits in the medical home. Newborn infants should be examined using inspection and red reflex testing to detect structural ocular abnormalities, such as cataract, corneal opacity, and ptosis. Instrument based screening, if available, should be first attempted between 12 months and 3 years of age and at annual well-child visits until acuity can be tested directly. Direct testing of visual acuity can often begin by 4 years of age, using age appropriate symbols (optotypes). Children found to have an ocular abnormality or who fail a vision assessment should be referred to a pediatric ophthalmologist or an eye care specialist appropriately trained to treat pediatric patients. PMID- 29756732 TI - [Relationship between DNA nuclease and the virulence of Streptococcus suis serotype 9]. AB - Objective: In addition to Streptococcus suis serotype 2, Streptococcus suis serotype 9 (SS9) is also a currently prevalent serotype and a zoonotic pathogen. In our previous study, SS9 DNA nuclease (SsnA) was considered as a candidate virulence factor. To clarify the impact of SsnA on SS9 virulence, we constructed ssnA mutant (DeltassnA) and studied its biological functions. Methods: We evaluated the virulence of wild type strain and DeltassnA in a zebrafish infection model and compared the adherence rate to HEp-2 cells, the survival rate in pig blood, and enzymatic activity between wild type stain and DeltassnA. Results: In a zebrafish infection experiment, the 50% lethal dose value of DeltassnA was 11.2-fold higher than that of wild type strain. The adherence rate of DeltassnA to HEp-2 cells was only 60.61% of the wild strain level. The survival rate of DeltassnA in pig blood was declined to 71.88% of wild strain level. The enzymatic activity assay showed that SsnA can degrade both linear and circular DNA. Conclusion: SsnA contributes to SS9 virulence in a zebrafish infection model, the adherence to HEp-2 cells, and the survival in pig blood. SsnA is indeed an essential virulence factor for SS9. PMID- 29756731 TI - [Advances in transformation and regulation biodegradation of chorinated hydrocarbons in landfill]. AB - Understanding the biotransformation mechanism of chlorinated hydrocarbons in contaminated site is of great significance to the in-situ bioremediation. Therefore, we summed up the overlapping composition of chlorinated hydrocarbons and analyzed statistically the concentration variations and degradation rate of chlorinated hydrocarbons in various landfill which were regarded as one of the most typical compound pollution sites. The statistical data indicated that chloralkane and chloroalkene concentration ranged 0.20 to 32.45 and 0.50 to 32.45 MUg/m3, respectively, which were the main components. We also found that biodegradation rates of chlorinated hydrocarbons decreased with the number of attached chlorine atoms in landfill cover. Then, we summarized the biodegradation mechanism of chlorinated hydrocarbons under different environmental conditions. The results implied that chlorinated hydrocarbons biodegradation incorporated aerobic co-metabolism, halorespiration and anaerobic reductive dechlorination involved in a wide range of substrates and a variety of functional microbes. Based on of these analyses, we constructed biodegradation models of chlorinated hydrocarbons in landfill cover. Finally, the possible development of chlorinated hydrocarbons biological removal in the future was predicated. PMID- 29756733 TI - [Community structure and diversity of culturable moderate halophilic bacteria isolated from Qrhan salt lake on Qinghai-Tibet Plateau]. AB - Objective: I studied the community structure and diversity of culturable moderate halophilic bacteria isolated from Qrhan Salt Lake. Methods: I isolated and cultured the moderate halophilic bacteria on different selective media. After the 16S rRNA gene sequences was amplified and measured, I constructed the phylogenic tree, analyzed the community structure and calculated the diversity indexes according to the 16S rRNA gene information. Results: A total of 421 moderate halophilic bacteria were isolated from water and mud samples in Qrhan Salt Lake. The 16S rRNA gene information showed that 4 potential novel species belonged to the family Bacillaceae. Eighty-three model strains belonged to 3 phylurms 6 families 16 genus. Among them, Bacillus sp., Oceanobacillus sp. and Halomonas sp. were dominant species. Diversity analysis showed that the diversity of strains isolated from water sample was higher than that from mud sample, but the dominance degree of strains isolated from mud sample was higher than that from water sample. Conclusion: The genetic diversity of moderate halophilic bacteria isolated from Qrhan Salt Lake was abundant. Also, there were dominant and novel species of culturable moderate halophilic bacteria in this lake. PMID- 29756734 TI - [Putative regulatory protein STM14_3514 decreases Salmonella Typhimurium invasion of epithelial cells]. AB - Objective: To study the function and mechanism of STM14_3514 gene that encoded in Salmonella pathogenicity island (SPI)-1 of Salmonella enterica serovar Typhimurium strain ATCC 14028. Methods: We constructed STM14_3514 mutant strain and a complemented strain of the mutant. Through mice experiment, attachment assays, invasion assays, macrophage replication assays, western blot, and Quantitative real-time PCR analysis (qRT-PCR), we compared the virulence of the mutant strain to that of the wild-type 14028. Results: STM14_3514 mutant shows increased virulence to mice, and the bacterial number of STM14_3514 mutant in liver, spleen, and ileum was more abundant than that of the wild-type strain. The increased virulence of STM14_3514 mutant is caused by its elevated invasion ability to epithelial cells (>2-fold and P<0.05). qRT-PCR and western blot results show that STM14_3514 reduced the expression of HilA and another SPI 1invasion locus. Moreover, the repression of HilA by STM14_3514 is mediated by HilC. Conclusion: STM14_3514 is a negative regulator in SPI-1, which can repress HilA and SPI-1invasion locus through HilC, and possibly contribute to the repression on SPI-1 after bacterial invasion. PMID- 29756735 TI - [Effect of amphipathic helix characteristics of FtsZ (236-245) domain on FtsZ assembly and its function in Escherichia coli strains]. AB - Objective: To study the effect of amphipathic helix characteristics of FtsZ (236 245) domain on FtsZ assembly and interaction of FtsZ with FtsA in Escherichia coli strains. Methods: We constructed FtsZ and its mutant's plasmids by molecular clone and site-directed mutagenesis, and purified targeted proteins using affinity chromatography. QN23-QN29 strains were constructed by linear DNA homologous recombination and P1 transduction. We observed cellular localization patterns of FtsZ and its mutants in E. coli by living cell imaging experiments, examined membrane binding properties of FtsZ mutants by membrane proteins isolation and Western blot analysis, and analyzed interaction of FtsZ/FtsZ* with FtsA by Co-immunoprecipitation and far Western blot. Native gel separation and in vitro polymerization experiments were done to check effects of FtsZ point mutation on FtsZ assembly. Results: Yfp-labeled FtsZE237A/K and FtsZE241A/K mutant proteins failed to localize in E. coli strains, assemble into functional Z ring structure, and had decreased function of FtsZ (wt). In vitro experiments showed that E237A/K and E241A/K mutations of FtsZ decreased the polymerization efficiency of FtsZ monomer, weakened FtsZ*-FtsA interaction and changed membrane binding properties of FtsZ. Conclusion: FtsZ E237 and E241 are critical amino acids that affect the amphipathic helix characteristics of FtsZ (236-245) domain, FtsZ assembly and FtsZ-FtsA interaction in E. coli strains. PMID- 29756736 TI - [Interactions between Escherichia coli and Staphylococcus aureus determined by genome-wide association analysis]. AB - Objective: We studied the interactions in a co-culture of two bacteria. Methods: By pairwise co-culturing of 36 Escherichia coli and 36 Staphylococcus aureus strains, we monitored the growth of each species in an interaction environment. We identified numerous Single Nucleotide Polymorphisms (SNPs) by whole-genome sequencing used as genetic markers to predict variations in phenotypic traits. Genome-wide association study (GWAS) was applied to identify loci that controlled competition between the two species. Results: In E. coli, 162 significant SNPs affected the change of maximum growth rate by comparing initials strains with those grown in co-culture, and 36 significant SNPs affected the change of maximum growth rate comparing monoculture and co-culture strains. Five of the significant E. coli genes we identified after annotation this time were also reported in other evolutionary studies. We also identified 85 significant SNPs in S. aureus that affected the change of maximum growth rate by comparing initial strains with those grown in monoculture. About the change of bacterial numbers, we found that 706 significant SNPs were associated in E. coli and 129 in S. aureus. Thirteen of the E. coli significant genes in this study were also verified in previous evolutionary reports Conclusion: We found several significant genes both in monoculture and co-culture affecting the interaction of E. coli and S. aureus. GWAS has the potential to study interspecific interactions of bacteria. PMID- 29756738 TI - [Effects of glucose on photosynthesis and growth of Chloralla sp. HN08 cells]. AB - Objective: To study the potential of using glucose as carbon source to produce microalgae biomass and biochemical components, such as photosynthetic pigments, lipids, carbohydrates and proteins by tropical marine microalgae Chloralla sp. HN08. Methods: We compared the growth characteristics of Chloralla sp. HN08 cells under photoautotrophic and mixotrophic (10 g/L glucose was added into the medium) conditions. The photosynthesis, specific growth rates, cell densities, and the content of cell's major components including lipids, starch, soluble sugar, and soluble protein were determined and compared. Results: Glucose (10 g/L in medium) could promote Chlorella growth and increase the final cell density under light condition. However, cells declined gradually under heterotrophic condition. Under mixotrophic condition, the specific growth rate and the final cell density were 6.8 and 1.3 times as that of cells under photoautotrophic condition, respectively. The content of soluble sugar, starch, and lipids in mixotrophic cells was also significantly higher (P<0.05) than that in photoautotrophic cells. However, the content of soluble protein and photosynthetic pigments of mixotrophic cells was significantly lower (P<0.05) than that of autotrophic cells. Algae culture with glucose addition showed a higher light saturation as well as respiration rate. No significant difference in net photosynthesis rate was found between autotrophic and mixotrophic cultures (P>0.05). Conclusion: Under light condition, glucose as a carbon source can promote lipids and starch accumulation, as well as biomass production. PMID- 29756737 TI - [Antibacterial activity of silver nanoparticles against multiple drug resistant strains]. AB - Objective: The objective of the study was to assess the antimicrobial activity of silver nanoparticles (AgNPs) against multiple drug resistant strains. Methods: Minimal inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of AgNPs against three model microbes, namely Escherichia coli, Staphylococcus aureus, Candida albicans were measured by microdilution broth method. Time-kill curve within 24 h was made according to colony count method after three model microbes were treated with a series concentration of AgNPs. Post-antibiotic effect was tested by colony count method. Finally, we determined the antimicrobial efficacy against multiple drug resistant strains in biological safety laboratory grade 2 (BSL-2). Results: AgNPs with a diameter of 5 nm to 30 nm were synthesized by the biological method. The zeta potential was -19.5 mV. The time-kill curve of the three model microbes showed time-dependent antibacterial activity. The effect of AgNPs on E. coli and C. albicans after "antibiotic effect" increased with time, there was no obvious "post-antibiotic effect" on S. aureus. Both MIC values and MBC values of AgNPs for the three model microbes were between 1 MUg/mL and 4 MUg/mL. However, the MIC value of AgNPs for the three human multidrug-resistant strains was 6 MUg/mL to 26 MUg/mL and MBC value of AgNPs was 10 MUg/mL to 32 MUg/mL. The MIC values of AgNPs for 14 animal multi-drug resistant strains were between 4 MUg/mL and 10 MUg/mL, and the MBC values were between 8 MUg/mL and 16 MUg/mL. The MBC/MIC values of all the tested strains were less than 2. Conclusion: AgNPs is a time-dependent antimicrobial agent with different "post-antibiotic effect", which can inhibit both human and animal-derived multi-drug resistant bacteria. PMID- 29756740 TI - [Two sample pooling strategies revealed different root-associated fungal diversity of Rhododendron species]. AB - Objective: ooling of multiple samples is widely used in studying general patterns of microbial communities that are heterogeneously structured in space. Pooling strategies and the number of sequence reads generate biases in the description of diversity and community structure of root-associated fungi. Therefore, we developed a molecular toolbox for fast and accurate identification of the root associated fungal community of Rododendron species. Methods: Multiple root samples of R. lutescens and R. bureavii were collected for DNA extraction. Effects of two different pooling strategies, i.e. pooling samples prior to vs. post PCR, on fungal species composition were studied by comparing results within host species. Results: Species richness and Shannon-Wiener index of fungal communities of clone library constructed by pooling samples after PCR were higher than that of pooling prior to PCR. High frequency fungal species were detected by both pooling strategies, whereas infrequent species detected by the two strategies differed. Notably, the prior to PCR pooling strategy effectively alleviated the unwanted amplification of host plant sequences when fungal specific primer ITS1f and ITS4 were used. Accumulation curves of fungal species suggested that sequencing at least 50 clones can fully reflect species composition of clone library of the two Rhododendron root-associated fungal community. Conclusion: Clone library constructed by post PCR pooling of samples is better in providing accurate views of fungal diversity and community structure of Rhododendron species. PMID- 29756739 TI - [Phylogenetic and genetic heterogeneity of 23 Acidithiobacillus strains isolated from different geographical locations]. AB - Objective: To study the phylogenetic and genetic heterogeneity of 23 Acidithiobacillus strains from various geographical locations, as well as the relationship between the DNA fingerprinting classification and geographical origin of Acidithiobacillus. Methods: Partial 16S-23S rRNA gene intergenic spacer (ITS) was used to construct corresponding phylogenetic trees based on the sequence homology. rus gene amplification and rep-PCR assay with two different primers (BOXAIR and ERIC) were performed to analyze genetic heterogeneity of Acidithiobacillus strains from diverse environment. Results: Acidithiobacillus revealed a great genetic heterogeneity. The whole isolates were classified into five groups by ITS sequence analysis. This result was similar with that obtained by rep-PCR. Acidithiobacillus ferrooxidans strains were always divided into two groups of phylogenetic and BOXAIR fingerprinting cluster analysis. However, these were clustered one group in the ERIC dendrogram. Genotypic analysis of the rus gene suggested that different iron oxidation pathways have been evolved in these closely related bacteria. Taken together, the iron oxidation pathway of Acidithiobacillus and phylogenetic groups have no obvious correlation. ITS gene has been proven very useful in distinguishing closely related species or subspecies of Acidithiobacillus, to BOXAIR-PCR, which has been recommended as reliable tool for genetic heterogeneity analysis of Acidithiobacillus. PMID- 29756741 TI - [Diversity of microbial community structure in the spermosphere of saline-alkali soil in shandong area]. AB - Objective: Three soil types in different salt contents were taken as the experiment objectives. We evaluated the effect of various saline alkali soil types on diversity of bacterial community structure in spermosphere soil during water absorption and germination of peanut seeds. Methods: The V3-V4 region of 16S ribosomal RNA genes was amplified using PCR, and the PCR products were then analyzed using Illumina high-throughput sequencing technology. Results: (1) The diversity of soil bacterial community in saline alkali soil was higher than that in non-saline alkali soil. Especially, the highest diversity was in spermosphere soil from Qingtuo. (2) The microflora structures in different soils were distinct at the class level. Soil bacteria in four samples were classified into six classes, including Proteobacteria, Actinobacteria, Actinobacteria, Bacteroidetes, Acidobacteria and Firmicutes. Proteobacteria and Actinobacteria groups were dominant in colonies. The analysis of whole samples colony structure showed that the difference of type and abundance at phylum and genus level during different adsorption time was most significant (P<0.05). (3) The analysis of beta diversity and phylogenetic distances of constructed phylogenetic trees revealed that the sequenced clones fell into two major groups within the domain bacteria. Conclusion: The diversity of bacteria community compositions in the high salt content soil was higher. There were obvious differences in microbial community structure of different soil types at class level, primarily in the Proteobacteria and Actinobacteria. The type and abundance of microbial colonies at both phylum and genus levels were affected by the seed germination time. However, there was no influence on the genetic distance between the samples from the same soil type. PMID- 29756742 TI - [Distribution, structure and sequence alignment, and metagenomics analysis of two nitrite reductases with NO forming]. AB - Objective: To reflect the importance of nitrite reductase (NIR) in the environment, we studied its distribution. Methods: The sequences of NIR were searched in the sequenced genome database at NCBI based on previous reported NIR sequences. The sequence similarity was done by multiple sequence alignment, and phylogenetic relationship was evaluated via constructing the phylogenetic tree. Furthermore, their distribution in the marine metagenome was studied by metagenomics. Results: The homologues of these two enzymes were 397 and 812 strains in sequenced genome, and the proportion was 8 and 15.7 percent, respectively. Almost all of archaea containing type II NIR. They have high identity by multiple sequence alignment analysis. The cofactor, the substrate and the cooper binding sites in type II were high conserved, suggesting that these enzymes had the specific function in denitrification. Phylogenetic analysis showed the two enzymes may have the common ancestor. In marine metagenome analysis, type I and II have 6 and 35 reads per 100000 reads, respectively, the two types of NIRs have the biggest proportion at the tropical south pacific area. Conclusion: Collectively, we suggested NIR, especially type II, play a key role in bioremediation of nitrogen contamination. PMID- 29756744 TI - Monitoring the Oxygen Reserve Index can contribute to the early detection of deterioration in blood oxygenation during one-lung ventilation. AB - BACKGROUND: Hypoxemia can occur during one-lung ventilation (OLV), but monitoring blood oxygenation using percutaneous oxygen saturation (SpO2) can be limited by detection latency, and SpO2 sometimes does not change during OLV. The Oxygen Reserve Index (ORiTM) is a novel index reported to detect impending desaturation before this is observed with SpO2 monitoring. This study assessed whether the ORi decreased earlier than SpO2 during OLV and evaluated its correlation with the partial pressure of arterial oxygen (PaO2) during OLV. METHODS: The study enrolled 15 patients undergoing elective thoracic surgery. The patient's trachea was intubated with a left-sided double-lumen endotracheal tube and the lungs were mechanically ventilated in pressure-control mode for 10 min, with the fraction of inspired oxygen set at 0.6. Right OLV was then initiated for 15 min or until SpO2 declined to 91%, while continuously recording the ORi and SpO2. PaO2 was measured 5 min before and every 3 min during OLV. Mean (SD) times from the start of OLV to the start of the decreases in ORi and SpO2 were calculated. RESULTS: ORi started decreasing significantly before SpO2 (ORi vs. SpO2: 171 [102] vs. 372 [231] s; P<0.01). ORi showed a significant, strong correlation with PaO2 (r2=0.671, P<0.01). CONCLUSIONS: ORi decreased earlier than SpO2 during OLV. This index could contribute to the early detection of deterioration in blood oxygenation during OLV. PMID- 29756743 TI - [Physiological function of membrane protein RHOGL009301 involved in transport of benzoate in Rhodococcus sp. R04]. AB - Objective: The physiological function of membrane protein RHOGL009301 in Rhodococcus sp. R04 and the metabolic properties of the mutant strain were studied to determine the relationship between the physiological function of the membrane protein and the transport of benzoate. Methods: The RHOGL009301 gene and the green fluorescent protein gene were fused for expressing in Rhodococcus erythropolis, and the location of RHOGL009301 was observed by Delta Vision. The RHOGL009301 gene was knocked out by homologous recombination, and the growth of wild strain and deficient strain in different carbon sources were compared. The internal and external metabolites of the wild strain and the deficient strain when grown on biphenyl and benzoate were measured by HPLC, and the changes of metabolite concentration in different growth conditions were analyzed. Results: A fusion gene that contained RHOGL009301 gene and the green fluorescent protein gene was co-expressed in Rhodococcus erythropolis and localized on the cell membrane. The deficient strain R04DeltaMP of RHOGL009301 gene was obtained. The biomass of the deficient strain was significantly reduced in biphenyl and benzoate culture, and its growth rate was slowed down. HPLC analysis showed that the deletion of RHOGL009301 gene inhibited the transport of benzoate. Conclusion: RHOGL009301 membrane protein is one of the proteins involved in metabolism and transport of benzoate. Based on sequence homology analysis, we can conclude that the membrane protein is a novel benzoate transport protein. PMID- 29756745 TI - Controversies in office-based anesthesia: obstructive sleep apnea considerations. AB - As the number of procedures being performed in the office-based anesthesia (OBA) setting are increasing, so are the number of patients presenting for surgery with obstructive sleep apnea (OSA). There continues to be controversy regarding whether these patients can be safely cared for in the OBA setting. To date, no national guideline has clearly addressed this issue and while some have extrapolated lessons from what has been published for OSA in the ambulatory surgery center (ASC) setting, some argue that there is a significant difference in the availability of resources in the ASC versus the OBA setting. Those opposing OSA patients for OBA setting point to the prevalence of "practice drift," and no federal oversight as overarching reasons why the OBA is not an appropriate setting. Proponents of the OBA setting argue that a well-equipped OBA can have similar resources, and therefore similar outcomes, as an OR in the ASC setting. In this paper we explore the divergent views on this topic and present some recommendations based on best evidence. PMID- 29756746 TI - Factors influencing consent to organ donation after brain death certification: a survey of 29 Intensive Care Units. AB - BACKGROUND: Family refusal (FR) to heart beating donation (HBD) in Intensive Care Unit (ICU) is increasing in recent years with a significant impact on the number of transplantable organs. Fostering setting humanization, quality of relationships, respect for will and family reliance towards ICU could be relevant in containing FR to organ donation (OD) in ICU. Our aims were to highlight the effects of structural features of ICUs and humanization determinants on FR in HBD process, and to describe visiting policies, structure and modalities of support in ICUs. METHODS: A survey was conducted among all the ICUs of the Tuscany Region included in the National Transplant System of the Ministry of Health in Italy. Data on ICUs' general and architectural characteristics, visiting policies and support for families were collected. Baseline characteristics of brain dead certified patients (BDCPs) were retrieved from the Registry of the Regional Transplant Centre. RESULTS: Twenty-nine (93.5%) ICUs out of 31 completed the survey. 330 BDCPs were managed during 2016 in the ICUs studied, with an opposition rate of 33.3%. The following independent factors for opposition emerged: BDCPs' age (OR=1.025; 95% CI: 1.007-1.042; P=0.005), ICU length of stay (LOS) (OR=1.065; 95% CI: 1.005-1.128; P=0.034) and the availability of an ICU team trained in procurement (OR=0.472; 95% CI: 0.275-0.811; P=0.007). CONCLUSIONS: Older age of BDCPs and a prolonged ICU LOS resulted in FR. ICU team specific education emerged as the only modifiable protective factor for oppositions, thus continuous and in-depth training programs for physicians and nurses could be of importance in preventing FR. PMID- 29756747 TI - Common controversies surrounding anesthesia for procedures in the Interventional Pulmonology Suite. AB - The number of anesthetics for both simple diagnostic and complex therapeutic procedures being performed in non-operating room locations (NORA) in dedicated Interventional Pulmonology Suites have been increasing in the past few years. Anesthesiologists must be familiar with the demands necessitated by the procedures performed by the interventionists and tailor the anesthetic to create a still field while carefully considering the patient's altered pharmacokinetics and reduced cardio-pulmonary function and choose a technique that allows prompt recovery and early discharge in these patients, many of whom are elderly and frail. In this article we will address controversies surrounding the use of topical analgesia in patients already anesthetized by a TIVA technique and the questions of choice of muscle relaxants and reversal agents and standard of monitoring during these procedures. PMID- 29756748 TI - MU-opioid receptor genetic polymorphisms and duration of epidural fentanyl analgesia during early labor. AB - BACKGROUND: Epidural fentanyl is commonly used for initiation of early labor analgesia. The aim of this prospective study is to test the hypothesis that duration of epidural fentanyl analgesia differs in nulliparous women requesting epidural analgesia in early labor who are variant allele carriers of the OPRM1 SNVs 118A>G rs1799971, IVS2+31G>A rs9479757, and IVS2+691G>C rs2075572. METHODS: Two hundred and twenty parturients who received epidural analgesia with fentanyl were included in the 118A>G analysis, and a 196 sub-cohort was included in the IVS2+31G>A and IVS2+691G>C exploratory analysis. Peripheral blood DNA was genotyped using Taqman allele discrimination assays. RESULTS: One hundred and seventy-four subjects (79%; 95% CI: 74-84) were homozygous for the wild type OPRM1 118A>G SNV (AA), and forty-six subjects (21%; 95% CI: 16-26) were heterozygous AG (N.=40) or homozygous GG (N.=6) for the variant allele. The minor allele frequency (MAF) was hence 12%. The MAFs for the IVS2+31G>A and IVS2+691G>C SNVs in the sub-cohort of 196 participants were 5% and 59% respectively. There was no significant difference in duration of epidural fentanyl analgesia for the three SNVs (161+/-68 and 143+/-51 min for wild type and allele carriers of the 118A>G SNV respectively [P=0.08]). Similarly, no significant differences were shown with the visual analog scale scores, side effects, and satisfaction for each of the three SNVs. CONCLUSIONS: OPRM1 SNVs did not affect the duration of epidural fentanyl administered for early labor analgesia in nulliparous women. These results should be confirmed in patients receiving epidural opioids in other clinical settings. PMID- 29756749 TI - Oral flurbiprofen spray effectively reduces postoperative sore throat and hoarseness: a prospective, randomized, double blind, placebo-controlled study. AB - BACKGROUND: Sore throat and hoarseness are common complications after surgery. Flurbiprofen spray has been successfully used for treatment of oral inflammations, but its effects on postoperative sore throat and hoarseness are unknown. We conducted this study to evaluate the effectiveness of flurbiprofen spray on postoperative sore throat and hoarseness, by comparing it with benzydamine hyrdrochloride spray and placebo. METHODS: One hundred fifty patients who were scheduled to undergo elective ear surgery were enrolled. Patients were randomized to three groups of 50 patients each; flurbiprofen oral spray, benzydamine hydrochloride oral spray and placebo spray groups. Patients received sprays just before intubation, and the incidence and severity of postoperative sore throat and hoarseness were evaluated by a blinded investigator at 0,1,6 and 24-hour post extubation. Patients were also questioned for possible side effects at all time points. RESULTS: The sore throat severity scores were significantly lower in treatment groups when compared to placebo group at all time points (p=0.003x10-8). Similarly, the incidence of sore throat was significantly lower in both of the treatment groups (p=0.007x10-4). The incidence of hoarseness and hoarseness scores were significantly lower in treatment groups when compared to placebo group (p=0.006x10-5 and p=0.005x10-4, respectively). While none of the patients complained of any adverse effects in flurbiprofen group, only two patients in benzydamine hydrochloride group experienced numbness. CONCLUSIONS: Both oral flurbiprofen and benzydamine hydrochloride sprays were found to be more effective than placebo in decreasing the incidence and severity of postoperative sore throat and hoarseness, with no adverse effects. PMID- 29756750 TI - Validation of the PMD100 and its NOL Index to detect nociception at different infusion regimen of remifentanil in patients under general anesthesia. AB - BACKGROUND: The NOL index is based on multiparametric analysis of heart rate (HR), skin conductance, wave plethysmography, and their time derivative. The aim of this study was to evaluate the NOL to detect standardized nociceptive stimuli with various remifentanil dosages under general anesthesia. METHODS: A prospective, observational study at a single center (NCT02602379) included 40 ASA I to III patients undergoing laparotomy under remifentanil-desflurane anesthesia with epidural analgesia. A tetanic stimulation was applied (forearm) at remifentanil intravenous (IV) infusion of 0.005, 0.05, 0.1, and 0.15 ug/kg/min. NOL and its variations were compared with other parameters namely heart rate, mean arterial pressure, Bispectral Index, and Analgesia Nociception Index (ANI). Receiver operating characteristic (ROC) curves were plotted to assess the response to both intubation and standardized stimulus under remifentanil infusion of 0.005 ug/kg/min. RESULTS: The post-stimulation NOL values at remifentanil doses of 0.005, 0.05, 0.1 and 0.15 ug/kg/min (39 [23-55], 15 [7-30], 8 [4-14] and 8.5 [4-15]) were significantly higher than pre-stimulation counterparts (P<0.0001). For all other parameters, there was also significant difference between pre- and post-stimulation values at all remifentanil dosages (P<0.0001). Area under the ROC curve (AUC) for the NOL during standardized stimulation was larger than for all other parameters at the exception of ANI (P=0.94). The AUC of NOL for nociception during tracheal intubation was greater (0.93 vs. 0.84 and 0.64 for ANI and HR, respectively). CONCLUSIONS: NOL monitoring is a promising index to assess the level of nociception in patients under general anesthesia. PMID- 29756751 TI - Reimagining the Risk of Long-Term Care. AB - U.S. law and policy on long-term care fail to address the insecurityAmerican families face due to prolonged illness and disability-a problem thatgrows more serious as the population ages and rates of disability rise. ThisArticle argues that, even worse, we have focused on only part of the problem. Itilluminates two ways that prolonged disability or illness can create insecurity.The first arises from the risk of becoming disabled or sick and needing long-termcare, which could be called "care-recipient" risk. The second arises out of therisk of becoming responsible for someone else's care, which I call "next-friend"risk. The law and social welfare policy has focused on the first, but this Articleargues that the second equally threatens the wellbeing of American families.While attempting to mitigate care-recipient risk, in fact, the law has steadilyexpanded next-friend risk, by reinforcing a structure of long-term care that reliesheavily on informal caregiving. Millions of informal caregivers face financialand nonmonetary harms that deeply threaten their own long-term security. Theseharms are disproportionately experienced by people who are alreadyvulnerable-women, minorities, and the poor. Scholars and policymakers havecatalogued and critiqued these costs but treat them as an unfortunate byproduct ofan inevitable system of informal care.This Article argues that if we, instead, understand becoming responsible forthe care of another as a social risk-just as we see the chance that a person willneed long-term care as a risk-it could fundamentally shift the way we approachlong-term care policy. In risk-theory terms, this Article proposes we reimaginethe risk of long-term care. PMID- 29756752 TI - Rehabilitation, Education, and the Integration of Individuals with Severe Brain Injury into Civil Society: Towards an Expanded Rights Agenda in Response to New Insights from Translational Neuroethics and Neuroscience. AB - Many minimally conscious patients are segregated in nursinghomes, and are without access to rehabilitative technologies that couldhelp them reintegrate into their communities. In this Article, we argue thatpersons in a minimally conscious state or who have the potential toprogress to such a state must be provided rehabilitative services instead ofbeing isolated in custodial care. The right to rehabilitative technologiesfor the injured brain stems by analogy to the expectation of free publiceducation for children and adolescents, and also by statute under theAmericans with Disabilities Act and under Supreme Court jurisprudence,namely the leading deinstitutionalization case, Olmstead v. L.C. ex rel.Zimring. PMID- 29756753 TI - An Evidence-Based Objection to Retributive Justice. AB - Advancements in neuroscience and related fields are beginning to show,with increasing clarity, that certain human behaviors stem from uncontrolled,mechanistic causes. These discoveries beg the question: If a given behaviorresults from some combination of biological predispositions, neurologicalcircumstances, and environmental influences, is that action unwilled andtherefore absolved of all attributions of credit, blame, and responsibility? Anumber of scholars in law and neuroscience who answer "yes" have consideredhow the absence of free will should impact criminal law's willingness to justifypunishments on the basis of retribution, with some arguing that criminal lawought to dispense with retributive justice because the concept of blameworthinessis out of touch with scientific reality. This Note posits a more practical reason forreform by reviewing available empirics on the way people perceive humanagency. The research suggests that as the science of human agency becomesincreasingly vivid and reductionistic, laypeople will become proportionally lesswilling to attribute blame, and these shifting societal intuitions will ultimatelydiminish criminal law's moral credibility. The practical effects of low moralcredibility might include diminished compliance, cooperation, and acquiescencewith criminal laws, as well as increased general deviance. Importantly, this Noteobserves that these effects will likely manifest even if people retain a belief infree will. Further, ontological reality plays no part in this Note's argument;whether we in fact have free will is irrelevant. This Note instead contributes tothe discourse by highlighting the implications of oncoming shifts in layconceptions of both particular behaviors and the natural world writ large. PMID- 29756754 TI - A Breakthrough with the TPP: The Tobacco Carveout. PMID- 29756755 TI - Revisiting Incentive-Based Contracts. AB - Incentive-based pay is rational, intuitive, and popular. Agency theory tells usthat a principal seeking to align its incentives with an agent's should be able tosimply pay the agent to achieve the principal's desired results. Indeed, thisstrategy has long been used across diverse industries-from executivecompensation to education, professional sports to public service-but with mixedresults. Now a new convert to incentive compensation has appeared on the scene:the United States' behemoth health-care industry. In many ways, the incentivemismatch story is the same. Insurance companies and employers are concernedabout constraining the cost of care, and patients are concerned about quality ofcare. Physicians lack an adequate financial incentive to pay attention to either.Health care's recent move away from the traditional fee-for servicecompensation model to incentive pay is perhaps unsurprising.But there is a problem: mixed preliminary evidence and potential mal-effectson vulnerable third party patients. This Article employs a new lens-the legaland behavioral literature on optimal contract specificity-to suggest whyincentive pay is problematic and why the health-care experience will be nodifferent than other industries. The use of incentive pay is a change in contractdraftingstrategy, a decision to write a more detailed, control-based contractrather than one that relies on discretion. The contracts literature suggests that thisstrategy will only work well where simple compliance is the goal rather thancreativity or innovation. The health industry will not succeed in implementingincentive pay better than other industries have. What it needs is to recognize thelimits of incentive pay and implement it sparingly. The new TrumpAdministration may be particularly primed to heed this call. PMID- 29756756 TI - Regulatory Disruption and Arbitrage in Health-Care Data Protection. AB - This article explains how the structure of U.S. health-care data protection(specifically its sectoral and downstream properties) has led to a chronicallyuneven policy environment for different types of health-care data. It examinesclaims for health-care data protection exceptionalism and competing demandssuch as data liquidity. In conclusion, the article takes the position that healthcare-data exceptionalism remains a valid imperative and that even currentconcerns about data liquidity can be accommodated in an exceptional protectivemodel. However, re-calibrating our protection of health-care data residingoutside of the traditional health-care domain is challenging, currently evenpolitically impossible. Notwithstanding, a hybrid model is envisioned withdownstream HIPAA model remaining the dominant force within the health caredomain, but being supplemented by targeted upstream and point-of useprotections applying to health-care data in disrupted spaces. PMID- 29756758 TI - Highly Active and Durable Core-Shell fct-PdFe@Pd Nanoparticles Encapsulated NG as an Efficient Catalyst for Oxygen Reduction Reaction. AB - Development of highly active and durable catalysts for oxygen reduction reaction (ORR) alternative to Pt-based catalyst is an essential topic of interest in the research community but a challenging task. Here, we have developed a new type of face-centered tetragonal (fct) PdFe-alloy nanoparticle-encapsulated Pd (fct PdFe@Pd) anchored onto nitrogen-doped graphene (NG). This core-shell fct PdFe@Pd@NG hybrid is fabricated by a facile and cost-effective technique. The effect of temperature on the transformation of face-centered cubic (fcc) to fct structure and their effect on ORR activity are systematically investigated. The core-shell fct-PdFe@Pd@NG hybrid exerts high synergistic interaction between fct PdFe@Pd NPs and NG shell, beneficial to enhance the catalytic ORR activity and excellent durability. Impressively, core-shell fct-PdFe@Pd@NG hybrid exhibits an excellent catalytic activity for ORR with an onset potential of ~0.97 V and a half-wave potential of ~0.83 V versus relative hydrogen electrode, ultrahigh current density, and decent durability after 10 000 potential cycles, which is significantly higher than that of marketable Pt/C catalyst. Furthermore, the core shell fct-PdFe@Pd@NG hybrid also shows excellent tolerance to methanol, unlike the commercial Pt/C catalyst. Thus, these findings open a new protocol for fabricating another core-shell hybrid by facile and cost-effective techniques, emphasizing great prospect in next-generation energy conversion and storage applications. PMID- 29756759 TI - ZnSe Microsphere/Multiwalled Carbon Nanotube Composites as High-Rate and Long Life Anodes for Sodium-Ion Batteries. AB - Sodium-ion batteries (SIBs) are considered as one of the most favorable alternative devices for sustainable development of modern society. However, it is still a big challenge to search for proper anode materials which have excellent cycling and rate performance. Here, zinc selenide microsphere and multiwalled carbon nanotube (ZnSe/MWCNT) composites are prepared via hydrothermal reaction and following grinding process. The performance of ZnSe/MWCNT composites as a SIB anode is studied for the first time. As a result, ZnSe/MWCNTs exhibit excellent rate capacity and superior cycling life. The capacity retains as high as 382 mA h g-1 after 180 cycles even at a current density of 0.5 A g-1. The initial Coulombic efficiency of ZnSe/MWCNTs can reach 88% and nearby 100% in the following cycles. The superior electrochemical properties are attributed to continuous electron transport pathway, improved electrical conductivity, and excellent stress relaxation. PMID- 29756757 TI - Suffrage for People with Intellectual Disabilities and Mental Illness: Observations on a Civic Controversy. AB - Most electoral democracies, including forty-three states in the United States,deny people the right to vote on the basis of intellectual disability or mentalillness. Scholars in several fields have addressed these disenfranchisements,including legal scholars who analyze their validity under U.S. constitutional lawand international-human-rights law, philosophers and political scientists whoanalyze their validity under democratic theory, and mental-health researcherswho analyze their relationship to scientific categories. This Note reviews thecurrent state of the debate across these fields and makes three contentions: (a)pragmatic political considerations have blurred the distinction betweendisenfranchisement provisions based on cognitive capacity and those based onpersonal status; (b) proposals that advocate voting by proxy trivialize the broadcivic purpose of the franchise; and (c) the persistence of disenfranchisement onthe basis of mental illness inevitably contributes to silencing socially disfavoredviews and lifestyles. Accordingly, the Note cautions reformers againstadvocating for capacity assessment or proxy voting, and emphasizes theimportance of disassociating the idea of mental illness from voting capacity. PMID- 29756760 TI - Preclinical Antiviral Testing for Dengue Virus Infection in Mouse Models and Its Association with Clinical Studies. AB - At present, there is no licensed antiviral drug against dengue virus (DENV) infection. Mouse models of DENV infection have been widely used for preclinical evaluation of antivirals. However, only in a few instances so far have the data obtained from preclinical mouse model testing been associated with data from clinical studies in humans. In this Review, we focus on the antiviral drugs targeting viral replication that have been tested in animals/humans and discuss how preclinical drug evaluation in suitable mouse/animal models may be more fruitfully used to inform early phase clinical testing. PMID- 29756761 TI - Digital Microarrays: Single-Molecule Readout with Interferometric Detection of Plasmonic Nanorod Labels. AB - DNA and protein microarrays are a high-throughput technology that allow the simultaneous quantification of tens of thousands of different biomolecular species. The mediocre sensitivity and limited dynamic range of traditional fluorescence microarrays compared to other detection techniques have been the technology's Achilles' heel and prevented their adoption for many biomedical and clinical diagnostic applications. Previous work to enhance the sensitivity of microarray readout to the single-molecule ("digital") regime have either required signal amplifying chemistry or sacrificed throughput, nixing the platform's primary advantages. Here, we report the development of a digital microarray which extends both the sensitivity and dynamic range of microarrays by about 3 orders of magnitude. This technique uses functionalized gold nanorods as single-molecule labels and an interferometric scanner which can rapidly enumerate individual nanorods by imaging them with a 10* objective lens. This approach does not require any chemical signal enhancement such as silver deposition and scans arrays with a throughput similar to commercial fluorescence scanners. By combining single-nanoparticle enumeration and ensemble measurements of spots when the particles are very dense, this system achieves a dynamic range of about 6 orders of magnitude directly from a single scan. As a proof-of-concept digital protein microarray assay, we demonstrated detection of hepatitis B virus surface antigen in buffer with a limit of detection of 3.2 pg/mL. More broadly, the technique's simplicity and high-throughput nature make digital microarrays a flexible platform technology with a wide range of potential applications in biomedical research and clinical diagnostics. PMID- 29756762 TI - Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa. AB - The permeability barrier of Gram-negative cell envelopes is the major obstacle in the discovery and development of new antibiotics. In Gram-negative bacteria, these difficulties are exacerbated by the synergistic interaction between two biochemically distinct phenomena, the low permeability of the outer membrane (OM) and active multidrug efflux. In this study, we used Pseudomonas aeruginosa and Escherichia coli strains with controllable permeability barriers, achieved through hyperporination of the OMs and varied efflux capacities, to evaluate the contributions of each of the barriers to protection from antibacterials. We analyzed antibacterial activities of beta-lactams and fluoroquinolones, antibiotics that are optimized for targets in the periplasm and the cytoplasm, respectively, and performed a machine learning-based analysis to identify physicochemical descriptors that best classify their relative potencies. Our results show that the molecular properties selected by active efflux and the OM barriers are different for the two species. Antibiotic activity in P. aeruginosa was better classified by electrostatic and surface area properties, whereas topology, physical properties, and atom or bond counts best capture the behavior in E. coli. In several cases, descriptor values that correspond to active antibiotics also correspond to significant barrier effects, highlighting the synergy between the two barriers where optimizing for one barrier promotes strengthening of the other barrier. Thus, both barriers should be considered when optimizing antibiotics for favorable OM permeability, efflux evasion, or both. PMID- 29756763 TI - Analysis of Ag(I) Biocide in Water Samples Using Anodic Stripping Voltammetry with a Boron-Doped Diamond Disk Electrode. AB - The electroanalytical performance of a new commercial boron-doped diamond disk and a traditional nanocrystalline thin-film electrode were compared for the anodic stripping voltammetric determination of Ag(I). The diamond disk electrode is more flexible than the planar film as the former is compatible with most electrochemical cell designs including those incorporating magnetic stirring. Additionally, mechanical polishing and surface cleaning are simpler to execute. Differential pulse anodic stripping voltammetry (DPASV) was used to detect Ag(I) in standard solutions after optimization of the deposition potential, deposition time and scan rate. The optimized conditions were used to determine the concentration of Ag(I) in a NASA simulated potable water sample and a NIST standard reference solution. The electrochemical results were validated by ICP OES measurements of the same solutions. The detection figures of merit for the disk electrode were as good or superior to those for the thin-film electrode. Detection limits were <=5 MUg L-1 (S/N = 3) for a 120 s deposition period, and response variabilities were <5% RSD. The polished disk electrode presented a more limited linear dynamic range presumably because of the reduced surface area available for metal phase formation. The concentrations of Ag(I) in the two water samples, as determined by DPASV, were in good agreement with the concentrations determined by ICP-OES. PMID- 29756764 TI - Formation Mechanism, Structural, and Upconversion Properties of Alkaline Rare Earth Fluoride Nanocrystals Doped With Yb3+/Er3+ Ions. AB - Ultrasmall (9-30 nm) Yb3+/Er3+-doped, upconverting alkaline rare-earth fluorides that are promising for future applications were synthesized by the microwave assisted hydrothermal method. The formation mechanism was proposed, indicating the influence of the stability of metal ions complexes with ethylenediaminetetraacetic acid on the composition of the product and tendency to form M2REF7 (M0.67RE0.33F2.33) cubic compounds in the M-RE-F systems. Their physicochemical properties (structure, morphology, and spectroscopic properties) are compared and discussed. The obtained nanoparticles exhibited emission of light in the visible spectra under excitation by 976 nm laser radiation. Excitation and emission spectra, luminescence decays, laser energy dependencies, and upconversion quantum yields were measured to determine the spectroscopic properties of prepared materials. The Yb3+/Er3+ pair of ions used as dopants was responsible for an intense yellowish-green emission. The upconversion quantum yields determined for the first time for M2REF7-based materials were 0.0192 +/- 0.001% and 0.0176 +/- 0.001% for Sr2LuF7:Yb3+,Er3+ and Ba2LuF7:Yb3+,Er3+ respectively, the two best emitting samples. These results indicated the prepared materials are good and promising alternatives for the most studied NaYF4:Yb3+,Er3+ nanoparticles. PMID- 29756765 TI - In Situ Lysosomal Cysteine-Specific Targeting and Imaging during Dexamethasone Induced Apoptosis. AB - Herein we utilize the similar though divergent nucleophilic properties of cysteine, homocysteine, and glutathione to achieve the selective detection of cysteine under mildly acidic conditions. This enables the specific in situ detection of lysosomal cysteine. Employing time-dependent fluorescent imaging of probe-labeled A549 cells, we demonstrate that dexamethasone-induced apoptosis is not dependent on lysosomal cysteine. This methodology can thus produce useful information about pathogenesis associated with cysteine and lysosomes. PMID- 29756766 TI - Ribulose Monophosphate Shunt Provides Nearly All Biomass and Energy Required for Growth of E. coli. AB - The ribulose monophosphate (RuMP) cycle is a highly efficient route for the assimilation of reduced one-carbon compounds. Despite considerable research, the RuMP cycle has not been fully implemented in model biotechnological organisms such as Escherichia coli, mainly since the heterologous establishment of the pathway requires addressing multiple challenges: sufficient formaldehyde production, efficient formaldehyde assimilation, and sufficient regeneration of the formaldehyde acceptor, ribulose 5-phosphate. Here, by efficiently producing formaldehyde from sarcosine oxidation and ribulose 5-phosphate from exogenous xylose, we set aside two of these concerns, allowing us to focus on the particular challenge of establishing efficient formaldehyde assimilation via the RuMP shunt, the linear variant of the RuMP cycle. We have generated deletion strains whose growth depends, to different extents, on the activity of the RuMP shunt, thus incrementally increasing the selection pressure for the activity of the synthetic pathway. Our final strain depends on the activity of the RuMP shunt for providing the cell with almost all biomass and energy needs, presenting an absolute coupling between growth and activity of key RuMP cycle components. This study shows the value of a stepwise problem solving approach when establishing a difficult but promising pathway, and is a strong basis for future engineering, selection, and evolution of model organisms for growth via the RuMP cycle. PMID- 29756769 TI - Prediction of New Phase and Electrochemical Properties of Li2S2 for the Application of Li-S Batteries. AB - The intermediate product Li2S2 plays a pivotal role in the charge/discharge process of lithium-sulfur batteries. However, the structural configuration and relevant properties of Li2S2 are unclear. In this work, by using ab initio calculations, we present results of novel phases, average open circuit voltages ( Vocs), and electronic properties of the stable Li2S2. Two new Li2S2 phases are predicted: orthorhombic ( Cmca) and orthorhombic ( Immm) structures. The calculated Vocs of hexagonal ( P63/ mmc), orthorhombic ( Cmca), and orthorhombic ( Immm) are 3.91, 3.95, and 3.88 V, respectively. In particular, the calculated band gap of the Immm structure is about 0.225 eV, which is smaller than that of Li2S. The narrow band gap of Li2S2 derives from the electronic lump between the Li s state and S 3p state for the orthorhombic structure. Therefore, the electronic properties of Li2S2 are markedly influenced by the structural configuration. PMID- 29756767 TI - Spatially Restricting Bioorthogonal Nucleoside Biosynthesis Enables Selective Metabolic Labeling of the Mitochondrial Transcriptome. AB - The cellular RNA pool in animals arises from two separate genomes stored in the nucleus and multiple mitochondria. Chemical methods to track nascent RNA synthesis are unable to distinguish between these two with stringency. Herein, we report that spatially restricting bioorthogonal nucleoside biosynthesis enables, for the first time, selective metabolic labeling of the RNA transcribed in the mitochondria. We envision that this approach could open the door for heretofore impossible analyses of mitochondrial RNA. Beyond our results revealed herein, our approach provides a roadmap for researchers to begin to design strategies to examine biomolecules within subcellular compartments. PMID- 29756768 TI - Facile Soaking Strategy Toward Simultaneously Enhanced Conductivity and Toughness of Self-Healing Composite Hydrogels Through Constructing Multiple Noncovalent Interactions. AB - Tough and stretchable conductive hydrogels are desirable for the emerging field of wearable and implanted electronics. Unfortunately, most existing conductive hydrogels have low mechanical strength. Current strategies to enhance mechanical properties include employing tough host gel matrices or introducing specific interaction between conductive polymer and host gel matrices. However, these strategies often involve additional complicated processes. Here, a simple yet effective soaking treatment is employed to concurrently enhance mechanical and conductive properties, both of which can be facilely tailored by controlling the soaking duration. The significant improvements are correlated with co-occurring mechanism of deswelling and multiple noncovalent interactions. The resulting optimal sample exhibits attractive combination of high water content (75 wt %), high tensile stress (~2.5 MPa), large elongation (>600%), reasonable conductivity (~25 mS/cm), and fast self-healing property with the aid of hot water. The potential application of gel as a strain sensor is demonstrated. The applicability of this method is not limited to conductive hydrogels alone but can also be extended to strengthen other functional hydrogels with weak mechanical properties. PMID- 29756771 TI - Resolution of Lipoprotein Subclasses by Charge Detection Mass Spectrometry. AB - Lipoproteins are micelle-like assemblies that are key players in the pathogenesis of atherosclerosis. High-density lipoprotein (HDL), low-density lipoproteins (LDL), and very low density lipoprotein (VLDL) are the three major classes present in fasting plasma. Within each class, there is a broad size distribution with wide variations in protein and lipid content. The development of better metrics for cardiovascular risk is thought to depend on better characterization of lipoprotein subclasses. Using charge detection mass spectrometry (CDMS), the mass distributions of HDL, LDL, and VLDL have been directly measured for the first time. In the case of HDL, seven distinct subpopulations were resolved using a two-dimensional correlation of charge and mass. The resolved components are assigned to HDL particles containing different numbers of the key structural proteins apolipoprotein A-I and apolipoprotein A-II. PMID- 29756770 TI - Versatile High-Throughput Fluorescence Assay for Monitoring Cas9 Activity. AB - The RNA-guided DNA nuclease Cas9 is now widely used for the targeted modification of genomes of human cells and various organisms. Despite the extensive use of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) systems for genome engineering and the rapid discovery and engineering of new CRISPR-associated nucleases, there are no high-throughput assays for measuring enzymatic activity. The current laboratory and future therapeutic uses of CRISPR technology have a significant risk of accidental exposure or clinical off-target effects, underscoring the need for therapeutically effective inhibitors of Cas9. Here, we develop a fluorescence assay for monitoring Cas9 nuclease activity and demonstrate its utility with S. pyogenes (Spy), S. aureus (Sau), and C. jejuni (Cje) Cas9. The assay was validated by quantitatively profiling the species specificity of published anti-CRISPR (Acr) proteins, confirming the reported inhibition of Spy Cas9 by AcrIIA4 and Cje Cas9 by AcrIIC1 and no inhibition of Sau Cas9 by either anti-CRISPR. To identify drug-like inhibitors, we performed a screen of 189 606 small molecules for inhibition of Spy Cas9. Of 437 hits (0.2% hit rate), six were confirmed as Cas9 inhibitors in a direct gel electrophoresis secondary assay. The high-throughput nature of this assay makes it broadly applicable for the discovery of additional Cas9 inhibitors or the characterization of Cas9 enzyme variants. PMID- 29756772 TI - Hierarchical Two-Dimensional Conductive Metal-Organic Framework/Layered Double Hydroxide Nanoarray for a High-Performance Supercapacitor. AB - A novel hierarchical nanoarray material based on a two-dimensional metal-organic framework (Ni-CAT) and a layered double hydroxide (NiCo-LDH) was fabricated on a nickel foam substrate. By taking advantage of the regular nanostructure and making full use of the high porosity and excellent conductivity, the hybrid material exhibits a high areal capacitance for a supercapacitor (3200 mF cm-2 at 1 mA cm-2). PMID- 29756773 TI - Combined Spectroelectrochemical and Simulated Insights into the Electrogenerated Chemiluminescence Coreactant Mechanism. AB - Electrogenerated chemiluminescence (ECL) based sensors have the intrinsic advantage of having zero theoretical background signal, derived from the electrochemical initiation of the luminescence process. Since the limit of detection (LOD) for sensors is defined as three times the noise of the background over the sensitivity of the system, further improvement to an ECL based detection limit is tied to improving sensitivity. Enhancing ECL sensitivity can be achieved through optimizing the mechanistic or kinetic performance of the reagents. While the mechanism for many luminophore-coreactant pairs have been established, the kinetics for the competing homogeneous reactions responsible for photon emission have not been directly resolved. This is due to the difficulty in experimentally probing and isolating a single homogeneous reaction while multiple simultaneous heterogeneous and homogeneous reactions are occurring. Combining the techniques of spectroelectrochemistry and finite element modeling, we monitor the homogeneous reactions for the coreactant pair, tris(2,2'-bipyridine)ruthenium(II) (Ru(BPY)32+) and tripropylamine (TPA). Corresponding trends found in the experimental absorbance and theoretical concentration profiles demonstrated that the reaction between Ru(BPY)33+ and TPA* intermediates proceeds significantly faster than the other available pathways. The identification of the oxidized intermediates as the dominant electron transfer pathway implies that the screening of luminophore and coreactant pairs that increase the stability of these kinetically labile intermediates would increase ECL sensitivity and ultimately performance. PMID- 29756774 TI - Selection, Identification, and Binding Mechanism Studies of an ssDNA Aptamer Targeted to Different Stages of E. coli O157:H7. AB - Enterohemorrhagic Escherichia coli O157:H7 ( E. coli O157:H7) is known as an important food-borne pathogen related to public health. In this study, aptamers which could bind to different stages of E. coli O157:H7 (adjustment phase, log phase, and stationary phase) with high affinity and specificity were obtained by the whole cell-SELEX method through 14 selection rounds including three counter selection rounds. Altogether, 32 sequences were obtained, and nine families were classified to select the optimal aptamer. To analyze affinity and specificity by flow cytometer, an ssDNA aptamer named Apt-5 was picked out as the optimal aptamer that recognizes different stages of E. coli O157:H7 specifically with the Kd value of 9.04 +/- 2.80 nM. In addition, in order to study the binding mechanism, target bacteria were treated by proteinase K and trypsin, indicating that the specific binding site is not protein on the cell membrane. Furthermore, when we treated E. coli O157:H7 with EDTA, the result showed that the binding site might be lipopolysaccharide (LPS) on the outer membrane of E. coli O157:H7. PMID- 29756775 TI - Heterogeneous Interaction of Various Natural Dust Samples with Isopropyl Alcohol as a Probe VOC. AB - The adsorption properties of mineral dust toward organic molecules are poorly characterized so far. Heterogeneous processes between trace gases and mineral particles can affect the oxidative capacity of the atmosphere as well as constitute additional sources or sinks for these species. The current study investigates the adsorption efficiencies of natural dust samples collected from North and West Africa, Saudi Arabia, and Arizona desert regions toward isopropyl alcohol (IPA), a common organic pollutant released in significant amounts in the atmosphere, which is used here as a probe molecule. Experiments are performed under atmospheric pressure, room temperature 296 K, over the concentration range (0.15-615) * 1013 molecules cm-3, and in the relative humidity (RH) range (0.01 85)%. The kinetic measurements are conducted inside a U-shaped flow reactor using zero air as bath gas and a chemical ionization mass spectrometer for real-time gas-phase monitoring. Kinetic and surface parameters such as initial uptake coefficients (gamma0) and adsorption equilibrium constants are measured. gamma0 is found to be independent of the IPA gas-phase concentration. However, concerning RH, gamma is independent up to ca. 20%, but a dramatic decrease is observed above that threshold implying a competition between water molecules and IPA after the formation of a water monolayer on the dust sample. These results are simulated using an empirical expression of the form gammaRH = gammadry - aRH b that allows the extrapolation of the uptake coefficient under any tropospheric RH conditions. Our uptake coefficient values show a linear correlation with the elemental Al/Si and Fe/Si ratios of the natural dusts studied. This was confirmed when comparing with data on inorganic species gathered from a comprehensive literature review (no such data exist for organics). To the best of our knowledge, this work is the first to demonstrate that initial uptakes are linearly correlated with the Al/Si ratio for both organic and inorganic species. PMID- 29756777 TI - Sensitive Assays by Nucleophile-Induced Rearrangement of Photoactivated Diarylethenes. AB - Upon light-induced isomerization, diarylethenes (DAEs) equipped with reactive aldehyde moieties rearrange selectively in the presence of amines, accompanied by decoloration. In a comprehensive study, the probe structure was optimized with regard to its inherent reactivity in the nucleophile-triggered rearrangement reaction. Detailed structure-reactivity relationships could be derived, in particular with regard to the type of integrated (het)aryl moieties as well as the location of the formyl residue, and the probes' intrinsic reactivity with primary and secondary amines was optimized. Utilizing an ancillary base, the initially formed rearrangement product can engage in a subsequent catalytic cycle, leading to an amplified decoloration process. This additional catalytic pathway allows us to enhance the sensitivity of our method and successfully discriminate between amines and thiols. Moreover, probes that exhibit strong analyte-induced fluorescence modulation have been designed to further decrease the detection limit by using a more sensitive read-out. The optimized DAE probes are promising molecular components for future programmable sensing materials and devices. PMID- 29756778 TI - Omnidispersible Hedgehog Particles with Multilayer Coatings for Multiplexed Biosensing. AB - Hedgehog particles (HPs) replicating the spiky geometry of pollen grains revealed surprisingly high dispersion stability regardless of whether their hydrophobicity/hydrophilicity matches that of the media or not. This property designated as omnidispersibility is attributed to the drastic reduction of van der Waals interactions between particles coated with stiff nanoscale spikes as compared to particles of the same dimensions with smooth surfaces. One may hypothesize but it remains unknown, however, whether HPs modified with polymers or nanoparticles (NPs) would retain this property. Surface modifications of the spikes will expand the functionalities of HPs, making possible their utilization as omnidispersible carriers. Here, we show that HPs carrying dense conformal coatings made by layer-by-layer (LBL/LbL) assembly maintain dispersion stability in environments of extreme polarity and ionic strength. HPs, surface-modified by multilayers of polymers and gold NPs, are capable of surface-enhanced Raman scattering (SERS) and overcome the limited colloidal stability of other SERS probes. The agglomeration resilience of HPs leads to a greater than one order of magnitude increase of SERS intensity as compared to colloids with smooth surfaces and enables simultaneous detection of several targets in complex media with high ionic strength. Omnidispersible optically active colloids open the door for rapid multiplexed SERS analysis in biological fluids and other applications. PMID- 29756776 TI - 19F Magic Angle Spinning NMR Spectroscopy and Density Functional Theory Calculations of Fluorosubstituted Tryptophans: Integrating Experiment and Theory for Accurate Determination of Chemical Shift Tensors. AB - The 19F chemical shift is a sensitive NMR probe of structure and electronic environment in organic and biological molecules. In this report, we examine chemical shift parameters of 4F-, 5F-, 6F-, and 7F-substituted crystalline tryptophan by magic angle spinning (MAS) solid-state NMR spectroscopy and density functional theory. Significant narrowing of the 19F lines was observed under fast MAS conditions, at spinning frequencies above 50 kHz. The parameters characterizing the 19F chemical shift tensor are sensitive to the position of the fluorine in the aromatic ring and, to a lesser extent, the chirality of the molecule. Accurate calculations of 19F magnetic shielding tensors require the PBE0 functional with a 50% admixture of a Hartree-Fock exchange term, as well as taking account of the local crystal symmetry. The methodology developed will be beneficial for 19F-based MAS NMR structural analysis of proteins and protein assemblies. PMID- 29756779 TI - Solvation Dynamics of HEHEHP Ligand at the Liquid-Liquid Interface. AB - Actinide-lanthanide separation (ALSEP) has been a topic of interest in recent years as it has been shown to selectively extract problematic metals from spent nuclear fuel. However, the process suffers from slow kinetics, prohibiting it from being applied to nuclear facilities. In an effort to improve the process, many fundamental studies have been performed, but the majority have only focused on the thermodynamics of separation. Therefore, to understand the mechanism behind the ALSEP process, molecular dynamics (MD) simulations were utilized to obtain the dynamics and solvation characteristics for an organic extractant, 2 ethylhexylphosphonic acid mono-2-ethylhexyl ester (HEHEHP). Simulations were conducted with both pure and biphasic solvent systems to evaluate the complex solvent interactions within the ALSEP extraction method. The MD simulations revealed solvation and dynamical behaviors that are consistent with the experimentally observed chemical properties of HEHEHP for the pure solvent systems (e.g., hydrophobic/hydrophilic behaviors of the polar head group and alkyl chains and dimer formation between the ligands within an organic solvent). When present in a biphasic solvent system, interfacial behaviors of the ligand revealed that, at low concentrations, the alkyl side chains of HEHEHP were parallel to the interfacial plane. Upon increasing the concentration to 0.75 M, tendency for the parallel orientation decreased and a more perpendicular-like orientation was observed. Analysis of ligand solvation energies in different solvents through the thermodynamic integration method demonstrated favorability toward n-dodecane and biphasic solvents, which is in agreement with the previous experimental findings. PMID- 29756780 TI - Copper(I)-Catalyzed N-O Bond Formation through Vinyl Nitrene Mediated Pathway under Mild Conditions. AB - Copper(I)-catalyzed N-O bond formation reactions through vinyl nitrene-mediated pathway were described. The reactions of N-alkoxylbenzamides and 2 H-azirines afforded alpha-amino oxime ethers in good to excellent yields at room temperature, which involved the cleavage of C-N and N-O bonds and the construction of new N-O and C-N bonds. It offers an efficient, regio- and stereoselective synthetic route for alpha-amino oxime ethers. PMID- 29756781 TI - Frequency-Swept Integrated and Stretched Solid Effect Dynamic Nuclear Polarization. AB - We investigate a new time domain approach to dynamic nuclear polarization (DNP), the frequency-swept integrated solid effect (FS-ISE), utilizing a high power, broadband 94 GHz (3.35 T) pulse EPR spectrometer. The bandwidth of the spectrometer enabled measurement of the DNP Zeeman frequency/field profile that revealed two dominant polarization mechanisms, the expected ISE, and a recently observed mechanism, the stretched solid effect (S2E). At 94 GHz, despite the limitations in the microwave chirp pulse length (10 MUs) and the repetition rate (2 kHz), we obtained signal enhancements up to ~70 for the S2E and ~50 for the ISE. The results successfully demonstrate the viability of the FS-ISE and S2E DNP at a frequency 10 times higher than previous studies. Our results also suggest that these approaches are candidates for implementation at higher magnetic fields. PMID- 29756782 TI - Regioselective Synthesis of Acylated N-Heterocycles via the Cascade Reactions of Saturated Cyclic Amines with 2-Oxo-2-arylacetic Acids. AB - A highly regioselective and versatile synthesis of acylated N-heterocycles from the cascade reactions of saturated cyclic amines with 2-oxo-2-arylacetic acids is presented. Mechanistically, the formation of the title compounds involves first a C(sp3)-H bond dehydrogenation of cyclic amine to give an enamine intermediate followed by its cross coupling with the acyl species in situ generated through the decarboxylation of 2-oxo-2-arylacetic acid. Interestingly, in this cascade process, the copper catalyst is believed to play a crucial role not only in dehydrogenation but also in the decarboxylation and cross coupling reaction. To the best of our knowledge, this is the first example in which different classes of acylated N-heterocycles were directly prepared from the readily available saturated cyclic amines by using 2-oxo-2-arylacetic acids as the noncorrosive and easy to handle acylating reagents. Compared with literature methods, this new protocol has the advantages such as readily obtainable substrates, broad substrate scope, high efficiency, and good selectivity. PMID- 29756783 TI - Structure and Enzymatic Properties of a Two-Domain Family GH19 Chitinase from Japanese Cedar ( Cryptomeria japonica) Pollen. AB - CJP-4 is an allergen found in pollen of the Japanese cedar Cryptomeria japonica. The protein is a two-domain family GH19 (class IV) Chitinase consisting of an N terminal CBM18 domain and a GH19 catalytic domain. Here, we produced recombinant CJP-4 and CBM18-truncated CJP-4 (CJP-4-Cat) proteins. In addition to solving the crystal structure of CJP-4-Cat by X-ray crystallography, we analyzed the ability of both proteins to hydrolyze chitin oligosaccharides, (GlcNAc) n, polysaccharide substrates, glycol chitin, and beta-chitin nanofiber and examined their inhibitory activity toward fungal growth. Truncation of the CBM18 domain did not significantly affect the mode of (GlcNAc) n hydrolysis. However, significant effects were observed when we used the polysaccharide substrates. The activity of CJP-4 toward the soluble substrate, glycol chitin, was lower than that of CJP-4 Cat. In contrast, CJP-4 exhibited higher activity toward beta-chitin nanofiber, an insoluble substrate, than did CJP-4-Cat. Fungal growth was strongly inhibited by CJP-4 but not by CJP-4-Cat. These results indicate that the CBM18 domain assists the hydrolysis of insoluble substrate and the antifungal action of CJP-4 Cat by binding to chitin. CJP-4-Cat was found to have only two loops (loops I and III), as reported for ChiA, an allergenic class IV Chitinase from maize. PMID- 29756784 TI - Valley Manipulation by Optically Tuning the Magnetic Proximity Effect in WSe2/CrI3 Heterostructures. AB - Monolayer valley semiconductors, such as tungsten diselenide (WSe2), possess valley pseudospin degrees of freedom that are optically addressable but degenerate in energy. Lifting the energy degeneracy by breaking time-reversal symmetry is vital for valley manipulation. This has been realized by directly applying magnetic fields or via pseudomagnetic fields generated by intense circularly polarized optical pulses. However, sweeping large magnetic fields is impractical for devices, and the pseudomagnetic fields are only effective in the presence of ultrafast laser pulses. The recent rise of two-dimensional (2D) magnets unlocks new approaches to controlling valley physics via van der Waals heterostructure engineering. Here, we demonstrate the wide continuous tuning of the valley polarization and valley Zeeman splitting with small changes in the laser-excitation power in heterostructures formed by monolayer WSe2 and 2D magnetic chromium triiodide (CrI3). The valley manipulation is realized via the optical control of the CrI3 magnetization, which tunes the magnetic exchange field over a range of 20 T. Our results reveal a convenient new path toward the optical control of valley pseudospins and van der Waals magnetic heterostructures. PMID- 29756785 TI - Prediction of Enhanced Catalytic Activity for Hydrogen Evolution Reaction in Janus Transition Metal Dichalcogenides. AB - Significant efforts have been made in improving the hydrogen evolution reaction (HER) catalytic activity in transition metal dichalcogenides (TMDs), which are promising nonprecious catalysts. However, previous attempts have exploited possible solutions to activate the inert basal plane, with little improvement. Among them, the most successful modification requires a careful manipulation of vacancy concentration and strain simultaneously. To fully realize the promise of TMD catalysts for HER in an easier and more effective way, a new means in tuning the HER catalytic activity is needed. Herein, we propose exploiting the inherent structural asymmetry in the recently synthesized family of Janus TMDs as a new means to stimulate HER activity. We report a density functional theory (DFT) study of various Janus TMD monolayers as HER catalysts, and identify the WSSe system as a promising candidate, where the basal plane can be activated without large applied tensile strains and in the absence of significant density of vacancies. We predict that it is possible to realize a strain-free Janus TMD based catalyst that can readily provide promising intrinsic HER catalytic performance. The calculated density of states and electronic structures reveal that the introduction of in-gap states and a shift in the Fermi level in hydrogen adsorbed systems due to Janus asymmetry is the origin of enhanced HER activity. Our results should pave the way to design high-performance and easy-accessible TMD-based HER catalysts. PMID- 29756786 TI - Rhodium(III)-Catalyzed Cascade [5 + 1] Annulation/5-exo-Cyclization Initiated by C-H Activation: 1,6-Diynes as One-Carbon Reaction Partners. AB - The catalytic [5 + 1] annulation/5-exo-cyclization reaction of amidines with diynes is reported herein. This protocol provides highly atom-economical access to fabricate two nitrogen-containing heterocycles in one step with high efficiency and selectivity. Significantly, this reaction represents the first example of using diyne as a one-carbon reaction partner in C-H functionalization. Kinetic isotope effects suggested that the catalytic cycle of this reaction is initiated by the cleavage of the ortho C-H bond in the N-phenyl ring of amidines, which is likely involved in the rate-limiting step. Calculations based on density functional theory (DFT) indicated that C-H activation and the formation of Rh(V) species via 5-exo-cyclization could be vital processes for this cascade transformation. PMID- 29756787 TI - Work stressors and partner social undermining: Comparing negative affect and psychological detachment as mechanisms. AB - With the mounting evidence that employees' work experiences spill over into the family domain and cross over to family members, it is important to understand the underlying mechanism through which work experiences affect the family domain and what factors may alleviate the adverse impact of work stress. Expanding previous research that mainly focused on the affect-based mechanism (negative affect), the present research investigated a resource-based mechanism (psychological detachment from work) in the relationship linking two work stressors (high workload and workplace incivility) with social undermining toward the partner at home. We also explored the relative strength of the mediating effects of the two mechanisms. In addition, we tested whether relationship satisfaction moderates the proposed effect of detachment on partner undermining. We tested these research questions using two studies with differing designs: a five-wave longitudinal study (N = 470) and a multisource study (N = 131). The results suggest that stressful work experiences affect the family domain via lack of detachment as well as negative affect, that the two pathways have comparable strength, and that high relationship satisfaction mitigates the negative effect of lack of detachment on partner undermining. In sum, this research extends the spillover-crossover model by establishing that poor psychological detachment from work during leisure time is an additional mechanism that links work and family. (PsycINFO Database Record PMID- 29756788 TI - Identifying job characteristics related to employed women's breastfeeding behaviors. AB - For employed mothers of infants, reconciliation of work demands and breastfeeding constitutes a significant challenge. The discontinuation of breastfeeding has the potential to result in negative outcomes for the mother (e.g., higher likelihood of obesity), her employer (e.g., increased absenteeism), and her infant (e.g., increased risk of infection). Given previous research findings identifying return to work as a major risk factor for breastfeeding cessation, we investigate what types of job characteristics relate to women's intentions to breastfeed shortly after giving birth and women's actual breastfeeding initiation and duration. Using job titles and job descriptors contained in a large Australian longitudinal cohort data set (N = 809), we coded job titles using the U.S. Department of Labor (DOL)'s Occupational Information Network (O*NET) database and extracted job characteristics. Hazardous working conditions and job autonomy were identified as significant determinants of women's breastfeeding intentions, their initiation of breastfeeding, and ultimately their breastfeeding continuation. Hence, we recommend that human resource professionals, managers, and public health initiatives provide breastfeeding-supportive resources to women who, based on their job characteristics, are at high risk to prematurely discontinue breastfeeding to ensure these mothers have equal opportunity to reap the benefits of breastfeeding. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29756789 TI - Emotional demands and alcohol use in corrections: A moderated mediation model. AB - This study examined predictors of alcohol use (i.e., drinking quantity and frequency) in a sample of correctional officers (COs). More specifically, based on the idea of drinking to cope, we predicted an indirect effect of emotional demands at work on COs' drinking through employee burnout (i.e., exhaustion and disengagement). We further proposed that this indirect effect would be moderated by recovery experiences outside of work (i.e., psychological detachment and mastery). Participants were 1,039 COs from 14 state correctional facilities. Results indicate that emotional demands were positively associated with burnout, burnout was positively associated with COs' drinking, and emotional demands had a significant indirect effect on COs' drinking through burnout. In addition, detachment moderated the indirect effect of emotional demands on drinking quantity through exhaustion (but not disengagement), whereas mastery moderated the indirect effect of emotional demands on drinking frequency through disengagement (but not exhaustion). Specifically, the strength of the indirect effects were strongest at the lowest levels of recovery experiences, suggesting that low levels of recovery from work may represent a significant risk factor for drinking to cope in COs. Therefore, COs should be encouraged to participate in activities outside of work that facilitate recovery from work demands. (PsycINFO Database Record PMID- 29756790 TI - A manual-based phenomenological art therapy for individuals diagnosed with moderate to severe depression (PATd): A randomized controlled study. AB - OBJECTIVE: This study investigated the effects of manual-based Phenomenological Art Therapy for individuals living with depression in addition to treatment as usual (PATd/TAU) compared with only treatment as usual (TAU) for individuals diagnosed with moderate to severe depression. METHOD: 79 adults (men = 29.1%) were included in this randomized-controlled-trial (RCT), multicenter study in Sweden with an intention-to-treat design. Participants were randomized into either the PATd/TAU-group (n = 43) or TAU-group (n = 36). Data were collected at baseline and at end of treatment. The main outcomes were depression levels and self-esteem. Secondary outcomes were suicide ideation and sickness absence. RESULTS: The PATd/TAU-group showed a significant decrease of depression levels. The PATd/TAU-group returned to work to a higher degree than the TAU-group. Self esteem significantly improved in both groups. Suicide ideation was unaffected. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Manual-based PATd works as expected, being an effective treatment, and contributes to recovery for individuals with moderate to severe depression. This outcome needs to be confirmed and its long term effects examined in further studies. (PsycINFO Database Record PMID- 29756791 TI - Individual and group cognitive processing therapy: Effectiveness across two veterans affairs posttraumatic stress disorder treatment clinics. AB - OBJECTIVE: In accordance with Veterans Affairs (VA) policy, VA posttraumatic stress disorder (PTSD) clinics offer evidence-based treatments including cognitive processing therapy (CPT). To facilitate access to care, CPT is offered in both group and individual formats in many VA PTSD clinics. Group and individual delivery of CPT have been directly compared in active duty samples, but these findings have not been extended to VA populations. The present article directly compares the effectiveness of group and individual CPT with a written trauma account (CPT+A) across two VA PTSD clinics. METHOD: Veterans (N = 465) completed initial evaluations and enrolled in either group CPT+A (N = 146) or individual CPT+A (N = 319). Self-report measures of PTSD and depression symptoms were collected at pre-, mid-, and posttreatment; combined across treatment sites; and analyzed using hierarchical linear modeling. RESULTS: PTSD and depression symptoms reduced significantly over the course of group and individual CPT+A. Medium treatment effects were found for group CPT+A (d = .66 for PTSD, d = .68 for depression), and large treatment effects were found for individual CPT+A (d = .96 for PTSD, d = .79 for depression). CONCLUSION: Individual CPT+A led to significantly greater PTSD and depression symptom reduction than group CPT+A, indicating that in VA outpatient PTSD clinic settings, individual CPT+A may be a more effective approach than group CPT-A. In addition, PTSD symptoms reduced significantly more for Caucasian veterans than for African American veterans during CPT+A, indicating the importance of providing culturally competent trauma focused care. (PsycINFO Database Record PMID- 29756792 TI - Reading the lines in the face: The contribution of angularity and roundness to perceptions of facial anger and joy. AB - Through 3 studies, we investigated whether angularity and roundness present in faces contributes to the perception of anger and joyful expressions, respectively. First, in Study 1 we found that angry expressions naturally contain more inward-pointing lines, whereas joyful expressions contain more outward pointing lines. Then, using image-processing techniques in Studies 2 and 3, we filtered images to contain only inward-pointing or outward-pointing lines as a way to approximate angularity and roundness. We found that filtering images to be more angular increased how threatening and angry a neutral face was rated, increased how intense angry expressions were rated, and enhanced the recognition of anger. Conversely, filtering images to be rounder increased how warm and joyful a neutral face was rated, increased the intensity of joyful expressions, and enhanced recognition of joy. Together these findings show that angularity and roundness play a direct role in the recognition of angry and joyful expressions. Given evidence that angularity and roundness may play a biological role in indicating threat and safety in the environment, this suggests that angularity and roundness represent primitive facial cues used to signal threat-anger and warmth-joy pairings. (PsycINFO Database Record PMID- 29756793 TI - The biosocial foundation of the early Vygotsky: Educational psychology before the zone of proximal development. AB - One of Lev Vygotsky's most widely known concepts in educational psychology is the zone of proximal development (ZPD), which he began to articulate in the last 2 years of his life and work (1933-1934). This article explores an earlier period in Vygotsky's career-well before he developed the concept of the ZPD-when he was actively involved in pedagogy and educational psychology. With reference to the research and teaching that Vygotsky carried out in Gomel and gathered together for publication some years later, this article highlights his initial conception of educational psychology, and then critically reviews four of his ideas from this first period, namely, (a) the pedagogical importance of the learner's individual experience ("ultimately, the child teaches himself"), (b) the pedagogical applications of interest ("from one interest of the child's to a new interest"), (c) the psychological value of play ("games are the child's first school of thought"), and (d) the link between life and education ("ultimately, only life educates"). (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29756795 TI - "Preparatory power posing affects nonverbal presence and job interview performance": Correction to Cuddy et al. (2015). AB - Reports an error in "Preparatory power posing affects nonverbal presence and job interview performance" by Amy J. C. Cuddy, Caroline A. Wilmuth, Andy J. Yap and Dana R. Carney (Journal of Applied Psychology, 2015[Jul], Vol 100[4], 1286-1295). In the article, the degrees of freedom associated with the three F-tests noted on pages 1289 and 1290 should be 1 and 59 (and not 1 and 60, as previously reported). Also, on p. 1290, in the first sentence under the "Mediation" heading, it should be noted that the dependent variables were regressed onto the mediators, and not the other way around. Finally, in Figures 2 and 3 (on p.< 1292), the beta weights reported for Nonverbal Presence should be .773 (p < .001) for Overall Performance as the dependent variable, and .456 (p < .001) for Hireability as the dependent variable. (The following abstract of the original article appeared in record 2015-04973-001.) The authors tested whether engaging in expansive (vs. contractive) "power poses" before a stressful job interview preparatory power posing-would enhance performance during the interview. Participants adopted high-power (i.e., expansive, open) poses or low-power (i.e., contractive, closed) poses, and then prepared and delivered a speech to 2 evaluators as part of a mock job interview. All interview speeches were videotaped and coded for overall performance and hireability and for 2 potential mediators: verbal content (e.g., structure, content) and nonverbal presence (e.g., captivating, enthusiastic). As predicted, those who prepared for the job interview with high- (vs. low-) power poses performed better and were more likely to be chosen for hire; this relation was mediated by nonverbal presence, but not by verbal content. Although previous research has focused on how a nonverbal behavior that is enacted during interactions and observed by perceivers affects how those perceivers evaluate and respond to the actor, this experiment focused on how a nonverbal behavior that is enacted before the interaction and unobserved by perceivers affects the actor's performance, which, in turn, affects how perceivers evaluate and respond to the actor. This experiment reveals a theoretically novel and practically informative result that demonstrates the causal relation between preparatory nonverbal behavior and subsequent performance and outcomes. (PsycINFO Database Record PMID- 29756794 TI - Neurodevelopment of conflict adaptation: Evidence from event-related potentials. AB - Conflict adaptation is key in how children self-regulate and assert cognitive control in a given situation compared with a previous experience. In the current study, we analyzed event-related potentials (ERPs) to identify age-related differences in conflict adaptation. Participants of different ages (5-year-old children, 10-year-old children, and adults) were subjected to a stimulus-stimulus (S-S) conflict control task (the flanker task) and a stimulus-response (S-R) conflict control task (the Simon task). The behavioral results revealed that all age groups had reliable conflict adaptation effects (CAEs), with faster response times on current incongruent trials preceded by incongruent trials (iI trials) compared with current incongruent trials preceded by congruent trials (cI trials). There were also faster response times on current congruent trials preceded by congruent trials (cC trials) compared with current congruent trials preceded by incongruent trials (iC trials). Moreover, children demonstrated higher CAE related RTs compared with adults. Electrophysiological results showed that both 10-year-old children and adults had reliable CAEs in the flanker task during conflict detection, with a less N2 amplitude on cI trials compared with iI trials. We also found smaller ERP related CAE values in adults compared with children in the Simon task. Our findings suggest a developmental improvement of conflict adaptation that could lead to a state of relative equilibrium, allowing individuals to better assimilate and accommodate potential environmental conflicts. The results may also indicate that the development of conflict adaption is affected by the specific characteristic of the different types of conflict. (PsycINFO Database Record PMID- 29756796 TI - Psychometric properties of the Chinese version of the Difficulties in Emotion Regulation Scale (DERS): Factor structure, reliability, and validity. AB - Numerous studies have identified the significant role of emotion regulation in an individual's psychological and social functioning. Ever since its development, the Difficulties in Emotion Regulation Scale (DERS) has been widely adopted as a comprehensive measure to assess emotion regulation problems among English speaking adults. To assess emotion regulation in adults from Chinese-speaking societies and to promote future cross-cultural examination of the emotion regulation processes, the authors aimed to develop a Chinese version of the DERS and provide an initial validation of this instrument. For the purpose of the current study, we recruited 862 Chinese adults from universities and local companies. The results indicated a similar six-factor solution in the Chinese version to the original version. Internal consistency and test-retest reliability were good. Concurrent validity was assessed by examining the correlations of the DERS and its subscales with measures of psychopathological symptoms and self regulation of negative mood. The results demonstrated strong correlations of the DERS subscales with the Symptom Checklist-90 (SCL-90) and the Generalized Expectancy for Negative Mood Regulation Scale, except for that between the awareness subscale and the SCL-90. For the convergent validity, most DERS subscales were significantly correlated with personality traits, emotional intelligence, and self-control ability, with several exceptions. These findings are discussed within the context of the relevant literature. (PsycINFO Database Record PMID- 29756797 TI - Age differences in regulating negative emotions via attentional deployment. AB - Although past theoretical work has proposed age-related gains in emotion regulation, the empirical evidence is not entirely consistent. In two laboratory studies, we investigated age differences in regulating negative emotions through attentional deployment by instructing participants to direct their attention either toward negative (up-regulation) or neutral (down-regulation) pictorial content. The regulation process (visual attention) was measured via eye-tracking and the regulation outcome (emotional experience) was assessed via self-report. We tested emotional arousal and attentional functioning as factors that may affect age differences in attentional deployment. The main analyses revealed that, first, during down-regulation trials, older adults were less likely to direct their attention toward neutral stimulus content than younger adults, but did not experience greater unpleasantness than younger adults. This indicates that older adults may use attentional deployment more efficiently to decrease negative emotions than younger adults. Second, emotional arousal did not affect age differences in emotion regulation process and outcome. Third, we obtained preliminary evidence that for older but not for younger adults, low cognitive control may impair the implementation of attentional deployment. Additional findings suggested that neither younger nor older adults were able to increase unpleasantness by attending toward negative stimulus content. Together, these findings suggest multidirectional age differences in attentional deployment process and outcome and underline the importance of considering age-related vulnerabilities in predicting changes in emotion regulations across the life span. (PsycINFO Database Record PMID- 29756800 TI - Cognitive complaints mediate the effect of cognition on emotional stability across 12 years in old age. AB - Previous research supports a positive relationship between cognition and emotional stability, although findings regarding healthy older adults are inconsistent. Additionally, little is known about the mechanisms that underlie this association. Thus, the present study investigated the mediating effect of cognitive complaints on the bidirectional longitudinal association between cognition and emotional stability in old age. The study sample consisted of 500 older individuals (M age = 62.97 years, SD = 0.91, range = 60-64 years; 52% male) from the Interdisciplinary Longitudinal Study on Adult Development. The results showed that cognitive complaints mediated the effect of cognition on emotional stability over 12 years even when taking baseline emotional stability, baseline cognitive complaints, depressive affect, gender, sensory functioning, and objective and subjective health into account. However, cognitive complaints did not mediate the effect of emotional stability on cognition. The results of the current study emphasize the importance of investigating cognition as a predictor of personality traits, and indicate that cognitive resources may serve as a protective factor for emotional stability in old age. (PsycINFO Database Record PMID- 29756798 TI - Affective experience across the adult lifespan: An accelerated longitudinal design. AB - Recent research investigating the course of affective development across the adult life span has incorporated both cross-sectional and longitudinal data in analyses to understand the aging-affect relationship. Most of these studies, however, have not provided an empirical test to determine whether the cross sectional and longitudinal data can be combined to infer developmental processes. Utilizing an age heterogeneous sample followed over a 10-year span (N = 1,019, Mage = 54.14 +/- 13.06), the present study used an accelerated longitudinal design to investigate whether cross-sectional age differences could be found in longitudinal aging trajectories of positive affect (PA), negative affect (NA), and their confluence (i.e., affect optimization, the experience of PA relative to NA). Additionally, age-related differences in poignancy, co-occurrences of PA and NA, were examined. Absence of cross-sectional age-differences in the estimated longitudinal aging trajectories of PA and affect optimization suggested that a developmental process could be inferred; whereas, the longitudinal aging trajectories for NA showed cross-sectional age differences. PA and affect optimization showed a cubic relationship with age; NA showed decreases across adulthood; and poignancy showed age-related increases across adulthood. Self rated health was investigated as a covariate in all models. Though somewhat more nuanced, the estimated trajectories for PA, NA, affect optimization, and poignancy provided support for theories of affective aging. The implications of these findings, directions for future research, and issues surrounding using cross-sectional data to infer developmental change are discussed. (PsycINFO Database Record PMID- 29756799 TI - It gets better with time: Enhancement of age-related positivity effect in the six months following a highly negative public event. AB - Age is associated with shifts toward more positive memory retrieval. The current study examined these shifts following a negative public event. Participants completed two surveys examining emotional responses to the 2013 Boston Marathon bombings, one immediately following the attack and another 6 months later. Age was associated with different effects of time on how individuals reflected on this event. Time was associated with an increased focus on negative components in young adults but a decreased focus in older adults. These findings reveal a role of time in age-related positivity effects. (PsycINFO Database Record PMID- 29756802 TI - Is subjective memory specific for memory performance or general across cognitive domains? Findings from the Seattle Longitudinal Study. AB - A growing body of research has examined whether people's judgments of their own memory functioning accurately reflect their memory performance at cross-section and over time. Relatively less is known about whether these judgments are specifically based on memory performance, or reflect general cognitive change. The aim of the present study was to examine longitudinal associations of subjective memory with performance in tests of episodic memory and a wide range of other cognitive tests, including the Wechsler Adult Intelligence Scale-Revised (WAIS-R) Block Design, Comprehension, Digit Span, Digit Symbol, and Vocabulary subtests. We applied latent growth curve models to five occasions over up to 16 years of neuropsychological assessments from 956 participants of the Seattle Longitudinal Study (SLS; 57% women; age at baseline: M = 65.1, SD = 11.4, 38 - 96 years). Results revealed that lower self-reported Frequency of Forgetting was significantly associated with better performance in all cognitive domains at baseline. The baseline correlation of Frequency of Forgetting with memory performance was stronger than its correlations with performance in other cognitive tests. Furthermore, additional analyses with baseline data showed that a latent memory performance factor reliably predicted Frequency of Forgetting after controlling for a general cognitive factor. Over time, steeper increases in Frequency of Forgetting were associated with steeper declines in tests of memory performance and in the Block Design and Digit Symbol subtests. Taken together, these findings suggest that although self-reported Frequency of Forgetting reflects performance in a broad range of other cognitive domains, it also shows some specificity for memory performance. (PsycINFO Database Record PMID- 29756801 TI - The relationship between subjective well-being and mortality within discordant twin pairs from two independent samples. AB - Prior research has shown robust associations between greater subjective well being (SWB) and reduced mortality. Whether this observed association is causal in nature or due instead to confounding genetic or environmental factors affecting both SWB and mortality is not well understood. We used a combined sample of 6,802 twins drawn from two cohorts: the Longitudinal Study of Middle-Aged Danish Twins (MADT; N = 2,815, baseline age between 45 and 69 years, M = 56.8, SD = 6.4) and the Longitudinal Study of Aging Danish Twins (LSADT; N = 3,987, baseline age between 70 and 97 years, M = 76.6, SD = 4.9). The relationship between SWB, encompassing measures of life satisfaction and affect, and all-cause mortality was evaluated using survival analyses at both the individual level and within twin pairs. Twin difference analyses were completed within 1,053 monozygotic (MZ) twin pairs and 1,143 dizygotic (DZ) twin pairs to control for genetic and shared environmental confounding. As expected, the individual-level results showed that higher levels of SWB were associated with reduced mortality: affect hazard ratio (HR) = .90, 95% confidence interval (CI) [.87, .94]; life satisfaction HR = .88, 95% CI [.84, .92]. The effect of SWB on reduced mortality remained significant within both MZ and DZ pairs, suggesting that the association is independent of genetic and nonshared environmental confounding factors. These findings, which generalized across both younger (MADT) and older (LSADT) cohorts of adults, remained significant when accounting for demographic factors, physical health, and cognitive functioning. (PsycINFO Database Record PMID- 29756804 TI - Unitization of word pairs in young and older adults: Encoding mechanisms and retrieval outcomes. AB - We investigated whether healthy older adults are able to use an episodic encoding strategy known as unitization, which allows for subsequent associative retrieval based on familiarity, to overcome their associative memory deficit. Young and healthy older participants were presented with word pairs either together with a definition that allowed to combine the word pairs to a new concept (high unitization condition), or together with a sentence frame (low unitization condition). In Experiment 1, an age-related reduction in performance on a standard associative recognition test was observed in both conditions. This deficit was unexpectedly not reduced, but tended to be larger in the high than the low unitization condition. According to receiver-operating characteristics, this difference was due to a reduction of recollection, but not familiarity, in the high unitization condition. Instead of a standard recognition test, Experiment 2 used a 2 alternative forced choice (2AFC) test designed to maximize the contribution of familiarity to associative recognition. Although the disadvantage of older adults in the high versus the low unitization condition was abolished, there was still no performance advantage for the high unitization condition. Event-related potentials (ERPs) recorded during the encoding phase of Experiment 1 suggest that, while young adults engage in predictive processing during unitization, older adults do not engage in such predictive processing, which may prevent them from using unitization to their advantage in the subsequent associative memory test. We discuss the task characteristics that have an impact on the effect of unitization conditions on associative memory in older adults. (PsycINFO Database Record PMID- 29756803 TI - Attitude toward own aging as a risk factor for cognitive disorder in old age: 12 year evidence from the ILSE study. AB - Previous research has demonstrated the harmful impact of subjective aging processes (e.g., negative age self-stereotyping) on normal cognitive aging in different domains of cognitive functioning, such as memory, executive function, and fluid abilities. Recently, subjective aging has also been linked to important biomarkers of Alzheimer's disease (AD) and dementia-related outcomes, indicating associations with pathological cognitive aging. With data from the Interdisciplinary Longitudinal Study of Adult Development and Aging (ILSE), the present study extends this research by examining the long-term effect of attitude toward own aging (ATOA) on expert-based clinical diagnosis of mild cognitive impairment (MCI) and AD in old age. In the study, 260 initially cognitively healthy participants with a mean age of 62.5 years were followed for 12 years. In the course of the study, 103 participants developed MCI and 14 received diagnosis of AD. Logistic regression models showed that baseline ATOA predicted future clinical diagnoses of MCI and AD 12 years later, while controlling for sociodemographic, genetic, and health variables. Although theoretically suggested, evidence for a mediating role of leisure-activity level and control beliefs was scarce. Our findings add to the emerging literature supporting negative views of aging as a risk factor for cognitive disorder in old age. (PsycINFO Database Record PMID- 29756805 TI - Age-related changes in working memory: Age affects relational but not conjunctive feature binding. AB - In contrast to long-term memory, age-related association deficits in working memory are found only inconsistently. The authors hypothesized that type of binding is critical for the occurrence of such deficits. Relational binding abilities (associating separate visual units) should degrade with age, whereas more automatic conjunctive binding abilities (associating features within an object) should not. They contrasted associative memory and item memory using a change-detection task with colors and shapes in younger (18-33 years) and older (64-82 years) healthy adults. Color was either a surface feature of the shape (conjunctive binding) or a feature of a shape-external frame (relational binding). In a direct test of associative memory, participants memorized color shape associations; in an indirect item memory test, participants were required to memorize only the shapes, and the authors measured the costs of ignoring task irrelevant color changes from study to test. In the direct test, associative memory was poorer when relational binding was required rather than conjunctive binding, and associative memory was poorer in the older group, but no age-related association deficit was apparent. In the indirect test, by contrast, type of binding interacted with age: younger participants showed study-test congruence effects independent of the type of binding, but older adults showed enhanced congruence effects for conjunctive stimuli, indicating intact or even enhanced conjunctive binding, and practically no costs for relational stimuli, indicating poor relational binding. This stimulus-specific effect of a task-irrelevant feature change indicates that relational and conjunctive binding in working memory are differently affected by healthy aging. (PsycINFO Database Record PMID- 29756807 TI - Changes in multisensory integration across the life span. AB - The study examined individual contributions of visual and auditory information on multisensory integration across the life span. In the experiment, children, young adults, and older adults participated in a variant of the Sound-Induced Flash Illusion where participants had to either ignore beeps and report how many flashes they saw or ignore flashes and report how many beeps they heard. Collapsed across age, auditory input had a stronger effect on visual processing than vice versa. However, relative contributions of auditory and visual information interacted with age, with young adults showing evidence of auditory dominance (only auditory input affected visual processing), whereas, multisensory integration effects were more symmetrical in children and older adults. The findings have implications for many tasks that require the processing of multisensory information. (PsycINFO Database Record PMID- 29756806 TI - Aging and the strategic use of context to control prospective memory monitoring. AB - Monitoring the environment for the occurrence of prospective memory (PM) targets is a resource-demanding process that produces cost to ongoing activities. The current study investigated younger and older adults' ability to monitor strategically, which involves the heightening and relaxation of monitoring when it is contextually appropriate thereby affording conservation of limited-capacity attentional resources. Participants performed a lexical-decision task in which words or nonwords were presented in upper or lower locations of the screen. The specific condition was correctly informed that PM targets ("tor" syllable) would occur only in word trials (simple cue; Experiment 1), in word trials in the upper location (complex cue; Experiments 2 and 3A), or in red trials in the upper location (complex cue; Experiment 3B), whereas the nonspecific condition was told that targets could appear in any context. The results showed that older adults generally exhibited similar monitoring patterns as younger adults. When context varied randomly on each trial, younger and older adults in the specific condition utilized simple (Experiment 1) but not complex (Experiment 2) contextual cues to reduce monitoring in unexpected contexts relative to the nonspecific condition. Notably, younger but not older adults were able to use the location dimension of the complex cue to reduce monitoring in unexpected (lower) contexts. When context varied more predictably (i.e., changed every eight trials), both younger and older adults were able to monitor strategically in response to the complex contextual cue (Experiments 3A and 3B). Together these findings suggest that context-sensitive PM monitoring processes generally remain intact with increased age. (PsycINFO Database Record PMID- 29756808 TI - Elastic Backbone Defines a New Transition in the Percolation Model. AB - The elastic backbone is the set of all shortest paths. We found a new phase transition at p_{eb} above the classical percolation threshold at which the elastic backbone becomes dense. At this transition in 2D, its fractal dimension is 1.750+/-0.003, and one obtains a novel set of critical exponents beta_{eb}=0.50+/-0.02, gamma_{eb}=1.97+/-0.05, and nu_{eb}=2.00+/-0.02, fulfilling consistent critical scaling laws. Interestingly, however, the hyperscaling relation is violated. Using Binder's cumulant, we determine, with high precision, the critical probabilities p_{eb} for the triangular and tilted square lattice for site and bond percolation. This transition describes a sudden rigidification as a function of density when stretching a damaged tissue. PMID- 29756809 TI - Topological Defects with Distinct Dipole Configurations in PbTiO_{3}/SrTiO_{3} Multilayer Films. AB - Distinct and novel features of nanometric electric topological defects, including dipole waves and dipole disclinations, are presently revealed in the PbTiO_{3} layers of PbTiO_{3}/SrTiO_{3} multilayer films by means of quantitative high resolution scanning transmission electron microscopy. These original dipole configurations are confirmed and explained by atomistic simulations and have the potential to act as functional elements in future electronics. PMID- 29756811 TI - Optimal Verification of Entangled States with Local Measurements. AB - Consider the task of verifying that a given quantum device, designed to produce a particular entangled state, does indeed produce that state. One natural approach would be to characterize the output state by quantum state tomography, or alternatively, to perform some kind of Bell test, tailored to the state of interest. We show here that neither approach is optimal among local verification strategies for 2-qubit states. We find the optimal strategy in this case and show that quadratically fewer total measurements are needed to verify to within a given fidelity than in published results for quantum state tomography, Bell test, or fidelity estimation protocols. We also give efficient verification protocols for any stabilizer state. Additionally, we show that requiring that the strategy be constructed from local, nonadaptive, and noncollective measurements only incurs a constant-factor penalty over a strategy without these restrictions. PMID- 29756812 TI - Strongly Enhanced Tunneling at Total Charge Neutrality in Double-Bilayer Graphene WSe_{2} Heterostructures. AB - We report the experimental observation of strongly enhanced tunneling between graphene bilayers through a WSe_{2} barrier when the graphene bilayers are populated with carriers of opposite polarity and equal density. The enhanced tunneling increases sharply in strength with decreasing temperature, and the tunneling current exhibits a vertical onset as a function of interlayer voltage at a temperature of 1.5 K. The strongly enhanced tunneling at overall neutrality departs markedly from single-particle model calculations that otherwise match the measured tunneling current-voltage characteristics well, and suggests the emergence of a many-body state with condensed interbilayer excitons when electrons and holes of equal densities populate the two layers. PMID- 29756813 TI - dc Resistivity of Quantum Critical, Charge Density Wave States from Gauge-Gravity Duality. AB - In contrast to metals with weak disorder, the resistivity of weakly pinned charge density waves (CDWs) is not controlled by irrelevant processes relaxing momentum. Instead, the leading contribution is governed by incoherent, diffusive processes which do not drag momentum and can be evaluated in the clean limit. We compute analytically the dc resistivity for a family of holographic charge density wave quantum critical phases and discuss its temperature scaling. Depending on the critical exponents, the ground state can be conducting or insulating. We connect our results to dc electrical transport in underdoped cuprate high T_{c} superconductors. We conclude by speculating on the possible relevance of unstable, semilocally critical CDW states to the strange metallic region. PMID- 29756814 TI - Gauged Supergravities and Spontaneous Supersymmetry Breaking from the Double Copy Construction. AB - Supergravities with gauged R symmetry and Minkowski vacua allow for spontaneous supersymmetry breaking and, as such, provide a framework for building supergravity models of phenomenological relevance. In this Letter, we initiate the study of double copy constructions for these supergravities. We argue that, on general grounds, we expect their scattering amplitudes to be described by a double copy of the type (spontaneously broken gauge theory)? (gauge theory with broken supersymmetry). We present a simple realization in which the resulting supergravity has U(1)_{R} gauge symmetry, spontaneously broken N=2 supersymmetry, and massive gravitini. This is the first instance of a double copy construction of a gauged supergravity and of a theory with spontaneously broken supersymmetry. The construction extends in a straightforward manner to a large family of gauged Yang-Mills-Einstein supergravity theories with or without spontaneous gauge symmetry breaking. PMID- 29756815 TI - Spin Hall and Spin Swapping Torques in Diffusive Ferromagnets. AB - A complete set of the generalized drift-diffusion equations for a coupled charge and spin dynamics in ferromagnets in the presence of extrinsic spin-orbit coupling is derived from the quantum kinetic approach, covering major transport phenomena, such as the spin and anomalous Hall effects, spin swapping, spin precession, and relaxation processes. We argue that the spin swapping effect in ferromagnets is enhanced due to spin polarization, while the overall spin texture induced by the interplay of spin-orbital and spin precession effects displays a complex spatial dependence that can be exploited to generate torques and nucleate or propagate domain walls in centrosymmetric geometries without the use of external polarizers, as opposed to the conventional understanding of spin-orbit mediated torques. PMID- 29756816 TI - Magnon Spin Hall Magnetoresistance of a Gapped Quantum Paramagnet. AB - Motivated by recent experimental work, we consider spin transport between a normal metal and a gapped quantum paramagnet. We model the latter as the magnonic Mott-insulating phase of an easy-plane ferromagnetic insulator. We evaluate the spin current mediated by the interface exchange coupling between the ferromagnet and the adjacent normal metal. For the strongly interacting magnons that we consider, this spin current gives rise to a spin Hall magnetoresistance that strongly depends on the magnitude of the magnetic field, rather than its direction. This Letter may motivate electrical detection of the phases of quantum magnets and the incorporation of such materials into spintronic devices. PMID- 29756817 TI - Chirping and Sudden Excitation of Energetic-Particle-Driven Geodesic Acoustic Modes in a Large Helical Device Experiment. AB - Energetic-particle-driven geodesic acoustic modes (EGAMs) observed in a Large Helical Device experiment are investigated using a hybrid simulation code for energetic particles interacting with a magnetohydrodynamic (MHD) fluid. The frequency chirping of the primary mode and the sudden excitation of the half frequency secondary mode are reproduced for the first time with the hybrid simulation using the realistic physical condition and the three-dimensional equilibrium. Both EGAMs have global spatial profiles which are consistent with the experimental measurements. For the secondary mode, the bulk pressure perturbation and the energetic particle pressure perturbation cancel each other out, and thus the frequency is lower than the primary mode. It is found that the excitation of the secondary mode does not depend on the nonlinear MHD coupling. The secondary mode is excited by energetic particles that satisfy the linear and nonlinear resonance conditions, respectively, for the primary and secondary modes. PMID- 29756818 TI - Mechanism for Unconventional Superconductivity in the Hole-Doped Rashba-Hubbard Model. AB - Motivated by the recent resurgence of interest in topological superconductivity, we study superconducting pairing instabilities of the hole-doped Rashba-Hubbard model on the square lattice with first- and second-neighbor hopping. Within the random phase approximation, we compute the spin-fluctuation-mediated pairing interactions as a function of filling. Rashba spin-orbit coupling splits the spin degeneracies of the bands, which leads to two van Hove singularities at two different fillings. We find that, for a doping region in between these two van Hove fillings, the spin fluctuations exhibit a strong ferromagnetic contribution. Because of these ferromagnetic fluctuations, there is a strong tendency towards spin-triplet f-wave pairing within this filling region, resulting in a topologically nontrivial phase. PMID- 29756819 TI - Evidence from Quantum Monte Carlo Simulations of Large-Gap Superfluidity and BCS BEC Crossover in Double Electron-Hole Layers. AB - We report quantum Monte Carlo evidence of the existence of large gap superfluidity in electron-hole double layers over wide density ranges. The superfluid parameters evolve from normal state to BEC with decreasing density, with the BCS state restricted to a tiny range of densities due to the strong screening of Coulomb interactions, which causes the gap to rapidly become large near the onset of superfluidity. The superfluid properties exhibit similarities to ultracold fermions and iron-based superconductors, suggesting an underlying universal behavior of BCS-BEC crossovers in pairing systems. PMID- 29756820 TI - Observation of Spin Superfluidity in a Bose Gas Mixture. AB - The spin dynamics of a harmonically trapped Bose-Einstein condensed binary mixture of sodium atoms is experimentally investigated at finite temperature. In the collisional regime the motion of the thermal component is shown to be damped because of spin drag, while the two condensates exhibit a counterflow oscillation without friction, thereby providing direct evidence for spin superfluidity. Results are also reported in the collisionless regime where the spin components of both the condensate and thermal part oscillate without damping, their relative motion being driven by a mean-field effect. We also measure the static polarizability of the condensed and thermal parts and we find a large increase of the condensate polarizability with respect to the T=0 value, in agreement with the predictions of theory. PMID- 29756821 TI - Estimating Coherence Measures from Limited Experimental Data Available. AB - Quantifying coherence has received increasing attention, and considerable work has been directed towards finding coherence measures. While various coherence measures have been proposed in theory, an important issue following is how to estimate these coherence measures in experiments. This is a challenging task, since the state of a system is often unknown in practical applications and the accessible measurements in a real experiment are typically limited. In this Letter, we put forward an approach to estimate coherence measures of an unknown state from any limited experimental data available. Our approach is not only applicable to coherence measures but can be extended to other resource measures. PMID- 29756822 TI - Neutron Skins and Neutron Stars in the Multimessenger Era. AB - The historical first detection of a binary neutron star merger by the LIGO-Virgo Collaboration [B. P. Abbott et al., Phys. Rev. Lett. 119, 161101 (2017)PRLTAO0031 900710.1103/PhysRevLett.119.161101] is providing fundamental new insights into the astrophysical site for the r process and on the nature of dense matter. A set of realistic models of the equation of state (EOS) that yield an accurate description of the properties of finite nuclei, support neutron stars of two solar masses, and provide a Lorentz covariant extrapolation to dense matter are used to confront its predictions against tidal polarizabilities extracted from the gravitational-wave data. Given the sensitivity of the gravitational-wave signal to the underlying EOS, limits on the tidal polarizability inferred from the observation translate into constraints on the neutron-star radius. Based on these constraints, models that predict a stiff symmetry energy, and thus large stellar radii, can be ruled out. Indeed, we deduce an upper limit on the radius of a 1.4M_{?} neutron star of R_{?}^{1.4}<13.76 km. Given the sensitivity of the neutron-skin thickness of ^{208}Pb to the symmetry energy, albeit at a lower density, we infer a corresponding upper limit of about R_{skin}^{208}?0.25 fm. However, if the upcoming PREX-II experiment measures a significantly thicker skin, this may be evidence of a softening of the symmetry energy at high densities-likely indicative of a phase transition in the interior of neutron stars. PMID- 29756823 TI - Gravitational-Wave Constraints on the Neutron-Star-Matter Equation of State. AB - The detection of gravitational waves originating from a neutron-star merger, GW170817, by the LIGO and Virgo Collaborations has recently provided new stringent limits on the tidal deformabilities of the stars involved in the collision. Combining this measurement with the existence of two-solar-mass stars, we generate a generic family of neutron-star-matter equations of state (EOSs) that interpolate between state-of-the-art theoretical results at low and high baryon density. Comparing the results to ones obtained without the tidal deformability constraint, we witness a dramatic reduction in the family of allowed EOSs. Based on our analysis, we conclude that the maximal radius of a 1.4 solar-mass neutron star is 13.6 km, and that the smallest allowed tidal deformability of a similar-mass star is Lambda(1.4 M_{?})=120. PMID- 29756824 TI - Single-Atom Heat Machines Enabled by Energy Quantization. AB - Quantization of energy is a quintessential characteristic of quantum systems. Here we analyze its effects on the operation of Otto cycle heat machines and show that energy quantization alone may alter and increase machine performance in terms of output work, efficiency, and even operation mode. We show that this difference in performance occurs in machines with inhomogeneous energy level scaling, while quantum machines with homogeneous level scaling behave like classical machines. Our results demonstrate that quantum thermodynamics enables the realization of classically inconceivable Otto machines, such as those with an incompressible working substance. We propose to measure these effects experimentally using a laser-cooled trapped ion as a microscopic heat machine. PMID- 29756825 TI - Precision Measurement of Phonon-Polaritonic Near-Field Energy Transfer between Macroscale Planar Structures Under Large Thermal Gradients. AB - Despite its strong potentials in emerging energy applications, near-field thermal radiation between large planar structures has not been fully explored in experiments. Particularly, it is extremely challenging to control a subwavelength gap distance with good parallelism under large thermal gradients. This article reports the precision measurement of near-field radiative energy transfer between two macroscale single-crystalline quartz plates that support surface phonon polaritons. Our measurement scheme allows the precise control of a gap distance down to 200 nm in a highly reproducible manner for a surface area of 5*5 mm^{2}. We have measured near-field thermal radiation as a function of the gap distance for a broad range of thermal gradients up to ~156 K, observing more than 40 times enhancement of thermal radiation compared to the blackbody limit. By comparing with theoretical prediction based on fluctuational electrodynamics, we demonstrate that such remarkable enhancement is owing to phonon-polaritonic energy transfer across a nanoscale vacuum gap. PMID- 29756827 TI - Scalar Hairy Black Holes in Four Dimensions are Unstable. AB - We present a numerical analysis of the stability properties of the black holes with scalar hair constructed by Herdeiro and Radu. We prove the existence of a novel gauge where the scalar field perturbations decouple from the metric perturbations, and analyze the resulting quasinormal mode spectrum. We find unstable modes with characteristic growth rates which for uniformly small hair are almost identical to those of a massive scalar field on a fixed Kerr background. PMID- 29756828 TI - Relaxation to a Phase-Locked Equilibrium State in a One-Dimensional Bosonic Josephson Junction. AB - We present an experimental study on the nonequilibrium tunnel dynamics of two coupled one-dimensional Bose-Einstein quasicondensates deep in the Josephson regime. Josephson oscillations are initiated by splitting a single one dimensional condensate and imprinting a relative phase between the superfluids. Regardless of the initial state and experimental parameters, the dynamics of the relative phase and atom number imbalance shows a relaxation to a phase-locked steady state. The latter is characterized by a high phase coherence and reduced fluctuations with respect to the initial state. We propose an empirical model based on the analogy with the anharmonic oscillator to describe the effect of various experimental parameters. A microscopic theory compatible with our observations is still missing. PMID- 29756826 TI - Excitation of the Isovector Spin Monopole Resonance via the Exothermic ^{90}Zr(^{12}N,^{12}C) Reaction at 175 MeV/u. AB - The (^{12}N, ^{12}C) charge-exchange reaction at 175 MeV/u was developed as a novel probe for studying the isovector spin giant monopole resonance (IVSMR), whose properties are important for better understanding the bulk properties of nuclei and asymmetric nuclear matter. This probe, now available through the production of ^{12}N as a secondary rare-isotope beam, is exothermic, is strongly absorbed at the surface of the target nucleus, and provides selectivity for spin transfer excitations. All three properties enhance the excitation of the IVSMR compared to other, primarily light-ion, probes, which have been used to study the IVSMR thus far. The ^{90}Zr(^{12}N,^{12}C) reaction was measured and the excitation energy spectra up to about 70 MeV for both the spin-transfer and non spin-transfer channels were deduced separately by tagging the decay by gamma emission from the ^{12}C ejectile. Besides the well-known Gamow-Teller and isobaric analog transitions, a clear signature of the IVSMR was identified. By comparing with the results from light-ion reactions on the same target nucleus and theoretical predictions, the suitability of this new probe for studying the IVSMR was confirmed. PMID- 29756829 TI - Hard Competition: Stabilizing the Elusive Biaxial Nematic Phase in Suspensions of Colloidal Particles with Extreme Lengths. AB - We use computer simulations to study the existence and stability of a biaxial nematic N_{b} phase in systems of hard polyhedral cuboids, triangular prisms, and rhombic platelets, characterized by a long (L), medium (M), and short (S) particle axis. For all three shape families, we find stable N_{b} states provided the shape is not only close to the so-called dual shape with M=sqrt[LS] but also sufficiently anisotropic with L/S>9,11,14,23 for rhombi, (two types of) triangular prisms, and cuboids, respectively, corresponding to anisotropies not considered before. Surprisingly, a direct isotropic-N_{b} transition does not occur in these systems due to a destabilization of N_{b} by a smectic (for cuboids and prisms) or a columnar (for platelets) phase at small L/S or by an intervening uniaxial nematic phase at large L/S. Our results are confirmed by a density functional theory provided the third virial coefficient is included and a continuous rather than a discrete (Zwanzig) set of particle orientations is taken into account. PMID- 29756830 TI - Inertial Movements of the Iris as the Origin of Postsaccadic Oscillations. AB - Recent studies on the human eye indicate that the pupil moves inside the eyeball due to deformations of the iris. Here we show that this phenomenon can be originated by inertial forces undergone by the iris during the rotation of the eyeball. Moreover, these forces affect the iris in such a way that the pupil behaves effectively as a massive particle. To show this, we develop a model based on the Newton equation on the noninertial reference frame of the eyeball. The model allows us to reproduce and interpret several important findings of recent eye-tracking experiments on saccadic movements. In particular, we get correct results for the dependence of the amplitude and period of the postsaccadic oscillations on the saccade size and also for the peak velocity. The model developed may serve as a tool for characterizing eye properties of individuals. PMID- 29756831 TI - Quasiperiodic Quantum Ising Transitions in 1D. AB - Unlike random potentials, quasiperiodic modulation can induce localization delocalization transitions in one dimension. In this Letter, we analyze the implications of this for symmetry breaking in the quasiperiodically modulated quantum Ising chain. Although weak modulation is irrelevant, strong modulation induces new ferromagnetic and paramagnetic phases which are fully localized and gapless. The quasiperiodic potential and localized excitations lead to quantum criticality that is intermediate to that of the clean and randomly disordered models with exponents of nu=1^{+} (exact) and z~1.9, Delta_{sigma}~0.16, and Delta_{gamma}~0.63 (up to logarithmic corrections). Technically, the clean Ising transition is destabilized by logarithmic wandering of the local reduced couplings. We conjecture that the wandering coefficient w controls the universality class of the quasiperiodic transition and show its stability to smooth perturbations that preserve the quasiperiodic structure of the model. PMID- 29756832 TI - High-Harmonic Generation in Solids with and without Topological Edge States. AB - High-harmonic generation in the two topological phases of a finite, one dimensional, periodic structure is investigated using a self-consistent time dependent density functional theory approach. For harmonic photon energies smaller than the band gap, the harmonic yield is found to differ by up to 14 orders of magnitude for the two topological phases. This giant topological effect is explained by the degree of destructive interference in the harmonic emission of all valence-band (and edge-state) electrons, which strongly depends on whether or not topological edge states are present. The combination of strong-field laser physics with topological condensed matter opens up new possibilities to electronically control strong-field-based light or particle sources or-conversely to steer by all optical means topological electronics. PMID- 29756833 TI - Universal Broadening of the Light Cone in Low-Temperature Transport. AB - We consider the low-temperature transport properties of critical one-dimensional systems that can be described, at equilibrium, by a Luttinger liquid. We focus on the prototypical setting where two semi-infinite chains are prepared in two thermal states at small but different temperatures and suddenly joined together. At large distances x and times t, conformal field theory characterizes the energy transport in terms of a single light cone spreading at the sound velocity v. Energy density and current take different constant values inside the light cone, on its left, and on its right, resulting in a three-step form of the corresponding profiles as a function of zeta=x/t. Here, using a nonlinear Luttinger liquid description, we show that for generic observables this picture is spoiled as soon as a nonlinearity in the spectrum is present. In correspondence of the transition points x/t=+/-v, a novel universal region emerges at infinite times, whose width is proportional to the temperatures on the two sides. In this region, expectation values have a different temperature dependence and show smooth peaks as a function of zeta. We explicitly compute the universal function describing such peaks. In the specific case of interacting integrable models, our predictions are analytically recovered by the generalized hydrodynamic approach. PMID- 29756834 TI - Anomalous Change in the de Haas-van Alphen Oscillations of CeCoIn_{5} at Ultralow Temperatures. AB - We perform de Haas-van Alphen (dHvA) measurements of the heavy-fermion superconductor CeCoIn_{5} down to 2 mK above the upper critical field. We find that the dHvA amplitudes show an anomalous suppression, concomitantly with a shift of the dHvA frequency, below the transition temperature T_{n}=20 mK. We suggest that the change is owing to magnetic breakdown caused by a field-induced antiferromagnetic (AFM) state emerging below T_{n}, revealing the origin of the field-induced quantum critical point (QCP) in CeCoIn_{5}. The field dependence of T_{n} is found to be very weak for 7-10 T, implying that an enhancement of AFM order by suppressing the critical spin fluctuations near the AFM QCP competes with the field suppression effect on the AFM phase. We suggest that the appearance of a field-induced AFM phase is a generic feature of unconventional superconductors, which emerge near an AFM QCP, including CeCoIn_{5}, CeRhIn_{5}, and high-T_{c} cuprates. PMID- 29756835 TI - Evidence of a Critical Phase Transition in Purely Temporal Dynamics with Long Delayed Feedback. AB - Experimental evidence of an absorbing phase transition, so far associated with spatiotemporal dynamics, is provided in a purely temporal optical system. A bistable semiconductor laser, with long-delayed optoelectronic feedback and multiplicative noise, shows the peculiar features of a critical phenomenon belonging to the directed percolation universality class. The numerical study of a simple, effective model provides accurate estimates of the transition critical exponents, in agreement with both theory and our experiment. This result pushes forward a hard equivalence of nontrivial stochastic, long-delayed systems with spatiotemporal ones and opens a new avenue for studying out-of-equilibrium universality classes in purely temporal dynamics. PMID- 29756837 TI - Nonlinear Electromagnetic Stabilization of Plasma Microturbulence. AB - The physical causes for the strong stabilizing effect of finite plasma beta on ion-temperature-gradient-driven turbulence, which far exceeds quasilinear estimates, are identified from nonlinear gyrokinetic simulations. The primary contribution stems from a resonance of frequencies in the dominant nonlinear interaction between the unstable mode, the stable mode, and zonal flows, which maximizes the triplet correlation time and therefore the energy transfer efficiency. A modification to mixing-length transport estimates is constructed, which reproduces nonlinear heat fluxes throughout the examined beta range. PMID- 29756836 TI - Two Clock Transitions in Neutral Yb for the Highest Sensitivity to Variations of the Fine-Structure Constant. AB - We propose a new frequency standard based on a 4f^{14}6s6p ^{3}P_{0} 4f^{13}6s^{2}5d (J=2) transition in neutral Yb. This transition has a potential for high stability and accuracy and the advantage of the highest sensitivity among atomic clocks to variation of the fine-structure constant alpha. We find its dimensionless alpha-variation enhancement factor to be K=-15, in comparison to the most sensitive current clock (Yb^{+} E3, K=-6), and it is 18 times larger than in any neutral-atomic clocks (Hg, K=0.8). Combined with the unprecedented stability of an optical lattice clock for neutral atoms, this high sensitivity opens new perspectives for searches for ultralight dark matter and for tests of theories beyond the standard model of elementary particles. Moreover, together with the well-established ^{1}S_{0}-^{3}P_{0} transition, one will have two clock transitions operating in neutral Yb, whose interleaved interrogations may further reduce systematic uncertainties of such clock-comparison experiments. PMID- 29756838 TI - Magnetic Excitations across the Metal-Insulator Transition in the Pyrochlore Iridate Eu_{2}Ir_{2}O_{7}. AB - We report a resonant inelastic x-ray scattering study of the magnetic excitation spectrum in a highly insulating Eu_{2}Ir_{2}O_{7} single crystal that exhibits a metal-insulator transition at T_{MI}=111(7) K. A propagating magnon mode with a 20 meV bandwidth and a 28 meV magnon gap is found in the excitation spectrum at 7 K, which is expected in the all-in-all-out magnetically ordered state. This magnetic excitation exhibits substantial softening as the temperature is raised towards T_{MI} and turns into a highly damped excitation in the paramagnetic phase. Remarkably, the softening occurs throughout the whole Brillouin zone including the zone boundary. This observation is inconsistent with the magnon renormalization expected in a local moment system and indicates that the strength of the electron correlation in Eu_{2}Ir_{2}O_{7} is only moderate, so that electron itinerancy should be taken into account in describing its magnetism. PMID- 29756839 TI - Generalized One-Band Model Based on Zhang-Rice Singlets for Tetragonal CuO. AB - Tetragonal CuO (T-CuO) has attracted attention because of its structure similar to that of the cuprates. It has been recently proposed as a compound whose study can give an end to the long debate about the proper microscopic modeling for cuprates. In this work, we rigorously derive an effective one-band generalized t J model for T-CuO, based on orthogonalized Zhang-Rice singlets, and make an estimative calculation of its parameters, based on previous ab initio calculations. By means of the self-consistent Born approximation, we then evaluate the spectral function and the quasiparticle dispersion for a single hole doped in antiferromagnetically ordered half filled T-CuO. Our predictions show very good agreement with angle-resolved photoemission spectra and with theoretical multiband results. We conclude that a generalized t-J model remains the minimal Hamiltonian for a correct description of single-hole dynamics in cuprates. PMID- 29756840 TI - Discriminative Cooperative Networks for Detecting Phase Transitions. AB - The classification of states of matter and their corresponding phase transitions is a special kind of machine-learning task, where physical data allow for the analysis of new algorithms, which have not been considered in the general computer-science setting so far. Here we introduce an unsupervised machine learning scheme for detecting phase transitions with a pair of discriminative cooperative networks (DCNs). In this scheme, a guesser network and a learner network cooperate to detect phase transitions from fully unlabeled data. The new scheme is efficient enough for dealing with phase diagrams in two-dimensional parameter spaces, where we can utilize an active contour model-the snake-from computer vision to host the two networks. The snake, with a DCN "brain," moves and learns actively in the parameter space, and locates phase boundaries automatically. PMID- 29756841 TI - Latent Computational Complexity of Symmetry-Protected Topological Order with Fractional Symmetry. AB - An emerging insight is that ground states of symmetry-protected topological orders (SPTOs) possess latent computational complexity in terms of their many body entanglement. By introducing a fractional symmetry of SPTO, which requires the invariance under 3-colorable symmetries of a lattice, we prove that every renormalization fixed-point state of 2D (Z_{2})^{m} SPTO with fractional symmetry can be utilized for universal quantum computation using only Pauli measurements, as long as it belongs to a nontrivial 2D SPTO phase. Our infinite family of fixed point states may serve as a base model to demonstrate the idea of a "quantum computational phase" of matter, whose states share universal computational complexity ubiquitously. PMID- 29756842 TI - Proton Decay into Charged Leptons. AB - We discuss proton and neutron decays involving three leptons in the final state. Some of these modes could constitute the dominant decay channel because they conserve lepton-flavor symmetries that are broken in all usually considered channels. This includes the particularly interesting and rarely discussed p >e^{+}e^{+}MU^{-} and p->MU^{+}MU^{+}e^{-} modes. As the relevant effective operators arise at dimension 9 or 10, observation of a three-lepton mode would probe energy scales of order 100 TeV. This allows us to connect proton decay to other probes such as rare meson decays or collider physics. UV completions of this scenario involving leptoquarks unavoidably violate lepton-flavor universality and could provide an explanation to the recent b->sMUMU anomalies observed in B-meson decays. PMID- 29756843 TI - Z Boson Decay into Light and Darkness. AB - We study the Z->gammagamma[over -] process in which the Z boson decays into a photon gamma and a massless dark photon gamma[over -], when the latter couples to standard-model fermions via dipole moments. This is a simple yet nontrivial example of how the Landau-Yang theorem-ruling out the decay of a massive spin-1 particle into two photons-is evaded if the final particles can be distinguished. The striking signature of this process is a resonant monochromatic single photon in the Z-boson center of mass together with missing momentum. LEP experimental bounds allow a branching ratio up to about 10^{-6} for such a decay. In a simplified model of the dark sector, the dark-photon dipole moments arise from one-loop exchange of heavy dark fermions and scalar messengers. The corresponding prediction for the rare Z->gammagamma[over -] decay width can be explored with the large samples of Z bosons foreseen at future colliders. PMID- 29756844 TI - pi and 4pi Josephson Effects Mediated by a Dirac Semimetal. AB - Cd_{3}As_{2} is a three-dimensional topological Dirac semimetal with connected Fermi-arc surface states. It has been suggested that topological superconductivity can be achieved in the nontrivial surface states of topological materials by utilizing the superconductor proximity effect. Here we report observations of both pi and 4pi periodic supercurrents in aluminum-Cd_{3}As_{2} aluminum Josephson junctions. The pi period is manifested by both the magnetic field dependence of the critical supercurrent and the appearance of half-integer Shapiro steps in the ac Josephson effect. Our macroscopic theory suggests that the pi period arises from interference between the induced bulk superconductivity and the induced Fermi-arc surface superconductivity. The 4pi period is manifested by the missing first Shapiro steps and is expected for topological superconductivity. PMID- 29756845 TI - Thermoelectric Power Factor Limit of a 1D Nanowire. AB - In the past decade, there has been significant interest in the potentially advantageous thermoelectric properties of one-dimensional (1D) nanowires, but it has been challenging to find high thermoelectric power factors based on 1D effects in practice. Here we point out that there is an upper limit to the thermoelectric power factor of nonballistic 1D nanowires, as a consequence of the recently established quantum bound of thermoelectric power output. We experimentally test this limit in quasiballistic InAs nanowires by extracting the maximum power factor of the first 1D subband through I-V characterization, finding that the measured maximum power factors conform to the theoretical limit. The established limit allows the prediction of the achievable power factor of a specific nanowire material system with 1D electronic transport based on the nanowire dimension and mean free path. The power factor of state-of-the-art semiconductor nanowires with small cross section and high crystal quality can be expected to be highly competitive (on the order of mW/m K^{2}) at low temperatures. However, they have no clear advantage over bulk materials at, or above, room temperature. PMID- 29756846 TI - Enabling Highly Effective Boiling from Superhydrophobic Surfaces. AB - A variety of industrial applications such as power generation, water distillation, and high-density cooling rely on heat transfer processes involving boiling. Enhancements to the boiling process can improve the energy efficiency and performance across multiple industries. Highly wetting textured surfaces have shown promise in boiling applications since capillary wicking increases the maximum heat flux that can be dissipated. Conversely, highly nonwetting textured (superhydrophobic) surfaces have been largely dismissed for these applications as they have been shown to promote formation of an insulating vapor film that greatly diminishes heat transfer efficiency. The current Letter shows that boiling from a superhydrophobic surface in an initial Wenzel state, in which the surface texture is infiltrated with liquid, results in remarkably low surface superheat with nucleate boiling sustained up to a critical heat flux typical of hydrophilic wetting surfaces, and thus upends this conventional wisdom. Two distinct boiling behaviors are demonstrated on both micro- and nanostructured superhydrophobic surfaces based on the initial wetting state. For an initial surface condition in which vapor occupies the interstices of the surface texture (Cassie-Baxter state), premature film boiling occurs, as has been commonly observed in the literature. However, if the surface texture is infiltrated with liquid (Wenzel state) prior to boiling, drastically improved thermal performance is observed; in this wetting state, the three-phase contact line is pinned during vapor bubble growth, which prevents the development of a vapor film over the surface and maintains efficient nucleate boiling behavior. PMID- 29756847 TI - Holographic Phonons. AB - We present a class of holographic massive gravity models that realize a spontaneous breaking of translational symmetry-they exhibit transverse phonon modes whose speed relates to the elastic shear modulus according to elasticity theory. Massive gravity theories thus emerge as versatile and convenient theories to model generic types of translational symmetry breaking: explicit, spontaneous, and a mixture of both. The nature of the breaking is encoded in the radial dependence of the graviton mass. As an application of the model, we compute the temperature dependence of the shear modulus and find that it features a glasslike melting transition. PMID- 29756848 TI - Strong-Isospin-Breaking Correction to the Muon Anomalous Magnetic Moment from Lattice QCD at the Physical Point. AB - All lattice-QCD calculations of the hadronic-vacuum-polarization contribution to the muon's anomalous magnetic moment to date have been performed with degenerate up- and down-quark masses. Here we calculate directly the strong-isospin-breaking correction to a_{MU}^{HVP} for the first time with physical values of m_{u} and m_{d} and dynamical u, d, s, and c quarks, thereby removing this important source of systematic uncertainty. We obtain a relative shift to be applied to lattice QCD results obtained with degenerate light-quark masses of deltaa_{MU}^{HVP,m_{u}?m_{d}}=+1.5(7)%, in agreement with estimates from phenomenology. PMID- 29756849 TI - Absolute Scale Quantitative Off-Axis Electron Holography at Atomic Resolution. AB - An absolute scale match between experiment and simulation in atomic-resolution off-axis electron holography is demonstrated, with unknown experimental parameters determined directly from the recorded electron wave function using an automated numerical algorithm. We show that the local thickness and tilt of a pristine thin WSe_{2} flake can be measured uniquely, whereas some electron optical aberrations cannot be determined unambiguously for a periodic object. The ability to determine local specimen and imaging parameters directly from electron wave functions is of great importance for quantitative studies of electrostatic potentials in nanoscale materials, in particular when performing in situ experiments and considering that aberrations change over time. PMID- 29756851 TI - Phase Transitions of the Polariton Condensate in 2D Dirac Materials. AB - For the quantum well in an optical microcavity, the interplay of the Coulomb interaction and the electron-photon (e-ph) coupling can lead to the hybridizations of the exciton and the cavity photon known as polaritons, which can form the Bose-Einstein condensate above a threshold density. Additional physics due to the nontrivial Berry phase comes into play when the quantum well consists of the gapped two-dimensional Dirac material such as the transition metal dichalcogenide MoS_{2} or WSe_{2}. Specifically, in forming the polariton, the e-ph coupling from the optical selection rule due to the Berry phase can compete against the Coulomb electron-electron (e-e) interaction. We find that this competition gives rise to a rich phase diagram for the polariton condensate involving both topological and symmetry breaking phase transitions, with the former giving rise to the quantum anomalous Hall and the quantum spin Hall phases. PMID- 29756850 TI - Search for Invisible Axion Dark Matter with the Axion Dark Matter Experiment. AB - This Letter reports the results from a haloscope search for dark matter axions with masses between 2.66 and 2.81 MUeV. The search excludes the range of axion photon couplings predicted by plausible models of the invisible axion. This unprecedented sensitivity is achieved by operating a large-volume haloscope at subkelvin temperatures, thereby reducing thermal noise as well as the excess noise from the ultralow-noise superconducting quantum interference device amplifier used for the signal power readout. Ongoing searches will provide nearly definitive tests of the invisible axion model over a wide range of axion masses. PMID- 29756852 TI - Protected Pseudohelical Edge States in Z_{2}-Trivial Proximitized Graphene. AB - We investigate topological properties of models that describe graphene on realistic substrates which induce proximity spin-orbit coupling in graphene. A Z_{2} phase diagram is calculated for the parameter space of (generally different) intrinsic spin-orbit coupling on the two graphene sublattices, in the presence of Rashba coupling. The most fascinating case is that of staggered intrinsic spin-orbit coupling which, despite being topologically trivial, Z_{2}=0, does exhibit edge states protected by time-reversal symmetry for zigzag ribbons as wide as micrometers. We call these states pseudohelical as their helicity is locked to the sublattice. The spin character and robustness of the pseudohelical modes is best exhibited on a finite flake, which shows that the edge states have zero g factor, carry a pure spin current in the cross section of the flake, and exhibit spin-flip reflectionless tunneling at the armchair edges. PMID- 29756853 TI - High-Density Quantum Sensing with Dissipative First Order Transitions. AB - The sensing of external fields using quantum systems is a prime example of an emergent quantum technology. Generically, the sensitivity of a quantum sensor consisting of N independent particles is proportional to sqrt[N]. However, interactions invariably occurring at high densities lead to a breakdown of the assumption of independence between the particles, posing a severe challenge for quantum sensors operating at the nanoscale. Here, we show that interactions in quantum sensors can be transformed from a nuisance into an advantage when strong interactions trigger a dissipative phase transition in an open quantum system. We demonstrate this behavior by analyzing dissipative quantum sensors based upon nitrogen-vacancy defect centers in diamond. Using both a variational method and a numerical simulation of the master equation describing the open quantum many-body system, we establish the existence of a dissipative first order transition that can be used for quantum sensing. We investigate the properties of this phase transition for two- and three-dimensional setups, demonstrating that the transition can be observed using current experimental technology. Finally, we show that quantum sensors based on dissipative phase transitions are particularly robust against imperfections such as disorder or decoherence, with the sensitivity of the sensor not being limited by the T_{2} coherence time of the device. Our results can readily be applied to other applications in quantum sensing and quantum metrology where interactions are currently a limiting factor. PMID- 29756854 TI - Hopping in the Crowd to Unveil Network Topology. AB - We introduce a nonlinear operator to model diffusion on a complex undirected network under crowded conditions. We show that the asymptotic distribution of diffusing agents is a nonlinear function of the nodes' degree and saturates to a constant value for sufficiently large connectivities, at variance with standard diffusion in the absence of excluded-volume effects. Building on this observation, we define and solve an inverse problem, aimed at reconstructing the a priori unknown connectivity distribution. The method gathers all the necessary information by repeating a limited number of independent measurements of the asymptotic density at a single node, which can be chosen randomly. The technique is successfully tested against both synthetic and real data and is also shown to estimate with great accuracy the total number of nodes. PMID- 29756856 TI - Global Anomaly Detection in Two-Dimensional Symmetry-Protected Topological Phases. AB - Edge theories of symmetry-protected topological phases are well known to possess global symmetry anomalies. In this Letter we focus on two-dimensional bosonic phases protected by an on-site symmetry and analyze the corresponding edge anomalies in more detail. Physical interpretations of the anomaly in terms of an obstruction to orbifolding and constructing symmetry-preserving boundaries are connected to the cohomology classification of symmetry-protected phases in two dimensions. Using the tensor network and matrix product state formalism we numerically illustrate our arguments and discuss computational detection schemes to identify symmetry-protected order in a ground state wave function. PMID- 29756855 TI - Post-Newtonian Dynamics in Dense Star Clusters: Highly Eccentric, Highly Spinning, and Repeated Binary Black Hole Mergers. AB - We present models of realistic globular clusters with post-Newtonian dynamics for black holes. By modeling the relativistic accelerations and gravitational-wave emission in isolated binaries and during three- and four-body encounters, we find that nearly half of all binary black hole mergers occur inside the cluster, with about 10% of those mergers entering the LIGO/Virgo band with eccentricities greater than 0.1. In-cluster mergers lead to the birth of a second generation of black holes with larger masses and high spins, which, depending on the black hole natal spins, can sometimes be retained in the cluster and merge again. As a result, globular clusters can produce merging binaries with detectable spins regardless of the birth spins of black holes formed from massive stars. These second-generation black holes would also populate any upper mass gap created by pair-instability supernovae. PMID- 29756857 TI - Emergent Chiral Spin State in the Mott Phase of a Bosonic Kane-Mele-Hubbard Model. AB - Recently, the frustrated XY model for spins 1/2 on the honeycomb lattice has attracted a lot of attention in relation with the possibility to realize a chiral spin liquid state. This model is relevant to the physics of some quantum magnets. Using the flexibility of ultracold atom setups, we propose an alternative way to realize this model through the Mott regime of the bosonic Kane-Mele-Hubbard model. The phase diagram of this model is derived using bosonic dynamical mean field theory. Focusing on the Mott phase, we investigate its magnetic properties as a function of frustration. We do find an emergent chiral spin state in the intermediate frustration regime. Using exact diagonalization we study more closely the physics of the effective frustrated XY model and the properties of the chiral spin state. This gapped phase displays a chiral order, breaking time reversal and parity symmetry, but is not topologically ordered (the Chern number is zero). PMID- 29756858 TI - First Monte Carlo Global Analysis of Nucleon Transversity with Lattice QCD Constraints. AB - We report on the first global QCD analysis of the quark transversity distributions in the nucleon from semi-inclusive deep-inelastic scattering (SIDIS), using a new Monte Carlo method based on nested sampling and constraints on the isovector tensor charge g_{T} from lattice QCD. A simultaneous fit to the available SIDIS Collins asymmetry data is compatible with g_{T} values extracted from a comprehensive reanalysis of existing lattice simulations, in contrast to previous analyses, which found significantly smaller g_{T} values. The contributions to the nucleon tensor charge from u and d quarks are found to be deltau=0.3(2) and deltad=-0.7(2) at a scale Q^{2}=2 GeV^{2}. PMID- 29756859 TI - Scalar, Axial, and Tensor Interactions of Light Nuclei from Lattice QCD. AB - Complete flavor decompositions of the matrix elements of the scalar, axial, and tensor currents in the proton, deuteron, diproton, and ^{3}He at SU(3)-symmetric values of the quark masses corresponding to a pion mass m_{pi}~806 MeV are determined using lattice quantum chromodynamics. At the physical quark masses, the scalar interactions constrain mean-field models of nuclei and the low-energy interactions of nuclei with potential dark matter candidates. The axial and tensor interactions of nuclei constrain their spin content, integrated transversity, and the quark contributions to their electric dipole moments. External fields are used to directly access the quark-line connected matrix elements of quark bilinear operators, and a combination of stochastic estimation techniques is used to determine the disconnected sea-quark contributions. The calculated matrix elements differ from, and are typically smaller than, naive single-nucleon estimates. Given the particularly large, O(10%), size of nuclear effects in the scalar matrix elements, contributions from correlated multinucleon effects should be quantified in the analysis of dark matter direct-detection experiments using nuclear targets. PMID- 29756861 TI - Antiferromagnetic Chern Insulators in Noncentrosymmetric Systems. AB - We investigate a new class of topological antiferromagnetic (AF) Chern insulators driven by electronic interactions in two-dimensional systems without inversion symmetry. Despite the absence of a net magnetization, AF Chern insulators (AFCI) possess a nonzero Chern number C and exhibit the quantum anomalous Hall effect (QAHE). Their existence is guaranteed by the bifurcation of the boundary line of Weyl points between a quantum spin Hall insulator and a topologically trivial phase with the emergence of AF long-range order. As a concrete example, we study the phase structure of the honeycomb lattice Kane-Mele model as a function of the inversion-breaking ionic potential and the Hubbard interaction. We find an easy z axis C=1 AFCI phase and a spin-flop transition to a topologically trivial xy plane collinear antiferromagnet. We propose experimental realizations of the AFCI and QAHE in correlated electron materials and cold atom systems. PMID- 29756860 TI - Realization of a Lambda System with Metastable States of a Capacitively Shunted Fluxonium. AB - We realize a Lambda system in a superconducting circuit, with metastable states exhibiting lifetimes up to 8 ms. We exponentially suppress the tunneling matrix elements involved in spontaneous energy relaxation by creating a "heavy" fluxonium, realized by adding a capacitive shunt to the original circuit design. The device allows for both cavity-assisted and direct fluorescent readouts, as well as state preparation schemes akin to optical pumping. Since direct transitions between the metastable states are strongly suppressed, we utilize Raman transitions for coherent manipulation of the states. PMID- 29756862 TI - Toward a Determination of the Proton-Electron Mass Ratio from the Lamb-Dip Measurement of HD. AB - Precision spectroscopy of the hydrogen molecule is a test ground of quantum electrodynamics (QED), and it may serve for the determination of fundamental constants. Using a comb-locked cavity ring-down spectrometer, for the first time, we observed the Lamb-dip spectrum of the R(1) line in the overtone of hydrogen deuteride (HD). The line position was determined to be 217 105 182.79+/ 0.03_{stat}+/-0.08_{syst} MHz (deltanu/nu=4*10^{-10}), which is the most accurate rovibrational transition ever measured in the ground electronic state of molecular hydrogen. Moreover, from calculations including QED effects up to the order m_{e}alpha^{6}, we obtained predictions for this R(1) line as well as for the HD dissociation energy, which are less accurate but signaling the importance of the complete treatment of nonadiabatic effects. Provided that the theoretical calculation reaches the same accuracy, the present measurement will lead to a determination of the proton-to-electron mass ratio with a precision of 1.3 parts per billion. PMID- 29756863 TI - Wave-Function Hybridization in Yu-Shiba-Rusinov Dimers. AB - Magnetic adsorbates on superconductors induce local bound states within the superconducting gap. These Yu-Shiba-Rusinov (YSR) states decay slowly away from the impurity compared to atomic orbitals, even in 3D bulk crystals. Here, we use scanning tunneling spectroscopy to investigate their hybridization between two nearby magnetic Mn adatoms on a superconducting Pb(001) surface. We observe that the hybridization leads to the formation of symmetric and antisymmetric combinations of YSR states. We investigate how the structure of the dimer wave functions and the energy splitting depend on the shape of the underlying monomer orbitals and the orientation of the dimer with respect to the Pb lattice. PMID- 29756865 TI - Crystalline Symmetry-Protected Majorana Mode in Number-Conserving Dirac Semimetal Nanowires. AB - One of the cornerstones for topological quantum computations is the Majorana zero mode, which has been intensively searched in fractional quantum Hall systems and topological superconductors. Several recent works suggest that such an exotic mode can also exist in a one-dimensional (1D) interacting double-wire setup even without long-range superconductivity. A notable instability in these proposals comes from interchannel single-particle tunneling that spoils the topological ground state degeneracy. Here we show that a 1D Dirac semimetal (DSM) nanowire is an ideal number-conserving platform to realize such Majorana physics. By inserting magnetic flux, a DSM nanowire is driven into a 1D crystalline-symmetry protected semimetallic phase. Interaction enables the emergence of boundary Majorana zero modes, which is robust as a result of crystalline symmetry protection. We also explore several experimental consequences of Majorana signals. PMID- 29756864 TI - First Direct Mass Measurements of Nuclides around Z=100 with a Multireflection Time-of-Flight Mass Spectrograph. AB - The masses of ^{246}Es, ^{251}Fm, and the transfermium nuclei ^{249-252}Md and ^{254}No, produced by hot- and cold-fusion reactions, in the vicinity of the deformed N=152 neutron shell closure, have been directly measured using a multireflection time-of-flight mass spectrograph. The masses of ^{246}Es and ^{249,250,252}Md were measured for the first time. Using the masses of ^{249,250}Md as anchor points for alpha decay chains, the masses of heavier nuclei, up to ^{261}Bh and ^{266}Mt, were determined. These new masses were compared with theoretical global mass models and demonstrated to be in good agreement with macroscopic-microscopic models in this region. The empirical shell gap parameter delta_{2n} derived from three isotopic masses was updated with the new masses and corroborates the existence of the deformed N=152 neutron shell closure for Md and Lr. PMID- 29756866 TI - Microscopic Investigation into the Electric Field Effect on Proximity-Induced Magnetism in Pt. AB - Electric field effects on magnetism in metals have attracted widespread attention, but the microscopic mechanism is still controversial. We experimentally show the relevancy between the electric field effect on magnetism and on the electronic structure in Pt in a ferromagnetic state using element specific measurements: x-ray magnetic circular dichroism (XMCD) and x-ray absorption spectroscopy (XAS). Electric fields are applied to the surface of ultrathin metallic Pt, in which a magnetic moment is induced by the ferromagnetic proximity effect resulting from a Co underlayer. XMCD and XAS measurements performed under the application of electric fields reveal that both the spin and orbital magnetic moments of Pt atoms are electrically modulated, which can be explained not only by the electric-field-induced shift of the Fermi level but also by the change in the orbital hybridizations. PMID- 29756868 TI - Test One to Test Many: A Unified Approach to Quantum Benchmarks. AB - Quantum benchmarks are routinely used to validate the experimental demonstration of quantum information protocols. Many relevant protocols, however, involve an infinite set of input states, of which only a finite subset can be used to test the quality of the implementation. This is a problem, because the benchmark for the finitely many states used in the test can be higher than the original benchmark calculated for infinitely many states. This situation arises in the teleportation and storage of coherent states, for which the benchmark of 50% fidelity is commonly used in experiments, although finite sets of coherent states normally lead to higher benchmarks. Here, we show that the average fidelity over all coherent states can be indirectly probed with a single setup, requiring only two-mode squeezing, a 50-50 beam splitter, and homodyne detection. Our setup enables a rigorous experimental validation of quantum teleportation, storage, amplification, attenuation, and purification of noisy coherent states. More generally, we prove that every quantum benchmark can be tested by preparing a single entangled state and measuring a single observable. PMID- 29756810 TI - Measurement of the Ratio of the B^{0}->D^{*-}tau^{+}nu_{tau} and B^{0}->D^{* }MU^{+}nu_{MU} Branching Fractions Using Three-Prong tau-Lepton Decays. AB - The ratio of branching fractions R(D^{*-})=B(B^{0}->D^{* }tau^{+}nu_{tau})/B(B^{0}->D^{*-}MU^{+}nu_{MU}) is measured using a data sample of proton-proton collisions collected with the LHCb detector at center-of-mass energies of 7 and 8 TeV, corresponding to an integrated luminosity of 3 fb^{-1}. For the first time, R(D^{*-}) is determined using the tau-lepton decays with three charged pions in the final state. The B^{0}->D^{*-}tau^{+}nu_{tau} yield is normalized to that of the B^{0}->D^{*-}pi^{+}pi^{-}pi^{+} mode, providing a measurement of B(B^{0}->D^{*-}tau^{+}nu_{tau})/B(B^{0}->D^{*-}pi^{+}pi^{ }pi^{+})=1.97+/-0.13+/-0.18, where the first uncertainty is statistical and the second systematic. The value of B(B^{0}->D^{*-}tau^{+}nu_{tau})=(1.42+/-0.094+/ 0.129+/-0.054)% is obtained, where the third uncertainty is due to the limited knowledge of the branching fraction of the normalization mode. Using the well measured branching fraction of the B^{0}->D^{*-}MU^{+}nu_{MU} decay, a value of R(D^{*-})=0.291+/-0.019+/-0.026+/-0.013 is established, where the third uncertainty is due to the limited knowledge of the branching fractions of the normalization and B^{0}->D^{*-}MU^{+}nu_{MU} modes. This measurement is in agreement with the standard model prediction and with previous results. PMID- 29756870 TI - Why Clothes Don't Fall Apart: Tension Transmission in Staple Yarns. AB - The problem of how staple yarns transmit tension is addressed within abstract models in which the Amontons-Coulomb friction laws yield a linear programing (LP) problem for the tensions in the fiber elements. We find there is a percolation transition such that above the percolation threshold the transmitted tension is in principle unbounded. We determine that the mean slack in the LP constraints is a suitable order parameter to characterize this supercritical state. We argue the mechanism is generic, and in practical terms, it corresponds to a switch from a ductile to a brittle failure mode accompanied by a significant increase in mechanical strength. PMID- 29756869 TI - Interfacial Dzyaloshinskii-Moriya Interaction: Effect of 5d Band Filling and Correlation with Spin Mixing Conductance. AB - The Dzyaloshinskii-Moriya interaction (DMI) at the heavy metal (HM) and ferromagnetic metal (FM) interface has been recognized as a key ingredient in spintronic applications. Here we investigate the chemical trend of DMI on the 5d band filling (5d^{3}-5d^{10}) of the HM element in HM/FM (FM=CoFeB,Co)/MgO multilayer thin films. DMI is quantitatively evaluated by measuring asymmetric spin wave dispersion using Brillouin light scattering. Sign reversal and 20 times modification of the DMI coefficient D have been measured as the 5d HM element is varied. The chemical trend can be qualitatively understood by considering the 5d and 3d bands alignment at the HM/FM interface and the subsequent orbital hybridization around the Fermi level. Furthermore, a correlation is observed between DMI and effective spin mixing conductance at the HM/FM interfaces. Our results provide new insights into the interfacial DMI for designing future spintronic devices. PMID- 29756871 TI - Demonstration of Protection of a Superconducting Qubit from Energy Decay. AB - Long-lived transitions occur naturally in atomic systems due to the abundance of selection rules inhibiting spontaneous emission. By contrast, transitions of superconducting artificial atoms typically have large dipoles, and hence their lifetimes are determined by the dissipative environment of a macroscopic electrical circuit. We designed a multilevel fluxonium artificial atom such that the qubit's transition dipole can be exponentially suppressed by flux tuning, while it continues to dispersively interact with a cavity mode by virtual transitions to the noncomputational states. Remarkably, energy decay time T_{1} grew by 2 orders of magnitude, proportionally to the inverse square of the transition dipole, and exceeded the benchmark value of T_{1}>2 ms (quality factor Q_{1}>4*10^{7}) without showing signs of saturation. The dephasing time was limited by the first-order coupling to flux noise to about 4 MUs. Our circuit validated the general principle of hardware-level protection against bit flip errors and can be upgraded to the 0-pi circuit [P. Brooks, A. Kitaev, and J. Preskill, Phys. Rev. A 87, 052306 (2013)PLRAAN1050 294710.1103/PhysRevA.87.052306], adding protection against dephasing and certain gate errors. PMID- 29756874 TI - Sub-Doppler Frequency Metrology in HD for Tests of Fundamental Physics. AB - Weak transitions in the (2,0) overtone band of the hydrogen deuteride molecule at lambda=1.38 MUm were measured in saturated absorption using the technique of noise-immune cavity-enhanced optical heterodyne molecular spectroscopy. Narrow Doppler-free lines were interrogated with a spectroscopy laser locked to a frequency comb laser referenced to an atomic clock to yield transition frequencies [R(1)=217105181895(20) kHz; R(2)=219042856621(28) kHz; R(3)=220704304951(28) kHz] at three orders of magnitude improved accuracy. These benchmark values provide a test of QED in the smallest neutral molecule, and they open up an avenue to resolve the proton radius puzzle, as well as constrain putative fifth forces and extra dimensions. PMID- 29756872 TI - Disentangled Cooperative Orderings in Artificial Rare-Earth Nickelates. AB - Coupled transitions between distinct ordered phases are important aspects behind the rich phase complexity of correlated oxides that hinder our understanding of the underlying phenomena. For this reason, fundamental control over complex transitions has become a leading motivation of the designer approach to materials. We have devised a series of new superlattices by combining a Mott insulator and a correlated metal to form ultrashort period superlattices, which allow one to disentangle the simultaneous orderings in RENiO_{3}. Tailoring an incommensurate heterostructure period relative to the bulk charge ordering pattern suppresses the charge order transition while preserving metal-insulator and antiferromagnetic transitions. Such selective decoupling of the entangled phases resolves the long-standing puzzle about the driving force behind the metal insulator transition and points to the site-selective Mott transition as the operative mechanism. This designer approach emphasizes the potential of heterointerfaces for selective control of simultaneous transitions in complex materials with entwined broken symmetries. PMID- 29756873 TI - Band Structure of the IV-VI Black Phosphorus Analog and Thermoelectric SnSe. AB - The success of black phosphorus in fast electronic and photonic devices is hindered by its rapid degradation in the presence of oxygen. Orthorhombic tin selenide is a representative of group IV-VI binary compounds that are robust and isoelectronic and share the same structure with black phosphorus. We measure the band structure of SnSe and find highly anisotropic valence bands that form several valleys having fast dispersion within the layers and negligible dispersion across. This is exactly the band structure desired for efficient thermoelectric generation where SnSe has shown great promise. PMID- 29756867 TI - Strong Neutron Pairing in core+4n Nuclei. AB - The emission of neutron pairs from the neutron-rich N=12 isotones ^{18}C and ^{20}O has been studied by high-energy nucleon knockout from ^{19}N and ^{21}O secondary beams, populating unbound states of the two isotones up to 15 MeV above their two-neutron emission thresholds. The analysis of triple fragment-n-n correlations shows that the decay ^{19}N(-1p)^{18}C^{*}->^{16}C+n+n is clearly dominated by direct pair emission. The two-neutron correlation strength, the largest ever observed, suggests the predominance of a ^{14}C core surrounded by four valence neutrons arranged in strongly correlated pairs. On the other hand, a significant competition of a sequential branch is found in the decay ^{21}O( 1n)^{20}O^{*}->^{18}O+n+n, attributed to its formation through the knockout of a deeply bound neutron that breaks the ^{16}O core and reduces the number of pairs. PMID- 29756875 TI - Frequency Combs in a Lumped-Element Josephson-Junction Circuit. AB - We investigate the dynamics of a microwave-driven Josephson junction capacitively coupled to a lumped-element LC oscillator. In the regime of driving where the Josephson junction can be approximated as a Kerr oscillator, this minimal nonlinear system has been previously shown to exhibit a bistability in phase and amplitude. In the present study, we characterize the full phase diagram and show that besides a parameter regime exhibiting bistability, there is also a regime of self-oscillations characterized by a frequency comb in its spectrum. We discuss the mechanism of comb generation which appears to be different from those studied in microcavity frequency combs and mode-locked lasers. We then address the fate of the comblike spectrum in the regime of strong quantum fluctuations, reached when nonlinearity becomes the dominant scale with respect to dissipation. We find that the nonlinearity responsible for the emergence of the frequency combs also leads to its dephasing, leading to broadening and ultimate disappearance of sharp spectral peaks. Our study explores the fundamental question of the impact of quantum fluctuations for quantum systems which do not possess a stable fixed point in the classical limit. PMID- 29756876 TI - Data-Driven Learning of Total and Local Energies in Elemental Boron. AB - The allotropes of boron continue to challenge structural elucidation and solid state theory. Here we use machine learning combined with random structure searching (RSS) algorithms to systematically construct an interatomic potential for boron. Starting from ensembles of randomized atomic configurations, we use alternating single-point quantum-mechanical energy and force computations, Gaussian approximation potential (GAP) fitting, and GAP-driven RSS to iteratively generate a representation of the element's potential-energy surface. Beyond the total energies of the very different boron allotropes, our model readily provides atom-resolved, local energies and thus deepened insight into the frustrated beta rhombohedral boron structure. Our results open the door for the efficient and automated generation of GAPs, and other machine-learning-based interatomic potentials, and suggest their usefulness as a tool for materials discovery. PMID- 29756877 TI - Multistage Coupling of Laser-Wakefield Accelerators with Curved Plasma Channels. AB - Multistage coupling of laser-wakefield accelerators is essential to overcome laser energy depletion for high-energy applications such as TeV-level electron positron colliders. Current staging schemes feed subsequent laser pulses into stages using plasma mirrors while controlling electron beam focusing with plasma lenses. Here a more compact and efficient scheme is proposed to realize the simultaneous coupling of the electron beam and the laser pulse into a second stage. A partly curved channel, integrating a straight acceleration stage with a curved transition segment, is used to guide a fresh laser pulse into a subsequent straight channel, while the electrons continue straight. This scheme benefits from a shorter coupling distance and continuous guiding of the electrons in plasma while suppressing transverse beam dispersion. Particle-in-cell simulations demonstrate that the electron beam from a previous stage can be efficiently injected into a subsequent stage for further acceleration while maintaining high capture efficiency, stability, and beam quality. PMID- 29756878 TI - Multiscale Relaxation Dynamics in Ultrathin Metallic Glass-Forming Films. AB - The density layering phenomenon originating from a free surface gives rise to the layerlike dynamics and stress heterogeneity in ultrathin Cu-Zr glassy films, which facilitates the occurrence of multistep relaxations in the timescale of computer simulations. Taking advantage of this condition, we trace the relaxation decoupling and evolution with temperature simply via the intermediate scattering function. We show that the beta relaxation hierarchically follows fast and slow modes in films, and there is a beta-relaxation transition as the film is cooled close to the glass transition. We provide the direct observation of particle motions responsible for the beta relaxation and reveal the dominant mechanism varying from the thermal activated to the cooperative jumps across the transition. PMID- 29756879 TI - Collective Dynamics and Strong Pinning near the Onset of Charge Order in La_{1.48}Nd_{0.4}Sr_{0.12}CuO_{4}. AB - The dynamics of charge-ordered states is one of the key issues in underdoped cuprate high-temperature superconductors, but static short-range charge-order (CO) domains have been detected in almost all cuprates. We probe the dynamics across the CO (and structural) transition in La_{1.48}Nd_{0.4}Sr_{0.12}CuO_{4} by measuring nonequilibrium charge transport, or resistance R as the system responds to a change in temperature and to an applied magnetic field. We find evidence for metastable states, collective behavior, and criticality. The collective dynamics in the critical regime indicates strong pinning by disorder. Surprisingly, nonequilibrium effects, such as avalanches in R, are revealed only when the critical region is approached from the charge-ordered phase. Our results on La_{1.48}Nd_{0.4}Sr_{0.12}CuO_{4} provide the long-sought evidence for the fluctuating order across the CO transition, and also set important constraints on theories of dynamic stripes. PMID- 29756880 TI - Ultrastrong Coupling Few-Photon Scattering Theory. AB - We study the scattering of individual photons by a two-level system ultrastrongly coupled to a waveguide. The scattering is elastic for a broad range of couplings and can be described with an effective U(1)-symmetric Hamiltonian. This simple model allows the prediction of scattering resonance line shapes, validated up to alpha=0.3, and close to the Toulouse point alpha=1/2, where inelastic scattering becomes relevant. Our predictions model experiments with superconducting circuits [P. Forn-Diaz et al., Nat. Phys. 13, 39 (2017)NPAHAX1745-247310.1038/nphys3905] and can be extended to study multiphoton scattering. PMID- 29756881 TI - Light-Induced Type-II Band Inversion and Quantum Anomalous Hall State in Monolayer FeSe. AB - Coupling a quantum anomalous Hall (QAH) state with a superconducting state offers an attractive approach to detect the signature alluding to a topological superconducting state [Q. L. He et al., Science 357, 294 (2017)SCIEAS0036 807510.1126/science.aag2792], but its explanation could be clouded by disorder effects in magnetic doped QAH materials. On the other hand, an antiferromagnetic (AFM) quantum spin Hall (QSH) state is identified in the well-known high temperature 2D superconductor of monolayer FeSe [Z. F. Wang et al., Nat. Mater. 15, 968 (2016)NMAACR1476-112210.1038/nmat4686]. Here, we report a light-induced type-II band inversion (BI) and a QSH-to-QAH phase transition in the monolayer FeSe. Depending on the handedness of light, a spin-tunable QAH state with a high Chern number of +/-2 is realized. In contrast to the conventional type-I BI resulting from intrinsic spin-orbital coupling (SOC), which inverts the band an odd number of times and respects time reversal symmetry, the type-II BI results from a light-induced handedness-dependent effective SOC, which inverts the band an even number of times and does not respect time reversal symmetry. The interplay between these two SOC terms makes the spin-up and -down bands of an AFM QSH state respond oppositely to a circularly polarized light, leading to the type II BI and an exotic topological phase transition. Our finding affords an exciting opportunity to detect Majorana fermions in one single material without magnetic doping. PMID- 29756882 TI - Diversity, Stability, and Reproducibility in Stochastically Assembled Microbial Ecosystems. AB - Microbial ecosystems are remarkably diverse, stable, and usually consist of a mixture of core and peripheral species. Here we propose a conceptual model exhibiting all these emergent properties in quantitative agreement with real ecosystem data, specifically species abundance and prevalence distributions. Resource competition and metabolic commensalism drive the stochastic ecosystem assembly in our model. We demonstrate that even when supplied with just one resource, ecosystems can exhibit high diversity, increasing stability, and partial reproducibility between samples. PMID- 29756884 TI - Observation of Poincare-Andronov-Hopf Bifurcation in Cyclotron Maser Emission from a Magnetic Plasma Trap. AB - We report the first experimental evidence of a controlled transition from the generation of periodic bursts of electromagnetic radiation into the continuous wave regime of a cyclotron maser formed in magnetically confined nonequilibrium plasma. The kinetic cyclotron instability of the extraordinary wave of weakly inhomogeneous magnetized plasma is driven by the anisotropic electron population resulting from electron cyclotron plasma heating in a MHD-stable minimum-B open magnetic trap. PMID- 29756883 TI - Spectroscopy of Pionic Atoms in ^{122}Sn(d,^{3}He) Reaction and Angular Dependence of the Formation Cross Sections. AB - We observed the atomic 1s and 2p states of pi^{-} bound to ^{121}Sn nuclei as distinct peak structures in the missing mass spectra of the ^{122}Sn(d,^{3}He) nuclear reaction. A very intense deuteron beam and a spectrometer with a large angular acceptance let us achieve a potential of discovery, which includes the capability of determining the angle-dependent cross sections with high statistics. The 2p state in a Sn nucleus was observed for the first time. The binding energies and widths of the pionic states are determined and found to be consistent with previous experimental results of other Sn isotopes. The spectrum is measured at finite reaction angles for the first time. The formation cross sections at the reaction angles between 0 degrees and 2 degrees are determined. The observed reaction-angle dependence of each state is reproduced by theoretical calculations. However, the quantitative comparison with our high-precision data reveals a significant discrepancy between the measured and calculated formation cross sections of the pionic 1s state. PMID- 29756885 TI - Designing Hysteresis with Dipolar Chains. AB - Materials that have hysteretic response to an external field are essential in modern information storage and processing technologies. A myriad of magnetization curves of several natural and artificial materials have previously been measured and each has found a particular mechanism that accounts for it. However, a phenomenological model that captures all the hysteresis loops and at the same time provides a simple way to design the magnetic response of a material while remaining minimal is missing. Here, we propose and experimentally demonstrate an elementary method to engineer hysteresis loops in metamaterials built out of dipolar chains. We show that by tuning the interactions of the system and its geometry we can shape the hysteresis loop which allows for the design of the softness of a magnetic material at will. Additionally, this mechanism allows for the control of the number of loops aimed to realize multiple-valued logic technologies. Our findings pave the way for the rational design of hysteretical responses in a variety of physical systems such as dipolar cold atoms, ferroelectrics, or artificial magnetic lattices, among others. PMID- 29756887 TI - Electronic Spectrum of Twisted Graphene Layers under Heterostrain. AB - We demonstrate that stacking layered materials allows a strain engineering where each layer is strained independently, which we call heterostrain. We combine detailed structural and spectroscopic measurements with tight-binding calculations to show that small uniaxial heterostrain suppresses Dirac cones and leads to the emergence of flat bands in twisted graphene layers (TGLs). Moreover, we demonstrate that heterostrain reconstructs, much more severely, the energy spectrum of TGLs than homostrain for which both layers are strained identically, a result which should apply to virtually all van der Waals structures opening exciting possibilities for straintronics with 2D materials. PMID- 29756886 TI - First Direct Observation of Runaway-Electron-Driven Whistler Waves in Tokamaks. AB - DIII-D experiments at low density (n_{e}~10^{19} m^{-3}) have directly measured whistler waves in the 100-200 MHz range excited by multi-MeV runaway electrons. Whistler activity is correlated with runaway intensity (hard x-ray emission level), occurs in novel discrete frequency bands, and exhibits nonlinear limit cycle-like behavior. The measured frequencies scale with the magnetic field strength and electron density as expected from the whistler dispersion relation. The modes are stabilized with increasing magnetic field, which is consistent with wave-particle resonance mechanisms. The mode amplitudes show intermittent time variations correlated with changes in the electron cyclotron emission that follow predator-prey cycles. These can be interpreted as wave-induced pitch angle scattering of moderate energy runaways. The tokamak runaway-whistler mechanisms have parallels to whistler phenomena in ionospheric plasmas. The observations also open new directions for the modeling and active control of runaway electrons in tokamaks. PMID- 29756889 TI - Nonadiabatic Dynamics in Single-Electron Tunneling Devices with Time-Dependent Density-Functional Theory. AB - We simulate the dynamics of a single-electron source, modeled as a quantum dot with on-site Coulomb interaction and tunnel coupling to an adjacent lead in time dependent density-functional theory. Based on this system, we develop a time nonlocal exchange-correlation potential by exploiting analogies with quantum transport theory. The time nonlocality manifests itself in a dynamical potential step. We explicitly link the time evolution of the dynamical step to physical relaxation timescales of the electron dynamics. Finally, we discuss prospects for simulations of larger mesoscopic systems. PMID- 29756888 TI - Rydberg Molecules for Ion-Atom Scattering in the Ultracold Regime. AB - We propose a novel experimental method to extend the investigation of ion-atom collisions from the so far studied cold, essentially classical regime to the ultracold, quantum regime. The key aspect of this method is the use of Rydberg molecules to initialize the ultracold ion-atom scattering event. We exemplify the proposed method with the lithium ion-atom system, for which we present simulations of how the initial Rydberg molecule wave function, freed by photoionization, evolves in the presence of the ion-atom scattering potential. We predict bounds for the ion-atom scattering length from ab initio calculations of the interaction potential. We demonstrate that, in the predicted bounds, the scattering length can be experimentally determined from the velocity of the scattered wave packet in the case of ^{6}Li^{+}-^{6}Li and from the molecular ion fraction in the case of ^{7}Li^{+}-^{7}Li. The proposed method to utilize Rydberg molecules for ultracold ion-atom scattering, here particularized for the lithium ion-atom system, is readily applicable to other ion-atom systems as well. PMID- 29756890 TI - Parametrization and Optimization of Gaussian Non-Markovian Unravelings for Open Quantum Dynamics. AB - We derive a family of Gaussian non-Markovian stochastic Schrodinger equations for the dynamics of open quantum systems. The different unravelings correspond to different choices of squeezed coherent states, reflecting different measurement schemes on the environment. Consequently, we are able to give a single shot measurement interpretation for the stochastic states and microscopic expressions for the noise correlations of the Gaussian process. By construction, the reduced dynamics of the open system does not depend on the squeezing parameters. They determine the non-Hermitian Gaussian correlation, a wide range of which are compatible with the Markov limit. We demonstrate the versatility of our results for quantum information tasks in the non-Markovian regime. In particular, by optimizing the squeezing parameters, we can tailor unravelings for improving entanglement bounds or for environment-assisted entanglement protection. PMID- 29756891 TI - Eigenstate Thermalization for Degenerate Observables. AB - Under unitary time evolution, expectation values of physically reasonable observables often evolve towards the predictions of equilibrium statistical mechanics. The eigenstate thermalization hypothesis (ETH) states that this is also true already for individual energy eigenstates. Here we aim at elucidating the emergence of the ETH for observables that can realistically be measured due to their high degeneracy, such as local, extensive, or macroscopic observables. We bisect this problem into two parts, a condition on the relative overlaps and one on the relative phases between the eigenbases of the observable and Hamiltonian. We show that the relative overlaps are unbiased for highly degenerate observables and demonstrate that unless relative phases conspire to cumulative effects, this makes such observables verify the ETH. Through this we elucidate potential pathways towards proofs of thermalization. PMID- 29756892 TI - Topological Floquet-Thouless Energy Pump. AB - We explore adiabatic pumping in the presence of a periodic drive, finding a new phase in which the topologically quantized pumped quantity is energy rather than charge. The topological invariant is given by the winding number of the micromotion with respect to time within each cycle, momentum, and adiabatic tuning parameter. We show numerically that this pump is highly robust against both disorder and interactions, breaking down at large values of either in a manner identical to the Thouless charge pump. Finally, we suggest experimental protocols for measuring this phenomenon. PMID- 29756893 TI - Selection Dynamics in Transient Compartmentalization. AB - Transient compartments have been recently shown to be able to maintain functional replicators in the context of prebiotic studies. Here, we show that a broad class of selection dynamics is able to achieve this goal. We identify two key parameters, the relative amplification of nonactive replicators (parasites) and the size of compartments. These parameters account for competition and diversity, and the results are relevant to similar multilevel selection problems, such as those found in virus-host ecology and trait group selection. PMID- 29756895 TI - Tunable, Flexible, and Efficient Optimization of Control Pulses for Practical Qubits. AB - Quantum computation places very stringent demands on gate fidelities, and experimental implementations require both the controls and the resultant dynamics to conform to hardware-specific constraints. Superconducting qubits present the additional requirement that pulses must have simple parameterizations, so they can be further calibrated in the experiment, to compensate for uncertainties in system parameters. Other quantum technologies, such as sensing, require extremely high fidelities. We present a novel, conceptually simple and easy-to-implement gradient-based optimal control technique named gradient optimization of analytic controls (GOAT), which satisfies all the above requirements, unlike previous approaches. To demonstrate GOAT's capabilities, with emphasis on flexibility and ease of subsequent calibration, we optimize fast coherence-limited pulses for two leading superconducting qubits architectures-flux-tunable transmons and fixed frequency transmons with tunable couplers. PMID- 29756896 TI - Three-Dimensional Non-Fermi-Liquid Behavior from One-Dimensional Quantum Critical Local Moments. AB - We study the temperature dependence of the electrical resistivity in a system composed of critical spin chains interacting with three-dimensional conduction electrons and driven to criticality via an external magnetic field. The relevant experimental system is Yb_{2}Pt_{2}Pb, a metal where itinerant electrons coexist with localized moments of Yb ions which can be described in terms of effective S=1/2 spins with a dominantly one-dimensional exchange interaction. The spin subsystem becomes critical in a relatively weak magnetic field, where it behaves like a Luttinger liquid. We theoretically examine a Kondo lattice with different effective space dimensionalities of the two interacting subsystems. We characterize the corresponding non-Fermi liquid behavior due to the spin criticality by calculating the electronic relaxation rate and the dc resistivity and establish its quasilinear temperature dependence. PMID- 29756894 TI - Fermiology and Superconductivity of Topological Surface States in PdTe_{2}. AB - We study the low-energy surface electronic structure of the transition-metal dichalcogenide superconductor PdTe_{2} by spin- and angle-resolved photoemission, scanning tunneling microscopy, and density-functional theory-based supercell calculations. Comparing PdTe_{2} with its sister compound PtSe_{2}, we demonstrate how enhanced interlayer hopping in the Te-based material drives a band inversion within the antibonding p-orbital manifold well above the Fermi level. We show how this mediates spin-polarized topological surface states which form rich multivalley Fermi surfaces with complex spin textures. Scanning tunneling spectroscopy reveals type-II superconductivity at the surface, and moreover shows no evidence for an unconventional component of its superconducting order parameter, despite the presence of topological surface states. PMID- 29756897 TI - Structure of the Lightest Tin Isotopes. AB - We link the structure of nuclei around ^{100}Sn, the heaviest doubly magic nucleus with equal neutron and proton numbers (N=Z=50), to nucleon-nucleon (NN) and three-nucleon (NNN) forces constrained by data of few-nucleon systems. Our results indicate that ^{100}Sn is doubly magic, and we predict its quadrupole collectivity. We present precise computations of ^{101}Sn based on three-particle two-hole excitations of ^{100}Sn, and we find that one interaction accurately reproduces the small splitting between the lowest J^{pi}=7/2^{+} and 5/2^{+} states. PMID- 29756899 TI - Clock-Work Trade-Off Relation for Coherence in Quantum Thermodynamics. AB - In thermodynamics, quantum coherences-superpositions between energy eigenstates behave in distinctly nonclassical ways. Here we describe how thermodynamic coherence splits into two kinds-"internal" coherence that admits an energetic value in terms of thermodynamic work, and "external" coherence that does not have energetic value, but instead corresponds to the functioning of the system as a quantum clock. For the latter form of coherence, we provide dynamical constraints that relate to quantum metrology and macroscopicity, while for the former, we show that quantum states exist that have finite internal coherence yet with zero deterministic work value. Finally, under minimal thermodynamic assumptions, we establish a clock-work trade-off relation between these two types of coherences. This can be viewed as a form of time-energy conjugate relation within quantum thermodynamics that bounds the total maximum of clock and work resources for a given system. PMID- 29756898 TI - Electron-Mediated Phonon-Phonon Coupling Drives the Vibrational Relaxation of CO on Cu(100). AB - We bring forth a consistent theory for the electron-mediated vibrational intermode coupling that clarifies the microscopic mechanism behind the vibrational relaxation of adsorbates on metal surfaces. Our analysis points out the inability of state-of-the-art nonadiabatic theories to quantitatively reproduce the experimental linewidth of the CO internal stretch mode on Cu(100) and it emphasizes the crucial role of the electron-mediated phonon-phonon coupling in this regard. The results demonstrate a strong electron-mediated coupling between the internal stretch and low-energy CO modes, but also a significant role of surface motion. Our nonadiabatic theory is also able to explain the temperature dependence of the internal stretch phonon linewidth, thus far considered a sign of the direct anharmonic coupling. PMID- 29756900 TI - Three-Dimensional Coupled Dynamics of the Two-Fluid Model in Superfluid ^{4}He: Deformed Velocity Profile of Normal Fluid in Thermal Counterflow. AB - The coupled dynamics of the two-fluid model of superfluid ^{4}He is numerically studied for quantum turbulence of the thermal counterflow in a square channel. We combine the vortex filament model of the superfluid and the Navier-Stokes equations of normal fluid. Simulations of the coupled dynamics show that the velocity profile of the normal fluid is deformed significantly by superfluid turbulence as the vortices become dense. This result is consistent with recently performed visualization experiments. We introduce a dimensionless parameter that characterizes the deformation of the velocity profile. PMID- 29756902 TI - Model for a Ferromagnetic Quantum Critical Point in a 1D Kondo Lattice. AB - Motivated by recent experiments, we study a quasi-one-dimensional model of a Kondo lattice with ferromagnetic coupling between the spins. Using bosonization and dynamical large-N techniques, we establish the presence of a Fermi liquid and a magnetic phase separated by a local quantum critical point, governed by the Kondo breakdown picture. Thermodynamic properties are studied and a gapless charged mode at the quantum critical point is highlighted. PMID- 29756901 TI - Elasticity in Physically Cross-Linked Amyloid Fibril Networks. AB - We provide a constitutive model of semiflexible and rigid amyloid fibril networks by combining the affine thermal model of network elasticity with the Derjaguin Landau-Vervey-Overbeek (DLVO) theory of electrostatically charged colloids. When compared to rheological experiments on beta-lactoglobulin and lysozyme amyloid networks, this approach provides the correct scaling of elasticity versus both concentration (G~c^{2.2} and G~c^{2.5} for semiflexible and rigid fibrils, respectively) and ionic strength (G~I^{4.4} and G~I^{3.8} for beta-lactoglobulin and lysozyme, independent from fibril flexibility). The pivotal role played by the screening salt is to reduce the electrostatic barrier among amyloid fibrils, converting labile physical entanglements into long-lived cross-links. This gives a power-law behavior of G with I having exponents significantly larger than in other semiflexible polymer networks (e.g., actin) and carrying DLVO traits specific to the individual amyloid fibrils. PMID- 29756904 TI - Next-to-Leading-Order QCD Corrections to Higgs Boson Plus Jet Production with Full Top-Quark Mass Dependence. AB - We present the next-to-leading-order QCD corrections to the production of a Higgs boson in association with one jet at the LHC including the full top-quark mass dependence. The mass of the bottom quark is neglected. The two-loop integrals appearing in the virtual contribution are calculated numerically using the method of sector decomposition. We study the Higgs boson transverse momentum distribution, focusing on the high p_{t,H} region, where the top-quark loop is resolved. We find that the next-to-leading-order QCD corrections are large but that the ratio of the next-to-leading-order to leading-order result is similar to that obtained by computing in the limit of large top-quark mass. PMID- 29756903 TI - Superconducting Open-Framework Allotrope of Silicon at Ambient Pressure. AB - Diamond Si is a semiconductor with an indirect band gap that is the basis of modern semiconductor technology. Although many metastable forms of Si were observed using diamond anvil cells for compression and chemical precursors for synthesis, no metallic phase at ambient conditions has been reported thus far. Here we report the prediction of pure metallic Si allotropes with open channels at ambient pressure, unlike a cubic diamond structure in covalent bonding networks. The metallic phase termed P6/m-Si_{6} can be obtained by removing Na after pressure release from a novel Na-Si clathrate called P6/m-NaSi_{6}, which is predicted through first-principles study at high pressure. We identify that both P6/m-NaSi_{6} and P6/m-Si_{6} are stable and superconducting with the critical temperatures of about 13 and 12 K at ambient pressure, respectively. The prediction of new Na-Si and Si clathrate structures presents the possibility of exploring new exotic allotropes useful for Si-based devices. PMID- 29756905 TI - Quantum Glass of Interacting Bosons with Off-Diagonal Disorder. AB - We study disordered interacting bosons described by the Bose-Hubbard model with Gaussian-distributed random tunneling amplitudes. It is shown that the off diagonal disorder induces a spin-glass-like ground state, characterized by randomly frozen quantum-mechanical U(1) phases of bosons. To access criticality, we employ the "n-replica trick," as in the spin-glass theory, and the Trotter Suzuki method for decomposition of the statistical density operator, along with numerical calculations. The interplay between disorder, quantum, and thermal fluctuations leads to phase diagrams exhibiting a glassy state of bosons, which are studied as a function of model parameters. The considered system may be relevant for quantum simulators of optical-lattice bosons, where the randomness can be introduced in a controlled way. The latter is supported by a proposition of experimental realization of the system in question. PMID- 29756906 TI - Highly Efficient Spin-to-Charge Current Conversion in Strained HgTe Surface States Protected by a HgCdTe Layer. AB - We report the observation of spin-to-charge current conversion in strained mercury telluride at room temperature, using spin pumping experiments. We show that a HgCdTe barrier can be used to protect the HgTe from direct contact with the ferromagnet, leading to very high conversion rates, with inverse Edelstein lengths up to 2.0+/-0.5 nm. The influence of the HgTe layer thickness on the conversion efficiency is found to differ strongly from what is expected in spin Hall effect systems. These measurements, associated with the temperature dependence of the resistivity, suggest that these high conversion rates are due to the spin momentum locking property of HgTe surface states. PMID- 29756907 TI - Cluster Adjacency Properties of Scattering Amplitudes in N=4 Supersymmetric Yang Mills Theory. AB - We conjecture a new set of analytic relations for scattering amplitudes in planar N=4 super Yang-Mills theory. They generalize the Steinmann relations and are expressed in terms of the cluster algebras associated to Gr(4,n). In terms of the symbol, they dictate which letters can appear consecutively. We study heptagon amplitudes and integrals in detail and present symbols for previously unknown integrals at two and three loops which support our conjecture. PMID- 29756908 TI - Orbital State Manipulation of a Diamond Nitrogen-Vacancy Center Using a Mechanical Resonator. AB - We study the resonant optical transitions of a single nitrogen-vacancy (NV) center that is coherently dressed by a strong mechanical drive. Using a gigahertz frequency diamond mechanical resonator that is strain coupled to a NV center's orbital states, we demonstrate coherent Raman sidebands out to the ninth order and orbital-phonon interactions that mix the two excited-state orbital branches. These interactions are spectroscopically revealed through a multiphonon Rabi splitting of the orbital branches which scales as a function of resonator driving amplitude and is successfully reproduced in a quantum model. Finally, we discuss the application of mechanical driving to engineering NV-center orbital states. PMID- 29756909 TI - Linear Hyperfine Tuning of Donor Spins in Silicon Using Hydrostatic Strain. AB - We experimentally study the coupling of group V donor spins in silicon to mechanical strain, and measure strain-induced frequency shifts that are linear in strain, in contrast to the quadratic dependence predicted by the valley repopulation model (VRM), and therefore orders of magnitude greater than that predicted by the VRM for small strains |epsilon|<10^{-5}. Through both tight binding and first principles calculations we find that these shifts arise from a linear tuning of the donor hyperfine interaction term by the hydrostatic component of strain and achieve semiquantitative agreement with the experimental values. Our results provide a framework for making quantitative predictions of donor spins in silicon nanostructures, such as those being used to develop silicon-based quantum processors and memories. The strong spin-strain coupling we measure (up to 150 GHz per strain, for Bi donors in Si) offers a method for donor spin tuning-shifting Bi donor electron spins by over a linewidth with a hydrostatic strain of order 10^{-6}-as well as opportunities for coupling to mechanical resonators. PMID- 29756914 TI - Surface Nanobubbles Are Stabilized by Hydrophobic Attraction. AB - The remarkably long lifetime of surface nanobubbles has perplexed researchers for two decades. The current understanding is that both contact line pinning and supersaturation of the ambient liquid are strictly required for the stability of nanobubbles, yet experiments show nanobubbles surviving in open systems and undersaturated environments. We find that this discrepancy can be addressed if the effects of an attractive hydrophobic potential at the solid substrate on the spatial distribution of the gas concentration is taken into account. We also show that, in our model, only substrate pinning is strictly required for stabilization; while hydrophobicity and supersaturation both aid stability, neither is mandatory-the absence of one can be compensated by an excess of the other. PMID- 29756916 TI - Phase Diagram of Dense H_{2}-He Mixtures: Evidence for Strong Chemical Association, Miscibility, and Structural Change. AB - The phase diagram of hydrogen-helium mixtures is presented to 75 GPa, underscoring the formation of metastable H_{2}-rich crystallite in He-rich fluid mixtures and the structural phase transition in He lattice at ~52 GPa. The Raman data also indicate a significant level of mixing between H_{2} and He even in solids, giving rise to new vibrational bands in He-rich solid at ~2400 cm^{-1} for H-He stretching and 140 cm^{-1} for the lattice phonon of H_{2} incorporated hcp He. Therefore, the present result signifies unexpected, strong chemical association of the interstitial-filled guest molecules (H_{2} or He) with the host lattice (hcp He or H_{2}) in this quantum solid mixture. PMID- 29756917 TI - Hyperfine-Structure-Induced Depolarization of Impulsively Aligned I_{2} Molecules. AB - A moderately intense 450 fs laser pulse is used to create rotational wave packets in gas phase I_{2} molecules. The ensuing time-dependent alignment, measured by Coulomb explosion imaging with a delayed probe pulse, exhibits the characteristic revival structures expected for rotational wave packets but also a complex nonperiodic substructure and decreasing mean alignment not observed before. A quantum mechanical model attributes the phenomena to coupling between the rotational angular momenta and the nuclear spins through the electric quadrupole interaction. The calculated alignment trace agrees very well with the experimental results. PMID- 29756915 TI - Erratum: Minkowski Flux Vacua of Type II Supergravities [Phys. Rev. Lett. 118, 011603 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.011603. PMID- 29756912 TI - Growth Mechanism and Origin of High sp^{3} Content in Tetrahedral Amorphous Carbon. AB - We study the deposition of tetrahedral amorphous carbon (ta-C) films from molecular dynamics simulations based on a machine-learned interatomic potential trained from density-functional theory data. For the first time, the high sp^{3} fractions in excess of 85% observed experimentally are reproduced by means of computational simulation, and the deposition energy dependence of the film's characteristics is also accurately described. High confidence in the potential and direct access to the atomic interactions allow us to infer the microscopic growth mechanism in this material. While the widespread view is that ta-C grows by "subplantation," we show that the so-called "peening" model is actually the dominant mechanism responsible for the high sp^{3} content. We show that pressure waves lead to bond rearrangement away from the impact site of the incident ion, and high sp^{3} fractions arise from a delicate balance of transitions between three- and fourfold coordinated carbon atoms. These results open the door for a microscopic understanding of carbon nanostructure formation with an unprecedented level of predictive power. PMID- 29756919 TI - Unexpected Phenomenology in Particle-Based Ice Absent in Magnetic Spin Ice. AB - While particle-based ices are often considered essentially equivalent to magnet based spin ices, the two differ essentially in frustration and energetics. We show that at equilibrium particle-based ices correspond exactly to spin ices coupled to a background field. In trivial geometries, such a field has no effect, and the two systems are indeed thermodynamically equivalent. In other cases, however, the field controls a richer phenomenology, absent in magnetic ices, and still largely unexplored: ice rule fragility, topological charge transfer, radial polarization, decimation induced disorder, and glassiness. PMID- 29756911 TI - Dirac Equation in (1+1)-Dimensional Curved Spacetime and the Multiphoton Quantum Rabi Model. AB - We introduce an exact mapping between the Dirac equation in (1+1)-dimensional curved spacetime (DCS) and a multiphoton quantum Rabi model (QRM). A background of a (1+1)-dimensional black hole requires a QRM with one- and two-photon terms that can be implemented in a trapped ion for the quantum simulation of Dirac particles in curved spacetime. We illustrate our proposal with a numerical analysis of the free fall of a Dirac particle into a (1+1)-dimensional black hole, and find that the Zitterbewegung effect, measurable via the oscillatory trajectory of the Dirac particle, persists in the presence of gravity. From the duality between the squeezing term in the multiphoton QRM and the metric coupling in the DCS, we show that gravity generates squeezing of the Dirac particle wave function. PMID- 29756913 TI - Quantification of Magnetic Surface and Edge States in an FeGe Nanostripe by Off Axis Electron Holography. AB - Whereas theoretical investigations have revealed the significant influence of magnetic surface and edge states on Skyrmonic spin texture in chiral magnets, experimental studies of such chiral states remain elusive. Here, we study chiral edge states in an FeGe nanostripe experimentally using off-axis electron holography. Our results reveal the magnetic-field-driven formation of chiral edge states and their penetration lengths at 95 and 240 K. We determine values of saturation magnetization M_{S} by analyzing the projected in-plane magnetization distributions of helices and Skyrmions. Values of M_{S} inferred for Skyrmions are lower by a few percent than those for helices. We attribute this difference to the presence of chiral surface states, which are predicted theoretically in a three-dimensional Skyrmion model. Our experiments provide direct quantitative measurements of magnetic chiral boundary states and highlight the applicability of state-of-the-art electron holography for the study of complex spin textures in nanostructures. PMID- 29756918 TI - Scissors Mode of Dipolar Quantum Droplets of Dysprosium Atoms. AB - We report on the observation of the scissors mode of a single dipolar quantum droplet. The existence of this mode is due to the breaking of the rotational symmetry by the dipole-dipole interaction, which is fixed along an external homogeneous magnetic field. By modulating the orientation of this magnetic field, we introduce a new spectroscopic technique for studying dipolar quantum droplets. This provides a precise probe for interactions in the system, allowing us to extract a background scattering length for ^{164}Dy of 69(4)a_{0}. Our results establish an analogy between quantum droplets and atomic nuclei, where the existence of the scissors mode is also only due to internal interactions. They further open the possibility to explore physics beyond the available theoretical models for strongly dipolar quantum gases. PMID- 29756921 TI - Nucleation- and Emergence-Limited Growth of Ice from Pores. AB - Nucleation of ice from vapor on atmospheric aerosols has been attributed to the condensation and freezing of supercooled water in small pores. Here we use wedge pores on mica to directly observe the growth of ice in confinement prior to the growth of bulk crystals. We report a transition in behavior with a decreasing temperature: At low temperatures, the limiting step is not nucleation but a free energy barrier associated with the growth of ice through a narrow pore mouth to become a bulk phase. PMID- 29756920 TI - Absence of Cyclotron Resonance in the Anomalous Metallic Phase in InO_{x}. AB - It is observed that many thin superconducting films with not too high disorder level (generally R_{N}/?<2000 Omega) placed in magnetic field show an anomalous metallic phase where the resistance is low but still finite as temperature goes to zero. Here we report in weakly disordered amorphous InO_{x} thin films that this anomalous metal phase possesses no cyclotron resonance and hence non-Drude electrodynamics. The absence of a finite frequency resonant mode can be associated with a vanishing downstream component of the vortex current parallel to the supercurrent and an emergent particle-hole symmetry of this metal, which establishes its non-Fermi-liquid character. PMID- 29756922 TI - Squeezing Enhances Quantum Synchronization. AB - It is desirable to observe synchronization of quantum systems in the quantum regime, defined by the low number of excitations and a highly nonclassical steady state of the self-sustained oscillator. Several existing proposals of observing synchronization in the quantum regime suffer from the fact that the noise statistics overwhelm synchronization in this regime. Here, we resolve this issue by driving a self-sustained oscillator with a squeezing Hamiltonian instead of a harmonic drive and analyze this system in the classical and quantum regime. We demonstrate that strong entrainment is possible for small values of squeezing, and in this regime, the states are nonclassical. Furthermore, we show that the quality of synchronization measured by the FWHM of the power spectrum is enhanced with squeezing. PMID- 29756923 TI - Residual and Destroyed Accessible Information after Measurements. AB - When quantum states are used to send classical information, the receiver performs a measurement on the signal states. The amount of information extracted is often not optimal due to the receiver's measurement scheme and experimental apparatus. For quantum nondemolition measurements, there is potentially some residual information in the postmeasurement state, while part of the information has been extracted and the rest is destroyed. Here, we propose a framework to characterize a quantum measurement by how much information it extracts and destroys, and how much information it leaves in the residual postmeasurement state. The concept is illustrated for several receivers discriminating coherent states. PMID- 29756924 TI - Controlling the Local Electronic Properties of Si(553)-Au through Hydrogen Doping. AB - We propose a quantitative and reversible method for tuning the charge localization of Au-stabilized stepped Si surfaces by site-specific hydrogenation. This is demonstrated for Si(553)-Au as a model system by combining density functional theory simulations and reflectance anisotropy spectroscopy experiments. We find that controlled H passivation is a two-step process: step edge adsorption drives excess charge into the conducting metal chain "reservoir" and renders it insulating, while surplus H recovers metallic behavior. Our approach illustrates a route towards microscopic manipulation of the local surface charge distribution and establishes a reversible switch of site-specific chemical reactivity and magnetic properties on vicinal surfaces. PMID- 29756925 TI - Publisher's Note: Theory of Light Emission from Quantum Noise in Plasmonic Contacts: Above-Threshold Emission from Higher-Order Electron-Plasmon Scattering [Phys. Rev. Lett. 114, 126803 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.114.126803. PMID- 29756926 TI - Beyond Positivity Bounds and the Fate of Massive Gravity. AB - We constrain effective field theories by going beyond the familiar positivity bounds that follow from unitarity, analyticity, and crossing symmetry of the scattering amplitudes. As interesting examples, we discuss the implications of the bounds for the Galileon and ghost-free massive gravity. The combination of our theoretical bounds with the experimental constraints on the graviton mass implies that the latter is either ruled out or unable to describe gravitational phenomena, let alone to consistently implement the Vainshtein mechanism, down to the relevant scales of fifth-force experiments, where general relativity has been successfully tested. We also show that the Galileon theory must contain symmetry breaking terms that are at most one-loop suppressed compared to the symmetry preserving ones. We comment as well on other interesting applications of our bounds. PMID- 29756927 TI - Low Dose X-Ray Speckle Visibility Spectroscopy Reveals Nanoscale Dynamics in Radiation Sensitive Ionic Liquids. AB - X-ray radiation damage provides a serious bottleneck for investigating microsecond to second dynamics on nanometer length scales employing x-ray photon correlation spectroscopy. This limitation hinders the investigation of real time dynamics in most soft matter and biological materials which can tolerate only x ray doses of kGy and below. Here, we show that this bottleneck can be overcome by low dose x-ray speckle visibility spectroscopy. Employing x-ray doses of 22-438 kGy and analyzing the sparse speckle pattern of count rates as low as 6.7*10^{-3} per pixel, we follow the slow nanoscale dynamics of an ionic liquid (IL) at the glass transition. At the prepeak of nanoscale order in the IL, we observe complex dynamics upon approaching the glass transition temperature T_{G} with a freezing in of the alpha relaxation and a multitude of millisecond local relaxations existing well below T_{G}. We identify this fast relaxation as being responsible for the increasing development of nanoscale order observed in ILs at temperatures below T_{G}. PMID- 29756928 TI - Hyperchaotic Dynamics for Light Polarization in a Laser Diode. AB - It is shown that a highly randomlike behavior of light polarization states in the output of a free-running laser diode, covering the whole Poincare sphere, arises as a result from a fully deterministic nonlinear process, which is characterized by a hyperchaotic dynamics of two polarization modes nonlinearly coupled with a semiconductor medium, inside the optical cavity. A number of statistical distributions were found to describe the deterministic data of the low dimensional nonlinear flow, such as lognormal distribution for the light intensity, Gaussian distributions for the electric field components and electron densities, Rice and Rayleigh distributions, and Weibull and negative exponential distributions, for the modulus and intensity of the orthogonal linear components of the electric field, respectively. The presented results could be relevant for the generation of single units of compact light source devices to be used in low dimensional optical hyperchaos-based applications. PMID- 29756929 TI - Anomalous Chained Turbulence in Actively Driven Flows on Spheres. AB - Recent experiments demonstrate the importance of substrate curvature for actively forced fluid dynamics. Yet, the covariant formulation and analysis of continuum models for nonequilibrium flows on curved surfaces still poses theoretical challenges. Here, we introduce and study a generalized covariant Navier-Stokes model for fluid flows driven by active stresses in nonplanar geometries. The analytical tractability of the theory is demonstrated through exact stationary solutions for the case of a spherical bubble geometry. Direct numerical simulations reveal a curvature-induced transition from a burst phase to an anomalous turbulent phase that differs distinctly from externally forced classical 2D Kolmogorov turbulence. This new type of active turbulence is characterized by the self-assembly of finite-size vortices into linked chains of antiferromagnetic order, which percolate through the entire fluid domain, forming an active dynamic network. The coherent motion of the vortex chain network provides an efficient mechanism for upward energy transfer from smaller to larger scales, presenting an alternative to the conventional energy cascade in classical 2D turbulence. PMID- 29756930 TI - Spectrum of Elementary Excitations in Galilean-Invariant Integrable Models. AB - The spectrum of elementary excitations in one-dimensional quantum liquids is generically linear at low momenta. It is characterized by the sound velocity that can be related to the ground-state energy. Here we study the spectrum at higher momenta in Galilean-invariant integrable models. Somewhat surprisingly, we show that the spectrum at arbitrary momentum is fully determined by the properties of the ground state. We find general exact relations for the coefficients of several terms in the expansion of the excitation energy at low momenta and arbitrary interaction and express them in terms of the Luttinger liquid parameter. We apply the obtained formulas to the Lieb-Liniger model and obtain several new results. PMID- 29756932 TI - Nonlocal and Nonadiabatic Effects in the Charge-Density Response of Solids: A Time-Dependent Density-Functional Approach. AB - The charge-density response of extended materials is usually dominated by the collective oscillation of electrons, the plasmons. Beyond this feature, however, intriguing many-body effects are observed. They cannot be described by one of the most widely used approaches for the calculation of dielectric functions, which is time-dependent density functional theory (TDDFT) in the adiabatic local density approximation (ALDA). Here, we propose an approximation to the TDDFT exchange correlation kernel which is nonadiabatic and nonlocal. It is extracted from correlated calculations in the homogeneous electron gas, where we have tabulated it for a wide range of wave vectors and frequencies. A simple mean density approximation allows one to use it in inhomogeneous materials where the density varies on a scale of 1.6 r_{s} or faster. This kernel contains effects that are completely absent in the ALDA; in particular, it correctly describes the double plasmon in the dynamic structure factor of sodium, and it shows the characteristic low-energy peak that appears in systems with low electronic density. It also leads to an overall quantitative improvement of spectra. PMID- 29756931 TI - Phase Diagram of Kob-Andersen-Type Binary Lennard-Jones Mixtures. AB - The binary Kob-Andersen (KA) Lennard-Jones mixture is the standard model for computational studies of viscous liquids and the glass transition. For very long simulations, the viscous KA system crystallizes, however, by phase separating into a pure A particle phase forming a fcc crystal. We present the thermodynamic phase diagram for KA-type mixtures consisting of up to 50% small (B) particles showing, in particular, that the melting temperature of the standard KA system at liquid density 1.2 is 1.028(3) in A particle Lennard-Jones units. At large B particle concentrations, the system crystallizes into the CsCl crystal structure. The eutectic corresponding to the fcc and CsCl structures is cutoff in a narrow interval of B particle concentrations around 26% at which the bipyramidal orthorhombic PuBr_{3} structure is the thermodynamically stable phase. The melting temperature's variation with B particle concentration at two constant pressures, as well as at the constant density 1.2, is estimated from simulations at pressure 10.19 using isomorph theory. Our data demonstrate approximate identity between the melting temperature and the onset temperature below which viscous dynamics appears. Finally, the nature of the solid-liquid interface is briefly discussed. PMID- 29756934 TI - Fission of Polyanionic Metal Clusters. AB - Size-selected dianionic lead clusters Pb_{n}^{2-}, n=34-56, are stored in a Penning trap and studied with respect to their decay products upon photoexcitation. Contrary to the decay of other dianionic metal clusters, these lead clusters show a variety of decay channels. The mass spectra of the fragments are compared to the corresponding spectra of the monoanionic precursors. This comparison leads to the conclusion that, in the cluster size region below about n=48, the fission reaction Pb_{n}^{2-}->Pb_{n-10}^{-}+Pb_{10}^{-} is the major decay process. Its disappearance at larger cluster sizes may be an indication of a nonmetal to metal transition. Recently, the pair of Pb_{10}^{-} and Pb_{n-10}^{ } were observed as pronounced fragments in electron-attachment studies [S. Konig et al., Int. J. Mass Spectrom. 421, 129 (2017)IMSPF81387 380610.1016/j.ijms.2017.06.009]. The present findings suggest that this combination is the fingerprint of the decay of doubly charged lead clusters. With this assumption, the dianion clusters have been traced down to Pb_{21}^{2-}, whereas the smallest size for the direct observation was as high as n=28. PMID- 29756933 TI - Qudit-Basis Universal Quantum Computation Using chi^{(2)} Interactions. AB - We prove that universal quantum computation can be realized-using only linear optics and chi^{(2)} (three-wave mixing) interactions-in any (n+1)-dimensional qudit basis of the n-pump-photon subspace. First, we exhibit a strictly universal gate set for the qubit basis in the one-pump-photon subspace. Next, we demonstrate qutrit-basis universality by proving that chi^{(2)} Hamiltonians and photon-number operators generate the full u(3) Lie algebra in the two-pump-photon subspace, and showing how the qutrit controlled-Z gate can be implemented with only linear optics and chi^{(2)} interactions. We then use proof by induction to obtain our general qudit result. Our induction proof relies on coherent photon injection or subtraction, a technique enabled by chi^{(2)} interaction between the encoding modes and ancillary modes. Finally, we show that coherent photon injection is more than a conceptual tool, in that it offers a route to preparing high-photon-number Fock states from single-photon Fock states. PMID- 29756935 TI - Relativistic and QED Effects in the Fundamental Vibration of T_{2}. AB - The hydrogen molecule has become a test ground for quantum electrodynamical calculations in molecules. Expanding beyond studies on stable hydrogenic species to the heavier radioactive tritium-bearing molecules, we report on a measurement of the fundamental T_{2} vibrational splitting (v=0->1) for J=0-5 rotational levels. Precision frequency metrology is performed with high-resolution coherent anti-Stokes Raman spectroscopy at an experimental uncertainty of 10-12 MHz, where sub-Doppler saturation features are exploited for the strongest transition. The achieved accuracy corresponds to a 50-fold improvement over a previous measurement, and it allows for the extraction of relativistic and QED contributions to T_{2} transition energies. PMID- 29756936 TI - Dynamics of Topological Excitations in a Model Quantum Spin Ice. AB - We study the quantum spin dynamics of a frustrated XXZ model on a pyrochlore lattice by using large-scale quantum Monte Carlo simulation and stochastic analytic continuation. In the low-temperature quantum spin ice regime, we observe signatures of coherent photon and spinon excitations in the dynamic spin structure factor. As the temperature rises to the classical spin ice regime, the photon disappears from the dynamic spin structure factor, whereas the dynamics of the spinon remain coherent in a broad temperature window. Our results provide experimentally relevant, quantitative information for the ongoing pursuit of quantum spin ice materials. PMID- 29756937 TI - Incomplete Thermalization from Trap-Induced Integrability Breaking: Lessons from Classical Hard Rods. AB - We study a one-dimensional gas of hard rods trapped in a harmonic potential, which breaks integrability of the hard-rod interaction in a nonuniform way. We explore the consequences of such broken integrability for the dynamics of a large number of particles and find three distinct regimes: initial, chaotic, and stationary. The initial regime is captured by an evolution equation for the phase space distribution function. For any finite number of particles, this hydrodynamics breaks down and the dynamics becomes chaotic after a characteristic timescale determined by the interparticle distance and scattering length. The system fails to thermalize over the timescale studied (10^{4} natural units), but the time-averaged ensemble is a stationary state of the hydrodynamic evolution. We close by discussing logical extensions of the results to similar systems of quantum particles. PMID- 29756938 TI - Electric Conductivity of Hot and Dense Quark Matter in a Magnetic Field with Landau Level Resummation via Kinetic Equations. AB - We compute the electric conductivity of quark matter at finite temperature T and a quark chemical potential MU under a magnetic field B beyond the lowest Landau level approximation. The electric conductivity transverse to B is dominated by the Hall conductivity sigma_{H}. For the longitudinal conductivity sigma_{?}, we need to solve kinetic equations. Then, we numerically find that sigma_{?} has only a mild dependence on MU and the quark mass m_{q}. Moreover, sigma_{?} first decreases and then linearly increases as a function of B, leading to an intermediate B region that looks consistent with the experimental signature for the chiral magnetic effect. We also point out that sigma_{?} at a nonzero B remains within the range of the lattice-QCD estimate at B=0. PMID- 29756939 TI - Transition from Propagating Polariton Solitons to a Standing Wave Condensate Induced by Interactions. AB - We explore phase transitions of polariton wave packets, first, to a soliton and then to a standing wave polariton condensate in a multimode microwire system, mediated by nonlinear polariton interactions. At low excitation density, we observe ballistic propagation of the multimode polariton wave packets arising from the interference between different transverse modes. With increasing excitation density, the wave packets transform into single-mode bright solitons due to effects of both intermodal and intramodal polariton-polariton scattering. Further increase of the excitation density increases thermalization speed, leading to relaxation of the polariton density from a solitonic spectrum distribution in momentum space down to low momenta, with the resultant formation of a nonequilibrium condensate manifested by a standing wave pattern across the whole sample. PMID- 29756940 TI - Dynamic Displacement Disorder of Cubic BaTiO_{3}. AB - The three-dimensional distribution of the x-ray diffuse scattering intensity of BaTiO_{3} has been recorded in a synchrotron experiment and simultaneously computed using molecular dynamics simulations of a shell model. Together, these have allowed the details of the disorder in paraelectric BaTiO_{3} to be clarified. The narrow sheets of diffuse scattering, related to the famous anisotropic longitudinal correlations of Ti ions, are shown to be caused by the overdamped anharmonic soft phonon branch. This finding demonstrates that the occurrence of narrow sheets of diffuse scattering agrees with a displacive picture of the cubic phase of this textbook ferroelectric material. The presented methodology allows one to go beyond the harmonic approximation in the analysis of phonons and phonon-related scattering. PMID- 29756942 TI - Exploration of Fermi-Pasta-Ulam Behavior in a Magnetic System. AB - We study nonlinear spin motion in one-dimensional magnetic chains. We find significant differences from the classic Fermi-Pasta-Ulam (FPU) problem examining nonlinear elastic motion in a chain. We find that FPU behavior, the transfer of energy among low order eigenmodes, does not occur in magnetic systems with only exchange and external fields, but does exist if a uniaxial anisotropy is also present. The FPU behavior may be altered or turned off through the magnitude and orientation of an external magnetic field. A realistic micromagnetic model shows such behavior could be measurable. PMID- 29756941 TI - Creating Complex Optical Longitudinal Polarization Structures. AB - In this Letter, we show that it is possible to structure the longitudinal polarization component of light. We illustrate our approach by demonstrating linked and knotted longitudinal vortex lines acquired upon nonparaxially propagating a tightly focused subwavelength beam. The remaining degrees of freedom in the transverse polarization components can be exploited to generate customized topological vector beams. PMID- 29756943 TI - Ultrafast Doublon Dynamics in Photoexcited 1T-TaS_{2}. AB - Strongly correlated materials exhibit intriguing properties caused by intertwined microscopic interactions that are hard to disentangle in equilibrium. Employing nonequilibrium time-resolved photoemission spectroscopy on the quasi-two dimensional transition-metal dichalcogenide 1T-TaS_{2}, we identify a spectroscopic signature of doubly occupied sites (doublons) that reflects fundamental Mott physics. Doublon-hole recombination is estimated to occur on timescales of electronic hopping h/J~14 fs. Despite strong electron-phonon coupling, the dynamics can be explained by purely electronic effects captured by the single-band Hubbard model under the assumption of weak hole doping, in agreement with our static sample characterization. This sensitive interplay of static doping and vicinity to the metal-insulator transition suggests a way to modify doublon relaxation on the few-femtosecond timescale. PMID- 29756944 TI - Improved Limits on Spin-Mass Interactions. AB - Very light particles with CP-violating couplings to ordinary matter, such as axions or axionlike particles, can mediate long-range forces between polarized and unpolarized fermions. We describe a new experimental search for such forces between unpolarized nucleons in two 250 kg Pb weights and polarized neutrons and electrons in a ^{3}He-K comagnetometer located about 15 cm away. We place improved constraints on the products of scalar and pseudoscalar coupling constants, g_{p}^{n}g_{s}^{N}<4.2*10^{-30} and g_{p}^{e}g_{s}^{N}<1.7*10^{-30} (95% C.L.) for axionlike particle masses less than 10^{-6} eV, which represents an order of magnitude improvement over the best previous neutron laboratory limit. PMID- 29756945 TI - Magnetic Trapping and Coherent Control of Laser-Cooled Molecules. AB - We demonstrate coherent microwave control of the rotational, hyperfine, and Zeeman states of ultracold CaF molecules, and the magnetic trapping of these molecules in a single, selectable quantum state. We trap about 5*10^{3} molecules for almost 2 s at a temperature of 70(8) MUK and a density of 1.2*10^{5} cm^{ 3}. We measure the state-specific loss rate due to collisions with background helium. PMID- 29756946 TI - Airy Wave Packets Accelerating in Space-Time. AB - Although diffractive spreading is an unavoidable feature of all wave phenomena, certain waveforms can attain propagation invariance. A lesser-explored strategy for achieving optical self-similar propagation exploits the modification of the spatiotemporal field structure when observed in reference frames moving at relativistic speeds. For such an observer, it is predicted that the associated Lorentz boost can bring to a halt the axial dynamics of a wave packet of an arbitrary profile. This phenomenon is particularly striking in the case of a self accelerating beam-such as an Airy beam-whose peak normally undergoes a transverse displacement upon free propagation. Here we synthesize an acceleration-free Airy wave packet that travels in a straight line by deforming its spatiotemporal spectrum to reproduce the impact of a Lorentz boost. The roles of the axial spatial coordinate and time are swapped, leading to "time diffraction" manifested in self-acceleration observed in the propagating Airy wave-packet frame. PMID- 29756947 TI - Influence of Magnetic Ordering between Cr Adatoms on the Yu-Shiba-Rusinov States of the beta-Bi_{2}Pd Superconductor. AB - We show that the magnetic ordering of coupled atomic dimers on a superconductor is revealed by their intragap spectral features. Chromium atoms on the superconductor beta-Bi_{2}Pd surface display Yu-Shiba-Rusinov bound states, detected as pairs of intragap excitations in tunneling spectra. By means of atomic manipulation with a scanning tunneling microscope's tip, we form Cr dimers with different arrangements and find that their intragap features appear either shifted or split with respect to single atoms. These spectral variations are associated with the magnetic coupling, ferromagnetic or antiferromagnetic, of the dimer, as confirmed by density functional theory simulations. The striking qualitative differences between the observed tunneling spectra prove that intragap Shiba states are extremely sensitive to the magnetic ordering on the atomic scale. PMID- 29756948 TI - Dynamics of Radially Expanding Liquid Sheets. AB - The process of atomization often involves ejecting thin liquid sheets at high speeds from a nozzle that causes the sheet to flap violently and break up into fine droplets. The flapping of the liquid sheet has long been attributed to the sheet's interaction with the surrounding gas phase. Here, we present experimental evidence to the contrary and show that the flapping is caused by the thinning of the liquid sheet as it spreads out from the nozzle exit. The measured growth rates of the waves agree remarkably well with the predictions of a recent theory that accounts for the sheet's thinning but ignores aerodynamic interactions. We anticipate these results to not only lead to more accurate predictions of the final drop-size distribution but also enable more efficient designs of atomizers. PMID- 29756950 TI - Single-Particle Mobility Edge in a One-Dimensional Quasiperiodic Optical Lattice. AB - A single-particle mobility edge (SPME) marks a critical energy separating extended from localized states in a quantum system. In one-dimensional systems with uncorrelated disorder, a SPME cannot exist, since all single-particle states localize for arbitrarily weak disorder strengths. However, in a quasiperiodic system, the localization transition can occur at a finite detuning strength and SPMEs become possible. In this Letter, we find experimental evidence for the existence of such a SPME in a one-dimensional quasiperiodic optical lattice. Specifically, we find a regime where extended and localized single-particle states coexist, in good agreement with theoretical simulations, which predict a SPME in this regime. PMID- 29756952 TI - First Higher-Multipole Model of Gravitational Waves from Spinning and Coalescing Black-Hole Binaries. AB - Gravitational-wave observations of binary black holes currently rely on theoretical models that predict the dominant multipoles (l=2,|m|=2) of the radiation during inspiral, merger, and ringdown. We introduce a simple method to include the subdominant multipoles to binary black hole gravitational waveforms, given a frequency-domain model for the dominant multipoles. The amplitude and phase of the original model are appropriately stretched and rescaled using post Newtonian results (for the inspiral), perturbation theory (for the ringdown), and a smooth transition between the two. No additional tuning to numerical-relativity simulations is required. We apply a variant of this method to the nonprecessing PhenomD model. The result, PhenomHM, constitutes the first higher-multipole model of spinning and coalescing black-hole binaries, and currently includes the (l,|m|)=(2,2),(3,3),(4,4),(2,1),(3,2),(4,3) radiative moments. Comparisons with numerical-relativity waveforms demonstrate that PhenomHM is more accurate than dominant-multipole-only models for all binary configurations, and typically improves the measurement of binary properties. PMID- 29756953 TI - Quantum and Private Capacities of Low-Noise Channels. AB - We determine both the quantum and the private capacities of low-noise quantum channels to leading orders in the channel's distance to the perfect channel. It has been an open problem for more than 20 yr to determine the capacities of some of these low-noise channels such as the depolarizing channel. We also show that both capacities are equal to the single-letter coherent information of the channel, again to leading orders. We thus find that, in the low-noise regime, superadditivity and degenerate codes have a negligible benefit for the quantum capacity, and shielding does not improve the private capacity beyond the quantum capacity, in stark contrast to the situation when noisier channels are considered. PMID- 29756951 TI - Experimental Characterization of Electron-Beam-Driven Wakefield Modes in a Dielectric-Woodpile Cartesian Symmetric Structure. AB - Photonic structures operating in the terahertz (THz) spectral region enable the essential characteristics of confinement, modal control, and electric field shielding for very high gradient accelerators based on wakefields in dielectrics. We report here an experimental investigation of THz wakefield modes in a three dimensional photonic woodpile structure. Selective control in exciting or suppressing of wakefield modes with a nonzero transverse wave vector is demonstrated by using drive beams of varying transverse ellipticity. Additionally, we show that the wakefield spectrum is insensitive to the offset position of strongly elliptical beams. These results are consistent with analytic theory and three-dimensional simulations and illustrate a key advantage of wakefield systems with Cartesian symmetry: the suppression of transverse wakes by elliptical beams. PMID- 29756949 TI - First Octahedral Spherical Hohlraum Energetics Experiment at the SGIII Laser Facility. AB - The first octahedral spherical hohlraum energetics experiment is accomplished at the SGIII laser facility. For the first time, the 32 laser beams are injected into the octahedral spherical hohlraum through six laser entrance holes. Two techniques are used to diagnose the radiation field of the octahedral spherical hohlraum in order to obtain comprehensive experimental data. The radiation flux streaming out of laser entrance holes is measured by six flat-response x-ray detectors (FXRDs) and four M-band x-ray detectors, which are placed at different locations of the SGIII target chamber. The radiation temperature is derived from the measured flux of FXRD by using the blackbody assumption. The peak radiation temperature inside hohlraum is determined by the shock wave technique. The experimental results show that the octahedral spherical hohlraum radiation temperature is in the range of 170-182 eV with drive laser energies of 71 kJ to 84 kJ. The radiation temperature inside the hohlraum determined by the shock wave technique is about 175 eV at 71 kJ. For the flat-top laser pulse of 3 ns, the conversion efficiency of gas-filled octahedral spherical hohlraum from laser into soft x rays is about 80% according to the two-dimensional numerical simulation. PMID- 29756954 TI - [Nutrition screening: looking for the efficiency]. PMID- 29756955 TI - Multicenter study of parenteral nutrition in non-critically ill elderly patients compared to younger patients - Study IAIOS-PN (Incidence and Assessment of Iatrogenesis in Older Subjects receiving Parenteral Nutrition). AB - OBJECTIVE: this study assessed the incidence of hyperglycemia, hypertriglyceridemia, and liver function test (LFT) alterations among patients older and younger than 65 years receiving parenteral nutrition (PN). A secondary objective was to compare the incidence of any of these three events. MATERIAL AND METHODS: inclusion criteria were non-critically ill adult inpatients receiving PN for >= 7 days in 15 hospitals in Spain. Exclusion criteria were hyperglycemia, hypertriglyceridemia, LFT alterations, sepsis, shock, pancreatic/hepatobiliary surgery, renal failure, diabetes mellitus (DM) type 1, insulin-treated DM type 2, acute DM complications, or obesity prior to PN. Patients were classified into groups YOUNG (aged 35-64) and OLD (aged 65-95). RESULTS: this study recruited 200 patients. Group YOUNG included 63 (31.5%) patients and OLD, 137 (68.5%). Hyperglycemia appeared in 37 (18.5%) patients, eight (12.7%) in group YOUNG and 29 (21.2%) in group OLD (p = 0.174). Hypertriglyceridemia appeared in only one (0.7%) patient. LFT alterations appeared in 141 (70.5%) patients, 44 (69.8%) in group YOUNG and 97 (70.8%) in group OLD (p = 1.000). The model for hyperglycemia included DM type 2, previous surgical procedure, and use of hyperglycemia inducing medications. The model for LFT alteration included previous surgical procedure, amount of lipids and amino acids, medications causing LFT alterations and a trend for age group. The model for any event included surgical procedure, DM type 2, and medications causing alterations. CONCLUSION: patients of >= 65 years receiving PN had similar incidences of hyperglycemia, hypertriglyceridemia, and LFT alterations as younger patients. Additionally, older patients had trends toward lower LFT alterations. PMID- 29756956 TI - Incidents and adverse events in enteral feeding tube users: warnings based on a cohort study. AB - INTRODUCTION: few studies clearly describe incidents or adverse events that occur during the enteral nutrition process, which hinders the identification of critical points. OBJECTIVE: to describe breaches of protocol, incidents and adverse events, during the period beginning with indications until the use of enteral feeding tube in an Emergency Department. METHODS: trained nurses prospectively monitored a cohort of adults in a Brazilian Emergency Department where use of enteral feeding tube was indicated and up to their use. The study sought to identify breaches of protocol, such as verbal orders to insert feeding tubes, or authorization of their use without X-rays to confirm the position of the feeding tubes. Incidents were characterized as events that could have caused harm to patients, while adverse events were those that did actually cause harm. The study was approved by the institution's Research Ethics Committee. RESULTS: in 150 feeding tube insertions, there were 169 breaches of protocol: verbal orders for feeding tube insertion (n = 59); no X-rays taken (n = 11); and no examination of the X-rays by physicians (n = 12). There were 30 incidents: unintentional removal of the feeding tube (n = 23); and administration of enteral nutrition after breach of preventive barriers. There was one adverse event: aspiration of enteral nutrition. CONCLUSION: there was a high frequency of breaches of safety protocols; many developed into incidents, and one resulted in an adverse event. PMID- 29756958 TI - Poor breastfeeding, complementary feeding and dietary diversity in children and their relationship with stunting in rural communities. AB - INTRODUCTION: stunted growth is the most common manifestation of malnutrition in Mexico. Breastfeeding, adequate introduction of complementary feeding and dietary diversity can avoid this. OBJECTIVE: to characterize the feeding practices in children 1-24 months of age in rural communities of Hidalgo and define their relationship with stunting. METHODS: a 24-hour recall was used to obtain information. Z-scores for length-for-age (ZLA), complementary feeding (CF) and minimal dietary diversity (MDD) were determined. The sample was divided into breastfed and not breastfed children. RESULTS: one hundred eighty nine mother child dyads were evaluated; 59.3% were breastfed and 40.7% were not. Stunting was found in 10.1% and was identified starting at the fourth month of life. This was accompanied by early CF close to the third month (57.0%) and by a reduction in exclusive breastfeeding during the second month of life to only 30%. The proportion of not breastfed children with stunting (27.5%) was almost twice that of breastfed children (12.0%) (p < 0.03). By age, mean ZLA was different with a trend towards stunting increasing with age (p < 0.05): 1-6 months -0.463 +/- 1.445; 7-12 months -0.669 +/- 1.225; and 13-24 months -0.985 +/- 0.917. MDD was greater in not breastfed children (69.7%) (p < 0.04) and by age greater in children 13-24 months (69.7%) (p < 0.02). CONCLUSIONS: the feeding practices of most mothers did not meet WHO recommendations. It is necessary to carry out nutrition education interventions aimed at mothers in rural population. PMID- 29756957 TI - Nutritional outcomes in children with epidermolysis bullosa: long-term follow-up. AB - BACKGROUND: some types of epidermolysis bullosa (EB) have extracutaneous manifestations. Manifestations that limit food intake and absorption may compromise nutritional status and increasing nutritional requirements. OBJECTIVES: to investigate the following nutritional status indicators: exclusive breastfeeding duration, problems caused by the introduction of complementary foods, birth weight and length, and growth curves of children with EB. METHODS: assessment was based on the World Health Organization (WHO) growth charts. The anthropometric data were stored in the WHO's programs Anthro and Anthro Plus. RESULTS: three and seven of the ten study children had EB simplex (EBS) and recessive dystrophic EB (RDEB), respectively. Four of the children with RDEB had problems when complementary foods were introduced. The difference between the chronological age and age-for-height at the 25th (A/H 25th) percentile (p) varied from four months to four years and two months. Most children with RDEB (85%) had weight-for-age (W/A) curve below p3 and low height-for-age (H/A), starting before age four years. One child with EBS had excess weight. CONCLUSIONS: anthropometric birth data, exclusive breastfeeding duration, and problems caused by the introduction of complementary foods are useful information for establishing the nutritional profile of children with EB. Supposedly, breastfeeding and no complementary feeding problems were not enough to prevent inadequate nutritional status, observed in the majority of the study children. The original presentation of the growth curves of children with EB may help to determine nutritional involvement and to establish how these children grow. The evaluation of growth curves with WHO as a standard suggests the need to establish growth curves adapted to the most serious type of EB and the need for permanent nutritional monitoring. PMID- 29756959 TI - Reduced serotonin levels after a lifestyle intervention in obese children: association with glucose and anthropometric measurements. AB - BACKGROUND: serotonin signaling participates in body weight regulation and glucose metabolism. However, little information is available on circulating serotonin levels in obese subjects after a weight loss program. We aimed to assess the effect of a lifestyle intervention on serotonin levels in obese children and possible associations with anthropometric and blood glucose measurements. METHODS: forty-four obese children were enrolled in a ten-week lifestyle intervention consisting of a moderate caloric restriction diet, nutritional education and familial involvement. They were distributed according to the weight loss response. Subjects who lost > 0.5 BMI-SDS were considered as high responders (HR; n = 22) and those who lost <= 0.5 BMI-SDS, as low responders (LR; n = 22). Anthropometric, biochemical parameters and plasma serotonin levels were measured as pre and post-intervention values. RESULTS: obese children (HR and LR groups) were able to reduce anthropometric indices and to improve glucose profile after the intervention. Interestingly, plasma serotonin levels were significantly (p ?0.05) reduced in all subjects (-35.14 nmol/l HR group and 30.63 nmol/l LR group). Moreover, multiple-adjusted regression models showed a significant association between pre-intervention (R2 = 0.224, B = 0.047; p = 0.004) and post-intervention (R2 = 0.140; B = 0.055; p = 0.042) plasma serotonin and glucose levels. In addition, in HR subjects changes in plasma serotonin were associated with changes in glucose levels (R2 = 0.292; b = 0.04; p = 0.045). Interestingly, pre and post-intervention plasma serotonin levels were inversely associated (p ?0.05) with anthropometric measures. CONCLUSIONS: serotonin levels were reduced after a lifestyle intervention independently of the program response. Moreover, plasma serotonin levels were associated with glucose and anthropometric measures in obese children. PMID- 29756960 TI - Socio-demographic variables and underlying pathologies associated to nutritional status of hospitalized children in a secondary-tertiary level hospital. AB - OBJECTIVE: the purpose was to evaluate the nutritional status in hospitalized children according to their socio-demographic variables, underlying pathology and based on hospital length of stay. METHODS: seven-hundred and sixty-three hospitalized patients of the Civil Hospital of Guadalajara Dr. Juan I. Menchaca were included in a cross-sectional study. The following anthropometric indices were taken: weight/length, weight/height, weight/age, length/age, height/age, head circumference/age and BMI/age. Data of socio-demographic variables and underlying pathology were also obtained. Student's t-test, Chi-squared test, ANOVA with post-hoc tests and logistic regression were used to identify the likelihood of risk of malnutrition. RESULTS: subjects were divided according to their hospital length of stay in lower than seven days and seven days or more. At the time of admission, children with stay of seven days or more showed a greater deficit in the height/age index (OR = 1.77 [95% CI 1.16-2.7], p = 0.007), head circumference (OR = 2.68 [95% CI 1.5-4.7], p <= 0.001) and BMI (OR = 2.9 [95% CI 1.9-4.4], p <= 0.001). Males had higher risk of moderate/severe malnutrition (OR = 1.87 [95% CI 1.22-2.85], p = 0.003) and higher deficit in head circumference (OR = 1.89 [95% CI 1.06-3.37], p = 0.029). Infants with gastrointestinal and respiratory problems had higher frequency of malnutrition at the time of admission than did those with other pathologies (p < 0.001). CONCLUSION: the pathological disease at time of admission and longer hospital length of stay increased the likelihood of malnutrition in male infants and preschool-aged children. There were demographic and educational risk factors in the home environment that could influence acute and chronic malnutrition. PMID- 29756961 TI - Prevalence of metabolic syndrome and its determinants in older Mexican non diabetic adults. AB - INTRODUCTION: the prevalence of metabolic syndrome (MetS) is high in older people, and several factors have been explored as main determinants. However, few data exist for older people from low- and middle-income countries. Therefore, our objective was to estimate the prevalence of MetS. Secondly, to explore which of the cardio-metabolic, body composition, inflammatory and demographic risk factors were associated with the prevalence of MetS in a population of older Mexican adults. METHODS: data for this analysis were collected in subjects over 60 years of age from northwest Mexico. Fasting and two-hour glucose, fasting insulin, homeostasis model assessment of insulin resistance, lipid profiles, markers of adiposity and inflammation, and blood pressure were assessed. In addition, anthropometry and body composition data, levels of physical activity and demographic variables were also considered. MetS was diagnosed by three different criteria. RESULTS: total sample size was 369 subjects. The prevalence of MetS varied widely, from 36% to 52% depending on the criteria applied, but regardless of the criteria, all subjects with MetS were heavier and more overweight, and had higher triglyceride values and lower values of total HDL-cholesterol compared to those without MetS (p < 0.0001). Final models adjusted for age showed that, regardless of the diagnostic criteria applied, fat mass, the homeostasis model assessment and some demographic variables were main determinants of MetS in this sample of older people without diabetes. CONCLUSIONS: the prevalence of MetS is relatively high in non-diabetic older adults and it was associated with some biological and demographic factors as the main determinats. PMID- 29756962 TI - Impact of APOE2allele on lipid profile change after a weight loss program. AB - BACKGROUND: apolipoprotein E (ApoE) polymorphism is a genetic determinant of lipid and lipoprotein levels and the risk for coronary heart disease. OBJECTIVE: to evaluate the impact of ApoE2allele in lipid plasma levels and the influence of a healthy hypocaloric diet plus a controlled physical activity on the lipid profile, we performed a study in a cohort of overweight and obese healthy subjects (Body Mass Index (BMI) between 25 and 34.9 kg.m-2). METHODS: one hundred eighty participants (96 women), aged 18-50 years participated in a 22 weeks weight loss intervention based on same dietary treatment and different controlled exercise programs. All subjects followed a hypocaloric diet (25-30% less energy intake than the daily energy expenditure). Blood samples were obtained for lipids measurements at the beginning and end of the study. RESULTS: after intervention, men of the E2 group showed the greatest decreases in low-density lipoprotein (LDL), triglycerides (TG) and total cholesterol (TC) values (p = 0.039; p = 0.001; p = 0.001; respectively). For high-density lipoprotein (HDL), E2 group had significant differences compared with E4 at pre- (p = 0.020) and post intervention values (p = 0.024). CONCLUSION: our results show great changes in men carrying ApoE2, mainly in TG and TC concentrations after treatment with hypocaloric diet and controlled exercise. Therefore, adding supervised training to nutritional intervention seems to be a good alternative for the reinforcement of the effect of the treatment. PMID- 29756964 TI - Acai improves non-alcoholic fatty liver disease (NAFLD) induced by fructose. AB - INTRODUCTION: the excessive consumption of fructose can cause liver damage, characteristic of non-alcoholic fatty liver disease (NAFLD) associated with changes in lipid metabolism and antioxidant defenses. Acai, the fruit of Euterpe oleraceaMart., has demonstrated numerous biological activities, including anti inflammatory, antioxidant, and lipid metabolism modulating action. OBJECTIVE: we evaluated the benefits of acai supplementation on liver damage caused by replacing starch with fructose in rats. METHODS: thirty male Fischerrats were divided into two groups, the control group (C, 10 animals), which consumed a standard diet (AIN-93M), and the fructose (F, 20 animals) group, which consumed a diet containing 60% of fructose. After eight weeks, 10 animals from the fructose group received 2% of lyophilized acai, and were called the acai fructose group (FA). The animals were fed ad libitumwith these diets for another ten weeks. Serum, hepatic and fecal lipid profile, antioxidant enzymes and carbonylated protein were assessed and histopathological characterization of the liver was performed. RESULTS: acai promoted the reduction of ALT activity in relation to the fructose group (F), reduced alkaline phosphatase to a level similar to that of the control group (C) in relation to the fructose group (F), and reduced catalase activity. The fruit also increased the ratio of total/oxidized glutathione (GSH/GSSG) and reduced the degree of macrovesicular steatosis and the number of inflammatory cells. CONCLUSION: the replacement of starch by fructose during this period was effective in promoting NAFLD. Acai showed attenuating effects on some markers of hepatic steatosis and inflammation. PMID- 29756963 TI - Cardiorespiratory fitness and fat oxidation during exercise as protective factors for insulin resistance in sedentary women with overweight or obesity. AB - INTRODUCTION: obesity is a global pandemic and it is the biggest risk factor for death worldwide nowadays. Studies suggest that both cardiorespiratory fitness and fat oxidation in exercise are related to insulin resistance and type 2 diabetes mellitus, and they could be used as metabolic fitness markers. OBJECTIVES: the aim of this study is to determine if cardiorespiratory fitness (VO2) and fat oxidation during exercise are protective factors of insulin resistance (IR) in sedentary women with obesity or overweight. METHODS: sixty women were selected for fat oxidation analysis and 55 for cardiorespiratory fitness analysis that fitted the inclusion and exclusion criteria. VO2, maximal fat oxidation (MFO) and the intensity where MFO is reached (FATmax) were determined through an incremental test on a cycle ergometer with gas analysis. The subjects with a Homeostatic model assessment of IR index greater or equal to 2.5 were considered as insulin-resistant. Participants were divided into 2 groups, IR group (n = 38) and Non-IR group (n = 22). RESULTS: VO2(%) and MFO were lower in the IR group (76.1% vs.83.2%; p = 0.015 and 1.08 mg * kg-1 * min-1 vs. 1.62 mg * kg-1 * min-1; p= 0.044, respectively) compared to the Non-IR group. There was an association between VO2(%) and IR (OR = 0.92, p = 0.017) and between MFO and IR (OR = 0.52, p = 0.035), both models adjusted for age and body mass index. CONCLUSIONS: VO2(%) and MFO are independent protective factors for IR. No association was found between FATmax and IR. PMID- 29756965 TI - Visceral adiposity index associated with behavioral and inflammatory parameters in adults: a population based study. AB - INTRODUCTION: the visceral adiposity index (VAI) is an indicator of fat distribution and function which is considered a predictor of cardiometabolic risk. OBJECTIVE: analyze the factors associated with VAI in Brazilian adults. METHODS: a cross-sectional population-based study was conducted with 854 adults, in Vicosa, MG, Brazil. A questionnaire was applied and anthropometric measurements, body composition and biochemical data were collected. Ordinal logistic regression was used to evaluate the factors associated with VAI. RESULTS: the increase in percentage of fat, uric acid concentration and ultra sensitive C reactive protein in the blood was positively associated with VAI in males. The level of physical activity in leisure was negatively associated. Among women, the increase in age, neck circumference, sitting time of more than 300 minutes, increased serum uric acid concentration and ultra-sensitive C reactive protein were associated with VAI. CONCLUSION: except for age, all other factors associated with VAI are modifiable, suggesting that adopting early intervention measures that promote changes in habits and alter the risk of increased visceral adiposity and consequently the appearance of comorbidities should be encouraged. PMID- 29756967 TI - Dual energy X-ray absorptiometry (DXA) reliability and intraobserver reproducibility for segmental body composition measuring. AB - BACKGROUND: the measurement precision of body composition can interfere on the diagnosis and prescription of diseases' treatment. Furthermore, with regard to dual energy X-rays absorptiometry (DXA), there may be important differences between the measures of regions of interest (ROI) automatically performed by DXA or manually by an evaluator, which can cause measurement error and influence the evaluation or diagnosis. AIM: thus, this study aimed to evaluate the measurement reliability of body composition by DXA and intraobserver reproducibility for the ROI measurement. METHODS: a total of 15 young adults were subjected to two full body scans by DXA, under the same conditions. The first scan of all volunteers was chosen and the extent of the ROI was performed, in two stages, separated by a period of 2 weeks, by a single trained evaluator. The coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated with a significance level of p < 0.05. RESULTS: high-precision measurements of DXA for whole body mass (ICC = 0.999; CV = 2.3%), fat mass (ICC = 0.998; CV = 1.6%), lean mass (ICC = 0.995; CV = 0.3%) and bone mineral content (ICC = 0.996; CV < 0.1%) were obtained. Further, it was observed high intraobserver reproducibility for ROI measurement, with ICC values ranging between 0.952 and 0.999. CONCLUSION: body composition measurement by DXA presents high reproducibility for whole body mass, fat mass, lean mass and bone mineral content and also high intraobserver reproducibility for the ROI measurement. PMID- 29756966 TI - [May pregestational body mass index be related to mother's psychological and physical condition during pregnancy?] AB - INTRODUCTION: pregestational Body Mass Index (BMI) affects mother's health during and after pregnancy and is related to negative outcomes such as low birth weight and preterm birth. Higher pregestational BMI may increase anxiety, stress and depression. OBJECTIVES: to assess potential differences on stress, psychopathological symptoms and physiological variables during pregnancy, among pregnant women with normal pregestational BMI rates and high pregestational BMI rates. METHODS: a sample of 156 pregnant women were longitudinally assessed during the three trimesters of pregnancy. They were divided into two groups: a group with normal pregestational BMI rates (n = 115) and a group with high pregestational BMI rates (n = 41). Stress levels, psychopathological symptoms, blood pressure and glucose blood levels were assessed. RESULTS: in the first trimester, significant differences were found between groups regarding pregnancy specific stress and some of the SCL-90-R subscales (depression, paranoid ideation and global wellness index). In the second trimester, there were differences regarding pregnancy-specific stress and some of the SCL-90-R subscales (somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, paranoid ideation and the general scales, global wellness index and symptoms free). In the third trimester, there were differences between groups regarding perceived stress and some of the SCL-90-R subscales (somatization, anxiety and the general scale symptoms free). Significant differences were found between groups on diastolic blood-pressure in the first trimester, and systolic and diastolic blood-pressure in the third trimester. CONCLUSIONS: higher pregestational BMI is related to higher psychological stress, higher psychopathological symptoms and elevated blood-pressure during pregnancy. PMID- 29756968 TI - The BFMNU method as an alternative to the methods in use based on energy: study of the correlation between food energy and body mass. AB - INTRODUCTION: to establish slimming guidelines and any other changing treatments is useful to know the individual's energy expenditure due to the fact that, nowadays, the incidence of many diseases related to the loss of lean mass and the accumulation of adipose tissue has increased. The dietary treatments are carried out on calculating the energy contained in food, and then put in relation to the total energy expended by the body in order to produce changes in body mass. OBJECTIVE: the aim of this study was to evaluate the correlation between the food energy and body mass of different subjects in various pathophysiological conditions. METHODS: one hundred and twenty subjects (male and female, aged 7-78 years old) were studied in various pathophysiological conditions and previously treated with the BFMNU (Biologia e Fisiologia Modellistica della Nutrizione Umana)method. RESULTS: a correlation coefficient R2 of 0.1256 was found between food energy of the diet usually followed by the subjects and their body mass. The correlation between food energy and food mass was with R2 of 0.211. The correlation between Delta% of food energy and Delta% of body mass of the subjects, obtained through dietary treatment with the BFMNU method, was 95.77 percent. CONCLUSIONS: the correlation between food energy and body mass is not significant, being a critical point about the diets designed on an energy basis. However, the body mass of an individual is determined by mass balance, regulated by corresponding metabolic rate, calculated by the BFMNU method, thanks to which the macronutrients in the diet are absorbed, redistributed and eliminated. A significant correlation, although not straight, is demonstrated between Delta% of food energy, supplied after processing through the dietary BFMNU method, and the Delta% of body mass, obtained following the dietetic path. PMID- 29756969 TI - [Validation of nutritional screening Malnutrition Screening Tool compared to other screening tools and the nutritional assessment in different social and health areas]. AB - INTRODUCTION: nutritional screenings are used to detect nutritional risk, allow early intervention and influence the prognosis. The Malnutrition Screening Tool (MST) is only validated in hospitalized patients and oncology outpatients. OBJECTIVES: to analyze the nutritional screening MST, Malnutrition Universal Screening Tool (MUST) and Mini Nutritional Assessment-Short Form (MNA-sf) compared to the nutritional assessment gold standard according to socio-sanitary areas and age groups; and to assess the utility of the MST in those areas where it has not been validated. MATERIAL AND METHODS: a total of 815 outpatient, hospitalized and institutionalized subjects were included in this study. MUST and MST screenings, and nutritional assessment were performed in all subjects. MNA-sf was also performed in subjects >= 65 years of age. Nutritional diagnosis was performed according to the SENPE-SEDOM consensus. RESULTS: in the outpatient cohort, three screenings have a validity (AUC ROC) greater than 0.8 compared to nutritional assessment. In the institutionalized, the MNA-sf generates false positives and the MUST is more valid than MST (AUC ROC = 0.815 and 0.763, respectively). In hospitalized patients, there are excellent results with MUST and MST. In all socio-sanitary areas the MST obtains a better positive predictive value. By age groups, MUST and MST are valid tools. CONCLUSIONS: in our study, the MST correctly diagnoses more than 80% of the patients (S = 69.4%, E = 94.2%), and has a good reliability and validity with respect to nutritional assessment not only in hospitalized patients and oncology outpatients, where it has already been validated. In our population, the MST was found to be valid in outpatient, institutionalized and hospitalized subjects. PMID- 29756970 TI - Critical overview of current anthropometric methods in comparison with a new index to make early detection of overweight in Spanish university students: the normalized weight-adjusted index. AB - BACKGROUND: overweight and obesity have been increasing, and university students are an important target for prevention programs. Previous studies have reported differences in the diagnosis between different anthropometric methods, so some students can be misclassified depending on the method used. OBJECTIVE: to evaluate the efficacy of different anthropometric methods to detect those university students in a probable status of overweight, including a comparison with a new proposed method, the normalized weight-adjusted index (NWAI). METHODS: different anthropometric methods (waist circumference, waist-hip ratio, waist height ratio, body mass index, conicity index, bioimpedance and Brozek, Siri and Heath-Carter equations) were calculated for 505 university students. By k-means cluster analysis, students with higher values according to variables involved in overweight were identified. Parameters of accuracy were calculated by operating characteristic curves. RESULTS: NWAI showed significant correlations with the most used methods. Prevalence of students with body fat excess varied from 5.9% to 48.4% for women and from 8.5% to 49.0% for men depending of the method employed, being demonstrated a great variability between the different methodologies. Body mass index for women and waist circumference for men resulted to be the most accurate methods to detect a probable situation of excess of body fat or cardiovascular risk associated. NWAI resulted also a good alternative for overweight classification. CONCLUSIONS: differences between anthropometric methods for overweight and cardiovascular disease risk classification were confirmed. Classical cut-off point may misdiagnose overweight or health risk in Spanish university students depending of the method employed. PMID- 29756971 TI - The relationship between socioeconomic status and beverage consumption in children: The Cuenca Study. AB - INTRODUCTION: beverage consumption constitutes a source of children's daily energy intake. Some authors have suggested that consumption of caloric beverages is higher in children with a low socioeconomic position because families limit their spending on healthy food in order to save money. OBJECTIVE: the aim of this study was to explore the relationship between socioeconomic status and Spanish children's beverage consumption. METHODS: a cross-sectional study was conducted in a sub-sample of 182 children (74 girls) aged 9-11 from the province of Cuenca (Spain). Beverage consumption was assessed using the YANA-C assessment tool, validated for HELENA study. Data for parental socioeconomic status were gathered by using self-reported occupation and education questions answered by parents and classified according to the scale proposed by the Spanish Society of Epidemiology. RESULTS: beverage intake was higher in children belonging to a middle-status family than in those of upper socioeconomic status (p = 0.037). The energy from beverages was similar in most water intake categories, except for water from beverages (p = 0.046). Regarding other beverages categories, middle status children had higher consumption levels. In contrast, lower status children drank more fruit juices and skimmed milk. All of these do not show statistically significant differences. CONCLUSIONS: our study did not find significant associations between beverages consumption and socioeconomic status in children. In fact, intake for most beverage categories was higher in middle-status children than in both other socioeconomic groups. Future research is needed in order to identify this complex relation between socioeconomic inequality and beverage intake behavior. PMID- 29756972 TI - Dietary patterns, physical activity, body mass index, weight-related behaviours and their interrelationship among Romanian university students-trends from 2003 to 2016. AB - INTRODUCTION: promotion of a healthy diet and involvement in physical activity among young people has an important impact on their actual and future lifestyle, health and well being. OBJECTIVES: this study investigates dietary patterns, physical activity, body mass index (BMI) and weight-related behaviours as well as their interrelationship among Romanian university students. METHODS: the study used anonymous questionnaires and was performed in Cluj-Napoca, Romania in 2003 (n = 320) and 2016 (n = 320). RESULTS: the factor analyse revealed three main dietary structures which were similar at both waves. The first one describes a varied diet. The second one shows a diet rich in white meat, dietary fibres and varied sources of carbohydrates. The last one refers to a diet containing red meat, fat, potatoes, sugar. The first dietary structure protects against overweight and it correlates positively with daily physical activity, while has a negative correlation with using several methods for losing weight. The second dietary factor is also protective for overweight, but has a positive correlation with using several methods for losing weight. It has a negative association with eating frequently in fast food restaurants and with daily physical activity. The last dietary structure is negatively associated with daily physical activity, while being positively associated with eating frequently in fast-food restaurants and with a higher BMI. CONCLUSIONS: the study presents trends in dietary patterns, physical activity, BMI and weight related behaviours among Romanian university students between 2003 and 2016 and highlights the existence of several main dietary structures, which seems stable over time. PMID- 29756973 TI - [Clinical and economic implications of disease-related malnutrition in a surgical service]. AB - INTRODUCTION: disease-related malnutrition (DRM) is currently a major challenge in our hospitals, both because of its high prevalence and because of the clinical and economic impact. Our study aims to assess the feasibility and importance of establishing a nutritional screening strategy in our Health Care System. PATIENTS AND METHODS: this is a prospective study carried out in a Surgery Ward. The nutritional risk was assessed by applying to patients MUST at admission and weekly until discharge. Nutritional evaluation and nutritional intervention were performed if required, as well as coding of diagnoses and nutritional procedures at discharge. Clinical data, length of stay (LOS) and hospital costs were analyzed. RESULTS: MUST detected 15.6% of patients at risk of malnutrition at admission. Patients with malnutrition at admission (MA) had four days longer LOS, higher annual mortality rate and urgent hospital readmissions in 2.4 and 2.0 times, respectively, one year after discharge. Age and urgent hospital admission were the factors associated with a higher annual mortality rate. Nine per cent of patients with an initial MUST < 2 suffered deterioration in their nutritional status during admission (DNS). These patients had longer LOS in seven days with equal comorbidity. Considering only the costs related to LOS in patients who presented MA or DNS, an overcost of 57% and 145%, respectively, was observed. CONCLUSION: patients with malnutrition on admission had longer LOS, higher mortality rate and urgent hospital readmissions one year after discharge. Patients who present MA or DNE cause an economic cost overrun. A nutritional screening tool is essential for the management and early detection of DRM. PMID- 29756974 TI - [Effects of lacto-vegetarian diet and stabilization core exercises on body composition and pain in women with fibromyalgia: randomized controlled trial]. AB - BACKGROUND: fibromyalgia is a disease of unknown origin characterized by chronic muscular pain. The lack of knowledge about this disease is one of the main causes that makes complex to make a diagnosis and an appropriate treatment. OBJECTIVE: the main objective of this study was to know the efficacy of a physiotherapy treatment combined with a lacto-vegetarian dietary-nutritional intervention, on low back pain and body composition in women with fibromyalgia. METHODS: twenty one women were randomly divided into three groups: A (core stabilization exercises + lacto-vegetarian diet), B (placebo + lacto-vegetarian diet) and C (control). The intervention lasted 4 weeks. Pain assessments (EVA scale) and body composition (bioimpedance) were performed at the beginning and at the end of the intervention. RESULTS: group A showed significant changes in pain reduction and body composition at the end of the intervention, increasing muscle mass and decreasing fat mass. In addition, this group significantly improved outcomes compared to groups B and C. The correlations showed a relationship between muscle mass and pain reduction referred to at the end of the study in patients in group A. CONCLUSIONS: four-week intervention program combining core stabilization exercises plus lacto-vegetarian diet in patients with fibromyalgia who have low back pain contributes to pain reduction and improved body composition. PMID- 29756975 TI - [Risk factors associated with type 2 diabetes in Chile]. AB - BACKGROUND: worldwide, prevalence of type 2 diabetes has doubled in the last years, mainly due to unhealthy lifestyle behaviours. They are many risk factors associated with diabetes, however, which factors are associated with diabetes in the Chilean population remains unknown. Therefore, the aim was to determine what risk factors are associated with the development of diabetes in Chile. METHODS: four thousand and seven hundred participants from the cross-sectional 2009-2010 National Health Survey were included in this study (4,162 normal; 538 diabetics). Risk factors assessed were socio-demographic, anthropometric, lifestyle, well being and comorbidities. The association between diabetes and risk factors was examined using logistic regression. RESULTS: the main non-modifiable risk factors associated with diabetes were age >= 45 year, female and family history of diabetes; whereas the main modifiable risk factors were hypertension, overweight, obesity, central obesity, physical inactivity and higher levels of sitting time. CONCLUSION: the identification of modifiable risk factors for DMT2 is key to control and decrease the prevalence of this pathology and to improve the quality of life of the population. PMID- 29756976 TI - [Dietary diversity in women who live in food insecurity settings in Mexico, beneficiaries of a food support program]. AB - INTRODUCTION: food diversity is an approximation of diet quality. In Mexico, the Food Support Program (PAL, by its acronym in Spanish) grants support to families facing food poverty, in form of cash (PAL EFECTIVO) or through monetary transfers on a card intended exclusively for the purchase of food (PAL SIN-HAMBRE), seeking to improve their food diversity. OBJECTIVE: to compare the dietary diversity in women beneficiaries of both schemes and their association with the level of food insecurity (FI) at household level. METHODS: a cross-sectional study was carried out in a national random sample of 243 women beneficiaries from PAL EFECTIVO and 277 from PAL SIN-HAMBRE in 14 states. A multinomial logistic regression model was constructed to measure the association between the FI perception index and its relationship with the PAL and the dietary diversity index. RESULTS: the PAL SIN HAMBRE scheme is associated with a lower probability of mild and severe FI with respect to the PAL EFECTIVO. The interaction between the type of scheme and the dietary diversity index showed that the PAL EFECTIVO had a lower probability of severe FI when the dietary diversity index was greater with respect to the PAL SIN-HAMBRE. CONCLUSIONS: the FI in the household and the low dietary diversity seem to be strongly associated in women of childbearing age and this relationship is higher in those beneficiaries of the PAL SIN-HAMBRE scheme. PMID- 29756977 TI - Effects of red wine, grape juice and resveratrol consumption on bone parameters of Wistar rats submitted to high-fat diet and physical training. AB - INTRODUCTION: intake of diets with high saturated fat may produce deleterious effects on bone mineralization. Lifestyle changes help reduce the bone loss observed in osteoporosis. Resveratrol, present in grape juice and red wine, has osteogenic and osteoinductive effects, being potentially beneficial for bone health. OBJECTIVE: to evaluate the effects of red grape juice, red wine and resveratrol consumption on bone parameters in Wistar rats submitted to a high-fat diet and physical training. METHOD: female Wistar rats, with 90 days of age, were divided into five groups and followed up for 60 days: a) control group; b) high fat group; c) grape juice group; d) red wine group; and e) resveratrol group. The different groups of animals performed a physical training protocol. Animal's weight and consumption were monitored weekly. After 60 days, femoral dimensions, bone mineral density (BMD) and bone mineral content (BMC) were evaluated. RESULTS: there was no difference in body mass; however, all groups consuming the high-fat diet had higher consumption (p < 0.05). RWG presented a greater distance between the epiphyses, femoral mass and BMC (p < 0.05). RWG and RG presented greater mean diaphysis point width and BMD (p < 0.05). CONCLUSION: the results suggest that the bioactive compounds present in red wine and resveratrol solution together with regular exercise were able to promote beneficial effects on bone health, even when associated with a high saturated fat diet. PMID- 29756978 TI - Comparative study of the nutritional status of vitamin A in pregnant women and in women who became pregnant or did not after Roux-en-Y gastric bypass. AB - INTRODUCTION: the changes in digestive physiology after Roux-en-Y gastric bypass (RYGB), as well as pregnancy, maximizes the risk of vitamin A deficiency (VAD) and both can result in harm to the mother and child health. OBJECTIVE: to compare the nutritional status of vitamin A among women who became pregnant or did not after RYGB and in pregnant women who did not undergo surgery, and to assess the impact of VAD on the mother and child health. METHODS: this is a cross-sectional study of the analytical type. The women were divided into: group 1 (G1) with 80 pregnant women; group 2 (G2) with 40 pregnant women who had previously undergone RYGB, both in their third trimester of pregnancy; and group 3 (G3) with 77 non pregnant women who had previously undergone RYGB. Serum concentrations of retinol and beta-carotene, night blindness (NB), gestational and neonatal intercurrences were investigated. The significance level adopted was p < 0.05. RESULTS: RYGB, per se,had a greater impact on the inadequacy of retinol, beta-carotene, and on the increased percentage of NB when compared to non-surgical pregnant women. When surgery was associated with pregnancy, more than 75% of inadequacy of retinol and beta-carotene was noted, as well as a higher percentage of individuals with NB. G2 also showed increased prevalence ratio for developing gestational and neonatal intercurrences, when compared to G1. CONCLUSION: RYGB provides greater negative impact on the nutritional status of vitamin A compared to pregnancy, and surgery associated with pregnancy can create even greater risks. PMID- 29756981 TI - [Costs associated to disease-related malnutrition and treatment: a literature review]. AB - INTRODUCTION: disease-related malnutrition has a high prevalence, with clinical consequences potentially severe for the patient, and of high economic impact for the healthcare system. OBJECTIVE: to perform a review of the literature regarding the economic burden of disease-related malnutrition, to assess complications, and to determine the usefulness of enteral or oral nutritional supplementation from a cost analysis perspective. METHODS: a review of the literature up to June 2016 was carried out regarding economic costs of disease-related malnutrition and cost analysis of nutritional treatment, with special focus on retrieval of systematic reviews, meta-analysis, and randomized clinical trials. RESULTS: a total of 31 publications were selected, 15 on costs of disease-related malnutrition and 16 on costs of treatment. Disease-related malnutrition increases health care costs in relation to a longer hospital stay, higher incidence of infectious and non infectious complications, greater need of treatment, increase in readmissions, more prolonged stay in the intensive care unit and/or the need of referral to continuing care centers at discharge. Publications regarding treatment with oral nutritional supplements suggest that these oral supplements are cost-effective and cost-beneficial both in ambulatory and hospitalized patients. CONCLUSIONS: disease-related malnutrition causes an increase in health care costs that could be minimized, among other approaches, by an early diagnosis and treatment for which oral nutritional supplements are cost-effective and cost-beneficial. PMID- 29756979 TI - Prevention of oral mucositis secondary to antineoplastic treatments in head and neck cancer by supplementation with oral glutamine. AB - OBJECTIVES: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. MATERIAL AND METHODS: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy +/- concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. RESULTS: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). CONCLUSION: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube. PMID- 29756980 TI - Alteration of inflammatory adipokines after four months of smoking abstinence in multidisciplinary intervention program. AB - BACKGROUND: many endocrine-metabolic changes are involved in smoking. OBJECTIVES: to evaluate serum concentrations of inflammatory adipokines in smokers at baseline and after four months of treatment for smoking cessation. METHODS: the serum concentrations of inflammatory cytokines were evaluated in smokers and abstinent. Nutritional assessment was based on measurements of body weight, height, and waist circumference (WC), to calculate body mass index (BMI), body adiposity index (BAI) and waist-to-height ratio (WHtR). Biochemical parameters were analyzed: total cholesterol, LDL-c, HDL-c, triglycerides, glucose, cortisol and insulin. The serum levels of leptin, adiponectin and ghrelin were determined by enzyme-linked immunosorbent assay (ELISA). The leptin/adiponectin ratio (L/A) was calculated. RESULTS: a total of 29 subjects were included in this study (22 women and seven men). The mean age of participants was 50.7 +/- 10.47 years. The medium values of WHtR and BAI were above of the proposed cutoff point, indicating abdominal obesity. The biochemical parameters did not present statistically significant differences when comparing the initial and final values. At the end of treatment, the abstinent had higher levels of adiponectin when compared to those who remained smoker (p = 0.024). There was an increase in leptin levels and L/A, and a reduction in adiponectin levels after the treatment in abstinent and smokers (p < 0.05). CONCLUSION: this study has demonstrated that smoking cessation improves adiponectin levels when compared with smokers. Leptin and L/A levels increased throughout the treatment in both groups. The increased values of leptin and L/A in abstinent participants may indicate risk of metabolic events associated with smoking history that should be investigated. PMID- 29756982 TI - Clinical-nutritional, inflammatory and oxidative stress predictors in hemodialysis mortality: a review. AB - The evaluation of clinical-nutrition status is essential to increase life quality and improve clinical outcomes of patients in hemodialysis (HD). In the absence of a gold standard, the goal of this integrative review was to present and discuss the latest scientific literature on the ability of clinical-nutritional indicators and inflammatory and oxidative stress markers to predict morbidity and mortality in HD. In this context, the lean and fat mass indexes have become good predictors of mortality in HD individuals, regardless of BMI. Subjective scoring systems have been more sensitive to malnutrition, and altogether anthropometric indicators may result in an early detection of mortality risk in this population. On the other hand, inflammation in HD, as assessed by C-reactive protein, is not only related to cardiometabolic alterations, but it is also one of the key-points in the development of malnutrition, exacerbated by the state of oxidative stress, which has been identified in this group by the increase of the serum levels of gamma-glutamyl transferase and malondialdehyde. PMID- 29756983 TI - [Endocrine disruptors in artificial nutrition]. AB - Phthalates are chemical compounds classified as endocrine disruptors which are present in practically every environment of daily life. In the field of artificial nutrition, they are relevant because they are found as plasticizers in infusion lines made with PVC. They are lipophilic molecules which weakly pair with PVC and, therefore, they are easily extracted by the fatty compounds that are part of both the parenteral and enteral nutrition, as various studies show. As endocrine disruptors, they directly affect the reproductive organs because of their antiandrogenic and estrogenic effects. They promote inflammation and oxidative stress and they are also related to the development of obesity, asthma, neurological and ophthalmic disorders, cholestasis and other gastrointestinal disorders. The legislation establishes the highest recommended exposure level for daily exposure; however, in the medical environment the exposure follows a different pattern, more occasional with very high peaks, for which there are no established thresholds, that is why it is recommended to avoid exposure whenever possible. The industry is working on the development of alternative plasticizers, for which the use experience is still limited. Currently, in the field of artificial nutrition it is recommended to use phthalate-free intravenous and enteral infusion lines. PMID- 29756985 TI - [Consensus document about the nutritional evaluation and management of eating disorders: anorexia nervosa, bulimia nervosa, binge eating disorder, and others. Executive abstract]. PMID- 29756984 TI - Sugar-sweetened beverage consumption and obesity in children's meta-analyses: reaching wrong answers for right questions. AB - BACKGROUND: Recent studies assert that sugar-containing drinks may play a key role in the etiology of obesity. However, scientific reviews show contradictory results. Whether there is just association or clear causation still is a matter of debate. It is also subject to discussion whether the quality/adequacy of the different studies may influence their outcome. OBJECTIVE: The aim of this study is to explore the most recent scientific evidence focused on sugar-sweetened beverages (SSB) and child obesity and to further analyze the adequacy of the meta analyses in terms of their results, with special emphasis in the methodology, clarity and transparence of their procedures. METHODS: Only meta-analyses of randomized control trial studies were selected. The search was performed on PubMed and Cochrane Website until January, 2016. Adherence to PRISMA was assessed. RESULTS: Six meta-analyses were included. All of them showed some degree of evidence of heterogeneity in theirs pool estimates. Two of them showed a positive association between SSB and obesity but the other four found no association. The adherence to the PRISMA criteria was higher in two of the meta analyses that showed opposite conclusions regarding the association or non association of SSB and obesity in children. Thus, there is no relation between the adequacy of the meta-analyses to the PRISMA criteria and the results obtained. CONCLUSION: The use of meta-analysis as a scientific tool still demand more polishing, agreement and spread out use by researchers. SSB are being accused of being a main cause of the existing obesity, but this subject requires a broader approach that includes a thorough analysis of diet and lifestyle and a stronger body of scientific evidence based on data from epidemiological studies conducted in different populations. PMID- 29756986 TI - [Dietetic treatment with fructose in a 5-year-old girl with recurrent D-lactic acidosis]. AB - D-lactic acidosis is an infrequent complication, mainly reported in patients with short bowel syndrome. It is characterized by recurrent episodes of encephalopathy with elevated serum D-lactic acid, usually associating metabolic acidosis. The presence of D-lactate-producing bacteria is necessary for the development of this complication. Other factors, such as the ingestion of large amounts of carbohydrates or reduced intestinal motility, contribute to D-lactic acidosis. We report a case of recurrent D-lactic acidosis in a 5-year-old girl with short bowel syndrome, due to a midgut volvulus. She initially received oral antibiotics in order to treat bacterial overgrowth, together with oral carbohydrates restriction. Nevertheless, recurrences did occur. Subsequently, 25% of the enteral nutrition was replaced for a formula containing fructose exclusively, while other fermentable sugars were restricted from the diet. After 16 years of follow up, further recurrences of D-lactic acidosis were not observed. PMID- 29756988 TI - More on Single-Beat Estimation of Right Ventriculoarterial Coupling in Pulmonary Arterial Hypertension. PMID- 29756987 TI - Can pediatricians recognize eating disorders? A case study of early-onset anorexia nervosa in a male child. AB - INTRODUCTION: this article examines a boy who was diagnosed with anorexia nervosa at eight years old. Pediatricians and family physicians encountered difficulties during the diagnosis and treatment stages due to the fact that early onset of the disease is rare. CASE REPORT: a boy aged eight years and four months presented with bradicardia, malnutrition and dehydration as far away from the preliminary diagnosis of anorexia nervosa investigated for possible organic pathologies at the pediatric ward. Finally, he was diagnosed with early-onset anorexia nervosa and anxiety disorder based on the Diagnostic and Statistical Manual of Mental Disorders 5. DISCUSSION: the case highlights two important points. First, this case report demonstrates a limited awareness of anorexia nervosa and of a psychosomatic or psychiatric origin of weight loss in children among physicians. Second, disrupted eating behaviors and mood changes may be predicting factors for the development of full-blown anorexia nervosa. PMID- 29756989 TI - Underdiagnosis and Overdiagnosis of Asthma. AB - Asthma is diagnosed on the basis of respiratory symptoms of wheeze, cough, chest tightness, and/or dyspnea together with physiologic evidence of variable expiratory airflow limitation. The prevalence of asthma varies widely around the world, ranging from 0.2% to 21.0% in adults and from 2.8% to 37.6% in 6- to 7 year-old children. Population-based studies in children, adults, and the elderly suggest that from 20% to 70% of people with asthma in the community remain undiagnosed and hence untreated. Underdiagnosis of asthma has been found to be associated with underreporting of respiratory symptoms by patients to physicians as well as poor socioeconomic status. On the opposite side of the spectrum, studies of patients with physician-diagnosed asthma suggest that 30-35% of adults and children diagnosed with asthma do not have current asthma, suggesting that asthma is also overdiagnosed in the community. Overdiagnosis of current asthma can occur because of physicians' failure to confirm variable airflow limitation at the time of diagnosis or when sustained clinical remission of disease goes unrecognized. In this review, we define under- and overdiagnosis and explore the prevalence and burden of under- and overdiagnosis of asthma both in patients and within healthcare systems. We further describe potential solutions to prevent under- and overdiagnosis of asthma. PMID- 29756990 TI - Dynamic Aggregation of Poly-N-Isopropylacrylamide Characterized Using Second Order Scattering. AB - A second-order scattering (SOS) method is presented for the characterization of aqueous particle suspensions undergoing aggregation. Scattering intensities are measured at 90 degrees by a standard fluorimeter and referenced against dynamic light scattering (DLS) measurements to determine particle size increase in a metal-promoted aggregation process for 0.05 mg/mL aqueous poly-N isopropylacrylamide (PNIPAm), MW ~10 k g/mol. Particle size increases monotonically from 30 nm to 210 nm at temperature 308 K. A further validation of the SOS method was performed using monodisperse polystyrene reference particles sized at 52 nm, 101 nm, 151 nm, and 206 nm, which demonstrated the technique's accuracy to within 6% and its versatility with respect to sample composition. The technique is ideal for monitoring colloidal stability and macromolecular assembly and it can be performed at lower concentrations than are typically used in DLS. PMID- 29756991 TI - The Immune Landscape of Non-Small-Cell Lung Cancer. Utility of Cytologic and Histologic Samples Obtained through Minimally Invasive Pulmonary Procedures. PMID- 29756992 TI - Evaluation of Silicon Wafer-Based Internal Reflection Elements for Use with in Situ Fourier Transform Infrared (FT-IR) Spectroscopy. AB - Silicon wafer-based internal reflection elements (IREs) present many practical advantages over the prisms conventionally used for attenuated total reflection (ATR) spectroscopy in the infrared. We examine two methods of using minimally prepared IREs that have appeared in the literature, edge-coupled (EC) and prism coupled (PC), in conjunction with a liquid flow cell. Polarization measurements show that radiation entering the PC-IRE becomes depolarized due to stress-induced birefringence, and transmission through the edge of the EC-IRE also affects the polarization state. Quantification of the noise and a calibration using a series of sodium acetate solutions show the sensitivity of the PC-IRE outweighs the lower noise obtainable with the EC-IRE. PMID- 29756993 TI - Development of Quantitative Analysis Techniques for Saccharification Reactions Using Raman Spectroscopy. AB - A technique for the analysis of saccharification reactions by a specific enzyme was developed on the basis of Raman spectroscopy using multivariate analysis. It is a microvolume, quantitative, and in situ technique, which can be used for studying saccharification processes in plant tissues. Prediction models for quantitative analysis of maltose, glucose, and starch were built with partial least squares regression (PLSR) analysis to monitor the saccharification process caused by alpha-amylase. We examined the reliability of the prediction models built using seven test samples. The spectral regions used to build the models were optimized for each sugar and were selected in such a manner that they did not overlap with strong protein and lipid bands that generally exist in plant tissues. The models were validated by monitoring the composition of reduced sugars and starch in a reactor and by comparing the results with those obtained by a conventional method. The results of Raman analysis and the conventional method showed good agreement for the reaction with alpha-amylase; however, it is not perfect for reactions with a different enzyme, especially beta-amylase. The results suggest that the present Raman technique is reliable and useful for sugar analysis. However, the prediction model built for a specific enzyme is valid only for that enzyme. PMID- 29756994 TI - New Insights into Complicated Grief in Bereaved Family Members Approached for Organ Donation. PMID- 29756995 TI - Guanidinoacetic acid supplementation in broiler chickens fed on corn-soybean diets affects performance in the finisher period and energy metabolites in breast muscle independent of diet nutrient density. AB - (1) Guanidinoacetic acid (GAA) is the single immediate endogenous precursor of creatine (Cr). It was hypothesised that dietary GAA would have different effects on performance and energy metabolites in breast muscle depending on the nutrient density (ND) of corn-soybean-based diets. (2) A total of 540 one-day-old male Ross 308 broilers were allocated to 9 dietary treatments with 6 replicates (10 birds each) in a 3 * 3 factorial arrangement with three levels of ND (low, 2800; medium, 2950 and high, 3100 kcal metabolizable energy (ME)/kg; and with the other nutrients being constant relative to ME) and supplemented with three levels of GAA (0, 0.6 and 1.2 g/kg) in a 42-d feeding trial. (3) In the starter and grower periods, increasing levels of ND improved body weight (BW), average daily gain (ADG), average daily feed intake (ADFI) and feed conversion ratio (FCR), with the exception of ADFI in the starter period. GAA supplementation did not affect performance characteristics. All performance indicators responded markedly to increasing ND in the finisher period, whereas the highest GAA level reduced ADFI compared to the unsupplemented control (156 vs. 162 g/d) and concomitantly FCR (1.81 vs. 1.93). No interactive effects were noted for any performance trait. The high ND diet resulted in more breast meat yield on d42, associated with higher fat content and darker colour compared to the other ND levels. The GAA supplementation did not affect carcass and breast traits. At the end of the experiment, Cr was elevated when feeding GAA at 1.2 g/kg (5455 vs. 4338 mg/kg fresh muscle). (4) To conclude, ND had a substantial effect on performance and carcass traits, whereas any effect of GAA was limited to FCR in the finisher period and independent of diet ND level. PMID- 29756997 TI - ARG1 Gene Polymorphisms and Their Association in Individuals with Essential Hypertension: A Case-Control Study. AB - The purpose of this study is to investigate the association of variant alleles (rs2781666 and rs2781667) at ARG1 to be involved in the generation of essential hypertension (EH) phenotypes in human subjects. The ARG1 noncoding polymorphisms (rs2781666; Chr6:131572419-G/T and rs2781667; Chr6:131573754-C/T) were investigated in 570 subjects, including 285 individuals diagnosed with EH. Determination of serum arginase activity and concentrations of nitric oxide catabolites were detected by the colorimetric enzymatic assay. Genetic typing of the noncoding polymorphisms, in ARG1, was performed using PCR and restriction digestion strategy. A significant increase in arginase activity was observed in individuals exhibiting EH phenotypes, compared with controls (p < 0.0001). Arginase showed negative correlation with serum nitrite and nitrate (r = -0.446 and r = -0.6075, respectively). A significant difference to be claimed in the distribution of SNPotypes, in rs2781666 and rs2781667, between cases and controls (p = 0.0086 and p = 0.0232; respectively). Interestingly, variant allele T, at both loci, is tightly linked to the disease phenotypes compared to the wild-type allele (p = 0.002; and p = 0.007, respectively). To our knowledge, this report is the first ever that described arginase activity, and the ARG1 polymorphism data of individuals originated in Pakistan, segregating EH phenotypes, thus, highlighting a novel risk factor for the disease. PMID- 29756998 TI - LDHA upregulation independently predicts poor survival in lung adenocarcinoma, but not in lung squamous cell carcinoma. AB - AIM: To investigate the potential prognostic value of LDHA in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). PATIENTS & METHODS: Molecular, clinicopathological and survival data in Cancer Genome Atlas-Lung Cancer were obtained for secondary analysis. RESULTS: LDHA expression was significantly upregulated in both LUAD and LUSC compared with normal lung tissues. LUSC tissues had even higher LDHA expression compared with LUAD tissues. Increased LDHA expression was an independent prognostic indicator in terms of overall survival (hazard ratio: 1.547, 95% CI: 1.253-1.911; p < 0.001) and recurrence-free survival (hazard ratio: 1.486, 95% CI: 1.161-1.900; p = 0.002) in LUAD, but not in LUSC. CONCLUSION: LDHA expression might only serve as an independent prognostic indicator of unfavorable overall survival and recurrence-free survival in LUAD, but not in LUSC. PMID- 29756999 TI - Non-financial conflicts of interest: Moving forward! PMID- 29756996 TI - TWSG1 Is a Novel Tumor Suppressor in Gastric Cancer. AB - Gastric cancer has a high incidence and mortality in the world, especially in China. The pathogenesis leading to the high heterogeneity of gastric cancer remains unclear. It is believed that TWSG1 is associated with a variety of tumors, but there are few studies related to gastric cancer. To investigate the biological significance of TWSG1, we evaluated the TWSG1 expression of the clinical samples and gastric cancer cell lines (BGC-823, MGC-803, and SGC-790) via stomach cancer tissue array, real-time PCR, and western blotting. Then, we used CCK-8 and flow cytometry to detect the function and mechanism of TWSG1 in gastric cell lines. The analysis showed that TWSG1 showed decreased expression in clinical samples and BGC-823, MGC-803, and SGC-7901 cells. And, overexpressed TWSG1 inhibited the cell cycle and proliferation, TWSG1 might influence the proliferation of SGC-7901 and MGC-803 by regulating the BMP signaling. However, the influence of TWSG1 on BGC-823 cell is not associated with the BMP signaling. In conclusion, all of our findings revealed that TWSG1 maybe serves as a tumor suppressor gene in gastric cancer and potential biomarker or therapeutic target for the diagnosis and treatment of gastric cancer. PMID- 29757000 TI - Adolescent Nocturnal Fears: a psychometric evaluation of the fear of sleep inventory (FoSI). AB - OBJECTIVE: Nocturnal fears are associated with trauma-related sleep disturbance in adults, yet research is limited addressing this relationship in adolescents. This study evaluated the validity of the Fear of Sleep Inventory (FoSI) as a measure of nocturnal fears broadly and in relation to trauma exposure in adolescents. PARTICIPANTS: Students ages 14-18 from two urban school-based health centers were the participants. METHODS: De-identified clinical data were utilized from a mental health screening battery. Two exploratory factor analyses (EFA) were conducted using the full 23-item FoSI and the 13-item short form. Cronbach's alpha and Pearson correlation coefficients were employed to examine the convergent and divergent validity of the total scores and the factors derived from the EFA with Insomnia Severity, probable PTSD, and parental monitoring respectively. RESULTS: The 23-item FoSI showed high internal consistency (alpha = .84); however, EFA yielded an unclear factor structure. Further analysis indicated that an 11-item FoSI yielded a clear 2-factor structure with subscales conceptualized as (a) Fear of Sleep and (b) Vigilant Behavior. CONCLUSIONS: The FoSI-11 demonstrates promise as a measure of nocturnal fears in adolescents and can help reveal distinctions between trauma-related nocturnal fears and nocturnal fears associated with psychological or environmental factors. It can be utilized as a screener to highlight adolescent nocturnal fears in large group settings, while also identifying individuals in need of further assessment of trauma exposure. Future studies should include the FoSI-11 to provide a more thorough examination of the role of adolescent nocturnal fears in the relationship between trauma and sleep disturbance. PMID- 29757001 TI - Exhaled Nitric Oxide Changes During Acclimatization to High Altitude: A Descriptive Study. AB - : Summerfield, Douglas T., Kirsten E. Coffman, Bryan J. Taylor, Amine N. Issa, and Bruce D. Johnson. Exhaled nitric oxide changes during acclimatization to high altitude: a descriptive study. High Alt Med Biol. 19:215-220, 2018. AIMS: This study describes differences in the partial pressures of exhaled nitric oxide (PeNO) between subjects fully acclimatized (ACC) to 5300 m and those who have just arrived to high altitude. METHODS: PeNO was determined in eight subjects newly exposed and nonacclimatized (non-ACC) to high altitude and compared with that in nine subjects who had ACC to high altitude for 1 month. In addition, systolic pulmonary artery pressure (sPAP) and arterial oxygen saturation (SaO2) were measured in all participants. These measurements were repeated in the non ACC group 5 and 9 days later. RESULTS: PeNO levels on day 1 were significantly higher in the non-ACC versus ACC cohort (8.7 +/- 3.5 vs. 3.9 +/- 2.2 nmHg, p = 0.004). As the non-ACC group remained at altitude, PeNO levels fell and were not different when compared with those of the ACC group by day 9 (5.9 +/- 2.4 vs. 3.9 +/- 2.2 nmHg, p = 0.095). Higher sPAP was correlated with lower PeNO levels in all participants (R = -0.50, p = 0.043). PeNO levels were not correlated with SaO2. CONCLUSIONS: As individuals acclimatized to high altitude, PeNO levels decreased. Even after acclimatization, PeNO levels continued to play a role in pulmonary vascular tone. PMID- 29757002 TI - A Gradual Effects Model for Single-Case Designs. AB - Single-case designs are a class of repeated measures experiments used to evaluate the effects of interventions for small or specialized populations, such as individuals with low-incidence disabilities. There has been growing interest in systematic reviews and syntheses of evidence from single-case designs, but there remains a need to further develop appropriate statistical models and effect sizes for data from the designs. We propose a novel model for single-case data that exhibit nonlinear time trends created by an intervention that produces gradual effects, which build up and dissipate over time. The model expresses a structural relationship between a pattern of treatment assignment and an outcome variable, making it appropriate for both treatment reversal and multiple baseline designs. It is formulated as a generalized linear model so that it can be applied to outcomes measured as frequency counts or proportions, both of which are commonly used in single-case research, while providing readily interpretable effect size estimates such as log response ratios or log odds ratios. We demonstrate the gradual effects model by applying it to data from a single-case study and examine the performance of proposed estimation methods in a Monte Carlo simulation of frequency count data. PMID- 29757003 TI - Transglutaminase 2 Mediates the Cytotoxicity of Resveratrol in a Human Cholangiocarcinoma and Gallbladder Cancer Cell Lines. AB - Resveratrol is a polyphenolic compound extracted from plants and is also a constituent of red wine. Our aim was to evaluate if the cytotoxic effect of resveratrol (RES) on cholangiocarcinoma (CC) and gallbladder cancer (GBC) cell lines could be abolished by TG2 inhibition. Human CC and GBC cell lines (SK-ChA-1 and MZ-ChA-1), grown in a three-dimensional cell culture system (MCTS, multicellular tumor spheroids), were treated for 72 h with RES (32, 64 uM) alone or combined with different TG2 inhibitors (Cystamine, B003, T101). We investigated: cells viability; cell morphology with light microscopy (LM) and transmission electron microscopy (TEM); immunoreactivity with immunohistochemistry; Q-Banding karyotype analysis; TG2 activity; Western blotting. RES treatment induced a significant inhibition of cell growth, ranging from 24% to 76% in both cell lines. The inhibitors successfully reduced TG2 activity without any variation of protein quantity as demonstrated by immunohistochemistry and Western blot. TG2 inhibition resulted in cell growth normalization. In addition, morphologic analysis by light and transmission electron microscopy confirmed the cytotoxic effect of RES and its reduction consequent to TG2 inhibition. Our data demonstrated a connection between the cytotoxic effect of RES in SK-ChA-1 and MZ-ChA-1 and TG2 activity. PMID- 29757004 TI - HPLC and NMR analysis of the phenyl-ethanoid glycosides pattern of Verbascum thapsus L. cultivated in the Etnean area. AB - In this work the HPLC and NMR analysis of the phenyl-ethanoid glycosides (PhGs) pattern of a cultivated exemplar of Verbascum thapsus L. (Scrophulariaceae) from the Etnean area (Sicily, Italy) was performed in order to verify their possible presence. Wild V. thapsus is well-known in ethnopharmacology due to the several beneficial effects that it is able to exert and which are primarily due to these compounds. So, it's extremely important that also cultivated exemplars of this species biosynthesize them in order to maintain their pharmacological properties. This study revealed the presence of seven PhGs in an unusual novel pattern. Thus, this exemplar is a very good potential source of this class of natural products and may be employed for several beneficial ethnopharmacological purposes. PMID- 29757005 TI - Four new C20-diterpenoid alkaloids from Aconitum rotundifolium. AB - Four new C20-diterpenoid alkaloids, rotundifosines D-G (1-4), along with eight known ones (5-12) were isolated from the whole plant of Aconitum rotundifolium Kar. & Kir. The structures of the compounds were elucidated on the basis of spectroscopic analyses, including HR-ESI-MS and 1D, 2D NMR. Rotundifosine F (3) is a rare C20-diterpenoid alkaloid with quaternary ammonium salt. Alkaloids 1-4, 5, 6, 9, and 12 were evaluated for cytotoxicity against MCF-7, HCT-116 and HepG2 human cancer cell lines. PMID- 29757006 TI - Continuity Between DSM-5 Section II and III Personality Disorders in a Dutch Clinical Sample. AB - The goal of this study was to evaluate the continuity across the Section II personality disorders (PDs) and the proposed Section III model of PDs in the Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]; American Psychiatric Association, 2013a ). More specifically, we analyzed association between the DSM-5 Section III pathological trait facets and Section II PDs among 110 Dutch adults (M age = 35.8 years, range = 19-60 years) receiving mental health care. We administered the Structured Clinical Interview for DSM-IV Axis II Disorders to all participants. Participants also completed the self-report Personality Inventory for DSM-5 (PID-5) as a measure of pathological trait facets. The distributions underlying the dependent variable were modeled as criterion counts, using negative binomial regression. The results provided some support for the validity of the PID-5 and the DSM-5 Section III Alternative Model, although analyses did not show a perfect match. Both at the trait level and the domain level, analyses showed mixed evidence of significant relationships between the PID-5 trait facets and domains with the traditional DSM-IV PDs. PMID- 29757007 TI - A Community-Based Qualitative Assessment of Knowledge, Barriers, and Promoters of Communicating about Family Cancer History among African-Americans. AB - Family cancer history (FCH) can shape prevention and early detection behaviors to decrease cancer risk. However, many individuals are unaware of increased risk for cancers based on family patterns. For some African-American communities, communication about FCH is rare and barriers have not been well studied. To optimize the use of FCH, it is crucial to understand how patients gather and share FCH with relatives and healthcare providers. We conducted four focus groups (n = 40) and seven key informant interviews (n = 9) to investigate knowledge, experiences, and barriers/promoters of FCH in the East Baltimore African-American community. Thematic analysis identified 14 distinct themes across six communication domains: participants' understanding of FCH, past FCH communication with family and providers, barriers to FCH communication, promoters of FCH communication, suggestions for future communication, and community health priorities. FCH was most often defined by narratives of family cancer experiences, and the majority of participants had shared little FCH with family members. Five psychosocial domains were commonly reported as barriers to sharing FCH: fear/denial, pride/dignity, selflessness/self-sacrifice, cancer fatalism, and distrust/skepticism of medical care. Diagnosis/death and caregiving/social support promoted FCH communication and encouraged cancer prevention behaviors such as screening. Although most participants had experienced cancer in their families, communication about FCH was low and psychosocial barriers were common. Understanding these communication domains in minority populations is crucial to developing interventions to address disparities in cancer prevention and control, particularly where effective screening and care recommendations exist for those with positive family histories. PMID- 29757008 TI - Inactivation of Escherichia coli by Ultrasound Combined with Nisin. AB - The aim of this study was to investigate the inactivation of nonpathogenic Escherichia coli in nutrient broth and milk through the use of either ultrasound (US) alone or US combined with nisin (US + nisin) treatments. The E. coli cells were treated at 0 to 55 degrees C, 242.04 to 968.16 W/cm2 for 0 to 15 min. The results showed that the inactivation of E. coli by US and US + nisin increased when the temperature, US power density, and treatment time were increased. The inactivation kinetics of E. coli in nutrient broth by US and US + nisin both conformed to linear models. The largest reductions of 2.89 and 2.93 log cycles by US and US + nisin, respectively, were achieved at 968.16 W/cm2 and at 25 degrees C for 15 min. The suspension media of the E. coli cells influenced the inactivation effect of US, while the growth phases of E. coli cells did not affect their resistance to US. Under all experiment conditions of this study, the differences between US and US + nisin in their respective inactivation effects on E. coli were not obvious. The results suggested that nisin had either no effect at all or a weak synergistic effect with US and that the E. coli cells were inactivated mainly by US, thus indicating that the inactivation of E. coli by US is an "all or nothing" event. PMID- 29757009 TI - Molecular and Phenotypic Analysis of Hemolytic Aeromonas Strains Isolated from Food in Egypt Revealed Clinically Important Multidrug Resistance and Virulence Profiles. AB - The aim of this study was to determine the public health significance of hemolytic Aeromonas species isolated from 213 food samples in Egypt, based on their virulence and antimicrobial-resistance potential. We recovered 63 strains, isolated from fish, raw milk, karish cheeses, and ras cheese in 29 (31.18%) of 93, 10 (25.00%) of 40, 13 (32.50%) of 40, and 11 (27.50%) of 40 samples, respectively. The most prevalent virulence gene was alt (50.79%), followed by aerA (34.92%), asa1 (39.68%), ahh1 (20.63%), act (11.11%), and ast (3.17%). Thirteen strains screened in this study carried no hemolysin gene, but only the alt gene, and another eight hemolytic strains screened, carried no virulence gene. The virulence signatures " ahh1+ aerA" and " alt+ act," in which the genes interact synergistically to induce severe diarrhea, were detected in two and four strains, respectively. Most showed resistance to third-generation cephalosporins, aztreonam, and imipenem, which indicates the complexity of the beta-lactamase production in our hemolytic Aeromonas strains. Fourteen (22.22%) of 63 strains carried one or more antimicrobial-resistance markers, including the blaCTX-M, blaTEM, tet(A), tet(E), and intI1 genes, which were detected in 6.34, 3.17, 3.17, 4.76, and 14.28% of isolates, respectively. In conclusion, the majority of hemolytic Aeromonas strains isolated from the intestinal contents of healthy fish and naturally contaminated milk and cheeses were not commensal but had developed multidrug-resistance and virulence profiles, indicating an emerging potential health risk. Importantly, screening for certain hemolysin genes may not be reliable in predicting the pathogenic potential of Aeromonas species and, thereby, the safety of analyzed foods. Our findings indicate that specific criteria are required for the phenotypic and molecular analysis of Aeromonas species in food items, particularly those eaten without further treatment, to ensure their safety. PMID- 29757010 TI - A Quantitative Risk Assessment of Human Salmonellosis from Consumption of Pistachios in the United States. AB - We developed a quantitative risk assessment model to assess the risk of human nontyphoidal salmonellosis from consumption of pistachios in the United States and to evaluate the impact of Salmonella treatments (1- to 5-log reductions). The exposure model estimating prevalence and contamination levels of Salmonella at consumption included steps in pistachio processing such as transport from grower to huller, removal of the hull through wet abrasion, separation of pistachio floaters (immature, smaller nuts) and sinkers (mature, larger nuts) in a flotation tank, drying, storage, and partitioning. The risks of illness per serving and per year were evaluated by including a Salmonella dose-response model and U.S. consumption data. The spread of Salmonella through float tank water, delay in drying resulting in growth, increased Salmonella levels through pest infestation during storage (pre- and posttreatment), and a simulation of the 2016 U.S. salmonellosis outbreak linked to consumption of pistachios were the modeled atypical situations. The baseline model predicted one case of salmonellosis per 2 million servings (95% CI: one case per 5 million to 800,000 servings) for sinker pistachios and one case per 200,000 servings (95% CI: one case per 400,000 to 40,000 servings) for floater pistachios when no Salmonella treatment was applied and pistachios were consumed as a core product (>80% pistachio) uncooked at home. Assuming 90% of the pistachio supply is sinkers and 10% is floaters, the model estimated 419 salmonellosis cases per year (95% CI: 200 to 1,083 cases) when no Salmonella treatment was applied. A mean risk of illness of less than one case per year was estimated when a minimum 4-log reduction treatment was applied to the U.S. pistachio supply, similar to the results of the Salmonella risk assessment for almonds. This analysis revealed that the predicted risk of illness per serving is higher for all atypical situations modeled compared with the baseline, and delay in drying had the greatest impact on consumer risk. PMID- 29757011 TI - Thermal Inactivation of Shiga Toxin-Producing Escherichia coli in Ground Beef with Varying Fat Content. AB - Decimal reduction time ( D-value) was calculated for six non-O157 Shiga toxin producing Escherichia coli (STEC) in a laboratory medium and ground beef. For the laboratory medium, an overnight culture of each strain of STEC was divided into 10-mL sample bags and heated in a water bath for a specific time on the basis of the temperatures. Survival curves were generated by plotting the surviving bacterial population against time, and a linear-log primary model was used to estimate the D-values from survival curves. The z-values (the temperature raised to reduce the D-value by one-tenth) were calculated by plotting the log D-values against temperature. Similarly, for ground beef, six fat contents, 5, 10, 15, 20, 25, and 30% of ground beef were formulated for this study. Inoculated meat was divided into 5-g pouches and submerged in a water bath set at specific temperatures (55, 60, 65, 68, and 71.1 degrees C). The average D-value for these strains in a laboratory medium was 17.96 min at 55 degrees C, which reduced significantly ( P < 0.05) to 1.58 min at 60 degrees C, and then further reduced ( P < 0.05) to 0.46 min at 65 degrees C. In ground beef, a negative correlation ( P < 0.05) between fat content of ground beef and D-values was observed at 55 degrees C. However, at temperatures greater than 60 degrees C, there was no impact ( P > 0.05) of fat content of ground beef on the thermal resistance of non O157 STECs. Irrespective of the fat content of ground beef, the D-values ranged from 15.93 to 11.69, 1.15 to 1.12, and 0.14 to 0.09 min and 0.05 at 55, 60, 65, and 68 degrees C, respectively. The data generated from this study can be helpful for the meat industry to develop predictive models for thermal inactivation of non-O157 STECs in ground beef with varying fat content. PMID- 29757013 TI - Impact of a Behavioral Sleep Intervention on New School Entrants' Social Emotional Functioning and Sleep: A Translational Randomized Trial. AB - OBJECTIVE/BACKGROUND: Determine the effects and costs of a brief behavioral sleep intervention, previously shown to improve child social-emotional functioning, sleep, and parent mental health, in a translational trial. PARTICIPANTS: Three hundred thirty-four school entrant children from 47 primary schools in Melbourne, Australia, with parent-reported moderate to severe behavioral sleep problems. METHODS: intervention group received sleep hygiene practices and standardized behavioral strategies delivered by trained school nurses in 2013 and 2014. Control group children could receive usual community care. RESULTS: Outcome measures: child social-emotional functioning (Pediatric Quality of Life Inventory 4.0 psychosocial health summary score-primary outcome), sleep problems (parent reported severity, Children's Sleep Habits Questionnaire), behavior, academic function, working memory, child and parent quality of life, and parent mental health. At six months post randomization, 145 (of 168) intervention and 155 (of 166) control families completed the primary outcome for which there was no difference. Intervention compared with control children had fewer sleep problems (35.2% vs. 52.7% respectively, OR 0.5; 95% CI 0.3 to 0.8, p = 0.002) and better sleep patterns (e.g., longer sleep duration). Their parents reported fewer symptoms of depression. All differences attenuated by 12 months. There was no difference in other outcomes at either time point. Intervention costs: $AUS 182/child. CONCLUSIONS: A brief behavioral sleep intervention, delivered by school nurses to children with behavioral sleep problems, does not improve social emotional functioning. Benefits to child sleep and parent mental health are evident at 6 but not 12 months. Approaches that increase intervention dosage may improve outcomes. PMID- 29757014 TI - Co-delivery of paclitaxel and tanespimycin in lipid nanoparticles enhanced anti gastric-tumor effect in vitro and in vivo. AB - Combined administration regimens are commonly used in cancer therapy to reduce cell toxicity and drug resistance. In this study, we use solid lipid nanoparticles (SLNs) as drug carriers and sought to investigate the effect of combined administration of paclitaxel (PTX) and tanespimycin (17-AAG) in gastric cancer. The SLNs loaded with paclitaxel and tanespimycin were prepared using the solvent injection method. The effect of encapsulated SLNs on cell viability and colony formation were measured in three human gastric cell lines. Cell apoptosis assay was carried out in MKN45 cells and xenograft model was used to investigate the effect of encapsulated SLNs in vitro and in vivo. The expression levels of proteins involved in oxidative stress and apoptosis were measured by western blotting analysis. The encapsulated SLNs reduced cell viabilities and colony formation in gastric cell lines. These SLNs could also induce apoptosis in MKN45 cells, inhibit growth of xenograft and influence the protein levels of Hsp90, MnSOD, Cleaved caspase 3 and Cleaved PARP. The effect of encapsulated SLNs exceeded that of single treatment of PTX or 17-AAG. The combination administration of PTX or 17-AAG resulted in a synergetic anti-cancer effect, probably via an increased oxidative stress and apoptosis levels. PMID- 29757015 TI - Novichok: a murderous nerve agent attack in the UK. PMID- 29757012 TI - Developmental Trajectory of Motor Deficits in Preschool Children with ADHD. AB - Motor deficits persisting into childhood (>7 years) are associated with increased executive and cognitive dysfunction, likely due to parallel neural circuitry. This study assessed the longitudinal trajectory of motor deficits in preschool children with ADHD, compared to typically developing (TD) children, in order to identify individuals at risk for anomalous neurological development. Participants included 47 children (21 ADHD, 26 TD) ages 4-7 years who participated in three visits (V1, V2, V3), each one year apart (V1=48-71 months, V2=60-83 months, V3=72 95 months). Motor variables assessed included speed (finger tapping and sequencing), total overflow, and axial movements from the Revised Physical and Neurological Examination for Subtle Signs (PANESS). Effects for group, visit, and group-by-visit interaction were examined. There were significant effects for group (favoring TD) for finger tapping speed and total axial movements, visit (performance improving with age for all 4 variables), and a significant group-by visit interaction for finger tapping speed. Motor speed (repetitive finger tapping) and quality of axial movements are sensitive markers of anomalous motor development associated with ADHD in children as young as 4 years. Conversely, motor overflow and finger sequencing speed may be less sensitive in preschool, due to ongoing wide variations in attainment of these milestones. PMID- 29757016 TI - Icatibant for the treatment of hereditary angioedema with C1-inhibitor deficiency in adolescents and in children aged over 2 years. AB - INTRODUCTION: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH HAE) is a rare disorder with life-threatening complications if untreated. It begins during childhood, and reduces the patient's quality of life. Therefore, the availability of an easily administered agent to relieve unpredictable HAE episodes is indispensable for this age group. Areas covered: Randomized, double blind, placebo-controlled, open-label extensions and prospective observational studies have proven the safety and efficacy of the subcutaneously administered bradykinin B2 receptor antagonist, icatibant, in the acute treatment of HAE episodes in adult C1-INH-HAE patients. Recently, a Phase 3, multicenter, open label, non-randomized, single-arm study demonstrated the efficacy, safety, and tolerability of icatibant as an acute treatment for pediatric patients aged 2 years to less than 18 years. Expert commentary: The clinical study in pediatric patients showed that icatibant undergoes rapid absorption, reaches a therapeutic level, and promptly relieves the symptoms. It is well tolerated, and the subcutaneous preparation, presented in a pre-filled syringe, ensures ease of use. It can be administered anytime, anywhere, and instantly - even by the patients themselves, or - in the case of children and adolescents - by a caregiver. Icatibant may greatly contribute to the improvement of the quality of life of pediatric patients. PMID- 29757019 TI - Optical Coherence Tomography Angiography in Glaucoma Care. AB - PURPOSE: To provide the reader with information on the principal techniques of optical coherence tomography angiography (OCTA); the current literature on OCTA reproducibility; its applications to glaucoma detection and monitoring of progression; and the role of OCTA in the assessment of the vascular component in glaucoma pathogenesis. METHODS: A literature review of the pertinent publications for the OCTA in relation to the development, techniques, and its use in glaucoma was carried out. RESULTS: Rapid improvements in optical coherence tomography (OCT) technology have allowed for enhancement of both image resolution and scanning speed, and the development of vascular assessment modality. OCTA is the non-invasive in vivo imaging of the vasculature located within the retina and optic nerve head area. The principle of OCTA is to use the variations in OCT signals caused by moving particles as the contrast mechanism for imaging of flow. Several algorithms which aim to maximize the contrast signal and minimize the noise have been developed including the phase-based techniques, intensity-based techniques (e.g., split-spectrum amplitude decorrelation angiography (SSADA)), and complex-based techniques (e.g., optical microangiography (OMAG)). With its reliable technique, high image resolution, and current availability, OCTA has been widely used in the assessment of posterior segment diseases including glaucoma in which ocular perfusion dysfunction has been proposed as a pathophysiological mechanism. CONCLUSION: OCTA may enhance our knowledge of glaucoma pathogenesis and offer an improvement in our ability to detect glaucomatous change. PMID- 29757021 TI - Advagraf(r) with or without an induction therapy for de novo kidney-transplant recipients. AB - INTRODUCTION: Cornerstone immunosuppressive therapy currently relies on immediate release tacrolimus, a calcineurin inhibitor (CNI) that is potentially nephrotoxic and is more diabetogenic than cyclosporine A. Two new formulations of tacrolimus have been launched: an extended-release formulation (Advagraf(r)/Astagraf XL(r), Astellas company) and a long-lasting formulation (Envarsus(r), Veloxis company). Area covered: Herein, we assess the efficacy of an extended-release formulation of tacrolimus (Advagraf(r)/Astagraf XL(r)) used in conjunction with or without an induction therapy (i.e., basiliximab) in de novo kidney-transplant recipients. To achieve this, we searched for suitable articles through PubMed. Expert commentary: Phases-III and -IV studies comparing Advagraf(r)/Astagraf XL(r) to Prograf(r) in association with mycophenolate mofetil (more than 2,500 patients) have demonstrated overall similar results with regards to patient/graft survival, biopsy-proven acute-rejection rate, and renal function (p > 0.05). A randomized controlled study in maintenance kidney transplant patients has shown (using electronic monitoring) that, as compared to Prograf(r), Advagraf(r) significantly improved adherence to medication. Other studies report that Advagraf(r)-treated patients receiving a mTOR-inhibitor agent (sirolimus or everolimus) instead of MMF: this was associated with good allograft outcome, and might also prevent late onset cytomegalovirus infection. Advagraf(r)-based immunosuppression given to de novo kidney-transplant recipients, with or without an induction therapy, provided excellent results compared to Prograf(r); it also increased patients' adherence to treatment. PMID- 29757018 TI - A current structural perspective on PXR and CAR in drug metabolism. AB - INTRODUCTION: Pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that play major roles in the expression of various drug metabolism enzymes and are known for their ligand promiscuity. As with other nuclear receptors, PXR and CAR are each composed of a ligand-binding domain (LBD) and a DNA-binding domain (DBD) connected by a hinge region. Areas covered: This review focuses on the information obtained over the last 15+ years from X-ray crystallography studies of the structure of PXR and CAR. Areas of focus include the mobility of each structure, based on temperature factors (B factors); multimeric interactions; the binding of coregulators and ligands; and how the crystal structures were obtained. The first use of hydrogen-deuterium exchange coupled with mass spectroscopy (HDX-MS) to study compound-protein interactions in the PXR-LBD is also addressed. Expert opinion: X-ray crystallography studies have provided us with an excellent understanding of how the LBDs of each receptor function; however, many questions remain concerning the structure of these receptors. Future research should focus on determining the co-crystal structure of an antagonist bound to PXR and on studying the structural aspects of the full-length CAR and PXR proteins. PMID- 29757020 TI - Recent advances in the treatment of Brugada syndrome. AB - INTRODUCTION: Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome characterized by ST-segment elevation in right precordial ECG leads and associated with sudden cardiac death in young adults. The ECG manifestations of BrS are often concealed but can be unmasked by sodium channel blockers and fever. Areas covered: Implantation of a cardioverter defibrillator (ICD) is first-line therapy for BrS patients presenting with prior cardiac arrest or documented VT. A pharmacological approach to therapy is recommended in cases of electrical storm, as an adjunct to ICD and as preventative therapy. The goal of pharmacological therapy is to produce an inward shift to counter the genetically-induced outward shift of ion channel current flowing during the early phases of the ventricular epicardial action potential. This is accomplished by augmentation of ICa using ??adrenergic agents or phosphodiesterase III inhibitors or via inhibition of Ito. Radiofrequency ablation of the right ventricular outward flow tract epicardium is effective in suppressing arrhythmogenesis in BrS patients experiencing frequent appropriate ICD-shocks. Expert commentary: Understanding of the pathophysiology and approach to therapy of BrS has advanced considerably in recent years, but there remains an urgent need for development of cardio-selective and ion-channel specific Ito blockers for treatment of BrS. PMID- 29757023 TI - Is it psychiatry or the psychiatrist that is changing? Outcome of the psychiatrist's evolution. PMID- 29757024 TI - Introduction to the Italian edition of the DSM-5. PMID- 29757022 TI - Clinical Outcome of 1064-nm Picosecond Neodymium-Doped Yttrium Aluminium Garnet Laser for the Treatment of Hypertrophic Scars. AB - BACKGROUND: Currently no study has evaluated the effect of the novel 1064-nm picosecond neodymium-doped:yttrium aluminium garnet laser (ps-Nd:YAG) for reducing Hypertrophic scarring (HS). OBJECTIVE: The aim of this study was to verify the efficacy and safety of a 1064-nm ps-Nd:YAG in the management of HS. MATERIALS AND METHODS: A retrospective chart review and photographic analysis were conducted on patients treated with a low-fluence 1064-nm ps-Nd:YAG for HS improvement. The Vancouver Scar Scale (VSS), 5-point Global Assessment Score (GAS), and patient satisfaction score were used to determine the effect of scar improvement. RESULTS: A total of 24 Korean patients (9 males and 15 females; mean age of 33.25 +/- 15.50 years) were retrospectively evaluated. Mean treatment settings were 1064-nm wavelength, 750 ps pulse duration, 7.94 mm spot size, 0.93 J/cm2 fluence, and 9.69 Hz frequency. The average VSS score decreased significantly (from 5.33 to 2.71) after laser treatment (p < 0.001). The average GAS (3.02 +/- 0.93) showed fair cosmetic improvement, and patient satisfaction scores (6.88 +/- 2.66) indicated moderate satisfaction. CONCLUSION: The novel low fluence 1064-nm ps-Nd:YAG could be considered as an effective and safe optional modality for the treatment of HS in Asian skin. PMID- 29757025 TI - Metaphors of pathology. PMID- 29757026 TI - Controversial aspects of community psychiatry: the Italian experience. PMID- 29757027 TI - Time for psychiatry: schizophrenia as a core issue of the difficulties of psychiatry. PMID- 29757028 TI - The legacy of Italian psychiatry. PMID- 29757017 TI - Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence. AB - INTRODUCTION: Since the initial approval of everolimus in 2011, there have been a number of important changes in therapeutic/diagnostic modalities as well as classification/staging systems of neuroendocrine tumors (NETs), which can significantly impact the use of everolimus in patients with advanced NETs. Areas covered: The efficacy of everolimus monotherapy and combination therapy demonstrated in clinical studies involving patients with advanced NETs are reviewed. Several factors affecting everolimus use are described including: the development and routine use of NET classification/staging systems; widespread use of molecular imaging modalities; side effects; drug resistance; and the availability of other treatment options. Furthermore, the current position of everolimus in the treatment approach is discussed, taking into account the recommendations from the recent guidelines. Expert opinion: Although everolimus demonstrated its high efficacy and tolerability in the RADIANT trials and other clinical studies, there still remain a number of controversies related to everolimus treatment in the management of NETs. The synergistic anti-growth effect of other agents in combination with everolimus or its effect on overall survival have not been established. The appropriate order of the use of everolimus in the treatment of advanced NETs still remains unclear, which needs to be defined in further studies and will be addressed in the new guidelines. PMID- 29757029 TI - Electroshock *?. PMID- 29757031 TI - The role of psychiatry in modern medicine. PMID- 29757030 TI - Italian psychiatry. PMID- 29757032 TI - A problem of institutional psychiatry: exclusion as a social and psychiatric category. PMID- 29757033 TI - Modesty and the elderly *?. PMID- 29757034 TI - Educational level and job status are the most important factors affecting compliance with oral antihistamine therapy for patients with chronic urticaria. AB - BACKGROUND: Management of chronic urticaria (CU) is often difficult with oral antihistamines (OAs) despite long-term use. OBJECTIVE: The aim of this study was to determine the extent of medication compliance (MC) and to assess the factors affecting the MC of patients with CU toward OA therapy. METHODS: A 43-item questionnaire was administered to 201 adult patients. A compliance score (CS) of 6 points was chosen as a cutoff point. A CS of 0-6 corresponds to poor compliance and score of 6-9, to good compliance. Subsequently, associations with compliant and poorly compliant groups were made by univariate and multivariate analyses. RESULTS: The median age and disease duration of all patients were 47 years (range: 18-88) and 15 months (range: 1.5-480), respectively. Overall, the rate of compliant and poorly compliant patients was 53.2% and 46.8%, respectively. Educational level and job status were significantly associated with MC. To have graduated from university and high school increased MC by 9.1-fold (p = .002, 95% confidence interval (CI): 2.26-36.37) and 3.6-fold (p = .019, 95% CI: 1.26 13.47), respectively, compared with illiterates. Patients who had worked previously and were currently looking for work were 4.8-fold (p = .032, 95% CI: 1.14-19.97) more compliant than patients who had never worked. CONCLUSION: Most patients with CU had good compliance with OAs. Educational level and job status were significant predictors of MC to OAs in CU. The impact and long-term effects of education and job status should be evaluated in different patient groups. PMID- 29757035 TI - Pediatric patients with psoriasis and psychiatric disorders: premorbidity and comorbidity in a case-control study. AB - BACKGROUND: Psychiatric disorders are thought to play an important role in the onset, exacerbation and course of several chronic dermatological diseases. We aimed to investigate psychiatric diagnoses in children with psoriasis before and during the disease and to examine potentially related factors. METHODS: A total of 108 children aged 8-16 years, 54 with a diagnosis of psoriasis and 54 healthy individuals, were included in the study. Participants were evaluated using The Kiddie Schedule for Affective Disorders and Schizophrenia, Present and Lifetime Version (K-SADS PL), Children's Dermatology Life Quality Index (CDLQI), Screen for Child Anxiety Related Emotional Disorders (SCARED) and Children's Depression Inventory (CDI), and the results were compared using statistical techniques. RESULTS: At least one psychiatric diagnosis was present in 70.3% of children with psoriasis and in 27.7% of the control group, the difference being significant (p = .0001). It was seen that 73.6% of children with a psychiatric diagnosis were psychiatric diagnoses in the premorbid period. Children with psoriasis were determined to have 9.21-fold greater risk of anxiety (p = .0001) and a 6.65-fold greater risk of depression (p = .0019) compared with the control group. CONCLUSIONS: A statistically significant increase in psychiatric disorders occurs in disease periods in cases of pediatric psoriasis. Moreover, a high prevalence of psychiatric disorders was detected in the premorbid process. We think that it is important for these to be considered in the management of the disease and in controlling exacerbation, and for the mechanisms involved to be elucidated. PMID- 29757036 TI - Determinants of antibiotic prescribing among doctors in a Nigerian urban tertiary hospital. AB - OBJECTIVES: The problem of antimicrobial resistance (AMR) has assumed pandemic dimensions especially among low-and middle-income countries such as Nigeria. Irrational use of currently available antimicrobial agents is a major contributory factor. There remains a paucity of documented information on the determinants of antibiotic prescribing among physicians in Nigeria to guide future strategies to reduce AMR. This study therefore aimed to investigate the patterns and determinants of antibiotic prescribing among doctors in a tertiary hospital in Nigeria as the first step to improve future antibiotic use in hospitals. METHODS: A cross-sectional survey of the determinants of antibiotic prescribing among doctors in the Lagos State University Teaching Hospital, Ikeja, was performed using a structured questionnaire. Information was obtained about the doctors and the factors determining their prescription of antibiotics. The results were summarized using descriptive statistics with Statistical Package for Social Science. RESULTS: Ninety-eight respondents were studied with a mean age of 36.24(9.01) years, a mean duration of practice of 10.68(9.25) years, and mainly males (64.3%). Ninety-seven percent prescribe antibiotics frequently, mostly based on clinical judgment and experience with rare laboratory supports. Factors of cost, drug availability, and information from pharmaceutical representatives influenced antibiotic prescribing. There were indications of nonexistence or nonfunctional institutional policies and guidelines regarding antimicrobial therapies. CONCLUSION: There is an urgent need to institute evidence-based institutional policies and guidelines for improving antimicrobial use among hospitals in Nigeria. This is already being followed up. PMID- 29757037 TI - The clinical implications of tests confirming COPD in subjects hospitalized with exacerbations. AB - BACKGROUND: The diagnosis of COPD in patients hospitalized for AECOPD can be confirmed by spirometry showing obstruction or radiographs showing emphysema. The evidence for COPD is sometimes absent or contradicts this diagnosis. The inaccurate attribution of the exacerbation to COPD can lead to suboptimal care and worse outcome. OBJECTIVES: We determined if the presence of tests that confirm the diagnosis of COPD has any implications on the course of the hospitalization and readmission rate. METHODS: We selected subjects hospitalized between 2012 and 2014 for AECOPD. We divided them into four hierarchical, mutually exclusive groups based on the presence of tests that confirm the diagnosis of COPD: spirometry (COPDSPIRO), radiology (COPDRAD), clinical diagnosis (COPDCLIN), and no COPD by spirometry (NotCOPD). We compared the presentation, hospital course, outcome, and readmission rate between the four groups. RESULTS: We identified 974 subjects: COPDSPIRO 22%, COPDRAD 24%, COPDCLIN 46% and 7% NotCOPD. The vital signs, use of respiratory support, admission to the MICU, and length of stay were similar between the groups. The age, gender, BMI, presence of comorbidities, and readmission rate were different between the groups. The NotCOPD group had the highest BMI (38 kg/m2), comorbidities, and 30 day all-cause readmission (17%). Logistic regression showed that serum creatinine and presence of any comorbidity were the independent predictors of 30-day all cause readmission. CONCLUSION: COPD was confirmed by spirometry or radiographs in half of the subjects hospitalized for AECOPD. The presence of confirmation did not influence the hospital course. The presence of confirmation was associated with different readmission rate, but was accounted for by the presence of comorbidities. PMID- 29757038 TI - Granuloma as a complication of polycaprolactone-based dermal filler injection: ultrasound and histopathology studies. AB - In aesthetic medicine, there has been an ongoing search for an ideal dermal filler to offer zero complication rate. Polycaprolactone-based dermal filler (PCL) has been available since 2009. The purpose of the paper was to present a case of granuloma as a complication of PCL injection, which has not been reported so far by other researchers. A 68-year-old female was injected with PCL. One year later, nodules accompanied by bluish skin discoloration developed within the injection site. Ultrasound and histopathology studies were performed. The examinations confirmed the presence of foreign body granuloma after PCL, which makes it the first reported case worldwide. The published data analyses showed general lack of studies and case reports to address this issue. The PCL, like an injection of any soft tissue filler, may lead to serious complications, such as granuloma formation. This makes further research legitimate and necessary. PMID- 29757039 TI - Opportunities and challenges in the design of selective TAAR1 agonists: an editorial. PMID- 29757041 TI - Successful treatment of acne keloidalis nuchae with erbium:YAG laser: a comparative study. AB - BACKGROUND: Acne keloidalis nuchae (AKN) is a chronic inflammatory disease involving hair follicles of the neck. It is a form of keloidal scarring alopecia that is often refractory to medical or surgical management. OBJECTIVE: To evaluate the efficacy of Er:YAG laser in the treatment of AKN as compared to long pulsed Nd:YAG laser. PATIENTS AND METHODS: This study was conducted on 30 male patients with AKN. Their ages ranged from 19 to 47 years with a mean age of 36.87 +/- 7.8 years. Patients were divided randomly into two groups of 15 patients, each receiving six sessions of either Er:YAG or long-pulsed Nd:YAG laser therapy. RESULTS: A statistically significant decrease in the number of papules was detected at the end of therapy in both groups, with a mean of 91.8% improvement in the Er:YAG group versus 88% in the Nd:YAG group. A significant decrease in plaques count was detected only in the Er: YAG group while a significant decrease in plaques size and consistency was recorded in both groups. CONCLUSION: The Er: YAG laser proved to be a potentially effective and safe modality both in the early and late AKN lesions. PMID- 29757040 TI - Cost-savings for biosimilars in the United States: a theoretical framework and budget impact case study application using filgrastim. AB - BACKGROUND: Biosimilars can directly reduce the cost of treating patients for whom a reference biologic is indicated by offering a highly similar, lower priced alternative. We examine factors related to biosimilar regulatory approval, uptake, pricing, and financing and the potential impact on drug expenditures in the U.S. METHODS: We developed a framework to illustrate how key factors including regulatory policies, provider and patient perception, pricing, and payer policies impact biosimilar cost-savings. Further, we developed a budget impact cost model to estimate savings from filgrastim biosimilars under various scenarios. The model uses publicly available data on disease incidence, treatment patterns, market share, and drug prices to estimate the cost-savings over a 5 year time horizon. RESULTS: We estimate five-year cost savings of $256 million, of which 18% ($47 million) are from reduced patient out-of-pocket costs, 34% ($86 million) are savings to commercial payers, and 48% ($123 million) are savings for Medicare. Additional scenarios demonstrate the impact of uncertain factors, including price, uptake, and financing policies. CONCLUSIONS: A variety or interrelated factors influence the development, uptake, and cost-savings for Biosimilars use in the U.S. The filgrastim case is a useful example that illustrates these factors and the potential magnitude of costs savings. PMID- 29757042 TI - Comparison of NAPSI and N-NAIL for evaluation of fingernail psoriasis in patients with moderate-to-severe plaque psoriasis treated using ustekinumab. AB - OBJECTIVE: We sought to determine the psoriatic nail feature which responds to ustekinumab treatment more effectively, and evaluate which between the Nail Psoriasis Severity Index (NAPSI) and the Nijmegen-Nail psoriasis Activity Index tooL (N-NAIL) better reflects the clinical improvement of nail psoriasis. METHODS: Thirty patients with moderate-to-severe plaque psoriasis were prospectively enrolled and treated with ustekinumab for 52 weeks. A single investigator evaluated the condition using the NAPSI and the N-NAIL with serial fingernail photographs. RESULTS: Of the 30 patients, 13 (43.3%) had fingernail psoriasis present at baseline. Mean NAPSI scores improved from 9.46 +/- 8.7 at baseline to 6.00 +/- 5.2 at week 52, but the improvement was not statistically significant (p = .09). Mean N-NAIL scores significantly improved from 5.46 +/- 5.1 at baseline to 3.92 +/- 3.7 at week 52 (p = .04). Of the psoriatic nail features, only the splinter hemorrhages significantly improved at week 52 compared to baseline. CONCLUSIONS: When comparing the mean scores between week 0 and 52, the N-NAIL score (p = .04) better reflected a significant improvement of nail psoriasis than the NAPSI (p = .09), and ustekinumab treatment resulted in a more rapid and effective improvement of splinter hemorrhages. PMID- 29757043 TI - Effect of Vitamin D Supplementation on 25(OH)D Status in Elite Athletes With Spinal Cord Injury. AB - Recent studies suggest that a substantial proportion of athletes with spinal cord injury have insufficient 25(OH) vitamin D (25(OH)D) status, which may be associated with decreased muscle strength. This study consisted of two parts: (a) to examine the effects of a 12- to 16-week vitamin D3 supplementation protocol on 25(OH)D concentration and (b) to determine whether subsequent 25(OH)D status impacts muscle performance in elite athletes with spinal cord injury. Thirty-four members (age: 33 +/- 15 years, weight: 69.6 +/- 28.2 kg, and height: 170.2 +/- 25.4 cm) of the U.S. and Canadian Paralympic program participated in the study. 25(OH)D concentrations and performance measures (handgrip strength and 20-m wheelchair sprint) were assessed pre- and postsupplementation. Participants were assigned a vitamin D3 supplementation protocol based on initial 25(OH)D concentrations. Participants with deficient 25(OH)D status (<50 nmol/L) received 50,000 IU/week for 8 weeks, and participants with insufficient status (50-75 nmol/L) received 35,000 IU/week for 4 weeks, after which both received a maintenance dose of 15,000 IU/week. Participants with sufficient status (>75 nmol/L) received the maintenance dose of 15,000 IU/week. 25(OH)D concentrations increased significantly (p < .001; 66.3 +/- 24.3 nmol/L and 111.3 +/- 30.8 nmol/L pre- and postsupplementation, respectively). About 26% of athletes had sufficient 25(OH)D concentrations presupplementation, and 91% had sufficient concentrations postsupplementation. About 62% of participants improved handgrip strength postsupplementation with no change in 20-m wheelchair sprint performance. The supplementation protocol was effective for achieving sufficient vitamin D concentrations in elite athletes with spinal cord injury. PMID- 29757045 TI - Combination therapy for bulky auricular keloids: a clinical experience. AB - Auricular keloids are common following ear piercing, infection, trauma, burns, or spontaneously, and they are highly resistant for treatment and are followed by severe cosmetic problems, especially for patients with bulky auricular keloids. The risk of recurrence and the need to return to the normal anatomy of external ear following resection is a challenge to the plastic surgeon. The authors present their experience of treating bulky auricular keloids with surgical excision, followed by immediate postoperative radiotherapy and intralesional steroid injection. PMID- 29757044 TI - Comparison of mental health outcomes among adults with psoriasis on biologic versus oral therapies: a population-based study. AB - PURPOSE: We sought to compare the impact of biologic versus oral therapies on mental health outcomes among adult U.S. residents with moderate-to-severe psoriasis. METHODS: We performed a nationwide, cross-sectional study comparing 2,303,534 (weighted) adults with moderate-to-severe psoriasis on biologic versus oral therapies and their associated mental health outcomes using the 2003-2015 Medical Expenditure Panel Survey (MEPS). Mental health outcomes were measured with the Kessler 6 (K6), a validated measure of psychological distress, and Patient Health Questionnaire 2 (PHQ2), a screening tool for depression. RESULTS: The mean K6 score for residents on biologic therapies was significantly lower than that of residents on oral therapies (2.72 [95% CI: 2.27-3.17] versus 3.70 [95% CI: 3.27-4.12]; p < .001). The mean PHQ2 score for residents on biologic therapies was also significantly lower than that of residents on oral therapies (0.540 [95% CI: 0.390-0.690] versus 0.890 [95% CI: 0.749-1.031]; p < .001). Based on adjusted multivariable linear regression models, biologic therapy was associated with significant reductions in K6 (p < .001) and PHQ2 (p = .016) scores compared to oral therapy. CONCLUSIONS: Therapeutic choices for psoriasis impact mental health outcomes. Biologic therapy is associated with reductions in psychological distress and depression as compared to oral therapy in the U.S. adult moderate-to-severe psoriasis population. PMID- 29757047 TI - Development and Implementation of a Nutrition Knowledge Questionnaire for Ultraendurance Athletes. AB - The nutritional intake of ultraendurance athletes is often poorly matched with the requirements of the sport. Nutrition knowledge is a mediating factor to food choice that could correct such imbalances. Therefore, the purpose of this study was to develop and validate a questionnaire to assess the nutrition knowledge of ultraendurance athletes. Nutritional knowledge was assessed using a modified sports nutrition knowledge questionnaire (ULTRA-Q). Four independent assessors with specialization in sports nutrition confirmed the content validity of the ULTRA-Q. Registered sports nutritionists, registered dietitians, and those without nutrition training completed the ULTRA-Q on two separate occasions. After the first completion, a significant difference in nutrition scores between groups (p <= .001) provided evidence of construct validity. After the second completion, intraclass correlation coefficients comparing nutrition scores between time points (.75-.95) provided evidence of test-retest reliability. Subsequently, experienced ultraendurance athletes (male: n = 74 and female: n = 27) completed the ULTRA-Q. Athletes also documented their sources of nutrition knowledge for ultraendurance events. The total nutrition knowledge score for ultraendurance athletes was 68.3% +/- 9.5%, and there were no significant differences in knowledge scores between males and females (67.4% +/- 9.6% and 70.7% +/- 9.3%, respectively) or between runners and triathletes (69.1% +/- 9.7% and 65.1% +/- 9.4%, respectively). In general, it appeared that ultraendurance athletes favored other athletes (73%) over nutrition experts (8%) as a source of nutritional information. The findings of this study indicate that ultraendurance athletes had a reasonable level of nutrition knowledge, but interathlete variability suggests a need for targeted nutrition education. PMID- 29757046 TI - Biologic treatment of recalcitrant pediatric psoriasis: a case series from a tertiary medical center. AB - BACKGROUND: There is a paucity of data on the use of biologic therapy in recalcitrant pediatric psoriasis. The current study presents pediatric psoriasis cases treated with biologic agents in a tertiary referral center. METHODS: In this retrospective case series, data were collected on all patients <=18 years old with severe psoriasis treated with biological therapy from 2010 through 2016 in a tertiary children's hospital. We included demographic data, previous systemic treatments, reason for discontinuation or switch to other systemic treatments, efficacy and side effects. RESULTS: There were 10 patients, mean age 5.75 (+/-3.3) years treated with biologic agents in our center; Etanercept was the most frequent biological treatment prescribed (n = 9) followed by adalimumab (n = 5) ustekinumab (n = 3) and infliximab (n = 2). Additional systemic therapy was added to the biological therapy in seven cases: Methotreaxate (n = 5), phototherapy (n = 4), cyclosporine A and colchicine (1 case each). The most common reason for discontinuation was secondary failure (5 for etanercept, 3 for adalimumab). Six patients failed one biological treatment and three patients failed two biological treatments. Four patients are still being treated with a first line biologic (Etanercept in all). Adverse events were rare. CONCLUSION: Biologic therapy is effective and safe in recalcitrant pediatric psoriasis. Larger series are needed to confirm our observation. PMID- 29757048 TI - Interprofessional education involving didactic TeamSTEPPS(r) and interactive healthcare simulation: A systematic review. AB - The didactic portion of TeamSTEPPS(r), which focuses on teaching teamwork and communication, coupled with interactive simulation methods provides a unique interprofessional education (IPE) learning environment. Across the literature there are a wide variety of such programs described, but there is not a consensus on the most effective methodology. A systematic review was therefore undertaken to synthesize, critically appraise, and evaluate existing literature on IPE programs that utilize didactic TeamSTEPPS in conjunction with interactive healthcare simulation. EBSCO and PubMed databases were searched from inception through March 2017 using predetermined inclusion and exclusion criteria. The initial search yielded 66 articles which was reduced to 42 peer-reviewed publications after duplicates were removed. An additional 2 articles were identified via hand search. Therefore, 44 articles were identified and reviewed and 11 studies met all inclusion criteria. Critical appraisal was performed using The Medical Education Research Study Quality Instrument and Newcastle-Ottawa Scale-Education instruments. The outcome measures associated with each program as well as specifics of the didactic portion and interactive healthcare simulation are further explored in this review. It is anticipated that the findings from this systematic review will aid in the development of future evidence-based interprofessional programs. PMID- 29757049 TI - Prevalence of Indicators of Low Energy Availability in Elite Female Sprinters. AB - Low energy availability (LEA), and subsequent relative energy deficiency in sport, has been observed in endurance, aesthetic, and team sport athletes, with limited data on prevalence in athletes in short-burst activities such as sprinting. We examined prevalence of signs and symptoms of LEA in elite female sprinters at the start of the training season (PRE), and at the end of a 5-month indoor training period (POST). Four of 13 female sprinters (31%) presented at PRE testing with at least one primary (amenorrhea, low bone mineral density, low follicle-stimulating hormone, luteinizing hormone, or estradiol, resting metabolic rate <=29 kcal/kg fat-free mass, Low Energy Availability in Females Questionnaire score >=8) and one secondary indicator of LEA (fasting blood glucose <4 mmol/L, free triiodothyronine <3.5 pmol/L, ferritin <25 MUg/L, low density lipoprotein cholesterol >3.0 mmol/L, fasting insulin <20 pmol/L, low insulin-like growth factor-1, systolic blood pressure <90 mmHg, and/or diastolic blood pressure <60 mmHg). At POST, seven out of 13 athletes (54%) presented with at least one primary and one secondary indicator of LEA, three of whom had also presented with indicators of LEA at PRE. Five out of 13 (39%) athletes had previous stress fracture history, though this was not associated with current indicators of LEA (PRE: r = .52, p = .07; POST: r = -.07, p = .82). In conclusion, elite female sprinters may present with signs and symptoms of LEA, even after off-season rest. Medical and coaching staff should be aware of the signs and symptoms of LEA and relative energy deficiency in sport and should include appropriate screening and intervention strategies when working with sprinters. PMID- 29757050 TI - Longitudinal Changes in Body Composition Assessed Using DXA and Surface Anthropometry Show Good Agreement in Elite Rugby Union Athletes. AB - Rugby union athletes have divergent body composition based on the demands of their on-field playing position and ethnicity. With an established association between physique traits and positional requirements, body composition assessment is routinely undertaken. Surface anthropometry and dual-energy X-ray absorptiometry (DXA) are the most common assessment techniques used, often undertaken synchronously. This study aims to investigate the association between DXA and surface anthropometry when assessing longitudinal changes in fat-free mass (FFM) and fat mass (FM) in rugby union athletes. Thirty-nine elite male rugby union athletes (age: 25.7 +/- 3.1 years, stature: 187.6 +/- 7.7 cm, and mass: 104.1 +/- 12.2 kg) underwent assessment via DXA and surface anthropometry multiple times over three consecutive international seasons. Changes in the lean mass index, an empirical measure to assess proportional variation in FFM, showed large agreement with changes in DXA FFM (r = .54, standard error of the estimate = 1.5%, p < .001); the strength of association was stronger among forwards (r = .63) compared with backs (r = .38). Changes in the sum of seven skinfolds showed very large agreement with changes in DXA FM (r = .73, standard error of the estimate = 5.8%, p < .001), with meaningful differences observed regardless of ethnicity (Whites: r = .75 and Polynesians: r = .62). The lean mass index and sum of seven skinfolds were able to predict the direction of change in FFM and FM 86% and 91% of the time, respectively, when DXA change was >1 kg. Surface anthropometry measures provide a robust indication of the direction of change in FFM and FM, although caution may need to be applied when interpreting magnitude of change, particularly with FM. PMID- 29757051 TI - Weight Regain, but not Weight Loss, Is Related to Competitive Success in Real Life Mixed Martial Arts Competition. AB - We aimed to describe the nutritional and behavioral strategies for rapid weight loss (RWL), investigate the effects of RWL and weight regain in winners and losers, and verify mood state and technical-tactical/time-motion parameters in mixed martial arts. The sample consisted of mixed martial arts athletes after a single real match and was separated into two groups: winners (n = 8; age: 25.4 +/ 6.1 years, height: 173.9 +/- 0.2 cm, habitual body mass: 89.9 +/- 17.3 kg) and losers (n = 7; age: 24.4 +/- 6.8 years, height: 178.4 +/- 0.9 cm, habitual body mass: 90.8 +/- 19.5 kg). Both groups exhibited RWL and weight regain, verified their macronutrient intake, underwent weight and height assessments, and completed two questionnaires (Profile of Mood States and RWL) at (a) 24 hr before weigh-in, (b) weigh-in, (c) postbout, and (d) during a validated time-motion and technical-tactical analysis during the bout. Variance analysis, repeated measures, and a logistic regression analysis were used. The main results showed significant differences between the time points in terms of total caloric intake as well as carbohydrate, protein, and lipid ingestion. Statistical differences in combat analysis were observed between the winners and losers in terms of high intensity relative time (58 [10-98] s and 32 [1-60] s, respectively), lower limb sequences (3.5 [1.0-7.5] sequences and 1.0 [0.0-1.0] sequences, respectively), and ground and pound actions (2.5 [0.0-4.5] actions and 0.0 [0.0-0.5] actions, respectively), and logistic regression confirmed the importance of high-intensity relative time and lower limb sequences on mixed martial arts performance. RWL and weight regain strategies were related to technical-tactical and time-motion patterns as well as match outcomes. Weight management should be carefully supervised by specialized professionals to reduce health risks and raise competitive performance. PMID- 29757053 TI - Applying a Low-FODMAP Dietary Intervention to a Female Ultraendurance Runner With Irritable Bowel Syndrome During a Multistage Ultramarathon. AB - Malabsorption of fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) in response to prolonged exercise may increase incidence of upper and lower gastrointestinal symptoms (GIS), which are known to impair exercise performance. This case study aimed to explore the impact of a low-FODMAP diet on exercise associated GIS in a female ultraendurance runner diagnosed with irritable bowel syndrome, competing in a 6-day 186.7-km mountainous multistage ultramarathon (MSUM). Irritable bowel syndrome symptom severity score at diagnosis was 410 and following a low-FODMAP diet (3.9 g FODMAPs/day) it reduced to 70. The diet was applied 6 days before (i.e., lead-in diet), and maintained during (5.1 g FODMAPs/day) the MSUM. Nutrition intake was analyzed through dietary analysis software. A validated 100-mm visual analog scale quantified GIS incidence and severity. GIS were modest during the MSUM (overall mean +/- SD: bloating 27 +/- 5 mm and flatulence 23 +/- 8 mm), except severe nausea (67 +/- 14 mm) experienced throughout. Total daily energy (11.7 +/- 1.6 MJ/day) intake did not meet estimated energy requirements (range: 13.9-17.9 MJ/day). Total daily protein [1.4 +/- 0.3 g.kg body weight (BW)-1.day-1], carbohydrate (9.1 +/- 1.3 g.kg BW-1.day 1), fat (1.1 +/- 0.2 g.kg BW-1.day-1), and water (78.7 +/- 6.4 ml.kg BW-1.day-1) intakes satisfied current consensus guidelines, except for carbohydrates. Carbohydrate intake during running failed to meet recommendations (43 +/- 9 g/hr). The runner successfully implemented a low-FODMAP diet and completed the MSUM with minimal GIS. However, suboptimal energy and carbohydrate intake occurred, potentially exacerbated by nausea associated with running at altitude. PMID- 29757054 TI - Preseason Body Composition Adaptations in Elite White and Polynesian Rugby Union Athletes. AB - During preseason training, rugby union (RU) athletes endeavor to enhance physical performance characteristics that are aligned with on-field success. Specific physique traits are associated with performance; therefore body composition assessment is routinely undertaken in elite environments. This study aimed to quantify preseason physique changes in elite RU athletes with unique morphology and divergent ethnicity. Twenty-two White and Polynesian professional RU athletes received dual-energy X-ray absorptiometry assessments at the beginning and conclusion of an 11-week preseason. Interactions between on-field playing position and ethnicity in body composition adaptations were explored, and the least significant change model was used to evaluate variations at the individual level. There were no combined interaction effects with the variables position and ethnicity and any body composition measure. After accounting for baseline body composition, Whites gained more lean mass during the preseason than Polynesians (2,425 +/- 1,303 g vs. 1,115 +/- 1,169 g; F = 5.4, p = .03). Significant main effects of time were found for whole body and all regional measures with fat mass decreasing (F = 31.1-52.0, p < .01), and lean mass increasing (F = 12.0-40.4, p < .01). Seventeen athletes (nine White and eight Polynesian) had a reduction in fat mass, and eight athletes (six White and two Polynesian) increased lean mass. This study describes significant and meaningful physique changes in elite RU athletes during a preseason period. Given the individualized approach applied to athletes in regard to nutrition and conditioning interventions, a similar approach to that used in this study is recommended to assess physique changes in this population. PMID- 29757055 TI - Urine Specific Gravity as a Practical Marker for Identifying Suboptimal Fluid Intake of Runners ~12-hr Postexercise. AB - The legitimacy of urine specific gravity (USG) as a stand-alone measure to detect hydration status has recently been challenged. As an alternative to hydration status, the purpose of this study was to determine the diagnostic capability of using the traditional USG marker of >1.020 to detect insufficient recovery fluid consumption with consideration for moderate versus high sweat losses (2.00-2.99 or >3% body mass, respectively). Adequate recovery fluid intake was operationally defined as >=100% beverage fluid intake plus food water from one or two meals and a snack. Runners (n = 59) provided 132 samples from five previous investigations in which USG was assessed 10-14 hr after 60-90 min runs in temperate-to-hot environments. Samples were collected after a meal (n = 58) and after waking (n = 74). When sweat losses exceeded 3% body mass (n = 60), the relationship between fluid replacement percentage and USG increased from r = -.55 to -.70. Correct diagnostic decision improved from 66.6 to 83.3%, and receiver operating characteristic area under the curve increased the diagnostic accuracy score from 0.76 to approaching excellent (0.86). Artifacts of significant prerun hyperhydration (eight of 15 samples has USG <1.005) may explain false positive diagnoses, while almost all (84%) cases of false positives were found when sweat losses were <3.0% of body mass. Evidence from this study suggests that euhydrated runners experiencing significant sweat losses who fail to reach adequate recovery fluid intake levels can be identified by USG irrespective of acute meal and fluid intake ~12-hr postrun. PMID- 29757052 TI - Multimodal characterization of a novel mutation causing vitamin B6-responsive gyrate atrophy. AB - PURPOSE: Gyrate atrophy (GA) is a rare chorioretinal degeneration that results in the deterioration of night and peripheral vision, eventually leading to blindness. The disorder is caused by mutations in the gene encoding ornithine aminotransferase (OAT), causing increased levels of plasma ornithine. Treatment revolves around lowering plasma ornithine levels, with vitamin B6 supplementation being the preferred treatment. Nevertheless, most patients do not respond to this therapy. Here, we report a rare case of vitamin B6-responsive GA caused by a novel mutation in OAT and characterize the presentation with multimodal imaging. METHODS: This is a single-patient case report with a clinical diagnosis based on history, multimodal retinal imaging, laboratory findings, and DNA sequencing analysis. We include a 3D structure prediction of the novel mutant protein. RESULTS: DNA sequencing analysis demonstrated that there is a homozygous, novel variant c.473A>C: p.Y158S in OAT. Upon undergoing two weeks of vitamin B6 supplementation, the patient exhibited a 28.5% reduction in plasma ornithine levels. In a follow-up visit two years later, plasma ornithine levels were reduced by 24.1% from the levels at initial presentation and disease progression was retarded based on clinical findings. CONCLUSION: One novel homozygous missense mutation in OAT was identified and considered to be pathogenic in a patient with GA. The response for the vitamin B6 supplementation was positive, which is rare in all the GA cases reported in the literature. Our data suggests that further studies regarding the relationship between genotype and responsiveness to vitamin B6 should be conducted. PMID- 29757057 TI - 'Necessary and sufficient' in biology is not necessarily necessary - confusions and erroneous conclusions resulting from misapplied logic in the field of biology, especially neuroscience. AB - In this article, we describe an incorrect use of logic which involves the careless application of the 'necessary and sufficient' condition originally used in formal logic. This logical fallacy is causing frequent confusion in current biology, especially in neuroscience. In order to clarify this problem, we first dissect the structure of this incorrect logic (which we refer to as 'misapplied N&S') to show how necessity and sufficiency in misapplied-N&S are not matching each other. Potential pitfalls of utilizing misapplied-N&S are exemplified by cases such as the discrediting of command neurons and other potentially key neurons, the distorting of truth in optogenetic studies, and the wrongful justification of studies with little meaning. In particular, the use of the word 'sufficient' in optogenetics tends to generate misunderstandings by opening up multiple interpretations. To avoid the confusion caused by the misleading logic, we now recommend using 'indispensable and inducing' instead of using 'necessary and sufficient.' However, we ultimately recommend fully articulating the limits of what our experiments suggest, not relying on such simple phrases. Only after this problem is fully understood and more rigorous language is demanded, can we finally interpret experimental results in an accurate way. PMID- 29757058 TI - Outcomes following hip and knee replacement in diabetic versus nondiabetic patients and well versus poorly controlled diabetic patients: a prospective cohort study. AB - Background and purpose - The impact of diabetes and glycemic control before joint replacement on clinical and patient-reported outcomes is unclear. We compared pain, function, complications, and length of hospital stay in diabetic and nondiabetic patients receiving primary total hip (THR) or knee replacement (TKR) and compared these outcomes in patients with poorly controlled versus well controlled diabetes. Patients and methods - We conducted a prospective cohort study of patients undergoing primary THR (n = 300) or TKR (n = 287) for osteoarthritis. Self-reported diabetes and glycemic control (HbA1c <= or >7%) extracted from medical notes were used. Adjusted comparisons were performed with generalized linear models including body mass index (BMI) and comorbidities. Results - Diabetes prevalence was 11% (THR 8%; TKR 14%). Diabetic patients were more likely to have a higher BMI and greater number of comorbidities. The median length of hospital stay was 1 day longer in diabetic patients (p = 0.004), but this attenuated after adjustments for BMI and comorbidities (p = 0.3). Inpatient pain was greater for diabetic patients but attenuated following adjustment. The 12-month postoperative WOMAC subscales were similar by diabetes status following adjustment. There was little evidence of difference in outcomes according to glycemic control. Interpretation - The associations between diabetes and worse postoperative outcomes in patients undergoing THR or TKR for osteoarthritis appear to be predominantly due to associated obesity and comorbidities. In diabetic patients there is little evidence of association between postoperative outcome and preoperative glycemic control. The underlying mechanisms and causal pathways of obesity, diabetes, and multimorbidity that lead to worse outcomes after joint replacement are not well known. PMID- 29757059 TI - Quantitative hemodynamic analysis of cerebral blood flow and neurovascular coupling using optical coherence tomography angiography. AB - Functional hyperemia in the rat cortex was investigated using high-speed optical coherence tomography (OCT) angiography and Doppler OCT. OCT angiography (OCTA) was performed to image the hemodynamic stimulus-response over a wide field of view. Temporal changes in vessel diameters in different vessel compartments, which were determined as the diameters of erythrocyte flows in OCT angiograms, were measured in order to monitor localized hemodynamic changes. Our results showed that the dilation of arterioles at the site of activation was accompanied by the dilation of upstream arteries. Relatively negligible dilation was observed in veins. An increase in the OCTA signal was observed during stimulus in multiple capillaries, which may imply that capillary blood flow increases as a result of the expanded arterial blood volume. These results agree with previous observations using two-photon laser scanning microscopy (TPLSM). Doppler OCT was performed to quantitatively measure stimulus-induced blood flow response in pial arteries. The measurement showed small but clear hemodynamic response in upstream arteries with diameters exceeding 100 [Formula: see text]m. Our results demonstrate the potential of OCTA and Doppler OCT for the investigation of neurovascular coupling in small animal models. PMID- 29757056 TI - Whey Protein Augments Leucinemia and Postexercise p70S6K1 Activity Compared With a Hydrolyzed Collagen Blend When in Recovery From Training With Low Carbohydrate Availability. AB - We examined the effects of whey versus collagen protein on skeletal muscle cell signaling responses associated with mitochondrial biogenesis and protein synthesis in recovery from an acute training session completed with low carbohydrate availability. In a repeated-measures design (after adhering to a 36 hr exercise-dietary intervention to standardize preexercise muscle glycogen), eight males completed a 75-min nonexhaustive cycling protocol and consumed 22 g of a hydrolyzed collagen blend (COLLAGEN) or whey (WHEY) protein 45 min prior to exercise, 22 g during exercise, and 22 g immediately postexercise. Exercise decreased (p < .05) muscle glycogen content by comparable levels from pre- to postexercise in both trials (~300-150 mmol/kg.dry weight). WHEY protein induced greater increases in plasma branched chain amino acids (p = .03) and leucine (p = .02) than COLLAGEN. Exercise induced (p < .05) similar increases in PGC-1alpha (fivefold) mRNA at 1.5 hr postexercise between conditions, although no effect of exercise (p > .05) was observed for p53, Parkin, and Beclin1 mRNA. Exercise suppressed (p < .05) p70S6K1 activity in both conditions immediately postexercise (~25 fmol.min-1.mg-1). Postexercise feeding increased p70S6K1 activity at 1.5 hr postexercise (p < .05), the magnitude of which was greater (p < .05) in WHEY (180 +/- 105 fmol.min-1.mg-1) versus COLLAGEN (73 +/- 42 fmol.min-1.mg-1). We conclude that protein composition does not modulate markers of mitochondrial biogenesis when in recovery from a training session deliberately completed with low carbohydrate availability. By contrast, whey protein augments postexercise p70S6K activity compared with hydrolyzed collagen, as likely mediated via increased leucine availability. PMID- 29757060 TI - Social Support, Family Empowerment, Substance Use, and Perceived Parenting Competency during Pregnancy for Women with Substance Use Disorders. AB - BACKGROUND: Parenting self-efficacy has been linked to positive parent and child outcomes however, little research exists on factors that influence parenting self efficacy among pregnant women with substance use disorders. OBJECTIVES: This study explored substance use severity, social support, and family empowerment as predictors of parenting self-efficacy among pregnant women (N = 71) entering SUD treatment. METHODS: The study used a quantitative cross-sectional design. RESULTS: Statistically significant positive correlations emerged between social support and parenting self-efficacy as well as family empowerment and parenting self-efficacy. Family empowerment and social support were also correlated. A backward elimination regression analysis revealed family empowerment to be the strongest predictor of parenting self-efficacy. No relationships were found among substance use severity and the study variables. CONCLUSIONS: When promoting parenting self-efficacy, both social support and family empowerment are important domains to consider for treatment planning and resource development among pregnant women with substance use disorders. PMID- 29757061 TI - Exercise-induced laryngeal obstruction in athletes: Contributory factors and treatment implications. AB - Otherwise healthy adolescent athletes presenting with respiratory symptoms consistent with exercise-induced laryngeal obstruction (EILO) are frequently encountered in clinical practice. The symptoms are often incorrectly considered to result from exercise-induced asthma, and may be wrongly treated as such. Given the potential implications for health and performance if EILO is left untreated, a more comprehensive understanding of contributory mechanisms is essential in order to create appropriate treatment procedures. Informed by knowledge from physical therapy, as well as the fields of voice rehabilitation and vocal pedagogy, this theoretical article presents a novel way of understanding and managing EILO by exploring bodily mechanisms and structures that may disturb laryngeal function during strenuous exercise. Firstly, the status quo of the EILO diagnosis, its aetiology and treatment options are reviewed. Secondly, considerations associated with laryngeal structures and mechanisms, and their potential influence on laryngeal movement and sensitivity are examined. Thirdly, the manner in which postural de-alignment and breathing pattern may interfere with laryngeal functioning will be discussed. Finally, interventions for voice disorders and singing and the relevance of these for EILO are evaluated. It is argued that clients with EILO should undergo a thorough physical examination to identify constrictions in the body as a whole - such as postural de-alignments and a dysfunctional breathing pattern - as these are hypothesized as playing a critical role in laryngeal tightness during exercise. Physical therapists possess particular skills and competence with regard to examining breathing patterns and postural de-alignments, and should be included in the treatment process of EILO. PMID- 29757062 TI - The Effect of 0.5% Timolol Maleate on Corneal(Lymph)Angiogenesis in a Murine Suture Model. AB - PURPOSE: To investigate the anti(lymph)angiogenic and anti-inflammatory effects of 0.5% timolol maleate in a murine corneal suture model. METHODS: Corneal neovascularization and lymphangiogenesis were compared in groups of mice that underwent corneal suture and were subsequently administered a subconjunctival injection of 0.5% timolol maleate, dexamethasone, or phosphate-buffered saline (PBS). Immunohistochemical staining and analysis were performed in each group. Real-time polymerase chain reaction (RT-PCR) was performed to quantify the expression of inflammatory cytokines [TNF-alpha and interleukin (IL)-6], vascular endothelial growth factor (VEGF)-A, VEGF-C, vascular endothelial growth factor receptor (VEGFR)-2, and VEGFR-3. RESULTS: When corneas from the timolol-treated group were compared to the PBS-treated group, we observed decreases in angiogenesis, lymphangiogenesis, and inflammatory infiltration in the timolol treated group (P value <0.05 in all respective comparisons). Corneas from the timolol-treated group showed reduced expression of VEGF-A, VEGF-C, TNF-alpha, IL 6, VEGFR-2, and VEGFR-3 compared to corneas from the PBS group (P value <0.05 in all respective comparisons). CONCLUSION: Blocking adrenergic signaling in the cornea with 0.5% timolol maleate decreased corneal neovascularization and lymphangiogenesis. PMID- 29757064 TI - Factors Associated with the Effectiveness of Intravenous Administration of Chlorpromazine for Delirium in Patients with Terminal Cancer. AB - BACKGROUND: Delirium in patients with terminal cancer is irreversible and increases treatment resistance, which leads to a deterioration in quality of life. OBJECTIVE: To investigate factors affecting the effectiveness and safety of intravenous chlorpromazine for irreversible delirium in patients with terminal cancer. DESIGN/MEASUREMENTS: Multiple regression analysis for factors affecting treatment effectiveness was carried out based on a retrospective comparison between responders and nonresponders to intravenous chlorpromazine. SETTING/SUBJECTS: Ninety-seven patients with terminal cancer who were treated with intravenous chlorpromazine for irreversible delirium were included. RESULTS: The rate of patients with >=50% improvement in mean Nursing Delirium Screening Scale score from pretreatment to day three of chlorpromazine treatment was 0.48 (95% confidence interval [CI]: 0.38-0.58). Factors affecting chlorpromazine treatment effectiveness were hyperactive delirium (odds ratio [OR]: 6.25, 95% CI: 1.14-34.5) and longer survival (OR: 1.096, 95% CI: 1.05-1.14). The mean chlorpromazine dose was low, at 17.9 mg/day. Adverse events were reported in 11 patients (11.3%) by day three of chlorpromazine treatment, and all were observed in patients who survived less than two weeks after chlorpromazine treatment. Patients who died, who had decreased blood pressure during chlorpromazine administration, and who showed acute akathisia all displayed shock index >=1. CONCLUSIONS: Intravenous administration of low-dose chlorpromazine may be an effective and safe treatment option for delirium in patients with terminal cancer who have hyperactive delirium, longer predictive prognosis, and shock index <1. PMID- 29757063 TI - Gut Microbiota Composition in Mid-Pregnancy Is Associated with Gestational Weight Gain but Not Prepregnancy Body Mass Index. AB - BACKGROUND: Pregnancy is a time of numerous hormonal, metabolic, and immunological changes for both the mother and the fetus. Furthermore, maternal gut microbiota composition (GMC) is altered during pregnancy. One major factor affecting GMC in pregnant and nonpregnant populations is obesity. The aim was to analyze associations between maternal overweight/obesity, as well as gestational weight gain (GWG) and GMC. Moreover, the modifying effect of depression and anxiety symptom scores on weight and GMC were investigated. METHODS: Study included 46 women from the FinnBrain Birth Cohort study, of which 36 were normal weight, and 11 overweight or obese according to their prepregnancy body mass index (BMI). Stool samples were collected in gestational week 24, and the GMC was sequenced with Illumina MiSeq approach. Hierarchical clustering was executed to illuminate group formation according to the GMC. The population was divided according to Firmicutes and Bacteroidetes dominance. Symptoms of depression, general anxiety, and pregnancy-related anxiety were measured by using standardized questionnaires. RESULTS: Excessive GWG was associated with distinct GMC in mid-pregnancy as measured by hierarchical clustering and grouping according to Firmicutes or Bacteroidetes dominance, with Bacteroidetes being prominent and Firmicutes being less prominent in the GMC among those with increased GWG. Reduced alpha diversity was observed among the Bacteroidetes dominated subjects. There were no zero-order effects between the abundances of bacterial genera or phyla, alpha or beta diversity, and prepregnancy BMI or GWG. CONCLUSION: Bacteroidetes-dominated GMC in mid-pregnancy is associated with increased GWG and reduced alpha diversity. PMID- 29757065 TI - The impact of an evolving profession on the frequency and perceived difficulty of ethical encounters among physical therapists in the clinic. AB - BACKGROUND: Ethical decision making is situated within dynamic contexts specific to practice standards and environments, contemporary policy, and responsive educational systems. Reflecting on an evolving profession lends insight into the role of ethical codes of conduct. OBJECTIVE: The purpose of this study was to gather information about the frequency and perceived difficulty physical therapists (PTs) experience with common ethical situations within contemporary clinical practice. METHODS: PTs within the United States were invited to participate in an online questionnaire replicating a 1980 study. Subjects were 336 PTs from a variety of practice environments. RESULTS: Just 1 item was reported as moderately/extremely difficult by contemporary respondents, compared to 16 items in the 1980 study. The number of items meeting moderate/high encounter frequency was similar between the two groups (2015 = 16/19; 1980 = 15/19). CONCLUSIONS: While today's PTs report that they encounter ethical situations at a frequency similar to PTs in 1980, these same PTs report these ethical challenges as minimally difficult when compared to PTs responding to the 1980 survey. It is proposed that a move toward autonomous practice, the elevation of the entry level professional degree, and changing health care policy and environments have been influential in shaping these changes over time. PMID- 29757066 TI - Reliability and clinical feasibility of measuring dual-task gait in the inpatient rehabilitation setting following traumatic brain injury. AB - BACKGROUND: To prepare patients with traumatic brain injury (TBI) for discharge from inpatient rehabilitation, physical therapists may incorporate dual-task gait activities. Reliability of common dual-task measures for people with TBI in inpatient rehabilitation is undetermined. Our purpose was to assess inter-rater and intra-rater reliability and clinical feasibility of dual-task measures [Walking While Talking Test (WWTT), Modified Walking and Remembering Task (mWART), Timed Up and Go-cognitive (TUG-COG)] in inpatient rehabilitation for patients with TBI. METHODS: A total of 22 individuals with TBI completing the dual-task measures (WWTT, Walking and Remembering Task (WART), and TUG-COG) in inpatient rehabilitation were rated concurrently by two physical therapists in a single testing session. Sessions were video recorded and rated by the same raters viewing the video 7-10 days later. Raters completed a survey assessing feasibility of conducting the dual-task measures in patients with TBI in inpatient rehabilitation. Data were analyzed by calculating ICC(2,1) for inter rater reliability and ICC(3,1) for intra-rater reliability. RESULTS: All dual task measures (WWTT, mWART, TUG-COG) had excellent inter-rater and intra-rater reliability. Raters considered dual-task measures feasible for patients with TBI during inpatient rehabilitation. CONCLUSIONS: The WWTT, mWART, and TUG-COG have excellent reliability and appear clinically feasible for incorporation into clinical practice in inpatient rehabilitation following TBI. PMID- 29757067 TI - A comparative study of the influence of alpha-lactose monohydrate particle morphology on granule and tablet properties after roll compaction/dry granulation. AB - The influence of particle morphology and size of alpha-lactose monohydrate on dry granules and tablets was studied. Four different morphologies were investigated: Two grades of primary crystals, which differed in their particle size and structure (compact crystals vs. agglomerates). The materials were roll compacted at different specific compaction forces and changes in the particle size distribution and the specific surface area were measured. Afterwards, two fractions of granules were pressed to tablets and the tensile strength was compared to that from tablets compressed from the raw materials. The specific surface area was increased induced by roll compaction/dry granulation for all materials. At increased specific compaction forces, the materials showed sufficient size enlargement. The morphology of lactose determined the strength of direct compressed tablets. In contrast, the strength of granule tablets was leveled by the previous compression step during roll compaction/dry granulation. Thus, the tensile strength of tablets compressed directly from the powder mixtures determined whether materials exhibited a loss in tabletability after roll compaction/dry granulation or not. The granule size had only a slight influence on the strength of produced tablets. In some cases, the fraction of smaller granules showed a higher tensile strength compared to the larger fraction. PMID- 29757068 TI - Physiotherapy interventions for patients with chronic pelvic pain: A systematic review of the literature. AB - OBJECTIVE: To summarize the available scientific evidence on physiotherapy interventions in the management of chronic pelvic pain (CPP). DATA SOURCES: A systematic review of randomized controlled trials was performed. An electronic search of MEDLINE, CINAHL, and Web of Science databases was performed to identify relevant randomized trials from 2010-2016. STUDY SELECTION: Manuscripts were included if at least one of the comparison groups received a physiotherapy intervention. Studies were assessed in duplicate for data extraction and risk of bias using the Physiotherapy Evidence Database scale PEDro. DATA EXTRACTION AND SYNTHESIS: Eight of the studies screened met the inclusion criteria. Four manuscripts studied the effects of electrotherapy including intravaginal electrical stimulation, short wave diathermy, respiratory-gated auricular vagal afferent nerve stimulation, percutaneous tibial nerve stimulation, and sono electro-magnetic therapy with positive results. Three studies focused on manual assessing the efficacy of myofascial versus massage therapy in two of them and ischemic compression for trigger points. CONCLUSIONS: Although physiotherapy interventions show some beneficial effects, evidence cannot support the results. Heterogeneity in terms of population phenotype, methodological quality, interpretation of results, and operational definition result in little overall evidence to guide treatment. PMID- 29757069 TI - Accuracy of a single measurement site for self-monitoring of patients with breast cancer at risk for lymphedema. AB - PURPOSE: Early detection of breast cancer-related lymphedema through simple self monitoring techniques may lead to early treatment and improved outcomes. METHODS: Prospective study of circumference measurements at four time points before, during, and after adjuvant chemotherapy with docetaxel, doxorubicin, and cyclophosphamide. Volume was calculated using the 10-cm interval circumference measurement method (reference test) and percentage difference between arms, for volume and circumference, was determined. First, the most valid single measurement location was determined by calculating Pearson's correlation coefficient relative to the reference test. Second, to evaluate the responsiveness to change over four time points, outcomes of the selected single measurement and the reference test were analyzed by repeated-measures ANOVA. Third, area under the curve (AUC) was used to determine the optimal sensitivity and specificity of the selected single measurement site (index test). Relationship between lymphedema (yes/no) and heaviness and swelling (yes/no) was analyzed using phi-coefficient. RESULTS: The measurement point 30 cm proximal to the styloid process showed the highest correlation with percentage difference in total arm volume (r = 0.80) and detected increased percentage difference between arms after treatment. Analyses showed high accuracy (AUC = 0.94; 95% CI 0.90 0.99) and good sensitivity (0.85) and specificity (0.85) using a cutoff score of 4% circumference difference between arms at this location. A moderate correlation between feelings of heaviness and swelling to lymphedema was observed (rphi = 0.64). CONCLUSIONS: Circumference difference between arms of 4% measured at 30 cm proximal to the styloid process can be used as a surveillance site for further monitoring of patients at risk for lymphedema and may contribute to early diagnosis. Feelings of heaviness or swelling have moderate relationship with lymphedema, which needs to be confirmed in clinical practice. PMID- 29757071 TI - Evaluation of the efficacy of an appeasing pheromone diffuser product vs placebo for management of feline aggression in multi-cat households: a pilot study. AB - Objectives Aggression and social tension among housemate cats is common and puts cats at risk of injury or relinquishment. The aim of this study was to evaluate the effectiveness of a new pheromone product in reducing aggression between housemate cats. Methods A new pheromone product (Feliway Friends) containing a proprietary cat-appeasing pheromone was evaluated for efficacy in reducing aggression between housemate cats via a randomized, double-blind, placebo controlled pilot trial of 45 multi-cat households (pheromone [n = 20], placebo [n = 25]) reporting aggression for at least 2 weeks. Each household had 2-5 cats. Participants attended an educational training meeting on day (D) -7 and the veterinary behaviorist described behaviors to be monitored for 7 weeks using the Oakland Feline Social Interaction Scale (OFSIS), which assessed the frequency and intensity of 12 representative aggressive interactions. Participants were also provided with instructions for handling aggressive events, including classical conditioning, redirection by positive reinforcement and not punishing or startling the cat for aggressive displays. Punishment techniques were strongly discouraged. Plug-in diffusers with the pheromone product or placebo were utilized from D0-D28. Participants completed a daily diary of aggressive events and weekly OFSIS assessments through to D42. Results Evolution of the OFSIS Aggression score according to treatment group in the full analysis set population revealed a significant effect on time and treatment group. The OFSIS-Aggression score decreased over time from D0-D28 in both groups (time factor P = 0.0001) with a significant difference in favor of the verum P = 0.06); similar results were found considering the D0-D42 period (time factor P = 0.0001 [D0] and P = 0.04 [D42]). Conclusions and relevance The OFSIS provided a quantifiable measure of the frequency and intensity of 12 inter-cat interactions reflecting conflict between cats. The cat-appeasing pheromone is a promising treatment for the management of aggression between housemate cats in multi-cat households. PMID- 29757070 TI - Racial/Ethnic Disparities in Diabetes Diagnosis and Glycemic Control Among Women of Reproductive Age. AB - BACKGROUND: Types 1 and 2 diabetes mellitus complicate pregnancies and threaten the health of women of reproductive age and their children. Among older adults, diabetes morbidity disproportionately burdens racial/ethnic minorities, but diabetes emergence among younger adults has not been as well characterized. The objective of this study was to describe the distribution of diagnosed diabetes, undiagnosed diabetes, suboptimal preconception glycemic control, and prediabetes among women of reproductive age across racial/ethnic backgrounds. MATERIALS AND METHODS: We analyzed data collected in 2007-2008 from 6774 nonpregnant women, ages 24-32, in the National Longitudinal Study of Adolescent to Adult Health (Add Health). Prediabetes and undiagnosed diabetes were identified by fasting glucose and glycosylated hemoglobin (A1C) and diagnosed diabetes by self-report or antihyperglycemic medication use. We used multinomial regression models to predict prediabetes or diabetes versus normoglycemia. Within women with diabetes, we used logistic regression to predict those being undiagnosed and having suboptimal preconception glycemic control based on A1C. RESULTS: The estimated prevalence of diabetes was 6.8%, of which 45.3% was undiagnosed. Diabetes prevalence varied by race/ethnicity (p < 0.001): 15.0% of non-Hispanic black women (75.6% undiagnosed), 7.5% of Hispanic women (48.1% undiagnosed), 4.8% of non-Hispanic white women (22.8% undiagnosed), and 4.5% of Asian women (11.4% undiagnosed). The prevalence of prediabetes was highest in non-Hispanic black (38.5%), followed by Hispanic (27.8%), Asian (25.1%), Native American (20.3%), and non-Hispanic white (16.6%) women. CONCLUSIONS: Racial/ethnic disparities exist among women of reproductive age with prediabetes and diabetes. Meeting their healthcare needs requires addressing health inequities and coordination of diabetes management with reproductive health. PMID- 29757073 TI - Breast Cancer Screening in Primary Care: A Call for Development and Validation of Patient-Oriented Shared Decision-Making Tools. AB - The latest recommendations on breast cancer screening in women from 40 to 49 years charge primary care providers (PCPs) with completing shared decision-making with women about screening mammography. However, there is a lack of supportive materials accompanying this directive. No easy-to-use risk assessment tool is available for PCPs to stratify women's risk. Neither is an evidence-based patient centered way to assess values surrounding mammography available. To provide the highest quality care for women of 40-49 years, further research should clarify ways to apply risk assessment and values clarification to individual women. PMID- 29757072 TI - Lactobacillus plantarum YS-3 Prevents Activated Carbon-Induced Constipation in Mice. AB - The aim of this study was to determine the effects of Lactobacillus plantarum YS 3 (LP-YS3) on activated carbon-induced constipation in Kunming mice. The results of the experiment show that the antigastric acid activity and bile salt tolerance of LP-YS3 were stronger than those of Lactobacillus bulgaricus (LB). LP-YS3 inhibited loss of body weight caused by constipation and further reductions in fecal weight, particle number, and water content in mice. Moreover, LP-YS3 elevated the gastrointestinal transit rate and reduced the time required for initial black stool defecation. LP-YS3 also elevated motilin (MTL), endothelin (ET), acetylcholinesterase (AChE), substance P (SP), and VIP serum levels and reduced somatostatin (SS) levels in constipated mice. Hematoxylin-eosin (H&E) staining revealed that high concentration of LP-YS3 reduced the incidence of injuries to small intestine villi and the intestinal wall compared to carbon induced constipation groups. Reverse transcription-polymerase chain reaction and western blot experiments demonstrated that LP-YS3 upregulated c-Kit, stem cell factor, and glial cell line-derived neurotrophic factor mRNA and protein expression and downregulated transient receptor potential vanilloid 1 and nitric oxide synthase expression in small intestine tissue from constipated mice. In conclusion, high concentrations of LP-YS3 had stronger and more beneficial effects than LB. Based on these results, we conclude that LP-YS3 can effectively inhibit constipation. PMID- 29757074 TI - Differences in Screening and Treatment for Antepartum Versus Postpartum Patients: Are Providers Implementing the Guidelines of Care for Perinatal Depression? AB - BACKGROUND: National guidelines recommend universal depression screening for perinatal patients and provide treatment recommendations to prevent adverse maternal/child health outcomes. However, providers rarely screen all patients, and most women with perinatal depression remain undertreated. This study investigated predictors of universal screening and guideline-congruent care for perinatal depression by obstetrician-gynecologists and examined differences in practices with pregnant and postpartum patients. MATERIALS AND METHODS: A random, national sample of obstetric providers (n = 483) from a three-wave mailing completed the survey. RESULTS: Regression analysis showed that providers universally screened (53.04% vs. 82.40%; p < 0.001) and implemented guideline congruent care (33.61% vs. 58.51%; p < 0.001) with pregnant patients at a lower rate than with postpartum patients. Predictors of antenatal universal screening included the following: external influences, including screening as a clinic priority (adjusted odds ratio [AOR] 1.85; 95% confidence intervals [CIs]: 1.42 2.40), and intrinsic factors related to familiarity with mental health providers. Predictors of universal postpartum screenings included the following: clinic priority (AOR 3.01; 95% CIs: 2.12-4.28), provider comfort with diagnosing depression (AOR 1.58; 95% CIs: 1.04-2.39), and provider belief of patients unlikely to disclose depression unprompted (AOR 0.40; 95% CIs: 0.24-0.68). The only predictor of guideline-congruent care with pregnant patients was provider motivation (AOR 1.32; 95% CIs: 1.09-1.61). Predictors of postpartum guideline congruent care included the following: comfort with prescribing antidepressants (AOR 1.98; 95% CIs: 1.53-2.57) and provider belief that depression will not resolve on its own (AOR 1.33; 95% CIs: 1.07-1.65). CONCLUSIONS: This study displays differences in perinatal depression care for pregnant and postpartum patients, particularly disparities for pregnant patients. The findings highlight facilitating factors for translating guidelines into routine practices. PMID- 29757075 TI - Unpacking Racial/Ethnic Disparities in Prenatal Care Use: The Role of Individual , Household-, and Area-Level Characteristics. AB - OBJECTIVE: To identify the contributions of individual-, household-, and area level characteristics to disparities in the use of prenatal care (PNC). METHODS: This study used individual-level data from the 2001 Early Childhood Longitudinal Study-Birth Cohort linked to county-level U.S. Census data (N ~ 5,200). I used nonlinear regression decomposition to quantify the contributions of several groups of factors-maternal health and pregnancy characteristics, preconception health behaviors, insurance coverage, PNC location, socioeconomic status (SES), and the social/economic and healthcare environments-to PNC disparities. RESULTS: Relative to whites, blacks and Hispanics were less likely to initiate first trimester PNC and to have adequate PNC. The models explained 61.20%-79.90% and 52.15%-79.09% of the disparities in PNC initiation and adequacy, respectively. The most important factor was SES, which explained 50.68%-79.92% of the black white gap and 37.50%-49.51% of the Hispanic-white gap in PNC use. Location of care, insurance status, and pregnancy characteristics also made significant contributions to these disparities. CONCLUSION: SES is a key driver of inequality in PNC, particularly black-white inequality. Addressing socioeconomic factors may improve PNC use among minorities. PMID- 29757076 TI - Economic Evaluation of Concussion Programs in the State of Idaho: The Collective Potential of Prevention and Clinical Care. AB - Concussion, or mild traumatic brain injury, especially among young children, teenagers, and young adults, is a significant problem in Ada County, Idaho, and the United States. Although much has been learned about concussion, considerable controversy and gaps in knowledge still exist in many areas of research, leading to variation in concussion assessment, treatment, and management protocols. Health systems can positively impact concussion outcomes through community education and outreach, and provision of timely, coordinated, evidence-based clinical care. Collectively, these measures serve to reduce concussion incidence (primary prevention), enable more timely recognition of concussion by parents, coaches, and teachers of youth athletes (secondary prevention), and improve treatment of concussion after it has occurred (tertiary prevention). Using the concussion prevention and clinical care coordination activities of St. Luke's Health System in Idaho as a benchmark, this analysis estimates the economic value of these preventive measures, in particular those preventive measures that target the pediatric population, for Ada County and the state of Idaho, and includes both year of injury and long-term costs of concussion. This study adopts a societal perspective, incorporating savings in direct medical, indirect, and quality of life costs. PMID- 29757077 TI - Investigating whether maternal memory specificity is indirectly associated with child memory specificity through maternal reminiscing. AB - Maternal reminiscing and remembering has a profound influence on the development of children's autobiographical remembering skills. The current study investigated the relationships between maternal memory specificity, maternal reminiscing and child memory specificity. Participants consisted of 40 mother-child dyads. Children's age ranged between 3.5 and 6 years. Mothers and children participated in individual assessments of autobiographical memory specificity. Dyads participated in a joint reminiscing task about three past emotional (happy, sad, stressful) events. A positive moderate association was found between maternal autobiographical memory specificity and child autobiographical memory specificity. Maternal autobiographical memory specificity was significantly correlated with mothers' focus on the task, involvement and reciprocity, resolution of negative feelings, and structuring of narratives in the mother child reminiscing task. Moderate positive associations were found between maternal focus and structuring and child memory specificity. There was no evidence to suggest maternal elaborative reminiscing style was significantly positively correlated with mother or child memory specificity. Finally, there was support for an indirect pathway between maternal memory specificity and child memory specificity through quality of support and guidance provided by the mother in maternal reminiscing. Theoretical and clinical implications are considered. PMID- 29757078 TI - Improving Value Through Community Pharmacy Partnerships. PMID- 29757079 TI - Epidemiology, Antimicrobial Resistance, and Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae in Clinical Bovine Mastitis in Tunisia. AB - Bovine mastitis is a major disease in dairy cattle that causes high economic losses annually. Staphylococci, streptococci, and coliforms are among the major pathogens responsible for such infections. While data on bovine mastitis are numerous in Europe where the efficacy of farm management was monitored, those are scarce in African countries. In this study, we reported the occurrence of Escherichia coli (118/372, 31.7%) and Klebsiella pneumoniae (77/372, 20.7%), two environmental pathogens known to cause bovine mastitis. Resistance phenotypes were frequently identified for tetracycline (E. coli, 46.6%/K. pneumoniae, 20.8%), sulfonamides-trimethoprim (17.8%/11.7%), gentamicin (19.5%/14.3%), and enrofloxacin (11.0%/6.5%). No carbapenem-resistant isolate was detected. Extended spectrum beta-lactamases (ESBLs) were detected on selective medium in three E. coli and six K. pneumoniae, all carrying the blaCTX-M-15 gene. The K. pneumoniae belonged to two highly uncommon sequence types (ST471 and ST1083), while E. coli clustered in the ST167/617 clones, which have been widely reported in humans, animals, and the environment. These data point out the necessity to improve farm management in Tunisia to reduce the occurrence of coliform-induced mastitis and to avoid the dissemination in this sector of ESBL-producing E. coli and K. pneumoniae, which are of public health concern. PMID- 29757080 TI - Singing for Lung Health: service evaluation of the British Lung Foundation programme. AB - AIMS: Singing for Lung Health (SLH) is a novel intervention for individuals with respiratory disease. Qualitative results suggest benefits to physical, mental and emotional health. Limited data also suggest objective improvements in measures of quality of life with SLH are achievable. It is not known how effective the SLH groups supported by the British Lung Foundation (BLF) in the UK are. The objective was to understand the clinical impact SLH has on individuals with respiratory disease. METHODS: The BLF conducted a questionnaire survey of singers with respiratory disease from new SLH groups set up in 2016-2017. Questionnaires were administered prior to participants' first session and after 12 weeks of singing. Health-related quality of life, patient activation, anxiety and breathlessness outcomes were included. Healthcare resource utilisation including general practitioner (GP) visits, hospitalisations and frequency of inhaler use were recorded. RESULTS: A total of 228 singers participated from 26 SLH groups in the UK. Participants were 70.7 (10.1) years old, 156 (68.4%) were female and 114 (47.5%) had chronic obstructive pulmonary disease (COPD). In all, 113 (49.5%) participants provided 12-week data. There were significant improvements in COPD Assessment Test (CAT) score (Mean = -1.4, CI: (-0.25 to -2.48) ( p = .017)). Furthermore, 45% of singers reported reduced GP visits ( p <= .001) and 18% reported reduced hospital admissions ( p = .01). However, there were no significant improvements in general quality of life, anxiety, patient activation, breathlessness or inhaler use. Baseline characteristics were not significantly different between people who completed the 12-week evaluation and those who did not. CONCLUSIONS: This service evaluation found that participants in SLH groups report improvement in respiratory health-related quality of life and a reduction in healthcare utilisation. SLH has potential economic and health benefits. Therefore, to confirm these findings, these endpoints should be evaluated further in large-scale randomised controlled trials (RCTs). PMID- 29757081 TI - 'The Great Fiasco' of the 1948 presidential election polls: status recognition and norms conflict in social science. AB - All three 'scientific' pollsters (Crossley, Gallup and Roper) wrongly predicted incumbent President Harry Truman's defeat in the 1948 presidential election, and thus faced a potentially serious legitimacy crisis. This 'fiasco' occurred at a most inopportune time. Social science was embroiled in a policy debate taking place in the halls of Congress. It was fighting a losing battle to be included, along with the natural sciences, in the National Science Foundation, for which legislation was being drafted. Faced with the failure of the polls, the Social Science Research Council (SSRC) intervened quickly to prevent social science's adversaries from using this event to degrade further its status. After all, many social scientists considered the sample survey as the paramount tool of social research, and sampling as one of social science's greatest innovation. Concurrently, there was an ongoing conflict among polling practitioners themselves-between advocates of probability sampling and users of quotas, like the pollsters. The SSRC committee appointed to evaluate the polling debacle managed to keep this contentious issue of sampling from becoming the centre of attention. Given the inauspicious environment in which this event happened, the SSRC did not wish to advertise the fact that the house of social science was in turmoil. PMID- 29757082 TI - Population Health Could Do Far More to Mitigate Health Disparities. PMID- 29757083 TI - The influence of Cu+ binding to hypoxanthine on stabilization of mismatches involving hypoxanthine and DNA bases: a DFT study. AB - In the present work, the influence of Cu+ binding to N3- and N7-positions of hypoxanthine on energetic, geometrical and topological properties of hypoxanthine guanine, hypoxanthine-adenine, hypoxanthine-cytosine, hypoxanthine-thymine and hypoxanthine-hypoxanthine mismatches is theoretically investigated. The calculations, in gas phase, are performed at B3LYP/6-311++G(3df,3pd) level of theory. Unlike the other mispairs, Cu+ binding to N3-position of hypoxanthine causes the proton transfer process from enol form of hypoxanthine to imino forms of adenine and cytosine. This process also occurs in all mismatches having enol form of hypoxanthine when Cu+ binds to N7-position of hypoxanthine. The mismatches are stabilized by hydrogen bonds. The influence of Cu+ on hydrogen bonds is also examined by atoms in molecules (AIM) and natural bond orbital (NBO) analyses. Communicated by Ramaswamy H. Sarma. PMID- 29757084 TI - Treatment of greywater by forward osmosis technology: role of the operating temperature. AB - Effects of operating conditions were investigated in terms of water flux, reverse salt flux (RSF) and pollutant rejection in a forward osmosis (FO) membrane system treating synthetic greywater. Changing cross-flow velocity had a slight impact on the performance of the FO membrane. Elevating operating temperature was more effective than increasing draw solution concentration to enhance the water flux. Further observation on the effect of heating mode showed that when the temperature was increased from 20 to 30 degrees C, heating the feed solution (FS) side was better than heating the draw solution (DS) side or heating both sides; further increasing the temperature to 40 and 50 degrees C, heating both the FS and DS achieved much higher water flux compared with only increasing the FS or DS temperature. Under isothermal conditions, a higher water flux and a lower RSF were achieved at 40 degrees C than at other temperatures. Changing either FS or DS temperature had similar influences on water flux and RSF. The FO process revealed high rejection of nitrate (95.7%-100%), ammonia nitrogen (98.8%-100%), total nitrogen (97.4%-99.9%), linear alkylbenzene sulfonate (100%) and Mg (97.5% 100%). A mathematical model that could well simulate the water flux evolution in the present FO system was recommended. PMID- 29757085 TI - Short Videos Addressing Barriers to Cooking with Vegetables in Young Adults: Pilot Testing. AB - OBJECTIVE: Digital platforms offer innovative opportunities for nutrition education to motivate young adults to improve eating behaviors and practices. This study aimed to pilot test short educational cooking videos for dissemination through a smartphone designed to address barriers to home cooking and vegetable consumption among young adults. METHOD: Instructional videos (1-3 min) were produced and acceptability and perceived effectiveness for reducing barriers was investigated. Short free-response questions explored enablers of home cooking and feedback on the videos was collected through open discussion. Qualitative findings were coded using NVivo 11. RESULTS: Three focus groups with 16 young adults (mean age = 21.1 years) were conducted. Videos were well received and 9 of 13 participants who had low motivation to cook at baseline reported an increase in motivation post-video viewing. Perception of time as a barrier was reduced for 10 of 16 participants and thematic analysis revealed that accessibility to ingredients, ability to conceptualize recipes, and cost-saving tips were key enablers to cooking with vegetables. CONCLUSIONS: Short cooking videos may be a useful tool in interventions to address barriers to vegetable preparation and consumption among young adults. Future research should identify whether improvements in attitudes and motivation translate to change in intake. PMID- 29757087 TI - Death certificate errors in one Saudi Arabian hospital. AB - Proper completion of death certificates is of vital importance. This study assessed the accuracy of death certification at one major hospital in Riyadh, Saudi Arabia. We collected all certificates from 1997 to 2016 and scored them on the degree of accuracy. We found no errors of incompleteness or missed contributors to death. However, in all certificates (100%), cause of death was either incorrect or absent; 75% provided no cause of death. Further large-scale studies should be conducted in other hospitals to determine the exact prevalence of these serious errors. PMID- 29757086 TI - Bereavement hallucinations after the loss of a spouse: Associations with psychopathological measures, personality and coping style. AB - Bereavement hallucinations (BHs) were assessed in 175 conjugally bereaved participants 4 years post loss, to explore whether BHs were: (a) associated with psychological distress and (b) predicted by sociodemographic variables, personality and/or coping style. Participants with BHs scored significantly higher than those without BHs on prolonged grief, post-traumatic stress, depression symptoms, and emotional loneliness. Hierarchical logistic regression analysis showed avoidant coping, openness to experience, and length of marriage to significantly predict BHs, while detached coping was negatively associated with BHs. This study suggests that BHs may be an indicator of psychological distress in bereavement. PMID- 29757088 TI - Decrease of inhibitory effect of 2-chlorophenol on nitrification in sequencing batch reactors. AB - The metabolic and kinetic behaviour of a nitrification process in the presence of 2-chlorophenol (2-CP) was evaluated in two sequencing batch reactors (SBR1, SBR2) inoculated with nitrifying sludge previously exposed to phenolic compounds. The SBR1 was inoculated with sludge previously exposed to 2-CP, while the SBR2 was inoculated with sludge previously exposed to p-cresol. An inhibitory effect of 20 mg 2-CP-C/L on both nitrification processes was observed, as specific rates decreased according to a control assay in the absence of 2-CP. However, the inhibitory effect decreased throughout the cycles. At the end of cycle 6, a stable nitrifying process was observed with the sludge previously exposed to 2-CP (SBR1), as an ammonium consumption efficiency and a nitrate production yield close to 99.6 +/- 0.3% and 0.99 +/- 0.02 were respectively achieved. Despite a complete ammonium consumption being achieved with the sludge previously exposed to p-cresol (SBR2), partial nitrification was observed as nitrate production yield accounted for 0.28 +/- 0.08 and nitrite was accumulated within the culture. Nevertheless, both nitrifying sludges had the ability to completely consume 2-CP. The use of SBR systems with nitrifying sludge previously exposed to 2-CP resulted in a better nitrification performance, thus it may be a good alternative for achieving a stable nitrifying respiratory process where complete and simultaneous ammonium and 2-CP consumption can be acquired. PMID- 29757089 TI - Potential source regions of air pollutants at a regional background station in Northern China. AB - Understanding the potential source regions of air pollutants and their relative contribution from surrounding areas are of great importance for air pollution control strategies in Northern China. Six years of measurement of air pollutants was conducted from 2005 to 2010 in Shangdianzi (SDZ) regional background station. During the study period, the annual average concentrations of sulfur dioxide (SO2), carbon monoxide (CO), nitrogen dioxide and ozone (Ox), and fine particle matter less than or equal to 2.5 MUm (PM2.5) range from 15.7 to 20.0 MUg/m3, 577.7 to 856.0 MUg/m3, 90.4 to 101.8 MUg/m3, and 39.8 to 62.4 MUg/m3, respectively. In this work, Potential Source Contribution Function (PSCF) and Trajectory Sector Analysis (TSA) methods are applied to identify locations of sources and their relatively contribution of air pollutants at SDZ. PSCF analysis shows that central Inner Mongolia, north Shanxi, west and south Hebei, and west Liaoning are all potential sources of SO2. The North China Plain (NCP) region, especially south Hebei and north Shandong, are major potential source regions for CO, Ox, and PM2.5. Therefore, reducing anthropogenic emissions from the coal industry, biomass burning, agricultural activities, and vehicles in these areas could be an effective way of controlling air pollution at SDZ. Based on the TSA results, the contributions of SO2, CO, Ox, and PM2.5 from long-distance transport are 5.5 MUg/m3, 301.4 MUg/m3, 14.8 MUg/m3, and 25.8 MUg/m3, accounting for approximately 22.6%, 32.3%, 13.1%, and 37.5% of the respective air pollutant concentrations at SDZ. PMID- 29757090 TI - Use of spectroscopic and zeta potential techniques to study the interaction between lysozyme and curcumin in the presence of silver nanoparticles at different sizes. AB - This article describes, for the first time, the effect of three different sizes of silver nanoparticles on the binding of curcumin to lysozyme as examined by spectroscopic and zeta potential techniques at physiological conditions. The binding constants of curcumin to lysozyme in the presence of silver nanoparticles were measured. Based on the results of synchronous fluorescence and three dimensional fluorescence spectroscopy, the presence of the different sizes of silver nanoparticles caused conformational changes in lysozyme during the binding of curcumin. Such changes were also observed when increasing the curcumin concentration. The results of fluorescence resonance energy transfer theory indicated that different sizes of silver nanoparticles could change the binding distance between curcumin and lysozyme. Based on the red edge excitation shift approach, we concluded that the limited mobility around the Trp residues decreased in the presence of silver nanoparticles with bigger size. Under resonance light scattering, the aggregation of curcumin on lysozyme in the presence of silver nanoparticles can play a major role in functional proteins. Communicated by Ramaswamy H. Sarma. PMID- 29757091 TI - Striving for liminality: Eating disorders and social suffering. AB - In this article, I argue that eating disorders constitute a form of social suffering, in which sufferers embody liminality as a response to, and a reflection of, oppressive sociality, structural violence, and institutional constraints. Based on the illness narratives of people with anorexia nervosa, bulimia nervosa, and their subclinical variants in Israel, the analysis draws the experiential, the social, and the structural into critical focus. These narratives, which delineate lived experiences of self-starving, bingeing, and purging, and the attendant viscerality of hunger, fullness, and emptiness, reveal how participants developed an embodied drawing inward and away, being at once within and without society for extended periods of time, through eating disordered practices. This liminal positioning, I argue, was a mode through which participants cultivated alternative (if temporary) personal spaces, negotiated identities, and anesthetized pain: processes many deemed essential to survival. Embedding the participants' narratives of eating disordered experiences within familial, societal, and political-economic forces that shaped their individual lives, I examine the participants' striving for liminality as at once intimately embodied and structurally mapped. The analysis suggests that policy initiatives for eating disorder prevention must address the social suffering that eating disorders manifest: suffering caused by structures and institutions that reinforce social inequality, violence, and injustice. PMID- 29757092 TI - Groundnut shell gasification performance in a fluidized bed gasifier with bubbling air as gasification medium. AB - This work was focused on finding the groundnut shell (GNS) gasification performance in a fluidized bed gasifier with bubbling air as gasification medium. GNS in powder form (a mixture of different particle size as given in table 8 in the article) was gasified using naturally available river sand as bed material, top of the bed feeding, conventional charcoal as bed heating medium, and two cyclones for proper cleaning and cooling the product gas. Experiments were performed using different operating conditions such as equivalence ratio (ER) between 0.29 and 0.33, bed temperature between 650 degrees C and 800 degrees C, and feedstock feeding rate between 36 and 31.7 kg/h. Different parameters were evaluated to study the gasifier performance such as gas yield, cold gas efficiency, carbon conversion efficiency (CCE), and high heating value. The most suitable ER value was found to be 0.31, giving the most stable bed temperature profile at 714.4 degrees C with 5-10% fluctuation. Cold gas efficiency and CCE at optimal ER of 0.31 was found to be 71.8% and 91%, respectively. PMID- 29757093 TI - Dispersal altering local states has a limited effect on persistence of a metapopulation. AB - Metapopulations are collections of local populations connected by dispersal. Metapopulation models often assume would-be colonists affect the states of local populations they disperse from and those they disperse to. Here, we build a new framework to include that effect and to assess the impact of dispersal. Our model predicts that a metapopulation will, in general, be found either in the state of global extinction or in the state of persistence. Our key finding is that dispersal, and the state changes associated with dispersal, have significant qualitative and quantitative effects on long-term dynamics only in a narrow range of parameter space. We conclude that life history features other than dispersal (e.g. mortality rate) have a greater influence over metapopulation persistence. We discuss the implications of our results for conservation biology, the future application of our model to the study of cooperative breeding, as well as our model's limitations. PMID- 29757094 TI - Implicit Sex Guilt Predicts Sexual Behaviors: Evidence for the Validity of the Sex Guilt Implicit Association Test. AB - Self-report measures of sexuality may be influenced by people's conscious concerns about confidentiality and social desirability. Alternatively, non conscious measures (e.g., implicit association tests; IATs) are designed to minimize these validity concerns. We constructed an IAT measure of sex guilt using 154 male and female university students. The sex guilt IAT demonstrated convergent validity as it correlated with various sexual behaviors and incremental validity as it improved the prediction of several sexual behaviors beyond that provided by the Mosher sex guilt scale. We conclude that a non conscious measure of sex guilt may complement the use of self-reports in studying sexual behaviors. PMID- 29757095 TI - Death preparation of Chinese rural elders. AB - In this qualitative study, we explored how Chinese rural elders narrate death related issues and death preparation. Adopting a phenomenological approach, we interviewed 14 participants regarding the particular actions they employ to prepare for death. The findings revealed a death preparation system for rural Chinese elders that is instrumental in how they converse about death, wish for a good death, make objects and symbols, and anticipate an afterlife as a worshiped ancestor rather than a wandering ghost. Family and family honor provide the context for death preparation. We discuss implications and the need for the death preparation education of younger generations. PMID- 29757097 TI - Stigma and suicidality among suicide attempt survivors: A qualitative study. AB - Among people with mental illness, stigma experiences can increase suicidality, and suicidality itself is associated with negative stereotypes. Suicide attempt survivors experience both mental illness stigma and suicide stigma, which could contribute to their increased risk for completed suicide. We interviewed 13 suicide attempt survivors regarding experiences and consequences of stigma and identified five stigma-related themes. Stigma led to substantial emotional strain, including loneliness and hopelessness, which are important precursors of suicidality. Our findings suggest that both mental illness stigma and suicide stigma can contribute to suicidality among people with mental illness in general, and in suicide attempt survivors specifically. PMID- 29757096 TI - When solving dyspareunia is not enough to restore sexual function in women with deep infiltrating endometriosis treated with dienogest. AB - OBJECTIVE: The aim of the study was evaluated dyspareunia and sexual function (SF) in women with deep endometriosis treated with Dienogest for 12 months. METHODS: Prospective cohort study set in University of Campinas, Brazil, including thirty women with sonographic diagnosis of deep endometriosis and sexual dysfunction treated with 2?mg/daily Dienogest for 12 months. SF parameters were assessed by Female Sexual Function Index (FSFI) before and after the treatment and dyspareunia was quantified through Visual Analogic Scale(VAS) during the follow ups performed every 3 months. Statistical analysis was performed by ANOVA test as well as Statistical Analysis System version 9.4. RESULTS: Women were on average 36.13 +/- 6.24 years old and all of them showed sexual dysfunction (FSFI = 17.6 +/- 5.7) before Dienogest; 88.3% had dyspareunia as main symptom related to deep endometriosis (VAS before 5,3+/-3,1). At the end of the treatment, dyspareunia showed a decrease of intensity (VAS after 3.7+/ 3.3; p = 0.0093) and an improvement on FSFI index was accomplished (p = 0.0023) however, it did not restore SF completely, considering FSFI cut-off <26.55. CONCLUSION: Long-term treatment for DIE with Dienogest has provided a decreasing in dyspareunia and also an enhancement on SF, although SF has not been restored to normal levels. PMID- 29757098 TI - A phenomenological study of siblings bereaved by suicide: A shared experience. AB - This interpretative phenomenological analysis explored the key issues in the grief experiences of seven young adults bereaved by the youth suicide of a sibling. We conducted semi-structured phone interviews from which we derived four themes describing the participants' experiences of: (a) the process of grief, (b) grief interactions (within families and outside), (c) continuing bonds, and (d) meaning-making and growth through grief. The stories highlight the impact of family relationships on the grieving process in siblings and the need for support to help family members better communicate, understand, and respect each other's needs as they process their grief. PMID- 29757099 TI - Right back like we left something: examining the commodification of Blackness in social services to address racial disparities - the case of Hartford. AB - Market-based approaches to addressing racial disparities have essentially re commodified Blackness. Utilizing Hartford, which contains the largest percentage of Blacks per capita in Connecticut, this article examines market-based approaches to address racial disparities while discussing Blackness as an enduring commodity that is tied to private sector profit. The study argues that market based approaches incentivize punitive approaches to social problems associated with Blackness. The study concludes by suggesting that addressing disparities utilizing markets requires reimagining policy incentives to focus on prevention and treatment of social problems associated with Blackness. Failure to reimagine policy incentives serves to commodify Blackness whereby industries benefit from the continuity of disparities rather than the elimination of disparities. PMID- 29757100 TI - Sexual Counselling in Women with Primary Infertility and Sexual Dysfunction: Use of the BETTER Model. AB - The aim of the study was to determine the effect of sexual counselling based on the BETTER model on female sexual health in the infertile women with sexual dysfunction. This is an experimental, prospective study carried out in an infertility clinic. The study included 70 women with primary infertility, of whom 35 were in the experimental group and 35 were in the control group. Female Sexual Function Scale and Golombok-Rust Sexual Satisfaction Scale were administered at the initial assessment and the final assessment. Two sessions of sexual counselling were given to the experimental group based on the BETTER model. A routine follow-up of the control group was performed. After the counselling, there was a statistically significant improvement in the mean scores for Female Sexual Function Scale and the total scores for Golombok-Rust Sexual Satisfaction Scale and its subscales in the experimental group compared to the control group. The women who had been infertile for 6 years and more had less improvement in sexual dysfunction and sexual dissatisfaction. The sexual counselling given in accordance with the BETTER model was found to be effective in improvement of sexual functions and sexual satisfaction in the women with one-two-years infertility. PMID- 29757101 TI - Identifying and Predicting Profiles of Medical Noncompliance: Pediatric Caregivers' Antibiotic Stewardship. AB - Sometimes compliance with medical recommendations is problematic. We investigated pediatric caregivers' (N = 606) patterns of noncompliance with antibiotic stewardship based on the obstacle hypothesis. We tested predictors of noncompliance framed by the obstacle hypothesis, dissonance theory, and psychological reactance. The results revealed four profiles of caregivers' stewardship: one marked by compliance (Stewards) and three marked by types of noncompliance (Stockers, Persuaders, and Dissenters). The covariate analysis showed that, although psychological reactance predicted being noncompliant, it was types of obstacles and discrepant experiences that predicted caregivers' patterns of noncompliance with antibiotic stewardship. Campaign planning often focuses on identifying the belief most associated with the targeted outcome, such as compliance. Noncompliance research, however, points out that persuaders may be successful to the extent to which they anticipate obstacles to compliance and address them in their influence attempts. A shift from medical noncompliance to patient engagement also affords an opportunity to consider how some recommendations create obstacles for others and to find positive ways to embrace conflicting needs, tensions, and reasons for refusal in order to promote collective goals. PMID- 29757102 TI - How religious and spiritual beliefs explain prolonged grief disorder symptoms. AB - This study investigated the importance of religious and spiritual beliefs in daily life in explaining prolonged grief disorder (PGD) symptomatology. Participants were 588 bereaved adults who completed a questionnaire. The importance of spiritual beliefs in daily life explained a small to medium, significant 3% of variance in PGD symptoms, but religious beliefs in daily life did not. Individuals who placed moderate importance on spiritual beliefs in their daily life may experience more intense grief. PMID- 29757103 TI - End-of-life trends and patterns among children in the US foster care system: 2005 2015. AB - Drawing on national, longitudinal Adoption and Foster Care Analysis, and Reporting System data (2005-2015), demographic, health, foster care, and geographic characteristics of decedents (N = 3653) aged 1-17 years were examined. On average, decedents were 6 years old, the highest proportion died as infants, and experienced significant trauma in their short lives either through maltreatment or exposure to parental substance use. A noted increase in Medicaid coverage among decedents over time suggests critical access to concurrent treatment and hospice care, but this is unavailable to children with private insurance. This study has policy implications related to the 2010 Affordable Care Act. PMID- 29757104 TI - Rehabilitation of drug abusers: the roles of perceptions, relationships and family supports. AB - The increase in the use, abuse and misuse of psychoactive substances is not just of concern to national government of different countries but poses a big problem to the international community as well as of a global public health challenge. The study explored the perceived influence of perceptions, relationships and family support on rehabilitation of drug abusers undergoing rehabilitation in a rehabilitation centre. The non-experimental study design was used. The study population was that of drug abuse patients undergoing rehabilitation in the Neuropsychiatric Hospital in Lagos. Purposive sampling technique was used to select the respondents. Forty drug abusers who were met the criteria of not being a psychotic, had undergone detoxification, in the last stages of rehabilitation and consented to voluntarily participate were interviewed using In-depth Interview Guide to collect qualitative data based on the objectives of the study. The data were manually content analysed. The drug abusers viewed their condition as a mental disorder, an illness, a bad and dangerous habit that can be treated. They viewed their relationship with their rehabilitation officers as professional and cordial, which is essential for the rehabilitation process. Financial, material and moral supports given by the family were identified as important catalysts for quick rehabilitation. Rehabilitation officers and policy makers should consider on improving on the role of professional relationships and family support in the rehabilitation process of drug abusers undergoing rehabilitation. PMID- 29757105 TI - Life after loss: Parent bereavement and coping experiences after infant death in the neonatal intensive care unit. AB - The death of an infant in the neonatal intensive care unit (NICU) is a profound and unexpected loss for parents that results in a complex process of coping with bereavement. A descriptive qualitative approach was used to explore parent bereavement and coping experiences after infant death in the NICU. The dual process model of coping with bereavement was used as a conceptual framework to help understand how parents cope with grief after infant death. Living with infant death was a process that resulted in major life changes and a process of oscillating among various coping strategies. PMID- 29757106 TI - A snapshot of Australian social workers in palliative care and their work with estranged clients. AB - This paper describes a mixed method survey that was administered to a group of Australian palliative care social workers (n = 27). Specifically, it aimed to investigate the ways that social workers understood and worked with clients who were estranged from family at the end of life. Respondents suggested that estrangement potentially impacted clients emotionally, practically, and existentially. They were challenged to make clear assessments, provide emotional support, encourage news ways of thinking about estrangement, to manage practical issues, work with the client's family, and monitor their own professional role. Theories and models of intervention and levels of training are also discussed. PMID- 29757108 TI - Cognitively active older adults' comprehension and metacomprehension of negated text. AB - : Background/Study context: Previous research has demonstrated that negated text is universally difficult to understand, and while readers are aware of the difficulty, they are not always able to direct this awareness to improve their comprehension of negation. The present research aimed to determine whether this holds true for older adults, even while maintaining good cognitive function through reading activity. METHODS: The study used an online paradigm, where young (age range 19-24) and older (age range 60-87) adults read passages, rated their comprehension, and answered questions about what they read. Data analysis included analysis of variance for comprehension accuracy and metacomprehension judgment as well as gamma correlation analysis for the relationship between these two variables to determine accuracy of metacomprehension judgments. RESULT: . Older readers, who took part in library activities and book discussion groups, had better comprehension than young adults overall and were also better able to judge their own comprehension of negative text. CONCLUSION: These results suggested that remaining cognitively active may help older adults not only maintain their ability to understand text but may also enhance their ability to assess their own comprehension of that text. In addition, these readers were likely able to use their experience with reading to compensate for any working memory deficits that may occur with age and which may detrimentally affect their ability to understand complex text constructions, such as negation. PMID- 29757109 TI - Losing a partner: Do continuing bonds bring solace or sorrow? AB - The purpose of this qualitative descriptive study, underpinned by the humanbecoming paradigm, was to bring forth a deeper understanding about continuing bonds with a deceased spouse and describe the transformative process of losing a partner. Each of six participants dialogued with researchers on three to four occasions about the life and death of their loved one, continuing bonds with the deceased, struggles they have encountered, and dreams of the future. It was discovered that participants told a story that changed over time, struggled with continuing bonds, suffered with loneliness and desired new intimate relationships. PMID- 29757111 TI - Older people's adoption of e-learning services: a qualitative study of facilitators and barriers. AB - This research investigates the facilitators and barriers for older people to adopt e-learning services using qualitative data of older people in a Chinese city. A qualitative approach was applied to explore the perceived facilitators and obstacles toward e-learning adoption with 10 older Chinese aged over 50. The results indicate the following: (1a) Age-related changes and cohort effects were found to be the internal barriers for the adoption of e-learning. (1b) Equipment problems, lack of time, and the availability of alternatives were found to have negative effects on the acceptance of e-learning services. It is notable that alternatives including the University of the Third Age (U3A) were found to be more attractive for older Chinese. (2a) Work requirements and flexibility of e learning services were found to have direct effects on the acceptance of services. (2b) User-friendly design and stimulation from family would facilitate older people to adopt. Practical implications of this research include that policymakers should consider investing more in education in later life and introducing e-learning services in public lectures and tutorials and that the age related barrier should be taken into consideration in the design phase of e learning services. U3As should consider integrating e-learning approaches and cooperating with the community. PMID- 29757110 TI - Massive pleural and pericardial effusion due to hypothyroidism in a patient with a surgically treated thyroid-stimulating hormone-producing pituitary adenoma. AB - Hypothyroidism is relatively rare etiology of serositis with effusion, but massive pleural effusion is very unusual. This is a report of massive pleural effusion in patient taking methimazole after surgical resection of thyroid stimulating hormone (TSH)-producing pituitary adenoma (TSHoma). The patient was clinically and biochemically hypothyroid and responded well to discontinuation of methimazole and thyroid hormone replacement therapy. When assessing patients with pleural effusion, we should not rely on laboratory test results alone, as a detailed medical history and thorough physical examination could be more useful. PMID- 29757112 TI - Does Age Impact Text-Message Dependence? AB - Little research has examined how age impacts texting dependence, despite the increased usage of texting and other social media applications in older adults. In the present study, three age groups (18-29 years of age, n = 135; 30-49 years of age, n = 58; 50-69 years of age, n = 19) were given the Self-Perceptions of Text Messaging Dependency Scale (SPTMDS). This self-report measure examines Emotion Reaction, Excessive Use, Disruption of Relationships with text Messages and Psychological/Behavioral Symptoms Concerning Heavy Usage). Results revealed that (a) texting dependence decreased across the three age groups and (b) that this decrease occurred for all four sub-scales of the SPTMDS (all p's < .01). These results have implications for how one aspect of social media (namely texting) is used and ultimately accepted by older adults. PMID- 29757113 TI - Performance Effects of Reward-Related Feedback on the Dimensional Change Card Sort Task. AB - The Dimensional Change Card Sort (DCCS) is one of the most widely used measures of preschool executive function, yet relatively little is known about how altering emotional demands of the task affects DCCS performance. This study examined the effects of emotionally evocative reward-related feedback on preschool children's performance on the DCCS in a sample of 105 children aged 3.5 4.5 years. In a within-subjects design, children completed the standard DCCS and a modified version of the DCCS in which sticker rewards were gained or lost after each trial. With a reward at stake, children were more accurate but had slower reaction time on the post-switch DCCS. Another sample (N = 20) of 3.5- to 4.5 year-olds who completed the standard DCCS twice without reward showed no change in performance, indicating results are not due to practice effects. Findings demonstrate preschool children's ability to adjust their approach to the DCCS in the presence of emotionally evocative reward-related feedback by prioritizing accuracy over speed. Trial-by-trial reward-related feedback may facilitate cognitive control in early childhood. PMID- 29757114 TI - Intolerance of uncertainty as the vulnerability factor among parents of childhood cancer survivors: A 3-month follow-up study. AB - PURPOSE: In a 3-month follow-up study, we assessed the intolerance of uncertainty in 61 parents of a childhood cancer survivor. The objective was to compare its prevalence over time. We tested these parents twice i.e., at treatment completion (time 1) and 3 months later (time 2). We hypothesized that this personality factor stayed stable and had aversive effects on cognitive processes. FINDINGS: Noticeable intolerance of uncertainty rates were found. At both assessments, results showed that this factor was central in the development of excessive worries, poor problem orientation, rumination, cognitive avoidance and positive beliefs about worry. Repeated measures revealed a decrease for anxiety and cognitive avoidance, and an increased level for somatic symptoms. CONCLUSIONS: Parents who are intolerant of uncertainty are at risk to display dysfunctional behaviors over time. Sensitizing health care professionals to the identification of this factor and its associated difficulties is essential for the implementation of efficient intervention strategies. PMID- 29757115 TI - Just Google It: An Approach on Word Frequencies Based on Online Search Result. AB - Word frequency is one of the most robust factors in the literature on word processing, based on the lexical corpus of a language. However, different sources might be used in order to determine the actual frequency of each word. Recent research has determined frequencies based on movie subtitles, Twitter, blog posts, or newspapers. In this paper, we examine a determination of these frequencies based on the World Wide Web. For this purpose, a Python script was developed to obtain frequencies of a word through online search results. These frequencies were employed to estimate lexical decision times in comparison to the traditional frequencies in a lexical decision task. It was found that the Google frequencies predict reaction times comparably to the traditional frequencies. Still, the explained variance was higher for the traditional database. PMID- 29757119 TI - Perspectives on Neuroscience and Behavior. PMID- 29757116 TI - Social marketing nutrition education for low-income population. AB - As access to healthy food (or lack thereof) could be considered a social justice issue, social workers should be concerned about this issue and willing to collaborate with colleagues of various disciplines to address it. This study was a formative evaluation conducted to understand best practices, recommendations, and feasibility of a social-marketing-based nutrition education program tailored to the needs of adults with limited income. The authors report findings from focus groups conducted with Cooperative Extension Agents (CEAs) and region coordinators (n = 45) and Supplemental Nutrition Assistance Program Education (SNAP-Ed) (n = 69) eligible participants to inform the development of a social marketing nutrition intervention for SNAP-Ed in Georgia. Barriers to healthy eating included cultural preferences, costs of healthy food, lack of time, and lack of availability. Social marketing has a potential to deliver effective and efficient SNAP-Ed targeted to large, limited-resource Georgians. Segmenting the low-income population based on geographical location as well as best methods for outreach can allow tailored messages to meet identified needs, lifestyles, and other variables that make these individuals most likely to respond to the program. Food security and nutrition education are topics of concern for all health care professionals interested in addressing complex health issues of many low-income adults. PMID- 29757120 TI - Prognostic significance of SRSF2 mutations in myelodysplastic syndromes and chronic myelomonocytic leukemia: a meta-analysis. AB - OBJECTIVE: Serine/arginine-rich splicing factor 2 (SRSF2) mutations were detected frequently in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) patients. However, its prognostic value has not yet been fully clarified. METHODS: In this meta-analysis, Hazard Ratio (HR) and 95% confidence interval (CI) for overall-survival (OS) were chosen to evaluate the prognostic impact of SRSF2 mutations and to compare SRSF2 mutations to those with wild-type. RESULTS: A total of 2056 patients from 12 studies were obtained. The pooled HRs for OSsuggested that patients with MDS had a poorer prognosis (HR = 1.780, 95% CI (1.410-2.249)), while analysis on SRSF2 mutations revealed no significant effect on the prognosis of CMML patients (HR = 1.091, 95% CI (0.925-1.286)). The frequency of SRSF2 mutations was found to be 11.5% and 39.8% in patients with MDS and CMML, respectively. DISCUSSION: This meta-analysis suggests that SRSF2 has a poor prognosis in patients with MDS, but no prognosis impact on patients with CMML. CONCLUSION: In conclusion, SRSF2 mutations were significantly related to the shorter OS in patients with MDS which may consider as an adverse prognostic risk factor. Whereas, analysis did not show any prognostic effect on OS of CMML patients with SRSF2 mutations. PMID- 29757122 TI - Dead on the table: A theoretical expansion of the vicarious trauma that operating room clinicians experience when their patients die. AB - The practice of operating room (OR) clinicians - nurses, surgeons, and anesthetists - is fundamentally about preserving life. Some patients, however, die in the OR. Clinicians are therefore vulnerable to moral and emotional trauma. In this paper, we discuss three forces that shape clinicians' moral and emotional experiences in OR care: biomedical values, normative death discourse, and socially (un)sanctioned grief. We suggest how each of these forces increases clinicians' vulnerability to feel traumatized when their patients die. We hope this discussion will stimulate clinicians and researchers to engage with social and cultural determinants of clinicians' experiences when patients die. PMID- 29757121 TI - Management of electrolyte disorders: also the method matters! AB - INTRODUCTION: For the last few decades, electrolyte determinations in plasma or serum are carried out by reliable potentiometric methods. In recent years, a marked technical evolution has taken place, where the clinical analysis of common analytes (e.g. electrolytes) is partly moving from centralised clinical core laboratories to near-patient point-of-care testing. METHODS: As the measuring principle used by point-of-care testing markedly differs from the one used in core laboratories, sodium results are not always interchangeable in critically ill patients due to the different sensitivity of the analytical methods for the electrolyte exclusion effect. RESULTS: This effect mainly occurs in patients with decreased plasma protein values. The observed differences in generated test results might significantly affect the judgment and the treatment of electrolyte disturbances. As technical solutions are not likely to occur in the near future, clinicians and laboratorians should be well aware of this growing problem. Mathematical correction of the sodium results for plasma protein concentration may resolve the problem to a certain extent. DISCUSSION: Although electrolyte determinations are generally very reliable, analytical interferences can occur for sodium rarely, mainly due to contamination by surfactants, benzalkonium in particular. For potassium, the major problem is hemolysis. To a lesser extent, leukocyte lysis and thrombocytopenia may also interfere. For chloride determination, the selectivity of the electrodes used is not ideal. Occasionally, false positive signals can be observed in presence of interfering ions (e.g. bromide). PMID- 29757123 TI - The Role of Humor in Messaging about the MMR Vaccine. AB - Outbreaks of vaccine-preventable diseases have increased due, in part, to misconceptions about vaccine safety (Kennedy et al., 2011). Extant literature has examined various messages designed to correct false beliefs about vaccination risks and to urge parents to vaccinate their children. The present study is designed to contribute to this literature by drawing on the broader research and theory on resistance to persuasion and correcting false beliefs. We examine the effects of a humorous (vs. non-humorous) message about the importance of the measles, mumps, and rubella vaccine on parents' vaccine hesitancy. Results revealed that compared to a more serious message, a satirical message reduced reactance and led to greater perceptions of measles severity, which reduced vaccine hesitancy. Practical and theoretical implications are discussed. PMID- 29757124 TI - Perception of livestock ecosystem services in grazing areas. AB - This study investigates how the ecosystem services (ES) linked to livestock grazing are perceived across countries. A total of 82 case studies collected from 42 countries via survey (53.7% cases from Europe and 46.3% from outside of Europe) have been analysed through a multivariate approach. In all, 18 non provisioning ES were considered. Overall, the reported impacts of livestock grazing on the different ES were much more positive than negative. Notably, a large proportion of respondents reported either positive or very positive impacts for some cultural ES, namely cultural, historic and natural heritage (84%), knowledge systems and educational values (77%), landscape values (74%), and for some supporting and regulating ES, namely habitat provision (66%), nutrient cycling (65%), and bush encroachment/fire control (66%). Based on multiple regression analysis, geographic origin, stakeholder type and species category, as well as protection status of the grazing area, had significant effects on the perception of the impacts. Respondents reported those impacts as more positive in Europe, in protected areas and where several species were present in the grazing area. A significantly larger proportion of respondents reported recognition of ES provided by the grazing livestock population in European countries (40.9%) compared with non-European countries (23.7%). Based on the survey responses it appears that in non-European countries absence of formal recognition, especially by policy makers, is a major challenge for the continued provision of ES in grazing systems. In Europe, where such recognition is already often included in legislation, the long-term sustainability of related policies and incentives to provide such services is viewed as a major issue by the respondents. PMID- 29757125 TI - Cross-Cultural Comparison of Genetic and Cultural Transmission of Smoking Initiation Using an Extended Twin Kinship Model. AB - BACKGROUND: Considerable evidence from twin and adoption studies indicates that genetic and shared environmental factors play a role in the initiation of smoking behavior. Although twin and adoption designs are powerful to detect genetic and environmental influences, they do not provide information on the processes of assortative mating and parent-offspring transmission and their contribution to the variability explained by genetic and/or environmental factors. METHODS: We examined the role of genetic and environmental factors in individual differences for smoking initiation (SI) using an extended kinship design. This design allows the simultaneous testing of additive and non-additive genetic, shared and individual-specific environmental factors, as well as sex differences in the expression of genes and environment in the presence of assortative mating and combined genetic and cultural transmission, while also estimating the regression of the prevalence of SI on age. A dichotomous lifetime 'ever' smoking measure was obtained from twins and relatives in the 'Virginia 30,000' sample and the 'Australian 25,000'. RESULTS: Results demonstrate that both genetic and environmental factors play a significant role in the liability to SI. Major influences on individual differences appeared to be additive genetic and unique environmental effects, with smaller contributions from assortative mating, shared sibling environment, twin environment, cultural transmission, and resulting genotype-environment covariance. Age regression of the prevalence of SI was significant. The finding of negative cultural transmission without dominance led us to investigate more closely two possible mechanisms for the lower parent offspring correlations compared to the sibling and DZ twin correlations in subsets of the data: (1) age * gene interaction, and (2) social homogamy. Neither of the mechanism provided a significantly better explanation of the data. CONCLUSIONS: This study showed significant heritability, partly due to assortment, and significant effects of primarily non-parental shared environment on liability to SI. PMID- 29757126 TI - Reply to Robert Vincent. PMID- 29757128 TI - Insights into the initiation of chromosome II replication of the pressure-loving deep-sea bacterium Photobacterium profundum SS9. AB - How DNA metabolism is adapted to survival of organisms such as the bacterium Photobacterium profundum SS9 at high pressure is unknown. Previously, a high pressure-sensitive P. profundum SS9 transposon mutant (FL31) was identified, with an insertion in a putative rctB gene. The Vibrio cholerae RctB protein is essential for replication initiation at the origin of chromosome II, oriCII. Using a plasmid-based system in E. coli we have identified the replication origin of chromosome II from P. profundum SS9 and have shown that the putative rctB gene, disrupted in FL31, is essential for oriCII function. Moreover, we found that a region corresponding to the V. cholerae oriCII incompatibility region (incII) exerts an inhibitory effect on P. profundum oriCII. The truncated rctB gene in FL31 confers insensitivity to incII inhibition, indicating that the C terminus of RctB is important for the negative regulation of replication. The RctB proteins of V. cholerae and P. profundum are partially interchangeable, but full functionality is achieved only with the cognate origin. Our findings provide the first characterization of the replication origin of chromosome II in a deep sea bacterium. PMID- 29757127 TI - Sulfurovum denitrificans sp. nov., an obligately chemolithoautotrophic sulfur oxidizing epsilonproteobacterium isolated from a hydrothermal field. AB - A novel marine sulfur-oxidizing bacterium, designated strain eps51T, was isolated from a surface rock sample collected from the hydrothermal field of Suiyo Seamount on the Izu-Bonin Arc in the Western Pacific Ocean. This bacterium was Gram-staining-negative, non-motile and rod-shaped. Strain eps51T grew chemolithoautotrophically, by sulfur-oxidizing respiration with elemental sulfur and thiosulfate as electron donors and used only carbon dioxide as a carbon source. Oxygen and nitrate were used as its electron acceptors. The isolate grew optimally at 30 degrees C, at pH 7.0 and with 3 % NaCl. The predominant fatty acids were C16 : 1omega7c, C18 : 1omega7c and C16 : 0. The respiratory quinone was menaquinone-6 and the genomic DNA G+C content was 40.0 mol%. Phylogenetic analysis based on 16S rRNA gene sequence revealed that eps51T represented a member of the genus Sulfurovum and the closest relative was Sulfurovum aggregans (96.7 %). Based on its phylogenetic position along with its physiological and chemotaxonomic characteristics, the name Sulfurovum denitrificans sp. nov. is proposed, with the type strain eps51T (=NBRC 102602T=DSM 19611T). PMID- 29757129 TI - Qingshengfania soli Zhang et al. 2015 is a later heterotypic synonym of Pseudochelatococcus lubricantis Kampfer et al. 2015. AB - Qingshengfania soli DSM 103870T was compared with Pseudochelatococcus lubricantis MPA 1113T to clarify the taxonomic relationship of both species because of their high phylogenetic relationship. 16S rRNA gene sequence comparisons demonstrated that these species share 100 % sequence similarity. Investigation of fatty acid patterns, substrate utilization, and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) profiles displayed no striking differences between the type strains of both species. DNA-DNA hybridization between both strains showed a 95 % (reciprocal 82 %) similarity, which clearly demonstrated that both strains are members of the same species. Due to priority of publication and validation of the name, Qingshengfania soli is reclassified as Pseudochelatococcus lubricantis, based on the estimated phylogenetic position derived from 16S rRNA gene sequence data, fatty acid, biochemical data, MALDI-TOF, and DNA-DNA hybridization results. PMID- 29757130 TI - Tranexamic acid to prevent post-partum haemorrhage. PMID- 29757131 TI - Red blood cell salvage analysis from clotted blood. AB - BACKGROUND: Blood clots discovered within body cavities intra-operatively are often manually broken up and placed in an autotransfusion device to recover autologous blood cells. This study evaluated the efficiency at which these red blood cells can be recovered from clot and to determine if these cells would be free of fibrin and clumping which might pose a risk of micro-emboli. MATERIALS AND METHODS: Whole blood was aliquoted into 25 mL volume samples. The blood was then allowed to clot, and after 24 hours the clotted blood was manually kneaded by hand for 1, 2, 3, or 5 minutes. One mL of the harvested blood was fixed and processed for scanning electron microscope imaging. Plasma from the rest of the sample was then separated and underwent spectrophotometry for analysis of relative free haemoglobin. RESULTS: Blood recovered from the clotted blood ranged from 60 to 80% as time increased from 1 to 5 minutes of kneading. Volume of erythrocytes recovered from 1 minute compared to 2 minutes was statistically significant but not significant between 2 minutes or any longer period of time. Imaging did not show any evidence of fibrin strands or significant cell fragmentation. Spectrophotometry showed a steady increase of observed absorption at 540 nm, indicative of free haemoglobin, as manual kneading time increased. DISCUSSION: Red blood cells were able to be efficiently recovered from clotted blood. Imaging studies did not show any evidence of red blood cells trapped within fibrin mesh. PMID- 29757132 TI - Safety and efficacy of tranexamic acid for prevention of obstetric haemorrhage: an updated systematic review and meta-analysis. AB - BACKGROUND: A number of clinical systematic review and meta-analysis have been published on the use of tranexamic in the obstetric setting. The aim of this meta analysis was to evaluate the safety and effectiveness of tranexamic acid in reducing blood loss when given prior to caesarean delivery. MATERIALS AND METHODS: We searched the Cochrane Wounds Specialized Register, Cochrane Central, MEDLINE (through PUBMED), Embase, and SCOPUS electronic databases. We also searched clinical trials registries for ongoing and unpublished studies, and checked reference lists to identify additional studies. We used no restrictions with respect to language and date of publication. Two review authors independently performed study selection, "Risk of bias" assessment, and data extraction. Initial disagreements were resolved by discussion, or by including a third review author when necessary. RESULTS: We found 18 randomised controlled trials (RCTs) that met our inclusion criteria. Overall, 1,764 women receiving intravenous tranexamic acid for prevention of bleeding following caesarean sections and 1,793 controls receiving placebo were enrolled in the 18 RCTs evaluated. The use of tranexamic acid compared to controls (placebo or no intervention) reduces post-partum haemorrhage >400 mL (risk ratio [RR] 0.40, 95% confidence interval [CI] 0.24-0.65; 5 trials with a total of 786 participants), severe post-partum haemorrhage >1,000 mL (RR 0.32, 95% CI: 0.12-0.84; 5 trials with a total of 1,850 participants), and need for red blood cell transfusion (RR 0.30, 95% CI: 0.18-0.49; 10 trials with a total of 1,873 participants). No particular safety concerns on the use of this antifibrinolytic agent emerged from the analysis of the 18 RCTs included. DISCUSSION: Overall, the results of this meta-analysis support the evidence of a beneficial effect of tranexamic acid in reducing blood loss and need for blood transfusion in pregnant women undergoing caesarean section. PMID- 29757133 TI - Haemolysis index for the screening of intravascular haemolysis: a novel diagnostic opportunity? AB - The diagnostic approach to patients with intravascular haemolysis remains challenging, since no first-line laboratory test seems to be entirely suitable for the screening of this condition. Recent evidence shows that an enhanced cell free haemoglobin (fHb) concentration in serum or plasma is a reliable marker of red blood cell injury, and may also predict clinical outcomes in patients with different forms of haemolytic anaemias. However, the routine use of the haemiglobincyanide assay, the current reference method for measuring fHb, seems unsuitable for a timely diagnosis of intravascular haemolysis, for many safety and practical reasons. The spectrophotometric assessment of fHb by means of the so-called haemolysis-index (H-index) has now become available in most clinical chemistry analysers. This measure allows an accurate, rapid and inexpensive assessment of fHb in a large number of serum or plasma samples, and its use has already proven to be useful for identifying some forms of haemolytic anaemias. Therefore, the aim of this article is to provide an update and a personal opinion about the potential clinical use of the H-index for screening patients with suspected intravascular haemolysis. PMID- 29757136 TI - On the cost-utility of methylene blue-photoinactivated plasma versus quarantine plasma in Spain. PMID- 29757135 TI - A nationwide retrospective study on prevalence of hepatitis E virus infection in Italian blood donors. AB - BACKGROUND: In Europe, hepatitis E virus (HEV) infection is mainly a food-borne zoonosis, but it can also be transmitted by blood transfusion. It is usually a mild and self-limited infection. However, immunocompromised persons, who are also those more likely to undergo blood transfusions, may develop chronic hepatitis and often cirrhosis. Since this is a potential threat to blood safety, we aimed to investigate HEV prevalence in Italian blood donors. MATERIALS AND METHODS: We used plasma donations collected during 2015-2016 by blood services (BS) scattered throughout the Italian regions and intended for the production of plasma-derived medicines. Plasma samples were tested for IgG and IgM anti-HEV and for HEV RNA using validated assays. Data concerning donor's age and sex, and the location of the BS were collected. RESULTS: A total of 10,011 plasma samples were tested. Overall IgG and IgM prevalence rates were 8.7 and 0.4%, respectively. No sample was HEV RNA-positive. IgG prevalence was significantly higher in males and in donors aged 44 years and over. IgG prevalence differed greatly according to region. Overall regional rates over 15% were found in Abruzzo and in Sardinia, and rates of 10-15% were found in Lazio, Umbria and the Marche. Considering IgG prevalence according to the province where the BS was located, rates over 30% were found in Sardinia and Abruzzo. Age, sex and donor's region of residence were independently associated with IgG positivity. BS location produced significant heterogeneity on prevalence rates within the regions. DISCUSSION: The detected IgG rate of 8.7% in this study represents one of the lowest seroprevalence rates reported among blood donors in Europe. Particularly high prevalence rates in some regions and provinces may be explained by local eating habits and/or intensive environmental HEV contamination. Before considering the introduction of HEV RNA screening for blood donations in Italy, further important issues should be addressed and prospective incidence and reliable cost-benefit studies are needed. PMID- 29757134 TI - Second-line therapy in paediatric warm autoimmune haemolytic anaemia. Guidelines from the Associazione Italiana Onco-Ematologia Pediatrica (AIEOP). PMID- 29757137 TI - Reversal of apixaban induced alterations in haemostasis by different coagulation factor concentrates in patients after hip or knee replacement surgery. AB - BACKGROUND: Apixaban is a direct oral anticoagulant (DOAC) with a specific inhibition of activated factor X (FXa). In case of bleeding or need of urgent surgery a direct antidote is not yet available. Off-label application of non specific haemostatic agents, such as prothrombin complex concentrate (PCC) and recombinant FVIIa (rFVIIa), has been reported to reverse the effects of apixaban in in vitro and animal studies. The aim of this study is to measure the reversal potential of PCC and rFVIIa in patients with prophylactic apixaban concentrations. MATERIAL AND METHODS: Whole blood from patients under prophylactic therapy with apixaban was spiked with two doses of PCC or rFVIIa. Thromboelastometry (ROTEM(r)), prothrombin time (PT), and activated partial prothrombin time (aPTT) were performed. RESULTS: Prolongations in PT and aPTT were corrected by the different concentrates with variable efficacies (PCC water' detector variant in which mass stopping-powers and microscopic interaction coefficients were set to those of water while preserving real material densities, and for a 'density -> 1' variant in which densities were set to 1 g cm-3, leaving mass stopping-powers and interaction coefficients at real levels. [Formula: see text] equalled 0.910 +/- 0.005 (2 standard deviations) for the real detector, was insignificantly different at 0.912 +/- 0.005 for the 'Z -> H2O' variant, but equalled 1.012 +/- 0.006 for the 'density -> 1' variant. For the 60017 diode in a 6 MV beam, then, [Formula: see text] was determined primarily by the detector's density rather than its atomic composition. Further calculations showed this remained the case in a 15 MV beam. Interestingly, the sensitive volume electron fluence was perturbed more by detector atomic composition than by density; however, the density-dependent perturbation varied with field-size, whereas the Z-dependent perturbation was relatively constant, little affecting [Formula: see text]. PMID- 29757159 TI - Sawtooth structure formation under nonlinear-regime ion bombardment. AB - Linear-regime Ar+ bombardment of Si produces symmetrical ripple structures at ion incidence angles above 45 degrees measured off-normal (Madi 2009 J. Phys.: Condens. Matter 21). In the nonlinear regime, new behaviors emerge. In this paper, we present experimental results of ion bombardment that continues into the nonlinear regime until pattern saturation at multiple ion incidence angles, showing the evolution of their grazing incidence small-angle x-ray scattering (GISAXS) spectra as well as atomic force microscopy topographs of the final, saturated structures. Asymmetric structures emerge parallel to the direction of the projected ion beam on the sample surface, constituting a height asymmetry not found in the linear regime. We then present simulations of surface height evolution under ion bombardment using a nonlinear partial differential equation developed by Pearson and Bradley (2015 J. Phys.: Condens. Matter 27 015010). We present simulated GISAXS spectra from these simulations, as well as simulated scattering from a sawtooth structure using the FitGISAXS software package (Babonneau 2010 J. Appl. Crystallogr. 43 929-36), and compare the simulated spectra to those observed experimentally. We find that these simulations reproduce many features of the sawtooth structures, as well as the nearly-flat final GISAXS spectra observed experimentally perpendicular to the sawtooth structures. However, the model fails to reproduce the final GISAXS spectra observed parallel to the sawtooth structures. PMID- 29757160 TI - Growth and quantum transport properties of vertical Bi2Se3 nanoplate films on Si substrates. AB - Controlling the growth direction (planar versus vertical) and surface-to-bulk ratio can lead to lots of unique properties for two-dimensional layered materials. We report a simple method to fabricate continuous films of vertical Bi2Se3 nanoplates on Si substrate and investigate the quantum transport properties of such films. In contrast to (001) oriented planar Bi2Se3 nanoplate film, vertical Bi2Se3 nanoplate films are enclosed by (015) facets, which possess high surface-to-bulk ratio that can enhance the quantum transport property of topological surface states. And by controlling the compactness of vertical Bi2Se3 nanoplates, we realized an effective tuning of the weak antilocalization effect from topological surface states in Bi2Se3 films. Our work paves a way for exploring the unique transport properties of this unconventional structure topological insulator film. PMID- 29757161 TI - Fast and straightforward analysis approach of charge transport data in single molecule junctions. AB - In this study, we introduce an efficient data sorting algorithm, including filters for noisy signals, conductance mapping for analyzing the most dominant conductance group and sub-population groups. The capacity of our data analysis process has also been corroborated on real experimental data sets of Au-1,6 hexanedithiol-Au and Au-1,8-octanedithiol-Au molecular junctions. The fully automated and unsupervised program requires less than one minute on a standard PC to sort the data and generate histograms. The resulting one-dimensional and two dimensional log histograms give conductance values in good agreement with previous studies. Our algorithm is a straightforward, fast and user-friendly tool for single molecule charge transport data analysis. We also analyze the data in a form of a conductance map which can offer evidence for diversity in molecular conductance. The code for automatic data analysis is openly available, well documented and ready to use, thereby offering a useful new tool for single molecule electronics. PMID- 29757163 TI - Novel secondary assembled micro/nano porous spheres ZnCo2O4 with superior electrochemical performances as lithium ion anode material. AB - In this work, novel secondary assembled micro/nano porous spheres ZnCo2O4 were firstly prepared by combining the hydrothermal method with post-synthesis calcinations. The structure and morphology of the obtained powder were characterized by x-ray powder diffraction and field emission-scanning electron microscopy. As the anode material of lithium-ion half-cells, the as-prepared ZnCo2O4 delivered a very high capacity, extra cycling stability and excellent rate capability. A discharge capacity of 950 mAh g-1 with up to 99.7% retention corresponding to the second cycle at 0.1 C was achieved after 90 cycles, which was an improved cyclability over previous reports. The higher current charge discharge and electrochemical impedance spectroscopy data indicate that the material's integrity was maintained. Therefore constructing the secondary assembled 3D micro/nano structure is an effective strategy to obtain the superior electrochemical performances. PMID- 29757162 TI - Effect of (1 1 1)-oriented strain on the structure and magnetic properties of La0.7Sr0.3MnO3 thin films. AB - Using strain, i.e. subtle changes in lattice constant in a thin film induced by the underlying substrate, opens up intriguing new ways to control material properties. We present a study of the effects of strain on structural and ferromagnetic properties of (1 1 1)pc-oriented La0.7Sr0.3MnO3 epitaxial thin films grown on NdGaO3, SrTiO3, and DyScO3 substrates. (The subscript pc denotes the pseudo-cubic symmetry.) The results show that La0.7Sr0.3MnO3 assumes a monoclinic unit cell on NdGaO3 and DyScO3 and a rhombohedral unit cell on SrTiO3. For La0.7Sr0.3MnO3 on NdGaO3 and DyScO3 a uniaxial magnetic anisotropy is found, while La0.7Sr0.3MnO3 on SrTiO3 is magnetically isotropic. The Neel model is used to explain the anisotropy of the thin films on NdGaO3 and SrTiO3, however, for La0.7Sr0.3MnO3 on DyScO3 the effect of octahedral rotations needs to be included through the single ion model. Through examination of the Curie temperature of the strained films we suggest that (1 1 1)-strain has a different effect on the Jahn Teller splitting of e g and t 2g electron levels than what is seen in (0 0 1)pc oriented La0.7Sr0.3MnO3 thin films. PMID- 29757164 TI - Real-time observation of slipping and rolling events in DLC wear nanoparticles. AB - Real-time observation of the actual contact area between surface interfaces at the nanoscale enables more precise examination of what happens during friction. We have combined micro electro mechanical system actuators and transmission electron microscopy (TEM) observation, to both apply and measure forces across nanoscale junctions and contacts. This custom-designed experimental system can measure the true surface area of a contact site from a lateral viewpoint, while simultaneously measuring the friction force. We scratched surfaces coated with diamond like carbon, a classical solid lubricant, and observed the formation of wear particles that slipped and rolled between the interface. TEM images showed that the shape of the surface at the nanoscale underwent permanent deformation when acted upon with forces as low as several tens of nano newtons. The results demonstrated the limitations of friction analyses relying on friction force measurements without real-time surface profiling. PMID- 29757165 TI - Absence of 2.5 power law for fractal packing in metallic glasses. AB - Atomic packing is still a mystery for topologically disordered amorphous solids owing primarily to the absence of Bragg diffraction in this class of materials. Among many hypotheses, fractal packing is suggested based on a scaling relation with '2.5 power law' found in multicomponent metallic glasses. Here we examine the atomic packing critically in a pure Tantalum metallic glass under hydrostatic pressure. Without complications of chemical compositions as in the multicomponent systems, the genuine amorphous structure along in the single component metallic glass exhibits a cubic scaling exponent that indicates absence of the 2.5 power law. However, fractal-like short- and medium-range icosahedral cluster packing is observed; but these substructures do not contribute to the fractal dimension through the power law scaling. PMID- 29757166 TI - Structural, electronic and vibrational properties of LaF3 according to density functional theory and Raman spectroscopy. AB - Crystal structure of LaF3 single crystal is refined in tysonite-type trigonal unit cell P [Formula: see text] c1 using density functional theory calculations and Raman spectroscopy. It is shown that trigonal structure with P [Formula: see text] c1 space group is more energy-efficient than hexagonal structure with space group P63 cm. Simulated Raman spectra obtained using LDA approximation is in much better agreement with experimental data than that obtained with PBE and PBEsol functionals of GGA. The calculated frequency value of silent mode B 2 in case of hexagonal structure P63 cm was found to be imaginary (unstable mode), thus the energy surface obtains negative curvature with respect to the corresponding normal coordinates of the mode which leads to instability of the hexagonal structure in harmonic approximation. The A 1g line at 214 cm-1 in Raman spectra of LaF3 related to the translation of F2 ions along c axis can be connected with F2 ionic conductivity. PMID- 29757167 TI - Understanding photoluminescence of metal nanostructures based on an oscillator model. AB - Scattering and absorption properties of metal nanostructures have been well understood based on the classic oscillator theory. Here, we demonstrate that photoluminescence of metal nanostructures can also be explained based on a classic model. The model shows that inelastic radiation of an oscillator resembles its resonance band after external excitation, and is related to the photoluminescence from metallic nanostructures. The understanding based on the classic oscillator model is in agreement with that predicted by a quantum electromagnetic cavity model. Moreover, by correlating a two-temperature model and the electron distributions, we demonstrate that both one-photon and two photon luminescence of the metal nanostructures undergo the same mechanism. Furthermore, the model explains most of the emission characteristics of the metallic nanostructures, such as quantum yield, spectral shape, excitation polarization and power dependence. The model based on an oscillator provides an intuitive description of the photoluminescence process and may enable rapid optimization and exploration of the plasmonic properties. PMID- 29757168 TI - The rate of denitrification using hydrodynamically disintegrated excess sludge as an organic carbon source. AB - This study investigates the potential of hydrodynamically disintegrated excess activated sludge when used as a supplementary carbon source for denitrification. Two objectives constituted this study: (i) to analyse the denitrification rate by using excess sludge subjected to hydrodynamic disintegration (HD), performed at different energy densities, as an organic carbon source, and (ii) to analyse the impact of hydrolysis of disintegrated sludge on the denitrification rate. Nitrate reduction tests were conducted to assess the denitrification rate for the following sources of organic carbon: thickened excess sludge disintegrated at three levels of energy density (70, 140 and 210 kJ/L), acetic acid solution and municipal wastewater after mechanical treatment. It was found that the HD of excess sludge conducted at different levels of energy density led to dissolved organic compounds characterised by various properties as donors of H+ in the denitrification process. The susceptibility of disintegrated sludge to anaerobic hydrolysis decreased along with the increasing energy density. The obtained organic carbon contributed to a lower increase in the denitrification rate in comparison to that when disintegrated sludge not subjected to hydrolysis was applied. PMID- 29757169 TI - Comparison of the degradation of molecular and ionic ibuprofen in a UV/H2O2 system. AB - The advanced oxidation technologies based on *OH can effectively degrade the pharmaceutical and personal care products under operating conditions of normal temperature and pressure. In this study, direct photolysis of ibuprofen (IBU) is slow due to the relatively low molar extinction coefficient and quantum yield. Compared to direct photolysis, the degradation kinetics of IBU was significantly enhanced in the UV/H2O2 system, mainly by *OH radical mediated oxidation. In the UV/H2O2 system, the degradation rate of ionic IBU was slightly faster than that of the molecular form. Kinetic analysis showed that the second-order reaction rate constant of ionic IBU (5.51 * 109 M-1 s-1) was higher than that of the molecular form (3.43 * 109 M-1 s-1). The pseudo first-order rate constant for IBU degradation (kobs) increased with increasing H2O2 dosage. kobs can be significantly decreased in the presence of natural organic matter (NOM), which is due to (i) NOM radical scavenging effects (dominant role) and (ii) UV absorption. The degradation of IBU was inhibited by HCO3-, which was attributed to its scavenging effect. Interestingly, when NO3- was present in aqueous solution, a slight increase in the degradation rate was observed, which was due to NO3- absorbing photons to generate *OH at a low quantum yield. No obvious effects were observed when SO42 and Cl- were present. PMID- 29757170 TI - Combining classifiers to detect faults in wastewater networks. AB - This work presents a methodology for automatic detection of structural faults in sewers from CCTV footage, which has been improved by combining the outputs of different machine learning techniques. The predictions of support vector machine and random forest classifiers are combined using three distinct techniques: 'both', 'most likely' and 'stacking'. Each technique is tested on CCTV data taken from real surveys covering a range of pipes at locations in the south-west of the UK. The best tested technique, stacking, offers a 5% increase in accuracy for minimal impact in efficiency, proving useful for future development and implementation of the fault detection methodology. PMID- 29757171 TI - The application of an efficient modified decolorizer in coagulation treatment of high color reclaimed water. AB - High color concentrations in inflows at reclaimed water treatment plants are typically considered as emergency situations, which must be solved using an appropriate decolorizing process. Using the decoloration mechanism of a modified dicyandiamide-formaldehyde polymer (DFP), a urea-formaldehyde polymer and a melamine-formaldehyde polymer (MFP) were prepared with ammonium chloride and ammonium sulfate as the modifiers. An orthogonal experiment indicated that a modified urea-formaldehyde polymer had no effect on decolorization; however, the MFP modified by ammonium chloride in number 16 (MMFP-C16), the DFP modified by ammonium chloride in number 9 (MDFP-C9) and modified by ammonium sulfate in number 6 (MDFP-S6) were successful. The removal rates were above 50% in acidic and reactive dye reclaimed water. Fourier transform infrared spectroscopy was used to microscopically analyze the differences in decolorization effect among the polymers. The effect of pH on decolorization was analyzed. Compared to the MDFP-C9 and MDFP-S6, the MMFP-C16 was not sensitive to changes in conditions. The pilot plant test proved that the three optimal decolorizers also had a good decolorizing effect, and MMFP-C16 was better both at decolorizing and floc sedimentation. Thus, the latter can be considered as an efficient modified decolorizer for rapid treatment of high color reclaimed water. PMID- 29757172 TI - Spectrophotometric determination of triclosan based on diazotization reaction: response surface optimization using Box-Behnken design. AB - A spectrophotometric method based on diazotization of aniline with triclosan has been developed for the determination of triclosan in water samples. The diazotization process involves two steps: (1) reaction of aniline with sodium nitrite in an acidic medium to form diazonium ion and (2) reaction of diazonium ion with triclosan to form a yellowish-orange azo compound in an alkaline medium. The resulting yellowish-orange product has a maximum absorption at 352 nm which allows the determination of triclosan in aqueous solution in the linear concentration range of 0.1-3.0 MUM with R2 = 0.998. The concentration of hydrochloric acid, sodium nitrite, and aniline was optimized for diazotization reaction to achieve good spectrophotometric determination of triclosan. The optimization of experimental conditions for spectrophotometric determination of triclosan in terms of concentration of sodium nitrite, hydrogen chloride and aniline was also carried out by using Box-Behnken design of response surface methodology and results obtained were in agreement with the experimentally optimized values. The proposed method was then successfully applied for analyses of triclosan content in water samples. PMID- 29757173 TI - The increase of process stability in removing ammonia nitrogen from wastewater. AB - This work focuses on the removal of ammonia nitrogen pollution from wastewaters in a two-stage laboratory model based on a combination of the nitritation and anammox processes with the biomass immobilized in a polyvinyl alcohol (PVA) matrix. Owing to the immobilization approach inside the PVA pellets, the bacterial activity remained nearly unchanged on an abrupt change in the environmental conditions. The nitritation kinetics were significantly dependent on the dissolved oxygen concentration. The critical dissolved oxygen concentration at which the nitritation process using the immobilized bacterial culture stops is 0.6 mg/L. The volumetric rate of nitrogen removal by the anammox bacteria was 158 mg/(L.d). The technology presented is well-suited for removing high ammonia nitrogen concentrations (>=300 mg/L). PMID- 29757174 TI - Magnetic solid-phase extraction for the analysis of bisphenol A, naproxen and triclosan in wastewater samples. AB - Magnetic Fe3O4 graphene oxide nanocomposite was synthesized by chemical coprecipitation method and characterized by scanning electron microscopy, Fourier transform infrared spectra and X-ray diffraction. A simple, rapid, convenient and environmentally friendly method was developed for separation and pre concentration of trace amounts of bisphenol A, naproxen and triclosan in wastewater samples by high performance liquid chromatography with magnetic Fe3O4 graphene oxide nanocomposite as the adsorbent for magnetic solid-phase extraction. Various parameters possibly influencing the extraction performance such as amount of the adsorbent, extraction time, sample pH and elution conditions were optimized. Under the optimal working conditions, the developed method showed good linearity (R > 0.9997) in the range of 1-200 MUg/L, and the limits of detection are between 0.5 and 0.8 MUg/L. The enrichment factors are in the range of 81-89. The repeatability of the method, expressed as relative standard deviation, is 3.36-4.26%. PMID- 29757175 TI - Techno-economic evaluation of simultaneous production of extra-cellular polymeric substance (EPS) and lipids by Cloacibacterium normanense NK6 using crude glycerol and sludge as substrate. AB - This study used the technical, economic analysis tool, SuperPro designer in evaluating a novel technology for simultaneous production of extracellular polymeric substance (EPS) and biodiesel using crude glycerol and secondary sludge. As renewable energy sources are depleting, the process utilizes municipal sewage sludge for production of EPS and biodiesel along with crude glycerol, which is a waste byproduct of biodiesel industry providing an alternate way for disposal of municipal sludge and crude glycerol. Newly isolated Cloacibacterium normanense NK6 is used as micro-organism in the study as it is capable of producing high EPS concentration, using activated sludge and crude glycerol as the sole carbon source. The technology has many environmental and economic advantages like the simultaneous production of two major products: EPS and lipids. Sensitivity analysis of the process revealed that biomass lipid content is a most significant factor where unit cost production of biodiesel was highly sensitive to lipid content during bioreaction. B7 biodiesel unit production cost can be lowered from $1 to $0.6 if the lipid content of the biomass is improved by various process parameter modifications. PMID- 29757176 TI - Benchmarking of energy consumption in municipal wastewater treatment plants - a survey of over 200 plants in Italy. AB - One of the largest surveys in Europe about energy consumption in Italian wastewater treatment plants (WWTPs) is presented, based on 241 WWTPs and a total population equivalent (PE) of more than 9,000,000 PE. The study contributes towards standardised resilient data and benchmarking and to identify potentials for energy savings. In the energy benchmark, three indicators were used: specific energy consumption expressed per population equivalents (kWh PE-1 year-1), per cubic meter (kWh/m3), and per unit of chemical oxygen demand (COD) removed (kWh/kgCOD). The indicator kWh/m3, even though widely applied, resulted in a biased benchmark, because highly influenced by stormwater and infiltrations. Plants with combined networks (often used in Europe) showed an apparent better energy performance. Conversely, the indicator kWh PE-1 year-1 resulted in a more meaningful definition of a benchmark. High energy efficiency was associated with: (i) large capacity of the plant, (ii) higher COD concentration in wastewater, (iii) separate sewer systems, (iv) capacity utilisation over 80%, and (v) high organic loads, but without overloading. The 25th percentile was proposed as a benchmark for four size classes: 23 kWh PE-1 y-1 for large plants > 100,000 PE; 42 kWh PE-1 y-1 for capacity 10,000 < PE < 100,000, 48 kWh PE-1 y-1 for capacity 2,000 < PE < 10,000 and 76 kWh PE-1 y-1 for small plants < 2,000 PE. PMID- 29757178 TI - New insights into the humic acid fouling mechanism of ultrafiltration membranes for different Ca2+ dosage ranges: results from micro- and macro-level analyses. AB - To reveal the mechanisms of the influence of Ca2+ on membrane fouling with humic acid (HA), the adhesion forces of HA with both other HA molecules and the membrane, the HA fouling layer structure, HA fouling experiments, and the HA rejections at a wide range of Ca2+ dosages were investigated. The results indicated that the effect of Ca2+ on HA fouling can be divided into three stages. At lower ionic strength (IS) of CaCl2, the change in electrostatic forces is the main factor in controlling HA fouling behavior; i.e., increasing Ca2+ dosages resulted in more serious membrane fouling. When the IS of CaCl2 reached 10 mM, HA aggregates became the dominant factor in the fouling process, which could result in a porous fouling layer accompanied by less membrane fouling. Interestingly, much weaker membrane fouling was observed when the IS increased to 100 mM and the HA rejection began to decline. This was because a stronger hydration repulsion force was generated, which could weaken the compactness of the fouling layer and the adhesion forces of HA with both the membrane and HA, while enabling smaller sized HA to pass more easily into the permeate, which led to less membrane fouling and a lower HA rejection. PMID- 29757179 TI - Low-dissolved-oxygen nitrification in tropical sewage: an investigation on potential, performance and functional microbial community. AB - Intensive aeration for nitrification is a major energy consumer in sewage treatment plants (STPs). Low-dissolved-oxygen (low-DO) nitrification has the potential to lower the aeration demand. However, the applicability of low-DO nitrification in the tropical climate is not well-understood. In this study, the potential of low-DO nitrification in tropical setting was first examined using batch kinetic experiments. Subsequently, the performance of low-DO nitrification was investigated in a laboratory-scale sequential batch reactor (SBR) for 42 days using real tropical sewage. The batch kinetic experiments showed that the seed sludge has a relatively high oxygen affinity. Thus, the rate of nitrification was not significantly reduced at low DO concentrations (0.5 mg/L). During the operation of the low-DO nitrification SBR, 90% of NH4-N was removed. The active low-DO nitrification was mainly attributed to the limited biodegradable organics in the sewage. Fluorescence in-situ hybridisation and 16S rRNA amplicon sequencing revealed the nitrifiers were related to Nitrospira genus and Nitrosomonadaceae family. Phylogenetic analysis suggests 47% of the operational taxonomic units in Nitrospira genus are closely related to a comammox bacteria. This study has demonstrated active low-DO nitrification in tropical setting, which is a more sustainable process that could significantly reduce the energy footprint of STPs. PMID- 29757177 TI - Formation of aerobic granular sludge and the influence of the pH on sludge characteristics in a SBR fed with brewery/bottling plant wastewater. AB - A laboratory-scale sequencing batch reactor (SBR) was operated for 450 days to assess aerobic granule formation when treating brewery/bottling plant wastewater by consistent application of a feast/famine regime. The experiment was divided into three major periods according to the different operational conditions: (I) no pH control and strong fluctuations in organic loading rate (OLR) (1.18 +/- 0.25 kgCOD.(m3.day)-1), (II) pH control and aeration control strategy to reduce OLR fluctuations (1.45 +/- 0.65 kgCOD.(m3.day)-1) and (III) no pH control and stable OLR (1.42 +/- 0.18 kgCOD.(m3.day)-1). Aerobic granule formation was successful after 80 days and maintained during the subsequent 380 days. The aerobic granular sludge was characterized by SVI5 and SVI30 values below 60 mL.g 1 and dominated by granular, dense structures. An oxygen uptake rate based aeration control strategy insured endogenous respiration at the end of the aerobic phase, resulting in stable SBR operation when the influent composition fluctuated. The quantitative polymerase chain reaction results show no significant enrichment of Accumulibacter or Competibacter during the granulation process. The 16S rRNA sequencing results indicate enrichment of other, possibly important species during aerobic granule formation while treating brewery wastewaters. PMID- 29757180 TI - Application of dielectric constant measurement in microwave sludge disintegration and wastewater purification processes. AB - It has been numerously verified that microwave radiation could be advantageous as a pre-treatment for enhanced disintegration of sludge. Very few data related to the dielectric parameters of wastewater of different origins are available; therefore, the objective of our work was to measure the dielectric constant of municipal and meat industrial wastewater during a continuous flow operating microwave process. Determination of the dielectric constant and its change during wastewater and sludge processing make it possible to decide on the applicability of dielectric measurements for detecting the organic matter removal efficiency of wastewater purification process or disintegration degree of sludge. With the measurement of dielectric constant as a function of temperature, total solids (TS) content and microwave specific process parameters regression models were developed. Our results verified that in the case of municipal wastewater sludge, the TS content has a significant effect on the dielectric constant and disintegration degree (DD), as does the temperature. The dielectric constant has a decreasing tendency with increasing temperature for wastewater sludge of low TS content, but an adverse effect was found for samples with high TS and organic matter contents. DD of meat processing wastewater sludge was influenced significantly by the volumetric flow rate and power level, as process parameters of continuously flow microwave pre-treatments. It can be concluded that the disintegration process of food industry sludge can be detected by dielectric constant measurements. From technical purposes the applicability of dielectric measurements was tested in the purification process of municipal wastewater, as well. Determination of dielectric behaviour was a sensitive method to detect the purification degree of municipal wastewater. PMID- 29757181 TI - Use of life cycle assessment to evaluate environmental impacts associated with the management of sludge and biogas. AB - Upflow anaerobic sludge blanket (UASB) reactors used in sewage treatment generate two by-products that can be reused: sludge and biogas. At the present time in Brazil, most of this resulting sludge is disposed of in sanitary landfills, while biogas is commonly burned off in low-efficiency flares. The aim of the present study was to use life cycle assessment to evaluate the environmental impacts from four different treatment and final destination scenarios for the main by-products of wastewater treatment plants. The baseline scenario, in which the sludge was sanitized using prolonged alkaline stabilization and, subsequently, directed toward agricultural applications and the biogas destroyed in open burners, had the most impact in the categories of global warming, terrestrial ecotoxicity, and human non-carcinogenic toxicity. The scenario in which heat resulting from biogas combustion is used to dry the sludge showed significant improvements over the baseline scenario in all the evaluated impact categories. The recovery of heat from biogas combustion decreased significantly the environmental impact associated with global warming. The combustion of dried sludge is another alternative to improve the sludge management. Despite the reduction of sludge volume to ash, there are environmental impacts inherent to ozone formation and terrestrial acidification. PMID- 29757182 TI - Nitrate removal from aquaculture effluents using woodchip bioreactors improved by adding sulfur granules and crushed seashells. AB - This study examined the effects on nitrate removal when adding sulfur granules and crushed seashells to a woodchip bioreactor treating aquaculture effluents. Using a central composite design, the two components were added at three levels (0.000, 0.125 and 0.250 m3/m3 bioreactor volume) to 13 laboratory-scale woodchip bioreactors, and a response surface method was applied to find and model the optimal mixture ratios with respect to reactor performance. Adding 0.125 m3/m3 sulfur granules improved the total N removal rate from 3.27 +/- 0.38 to 8.12 +/- 0.49 g N/m3/d compared to pure woodchips. Furthermore, the inclusion of crushed seashells together with sulfur granules helped to maintain the pH above 7.4 and prevent a production (i.e., release) of nitrite. According to the modeled response surfaces, a sulfur granule:crushed seashell:woodchip mixture ratio containing about 0.2 m3 sulfur granules and 0.1 m3 crushed seashells per m3 reactor volume would give the best results with respect to high N removal and minimal nitrite release. In conclusion, the study showed that N removal in woodchip bioreactors may be improved by adding sulfur granules and seashells, contributing to the optimization of woodchip performance in treating aquaculture effluents. PMID- 29757184 TI - The influence of antibiotics on wastewater treatment processes and the development of antibiotic-resistant bacteria. AB - The influence of antibiotics, namely doxycycline, gentamicin, penicillin, nitrofurantoin, and rifampicin, on wastewater treatment was assessed. The presence of 100-300 MUg/L of antibiotics (63.52-134.41 mg/g.d.w.d) marginally influenced organic matter degradation, without impacting nitrogen or phosphorus concentrations. However, a significant increase in the number of antibiotic resistant bacteria was observed, which varied with different antibiotics. The largest number of bacteria became resistant to nitrofurantoin and penicillin. After the process, some multi-resistant strains were isolated from the sludge. Two of them revealed the activity of carbapenamase, the enzyme directly related to resistance against beta-lactam antibiotics. PMID- 29757183 TI - Porous PVDF/PANI ion-exchange membrane (IEM) modified by polyvinylpyrrolidone (PVP) and lithium chloride in the application of membrane capacitive deionisation (MCDI). AB - In this work, polyvinylidene fluoride (PVDF)/polyaniline (PANI) heterogeneous anion-exchange membranes filled with pore-forming agents polyvinylpyrrolidone (PVP) and lithium chloride were prepared by the solution-casting technique using the solvent 1-methyl-2-pyrrolidone (NMP) and a two-step phase inversion procedure. Key properties of the as-prepared membranes, such as hydrophilicity, water content, ion exchange capacity, fixed ion concentration, conductivity and transport number were examined and compared between membranes in different conditions. The pore-forming hydrophilic additives PVP and lithium chloride to the casting solution appeared to improve the ion-exchange membranes (IEMs) by increasing the conductivity, transport number and hydrophilicity. The effects of increasing membrane drying time on the porosity of the as-prepared membranes were found to lower membrane porosity by reducing membrane water content. However, pore-forming agents were found to be able to stabilise membrane transport number with different drying times. As-prepared PVDF/PANI anion-exchange membrane with pore-forming agent is demonstrated to be a more efficient candidate for water purification (e.g. desalination) and other industrial applications. PMID- 29757186 TI - Evaluating the excess sludge reduction in activated sludge system with ultrasonic treatment. AB - Ultrasonic treatment for enhancing biological processes has recently attracted considerable attention in wastewater treatment. In this study, we systematically investigated the mixed liquor properties of activated sludge under ultrasonic treatment. The sludge samples were collected from the aerobic tank of a full scale membrane bioreactor (MBR) treating municipal wastewater, and the volatile suspended solids (VSS) concentration was approximately 6.0 g/L. The results showed that ultrasonic treatment induced floc disintegration, organics release, temperature increase, microbial activity and pH variation. The maximum mg soluble chemical oxygen demand (COD) per mg VSS released was estimated to be 0.147 using the Monod equation. The exponential increase in the concentration of dissolved organic matter is related to the loss of relative heterotrophic bacterial activity. A sonolysis-cryptic growth model was demonstrated to be capable of describing ultrasonic sludge reduction, which would support the further development of ultrasonic treatment technology in activated sludge systems. PMID- 29757185 TI - Adsorbing low concentrations of Cr(VI) onto CeO2@ZSM-5 and the adsorption kinetics, isotherms and thermodynamics. AB - The CeO2@ZSM-5 was prepared by the dipping method. We used ZSM-5 and CeO2 as the carrier and load components, respectively. The aim was to reduce the low concentration of Cr(VI) in simulated wastewater (the concentration of Cr(VI) ranged from 0.2 to 1 mg/L). The characteristics of ZSM-5 and CeO2@ZSM-5 samples were determined by X-ray powder diffraction (XRD), scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR) and Brunauer Emmett-Teller (BET). Characterization results showed that the particle size, BET surface area and pore volume for CeO2@ZSM-5 was around 0.783 nm, 421.307 m2/g and 0.313 m3/g, respectively. In addition, the optimum conditions were obtained by the orthogonal test, and the details were as follows: optimal pH, adsorbent dose, initial concentration of Cr(VI) and equilibrium time were 3, 5 g/L, 0.6 mg/L and 70 min respectively. The removal of Cr(VI) was 99.56% in these conditions. The pseudo-second-order model best described the adsorption kinetics of Cr(VI) onto CeO2@ZSM-5. Isotherm data were treated according to Langmuir, Freundlich and Temkin isotherm models. The results showed that the Freundlich adsorption isotherm model fitted best in the temperature range studied. Adsorption capacity increased with temperature, showing the endothermic nature of Cr(VI) adsorption. The desorption results showed the best recovery of Cr(VI) using 0.1 M HCl. PMID- 29757187 TI - Sewer catchment effects on wastewater and biosolids odour management. AB - The composition of wastewater in sewer catchments is known to affect the performance of wastewater treatment plants (WWTPs). However, there is limited knowledge as to how catchment characteristics, such as types of catchment industries, impact odour emissions from downstream sludge processing and biosolids management. Odorous emissions from biosolids processing at WWTPs can represent a significant community impact when the local population is exposed to odours. The main odorants emitted from biosolids are volatile sulfur compounds (VSCs), however, volatile organic compounds (VOCs) in emissions may also be perceptable after the removal of VSCs in odour abatement systems. Types of compounds present in emissions throughout biosolids processing at five WWTPs of varying sizes and levels of treatment (primary only and primary and secondary) were analysed. The ratio of total VSCs to VOCs in emissions, and the sensorial importance of each class varied between the sites. As a number of the VOCs in emissions were of industrial origin, this variation is likely dependent on industrial flows into the upstream sewer catchment. The impact of different emission compositions on both activated carbon and biologically based odour abatement systems were discussed. PMID- 29757188 TI - MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. AB - Immune imbalance of T lymphocyte subsets is a hallmark of psoriasis, but the molecular mechanisms underlying this aspect of psoriasis pathology are poorly understood. Here, we report that microRNA-210 (miR-210), a miR that is highly expressed in both psoriasis patients and mouse models, induces helper T (Th) 17 and Th1 cell differentiation but inhibits Th2 differentiation through repressing STAT6 and LYN expression, contributing to several aspects of the immune imbalance in psoriasis. Both miR-210 ablation in mice and inhibition of miR-210 by intradermal injection of antagomir-210 blocked the immune imbalance and the development of psoriasis-like inflammation in an imiquimod-induced or IL-23 induced psoriasis-like mouse model. We further showed that TGF-beta and IL-23 enhance miR-210 expression by inducing HIF-1alpha, which recruits P300 and promotes histone H3 acetylation in the miR-210 promoter region. Our results reveal a crucial role for miR-210 in the immune imbalance of T lymphocyte subsets in psoriasis and suggest a potential therapeutic avenue. PMID- 29757190 TI - Reversing the curse on PPARgamma. AB - Thiazolidinediones (TZDs) are the only antidiabetic drugs that reverse insulin resistance. They have been a valuable asset in the treatment of type 2 diabetes, but their side effects have curtailed widespread use in the clinic. In this issue of the JCI, Kraakman and colleagues provide evidence that deacetylation of the nuclear receptor PPARgamma improves the therapeutic index of TZDs. These findings should revitalize the quest to employ insulin sensitization as a first-line approach to managing type 2 diabetes. PMID- 29757189 TI - Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B. AB - Notch 1/2 genes play tumor-suppressing functions in squamous cell carcinoma (SCC), a very common malignancy in skin and internal organs. In contrast with Notch, we show that the transcription factor CSL (also known as RBP-Jkappa), a key effector of canonical Notch signaling endowed with intrinsic transcription repressive functions, plays a tumor-promoting function in SCC development. Expression of this gene decreased in upper epidermal layers and human keratinocytes (HKCs) undergoing differentiation, while it increased in premalignant and malignant SCC lesions from skin, head/neck, and lung. Increased CSL levels enhanced the proliferative potential of HKCs and SCC cells, while silencing of CSL induced growth arrest and apoptosis. In vivo, SCC cells with increased CSL levels gave rise to rapidly expanding tumors, while cells with silenced CSL formed smaller and more differentiated tumors with enhanced inflammatory infiltrate. Global transcriptomic analysis of HKCs and SCC cells with silenced CSL revealed major modulation of apoptotic, cell-cycle, and proinflammatory genes. We also show that the histone demethylase KDM6B is a direct CSL-negative target, with inverse roles of CSL in HKC and SCC proliferative capacity, tumorigenesis, and tumor-associated inflammatory reaction. CSL/KDM6B protein expression could be used as a biomarker of SCC development and indicator of cancer treatment. PMID- 29757191 TI - Disease-driving CD4+ T cell clonotypes persist for decades in celiac disease. AB - Little is known about the repertoire dynamics and persistence of pathogenic T cells in HLA-associated disorders. In celiac disease, a disorder with a strong association with certain HLA-DQ allotypes, presumed pathogenic T cells can be visualized and isolated with HLA-DQ:gluten tetramers, thereby enabling further characterization. Single and bulk populations of HLA-DQ:gluten tetramer-sorted CD4+ T cells were analyzed by high-throughput DNA sequencing of rearranged TCR alpha and -beta genes. Blood and gut biopsy samples from 21 celiac disease patients, taken at various stages of disease and in intervals of weeks to decades apart, were examined. Persistence of the same clonotypes was seen in both compartments over decades, with up to 53% overlap between samples obtained 16 to 28 years apart. Further, we observed that the recall response following oral gluten challenge was dominated by preexisting CD4+ T cell clonotypes. Public features were frequent among gluten-specific T cells, as 10% of TCR-alpha, TCR beta, or paired TCR-alphabeta amino acid sequences of total 1813 TCRs generated from 17 patients were observed in 2 or more patients. In established celiac disease, the T cell clonotypes that recognize gluten are persistent for decades, making up fixed repertoires that prevalently exhibit public features. These T cells represent an attractive therapeutic target. PMID- 29757192 TI - CD155 loss enhances tumor suppression via combined host and tumor-intrinsic mechanisms. AB - Critical immune-suppressive pathways beyond programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) require greater attention. Nectins and nectin like molecules might be promising targets for immunotherapy, since they play critical roles in cell proliferation and migration and exert immunomodulatory functions in pathophysiological conditions. Here, we show CD155 expression in both malignant cells and tumor-infiltrating myeloid cells in humans and mice. Cd155-/- mice displayed reduced tumor growth and metastasis via DNAM-1 upregulation and enhanced effector function of CD8+ T and NK cells, respectively. CD155-deleted tumor cells also displayed slower tumor growth and reduced metastases, demonstrating the importance of a tumor-intrinsic role of CD155. CD155 absence on host and tumor cells exerted an even greater inhibition of tumor growth and metastasis. Blockade of PD-1 or both PD-1 and CTLA4 was more effective in settings in which CD155 was limiting, suggesting the clinical potential of cotargeting PD-L1 and CD155 function. PMID- 29757194 TI - The expanding constellation of immune checkpoints: a DNAMic control by CD155. AB - The clinical benefits that have been achieved for a group of cancer patients with metastatic disease on checkpoint inhibitor therapy have kindled intense interest in understanding tumor-induced escape from T lymphocyte control. Other lymphoid cells also participate in tumor control; in particular, NK cells can limit hematogenous cancer metastasis spread and are also subject to negative regulation by developing cancers. In this issue of the JCI, Li and colleagues define an unanticipated role for the stress-induced protein CD155 in cancer metastasis. The presence of CD155 on the surface of cancer cells was shown to promote tumor invasiveness, while its upregulation in tumor environment-infiltrating myeloid cells restrained antitumor immunity by impairing antitumor T lymphocytes and NK cell function. Together, these results support further exploration of strategies for targeting CD155. PMID- 29757193 TI - Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation. AB - Eya proteins are critical developmental regulators that are highly expressed in embryogenesis but downregulated after development. Amplification and/or re expression of Eyas occurs in many tumor types. In breast cancer, Eyas regulate tumor progression by acting as transcriptional cofactors and tyrosine phosphatases. Intriguingly, Eyas harbor a separate threonine (Thr) phosphatase activity, which was previously implicated in innate immunity. Here we describe what we believe to be a novel role for Eya3 in mediating triple-negative breast cancer-associated immune suppression. Eya3 loss decreases tumor growth in immune competent mice and is associated with increased numbers of infiltrated CD8+ T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased CD8+ T cell signature. Our data uncover a role for Eya3 in mediating tumor-associated immune suppression, and suggest that its inhibition may enhance checkpoint therapies. PMID- 29757195 TI - Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. AB - Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies. PMID- 29757197 TI - Pharmacological Treatment for Long-Term Patients with Schizophrenia and Its Effects on Sleep in Daily Clinical Practice: A Pilot Study. AB - Background: Pharmacological treatment is still the key intervention in the disease management of long-term patients with schizophrenia; however, how it affects sleep and whether gender differences exist remains unclear. Methods: Forty-six long-term outpatients with schizophrenia entered the study. The numbers of antipsychotics, sleep medications, antidepressants, and anxiolytics were analyzed. Moreover, all patients were tested using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). Correlation analyses were conducted between the medication used and the scores on the two subjective sleep inventories. Results: A large variability, ranging from 0 to 8, in the total number of psychiatric drugs per person was found between the patients. Despite ongoing pharmacological treatment, the patients scored high on the PSQI, but not on the ESS; this indicates that they report problems with sleep, but not with daytime sleepiness. A significant positive correlation between the use of antipsychotics and the ESS score, but not the PSQI score, was found; moreover, no gender differences were found. Conclusions: A large variability exists in the pharmacological treatment of long-term patients with schizophrenia. To date, patients' sleep problems have been insufficiently treated, and gender differences have not been adequately accounted for in the pharmacological treatment of schizophrenia. More and larger international clinical studies are warranted to verify the findings of the present preliminary pilot study before any firm conclusions can be drawn and before any changes to the drug treatment of male and female patients with schizophrenia can be recommended. PMID- 29757198 TI - Drug Delivery System for Emodin Based on Mesoporous Silica SBA-15. AB - In this study mesoporous silica SBA-15 was evaluated as a vehicle for the transport of cytotoxic natural product emodin (EO). SBA-15 was loaded with different quantities of EO (SBA-15|EO1-SBA-15|EO5: 8-36%) and characterized by traditional methods. Several parameters (stabilities) and the in vitro behavior on tumor cell lines (melanoma A375, B16 and B16F10) were investigated. SBA-15 suppresses EO release in extremely acidic milieu, pointing out that EO will not be discharged in the stomach. Furthermore, SBA-15 protects EO from photodecomposition. In vitro studies showed a dose dependent decrease of cellular viability which is directly correlated with an increasing amount of EO in SBA-15 for up to 27% of EO, while a constant activity for 32% and 36% of EO in SBA-15 was observed. Additionally, SBA-15 loaded with EO (SBA-15|EO3) does not disturb viability of peritoneal macrophages. SBA-15|EO3 causes inhibition of tumor cell proliferation and triggers apoptosis, connected with caspase activation, upregulation of Bax, as well as Bcl-2 and Bim downregulation along with amplification of poly-(ADP-ribose)-polymerase (PARP) cleavage fragment. Thus, the mesoporous SBA-15 is a promising carrier of the water-insoluble drug emodin. PMID- 29757196 TI - Leukotriene receptors as potential therapeutic targets. AB - Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets. PMID- 29757199 TI - Supporting Mothers of Very Preterm Infants and Breast Milk Production: A Review of the Role of Galactogogues. AB - Human milk, either mother’s own milk or donor human milk, is recommended as the primary source of nutrition for very preterm infants. Initiatives should be in place in neonatal units to provide support to the mother as she strives to initiate and maintain a supply of breast milk for her infant. The use of galactogogues are considered when these initiatives alone may not be successful in supporting mothers in this endeavor. Although there are non-pharmacologic compounds, this review will focus on the pharmacologic galactogogues currently available and the literature related to their use in mothers of very preterm infants. PMID- 29757200 TI - A Rationally Designed Hsp70 Variant Rescues the Aggregation-Associated Toxicity of Human IAPP in Cultured Pancreatic Islet beta-Cells. AB - Molecular chaperones are key components of the protein homeostasis system against protein misfolding and aggregation. It has been recently shown that these molecules can be rationally modified to have an enhanced activity against specific amyloidogenic substrates. The resulting molecular chaperone variants can be effective inhibitors of protein aggregation in vitro, thus suggesting that they may provide novel opportunities in biomedical and biotechnological applications. Before such opportunities can be exploited, however, their effects on cell viability should be better characterised. Here, we employ a rational design method to specifically enhance the activity of the 70-kDa heat shock protein (Hsp70) against the aggregation of the human islet amyloid polypeptide (hIAPP, also known as amylin). We then show that the Hsp70 variant that we designed (grafted heat shock protein 70 kDa-human islet amyloid polypeptide, GHsp70-hIAPP) is significantly more effective than the wild type in recovering the viability of cultured pancreatic islet β-cells RIN-m5F upon hIAPP aggregation. These results indicate that a full recovery of the toxic effects of hIAPP aggregates on cultured pancreatic cells can be achieved by increasing the specificity and activity of Hsp70 towards hIAPP, thus providing evidence that the strategy presented here provides a possible route for rationally tailoring molecular chaperones for enhancing their effects in a target-dependent manner. PMID- 29757201 TI - Antioxidant Structure-Activity Relationship Analysis of Five Dihydrochalcones. AB - The study determined the comparative antioxidant capacities of five similar dihydrochalcones: phloretin, phloridzin, trilobatin, neohesperidin dihydrochalcone, and naringin dihydrochalcone. In the ferric-reducing antioxidant power (FRAP) assay, the antioxidant activities of pairs of dihydrochalcones had the following relationship: phloretin > phloridzin, phloretin > trilobatin, trilobatin > phloridzin, trilobatin > naringin dihydrochalcone, and neohesperidin dihydrochalcone > naringin dihydrochalcone. Similar relative antioxidant levels were also obtained from 1,1-diphenyl-2-picryl-hydrazl radical (DPPH•) scavenging, 2,2′-azino-bis(3-ethylbenzo-thiazoline-6-sulfonic acid) (ABTS•+)-scavenging, and superoxide radical (•O2−)-scavenging assays. Using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC−ESI−Q−TOF−MS/MS) analysis for the reaction products with DPPH•, phloretin, phloridzin, and trilobatin were found to yield both dihydrochalcone-DPPH adduct and dihydrochalcone-dihydrochalcone dimer, whereas naringin dihydrochalcone gave a naringin dihydrochalcone-DPPH adduct, and neohesperidin dihydrochalcone gave a dimer. In conclusion, the five dihydrochalcones may undergo redox-based reactions (especially electron transfer (ET) and hydrogen atom transfer (HAT)), as well as radical adduct formation, to exert their antioxidant action. Methoxylation at the ortho-OH enhances the ET and HAT potential possibly via p-π conjugation, whereas the glycosylation of the OH group not only reduces the ET and HAT potential but also hinders the ability of radical adduct formation. The 2′,6′-di-OH moiety in dihydrochalcone possesses higher ET and HAT activities than the 2′,4′ di-OH moiety because of its resonance with the adjacent keto group. PMID- 29756910 TI - Search for High-Mass Resonances Decaying to taunu in pp Collisions at sqrt[s]=13 TeV with the ATLAS Detector. AB - A search for high-mass resonances decaying to taunu using proton-proton collisions at sqrt[s]=13 TeV produced by the Large Hadron Collider is presented. Only tau-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb^{-1}. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible taunu production cross section. Heavy W^{'} bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2-3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level. PMID- 29757204 TI - The First Result of Relative Positioning and Velocity Estimation Based on CAPS. AB - The Chinese Area Positioning System (CAPS) is a new positioning system developed by the Chinese Academy of Sciences based on the communication satellites in geosynchronous orbit. The CAPS has been regarded as a pilot system to test the new technology for the design, construction and update of the BeiDou Navigation Satellite System (BDS). The system structure of CAPS, including the space, ground control station and user segments, is almost like the traditional Global Navigation Satellite Systems (GNSSs), but with the clock on the ground, the navigation signal in C waveband, and different principles of operation. The major difference is that the CAPS navigation signal is first generated at the ground control station, before being transmitted to the satellite in orbit and finally forwarded by the communication satellite transponder to the user. This design moves the clock from the satellite in orbit to the ground. The clock error can therefore be easily controlled and mitigated to improve the positioning accuracy. This paper will present the performance of CAPS-based relative positioning and velocity estimation as assessed in Beijing, China. The numerical results show that, (1) the accuracies of relative positioning, using only code measurements, are 1.25 and 1.8 m in the horizontal and vertical components, respectively; (2) meanwhile, they are about 2.83 and 3.15 cm in static mode and 6.31 and 10.78 cm in kinematic mode, respectively, when using the carrier-phase measurements with ambiguities fixed; and (3) the accuracy of the velocity estimation is about 0.04 and 0.11 m/s in static and kinematic modes, respectively. These results indicate the potential application of CAPS for high-precision positioning and velocity estimation and the availability of a new navigation mode based on communication satellites. PMID- 29757203 TI - Comparative in Silico Analysis of Ferric Reduction Oxidase (FRO) Genes Expression Patterns in Response to Abiotic Stresses, Metal and Hormone Applications. AB - The ferric reduction oxidase (FRO) gene family is involved in various biological processes widely found in plants and may play an essential role in metal homeostasis, tolerance and intricate signaling networks in response to a number of abiotic stresses. Our study describes the identification, characterization and evolutionary relationships of FRO genes families. Here, total 50 FRO genes in Plantae and 15 ‘FRO like’ genes in non-Plantae were retrieved from 16 different species. The entire FRO genes have been divided into seven clades according to close similarity in biological and functional behavior. Three conserved domains were common in FRO genes while in two FROs sub genome have an extra NADPH-Ox domain, separating the function of plant FROs. OsFRO1 and OsFRO7 genes were expressed constitutively in rice plant. Real-time RT-PCR analysis demonstrated that the expression of OsFRO1 was high in flag leaf, and OsFRO7 gene expression was maximum in leaf blade and flag leaf. Both genes showed vigorous expressions level in response to different abiotic and hormones treatments. Moreover, the expression of both genes was also substantial under heavy metal stresses. OsFRO1 gene expression was triggered following 6 h under Zn, Pb, Co and Ni treatments, whereas OsFRO7 gene expression under Fe, Pb and Ni after 12 h, Zn and Cr after 6 h, and Mn and Co after 3 h treatments. These findings suggest the possible involvement of both the genes under abiotic and metal stress and the regulation of phytohormones. Therefore, our current work may provide the foundation for further functional characterization of rice FRO genes family. PMID- 29757205 TI - Label-Free G-Quadruplex Aptamer Fluorescence Assay for Ochratoxin A Using a Thioflavin T Probe. AB - Ochratoxin A (OTA) is one of the most common mycotoxins contaminating feed and foodstuffs. Therefore, a great deal of concern is associated with AFB1 toxicity. In this work, a fast and sensitive fluorescence aptamer biosensor has been proposed for the OTA assay. In the absence of OTA, the OTA aptamer can form a G quadruplex structure with thioflavin T (ThT) dye, which results in increased fluorescence. After joining OTA, OTA aptamer combines with OTA and the G quadruplex can be formed. Only faint fluorescence was finally observed when ThT weakly reacts with the quadruplex. Through this test method, the entire reaction and analysis process of OTA can be completed in 10 min. Under optimal experimental conditions (600 nM OTA-APT, 7 μM ThT, and 3 min incubation time), this proposed assay has a good limit of detection (LOD) of 0.4 ng/mL and shows a good linear relationship within the range of 1.2-200 ng/mL under the best experimental conditions. This method has a high specificity for OTA relative to Ochratoxin B (23%) and Aflatoxin B1 (13%). In addition, the quantitative determination of this method in real samples has been validated using a sample of red wine supplemented with a range of OTA concentrations (1.2 ng/mL, 12 ng/mL, and 40 ng/mL) with recoveries of 96.5% to 107%. PMID- 29757202 TI - Genome Sequences of Akhmeta Virus, an Early Divergent Old World Orthopoxvirus. AB - Annotated whole genome sequences of three isolates of the Akhmeta virus (AKMV), a novel species of orthopoxvirus (OPXV), isolated from the Akhmeta and Vani regions of the country Georgia, are presented and discussed. The AKMV genome is similar in genomic content and structure to that of the cowpox virus (CPXV), but a lower sequence identity was found between AKMV and Old World OPXVs than between other known species of Old World OPXVs. Phylogenetic analysis showed that AKMV diverged prior to other Old World OPXV. AKMV isolates formed a monophyletic clade in the OPXV phylogeny, yet the sequence variability between AKMV isolates was higher than between the monkeypox virus strains in the Congo basin and West Africa. An AKMV isolate from Vani contained approximately six kb sequence in the left terminal region that shared a higher similarity with CPXV than with other AKMV isolates, whereas the rest of the genome was most similar to AKMV, suggesting recombination between AKMV and CPXV in a region containing several host range and virulence genes. PMID- 29757206 TI - The Effect of Ultrafine-Grained Microstructure on Creep Behaviour of 9% Cr Steel. AB - The effect of ultrafine-grained size on creep behaviour was investigated in P92 steel. Ultrafine-grained steel was prepared by one revolution of high-pressure torsion at room temperature. Creep tensile tests were performed at 873 K under the initially-applied stress range between 50 and 160 MPa. The microstructure was investigated using transmission electron microscopy and scanning electron microscopy equipped with an electron-back scatter detector. It was found that ultrafine-grained steel exhibits significantly faster minimum creep rates, and there was a decrease in the value of the stress exponent in comparison with coarse-grained P92 steel. Creep results also showed an abrupt decrease in the creep rate over time during the primary stage. The abrupt deceleration of the creep rate during the primary stage was shifted, with decreasing applied stress with longer creep times. The change in the decline of the creep rate during the primary stage was probably related to the enhanced precipitation of the Laves phase in the ultrafine-grained microstructure. PMID- 29757209 TI - Immunization Offer Targeting Migrants: Policies and Practices in Italy. AB - The unprecedented flow of migrants over the last three years places Italy in front of new issues regarding medical care from the rescue phase up to the integration into the national health services, including preventive actions. We used online questionnaires to investigate the Italian national and regional policies for immunization offer targeting asylum seekers, refugees, irregular migrants and unaccompanied minors. Another questionnaire was used to assess how these policies are translated into practice in migrant reception centres and community health services. Questionnaires were filled out at the national level, in 14 out of 21 Regions/Autonomous Provinces, and in 36 community health services and 28 migrant reception centres. Almost all responders stated that all vaccinations included in the National Immunization Plan are offered to migrant children and adolescents. The situation concerning adults is fragmented, with most of the Regions and local centres offering more vaccines than the national offer-which include polio, tetanus and measles-mumps-rubella. Data on immunized immigrants is archived at the regional/local level with different methods and not available at the national level. Further efforts to ensure consistency in vaccine provision and adequate mechanisms of exchanging data are needed to guarantee a complete vaccination offer and avoid unnecessary health actions, including unnecessary re-vaccination. PMID- 29757211 TI - Convolutional Neural Network-Based Embarrassing Situation Detection under Camera for Social Robot in Smart Homes. AB - Recent research has shown that the ubiquitous use of cameras and voice monitoring equipment in a home environment can raise privacy concerns and affect human mental health. This can be a major obstacle to the deployment of smart home systems for elderly or disabled care. This study uses a social robot to detect embarrassing situations. Firstly, we designed an improved neural network structure based on the You Only Look Once (YOLO) model to obtain feature information. By focusing on reducing area redundancy and computation time, we proposed a bounding-box merging algorithm based on region proposal networks (B RPN), to merge the areas that have similar features and determine the borders of the bounding box. Thereafter, we designed a feature extraction algorithm based on our improved YOLO and B-RPN, called F-YOLO, for our training datasets, and then proposed a real-time object detection algorithm based on F-YOLO (RODA-FY). We implemented RODA-FY and compared models on our MAT social robot. Secondly, we considered six types of situations in smart homes, and developed training and validation datasets, containing 2580 and 360 images, respectively. Meanwhile, we designed three types of experiments with four types of test datasets composed of 960 sample images. Thirdly, we analyzed how a different number of training iterations affects our prediction estimation, and then we explored the relationship between recognition accuracy and learning rates. Our results show that our proposed privacy detection system can recognize designed situations in the smart home with an acceptable recognition accuracy of 94.48%. Finally, we compared the results among RODA-FY, Inception V3, and YOLO, which indicate that our proposed RODA-FY outperforms the other comparison models in recognition accuracy. PMID- 29757208 TI - DOW-PR DOlphin and Whale Pods Routing Protocol for Underwater Wireless Sensor Networks (UWSNs). AB - Underwater Wireless Sensor Networks (UWSNs) have intrinsic challenges that include long propagation delays, high mobility of sensor nodes due to water currents, Doppler spread, delay variance, multipath, attenuation and geometric spreading. The existing Weighting Depth and Forwarding Area Division Depth Based Routing (WDFAD-DBR) protocol considers the weighting depth of the two hops in order to select the next Potential Forwarding Node (PFN). To improve the performance of WDFAD-DBR, we propose DOlphin and Whale Pod Routing protocol (DOW PR). In this scheme, we divide the transmission range into a number of transmission power levels and at the same time select the next PFNs from forwarding and suppressed zones. In contrast to WDFAD-DBR, our scheme not only considers the packet upward advancement, but also takes into account the number of suppressed nodes and number of PFNs at the first and second hops. Consequently, reasonable energy reduction is observed while receiving and transmitting packets. Moreover, our scheme also considers the hops count of the PFNs from the sink. In the absence of PFNs, the proposed scheme will select the node from the suppressed region for broadcasting and thus ensures minimum loss of data. Besides this, we also propose another routing scheme (whale pod) in which multiple sinks are placed at water surface, but one sink is embedded inside the water and is physically connected with the surface sink through high bandwidth connection. Simulation results show that the proposed scheme has high Packet Delivery Ratio (PDR), low energy tax, reduced Accumulated Propagation Distance (APD) and increased the network lifetime. PMID- 29757214 TI - Microbial Community Analysis of Sauerkraut Fermentation Reveals a Stable and Rapidly Established Community. AB - Despite recent interest in microbial communities of fermented foods, there has been little inquiry into the bacterial community dynamics of sauerkraut, one of the world’s oldest and most prevalent fermented foods. In this study, we utilize 16S rRNA amplicon sequencing to profile the microbial community of naturally fermented sauerkraut throughout the fermentation process while also analyzing the bacterial communities of the starting ingredients and the production environment. Our results indicate that the sauerkraut microbiome is rapidly established after fermentation begins and that the community is stable through fermentation and packaging for commercial sale. Our high-throughput analysis is in agreement with previous studies that utilized traditional microbiological assessments but expands the identified taxonomy. Additionally, we find that the microbial communities of the starting ingredients and the production facility environment exhibit low relative abundance of the lactic acid bacteria that dominate fermented sauerkraut. PMID- 29757212 TI - Vibro-Perception of Optical Bio-Inspired Fiber-Skin. AB - In this research, based on the principle of optical interferometry, the Mach Zehnder and Optical Phase-locked Loop (OPLL) vibro-perception systems of bio inspired fiber-skin are designed to mimic the tactile perception of human skin. The fiber-skin is made of the optical fiber embedded in the silicone elastomer. The optical fiber is an instinctive and alternative sensor for tactile perception with high sensitivity and reliability, also low cost and susceptibility to the magnetic interference. The silicone elastomer serves as a substrate with high flexibility and biocompatibility, and the optical fiber core serves as the vibro perception sensor to detect physical motions like tapping and sliding. According to the experimental results, the designed optical fiber-skin demonstrates the ability to detect the physical motions like tapping and sliding in both the Mach Zehnder and OPLL vibro-perception systems. For direct contact condition, the OPLL vibro-perception system shows better performance compared with the Mach-Zehnder vibro-perception system. However, the Mach-Zehnder vibro-perception system is preferable to the OPLL system in the indirect contact experiment. In summary, the fiber-skin is validated to have light touch character and excellent repeatability, which is highly-suitable for skin-mimic sensing. PMID- 29757213 TI - Study of the Kinetics and Equilibrium of the Adsorption of Oils onto Hydrophobic Jute Fiber Modified via the Sol-Gel Method. AB - A new kind of hydrophobic and oil sorbent based on jute fiber was successfully prepared by the integration of silica onto a fiber surface via the sol-gel method and subsequent hydrophobic modification with octadecyltrichlorosilane (OTS). Compared with the hydrophilic raw fiber, the modified fiber had a water contact angle (CA) of 136.2°, suggesting that the material has good hydrophobicity. Furthermore, the ability of oil in the oil/water system (taking diesel for example) to absorb was revealed by the kinetics, the isotherm equation, and the thermodynamic parameters. Adsorption behavior was kinetically investigated using pseudo first-order and pseudo second-order models. The data mostly correlated with the pseudo first-order model. The equilibrium adsorption at 298 K was assessed by using the Langmuir and Freundlich isotherm models. The Freundlich model had greater consistency with the experimental data. The obtained thermodynamic parameters demonstrate that the adsorption of diesel is spontaneous, favorable, and exothermic. PMID- 29757207 TI - Maternal Anemia and Low Birth Weight: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To systematically analyze the relationship between maternal anemia and low birth weight. METHODS: A search of studies was conducted in the main databases (Medline, Embase, Scopus, Web of Science, SciELO, and Lilacs), the gray literature, and the reference lists of selected articles. Cohort and case-control studies that met the eligibility criteria were included in the review. There was no limitation on the language or date of publication. Article selection and data extraction were performed by two independent reviewers. Meta-analyses with random effects, subgroup analyses and meta-regressions were performed. Publication bias was measured using Egger regression and visual funnel plot inspection. RESULTS: A total of 7243 articles were found, of which 71 comprised the systematic review and 68 were included in the meta-analyses. Maternal anemia was associated with low birth weight with an adjusted OR: 1.23 (95% CI: 1.06-1.43) and I2: 58%. The meta-regressions confirmed that the sample size and the methodological quality may partially explain the statistical heterogeneity. CONCLUSIONS: Maternal anemia was considered a risk factor for low birth weight. PMID- 29757210 TI - Dermatitis Herpetiformis: A Common Extraintestinal Manifestation of Coeliac Disease. AB - Dermatitis herpetiformis (DH) is a common extraintestinal manifestation of coeliac disease presenting with itchy papules and vesicles on the elbows, knees, and buttocks. Overt gastrointestinal symptoms are rare. Diagnosis of DH is easily confirmed by immunofluorescence biopsy showing pathognomonic granular immunoglobulin A (IgA) deposits in the papillary dermis. A valid hypothesis for the immunopathogenesis of DH is that it starts from latent or manifest coeliac disease in the gut and evolves into an immune complex deposition of high avidity IgA epidermal transglutaminase (TG3) antibodies, together with the TG3 enzyme, in the papillary dermis. The mean age at DH diagnosis has increased significantly in recent decades and presently is 40-50 years. The DH to coeliac disease prevalence ratio is 1:8 in Finland and the United Kingdom (U.K.). The annual DH incidence rate, currently 2.7 per 100,000 in Finland and 0.8 per 100,000 in the U.K., is decreasing, whereas the reverse is true for coeliac disease. The long-term prognosis of DH patients on a gluten-free diet is excellent, with the mortality rate being even lower than for the general population. PMID- 29757217 TI - Caveats to Exogenous Organic Delivery from Ablation, Dilution, and Thermal Degradation. AB - A hypothesis in prebiotic chemistry argues that organics were delivered to the early Earth in abundance by meteoritic sources. This study tests that hypothesis by measuring how the transfer of organic matter to the surface of Earth is affected by energy-dissipation processes such as ablation and airbursts. Exogenous delivery has been relied upon as a source of primordial material, but it must stand to reason that other avenues (i.e., hydrothermal vents, electric discharge) played a bigger role in the formation of life as we know it on Earth if exogenous material was unable to deliver significant quantities of organics. For this study, we look at various properties of meteors such as initial velocity and mass of the object, and atmospheric composition to see how meteors with different initial velocities and masses ablate. We find that large meteors do not slow down fast enough and thus impact the surface, vaporizing their components; fast meteors with low masses are vaporized during entry; and meteors with low velocities and high initial masses reach the surface. For those objects that survive to reach the surface, about 60 to >99% of the mass is lost by ablation. Large meteors that fragment are also shown to spread out over increasingly larger areas with increasing mass, and small meteors (~1 mm) are subjected to intense thermal heating, potentially degrading intrinsic organics. These findings are generally true across most atmospheric compositions. These findings provide several caveats to extraterrestrial delivery models that—while a viable point source of organics—likely did not supply as much prebiotic material as an effective endogenous production route. PMID- 29757216 TI - Sphingosine-1-Phosphate Receptor 1 Is Involved in Non-Obese Diabetic Mouse Thymocyte Migration Disorders. AB - NOD (non-obese diabetic) mice spontaneously develop type 1 diabetes following T cell-dependent destruction of pancreatic β cells. Several alterations are observed in the NOD thymus, including the presence of giant perivascular spaces (PVS) filled with single-positive (SP) CD4+ and CD8+ T cells that accumulate in the organ. These cells have a decreased expression of membrane CD49e (the α5 integrin chain of the fibronectin receptor VLA-5 (very late antigen-5). Herein, we observed lower sphingosine-1-phosphate receptor 1 (S1P1) expression in NOD mouse thymocytes when compared with controls, mainly in the mature SP CD4+CD62Lhi and CD8+CD62Lhi subpopulations bearing the CD49e− phenotype. In contrast, differences in S1P1 expression were not observed in mature CD49e+ thymocytes. Functionally, NOD CD49e− thymocytes had reduced S1P-driven migratory response, whereas CD49e+ cells were more responsive to S1P. We further noticed a decreased expression of the sphingosine-1-phosphate lyase (SGPL1) in NOD SP thymocytes, which can lead to a higher sphingosine-1-phosphate (S1P) expression around PVS and S1P1 internalization. In summary, our results indicate that the modulation of S1P1 expression and S1P/S1P1 interactions in NOD mouse thymocytes are part of the T-cell migratory disorder observed during the pathogenesis of type 1 diabetes. PMID- 29757218 TI - Detection of Specific ZIKV IgM in Travelers Using a Multiplexed Flavivirus Microsphere Immunoassay. AB - Zika virus (ZIKV) has spread widely in the Pacific and recently throughout the Americas. Unless detected by RT-PCR, confirming an acute ZIKV infection can be challenging. We developed and validated a multiplexed flavivirus immunoglobulin M (IgM) microsphere immunoassay (flaviMIA) which can differentiate ZIKV-specific IgM from that due to other flavivirus infections in humans. The flaviMIA bound 12 inactivated flavivirus antigens, including those from ZIKV and yellow fever virus (YFV), to distinct anti-flavivirus antibody coupled beads. These beads were used to interrogate sera from patients with suspected ZIKV infection following travel to relevant countries. FlaviMIA results were validated by comparison to the ZIKV plaque reduction neutralization test (PRNT). The results highlight the complexity of serological ZIKV diagnosis, particularly in patients previously exposed to or vaccinated against other flaviviruses. We confirmed 99 patients with ZIKV infection by a combination of RT-PCR and serology. Importantly, ZIKV antibodies could be discriminated from those ascribed to other flavivirus infections. Serological results were sometimes confounded by the presence of pre-existing antibodies attributed to previous flavivirus infection or vaccination. Where RT PCR results were negative, testing of appropriately timed paired sera was necessary to demonstrate seroconversion or differentiation of recent from past infection with or exposure to ZIKV. PMID- 29757215 TI - The Rules and Functions of Nucleocytoplasmic Shuttling Proteins. AB - Biological macromolecules are the basis of life activities. There is a separation of spatial dimension between DNA replication and RNA biogenesis, and protein synthesis, which is an interesting phenomenon. The former occurs in the cell nucleus, while the latter in the cytoplasm. The separation requires protein to transport across the nuclear envelope to realize a variety of biological functions. Nucleocytoplasmic transport of protein including import to the nucleus and export to the cytoplasm is a complicated process that requires involvement and interaction of many proteins. In recent years, many studies have found that proteins constantly shuttle between the cytoplasm and the nucleus. These shuttling proteins play a crucial role as transport carriers and signal transduction regulators within cells. In this review, we describe the mechanism of nucleocytoplasmic transport of shuttling proteins and summarize some important diseases related shuttling proteins. PMID- 29757219 TI - Melatonin and Expression of Tryptophan Decarboxylase Gene (TDC) in Herbaceous Peony (Paeonia lactiflora Pall.) Flowers. AB - Melatonin is a bioactive, edible ingredient that promotes human health and exists widely in plants, but little is known about its biosynthetic routes and underlying molecular mechanisms in the herbaceous peony. In this contribution, we found that herbaceous peony flowers are rich in melatonin that is found in the greatest quantities in the white series, followed by the ink series, the red series and then the pink series. On this basis, the melatonin content fluctuates during flower development and peaks during the bloom stage. Moreover, it is apparent that sun exposure and blue light induce melatonin production whereas green light restrains it during a 24-h light/dark cycle of melatonin content, as there were ‘dual peaks’ at 2 p.m. and 2 a.m. Additionally, the corresponding expression pattern of the herbaceous peony tryptophan decarboxylase gene (TDC) was positively related with melatonin production. These results suggest that color series, development stage and light play an important role in melatonin accumulation, and that TDC is a rate-limiting gene in melatonin biosynthesis. PMID- 29757221 TI - Children's Imaginaries of Human-Robot Interaction in Healthcare. AB - This paper analyzes children’s imaginaries of Human-Robots Interaction (HRI) in the context of social robots in healthcare, and it explores ethical and social issues when designing a social robot for a children’s hospital. Based on approaches that emphasize the reciprocal relationship between society and technology, the analytical force of imaginaries lies in their capacity to be embedded in practices and interactions as well as to affect the construction and applications of surrounding technologies. The study is based on a participatory process carried out with six-year-old children for the design of a robot. Imaginaries of HRI are analyzed from a care-centered approach focusing on children’s values and practices as related to their representation of care. The conceptualization of HRI as an assemblage of interactions, the prospective bidirectional care relationships with robots, and the engagement with the robot as an entity of multiple potential robots are the major findings of this study. The study shows the potential of studying imaginaries of HRI, and it concludes that their integration in the final design of robots is a way of including ethical values in it. PMID- 29757223 TI - Effect of Cementite on the Hydrogen Diffusion/Trap Characteristics of 2.25Cr-1Mo 0.25V Steel with and without Annealing. AB - Hydrogen embrittlement (HE) is a critical issue that affects the reliability of hydrogenation reactors. The hydrogen diffusivity/trap characteristics of 2.25Cr 1Mo-0.25V steel are important parameters mainly used to study the HE mechanism of steel alloys. In this work, the hydrogen diffusivity/trap characteristics of heat treated (annealed) and untreated 2.25Cr-1Mo-0.25V steel were studied using an electrochemical permeation method. The microstructures of both 2.25Cr-1Mo-0.25V steels were investigated by metallurgical microscopy. The effect of cementite on the hydrogen diffusivity/trap mechanisms was studied using thermodynamics-based and Lennard-Jones potential theories. The results revealed that the cementite located at the grain boundaries and at the interfaces of lath ferrite served as a kind of hydrogen trap (i.e., an irreversible hydrogen trap). In addition, hydrogen was transported from ferrite to cementite via up-hill diffusion, thereby supporting the hypothesis of cementite acting as a hydrogen trap. PMID- 29757222 TI - Association of Habitually Low Intake of Dietary Calcium with Blood Pressure and Hypertension in a Population with Predominantly Plant-Based Diets. AB - This study aimed to assess the association of habitually low dietary calcium intake with blood pressure or hypertensive risk using data from the China Health and Nutrition Survey (CHNS) in 2009. We included 6298 participants (2890 men and 3408 women) aged 18 years or older in this analysis. Food intakes were measured by 3-day 24-h individual recalls combined with a weighing and measuring of household food inventory. The participants were divided into normotensive, pre hypertensive and hypertensive groups according to their mean blood pressure of three repeated measurements. Six intake levels were decided by percentiles of gender-specific dietary calcium intakes (P0-10, P10-30, P30-50, P50-70, P70-90, and P90-100). Average dietary calcium intakes were 405 mg/day for men and 370 mg/day for women, 80% and 84% of which were derived from plant-based food in men and women, respectively. Multiple linear regression analyses showed that dietary calcium intakes were not related with blood pressure in both genders (all P > 0.05). Logistic regression analyses showed a lower risk of pre-hypertension with higher dietary calcium intakes in women (all Pfor trend < 0.001), but not in men; no association between dietary calcium intake and hypertensive risk was found in both genders (all Pfor trend > 0.05). This study suggests that there are no conclusive associations of habitually low dietary calcium intake with blood pressure or hypertensive risk in Chinese individuals consuming predominantly plant-based diets. PMID- 29757220 TI - Annexins-Coordinators of Cholesterol Homeostasis in Endocytic Pathways. AB - The spatiotemporal regulation of calcium (Ca2+) storage in late endosomes (LE) and lysosomes (Lys) is increasingly recognized to influence a variety of membrane trafficking events, including endocytosis, exocytosis, and autophagy. Alterations in Ca2+ homeostasis within the LE/Lys compartment are implicated in human diseases, ranging from lysosomal storage diseases (LSDs) to neurodegeneration and cancer, and they correlate with changes in the membrane binding behaviour of Ca2+ binding proteins. This also includes Annexins (AnxA), which is a family of Ca2+ binding proteins participating in membrane traffic and tethering, microdomain organization, cytoskeleton interactions, Ca2+ signalling, and LE/Lys positioning. Although our knowledge regarding the way Annexins contribute to LE/Lys functions is still incomplete, recruitment of Annexins to LE/Lys is greatly influenced by the availability of Annexin bindings sites, including acidic phospholipids, such as phosphatidylserine (PS) and phosphatidic acid (PA), cholesterol, and phosphatidylinositol (4,5)-bisphosphate (PIP2). Moreover, the cytosolic portion of LE/Lys membrane proteins may also, directly or indirectly, determine the recruitment of Annexins to LE. Strikingly, within LE/Lys, AnxA1, A2, A6, and A8 differentially contribute to cholesterol transport along the endocytic route, in particular, cholesterol transfer between LE and other compartments, positioning Annexins at the centre of major pathways mediating cellular cholesterol homeostasis. Underlying mechanisms include the formation of membrane contact sites (MCS) and intraluminal vesicles (ILV), as well as the modulation of LE cholesterol transporter activity. In this review, we will summarize the current understanding how Annexins contribute to influence LE/Lys membrane transport and associated functions. PMID- 29757224 TI - Insights into Abiotically-Generated Amino Acid Enantiomeric Excesses Found in Meteorites. AB - Biology exhibits homochirality, in that only one of two possible molecular configurations (called enantiomers) is used in both proteins and nucleic acids. The origin of this phenomenon is currently unknown, as nearly all known abiotic mechanisms for generating these compounds result in equal (racemic) mixtures of both enantiomers. However, analyses of primitive meteorites have revealed that a number of amino acids of extraterrestrial origin are present in enantiomeric excess, suggesting that there was an abiotic route to synthesize amino acids in a non-racemic manner. Here we review the amino acid contents of a range of meteorites, describe mechanisms for amino acid formation and their potential to produce amino acid enantiomeric excesses, and identify processes that could have amplified enantiomeric excesses. PMID- 29757225 TI - ZnO/CuO/M (M = Ag, Au) Hierarchical Nanostructure by Successive Photoreduction Process for Solar Hydrogen Generation. AB - To date, solar energy generation devices have been widely studied to meet a clean and sustainable energy source. Among them, water splitting photoelectrochemical cell is regarded as a promising energy generation way for splitting water molecules and generating hydrogen by sunlight. While many nanostructured metal oxides are considered as a candidate, most of them have an improper bandgap structure lowering energy transition efficiency. Herein, we introduce a novel wet based, successive photoreduction process that can improve charge transfer efficiency by surface plasmon effect for a solar-driven water splitting device. The proposed process enables to fabricate ZnO/CuO/Ag or ZnO/CuO/Au hierarchical nanostructure, having an enhanced electrical, optical, photoelectrochemical property. The fabricated hierarchical nanostructures are demonstrated as a photocathode in the photoelectrochemical cell and characterized by using various analytic tools. PMID- 29757227 TI - Combining Fog Computing with Sensor Mote Machine Learning for Industrial IoT. AB - Digitalization is a global trend becoming ever more important to our connected and sustainable society. This trend also affects industry where the Industrial Internet of Things is an important part, and there is a need to conserve spectrum as well as energy when communicating data to a fog or cloud back-end system. In this paper we investigate the benefits of fog computing by proposing a novel distributed learning model on the sensor device and simulating the data stream in the fog, instead of transmitting all raw sensor values to the cloud back-end. To save energy and to communicate as few packets as possible, the updated parameters of the learned model at the sensor device are communicated in longer time intervals to a fog computing system. The proposed framework is implemented and tested in a real world testbed in order to make quantitative measurements and evaluate the system. Our results show that the proposed model can achieve a 98% decrease in the number of packets sent over the wireless link, and the fog node can still simulate the data stream with an acceptable accuracy of 97%. We also observe an end-to-end delay of 180 ms in our proposed three-layer framework. Hence, the framework shows that a combination of fog and cloud computing with a distributed data modeling at the sensor device for wireless sensor networks can be beneficial for Industrial Internet of Things applications. PMID- 29757228 TI - The Development of a Multiple-Item Annoyance Scale (MIAS) for Transportation Noise Annoyance. AB - In 2001, Team#6 of the International Commission on Biological Effects of Noise (ICBEN) recommended the use of two single international standardised questions and response scales. This recommendation has been widely accepted in the scientific community. Nevertheless, annoyance can be regarded as a multidimensional construct comprising the three elements: (1) experience of an often repeated noise-related disturbance and the behavioural response to cope with it, (2) an emotional/attitudinal response to the sound and its disturbing impact, and (3) the perceived control or coping capacity with regard to the noise situation. The psychometric properties of items reflecting these three elements have been explored for aircraft noise annoyance. Analyses were conducted using data of the NORAH-Study (Noise-Related Annoyance, Cognition, and Health), and a multi-item noise annoyance scale (MIAS) has been developed and tested post hoc by using a stepwise process (exploratory and confirmatory factor analyses). Preliminary results were presented to the 12th ICBEN Congress in 2017. In this study, the validation of MIAS is done for aircraft noise and extended to railway and road traffic noise. The results largely confirm the concept of MIAS as a second-order construct of annoyance for all of the investigated transportation noise sources; however, improvements can be made, in particular with regard to items addressing the perceived coping capacity. PMID- 29757226 TI - Inflammation, not Cholesterol, Is a Cause of Chronic Disease. AB - Since the Seven Countries Study, dietary cholesterol and the levels of serum cholesterol in relation to the development of chronic diseases have been somewhat demonised. However, the principles of the Mediterranean diet and relevant data linked to the examples of people living in the five blue zones demonstrate that the key to longevity and the prevention of chronic disease development is not the reduction of dietary or serum cholesterol but the control of systemic inflammation. In this review, we present all the relevant data that supports the view that it is inflammation induced by several factors, such as platelet activating factor (PAF), that leads to the onset of cardiovascular diseases (CVD) rather than serum cholesterol. The key to reducing the incidence of CVD is to control the activities of PAF and other inflammatory mediators via diet, exercise, and healthy lifestyle choices. The relevant studies and data supporting these views are discussed in this review. PMID- 29757231 TI - Speckle Filtering of GF-3 Polarimetric SAR Data with Joint Restriction Principle. AB - Polarimetric SAR (PolSAR) scattering characteristics of imagery are always obtained from the second order moments estimation of multi-polarization data, that is, the estimation of covariance or coherency matrices. Due to the extra paths that signal reflected from separate scatterers within the resolution cell has to travel, speckle noise always exists in SAR images and has a severe impact on the scattering performance, especially on single look complex images. In order to achieve high accuracy in estimating covariance or coherency matrices, three aspects are taken into consideration: (1) the edges and texture of the scene are distinct after speckle filtering; (2) the statistical characteristic should be similar to the object pixel; and (3) the polarimetric scattering signature should be preserved, in addition to speckle reduction. In this paper, a joint restriction principle is proposed to meet the requirement. Three different restriction principles are introduced to the processing of speckle filtering. First, a new template, which is more suitable for the point or line targets, is designed to ensure the morphological consistency. Then, the extent sigma filter is used to restrict the pixels in the template aforementioned to have an identical statistic characteristic. At last, a polarimetric similarity factor is applied to the same pixels above, to guarantee the similar polarimetric features amongst the optional pixels. This processing procedure is named as speckle filtering with joint restriction principle and the approach is applied to GF-3 polarimetric SAR data acquired in San Francisco, CA, USA. Its effectiveness of keeping the image sharpness and preserving the scattering mechanism as well as speckle reduction is validated by the comparison with boxcar filters and refined Lee filter. PMID- 29757229 TI - Effect of Dietary Sugar Intake on Biomarkers of Subclinical Inflammation: A Systematic Review and Meta-Analysis of Intervention Studies. AB - It has been postulated that dietary sugar consumption contributes to increased inflammatory processes in humans, and that this may be specific to fructose (alone, in sucrose or in high-fructose corn syrup (HFCS)). Therefore, we conducted a meta-analysis and systematic literature review to evaluate the relevance of fructose, sucrose, HFCS, and glucose consumption for systemic levels of biomarkers of subclinical inflammation. MEDLINE, EMBASE, and Cochrane libraries were searched for controlled intervention studies that report the effects of dietary sugar intake on (hs)CRP, IL-6, IL-18, IL-1RA, TNF-α, MCP 1, sICAM-1, sE-selectin, or adiponectin. Included studies were conducted on adults or adolescents with ≥20 participants and ≥2 weeks duration. Thirteen studies investigating 1141 participants were included in the meta-analysis. Sufficient studies (≥3) to pool were only available for (hs)CRP. Using a random effects model, pooled effects of the interventions (investigated as mean difference (MD)) revealed no differences in (hs)CRP between fructose intervention and glucose control groups (MD: −0.03 mg/L (95% CI: −0.52, 0.46), I2 = 44%). Similarly, no differences were observed between HFCS and sucrose interventions (MD: 0.21 mg/L (−0.11, 0.53), I2 = 0%). The quality of evidence was evaluated using Nutrigrade, and was rated low for these two comparisons. The limited evidence available to date does not support the hypothesis that dietary fructose, as found alone or in HFCS, contributes more to subclinical inflammation than other dietary sugars. PMID- 29757233 TI - Polarization Smoothing Generalized MUSIC Algorithm with Polarization Sensitive Array for Low Angle Estimation. AB - Direction of Arrival (DOA) estimation of low-altitude targets is difficult due to the multipath coherent interference from the ground reflection image of the targets, especially for very high frequency (VHF) radars, which have antennae that are severely restricted in terms of aperture and height. The polarization smoothing generalized multiple signal classification (MUSIC) algorithm, which combines polarization smoothing and generalized MUSIC algorithm for polarization sensitive arrays (PSAs), was proposed to solve this problem in this paper. Firstly, the polarization smoothing pre-processing was exploited to eliminate the coherence between the direct and the specular signals. Secondly, we constructed the generalized MUSIC algorithm for low angle estimation. Finally, based on the geometry information of the symmetry multipath model, the proposed algorithm was introduced to convert the two-dimensional searching into one-dimensional searching, thus reducing the computational burden. Numerical results were provided to verify the effectiveness of the proposed method, showing that the proposed algorithm has significantly improved angle estimation performance in the low-angle area compared with the available methods, especially when the grazing angle is near zero. PMID- 29757232 TI - Ultrasonically Modified Amended-Cloud Point Extraction for Simultaneous Pre Concentration of Neonicotinoid Insecticide Residues. AB - An effective pre-concentration method, namely amended-cloud point extraction (CPE), has been developed for the extraction and pre-concentration of neonicotinoid insecticide residues. The studied analytes including clothianidin, imidacloprid, acetamiprid, thiamethoxam and thiacloprid were chosen as a model compound. The amended-CPE procedure included two cloud point processes. Triton™ X-114 was used to extract neonicotinoid residues into the surfactant-rich phase and then the analytes were transferred into an alkaline solution with the help of ultrasound energy. The extracts were then analyzed by high-performance liquid chromatography (HPLC) coupled with a monolithic column. Several factors influencing the extraction efficiency were studied such as kind and concentration of surfactant, type and content of salts, kind and concentration of back extraction agent, and incubation temperature and time. Enrichment factors (EFs) were found in the range of 20-333 folds. The limits of detection of the studied neonicotinoids were in the range of 0.0003-0.002 µg mL−1 which are below the maximum residue limits (MRLs) established by the European Union (EU). Good repeatability was obtained with relative standard deviations lower than 1.92% and 4.54% for retention time (tR) and peak area, respectively. The developed extraction method was successfully applied for the analysis of water samples. No detectable residues of neonicotinoids in the studied samples were found. PMID- 29757230 TI - Exercise and Nutrition Strategies to Counteract Sarcopenic Obesity. AB - As the population is aging rapidly, there is a strong increase in the number of individuals with chronic disease and physical limitations. The decrease in skeletal muscle mass and function (sarcopenia) and the increase in fat mass (obesity) are important contributors to the development of physical limitations, which aggravates the chronic diseases prognosis. The combination of the two conditions, which is referred to as sarcopenic obesity, amplifies the risk for these negative health outcomes, which demonstrates the importance of preventing or counteracting sarcopenic obesity. One of the main challenges is the preservation of the skeletal muscle mass and function, while simultaneously reducing the fat mass in this population. Exercise and nutrition are two key components in the development, as well as the prevention and treatment of sarcopenic obesity. The main aim of this narrative review is to summarize the different, both separate and combined, exercise and nutrition strategies so as to prevent and/or counteract sarcopenic obesity. This review therefore provides a current update of the various exercise and nutritional strategies to improve the contrasting body composition changes and physical functioning in sarcopenic obese individuals. PMID- 29757234 TI - Effect of UVC Radiation on Hydrated and Desiccated Cultures of Slightly Halophilic and Non-Halophilic Methanogenic Archaea: Implications for Life on Mars. AB - Methanogens have been considered models for life on Mars for many years. In order to survive any exposure at the surface of Mars, methanogens would have to endure Martian UVC radiation. In this research, we irradiated hydrated and desiccated cultures of slightly halophilic Methanococcus maripaludis and non-halophilic Methanobacterium formicicum for various time intervals with UVC (254 nm) radiation. The survivability of the methanogens was determined by measuring methane concentrations in the headspace gas samples of culture tubes after re inoculation of the methanogens into their growth-supporting media following exposure to UVC radiation. Hydrated M. maripaludis survived 24 h of UVC exposure, while in a desiccated condition they endured for 16 h. M. formicicum also survived UVC radiation for 24 h in a liquid state; however, in a desiccated condition, the survivability of M. formicicum was only 12 h. Some of the components of the growth media could have served as shielding agents that protected cells from damage caused by exposure to ultraviolet radiation. Overall, these results suggest that limited exposure (12-24 h) to UVC radiation on the surface of Mars would not necessarily be a limiting factor for the survivability of M. maripaludis and M. formicicum. PMID- 29757236 TI - An Effective Delay Reduction Approach through a Portion of Nodes with a Larger Duty Cycle for Industrial WSNs. AB - For Industrial Wireless Sensor Networks (IWSNs), sending data with timely style to the stink (or control center, CC) that is monitored by sensor nodes is a challenging issue. However, in order to save energy, wireless sensor networks based on a duty cycle are widely used in the industrial field, which can bring great delay to data transmission. We observe that if the duty cycle of a small number of nodes in the network is set to 1, the sleep delay caused by the duty cycle can be effectively reduced. Thus, in this paper, a novel Portion of Nodes with Larger Duty Cycle (PNLDC) scheme is proposed to reduce delay and optimize energy efficiency for IWSNs. In the PNLDC scheme, a portion of nodes are selected to set their duty cycle to 1, and the proportion of nodes with the duty cycle of 1 is determined according to the energy abundance of the area in which the node is located. The more the residual energy in the region, the greater the proportion of the selected nodes. Because there are a certain proportion of nodes with the duty cycle of 1 in the network, the PNLDC scheme can effectively reduce delay in IWSNs. The performance analysis and experimental results show that the proposed scheme significantly reduces the delay for forwarding data by 8.9~26.4% and delay for detection by 2.1~24.6% without reducing the network lifetime when compared with the fixed duty cycle method. Meanwhile, compared with the dynamic duty cycle strategy, the proposed scheme has certain advantages in terms of energy utilization and delay reduction. PMID- 29757237 TI - Investigation of the Anti-Prostate Cancer Properties of Marine-Derived Compounds. AB - This review focuses on marine compounds with anti-prostate cancer properties. Marine species are unique and have great potential for the discovery of anticancer drugs. Marine sources are taxonomically diverse and include bacteria, cyanobacteria, fungi, algae, and mangroves. Marine-derived compounds, including nucleotides, amides, quinones, polyethers, and peptides are biologically active compounds isolated from marine organisms such as sponges, ascidians, gorgonians, soft corals, and bryozoans, including those mentioned above. Several compound classes such as macrolides and alkaloids include drugs with anti-cancer mechanisms, such as antioxidants, anti-angiogenics, antiproliferatives, and apoptosis-inducing drugs. Despite the diversity of marine species, most marine derived bioactive compounds have not yet been evaluated. Our objective is to explore marine compounds to identify new treatment strategies for prostate cancer. This review discusses chemically and pharmacologically diverse marine natural compounds and their sources in the context of prostate cancer drug treatment. PMID- 29757240 TI - Multifunctional Hierarchical Surface Structures by Femtosecond Laser Processing. AB - Hierarchical surface structures were fabricated on fused silica by using a fs laser with a pulse duration τ = 300 fs and a wavelength λ = 512 nm. The resulting surface structures were characterized by scanning electron microscopy, atomic force microscopy and white light interference microscopy. The optical properties were analyzed by transmittance measurements using an integrating sphere and the wettability was evaluated by measuring the water contact angle θ. The silanization of structured fused silica surfaces with trichloro(1H,1H,2H,2H-perfluorooctyl)silane allows to switch the wettability from superhydrophilic (θ = 0°) to superhydrophobic behavior with θ exceeding 150°. It was shown that the structured silica surfaces are a suitable master for negative replica casting and that the hierarchical structures can be transferred to polystyrene. The transmittance of structured fused silica surfaces decreases only slightly when compared to unstructured surfaces, which results in high transparency of the structured samples. Our findings facilitate the fabrication of transparent glass samples with tailored wettability. This might be of particular interest for applications in the fields of optics, microfluidics, and biomaterials. PMID- 29757239 TI - Preparation, Physicochemical and Antioxidant Properties of Acid- and Pepsin Soluble Collagens from the Swim Bladders of Miiuy Croaker (Miichthys miiuy). AB - Collagen is one of the most useful biomaterials and widely applied in functional food and cosmetics. However, some consumers have paid close attention to the safety of mammalian collagens because of the outbreaks of bovine spongiform encephalopathy (BSE), foot-and-mouth disease (FMD), and other prion diseases. Therefore, there is a strong demand for developing alternative sources of collagen, with one promising source being from the process by-products of commercial fisheries. In this report, acid-soluble collagen (ASC-SB) and pepsin soluble collagen (PSC-SB) from swim bladders of miiuy croaker (Miichthys miiuy) were isolated with yields of 1.33 +/- 0.11% and 8.37 +/- 0.24% of dry swim bladder weight. Glycine was the major amino acid present, with a content of 320.5 (ASC-SB) and 333.6 residues/1000 residues (PSC-SB). ASC-SB and PSC-SB had much lower denaturation temperatures compared to mammalian collagen, a consequence of low imino acid contents (196.7 and 199.5 residues/1000 residues for ASC-SB and PSC-SB, respectively). The data of amino acid composition, SDS-PAGE pattern, UV and FTIR spectra confirmed that ASC-SB and PSC-SB were mainly composed of type I collagen. FTIR spectra data indicated there were more hydrogen bonding and intermolecular crosslinks in ASC-SB. These collagens showed high solubility in the acidic pH ranges and low NaCl concentrations (less than 2%). The Zeta potential values of ASC-SB and PSC-SB were 6.74 and 6.85, respectively. ASC-SB and PSC-SB presented irregular, dense, sheet-like films linked by random-coiled filaments under scanning electron microscopy. In addition, ASC-SB and PSC-SB could scavenge DPPH radical, hydroxyl radical, superoxide anion radical, and ABTS radical in a dose-dependent manner. Overall, the results indicate that collagens from the swim bladders of miiuy croaker are a viable substitute for mammalian collagen, with potential functional food and cosmeceutical applications. PMID- 29757238 TI - The Initiation of Th2 Immunity Towards Food Allergens. AB - In contrast with Th1 immune responses against pathogenic viruses and bacteria, the incipient events that generate Th2 responses remain less understood. One difficulty in the identification of universal operating principles stems from the diversity of entities against which cellular and molecular Th2 responses are produced. Such responses are launched against harmful macroscopic parasites and noxious substances, such as venoms, but also against largely innocuous allergens. This suggests that the established understanding about sense and recognition applied to Th1 responses may not be translatable to Th2 responses. This review will discuss processes and signals known to occur in Th2 responses, particularly in the context of food allergy. We propose that perturbations of homeostasis at barrier sites induced by external or internal subverters, which can activate or lower the threshold activation of the immune system, are the major requirement for allergic sensitization. Innate signals produced in the tissue under these conditions equip dendritic cells with a program that forms an adaptive Th2 response. PMID- 29757241 TI - Sparsity-Driven Reconstruction Technique for Microwave/Millimeter-Wave Computational Imaging. AB - Numerous prototypes of computational imaging systems have recently been presented in the microwave and millimeter-wave domains, enabling the simplification of associated active architectures through the use of radiating cavities and metasurfaces that can multiplex signals encoded in the physical layer. This paper presents a new reconstruction technique leveraging the sparsity of the signals in the time-domain and decomposition of the sensing matrix. PMID- 29757242 TI - Hybrid Transverse Polar Navigation for High-Precision and Long-Term INSs. AB - Transverse navigation has been proposed to help inertial navigation systems (INSs) fill the gap of polar navigation ability. However, as the transverse system does not have the ability of navigate globally, a complicated switch between the transverse and the traditional algorithms is necessary when the system moves across the polar circles. To maintain the inner continuity and consistency of the core algorithm, a hybrid transverse polar navigation is proposed in this research based on a combination of Earth-fixed-frame mechanization and transverse-frame outputs. Furthermore, a thorough analysis of kinematic error characteristics, proper damping technology and corresponding long term contributions of main error sources is conducted for the high-precision INSs. According to the analytical expressions of the long-term navigation errors in polar areas, the 24-h period symmetrical oscillation with a slowly divergent amplitude dominates the transverse horizontal position errors, and the first order drift dominates the transverse azimuth error, which results from the gyro drift coefficients that occur in corresponding directions. Simulations are conducted to validate the theoretical analysis and the deduced analytical expressions. The results show that the proposed hybrid transverse navigation can ensure the same accuracy and oscillation characteristics in polar areas as the traditional algorithm in low and mid latitude regions. PMID- 29757243 TI - A Hybrid TDMA/CSMA-Based Wireless Sensor and Data Transmission Network for ORS Intra-Microsatellite Applications. AB - To achieve launch-on-demand for Operationally Responsive Space (ORS) missions, in this article, an intra-satellite wireless network (ISWN) is presented. It provides a wireless and modularized scheme for intra-spacecraft sensing and data buses. By removing the wired data bus, the commercial off-the-shelf (COTS) based wireless modular architecture will reduce both the volume and weight of the satellite platform, thus achieving rapid design and cost savings in development and launching. Based on the on-orbit data demand analysis, a hybrid time division multiple access/carrier sense multiple access (TDMA/CSMA) protocol is proposed. It includes an improved clear channel assessment (CCA) mechanism and a traffic adaptive slot allocation method. To analyze the access process, a Markov model is constructed. Then a detailed calculation is given in which the unsaturated cases are considered. Through simulations, the proposed protocol is proved to commendably satisfy the demands and performs better than existing schemes. It helps to build a full-wireless satellite instead of the current wired ones, and will contribute to provide dynamic space capabilities for ORS missions. PMID- 29757235 TI - Clinically Applicable Inhibitors Impacting Genome Stability. AB - Advances in technology have facilitated the molecular profiling (genomic and transcriptomic) of tumours, and has led to improved stratification of patients and the individualisation of treatment regimes. To fully realize the potential of truly personalised treatment options, we need targeted therapies that precisely disrupt the compensatory pathways identified by profiling which allow tumours to survive or gain resistance to treatments. Here, we discuss recent advances in novel therapies that impact the genome (chromosomes and chromatin), pathways targeted and the stage of the pathways targeted. The current state of research will be discussed, with a focus on compounds that have advanced into trials (clinical and pre-clinical). We will discuss inhibitors of specific DNA damage responses and other genome stability pathways, including those in development, which are likely to synergistically combine with current therapeutic options. Tumour profiling data, combined with the knowledge of new treatments that affect the regulation of essential tumour signalling pathways, is revealing fundamental insights into cancer progression and resistance mechanisms. This is the forefront of the next evolution of advanced oncology medicine that will ultimately lead to improved survival and may, one day, result in many cancers becoming chronic conditions, rather than fatal diseases. PMID- 29757244 TI - A Key Pre-Distribution Scheme Based on u-PBIBD for Enhancing Resilience in Wireless Sensor Networks. AB - Many key pre-distribution (KPD) schemes based on combinatorial design were proposed for secure communication of wireless sensor networks (WSNs). Due to complexity of constructing the combinatorial design, it is infeasible to generate key rings using the corresponding combinatorial design in large scale deployment of WSNs. In this paper, we present a definition of new combinatorial design, termed “µ-partially balanced incomplete block design (µ PBIBD)”, which is a refinement of partially balanced incomplete block design (PBIBD), and then describe a 2-D construction of µ-PBIBD which is mapped to KPD in WSNs. Our approach is of simple construction which provides a strong key connectivity and a poor network resilience. To improve the network resilience of KPD based on 2-D µ-PBIBD, we propose a KPD scheme based on 3 D Ex-µ-PBIBD which is a construction of µ-PBIBD from 2-D space to 3-D space. Ex-µ-PBIBD KPD scheme improves network scalability and resilience while has better key connectivity. Theoretical analysis and comparison with the related schemes show that key pre-distribution scheme based on Ex-µ-PBIBD provides high network resilience and better key scalability, while it achieves a trade-off between network resilience and network connectivity. PMID- 29757245 TI - Rapid Automatized Naming, Verbal Working Memory, and Rhythm Discrimination as Predictors of Reading in Italian Undergraduate Students with and without Dyslexia. AB - Whereas the clinical manifestations and the neuropsychological predictors of Developmental Dyslexia (DD) are already well documented in Italian-speaking children, empirical evidence on DD in Italian adults is in contrast rather scarce. The aim of the present study was to investigate the role of a subset of neuropsychological skills, which have been identified by previous literature to be related to reading, in the decoding abilities of a group of Italian undergraduates with and without DD. For this purpose, 39 university students aged between 19 and 27 years, 19 of whom with a diagnosis of DD, underwent an assessment battery including standardized reading tests, rapid automatized naming (RAN), verbal working memory, and rhythmic pattern discrimination tests. Cross group differences confirmed significantly lower performances of undergraduates with DD in all measures but rhythm discrimination, compared to typical readers, thus showing a non-compensated neuropsychological profile. Regression analyses showed that, while reading speed was strongly and uniquely predicted by RAN speed, reading accuracy was concurrently predicted by RAN and rhythmic abilities. Finally, RAN speed emerged as a strong predictor of reading performance and risk of receiving a diagnosis of DD. PMID- 29757246 TI - A Novel Mach-Zehnder Interferometer Using Eccentric-Core Fiber Design for Optical Coherence Tomography. AB - A novel Mach-Zehnder interferometer using eccentric-core fiber (ECF) design for optical coherence tomography (OCT) is proposed and demonstrated. Instead of the commercial single-mode fiber (SMF), the ECF is used as one interference arm of the implementation. Because of the offset location of the eccentric core, it is sensitive to directional bending and the optical path difference (OPD) of two interference arms can be adjusted with high precision. The birefringence of ECF is calculated and experimentally measured, which demonstrates the polarization sensitivity of the ECF proposed in the paper is similar to that of SMF. Such a structure can replace the reference optical delay line to form an all-fiber passive device. A mirror is used as a sample for analyzing the ECF bending responses of the system. Besides, four pieces of overlapping glass slides as sample are experimentally measured as well. PMID- 29757247 TI - Enrichment and Purification of Total Ginkgo Flavonoid O-Glycosides from Ginkgo Biloba Extract with Macroporous Resin and Evaluation of Anti-Inflammation Activities In Vitro. AB - In the present study, the performance and separation characteristics of six macroporous resins for the enrichment and purification of total ginkgo flavonoid O-glycosides (TGFs) (quercetin (I), kaempferol (II), isorhamnetin (III)) from Ginkgo Biloba extracts (EGB) are evaluated. The adsorption and desorption properties of TGFs are studied on macroporous resins, including D101, D201, AB-8, HPD400, D301, and D311. Along with the results, AB-8 resin exhibits the best adsorption and desorption capacity for these three ginkgo flavonoid O-glycosides among the six resins. Adsorption isotherms are created on AB-8 resin and fit well to the Langmuir (R2 > 0.96) and Freundlich (R2 > 0.92, 0.3 < 1/n < 0.7) models. After the treatment with gradient elution on AB-8 resin packed chromatography column, the contents of the three main ginkgo flavonoid O-glycosides (I, II, and III) increase from 8.93%, 9.88%, and 6.11% in the extracts to 30.12%, 35.21%, and 14.14%, respectively, in the product. The recoveries of compounds I, II, and III are 88.76%, 93.78%, and 60.90%, respectively. Additionally, the anti-inflammatory effects of TGFs are evaluated in LPS-treated RAW 264.7 macrophages, and the result demonstrates that TGFs could significantly inhibit LPS-induced NO release in vitro in a dose-dependent manner compared with the control group. These findings suggest that TGFs could potentially be natural antioxidants and anti inflammatory ingredients that could be used in pharmaceutical products and functional food additives. PMID- 29757248 TI - Monitoring of Cardiorespiratory Signals Using Thermal Imaging: A Pilot Study on Healthy Human Subjects. AB - Heart rate (HR) and respiratory rate (RR) are important parameters for patient assessment. However, current measurement techniques require attachment of sensors to the patient’s body, often leading to discomfort, stress and even pain. A new algorithm is presented for monitoring both HR and RR using thermal imaging. The cyclical ejection of blood flow from the heart to the head (through carotid arteries and thoracic aorta) leads to periodic movements of the head; these vertical movements are used to assess HR. Respiratory rate is estimated by using temperature fluctuations under the nose during the respiratory cycle. To test the viability and feasibility of this approach, a pilot study was conducted with 20 healthy subjects (aged 18-36 and 1 aged 50 years). The study consisted of two phases: phase A (frontal view acquisitions) and phase B (side view acquisitions). To validate the results, photoplethysmography and thoracic effort (piezoplethysmography) were simultaneously recorded. High agreement between infrared thermography and ground truth/gold standard was achieved. For HR, the root-mean-square errors (RMSE) for phases A and B were 3.53 +/- 1.53 and 3.43 +/- 1.61 beats per minute, respectively. For RR, the RMSE between thermal imaging and piezoplethysmography stayed around 0.71 +/- 0.30 breaths per minute (phase A). This study demonstrates that infrared thermography may be a promising, clinically relevant alternative for the assessment of HR and RR. PMID- 29757249 TI - Frequency Invariability of (Pb,La)(Zr,Ti)O3 Antiferroelectric Thick-Film Micro Cantilevers. AB - Micro-electromechanical systems comprising antiferroelectric layers can offer both actuation and transduction to integrated technologies. Micro-cantilevers based on the (Pb0.97La0.02)(Zr0.95Ti0.05)O3 (PLZT) antiferroelectric thick film are fabricated by the micro-nano manufacturing process, to utilize the effect of phase transition induced strain and sharp phase switch of antiferroelectric materials. When micro-cantilevers made of antiferroelectric thick films were driven by sweep voltages, there were two resonant peaks corresponding to the natural frequency shift from 27.8 to 27.0 kHz, before and after phase transition. This is the compensation principle for the PLZT micro-cantilever to tune the natural frequency by the amplitude modulation of driving voltage, rather than of frequency modulation. Considering the natural frequency shift about 0.8 kHz and the frequency tuning ability about 156 Hz/V before the phase transition, this can compensate the frequency shift caused by increasing temperature by tuning only the amplitude of driving voltage, when the ultrasonic micro-transducer made of antiferroelectric thick films works for such a long period. Therefore, antiferroelectric thick films with hetero-structures incorporated into PLZT micro cantilevers not only require a lower driving voltage (no more than 40 V) than rival bulk piezoelectric ceramics, but also exhibit better performance of frequency invariability, based on the amplitude modulation. PMID- 29757251 TI - Integral Sensor Fault Detection and Isolation for Railway Traction Drive. AB - Due to the increasing importance of reliability and availability of electric traction drives in Railway applications, early detection of faults has become an important key for Railway traction drive manufacturers. Sensor faults are important sources of failures. Among the different fault diagnosis approaches, in this article an integral diagnosis strategy for sensors in traction drives is presented. Such strategy is composed of an observer-based approach for direct current (DC)-link voltage and catenary current sensors, a frequency analysis approach for motor current phase sensors and a hardware redundancy solution for speed sensors. None of them requires any hardware change requirement in the actual traction drive. All the fault detection and isolation approaches have been validated in a Hardware-in-the-loop platform comprising a Real Time Simulator and a commercial Traction Control Unit for a tram. In comparison to safety-critical systems in Aerospace applications, Railway applications do not need instantaneous detection, and the diagnosis is validated in a short time period for reliable decision. Combining the different approaches and existing hardware redundancy, an integral fault diagnosis solution is provided, to detect and isolate faults in all the sensors installed in the traction drive. PMID- 29757252 TI - Biological Oscillators in Nanonetworks-Opportunities and Challenges. AB - One of the major issues in molecular communication-based nanonetworks is the provision and maintenance of a common time knowledge. To stay true to the definition of molecular communication, biological oscillators are the potential solutions to achieve that goal as they generate oscillations through periodic fluctuations in the concentrations of molecules. Through the lens of a communication systems engineer, the scope of this survey is to explicitly classify, for the first time, existing biological oscillators based on whether they are found in nature or not, to discuss, in a tutorial fashion, the main principles that govern the oscillations in each oscillator, and to analyze oscillator parameters that are most relevant to communication engineer researchers. In addition, the survey highlights and addresses the key open research issues pertaining to several physical aspects of the oscillators and the adoption and implementation of the oscillators to nanonetworks. Moreover, key research directions are discussed. PMID- 29757253 TI - Association of Cardiovascular Health with Epicardial Adipose Tissue and Intima Media Thickness: The Kardiovize Study. AB - Background: Intima-media thickness (IMT) has been proposed as a measurement of subclinical atherosclerosis and has been associated with cardiovascular disease (CVD). Epicardial adipose tissue (EAT) is a fat depot between the pericardium and myocardium and has been associated with coronary atherosclerosis. The relationship between IMT and EAT thickness has not been reported before. We investigated the relationship between EAT thickness, IMT, CVD risk factors, and ideal cardiovascular health (CVH) metrics using subjects from the Kardiovize Brno 2030 cohort study, a random urban sample population in Central Europe. Methods: We studied 102 individuals (65 males) aged 25-64 years (median = 37 years) with no current or past CVD history. We measured IMT using a vascular ultrasound and EAT thickness using transthoracic echocardiography, and collected data on anthropometric factors, CVD risk factors, and CVH score. Correlation tests and multiple linear regression models were applied. Results: In the age- and gender adjusted model, we demonstrated that, among CVD risk factors, only BMI was significantly and positively associated with EAT thickness (β = 0.182, SE = 0.082, p = 0.030), while no significant associations with IMT were evident. Although both EAT thickness and IMT were negatively correlated with CVH score (r = −0.45, p < 0.001, and r = −0.38, p < 0.001, respectively), we demonstrated that overall CVH score (β = −0.262; SE = 0.077; p = 0.001), as well as BMI (β = −1.305; SE = 0.194; p < 0.001) and blood pressure CVH metrics (β = −0.607; SE = 0.206; p = 0.004) were significantly associated with EAT thickness but not with IMT. Conclusions: Our study is important as it demonstrated for the first time that CVH is associated with EAT thickness. Interestingly, this relationship seems to be dependent on BMI and blood pressure rather than on the other CVH metrics. However, outcome-driven studies are required to confirm these findings. PMID- 29757254 TI - The Importance of Nidotherapy and Environmental Change in the Management of People with Complex Mental Disorders. AB - Much has been done in the last 50 years to achieve a better understanding of the psychosocial causes and other factors influencing the manifestation of mental illness, but there has been a conspicuous omission. Although gross environmental deficiencies were exposed in old mental institutions, 70 years ago the more subtle maladaptive settings that reinforce chronicity in mental illness have often been forgotten. In this review, the potential of systematic environmental manipulation as a treatment (nidotherapy) and other similar forms of management, used many times in the past but now mainly in forensic settings, is examined. There is now accumulating evidence, reinforced by controlled trials, that planned environmental change, preferably carried out with the full cooperation of the patient, can be a major contributor to therapeutic benefit. It is also very cost effective. All forms of the environment, physical, social and personal, can be addressed in making assessments, and once a planned way forward has been chosen, progress can be monitored by personnel with limited mental health experience. These interventions have applications in general mental health and occupational health services and deserve much wider use. PMID- 29757255 TI - Assessment of a Targeted Trap-Neuter-Return Pilot Study in Auckland, New Zealand. AB - There is a need for effective and humane management tools to manage urban stray cats and minimise negative impacts associated with stray cats. One such tool is targeted trap-neuter-return (TTNR), but no concerted implementation of this technique or formal assessments have been reported. To address this deficit, a TTNR programme was implemented and assessed in one Auckland suburb from May 2015 to June 2016; the programme sterilised and returned 348 cats (4.2 cats/1000 residents). Assessment was based on the number of incoming felines; stray, unsocialised cats euthanased; unsocialised, unowned cats sterilised and returned (independently of the TTNR programme); and neonatal/underage euthanasias. Incoming stray felines, underage euthanasias, and unsocialised stray cat euthanasias were all reduced for the targeted suburb when compared for the years before and after the programme (the percentage reduction in these parameters was −39, −17, −34, −7, and −47, respectively). These outcome measures had a greater reduction in the targeted suburb compared to the Auckland suburbs not targeted by the TTNR programme (p < 0.01), although causation cannot be inferred, as a variety of reasons could have contributed to the changes. This pilot programme suggests that TTNR could be a valuable, humane cat management tool in urban New Zealand, and further assessment is warranted. PMID- 29757250 TI - Ascidian Toxins with Potential for Drug Development. AB - Ascidians (tunicates) are invertebrate chordates, and prolific producers of a wide variety of biologically active secondary metabolites from cyclic peptides to aromatic alkaloids. Several of these compounds have properties which make them candidates for potential new drugs to treat diseases such as cancer. Many of these natural products are not produced by the ascidians themselves, rather by their associated symbionts. This review will focus mainly on the mechanism of action of important classes of cytotoxic molecules isolated from ascidians. These toxins affect DNA transcription, protein translation, drug efflux pumps, signaling pathways and the cytoskeleton. Two ascidian compounds have already found applications in the treatment of cancer and others are being investigated for their potential in cancer, neurodegenerative and other diseases. PMID- 29757256 TI - Social Networks and Health: Understanding the Nuances of Healthcare Access between Urban and Rural Populations. AB - Communities and individuals in many sub-Saharan African countries often face limited access to healthcare. Hence, many rely on social networks to enhance their chances for adequate health care. While this knowledge is well-established, little is known about the nuances of how different population groups activate these networks to improve access to healthcare. This paper examines how rural and urban dwellers in the Ashanti Region in Ghana distinctively and systematically activate their social networks to enhance access to healthcare. It uses a qualitative cross-sectional design, with in-depth interviews of 79 primary participants (28 urban and 51 rural residents) in addition to the views of eight community leaders and eight health personnel. It was discovered that both intimate and distanced social networks for healthcare are activated at different periods by rural and urban residents. Four main stages of social networks activation, comprising different individuals and groups were observed among rural and urban dwellers. Among both groups, physical proximity, privacy, trust and sense of fairness, socio-cultural meaning attached to health problems, and perceived knowledge and other resources (mainly money) held in specific networks inherently influenced social network activation. The paper posits that a critical analysis of social networks may help to tailor policy contents to individuals and groups with limited access to healthcare. PMID- 29757257 TI - mTOR Pathway in Papillary Thyroid Carcinoma: Different Contributions of mTORC1 and mTORC2 Complexes for Tumor Behavior and SLC5A5 mRNA Expression. AB - The mammalian target of rapamycin (mTOR) pathway is overactivated in thyroid cancer (TC). We previously demonstrated that phospho-mTOR expression is associated with tumor aggressiveness, therapy resistance, and lower mRNA expression of SLC5A5 in papillary thyroid carcinoma (PTC), while phospho-S6 (mTORC1 effector) expression was associated with less aggressive clinicopathological features. The distinct behavior of the two markers led us to hypothesize that mTOR activation may be contributing to a preferential activation of the mTORC2 complex. To approach this question, we performed immunohistochemistry for phospho-AKT Ser473 (mTORC2 effector) in a series of 182 PTCs previously characterized for phospho-mTOR and phospho-S6 expression. We evaluated the impact of each mTOR complex on SLC5A5 mRNA expression by treating cell lines with RAD001 (mTORC1 blocker) and Torin2 (mTORC1 and mTORC2 blocker). Phospho-AKT Ser473 expression was positively correlated with phospho-mTOR expression. Nuclear expression of phospho-AKT Ser473 was significantly associated with the presence of distant metastases. Treatment of cell lines with RAD001 did not increase SLC5A5 mRNA levels, whereas Torin2 caused a ~6 fold increase in SLC5A5 mRNA expression in the TPC1 cell line. In PTC, phospho-mTOR activation may lead to the activation of the mTORC2 complex. Its downstream effector, phospho AKT Ser473, may be implicated in distant metastization, therapy resistance, and downregulation of SLC5A5 mRNA expression. PMID- 29757258 TI - Lipid Nanoparticles Decorated with TNF-Related Aptosis-Inducing Ligand (TRAIL) Are More Cytotoxic than Soluble Recombinant TRAIL in Sarcoma. AB - Sarcomas are rare and heterogeneous cancers classically associated with a poor outcome. Sarcomas are 1% of the cancer but recent estimations indicate that sarcomas account for 2% of the estimated cancer-related deaths. Traditional treatment with surgery, radiotherapy, and chemotherapy has improved the outcome for some types of sarcomas. However, novel therapeutic strategies to treat sarcomas are necessary. TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand initially described as capable of inducing apoptosis on tumor cell while sparing normal cells. Only few clinical trials have used TRAIL-based treatments in sarcoma, but they show only low or moderate efficacy of TRAIL. Consequently, novel TRAIL formulations with an improved TRAIL bioactivity are necessary. Our group has developed a novel TRAIL formulation based on tethering this death ligand on a lipid nanoparticle surface (LUV-TRAIL) resembling the physiological secretion of TRAIL as a trasmembrane protein inserted into the membrane of exosomes. We have already demonstrated that LUV-TRAIL shows an improved cytotoxic activity when compared to soluble recombinant TRAIL both in hematological malignancies and epithelial-derived cancers. In the present study, we have tested LUV-TRAIL in several human sarcoma tumor cell lines with different sensitivity to soluble recombinant TRAIL, finding that LUV-TRAIL was more efficient than soluble recombinant TRAIL. Moreover, combined treatment of LUV-TRAIL with distinct drugs proved to be especially effective, sensitizing even more resistant cell lines to TRAIL. PMID- 29757259 TI - Two Novel Hypovirulence-Associated Mycoviruses in the Phytopathogenic Fungus Botrytis cinerea: Molecular Characterization and Suppression of Infection Cushion Formation. AB - Botrytis cinerea is a necrotrophic fungus causing disease on many important agricultural crops. Two novel mycoviruses, namely Botrytis cinerea hypovirus 1 (BcHV1) and Botrytis cinerea fusarivirus 1 (BcFV1), were fully sequenced. The genome of BcHV1 is 10,214 nt long excluding a poly-A tail and possesses one large open reading frame (ORF) encoding a polyprotein possessing several conserved domains including RNA-dependent RNA polymerase (RdRp), showing homology to hypovirus-encoded polyproteins. Phylogenetic analysis indicated that BcHV1 may belong to the proposed genus Betahypovirus in the viral family Hypoviridae. The genome of BcFV1 is 8411 nt in length excluding the poly A tail and theoretically processes two major ORFs, namely ORF1 and ORF2. The larger ORF1 encoded polypeptide contains protein domains of an RdRp and a viral helicase, whereas the function of smaller ORF2 remains unknown. The BcFV1 was phylogenetically clustered with other fusariviruses forming an independent branch, indicating BcFV1 was a member in Fusariviridae. Both BcHV1 and BcFV1 were capable of being transmitted horizontally through hyphal anastomosis. Infection by BcHV1 alone caused attenuated virulence without affecting mycelial growth, significantly inhibited infection cushion (IC) formation, and altered expression of several IC formation-associated genes. However, wound inoculation could fully rescue the virulence phenotype of the BcHV1 infected isolate. These results indicate the BcHV1-associated hypovirulence is caused by the viral influence on IC-formation associated pathways. PMID- 29757261 TI - Design of an Inertial-Sensor-Based Data Glove for Hand Function Evaluation. AB - Capturing hand motions for hand function evaluations is essential in the medical field. Various data gloves have been developed for rehabilitation and manual dexterity assessments. This study proposed a modular data glove with 9-axis inertial measurement units (IMUs) to obtain static and dynamic parameters during hand function evaluation. A sensor fusion algorithm is used to calculate the range of motion of joints. The data glove is designed to have low cost, easy wearability, and high reliability. Owing to the modular design, the IMU board is independent and extensible and can be used with various microcontrollers to realize more medical applications. This design greatly enhances the stability and maintainability of the glove. PMID- 29757260 TI - Involvement of MAFB and MAFF in Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion. AB - Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma (HCC). All-trans-retinoic acid (ATRA) was used in the in vitro experiments. Cell invasiveness was measured using trans-well invasion assay. ATRA significantly increased TFPI2 expression through RARα in a human HCC cell line known as HuH7. TFPI2 was vital in the ATRA-mediated suppression of HuH7 cell invasion. The musculo-aponeurotic fibrosarcoma oncogene homolog B (MAFB) significantly enhanced the activation of the TFPI2 promoter via RARα while MAFF inhibited it. The knockdown of RARα or MAFB counteracted the ATRA-mediated suppression of HuH7 cell invasion while the knockdown of MAFF inhibited the invasion. TFPI2 expression in HCC tissues was significantly downregulated possibly due to the decreased expression of RARβ and MAFB. Patients with HCC expressing low MAFB and high MAFF levels showed the shortest disease-free survival time. These results suggest that MAFB and MAFF play critical roles in the antitumor effects of retinoids by regulating the expression of retinoid target genes such as TFPI2 and can be promising for developing therapies to combat HCC invasion. PMID- 29757262 TI - Preliminary Assessment of Hurricane Harvey Exposures and Mental Health Impact. AB - Hurricane Harvey made landfall in Houston, Texas on 25 August 2017, the psychological and physical effects of which are still unknown. We assessed hurricane exposure and the immediate mental health needs of the population to define public health priorities for a larger epidemiological study. Convenience sampling was used to recruit participants (n = 41) from the greater Houston area aged ≥18 years. Participants completed a questionnaire about demographics, hurricane exposures, and physical/mental health. Post-Traumatic Stress Disorder (PTSD) was measured with the Post-Traumatic Stress Disorder Checklist-S (PCL-S; a score ≥30 indicated probable PTSD symptoms). The Patient Health Questionnaire 4 (PHQ-4) was used to assess symptoms of depression and generalized anxiety disorder. The average PTSD score was 32.9 (SD = 17.1); a total of 46% of participants met the threshold for probable PTSD. Increased overall hurricane exposure (adjusted odds ratio (ORadj) 1.42; 95% confidence interval (CI): 1.06 2.05) and property-related exposure (ORadj 1.53; 95% CI: 1.07-2.18) were both statistically significantly associated with increased odds of probable PTSD symptoms. A perception of chemical/toxin exposure due to Hurricane Harvey was reported by 44% of participants. A higher number of personal or property exposures were associated with greater mental health symptoms three weeks post hurricane. This work has implications for the ongoing response to Hurricane Harvey and for assessing the immediate needs of the population. PMID- 29757263 TI - Impacts of Different Functional Groups on the Kinetic Rates of alpha-Amine Ketoximesilanes Hydrolysis in the Preparation of Room Temperature Vulcanized Silicone Rubber. AB - α-Amine ketoximesilanes are proven to be effective crosslinkers in the preparation of ketone-oxime one-component room temperature vulcanized (RTV) silicone rubber without the use of toxic metal catalyst. This work aimed to investigate the hydrolysis kinetic of α-amine ketoximesilanes, which is vitally important for the preparation of RTV silicone rubber. Five kinds of α-amine ketoximesilanes, namely α-(N,N diethyl)aminomethyltri(methylethylketoxime)silane (DEMOS), α-(N,N-di-n butyl)aminomethyltri(methylethylketoxime)silane (DBMOS), α-(N-n butyl)aminomethyltri(methylethylketoxime)silane (n-BMOS), α-(N cyclohexyl)aminomethyltri(methylethylketoxime)silane (CMOS) and α-(β aminomethyl)aminomethyltri(methylethylketoxime)silane (AEMOS), were successfully obtained and confirmed using Fourier transform infrared spectrometer (FT-IR) and hydrogen-1 nuclear magnetic resonance ( 1H NMR). Kinetics of hydrolysis reactions were measured by FT-IR and conductivity. Our results illustrated that the kinetic constant rates ranged from 12.2 × 10−4 s−1 to 7.6 × 10−4 s−1, with the decreasing order of DEMOS > n-BMOS > DBMOS > CMOS > AEMOS at the given temperature and humidity. Better performances of thermal stability could be achieved when using the α-amine ketoximesilanes as crosslinkers in the preparation of RTV silicon rubber than that of RTV silicone rubber with the use of methyltri(methylethylketoxime)silane (MOS) as a crosslinker and organic tin as a catalyst. PMID- 29757264 TI - Characterization of a Microbial Consortium for the Bioremoval of Polycyclic Aromatic Hydrocarbons (PAHs) in Water. AB - Pollution of freshwater ecosystems from polycyclic aromatic hydrocarbons (PAHs) is a global concern. The US Environmental Protection Agency (EPA) has included the PAHs pyrene, phenanthrene, and naphthalene among the 16 priority compounds of special concern for their toxicological effects. The aim of this study was to adapt and characterize a microbial consortium from ore waste with the potential to remove these three PAHs from water. This microbial consortium was exposed to the target PAHs at levels of 5, 10, 20, 50, and 100 mg L−1 for 14 days. PAH bioremoval was measured using the analytical technique of solid phase microextraction, followed by gas chromatography mass spectrometry (SPME-GC/MS). The results revealed that up to 90% of the target PAHs can be removed from water after 14 days at a concentration level of 100 mg L−1. The predominant group of microorganisms identified at the phylum taxonomic level were the Proteobacteria, while the Actinobacteria were the predominant subgroup. The removal of phenanthrene, naphthalene, and pyrene predominantly occurred in specimens of genera Stenotrophomonas, Williamsia, and Chitinophagaceae, respectively. This study demonstrates that the use of specific microorganisms is an alternative method of reducing PAH levels in water. PMID- 29757265 TI - Application and Comparison of the MODIS-Derived Enhanced Vegetation Index to VIIRS, Landsat 5 TM and Landsat 8 OLI Platforms: A Case Study in the Arid Colorado River Delta, Mexico. AB - The Enhanced Vegetation Index (EVI) is a key Earth science parameter used to assess vegetation, originally developed and calibrated for the Moderate Resolution Imaging Spectroradiometer (MODIS) aboard the Terra and Aqua satellites. With the impending decommissioning of the MODIS sensors by the year 2020/2022, alternative platforms will need to be used to estimate EVI. We compared Landsat 5 (2000-2011), 8 (2013-2016) and the Visible Infrared Imaging Radiometer Suite (VIIRS; 2013-2016) to MODIS EVI (2000-2016) over a 420,083-ha area of the arid lower Colorado River Delta in Mexico. Over large areas with mixed land cover or agricultural fields, we found high correspondence between Landsat and MODIS EVI (R2 = 0.93 for the entire area studied and 0.97 for agricultural fields), but the relationship was weak over bare soil (R2 = 0.27) and riparian vegetation (R2 = 0.48). The correlation between MODIS and Landsat EVI was higher over large, homogeneous areas and was generally lower in narrow riparian areas. VIIRS and MODIS EVI were highly similar (R2 = 0.99 for the entire area studied) and did not show the same decrease in performance in smaller, narrower regions as Landsat. Landsat and VIIRS provide EVI estimates of similar quality and characteristics to MODIS, but scale, seasonality and land cover type(s) should be considered before implementing Landsat EVI in a particular area. PMID- 29757266 TI - Spatial and Temporal Control of T Cell Activation Using a Photoactivatable Agonist. AB - T lymphocytes engage in rapid, polarized signaling, occurring within minutes following TCR activation. This induces formation of the immunological synapse, a stereotyped cell-cell junction that regulates T cell activation and directionally targets effector responses. To study these processes effectively, an imaging approach that is tailored to capturing fast, polarized responses is necessary. This protocol describes such a system, which is based on a photoactivatable peptide-major histocompatibility complex (pMHC) that is non-stimulatory until it is exposed to ultraviolet light. Targeted decaging of this reagent during videomicroscopy experiments enables precise spatiotemporal control of TCR activation and high-resolution monitoring of subsequent cellular responses by total internal reflection (TIRF) imaging. This approach is also compatible with genetic and pharmacological perturbation strategies. This allows for the assembly of well-defined molecular pathways that link TCR signaling to the formation of the polarized cytoskeletal structures that underlie the immunological synapse. PMID- 29757267 TI - Assessment of the Effects of Endocrine Disrupting Compounds on the Development of Vertebrate Neural Network Function Using Multi-electrode Arrays. AB - Bis-phenols, such as bis-phenol A (BPA) and bis-phenol-S (BPS), are polymerizing agents widely used in the production of plastics and numerous everyday products. They are classified as endocrine disrupting compounds (EDC) with estradiol-like properties. Long-term exposure to EDCs, even at low doses, has been linked with various health defects including cancer, behavioral disorders, and infertility, with greater vulnerability during early developmental periods. To study the effects of BPA on the development of neuronal function, we used an in vitro neuronal network derived from the early chick embryonic brain as a model. We found that exposure to BPA affected the development of network activity, specifically spiking activity and synchronization. A change in network activity is the crucial link between the molecular target of a drug or compound and its effect on behavioral outcome. Multi-electrode arrays are increasingly becoming useful tools to study the effects of drugs on network activity in vitro. There are several systems available in the market and, although there are variations in the number of electrodes, the type and quality of the electrode array and the analysis software, the basic underlying principles, and the data obtained is the same across the different systems. Although currently limited to analysis of two dimensional in vitro cultures, these MEA systems are being improved to enable in vivo network activity in brain slices. Here, we provide a detailed protocol for embryonic exposure and recording neuronal network activity and synchrony, along with representative results. PMID- 29757268 TI - Well-aligned Vertically Oriented ZnO Nanorod Arrays and their Application in Inverted Small Molecule Solar Cells. AB - This manuscript describes how to design and fabricate efficient inverted solar cells, which are based on a two-dimensional conjugated small molecule (SMPV1) and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM), by utilizing ZnO nanorods (NRs) grown on a high quality Al-doped ZnO (AZO) seed layer. The inverted SMPV1:PC71BM solar cells with ZnO NRs that grew on both a sputtered and sol-gel processed AZO seed layer are fabricated. Compared with the AZO thin film prepared by the sol-gel method, the sputtered AZO thin film exhibits better crystallization and lower surface roughness, according to X-ray diffraction (XRD) and atomic force microscope (AFM) measurements. The orientation of the ZnO NRs grown on a sputtered AZO seed layer shows better vertical alignment, which is beneficial for the deposition of the subsequent active layer, forming better surface morphologies. Generally, the surface morphology of the active layer mainly dominates the fill factor (FF) of the devices. Consequently, the well aligned ZnO NRs can be used to improve the carrier collection of the active layer and to increase the FF of the solar cells. Moreover, as an anti-reflection structure, it can also be utilized to enhance the light harvesting of the absorption layer, with the power conversion efficiency (PCE) of solar cells reaching 6.01%, higher than the sol-gel based solar cells with an efficiency of 4.74%. PMID- 29757269 TI - Combining Quantitative Food-intake Assays and Forcibly Activating Neurons to Study Appetite in Drosophila. AB - Food consumption is under the tight control of the brain, which integrates the physiological status, palatability, and nutritional contents of the food, and issues commands to start or stop feeding. Deciphering the processes underlying the decision-making of timely and moderate feeding carries major implications in our understanding of physiological and psychological disorders related to feeding control. Simple, quantitative, and robust methods are required to measure the food ingestion of animals after experimental manipulation, such as forcibly increasing the activities of certain target neurons. Here, we introduced dye labeling-based feeding assays to facilitate the neurogenetic study of feeding control in adult fruit flies. We review available feeding assays, and then describe our methods step-by-step from setup to analysis, which combine thermogenetic and optogenetic manipulation of neurons controlling feeding motivation with dye-labeled food intake assay. We also discuss the advantages and limitations of our methods, compared with other feeding assays, to help readers choose an appropriate assay. PMID- 29757270 TI - Establishing Mouse Models for Zika Virus-induced Neurological Disorders Using Intracerebral Injection Strategies: Embryonic, Neonatal, and Adult. AB - The Zika virus (ZIKV) is a flavivirus currently endemic in North, Central, and South America. It is now established that the ZIKV can cause microcephaly and additional brain abnormalities. However, the mechanism underlying the pathogenesis of ZIKV in the developing brain remains unclear. Intracerebral surgical methods are frequently used in neuroscience research to address questions about both normal and abnormal brain development and brain function. This protocol utilizes classical surgical techniques and describes methods that allow one to model ZIKV-associated human neurological disease in the mouse nervous system. While direct brain inoculation does not model the normal mode of virus transmission, the method allows investigators to ask targeted questions concerning the consequence after ZIKV infection of the developing brain. This protocol describes embryonic, neonatal, and adult stages of intraventricular inoculation of ZIKV. Once mastered, this method can become a straightforward and reproducible technique that only takes a few hours to perform. PMID- 29757271 TI - The Isolation and Culture of Primary Epicardial Cells Derived from Human Adult and Fetal Heart Specimens. AB - The epicardium, an epithelial cell layer covering the myocardium, has an essential role during cardiac development, as well as in the repair response of the heart after ischemic injury. When activated, epicardial cells undergo a process known as epithelial to mesenchymal transition (EMT) to provide cells to the regenerating myocardium. Furthermore, the epicardium contributes via secretion of essential paracrine factors. To fully appreciate the regenerative potential of the epicardium, a human cell model is required. Here we outline a novel cell culture model to derive primary epicardial derived cells (EPDCs) from human adult and fetal cardiac tissue. To isolate EPDCs, the epicardium is dissected from the outside of the heart specimen and processed into a single cell suspension. Next, EPDCs are plated and cultured in EPDC medium containing the ALK 5-kinase inhibitor SB431542 to maintain their epithelial phenotype. EMT is induced by stimulation with TGFbeta. This method enables, for the first time, the study of the process of human epicardial EMT in a controlled setting, and facilitates gaining more insight in the secretome of EPDCs that may aid heart regeneration. Furthermore, this uniform approach allows for direct comparison of human adult and fetal epicardial behavior. PMID- 29757272 TI - Visualization of Cellular Electrical Activity in Zebrafish Early Embryos and Tumors. AB - Bioelectricity, endogenous electrical signaling mediated by ion channels and pumps located on the cell membrane, plays important roles in signaling processes of excitable neuronal and muscular cells and many other biological processes, such as embryonic developmental patterning. However, there is a need for in vivo electrical activity monitoring in vertebrate embryogenesis. The advances of genetically encoded fluorescent voltage indicators (GEVIs) have made it possible to provide a solution for this challenge. Here, we describe how to create a transgenic voltage indicator zebrafish using the established voltage indicator, ASAP1 (Accelerated Sensor of Action Potentials 1), as an example. The Tol2 kit and a ubiquitous zebrafish promoter, ubi, were chosen in this study. We also explain the processes of Gateway site-specific cloning, Tol2 transposon-based zebrafish transgenesis, and the imaging process for early-stage fish embryos and fish tumors using regular epifluorescent microscopes. Using this fish line, we found that there are cellular electric voltage changes during zebrafish embryogenesis, and fish larval movement. Furthermore, it was observed that in a few zebrafish malignant peripheral nerve sheath tumors, the tumor cells were generally polarized compared to the surrounding normal tissues. PMID- 29757273 TI - Isolation and RNA Extraction of Neurons, Macrophages and Microglia from Larval Zebrafish Brains. AB - To gain a detailed understanding of the role of different CNS cells during development or the establishment and progression of brain pathologies, it is important to isolate these cells without changing their gene expression profile. The zebrafish model provides a large number of transgenic fish lines in which specific cell types are labelled; for example neurons in the NBT:DsRed line or macrophages/microglia in the mpeg1:eGFP line. Furthermore, antibodies have been developed to stain specific cells, such as microglia with the 4C4 antibody. Here, we describe the isolation of neurons, macrophages and microglia from larval zebrafish brains. Central to this protocol is the avoidance of an enzymatic tissue digestion at 37 degrees C, which could modify cellular profiles. Instead a mechanical system of tissue homogenization at 4 degrees C is used. This protocol entails homogenization of brains into cell suspension, their immuno staining and the isolation of neurons, macrophages and microglia by FACS. Afterwards, we extracted RNA from those cells and evaluated their quality/quantity. We managed to obtain RNA of high quality (RNA Integrity Number (RIN) > 7) to perform qPCR on macrophages/microglia and neurons, and transcriptomic analysis on microglia. This approach enables a better characterization of these cells, as well as a clearer understanding about their role in development and pathologies. PMID- 29757274 TI - Syntheses, Crystallization, and Spectroscopic Characterization of 3,5-Lutidine N Oxide Dehydrate. AB - The synthesis of 3,5-lutidine N-oxide dehydrate, 1, was achieved in the synthesis route of 2-amino-pyridine-3,5-dicarboxylic acid. Ochiai first used the methodology for non-substituted pyridines in 1957 in a 12 h process, but no X-ray suitable crystals were obtained. The substituted ring used in the methodology presented here clearly influenced the addition of water molecules into the asymmetric unit, which confers a different nucleophilic strength in 1. The X-ray suitable crystal compound 1 was possible due to the stabilization of the negative charge in the oxygen by the presence of two water molecules where the hydrogen atoms donate positive charge into the ring; such water molecules serve well to construct a supramolecular interaction. The hydrated molecules may be possible for the alkaline system that is reached by adjusting the pH to 10. Importantly, the double methyl substituted ring and a reaction time of 5 h, makes it a more versatile method and with wider chemical applications for future ring insertions. PMID- 29757275 TI - Isolation of Primary Human Decidual Cells from the Fetal Membranes of Term Placentae. AB - The decidua, also known as the pregnant endometrium, is a critically important reproductive tissue. Decidual cells, comprised mainly of decidualized stromal cells and immune cells, are responsible for the secretion of hormonal and inflammatory factors which are critical for successful blastocyst implantation, placental development and play a role in the initiation of labor at term and preterm. Many pregnancy complications can arise from perturbations of a fine balance of different cell populations comprising decidua. Alterations in the proportion of specific decidual cell types may disrupt these crucial processes and increase the risk of developing serious complications of pregnancy, such as embryo implantation failure, intrauterine growth restriction, preeclampsia and preterm labor. The protocol outlined here demonstrates a cost and time effective method for the isolation of primary human decidual cells collected from the fetal membranes of term placentae. By combining enzymatic digestion and gentle mechanical disruption of the decidual tissue, a high yield of decidual cells was obtained with virtually no chorion contamination. Importantly, isolated decidual cells were characterized (stromal cells (55-60%), leukocytes (35%), epithelial (1%) or trophoblast (0.01%) cells) and maintained high viability (80%) which was confirmed by multicolor imaging flow cytometry assay. This protocol is specific to the decidua parietalis and can be adapted to first and second trimester placentae. Once isolated, decidual cells can be used for a multitude of experimental applications aiming to understand the role of different decidual cell sub-populations in pregnancy complications. PMID- 29757276 TI - Fluorescence Molecular Tomography for In Vivo Imaging of Glioblastoma Xenografts. AB - Tumorigenicity is the capability of cancer cells to form a tumor mass. A widely used approach to determine if the cells are tumorigenic is by injecting immunodeficient mice subcutaneously with cancer cells and measuring the tumor mass after it becomes visible and palpable. Orthotopic injections of cancer cells aim to introduce the xenograft in the microenvironment that most closely resembles the tissue of origin of the tumor being studied. Brain cancer research requires intracranial injection of cancer cells to allow the tumor formation and analysis in the unique microenvironment of the brain. The in vivo imaging of intracranial xenografts monitors instantaneously the tumor mass of orthotopically engrafted mice. Here we report the use of fluorescence molecular tomography (FMT) of brain tumor xenografts. The cancer cells are first transduced with near infrared fluorescent proteins and then injected in the brain of immunocompromised mice. The animals are then scanned to obtain quantitative information about the tumor mass over an extended period of time. Cell pre-labeling allows for cost effective, reproducible, and reliable quantification of the tumor burden within each mouse. We eliminated the need for injecting imaging substrates, and thus reduced the stress on the animals. A limitation of this approach is represented by the inability to detect very small masses; however, it has better resolution for larger masses than other techniques. It can be applied to evaluate the efficacy of a drug treatment or genetic alterations of glioma cell lines and patient-derived samples. PMID- 29757277 TI - Profiling DNA Replication Timing Using Zebrafish as an In Vivo Model System. AB - DNA replication timing is an important cellular characteristic, exhibiting significant relationships with chromatin structure, transcription, and DNA mutation rates. Changes in replication timing occur during development and in cancer, but the role replication timing plays in development and disease is not known. Zebrafish were recently established as an in vivo model system to study replication timing. Here is detailed the protocols for using the zebrafish to determine DNA replication timing. After sorting cells from embryos and adult zebrafish, high-resolution genome-wide DNA replication timing patterns can be constructed by determining changes in DNA copy number through analysis of next generation sequencing data. The zebrafish model system allows for evaluation of the replication timing changes that occur in vivo throughout development, and can also be used to assess changes in individual cell types, disease models, or mutant lines. These methods will enable studies investigating the mechanisms and determinants of replication timing establishment and maintenance during development, the role replication timing plays in mutations and tumorigenesis, and the effects of perturbing replication timing on development and disease. PMID- 29757278 TI - A Microbiomechanical System for Studying Varicosity Formation and Recovery in Central Neuron Axons. AB - Axonal varicosities are enlarged structures along the shafts of axons with a high degree of heterogeneity. They are present not only in brains with neurodegenerative diseases or injuries, but also in the normal brain. Here, we describe a newly-established micromechanical system to rapidly, reliably, and reversibly induce axonal varicosities, allowing us to understand the mechanisms governing varicosity formation and heterogeneous protein composition. This system represents a novel means to evaluate the effects of compression and shear stress on different subcellular compartments of neurons, different from other in vitro systems that mainly focus on the effect of stretching. Importantly, owing to the unique features of our system, we recently made a novel discovery showing that the application of pressurized fluid can rapidly and reversibly induce axonal varicosities through the activation of a transient receptor potential channel. Our biomechanical system can be utilized conveniently in combination with drug perfusion, live cell imaging, calcium imaging, and patch clamp recording. Therefore, this method can be adopted for studying mechanosensitive ion channels, axonal transport regulation, axonal cytoskeleton dynamics, calcium signaling, and morphological changes related to traumatic brain injury. PMID- 29757279 TI - Engineering 'Golden' Fluorescence by Selective Pressure Incorporation of Non canonical Amino Acids and Protein Analysis by Mass Spectrometry and Fluorescence. AB - Fluorescent proteins are fundamental tools for the life sciences, in particular for fluorescence microscopy of living cells. While wild-type and engineered variants of the green fluorescent protein from Aequorea victoria (avGFP) as well as homologs from other species already cover large parts of the optical spectrum, a spectral gap remains in the near-infrared region, for which avGFP-based fluorophores are not available. Red-shifted fluorescent protein (FP) variants would substantially expand the toolkit for spectral unmixing of multiple molecular species, but the naturally occurring red-shifted FPs derived from corals or sea anemones have lower fluorescence quantum yield and inferior photo stability compared to the avGFP variants. Further manipulation and possible expansion of the chromophore's conjugated system towards the far-red spectral region is also limited by the repertoire of 20 canonical amino acids prescribed by the genetic code. To overcome these limitations, synthetic biology can achieve further spectral red-shifting via insertion of non-canonical amino acids into the chromophore triad. We describe the application of SPI to engineer avGFP variants with novel spectral properties. Protein expression is performed in a tryptophan auxotrophic E. coli strain and by supplementing growth media with suitable indole precursors. Inside the cells, these precursors are converted to the corresponding tryptophan analogs and incorporated into proteins by the ribosomal machinery in response to UGG codons. The replacement of Trp-66 in the enhanced "cyan" variant of avGFP (ECFP) by an electron-donating 4-aminotryptophan results in GdFP featuring a 108 nm Stokes shift and a strongly red-shifted emission maximum (574 nm), while being thermodynamically more stable than its predecessor ECFP. Residue specific incorporation of the non-canonical amino acid is analyzed by mass spectrometry. The spectroscopic properties of GdFP are characterized by time resolved fluorescence spectroscopy as one of the valuable applications of genetically encoded FPs in life sciences. PMID- 29757280 TI - Microinjection of Western Corn Rootworm, Diabrotica virgifera virgifera, Embryos for Germline Transformation, or CRISPR/Cas9 Genome Editing. AB - The western corn rootworm (WCR) is an important pest of corn and is well known for its ability to rapidly adapt to pest management strategies. Although RNA interference (RNAi) has proved to be a powerful tool for studying WCR biology, it has its limitations. Specifically, RNAi itself is transient (i.e. does not result in long-term Mendelian inheritance of the associated phenotype), and it requires knowing the DNA sequence of the target gene. The latter can be limiting if the phenotype of interest is controlled by poorly conserved, or even novel genes, because identifying useful targets would be challenging, if not impossible. Therefore, the number of tools in WCR's genomic toolbox should be expanded by the development of methods that could be used to create stable mutant strains and enable sequence-independent surveys of the WCR genome. Herein, we detail the methods used to collect and microinject precellular WCR embryos with nucleic acids. While the protocols described herein are aimed at the creation of transgenic WCR, CRISPR/Cas9-genome editing could also be performed using the same protocols, with the only difference being the composition of the solution injected into the embryos. PMID- 29757281 TI - Analyses of Mitochondrial Calcium Influx in Isolated Mitochondria and Cultured Cells. AB - Ca2+ handling by mitochondria is a critical function regulating both physiological and pathophysiological processes in a broad spectrum of cells. The ability to accurately measure the influx and efflux of Ca2+ from mitochondria is important for determining the role of mitochondrial Ca2+ handling in these processes. In this report, we present two methods for the measurement of mitochondrial Ca2+ handling in both isolated mitochondria and cultured cells. We first detail a plate reader-based platform for measuring mitochondrial Ca2+ uptake using the Ca2+ sensitive dye calcium green-5N. The plate reader-based format circumvents the need for specialized equipment, and the calcium green-5N dye is ideally suited for measuring Ca2+ from isolated tissue mitochondria. For our application, we describe the measurement of mitochondrial Ca2+ uptake in mitochondria isolated from mouse heart tissue; however, this procedure can be applied to measure mitochondrial Ca2+ uptake in mitochondria isolated from other tissues such as liver, skeletal muscle, and brain. Secondly, we describe a confocal microscopy-based assay for measurement of mitochondrial Ca2+ in permeabilized cells using the Ca2+ sensitive dye Rhod-2/AM and imaging using 2 dimensional laser-scanning microscopy. This permeabilization protocol eliminates cytosolic dye contamination, allowing for specific recording of changes in mitochondrial Ca2+. Moreover, laser-scanning microscopy allows for high frame rates to capture rapid changes in mitochondrial Ca2+ in response to various drugs or reagents applied in the external solution. This protocol can be applied to measure mitochondrial Ca2+ uptake in many cell types including primary cells such as cardiac myocytes and neurons, and immortalized cell lines. PMID- 29757282 TI - Optimizing the Use of a Liquid Handling Robot to Conduct a High Throughput Forward Chemical Genetics Screen of Arabidopsis thaliana. AB - Chemical genetics is increasingly being employed to decode traits in plants that may be recalcitrant to traditional genetics due to gene redundancy or lethality. However, the probability of a synthetic small molecule being bioactive is low; therefore, thousands of molecules must be tested in order to find those of interest. Liquid handling robotics systems are designed to handle large numbers of samples, increasing the speed with which a chemical library can be screened in addition to minimizing/standardizing error. To achieve a high-throughput forward chemical genetics screen of a library of 50,000 small molecules on Arabidopsis thaliana (Arabidopsis), protocols using a bench-top multichannel liquid handling robot were developed that require minimal technician involvement. With these protocols, 3,271 small molecules were discovered that caused visible phenotypic alterations. 1,563 compounds induced short roots, 1,148 compounds altered coloration, 383 compounds caused root hair and other, non-categorized, alterations, and 177 compounds inhibited germination. PMID- 29757283 TI - Protocol for Acute and Chronic Ecotoxicity Testing of the Turquoise Killifish Nothobranchius furzeri. AB - The killifish Nothobranchius furzeri is an emerging model organism in the field of ecotoxicology and its applicability in acute and chronic ecotoxicity testing has been demonstrated. Overall, the sensitivity of the species to toxic compounds is in the range with, or higher than, that of other model species. This work describes protocols for acute, chronic, and multigenerational bioassays of single and combined stressor effects on N. furzeri. Due to its short maturation time and life-cycle, this vertebrate model allows the study of endpoints such as maturation time and fecundity within four months. Transgenerational full life cycle exposure trials can be performed in as little as 8 months. Since this species produces eggs that are drought-resistant and remain viable for years, the on-site culture of the species is not needed but individuals can be recruited when required. The protocols are designed to measure life-history traits (mortality, growth, fecundity, weight) and critical thermal maximum. PMID- 29757284 TI - Near-Infrared Temperature Measurement Technique for Water Surrounding an Induction-heated Small Magnetic Sphere. AB - A technique to measure the temperature of water and non-turbid aqueous media surrounding an induction-heated small magnetic sphere is presented. This technique utilizes wavelengths of 1150 and 1412 nm, at which the absorption coefficient of water is dependent on temperature. Water or a non-turbid aqueous gel containing a 2.0-mm- or 0.5-mm-diameter magnetic sphere is irradiated with 1150 nm or 1412 nm incident light, as selected using a narrow bandpass filter; additionally, two-dimensional absorbance images, which are the transverse projections of the absorption coefficient, are acquired via a near-infrared camera. When the three-dimensional distributions of temperature can be assumed to be spherically symmetric, they are estimated by applying inverse Abel transforms to the absorbance profiles. The temperatures were observed to consistently change according to time and the induction heating power. PMID- 29757286 TI - Measurements of Local Instantaneous Convective Heat Transfer in a Pipe - Single and Two-phase Flow. AB - This manuscript provides step by step description of the manufacturing process of a test section designed to measure the local instantaneous heat transfer coefficient as a function of the liquid flow rate in a transparent pipe. With certain amendments, the approach is extended to gas-liquid flows, with a particular emphasis on the effect of a single elongated (Taylor) air bubble on heat transfer enhancement. A non-invasive thermography technique is applied to measure the instantaneous temperature of a thin metal foil heated electrically. The foil is glued to cover a narrow slot cut in the pipe. The thermal inertia of the foil is small enough to detect the variation in the instantaneous foil temperature. The test section can be moved along the pipe and is long enough to cover a considerable part of the growing thermal boundary layer. At the beginning of each experimental run, a steady state with a constant water flow rate and heat flux to the foil is attained and serves as the reference. The Taylor bubble is then injected into the pipe. The heat transfer coefficient variations due to the passage of a Taylor bubble propagating in a vertical pipe is measured as function of the distance of the measuring point from the bottom of the moving Taylor bubble. Thus, the results represent the local heat transfer coefficients. Multiple independent runs preformed under identical conditions allow accumulating sufficient data to calculate reliable ensemble-averaged results on the transient convective heat transfer. In order to perform this in a frame of reference moving with the bubble, the location of the bubble along the pipe has to be known at all times. Detailed description of measurements of the length and of the translational velocity of the Taylor bubbles by optical probes is presented. PMID- 29757285 TI - Microfluidic Chips for In Situ Crystal X-ray Diffraction and In Situ Dynamic Light Scattering for Serial Crystallography. AB - This protocol describes fabricating microfluidic devices with low X-ray background optimized for goniometer based fixed target serial crystallography. The devices are patterned from epoxy glue using soft lithography and are suitable for in situ X-ray diffraction experiments at room temperature. The sample wells are lidded on both sides with polymeric polyimide foil windows that allow diffraction data collection with low X-ray background. This fabrication method is undemanding and inexpensive. After the sourcing of a SU-8 master wafer, all fabrication can be completed outside of a cleanroom in a typical research lab environment. The chip design and fabrication protocol utilize capillary valving to microfluidically split an aqueous reaction into defined nanoliter sized droplets. This loading mechanism avoids the sample loss from channel dead-volume and can easily be performed manually without using pumps or other equipment for fluid actuation. We describe how isolated nanoliter sized drops of protein solution can be monitored in situ by dynamic light scattering to control protein crystal nucleation and growth. After suitable crystals are grown, complete X-ray diffraction datasets can be collected using goniometer based in situ fixed target serial X-ray crystallography at room temperature. The protocol provides custom scripts to process diffraction datasets using a suite of software tools to solve and refine the protein crystal structure. This approach avoids the artefacts possibly induced during cryo-preservation or manual crystal handling in conventional crystallography experiments. We present and compare three protein structures that were solved using small crystals with dimensions of approximately 10-20 um grown in chip. By crystallizing and diffracting in situ, handling and hence mechanical disturbances of fragile crystals is minimized. The protocol details how to fabricate a custom X-ray transparent microfluidic chip suitable for in situ serial crystallography. As almost every crystal can be used for diffraction data collection, these microfluidic chips are a very efficient crystal delivery method. PMID- 29757288 TI - Synthesis of Platinum-nickel Nanowires and Optimization for Oxygen Reduction Performance. AB - Platinum-nickel (Pt-Ni) nanowires were developed as fuel cell electrocatalysts, and were optimized for the performance and durability in the oxygen reduction reaction. Spontaneous galvanic displacement was used to deposit Pt layers onto Ni nanowire substrates. The synthesis approach produced catalysts with high specific activities and high Pt surface areas. Hydrogen annealing improved Pt and Ni mixing and specific activity. Acid leaching was used to preferentially remove Ni near the nanowire surface, and oxygen annealing was used to stabilize near surface Ni, improving durability and minimizing Ni dissolution. These protocols detail the optimization of each post-synthesis processing step, including hydrogen annealing to 250 degrees C, exposure to 0.1 M nitric acid, and oxygen annealing to 175 degrees C. Through these steps, Pt-Ni nanowires produced increased activities more than an order of magnitude than Pt nanoparticles, while offering significant durability improvements. The presented protocols are based on Pt-Ni systems in the development of fuel cell catalysts. These techniques have also been used for a variety of metal combinations, and can be applied to develop catalysts for a number of electrochemical processes. PMID- 29757287 TI - Combinational Treatment of Trichostatin A and Vitamin C Improves the Efficiency of Cloning Mice by Somatic Cell Nuclear Transfer. AB - Somatic cell nuclear transfer (SCNT) provides a unique opportunity to directly produce a cloned animal from a donor cell, and it requires the use of skillful techniques. Additionally, the efficiencies of cloning have remained low since the successful production of cloned animals, especially mice. There have been many attempts to improve the cloning efficiency, and trichostatin A (TSA), a histone deacetylase inhibitor, has been widely used to enhance the efficiency of cloning. Here, we report a dramatically improved cloning method in mice. This somatic cell nuclear transfer method involves usage of Hemagglutinating virus of Japan Envelope (HVJ-E), which enables easy manipulation. Moreover, the treatment using two small molecules, TSA and vitamin C (VC), with deionized bovine serum albumin (dBSA), is highly effective for embryonic development. This approach requires neither additional injection nor genetic manipulation, and thus presents a simple, suitable method for practical use. This method could become a technically feasible approach for researchers to produce genetically modified animals from cultured cells. Furthermore, it might be a useful way for the rescue of endangered animals via cloning. PMID- 29757289 TI - Use of Two Dimensional Semi-denaturing Detergent Agarose Gel Electrophoresis to Confirm Size Heterogeneity of Amyloid or Amyloid-like Fibers. AB - Amyloid or amyloid-like fibers have been associated with many human diseases, and are now being discovered to be important for many signaling pathways. The ability to readily detect the formation of these fibers under various experimental conditions is essential for understanding their potential function. Many methods have been used to detect the fibers, but not without some drawbacks. For example, electron microscopy (EM), or staining with Congo Red or Thioflavin T often requires purification of the fibers. On the other hand, semi-denaturing detergent agarose gel electrophoresis (SDD-AGE) allows detection of the SDS-resistant amyloid-like fibers in the cell extracts without purification. In addition, it allows the comparison of the size difference of the fibers. More importantly, it can be used to identify specific proteins within the fibers by Western blotting. It is less time consuming and more easily accessible to a wider number of labs. SDD-AGE results often show variable degree of heterogeneity. It raises the question whether part of the heterogeneity results from the dissociation of the protein complex during the electrophoresis in the presence of SDS. For this reason, we have employed a second dimension of SDD-AGE to determine if the size heterogeneity seen in SDD-AGE is truly a result of fiber heterogeneity in vivo and not a result of either degradation or dissociation of some of the proteins during electrophoresis. This method allows fast, qualitative confirmation that the amyloid or amyloid-like fibers are not partially dissociating during the SDD AGE process. PMID- 29757291 TI - Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration. AB - With an increasing incidence of prostate cancer, identification of new tumor drivers or modulators is crucial. Genetically engineered mouse models (GEMM) for prostate cancer are hampered by tumor heterogeneity and its complex microevolution dynamics. Traditional prostate cancer mouse models include, amongst others, germline and conditional knockouts, transgenic expression of oncogenes, and xenograft models. Generation of de novo mutations in these models is complex, time-consuming, and costly. In addition, most of traditional models target the majority of the prostate epithelium, whereas human prostate cancer is well known to evolve as an isolated event in only a small subset of cells. Valuable models need to simulate not only prostate cancer initiation, but also progression to advanced disease. Here we describe a method to target a few cells in the prostate epithelium by transducing cells by viral particles. The delivery of an engineered virus to the murine prostate allows alteration of gene expression in the prostate epithelia. Virus type and quantity will hereby define the number of targeted cells for gene alteration by transducing a few cells for cancer initiation and many cells for gene therapy. Through surgery-based injection in the anterior lobe, distal from the urinary track, the tumor in this model can expand without impairing the urinary function of the animal. Furthermore, by targeting only a subset of prostate epithelial cells the technique enables clonal expansion of the tumor, and therefore mimics human tumor initiation, progression, as well as invasion through the basal membrane. This novel technique provides a powerful prostate cancer model with improved physiological relevance. Animal suffering is limited, and since no additional breeding is required, overall animal count is reduced. At the same time, analysis of new candidate genes and pathways is accelerated, which in turn is more cost efficient. PMID- 29757290 TI - The Lambda Select cII Mutation Detection System. AB - A number of transgenic animal models and mutation detection systems have been developed for mutagenicity testing of carcinogens in mammalian cells. Of these, transgenic mice and the Lambda (lambda) Select cII Mutation Detection System have been employed for mutagenicity experiments by many research groups worldwide. Here, we describe a detailed protocol for the Lambda Select cII mutation assay, which can be applied to cultured cells of transgenic mice/rats or the corresponding animals treated with a chemical/physical agent of interest. The protocol consists of the following steps: (1) isolation of genomic DNA from the cells or organs/tissues of transgenic animals treated in vitro or in vivo, respectively, with a test compound; (2) recovery of the lambda shuttle vector carrying a mutational reporter gene (i.e., cII transgene) from the genomic DNA; (3) packaging of the rescued vectors into infectious bacteriophages; (4) infecting a host bacteria and culturing under selective conditions to allow propagation of the induced cII mutations; and (5) scoring the cII-mutants and DNA sequence analysis to determine the cII mutant frequency and mutation spectrum, respectively. PMID- 29757292 TI - Desthiobiotin-Streptavidin-Affinity Mediated Purification of RNA-Interacting Proteins in Mesothelioma Cells. AB - The in vitro RNA-pulldown is still largely used in the first steps of protocols aimed at identifying RNA-binding proteins that recognize specific RNA structures and motifs. In this RNA-pulldown protocol, commercially synthesized RNA probes are labeled with a modified form of biotin, desthiobiotin, at the 3' terminus of the RNA strand, which reversibly binds to streptavidin and thus allows elution of proteins under more physiological conditions. The RNA-desthiobiotin is immobilized through interaction with streptavidin on magnetic beads, which are used to pull down proteins that specifically interact with the RNA of interest. Non-denatured and active proteins from the cytosolic fraction of mesothelioma cells are used as the source of proteins. The method described here can be applied to detect the interaction between known RNA binding proteins and a 25 nucleotide (nt) long RNA probe containing a sequence of interest. This is useful to complete the functional characterization of stabilizing or destabilizing elements present in RNA molecules achieved using a reporter vector assay. PMID- 29757293 TI - A Rapid and Facile Pipeline for Generating Genomic Point Mutants in C. elegans Using CRISPR/Cas9 Ribonucleoproteins. AB - The clustered regularly interspersed palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9) prokaryotic adaptive immune defense system has been co-opted as a powerful tool for precise eukaryotic genome engineering. Here, we present a rapid and simple method using chimeric single guide RNAs (sgRNA) and CRISPR-Cas9 Ribonucleoproteins (RNPs) for the efficient and precise generation of genomic point mutations in C. elegans. We describe a pipeline for sgRNA target selection, homology-directed repair (HDR) template design, CRISPR-Cas9-RNP complexing and delivery, and a genotyping strategy that enables the robust and rapid identification of correctly edited animals. Our approach not only permits the facile generation and identification of desired genomic point mutant animals, but also facilitates the detection of other complex indel alleles in approximately 4 - 5 days with high efficiency and a reduced screening workload. PMID- 29757294 TI - Value of transfusion independence in severe aplastic anemia from patients' perspectives - a discrete choice experiment. AB - Background: Aplastic anemia is a rare, serious blood disorder due to bone marrow failure to produce blood cells. Transfusions are used to reduce risk of bleeding, infection and relieve anemia symptoms. In severe patients, transfusions may be required more than once/week. It is unclear from the patient perspective the impact that transfusions have on quality of life. This study aimed to elicit patient preferences for attributes associated with severe aplastic anemia (SAA) treatment, including transfusion independence. Methods: An online discrete choice experiment (DCE) was conducted among patients with SAA who experienced insufficient response to immunosuppressive therapy and transfusion dependence for >=3 months in the past 2 years. Recruitment occurred through the Aplastic Anemia and Myelodysplastic Syndromes International Foundation and referrals from clinical sites in the US and France. Respondents chose between hypothetical treatment pairs characterized by a common set of attributes: transfusions frequency, fatigue, risk of infection, and risk of serious bleeding. Conditional logit model with effects coding was used to estimate part-worth utilities for different attribute levels and the relative importance of each attribute. Predicted utility scores for transfusion frequency levels were reported. Results: Thirty patients completed the survey. Most were age >= 40 years (73.3%), female (70.0%), and from the US (86.7%). 33.3% underwent bone marrow transplant; 36.7% received iron chelation therapy. Patients largely agreed that transfusion independence would result in less burden on time and costs, greater control and quality of life, less fatigue (86.7% noted each) and less scheduling around medical appointments (83.3%). The DCE found highest relative importance for risk of bleeding (0.30), followed by risk of infection (0.28), fatigue (0.23), and frequency of transfusions (0.20). More frequent transfusions resulted in lower utility, particularly when increasing monthly transfusions frequency from 4 (0.57) to 8 (0.35). Conclusions: Our study showed that higher utility was associated with fewer transfusions in SAA patients with insufficient response to immunosuppressive therapy. While risk of bleeding, risk of infection, and fatigue were more important for patient treatment preferences, frequency of transfusions was also important. PMID- 29757295 TI - Patient experience in systemic lupus erythematosus: development of novel patient reported symptom and patient-reported impact measures. AB - Background: Comprehensive assessment of systemic lupus erythematosus (SLE) and its treatment requires patient-reported outcome (PRO) measures to capture impacts and fluctuating symptoms. The objective of this study was to develop PROs, in accordance with the Food and Drug Administration (FDA) PRO Guidance, to assess fluctuations in SLE symptoms and its impact. Methods: Following independent review board approval, six US rheumatology practices recruited patients with SLE to participate in concept elicitation (CE) interviews, in order to identify important SLE symptoms and their impacts. The SLE Symptom Severity Diary (SSD) and SLE Impact Questionnaire (SIQ) were drafted based on CE interview results and clinician input. The PROs were revised based on patient feedback from cognitive debriefing (CD) interviews, clinician feedback, and a translatability assessment. Results: Forty-one patients completed CE interviews. Commonly-reported symptoms included fatigue (98%), joint pain (93%), and rash (88%). The most frequently reported impact was difficulty with chores/housework (61%). Eighteen patients completed CD interviews. The PROs were considered comprehensive, clear, and relevant.The SSD contains 17 items assessing energy/vitality, joint and muscle pain/stiffness/swelling, flu-like symptoms, cognition, numbness/tingling, skin symptoms and hair loss using an 11-point numeric response scale and a 24-h recall period (with the exception of hair loss). It also evaluates steroid status and dose. The SIQ contains 50 items, uses a 5-point Likert scale and a 7-day recall period, to assess disease impacts including patients' ability to make plans, work, and physical/social/emotional functioning. Conclusion: The SSD and SIQ are comprehensive SLE-specific PROs developed in accordance with the FDA PRO Guidance. Following assessment of their measurement properties, they may be useful in clinical studies and clinical practice to measure fluctuations in, and the impact of, symptoms in patients with SLE. PMID- 29757296 TI - Japanese translation and linguistic validation of the US National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). AB - Background: The US National Cancer Institute (NCI) has developed the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to capture patients' self-reported symptomatic adverse events in cancer clinical trials. The aim of this study was to develop and linguistically validate a Japanese translation of PRO-CTCAE. Forward- and back-translations were produced, and an independent review was performed by the Japan Clinical Oncology Group (JCOG) Executive Committee and the US NCI. We then conducted cognitive interviews with 21 patients undergoing cancer treatment. Participants were asked to complete the PRO-CTCAE and were interviewed using semi-structured scripts and predetermined probes to investigate whether any items were difficult to understand or answer. The interviews were recorded and transcribed, and a thematic analysis was performed. The data were split into two categories: 1) remarks on the items and 2) remarks on the questionnaire in general. Results: Twenty-one cancer patients undergoing chemotherapy or hormone therapy were interviewed at the University of Tokyo Hospital and the Kansai Medical University Hirakata Hospital during 2011 and 2012. Thirty-three PRO-CTCAE items were evaluated as "difficult to understand," and 65 items were evaluated as "difficult to answer" by at least one respondent. However, on further investigation, only 24 remarks were categorized as "comprehension difficulties" or "clarity" issues. Most of these remarks concerned patients' difficulties with rating their experience of individual symptomatic events. Conclusions: The study provides preliminary evidence supporting the linguistic validity of the Japanese version of PRO-CTCAE. Further cognitive interviewing is warranted for PRO-CTCAE items relating to sexuality and anxiety and for response options on severity attribute items. PMID- 29757297 TI - Exploring the quality of life issues in people with retinal diseases: a qualitative study. AB - Background: The lack of an appropriate retina-specific patient-reported outcome instrument restricts the understanding of the full impact of hereditary retinal diseases and other less common but potentially blinding acquired retinal diseases such as, vascular occlusions, epiretinal membrane, macular hole, central serous retinopathy and other vitreoretinopathies on quality of life. This study aims to explore the quality of life issues in people with hereditary retinal diseases and acquired retinal diseases to develop disease-specific patient-reported outcome instruments. Methods: A qualitative research methodology to understand the lived experiences of people with retinal diseases was carried out. Data were collected through semistructured interviews. The coding, aggregation and theme development was carried out using the NVivo -10 software. Results: Seventy-nine interviews were conducted with participants with hereditary retinal diseases (n = 32; median age = 57 years) and acquired retinal diseases (n = 47; median age = 73 years). We identified nine quality of life themes (domains) relevant to people with retinal diseases. Difficulty in performing important day-to-day activities (activity limitation) was the most prominent quality of life issue in the hereditary retinal diseases group whereas concerns about health, disease outcome and personal safety (health concerns) was the most prominent quality of life issue in the acquired retinal diseases group. Participants with hereditary retinal diseases had more issues with social interaction (social well-being), problems with mobility and orientation (mobility), and effect on work and finance (economic) than participants with acquired retinal diseases. On the contrary, participants with acquired retinal diseases reported more inconveniences (conveniences) than participants with hereditary retinal diseases, which were mostly attributed to treatment. Participants with hereditary retinal diseases were coping better compared to participants with acquired retinal diseases. Conclusions: Our study found that participants with both hereditary and acquired retinal diseases are living with myriad of disease-specific quality of life issues. Many of these issues are completely different and unique to each disease group. Hence, these group of diseases would need separate patient-reported outcome instruments to capture the disease-specific quality of life impacts. PMID- 29757298 TI - Correction to: Cardiopulmonary exercise testing (CPET) in the United Kingdom-a national survey of the structure, conduct, interpretation and funding. AB - [This corrects the article DOI: 10.1186/s13741-017-0082-3.]. PMID- 29757299 TI - Patient-Reported Outcome (PRO) Consortium translation process: consensus development of updated best practices. AB - This paper describes the rationale and goals of the Patient-Reported Outcome (PRO) Consortium's instrument translation process. The PRO Consortium has developed a number of novel PRO measures which are in the process of qualification by the U.S. Food and Drug Administration (FDA) for use in clinical trials where endpoints based on these measures would support product labeling claims. Given the importance of FDA qualification of these measures, the PRO Consortium's Process Subcommittee determined that a detailed linguistic validation (LV) process was necessary to ensure that all translations of Consortium-developed PRO measures are performed using a standardized approach with the rigor required to meet regulatory and pharmaceutical industry expectations, as well as having a clearly defined instrument translation process that the translation industry can support. The consensus process involved gathering information about current best practices from 13 translation companies with expertise in LV, consolidating the findings to generate a proposed process, and obtaining iterative feedback from the translation companies and PRO Consortium member firms on the proposed process in two rounds of review in order to update existing principles of good practice in LV and to provide sufficient detail for the translation process to ensure consistency across PRO Consortium measures, sponsors, and translation companies. The consensus development resulted in a 12-step process that outlines universal and country-specific new translation approaches, as well as country-specific adaptations of existing translations. The PRO Consortium translation process will play an important role in maintaining the validity of the data generated through these measures by ensuring that they are translated by qualified linguists following a standardized and rigorous process that reflects best practice. PMID- 29757300 TI - A systematic evaluation of compliance and reporting of patient-reported outcome endpoints in ovarian cancer randomised controlled trials: implications for generalisability and clinical practice. AB - Background: This study aimed to evaluate the patient-reported outcome (PRO) content of ovarian cancer randomised-controlled trial (RCT) publications, describe PRO compliance, and explore potential relationships among these and completeness of PRO protocol content. Methods: Publications of Phase III ovarian cancer RCTs with PRO endpoints were identified by Medline and Cochrane systematic search: January 2000 to February 2016. Two reviewers determined the number of Consolidated Standards of Reporting Trials (CONSORT)-PRO Extension items addressed in publications. Compliance rates (defined as the proportion of participants included in the principal PRO analysis, of those from whom PRO assessments were expected) were extracted. The relationship between CONSORT-PRO score and compliance rates was explored using scatter plots. Additionally CONSORT PRO score and PRO compliance rates respectively were compared with corresponding PRO protocol scores obtained from a previous study. Results: Thirty-six eligible RCTs (n = 33 with secondary PRO endpoint) were identified and analysed. The average number of CONSORT-PRO items addressed in publications was 6.7 (48%; Range 0-13.5/14). Three RCTs did not report PRO results; in 1 case due to poor compliance. Some compliance information was reported in 26 RCTs, but was considered complete for only 10 (28%) RCTs. Compliance rates were poor overall, ranging from 59 to 83%; therefore missing PRO data from 17 to 41% of participants in these trials could have been avoided.Of the 26 (73%) RCTs for which PRO protocol completeness scores were available, 6 RCTs reported complete compliance information and the 3 of these RCTs with highest PRO compliance had highest protocol checklist scores. Conclusions: Few RCTs reported PRO compliance information in a manner enabling assessment of the generalisability of PRO results. This information is particularly important in RCTs of advanced ovarian cancer because it is important to be able to determine if missing data was due to worsening illness compared to methodological issues. Poor compliance appeared related to poor PRO protocol content, and in one case prevented PRO results from being reported, highlighting the need to address compliance strategies in the protocol. Adhering to protocol and CONSORT-PRO reporting guidance should improve PRO implementation and reporting respectively in ovarian cancer RCTs and allow results to meaningfully inform clinical practice. PMID- 29757301 TI - The content validity of the PSS in patients with plaque psoriasis. AB - Background: The primary objective of this study was to evaluate the content validity of the Psoriasis Symptom Scale (PSS), with a specific focus on understanding of the content of the PRO measure by conducting one-on-one interviews with patients with moderate to severe plaque psoriasis. This was a cross-sectional, qualitative study conducted with 20 patients with plaque psoriasis who participated in in-person, one-on-one interviews. Participants were asked to describe their psoriasis symptoms, completed the PSS, and were cognitively debriefed on its content. Interviews were conducted in two separate rounds. Following Round 1, the study data were examined to determine if modifications to the PSS were required. All interviews were audio-recorded and transcribed. Sociodemographic and clinical data were collected for sample descriptive purposes. Results: The 20 study participants had a mean age of 50.2 +/- 12.0 years (range: 25.0-73.0), and 55% were female. Thirty-five percent of the sample reported their psoriasis severity as moderate or severe. The average time since diagnosis of plaque psoriasis was almost 18 years, ranging from less than one to over 38 years. The most frequently reported symptoms and signs during the concept elicitation portion of the interviews included redness (N = 20, 100%), itching (n = 20, 100%), pain (n = 15, 75%), burning (n = 13, 65%), and flaking (n = 11, 55%). Overall, participants provided positive feedback on the PSS and felt that it was comprehensive and relevant to their experience with psoriasis. The item meaning and response options were well-understood for the majority of the items. Findings indicate that for the patient-reported symptom of redness, which is also a sign that can be reported by clinicians, redness or the perception of redness is most accurately captured by patient report. Study results did not support modifications to the instrument and no changes to the PSS were recommended. Conclusion: The evidence gained in this study provided support for the content validity of the PSS for use as clinical trial endpoint among patients with plaque psoriasis. This study found that the symptoms included in the PSS are important to and well-understood by patients with plaque psoriasis. The PSS is appropriate for inclusion in future studies designed to measure the effect of treatment on psoriasis-related symptoms. PMID- 29757302 TI - The responsiveness of the PROMIS instruments and the qDASH in an upper extremity population. AB - Background: This study evaluated the responsiveness of several PROMIS patient reported outcome measures in patients with hand and upper extremity disorders and provided comparisons with the qDASH instrument. Methods: The PROMIS Upper Extremity computer adaptive test (UE CAT) v1.2, the PROMIS Physical Function (PF) CAT v1.2, the PROMIS Pain Interference (PI) CAT v1.1 and the qDASH were administered to patients presenting to an orthopaedic hand clinic during the years 2014-2016, along with anchor questions. The responsiveness of these instruments was assessed using anchor based methods. Changes in functional outcomes were evaluated by paired-sample t-test, effect size, and standardized response mean. Results: There were a total of 255 patients (131 females and 124 males) with an average age of 50.75 years (SD = 15.84) included in our study. Based on the change and no change scores, there were three instances (PI at 3 months, PI >3 months, and qDASH >3 months follow-ups) where scores differed between those experiencing clinically meaningful change versus no clinically meaningful change. Effect sizes for the responsiveness of all instruments were large and ranged from 0.80-1.48. All four instruments demonstrated high responsiveness, with a standardized response mean ranging from 1.05 to 1.63. Conclusion: The PROMIS UE CAT, PF CAT, PI CAT, and qDASH are responsive to patient-reported functional change in the hand and upper extremity patient population. PMID- 29757303 TI - Barnhoft: a hip specific 6-item questionnaire for children. AB - Background: Health-related quality of life instruments, both general and more disease specific, would ideally be included in the evaluation of outcome in paediatric orthopaedics. The aim of this study was to translate and culturally adapt an instrument measuring hip function and pain for Swedish children 8-15 years old with a hip disorder. Methods: Translation of an established questionnaire for hip disorder in children, CHOHES, was performed and called Barnhoft. Retrospective and cognitive debriefing interviews were conducted with 15 healthy children to test for the comprehensibility of the instrument. Children with slipped capital femoral epiphysis (n = 25) and healthy children (n = 35) participated in further testing through test-retest and with the comparison of answers given in a general health-related quality of life test, EQ-5D-Y (www.euroqol.org). A multi-professional expert committee supervised the process and judged the content validity. Results: The test-retest method with a weighted Cohen's kappa showed a good stability of the instrument. The construct validity for the pain domain (1-item) in EQ-5D-Y compared to the pain domain in Barnhoft showed a Spearman's correlation coefficient of 0.73. The degree of hip pain in Barnhoft was also compared with the item "doing usual activities" in EQ-5D-Y with a Spearman's correlation coefficient of 0.67. Conclusion: Barnhoft could be used as a simple 6-item questionnaire to identify children with pain and/or functional limitations due to sequelae related to a hip disease in childhood. PMID- 29757304 TI - Development of the Weight-Related Sign and Symptom Measure. AB - Background: Overweight and obesity have been associated with physical and emotional signs & symptoms. Research has shown that modest weight loss can mitigate some symptoms in individuals with overweight or obesity. This study's purpose was to conduct concept elicitation (CE) interviews to provide documented qualitative support for the development of the Weight-Related Sign and Symptom Measure (WRSSM) to assess weight-related signs/symptoms in U.S. adults with overweight or obesity, with or without type 2 diabetes (T2DM).Eight focus groups were conducted in the U.S. with adults with overweight or obesity to understand weight-related sign/symptom impact from the patient perspective. Individual interviews were conducted with clinical experts to understand the impact of overweight or obesity on patient signs and symptoms. Transcripts were analyzed to identify symptoms and observable signs. A clinical challenge was conducted with clinical experts to confirm the signs/symptoms were clinically relevant, important to patients, and would improve with modest weight loss. Cognitive debriefing (CD) was conducted with individuals with overweight or obesity to confirm readability and symptom relevance. Results: CE interviews were conducted with four clinical experts, and 61 people, 32% of whom had T2DM, participated in the focus groups. Analyses identified two major areas of obesity impacts: weight related physical signs/symptoms, and emotional impacts. The most frequently reported physical signs/symptoms were feeling tired (74%), shortness of breath (69%), and joint pain (64%). The most often reported emotional impacts included poor self-image (72%) and depression (51%). Twelve signs/symptoms were identified during item generation and included on the preliminary measure. Twelve adults with overweight/obesity, who were not part of the focus groups, participated in CD. After the CD, a validation-ready, 10-item WRSSM measure was generated. Conclusions: Findings provide evidence of content validity for the validation ready WRSSM in U.S. adults with overweight or obesity, including people with and without T2DM. PMID- 29757305 TI - Health-related quality of life in colorectal cancer survivors: are there differences between sporadic and hereditary patients? AB - Purpose: To compare health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors with sporadic CRC to those with hereditary cancer, specifically Lynch syndrome (LS). Methods: Participants completed a mailed self-administered questionnaire that assessed, among other things, demographics, clinical characteristics, and health-related quality of life. Using a case-case design, CRC survivors with LS or sporadic cancer were matched on age, sex, race/ethnicity, cancer stage, geography, and time since diagnosis. Participants were recruited from patient registries at The University of Texas MD Anderson Cancer Center (MD Anderson) (n = 33 LS; n = 75 sporadic) and through social media (n = 42 LS). The final sample included 71 LS and 74 sporadic CRC survivors. Results: For LS patients, the mean FACT-C HRQoL score was 84.8 (11.9) [Median = 86.0; Interquartile Range-17] compared to sporadic patients mean score of 85.8 (16.7) [Median = 92.0; Interquartile Range-21], which indicates high quality of life for both groups. LS patients and sporadic CRC patients had similar HRQoL mean scores across 7 different HRQoL metrics, with no significant differences between groups. Exploratory regression analyses indicate some differences in known predictors of HRQoL by group despite no bivariate differences. Conclusions: HRQoL is an important component of survivorship in CRC patients. Given the clinical distinctions between LS and sporadic patients, we expected to find significant differences between these patients. However, the patients' experiences/quality of life does not appear to illustrate such a clear dissimilarity within CRC survivors. Given the limited data in this area, larger studies, ideally with data obtained from multiple sites, is needed to better investigate the alignment between clinical determination and patient experience as well as to explore the relationship between HRQOL, treatment regimens, and health outcomes. PMID- 29757306 TI - Measurement of alienation among adolescents: construct validity of three scales on powerlessness, meaninglessness and social isolation. AB - Background: Psychological alienation is an important concept in the study of adolescents' health and behavior but no gold standard for measuring alienation among adolescents exists. There is a need for new scales with high validity for use in adolescent health and social research. The purpose of the present study was to develop and validate alienation scales in accordance with Seeman's conceptualization of alienation focusing on three independent variants specifically relevant in adolescent health research: powerlessness, meaninglessness and social isolation. Methods: Cross-sectional data from 3083 adolescents aged 13 to 15 years from the Danish contribution to the cross national study Health Behaviour in School-aged Children (HBSC) were used. We identified and developed items, addressed content and face validity through interviews, and examined the criterion-related construct validity of the scales using graphical loglinear Rasch models (GLLRM). Results: The three scales each comprised three to five face valid items. The powerlessness scale reflected the adolescent's expectancy as to whether his/her behavior can determine the outcome or reinforcement he/she seeks. The meaninglessness scale reflected the expectancy as to whether satisfactory predictions regarding the effects of one's behavior are possible. Finally, the social isolation scale reflected whether the adolescent had a low expectancy for inclusion and social acceptance. All scales contained some uniform local dependency and differential item functioning. However, only to a limited degree, which could be accounted for using GLLRM. Thus the scales fitted GLLRMs and can therefore be considered to be essentially construct valid and essentially objective. Conclusion: The three alienation scales appear to be content and face valid and fulfill the psychometric properties of a good construct valid reflective scale. This suggests that the scales may be appropriate in future large-scale surveys to examine the relation between alienation and a range of adolescent health outcomes such as health, behavior and wellbeing. PMID- 29757307 TI - Development of the Impact of Juvenile Metachromatic Leukodystrophy on Physical Activities scale. AB - Background: Metachromatic leukodystrophy (MLD) is a rare disease with three forms based on the age at onset of signs and symptoms. The objective of this study was to develop a caregiver-reported clinical outcome assessment that measures impairments in physical functioning related to activities of daily living in patients with juvenile MLD. Methods: A targeted literature review and exploration of proprietary research, including a conceptual model, were conducted. Concept elicitation interviews were conducted to elicit additional concepts related to impairments in patients' physical functioning with caregivers of five individuals with juvenile MLD. Based on the research review and concept elicitation interviews, the conceptual model was updated and the Impact of Juvenile Metachromatic Leukodystrophy on Physical Activities (IMPA) scale draft items were created. Cognitive debriefing interviews were conducted with six additional caregivers to finalize the conceptual model and to refine the IMPA scale. Results: Initially, 17 potentially important concepts were identified and addressed in the draft IMPA scale. Following the cognitive debriefing interviews, 15 activities/items remained: brush teeth, comb/brush hair, bathe/shower, dress self, eat, drink, use pencil/crayon, sit upright, use toilet, get on/off toilet, walk, use stairs, get in/out of bed, get in/out of chair/wheelchair, and get in/out of vehicle. Items that did not uniquely contribute to the purpose of the instrument were removed. Conclusion: The IMPA scale, developed according to regulatory standards, provides a means of detecting changes in activities of daily living in individuals with juvenile MLD and can hence be used in future studies to measure benefits of therapeutic interventions. PMID- 29757308 TI - Content validation of the SF-36v2(r) health survey with AL amyloidosis patients. AB - Background: This study examined the content validity of the SF-36v2(r) Health Survey (SF-36v2) in patients with AL amyloidosis using qualitative interviews with physicians and patients. The study included three distinct phases of qualitative research: concept elicitation interviews among physicians, concept elicitation interviews among patients, and cognitive debriefing interviews among patients. The concept elicitation interviews focused on areas of health-related quality of life that are affected by AL amyloidosis and may be affected by treatment, while patient cognitive debriefings aimed to confirm whether the SF 36v2 instructions, recall period, items, and response choices were comprehensive and understandable to AL amyloidosis patients. Results: Physicians discussed the importance of measuring physical functioning, general health, mental/emotional health, sleep, fatigue, and work impact; though they also reported that they do not routinely use a standard Patient-Reported Outcome (PRO) measure of health related quality of life. Patients described social, physical, role, and emotional impacts of AL amyloidosis and various treatments. Cognitive debriefing interviews confirmed the relevance of the concepts measured by the SF-36v2 and indicated that patients found the SF-36v2 both easy to understand and complete, that the SF 36v2 instructions and items were comprehensive and understandable without change, and the response choices and recall period were appropriate for use with patients with AL amyloidosis. Conclusions: The findings support the content validity of the SF-36v2 as an appropriate measure of health-related quality of life in patients with AL amyloidosis. PMID- 29757309 TI - The Japanese version of the National Cancer Institute's patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE): psychometric validation and discordance between clinician and patient assessments of adverse events. AB - Background: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute as an adverse event assessment system to evaluate patients' symptoms, which tend to be underestimated in cancer clinical trials. The aim of this study was to assess the psychometric properties of the Japanese version of the PRO CTCAE and the degree of adverse event assessment discordance between clinicians and patients. Methods: A total of 187 cancer patients receiving systemic therapy were enrolled. Reproducibility, criterion validity, and responsiveness of the Japanese version of PROCTCAE were assessed. The EORTC QLQ-C30 was used as an external anchor. Discordance of assessment of adverse events between clinician and patients were also assessed using the CTCAE and PRO-CTCAE. Results: A total of 187 participants (187 for criterion validity, 80 for reproducibility, and 100 for responsiveness), were analyzed (Mage = 62.4 years). All patients responded to at least one symptom item (M = 16). The mean (SD) intra-class correlation coefficients of overall reproducibility for the Japanese PRO-CTCAE was 0.63 (0.02). The correlation coefficient for the corresponding items in the EORTC QLQ C30 and the Japanese PRO-CTCAE was high (Pearson r = 0.56-0.76). The analysis of responsiveness revealed significant dose-response trends (Jonckheere-Terpstra test, ps < 0.001). Depending on the adverse events, a discrepancy was observed in evaluation between the clinician and patient. Conclusions: These results revealed that there is underestimation in the assessment of adverse events in Japan, and that the Japanese version of the PRO-CTCAE had acceptable reliability and validity for common and clinically important symptoms. PMID- 29757311 TI - Towards the use of mixed methods inquiry as best practice in health outcomes research. AB - Mixed methods research (MMR) has found an increased interest in the field of health outcomes research. Consideration for both qualitative and quantitative perspectives has become key to contextualising patient experiences in a clinically meaningful measurement framework. The purpose of this paper is to outline a process for incorporating MMR in health outcomes research to guide stakeholders in their understanding of the essence of mixed methods inquiry. In addition, this paper will outline the benefits and challenges of MMR and describe the types of support needed for designing and conducting robust MMR measurement studies. MMR involves the application of a well-defined and pre-specified research design that articulates purposely and prospectively, qualitative and quantitative components to generate an integrated set of evidence addressing a single research question. Various methodological design options are possible depending on the research question. MMR designs allow a research question to be studied thoroughly from different perspectives. When applied, it allows the strengths of one approach to complement the restrictions of another. Among other applications, MMR can be used to enhance the creation of conceptual models and development of new instruments, to interpret the meaningfulness of outcomes in a clinical study from the patient perspective, and inform health care policy. Robust MMR requires research teams with experience in both qualitative and quantitative research. Moreover, a thorough understanding of the underlying principles of MMR is recommended at the point of study conception all the way through to implementation and knowledge dissemination. The framework outlined in this paper is designed to encourage health outcomes researchers to apply MMR to their research and to facilitate innovative, patient-centred methodological solutions to address the complex challenges of the field. PMID- 29757310 TI - The development of a patient-reported outcome measure for patients with obstructive sleep apnea: the Patient-Reported Apnea Questionnaire (PRAQ). AB - Background: Obstructive sleep apnea (OSA) is a chronic condition that can have a wide range of consequences for a patient's health-related quality of life. Monitoring aspects of quality of life in clinical practice has the potential to improve the patient-centeredness of care for patients with OSA. The aim of this article is to describe the development of the Patient-Reported Apnea Questionnaire (PRAQ), a patient-reported outcome measure (PROM) that is designed for use in clinical practice on an individual patient level, as well as subsequent outcome measurement on an aggregate level. Methods: We used the items of available PROMs for OSA to create a new PROM with focus on its applicability in clinical practice. We used a tailored development process to come to a selection of domains and items. Patients and healthcare professionals were intensively involved in the development of the PRAQ via membership of the development team, online surveys and focus groups, as well as two rounds of cognitive validation. Results: This first version of the PRAQ consists of 43 items and 10 preliminary domains, and covers the aspects of quality of life that healthcare professionals and patients wish to discuss in clinical practice. Patients indicate that PRAQ is comprehensive and that its length is acceptable. Comprehensive patient involvement has ensured good content validity for the PRAQ. Conclusions: This article shows how a PROM can be developed with a specific focus on its applicability in clinical practice. PMID- 29757312 TI - Care-related Quality of Life of informal caregivers of the elderly after a hip fracture. AB - Background: Reforms in the Dutch healthcare system in combination with the aging of the population will lead to a strong increase in the demand for informal care in the Netherlands. A hip fracture is one of the most important causes of hospital admissions among frail elderly and informal caregivers experience stress that may have significantly negative impact on the caregivers' Quality of Life. The purpose of the study was to determine the nature, intensity and the care related Quality of Life (CarerQoL) of informal caregivers of elderly patients in the first six months after a hip fracture. In this cross-sectional study, were interviewed the primary informal caregivers of patients with a hip fracture about the informal care provided after one, three or six months following the injury. The CarerQoL of the informal caregivers was measured with the CarerQoL-7D instrument. Results: In total, 123 primary informal caregivers were included. The CarerQoL-7D score was on average 83.7 (SD 15.0) after one, three and six months, and there were no major differences between the measurement time points. The average amount of informal care provided per patient per week was 39.5 during the first six months.Partners of patients with a hip fracture provided significantly more hours of informal care (beta 34.0; 95% CI: 20.9 - 47.1). Female informal caregivers stated a significantly lower level of CarerQoL (beta -7.8; 95% CI: 13.3 - -2.3). Female caregivers were 3.0 times more likely to experience relational problems (aOR 3.02; 95% CI 1.08-8.43). Caregivers provided care at 6 months were associated with physical health problems (aOR 2.54; 95% CI 1.05 6.14). Conclusions: Informal caregivers, especially partners, are faced with providing care of greater intensity to elderly patients during the first six months after a hip fracture. The CarerQoL was not associated with the intensity of the provided informal care. However, this study shows that a considerable group of informal caregivers for elderly patients with a hip fracture experienced relational, physical and mental health problems that stemmed from providing intensive informal care during the first six months. PMID- 29757313 TI - A comparison of three methods to generate a conceptual understanding of a disease based on the patients' perspective. AB - Background: The Food and Drug Administration patient-reported outcome (PRO) guidance provides standards for PRO development, but these standards bring scientific and logistical challenges which can result in a lengthy and expensive instrument development process. Thus, more pragmatic methods are needed alongside traditional approaches. Methods: Partnering with the National Ankylosing Spondylitis (AS) Society, we compared three methods for eliciting patient experiences: 1) concept elicitation (CE) interviews with 12 individuals with AS, 2) "group concept mapping" (GCM) with 16 individuals with AS, 3) a social media review (SMR) of AS online chatrooms. Three conceptual models were developed and compared to explore data breadth/depth, as well as the practicalities and patient centeredness. Results: Overlap in concepts was observed between conceptual models; 35% of symptoms were identified by all methods. The SMR approach identified the most concepts (n = 23), followed by CE interviews (n = 18), and GCM (n = 15). Eight symptoms were uniquely identified using GCM and SMR. Eliciting in-depth data was challenging for SMR as detail was not always provided. Insight into the relationships between symptoms was obtained as a "concept map" in GCM, via effective probing within interviews, and through the subject's descriptions in SMR. Practical investment varied; CE interviews were the most resource intensive, whereas SMR was the least. Individuals in GCM and CE interviews reported high engagement. Conclusions: Primary CE interviews achieved the greatest depth in conceptual understanding of patient experience; however, novel methods (GCM, SMR) provide complementary approaches for identifying measurement concepts. Each method has strengths and weaknesses and should be selected based on specific research objectives. PMID- 29757314 TI - Methodological considerations in using patient reported measures in dialysis clinics. AB - Patient reported measures (PRMs), including patient-reported outcomes, play a critical role in dialysis care. The usage of PRMs is extensive in dialysis clinics. While there are excellent PRMs to choose from, and their implementation as part of quality improvement and performance monitoring is extensive, there are still methodological challenges to be addressed. In this paper, we identify key methodological concerns around use of PRMs in dialysis centers in the United States and make recommendations for improving the use of PRMs in dialysis related to Selection of PRMs, Mode of Administration, and Support for PRM Use. These recommendations include: (1) Continue the use of Kidney Disease Quality of Life 36-item survey (KDQOLTM-36) for dialysis centers' internal quality improvement activities and the In-Center Hemodialysis Consumer Assessment of Health Care Providers and Systems (ICH-CAHPS survey(r)) for public dialysis center performance monitoring, but promote efforts to modify these instruments by incorporating PROMIS general health items (KDQOL-36) and reducing the length of the ICH-CAHPS. (2) Adopt a PRM of whether dialysis patients have been informed about all dialysis and transplant options. (3) Evaluate equivalence between electronic and paper versions of PRMs prior to widespread use of electronic administration. (4) Explore reimbursement of costs of PRM administration by the Centers for Medicare and Medicaid Services and kidney organizations. (5) Continue development of provider trainings in PRM administration and interpretation. These recommendations will help dialysis care decision-makers, clinicians, and applied researchers take the next steps toward enhancing PRM use in dialysis. PMID- 29757315 TI - A multi-center prospective cohort study to evaluate the effect of differential pricing and health systems strengthening on access to medicines and management of hypertension and diabetes in Ghana: A study protocol. AB - Background: There is evidence to suggest that the prevalence of non-communicable diseases (NCDs), in particular cardiovascular diseases and diabetes, are being recognized as forming a substantial proportion of the burden of disease among populations in Low- and Middle-Income Countries (LMICs). Access to treatment is likely a key barrier to the control and prevention of NCD outcomes. Differential pricing, an approach used to price drugs based on the purchasing power of patients in different socioeconomic segments, has been shown to be beneficial and leads to improved access and affordability. Methods: This is a quasi-experimental study, with a pragmatic trial design, to be conducted over the course of three years. A mixed methods design will be used to evaluate the effects of health systems strengthening and differential pricing on the management of diabetes, hypertension and selected cancers in Ghana. A public private partnership was established between all sites that will receive multi-level interventions, including health systems strengthening and access to medicines interventions. Study populations and sites: Study participants will include individuals with new or recently diagnosed hypertension and diabetes (n=3,300), who present to two major referral hospitals, Komfo Anokye Teaching Hospital and Tamale Teaching Hospital, as well as three district hospitals, namely Kings Medical Centre, Agogo Presbyterian District Hospital, and Atua Government Hospital. Discussion: The objective of this study aims to test approaches intended to improve access to drugs for the treatment of hypertension and diabetes, and improve disease control. Patients with these conditions will benefit from health systems strengthening interventions (education, counseling, improved management of disease), and increased access to innovative medicines via differential pricing. Pilot programs also will facilitate health system strengthening at the participating institutions, which includes training of clinicians and updating of guidelines and production of protocols for the treatment of diabetes, hypertension and cancer. PMID- 29757316 TI - Journal of Patient-Reported Outcomes: aims and scope. PMID- 29757317 TI - Clinician's Commentary on Lacey et al.1. PMID- 29757318 TI - Use of Protective Behavioral Strategies among Young Adult Veteran Marijuana Users. AB - Young adult veterans are at risk for problematic marijuana use and associated consequences, which is partially due to their high rates of Posttraumatic Stress Disorder (PTSD), depression, and problematic substance use. Veterans tend to endorse more severe and chronic mental health symptoms compared to their civilian counterparts and they identify marijuana use as a method to cope with their symptoms. Given the prevalence of marijuana use among veterans in the community and in clinical settings, it is important to explore the factors that may help minimize harm associated with use for those that choose to use the drug. The present study sought to examine the impact of protective behavioral strategies on the relationship between mental health symptoms and marijuana use and consequences in a sample of 180 young adult veteran marijuana users. Participants were recruited via social media advertisements and completed measures of marijuana use and consequences, protective behavioral strategies, and PTSD and depression symptoms. Findings indicated that more frequent use of protective behavioral strategies was associated with less marijuana use and consequences. Participants who screened positive for PTSD or depression reported more marijuana consequences than did those not positive on these screeners. Regression analyses revealed protective strategies moderated the relationship between PTSD and marijuana consequences such that young veterans who endorsed more PTSD symptoms and infrequent use of protective strategies reported the most marijuana consequences. No moderating effects were found for the relationship between depression and marijuana consequences. Findings have clinical implications for working with young veterans. PMID- 29757319 TI - Validation of the French version of the Functional, Communicative and Critical Health Literacy scale (FCCHL). AB - Background: Health literacy is a key asset, defined as the capacity to acquire, understand and use information in ways which promote and maintain good health. Objectives: To assess the reliability and validity of the French translation of the Functional, Communicative and Critical Health Literacy (FCCHL) scale. Methods/participants: A cross-sectional survey using an online questionnaire was proposed to all members of Seintinelles association. Exploratory and confirmatory factorial analyses were conducted. Results: Data from 2342 respondents (45.8% had cancer history) were analysed. The FCCHL scale was well-accepted (missing value by item <=0.7%). Factor analysis revealed an acceptable fit of three-factor model (comparative fit index = 0.922, root mean square error of approximation = 0.065 and standardized root mean square residual = 0.052). The FCCHL showed satisfactory reliability (alpha = 0.77) and scalar invariance was reached for education and deprivation, but not for age. Known group validity was verified as mean scale scores differed according to education, deprivation and age, as expected. Conclusion: The French version of the FCCHL provides a brief reliable and valid measure to explore the dimensions of health literacy. It could be used by health professionals to screen for health literacy level in order to develop this skill and to tailor health communication. PMID- 29757321 TI - Leveraging pediatric PROMIS item banks to assess physical functioning in children at risk for severe functional loss. AB - Background: Pediatric neuromuscular illnesses often result in decreased health related quality of life (HRQL), notably in physical functioning. Generic HRQL measures have been developed for use in general populations, but may not adequately assess patients with severe functional loss. To address this measurement gap, we created two custom parent-proxy physical functioning short forms for use among children at risk for low levels of functioning, using pediatric Patient Reported Outcomes Measurement Information System (PROMIS) item banks for Upper Extremity and Mobility. Methods: Two custom short forms from PROMIS Upper Extremity (13 items) and Mobility (13 items) parent-proxy item banks were created and administered to parents of children (ages 5 - 22 years) enrolled in an integrated care program for management of chronic respiratory insufficiency, largely due to neuromuscular illnesses. Standardized PROMIS T scores have a mean of 50 (SD = 10); higher scores indicate better functioning. Physicians rated clinical severity. Single proxy-rated items on mental and physical health from the Child Health Rating Inventories (CHRIs) global health scale were completed by parents. Psychometric properties, including known groups comparisons, were explored. Results: Fifty-seven parents completed the parent proxy custom PROMIS short forms. The mean Upper Extremity T-score was 21 (SD = 13); the mean Mobility T-score was 22 (SD = 11). Some participants scored at the measurement floor; two items on assistive devices did not perform well in this sample and were excluded from the Mobility T-score. Known groups comparisons showed that those with lower clinical severity had better median Upper Extremity (22 vs. 14, p < 0.001) and Mobility (28 vs. 16, p = 0.004) function than those with worse clinical severity. Both Upper Extremity and Mobility T-scores were higher in the subgroups defined by better physical and mental health, as measured by the CHRIs. Conclusions: Upper Extremity and Mobility T-scores were nearly three standard deviations below the PROMIS pediatric calibration population mean. Preliminary psychometrics demonstrated the potential to more accurately measure lower physical functioning using items from PROMIS item banks. However, some participants scored at the measurement floor despite targeting items at the lower end of the scale. Further short form refinement, enrichment of the item banks, and larger-scale field testing are needed. PMID- 29757322 TI - Psychometric validation of the Dysphagia Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension. AB - Background: Eosinophilic esophagitis (EoE) is characterized by high levels of eosinophils in the esophageal mucosa. Patients with the disease present with a range of symptoms, including dysphagia (difficulty swallowing). The aim of this analysis was to assess the psychometric properties of the Dysphagia Symptom Questionnaire (DSQ), a patient-reported outcome (PRO) measure of dysphagia associated with EoE. Psychometric properties of the DSQ were assessed using data collected from a 12-week, phase 2, multicenter, randomized, double-blind, placebo controlled trial of budesonide oral suspension in adolescents and adults (11-40 years old) with EoE. Results: The study population comprised 93 patients with EoE; 94.6% of whom were white, 68.8% were male and the mean age (standard deviation) was 21.6 (7.7) years. Patients had been diagnosed with EoE for a mean of 37.6 months before study initiation. The DSQ was feasible to implement with few item-level data missing at baseline. Item discrimination was high, with floor and ceiling effects below the predefined threshold (<=9%). Higher DSQ scores corresponded with presence and increased severity of dysphagia, indicative of strong item discrimination among patients at baseline (threshold >50%). The DSQ was able to detect changes in symptoms over time and produced similar outcomes to those from physician- and other patient-rated measures, supportive of construct validity. The DSQ had strong test-retest reliability (intraclass correlation coefficient, r = 0.82); and was also responsive to disease-level changes, with higher DSQ scores corresponding to increased esophageal eosinophilic burden. Lastly, the percentage changes in the minimal clinically important difference and clinically important difference in DSQ score were estimated at -27.4% and -55.4%, respectively. Conclusions: These analyses support the DSQ as a valid and reliable measure of dysphagia in patients with EoE. Changes in DSQ scores suggest a level of agreement between clinician, patient and histologic response. The DSQ should therefore be considered a viable PRO measure of dysphagia for use in future therapeutic studies of EoE. PMID- 29757320 TI - The Swedish RAND-36 Health Survey - reliability and responsiveness assessed in patient populations using Svensson's method for paired ordinal data. AB - Background: The Short Form 36-Item Survey is one of the most commonly used instruments for assessing health-related quality of life. Two identical versions of the original instrument are currently available: the public domain, license free RAND-36 and the commercial SF-36.RAND-36 is not available in Swedish. The purpose of this study was threefold: to translate and culturally adapt the RAND 36 into Swedish; to evaluate its reliability and responsiveness using Svensson's method for paired ordered categorical data; and to assess the usability of an electronic version of the questionnaire.The translation process included forward and backward translations and reconciliation. Test-retest reliability was examined during a period of two-weeks in 84 patients undergoing dialysis for chronic kidney disease. Responsiveness was examined in 97 patients before and 2 months after a cardiac rehabilitation program. Usability tests and cognitive debriefing of the electronic questionnaire were carried out with 18 patients. Results: The Swedish translation of the RAND-36 was conceptually equivalent to the English version. Test-retest reliability was supported by non-significant relative position (RP) values among dialysis patients for all RAND-36 subscales (range - 0.02 to 0.10; all confidence intervals (CI) included zero). Responsiveness was demonstrated by significant improvements in RP values among cardiac rehabilitation patients for all subscales (range 0.22-0.36; lower limits of all CI > 0.1) except two subscales (General health, RP -0.02; CI -0.13 to 0.10; and Role functioning/emotional, RP 0.03; CI -0.09 to 0.16). In cardiac rehabilitation patients, sizable individual variation (RV > 0.2) was also shown for the Pain, Energy/fatigue and Social functioning subscales.The electronic version of RAND-36 was found easy and intuitive to use. Conclusions: Our results provide evidence supporting the reliability and responsiveness of the newly translated Swedish RAND-36 and the user-friendliness of the electronic version. Svensson's method for paired ordinal data was able to characterize not only the direction and size of differences among the patients' responses at different time points but also variations in response patterns within groups. The method is therefore, besides being suitable for ordinal data, also an important and novel tool for gaining insights into patients' response patterns to treatment or interventions, thus informing individualized care. PMID- 29757323 TI - A utility valuation study assessing the impact of postprandial glucose control on quality of life of individuals with type 1 or type 2 diabetes. AB - Background: Consideration of health-related quality of life (HRQOL) in diabetes has been associated with long-term and short-term complications such as hypoglycaemia, but not with short-term glucose control. This study aimed to collect health utilities related to different degrees of poorly controlled postprandial glucose (PPG) and its impact on HRQOL in the UK and in Sweden. Methods: Three health state descriptions were developed based on literature reviews and interviews with people with diabetes and healthcare professionals, characterising mild, moderate and severe impact of postprandial hyperglycaemic symptoms on HRQOL. Time Trade-Off (TTO) interviews with a 10-year trade-off period were conducted with samples of the UK general public and of Swedish people with diabetes. Mean TTO-derived health state values were expressed on a scale from 0 (death) to 1 (full health). Results: One hundred fifty participants from the general population were interviewed in the UK (57% female, mean age 35 years) and 150 participants with diabetes in Sweden (64% female, mean age 51 years, 42% type 1 and 58% type 2 diabetes). The mean TTO-derived health state values were for the UK and Swedish participants: mild impact of poorly PPG control (0.89/0.76); moderate (0.75/0.71); severe (0.56/0.58). Conclusions: Glucose lowering treatments associated with improved control over PPG levels could have important benefits to people with type 1 and type 2 diabetes since findings suggest that increasing severity in postprandial hyperglycaemic symptoms is perceived as having significant negative impact on HRQOL of individuals with type 1 or type 2 diabetes. PMID- 29757324 TI - Feasibility and acceptability of electronic symptom surveillance with clinician feedback using the Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) in Danish prostate cancer patients. AB - Background: The aim was to examine the feasibility, acceptability and clinical utility of electronic symptom surveillance with clinician feedback using a subset of items drawn from the Patient-Reported Outcomes version of Common Terminology Criteria for Adverse Events (PRO-CTCAE) in a cancer treatment setting. Methods: Danish-speaking men with castration-resistant metastatic prostate cancer receiving treatment at the Department of Oncology, Rigshospitalet, Copenhagen between March 9, 2015 and June 8, 2015 were invited to participate (n = 63 eligible). Participants completed the PRO-CTCAE questionnaire on tablet computers using AmbuFlex software at each treatment visit in the outpatient clinic. In total, 22 symptomatic toxicities (41 PRO-CTCAE items), corresponding to the symptomatic adverse-events profile associated with the regimens commonly used for prostate cancer treatment (Docetaxel, Cabazitaxel, Abiraterone, Alpharadin), were selected. Participants' PRO-CTCAE responses were presented graphically to their treating oncologists via an AmbuFlex dashboard, for real-time use to enhance the patient-clinician dialogue that occurs during the consultation prior to each treatment cycle. Technical and clinical barriers and acceptability were evaluated through semi-structured interviews with both patients and oncologists. Patients receiving active treatment at the end of the study period completed an evaluation questionnaire. Results: Fifty-four out of sixty-three (86%) eligible patients were enrolled. The PRO-CTCAE questionnaire was completed a total of 168 times by 54 participants (median number per patient was 3, range 1-5). Eight surveys were missed, resulting in a compliance rate of 97%. At the end of the study period, 35 patients (65%) were still receiving active treatment and completed the evaluation questionnaire. Patients reported that their PRO-CTCAE responses served as a communication tool. Oncologists stated that the availability of the PRO-CTCAE self-reports during the consultation improved patient-clinician communication about side effects. Conclusion: Electronic capture of symptomatic toxicities using PRO-CTCAE and the submission of self-reports to clinicians prior to consultation were feasible among metastatic prostate cancer patients receiving chemotherapy in an outpatient setting, and this procedure was acceptable to both patients and clinicians. Continued research, including a cluster-randomized trial, will evaluate the effects of submitting patients' PRO-CTCAE results to clinicians prior to consultation on the quality of side-effects management and resultant clinical outcomes. PMID- 29757325 TI - Two-item PROMIS(r) global physical and mental health scales. AB - Background: Self-reports of health provide useful information about function and well-being that can improve communication between patients and clinicians. Global health items provide summary information that are predictive of health care utilization and mortality. There is a need for parsimonious global health scales for use in large sample surveys. This study evaluates the reliability and validity of brief measures of global physical health and mental health in the Patient Reported Outcomes Measurement and Information System (PROMIS(r)) project. Methods: A total of 21,133 persons included in the PROMIS development sample: 52% female; 82% White, 9% Black, 9% Hispanic; median age of 50 years. We identified two global physical health items (GPH-2) and two global mental health items (GMH 2) with highest discrimination parameters and compared their reliabilities and construct validity to that of the original 4-item scales (GPH-4 and GMH-4) and a single global health item (Global01). Results: Internal consistency reliability was 0.73 for the GPH-2 (versus 0.81 for the GPH-4) and 0.81 for the GMH-2 (versus 0.86 for the GMH-4). Marginal reliabilities were 0.55 for Global01, 0.70 for GPH 2, 0.79 for GPH-4, 0.80 for GMH-2, and 0.86 for GMH-4. The product-moment correlation between the GPH-2 and GPH-4 was 0.94 and between GMH-2 and GMH-4 was 0.97. The 2-item and 4-item versions of the scales had similar correlations with PROMIS domain scores, the EQ-5D-3L and comorbidities, but the 4-item scales were more strongly correlated with these measures. Conclusions: Adding a single item to a large cross-sectional population survey can cost as much as $100,000. The 2 item variants of the PROMIS global health scales reduce the cost of use on national surveys by 50%, a substantial cost savings. These briefer scales are also more practical for use in clinical practice. The 2-item versions of the PROMIS global health scales display adequate reliability for group comparisons and their associations with other indicators of health are similar to that of the original 4-item scales. The briefer scales are psychometrically sound and reduce burden of survey administration. PMID- 29757326 TI - Qualitative methods in the development of a parent survey of children's oral health status. AB - Background: Parents' perceptions of their 8-17-year-old children's oral health status were assessed using a sample from diverse dental clinics in Greater Los Angeles County to identify constructs for a survey instrument. Methods: Focus groups with 29 parents or guardians were conducted to identify themes that informed development of survey items. The draft items were administered to a different group of 32 parents or guardians in cognitive interviews, and revised for subsequent field-testing. Results: Thematic and narrative analyses were performed after the focus groups and key lay-oriented dimensions were uncovered, notably the relationship between oral health, systemic health and the life course. In the cognitive interviews, parents entered multiple responses to questions related to the look of their child's teeth, and their overall perception of tooth color. Parents also assessed their child's fear or discomfort with the dental experience, and other social and psychological concerns related to oral health status. The temporal dimensions of certain items were specified; for example, oral pain and mood items were revised to include duration of the symptom or mood state. As parents tended to confuse oral health maintenance and prevention, these two related concepts were separated into two items. Based on the qualitative work, we revised items in preparation for a field test. Conclusions: As a PRO measurement study, qualitative research informed a field test survey to assess factors associated with oral health status and the individual's perceptions and subjective views of these constructs for eventual item development for epidemiological and clinical use. PMID- 29757327 TI - Psychometric evaluation of a caregiver diary for the assessment of symptoms of respiratory syncytial virus. AB - Background: There are no clinical outcome assessment (COA) tools developed in accordance with Food and Drug Administration (FDA) guidance suitable for the evaluation of symptoms associated with respiratory syncytial virus (RSV) infection among infants. The Gilead RSV Caregiver Diary (GRCD) is being developed to fulfill this need; the present research evaluates the GRCD and documents its reliability, validity, and responsiveness among children < 24 months of age with acute RSV infection. Methods: A prospective, observational study was conducted in the United States during the 2014-2015 northern hemisphere winter season. Subjects were < 24-month, full-term, previously healthy infants with confirmed RSV infection and <=5 days of symptoms. The GRCD was completed twice daily for 14 days by caregivers. Additional data were collected during the initial visit, subsequent visits, and end-of-study interview. Test-retest reliability (kappa and intraclass correlation coefficients [ICCs]), construct validity (correlations and factor analyses), discriminating ability (analyses of variance and chi-square), and responsiveness (effect sizes and standardized response means) were evaluated. Results: A total of 103 subjects were enrolled (mean age 7.4 +/- 5.3 months). GRCD items were grouped into different subscales according to question content, which, with the exception of the behavior impact domain (ICC = 0.43), demonstrated internal consistency (alphas = 0.78-0.94) and test-retest reliability (ICCs = 0.77-0.94). Hypothesized correlations with parent global ratings of RSV severity ranged from 0.45 to 0.70 and provided support for construct validity. Support for discriminating ability was limited. Effect sizes ranged from - 1.48 to - 4.40, indicating the GRCD was responsive to change. Conclusions: These psychometric analyses support the validity, reliability, and responsiveness of the GRCD for assessing RSV symptoms in children < 24 months of age. PMID- 29757329 TI - Supporting Dynamic Quantization for High-Dimensional Data Analytics. AB - : Similarity searches are at the heart of exploratory data analysis tasks. Distance metrics are typically used to characterize the similarity between data objects represented as feature vectors. However, when the dimensionality of the data increases and the number of features is large, traditional distance metrics fail to distinguish between the closest and furthest data points. Localized distance functions have been proposed as an alternative to traditional distance metrics. These functions only consider dimensions close to query to compute the distance/similarity. Furthermore, in order to enable interactive explorations of high-dimensional data, indexing support for ad-hoc queries is needed. In this work we set up to investigate whether bit-sliced indices can be used for exploratory analytics such as similarity searches and data clustering for high dimensional big-data. We also propose a novel dynamic quantization called Query dependent Equi-Depth (QED) quantization and show its effectiveness on characterizing high-dimensional similarity. When applying QED we observe improvements in kNN classification accuracy over traditional distance functions. ACM Reference format: Gheorghi Guzun and Guadalupe Canahuate. 2017. Supporting Dynamic Quantization for High-Dimensional Data Analytics. In Proceedings of Ex ploreDB'17, Chicago, IL, USA, May 14-19, 2017, 6 pages. https://doi.org/http://dx.doi.org/10.1145/3077331.3077336. PMID- 29757328 TI - Development and psychometric validation of the Nausea/Vomiting Symptom Assessment patient-reported outcome (PRO) instrument for adults with secondary hyperparathyroidism. AB - Background: We developed the Nausea/Vomiting Symptom Assessment (NVSA(c)) patient reported outcome (PRO) instrument to capture patients' experience with nausea and vomiting while on calcimimetic therapy to treat secondary hyperparathyroidism (SHPT) related to end-stage kidney disease. This report summarizes the content validity and psychometric validation of the NVSA(c). Methods: The two NVSA(c) items were drafted by two health outcomes researchers, one medical development lead, and one regulatory lead: it yields three scores: the number of days of vomiting or nausea per week, the number of vomiting episodes per week, and the mean severity of nausea. An eight-week prospective observational study was conducted at ten dialysis centers in the U.S. with 91 subjects. Criterion measures included in the study were the Functional Living Index-Emesis, Kidney Disease Quality of Life Instrument, EQ-5D-5 L, Static Patient Global Assessment, and Patient Global Rating of Change. Analyses included assessment of score distributions, convergent and known-groups validity, test-retest reliability, ability to detect change, and thresholds for meaningful change. Results: Qualitative interviews verified that the NVSA(c) captures relevant aspects of nausea and vomiting. Patients understood the NVSA(c) instructions, items, and response scales. Correlations between the NVSA(c) and related and unrelated measures indicated strong convergent and discriminant validity, respectively. Mean differences between externally-defined vomiting/nausea groups supported known-groups validity. The scores were stable in subjects who reported no change on the Patient Global Rating of Change indicating sufficient test-retest reliability. The no-change group had mean differences and effect sizes close to zero; mean differences were mostly positive for a worsening group and mostly negative for the improvement group with predominantly medium or large effect sizes. Preliminary thresholds for meaningful worsening were 0.90 days for number of days of vomiting or nausea per week, 1.20 for number of episodes of vomiting per week, and 0.40 for mean severity of nausea. Conclusions: The NVSA(c) instrument demonstrated content validity, convergent and known-groups validity, test-retest reliability, and the ability to detect change. Preliminary thresholds for minimally important change should be further refined with additional interventional research. The NVSA(c) may be used to support study endpoints in clinical trials comparing the nausea/vomiting profile of novel SHPT therapies. PMID- 29757330 TI - Design and development of the MacTSQ measure of satisfaction with treatment for macular conditions used within the IVAN trial. AB - Background: The purpose of the study was to design a measure of patient satisfaction with treatment for macular disease, the MacTSQ, and to carry out psychometric evaluation of the measure. The measure was designed along the lines of the widely used Diabetes Treatment Satisfaction Questionnaire (DTSQ) and sister measures of treatment satisfaction for other conditions including diabetic retinopathy. Information was also gathered during in-depth interviews with 20 people who had experienced one of a range of treatments for macular degeneration. In a prospective study, the newly designed 16-item MacTSQ, was used in a multi centre, randomised, double-blind clinical trial (the IVAN study) comparing two treatments for neovascular age-related macular degeneration and two treatment schedules: 1. continual monthly treatments (continuous arm), 2. initial 3 monthly treatments then monitoring and retreatment if necessary (discontinuous arm). The MacTSQ was administered after the first three treatments and at 12 and 24 months. Psychometric development was carried out using data from 137 patients. Sensitivity and validity of the MacTSQ were investigated using baseline and 12 month data. Results: Exploratory factor analysis yielded two subscales i) convenience, information and overall satisfaction (6 Items: Cronbach's alpha = 0.740), and ii) safety, efficacy and discomfort (6 Items: alpha = 0.776). Twelve items also loaded on to a single scale (alpha = 0.815). Three items were removed from the scale but retained in the questionnaire for separate analysis where required. Greater satisfaction was reported at time 2 (12 months) than time 1 (after 3 monthly injections) on the safety, efficacy and discomfort subscale (W = 3000.500. p = 0.024, n = 108). Participants whose vision improved reported greater satisfaction than those who had no improvement e.g. U = 1599, p = 0.033. Those in the discontinuous arm reported greater satisfaction on subscale 1 than those in the continuous arm at time one (U = 1870, p = 0.04) and time 2 (U = 1132.5, p = 0.023). This finding suggested a better experience in the discontinuous arm. Conclusions: The MacTSQ will be valuable in investigating treatment satisfaction in clinical trials of new treatments or in a routine clinic situation and may highlight ways to improve patients' experience of treatment. PMID- 29757331 TI - Erratum. AB - [This corrects the article on p. 148 in vol. 17, PMID: 29404145.]. PMID- 29757332 TI - Clinician's Commentary on Maharaj et al.1. PMID- 29757333 TI - Understanding and measuring symptoms and health status in asthma COPD overlap: content validity of the EXACT and SGRQ. AB - Background: Asthma-chronic obstructive pulmonary disease overlap (ACO) differs from asthma and chronic obstructive pulmonary disease (COPD) in demographics, phenotypic characteristics and outcomes, yet the patient experience of ACO is poorly characterized. We aimed to understand and compare the patient experience of symptoms and domains of impact in ACO relative to COPD, and assess the content validity of existing patient-reported outcome (PRO) instruments in ACO. Methods: This US qualitative, interview study included patients who met American Thoracic Society/European Respiratory Society spirometric criteria for COPD. Additionally, patients with ACO demonstrated reversibility (forced expiratory volume in 1 s [FEV1] increase >= 12% and >= 200 mL) to albuterol/salbutamol and an FEV1/forced vital capacity ratio < 0.7. Patients took part in concept elicitation (CE) to explore symptoms and impacts of obstructive lung disease. The Exacerbations of Chronic Pulmonary Disease Tool (EXACT), St George's Respiratory Questionnaire (SGRQ) and a daily wheeze assessment were cognitively debriefed to assess relevance and comprehensiveness. Interviews were analyzed using Atlas.Ti. Concept saturation was evaluated at the symptom level. Results: Twenty patients with ACO and 10 patients with COPD were recruited. Patients from both groups indicated that shortness of breath was their most frequent and bothersome symptom. The most frequently reported symptoms in both groups were shortness of breath, cough, wheezing, difficulty breathing, mucus/phlegm, chest tightness, and tiredness, weakness or fatigue. The onset, severity, frequency and duration of symptoms were consistently described across both groups, although a higher proportion of patients with ACO experienced exacerbations versus those with COPD. Impacts on daily living, physical impacts and emotional impacts were commonly described (ACO: 90-100%, COPD: 80-100%). Concept saturation was achieved in both groups. Overall, the EXACT, SGRQ and daily wheeze assessment were well understood and relevant to most patients with ACO or COPD (50-100%) and patients generally found the assessments easy to complete. The PRO instruments adequately captured symptoms described during CE, demonstrating high content validity in ACO and COPD. Conclusions: Patients with ACO and COPD experienced similar symptoms and impacts. The EXACT, SGRQ and assessment of wheeze were well understood and captured concepts relevant to patients with ACO. PMID- 29757334 TI - Development of a novel observer-reported outcome measure for the assessment of Respiratory Syncytial Virus (RSV) infection symptoms in pediatric clinical trials. AB - Background: Respiratory syncytial virus (RSV) is a seasonal infection affecting most children by 2 years of age and the leading cause of lower respiratory tract infection requiring hospitalization in infants. Novel antiviral medications are in development to improve the clinical outcomes of RSV; however, no clinical outcome assessments (COAs) for RSV have been developed in alignment with the United States Food and Drug Administration patient-reported outcome guidance to assist in the evaluation of new therapies. To address this need, an observer reported outcome (ObsRO) measure designed to assess observable RSV symptoms was created. Methods: The literature was reviewed to evaluate existing COAs and identify constructs of interest. Individual caregiver interviews elicited concepts that informed item development, and candidate items were subsequently evaluated in two rounds of cognitive testing. Separate cohorts of caregivers of RSV-infected nonhospitalized and hospitalized infants participated. Therapeutic area experts provided input throughout the instrument development process. Results: Caregivers of 39 children < 24 months old with RSV (31 nonhospitalized, 8 hospitalized) participated in in-depth, individual interviews during concept elicitation and cognitive debriefing, resulting in 21 concepts identified as potentially observable and relevant to young children with RSV. The item pool was reduced to 12 cardinal symptoms and behavior impacts reported to be directly observable by caregivers, with 10 daytime and 9 nighttime symptoms to capture diurnal variation in severity. Conclusions: The RSV Caregiver Diary assesses RSV symptom severity and change from the parent or caregiver perspective in a standardized manner to measure treatment benefit. Following psychometric evaluation and refinement, this tool is expected to be suitable for assisting in the clinical development of RSV therapeutics. PMID- 29757335 TI - On the Expectation-Maximization Algorithm for Rice-Rayleigh Mixtures With Application to Noise Parameter Estimation in Magnitude MR Datasets. AB - Magnitude magnetic resonance (MR) images are noise-contaminated measurements of the true signal, and it is important to assess the noise in many applications. A recently introduced approach models the magnitude MR datum at each voxel in terms of a mixture of upto one Rayleigh and an a priori unspecified number of Rice components, all with a common noise parameter. The Expectation-Maximization (EM) algorithm was developed for parameter estimation, with the mixing component membership of each voxel as the missing observation. This paper revisits the EM algorithm by introducing more missing observations into the estimation problem such that the complete (observed and missing parts) dataset can be modeled in terms of a regular exponential family. Both the EM algorithm and variance estimation are then fairly straightforward without any need for potentially unstable numerical optimization methods. Compared to local neighborhood- and wavelet-based noise-parameter estimation methods, the new EM-based approach is seen to perform well not only on simulation datasets but also on physical phantom and clinical imaging data. PMID- 29757336 TI - Formulas for the Detection beta-Thalassemia Carriers Are Affected by Changes in Red Cell Parameters. PMID- 29757338 TI - Automated segmentation of the choroid in EDI-OCT images with retinal pathology using convolution neural networks. AB - The choroid plays a critical role in maintaining the portions of the eye responsible for vision. Specific alterations in the choroid have been associated with several disease states, including age-related macular degeneration (AMD), central serous choroiretinopathy, retinitis pigmentosa and diabetes. In addition, choroid thickness measures have been shown as a predictive biomarker for treatment response and visual function. Where several approaches currently exist for segmenting the choroid in optical coherence tomography (OCT) images of healthy retina, very few are capable of addressing images with retinal pathology. The difficulty is due to existing methods relying on first detecting the retinal boundaries before performing the choroidal segmentation. Performance suffers when these boundaries are disrupted or suffer large morphological changes due to disease, and cannot be found accurately. In this work, we show that a learning based approach using convolutional neural networks can allow for the detection and segmentation of the choroid without the prerequisite delineation of the retinal layers. This avoids the need to model and delineate unpredictable pathological changes in the retina due to disease. Experimental validation was performed using 62 manually delineated choroid segmentations of retinal enhanced depth OCT images from patients with AMD. Our results show segmentation accuracy that surpasses those reported by state of the art approaches on healthy retinal images, and overall high values in images with pathology, which are difficult to address by existing methods without pathology specific heuristics. PMID- 29757339 TI - Novel antimony(iii) hydroxamic acid complexes as potential anti-leishmanial agents. AB - Reaction of benzohydroxamic acid (Bha), 2-pyridinehydroxamic acid (2-pyha), 2 amino-phenylhydroxamic acid (2-NH2-pha) and salicylhydroxamic acid (Sha) with SbCl3 in ethanol gave the corresponding novel hydroxamato Sb(iii) complexes, [Sb(Bha-1H)2Cl] 1, [SbCl2(2-pyha-1H)] 2, [Sb(2-NH2-pha-1H)(2-NH3-pha-1H)]Cl23 and [SbCl(Sha-1H)2] 4. In all cases the hydroxamic acids coordinate to the Sb centres in the typical bidentate hydroxamato (O,O') coordination mode, via the carbonyl oxygen and deprotonated hydroxyl group. Reaction of the histone deacetylase inhibitor (HDACi) suberoylanilidehydroxamic acid (SAHA) with Sb(OEt)3 gave the Sb(iii) hydroxamato/hydroximato complex, [Sb(SAHA-1H)(SAHA-2H)] 6. All test complexes significantly inhibited the promastigote proliferation of Leishmania amazonensis and L. chagasi and induced substantial changes in the general morphology of the parasites, including reduction in size and loss of flagellum, when compared to the untreated promastigotes. A dose-response approach using the test complexes showed a decreased in plasma membrane permeability and the mitochondrial dehydrogenase activities of the Leishmania species. [Sb(Bha-1H)2Cl] exhibited the best activity and was superior to the Sb HDACi complex 6. Though 1 exhibited noteworthy anti-leishmanial activity, the selectivity indexes determined suggest that [Sb(2-NH2-pha-1H)(2-NH3-pha-1H)]Cl23 is the test complex that merits further investigation as a potential anti-leishmanial agent. PMID- 29757341 TI - Role of a polymeric component in the phase separation of ternary fluid mixtures: a dissipative particle dynamics study. AB - We present the results from dissipative particle dynamics (DPD) simulations of phase separation dynamics in ternary (ABC) fluids mixture in d = 3 where components A and B represent the simple fluids, and component C represents a polymeric fluid. Here, we study the role of polymeric fluid (C) on domain morphology by varying composition ratio, polymer chain length, and polymer stiffness. We observe that the system under consideration lies in the same dynamical universality class as a simple ternary fluids mixture. However, the scaling functions depend upon the parameters mentioned above as they change the time scale of the evolution morphologies. In all cases, the characteristic domain size follows l(t) ~ tphi with dynamic growth exponent phi, showing a crossover from the viscous hydrodynamic regime (phi = 1) to the inertial hydrodynamic regime (phi = 2/3) in the system at late times. PMID- 29757340 TI - Polyethylene glycol and octa-arginine dual-functionalized nanographene oxide: an optimization for efficient nucleic acid delivery. AB - The successful application of nucleic acid-based therapy for the treatment of various cancers is largely dependent on a safe and efficient delivery system. A dual-functionalized graphene oxide (GO)-based nanocarrier with the conjugation of aminated-polyethylene glycol (PEG-diamine) and octa-arginine (R8) for the intracellular delivery of nucleic acids is proposed. The functionalized sites are covalently co-conjugated and the PEG : R8 molar ratio is optimized at 10 : 1 to achieve a hydrocolloidally stable size of 252 +/- 2.0 nm with an effective charge of +40.97 +/- 1.05 and an amine-rich content of 10.87 +/- 0.4 MUmol g-1. The uptake of the nanocarrier in breast cancer cell lines, MCF-7 and MDA-MB 231, is investigated. The siRNA and pDNA condensation ability in the presence and absence of enzymes and the endosomal buffering capacity, as well as the intracellular localization of the gene/nanocarrier complex are also evaluated. Furthermore, the delivery of functional genes associated with the nanocarrier is assessed using c Myc protein knockdown and EGFP gene expression. The effective uptake of the nanocarrier by the cells shows superior cytocompatibility, and protects the siRNA and pDNA against enzyme degradation while inhibiting their migration with N : P ratios of 10 and 5, respectively. The co-conjugation of PEG-diamine and the cationic cell-penetrating peptide (CPP) into the GO nanocarrier also provides a superior internalization efficacy of 85% in comparison with a commercially available transfection reagent. The c-Myc protein knockdown and EGFP expression, which are induced by the nanocarrier, confirm that the optimized PEG-diamine/R8 functionalized GO could effectively deliver pDNA and siRNA into the cells and interfere with gene expression. PMID- 29757342 TI - Deconstructing collagen piezoelectricity using alanine-hydroxyproline-glycine building blocks. AB - Collagen piezoelectricity has been the focus of a large number of experimental and theoretical studies for over fifty years. Less is known about the piezoelectric properties of its building blocks, in particular but not limited to, proline and hydroxyproline. Spurred by the recent upsurge of interest in piezoelectricity in organic crystals including our own report of unprecedentedly high piezoelectricity in amino acid glycine, we predict and measure the piezoelectric properties of collagen subcomponents in single crystalline forms and the collagen-like alanine-hydroxyproline-glycine trimer peptide. We map the modulation of piezoelectric charge constants in collagen building blocks as the crystal symmetry is lowered and the molecule size increases, finding strong evidence for amino acid-level barcoding of collagen piezoelectricity that can in turn be tuned using very simple chemistry. The simple addition of an -OH group can increase piezoelectric constants by up to two orders of magnitude (d25 = 25 +/- 5 pC N-1) as measured in Y-cut hydroxyproline crystals. The value is similar to that obtained from thermoelectrically poled commercial polyvinylidene di fluoride (PVDF) films. Overall, our findings support a simple block by block approach in which first principles calculations can guide the understanding and re-engineering of piezoelectric biomolecules. PMID- 29757344 TI - Complex integration of intrinsic and peripheral signaling is required for pituitary gland development. AB - The coordination of pituitary development is complicated and requires input from multiple cellular processes. Recent research has provided insight into key molecular determinants that govern cell fate specification in the pituitary. Moreover, increasing research aimed to identify, characterize, and functionally describe the presumptive pituitary stem cell population has allowed for a better understanding of the processes that govern endocrine cell differentiation in the developing pituitary. The culmination of this research has led to the ability of investigators to recapitulate some of embryonic pituitary development in vitro, the first steps to developing novel regenerative therapies for pituitary diseases. In this current review, we cover the major players in pituitary stem/progenitor cell function and maintenance, and the key molecular determinants of endocrine cell specification. In addition, we discuss the contribution of peripheral hormonal regulation of pituitary gland development, an understudied area of research. PMID- 29757343 TI - Dietary fiber intervention on gut microbiota composition in healthy adults: a systematic review and meta-analysis. AB - Background: Dysfunction of the gut microbiota is frequently reported as a manifestation of chronic diseases, and therefore presents as a modifiable risk factor in their development. Diet is a major regulator of the gut microbiota, and certain types of dietary fiber may modify bacterial numbers and metabolism, including short-chain fatty acid (SCFA) generation. Objective: A systematic review and meta-analysis were undertaken to assess the effect of dietary fiber interventions on gut microbiota composition in healthy adults. Design: A systematic search was conducted across MEDLINE, EMBASE, CENTRAL, and CINAHL for randomized controlled trials using culture and/or molecular microbiological techniques evaluating the effect of fiber intervention on gut microbiota composition in healthy adults. Meta-analyses via a random-effects model were performed on alpha diversity, prespecified bacterial abundances including Bifidobacterium and Lactobacillus spp., and fecal SCFA concentrations comparing dietary fiber interventions with placebo/low-fiber comparators. Results: A total of 64 studies involving 2099 participants were included. Dietary fiber intervention resulted in higher abundance of Bifidobacterium spp. (standardized mean difference (SMD): 0.64; 95% CI: 0.42, 0.86; P < 0.00001) and Lactobacillus spp. (SMD: 0.22; 0.03, 0.41; P = 0.02) as well as fecal butyrate concentration (SMD: 0.24; 0.00, 0.47; P = 0.05) compared with placebo/low-fiber comparators. Subgroup analysis revealed that fructans and galacto-oligosaccharides led to significantly greater abundance of both Bifidobacterium spp. and Lactobacillus spp. compared with comparators (P < 0.00001 and P = 0.002, respectively). No differences in effect were found between fiber intervention and comparators for alpha-diversity, abundances of other prespecified bacteria, or other SCFA concentrations. Conclusions: Dietary fiber intervention, particularly involving fructans and galacto-oligosaccharides, leads to higher fecal abundance of Bifidobacterium and Lactobacillus spp. but does not affect alpha-diversity. Further research is required to better understand the role of individual fiber types on the growth of microbes and the overall gut microbial community. This review was registered at PROSPERO as CRD42016053101. PMID- 29757337 TI - Emerging good practices for Translatability Assessment (TA) of Patient-Reported Outcome (PRO) measures. AB - This paper presents emerging Good Practices for Translatability Assessment (TA) of Patient-Reported Outcome (PRO) Measures. The ISOQOL Translation and Cultural Adaptation Special Interest Group (TCA-SIG) undertook the review of several TA approaches, with the collaboration of organizations who are involved in conducting TA, and members of the TCA-SIG. The effort led to agreement by the writing group on Good Practices for 1) the terminology to be used in referring to translatability process, 2) the best definition of TA, 3) the methodology that is recommended at each step of the process, 4) the persons involved in TA, 5) the timing of assessment, 6) the review criteria for TA, and 7) the recommendations to be made at the end of the TA process. With input from the TCA-SIG membership and in consultation with experts in the field, these emerging good practices can guide the future use of TA in the development of PROs. PMID- 29757346 TI - Effectiveness of a multifaceted intervention to reduce night-time sedative use in a rehabilitation unit: a pre-post intervention study. AB - Background: night-time sedation prescribed during a hospital stay can result in long-term use of such medications in older people. We examined the effectiveness of a multifaceted intervention to reduce night time sedation in an inpatient rehabilitation unit. Methods: an initial retrospective survey of night-time sedative use was followed by prospective re-evaluation after a number of changes were made including education of staff and of patients regarding the potential hazards of sedative medications, measures to promote sleep hygiene and facilitate a 'quiet time' after 10 pm and development of a withdrawal protocol for patients on long-term night sedation. The primary outcome measures were the proportions of patients started on night sedation in the unit and the proportion of those using night sedation where a dose reduction was attempted before and after the intervention. Results: night sedation was prescribed for 22/68 (32.4%) subjects in the pre- and 23/169 (13.6%) subjects in the post-intervention surveys (P = 0.001); medication started while in the unit dropped from 10 (14.7%) to 1 (0.6%) (P < 0.0001). There was an improvement in the proportion of patients using night sedation where an attempt was made to reduce the dosage of or eliminate sedative drug use prior to discharge after the intervention was introduced (3/22 (13.6%) vs 14/23 (60.9%) (P = 0.001)). Conclusions: a multifaceted intervention, including ongoing education, audit and feedback and changes to unit practices to promote a 'quiet time' at night, leads to a substantial reduction in the use of night sedation in inpatients. PMID- 29757345 TI - Does Socioeconomic Status Modify the Association Between Preterm Birth and Children's Early Cognitive Ability and Kindergarten Academic Achievement in the United States? AB - Being born preterm and being raised in poverty are each linked with adverse cognitive outcomes. Using data from 5,250 singletons born in the US in 2001 and enrolled in the Early Childhood Longitudinal Study-Birth Cohort, we examined whether household socioeconomic status (SES) modified the association between preterm birth (PTB) and children's scores on cognitive assessments at 2 years and reading and mathematics assessments at kindergarten age. Gestational age was measured from birth certificates and categorized as early preterm, moderate preterm, late preterm, early term, and term. SES was measured at 9 months using a composite of parental education, occupation, and income. PTB was associated with 0.1-0.6 standard deviation (SD) deficits in 2-year cognitive ability and kindergarten mathematics scores, and with 0.1-0.4 SD deficits in kindergarten reading scores. Children living in the lowest (versus highest) SES quintile scored 0.6 SD lower on 2-year cognitive ability, 1.1 SD lower on kindergarten reading, and 0.9 SD lower on kindergarten mathematics. The association between PTB and cognitive outcomes did not differ by postnatal SES. However, children who were both born preterm and lived in lower SES households had the poorest performance on all three outcomes and therefore may represent a uniquely high risk group. PMID- 29757348 TI - A case of undiagnosed pseudohyperkalaemia following a splenectomy. AB - Pseudohyperkalaemia is defined as a rise in serum potassium with concomitantly normal plasma potassium. The case of long undiagnosed pseudohyperkalaemia in an 84-year-old lady with thrombocytosis post splenectomy is presented. Presenting a historical perspective and the multifactorial aetiology of pseudohyperkalaemia the author underlines the importance of detecting apparent hyperkalaemia by testing the plasma potassium. Awareness of the possible causes of pseudohyperkalaemia increases the likelihood of it being detected earlier thereby decreasing the risk of harming the patient. Unnecessary treatment and investigation of pseudohyperkalaemia can cause harm to the patient in the form of undesired side effects, unnecessary investigations and concerns, and potentially dangerous iatrogenically induced cardiac arrhythmias. PMID- 29757349 TI - Base-pair resolution detection of transcription factor binding site by deep deconvolutional network. AB - Motivation: Transcription factor (TF) binds to the promoter region of a gene to control gene expression. Identifying precise TF binding sites (TFBSs) is essential for understanding the detailed mechanisms of TF-mediated gene regulation. However, there is a shortage of computational approach that can deliver single base pair resolution prediction of TFBS. Results: In this paper, we propose DeepSNR, a Deep Learning algorithm for predicting TF binding location at Single Nucleotide Resolution de novo from DNA sequence. DeepSNR adopts a novel deconvolutional network (deconvNet) model and is inspired by the similarity to image segmentation by deconvNet. The proposed deconvNet architecture is constructed on top of 'DeepBind' and we trained the entire model using TF specific data from ChIP-exonuclease (ChIP-exo) experiments. DeepSNR has been shown to outperform motif search-based methods for several evaluation metrics. We have also demonstrated the usefulness of DeepSNR in the regulatory analysis of TFBS as well as in improving the TFBS prediction specificity using ChIP-seq data. Availability and implementation: DeepSNR is available open source in the GitHub repository (https://github.com/sirajulsalekin/DeepSNR). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29757347 TI - Role of inhibitory control in modulating focal seizure spread. AB - Focal seizure propagation is classically thought to be spatially contiguous. However, distribution of seizures through a large-scale epileptic network has been theorized. Here, we used a multielectrode array, wide field calcium imaging, and two-photon calcium imaging to study focal seizure propagation pathways in an acute rodent neocortical 4-aminopyridine model. Although ictal neuronal bursts did not propagate beyond a 2-3-mm region, they were associated with hemisphere wide field potential fluctuations and parvalbumin-positive interneuron activity outside the seizure focus. While bicuculline surface application enhanced contiguous seizure propagation, focal bicuculline microinjection at sites distant to the 4-aminopyridine focus resulted in epileptic network formation with maximal activity at the two foci. Our study suggests that both classical and epileptic network propagation can arise from localized inhibition defects, and that the network appearance can arise in the context of normal brain structure without requirement for pathological connectivity changes between sites. PMID- 29757350 TI - Implementation of guidelines in eosinophilic esophagitis at an academic pediatric practice. AB - Guidelines for eosinophilic esophagitis (EoE) require high-dose PPI (HD-PPI) trial to evaluate for PPI-responsive esophageal eosinophilia (PPI-REE) prior to EoE diagnosis and dedicated therapy. This involves a second esophagogastroduodenoscopy (EGD) to assess for PPI-REE. This study is to evaluate adherence to current guidelines in evaluation of PPI-REE and EoE. Retrospective review of new patients treated with HD-PPI after an index EGD showing >15 eos/hpf in esophageal biopsies. One hundred and eighty patients had an index EGD with esophageal eosinophilia of >15 eos/hpf. Of these, 97/180 (53.8%) received HD-PPI; remaining 83/180 were prescribed other interventions without a HD-PPI trial. Of the 180 patients, 143 (79.4%) patients returned for follow-up and of whom 96/143 (67.1%) underwent repeat EGD. Adherence to guidelines improves with time. Patients are vested in care. PMID- 29757351 TI - M10, a novel derivative of Myricetin, prevents ulcerative colitis and colorectal tumor through attenuating robust endoplasmic reticulum stress. AB - Chronic gut inflammation disposes to an increased risk of colitis-associated cancer. Chemoprevention is an attractive complementary strategy. We aimed to evaluate the chemopreventive effects of M10, a novel derivative of Myricetin, in the murine azoxymethane/dextran sodium sulfate model. Oral administration of M10 at 50-100 mg/kg once a day for consecutive 12 weeks significantly prevented ulcerative colitis (UC) and colorectal tumor. Pathological analysis of intestines showed that M10 reduced the degree of chronic inflammation and prevented the progression of colorectal tumorigenesis. Flow cytometry analysis of the immunocytes isolated from intraepithelial and lamina propria showed that M10 prevented the infiltration of myeloid-derived suppressor cells and increased CD8+T and CD4+T cells in colorectal tissues. Enzyme-linked immunosorbent analysis revealed the reduction of pro-inflammatory mediators granulocyte-macrophage colony-stimulating factor/macrophage colony-stimulating factor, IL-6 and TNF alpha in colonic mucosa. Western blot assay also showed M10 prevention of the NF kappaB/IL-6/STAT3 pathways and the biomarkers of inflammation and colorectal tumorigenesis. Electron microscopy analysis revealed that M10 prevent robust endoplasmic reticulum (ER) stress-induced autophagy in inflamed colonic mucosal cells. In conclusion, oral administration of Myricetin derivative M10 exerts chemoprevention of UC and colorectal tumor in mice. The mechanism of chemoprevention is associated with the reduction of biomarkers of chronic inflammation and proliferation through attenuating robust ER stress in inflamed colonic mucosal cells. M10 exerts chemoprevention activity without evidence of toxicity in mice. These results justify further evaluation of M10 in clinical trials. M10 could develop a promising regimen in the chemoprevention of colitis and colorectal cancer. PMID- 29757352 TI - Evaluation of the Impact of a Rotavirus Vaccine Program on Pediatric Acute Gastroenteritis Hospitalizations: Estimating the Overall Effect Attributable to the Program as a Whole and as a Per-Unit Change in Rotavirus Vaccine Coverage. AB - Estimation of the overall effect of a vaccine program is essential, but the effect is typically estimated for a whole program. We estimated the overall effect of the Quebec rotavirus vaccine program, launched in November 2011, and the effect for each 10% increase in rotavirus vaccine coverage on pediatric hospitalizations for all-cause acute gastroenteritis. We implemented negative binomial regressions adjusted for seasonality, long-term trends, and infection dynamics, to estimate the effect of the vaccine program as: 1) a dichotomous variable, representing program presence/absence, and linear term to account for changes in trend in the period after the program began; and 2) a continuous variable, representing rotavirus vaccine coverage. Using exposure 1, the vaccine program was associated with a 51.2% (95% confidence interval (CI): 28.5, 66.7) relative decline in adjusted weekly hospitalization rates for all-cause acute gastroenteritis as of December 28, 2014. Using exposure 2, a 10% increase in rotavirus >=1-dose coverage was associated with a 7.1% (95% CI: 3.5, 10.5) relative decline in adjusted weekly rates, with maximum coverage of 87.0% associated with a 47.2% (95% CI: 26.9, 61.9) relative decline. Estimation of the overall effect attributable to a change in vaccine coverage might be a useful addition to standard measurement of the overall effect. PMID- 29757353 TI - Development and evaluation of a deep learning model for protein-ligand binding affinity prediction. AB - Motivation: Structure based ligand discovery is one of the most successful approaches for augmenting the drug discovery process. Currently, there is a notable shift towards machine learning (ML) methodologies to aid such procedures. Deep learning has recently gained considerable attention as it allows the model to 'learn' to extract features that are relevant for the task at hand. Results: We have developed a novel deep neural network estimating the binding affinity of ligand-receptor complexes. The complex is represented with a 3D grid, and the model utilizes a 3D convolution to produce a feature map of this representation, treating the atoms of both proteins and ligands in the same manner. Our network was tested on the CASF-2013 'scoring power' benchmark and Astex Diverse Set and outperformed classical scoring functions. Availability and implementation: The model, together with usage instructions and examples, is available as a git repository at http://gitlab.com/cheminfIBB/pafnucy. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29757354 TI - A Modified Inverted Nipple Correction Technique That Preserves Breastfeeding. AB - Background: An inverted nipple may affect the appearance of the breasts and breastfeeding, but traditional surgical procedures might injure the normal lactiferous ducts and damage sensory functions. Objectives: The aim of the study was to propose a minimally invasive and reliable method that preserves breastfeeding and corrects Grade I and II inverted nipples. Methods: This was a randomized controlled trial of 230 female patients with unilateral or bilateral inverted nipples and 30 patients with normal nipples who visited the Preconception Counseling Department of our hospital from February 2009 to January 2016. The nipples in the distractor group underwent an operation with a distractor, while the control nipples were treated with daily exercises. The intervention lasted 6 months. The primary endpoint was full-term pregnancy breastfeeding for 4 months. The secondary endpoint was the completion of lactation without obvious complications such as mastitis and nipple craze. Results: Grade I and II nipples achieved increased height after the distractor was worn for 6 months and at 37 weeks of pregnancy (P<0.05), while the control nipples achieved only a marginal improvement at 37 weeks of pregnancy. In the distractor group, the success rates were 84.9% and 79.3% for Grade I and II nipples, respectively, compared with the control group (52.5% and 38.9%, respectively) (P<0.05). After treatment with the distractor for 6 months, nipples in the distractor group showed no complications such as skin numbness and nipple necrosis. Conclusions: The use of a distractor is a reliable and minimally invasive method for correcting Grade I and II inverted nipples while preserving breastfeeding. PMID- 29757355 TI - A Prospective Study to Monitor for Tuberculosis During Anti-tumour Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease and Immune-mediated Inflammatory Diseases. AB - Background: Biologic therapies have revolutionised the treatment of immune mediated diseases including inflammatory bowel disease [IBD] and rheumatological disorders. However, biologic treatments are associated with an increased risk of reactivation of latent tuberculosis. Data from regular monitoring for latent tuberculosis infection [LTBI] during biologic treatment are lacking. Methods: Consecutive patients eligible for biologic therapies were screened for LTBI and prospectively followed up for 3 years. Incidence and risk factors of latent tuberculosis tests conversion (interferon gamma release assays [IGRA], tuberculin skin tests [TST], and chest radiography [CXR]) with clinical outcomes were studied. Results: A total of 108 patients [83 IBD; 25 rheumatological disorders] were included. At baseline, 18/108 [16.7%] patients [five IBD; 13 rheumatological disorders] were tested positive for LTBI. Of these, 14/18 [77.8%] patients received isoniazid monotherapy for 9 months. Of the remainder, 17/90 [18.9%] patients had LTBI test conversion while on biologic therapies and of these 14/17 [82.4%] received isoniazid monotherapy for 9 months. Age, sex, smoking status, alcohol use, travel history, disease type, and immunosuppressive therapy were not associated with LTBI test conversion. In subjects with IGRA conversion, serial IGRA levels normalised after completion of isoniazid except in one patient whose IGRA remained persistently elevated despite isoniazid and who subsequently developed active TB. Conclusions: Conversion of LTBI is common and occurred early during biologic therapy in an area with intermediate TB burden. Subjects with latent TB tests conversion and persistently high IGRA levels may have an increased risk of TB reactivation or development of active TB, and they require close observation or intensive workup for active TB. PMID- 29757356 TI - Developing a diagnostic understanding of GERD phenotypes through the analysis of levels of mucosal injury, immune activation, and psychological comorbidity. AB - Patients with gastroesophageal reflux disease (GERD) can present with typical or atypical symptoms. The aim of this study is to explore the underlying physiological and psychological mechanisms that lead to different symptomatic manifestations of GERD. A total of 238 patients diagnosed with GERD underwent gastroscopy, 24 h multichannel intraluminal impedance-pH (MII-pH) monitoring, and psychological assessment with questionnaires. Patient symptoms were used to classify GERD into phenotypes of typical reflux syndrome (TRS, n = 87), reflux chest pain syndrome (RCS, n = 98), and extraesophageal syndromes (EES, n = 53). 38 healthy volunteers served as controls. Reflux parameters and baseline impedance values (BIVs) were acquired from MII-pH monitoring results. A subset of subjects were biopsied from the lower esophagus; certain immune cells were stained with immunohistochemistry. BIVs in GERD patients (TRS, RCS, and EES) were significantly lower than in healthy controls and TRS patients exhibited the lowest BIVs (all P < 0.01). This indicated that the extent of mucosal injury differed across groups. TRS patients had higher acid exposure time (AET) compared to RCS, EES and controls (all P < 0.05). RCS patients had more intraepithelial T lymphocyte (IEL) and mast cell (MC) infiltration, and higher psychometric scores compared to TRS patients and controls (all P < 0.05), suggesting a possible stress-related esophageal hypersensitivity basis. TRS patients are characterized by acid reflux and correlated mucosal injury, which explains their typical reflux symptoms. RCS patients exhibit less acid-related injury but possible psychological stress-related esophageal hypersensitivity, which could be the main cause of their esophageal pain. PMID- 29757357 TI - The revival of the Gini importance? AB - Motivation: Random forests are fast, flexible and represent a robust approach to analyze high dimensional data. A key advantage over alternative machine learning algorithms are variable importance measures, which can be used to identify relevant features or perform variable selection. Measures based on the impurity reduction of splits, such as the Gini importance, are popular because they are simple and fast to compute. However, they are biased in favor of variables with many possible split points and high minor allele frequency. Results: We set up a fast approach to debias impurity-based variable importance measures for classification, regression and survival forests. We show that it creates a variable importance measure which is unbiased with regard to the number of categories and minor allele frequency and almost as fast as the standard impurity importance. As a result, it is now possible to compute reliable importance estimates without the extra computing cost of permutations. Further, we combine the importance measure with a fast testing procedure, producing p-values for variable importance with almost no computational overhead to the creation of the random forest. Applications to gene expression and genome-wide association data show that the proposed method is powerful and computationally efficient. Availability and implementation: The procedure is included in the ranger package, available at https://cran.r-project.org/package=ranger and https://github.com/imbs-hl/ranger. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29757359 TI - Commentary on: Novel Proteomic Assay of Breast Implants Reveals Proteins with Significant Binding Differences: Implications for Surface Coating and Biocompatibility. PMID- 29757360 TI - Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy. AB - Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase based screening method can reduce the hospital stay by one day and reduced costs by ~$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ~$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate. PMID- 29757358 TI - Infectivity of Chronic Malaria Infections and Its Consequences for Control and Elimination. AB - Assessing the importance of targeting the chronic Plasmodium falciparum malaria reservoir is pivotal as the world moves toward malaria eradication. Through the lens of a mathematical model, we show how, for a given malaria prevalence, the relative infectivity of chronic individuals determines what intervention tools are predicted be the most effective. Crucially, in a large part of the parameter space where elimination is theoretically possible, it can be achieved solely through improved case management. However, there are a significant number of settings where malaria elimination requires not only good vector control but also a mass drug administration campaign. Quantifying the relative infectiousness of chronic malaria across a range of epidemiological settings would provide essential information for the design of effective malaria elimination strategies. Given the difficulties obtaining this information, we also provide a set of epidemiological metrics that can be used to guide policy in the absence of such data. PMID- 29757361 TI - Effects of Rhinoplasty on Labyrinthine Function. AB - Background: Rhinoplasty is a common surgical procedure that is requested and accepted by patients for cosmetic and functional reasons. Osteotomies are performed on nasal bone, maxillary crest, or vomer to fix the deviations of the nasal dorsum or septum. During the percussion of the osteotomes with the surgical mallet, the vibration energy diffuses to the cranium. Auditory and vestibular systems may be affected by these vibrations. Objectives: To assess the effects of rhinoplasty, in which osteotomies were performed using a hammer, on the audiovestibular system. Methods: Thirty adults who underwent rhinoplasty were included in the study group. Ten age and gender matched adults who had nasal surgery without surgical mallet or osteotome served as the control group. The patients in both groups were assessed using pure tone audiometry, tympanometry, distortion product otoacoustic emission testing, and vestibular-evoked myogenic potential, as well as video head impulse tests (vHIT) before the operation and 1 week after the operation. Results: On auditory assessment, there was no significant difference between the study and control groups regarding pure tone thresholds at frequencies of 250 Hz to 8 kHz (P > 0.05) as well as otoacoustic emissions. The vestibular assessment performed by using vestibular-evoked myogenic potential and vHIT did not reveal a statistically significant difference between the groups, before surgery or after surgery (P > 0.05). Conclusions: Rhinoplasty appears to be a safe operation in terms of audiovestibular functions, and osteotomy, in which a hammer is usually used, does not have an impact on hearing or balance functions of the ear. Level of Evidence 2: PMID- 29757362 TI - Is a 500-Cell Count Necessary for Bone Marrow Differentials?: A Proposed Analytical Method for Validating a Lower Cutoff. AB - Objectives: By convention, 500 cells are counted for bone marrow aspirate differentials. Evidence supporting such a cutoff is lacking. We hypothesized that 300-cell counts could be sufficient. Methods: Cell count results from 165 cases, for which values were recorded at 300 and 500 cells, were analyzed. We tested for statistical differences and changes in diagnostic classification between the two cutoffs. Results: Three hundred cell counts did not produce diagnostically different results, particularly for myeloblasts and plasma cells, where cell percentages are critical for disease classification. Method comparison analysis did not reach statistical significance for any cell type when comparing the two methods. Bias plots showed narrow, even spread about the mean bias. Contingency table analysis yielded no significant diagnostic discrepancies. Conclusions: Performing differential counts on 300 cells would produce clinically and statistically similar results to 500 cells. Reducing the cell number counted has potential cost/labor reductions without affecting quality of care. PMID- 29757363 TI - Targeting Endothelial Ligands: ICAM-1/alicaforsen, MAdCAM-1. AB - Specific blockade of the endothelial ligands intercellular adhesion molecule-1 [ICAM-1] and mucosal addressin cell adhesion molecule [MAdCAM] involved in leukocyte recruitment to the site of inflammation as therapeutic targets in inflammatory bowel disease [IBD] has been recognized from their overexpression in the inflamed mucosa and successful intervention based on these ligands in preclinical animal models. Interventions to target ICAM-1 in human IBD are confined to the ICAM-1 anti-sense oligonucleotide alicaforsen. While results with parenteral formulations of alicaforsen in Crohn's disease have largely been negative, efficacy signals derived from studies with an enema formulation in ulcerative colitis and pouchitis are promising and have led to a Food and Drug Administration Fast-Track designation for the latter. A large phase III programme in pouchitis is underway. Phase II studies with the anti-MAdCAM-1 antibody [SHP647] delivered positive results in ulcerative colitis and anti-inflammatory signals in Crohn's disease. Furthermore, it was shown that SHP647 does not affect the number and composition of cells in cerebrospinal fluid, suggesting that the compound is not affecting immune surveillance in the central nervous system. In addition, both alicaforsen and SHP647 are promising compounds based on the clear safety profile observed so far. PMID- 29757364 TI - Ventricular tachycardia due to isolated non-compaction of the right ventricle. PMID- 29757365 TI - Multifaceted Roles of Beige Fat in Energy Homeostasis Beyond UCP1. AB - Beige adipocytes are an inducible form of thermogenic adipose cells that emerge within the white adipose tissue in response to a variety of environmental stimuli, such as chronic cold acclimation. Similar to brown adipocytes that reside in brown adipose tissue depots, beige adipocytes are also thermogenic; however, beige adipocytes possess unique, distinguishing characteristics in their developmental regulation and biological function. This review highlights recent advances in our understanding of beige adipocytes, focusing on the diverse roles of beige fat in the regulation of energy homeostasis that are independent of the canonical thermogenic pathway via uncoupling protein 1. PMID- 29757366 TI - A systematic review and meta-analysis reveals pervasive effects of germline mitochondrial replacement on components of health. AB - BACKGROUND: Mitochondrial replacement, a form of nuclear transfer, has been proposed as a germline therapy to prevent the transmission of mitochondrial diseases. Mitochondrial replacement therapy has been licensed for clinical application in the UK, and already carried out in other countries, but little is known about negative or unintended effects on the health of offspring born using this technique. OBJECTIVE AND RATIONALE: Studies in invertebrate models have used techniques that achieve mitochondrial replacement to create offspring with novel combinations of mitochondrial and nuclear genotype. These have demonstrated that the creation of novel mitochondrial-nuclear interactions can lead to alterations in offspring characteristics, such as development rates, fertility and longevity. However, it is currently unclear whether such interactions could similarly affect the outcomes of vertebrate biomedical studies, which have sought to assess the efficacy of the replacement therapy. SEARCH METHODS: This systematic review addresses whether the effects of mitochondrial replacement on offspring characteristics differ in magnitude between biological (conducted on invertebrate models, with an ecological or evolutionary focus) and biomedical studies (conducted on vertebrate models, with a clinical focus). Studies were selected based on a key-word search in 'Web of Science', complemented by backward searches of reviews on the topic of mitochondrial-nuclear (mito-nuclear) interactions. In total, 43 of the resulting 116 publications identified in the search contained reliable data to estimate effect sizes of mitochondrial replacement. We found no evidence of publication bias when examining effect-size estimates across sample sizes. OUTCOMES: Mitochondrial replacement consistently altered the phenotype, with significant effects at several levels of organismal performance and health, including gene expression, anatomy, metabolism and life-history. Biomedical and biological studies, while differing in the methods used to achieve mitochondrial replacement, showed only marginally significant differences in effect-size estimates (-0.233 [CI: -0.495 to -0.011]), with larger effect-size estimates in biomedical studies (0.697 [CI: 0.450-0.956]) than biological studies (0.462 [CI: 0.287-0.688]). Humans showed stronger effects than other species. Effects of mitochondrial replacement were also stronger in species with a higher basal metabolic rate. Based on our results, we conducted the first formal risk analysis of mitochondrial replacement, and conservatively estimate negative effects in at least one in every 130 resulting offspring born to the therapy. WIDER IMPLICATIONS: Our findings suggest that mitochondrial replacement may routinely affect offspring characteristics across a wide array of animal species, and that such effects are likely to extend to humans. Studies in invertebrate models have confirmed mito-nuclear interactions as the underpinning cause of organismal effects following mitochondrial replacement. This therefore suggests that mito nuclear interactions are also likely to be contributing to effects seen in biomedical studies, on vertebrate models, whose effect sizes exceeded those of biological studies. Our results advocate the use of safeguards that could offset any negative effects (defining any unintended effect as being negative) mediated by mito-nuclear interactions following mitochondrial replacement in humans, such as mitochondrial genetic matching between donor and recipient. Our results also suggest that further research into the molecular nature of mito-nuclear interactions would be beneficial in refining the clinical application of mitochondrial replacement, and in establishing what degree of variation between donor and patient mitochondrial DNA haplotypes is acceptable to ensure 'haplotype matching'. PMID- 29757367 TI - Successful total endovascular repair of a giant salmonella-infected painful thoraco-abdominal aortic pseudoaneurysm. AB - Endovascular approach is now a safe and effective technique for the elective treatment of a thoraco-abdominal aneurysm. This technique has significantly reduced the morbi-mortality for elective surgery. Moreover, it can permit to treat patients with a high surgical risk who are not eligible for open surgery. The permanent availability of endovascular material opens the door for treating a complex emergency thoraco-abdominal aneurysm. Here, we present the case of an 81 year-old man who had a rapidly evolving salmonella-infected aortic thoraco abdominal Type IV pseudoaneurysm. Total endovascular treatment using aortic endoprosthesis, chimneys for coeliac trunk and superior mesenteric artery and periscopes for renal arteries was performed and permitted to obtain the complete exclusion of the pseudoaneurysm. The patient was event free and discharged from hospital after a few days with an antibiotic treatment adapted for salmonella. He was still event free 10 months after surgery. Endovascular technique might be a viable option even for an emergency infected complex thoraco-abdominal aortic aneurysm. Secondary open surgery should be discussed under the benefit-risk balance. PMID- 29757369 TI - Statistical primer: sample size and power calculations-why, when and how? AB - When designing a clinical study, a fundamental aspect is the sample size. In this article, we describe the rationale for sample size calculations, when it should be calculated and describe the components necessary to calculate it. For simple studies, standard formulae can be used; however, for more advanced studies, it is generally necessary to use specialized statistical software programs and consult a biostatistician. Sample size calculations for non-randomized studies are also discussed and two clinical examples are used for illustration. PMID- 29757370 TI - The Role of Clinical-Demographic Characteristics in Ophthalmic Manifestations of Inflammatory Bowel Disease. PMID- 29757371 TI - Outcomes of total anomalous pulmonary venous drainage repair in neonates with univentricular circulation. AB - Survival after surgery for isolated total anomalous pulmonary venous drainage has improved in the current era. However, outcomes of total anomalous pulmonary venous drainage repair in patients with univentricular circulation are associated with high mortality. Furthermore, outcomes of surgery in neonates with univentricular circulation are rarely reported among larger studies. Hence, we reviewed our experience (n = 19) with this population at a single institution (between 1986 and 2015) to identify specific subgroups with high mortality. We found patients with right ventricular dominance had the highest early mortality (54%; 7 of 13) when compared with patients (17%; 1 of 6) with left ventricle and biventricular dominance. Five patients (26%; 5 of 19) underwent reoperation for postoperative pulmonary venous obstruction. There were 5 long-term survivors. In conclusion, total anomalous pulmonary venous drainage repair in neonates with univentricular circulation is rare and is associated with high mortality and reoperation. PMID- 29757372 TI - Does safe disposal of child faeces matter? An assessment of access to improved sanitation and child faeces disposal behaviour and diarrhoea in rural Nepal. AB - Background: Improper disposal of child faeces is a major source of faecal pathogens that cause diarrhoeal disease. However, this has received relatively less attention in sanitation evaluation literature, which has tended to focus on sanitation provision, implicitly assuming that child faeces disposal behaviour also improves with sanitation. We examined the impact of improved sanitation without safe disposal (households with improved sanitation but not disposing of child faeces in improved sanitation) and improved sanitation with safe disposal (households with improved sanitation and disposal of child faeces in improved sanitation) on diarrhoeal prevalence in rural Nepal. Methods: Data from the Nepal Demographic Health Survey 2011 for 3377 children <5 y of age were used to answer the research question using quasi-experimental methods. Results: Improved sanitation with safe disposal was associated with a 3.3 percentage point (standard error [SE] 0.016) to 6.6 percentage point (SE 0.023) lower prevalence of diarrhoea among children <5 y of age compared with matched households without access to improved sanitation. No effect was observed for households having improved sanitation without safe disposal compared with matched households without access to improved sanitation. Improved sanitation with safe disposal was also associated with a 4.0 percentage point (SE 0.023) lower prevalence of diarrhoea in low economic status households (bottom two quintiles). Conclusions: Our results suggest that sanitation programmes need to focus on behavioural interventions as well as increasing access to sanitation facilities. PMID- 29757373 TI - Response to Letter to the Editor: "Dubious Conclusions on TSPO Function". PMID- 29757374 TI - Statistical primer: how to deal with missing data in scientific research? AB - Missing data are a common challenge encountered in research which can compromise the results of statistical inference when not handled appropriately. This paper aims to introduce basic concepts of missing data to a non-statistical audience, list and compare some of the most popular approaches for handling missing data in practice and provide guidelines and recommendations for dealing with and reporting missing data in scientific research. Complete case analysis and single imputation are simple approaches for handling missing data and are popular in practice, however, in most cases they are not guaranteed to provide valid inferences. Multiple imputation is a robust and general alternative which is appropriate for data missing at random, surpassing the disadvantages of the simpler approaches, but should always be conducted with care. The aforementioned approaches are illustrated and compared in an example application using Cox regression. PMID- 29757368 TI - The long noncoding RNA landscape of neuroendocrine prostate cancer and its clinical implications. AB - Background: Treatment-induced neuroendocrine prostate cancer (tNEPC) is an aggressive variant of late-stage metastatic castrate-resistant prostate cancer that commonly arises through neuroendocrine transdifferentiation (NEtD). Treatment options are limited, ineffective, and, for most patients, result in death in less than a year. We previously developed a first-in-field patient derived xenograft (PDX) model of NEtD. Longitudinal deep transcriptome profiling of this model enabled monitoring of dynamic transcriptional changes during NEtD and in the context of androgen deprivation. Long non-coding RNA (lncRNA) are implicated in cancer where they can control gene regulation. Until now, the expression of lncRNAs during NEtD and their clinical associations were unexplored. Results: We implemented a next-generation sequence analysis pipeline that can detect transcripts at low expression levels and built a genome-wide catalogue (n = 37,749) of lncRNAs. We applied this pipeline to 927 clinical samples and our high-fidelity NEtD model LTL331 and identified 821 lncRNAs in NEPC. Among these are 122 lncRNAs that robustly distinguish NEPC from prostate adenocarcinoma (AD) patient tumours. The highest expressed lncRNAs within this signature are H19, LINC00617, and SSTR5-AS1. Another 742 are associated with the NEtD process and fall into four distinct patterns of expression (NEtD lncRNA Class I, II, III, and IV) in our PDX model and clinical samples. Each class has significant (z-scores >2) and unique enrichment for transcription factor binding site (TFBS) motifs in their sequences. Enriched TFBS include (1) TP53 and BRN1 in Class I, (2) ELF5, SPIC, and HOXD1 in Class II, (3) SPDEF in Class III, (4) HSF1 and FOXA1 in Class IV, and (5) TWIST1 when merging Class III with IV. Common TFBS in all NEtD lncRNA were also identified and include E2F, REST, PAX5, PAX9, and STAF. Interrogation of the top deregulated candidates (n = 100) in radical prostatectomy adenocarcinoma samples with long-term follow-up (median 18 years) revealed significant clinicopathological associations. Specifically, we identified 25 that are associated with rapid metastasis following androgen deprivation therapy (ADT). Two of these lncRNAs (SSTR5-AS1 and LINC00514) stratified patients undergoing ADT based on patient outcome. Discussion: To date, a comprehensive characterization of the dynamic landscape of lncRNAs during the NEtD process has not been performed. A temporal analysis of the PDX-based NEtD model has for the first time provided this dynamic landscape. TFBS analysis identified NEPC-related TF motifs present within the NEtD lncRNA sequences, suggesting functional roles for these lncRNAs in NEPC pathogenesis. Furthermore, select NEtD lncRNAs appear to be associated with metastasis and patients receiving ADT. Treatment-related metastasis is a clinical consequence of NEPC tumours. Top candidate lncRNAs FENDRR, H19, LINC00514, LINC00617, and SSTR5-AS1 identified in this study are implicated in the development of NEPC. We present here for the first time a genome-wide catalogue of NEtD lncRNAs that characterize the transdifferentiation process and a robust NEPC lncRNA patient expression signature. To accomplish this, we carried out the largest integrative study that applied a PDX NEtD model to clinical samples. These NEtD and NEPC lncRNAs are strong candidates for clinical biomarkers and therapeutic targets and warrant further investigation. PMID- 29757375 TI - Establishing the Feasibility of a Tablet-Based Consent Process with Older Adults: A Mixed-Methods Study. AB - Purpose of the Study: This mixed-methods study explored the feasibility and acceptability of using a tablet-based research consent process with adults aged >=65 years. Design and Methods: In the first phase, focus group participants reported on their perceptions of a tablet-based consent process. In the second phase, older adults were randomized to view either a tablet-based or paper-based consent for a mock clinical trial. Measurements included: time to complete, adverse/unexpected events, user-friendliness, immediate comprehension, and retention at a 1-week delay. Results: Focus group participants (N = 15) expressed interest in the novel format, cautioning that peers would need comprehensive orientation to use the technology. In the randomized pilot (N = 20), retention was 100% and all participants completed the protocol without the occurrence of adverse/unexpected events. Although the participants took longer to complete the tablet-based consent than the paper-based version, user-friendliness, immediate comprehension, and retention of the tablet-based consent were similar to the paper-based consent. Discussion and Implications: The findings suggest that a tablet-based consent process is feasible to implement with older adults and acceptable to this population, but we would underscore that efforts to optimize design of tablet-based consent forms for older adults are warranted. PMID- 29757377 TI - Scaling up a tobacco control intervention in low resource settings: a case example for school teachers in India. AB - Research on processes of bringing effective tobacco control interventions to scale to increase quit rates among tobacco users is uncommon. This study examines processes to bring to scale one such intervention for school teachers, i.e. Tobacco Free Teacher-Tobacco Free Society (TFT-TFS). This intervention provides a foundation for an effective and low cost approach to promote cessation through schools. The present study was conducted in the states of Bihar and Maharashtra in 2014 using quantitative and qualitative methods. Focus group discussions (FGDs) were analysed using immersion crystallization method. The data presented are from a survey of 291 principals and seven FGDs. This study examined characteristics of principals and teachers, organizational environment, external environmental factors and program characteristics to determine facilitators and barriers for successful dissemination and implementation of the TFT-TFS program. Some facilitators were, incorporation of the program in existing channels like staff meetings and trainings, certification and recognition by the department of education; while some barriers were routine time bound duties (mainly teaching) of teachers and prevalence of tobacco use among teachers and administrators. Principals and teachers expressed a need and high level of interest in the adoption and implementation of the TFT-TFS program in their schools. PMID- 29757376 TI - The role of perceived benefits and barriers in colorectal cancer screening in intervention trials among African Americans. AB - The Health Belief Model (HBM) is widely used in health behavior interventions. The lack of diverse samples in the development of this theory warrants additional study on how it performs among minorities. While studies have utilized HBM to address colorectal cancer (CRC) screening, limited information exists confirming how these constructs influence screening. Data from three CRC screening trials were used to examine how perceived benefits/barriers perform among African Americans (AA) and whether they serve as mechanisms of the intervention effects on screening. The data were collected in AA churches (Study 1: N = 103; Study 2: N = 285; Study 3: N = 374) where lay members conducted CRC education to increase screening. Participants perceived benefits from colonoscopy (M = 2.4/3, SD = 0.87) and perceived few barriers (M = 0.63/8, SD = 1.1). Benefits were perceived for the fecal occult blood test (M = 11.4/15, SD = 2.1), and few barriers were reported (M = 11.7/30, SD = 3.4). Benefits more consistently predicted pre intervention screening relative to barriers. For Study 3, individuals with fewer barriers reported a greater increase in colonoscopy screening at 12-months versus those with higher barriers (OR = 0.595, 95% CI = 0.368-0.964), P = 0.035). Benefits/barriers did not mediate the relationship. Potential measurement limitations, particularly for barriers, were uncovered and further research on how to assess factors preventing AA from screening is needed. PMID- 29757378 TI - Self-Expandable Metal Stent in the Treatment of Refractory Long Pouch Inlet Stricture. PMID- 29757379 TI - Quiescin sulfhydryl oxidase 1 (QSOX1) glycosite mutation perturbs secretion but not Golgi localization. AB - Quiescin sulfhydryl oxidase 1 (QSOX1) catalyzes the formation of disulfide bonds in protein substrates. Unlike other enzymes with related activities, which are commonly found in the endoplasmic reticulum, QSOX1 is localized to the Golgi apparatus or secreted. QSOX1 is upregulated in quiescent fibroblast cells and secreted into the extracellular environment, where it contributes to extracellular matrix assembly. QSOX1 is also upregulated in adenocarcinomas, though the extent to which it is secreted in this context is currently unknown. To achieve a better understanding of factors that dictate QSOX1 localization and function, we aimed to determine how post-translational modifications affect QSOX1 trafficking and activity. We found a highly conserved N-linked glycosylation site to be required for QSOX1 secretion from fibroblasts and other cell types. Notably, QSOX1 lacking a glycan at this site arrives at the Golgi, suggesting that it passes endoplasmic reticulum quality control but is not further transported to the cell surface for secretion. The QSOX1 transmembrane segment is dispensable for Golgi localization and secretion, as fully luminal and transmembrane variants displayed the same trafficking behavior. This study provides a key example of the effect of glycosylation on Golgi exit and contributes to an understanding of late secretory sorting and quality control. PMID- 29757380 TI - Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships. AB - Objectives: Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. Patients and methods: A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. Results: A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg.day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg.day/L. In children, this decreased to 1.8% after allometric dosing simulation. Conclusions: The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study. PMID- 29757381 TI - The parasitic nematode Oesophagostomum dentatum synthesizes unusual glycosaminoglycan-like O-glycans. AB - O-glycosylation is probably one of the most varied sets of post-translational modifications across all organisms, but amongst the most refractory to analyze. In animals, O-xylosylation of serine residues represents the first stage in the synthesis of glycosaminoglycans, whose repeat regions are generally analyzed as fragments resulting from enzymatic or chemical degradation, whereas their core regions can be isolated by beta-elimination or endo-beta-xylosidase digestion. In the present study, we show that hydrazinolysis can be employed for release of glycosaminoglycan-type oligosaccharides from nematodes prior to fluorescent labeling with 2-aminopyridine. While various [HexNAcHexA]nGal2Xyl oligosaccharides were isolated from the model organism Caenorhabditis elegans, more unusual glycosaminoglycan-type glycans were found to be present in the porcine parasite Oesophagostomum dentatum. In this case, as judged by MS/MS before and after hydrofluoric acid or beta-galactosidase digestion, core sequences with extra galactose and phosphorylcholine residues were detected as [(+/-PC)HexNAcHexA]n(+/-PC)Galbeta3-(+/-Galbeta4)Galbeta4Xyl. Thus, hydrazinolysis and fluorescent labeling can be combined to analyze unique forms of O-xylosylation, including new examples of zwitterionic glycan modifications. PMID- 29757382 TI - De novo genome assembly of the red silk cotton tree (Bombax ceiba). AB - Background: Bombax ceiba L. (the red silk cotton tree) is a large deciduous tree that is distributed in tropical and sub-tropical Asia as well as northern Australia. It has great economic and ecological importance, with several applications in industry and traditional medicine in many Asian countries. To facilitate further utilization of this plant resource, we present here the draft genome sequence for B. ceiba. Findings: We assembled a relatively intact genome of B. ceiba by using PacBio single-molecule sequencing and BioNano optical mapping technologies. The final draft genome is approximately 895 Mb long, with contig and scaffold N50 sizes of 1.0 Mb and 2.06 Mb, respectively. Conclusions: The high-quality draft genome assembly of B. ceiba will be a valuable resource enabling further genetic improvement and more effective use of this tree species. PMID- 29757383 TI - Considerations of antiviral treatment to interrupt mother-to-child transmission of hepatitis B virus in China. AB - Background: Treating high-risk women with antivirals in their third trimester is a promising intervention to further reduce perinatal transmission in neonates born to hepatitis B surface antigen positive [HBsAg(+)] mothers. Methods: We estimated the number of perinatal infections based on coverage and effectiveness of hepatitis B immunization. We compared cost-effectiveness of different approaches to identify high-risk women for antiviral treatment, by region and urban/rural residence. Results: Of the 16.59 million live births in 2015, 1.04 million infants (6.3%) were born to HBsAg(+) mothers and 268 201 infants (1.6%) to HBsAg(+) and HBeAg(+) dual-positive mothers. Despite immunoprophylaxis, 51 478 perinatal hepatitis B virus (HBV) transmissions were estimated to have occurred from HBsAg and HBeAg dual-positive mothers in 2015. Using HBeAg or HBV viral load testing to identify high-risk pregnant women and to treat them with Tenofovir, the incremental cost ranged from US$68.2 million to US$90.3 million. Assuming HBV viral load testing is available and used to guide treatment and all women with HBV viral loads >200 000 IU/ml are treated, 25 912 infections would be averted at a projected cost of US$3500 per infection averted. Conclusions: Identifying high risk pregnant women and providing them with antiviral treatment is feasible and cost-effective to interrupt perinatal HBV transmissions. Policy options should be urgently explored in order for China to reach the HBV elimination goal of 0.1% prevalence among children by 2030. PMID- 29757384 TI - Corrigendum. PMID- 29757385 TI - Adapting improvements to context: when, why and how? PMID- 29757386 TI - Impact of vaccine stock-outs on infant vaccination coverage: a hospital-based survey from South Africa. AB - Introduction: National population-based immunization coverage surveys provide data for validating official administrative coverage figures. However, these costly and logistically challenging surveys are conducted infrequently. This hospital-based records review determined coverage of birth-dose vaccines, fully immunized under 1-y-old coverage (FIC) of 12- to 59-mo-old children; and the reasons for missed vaccinations. Methods: Rotavirus surveillance in South Africa is based on under-5-y-old children being treated for diarrhoea, and includes photocopying the official vaccination document and collecting data on reasons for missed vaccinations. These data were captured from all 508 records collected from 2011 to 2014, and subjected to descriptive statistical analysis. Results: Bacille Calmette Guerin coverage was 99%; oral polio vaccine birth dose (OPV(0)) coverage was 99%. Coverage for 12- to 59-mo-olds ranged from 75% for the pneumococcal conjugate vaccine third dose to 99% for OPV(0). Several instances of subsequent doses being recorded without prior doses being received resulted in a FIC of 55%. In total, 207 vaccinations were missed by 88 children. Vaccine stock-outs were responsible for 62% of missed vaccinations. Conclusions: Efforts to improve vaccine stock management at facility and district levels should be implemented, and should include vaccinator training and supervision to eliminate vaccine stock outs and missed vaccination opportunities. PMID- 29757387 TI - E-learning on antibiotic prescribing-the role of autonomous motivation in participation: a prospective cohort study. AB - Objectives: E-learning is increasingly used in education on antimicrobial stewardship, but participation rates are often low. Insight into factors that affect participation is therefore needed. Autonomous motivation is associated with higher achievements in medical education and could also play a role in e learning participation. We therefore aimed to investigate the role of residents' autonomous motivation in their participation in e-learning on antibiotic prescribing. Methods: We performed a multicentre cohort study in two academic and two teaching hospitals. Residents who filled out questionnaires on antibiotic knowledge, the perceived importance of antibiotics and motivation [Self Regulation Questionnaire - Academic (SRQ-a)] received e-learning access. We used the SRQ-a to calculate relative autonomous motivation (RAM), an index that estimates the amount of autonomous motivation compared with the amount of controlled motivation. We then analysed associations between RAM and participation in e-learning with logistic regression. Results: Eighty-six residents participated (74% female, mean age 30 years). Overall e-learning participation was 58% (n = 50). Participation was 41% in residents with negative RAM (i.e. more controlled motivation) and 62% in residents with positive RAM (i.e. more autonomous motivation). RAM was positively associated with participation, adjusted for residency in an academic hospital (adjusted OR 2.6, 95% CI 1.5-4.6). Conclusions: Participation in non-obligatory e-learning on antibiotic prescribing is higher in residents with more autonomous motivation. Interventions to increase autonomous motivation could improve participation. Preceding e-learning on antibiotic prescribing with face-to-face education, to explain the importance of the subject, could enhance autonomous motivation and thus optimize e-learning efficiency. PMID- 29757388 TI - An unusual case of cerebrovascular accident in a child. PMID- 29757389 TI - Manual handling of burdens as a predictor of birth outcome-a Finnish Birth Register Study. AB - Background: Negative effects of manual handling of burdens on pregnancy outcomes are not elucidated in Finland. This study examines the association between perinatal outcomes and occupational exposure to manual handling of burdens. Methods: The study cohort was identified from the Finnish Medical Birth Register (MBR, 1997-2014) and information on exposure from the Finnish job-exposure matrix (FINJEM) 1997-2009. The cohort included all singleton births of mothers who were classified as 'service and care workers' representing the exposure group (n=74 286) and 'clerks' as the reference (n=13 873). Study outcomes were preterm birth (PTB) (<37 weeks), low birthweight (LBW) (<2500 g), small for gestational age (<2.5th percentile), perinatal death (stillbirth or early neonatal death within first seven days) and eclampsia. We used logistic regression analysis to calculate odds ratio (OR) and adjusted for maternal age, marital status, BMI, parity and smoking during pregnancy. Results: The risks of PTB [OR 1.16, 95% confidence interval (CI) 1.06-1.27], LBW (OR 1.12, 95% CI 1.01-1.25) and perinatal death (OR 1.51, 95% CI 1.09-2.09) were significantly higher among the high exposure group than in the reference group. All adverse outcomes were statistically insignificant among primiparous women except perinatal death (OR=1.95, 95% CI 1.13-3.39). Conclusions: The study indicates that the risk of adverse pregnancy outcomes might be more common among women that are highly exposed to occupational manual handling of burdens. The results should be interpreted with caution due to the use of occupational level exposure. Further studies with information on individual level exposure and start of maternity leave are recommended. PMID- 29757390 TI - Battery longevity of implantable cardioverter-defibrillators and cardiac resynchronization therapy defibrillators: technical, clinical and economic aspects. An expert review paper from EHRA. AB - In recent years an extension of devices longevity has been obtained for implantable cardioverter-defibrillators (ICDs), including ICDs for cardiac resynchronization therapy (CRT-D) through improved battery chemistry and device technology and this implies important clinical benefits (reduced need for device replacements and associated complications, particularly infections), as well as economic benefits, in line with patient preferences and needs. From a clinical point of view, the availability of this improvement in technology allows to better tune the choice of the device to be implanted, taking into account that the reasons supporting the value of an extended device longevity as a clinical priority may differ according to the clinical setting (purely electrical diseases or left ventricular dysfunction/heart failure, respectively). From an economic point of view, extension of device longevity may have an important impact in reducing long-term costs of device therapy, with substantial daily savings in favour of devices with extended longevity, up to 30%, depending on clinical scenarios. In studies based on projections, an extension of device longevity allowed to calculate that the cost per day of ICDs may be substantially reduced, and this allows to overcome the frequent perception of ICD and CRT-D devices as treatments with unaffordable costs and to overturn the misconception that up front costs are the only metric with which to value device treatments. In view of its clinical and economic value, device longevity should be a determining factor in device choice by physicians and healthcare commissioners and should be appropriately considered and valued in comparative tenders. PMID- 29757391 TI - Plant Cuttings. PMID- 29757392 TI - Thyroid Function in Early Pregnancy, Child IQ, and Autistic Traits: A Meta Analysis of Individual Participant Data. AB - Context: Low maternal free T4 (FT4) has been associated with poor child neurodevelopment in some single-center studies. Evidence remains scarce for the potential adverse effects of high FT4 and whether associations differ in countries with different iodine status. Objective: To assess the association of maternal thyroid function in early pregnancy with child neurodevelopment in countries with a different iodine status. Design, Setting, and Participants: Meta analysis of individual participant data from 9036 mother-child pairs from three prospective population-based birth cohorts: INMA [Infancia y Medio Ambiente (Environment and Childhood project) (Spain)], Generation R (Netherlands), and ALSPAC (Avon Longitudinal Study of Parents and Children, United Kingdom). The exclusion criteria were multiple pregnancies, fertility treatments, thyroid interfering medication usage, and known thyroid disease. Main Outcomes: Child nonverbal IQ at 5 to 8 years of age, verbal IQ at 1.5 to 8 years of age, and autistic traits within the clinical range at 5 to 8 years of age. Results: FT4 <2.5th percentile was associated with a 3.9-point (95% CI, -5.7 to -2.2) lower nonverbal IQ and a 2.1-point (95% CI, -4.0 to -0.1) lower verbal IQ. A suggestive association of hypothyroxinemia with a greater risk of autistic traits was observed. FT4 >97.5th percentile was associated with a 1.9-fold (95% CI, 1.0 to 3.4) greater risk of autistic traits. No independent associations were found with TSH. Conclusions: Low maternal FT4 was consistently associated with a lower IQ across the cohorts. Further studies are needed to replicate the findings of autistic traits and investigate the potential modifying role of maternal iodine status. FT4 seems a reliable marker of fetal thyroid state in early pregnancy, regardless of the type of immunoassay. PMID- 29757393 TI - SNPnexus: assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. AB - Broader functional annotation of genetic variation is a valuable means for prioritising phenotypically-important variants in further disease studies and large-scale genotyping projects. We developed SNPnexus to meet this need by assessing the potential significance of known and novel SNPs on the major transcriptome, proteome, regulatory and structural variation models. Since its previous release in 2012, we have made significant improvements to the annotation categories and updated the query and data viewing systems. The most notable changes include broader functional annotation of noncoding variants and expanding annotations to the most recent human genome assembly GRCh38/hg38. SNPnexus has now integrated rich resources from ENCODE and Roadmap Epigenomics Consortium to map and annotate the noncoding variants onto different classes of regulatory regions and noncoding RNAs as well as providing their predicted functional impact from eight popular non-coding variant scoring algorithms and computational methods. A novel functionality offered now is the support for neo-epitope predictions from leading tools to facilitate its use in immunotherapeutic applications. These updates to SNPnexus are in preparation for its future expansion towards a fully comprehensive computational workflow for disease associated variant prioritization from sequencing data, placing its users at the forefront of translational research. SNPnexus is freely available at http://www.snp-nexus.org. PMID- 29757394 TI - A barley powdery mildew fungus non-autonomous retrotransposon encodes a peptide that supports penetration success on barley. AB - Pathogens overcome plant immunity by means of secreted effectors. Host effector targets often act in pathogen defense, but might also support fungal accommodation or nutrition. The barley ROP GTPase HvRACB is involved in accommodation of fungal haustoria of the powdery mildew fungus Blumeria graminis f.sp. hordei (Bgh) in barley epidermal cells. We found that HvRACB interacts with the ROP-interactive peptide 1 (ROPIP1) that is encoded on the active non-long terminal repeat retroelement Eg-R1 of Bgh. Overexpression of ROPIP1 in barley epidermal cells and host-induced post-transcriptional gene silencing (HIGS) of ROPIP1 suggested that ROPIP1 is involved in virulence of Bgh. Bimolecular fluorescence complementation and co-localization supported that ROPIP1 can interact with activated HvRACB in planta. We show that ROPIP1 is expressed by Bgh on barley and translocated into the cytoplasm of infected barley cells. ROPIP1 is recruited to microtubules upon co-expression of MICROTUBULE ASSOCIATED ROP GTPase ACTIVATING PROTEIN (HvMAGAP1) and can destabilize cortical microtubules. The data suggest that Bgh ROPIP targets HvRACB and manipulates host cell microtubule organization for facilitated host cell entry. This points to a possible neo functionalization of retroelement-derived transcripts for the evolution of a pathogen virulence effector. PMID- 29757395 TI - Genotyping and Whole-Genome Sequencing to Identify Tuberculosis Transmission to Pediatric Patients in British Columbia, Canada, 2005-2014. AB - Background: Tuberculosis (TB) in children is often an indicator of recent transmission. Genotyping and whole-genome sequencing (WGS) can enhance pediatric TB investigations by confirming or refuting transmission events. Methods: Mycobacterium tuberculosis isolates from all pediatric patients <18 years with culture-confirmed TB in British Columbia (BC) from 2005 to 2014 (n = 49) were genotyped by Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat (MIRU-VNTR) and compared with adult isolates. Genotypically clustered cases underwent WGS. Clinical, demographic, and contact data were reviewed for each case. Results: Twenty-three children were Canadian-born, 7 to Canadian-born parents (CBP) and 16 to foreign-born parents (FBP). Of the 26 foreign-born children, all were born in Asia (81%) or Africa (19%). Using molecular and epidemiological data, we determined that 15 children had acquired their infection within BC, and household transmission explained all 7 Canadian-born (FBP) children that acquired TB locally. In contrast, 6 of 7 Canadian-born (CBP) children were exposed via a non-household community source. Eight Canadian-born (FBP) children acquired their infections through travel to their parents' place of birth. All but 1 of the foreign-born children acquired their infection outside of BC. Conclusions: Genotyping and genomic data reveal that drivers of pediatric transmission vary according to a child's age, birthplace, and their parents' place of birth. PMID- 29757397 TI - Uncovering key small RNAs associated with gametocidal action in wheat. AB - Gametocidal (Gc) chromosomes can kill gametes that lack them by causing chromosomal breakage to ensure their preferential transmission, and they have been exploited in genetic breeding. The present study investigated the possible roles of small RNAs (sRNAs) in Gc action. By sequencing two small RNA libraries from the anthers of Triticum aestivum cv. Chinese Spring (CS) and the Chinese Spring-Gc 3C chromosome monosomic addition line (CS-3C), we identified 239 conserved and 72 putative novel miRNAs, including 135 differentially expressed miRNAs. These miRNAs were predicted to target multiple genes with various molecular functions relevant to the features of Gc action, including sterility and genome instability. The transgenic overexpression of miRNA, which was up regulated in CS-3C, reduced rice fertility. The CS-3C line exhibited a genome wide reduction in 24 nt siRNAs compared with that of the CS line, particularly in transposable element (TE) and repetitive DNA sequences. Corresponding to this reduction, the bisulfite sequencing analysis of four retro-TE sequences showed a decrease in CHH methylation, typical of RNA-directed DNA methylation (RdDM). These results demonstrate that both miRNA-directed regulation of gene expression and siRNA-directed DNA methylation of target TE loci could play a role in Gc action. PMID- 29757396 TI - Hetero-fertilization together with failed egg-sperm cell fusion supports single fertilization involved in in vivo haploid induction in maize. AB - In vivo doubled-haploid technology is widely applied in commercial maize breeding programs because of its time-saving and cost-reducing features. The production of maize haploids primarily depends on the use of Stock6-derived haploid inducer lines. Although the gene underlying haploid induction, MTL/ZmPLA1/NLD, was cloned recently, the mechanism of haploid induction is still unknown. Hetero fertilization can occur via a single fertilization, which provides a means to investigate single-fertilization events by studying the hetero-fertilization phenomenon. In this study, we found that the hetero-fertilization rate increased significantly when female maize lines were first individually crossed with pollen from the inducer CAU5 in dual-pollination experiments 4 h before a second pollination with common lines. We also examined embryogenesis during haploid induction by confocal laser-scanning microscopy and observed single-fertilized ovules, indicating that single fertilization occurred during haploid induction. We therefore postulate that both single fertilization and chromosome elimination contribute to haploid induction in maize. We also propose a scheme for the formation of hetero-fertilized and haploid kernels. Our results provide an efficient approach to identify hetero-fertilized kernels for research on interactions between embryo and endosperm. PMID- 29757399 TI - Associations of Dehydroepiandrosterone Sulfate With Cardiometabolic Risk Factors in Prepubertal Children. AB - Context: Premature adrenarche (PA) has been associated with overweight and insulin resistance, but the associations of serum dehydroepiandrosterone sulfate (DHEAS) concentration with other cardiometabolic risk factors are uncertain. Objective: To examine the associations of serum DHEAS concentration with several cardiometabolic risk factors in children. Design: Cross-sectional data from the Physical Activity and Nutrition in Children Study. Participants: Population sample of 207 girls and 225 boys aged 7.6 +/- 0.4 years. Main Outcome Measures: Cardiometabolic risk factors by serum DHEAS concentration. Results: DHEAS correlated positively with body mass index standard deviation score, body fat percentage, lean body mass, high-sensitivity C-reactive protein (hs-CRP), and alanine aminotransferase (ALT) when adjusted for age and sex. The associations of DHEAS with hs-CRP and ALT disappeared when adjusted also for body fat percentage. When further adjusted for birth weight SD score, DHEAS correlated negatively with low-density lipoprotein (LDL) cholesterol and LDL/high-density lipoprotein (HDL) cholesterol ratio. LDL cholesterol was lower in children with DHEAS >=40 ug/dL than in those with DHEAS <40 ug/dL, adjusted for age, sex, and body fat percentage (86.5 vs 92.3 mg/dL, P = 0.029). This association strengthened after further adjustment for birth weight SD score (85.3 vs 92.3 mg/dL, P = 0.012). Conclusion: Higher DHEAS is not associated with an increased cardiometabolic risk in prepubertal children. Instead, it may be protective, evidenced by an association with lower LDL cholesterol and LDL/HDL cholesterol ratio. The increased cardiometabolic risk in PA shown in many studies may be due to low birth weight and childhood overweight associated with PA. PMID- 29757400 TI - Predicting the Ability of Wounds to Heal Given Any Burn Size and Fluid Volume: An Analytical Approach. AB - The intrinsic relationship between fluid volume and open wound size (%) has not been previously examined. Therefore, we conducted this study to investigate whether open wound size can be predicted from fluid volume plus other significant factors over time and to evaluate how machine learning may perform in predicting open wound size. This retrospective study involved patients with at least 20% TBSA burned. Various predictive models were developed and compared using goodness of-fit statistics (R2, error [mean absolute error (MAE), root mean squared error (RMSE)]). Bland-Altman analysis was also performed to determine bias. A total of 121 patients were included in the analysis. Median TBSA burned was 31% (interquartile range: 26-46%). Average crystalloid volumes were 4.0 +/- 2.7 ml/kg/TBSA in the first 24 hours. There were 24 (20%) patients who died. Importantly, multivariate analysis identified seven independent predictors of open wound size. Also, machine learning analysis was able to stratify patients based on the 20th day after admission, ~40% TBSA burned, and fluid volumes. Models for predicting open wound size varied in performance (R2 = .79-.90, MAE = 3.97-7.52, RMSE = 7.11-10.69). Notably, a combined machine learning model using only four features (fluid volume, days since admission, TBSA burned, age) performed the best and was sufficient to predict open wound size, with >90% goodness of fit and <4% absolute error. Bland-Altman analysis showed that there were no biases in the models. Open wound size can be predicted reliably using machine learning and fluid volume, days since admission, TBSA burned, and age. Future work will be needed to validate the utility of this study's models in a clinical environment. PMID- 29757401 TI - Viral Therapy Gets Personal: A Potential Gene Signature to Predict Susceptibility to Measles Virus Oncolysis. PMID- 29757402 TI - Adherence to Healthful Dietary Patterns Is Associated with Lower Risk of Hearing Loss in Women. AB - Background: Specific nutrients have been associated with hearing status, but associations between healthful dietary patterns and risk of hearing loss have not been prospectively evaluated. Objective: We sought to prospectively examine the relations between adherence to the Alternate Mediterranean diet (AMED), the Dietary Approaches to Stop Hypertension (DASH), and the Alternative Healthy Eating Index-2010 (AHEI-2010), and risk of hearing loss. Methods: We conducted a longitudinal cohort study (1991-2013) of 81,818 women in the Nurses' Health Study II, aged 27-44 y at baseline. We assessed diet every 4 y with the use of food frequency questionnaires and calculated AMED, DASH, and AHEI-2010 adherence scores. Baseline and updated information from validated biennial questionnaires was used in Cox proportional hazards regression models to examine independent associations between adherence scores and risk of self-reported moderate or worse hearing loss. Results: During >1 million person-years of follow-up, 2306 cases of moderate or worse hearing loss were reported. Higher cumulative average AMED and DASH scores were significantly inversely associated with risk of hearing loss. For women with scores in the highest compared with the lowest quintile, the multivariable-adjusted relative risks (MVRRs) of hearing loss were 0.70 (95% CI: 0.60, 0.82) (P-trend <0.001) for AMED and 0.71 (95% CI: 0.61, 0.83) (P-trend <0.001) for DASH. Higher recent AHEI-2010 score was also associated with lower risk [MVRR = 0.79 (95% CI: 0.69, 0.91); P-trend <0.001]. Among participants with additional hearing-related information (n = 33,102), higher cumulative average adherence scores for all 3 dietary patterns were associated with lower risk; the MVRR was 0.63 (95% CI: 0.49, 0.81) for AMED, 0.64 (95% CI: 0.50, 0.83) for DASH, and 0.71 (95% CI: 0.56, 0.89) for AHEI-2010. Conclusion: Adherence to healthful dietary patterns is associated with lower risk of hearing loss in women. Consuming a healthy diet may be helpful in reducing the risk of acquired hearing loss. PMID- 29757403 TI - The Ancestral Pace of Variant Reclassification. PMID- 29757405 TI - Platelets Drive Inflammation and Target Gray Matter and the Retina in Autoimmune Mediated Encephalomyelitis. AB - Despite growing evidence for platelets as active players in infection and immunity, it remains unresolved whether platelets contribute to, or are key elements in the development of neuroinflammation. Using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis, we identified platelet accumulation in the circulation by 7-day postinduction (dpi), ahead of clinical onset which occurs at 13-14 dpi. By inducing platelet depletion between 7 and 16 dpi, we demonstrate an association between platelet accumulation in the spinal cord and disease development. Additionally, we provide evidence for platelet infiltration in the white and gray matter parenchyma, but with different outcomes. Thus, while in white matter platelets are clearly associated with lesions, in gray matter large-scale platelet infiltration and expression of the platelet-specific molecule PF4 are detectable prior to T cell entry. In the retina, platelet accumulation also precedes clinical onset and is associated with significant increase in retinal thickness in experimental relative to control animals. Platelet accumulation increases over the disease course in this tissue, but without subsequent T cell infiltration. These findings provide definitive confirmation that platelet accumulation is key to EAE pathophysiology. Furthermore, they suggest an undescribed and, most importantly, therapeutically targetable mechanism of neuronal damage. PMID- 29757404 TI - Analysis of pcC13-62 promoters predicts a link between cis-element variations and desiccation tolerance in Linderniaceae. AB - Reproductive structures of plants (e.g. seeds) and vegetative tissues of resurrection plants can tolerate desiccation. Many genes encoding desiccation related proteins (DRPs) have been identified in the resurrection plant Craterostigma plantagineum, but the function of these genes remains mainly hypothetical. Here, the importance of the DRP gene pcC13-62 for desiccation tolerance is evaluated by analysing its expression in C. plantagineum and in the closely related desiccation-tolerant species Lindernia brevidens and the desiccation-sensitive species Lindernia subracemosa. Quantitative analysis revealed that pcC13-62 transcripts accumulate at a much lower level in desiccation-sensitive species than in desiccation-tolerant species. The study of pcC13-62 promoters from these species demonstrated a correlation between promoter activity and gene expression levels, suggesting transcriptional regulation of gene expression. Comparison of promoter sequences identified a dehydration responsive element motif in the promoters of tolerant species that is required for dehydration-induced beta-glucuronidase (GUS) accumulation. We hypothesize that variations in the regulatory sequences of the pcC13-62 gene occurred to establish pcC13-62 expression in vegetative tissues, which might be required for desiccation tolerance. The pcC13-62 promoters could also be activated by salt stress in Arabidopsis thaliana plants stably transformed with promoter::GUS constructs. PMID- 29757406 TI - Effect of antibiotic treatment on the formation of non-spore Clostridium difficile persister-like cells. AB - Background: The spore is the virulence factor identified to be involved in the recurrence of the disease caused by Clostridium difficile. Objectives: To demonstrate that lethal antibiotic concentrations induce the appearance of C. difficile persister-like non-spore cells. Methods: C. difficile and derivative spo0A mutant strains were tested for their susceptibility to antibiotics, as determined using an agar dilution method. Persister-cell generation was determined for all strains using up to 10 * the MIC of every antibiotic for up to 6 days. Results: Using up to 10 * the MIC of every antibiotic, we were able to induce the appearance of persister-like behaviour since biphasic killing curves could be observed in response to treatment antibiotics. Conclusions: To the best of our knowledge, this work provides, for the first time, experimental evidence of the appearance of C. difficile persister-like cells, opening a new research avenue in the pathogenesis of this nosocomial pathogen. PMID- 29757407 TI - Transcriptome and metabolome analyses provide insights into root and root released organic anion responses to phosphorus deficiency in oat. AB - Roots and root-released organic anions play important roles in uptake of phosphorus (P), an essential macronutrient for food production. Oat, ranking sixth in the world's cereal production, contains valuable nutritional compounds and can withstand poor soil conditions. Our aim was to investigate root transcriptional and metabolic responses of oat grown under P-deficient and P sufficient conditions. We conducted a hydroponic experiment and measured root morphology and organic anion exudation, and analysed changes in the transcriptome and metabolome. Oat roots showed enhanced citrate and malate exudation after 4 weeks of P deficiency. After 10 d of P deficiency, we identified 9371 differentially expressed transcripts with a 2-fold or greater change (P<0.05): 48 sequences predicted to be involved in organic anion biosynthesis and efflux were consistently up-regulated; 24 up-regulated transcripts in oat were also found to be up-regulated upon P starvation in rice and wheat under similar conditions. Phosphorylated metabolites (i.e. glucose-6-phosphate, myo-inositol phosphate) were reduced dramatically, while citrate and malate, some sugars and amino acids increased slightly in P-deficient oat roots. Our data are consistent with a strategy of increased organic anion efflux and a shift in primary metabolism in response to P deficiency in oat. PMID- 29757409 TI - Secretogranin-II plays a critical role in zebrafish neurovascular modeling. AB - Secretoneurin (SN) is a neuropeptide derived from specific proteolytic processing of the precursor secretogranin II (SgII). In zebrafish and other teleosts, there are two paralogs named sgIIa and sgIIb. Our results showed that neurons expressing sgIIb were aligned with central arteries in the hindbrain, demonstrating a close neurovascular association. Both sgIIb-/- and sgIIa-/-/sgIIb /- mutant embryos were defective in hindbrain central artery development due to impairment of migration and proliferation of central artery cells. Further study revealed that sgIIb is non-cell autonomous and required for central artery development. Hindbrain arterial and venous network identities were not affected in sgIIb-/- mutant embryos, and the mRNA levels of Notch and VEGF pathway-related genes were not altered. However, the activation of MAPK and PI3K/AKT pathways was inhibited in sgIIb-/- mutant embryos. Reactivation of MAPK or PI3K/AKT in endothelial cells could partially rescue the central artery developmental defects in the sgIIb mutants. This study provides the first in vivo evidence that sgIIb plays a critical role in neurovascular modeling of the hindbrain. Targeting the SgII system may, therefore, represent a new avenue for the treatment of vascular defects in the central nervous system. PMID- 29757408 TI - Comparison of antibiotic prescribing and antimicrobial resistance in urinary tract infections at the municipal level among women in two Nordic regions. AB - Objectives: To describe and compare the prescribing of antibiotics used for urinary tract infections and its correlation with resistance in Escherichia coli in urinary samples across two adjacent regions-the Capital Region and the Skaane Region-and their municipalities in Denmark and Sweden. Methods: The Capital Region consists of 29 municipalities and 725 960 female inhabitants aged >=18 years and the Skaane Region consists of 33 municipalities and 515 668 female inhabitants aged >=18 years. Aggregated data from outpatient care on the prescribing of pivmecillinam, trimethoprim and nitrofurantoin from both regions were analysed. The Department of Clinical Microbiology in both regions provided data on E. coli resistance in urinary samples from women aged >=18 years. Data were measured as the number of prescriptions/1000 women/year, number of DDDs/1000 women/year and DDDs/prescription. Correlation analyses between antibiotic prescribing and antibiotic resistance rates were performed. Results: Antibiotic prescribing and resistance rates were significantly higher in the Capital Region compared with the Skaane Region. Large variations in prescription and resistance rates were found at the municipal level, but there were no correlations between the antibiotic prescription and resistance rates when each region was analysed separately. Conclusions: Although closely related, there are large differences in antibiotic prescribing and antibiotic resistance. It is suggested that the regional guidelines are an important driver and explanatory factor for the variations; however, further research is needed in this new field and factors such as the influence of cultural aspects should be the target of further research. PMID- 29757410 TI - Chronic kidney disease and peripheral nerve function in the Health, Aging and Body Composition Study. AB - Background: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. Methods: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999-2000) and nerve function measurements at Year 4 (2000-01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as <=60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. Results: Participants with CKD (n = 476) were older (77 +/- 3 versus 75 +/- 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1-2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1-1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1 2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1-2.0)]. Conclusions: CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes. PMID- 29757412 TI - Development of a Provincial initiative to improve glucose control in critically ill patients. AB - Objective: To describe the development, implementation and initial evaluation of an initiative to improve glucose control in critically ill patients. Design: Glucose control in critically ill patients was chosen by critical care leaders as a target for improvement. This was an observational study to document changes in processes and measures of glucose control in each intensive care unit (ICU). ICU nurse educators were interviewed to document relevant changes between April 2012 and April 2016. Setting: 16 ICUs in British Columbia, Canada. Participants: ICU leaders. Intervention(s): A community of practice (CoP) was formed, guidelines were adopted, two learning sessions were held, and an electronic system to collect data was created. Then, each ICU introduced their own educational and process interventions. Main Outcome Measure(s): Average hyperglycemic index (area under the curve of serum glucose concentration versus time above the upper limit (10 mmol/l) divided by time on insulin infusion), number of hypoglycemic events (<3.5 mmol/l) divided by time on insulin infusion and standardized mortality rate (actual/predicted hospital mortality) for each 3-month period. Results: Although there were some isolated points and short trends that indicated special cause variation, there were no major trends over time and no obvious association with any of the process changes for each hospital. However, the average hyperglycemic index was higher in some of the smaller hospitals than in the larger hospitals. Conclusions: In this, 4-year observation of glucose control in ICUs within a CoP, the lack of sustained improvement suggests the need for more active and durable interventions. PMID- 29757411 TI - Modulation of H-NS transcriptional silencing by magnesium. AB - The bacterial histone-like protein H-NS silences AT-rich DNA, binding DNA as 'stiffened' filaments or 'bridged' intrastrand loops. The switch between these modes has been suggested to depend on the concentration of divalent cations, in particular Mg2+, with elevated Mg2+ concentrations associated with a transition to bridging. Here we demonstrate that the observed binding mode is a function of the local concentration of H-NS and its cognate binding sites, as well as the affinity of the interactions between them. Mg2+ does not control a binary switch between these two modes but rather modulates the affinity of this interaction, inhibiting the DNA-binding and silencing activity of H-NS in a continuous linear fashion. The direct relationship between conditions that favor stiffening and transcriptional silencing activity suggests that although both modes can occur in the cell, stiffening is the predominant mode of binding at silenced genes. PMID- 29757413 TI - Evaluation of Iron Stores by Zinc Protoporphyrin Analysis in Blood Donors. AB - Background: Zinc protoporphyrin (ZPP) testing has been studied previously as a substitute for ferritin (fer) testing of blood donors in determining iron stores. Objective: To determine whether ZPP testing could be performed using specimens collected via the capillary (cap) finger-stick (FS) method, similar to predonation hemoglobin (HB) testing. Also, we evaluated the correlation among FS HB, venous (ven) ZZP, FS ZPP, and ven fer levels as predictors of iron depletion. Methods: Blood donations from 328 study participants were evaluated using FS HB assay; we also performed ven ZPP, cap ZPP, and ven fer testing. We assessed the donors for subclinical iron deficiency (fer levels <26 ng/mL and ZPP levels >100 MUmol/mol heme). Results: Subclinical iron deficiency was present among first time and repeat blood donors at all HB levels. Variation among test results (FS HB, ven fer, ven ZPP, and FS ZPP) was statistically significant (P <.001). Conclusion: Insufficient correlation existed regarding FS HB and ven fer test results to support use of ZPP to determine iron stores in blood donors. PMID- 29757415 TI - Insects for Income Generation Through Animal Feed: Effect of Dietary Replacement of Soybean and Fish Meal With Black Soldier Fly Meal on Broiler Growth and Economic Performance. AB - The ever-increasing animal feed costs are driving many vulnerable communities involved in animal husbandry out of business. The high cost is mainly driven by the protein source, which represents the most expensive component in animal feed. In conventional feed, protein is obtained mainly from soybean and fish meal (SFM). The present study explored potential of partially replacing this SFM with black soldier fly prepupae meal (BSFPM) in Cobb 500 broiler chicken diets. A SFM based diet was compared to three experimental diets formulated by partially substituting SFM with BSFPM at 13.8, 27.4, and 42.0% of the crude protein (CP) in the starter feed and 11.0, 37.2, and 55.5% of the CP in the finisher feed of diets D1, D2, and D3, respectively. Dietary effects on average daily feed intake, average daily body weight gain, feed conversion ratio, carcass characteristics, breast meat sensory attributes, and the economic implication of their use in broiler production were evaluated. Replacement of SFM with BSFPM did not affect daily feed intake, daily body weight gain, feed conversion ratio, aroma or taste of cooked breast meat. A 16.0% higher Cost Benefit Ratio and 25.0% better Return on Investment was recorded when the birds were reared on the highest concentration of black soldier fly (D3) compared to the conventional diet which was 19.0% more expensive. The implication of these findings for the promotion of insect mass production enterprises for animal feed protein, and their potential for income generation and job creation particularly in developing countries is discussed. PMID- 29757414 TI - Vaccination coverage in systemic lupus erythematosus-a cross-sectional analysis of the German long-term study (LuLa cohort). AB - Objectives: Vaccinations are an important measure to prevent infections in immunocompromised patients. The knowledge of vaccination coverage and reasons for non-vaccination in patients with SLE is scarce. The aim of this study was to assess coverage rates of selected vaccinations in a representative sample of SLE patients and to identify predictors for non-vaccination. Methods: In 2013, information on selected vaccinations (coverage, application and reservations) and on demographics, clinical parameters and health beliefs was assessed by means of a self-reported questionnaire among a representative sample of SLE patients in Germany (LuLa cohort). Results: Five hundred and seventy-nine patients participated. Vaccination status was primarily checked by their general practitioner (57.3%). Of all the patients, 24.9% did not get their vaccination status checked at all, 16.1% had generally been advised against the use of vaccinations by a physician, and 37.5% stated that they had rejected vaccinations themselves. Their main reasons were fears of developing a lupus flare (21.8%) or adverse events (13.5%). A greater belief by patients in the doctor controlling one's health and the general benefit of medication prevented the rejection of vaccines. Vaccination coverage was low for all recorded vaccinations (tetanus 65.8%, influenza 45.2%, pneumococcus 32.2% and meningococcus 6.1%). Older age was predictive of receiving influenza and pneumococcal vaccination. The same applies for CSs >7.5 mg for receiving influenza vaccination. Conclusion: Vaccination coverage in SLE patients is poor and reflects insufficient implementation of national and international recommendations. Rheumatologists need to recognize patients' reservations against vaccinations, to communicate their importance and safety and to give individual recommendations to patients and their health-care providers. Trial registration: German Clinical Trials Register, www.germanctr.de, DRKS00011052. PMID- 29757416 TI - Early Changes in CD4+ T-Cell Activation During Blood-Stage Plasmodium falciparum Infection. AB - We examined transcriptional changes in CD4+ T cells during blood-stage Plasmodium falciparum infection in individuals without a history of previous parasite exposure. Transcription of CXCL8 (encoding interleukin 8) in CD4+ T cells was identified as an early biomarker of submicroscopic P. falciparum infection, with predictive power for parasite growth. Following antiparasitic drug treatment, a CD4+ T-cell regulatory phenotype developed. PD1 expression on CD49b+CD4+ T (putative type I regulatory T) cells after drug treatment negatively correlated with earlier parasite growth. Blockade of PD1 but no other immune checkpoint molecules tested increased interferon gamma and interleukin 10 production in an ex vivo antigen-specific cellular assay at the peak of infection. These results demonstrate the early development of an immunoregulatory CD4+ T-cell phenotype in blood-stage P. falciparum infection and show that a selective immune checkpoint blockade may be used to modulate early developing antiparasitic immunoregulatory pathways as part of malaria vaccine and/or drug treatment protocols. PMID- 29757418 TI - Associations of Arsenic Exposure With Telomere Length and Naive T Cells in Childhood-A Birth Cohort Study. AB - There is limited knowledge of association between arsenic exposure and telomere length (TL) and signal joint T-cell receptor excision circle (sjTREC) that are potential biomarkers of immune senescence and disease susceptibility. We aimed to clarify whether long-term inorganic arsenic exposure influences TL and sjTRECs in childhood. Children born in a longitudinal mother-child cohort were followed-up at 4.5 (n = 275) and 9 years (n = 351) of age. Arsenic exposure was assessed by metabolite concentrations in urine (U-As) from mothers at gestational week 8 (prenatal) and their children at 4.5 and 9 years. TL and sjTRECs were determined in blood cells using quantitative PCR. The oxidative DNA damage marker 8-hydroxy 2'-deoxyguanosine (8-OHdG) in plasma was measured by ELISA. In multivariable adjusted spline regression analyses, both prenatal and childhood arsenic exposure above U-As of 45 ug/l were significantly inversely associated with TL and sjTRECs at 9 years. Fraction of monomethylarsonic acid (MMA) above spline knot 7% were significantly inversely associated with both TL and sjTRECs reflecting increased toxicity due to less-efficient arsenic metabolism in 9--year-old children. Prenatal and childhood arsenic exposure were positively associated with 8-OHdG at 9 years which in turn was inversely associated with sjTRECs at 9 years. However, adjustment with 8-OHdG did not change the estimates of the association of U-As with sjTRECs reflecting little contribution from 8-OHdG-induced oxidative stress. Our findings suggest that chronic arsenic exposure from early life can result in TL attrition and lower production of naive T cells potentially leading to immunosenescence and immunodeficiency. PMID- 29757417 TI - Marination and cooking performance of portioned broiler breast fillets with the wooden breast condition. AB - The wooden breast (WB) condition in broiler breast meat negatively influences technological meat quality. However, it is unknown if the WB effects are uniform throughout the Pectoralis major. The objective of this study was to determine the effects of WB on the marination and cooking performance of the dorsal and ventral portions of broiler breast fillets. Sixty butterfly breast fillets were collected from the deboning line of a commercial plant and sorted into normal (no WB) and severe WB categories. Each fillet was horizontally portioned into dorsal and ventral halves. Portions from one side of each butterfly were used as non marinated controls, while portions from the other side were vacuum-tumble marinated (16 rpm, -0.6 atm, 4 degrees C, 20 min) with 20% (wt/wt) marinade to meat ratio. Marinade was formulated to target a final concentration of 0.75% salt and 0.45% sodium tripolyphosphate in the final product. Samples were cooked to 78 degrees C in a combination oven. Marinade uptake and retention were lower (P < 0.001) in both the ventral and dorsal portions of the WB fillets. The dorsal portions had greater (P < 0.001) marinade uptake and retention than the ventral portions in both normal and WB fillets. For non-marinated samples, cook loss was greater (P < 0.05) in both the ventral and dorsal portions of WB fillets. In marinated samples, however, cook loss was similar between the dorsal portions of normal and WB fillets. Final cooked product yield was calculated based on pre marination and post-cook weights. Non-marinated WB samples exhibited lower (P < 0.001) cooked product yields than normal samples in both portions. For marinated samples, cooked product yields were greater (P < 0.001) in the dorsal portions. Data demonstrated that the dorsal portion of the Pectoralis major more readily absorbs and retains marinade during vacuum tumbling and storage than the ventral portion. Although the WB condition negatively influenced marination and cooking performance in both fillet portions, the effects were less severe in the dorsal portion. PMID- 29757419 TI - Letter to the Editor: Dubious Conclusions on TSPO Function. PMID- 29757420 TI - MEASUREMENTS OF SPATIAL CORRELATIONS OF IONISATION CLUSTERS IN THE TRACK OF CARBON IONS-FIRST RESULTS. AB - An attempt towards an experimental set up which could provide the experimental data on correlation processes occurred simultaneously in two distanced DNA targets within a charged particle track is presented. A modified Jet Counter nanodosemeter was used in two experiments with carbon ions with mean energies of 52 and 23 MeV. The probability distributions of the correlated pairs of ionisation clusters produced in two neighbouring sensitive volumes are presented. A question of potential new descriptors of radiation quality is raised. PMID- 29757422 TI - Assessing the Impacts of Positive Selection on Coalescent-Based Species Tree Estimation and Species Delimitation. AB - The assumption of strictly neutral evolution is fundamental to the multispecies coalescent model and permits the derivation of gene tree distributions and coalescent times conditioned on a given species tree. In this study, we conduct computer simulations to explore the effects of violating this assumption in the form of species-specific positive selection when estimating species trees, species delimitations, and coalescent parameters under the model. We simulated data sets under an array of evolutionary scenarios that differ in both speciation parameters (i.e., divergence times, strength of selection) and experimental design (i.e., number of loci sampled) and incorporated species-specific positive selection occurring within branches of a species tree to identify the effects of selection on multispecies coalescent inferences. Our results highlight particular evolutionary scenarios and parameter combinations in which inferences may be more, or less, susceptible to the effects of positive selection. In some extreme cases, selection can decrease error in species delimitation and increase error in species tree estimation, yet these inferences appear to be largely robust to the effects of positive selection under many conditions likely to be encountered in empirical data sets. PMID- 29757421 TI - Stereotactic Radiosurgery for Acromegaly: An International Multicenter Retrospective Cohort Study. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a treatment option for persistent or recurrent acromegaly secondary to a growth hormone secreting pituitary adenoma, but its efficacy is inadequately defined. OBJECTIVE: To assess, in a multicenter, retrospective cohort study, the outcomes of SRS for acromegaly and determine predictors. METHODS: We pooled and analyzed data from 10 participating institutions of the International Gamma Knife Research Foundation for patients with acromegaly who underwent SRS with endocrine follow-up of >=6 mo. RESULTS: The study cohort comprised 371 patients with a mean endocrine follow-up of 79 mo. IGF-1 lowering medications were held in 56% of patients who were on pre-SRS medical therapy. The mean SRS treatment volume and margin dose were 3.0 cm3 and 24.2 Gy, respectively. The actuarial rates of initial and durable endocrine remission at 10 yr were 69% and 59%, respectively. The mean time to durable remission after SRS was 38 mo. Biochemical relapse after initial remission occurred in 9%, with a mean time to recurrence of 17 mo. Cessation of IGF-1 lowering medication prior to SRS was the only independent predictor of durable remission (P = .01). Adverse radiation effects included the development of >=1 new endocrinopathy in 26% and >=1 cranial neuropathy in 4%. CONCLUSION: SRS is a definitive treatment option for patients with persistent or recurrent acromegaly after surgical resection. There appears to be a statistical association between the cessation of IGF-1 lowering medications prior to SRS and durable remission. PMID- 29757423 TI - Xylem embolism measured retrospectively is linked to canopy dieback in natural populations of Eucalyptus piperita following drought. AB - Manipulative experiments have suggested that embolism-induced hydraulic impairment underpins widespread tree mortality during extreme drought, yet in situ evidence is rare. One month after drought-induced leaf and branch dieback was observed in field populations of Eucalyptus piperita Sm. in the Blue Mountains (Australia), we measured the level of native stem embolism and characterized the extent of leaf death in co-occurring dieback and healthy (non dieback) trees. We found that canopy dieback-affected trees showed significantly higher levels of native embolism (26%) in tertiary order branchlets than healthy trees (11%). Furthermore, there was a significant positive correlation (R2 = 0.51) between the level of leaf death and the level of native embolism recorded in branchlets from dieback-affected trees. This retrospective study suggests that hydraulic failure was the primary mechanism of leaf and branch dieback in response to a natural drought event in the field. It also suggests that post drought embolism refilling is minimal or absent in this species of eucalypt. PMID- 29757424 TI - Continuous monitoring of kidney transplant perfusion with near-infrared spectroscopy. AB - Background: Current reliance on clinical, laboratory and Doppler ultrasound (DUS) parameters for monitoring kidney transplant perfusion in the immediate post operative period in children risks late recognition of allograft hypoperfusion and vascular complications. Near-infrared spectroscopy (NIRS) is a real-time, non invasive technique for monitoring tissue oxygenation percutaneously. NIRS monitoring of kidney transplant perfusion has not previously been validated to the gold standard of DUS. We examined whether NIRS tissue oxygenation indices can reliably assess blood flow in established paediatric kidney transplants. Methods: Paediatric kidney transplant recipients ages 1-18 years with stable allograft function were eligible. Participants underwent routine DUS assessment of kidney transplant perfusion, including resistive index (RI) and peak systolic velocity at the upper and lower poles. NIRS data [tissue oxygenation index (TOI%)] were recorded for a minimum of 2 min with NIRS sensors placed on the skin over upper and lower allograft poles. Results: Twenty-nine subjects with a median age of 13.3 (range 4.8-17.8) years and a median transplant vintage of 26.5 months participated. Thirteen (45%) were female and 20 (69%) were living donor kidney recipients. NIRS monitoring was well tolerated by all, with 96-100% valid measurements. Significant negative correlations were observed between NIRS TOI% and DUS RI at both the upper and lower poles (r = -0.4 and -0.6, P = 0.04 and 0.001, respectively). Systolic blood pressure but not estimated glomerular filtration rate also correlated with NIRS TOI% (P = 0.01). Conclusions: NIRS indices correlate well with DUS perfusion and haemodynamic parameters in established paediatric kidney transplant recipients. Further studies are warranted to extend NIRS use for continuous real-time monitoring of early post transplant perfusion status. PMID- 29757425 TI - Four-Dimensional Flow MRI Analysis of Cerebral Blood Flow Before and After High Flow Extracranial-Intracranial Bypass Surgery With Internal Carotid Artery Ligation. AB - BACKGROUND: The hemodynamic changes that occur after high-flow (extracranial intracranial) EC-IC bypass surgery with internal carotid artery (ICA) ligation are not well known. OBJECTIVE: To assess blood flow changes after high-flow EC-IC bypass with ICA ligation by time-resolved 3-dimensional phase-contrast (4D Flow) magnetic resonance imaging (MRI). METHODS: We enrolled 11 patients who underwent high-flow EC-IC bypass. 4D Flow MRI was performed before and after surgery to quantify the blood flow volume (BFV) of the ipsilateral ICA (BFViICA), bypass artery (BFVbypass), contralateral ICA (BFVcICA), and basilar artery (BFVBA). Subsequently, we calculated the total BFV (BFVtotal = BFViICA + BFVcICA + BFVBA [before surgery], BFVcICA + BFVBA + BFVbypass [after surgery]). The BFV changes after bypass was statistically analyzed. RESULTS: BFVbypass was slightly lower than BFViICA, but the difference was not statistically significant (3.84 +/- 0.94 vs 4.42 +/- 1.38 mL/s). The BFVcICA and BFVBA significantly increased after bypass surgery (BFVcICA 5.89 +/- 1.44 vs 7.22 +/- 1.37 mL/s [P = .0018], BFVBA 3.06 +/- 0.41 vs 4.12 +/- 0.38 mL/s [P < .001]). The BFVtotal significantly increased after surgery (13.37 +/- 2.58 vs 15.18 +/- 1.77 mL/s [P = .015]). There was no evidence of hyperperfusion syndrome in any cases. CONCLUSION: After high flow EC-IC bypass with permanent ICA ligation, the bypass artery could partially compensate for the loss of BFV of the sacrificed ICA. The increased flow of the contralateral ICA and BA supply collateral blood flow. Clinically irrelevant hyperperfusion was observed. PMID- 29757426 TI - Releasing the complement brakes: is myeloperoxidase the missing link between factor H and C5a in anti-neutrophil cytoplasmic antibody vasculitis? PMID- 29757427 TI - Intra-annual wood formation of subtropical Chinese red pine shows better growth in dry season than wet season. AB - China's subtropical forests play a vital role in sequestering global carbon; therefore, it is critical to conduct a precise investigation of intra-annual wood formation in these ecosystems to clarify the mechanisms behind this. Two field experiments were established in Chinese subtropical forests to monitor weekly the intra-annual xylem formation of Pinus massoniana Lamb. from January to December 2015, using the recently developed micro-sampling approach. The effects of climate on wood formation were also assessed using linear or mixed models. Results indicate that there is an inactive period that might be semi-dormancy in subtropical pine ecosystems in January compared with the complete dormancy in temperate and boreal ecosystems and the fully active or short-term dormancy in tropical ecosystems. The duration of xylem formation of Chinese red pine in subtropical China in 2015 was 4-6 months longer than temperate and boreal forests. Moreover, trees were found to grow better during the dry season than the wet season, indicating that the Chinese red pine ecosystem is more strongly regulated by net energy than by environmental factors. Our findings indicate that China's subtropical pine forests may benefit from the expected longer dry seasons, possibly leading to better forest growth and improved carbon sequestration under continued climate warming. PMID- 29757428 TI - Micro-Hotspots of Risk in Urban Cholera Epidemics. AB - Targeted interventions have been delivered to neighbors of cholera cases in major epidemic responses globally despite limited evidence for the impact of such targeting. Using data from urban epidemics in Chad and Democratic Republic of the Congo, we estimate the extent of spatiotemporal zones of increased cholera risk around cases. In both cities, we found zones of increased risk of at least 200 meters during the 5 days immediately after case presentation to a clinic. Risk was highest for those living closest to cases and diminished in time and space similarly across settings. These results provide a rational basis for rapidly delivering targeting interventions. PMID- 29757430 TI - Genome-Wide Analysis of SNPs Is Consistent with No Domestic Dog Ancestry in the Endangered Mexican Wolf (Canis lupus baileyi). AB - The Mexican gray wolf (Canis lupus baileyi) was historically distributed throughout the southwestern United States and northern Mexico. Extensive predator removal campaigns during the early 20th century, however, resulted in its eventual extirpation by the mid 1980s. At this time, the Mexican wolf existed only in 3 separate captive lineages (McBride, Ghost Ranch, and Aragon) descended from 3, 2, and 2 founders, respectively. These lineages were merged in 1995 to increase the available genetic variation, and Mexican wolves were reintroduced into Arizona and New Mexico in 1998. Despite the ongoing management of the Mexican wolf population, it has been suggested that a proportion of the Mexican wolf ancestry may be recently derived from hybridization with domestic dogs. In this study, we genotyped 87 Mexican wolves, including individuals from all 3 captive lineages and cross-lineage wolves, for more than 172000 single nucleotide polymorphisms. We identified levels of genetic variation consistent with the pedigree record and effects of genetic rescue. To identify the potential to detect hybridization with domestic dogs, we compared our Mexican wolf genotypes with those from studies of domestic dogs and other gray wolves. The proportion of Mexican wolf ancestry assigned to domestic dogs was only between 0.06% (SD 0.23%) and 7.8% (SD 1.0%) for global and local ancestry estimates, respectively; and was consistent with simulated levels of incomplete lineage sorting. Overall, our results suggested that Mexican wolves lack biologically significant ancestry with dogs and have useful implications for the conservation and management of this endangered wolf subspecies. PMID- 29757429 TI - AlloFinder: a strategy for allosteric modulator discovery and allosterome analyses. AB - Allostery tweaks innumerable biological processes and plays a fundamental role in human disease and drug discovery. Exploration of allostery has thus been regarded as a crucial requirement for research on biological mechanisms and the development of novel therapeutics. Here, based on our previously developed allosteric data and methods, we present an interactive platform called AlloFinder that identifies potential endogenous or exogenous allosteric modulators and their involvement in human allosterome. AlloFinder automatically amalgamates allosteric site identification, allosteric screening and allosteric scoring evaluation of modulator-protein complexes to identify allosteric modulators, followed by allosterome mapping analyses of predicted allosteric sites and modulators in human proteome. This web server exhibits prominent performance in the reemergence of allosteric metabolites and exogenous allosteric modulators in known allosteric proteins. Specifically, AlloFinder enables identification of allosteric metabolites for metabolic enzymes and screening of potential allosteric compounds for disease-related targets. Significantly, the feasibility of AlloFinder to discover allosteric modulators was tested in a real case of signal transduction and activation of transcription 3 (STAT3) and validated by mutagenesis and functional experiments. Collectively, AlloFinder is expected to contribute to exploration of the mechanisms of allosteric regulation between metabolites and metabolic enzymes, and to accelerate allosteric drug discovery. The AlloFinder web server is freely available to all users at http://mdl.shsmu.edu.cn/ALF/. PMID- 29757431 TI - Long-term quality of life in adult survivors after the arterial switch operation. AB - OBJECTIVES: We sought to determine the quality of life after the arterial switch operation (ASO) using the Short Form 36 questionnaire in adult survivors. METHODS: All patients (n = 107) who underwent the ASO and were 18 years of age or older living in the Australian state of Victoria with a contact telephone number were identified from the hospital database. Fifty-one (48%) patients were 18-24 years old and 56 (52%) patients were 25-34 years old. Patients completed the Short Form 36 quality of life questionnaire via telephone. The results of the 8 domains of the Short Form 36 questionnaire and the derived health state summary score (Short Form 6-Dimension) were compared against mean scores from age-matched Australian population data. RESULTS: Compared with the Australian population age matched data, 18- to 24-year-old ASO patients ranked their health higher in 3 of the 8 domains (P < 0.01). The 25-34 age group ranked their health higher in 4 of the 8 domains (P < 0.01). No statistically significant differences in the mean Short Form 6-Dimension scores were observed in the 18-24 age group (0.769 for ASO patients vs 0.772 for Australian population, P = 0.85) or the 25-34 age group (0.795 for ASO patients vs 0.780 for Australian population, P = 0.33). CONCLUSIONS: Young adult survivors of the ASO have similar outcomes to age matched controls in quality of life measured by Short Form 6-Dimension. PMID- 29757432 TI - ESTIMATION OF EFFECTIVE DOSE FROM EXTERNAL EXPOSURE DUE TO SHORT-LIVED NUCLIDES IN THE PREFECTURES SURROUNDING FUKUSHIMA. AB - The Fukushima Daiichi Nuclear Power Plant (FDNPP) accident resulted in a release of radionuclides into the environment. Since the accident, measurements of radiation in the environment such as air dose rate and deposition density of radionuclides have been performed by various organizations and universities. In particular, Japan Atomic Energy Agency (JAEA) has been performing observations of air dose rate using a car-borne survey system continuously over widespread areas. Based on the data measured by JAEA, we estimated effective dose from external exposure in the prefectures surrounding Fukushima. Since car-borne survey started a few months after the accident, the main contribution to measured data comes from 137Cs and 134Cs whose half-lives are relatively long. Using air dose rate of 137Cs and 134Cs and the ratio of deposition density of short-lived nuclides to that of 137Cs and 134Cs, we also estimated contributions to the effective dose from other short-lived nuclides. PMID- 29757433 TI - The Effects of Useful Field of View Training on Brain Activity and Connectivity. AB - Objectives: Useful Field of View training (UFOVt) is an adaptive computerized cognitive intervention that improves visual attention and transfers to maintained health and everyday functioning in older adults. Although its efficacy is well established, the neural mechanisms underlying this intervention are unknown. This pilot study used functional MRI (fMRI) to explore neural changes following UFOVt. Method: Task-driven and resting-state fMRI were used to examine changes in brain activity and connectivity in healthy older adults randomized to 10 hr of UFOVt (n = 13), 10 hr of cognitively stimulating activities (CSA; n = 11), or a no-contact control (NC; n = 10). Results: UFOVt resulted in reduced task-driven activity in the majority of regions of interest (ROIs) associated with task performance, CSA resulted in reduced activity in one ROI, and there were no changes within the NC group. Relative to NC, UFOVt reduced activity in ROIs involved in effortful information processing. There were no other significant between-group task-based differences. Resting-state functional connectivity between ROIs involved in executive function and visual attention was strengthened following UFOVt compared with CSA and NC. Discussion: UFOVt enhances connections needed for visual attention. Together with prior work, this study provides evidence that improvement of the brain's visual attention efficiency is one mechanism underlying UFOVt. PMID- 29757434 TI - HDAC3-Selective Inhibition Activates Brown and Beige Fat Through PRDM16. AB - It has been reported that class I histone deacetylase (HDAC) inhibition increases thermogenesis in fat, but adipocyte-specific Hdac3 deletions have presented inconsistent results. In this study, we observed that HDAC3 protein levels were lower in brown fat compared with inguinal subcutaneous adipose tissue, and they decreased in both fat depots upon cold exposure. PR domain-containing 16 (PRDM16) physically interacted with HDAC3, and treatment with HDAC3-selective inhibitor RGFP966 induced thermogenic gene expression in murine and human fat cultures. This induction was blunted in the absence of PRDM16. Our results provide evidence that HDAC3 is involved in thermogenesis, suggesting selective inhibition of HDAC3 in brown and beige fat might hold therapeutic potential for counteracting human obesity and metabolic disorders. PMID- 29757435 TI - Antiviral effect of baicalin phospholipid complex against duck hepatitis A virus type 1. AB - Duck hepatitis A virus type 1 (DHAV-1) is one of the main pathogens of ducklings and causes a high mortality rate. Baicalin (BA) has potent antiviral effect, but the solubility is very poor. In order to increase the absorption, solubility, and pharmacological activity, the phospholipid complex was used to modify BA in present study. Therefore, BA phospholipid complex (BAPC) was prepared. The anti DHAV-1 abilities of BA and BAPC in vitro was evaluated by cell counting kit-8 and reverse transcription quantitative PCR. The curative effects of BA and BAPC on ducklings which were infected by DHAV-1 in addition to the ALT and AST levels were also detected. The results indicated the anti-DHAV-1 ability of BAPC was stronger than that of BA both in vitro and in vivo. To explore the anti-DHAV-1 mechanism, the influence of BAPC on DHAV-1 adsorption, replication, and release was studied. Furthermore, the anti-oxidative and immuno-enhancing abilities of BAPC in the treatment of infected ducklings were also determined. The results showed BAPC inhibited DHAV-1 adsorption, replication and release. Furthermore, it played anti-oxidative and immno-enhancing roles in the treatment, and the immno enhancing role was crucial to the treatment. PMID- 29757436 TI - Continuous PTH in Male Mice Causes Bone Loss Because It Induces Serum Amyloid A. AB - Increased bone resorption is considered to explain why intermittent PTH is anabolic for bone but continuous PTH is catabolic. However, when cyclooxygenase-2 (COX2) is absent in mice, continuous PTH becomes anabolic without decreased resorption. In murine bone marrow stromal cells (BMSCs), serum amyloid A (SAA)3, induced in the hematopoietic lineage by the combination of COX2-produced prostaglandin and receptor activator of nuclear factor kappaB ligand (RANKL), suppresses PTH-stimulated osteoblast differentiation. To determine whether SAA3 inhibits the anabolic effects of PTH in vivo, wild-type (WT) and SAA3 knockout (KO) mice were infused with PTH. In WT mice, continuous PTH induced SAA3 and was catabolic for bone. In KO mice, PTH was anabolic, increasing trabecular bone, serum markers of bone formation, and osteogenic gene expression. In contrast, PTH increased all measurements associated with bone resorption, as well as COX2 gene expression, similarly in KO and WT mice. SAA1 and SAA2 in humans are likely to have analogous functions to SAA3 in mice. RANKL induced both SAA1 and SAA2 in human bone marrow macrophages in a COX2-dependent manner. PTH stimulated osteogenesis in human BMSCs only when COX2 or RANKL was inhibited. Addition of recombinant SAA1 or SAA2 blocked PTH-stimulated osteogenesis. In summary, SAA3 suppresses the bone formation responses but not the bone resorption responses to PTH in mice, and in the absence of SAA3, continuous PTH is anabolic. In vitro studies in human bone marrow suggest that SAA may be a target for enhancing the therapeutic effects of PTH in treating osteoporosis. PMID- 29757437 TI - Fumigation Activity of Ethyl Formate and Phosphine Against Tetranychus urticae (Acari: Tetranychidae) on Imported Sweet Pumpkin. AB - This study investigated an alternative fumigant for imported sweet pumpkin. Laboratory fumigations with ethyl formate (EF) and phosphine (PH3) alone and in combination were conducted at different temperatures in 12-liter desiccators to determine their efficacy and synergism against adults and eggs of two-spotted spider mites (Tetranychus urticae Koch), a major pest of sweet pumpkins; larger scale fumigations with EF were also performed to evaluate the impact of EF fumigation on the postharvest quality of sweet pumpkin and EF absorption. EF fumigation of 4 h achieved 100% control of both adults and eggs at 10 degrees C. Efficacy of EF also increased with temperature. Conversely, PH3 fumigation for 4 and 6 h was not effective against either adults or eggs, and no synergism between EF and PH3 was observed. In larger scale fumigation tests, EF at 60 g/m3 for 4 h resulted in 100% control of both adults and eggs at 10 degrees C, without causing injury to the sweet pumpkins. These results suggest that EF has the potential to be a safe and effective alternative to methyl bromide fumigation for controlling two-spotted spider mites on sweet pumpkin. PMID- 29757438 TI - The Krampus and the Old, Dark Christmas - Full-thickness contact alkali burn with soot, milking grease and baby oil. AB - A chemical alkali burn caused by ash and soot is quite rare, resulting from its high pH-value, and underestimated in its potential to cause injury. In folkloric medicine ash was purportedly used to relieve pain. We present an unusual case of a 27-year-old man who used a self-mixed cream of soot of wooden pellets, milking grease and baby oil to blacken his face and hands for a traditional Krampus procession. PMID- 29757440 TI - OCCUPATIONAL DOSE DURING ADULT INTERVENTIONAL CARDIOLOGY: FIRST VALUES WITH PERSONAL ACTIVE DOSIMETERS IN CHILE. AB - The objective of this article is to present initial occupational dose values using digital active personal dosimeters for medical staff during adult interventional cardiology procedures in a public hospital in Chile. Personal dose equivalent Hp(10) over the lead apron of physician, nurse and radiographer were measured during 59 procedures. Mean values of occupational dose Hp(10) per procedure were 47.6, 6.2 and 4.3 MUSv for physician, nurse and radiographer, respectively. If no protective tools are used, physician dose can exceed the new eye lens dose limit. PMID- 29757439 TI - Risk of thrombosis with anti-phospholipid syndrome in systemic lupus erythematosus treated with thrombopoietin-receptor agonists. AB - Objectives: The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods: This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results: We included 18 patients with SLE-ITP treated with TPO RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion: Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy. PMID- 29757442 TI - Effect of Intravenous Fluid Volumes on the Adrenal Glucocorticoid Response After Burn Injury in Swine. AB - Severe thermal injury induces metabolic and physiological stress, prompting a disruption in the hypothalamic-pituitary-adrenal axis. The objective of this study was to evaluate potential confounding effects of Lactated Ringer's (LR) resuscitation on adrenal damage and cortisol production following burn. Anesthetized swine were instrumented with jugular catheters and sustained 40% TBSA burns from brass probes heated to 100 degrees C. Animals recovered to consciousness and received IV fluid resuscitation with LR at two different volumes: 15 ml/kg/d (limited volume [LV], n = 6) or 2 ml/kg/%TBSA/d (modified Brooke [MB], n = 6). Nonburned animals (Sham) were both oral and IV fluid restricted (S-FR, n = 4) to induce stress. Computed tomography (CT) angiographies were performed at baseline (BL) and 48 hours postburn, while blood and urine samples were collected at BL, 6, 24, and 48 hours postburn, with euthanasia at 48 hours for adrenal harvesting. Urinary cortisol was elevated following burn/surgery in all animals and returned back to BL in S-FR (404 +/- 48 pg/mg creatinine) but not MB (1332 +/- 176 pg/mg creatinine; P = .005) or LV (1223 +/- 335 pg/mg creatinine; P = .07) by 48 hours. Gene expression of cleavage enzymes (3beta-HSD, CYP17, CYP11, and CYP21) along the cortisol synthesis pathway showed minimal changes. Adrenal apoptosis (Terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL] staining) was greatest in the MB group (P <= .01) when compared to S-FR, partly due to elevations in c-Jun N-terminal kinase. Adrenal hemorrhaging was also greatest in MB animals, with no differences in tissue volume or wet-to-dry ratio. However, tissue levels of cytokines IL-1beta, IL-10, and IL-12 were greatest in LV. Burn injury elevates urinary cortisol and compromises adrenal gland integrity, which is affected by IV fluid volume. PMID- 29757441 TI - The Safety and Efficacy of Propranolol in Reducing the Hypermetabolic Response in the Pediatric Burn Population. AB - Pediatric burn patients often have hypertension and tachycardia for several years post-injury. Propranolol has shown to be effective in treating the hypermetabolic state secondary to a major burn injury. This study was conducted to document a safe and effective dosing regimen for three different age groups. One hundred four burn-injured children with a 30% to 92% total body surface area burn were treated for 1 to 2 years with propranolol in the outpatient setting. Guardians of the patients were instructed on how to take and monitor the systolic blood pressure and heart rate, and document their vital signs several times a day. The documentation was reviewed with the guardian and patient, and based on age specific vital sign parameters, propranolol dosing adjustment was done to measure at least 15% to 20% reduction in admission heart rate. Mean doses for the age groups were as follows: 0 to 3 years 5.2 +/- 2.8 mg/kg/day, 4 to 10 years 4.2 +/- 1.8 mg/kg/day, and 11 to 18 years 2.9 +/- 1.4 mg/kg/day. The propranolol dose decreased as time post-burn increased. On selected patients, propranolol was stopped due to changes in the heart rate, but at all times, it was safe and effective. No adverse effects were noted. The dosing regimen was not affected by burn size or gender. Propranolol can be safely stopped abruptly with no rebound hypertension. Individuals older than 10 years required a lower dose per kilogram following the burn injury than prepubertal burn survivors. Propranolol proved to be both safe and effective in the management of cardiovascular changes occurring in the hypermetabolic state. PMID- 29757443 TI - Impact of Genetic Polymorphism in the beta2-Receptor Gene on Risk of Severe Hypoglycemia in Patients With Type 1 Diabetes. AB - Context: Severe hypoglycemic events are unevenly distributed in people with type 1 diabetes, making a genetic influence probable. Of the common adrenoceptor beta 2 receptor gene (ADRB2) polymorphisms, the Arg16 allele is associated with receptor downregulation and reduced agonist-mediated endogenous glucose production. Objective: We tested the hypothesis that the Arg16 variant is associated with severe hypoglycemia. Method: A cohort of 311 patients with type 1 diabetes reported severe hypoglycemic events retrospectively in a validated questionnaire. The patients were characterized by diabetes history, state of hypoglycemia awareness, C-peptide status, HbA1c, and ADRB2 genotype. Results: The ADRB2 Gly16Arg genotype distribution was in Hardy-Weinberg equilibrium. The rate of severe hypoglycemia differed among all genotypes (P = 0.01). Patients homozygous for the Arg16 genotype (AA; n = 60) had a relative rate (RR) of severe hypoglycemia of 2.2 (95% CI, 1.3 to 3.6) compared with patients homozygous for the Gly16 genotype (GG; n = 116; P = 0.002). Among patients with impaired awareness or unawareness (n = 175), those with the AA genotype (n = 33) had an RR of severe hypoglycemia of 3.2 (95% CI, 1.7 to 6.0) compared with patients with the GG genotype (n = 58; P < 0.000). Genotype was not associated with state of hypoglycemia awareness per se, as assessed by any of three classification methods. The difference was not explained by other risk factors. Conclusion: Genetic polymorphism in ADRB2 is associated with risk of severe hypoglycemia in individuals with type 1 diabetes, especially in those with impaired hypoglycemia awareness. PMID- 29757444 TI - Physical Activity, Sedentary Time, and Associated Factors in Recipients of Solid Organ Transplantation. AB - Background: Short-term survival after solid-organ transplantation has substantially improved, and the focus has shifted to long-term survival, including the role of physical activity (PA). Knowledge about PA and sedentary time in recipients of solid-organ transplantation is limited, and identification of the levels and associated factors is necessary for intervention development. Objective: The objectives of this study were to investigate the level of PA and sedentary time in recipients of solid-organ transplantation and to identify factors associated with these behaviors. Design: The design consisted of a cross sectional survey. Methods: Questionnaires on PA level, sedentary time, and potential associated factors were used for recipients of solid-organ transplantation (kidney, liver, lung, and heart [N = 656]). Multiple regression analyses with a variable selection procedure were used. Results: Fewer than 60% of the recipients fulfilled the PA guideline. Factors significantly associated with a lower level of PA included being a woman, younger age (nonlinear), not actively working or being retired, physical limitations, and low expectations and self-confidence. Factors significantly associated with less sedentary time included exercise self-efficacy and not actively working or being retired. Significantly associated with more sedentary time were a high education level, fear of negative effects, physical limitations, and the motivator "health and physical outcomes." The type of transplantation did not significantly influence either of the outcome measures. Limitations: The design did not allow for causal inferences to be made. The studied associated factors were limited to individual and interpersonal factors. Self-reported measures of PA and sedentary time were used. Conclusions: In intervention development directed at increasing the level of PA and reducing sedentary time in recipients of solid-organ transplantation, attention should be paid to physical limitations, fear of negative effects, low expectations and self-confidence, health and physical outcomes, and exercise self efficacy. PMID- 29757446 TI - Letter: The Prevalence of Burnout Among US Neurosurgery Residents. PMID- 29757445 TI - Lessons learned from merging wet lab experiments with molecular simulation to improve mAb humanization. AB - Humanized monoclonal antibodies (mAbs) are among the most promising modern therapeutics, but defined engineering strategies are still not available. Antibody humanization often leads to a loss of affinity, as it is the case for our model antibody Ab2/3H6 (PDB entry 3BQU). Identifying appropriate back-to mouse mutations is needed to restore binding affinity, but highly challenging. In order to get more insight, we have applied molecular dynamics simulations and correlated them to antibody binding and expression in wet lab experiments. In this study, we discuss six mAb variants and investigate a tyrosine conglomeration, an isopolar substitution and the improvement of antibody binding towards wildtype affinity. In the 3D structure of the mouse wildtype, residue R94h is surrounded by three tyrosines which form a so-called 'tyrosine cage'. We demonstrate that the tyrosine cage has a supporting function for the CDRh3 loop conformation. The isopolar substitution is not able to mimic the function appropriately. Finally, we show that additional light chain mutations can restore binding to wildtype-comparable level, and also improve the expression of the mAb significantly. We conclude that the variable light chain of Ab2/3H6 is of underestimated importance for the interaction with its antigen mAb 2F5. PMID- 29757447 TI - Humic acid and enzymes inclusion in canola-based diets generate different responses in growth performance, protein utilization dynamics, and hemato biochemical parameters in broiler chickens. AB - The current study was conducted to investigate the effect of a humic acid and enzymes on growth performance, protein utilization, and blood parameters in broilers fed canola-based diets. Canola meal (CM) is characterized as low protein compared to soybean meal. Two-hundred-twenty broiler chickens were randomly allotted to the following 5 dietary treatments: 1. Control (commercial broiler diet); 2. CM (17.5% canola meal inclusion); 3. CMEnz (CM + 0.3 g/kg enzymes [Axtra XAP]); 4. CMPh (CM + 1.5% potassium humate, PH) and 5. CMEnzPh (CM + 1.5% PH + 0.3 g/kg Axtra XAP). Each treatment was replicated 4 times with each pen holding 11 birds as the experimental unit. The feeding trial was conducted over a grower (15 to 28 d) and a finisher phase (29 to 42 d). Diet did not affect (P > 0.05) feed intake across either grower or finisher phase but affected average daily gain (ADG) in the grower phase. In the grower phase, broilers fed CM had the highest ADG (71+/- 1.08 g/d), while the control (63.75 +/- 1.08 g/d) had the lowest. However, control chickens had the highest feed conversion ratio (FCR) (1.65), while those fed CM (1.47) had the lowest. Diet significantly affected total white blood cell and white blood cell differential, which were consistently high in broilers fed CMEnzPh. With regard to serum metabolites, CM had the highest levels (P < 0.05) of aspartate aminotransferase (AST) (406.86 +/- 38.07 IU/L), while CMEnzPh (254.17 +/- 41.11 IU/L) had the lowest levels. Additionally, broilers fed CMPh had the highest (P < 0.05) serum sodium content (150.57 +/- 0.69 mmol/l). Overall, canola meal, in the presence of enzymes and humic acid, was shown to have great potential as an alternative replacement of soybean meal in broiler diets. The findings from the study can, therefore, contribute to the design of low-cost canola-based feed formulations that will improve growth performance and health status in poultry farming systems in the future. PMID- 29757449 TI - Composite Hemangioendothelioma Settled in the Paraspinal Region: A Rare Case Report. AB - Composite Hemangioendothelioma (CHE) is a very rare, low-grade malignant vascular tumor. It is most commonly seen as one or more nodules on both sides of the fingers and toes. This tumor is rarely settled in the paraspinal muscles. The age of onset is usually between the ages of 21 and 72 (1), with average age of 39.5 41 years. The treatment is gross total removal of the lesion. The definitive diagnosis is made histopathologically. Our case was a 54-year-old male patient. He had a complaint of low back pain. A lumbar spine MRI revealed that it was settled in the right paravertebral muscle in the posterior vicinity of the transverse process between the right paraspinal muscle planes. The mass was removed grossly and totally. The diagnosis of CHE was made histopathologically. In this article, we presented a case of CHE a rare tumor settled in the paraspinal region a rare site. PMID- 29757448 TI - Quantitative prevalence and characterization of Campylobacter from chicken and duck carcasses from poultry slaughterhouses in South Korea. AB - The objective of this study was to assess the quantitative prevalence, antibiotic resistance, and molecular subtyping pattern of Campylobacter isolates from chicken and duck products from poultry slaughterhouses in South Korea. A total of 240 chicken (n = 120) and duck (n = 120) carcass samples collected from 12 poultry slaughterhouses between June 2014 and February 2015 in 12 South Korean cities was tested, and 131 samples were positive for Campylobacter. Duck samples showed a higher prevalence (P < 0.05; 93 out of 120) compared to chicken samples (38 out of 120), whereas Campylobacter cell populations from positives were lower (P < 0.05) in ducks (mean count: 183.8 CFU/mL) than in chicken samples (mean count: 499.7 CFU/mL). Most isolates were resistant to nalidixic acid (93.9%), ciprofloxacin (95.4%), tetracycline (72.5%), or enrofloxacin (88.5%), but only a few strains were resistant to chloramphenicol (0.8%) or erythromycin (3.1%). Most of the tested strains were classified into diverse pulsotypes according to repetitive element sequence-based-PCR banding patterns, indicating the diversity of Campylobacter isolates present in chicken and duck samples from poultry slaughterhouses. The emergence of Campylobacter contamination and antibiotic resistant strains in food animals poses a potential risk to public health and should be regularly monitored for developing proper control measures. PMID- 29757450 TI - A case report of a 4-year-old boy with intradural spinal cord abscess successfully treated with adjuvant hyperbaric oxygen therapy. AB - Intradural spinal cord abscesses are rare infections in early childhood and usually result from pre-existing congenital anomalies of the spinal column. The formation of abscess may be the result of hematogenous spread. It is treated by surgical and parenteral antibiotic treatment, but some special cases may require additional treatments. This article presents a 4-year-old male patient who was operated because of spina bifida (meningocele and tethered cord) at the external center, and upon complains of not being able to walk after one month, he was operated with the diagnosis of spinal intradural abscess and referred to us to continue his treatment. The patient was taken into an emergency operation when the spinal magnetic resonance imaging (MRI) taken in our hospital showed a progression of intradural abscess. Due to no regression of neurological deficits in the follow-up and with the risk of a second operation, application of antimicrobial therapy as well as hyperbaric oxygen therapy (HBOT) was planned. At the end of 20 HBOT treatment sessions, the patient started to walk with support and the antibiotic treatment was completed in six weeks. In situations where surgical and antimicrobial treatment, the main treatments for children with critical spinal abscess are unresponsive, HBOT should be considered as an additional treatment method. PMID- 29757451 TI - Effects of Zinc Oxide on mRNA Expression of Genes in Brain Tissue of Rats. AB - AIM: Zinc oxide nanoparticles are flexible platforms for biotechnology and biomedical applications. To investigate the expression level of the DR4, DR5, OPG, DcR1 and DcR2 in brain tissue. MATERIAL AND METHODS: The expression of DR4, DR5, OPG, DcR1, DcR2 and beta-actin were measured through RT-PCR and western blotting in brain tissues of all three groups. The mRNA expression levels of DR4, DR5, OPG, DcR1 and DcR2 was investigated by using the RT-PCR and western blotting methods. RESULTS: Thirty rats in the three groups were used in order to determine of DR4, DR5, OPG, DcR1, DcR2 and beta-actin (control) genes expression. The DR4, DR5, OPG, DcR1, DcR2 genes showed a decrease in gene expression levels when they were analyzed by RT-PCR and western blotting in ZnO-NP group. CONCLUSION: Overexpression of DR4, DR5, OPG, DcR1 and DcR2 was observed in brain tissues. The increased expression of the DR4, DR5, OPG, DcR1 and DcR2 may play important role in ZnO-NP of brain tumors. PMID- 29757452 TI - Prevalence of anomalously originating occipital artery in a group of Turkish individuals: A retrospective study using angiography. AB - AIM: Although it is well known that the occipital artery (OA) originates from the external carotid artery (ECA), the incidence of variations remains unknown. In our study, we investigated the prevalence of anomalously originating OA using angiography in a group of Turkish individuals. MATERIAL AND METHODS: The images recorded in the picture archiving and communication system for a total of 114 patients, in which the whole vertebral artery, as well as the ECA and its branches, were visualized, were retrospectively reviewed. Images were obtained using a Toshiba INFNX-i 8000V (Canon Medical Systems, Otawara, Tochigi, Japan) angiography device. RESULTS: We diagnosed 11 cases (12 arteries) with anomalously originating OA, representing a prevalence of 9.64%. In 7 cases, the ascending pharyngeal artery and OA originated with a common root from the ECA (8 arteries); and in 4 patients, OA originated from the distal part of the ECA (C1vertebral level). CONCLUSION: As for many vascular structures, the prevalence of OA variations may vary according to the population under question and the examination method used. Our study has shown that in a sample from the Turkish population, the prevalence of anomalously originating OA was much higher than that stated in the literature, which used magnetic resonance angiography. To avoid complications, the high prevalence of this anomaly must be taken into account during surgeries that require the use of OA, endarterectomies, and endovascular interventions. PMID- 29757453 TI - Intracranial medulloepithelioma in a child: a case report. AB - Intracranial medulloepithelioma is extremely rare and highly malignant in central nervous system. It is a kind of fast-growing tumor and shows a propensity to spread widely throughout the central nervous system. It commonly occurs in infants and young children. We reported a rare case of 2 years old female child with a huge mass diagnosed as medulloepithelioma. Though radiological examination was characteristic for the neoplasm, it was not enough to make a definite diagnosis. Combining with histopathological examination was contributing to diagnose medulloepithelioma and differentiate it from other central nervous system tumors. We aimed at more understanding and knowledge of intracranial medulloepithelioma via reporting this case. PMID- 29757454 TI - Non-pharmacological interventions for treating chronic prostatitis/chronic pelvic pain syndrome. AB - BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder in which the two main clinical features are pelvic pain and lower urinary tract symptoms. There are currently many approaches for its management, using both pharmacological and non-pharmacological interventions. The National Institute of Health - Chronic Prostatitis Symptom Index (NIH-CPSI) score is a validated measure commonly used to measure CP/CPPS symptoms. OBJECTIVES: To assess the effects of non-pharmacological therapies for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). SEARCH METHODS: We performed a comprehensive search using multiple databases, trial registries, grey literature and conference proceedings with no restrictions on the language of publication or publication status. The date of the latest search of all databases was August 2017. SELECTION CRITERIA: We included randomised controlled trials. Inclusion criteria were men with a diagnosis of CP/CPPS. We included all available non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently classified studies and abstracted data from the included studies, performed statistical analyses and rated quality of evidence (QoE) according to the GRADE methods. MAIN RESULTS: We included 38 unique studies with 3290 men with CP/CPPS across 23 comparisons.1. Acupuncture: (three studies, 204 participants) based on short-term follow-up, acupuncture probably leads to clinically meaningful reduction in prostatitis symptoms compared with sham procedure (mean difference (MD) in total NIH-CPSI score -5.79, 95% confidence interval (CI) -7.32 to -4.26, high QoE). Acupuncture may result in little to no difference in adverse events (low QoE). Acupuncture may not reduce sexual dysfunction when compared with sham procedure (MD in the International Index of Erectile Function (IIEF) Scale -0.50, 95% CI -3.46 to 2.46, low QoE). Acupuncture may also lead to a clinically meaningful reduction in prostatitis symptoms compared with standard medical therapy (MD -6.05, 95% CI -7.87 to -4.24, two studies, 78 participants, low QoE). We found no information regarding quality of life, depression or anxiety.2. Lifestyle modifications: (one study, 100 participants) based on short-term follow-up, lifestyle modifications may be associated with a reduction in prostatitis symptoms compared with control (risk ratio (RR) for improvement in NIH-CPSI scores 3.90, 95% CI 2.20 to 6.92, very low QoE). We found no information regarding adverse events, sexual dysfunction, quality of life, depression or anxiety.3. Physical activity: (one study, 85 participants) based on short-term follow-up, a physical activity programme may cause a small reduction in prostatitis symptoms compared with control (NIH-CPSI score MD -2.50, 95% CI -4.69 to -0.31, low QoE). This programme may not reduce anxiety or depression (low QoE). We found no information regarding adverse events, sexual dysfunction or quality of life.4. Prostatic massage: (two studies, 115 participants) based on short-term follow-up, we are uncertain whether the prostatic massage reduces or increases prostatitis symptoms compared with control (very low QoE). We found no information regarding adverse events, sexual dysfunction, quality of life, depression or anxiety.5. Extracorporeal shockwave therapy: (three studies, 157 participants) based on short-term follow-up, extracorporeal shockwave therapy reduces prostatitis symptoms compared with control (NIH-CPSI score MD -6.18, 95% CI -7.46 to -4.89, high QoE). These results may not be sustained at medium-term follow-up (low QoE). This treatment may not be associated with a greater incidence of adverse events (low QoE). This treatment probably improves sexual dysfunction (MD in the IIEF Scale MD 3.34, 95% CI 2.68 to 4.00, one study, 60 participants, moderate QoE). We found no information regarding quality of life, depression or anxiety.6. Transrectal thermotherapy compared to medical therapy: (two studies, 237 participants) based on short-term follow-up, transrectal thermotherapy alone or in combination with medical therapy may decrease prostatitis symptoms slightly when compared with medical therapy alone (NIH-CPSI score MD -2.50, 95% CI -3.82 to -1.18, low QoE). One included study reported that participants may experience transient adverse events. We found no information regarding sexual dysfunction, quality of life, depression or anxiety.7. Other interventions: there is uncertainty about the effects of most of the other interventions included in this review. We found no information regarding psychological support or prostatic surgery. AUTHORS' CONCLUSIONS: Based on the findings of moderate quality evidence, this review found that some non-pharmacological interventions such as acupuncture and extracorporeal shockwave therapy are likely to result in a decrease in prostatitis symptoms and may not be associated with a greater incidence of adverse event. The QoE for most other comparisons was predominantly low. Future clinical trials should include a full report of their methods including adequate masking, consistent assessment of all patient-important outcomes including potential treatment-related adverse events and appropriate sample sizes. PMID- 29757456 TI - Cancer research in the United States: A critical review of current status and proposal for alternative models. PMID- 29757455 TI - Cells, cytokines, chemokines, and cancer stress: A biobehavioral study of patients with chronic lymphocytic leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia, with profound disease-related cellular, humoral, and innate immune suppression. The objective of this study was to study the correlations between stress and disease-specific, negative prognostic cellular, cytokine, and chemokine markers in patients with CLL. METHODS: A single-group, observational design was used. Patients with relapsed/refractory CLL (N = 96) who were entering a phase 2 trial of an experimental therapy (ibrutinib) were studied. Before the first dose, a validated self-report measure of stress (the Impact of Event Scale) was completed, and blood was drawn for absolute lymphocyte counts (ALCs) and for cytokine and chemokine enzyme-linked immunosorbent assays. Multiple linear regression models tested stress as a concurrent predictor of ALCs; of cytokines (tumor necrosis factor alpha [TNFalpha], a proliferation-inducing ligand [APRIL], B-cell activating factor [BAFF], interleukin 6 [IL-6], IL-10, IL-16, and vascular endothelial growth factor [VEGF]); and of the chemokine (C-C motif) ligand 3 (CCL3). RESULTS: Controlling for relevant demographic variables, comorbidities, CLL genetic risk (deletion of the short arm of chromosome 17 [del17p]), and correlates of inflammation, stress predicted higher ALCs (P < .05), and higher levels of TNFalpha (P < .05), IL-16 (P < .01), and CCL3 (P < .05). Stress was not associated with APRIL, BAFF, IL-6, IL-10, or VEGF. CONCLUSIONS: Novel biobehavioral data from patients with relapsed/refractory CLL demonstrate that stress is related to heightened levels of cellular, cytokine, and chemokine markers associated previously with progressive disease in CLL. The current results indicate that stress is related to immune and inflammatory processes that contribute to cancer cell proliferation and survival. These data provide a first look into these processes. Cancer 2018. (c) 2018 American Cancer Society. PMID- 29757457 TI - The role of adjuvant treatment in early-stage oral cavity squamous cell carcinoma: An international collaborative study. AB - BACKGROUND: Up to half of patients with oral cavity squamous cell carcinoma (OCSCC) have stage I to II disease. When adequate resection is attained, no further treatment is needed; however, re-resection or radiotherapy may be indicated for patients with positive or close margins. This multicenter study evaluated the outcomes and role of adjuvant treatment in patients with stage I to II OCSCC. METHODS: Overall survival (OS), disease-specific survival, local-free survival, and disease-free survival rates were calculated with Kaplan-Meier analysis. RESULTS: Of 1257 patients with T1-2N0M0 disease, 33 (2.6%) had positive margins, and 205 (16.3%) had close margins. The 5-year OS rate was 80% for patients with clear margins, 52% for patients with close margins, and 63% for patients with positive margins (P < .0001). In a multivariate analysis, age, depth of invasion, and margins were independent predictors of outcome. Close margins were associated with a >2-fold increase in the risk of recurrence (P < .0001). The multivariate analysis revealed that adjuvant treatment significantly improved the outcomes of patients with close/positive margins (P = .002 to .03). CONCLUSIONS: Patients with stage I to II OCSCC and positive/close margins have poor long-term outcomes. For this population, adjuvant treatment may be associated with improved survival. Cancer 2018;124:2948-55. (c) 2018 American Cancer Society. PMID- 29757458 TI - Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets. AB - Frequent or continuous headache, often refractory to medical therapy, is a common occurrence after head trauma. In addition to being the most common acute symptom after traumatic brain injury (TBI), headache is also one of the most persistent and disabling symptoms. Different studies indicate that 18-58% of those suffering a TBI will have significant headache at 1 year following the trauma. In addition to being disabling on its own, posttraumatic headache (PTH) is a predictor of overall outcome after concussion. Despite its remarkable prevalence and associated social and economic costs, many fundamental and important questions about PTH remain unanswered. The purpose of this review is to identify key questions regarding the clinical characteristics of posttraumatic headache, its basic mechanisms, and its optimal management. We discuss phenotypic features of PTH, pathophysiological mechanisms of TBI including potential overlaps with those of migraine and other primary headache disorders, and potential novel targets for treatment. We suggest different strategies to finding answers to the questions regarding PTH in order to advance the understanding of the disorder and develop more effective therapies. PMID- 29757461 TI - Accumulation of transposable elements in selfing populations of Arabidopsis lyrata supports the ectopic recombination model of transposon evolution. AB - Transposable elements (TE) can constitute a large fraction of plant genomes, yet our understanding of their evolution and fitness effect is still limited. Here we tested several models of evolution that make specific predictions about differences in TE abundance between selfing and outcrossing taxa, and between small and large populations. We estimated TE abundance in multiple populations of North American Arabidopsis lyrata differing in mating system and long-term size, using transposon insertion display on several TE families. Selfing populations had higher TE copy numbers per individual and higher TE allele frequencies, supporting models which assume that selection against TEs acts predominantly against heterozygotes via the process of ectopic recombination. In outcrossing populations differing in long-term size, the data supported neither a model of density-regulated transposition nor a model of direct deleterious effect. Instead, the population structure of TEs revealed that outcrossing populations tended to split into western and eastern groups - as previously detected using microsatellite markers - whereas selfing populations from west and east were less differentiated. This, too, agrees with the model of ectopic recombination. Overall, our results suggest that TE elements are nearly neutral except for their deleterious potential to disturb meiosis in the heterozygous state. PMID- 29757459 TI - Individual meaning-centered psychotherapy for the treatment of psychological and existential distress: A randomized controlled trial in patients with advanced cancer. AB - BACKGROUND: Patients with advanced cancer have high rates of psychological distress, including depression, anxiety, and spiritual despair. This study examined the effectiveness of individual meaning-centered psychotherapy (IMCP) in comparison with supportive psychotherapy (SP) and enhanced usual care (EUC) in improving spiritual well-being and quality of life and reducing psychological distress in patients with advanced cancer. METHODS: Patients (n = 321) were randomly assigned to IMCP (n = 109), SP (n = 108), or EUC (n = 104). Assessments were conducted at 4 time points: before intervention, midtreatment (4 weeks), 8 weeks after treatment, and 16 weeks after treatment. RESULTS: Significant treatment effects (small to medium in magnitude) were observed for IMCP, in comparison with EUC, for 5 of 7 outcome variables (quality of life, sense of meaning, spiritual well-being, anxiety, and desire for hastened death), with Cohen's d ranging from 0.1 to 0.34; no significant improvement was observed for patients receiving SP (d < 0.15 and P > .05 for all variables). The effect of IMCP was significantly greater than the effect of SP for quality of life and sense of meaning (d = 0.19) but not for the remaining study variables. CONCLUSIONS: This study provides further support for the efficacy of IMCP as a treatment for psychological and existential/spiritual distress in patients with advanced cancer. Significant treatment effects (small to moderate effect sizes) were observed in comparison with usual care, and somewhat more modest differences in improvement (small effect sizes) were observed in comparison with SP. Thus, the benefits of meaning-centered psychotherapy appear to be unique to the intervention and highlight the importance of addressing existential issues with patients approaching the end of life. Cancer 2018. (c) 2018 American Cancer Society. PMID- 29757460 TI - Evaluating Behavioral Economic Models of Heavy Drinking Among College Students. AB - BACKGROUND: Heavy drinking among college students is a significant public health concern that can lead to profound social and health consequences, including alcohol use disorder. Behavioral economics posits that low future orientation and high valuation of alcohol (alcohol demand) combined with deficits in alternative reinforcement increase the likelihood of alcohol misuse. Despite this, no study has examined the incremental utility of all 3 variables simultaneously in a comprehensive model. METHODS: This study uses structural equation modeling to test the associations between behavioral economic variables-alcohol demand (latent), future orientation (measured with a delay discounting task and the Consideration of Future Consequences [CFC] scale), and proportionate substance related reinforcement-and alcohol consumption and problems among 393 heavy drinking college students. Two models are tested as follows: (i) an iteration of the reinforcer pathology model that includes an interaction between future orientation and alcohol demand; and (ii) an alternative model evaluating the interconnectedness of behavioral economic variables in predicting problematic alcohol use. RESULTS: The interaction effects in Model 1 were nonsignificant. Model 2 suggests that greater alcohol demand and proportionate substance-related reinforcement are associated with greater alcohol consumption and problems. Furthermore, CFC was associated with alcohol-related problems and lower proportionate substance-related reinforcement but was not significantly associated with alcohol consumption or alcohol demand. Finally, greater proportionate substance-related reinforcement was associated with greater alcohol demand. CONCLUSIONS: Our results support the validity of the behavioral economic reinforcer pathology model as applied to young adult heavy drinking. PMID- 29757462 TI - Effect of guava and vitamin C supplementation on experimental gingivitis: A randomized clinical trial. AB - OBJECTIVE: To study the effect of guava and synthetic vitamin C on the development of gingival inflammation during experimental gingivitis. MATERIAL AND METHODS: Participants were randomly assigned to three groups supplemented daily with either 200 g guava, 200 mg synthetic vitamin C or water. The study included a 14 days pre-experimental period with oral hygiene instructions, scaling, prophylaxis and supplementation. Thereafter, experiment gingivitis was initiated, while continuing supplementation. At baseline, Day 7 and Day 14 of experimental gingivitis, Plaque Index (PlI) and Gingival Index (GI) were assessed. During the entire study, dietary fruit/vegetables intake was minimal. RESULTS: PlI increased in guava, vitamin C and control group (DeltaPlI: 1.30, 1.61 and 1.79, respectively). However, the guava group developed significantly less plaque compared to the control group. The GI increase in both guava and vitamin C group was significantly less than the increase in the control group (DeltaGI: 0.10, 0.24 and 0.87, respectively). CONCLUSION: In a population of young nonsmoking adults, consumption of either 200 g guava/day or 200 mg synthetic vitamin C/day, prior to and during the oral hygiene abstention period, has a preventive effect on the development of experimental gingivitis as compared to the control group that developed the usual amount of experimental gingivitis. PMID- 29757463 TI - Depression-related behavioural and neuroendocrine changes in the Spontaneously Diabetic Torii (SDT) fatty rat, an animal model of type 2 diabetes mellitus. AB - Depression is one of the most common psychiatric diseases and is commonly comorbid with type 1 or 2 diabetes mellitus (DM). However, the pathophysiology underlying the depressive state in DM remains poorly understood. Animal models are useful tools to investigate the association between depression and DM. In the present study we investigated whether the Spontaneously Diabetic Torii (SDT) fatty rat, a novel animal model of type 2 DM, shows depression-related features. We assessed depression-like behaviour, hyperactivation of the hypothalamic pituitary-adrenal (HPA) axis, and neurotransmitter levels in the brain. Behaviour was evaluated using a forced swimming test, and the HPA axis was evaluated with changes in plasma corticosterone levels after a swimming stress exposure or dexamethasone challenge. In addition, serotonin (5-hydroxytryptamine; 5-HT), noradrenaline, glutamate and gamma-aminobutyric acid (GABA) concentrations in the frontal cortex, hippocampus and brain stem were measured. In the forced swimming test, SDT fatty rats exhibited increased duration of immobility compared with control Sprague-Dawley (SD) rats. Moreover, basal corticosterone levels were significantly elevated in SDT fatty compared with control SD rats. However, there were no stress-induced increases or changes in dexamethasone-induced suppression of corticosterone in SDT fatty compared with control SD rats. Furthermore, there were significant changes in 5-HT concentrations in the prefrontal cortex, and in GABA and glutamate concentrations in the hippocampus in SDT fatty compared with controls. The results of the present study suggest that the SDT fatty rat may be an appropriate model for diabetes with comorbid depression associated with neurotransmitter impairments and aberrant basal HPA hyperactivity. PMID- 29757464 TI - Ultrasonography for noninvasive and real-time evaluation of peri-implant tissue dimensions. AB - AIM: Existing methods for evaluating marginal bone loss and tissue biotype around dental implants present with many limitations. The aim of this study was to examine the accuracy of high-resolution, 3-dimensional ultrasound to measure peri implant tissue dimensions. MATERIAL AND METHODS: A 25-MHz ultrasound probe prototype was used to scan peri-implant tissues of 17 implants from seven fresh human cadavers. Four ultrasonic measurements were made as follows: the marginal bone level/thickness, and mucosal level/thickness. The readings were statistically compared to cone beam computed tomography (CBCT) and/or open bone measurements. RESULTS: The correlations (r) between the ultrasound and direct/CBCT readings of the four parameters ranged from 0.85 to 0.98 (p < 0.0001). The mean absolute difference in the four parameters between ultrasound direct and ultrasound-CBCT ranged from 0.033 to 0.24 mm. CONCLUSION: Encouraging evidence is shown that ultrasound can accurately measure peri-implant tissue dimensions. Following clinical trial validations, ultrasound offers potential as a valuable tool to evaluate long-term peri-implant tissue stability without concerns of ionizing radiation and image artefacts around implants. PMID- 29757465 TI - Transition-Metal-Catalyzed Decarbonylative Coupling Reactions: Concepts, Classifications, and Applications. AB - Transition metal-catalyzed decarbonylative coupling reactions have emerged as a powerful alternative to conventional cross-coupling protocols due to the advantages associated with the use of carbonyl-containing functionalities as coupling electrophiles instead of commonly used organohalides or sulfates. A wide variety of novel transformations based on this concept have been successfully achieved, including decarbonylative carbon-carbon and carbon-heteroatom bond forming reactions. In this Review, we summarize the recent progress in this field and present a comprehensive overview of metal-catalyzed decarbonylative coupling reactions with carbonyl derivatives. PMID- 29757466 TI - NADPH oxidase activation in neutrophils: Role of the phosphorylation of its subunits. AB - Neutrophils are key cells of innate immunity and during inflammation. Upon activation, they produce large amounts of superoxide anion (O2 -. ) and ensuing reactive oxygen species (ROS) to kill phagocytized microbes. The enzyme responsible for O2 -. production is called the phagocyte NADPH oxidase. This is a multicomponent enzyme system that becomes active after assembly of four cytosolic proteins (p47phox , p67phox , p40phox and Rac2) with the transmembrane proteins (p22phox and gp91phox , which form the cytochrome b558 ). gp91phox represents the catalytic subunit of the NADPH oxidase and is also called NOX2. NADPH oxidase derived ROS are essential for microbial killing and innate immunity; however, excessive ROS production induces tissue injury and prolonged inflammatory reactions that contribute to inflammatory diseases. Thus, NADPH oxidase activation must be tightly regulated in time and space to limit ROS production. NADPH oxidase activation is regulated by several processes such as phosphorylation of its components, exchange of GDP/GTP on Rac2 and binding of p47phox and p40phox to phospholipids. This review aims to provide new insights into the role of the phosphorylation of the NADPH oxidase components, that is gp91phox , p22phox , p47phox , p67phox and p40phox , in the activation of this enzyme. PMID- 29757467 TI - Severe tricuspid regurgitation due to interactions with right ventricular permanent pacemaker or defibrillator leads. AB - Although thought to be a rare event, permanent pacemakers and implantable cardioverter-defibrillators with right ventricular intracardiac leads have the potential to induce tricuspid valve dysfunction. Adverse lead-valve interactions can take place through a variety of mechanisms including damage at the time of implantation, leaflet pinning, or long-term fibrosis encapsulating the leaflet tissue. Clinical manifestations can display a wide range of severity, as well as a highly variable time span between implantation and hemodynamic deterioration. This review aims to describe the potential pathophysiologic effects of intracardiac device leads on the tricuspid valve, with a focus on ideal diagnostic strategies and treatment options once lead-induced valvular dysfunction is suspected. PMID- 29757468 TI - Treatment of class III multiple gingival recessions: Prognostic factors for achieving a complete root coverage. AB - BACKGROUND: This report is intended to present a supplemental analysis of data from a prior report (Aroca et al., ) to investigate factors associated with a complete root coverage at 1 year. The purpose of the prior report was to investigate at 1 year the adjunction effect of EMD for the treatment of Miller's class III recession defects using a coronally advanced modified tunnel/CTG technique with (test group) or without (control group). The purpose of this report was to investigate additional factors associated with root coverage in the same data set. MATERIALS AND METHODS: On the 138 observations collected from 20 patients, a regression model was used to highlight the relationship between the percentages of root coverage (RC) and three following covariates: the distance from the tip of the papilla and the contact point (DCP) at baseline, the group membership (control vs. test) and tooth position in the mouth (maxillary vs. mandibular). RESULTS: The statistical analysis showed that there was a significant effect of the DCP at baseline (p = 0.01) and of the tooth type (p < .001) on the percentage of RC at 1 year, whereas no significant difference between the two techniques (group membership effect) was shown (p = 0.69). CONCLUSION: The probability to obtain a complete root coverage decreases when the DCP at baseline increases. Moreover, maxillary teeth are more likely to give better RC than mandibular teeth. However, in this analysis similar to the last, there was no group effect. PMID- 29757469 TI - Soil microclimate changes affect soil fungal communities in a Mediterranean pine forest. AB - Soil microclimate is a potentially important regulator of the composition of plant-associated fungal communities in climates with significant drought periods. Here, we investigated the spatio-temporal dynamics of soil fungal communities in a Mediterranean Pinus pinaster forest in relation to soil moisture and temperature. Fungal communities in 336 soil samples collected monthly over 1 year from 28 long-term experimental plots were assessed by PacBio sequencing of ITS2 amplicons. Total fungal biomass was estimated by analysing ergosterol. Community changes were analysed in the context of functional traits. Soil fungal biomass was lowest during summer and late winter and highest during autumn, concurrent with a greater relative abundance of mycorrhizal species. Intra-annual spatio temporal changes in community composition correlated significantly with soil moisture and temperature. Mycorrhizal fungi were less affected by summer drought than free-living fungi. In particular, mycorrhizal species of the short-distance exploration type increased in relative abundance under dry conditions, whereas species of the long-distance exploration type were more abundant under wetter conditions. Our observations demonstrate a potential for compositional and functional shifts in fungal communities in response to changing climatic conditions. Free-living fungi and mycorrhizal species with extensive mycelia may be negatively affected by increasing drought periods in Mediterranean forest ecosystems. PMID- 29757470 TI - Sinus augmentation using rhBMP-2/ACS in a mini-pig model: Influence of an adjunctive ceramic bone biomaterial. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 in an absorbable collagen sponge carrier (rhBMP-2/ACS) has been shown to support significant bone formation when used to augment the maxillary sinus for implant dentistry. Nevertheless, bone biomaterials have been suggested to extend rhBMP-2/ACS with limited support of the merits of such approaches. OBJECTIVES: To evaluate local bone formation/dental implant osseointegration following implantation of rhBMP 2/ACS combined with a ceramic bone biomaterial using a mini-pig sinus augmentation model. METHODS: Twelve adult Gottingen mini-pigs received rhBMP 2/ACS (rhBMP-2 adjusted to 0.43 mg/cc) alone or combined with an off-the-shelf biphasic ceramic (15%/85% HA/beta-TCP) biomaterial at 3:1, 1:1 and 1:3 ratios randomized to contra-lateral maxillary sinus sites yielding rhBMP-2/ACS fractions of 100%, 75%, 50% and 25%, respectively. A 4-cc implant volume was used for all sites. Two threaded dental implants (o4.0 * 11.5 mm) were placed at each site. The animals were euthanized at 8 weeks for histologic analysis. RESULTS: Surgical execution and healing were generally uneventful, infraorbital local swelling was observed in all animals until suture removal. rhBMP-2/ACS combined with the ceramic biomaterial did not significantly enhance local bone formation (range 9.0 +/- 1.5 to 9.7 +/- 2.1 mm) compared with rhBMP-2/ACS alone (8.6 +/- 1.1 mm; p > 0.05). Variations in rhBMP-2/ACS to ceramic matrix ratios yielding rhBMP-2 doses approximating 0.4, 0.9, 1.3 and 1.7 mg/sinus did not appreciably influence bone formation/osseointegration. CONCLUSIONS: Whereas rhBMP-2/ACS supports significant bone formation/osseointegration in the mini-pig sinus augmentation model and thus appears an effective alternative for sinus augmentation procedures, adding a ceramic biomaterial to rhBMP-2/ACS does not produce meaningful biological advantages. PMID- 29757471 TI - Image-based retrospective 4D MRI in external beam radiotherapy: A comparative study with a digital phantom. AB - PURPOSE: Several image-based retrospective sorting methods of 4D magnetic resonance imaging (4D MRI) have been proposed for respiratory motion reconstruction in external beam radiotherapy. However, the optimal strategy for providing accurate and artifact-free 4D MRI, ideally corresponding to an average breathing cycle, is not yet defined. This study presents a proactive comparison of three published image-based sorting methods, to define a groundwork for benchmarking in 4D MRI. METHODS: Three published 4D MRI methods were selected for image retrospective sorting: body area, mutual information, and navigator slice. The three image-based methods were compared against a conventional retrospective sorting method based on an external surrogate. Comparisons were performed by means of an MRI digital phantom, derived from the XCAT CT phantom generated with different patient-derived signals, for a total of 12 cases. Specific multislice MRI acquisitions were simulated for slice sorting and sagittal, coronal, and axial orientations were tested. An average 4D cycle was generated as ground truth. RESULTS: Individual and grouped patient analyses showed better performance of the navigator slice and mutual information in amplitude binning with respect to the body area strategy. Binning artifacts were reduced on the diaphragm with the slice navigator method due to the acquired internal information. Tumor motion description accurately matched the ground truth in the mutual information strategy with amplitude binning. The body area method followed the performance of the external surrogate and presented larger errors, since was not correlated with the internal anatomy. Sagittal and coronal orientations reported lower errors than axial slicing. Individual analysis showed the need of a patient-specific evaluation for the selection of the best method. CONCLUSIONS: A comparison between three different image-based retrospective sorting methods for 4D MRI is proposed, providing guidelines for benchmark definition in MRI-guided radiotherapy. PMID- 29757472 TI - Technical Note: Predicting dose distribution with replacing stopping power ratio for inter-fractional motion and intra-fractional motion during carbon ion radiotherapy with passive irradiation method for stage I lung cancer. AB - PURPOSE: We designed and evaluated a simple method for predicting the effects of intra-fractional and/or inter-fractional motion on dose distribution during carbon ion radiotherapy (CIRT) for solitary-lesion stage I lung cancer. METHODS: The proposed method uses computed tomography (CT) images from treatment planning and intra-tumoral and/or inter-tumoral displacement. The predicted dose distribution (PDD) was calculated by replacing the current tumor region with the stopping power ratio (SPR) of the lung and replacing the moved tumor region with the SPR of the tumor. The actual dose distribution (ADD) was calculated without the replacement. Ten patients with solitary-lesion stage I lung cancer were retrospectively studied to evaluate the prediction method's accuracy. Four PDDs for intra-fractional motion (gate-in, exhalation, gate-out, inhalation phases during four-dimensional CT) and two PDDs for inter-fractional motion (CT images acquired 1-2 days before treatment) with bone- and tumor-matching methods were compared with each of six ADDs on each CT scan. Percentages of the planning/clinical target volumes (PTV/CTV) receiving >95% of the prescribed dose (V95 ) and of minimum doses covering 95% of the PTV/CTV (D95 ) were compared with dose volume histogram parameters. RESULTS: The maximum tumor displacements occurred in the superior-inferior direction, with intra-fractional motion values of 3.75 and 8.97 mm for the superior and inferior directions, respectively, and inter-fractional values of 9.61 and 4.10 mm. The maximum average error for PTV V95 regarding intra-fractional motion was -0.43% for the gate-out phase and 0.63% for the inhalation phase. There were no significant differences for these parameters (P = 0.541, P = 0.571). Average errors for PTV and CTV V95 with inter fractional motion with bone matching were 2.2% and 2.9%, respectively, with no significant differences (P = 0.387, P = 0.155). CONCLUSIONS: The accuracy of the proposed method was good. Hence, it is feasible to use the proposed method during CIRT to predict dose distribution with respect to intra-fractional motion and/or inter-fractional motion of the tumor in patients with solitary-lesion stage I lung cancer. PMID- 29757473 TI - Iterative inversion of deformation vector fields with feedback control. AB - PURPOSE: Often, the inverse deformation vector field (DVF) is needed together with the corresponding forward DVF in four-dimesional (4D) reconstruction and dose calculation, adaptive radiation therapy, and simultaneous deformable registration. This study aims at improving both accuracy and efficiency of iterative algorithms for DVF inversion, and advancing our understanding of divergence and latency conditions. METHOD: We introduce a framework of fixed point iteration algorithms with active feedback control for DVF inversion. Based on rigorous convergence analysis, we design control mechanisms for modulating the inverse consistency (IC) residual of the current iterate, to be used as feedback into the next iterate. The control is designed adaptively to the input DVF with the objective to enlarge the convergence area and expedite convergence. Three particular settings of feedback control are introduced: constant value over the domain throughout the iteration; alternating values between iteration steps; and spatially variant values. We also introduce three spectral measures of the displacement Jacobian for characterizing a DVF. These measures reveal the critical role of what we term the nontranslational displacement component (NTDC) of the DVF. We carry out inversion experiments with an analytical DVF pair, and with DVFs associated with thoracic CT images of six patients at end of expiration and end of inspiration. RESULTS: The NTDC-adaptive iterations are shown to attain a larger convergence region at a faster pace compared to previous nonadaptive DVF inversion iteration algorithms. By our numerical experiments, alternating control yields smaller IC residuals and inversion errors than constant control. Spatially variant control renders smaller residuals and errors by at least an order of magnitude, compared to other schemes, in no more than 10 steps. Inversion results also show remarkable quantitative agreement with analysis-based predictions. CONCLUSION: Our analysis captures properties of DVF data associated with clinical CT images, and provides new understanding of iterative DVF inversion algorithms with a simple residual feedback control. Adaptive control is necessary and highly effective in the presence of nonsmall NTDCs. The adaptive iterations or the spectral measures, or both, may potentially be incorporated into deformable image registration methods. PMID- 29757476 TI - Limitations of treating pregnant women based solely on vaginal pH. PMID- 29757475 TI - Rapid analysis of fentanyls and other novel psychoactive substances in substance use disorder patient urine using paper spray mass spectrometry. AB - RATIONALE: Drug overdose deaths due to fentanyls and other novel psychoactive substances (NPS) are on the rise. The higher potencies of fentanyl analogs compared with morphine require new technologies to identify and quantitate NPS. METHODS: Paper spray tandem mass spectrometry (MS/MS) and high-resolution mass spectrometry were used to identify and measure fentanyl analogs as well as common drugs of abuse in urine samples from substance use disorder clinics. Ten microliter urine samples were deposited directly on paper spray cartridges previously loaded with internal standards, dried, and analyzed with no other sample treatment. Quantitative results were obtained using MS/MS. Individual drugs were identified using high-resolution accurate mass spectrometry, and confirmed by data-dependent MS/MS. RESULTS: Calibration curves in urine were linear over a range of 0.5-50 ng/mL with R2 of 0.99 or better for eight representative fentanyl analogs. Cartridges preloaded with internal standards demonstrated satisfactory quantitative results compared with LC/MS. Direct identification and confirmation of fentanyl analogs and other common drugs of abuse in urine using high-resolution accurate mass and MS/MS fragmentation were demonstrated at low picogram levels. CONCLUSIONS: Paper spray mass spectrometry can reliably identify and quantitate fentanyl analogs and other drugs of abuse in urine. Using paper spray cartridges as collection devices reduces exposure and transportation risks associated with biological fluids. Cartridges preloaded with labeled internal standards can be effective for targeted screening of fentanyl analogs and other drugs of abuse. PMID- 29757474 TI - Automated patient-specific transperineal ultrasound probe setups for prostate cancer patients undergoing radiotherapy. AB - PURPOSE: The use of ultrasound imaging is not widespread in prostate cancer radiotherapy workflows, despite several advantages (eg, allowing real-time volumetric organ tracking). This can be partially attributed to the need for a trained operator during acquisition and interpretation of the images. We introduce and evaluate an algorithm that can propose a patient-specific transperineal ultrasound probe setup, based on a CT scan and anatomical structure delineations. The use of this setup during the simulation and treatment stage could improve usability of ultrasound imaging for relatively untrained operators (radiotherapists with less than 1 yr experience with ultrasound). METHODS: The internal perineum boundaries of three prostate cancer patients were identified based on bone masks extracted from their CT scans. After projection of these boundaries to the skin and exclusion of specific areas, this resulted in a skin area accessible for transperineal ultrasound probe placement in clinical practice. Several possible probe setups on this area were proposed by the algorithm and the optimal setup was automatically selected. In the end, this optimal setup was evaluated based on a comparison with a corresponding transperineal ultrasound volume acquired by a radiation oncologist. RESULTS: The algorithm-proposed setups allowed visualization of 100% of the clinically required anatomical structures, including the whole prostate and seminal vesicles, as well as the adjacent edges of the bladder and rectum. In addition, these setups allowed visualization of 94% of the anatomical structures, which were also visualized by the physician during the acquisition of an actual ultrasound volume. CONCLUSION: Provided that the ultrasound probe setup proposed by the algorithm, is properly reproduced on the patient, it allows visualization of all clinically required structures for image guided radiotherapy purposes. Future work should validate these results on a patient population and optimize the workflow to enable a relatively untrained operator to perform the procedure. PMID- 29757477 TI - Reading of the non-template DNA by transcription elongation factors. AB - Unlike transcription initiation and termination, which have easily discernable signals, such as promoters and terminators, elongation is regulated through a dynamic network involving RNA/DNA pause signals and states-rather than sequence specific protein interactions. A report by Nedialkov et al. () provides experimental evidence for sequence-specific recruitment of elongation factor RfaH to transcribing RNA polymerase (RNAP) and outlines the mechanism of gene expression regulation by restraint ('locking') of the DNA non-template strand. According to this model, the elongation complex pauses at the so called 'operon polarity sequence' (found in some long bacterial operons coding for virulence genes), when the usually flexible non-template DNA strand adopts a distinct hairpin-loop conformation on the surface of transcribing RNAP. Sequence-specific binding of RfaH to this DNA segment facilitates conversion of RfaH from its inactive closed to its active open conformation. The interaction network formed between RfaH, non-template DNA and RNAP locks DNA in a conformation that renders RNAP resistant to pausing and termination. The effects of such locking on elongation can be mimicked by restraint of the non-template strand due to its shortening. This work advances our understanding of transcription regulation and has important implications for the action of general elongation factors, such as NusG, which lack apparent sequence-specificity, as well as for the mechanisms of other linked processes, such as transcription-coupled DNA repair. PMID- 29757478 TI - Varying the rate of intravenous cocaine infusion influences the temporal dynamics of both drug and dopamine concentrations in the striatum. AB - The faster drugs of abuse reach the brain, the greater is the risk of addiction. Even small differences in the rate of drug delivery can influence outcome. Infusing cocaine intravenously over 5 vs. 90-100 s promotes sensitization to the psychomotor and incentive motivational effects of the drug and preferentially recruits mesocorticolimbic regions. It remains unclear whether these effects are due to differences in how fast and/or how much drug reaches the brain. Here, we predicted that varying the rate of intravenous cocaine infusion between 5 and 90 s produces different rates of rise of brain drug concentrations, while producing similar peak concentrations. Freely moving male Wistar rats received acute intravenous cocaine infusions (2.0 mg/kg/infusion) over 5, 45 and 90 s. We measured cocaine concentrations in the dorsal striatum using rapid-sampling microdialysis (1 sample/min) and high-performance liquid chromatography-tandem mass spectrometry. We also measured extracellular concentrations of dopamine and other neurochemicals. Regardless of infusion rate, acute cocaine did not change concentrations of non-dopaminergic neurochemicals. Infusion rate did not significantly influence peak concentrations of cocaine or dopamine, but concentrations increased faster following 5-s infusions. We also assessed psychomotor activity as a function of cocaine infusion rate. Infusion rate did not significantly influence total locomotion, but locomotion increased earlier following 5-s infusions. Thus, small differences in the rate of cocaine delivery influence both the rate of rise of drug and dopamine concentrations, and psychomotor activity. A faster rate of rise of drug and dopamine concentrations might be an important issue in making rapidly delivered cocaine more addictive. PMID- 29757479 TI - Image cytometry DNA ploidy analysis: Correlation between two semi-automated methods. AB - BACKGROUND AND OBJECTIVES: Quantitation of cell DNA content, DNA ploidy, has been established as a research and prognostic technique for decades. A variety of instruments have been used although only a few commercially available systems have established quality assurance and published outcome data. The aim of this study was to compare two automated systems. METHODS: Nuclear monolayers were obtained from 112 oral biopsies by enzyme digestion and Feulgen staining. These were scanned on both the Fairfield and the Ploidy Work Station (PWS) systems. The overall ploidy diagnosis, number of epithelial nuclei, coefficient of variation (CV) and 5c exceeding rate (5CER) were compared by quantile-quantile plots, t test, Wilcoxon and Spearman's tests. RESULTS: The PWS system identified more nuclei (p < 0.0001) at a lower CV (p < 0.0001). Using the PWS system, fewer samples were classified as indeterminate. No difference between 5CER was found between systems (p > 0.54). There was complete concordance between the two systems in terms of DNA ploidy diagnosis. CONCLUSIONS: The PWS system is comparable to the Fairfield system for determination of DNA ploidy and has advantages that may lead to improved performance. PMID- 29757480 TI - Pinenes: Abundant and Renewable Building Blocks for a Variety of Sustainable Polymers. AB - Pinenes, a group of monoterpenes containing a double bond, are very suitable renewable building blocks for a variety of sustainable polymers and materials. Their abundance from mainly non-edible parts of plants as well as the feasibility to isolate them render these molecules unique amongst the variety of biomass that is utilizable for novel materials. Accordingly, their use for the synthesis of biobased polymers has been investigated intensively, and strong progress has been made with this especially within the past 2-3 years. Direct cationic or radical polymerization via the double bonds as well as polymerization upon their further functionalization can afford a variety of sustainable polymers suitable for many applications, which is summarized in this Minireview. PMID- 29757481 TI - Severe White Matter Astrocytopathy in CADASIL. AB - Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterised by strategic white matter (WM) hyperintensities on MRI. Pathological features include WM degeneration, arteriolosclerosis, lacunar infarcts and the deposition of granular osmiophilic material. Based on the hypothesis that the gliovascular unit is compromised, we assessed the nature of astrocyte damage in the deep WM of CADASIL subjects. Methods We evaluated post-mortem brains from CADASIL, cerebral small vessel disease, similar age cognitively normal and older control subjects. Standard immunohistochemical, immunofluorescent and unbiased stereological methods were used to evaluate the distribution of astrocytes, microvessels and autophagy markers in five different brain regions. Results Compared to the controls, the deep WM of CADASIL subjects overall showed increased numbers of glial fibrillary acidic protein (GFAP)-positive clasmatodendritic astrocytes (P=0.037) and a decrease in the percentage of normal appearing astrocytes (P=0.025). In accord with confluent WM hyperintensities , the anterior temporal pole contained abundant clasmatodendritic astrocytes with displaced aquaporin 4 immunoreactivity. Remarkably, we also found strong evidence for the immunolocalisation of autophagy markers including microtubule associated protein 1, light chain 3 (LC3) and sequestosome 1/p62 and Caspase-3 in GFAP-positive clasmatodendritic cells, particularly within perivascular regions of the deep WM. LC3 was co-localised in more than 90% of the GFAP-positive clasmatodendrocytes. Conclusions Our novel findings show astrocytes undergo autophagy-like cell death in CADASIL, with the anterior temporal pole being highly vulnerable. We propose astrocytes transform from normal appearing type A to hypertrophic type B and eventually to clasmatodendritic type C cells. These observations also suggest the gliovascular unit of the deep WM is severely impaired in CADASIL. This article is protected by copyright. All rights reserved. PMID- 29757484 TI - Reversible SC-SC Transformation involving [4+4] Cycloaddition of Anthracene: A Single-Ion to Single-Molecule Magnet and Yellow-Green to Blue-White Emission. AB - In search of magneto-optic materials, the mononuclear compounds LnIII (depma)(NO3 )3 (hmpa)2 (Ln=Dy, Gd) were synthesized. The anthracene moieties undergo [4+4] dimerization when irradiated at 365 nm without loss of crystallinity. The Dy compound switches from a single-ion to a single-molecule magnet with doubling of the spin reversal barrier energy and from yellow-green to blue-white emission. The dimerization is reversed by heating at 100 degrees C or partially on light irradiating at 254 nm. The results suggest that lanthanide phosphonates with anthracene are promising smart materials displaying synergistic magneto-optic property. PMID- 29757482 TI - Copper-Mediated Polymerization without External Deoxygenation or Oxygen Scavengers. AB - As a method for overcoming the challenge of rigorous deoxygenation in copper mediated controlled radical polymerization processes [e.g., atom-transfer radical polymerization (ATRP)], reported here is a simple Cu0 -RDRP (RDRP=reversible deactivation radical polymerization) system in the absence of external additives (e.g., reducing agents, enzymes etc.). By simply adjusting the headspace of the reaction vessel, a wide range of monomers, namely acrylates, methacrylates, acrylamides, and styrene, can be polymerized in a controlled manner to yield polymers with low dispersities, near-quantitative conversions, and high end-group fidelity. Significantly, this approach is scalable (ca. 125 g), tolerant to elevated temperatures, compatible with both organic and aqueous media, and does not rely on external stimuli which may limit the monomer pool. The robustness and versatility of this methodology is further demonstrated by the applicability to other copper-mediated techniques, including conventional ATRP and light-mediated approaches. PMID- 29757483 TI - Synchronous Chemoradiation Nanovesicles by X-Ray Triggered Cascade of Drug Release. AB - The approach of concurrent-to-synchronous chemoradiation has now been advanced by well-designed nanovesicles that permit X-ray irradiation-triggered instant drug release. The nanovesicles consist of Au nanoparticles tethered with irradiation labile linoleic acid hydroperoxide (LAHP) molecules and oxidation-responsive poly(propylene sulfide)-poly(ethylene glycol) (PPS-PEG) polymers, where DOX were loaded in the inner core of the vesicles (Au-LAHP-vDOX). Upon irradiation, the in situ formation of hydroxyl radicals from LAHP molecules triggers the internal oxidation of PPS from being hydrophobic to hydrophilic, leading to degradation of the vesicles and burst release of cargo drugs. In this manner, synchronous chemoradiation showed impressive anticancer efficacy both in vitro and in a subcutaneous mouse tumor model by one-dose injection and one-time irradiation. PMID- 29757485 TI - Tobacco smoking decreases clinical symptoms of gingivitis in patients with type 1 diabetes-a cross-sectional study. AB - OBJECTIVE: Periodontal disease may develop on the background of microvascular complications of diabetes. However, some modifying factors, such as tobacco smoking, should be taken into consideration when assessing risk of development of chronic complications. The aim of the study was the clinical assessment of the periodontal status in patients with type 1 diabetes according to tobacco smoking. SUBJECTS AND METHODS: A total of 362 subjects aged 29 (IQR 22-35) years, type 1 diabetes duration 12 (8-18) years, hemoglobin A1c, HbA1c 8.0 (7.2-9.1)% were included. We used Gingival Index, Approximal Plaque Index, and Sulcus Bleeding Index to assess periodontal health. Patients were divided into two subgroups according to current cigarette smoking. RESULTS: No differences in age, diabetes duration, and chronic complications were found between subgroups. A better metabolic control of diabetes expressed by lower HbA1c (p = 0.00001) and triglyceride levels (p = 0.004) was shown in nonsmokers. Smokers presented significantly lower gingival bleeding, p = 0.009. HbA1c correlated with API in study group (Rs = 0.16; p = 0.002) and in nonsmokers subgroup (Rs = 0.2;p = 0.004), however, not in smoker's subgroup. In multivariable regression analysis, smoking cigarettes (beta = -0.26; p = 0.0002), hs-CRP (beta = 0.15; p = 0.03) and age (beta = -0.19; p = 0.007) occurred to be independent predictors of SBI after adjustment for confounding variables (R2 = 0.13; p = 0.001). CONCLUSIONS: Patients with type 1 diabetes smoking cigarettes presented lower gingival sulcus bleeding and worse metabolic control of diabetes than nonsmoking patients. PMID- 29757486 TI - Global status of diabetes prevention and prospects for action: A consensus statement. AB - Primary prevention of type 2 diabetes (T2D) should be achievable through the implementation of early and sustainable measures. Several randomized control studies that found success in preventing the progression to T2D in high-risk populations have identified early and intensive intervention based on an individualized prevention model as the key factor for participant benefit. The global prevalence of both overweight and obesity has now been widely recognized as the major epidemic of the 21st century. Obesity is a major risk factor for the progression from normal glucose tolerance to prediabetes and then to T2D. However, not all obese individuals will develop prediabetes or progress to diabetes. Intensive, multicomponent behavioural interventions for overweight and obese adults can lead to weight loss. Diabetes medications, including metformin, GLP-1 agonists, glitazones, and acarbose, can be considered for selected high risk patients with prediabetes when lifestyle-based programmes are proven unsuccessful. Nutrition education is the cornerstone of a healthy lifestyle. Also, physical activity is an integral part of the prediabetes management plan and one of the main pillars in the prevention of diabetes. Mobile phones, used extensively worldwide, can facilitate communication between health professionals and the general population, and have been shown to be helpful in the prevention of T2D. Universal screening is needed. Noninvasive risk scores should be used in all countries, but they should be locally validated in all ethnic populations focusing on cultural differences around the world. Lifestyle interventions reduce the progression to prediabetes and diabetes. Nevertheless, many questions still need to be answered. PMID- 29757487 TI - Fluctuating Carbonaceous Networks with a Persistent Molecular Shape: A Saddle Shaped Geodesic Framework of 1,3,5-Trisubstituted Benzene (Phenine). AB - A saddle-shaped macromolecule has been synthesized. The molecule was designed as a geodesic saddle with 1,3,5-trisubstituted benzene (named phenine) as the fundamental unit. The phenines were woven into a polygonal framework that was composed of 168 sp2 -hybridized carbon atoms. The saddle-shaped structure with unique symmetry showed atypical conformational changes. The biaryl linkages in this molecule had a small energy barrier for rotation, and these structural fluctuations resulted in seven 1 H NMR resonances representing 84 aromatic hydrogen atoms. Nevertheless, the overall saddle shape of the molecule was persistent, and the "up" and "down" orientations of phenine moieties circulated to give average 1 H resonances. The structural characteristics of this molecule, including the anomalous entropy-driven dimerization, may deepen our understanding of defect-rich graphitic sheets. PMID- 29757488 TI - Atomically Precise Multimetallic Semiconductive Nanoclusters with Optical Limiting Effects. AB - For the first time, multinuclear noble-metal clusters have been successfully stabilized by Ti-oxo clusters. Two unprecedented Ag6 @Ti16 -oxo nanoclusters with precise atomic structures were prepared and characterized. The octahedral Ag6 core has strong Ag-Ag bonds (ca. 2.7 A), and is further stabilized by direct Ag-O Ti coordination interactions. Moreover, as a result of different acidic/redox conditions in synthesis, the Ag6 core can adopt diverse geometric configurations inside the Ti16 -O shell. Correspondingly, structural differences greatly influence their optical limiting effects. The transmittance reduction activity of the clusters towards 532 nm laser shows a nearly linear concentration dependence, and can be optimized up to about 43 %. This work not only opens a new direction for multimetallic semiconductive nanoclusters with interesting optical properties, but also provides molecular models for important noble-metal/TiO2 heterogeneous materials. PMID- 29757490 TI - A tale of atypia: What can we learn from this? PMID- 29757489 TI - Emergency Department Discharge of Pulmonary Embolus Patients. AB - BACKGROUND: Hospitalization for low-risk pulmonary embolism (PE) is common, expensive, and of questionable benefit. OBJECTIVE: The objective was to determine if low-risk PE patients discharged from the emergency department (ED) on rivaroxaban require fewer hospital days compared to standard of care (SOC). METHODS: Multicenter, open-label randomized trial in low-risk PE defined by Hestia criteria. Adult subjects were randomized to early ED discharge on rivaroxaban or SOC. Primary outcome was total number of initial hospital hours, plus hours of hospitalization for bleeding or venous thromboembolism (VTE), 30 days after randomization. A 90-day composite safety endpoint was defined as major bleeding, clinically relevant nonmajor bleeding, and mortality. RESULTS: Of 114 randomized subjects, 51 were early discharge and 63 were SOC. Of 112 (98.2%) receiving at least one dose of study drug, 99 (86.8%) completed the study. Initial hospital LOS was 4.8 hours versus 33.6 hours, with a mean difference of 28.8 hours (95% confidence interval [CI] = -42.55 to -15.12 hours) for early discharge versus SOC, respectively. At 90 days, mean total hospital days (for any reason) were less for early discharge than SOC, 19.2 hours versus 43.2 hours, with a mean difference of 26.4 hours (95% CI = -46.97 to -3.34 hours). At 90 days, there were no bleeding events, recurrent VTE, or deaths. The composite safety endpoint was similar in both groups, with a difference in proportions of 0.005 (95% CI = -0.18 to 0.19). Total costs were $1,496 for early discharge and $4,234 for SOC, with a median difference of $2,496 (95% CI = -$2,999 to -$2,151). CONCLUSIONS: Low-risk ED PE patients receiving early discharge on rivaroxaban have similar outcomes to SOC, but fewer total hospital days and lower costs over 30 days. PMID- 29757491 TI - Evaluation of a hepatitis C clinical care coordination programme's effect on treatment initiation and cure: A surveillance-based propensity score matching approach. AB - Hepatitis C (HCV) is a viral infection that if left untreated can severely damage the liver. Project INSPIRE was a 3 year HCV care coordination programme in New York City (NYC) that aimed to address barriers to treatment initiation and cure by providing patients with supportive services and health promotion. We examined whether enrolment in Project INSPIRE was associated with differences in HCV treatment and cure compared with a demographically similar group not enrolled in the programme. INSPIRE participants in 2015 were matched with a cohort of HCV infected persons identified in the NYC surveillance registry, using full optimal matching on propensity scores and stratified by INSPIRE enrolment status. Conditional logistic regression was used to assess group differences in the two treatment outcomes. Two follow-up sensitivity analyses using individual pair matched sets and the full unadjusted cohort were also conducted. Treatment was initiated by 72% (790/1130) of INSPIRE participants and 36% (11 960/32 819) of study-eligible controls. Among initiators, 65% (514/790) of INSPIRE participants compared with 47% (5641/11 960) of controls achieved cure. In the matched analysis, enrolment in INSPIRE increased the odds of treatment initiation (OR: 5.25, 95% CI: 4.47-6.17) and cure (OR: 2.52, 95% CI: 2.00-3.16). Results from the sensitivity analyses showed agreement with the results from the full optimal match. Participation in the HCV care coordination programme significantly increased the probability of treatment initiation and cure, demonstrating that care coordination for HCV-infected individuals improves treatment outcomes. PMID- 29757492 TI - Investigation of Variations in the Human Urine Metabolome amongst European Populations: An Exploratory Search for Biomarkers of People at Risk-of-Poverty. AB - SCOPE: According to Eurostat 2016, approximately 119 million European citizens live at-risk-of-poverty (ROP). This subpopulation is highly diverse by ethnicity, age, and culture in the different EU states, but they all have in common a low income that could represent an increased risk of nutrient deficiencies due to poor nutritional habits. This study aims to investigate the human urine metabolome in the search of common biomarkers representing dietary deficiencies amongst European populations at ROP. METHODS AND RESULTS: 2732 urine samples were collected from 1391 subjects across five different European countries, including the United Kingdom, Finland, Italy, Lithuania, and Serbia, and analyzed using 1 H NMR spectroscopy. The resulting urine metabolome data were explored according to study design factors including economic status, country, and gender. CONCLUSION: Partitioning of the effects derived from the study design factors using ANOVA simultaneous component analysis (ASCA) revealed that country and gender effects were responsible for most of the systematic variation. The effect of economic status was, as expected, much weaker than country and gender, but more pronounced in Lithuania than in other countries. Citrate and hippurate were among the most powerful ROP biomarkers. The possible relationship between these markers and nutritional deficiencies amongst the ROP population is discussed. PMID- 29757493 TI - Egg Yolk Provides Th2 Adjuvant Stimuli and Promotes Sensitization to Egg White Allergens in BALB/c Mice. AB - SCOPE: Egg is the second most frequent source of allergic reactions in children. Egg yolk (EY) amounts to one-third in weight of a fresh whole egg, but its contribution to egg allergy has not been investigated in depth. This study assesses whether EY influences the capacity of egg white (EW) to sensitize and trigger allergic responses. METHODS AND RESULTS: BALB/c mice were exposed to EW, EY, and their mixture, using models of orally (with and without adjuvant) and adjuvant-free intraperitoneally induced allergy. In vitro assays were also conducted to examine epithelial and dendritic cell (DC) functions. Results showed that EY played a role during the sensitizing phase of allergy. EY exerted local Th2-biasing effects through the upregulation of intestinal IL-33 expression and it also favored Th2 polarization directly during DC presentation of allergens to T cells. CONCLUSION: The results obtained reveal that EY provides Th2-adjuvant stimuli to the immune system that may increase the susceptibility to develop egg allergy. The joint administration of EW and EY may be a trigger for initiation or maintenance of egg allergy with implications in prevention strategies regarding egg introduction in the diet of susceptible children. PMID- 29757494 TI - Multifunctional Smart Skin Adhesive Patches for Advanced Health Care. AB - A skin adhesive patch is the most fundamental and widely used medical device for diverse health-care purposes. Conventional skin adhesive patches have been mainly utilized for routine medical purposes such as wound management, fixation of medical devices, and simple drug release. In contrast to traditional skin adhesive patches, recently developed patches incorporate multiple key functions of bulky medical devices into a thin, flexible patch based on emerging nanomaterials and flexible electronic technologies. Consequently, the meaning of the term "skin adhesive patch" becomes broader and smarter compared to the traditional term. This review summarizes recent efforts undertaken in the development of multifunctional advanced skin adhesive patches, and briefly describes future directions and challenges toward the next generation of smart skin adhesive patches for ubiquitous personalized health care. PMID- 29757495 TI - A 20-year and 46,000-specimen journey to Paris reveals the influence of reporting systems and passive peer feedback on pathologist practice patterns. AB - BACKGROUND: An important goal of The Paris System for Reporting Urinary Cytology (TPS) is to reduce unnecessary atypical diagnoses given to urinary tract cytology (UTC) specimens. Since implementation of TPS at the study institution in 2016, the institutional atypical rate has declined only slightly. The authors speculated that TPS might not have had an immediate impact because several faculty members were involved in TPS committees and because TPS contains elements that already had been integrated into institutional practice. To identify factors contributing to alterations in the institutional atypical rate, the authors examined their practice over the last 22 years. METHODS: UTC specimens submitted to the study laboratory between August 11, 1995, and August 10, 2017, were identified. Specimens were linked to the responsible pathologist, specimen diagnosis and type, association with high-grade urothelial carcinoma, and relevant cytomorphologic features. RESULTS: An increase in the institutional atypical rate occurred between 2002 and 2005. The atypical rate among individual pathologists also peaked during this same time. The increase coincided with an increase in the use of UTC and the arrival of a pathologist with a higher rate of atypical diagnoses. A substantial decrease in the institutional atypical rate occurred between 2005 and 2010 and coincided with the creation of the Johns Hopkins Hospital Template, the authors' first standardized reporting system for UTC specimens. CONCLUSIONS: The use of reporting systems (Johns Hopkins Hospital Template and TPS) has coincided with decreases in the institutional atypical rate at the study institution. An individual pathologist may influence the practice patterns of his or her colleagues, resulting in fluctuations in the institutional rate of atypia over time. Cancer Cytopathol 2018;126:381-9. (c) 2018 American Cancer Society. PMID- 29757496 TI - Skin temperature may not yield human brown adipose tissue activity in diverse populations. PMID- 29757497 TI - Effectiveness of a transition plan at discharge of patients hospitalized with heart failure: a before-and-after study. AB - AIMS: We evaluated the effectiveness of a multidisciplinary transition plan to reduce early readmission among heart failure patients. METHODS AND RESULTS: We conducted a before-and-after study in a tertiary internal medicine department, comparing 3 years of retrospective data (pre-intervention) and 13 months of prospective data (intervention period). Intervention was the introduction in 2013 of a transition plan performed by a multidisciplinary team. We included all consecutive patients hospitalized with symptomatic heart failure and discharged to home. The outcomes were the fraction of days spent in hospital because of readmission, based on the sum of all days spent in hospital, and the rate of readmission. The same measurements were used for those with potentially avoidable readmissions. Four hundred thirty-one patients were included and compared with 1441 patients in the pre-intervention period. Of the 431 patients, 138 received the transition plan while 293 were non-completers. Neither the fraction of days spent for readmissions nor the rate of readmission decreased during the intervention period. However, non-completers had a higher rate of the fraction of days spent for 30 day readmission (19.2% vs. 16.1%, P = 0.002) and for potentially avoidable readmission (9.8% vs. 13.2%, P = 0.001). The rate of potentially avoidable readmission decreased from 11.3% (before) to 9.9% (non completers) and 8.7% (completers), reaching the adjusted expected range given by SQLape(r) (7.7-9.1%). CONCLUSIONS: A transition plan, requiring many resources, could decrease potentially avoidable readmission but shows no benefit on overall readmission. Future research should focus on potentially avoidable readmissions and other indicators such as patient satisfaction, adverse drug events, or adherence. PMID- 29757499 TI - Silica Gel as a Promoter of Sequential Aza-Michael/Michael Reactions of Amines and Propiolic Esters: Solvent- and Metal-Free Synthesis of Polyfunctionalized Conjugated Dienes. AB - We present an efficient, simple, metal- and solvent-free silica-gel-promoted synthesis of functionalized conjugated dienes by sequential aza-Michael/Michael reactions by starting from commercially available primary amines and propiolic esters. The scope and usefulness of the method is demonstrated for 31 examples, including a range of propiolic esters, aliphatic amines, and differently substituted aromatic amines. For aliphatic amines, the products were obtained within 0.5 to 4 h in 52 to 85 % yield, compared with 3.5 to 22 h under classical solution-phase synthesis, which proceeds with similar or lower yields. The method was found to be particularly useful for weakly nucleophilic aromatic amines, which provided products in 21 to 73 % yield over 2.5 to 9.5 h compared with yields of 0 to 49 % over 1 to 6 d under standard solution-phase conditions, and for more hydrophobic esters that gave products in yields of 47 to 79 % over 1 to 3 h compared with 0 to 45 % over 4 to 114 h in solvent. PMID- 29757498 TI - Clinical determinants of successful weaning from extracorporeal membrane oxygenation in patients with fulminant myocarditis. AB - AIMS: Patients with fulminant myocarditis (FM) often present with cardiogenic shock and require mechanical circulatory support, including extracorporeal membrane oxygenation (ECMO) and ventricular assist device (VAD) implantation. This study sought to clarify the determinants of successful weaning from ECMO in FM patients. METHODS AND RESULTS: We studied 37 consecutive FM patients supported by ECMO as the initial form of mechanical circulatory support between January 1995 and December 2014 in our hospital. Twenty-two (59%) patients were successfully weaned from ECMO, while 15 (41%) were not. There were significant differences in levels of peak creatine kinase and those of its MB isoform (CK MB), left ventricular posterior wall thickness (LVPWT), and prevalence of cardiac rhythm disturbances. Receiver operating characteristic curve analysis revealed that a peak CK-MB level of 185 IU/L and LVPWT of 11 mm were the optimal cut-off values for predicting successful weaning from ECMO (areas under the curve, 0.89 and 0.85, respectively). During the follow-up [median 48 (interquartile range 8 147) months], 83% of FM patients who were weaned from ECMO survived, with preserved fractional shortening based on echocardiography. Of the 15 FM patients who were not weaned from ECMO, nine bridged to VAD, and only two were successfully weaned from VAD and survived. CONCLUSIONS: These results indicate that myocardial injury, as evidenced by CK-MB and LVPWT, and prolonged presence of cardiac rhythm disturbances are important clinical determinants of successful weaning from ECMO. PMID- 29757500 TI - Immunohistochemistry for histone H3G34W and H3K36M is highly specific for giant cell tumor of bone and chondroblastoma, respectively, in FNA and core needle biopsy. AB - BACKGROUND: Diagnosing giant cell-rich bone tumors can be challenging on limited biopsies. H3 histone family member 3A (H3F3A) (G34W/V/R/L) mutations are present in the majority of giant cell tumors (GCTs) of bone and H3 histone family member 3B (H3F3B) (K36M) mutations are present in nearly all chondroblastomas, but are absent in histologic mimics. Mutation-specific immunohistochemistry (IHC) is highly specific for GCT and chondroblastoma in surgical excisions. The objective of the current study was to validate H3G34W and H3K36M IHC in the diagnosis of giant cell-rich bone tumors on fine-needle aspiration and core needle biopsy specimens. METHODS: IHC was performed using monoclonal antibodies against histone H3.3 G34W and K36M in GCTs of bone (26 cases, including 2 malignant cases), GCT of Paget disease (1 case), chondroblastoma (8 cases), aneurysmal bone cyst (7 cases), and osteosarcoma (13 cases) with available fine-needle aspiration and/or core needle biopsy specimens from 2 institutions. H3F3A and H3F3B Sanger sequencing was performed on all 4 H3G34W IHC-negative GCTs. RESULTS: IHC for H3G34W was positive in 22 of 26 GCTs (85%) and negative in all histologic mimics. IHC for H3K36M was positive in all 8 chondroblastomas and negative in all histologic mimics. IHC results were concordant between biopsy and surgical specimens in 152 of 158 samples (96%). Sequencing identified alternate H3F3A G34L and G34V mutations in 1 IHC-negative GCT each, but no mutation was found in the remaining 2 cases. CONCLUSIONS: H3G34W and H3K36M IHC is highly specific for GCT and chondroblastoma, respectively, among giant cell-rich bone tumors, and is useful for confirming the diagnosis in limited biopsies. The presence of alternate H3F3A mutations accounts for the H3G34W IHC negativity in a subset of GCT of bone cases. Cancer Cytopathol 2018. (c) 2018 American Cancer Society. PMID- 29757501 TI - Important considerations for the utilisation of methanolysis in steroid analysis. AB - The effective analysis of anabolic-androgenic steroids in urine usually requires a suitable deconjugation method for the analysis of phase II metabolites such as sulphates and glucuronides. Acid hydrolysis using methanolysis is one adopted method of deconjugation that efficiently and rapidly cleaves both sulphates and glucuronides contemporaneously. The formation of artefactual by-products is a known disadvantage of this harsh method. However, the possible promotion of deuterium-hydrogen exchange of isotopically labelled internal standards has received little attention in the literature. This report demonstrates a complete deuterium-hydrogen exchange from deuterium labelled D9 -progesterone to progesterone driven by the acidic conditions of the methanolysis. The likely mechanisms of this exchange reaction are postulated, and the results compared to other deuterated steroids. This finding highlights the importance for careful consideration when selecting labelled internal standards in a conjunction with methanolysis. PMID- 29757502 TI - Pest occurrence of Aedes rossicus close to the Arctic Circle in northern Sweden. AB - Major nuisance species are found among the floodwater mosquitoes and snow-pool mosquitoes, with the former being the main reason for mosquito control in most areas. Nuisance species vary with the area, and previous reports from northern areas conclude that the nuisance is most often caused by snow-pool mosquitoes. We investigated the mosquito fauna and abundances of host-seeking females using CDC traps baited with carbon dioxide, in Overtornea city near the Arctic Circle in northern Sweden, after earlier complaints about massive mosquito nuisance. The abundance of host-seeking female mosquitoes was high in 2014, with a maximum of ~15,400 individuals per CDC trap night, of which 89% was the floodwater mosquito Aedes rossicus. Surprisingly, the main nuisance species was a floodwater mosquito, occurring at the northernmost location it has ever been recorded in Sweden. Our report is probably the first documentation of such large numbers of Aedes rossicus in any locality and probably the first documentation of a severe floodwater mosquito nuisance near the Arctic Circle. Given the historical data on river discharge in the area, the nuisance is recurrent. We conclude that in northern localities, as well as in more southern localities, production of floodwater mosquitoes is a natural component of the floodplain fauna of rivers with a fluctuating water flow regime. Also, the floodwater mosquitoes Aedes sticticus and Aedes vexans were found north of their formerly known distribution in Sweden. PMID- 29757503 TI - Effects of scarcity and excess of larval food on life history traits of Aedes aegypti (Diptera: Culicidae). AB - Few studies have assessed the effects of food scarcity or excess on the life history traits of Aedes aegypti (L.) (Diptera: Culicidae) independently from larval density. We assessed immature survival, development time, and adult size in relation to food availability. We reared cohorts of 30 Ae. aegypti larvae from newly hatched to adult emergence with different food availability. Food conditions were kept constant by transferring larvae each day to a new food solution. Immature development was completed by some individuals in all treatments. The shortest development time, the largest adults, and the highest survival were observed at intermediate food levels. The most important effects of food scarcity were an extension in development time, a decrease in the size of adults, and a slight decrease in survival, while the most important effects of food excess were an important decrease in survival and a slight decrease in the size of adults. The variability in development time and adult size within sex and treatment increased at decreasing food availability. The results suggest that although the studied population has adapted to a wide range of food availabilities, both scarcity and excess of food have important negative impacts on fitness. PMID- 29757504 TI - A comparison of the Nzi, Horse Pal(r) and Bite-Lite(r) H-traps and selected baits for the collection of adult Tabanidae in Florida and North Carolina. AB - Despite the veterinary and medical importance of horse flies, deer flies, and yellow flies, only a few trap types have been evaluated to monitor adult population dynamics. Currently, three trap types are being utilized (H-trap, Horse Pal(r) (HP), and Nzi trap), but no head-to-head comparisons have been reported. Thus, we conducted comparative trapping studies in Florida and North Carolina. At two study sites in Florida, the efficacy of all three trap types was compared, but only the H-trap and HP were compared in North Carolina. Although trap type was significant at all sites, the trap type which caught the most specimens was not the same. In Florida at the Lower Suwannee Wildlife Refuge (LSWR) site, the H-trap caught the most specimens (2,006), followed in decreasing order by Nzi (938) and HP (541). At the Cedar Ridge Ranch site, the Nzi caught significantly more specimens (1,439) than the H-trap (215) and HP (161), which were not significantly different from each other. In North Carolina, the H-trap caught approximately twice as many specimens as the HP (1,458 vs 720). These trap comparison studies were followed up by a study on the efficacy of various bait combinations: (No Bait (NB), dry ice only (DI), Trap Tech Lure (TTL) only, and DI + TTL), which was conducted only at the two Florida sites with H-traps. At both sites, bait combinations significantly affected trap collections. One pattern (DI +TTL > DI > TTL > NB) was recorded at the LSWR, while at the Cedar River Ranch the pattern was DI > DI +TTL > TTL > NB. Our data showed that trap type and bait combination significantly influence overall adult tabanid abundance as well as individual species composition. PMID- 29757505 TI - Diversity, distribution, abundance, and feeding pattern of tropical ornithophilic mosquitoes. AB - Bird-biting mosquitoes act as bridge vectors of diverse pathogens of emerging infectious diseases. In this study, we report for the first time the abundance, diversity, distribution, and feeding pattern of bird-biting mosquitoes on an island where avifaunal diversity is rich. Monthly mosquito collections were done at six different habitats in three different climatic zones using bird-baited traps over a year. Collected mosquitoes were identified using morphological and molecular tools. A total of 2,655 bird-biting mosquitoes of eight genera and 25 species were identified. Of these, 52% were Culex species, which represents 35% of the Culex species in the country. The most abundant species were Culex sitiens, Cx. pseudovishnui, Cx. nigropunctatus and Cx. quinquefasciatus, whereas the latter two were common to all habitats. The highest abundance was reported in lowland forests (49.6%), while it was lowest in highland forests (22.3%). Highest species similarity was reported from highland forests. Seasonal variations of the most abundant species were significantly different in selected habitats (p< 0.05). Two distinct biting peaks were identified, from 06:00 to 21:00 and 22:00 to 02:00. The biting nature of identified ornithophilic mosquitoes suggests the potential vector status of these mosquitoes. PMID- 29757507 TI - Mosquito traps for urban surveillance: collection efficacy and potential for use by citizen scientists. AB - Mosquito-borne diseases are a pervasive public health problem on a global scale, and effective management of them requires well-designed surveillance programs for both vectors and pathogens. Mosquito traps are a common component of such programs, and their reach can be expanded by engaging citizen scientists. In this study in a southern Australian city, we compared the mosquito collection efficacy of two types of traps and assessed their suitability for use in citizen science programs. BG Sentinels and BG Gravid Aedes Trap (BG-GAT) traps both collected Aedes and Culex species in similar proportions, albeit with the former collecting approximately nine times as many mosquitoes. However, BG Sentinels have a greater per unit cost than BG-GATs and are restricted to deployment near power outlets. Importantly, despite being devised for collection of Aedes (Stegomyia) dengue vectors (such as Aedes aegypti), both traps can be effectively used in temperate climates for collection of a range of mosquito species. These traps could conceivably be used in citizen science programs to enhance the reach of surveillance at reduced cost. PMID- 29757506 TI - Controversies over the scientific name of the principal mosquito vector of yellow fever virus - expediency versus validity. AB - The history of the scientific name of the yellow fever mosquito, the vector of yellow fever virus, ranges from 1757 to the early twenty-first century. In his 1757 work Iter Palaestinum, Frederic Hasselquist gave the name Culex aegypti to a mosquito species responsible for fierce attacks on humans in Egypt. That name was never later ascribed to Hasselquist as author, but to Linnaeus, although the name never appeared in any of Linnaeus' publications. In Cuba, at the end of the nineteenth century, the vector of the unknown infectious agent of yellow fever was first identified as Culex mosquito and later more validly named Stegomyia fasciata. Mosquito taxonomists differed strongly about the name of the mosquito through much of the twentieth century. Interventions by the International Commission on Zoological Nomenclature imposed a biologically invalid specific name, and in the early twenty-first century a phylogenetic analysis of the culicid tribe Aedini restored the genus Stegomyia from a century earlier. That action was short-lived. A phylogenetic reassessment resulted in the return of Stegomyia to subgeneric rank in Aedes; thus, the name of the yellow fever mosquito survives in the traditional classification of convenience as the trinomial Aedes (Stegomyia) aegypti (Linnaeus). PMID- 29757508 TI - Parasite load and new soft tick record (Ixodida: Argasidae) on the bat species Balantiopteryx plicata and Pteronotus parnellii in Oaxaca, Mexico. PMID- 29757509 TI - Diel patterns of Aedes aegypti (Diptera: Culicidae) after resurgence in St. Augustine, Florida as collected by a mechanical rotator trap. PMID- 29757510 TI - Attraction of Culex pipiens to uropygial gland secretions does not explain feeding preference for American robins. AB - Culex pipiens, the endemic mosquito vector of West Nile virus in eastern North America, is responsible for maintenance of the virus in avian reservoir hosts, the most important of which appears to be the American robin. One reason for the greater involvement of robins is believed to be the feeding preference of Cx. pipiens, however, the basis of this preference is not understood. We tested the hypothesis that the species-specific chemical profile of avian uropygial gland secretions are used by Cx. pipiens as cues to locate birds and, therefore, may contribute to the observed feeding preferences. We used gas chromatography-mass spectrometry to identify the semi-volatile components of the uropygial gland secretions of American robins and two other common reservoir host species, the house sparrow and European starling. We found that the chemical composition of the robin secretions was different from those of the sparrows and starlings. Through behavioral choice trials conducted in a dual-port olfactometer, we also found that Cx. pipiens did not prefer the secretions of robins over the other two species. Surprisingly, however, we found that Cx pipiens were more often attracted to live starlings over robins and to the secretions of starlings over those of robins. PMID- 29757511 TI - Ixodes ricinus parasitism of birds increases at higher winter temperatures. AB - Increasing winter temperatures are expected to cause seasonal activity of Ixodes ricinus ticks to extend further into the winter. We caught birds during winter months (November to February) at a site in the west of Scotland over a period of 24 years (1993-1994 to 2016-2017) to quantify numbers of attached I. ricinus and to relate these to monthly mean temperature. No adult ticks were found on any of the 21,731 bird captures, but 946 larvae and nymphs were found, with ticks present in all winter months, on 16 different species of bird hosts. All ticks identified to species were I. ricinus. I. ricinus are now active throughout the year in this area providing temperature permits. No I. ricinus were present in seven out of eight months when the mean temperature was below 3.5o C. Numbers of I. ricinus attached to birds increased rapidly with mean monthly temperatures above 7o C. Winter temperatures in Scotland have been above the long-term average in most years in the last two decades, and this is likely to increase risk of tick-borne disease. PMID- 29757512 TI - Description of a new species of Nesotriatoma Usinger, 1944 from Cuba and revalidation of synonymy between Nesotriatoma bruneri (Usinger, 1944) and N. flavida (Neiva, 1911) (Hemiptera, Reduviidae, Triatominae). AB - Nesotriatoma confusa sp. nov. (Hemiptera, Reduviidae, Triatominae) is described based on specimens from Cuba. From one male, one female, and eleven nymphs of a then-undescribed species of Nesotriatoma collected in Cuba, a colony was formed and its specimens were used to describe N. confusa sp. nov. Characters were observed on the head, thorax, abdomen, female external genitalia, and male genitalia with optical microscopy and scanning electron microscopy. We concluded that N. bruneri (Usinger, ) was indeed a synonym of N. flavida (Neiva, ) as previously proposed. PMID- 29757514 TI - Two novel mutations in the voltage-gated sodium channel associated with knockdown resistance (kdr) in the dengue vector Aedes aegypti in Vietnam. PMID- 29757513 TI - Genetic characters of the globally spread tiger mosquito, Aedes albopictus (Diptera, Culicidae): implications from mitochondrial gene COI. AB - There has been a rapid global expansion of Aedes albopictus, with varying biological characters and vector competence according to geographic and evolutionary origins of the invading populations. Based on mitochondrial gene cytochrome c oxidase I (COI) sequences from both native and invasive regions, genetic characters of Ae. albopictus were examined. Phylogenetic analyses indicate lineage differentiation in the original areas, and only one of the lineages was involved in the worldwide expansion. Multiple invasions were detected in populations in Africa and the Americas, whereas no obvious genetic structure was found in European populations. Asian populations showed high genetic diversity, with 42 private haplotypes being detected in this region. In addition, other genetic divergence has occurred, as in Japan and Pakistan, where populations showed significant differences from all other Asian populations. Altogether, populations in China displayed the highest genetic diversity (Hd=0.946, pi=1.609%) and significantly negative Tajima's D (-1.88475) and Fu's FS (-24.43873). This result may be attributable to the insecticide interventions used to control dengue epidemics. PMID- 29757515 TI - A new record of Anopheles (Stethomyia) kompi Edwards from Sergipe, northeastern Brazil. PMID- 29757516 TI - Species composition and nocturnal activity of phlebotomine sand flies (Diptera: Psychodidae) inhabiting a limestone cave in Thailand. AB - We investigated the nocturnal activity of cave-dwelling sand flies at different time intervals and determined their species composition and seasonal variation. Sand flies were captured on one night each month using CDC light traps from 18:00 06:00 with the collecting bag being changed every two h between February, 2010 and January, 2011. A total of 18,709 individuals, including 10,740 males and 7,969 females, was collected. The overall ratio between male and female specimens was 1:0.74. The collected specimens included 14 species from four genera, Chinius, Idiophlebotomus, Phlebotomus, and Sergentomyia. Sergentomyia phadangensis was the most abundant species (comprising 31.9% of the collected individuals), followed by Se. anodontis (22.8%) and Ph. mascomai (18.2%). The highest number of specimens was collected in July (15.6%), followed by May (15.5%) with the peak of collection recorded at the time interval of 00:01-02:00, followed by 22:01-00:00. However, there were no significant differences observed among time intervals of sand fly collections (p=0.154). Observations of the nocturnal activity of male and female sand flies throughout the night suggest that phlebotomine sand flies show the greatest activity level after midnight. PMID- 29757517 TI - Modeling a single season of Aedes albopictus populations based on host-seeking data in response to temperature and precipitation in eastern Tennessee. AB - In the southern Appalachia of the U.S., Aedes mosquitoes maintain and transmit La Crosse virus (LACV) which causes La Crosse encephalitis, a neuroinvasive disease of children. In response to mosquito outbreaks, communities organize prevention, detection, and response measures that are dependent on local characteristics of the mosquito population and the community. Knowing Ae. albopictus is an accessory vector of LACV and a nuisance biter, our objective was to build a system of ordinary differential equations to model dynamics in a single season using our data and readily available environmental variables that can reflect the abundance and activity of Ae. albopictus. Consequently, we built an Ae. albopictus single season mathematical model for eastern Tennessee to fit our 2013 mosquito collection data in order to understand the population fluctuations. We included precipitation, temperature, and rate of change of temperature in the model because Aedes mosquitoes oviposit desiccant tolerant eggs with peak activity occurring over 26 degrees C and those data are readily available and used frequently as forecast predictors. Our ordinary differential equation model accurately fits the data and facilitates predictions and better understanding of Ae. albopictus populations in southern Appalachia. PMID- 29757519 TI - Re-examination of the taxonomic status of Anopheles hyrcanus and An. pseudopictus using a multilocus genetic approach. PMID- 29757518 TI - Mosquito species composition and phenology (Diptera, Culicidae) in two German zoological gardens imply different risks of mosquito-borne pathogen transmission. AB - Due to their large diversity of potential blood hosts, breeding habitats, and resting sites, zoological gardens represent highly interesting places to study mosquito ecology. In order to better assess the risk of mosquito-borne disease agent transmission in zoos, potential vector species must be known, as well as the communities in which they occur. For this reason, species composition and dynamics were examined in 2016 in two zoological gardens in Germany. Using different methods for mosquito sampling, a total of 2,257 specimens belonging to 20 taxa were collected. Species spectra depended on the collection method but generally differed between the two zoos, while species compositions and relative abundances varied seasonally in both of them. As both sampled zoos were located in the same climatic region and potential breeding sites within the zoos were similar, the differences in mosquito compositions are attributed to immigration of specimens from surrounding landscapes, although the different sizes of the zoos and the different blood host populations available probably also have an impact. Based on the differences in species composition and the various biological characteristics of the species, the risk of certain pathogens to be transmitted must also be expected to differ between the zoos. PMID- 29757520 TI - Controlling Culex pipiens: antagonists are more efficient than a neonicotinoid insecticide. AB - Species vulnerability to pesticides depends on physiological sensitivity, the potential to recover, and the ecological context. We assessed the vulnerability of the mosquito Culex pipiens to a repeated treatment with thiacloprid in outdoor microcosms with and without antagonists (competitive and predatory invertebrates). Microcosms were treated repeatedly (three times) with thiacloprid at a concentration of 0.1, 1, or 10 ug/liter. In microcosms without antagonists, the abundance of Cx. pipiens larvae decreased moderately after the second and the third exposures to 10 ug/liter thiacloprid. In microcosms with antagonists, the abundance of Cx. pipiens larvae declined to approximately zero in the control group and the low concentration treatments during the five weeks of observation. By contrast, the abundance of Cx. pipiens larvae temporarily increased at 10 ug/liter thiacloprid after the second and third contamination. We explained this positive effect on the development of Cx. pipiens because of the decrease in competition due to the elimination of sensitive antagonists combined with the high recovery potential of Cx. pipiens. Based on these results, natural antagonists must be supported for the sustainable control of mosquitoes. PMID- 29757521 TI - Scanning electron microscopy of the eggs of Coquillettidia shannoni (Lane & Antunes, 1937) and Phoniomyia quasilongirostris (Theobald, 1907) (Diptera: Culicidae). PMID- 29757523 TI - The influence of ecological factors on mosquito abundance and occurrence in Galapagos. AB - We sampled mosquitoes across 18 sites established at different elevations and stretching from the north to the south of Isla Santa Cruz, Galapagos. Two commonly occurring species, Ae. taeniorhynchus and Cx. quinquefasciatus, were collected along with environmental variables characteristic of the trapping sites to assess their influence on mosquito abundance and occurrence in the dry season of 2015. We captured Ae. taeniorhynchus at 14 out of 18 sites and Cx. quinquefasciatus at low and high elevation sites on Santa Cruz. We utilized two generalized linear models; the first assessed the influence of environmental variables on abundances of Ae. taeniorhynchus and the second assessed the influence of these variables on the presence of Cx. quinquefasciatus. Populations of both mosquito species declined with elevation. Rainfall data were limited, as we sampled during the dry season of 2015. Distance to mangroves and maximum humidity were significant in influencing the abundance of Ae. taeniorhynchus, while maximum humidity was found to significantly influence the presence of Cx. quinquefasciatus. Both species occurred in sites where temperature, precipitation, and humidity should allow for mosquito development as well as parasitic development of the protozoan parasites that cause avian malaria. Further research involving year-round sampling of mosquitoes and accompanying meteorological data as well as experimental studies on vector competence are required to understand disease dynamics of parasites such as avian malaria in Galapagos. PMID- 29757522 TI - Evidence of natural Wolbachia infections and molecular identification of field populations of Culex pipiens complex (Diptera: Culicidae) mosquitoes in western Turkey. AB - Establishing reliable risk projection information about the distribution pattern of members of the Culex pipiens complex is of particular interest, as these mosquitoes are competent vectors for certain disease-causing pathogens. Wolbachia, a maternally inherited bacterial symbiont, are distributed in various arthropod species and can induce cytoplasmic incompatibility, i.e., reduced egg hatch, in certain crosses. It is being considered as a tool for population control of mosquito disease vectors. The Aegean region is characterized by highly populated, rural, and agricultural areas and is also on the route of the migratory birds. In this study, a fragment of the 658 bp of the mitochondrial cytochrome c oxidase subunit 1 (COI) gene, which includes the barcode region, was employed to differentiate Cx. pipiens complex species found in this region. Moreover, for the first time, the prevalence of Wolbachia endobacteria in these natural populations was examined using PCR amplification of a specific wsp gene. Our results revealed a widespread (more than 90%, n=121) presence of the highly efficient West Nile virus vector Cx. quinquefasciatus in the region. We also found that Wolbachia infection is widespread; the average prevalence was 62% in populations throughout the region. This study provided valuable information about the composition of Cx. pipiens complex mosquitoes and the prevalence of Wolbachia infection in these populations in the Aegean region. This information will be helpful in tracking mosquito-borne diseases and designing and implementing Wolbachia-based control strategies in the region. PMID- 29757524 TI - Mosquito (Diptera: Culicidae) grouping based on larval habitat characteristics in high mountain ecosystems of Antioquia, Colombia. AB - Information about mosquito ecology in the high mountain ecosystems of the Neotropical region is sparse. In general, few genera and species have been reported in these ecosystems and there is no information available on habitats and the mosquitoes occupying them. In the present study, specimens collected from NW Colombia in HME were grouped using larval habitat data via an Operational Taxonomic Unit (OTU) determination. A total of 719 mosquitoes was analyzed belonging to 44 OTUs. The analysis considered habitat features and clustered the specimens into six groups from A-F. Five of these included species from different genera, suggesting common habitat requirements. Group E with four genera, seven subgenera, and six species occupied the highest areas (above 3,000 m), whereas three groups (B, D, F) were detected at lower altitudes (1,960-2,002 m). Bromeliads were the most common larval habitat, with 47% (335/719) of the specimens; five genera, six subgenera, and eight species were identified and classified into 66% (29/44) of the OTUs. This work showed some similarities to the habitat requirements and provides a grouping system that constitutes an important baseline for the classification of mosquito fauna from high mountain ecosystems according to altitude and larval habitat. PMID- 29757525 TI - Entomological surveys of Lutzomyia flaviscutellata and other vectors of cutaneous leishmaniasis in municipalities with records of Leishmania amazonensis within the Braganca region of Para State, Brazil. AB - In southeast Amazon, Lutzomyia (Nyssomyia) flaviscutellata is the incriminated vector of Leishmania (Leishmania) amazonensis, a causative agent of zoonotic cutaneous leishmaniasis (CL). The optimal methods for surveying Lu. flaviscutellata were investigated in the Braganca region, northeast Para State, Brazil, selected for the presence of Le. amazonensis. The performances of modified Disney traps and CDC light traps were compared in four ecotopes within and around four village transects during the wet and dry seasons. The physiological age of female sand flies was estimated and natural infection by flagellates was evaluated by dissection. Disney traps were better for detecting the presence of Lu. flaviscutellata, while CDC traps performed well for detecting Lutzomyia (Nyssomyia) antunesi, suspected vector of Leishmania lindenbergi. The former was more abundant during the wet season, when female flies were naturally infected with Le. amazonensis. These findings identified the environments of local transmission. In order to improve surveys of Lu. flaviscutellata as part of integrated epidemiological surveillance of CL, our recommendations include focusing vector surveys with Disney traps on forest fragments where people work, during the seasonal peak of the vector. Further field studies are required to make model-based predictions of seasonal variations in the vectorial capacity of vector populations. PMID- 29757526 TI - Drivers of flea (Siphonaptera) community structure in sympatric wild carnivores in northwestern Mexico. AB - Host identity, habitat type, season, and interspecific interactions were investigated as determinants of the community structure of fleas on wild carnivores in northwestern Mexico. A total of 540 fleas belonging to seven species was collected from 64 wild carnivores belonging to eight species. We found that the abundances of some flea species are explained by season and host identity. Pulex irritans and Echidnophaga gallinacea abundances were significantly higher in spring than in fall season. Flea communities on carnivore hosts revealed three clusters with a high degree of similarity within each group that was explained by the flea dominance of E. gallinacea, P. simulans, and P. irritans across host identity. Flea abundances did not differ statistically among habitat types. Finally, we found a negative correlation between the abundances of three flea species within wild carnivore hosts. Individual hosts with high loads of P. simulans males usually had significantly lower loads of P. irritans males or tend to have lower loads of E. gallinacea fleas and vice-versa. Additionally, the logistic regression model showed that the presence of P. simulans males is more likely to occur in wild carnivore hosts in which P. irritans males are absent and vice-versa. These results suggest that there is an apparent competitive exclusion among fleas on wild carnivores. The study of flea community structure on wild carnivores is important to identify the potential flea vectors for infectious diseases and provide information needed to design programs for human health and wildlife conservation. PMID- 29757527 TI - Life history of two abundant populations of Dipetalogaster maximus (Uhler, 1894) (Hemiptera: Reduviidae: Triatominae) in northwestern Mexico. AB - We focused on the analysis of biological parameters of two different abundant populations of Dipetalogaster maximus (Uhler) (Hemiptera: Reduviidae: Triatominae) from northwestern Mexico. The biological parameters were related to hatching of eggs, life cycle, and meal needed for molting by each instar of two populations from environmentally similar areas (El Fandango and San Dionisio) with a similar number of available hosts as blood meal sources. The D. maximus populations from the two locations were evaluated and compared. No significant differences (P>0.05) were recorded for the average hatching time of the two cohorts. The median egg-to-adult development time and the number of blood meals at each nymphal group were significantly shorter (P<0.05) for the El Fandango cohort. The number of obtained females at the end of the cycles, number of eggs laid, and rate of egg hatching were significantly higher (P<0.05) for the El Fandango cohort. These results contribute to the estimation of abundances of the studied populations of D. maximus in areas where many tourists go for camping and have an increased risk of being bitten and infected by this species. PMID- 29757529 TI - Fibre-based scaffolding techniques for tendon tissue engineering. AB - Tendon refers to a band of tough, regularly arranged, and connective tissue connecting muscle and bone, transferring strength from muscle to bone, and enabling articular stability and movement. The limitations of natural tendon grafts motivate the scaffold-based tissue engineering (TE) approaches, which aim to build patient-specific biological substitutes that can repair the damaged or diseased tissues. Advances in engineering and knowledge of chemistry and biology have brought forth numerous fibre-based technologies, including electrospinning, electrohydrodynamic jet printing, electrochemical alignment technique, and other fibre-assembly technologies, which enable the fabrication of tendon tissue structure in 3-dimension. Textile techniques such as knitting and braiding have also been performed based on the fibrous materials to produce more complex structure. These scaffolds showed great similarity with native tendons in architectural features, mechanical properties, and facilitate biological functionality such as cellular adhesion, ingrowth, proliferation, and differentiation towards tendon tissue. Herein, we review the techniques that have been used to assemble fibres into scaffolds for tendon TE application. The morphological structures, mechanical properties, materials, degradation characteristics, and biological activities of the induced scaffolds were compared. The existing challenges and future prospects of fibre-based tendon TE have also been discussed. PMID- 29757528 TI - Downregulation of HOXA13 sensitizes human esophageal squamous cell carcinoma to chemotherapy. AB - BACKGROUND: Chemoresistance often develops in esophageal squamous cell carcinoma (ESCC), leading to poor prognosis. HOX genes play a crucial role in embryonic development and cell differentiation. Studies have recently linked HOX with chemoresistance, thus we explored whether HOXA13 is involved in ESCC chemoresistance. METHODS: One hundred thirty-one ESCC patients who received neoadjuvant chemotherapy were enrolled. HOXA13 expression was examined by immunohistochemistry. RNA interference was used to knock down the HOXA13 expression in KYSE70 and transfected HOXA13 plasmid to overexpress HOXA13 in KYSE510 cells. We examined half-maximal inhibitory concentration of cisplatin, apoptosis, and epithelial-to-mesenchymal transition (EMT) in ESCC cell lines with different HOXA13 expression levels by cell counting kit-8, flow cytometry, and transwell analysis. RESULTS: The median survival of patients with high HOXA13 expression was significantly shorter than those with low expression (P = 0.027). HOXA13 was associated with worse tumor regression grade (P = 0.009). Low HOXA13 expressed cells decreased the half-maximal inhibitory concentration of cisplatin (P < 0.05), increased cisplatin-induced apoptosis (P < 0.05), and decreased EMT (P < 0.05) compared with high HOXA13 expressed cells. In low HOXA13 expressed cells, cleaved caspase-3 and cleaved PARP expression induced by cisplatin increased, while expression of E-cadherin and Snail protein, markers of EMT, was upregulated and downregulated, respectively. EMT decreased in low HOXA13 expressed cells. CONCLUSION: High HOXA13 expression was associated with inferior tumor regression grade and poor overall survival in ESCC patients treated with neoadjuvant chemotherapy. HOXA13 increased cisplatin-resistance and promoted EMT in ESCC cells. PMID- 29757530 TI - NEW FOR YOU! These innovative products aim to help make diabetes self-management easier. PMID- 29757531 TI - THE TRUTH ABOUT DIABULIMIA. PMID- 29757532 TI - What's New in Diabetes Research? AB - The drive to discover new and innovative solutions for managing diabetes is international. The Diabetes UK Professional Conference, held in Glasgow in March 2016, presented many of these advances and developments, including new insights into diabulimia; the role of mindfulness in diabetes management; risk factors for Type 2 diabetes in the younger generations; and new discoveries in glucose monitoring and management. Through interviews conducted with the presenters of these topics, Dr. Nicola Davies explores the latest innovations in diabetes research. PMID- 29757533 TI - THE MISSED DIAGNOSIS OF TYPE 1 DIABETES. When It's Not Just the Stomach Flu. PMID- 29757534 TI - CLOSED-LOOP INSULIN DELIVERY. PMID- 29757535 TI - SENSING THE BIG PICTURE WITH CONTINUOUS GLUCOSE MONITORING. AB - When you have diabetes, monitoring your blood glucose is a crucial part of your treatment plan. Knowing your blood glucose values can help you avoid short-term problems such as hyperglycemia (high blood glucose) and hypoglycemia (low blood glucose). Ongoing optimal blood glucose control can help you prevent or delay long-term diabetes complications such as diabetes-related eye disease, kidney disease and nerve damage. PMID- 29757536 TI - Rice and Rice Mixes. PMID- 29757537 TI - Is Metabolic Surgery for You? PMID- 29757538 TI - Take 5. Workplace Ergonomics and Strength Training for the Upper Body. PMID- 29757539 TI - GETTING TO KNOW YOU. ERIC PASLAY. AB - If you're a country music fan, you've probably heard of Eric Paslay; 33, a Nashville-based platinum-selling singer/songwriter. After starting to play guitar at age 15, Paslay knew by 18 that music was his path. In 2011, he signed with EMI Records Nashville, and since then he has had five number one hits, including four recorded by other artists such as Rascal Flatts as well as "Friday Night," the lead single from his self-titled debut album. His latest album, "Dressed in Black," includes the single "Angels in This Town." PMID- 29757541 TI - A Study of Clinical, Bacteriological & Histopathological Correlation in Leprosy Cases attending a Government Medical College in Western Odisha: Some Observations. AB - The study was undertaken in VSS Institute of Medical Sciences to observe the clinical, bacteriological and histological diagnosis of leprosy patients attending the hospital who consented to undergo slit skin smear (SSS) examination, punch biopsy and participate in the study. Fifty leprosy patients aged 5 to 70 years, which included 41 male and 9 female patients participated in the study. These included 4 TT, 24 BT, 2 BB, 5 BL and 15 ILL clinically diagnosed patients as per the IAL classification (1982 ). SSS were undertaken from 4 sites, stained with ZN stain and BI calculated as per Ridley Scale. Four patients were skin smear negative all TT). Of the 24 BT patients enrolled in the study, 11 were skin smear negative while 13 were smear positive (BI ranging from 1+ to 4+); Both the BB cases, all 5 BL cases, and all the 15 LL cases were smear positive (BI range 2+ to 6+). Histologically there was complete parity and correlation in.the TT group, while the correlation was observed to be 83%, 50%, 60%, and 93% in the clinically diagnosed BT, BB, BL and LL patients respectively. The sample size in the study was small, however, the overall bacteriological skin smear negativity/positivity correlation was observed to be 53.6% for paucibacillary (TT+BT) disease and 100% for MB (BB, BL and LL) disease Histological correlation was 100%, 83%, 50%, 60% and 93% respectively for clinically diagnosed TT, BT, BB, BL and LL disease. A sizeable number of BT patients were found to be bacteriologically positive and were therefore being treated with lesser number of drugs as well duration under programme conditions, Although there is inter observer variation and overlapping of clinical and histological diagnosis in the borderline patients (BT, BB & BL), bacteriological and histological confirmation helps in deciding on adequate treatmeht and should be undertaken. PMID- 29757540 TI - Clinico-radiological Correlation of Bone Changes in Leprosy Patients Presenting with Disabilities/Deformities. AB - Leprosy is a medical - social disease, it is associated with stigma in the society due to the resulting deformities in some persons. Although stigma has decreased after the widespread use of MDT, some disabilities do occur which are mostly due to late initiation of treatment and inappropriate care. Besides the nerve and skin involvement bone changes have been reported to be common in leprosy. These bony changes need to be understood in the present MDT era specially in the context of clinical spectrum and duration of disease/ deformities. Fifty clinically diagnosed and histologically classified leprosy patients with deformities/ disabilities of either hands/feet/face who attended the OPD of Department of Dermatology, Venereology and Leprosy, Government Medical College, Amritsar were examined and evaluated in the study. Radiological examination of hands, feet and skull was done in each case and the bone changes in hands and feet; and skull and paranasal sinus changes were correlated with clinical parameters. Bone changes were observed in 90% of cases radiologically. Specific bone changes in hands and feet, non-specific bone changes in hands, feet, skull and paranasal sinuses were seen in 66%, 82% and 32% of cases respectively. Common specific bone changes in hands and feet observed were primary periostitis (14%), honey combing (46%), bone cyst (36%), thinning and irregularity of cortex (28%) and area of bone destruction (20%); Among the non specific bone changes observed were contracted fingers/claw hands/claw toes (64%) and absorption of terminal phalanges (40%). The maxillary sinus, and paranasal sinus changes were the most common radiological findings observed in skull. The study of the radiological changes may help the clinicians to understand the gravity of the situation and undertake steps for timely prevention of permanent loss of function and the occurrence of deformities and disabilities. PMID- 29757542 TI - Evaluation of Myelin Sheath Marker Krox-20 for Detection of Early Disability in Leprosy. AB - Early diagnosis of nerve damage in leprosy is quite important for preventing the deformities. With an aim to find a good marker we have investigated Krox-20 as early peripheral nerve damage indicator in leprosy. Ambulatory patients of Kediri Leprosy Hospital, Malang, Indonesia have been studied. Degree of disability was measured based on WHO's criteria. Immunohistochemistry was.used to study the expression of Krox-20 on Schwann cells on nerve twigs in skin biopsies from leprosy cases. Receiver Operating Characteristic (ROC) curve was used to determine cut off value. Of all 79 leprosy patients studied, 36 patiens had degree of disability 0, and 43 patients had degree of disability 1. Analysis of ROC curve shown that cut off value for Krox- 20, was 8 and the cases in whom degree of disability was 0 (zero) had significantly higher mean values than those with degree of disability 1 (mean: 12.56 vs 4.24 (p<0.05)). Krox-20 appears to be a potentially good biomarker to identify early peripheral nerve damage in leprosy. PMID- 29757543 TI - Profile of Childhood Leprosy Cases Attending a Tertiary Care Centre. AB - In spite of 33 years of use of Multidrug Treatment (MDT) implemented by National Leprosy Eradication Programme (NLEP), leprosy continues to be a major public health problem in some regions of India. Recent increase in number of cases of leprosy at our tertiary care centre especially in children encouraged us to undertake a descriptive study for last 5 years. Records were analysed to describe the clinical pattern of leprosy in children below 15 years pertaining to the period 2010 to 2014. Amongst 664 leprosy cases registered during 2010 to 2014, 86 were found to be children between 0-15 years of age (13.1%). The number of newly detected children with leprosy increased from 7 cases (8%) in the year 2010 to 29 cases (34%) in the year 2014. Majority of patients of childhood category belonged to 10-15 years of age group 51/86 (59%), with a male preponderance. PB cases were significantly more (71%) than cases of MB (29%). Borderline tuberculoid leprosy was the commonest type seen (77%). Grade l and grade 2 deformity were observed in 8% and 6% of childhood cases respectively. 91% of these childhood cases had history of BCG vaccination: 21% of children had a contact in family or neighbourhood which shows the importance of asking the patients to bring family contacts specially children for examination or public health workers being asked to approach the families for check up of contacts. Active surveys/school surveys to find cases specially in female children should be considered. As this is a hospital based study it may be indicative of trends only which should be followed by properly designed field based studies. PMID- 29757544 TI - Histoid Leprosy Presenting with Keloid Like Lesions. AB - A 42 year old male presented with multiple, discrete, hyperpigmented, firm, non elastic, non tender papules and plaques on the posterior trunk of 5 months duration, resembling keloid. The patient had also a few skin colored papules on the anterior trunk and face. The sensations over the skin lesions were intact. The patient had glove and stocking type of anesthesia and bilaterally thickened, non tender peripheral nerve trunks. The slit skin smear for acid fast bacilli from the ear lobes, skin lesions and normal skin were highly positive for Mycobacterium leprae. A skin biopsy showed a well defined collection of spindle shaped histiocytes in the dermis packed with acid fast bacilli. We are presenting here a case of histoid leprosy presenting with keloid like lesions, probably the rarest presentation of histoid leprosy. PMID- 29757545 TI - Leprosy: A Great Mimicking Disease. AB - Leprosy may mask a variety of diseases. One such disease is systemic lupus erythematosus. The early differentiation between the two diseases is of utmost importance to institute appropriate treatment and reduce patient morbidity and mortality. Leprosy is a communicable, chronic granulomatous disease caused by Mycobacterium leprae. This clinically manifests predominantly with neurological and cutaneous features. However, it may also manifest with a variety of autoimmune phenomena indicative of autoimmune diseases, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis. Infection with Mycobocterium leprae not only mimics lupus flares, but possibly may also act as a trigger for lupus reactivation; however, its relationship is still not fully understood and explored. We report a case that was diagnosed as leprosy but retrospective analysis revealed that it was probablythe initial manifestations of Lupus. During hospitalization the patient suddenly developed hypoxia and was found to have pulmonary haemorrhage. He was successfully managed with steroids, Mycophenolatemofetil along with other supportive treatment. Our case highlights the rare presentation of pulmonary haemorrhage in a male lupus patient and focuses on leprosy mimicking lupus. PMID- 29757546 TI - Elastophagocytosis and Elastolysis in Leprosy. AB - Elastophagocytosis is the engulfment of the elastic fibres by the histiocytes, multinucleated giant cells, or both. The cutaneous lesions showing elastophagocytosis are annular elastolytic giant cell granuloma, actinic keratoses, persistent insect-bite reactions, elastosis perforans serpiginosa, foreign body granuloma. Occasionally, it may occur in infectious diseases like leprosy, granulomatous syphilis, North-American blastomycosis, bacterial folliculitis, and cutaneous leishmaniasis. We report a case of lepromatous leprosy with necrotic erythema nodosum leprosum with secondary anetoderma. Histopathology from the atrophic macule of anetoderma revealed periappendageal, perineural infiltration, elastophagocytosis and reduction in elastic fibres. PMID- 29757548 TI - [MEDICAL ASPECTS IN THE DIAGNOSIS AND TREATMENT OF ATTENTION DEFICIT/HYPERACTIVITY DISORDER]. PMID- 29757547 TI - Ultrasonographic Features of Ulnar Nerve Affected by Hansen's Disease. AB - Leprosy continues to be a major public health problem in some areas of our country. It predominantly afflicts peripheral nerves and skin and may lead to deformities. Social stigma as a result of deformities further plagues the situation. Prompt and early diagnosis coupled with adequate treatment, concurrent rehabilitative strategies if deformities do occur, and health education help to control the problem. Definitive diagnosis of leprosy has traditionally been based on assessment of slit skin smears (SSS) after AFB-staining and characteristic histopathology after biopsyof the lesion. However, recently, thickening of the peripheral nerves has been demonstrated by ultrasonography and this can be used as a sensitive tool to assess and measure enlargement of peripheral nerves, which are hallmarks for leprosy especially in clinical settings. In this report, the ultrasonographic findings of ulnar nerve enlargement due to leprosy in a fourteen year-old male patient are described. PMID- 29757549 TI - [Analysis of the efficacy and compliance of conventional immunotherapy and rush immunotherapy in patients with allergic rhinitis]. AB - Objective:To analyze the efficacy and compliance of conventional immunotherapy(CIT)and rush immunotherapy(RIT)in patients with allergic rhinitis.Method:This trial was a prospective study involved 404 patients with persistent AR who were allergic to house dust mite.328 patients were assigned to the conventional immunotherapy reaching the maintenance dose within 14 weeks,and 76 patients were assigned to the rush immunotherapy reaching the maintenance dose within 1 week.The visual analog scale(VAS)score and the patients' compliance were recorded during treatment and follow-up.Result:After CIT and RIT,the VAS score were significantly reduced in each group,but the decrement of VAS score of RIT group was more evident than that of CIT in half ayear(P<0.05).After 5 years follow-up,the VAS score of two groups was also significantly reduced.The rate of treatment continuation of CIT group in 1 year,2 years and 3 years were 18.5%,39.0% and 57.3%,higher than RIT group(11.8%,26.3%,42.1%),respectively.Conclusion:Both CIT and RIT were beneficial for allergic rhinitis patients,and the clinical efficacy lasts for at least 5 years.But RIT has the superiority of faster onset and better compliance. PMID- 29757550 TI - [Assessment of the horizontal semicircular canal function after cochlear implantation by video head impulse test and caloric test]. AB - Objective:To analyze the functional change of horizontal semicircular canals after cochlear implantation.Method:Eighteen patients were enrolled in this study.Their vestibular function was evaluated by using the caloric test and video head impulse test before and one week,one month after CI surgery,respectively.The unilateral weakness(UW),slow phase velocity(SPV)in caloric test and gain in video head impulse test(vHIT-G)were observed.Caloric test was abnormal when UW>25% or SPV mean<6 degrees /s,while vHIT was abnormal when vHIT-G<0.8.Result:The SPV of the implanted ear were[(10.36+/-8.01) degrees /s;(14.77+/-14.24) degrees /s]pre operatively,[(6.45+/-7.52) degrees /s;(5.14+/-4.67) degrees /s]1 week post operatively and[(6.05+/-3.86) degrees /s;(6.27+/-4.17) degrees /s]1 month post operatively.Statistically significant difference(P<0.05)was found between pre-and post-operative period.The vHIT-G of the implanted ear were(0.73+/-0.33)pre operatively,(0.65+/-0.32)1 week post-operatively and(0.71+/-0.36)1 month post operatively.There was no statistically significant difference of vHIT-G between preand post-operative period(P(pre-operative/1 week post-operative)=0.084,P(pre operative/1 month post-operative)=0.679).Four patients presented with vertigo and one of them manifested slight unsteadiness post-operatively.All symptoms resolved within 7 days.These symptoms had no correlate with age,gender,implantedear and results of vestibular test.Conclusion:Cochlear implantation can affect the horizontal semicircular canal function,and the video head impulse test and caloric test should be used in a complementary fashion. PMID- 29757552 TI - [The influence of sublingual immunotherapy on quality of life in children with allergic rhinitis]. AB - Objective:To analyze the impact of sublingual immunotherapy(SLIT)on the quality of life in children with allergic rhinitis.Method:Fifty children with allergic rhinitis who have received sublingual immunotherapy were enrolled in this study.Quality of life was evaluated via measurement of VAS score and rhinoconjunctivitis quality of life questionnaire(RQLQ)before and after treatment.Result:Twenty patients after treatment had complete remission,13 cases were partly alleviated and 17 cases had no response.The total effective rate was 66%.The Multi-VAS scores and Uni-VAS scores in each observation time point(at half a year,one year,two years after treatment)had statistically significant difference compared with that of pre-treatment with SLIT(P<0.05).According to RQLQ scores,the quality of life,nasal symptoms,conjunctiva symptoms,non nasal(ocular)symp-toms,behaviors and emotional responses were greatly improved in each time point compared with that of pretreatment(P<0.05).Symptomatic treatment scores in each time point after treatment were significantly different and had a positive correlation with the scores of RQLQ(P<0.05).Conclusion:SLIT can improve the nasal allergic symptoms,children's life quality and reduce the use of symptomatic treatment medicines. PMID- 29757551 TI - [Expression and clinical significance of long non-coding RNA LINC00520 in laryngeal squamous cell carcinoma]. AB - Objective:To investigate the expression of LINC00520 in laryngeal squamous cell carcinoma(LSCC),and analyze its relevance and roles in carcinogenesis and development of LSCC.Method:The expression of LINC00520 in laryngeal squamous cell carcinoma tissue and paired adjacent normal tissue was determined by real-time PCR.The relationship between the expression of LINC00520 and the clinicopathological characteristics including clinical stage,pathological type,histological grade and lymph node metastasis of LSCC was analyzed.Result:(1)The LINC00520 expression level was significantly upregulated in LSCC tissues compared to that of paired adjacent normal tissues(P<0.000 1).(2)There were no statistical differences of the LINC00520 expression level among supraglottic,glottic and subglottic LSCCs(P>0.05).The LINC00520 expression level had no significant changes in poorly differentiated LSCC compared with that of well and moderately differentiated counterparts(P>0.05).Moreover,the expression of LINC00520 had no significant difference between T1+T2 stage and T3+T4 stage LSCC tissues(P>0.05).Interestingly,the LINC00520 level in LSCC with lymph node metastasis was significantly higher than that in patients without lymph node metastasis(P<0.01).Conclusion:Upregulation of LINC00520 in LSCC may contribute to its metastasis. PMID- 29757553 TI - [The manifestation of videonystamography in the patients with posterior circulation ischemia vertigo]. AB - Objective:To investigate the changes of vedionystamography(VNG)in patients with posterior circulation ischemia vertigo(PCIV).Method:Fifty patients who complained of vertigo and imbalance with PCI were selected as experimental group for testing of visual nystamography(VNG).Thirty normal subjects were chosen as control group.The result was analyzed.Result:The results of VNG in PCIV group and the control group were compared.The abnormal ratio were as follows:(4%,0;P>0.05)for Spontaneous nystagmus,(68%,10%;P<0.01)for Saccade Test,(42.0%,6.7%;P<0.01)for Tracking Test,(44%,0;P<0.01)for Optokinetic Test,(78%,10%;P<0.01)for Positional Test,respectively.The intensity of positional nystagmus in those patients was(4.12+/-3.46) degrees /s,which was much higher than that of the control group(P<0.01).One or more abnormal findings for visual-oculomotor system examination were shown in 37 patients(74%).Conclusion:Both vestibular central and peripheral system can be involved in PCIV.VNG test has clinical significance in differential diagnosis and lesion location.The abnormal ratio of visual nystamography in PCIV group reaches 92%(46/50).These results suggest that VNG be used as an important accessory diagnostic tool for patients with PCIV. PMID- 29757554 TI - [Influence of different levels of skin pricking test on the short-term efficacy of subcutaneous immunotherapy in allergic rhinitis]. AB - Objective:To explore the effect of different levels of skin pricking test on short-term efficacy of subcutaneous immunotherapy with allergic rhinitis.Method:Thirty-one AR patients were included in our study.All the patients had received subcutaneous immunotherapy for 1 year.According to the levels of SPT the patients were divided into 3 groups(grade 2,10 persons;grade 3,10 persons and grade 4,11 persons).Of all the patients,the nasal symptoms visual analogue scale(VAS)score,medication score and rhinoconjunctivitis quality of life questionnaire(RQLQ)were investigated both before and after receiving 1 year subcutaneous immunotherapy.Result:The total effective rate of VAS score,RQLQ score and medication score was 61.30%,58.06% and 64.52% respectively,but there was no statistical difference among the 3 groups after 1 year subcutaneous immunotherapy(P=0.573,0.136,0.699,P>0.05).Conclusion:This study confirms the short efficacy of subcutaneous immunotherapy in AR patients with different levels of SPT.But the level of SPT was not an objective index for shortterm efficacy of subcutaneous immunotherapy of AR. PMID- 29757555 TI - [Submucosal injection of pharyngeal ostium of Eustachian tube for diagnosis of patulous Eustachian tube]. AB - Objective:To evaluate the clinical value of submucosal injection of pharyngeal ostium of Eustachian tube in diagnosing patulous Eustachian tube(PET).Method:Twenty-six patients(32 sides),whose the symptoms were consistent with PET,were enrolled from March 2014 to May 2016.The symptoms and signs of all patients were evaluated after submucosal injection of saline into the Eustachian tube.Result:Immediately after submucosal injection of saline into the Eustachian tube,the symptoms and signs disappeared in 24 cases(29 sides),and improved in 2 cases(3 sides).The resolution and/or improvement of symptoms and signs lasted for less than 24 hours in 12 patients,for more than 24 hours in 9 patients,and for more than 48 hours in 4 patients.No adverse reactions were observed.Conclusion:Submucosal injection may be a simple and practical method for auxiliary diagnosis of PET,and may be used in preoperative evaluation of Eustachian tuboplasty. PMID- 29757556 TI - [Clinical curative effect and changes of serum immunology of Traditional Chinese Medicine combined with surgical treatment on the adult onset recurrent respiratory papillomatosis]. AB - Objective:To observe the outcomes of Traditional Chinese Medicine combined with CO_2 laser surgery on the clinical course and serum immunological indexes of Adult onset Recurrent Respiratory Papillomatosis.Method:69 cases of adult recurrent respiratory papilloma patients who enrolled in Beijing Tongren Hospital from September 2014 to March 2016 were divided randomly into two groups.The Chinese medicine surgery group were treated with traditional Chinese medicine combined with CO_2 laser surgery and the surgery group were treated with CO_2 laser surgery alone.All patients were followed up for more than one year.Relapse time and Derkay score were examed and analyzed between two groups before and after treatment.The detection of aperipheral blood immunoglobulin,T cell subsets,percentage of B cell and NK cell and IgG subtype examed every six month.Result:There was no significant difference between two group in Derkay score,lesion recurrence time and the index of immunology before the treatment(P>0.05).However,the recurrence time after treatment [(14.11+/ 1.57)months]prolonged than before treatment[(10.85+/-2.33)months]in the experimental group.The examination of IgG [(1 539.84+/-388.20)mg/dl],percentage of total T lymphocytes[(85.14+/-22.24)%],Th cells[(47.34+/-19.07)%],B lymphocytes[(12.55+/-5.26)%]in treatment of traditional Chinese medicine was higher than that before treatment of serum IgG [(1 225.14+/-260.27)mg/dl],T cells [(69.68+/-11.12)%],Th [(41.97+/-10.92)%],B lymphocytes[(10.30+/-5.45)%].The difference was statistically significant(P<0.01).Conclusion:The curative effect of traditional Chinese medicine combined with laser surgery for the treatment of adult recurrent respiratory papillomatosis,can effectively prolong the recurrence time of patients,improve their immune cell antiviral ability and be worthy of clinical popularization and application. PMID- 29757557 TI - [Effects of ginkgo biloba extract combined with glucocorticoid on olfactory function and inflammatory cytokines in mice with allergic rhinitis]. AB - Objective:To determine whether ginkgo biloba extract(GBE)combined with dexamethasone(DEX)plays a role in the treatment of allergic rhinitis-related olfactory dysfunction using an animal model.Method:Six week old BALB/C mice were sensitized and challenged with ovalbumin.30 sensitized mice were divided into three groups:Group 1 was given high-dose GBE and DEX(n=10);Group 2 was given low dose GBE and DEX(n=10);Group 3 was given DEX alone(n=10).We assessed the histology of the olfactory mucosa and serum IL-4,IFN-gamma,and caspase 1.Result:A significant higher fraction of mice in group 1 could find the food pellet within300 scompared to group 3(P<0.05).Caspase-1 levels improved during the second week compared with the first week in each group.IFN-gammalevels were significantly lower during the second week compared with the first week(P<0.05,all).IL-4 levels also were significantly lower during the second week compared with the first week in all groups except those receiving DEX alone.IFN gamma/IL-4 levels in each group were significantly lower during the second week compared with the first week(P<0.05,all).Conclusion:In this animal model of allergic rhinitis-related olfactory dysfunction,the addition of ginkgo biloba extract to dexamethasone have a better anti-inflammatory effect,which can partly improve the therapeutic effect on olfactory dysfunction caused by allergic rhinitis. PMID- 29757558 TI - [Clinical features of the recurrence of idiopathic benign paroxysmal positional vertigo]. AB - Objective:To investigate the clinical features of the recurrence of idiopathic benign paroxysmal positional vertigo(IBPPV)patients.Method:Patients with IBPPV were enrolled and were followed-up for 36 months after being well controlled.The data of the patients including age,gender,and co morbidities(hypertension,diabetes,hyperlipidemia)were analyzed.Characteristics of the patients with recurrent BPPV were compared with those without recurrence.Result:Two hundred and one patients were enrolled and twenty two(10.9%)patients presented recurrent IBPPV within 36 months.Among them,about 16% showed changes in the involved semicircular canals.50% recurrence occurred within 6 months after the first treatment.The recurrence rate of BPPV in 50-60 years old patients(50%)is higher than other patients(P=0.04).No significant difference in terms of gender or co morbidities(hypertension,diabetes,hyperlipidemia)was observed between the two groups.Conclusion:The incidence of recurrence in idiopathic BPPV patients was 10.9%in the present study.The mean period of 50% recurrence after a symptom-free interval was about 6 months.Furthermore,different semicircular canals were involved in about 50% of patients during recurrence.BPPV recurrence was not correlated with age,gender or co-morbiditie. PMID- 29757559 TI - [CT observation of retromaxillary posterior ethmoid]. AB - Objective:To investigate the morphologic characteristics of the retromaxillary posterior ethmoid.Method:A total of 103 outpatients encountered in our hospital during March 2012 and December 2012,who completed paranasal sinus CT examination,were included in this study.Patients had no sinus trauma,surgery or tumor history.Their paranasal sinus CT scans were analyzed from scheduled axial and coronal plane.The incidence and imaging features of the retromaxillary posterior ethmoid were observed.Result:The retromaxillary posterior ethmoid(RMPE)was the posterior ethmoid cell that expanded along the lamina papyracea toward the infraorbital region.RMPE was located behind the posterior wall of the maxillary sinus and under the orbital floor.The occurrence rate of the RMPE was 74.3%.The ethmomaxillary septum is the bony septum the between the maxillary sinus and posterior ethmoid.Anatomical confirmation of RMPE is based mainly on the presence of the ethmomaxillary septum.RMPE is located at the back of ethmomaxillary septum.The sagittal angulation of the ethmomaxillary septum ranged from 22 to 87 degrees,with an average of(50.34+/ 12.10)degrees.Conclusion:The ethmomaxillary septum is important for anatomic recognition of the RMPE.Accurate identification of the RMPE before ESS can help improve the removal of the posterior ethmoid sinus. PMID- 29757560 TI - [Application of image guided technique in rhino-orbital related endoscopic surgery]. AB - Objective:To review retrospectively six cases of rhino-orbital related endoscopic surgeries aided by Fusion electromagnetic system,to explore the indications and clinical value of image guided technique in endonasal endoscopic surgery.Method:Retrospective research methods were used.In this study,six cases of nasal endoscopic sinus surgery using Fusion electromagnetic system were analyzed,including 1 nasal penetrating foreign body,2 optic nerve decompressions,1 orbital apex hemangioma,1 sieve frontal sinus cyst,1 intraorbital mass biopsy.The preparation time of navigation system,the accuracy of intraoperative positioning and surgical coherence,intraoperative and postoperative complications of surgery were recorded.Result:The average preparation time was(8.13 +/- 1.858)min.In the navigation,the sinus ostium,orbital cardboard,skull base,optic nerve,internal carotid artery and other important structures can be accurately located in all patients,while registrations had been accurate within 1 mm.Six patients were successfully operated by image guided technique.There was no intracranial or intraorbital complications due to intraoperation error.Conclusion:Image guided technique allows for a truely microinvasive and accurate rhino-orbital related endoscopic surgeries.It requires less preoperative preparation time,has high surgical navigation accuracy,improves the surgical coherence and safety,and reduces the surgical complicationgs.However,as an auxiliary tool,it can not replace the surgeon's anatomical knowledge,surgical training and clinical experience. PMID- 29757561 TI - [Retrospective analysis of 188 cases of parapharyngeal space tumors]. AB - Objective:To explore the diagnosis,treatment,surgical approach and prognosis of parapharyngeal space tumors.Method:The clinical data of 188 patients with parapharyngeal space tumor who were treated from January 2007 to December 2016 were analyzed retrospectively.All patients underwent imaging examination before operation.Surgical approach was as follows:transcervical approach applied in 159 cases,endoscopic-assisted transnasal approach in 9 cases,transcervical transmandibular approach in 8 cases,transcervical-transparotid approach in 8 cases,transoral approach in 7 cases,and infratemporal fossa approach in 4 case.Result:Of the 188 cases,the tumor was benign in nature in 168 cases(89%)and malignant in 20 cases(11%).Complications occurred in 28(15%)patients,with the most common symptom being hoarseness.168 cases of benign tumors were followed up for 10 months to 10 years,and 3 cases were lost and 4 cases had recurrence.All cases underwent re-operation.Patients with malignant tumors received combined treatment after surgery,and 3 cases were lost to follow-up,1 case died of recurrence 9 months after surgery,the rest survived.Conclusion:Surgery is the preferred method for treating parapharyngeal space tumors and postoperative recurrence rate is pretty low.Endoscopy provides a new surgical management method,helping to reduce postoperative complications and recurrence rate. PMID- 29757562 TI - [Effect observation of cleaning up the external auditory canal by otoendoscope combined with Clotrimazole Ointment in the treatment of pregnancy with otitis externa mycotica]. AB - Objective:To investigate the clinical effect of cleaning up the external auditory canal under otoendoscope combined with Clotrimazole Ointment in the treatment of pregnancy with otitis externa mycotica.Method:From May 2015 to May 2017,16 cases of pregnant patients(19 ears)with otitis externa mycotica were divided into two groups:pure cleaning up group and cleaning up combined with medication group.In the pure cleaning up group,external auditory canal were only cleaned up under otoendoscope conventionally in 9 patients(11 ears),while in the cleaning up combined with medication group,Clotrimazole Ointment was topically applied after cleaning up the external auditory canal under otoendoscope in 7 patients(8 ears).After treatment of 2 weeks,the clinical curative effect,adverse reaction and average time interval to take effect were compared at the end of treatment.Result:The total effective rate(100%)in cleaning up combined with medication group's was significantly better than that in pure cleaning up group's(81.81%)(P<0.05);The average time interval to take effect in cleaning up combined with medication groupwas significantly shorter than that in pure cleaning up group's[(2.71+/-0.70)d vs(5.40+/-1.96)d,P<0.05].After the two-week treatment,there was a four-week follow-up.Only one patient in pure cleaning up group relapsed.After two-week treatment by Clotrimazole Ointment,this patient was cured.Conclusion:Cleaning up the external auditory canal under otoendoscope combined with Clotrimazole Ointment is effective and safe for the treatment of otitis externa mycotica in pregnant women.The addition of topical application of Clotrimazole Ointment further improve the therapeutic efficacy,as compared to the conventional method of cleaning up the external auditory canal under otoendoscope.We suggest clinical application of this method. PMID- 29757563 TI - [Long-term results of endolymphatic sac mastoid drainage for Meniere disease]. AB - Objective:To investigate the long-term efficacy of endolymphatic sac mastoid drainage for Meniere disease.Method:Data from 26 patients diagnosed with MD strictly meeting the criteria issued by " Guideline of diagnosis and treatment of Meniere disease(2017)" from 2006 to 2015 were analyzed in this study.Endolymphatic sac mastoid shunt surgery was performed for each patient.The therapeutic effect was evaluated against the " Guideline of diagnosis and treatment of Meniere disease(2017)".Vertigo control and auditory function were measured after at least two years follow up.Result:In 26 cases,16 cases were male and 10 cases were femaleThe age ranged from 24 to 71 years old,with an average of 52.04 years.The disease duration ranged from 1 to 32 years.22 cases were diagnosed as unilateral Meniere disease,and bilateral involvement was identified in 4 cases,thus a total of 30 ears were included.According to the preoperative staging of hearing,there were 0 cases in stage one,5 cases in stage two,16 in stage three and 9 cases in stage four.15 cases(57.7%)achieved class A vertigo conrol(complete control),9 cases(34.6%)class B(substantial control)and 2 cases(7.7%)class D(no control).The severity of vertigo and its impact on daily life were improved in 24 cases(92.3%)with a score of 0 point,and 2 cases(7.7%)scored 2 points.Post-operative hearing was improved in 3 cases(11.5%),unchanged in 16 cases(61.6%)and worsened in 7 cases(26.9%).After operation,tinnitus disappeared in 5 cases(19.2%),reduced in 13 case(50%)and unchanged in 8 cases(30.8%).Conclusion:Endolymphatic sac mastoid drainage was an effective and safe management for intractable Meniere disease patients with pre operative residual hearing.The occurrence of complication was unsual.The patients who are in stage four could gain benifits from the surgery. PMID- 29757564 TI - [Re-operation treatment in uremic patients complicated with persistent secondary hyperparathyroidism after parathyroidectomy with autotransplantation]. AB - Objective:To analyze the clinical profile and therapeutic effect of re-operation treatment in uremic patients complicated with persistent secondary hyperparathyroidism(SHPT)after parathyroidectomy with autotransplantation.Method:Twelve persistent SHPT patients who were treated with reoperation of paramyroidectomy(PTX)were enrolled in this study during the period from Jan 2014 to Jul 2017 in our hospital.We evaluated the location of the remaining parathyroid glands by ultrasonography,dual-phase 99 Tcm-sestamibi scintigraphy,CT and MR imaging of the neck before the operation.We resected the parathyroid gland tissue in situ,and the ectopic parathyroid glands hiding in thymus,mediastinal,tracheal esophageal groove,thyroid gland and other locations in the neck.During the surgery,nanocarbon imaging was used to help identify the parathyroid gland and parathyroid hormone assay(IOPTH)was measured at the end of the surgery.We observed the changes of clinical symptoms after the surgery and collected blood parameters including serum intact aramyroidhomone(i PTH),calcium(Ca),phosphoms(P),calcium and phosphorus product before and after surgery.Complications and failure were also analyzed.Result:All the 12 patients underwented successful operation.The postoperative pathological results were hyperplastic parathyroid glands tissue.22 parathyroid glands were resected,among which 14 were located at the neck in situ,8 were ectopic,i.e.,located at thymus in 4 cases,superior mediastinum in 2 cases and thyroid parenchyma in 2 cases.The clinical symptoms were significantly improved including osteoarthritis,skin itching and limb weakness.The levels of serum iPTH,calcium,phosphorus and calcium and phosphorus product were significantly lower than those before operation(P<0.05).Ten patients presented hypocalcemia after surgery and the level of calcium returned to normal after supplement of calcium.Temporary injury of laryngeal nerve was found in4 cases,but there was no patient with transient bucking,dyspnea or death.No recurrence was found during 1 year follow up.Conclusion:It was very important to locate the residual parathyroid gland accurately with a variety of imaging methods in uremic patients complicated with persistent or recurrent SHPT when they needed re-operation.Surgeons should explorate ectopic parathyroid gland according to the concept of the superior mediastinum dissection and the central compartment neck dissection.Meanwhile,the use of nanocarbon assisted parathyroid gland negative imaging and rapid IOPTH can significantly improve the success rate of surgery and reduce surgical complications. PMID- 29757565 TI - [The development of techniques served to widen the lateral velopharyngeal space for treating OSAHS]. AB - Since Fujita first described uvulopalatopharyngoplasty(UPPP)in 1981,UPPP and its modified procedures have been widely used to treat obstructive sleep apnea and hyponea syndrome(OSAHS).However,despite of its wide application,the success rates was uncertain,ranging from 20% to 80%,with patients of varing Friedman stages.It is well known that the principle of UPPP is to remove the redundant tissue of palate,elongated uvula and hypertrophic tonsils in order to widen the anteroposterior space at the level of palate.But recently,surgeons have found that not only the collapse of soft palate but also the collapse of lateral wall at the palate level can contribute to the obstruction of upper airway at the level of palate.As a result,many surgeries which can widen the lateral velopharyneal space have sprung up in these years.This review focuses on the development of techniques that emphasize the enlargement of lateral velopharyneal space in patients with OSAHS. PMID- 29757566 TI - [Traffic-related air pollution and allergic rhinitis]. AB - Exposure to traffic-related air pollutants(TRAP)has been implicated in airway allergic diseases.Recent findings include epidemiologic and mechanistic studies that shed new light on the impact of TRAP on allergic rhinitis(AR)and the biology underlying this impact.These studies have found that oxidative stress induced by TRAP could affect the axis of epithelial cell-dendritic cell-T cell towards a T helper 2 immune response,which is the major mechanism between TRAP and AR.Further,epigenetics and microRNA might be involved in this process.Our review will summarize the most recent findings in each of these areas. PMID- 29757567 TI - [Study on the application of mast cells in the pathogenesis of allergic rhinitis]. AB - The pathogenesis of allergic rhinitis(AR)is extremely complex.In recent years,a variety of allergens and other complexes have been developed to induce a series of signal transduction mechanisms by activating mast cells.Intracellular media release(mast cells,MCs)play an important role in the pathogenesis of AR.In this paper,we reviewed the progress of mast cells in the pathogenesis of allergic rhinitis in recent years in order to further understand its role in the pathogenesis of allergic rhinitis and provide new ideas on the therapeutic target for allergic rhinitis. PMID- 29757568 TI - Acute kidney injury following radical cystectomy and urinary diversion: predictors and associated morbidity. AB - INTRODUCTION: Acute kidney injury (AKI) after major surgeries is associated with significant morbidity and mortality. We aim to report incidence, predictors and associated comorbidities of AKI after radical cystectomy in a large cohort of patients. MATERIALS AND METHODS: We conducted a retrospective analysis of 1000 patients who underwent open radical cystectomy in a tertiary referral center. Perioperative serum creatinine measurements were used to define AKI according to the RIFLE criteria (as Risk, Injury and Failure). The predictors of AKI after surgery were determined using univariate and multivariate analyses. RESULTS: Out of 988 evaluable patients, AKI developed in 46 (4.7%). According to RIFLE criteria; AKI-Risk, AKI-Injury and AKI-Failure occurred in 26 (2.6%), 9 (0.9%) and 11 (1.1%) patients, respectively. Multivariate analysis showed that performing nephroureterectomy with cystectomy (Odds ratio [OR]: 4.3; 95% Confidence interval [CI]: 1.3-13.6; p=0.01) and the development of high grade complications (OR: 3.8; 95% CI 1.9-7.2; p<0.0001) were independently associated with AKI. CONCLUSIONS: AKI is a significant morbidity after radical cystectomy and the term should be included during routine cystectomy morbidity assessment. PMID- 29757570 TI - Incidence and treatment of malignant tumors of the genitourinary tract in renal transplant recipients. AB - PURPOSE: To provide data of the incidence and management of common urological malignancies in renal transplant recipients. MATERIALS AND METHODS: We conducted a retrospective analysis of a prospective database from August 1967 to August 2015. A descriptive analysis of the sample was performed. RESULTS: Among 1256 consecutive RTR a total of 88 patients developed malignancies (7%). There were 18 genitourinary tumors in the 16 patients (20.45% of all malignant neoplasms), incidence of 1.27%. The most common neoplasm encounter was renal cancer (38.8%), followed by urothelial carcinoma (33.3%). Median follow up of transplantation was 197 months (R, 36-336). Mean time from RT to cancer diagnosis 89+/-70 months (R, 12-276). CsA and AZA was the most common immunosuppression regimen in 68.75%. Mean follow-up after diagnosis was 103+/-72 months (R 10-215). Recurrence free survival rate of 100%. Overall survival of 89.5% of the sample; there were two non-related cancer deaths during follow up. CONCLUSIONS: The incidence of neoplasms in RTR was lower than in other series, with favorable functional and oncologic results after treatment. This suggests that actions to reduce the risk of these malignancies as well as a strict follow-up are mandatory for an early detection and treatment. PMID- 29757569 TI - Pro - inflammatory cytokines and metalloproteinase activation in polypropylene mesh implant in rat subcutaneous tissue. AB - AIMS AND OBJECTIVES: Polypropylene meshes have been increasingly adopted for correction of pelvic organ prolapse due to its lower recurrence rate when compared to surgeries without meshes. The study of the interaction of these materials with the host tissue may contribute to the development of materials with best biocompatibility and, consequently, less complication rates. MATERIALS AND METHODS: The present study compares the inflammatory reaction of standard weight (SW) and lightweight (LW) meshes (72 g/m216g/m2 respectively), implanted in the abdomen of 20 adult rats, which were euthanized in four or 30 days. Quantification of pro-inflammatory markers, IL-1 and TNF-alpha, and of metalloproteinases, MMP2 and MMP3, were carried out through immunohistochemistry with AxioVision (r) software. RESULTS: There were no significant differences in the quantification of IL-1 and TNF-alpha in LW versus SW meshes. However, IL-1 quantification increased along time (30 days >4 days, p=0.0269). Also, MMP-2 quantification was similar to SW and LW and both presented a significant increase along time (30 days >4 days, p < 0.0001). MMP-3 quantification also showed no difference between the SW and LW groups, but increased along time (30 days >4 days, p=0.02). CONCLUSIONS: Mesh's density did not influence the quantification of pro-inflammatory cytokines IL-1 and TNF-alpha and metalloproteinases 2 and 3. The increased expression of IL-1, MMP-2 and MMP-3 over time could represent a longstanding inflammatory response after PP mesh implantation. Possibly, the occurrence of adverse events following PP prosthetic implants can be influenced by other factors, not solely related to the amount of implanted material. PMID- 29757572 TI - Comparison of the Kelly's plication and TOT simultaneously with vaginal hysterectomy, on the incontinence, and sexual functions. AB - PURPOSE: To compare the effect of vaginal hysterectomy-anterior/posterior colporrhaphy with Kelly's plication(VH-KP), versus vaginal hysterectomy anterior/posterior colporrhaphy-transobturator tape(VH-TOT) surgeries on incontinence, quality of life, and sexual functions in patients with pelvic organ prolapse(POP), and concurrent obvious stress urinary incontinence(SUI). MATERIALS AND METHODS: Between 2013 and 2017, fifty patients treated with VH-KP(n = 25), and VH-TOT(n = 25) due to POP and SUI, were evaluated prospective consecutively. Age, parity, duration of urinary incontinence,and the daily pad use were recorded. Patients were filled "rinary Distress Inventory-6(UDI-6)", "Incontinence Impact Questionnaire 7(IIQ-7)" and "Index of Female Sexual Function(IFSI)" questionnaire forms at preoperatively,and postoperative 6th month. No usage of pads was accepted as subjective cure rate.Intraoperative,and postoperative complications were noted. RESULTS: There was no statistically significant difference between two groups, for the mean age of the patients, parity, duration of SUI, and the daily pad use, preoperatively (p > 0.05). Decreased UDI-6 scores, IIQ-7 scores and daily pad usage, and increased IFSF scores were found statistical significantly in each group, at the postoperative 6 th month (p < 0.05). However, VH-TOT group had higher improvement rates, on UDI-6 scores (69.5% vs 63.0%, p = 0.04). In addition, it was notable that the the rates of the patients had IFSF scores >= 25 was higher in VH-KP group (p = 0.05). Four (16%) patients had recurrent SUI in the VH-KP group (p = 0.039) and vaginal extrusion occurred in 2 (8%) patients in the VH-TOT group (p = 0.153), postoperatively. CONCLUSIONS: Although the effects of VH-TOT surgery are superior to conventional methods for incontinence and quality of life; negative effects on sexual functions are notable. In addition, although recurrence rates of TOT are low, complications such as vaginal extrusion are accompanied by drawbacks of mesh usage. PMID- 29757571 TI - Localized chromophobe renal cell carcinoma: preoperative imaging judgment and laparoscopic simple enucleation for treatment. AB - OBJECTIVE: To evaluate the preoperative imaging manifestation and therapeutic effect of laparoscopic simple enucleation (SE) for localized chromophobe renal cell carcinoma (chRCC). MATERIALS AND METHODS: Clinical data of 36 patients who underwent laparoscopic SE of localized chRCC at our institute were retrospectively analyzed. All patients underwent preoperative renal protocol CT (unenhanced, arterial, venous, and delayed images). CT scan characteristics were evaluated. After intraoperative occlusion of the renal artery, the tumor was free bluntly along the pseudocapsule and enucleated totally. The patients were followed up regularly after the operation. RESULTS: Mean tumor diameter was 3.9+/ 1.0 cm, 80% of tumors were homogeneous and all the tumors had complete pseudocapsule. The attenuation values were slightly lower than normal renal cortex and degree of enhancement of the tumors were significantly lower than normal renal cortex. Mean operation time was 104.3+/-18.2 min. Mean warm ischemia time (WIT) was 21.3+/-3.5 min. Mean blood loss was 78.6+/-25.4 mL. No positive surgical margin was identified. Mean postoperative hospital stay was 5.3+/-1.5 d. Hematuria occurred in 3 patients and all disappeared within 3 days. After a mean follow-up of 32.1+/-20.6 months, no patient had local recurrence or metastatic progression. CONCLUSION: Localized chRCCs have a great propensity for homogeneity and complete pseudocapsule. The attenuation values were slightly lower than normal renal cortex and small degree of enhancement. Laparoscopic SE is a safe and effective treatment for localized chRCC. The oncological results were satisfactory. PMID- 29757574 TI - Penile refracture: a preliminary report. AB - OBJECTIVE: To report our institutional experience with penile refracture, including demographic data, recurrence time, etiology and operative findings in the first and second episodes. MATERIALS AND METHODS: Between January 1982 and September 2017, 281 patients underwent surgical treatment for penile fracture (PF) at our institution. Demographic data, clinical presentation, besides operative findings and follow-up of patients with relapsed PF were retrospectively assessed by reviewing medical records. RESULTS: Of a total of 281 cases of PF operated at our institution, 3 (1.06%) patients experienced two episodes of trauma. Age ranged from 38 - 40 years (mean: 39.3). The recurrence time varied from 45 to 1560 days (mean: 705). Two patients presented the new fracture episode at the same site of the previous lesion, while in the other case the lesion was observed at another site. CONCLUSION: Recurrent FP is an extremely rare entity. The risk factors for its occurrence are still unknown. Although the lesion of the corpus cavernosum ipsilateral to the scar tissue of the prior FP is more common, contralateral rupture may be present. Nevertheless, prospective studies with larger samples should be conducted. PMID- 29757575 TI - Prognostic role of preoperative albumin to globulin ratio in predicting survival of clear cell renal cell carcinoma. AB - PURPOSE: To investigate the prognostic role of preoperative albumin/globulin ratio (AGR) in predicting disease-free survival (DFS) and overall survival (OS) in localized and locally advanced clear cell renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: 162 patients who met the criteria specified were included in the study. The DFS and OS ratios were determined using the Kaplan-Meier method. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors affecting DFS and OS. RESULTS: Median follow-up period was 27.5 (6-89) months. There was a statistically significant relationship between low AGR and high pathological tumor (pT) stage, presence of collecting system invasion, presence of tumor necrosis, and a high platelet count (p = 0.012, p = 0.01, p = 0.001, and p = 0.004, respectively). According to the Kaplan Meier survival analysis, both OS and DFS were found to be significantly lower in the low AGR group (p = 0.006 and p = 0.012). In the multivariate Cox regression analysis, collecting system invasion and tumor necrosis were found to be independent prognostic factors in predicting OS and pT stage was found to be an independent prognostic factor in predicting DFS (HR: 4.08, p = 0.043; HR: 8.64, p = 0.003 and HR: 7.78, p = 0.041, respectively). CONCLUSION: In our study, low AGR was found to be associated with increased mortality and disease recurrence in localized and locally advanced RCC. PMID- 29757576 TI - Re: Transition to adulthood with a bladder augmentation: histopathologic concerns. PMID- 29757577 TI - Supposed pituitary-production of human chorionic Gonadotropin induced by androgen deprivation therapy. AB - INTRODUCTION: The main cause of slightly elevated human chorionic gonadotropin (HCG) after successful treatment of male germ cell tumors is considered to be pituitary-derived HCG. It is well known that pituitary-derived HCG is frequently detected in postmenopausal women. We evaluated the status of serum HCG in men with elevated gonadotropins, which were induced by androgen deprivation therapy, using commercially available assays. MATERIALS AND METHODS: We enrolled 44 patients with prostate cancer, who underwent luteinizing-hormone releasing hormone agonist treatment. We measured serum follicle-stimulating hormone (FSH), serum luteinizing hormone (LH), serum total HCG, serum free HCG-beta subunit, and urine total HCG 3 times per patient, on the day of treatment initiation, the next day, and 3 months after. RESULTS: On the day after treatment initiation, serum and urine HCG was detected in 61% and 73% of patients, respectively. Markedly strong correlations were observed between serum/urine HCG and FSH/LH. In particular, receiver operating characteristic curve analysis indicated excellent area under the curve (0.977, 95% confidence interval 0.951-1.003)) for serum HCG detectable LH. At the cutoff value of 21.07 mIU/mL for serum HCG-detectable LH, the sensitivity and specificity were 96.7% and 95.3%, respectively. Serum HCG beta was not detectable at any times in any patients. CONCLUSIONS: Suggested pituitary-derived HCG can be frequently detected in patients with elevated gonadotropins, and there is a firm association between HCG detection and gonadotropin levels. PMID- 29757573 TI - Low serum melatonin levels are associated with erectile dysfunction. AB - OBJECTIVE: Melatonin is a hormone secreted from the pineal gland and has anti oxidative and anti-inflammatory effects. Oxidative stress is considered as an important factor in the etiology of erectile dysfunction (ED), and in many experimental models, positive results have been obtained with melatonin treatment. This study aimed to measure serum melatonin levels in ED patients and to investigate the possible relationship between ED and melatonin levels. MATERIALS AND METHODS: Sixty-two patients diagnosed with mild, moderate or severe ED according to the five-item International Erectile Function Index (IIEF-5) and 22 healthy individuals were included in the study. The serum melatonin levels, anthropometric data, and other biochemical and hormonal parameters of all the subjects were recorded. Detailed anamnesis was also obtained in terms of diabetes, hypertension, cardiovascular diseases, smoking status, and alcohol use. RESULTS: The serum melatonin level was found 34.2+/-13.3 ng/dL in the mild ED group, 33.3+/-14.7 ng/dL in the moderate ED group, 34.8+/-17.2 ng/dL in the severe ED group, and 44.6+/-16.5 ng/dL in the control group. The serum melatonin levels were significantly lower in all ED groups compared to the control group (p=0.019). There was no significant difference in the serum melatonin levels between the three ED groups. Diabetes, hypertension, cardiovascular diseases, smoking and alcohol use were not significantly different between the ED groups (p>0.05). CONCLUSION: We consider that if our findings are supported by further studies with larger populations, the measurement of the serum melatonin level may have a future role in the diagnosis and treatment of ED. PMID- 29757578 TI - Seasonal variations in urinary calcium, volume, and vitamin d in kidney stone formers. AB - OBJECTIVES: To investigate the seasonal variations in urinary calcium, serum vitamin D, and urinary volume in patients with a history of nephrolithiasis. MATERIALS AND METHODS: Patients included were those who completed a 24-hour urine metabolic evaluation on two occasions; one in summer (June-Aug) and one in winter (Nov-Jan), and who had not started any medications or been instructed on dietary modifications in the interval between the two tests that may have impacted the results. Patients were excluded if they were on thiazide diuretics or were taking calcium and / or Vitamin D supplementation. Welch's t-test was used to compare the difference in average summer and winter values. Unpaired Student t-test was used to compare baseline parameters (age, BMI), and Paired Student t-test was used to compare average seasonal measurements in men vs. women. RESULTS: 136 patients were identified who were not taking calcium or vitamin D supplements or thiazide diuretics, and who were not instructed on dietary modifications in the interval between the two measured parameters. No significant differences were observed when comparing male to female baseline parameters of age or BMI (Table 1). Average 24-hour urine calcium was higher (226.60) in the winter than in summer (194.18) and was significant in males (p = 0.014) and females (p < 0.001). No significant seasonal difference was seen in 24-hour urine volume or serum vitamin D levels. CONCLUSIONS: Urinary calcium is higher in winter months compared to summer months. As such, tailoring medical preventative strategies to the time of year may be helpful. PMID- 29757579 TI - Isolated low grade prenatally detected unilateral hydronephrosis: do we need long term follow-up? AB - PURPOSE: To assess the need for postnatal evaluation and the medium term outcome in patients with isolated unilateral low grade prenatally detected hydronephrosis. MATERIALS AND METHODS: We prospectively selected 424 patients (690 kidney units) with a prenatal diagnosis of urinary tract dilatation between 2010 and 2013. We included only those patients with isolated unilateral low-grade hydronephrosis who underwent at least 2 postnatal ultrasound examinations. The Society for Fetal Urology (SFU) grading system was utilized for assessment of the hydronephrosis. We excluded patients with bilateral dilation or other urological abnormalities. The fate of hydronephrosis including resolution, stability or worsening was documented. RESULTS: A total of 66 infants (44 boys and 22 girls) with antenatally diagnosed unilateral urinary tract dilation (23 right and 43 left) were identified. Ultrasounds showed SFU grade 1 hydronephrosis in 32 patients (48%) and SFU grade 2 hydronephrosis in 34 (52%). After a mean follow-up period of 32 months (range 12 to 60), 37 patients (56%) had complete resolution of hydronephrosis while the remaining 29 were stable (44%). None of our patients developed UTIs during follow-up and none required surgical intervention. CONCLUSIONS: Prenatally detected, isolated unilateral low-grade hydronephrosis usually have a favorable prognosis. All cases in our cohort showed either stability or resolution of hydronephrosis without any harmful consequences. Based on our findings on medium-term in this category of patients, long-term follow-up is not warranted. PMID- 29757580 TI - Comparison of renal function after robot - assisted laparoscopic radical prostatectomy versus retropubic radical prostatectomy. AB - PURPOSE: To investigate the effect of robot assisted laparoscopic radical prostatectomy (RALP) and open retropubic radical prostatectomy (RRP) on early renal function in this study. MATERIALS AND METHODS: Preoperative and postoperative urea, creatinine, Hb, eGFR values of patients who had undergone RALP and RRP with prostate cancer (PCa) diagnosis were recorded in our clinic. The percentages of change in these values are calculated. Preoperative and postoperative urea, creatinine, Hb and eGFR changes were compared with each other. Student-t test was used for intergroup comparison, and paired sample t test was used to compare changes between preoperative and postoperative values of the same group. RESULTS: There were 160 and 93 patients in the RALP and RRP group, respectively. In the RALP group, postoperative urea and creatinine increased significantly compared to preoperative baseline values while eGFR was decreased (p = 0.0001, p = 0.001, p = 0.0001, respectively). Except for Hb in the RRP group, the changes in these values were statistically insignificant (p = 0.50, p = 0.75, p = 0.30, respectively). CONCLUSIONS: We should be more careful when we perform RALP in patients at risk of impaired renal function despite being a minimally invasive surgical method with superior visual characteristics. PMID- 29757581 TI - Transmyometrial embryo transfer as a useful method to overcome difficult embryo transfers - a single-center retrospective study. AB - OBJECTIVE: Pregnancy after an embryo transfer depends largely on embryo quality, endometrial receptivity, and the technique used in the embryo transfer. Embryo transfers have been reported as inevitably traumatic and difficult for 5-7% of patients in assisted reproduction treatment. In these cases, transmyometrial embryo transfer should be considered as a suitable method to overcome difficult embryo transfers. The aim of this study was to report our experience with this technique and analyze its causes, results and complications. METHODS: Since 1993, 39 women (40 cycles of assisted reproductive technology treatment) were submitted to transmyometrial embryo transfers in our center. The procedures were carried out as described by the Towako group. RESULTS: The enrolled female patients had a mean age of 34 years and a mean baseline FSH level of 6.89 IU/mL. The median number of retrieved oocytes was 7.50 and a mean of 2.63 embryos were transferred. Implantation rate was 9.5%. With respect to clinical results, pregnancy and miscarriage rates were 25% and 30%, respectively. Since there were two twin pregnancies, the live birth rate was 22.5% (9/40). No major complications were reported. CONCLUSION: Transmyometrial embryo transfer can and should be an option in cases of difficult/impossible transcervical embryo transfer. PMID- 29757583 TI - What Immunological Defects Predispose to Non-tuberculosis Mycobacterial Infections? AB - Nontuberculous mycobacteria (NTM) are categorized as one of the large and diverse groups of environmental organisms which are abundant in water and soil. NTM cause a variety of diseases in humans that mainly affect the lung. A predisposition to pulmonary NTM is evident in patients with parenchymal structural diseases including bronchiectasis, emphysema, tuberculosis (TB), cystic fibrosis (CF), rheumatologic lung diseases and other chronic diseases with pulmonary manifestations. Lung infections are not the only consequences of being infected by NTM as they can also infect skin and soft tissue and may also cause lymphadenitis (predominantly in young children) and disseminated disease in human immunodeficiency virus (HIV)-infected patients or those with severely compromised immune system. NTM are also found in many subjects without any known risk factors. Although the recent advances in imaging and microbiologic techniques including gene sequencing have provided a better view of the problems caused by NTM and has enhanced our understanding of the disease, many uncertainties regarding the immunologic response to NTM still exist. There is also limited data on the immunogenetics of NTM infection. Here, the authors reviewed the main immunogenetic defects as well as other immunological conditions which are associated with an increased the risk of NTM infections. PMID- 29757582 TI - Effects of orlistat on serum androgen levels among iranian obese women with polycystic ovarian syndrome. AB - INTRODUCTION: Polycystic ovary syndrome is one of the most common endocrinopathies in young women, and it affects 6% to 8% of women in reproductive age. Hyperandrogenism is the hallmark of polycystic ovary syndrome. The aim of the present study was to evaluate the effects of orlistat on weight loss and serum androgen levels among Iranian women with polycystic ovary syndrome. METHODS: The present study was carried out in the clinic of Infertility and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Thirty-two patients with polycystic ovary syndrome were randomly enrolled. We measured serum androgens (Testosterone, 17alpha hydroxyprogesterone, dehydroepiandrosterone and sex hormone-binding globulin) before and after 12 weeks of treatment with orlistat. We used the Rotterdam Criteria for all patients and transvaginal sonography was performed. RESULTS: The mean age of patients was 27.75+/-6.22 and the mean body mass index was 32.69+/ 0.94 kg/m2. Comparing with baseline, treatment with orlistat resulted in a significant reduction in weight, BMI, and waist circumference (p=0.001). We also found a remarkable reduction in total testosterone levels (p>0.001). Treatment improved the sex hormone-binding globulin plasma levels, but the improvement was not statistically significant. There was no reduction in other androgen levels. CONCLUSION: This study showed a significant reduction of weight and total testosterone level - the most important androgen in polycystic ovary syndrome - after 12 weeks of treatment with orlistat. Therefore, it seems that a short course of orlistat can be useful in the management of patients with polycystic ovary syndrome. PMID- 29757584 TI - Effects of Nerve Growth Factor shRNA Inhibition on Asthma Phenotypes in a Mouse Model of Asthma. AB - Nerve growth factor (NGF) plays an important role in airway hyper-responsiveness (AHR). In this study, we aimed at investigating the effect of NGF inhibition on AHR and other asthma phenotypes in a mouse model of asthma. 12 mice in each group were injected with lentiviral vectors expressing non-targeting shRNA (sham shRNA), targeting NGF (shRNA-1 and shRNA-2), or normal saline for control before the asthma models were established. Peak inspiratory pressure (PIP), NGF levels in bronchoalveolar lavage fluid (BALF), and bronchoconstriction in response to acetylcholine (ACh) were measured. Immunohistochemistry semi-quantitative analysis of muscarinic acetylcholine receptor M3 (mAChR M3) and alpha-smooth muscle actin (a-SMA) were measured by Image Pro Plus (IPP), and qRT-PCR analysis of mRNAs of cholinergic receptors, muscarinic 3 (Chrm3), Ngf and Tropomyosin receptor kinase A (TrkA) were performed. Immunohistochemistry showed mAChR M3 was overexpressed and a-SMA was hyperplasia in control and sham shRNA, semi quantitative analysis revealed optical density (OD) values were significantly higher than shRNA-1 and shRNA-2, (p<0.001). BALF NGF levels were significantly higher in control and sham shRNA (457.16+/-45.32, 676.43+/-111.64) compared with shRNA-1 and shRNA-2 (261.56+/-25.81, 129.12+/-15.96 pg/mL) (p<0.001). PIP was significantly higher in control, compared with shRNA-1, shRNA-2, (p=0.045, 0.003), bronchoconstriction response to ACh was significantly higher in sham shRNA, compared with shRNA-1, shRNA-2, (p=0.02, 0.006). Expression of mRNAs of Chrm3, Ngf and TrkA genes in sham shRNA group were higher than shRNA-1 and shRNA 2. Inhibiting NGF via NGF-targeting shRNAs appears to lessen the severity of asthma phenotypes in this mouse model of asthma. PMID- 29757585 TI - IgE Sensitization to Inhalant Allergens and Its Association with Allergic Diseases in Adults. AB - Allergic sensitization to inhalant allergens could be considered as a predictor in allergic diseases. The objective of this study was to assess IgE-mediated sensitization to inhalant allergens in allergic and non-allergic adults as well as the evaluation of its association with allergic diseases. This cross-sectional study was conducted from 2013 to 2016 in 604 allergic and 102 non-allergic adults selected from blood donor volunteers in Tehran, Iran. After taking informed consent, a standard questionnaire was filled to determine asthma, allergic rhinitis and/or conjunctivitis and atopic dermatitis in participants. Specific IgE assay to common inhalant allergens was performed for all subjects. Logistic regression analysis was used to evaluate the impact of IgE sensitization on allergic diseases. A total of 371(61.4%) allergic subjects and 41(40.2%) non allergic patients were males. The weeds (especially saltwort) and grasses (particularly meadow fescue and ryegrass) were identified as the most common inhalant allergens. The prevalence of IgE sensitization to trees, weeds, and grasses was higher in subjects with allergic rhino-conjunctivitis and trees sensitization was a significant factor in them [OR=2.32, 95% CI (1.58-3.41)]. IgE sensitization to any inhalant allergens could be a predictor for allergic rhinitis, conjunctivitis and rhino-conjunctivitis in adults [OR=2.20, 95% CI (1.54-3.15], [OR=1.81, 95% CI (1.28-2.54)] and [OR=2.55, 95% CI (1.72-3.78)], respectively. With an increase in the sum of specific IgE concentrations, the prevalence of allergic conjunctivitis and rhino-conjunctivitis also increased. Our results showed the association between positive specific IgE and its concentration with some allergic diseases which could help physicians to prevent such diseases by recognizing and treating them, particularly in individuals with a positive family history of allergic diseases. PMID- 29757586 TI - Production of Recombinant Protein of Salsola Kali (Sal k1) Pollen Allergen in Lactococcus Lactis. AB - The Salsola kali pollen is considered the main cause of allergic sensitization in desert and semi-desert regions. We have constructed recombinant Lactococcus lactis producing Sal k1 protein with the aim of using it as a mucosal vaccine for specific immunotherapy. The Sal k1 gene was amplified, and transferred into a PNZ 8148 plasmid. The PNZ8148-Sal k1 recombinant plasmid was transformed into competent E.coli strain MC1061 for replication, and then was isolated and cloned into competent L. lactis by electroporation. The cloning was verified by PCR and gene sequencing. The production of recombinant Sal K1 (rSal K1) protein was induced by nisin. The rSal K1 protein was purified by affinity chromatography and dialysis, and confirmed by SDS-PAGE and western blot analyses. The recombinant L. lactis was successfully constructed. Production of a 40-kDa rSal k1 protein with the L. lactis was shown by sodium dodecyl sulfate-polyacrylamid gel electrophoresis (SDS-PAGE) analysis. In addition, western blot analysis using specific mouse anti-Sal k1 polyclonal antibodies and sensitive human sera verified the 40-kD protein as rSal k1 allergen. This study demonstrated that L. lactis may be used as a promising live delivery system for recombinant Sal k1 protein without altering its immunoreactivity; however, its efficacy in the context of the immune system is suggested to be pursued in future studies. PMID- 29757587 TI - Development and Evaluation of a Novel ELISA for Detection of Antibodies against HTLV-I Using Chimeric Peptides. AB - We aimed to develope a peptide-based indirect ELISA to detect antibodies against Human T-lymphotropic virus type I (HTLV-I). Two chimeric peptides (CP-1 and CP-2) were designed using linear immunodominant epitopes of gp-46-I, and gp21-I proteins, according to the sequence from Uniprot database. These peptides were studied initially in the ELISA using infected sera. The most promising peptideCP 1, was used to develop a peptide ELISA for detection of HTLV-I infected sera. The optimal conditions for CP-1ELISA were: the optimum coating buffer was 100mM NaHCO3, pH 9.6; coating peptide concentration was 10 ug/mL; the optimal blocking buffer was5% fetal bovine serum (FBS); the secondary antibody concentration was 1:2000; and serum dilution was 1:20. 20serum samples from HTLV-I infected patients were evaluated by ELISA developed. CP-1 showed high antigenicity while lacking any cross-reactivity with normal human sera. The results of evaluations indicated that in comparison with commercial ELISA, CP-1 ELISA showed good sensitivity and specificity. With further validation, CP-1as described in the present study could be introduced as novel reliable and cost-effective candidates for the high-specific screening of HTLV-I/-II infections in endemic regions. PMID- 29757588 TI - Association of Regulatory T Cells with Diabetes Type-1 and Its Renal and Vascular Complications Based on the Expression of Forkhead Box Protein P3 (FoxP3), Helios and Neurophilin-1. AB - In recent years, it has been recognized that regulatory T cells (Tregs) play a critical role in maintaining immune tolerance. Moreover, the expression of two markers named Helios and neurophilin-1 (NRP-1) has been highlighted in such cells. Helios, an intracellular transcription marker, largely differentiates twomost operative sub group of Tregs, namely naturally occurring (nTreg) and induced (iTreg) Tregs, and NRP-1 is reckoned as a membranous activity marker of Tregs. We aimed to count peripheral mononuclear cells expressing such markers in a group of type 1 diabetes patients to elucidate the possible role of Tregs in the pathogenesis of such disease and its complications. Blood samples from 61 adult patients with type 1 diabetes and 61 sex and age-matched healthy controls were tested to count two types of Tregs, namely naturally occurring and inducible types, according to the expression of cell surface markers of CD4/CD25/CD47 FITC/PE/APC and intracellular markers of FoxP3/Helios-PE-CY5/eFlour450 by flow cytometry, respectively.We also investigated the relation between expression of such markers with HbA1c, urine albumin/creatinine ratio (UACR), and common carotid intima thickness (CIMT). The circulatory frequency of both Helios+ and Helios- T-cells were significantly decreased in patients compared to those in healthy controls (p<0.001). There was also a significant decrease in circulatory frequency of Helios+ NRP-1+ and Helios- NRP-1+ cells in the patients compared to controls (p=0.029). According to expression of Helios and NRP-1 markers, the number and function of both Tregs were decreased in diabetic patients. Moreover, the neurophilin expression was inversely associated with complications of type 1 diabetes. PMID- 29757589 TI - The Effect of Differentially Designed Fusion Proteins to Elicit Efficient Anti human Thyroid Stimulating Hormone Immune Responses. AB - The production of human thyroid stimulating hormone (hTSH) immunoassays requires specific antibodies against hTSH which is a cumbersome process. Therefore, producing specific polyclonal antibodies against engineered recombinant fusion hTSH antigens would be of great significance. The best immunogenic region of the hTSH was selected based on in silico analyses and equipped with two different fusions. Standard methods were used for protein expression, purification, verification, structural evaluation, and immunizations of the white New Zealand rabbits. Ultimately, immunized serums were used for antibody titration, purification and characterization (specificity, sensitivity and cross reactivity). The desired antigens were successfully designed, sub-cloned, expressed, confirmed and used for in vivo immunization. Structural analyses indicated that only the bigger antigen has showed changed 2 dimensional (2D) and 3D structural properties in comparison to the smaller antigen. The raised polyclonal antibodies were capable of specific and sensitive hTSH detection, while the cross reactivity with the other members of the glycoprotein hormone family was minimum and negligible. The fusion which was solely composed of the tetanus toxin epitopes led to better protein folding and was capable of immunizing the host animals resulting into high titer antibody. Therefore, the minimal fusion sequences seem to be more effective in eliciting specific antibody responses. PMID- 29757590 TI - Imbalance of Peripheral Blood T Helper Type 17 Responses in Patients with Vitiligo. AB - There is growing evidence to suggest that Th cells play pivotal roles in a variety of chronic inflammatory diseases, including vitiligo. However, the exact role of different subsets of Th cells in the pathogenesis of vitiligo is still a question. The purpose of present study was to determine the mRNA expression level of Th17 master transcription factor retinoic acid receptor-related orphan receptors gamma (RORgammat) and cytokine mRNA and protein expression profiles of Th17 cells. 22 patients with vitiligo and 22 normal subjects were enrolled in the study. Gene expression profiles of freshly isolated peripheral blood mononuclear cells (PBMCs) were determined by quantitative real-time reverse transcriptase PCR (qRT-PCR). Plasma concentrations of IL-17A and IL-22 were also assayed using ELISA kits. The results showed that RORgammat, IL-17A and IL-22 mRNA expression were increased in patients remarkably compared to healthy controls (p<0.05). Furthermore, plasma IL-17A and IL-22 levels were also higher in vitiligo patients versus controls (p<0.001). These data suggest that a deregulated Th17 adaptive immune response may contribute to the pathogenesis of vitiligo. PMID- 29757591 TI - Evaluating Serum Levels of IL-33, IL-36, IL-37 and Gene Expression of IL-37 in Patients with Psoriasis Vulgaris. AB - Serum levels of interleukin (IL)-33, IL-36 and IL-37 have been reported to be up regulated in various T helper (Th)1/Th17 mediated autoimmune/inflammatory diseases. Although IL-33 and IL-36 expression are increased in skin lesions of patients with psoriasis, their serum levels in such patients have not yet been adequately studied. We aimed to evaluate serum level of IL-33, IL-36 and IL-37 cytokines and IL-37 gene expression in patients with autoimmune/inflammatory disease of psoriasis and to explore their correlation with disease severity. Such evaluation further clarifies disease pathogenesis and may be utilized in clinical practice. 47 patients with psoriasis vulgaris and 47 healthy individuals were included. Serum IL-33, IL-36 and IL-37 levels were measured by Elisa and gene expression of IL-37 measured by real time PCR in all participants. The disease activity was assessed by the psoriasis area and severity index (PASI). Linear Correlation between interleukin measures and PASI score was calculated. Also sensitivity and specificity of such measurements were determined. Serum IL-36 and 37 levels in patients with psoriasis vulgaris were significantly higher than those in healthy controls and positively correlated with disease activity (PASI score). Serum IL-33 levels in patients were equal to those in healthy controls but positively correlated with disease activity. Serum IL-36 levels were significantly higher than serum IL-33 levels. Gene expression of IL-37 levels in patients were higher than healthy controls but was not correlated with disease activity. Serum IL-36 and IL-37 levels are generally increased in psoriasis vulgaris and correlated with disease severity. Therefore, serum IL-36 and IL-37 levels may be markers of treatment and diagnosis of psoriasis. PMID- 29757592 TI - The Profile of Toll-like Receptor 2 (TLR2), TLR4 and Their Cytosolic Downstream Signaling Pathway in Common Variable Immunodeficiency (CVID) Patients. AB - Common variable immunodeficiency (CVID) is the most common clinical primary antibody deficiency, characterized by increased susceptibility to recurrent bacterial infections. Since Toll-like receptors (TLRs) play an important role in the maturation and differentiation of B-cells, TLRs' defect can be involved in the pathogenesis of CVID. Therefore, we evaluated the expression of TLR2 and TLR4 and their signaling pathway; also their association with autoimmunity, B-cell subtypes and response to pneumovax-23 were assessed in CVID patients. Sixteen CVID patients were enrolled in the study. Flow cytometry was used for assessing the protein expression of TLR2 and TLR4, and real-time PCR was used for gene expression of myeloid differentiation primary response 88 (MyD88) and toll interacting protein (Tollip). We found a higher protein expression of TLR2 in CVID patients which was associated with lower number of end stage B-cells and hyporesponse to pneumovax-23 vaccination. We showed a lower mRNA expression of MyD88 and an almost equal Tollip mRNA expression in CVID patients compared with controls. There was a profound association between MyD88 gene expression and autoimmunity in CVID patients. According to the presence of the lower number of end stage B-cells and poor vaccine response in CVID patients and their correlation with the higher expression of TLR2, we hypothesized that there is a functional defect in this receptor and/or its downstream in the peripheral blood mononuclear cells (PBMCs) of CVID patients. PMID- 29757593 TI - Severe Combined Immunodeficiency: A Case Series and Review from a Tertiary Pediatric Hospital. AB - Severe combined immunodeficiency syndrome (SCID) is a life-threatening condition leading to early infant death as a result of severe infection, due to impaired cellular and humoral immune systems. Various forms of SCID are classified based on the presence or absence of T cells, B cells and natural killer cells. Patients usually present with recurrent infections and failure to thrive. Definitive treatment is hematopoietic stem cell transplantation. To achieve the best outcome, it should be performed prior to the development of severe infection. In This study, we described 10 patients (6 male and 4 female) with SCID who were admitted to Mofid Children Hospital, Tehran, Iran, from 2006 to 2013. We reviewed patients' clinical manifestation, laboratory data, family history and outcome. The mean age at the time of diagnosis was 131.8 days. One patient had non consanguineous parents. Seven patients received BCG vaccine before the diagnosis of SCID, three of them showed disseminated BCG infection. One patient presented with invasive pulmonary aspergillosis. Flow cytometric analysis showed T-B+NK- in three patients, T-B-NK+ in five patients, T-B-NK- in one patient, and T-B+NK+ in one patient. This study highlights the importance of early diagnosis and patient referral before the occurrence of serious infection. PMID- 29757594 TI - Transport IVF-ICSI: Results of a 25-year experience. AB - OBJECTIVE: This report presents a summary of the outcomes achieved at ART center FERTILAB in Buenos Aires, Argentina, with transport IVF-ICSI for 25 years (1990 2014). METHODS: This report included all patients submitted to oocyte retrieval for IVF-ICSI whose oocytes were transported from sites of aspiration located 0.5 58 kilometers away from the central laboratory. The numeric data herein reported were taken from annual reports submitted by our institution (Fertilab) and, for purposes of comparison, by all Argentinian centers to the Latin American Registry of Assisted Reproduction (RLA) within the same time period. RESULTS: From 1990 to 2014, 5091 aspirations followed by oocyte transport were performed in our center, resulting in 1258 pregnancies after fresh embryo transfers. The mean pregnancy/aspiration rate for the 25-year period was 24.71%. To validate the efficacy of our transport system, our results were compared to the outcomes of Argentinian centers reporting to RLA Argentina in the period ranging from 1990 to 2014. A total of 79,062 aspirations were performed, yielding 20,047 pregnancies and a pregnancy/aspiration rate of 25.36%. Delivery/aspirations rates were 15.34% for Fertilab patients and 14.79% for RLA Argentina centers. CONCLUSION: The results showed that the differences in clinical outcomes between our center and the bulk of Argentinian centers were not statistically significant, indicating that oocyte transport does not decrease the effectiveness of IVF-ICSI and might be advantageous under certain circumstances. PMID- 29757597 TI - Near-Infrared Light-Excited Upconverting Persistent Nanophosphors in Vivo for Imaging-Guided Cell Therapy. AB - Optical imaging for biological applications is in need of more sensitive tool. Persistent luminescent nanophosphors enable highly sensitive in vivo optical detection and almost completely avoid tissue autofluorescence. Nevertheless, the actual persistent luminescent nanophosphors necessitate ex vivo activation before systemic operation, which severely restricted the use of long-term imaging in vivo. Hence, we introduced a novel generation of optical nanophosphors, based on (Zn2SiO4:Mn):Y3+, Yb3+, Tm3+ upconverting persistent luminescent nanophosphors; these nanophosphors can be excited in vivo through living tissues by highly penetrating near-infrared light. We can trace labeled tumor therapeutic macrophages in vivo after endocytosing these nanophosphors in vitro and follow macrophages biodistribution by a simple whole animal optical detection. These nanophosphors will open novel potentials for cell therapy research and for a variety of applications in diagnosis in vivo. PMID- 29757598 TI - Switching Brake Materials To Extremely Wear-Resistant Self-Lubrication Materials via Tuning Interface Nanostructures. AB - Tribological performance of motion components is one of the key aspects that must be considered in a wide range of applications such as vehicles, aircrafts, and manufacturing equipment. This work demonstrates that further addition of only low loading hard nanoparticles into a formulated nonasbestos organic brake material directly switches its functionality to a self-lubrication material. More importantly, the newly developed nanocomposites exhibit an extremely low wear rate. Comprehensive investigations on the friction interface reveal that the great friction and wear reduction are due to the formation of a nanostructured lubricious tribofilm. Tribofilm formation is continuously fed by complex molecular species released from the bulk nanocomposites, for which nanoparticles digested within the tribofilm greatly enhance its robustness and lubricity. This work gains insight into the crucial role of the interface nanostructure and paves a route for developing extremely wear-resistant self-lubrication composites for numerous applications. PMID- 29757599 TI - Native Alanine Substitution in the Glycine Hinge Modulates Conformational Flexibility of Heme Nitric Oxide/Oxygen (H-NOX) Sensing Proteins. AB - Heme nitric oxide/oxygen sensing (H-NOX) domains are direct NO sensors that regulate a variety of biological functions in both bacteria and eukaryotes. Previous work on H-NOX proteins has shown that upon NO binding, a conformational change occurs along two glycine residues on adjacent helices (termed the glycine hinge). Despite the apparent importance of the glycine hinge, it is not fully conserved in all H-NOX domains. Several H-NOX sensors from the family Flavobacteriaceae contain a native alanine substitution in one of the hinge residues. In this work, the effect of the increased steric bulk within the Ala Gly hinge on H-NOX function was investigated. The hinge in Kordia algicida OT-1 ( Ka H-NOX) is composed of A71 and G145. Ligand-binding properties and signaling function for this H-NOX were characterized. The variant A71G was designed to convert the hinge region of Ka H-NOX to the typical Gly-Gly motif. In activity assays with its cognate histidine kinase (HnoK), the wild type displayed increased signal specificity compared to A71G. Increasing titrations of unliganded A71G gradually inhibits HnoK autophosphorylation, while increasing titrations of unliganded wild type H-NOX does not inhibit HnoK. Crystal structures of both wild type and A71G Ka H-NOX were solved to 1.9 and 1.6 A, respectively. Regions of H-NOX domains previously identified as involved in protein-protein interactions with HnoK display significantly higher b-factors in A71G compared to wild-type H-NOX. Both biochemical and structural data indicate that the hinge region controls overall conformational flexibility of the H-NOX, affecting NO complex formation and regulation of its HnoK. PMID- 29757600 TI - DARK Classics in Chemical Neuroscience: Morphine. AB - As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Serturner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States. Morphine is a molecule of great cultural relevance, as the agent that single-handedly transformed our understanding of pharmacognosy, receptor dynamics, and substance abuse and dependence disorders. PMID- 29757601 TI - Fluorescence Detection of Bone Microcracks Using Monophosphonated Carbon Dots. AB - Phosphonated compounds, in particular, bisanalogs are widely applied in clinical settings for the treatment of severe bone turnovers and recently as imaging probes when conjugated with organic fluorophores. Herein, we introduce a bone seeking luminescent probe that shows a high binding affinity toward bone minerals based on monophosphonated carbon dots (CDs). Spheroidal CDs tethered with PEG monophosphates are synthesized in a one-pot hydrothermal method and are physicochemically characterized, where the retention of phosphonates is confirmed by 13P NMR and X-ray photoelectron spectroscopy. Interestingly, the high abundance of multiple monodentate phosphonates exhibited strong binding to hydroxyapatite, the main bone mineral constituent. The remarkable optophysical properties of monophosphonated CDs were confirmed in an ex vivo model of the bovine cortical bone where the imaging feasibility of microcracks, which are calcium-rich regions, was demonstrated. The in vivo studies specified the potential application of monophosphonated CDs for imaging when injected intramuscularly. The biodigestible nature and cytocompatibility of the probe presented here obviate the demand for a secondary fluorophore, while offering a nanoscale strategy for bone targeting and can eventually be employed for potential bone therapy in the future. PMID- 29757603 TI - Alzheimer's Disease, Dendritic Spines, and Calcineurin Inhibitors: A New Approach? AB - Therapeutics to effectively treat Alzheimer's disease (AD) are lacking. In vitro, animal and human studies have implicated the excessive activation of the protein phosphatase calcineurin (CN) as an early step in the pathogenesis of AD. We discuss recent data showing that the prolyl isomerase Pin1 is suppressed by CN mediated dephosphorylation induced by Abeta42 signaling. Pin1 loss directly leads to the reductions in dendritic spines and synapses characteristic of early AD pathology. Pin1 activity, and synapse and dendritic spine numbers are rescued by FK506, a highly specific and United States Food and Drug Administration approved CN inhibitor. Solid organ transplant recipients chronically treated with FK506 showed much lower AD incidence than expected. As such, we suggest prospective clinical trials to determine if systemic FK506 can normalize CN activity in the brain, preserve Pin1 function and support synaptic health in early AD. PMID- 29757602 TI - Visualization of Electronic Multiple Ordering and Its Dynamics in High Magnetic Field: Evidence of Electronic Multiple Ordering Crystals. AB - Constituent atoms and electrons determine matter properties together, and they can form long-range ordering respectively. Distinguishing and isolating the electronic ordering out from the lattice crystal is a crucial issue in contemporary materials science. However, the intrinsic structure of a long-range electronic ordering is difficult to observe because it can be easily affected by many external factors. Here, we present the observation of electronic multiple ordering (EMO) and its dynamics at the micrometer scale in a manganite thin film. The strong internal couplings among multiple electronic degrees of freedom in the EMO make its morphology robust against external factors and visible via well defined boundaries along specific axes and cleavage planes, which behave like a multiple-ordered electronic crystal. A strong magnetic field up to 17.6 T is needed to completely melt such EMO at 7 K, and the corresponding formation, motion, and annihilation dynamics are imaged utilizing a home-built high-field magnetic force microscope. The EMO is parasitic within the lattice crystal house, but its dynamics follows its own rules of electronic correlation, therefore becoming distinguishable and isolatable as the electronic ordering. Our work provides a microscopic foundation for the understanding and control of the electronic ordering and the designs of the corresponding devices. PMID- 29757604 TI - A Symmetric Molecule Produced by Mycobacteria Generates Cell-Length Asymmetry during Cell-Division and Thereby Cell-Length Heterogeneity. AB - Diadenosine polyphosphates, Ap(2-7)A, which contain two adenosines in a 5',5' linkage through phosphodiester bonds involving 2-7 phosphates, regulate diverse cellular functions in all organisms, from bacteria to humans, under normal and stress conditions. We had earlier reported consistent occurrence of asymmetric constriction during division (ACD) in 20-30% of dividing mycobacterial cells in culture, irrespective of different growth media, implying exogenous action of some factor of mycobacterial origin. Consistent with this premise, concentrated culture supernatant (CCS), but not the equivalent volume-wise concentrated unused medium, dramatically enhanced the ACD proportion to 70-90%. Mass spectrometry and biochemical analyses of the bioactive fraction from CCS revealed the ACD effecting factor to be Ap6A. Synthetic Ap6A showed a mass spectrometry profile, biochemical characteristics, and bioactivity identical to native Ap6A in the CCS. Thus, the present work reveals a novel role for Ap6A in generating cell-length asymmetry during mycobacterial cell-division and thereby cell-length heterogeneity in the population. PMID- 29757605 TI - Structural Basis for Natural Product Selection and Export by Bacterial ABC Transporters. AB - Bacteria under stress produce ribosomally synthesized and post-translationally modified peptides (RiPPs) to target closely related species, such as the lasso peptide microcin J25 (MccJ25). These peptides are also toxic to the producing organisms that utilize dedicated ABC transporters to achieve self-immunity. MccJ25 is exported by the Escherichia coli ABC transporter McjD through a complex mechanism of recognition that has remained elusive. Here, we used biomolecular NMR to study this interaction and identified a region of the toxic peptide that is crucial to its recognition by the ABC transporter. Our study provides evidence that McjD is highly specific to MccJ25 and not to other RiPPs or antibiotics, unlike multidrug ABC transporters. Additionally, we show that MccJ25 is not exported by another natural product ABC transporter. Therefore, we propose that specific interactions between natural product ABC transporters and their substrate provides them with their high degree of specificity. Taken together, these findings suggest that ABC transporters might have acquired structural elements in their binding cavity to recognize and allow promiscuous export of a larger variety of compounds. PMID- 29757606 TI - Monobody-Mediated Alteration of Lipase Substrate Specificity. AB - Controlling the catalytic properties of enzymes remain an important challenge in chemistry and biotechnology. We have recently established a strategy for altering enzyme specificity in which the addition of proxy monobodies, synthetic binding proteins, modulates the specificity of an otherwise unmodified enzyme. Here, in order to examine its broader applicability, we employed the strategy on Candida rugosa lipase 1 (CRL1), an enzyme with a tunnel-like substrate binding site. We successfully identified proxy monobodies that restricted the substrate specificity of CRL1 toward short-chain fatty acids. The successes with this enzyme system and a beta-galactosidase used in the previous work suggest that our strategy can be applied to diverse enzymes with distinct architectures of substrate binding sites. PMID- 29757607 TI - Dual pH-Responsive Shell-Cleavable Polycarbonate Micellar Nanoparticles for in Vivo Anticancer Drug Delivery. AB - To exploit tumor and intracellular microenvironments, pH-responsive diblock copolymers of poly(ethylene glycol) and catechol-functionalized polycarbonate with acid-labile acetal bond as the linker are synthesized to prepare micellar nanoparticles that shed the shell at acidic tumor tissues and inside cancer cells, hence accelerating drug release at the target. The pH-dependent cleavage of the shell is demonstrated at pH 5.0 and 6.5 using 1H NMR. Bortezomib (BTZ, an anticancer drug containing a phenylboronic acid group) is conjugated to the polymers through formation of pH-responsive boronate ester bond between boronic acid and catechol in the polymers. Dual pH-responsive bortezomib-polymer conjugates (BTZ-PC) self-assemble into micellar nanoparticles of small size (<110 nm) with narrow size distribution and high drug loading capacity. Acidic pH accelerates BTZ release from BTZ-PC micelles and enhances intracelluar uptake of the micelles, hence increasing in vitro cytotoxicity against human breast cancer cells. More importantly, the BTZ-PC micelles achieve a stronger antitumor effect in a human breast cancer BT-474 xenograft mouse model than free BTZ and mitigate in vivo hepatotoxicity of BTZ. These dual pH-responsive shell-cleavable nanoparticles are a potentially promising carrier for BTZ delivery. PMID- 29757608 TI - The Fight Against Antimicrobial Resistance Is Confounded by a Global Increase in Antibiotic Usage. AB - Antimicrobial resistance is a serious threat to global health. Despite numerous initiatives designed to curb excessive and inappropriate use of antibiotics, a recent report ( Klein et al. ( 2018 ) Proc. Natl. Acad. Sci. U. S. A. , 115 , E3463 ) finds that there was a substantial increase in global antibiotic consumption by humans from 2000 to 2015 and predicts a further 200% increase by 2030. Alarmingly, much of this growth is occurring in "last-resort" antibiotics. The study excludes the extensive use of antibiotics in agriculture and aquaculture. This Viewpoint examines the report's findings and discusses them in the context of other recent developments in antimicrobial resistance. PMID- 29757609 TI - Permselective SPEEK/Nafion Composite-Coated Separator as a Potential Polysulfide Crossover Barrier Layer for Li-S Batteries. AB - Minimizing the shuttle effect by constraining polysulfides to the cathode compartment and activating the passive layer between cathode and separator are highly important for improving the Li-S cell performance, Coulombic efficiency, and cycle life. Here, we report a submicron thin coating of permselective sulfonated poly(ether ether ketone) (SPEEK) composite layer on the separator that would reduce polysulfide crossover, imparting a significant improvement in cycle life. It is observed that SPEEK increases the stability, and adding Nafion improves the capacity value. Among different ratios of Nafion and SPEEK (25:75, 50:50, and 75:25), the composite with a SPEEK/Nafion ratio of 50:50 showed a controlled shuttle effect with a stable cell capacity of 600 mA h g-1 up to 300 cycles. This modified separator with permselective coatings not only reduces the polysulfide shuttle but also improves the wettability and interfacial contact, which results in an improvement in average cell potential and lithium diffusivity. It is demonstrated here that the combination of functional (ionomer coating on separator) and nonfunctional (extra cathode layer) physical barriers effectively suppresses the polysulfide crossover and improves the electrochemical performance of Li-S batteries. The cell shows an initial capacity of 1300 mA h g 1 and a capacity retention of 650 mA h g-1 over 500 cycles with a 6 mg/cm2 sulfur loading. PMID- 29757610 TI - Self-Reconstructed Formation of a One-Dimensional Hierarchical Porous Nanostructure Assembled by Ultrathin TiO2 Nanobelts for Fast and Stable Lithium Storage. AB - Owing to their unique structural advantages, TiO2 hierarchical nanostructures assembled by low-dimensional (LD) building blocks have been extensively used in the energy-storage/-conversion field. However, it is still a big challenge to produce such advanced structures by current synthetic techniques because of the harsh conditions needed to generate primary LD subunits. Herein, a novel one dimensional (1D) TiO2 hierarchical porous fibrous nanostructure constructed by TiO2 nanobelts is synthesized by combining a room-temperature aqueous solution growth mechanism with the electrospinning technology. The nanobelt-constructed 1D hierarchical nanoarchitecture is evolves directly from the amorphous TiO2/SiO2 composite fibers in alkaline solutions at ambient conditions without any catalyst and other reactant. Benefiting from the unique structural features such as 1D nanoscale building blocks, large surface area, and numerous interconnected pores, as well as mixed phase anatase-TiO2(B), the optimum 1D TiO2 hierarchical porous nanostructure shows a remarkable high-rate performance when tested as an anode material for lithium-ion batteries (107 mA h g-1 at ~10 A g-1) and can be used in a hybrid lithium-ion supercapacitor with very stable lithium-storage performance (a capacity retention of ~80% after 3000 cycles at 2 A g-1). The current work presents a scalable and cost-effective method for the synthesis of advanced TiO2 hierarchical materials for high-power and stable energy-storage/-conversion devices. PMID- 29757612 TI - Autofluorescence-Free Immunoassay Using X-ray Scintillating Nanotags. AB - Autofluorescence background in complex biological samples is a major challenge in achieving high sensitivity of fluorescence immunoassays (FIA). Here we report an X-ray luminescence-based immunoassay for high-sensitivity detection of biomarkers using X-ray scintillating nanotags. Due to the weak scattering and absorption of most biological chromophores by X-ray excitation, a low-dose X-ray source can be used to produce intense scintillating luminescence from the nanotags for autofluorescence-free biosensing. To demonstrate this concept, we designed and synthesized NaGdF4:Tb@NaYF4 core/shell nanoparticles as kind of high-efficiency X ray scintillating nanotags, which are able to convert high-energy X-ray photons to visible light without autofluorescence in biological samples. Notably, strong X-ray absorption and minimized surface quenching arising from the heavy Gd3+/Tb3+ atoms and core/shell architecture of the nanoparticles were found to be critically important for high-efficiency X-ray excited luminescence for high sensitivity biosensing. Our method allows for sensing alpha-fetoprotein (AFP) biomarkers with a detection limit down to 0.25 ng/mL. Moreover, the as-described X-ray luminescence immunoassay exhibited an excellent biological specificity, high stability, and sample recovery, implying an opportunity for applications in complex biological samples. Consequently, our method can be readily extended for multiplexing sensing and medical diagnosis. PMID- 29757613 TI - Confocal Raman Microscopy for in Situ Measurement of Phospholipid-Water Partitioning into Model Phospholipid Bilayers within Individual Chromatographic Particles. AB - The phospholipid-water partition coefficient is a commonly measured parameter that correlates with drug efficacy, small-molecule toxicity, and accumulation of molecules in biological systems in the environment. Despite the utility of this parameter, methods for measuring phospholipid-water partition coefficients are limited. This is due to the difficulty of making quantitative measurements in vesicle membranes or supported phospholipid bilayers, both of which are small volume phases that challenge the sensitivity of many analytical techniques. In this work, we employ in situ confocal Raman microscopy to probe the partitioning of a model membrane-active compound, 2-(4-isobutylphenyl) propionic acid or ibuprofen, into both hybrid- and supported-phospholipid bilayers deposited on the pore walls of individual chromatographic particles. The large surface-area-to volume ratio of chromatographic silica allows interrogation of a significant lipid bilayer area within a very small volume. The local phospholipid concentration within a confocal probe volume inside the particle can be as high as 0.5 M, which overcomes the sensitivity limitations of making measurements in the limited membrane areas of single vesicles or planar supported bilayers. Quantitative determination of ibuprofen partitioning is achieved by using the phospholipid acyl-chains of the within-particle bilayer as an internal standard. This approach is tested for measurements of pH-dependent partitioning of ibuprofen into both hybrid-lipid and supported-lipid bilayers within silica particles, and the results are compared with octanol-water partitioning and with partitioning into individual optically trapped phospholipid vesicle membranes. Additionally, the impact of ibuprofen partitioning on bilayer structure is evaluated for both within-particle model membranes and compared with the structural impacts of partitioning into vesicle lipid bilayers. PMID- 29757611 TI - Simple Synthetic Molecular Hydrogels from Self-Assembling Alkylgalactonamides as Scaffold for 3D Neuronal Cell Growth. AB - In this work, we demonstrated that the hydrogel obtained from a very simple and single synthetic molecule, N-heptyl-galactonamide was a suitable scaffold for the growth of neuronal cells in 3D. We evidenced by confocal microscopy the presence of the cells into the gel up to a depth of around 200 MUm, demonstrating that the latter was permissive to cell growth and enabled a true 3D colonization and organization. It also supported successfully the differentiation of adult human neuronal stem cells (hNSCs) into both glial and neuronal cells and the development of a really dense neurofilament network. So the gel appears to be a good candidate for neural tissue regeneration. In contrast with other molecular gels described for cell culture, the molecule can be obtained at the gram scale by a one-step reaction. The resulting gel is very soft, a quality in accordance with the aim of growing neuronal cells, that requires low modulus substrates similar to the brain. But because of its fragility, specific procedures had to be implemented for its preparation and for cell labeling and confocal microscopy observations. Notably, the implementation of a controlled slow cooling of the gel solution was needed to get a very soft but nevertheless cohesive gel. In these conditions, very wide straight and long micrometric fibers were formed, held together by a second network of flexible narrower nanometric fibers. The two kinds of fibers guided the neurite and glial cell growth in a different way. We also underlined the importance of a tiny difference in the molecular structure on the gel performances: parent molecules, differing by a one-carbon increment in the alkyl chain length, N-hexyl-galactonamide and N-octyl-galactonamide, were not as good as N-heptyl-galactonamide. Their differences were analyzed in terms of gel fibers morphology, mechanical properties, solubility, chain parity, and cell growth. PMID- 29757615 TI - Hyperspectral Stimulated Raman Scattering Microscopy Unravels Aberrant Accumulation of Saturated Fat in Human Liver Cancer. AB - Lipid metabolism is dysregulated in human cancers. The analytical tools that could identify and quantitatively map metabolites in unprocessed human tissues with submicrometer resolution are highly desired. Here, we implemented analytical hyperspectral stimulated Raman scattering microscopy to map the lipid metabolites in situ in normal and cancerous liver tissues from 24 patients. In contrast to the conventional wisdom that unsaturated lipid accumulation enhances tumor cell survival and proliferation, we unexpectedly visualized substantial amount of saturated fat accumulated in cancerous liver tissues, which was not seen in majority of their adjacent normal tissues. Further analysis by mass spectrometry confirmed significant high levels of glyceryl tripalmitate specifically in cancerous liver. These findings suggest that the aberrantly accumulated saturated fat may have great potential to be a metabolic biomarker for liver cancer. PMID- 29757614 TI - Preserving Cellulose Structure: Delignified Wood Fibers for Paper Structures of High Strength and Transparency. AB - To expand the use of renewable materials, paper products with superior mechanical and optical properties are needed. Although beating, bleaching, and additives are known to improve industrially produced Kraft pulp papers, properties are limited by the quality of the fibers. While the use of nanocellulose has been shown to significantly increase paper properties, the current cost associated with their production has limited their industrial relevance. Here, using a simple mild peracetic acid (PAA) delignification process on spruce, we produce hemicellulose rich holocellulose fibers (28.8 wt %) with high intrinsic strength (1200 MPa for fibers with microfibrillar angle smaller than 10 degrees ). We show that PAA treatment causes less cellulose/hemicellulose degradation and better preserves cellulose nanostructure in comparison to conventional Kraft pulping. High-density holocellulose papers with superior mechanical properties (Young's modulus of 18 GPa and ultimate strength of 195 MPa) are manufactured using a water-based hot pressing process, without the use of beating or additives. We propose that the preserved hemicelluloses act as "glue" in the interfiber region, improving both mechanical and optical properties of papers. Holocellulose fibers may be affordable and applicable candidates for making special paper/composites where high mechanical performance and/or optical transmittance are of interest. PMID- 29757616 TI - Solid-Phase Microextraction of DNA from Mycobacteria in Artificial Sputum Samples To Enable Visual Detection Using Isothermal Amplification. AB - Point-of-care (POC) technologies for the detection of pathogens in clinical samples are highly valued due to their speed, ease of use, and cost effectiveness. Furthermore, they are ideally suited for resource-limited settings where expensive and sophisticated laboratory equipment may not be readily available. In this study, a rapid method based on solid-phase microextraction (SPME) of mycobacterial DNA with subsequent isothermal amplification and visual detection was developed. Direct coupling of the SPME desorption solution (1 M NaCl) to the isothermal reaction system was achieved to circumvent dilution steps and improve detection limits. Using this method, DNA was preconcentrated from lysed mycobacteria in just 2 min, subjected to isothermal multiple-self-matching initiated amplification (IMSA), and the amplicons were detected visually. With a total analysis times of less than 2 h, the optimized method was capable of extracting and visually detecting mycobacterial DNA from artificial sputum samples containing clinically relevant concentrations of mycobacteria (107 colony forming units/mL), demonstrating its potential for future POC applications. PMID- 29757617 TI - Freeze-Casting Produces a Graphene Oxide Aerogel with a Radial and Centrosymmetric Structure. AB - We report the assembly of graphene oxide (G-O) building blocks into a vertical and radially aligned structure by a bidirectional freeze-casting approach. The crystallization of water to ice assembles the G-O sheets into a structure, a G-O aerogel whose local structure mimics turbine blades. The centimeter-scale radiating structure in this aerogel has many channels whose width increases with distance from the center. This was achieved by controlling the formation of the ice crystals in the aqueous G-O dispersion that grew radially in the shape of lamellae during freezing. Because the shape and size of ice crystals is influenced by the G-O sheets, different additives (ethanol, cellulose nanofibers, and chitosan) that can form hydrogen bonds with H2O were tested and found to affect the interaction between the G-O and formation of ice crystals, producing ice crystals with different shapes. A G-O/chitosan aerogel with a spiral pattern was also obtained. After chemical reduction of G-O, our aerogel exhibited elasticity and absorption capacity superior to that of graphene aerogels with "traditional" pore structures made by conventional freeze-casting. This methodology can be expanded to many other configurations and should widen the use of G-O (and reduced G-O and "graphenic") aerogels. PMID- 29757618 TI - Does Size Matter? An Experimental Evaluation of the Relative Abundance and Decay Rates of Aquatic Environmental DNA. AB - Environmental DNA (eDNA) is increasingly used to monitor aquatic macrofauna. Typically, short mitochondrial DNA fragments are targeted because these should be relatively more abundant in the environment as longer fragments will break into smaller fragments over time. However, longer fragments may permit more flexible primer design and increase taxonomic resolution for eDNA metabarcoding analyses, and recent studies have shown that long mitochondrial eDNA fragments can be extracted from environmental water samples. Nuclear eDNA fragments have also been proposed as targets, but little is known about their persistence in the aquatic environment. Here we measure the abundance of mitochondrial eDNA fragments of different lengths and of short nuclear eDNA fragments, originating from captive fish in experimental tanks, and we test whether longer mitochondrial and short nuclear fragments decay faster than short mitochondrial fragments following fish removal. We show that when fish are present, shorter mitochondrial fragments are more abundant in water samples than both longer mitochondrial fragments and short nuclear eDNA fragments. However, the rate of decay following fish removal was similar for all fragment types, suggesting that the differences in abundance resulted from differences in the rates at which different fragment types were produced rather than differences in their decay rates. PMID- 29757619 TI - Transparent, Flexible, and Strong 2,3-Dialdehyde Cellulose Films with High Oxygen Barrier Properties. AB - 2,3-Dialdehyde cellulose (DAC) of a high degree of oxidation (92% relative to AGU units) prepared by oxidation of microcrystalline cellulose with sodium periodate (48 degrees C, 19 h) is soluble in hot water. Solution casting, slow air drying, hot pressing, and reinforcement by cellulose nanocrystals afforded films (~100 MUm thickness) that feature intriguing properties: they have very smooth surfaces (SEM), are highly flexible, and have good light transmittance for both the visible and near-infrared range (89-91%), high tensile strength (81-122 MPa), and modulus of elasticity (3.4-4.0 GPa) depending on hydration state and respective water content. The extraordinarily low oxygen permeation of <0.005 cm3 MUm m-2 day-1 kPa-1 (50% RH) and <0.03 cm3 MUm m-2 day-1 kPa-1 (80% RH) can be regarded as a particularly interesting feature of DAC films. The unusually high initial contact angle of about 67 degrees revealed a rather low hydrophilicity compared to other oxidatively modified or unmodified cellulosic materials which is most likely the result of inter- and intramolecular hemiacetal and hemialdal formation during drying and pressing. PMID- 29757620 TI - Separation of Protactinium Employing Sulfur-Based Extraction Chromatographic Resins. AB - Protactinium-230 ( t1/2 = 17.4 d) is the parent isotope of 230U ( t1/2 = 20.8 d), a radionuclide of interest for targeted alpha therapy (TAT). Column chromatographic methods have been developed to separate no-carrier-added 230Pa from proton irradiated thorium targets and accompanying fission products. Results reported within demonstrate the use of novel sulfur bearing chromatographic extraction resins for the selective separation of protactinium. The recovery yield of 230Pa was 93 +/- 4% employing a R3P?S type commercially available resin and 88 +/- 4% employing a DGTA (diglycothioamide) containing custom synthesized extraction chromatographic resin. The radiochemical purity of the recovered 230Pa was measured via high purity germanium gamma-ray spectroscopy to be >99.5% with the remaining radioactive contaminant being 95Nb due to its similar chemistry to protactinium. Measured equilibrium distribution coefficients for protactinium, thorium, uranium, niobium, radium, and actinium on both the R3P?S type and the DGTA resin in hydrochloric acid media are reported, to the best of our knowledge, for the first time. PMID- 29757621 TI - Significant Enhancement of Visible-Light-Driven Hydrogen Evolution by Structure Regulation of Carbon Nitrides. AB - Photocatalytic water splitting for hydrogen evolution by utilizing solar energy has a great significance for high-density solar energy storage and environmental sustainability. Here, a defect-rich amorphous carbon nitride (DACN) photocatalyst has been synthesized by simply direct calcination of the rationally size-reduced urea crystals. The introduction of nitrogen vacancies combined with disordered structure cause a broad visible-light-reponsive range, countless lateral edge/exposed surface bonding sites, and quenched radiative recombination, suggesting that this DACN enhances photocatalytic activity for hydrogen production. A record high hydrogen evolution rate of 37,680 MUmol h-1 g-1 under visible-light irradiation and an extraordinary apparent quantum efficiency of 34.4% at 400 nm were achieved, higher than most of the existing graphitic carbon nitride-based photocatalysts. PMID- 29757622 TI - Iron Vacancies Accommodate Uranyl Incorporation into Hematite. AB - Radiotoxic uranium contamination in natural systems and nuclear waste containment can be sequestered by incorporation into naturally abundant iron (oxyhydr)oxides such as hematite (alpha-Fe2O3) during mineral growth. The stability and properties of the resulting uranium-doped material are impacted by the local coordination environment of incorporated uranium. While measurements of uranium coordination in hematite have been attempted using extended X-ray absorption fine structure (EXAFS) analysis, traditional shell-by-shell EXAFS fitting yields ambiguous results. We used hybrid functional ab initio molecular dynamics (AIMD) simulations for various defect configurations to generate synthetic EXAFS spectra which were combined with adsorbed uranyl spectra to fit experimental U L3-edge EXAFS for U6+-doped hematite. We discovered that the hematite crystal structure accommodates a trans-dioxo uranyl-like configuration for U6+ that substitutes for structural Fe3+, which requires two partially protonated Fe vacancies situated at opposing corner-sharing sites. Surprisingly, the best match to experiment included significant proportions of vacancy configurations other than the minimum energy configuration, pointing to the importance of incorporation mechanisms and kinetics in determining the state of an impurity incorporated into a host phase under low temperature hydrothermal conditions. PMID- 29757623 TI - Epitaxial Welding of Carbon Nanotube Networks for Aqueous Battery Current Collectors. AB - Carbon nanomaterials are desirable candidates for lightweight, highly conductive, and corrosion-resistant current collectors. However, a key obstacle is their weak interconnection between adjacent nanostructures, which renders orders of magnitude lower electrical conductivity and mechanical strength in the bulk assemblies. Here we report an "epitaxial welding" strategy to engineer carbon nanotubes (CNTs) into highly crystalline and interconnected structures. Solution based polyacrylonitrile was conformally coated on CNTs as "nanoglue" to physically join CNTs into a network, followed by a rapid high-temperature annealing (>2800 K, overall ~30 min) to graphitize the polymer coating into crystalline layers that also bridge the adjacent CNTs to form an interconnected structure. The contact-welded CNTs (W-CNTs) exhibit both a high conductivity (~1500 S/cm) and a high tensile strength (~120 MPa), which are 5 and 20 times higher than the unwelded CNTs, respectively. In addition, the W-CNTs display chemical and electrochemical stabilities in strong acidic/alkaline electrolytes (>6 mol/L) when potentiostatically stressing at both cathodic and anodic potentials. With these exceptional properties, the W-CNT films are optimal as high-performance current collectors and were demonstrated in the state-of-the-art aqueous battery using a "water-in-salt" electrolyte. PMID- 29757624 TI - Steric Control of the Rate-Limiting Step of UDP-Galactopyranose Mutase. AB - Galactose is an abundant monosaccharide found exclusively in mammals as galactopyranose (Gal p), the six-membered ring form of this sugar. In contrast, galactose appears in many pathogenic microorganisms as the five-membered ring form, galactofuranose (Gal f). Gal f biosynthesis begins with the conversion of UDP-Gal p to UDP-Gal f catalyzed by the flavoenzyme UDP-galactopyranose mutase (UGM). Because UGM is essential for the survival and proliferation of several pathogens, there is interest in understanding the catalytic mechanism to aid inhibitor development. Herein, we have used kinetic measurements and molecular dynamics simulations to explore the features of UGM that control the rate limiting step (RLS). We show that UGM from the pathogenic fungus Aspergillus fumigatus also catalyzes the isomerization of UDP-arabinopyranose (UDP-Ara p), which differs from UDP-Gal p by lacking a -CH2-OH substituent at the C5 position of the hexose ring. Unexpectedly, the RLS changed from a chemical step for the natural substrate to product release with UDP-Ara p. This result implicated residues that contact the -CH2-OH of UDP-Gal p in controlling the mechanistic path. The mutation of one of these residues, Trp315, to Ala changed the RLS of the natural substrate to product release, similar to the wild-type enzyme with UDP-Ara p. Molecular dynamics simulations suggest that steric complementarity in the Michaelis complex is responsible for this distinct behavior. These results provide new insight into the UGM mechanism and, more generally, how steric factors in the enzyme active site control the free energy barriers along the reaction path. PMID- 29757625 TI - Structure and Kinetics of the S-(+)-1-Amino-2-propanol Dehydrogenase from the RMM Microcompartment of Mycobacterium smegmatis. AB - S-(+)-1-Amino-2-propanol dehydrogenase (APDH) is a short-chain dehydrogenase/reductase associated with the incompletely characterized Rhodococcus and Mycobacterium bacterial microcompartment (RMM). We enzymatically characterized the APDH from M. smegmatis and showed it is highly selective, with a low micromolar Km for S-(+)-1-amino-2-propanol and specificity for NADP(H). A paralogous enzyme from a nonmicrocompartment-associated operon in the same organism was also shown to have a similar activity. We determined the structure of APDH in both apo form (at 1.7 A) and as a ternary enzyme complex with NADP+ and aminoacetone (at 1.9 A). Recognition of aminoacetone was mediated by strong hydrogen bonds to the amino group by Thr145 and by Glu251 from the C-terminus of an adjacent protomer. The substrate binding site entirely encloses the substrate, with close contacts between the aminoacetone methyl group and Phe95, Trp154, and Leu195. Kinetic characterization of several of these residues confirm their importance in enzyme functioning. Bioinformatics analysis of APDH homologues implies that many nonmicrocompartment APDH orthologues partake in an aminoacetone degradation pathway that proceeds via an aminopropanol O-phosphate phospholyase. RMM microcompartments may mediate a similar pathway, though possibly with differences in the details of the pathway that necessitates encapsulation behind a shell. PMID- 29757626 TI - Detection of Redox State Evolution during Wound Healing Process Based on a Redox Sensitive Wound Dressing. AB - To detect the redox state evolution during wound healing process, a redox sensitive surface-enhanced Raman scattering (SERS) probe was constructed by attaching anthraquinone as a redox-sensitive molecule onto gold nanoshells, and the redox-sensitive SERS probes were loaded on one surface of a chitosan membrane as a redox-sensitive wound dressing. The redox-sensitive wound dressing covered an acute wound as both a wound dressing and a redox state sensor. The spatiotemporal evolution of the redox states of the healing wound was obtained by collecting the SERS spectra of the SERS probes in situ and noninvasively. The domains with the lowest redox potential moved from the edge to the center of a wound during normal wound healing process, and high concentration of glucose blocked the movement of the domains and the healing process. The redox-sensitive wound dressing and the method of detecting redox states of the wound provide a new path for detection in vivo, which would benefit the understanding and therapy of wound healing and other pathophysiological processes. PMID- 29757627 TI - Microplastic Disguising As Soil Carbon Storage. PMID- 29757628 TI - Facile Method for the Controllable Synthesis of Cs xPb yBr z-Based Perovskites. AB - We report a facile method to realize the selective synthesis of Cs xPb yBr z based perovskites, including CsPbBr3, Cs4PbBr6 and CsPb2Br5. The use of an appropriate amount of N, N-dimethylformamide (DMF) solvent is experimentally determined to play a critical role in the controlled formation of various perovskite products. With continuously increasing DMF concentration, first CsPbBr3 nanocrystals with tunable size can be achieved, and then the production of Cs4PbBr6 and CsPb2Br5 perovskite analogues is successively realized. Our findings present a novel path for the controlled synthesis of other perovskite analogues for specific applications. PMID- 29757630 TI - Understanding the Role of Extracellular Polymeric Substances on Ciprofloxacin Adsorption in Aerobic Sludge, Anaerobic Sludge, and Sulfate-Reducing Bacteria Sludge Systems. AB - Extracellular polymeric substances (EPS) of microbial sludge play a crucial role in removal of organic micropollutants during biological wastewater treatment. In this study, we examined ciprofloxacin (CIP) removal in three parallel bench-scale reactors using aerobic sludge (AS), anaerobic sludge (AnS), and sulfate-reducing bacteria (SRB) sludge. The results showed that the SRB sludge had the highest specific CIP removal rate via adsorption and biodegradation. CIP removal by EPS accounted up to 35. 6 +/- 1.4%, 23.7 +/- 0.6%, and 25.5 +/- 0.4% of total removal in AS, AnS, and SRB sludge systems, respectively, at influent CIP concentration of 1000 MUg/L, which implied that EPS played a critical role in CIP removal. The binding mechanism of EPS on CIP adsorption in three sludge systems were further investigated using a series of batch tests. The results suggested that EPS of SRB sludge possessed stronger hydrophobicity (proteins/polysaccharides (PN/PS) ratio), higher availability of adsorption sites (binding sites ( n)), and higher binding strength (binding constant ( Kb)) between EPS and CIP compared to those of AS and AnS. The findings of this study provide an insight into the role of EPS in biological process for treating CIP-laden wastewaters. PMID- 29757629 TI - Signature of Antibody Domain Exchange by Native Mass Spectrometry and Collision Induced Unfolding. AB - The development of domain-exchanged antibodies offers a route to high-affinity targeting to clustered multivalent epitopes, such as those associated with viral infections and many cancers. One strategy to generate these antibodies is to introduce mutations into target antibodies to drive domain exchange using the only known naturally occurring domain-exchanged anti-HIV (anti-human immunodeficiency virus) IgG1 antibody, 2G12 , as a template. Here, we show that domain exchange can be sensitively monitored by ion-mobility mass spectrometry and gas-phase collision-induced unfolding. Using native 2G12 and a mutated form that disrupts domain exchange such that it has a canonical IgG1 architecture ( 2G12 I19R ), we show that the two forms can be readily distinguished by their unfolding profiles. Importantly, the same signature of domain exchange is observed for both intact antibody and isolated Fab fragments. The development of a mass spectrometric method to detect antibody domain exchange will enable rapid screening and selection of candidate antibodies engineered to exhibit this and other unusual quaternary antibody architectures. PMID- 29757631 TI - Understanding Which Residues of the Active Site and Loop Structure of a Tyrosine Aminomutase Define Its Mutase and Lyase Activities. AB - Site-directed mutations and substrate analogues were used to gain insights into the branch-point reaction of the 3,5-dihydro-5-methylidene-4 H-imidazol-4-one (MIO)-tyrosine aminomutase from Oryza sativa ( OsTAM). Exchanging the active residues of OsTAM (Y125C/N446K) for those in a phenylalanine aminomutase TcPAM altered its substrate specificity from tyrosine to phenylalanine. The aminomutase mechanism of OsTAM surprisingly changed almost exclusively to that of an ammonia lyase making cinnamic acid (>95%) over beta-phenylalanine [Walter, T., et al. (2016) Biochemistry 55, 3497-3503]. We hypothesized that the missing electronics or sterics on the aryl ring of the phenylalanine substrate, compared with the sizable electron-donating hydroxyl of the natural tyrosine substrate, influenced the unexpected lyase reactivity of the OsTAM mutant. The double mutant was incubated with 16 alpha-phenylalanine substituent analogues of varying electronic strengths and sterics. The mutant converted each analogue principally to its acrylate with ~50% conversion of the p-Br substrate, making only a small amount of the beta-amino acid. The inner loop structure over the entrance to the active site was also mutated to assess how the lyase and mutase activities are affected. An OsTAM loop mutant, matching the loop residues of TcPAM, still chiefly made >95% of the acrylate from each substrate. A combined active site:loop mutant was most reactive but remained a lyase, making 10-fold more acrylates than other mutants did. While mutations within the active site changed the substrate specificity of OsTAM, continued exploration is needed to fully understand the interplay among the inner loop, the substrate, and the active site in defining the mutase and lyase activities. PMID- 29757632 TI - An Efficient Method for the Expression and Purification of Abeta(M1-42). AB - Advances in amyloid research rely on improved access to the beta-amyloid peptide, Abeta. N-Terminal methionine-extended Abeta, Abeta(M1-42), is a readily expressed and widely used form of Abeta with properties comparable to those of the natural Abeta(1-42) peptide. Expression of Abeta(M1-42) is simple to execute and avoids an expensive and often difficult enzymatic cleavage step associated with expression and isolation of Abeta(1-42). This paper reports an efficient method for the expression and purification of Abeta(M1-42) and 15N-labeled Abeta(M1-42). This method affords the pure peptide at ~19 mg/L of bacterial culture through simple and inexpensive steps in 3 days. This paper also reports a simple method for the construction of recombinant plasmids and the expression and purification of Abeta(M1-42) peptides containing familial mutations. We anticipate that these methods will enable experiments that would otherwise be hindered by insufficient access to Abeta. PMID- 29757633 TI - Glycosylation Fosters Interactions between Model Sea Urchin Spicule Matrix Proteins. Implications for Embryonic Spiculogenesis and Biomineralization. AB - The formation of embryonic mineralized skeletal elements (spicules) in the sea urchin requires the participation of proteins, many of which may interact with one another and assist in the creation of an extracellular matrix wherein mineral formation takes place. To probe this, we created a sea urchin spicule recombinant model protein pair system wherein we tested the interactions between two major spicule proteins, SpSM50 and the glycoprotein, SpSM30B/C. Both proteins are strong hydrogelators that manipulate early and later events in mineral formation. We discovered that the anionic glycan moieties of SpSM30B/C are required for interaction with the SpSM50 protein and that these interactions are Ca(II) independent. In addition, when these proteins form a complex, they create hybrid hydrogel particles that are physically distinct from their individual counterparts. Thus, glycan-mediated interactions play an important role in in vitro spicule protein assembly and most likely within the spicule itself. PMID- 29757634 TI - Photosynthetic Traits of Plants and the Biochemical Profile of Tomato Fruits Are Influenced by Grafting, Salinity Stress, and Growing Season. AB - Changes in the photosynthetic traits of plants and metabolic composition of fruits of two tomato cultivars, grafted onto two rootstocks, grown in three salinity levels were studied in two growing periods during the season. Increased salinity stress conditions lowered water potential, stomatal conductance, and transpiration rate of grafted tomato plants, in both growing periods. Water deficit induced stomatal closure, which resulted in stomatal limitation of photosynthesis. The proline content in tomato leaves increased and was closely correlated with salinity. Some of the quality parameters of tomato fruits were affected by rootstock. The sugar/acid ratio was the highest in fruits of 'Belle'/'Maxifort' grafts. With increasing salt stress conditions from 40 to 60 mM NaCl, the lycopene content increased and ascorbic acid content decreased in fruits of 'Gardel'/'Maxifort' grafts, indicating the ability of this scion/rootstock combination to mitigate the toxicity effect of salinity stress. A higher phenolics concentration in fruits from the first growing period may be an additional indicator of stress, caused by higher temperatures and solar radiation, compared with the later period. PMID- 29757636 TI - Synthesis of 2-Acylindoles via Ag- and Cu-Catalyzed anti-Michael Hydroamination of beta-(2-Aminophenyl)-alpha,beta-ynones: Experimental Results and DFT Calculations. AB - beta-(2-Aminophenyl)-alpha,beta-ynones afforded 3-unsubstituted 2-acylindoles in good yields in the presence of 20 mol % AgOTf under (microwave) MW heating. The use CuOTf as a catalyst resulted in a similar reaction outcome, generally with a lower efficiency. This transformation represents the first example of 5- endo-dig cyclization of 2-alkynylanilines bearing an acyl group linked to the triple bond. By contrast with the previously reported gold-catalyzed reaction of beta-(2 aminophenyl)-alpha,beta-ynones, which resulted in the formation of dibenzo[1,5]diazocines through a sequential process triggered by an intermolecular hydroamination, a selective intramolecular anti-Michael hydroamination was observed in the present study by silver/copper catalysis. Density functional theory calculations on the Ag-catalyzed reaction revealed that the catalyst induces an electrostatic arrangement in the TS coherent with the experimentally observed cyclization. PMID- 29757637 TI - Peptide Sequence and Solvent as Levers to Control Disulfide Connectivity in Multiple Cysteine Containing Venom Toxins. AB - Judicious choice of solvent, temperature, and strategic mutations along a peptide backbone can minimize formation of non-native disulfide bond isoforms in chemical synthesis of multiple cysteine containing venom toxins. By exploiting these controls, one can drive the population distribution in favor of a particular isoform. Some chosen ionic liquids (ILs), like 1-ethyl-3-methyl-imidazolium acetate, [Im21][OAc], have proven efficient in favoring the native globular isoform in some conotoxins. To comprehend such a preference, we report an explicit solvent replica exchange molecular dynamics (REMD) study of two conotoxins, AuIB and GI, solvated in either neat water or ~50% (v/v) mixture of water-[Im21][OAc]. Our simulations indicate that compared to neat water, the probability of obtaining native globular isoform of AuIB significantly increases in a water-IL mixture at 305 K. Strikingly, and aligned with experimental observations, peptide GI does not favor the native connectivity in the water-IL mixture. In presence of IL, strong solvent mediated fluctuations of the GI backbone are observed in our simulations. Uneven ion accumulation along the backbone owing to strong H-bonding interactions of some GI residues with IL ions, especially the anion OAc-, restricts conformational freedom of the peptide. Estimation of backbone entropy and Helmholtz free energy corroborates the lack of conformational freedom in GI as compared to AuIB, especially in the presence of IL. In line with prior experiments, simulations of GI mutants indicate that one could possibly force a given pair of Cys residues to come closer by strategically mutating GI residues with glycine and/or alanine, resulting in the breakage/formation of helix-like motifs. PMID- 29757635 TI - Accurate Measurement of Residual Dipolar Couplings in Large RNAs by Variable Flip Angle NMR. AB - NMR approaches using nucleotide-specific deuterium labeling schemes have enabled structural studies of biologically relevant RNAs of increasing size and complexity. Although local structure is well-determined using these methods, definition of global structural features, including relative orientations of independent helices, remains a challenge. Residual dipolar couplings, a potential source of orientation information, have not been obtainable for large RNAs due to poor sensitivity resulting from rapid heteronuclear signal decay. Here we report a novel multiple quantum NMR method for RDC determination that employs flip angle variation rather than a coupling evolution period. The accuracy of the method and its utility for establishing interhelical orientations are demonstrated for a 36 nucleotide RNA, for which comparative data could be obtained. Applied to a 78 kDa Rev response element from the HIV-1 virus, which has an effective rotational correlation time of ca. 160 ns, the method yields sensitivity gains of an order of magnitude or greater over existing approaches. Solution-state access to structural organization in RNAs of at least 230 nucleotides is now possible. PMID- 29757638 TI - Antinociceptive Diterpenoids from the Leaves and Twigs of Rhododendron decorum. AB - Three new leucothane-type (1-3), two new micrathane-type (4, 5), eight new grayanane-type diterpenoids (6-13), and four known compounds were obtained from the ethanol extract of the leaves and twigs of Rhododendron decorum. The structures were determined based on NMR spectra, quantum chemical calculations, and X-ray crystallography. The antinociceptive activities of compounds 1, 3, 4, 6, 8, 10-13, and 15-17 were evaluated via the acetic acid-induced writhing test. Compounds 1, 8, 11-13, and 15 exhibited significant antinociceptive activities. In particular, 12 and 15 were found to be effective at doses of 0.8 and 0.08 mg/kg, respectively. PMID- 29757639 TI - A Helicene Nanoribbon with Greatly Amplified Chirality. AB - We report the synthesis and characterization of a chiral, shape-persistent, perylene-diimide-based nanoribbon. Specifically, the fusion of three perylene diimide monomers with intervening naphthalene subunits resulted in a helical superstructure with two [6]helicene subcomponents. This pi-helix-of-helicenes exhibits very intense electronic circular dichroism, including one of the largest Cotton effects ever observed in the visible range. It also displays more than an order of magnitude increase in circular dichroism for select wavelengths relative to its smaller homologue. These impressive chiroptical properties underscore the potential of this new nanoribbon architecture in the context of chiral electronic materials. PMID- 29757640 TI - Supramolecular Properties of a Monocarboxylic Acid-Functionalized "Texas-Sized" Molecular Box. AB - A new carboxylic acid-functionalized "Texas-sized" molecular box TxSB-CO2H has been prepared by combining two separate building blocks via an iodide-catalyzed macrocyclization reaction. A single-crystal X-ray diffraction analysis revealed a paired "clip-like" dimer in the solid state. Concentration-dependent behavior is seen for samples of TxSB-CO2H as prepared, as inferred from 1H NMR spectroscopic studies carried out in DMSO- d6. However, in the presence of excess acid (1% by weight of deuterated trifluoracetic acid; TFA- d1), little evidence of aggregation is seen in DMSO- d6 except at the highest accessible concentrations. In contrast, the conjugate base form, TxSB-CO2-, produced in situ via the addition of excess triethylamine to DMSO- d6 solutions of TxSB-CO2H acts as a self-complementary monomer that undergoes self-assembly to stabilize a formal oligomer ([TxSB-CO2-] n) with a degree of polymerization of approximately 5-6 at a concentration of 70 mM. Evidence in support of the proposed oligomerization of TxSB-CO2- in solution and in the solid state came from one- and two-dimensional 1H NMR spectroscopy, X-ray crystallography, dynamic light scattering (DLS), and scanning electron microscopy (SEM). A series of solution-based analyses carried out in DMSO and DMSO- d6 provide support for the notion that the self-assembled constructs produced from TxSB-CO2- are responsive to environmental stimuli, including exposure to the acetate anion (as its tetrabutylammonium, TBA+, salt), and changes in overall concentration, temperature, and protonation state. The resulting transformations are thought to reflect the reversible nature of the underlying noncovalent interactions. They also permit the stepwise interconversion between TxSB-CO2H and [TxSB-CO2-] n via the sequential addition of triethylamine and TFA- d1. The present work thus serves to illustrate how appropriately functionalized molecular box-type macrocycles may be used to develop versatile stimuli-responsive materials. It also highlights how aggregated forms seen in the solid state are not necessarily retained under competitive solution-phase conditions. PMID- 29757641 TI - Molecular Dynamics Simulations of Substrate Hydrophilicity and Confinement Effects in Capped Nafion Films. AB - Nafion nanocomposites for energy-related applications are being used extensively because of the attractive properties such as enhanced water retention, low unwanted crossover of electrolytes, and high proton conductivity. We present the results of the molecular dynamics modeling of Nafion films confined between two walls (substrates) of different polymer-wall interaction strengths and of different separation distances to model Nafion nanocomposites. Our goal is to provide insights into the effects of varying hydrophilicity and volume fraction of fillers/nanoparticles on the internal structure and water transport inside the Nafion membrane. The sulfur-sulfur radial distribution function first peak distance and the sulfur-oxygen (water) coordination number in the first hydration shell were negligibly affected by the wall (substrate) hydrophilicity or the film thickness. The Nafion side chains were found to bend toward the substrates with high hydrophilicity which is in qualitative agreement with existing experiments. The amount of bending was observed to reduce with increasing film thickness. However, the side-chain length did not show any noticeable variation with wall (substrate) hydrophilicity or film thickness. The water clusters became smaller and more isolated clusters emerged for highly hydrophilic substrates. In addition, the water cluster sizes showed a decreasing trend with decreasing film thickness in the case of hydrophilic substrates, which has also been observed in experiments of supported Nafion films. The in-plane water diffusion was enhanced considerably for hydrophilic substrates, and this mechanism has also been proposed previously in experiments. The in-plane water diffusion was also found to be a strong function of the substrate selectivity toward the hydrophilic phase. Our simulations can help provide more insights to experimentalists for choosing or modifying nanoparticles for Nafion nanocomposites. PMID- 29757643 TI - Peridinin Torsional Distortion and Bond-Length Alternation Introduce Intramolecular Charge-Transfer and Correlated Triplet Pair Intermediate Excited States. AB - The nature of intramolecular charge transfer (ICT) and the mechanism of intramolecular singlet fission (SF) in peridinin remain open research questions. Obtaining an understanding of the population evolution from the bright state to dark state following a photoinduced electronic transition is critical. Unambiguously describing this evolution in peridinin, and light-harvesting carotenoids in general, has proven elusive experimentally and computationally. To offer a balanced description of the bright- and dark-state electronic structures, we here apply ab initio multireference perturbation theory quantum chemistry-the density matrix renormalization group self-consistent field and complete-active space self-consistent field with second-order N-electron valence perturbation theory. At traditional bright- (S2) and dark-state (S1) optimized geometries, we find that an additional correlated triplet pair state and ICT state are derived from the canonical polyene Bu (S3) and 3Ag (S4) dark singlet excited states, respectively. Whereas the S3 state's physical properties are insensitive to peridinin's allene-tail donor and lactone ring acceptor functionalization, the S4 state exhibits a markedly enhanced oscillator strength and highest occupied molecular orbital-lowest unoccupied molecular orbital transition density. These changes suggest that the ICT character stems from mixing between the bright S2 and putatively dark S4. PMID- 29757642 TI - Pesticidal Activity of Nanostructured Metal Oxides for Generation of Alternative Pesticide Formulations. AB - Herein, nanostructured metal oxides of essential soil nutrient elements (i.e., CuO and CaO) with definite shape and size were simply synthesized, and their pesticidal activities against cotton leafworm ( Spodoptera littoralis) were explored for the first time. These metal oxide nanostructures represented novel economic and ecofriendly nanopesticides for sustainable plant protection and might boost the nutrient content of soil. The results showed that CuO nanoparticles (NPs) and CaO NPs exhibited potential entomotoxic effects against S. littoralis. Interestingly, CuO NPs exhibited fast entomotoxic effect with LC50 = 232.75 mg/L after 3 days, while CaO NPs showed a slow entomotoxic effect with LC50 = 129.03 mg/L after 11 days of post-treatments. The difference in the pesticidal activity of the metal oxides is related to their physical characteristics and interfacial surfaces upon insect midgut and cuticle layer of insect body wall. Thus, nanoengineered metal oxides might be utilized to generate an alternative and cost-effective pesticide formulation in the near future. PMID- 29757644 TI - Self-Assembly of a Thermally Responsive Double-Hydrophilic Copolymer in Ethanol Water Mixtures: The Effect of Preferential Adsorption and Co-Nonsolvency. AB - Lower alcohols can induce a combined collapse-swelling de-mixing transition (lower critical solution temperature (LCST)-type co-nonsolvency) in aqueous solutions of poly( N-isopropylacrylamide) (PNIPAM) by interacting with the polymer's amide groups. This interaction results in an increase of the total surface area of hydrophobic sites and destabilizes the chains. Here, we make use of this phenomenon to drive the counterintuitive self-assembly of a PNIPAM containing double-hydrophilic graft copolymer in water-ethanol mixtures at T ? LCST. Rheological frequency sweeps are used to quantify the distinct solvation states of PNIPAM at various temperatures and ethanol concentrations. The energy stored through elastic deformation at the de-mixing transition is simply related to the solvent binding. We find that the storage modulus decreases progressively, but nonlinearly with ethanol concentration, which evidences a preferential solvation pattern. Analogously, through a combination of dynamic light scattering and transmission electron microscope analyses, we demonstrate that a low temperature structure variation takes place by adding ethanol following a similar solvent-content morphology dependent model. PMID- 29757647 TI - Nucleophilic Opening of Donor-Acceptor Cyclopropanes with Indoles via Hydrogen Bond Activation with 1,1,1,3,3,3-Hexafluoroisopropanol. AB - The treatment of donor-acceptor cyclopropanes with the a strong hydrogen bond donor, HFIP, activated the cyclopropanes (via presumed hydrogen bonding) toward homo-Michael additions with indoles as the nucleophiles. This reaction proceeded without the need for high pressure or catalysis. PMID- 29757646 TI - Inhibition of Breast Cancer Cell Migration by Cyclotides Isolated from Pombalia calceolaria. AB - Two new bracelet cyclotides from roots of Pombalia calceolaria with potential anticancer activity have been characterized in this work. The cyclotides Poca A and B (1 and 2) and the previously known CyO4 (3) were de novo sequenced by MALDI TOF/TOF mass spectrometry (MS). The MS2 spectra were examined and the amino acid sequences were determined. The purified peptides were tested for their cytotoxicity and effects on cell migration of MDA-MB-231, a triple-negative breast cancer cell line. The isolated cyclotides reduced the number of cancer cells by more than 80% at 20 MUM, and the concentration-related cytotoxic responses were observed with IC50 values of 1.8, 2.7, and 9.8 MUM for Poca A (1), Poca B (2), and CyO4 (3), respectively. Additionally, the inhibition of cell migration (wound-healing assay) exhibited that CyO4 (3) presents an interesting activity profile, in being able to inhibit cell migration (50%) at a subtoxic concentration (2 MUM). The distribution of these cyclotides in the roots was analyzed by MALDI imaging, demonstrating that all three compounds are present in the phloem and cortical parenchyma regions. PMID- 29757649 TI - Functional Annotation of Proteins Encoded by the Minimal Bacterial Genome Based on Secondary Structure Element Alignment. AB - In synthetic biology, one of the key focuses is building a minimal artificial cell which can provide basic chassis for functional study. Recently, the J. Craig Venter Institute published the latest version of the minimal bacterial genome JCVI-syn3.0, which only encoded 438 essential proteins. However, among them functions of 149 proteins remain unknown because of the lack of effective annotation method. Here, we report a secondary structure element alignment method called SSEalign based on an effective training data set extracting from various bacterial genomes. The experimentally validated homologous genes in different species were selected as training positives, while unrelated genes in different species were selected as training negatives. Moreover, SSEalign used a set of well-defined basic alignment elements with the backtracking line search algorithm to derive the best parameters for accurate prediction. Experimental results showed that SSEalign achieved 88.2% test accuracy, which is better than the existing prediction methods. SSEalign was subsequently applied to identify the functions of those unannotated proteins in the latest published minimal bacteria genome JCVI-syn3.0. Results indicated that at least 136 proteins out of 149 unannotated proteins in the JCVI-syn3.0 genome could be annotated by SSEalign. Our method is effective for the identification of protein homology in JCVI-syn3.0 and can be used to annotate those hypothetical proteins in other bacterial genomes. PMID- 29757648 TI - Potential Energy Surface for Large Barrierless Reaction Systems: Application to the Kinetic Calculations of the Dissociation of Alkanes and the Reverse Recombination Reactions. AB - The isodesmic reaction method is applied to calculate the potential energy surface (PES) along the reaction coordinates and the rate constants of the barrierless reactions for unimolecular dissociation reactions of alkanes to form two alkyl radicals and their reverse recombination reactions. The reaction class is divided into 10 subclasses depending upon the type of carbon atoms in the reaction centers. A correction scheme based on isodesmic reaction theory is proposed to correct the PESs at UB3LYP/6-31+G(d,p) level. To validate the accuracy of this scheme, a comparison of the PESs at B3LYP level and the corrected PESs with the PESs at CASPT2/aug-cc-pVTZ level is performed for 13 representative reactions, and it is found that the deviations of the PESs at B3LYP level are up to 35.18 kcal/mol and are reduced to within 2 kcal/mol after correction, indicating that the PESs for barrierless reactions in a subclass can be calculated meaningfully accurately at a low level of ab initio method using our correction scheme. High-pressure limit rate constants and pressure dependent rate constants of these reactions are calculated based on their corrected PESs and the results show the pressure dependence of the rate constants cannot be ignored, especially at high temperatures. Furthermore, the impact of molecular size on the pressure-dependent rate constants of decomposition reactions of alkanes and their reverse reactions has been studied. The present work provides an effective method to generate meaningfully accurate PESs for large molecular system. PMID- 29757650 TI - Analytical Model for Diffusive Evaporation of Sessile Droplets Coupled with Interfacial Cooling Effect. AB - Current analytical models for sessile droplet evaporation do not consider the nonuniform temperature field within the droplet and can overpredict the evaporation by 20%. This deviation can be attributed to a significant temperature drop due to the release of the latent heat of evaporation along the air-liquid interface. We report, for the first time, an analytical solution of the sessile droplet evaporation coupled with this interfacial cooling effect. The two-way coupling model of the quasi-steady thermal diffusion within the droplet and the quasi-steady diffusion-controlled droplet evaporation is conveniently solved in the toroidal coordinate system by applying the method of separation of variables. Our new analytical model for the coupled vapor concentration and temperature fields is in the closed form and is applicable for a full range of spherical-cap shape droplets of different contact angles and types of fluids. Our analytical results are uniquely quantified by a dimensionless evaporative cooling number Eo whose magnitude is determined only by the thermophysical properties of the liquid and the atmosphere. Accordingly, the larger the magnitude of Eo, the more significant the effect of the evaporative cooling, which results in stronger suppression on the evaporation rate. The classical isothermal model is recovered if the temperature gradient along the air-liquid interface is negligible ( Eo = 0). For substrates with very high thermal conductivities (isothermal substrates), our analytical model predicts a reversal of temperature gradient along the droplet-free surface at a contact angle of 119 degrees . Our findings pose interesting challenges but also guidance for experimental investigations. PMID- 29757651 TI - One-Pot Synthesis of Trisubstituted Triazenes from Grignard Reagents and Organic Azides. AB - A simple and versatile method for the preparation of linear, trisubstituted triazenes is reported. The procedure is based on the reaction of Grignard reagents with 1-azido-4-iodobutane or 4-azidobutyl-4-methylbenzenesulfonate. These organic azides enable the regioselective formation of triazenes via an intramolecular cyclization step. The new method can be used for the preparation of aryl, heteroaryl, vinyl, and alkyl triazenes. The synthetic utility of vinyl triazenes is demonstrated by acid-induced C-N, C-O, C-F, C-P, and C-S bond forming reactions. PMID- 29757653 TI - Metabolism of an Oxime-Linked Antibody Drug Conjugate, AGS62P1, and Characterization of Its Identified Metabolite. AB - AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1kappa monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time. AGS62P1 metabolism was assessed in xenograft tumor-bearing mice and rats treated with the ADC using liquid chromatography and mass spectrometry-based methods described herein. In this study, we identified the metabolite of AGS62P1 as pAF-AGL-0185-30, which contains a fragment resulting from the catabolism of the antibody component of the ADC and hydrolysis of the terminal amide portion of the linker-payload. We demonstrated that the metabolite of AGS62P1 is tolerated in rats above 1.5 mg/kg and above 0.334 mg/kg in cynomolgus monkeys when given as a single dose. Furthermore, we established in vitro that pAF-AGL-0185-30 does not significantly inhibit hERG or cytochrome P450 family enzymes (CYPs). PMID- 29757652 TI - Supramolecular Nucleoside-Based Gel: Molecular Dynamics Simulation and Characterization of Its Nanoarchitecture and Self-Assembly Mechanism. AB - Among the diversity of existing supramolecular hydrogels, nucleic acid-based hydrogels are of particular interest for potential drug delivery and tissue engineering applications because of their inherent biocompatibility. Hydrogel performance is directly related to the nanostructure and the self-assembly mechanism of the material, an aspect that is not well-understood for nucleic acid based hydrogels in general and has not yet been explored for cytosine-based hydrogels in particular. Herein, we use a broad range of experimental characterization techniques along with molecular dynamics (MD) simulation to demonstrate the complementarity and applicability of both approaches for nucleic acid-based gelators in general and propose the self-assembly mechanism for a novel supramolecular gelator, N4-octanoyl-2'-deoxycytidine. The experimental data and the MD simulation are in complete agreement with each other and demonstrate the formation of a hydrophobic core within the fibrillar structures of these mainly water-containing materials. The characterization of the distinct duality of environments in this cytidine-based gel will form the basis for further encapsulation of both small hydrophobic drugs and biopharmaceuticals (proteins and nucleic acids) for drug delivery and tissue engineering applications. PMID- 29757654 TI - Direct Observation of Large Flexoelectric Bending at the Nanoscale in Lanthanide Scandates. AB - There is a growing interest in the flexoelectric effect, since at the nanoscale it is predicted to be very large. However, there have been no direct observations of flexoelectric bending consistent with current theoretical work that implies strains comparable to or exceeding the yield strains of typical materials. Here we show a direct observation of extraordinarily large, two-dimensional reversible bending at the nanoscale in dysprosium scandate due to the converse flexoelectric effect, with similar results for terbium and gadolinium scandate. Within a transmission electron microscope, thin features bend up to 90 degrees with radii of curvature of about 1 MUm, corresponding to very large nominal strains. Analysis including independent experimental determination of the flexoelectric coefficient is semiquantitatively consistent with interpreting the results as due to flexoelectricity. These results experimentally demonstrate large flexoelectric bending at the nanoscale. PMID- 29757655 TI - Copper-Catalyzed Ring-Expansion Cascade of Azirines with Alkynes: Synthesis of Multisubstituted Pyridines at Room Temperature. AB - The first intermolecular ring-expansion cascade of azirines with alkynes for the synthesis of pyridines, enabled by a copper/triethylamine catalytic system via simultaneous generation and utilization of yne-enamine and skipped-yne-imine intermediates, is reported. Experimental as well as computational mechanistic studies revealed that the role of triethylamine is crucial in deciding the reaction pathway toward the pyridine products. This process offers a novel, one step, direct, and practical strategy for the rapid construction of highly substituted pyridines under exceedingly mild conditions, and an installed alkyne functionality. PMID- 29757656 TI - Multilevel Morphology of Complex Nanoporous Materials. AB - This work exploits gas adsorption and small-angle X-ray scattering (SAXS) to determine the morphology of complex nanoporous materials. We resolve multiple classes of porosity including previously undetected large-scale texture that significantly compromises the canonical interpretation of gas adsorption. Specifically, a UVM-7 class mesoporous silica was synthesized that has morphological features on three length scales: macropores due to packing of 150 nm globules, 1.9 nm radius spherical mesopores inside the globules, and >7 nm pockets on and between the globules. The total and external surface areas, as well as the mesopore volume, were determined using gas adsorption (alphas-plot) and SAXS. A new approach was applied to the SAXS data using multilevel fitting to determine the surface areas on multiple length scales. The SAXS analysis code is applicable to any two-phase system and is freely available to the public. The total surface area determined by SAXS was 12% greater than that obtained by gas adsorption. The macropore interfacial area, however, is only 30% of the external surface area determined by the alphas-plot. The overestimation of the external surface area by the alphas-plot method is attributed to capillary condensation in nanoscale surface irregularities. The discrepancy is resolved assuming that the macropore-globule interfaces harbor fractally distributed nooks and crannies, which lead to gas adsorption at pressures above the mesopore filling pressure. PMID- 29757657 TI - Morphology of Poly(styrene- co-butadiene) Random Copolymer Thin Films and Nanostructures on a Graphite Surface. AB - We studied the morphology of poly(styrene- co-butadiene) random copolymers on a graphite surface. Polymer solutions were spin coated onto graphite, at various concentrations and molecular weights. The polymer films and nanostructures were imaged using atomic force microscopy. Above the overlap concentration, thin films formed. However, total wetting did not occur, despite the polymers being well above their Tg. Instead, dewetting was observed, suggesting the films were in a state of metastable equilibrium. At lower concentrations, the polymers formed networks, nanoislands, and nanoribbons. Ordered nanopatterns were observed on the surface; the polymers orientated themselves due to pi-pi stacking interactions reflecting the crystalline structure of the graphite. At the lowest concentration, this ordering was very pronounced. At higher concentrations, it was less defined but still statistically significant. Higher degrees of ordering were observed with poly(styrene- co-butadiene) than polystyrene and polybutadiene homopolymers as the copolymer's aromatic rings are distributed along a flexible chain, which maximizes pi-pi stacking. At the two lowest concentrations, the size of the nanoislands and nanoribbons remained similar with varying molecular weight. However, at higher concentrations, the polymer network features were largest at the lowest molecular weight, indicating that in this case, a large proportion of shorter chains stay on top of the adsorbed ones. The contact angles of the polymer nanostructures remained mostly constant with size, which is due to the strong polymer/graphite adhesion dominating over line tension and entropic effects. PMID- 29757658 TI - A Macropinocytosis-Intensifying Albumin Domain-Based scFv Antibody and Its Conjugate Directed against K-Ras Mutant Pancreatic Cancer. AB - Enhanced macropinocytosis has been found in K-Ras mutant pancreatic cancer cells, through which albumin can massively enter into the K-Ras-driven cancer cells, suggesting its role in serving as a macropinocytosis-intensifying drug delivery carrier. In the present study, a novel recombinant protein Fv-LDP-D3 and its reconstituted analogue Fv-LDP-D3-AE were designed and prepared. Fv is the fragment of an anti-EGFR antibody, D3 is the domain III of human serum albumin (HSA), LDP is the apoprotein of the antitumor antibiotic lidamycin (LDM), and AE is an extremely cytotoxic enediyne chromophore derived from LDM. As shown, the recombinant protein Fv-LDP-D3 presented intensive and selective binding capacity to pancreatic cancer cells and inhibited cell proliferation by blocking EGFR signaling. Moreover, Fv-LDP-D3 showed prominent tumor imaging in pancreatic carcinoma xenograft. The reconstituted, enediyne-integrated analogue Fv-LDP-D3-AE displayed highly potent cytotoxicity to pancreatic cancer cells through apoptosis induction and G2/M arrest. Fv-LDP-D3 and Fv-LDP-D3-AE markedly inhibited the tumor growth of the pancreatic carcinoma AsPC-1 xenograft. Study results indicated that the novel recombinant protein displays both EGFR-targeting and macropinocytosis-intensifying attributes, presenting a new format of scFv antibody that integrates with albumin domain III. It might be a feasible strategy to develop targeted drugs for K-Ras mutant pancreatic cancer. PMID- 29757659 TI - Bone Marrow-Derived Mesenchymal Stem Cells Promoted Cutaneous Wound Healing by Regulating Keratinocyte Migration via beta2-Adrenergic Receptor Signaling. AB - Mesenchymal stem cells (MSCs) play an important role in cutaneous wound healing; however, the functional mechanisms involved in the healing process are poorly understood. A series of studies indicate that keratinocytes that migrate into the wound bed rely on an epithelial-mesenchymal transition (EMT)-like process to initiate re-epithelialization. We therefore examined whether bone marrow-derived MSCs (BMSCs) could affect biological behavior and induce EMT-like characteristics in the human epidermal keratinocytes (HEKs) and in the immortalized human keratinocyte cell line HaCaT cells, and we investigated the signaling pathways of BMSC-mediated phenotypic changes. By assessing the expression of EMT-related markers including E-cadherin, alpha-SMA, and Snail family transcription factors by beta2-adrenergic receptor (beta2-AR) blockage using ICI-118,551, a beta2-AR selective antagonist, or beta2-AR small interfering RNA (siRNA), we showed an involvement of beta2-AR signaling in the induction of EMT-like alterations in human keratinocytes in vitro. beta2-AR signaling also affected collective and individual cell migration in human keratinocyte cell lines, which was attenuated by administration of ICI-118,551. Treating the cells with BMSC-conditioned media (BMSC-CM) not only recapitulated the effect of isoproterenol (ISO) on cell migration but also induced the expression of beta2-AR and a panel of proteins associated with mesenchymal phenotype in HEKs and HaCaT cells. Similarly, a blockade of the beta2-AR by either ICI-118,551 or beta2-AR siRNAs reversed both responses of the epidermal keratinocyte cell lines relative to BMSC-CM exposure. These results were further verified in our vivo findings and indicated that the exogenous application of MSCs promoted cutaneous wound healing and endowed the keratinocytes surrounding the wound area with an increased migratory phenotype through activation of beta2-AR signaling. Our findings suggest a biochemical mechanism underlying the function of MSCs in wound re-epithelization, which provides a reliable theoretical basis for the wide application of MSCs in the treatment of chronic wounds. PMID- 29757660 TI - Airway Pressure Release Ventilation: A Therapy in Search of a Disease? PMID- 29757661 TI - A Pivotal Field Study to Support the Registration of Levothyroxine Sodium Tablets for Canine Hypothyroidism. AB - A prospective, pivotal, multicenter field study to evaluate the dose regimen, effectiveness, and safety of levothyroxine sodium tablets, USP for the treatment of hypothyroidism and hypothyroidism-associated clinical signs in dogs was conducted. Ninety-two dogs diagnosed with primary hypothyroidism met the entrance criteria and were enrolled into the study. Levothyroxine sodium was administered to each dog on a daily basis either as the whole dose q 24 hr or as half the dose q 12 hr. Dosing started at 0.1 mg/10 lb (0.022 mg/kg) and continued for approximately 6 mo to Day 182. During this time, the thyroid status of each dog was evaluated at monthly intervals. For the determination of effectiveness, dogs classified as euthyroid at Day 182, based on their thyroid hormone values, were considered treatment successes. Results of the statistical analysis showed that there was no difference between the two dosing regimens (P = .11) and that when the data from both groups were pooled, the overall success rate was 75.64% (95% confidence interval = 66.34%). By Day 182, improvement and/or resolution of hypothyroidism-associated clinical signs was observed in all categories. No abnormal trends in the reported adverse events were observed. PMID- 29757662 TI - A Review of the Surgical Management of Perineal Hernias in Dogs. AB - Perineal hernia refers to the failure of the muscular pelvic diaphragm to support the rectal wall, resulting in herniation of pelvic and, occasionally, abdominal viscera into the subcutaneous perineal region. The proposed causes of pelvic diaphragm weakness include tenesmus associated with chronic prostatic disease or constipation, myopathy, rectal abnormalities, and gonadal hormonal imbalances. The most common presentation of perineal hernia in dogs is a unilateral or bilateral nonpainful swelling of the perineum. Clinical signs do occur, but not always. Clinical signs may include constipation, obstipation, dyschezia, tenesmus, rectal prolapse, stranguria, or anuria. The definitive diagnosis of perineal hernia is based on clinical signs and findings of weak pelvic diaphragm musculature during a digital rectal examination. In dogs, perineal hernias are mostly treated by surgical intervention. Appositional herniorrhaphy is sometimes difficult to perform as the levator ani and coccygeus muscles are atrophied and unsuitable for use. Internal obturator muscle transposition is the most commonly used technique. Additional techniques include superficial gluteal and semitendinosus muscle transposition, in addition to the use of synthetic implants and biomaterials. Pexy techniques may be used to prevent rectal prolapse and bladder and prostate gland displacement. Postoperative care involves analgesics, antibiotics, a low-residue diet, and stool softeners. PMID- 29757663 TI - Bicipital Tendinopathy and Carpal Valgus Following a Distant Direct Thoracoabdominal Skin Flap in a German Shepherd with Necrotizing Fasciitis. AB - A 4 mo old German shepherd dog was presented following an acute onset lameness and swelling of the thoracic limb. Clinical signs, surgical findings, and culture results were consistent with a diagnosis of necrotizing fasciitis. Initial management consisted of extensive surgical debridement, wound lavage, and bandaging. Surgical closure was achieved with an axillary fold flap and distant direct single-pedicle thoracoabdominal flap. Three mo later, following deterioration of the lameness that was associated with carpal valgus, carpal subluxation, and tendinopathy of the distal radial insertion of the biceps brachii tendon, a closing wedge pancarpal arthrodesis and tenotomy of the biceps brachii tendon was performed. We hypothesize that extensive soft tissue trauma and subsequent fibrosis and tendon contracture following soft tissue reconstruction contributed to the complications seen. To the authors' knowledge, this is the first report of carpal valgus deformity and biceps brachii tendinopathy following a distant direct skin flap and axillary skin fold flap. PMID- 29757664 TI - Reverse Saphenous Conduit Flap in 19 Dogs and 1 Cat. AB - The purpose of this retrospective study was to report the outcomes of 19 dogs and 1 cat undergoing reverse saphenous conduit flap between 1999 and 2016. Reverse saphenous conduit flap was used to treat traumatic wounds and wounds resulting from tumor excision in the hind limb; the majority of cases had medial shearing injuries. All animals had complete flap survival. In five animals (20%), minor donor site dehiscence occurred, which did not require surgery. Other postoperative complications included signs of severe venous congestion in one dog. Reverse saphenous conduit flap is a useful technique to repair skin defects of the distal hind limb. PMID- 29757665 TI - Comparison of Compounded, Generic, and Innovator-Formulated Itraconazole in Dogs and Cats. AB - The triazole antifungal itraconazole may be cost prohibitive in brand name form; therefore, compounded and generic products are often used as alternatives. Itraconazole blood concentrations have not been studied in clinical patients receiving these formulations. Itraconazole bioassay was performed on serum/plasma from 95 dogs and 20 cats receiving itraconazole (compounded from bulk powder, generic pelletized, or brand name) for systemic mycosis treatment. Mean itraconazole concentration was lower in the compounded group (n = 42) as compared with the generic (n = 40) or brand name (n = 33) groups (0.5 ug/mL versus 8.3 ug/mL and 6.5 ug/mL, respectively; P < .001). No statistical difference was observed between itraconazole concentrations in the generic and brand name groups. Forty animals (95.2%) in the compounded group had subtherapeutic (<1.0 ug/mL) values. All cats in this group (n = 10) had undetectable itraconazole concentrations. Some animals in the generic and brand name groups had subtherapeutic values (12.5 and 12.1%, respectively) or potentially toxic values (>10 ug/mL; 37.5 and 24%, respectively). Compounded itraconazole should be avoided, but generic itraconazole appears to serve as a reasonable alternative to brand name itraconazole. Therapeutic drug monitoring may be beneficial in all cases. PMID- 29757666 TI - Deslorelin Implant Treatment for Hair Cycle Arrest (Alopecia X) in Two Intact Male Keeshonden. AB - Alopecia in dogs occurs secondary to a variety of underlying inflammatory and noninflammatory conditions. Hair cycle arrest (alopecia X) is a noninflammatory alopecia that is frustrating to diagnose and treat due to lack of understanding of disease pathogenesis. A variety of therapies for hair cycle arrest have been described with inconsistent efficacy in different dog breeds and sexes; no definitive treatment is available. This report describes the use of a deslorelin acetate implant in two sexually intact adult male keeshonden, both diagnosed with hair cycle arrest. The dogs had progressive alopecia of the trunk that spared the head and distal limbs present for at least 2 yr. Diagnosis of hair cycle arrest was made based on clinical features, dermatohistopathology, and lack of systemic abnormalities. Treatment with a single subcutaneous 4.7 mg deslorelin acetate implant resulted in profuse hair regrowth within 3.5 mo that endured for at least 14 mo. Deslorelin implantation is a management option that is safe, affordable, and appears effective for sexually intact male keeshonden with hair cycle arrest. PMID- 29757667 TI - Safety and Tolerability of Hyperbaric Oxygen Therapy in Cats and Dogs. AB - This prospective clinical trial was designed to evaluate the safety of hyperbaric oxygen therapy (HBOT) in a population of cats and dogs with a variety of naturally occurring diseases. Seventy-eight dogs and twelve cats with various naturally occurring disease conditions, who had the potential to benefit from HBOT, were enrolled in the study. These patients were treated with HBOT in a monoplace hyperbaric oxygen chamber at 2 air pressure absolute for a treatment length of either 45 min or 60 min. There were 230 hyperbaric oxygen treatments performed during the study period. No major adverse effects were observed. There were 76 minor adverse effects recorded, which were not considered to be of clinical significance. Hyperbaric oxygen therapy was well tolerated and there were no major adverse effects recorded during treatment. PMID- 29757668 TI - A Case of Parasitic Twinning or Caudal Duplication in a Dog. AB - A 6 mo old 13.5 kg (29.7 lb) male intact American Staffordshire terrier was evaluated for a history of supernumerary pelvic limbs, with malodorous discharge from a supernumerary penis. Imaging (radiographs, abdominal ultrasound, and computed tomography with excretory urogram) showed a supernumerary pelvis with associated pelvic limbs, no osseous continuity with the primary spinal column, a colonic diverticulum extending to the supernumerary pelvis, an enlarged left kidney with a ureter connecting to a single bladder, right renal aplasia, a single descended testicle in the primary scrotum, an intra-abdominal cryptorchid testicle, and two unidentifiable soft tissue masses. At surgery, a single ileum was present with a primary and accessory cecum and colon and the accessory colon entering the supernumerary pelvis. The accessory cecum and colon, right kidney, two unknown soft tissue masses, and the single descended testicle were removed. The right kidney had a ureter that anastomosed with the accessory colon at its entry into the supernumerary pelvis. The supernumerary pelvis and hind limbs were not removed. Five months after surgery, the dog was reported to be doing well clinically. Caudal duplication is extremely rare in veterinary medicine. The appearance of supernumerary external structures may indicate internal connections as well. PMID- 29757669 TI - Historical Prevalence of Radiological Appendicular Osteoarthritis in Cats (1972 1973). AB - Interest in feline osteoarthritis has grown recently; this might be due to increased prevalence or increased awareness. This study records the presence of appendicular osteoarthritis in a subset of the United Kingdom cat population in the 1970s and estimates its prevalence. One hundred cats euthanized in 1972-1973 had a series of skeletal radiographic images taken post mortem. Each joint was put into a set with or without osteoarthritis according to the presence or absence of a specified set of radiographic features. Limited historical data were analyzed. The prevalence of osteoarthritis in these cats was 74%. There is no evidence that feline osteoarthritis is a "novel" disease. The prevalence was similar to recent prospective radiological surveys. Recent interest in the condition may have derived from more attention being paid to feline medicine and welfare. PMID- 29757670 TI - Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis. AB - The progressive damage in rheumatoid arthritis (RA) has been linked to an increase in inflammatory Th1/Th17 cells and a decrease in number or function of immunomodulatory regulatory T cells (Tregs). Many therapies that are effective in RA are shown to affect Th1/Th17 cells and/or Tregs. One such therapy, abatacept, utilizes a physiologic immunomodulatory molecule called cytotoxic lymphocyte antigen-4 (CTLA-4) which causes contact-dependent inhibition of inflammatory T cell activation. Recent advances in CTLA-4 research has uncovered the method by which this occurs physiologically but the actions of the CTLA-4Ig fusion protein are still not fully understood. The reported effects of the drug on Treg population number and suppressor function have been very mixed. In this review, we will discuss the current literature surrounding the effects of abatacept in rheumatoid arthritis and explore potential explanations for the differences in results. Future opportunities in this area include contributions to a unified definition for different immune cell populations, LAG3+ Tregs which may pose an avenue for further study or the stratification of patients with regards to their specific disease characteristics, resulting in optimized treatment for disease remission. PMID- 29757672 TI - Enzyme-Based Ultrasensitive Electrochemical Biosensors for Rapid Assessment of Nitrite Toxicity: Recent Advances and Perspectives. AB - In the present era of rapid international globalization and industrialization, intensive use of nitrite as a fertilizing agent in agriculture, preservative, dyeing agent, food additive and as corrosion inhibitor in industrial sectors is adversely effecting environment, natural habitats and human health. The issue of toxicity and carcinogenicity due to excessive ingestion of nitrites via the dietary intake has led to an imminent need for its efficient real-time monitoring in situ. Nitrite detection employing electrochemical biosensors has been gaining high credibility in the field of clinical research. Nitrite biosensors have emerged as an outstanding choice for portable point of care testing of nitrite quantification owing to the excellent properties, such as rapidity, miniaturization, ultra-low limits of detection, multiplexing and enhanced detection sensitivity. The article is enclosed with an interesting outlook on latest emerging trends in the development of nitrite biosensors utilizing nanomaterials, such as metal nanoparticles, carbon nanotubes, metal oxide nanoparticles, nanocomposites, polymers and biomaterials. The present review embarks on the highlights relevant to the nitrite quantification in real samples, then proceeds with a meticulous description of the most pertinent electrochemical nitrite biosensors, which have been proposed by adopting diverse materials and strategies of fabrication and finally end with the achievements and future outlook signifying the application of these nanoengineered biosensors for environmental surveillance and human safety. PMID- 29757673 TI - Rapamycin-insensitive mechanistic target of rapamycin regulates basal and resistance exercise-induced muscle protein synthesis. AB - We investigated whether rapamycin-insensitive mechanistic target of rapamycin (mTOR) signaling plays a role in regulating resistance exercise-induced muscle protein synthesis. We used a rodent model of resistance exercise and compared the effect of rapamycin, an allosteric mTOR inhibitor, with the effect of AZD8055, an ATP-competitive mTOR kinase inhibitor. The right gastrocnemius muscle of male Sprague-Dawley rats age 11 wk was contracted isometrically via percutaneous electrical stimulation (100 Hz, 5 sets of ten 3-s contractions, 7 s of rest between contractions, 3 min of rest between sets), and the left gastrocnemius muscle served as control. Vehicle, rapamycin, or AZD8055 were intraperitoneally injected 1 h before resistance exercise. Results indicated that both rapamycin and AZD8055 inhibited mTOR complex 1 (mTORC1)/70-kDa ribosomal protein S6 kinase signaling similarly, whereas mTORC1/eukaryotic translation initiation factor 4E binding protein 1 signaling was greatly inhibited by AZD8055. Moreover, only AZD8055 inhibited the phosphorylation of Akt at Ser473, a downstream target of mTORC2. AZD8055, but not rapamycin, completely inhibited the resistance exercise induced increase in muscle protein synthesis. We conclude that the resistance exercise-induced increase in muscle protein synthesis is an mTOR signaling dependent process. Furthermore, both rapamycin-sensitive and -insensitive mTOR signaling regulate this event.-Ogasawara, R., Suginohara, T. Rapamycin insensitive mechanistic target of rapamycin regulates basal and resistance exercise-induced muscle protein synthesis. PMID- 29757671 TI - Timeline: A web application for assessing the timing and details of health behaviors. AB - BACKGROUND: Timeline Followback (TLFB) interview methods are used to assess a variety of health behaviors, including alcohol use, drug use, and sexual behavior. While several online TLFBs have been developed, most focus on single behaviors, and few studies have explored their validity in assessing multiple risk behaviors using a single online TLFB. OBJECTIVE: To examine the validity of a customizable web application (Timeline) for assessing alcohol use, drug use, and sexual behavior among high-risk men who have sex with men. METHODS: Participants (N = 15 men) completed standardized survey instruments before undergoing a 30-day daily diary procedure where they submitted daily reports of health risk behaviors via smartphone. They then completed a Timeline at the end of the 30-day period covering the same time interval. RESULTS: Comparing a baseline administration of Timeline with popular surveys of health risk behaviors supported Timeline's validity (r = 0.41-0.59 for alcohol use, r = 0.83 for drug use, and r = 0.34-0.52) for sexual behaviors. While participants reported similar amounts of each behavior via daily diary as they did on a follow-up Timeline (r = 0.55-0.88 for alcohol use, r = 0.69 for drug use, and r = 0.87-0.92 for sexual behaviors), results provided evidence of underreporting on the Timeline. Timing of behaviors also frequently disagreed across these methods. CONCLUSIONS: Timeline is valid for assessing overall engagement in alcohol use, drug use, and sexual behavior over a 30-day window. However, researchers interested in the specific timing of behaviors within assessment intervals should use smaller follow-up intervals (e.g., 7 days, 14 days) or more intensive reporting methods (e.g., daily diary). PMID- 29757674 TI - Eicosapentaenoic acid induces DNA demethylation in carcinoma cells through a TET1 dependent mechanism. AB - In cancer cells, global genomic hypomethylation is found together with localized hypermethylation of CpG islands within the promoters and regulatory regions of silenced tumor suppressor genes. Demethylating agents may reverse hypermethylation, thus promoting gene re-expression. Unfortunately, demethylating strategies are not efficient in solid tumor cells. DNA demethylation is mediated by ten-eleven translocation enzymes (TETs). They sequentially convert 5 methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which is associated with active transcription; 5-formylcytosine; and finally, 5-carboxylcytosine. Although alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid, the major n-3 polyunsaturated fatty acids, have anti-cancer effects, their action, as DNA-demethylating agents, has never been investigated in solid tumor cells. Here, we report that EPA demethylates DNA in hepatocarcinoma cells. EPA rapidly increases 5hmC on DNA, inducing p21Waf1/Cip1 gene expression, which slows cancer cell-cycle progression. We show that the underlying molecular mechanism involves TET1. EPA simultaneously binds peroxisome proliferator-activated receptor gamma (PPARgamma) and retinoid X receptor alpha (RXRalpha), thus promoting their heterodimer and inducing a PPARgamma-TET1 interaction. They generate a TET1 PPARgamma-RXRalpha protein complex, which binds to a hypermethylated CpG island on the p21 gene, where TET1 converts 5mC to 5hmC. In an apparent shuttling motion, PPARgamma and RXRalpha leave the DNA, whereas TET1 associates stably. Overall, EPA directly regulates DNA methylation levels, permitting TET1 to exert its anti-tumoral function.-Ceccarelli, V., Valentini, V., Ronchetti, S., Cannarile, L., Billi, M., Riccardi, C., Ottini, L., Talesa, V. N., Grignani, F., Vecchini, A., Eicosapentaenoic acid induces DNA demethylation in carcinoma cells through a TET1-dependent mechanism. PMID- 29757676 TI - Wandering in Dementia and Trust as an Anticipatory Action. AB - The increase of dementia makes cognitive disorder a global challenge. Even if wandering is not a symptom of dementia in general, professionals and scientists dominate the definition of wandering as an aimless movement of people with cognitive impairment, mainly dementia. In consequence, professional types of wandering management were elaborated trying to avoid or replace it. However, this can cause negative effects. The article analyses an apparently common informal type of wandering management. It consists of slipping an address paper in the wallet of the ill person. The analysis reveals that this practice is normatively structured by a gift of trust. PMID- 29757675 TI - Review of Methods for the Detection and Determination of Malachite Green and Leuco-Malachite Green in Aquaculture. AB - Malachite green (MG) has been widely used in the aquaculture industry as a fungicide and parasiticide because of its high efficiency and low cost, and it is commonly found in aquatic products and environmental water. However, MG and its primary metabolite, leuco-malachite green (LMG), are also toxic inorganic contaminants that are hazardous to the health of humans and other organisms. A variety of methods have been proposed in recent years for detecting and monitoring MG and LMG. This article was compiled as a general review of the methods proposed for MG and LMG detection, and several important detection parameters, such as the limit of detection, recovery and relative standard deviation, were tabulated. The analytical methods for the determination of MG and LMG in various matrices include high-performance liquid chromatography separation based methods, liquid chromatography tandem mass spectrometry, surface-enhanced Raman spectroscopy, electrochemical methods, immunological assays, spectrophotometry and fluorescent methods which were described in detail in this article. In addition, some sample preparation techniques were also described. This review can provide expert guidance to the reader on the advantages, disadvantages and applicability of the different methodologies. This review also discussed challenges and several perspectives on the future trends in the determination of MG and LMG. PMID- 29757678 TI - Teaching Tip: A Method for Evaluating Learning Evidence when Using Cumulative Final Examinations. AB - Cumulative final examinations create a unique opportunity to investigate repeated measures of an examinee's performance. This article outlines a framework for evaluating authentic learning evidence when presented with repeated measurement opportunities. The article explains how to apply the framework, including how to conduct the procedure using Microsoft Excel. Others are encouraged to adopt this framework when appropriate to evaluate authentic learning evidence. PMID- 29757679 TI - Teaching Slaughter: Mapping Changes in Emotions in Veterinary Students during Training in Humane Slaughter. AB - As part of their training, Dutch veterinary students learn how to carry out the humane slaughter of livestock, which many students consider emotionally challenging. The aims of this study were to plot changes in self-reported emotions in veterinary students at different time points during an educational program on humane slaughter using emotion cards and to assess the change in reported emotions after adding a video and a short period of self-reflection to the program. Emotions were mapped in five groups of students at the beginning, middle, and end of the program by asking them to select from 40 cards depicting emotions in photo and text. Then two changes were made to the course program: a video of an expert slaughterman stunning and bleeding a bovine was shown, and the students were requested to spend 2 minutes picturing themselves carrying out the same procedures. To evaluate the effect of these improvements to the course, the five groups of students were asked in the same way to indicate their emotions at the same three time points. Adding the video and short period of self-reflection did not change the emotions reported by students. Our results indicate that instruction in humane slaughter techniques involves a significant mental challenge for students. The use of emotion cards by teachers could provide useful insights into emotional aspects of the more challenging programs for students. PMID- 29757677 TI - MicroRNA Dysregulation in Pulmonary Arteries from Chronic Obstructive Pulmonary Disease. Relationships with Vascular Remodeling. AB - Pulmonary vascular remodeling is an angiogenic-related process involving changes in smooth muscle cell (SMC) homeostasis, which is frequently observed in chronic obstructive pulmonary disease (COPD). MicroRNAs (miRNAs) are small, noncoding RNAs that regulate mRNA expression levels of many genes, leading to the manifestation of cell identity and specific cellular phenotypes. Here, we evaluate the miRNA expression profiles of pulmonary arteries (PAs) of patients with COPD and its relationship with the regulation of SMC phenotypic change. miRNA expression profiles from PAs of 12 patients with COPD, 9 smokers with normal lung function (SK), and 7 nonsmokers (NS) were analyzed using TaqMan Low Density Arrays. In patients with COPD, expression levels of miR-98, miR-139-5p, miR-146b-5p, and miR-451 were upregulated, as compared with NS. In contrast, miR 197, miR-204, miR-485-3p, and miR-627 were downregulated. miRNA-197 expression correlated with both airflow obstruction and PA intimal enlargement. In an in vitro model of SMC differentiation, miR-197 expression was associated with an SMC contractile phenotype. miR-197 inhibition blocked the acquisition of contractile markers in SMCs and promoted a proliferative/migratory phenotype measured by both cell cycle analysis and wound-healing assay. Using luciferase assays, Western blot, and quantitative PCR, we confirmed that miR-197 targets the transcription factor E2F1. In PAs from patients with COPD, levels of E2F1 were increased as compared with NS. In PAs of patients with COPD, remodeling of the vessel wall is associated with downregulation of miR-197, which regulates SMC phenotype. The effect of miR-197 on PAs might be mediated, at least in part, by the key proproliferative factor, E2F1. PMID- 29757680 TI - Comparison of Two Veterinary Emergency and Critical Care Clerkship Grading Protocols. AB - Universal guidelines for evaluating veterinary students' clinical clerkship performance are unavailable. At our institution, each service determines its own grading protocol. In this study, researchers compared clinician, staff, and student perceptions of a traditional and newly devised grading practice on the Emergency and Critical Care (ECC) clerkship. ECC clinicians and technicians were asked to assess the existing grading protocol for the clerkship. The system was then revised to better align with clerkship objectives. The revised protocol evaluated students on 12 items encompassing knowledge, clinical, and communication skills. Following the assignment of values for each category, letter grades were calculated automatically. Clinicians and staff were invited to rate the revised grading system. Throughout the study period, a corresponding survey was sent to students shortly after they had received their clerkship grades. Students' open-ended comments were analyzed qualitatively to identify common themes. Clinicians and technicians reported that the revised protocol was more inclusive and better able to provide fair and accurate assessments of students' performances. Students were generally satisfied with both grading protocols, however, in the open-ended comments students' frequently expressed desire for more directed and timely feedback on their performance. The results of this study indicate that the graders' believed that the revised evaluation protocol provides opportunities to provide fair and accurate assessments of student performance. Overall, students were satisfied with the new protocol and have a desire for tailored feedback provided in a timely fashion. PMID- 29757683 TI - Electrochemical Enzyme Biosensors Revisited: Old Solutions for New Problems. AB - Worldwide legislation is driving the development of novel and highly efficient analytical tools for assessing the composition of every material that interacts with Consumers or Nature. The biosensor technology is one of the most active R&D domains of Analytical Sciences focused on the challenge of taking analytical chemistry to the field. Electrochemical biosensors based on redox enzymes, in particular, are highly appealing due to their usual quick response, high selectivity and sensitivity, low cost and portable dimensions. This review paper aims to provide an overview of the most important advances made in the field since the proposal of the first biosensor, the well-known hand-held glucose meter. The first section addresses the current needs and challenges for novel analytical tools, followed by a brief description of the different components and configurations of biosensing devices, and the fundamentals of enzyme kinetics and amperometry. The following sections emphasize on enzyme-based amperometric biosensors and the different stages of their development. PMID- 29757682 TI - A scoping review of the nature and outcomes of extended rehabilitation programmes after very severe brain injury. AB - PRIMARY OBJECTIVE: Many adults with very severe acquired brain injury (ABI) do not receive adequate rehabilitation, limiting their recovery and leading to admission to inappropriate living environments. The aim of this scoping review was to map the existing literature relating to the nature and outcomes of rehabilitation programmes for adults experiencing prolonged recovery after very severe ABI. DESIGN: A comprehensive scoping of the literature was undertaken, including systematic searching of databases, grey literature, and hand searching. Eligible studies had to report on (a) extended rehabilitation for (b) adults with very severe ABI and complex support needs and describe (c) the outcomes of the intervention. RESULTS: From an initial total of 17,829 citations, 18 records were retained for review. Data extraction focused on (i) participant characteristics, (ii) programme information, and (iii) programme outcomes. Studies were characterised by substantial diversity. However, findings suggested that extended rehabilitation assisted participants to live more independently in more home-like environments and contributed towards significant savings in their lifetime care costs. CONCLUSIONS: Extended specialised rehabilitation can maximise the independence and participation of adults with very severe ABI. Advocacy is required to ensure that adults with very severe injuries have access to individually tailored, non-time-limited intervention programmes. PMID- 29757681 TI - Lung-Resident Mesenchymal Stromal Cells Reveal Transcriptional Dynamics of Lung Development in Preterm Infants. PMID- 29757684 TI - An account of the real-life hepatitis C management in a single specialized viral hepatitis treatment centre in Egypt: results of treating 7042 patients with 7 different direct acting antiviral regimens. AB - BACKGROUND: A large Egyptian treatment program for HCV was launched in2014 after the introduction of direct-acting antiviral agents (DAAs). This program depended mainly on establishing specialized independent centres for HCV treatment. These centres represent the major strengths in the Egyptian model of care, as they provide integrated care for HCV patients and have enabled Egypt to treat more than one million patients in 3 years. The New Cairo Viral Hepatitis Treatment Center (NCVHTC) is an example of these specialized centres. METHODS: The Egyptian experience in the management of HCV was evaluated by analysing the data of real life HCV management in the NCVHTC from 2014 to 2017. Results of different treatment regimens in addition to their strengths, limitations and areas for improvement are discussed in this report. RESULTS: A total of 7042 HCV patients have been evaluated for treatment in the NCVHTC. Among them, 5517 patients received treatment by seven different DAA regimens with excellent results. CONCLUSIONS: All regimens were highly effective at treating HCV in a real-life setting, apart from SOF/RBV, which was the least effective. A nationwide screening program and enhancing the follow-up of treated patients are the main missing pillars in the Egyptian model. PMID- 29757685 TI - The effect of standardizing treatment when managing neonatal abstinence syndrome. AB - OBJECTIVE: Standardizing treatment of neonatal abstinence syndrome (NAS) is currently recommended; however, single institution prospective studies are lacking regarding the success of this approach. The study objective was to evaluate overall newborn response and length of stay (LOS) of neonates treated for NAS following the institution of a strict standardized treatment protocol. METHODS: From 1 January 2014 to 30 June 2016, a prospective cohort study was performed collecting neonatal outcomes before and after the standardization of a strict NAS morphine weaning treatment protocol. The primary outcome measure was length of stay. The standardized protocol was fully instituted in June 2015. RESULTS: A total of 395 neonates were treated for NAS during the study. The LOS for the 17 months prior to the initiation of this protocol was 23.31 (+/-6.2) days (233 neonates). The LOS in the 13 months after protocol initiation was 18.17 (+/-5.1) days (162 neonates). This was a difference of 5.14 days (95%CI 4.0-6.3 days) less in LOS (p < .0001). CONCLUSIONS: These data demonstrate that the initiation of a standardized NAS treatment protocol can significantly improve neonatal response and decrease LOS. It is recommended that institutions with nurseries that treat infants with NAS develop standardized treatment protocols to improve care for this complicated patient population. PMID- 29757687 TI - A Review of Analytical Methods for p-Coumaric Acid in Plant-Based Products, Beverages, and Biological Matrices. AB - p-Coumaric acid (p-CA), also known as 4-hydroxycinnamic acid, is a phenolic acid, which has been widely studied due to its beneficial effects against several diseases and its wide distribution in the plant kingdom. This phenolic compound can be found in the free form or conjugated with other molecules; therefore, its bioavailability and the pathways via which it is metabolized change according to its chemical structure. p-CA has potential pharmacological effects because it has high free radical scavenging, anti-inflammatory, antineoplastic, and antimicrobial activities, among other biological properties. It is therefore essential to choose the most appropriate and effective analytical method for qualitative and quantitative determination of p-CA in different matrices, such as plasma, urine, plant extracts, and drug delivery systems. The most-reported analytical method for this purpose is high-performance liquid chromatography, which is mostly coupled with some type of detectors, such as UV/Vis detector. However, other analytical techniques are also used to evaluate this compound. This review presents a summary of p-CA in terms of its chemical and pharmacokinetic properties, pharmacological effects, drug delivery systems, and the analytical methods described in the literature that are suitable for its quantification. PMID- 29757688 TI - The Self-perception of Text-message Dependency Scale (STDS): Psychometric update based on a United States sample. AB - BACKGROUND: Some have suggested that text messaging is an addictive behavior. However, this characterization is uncertain, partly due to lack of well-validated measures of text messaging attitudes and behaviors. One standard instrument for measuring text messaging attitudes and behaviors is the Self-perception of Text message Dependency Scale (STDS), though the psychometric properties of this scale have only been examined with a sample of Japanese youth. OBJECTIVES: The primary objective of this study was to evaluate the STDS in the United States to determine its utility as a measure of text messaging dependence. We were interested in examining the factor structure and determining the extent to which this scale would correlate with two important outcome measures: motor vehicle accidents (MVAs) and moving violations. METHODS: We analyzed data from 468 adults (age 18-74; 274 women) recruited via Amazon's Mechanical Turk (mTurk) service. Participants completed the STDS and provided information about their driving related incidents in the past year. RESULTS: First we performed a confirmatory factor analysis, which supported the instrument's original factor structure. Then we tested the relationship between scores on the STDS and two important variables, MVAs and moving violations. We found that the STDS significantly correlated with both MVAs and moving violations. CONCLUSION: The present study confirms that the STDS is a potentially useful instrument for studying texting dependence in the United States and with adults of all ages. The instrument may be particularly useful in predicting motor vehicle outcomes. PMID- 29757686 TI - Predictors of Unemployment After Breast Cancer Surgery: A Systematic Review and Meta-Analysis of Observational Studies. AB - Purpose Breast cancer surgery is associated with unemployment. Identifying high risk patients could help inform strategies to promote return to work. We systematically reviewed observational studies to explore factors associated with unemployment after breast cancer surgery. Methods We searched MEDLINE, EMBASE, CINAHL, and PsycINFO to identify studies that explored risk factors for unemployment after breast cancer surgery. When possible, we pooled estimates of association for all independent variables reported by more than one study. Results Twenty-six studies (46,927 patients) reported the association of 127 variables with unemployment after breast cancer surgery. Access to universal health care was associated with higher rates of unemployment (26.6% v 15.4%; test of interaction P = .05). High-quality evidence showed that unemployment after breast cancer surgery was associated with high psychological job demands (odds ratio [OR], 4.26; 95% CI, 2.27 to 7.97), childlessness (OR, 1.30; 95% CI, 1.11 to 1.53), lower education level (OR, 1.15; 95% CI, 1.05 to 1.25), lower income level (OR, 1.46; 95% CI, 1.24 to 1.73), cancer stage II, III or IV (OR, 1.43; 95% CI, 1.13 to 1.82), and mastectomy versus breast-conserving surgery (OR, 1.18; 95% CI, 1.07 to 1.30). Moderate-quality evidence suggested an association with high physical job demands (OR, 2.11; 95%CI, 1.52 to 2.93), African-American ethnicity (OR, 1.89; 95% CI, 1.21 to 2.96), and receipt of chemotherapy (OR, 1.95; 95% CI, 1.36 to 2.79). High-quality evidence demonstrated no significant association with part-time hours, blue-collar work, tumor size, positive lymph nodes, or receipt of radiotherapy or endocrine therapy; moderate-quality evidence suggested no association with age, marital status, or axillary lymph node dissection. Conclusion Addressing high physical and psychological job demands may be important in reducing unemployment after breast cancer surgery. PMID- 29757689 TI - Effect of traffic density on drivers' lane change and overtaking maneuvers in freeway situation-A driving simulator-based study. AB - OBJECTIVE: The aim of this study is to examine the effect of traffic density on drivers' lane change and overtaking maneuvers. The differences between drivers' left and right lane changing/overtaking maneuvers were also investigated. METHOD: A driving simulator experiment was conducted and 24 participants took part in this experiment. Based on the driving simulation data, lane change frequency, time duration, average speed, and acceleration were extracted as key variables of lane change maneuvers; overtaking frequency, overtaking duration, initial overtaking distance and headway, instantaneous speed, and acceleration before overtaking were analyzed as the key overtaking variables. One-way repeated measures analysis of variance (ANOVA), the Friedman test, and the Wilcoxon signed rank test were adopted for hypothesis tests with a significance level of .05. Further pairwise comparisons were performed with a Bonferroni correction for multiple comparisons. RESULTS: Some significant differences in lane change and overtake behaviors were observed among different traffic densities: (1) both lane change and overtaking frequencies significantly increase with traffic density; (2) the average lane change acceleration and instantaneous overtaking acceleration significantly increase with traffic density; (3) as the traffic density increases, the initial overtaking distance and headway decrease. As for the effect of the directions of maneuvers, the (1) time duration of lane change and overtaking from the right side was significantly shorter than that from the left side; (2) right initial overtaking distance/headway was smaller than that of the left side; (3) right instantaneous overtaking acceleration was significantly higher than the left instantaneous acceleration. CONCLUSIONS: The results showed that as traffic density increases, drivers' lane changing and overtaking intentions are enhanced. Both initial overtaking distance and headway decrease with traffic density, which might influence road safety. In addition, drivers do not show a preference on the directions of lane change or overtaking according to frequency. However, drivers tend to be more decisive and reckless when overtaking on the right because of a smaller distance/headway before overtaking, higher instantaneous acceleration, and a more restricted field of view compared with overtaking on the left. PMID- 29757690 TI - Market Stabilization Stalls; States Step In. AB - As federal efforts to stabilize the individual market foundered on abortion coverage, states adopted a variety of approaches. The 2019 payment notice broadened states' options in implementing the ACA. PMID- 29757691 TI - A patent review of butyrylcholinesterase inhibitors and reactivators 2010-2017. AB - INTRODUCTION: Butyrylcholinesterase (BuChE) has obtained a renewed interest as therapeutic target in Alzheimer's disease (AD), when changes in BuChE activity and expression along disease progression were highlighted as well as correlation between BuChE levels and cognitive function. Areas covered: During the last eight years, fourteen patents on BuChE inhibitors (BuChEI) have been submitted. Only three of them relate to BuChE selective inhibitors, while four of them focus on multitarget inhibitors which address different key pathological factors other than BuChE. Two patents report on non-selective acetylcholinesterase (AChE)/BuChE inhibitors, while four patents deal with natural compounds and their derivatives. One patent relates to antitoxic agents to treat exposure to ChEI pesticides and nerve agents. Expert opinion: Increasing evidence supports BuChE as a more beneficial target in moderate-to-severe forms of AD in comparison to the well known AChE. However, hitting a single pathological target is likely not sufficient to halt the disease progression. Therefore, patented BuChE inhibitors with a multifunctional profile may open new therapeutic avenues, since the additional activities could reinforce the therapeutic effects. Unfortunately, in vivo studies are limited and key parameters, such as ADMET data, are missing. This lack of information makes difficult to forecast the development of patented BuChEIs into effective drug candidates. PMID- 29757692 TI - Integrative omics - from data to biology. AB - INTRODUCTION: Multi-omic approaches are promising a broader view on cellular processes and a deeper understanding of biological systems. with strongly improved high-throughput methods the amounts of data generated have become huge, and their handling challenging. Area Covered: New bioinformatic tools and pipelines for the integration of data from different omics disciplines continue to emerge, and will support scientists to reliably interpret data in the context of biological processes. comprehensive data integration strategies will fundamentally improve systems biology and systems medicine. to present recent developments of integrative omics, the gottingen proteomics forum (gpf) organized its 6th symposium on the 23rd of november 2017, as part of a series of regular gpf symposia. more than 140 scientists attended the event that highlighted the challenges and opportunities but also the caveats of integrating data from different omics disciplines. Expert commentary: The continuous exponential growth in omics data require similar development in software solutions for handling this challenge. Integrative omics tools offer the chance to handle this challenge but profound investigations and coordinated efforts are required to boost this field. PMID- 29757693 TI - A Rotator Cuff Tear Concomitant With Shoulder Stiffness Is Associated With a Lower Retear Rate After 1-Stage Arthroscopic Surgery. AB - BACKGROUND: Few studies have reported on the radiological characteristics and repair integrity of coexistent rotator cuff tears (RCTs) and shoulder stiffness after simultaneous arthroscopic rotator cuff repair and capsular release. PURPOSE: To evaluate the radiological characteristics and repair integrity of 1 stage arthroscopic surgery of RCTs concomitant with shoulder stiffness. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Among patients who underwent arthroscopic repair of full-thickness RCTs, the stiff group underwent simultaneous capsular release for shoulder stiffness, and the nonstiff group had no stiffness. Symptom duration, prevalence of diabetes, tear size, tendon involvement (type 1, supraspinatus; type 2, supraspinatus and subscapularis; and type 3, supraspinatus and infraspinatus; type 4, supraspinatus, subscapularis, and infraspinatus), and fatty infiltration (Goutallier stages 0-4) were evaluated. A retear was appraised using magnetic resonance imaging, and clinical outcomes were assessed using range of motion, the Korean Shoulder Scoring System (KSS), and the University of California, Los Angeles (UCLA) shoulder score. RESULTS: The stiff group showed a significantly lower retear rate (1/39, 2.6%) than the nonstiff group (47/320, 14.7%) ( P = .043). There were significant differences in symptom duration (7.4 +/- 6.6 vs 15.0 +/- 23.7 months, respectively; P < .001), mediolateral tear size (18.9 +/- 8.9 vs 24.1 +/- 12.0 mm, respectively; P = .002), tendon involvement (94.9%, 5.1%, 0.0%, and 0.0% vs 85.3%, 6.9%, 7.8%, and 0.0%, respectively; P = .048), and fatty infiltration of the subscapularis (66.7%, 33.3%, 0.0%, 0.0%, and 0.0% vs 31.9%, 61.3%, 5.6%, 1.3%, and 0.0%, respectively; P < .001) and teres minor (74.4%, 20.5%, 5.1%, 0.0%, and 0.0% vs 47.2%, 48.8%, 3.8%, 0.0%, and 0.3%, respectively; P = .007) between the stiff and nonstiff groups. Preoperatively, the stiff group showed significantly worse forward flexion (95.9 degrees +/- 23.6 degrees vs 147.7 degrees +/- 4.2 degrees , respectively; P < .001), external rotation (17.4 degrees +/- 10.1 degrees vs 51.6 degrees +/- 12.1 degrees , respectively; P < .001), and internal rotation (L5 vs L2, respectively; P < .001) and lower KSS (52.1 +/- 13.8 vs 66.3 +/- 13.5, respectively; P < .001) and UCLA scores (18.7 +/ 4.8 vs 22.5 +/- 4.5, respectively; P < .001) than the nonstiff group. However, these differences became insignificant from 3 months postoperatively for forward flexion ( P > .05) and KSS ( P > .05) and UCLA scores ( P > .05), from 1 year postoperatively for external rotation ( P > .05), and at the last follow-up for internal rotation ( P > .05). A multiple logistic regression analysis revealed that only mediolateral tear size (odds ratio, 1.043; P = .014) and type 2 tendon involvement (odds ratio, 4.493; P = .003) were independent predictors of a retear. CONCLUSION: RCTs concomitant with shoulder stiffness showed a smaller mediolateral tear size, anterosuperior tendon involvement, and less severe fatty infiltration preoperatively and better repair integrity postoperatively than RCTs without stiffness. Furthermore, the clinical outcomes and range of motion at final follow-up were similar between the 2 groups. PMID- 29757694 TI - Correction to: Prevalence and Quinolone Susceptibilities of Salmonella Isolated from the Feces of Preharvest Cattle Within Feedlots that Used a Fluoroquinolone to Treat Bovine Respiratory Disease, by Smith, A.B., Renter, D.G., Cernicchiaro, N., Shi, X., and Nagaraja, T.G. Foodborne Path Dis 2016;6:303-308. DOI: 10.1089/fpd.2015.2081. PMID- 29757695 TI - Re: "Herbal Use During Breastfeeding" by Anderson (Breastfeed Med 2017;12(9):507 509). PMID- 29757696 TI - A refugee patient with meningococcal meningitis type B. PMID- 29757697 TI - Molecular drivers of metastatic castrate-resistant prostate cancer: New roads to resistance. AB - Numerous growth-inducing signaling pathways have been implicated in the development of metastatic castrate-resistant prostate cancer, but their cross talk with androgen receptor functions remains poorly understood. A recent study published in Science Signaling by Chen et al. 1 has identified a novel androgen mediated signaling axis driven by loss of SPDEF and gain of TGFBI to facilitate metastasis, which may explain the acquisition of resistance to androgen deprivation therapy. These findings suggest that therapeutic inhibition of androgen signaling may inadvertently promote castrate resistance by inhibiting tumor suppressive functions of the androgen receptor. PMID- 29757698 TI - Prediction of non-linear pharmacokinetics in humans of an antibody-drug conjugate (ADC) when evaluation of higher doses in animals is limited by tolerability: Case study with an anti-CD33 ADC. AB - For antibody-drug conjugates (ADCs) that carry a cytotoxic drug, doses that can be administered in preclinical studies are typically limited by tolerability, leading to a narrow dose range that can be tested. For molecules with non-linear pharmacokinetics (PK), this limited dose range may be insufficient to fully characterize the PK of the ADC and limits translation to humans. Mathematical PK models are frequently used for molecule selection during preclinical drug development and for translational predictions to guide clinical study design. Here, we present a practical approach that uses limited PK and receptor occupancy (RO) data of the corresponding unconjugated antibody to predict ADC PK when conjugation does not alter the non-specific clearance or the antibody-target interaction. We used a 2-compartment model incorporating non-specific and specific (target mediated) clearances, where the latter is a function of RO, to describe the PK of anti-CD33 ADC with dose-limiting neutropenia in cynomolgus monkeys. We tested our model by comparing PK predictions based on the unconjugated antibody to observed ADC PK data that was not utilized for model development. Prospective prediction of human PK was performed by incorporating in vitro binding affinity differences between species for varying levels of CD33 target expression. Additionally, this approach was used to predict human PK of other previously tested anti-CD33 molecules with published clinical data. The findings showed that, for a cytotoxic ADC with non-linear PK and limited preclinical PK data, incorporating RO in the PK model and using data from the corresponding unconjugated antibody at higher doses allowed the identification of parameters to characterize monkey PK and enabled human PK predictions. PMID- 29757699 TI - Current status and future directions of invasive pneumococcal diseases and prophylactic approaches to control them. AB - Streptococcus pneumoniae is a major human bacterial pathogen responsible for millions of deaths each year and significantly more illnesses worldwide. With over 90 different serotypes, providing effective vaccine programs has been a continuing challenge. Since 1983, the world has been introduced to four different pneumococcal vaccines (PPSV23, PCV7, PCV10, and PCV13) each with their own complications and successes. Since vaccination programs began, a decrease in the overall rate of pneumococcal pneumonia and associated diseases has been observed, notably in higher risk populations. However, with a decrease in incidence of vaccine type pneumococcal serotypes, increases in non-vaccine serotypes of the bacteria have been observed along with serotype switching. Additionally, a rise in antibiotic resistant strains of S. pneumoniae is noted. Here we discuss both the positive and negative clinical manifestations of pneumonia vaccine programs and discuss the challenges in pneumococcal vaccine design. PMID- 29757701 TI - The Decoy Effect as a Nudge: Boosting Hand Hygiene With a Worse Option. AB - This article provides the first test of the decoy effect as a nudge to influence real-world behavior. The decoy effect is the phenomenon that an additional but worse option can boost the appeal of an existing option. It has been widely demonstrated in hypothetical choices, but its usefulness in real-world settings has been subject to debate. In three longitudinal experiments in food-processing factories, we tested two decoy sanitation options that were worse than the existing sanitizer spray bottle. Results showed that the presence of a decoy, but not an additional copy of the original sanitizer bottle in a different color, drastically increased food workers' hand sanitizer use from the original sanitizer bottle and, consequently, improved workers' passing rate in hand sanitation tests from 60% to 70% to above 90% for 20 days. These findings indicate that the decoy effect can be a powerful nudge technique to influence real-world behavior. PMID- 29757700 TI - Adhesion characteristics of porcine pancreatic islets and exocrine tissue to coating materials. AB - Since the report of the Edmonton protocol in 2000, islet transplantation has been implemented worldwide, and xenotransplantation using porcine islets has also been reported. In addition, many basic experiments using pancreatic islets and exocrine tissue after isolation have been reported. Recently, exocrine cells have been found to be essential for inducing the differentiation of pancreatic islets. Therefore, the importance of the culture conditions for pancreatic tissue when conducting experiments using pancreatic tissue is also increasing. In this study, we focused on the coat material and examined the adhesive properties of porcine pancreatic islets and exocrine tissue after isolation. Porcine islet isolation was performed, and isolated islets (purity >=95%) and exocrine tissue (purity >=99%) were used to achieve adhesion to several extracellular matrixes, fibronectin, collagen type I, collagen type IV, laminin I, fibrinogen, and bovine serum albumin (BSA). DMEM with 0.5% FBS was used as the assay medium. For exocrine tissue, the adhesion was promoted in fibronectin, collagen type I, laminin I, and fibrinogen. The adhesive ability to fibronectin was more than twice that to BSA, while the adhesive ability to collagen type I, laminin I, and fibrinogen was less than twice that to BSA. For islets, the adhesive ability to fibronectin was weaker than that of exocrine tissue. Furthermore, the adhesion effect in fibronectin was obtained within 30 minutes and in medium containing little serum for both islets and exocrine tissues. These data suggest that fibronectin may be useful for the adhesion of pancreatic tissue. PMID- 29757702 TI - Genetic Diversity of Toxoplasma gondii Isolates From Free-Range Chickens In Bahia, Brazil. AB - The genotyping of 25 isolates of Toxoplasma gondii from free-range chickens in the state of Bahia, Brazil, was performed by PCR-restriction fragment length polymorphism using 11 genetic markers: SAG1, 5'+3'SAG2, alt.SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, Apico, and CS3. The analysis revealed 8 genotypes, 3 of which had not been previously reported. Four genotypes were represented by single isolates, whereas the other genotypes were represented by 2 or more isolates. Five isolates showed mixed infections, and 2 of them were identical. None of the clonal types I, II, or III were found, but 2 isolates corresponded to the Brazilian clonal lineage BrIII. There was a single allele for the c22-8 marker. The CS3 marker demonstrated efficiency in the evaluation of virulence in mice. This study reaffirms the diverse genetic variability of T. gondii in Brazil. PMID- 29757703 TI - Hepatitis B virus infection among asymptomatic residents of low income community in Ibadan, Southwest, Nigeria. AB - INTRODUCTION: Hepatitis B Virus (HBV) infection is one of the most infectious diseases worldwide and a major public health concern. In spite of efforts at controlling the scourge globally, HBV continues to thrive in developing countries, such as Nigeria due to ignorance on its mode of transmission and its asymptomatic nature in the populace. Therefore, this community-based study was carried out in Yemetu community in Ibadan, Nigeria to determine the burden of HBV infection among asymptomatic residents of this community. METHODOLOGY: Blood samples were aseptically collected from consenting 150 participants, male (m = 49) and female (f = 101), age ranged 15->55 years (Median age = 27.3 years). Astructured questionnaire was used to capture demographic data and other relevant information from these participants. Sera from these samples were tested for HBsAg using a 3rd generation Enzyme-Linked Immunosorbent-Assay (ELISA) Wantai HBV Diagnostics kit. Data were analyzed using Chi-square and ANOVA at 95% CI with P < 0.05 considered as significant. RESULTS: An overall seroprevalence rate for HBV in this study was 7.3%. HBV infection was higher among male (8.2%) than in female (6.7%), 1.4 times higher in male compared to their female counterparts (OR = 1.37, 95%CI 1.01-2.06) and also statistically significant (P = 0.043). Participants in the age groups 25-34 (10.3%) and >55 (4.2%) years had highest and lowest rates of HBV infection, respectively. Further analysis of the results by occupation shows that HBV infection was highest among Artisans (10.7%), followed by Students (6.9%) and Traders (6.9%) and lowest (5.6%) among Civil servants who are sexually active, married and unmarried. However, these differences were not statistically significant (P = 0.081). CONCLUSION: This study reported relatively high prevalence for HBV infection among asymptomatic population, which is of public health importance and this calls for urgent attention. Therefore, public sensitization on HBV transmission and control for all through voluntary counseling and testing is advocated. PMID- 29757704 TI - Dynamics of 'Candidatus Liberibacter asiaticus' Colonization of New Growth of Citrus. AB - 'Candidatus Liberibacter asiaticus' is a phloem-colonizing intracellular bacterial pathogen of citrus associated with the disease huanglongbing. A study of patterns of colonization and bacterial population growth in new growth of different citrus types was conducted by pruning infected citron, sweet orange, sour orange, mandarin, citrange, and Citrus macrophylla trees to force the growth of axillary and adventitious shoots. The first three leaves on newly emerged shoots were collected at 30, 60, and 90 days to assess colonization and population growth of 'Ca. L. asiaticus' using real time PCR (qPCR). Single trials were conducted with mandarin and citron, two trials each for citrange, sour orange and sweet orange, and four trials for C. macrophylla. In citron the proportion of colonized leaves increased significantly over time, with 67, 85, and 96% of leaves colonized at 30, 60, and 90 days, respectively. For the other citrus types, the exact proportion of colonized leaves differed, but colonization exceeded 60% in mandarin, sour orange, and citrange, and exceeded 80% at 30 days in two trials with sweet orange and three trials with C. macrophylla, but there was no significant increase in the proportion of colonized leaves at 60 and 90 days. Bacteria were readily detected by 30 days in new leaves of all citrus types. Differences in the growth of the bacterial population between citrus types and at different times of the year were noted, but common trends were apparent. In general, bacterial titers peaked at 60 days, except in leaves of C. macrophylla where bacterial titers peaked at 30 days. The early and consistently high proportion of leaf colonization observed for new growth of sweet orange during two trials and for C. macrophylla during three trials indicates a near synchronous colonization of new leaves by 30 days. PMID- 29757705 TI - Mitotic kinesins in action: diffusive searching, directional switching, and ensemble coordination. AB - Mitotic spindle assembly requires the collective action of multiple microtubule motors that coordinate their activities in ensembles. However, despite significant advances in our understanding of mitotic kinesins at the single-motor level, multi-motor systems are challenging to reconstitute in vitro and thus less well understood. Recent findings highlighted in this perspective demonstrate how various properties of kinesin-5 and -14 motors-diffusive searching, directional switching, and multivalent interactions-allow them to achieve their physiological roles of cross-linking parallel microtubules and sliding antiparallel ones during cell division. Additionally, we highlight new experimental techniques that will help bridge the gap between in vitro biophysical studies and in vivo cell biology investigations and provide new insights into how specific single-molecule mechanisms generate complex cellular behaviors. PMID- 29757707 TI - Universal rotavirus vaccination program in Sicily: Reduction in health burden and cost despite low vaccination coverage. AB - Rotavirus is considered the main cause of severe gastroenteritis and nosocomial infections in Pediatric units, especially during late winter and early spring season in temperate region. In 2013 Sicilian Region, for the first time in Italy, introduced universal Rotavirus vaccination. This study aims to estimate health and economic impact on rotavirus Gastroenteritis (RVGE) among children aged 0-59 months in Sicily, after rotavirus vaccine introduction. We analyzed hospital discharge records including a diagnosis of RVGE occurred from 1st January 2009 to 31st December 2016 among hospitalized children aged 0 to 59 months, residents in Sicily. RVGEs were defined as all hospitalizations with an ICD-9-CM diagnosis code of 008.61 on first or any diagnosis position. Also an economic impact analysis on Health Regional System was conducted. We observed a consistent decline of hospitalization after rotavirus vaccination introduction from 394 per 100,000 in 2009-2012 to 220 per 100,000 in 2013-2016. We found a change in the peak of reported cases by at least one month from March-April in the pre vaccination period to May-June in the post-vaccination period. Since 2013, we estimated that the annual average cost saved is 1,134,056 ? when considering direct and indirect costs to health care as well as vaccination costs. Our study is the first analysis conducted as far as we are aware in a high-income setting with poor coverage (lower than 50%), demonstrating a significant reduction of RVGE hospitalizations in Sicily after vaccine introduction. Moreover, was observed a consistent impact of vaccination on health care cost saving. PMID- 29757710 TI - What went right? An analysis of the protective factors in aviation near misses. AB - Learning from successful safety outcomes, or what went right, is an important emerging component of maintaining safe systems. Accordingly, there are increasing calls to study normal performance in near misses as a part of safety management activities. Despite this, there is limited guidance on how to accomplish this in practice. This article presents a study in which using Rasmussen's risk management framework to analyse 16 serious incidents from the aviation domain. The findings show that a network of protective factors prevents accidents with factors identified across the sociotechnical system. These protective networks share many properties with those identified in accidents. The article demonstrates that is possible to identify these networks of protective factors from incident investigation reports. The theoretical implications of these results and future research opportunities are discussed. Practitioner Statement: The analysis of near misses is an important part of safety management activities. This article demonstrates that Rasmussen?s risk management framework can be used to identify networks of protective factors which prevent accidents. Safety practitioners can use the framework described to discover and support the system wide networks of protective factors. PMID- 29757706 TI - The vesicular stomatitis virus-based Ebola virus vaccine: From concept to clinical trials. AB - The devastating Ebola virus (EBOV) epidemic in West Africa in 2013-2016 accelerated the progress of several vaccines and antivirals through clinical trials, including the replication-competent vesicular stomatitis virus-based vaccine expressing the EBOV glycoprotein (VSV-EBOV). Extensive preclinical testing in animal models demonstrated the prophylactic and post-exposure efficacy of this vaccine, identified the mechanism of protection, and suggested it was safe for human use. Based on these data, VSV-EBOV was extensively tested in phase 1-3 clinical trials in North America, Europe and Africa. Although some side effects of vaccination were observed, these clinical trials showed that the VSV EBOV was safe and immunogenic in humans. Moreover, the data supported the use of VSV-EBOV as an emergency vaccine in individuals at risk for Ebola virus disease. In this review, we summarize the results of the extensive preclinical and clinical testing of the VSV-EBOV vaccine. PMID- 29757708 TI - Complete blood count alterations due to the opioid use: what about the lymphocyte related ratios, especially in monocyte to lymphocyte ratio and platelet to lymphocyte ratio? AB - This study was designed to compare the complete blood count values of opioid users (N = 61) and healthy subjects (N = 61), particularly monocyte-to-lymphocyte ratio (MLR) and platelet-to-lymphocyte ratio (PLR). PLR, MLR, and percentage of monocyte (MONO%) were significantly lower in opioid use disorder (OUD) group (P = 0.012, P = 0.005, P = 0.000). The area under the ROC curve of MLR and PLR levels for OUD was 0.349 and 0.368. MONO% correlated with substance use duration. Measurements like lymphocyte-related ratios and MONO% in opioid use can be important in substance monitoring, detection, and differentiation of acute and chronic conditions. PMID- 29757711 TI - Misleading Health Consumers Through Violations of Communicative Norms: A Case Study of Online Diabetes Education. AB - Communication is a cooperative endeavor that goes well beyond decoding sentences' literal meaning. Listeners actively construe the meaning of utterances from both their literal meanings and the pragmatic principles that govern communication. When communicators make pragmatically infelicitous statements, the effects can be similar to paltering-misleading speech that evokes false inferences from true statements. The American Diabetes Association's (ADA's) "Diabetes Myths" website provides a real-world case study in such misleading communications. Calling something a myth implies that it is clearly false. Instead, the ADA's "myths" are false only because of some technicality or uncharitable reading. We compared participants' baseline knowledge of diabetes with that of participants who read either the ADA's myths or the myths rewritten as questions that do not presuppose the statement is false. As predicted, exposure to the ADA's "myths," but not to the rephrased questions, reduced basic knowledge of diabetes. Our findings underscore the need to consider psycholinguistic principles in mass communications. PMID- 29757709 TI - How to assess the best immunohistochemical panel in the diagnosis of malignant pleural mesothelioma in a pathology lab. AB - BACKGROUND: malignant pleural mesothelioma (MPM) is a rare tumor with a challenging diagnosis. Even if, clinical data are mandatory to suspect the diagnosis, the positive diagnosis is based on microscopic features. Morphologic features are still the port of call of the diagnosis but their non specific character and the multiplicity of differential diagnoses made the immunohistochemical markers mandatory for the diagnosis. Many antibodies with a positive diagnostic value including claretinin, mesothelin, WT1 and antibodies with a negative diagnostic value including TTF1, EMA, CD15 are recommended by the scientific societies. This is due to the diagnostic limits of every antibody which necessitate the association of multiple antibodies. In the diagnostic demarch, pathologists deal with different antibodies and clones. Even if many recommendations are available, every pathology lab has to experiment its own antibodies in order to optimize the routine diagnostic demarch especially in low income country. Our aim was to assess the diagnostic value of different antibodies available in our lab and to recommend a decisional flowchart. PATIENTS AND METHODS: we conducted a retrospective study about 30 MPM diagnosed over a 20 year-period. The different techniques were realized manually. The different antibodies used were anti-calretinin, anti-Epithelial Membrane Antigen (EMA), anti-mesothelin, anti-Thyroid Transcription Factor 1 (TTF1), anti-ACE, anti cytokeratin, anti-vimentin, anti-CD15, anti-cytokeratin 5/6, anti-bcl2, and anti CD99 and anti-CD34 antibodies. The sensitivity and specificity of these antibodies were assessed. RESULTS: the microscopic exam concluded to an epithelioid mesothelioma (EM) in 17 cases, sarcomatoid mesothelioma (SM) in four cases and biphasic mesothelioma (BM) in nine cases. The immunohistochemical study was performed in all cases. A mean of eight antibodies was used in every case, average 4 to 20 antibodies. The immunohistochemical study was repeated from 2 to 5 times in 15 cases and concerned a mean of 3 antibodies per case. In EM and BM, the antibodies with positive predictive value and highest sensitivity were calretinin, EMA, cytokeratin, and vimentin reaching respectively a sensitivity of 86.2%, 89.7%, 92.9% and 89.3%. The most valuable antibodies with negative predictive value were TTF1, CD15 and ACE that presented a specificity reaching respectively 100%. In sarcomatoid mesothelima, the most sensitive antibody was the cytokeratin antibody. CONCLUSION: these results yielded to a diagnostic flowchart that we can use in routine practice and that is in accordance with the literature findings. Many diagnostic and technical pitfalls have to be known by pathologists when dealing with MPM. PMID- 29757712 TI - Genetic variability of Ganoderma zonatum infecting palms in Florida. AB - Ganoderma zonatum is a lethal pathogen of palms (Arecaceae) in Florida (USA) because it degrades the wood of the lowest section of the palm trunk. This fungus is widespread throughout Florida, where it has been observed on over 60 species of palms. The authors examined the genetic variability of 25 isolates of G. zonatum obtained in Florida from 12 different palm species and representing 17 unique property locations in eight counties to determine if G. zonatum represents a species complex. The three genomic regions examined were the nuc rDNA ITS1-5.8S ITS2 region (ITS), the coding region for RNA polymerase II subunit 2 (rpb2) domains 6 and 7, and the partial gene for translation elongation factor 1alpha (tef1alpha). The results indicated that variability among these three genomic regions was minimal, and the variability observed was not related to palm host or geographic region within Florida. Thus, in the geographic region surveyed, G. zonatum does not appear to represent a species complex. PMID- 29757713 TI - Conceptual frameworks for the workplace change adoption process: elements integration from decision making and learning cycle process. AB - : Sound workplace ergonomics and safety-related interventions may be resisted by employees, and this may be detrimental to multiple stakeholders. Understanding fundamental aspects of decision-making, behavioural change, and learning cycles may provide insights into pathways influencing employees' acceptance of interventions. This manuscript reviews published literature on thinking processes and other topics relevant to decision making and incorporates the findings into two new conceptual frameworks of the workplace change adoption process. Such frameworks are useful for thinking about adoption in different ways and testing changes to traditional intervention implementation processes. Moving forward, it is recommended that future research focuses on systematic exploration of implementation process activities that integrate principles from the research literature on sense-making, decision-making, and learning processes. Such exploration may provide the groundwork for development of specific implementation strategies that are theoretically grounded and provide a revised understanding of how successful intervention adoption processes work. Practitioner summary: Adoption and acceptance of workplace changes may be facilitated through sound implementation strategies. This manuscript explores several principles of sense making and decision-making processes that can potentially be used by industrial practitioners to inform the design and development of implementation strategies for interventions that improve workplace ergonomics and safety. ABBREVIATIONS: Musculoskeletal Disorders (MSDs); National Institute for Occupational Safety and Health (NIOSH); National Occupational Research Agenda (NORA); Health and Safety Executive (HSE). PMID- 29757714 TI - A comparison of economy and sagittal plane trunk movements among back-, back/front- and head-loading. AB - It has been suggested that freedom of movement in the trunk could influence load carriage economy. This study aimed to compare the economy and sagittal plane trunk movements associated with three load carriage methods that constrain posture differently. Eighteen females walked at 3 km.h-1 with loads of 0, 3, 6, 9, 12, 15 and 20 kg carried on the back, back/front and head. Load carriage economy was assessed using the Extra Load Index (ELI). Change in sagittal plane trunk forward lean and trunk angle excursion from unloaded to loaded walking were assessed. Results show no difference in economy between methods (p = .483), despite differences in the change in trunk forward lean (p = .001) and trunk angle excursion (p = .021) from unloaded to loaded walking. We conclude that economy is not different among the three methods of load carriage, despite significant differences in sagittal plane trunk movements. Practitioner summary: This article shows, based on mean data, that there is no difference in economy among back, back/front and head-loading, despite differences in trunk movement. It is possible a combination of factors align to influence individual economy, rather than a single set of factors, applicable to all individuals for each method. PMID- 29757715 TI - Accuracy of a mobile app to identify suspect asbestos-containing material in Australian residential settings. AB - In situ asbestos in the built environment is a remaining source of exposure in countries that have prohibited the manufacture and use of asbestos. However, it is difficult to identify in situ asbestos-containing material in residential settings. The objective of this study was to evaluate the accuracy of the mobile phone application ("app"), ACM Check, in identifying in situ asbestos located inside and outside of homes compared with onsite inspections conducted by an experienced environmental consultant. A cross-sectional study was undertaken that involved participants completing ACM Check on their homes built pre-1990 and located throughout metropolitan Perth, Western Australia, and an onsite inspection conducted at each home by an environmental consultant. Cohen's kappa statistic was calculated to evaluate the strength of agreement between the two methods. The 40 houses sampled were built between 1898 and 1988 with a median year of 1966. Thirty-eight (95%) homes had at least one type of material categorized as positive for asbestos by both ACM Check and the environmental consultant (kappa = 1.00). Agreement between the two methods differed when categorizing specific materials as positive or negative for asbestos with substantial agreement for fencing (kappa = 0.918), outbuilding walls (kappa = 0.844), backing board to electrical meter box (kappa = 0.826), exterior wall cladding (kappa = 0.771), and interior walls (kappa = 0.754), and fair agreement for outbuilding roofs (kappa = 0.375) and interior flooring (kappa = 0.304). ACM Check is a tool that can be used by tradespeople, home renovators, and householders to screen residential settings for the presence of in situ asbestos containing material. Mobile phone apps have the potential to be developed or modified for use in other countries to help users identify asbestos and reduce their risk of asbestos exposure. PMID- 29757716 TI - US Assessment of Sports-related Hip Injuries. AB - Traumatic and overuse hip injuries occur frequently in amateur and professional athletes. After clinical assessment, imaging plays an important role in diagnosis and in defining care management of these injuries. Ultrasonography (US) is being increasingly used in assessment of hip injuries because of the wide availability of US machines, the lower cost, and the unique real-time imaging capability, which allows both static and dynamic evaluation as well as guidance of point-of care interventions such as fluid aspiration and steroid injection. Accurate diagnosis of hip injuries is often challenging, given the complex soft-tissue anatomy of the hip and the wide spectrum of injuries that can occur. To conduct a skillful US evaluation of hip injuries, physicians must have pertinent knowledge of the normal anatomy and should make judicious use of surface anatomy landmarks while using a compartmentalized diagnostic approach. In this article, common sports-related injuries of the anterior, lateral, and posterior hip compartments are discussed. This review includes assessment of joint effusion, acetabular labral tear, acute and chronic tendon injuries including tendinopathy, partial and full-thickness tears, snapping hip syndromes, relevant US-guided procedures, and some other conditions such as Morel-Lavallee lesion and perineal nodular induration. Principles of care management and current knowledge on imaging findings that may affect return to activity are also presented. Using an oriented US examination technique and having knowledge of the normal hip anatomy will help physicians characterize US findings of common sports-related hip injuries and make accurate diagnoses. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29757717 TI - Radiographic and CT Features of Viral Pneumonia. AB - Viruses are the most common causes of respiratory infection. The imaging findings of viral pneumonia are diverse and overlap with those of other nonviral infectious and inflammatory conditions. However, identification of the underlying viral pathogens may not always be easy. There are a number of indicators for identifying viral pathogens on the basis of imaging patterns, which are associated with the pathogenesis of viral infections. Viruses in the same viral family share a similar pathogenesis of pneumonia, and the imaging patterns have distinguishable characteristics. Although not all cases manifest with typical patterns, most typical imaging patterns of viral pneumonia can be classified according to viral families. Although a definite diagnosis cannot be achieved on the basis of imaging features alone, recognition of viral pneumonia patterns may aid in differentiating viral pathogens, thus reducing the use of antibiotics. Recently, new viruses associated with recent outbreaks including human metapneumovirus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus have been discovered. The imaging findings of these emerging pathogens have been described in a few recent studies. This review focuses on the radiographic and computed tomographic patterns of viral pneumonia caused by different pathogens, including new pathogens. Clinical characteristics that could affect imaging, such as patient age and immune status, seasonal variation and community outbreaks, and pathogenesis, are also discussed. The first goal of this review is to indicate that there are imaging features that should raise the possibility of viral infections. Second, to help radiologists differentiate viral infections, viruses in the same viridae that have similar pathogenesis and can have similar imaging characteristics are shown. By considering both the clinical and radiologic characteristics, radiologists can suggest the diagnosis of viral pneumonia. (c)RSNA, 2018. PMID- 29757718 TI - US of Right Upper Quadrant Pain in the Emergency Department: Diagnosing beyond Gallbladder and Biliary Disease. AB - Acute cholecystitis is the most common diagnosable cause for right upper quadrant abdominal (RUQ) pain in patients who present to the emergency department (ED). However, over one-third of patients initially thought to have acute cholecystitis actually have RUQ pain attributable to other causes. Ultrasonography (US) is the primary imaging modality of choice for initial imaging assessment and serves as a fast, cost-effective, and dynamic modality to provide a definitive diagnosis or a considerably narrowed list of differential possibilities. Multiple organ systems are included at standard RUQ US, and a variety of ultrasonographically diagnosable disease processes can be identified, including conditions of hepatic, pancreatic, adrenal, renal, gastrointestinal, vascular, and thoracic origin, all of which may result in RUQ pain. In certain cases, subsequent computed tomography, magnetic resonance (MR) imaging, MR cholangiopancreatography, or cholescintigraphy may be considered, depending on the clinical situation and US findings. Familiarity with the spectrum of disease processes outside of the gallbladder and biliary tree that may manifest with RUQ pain and recognition at US of these alternative conditions is pivotal for early diagnosis and appropriate management. Diagnosis at the time of initial US can reduce unnecessary imaging and its consequences, including excess cost, radiation exposure, nephrotoxic contrast medium use, and time to diagnosis, thereby translating into improved patient care and outcome. This article (a) reviews the causes of RUQ pain identifiable at US using an organ-system approach, (b) illustrates the US appearance of select conditions from each organ system with multimodality imaging correlates, and (c) discusses the relevant pathophysiology and treatment of these entities to aid in efficient direction of management. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29757719 TI - Providing MR Imaging for Cervical Cancer Brachytherapy: Lessons for Radiologists. AB - Brachytherapy (BT), the use of a locally placed or implanted radioactive source for treatment of an adjacent tumor, is an important component in the treatment of patients with both early- and advanced-stage cervical cancer and is increasingly part of the standard treatment protocol. When it is feasible, many radiation oncologists choose to include a magnetic resonance (MR) imaging examination for planning BT treatment (ie, an MR imaging examination after placement of the applicator but before radiation dosing). MR imaging provides excellent soft tissue contrast and allows radiation oncologists to individualize the radiation dose to the target volume and minimize the dose to adjacent organs that are at risk for radiation damage. However, traditionally, the radiology department has not performed imaging studies for planning, and the requirements are different compared with those of standard diagnostic imaging. In addition, many applicators are available for use in BT treatment of cervical cancer, and each must considered separately to determine MR safety and to define the best imaging parameters. Starting and supporting a robust gynecologic BT program includes implementing imaging protocols that are helpful to both radiation oncologists and diagnostic radiologists. By becoming more familiar with this treatment modality and the logistics of imaging patients undergoing BT, radiologists can provide imaging support for colleagues in the radiation oncology department and better care for patients. (c)RSNA, 2018. PMID- 29757720 TI - Troubleshooting Image Quality and Other Problems by Using the DICOM Header: RadioGraphics Fundamentals | Online Presentation. PMID- 29757721 TI - Spectrum of Extratesticular and Testicular Pathologic Conditions at Scrotal MR Imaging. AB - Diagnostic workup of scrotal lesions should begin with a complete clinical history and physical examination, including analysis of risk factors such as family history of testicular cancer, personal history of tumor in the contralateral testis, and cryptorchidism, followed by imaging. Scrotal ultrasonography (US) with a combination of gray-scale and color Doppler techniques has been the first-line imaging modality for evaluation of testicular and extratesticular lesions because of its low cost, wide availability, and high diagnostic accuracy. However, US has limitations related to operator dependence, the relatively small field of view, and lack of tissue characterization. Magnetic resonance (MR) imaging, because of its superior soft-tissue contrast and multiplanar capabilities, is increasingly being used as a supplemental diagnostic problem-solving tool in cases where scrotal US findings are inconclusive or nondiagnostic. In addition to morphology, lesion location, and tissue characterization (eg, fat, blood products, granulation tissue, and fibrosis), scrotal MR imaging provides important information that can affect surgical planning and improve patient care. MR imaging also is helpful for differentiating testicular and extratesticular lesions, distinguishing between benign and malignant lesions, and evaluating the local extent of disease. This review discusses the anatomy and MR imaging features of testicular and extratesticular neoplastic and nonneoplastic conditions and describes relevant MR imaging techniques. (c)RSNA, 2018 Contact information that appeared in the print version of this article was updated in the online version on May 14, 2018. PMID- 29757722 TI - Urethrography for Assessment of the Adult Male Urethra: RadioGraphics Fundamentals | Online Presentation. PMID- 29757723 TI - CT and MR Imaging Features of Artificial Urinary Sphincters, Penile Prostheses, and Other Devices in the Male Lower Genitourinary Tract. AB - Urinary incontinence and erectile dysfunction are relatively common conditions in the aging male population. Surgical interventions for urinary incontinence include placement of an artificial urinary sphincter (AUS), perineal sling, or sacral nerve stimulator and injections of periurethral bulking agents. Erectile dysfunction can be treated surgically with placement of a penile prosthesis. The complications of these devices can be broadly categorized as device component malposition, malfunction, and infection. This article focuses on AUSs, penile prostheses, and their complications. Familiarity with these devices and their complications allows the radiologist to effectively describe these implants in radiologic reports and to recognize complications when they occur. This article reviews the normal cross-sectional radiologic appearance of the most common implants used to surgically treat male urinary incontinence and erectile dysfunction, as well as the potential complications associated with these devices. (c)RSNA, 2018. PMID- 29757724 TI - Neuroimaging Findings of Organic Acidemias and Aminoacidopathies. AB - Although individual cases of inherited metabolic disorders are rare, overall they account for a substantial number of disorders affecting the central nervous system. Organic acidemias and aminoacidopathies include a variety of inborn errors of metabolism that are caused by defects in the intermediary metabolic pathways of carbohydrates, amino acids, and fatty acid oxidation. These defects can lead to the abnormal accumulation of organic acids and amino acids in multiple organs, including the brain. Early diagnosis is mandatory to initiate therapy and prevent permanent long-term neurologic impairments or death. Neuroimaging findings can be nonspecific, and metabolism- and genetics-based laboratory investigations are needed to confirm the diagnosis. However, neuroimaging has a key role in guiding the diagnostic workup. The findings at conventional and advanced magnetic resonance imaging may suggest the correct diagnosis, help narrow the differential diagnosis, and consequently facilitate early initiation of targeted metabolism- and genetics-based laboratory investigations and treatment. Neuroimaging may be especially helpful for distinguishing organic acidemias and aminoacidopathies from other more common diseases with similar manifestations, such as hypoxic-ischemic injury and neonatal sepsis. Therefore, it is important that radiologists, neuroradiologists, pediatric neuroradiologists, and clinicians are familiar with the neuroimaging findings of organic acidemias and aminoacidopathies. (c)RSNA, 2018. PMID- 29757725 TI - Acute Mesenteric Ischemia: Multidetector CT Findings and Endovascular Management. AB - Acute mesenteric ischemia is a rare life-threatening condition that accounts for approximately one in 1000 hospital admissions. The mortality rate is 50%-69% owing to the absence of specific symptoms and laboratory data, which makes early detection of this condition difficult. If the use of contrast material is possible, biphasic contrast material-enhanced multidetector computed tomography (CT) is the first-line imaging test for early diagnosis of the disease and for differentiation from other causes of acute abdomen. Multidetector CT can depict mesenteric ischemia, its underlying causes, and its severity. Mesenteric ischemia is classified as either acute or chronic. The causes of AMI include arterial embolism, arterial thrombosis, venous thrombosis, and nonocclusive mesenteric ischemia, among which arterial causes are far more common than venous causes. Recently, endovascular procedures such as thrombolysis, thrombectomy, thrombus fragmentation, and stent placement have been successfully and safely performed when the ischemia is reversible. Online DICOM image stacks are available for this article. (c)RSNA, 2018. PMID- 29757726 TI - Mediastinal and Pleural MR Imaging in Daily Practice. PMID- 29757727 TI - Invited Commentary: Handheld or Automated-Staying Focused on the Goals of Screening US, with Response from Drs van Zelst and Mann. PMID- 29757728 TI - Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the Art Review. PMID- 29757729 TI - Invited Commentary: Early Lung Cancer and Cystic Airspaces. PMID- 29757730 TI - Egocentric Temporal Action Proposals. AB - We present an approach to localize generic actions in egocentric videos, called temporal action proposals (TAPs), for accelerating the action recognition step. An egocentric TAP refers to a sequence of frames that may contain a generic action performed by the wearer of a head-mounted camera, e.g., taking a knife, spreading jam, pouring milk, or cutting carrots. Inspired by object proposals, this paper aims at generating a small number of TAPs, thereby replacing the popular sliding window strategy, for localizing all action events in the input video. To this end, we first propose to temporally segment the input video into action atoms, which are the smallest units that may contain an action. We then apply a hierarchical clustering algorithm with several egocentric cues to generate TAPs. Finally, we propose two actionness networks to score the likelihood of each TAP containing an action. The top ranked candidates are returned as output TAPs. Experimental results show that the proposed TAP detection framework performs significantly better than relevant approaches for egocentric action detection. PMID- 29757731 TI - Robust LSTM-Autoencoders for Face De-Occlusion in the Wild. AB - Face recognition techniques have been developed significantly in recent years. However, recognizing faces with partial occlusion is still challenging for existing face recognizers, which is heavily desired in real-world applications concerning surveillance and security. Although much research effort has been devoted to developing face de-occlusion methods, most of them can only work well under constrained conditions, such as all of faces are from a pre-defined closed set of subjects. In this paper, we propose a robust LSTM-Autoencoders (RLA) model to effectively restore partially occluded faces even in the wild. The RLA model consists of two LSTM components, which aims at occlusion-robust face encoding and recurrent occlusion removal respectively. The first one, named multi-scale spatial LSTM encoder, reads facial patches of various scales sequentially to output a latent representation, and occlusion-robustness is achieved owing to the fact that the influence of occlusion is only upon some of the patches. Receiving the representation learned by the encoder, the LSTM decoder with a dual channel architecture reconstructs the overall face and detects occlusion simultaneously, and by feat of LSTM, the decoder breaks down the task of face de-occlusion into restoring the occluded part step by step. Moreover, to minimize identify information loss and guarantee face recognition accuracy over recovered faces, we introduce an identity-preserving adversarial training scheme to further improve RLA. Extensive experiments on both synthetic and real data sets of faces with occlusion clearly demonstrate the effectiveness of our proposed RLA in removing different types of facial occlusion at various locations. The proposed method also provides significantly larger performance gain than other de-occlusion methods in promoting recognition performance over partially-occluded faces. PMID- 29757732 TI - Person Re-Identification With Metric Learning Using Privileged Information. AB - Despite the promising progress made in recent years, person re-identification remains a challenging task due to complex variations in human appearances from different camera views. This paper presents a logistic discriminant metric learning method for this challenging problem. Different with most existing metric learning algorithms, it exploits both original data and auxiliary data during training, which is motivated by the new machine learning paradigm-learning using privileged information. Such privileged information is a kind of auxiliary knowledge, which is only available during training. Our goal is to learn an optimal distance function by constructing a locally adaptive decision rule with the help of privileged information. We jointly learn two distance metrics by minimizing the empirical loss penalizing the difference between the distance in the original space and that in the privileged space. In our setting, the distance in the privileged space functions as a local decision threshold, which guides the decision making in the original space like a teacher. The metric learned from the original space is used to compute the distance between a probe image and a gallery image during testing. In addition, we extend the proposed approach to a multi-view setting which is able to explore the complementation of multiple feature representations. In the multi-view setting, multiple metrics corresponding to different original features are jointly learned, guided by the same privileged information. Besides, an effective iterative optimization scheme is introduced to simultaneously optimize the metrics and the assigned metric weights. Experiment results on several widely-used data sets demonstrate that the proposed approach is superior to global decision threshold-based methods and outperforms most state-of-the-art results. PMID- 29757733 TI - Object Classification With Joint Projection and Low-Rank Dictionary Learning. AB - For an object classification system, the most critical obstacles toward real world applications are often caused by large intra-class variability, arising from different lightings, occlusion, and corruption, in limited sample sets. Most methods in the literature would fail when the training samples are heavily occluded, corrupted or have significant illumination or viewpoint variations. Besides, most of the existing methods and especially deep learning-based methods, need large training sets to achieve a satisfactory recognition performance. Although using the pre-trained network on a generic large-scale data set and fine tune it to the small-sized target data set is a widely used technique, this would not help when the content of base and target data sets are very different. To address these issues simultaneously, we propose a joint projection and low-rank dictionary learning method using dual graph constraints. Specifically, a structured class-specific dictionary is learned in the low-dimensional space, and the discrimination is further improved by imposing a graph constraint on the coding coefficients, that maximizes the intra-class compactness and inter-class separability. We enforce structural incoherence and low-rank constraints on sub dictionaries to reduce the redundancy among them, and also make them robust to variations and outliers. To preserve the intrinsic structure of data, we introduce a supervised neighborhood graph into the framework to make the proposed method robust to small-sized and high-dimensional data sets. Experimental results on several benchmark data sets verify the superior performance of our method for object classification of small-sized data sets, which include a considerable amount of different kinds of variation, and may have high-dimensional feature vectors. PMID- 29757734 TI - Sequential Subspace Clustering via Temporal Smoothness for Sequential Data Segmentation. AB - This paper develops a novel sequential subspace clustering method for sequential data. Inspired by the state-of-the-art methods, ordered subspace clustering, and temporal subspace clustering, we design a novel local temporal regularization term based on the concept of temporal predictability. Through minimizing the short-term variance on historical data, it can recover the temporal smoothness relationships in sequential data. Moreover, we claim that the local temporal regularization is more important than the global structural regularization for a specific task, such as sequential subspace clustering, which leads to a concise minimization objective function. To solve the bi-convex objective function, a simple and efficient optimization algorithm based on the alternate convex search method is devised to jointly learn the coding matrix and the dictionary. Furthermore, five baseline methods are also devised for comparison with our proposed method from different aspects. Extensive experimental results and comparisons with the state-of-the-art methods on three data sets demonstrate the effectiveness of the proposed temporal smoothness sequential subspace clustering method for sequential data. PMID- 29757736 TI - A Backprojection Slice Theorem for Tomographic Reconstruction. AB - Fast image reconstruction techniques are becoming important with the increasing number of scientific cases in high resolution micro and nano tomography. The processing of the large scale 3D data demands new mathematical tools for the tomographic reconstruction. Due to the high computational complexity of most current algorithms, big data sizes demands powerful hardware and more sophisticated numerical techniques. Several reconstruction algorithms are dependent on a mathematical tool called backprojection (a transposition process). A conventional implementation of the backprojection operator has cubic computational complexity. In the present manuscript we propose a new fast backprojection operator for the processing of tomographic data, providing a low cost algorithm for this task. We compare our formula against other fast transposition techniques, using real and simulated large data sets. PMID- 29757735 TI - From Sparse Coding Significance to Perceptual Quality: A New Approach for Image Quality Assessment. AB - An increasing number of image processing applications require an automated quality prediction of the visual content as perceived by humans. Since, sparse coding is suggested to be an underlying strategy of the brain's neural system, it would be logical to assume that specific tasks like quality assessment also attempt to adhere to this strategy. However, existing perceptual quality predictors, often mimicking the different stages of the human visual system and deploying machine learning strategies, such as neural networks, rarely integrate the concept of sparse coding in their design. In this paper, we first investigate the validity of such assumption by performing an empirical analysis on the relation between the structural information of the scene-captured via sparseness significance-and perceptual quality. Subsequently, we propose a new approach to integrate the significance of sparse coding features in the future imagequality measure (IQM) designs. We utilize the Fourier transform as a case study, which leads to a new IQM called sparseness significance ranking measure (SSRM). This measure essentially deploys a Fourier basis for sparse coding, a ranking mechanism based upon the amplitudes of the sparse coefficients and subsequently a complex correlation metric that assesses the correspondence between the ranked coefficient amplitude profiles of the reference and the distorted image. Moreover, we introduce a new methodology, namely separation ratio analysis, to assess the prediction quality of individual features or quality predictors given a target perceptual quality. The quality predictions by the proposed SSRM show excellent compatibility with perceptual quality scores. A set of routine benchmarking experiments utilizing the LIVE and CSIQ, IVC and TID2008 databases indicates a highly competitive performance with state of the art IQMs. Moreover, it delivers this performance at a low computational cost. PMID- 29757738 TI - Robust Quantization for General Similarity Search. AB - The recent years have witnessed the emerging of vector quantization (VQ) techniques for efficient similarity search. VQ partitions the feature space into a set of codewords and encodes data points as integer indices using the codewords. Then the distance between data points can be efficiently approximated by simple memory lookup operations. By the compact quantization, the storage cost, and searching complexity are significantly reduced, thereby facilitating efficient large-scale similarity search. However, the performance of several celebrated VQ approaches degrades significantly when dealing with noisy data. In addition, it can barely facilitate a wide range of applications as the distortion measurement only limits to l2 norm. To address the shortcomings of the squared Euclidean (l2,2 norm) loss function employed by the VQ approaches, in this paper, we propose a novel robust and general VQ framework, named RGVQ, to enhance both robustness and generalization of VQ approaches. Specifically, a lp,q-norm loss function is proposed to conduct the lp-norm similarity search, rather than the l2 norm search, and the q-th order loss is used to enhance the robustness. Despite the fact that changing the loss function to lp,q norm makes VQ approaches more robust and generic, it brings us a challenge that a non-smooth and non-convex orthogonality constrained lp,q-norm function has to be minimized. To solve this problem, we propose a novel and efficient optimization scheme and specify it to VQ approaches and theoretically prove its convergence. Extensive experiments on benchmark data sets demonstrate that the proposed RGVQ is better than the original VQ for several approaches, especially when searching similarity in noisy data. PMID- 29757737 TI - Hierarchical Vertex Regression-Based Segmentation of Head and Neck CT Images for Radiotherapy Planning. AB - Segmenting organs at risk from head and neck CT images is a prerequisite for the treatment of head and neck cancer using intensity modulated radiotherapy. However, accurate and automatic segmentation of organs at risk is a challenging task due to the low contrast of soft tissue and image artifact in CT images. Shape priors have been proved effective in addressing this challenging task. However, conventional methods incorporating shape priors often suffer from sensitivity to shape initialization and also shape variations across individuals. In this paper, we propose a novel approach to incorporate shape priors into a hierarchical learning-based model. The contributions of our proposed approach are as follows: 1) a novel mechanism for critical vertices identification is proposed to identify vertices with distinctive appearances and strong consistency across different subjects; 2) a new strategy of hierarchical vertex regression is also used to gradually locate more vertices with the guidance of previously located vertices; and 3) an innovative framework of joint shape and appearance learning is further developed to capture salient shape and appearance features simultaneously. Using these innovative strategies, our proposed approach can essentially overcome drawbacks of the conventional shape-based segmentation methods. Experimental results show that our approach can achieve much better results than state-of-the-art methods. PMID- 29757739 TI - Multi-Task Convolutional Neural Network for Pose-Invariant Face Recognition. AB - This paper explores multi-task learning (MTL) for face recognition. First, we propose a multi-task convolutional neural network (CNN) for face recognition, where identity classification is the main task and pose, illumination, and expression (PIE) estimations are the side tasks. Second, we develop a dynamic weighting scheme to automatically assign the loss weights to each side task, which solves the crucial problem of balancing between different tasks in MTL. Third, we propose a pose-directed multi-task CNN by grouping different poses to learn pose-specific identity features, simultaneously across all poses in a joint framework. Last but not least, we propose an energy-based weight analysis method to explore how CNN-based MTL works. We observe that the side tasks serve as regularizations to disentangle the PIE variations from the learnt identity features. Extensive experiments on the entire multi-PIE dataset demonstrate the effectiveness of the proposed approach. To the best of our knowledge, this is the first work using all data in multi-PIE for face recognition. Our approach is also applicable to in-the-wild data sets for pose-invariant face recognition and achieves comparable or better performance than state of the art on LFW, CFP, and IJB-A datasets. PMID- 29757740 TI - Learning-Based Restoration of Backlit Images. AB - Backlighting is a commonly encountered ill illumination condition that can cause serious degradation of image quality. In this paper, we propose a learning-based spatially adaptive technique of optimal tone mapping to restore backlit images. Object surfaces illuminated from behind in a scene are detected by a soft binary classifier that is constructed via supervised learning. Two optimal tone mapping functions, one for backlit regions and the other for the remainder of the image, are used and their outputs are fused to restore illegible surface details in backlit regions and at the same time improve contrast in overexposed regions, if any. Experimental results demonstrate the superior performance of the proposed new technique over existing image enhancement techniques on backlit photographs. PMID- 29757742 TI - Single Image Dehazing Using Color Ellipsoid Prior. AB - In this paper, we propose a new single-image dehazing method. The proposed method constructs color ellipsoids that are statistically fitted to haze pixel clusters in RGB space and then calculates the transmission values through color ellipsoid geometry. The transmission values generated by the proposed method maximize the contrast of dehazed pixels, while preventing over-saturated pixels. The values are also statistically robust because they are calculated from the averages of the haze pixel values. Furthermore, rather than apply a highly complex refinement process to reduce halo or unnatural artifacts, we embed a fuzzy segmentation process into the construction of the color ellipsoid so that the proposed method simultaneously executes the transmission calculation and the refinement process. The results of an experimental performance evaluation verify that compared with prevailing dehazing methods the proposed method performs effectively across a wide range of haze and noise levels without causing any visible artifacts. Moreover, the relatively low complexity of the proposed method will facilitate its real-time applications. PMID- 29757741 TI - Saliency Detection via Absorbing Markov Chain With Learnt Transition Probability. AB - In this paper, we propose a bottom-up saliency model based on absorbing Markov chain (AMC). First, a sparsely connected graph is constructed to capture the local context information of each node. All image boundary nodes and other nodes are, respectively, treated as the absorbing nodes and transient nodes in the absorbing Markov chain. Then, the expected number of times from each transient node to all other transient nodes can be used to represent the saliency value of this node. The absorbed time depends on the weights on the path and their spatial coordinates, which are completely encoded in the transition probability matrix. Considering the importance of this matrix, we adopt different hierarchies of deep features extracted from fully convolutional networks and learn a transition probability matrix, which is called learnt transition probability matrix. Although the performance is significantly promoted, salient objects are not uniformly highlighted very well. To solve this problem, an angular embedding technique is investigated to refine the saliency results. Based on pairwise local orderings, which are produced by the saliency maps of AMC and boundary maps, we rearrange the global orderings (saliency value) of all nodes. Extensive experiments demonstrate that the proposed algorithm outperforms the state-of-the art methods on six publicly available benchmark data sets. PMID- 29757743 TI - Local All-Pass Geometric Deformations. AB - This paper deals with the estimation of a deformation that describes the geometric transformation between two images. To solve this problem, we propose a novel framework that relies upon the brightness consistency hypothesis-a pixel's intensity is maintained throughout the transformation. Instead of assuming small distortion and linearizing the problem (e.g. via Taylor Series expansion), we propose to interpret the brightness hypothesis as an all-pass filtering relation between the two images. The key advantages of this new interpretation are that no restrictions are placed on the amplitude of the deformation or on the spatial variations of the images. Moreover, by converting the all-pass filtering to a linear forward-backward filtering relation, our solution to the estimation problem equates to solving a linear system of equations, which leads to a highly efficient implementation. Using this framework, we develop a fast algorithm that relates one image to another, on a local level, using an all-pass filter and then extracts the deformation from the filter-hence the name "Local All-Pass" (LAP) algorithm. The effectiveness of this algorithm is demonstrated on a variety of synthetic and real deformations that are found in applications, such as image registration and motion estimation. In particular, when compared with a selection of image registration algorithms, the LAP obtains very accurate results for significantly reduced computation time and is very robust to noise corruption. PMID- 29757744 TI - (Block) Chain Reaction: A Blockchain Revolution Sweeps into Health Care, Offering the Possibility for a Much-Needed Data Solution. AB - Electronic health records may have digitized patient data, but getting that data from one clinician to another remains a huge challenge, especially since patients often have multiple doctors ordering tests, prescribing drugs, and providing treatment. Many experts now believe that blockchain technology might be just the thing to get a patient's pertinent medical information from where it is stored to where it is needed, as well as to allow patients to easily view their own medical histories. In addition, blockchain technology might also be able to help with other aspects of health care, such as improving the insurance claim or other administrative processes within healthcare networks and making health-related population data available to biomedical researchers. PMID- 29757745 TI - Hospital CIO Explains Blockchain Potential: An Interview with Beth Israel Deaconess Medical Center's John Halamka. AB - Work is already underway to bring blockchain technology to the healthcare industry, and hospital administrators are trying to figure out what it can do for them, their clinicians, and their patients. That includes administrators at Beth Israel Deaconess Medical Center, a leading academic medical center located in Boston. PMID- 29757746 TI - Biomedical Materials Learn to Heal Themselves: Self-Healing Polymers, Hydrogels, and Artificial Muscles Are Mimicking Nature's Repair Mechanisms. AB - Maintaining sterility in emergency and operating rooms can be challenging, especially in cases of highly infectious disease outbreaks or toxic spills. A simple nick in a surgical glove under such circumstances could have deadly consequences. But, now, a variety of promising new materials in development may lead to everything from self-healing gloves and bandages to bone, blood vessel, and muscle scaffolding implants that could repair themselves the way tissues do. In some cases, repair might be triggered by an external stimulus, such as heat; in other cases, these materials would naturally heal by themselves over time. PMID- 29757747 TI - The Human Touch: Practical and Ethical Implications of Putting AI and Robotics to Work for Patients. AB - We live in a time when science fiction can quickly become science fact. Within a generation, the Internet has matured from a technological marvel to a utility, and mobile telephones have redefined how we communicate. Health care, as an industry, is quick to embrace technology, so it is no surprise that the application of programmable robotic systems that can carry out actions automatically and artificial intelligence (AI), e.g., machines that learn, solve problems, and respond to their environment, is being keenly explored. PMID- 29757748 TI - The Robotics Revolution Will Be Soft: Soft Robotics Proliferate-Along with Their Sources of Inspiration. AB - When soft robotics first emerged, it was defined (as breakthroughs often are) by what it was that its traditional counterparts were not, i.e., soft. A decade in, the nomenclature remains apt. The pliant materials used in soft robotics are often both a defining trait and a source of advantage. Soft robots continue to make headlines with their ability to squeeze, octopus-like, through narrow crevices; change shape; and survive impacts that would crush a traditional rigid robot. They distinguish themselves from their hard counterparts with their damage resilience, complex movements, and suitability for use with the human body. PMID- 29757749 TI - Cyberattacks on Devices Threaten Data and Patients: Cybersecurity Risks Come with the Territory. Three Experts Explain What You Need to Know. AB - Every device that contains a computer component is open to cyberattacks, and that potential escalates when the device is connected to another device, an information technology (IT) network, or the Internet. This is especially troublesome when it comes to medical devices, because patient care hangs in the balance. PMID- 29757750 TI - Expression of Editorial Concern, Correction of Conflict of Interest and Affiliation, and Data Corrections. AB - [This corrects the article DOI: 10.2196/publichealth.9490.]. PMID- 29757751 TI - Expression of Editorial Concern, Correction of Conflict of Interest and Affiliation. AB - [This corrects the article DOI: 10.2196/resprot.7993.]. PMID- 29757752 TI - High speed chalcogenide glass electrochemical metallization cells with various active metals. AB - We fabricated electrochemical metallization cells using a GaLaSO solid electrolyte, an InSnO inactive electrode and active electrodes consisting of various metals (Cu, Ag, Fe, Cu, Mo, Al). Devices with Ag and Cu active metals showed consistent and repeatable resistive switching behaviour, and had a retention of 3 and >43 days, respectively; both had switching speeds of <5 ns. Devices with Cr and Fe active metals displayed incomplete or intermittent resistive switching, and devices with Mo and Al active electrodes displayed no resistive switching ability. Deeper penetration of the active metal into the GaLaSO layer resulted in greater resistive switching ability of the cell. The off state resistivity was greater for more reactive active metals which may be due to a thicker intermediate layer. PMID- 29757753 TI - Unified mechanism of the surface Fermi level pinning in III-As nanowires. AB - Fermi level pinning at the oxidized (110) surfaces of III-As nanowires (GaAs, InAs, InGaAs, AlGaAs) is studied. Using scanning gradient Kelvin probe microscopy, we show that the Fermi level at oxidized cleavage surfaces of ternary Al x Ga1-x As (0 <= x <= 0.45) and Ga x In1-x As (0 <= x <= 1) alloys is pinned at the same position of 4.8 +/- 0.1 eV with regard to the vacuum level. The finding implies a unified mechanism of the Fermi level pinning for such surfaces. Further investigation, performed by Raman scattering and photoluminescence spectroscopy, shows that photooxidation of the Al x Ga1-x As and Ga x In1-x As nanowires leads to the accumulation of an excess of arsenic on their crystal surfaces which is accompanied by a strong decrease of the band-edge photoluminescence intensity. We conclude that the surface excess arsenic in crystalline or amorphous forms is responsible for the Fermi level pinning at oxidized (110) surfaces of III-As nanowires. PMID- 29757754 TI - Should Nonsteroidal Anti-inflammatory Drugs be Contraindicated in the Perioperative Period After Spinal Fusion Surgery? PMID- 29757755 TI - Sinking Skin Flap Syndrome After Decompressive Craniectomy: A Case Report. AB - Sinking skin flap syndrome is a rare complication of decompressive craniectomy characterized by a sunken skin flap, neurological deterioration, and paradoxical herniation of the brain. An absent cranium allows for external compression via atmospheric pressure, causing alterations in cerebral blood flow, cerebral spinal fluid flow, and glucose metabolism, which ultimately leads to cortical dysfunction. This case report describes a patient with relatively early onset of variable neurological symptoms and imaging correlation, leading to a diagnosis and definitive therapeutic intervention with cranioplasty. Prompt recognition is critical to avoid potentially devastating neurological outcomes in this rare, but underreported condition. PMID- 29757756 TI - Extraforaminal Lumbar Nerve Root Stimulation for Neuropathic Pain: A Case Report. AB - Electrical stimulation of the spinal cord is commonly used to treat neuropathic pain. However, epidural space adhesion caused by previous surgery may interfere with precise electrical lead placement. We here report a case of successful placement of electrical leads via an extraforaminal approach in the management of recurrent pain after primary spinal cord stimulation. Extraforaminal nerve root stimulation may be an alternative choice for repeated epidural spinal cord stimulation in cases of recurrent neuropathic pain. PMID- 29757757 TI - Use of an Airway Exchange Catheter-Assisted Extubation With Continuous End-Tidal Carbon Dioxide Monitoring in a Pediatric Patient With a Known Difficult Airway: A Case Report. AB - Tracheal extubation in children with known difficult airways is associated with an increased risk of adverse events. Currently, there is no reliable measure to predict the need for emergent reintubation due to airway inadequacy. Airway exchange catheter-assisted extubation has been shown to be a useful adjunct in decreasing the risk of adverse events due to failed extubation. We report a case of using an airway exchange catheter-assisted extubation with continuous end tidal carbon dioxide monitoring for a pediatric patient with a known difficult airway. PMID- 29757758 TI - Ultrasound-guided Pulsed Radiofrequency in the Management of Thoracic Postherpetic Neuralgia: A Randomized, Double-blinded, Controlled Trial. AB - OBJECTIVES: This study was designed to evaluate the efficacy and safety of ultrasound-guided pulsed radiofrequency (PRF) for the intercostal nerves (ICNs) in the management of thoracic postherpetic neuralgia. METHODS: After 2 weeks of treatment by pregabalin 150 mg/12 hours, patients were randomly allocated into 2 groups. The PRF group, after ultrasound-guided localization of the ICN of the affected thoracic dermatome, sensory stimulation of the ICN was tested. Thereafter, the patient received 2 cycles PRF at 42 degrees C temperature, for 120 seconds. The sham group, after stimulation, the same time was spent to mimic PRF. The same procedures were repeated to the upper and lower adjacent ICNs. Pain intensity using Visual Analogue Scale (VAS), and total analgesics consumption were assessed at the baseline, every 2 weeks for 6 months then after 9 and 12 months. The duration of effective pain relief was recorded. Quality of life was evaluated using self-evaluation questionnaires (SF-36) at baseline then after 1, 3, 6, and 12 months. RESULTS: PRF group expressed a significant decrease on the VAS throughout the study period. VAS<30 was reported in the PRF group until the 22nd week. Pregabalin and acetaminophen consumption was significantly lower in the PRF group. The 8 domains of the SF-36 revealed a significant improvement in the PRF group when compared with the sham group throughout the study period except for the physical role which displayed nonsignificant improvement. CONCLUSIONS: Ultrasound-guided PRF for ICNs in combination with pharmacotherapy seems to be a safe and effective treatment modality for postherpetic neuralgia. PMID- 29757759 TI - Mechanical Circulatory Support of the Right Ventricle for Adult and Pediatric Patients With Heart Failure. AB - The clinical implementation of mechanical circulatory assistance for a significantly dysfunctional or failing left ventricle as a bridge-to-transplant or bridge-to-recovery is on the rise. Thousands of patients with left-sided heart failure are readily benefitting from these life-saving technologies, and left ventricular failure often leads to severe right ventricular dysfunction or failure. Right ventricular failure (RVF) has a high rate of mortality caused by the risk of multisystem organ failure and prolonged hospitalization for patients after treatment. The use of a blood pump to support the left ventricle also typically results in an increase in right ventricular preload and may impair right ventricular contractility during left ventricular unloading. Patients with RVF might also suffer from severe pulmonary dysfunction, cardiac defects, congenital heart disease states, or a heterogeneity of cardiophysiologic challenges because of symptomatic congestive heart failure. Thus, the uniqueness and complexity of RVF is emerging as a new domain of significant clinical interest that motivates the development of right ventricular assist devices. In this review, we present the current state-of-the-art for clinically used blood pumps to support adults and pediatric patients with right ventricular dysfunction or failure concomitant with left ventricular failure. New innovative devices specifically for RVF are also highlighted. There continues to be a compelling need for novel treatment options to support patients with significant right heart dysfunction or failure. PMID- 29757760 TI - Cannula Tip With Integrated Volume Sensor for Rotary Blood Pump Control: Early Stage Development. AB - The lack of direct measurement of left ventricular unloading is a significant impediment to the development of an automatic speed control system for continuous flow left ventricular assist devices (cf-LVADs). We have developed an inlet cannula tip for cf-LVADs with integrated electrodes for volume sensing based on conductance. Four platinum-iridium ring electrodes were installed into grooves on a cannula body constructed from polyetheretherketone (PEEK). A sinusoidal current excitation waveform (250 MUA pk-pk, 50 kHz) was applied across one pair of electrodes, and the conductance-dependent voltage was sensed across the second pair of electrodes. The conductance catheter was tested in an acute ovine model (n = 3) in conjunction with the HeartMate II rotary blood pump to provide circulatory support and unload the ventricle. Echocardiography was used to measure ventricular size during pump support for verification for the conductance measurements. The conductance measurements correlated linearly with the echocardiography dimension measurements more than the full range of pump support from minimum support to suction. This cannula tip will enable the development of automatic control systems to optimize pump support based on a real-time measurement of ventricular size. PMID- 29757761 TI - Aspirin Resistance: Cardiovascular Risk Game Changer. AB - BACKGROUND: Aspirin (ASA) is the most used medication on the globe. ASA is a primary pillar of the secondary prevention of cardiovascular atherothromboembolic events. However, a fraction of the population does not respond to ASA as expected in a unique phenomenon called ASA resistance. Multiple mechanisms were described and studied in the literature to explain this phenomenon. AREA OF UNCERTAINTY: ASA resistance is an interesting phenomenon that is worth studying and reviewing. Mechanisms behind this resistance are various and although the rarity of some, it is crucial for the modern health provider to be aware of such phenomenon and its possible explanations to provide more efficient preventive cardiology practice. Our study aimed to review and conclude the evidence behind ASA resistance and its implication on the cardiovascular health. DATA SOURCES: We searched databases like PubMed, EMBASE, Ovid by midline, and Google Scholar for published articles and abstracts. RESULTS: Our systemic search revealed more than 100 articles in relation to ASA resistance. We selected 40 articles, which were relevant for this review. Various mechanisms were described in the literature, with few of them very well documented and understood. Main mechanisms include medication nonadherence, interaction with proton pump inhibitors, esterase-mediated ASA inactivation, post-coronary artery bypass grafting (CABG) MRP-4-mediated ASA consumption, cyclooxygenase-1 (COX-1) polymorphisms, high platelet turnover associated regeneration of platelet COX-1, and the documented platelet ability of de novo COX-1 synthesis in response to thrombin and fibrinogen. CONCLUSION: Multiple mechanisms of ASA resistance were described in the literature. Awareness of such interaction is important for medical practitioners. Bottom line, further studies and reviews are needed to further study this phenomenon and its implication on the cardiovascular health and hence reaching a valid evidence based conclusion that might change the practice and improve the patient preventive health care. PMID- 29757762 TI - CORR Insights(r): How Often Do Acetabular Erosions Occur After Bipolar Hip Endoprostheses in Patients With Malignant Tumors and Are Erosions Associated With Outcomes Scores? PMID- 29757763 TI - CORR Insights(r): Does Orthopaedic Outpatient Care Reduce Emergency Department Utilization After Total Joint Arthroplasty? PMID- 29757764 TI - CORR Insights(r): External Validation and Optimization of the SPRING Model for Prediction of Survival After Surgical Treatment of Bone Metastases of the Extremities. PMID- 29757765 TI - Ultrasound-Guided Injection of Botulinum Toxin for Cricopharyngeal Dysphagia. PMID- 29757766 TI - Co-morbidities Associated With Early Mortality in Adults With Spina Bifida. AB - OBJECTIVE: The aims of this quality improvement project were to identify secondary conditions and medical co-morbidities in adult patients with spina bifida and to determine which factors were associated with an earlier age of death. DESIGN: Retrospective chart review of 487 patients who attended the University of Pittsburgh Medical Center Adult Spina Bifida Clinic between August 1, 2005, and June 6, 2017, was conducted. RESULTS: Of 487 patients who had received care at the University of Pittsburgh Medical Center Adult Spina Bifida Clinic, 48 were deceased. The most commonly reported causes of death included infection, respiratory failure, renal failure, shunt malfunction, and metastatic cancer. Underlying co-morbidities and secondary conditions included hydrocephalus, Chiari II malformation, tethered cord, scoliosis, and abnormal renal function. In deceased patients, earlier age of death was significantly associated with myelomeningocele subtype and the presence of hydrocephalus and Chiari II malformation. CONCLUSIONS: Clinicians treating individuals with spina bifida should be aware of the potential for earlier mortality in individuals with myelomeningocele, hydrocephalus, and Chiari II malformation, especially with regard to infection, respiratory failure, renal failure, shunt malfunction, and cancer. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Discuss the importance of recognizing co-morbidities in adult individuals with spina bifida; (2) Describe secondary conditions and medical co-morbidities associated with spina bifida; and (3) Identify which conditions are associated with earlier age of death in adult individuals with spina bifida. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. PMID- 29757767 TI - The Prevalence of Scoliosis in Spina Bifida Subpopulations: A Systematic Review. AB - Prevalence of scoliosis within spina bifida subpopulations is important for diagnostics and therapeutic purposes. This review determined the prevalence of scoliosis within spina bifida subpopulations by means of a systematic literature review by using the following databases: Medline PubMed, Embase, Cochrane, and Pedro. All Dutch- and English-written literature using the MESH terms "spinal dysraphism," "neural tube defects," and "scoliosis" was analyzed using the exclusion criteria: animal studies, case reports, studies regarding the prevalence of spina bifida among patients with scoliosis, studies with inclusion of patients with scoliosis of less than 11 degrees without possibility to identify subgroups with scoliosis of greater than 10 degrees, studies without an own study group, articles comprising the same patient group as another article, neural tube defects besides spina bifida, and articles without specification of spina bifida subtype. It resulted in six articles, two concerning diastematomyelia (103 patients, 82 females and 21 males) and four about myelomeningocele (479 patients, 283 females and 196 males) with an overall weighted prevalence of scoliosis (20-degree Cobb angle cutoff) of 44.4% and 52.5%, respectively. It can be concluded that most studies have a lot of methodological flaws, so there is a need for further research with standardization of data collection to allow comparison of different data. PMID- 29757768 TI - Labrys. PMID- 29757769 TI - Delayed Tension Pneumomediastinum after Cardiac Surgery. PMID- 29757770 TI - The Unmet Supportive Care Needs of Arab Australian and Arab Jordanian Cancer Survivors: An International Comparative Survey. AB - BACKGROUND: Research exploring the unmet supportive care needs of Arab cancer survivors is limited, with most conducted with immigrant groups. No study has compared the unmet supportive care needs of immigrant Arab cancer survivors with Arab cancer survivors living in their native country. OBJECTIVE: To explore the unmet supportive care needs of both Arab Australian and Arab Jordanian cancer survivors. METHODS: Arab people living in Sydney, Australia, and Amman, Jordan, and diagnosed with cancer within the last 5 years were invited to complete a questionnaire that measured unmet supportive care needs, depression, and language acculturation. Multiple regression analysis was performed to identify predictors of unmet supportive care needs. RESULTS: Seventy-seven Arab Jordanian and 66 Arab Australian cancer survivors were recruited. Australian participants were older than their Jordanian counterparts (61.5 vs 52.3 years; P < .001) and reported higher levels of overall unmet needs (44.9 vs 36.1; P = .012). Controlling for age and stage of cancer diagnosis, higher levels of depression (beta = .34) and living in Australia (beta = .26) were significant predictors of unmet needs and explained almost 17% of the variance. CONCLUSIONS: These findings have extended our understanding of the unmet supportive care needs of Arab cancer survivors and confirm disparities in unmet needs in immigrant populations. IMPLICATIONS FOR PRACTICE: Greater attention is needed to ensure the supportive care needs are met for immigrant patients with cancer. Additional strategies to address physical and psychological needs are particularly needed in this group. PMID- 29757771 TI - Age Differences in the Coping Strategies of Patients With Colorectal Cancer. AB - BACKGROUND: Colon and/or rectum cancer (CRC) patients use various strategies to cope with their condition, and these can vary between age groups. OBJECTIVES: The aims of this study were to investigate differences between psychosocial/spiritual variables and coping strategies in CRC patients of different age groups (younger vs older) and to identify the predictors of coping for both age groups. METHODS: A cross-sectional descriptive study was conducted at 3 outpatient clinics in Korea. The Hospital Anxiety and Depression Scale, Social Support Scale, and Self Transcendence Scale were used to measure psychosocial and spiritual variables; the Mini-Mental Adjustment to Cancer Scale was used to assess cancer-specific coping strategies. RESULTS: Both younger and older patients who were psychologically distressed used more maladaptive coping. Individuals who received less social support from healthcare providers used more maladaptive coping strategies. For younger patients, self-transcendence was the only significant predictor of both adaptive and maladaptive coping strategies; for older patients, Hospital Anxiety and Depression Scale score was the only significant predictor of maladaptive coping. CONCLUSION: Differences in psychological distress, social support, and self-transcendence due to age are important protective or risk factors for the use of coping strategies among CRC patients. IMPLICATIONS FOR PRACTICE: Considering our findings, we encourage healthcare professionals to be aware of patients' coping strategies and take them into account when planning age specific interventions related to coping, before hospital discharge. PMID- 29757773 TI - Predicting self-reported disability level by a number of pain sites marked on pain drawing. AB - To evaluate the connection between the number of pain sites (head and neck, upper extremities, trunk, and lower extremities) marked on pain drawing and general disability level measured by a 12-item WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) score. A cross-sectional survey of 1988 patients with chronic musculoskeletal pain was conducted. Analysis of variance with contrasts was performed along with regression analysis. Despite the relatively mild median disability level measured as WHODAS 2.0 total score at 25%, the majority of the participants experienced, in the last month, severe pain with 8.1 points on a 0 10 numeric rating scale. Only 1% had left the pain drawing unmarked. Otherwise, 15% had marks in one area, 34% in two, 23% in three, and 27% in all four areas. The characteristics of those groups were similar except for disability. Disability level was 30-50% worse when pain was experienced in all four sites. The analysis of variance showed that both the number of pain sites and pain severity affected disability level (P<0.0001). There were differences in disability levels between each group pair. The regression analysis showed a linear relationship between disability and number of pain sites - marking one area more predicted increase in WHODAS 2.0 total score approximately by 5%. The number of sites marked on a pain drawing correlated with disability severity. Increase in this number may serve as an easy screening predictor of functional deterioration in people with chronic musculoskeletal pain. PMID- 29757772 TI - Systematic analysis of annual health resource utilization and costs in hospitalized patients with inflammatory bowel disease in Switzerland. AB - BACKGROUND AND AIMS: Real-life data on health resource utilization and costs of hospitalized patients with inflammatory bowel disease are lacking in Switzerland. We aimed to assess health resource utilization and costs during a 1-year follow up period starting with an index hospitalization. PATIENTS AND METHODS: On the basis of claims data of the Helsana health insurance group, health resource utilization was assessed and costs reimbursed by mandatory basic health insurance [in Swiss Francs (CHF); 1 CHF=0.991 US$] were calculated during a 1-year follow up period starting with an index hospitalization in the time period between 1 January 2013 and 31 December 2014. RESULTS: Of 202 002 patients with at least one hospitalization in 2013-2014, a total of 270 (0.13%) patients had inflammatory bowel disease as main diagnosis [112 (41.5%) ulcerative colitis (UC), 158 (58.5%) Crohn's disease (CD), 154/270 (57.0%) females]. In comparison with patients with UC, patients with CD were significantly more frequently treated with biologics (45.6 vs. 20.5%, P<0.001) and more frequently underwent surgery during index hospitalization (27.8 vs. 9.8%, P=0.002). Compared with patients with UC, those with CD had significantly more consultations [odds ratio (OR): 1.06, 95% confidence interval (CI): 1.01-1.12, P=0.016], higher median annual total costs (OR: 1.25, 95% CI: 1.05-1.48, P=0.012), and higher outpatient costs (OR: 1.33, 95% CI: 1.07-1.66, P=0.011). In the bivariate model, median total costs for patients with CD and those with UC were 24 270 and 17 270 CHF, respectively (P=0.032). CONCLUSION: When compared with patients with UC, hospitalized patients with CD have during a 1-year follow-up a higher rate of outpatient consultations and generate higher costs. PMID- 29757776 TI - Do Not Opiate! Anesthesiologists Must Be Prepared to Care for Patients Who Sign a "Nonopioid Directive". PMID- 29757777 TI - In Response. PMID- 29757775 TI - Development and Calibration of a Mathematical Model of Anal Carcinogenesis for High-Risk HIV-Infected Men. AB - OBJECTIVES: Men who have sex with men who are living with HIV are at highest risk for anal cancer. Our objective was to use empirical data to develop a comprehensive disease simulation model that reflects the most current understanding of anal carcinogenesis, which is uniquely positioned to evaluate future anal cancer screening strategies and provide insight on the unobservable course of the disease. SETTING: North America. METHODS: The individual-based simulation model was calibrated leveraging primary data from empirical studies, such as a longitudinal HIV-positive men who have sex with men cohort study [Human Immunodeficiency and Papilloma Virus Research Group (HIPVIRG); n = 247] and the North American AIDS Cohort Collaboration on Research and Design [(NA-ACCORD); n = 13,146]. We used the model to infer unobservable progression probabilities from high-grade precancer to invasive anal cancer by CD4 nadir and human papillomavirus (HPV) genotype. RESULTS: The calibrated model had good correspondence to data on genotype- and age-specific HPV prevalence; genotype frequency in precancer and cancer; and age- and nadir CD4-specific cancer incidence. The model-projected progression probabilities differed substantially by HPV genotype and nadir CD4 status. For example, among individuals with CD4 nadir <200, the median monthly progression probability from a high-grade lesion to invasive cancer was 0.054% (ie, 6.28% 10-year probability) and 0.004% (ie, 0.48% 10-year probability) for men with an HPV-16 infection versus without a detectable HPV infection, respectively. CONCLUSIONS: We synthesized existing evidence into a state-of-the-art anal cancer disease simulation model that will be used to quantify the tradeoffs of harms and benefits of alternative strategies, understand critical uncertainties, and inform national anal cancer prevention policy. PMID- 29757774 TI - Can telerehabilitation games lead to functional improvement of upper extremities in individuals with Parkinson's disease? AB - Parkinson's disease (PD) is treated by medication, less with deep brain stimulation and physiotherapy. Different opinions on the clinical meaningfulness of the physiotherapy or recommended intensive physiotherapy were found. Our objectives were to design intensive target-based physiotherapy for upper extremities suitable for telerehabilitation services and examine the clinical meaningfulness of the exergaming at an unchanged medication plan. A telerehabilitation exergaming system using the Kinect sensor was developed; 28 patients with PD participated in the study. The system followed the participants' movements and adapted the difficulty level of the game in real time. The outcomes of the study showed that seven out of 26 participants could set up the equipment at home alone. Clinical outcomes of Box and Blocks Test (mean: 47 vs. 52, P=0.002, Cohen's d=0.40), UPDRS III (mean: 27 vs. 29, P=0.001, d=0.22), and daily activity Jebsen's test; writing a letter (mean: 24.0 vs. 20.6, P=0.003, d=0.23); and moving light objects (mean: 4.4 vs. 3.9, P=0.006, d=0.46) were statistically significant (P<0.05) and considered clinically meaningful. The Nine-Hole Peg Test showed a statistically nonsignificant improvement (mean: 28.0 vs. 26.5, P=0.089, d=0.22). The participants claimed problems with mobility but less with activities of daily living and emotional well-being (PDQ-39). The findings lead to preliminary conclusions that exergaming is feasible, but may require technical assistance, whereas clinically meaningful results could be achieved according to validated instruments and an unchanged medication plan in individuals with PD. PMID- 29757778 TI - A Contemporary Analysis of Medicolegal Issues in Obstetric Anesthesia Between 2005 and 2015. AB - BACKGROUND: Detailed reviews of closed malpractice claims have provided insights into the most common events resulting in litigation and helped improve anesthesia care. In the past 10 years, there have been multiple safety advancements in the practice of obstetric anesthesia. We investigated the relationship among contributing factors, patient injuries, and legal outcome by analyzing a contemporary cohort of closed malpractice claims where obstetric anesthesiology was the principal defendant. METHODS: The Controlled Risk Insurance Company (CRICO) is the captive medical liability insurer of the Harvard Medical Institutions that, in collaboration with other insurance companies and health care entities, contributes to the Comparative Benchmark System database for research purposes. We reviewed all (N = 106) closed malpractice cases related to obstetric anesthesia between 2005 and 2015 and compared the following classes of injury: maternal death and brain injury, neonatal death and brain injury, maternal nerve injury, and maternal major and minor injury. In addition, settled claims were compared to the cases that did not receive payment. chi, analysis of variance, Student t test, and Kruskal-Wallis tests were used for comparison between the different classes of injury. RESULTS: The largest number of claims, 54.7%, involved maternal nerve injury; 77.6% of these claims did not receive any indemnity payment. Cases involving maternal death or brain injury comprised 15.1% of all cases and were more likely to receive payment, especially in the high range (P = .02). The most common causes of maternal death or brain injury were high neuraxial blocks, embolic events, and failed intubation. Claims for maternal major and minor injury were least likely to receive payment (P = .02) and were most commonly (34.8%) associated with only emotional injury. Compared to the dropped/denied/dismissed claims, settled claims more frequently involved general anesthesia (P = .03), were associated with delays in care (P = .005), and took longer to resolve (3.2 vs 1.3 years; P < .0001). CONCLUSIONS: Obstetric anesthesia remains an area of significant malpractice liability. Opportunities for practice improvement in the area of severe maternal injury include timely recognition of high neuraxial block, availability of adequate resuscitative resources, and the use of advanced airway management techniques. Anesthesiologists should avoid delays in maternal care, establish clear communication, and follow their institutional policy regarding neonatal resuscitation. Prevention of maternal neurological injury should be directed toward performing neuraxial techniques at the lowest lumbar spine level possible and prevention/recognition of retained neuraxial devices. PMID- 29757781 TI - Misconceptions Surrounding Penicillin Allergy: Implications for Anesthesiologists. AB - Administration of preoperative antimicrobial prophylaxis, often with a cephalosporin, is the mainstay of surgical site infection prevention guidelines. Unfortunately, due to prevalent misconceptions, patients labeled as having a penicillin allergy often receive alternate and less-effective antibiotics, placing them at risk of a variety of adverse effects including increased morbidity and higher risk of surgical site infection. The perioperative physician should ascertain the nature of previous reactions to aid in determining the probability of the prevalence of a true allergy. Penicillin allergy testing may be performed but may not be feasible in the perioperative setting. Current evidence on the structural determinants of penicillin and cephalosporin allergies refutes the misconception of cross-reactivity between penicillins and cefazolin, and there is no clear evidence of an increased risk of anaphylaxis in cefazolin naive, penicillin-allergic patients. A clinical practice algorithm for the perioperative evaluation and management of patients reporting a history of penicillin allergy is presented, concluding that cephalosporins can be safely administered to a majority of such patients. PMID- 29757780 TI - Effects of Intraoperative Opioid Use on Recurrence-Free and Overall Survival in Patients With Esophageal Adenocarcinoma and Squamous Cell Carcinoma. AB - BACKGROUND: Perioperative opioid use is associated with poor survival in patients with esophageal squamous cell carcinoma. The most common histological type of esophageal cancer in western countries is adenocarcinoma. The objective of this study was to evaluate the association between intraoperative opioid consumption and survival in patients with adenocarcinoma and squamous cell carcinoma of the esophagus. METHODS: Records of patients who had undergone esophageal cancer surgery between January 2000 and January 2017 were reviewed. Comparisons were made between patients who received high versus low intraoperative doses of opioids. Groups were divided using the recursive partitioning method. Multicovariate Cox proportional hazards models were fitted to evaluate the impact of intraoperative opioid use on recurrence-free survival (RFS) and overall survival (OS). RESULTS: For patients with esophageal squamous cell carcinoma, the univariable analysis indicated that lower opioid dosages (<710 MUg fentanyl equivalents) were significantly associated with worse RFS (P = .009) and OS (P = .002). With the adjustment of age, stage, and adjuvant chemotherapy, multivariable analysis confirmed significant associations between higher dosages of intraoperative fentanyl equivalents and better RFS (P = .002; hazard ratio [HR], 0.376; 95% confidence interval [CI], 0.201~0.704). Likewise, higher intraoperative fentanyl equivalents administered was associated with improved OS (P = .002; HR, 0.346; 95% CI, 0.177~0.676). In the adenocarcinoma population, the association between intraoperative opioid dosage and RFS (P = .15) or OS (P = .36) was not significant from univariable analysis. With the adjustment of age, body mass index, tumor staging, neoadjuvant chemotherapy, and adjuvant chemotherapy, multivariable analysis demonstrated marginal significant association between intraoperative fentanyl equivalents and RFS (P = .0866; HR, 0.806; 95% CI, 0.629~1.032). The association between intraoperative fentanyl equivalents and OS was not significant (P = .51). CONCLUSIONS: The results of this study indicate that the amounts of intraoperative opioids used are associated with recurrence and OS in patients with esophageal squamous cell carcinoma. The association between the dose of intraoperative opioids used and RFS was marginally significant in patients with adenocarcinoma. Until confirmation on our findings by future studies, opioids should continue to be a key component of balanced anesthesia in patients with esophageal cancer. PMID- 29757783 TI - Absolute Risks Of Obstetric Outcomes Risks By Maternal Age At First Birth: A Population-Based Cohort: Erratum. PMID- 29757782 TI - Newborn Apgar Score and Prediction of Maternal Death. PMID- 29757779 TI - The Perioperative Care of the Transgender Patient. AB - An estimated 25 million people identify as transgender worldwide, approximately 1 million of whom reside in the United States. The increasing visibility and acceptance of transgender people makes it likely that they will present in general surgical settings; therefore, perioperative health care providers must develop the knowledge and skills requisite for the safe management of transgender patients in the perioperative setting. Extant guidelines, such as those published by the World Professional Association for Transgender Health and the University of California San Francisco Center of Excellence for Transgender Health, serve as critical resources to those caring for transgender patients; however, they do not address their unique perioperative needs. It is essential that anesthesia providers develop the knowledge and skills necessary for safely managing transgender patients in the perioperative setting. This review provides an overview of relevant terminology, the imperative for the provision of culturally sensitive care, and guidelines for preoperative, intraoperative, and postoperative management of the transgender patient. PMID- 29757785 TI - Global emergence of nurse practitioner/advanced practice nursing roles. PMID- 29757784 TI - Keywords matter: A critical factor in getting published work discovered. PMID- 29757786 TI - Management of venous thromboembolism with non-vitamin K oral anticoagulants: A review for nurse practitioners and pharmacists. AB - BACKGROUND AND PURPOSE: Venous thromboembolism (VTE), comprising deep-vein thrombosis and pulmonary embolism, is associated with significant morbidity and mortality. Non-vitamin K oral anticoagulants (NOACs), including apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban, are as effective and safe as vitamin K antagonists (VKAs) for primary prophylaxis, treatment, and/or secondary prevention of VTE and present significant advantages in convenience of use. This review provides guidance to nurse practitioners (NPs) and pharmacists on NOAC usage for the management of VTE and examines how traditional anticoagulation clinics can adapt to cater to patients on NOACs. METHODS: A review of the scientific literature pertaining to treatment guideline recommendations, large randomized clinical trials, and real-world evidence studies related to VTE management was conducted. CONCLUSIONS: With current data suggesting that NOACs may present as better alternatives over VKAs for the management of VTE, comprehensively educating NPs and pharmacists can help incorporate these agents in their clinical practice. IMPLICATIONS FOR PRACTICE: Repurposing anticoagulation clinics, led by well-informed NPs and pharmacists, will allow effective integration and optimal management of patients with VTE taking NOACs as well as those taking VKAs. PMID- 29757787 TI - Screening for childhood adversity among adult primary care patients. AB - BACKGROUND AND PURPOSE: Over half of Americans reports a history of adverse childhood experiences (ACEs), which have been associated with many chronic health conditions. Yet primary care providers infrequently screen patients for ACEs and fail to consider the relationship between ACEs and adult health. Therefore, the purposes of this study were to test the effectiveness and feasibility of a screening interview for ACEs and to confirm the prevalence of ACEs among individuals with chronic health conditions. METHODS: Screening interviews were conducted with 71 adults in a primary care setting. Patients' ACE history, nurse practitioner comfort with screening, time to screen, and patient follow-up care recommendations were gathered through questionnaires. Adverse childhood experience prevalence was analyzed by descriptive statistics. Relationships between ACEs, number of clinic visits, time to screen, and follow-up care recommendations were analyzed by bivariate statistics. CONCLUSIONS: Over half of participants reported more than four ACEs, with ACEs common among participants with chronic health conditions (93%). Adverse childhood experience scores were positively correlated with number of clinic visits, time to screen, and recommendations for follow-up care. Findings support screening primary care patients for ACEs. IMPLICATIONS FOR PRACTICE: Adverse childhood experiences are prevalent among primary care patients with chronic conditions. Using interviews to screen for ACEs in primary care settings is effective and feasible. PMID- 29757788 TI - The primary care provider and the patient living in poverty: Applying the Bridges to Health and Healthcare model to NP practice. AB - BACKGROUND AND PURPOSE: There is a much recent emphasis on the social determinants of health, and poverty is the most influential of these. It is not enough merely to understand the influence of poverty on health-the primary care provider must understand how to effectively treat patients who live in poverty. METHODS: This article applies the Bridges to Health and Healthcare model for understanding poverty to primary care practice from an individual provider's perspective. The article walks the reader through the implications of generational poverty for the primary care clinician in a typical office visit from history taking to following up. CONCLUSIONS: Most primary care practitioners approach patients from a middle-class perspective. Awareness of the challenges and different perspectives of those in generational poverty can enhance care and outcomes. IMPLICATIONS FOR PRACTICE: The individual provider can use the understanding of driving forces, resources, language and cognition, environment, and relationships provided by the Bridges to Health and Healthcare model to benefit patients in generational poverty. PMID- 29757789 TI - Sociocultural factors influencing infant-feeding choices among African immigrant women living with HIV: A synthesis of the literature. AB - BACKGROUND AND PURPOSE: The World Health Organizations (WHO) strategy is to eliminate pediatric HIV. HIV prevention guidelines in high-income countries recommend mothers living with HIV avoid breastfeeding. Yet, breastfeeding is promoted as the normal and unequalled method of feeding infants. This creates a paradox for mothers coming from cultures where breastfeeding is an expectation and formula feeding suggests illness. Therefore, the purpose of this literature review is to examine the context influencing infant feeding among African immigrant women living with HIV to develop interventions to reduce the risk of HIV mother-to-child transmission. METHODS: Using the PEN-3 cultural model as a guide, we selected 45 empirical studies between 2001 and 2016 using 5 electronic databases on the sociocultural factors influencing infant-feeding choices and practices among African women from HIV endemic countries. CONCLUSIONS: Findings are congruent with the importance of culture when developing guidelines. Our review provides support that culture-centered interventions are crucial toward achieving the WHO's strategy to eliminate pediatric HIV. IMPLICATIONS FOR PRACTICE: Understanding the sociocultural determinants of infant-feeding choices is critical to the development of prevention initiatives to eliminate pediatric HIV. PMID- 29757790 TI - Barriers to implementation of long-acting reversible contraception: A systematic review. AB - BACKGROUND AND PURPOSE: Long-acting reversible contraception (LARC) is one of the most effective forms of contraception available. The utilization of LARC remains low despite being recommended by major health organizations such as Centers for Disease Control and Prevention, American Congress of Obstetricians and Gynecologists, American Academy of Pediatrics, American Academy of Family Physicians, and the National Committee for Quality Assurance. Health care professionals play an essential role in the potential increased use of LARC. This review aims to highlight key barriers to the utilization of LARC and discuss interventions to address this issue. METHODS: A systematic review of 14 peer reviewed articles focused on LARC utilization rates that help identify barriers to the utilization of LARC in current education and practice. Articles were evaluated for strength of research design using the Johns Hopkins Nursing Evidence-Based Practice Research Evidence Appraisal tool. CONCLUSIONS: Three categories affecting LARC utilization emerged: deficits in provider education/competency, lack of hands-on training, and barriers to practice. IMPLICATIONS FOR PRACTICE: The importance of including LARC training and education in the advanced practice nursing curriculum and providing opportunities for continuing education with LARC is demonstrated. PMID- 29757791 TI - Barriers to implementation of long-acting reversible contraception: A systematic review. PMID- 29757792 TI - Baclofen Pump Replacement in a Patient With End-Stage Amyotrophic Lateral Sclerosis: A Case Report Demonstrating Transversus Abdominis Plane Block as the Sole Anesthetic. AB - A patient with end-stage amyotrophic lateral sclerosis (ALS) presented for Baclofen pump replacement. She underwent a left transversus abdominis plane block to anesthetize the left lower quadrant of the abdomen. No sedatives or analgesics were administered, and the procedure was successfully completed without complication. It is prudent to consider anesthetic plans that avoid complications associated with general or neuraxial anesthesia in patients with ALS. This case report demonstrates successful placement of a transversus abdominis plane block in a patient with ALS and offers a safe anesthetic technique that can be performed in other high-risk patients. PMID- 29757793 TI - Technique Utilizing a Modified Oral Ring-Adair-Elwyn Tube to Provide Continuous Oxygen and Sevoflurane Delivery During Nasotracheal Intubation in an Infant With a Difficult Airway: A Case Report. AB - Managing the airway of an infant with Pierre Robin sequence (PRS) is particularly challenging for anesthesiologists. Patients with PRS have the triad of micrognathia, glossoptosis, and airway obstruction that potentially and frequently leads to difficulty with both ventilation and intubation. Thus continuous oxygenation and spontaneous ventilation during intubation are essential. We describe a new method to deliver continuous oxygen and volatile anesthetic during nasotracheal intubation in an infant with PRS. PMID- 29757794 TI - Delayed Post Caudal Catheter Placement Pseudomeningocele: A Case Report. AB - We present a rare case of a 7-month-old infant who developed a pseudomeningocele 16 days after an uneventful caudal catheter placement. The patient did not exhibit neurological deficits or signs of infection, and the mass increased in size with Valsalva maneuver. Pseudomeningocele, an abnormal collection of cerebrospinal fluid around an opening in the dura mater, can be iatrogenic or traumatic. Regional anesthesia is rarely the cause. Recognizing diagnostic features such as the lack of infectious signs and mass compressibility can prevent misdiagnosis and inappropriate invasive treatment. PMID- 29757795 TI - Safe Labeling Practices to Minimize Medication Errors in Anesthesia: 5 Case Reports and Review of the Literature. AB - Drug error is a significant hazard to patient health. Poor, incorrect, and inconsistent labeling of injectable medicines and fluids, and the devices used to deliver these, has been identified as a patient safety issue. We report 5 cases of medication error as a consequence of incorrect or inappropriate labeling and analyze their cause. Recommendations for safe and practical labeling practices in anesthesia based on a review of the literature are presented. Implementation of the recommended labeling practices can reduce the risk of medication error and contribute to the safe administration of drugs. PMID- 29757797 TI - Combined Selective Nerve Blockade and Local Infiltration Analgesia in a Total Shoulder Arthroplasty Patient With Chronic Pain and Severe Restrictive Lung Disease: A Case Report: Erratum. PMID- 29757796 TI - Mental Nerve Blocks for Lip Brachytherapy: A Case Report. AB - High dose rate interstitial brachytherapy is a commonly performed procedure for carcinoma of the lower lip. Placement of the brachytherapy catheters can be painful and may require monitored anesthesia care or general anesthesia. We present the use of bilateral mental nerve blocks with minimal sedation to facilitate placement of brachytherapy catheters. PMID- 29757798 TI - Tinnitus Severity Is Related to the Sound Exposure of Symphony Orchestra Musicians Independently of Hearing Impairment. AB - OBJECTIVES: Tinnitus can be debilitating and with great impact of musicians professional and private life. The objectives of the study were therefore to: (1) describe the epidemiology of tinnitus including its severity in classical orchestra musicians, (2) investigate the association between tinnitus severity in classical musicians and their cumulative lifetime sound exposure, and (3) the association between tinnitus and hearing thresholds. DESIGN: The study population included all musicians from five Danish symphony orchestras. Answers regarding their perception of tinnitus were received from 325 musicians, and 212 musicians were also tested with audiometry. Any tinnitus and severe tinnitus were two definitions of tinnitus used as outcomes and analyzed in relation to an estimation of the cumulative lifetime sound exposure from sound measurements and previously validated questionnaires and the average hearing threshold of 3, 4, and 6 kHz. RESULTS: Thirty-five percentage of all musicians (31% female and 38% of male musicians) reported having experienced at least one episode of tinnitus lasting for more than 5 minutes during their life. Severe tinnitus with a severe impact on daily life was reported by 19% of the musicians (18% of female and 21% of male musicians). The severity of tinnitus was associated with increased lifetime sound exposure but not to poorer high frequency hearing thresholds when the lifetime sound exposure was considered. The odds ratio for an increase in one unit of tinnitus severity was 1.25 (95% CI, 1.12-1.40) for every 1 dB increase in lifetime sound exposure. CONCLUSION: Musicians frequently report tinnitus. Any tinnitus and severe tinnitus are significantly associated with the cumulative lifetime sound exposure, which was shown to be the most important factor not only for the prevalence but also for the severity of tinnitus-even in musicians without hearing loss. High-frequency hearing thresholds and tinnitus severity were correlated only if the cumulative lifetime sound exposure was excluded from the analyses.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29757799 TI - Improved Detection of Vowel Envelope Frequency Following Responses Using Hotelling's T2 Analysis. AB - OBJECTIVES: Objective detection of brainstem responses to natural speech stimuli is an important tool for the evaluation of hearing aid fitting, especially in people who may not be able to respond reliably in behavioral tests. Of particular interest is the envelope frequency following response (eFFR), which refers to the EEG response at the stimulus' fundamental frequency (and its harmonics), and here in particular to the response to natural spoken vowel sounds. This article introduces the frequency-domain Hotelling's T (HT2) method for eFFR detection. This method was compared, in terms of sensitivity in detecting eFFRs at the fundamental frequency (HT2_F0), to two different single-channel frequency domain methods (F test on Fourier analyzer (FA) amplitude spectra [FA-F-Test] and magnitude-squared coherence [MSC]) in detecting envelope following responses to natural vowel stimuli in simulated data and EEG data from normal-hearing subjects. Sensitivity was assessed based on the number of detections and the time needed to detect a response for a false-positive rate of 5%. The study also explored whether a single-channel, multifrequency HT2 (HT2_3F) and a multichannel, multifrequency HT2 (HT2_MC) could further improve response detection. DESIGN: Four repeated words were presented sequentially at 70 dB SPL LAeq through ER-2 insert earphones. The stimuli consisted of a prolonged vowel in a /hVd/ structure (where V represents different vowel sounds). Each stimulus was presented over 440 sweeps (220 condensation and 220 rarefaction). EEG data were collected from 12 normal-hearing adult participants. After preprocessing and artifact removal, eFFR detection was compared between the algorithms. For the simulation study, simulated EEG signals were generated by adding random noise at multiple signal to noise ratios (SNRs; 0 to -60dB) to the auditory stimuli as well as to a single sinusoid at the fluctuating and flattened fundamental frequency (f0). For each SNR, 1000 sets of 440 simulated epochs were generated. Performance of the algorithms was assessed based on the number of sets for which a response could be detected at each SNR. RESULTS: In simulation studies, HT2_3F significantly outperformed the other algorithms when detecting a vowel stimulus in noise. For simulations containing responses only at a single frequency, HT2_3F performs worse compared with other approaches applied in this study as the additional frequencies included do not contain additional information. For recorded EEG data, HT2_MC showed a significantly higher response detection rate compared with MSC and FA-F-Test. Both HT2_MC and HT2_F0 also showed a significant reduction in detection time compared with the FA-F-Test algorithm. Comparisons between different electrode locations confirmed a higher number of detections for electrodes close to Cz compared to more peripheral locations. CONCLUSION: The HT2 method is more sensitive than FA-F-Test and MSC in detecting responses to complex stimuli because it allows detection of multiple frequencies (HT2_F3) and multiple EEG channels (HT2_MC) simultaneously. This effect was shown in simulation studies for HT2_3F and in EEG data for the HT2_MC algorithm. The spread in detection time across subjects is also lower for the HT2 algorithm, with decision on the presence of an eFFR possible within 5 min. PMID- 29757800 TI - Are You There for Me? Joint Engagement and Emotional Availability in Parent-Child Interactions for Toddlers With Moderate Hearing Loss. AB - OBJECTIVES: This study examined joint engagement and emotional availability of parent-child interactions for toddlers with moderate hearing loss (MHL) compared with toddlers with normal hearing (NH) and in relation to children's language abilities. DESIGN: The participants in this study were 25 children with MHL (40 to 60 dB hearing loss) and 26 children with NH (mean age: 33.3 months). The children and their parents were filmed during a 10-minute free play session in their homes. The duration of joint engagement and success rate of initiations were coded next to the level of emotional availability reflected by the Emotional Availability Scales. Receptive and expressive language tests were administered to the children to examine their language ability. RESULTS: Groups differed in joint engagement: children with MHL and their parents were less successful in establishing joint engagement and had briefer episodes of joint engagement than children with NH and their parents. No differences between groups were found for emotional availability measures. Both joint engagement and emotional availability measures were positively related to children's language ability. CONCLUSIONS: Children with MHL and their parents are emotional available to each other. However, they have more difficulties in establishing joint engagement with each other and have briefer episodes of joint engagement compared with children with NH and their parents. The parent-child interactions of children with better language abilities are characterized with higher levels of emotional availability and longer episodes of joint engagement. The results imply that interactions of children with MHL and their parents are an important target for family-centered early intervention programs. PMID- 29757801 TI - Effects of Additional Low-Pass-Filtered Speech on Listening Effort for Noise-Band Vocoded Speech in Quiet and in Noise. AB - OBJECTIVES: Residual acoustic hearing in electric-acoustic stimulation (EAS) can benefit cochlear implant (CI) users in increased sound quality, speech intelligibility, and improved tolerance to noise. The goal of this study was to investigate whether the low-pass-filtered acoustic speech in simulated EAS can provide the additional benefit of reducing listening effort for the spectrotemporally degraded signal of noise-band-vocoded speech. DESIGN: Listening effort was investigated using a dual-task paradigm as a behavioral measure, and the NASA Task Load indeX as a subjective self-report measure. The primary task of the dual-task paradigm was identification of sentences presented in three experiments at three fixed intelligibility levels: at near-ceiling, 50%, and 79% intelligibility, achieved by manipulating the presence and level of speech-shaped noise in the background. Listening effort for the primary intelligibility task was reflected in the performance on the secondary, visual response time task. Experimental speech processing conditions included monaural or binaural vocoder, with added low-pass-filtered speech (to simulate EAS) or without (to simulate CI). RESULTS: In Experiment 1, in quiet with intelligibility near-ceiling, additional low-pass-filtered speech reduced listening effort compared with binaural vocoder, in line with our expectations, although not compared with monaural vocoder. In Experiments 2 and 3, for speech in noise, added low-pass filtered speech allowed the desired intelligibility levels to be reached at less favorable speech-to-noise ratios, as expected. It is interesting that this came without the cost of increased listening effort usually associated with poor speech-to-noise ratios; at 50% intelligibility, even a reduction in listening effort on top of the increased tolerance to noise was observed. The NASA Task Load indeX did not capture these differences. CONCLUSIONS: The dual-task results provide partial evidence for a potential decrease in listening effort as a result of adding low-frequency acoustic speech to noise-band-vocoded speech. Whether these findings translate to CI users with residual acoustic hearing will need to be addressed in future research because the quality and frequency range of low frequency acoustic sound available to listeners with hearing loss may differ from our idealized simulations, and additional factors, such as advanced age and varying etiology, may also play a role.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29757803 TI - Fever and Debilitating Myalgia. PMID- 29757804 TI - Esophageal Aphthae and Ulcers Due to Behcet Disease as Cause of Neck and Precordial Chest Pain. PMID- 29757805 TI - Response to Crestani Letter to the Editor. PMID- 29757802 TI - Assessing Unwanted Variations in Rheumatology Clinic Previsit Rooming. AB - BACKGROUND: Rheumatologists face time pressures similar to primary care but have not generally benefitted from optimized team-based rooming during the time from the waiting room until the rheumatologist enters the room. OBJECTIVE: The aim of this study was to assess current capacity for population management in rheumatology clinics; we aimed to measure the tasks performed by rheumatology clinic staff (medical assistants or nurses) during rooming. METHODS: We performed a cross-sectional time-study and work-system analysis to measure rooming workflows at 3 rheumatology clinics in an academic multispecialty practice during 2014-2015. We calculated descriptive statistics and compared frequencies and durations using Fisher exact test and analysis of variance. RESULTS: Observing 190 rheumatology clinic previsit rooming sequences (1419 minutes), we found many significant variations. Total rooming duration varied by clinic (median, 6.75 8.25 minutes; P < 0.001). Vital sign measurement and medication reconciliation accounted for more than half of rooming duration. Among 3 clinics, two of 15 tasks varied significantly in duration, and 9 varied in frequency. Findings led clinic leaders to modify policies and procedures regarding 6 high-variation tasks streamlining assessment of weight, height, pain scores, tobacco use, disease activity, and refill needs. CONCLUSIONS: Assessing rheumatology rooming tasks identified key opportunities to improve quality and efficiency without burdening providers. This project demonstrated user-friendly methods to identify opportunities to standardize rooming and support data-driven decisions regarding rheumatology clinic practice changes to improve population management in rheumatology. PMID- 29757806 TI - Medical Cannabis for the Treatment of Fibromyalgia. PMID- 29757807 TI - THICKNESSES OF CENTRAL MACULAR, RETINAL NERVE FIBER, AND GANGLION CELL INNER PLEXIFORM LAYERS IN PATIENTS WITH HYPERTENSION. AB - PURPOSE: To compare retinal thickness between patients with chronic hypertension without retinopathy, hypertensive retinopathy, Keith-Wagener-Barker Grade IV status, and normal controls using spectral domain optical coherence tomography. METHODS: In this retrospective study, we analyzed patients who visited our retinal clinic from January 2013 to February 2016. Of those included, 58 eyes of 58 patients were in the healthy control group (Group A), 37 eyes of 37 patients were in the chronic hypertension without retinopathy group (disease duration of at least 10 years; Group B), and 31 eyes of 31 patients with relieved hypertensive retinopathy (Grade IV hypertensive retinopathy a year or more ago but no longer had hypertensive retinopathy at the time of the study; Group C). The thicknesses of the central macula, retinal nerve fiber layer (RNFL), and ganglion cell inner plexiform layer (GCIPL) were measured by spectral domain optical coherence tomography in each group. RESULTS: The average thicknesses of the central macula, RNFL, and GCIPL layers were lower in Group B than in Group A (P < 0.001, 0.001, and <0.001, respectively). The thicknesses of the three layers were lower in Group C than in Group B (P < 0.001, <0.001, and <0.001, respectively). Of the three groups, the average thicknesses of the central macula, RNFL, and GCIPL were lowest in the Group C (P < 0.001, <0.001, and <0.001, respectively). CONCLUSION: The central macula, RNFL, and GCIPL in Group B were significantly thinner than those of healthy eyes, and these retinal changes were more prominent in Group C. Thus, the effects of retinal changes associated with hypertension should be considered when analyzing the thicknesses of the central macular, RNFL, and GCIPL layers in patients with ocular disorders, including retinal, glaucoma, and neuro-ophthalmological diseases. PMID- 29757808 TI - The Efficacy of Deep Sclerectomy on Posture-induced Intraocular Pressure Changes. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of nonpenetrating deep sclerectomy (NPDS) on posture-induced intraocular pressure (IOP) changes in open-angle glaucoma (OAG). MATERIALS AND METHODS: Twenty-five eyes of 25 patients with OAG that underwent NPDS were included in this study. IOP was measured with the IcarePro (ICP) tonometer in the sitting, supine, dependent lateral decubitus position (DLDP), and nondependent lateral decubitus position (NDLDP) before surgery, and at 1 and 3 months after surgery. RESULTS: The mean baseline IOP measured in the sitting position was 20.5+/-8.4 mm Hg with Goldmann applanation tonometry and 19.6+/-6.5 mm Hg with ICP. At 1 and 3 months after NPDS, mean IOP decreased significantly in each position (P<0.001). At each time point, mean IOP was higher in all lying positions than in the sitting position (P<0.001) and higher in the DLDP than in the supine and NDLDP positions (P<0.001 and P=0.001). Posture-induced IOP changes between the sitting and supine position, DLDP, and NDLDP, respectively, were significantly reduced by 77% (P=0.009), 60% (P=0.001), and 82% (P=0.01) at 1 month and by 79% (P=0.004), 70% (P<0.001), and 79% (P<0.001) at 3 months after surgery. The IOP fluctuation reduction was significantly inferior when considering sitting-DLDP than other postural changes. CONCLUSIONS: NPDS is effective in lowering the mean IOP in all body positions and also the postural IOP fluctuations. The mean IOP in the DLDP remained higher than in the other body positions. This posture should be avoided in patients with asymmetric OAG. PMID- 29757809 TI - Applicability of ISNT Rule Using BMO-MRW to Differentiate Between Healthy and Glaucomatous Eyes. AB - PURPOSE: We evaluated the applicability of the ISNT rule using Bruch's membrane opening minimum rim width (BMO-MRW) in healthy eyes and eyes with normal tension glaucoma (NTG). MATERIALS AND METHODS: In total, 124 healthy eyes and 136 NTG eyes were analyzed. Using 2-dimensional disc photographs, neuroretinal rim (NRR) thickness was measured at the superior, inferior, nasal, and temporal sides of the optic disc. Using spectral domain-optical coherence tomography, BMO-MRW was measured at the same regions. We compared the applicability of the ISNT rule in healthy and NTG eyes between these 2 methods. If the NRR was not clearly distinguished on disc photographs, the eye was classified into the "indistinguishable NRR" group and we only tested applicability of the ISNT rule using BMO-MRW. RESULTS: The specificity of "violation of the ISNT rule" for the diagnosis of glaucoma was higher when BMO-MRW was used (66.3%) than using disc photographs (42.2%), whereas the sensitivity did not show a significant difference between the 2 methods (91.7% vs. 86.5%). Compared with eyes with distinguishable NRR (179 eyes), eyes with indistinguishable NRR (81 eyes) had higher axial length, more negative refractive error, and higher tilt ratio (P<0.001). The diagnostic ability of "violation of ISNT rule" using BMO-MRW was not significantly different between eyes with indistinguishable NRR and those with distinguishable NRR (P>0.05). CONCLUSIONS: Application of the ISNT rule using BMO-MRW shows superiority in distinguishing between healthy and glaucomatous optic discs compared with disc photographs. The ISNT rule can be applied using BMO-MRW even when NRR is indistinguishable on disc photographs, such as in myopic tilted discs. PMID- 29757810 TI - Changes in Ocular Hypotensive Drug Usage for Glaucoma Treatment After Cataract Surgery: A Nationwide Population-based Study in Taiwan. AB - PURPOSE: The aims of this study were to observe the changes in the demand for prescriptions of ocular hypertensive drug (OHD) after cataract surgery, to investigate patterns of change in the required OHD amount in open-angle glaucoma (OAG) and angle-closure glaucoma (ACG) cases, and to determine the associated factors related to the change. MATERIALS AND METHODS: This population-based cohort study using the Taiwan National Health Insurance Research Database enrolled patients with glaucoma who underwent bilateral cataract surgeries within 2 years between 2001 and 2012. The major dependent variables were the total amounts of OHDs prescribed within 1 year before the first cataract surgery and 1 year after the second cataract surgery. We compared the overall change in the required OHD amount before and after cataract surgery and further explored potential factors affecting the change. RESULTS: Among the 440 patients, there were more cases of ACG than OAG (68.6% vs. 31.4%). The total OHD amount prescribed reduced significantly after cataract surgery in patients with OAG (median, from 12 to 6 bottles before and after the surgery, P<0.0001) and ACG (median, from 10 to 3 bottles, P<0.0001), and the reduction was sustained for 5 years. The reduction was significantly larger in patients with ACG and higher demand for OHD (P=0.0157). Among the OAG cases, the reduction was significantly larger in patients who were female individuals (P=0.0138), treated in clinics (P=0.0305), and exhibited high demand for OHD (P=0.0282). CONCLUSIONS: The prescriptions of OHDs by glaucoma patients reduced considerably after cataract surgery. Although the reduction proportion of the demand for OHD after cataract surgery was significantly larger in patients with ACG than in those with OAG, the reduction was sustained for 5 years in both types of glaucoma. PMID- 29757812 TI - Plateau Iris: The Terminology and Clinical Relevance. PMID- 29757811 TI - Ultrasound Biomicroscopic Diagnosis of Angle-closure Mechanisms in Vietnamese Subjects With Unilateral Angle-closure Glaucoma. PMID- 29757813 TI - Estimating the Economic Burden Related to Older Adult Falls by State. AB - OBJECTIVE: Unintentional falls in older adults (persons 65 years of age and older) impose a significant economic burden on the health care system. Methods for calculating state-specific health care costs are limited. This study describes 2 methods to estimate state-level direct medical spending due to older adult falls and explains their differences, advantages, and limitations. DESIGN: The first method, partial attributable fraction, applied a national attributable fraction to the total state health expenditure accounts in 2014 by payer type (Medicare, Medicaid, and private insurance). The second method, count applied to cost, obtained 2014 state counts of older adults treated and released from an emergency department and hospitalized because of a fall injury. The counts in each state were multiplied by the national average lifetime medical costs for a fall-related injury from the Web-based Injury Statistics Query and Reporting System. Costs are reported in 2014 US dollars. SETTING: United States. PARTICIPANTS: Older adults. MAIN OUTCOME MEASURE: Health expenditure on older adult falls by state. RESULTS: The estimate from the partial attributable fraction method was higher than the estimate from the count applied to cost method for all states compared, except Utah. Based on the partial attributable fraction method, in 2014, total personal health care spending for older adult falls ranged from $48 million in Alaska to $4.4 billion in California. Medicare spending attributable to older adult falls ranged from $22 million in Alaska to $3.0 billion in Florida. For the count applied to cost method, available for 17 states, the lifetime medical costs of 2014 fall-related injuries ranged from $68 million in Vermont to $2.8 billion in Florida. CONCLUSIONS: The 2 methods offer states options for estimating the economic burden attributable to older adult fall injuries. These estimates can help states make informed decisions about how to allocate funding to reduce falls and promote healthy aging. PMID- 29757814 TI - MACULAR HOLE FORMATION FOLLOWED BY SPONTANEOUS CLOSURE AFTER PNEUMATIC RETINOPEXY IN A PATIENT WITH DIABETIC MACULAR EDEMA. AB - PURPOSE: To report early formation and spontaneous closure of a full-thickness macular hole that developed after successful pneumatic retinopexy in a patient who had been undergoing treatment for diabetic macular edema. METHODS: Case report of a 68-year-old man with bilateral nonproliferative diabetic retinopathy who was currently undergoing anti-vascular endothelial growth factor treatment for bilateral diabetic macular edema. RESULTS: On presentation, visual acuity was 20/200 in the left eye, and examination revealed a bullous, macula-off retinal detachment with a single horseshoe tear at 12 o'clock in the left eye. Pneumatic retinopexy was performed followed by laser augmentation 3 days later. Three weeks postoperatively, he returned with visual acuity of 20/50 and a full-thickness macular hole in the left eye. Although he elected for initial observation, he returned 2 weeks later with visual acuity of 20/50 in both eyes and a retinal detachment with a single break at 10 o'clock in the right eye. The macular hole in the left eye had spontaneously resolved. Pneumatic retinopexy was performed to the right eye. Over 1 year after bilateral pneumatic retinopexy, his retina remains without recurrence of a macular hole in the left eye. CONCLUSION: In the early postoperative period after pneumatic retinopexy to repair a retinal detachment, a macular hole can form and spontaneously close. PMID- 29757815 TI - The vocabulary of science. PMID- 29757816 TI - Attitudes and perceptions about cigarette smoking among nonsmoking high school students. AB - PURPOSE: To explore the association between cigarette smoking intention and attitude, subjective norm, and perceived behavioral control as identified by the Theory of Planned Behavior (TPB) in a cohort of nonsmoking teenagers. METHODS: A convenience sample of 76 nonsmoking students from a rural Northeastern Pennsylvania high school completed a self-administered questionnaire based on the TPB, which included cigarette smoking behavior, intention, and the direct measures of attitude, subjective norm, and perceived behavioral control. CONCLUSIONS: Regression analyses demonstrated that all three independent variables (attitude, subjective norm, and perceived behavioral control) contributed significantly to the respondents' intention to not smoke cigarettes, accounting for 64% of the variance. These findings may have implications for promoting nonsmoking behavior. IMPLICATIONS FOR PRACTICE: This is the first study to examine the efficacy of the TPB in predicting the intention to not smoke in a cohort of all nonsmokers. The intention to not smoke was significantly correlated with the respondents' negative general attitudes toward cigarette smoking, belief that significant others would disapprove of their cigarette smoking, and positive tobacco refusal self-efficacy. Understanding the factors associated with nonsmoking behavior in teenagers is important information for nurse practitioners, as we develop strategies to encourage and reinforce cigarette smoking abstinence. PMID- 29757818 TI - Surrogates' experiences of engaging in Physician Orders for Life-Sustaining Treatment discussions for persons with advanced dementia. AB - BACKGROUND AND PURPOSE: Little is known about surrogates' experiences of engaging in Physician Orders for Life-Sustaining Treatment (POLST) discussions. This study describes family surrogates' experiences when engaging in POLST discussions with primary care providers. METHODS: Semistructured interviews were conducted with 10 family surrogates of individuals with advanced dementia who were enrolled in a Program of All-Inclusive Care for the Elderly or resided in a nursing home. Interviews were analyzed using directed content analysis based on the conceptual model of communication and surrogate decision making by Torke et al. RESULTS AND CONCLUSION:: Surrogates reported that clear explanations of clinical information and the opportunity to ask questions and reiterate what they heard were helpful in making treatment decisions. Moreover, surrogates reported feeling respected and understood when providers expressed concern for them or their family member with advanced dementia and asked them about their emotional responses to decision making. Although nine surrogates reported very positive communication with providers, one surrogate expressed discomfort with the interaction and described feeling pressured to make health care decisions. IMPLICATIONS FOR PRACTICE: With effective communication, family surrogates feel emotionally supported during communication and decision-making processes. Providers are encouraged to focus on developing expert communication skills for end-of-life care discussions. PMID- 29757817 TI - Brief report of a novel advanced practice provider-led course for ultrasound novices. AB - BACKGROUND AND PURPOSE: Formal training for ultrasound use is essential for critical care providers. Despite a national increase in the utilization of advanced practice providers in critical care, ultrasound education is not routinely provided in their training programs. This study describes and evaluates a 1-day advanced care provider (APP)-led course designed to provide fellow APPs with the skills to obtain and evaluate basic ultrasound images. METHODS: A 15 question pretest was administered via anonymous use of a clicker response system. Participants had didactic lectures followed by hands-on experience with live models and instructor. Posttest was administered after achievement of basic ultrasound views. Postcourse evaluations were also administered. CONCLUSIONS: Pretest and posttest questions included identifying anatomy, pathology, quantifying cardiac function, and clinical decision making. Scores improved from 58% on the pretest to 78% on the posttest. All participants acknowledged the need for the course and their ability to transfer the course into practice. IMPLICATIONS FOR PRACTICE: This course established that APPs can both teach and learn from their peers in a formal setting. In addition, this course demonstrated that an APP-led course with a combined hands-on and didactic approach is an effective method for critical care ultrasound skills acquisition in ultrasound novice APPs. PMID- 29757819 TI - Job satisfaction and empowerment of self-employed nurse practitioners: A mixed methods study. AB - BACKGROUND AND PURPOSE: Self-employed nurse practitioners (NPs) have been part of the American health care landscape since the 1970s, owning practices throughout the United States. The purpose of this study was to explore and measure the 2 characteristics of job satisfaction and empowerment in self-employed NPs practicing within the 50 states and District of Columbia and to explore factors that influence these characteristics. METHODS: A convergent parallel design, mixed methods study, using a survey and semistructured interviews, was completed. The survey included the Misener Job Satisfaction Survey and Conditions of Work Effectiveness Questionnaire II. CONCLUSIONS: Self-employed NPs are satisfied and empowered. The more empowered, the higher their level of job satisfaction. Over 40% practiced with full practice authority in a rural location, and 50% had over 10 years of experience as both an RN and NP. Their experience in private practice was explored further in the interviews. IMPLICATIONS FOR PRACTICE: This study identifies barriers to job satisfaction and empowerment in self-employed NPs, including physician oversight and lack of business management education. Continuing work to remove restricted and reduced state regulatory environments and to provide education on business management may increase the number of NPs in private practice, expanding access to health care in the United States. PMID- 29757820 TI - Longitudinal study of advanced practice nurses' implementation of screening intervals for cervical cancer screening. AB - BACKGROUND AND PURPOSE: The past two decades brought changes in cervical cancer screening guidelines. Frequent modifications and earlier lack of agreement about recommendations created confusion. The purpose of this study was to explore to what extent advanced practice nurses (APNs) adopted cervical cancer screening guidelines. METHODS: A longitudinal survey of 358 APNs conducted in three New England states regarding cervical cancer screening practices in 2008, 2012, and 2015. CONCLUSIONS: Advanced practice nurses are incorporating guidelines at a high rate. Advanced practice nurses found it easier to incorporate guidelines to delay screening until the age of 21 years, to discontinue screening after total hysterectomy for benign reasons, and to discontinue screening at the age of 65 years. In 2012, 15% of APNs were screening women aged 21-29 years every 3 years; by 2015, this rate rose to 72%. By 2015, half of APNs were screening low-risk women aged 30-64 every 5 years. Because screening practices changed, APNs questioned the need to perform screening pelvic and breast examinations. Advanced practice nurses no longer perform screening pelvic examinations (93%) or breast examinations (75%) in adolescents. IMPLICATIONS FOR PRACTICE: Some APNs indicated that office-based practice standards are barriers to adherence to guidelines. Advanced practice nurses need to be involved in practice committees to ensure that evidence guides practice decisions. PMID- 29757821 TI - Relationships among factors affecting advanced practice registered nurses' job satisfaction and intent to leave: A systematic review. AB - BACKGROUND AND PURPOSE: This systematic review explores relationships between advanced practice registered nurses' (APRN) job satisfaction and intent to leave. There exists a dearth of APRN providers compared with the ever-growing need for their services. Furthermore, the organizational costs associated with the APRN turnover are extremely high. It, therefore, behooves practice administrators to understand what factors most contribute to APRN job satisfaction and retention. METHODS: A search of research databases CINAHL, PubMed, and PsycINFO, using keywords "Advanced Practice Registered Nurse," "job satisfaction," "intent to leave," "anticipated turnover," and "Nurse Practitioner" to yield articles included in this review. CONCLUSIONS: The strength of existing evidence for this topic is weak. Studies have found that extrinsic factors, such as administrative support and salary, significantly contribute to job dissatisfaction, whereas intrinsic factors, such as autonomy and finding work meaningful, most significantly contribute to job satisfaction. Additional research is needed to better understand the factors relating to APRN job satisfaction and dissatisfaction, and how those factors influence practitioners' intent to leave. IMPLICATIONS FOR PRACTICE: Efforts to improve APRN job satisfaction will have positive implications for provider retention, practices, and patients. Administrators should consider the job satisfaction factors identified herein when implementing practice improvement and retention efforts. PMID- 29757822 TI - An Exploration of the Impact of the "Open Gym" Scheduling Model of Cardiovascular Rehabilitation on Completion, Attendance, and Health Outcomes. AB - PURPOSE: To explore the effects of implementation of the "Open Gym" (OG) scheduling model of cardiovascular rehabilitation administration on the rate of patient engagement and change in commonly measured clinical outcomes. Little data exist on the potential benefits of the OG model on patient completion, attendance, and clinical outcomes. METHODS: A retrospective chart review was conducted that included the 1-y period both before and after OG model implementation. Bootstrapped regression and analysis of variance were utilized to determine (1) whether the scheduling model is associated with number of sessions attended and program completion, and (2) among those who meet their goals and thus complete the program, if the scheduling model predicts change in cardiovascular rehabilitation clinical outcomes (ie, percent weight change, 6-min walk distance, and peak metabolic equivalents during exercise) when controlling for baseline values. Follow-up analyses controlled for and explored interactions related to age, race, and sex. RESULTS: In this racially diverse sample (34% nonwhite), patients under either the OG model (n = 125) or the Traditional model (n = 82) attended an equivalent number of sessions and were just as likely to complete their treatment. However, clinical outcomes favored the Traditional model, even as more patients participated in the OG model, especially racial minority patients. CONCLUSIONS: Although the OG model is more consistent with patient-centered care, gains in functional capacity may be diminished. Furthermore, better controlled experiments are needed to examine the effects of implementing the OG model and should include measures of possible mechanisms influencing racial differences. PMID- 29757823 TI - Reliability, Validity, and Responsiveness of the Incremental Shuttle Walk Test in Patients With Interstitial Lung Disease. AB - PURPOSE: To determine the reliability, validity, and responsiveness of the incremental shuttle walk test (ISWT) in patients with interstitial lung disease (ILD). METHODS: This was a cross-sectional longitudinal study. Patients (n = 27, 10 males; mean age +/- SD, 61 +/- 9.8 y) with ILD of any etiology, who participated in an outpatient pulmonary rehabilitation (PR) program, were recruited. Reliability was determined by comparing the distance covered in meters between the ISWT-1 and the ISWT-2. Validity was assessed by correlating the distance covered in the ISWT-1, with the maximum oxygen consumption ((Equation is included in full-text article.)O2max) obtained through cardiopulmonary exercise testing and distance covered during the 6-min walk test (6MWT). Responsiveness was assessed by comparing the distance covered in the ISWT-3, undertaken after the completion of PR, to the ISWT-1. RESULTS: The distance covered was equivalent between the ISWT-1 (216.7 +/- 64.9 m) and the ISWT-2 (220.7 +/- 67.3 m), with an excellent intraclass correlation coefficient (ICC2,1 = 0.91; 95% CI, 0.81-0.95). The standard error of measurement and minimal detectable change at the 95% CI (MDC95) values for the ISWT were 19.5 m and 53.9m, respectively. There were significant correlations between the distance covered on the ISWT and (Equation is included in full-text article.)O2max (r = 0.79, P < .0001) and the distance covered on the 6MWT (r = 0.76, P < .0001). Following PR, the change in the ISWT distance showed large effect size (ES = 0.85) and standardized response mean (SRM = 1.58). CONCLUSIONS: The ISWT is a reliable, valid, and responsive measure of estimated functional capacity in patients with ILD. PMID- 29757824 TI - Improvements in Key Cardiopulmonary Exercise Testing Variables Following Cardiac Rehabilitation in Patients With Coronary Artery Disease. AB - PURPOSE: Improvements in cardiorespiratory fitness ((Equation is included in full text article.)O2peak) post-cardiac rehabilitation (post-CR) are used to gauge therapeutic efficacy. The aim of the present study was to assess the effect of supervised CR on other cardiopulmonary exercise testing (CPX) variables, specifically those that reflect ventilatory efficiency and (Equation is included in full-text article.)O2 changes in relation to changes in work rate (WR). METHODS: Patients (n = 142; mean age 63 +/- 9 y; 23% female) with coronary artery disease (CAD) participated in supervised CR for 3 to 6 mo completing 60 +/- 17 sessions (range: 32-96 sessions), with intensity derived from the baseline CPX. CPX was completed at baseline and post-CR on a cycle ergometer. The minimum heart rate (HR) during cycling was set 5 to 10 beats/min above the HR at ventilatory anaerobic threshold (VAT) while the maximum HR remained below the ischemic threshold observed during CPX, and this intensity was maintained for 25 min. (Equation is included in full-text article.)O2peak, peak O2 pulse, the minute ventilation/carbon dioxide production ((Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2) slope, the oxygen uptake efficiency slope (OUES), and the Delta(Equation is included in full-text article.)O2/DeltaWR slope were determined at baseline and post-CR. RESULTS: Following CR, there were significant improvements (all P < .001) in (Equation is included in full-text article.)O2peak (17.7 +/- 4.7 mL/kg/min vs 20.9 +/- 5.4 mL/kg/min), peak O2 pulse (11.6 +/- 3.2 mL/beat vs 13.4 +/- 3.6 mL/beat), (Equation is included in full-text article.)E/(Equation is included in full-text article.)CO2 slope (28.4 +/- 5.3 vs 27.5 +/- 4.7), OUES (1.8 +/- 0.5 vs 2.0 +/- 0.6), and Delta(Equation is included in full-text article.)O2/DeltaWR slope (9.1 +/- 1.2 mL/min/W vs 9.6 +/- 1.1 mL/min/W). CONCLUSION: Key markers of ventilatory efficiency and (Equation is included in full-text article.)O2 kinetics during CPX significantly improve following CR. Expanding the list of variables assessed via CPX may provide better resolution in validation of CR therapeutic efficacy in patients with CAD. PMID- 29757825 TI - Self-efficacy Predicts Success in an Exercise Training-Only Model of Pulmonary Rehabilitation for People With COPD. AB - PURPOSE: To determine whether people with chronic obstructive pulmonary disease (COPD) have characteristics that predict a clinically meaningful response to pulmonary rehabilitation (PR) that includes an education component compared with exercise training alone. METHODS: Participants were classified as responders or nonresponders to 2 models of PR; exercise training and education (ET + ED, n = 113) or exercise training alone (ET, n = 85). Responders were defined as those who achieved a clinically meaningful change in 6-min walk distance (6MWD) or any of the 4 domains of the Chronic Respiratory Questionnaire (CRQ). Baseline characteristics were compared between responders and nonresponders. The associations between baseline data and change in 6MWD and CRQ following PR were examined, and a binary logistic regression analysis was conducted for each model and primary outcome. RESULTS: There were no significant differences between the PR models in proportion of responders (ET + ED 92% vs ET 93%). Lower baseline CRQ scores predicted response in respective CRQ domains for fatigue, emotion, and mastery in the ET + ED group, and for dyspnea, fatigue, and mastery in the ET group. Higher baseline self-efficacy predicted 6MWD response and higher socioeconomic status predicted response in CRQ fatigue in the ET model only. There was no predictor of 6MWD response in the ET + ED group. CONCLUSIONS: Baseline characteristics did not reliably predict a clinically meaningful response to PR that included education. For exercise training alone, higher self efficacy was a significant predictor for greater improvements in 6MWD, suggesting that those with higher confidence should be considered for this model. PMID- 29757826 TI - Physical Activity Levels Predict Exercise-induced Hypoalgesia in Older Adults. AB - : Prior research indicates that older adults exhibit a deficient capacity to activate multiple pain inhibitory mechanisms, including pain inhibition after acute exercise termed exercise-induced hypoalgesia (EIH). The influence of physical activity levels and psychological processes on EIH in older adults remains unclear. PURPOSE: This study examined potential psychological and physical activity predictors of the magnitude of EIH after submaximal isometric exercise in healthy older adult men and women. METHODS: Fifty-two healthy older adults completed a test of EIH, the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia, and wore an accelerometer on the hip for 1 wk to assess physical activity levels. For the test of EIH, participants complete a 3-min isometric handgrip at 25% of maximum voluntary contraction. Pressure pain thresholds (PPT) and a 30-s continuous heat pain test were completed before and immediately after the exercise. RESULTS: Mixed-model ANOVA revealed that older adults demonstrated significantly decreased PPT after isometric exercise (P = 0.030), and no changes on the heat pain trials from pretest to posttest (P > 0.05). A multiple regression revealed that accumulated moderate to vigorous physical activity (MVPA) per week significantly predicted the change in PPT after exercise (beta = 0.35, P = 0.012). Participants who averaged greater MVPA experienced a greater increase in PPT after exercise. No relationships were found with EIH and the psychological variables. CONCLUSIONS: Older adults did not exhibit EIH after submaximal isometric exercise. However, those who did more MVPA per week experienced a greater magnitude of pain inhibition after acute exercise. PMID- 29757827 TI - Men's health awareness: Change through education. PMID- 29757829 TI - Review of prolonged care services codes. PMID- 29757828 TI - Transition: The road to becoming a nurse practitioner. PMID- 29757830 TI - Borderline personality disorder: Implications and best practice recommendations. PMID- 29757831 TI - A patient with autonomic imbalance: Treating symptomatic neurogenic orthostatic hypotension. PMID- 29757833 TI - Advance care planning and anticipatory decision making in patients with Alzheimer disease. PMID- 29757832 TI - Advance care planning and anticipatory decision making in patients with Alzheimer disease. AB - Early advance care planning and anticipatory decision making in the Alzheimer disease (AD) trajectory is a strategy NPs can incorporate to improve managing uncertainty around common decisions. This article explores decisions patients and caregivers face along the AD trajectory and provides resources for patients, caregivers, and NPs. PMID- 29757834 TI - Hypertension management options: 2017 guideline. AB - The new hypertension guideline lowers the definition of high BP to 130/80 mm Hg. This means that millions of adults will now be diagnosed with hypertension and that many of those taking antihypertensive drugs are not at goal. The challenge is to communicate the change, the strength of evidence behind the change, and the options available to patients. Healthcare providers must be knowledgeable of the new guideline and must be ready to meet this challenge. PMID- 29757835 TI - Hypertension management options: 2017 guideline. PMID- 29757836 TI - Family history of substance use disorder and chronic pain management. AB - The use of family history of substance use disorder information as part of a comprehensive assessment of chronic pain can provide important data for treatment. This case example illustrates assessment, patient education, and brief motivational interviewing with referral to appropriate resources. PMID- 29757837 TI - Antipsychotic use in older adults: Canadian best practices. AB - Due to the physiologic changes of aging, managing behavioral issues and antipsychotic use is associated with adverse reactions that are more complex in older adults than in younger adults. Therefore, appropriate prescribing and evaluating the need to continue antipsychotics are necessary to enhance optimum patient outcomes. This article discusses best practice recommendations for NPs in Canada to help ensure safe use of antipsychotic medications in the older adult population. PMID- 29757839 TI - Looking forward to better weather and cake. PMID- 29757840 TI - Listening to stories from women with heart disease: My experience as a nurse practitioner. PMID- 29757841 TI - Results of a national survey of certified nurse coaches with implications for advanced practice nurses. AB - BACKGROUND AND PURPOSE: Evidence suggests that nurse-coaching can improve health outcomes, but application of this skill is not well understood. The purpose of this study is to describe the practices of nurse coaches including their work settings, clients/health conditions, motivations behind becoming certified as coaches, and the personal benefits experienced by nurse coaches. METHODS: A cross sectional online survey was emailed to certified nurse coaches (n = 315); 164 completed the survey, including 68 (41.5%) advanced practice nurses. CONCLUSIONS: The most frequent conditions seen by coaches included the following: anxiety/stress (n = 39, 27.1%), cardiometabolic conditions (n = 24, 16.7%), and pain (n = 20, 13.9%). Coaching varied in frequency, method (individual versus group), and mode (in-person, by phone, or electronically). Participants became coaches to gain skills for enhancing their practice, deliver care that fits with their values and philosophy, meet personal needs (starting a private practice and improve their own self-care), attain credentials/validation, and empower others. The majority agreed/strongly agreed that since becoming a nurse coach, their own interpersonal relationships (80.3%), health/health behaviors (84.8%), and job satisfaction (70.7%) improved. IMPLICATIONS FOR PRACTICE: Nurse practitioners may be strategically situated to provide coaching and have the knowledge and skills needed to intervene with medically complex, at-risk populations. PMID- 29757842 TI - Asthma action plans in the adult population: Rediscovering an invaluable tool in today's health care domain. AB - BACKGROUND AND PURPOSE: Asthma in adults remains a leading cause of morbidity, mortality, and increased health care costs. Asthma action plans (AAPs) have demonstrated improved health outcomes in this populace; however, AAPs continue to be underused by providers. This article aims to re-emphasize the importance of AAPs for adults and refresh providers on the effectiveness and methods to use this indispensable tool. METHODS: A literature search of MEDLINE, PubMed, Google Scholar, and CINAHL was performed, and subsequent findings were reported. CONCLUSIONS: With proper involvement and inclusion of the patient in the creation of an AAP, adult patients can greatly improve their self-management capabilities through its use. IMPLICATIONS FOR PRACTICE: By recognizing the importance and success of AAPs for adults, providers can improve their personal practice through increased AAP delivery. Understanding today's available platforms and formats for AAPs will allow providers a widened subject knowledge base and increased adaptation of patient AAP needs for the adult population. Increased provider knowledge can potentially increase AAP use for adults, as well as improve overall patient outcomes. PMID- 29757843 TI - Strategies used to facilitate the discussion of advance care planning with older adults in primary care settings: A literature review. AB - BACKGROUND AND PURPOSE: The purpose of this literature review was to evaluate strategies used in primary care settings to initiate advance care planning (ACP) conversations leading to the completion of an advance directive (AD). Approximately 50% of older adults have an AD; few talk to their primary care provider (PCP) about end-of-life wishes. The Institute of Medicine report and recent changes in Medicare reimbursement policies create opportunities for PCPs to address ACP in primary care settings. METHODS: We used a systematic review approach. The search included seven Elton B. Stephens Company databases, limited to English language and peer-reviewed publications from 1991 to 2017 using 10 key words. CONCLUSIONS: Effective interventions were educational materials using various methods of delivery, computer-generated triggers for PCPs, inclusion of multidisciplinary professionals for content delivery, and patient preparation for PCP visit. IMPLICATIONS FOR PRACTICE: The identified strategies provide a starting point for PCPs to consider increasing the ACP discussion with their patients. Primary care providers must create opportunities to meet the needs of their patients and their families. Established guidelines and reimbursement for ACP challenge PCPs to identify and contribute to the formulation of best practices to facilitate AD completion in primary care settings. PMID- 29757844 TI - Predictors of nurse practitioner retention. AB - BACKGROUND AND PURPOSE: Increased utilization of nurse practitioners (NPs) has been proposed to reduce the shortage of primary care providers, so identifying factors related to retention of NPs is important for health care organizations. The purpose of this study was to examine the relationship of Misener Nurse Practitioner Job Satisfaction Scale factors and nurse demographic characteristics with NP retention, as defined by the number of years at the current position and intention to leave the current position within 5 years. METHODS: A survey was distributed via email to members of the Texas NP Organization. CONCLUSIONS: Three hundred fifteen NPs participated in the study. Years of experience (p < .001), salary (p = .018), and benefits (p = .007) were significantly associated with longer duration of employment at the current position, after controlling for the other variables in the linear regression model. After adjusting for the other variables in the logistic regression model, higher challenge/autonomy factor scores (p = .016) and higher annual salary (p = .032) were associated with significantly lower odds of intention to leave the current position within 5 years. IMPLICATIONS FOR PRACTICE: Interventions to increase NP autonomy and facilitate employment in positions with more competitive salaries are likely to improve NP retention. PMID- 29757845 TI - Impact of the acute care nurse practitioner in reducing the number of unwarranted daily laboratory tests in the intensive care unit. AB - BACKGROUND: Frequent laboratory testing may be necessary at times for critically ill patients. However, the practice of indiscriminate laboratory test ordering is common. PURPOSE: The purpose of this quality improvement project was to assess the effectiveness of the acute care nurse practitioner (ACNP) in reducing the number of unwarranted laboratory tests ordered for ICU patients. To determine whether the presence of an ACNP would make a difference, an ACNP was present on daily ICU multidisciplinary rounds to facilitate the discussion of the laboratory testing needs for each patient for the following 24-hour period. CONCLUSIONS: Eighty-one patients were enrolled in the project, 41 in the comparison and 40 in the intervention group. No significant differences were noted between the two groups. The project demonstrated that although there was an increase in tests ordered for the intervention group, the increase was brought about by an increase in specific individual tests rather than an increase in panels of laboratory tests. A reduction in patient cost was observed for the number of tests ordered. No increase in adverse events was noted. IMPLICATIONS FOR PRACTICE: Acute care nurse practitioner presence on multidisciplinary rounds may be an effective method to change the practice toward the ordering of tests based on clinical indication. PMID- 29757846 TI - Increasing diabetic patient engagement and self-reported medication adherence using a web-based multimedia program. AB - BACKGROUND AND PURPOSE: Evidence-based, multimedia applications to supplement clinical care can improve patient engagement and clinical outcomes. Patients with diabetes with potentially devastating complication of foot ulcers present a substantial opportunity to improve engagement. This project examines how providing an online, multimedia self-management program affects patient engagement and self-reported medication adherence scores within 4-6 weeks compared with preprogram scores. METHODS: Participants included 14 adult, diabetic outpatients receiving care at a Wound Care Center in suburban New York. Participants watched a Type 2 diabetes Emmi educational module on an electronic tablet during a routine wound treatment visit. Self-reported medication adherence was measured immediately before and at 4-6 weeks after the educational intervention. Patient engagement was measured immediately before, immediately after, and at 4-6 weeks postintervention. CONCLUSIONS: Self-reported medication adherence results demonstrated a modest increase at the delayed postintervention time. In addition, there was a large increase in engagement scores at the delayed postintervention time. The direction of change for both measures was consistent with the intervention being effective. IMPLICATIONS FOR PRACTICE: Incorporating this type of novel, multimedia patient education resource may provide opportunities to enhance diabetes care. PMID- 29757847 TI - Organophosphate insecticide exposure: A clinical consideration of chlorpyrifos regulation. AB - BACKGROUND AND PURPOSE: In March 2017, the Environmental Protection Agency (EPA) reversed course on a proposal to ban the agricultural use of the organophosphate (OP) insecticide chlorpyrifos (CPF). The purpose of this article is to examine the evidence leading to this controversial decision and provide clinically applicable health promotion guidance for nurse practitioners on CPF exposure and risk reduction measures. METHODS: Environmental Protection Agency documents on CPF regulation and corresponding research referenced within the EPA reports are reviewed. Evidence-based health promotion strategies obtained through PubMed, CINAHL, Center for Disease Control and Prevention, and National Institutes of Health sources are summarized. CONCLUSIONS: Available data suggest a potential association between CPF exposure and adverse neurodevelopmental outcomes. Particularly vulnerable populations are pregnant women, children younger than two years, and agricultural workers. There may be genetic variability in susceptibility to environmental toxins. IMPLICATIONS FOR PRACTICE: Because of the extensive use of the OP CPF in agriculture and other community-based settings throughout the United States, nurse practitioners should be knowledgeable of the evidence regarding CPF exposure and be prepared to provide health promotion guidance to patients in clinical practice. Nurse practitioners should also consider their role in advocacy for healthy environments and the protection of vulnerable populations as it relates to agricultural insecticide exposure. PMID- 29757848 TI - Organophosphate insecticide exposure: A clinical consideration of chlorpyrifos regulation. PMID- 29757849 TI - Ocular Surface Findings in Patients With Lichen Planopilaris. AB - PURPOSE: Lichen planopilaris (LPP) is a chronic lymphocytic- mediated disorder that selectively involves hair follicles, leading to cicatricial alopecia. The eyelash follicle and meibomian gland (MG) might also be involved in the disease process leading to ocular surface problems. METHODS: In this Cross-sectional case -control study, twenty-three patients with histologically confirmed LPP and 23 healthy controls were recruited in this controlled study. To quantify the signs and symptoms of LPP, we used the Lichen Planopilaris Activity Index. The ophthalmologic examination was performed by the same ophthalmologist at Farabi Eye Hospital. RESULTS: Patients with LPP had a statistically significant lower tear breakup time (worse test outcome) compared with the control (7.1 6 4.1 vs. 9.6 6 4.4; respectively, P = 0.011). Both MG quality score and expressibility were higher in patients with LPP than in control subjects (14.1 6 4.3 vs. 9.3 6 4.4; P = 0.001; 1.5 6 1.0 vs. 0.4 6 0.8; P = 0.001; respectively). The Schirmer test score was not different between groups. A significant but weak correlation was found between the Lichen Planopilaris Activity Index and tear breakup time. Other ophthalmologic examinations including conjunctiva, lid margin shape, intraocular pressure, and funduscopy were normal in patients with LPP. CONCLUSIONS: Patients with LPP, scored worse in ocular surface tests. This finding warrants special scrutiny for dry eye and MG dysfunction in these patients. PMID- 29757850 TI - Corneal Irregular Astigmatism and Curvature Changes After Small Incision Lenticule Extraction: Three-Year Follow-Up. AB - PURPOSE: To evaluate the long-term changes in anterior and posterior corneal irregular astigmatism and curvatures after small incision lenticule extraction (SMILE). METHODS: Fifty eyes of 28 patients underwent SMILE for myopic astigmatism. All procedures were performed using the VisuMax(r) femtosecond laser. A Scheimpflug camera was used for preoperative and 3-year postoperative tomography. Anterior and posterior corneal Fourier parameters (spherical component, regular astigmatism, asymmetry, and irregularity) and curvature data were evaluated and compared within 2 subgroups according to the magnitude of the refractive correction (low myopia group: spherical equivalent (SEQ) >= -6 D; high myopia group: (SEQ) < -6 D). Associations between all studied parameters were examined. RESULTS: Three years postoperatively, an increase in anterior corneal curvatures and Fourier parameters was detected and the results were strongly correlated with the preoperative SEQ, lenticule thickness, and volume. At the posterior cornea, the flattest radius, corneal astigmatism, spherical component, regular astigmatism, and irregularity decreased only in the high myopia group. A correlation was found between changes in posterior astigmatism and changes in anterior radii (R = 0.349, P = 0.014), SEQ (R = 0.396, P = 0.0049), and lenticule thickness (R = -0.414, P = 0.0031). Moreover, changes in posterior corneal irregularity correlated with the changes in anterior and posterior radii (R = 0.3, P = 0.034, and R = 0.449, P = 0.0012, respectively), changes in preoperative SEQ (R = 0.284, P = 0.0477), and lenticule thickness (R = -0.311, P = 0.0298). CONCLUSIONS: Three years after SMILE, there was a reduction of posterior astigmatism in high refractive corrections. This could result in undercorrection in high refractive treatments. Total irregularities increased despite the compensatory effect of the posterior corneal surface. PMID- 29757852 TI - Comparison of Corneal Collagen Cross-Linking Protocols Measured With Scheimpflug Tomography. AB - PURPOSE: To evaluate the effectiveness of corneal collagen cross-linking with Dresden and accelerated protocols to treat keratoconus by Scheimpflug tomography. METHODS: Fifty-eight eyes with manifest keratoconus were measured preoperatively at least twice with the Pentacam. The difference of relevant variables for keratoconus progression (eg, D value, thinnest pachymetry, Kmax) was established. After evident progression, patients underwent corneal cross-linking (29 eyes with the Dresden protocol and 29 eyes with the accelerated protocol). Postoperatively, variables used for defining manifest progression were compared again by measuring the difference between 2 measurements. RESULTS: Preoperatively, the mean D value was 9.6 +/- 4.8 for the Dresden cohort and 8.3 +/- 5.1 for the accelerated cohort. There was no significant difference between both cohorts in terms of the mean preoperative difference in the D value (0.59 +/- 1.7 for the Dresden cohort vs. 0.4 +/- 1.49, P = 1). Postoperatively, however, a significant difference (P < 0.01 for the accelerated corhort) was found (Dresden: -0.47 +/- 0.88 vs. accelerated: 0.04 +/- 0.67). Regression analysis showed that keratoconus progression was significant in both study groups preoperatively (with a significant reduction of corneal thickness and increase in the D value). Postoperative data show an improvement in all observed keratoconus indices in both study groups and stagnation in progression for the accelerated cohort, P = 0.774, for the D value and a regression in manifestation for the Dresden cohort (decrease in the D value, P < 0.01). CONCLUSIONS: Before operative intervention, Scheimpflug imaging showed signs of a progressive disease in all eyes. Both conventional Dresden protocol and accelerated pulsed corneal collagen cross linking techniques effectively stopped this progression. PMID- 29757851 TI - Effect of Posterior Corneal Vesicles on Corneal Endothelial Cell Density and Anisometropic Amblyopia. AB - PURPOSE: To evaluate the effect of corneal vesicles in patients with posterior corneal vesicles (PCV) on corneal endothelial cell (CEC) density and the acquisition of amblyopia. METHODS: In this retrospective study of patients with PCV (18 eyes of 14 patients), CEC density was examined by noncontact specular microscopy during each follow-up examination. Best-corrected visual acuity and the objective refractive error were also examined. RESULTS: Of the 14 total patients, 10 were diagnosed with PCV and 4 were diagnosed with bilateral suspected PCV or posterior polymorphous corneal dystrophy (PPCD), and in all patients, no ocular abnormality other than corneal vesicles was observed. In patients with PCV and patients with bilateral suspected PCV or PPCD, mean CEC density was 1131 +/- 338 and 1095 +/- 492 cells/mm, respectively. In both PCV group and the bilateral suspected PCV or PPCD-group patients who were followed for 164.2 +/- 25.4 months (range: 123-186 months), CEC density tended not to decrease. In patients with PCV, the mean best-corrected visual acuity of the unaffected eyes was significantly higher than that of the affected eyes with corneal vesicles (-0.10 +/- 0.06 and 0.05 +/- 0.13, respectively, P = 0.012). Four of 9 affected eyes (1 eye was excluded because of retinal atrophy) exhibited amblyopia, and all 4 eyes had astigmatism higher than 2 diopters. CONCLUSIONS: Although CEC density of patients with PCV in this study was found to be stable over a long-term follow-up period, strict attention should be given to the possibility of amblyopia in eyes with PCV. PMID- 29757853 TI - Multiplex Polymerase Chain Reaction Assay for Screening of Mycotoxin Genes From Ocular Isolates of Fusarium species. AB - PURPOSE: To identify mycotoxin genes among clinical ocular isolates of Fusarium species and to correlate these with clinical outcomes of Fusarium keratitis. METHODS: Fifty-four clinical isolates of Fusarium were retrieved from the Bascom Palmer Eye Institute Ocular Microbiology Laboratory data bank. Multiplex polymerase chain reactions were run to confirm the identification of Fusarium species [internal transcribed spacer sequence, translation elongation factor 1 alpha (TEF) and beta-tubulin] and to detect the presence of genes encoding production of fumonisin B mycotoxins (FUM1 and FUM8) and trichothecene mycotoxins (deoxynivalenol and nivalenol). The presence or absence of mycotoxins was compared with patient outcomes. RESULTS: Forty-three (79%) of the 54 isolates were confirmed as Fusarium species, by an internal transcribed spacer sequence in 3 (5.6%) and by TEF in 43 (79.6%) of the 54 isolates. Fumonisin biosynthetic gene 1 (FUM1) was detected in 57.4% (n = 31/54) of the Fusarium isolates. No FUM8, deoxynivalenol genes, and nivalenol genes were detected among these in the clinical isolates group. Initial best-corrected visual acuity ranged from 20/25 to 20/80 in the FUM1 gene-negative group and from 20/20 to light perception in the FUM1 gene-positive group. There was no difference in the time to cure between both groups. The presence of FUM1 genes in 5 fungal isolates seemed to be associated with progression to penetrating keratoplasty in the 5 patients from whom the fungi were isolated. Fusarium solani was recovered from all patients requiring penetrating keratoplasty. CONCLUSIONS: Fumonisin B biosynthetic gene 1 may be common among clinical Fusarium isolates and contribute to worse initial visual acuity and high-risk progression to penetrating keratoplasty. PMID- 29757855 TI - Reply. PMID- 29757854 TI - Re: Amniotic Membrane Grafts to Reduce Pterygium Recurrence. PMID- 29757856 TI - Reply. PMID- 29757857 TI - BRCA1-Associated Protein-1 Tumor Predisposition Syndrome in a Patient With Numerous Basal Cell Carcinomas. PMID- 29757859 TI - Nail Brace Application: A Noninvasive Treatment for Ingrown Nails in Pediatric Patients. PMID- 29757860 TI - Confluent Verruca Vulgaris Arising Within Bilateral Eyebrow Tattoos: Successful Treatment With Ablative Laser and Topical 5% Imiquimod Cream. PMID- 29757858 TI - Classification of Foreign Body Reactions due to Industrial Silicone Injection. AB - BACKGROUND: A foreign body reaction (FBR) is a typical tissue response to a biomaterial that has been injected or implanted in human body tissue. There has been a lack of data on the classification of foreign body reaction to silicone injection, which can describe the pattern of body tissue responses to silicone. OBJECTIVE: Determine the foreign body reaction to silicone injection. METHOD: We modified the classification proposed by Duranti and colleagues, which has categorized a FBR to hyaluronic acid injection into a new classification of an FBR to silicone injection. A cohort study of 31 women suffering from silicone induced granulomas on their chin was conducted. Granulomatous tissue and submental skin were stained with hematoxylin-eosin and evaluated. RESULTS: Our data revealed that there were at least 7 categories of FBRs to silicone injection that could be developed. Categories 1 to 4 showed inflammatory activity, and categories 5 to 8 showed tissue repair by fibrosis. CONCLUSION: Using histopathological staining, we are able to sequence the steps of body reactions to silicone injection. Initial inflammatory reaction is then replaced by fibrosis process repairing the damaged tissues. The process depends on the host immune tolerance. PMID- 29757861 TI - Why Do a Fellowship in Advanced Dermatologic Surgery? PMID- 29757862 TI - Surgical Cadaver Curriculum. PMID- 29757863 TI - Efficacy Using a Modified Technique for Tissue Stabilized-Guided Subcision for the Treatment of Mild-to-Moderate Cellulite of the Buttocks and Thighs. AB - BACKGROUND: Cellulite can be significantly improved using vacuum-assisted tissue stabilized-guided subcision (TS-GS). However, the treatment of shallow and linear cellulite has remained problematic. OBJECTIVE: In this retrospective study, we describe a modified technique of vacuum-assisted TS-GS. The aim is to demonstrate that this new limited-release technique is an effective treatment for long ripples and interconnected shallow dimples, which are characteristic of mild-to moderate cellulite. METHODS: Patients with mild-to-moderate cellulite were treated with limited-release vacuum-assisted TS-GS. All subcisions were performed at the 6-mm depth and a minimum of 3 mm between each dimple. Using a 4-point scale, 2 raters graded cellulite improvement on evaluation of prephotographs and postphotographs. RESULTS: A total of 23 female patients were included in this study. The pre- and post-treatment photographs were correctly identified in 22 of the 23 patients (95.6%). The average cellulite improvement was 2.9 of 4 for the buttocks and 2.8 of 4 for the posterior thighs. Global cellulite improvement was reported at 3.1 of 4. CONCLUSION: The results demonstrate that modified, limited release, vacuum-assisted TS-GS can be an effective and safe method for the treatment of long ripples and shallow dimples that are characteristics of mild-to moderate cellulite. PMID- 29757864 TI - Letter to the Editor: Blood-loss Management in Spine Surgery. PMID- 29757865 TI - Reply to the Letter to the Editor: Blood-loss Management in Spine Surgery. PMID- 29757866 TI - Giving constructive feedback-constructively. PMID- 29757867 TI - Damage control: Differentiating incontinence-associated dermatitis from pressure injury. PMID- 29757868 TI - Caring for a patient with a desmoid tumor. PMID- 29757869 TI - End-of-Life Care for Patients With Advanced Ovarian Cancer Is Aggressive Despite Hospice Intervention: A Population-Based Study. AB - OBJECTIVE: To date, few studies have examined end-of-life (EOL) care and healthcare costs for patients with ovarian cancer. We evaluated the effects of hospice care on the quality of EOL care and healthcare costs for patients with ovarian cancer in the final month of life. MATERIALS AND METHODS: We conducted a population-based study and analyzed data from Taiwan's Longitudinal Health Insurance Database, which contains claims information for medical records of patients, healthcare costs, and insurance system exit dates: our proxy for death between 1997 and 2011. RESULTS: A total of 176 women who died of ovarian cancer were investigated. Of these patients, 32 (18.2%) had received hospice care. Univariate analysis revealed that the patients with hospice care (H group) had lower proportions of intensive care unit admission (0% vs 15.3%) and cardiopulmonary resuscitation (0% vs 18.1%). The mean health care cost per person during the final month of life for H group was approximately 5.5% significantly higher than patients without hospice care (non-H group) (US $3121 +/- $376 vs $2957 +/- $347). The effects of hospice care on intensive care unit admission, receipt of cardiopulmonary resuscitation, and more than 1 emergency room visit could not be assessed because no cases of these 3 occurrences were observed among the H group by the multivariate regression model. No significant difference was observed between the H and non-H groups in terms of chemotherapy during the final 2 weeks of life. The H group had higher probabilities for more than 1 hospitalization and death in acute hospitals after adjusting for confounders. CONCLUSIONS: The aggressiveness of EOL cancer care and healthcare costs could not be offset in the final month of life among women with advanced ovarian cancer who received hospice care. The factors of more hospitalizations and dying in hospital warrant further investigation. PMID- 29757870 TI - Changing Clinical Practice: Evaluation of Implementing Recommendations for Opportunistic Salpingectomy in British Columbia and Ontario. AB - OBJECTIVE: The aim of the study was to explore the factors that contributed to the adoption of opportunistic salpingectomies (removal of fallopian at the time of hysterectomy or in lieu of tubal ligation) by gynecologic surgeons in British Columbia (where a knowledge translation initiative took place) and in Ontario (a comparator where no knowledge translation initiative took place). We aimed to understand why the knowledge translation initiative undertaken by OVCARE in British Columbia resulted in such a dramatic uptake in opportunistic salpingectomy. METHODS: We undertook a qualitative evaluation of clinicians' decisions about whether or not they should adopt the practice of opportunistic salpingectomy based on interviews with gynecologic surgeons in British Columbia and Ontario (n = 28). The analysis draws from the Consolidated Framework for Implementation Research. RESULTS: Regional cohesion combined with practice change information exposure and thought leader support were important in explaining differences in adoption levels between participants. The British Columbian knowledge translation campaign was successful because provincial thought leaders exposed gynecologic surgeons to recommendations through multiple sources within a highly socially cohesive environment wherein clinicians felt pressure to adopt the recommendations. In both provinces, high adopters often believed that the workload and surgical risk associated with the adoption was low and the potential benefit-because of limited ovarian cancer detection and treatment options-was high. CONCLUSION: This research points to the important role that local professional networks can play in encouraging clinicians to change their practice by creating a cohesive regional environment where clinicians are repeatedly exposed to important information and supported in their practice change by local thought leaders. PMID- 29757871 TI - Influence of Prognostic Factors on Lymph Node Involvement in Endometrial Cancer: A Single-Center Experience. AB - OBJECTIVE: The requirement for and extent of lymphadenectomy in endometrial cancer is still controversial. Clinicopathological prognostic factors could be helpful to predict lymph node involvement and avoid therefore unnecessary lymphadenectomy. The aim of this study was to investigate which factors can predict lymph node involvement and how lymph node metastases are distributed in the pelvic and para-aortic regions. METHODS: This retrospective analysis was performed by analyzing data from patients with endometrial cancer treated with standard surgery and lymphadenectomy at the Department of Gynecology and Obstetrics of the University Hospital Ulm in 2000 to 2013. RESULTS: One hundred twenty-five patients received pelvic lymphadenectomy with a median of 25 removed nodes, and 111 patients additionally received para-aortic lymphadenectomy with a median of 12 removed nodes. Metastatic lymph nodes were found in 24.8% of the patients, and a multivariate logistic regression showed that lymphovascular space invasion, histological type, and tumor stage significantly and independently predicted lymph node involvement. Of the 111 patients with both pelvic and para aortic lymphadenectomy, 18 (16.2%) patients had metastatic para-aortic nodes, and 3 (2.7%) patients had isolated positive para-aortic lymph nodes without involvement of pelvic lymph nodes. DISCUSSION: Lymphovascular space invasion, histological type, and tumor stage are significant predictors of lymph node involvement in endometrial cancer. In patients at high risk of nodal involvement, lymphadenectomy should be performed systematically up to the renal vein. Large and carefully designed prospective studies are needed to evaluate patient cohorts for which a complete lymphadenectomy provides a survival benefit. In the future, the increasing use of sentinel node biopsy may facilitate a more personalized treatment of patients with endometrial cancer. PMID- 29757872 TI - Pattern of Care, Health Care Disparities, and Their Impact on Survival Outcomes in Stage IVB Cervical Cancer: A Nationwide Retrospective Cohort Study. AB - OBJECTIVE: Although locally advanced cervical cancer can be cured, patients with stage IVB disease have poor prognosis with limited treatment options. Our aim was to describe the pattern of care and analyze health disparity variables that may account for differences in treatment modalities and survival in this population. METHODS: The National Cancer Database was queried for patients diagnosed between 2004 and 2013 with metastatic squamous cell carcinoma or adenocarcinoma of the cervix. Codes representing parenchymal and lymphatic metastasis (beyond the para aortic radiation fields) were used to identify the cohort. Variables included age, race, insurance status, comorbidity, treatment modality, and outcomes. We used Kaplan-Meier methods to compare survival curves and Cox proportional hazards to estimate the association between variables and overall survival (OS). Log-rank method was used to compare Kaplan-Meier curves. RESULTS: There were 4576 patients identified. The majority was white (59.7%); 19.5% were Hispanic, and 9.6% were black. Fifty-one percent had Medicare/Medicaid; 33.7% had private, and 12.5% had no insurance. The majority (56.3%) received chemotherapy (CMT) alone or in combination with radiation therapy (RT) and/or surgery. Median follow-up was 7.3 months (0-124.8 months). Median OS was 11.5 months (10.5-12.5 months). Higher probability of receiving CMT and RT was associated with having private insurance (P < 0.001). Significant prognostic values positively affecting survival on multivariate analysis included black and Asian race, private insurance, comorbidity index of 0, metastatic site at initial presentation (lung), and treatment modality. Patients treated with CMT + RT with or without surgery had significantly better median OS (12 months) compared with those treated with CMT alone (8.3 months), RT alone (4.8 months), or those untreated (2.3 months) (P < 0.001). CONCLUSIONS: Insurance status influences treatment options in patients with distant metastatic cervical cancer. Race, comorbidity index, metastatic site, and suboptimal treatment appear to affect survival outcomes. Regardless of treatment, survival was extremely limited. PMID- 29757873 TI - Management of Vertebral Metastasis in Patients With Uterine Cervical Cancer. AB - AIM: We sought to identify risk factors and management options for uterine cervical cancer (UCC) patients with a vertebral metastasis (VM) treated over the course of 23 years. METHODS: Among 844 UCC patients, 18 were diagnosed with a VM. Thirty-six control patients with UCC but without recurrence were matched to these 18 in terms of stage and histological tumor type using a dependent random sampling method. A logistic regression analysis was used to identify factors prognostic of VM; the results are presented as odds ratios with 95% confidence intervals (CIs). RESULTS: The mean survival time after VM treatment commenced was 12.1 +/- 2.7 months (95% CI, 5.3-12.6 months) in patients who received chemotherapy (CT) and 15.0 +/- 2.3 months (95% CI, 9.7-14.2 months) in those treated via chemoradiotherapy (CRT) (P = 0.566). In patients who underwent CT, the 1- and 2-year survival rates after recurrence were 19.2% and 0%, respectively. However, these figures were 50% and 8.3% in those treated via CRT. Both lymphovascular space invasion and mean corpuscular volume were risk factors for VM. Cox regression analysis showed that these prognostic factors had no effect on survival duration after recurrence. The locations and percentages of vertebra metastasis were as follows: 11.1% lumbar 4, 27.7% lumbar 5, 22.2% lumbar 4-5, 16.7% lumbar 3-4-5, 5.6% lumbar 2-3, 5.6% lumbar 2-3-4, 5.6% lumbar 3-4 5/sacral 1, and 5.6% thoracic 11-12/lumbar 1-2. CONCLUSIONS: We found that patients with lymphovascular space invasion were at high risk of isolated VM and that the survival times after CT and CRT were similar. Because most VMs are seen in the vertebral space within the borders of radiation therapy, borders of external beam radiotherapy should be carefully determined for each patient. PMID- 29757875 TI - Surgery and Platinum/Etoposide-Based Chemotherapy for the Treatment of Epithelioid Trophoblastic Tumor. AB - OBJECTIVE: Epithelioid trophoblastic tumor (ETT) is a rare variant of gestational trophoblastic neoplasia that develops from chorionic-type intermediate trophoblast, simulates carcinoma, presents years after a pregnancy event, is associated with low or normal human chorionic gonadotropin levels, and is relatively resistant to chemotherapy. Our aim was to identify the role of surgery in combination with platinum/etoposide-based chemotherapy in the management of both localized and metastatic ETT. METHODS: A retrospective review was performed of women with ETT treated at a gestational trophoblastic disease center from 2010 to 2016. RESULTS: Five patients were identified who had complete records. Mean age was 38.0 years. Three women presented with abnormal uterine bleeding, 2 women presented with respiratory complaints, and 1 woman was asymptomatic. Two women had no identifiable antecedent pregnancy, 2 women had spontaneous abortions, and 1 woman had a normal term delivery before diagnosis. Four (80%) of 5 women had metastatic pulmonary disease. All 5 women underwent hysterectomy, and 3 women had resection of metastatic pulmonary disease. The 4 women with metastatic disease were also treated with chemotherapy. All 5 women are currently without evidence of disease. CONCLUSIONS: Surgery, including hysterectomy and resection of metastatic disease, is an important component in the treatment of women with ETT. Adjuvant chemotherapy with a platinum/etoposide-containing regimen should be used in women with metastatic disease. All 5 women with ETT in this series were cured using this approach, including the 4 who had metastatic disease. PMID- 29757874 TI - The Clearance of Serum Human Epididymis Protein 4 Following Primary Cytoreductive Surgery for Ovarian Carcinoma. AB - OBJECTIVE: The aim of this study was to examine the clearance of serum human epididymis protein 4 (HE4) in the immediate postoperative period in patients undergoing maximal effort cytoreductive surgery for ovarian carcinoma. METHODS: The study was performed at a tertiary gynecologic oncology center. The surgery was performed by accredited gynecological oncologists. RESULTS: Preoperative and serial postoperative venous blood samples at 4, 8, 24, 48, 72, 96, and 120 hours were taken from 10 sequential patients. Pretreatment HE4 is considered elevated at greater than 70 pmol/L. Human epididymis protein 4 was greater than 70 pmol/L in 7 patients, including all patients with high-grade serous carcinoma. Patients with preoperative elevation of serum HE4 and complete cytoreduction cleared more than 80% of serum HE4 in the first 4 hours and more than 88% within 5 days of surgery. One patient with incomplete cytoreduction of high-grade serous carcinoma had 66% clearance at 4 hours and a plateau thereafter. CONCLUSIONS: Human epididymis protein 4 derived from ovarian carcinoma had a short half-life of less than 4 hours in the circulation when cytoreductive surgery was complete. Sustained low HE4 following surgery could be a useful indicator of the completeness of cytoreduction. Plateau or rise in serum HE4 could suggest persistent disease. Comparison of values on day 1 and day 4 or 5 might have value in assessing the completeness of cytoreduction. PMID- 29757877 TI - Report From the 20th Meeting of the European Society of Gynaecological Oncology (ESGO 2017). AB - This is a report from the 20th Meeting of the European Society of Gynaecological Oncology (ESGO) held in Vienna, Austria on November 4 to 7, 2017. The conference offered state-of-the-art educational sessions and oral and poster abstract presentations. The general sessions throughout the meeting focused not only on prevention, screening, diagnosis, treatment, and translational research but also emerging trends, and current innovations in gynecological cancers were discussed. The ESGO-European Society for Radiotherapy and Oncology-European Society of Pathology guidelines on management of cervical cancers were reported for the first time in public. Here, we highlight the key results of the latest trials for gynecological cancers presented for the first time at the ESGO 2017 Meeting and added great value to the congress scientific level. PMID- 29757878 TI - Retractions in nursing literature: Responsibilities of nurse authors, reviewers, and editors. PMID- 29757879 TI - Hurricane Katrina: A nurse practitioner's experience. AB - Storm preparedness and recovery has shown much improvement since Hurricane Katrina hit Louisiana in 2005, during which more than 1,000 people died. The floodwaters did not recede for weeks. The purpose of this article is to provide readers with information on the lived experience of a nurse practitioner during Hurricane Katrina. Health care providers are not immune from the life-changing effects of a disaster. Readers are provided resources to access disaster preparedness information. PMID- 29757876 TI - A Randomized Trial of Prophylactic Extended Carboplatin Infusion to Reduce Hypersensitivity Reactions in Recurrent Ovarian Cancer. AB - OBJECTIVE: Hypersensitivity with repeated exposure to platinum agents is common and can preclude continued treatment, even in patients with disease that remains platinum sensitive. We sought to compare the effects of prophylactic, extended carboplatin infusion versus standard infusion on the rate of carboplatin hypersensitivity reactions (HSRs) in women with recurrent ovarian cancer. METHODS: This was a single-institution, randomized, nonblinded trial comparing a graded, 3-hour extended infusion of carboplatin with a standard 30-minute infusion in patients with recurrent ovarian cancer who were enrolled from January 2011 to April 2015. The study was designed to detect a decrease in the HSR rate from 20% (standard infusion) to 5% (extended infusion) assuming a type 1 error of 10% and power of 80% using a 1-sided test. RESULTS: Of 146 enrolled patients, 114 were evaluable. Fifteen (13%) had an HSR-11% (6/56) in the extended-infusion and 16% (9/58) in the standard-infusion groups (P = 0.582). Planned treatment completion was achieved in 50 (89%) of 56 patients and 49 (84%) of 58 patients, respectively. Of 25 patients who received single-agent carboplatin, 8 (32%) had an HSR (53% of all patients who had an HSR [8/15]). Of 23 patients who received carboplatin with gemcitabine, 4 (17%) had an HSR (27% of all patients who had an HSR [4/15]). Of 8 patients who received carboplatin with paclitaxel, 3 (38%) had an HSR (20% of all patients who had an HSR [3/15]). There were no HSRs with pegylated liposomal doxorubicin, the most commonly given concurrent chemotherapy (46% of all patients). CONCLUSIONS: A prophylactic, extended carboplatin infusion was not associated with a decreased HSR rate. The overall low HSR rate suggests that premedication may help reduce HSRs. PMID- 29757880 TI - Leveraging health care reform to accelerate nurse practitioner full practice authority. AB - BACKGROUND AND PURPOSE: Since development of the nurse practitioner (NP) role, NPs have been advocating for policy allowing them to practice to the full extent of their training. The aim of this research was to determine whether passage of the Affordable Care Act (ACA) had an impact on expansion of NPs' scope of practice. METHODS: This was a retrospective descriptive study of NPs' scope of practice legislation from 1994 to 2016 using regulatory theory. Data sources included annual reports on NP legislation and state-level legislative and media coverage. CONCLUSIONS: Eight states adopted full practice authority (FPA) from 2011 to 2016, representing a two-fold increase compared with the previous 10 years. Seven states adopted Medicaid expansion. Nursing interest groups and politicians shaped their argument in favor of FPA around the increasingly insured population because of the ACA, provider shortages, and rural health care access issues. IMPLICATIONS FOR PRACTICE: Shaping the discourse of FPA beyond the benefits to the NP profession makes way for broader political interest and participation. Although the future of the ACA is unknown, as the 28 states without FPA continue to advocate for legislative change, they could benefit from the strategies of these newly adapted FPA states. PMID- 29757881 TI - Health and educational implications of prematurity in the United States: National Survey of Children's Health 2011/2012 data. AB - BACKGROUND AND PURPOSE: Preterm birth is a significant public health issue, with children born prematurely experiencing educational and health difficulties throughout childhood. The aim of the descriptive secondary data analysis was to compare health implications and educational experiences in children born prematurely compared with children born at term. METHODS: The 2011/2012 National Survey of Children's Health data set was explored using separate chi-square tests of homogeneity to investigate differences in the occurrence of chronic health conditions and educationally relevant outcomes: individualized family services plan/individualized education plan (IFSP/IEP), and grade repetition between children born prematurely compared with those born at term. CONCLUSIONS: The six most frequently occurring chronic health conditions that disproportionally affected children born prematurely include the following: attention deficit disorder/attention deficit hyperactive disorder (odds ratio [OR], 1.59), anxiety (OR, 1.63), asthma (OR, 1.7), learning disability (OR, 2.07), speech problems (OR, 2.27), and developmental delay (OR, 3.17). Preterm birth negatively affects the educational experience of CBP as measured by increased report of IFSP/IEP and repeated grades across all age categories. IMPLICATIONS FOR PRACTICE: All health care providers have an important role in preventing preterm birth and in supporting the children and families affected by preterm birth. Appreciation of the incidence and prevalence of the health conditions and educational difficulties associated with preterm birth is essential for facilitating access to appropriate resources. Beyond patient interactions, these modifiable yet additive factors should inform health policy and planning. PMID- 29757882 TI - American Association of Nurse Practitioners National Nurse Practitioner sample survey: Update on acute care nurse practitioner practice. AB - BACKGROUND AND PURPOSE: Data from national surveys on the practice of nurse practitioners (NPs) provides valuable information on aspects of practice, demographic characteristics of providers and patients, plans for continued employment, and role satisfaction. The American Association of Nurse Practitioners (AANP) has been conducting the AANP Sample Survey since 1988. METHODS: The most recent AANP Sample Survey was conducted in 2016 with a random stratified survey of 40,000 NPs. Data were collected bimodally, by internet and mail surveys. Responses were received from 3,970 respondents (9.9% response rate), with 335 respondents reporting NP certification in acute care as adult gerontology acute care and/or pediatric acute care. RESULTS: Almost all acute care nurse practitioners (ACNPs) reported that they were clinically practicing in 2016 (99.3%), with the top three areas encompassing cardiovascular (20.5%), critical care (12.1%), and hospitalist roles (6.3%). More than 1 in 4 ACNPs worked in a hospital inpatient setting, with 16.1% reporting work in a hospital outpatient clinic, 7.7% in a private group practice, 6.5% at a public university, and some in combined roles covering both inpatient and outpatient care, or on consultation service or specialty-based teams. On average, 34.1% of the patients ACNPs saw were between the ages of 66 and 85 years, and 11.2% were 85 years and older. The top 3 medication classes in which ACNPs regularly prescribe were diuretics (31.9%), analgesic narcotics (31.2%), and antibiotics (27.3%). Majority (88%) report satisfaction with the role, and approximately one third (31.1%) expect to continue to work in their current practice for more than 10 years. IMPLICATIONS FOR PRACTICE: The findings of the 2016 AANP National NP Sample Survey data related to ACNP practice identify expansion of work settings, practice consistent with acute care scope of practice, role satisfaction, and intent to continue working. Continued monitoring of practice components and employment is indicated to track ACNP workforce trends. PMID- 29757883 TI - Blended tube feeding prevalence, efficacy, and safety: What does the literature say? AB - BACKGROUND AND PURPOSE: For most of human history, physicians used blended whole foods for patients who are unable to eat by mouth. However, by the 1960s and 1970s, advances in enteral nutrition resulted in the gradual displacement of blenderized tube feedings (BTFs) with commercial formulas. There are advantages and disadvantages to commercial formulas and BTFs. The purpose of this article was to review the literature for the incidence of blended tube feeding use and its safety, efficacy, and implications for clinical practice. METHODS: A search of the scientific literature in PubMed, CINAHL, Cochrane, ProQuest, and Ovid was conducted using the keywords "blenderized tube feeding" and "blended tube feeding." Articles were divided into two categories: 1) frequency of use and experiences of BTF in patients or caregivers and health care providers and 2) safety/efficacy studies. CONCLUSIONS: The literature review shows a rising interest in BTF, with more research on efficacy indicated. IMPLICATIONS FOR PRACTICE: The use of BTF is primarily patient or caregiver driven. Blenderized tube feeding requires oversight by health care providers just as commercial formulas. Health care providers should be aware of the use of BTF and the effect it can have on different patient populations regarding content, cost, safety, and efficacy in the clinical and home settings. PMID- 29757885 TI - Maximizing your "nutrition minute": Bridging nutritional gaps across the life span. AB - BACKGROUND AND PURPOSE: Poor diet quality has been associated with increased mortality and an increased risk of chronic disease. Given the shortfalls in the typical American diet and the prevalence of nutrition-related chronic disease among US adults, the need for nutrition education is paramount. Nurse practitioners (NPs) are well placed to provide basic nutrition counseling but often face challenges to making this a reality. In a typical office visit, the time available to discuss diet and nutrition can be as little as one minute or less. METHODS: Nutritional issues of concern facing specific age and risk groups are reviewed. The "Nutrition Minute," a tool comprising 5 questions that enable NPs to identify patients at higher risk of nutritional shortfalls, has been developed. CONCLUSIONS: Nutrition counseling includes discussion of not only fat, carbohydrate, and protein intake, but also micronutrient intake. Although a food first approach to nutrition is preferred, nutritional shortfalls exist even in the best diets. Supplementation with a multivitamin is an effective approach to bridge many nutritional gaps and can be recommended for many patients with poor diet quality. In addition to shortfalls apparent from a patient's diet, nutritional needs change across the life span (e.g., women of childbearing age and older persons) and in those with certain medical conditions such as diabetes and obesity. IMPLICATIONS FOR PRACTICE: Although NPs clearly have an important role to play in the nutrition management of many patients, they should work in collaboration with registered dietitians wherever possible, especially for medical nutrition therapy in those patients needing specialist counseling, such as those with diabetes, obesity, cardiovascular disease, and renal disease. PMID- 29757884 TI - Blended tube feeding prevalence, efficacy, and safety: What does the literature say? PMID- 29757886 TI - Perioperative lidocaine infusions for the prevention of chronic postsurgical pain: a systematic review and meta-analysis of efficacy and safety. AB - Chronic postsurgical pain (CPSP) occurs in 12% of surgical populations and is a high priority for perioperative research. Systemic lidocaine may modulate several of the pathophysiological processes linked to CPSP. This systematic review aims to identify and synthesize the evidence linking lidocaine infusions and CPSP. The authors conducted a systematic literature search of the major medical databases from inception until October 2017. Trials that randomized adults without baseline pain to perioperative lidocaine infusion or placebo were included if they reported on CPSP. The primary outcome was the presence of procedure-related pain at 3 months or longer after surgery. The secondary outcomes of pain intensity, adverse safety events, and local anesthetic toxicity were also assessed. Six trials from 4 countries (n = 420) were identified. Chronic postsurgical pain incidence was consistent with existing epidemiological data. Perioperative lidocaine infusions significantly reduced the primary outcome (odds ratio, 0.29; 95% confidence interval, 0.18-0.48), although the difference in intensity of CPSP assessed by the short-form McGill Pain Questionnaire (4 trials) was not statistically significant (weighted mean difference, -1.55; 95% confidence interval, -3.16 to 0.06). Publication and other bias were highly apparent, as were limitations in trial design. Each study included a statement reporting no adverse events attributable to lidocaine, but systematic safety surveillance strategies were absent. Current limited clinical trial data and biological plausibility support lidocaine infusions use to reduce the development of CPSP without full assurances as to its safety. This hypothesis should be addressed in future definitive clinical trials with comprehensive safety assessment and reporting. PMID- 29757887 TI - Lidocaine infusions and preventative analgesia: can the answer to our prayers be hiding right under our noses? PMID- 29757888 TI - CTCA Image Quality Improvement by Using Snapshot Freeze Technique Under Prospective and Retrospective Electrocardiographic Gating: Erratum. PMID- 29757891 TI - Spinal Epidural Abscess in an Infant Presenting as Fever and Respiratory Distress. AB - A 9-month-old healthy female presented during winter to the emergency department with a chief complaint of fever and prominent respiratory symptoms. She was discharged on oseltamivir with a presumptive diagnosis of influenza. She returned to the emergency department 2 days later with continued fever and more upper respiratory symptoms. She was admitted for intravenous hydration to the observation unit with a diagnosis of viral illness (with viral testing that returned positive for adenovirus) and dehydration. When her high fevers continued, bloodwork that was concerning for leukocytosis, elevated inflammatory markers, and elevated alkaline phosphatase was obtained. During her workup for fever, a full body magnetic resonance imaging was performed, which revealed the diagnosis of a C3 to L5 spinal epidural abscess. This case demonstrates the difficulty of making this important diagnosis in a preverbal child presenting with a concurrent virus during winter viral season. PMID- 29757890 TI - Pediatric Carbon Monoxide Poisoning in Southern Israel: A Cross-Sectional Study. AB - OBJECTIVES: This study aimed to describe the epidemiology and clinical burden of unintended carbon monoxide (CO) poisoning among children in the Negev region of southern Israel. METHODS: This was a cross-sectional retrospective study of CO poisoning patients admitted to Soroka University Medical Center in 2011 through 2015. RESULTS: Overall, 43 cases of CO poisoning were recorded among children younger than 18 years. Five patients died, all upon admission. Poisoning due to smoke "per se" and due to CO emitted from heating devices were responsible for 28 (65.1%) and 14 (32.6%) cases, respectively. Eight (18.6%) patients suffered from convulsions, and 13 (43.3%) of 30 evaluable patients complained of headaches. Twenty-two (51.2%) were found unconscious in the field, and 7 (16.3%) were unconscious at examination at the emergency department. The average carboxyhemoglobin level on admission was 10.5% +/- 10.4% (level ranging from 0.1% to 46.2%). Treatment included oxygen in 34 patients (79%) and hyperbaric oxygen therapy in 8 patients (19%). No differences were found between Bedouin and Jewish children in sex, age, residence area, source of CO poisoning, symptoms severity, and need for hyperbaric oxygen therapy. More patients with exposure to water heating devices were older than 4 years, lived in villages, and were diagnosed as having loss of consciousness in the field compared with those exposed to smoke inhalation. CONCLUSIONS: Carbon monoxide poisoning in children is frequent in southern Israel. Education about prevention, implementation of safer standards for home heating systems, and government supervision are required management strategies to decrease the CO poisoning incidence in southern Israel. PMID- 29757892 TI - Exposures to Single-Use Detergent Sacs Reported to a Statewide Poison Control System, 2013-2015. AB - BACKGROUND: Single-use detergent sacs (SUDSs) represent a relatively new household hazard to children. Brand differences and packaging changes may contribute to differential risks with accidental exposure. We sought to identify high-risk features from SUDS exposures in children and to assess whether product packaging changed trends in SUDS exposures reported to poison centers. METHODS: In this institutional review board-approved, retrospective chart review of SUDS exposures from January 2013 to August 2015, deidentified case records of a large statewide poison control system were extracted and analyzed for clinical associations and trends. Clinical and demographic data were gathered, and outcomes were analyzed for differences by brand type, presenting complaints, and occurrence in relation to SUDS packaging changes. RESULTS: There were 3502 SUDS exposures, with 3343 (95%) in children 5 years or younger. Metabolic, central nervous system, and pulmonary effects were significantly associated with moderate or severe outcome (P < 0.05). Forty patients received invasive procedures such as endoscopy, bronchoscopy, and/or endotracheal intubation, and more than half had mucosal lesions discovered by the diagnostic procedure. The presence of stridor, wheezing, drooling, lethargy, and exposure to the brand All Mighty Pacs were all significant predictors of moderate or severe outcome (P < 0.05). After the implementation of packaging changes, there was a transient decline in the number of exposures to the Tide Pods product. CONCLUSION: Central nervous system and respiratory effects as well as certain brand types predict serious outcomes from SUDS exposures. Manufacturing changes had a brief beneficial effect on the volume of SUDS exposures reported between 2013 and 2015. PMID- 29757889 TI - Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma. AB - In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma. PMID- 29757893 TI - Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation. AB - BACKGROUND: Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation. METHODS: This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders. RESULTS: Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation. CONCLUSION: Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher. PMID- 29757895 TI - A Novel Technique in the Treatment of Lymphoceles After Renal Transplantation: C Arm Cone Beam CT-Guided Percutaneous Embolization of Lymphatic Leakage After Lymphangiography. AB - BACKGROUND: We aimed to evaluate the efficacy of percutaneous embolization after lymphangiography using C-arm cone-beam computed tomography (CBCT) performed at the site of lymphatic leakage in patients with postrenal transplant lymphocele. METHODS: Between July 2014 and August 2017, 13 patients not responding to percutaneous ethanol sclerotherapy and conservative treatment for recurrent lymphocele after renal transplant were included. The mean age of the patients was 56.38 +/- 9.91 (range, 36-70) years, and it comprised 9 men and 4 women. All patients underwent intranodal lymphangiography. C-arm CBCT-guided percutaneous embolization was performed in patients with confirmed lymphatic leakage. Patients who had no lymphatic leakage underwent drainage with fibrin glue injection. RESULTS: Lymphatic leakage was observed in 9 patients after lymphangiography, and they underwent CBCT-guided percutaneous N-butyl-2-cyanoacrylate embolization. The volume of lymphatic drainage reduced to less than 10 mL in 8 patients. One patient who was not responding to embolization was treated surgically, after percutaneous drainage and fibrin glue injection. Lymphatic leakage was not observed in 4 patients after lymphangiography. Of these, 3 patients showed a reduction in the amount of lymphatic drainage after lymphangiography. All 4 patients underwent percutaneous drainage and fibrin glue injection. One patient did not respond to the treatment and was treated surgically. Prelymphangiography and postlymphangiography and embolization, the volume of lymphatic drainage was 113.07 +/- 21.75 mL, and 53.84 +/- 30.96 mL, respectively, and statistically significant decrease was detected (P < 0.005). CONCLUSIONS: Lymphangiography and CBCT-guided percutaneous embolization procedures might be an effective treatment method for patients with lymphocele refractory to treatment. PMID- 29757894 TI - Immunosuppression Is Associated With Clinical Features and Relapse Risk of B Cell Posttransplant Lymphoproliferative Disorder: A Retrospective Analysis Based on the Prospective, International, Multicenter PTLD-1 Trials. AB - BACKGROUND: Current guideline recommendations for immunosuppression reduction after diagnosis of posttransplant lymphoproliferative disorder (PTLD) include stopping antimetabolites, reducing calcineurin inhibitors, and maintaining corticosteroids. However, the effect of immunosuppression on PTLD relapse risk after up-to-date therapy is unclear. METHODS: This is a retrospective analysis of immunosuppression, patient baseline characteristics, and relapse risk measured as landmark time to progression (TTP) starting 1 year after start of therapy in 159 patients with B cell PTLD after solid organ transplantation treated in the prospective, international, multicenter PTLD-1 trials with either sequential treatment (rituximab followed by cyclophosphamide (CHOP-21 chemotherapy) 750 mg/m intravenously [IV] day (d) 1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (maximum, 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days) or risk stratified sequential treatment (rituximab followed by rituximab or rituximab (R CHOP-21 immunochemotherapy) 375 mg/m IV day (d) 1, cyclophosphamide 750 mg/m IV d1, doxorubicin 50 mg/m IV d1, vincristine 1.4 mg/m (max. 2 mg) IV d1, and prednisone 50 mg/m PO d1-5, every 21 days). RESULTS: Patient baseline characteristics at diagnosis of PTLD differed significantly depending on immunosuppression before diagnosis. Compared with immunosuppression before diagnosis, significantly fewer patients received an antimetabolite or a calcineurin inhibitor (CNI) after diagnosis of PTLD. Relapse risk measured as landmark TTP was significantly higher for patients on corticosteroids compared to all others (P = 0.010) as well as for patients on ciclosporin compared with those on tacrolimus (P = 0.002), but similar for those on antimetabolites compared with all others (P = 0.912). In a Cox regression analysis of landmark TTP, corticosteroid-containing immunosuppression after diagnosis of PTLD (P = 0.002; hazard ratio, 11.195) and age (P = 0.001; hazard ratio, 1.076/year) were identified as independent, significant risk factors for PTLD relapse. CONCLUSIONS: In the prospective PTLD-1 trials, corticosteroid use after diagnosis of PTLD is associated with an increased risk of relapse, whereas the use of antimetabolites is not. These findings require prospective validation. PMID- 29757896 TI - Response to Commentary. PMID- 29757897 TI - Coagulation Defects in the Cirrhotic Patient Undergoing Liver Transplantation. AB - Patients with cirrhosis undergoing liver transplantation have unique challenges with regard to the prevention and management of thrombosis and hemorrhage. Patients with cirrhosis have an unstable balance of the coagulation system due to defects in both prothrombotic and antithrombotic components. These changes make laboratory monitoring challenging, prophylaxis against bleeding and thrombosis controversial, and therapy for the same uncertain. When cirrhotic patients undergo liver transplantation, they frequently have significant transfusion requirements. Emerging evidence may help aid in predicting which recipients will have the greatest blood product requirements, but the ideal blood product regimen to support them through the surgical procedure remains elusive. After these patients receive a liver they are at risk for both venous and arterial thrombotic complications. Unique to liver transplantation is the possibility of acquiring an inherited defect in coagulation, most commonly leading to a predisposition to thrombosis. Further high-quality prospective studies focusing on the management of cirrhotic patients are needed to better guide clinicians. PMID- 29757898 TI - Development of a Predictive Model for Deceased Donor Organ Yield. PMID- 29757899 TI - Determination of Minimal Hemoglobin Level Necessary for Normothermic Porcine Ex Situ Liver Perfusion. AB - BACKGROUND: In current studies of ex situ liver perfusion there exists considerable variability in perfusate composition, including the type of oxygen carrier. Herein, we aim to clarify the minimal hemoglobin level necessary during normothermic porcine ex situ liver perfusion. METHODS: Livers procured from 35 to 45 kg domestic pigs were connected to our experimental ex situ circuit (n = 10). In the treatment group, perfusate was sequentially diluted hourly to predetermined hemoglobin levels. At the end of each hemoglobin dilution, perfusate samples were analyzed for liver transaminases, lactate dehydrogenase (LD), total bilirubin, and lactate levels. Liver oxygen consumption was measured. In the control group, livers were perfused continually for a duration of 24 hours at target hemoglobin levels of 30 and 20 g/L. RESULTS: Rising liver transaminases, significantly higher lactate (P < 0.001), and LD levels (P < 0.001) were noted at lower perfusate hemoglobin levels in the treatment group. Liver oxygen utilization (P < 0.001) and hepatic artery oxygen delivery (P < 0.001) were significantly lower at lower hemoglobin levels, whereas liver vessel resistance remained relatively constant. Histology demonstrated increasing parenchymal damage at lower hemoglobin levels. In control livers, higher perfusate transaminases, higher lactate, and LD levels were noted at a perfusion hemoglobin level of 20 g/L. CONCLUSIONS: Ex situ liver function decompensated during perfusion between a mean hemoglobin level of 30 to 20 g/L, as evidenced by notably rising lactate and LD levels. This study demonstrates optimal hemoglobin concentration during normothermic ex situ liver perfusion to ensure a fully metabolically functioning graft. PMID- 29757900 TI - Detection of Complement-binding Donor-specific Antibodies, Not IgG-antibody Strength Nor C4d Status, at Antibody-mediated Rejection Diagnosis Is an Independent Predictor of Kidney Graft Failure. AB - BACKGROUND: Antibody-mediated rejection (AMR) remains associated with reduced kidney graft survival and no clear prognostic marker is available. METHODS: We investigated whether donor-specific antibodies (DSA) ability to bind C1q in comparison with AMR C4d status, both indirect signs of complement activation, improve risk stratification at time of AMR. Hence, among 467 patients in whom 1 or more graft biopsies were performed between 2008 and 2015, we included 56 with AMR according to Banff '15 criteria. Using concurrent sera, we prospectively identified DSA by single-antigen beads (IgG and C1q) assays. RESULTS: Antibody mediated rejection C4d (+) (n = 28) was associated with preformed DSA (P = 0.007), whereas DSA C1q (+) (n = 25) cases had stronger IgG-DSA (P < 0.001). At AMR, graft function was similar between DSA C1q groups, but in the first year after, it improved in DSA C1q (-), whereas a steady decline was observed in DSA C1q (+) cases, remaining significantly lower from 1 year until 4 years after AMR. DSA C1q (+) was significantly associated with reduced graft survival (P = 0.021), whereas AMR C4d (+) was not (P = 0.550). Importantly, a similar negative impact of DSA C1q (+) on graft survival was observed within AMR C4d (+) (P = 0.040) and (-) (P = 0.036), cases. In multivariable analysis, DSA C1q (+) (hazard ratio, 3.939, P = 0.005) and de novo DSA (hazard ratio, 4.409, P = 0.033) were independent predictors of graft failure, but stronger IgG-DSA was not. Similar results were obtained considering C1q-DSA and IgG-DSA strength as continuous variables. CONCLUSIONS: C1q-DSA assessment at AMR can be a valuable tool in detecting patients with higher risk of graft failure. PMID- 29757901 TI - Revascularization Time in Liver Transplantation: Independent Prediction of Inferior Short- and Long-term Outcomes by Prolonged Graft Implantation. AB - BACKGROUND: Strategies for successful transplantation are much needed in the era of organ shortage, and there has been a resurgence of interest on the impact of revascularization time (RT) on outcomes in liver transplantation (LT). METHODS: All primary LT performed in Birmingham between 2009 and 2014 (n = 678) with portal reperfusion first were stratified according to RT (<44 minutes vs >=44 minutes) and graft quality (standard liver graft [SLG], Donor Risk Index < 2.3 vs marginal liver graft [MLG], Donor Risk Index >= 2.3). RESULTS: Revascularization time of 44 minutes or longer resulted in significantly greater incidence of early allograft dysfunction (EAD) (29% vs 47%, P < 0.001), posttransplant acute kidney injury (AKI) (39% vs 60%, P < 0.001), and new-onset AKI (37% vs 56%, P < 0.001), along with poor long-term outcome (3-year graft survival 92% vs 83%, P = 0.001; 3 year patient survival 87% vs 79%, P = 0.004). On multivariable analysis, RT >= 44 was a significant independent predictor of EAD, renal dysfunction, and overall graft survival, but not patient survival. The cumulative effect of prolonged revascularization in marginal grafts (MLG) resulted in the worst transplant outcome compared with all other groups, which could be mitigated by rapid revascularization (SLG, SLG, MLG vs MLG; EAD 24%, 39%, 39% vs 69%; AKI 32%, 46%, 51% vs 70%; 3-year graft survival 94%, 87%, 88% vs 70%, respectively; each P < 0.001). Factors associated with lack of abdominal space, larger grafts, and surgical skills were predictive of RT >= 44. CONCLUSIONS: Shorter graft revascularization is a protective factor in LT, particularly in the setting of graft marginality. Careful graft-recipient matching and emphasis on surgical expertise may aid in achieving better outcomes in LT. PMID- 29757902 TI - Differential Impact of T-bet and IFNgamma on Pancreatic Islet Allograft Rejection. AB - BACKGROUND: T cell-mediated graft rejection is mostly correlated with potent Th1 responses. However, because IFNgamma mice reject their graft as efficiently as wild-type (WT) mice, the exact contribution of IFNgamma and its transcription factor T-bet remains a matter of debate. Here, we address this question in the context of pancreatic islet allograft to better inform the molecular pathways that hampers islet survival in vivo. METHODS: Pancreatic islets from BALB/c mice were transplanted in WT, IFNgamma, or T-bet C57BL/6 mice. Graft survival and the induction of effector and cytotoxic T-cell responses were monitored. RESULTS: Rejection of fully mismatched islet allografts correlated with high expression of both IFNgamma and T-bet in WT recipients. However, allogeneic islets were permanently accepted in T-bet mice, in contrast to IFNgamma hosts. Long-term survival correlated with decreased CD4 and CD8 T-cell infiltrates, drastically reduced donor-specific IFNgamma and tumor necrosis factor tumor necrosis factor alpha responses and very low expression of the cytotoxic markers granzyme B, perforin, and FasLigand. In addition, in vitro and in vivo data pointed to an increased susceptibility of T-bet CD8 T cell to apoptosis. These observations were not reported in IFNgamma mice, which have set up compensatory effector mechanisms comprising an increased expression of the transcription factor Eomes and cytolytic molecules as well as tumor necrosis factor alpha-mediated but not IL-4 nor IL-17-mediated allogeneic responses. CONCLUSIONS: Anti-islet T-cell responses require T-bet but not IFNgamma-dependent programs. Our results provide new clues on the mechanisms dictating islet rejection and may help refine the therapeutic/immunosuppressive regimens applied in diabetic patients receiving islets or pancreas allografts. PMID- 29757904 TI - Early and Late Hepatitis B Reactivation After IFN- or DAA-based Therapy of Recurrent Hepatitis C in Anti-HBc-positive Liver Transplant Recipients. PMID- 29757905 TI - Caspase Inhibition: Optimizing Grafts for Transplantation. PMID- 29757906 TI - Preventing Antibody-mediated Rejection During Transplantation: The Potential of Tfr Cells. PMID- 29757908 TI - Primary Graft Dysfunction: The Devil is in the details. PMID- 29757909 TI - Live Donor Kidney Transplantation: Altruism Alone Is Not Always Enough! PMID- 29757903 TI - Contemporary Strategies and Barriers to Transplantation Tolerance. AB - The purpose of this review is to discuss immunologic tolerance as it applies to solid organ transplantation and to identify barriers that hinder the achievement of this long-term goal. First, the definition of tolerance and an introduction of mechanisms by which tolerance exists or can be achieved will be discussed. Next, a review of contemporary attempts at achieving transplant tolerance will be described. Finally, a discussion of the humoral barriers to transplantation tolerance and potential ways to overcome these barriers will be presented. PMID- 29757910 TI - ISHLT Primary Graft Dysfunction incidence, risk factors and outcome: a UK National Study. AB - BACKGROUND: Heart transplantation (HTx) remains the most effective long-term treatment for advanced heart failure. Primary graft dysfunction (PGD) continues to be a potentially life-threatening early complication. In 2014, a consensus statement released by ISHLT established diagnostic criteria for PGD. We studied the incidence of PGD across the UK. METHODS: We analysed the medical records of all adult patients who underwent heart transplantation between October 2012 October 2015 in the 6 UK heart transplant centers Preoperative donor and recipient characteristics, intraoperative details and posttransplant complications were compared between the PGD and non PGD groups using the ISHLT definition. Multivariable analysis was performed using logistic regression. RESULTS: The incidence of ISHLT PGD was 36%. Thirty-day all-cause mortality in those with and without PGD was 31(19%) vs 13(4.5%) (p=0.0001). Donor, recipient and operative factors associated with PGD were: recipient diabetes mellitus (p=0.031), recipient preoperative BIVAD(p<0.001) and preoperative ECMO (p=0.023), female donor to male recipient gender mismatch(p=0.007) older donor age (p=0.010) and intracerebral haemorrhage/thrombosis in donor (p=0.023). Intra-operatively, implant time (p=0.017) and bypass time(p<0.001) were significantly longer in the PGD cohort. Perioperatively, patients with PGD received more blood products (p<0.001). Risk factors identified by multivariable logistic regression were donor age (p=0.014), implant time (p=0.038), female: male mismatch (p=0.033), recipient diabetes (p=0.051) and preoperative VAD/ECMO support (p=0.012), CONCLUSION: This is the first national study to examine the incidence and significance of PGD after heart transplantation using the ISHLT definition. PGD remains a frequent early complication of heart transplantation and is associated with increased mortality. PMID- 29757911 TI - Caspase Inhibition During Cold Storage Improves Graft Function and Histology in a Murine Kidney Transplant Model. AB - BACKGROUND: Prolonged cold ischemia is a risk factor for delayed graft function of kidney transplants, and is associated with caspase-3-mediated apoptotic tubular cell death. We hypothesized that treatment of tubular cells and donor kidneys during cold storage with a caspase inhibitor before transplant would reduce tubular cell apoptosis and improve kidney function after transplant. METHODS: Mouse tubular cells were incubated with either dimethyl sulfoxide (DMSO) or Q-VD-OPh during cold storage in saline followed by rewarming in normal media. For in vivo studies, donor kidneys from C57BL/6 mice were perfused with cold saline, DMSO (vehicle), or QVD-OPh. Donor kidneys were then recovered, stored at 4 degrees C for 60 minutes, and transplanted into syngeneic C57BL/6 recipients. RESULTS: Tubular cells treated with a caspase inhibitor had significantly reduced capsase-3 protein expression, caspase-3 activity, and apoptotic cell death compared with saline or DMSO (vehicle) in a dose-dependent manner. Treatment of donor kidneys with a caspase inhibitor significantly reduced serum creatinine and resulted in significantly less tubular cell apoptosis, BBI, tubular injury, cast formation, and tubule lumen dilation compared with DMSO and saline-treated kidneys. CONCLUSIONS: Caspase inhibition resulted in decreased tubular cell apoptosis and improved renal function after transplantation. Caspase inhibition may be a useful strategy to prevent cold ischemic injury of donor renal grafts. PMID- 29757913 TI - Association Between Muscle Wasting and Muscle Strength in Patients WHO Developed Severe Sepsis and Septic Shock. AB - PURPOSE: To evaluate the association between the rectus femoris cross-sectional area (RFCSA) and the muscular strength obtained at the bedside in patients forwarded to the intensive care unit (ICU) for severe sepsis and septic shock. METHODS: A prospective cohort study. RFCSA was assessed by ultrasound on the following day of the ICU admission and monitored during hospitalization. The patients performed clinical tests of muscle strength (Medical Research Council (MRC) scale and handgrip dynamometry), when they could understand the verbal commands of the examiners. RESULTS: In 37 patients hospitalized for sepsis there was a significant decline in RFCSA of 5.18 (4.49-5.96)cm on the 2nd day of ICU for 4.37 (3.71-5.02)cm at hospital discharge. Differently, the handgrip strength showed an increase from the awakening of 12.00 (7.00-20.00)Kgf to 19.00 (14.00 26.00)Kgf until hospital discharge. Patients in mechanical ventilation had a greater tendency to decline in the RFCSA compared to patients who did not receive mechanical ventilation, however without being significant (p = 0.08). There was a negative association between RFCSA delta (2nd day of ICU - ICU discharge) and handgrip strength (r = 0.51, p < 0.05), and a male and SOFA score positive association with the RFCSA delta. CONCLUSION: There was an association of RFCSA with clinical muscle strength tests. In addition, it has been shown that sepsis can lead to short-term muscle degradation, regardless of whether they are submitted to mechanical ventilation or not. PMID- 29757912 TI - Dysfunction of Iron Metabolism and Iron-Regulatory Proteins in the Rat Hippocampus After Heat Stroke. AB - Heat stroke, the most serious type of heat illness, refers to the presence of hyperthermia (core temperature >40 degrees C), accompanied by central nervous system dysfunction. The hippocampus is a particularly vulnerable region in the early stage of heat stroke. Increasing evidence suggests that dysregulation of brain iron metabolism is involved in many neurodegenerative diseases. However, whether heat stroke causes dysfunction of iron metabolism, as well as iron regulatory proteins, in the hippocampus remains unknown. The present study was conducted to explore the effects on spatial learning and memory, as well as iron content, ferroportin 1 (Fpn1), and hepcidin expression in the hippocampus after heat stroke in rats. Compared with the Sham group, learning ability and memory declined in rats after heat stroke. Iron concentration was significantly increased in the hippocampus. Expression of Fpn1 protein significantly decreased in the hippocampus, while expression of hepcidin increased. Interestingly, Fpn1 mRNA expression in the hippocampus increased. Our data thereby indicate that heat stroke can decrease learning ability and memory in rats. The mechanism may be related to changes of iron levels, as well as Fpn1 and hepcidin expression, in the hippocampus. Furthermore, hepcidin may rapidly decrease cellular Fpn1 protein levels, even under conditions of iron loading, indicating that hepcidin is a more dominant regulator of Fpn1 than is iron. PMID- 29757914 TI - Peer review and journal quality. PMID- 29757916 TI - Filling the gaps: Preparing nurse practitioners for hospitalist practice. AB - Over the last 20 years, the emergence of the hospitalist has changed the face of medicine. Hospitalists may serve as either general or specialty-focused providers caring for acutely ill patients in the hospital setting. As the demands and constraints of hospital-specific patient management have continued to grow, an increased need for inclusion of nurse practitioners (NP) into current hospitalist staffing models has occurred. A hospitalist-focused educational model has been developed to better prepare NP students for a variety of hospitalist roles after graduation. A hospitalist focused masters-level curriculum is discussed, as well as opportunities for advanced hospitalist education with post-graduate opportunities. PMID- 29757917 TI - Nurse practitioners' completion of Physician Orders for Scope of Treatment forms in West Virginia: A secondary analysis of 12 months of data from the state registry. AB - BACKGROUND AND PURPOSE: Advanced care planning documents, such as the Physician Orders for Life-Sustaining Treatment (POLST), require authorized medical provider signatures; only recently have nurse practitioners (NPs) been authorized to sign these forms. Recent legislation in West Virginia (WV) granting NPs signatory authority on POLST forms and the creation of a statewide registry provides an opportunity to examine the completion rates. The aim of this study was to investigate how recent legislation allowing NPs signatory authority for POLST forms has affected POLST completion. METHODS: Data were obtained from the WV statewide registry of POST forms completed by all authorized personnel. Forms submitted by NPs were compared with those completed by physicians on patient demographics, setting, resuscitation status, level of medical intervention, and errors. Variables were cross-tabulated by provider type to determine whether and how NP POST completion differed from that of physicians. CONCLUSIONS: Forty-five NPs submitted 430 POST forms to the WV registry, which constituted 14.4% of the POST forms received. Ten NPs in community and hospital specialist palliative care teams submitted more than two thirds of these 430 forms. Nurse practitioner completed POST forms were more likely to order do not resuscitate and comfort measures than POST forms ordered by physicians (both p < .001) and to be without errors (p < .001). IMPLICATIONS FOR PRACTICE: Nurse practitioners practicing in specialist palliative care roles in communities and hospitals have embraced the use of POST and followed through on complete and accurate completion of the forms. With this signatory authority, primary and specialist NPs have the potential to improve end-of-life care. PMID- 29757918 TI - Regulation of pediatric intensive care unit nurse practitioner practice: A national survey. AB - PURPOSE: To describe the extent to which organizational regulation of pediatric intensive care unit (PICU) nurse practitioner (NP) practice and prescriptive authority aligns with state scope-of-practice (SSOP) regulations, to examine differences between PICU medical directors' and NPs' report of regulation, and to describe organizational-level restriction of PICU NP practice. METHODS: A 34-item national, quantitative cross-sectional descriptive survey of US PICU medical directors and NPs included demographic, institutional characteristics, and PICU NP regulation and role-related questions. Invitations to participate were sent between October 2016 and January 2017. RESULTS: Respondents (n = 121, 60 PICU NPs and 61 PICU medical directors) reported that 30% of PICU NPs have additional organizational restrictions beyond their SSOP practice authority and 11% have prescriptive authority regulations that exceed those required by the SSOP regulations. Medical directors and lead NPs showed agreement in reports of NP practice regulation. Variation in organizational-level restrictions of privileging, billing, and reporting structure practices were identified. IMPLICATIONS FOR PRACTICE: As more states move to full SSOP regulatory environments, organizational regulation of NP practice can impede attainment of full practice authority. Future research is needed to determine whether variations in regulation of PICU NP practice influence patient outcomes, interdisciplinary collaboration, and NP role actualization. PMID- 29757907 TI - T Follicular Regulatory Cells and Antibody Responses in Transplantation. AB - De novo donor-specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitization, limiting future transplant options. Forming high-affinity, long lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. T follicular regulatory cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses.An imbalance between helper function and regulatory function can lead to excessive antibody production. High proportions of Tfh cells have been associated with DSA formation in transplantation; therefore, Tfr cells are likely to play an important role in limiting DSA production. Understanding the signals that govern Tfr cell development and the balance between helper and regulatory function within the GC is key to understanding how these cells might be manipulated to reduce the risk of DSA development.This review discusses the development and function of Tfr cells and their relevance to transplantation. In particular how current and future immunosuppressive strategies might allow us to skew the ratio between Tfr and Tfh cells to increase or decrease the risk of de novo DSA formation. PMID- 29757920 TI - Alaska nurse practitioners' barriers to use of prescription drug monitoring programs. AB - BACKGROUND AND PURPOSE: Prescription drug monitoring programs (PDMPs) have begun to demonstrate themselves as useful tools in enhancing safe and responsible prescription of controlled substances. The purpose of this project was to describe current practice, beliefs, and barriers of Alaska nurse practitioners (NPs) regarding the Alaska PDMP. METHODS: A questionnaire was sent to 635 Alaskan NPs with a 33% return rate. The data depicted prescribing habits, barriers to use, barriers to registering, and opinions on how to make the PDMP more clinically useful. CONCLUSIONS: More attention is needed to maximize PDMP exposure and incorporation into daily workflow if it is to achieve full potential. Registered users should be able to delegate PDMP authority to select staff members to reduce time commitments and increase usage. Many providers felt that assigning unique patient identifiers could prevent consumers from filling prescriptions under aliases. Finally, an overwhelming majority of users wanted faster data entry and proactive reports. IMPLICATIONS FOR PRACTICE: This project explored the differences between PDMP users and nonusers and outlined NP suggestions for process improvement. A better understanding of PDMP use will aid providers in safe prescribing while curbing the prescription drug epidemic and ultimately reducing abuse, misuse, and death from overdose. PMID- 29757919 TI - Prevalence of ototoxic medication use among older adults in Beaver Dam, Wisconsin. AB - BACKGROUND AND PURPOSE: Drug-related ototoxicity may exacerbate presbycusis (age related hearing loss); yet, few data are available on the prevalence of ototoxic medication use by older adults. The purposes of this study were to assess the impact of aging and ototoxicity on hearing loss, the prevalence of ototoxic medication use, and select characteristics associated with ototoxic medication use among older adults. METHODS: Cross-sectional analyses were conducted using select variables extracted from the baseline and 10-year follow-up assessments of the two population-based epidemiological studies to compare two points in time. RESULTS: Ninety-one percent of the sample was taking a medication reported to be ototoxic. Nonsteroidal anti-inflammatory drugs were the most commonly used (75.2%), followed by acetaminophen (39.9%) and diuretics (35.6%). Hypertension, diabetes, cardiovascular disease, and history of smoking were associated with ototoxic medication use. Participants with hearing loss were taking a significantly greater number of ototoxic medications than those without hearing loss. CONCLUSION: Known ototoxic medications are widely used. Any subsequent ototoxicity may interact with age changes and a more severe hearing loss than that associated with only age. IMPLICATIONS FOR PRACTICE: Nurse practitioners should inform older adults about the possibility of drug-related ototoxicity and monitor hearing acuity of all older adults taking known ototoxic medications. PMID- 29757921 TI - Systematic review of advanced practice nurses' skin cancer detection knowledge and attitudes, clinical skin examination, lesion detection, and training. AB - BACKGROUND AND PURPOSE: Skin cancer is the most common malignancy in the United States; early detection reduces the public health burden. This systematic review updates the state of advanced practice nurses' skin cancer knowledge and attitudes, performance of and barriers to clinical skin examination (CSE), recognition of skin lesions, and related training activities. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement guided a search of eight literature databases that yielded 12 studies from 2010 to 2016. The United States Preventive Services Task Force's Levels of Certainty guided evidence assessment. CONCLUSIONS: The studies mainly targeted or included nurse practitioners. Collectively, participants had variable, suboptimal skin cancer knowledge, even after an intervention. A slight majority performed CSE during annual visits but agreed that CSE was important and within their scope of practice. Major CSE barriers were lack of time, training, and confidence. Participants who received training were more proficient in identifying suspicious versus benign lesions. Few skin cancer detection training opportunities for nurses exist. IMPLICATIONS: The level of certainty of the evidence for skin cancer detection by advanced practice nurses and their impact on the skin cancer problem remain low. These nurses would benefit from accessible and efficacious CSE and lesion training. PMID- 29757922 TI - What's New in Shock, June 2018? PMID- 29757924 TI - Placebo versus low-dose ketamine infusion in addition to remifentanil target controlled infusion for conscious sedation during oocyte retrieval: A double blinded, randomised controlled trial. AB - BACKGROUND: Currently, there is no gold standard for monitored anaesthesia care during oocyte retrieval. OBJECTIVE: In our institution, the standard is a conscious sedation technique using a target-controlled infusion (TCI) of remifentanil, titrated to maintain a visual analogue pain score less than 30 mm. This protocol is well accepted by patients but is associated with frequent episodes of respiratory depression. The main objective of this study was to evaluate whether the addition of a continuous intravenous infusion of ketamine could reduce these episodes. DESIGN: Controlled, randomised, prospective, double blinded study. SETTING: The current study was conducted in a tertiary-level hospital in Brussels (Belgium) from December 2013 to June 2014. PATIENTS: Of the 132 women undergoing oocyte retrieval included, 121 completed the study. INTERVENTION: After randomisation, patients received either a ketamine infusion (40 MUg kg min over 5 min followed by 2.5 MUg kg min) or a 0.9% saline infusion in addition to the variable remifentanil TCI. MAIN OUTCOME MEASURES: The primary outcome was the number of respiratory depression episodes. Effect site target remifentanil concentrations, side effects, pain score, patient satisfaction and incidence of pregnancy were also recorded. RESULTS: No significant difference in the incidence of respiratory events was noted (pulse oximetry oxygen saturation < 95% was 49% in the ketamine group and 63% in the control group; P = 0.121). No patient required ventilatory support. In the ketamine group, visual analogue pain score and remifentanil concentrations were significantly reduced, but the latter remained above 2 ng ml. Postoperative nausea was less frequent in the ketamine group, 4 versus 15% (P = 0.038). The addition of ketamine did not influence length of stay nor patient satisfaction. CONCLUSION: The addition of low plasma levels of ketamine to a TCI remifentanil conscious sedation technique did not decrease the incidence nor the severity of respiratory depression. Continuous monitoring of capnography and oxygen saturation is always required. TRIAL REGISTRATION: EUDRACT number 2013-003040-23. PMID- 29757923 TI - The Antimalarial Drug Artesunate Attenuates Cardiac Injury in A Rodent Model of Myocardial Infarction. AB - Ischemic heart disease remains the leading cause of morbidity and mortality in the Western world. Artesunate is the WHO-recommended drug of choice for complicated malaria (with organ failure). The administration of high doses of artesunate is safe in healthy volunteers (up to 8 mg/kg i.v.) and patients with severe malaria (2.4 mg/kg i.v.). We investigated the effects of artesunate (1 mg/kg) or its active metabolite dihydroartemisinin (DHA; 0.1 mg/kg) in a model of transient myocardial ischemia/reperfusion (I/R) and evaluated the mechanism of action of the observed cardioprotective effects of artesunate and DHA. We report here for the first time that the administration of artesunate at the onset of reperfusion attenuates the myocardial injury associated with I/R. The observed beneficial effects of artesunate are associated with activation of the PI3K/Akt/ERK 1/2 (RISK) pathway, activation of endothelial nitric oxide synthase, inhibition of glycogen synthase kinase-3beta, inhibition of nuclear factor kappa B, and activation of the STAT3 (SAFE) pathway. In conclusion, as artesunate has an excellent safety profile, the above data should stimulate clinical trials in patients with acute coronary syndromes. PMID- 29757925 TI - A modified CO2/O2 Guedel airway improves capnographic accuracy compared with a CO2/O2 nasal cannula: An infant manikin study. AB - BACKGROUND: Capnography via a CO2/O2 nasal cannula is commonly used for respiratory monitoring during sedation. However, signal disturbances are frequently encountered, especially in young children. OBJECTIVE: Sampling ports placed closer to the trachea have been shown to result in improved signal quality. In a manikin model of a 6-month-old infant we compared capnography from a modified Guedel airway with a CO2 port located at the tip with that from a CO2/O2 nasal cannula. DESIGN: A comparison study using an artificial model of a breathing 6-month-old infant. SETTING: Department of Paediatrics, Inselspital Bern, Switzerland, from March 2016 to June 2016. MATERIAL: Modified CO2/O2 Guedel airway. INTERVENTIONS: Capnography using a modified CO2/O2 Guedel airway or a CO2/O2 nasal cannula was performed for tidal volumes of 20 to 80 ml (in steps of 20 ml), respiratory rates of 20 to 60 min (in steps of 10 min) and with different O2 flows (0 to 2 l min, in steps of 0.5 l). MAIN OUTCOME MEASURES: Comparison of differences between tracheal and device CO2. Secondary outcomes included the effect of various respiratory settings and O2 flows on the CO2 difference. RESULTS: The tracheal to device CO2 difference was significantly smaller when using a modified CO2/O2 Guedel airway vs. a CO2/O2 nasal cannula: Mean +/- SD, 16.8 +/- 4.9 vs. 24.1 +/- 5.9 mmHg, P less than 0.0001. An O2 flow of 0.5 to 2 l min did not influence the tracheal to device CO2 difference with the modified CO2/O2 Guedel airway in contrast to the CO2/O2 nasal cannula where there were significant differences (P < 0.0001). The effect of various tidal volumes and respiratory rates proved to be similar in both devices. CONCLUSION: Capnography traces derived from a sample port at the tip of a modified CO2/O2 Guedel airway were more accurate than those obtained from a CO2/O2 nasal cannula. TRIAL REGISTRATION: Not applicable. PMID- 29757926 TI - Duration of the action of rocuronium in patients with BMI of less than 25: An observational study. AB - BACKGROUND: The duration of rocuronium in patients with BMI more than 30 kg m is prolonged. Whether the reverse is true when BMI is less than 18.5 kg m is unclear. OBJECTIVE: The objective of this study was to investigate whether a BMI less than 25 kg m affects the duration of rocuronium in doses adjusted for actual body weight. DESIGN: A prospective, observational, single-centre study. SETTING: The operating room of a teaching hospital from 1 June 2008 to 30 June 2015. PATIENTS: Thirty patients with American Society of Anesthesiologists physical status I or II who were scheduled to undergo elective surgery (BMI < 25 kg m, aged 23 to 74 years) maintained by 0.7 minimum alveolar concentration sevoflurane and remifentanil. MAIN OUTCOME MEASURES: Repetitive train-of-four stimulation was applied and contractions of the adductor pollicis muscle were recorded. Duration of the initial dose of rocuronium (D1) was defined as the time from injection of rocuronium 0.6 mg kg to return of first twitch height to 25% of the control. Duration of additional doses (D2) was the time from a supplement of 0.15 mg kg rocuronium to return of first twitch height to 25% of the control. The relationship between D1 or D2 and BMI was examined using linear regression analysis. RESULTS: Linear regression analysis revealed a significant correlation between duration of initial dose and BMI (R = 0.246; P = 0.00531). A significant correlation between the duration of the additional dose and BMI was also found (R = 0.316; P = 0.00122). CONCLUSION: The lower the BMI, the shorter the duration of rocuronium at initial and additional doses determined by the actual body weight in adult patients with a BMI less than 25 kg m. TRIAL REGISTRATION: www.umin.ac.jp/ctr/index/htm with registry number UMIN 00009337 and UMIN 000015407. PMID- 29757927 TI - Association between Actual and Perceived Obesity Weaker among Black than White Children. AB - Although actual obesity is expected to be associated with perceived overweight, some recent studies in adults have suggested that this link may be smaller for Blacks than Whites. It is unknown, however, whether the same trend holds for children or not. This study explored the heterogeneity of the association between actual and perceived obesity in a national sample of American children by race, gender, and their intersection. Health Behavior in School-Aged Children (HBSC), 2009-2010, is a national study of children 17 years or less in the United States. This analysis included a total number of 8860 children, including 6581 (74.28%) White and 2279 (25.72%) Black children. Actual obesity, defined as a body mass index (BMI) greater than 95% of the age- and gender-percentile, was the independent variable. Perceived overweight was the main outcome. We ran linear regression models with and without interaction terms between race, gender, and actual obesity. We also ran race- and gender-specific linear regression models. In the pooled sample, actual obesity was positively associated with perceived overweight. We found an interaction between race and obesity, suggesting stronger association between actual obesity and perceived overweight for White than Black children. Gender or intersection of race and gender did not alter the association between actual obesity and perceived overweight. The link between actual obesity and perceived overweight depends on race of the child. Inaccurately perceived weight may be one of many mechanisms behind the disproportionately higher rate of obesity burden among Black children in the United States. As perceived overweight plays a salient role for weight control behaviors, Black children with obesity may need some help to perceive themselves as obese. Training programs should target Blacks to increase the accuracy of their weight and body size evaluation and perception as an essential step for reducing the burden of obesity among Black children. PMID- 29757928 TI - Understanding of Information about Medicines Use among Parents of Pre-School Children in Serbia: Parental Pharmacotherapy Literacy Questionnaire (PTHL-SR). AB - Parental health literacy plays an important role in children’s health, Experiences from pharmacy practice show that is necessary to check if parents understand instructions about use of medicines for children. This study aimed to assess pharmacotherapy literacy of parents of pre-school children and to examine association of parental pharmacotherapy literacy level with parent’s socio demographic characteristics. The study was cross-sectional, conducted among parents of pre-school children (1-7 years of age), in kindergartens in several municipalities of Belgrade, Serbia, during regular parents meetings, from May to October 2016. Functional health literacy was measured by the Serbian version of the Short Test of Functional Health Literacy in Adults (S-TOFHLA). Parental pharmacotherapy literacy was assessed with newly constructed PTHL-SR questionnaire with good psychometric characteristics (Parental pharmacotherapy literacy questionnaire—Serbian). Overall, 813 parents participated in the study, mostly females (81.30%), between 30 to 40 years of age (70.85%) with two children (56.70%). Almost all of our study participants (99%) had adequate health literacy as assessed by S-TOFHLA. Mean score on PTHL-SR was 72.83% (standard deviation was 13.37), with better results among females than males (72% of women were in the group of highest PTHL-SR results). Our study showed that many parents (76.5%) knew the appropriate usage of non-prescription medicine for children, 57.2% parents were able to correctly calculate the dose of oral syrup for a child, and only 43.3% were able to interpret non-prescription dosage information written on the package. The majority of parents (61.3%) would make a dosage to child based on age and not on their weight. Every fifth parent with adequate functional health literacy measured by S-TOFHLA test, achieved the lowest results measured by PTHL-SR. Higher performance of the PTHL-SR was significantly correlated with education (p < 0.001), female sex (p < 0.001), married parents and those living in common-law (p < 0.001), older parents (p < 0.05) and parents who have more children (p < 0.05), and are non-smokers (p < 0.05). These results provide evidence that limitations in understanding common information about use of medicines are widespread among parents of pre-school children and encourage efforts for further investigation. PTHL-SR questionnaire may be a useful tool for identification of parents who need more instructions and assistance from healthcare providers, above all in providing better communication, written or spoken at community pharmacy settings. PMID- 29757929 TI - Transitioning Bodies. The Case of Self-Prescribing Sexual Hormones in Gender Affirmation in Individuals Attending Psychiatric Services. AB - Self-prescribing of sexual hormones for gender affirmation is a potentially widespread and poorly studied phenomenon that many clinicians are unaware of. The uncontrolled use of hormones poses significant health hazards, which have not been previously reported in the literature. We have collected seven clinical cases in general adult psychiatry settings (both inpatient and outpatients), describing transgender and gender non-conforming individuals' (TGNC) self prescribing and self-administering hormones bought from the Internet without any medical consultation. Among these cases, two were taking androgens, and the rest were taking oestrogens. The main reason for self-administration of hormones seems to be the lack of access to specialised care due to discrimination and long waiting lists. We advocate for clinicians to be aware of the phenomenon and proactively help TGNC individuals by enquiring about self-prescribing of hormones, providing information and referring to the most appropriate treatment centre as well as encourage a public debate on the discrimination and the stigma that TGNC population suffer from. Overall, there is an urgent need for the implementation of different and innovative health care services for TGNC individuals as well as more targeted prevention strategies on such underreported and highly risky behaviours. Furthermore, it is necessary for every clinician involved in the care for TGNC people to be aware of their special needs and be able to be an allied and an advocate to help in reducing stigma and discrimination that affect the access to care for this often underserved population. PMID- 29757930 TI - Comprehension of Top 200 Prescribed Drugs in the US as a Resource for Pharmacy Teaching, Training and Practice. AB - Pharmacists have access to a plethora of information related to drugs. Online compendia concerning top 200 prescribed drugs are readily-accessible, comparatively-easy to search. While these resources provide some information about the commonly prescribed drugs, they lack in furnishing in-depth knowledge to pharmacy students, pharmacists and other healthcare professionals. The aim of this paper is to present the relevant details of top 200 most prescribed drugs in the United States. The names and therapeutic classes of top 200 prescribed drugs were compiled from online resources. The pharmacological actions of drugs, any reported adverse reactions and black box warnings are collected from drug bank resources, such as AccessPharmacy and Lexicomp. The paper provides comprehensive information about top 200 prescribed drugs, which includes generic names, pharmacological action, route of administration and adverse reaction profile including black box warning when applicable. Overall, the drug list may serve as an easy access of ideas for pharmacists, researchers and other healthcare professionals interested in developing new strategies for treating patients with various ailments. PMID- 29757931 TI - In Vitro Human Microbiota Response to Exposure to Silver Nanoparticles Biosynthesized with Mushroom Extract. AB - The ability to orally administer silver nanoparticles (AgNPs) in enteric capsules implies a direct interaction with the colon microbiota. The in vitro effect provides a portrayal of the functional properties under in vivo conditions. The purpose of this study was to describe a green AgNP synthesis process, using aqueous extract from Lactarius piperatus mushroom, and to characterize the nanomaterial. We determined its antimicrobial and antioxidant effects in vitro in the microbiota of healthy individuals via the GIS1 system-a colon transit simulator. Per the quantitative polymerase chain reaction (qPCR) results, the antimicrobial properties of the AgNPs affected the initial share of different enteric species by decreasing the Bacteroides, Enterobacteriaceae, and Lactobacillus populations and favoring the Bifidobacterium group. The association between AgNPs and wild mushroom L. piperatus extract had a synergistic antibacterial activity against various pathogenic microorganisms while the mushroom extract reduced biofilm formation. Administration of AgNP maintained its constant antioxidant status, and it was correlated with a reduction in ammonium compounds. The physicochemical characterization of these NPs complemented their biochemical characterization. The maximum ultraviolet-visible spectroscopy (UV VIS) absorbance was observed at 440 nm, while the Fourier transform infrared (FT IR) spectrum reached a peak at 3296 cm-1, which was correlated with the high performance liquid chromatographic analysis (HPLC). The major phenolic compound was homogentisic acid. The size (49 +/- 16 nm in diameter) and spherical shape of the NPs were correlated with their biological effects in vitro. PMID- 29757932 TI - SOX7 Target Genes and Their Contribution to Its Tumor Suppressive Function. AB - SOX7 is a transcription factor and acts as a tumor suppressor, but its target genes in cancers are poorly explored. We revealed SOX7-mediated gene expression profile in breast cancer cells using microarray chips and discovered multiple altered signaling pathways. When combinatorially analyzing the microarray data with a gene array dataset from 759 breast cancer patients, we identified four genes as potential targets of SOX7 and validated them by quantitative PCR and chromatin immunoprecipitation assays. Among these four genes, we determined that SOX7-activated SPRY1 and SLIT2, and SOX7-repressed TRIB3 and MTHFD2 could all differentially contribute to SOX7-mediated tumor suppression. Overall, we identified multiple cancer-related pathways mediated by SOX7 and for the first time revealed SOX7-regulated target genes in a cancer-relevant context. PMID- 29757934 TI - Comparison of Synthetic Media Designed for Expansion of Adipose-Derived Mesenchymal Stromal Cells. AB - Mesenchymal stromal cells (MSCs) are multipotent cells that can differentiate into various cell types, such as osteoblasts, myocytes, and adipocytes. This characteristic makes the cells a useful tool in developing new therapies for a number of common maladies and diseases. The utilization of animal-derived growth serum, such as fetal bovine serum (FBS), for the expansion of MSCs has traditionally been used for cell culture. However, in clinical applications, animal-derived products present limitations and safety concerns for the recipient, as exposure to animal (xeno-) antigens and infectious agents is possible. Multiple synthetic, xeno-free media have been developed to combat these limitations of animal-derived growth serum and have the potential to be used in ex vivo MSC expansion for clinical use. The goal of this study was to determine if xeno-free media are adequate to significantly and efficiently expand MSCs derived from adipose tissue. MSCs were cultured in both standard FBS-containing as well as xeno-free media. The media were compared for cell yield, viability, and phenotypic expression via flow cytometry and directed differentiation. The xeno-free media that were tested were StemMACS MSC Expansion Media (Miltenyi Biotec, Bergisch Gladbach, Germany), PLTMax Human Platelet Lysate (Sigma-Aldrich, St. Louis, MO, USA), and MesenCult-hPL media (Stemcell Technologies, Vancouver, BC, Canada). All xeno-free media showed promise as a feasible replacement for animal-derived growth serums. The xeno-free media expanded MSCs more quickly than the FBS-containing medium and also showed great similarity in cell viability and phenotypic expression. In fact, each xeno-free media produced a greater viable cell yield than the standard FBS-containing medium. PMID- 29757933 TI - Improving Physical Fitness and Cognitive Functions in Middle School Students: Study Protocol for the Chinese Childhood Health, Activity and Motor Performance Study (Chinese CHAMPS). AB - Background: Sedentary lifestyles and their associated harmful consequences are public health concerns that impact more than half of the world's youth population in both developed and developing countries. Methods: The Chinese Childhood Health; Activity and Motor Performance Study (Chinese CHAMPS) was a cluster randomized controlled trial to modify school physical activity policies and the physical education (PE) curriculum; using teacher training and parent engagement to increase opportunities and support students' physical activity and healthy eating. Using a 2 * 2 factorial design, the study tested the incremental effects of increasing the amount and intensity of physical activity, alongside adding support for healthy eating, on health-related and cognitive function outcomes in Chinese middle school students. Results: The intervention was implemented by PE teachers in 12 middle schools in three Chinese cities, with a targeted enrollment of 650 students from August 2015-June 2016. The assessment of the outcomes involved a test battery of physical fitness and cognitive functioning at both baseline and at the end of the intervention. Process information on implementation was also collected. Discussion: The Chinese CHAMPS is a multi level intervention that is designed to test the influences of policy and environmental modifications on the physical activity and eating behaviors of middle school students. It also addresses some key weaknesses in school-based physical activity interventions. PMID- 29757935 TI - Synthesis and Broadband Spectra Photocatalytic Properties of Bi2O2(CO3)1-xSx. AB - High efficiency photocatalyst Bi2O2(CO3)1-xSx was synthesized conveniently with chemical bath precipitation using Bi2O2CO3 as the precursor. The microstructures of the samples are systematically characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), ultraviolet photoelectron spectroscopy (UPS) and UV-Vis spectroscopy; the optical and photocatalytic properties are carefully tested as well. The content of S, which was tuned through the controlling of the precipitation process, was verified to have an intense effect over the photocatalytic properties. A nearly saturated S ratio and the best photocatalytic performance were observed in specimens with the most S content. Our study reveals that, with negligible influence of the morphology and crystal structure, Bi2O2(CO3)1-xSx possessed a broadened optical absorption regionfromultraviolet to visible light, and enhanced photocatalytic activity in comparison to precursor Bi2O2CO3 in photocatalytic degradation of Congo Red aqueous solution. PMID- 29757936 TI - Formula Milk Supplementation on the Postnatal Ward: A Cross-Sectional Analytical Study. AB - Breastfeeding rates are low in the UK, where approximately one quarter of infants receive a breastmilk substitute (BMS) in the first week of life. We investigated the reasons for early BMS use in two large maternity units in the UK, in order to understand the reasons for the high rate of early BMS use in this setting. Data were collected through infant feeding records, as well as maternal and midwife surveys in 2016. During 2016, 28% of infants received a BMS supplement prior to discharge from the hospital maternity units with only 10% supplementation being clinically indicated. There was wide variation in BMS initiation rates between different midwives, which was associated with ward environment and midwife educational level. Specific management factors associated with non-clinically indicated initiation of BMS were the absence of skin-to-skin contact within an hour of delivery (p = 0.01), and no attendance at an antenatal breastfeeding discussion (p = 0.01). These findings suggest that risk of initiating a BMS during postnatal hospital stay is largely modifiable. Concordance with UNICEF Baby Friendly 10 steps, attention to specific features of the postnatal ward working environment, and the targeting of midwives and mothers with poor educational status may all lead to improved exclusive breastfeeding rates at hospital discharge. PMID- 29757937 TI - Factors Associated with Maternal Wellbeing at Four Months Post-Partum in Ireland. AB - This study aimed to examine factors associated with maternal wellbeing at four months post-partum in the Irish context. Socio-demographic, health behaviour and infant feeding data were collected in pregnancy, at birth and at 17 weeks post partum. Maternal distress, body image and resilience were measured at 17 weeks post-partum. Binary logistic regression predicted maternal distress and statistical significance was taken at p < 0.05. One hundred and seventy-two women were followed-up in pregnancy, at birth and at 17 weeks post-partum. Three in five (61.6%, n106) initiated breastfeeding. At 17 weeks post-partum, 23.8% (n41) were exclusively or partially breastfeeding and over a third (36.0%, n62) of all mothers were at risk of distress. In multivariate analyses, independent predictors of distress included: low maternal resilience (p < 0.01, odds ratio (OR): 7.22 (95% confidence interval [CI]: 2.49-20.95)); unsatisfactory partner support (p = 0.02, OR: 3.89 (95% CI: 1.20-12.65)); older age (p = 0.02, OR: 1.11 (95% CI: 1.02-1.21)); and breastfeeding (p = 0.01, OR: 2.89 (95% CI: 1.29-6.47)). Routine assessment of emotional wellbeing and targeted interventions are needed to promote a more healthful transition to motherhood among women in Ireland. PMID- 29757940 TI - Development and Performance Evaluation of Image-Based Robotic Waxing System for Detailing Automobiles. AB - Waxing is an important aspect of automobile detailing, aimed at protecting the finish of the car and preventing rust. At present, this delicate work is conducted manually due to the need for iterative adjustments to achieve acceptable quality. This paper presents a robotic waxing system in which surface images are used to evaluate the quality of the finish. An RGB-D camera is used to build a point cloud that details the sheet metal components to enable path planning for a robot manipulator. The robot is equipped with a multi-axis force sensor to measure and control the forces involved in the application and buffing of wax. Images of sheet metal components that were waxed by experienced car detailers were analyzed using image processing algorithms. A Gaussian distribution function and its parameterized values were obtained from the images for use as a performance criterion in evaluating the quality of surfaces prepared by the robotic waxing system. Waxing force and dwell time were optimized using a mathematical model based on the image-based criterion used to measure waxing performance. Experimental results demonstrate the feasibility of the proposed robotic waxing system and image-based performance evaluation scheme. PMID- 29757938 TI - PIEZO1 Channel Is a Potential Regulator of Synovial Sarcoma Cell-Viability. AB - Detection of mechanical stress is essential for diverse biological functions including touch, audition, and maintenance of vascular myogenic tone. PIEZO1, a mechano-sensing cation channel, is widely expressed in neuronal and non-neuronal cells and is expected to be involved in important biological functions. Here, we examined the possibility that PIEZO1 is involved in the regulation of synovial sarcoma cell-viability. Application of a PIEZO1 agonist Yoda1 effectively induced Ca2+ response and cation channel currents in PIEZO1-expressing HEK (HEK-Piezo1) cells and synovial sarcoma SW982 (SW982) cells. Mechanical stress, as well as Yoda1, induced the activity of an identical channel of conductance with 21.6 pS in HEK-Piezo1 cells. In contrast, Yoda1 up to 10 μM had no effects on membrane currents in HEK cells without transfecting PIEZO1. A knockdown of PIEZO1 with siRNA in SW982 cells abolished Yoda1-induced Ca2+ response and significantly reduced cell cell-viability. Because PIEZO1 is highly expressed in SW982 cells and its knockdown affects cell-viability, this gene is a potential target against synovial sarcoma. PMID- 29757939 TI - Heterogeneity in the Relationship between Disinfection By-Products in Drinking Water and Cancer: A Systematic Review. AB - The epidemiological evidence demonstrating the effect of disinfection by-products (DBPs) from drinking water on colon and rectal cancers is well documented. However, no systematic assessment has been conducted to assess the potential effect measure modification (EMM) in the relationship between DBPs and cancer. The objective of this paper is to conduct a systematic literature review to determine the extent to which EMM has been assessed in the relationship between DBPs in drinking water in past epidemiological studies. Selected articles (n = 19) were reviewed, and effect estimates and covariates that could have been used in an EMM assessment were gathered. Approximately half of the studies assess EMM (n = 10), but the majority of studies only estimate it relative to sex subgroups (n = 6 for bladder cancer and n = 2 both for rectal and colon cancers). Although EMM is rarely assessed, several variables that could have a potential modification effect are routinely collected in these studies, such as socioeconomic status or age. The role of environmental exposures through drinking water can play an important role and contribute to cancer disparities. We encourage a systematic use of subgroup analysis to understand which populations or territories are more vulnerable to the health impacts of DBPs. PMID- 29757941 TI - Exploring How the Home Environment Influences Eating and Physical Activity Habits of Low-Income, Latino Children of Predominantly Immigrant Families: A Qualitative Study. AB - : Latinos are the largest and fastest growing minority population group in the United States, and children in low-income Latino families are at elevated risk of becoming overweight or having obesity. A child’s home is an important social environment in which he/she develops and maintains dietary and physical activity (PA) habits that ultimately impact weight status. Previous research suggests the parents are central to creating a home environment that facilitates or hinders the development of children’s early healthy eating and PA habits. Therefore, the purpose of this study was to explore low-income Latino parents’ beliefs, parenting styles, and parenting practices related to their children’s eating and PA behaviors while at home. METHODS: Qualitative study using focus group discussions (FGDs) with 33 low-income Latino parents of preschool children 2 to 5 years of age. FGDs were transcribed verbatim and analyzed using thematic analysis. RESULTS: Data analyses revealed that most parents recognize the importance of healthy eating and PA for their children and themselves. However, daily life demands including conflicting schedules, long working hours, financial constraints, and neighborhood safety concerns, etc., impact parents’ ability to create a home environment supportive of these behaviors. CONCLUSIONS: This study provides information about how the home environment may influence low-income Latino preschool children’s eating and PA habits, which may be useful for health promotion and disease prevention efforts targeting low-income Latino families with young children, and for developing home-based and parenting interventions to prevent and control childhood obesity among this population group. Pediatric healthcare providers can play an important role in facilitating communication, providing education, and offering guidance to low-income Latino parents that support their children’s development of early healthy eating and PA habits, while taking into account daily life barriers faced by families. Moreover, pediatric healthcare providers also can play an important role in the integration and coordination of home-visitations to complement office-based visits and provide a continuum of care to low-income Latino families. PMID- 29757942 TI - Biomedical Potential of Ultrafine Ag Nanoparticles Coated on Poly (Gamma-Glutamic Acid) Hydrogel with Special Reference to Wound Healing. AB - In wound care management, the prevention of wound infection and the retention of an appropriate level of moisture are two major challenges. Therefore, designing an excellent antibacterial hydrogel with a suitable water-adsorbing capacity is very important to improve the development of wound dressings. In this paper, a novel silver nanoparticles/poly (gamma-glutamic acid) (γ-PGA) composite dressing was prepared for biomedical applications. The promoted wound-healing ability of the hydrogels were systematically evaluated with the aim of attaining a novel and effective wound dressing. A diffusion study showed that hydrogels can continuously release antibacterial factors (Ag). Hydrogels contain a high percentage of water, providing an ideal moist environment for tissue regeneration, while also preventing contraction of the wound. Moreover, an in vivo, wound-healing model evaluation of artificial wounds in mice indicated that silver/γ-PGA hydrogels could significantly promote wound healing. Histological examination revealed that hydrogels can successfully help to reconstruct intact epidermis and collagen deposition during 14 days of impaired wound healing. Overall, this research could shed new light on the design of antibacterial silver/γ-PGA hydrogels with potential applications in wound dressing. PMID- 29757943 TI - Adsorption Performance Analysis of Alternative Reactive Media for Remediation of Aquifers Affected by Heavy Metal Contamination. AB - A series of experimental batch tests has been carried out with the aim of improving the knowledge of fundamental processes related to the fate and behavior of heavy metals that can be of environmental concern in groundwater. The analysis of contaminants (i.e., Cu, Zn, Cd and Pb) dynamics in different environmental compartments is specifically addressed by comparing the removal efficiencies of different types of reactive materials, three natural (i.e., vegetal fibers, natural limestone and natural zeolite) and one synthetic (i.e., synthetic zeolite). Results stemming from these reactive media has been compared with the outcomes related to the same test performed using zero valent iron which is the reactant usually employed for heavy metals remediation. All tested reactants exhibited important removal percentages, even larger than 90% in most cases, achieved in a contact time ranging between about 12 h and slightly longer than a day (i.e., 30 h). Maximum adsorption percentages are observed for pH ranging between 4 and 8 for all tested materials and contaminants. Our findings provided relevant evidence, to both researchers and technicians, on the competitiveness of the explored alternative mediums with respect to the classical reactants usually employed for heavy metals remediation. PMID- 29757944 TI - Dyslexia and Fonts: Is a Specific Font Useful? AB - Nowadays, several books published in different fonts advertised as being particularly suitable for dyslexics are available on the market. Our research aimed to assess the significance of a specific reading font especially designed for dyslexia, called EasyReadingTM. The performances of good readers and dyslexics were compared. Fourth grade primary school students (533 students in total) were assessed based on reading tasks presented with two different layouts: the popular Times New Roman and EasyReadingTM, in order to investigate whether children's performances were influenced by the fonts used. The results of the study were both statistically and clinically significant, proving that EasyReadingTM can be considered a compensating tool for readers with dyslexia, and a simplifying font for all categories of readers. PMID- 29757945 TI - Effectiveness and Safety of Dietetic Supplementation of a New Nutraceutical on Lipid Profile and Serum Inflammation Biomarkers in Hypercholesterolemic Patients. AB - Background: To assess the effectiveness and safety of a new nutraceutical (NC) on lipid profile, inflammation biomarkers and creatine phosphokinase (CPK) serum levels in hypercholesterolemic patients. Methods: 40 patients underwent hypolipemic treatment with NC. Initial and final (after 12 weeks) screening included medical history, physical examination, and measurement of serum lipid profile (total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides), hepatic (GOT, GPT, gammaGT), and renal (serum creatinine and urea) functions, CPK level and many inflammation biomarkers (hs-CRP and fibrinogen). At the screening visit, all patients were instructed to follow a normocaloric and hypolipidic diet during the study period. Results: The treatment with supplementation of NC demonstrated a significant reduction of serum total cholesterol (224 +/- 11.2 mg/dL vs. 178 +/- 10.7; p < 0.001), LDL-cholesterol (141 +/- 10.6 vs. 116 + 10.1; p < 0.001), triglycerides (183 +/- 13 vs. 159 +/- 11.5; p < 0.01), serum inflammatory biomarkers as hs-CRP (2.24 +/- 0.83 vs. 1.76 +/- 0.61 mg/dL; p < 0.01), fibrinogen (315 +/- 43 vs. 199 +/- 41 mg/dL; p < 0.01) and a significantly increase of HDL-cholesterol (44 +/- 7 vs. 53 +/- 7 mg/dL; p < 0.01). Hepatic and renal function and serum CPK were normal. No adverse events was reported. Conclusions: The treatment with NC has demonstrated a significant reduction of LDL-cholesterol (-17.73%), total cholesterol (-20.53%) and triglycerides ( 13.1%), with a significant increase of HDL-cholesterol values (+20.45%). The improvement of lipid profile was associated with a significant reduction of serum inflammation biomarkers as hs-PCR (-27%) and fibrinogen (-36.8%) with good tolerability profile. PMID- 29757946 TI - Role of Venous Sampling in the Diagnosis of Endocrine Disorders. AB - Venous sampling is the gold standard for localizing abnormal hormone secretion in several endocrine disorders. The most common indication for venous sampling is in the workup of primary aldosteronism, adrenocorticotropic hormone-dependent Cushing's syndrome, and hyperparathyroidism. In experienced hands, venous sampling is safe and accurate. This review discusses the role of venous sampling in the workup of endocrine disease, describing the underlying anatomy and pathophysiology, as an understanding of these concepts is essential for technical and clinical success. PMID- 29757950 TI - Changes in Arsenic, Copper, Iron, Manganese, and Zinc Levels Resulting from the Application of Poultry Litter to Agricultural Soils. AB - Twelve applications of poultry litter were made to a 2.1-ha field located in the Shenandoah Valley of Virginia, United States (USA), between March 1999 and August 2014. The field was planted with bermudagrass (Cynodon dactylon) and used as a pasture on an active farm. Copper, iron, manganese, zinc, and arsenic concentrations in the poultry litter were measured, and the application rates of these metals were calculated. The median application rates were: Cu, 1.32 kg/ha, Fe, 5.57 kg/ha, Mn, 1.80 kg/ha, Zn, 1.39 kg/ha, and As, 0.011 kg/ha. Twelve surface and subsurface soil samples were taken from the treated field in February 2016. Twelve samples were also taken from a comparison site. The comparison site was directly adjacent to the study site, consisted of the same soil type, and had been maintained as an undisturbed forest. Extractable Cu, Fe, Mn, Zn, and As concentrations in the soil samples were determined by atomic absorption spectroscopy, and the results of the chemical analysis were analyzed by ANOVA. Fe and Mn were depleted from the soil in the treated field, while Cu and Zn levels increased over the 12 years of treatment and grazing, and arsenic levels were unchanged in both the surface and subsurface soils between the comparison and the study site. The changes observed for Cu, Fe, Mn, and Zn are within the critical deficiency level and critical toxicity level for these metals, and no arsenic remains in the soil from roxarsone feed supplements, which were added to the poultry feed when the litter was applied to the study site. PMID- 29757947 TI - Membrane Remodeling as a Key Player of the Hepatotoxicity Induced by Co-Exposure to Benzo[a]pyrene and Ethanol of Obese Zebrafish Larvae. AB - The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes an important public health concern worldwide. Including obesity, numerous risk factors of NAFLD such as benzo[a]pyrene (B[a]P) and ethanol have been identified as modifying the physicochemical properties of the plasma membrane in vitro thus causing membrane remodeling-changes in membrane fluidity and lipid-raft characteristics. In this study, the possible involvement of membrane remodeling in the in vivo progression of steatosis to a steatohepatitis-like state upon co exposure to B[a]P and ethanol was tested in obese zebrafish larvae. Larvae bearing steatosis as the result of a high-fat diet were exposed to ethanol and/or B[a]P for seven days at low concentrations coherent with human exposure in order to elicit hepatotoxicity. In this condition, the toxicant co-exposure raised global membrane order with higher lipid-raft clustering in the plasma membrane of liver cells, as evaluated by staining with the fluoroprobe di-4-ANEPPDHQ. Involvement of this membrane's remodeling was finally explored by using the lipid raft disruptor pravastatin that counteracted the effects of toxicant co-exposure both on membrane remodeling and toxicity. Overall, it can be concluded that B[a]P/ethanol co-exposure can induce in vivo hepatotoxicity via membrane remodeling which could be considered as a good target mechanism for developing combination therapy to deal with steatohepatitis. PMID- 29757948 TI - Streptomyces Differentiation in Liquid Cultures as a Trigger of Secondary Metabolism. AB - Streptomyces is a diverse group of gram-positive microorganisms characterised by a complex developmental cycle. Streptomycetes produce a number of antibiotics and other bioactive compounds used in the clinic. Most screening campaigns looking for new bioactive molecules from actinomycetes have been performed empirically, e.g., without considering whether the bacteria are growing under the best developmental conditions for secondary metabolite production. These screening campaigns were extremely productive and discovered a number of new bioactive compounds during the so-called "golden age of antibiotics" (until the 1980s). However, at present, there is a worrying bottleneck in drug discovery, and new experimental approaches are needed to improve the screening of natural actinomycetes. Streptomycetes are still the most important natural source of antibiotics and other bioactive compounds. They harbour many cryptic secondary metabolite pathways not expressed under classical laboratory cultures. Here, we review the new strategies that are being explored to overcome current challenges in drug discovery. In particular, we focus on those aimed at improving the differentiation of the antibiotic-producing mycelium stage in the laboratory. PMID- 29757953 TI - Performance of Nanocomposite Membranes Containing 0D to 2D Nanofillers for CO2 Separation: A Review. AB - Membrane technology has the potential to be an eco-friendly and energy-saving solution for the separation of CO2 from different gaseous streams due to the lower cost and the superior manufacturing features. However, the performances of membranes made of conventional polymers are limited by the trade-off between the permeability and selectivity. Improving the membrane performance through the addition of nanofillers within the polymer matrix offers a promising strategy to achieve superior separation performance. This review aims at providing a complete overview of the recent advances in nanocomposite membranes for enhanced CO2 separation. Nanofillers of various dimensions and properties are categorized and effects of nature and morphology of the 0D to 2D nanofillers in the corresponding nanocomposite membranes of different polymeric matrixes are discussed with regard to the CO2 permeation properties. Moreover, a comprehensive summary of the performance data of various nanocomposite membranes is presented. Finally, the advantages and challenges of various nanocomposite membranes are discussed and the future research and development opportunities are proposed. PMID- 29757952 TI - Novel N4-Like Bacteriophages of Pectobacterium atrosepticum. AB - Pectobacterium atrosepticum is an economically important phytopathogen that is responsible for potato blackleg and soft rot, and for which current control strategies are limited. In this study, stem samples of potato crops exhibiting blackleg were taken from three farms in Co. Cork, Ireland, and they were found to be infected with P. atrosepticum. Three closely related bacteriophages (phages) that are specific to this phytopathogen were isolated and characterized, namely vB_PatP_CB1, vB_PatP_CB3, and vB_PatP_CB4 (abbreviated as CB1, CB3, and CB4). Both CB1 and CB3 were determined to infect 12 strains and CB4 10 strains of the 19 strains of P. atrosepticum tested. Morphology, latent periods, burst sizes, and their stability at various temperatures and pHs were also examined. Genome sequencing of the three phages revealed that they shared a minimum nucleotide identity of 93% with each other. Their genomes exhibited an Enquartavirinae genome organization, possessing several conserved proteins that were associated with phages of this group, like the type species Escherichia virus N4. Tandem electrospray ionization-mass spectrometry (ESI-MS/MS) allowed for the identification of ten structural proteins that form the virion of CB1, six that are conserved in phage N4. Biocontrol experiments demonstrated that the phages suppress soft rot formation upon co-inoculation with P. atrosepticum on whole tubers. The results of this study indicate that CB1 related phages could be good candidates for phage-based control. PMID- 29757949 TI - Effects of Dietary Intake of Japanese Mushrooms on Visceral Fat Accumulation and Gut Microbiota in Mice. AB - A lot of Japanese people are generally known for having a healthy diet, and consume a variety of mushrooms daily. Many studies have reported anti-obesity effects of mushrooms, but few have investigated the effects of consuming a variety of edible mushroom types together in realistic quantities. In this study, we investigated whether supplementation with a variety of mushroom types affects visceral fat accumulation and gut microbiota in mice. The most popular mushroom varieties in Japan were lyophilized and mixed according to their local production ratios. C57BL/6J mice were fed a normal diet, high-fat (HF) diet, HF with 0.5% mushroom mixture (equivalent to 100 g mushrooms/day in humans) or HF with 3% mushroom mixture (equivalent to 600 g mushrooms/day in humans) for 4 weeks. The mice were then sacrificed, and blood samples, tissue samples and feces were collected. Our results show that mushroom intake suppressed visceral fat accumulation and increased the relative abundance of some short chain fatty acid- and lactic acid-producing gut bacteria. These findings suggest that mushroom intake is an effective strategy for obesity prevention. PMID- 29757951 TI - Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. AB - Caffeine is the most widely consumed psychoactive compound worldwide. It is mostly found in coffee, tea, energizing drinks and in some drugs. However, it has become really easy to obtain pure caffeine (powder or tablets) on the Internet markets. Mechanisms of action are dose-dependent. Serious toxicities such as seizure and cardiac arrhythmias, seen with caffeine plasma concentrations of 15 mg/L or higher, have caused poisoning or, rarely, death; otherwise concentrations of 3-6 mg/kg are considered safe. Caffeine concentrations of 80-100 mg/L are considered lethal. The aim of this systematic review, performed following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) statement for the identification and selection of studies, is to review fatal cases in which caffeine has been recognized as the only cause of death in order to identify potential categories at risk. A total of 92 cases have been identified. These events happened more frequently in infants, psychiatric patients, and athletes. Although caffeine intoxication is relatively uncommon, raising awareness about its lethal consequences could be useful for both clinicians and pathologists to identify possible unrecognized cases and prevent related severe health conditions and deaths. PMID- 29757954 TI - Consumer Preference and Attitude Regarding Online Food Products in Hanoi, Vietnam. AB - This study aimed to examine: (1) how the Internet has changed consumers food buying behavior and identify its associated factors; (2) consumers' concern about food safety information of online food products. A cross-sectional study was performed from October to December 2015 in Hanoi-a Vietnamese epicenter of food service. One thousand seven hundred and thirty six (1736) customers were randomly chosen from food establishments of 176 communes. Data were collected through face to-face interviews using structured questionnaires. The majority of participants reported using the Internet to search for food products (81.3%). The most crucial factors influencing food purchases through the Internet were convenience (69.1%) and price (59.3%). Only one-third of participants selected products based on accurate evidence about food safety certification or food origin. The majority of participants were concerned about the expiration date (51.6%), while brand (9.8%) and food licensing information (11.3%) were often neglected. People who were:(1) female, (2) highly influenced by online relationships, and (3) having difficulty in doing usual activities were more likely to look for online food products. These findings produce practical advice to consumers when purchasing their desired food products on the Internet, to online food retailers and to the Government of Vietnam to implement appropriate legislation regarding trading online food products. PMID- 29757955 TI - Enrichment in the Sucker and Weaner Phase Altered the Performance of Pigs in Three Behavioural Tests. AB - We tested the hypothesis that provision of enrichment in the form of enrichment blocks during the sucker and weaner phases would affect the behaviour of pigs. We measured the performance of pigs in an open field/novel object test, a maze test, an executive function test and the cortisol response of the pigs after exposure to an open field test. The provision of enrichment blocks altered the behaviour of the pigs in all three tests and these changes suggest an increased willingness to explore and possibly an increased ability to learn. The behavioural tests highlighted that young pigs have the capacity to learn complex tasks. Our findings support the notion that the benefits of enrichment cannot be evaluated by measuring the interactions the animal has with the enrichments in the home pen and it may simply be beneficial to live in a more complex environment. We have highlighted that the early rearing environment is important and that the management and husbandry at an early age can have long-term implications for pigs. The enrichment we used in this study was very simple, an enrichment block, and we provide evidence suggesting the provision of enrichment effected pig behavioural responses. Even the simplest of enrichments may have benefits for the welfare and development of young pigs and there is merit in developing enrichment devices that are suitable for use in pig production. PMID- 29757958 TI - Hydroxypropyl-beta-cyclodextrin for Delivery of Baicalin via Inclusion Complexation by Supercritical Fluid Encapsulation. AB - Over the years, various methods have been developed to enhance the solubility of insoluble drugs; however, most of these methods are time-consuming and labor intensive or involve the use of toxic materials. A method that can safely and effectively enhance the solubility of insoluble drugs is lacking. This study adopted baicalin as an insoluble drug model, and used hydroxypropyl-beta cyclodextrin for the delivery of baicalin via the inclusion complexation by supercritical fluid encapsulation. Different parameters for the complex preparation as well as the physicochemical properties of the complex have been investigated. Our results showed that when compared to the conventional solution mixing approach, supercritical fluid encapsulation enables a more precise control of the properties of the complex, and gives higher loading and encapsulation efficiency. It is anticipated that our reported method can be useful in enhancing the preparation efficiency of inclusion complexes, and can expand the application potential of insoluble herbal ingredients in treatment development and pharmaceutical formulation. PMID- 29757961 TI - Determination of Tumor Marker Carcinoembryonic Antigen with Biosensor Based on Optical Quantum Weak Measurements. AB - A phase-sensitive weak measurement biosensor was proposed for the detection of carcinoembryonic antigen (CEA), one common category of tumor markers. The total internal reflection (TIR) at the interface of the prism without precious metal coating was exploited to introduce the phase delay between horizontal and vertical polarizations, which can be determined through the central wavelength shift of output spectra for the sensing of the refractive index of the sample. In the weak measurement analysis, the specific binding reaction of tumor markers with a refractive index change on the surface of the prism can be monitored in real time through the central wavelength shift. With the specific absorption measurement, the feasibility of this weak measurement-based biosensor was experimentally demonstrated. We provide a low cost and convenient approach for tumor marker detection. PMID- 29757959 TI - Association of Genetic Variation in the Epithelial Sodium Channel Gene with Urinary Sodium Excretion and Blood Pressure. AB - This study was performed to investigate whether genetic variation in the epithelial sodium channel (ENaC) is associated with 24-h urinary sodium excretion and blood pressure. A total of 3345 participants of the KoGES_Ansan and Ansung study were eligible for this study. Genomic DNA samples were isolated from peripheral blood and genotyped on the Affymetrix Genome-Wide Human SNP Array 5.0. Thirty-four single nucleotide polymorphisms (SNPs) were extracted for gene regions (SCNN1A, SCNN1B, and SCNN1G) as additive components by using Plink. Twenty-four-hour sodium excretions were estimated from spot urine samples using the Tanaka formula. The general linear model (GLM) was applied to assess the association between SNPs and urinary sodium excretion or blood pressure. In the SCNN1G gene, six SNPs (rs4073291, rs12934362, rs7404408, rs4494543, rs5735, and rs6497657) were significantly different in 24-h urinary sodium excretion according to gene variants. However, no difference was found in blood pressure among participants with gene variants of ENaC. Our finding indicated that 24-h urinary sodium excretions were different according to variants of the SCNN1G gene in large samples. Further studies to replicate these findings are warranted. PMID- 29757962 TI - The Relationship between Shoe Fitting and Foot Health of Persons with Down Syndrome: A Case Control Study. AB - Background: Down syndrome is the most common chromosomal abnormality and a cause of intellectual disability. It is also associated with orthopaedic and musculoskeletal problems of the locomotive apparatus, especially of the feet. These problems are believed to have a harmful effect on health, social functioning, and mobility. In addition, these persons generally don't have access to podiatric health services, even when their foot problems are well known, because of limited access to healthcare facilities. The goal of our research was to evaluate and compare the foot health status of study participants with and without Down syndrome and to determine whether inadequate footwear is being used with normalized reference values. Methods: A total of 105 participants with and without Down syndrome, with a mean age of 35.71 (SD = 12.93) years, were enrolled in the study. They self-reported demographic data and their clinical characteristic data were recorded. Measurements of their foot and shoe fitting were taken at all stages of the research process. Ninety-two percent of the participants with Down syndrome had foot problems. Results: Only 12 (24%) participants with Down syndrome used bilateral shoes that met the requirements of their feet compared to their controls (50 participants, 90.9% for the right foot; 46 participants, 83.6% for the left foot). Participants with Down syndrome presented statistically significant differences with respect to controls and wore incorrectly sized shoe. Conclusions: Evaluation of foot length and width may prevent development of foot deformities, as well as to improve general health. PMID- 29757956 TI - Osteogenic Differentiation Modulates the Cytokine, Chemokine, and Growth Factor Profile of ASCs and SHED. AB - Great efforts have been made to improve bone regeneration techniques owing to a growing variety of sources of stem cells suitable for autologous transplants. Specifically, adipose-derived stem cells (ASCs) and stems cells from human exfoliated deciduous teeth (SHED) hold great potential for bone tissue engineering and cell therapy. After a preliminary characterization of the main biomolecules ASCs and SHED released in their conditioned media, cells were kept both in normal and osteo-inducing conditions. Conventional assays were performed to prove their osteogenic potential such as quantitative real-time polymerase chain reaction (qRT-PCR) (for RUNX-2, collagen type I, osteopontin and osteonectin), alkaline phosphatase activity, osteocalcin production, and von Kossa staining. Conditioned media were tested again after the osteogenic induction and compared to maintaining condition both at base line and after 14 days of culture. The osteogenic condition inhibited the release of all the biomolecules, with the exception, concerning SHED, of growth-regulated alpha protein precursor (GROalpha), and, to a lesser extent, interleukin (IL)-8. In conclusion, our data support that undifferentiated ASCs and SHED may be preferable to committed ones for general cell therapy approaches, due to their higher paracrine activity. Osteoinduction significantly affects the cytokine, chemokine, and growth factor profile in a differential way, as SHED kept a more pronounced pro-angiogenic signature than ASCs. PMID- 29757960 TI - Comparison of Factors Associated with Fear of Falling between Older Adults with and without a Fall History. AB - Background: Although fear of falling (FOF) has been studied since FOF has negative consequences for the elderly, there is limited information about the risk factors of FOF, including the environment. The purpose of this study was to describe individual and environmental factors of FOF between those with and without a fall history from an ecological aspect and to examine whether individual and environmental factors differently affect the FOF according to the state of fall history in community-dwelling older adults in Korea. Methods: Data from the 2014 Survey of Living Conditions and Welfare Needs of Korean Older Adults were used. Participants were 7730 older adults. Hierarchical logistic regression analysis was conducted to examine the predictors of FOF. Results: According to the ecological model, female and discomfort with the neighborhood environment were significantly associated with greater odds of reporting FOF in both older adults with fall history and those without. A significant interaction was not observed between any variable of FOF in participants with and without a fall history. Conclusions: An ecological model including individual and environmental factors should be considered when conducting research and designing programs and decision policies related to FOF for older adults with and without a history of falling. PMID- 29757957 TI - Arthroprotective Effects of Cf-02 Sharing Structural Similarity with Quercetin. AB - In this study, we synthesized hundreds of analogues based on the structure of small-molecule inhibitors (SMIs) that were previously identified in our laboratory with the aim of identifying potent yet safe compounds for arthritis therapeutics. One of the analogues was shown to share structural similarity with quercetin, a potent anti-inflammatory flavonoid present in many different fruits and vegetables. We investigated the immunomodulatory effects of this compound, namely 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02), in a side-by-side comparison with quercetin. Chondrocytes were isolated from pig joints or the joints of patients with osteoarthritis that had undergone total knee replacement surgery. Several measures were used to assess the immunomodulatory potency of these compounds in tumor necrosis factor (TNF-α)-stimulated chondrocytes. Characterization included the protein and mRNA levels of molecules associated with arthritis pathogenesis as well as the inducible nitric oxide synthase (iNOS)-nitric oxide (NO) system and matrix metalloproteinases (MMPs) in cultured chondrocytes and proteoglycan, and aggrecan degradation in cartilage explants. We also examined the activation of several important transcription factors, including nuclear factor-kappaB (NF-κB), interferon regulatory factor-1 (IRF-1), signal transducer and activator of transcription-3 (STAT-3), and activator protein-1 (AP 1). Our overall results indicate that the immunomodulatory potency of Cf-02 is fifty-fold more efficient than that of quercetin without any indication of cytotoxicity. When tested in vivo using the induced edema method, Cf-02 was shown to suppress inflammation and cartilage damage. The proposed method shows considerable promise for the identification of candidate disease-modifying immunomodulatory drugs and leads compounds for arthritis therapeutics. PMID- 29757963 TI - Acute Toxicity of an Emerging Insecticide Pymetrozine to Procambarus clarkii Associated with Rice-Crayfish Culture (RCIS). AB - This study aims to evaluate the acute toxicity of pymetrozine to juvenile Procambarus clarkii. Two 96-h toxicity tests were conducted to assess the lethal concentration 50 (LC50) values, behaviors, and histopathology (at 50% of the 96 h LC50) after pymetrozine exposure. The results showed high toxicity of pymetrozine to juvenile P. clarkii in a dose and time dependent manner, with a decreasing LC50 from 1.034 mg/L at 24 h to 0.479 mg/L at 96 h. The maximum allowable concentration (MAC) of pymetrozine for P. clarkii was 0.106 mg/L. Behavioral abnormalities were observed in pymetrozine-treated crayfish, such as incunabular hyperexcitability, subsequent disequilibrium, lethargy, and increased defecation. Significant lesions were observed in all pymetrozine-treated tissues, including: (1) in gill, hemocytic infiltration and 33.27% of epithelial cells lesions; (2) in perigastric organs, 64.37%, 29.06%, and 13.99% of tubules with lumen atrophy, vacuolation, and cell lysis, respectively; (3) in heart, 2.5%, 8.55% and 7.74% of hemocytic infiltration, vacuolization, and hyperplasia, respectively; (4) in stomach, 80.82%, 17.77%, 6.98%, 5.24% of cuticula swelling, vacuolization, muscle fragmentation, hemocytic infiltration, respectively; (5) in midgut, 7.45%, 10.98%, 6.74%, and 13.6% of hyperplasia, tissue lysis and vacuolation, hemocytic infiltration, muscle fracture; and (6) in abdominal muscle, 14.09% of myofiber fracture and lysis. This research demonstrates that pymetrozine is highly toxic to juvenile P. clarkii, with significant effects on mortality, behavior and histopathology at concentrations of <=1.1 mg/L, while the estimated practical concentration of pymetrozine in rice-crayfish culture water was around 20 times lower than the calculated MAC. PMID- 29757965 TI - Nutrition of Six Selected Neo-Tropical Mammals in Trinidad and Tobago with the Potential for Domestication. AB - This review highlights the available literature on the nutrition of six neo tropical animals with the potential for domestication-the agouti (Dasyprocta leporina/D. aguti), lappe (Agouti paca), capybara (Hydrochoerus hydrochaeris), manicou/opossum (Didelphis marsupialis insularis), collared peccary (Peccary tajucu) and the red brokcet deer (Mazama americana). Over 100 references were used, spanning over 100 years. The earliest being 1915 and the most recent being 2018. The references used in this review were synthesized to give a detailed look of the dentition, anatomy of the gastrointestinal tract and type of feed these animals consume. Nutritional requirements of the animals are required to understand what is needed for growth, maintenance and reproduction of each physiological stage. The agouti (D. leporina/D. aguti) was observed to be a monogastric mammal that fed primarily on fruits, seeds, animal matter and practiced caecotrophy. The lappe/paca (C. paca/A. paca) was described as a strict herbivore and a frugivore which practiced caecotrophy, with a diet that varied throughout the year, according to food availability. The capybara (H. hydrochaeris) was found to be the largest known rodent and was described as a semiaquatic hindgut fermenter that practiced caecotrophy. The manicou/opossum (D. marsupialis insularis) was found to be an omnivore with a simple stomach. The collared peccary (T. tajacu) was found to be frugivorous. Their unique stomach enabled them to consume a wide variety of feedstuff, allowing them to be found in a wide range of habitats. The red brocket deer (M. americana), a ruminant, was described as a browser that consumed mainly fruits and seeds and they frequented mineral lick. Knowledge of what they consume in the wild is important, so that we know what to feed in captivity. There is also the need to evaluate captive diets while trying to domesticate these mammals and develop nutrient requirement tables for these neo-tropical animals. Finally, an understanding of the dentition and gastrointestinal tract is important to increase efficiency (nutritional and cost). These six neo-tropical mammals were chosen due to their prevalence as game species in Trinidad and Tobago. PMID- 29757966 TI - CNT Foam-Embedded Micro Gas Preconcentrator for Low-Concentration Ethane Measurements. AB - Breath analysis has become increasingly important as a noninvasive process for the clinical diagnosis of patients suffering from various diseases. Many commercial gas preconcentration instruments are already being used to overcome the detection limits of commercial gas sensors for gas concentrations which are as low as ~100 ppb in exhaled breath. However, commercial instruments are large and expensive, and they require high power consumption and intensive maintenance. In the proposed study, a micro gas preconcentrator (MU-PC) filled with a carbon nanotube (CNT) foam as an adsorbing material was designed and fabricated for the detection of low-concentration ethane, which is known to be one of the most important biomarkers related to chronic obstructive pulmonary disease (COPD) and asthma. A comparison of the performance of two gas-adsorbing materials, i.e., the proposed CNT foam and commercial adsorbing material, was performed using the developed MU-PC. The experimental results showed that the synthesized CNT foam performs better than a commercial adsorbing material owing to its lower pressure drop and greater preconcentration efficiency in the MU-PC. The present results show that the application of CNT foam-embedded MU-PC in portable breath analysis systems holds great promise. PMID- 29757964 TI - Comparative Transcriptome Analysis of Waterlogging-Sensitive and Waterlogging Tolerant Chrysanthemum morifolium Cultivars under Waterlogging Stress and Reoxygenation Conditions. AB - Waterlogging stress is among the most severe abiotic stressors in the breeding and the production of Chrysanthemum morifolium. However, the mechanism underlying the response to waterlogging and post-waterlogging reoxygenation in C. morifolium remains unknown. In this study, we compared the differences between the transcriptomes of two chrysanthemum cultivars, i.e., the waterlogging-tolerant cultivar "Nannongxuefeng" and the waterlogging-sensitive cultivar "Qinglu", by performing RNA-seq to elucidate the possible mechanism of waterlogging and reoxygenation in C. morifolium. "Nannongxuefeng" had a higher ethylene production under the waterlogging and reoxygenation conditions. Furthermore, the expression of transcription factors and genes that are involved in the hormone response, N end rule pathway and ROS signaling significantly differed between the two cultivars. "Nannongxuefeng" and "Qinglu" significantly differed in their response to waterlogging and reoxygenation, providing a deeper understanding of the mechanism underlying the response to waterlogging and guidance for the breeding of C. morifolium. PMID- 29757968 TI - Erratum: Dan Li et al.; Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma. Genes 2018, 9, 12. AB - The authors wish to make the following change to their paper [...]. PMID- 29757969 TI - Personality Traits, Strategies for Coping with Stress and the Level of Internet Addiction-A Study of Polish Secondary-School Students. AB - Among the many contributing factors in addictions there are also those describing the individual characteristics and ways of dealing with various life challenges. Despite numerous studies in this area, there is still no unambiguous data on the nature and specificity of this relationship in different age groups. The aim of the study was to assess the relationship between personality dimensions and strategies of coping with stress and the level of Internet addiction. The study was funded by the Ministry of Health under grant no. 93/HM/2015. The study was carried out in a group of 383 persons aged 15 to 19 (M = 16.6, SD = 0.77) attending secondary schools. The following research tools were used: Ten Item Personality Measure, Brief Cope and Internet Addiction Test. Both specific personality traits and styles of coping with stress are related to the addiction to the analysed medium. The personality traits most strongly associated with the risky Internet use were conscientiousness and emotional stability. An association was demonstrated between Internet addiction and the use of coping strategies, such as disengagement, substance use and self-blame. The results obtained demonstrate a major role of personality-related factors in the development of Internet addiction. The attitude to difficulties seems to be the key issue. The findings presented also make it possible to delineate the areas for improvement (e.g., through psychoeducational interventions) to protect young people from the risk of developing the addiction. PMID- 29757970 TI - The Effect of the Traverse Feed Rate on the Microstructure and Mechanical Properties of Laser Deposited Fe3Al (Zr,B) Intermetallic Alloy. AB - The results of the fabrication of components made with Fe-30%Al-0.35%Zr-0.1%B alloy powder using the Laser Engineered Net Shaping (LENSTM) system operated at different traverse feed rates are described in this paper. The temperature of the molten metal pool was recorded during this process. Depending on the assumed feed rate, the formation of Zr-based precipitates with various morphologies and distributions was observed in the structure of the investigated material. It was found that as the traverse speed increased, spheroidization, refinement, and a more homogeneous distribution of these precipitates occurred. PMID- 29757967 TI - Epigenetics of Subcellular Structure Functioning in the Origin of Risk or Resilience to Comorbidity of Neuropsychiatric and Cardiometabolic Disorders. AB - Mechanisms controlling mitochondrial function, protein folding in the endoplasmic reticulum (ER) and nuclear processes such as telomere length and DNA repair may be subject to epigenetic cues that relate the genomic expression and environmental exposures in early stages of life. They may also be involved in the comorbid appearance of cardiometabolic (CMD) and neuropsychiatric disorders (NPD) during adulthood. Mitochondrial function and protein folding in the endoplasmic reticulum are associated with oxidative stress and elevated intracellular calcium levels and may also underlie the vulnerability for comorbid CMD and NPD. Mitochondria provide key metabolites such as nicotinamide adenine dinucleotide (NAD+), ATP, alpha-ketoglutarate and acetyl coenzyme A that are required for many transcriptional and epigenetic processes. They are also a source of free radicals. On the other hand, epigenetic markers in nuclear DNA determine mitochondrial biogenesis. The ER is the subcellular organelle in which secretory proteins are folded. Many environmental factors stop the ability of cells to properly fold proteins and modify post-translationally secretory and transmembrane proteins leading to endoplasmic reticulum stress and oxidative stress. ER functioning may be epigenetically determined. Chronic ER stress is emerging as a key contributor to a growing list of human diseases, including CMD and NPD. Telomere loss causes chromosomal fusion, activation of the control of DNA damage-responses, unstable genome and altered stem cell function, which may underlie the comorbidity of CMD and NPD. The length of telomeres is related to oxidative stress and may be epigenetically programmed. Pathways involved in DNA repair may be epigenetically programmed and may contribute to diseases. In this paper, we describe subcellular mechanisms that are determined by epigenetic markers and their possible relation to the development of increased susceptibility to develop CMD and NPD. PMID- 29757971 TI - Comparison of the Conventional and Electroenhanced Direct-Immersion Solid-Phase Microextraction for Sampling of Nicotine in Biological Fluids of the Human Body. AB - A stainless steel fiber was made porous and adhesive by platinization and then coated by nanostructured polypyrrole (PPy), using an appropriate electrophoretic deposition (EPD) method. The morphological surface structure and functional groups of the PPy-coated fiber were studied using SEM (Scanning electron microscope) instrument. The prepared fiber was used for comparison of direct immersion (DI) and electroenhanced direct immersion solid-phase microextraction (EE-DI-SPME) of nicotine in human plasma and urine samples followed by gas chromatography flame ionization detector (GC-FID) determination. The effects of the influential experimental parameters on the efficiency of the DI-SPME and EE DI-SPME methods, including the pH and ionic strength of the sample solution, applied Direct current (DC) voltage, extraction temperature and time and stirring rate, were optimized. Under the optimal conditions, the calibration curves for the DI-SPME-GC-FID and EE-DI-SPME-GC-FID methods were linear over the ranges of 0.1-10.0 MUg mL-1 and 0.001-10.0 MUg mL-1, respectively. The relative standard deviations (RSDs, n = 6) were found to be 6.1% and 4.6% for the DI and EE strategies, respectively. The LODs (limit of detection) of the DI-SPME-GC-FID and EE-DI-SPME-GC-FID methods were found to be 10 and 0.3 ng mL-1, respectively. The relative recovery values (for the analysis of 1 ug mL-1 nicotine) were found to be 91-110% for EE-DI-SPME and 75-105% for DI-SPME. The enrichment factors for DI SPME and EE-DI-SPME sampling were obtained as 38,734 and 50,597, respectively. The results indicated that EE-SPME was more efficient for quantitation of nicotine in biological fluids. The developed procedure was successfully carried out for the extraction and measurement of nicotine in real plasma and urine samples. PMID- 29757972 TI - Short-Term Soy Protein Isolate Feeding Prevents Liver Steatosis and Reduces Serum ALT and AST Levels in Obese Female Zucker Rats. AB - Non-alcoholic fatty liver disease is a common liver disorder worldwide and is associated with obesity. We investigated effects of obesity and short-term intake of soy protein with isoflavones (SPI) on body weight change, energy intake, liver steatosis, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leptin levels. Seventeen lean and seventeen obese (fa/fa) female Zucker rats were randomly assigned to either casein or SPI diet for 8 weeks. Body weight was recorded twice weekly; feed intake was measured weekly. Livers were examined histologically, and serum AST, ALT, and leptin levels were measured. Obese soy-fed (OS) rats gained more weight but had lower liver steatosis than obese casein-fed (OC) rats. Energy intake for OS versus OC rats were only different at weeks 2 and 3. Serum AST and ALT levels were lower in OS versus OC rats. Obesity increased serum leptin levels for both diets. In summary, short term SPI intake reduced liver steatosis, and the only time points at which the mean energy intakes of OS and OC rats differed were at weeks 2 and 3, where OS rats had a higher mean energy intake, which may have accounted for the increased body weight in OS rats. PMID- 29757974 TI - Evidencing Protective and Risk Factors for Harmful Alcohol Drinking in Adolescence: A Prospective Analysis of Sport-Participation and Scholastic Achievement in Older Adolescents from Croatia. AB - Background: The prevalence of alcohol drinking (AD) in Croatian adolescents is alarming, but there is an evident lack of prospective analyses of the protective/risk factors of AD. This study aimed to prospectively investigate the relationships between scholastic and sport factors and harmful alcohol drinking (HD) in older adolescents. Methods: The participants (n = 644, 53.7% females) were 16 years of age at study baseline and were tested at baseline and again 20 months later (follow-up). The predictors included four variables of scholastic achievement and four factors evidencing involvement in sport. Criterion was AD observed on the Alcohol Use Disorders Identification Test (AUDIT), and results were later categorized into harmful drinking (HD) and non-harmful drinking (NHD). The HD at baseline, HD at follow-up and HD initiation during the study course were observed as criteria in logistic regression analyses, which were additionally controlled for confounders (age, gender, socioeconomic status, and conflict with parents). Results: With 22% and 29% adolescents who reported HD at baseline and follow-up, respectively, the prevalence of HD remains among the highest in Europe. Scholastic failure was systematically related to HD at baseline and follow-up, but scholastic variables did not predict HD initiation during the course of the study. The higher odds for HD at baseline were evidenced for current and former team sport athletes. Those who quit individual sport were more likely to engage in HD at follow-up. Longer involvement in sport (OR: 2.10, 95% CI: 1.18-3.72), higher sport result (OR: 3.15, 95% CI: 1.19-8.34), and quitting individual sport (OR: 13.13, 95% CI: 2.67-64.62) were predictive of HD initiation. Conclusions: The results indicated specific associations between sport factors with HD initiation, which is understandable knowing the high stress placed on young athletes in this period of life, mainly because of the forthcoming selection between junior (amateur) and senior (professional) level. The results did not allow interpretation of the cause-effect relationship between scholastic failure and HD in the studied period. PMID- 29757975 TI - A Novel Strain Sensor with Large Measurement Range Based on All Fiber Mach Zehnder Interferometer. AB - We have proposed a high sensitive photonic crystal fiber (PCF) strain sensor based on the Mach-Zehnder interferometer (MZI). The sensing head is formed by all fiber in-line single mode-multimode-photonic-crystal-single mode fiber (SMPS) structure, using only the splicing method. Such a strain sensor exhibited a high sensitivity of -2.21 pm/MUepsilon within a large measurement range of up to 5000 MUepsilon and a large fringe visibility of up to 24 dB. Moreover, it was found that the strain sensitivity was weekly dependent of the length of PCF or MMF. In addition, the sensor exhibited the advantages of simplicity of fabrication, high sensitivity and larger fringe visibility. PMID- 29757977 TI - ZnO- and TiO2-Based Nanostructures. AB - Transition-metal oxide (TMO) nanostructures are the focus of current research efforts in nanotechnology since they are the most common minerals on Earth, and also thanks to their special shapes, compositions, and chemical and physical properties.[...]. PMID- 29757973 TI - A New Strategy to Control and Eradicate "Undruggable" Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology. AB - Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future. PMID- 29757978 TI - Diet-Induced Weight Loss Has No Effect on Psychological Stress in Overweight and Obese Adults: A Meta-Analysis of Randomized Controlled Trials. AB - The effect of weight loss on psychological stress is unknown. The study aimed to investigate the effect of diet-induced weight loss in overweight and obese adults on psychological measures of stress through a meta-analysis of randomized controlled trials (RCTs). Databases including Medline Complete, Embase and PsycINFO were searched up to February 2018 for diet-induced weight loss RCTs, which included self-reported assessment of psychological stress. The mean difference between the intervention and control group of changes in stress (intervention-baseline) was used. Ten RCTs were included with 615 participants (502 women, age range 20-80 years). Overall, there was no change in stress (mean difference -0.06, 95% CI: -0.17, 0.06, p = 0.33) and no change in the five studies with a significant reduction in weight in the intervention group compared to a control group that lost no weight (mean difference in weight -3.9 Kg, 95% CI: -5.51, -2.29, p < 0.0001; mean difference in stress 0.04, 95% CI: -0.17, 0.25, p = 0.71). For all analyses, there was low heterogeneity. The benefits of weight loss for those who are overweight and obese do not appear to either increase or reduce psychological stress at the end of the weight loss period. PMID- 29757976 TI - Fatty Acid beta-Oxidation Is Essential in Leptin-Mediated Oocytes Maturation of Yellow Catfish Pelteobagrus fulvidraco. AB - Although several studies have been conducted to study leptin function, information is very scarce on the molecular mechanism of leptin in fatty acid beta-oxidation and oocytes maturation in fish. In this study, we investigated the potential role of fatty acid beta-oxidation in leptin-mediated oocytes maturation in Pelteobagrus fulvidraco. Exp. 1 investigated the transcriptomic profiles of ovary and the differential expression of genes involved in beta-oxidation and oocytes maturation following rt-hLEP injection; rt-hLEP injection was associated with significant changes in the expression of genes, including twenty-five up regulated genes (CPT1, Acsl, Acadl, Acadm, Hadhb, Echsl, Hsd17b4, Acca, PPARalpha, CYP8B1, ACOX1, ACBP, MAPK, RINGO, Cdc2, MEK1, IGF-1R, APC/C, Cdk2, GnRHR, STAG3, SMC1, FSHbeta and C-Myc) and ten down-regulated gene (PPARgamma, FATCD36, UBC, PDK1, Acads, Raf, Fizzy, C3H-4, Raf and PKC), involved in fatty acid beta-oxidation and oocytes maturation. In Exp. 2, rt-hLEP and specific inhibitors AG490 (JAK-STAT inhibitor) were used to explore whether leptin induced oocytes maturation, and found that leptin incubation increased the diameters of oocytes and percentage of germinal vesicle breakdown (GVBD)-MII oocytes, up regulated mRNA levels of genes involved in oocytes maturation and that leptin induced oocyte maturation was related to activation of JAK-STAT pathway. In Exp. 3, primary oocytes of P. fulvidraco were treated with (R)-(+)-etomoxir (an inhibitor of beta-oxidation) or l-carnitine (an enhancer of beta-oxidation) for 48 h under rt-hLEP incubation. Exp. 3 indicated that the inhibition of fatty acid beta-oxidation resulted in the down-regulation of gene expression involved in oocytes maturation, and repressed the leptin-induced up-regulation of these gene expression. Activation of fatty acid beta-oxidation improved the maturation rate and mean diameter of oocytes, and up-regulated gene expression involved in oocytes maturation. Leptin is one of the main factors that links fatty acid beta oxidation with oocyte maturation; beta-oxidation is essential for leptin-mediated oocyte maturation in fish. PMID- 29757980 TI - Determination of Ten Macrolide Drugs in Environmental Water Using Molecularly Imprinted Solid-Phase Extraction Coupled with Liquid Chromatography-Tandem Mass Spectrometry. AB - With the extensive application of antibiotics in livestock, their contamination of the aquatic environment has received more attention. Molecularly imprinted polymer (MIP), as an eco-friendly and durable solid-phase extraction material, has shown great potential for the separation and enrichment of antibiotics in water. This study aims at developing a practical and economical method based on molecularly imprinted solid phase extraction (MISPE) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously detecting ten macrolide drugs in different sources of water samples. The MIP was synthesized by bulk polymerization using tylosin as the template and methacrylic acid as the functional monomer. The MIP exhibited a favorable load-bearing capacity for water (>90 mL), which is more than triple that of non-molecularly imprinted polymers (NIP). The mean recoveries of macrolides at four spiked concentration levels (limit of quantification, 40, 100, and 400 ng/L) were 62.6 100.9%, with intra-day and inter-day relative standard deviations below 12.6%. The limit of detection and limit of quantification were 1.0-15.0 ng/L and 3.0 40.0 ng/L, respectively. Finally, the proposed method was successfully applied to the analysis of real water samples. PMID- 29757983 TI - A Combined Gravity Compensation Method for INS Using the Simplified Gravity Model and Gravity Database. AB - In recent decades, gravity compensation has become an important way to reduce the position error of an inertial navigation system (INS), especially for a high precision INS, because of the extensive application of high precision inertial sensors (accelerometers and gyros). This paper first deducts the INS's solution error considering gravity disturbance and simulates the results. Meanwhile, this paper proposes a combined gravity compensation method using a simplified gravity model and gravity database. This new combined method consists of two steps all together. Step 1 subtracts the normal gravity using a simplified gravity model. Step 2 first obtains the gravity disturbance on the trajectory of the carrier with the help of ELM training based on the measured gravity data (provided by Institute of Geodesy and Geophysics; Chinese Academy of sciences), and then compensates it into the error equations of the INS, considering the gravity disturbance, to further improve the navigation accuracy. The effectiveness and feasibility of this new gravity compensation method for the INS are verified through vehicle tests in two different regions; one is in flat terrain with mild gravity variation and the other is in complex terrain with fierce gravity variation. During 2 h vehicle tests, the positioning accuracy of two tests can improve by 20% and 38% respectively, after the gravity is compensated by the proposed method. PMID- 29757981 TI - Borylation of alpha,beta-Unsaturated Acceptors by Chitosan Composite Film Supported Copper Nanoparticles. AB - We describe here the preparation of copper nanoparticles stabilized on a chitosan/poly (vinyl alcohol) composite film. This material could catalyze the borylation of alpha,beta-unsaturated acceptors in aqueous media under mild conditions. The corresponding organoboron compounds as well as their converted beta-hydroxyl products were all obtained in good to excellent yields. It is noteworthy that this catalyst of copper nanoparticles can be easily recycled eight times and remained catalytically reactive. This newly developed methodology provides an efficient and sustainable pathway for the synthesis of organoboron compounds and application of copper nanoparticles. PMID- 29757982 TI - Dose-Response Relationships between Second-Hand Smoke Exposure and Depressive Symptoms among Adolescents in Guangzhou, China. AB - There has been little focus on the possible association between second-hand smoke (SHS) exposure and depressive symptoms among adolescents. Thus, this study aimed to explore the dose-response relationships between SHS exposure and depressive symptoms among adolescents and differentiate these associations in setting specific exposure and severity-specific outcomes. A cross-sectional study was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Univariable and multivariable logistic regression models were used to explore the potential associations between SHS exposure and depressive symptoms. Among 3575 nonsmoking students, 29.6% were classified as having probable depressive symptoms and 9.6% had severe depressive symptoms. There were monotonically increasing dose-response relationships between setting-specific (public places, homes, or indoor/outdoor campuses) SHS exposure and severity-specific (probable or severe) depressive symptoms. When examining these relations by source of exposure, we also observed similar dose-response relationships for SHS exposure in campuses from smoking teachers and from smoking classmates. Our findings suggest that regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms among adolescents, and highlight the need for smoke-free environments to protect the health of adolescents. PMID- 29757979 TI - Cost-Effectiveness of Product Reformulation in Response to the Health Star Rating Food Labelling System in Australia. AB - The Health Star Rating (HSR) system is a voluntary front-of-pack labelling (FoPL) initiative endorsed by the Australian government in 2014. This study examines the impact of the HSR system on pre-packaged food reformulation measured by changes in energy density between products with and without HSR. The cost-effectiveness of the HSR system was modelled using a proportional multi-state life table Markov model for the 2010 Australian population. We evaluated scenarios in which the HSR system was implemented on a voluntary and mandatory basis (i.e., HSR uptake across 6.7% and 100% of applicable products, respectively). The main outcomes were health-adjusted life years (HALYs), net costs, and incremental cost effectiveness ratios (ICERs). These were calculated with accompanying 95% uncertainty intervals (95% UI). The model predicted that HSR-attributable reformulation leads to small reductions in mean population energy intake (voluntary: 0.98 kJ/day [95% UI: -1.08 to 2.86]; mandatory: 11.81 kJ/day [95% UI: -11.24 to 36.13]). These are likely to result in reductions in mean body weight (voluntary: 0.01 kg [95% UI: -0.01 to 0.03]; mandatory: 0.11 kg [95% UI: -0.12 to 0.32], and HALYs (voluntary: 4207 HALYs [95% UI: 2438 to 6081]; mandatory: 49,949 HALYs [95% UI: 29,291 to 72,153]). The HSR system evaluated via changes in reformulation could be considered cost-effective relative to a willingness-to-pay threshold of A$50,000 per HALY (voluntary: A$1728 per HALY [95% UI: dominant to 10,445] and mandatory: A$4752 per HALY [95% UI: dominant to 16,236]). PMID- 29757985 TI - The Influence of Professional Identity, Job Satisfaction, and Work Engagement on Turnover Intention among Township Health Inspectors in China. AB - Health inspectors are part of the public health workforce in China, and its shortage has been identified as an urgent priority that should be addressed. Turnover is one of the main contributors to the shortage problem. This research assessed the influence of professional identity, job satisfaction and work engagement on turnover intention of township health inspectors and explored the intermediary effect of job satisfaction and work engagement between professional identity and turnover intention among township health inspectors in China. Data were collected from 2426 township health inspectors in Sichuan Province, China. We used structural equation modeling (SEM) to test the hypothesized relationship among the variables. Results showed that a total of 11.3% of participants had a high turnover intention and 34.0% of participants had a medium turnover intention. Job satisfaction had a direct negative effect on turnover intention (beta = -0.38, p < 0.001), work engagement had a direct negative effect on turnover intention (beta = -0.13, p < 0.001), and professional identity had an indirect negative effect on turnover intention through the mediating effect of job satisfaction and work engagement. Our results strongly confirmed that professional identity, job satisfaction and work engagement were strong predicators of turnover intention. According to the results, desirable work environment, quality facilities, fair compensation and adequate advancement opportunities should be emphasized to improve job satisfaction. The turnover intention of health inspectors could be reduced through improving professional identity, enhancing job satisfaction and work engagement. PMID- 29757984 TI - Integrative Bioinformatics and Functional Analyses of GEO, ENCODE, and TCGA Reveal FADD as a Direct Target of the Tumor Suppressor BRCA1. AB - BRCA1 is a multifunctional tumor suppressor involved in several essential cellular processes. Although many of these functions are driven by or related to its transcriptional/epigenetic regulator activity, there has been no genome-wide study to reveal the transcriptional/epigenetic targets of BRCA1. Therefore, we conducted a comprehensive analysis of genomics/transcriptomics data to identify novel BRCA1 target genes. We first analyzed ENCODE data with BRCA1 chromatin immunoprecipitation (ChIP)-sequencing results and identified a set of genes with a promoter occupied by BRCA1. We collected 3085 loci with a BRCA1 ChIP signal from four cell lines and calculated the distance between the loci and the nearest gene transcription start site (TSS). Overall, 66.5% of the BRCA1-bound loci fell into a 2-kb region around the TSS, suggesting a role in transcriptional regulation. We selected 45 candidate genes based on gene expression correlation data, obtained from two GEO (Gene Expression Omnibus) datasets and TCGA data of human breast cancer, compared to BRCA1 expression levels. Among them, we further tested three genes (MEIS2, CKS1B and FADD) and verified FADD as a novel direct target of BRCA1 by ChIP, RT-PCR, and a luciferase reporter assay. Collectively, our data demonstrate genome-wide transcriptional regulation by BRCA1 and suggest target genes as biomarker candidates for BRCA1-associated breast cancer. PMID- 29757988 TI - A Lightweight Protocol for Secure Video Streaming. AB - The Internet of Things (IoT) introduces many new challenges which cannot be solved using traditional cloud and host computing models. A new architecture known as fog computing is emerging to address these technological and security gaps. Traditional security paradigms focused on providing perimeter-based protections and client/server point to point protocols (e.g., Transport Layer Security (TLS)) are no longer the best choices for addressing new security challenges in fog computing end devices, where energy and computational resources are limited. In this paper, we present a lightweight secure streaming protocol for the fog computing "Fog Node-End Device" layer. This protocol is lightweight, connectionless, supports broadcast and multicast operations, and is able to provide data source authentication, data integrity, and confidentiality. The protocol is based on simple and energy efficient cryptographic methods, such as Hash Message Authentication Codes (HMAC) and symmetrical ciphers, and uses modified User Datagram Protocol (UDP) packets to embed authentication data into streaming data. Data redundancy could be added to improve reliability in lossy networks. The experimental results summarized in this paper confirm that the proposed method efficiently uses energy and computational resources and at the same time provides security properties on par with the Datagram TLS (DTLS) standard. PMID- 29757987 TI - Genomic Regions Analysis of Seedling Root Traits and Their Regulation in Responses to Phosphorus Deficiency Tolerance in CSSL Population of Elite Super Hybrid Rice. AB - Phosphorus (P) is the essential macro-element supporting rice productivity. Quantitative trait loci (QTL) underlying related traits at the seedling stage under two different phosphorus levels was investigated in rice using a population of 76 Chromosomal Sequence Substitution Lines (CSSLs) derived from a cross between the maintainer variety XieqingzaoB (P stress tolerant) and the restorer variety Zhonghui9308 (P stress sensitive); the parents of super hybrid rice Xieyou9308. A genetic linkage map with 120 DNA marker loci was constructed. At logarithmic odd (LOD) value of 2.0, a total of seven QTLs were detected for studied traits under two P levels and their relative ratio. The LOD values ranged from 2.00 to 3.32 and explaining 10.82% to 18.46% of phenotypic variation. Three QTLs were detected under low phosphorus (P-), one under normal (P+) and three under their relative ratio (P-/P+) on the rice chromosomes 3, 5, 6, 8 and 10. No significant QTLs were found for shoot dry weight (SDW) and total dry weight (TDW). The pleiotropic QTLs influencing root number (qRN5) and root dry weight (qRDW5) as novel QTLs under P- level were detected near marker RM3638 on chromosome 5, which considered to directly contributing to phosphorus deficiency tolerance in rice. These QTLs need further analysis, including the fine mapping and cloning, which may use in molecular marker assisted breeding. PMID- 29757989 TI - Synthesis and Evaluation of Antiplasmodial Activity of 2,2,2 Trifluoroethoxychalcones and 2-Fluoroethoxy Chalcones against Plasmodium falciparum in Culture. AB - A new class of compounds comprising two series of chalcones with 2,2,2 trifluoroethoxy group and 2-fluoroethoxy groups were synthesized and screened for in vitro antiplasmodial activity against Plasmodium falciparum (3D7) using the [3H] hypoxanthine incorporation inhibition assay. Chalcones with 2,2,2 trifluoroethoxy groups substituted on the p- and m-positions of the 1-phenyl ring showed weak antiplasmodial activity, while compounds substituted on the o position of the 1-phenyl ring displayed enhanced antiplasmodial activity, thus indicating that 2,2,2-trifluoroethoxy groups on the 1-phenyl ring of chalcones show position-dependent antiplasmodial activity. Of the 34 compounds synthesized, chalcones 3a and 3f exhibited significant inhibitory effects, with IC50 values of 3.0 MUg/mL and 2.2 MUg/mL, respectively. Moreover, these compounds 3a and 3f showed profound antiplasmodial activity in combination with artemisinin in vitro. The most active molecules, 3a, and 3f, were further assessed for their cytotoxicity towards mammalian Vero cells and the selectivity index (SI) values are 8.6, and 8.2 respectively, being considered non-toxic. We also studied the antiplasmodial activity of 2-fluoroethoxychalcones to discern the effect of the number of fluorine atoms in the fluoroethoxy group. Our results showed that chalcones with 2-fluoroethoxy group on the 1-phenyl ring exhibited more enhanced inhibitory effects on the growth of parasites than their trifluoro analogues, which reveals that monofluoroethoxy group is generally more effective than trifluoroethoxy group in the inhibition of parasite growth. Thus o-2,2,2 trifluoroethoxychalcones (Series 3) and 2-fluoroethoxychalcones may serve as good antiplasmodial candidates for future further development. PMID- 29757991 TI - A Review: The Bioactivities and Pharmacological Applications of Polygonatum sibiricum polysaccharides. AB - Traditional Chinese Medicine (TCM) has been widely used in China and is regarded as the most important therapeutic. Polygonatum sibiricum (PS), a natural plant used in traditional Chinese medicine, has various functions associated with a number of its components. There are many compositions in PS including polysaccharides, steroids, anthraquinone, alkaloids, cardiac glycosides, lignin, vitamins, various acids, and so on. Of these, polysaccharides play a significant role in PS-based therapeutics. This article summarizes Polygonatum sibiricum polysaccharides (PSP) have many pharmacological applications and biological activities, such as their antioxidant activity, anti-aging activity, an anti fatigue effect, immunity enhancement effect, antibacterial effect, anti inflammatory effect, hypolipidemic and antiatherosclerotic effects, anti osteoporosis effect, liver protection, treatment of diabetes mellitus (DM), anti cancer effect, and may help prevent Alzheimer's disease, and so on. This review summarized the extraction method, purification method, compositions, pharmacological applications, biological activities, biosynthesis, and prospects of PSP, providing a basis for further study of PS and PSP. PMID- 29757990 TI - Tick Paralysis: Solving an Enigma. AB - In comparison to other arachnids, ticks are major vectors of disease, but less than 8% of the known species are capable of inducing paralysis, as compared to the ~99-100% arachnids that belong to venomous classes. When considering the potential monophyly of venomous Arachnida, this review reflects on the implications regarding the classification of ticks as venomous animals and the possible origin of toxins. The origin of tick toxins is compared with scorpion and spider toxins and venoms based on their significance, functionality, and structure in the search to find homologous venomous characters. Phenotypic evaluation of paralysis, as caused by different ticks, demonstrated the need for expansion on existing molecular data of pure isolated tick toxins because of differences and discrepancies in available data. The use of in-vivo, in-vitro, and in-silico assays for the purification and characterization of paralysis toxins were critically considered, in view of what may be considered to be a paralysis toxin. Purified toxins should exhibit physiologically relevant activity to distinguish them from other tick-derived proteins. A reductionist approach to identify defined tick proteins will remain as paramount in the search for defined anti-paralysis vaccines. PMID- 29757992 TI - Nanostructured Graphene: An Active Component in Optoelectronic Devices. AB - Nanostructured and chemically modified graphene-based nanomaterials possess intriguing properties for their incorporation as an active component in a wide spectrum of optoelectronic architectures. From a technological point of view, this aspect brings many new opportunities to the now well-known atomically thin carbon sheet, multiplying its application areas beyond transparent electrodes. This article gives an overview of fundamental concepts, theoretical backgrounds, design principles, technological implications, and recent advances in semiconductor devices that integrate nanostructured graphene materials into their active region. Starting from the unique electronic nature of graphene, a physical understanding of finite-size effects, non-idealities, and functionalizing mechanisms is established. This is followed by the conceptualization of hybridized films, addressing how the insertion of graphene can modulate or improve material properties. Importantly, it provides general guidelines for designing new materials and devices with specific characteristics. Next, a number of notable devices found in the literature are highlighted. It provides practical information on material preparation, device fabrication, and optimization for high-performance optoelectronics with a graphene hybrid channel. Finally, concluding remarks are made with the summary of the current status, scientific issues, and meaningful approaches to realizing next-generation technologies. PMID- 29757993 TI - Profiling Redox and Energy Coenzymes in Whole Blood, Tissue and Cells Using NMR Spectroscopy. AB - Coenzymes of cellular redox reactions and cellular energy, as well as antioxidants mediate biochemical reactions fundamental to the functioning of all living cells. Conventional analysis methods lack the opportunity to evaluate these important redox and energy coenzymes and antioxidants in a single step. Major coenzymes include redox coenzymes: NAD+ (oxidized nicotinamide adenine dinucleotide), NADH (reduced nicotinamide adenine dinucleotide), NADP+ (oxidized nicotinamide adenine dinucleotide phosphate) and NADPH (reduced nicotinamide adenine dinucleotide phosphate); energy coenzymes: ATP (adenosine triphosphate), ADP (adenosine diphosphate) and AMP (adenosine monophosphate); and antioxidants: GSSG (oxidized glutathione) and GSH (reduced glutathione). We show here that a simple 1H NMR experiment can measure these coenzymes and antioxidants in tissue and whole blood apart from a vast pool of other metabolites. In addition, focused on the goal of identification of coenzymes in subcellular fractions, we demonstrate analysis of coenzymes in the cytoplasm using breast cancer cells. Owing to their unstable nature, or low concentrations, most of the coenzymes either evade detection or lose their integrity when established sample preparation and analysis methods are used. To overcome this challenge, here we describe the development of new methods to detect these molecules without affecting the integrity of other metabolites. We used an array of 1D and 2D NMR methods, chemical shift databases, pH measurements and spiking with authentic compounds to establish the identity of peaks for the coenzymes and antioxidants in NMR spectra. Interestingly, while none of the coenzymes and antioxidants were detected in plasma, they were abundant in whole blood. Considering that the coenzymes and antioxidants represent a sensitive measure of human health and risk for numerous diseases, the presented NMR methods to measure them in one step potentially open new opportunities in the metabolomics field. PMID- 29757995 TI - A Personalized QoS Prediction Approach for CPS Service Recommendation Based on Reputation and Location-Aware Collaborative Filtering. AB - With the rapid development of cyber-physical systems (CPS), building cyber physical systems with high quality of service (QoS) has become an urgent requirement in both academia and industry. During the procedure of building Cyber physical systems, it has been found that a large number of functionally equivalent services exist, so it becomes an urgent task to recommend suitable services from the large number of services available in CPS. However, since it is time-consuming, and even impractical, for a single user to invoke all of the services in CPS to experience their QoS, a robust QoS prediction method is needed to predict unknown QoS values. A commonly used method in QoS prediction is collaborative filtering, however, it is hard to deal with the data sparsity and cold start problem, and meanwhile most of the existing methods ignore the data credibility issue. Thence, in order to solve both of these challenging problems, in this paper, we design a framework of QoS prediction for CPS services, and propose a personalized QoS prediction approach based on reputation and location aware collaborative filtering. Our approach first calculates the reputation of users by using the Dirichlet probability distribution, so as to identify untrusted users and process their unreliable data, and then it digs out the geographic neighborhood in three levels to improve the similarity calculation of users and services. Finally, the data from geographical neighbors of users and services are fused to predict the unknown QoS values. The experiments using real datasets show that our proposed approach outperforms other existing methods in terms of accuracy, efficiency, and robustness. PMID- 29757996 TI - Design of a Low-Power, Small-Area AEC-Q100-Compliant SENT Transmitter in Signal Conditioning IC for Automotive Pressure and Temperature Complex Sensors in 180 Nm CMOS Technology. AB - In this paper, a low-power and small-area Single Edge Nibble Transmission (SENT) transmitter design is proposed for automotive pressure and temperature complex sensor applications. To reduce the cost and size of the hardware, the pressure and temperature information is processed with a single integrated circuit (IC) and transmitted at the same time to the electronic control unit (ECU) through SENT. Due to its digital nature, it is immune to noise, has reduced sensitivity to electromagnetic interference (EMI), and generates low EMI. It requires only one PAD for its connectivity with ECU, and thus reduces the pin requirements, simplifies the connectivity, and minimizes the printed circuit board (PCB) complexity. The design is fully synthesizable, and independent of technology. The finite state machine-based approach is employed for area efficient implementation, and to translate the proposed architecture into hardware. The IC is fabricated in 1P6M 180 nm CMOS process with an area of (116 MUm * 116 MUm) and 4.314 K gates. The current consumption is 50 MUA from a 1.8 V supply with a total 90 MUW power. For compliance with AEC-Q100 for automotive reliability, a reverse and over voltage protection circuit is also implemented with human body model (HBM) electro-static discharge (ESD) of +6 kV, reverse voltage of -16 V to 0 V, over voltage of 8.2 V to 16 V, and fabricated area of 330 MUm * 680 MUm. The extensive testing, measurement, and simulation results prove that the design is fully compliant with SAE J2716 standard. PMID- 29757986 TI - Medicinal Plants Used in the Treatment of Human Immunodeficiency Virus. AB - Since the beginning of the epidemic, human immunodeficiency virus (HIV) has infected around 70 million people worldwide, most of whom reside is sub-Saharan Africa. There have been very promising developments in the treatment of HIV with anti-retroviral drug cocktails. However, drug resistance to anti-HIV drugs is emerging, and many people infected with HIV have adverse reactions or do not have ready access to currently available HIV chemotherapies. Thus, there is a need to discover new anti-HIV agents to supplement our current arsenal of anti-HIV drugs and to provide therapeutic options for populations with limited resources or access to currently efficacious chemotherapies. Plant-derived natural products continue to serve as a reservoir for the discovery of new medicines, including anti-HIV agents. This review presents a survey of plants that have shown anti-HIV activity, both in vitro and in vivo. PMID- 29757994 TI - Bioinformatics Meets Virology: The European Virus Bioinformatics Center's Second Annual Meeting. AB - The Second Annual Meeting of the European Virus Bioinformatics Center (EVBC), held in Utrecht, Netherlands, focused on computational approaches in virology, with topics including (but not limited to) virus discovery, diagnostics, (meta )genomics, modeling, epidemiology, molecular structure, evolution, and viral ecology. The goals of the Second Annual Meeting were threefold: (i) to bring together virologists and bioinformaticians from across the academic, industrial, professional, and training sectors to share best practice; (ii) to provide a meaningful and interactive scientific environment to promote discussion and collaboration between students, postdoctoral fellows, and both new and established investigators; (iii) to inspire and suggest new research directions and questions. Approximately 120 researchers from around the world attended the Second Annual Meeting of the EVBC this year, including 15 renowned international speakers. This report presents an overview of new developments and novel research findings that emerged during the meeting. PMID- 29757998 TI - Highly Efficient, Low-Cost, and Magnetically Recoverable FePt-Ag Nanocatalysts: Towards Green Reduction of Organic Dyes. AB - Nowadays, synthetic organic dyes and pigments discharged from numerous industries are causing unprecedentedly severe water environmental pollution, and conventional water treatment processes are hindered due to the corresponding sophisticated aromatic structures, hydrophilic nature, and high stability against light, temperature, etc. Herein, we report an efficient fabrication strategy to develop a new type of highly efficient, low-cost, and magnetically recoverable nanocatalyst, i.e., FePt-Ag nanocomposites, for the reduction of methyl orange (MO) and rhodamine B (RhB), by a facile seed deposition process. X-ray diffraction results elaborate that the as-synthesized FePt-Ag nanocomposites are pure disordered face-centered cubic phase. Transmission electron microscopy studies demonstrate that the amount of Ag seeds deposited onto the surfaces of FePt nanocrystals increases when increasing the additive amount of silver colloids. The linear correlation of the MO and RhB concentration versus reaction time catalyzed by FePt-Ag nanocatalysts is in line with pseudo-first-order kinetics. The reduction rate constants of MO and RhB increase with the increase of the amount of Ag seeds. FePt-Ag nanocomposites show good separation ability and reusability, and could be repeatedly applied for nearly complete reduction of MO and RhB for at least six successive cycles. Such cost-effective and recyclable nanocatalysts provide a new material family for use in environmental protection applications. PMID- 29757997 TI - Tetragonia tetragonioides (Pall.) Kuntze Regulates Androgen Production in a Letrozole-Induced Polycystic Ovary Syndrome Model. AB - Tetragonia tetragonioides (Pall.) Kuntze (TTK) is a medicinal plant traditionally used to treat various diseases such as diabetic, inflammatory, and female-related disorders. Polycystic ovary syndrome (PCOS) is a common endocrinological disorder in women of reproductive age, and hyperandrogenism is a prominent feature of PCOS resulting in anovulation and infertility. In this study, we investigated the effects of a TTK extract on androgen generation and regulation of steroidogenic enzymes in vitro and in vivo. Human adrenocortical NCI-H295R cells were used to assess the effects of TTK extract on production of dehydroepiandrosterone and testosterone, as well as the protein expression of steroidogenic enzymes. Further, a letrozole-induced PCOS rat model was used in vivo to assess whether dietary administration of TTK extract restores normal hormones and reduces PCOS symptoms. TTK extract significantly inhibited forskolin (FOR)-induced androgen production in NCI-H295R cells and serum luteinizing hormone, testosterone, and follicular cysts, but not estradiol, were reduced in letrozole-induced PCOS rats orally administered the TTK extract. In addition, TTK extract inhibits androgen biosynthesis through the ERK-CREB signaling pathway, which regulates CYP17A1 or HSD3B2 expression. TTK extract could be utilized for the prevention and treatment of hyperandrogenism and other types of PCOS. PMID- 29757999 TI - Betulin-3,28-diphosphate. Physico-Chemical Properties and In Vitro Biological Activity Experiments. AB - Betulin-3,28-diphosphate (BDP) obtained by phosphorylation of betulin using POCl3 has two main structural forms-BDP-1 and BDP-2-which differ in ethanol solubility, melting point, FTIR spectra, thermoanalytical characteristics and biological activity. Betulin-3,28-diphosphate and its sodium salt (Na-BDP) were characterized using 13C and 31P-NMR spectra, powder XRD experiments, as well as differential scanning calorimetry (DSC) and thermogravimetric analysis (TG) methods. The exo-effects at 193 +/- 8 degrees C for ethanol soluble BDP-1 samples (-19.7 +/- 0.2 kJ?mol-1) were about three times less than for ethanol insoluble BDP-2 samples f (-70.5 +/- 0.7 kJ?mol-1). The DSC curves of Na-BDP-1 and Na-BDP-2 characterized the endo-effects having a maximum at 95-112 degrees C. Water-soluble Na-BDP-1 was obtained as needle-like crystals, unlike poorly crystalline Na-BDP-2, whereas BDP-1 and BDP-2 aged with time and were isolated as amorphous substances. In vitro experiments on rats showed that compared to the control, Na-BDP-1 increased catalase and SOD activity and improved energy metabolism more effectively than Na-BDP-2. PMID- 29758000 TI - Degree-of-Freedom Strengthened Cascade Array for DOD-DOA Estimation in MIMO Array Systems. AB - In spatial spectrum estimation, difference co-array can provide extra degrees-of freedom (DOFs) for promoting parameter identifiability and parameter estimation accuracy. For the sake of acquiring as more DOFs as possible with a given number of physical sensors, we herein design a novel sensor array geometry named cascade array. This structure is generated by systematically connecting a uniform linear array (ULA) and a non-uniform linear array, and can provide more DOFs than some exist array structures but less than the upper-bound indicated by minimum redundant array (MRA). We further apply this cascade array into multiple input multiple output (MIMO) array systems, and propose a novel joint direction of departure (DOD) and direction of arrival (DOA) estimation algorithm, which is based on a reduced-dimensional weighted subspace fitting technique. The algorithm is angle auto-paired and computationally efficient. Theoretical analysis and numerical simulations prove the advantages and effectiveness of the proposed array structure and the related algorithm. PMID- 29758001 TI - An Antimicrobial Peptide-Loaded Gelatin/Chitosan Nanofibrous Membrane Fabricated by Sequential Layer-by-Layer Electrospinning and Electrospraying Techniques. AB - Guided bone regeneration (GBR) technique is widely used in the treatment of bone defects caused by peri-implantitis, periodontal disease, etc. However, the GBR membranes commonly used in clinical treatments currently have no antibacterial activity. Therefore, in this study, sequential layer-by-layer electrospinning and electrospraying techniques were utilized to prepare a gelatin (Gln) and chitosan (CS) composite GBR membrane containing hydroxyapatite nanoparticles (nHAp) and antimicrobial peptide (Pac-525)-loaded PLGA microspheres (AMP@PLGA-MS), which was supposed to have osteogenic and antibacterial activities. The scanning electron microscope (SEM) observation showed that the morphology of the nanofibers and microspheres could be successfully produced. The diameters of the electrospun fibers with and without nHAp were 359 +/- 174 nm and 409 +/- 197 nm, respectively, and the mechanical properties of the membrane were measured according to the tensile stress-strain curve. Both the involvement of nHAp and the chemical crosslinking were able to enhance their tensile strength. In vitro cell culture of rat bone marrow mesenchymal stem cells (rBMSCs) indicated that the Gln/CS composite membrane had an ideal biocompatibility with good cell adhesion, spreading, and proliferation. In addition, the Gln/CS membrane containing nHAp could promote osteogenic differentiation of rBMSCs. Furthermore, according to the in vitro drug release assay and antibacterial experiments, the composite GBR membrane containing AMP@PLGA-MS exhibited a long-term sustained release of Pac-525, which had bactericidal activity within one week and antibacterial activity for up to one month against two kinds of bacteria, S. aureus and E. coli. Our results suggest that the antimicrobial peptide-loaded Gln/CS composite membrane (AMP@PLGA-MS@Gln/CS/nHAp) has a great promise in bone generation-related applications for the unique functions of guiding bone regeneration and inhibiting bacterial infection as well. PMID- 29758002 TI - Modelling of Cavity Optomechanical Magnetometers. AB - Cavity optomechanical magnetic field sensors, constructed by coupling a magnetostrictive material to a micro-toroidal optical cavity, act as ultra sensitive room temperature magnetometers with tens of micrometre size and broad bandwidth, combined with a simple operating scheme. Here, we develop a general recipe for predicting the field sensitivity of these devices. Several geometries are analysed, with a highest predicted sensitivity of 180 p T / Hz at 28 MU m resolution limited by thermal noise in good agreement with previous experimental observations. Furthermore, by adjusting the composition of the magnetostrictive material and its annealing process, a sensitivity as good as 20 p T / Hz may be possible at the same resolution. This method paves a way for future design of magnetostrictive material based optomechanical magnetometers, possibly allowing both scalar and vectorial magnetometers. PMID- 29758003 TI - Time-Sharing-Based Synchronization and Performance Evaluation of Color Independent Visual-MIMO Communication. AB - In the field of communication, synchronization is always an important issue. The communication between a light-emitting diode (LED) array (LEA) and a camera is known as visual multiple-input multiple-output (MIMO), for which the data transmitter and receiver must be synchronized for seamless communication. In visual-MIMO, LEDs generally have a faster data rate than the camera. Hence, we propose an effective time-sharing-based synchronization technique with its color independent characteristics providing the key to overcome this synchronization problem in visual-MIMO communication. We also evaluated the performance of our synchronization technique by varying the distance between the LEA and camera. A graphical analysis is also presented to compare the symbol error rate (SER) at different distances. PMID- 29758004 TI - Hand-Held Refractometer-Based Measurement and Excess Permittivity Analysis Method for Detection of Diesel Oils Adulterated by Kerosene in Field Conditions. AB - Adulteration of fuels is a major problem, especially in developing and third world countries. One such case is the adulteration of diesel oil by kerosene. This problem contributes to air pollution, which leads to other far-reaching adverse effects, such as climate change. The objective of this study was to develop a relatively easy measurement method based on an inexpensive, handheld Abbe refractometer for the detection of adulteration and estimation of the ascending order of the amount of kerosene present in adulterated samples in field conditions. We achieved this by increasing the volume of pure diesel sample in the adulterated diesel oil, and measuring the trend of refractive index change, and next, exploiting the true and ideal permittivities of the binary mixture. The permittivity can be obtained with the aid of the measured refractive index of a liquid. Due to the molecular interactions, the true and ideal permittivities of diesel-kerosene binary liquid mixture have a mismatch which can be used to screen for adulterated diesel oils. The difference between the true and the ideal permittivity is the so-called excess permittivity. We first investigated a training set of diesel oils in laboratory in Finland, using the accurate table model Abbe refractometer and depicting the behavior of the excess permittivity of the mixture of diesel oil and kerosene. Then, we measured same samples in the laboratory using a handheld refractometer. Finally, preliminary field measurements using the handheld device were performed in Tanzania to assess the accuracy and possibility of applying the suggested method in field conditions. We herein show that it is not only possible to detect even relatively low adulteration levels of diesel in kerosene-namely, 5%, 10%, and 15%-but also it is possible to monitor the ascending order of adulteration for different adulterated diesel samples. We propose that the method of increasing the volume of an unknown (suspected) diesel oil sample by adding a known authentic diesel sample and monitoring excess permittivity is useful for the screening of adulterated diesel oil in field measurement conditions. PMID- 29758006 TI - Multi-Touch Tabletop System Using Infrared Image Recognition for User Position Identification. AB - A tabletop system can facilitate multi-user collaboration in a variety of settings, including small meetings, group work, and education and training exercises. The ability to identify the users touching the table and their positions can promote collaborative work among participants, so methods have been studied that involve attaching sensors to the table, chairs, or to the users themselves. An effective method of recognizing user actions without placing a burden on the user would be some type of visual process, so the development of a method that processes multi-touch gestures by visual means is desired. This paper describes the development of a multi-touch tabletop system using infrared image recognition for user position identification and presents the results of touch gesture recognition experiments and a system-usability evaluation. Using an inexpensive FTIR touch panel and infrared light, this system picks up the touch areas and the shadow area of the user's hand by an infrared camera to establish an association between the hand and table touch points and estimate the position of the user touching the table. The multi-touch gestures prepared for this system include an operation to change the direction of an object to face the user and a copy operation in which two users generate duplicates of an object. The system usability evaluation revealed that prior learning was easy and that system operations could be easily performed. PMID- 29758005 TI - A Review of the Ongoing Research on Zika Virus Treatment. AB - The Zika fever is an arboviral disease resulting from the infection with Zika virus (ZIKV). The virus is transmitted to humans by the bite of Aedes mosquitos, mainly Aedes aegypti and Aedes albopictus. ZIKV has been detected for decades in African and Asian regions and, since 2007, has spread to other continents; among them, infections are most reported in the Americas. This can be explained by the presence of vectors in highly populated and tropical regions where people are susceptible to contamination. ZIKV has been considered by the World Health Organization a serious public health problem because of the increasing number of cases of congenital malformation and neurological disorders related to its infection, such as microcephaly, Guillain-Barre syndrome, meningoencephalitis, and myelitis. There is no vaccine or specific antiviral against ZIKV. The infection is best prevented by avoiding mosquito bite, and the treatment of infected patients is palliative. In this context, the search for efficient antivirals is necessary but remains challenging. Here, we aim to review the molecules that have been described to interfere with ZIKV life cycle and discuss their potential use in ZIKV therapy. PMID- 29758008 TI - The Evaluation of Damage Effects on MgO Added Concrete with Slag Cement Exposed to Calcium Chloride Deicing Salt. AB - Concrete systems exposed to deicers are damaged in physical and chemical ways. In mitigating the damage from CaCl2 deicers, the usage of ground slag cement and MgO are investigated. Ordinary Portland cement (OPC) and slag cement are used in different proportions as the binding material, and MgO in doses of 0%, 5%, 7%, and 10% are added to the systems. After 28 days of water-curing, the specimens are immersed in 30% CaCl2 solution by mass for 180 days. Compressive strength test, carbonation test, chloride penetration test, chloride content test, XRD analysis, and SEM-EDAX analysis are conducted to evaluate the damage effects of the deicing solution. Up to 28 days, plain specimens with increasing MgO show a decrease in compressive strength, an increase in carbonation resistance, and a decrease in chloride penetration resistance, whereas the S30- and S50- specimens show a slight increase in compressive strength, an increase in carbonation resistance, and a slight increase in chloride penetration resistance. After 180 days of immersion in deicing solution, specimens with MgO retain their compressive strength longer and show improved durability. Furthermore, the addition of MgO to concrete systems with slag cement induces the formation of magnesium silicate hydrate (M-S-H) phases. PMID- 29758007 TI - Characterization of Rhamnolipids Produced by an Arctic Marine Bacterium from the Pseudomonas fluorescence Group. AB - The marine environment is a rich source of biodiversity, including microorganisms that have proven to be prolific producers of bioactive secondary metabolites. Arctic seas are less explored than warmer, more accessible areas, providing a promising starting point to search for novel bioactive compounds. In the present work, an Arctic marine Pseudomonas sp. belonging to the Pseudomonas (P.) fluorescence group was cultivated in four different media in an attempt to activate biosynthetic pathways leading to the production of antibacterial and anticancer compounds. Culture extracts were pre-fractionated and screened for antibacterial and anticancer activities. One fraction from three of the four growth conditions showed inhibitory activity towards bacteria and cancer cells. The active fractions were dereplicated using molecular networking based on MS/MS fragmentation data, indicating the presence of a cluster of related rhamnolipids. Six compounds were isolated using HPLC and mass-guided fractionation, and by interpreting data from NMR and high-resolution MS/MS analysis; the structures of the compounds were determined to be five mono-rhamnolipids and the lipid moiety of one of the rhamnolipids. Molecular networking proved to be a valuable tool for dereplication of these related compounds, and for the first time, five mono rhamnolipids from a bacterium within the P. fluorescence group were characterized, including one new mono-rhamnolipid. PMID- 29758009 TI - A Review on the Weight-Loss Effects of Oxidized Tea Polyphenols. AB - The mechanistic systems in the body through which tea causes weight loss are complex and multi-dimensional. Additionally, the bioactive components in tea such as catechins, caffeine, and products of tea polyphenol oxidation vary greatly from one major tea type to the next. Green tea has been the primary subject of consideration for investigation into the preventative health effects of tea because it contains the highest levels of phenolic compounds and retains the highest antioxidant capabilities of any major tea type. However, recent research suggests decreasing body fat accumulation has little to do with antioxidant activity and more to do with enzyme inhibition, and gut microbiota interactions. This paper reviews several different tea polyphenol-induced weight-loss mechanisms, and purposes a way in which these mechanisms may be interrelated. Our original 'short-chain fatty acid (SCFA) hypothesis' suggests that the weight-loss efficacy of a given tea is determined by a combination of carbohydrate digestive enzyme inhibition and subsequent reactions of undigested carbohydrates with gut microbiota. These reactions among residual carbohydrates, tea polyphenols, and gut microbiota within the colon produce short-chain fatty acids, which enhance lipid metabolism through AMP-activated protein kinase (AMPK) activation. Some evidence suggests the mechanisms involved in SCFA generation may be triggered more strongly by teas that have undergone fermentation (black, oolong, and dark) than by non-fermented (green) teas. We discussed the mechanistic differences among fermented and non-fermented teas in terms of enzyme inhibition, interactions with gut microbiota, SCFA generation, and lipid metabolism. The inconsistent results and possible causes behind them are also discussed. PMID- 29758010 TI - Combined Transcriptomics, Proteomics and Bioinformatics Identify Drug Targets in Spinal Cord Injury. AB - Spinal cord injury (SCI) causes irreversible tissue damage and severe loss of neurological function. Currently, there are no approved treatments and very few therapeutic targets are under investigation. Here, we combined 4 high-throughput transcriptomics and proteomics datasets, 7 days and 8 weeks following clinically relevant rat SCI to identify proteins with persistent differential expression post-injury. Out of thousands of differentially regulated entities our combined analysis identified 40 significantly upregulated versus 48 significantly downregulated molecules, which were persistently altered at the mRNA and protein level, 7 days and 8 weeks post-SCI. Bioinformatics analysis was then utilized to identify currently available drugs with activity against the filtered molecules and to isolate proteins with known or unknown function in SCI. Our findings revealed multiple overlooked therapeutic candidates with important bioactivity and established druggability but with unknown expression and function in SCI including the upregulated purine nucleoside phosphorylase (PNP), cathepsins A, H, Z (CTSA, CTSH, CTSZ) and proteasome protease PSMB10, as well as the downregulated ATP citrate lyase (ACLY), malic enzyme (ME1) and sodium-potassium ATPase (ATP1A3), amongst others. This work reveals previously unappreciated therapeutic candidates for SCI and available drugs, thus providing a valuable resource for further studies and potential repurposing of existing therapeutics for SCI. PMID- 29758012 TI - The Long Non-Coding RNA MIR503HG Enhances Proliferation of Human ALK-Negative Anaplastic Large-Cell Lymphoma. AB - Anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALCL) is a rare type of highly malignant, non-Hodgkin lymphoma. Currently, only a few gene rearrangements have been linked to ALK-negative ALCL progression. However, the specific molecular mechanisms underlying the growth of ALK-negative ALCL tumors remain unclear. Here, we investigated aberrantly expressed, long non coding RNAs (lncRNAs) in ALK-negative ALCL and assessed their potential biological function. MIR503HG (miR-503 host gene) was highly expressed in ALK negative cell lines and was significantly upregulated in tumors in mice formed from ALK-negative ALCL cell lines. Depletion of MIR503HG suppressed tumor cell proliferation in vivo and in vitro; conversely, its overexpression enhanced tumor cell growth. MIR503HG-induced proliferation was mediated by the induction of microRNA-503 (miR-503) and suppression of Smurf2, resulting in stabilization of the tumor growth factor-beta receptor (TGFBR) and enhanced tumor cell growth. Collectively, these findings support a potential role for MIR503HG in cancer cell proliferation through the miR-503/Smurf2/TGFBR axis and indicate that MIR503HG is a potential marker in ALK-negative ALCL. PMID- 29758011 TI - Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma-A Review. AB - It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)-the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. PMID- 29758016 TI - A Novel DFT-Based DOA Estimation by a Virtual Array Extension Using Simple Multiplications for FMCW Radar. AB - We propose a novel discrete Fourier transform (DFT)-based direction of arrival (DOA) estimation by a virtual array extension using simple multiplications for frequency modulated continuous wave (FMCW) radar. DFT-based DOA estimation is usually employed in radar systems because it provides the advantage of low complexity for real-time signal processing. In order to enhance the resolution of DOA estimation or to decrease the missing detection probability, it is essential to have a considerable number of channel signals. However, due to constraints of space and cost, it is not easy to increase the number of channel signals. In order to address this issue, we increase the number of effective channel signals by generating virtual channel signals using simple multiplications of the given channel signals. The increase in channel signals allows the proposed scheme to detect DOA more accurately than the conventional scheme while using the same number of channel signals. Simulation results show that the proposed scheme achieves improved DOA estimation compared to the conventional DFT-based method. Furthermore, the effectiveness of the proposed scheme in a practical environment is verified through the experiment. PMID- 29758014 TI - Investigating the Epigenetic Discrimination of Identical Twins Using Buccal Swabs, Saliva, and Cigarette Butts in the Forensic Setting. AB - Monozygotic (MZ) twins are typically indistinguishable via forensic DNA profiling. Recently, we demonstrated that epigenetic differentiation of MZ twins is feasible; however, proportions of twin differentially methylated CpG sites (tDMSs) identified in reference-type blood DNA were not replicated in trace-type blood DNA. Here we investigated buccal swabs as typical forensic reference material, and saliva and cigarette butts as commonly encountered forensic trace materials. As an analog to a forensic case, we analyzed one MZ twin pair. Epigenome-wide microarray analysis in reference-type buccal DNA revealed 25 candidate tDMSs with >0.5 twin-to-twin differences. MethyLight quantitative PCR (qPCR) of 22 selected tDMSs in trace-type DNA revealed in saliva DNA that six tDMSs (27.3%) had >0.1 twin-to-twin differences, seven (31.8%) had smaller (<0.1) but robustly detected differences, whereas for nine (40.9%) the differences were in the opposite direction relative to the microarray data; for cigarette butt DNA, results were 50%, 22.7%, and 27.3%, respectively. The discrepancies between reference-type and trace-type DNA outcomes can be explained by cell composition differences, method-to-method variation, and other technical reasons including bisulfite conversion inefficiency. Our study highlights the importance of the DNA source and that careful characterization of biological and technical effects is needed before epigenetic MZ twin differentiation is applicable in forensic casework. PMID- 29758015 TI - Determinants and Temporal Trends of Perfluoroalkyl Substances in Pregnant Women: The Hokkaido Study on Environment and Children's Health. AB - Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m2 had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5-24.9 kg/m2). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study. PMID- 29758017 TI - The Effects of Dabigatran and Rivaroxaban on Markers of Polymorphonuclear Leukocyte Activation. AB - Dabigatran is an oral direct thrombin inhibitor, and rivaroxaban, a factor Xa inhibitor. Dabigatran has been implicated in the etiology of acute coronary syndromes and as these occur following inflammatory changes in the endothelium, we investigated the inflammatory potential of these agents in vitro. In order to do so, polymorphonuclear leukocytes (PMNL) were isolated from heparinized venous blood from non-smoking, healthy adults and exposed to dabigatran or rivaroxaban (0.5-10 uM). Generation of reactive oxygen species (ROS), elastase release, cytosolic Ca2+ fluxes, neutrophil extracellular trap (NET) formation and cell viability were measured using chemiluminescence, spectrophotometric and flow cytometric procedures respectively. However, with the exception of modest inhibitory effects on elastase release, neither agent at concentrations of up to 10 uM affected these markers of PMNL activation. Although no pro-inflammatory effects of dabigatran nor any difference between the two test agents were detected in vitro, the existence of a pro-inflammatory mechanism involving the generation of thrombin during dabigatran therapy cannot be fully excluded. PMID- 29758013 TI - Selenium-Dependent Antioxidant Enzymes: Actions and Properties of Selenoproteins. AB - Unlike other essential trace elements that interact with proteins in the form of cofactors, selenium (Se) becomes co-translationally incorporated into the polypeptide chain as part of 21st naturally occurring amino acid, selenocysteine (Sec), encoded by the UGA codon. Any protein that includes Sec in its polypeptide chain is defined as selenoprotein. Members of the selenoproteins family exert various functions and their synthesis depends on specific cofactors and on dietary Se. The Se intake in productive animals such as chickens affect nutrient utilization, production performances, antioxidative status and responses of the immune system. Although several functions of selenoproteins are unknown, many disorders are related to alterations in selenoprotein expression or activity. Selenium insufficiency and polymorphisms or mutations in selenoproteins' genes and synthesis cofactors are involved in the pathophysiology of many diseases, including cardiovascular disorders, immune dysfunctions, cancer, muscle and bone disorders, endocrine functions and neurological disorders. Finally, heavy metal poisoning decreases mRNA levels of selenoproteins and increases mRNA levels of inflammatory factors, underlying the antagonistic effect of Se. This review is an update on Se dependent antioxidant enzymes, presenting the current state of the art and is focusing on results obtained mainly in chicken. PMID- 29758018 TI - The Work Ability of Hong Kong Construction Workers in Relation to Individual and Work-Related Factors. AB - The shortage in Hong Kong of construction workers is expected to worsen in future due to the aging population and increasing construction activity. Construction work is dangerous and to help reduce the premature loss of construction workers due to work-related disabilities, this study measured the work ability of 420 Hong Kong construction workers with a Work Ability Index (WAI) which can be used to predict present and future work performance. Given the importance of WAI, in this study the effects of individual and work-related factors on WAI were examined to develop and validate a WAI model to predict how individual and work related factors affect work ability. The findings will be useful for formulating a pragmatic intervention program to improve the work ability of construction workers and keep them in the work force. PMID- 29758019 TI - Ginkgo Biloba L. Extract Reduces H2O2-Induced Bone Marrow Mesenchymal Stem Cells Cytotoxicity by Regulating Mitogen-Activated Protein Kinase (MAPK) Signaling Pathways and Oxidative Stress. AB - BACKGROUND The oxidative stress environment of pathological tissue has an adverse effect on the survival of bone marrow mesenchymal stem cells (BMSCs) transplantation. Ginkgo biloba L. extract (EGB) has a potent antioxidant effect. In this research, we assessed the protective effects of EGB and EGB-Containing Serum (EGB CS) on BMSCs against injury induced by hydrogen peroxide (H2O2). MATERIAL AND METHODS BMSCs were pretreated with EGB or EGB CS and treated with H2O2. The cell counting kit-8 (CCK-8) method was utilized to detect cell viability. The DCFH-DA Fluorescent Kit method was used to detect intracellular ROS level. Malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and (CAT) were determined. The Hoechst staining assay and qRT-PCR assay were utilized to evaluate the effect of EGB on cell apoptosis. Mitogen-activated protein kinases (MAPKs) signaling pathway were detected by western blot analysis. RESULTS Compared to the H2O2 group, the number of apoptotic cells in the EGB and EGB CS pretreated groups significantly decreased. The mRNA expression ratio of Bax/Bcl-2 was also decreased. EGB and EGB CS can reduce the production of ROS in BMSCs exposed to H2O2. SOD, GSH-Px and CAT activities were significantly higher compared with those with H2O2 group. Furthermore, EGB or EGB CS pretreatment decreased the protein levels of p-p38MAPK and p-JNK in BMSCs compared to the H2O2 group. CONCLUSIONS Our findings suggested that EGB and EGB CS have protective effect on BMSCs against oxidative stress injury and increase the survival rate of BMSCs transplantation by regulating p38MAPK and JNK signaling. PMID- 29758021 TI - Testing the psychometric properties of the Environmental Attitudes Inventory on undergraduate students in the Arab context: A test-retest approach. AB - The Environmental Attitudes Inventory (EAI) was developed to evaluate the multidimensional nature of environmental attitudes; however, it is based on a dataset from outside the Arab context. This study reinvestigated the construct validity of the EAI with a new dataset and confirmed the feasibility of applying it in the Arab context. One hundred and forty-eight subjects in Study 1 and 130 in Study 2 provided valid responses. An exploratory factor analysis (EFA) was used to extract a new factor structure in Study 1, and confirmatory factor analysis (CFA) was performed in Study 2. Both studies generated a seven-factor model, and the model fit was discussed for both the studies. Study 2 exhibited satisfactory model fit indices compared to Study 1. Factor loading values of a few items in Study 1 affected the reliability values and average variance extracted values, which demonstrated low discriminant validity. Based on the results of the EFA and CFA, this study showed sufficient model fit and suggested the feasibility of applying the EAI in the Arab context with a good construct validity and internal consistency. PMID- 29758023 TI - Genetic variability in Brazilian Capsicum baccatum germplasm collection assessed by morphological fruit traits and AFLP markers. AB - Capsicum baccatum is one of the main pepper species grown and consumed in South America. In Brazil, it is commonly cultivated by family farmers, using mostly the genotypes bishop's hat genotypes (locally cambuci) and red chili pepper (dedo-de moca). This study had the objective of characterizing 116 C. baccatum accessions from different regions of Brazil, based on morphological fruit descriptors and AFLP (Amplified Fragment Length Polymorphisms) markers. Broad phenotypic variability among the C. baccatum accessions was detected when using morphological fruit descriptors. The Ward modified location model (Ward-MLM) discriminated five groups, based mainly on fruit shape. Six combinations of AFLP primers detected polymorphism in 97.93% of the 2466 identified bands, indicating the high genetic variability in the accessions. The UPGMA coincided with the Bayesian clustering analysis and three large groups were formed, separating the wild variety C. baccatum var. praetermissum from the other accessions. There was no relation between genetic distance and geographical origin of the accessions, probably due to the intense exchange of fruits and seeds between farmers. Morphological descriptors used together with AFLP markers proved efficient in detecting the levels of genetic variability among the accessions maintained in the germplasm collections. These results can be used as an additional source of helpful information to be exploited in C. baccatum breeding programs. PMID- 29758020 TI - Defining ICR-Mo, an intrinsic colistin resistance determinant from Moraxella osloensis. AB - Polymyxin is the last line of defense against severe infections caused by carbapenem-resistant gram-negative pathogens. The emergence of transferable MCR 1/2 polymyxin resistance greatly challenges the renewed interest in colistin (polymyxin E) for clinical treatments. Recent studies have suggested that Moraxella species are a putative reservoir for MCR-1/2 genetic determinants. Here, we report the functional definition of ICR-Mo from M. osloensis, a chromosomally encoded determinant of colistin resistance, in close relation to current MCR-1/2 family. ICR-Mo transmembrane protein was prepared and purified to homogeneity. Taken along with an in vitro enzymatic detection, MALDI-TOF mass spectrometry of bacterial lipid A pools determined that the ICR-Mo enzyme might exploit a possible "ping-pong" mechanism to accept the phosphoethanolamine (PEA) moiety from its donor phosphatidylethanolamine (PE) and then transfer it to the 1(or 4')-phosphate position of lipid A via an ICR-Mo-bound PEA adduct. Structural decoration of LPS-lipid A by ICR-Mo renders the recipient strain of E. coli resistant to polymyxin. Domain swapping assays indicate that the two domains of ICR-Mo cannot be functionally-exchanged with its counterparts in MCR-1/2 and EptA, validating its phylogenetic position in a distinct set of MCR-like genes. Structure-guided functional mapping of ICR-Mo reveals a PE lipid substrate recognizing cavity having a role in enzymatic catalysis and the resultant conference of antibiotic resistance. Expression of icr-Mo in E. coli significantly prevents the formation of reactive oxygen species (ROS) induced by colistin. Taken together, our results define a member of a group of intrinsic colistin resistance genes phylogenetically close to the MCR-1/2 family, highlighting the evolution of transferable colistin resistance. PMID- 29758024 TI - Hatchling survival to breeding age in Northern Pine Snakes (Pituophis melanoleucus) in the New Jersey Pine Barrens: Human effects on recruitment from 1986 to 2017. AB - To conserve threatened/endangered species, we need to understand the factors contributing to reproductive success and recruitment to reproductive stage. Obtaining this information is difficult for snakes because they are secretive, are not easy to locate at the same stage each year, and are sometimes sparsely distributed. We determined nest fate, hatchling growth and survival to age 5 years, and recruitment to breeding age of Northern Pine Snakes (Pituophis melanoleucus) in New Jersey Pine Barrens from 1986 to 2017. Pine Snakes are 'threatened' in New Jersey and in other states, and are at risk because of increased human population, habitat loss, predation, and poaching. Age of first breeding was 4-years, based on snout-vent length of gravid and laying females, and snout-vent length of females followed as hatchlings to 5-years. Mean clutch size (+ 1 SE) was 9.5 + 0.3 (N = 53). The annual percent of nests in which eggs hatched averaged 25% (N = 288 nests), and varied among 5-year periods (5% to 30%/year). Of lab-reared hatchlings released into natal nests (N = 90), 26% (2015) and 32% (2016) reached hibernacula excavated in 2016 and 2017. The sex ratio of hatchlings reaching hibernation sites (N = 181) between 1986 and 2015 was skewed toward females (74/106, 59% females), and varied among 5-year periods (47-75% females). Once hatchlings reached a hibernaculum, there was a sex-related difference in survival. For hatchlings reaching a monitored hibernaculum, survival to 3-years was 35% in females and 40% in males, and to 4-years was 25% in females and 33% in males. Using these data, only 10% of females reached 3 years (first possible breeding age), and 7% survived to 4-years. Methodological problems with determining survival rates during these early critical years are discussed. PMID- 29758026 TI - Healthcare costs for the elderly in Japan: Analysis of medical care and long-term care claim records. AB - BACKGROUND: The population is aging rapidly in many developed countries. Such countries need to respond to the growing demand and expanding costs of healthcare (HC) for the elderly. Therefore, it is important to investigate the factors correlating such HC costs. In Japan, HC is composed of two sections, namely medical care (MC) and long-term care (LTC). While many studies have examined MC and LTC costs on their own, few studies have conducted comprehensive investigations of HC costs. The aim of this study is to examine the risk factors that influence HC costs for the elderly who enroll in the LTC insurance system in Japan. METHODS: The inclusion criteria in the present study are as follows: being 65 years of age, or older; certified eligibility for, and use of services offered by the LTC insurance system at home or in an institutional setting in December 2009; and being covered by the National Health Insurance (NHI) system. MC and LTC insurance data were obtained from claim records for the elderly in July and December of 2007, 2008, and 2009 (i.e., a total of six survey points). Panel data, per subject, were constructed using MC and LTC claim records. The sample included 810 subjects and 4029 observations. RESULTS: We estimated a regression equation with a censored dependent variable using a Tobit model. Significant associations between MC or LTC costs and interaction terms (household composition * seasonal effects) were investigated. MC costs significantly decreased and LTC costs significantly increased among subjects living alone during winter. Income level was also a positive determinant of MC costs, while eligibility level was a positive determinant of LTC costs. CONCLUSIONS: We recommend that the health policy for the elderly focus more on seasonal effects, household composition, and income level, as well as on eligibility level. PMID- 29758022 TI - Determinants of hardship financing in coping with out of pocket payment for care seeking of under five children in selected rural areas of Bangladesh. AB - BACKGROUND: Around 63% of total health care expenditure in Bangladesh is mitigated through out of pocket payment (OOP). Heavy reliance on OOP at the time of care seeking poses great threat for financial impoverishment of the households. Households employ different strategies to cope with the associated financial hardship. OBJECTIVE: The aim of this paper is to understand the determinants of hardship financing in coping with OOP adopted for health care seeking of under five childhood illnesses in rural setting of Bangladesh. METHODS: A community based cross sectional survey was conducted during August to October, 2014 in 15 low performing sub-districts of northern and north-east regions of Bangladesh. Of the 7039 mothers of under five children surveyed, 1895 children who suffered from illness and sought care for their illness episodes were reported in this study. Descriptive statistics and ordinal regression analysis were conducted. RESULTS: A total number of 7,039 under five children reported to have suffered illness by their mothers. Among these children 37% suffered from priority illness. Care was sought for 88% children suffering from illnesses. Among them 26% went to a public or private sector medically trained provider. 5% of households incurred illness cost more than 10% of the household's monthly expenditure. The need for assistance was higher among those compared to others (31% vs 13%). Different financing mechanisms adopted to meet OOP are loan with interest (6%), loan without interest (9%) and financial help from relatives (6%) Need for financial assistance varied from 19% among households in the lowest quintile to 9% in the highest wealth. Ordinal regression analysis revealed that burden of hardship financing increases by 2.17 times when care is sought from a private trained provider compared to care seeking from untrained provider (CI: 1.49, 3.17). Similarly, for families that incur a health care expenditure that is more than 10% of their total monthly expenditure (CI:1.46, 3.88), the probability of falling into more severe financial burden increases by 2.4 times. We also found severity of the hardship financing to be around half for households with monthly income of more than BDT 7500 (OR = 0.56, CI: 0.37, 0.86). The burden increased by 2.10 times for households with a deficit (CI: 1.53, 2.88) between their monthly income and expenditure. The interaction between family income and severity of illness showed to significantly affect the scale of hardship financing. Children suffering from priority illness belonging to poor households were found have two times (CI: 1.09, 3.47) higher risks of suffering from hardship financing. CONCLUSION AND POLICY IMPLICATIONS: Findings from this study will help the policy makers to identify the target groups and thereby design effective health financing programs. PMID- 29758027 TI - Single-generation effects on terpenoid defenses in lodgepole pine populations following mountain pine beetle infestation. AB - The recent mountain pine beetle outbreak in western Canada provides an opportunity to study the selection and heritability of tree defenses. We examined terpenoid-based defenses of seedling lodgepole pines which were offspring of mature trees subjected to high levels of mountain pine beetle selective pressure. Seedlings were grown from one of three types of cones: old cones on live trees; young cones on live trees; and cones on trees killed by beetles. Offspring thus represented crosses of non-surviving (NS) x surviving (S), S x S, and NS x NS parents, respectively. Methyl jasmonate was used to induce a defensive reaction in the seedlings. Seed source had a significant effect on levels of ten different terpenes, but not on total terpene concentrations. When the seedlings were grouped by location and treatment type, the seedlings of different cone types could be almost entirely distinguished by terpene profiles. PMID- 29758025 TI - CLCA2 is a positive regulator of store-operated calcium entry and TMEM16A. AB - The Chloride Channel Accessory (CLCA) protein family was first characterized as regulators of calcium-activated chloride channel (CaCC) currents (ICaCC), but the mechanism has not been fully established. We hypothesized that CLCAs might regulate ICaCC by modulating intracellular calcium levels. In cells stably expressing human CLCA2 or vector, we found by calcium imaging that CLCA2 moderately enhanced intracellular-store release but dramatically increased store operated entry of calcium upon cytosolic depletion. Moreover, another family member, CLCA1, produced similar effects on intracellular calcium mobilization. Co immunoprecipitation revealed that CLCA2 interacted with the plasma membrane store operated calcium channel ORAI-1 and the ER calcium sensor STIM-1. The effect of CLCA2 on ICaCC was tested in HEK293 stably expressing calcium-activated chloride channel TMEM16A. Co-expression of CLCA2 nearly doubled ICaCC in response to a calcium ionophore. These results unveil a new mechanism by which CLCA family members activate ICaCC and suggest a broader role in calcium-dependent processes. PMID- 29758028 TI - A surgical simulator for peeling the inner limiting membrane during wet conditions. AB - The present study was performed to establish a novel ocular surgery simulator for training in peeling of the inner limited membrane (ILM). This simulator included a next-generation artificial ILM with mechanical properties similar to the natural ILM that could be peeled underwater in the same manner as in actual surgery. An artificial eye consisting of a fundus and eyeball parts was fabricated. The artificial eye was installed in the eye surgery simulator. The fundus part was mounted in the eyeball, which consisted of an artificial sclera, retina, and ILM. To measure the thickness of the fabricated ILM on the artificial retina, we calculated the distance of the step height as the thickness of the artificial ILM. Two experienced ophthalmologists then assessed the fabricated ILM by sensory evaluation. The minimum thickness of the artificial ILM was 1.9 +/- 0.3 MUm (n = 3). We were able to perform the peeling task with the ILM in water. Based on the sensory evaluation, an ILM with a minimum thickness and 1000 degrees of polymerization was suitable for training. We installed the eye model on an ocular surgery simulator, which allowed for the performance of a sequence of operations similar to ILM peeling. In conclusion, we developed a novel ocular surgery simulator for ILM peeling. The artificial ILM was peeled underwater in the same manner as in an actual operation. PMID- 29758029 TI - Forest resources of nations in relation to human well-being. AB - A universal turnaround has been detected in many countries of the World from shrinking to expanding forests. The forest area of western Europe expanded already in the 19th century. Such early trends of forest resources cannot be associated with the rapid rise of atmospheric carbon dioxide nor with the anthropogenic climate change, which have taken place since the mid 20th century. Modern, most recent spatial patterns of forest expansions and contractions do not correlate with the geography of climate trends nor with dry versus moist areas. Instead, the forest resources trends of nations correlate positively with UNDP Human Development Index. This indicates that forest resources of nations have improved along with progress in human well-being. Highly developed countries apply modern agricultural methods on good farmlands and abandon marginal lands, which become available for forest expansion. Developed countries invest in sustainable programs of forest management and nature protection. Our findings are significant for predicting the future of the terrestrial carbon sink. They suggest that the large sink of carbon recently observed in forests of the World will persist, if the well-being of people continues to improve. However, despite the positive trends in domestic forests, developed nations increasingly outsource their biomass needs abroad through international trade, and all nations rely on unsustainable energy use and wasteful patterns of material consumption. PMID- 29758031 TI - The mass use of deltamethrin collars to control and prevent canine visceral leishmaniasis: A field effectiveness study in a highly endemic area. AB - BACKGROUND: Visceral leishmaniasis (VL) is a zoonosis of great importance. Limitations in current VL control measures compromise efficacy, indicating the need to implement new strategies. The aim of this study was to evaluate the effectiveness of the mass use of deltamethrin-impregnated collars in dogs as a public health measure to control and prevent canine visceral leishmaniasis (CVL). METHODOLOGY: An interventional study was implemented in two endemic areas in the district of Monte Gordo (Bahia-Brazil): an intervention area, in which VL seronegative dogs were collared, and a control area in which only conventional CVL control measures were applied. At baseline, seropositive dogs were removed and seronegative dogs were included. Dogs were then reevaluated every 7-8 months for almost two years. At each time point, dogs in the intervention area that remained seronegative received new collars and newly identified seronegative dogs were included and collared. The local zoonosis control authorities were notified of any dogs that tested seropositive in both areas, which were subsequently marked for euthanasia as mandated by the Brazilian Ministry of Health. PRINCIPAL FINDINGS: In the first serological survey, seroprevalence was similar in both areas. At the second evaluation, significant reductions in seroprevalence were seen in both areas, while seroprevalence in the intervention area reduced to 6.0% during the final evaluation versus an increase of 11.0% in the control area. This significant increase and the estimated relative risk (RR = 0.55) indicated protection against CVL in the intervention area. Although CVL incidence did not differ significantly between the areas, an increased tendency was observed in the control area, which could be due to low seroconversion rates throughout the study or a high loss to follow-up. CONCLUSIONS/SIGNIFICANCE: Although our evaluation of the effectiveness of deltamethrin-impregnated collars as a community-wide public health control measure was inconclusive, this measure likely provides protection over time. In endemic areas of Brazil, this strategy represents an operational challenge for local zoonosis control authorities, indicating the need for adjustments, including improved collar design. PMID- 29758030 TI - Characterization of a Trichinella spiralis putative serine protease. Study of its potential as sero-diagnostic tool. AB - BACKGROUND: Trichinellosis is a serious zoonositc parasitosis worldwide. Because its clinical manifestations aren't specific, the diagnosis of trichinellosis is not easy to be made. Trichinella spiralis muscle larva (ML) excretory-secretory (ES) antigens are the most widely applied diagnostic antigens for human trichinellosis, but the major drawback of the ES antigens for assaying anti Trichinella antibodies is the false negative in the early Trichinella infection period. The aim of this study was to characterize the T. spiralis putative serine protease (TsSP) and to investigate its potential use for diagnosis of trichinellosis. METHODOLOGY/PRINCIPAL FINDINGS: The full-length TsSP sequence was cloned and expressed, and recombinant TsSP (rTsSP) was purified by Ni-NTA Sefinose Column. On Western blotting analysis the rTsSP was recognized by T. spiralis-infected mouse serum, and the natural TsSP was identified in T. spiralis ML crude and ES antigens by using anti-rTsSP serum. Expression of TsSP was detected at various T. spiralis developmental stages (newborn larvae, muscle larvae, intestinal infective larvae and adult worms). Immunolocalization identified the TsSP principally in cuticles and stichosomes of the nematode. The sensitivity of rTsSP-ELISA and ES-ELISA was 98.11% (52/53) and 88.68% (47/53) respectively (P > 0.05) when the sera from trichinellosis patients were examined. However, while twenty-one serum samples of trichinellosis patients' sera at 19 days post-infection (dpi) were tested, the sensitivity (95.24%) of rTsSP-ELISA was distinctly higher than 71.43% of ES-ELISA (P < 0.05). The specificity (99.53%) of rTsSP-ELISA was remarkably higher than 91.98% of ES-ELISA (P < 0.01). Only one out of 20 serum samples of cysticercosis patients cross-reacted with the rTsSP. Specific anti-Trichinella IgG in infected mice was first detected by rTsSP ELISA as soon as 7 dpi and antibody positive rate reached 100% on 10 dpi, whereas the ES-ELISA did not permit detection of 100% of infected mice before 16 dpi. CONCLUSIONS: The rTsSP is a potential early diagnostic antigen for human trichinellosis. PMID- 29758032 TI - A loop-counting method for covariate-corrected low-rank biclustering of gene expression and genome-wide association study data. AB - A common goal in data-analysis is to sift through a large data-matrix and detect any significant submatrices (i.e., biclusters) that have a low numerical rank. We present a simple algorithm for tackling this biclustering problem. Our algorithm accumulates information about 2-by-2 submatrices (i.e., 'loops') within the data matrix, and focuses on rows and columns of the data-matrix that participate in an abundance of low-rank loops. We demonstrate, through analysis and numerical experiments, that this loop-counting method performs well in a variety of scenarios, outperforming simple spectral methods in many situations of interest. Another important feature of our method is that it can easily be modified to account for aspects of experimental design which commonly arise in practice. For example, our algorithm can be modified to correct for controls, categorical- and continuous-covariates, as well as sparsity within the data. We demonstrate these practical features with two examples; the first drawn from gene-expression analysis and the second drawn from a much larger genome-wide-association-study (GWAS). PMID- 29758033 TI - Phylogenetic relationships, biofilm formation, motility, antibiotic resistance and extended virulence genotypes among Escherichia coli strains from women with community-onset primitive acute pyelonephritis. AB - The present work set out to search for a virulence repertoire distinctive for Escherichia coli causing primitive acute pyelonephritis (APN). To this end, the virulence potential of 18 E. coli APN strains was genotypically and phenotypically assessed, comparatively with 19 strains causing recurrent cystitis (RC), and 16 clinically not significant (control, CO) strains. Most of the strains belong to phylogenetic group B1 (69.8%; p<0.01), and APN strains showed unique features, which are the presence of phylogroup A, and the absence of phylogroup B2 and non-typeable strains. Overall, the most dominant virulence factor genes (VFGs) were ecpA and fyuA (92.4 and 86.7%, respectively; p<0.05), and the mean number of VFGs was significantly higher in uropathogenic strains. Particularly, papAH and malX were exclusive for uropathogenic strains. APN and RC strains showed a significantly higher prevalence of fyuA, usp, and malX than of CO strains. Compared to RC strains, APN ones showed a higher prevalence of iha, but a lower prevalence of iroN, cnf1, and kpsMT-II. Hierarchical cluster analysis showed a higher proportion of two gene clusters (malX and usp, and fyuA and ecpA) were detected in the APN and RC groups than in CO, whereas iutA and iha clusters were detected more frequently in APN strains. The motility level did not differ among the study-groups and phylogroups considered, although a higher proportion of swarming strains was observed in APN strains. Antibiotic-resistance rates were generally low except for ampicillin (37.7%), and were not associated with specific study- or phylogenetic groups. APN and RC strains produced more biofilm than CO strains. In APN strains, iha was associated with higher biofilm biomass formation, whereas iroN and KpSMT-K1 were associated with a lower amount of biofilm biomass. Further work is needed to grasp the virulence and fitness mechanisms adopted by E. coli causing APN, and hence develop new therapeutic and prophylactic approaches. PMID- 29758034 TI - Interactions among genes involved in reverse cholesterol transport and in the response to environmental factors in dyslipidemia in subjects from the Xinjiang rural area. AB - Gene-gene and gene-environment interactions may be partially responsible for dyslipidemia, but studies investigating interactions in the reverse cholesterol transport system (RCT) are limited. We explored these interactions in a Xinjiang rural population by genotyping five SNPs using SNPShot technique in APOA1, ABCA1, and LCAT, which are involved in the RCT (690 patients, 743 controls). We conducted unconditional logistical regression analysis to evaluate associations and generalized multifactor dimensionality reduction to evaluate interactions. Results revealed significant differences in rs670 and rs2292318 allele frequencies between cases and controls (P<0.025). rs670 G allele carriers were more likely to develop dyslipidemia than A allele carriers (OR = 1.315, OR 95% CI: 1.067-2.620; P = 0.010). rs2292318 T allele carriers were more likely to develop dyslipidemia than A allele carriers (OR = 1.264, OR 95% CI: 1.037-1.541; P = 0.020). Gene-gene interaction model APOA1rs670-ABCA1rs1800976-ABCA1rs4149313 LCATrs1109166 (P = 0.0107) and gene-environment interaction model ABCA1rs1800976 ABCA1rs4149313-LCATrs1109166-obesity-smoking were optimal dyslipidemia predictors (P = 0.0107) and can interact (4). Differences in A-C-A-C-A and G-G-G-T-G haplotype frequencies were observed (P<0.05). Serum lipid profiles could be partly attributed to RCT gene polymorphisms. Thus, dyslipidemia is influenced by APOA1, ABCA1, LCAT, environmental factors, and their interactions. PMID- 29758035 TI - Changes in macular pigment optical density after membrane peeling. AB - INTRODUCTION: To highlight the differences in macular pigment optical density (MPOD) between eyes with vitreoretinal interface syndrome and healthy control eyes, to assess the changes in MPOD in eyes treated with macular peeling, to investigate the relationships between MPOD changes and measures of retinal sensitivity such as best corrected visual acuity (BCVA) and microperimetry. METHODS: In this cross-sectional comparative study, 30 eyes affected by idiopathic epiretinal membrane (iERM, 15eyes) or full-thickness macular hole (FTMH, 15eyes) were compared with 60 eyes from 30 healthy age-matched patients. MPOD values (mean MPOD, maximum MPOD, MPOD area, and MPOD volume) were measured in a range of 4 degrees -7 degrees of eccentricity around the fovea, using the one-wavelength reflectometry method (Visucam 200, Carl-Zeiss Meditec). Patients affected by iERM and FTMH were treated with vitrectomy and epiretinal membrane inner limiting membrane (ERM-ILM) peeling, with follow-up examinations performed preoperatively and 6 months postoperatively. The main outcome measures were the differences in MPOD between eyes with vitreoretinal interface syndrome and healthy eyes, changes in MPOD after ERM-ILM peeling, and relationships between MPOD and functional changes. RESULTS: Mean MPOD differed significantly between control eyes and those with iERM (P = .0001) or FTMH (P = .0006). The max MPOD and MPOD area increased, but not significantly. After peeling, the only significant change in MPOD was in MPOD volume (P = .01). In the ERM group, postoperative mean MPOD correlated significantly with best-corrected visual acuity (r = .739, P = .002). CONCLUSIONS: MPOD was reduced in patients with iERM or FTMH compared with healthy eyes. We found a significant correlation between the mean postoperative MPOD and postoperative BCVA, hypothesizing that the postoperative increase in mean MPOD could be due to a change in distribution for unfolding and expansion of the fovea after the peeling. MOPD may be considered as a prognostic factor associated with a good visual prognosis in patients with iERM. PMID- 29758036 TI - Benzoxaborole treatment perturbs S-adenosyl-L-methionine metabolism in Trypanosoma brucei. AB - The parasitic protozoan Trypanosoma brucei causes Human African Trypanosomiasis and Nagana in other mammals. These diseases present a major socio-economic burden to large areas of sub-Saharan Africa. Current therapies involve complex and toxic regimens, which can lead to fatal side-effects. In addition, there is emerging evidence for drug resistance. AN5568 (SCYX-7158) is a novel benzoxaborole class compound that has been selected as a lead compound for the treatment of HAT, and has demonstrated effective clearance of both early and late stage trypanosomiasis in vivo. The compound is currently awaiting phase III clinical trials and could lead to a novel oral therapeutic for the treatment of HAT. However, the mode of action of AN5568 in T. brucei is unknown. This study aimed to investigate the mode of action of AN5568 against T. brucei, using a combination of molecular and metabolomics-based approaches.Treatment of blood-stage trypanosomes with AN5568 led to significant perturbations in parasite metabolism. In particular, elevated levels of metabolites involved in the metabolism of S-adenosyl-L-methionine, an essential methyl group donor, were found. Further comparative metabolomic analyses using an S-adenosyl-L-methionine-dependent methyltransferase inhibitor, sinefungin, showed the presence of several striking metabolic phenotypes common to both treatments. Furthermore, several metabolic changes in AN5568 treated parasites resemble those invoked in cells treated with a strong reducing agent, dithiothreitol, suggesting redox imbalances could be involved in the killing mechanism. PMID- 29758038 TI - Novel high-resolution computed tomography-based radiomic classifier for screen identified pulmonary nodules in the National Lung Screening Trial. AB - PURPOSE: Optimization of the clinical management of screen-detected lung nodules is needed to avoid unnecessary diagnostic interventions. Herein we demonstrate the potential value of a novel radiomics-based approach for the classification of screen-detected indeterminate nodules. MATERIAL AND METHODS: Independent quantitative variables assessing various radiologic nodule features such as sphericity, flatness, elongation, spiculation, lobulation and curvature were developed from the NLST dataset using 726 indeterminate nodules (all >= 7 mm, benign, n = 318 and malignant, n = 408). Multivariate analysis was performed using least absolute shrinkage and selection operator (LASSO) method for variable selection and regularization in order to enhance the prediction accuracy and interpretability of the multivariate model. The bootstrapping method was then applied for the internal validation and the optimism-corrected AUC was reported for the final model. RESULTS: Eight of the originally considered 57 quantitative radiologic features were selected by LASSO multivariate modeling. These 8 features include variables capturing Location: vertical location (Offset carina centroid z), Size: volume estimate (Minimum enclosing brick), Shape: flatness, Density: texture analysis (Score Indicative of Lesion/Lung Aggression/Abnormality (SILA) texture), and surface characteristics: surface complexity (Maximum shape index and Average shape index), and estimates of surface curvature (Average positive mean curvature and Minimum mean curvature), all with P<0.01. The optimism-corrected AUC for these 8 features is 0.939. CONCLUSIONS: Our novel radiomic LDCT-based approach for indeterminate screen-detected nodule characterization appears extremely promising however independent external validation is needed. PMID- 29758039 TI - Effects of palonosetron for prophylaxis of postoperative nausea and vomiting in high-risk patients undergoing total knee arthroplasty: A prospective, randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The preemptive multimodal pain protocols used in total knee arthroplasty (TKA) often cause emesis postoperatively. We investigated whether palonosetron prophylaxis reduces postoperative nausea and vomiting (PONV) in high risk patients after TKA. METHODS: We randomized 120 female patients undergoing TKA to receive either palonosetron (0.075 mg, intravenous) or no antiemetic prophylaxis (0.9% saline, control group). All patients were given spinal anesthesia, a continuous femoral nerve block, and fentanyl-based intravenous patient controlled analgesia. Patients undergoing staged bilateral TKA were assigned to one group for the first knee and the other group for the second knee. The overall incidence of PONV, the incidences of both nausea and vomiting, severity of nausea, complete response, requirement for rescue antiemetics, pain level, opioid consumption, and satisfaction scores were evaluated during three periods: 0-2, 2-24, and 24-48 h postoperatively. We also compared PONV and pain between the first and second TKA. RESULTS: The incidence of PONV during the first 48 h was lower in the palonosetron group compared with the controls (22 vs. 41%, p = 0.028), especially 2-24 h after surgery, as was the nausea and vomiting respectively. The severity of nausea was lower in the palonosetron group (p = 0.010). The complete response rate (93 vs. 73%, p = 0.016) and satisfaction score (84 +/- 12 vs. 79 +/- 15, p = 0.032) were higher in the palonosetron group during 2-24 h after surgery. Patients who underwent a second operation complained of more severe pain, and consumed more opioids than those of the first operation. There was no difference in the incidence of PONV between the first and second operations. CONCLUSIONS: Palonosetron prophylaxis reduced the incidence and severity of PONV in high-risk patients managed with multimodal pain protocol for 48 h, notably 2-24 h after TKA. PMID- 29758040 TI - Early school failure predicts teenage pregnancy and marriage: A large population based cohort study in northern Malawi. AB - BACKGROUND: School dropout has been linked to early pregnancy and marriage but less is known about the effect of school performance. We aimed to assess whether school performance influenced age at sexual debut, pregnancy and marriage, and from what age school drop-out and performance were associated with these later life events. METHODS: Data from 2007-2016 from a demographic surveillance site in northern Malawi with annual updating of schooling status and grades, and linked sexual behaviour surveys, were analysed to assess the associations of age specific school performance (measured as age-for-grade) and status (in or out of school) on subsequent age at sexual debut, pregnancy and marriage. Landmark analysis with Cox regression was used to estimate hazard ratios of sexual debut, pregnancy and marriage by schooling at selected (landmark) ages, controlling for socio-economic factors. RESULTS: Information on at least one outcome was available for >16,000 children seen at ages 10-18. Sexual debut was available on a subset aged >=15 by 2011. For girls, being out of school was strongly associated with earlier sexual debut, pregnancy and marriage. For example, using schooling status at age 14, compared to girls in primary, those who had dropped out had adjusted hazard ratios of subsequent sexual debut, pregnancy and marriage of 5.39 (95% CI 3.27-8.86), 2.39 (1.82-3.12), and 2.76 (2.08-3.67) respectively. For boys, the equivalent association with sexual debut was weak, 1.92 (0.81 4.55), but that with marriage was strong, 3.74 (2.28-6.11), although boys married later. Being overage-for-grade was not associated with sexual debut for girls or boys. For girls, being overage-for-grade from age 10 was associated with earlier pregnancy and marriage (e.g. adjusted hazard ratio 2.84 (1.32-6.17) for pregnancy and 3.19 (1.47-6.94) for marriage, for those >=3 years overage compared to those on track at age 10). For boys, overage-for-grade was associated with earlier marriage from age 12, with stronger associations at older ages (e.g. adjusted hazard ratio 2.41 (1.56-3.70) for those >=3 years overage compared to those on track at age 14). For girls >=3 years overage at age 14, 39% were pregnant before they were 18, compared to 18% of those who were on track. The main limitation was the use of reported ages of sexual debut, pregnancy and marriage. CONCLUSIONS: School progression at ages as young as 10 can predict teenage pregnancy and marriage, even after adjusting for socio-economic factors. Early education interventions may reduce teenage pregnancy and marriage as well as improving learning. PMID- 29758037 TI - A systematic review of human and animal leptospirosis in the Pacific Islands reveals pathogen and reservoir diversity. AB - BACKGROUND: The Pacific Islands have environmental conditions highly favourable for transmission of leptospirosis, a neglected zoonosis with highest incidence in the tropics, and Oceania in particular. Recent reports confirm the emergence and outbreaks of leptospirosis in the Pacific Islands, but the epidemiology and drivers of transmission of human and animal leptospirosis are poorly documented, especially in the more isolated and less developed islands. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a systematic review of human and animal leptospirosis within 25 Pacific Islands (PIs) in Polynesia, Melanesia, Micronesia, as well as Easter Island and Hawaii. We performed a literature search using four international databases for articles published between January 1947 and June 2017. We further included grey literature available on the internet. We identified 148 studies describing leptospirosis epidemiology, but the number of studies varied significantly between PIs. No data were available from four PIs. Human leptospirosis has been reported from 13 PIs, with 63% of all studies conducted in Hawaii, French Polynesia and New Caledonia. Animal leptospirosis has been investigated in 19 PIs and from 14 host species, mainly pigs (18% of studies), cattle (16%) and dogs (11%). Only 13 studies provided information on both human and animal leptospirosis from the same location. Serology results were highly diverse in the region, both in humans and animals. CONCLUSIONS/SIGNIFICANCE: Our study suggests that, as in other tropical regions, leptospirosis is widespread in the PIs while showing some epidemiological heterogeneity. Data are scarce or absent from many PIs. Rodents, cattle, pigs and dogs are all likely to be important carriers, but the relative importance of each animal species in human infection needs to be clarified. Epidemiological surveys with appropriate sampling design, pathogen typing and data analysis are needed to improve our understanding of transmission patterns and to develop effective intervention strategies. PMID- 29758042 TI - A taxonomy and rating system to measure situation awareness in resuscitation teams. AB - Team SA involves a common perspective between two or more individuals regarding current environmental events, their meaning, and projected future status. Team SA has been theorized to be important for resuscitation team effectiveness. Accordingly, multidimensional frameworks of observable behaviors relevant to resuscitation teams are needed to understand more deeply the nature of team SA, its implications for team effectiveness, and whether it can be trained. A seven dimension team resuscitation SA framework was developed following a literature review and consensus process using a modified Delphi approach with a group of content experts. We applied a pre-post design within a day-long team training program involving four video-recorded simulated resuscitation events and 42 teams across Canada. The first and fourth events represented "pre" and "post" training events, respectively. Teams were scored on SA five times within each 15-minute event. Distractions were introduced to investigate whether SA scores would be affected. The current study provides initial construct validity evidence for a new measure of SA and explicates SA's role in resuscitation teams. PMID- 29758041 TI - Acute effects of insulin on circulating natriuretic peptide levels in humans. AB - BACKGROUND: The natriuretic peptide hormones play an important role in salt and blood pressure regulation. In observational studies, obesity and insulin resistance have been consistently associated with lower concentrations of natriuretic peptides. It has been proposed that insulin influences natriuretic peptide production. OBJECTIVE: We sought to determine the acute effects of insulin administration on natriuretic peptide concentrations. METHODS: 31 men and women (11 lean, 10 overweight, and 10 obese), ages 30-70 years, without cardiovascular disease or overt diabetes underwent a hyperinsulinemic-euglycemic insulin clamp. Plasma concentrations of N-terminal pro atrial natriuretic peptide (NT-proANP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) were measured at baseline and steady-state (the final 30 minutes of the clamp protocol). RESULTS: From baseline to steady-state, insulin levels increased from a mean level of 9.5 to 176.7 MUU/ml (p<0.001). Over this period, circulating NT proANP concentrations decreased by 9% (-1933 ng/L, p = 0.01). The changes in NT proANP did not differ between lean, overweight, and obese individuals. Steady state NT-proANP levels, adjusted for baseline, were lower in individuals with greater insulin resistance, independent of BMI. In contrast to NT-proANP, NT proBNP levels did not change significantly during the clamp (p = 0.41). CONCLUSION: Insulin administration was associated with a moderate decrease in circulating NT-proANP, but not NT-proBNP. The lowest NT-proANP concentrations were found in insulin-resistant individuals. Further investigations are warranted to elucidate potential mechanisms underlying the effects of insulin on the cardiac hormonal axis. PMID- 29758043 TI - Isthmin 1 (ism1) is required for normal hematopoiesis in developing zebrafish. AB - Hematopoiesis is an essential and highly regulated biological process that begins with hematopoietic stem cells (HSCs). In healthy organisms, HSCs are responsible for generating a multitude of mature blood cells every day, yet the molecular pathways that instruct HSCs to self-renew and differentiate into post-mitotic blood cells are not fully known. To understand these molecular pathways, we investigated novel genes expressed in hematopoietic-supportive cell lines from the zebrafish (Danio rerio), a model system increasingly utilized to uncover molecular pathways important in the development of other vertebrate species. We performed RNA sequencing of the transcriptome of three stromal cell lines derived from different stages of embryonic and adult zebrafish and identified hundreds of highly expressed transcripts. For our studies, we focused on isthmin 1 (ism1) due to its shared synteny with its human gene ortholog and because it is a secreted protein. To characterize ism1, we performed loss-of-function experiments to identify if mature blood cell production was disrupted. Myeloid and erythroid lineages were visualized and scored with transgenic zebrafish expressing lineage specific markers. ism1 knockdown led to reduced numbers of neutrophils, macrophages, and erythrocytes. Analysis of clonal methylcellulose assays from ism1 morphants also showed a reduction in total hematopoietic stem and progenitor cells (HSPCs). Overall, we demonstrate that ism1 is required for normal generation of HSPCs and their downstream progeny during zebrafish hematopoiesis. Further investigation into ism1 and its importance in hematopoiesis may elucidate evolutionarily conserved processes in blood formation that can be further investigated for potential clinical utility. PMID- 29758045 TI - The microbial killing capacity of aqueous and gaseous ozone on different surfaces contaminated with dairy cattle manure. AB - A high reactivity and leaving no harmful residues make ozone an effective disinfectant for farm hygiene and biosecurity. Our objectives were therefore to (1) characterize the killing capacity of aqueous and gaseous ozone at different operational conditions on dairy cattle manure-based pathogens (MBP) contaminated different surfaces (plastic, metal, nylon, rubber, and wood); (2) determine the effect of microbial load on the killing capacity of aqueous ozone. In a crossover design, 14 strips of each material were randomly assigned into 3 groups, treatment (n = 6), positive-control (n = 6), and negative-control (n = 2). The strips were soaked in dairy cattle manure with an inoculum level of 107-108 for 60 minutes. The treatment strips were exposed to aqueous ozone of 2, 4, and 9 ppm and gaseous ozone of 1and 9 ppm for 2, 4, and 8 minutes exposure. 3MTM PetrifilmTM rapid aerobic count plate and plate reader were used for bacterial culture. On smooth surfaces, plastic and metal, aqueous ozone at 4 ppm reduced MBP to a safe level (>=5-log10) within 2 minutes (6.1 and 5.1-log10, respectively). However, gaseous ozone at 9 ppm for 4 minutes inactivated 3.3 log10 of MBP. Aqueous ozone of 9 ppm is sufficient to reduce MBP to a safe level, 6.0 and 5.4- log10, on nylon and rubber surfaces within 2 and 8 minutes, respectively. On complex surfaces, wood, both aqueous and gaseous ozone at up to 9 ppm were unable to reduce MBP to a safe level (3.6 and 0.8-log10, respectively). The bacterial load was a strong predictor for reduction in MBP (P<0.0001, R2 = 0.72). We conclude that aqueous ozone of 4 and 9 ppm for 2 minutes may provide an efficient method to reduce MBP to a safe level on smooth and moderately rough surfaces, respectively. However, ozone alone may not an adequate means of controlling MBP on complex surfaces. PMID- 29758044 TI - Prickle is phosphorylated by Nemo and targeted for degradation to maintain Prickle/Spiny-legs isoform balance during planar cell polarity establishment. AB - Planar cell polarity (PCP) instructs tissue patterning in a wide range of organisms from fruit flies to humans. PCP signaling coordinates cell behavior across tissues and is integrated by cells to couple cell fate identity with position in a developing tissue. In the fly eye, PCP signaling is required for the specification of R3 and R4 photoreceptors based upon their positioning relative to the dorso-ventral axis. The 'core' PCP pathway involves the asymmetric localization of two distinct membrane-bound complexes, one containing Frizzled (Fz, required in R3) and the other Van Gogh (Vang, required in R4). Inhibitory interactions between the cytosolic components of each complex reinforce asymmetric localization. Prickle (Pk) and Spiny-legs (Pk-Sple) are two antagonistic isoforms of the prickle (pk) gene and are cytoplasmic components of the Vang complex. The balance between their levels is critical for tissue patterning, with Pk-Sple being the major functional isoform in the eye. Here we uncover a post-translational role for Nemo kinase in limiting the amount of the minor isoform Pk. We identified Pk as a Nemo substrate in a genome-wide in vitro band-shift screen. In vivo, nemo genetically interacts with pkpk but not pksple and enhances PCP defects in the eye and leg. Nemo phosphorylation limits Pk levels and is required specifically in the R4 photoreceptor like the major isoform, Pk-Sple. Genetic interaction and biochemical data suggest that Nemo phosphorylation of Pk leads to its proteasomal degradation via the Cullin1/SkpA/Slmb complex. dTAK and Homeodomain interacting protein kinase (Hipk) may also act together with Nemo to target Pk for degradation, consistent with similar observations in mammalian studies. Our results therefore demonstrate a mechanism to maintain low levels of the minor Pk isoform, allowing PCP complexes to form correctly and specify cell fate. PMID- 29758046 TI - Development and characterization of the first dsRNA-resistant insect population from western corn rootworm, Diabrotica virgifera virgifera LeConte. AB - The use of dsRNA to control insect pests via the RNA interference (RNAi) pathway is being explored by researchers globally. However, with every new class of insect control compounds, the evolution of insect resistance needs to be considered, and understanding resistance mechanisms is essential in designing durable technologies and effective resistance management strategies. To gain insight into insect resistance to dsRNA, a field screen with subsequent laboratory selection was used to establish a population of DvSnf7 dsRNA-resistant western corn rootworm, Diabrotica virgifera virgifera, a major maize insect pest. WCR resistant to ingested DvSnf7 dsRNA had impaired luminal uptake and resistance was not DvSnf7 dsRNA-specific, as indicated by cross resistance to all other dsRNAs tested. No resistance to the Bacillus thuringiensis Cry3Bb1 protein was observed. DvSnf7 dsRNA resistance was inherited recessively, located on a single locus, and autosomal. Together these findings will provide insights for dsRNA deployment for insect pest control. PMID- 29758047 TI - Microphytobenthos primary production estimated by hyperspectral reflectance. AB - The use of remote sensing techniques allows monitoring of photosynthesis at the ecosystem level and improves our knowledge of plant primary productivity. The main objective of the current study was to develop a remote sensing based method to measure microphytobenthos (MPB) primary production from intertidal mudflats. This was achieved by coupling hyperspectral radiometry (reflectance, rho and second derivative, deltadelta) and PAM-fluorometry (non-sequential light curves, NSLC) measurements. The latter allowed the estimation of primary production using a light use efficiency parameter (LUE) and electron transport rates (ETR) whereas rho allowed to estimate pigment composition and optical absorption cross-section (a*). Five MPB species representative of the main growth forms: epipelic (benthic motile), epipsammic (benthic motile and non motile) and tychoplanktonic (temporarily resuspended in the water column) were submitted to increasing light intensities from dark to 1950 MUmol photons.m-2.s-1. Different fluorescence patterns were observed for the three growth-forms and were linked to their xanthophyll cycle (de-epoxydation state). After spectral reflectance measurements, a* was retrieved using a radiative transfer model and several radiometric indices were tested for their capacity to predict LUE and ETR measured by PAM-fluorometry. Only one radiometric index was not species or growth form specific, i.e. deltadelta496/508. This index was named MPBLUE and could be used to predict LUE and ETR. The applicability of this index was tested with simulated bands of a wide variety of hyperspectral sensors at spectral resolutions between 3 and 15 nm of Full Width at Half Maximum (FWHM). PMID- 29758049 TI - User evaluations offer promise for pod-intravaginal ring as a drug delivery platform: A mixed methods study of acceptability and use experiences. AB - BACKGROUND: Effective HIV prevention requires efficient delivery of safe and efficacious drugs and optimization of user adherence. The user's experiences with the drug, delivery system, and use parameters are critical to product acceptability and adherence. Prevention product developers have the opportunity to directly control a drug delivery system and its impact on acceptability and adherence, as well as product efficacy. Involvement of potential users during preclinical design and development can facilitate this process. We embedded a mixed methods user evaluation study into a safety and pharmacokinetics (PK) trial of a pod-intravaginal ring delivering antiretroviral agents. METHODOLOGY: Women enrolled in two cohorts, ultimately evaluating the safety/PK of a pod-IVRs delivering TDF-alone, TDF-FTC, and/or TDF-FTC-MVC. A 7-day use period was targeted for each pod-IVR, regardless of drug or drug combination. During the clinical study, participants provided both quantitative (i.e., survey) and qualitative (i.e., in-depth interview) data capturing acceptability, perceptibility, and adherence behaviors. Initial sexual and reproductive health history surveys, daily diaries, a final acceptability and willingness to use survey, and a qualitative in-depth interview comprised the user evaluation data for each pod-IVR experienced by the participants. FINDINGS: Overall, the majority of participants (N = 10) reported being willing to use the pod-IVR platform for HIV prevention should it advance to market. Confidence to use the pod-IVR (e.g., insertion, removal) was high. There were no differences noted in the user experience of the pod-IVR platform; that is, whether the ring delivered TDF alone, TDF-FTC, or TDF-FTC-MVC, users' experiences of the ring were similar and acceptable. Participants did report specific experiences, both sensory and behavioral, that impacted their use behaviors with respect to the ring, and which could ultimately impact acceptability and adherence. These experiences, and user evaluations elicited by them, could both challenge use or be used to leverage use in future trials and product rollout once fully articulated. CONCLUSIONS: High willingness-to-use data and lack of salient differences in user experiences related to use of the pod-IVR platform (regardless of agents delivered) suggests that the pod-IVR is a feasible and acceptable drug delivery device in and of itself. This finding holds promise both for an anti-HIV pod-IVR and, potentially, a multipurpose prevention pod-IVR that could deliver both prevention for sexually transmitted infections (STIs) including HIV and contraception. Given the very early clinical trial context, further acceptability, perceptibility, and adherence data should continue to be explored, in the context of longer use periods (e.g., 28-day ring use), and in the contexts of sexual activity and menses. Using early design and development contexts to gain insights into potential challenges and facilitators of drug delivery systems such as the pod IVR could save valuable resources and time as a potential biomedical technology moves through the clinical trial pipeline and into real-world use. PMID- 29758050 TI - An assessment of false positive rates for malaria rapid diagnostic tests caused by non-Plasmodium infectious agents and immunological factors. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) can produce false positive (FP) results in patients with human African trypanosomiasis and rheumatoid factor (RF), but specificity against other infectious agents and immunological factors is largely unknown. Low diagnostic specificity caused by cross-reactivity may lead to over-estimates of the number of malaria cases and over-use of antimalarial drugs, at the cost of not diagnosing and treating the true underlying condition. METHODS: Data from the WHO Malaria RDT Product Testing Programme was analysed to assess FP rates of 221 RDTs against four infectious agents (Chagas, dengue, Leishmaniasis and Schistosomiasis) and four immunological factors (anti-nuclear antibody, human anti-mouse antibody (HAMA), RF and rapid plasma regain). Only RDTs with a FP rate against clean negative samples less than 10% were included. Paired t-tests were used to compare product-specific FP rates on clean negative samples and samples containing non-Plasmodium infectious agents and immunological factors. RESULTS: Forty (18%) RDTs showed no FP results against any tested infectious agent or immunological factor. In the remaining RDTs significant and clinically relevant increases in FP rates were observed for samples containing HAMA and RF (P<0.001). There were significant correlations between product-matched FP rates for RF and HAMA on all RDT test bands (P<0.001), and FP rates for each infectious agent and immunological factor were also correlated between test bands of combination RDTs (P<=0.002). CONCLUSIONS: False positive results against non-Plasmodium infectious agents and immunological factors does not appear to be a universal property of malaria RDTs. However, since many malaria RDTs have elevated FP rates against HAMA and RF positive samples practitioners may need to consider the possibility of false positive results for malaria in patients with conditions that stimulate HAMA or RF. PMID- 29758048 TI - Adult height and all-cause and cause-specific mortality in the Japan Public Health Center-based Prospective Study (JPHC). AB - Adult height is determined by both genetic characteristics and environmental factors in early life. Although previous studies have suggested that adult height is associated with risk of mortality, comprehensive associations between height and all-cause and cause-specific mortality in the Japanese population are unclear. We aimed to evaluate the associations between adult height and all-cause and cause-specific mortality among Japanese men and women in a prospective cohort study. We investigated 107,794 participants (50,755 men and 57,039 women) aged 40 to 69 years who responded to the baseline questionnaire in the Japan Public Health Center-based Prospective Study. Participants were classified by quartile of adult height obtained from a self-reported questionnaire in men (<160cm, 160 163cm, 164-167cm, >=168cm) and women (<149cm, 149-151cm, 152-155cm, >=156cm). Hazard ratios (HR) and 95% confidence intervals (CI) for mortality from all cause, cancer, heart disease, cerebrovascular disease, respiratory disease, and other cause mortality were calculated using Cox proportional hazards models. During follow-up, 12,320 men and 7,030 women died. Taller adult height was associated with decreased risk for mortality from cerebrovascular disease (HR <160cm vs. >=168cm (95% CI) = 0.83 (0.69-0.99); HR for 5-cm increment (95% CI) = 0.95 (0.90-0.99)) and respiratory disease (HR <160cm vs. >=168cm (95% CI) = 0.84 (0.69-1.03); HR for 5-cm increment (95% CI) = 0.92 (0.87-0.97)), but was also associated with increased risk for overall cancer mortality (HR <160cm vs. >=168cm (95% CI) = 1.17 (1.07-1.28); HR for 5-cm increment (95% CI) = 1.04 (1.01 1.07)) in men. Taller adult height was also associated with decreased risk for mortality from cerebrovascular disease (HR <149cm vs. >=156cm (95% CI) = 0.84 (0.66-1.05); HR for 5-cm increment (95% CI) = 0.92 (0.86-0.99)) in women. Our results confirmed that adult height is associated with cause-specific mortality in a Japanese population. PMID- 29758051 TI - The effect of acylation with fatty acids and other modifications on HLA class II:peptide binding and T cell stimulation for three model peptides. AB - Immunogenicity is a major concern in drug development as anti-drug antibodies in many cases affect both patient safety and drug efficacy. Another concern is often the limited half-life of drugs, which can be altered by different chemical modifications, like acylation with fatty acids. However, acylation with fatty acids has been shown in some cases to modulate T cell activation. Therefore, to understand the role of acylation with fatty acids on immunogenicity we tested three immunogenic non-acylated peptides and 14 of their acylated analogues for binding to 26 common HLA class II alleles, and their ability to activate T cells in an ex vivo T cell assay. Changes in binding affinity associated with acylation with fatty acids were typically modest, though a significant decrease was observed for influenza HA acylated with a stearic acid, and affinities for DQ alleles were consistently increased. Importantly, we showed that for all three immunogenic peptides acylation with fatty acids decreased their capacity to activate T cells, a trend particularly evident with longer fatty acids typically positioned within the peptide HLA class II binding core region, or when closer to the C-terminus. With these results we have demonstrated that acylation with fatty acids of immunogenic peptides can lower their stimulatory capacity, which could be important knowledge for drug design and immunogenicity mitigation. PMID- 29758053 TI - Behavior and physiology of two different sow breeds in a farrowing environment during late 35-day lactation. AB - To improve the overall welfare levels of sows and to reduce stress levels at late 35-day lactation, we selected targeted behavioral indicators that might be associated with stress. Therefore, we monitored and evaluated the adaptive capability of two different breeds of sows to the farrowing environment. In this study, Damin sows (Large White * Min pig sows, n = 20) and Large White sows (n = 20) were farrowed in individual pens. Saliva was collected and tested for cortisol density at -15 min, and then at +15, 30, 60, 90, 120, 180 and 240 min after an adrenocorticotropic hormone (ACTH) stimulation test conducted at 20, 27 and 34 d post-partum. The postures, including ventral and lateral recumbency to other postures, defecating, urinating, sham-chewing and bar-biting behavior, were observed by video from 07:00 to 09:00 and from 13:00 to 15:00 on the 7th day of each week from the 3rd to the 5th week post-parturition. In addition, the concentrations of salivary interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and secretory immunoglobulin (SIgA) were assayed after the observed behaviors. The results showed no significant difference between Damin sows and Large White sows in terms of behaviors at the 3rd week. Additionally, there were no significant differences between Damin and Large White sows in terms of the behaviors of ventral recumbency and bar-biting with the exception of lateral recumbency to other postures, sham-chewing, defecation and urination in the fifth week. Meanwhlie, there was significant difference between two breeds in term of ventral recumbency at the 4th week. The result of the ACTH test showed a significant difference between the Damin and Large White sows by the 27th and 34th days postpartum (P<0.01). In addition, the serological concentrations of IL 6 and TNF-alpha were not significantly different between the two breeds at the 3rd week postpartum. However, these indicators were significantly different at the 5th week postpartum (P = 0.000, and P = 0.003, respectively). The SIgA concentrations in saliva were significantly different between breeds at the 3rd week postpartum (P<0.01). In conclusion, both breeds of sows maybe in a state of stress after the 4th week postpartum. However, the Damin sows may be better than the Large White sows in terms of adapting to this farrowing environment. PMID- 29758054 TI - Effect of fusion protein cleavage site sequence on generation of a genotype VII Newcastle disease virus vaccine. AB - Newcastle disease (ND) causes severe economic loss to poultry industry worldwide. Frequent outbreaks of ND in commercial chickens vaccinated with live vaccines suggest a need to develop improved vaccines that are genetically matched against circulating Newcastle disease virus (NDV) strains. In this study, the fusion protein cleavage site (FPCS) sequence of NDV strain Banjarmasin/010 (Banj), a genotype VII NDV, was individually modified using primer mutagenesis to those of avian paramyxovirus (APMV) serotypes 2, 7 and 8 and compared with the recombinant Banjarmasin (rBanj) with avirulent NDV LaSota cleavage site (rBanj-LaSota). These FPCS mutations changed the in vitro cell-to-cell fusion activity and made rBanj FPCS mutant viruses highly attenuated in chickens. When chickens immunized with the rBanj FPCS mutant viruses and challenged with the virulent Banj, there was reduced challenge virus shedding observed compared to chickens immunized with the heterologous vaccine strain LaSota. Among the genotype VII NDV Banj vaccine candidates, rBanj-LaSota and rBanj containing FPCS of APMV-8 induced highest neutralizing antibody titers and protected chickens with reduced challenge virus shedding. These results show the effect of the F protein cleavage site sequence in generating genotype VII matched NDV vaccines. PMID- 29758055 TI - Active recovery affects the recovery of the corticospinal system but not of muscle contractile properties. AB - PURPOSE: Active recovery is often used by athletes after strenuous exercise or competition but its underlying mechanisms are not well understood. We hypothesized that active recovery speeds-up recovery processes within the muscle and the central nervous system (CNS). METHODS: We assessed muscular and CNS recovery by measuring the voluntary activation (VA) in the vastus lateralis muscle with transcranial magnetic stimulation (VATMS) and peripheral nerve stimulation (VAPNS) during maximal voluntary contractions (MVC) of the knee extensors in 11 subjects. Measurements were performed before and after a fatiguing cycling time-trial, after an active and a passive recovery treatment and after another fatiguing task (1 min MVC). The measurements were performed a second time 24 h after the time-trial. RESULTS: We observed a time * group interaction effect for VATMS (p = 0.013). Post-hoc corrected T-tests demonstrated an increased VATMS after active recovery when measured after the 1 min MVC performed 24 h after the time-trial (mean +/- SD; 95.2 +/- 4.1% vs. 89.2 +/- 6.6%, p = 0.026). No significant effects were observed for all other variables. CONCLUSIONS: Active recovery increased aspects of central, rather than muscle recovery. However, no effect on MVC was seen, implying that even if active recovery speeds up CNS recovery, without affecting the recovery of muscle contractile properties, this doesn't translate into increases in overall performance. PMID- 29758052 TI - Decreased circulating T regulatory lymphocytes in obese patients undergoing bariatric surgery. AB - OBJECTIVE: It has been previously demonstrated that T lymphocytes may be involved in the development of hypertension and microvascular remodeling, and that circulating T effector lymphocytes may be increased in hypertension. In particular, Th1 and Th 17 lymphocytes may contribute to the progression of hypertension and microvascular damage while T-regulatory (Treg) lymphocytes seem to be protective in this regard. However, no data is available about patients with severe obesity, in which pronounced microvascular alterations were observed. DESIGN AND METHODS: We have investigated 32 severely obese patients undergoing bariatric surgery, as well as 24 normotensive lean subjects and 12 hypertensive lean subjects undergoing an elective surgical intervention. A peripheral blood sample was obtained before surgery for assessment of CD4+ T lymphocyte subpopulations. Lymphocyte phenotype was evaluated by flow cytometry in order to assess T-effector and Treg lymphocytes. RESULTS: A marked reduction of several Treg subpopulations was observed in obese patients compared with controls, together with an increased in CD4+ effector memory T-effector cells. CONCLUSION: In severely obese patients, Treg lymphocytes are clearly reduced and CD4+ effector memory cells are increased. It may be hypothesized that they might contribute to the development of marked microvascular alterations previously observed in these patients. PMID- 29758056 TI - Assessment of the behaviour and survival of nematodes under low oxygen concentrations. AB - Oxygen is required for the completion of almost all known metazoan lifecycles, but many metazoans harbour abilities to withstand varying degrees and periods of hypoxia. Caenorhabditis elegans, one of the most popular model organism is extensively used as a model for the study of hypoxia and anoxia biology and it has been found that this nematode is capable of tolerance to varying degrees of hypoxia. Considering the extremely high diversity of nematodes, the effects of low oxygen concentration and mechanisms of adaptation to oxygen depletion differ among species. In this study, we used a simple assay to examine anoxia tolerance in four nematode species, including three free-living and one plant parasitic nematode. We found that the plant parasitic nematode Bursaphelenchus xylophilus can survive more than 14 days under anoxic conditions. Comparisons of behaviour during anoxia induction and the repertoire of oxygen sensation genes among the tested species suggested the existence of different oxygen sensation systems between B. xylophilus and C. elegans, which quickly introduce suspended animation in response to oxygen depletion to survive long-term anoxia. PMID- 29758057 TI - ANKK1 is found in myogenic precursors and muscle fibers subtypes with glycolytic metabolism. AB - Ankyrin repeat and kinase domain containing 1 (ANKK1) gene has been widely related to neuropsychiatry disorders. The localization of ANKK1 in neural progenitors and its correlation with the cell cycle has suggested its participation in development. However, ANKK1 functions still need to be identified. Here, we have further characterized the ANKK1 localization in vivo and in vitro, by using immunolabeling, quantitative real-time PCR and Western blot in the myogenic lineage. Histologic investigations in mice and humans revealed that ANKK1 is expressed in precursors of embryonic and adult muscles. In mice embryos, ANKK1 was found in migrating myotubes where it shows a polarized cytoplasmic distribution, while proliferative myoblasts and satellite cells show different isoforms in their nuclei and cytoplasm. In vitro studies of ANKK1 protein isoforms along the myogenic progression showed the decline of nuclear ANKK1-kinase until its total exclusion in myotubes. In adult mice, ANKK1 was expressed exclusively in the Fast-Twitch muscles fibers subtype. The induction of glycolytic metabolism in C2C12 cells with high glucose concentration or treatment with berberine caused a significant increase in the ANKK1 mRNA. Similarly, C2C12 cells under hypoxic conditions caused the increase of nuclear ANKK1. These results altogether show a relationship between ANKK1 gene regulation and the metabolism of muscles during development and in adulthood. Finally, we found ANKK1 expression in regenerative fibers of muscles from dystrophic patients. Future studies in ANKK1 biology and the pathological response of muscles will reveal whether this protein is a novel muscle disease biomarker. PMID- 29758060 TI - Genetic variation in humoral response to an Escherichia coli O157:H7 vaccine in beef cattle. AB - Individuals often respond differently to the same vaccine; some of this variation may be caused by genetic differences among animals. Our objective was to estimate heritability and identify genomic regions associated with humoral response to an Escherichia coli O157:H7 vaccine in beef cattle. Crossbred beef cattle (n = 651) were vaccinated with a commercially available E. coli O157:H7 vaccine. Serum was collected at time of initial vaccination (d 0), booster (d 21), and d 56 after initial vaccination. Total antibodies specific to siderophore receptor and porin proteins in the vaccine were quantified by enzyme-linked immunosorbent assay. Genomic DNA was isolated from whole blood and genotyped with the bovine GeneSeek Genomic Profiler-High Density 78K or 26K Single Nucleotide Polymorphism BeadChip and imputed to 777,000 SNP genotypes. Heritability was estimated by restricted maximum likelihood (REML) using both 1) pedigree and 2) genomic relationships among individuals. Fixed effects were contemporary group, calf age, sex, principal components from SNP genotype data, and pedigree-derived heterozygosity effects. Additive and dominance effects of SNPs were estimated individually while accounting for contemporary group, sex, and the top 20 principal components calculated from the genomic relationship matrix. Heritability of initial response to vaccination (d 21 -d 0) was 0.10 +/- 0.175 using pedigree relationships and 0.14 +/- 0.149 using genomic relationships, but neither estimate was statistically different from zero. Heritability of booster (d 56 -d 21) and overall (d 56 -d 0) responses were low and not statistically significant from zero. There were no clusters of linked SNP associated with vaccine response, but eight regionally isolated SNPs were significantly associated with initial or overall response to vaccination. Regional genetic variation for initial response to an E. coli O157:H7 vaccine was observed, although overall heritability of this response was not statistically significant from zero. PMID- 29758058 TI - Structural studies and molecular dynamics simulations suggest a processive mechanism of exolytic lytic transglycosylase from Campylobacter jejuni. AB - The bacterial soluble lytic transglycosylase (LT) breaks down the peptidoglycan (PG) layer during processes such as cell division. We present here crystal structures of the soluble LT Cj0843 from Campylobacter jejuni with and without bulgecin A inhibitor in the active site. Cj0843 has a doughnut shape similar but not identical to that of E. coli SLT70. The C-terminal catalytic domain is preceded by an L-domain, a large helical U-domain, a flexible linker, and a small N-terminal NU-domain. The flexible linker allows the NU-domain to reach over and complete the circular shape, using residues conserved in the Epsilonproteobacteria LT family. The inner surface of the Cj0843 doughnut is mostly positively charged including a pocket that has 8 Arg/Lys residues. Molecular dynamics simulations with PG strands revealed a potential functional role for this pocket in anchoring the negatively charged terminal tetrapeptide of the PG during several steps in the reaction including homing and aligning the PG strand for exolytic cleavage, and subsequent ratcheting of the PG strand to enhance processivity in degrading PG strands. PMID- 29758059 TI - Divergent humoral responses to 23-valent pneumococcal polysaccharide vaccine in critically-ill burn and neurosurgical patients. AB - INTRODUCTION: Critically ill hospitalized patients are at increased risk of infection so we assessed the immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPSV23) administered within six days of injury. METHODS: This prospective observational study compared the immunogenicity of PPSV23 among critically ill burn and neurosurgical patients at a tertiary, academic medical center. Patients received PPSV23 vaccination within six days of ICU admission per standard of care. Consent was obtained to measure concentrations of vaccine specific IgG to 14 of 23 serotype capsule-specific IgG in serum prior to and 14 35 days following PPSV23. A successful immunologic response was defined as both a >=2-fold rise in capsule-specific IgG from baseline and concentrations of >1 mcg/mL to 10 of 14 measured vaccine serotypes. Immunologic response was compared between burn and neurosurgical patients. Multiple variable regression methods were used to explore associations of clinical and laboratory parameters to immunologic responses. RESULTS: Among the 16 burn and 27 neurosurgical patients enrolled, 87.5% and 40.7% generated a successful response to the vaccine, respectively (p = 0.004). Both median post-PPSV23 IgG concentrations (7.79 [4.56 18.1] versus 2.93 [1.49-8.01] mcg/mL; p = 0.006) and fold rises (10.66 [7.44 14.56] versus 3.48 [1.13-6.59]; p<0.001) were significantly greater in burn compared with neurosurgical patients. Presence of burn injury was directly and days from injury to immunization were inversely correlated with successful immunologic response (both p<0.03). Burn injury was associated with both increased median antibody levels post-PPSV23 and fold rise to 14 vaccine serotypes (p<0.03), whereas absolute lymphocyte count was inversely correlated with median antibody concentrations (p = 0.034). CONCLUSION: Critically ill burn patients can generate successful responses to PPSV23 during acute injury whereas responses among neurosurgical patients is comparatively blunted. Further study is needed to elucidate the mechanisms of differential antigen responsiveness in these populations, including the role of acute stress responses, as well as the durability of these antibody responses. PMID- 29758062 TI - Correction: Interacting Virus Abundance and Transmission Intensity Underlie Tomato Spotted Wilt Virus Incidence: An Example Weather-Based Model for Cultivated Tobacco. AB - [This corrects the article DOI: 10.1371/journal.pone.0073321.]. PMID- 29758061 TI - Predictive score of sarcopenia occurrence one year after bariatric surgery in severely obese patients. AB - BACKGROUND AND AIM: Sarcopenic obesity is a risk factor of morbidity and mortality. The aim of this study was to generate a predictive score of sarcopenia occurrence one year after bariatric surgery. PATIENTS AND METHODS: We conducted an observational prospective cohort study on a total of 184 severely obese patients admitted to our institution to undergo sleeve gastrectomy. Skeletal muscle cross-sectional area at the third lumbar vertebrae (SMA, cm2) was measured from the routinely performed computed tomography. The skeletal muscle index (SMI) was calculated as follows: SMA/height2 (cm2/m2). Sarcopenia was defined as an SMI < 38.5 cm2/m2 for women and < 52.4 cm2/m2 for men. Measurements were performed at surgery and one year later. RESULTS: Most of the included patients were female (79%), with a mean age of 42+/-0.9 years and body mass index of 43.2+/-0.5 kg/m2. Fifteen patients (8%) had sarcopenia before surgery and 59 (32%) at the one-year follow-up. Male gender (p<0.0001), SMA before surgery (p<0.0001), and SMI before surgery (p<0.0001) significantly correlated with the occurrence of sarcopenia one year after surgery by multivariate analysis. Two predictive sarcopenia occurrence scores were constructed using SMA and gender (SS1 score) or SMI and gender (SS2 score). The area under receiver operating characteristic (AUROC) curve of the SS2 score was significantly greater than that of the SS1 score for the diagnosis of postoperative sarcopenia occurrence (0.95+/-0.02 versus 0.90+/-0.02; p<0.01). A cut-off value for the SS2 score of 0.53 had a sensitivity of 90%, a specificity of 91%, a positive predictive value of 83%, and a negative predictive value of 95%. In the group of patients without baseline sarcopenia, the SS2 score had still an excellent AUROC of 0.92+/-0.02. A cut-off of 0.55 predicted development of sarcopenia one year after sleeve gastrectomy in these patients with a sensitivity of 87%, a specificity of 88%, and negative predictive value of 95%. CONCLUSION: The SS2 score has excellent predictive value for the occurrence of sarcopenia one year after sleeve gastrectomy. This score can be used to target early intensification of nutritional and dietetic follow-up to the predicted high risk population. PMID- 29758063 TI - The impact of antibiotic use on transmission of resistant bacteria in hospitals: Insights from an agent-based model. AB - Extensive antibiotic use over the years has led to the emergence and spread of antibiotic resistant bacteria (ARB). Antibiotic resistance poses a major threat to public health since for many infections antibiotic treatment is no longer effective. Hospitals are focal points for ARB spread. Antibiotic use in hospitals exerts selective pressure, accelerating the spread of ARB. We used an agent-based model to explore the impact of antibiotics on the transmission dynamics and to examine the potential of stewardship interventions in limiting ARB spread in a hospital. Agents in the model consist of patients and health care workers (HCW). The transmission of ARB occurs through contacts between patients and HCW and between adjacent patients. In the model, antibiotic use affects the risk of transmission by increasing the vulnerability of susceptible patients and the contagiousness of colonized patients who are treated with antibiotics. The model shows that increasing the proportion of patients receiving antibiotics increases the rate of acquisition non-linearly. The effect of antibiotics on the spread of resistance depends on characteristics of the antibiotic agent and the density of antibiotic use. Antibiotic's impact on the spread increases when the bacterial strain is more transmissible, and decreases as resistance prevalence rises. The individual risk for acquiring ARB increases in parallel with antibiotic density both for patients treated and not treated with antibiotics. Antibiotic treatment in the hospital setting plays an important role in determining the spread of resistance. Interventions to limit antibiotic use have the potential to reduce the spread of resistance, mainly by choosing an agent with a favorable profile in terms of its impact on patient's vulnerability and contagiousness. Methods to measure these impacts of antibiotics should be developed, standardized, and incorporated into drug development programs and approval packages. PMID- 29758064 TI - Risk perception and sex behaviour in pregnancy and breastfeeding in high HIV prevalence settings: Programmatic implications for PrEP delivery. AB - HIV acquisition during pregnancy and breastfeeding significantly contributes toward paediatric HIV infection; however, little is known about risk behaviours in HIV-uninfected pregnant and postpartum women. We conducted twenty-six in-depth interviews between July and December 2016 using a semi-structured interview guide among HIV-uninfected pregnant and recently postpartum women at-risk of HIV acquisition (defined as reporting >=1 of the following: partner's serostatus unknown or HIV-infected, recent condomless sex in pregnancy, and/or alcohol use during pregnancy) who attended primary healthcare services. Our study contextualizes factors related to risky sexual behaviours during pregnancy and postpartum periods and assesses knowledge and hypothetical acceptability of pre exposure prophylaxis (PrEP) in pregnancy. Translated and transcribed data were coded and analysed by three researchers using a thematic analysis approach. In interviews with HIV-uninfected pregnant/postpartum women at-risk of HIV acquisition, we identified common themes associated with sexual risk behaviours during pregnancy, including: lack of control over decisions in sex and condom use in pregnancy, low perceived risk (e.g. beliefs that their partner has the same HIV-negative serostatus), and socio-cultural beliefs around condom use during pregnancy (e.g. contact with sperm is essential for baby's development). PrEP knowledge was low among HIV-uninfected pregnant and breastfeeding women, and potential acceptability was good, though primary concerns were around the potential impact on the infant. While mothers presented a clear desire to protect themselves from HIV acquisition once pregnant, they also reported lack of control, and socio-cultural beliefs, like sex is good for the baby, that increased their risk of seroconversion. Mothers had limited PrEP awareness but reported hypothetical willingness to use PrEP because of concerns over HIV acquisition and onward mother to child transmission. PMID- 29758065 TI - The genetic component of preeclampsia: A whole-exome sequencing study. AB - Preeclampsia is a major cause of maternal and perinatal deaths. The aetiology of preeclampsia is largely unknown but a polygenetic component is assumed. To explore this hypothesis, we performed an in-depth whole-exome sequencing study in women with (cases, N = 50) and without (controls, N = 50) preeclampsia. The women were identified in an unselected cohort of 2,545 pregnant women based on data from the Danish National Patient Registry and the Medical Birth Registry. Matching DNA was obtained from a biobank containing excess blood from routine antenatal care visits. Novogene performed the whole-exome sequencing blinded to preeclampsia status. Variants for comparison between cases and controls were filtered in the Ingenuity Variant Analysis software. We applied two different strategies; a disease association panel approach, which included variants in single genes associated with established clinical risk factors for preeclampsia, and a gene panel approach, which included biological pathways harbouring genes previously reported to be associated with preeclampsia. Variant variability was compared in cases and controls at the level of biological processes, signalling pathways, and in single genes. Regardless of the applied strategy and the level of variability examined, we consistently found positive correlations between variant numbers in cases and controls (all R2s>0.88). Contrary to what was expected, cases carried fewer variants in biological processes and signalling pathways than controls (all p-values <=0.02). In conclusion, our findings challenge the hypothesis of a polygenetic aetiology for preeclampsia with a common network of susceptibility genes. The greater genetic diversity among controls may suggest a protective role of genetic diversity against the development of preeclampsia. PMID- 29758067 TI - Correction: Identification of Functional Candidates amongst Hypothetical Proteins of Treponema pallidum ssp. pallidum. AB - [This corrects the article DOI: 10.1371/journal.pone.0124177.]. PMID- 29758066 TI - Utility of social networks and online data collection in nursing research: Analysis of Spanish nurses' level of knowledge about palliative care. AB - INTRODUCTION: Internet-based social networks are used by nurses with different purposes, including the creation of working groups and to share and create knowledge. PURPOSE: To evaluate the utility of social networks in the dissemination of an online questionnaire and to measure Spanish RNs' knowledge about palliative care. METHODS: A descriptive cross-sectional study was carried out. Using social networks we distributed an online questionnaire with the Spanish version of Palliative Care Quiz for Nurses (PCQN-SV) throughout August 2015. RESULTS: A direct relationship between the number of responses and the questionnaire's apparitions in each social network was found. Comparing the results obtained by the 446 RNs participating in this study with those obtained in the study to pilot the PCQN-SV we identify that differences found are related to the participants' features (years of experience and hours of training in palliative care) and not to the type of questionnaire they answered. CONCLUSIONS: Social networks have shown to be a useful tool for nursing research by its ability, to recruit participants as well as to collect data, so their role as an instrument of research should be considered. PMID- 29758068 TI - Differentially abundant proteins associated with heterosis in the primary roots of popcorn. AB - Although heterosis has significantly contributed to increases in worldwide crop production, the molecular mechanisms regulating this phenomenon are still unknown. In the present study, we used a comparative proteomic approach to explore hybrid vigor via the proteome of both the popcorn L54 ? and P8 ? genotypes and the resultant UENF/UEM01 hybrid cross. To analyze the differentially abundant proteins involved in heterosis, we used the primary roots of these genotypes to analyze growth parameters and extract proteins. The results of the growth parameter analysis showed that the mid- and best-parent heterosis were positive for root length and root dry matter but negative for root fresh matter, seedling fresh matter, and protein content. The comparative proteomic analysis identified 1343 proteins in the primary roots of hybrid UENF/UEM01 and its parental lines; 220 proteins were differentially regulated in terms of protein abundance. The mass spectrometry proteomic data are available via ProteomeXchange with identifier "PXD009436". A total of 62 regulated proteins were classified as nonadditive, of which 53.2% were classified as high parent abundance (+), 17.8% as above-high parent abundance (+ +), 16.1% as below-low parent abundance (- -), and 12.9% as low parent abundance (-). A total of 22 biological processes were associated with nonadditive proteins; processes involving translation, ribosome biogenesis, and energy-related metabolism represented 45.2% of the nonadditive proteins. Our results suggest that heterosis in the popcorn hybrid UENF/UEM01 at an early stage of plant development is associated with an up-regulation of proteins related to synthesis and energy metabolism. PMID- 29758069 TI - Strengthening primary eye care in South Africa: An assessment of services and prospective evaluation of a health systems support package. AB - Visual impairment is a significant public health concern, particularly in low- and middle-income countries where eye care is predominantly provided at the primary healthcare (PHC) level, known as primary eye care. This study aimed to perform an evaluation of primary eye care services in three districts of South Africa and to assess whether an ophthalmic health system strengthening (HSS) package could improve these services. Baseline surveys were conducted in Cape Winelands District, Johannesburg Health District and Mopani District at 14, 25 and 36 PHC facilities, respectively. Thereafter, the HSS package, comprising group training, individual mentoring, stakeholder engagement and resource provision, was implemented in 20 intervention sites in Mopani District, with the remaining 16 Mopani facilities serving as control sites. At baseline, less than half the facilities in Johannesburg and Mopani had dedicated eye care personnel or sufficient space to measure visual acuity. Although visual acuity charts were available in most facilities, <50% assessed patients at the correct distance. Median score for availability of nine essential drugs was <70%. Referral criteria knowledge was highest in Cape Winelands and Johannesburg, with poor clinical knowledge across all districts. Several HSS interventions produced successful outcomes: compared to control sites there was a significant increase in the proportion of intervention sites with eye care personnel and resources such as visual acuity charts (p = 0.02 and <0.01, respectively). However, engaging with district pharmacists did not improve availability of essential drugs (p = 0.47). Referral criteria knowledge improved significantly in intervention sites (p<0.01) but there was no improvement in clinical knowledge (p = 0.76). Primary eye care in South Africa faces multiple challenges with regard to organisation of care, resource availability and clinical competence. The HSS package successfully improved some aspects of this care, but further development is warranted together with debate regarding the positioning of eye services at PHC level. PMID- 29758070 TI - Rapamycin-independent IGF2 expression in Tsc2-null mouse embryo fibroblasts and human lymphangioleiomyomatosis cells. AB - Lymphangioleiomyomatosis (LAM) is a rare, almost exclusively female lung disease linked to inactivating mutations in tuberous sclerosis complex 2 (TSC2), a tumor suppressor gene that controls cell metabolic state and growth via regulation of the mechanistic target of rapamycin (mTORC1) signaling. mTORC1 is frequently activated in human cancers and, although the mTORC1 inhibitor rapamycin has a cytostatic effect, it is, in general, unable to elicit a robust curative effect or tumor regression. Using RNA-Seq, we identified (1) Insulin-like Growth Factor (IGF2) as one of the genes with the highest fold-change difference between human TSC2-null and TSC2-expressing angiomyolipoma cells from a patient with LAM, and (2) the mouse IGF2 homolog Igf2, as a top-ranking gene according to fold change between Tsc2-/- and Tsc2+/+ mouse embryo fibroblasts (MEFs). We extended transcript-level findings to protein level, observing increased Igf2 protein expression and Igf2 secretion by Tsc2-/- MEFs. Increased Igf2 expression was not due to epigenetic imprinting, but was partially mediated through the Stat3 pathway and was completely insensitive to rapamycin treatment. An siRNA-mediated decrease of Igf2 resulted in decreased Stat3 phosphorylation, suggesting presence of an autocrine Igf2/Stat3 amplification cycle in Tsc2-/- MEFs. In human pulmonary LAM lesions and metastatic cell clusters, high levels of IGF2 were associated with mTORC1 activation. In addition, treatment of three primary IGF2 expressing LAM lung cell lines with rapamycin did not result in IGF2 level changes. Thus, targeting of IGF2 signaling may be of therapeutic value to LAM patients, particularly those who are unresponsive to rapamycin. PMID- 29758071 TI - The long-term impact of community mobilisation through participatory women's groups on women's agency in the household: A follow-up study to the Makwanpur trial. AB - Women's groups practicing participatory learning and action (PLA) in rural areas have been shown to improve maternal and newborn survival in low-income countries, but the pathways from intervention to impact remain unclear. We assessed the long term impact of a PLA intervention in rural Nepal on women's agency in the household. In 2014, we conducted a follow-up study to a cluster randomised controlled trial on the impact of PLA women's groups from 2001-2003. Agency was measured using the Relative Autonomy Index (RAI) and its subdomains. Multi-level regression analyses were performed adjusting for baseline socio-demographic characteristics. We additionally adjusted for potential exposure to subsequent PLA groups based on women's pregnancy status and conduct of PLA groups in areas of residence. Sensitivity analyses were performed using two alternative measures of agency. We analysed outcomes for 4030 mothers (66% of the cohort) who survived and were recruited to follow-up at mean age 39.6 years. Across a wide range of model specifications, we found no association between exposure to the original PLA intervention with women's agency in the household approximately 11.5 years later. Subsequent exposure to PLA groups was not associated with greater agency in the household at follow-up, but some specifications found evidence for reduced agency. Household agency may be a prerequisite for actualising the benefits of PLA groups rather than a consequence. PMID- 29758072 TI - Sex differences in associations between multimorbidity and physical function domains among community-dwelling adults in Singapore. AB - OBJECTIVES: The aims of the study were to identify the associations between multimorbidity and specific physical function domains among community-dwelling adults in Singapore, and to examine sex differences in the associations. METHODS: This study was conducted using baseline data of 1,940 participants in the Population Health Index Survey conducted in the Central Region of Singapore from November 2015 to November 2016. Physical function was assessed using the Function Component of the Late-life Function and Disability Instrument and compared between men and women. Multiple linear regressions were conducted to examine associations between multimorbidity and different physical function domains for all participants, and in men and women separately. RESULTS: The prevalence of multimorbidity in the study population was 35.0% for adults aged 21 years and above, with no differences between men and women. Multimorbidity was associated with reduced upper extremity function, basic and advanced lower extremity function, and overall function in men and women after adjusting for demographic factors. Multimorbidity had a stronger association with advanced lower extremity function and overall physical function in women than in men. CONCLUSIONS: The findings of this study indicate that multimorbidity is associated with physical function domains in men and women, and in particular advanced lower extremity for women. Effective community-based interventions need to be implemented to preserve physical function in individuals with multimorbidity to keep them functionally independent and physically active in the community. Additional focus on advanced lower extremity function for women is needed. PMID- 29758073 TI - Effects of computer-assisted navigation versus conventional total knee arthroplasty on the levels of inflammation markers: A prospective study. AB - Total knee arthroplasty (TKA) is a well-established modality for the treatment of advanced knee osteoarthritis (OA). However, the detrimental effects of intramedullary reaming used in conventional TKA for distal femur cutting are of concern. Avoiding intramedullary reaming with the use of computer-assisted navigation TKA can not only provide superior prosthetic alignment, but also mitigate perioperative blood loss and the dissipation of marrow emboli. We quantified local and systemic concentrations of inflammation markers for both techniques. Forty-four participants undergoing computer-assisted navigation and 53 receiving conventional TKA for advanced knee OA were recruited between 2013/02/08 and 2015/12/09. Blood samples were collected from all participants at baseline then again at 24 and 72 hours postoperatively and analyzed by ELISA for interleukin 6 (IL-6), IL-10, tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta 1 (TGF-beta1); these markers were also measured in Hemovac drain fluid collected at 24 and 72 hours. Serum levels of IL-6, IL-10, TNF-alpha and TGF-beta1(unit for all markers: pg/mL) were increased from baseline by smaller increments in the navigation TKA cohort compared with the conventional TKA group at 24 hours (17.06 vs 29.39, p = 0.02; 0.51 vs 0.83, p = 0.16; -0.04 vs 0.36, p < 0.01 and -48.18 vs 63.24, p< 0.01, respectively) and at 72 hours (12.27 vs 16.87, p = 0.01; -0.40 vs 0.48, p < 0.01; 0.58 vs 0.98, p = 0.07 and -55.16 vs 63.71, p < 0.01, respectively). IL-10 levels in drainage fluids collected 24 hours after TKA were also significantly lower in the navigation group versus the conventional TKA group (8.55 vs 12.32, p < 0.01). According to our evidence, the merits of computer-assisted navigation TKA are augmented by low levels of inflammation markers. PMID- 29758074 TI - Comparison of the effect of dietary copper nanoparticles and one copper (II) salt on the copper biodistribution and gastrointestinal and hepatic morphology and function in a rat model. AB - The aim of the study was to investigate the effect of two forms (CuCO3 (CuS); and Cu nanoparticles (CuNP)) and dosages (standard 6.5 mg/kg (H), half of the standard (L)) of additional dietary Cu administered to growing rats on gastrointestinal and hepatic function and morphology. Copper in the form of CuNP vs CuS caused lower Cu faecal/urinal excretion and increased Cu accumulation in the brain tissue. Hepatic high-grade hydropic degeneration and necrotic lesions were observed only in the CuNP-H animals. In the lower gut, the dietary application of CuNP stifled bacterial enzymatic activity of caecal gut microbiota and resulted in lower SCFA production. That diminishing effect of CuNP on caecal microbiota activity was accompanied by a relative increase in the secretion of glycoside hydrolases by bacterial cells. The results showed that in comparison to Cu from CuCO3, Cu nanoparticles to a greater extent were absorbed from the intestine, accumulated in brain tissue, exerted antimicrobial effect in the caecum, and at higher dietary dose caused damages in the liver of rats. PMID- 29758075 TI - Effectiveness and safety of Rituximab in multiple sclerosis: an observational study from Southern Switzerland. AB - BACKGROUND: Despite positive results from phase II and observational studies, Rituximab (RTX) is not currently approved for multiple sclerosis (MS) treatment and can only be used off-label. OBJECTIVE: To characterize MS patients treated with RTX and investigate its effectiveness and safety in a clinical practice setting. METHODS: Observational analysis of data collected from MS patients at the Neurocenter of Southern Switzerland. Relapses, EDSS worsening, MRI lesion accrual and "evidence of disease activity" (EDA) status were described by Cox regression. RTX and natalizumab treated patients were matched by propensity scores. RESULTS: Out of 453 MS patients, 82 were treated with RTX, 43 (52.4%) relapsing-remitting (RRMS) and 39 (47.6%) progressive MS (median age = 48 [40-54] years, females n = 60 [73.2%], EDSS = 4.0 [2.5-6.0], median follow-up = 1.5 [1.0 2.5] years). Three relapses occurred and 59 (75.6%) patients had not EDA at follow-up end. Time to EDA was similar in RTX and natalizumab treated RRMS patients (HR = 1.64, 95%CI = 0.46-5.85, p = 0.44). Twenty-four patients presented non infusion related adverse events (infections), requiring RTX discontinuation in 6 individuals. CONCLUSION: These results provide further evidence for RTX being effective in MS treatment, to a similar extent to natalizumab in RRMS. Clinicians must be vigilant for the potential occurrence of infections. PMID- 29758077 TI - Correction: Pattern or process? Evaluating the peninsula effect as a determinant of species richness in coastal dune forests. AB - [This corrects the article DOI: 10.1371/journal.pone.0173694.]. PMID- 29758076 TI - High throughput generation and characterization of replication-competent clade C transmitter-founder simian human immunodeficiency viruses. AB - Traditional restriction endonuclease-based cloning has been routinely used to generate replication-competent simian-human immunodeficiency viruses (SHIV) and simian tropic HIV (stHIV). This approach requires the existence of suitable restriction sites or the introduction of nucleotide changes to create them. Here, using an In-Fusion cloning technique that involves homologous recombination, we generated SHIVs and stHIVs based on epidemiologically linked clade C transmitted/founder HIV molecular clones from Zambia. Replacing vif from these HIV molecular clones with vif of SIVmac239 resulted in chimeric genomes used to generate infectious stHIV viruses. Likewise, exchanging HIV env genes and introducing N375 mutations to enhance macaque CD4 binding site and cloned into a SHIVAD8-EO backbone. The generated SHIVs and stHIV were infectious in TZMbl and ZB5 cells, as well as macaque PBMCs. Therefore, this method can replace traditional methods and be a valuable tool for the rapid generation and testing of molecular clones of stHIV and SHIV based on primary clinical isolates will be valuable to generate rapid novel challenge viruses for HIV vaccine/cure studies. PMID- 29758079 TI - Retraction: A tree of life based on ninety-eight expressed genes conserved across diverse eukaryotic species. PMID- 29758078 TI - The provision of written information and its effect on levels of pain and anxiety during electrodiagnostic studies: A randomised controlled trial. AB - OBJECTIVE: The provision of written information is a low-cost and readily available intervention that has been found to reduce pain and anxiety in a variety of clinical settings. The current study was undertaken to determine if information provision may improve patients' experience during conventional electrodiagnostic studies. METHODS: 128 participants were recruited from a tertiary teaching hospital who were referred for electrodiagnostic studies. They were randomized into 2 groups where the intervention group was provided with written information about the electrodiagnostic testing. Patients were invited to complete a questionnaire that included pain and anxiety using a visual analogue scale (VAS) following the testing. All participants underwent nerve conduction studies (NCS) whilst a subset also underwent subsequent needle electromyography (EMG). RESULTS: Those who received information had a statistically significant lower perception of anxiety during NCS, whilst only females who received information had a statistically significant lower perception of pain to both NCS and EMG. CONCLUSIONS: The provision of written information can reduce the degree of pain and anxiety experienced during electrodiagnostic testing. SIGNIFICANCE: Improving patient comfort and tolerability during electrodiagnostic testing may have practical implications towards more reliable and accurate results obtained from such investigations that may in turn improve patient diagnosis and management. PMID- 29758080 TI - Correction: MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005032.]. PMID- 29758081 TI - Correction: Sex, pregnancy and aortic disease in Marfan syndrome. AB - [This corrects the article DOI: 10.1371/journal.pone.0181166.]. PMID- 29758083 TI - Correction: Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study. AB - [This corrects the article DOI: 10.1371/journal.pone.0195413.]. PMID- 29758085 TI - Utilization of X-ray Computed Tomography for the Exclusion of a Specific Caliber and Bullet Type in a Living Shooting Victim. AB - A bystander claimed to have been shot by a police officer, and CT scans were used to match qualitative and quantitative aspects of the unremoved bullet with police issued 9 mm Luger ammunition. CT scan methodology proved a valid approach for the measurement of bullets based on calculated measurement capability and correlation with "gold standard" physical measurement by vernier caliper. Measurements regarding length and base diameter, as well as length/diameter ratio, were insufficient to unambiguously identify a specific caliber, or a bullet of specific mass within a caliber class. It was, however, possible to exclude a bullet of specific design and mass with well-characterized precision and accuracy values under selected CT scan conditions. A 9 mm Luger bullet (115 gr FMJ RN) was excluded from involvement in a shooting based on qualitative bullet shape combined with length, base, and ratio measurements of the bullet in-situ for the victim. PMID- 29758087 TI - Pembrolizumab-associated mucous membrane pemphigoid in a patient with Merkel cell carcinoma. PMID- 29758088 TI - Assessment of treatment-seeking behaviour in patients with psoriasis. PMID- 29758086 TI - Cholinergic excitation complements glutamate in coding visual information in retinal ganglion cells. AB - KEY POINTS: Starburst amacrine cells release GABA and ACh. This study explores the coordinated function of starburst-mediated cholinergic excitation and GABAergic inhibition to bistratified retinal ganglion cells, predominantly direction-selective ganglion cells (DSGCs). In rat retina, under our recording conditions, starbursts were found to provide the major excitatory drive to a sub population of ganglion cells whose dendrites co-stratify with starburst dendrites (putative DSGCs). In mouse retina, recordings from genetically identified DSGCs at physiological temperatures reveal that ACh inputs dominate the response to small spot-high contrast light stimuli, with preferential addition of bipolar cell input shifting the balance towards glutamate for larger spot stimuli In addition, starbursts also appear to gate glutamatergic excitation to DSGCs by postsynaptic and possibly presynaptic inhibitory processes ABSTRACT: Starburst amacrine cells release both GABA and ACh, allowing them to simultaneously mediate inhibition and excitation. However, the precise pre- and postsynaptic targets for ACh and GABA remain under intense investigation. Most previous studies have focused on starburst-mediated postsynaptic GABAergic inhibition and its role in the formation of directional selectivity in ganglion cells. However, the significance of postsynaptic cholinergic excitation is only beginning to be appreciated. Here, we found that light-evoked responses measured in bi-stratified rat ganglion cells with dendrites that co-fasciculate with ON and OFF starburst dendrites (putative direction-selective ganglion cells, DSGCs) were abolished by the application of nicotinic receptor antagonists, suggesting ACh could act as the primary source of excitation. Recording from genetically labelled DSGCs in mouse retina at physiological temperatures revealed that cholinergic synaptic inputs dominated the excitation for high contrast stimuli only when the size of the stimulus was small. Canonical glutamatergic inputs mediated by bipolar cells were prominent when GABA/glycine receptors were blocked or when larger spot stimuli were utilized. In mouse DSGCs, bipolar cell excitation could also be unmasked through the activation of mGluR2,3 receptors, which we show suppresses starburst output, suggesting that GABA from starbursts serves to inhibit bipolar cell signals in DSGCs. Taken together, these results suggest that starbursts amplify excitatory signals traversing the retina, endowing DSGCs with the ability to encode fine spatial information without compromising their ability to encode direction. PMID- 29758089 TI - Current commercial techniques for MRI-guided attenuation correction are insufficient and will limit the wider acceptance of PET/MRI technology in the clinic. PMID- 29758090 TI - Early investigations in drug delivery of onabotulinum toxin A using combined fractional ablative laser with impact ultrasound vs. injections of onabotulinum toxin A for palmar hyperhidrosis: a right-left comparison trial. PMID- 29758082 TI - Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas. AB - Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP 9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP 9 primarily in macrophages in both murine and human lung tissues infected with M. tuberculosis, suggesting the importance of MMP-9 in TB pathogenesis. These data suggest that the relapse rates in M. tuberculosis-infected mice may be non specifically improved by administration of antibodies in conjunction with standard TB treatments. Future studies are needed to evaluate the mechanism(s) leading to improved outcomes with adjunctive antibody treatments. PMID- 29758091 TI - Z-Transform Method for Pairwise Osteometric Pair-matching. AB - A new pairwise osteometric pair-matching approach based on the Z-transform method is presented. In contrast to previous methods that perform a global t-test on the summed skeletal element pair measurement distances, this approach performs t tests on each individual distance, facilitating the capture of measurement specific variation. This new approach is compared to published pairwise sorting methods using a standard reference dataset of postcranial remains maintained by the Defense POW/MIA Accounting Agency. Receiver operating characteristic curve analysis indicates significantly improved performance for the clavicle and radius over all previous methods (p < 0.01). The z-transform method weighted by the effect size outperformed the t-test (Byrd and Adams) and the mean t-test (Lynch) for all elements (p < 0.01). The method performed better than the absolute value t-test (Lynch) for five elements (p < 0.01) and performed at least as well for the remainder. To facilitate usability all methods are available at: https://github.com/spawaskar-cora/z-transform-method. PMID- 29758092 TI - Langerhans cells express human beta-defensin 3: relevance for immunity during skin ageing. PMID- 29758094 TI - Is melanoma mortality declining in Spain? Analysis of trends from 1975 to 2016. PMID- 29758093 TI - Effects of Human Electro-Muscular Incapacitation (HEMI) Devices on Cardiovascular Changes in Anesthetized Swine as Measured by Transesophageal Echocardiography (TEE). AB - The abundance of, and reliance upon, human electro-muscular incapacitation (HEMI) devices, especially in law enforcement, has generated scrutiny and examination of these technologies. The purpose of this study was to examine cardiovascular effects resulting from typical (5 sec) and longer activation (20 sec) HEMI applications studying myocardial function and peripheral vascular system using a combination of invasive cardiovascular catheters and transesophageal echocardiography (TEE). Six healthy swine (Sus scrofa) 3-5 months in age and weighing between 60 and 86 kg were anesthetized and exposed to the TASER Model X26 waveform while transesophageal echocardiography was performed. Stroke volume was shown to statistically decrease during HEMI application indicating an increase in systemic vascular resistance, but HEMI application did not result in myocardial dysfunction ("cardiac stunning"). PMID- 29758096 TI - Low maternal serum concentrations of mannose-binding lectin are associated with the risk of shorter duration of pregnancy and lower birthweight. AB - Chronic inflammation has been implicated as the underlying mechanism responsible for the pathophysiology of preterm labour. Mannose-binding lectin (MBL) plays a central role in the innate immune response and is thus an important component of the first line of defense. The aim of this study was to investigate whether serum concentrations of MBL correlated with the incidence of preterm birth and low birthweight in a cohort of women with signs of threatened preterm birth. A cohort of 60 patients who presented with regular contractions and/or short cervix (group A) between 24 and 32 weeks of gestation and 20 healthy controls (group B) who had no pregnancy complications and delivered at term were recruited into a prospective study. The following outcomes were recorded: presence of preterm labour and birthweight in all patients. MBL and high sensitivity C-reactive protein levels were measured in all serum samples. The serum concentrations of MBL were significantly reduced in patients with threatened preterm labour (Group A), compared to the control Group B. Furthermore, infants born to Group A mothers with MBL deficiency (n = 13, MBL <=100 ng/mL) had significantly lower birthweights, compared to those born to Group A women with normal MBL serum concentrations (P < .0001). Our small cohort study demonstrated a strong association between MBL deficiency and preterm delivery, and associated low birthweight. MBL deficiency could thus be considered an important risk factor for preterm birth. PMID- 29758095 TI - Reuse of public, genome-wide, murine eosinophil expression data for hypotheses development. AB - The eosinophil (Eos) surface phenotype and activation state is altered after recruitment into tissues and after exposure to pro-inflammatory cytokines. In addition, distinct Eos functional subsets have been described, suggesting that tissue-specific responses for Eos contribute to organ homeostasis. Understanding the mechanisms by which Eos subsets achieve their tissue-specific identity is currently an unmet goal for the eosinophil research community. Publicly archived expression data can be used to answer original questions, test and generate new hypotheses, and serve as a launching point for experimental design. With these goals in mind, we investigated the effect of genetic background, culture methods, and tissue residency on murine Eos gene expression using publicly available, genome-wide expression data. Eos differentiated from cultures have a gene expression profile that is distinct from that of native homeostatic Eos; thus, researchers can repurpose published expression data to aid in selecting the appropriate culture method to study their gene of interest. In addition, we identified Eos lung- and gastrointestinal-specific transcriptomes, highlighting the profound effect of local tissue environment on gene expression in a terminally differentiated granulocyte even at homeostasis. Expanding the "toolbox" of Eos researchers to include public-data reuse can reduce redundancy, increase research efficiency, and lead to new biological insights. PMID- 29758098 TI - What is your diagnosis? Mandibular mass in a cat. PMID- 29758097 TI - Persistence of Polydimethylsiloxane Condom Lubricants. AB - Polydimethylsiloxane (PDMS) is commonly used to lubricate condoms. The detection of PDMS on swabs from complainants can be used to support an allegation of sexual assault. Previous research has focused on establishing analytical techniques for detecting PDMS. This research examined the persistence of PDMS on the penis, in the vagina, in the mouth, and on skin. The longest PDMS detection times were 20 h on the penis, 35 h in the vagina, and 52 h on skin. PDMS was detected up to 4 h in the mouth if the participant did not eat or drink and up to 9 h if the participant slept. PDMS was not detected in the mouth after eating or drinking. The presence of biological fluids had no detrimental effect on the analysis. Aqueous extraction of swabs for DNA did not remove any significant amount of PDMS; hence, swab remains could be subsequently analyzed for PDMS. PMID- 29758099 TI - The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for Essential Tremor. AB - PURPOSE: To analyze clinical data indicating a reduction in the induced energy temperature efficiency relationship during transcranial focused ultrasound (FUS) Essential Tremor (ET) thalamotomy treatments at higher acoustic powers, establish its relationship with the spatial distribution of the focal temperature elevation, and explore its cause. METHODS: A retrospective observational study of patients (n = 19) treated between July 2015 and August 2016 for (ET) by FUS thalamotomy was performed. These data were analyzed to compare the relationships between the applied power, the applied energy, the resultant peak temperature achieved in the brain, and the dispersion of the focal volume. Full ethics approval was received and all patients provided signed informed consent forms before the initiation of the study. Computer simulations, animal experiments, and clinical system tests were performed to determine the effects of skull heating, changes in brain properties and transducer acoustic output, respectively. All animal procedures were approved by the Animal Care and Use Committee and conformed to the guidelines set out by the Canadian Council on Animal Care. MATLAB was used to perform statistical analysis. RESULTS: The reduction in the energy efficiency relationship during treatment correlates with the increase in size of the focal volume at higher sonication powers. A linear relationship exists showing that a decrease in treatment efficiency correlates positively with an increase in the focal size over the course of treatment (P < 0.01), supporting the hypothesis of transient skull and tissue heating causing acoustic aberrations leading to a decrease in efficiency. Changes in thermal conductivity, perfusion, absorption rates in the brain, as well as ultrasound transducer acoustic output levels were found to have minimal effects on the observed reduction in efficiency. CONCLUSIONS: The reduction in energy-temperature efficiency during high-power FUS treatments correlated with observed increases in the size of the focal volume and is likely caused by transient changes in the tissue and skull during heating. PMID- 29758100 TI - Diagnostic approach to low-renin hypertension. AB - Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms. PMID- 29758101 TI - Model-based reconstruction for simultaneous multislice and parallel imaging accelerated multishot diffusion tensor imaging. AB - PURPOSE: Multishot interleaved echo-planar imaging (iEPI) can achieve higher image resolution than single-shot EPI for diffusion tensor imaging (DTI), but its application is limited by the prolonged acquisition time. To reduce the acquisition time, a novel model-based reconstruction for simultaneous multislice (SMS) and parallel imaging (PI) accelerated iEPI DTI is proposed. MATERIALS AND METHODS: DTI datasets acquired by iEPI with SMS and PI acceleration can be regarded as 3D k-space data, which is undersampled along both the slice and phase encoding directions. Instead of reconstruction of individual diffusion-weighted image, diffusion tensors are directly estimated by the joint reconstruction of undersampled 3D k-space from all diffusion-encoding directions using a model based formulation to exploit the correlation across different directions. DTI simulation and in vivo acquisition were used to demonstrate the superior performance of the proposed method. RESULTS: The proposed method reduced the estimation errors and artifacts than traditional parallel imaging reconstruction in DTI simulation. In the in vivo DTI experiment, the acquisition time of 4-shot iEPI was reduced from 11 min 7 s to 3 min 53 s with an acceleration factor of 4, and the image quality and precision of quantitative parameters were comparable with the fully sampled acquisition. CONCLUSIONS: The proposed model-based reconstruction for iEPI DTI with SMS and PI can achieve fourfold acceleration while maintaining high accuracy for tensor measurements. PMID- 29758103 TI - Evaluation of the basophil activation test and skin prick testing for the diagnosis of sesame food allergy. AB - BACKGROUND: The prevalence of sesame food allergy (SFA) has increased over recent years, with the potential of anaphylactic reactions upon exposure. Oral food challenge (OFC) remains the diagnostic standard, yet its implementation may be risky. Commercial skin prick tests (SPT) have a low sensitivity. Investigation of alternate diagnostic methods is warranted. OBJECTIVE: To evaluate the utility of SPT and the basophil activation test (BAT) for SFA diagnosis. METHODS: Eighty-two patients with suspected SFA completed an open OFC to sesame or reported a recent confirmed reaction. Patients were administered skin prick tests (SPT) with commercial sesame seed extract (CSSE) and a high protein concentration sesame extract (HPSE) (100 mg/mL protein). Whole blood from 80 patients was stimulated with sesame seed extract (40-10 000 ng/mL protein) for BAT), assessing CD63 and CD203c as activation markers. RESULTS: Sixty patients (73%) had IgE-mediated reactions to sesame, and 22 (27%) did not react. Receiver operating characteristic (ROC) curve analysis demonstrated an area under the curve (AUC) of 0.87 for HPSE-SPT and 0.66 for CSSE-SPT. At 1000 ng/mL of sesame protein, induction of CD63 and CD203c was weakly but significantly associated with OFC eliciting dose by rank (Spearman's rho = -.42 (P < .01) and -.35 (P < .05) for CD63 and CD203c, respectively). By ROC analysis, the AUC was 0.86 for CD63 and was 0.81 for CD203c sesame-induced basophil expression. Using HPSE-SPT as a first test to definitively diagnose (n = 24) or rule-out (n = 5) SFA and BAT as a second test to diagnose the remainder results in the correct classification of 73 of 80 (91%) patients, leaving one false negative and 4 false positive patients. Two BAT non-responders remain unclassified by this algorithm. CONCLUSIONS & CLINICAL RELEVANCE: While prospective cohort validation is necessary, joint utilization of BAT and SPT with HPSE extract may obviate the need for OFC in most SFA patients. PMID- 29758105 TI - Transcriptional profiling of eosinophil subsets in interleukin-5 transgenic mice. AB - Eosinophils are important in fighting parasitic infections and are implicated in the pathogenesis of asthma and allergy. IL-5 is a critical regulator of eosinophil development, controlling proliferation, differentiation, and maturation of the lineage. Mice that constitutively express IL-5 have in excess of 10-fold more eosinophils in the hematopoietic organs than their wild type (WT) counterparts. We have identified that much of this expansion is in a population of Siglec-F high eosinophils, which are rare in WT mice. In this study, we assessed transcription in myeloid progenitors, eosinophil precursors, and Siglec F medium and Siglec-F high eosinophils from IL-5 transgenic mice and in doing so have created a useful resource for eosinophil biologists. We have then utilized these populations to construct an eosinophil trajectory based on gene expression and to identify gene sets that are associated with eosinophil lineage progression. Cell cycle genes were significantly associated with the trajectory, and we experimentally demonstrate an increasing trend toward quiescence along the trajectory. Additionally, we found gene expression changes associated with constitutive IL-5 signaling in eosinophil progenitors, many of which were not observed in eosinophils. PMID- 29758104 TI - Restricted Speciation and Supramolecular Assembly in the 5f Block. AB - Hybrid materials bearing elements from the 5f block display a rich diversity of coordination geometries, connectivities, and assembly motifs. Exemplary in this regard have been uranyl coordination polymers, which feature a wide range of secondary building units resulting from hydrolysis and oligomerization of the [UO2 ]2+ cation. An alternative approach to novel materials, however, suppresses hydrolysis and relies on non-covalent interactions (e.g. hydrogen or halogen bonding) to direct assembly of a more limited suite of species or building units. This may be achieved through the use of high-anion media to promote singular actinyl anions that are assembled with organic cations, or by way of functionalized chelating ligands that produce complexes suited for assembly through peripheral donor/acceptor sites. Presented in this Concept article is therefore an overview of our efforts in this arena. We highlight examples of each approach, share our thoughts regarding delineation of assembly criteria, and discuss the opportunities for exploring structure-property relationships in these systems. PMID- 29758106 TI - Sputum-to-serum hydrogen sulphide ratio as a novel biomarker of predicting future risks of asthma exacerbation. AB - BACKGROUND: Increased level of hydrogen sulphide (H2 S) in sputum is reported to be a new biomarker of neutrophilic airway inflammation in chronic airway disorders. However, the relationship between H2 S and disease activity remains unclear. OBJECTIVE: We investigated whether H2 S levels could vary during different conditions in asthma. METHOD: H2 S levels in sputum and serum were measured using a sulphide-sensitive electrode in 47 stable asthmatic subjects (S BA), 21 uncontrolled asthmatic subjects (UC-BA), 26 asthmatic subjects with acute exacerbation (AE-BA) and 15 healthy subjects. Of these, H2 S levels during stable, as well as exacerbation states, were obtained in 13 asthmatic subjects. RESULTS: Sputum H2 S levels were significantly higher in the AE-BA subjects compared to the UC-BA and healthy subjects (P < .05). However, serum H2 S levels in the AE-BA subjects were lower than in the S-BA subjects (P < .001) and similar to those in healthy subjects. Thus, the sputum-to-serum ratio of H2 S (H2 S ratio) in the AE-BA subjects was significantly higher than in the S-BA, UC-BA and healthy subjects (P < .05). Among all subjects, sputum H2 S levels showed a trend to decrease with FEV1 %predicted and significantly positive correlations with sputum neutrophils (%), sputum IL-8 and serum IL-8. A multiple linear regression analysis showed that sputum H2 S was independently associated with increased sputum neutrophils (%) and decreased FEV1 %predicted (P < .05). The cut-off level of H2 S ratio to indicate an exacerbation was >=0.34 (area under the curve; 0.88, with a sensitivity of 81.8% and specificity of 72.7%, P < .001). Furthermore, half of the asthmatic subjects with H2 S ratios higher than the cut-off level experienced asthma exacerbations over the following 3 months after enrolment. CONCLUSIONS: The H2 S ratio may provide useful information on predicting future risks of asthma exacerbation, as well as on obstructive neutrophilic airway inflammation as one of the non-Th2 biomarkers, in asthma. PMID- 29758102 TI - Purine metabolism controls innate lymphoid cell function and protects against intestinal injury. AB - Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)-interleukin (IL)-22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5'-triphosphate (eATP) into adenosine, exacerbates dextran-sulfate sodium-induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL-22 producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL-22. Mechanistically, activation of ILC3s for IL-22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase-mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine ILC3 axis. PMID- 29758109 TI - Ex vivo effects of insulin on the structural integrity of equine digital lamellae. AB - BACKGROUND: Laminitis has a considerable impact on the equine industry. Endocrinopathic laminitis is the most common form and affected horses often have hyperinsulinaemia due to an underlying metabolic disorder. OBJECTIVES: The aim of this study was to determine if insulin weakens the structural integrity of digital lamellae and to develop an ex vivo model for the study of hyperinsulinaemia-induced lamellar failure. STUDY DESIGN: Ex vivo experiment. METHODS: Biomechanical testing was used to assess the structural integrity of lamellar explants exposed to either medium alone (control) or medium supplemented with insulin. Lamellar explants comprised of hoof wall, lamellar tissue and distal phalanx were harvested from four adult horses with no evidence of inflammatory disease or pre-existing disease of the digit. Following an equilibration period, explants were incubated in medium or medium supplemented with insulin (2.5 MUg/ml) for 8 h prior to biomechanical testing to obtain load (N), stress (MPa), elongation to failure (mm), and Young's modulus (MPa) for each explant. Significant differences were assessed using a mixed linear model with horses as a random factor and control or insulin-treated group as a fixed factor. RESULTS: Lamellar explants incubated in medium supplemented with insulin failed at significantly lower load (P = 0.0001) and lower stress (P = 0.001) and had greater elongation to failure (P = 0.02). MAIN LIMITATIONS: In addition to the ex vivo nature of the study, location-dependent variability in explant structural integrity and variable diffusion of nutrients due to explant size may have been limitations. However, the study design attempted to account for these limitations through random assignment of explants to treatment groups independent of location and by evaluating stress to failure. CONCLUSIONS: Insulin weakens the structural integrity of equine lamellar explants and an ex vivo model for evaluation of hyperinsulinaemia-induced lamellar failure was established. The summary is available in Spanish - see Supporting Information. PMID- 29758107 TI - Locking the nontemplate DNA to control transcription. AB - Universally conserved NusG/Spt5 factors reduce RNA polymerase pausing and arrest. In a widely accepted model, these proteins bridge the RNA polymerase clamp and lobe domains across the DNA channel, inhibiting the clamp opening to promote pause-free RNA synthesis. However, recent structures of paused transcription elongation complexes show that the clamp does not open and suggest alternative mechanisms of antipausing. Among these mechanisms, direct contacts of NusG/Spt5 proteins with the nontemplate DNA in the transcription bubble have been proposed to prevent unproductive DNA conformations and thus inhibit arrest. We used Escherichia coli RfaH, whose interactions with DNA are best characterized, to test this idea. We report that RfaH stabilizes the upstream edge of the transcription bubble, favoring forward translocation, and protects the upstream duplex DNA from exonuclease cleavage. Modeling suggests that RfaH loops the nontemplate DNA around its surface and restricts the upstream DNA duplex mobility. Strikingly, we show that RfaH-induced DNA protection and antipausing activity can be mimicked by shortening the nontemplate strand in elongation complexes assembled on synthetic scaffolds. We propose that remodeling of the nontemplate DNA controls recruitment of regulatory factors and R-loop formation during transcription elongation across all life. PMID- 29758108 TI - Comparison of transplant-specific prognostic scoring systems in haploidentical transplantation for myelodysplastic syndrome. AB - OBJECTIVES: We intended to identify the predictive abilities of recently published transplant-specific prognostic scoring systems in patients with myelodysplastic syndrome (MDS) receiving haploidentical transplantation. METHODS: The outcomes of 73 patients with MDS receiving haploidentical transplantation were analyzed, according to the MTPSS, the TRI, and the CIBMTR scoring systems. RESULTS: The median age of patients at transplantation was 50 (range, 19-69) years. The IPSS-R cytogenetic risks of very good/good, intermediate, and poor/very poor were, respectively, observed in 35 (48.0%), 25 (34.2%), and 13 (17.8%) patients, including 4 (5.5%) with a monosomal karyotype. Pretransplant treatment failure and high (>=3) HCT-CI were observed in 30 (41.1%) and 35 (48.0%) patients, respectively. With survivor's median follow-up of 42.3 months, the overall survival rate at 4 years of all patients was 65.5% (95% CI, 52.4 75.9). The MTPSS (100%, 77.3%, 62.5%, and 42.0% at 4 years; P = .02) and the TRI (100%, 79.9%, 76.0%, and 17.1% at 4 years; P < .01) differentiate proportionally overall survival rates according to their 4 risk groups, whereas the CIBMTR scoring system did not (P = .17). CONCLUSIONS: Our results suggest the potential ability of the MPTSS and the TRI as prognostic tools for patients with MDS receiving haploidentical transplantation. PMID- 29758110 TI - Can quantitative computed tomography detect bone morphological changes associated with catastrophic proximal sesamoid bone fracture in Thoroughbred racehorses? AB - BACKGROUND: Fracture of the proximal sesamoid bones continues to be the most common fatal musculoskeletal injury in US racehorses. Identifying factors that influence fracture risk could lead to screening techniques to reduce catastrophic injury rates and improve animal welfare. OBJECTIVES: To identify morphological differences between proximal sesamoid bones of the contralateral limb of fracture and control horses and assess the feasibility of computed tomography (CT) to detect traits associated with proximal sesamoid bone fracture. We hypothesised that horses with proximal sesamoid bone fracture would have greater bone density. STUDY DESIGN: Cross-sectional cadaver morphological study. METHODS: Proximal sesamoid bone morphology was measured using high-resolution micro-CT images from 16 Thoroughbred racehorses (eight fracture, eight control) euthanised on New York racetracks. Nominal logistic regression models and receiver operating characteristic curves were created to assess the ability of CT-derived morphological traits to accurately classify fracture horses vs. controls. RESULTS: Bone volume fraction was greater in the fracture group (90.39 +/- 1.76%) as compared to controls (87.20 +/- 2.79%, P<0.0001). Bone volume fraction, bone width, trabecular thickness and degree of anisotropy were significantly different between fracture and control horses. Receiver operating characteristic curves showed that a combined model that incorporates bone volume fraction and width can identify fracture from control horses with an area under the curve of 0.938, indicating high accuracy at classifying fracture horses from controls. MAIN LIMITATIONS: The number of horses per group is small, although the total number of sesamoids imaged is reasonable (n = 62). In vivo CT at the resolution performed in this study is currently unattainable; however, density and width could be measured with quantitative CT. CONCLUSIONS: Differences in proximal sesamoid bone morphology were identified between fracture and control horses. As improved technology becomes accessible, quantitative CT could potentially be used as a clinical imaging technique to estimate proximal sesamoid bone fracture risk in Thoroughbred racehorses. PMID- 29758111 TI - Genetic profiles of transcriptomic clusters of childhood asthma determine specific severe subtype. AB - BACKGROUND: Previous studies have defined transcriptomic subtypes of adult asthma using samples of induced sputum and bronchial epithelium; however, those procedures are not readily applicable in the clinic, especially for childhood asthma. OBJECTIVE: We aim to dissect the transcriptomic clusters of childhood asthma using highly variably expressed genes of peripheral blood mononuclear cells (PBMC) among patients. METHODS: Gene expression of PBMC from 133 asthmatic children and 11 healthy controls was measured with Illumina microarrays. We applied the k-means clustering algorithm of 2048 genes to assign asthmatic children into clusters. Genes with differential expression between asthma clusters and healthy controls were used to investigate whether they could identify severe asthma of children and adults. RESULTS: We identified 3 asthma clusters with distinct inflammatory profiles in peripheral blood. Cluster 1 had the highest eosinophil count. Cluster 2 showed lower counts of both eosinophils and neutrophils. Cluster 3 had the highest neutrophil count and the poorest treatment control. Compared with other patients, Cluster 3 exhibited a unique gene expression pattern which was associated with changes in the glucocorticoid signalling and activation of the T helper 1/T helper 17 (TH 1/TH 17) immune pathways. In the validation studies, an 84-gene signature could identify severe asthma in children on leucocytes, as well as severe asthma in adults on CD8+ T cells. CONCLUSIONS AND CLINICAL RELEVANCE: Gene expression profiling of PBMC is useful for the identification of TH 1/TH 17-mediated asthma with poor treatment control. PBMC and CD8+ T cells could be important targets for the investigation and identification of severe asthma. PMID- 29758113 TI - Women of Size and Pregnancy. PMID- 29758112 TI - Novel and emerging therapies for cholestatic liver diseases. AB - While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation. PMID- 29758114 TI - Time well spent in recanalizing complex cerebrovascular occlusions. PMID- 29758115 TI - Antepartum Care of Women Who Are Obese During Pregnancy: Systematic Review of the Current Evidence. AB - INTRODUCTION: Nearly 40% of US women of childbearing age are obese. Obesity during pregnancy is associated with multiple risks for both the woman and fetus, yet clinicians often feel unprepared to provide optimal antepartum care for this group of women. We collected and reviewed current evidence concerning antepartum care of women who are obese during pregnancy. METHODS: We conducted a systematic review using PRISMA guidelines. Current evidence relating to the pregnancy care of women with a prepregnancy body mass index of 30kg/m2 or higher was identified using MEDLINE databases via PubMed, Embase, and Web of Science Core Collection between January 2012 and February 2018. RESULTS: A total of 354 records were located after database searches, of which 63 met inclusion criteria. Topic areas for of included studies were: pregnancy risk and outcomes related to obesity, communication between women and health care providers, gestational weight gain and activity/diet, diabetic disorders, hypertensive disorders, obstructive sleep apnea, mental health, pregnancy imaging and measurement, late antepartum care, and preparation for labor and birth. DISCUSSION: Midwives and other health care providers can provide better antepartum care to women who are obese during pregnancy by incorporating evidence from the most current clinical investigations. PMID- 29758116 TI - Two Bacterial Diterpene Synthases from Allokutzneria albata Produce Bonnadiene, Phomopsene, and Allokutznerene. AB - Two diterpene synthases from Allokutzneria albata were studied for their products, resulting in the identification of the new compound bonnadiene from the first enzyme. Although phylogenetically unrelated to fungal phomopsene synthase, the second enzyme produced a mixture of phomopsene and a biosynthetically linked new compound, allokutznerene, as well as spiroviolene. Both enzymes were subjected to in-depth mechanistic studies involving isotopic labelling experiments, metal-cofactor variation, and site-directed mutagenesis. Oxidation products of phomopsene and allokutznerene are also discussed. PMID- 29758117 TI - Associations Among Nursing Work Environment and Health-Promoting Behaviors of Nurses and Nursing Performance Quality: A Multilevel Modeling Approach. AB - PURPOSE: This study aimed to determine the relationships among the unit-level nursing work environment and individual-level health-promoting behaviors of hospital nurses in South Korea and their perceived nursing performance quality. METHODS: This study used a cross-sectional design. Data were collected using self reported questionnaires from 432 nurses in 57 units at five hospitals in South Korea. Nursing performance quality, nursing work environment, and health promoting behaviors were measured using the Six Dimension Scale of Nursing Performance, Practice Environment Scale of the Nursing Work Index, and Health Promoting Lifestyle Profile-II, respectively. RESULTS: Nurses working in units with nurse managers who were characterized by better ability and by quality leadership, and who provided more support to nurses exhibited significantly greater health responsibility and physical activity. Nurses working with sufficient staffing and resources reported better stress management. Positive collegial nurse-physician relationships in units were significantly associated with more healthy eating among nurses. Nurses working in units with sufficient staffing and resources, and who had a higher level of spiritual growth and health responsibility, were more likely to perceive their nursing performance quality as being higher. CONCLUSIONS: To improve the quality of nursing practice, hospitals should focus on helping nurses maintain healthy lifestyles, as well as improving their working conditions in South Korea. Organizational support for adequate human resources and materials, mutual cooperation among nurses and physicians, and workplace health-promotion interventions for spiritual growth and health responsibility are needed. CLINICAL RELEVANCE: Organizational efforts to provide sufficient staffing and resources, boost the development of personal resources among nurses, and promote nurses' responsibility for their own health could be effective strategies for improving nursing performance quality and patient outcomes. PMID- 29758118 TI - Hemostasis biomarkers in multiple sclerosis. AB - BACKGROUND AND PURPOSE: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. METHODS: In all, 138 MS patients [85 with relapsing-remitting MS (RR-MS) and 53 with progressive MS (P MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. RESULTS: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. CONCLUSIONS: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected. PMID- 29758121 TI - The perspectives of former recipients and experts on stigmatization related to electroconvulsive therapy in Denmark: A focus group study. AB - WHAT IS KNOWN ON THE SUBJECT?: Electroconvulsive therapy (ECT) has existed worldwide for nearly 80 years. ECT is a fast-working and potentially life-saving treatment, but it is considered controversial. Although frequently mentioned, stigmatization in relation to ECT has not been systematically explored so far. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This paper provides new insight into both recipient and expert perspectives on ECT. It identifies several issues of stigmatization related to ECT and suggests that full recovery following ECT might be jeopardized due to both stigmatization and self-stigmatization. The study suggests that most of the stigmatizing behaviors can be ascribed to (a lack of) available knowledge of and experience with ECT. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Being aware of and listening to the needs of former ECT-recipients seems essential to increase their treatment options and support care as well as a will to prioritize this patient group. For example, by addressing the potential stigma issues in follow-up groups and helping to distribute sober, factual information about ECT in society. Providing written information and psychoeducation for patients and relatives before, during, and after ECT, in addition to supporting active use of diaries, might be valuable remedies for helping patients feel adequately informed and able to accept the pros and cons of ECT during and after treatment period. ABSTRACT: Introduction Electroconvulsive therapy (ECT) has existed worldwide for nearly 80 years. Although fast-working and potentially life-saving treatment, ECT is regarded as a strongly controversial treatment and stigmatization is frequently mentioned in relation to it. However, no systematic research in this area has taken place so far. Aim The aim of this qualitative study was to explore the experiences and attitudes of former recipients of ECT and of experts professionally involved with ECT to identify potential stigmatization. Method Two focus groups, one comprising four recipients of ECT and the other seven professional experts, were conducted. Data from each focus group were analyzed separately using a framework-analysis. Results The analysis yielded three major themes for the first focus group interview: ambivalent attitudes, discrediting and exclusion, and survival strategies and three major themes for the second focus group interview: dramatic depictions of ECT, an overlooked and rare treatment, and anti-stigmatization strategies. Discussion and implications for practice Stigmatizing attitudes and behaviors in relation to ECT are closely related to one's personal and factual knowledge, and there is a great need for multi-facetted approaches if social acceptance and recognition are to be achieved. This study provides new knowledge on a scarcely examined area while also introducing suitable methods for anti stigmatization and empowerment. PMID- 29758119 TI - Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D -driven tumor promotion. AB - Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen inducible double mutant (K-rasG12D -expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably-treated K-rasG12D -expressing mice did not. H&E staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly-mutant vs K-rasG12D mice revealed that cell proliferation and cell size increased approximately 2-fold relative to K-rasG12D -expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K rasG12D -only mice. Moreover, AKT phosphorylation increased in K-rasG12D expressing/Ppp6c-deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. Finally, increased numbers of K14-positive cells were present in the suprabasal layer of doubly mutant mice, indicating abnormal keratinocyte differentiation, and gammaH2AX positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K-rasG12D -dependent tumor promotion. PMID- 29758122 TI - Association of Gestational Weight Gain with Prenatal Care Model. AB - INTRODUCTION: The objective of this study was to compare gestational weight gain (GWG) among women in group and traditional prenatal care. METHODS: This is a retrospective cohort study of women who received prenatal care between 2011 and 2015 in a setting in which low-risk women had the option of group prenatal care. Women with height and initial and final weight were eligible. Women who chose group prenatal care were compared with women who chose traditional prenatal care and gave birth during the same study period. A propensity score analysis was used to create a matched control group from women who received traditional prenatal care. Bivariable comparisons of demographics, maternal characteristics, and GWG as a categorical variable (inadequate, adequate, or excessive per the 2009 Institute of Medicine guidelines) were performed with chi-square or Wilcoxon rank sum tests. A logistic regression analysis was performed to estimate the association of group prenatal care with excessive GWG. RESULTS: The final sample included 818 women who received either group or traditional prenatal care and were matched according to age, body mass index (BMI), nulliparity, and marital status. In the unadjusted analysis, women in group prenatal care had lower odds of excessive GWG (odds ratio [OR], 0.75; 95% CI, 0.57-0.99), but the statistical significance of this finding did not persist in the adjusted analysis (OR, 0.77; 95% CI, 0.45-1.30). When the analyses were limited to women who had at least 5 group or traditional prenatal care visits, there were no differences in excessive GWG in unadjusted (OR, 0.83; 95% CI, 0.59-1.16) or adjusted (OR, 0.97; 95% CI, 0.24-3.96) analyses. DISCUSSION: In this propensity score matched cohort study of predominantly Hispanic women, there were no differences in excessive GWG between women in group compared with traditional prenatal care. Further study is indicated to determine the relationship between prenatal care model and GWG outcomes. PMID- 29758120 TI - Concomitant administration of radiation with eribulin improves the survival of mice harboring intracerebral glioblastoma. AB - Glioblastoma is the most common and devastating type of malignant brain tumor. We recently found that eribulin suppresses glioma growth in vitro and in vivo and that eribulin is efficiently transferred into mouse brain tumors at a high concentration. Eribulin is a non-taxane microtubule inhibitor approved for breast cancer and liposarcoma. Cells arrested in M-phase by chemotherapeutic agents such as microtubule inhibitors are highly sensitive to radiation-induced DNA damage. Several recent case reports have demonstrated the clinical benefits of eribulin combined with radiation therapy for metastatic brain tumors. In this study, we investigated the efficacy of a combined eribulin and radiation treatment on human glioblastoma cells. The glioblastoma cell lines U87MG, U251MG and U118MG, and SJ28 cells, a patient-derived sphere culture cell line, were used to determine the radiosensitizing effect of eribulin using western blotting, flow cytometry and clonogenic assay. Subcutaneous and intracerebral glioma xenografts were generated in mice to assess the efficacy of the combined treatment. The combination of eribulin and radiation enhanced DNA damage in vitro. The clonogenic assay of U87MG demonstrated the radiosensitizing effect of eribulin. The concomitant eribulin and radiation treatment significantly prolonged the survival of mice harboring intracerebral glioma xenografts compared with eribulin or radiation alone (P < .0001). In addition, maintenance administration of eribulin after the concomitant treatment further controlled brain tumor growth. Aberrant microvasculature was decreased in these tumors. Concomitant treatment with eribulin and radiation followed by maintenance administration of eribulin may serve as a novel therapeutic strategy for glioblastomas. PMID- 29758125 TI - Carole Joffe: Inside George Tiller's Clinic. PMID- 29758123 TI - Clinical outcomes of hepatitis C treatment before and after kidney transplantation and its impact on time to transplant: A multicenter study. AB - Waitlist time for kidney transplantation is long but may be shortened with the utilization of hepatitis C positive allografts. We retrospectively reviewed the course of 36 hepatitis C positive patients awaiting kidney transplantation at 2 large centers within the same health system, with near-identical care delivery models with the exception of timing of hepatitis C treatment, to determine the impact of timing of hepatitis C treatment on access to transplant, waitlist time, and treatment efficacy and tolerability. The majority of patients had hepatitis C genotype 1a or 1b, and all received direct acting antiviral therapy with 100% treatment response. One patient underwent transplantation in the pretransplant treatment group. The 1-year transplantation rate was 12.5% vs 67.9% (P = .0013) in those treated posttransplantation. The median waitlist time in the posttransplant group was 122 (interquartile range [IQR] 21.5, 531.0) days, which was significantly shorter than the center's regional and national wait time. Pathologic review revealed no difference in allograft quality. Overall treatment related adverse events were not different between the 2 groups. A strategy of posttransplant hepatitis C treatment increased access to transplant and reduced waitlist time. Delaying treatment until after transplant did not appear to adversely affect recipients' kidney allograft or overall survival. PMID- 29758124 TI - Use of Electronic Patient Portals in Pregnancy: An Overview. AB - Electronic patient portals are increasingly utilized in contemporary health care systems. Patient portal use has been found to be beneficial in multiple specialties, particularly in management of chronic diseases. However, there are disparities within portal use. For example, individuals who are racial and ethnic minorities and persons from lower socioeconomic status are less likely to enroll and use patient portals than non-Hispanic white persons and persons with higher socioeconomic status. Because portal use and, specifically, patient-provider secure messaging has been associated with favorable health outcomes, disparities in use of these portals could affect health outcomes. Electronic patient portal use by childbearing women has not been well studied, and data on portal use during pregnancy are limited. This article reviews the current literature regarding electronic patient portal use and highlights the need for further maternity care-focused research regarding this new avenue of care delivery during pregnancy. PMID- 29758126 TI - Abrogating fibrinolysis does not improve bleeding or rFVIIa/rFVIII treatment in a non-mucosal venous injury model in haemophilic rodents. AB - : Essentials The efficacy of systemic antifibrinolytics for hemophilic non mucosal bleeding is undetermined. The effect of systemically inhibiting fibrinolysis in hemophilic mice and rats was explored. Neither bleeding nor the response to factor treatment was improved after inhibiting fibrinolysis. The non mucosal bleeding phenotype in hemophilia A appears largely unaffected by fibrinolysis. SUMMARY: Background Fibrinolysis may exacerbate bleeding in patients with hemophilia A (HA). Accordingly, antifibrinolytics have been used to help maintain hemostatic control. Although antifibrinolytic drugs have been proven to be effective in the treatment of mucosal bleeds in the oral cavity, their efficacy in non-mucosal tissues remain an open question of significant clinical interest. Objective To determine whether inhibiting fibrinolysis improves the outcome in non-mucosal hemophilic tail vein transection (TVT) bleeding models, and to determine whether a standard ex vivo clotting/fibrinolysis assay can be used as a predictive surrogate for in vivo efficacy. Methods A highly sensitive TVT model was employed in hemophilic rodents with a suppressed fibrinolytic system to examine the effect of inhibiting fibrinolysis on bleeding in non-mucosal tissue. In mice, induced and congenital hemophilia models were combined with fibrinolytic attenuation achieved either genetically or pharmacologically (tranexamic acid [TXA]). In hemophilic rats, tail bleeding was followed by whole blood rotational thromboelastometry evaluation of the same animals to gauge the predictive value of such assays. Results The beneficial effect of systemic TXA therapy observed ex vivo could not be confirmed in vivo in hemophilic rats. Furthermore, neither intravenously administered TXA nor congenital knockout of the fibrinolytic genes encoding plasminogen or tissue-type plasminogen activator markedly improved the TVT bleeding phenotype or response to factor therapy in hemophilic mice. Conclusions The findings here suggest that inhibition of fibrinolysis is not effective in limiting the TVT bleeding phenotype of HA rodents in non-mucosal tissues. PMID- 29758127 TI - Evaluating the Impact of EBP Education: Development of a Modified Fresno Test for Acute Care Nursing. AB - BACKGROUND: Proficiency in evidence-based practice (EBP) is essential for relevant research findings to be integrated into clinical care when congruent with patient preferences. Few valid and reliable tools are available to evaluate the effectiveness of educational programs in advancing EBP attitudes, knowledge, skills, or behaviors, and ongoing competency. The Fresno test is one objective method to evaluate EBP knowledge and skills; however, the original and modified versions were validated with family physicians, physical therapists, and speech and language therapists. AIMS: To adapt the Modified Fresno-Acute Care Nursing test and develop a psychometrically sound tool for use in academic and practice settings. METHODS: In Phase 1, modified Fresno (Tilson, 2010) items were adapted for acute care nursing. In Phase 2, content validity was established with an expert panel. Content validity indices (I-CVI) ranged from .75 to 1.0. Scale CVI was .95%. A cross-sectional convenience sample of acute care nurses (n = 90) in novice, master, and expert cohorts completed the Modified Fresno-Acute Care Nursing test administered electronically via SurveyMonkey. FINDINGS: Total scores were significantly different between training levels (p < .0001). Novice nurses scored significantly lower than master or expert nurses, but differences were not found between the latter cohorts. Total score reliability was acceptable: (interrater [ICC (2, 1)]) = .88. Cronbach's alpha was 0.70. Psychometric properties of most modified items were satisfactory; however, six require further revision and testing to meet acceptable standards. LINKING EVIDENCE TO ACTION: The Modified Fresno-Acute Care Nursing test is a 14-item test for objectively assessing EBP knowledge and skills of acute care nurses. While preliminary psychometric properties for this new EBP knowledge measure for acute care nursing are promising, further validation of some of the items and scoring rubric is needed. PMID- 29758128 TI - Nurses' Perceptions of Patient Safety Culture in Three Hospitals in Saudi Arabia. AB - PURPOSE: To assess the present patient safety culture of three general hospitals in Saudi Arabia, as perceived by nurses. DESIGN: This study utilized a descriptive, cross-sectional design. METHODS: A convenience sample of 351 nurses working in three general hospitals in the central region of Saudi Arabia was surveyed in this study using the Hospital Survey of Patients' Safety Culture (HSOPSC) from October 2016 to April 2017. RESULTS: From the 12 composites of the HSOPSC, the nurses perceived only the following two patient safety areas as strengths: teamwork within units and organizational learning-continuous improvement. Six areas of patient safety were identified as weaknesses, namely overall perception of patient safety, handoffs and transitions, communication openness, staffing, frequency of events reported, and nonpunitive response to errors. Nationality, educational attainment, hospital, length of service in the hospital, work area or unit, length of service in the current work area or unit, current position, and direct patient contact or interaction were significant predictors of the nurses' perceived patient safety culture. CONCLUSIONS: The findings in this study clarify the current status of patient safety culture in three hospitals in the Kingdom of Saudi Arabia. CLINICAL RELEVANCE: The present findings should be considered by policymakers, hospital leaders, and nurse executives in creating interventions aimed at improving the patient safety culture in hospitals. A multidimensional network intervention targeting the different dimensions of patient safety culture and involving different organizational levels should be implemented to improve patient safety. PMID- 29758129 TI - Twenty-four-hour normothermic perfusion of discarded human kidneys with urine recirculation. AB - Transportable normothermic kidney perfusion for 24 hours or longer could enable viability assessment of marginal grafts, increased organ use, and improved transplant logistics. Eleven clinically declined kidneys were perfused normothermically, with 6 being from donors after brain death (median cold ischemia time 33 +/- 36.9 hours) and 5 being from donors after circulatory death (36.2 +/- 38.3 hours). Three kidneys were perfused using Ringer's lactate to replace excreted urine volume, and 8 kidneys were perfused using urine recirculation to maintain perfusate volume without fluid replenishment. In all cases, normothermic perfusion either maintained or slightly improved the histopathologically assessed tubular condition, and there was effective urine production in kidneys from both donors after brain death and donors after circulatory death (2367 +/- 1798 mL vs 744.4 +/- 198.4 mL, respectively; P = .44). Biomarkers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1 were successfully detected and quantified in the perfusate. All kidneys with urine recirculation were readily perfused for 24 hours (n = 8) and exhibited physiological perfusate sodium levels (140.7 +/- 1.2 mmol/L), while kidneys without urine recirculation (n = 3) achieved a reduced normothermic perfusion time of 7.7 +/- 1.5 hours and significantly higher perfusate sodium levels (159.6 +/- 4.63 mmol/:, P < .01). Normothermic machine perfusion of human kidneys for 24 hours appears to be feasible, and urine recirculation was found to facilitate the maintenance of perfusate volume and homeostasis. PMID- 29758130 TI - Pediatric heart transplantation at adult-specialty centers in the United States: A multicenter registry analysis. AB - Recent Organ Procurement and Transplantation Network bylaw revisions mandate that US transplant programs have an "approved pediatric component" in order to perform heart transplantation (HT) in patients <18 years old. The impact of this change on adolescents, a group known to be at high risk for graft loss and nonadherence, is unknown. We studied all US primary pediatric (age <18 years) HT from 2000 to 2015 to compare graft survival between centers organized mainly for adult versus pediatric care. Centers were designated as pediatric- or adult-specialty care according to the ratio of pediatric:adult HT performed and minimum age of HT (pediatric-specialty defined as ratio>0.7; adult-specialty ratio<0.05 and minimum age >8 years). In propensity score-matched cohorts, we observed no difference in graft loss by center type (median survival: adult 12.4 years vs pediatric 9.2 years, P = .174). Compared to the matched pediatric cohort, adult-specialty center recipients lived closer to their transplant center (31 vs 45 miles, P = .012), and trended toward fewer out-of-state transplants (15 vs 25%, P = .082). Our data suggest that select adolescents can achieve similar midterm graft survival at centers organized primarily for adult HT care. Regardless of post-HT setting, the development of care models that demonstrably improve adherence may be of greatest benefit to improving survival of this high-risk population. PMID- 29758131 TI - The outer membrane Omp85-like protein P39 influences metabolic homeostasis in mature Arabidopsis thaliana. AB - The Omp85 proteins form a large membrane protein family in bacteria and eukaryotes. Omp85 proteins are composed of a C-terminal beta-barrel-shaped membrane domain and one or more N-terminal polypeptide transport-associated (POTRA) domains. However, Arabidopsis thaliana contains two genes coding for Omp85 proteins without a POTRA domain. One gene is designated P39, according to the molecular weight of the encoded protein. The protein is targeted to plastids and it was established that p39 has electrophysiological properties similar to other Omp85 family members, particularly to that designated as Toc75V/Oep80. We analysed expression of the gene and characterised two T-DNA insertion mutants, focusing on alterations in photosynthetic activity, plastid ultrastructure, global expression profile and metabolome. We observed pronounced expression of P39, especially in veins. Mutants of P39 show growth aberrations, reduced photosynthetic activity and changes in plastid ultrastructure, particularly in the leaf tip. Further, they display global alteration of gene expression and metabolite content in leaves of mature plants. We conclude that the function of the plastid-localised and vein-specific Omp85 family protein p39 is important, but not essential, for maintenance of metabolic homeostasis of full-grown A. thaliana plants. Further, the function of p39 in veins influences the functionality of other plant tissues. The link connecting p39 function with metabolic regulation in mature A. thaliana is discussed. PMID- 29758133 TI - Reflections On Oral Health. PMID- 29758132 TI - OKLAHOMA DENTAL ASSOCIATION MEDIATION REVIEW CASE STUDY. Mediation. Dispute resolution process. PMID- 29758134 TI - The Cost of Delaying the Removal of Wisdom Teeth. PMID- 29758135 TI - "NEW" medication and vaccination guidelines for RNs. PMID- 29758137 TI - BLAMED. UNDESERVING. HELPLESS. How media view OLDER ADULTS. PMID- 29758138 TI - Discourse analysis of Western Canadian print news media: AGING AND HEALTH CARE. PMID- 29758136 TI - FRESH THINKING. Another appropriate and proportionate approach to complaint resolution. AB - A registered nurse accesses the Netcare clinical record of a friend who isn't in their care. The member has no authority to do so and this is a breach of the patient's privacy Under the Health Professions Act, the RN's manager is required to submit a complaint to CARNA when a member has been suspended or terminated for what the employer believes is unprofessional conduct. Breach of privacy falls within that definition. What is the appropriate course of action for CARNA to address this breach of professional conduct? PMID- 29758139 TI - SLEEP, SENIORS AND SEDATIVES. AB - Some long-term care facilities have implemented sleep strategies for their patients that have resulted in less falls, more cooperation and less patient aggression. PMID- 29758140 TI - Improving patient flow through collaboration. AB - For over two decades, capacity issues within Edmonton hospitals have existed. Crowded emergency departments with numerous patients waiting for admission into inpatient beds has made patient flow a topic at all administrative levels for all services. From a systems perspective, most strategies have simply displaced the problem from one part of the system to another. If we are going to make a true difference, a "big picture" systems approach is required and traditional ways of doing business need to be challenged. Like any discussion around flow, inputs and outputs must have a level of equilibrium and equality, or bottlenecks will occur. Although patient flow has been a huge focus across the continuum of care, discharge planning traditionally has remained with the provider where the patient currently is, as opposed to where the team feels the patient's end destination will be. PMID- 29758142 TI - Protecting the public in action. PMID- 29758141 TI - UNDERSTANDING HUMAN OVER-RELIANCE ON TECHNOLOGY. AB - THROUGH THE ANALYSIS OF AN INCIDENT RECEIVED FROM THE NATIONAL SYSTEM FOR INCIDENT REPORTING (NSIR), THIS ISMP CANADA SAFETY BULLETIN HIGHLIGHTS HUMAN OVER RELIANCE ON TECHNOLOGY BY INTRODUCING TWO RELATED HUMAN COGNITIVE LIMITATIONS: AUTOMATION BIAS AND AUTOMATION COMPLACENCY. PMID- 29758143 TI - Should I sign this form my patient asked me to sign? AB - Registered nurses and nurse practitioners may be asked by patients to sign many different types of forms. These forms may be government-issued, employer-related or exist due to certain legislation. You may be asked to sign forms related to disability, injury or the provision of reimbursement from an insurance carrier or board, including worker's compensation. When you are asked to sign a form, should you sign it? PMID- 29758144 TI - Ask a CNPS Lawyer. PMID- 29758145 TI - ADVOCATING for the rights of older adults. A message from the Alberta Gerontological Nurses Association. PMID- 29758146 TI - 10 NUTRITION TIPS for shift workers. PMID- 29758148 TI - MOVING FORWARD. Improving our cultural competency of Canada's Indigenous populations. AB - Indigenous people in Canada face many barriers to accessing primary health-care services, and a lack of cultural competency by health-care providers may be one of the reasons why. Chelsea Crowshoe, a senior advisor with Alberta Health Services and member of the Piikani First Nation, is hoping to break this barrier by promoting the importance of cultural knowledge and respect to health-care providers Alberta-wide. "My role is developing educational opportunities for health-care providers, and we've started within the awareness and sensitivity level of information," she says. "We believe the program is a two-way street, so not only are we supporting the providers but looking at the way other programs develop their resources and how different health-care policies and guidelines could support traditional ceremonies, like smudging for example." PMID- 29758147 TI - BREAKING the chain of infection: What RNs need to know. PMID- 29758149 TI - Nurse practitioner LEADERSHIP in face of OPIOID CRISIS. AB - Opioid misuse has been a growing problem in Alberta and throughout Canada and the U.S. in recent years. According to Alberta Health, the number of fentanyl-related overdose deaths in Alberta rose from six in 2011 to over 300 in 2016. This alarming increase in substance abuse is a national health crisis. PMID- 29758150 TI - It's all relative: caring for a family member. AB - As she hangs up the phone, Ling realizes she has a decision to make. Her sister, Naomi, is being discharged after an unexpected hospitalization and will need nursing care at home for several weeks. As a registered nurse, Ling is used to fielding requests for minor care and advice from family members and friends. This situation however, will be more difficult to navigate. She knows her family will want her to be involved in Naomi's care, and if she's honest with herself, she would like to be as well. But would it be the best approach for everyone involved? How will Ling keep separate her roles as nurse and sister? PMID- 29758151 TI - Clinical Effects of Stabilized Stannous Fluoride Dentifrice in Reducing Plaque Microbial Virulence II: Metabonomic Changes. AB - OBJECTIVES: The clinical effects of stannous fluoride (SnF2) dentifrice in reducing symptoms of gingivitis and reducing the virulence of subgingival plaque through suppression of activation of gene expression in toll receptor based reporter cells were previously reported. This study expanded analysis of the clinical study to include evaluation of dentifrice effects on salivary metabolites using 1H Nuclear Magnetic Resonance (1H NMR) systems biology-based metabonomics. METHODS: The clinical design was reported previously (J Clin Dent2017;28:16-26). Participants included a cohort exhibiting high and low levels of gingival disease as presented at initiation of the study. Participants provided morning lavage saliva samples at baseline. Following this, participants were provided with a hygiene intervention, including a stabilized SnF2 dentifrice and a new soft bristle manual toothbrush. Following two and four weeks of assigned dentifrice use, participants again collected morning lavage saliva samples. Samples were analyzed by 1HNMR spectroscopy on a Bruker 600MHz NMR spectrometer. System-wide analyses were carried out by partial least squared (PLS) comparisons of aggregate spectra, and discrete metabolites with established spectral signatures were likewise directly compared. RESULTS: PLS analysis showed significant differences in saliva composition for saliva collected from high bleeding and low bleeding cohorts. Clear shifts in saliva composition were observed in system-wide PLS analysis following intervention of SnF2 dentifrice for both cohorts. A number of discrete spectral changes were consistently observed with SnF2 dentifrice intervention, most notably including reductions in propionic acid and butyric acid, key short chain fatty acids associated with anaerobic metabolism in dental plaques. CONCLUSIONS: These results collectively demonstrate that SnF2 dentifrice treatment was associated with broad scale modifications in saliva composition following intervention in both high and low diseased cohorts. Changes in overall salivary composition and specific reductions in saliva concentrations of propionic and butyric acid reductions occurred coincident with clinical improvements in gingivitis and gingival bleeding. These results provide support for the hypothesis that the effectiveness of SnF2 dentifrice in improving gingival health is associated with a modification of microbiome metabolism, including suppression of short chain fatty acid metabolites. PMID- 29758152 TI - Efficacy of Teeth Whitening with a Mouthwash: In Vitro and In Vivo Approaches. AB - OBJECTIVES: Two different studies were conducted to evaluate the whitening efficacy of a mouthwash versus a placebo using in vitro and in vivomodels. The tested mouthwash was formulated with no oxidizing or abrasive agents containing chlorhexidine (CHX) and polyvinylpyrrolidone (PVP). METHODS: The purpose of the in vitro study was to determine whether the mouthwash formulation OC15AB could reduce the accumulation of staining in an accepted stain model. Bovine central incisors were cut to obtain enamel specimens of ~8 * 8 mm2. The specimens were then immersed in human saliva (room temperature, slight stirring) for one hour to allow a pellicle film to form. They were then placed in contact with a staining solution containing coffee and tea. The amount of stain (tooth color) was quantified photometrically (Minolta C221 colorimeter) using the L* value of the L*a*b* scale. The purpose of the in vivo study was to evaluate the whitening power and tolerability of OC15AB versus a placebo mouthwash in a double-blind, randomized clinical study. In total, 40 subjects were divided randomly into two homogeneous groups. Each group used a different mouthwash (OC15AB or placebo) for 56 consecutive days. During this period, clinical and instrumental parameters, namely variations in tooth color and mucosal and gum alterations, were evaluated. The in vivo study analyses used a two-sided Student's t-test. Evaluations within groups used t-tests for paired data. RESULTS: From the in vitro test, OC15AB had a significant effect in reducing stain accumulation over the entire treatment period. The in vivo test showed that OC15AB was well tolerated and had whitening power in the subjects. OC15AB demonstrated a statistically significant reduction in extrinsic tooth staining from baseline and versus the placebo. CONCLUSIONS: The in vitro and in vivo methods used to investigate the whitening efficacy of the mouthwash formulation produced similar and consistent results. The experimental model used is an important tool in the search for new technologies for teeth whitening. Our preliminary experimental data confirm the possibility of achieving a whitening effect using a mouthwash formulation with no oxidizing or abrasive agents containing CHX and PVP. The formulation tested demonstrated a significant reduction, in vitro and in vivo, in extrinsic tooth staining from baseline and versus the placebo. PMID- 29758153 TI - An Exploratory Clinical Study to Monitor Clinical Efficacy of an Occluding Technology Dentifrice in Providing Short Term Relief from Dentinal Hypersensitivity. AB - OBJECTIVES: To examine dentin hypersensitivity (DH) at multiple time points over a 14-day period in participants who brushed twice daily with a 0.454% SnF2 dentifrice (Test) compared to a 0.76% sodium monofluorophosphate dentifrice with no known anti-sensitivity properties (Control). METHODS: This was a two-week, single-center, randomized, controlled, examiner-blind, two-treatment, parallel group study in healthy participants with DH. The sensitivity of two selected test teeth and of all sensitive teeth was assessed at baseline and after one, three, seven, 10, and 14 days' treatment in response to evaporative (air) Schiff sensitivity score and visual analogue scale [VAS]) and tactile (tactile threshold) stimuli. DH was also monitored using a shortened version of the Dentin Hypersensitivity Experience Questionnaire (DHEQ) and a single "Tooth Sensitivity Question" (TSQ). RESULTS: Both groups had mean Schiff sensitivity scores that were statistically significantly improved from baseline on all days for the two test teeth and all qualifying teeth (p < 0.0001). There was a statistically significant difference between the dentifrices at Day 1 only, in favor of the Control dentifrice, for the two test teeth (0.28 [95% confidence intervals 0.03,0.53] p = 0.0282) or all qualifying teeth (0.17 [0.02,0.32] p = 0.0273). For tactile threshold, both dentifrices were statistically significantly improved from baseline from Day 3 onwards, with the Test dentifrice showing an improvement at Day 1 (p < 0.05). There were no significant statistical between-treatment differences at any time point. DHEQ questions revealed most participants experienced "sensitivity," "twinging," and "pain," with cold stimuli rated as the highest DH-eliciting. DHEQ Section 1 rating scores improved with the Test dentifrice, but not significantly statistically. DHEQ Section 2 scores statistically significantly improved with both dentifrices (p < 0.0002) with no differences between them. TSQ scores for both groups reduced over the time period. Both dentifrices were generally well-tolerated. CONCLUSIONS: In this study, use of both the Test and Control dentifrices led to DH relief with few statistically significant differences between them. The DHEQ and TSQ showed a reduction of pain during the study period, but there was still a high level of discomfort. Further research on short term relief of DH is required. PMID- 29758154 TI - An 8-Week Clinical Comparison of an Oscillating-Rotating Electric Rechargeable Toothbrush and a Sonic Toothbrush in the Reduction of Gingivitis and Plaque. AB - OBJECTIVES: To evaluate and compare the efficacy of a marketed oscillating rotating electric rechargeable toothbrush to a marketed sonic toothbrush in the reduction of gingivitis and plaque over an 8-week period. METHODS: This was a randomized, examiner-blind, parallel group, eight-week study. Subjects with presence of mild-to-moderate plaque and gingivitis received an oral examination and were evaluated for baseline gingivitis (Modified Gingival Index; MGI), gingival bleeding (Gingival Bleeding Index; GBI), and plaque (Rustogi Modified Navy Plaque Index). Qualified subjects were randomly assigned to an entry-level oscillating-rotating electric rechargeable brush handle (Oral-B(r) PRO 1000, D16U) with a round brush head with angled bristles (Oral-B(r) CrossAction, EB50) or a premium sonic brush (Philips Sonicare(r) Diamond Clean Toothbrush with AdaptiveClean brush head). One hundred and fifty subjects were instructed to brush twice daily with their assigned brush and a fluoride dentifrice for eight weeks before returning for an oral examination and gingivitis and plaque evaluations. The same methods were used at baseline and Week 8 for all evaluations. RESULTS: One hundred and forty-eight subjects completed the study, 74 in each group. After eight weeks of use, both brushes reduced MGI, GBI, total number of bleeding sites, whole mouth plaque, gingival margin plaque, and proximal plaque (p < 0.001 for each). The oscillating-rotating brush provided statistically significantly greater reductions than the sonic brush for all gingivitis measures, with a 34.8%, 48.4%, and 42.6% greater reduction for MGI, GBI, and number of bleeding sites, respectively, after eight weeks of use (p < 0.001 for each). Significantly greater whole mouth (26.2%) and proximal (38.5%) plaque reductions were also demonstrated at Week 8 for the oscillating-rotating brush versus the sonic brush (p < 0.001). CONCLUSIONS: The entry-level oscillating-rotating brush performed better than the premium sonic brush in the reduction of plaque and gingivitis in this eight-week randomized and examiner blind study. PMID- 29758155 TI - Six-Month Evaluation of a Sodium Bicarbonate-Containing Toothpaste for Reduction of Established Gingivitis: A Randomized USA-Based Clinical Trial. AB - OBJECTIVES: Short-term use of sodium bicarbonate (NaHCO3)-containing toothpaste reduces plaque and improves clinical measures of gingivitis. To examine this over a longer period, we compared efficacy and tolerability of twice-daily brushing for 24 weeks with 67% or 0% NaHCO3-containing toothpastes in USA-based participants with moderate gingivitis (Clinicaltrials.gov:NCT02207400). METHODS: This was a six-month, randomized, examiner-blind, parallel-group, clinical trial. Investigators randomized adults with blood in expectorate after brushing and >= 20 gingival bleeding sites to 67% NaHCO3 (n = 123; n = 107 completed study) or 0% NaHCO3 (n = 123; n = 109 completed study) toothpastes. Primary efficacy variables included between-treatment differences in number of bleeding sites and Modified Gingival Index (MGI) score at 24 weeks. Secondary efficacy variables included Bleeding Index and Turesky modification of the Quigley-Hein Plaque Index (overall and interproximal sites) at six, 12, and 24 weeks. A subset of 50 participants underwent sampling to assess plaque microbiology over the course of treatment. RESULTS: Compared with the 0% NaHCO3 toothpaste, the 67% NaHCO3 toothpaste produced statistically significant improvements at Week 24 in number of bleeding sites (46.7% difference) and MGI (33.9% difference), and for all other endpoints (all p < 0.0001). There was no significant between-treatment difference in the proportion of participants harboring opportunistic pathogens. Products were generally well tolerated, with two and five treatment-related adverse events reported in the 67% and 0% NaHCO3 toothpaste groups, respectively. CONCLUSIONS: Gingival bleeding, gingivitis, and plaque indices were significantly improved at six, 12, and 24 weeks with twice-daily brushing with 67% NaHCO3-containing toothpaste in participants with moderate gingivitis. PMID- 29758156 TI - Functional Bioinorganic Hybrids from Enzymes and Luminescent Silicon-Based Nanoparticles. AB - This study reports the preparation of functional bioinorganic hybrid materials exhibiting catalytic activity and photoluminescent properties arising from the combination of enzymes and freestanding silicon-based nanoparticles. The hybrid materials reported herein have potential applications in biological sensing/imaging and theranostics, as they combine long-lived silicon-based nanoparticle photoluminescence with substrate-specific enzymatic activity. Thermal hydrosilylation of undecenoic acid and alkene-terminated poly(ethylene oxide) with hydride-terminated silicon nanocrystals afforded nanoparticles functionalized with a mixed surface made up of carboxylic acid and poly(ethylene oxide) moieties. These silicon-based nanoparticles were subsequently conjugated with prototypical enzymes through the carbodiimide-mediated amide coupling reaction in order to form bioinorganic hybrids that display solubility and photostability in phosphate buffer, photoluminescence (lambdamax = 630 nm), and enzymatic activity. They were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), dynamic light scattering analysis (DLS), photoluminescence spectroscopy, and pertinent enzyme activity assays. PMID- 29758157 TI - Nanocellulose Fragmentation Mechanisms and Inversion of Chirality from the Single Particle to the Cholesteric Phase. AB - Understanding how nanostructure and nanomechanics influence physical material properties on the micro- and macroscale is an essential goal in soft condensed matter research. Mechanisms governing fragmentation and chirality inversion of filamentous colloids are of specific interest because of their critical role in load-bearing and self-organizing functionalities of soft nanomaterials. Here we provide a fundamental insight into the self-organization across several length scales of nanocellulose, an important biocolloid system with wide-ranging applications as structural, insulating, and functional material. Through a combined microscopic and statistical analysis of nanocellulose fibrils at the single particle level, we show how mechanically and chemically induced fragmentations proceed in this system. Moreover, by studying the bottom-up self assembly of fragmented carboxylated cellulose nanofibrils into cholesteric liquid crystals, we show via direct microscopic observations that the chirality is inverted from right-handed at the nanofibril level to left-handed at the level of the liquid crystal phase. These results improve our fundamental understanding of nanocellulose and provide an important rationale for its application in colloidal systems, liquid crystals, and nanomaterials. PMID- 29758158 TI - Equilibrium Contact Angle and Adsorption Layer Properties with Surfactants. AB - The three-phase contact line of a droplet on a smooth surface can be characterized by the Young equation. It relates the interfacial energies to the macroscopic contact angle thetae. On the mesoscale, wettability is modeled by a film-height-dependent wetting energy f( h). Macro- and mesoscale descriptions are consistent if gamma cos thetae = gamma + f( ha), where gamma and ha are the liquid-gas interface energy and the thickness of the equilibrium liquid adsorption layer, respectively. Here, we derive a similar consistency condition for the case of a liquid covered by an insoluble surfactant. At equilibrium, the surfactant is spatially inhomogeneously distributed, implying a nontrivial dependence of thetae on surfactant concentration. We derive macroscopic and mesoscopic descriptions of a contact line at equilibrium and show that they are consistent only if a particular dependence of the wetting energy on the surfactant concentration is imposed. This is illustrated by a simple example of dilute surfactants, for which we show excellent agreement between theory and time dependent numerical simulations. PMID- 29758159 TI - Redox-Responsive Micellar Nanoparticles from Glycosaminoglycans for CD44 Targeted Drug Delivery. AB - Cancer progression is associated with overexpression of various receptors at the cell surface. Among these, CD44 is known to recognize and bind specifically hyaluronan (HA) and interact with less affinity to other glycosaminoglycans (GAGs), such as chondroitin sulfate (CS). In this study, we describe a simple method to obtain micellar nanoparticles with a GAG shell (HA or CS) as potential drug delivery systems that target cancer cells overexpressing CD44. Alkanethiol was conjugated at the reducing end of the respective GAG using highly efficient oxime chemistry. The alkane moiety confers amphiphilic behavior to the obtained conjugates and triggers their self-assembly into micellar nanoparticles, while the thiol group adds redox-responsiveness to the system. The properties of the particles depend on the used GAG: HA amphiphiles form more dense, smaller assemblies that are redox sensitive. Both systems allow encapsulation of either hydrophobic or hydrophilic cargos with high efficiency. We demonstrate that the GAGs exposed on the surface of the nanoparticles are with preserved bioactivity and recognized by the cellular receptors: the particles were internalized via CD44 dependent pathways. PMID- 29758160 TI - Aggregation and Stabilization of Colloidal Spheroids by Oppositely Charged Spherical Nanoparticles. AB - Heteroaggregation of colloids is an important yet complex physical process involving colloidal/nanosized particles and is relevant in river delta formation, paper-making, water treatment, blood flocculation, and so on. Despite the earlier studies on oppositely charged spherical colloids, heteroaggregation of colloids of different shapes is less explored. In this regard, we report an experimental study to investigate the colloidal stability of mixture of positively charged spheroidal hematite and negatively charged spherical silica nanoparticles. In this study, pH and surface area ratio (silica to hematite, SS-H) are varied to tune the colloidal stability/instability of the suspension. At pH 6.5 and low SS H, the silica particles adsorb onto the hematite particles and reduce the effective charge of the latter, leading to aggregation and resulting in unstable dispersions. At higher SS-H, adsorption of silica on hematite leads to overcharging and charge reversal, which leads to a stable dispersion. Similar experiments were performed at pH 2.4 and 3.5, and the crossover from unstable to stable dispersion is observed as a function of SS-H. Calculation of Derjaguin, Landau, Verwey, and Overbeek (DLVO) interaction between particles in the binary mixture, as a function of pH and SS-H, based on the aggregate size and zeta potential, explains the transition from unstable to stable dispersion. The size and zeta potential of heteroaggregates in the dispersion were analyzed by dynamic light scattering (DLS) technique. Adsorption of silica nanoparticles on hematite particles was visualized by scanning electron microscopy (SEM). The study provides a framework based on DLVO interactions to stabilize or destabilize a colloidal dispersion of nonspherical particles by controlled addition of oppositely charged spherical colloids, which is a feat that is not possible with simple salt. The stability ratio ( W) calculated from DLVO interactions demark the unstable-stable dispersion regions, which is found to be in agreement with the experimental results. PMID- 29758161 TI - Electrical Field Guided Electrospray Deposition for Production of Gradient Particle Patterns. AB - Our previous work demonstrated the uniform particle pattern formation on the substrates using electrical field guided electrospray deposition. In this work, we reported for the first time the fabrication of gradient particle patterns on glass slides using an additional point, line, or bar electrode based on our previous electrospray deposition configuration. We also demonstrated that the polydimethylsiloxane (PDMS) coating could result in the formation of uniform particle patterns instead of gradient particle patterns on glass slides using the same experimental setup. Meanwhile, we investigated the effect of experimental configurations on the gradient particle pattern formation by computational simulation. The simulation results are in line with experimental observations. The formation of gradient particle patterns was ascribed to the gradient of electric field and the corresponding focusing effect. Cell patterns can be formed on the particle patterns deposited on PDMS-coated glass slides. The formed particle patterns hold great promise for high-throughput screening of biomaterial cell interactions and sensing. PMID- 29758162 TI - Tuning Liposome Membrane Permeability by Competitive Coiled Coil Heterodimerization and Heterodimer Exchange. AB - Membrane-active peptides that enable the triggered release of liposomal cargo are of great interest for the development of liposome-based drug delivery systems but require peptide-lipid membrane interactions that are highly defined and tunable. To this end, we have explored the possibility to use the competing interactions between membrane partitioning and heterodimerization and the folding of a set of four different de novo designed coiled coil peptides. Covalent conjugation of the cationic peptides triggered rapid destabilization of membrane integrity and the release of encapsulated species. The release was inhibited when introducing complementary peptides as a result of heterodimerization and folding into coiled coils. The degree of inhibition was shown to be dictated by the coiled coil peptide heterodimer dissociation constants, and liposomal release could be reactivated by a heterodimer exchange to render the membrane bound peptide free and thus membrane-active. The possibility to tune the permeability of lipid membranes using highly specific peptide-folding-dependent interactions delineates a new possible approach for the further development of responsive liposome-based drug delivery systems. PMID- 29758164 TI - Biosynthesis of Eupatolide-A Metabolic Route for Sesquiterpene Lactone Formation Involving the P450 Enzyme CYP71DD6. AB - Sesquiterpene lactones are a class of natural compounds well-known for their bioactivity and are characteristic for the Asteraceae family. Most sesquiterpene lactones are considered derivatives of germacrene A acid (GAA). GAA can be stereospecifically hydroxylated by the cytochrome P450 enzymes (CYP) Lactuca sativa costunolide synthase CYP71BL2 (LsCOS) and Helianthus annuus GAA 8beta hydroxylase CYP71BL1 (HaG8H) at C6 (in alpha-orientation) or C8 (in beta orientation), respectively. Spontaneous subsequent lactonization of the resulting 6alpha-hydroxy-GAA leads to costunolide, whereas 8beta-hydroxy-GAA has not yet been reported to cyclize to a sesquiterpene lactone. Sunflower and related species of the Heliantheae tribe contain sesquiterpene lactones mainly derived from inunolide (7,8-cis lactone) and eupatolide (8beta-hydroxy-costunolide) precursors. However, the mechanism of 7,8-cis lactonization in general, and the 6,7-trans lactone formation in the sunflower tribe, remain elusive. Here, we show that, in plant cells, heterologous expression of CYP71BL1 leads to the formation of inunolide. Using a phylogenetic analysis of enzymes from the CYP71 family involved in sesquiterpenoid metabolism, we identified the CYP71DD6 gene, which was able to catalyze the 6,7-trans lactonization in sunflowers, using as a substrate 8beta-hydroxy-GAA. Consequently, CYP71DD6 resulted in the synthesis of eupatolide, thus called HaES ( Helianthus annuus eupatolide synthase). Thus, our study shows the entry point for the biosynthesis of two distinct types of sesquiterpene lactones in sunflowers: the 6,7-trans lactones derived from eupatolide and the 7,8-cis lactones derived from inunolide. The implications for tissue-specific localization, based on expression studies, are discussed. PMID- 29758163 TI - Lithium Dendrite Suppression and Enhanced Interfacial Compatibility Enabled by an Ex Situ SEI on Li Anode for LAGP-Based All-Solid-State Batteries. AB - The electrode-electrolyte interface stability is a critical factor influencing cycle performance of All-solid-state lithium batteries (ASSLBs). Here, we propose a LiF- and Li3N-enriched artificial solid state electrolyte interphase (SEI) protective layer on metallic lithium (Li). The SEI layer can stabilize metallic Li anode and improve the interface compatibility at the Li anode side in ASSLBs. We also developed a Li1.5Al0.5Ge1.5(PO4)3-poly(ethylene oxide) (LAGP-PEO) concrete structured composite solid electrolyte. The symmetric Li/LAGP-PEO/Li cells with SEI-protected Li anodes have been stably cycled with small polarization at a current density of 0.05 mA cm-2 at 50 degrees C for nearly 400 h. ASSLB-based on SEI-protected Li anode, LAGP-PEO electrolyte, and LiFePO4 (LFP) cathode exhibits excellent cyclic stability with an initial discharge capacity of 147.2 mA h g-1 and a retention of 96% after 200 cycles. PMID- 29758165 TI - IFN-gamma: A Driver of Cough Hypersensitivity Pathways in Chronic Cough? PMID- 29758166 TI - Does Online Technology Make Us More or Less Sociable? A Preliminary Review and Call for Research. AB - How does online technology affect sociability? Emerging evidence-much of it inconclusive-suggests a nuanced relationship between use of online technology (the Internet, social media, and virtual reality) and sociability (emotion recognition, empathy, perspective taking, and emotional intelligence). Although online technology can facilitate purely positive behavior (e.g., charitable giving) or purely negative behavior (e.g., cyberbullying), it appears to affect sociability in three ways, depending on whether it allows a deeper understanding of people's thoughts and feelings: (a) It benefits sociability when it complements already-deep offline engagement with others, (b) it impairs sociability when it supplants deeper offline engagement for superficial online engagement, and (c) it enhances sociability when deep offline engagement is otherwise difficult to attain. We suggest potential implications and moderators of technology's effects on sociability and call for additional causal research. PMID- 29758167 TI - Myeloid Regulatory Cells: New and Exciting Players in the Immunology of Lung Cancer. PMID- 29758168 TI - Increasing Physical Activity in Chronic Obstructive Pulmonary Disease One Step at a Time. PMID- 29758169 TI - Nutritional recovery from a low-protein diet during pregnancy does not restore the kinetics of insulin secretion and Ca2+ or alterations in the cAMP/PKA and PLC/PKC pathways in islets from adult rats. AB - We investigated the insulin release induced by glucose, the Ca2+ oscillatory pattern, and the cyclic AMP (cAMP)/protein kinase A (PKA) and phospholipase C (PLC)/protein kinase C (PKC) pathways in islets from adult rats that were reared under diets with 17% protein (C) or 6% protein (LP) during gestation, suckling, and after weaning and in rats receiving diets with 6% protein during gestation and 17% protein after birth (R). First-phase glucose-induced insulin secretion was reduced in LP and R islets, and the second phase was partially restored in the R group. Glucose stimulation did not modify intracellular Ca2+ concentration, but it reduced the Ca2+ oscillatory frequency in the R group compared with the C group. Intracellular cAMP concentration was higher and PKA-Calpha expression was lower in the R and LP groups compared with the C group. The PKCalpha content in islets from R rats was lower than that in C and LP rats. Thus, nutritional recovery from a low-protein diet during fetal life did not repair the kinetics of insulin release, impaired Ca2+ handling, and altered the cAMP/PKA and PLC/PKC pathways. PMID- 29758170 TI - Comparison of Human Milk Fatty Acid Composition of Women From Cambodia and Australia. AB - BACKGROUND: Human milk is a rich source of omega-3 long-chain polyunsaturated fatty acids, which are postulated to be important for brain development. There is a lack of data on the human milk fatty acid composition of Cambodian women compared with data from Western women. Research Aim: The aim of this study was to determine the human milk fatty acid composition of women living in Cambodia and compare it with that of women living in Australia. METHOD: Human milk samples from Cambodian ( n = 67) and Australian ( n = 200) mothers were collected at 3 to 4 months postpartum. Fatty acid composition was analyzed using capillary gas chromatography followed by Folch extraction with chloroform/methanol (2:1 v/v), and fat content was measured gravimetrically. RESULT: Compared with Australian participants, human milk from Cambodian participants contained a significantly lower level of total fat (2.90 vs. 3.45 g/dL, p = .028), lower percentages of linoleic acid (9.30% vs. 10.66%, p < .0001) and alpha-linolenic acid (0.42% vs. 0.95%, p < .0001), but higher percentages of arachidonic acid (0.68% vs. 0.38%, p < .0001) and docosahexaenoic acid (0.40% vs. 0.23%, p < .0001). CONCLUSION: Differences in human milk fatty acid composition between Cambodian and Australian participants may be explained by differences in the dietary patterns between the two populations. PMID- 29758171 TI - Aedes aegypti(Linnaeus) larvae from dengue outbreak areas in Selangor showing resistance to pyrethroids but susceptible to organophosphates. AB - The resistance status of Selangor Aedes aegypti (Linnaeus) larvae against four major groups of insecticides (i.e., organochlorines, carbamates, organophosphates and pyrethroids) was investigated. Aedes aegypti were susceptible against temephos (organophosphate), although resistance (RR50 = 0.21-2.64) may be developing. The insecticides susceptibility status of Ae. aegypti larvae were found heterogeneous among the different study sites. Results showed that Ae. aegypti larvae from Klang, Sabak Bernam and Sepang were susceptible against all insecticides tested. However, other study sites exhibited low to high resistance against all pyrethroids (RR50 = 1.19-32.16). Overall, the application of synergists ethacrynic acid, S.S.S.- tributylphosphorotrithioate and piperonyl butoxide increased the toxicity of insecticides investigated. However, the application failed to increase the mortality to susceptible level (>97%) for certain populations, therefore there are chances of alteration of target site resistance involved. Biochemical assays revealed that alpha-esterase, (Gombak, Kuala Langat, Kuala Selangor and Sabak Bernam strains) beta-esterase (Klang and Sabak Bernam strains), acetylcholinesterase (Kuala Selangor and Sabak Bernam strains), glutathione-S-transferase (Kuala Selangor and Sabak Bernam strains) and mono-oxygenases (Gombak, Hulu Langat, Hulu Selangor and Kuala Langat strains) were elevated. Spearman rank-order correlation indicated a significant correlation between resistance ratios of: DDT and deltamethrin (r = 0.683, P = 0.042), cyfluthrin and deltamethrin (r = 0.867, P =0.002), cyflyuthrin and lambdacyhalothrin (r = 0.800, P =0.010), cyfluthrin and permethrin (r = 0.770, P =0.015) deltamethrin and permethrin (r = 0.803, P =0.088), propoxur and malathion (r = 0.867, P = 0.002), malathion and temephos (r = 0.800, P = 0.010), etofenprox and MFO enzyme (r = 0.667, P =0.050). The current study provides baseline information for vector control programs conducted by local authorities. The susceptibility status of Ae. aegypti should be monitored sporadically to ensure the effectiveness of current vector control strategy in Selangor. PMID- 29758172 TI - Electronic Informed Consent to Facilitate Recruitment of Pregnant Women Into Research. AB - Methods to obtain informed consent digitally or electronically may increase the participation of racially and geographically diverse pregnant women in prospective research, which is essential to improve the evidence base for maternity care. We evaluated the feasibility and utility of e-consent in the first year of a multiyear clinical trial involving pregnant women. Of the 86 women screened, 71 were eligible, 65 (93% of eligible) agreed to review the e consent form, and 61 (86% of eligible) completed the e-consent process. Of the interested women who were sent the e-consent link, all were able to complete the e-consent process, even those who reported low health literacy. Women of all racial and ethnic groups were equally likely to consent, and the sample of women who consented was consistent with practice demographics. E-consent is feasible and easy to use with pregnant women and may expedite enrollment of a representative sample. PMID- 29758173 TI - Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants. AB - BACKGROUND: There is limited evidence that Brugada Syndrome (BrS) is due to SCN1B variants (BrS5). This gene may be inappropriately included in routine genetic testing panels for BrS or Sudden Arrhythmic Death Syndrome (SADS). OBJECTIVE: We sought to characterize the genotype-phenotype correlation in families who had BrS and SADS with reportedly pathogenic SCN1B variants and to review their pathogenicity. METHODS: Families with BrS and SADS were assessed from 6 inherited arrhythmia centers worldwide, and a comprehensive literature review was performed. Clinical characteristics including relevant history, electrocardiographic parameters and drug provocation testing results were studied. SCN1B genetic testing results were reclassified using American College of Medical Genetics criteria. RESULTS: A total of 23 SCN1B genotype-positive individuals were identified from 8 families. Four probands (17%) experienced ventricular fibrillation or sudden cardiac death at the time of presentation. All family members were free from syncope or ventricular arrhythmias. Only 2 of 23 genotype-positive individuals (9%) demonstrated a spontaneous BrS electrocardiographic pattern. Drug challenge testing for BrS in 87% (13 of 15) was negative. There was no difference in PR interval (161 +/- 7 ms vs 165 +/- 9 ms; P = .83), QRS duration (101 +/- 6 ms vs 89 +/- 5 ms; P = .35), or corrected QT interval (414 +/- 35 ms vs 405 +/- 8 ms; P = .7) between genotype-positive and genotype-negative family members. The overall frequency of previously implicated SCN1B variants in the Genome Aggregation Database browser is 0.004%, exceeding the estimated prevalence of BrS owing to SCN1B (0.0005%), including 15 of 23 individuals (65%) who had the p.Trp179X variant. CONCLUSION: The lack of genotype phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS. PMID- 29758175 TI - Do Different Modes of Delivering Postoperative Instructions to Patients Help Reduce the Side Effects of Tooth Extraction? A Randomized Clinical Trial. AB - PURPOSE: Postoperative instructions that are properly delivered can decrease postextraction side effects, such as stress, anxiety, and pain, in patients undergoing dental extraction. This study examined the role of the mode of delivering postoperative instructions in decreasing the side effects of dental extraction and increasing patient satisfaction after the procedure. MATERIALS AND METHODS: This randomized clinical trial was conducted on a population of 120 patients presenting to the oral and maxillofacial outpatient clinic affiliated with the Shiraz University of Medical Sciences (Shiraz, Iran) in 2015. The patients were randomly assigned to 3 groups of 40 per group. The first group received only verbal instructions after their surgical procedure. The second group received only written instructions. The third group received verbal and written instructions. Details on the patient's age, gender, and formal education were recorded before the operation using a questionnaire. The second part of the questionnaire was completed by patients 1 week after their tooth extraction and recorded their postoperative pain, bleeding, swelling, and satisfaction. Data were analyzed using the Mann-Whitney test, Kruskal-Wallis test, chi2 test, and analysis of covariance at a significance level of 95%. RESULTS: Of the 120 participants, 77 were women and 43 were men; the participants' mean age was 36.45 +/- 10.69 years. The results showed that the mode of delivering instructions had a marked relation with pain and patient satisfaction. Pain intensity was significantly higher in the verbal instructions group compared with the written instructions (P = .002) and verbal plus written instructions (P = .000) groups. CONCLUSION: The mode of delivering postoperative instructions meaningfully affected pain intensity and general patient satisfaction. Patients who received verbal instructions reported the most intense pain and the least satisfaction, and patients who received verbal and written instructions were the most satisfied. PMID- 29758176 TI - Women's satisfaction, use, storage and disposal of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) during a randomized trial. AB - OBJECTIVE: To describe women's experiences with subcutaneous depot medroxyprogesterone acetate (DMPA-SC) to inform scale-up of self-administered DMPA-SC. STUDY DESIGN: We conducted a 12-month randomized controlled trial in Malawi to measure DMPA-SC continuation rates. A total of 731 women presenting at six Ministry of Health clinics or to community health workers (CHWs) in rural communities were randomized to receive DMPA-SC administered by a provider or be trained to self-inject DMPA-SC. Data collectors contacted women after the reinjection window at 3, 6 and 9 months to collect data on satisfaction and use; self-injectors were also queried about storage and disposal of DMPA-SC. We compared frequencies of injection experiences and satisfaction by study group and over time. RESULTS: Ninety-two percent of women who self-injected felt it was easy to do the first time. Women in the self-administered group primarily gave themselves the injection versus having someone else inject them; stored DMPA-SC mostly in bags, often in ways to keep the product away from others; and properly disposed of DMPA-SC in pit latrines. Women in both groups used printed calendars to remember when to get/be given their next injection. Both groups reported high satisfaction with DMPA-SC. CONCLUSIONS: Women in low-resource settings can be successfully trained by public sector CHWs and clinic-based providers to self inject and to appropriately store and dispose of DMPA-SC. DMPA-SC and self injection are acceptable and feasible in a low-resource setting. IMPLICATIONS: Self-administered and provider-administrated DMPA-SC should be scaled up, and the lessons learned during our trial should be applied to future scale-up efforts. PMID- 29758177 TI - The efficacy of antenatal steroid therapy is dependent on the duration of low concentration fetal exposure: evidence from a sheep model of pregnancy. AB - BACKGROUND: Antenatal corticosteroids are among the most important and widely used interventions to improve outcomes for preterm infants. Antenatal corticosteroid dosing regimens remain unoptimized and without maternal weight adjusted dosing. We, and others, have hypothesized that, once a low concentration of maternofetal steroid exposure is achieved and maintained, the duration of the steroid exposure determines treatment efficacy. Using a sheep model of pregnancy, we tested the relationship among steroid dose, duration of exposure, and treatment efficacy. OBJECTIVE: The study was conducted to investigate the relative importance of duration and magnitude of fetal corticosteroid exposure to mature the preterm fetal ovine lung. STUDY DESIGN: Ewes with single fetuses at 120 days gestation received an intravenous bolus (loading dose) followed by a maintenance infusion of betamethasone phosphate to target 12-hour fetal plasma betamethasone concentrations of (1) 20 ng/mL, (2) 10 ng/mL, or (3) 2 ng/mL. In a subsequent experiment, fetal plasma betamethasone concentrations were targeted at 2 ng/mL for 26 hours. Negative control animals received sterile saline solution. Positive control animals received 2 intramuscular injections of 0.25 mg/kg Celestone Chronodose (betamethasone phosphate + betamethasone acetate) spaced at 24 hours. Preterm lambs were delivered surgically and ventilated 48 hours after treatment commenced. Maternal and fetal plasma betamethasone concentrations were confirmed by mass spectrometry in a parallel study of chronically catheterized, corticosteroid-treated ewes and fetuses. RESULTS: The loading and maintenance doses were achieved and maintained the desired fetal plasma betamethasone concentrations of approximately 20, 10, and 2 ng/mL for 12 hours. Compared with the 12-hour infusion-treated animals, lambs from the positive control (2 intramuscular doses of 0.25 mg/kg Celestone Chronodose) group had the greatest functional lung maturation (compliance, gas exchange, arterial pH) and molecular evidence of maturation (glucocorticoid receptor signaling activation), despite having maximum fetal plasma betamethasone concentrations 2.5 times lower than animals in the 20 ng/mL betamethasone infusion group. Lambs from the 12-hour 2 ng/mL betamethasone infusion group had little functional lung maturation. In contrast, lambs from the 26-hour 2-ng/mL betamethasone infusion group had functional lung maturation equivalent to lambs from the positive control group. CONCLUSION: In preterm lambs that were exposed to antenatal corticosteroids, high maternofetal plasma betamethasone concentrations did not correlate with improved lung maturation. The largest and most consistent improvements in lung maturation were in animals that were exposed to either the clinical course of Celestone Chronodose or a low-dose betamethasone phosphate infusion to achieve a fetal plasma betamethasone concentration of approximately 2 ng/mL for 26 hours. The duration of low-concentration maternofetal steroid exposure, not total dose or peak drug exposure, is a key determinant for antenatal corticosteroids efficacy. These findings underscore the need to develop an optimized steroid dosing regimen that may improve both the efficacy and safety of antenatal corticosteroids therapy. PMID- 29758178 TI - Lin28a regulates neurogliogenesis in mammalian retina through the Igf signaling. AB - In the developing central nervous system (CNS) the majority of neurons are born before the generation of glia. Emerging evidence implicates heterochronic gene, Lin28 in the temporal switch between two distinct lineages. However, the respective contributions of Lin28a and Lin28b in neurogliogenesis remain poorly understood. Here, we have examined the relative involvement of Lin28a and Lin28b in mammalian retina, a simple and accessible CNS model where neurogliogenic decision largely occurs postnatally. Examination of Lin28a/b involvement during late histogenesis by the perturbation of function approaches revealed that while Lin28b did not influence differentiation in general Lin28a facilitated and antagonized the generation of neurons and glia, respectively. Silencing of Lin28a expression in vitro and its conditional deletion in vivo during early histogenesis led to premature generation of glia. The instructive role of Lin28a on neuronal differentiation was revealed by its influence to suppress glial specific genes and directly differentiate glia along the neuronal lineage. This function of Lin28a is likely mediated through the Igf signaling, as inhibition of the pathway abrogated Lin28a-mediated neurogliogenesis. Thus, our observations suggest that Lin28a is an important intrinsic factor that acts in concert with cell-extrinsic factors like Igfs, coordinating the developmental bias of the progenitors and niche, respectively, for the successive generation of neurons and glia. PMID- 29758174 TI - G protein-coupled estrogen receptor (GPER) deficiency induces cardiac remodeling through oxidative stress. AB - Oxidative stress has been implicated in the unfavorable changes in cardiac function and remodeling that occur after ovarian estrogen loss. Using ovariectomized rat models, we previously reported that the cardioprotective actions of estrogen are mediated by the G protein-coupled estrogen receptor (GPER). Here, in 9-month-old, female cardiomyocyte-specific GPER knockout (KO) mice vs sex- and age-matched wild-type (WT) mice, we found increased cardiac oxidative stress and oxidant damage, measured as a decreased ratio of reduced glutathione to oxidized glutathione, increased 4-hydroxynonenal and 8-hydroxy-2' deoxyguanosine (8-oxo-DG) staining, and increased expression of oxidative stress related genes. GPER KO mice also displayed increased heart weight, cardiac collagen deposition, and Doppler-derived filling pressure, and decreased percent fractional shortening and early mitral annular velocity compared with WT controls. Treatment of GPER KO mice for 8 weeks with phosphonium [10-(4,5 dimethoxy-2-methyl 3,6-dioxo-1,4-cyclohexadien-1-yl)decyl] triphenyl-,mesylate (MitoQ), a mitochondria-targeted antioxidant, significantly attenuated these measures of cardiac dysfunction, and MitoQ decreased 8-oxo-DG intensity compared with treatment with an inactive comparator compound, (1 decyl)triphenylphosphonium bromide (P <0.05). A real-time polymerase chain reaction array analysis of 84 oxidative stress and antioxidant defense genes revealed that MitoQ attenuates the increase in NADPH oxidase 4 and prostaglandin endoperoxide synthase 2 and the decrease in uncoupling protein 3 and glutathione S-transferase kappa 1 seen in GPER KO mice. Our findings suggest that the cardioprotective effects of GPER include an antioxidant role and that targeted strategies to limit oxidative stress after early noncancerous surgical extirpation of ovaries or menopause may help limit alterations in cardiac structure and function related to estrogen loss. PMID- 29758179 TI - Regeneration of the germline in the annelid Capitella teleta. AB - The germline is essential for sexual reproduction and survival of the species. In many metazoans, the developmental potential to generate a distinct germline is segregated from somatic cell lineages early in embryogenesis, suggesting that the unique features of the germline must be established from its onset. Previous studies suggest that germ cells cannot regenerate once removed from the embryo, but few animals have been experimentally tested. We investigated the ability of the germline to regenerate in a lophotrochozoan, the segmented worm Capitella teleta, which has a stereotyped cell lineage program by deleting the germline precursor (cell 3D) in early stage embryos using an infrared laser. Larvae and juveniles resulting from germline deletions were examined for presence of multipotent progenitor cells (MPCs), stem cells that form the germ cells and somatic stem cells. In contrast to control deletions of a non-germline macromere, most larvae resulting from deletion of cell 3D lacked MPCs as assayed by expression of germline markers CapI-vasa, CapI-nanos and Ct-piwi1, but showed persistent expression of these markers in the somatic posterior growth zone. However, approximately 13% of experimental larvae had MPCs, indicative of some germline regeneration. In contrast, by two weeks post-metamorphosis, all juveniles resulting from deletion of cell 3D had MPCs, as detected by CapI-vasa expression. Furthermore, when raised to adulthood, most animals developed reproductive structures and were fertile. In another set of deletions, both the D quadrant mesodermal and germline progenitors were removed. These juveniles also regenerated MPCs. Surprisingly, this deletion caused substantial ectopic expression of CapI-vasa and CapI-nanos in other larval tissues. Our results indicate that C. teleta can regenerate the germline following removal of the germline progenitors in the early embryo. The dramatic difference in ability to regenerate the germline between the larval and adult stages suggests that there are two distinct compensation events at two phases of the life cycle: a regulative event in the early stage larva and a stem cell transition event after metamorphosis, when the animals are capable of substantial body regeneration. PMID- 29758180 TI - Predicting the unknown: Novelty processing depends on expectations. AB - Fulfilled predictions lead to neural suppression akin to repetition suppression, but it is currently unclear if such effects generalize to broader stimulus categories in the absence of exact expectations. In particular, does expecting novelty alter the way novel stimuli are processed? In the present study, the effects of expectations on novelty processing were investigated using event related potentials, while controlling for the effect of repetition. Sequences of five stimuli were presented in a continuous way, such that the last stimulus of a 5-stimulus sequence was followed by the first stimulus of a new 5-stimulus sequence without interruption. The 5-stimulus sequence was predictable: the first three stimuli were preceded by a cue indicating that the next stimulus was likely to be a standard stimulus, and the last two by a cue indicating that the next stimulus was likely to be novel. On some trials a cue typically predicting a standard was in fact followed by an unexpected novel stimulus. This design allowed to investigate the independent effects of (violated) expectations and repetition on novelty processing. The initial detection of expected novels was enhanced compared to unexpected novels, as indexed by a larger anterior N2. In contrast, the orienting response, as reflected by a novelty P3, was reduced for expected compared to unexpected novels. Although the novel stimuli were never repeated themselves, they could be presented after one another in the sequence. Such a category repetition affected the processing of novelty, as evidenced by an enhanced anterior N2, and a reduced novelty P3 for novels preceded by other novels. Taken together, the current study shows that novelty processing is influenced by expectations. PMID- 29758181 TI - Development and Validation of Web-Based Nomograms to Precisely Predict Conditional Risk of Site-Specific Recurrence for Patients With Completely Resected Non-small Cell Lung Cancer: A Multiinstitutional Study. AB - BACKGROUND: There is currently no consensus regarding the optimal postoperative follow-up strategy for patients with completely resected non-small cell lung cancer (NSCLC). We aimed to develop web-based nomograms to precisely predict site specific postoperative recurrence in patients with NSCLC and to guide individual surveillance strategies including when to follow up and what diagnostic tests to perform. METHODS: We investigated the pattern of recurrence in a series of 2,017 patients with NSCLC (squamous cell carcinoma and nonlepidic invasive adenocarcinoma) who underwent complete surgical resection at Fudan University Shanghai Cancer Center (development cohort), and developed web-based clinicopathologic prediction models for conditional risk of site-specific recurrence based on Cox regression. The variables used in the analysis included sex, age, smoking history, tumor size, tumor histology, lymphovascular invasion, visceral pleural invasion, and pathologic TNM stage. A separate cohort of 3,308 patients with NSCLC from Shanghai Chest Hospital was used for external validation. RESULTS: In the development cohort and the external validation cohort for the established nomograms to predict overall recurrence, thorax recurrence, abdomen recurrence, neck recurrence, brain recurrence, and bone recurrence, the C statistics of Harrell et al were 0.743 and 0.748, 0.728 and 0.703, 0.760 and 0.749, 0.779 and 0.757, 0.787 and 0.784, and 0.777 and 0.739, respectively. The calibration plots showed optimal agreement between nomogram-predicted 3-year recurrence-free survival and actual 3-year recurrence-free survival. CONCLUSIONS: These user-friendly nomograms can precisely predict site-specific recurrence in patients with completely resected NSCLC, based on clinicopathologic features. They may help physicians to make individual postoperative follow-up plans. PMID- 29758182 TI - Exploratory behavior is linked to stress physiology and social network centrality in free-living house finches (Haemorhous mexicanus). AB - Animal personality has been linked to individual variation in both stress physiology and social behaviors, but few studies have simultaneously examined covariation between personality traits, stress hormone levels, and behaviors in free-living animals. We investigated relationships between exploratory behavior (one aspect of animal personality), stress physiology, and social and foraging behaviors in wild house finches (Haemorhous mexicanus). We conducted novel environment assays after collecting samples of baseline and stress-induced plasma corticosterone concentrations from a subset of house finches. We then fitted individuals with Passive Integrated Transponder tags and monitored feeder use and social interactions at radio-frequency identification equipped bird feeders. First, we found that individuals with higher baseline corticosterone concentrations exhibit more exploratory behaviors in a novel environment. Second, more exploratory individuals interacted with more unique conspecifics in the wild, though this result was stronger for female than for male house finches. Third, individuals that were quick to begin exploring interacted more frequently with conspecifics than slow-exploring individuals. Finally, exploratory behaviors were unrelated to foraging behaviors, including the amount of time spent on bird feeders, a behavior previously shown to be predictive of acquiring a bacterial disease that causes annual epidemics in house finches. Overall, our results indicate that individual differences in exploratory behavior are linked to variation in both stress physiology and social network traits in free-living house finches. Such covariation has important implications for house finch ecology, as both traits can contribute to fitness in the wild. PMID- 29758185 TI - Elucidating the bactericidal mechanism of action of the linear antimicrobial tetrapeptide BRBR-NH2. AB - Linear antimicrobial peptides, with their rapid bactericidal mode of action, are well-suited for development as topical antibacterial drugs. We recently designed a synthetic linear 4-residue peptide, BRBR-NH2, with potent bactericidal activity against Staphylococcus aureus (MIC 6.25 MUM), the main causative pathogen of human skin infections with an unknown mechanism of action. Herein, we describe a series of experiments conducted to gain further insights into its mechanism of action involving electron microscopy, artificial membrane dye leakage, solution- and solid-state NMR spectroscopy followed by molecular dynamics simulations. Experimental results point towards a SMART (Soft Membranes Adapt and Respond, also Transiently) mechanism of action, suggesting that the peptide can be developed as a topical antibacterial agent for treating drug-resistant Staphylococcus aureus infections. PMID- 29758187 TI - Antigenic targets of CAR T Cell Therapy. A retrospective view on clinical trials. AB - Chimeric antigen receptor (CAR) T cell therapy is anticipated to be increasingly implemented in the context of cancer treatment after two current FDA approval of anti-CD19 CAR-T cells (KymriahTM & YescartaTM). The success of CD19 is mainly attributable to the proper selection of the antigen, CD19, as the target of the disease, highlighting the importance of target selection for other CAR therapies. Therefore, here we performed a global analysis of targets that are the prime focus for various CAR T cell therapies in human clinical trials. PMID- 29758183 TI - Increasing Cardiomyocyte Atrogin-1 Reduces Aging-Associated Fibrosis and Regulates Remodeling in Vivo. AB - The muscle-specific ubiquitin ligase atrogin-1 (MAFbx) has been identified as a critical regulator of pathologic and physiological cardiac hypertrophy; it regulates these processes by ubiquitinating transcription factors [nuclear factor of activated T-cells and forkhead box O (FoxO) 1/3]. However, the role of atrogin 1 in regulating transcription factors in aging has not previously been described. Atrogin-1 cardiomyocyte-specific transgenic (Tg+) adult mice (alpha-major histocompatibility complex promoter driven) have normal cardiac function and size. Herein, we demonstrate that 18-month-old atrogin-1 Tg+ hearts exhibit significantly increased anterior wall thickness without functional impairment versus wild-type mice. Histologic analysis at 18 months revealed atrogin-1 Tg+ mice had significantly less fibrosis and significantly greater nuclei and cardiomyocyte cross-sectional analysis. Furthermore, by real-time quantitative PCR, atrogin-1 Tg+ had increased Col 6a4, 6a5, 6a6, matrix metalloproteinase 8 (Mmp8), and Mmp9 mRNA, suggesting a role for atrogin-1 in regulating collagen deposits and MMP-8 and MMP-9. Because atrogin-1 Tg+ mice exhibited significantly less collagen deposition and protein levels, enhanced Mmp8 and Mmp9 mRNA may offer one mechanism by which collagen levels are kept in check in the aged atrogin-1 Tg+ heart. In addition, atrogin-1 Tg+ hearts showed enhanced FoxO1/3 activity. The present study shows a novel link between atrogin-1-mediated regulation of FoxO1/3 activity and reduced collagen deposition and fibrosis in the aged heart. Therefore, targeting FoxO1/3 activity via the muscle-specific atrogin-1 ubiquitin ligase may offer a muscle-specific method to modulate aging related cardiac fibrosis. PMID- 29758184 TI - Therapeutic Penetrating Keratoplasty Button Cultures in The Mycotic Ulcer Treatment Trial II: A Randomized Trial Comparing Oral Voriconazole Versus Placebo. AB - OBJECTIVE: To compare oral voriconazole vs placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis. DESIGN: Non prespecified, secondary case-control analysis from a multicenter, double-masked, randomized placebo-controlled clinical trial. METHODS: Study Participants: Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 or worse who eventuated to therapeutic penetrating keratoplasty (TPK). INTERVENTION: Study participants were randomized to oral voriconazole vs oral placebo; all received topical antifungal drops. MAIN OUTCOME MEASURES: TPK button culture positivity. RESULTS: A total of 95 of 194 (49.5%) study participants enrolled at Madurai, Coimbatore, or Pondicherry, India eventuated to TPK in an average of 20.9 days (standard deviation 15.2 days, range 2-71 days). TPK button cultures were available for 67 of 95 (71%) of the TPKs performed and were positive for filamentous fungus in 45 of 67 (67%) cases. For each 1-day increase in the time to TPK there was 0.94-fold decreased odds of fungal culture positivity (95% confidence interval [CI] 0.90-0.98, P = .005). Those randomized to oral voriconazole had 1.26-fold increased odds of TPK button culture positivity after controlling for time to TPK and baseline organism, but this was not statistically significant (95% CI 0.32-4.87; P = .74). Those who underwent TPK for lack of response to medical therapy were 10.64-fold more likely to be culture positive than if the indication for surgery was perforation and this was statistically significant (95% CI 2.16-51.70; P = .003). CONCLUSIONS: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. Infection rather than inflammation appears to be the reason for the worsening clinical picture in many of these patients. PMID- 29758186 TI - Supplementation with l-glutathione improves oxidative status and reduces protein nitration in myenteric neurons in the jejunum in diabetic Rattus norvegicus. AB - Diabetes mellitus is a syndrome with multiple etiologies, characterized by chronic hyperglycemia that increases the production of reactive oxygen species and decreases antioxidant defenses. The present study evaluated oxidative stress parameters and protein nitration in myenteric neurons in the jejunum in diabetic rats supplemented with l-glutathione. Rats (90 days of age) were distributed into four groups (n = 6/group): normoglycemic (N), normoglycemic supplemented with l glutathione (NGT), diabetic (D), and diabetic supplemented with l-glutathione (DGT). At 210 days of age, the animals were sacrificed, and the jejunum was collected, washed, and subjected to various procedures: tert-butyl hydroperoxide chemiluminescence (CL), determination of total antioxidant capacity (TAC), determination of catalase activity, quantification of nitric oxide (NO), and double-labeling of HuC/D-immunoreactive myenteric neurons and nitrotyrosine (3 NT). Diabetes increased oxidative stress in the jejunum in the D group, reflected by increases in lipid peroxidation, TAC, catalase activity, and NO. The D group exhibited an increase in the percentage of myenteric neurons that were double labeled with 3-NT. Supplementation with l-glutathione did not cause differences in the average CL curves between the D and DGT groups, but reductions of TAC and catalase activity were observed. Supplementation with l-glutathione promoted a reduction of neurons that contained 3-NT in the DGT group. Diabetes mellitus promoted oxidative stress in the jejunum, and supplementation with l-glutathione improved oxidative status by preventing protein nitration in myenteric neurons in diabetic animals that received supplementation. PMID- 29758188 TI - Tuft cells: Distribution and connections with nerves and endocrine cells in mouse intestine. AB - Tuft cells are gastrointestinal (GI) sensory cells recognized by their characteristic shape and their microvilli "tuft". Aims of the present study were to elucidate their regional distribution and spatial connections with satiety associated endocrine cells and nerve fibers throughout the intestinal tract. C57BL/6 J mice were used in the experiments. The small intestine was divided into five segments, and the large intestine was kept undivided. The segments were coiled into "Swiss rolls". Numbers and topographic distribution of tuft cells and possible contacts with endocrine cells and nerve fibers were estimated in the different segments, using immunocytochemistry. Tuft cells were found throughout the intestines; the highest number was in proximal small intestine. Five percent of tuft cells were found in close proximity to cholecystokinin-immunoreactive (IR) endocrine cells and up to 10% were in contact with peptide YY- and glucagon like peptide-1-IR endocrine cells. Sixty percent of tuft cells in the small intestine and 40% in the large intestine were found in contact with nerve fibers. Calcitonin gene-related peptide-IR fibers constituted one-third of the fiber contacts in the small intestine and two-thirds in the large intestine. These observations highlight the possibility of tuft cells as modulators of GI activities in response to luminal signaling. PMID- 29758189 TI - Audiovisual perception in amblyopia: A review and synthesis. AB - Amblyopia is a common developmental sensory disorder that has been extensively and systematically investigated as a unisensory visual impairment. However, its effects are increasingly recognized to extend beyond vision to the multisensory domain. Indeed, amblyopia is associated with altered cross-modal interactions in audiovisual temporal perception, audiovisual spatial perception, and audiovisual speech perception. Furthermore, although the visual impairment in amblyopia is typically unilateral, the multisensory abnormalities tend to persist even when viewing with both eyes. Knowledge of the extent and mechanisms of the audiovisual impairments in amblyopia, however, remains in its infancy. This work aims to review our current understanding of audiovisual processing and integration deficits in amblyopia, and considers the possible mechanisms underlying these abnormalities. PMID- 29758190 TI - Conserved characteristics of ocular refractive development - Did the eye evolve once? AB - It has been speculated that the unitary eyes of vertebrates and molluscs, and the compound eyes of insects and crustaceans, evolved separately. On the other hand, the common use of rhodopsin as a photoreceptor molecule, and the conservation of Pax6 as a master control gene for eye development, suggest instead that the eye evolved once. Yet, recently the molecular genetics that had seemed to suggest a definitive answer to this evolutionary point has once again become cloudy. Here we propose an alternative approach to addressing the question of eye evolution through comparative analyses of physiological optics. Serendipitous discoveries involving form deprivation and defocusing with young monkeys and chicks demonstrated the conserved importance of visual experience on eye development. Similar results have been demonstrated in teleosts, although differences exist in eye anatomy, physiology and optics. In particular, since fish grow throughout life, these effects can also be demonstrated in adults. In comparison, the cephalopod eye is an often-cited example of convergent evolution with the vertebrate eye, although considerable developmental differences exist. Nevertheless, squid eyes from animals raised under alternative lighting exhibit anatomical and refractive changes that agree with those found in vertebrates. Together, these observations provide functional and structural support for the view that the eye evolved once. Because of their very compressed lifespans (only one to two years) cephalopods may be ideal animal models for the study of ocular refractive development. PMID- 29758191 TI - An atypical infection of the esophagus mimicking malignancy. PMID- 29758192 TI - Gastric mucosal metastasis of prostate cancer. PMID- 29758194 TI - Knockdown of Trnau1ap inhibits the proliferation and migration of NIH3T3, JEG-3 and Bewo cells via the PI3K/Akt signaling pathway. AB - The tRNA selenocysteine 1 associated protein 1 (Trnau1ap, initially named SECp43) is involved in Selenocysteine (Sec) biosynthesis and incorporation into selenoproteins, which play a key role in biological processes, such as embryonic development. We previously reported that downregulation of Trnau1ap inhibited proliferation of cardiomyocyte-like H9c2 cells. However, the effects of Trnau1ap on cell proliferation and migration of embryonic development are not known, and the mechanisms remain elusive. Herein, lentiviral shRNA vectors were transfected in NIH3T3, JEG-3 and Bewo cells (embryonic, trophoblast and placental cells). We found that knockdown of Trnau1ap resulted in reduced expression levels of selenoproteins. The data of Cell Count Kit-8 (CCK-8) assay and wound scratch assay revealed the proliferation and migration rates were reduced in the Trnau1ap shRNA groups. Furthermore, western blot analysis showed that the phosphorylation level of Akt in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was attenuated. These results indicate that Trnau1ap plays an important role in regulation of cell proliferation and migration through the PI3K/Akt signaling pathway, as well as being essential for embryonic development by regulating the expression of selenoproteins. PMID- 29758193 TI - Inhibition of pancreatic cancer Panc1 cell migration by omeprazole is dependent on aryl hydrocarbon receptor activation of JNK. AB - Several aryl hydrocarbon receptor (AhR)-active pharmaceuticals were screened as inhibitors of pancreatic cancer cell invasion and identified two compounds, omeprazole, that inhibited invasion. Inhibition of highly invasive Panc1 cell invasion by omeprazole involves an AhR-dependent non-genomic pathway, and omeprazole-mediated inhibition of Panc1 cell invasion was dependent on Jun-N terminal kinase (JNK) and mitogen-activated kinase kinase 7 (MKK7). The failure of omeprazole to induce nuclear translocation of the AhR was not due to overexpression of cytosolic AhR partner proteins Hsp90 or XAP2, and results of DNA sequencing show that the AhR expressed in Panc1 cells was not mutated. Results of RNAseq studies indicate that omeprazole induced an AhR-dependent downregulation of several pro-invasion factors including activated leukocyte cell adhesion molecule (ALCAM), long chain fatty acid CoA-synthase (CSL4), stathmin 3 (STMN3) and neuropillin 2 (NRP2), and the specific functions of these genes are currently being investigated. PMID- 29758195 TI - A miR-124/ITGA3 axis contributes to colorectal cancer metastasis by regulating anoikis susceptibility. AB - Metastasis is the major cause for the death of patients with colorectal cancer (CRC). Anoikis resistance enhances the survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs. miR-124 is a pleiotropically tumor suppressive small non-coding molecule. However, its role and mechanism in the regulation of cancer cell anoikis are still unknown. Here, we found that overexpression of miR-124 promotes anoikis of CRC cells in vitro and in vivo. In silico analysis and the experimental evidence supported that ITGA3 is a bona fide target of miR-124. Moreover, we identifies that ITGA3 plays a critical role in the regulation of anoikis sensitivity in CRC cells. Finally, our analysis in TCGA datasets demonstrates that high levels of ITGA3 are closely associated with poor prognosis in CRC patients. Collectively, we establish a functional link between miR-124 and anoikis susceptibility and provide that a miR-124/ITGA3 axis could be a potential target for the treatment of metastatic CRC. PMID- 29758197 TI - Berberine and zinc oxide-based nanoparticles for the chemo-photothermal therapy of lung adenocarcinoma. AB - Organic/inorganic hydrid nanoparticles (NPs) composed of berberine (BER) and zinc oxide (ZnO) were developed for the therapy of lung cancers. Without the use of pharmaceutical excipients, NPs were fabricated with only dual anticancer agents (BER and ZnO) by facile blending method. The mean weight ratio between BER and ZnO in BER-ZnO NPs was 39:61 in this study. BER-ZnO NPs dispersed in water exhibited 200-300 nm hydrodynamic size under 5 mg/mL concentration. The exposure of both BER and ZnO in the outer layers of BER-ZnO NPs was identified by X-ray photoelectron spectroscopy analysis. The amorphization of BER and the maintenance of ZnO structure were observed in the results of X-ray powder diffractometer analysis. Improved antiproliferation efficacy, based on the chemo-photothermal therapeutic efficacy, of BER-ZnO NPs in A549 (human lung adenocarcinoma) cells was presented. According to the blood tests in rats after intravenous administration, BER-ZnO NPs did not induce severe hepatotoxicity, renal toxicity, and hemotoxicity. Developed BER-ZnO NPs can be used efficiently and safely for the chemo-photothermal therapy of lung cancers. PMID- 29758196 TI - Temozolomide combined with PD-1 Antibody therapy for mouse orthotopic glioma model. AB - PURPOSE: Temozolomide (TMZ) is the most frequent adjuvant chemotherapy drug in gliomas. PDL1 expresses on various tumors, including gliomas, and anti-PD-1 antibodies have been approved for treating some tumors by FDA. This study was to evaluate the therapeutical potential of combined TMZ with anti-PD-1 antibody therapy for mouse orthotopic glioma model. METHODS: We performed C57BL/6 mouse orthotopic glioma model by stereotactic intracranial implantation of glioma cell line GL261, mice were randomly divided into four groups: (1) control group; (2) TMZ group; (3) anti-PD-1 antibody group; (4) TMZ combined with anti-PD-1 antibody group. Then the volume or size of tumor was assessed by 7.0 T MRI and immunohistochemistry, and the number of CD4 and CD8 infiltrating cells in brain tumor and spleen was evaluated by immunohistochemistry. Western blot was used to evaluate the expression of PDL1. Furthermore, Overall survival of each group mice was also evaluated. RESULTS: Overall survival was significantly improved in combined group compared to other groups (chi2 = 32.043, p < 0.01). The volume or size of tumor was significantly decreased in combined group compared with other groups (F = 42.771, P < 0.01). And the number of CD4 and CD8 infiltrating cells in brain tumor was also obviously increased in combined group (CD4 F = 45.67, P < 0.01; CD8 F = 53.75, P < 0.01). CONCLUSION: Anti-PD1 antibody combined with TMZ therapy for orthotopic mouse glioma model could significantly improve the survival time of tumor-bear mice. Thus, this study provides the effective preclinical evidence for support clinical chemotherapy combined with immunotherapy for glioma patients. PMID- 29758198 TI - The lncRNA TUG1/miR-145-5p/FGF10 regulates proliferation and migration in VSMCs of hypertension. AB - Vascular remodeling is a characteristic pathological feature of hypertension, it can cause of increasing vascular resistance and decrease of compliance. Vascular smooth muscle cell (VSMCs) dysfunction is the important foundation of vascular remodeling. Increasing evidences have revealed that lncRNA is an important regulatory factor of VSMC function. In this paper, we explored the function of lncRNA TUG1 in vascular remodeling of hypertension. Here, we found that lncRNA TUG1 was highly expressed in aorta of spontaneously hypertensive rats (SHR) rats and promoted the proliferation and migration of VSMCs (SHR-VSMCs). Bioinformatics analyze showed that lncRNA TUG1 sequence had miR-145-5p binding sites. Luciferase reporter test, RNA pulldown and qRT-PCR showed that lncRNA TUG1 could bind miR 145-5p. Similarly, bioinformatics analyze found that FGF10 3 'UTR contained miR 145-5p binding sites. Luciferase reporter test, qRT-PCR and Western blot were shown that miR-145-5p inhibited FGF10 expression by binding to its 3 'UTR. MTT showed that miR-145-5p inhibited and FGF10 promoted SHR-VMSCs proliferation and migration. Overexpression of miR-145-5p or knocking down of FGF10 after overexpresion of lncRNA TUG1 could rescue the proliferation and migration promoted by lncRNA TUG1. LncRNA TUG1 and FGF10 promoted and miR-145-5p suppressed the expression of beta-catenin, TCF and LEF in SHR-VSMCs. Therefore, lncRNA TUG1/miR-145-5p/FGF10 promotes the proliferation and migration of VSMCs in hypertensive state by activating the Wnt/beta-catenin pathway. PMID- 29758199 TI - PAFAH1B2 is a HIF1a target gene and promotes metastasis in pancreatic cancer. AB - Platelet-activating factor acetylhydrolase IB subunit beta (PAFAH1B2) plays important roles in inflammation and anaphylaxis. However, its primary function in pancreatic cancer remains unclear. In the current study, we report that PAFAH1B2 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and correlated inversely with patient survival. PAFAH1B2 overexpression induced epithelial mesenchymal transition (EMT), migration and invasion in vitro and metastasis in vivo. Conversely, silencing PAFAH1B2 inhibited these aggressive phenotypes. Moreover, PAFAH1B2 overexpression in PDAC cells was directly mediated by HIF1a. PAFAH1B2 expression in PDAC clinical specimens correlated positively with HIF1a expression. Overall, our results defined PAFAH1B2 as a target gene of HIF1a and a critical driver of PDAC metastatic behaviors. PMID- 29758200 TI - MicroRNA-299-3p regulates proliferation, migration and invasion of human ovarian cancer cells by modulating the expression of OCT4. AB - Ovarian cancer is among the most prevalent and lethal types of cancers in women. Several factors such as late diagnosis, unavailability of the reliable biomarkers, frequent relapses and dearth of efficient therapeutic targets form bottleneck in the treatment of ovarian cancers. In this study we investigated the potential of less studied miR-299-3p as the therapeutic target for the treatment of ovarian cancer. The results of the present investigation revealed that miR-299 is significantly upregulated in the ovarian cancers and suppression of its expression inhibits the proliferation by induction of apoptosis as well suppresses migration and invasion of the SKOV3 cancers cells. Further, OCT-4 was found to be putative target of miR-99-3p in ovarian cancer and inhibition of OCT 4 had similar effects as that of miR-299 inhibition on cell migration and invasion. Intriguingly, even overexpression of miR-299-3p could not rescue the effects of OCT-4 suppression on SKOV3 cell proliferation, migration and invasion. On contrary, overexpression of OCT-4 in SKOV3 cells transfected with miR-299-3p transfected could nullify the effects of miR-200-3p on proliferation, migration and invasion of the SKOV3 cells. Taken together, miR-299-3p regulated cell proliferation and metastasis by modulating the expression of OCT-4 and as such may prove to be an important therapeutic target. PMID- 29758201 TI - Dietary vitamin A impacts DNA methylation patterns of adipogenesis-related genes in suckling rats. AB - We previously showed that vitamin A supplementation in early life impacts white adipose tissue (WAT) biology. We here studied the vitamin's effects on DNA methylation of genes crucial for WAT cell development, determination and metabolism. CpG promoter methylation and mRNA expression of Pparg, Zfp423, Pcna, and Rbp4 was compared in inguinal WAT of 21-day-old rats supplemented during the suckling period with vehicle (controls) or an emulsion of vitamin A as retinyl ester (RE) or beta-carotene (BC). The methylation profile of promoters was affected by vitamin A supplementation with pronounced differences between the RE and BC groups. In the RE group, hypermethylation of the Rbp4 (at multiple CpGs) and the Pparg2 (at a specific CpG) promoters and hypomethylation of the Pcna promoter (at multiple CpGs) was observed, together with inverse changes in gene expression levels. In the BC group, hypomethylation of the Rbp4 and hypermethylation of the Pcna promoter at distinct CpGs was observed, with no effects on gene expression. In both supplemention groups, hypomethylation and increased expression was found for Zfp423. Thus, modest vitamin A supplementation in early postnatal life impacts methylation marks in developing WAT. Differential epigenetic effects of RE and BC in early life may affect adipose tissue programming activity. PMID- 29758202 TI - Mounting evidence validates Ursolic Acid directly activates SIRT1: A powerful STAC which mimic endogenous activator of SIRT1. AB - Ursolic Acid (UA), a pentacyclic triterpenoid compound, plays a vital role in aging process. However, the role of UA in the regulation of aging and longevity is still controversial as we have previously demonstrated that UA increases SIRT1 protein level in aged-mice. Here, we reveal that UA directly activates SIRT1 in silico, in vitro and in vivo. We have identified that UA binds to outer surface of SIRT1 and leads to tight binding of substrates to enzyme in comparison with Resveratrol (RSV) and control. Furthermore, our results indicate that UA drives the structure of SIRT1 toward a closed state (an active form of enzyme). Interestingly, our experimental findings are in agreement with the molecular dynamic results. Based on our data, UA increases the affinity of enzyme for both substrates with decreasing Km value, while enhances the Vmax of enzyme. Additionally, we have determined that UA heightened SIRT1 catalytic efficiency by 2 folds compared with RSV. Thereby, to identify the endogenous activator of SIRT1, UA was administrated to aged-mice and then the tissues were isolated. According to our results, it can be concluded that UA increases SIRT1 activity and mimics Lamin A and AROS behavior in the living cells. PMID- 29758203 TI - Pretreatment neutrophil-lymphocyte and platelet-lymphocyte ratio predict clinical outcome and prognosis for cervical Cancer. AB - Variations in systemic inflammatory response biomarker levels have been associated with adverse clinical outcome in various malignancies. In this study, we aimed to evaluate the predictive and prognostic role of the pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in cervical cancer. We retrospectively investigated 616 patients who underwent initial radical hysterectomy with pelvic lymphadenectomy for cervical cancer between July 2012 and December 2014 in China. Their clinical and histopathological markers and complete blood counts were obtained and analyzed. Then we chose the group of 339 of the total 616 patients who were not combined preoperative radiotherapy or chemotherapy for the survival analysis. Prognostic factors were assessed by univariate and multivariate analyses. The ROC curve revealed NLR and PLR had significant ability to predict parametrial involvement, and the cutoff values for NLR and PLR were 2.5 and 138.8 respectively. Clinicopathologic analysis showed that NLR was linked to age, parametrial involvement, tumor-invasion depth and histologic grade, and PLR was related to age, parametrial involvement, tumor-invasion depth and FIGO stage. Univariate analysis identified high PLR as a significant poor predictor for progression-free survival (PFS) and overall survival (OS), and NLR exhibited no predict power on OS or PFS. Multivariable analysis showed that PLR was an independent predictor of PFS, but not OS. NLR and PLR were associated with the clinical characteristics of cervical cancer. Additionally, PLR had independence prognostic value for PFS in patients with cervical cancer receiving radical hysterectomy with pelvic lymphadenectomy. PMID- 29758204 TI - Association between hippuric acid and left ventricular hypertrophy in maintenance hemodialysis patients. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is one of the most common cardiac abnormalities in patients with end-stage renal disease. Hippuric acid (HA), a harmful uremic toxin, is known to be elevated in patients with uremia, and serum HA levels are associated with neurological symptoms, metabolic acidosis, and accelerated renal damage associated with chronic kidney disease. However, the pathophysiological role of HA in patients with uremia remains unclear. We investigated the association between serum HA levels and echocardiographic measurements in patients undergoing hemodialysis (HD) treatment. METHODS: Eighty consecutive patients treated at a single HD center (44 males, 36 females; mean age 66 y, mean HD duration 6 y) were included in this study. Comprehensive echocardiography was performed after HD. Blood samples were obtained before HD. RESULTS: Pearson's correlation analysis revealed that serum HA levels were positively correlated with diastolic blood pressure, serum creatinine, left ventricular mass index, end diastolic interventricular septal thickness, left ventricular end-diastolic diameter, left ventricular end systolic diameter, end systolic left ventricular posterior wall thickness, and left atrium diameter, and negatively correlated with age. Furthermore, the HD patients with LVH had higher median serum HA levels than those without LVH (34.2 vs. 18.1 MUg/ml, p = 0.003). Multiple logistic regression analysis revealed that HA was independently associated with LVH even after adjusting for known biomarkers. Moreover, the receiver operator characteristics curve of HA showed that a HA level of >26.9 MUg/ml was associated with LVH. CONCLUSIONS: HA was significantly associated with LVH. HA could be a novel biomarker of left ventricular overload, which is closely associated with an increased risk of death in HD patients. PMID- 29758205 TI - Performance of P16/Ki67 dual staining in triaging hr-HPV-positive population during cervical Cancer screening in the younger women. AB - BACKGROUND: Cervical cancer is the most common malignancy from the female reproductive tract, and usually develops from low-grade or high-grade squamous intraepithelial lesions (LSIL or HSIL). Detecting the precancerous lesion during the LSIL-HSIL-invasive cancer sequelae can effectively interrupt the oncogenesis and decrease the incidence of invasive carcinoma. The aim of this study is to evaluate the performance of P16/Ki67 dual staining in triaging hr-HPV-positive population. METHODS: Conventional gynecological examination, cervical cytology and hr-HPV testing were given to all patients. Specimens were collected for cytology examination and HPV genotyping. According to cytology results, patients were divided into cervical cancer group, HSIL group, LSIL group and benign lesion group. Sensitivity and specificity of the dual staining method in each histopathologic group was obtained and compared. RESULTS: Among the108 patients participated in the study, 65 were diagnosed as normal, 15 as LSIL, 20 as HSIL and 8 as CC, by histopathologic examination. Dual staining of p16/Ki67 on cytology specimen provided a positive predictive value of 86% and the negative predictive value of 96%. The sensitivity approached 96.43% when combining ThinPrep cytological test (TCT) with the dual staining, with a specificity of 60% in detecting HSIL. Joint detection of TCT and p16/Ki67 dual staining displayed the highest specificity among all the attempted combinations of detection methods. CONCLUSIONS: This study demonstrated that p16/Ki-67 dual staining represents an effective method for cervical cancer screening. Application of this method could lead to a reduction of unnecessary colposcopy referrals and misdiagnosis. PMID- 29758206 TI - Invited Commentary. PMID- 29758208 TI - Invited Commentary. PMID- 29758207 TI - Lung Cancer Invading a Coronary Graft: Role of Coronary Intervention and Robotic Surgery. AB - The treatment of primary lung cancer of the left upper lobe in those patients with prior coronary artery bypass graft is difficult to plan and execute due to the potential for invasion into coronary grafts, particularly the left internal mammary artery. We present a patient with squamous cell carcinoma invading into coronary artery bypass grafts, but which is successfully treated by a combination of percutaneous coronary intervention followed by video-assisted thoracoscopic surgery. PMID- 29758209 TI - Bilateral Internal Mammary Artery Use in Diabetic Patients: Friend or Foe? AB - BACKGROUND: Bilateral internal mammary artery (BIMA) grafting in diabetic patients undergoing coronary artery bypass grafting remains controversial. Our study compared morbidity and mortality between (1) diabetic and nondiabetic BIMA patients and (2) diabetic BIMA versus diabetic patients who underwent left internal mammary artery (LIMA) grafting only. METHODS: Patients who underwent isolated coronary artery bypass grafting from July 2011 to June 2016 at any of the 10 Maryland Cardiac Surgery Quality Initiative centers were propensity scored across 16 variables. Diabetic BIMA patients were matched 1:1 by nearest neighbor matching to nondiabetic BIMA patients and were separately matched 1:1 to diabetic LIMA patients. We calculated observed-to-expected (O/E) ratios for composite morbidity/mortality, operative mortality, unplanned reoperation, stroke, renal failure, prolonged ventilation, and deep sternal wound infection and compared ratios among matched populations. RESULTS: During the study period, 812 coronary artery bypass grafting patients received BIMA grafts, including 302 patients (37%) with diabetes. We matched 259 diabetic and nondiabetic BIMA patients. O/E ratios were higher in matched diabetic (versus nondiabetic) BIMA patients when comparing composite morbidity/mortality, reoperation, stroke, renal failure, and prolonged ventilation (all O/E ratios >1.0); however, the O/E ratio for operative mortality was higher in nondiabetic BIMA patients. We additionally matched 292 diabetic BIMA to diabetic LIMA patients. Diabetic BIMA patients had a higher O/E ratio for composite morbidity/mortality, operative mortality, stroke, renal failure, and prolonged ventilation. CONCLUSIONS: In this statewide analysis, diabetic patients who received BIMA grafts (compared with diabetic patients with LIMA grafts or nondiabetic patients with BIMA grafts) had higher O/E ratios for composite morbidity/mortality as a result of higher O/E ratios for major complications. PMID- 29758210 TI - Invited Commentary. PMID- 29758211 TI - Localized Tracheal Amyloidosis. PMID- 29758212 TI - Invited Commentary. PMID- 29758213 TI - Converting Atoms Into Bytes. PMID- 29758214 TI - Transcatheter Aortic Valve Replacement: Comparing Transfemoral, Transcarotid, and Transcaval Access. AB - BACKGROUND: Despite newer-generation valves using smaller-sized sheaths, 10% to 20% of patients undergoing transcatheter aortic valve replacement (TAVR) require nonfemoral artery access for valve delivery. To avoid a transthoracic procedure, we have used transcarotid (TC) and transcaval (TCav) approaches in these patients. This study compared the results of a contemporary experience with transfemoral (TF), TC, and TCav approaches. METHODS: Between January 2015 and March 2017, 491 patients underwent TAVR at our institution, of which 463 were included in this analysis. Valve delivery was TF in 373 patients, TCav in 58, and TC in 32. Patient characteristics and outcomes, including 1-year survival, were compared. RESULTS: Preoperative demographics and postoperative outcomes were similar for the three groups with several exceptions. TCav patients had higher The Society of Thoracic Surgeons risk score than TF patients (8.0 +/- 5.2 vs 6.1 +/- 4.3, p = 0.004). Lung disease, cerebrovascular disease, and peripheral vascular disease were more common in TC and TCav patients. Median length of stay was 2 days for TF, 3 days for TC, and 4 days for TCav (TF vs TCav, p = 0.001). Procedural mortality, percentage discharged home, and the 30-day readmission rate were similar for all. Unadjusted Kaplan-Meier survival was also similar at 1 year (TF, 86%; TC, 83%; TCav, 80%). CONCLUSIONS: Patients unsuitable for TF TAVR treated with TC or TCav access had 30-day/in-hospital and 1-year survival similar to a contemporary cohort undergoing TF access. Avoiding surgical entry to the chest may offer procedural and intermediate-term outcomes equivalent to TF TAVR. PMID- 29758217 TI - The Ebbinghaus illusion in contrast-defined and orientation-defined stimuli. AB - In the retinal image of the natural world, edges and shapes can be defined by first-order attributes, such as luminance, and second-order attributes, such as contrast and texture. Previous studies have suggested that, in the human visual system, these attributes are initially detected separately and integrated later. Thus, comparing the strength of different geometrical optical illusions in stimuli, in which different elements are defined by the same or different attributes, is helpful to investigate at which stage the underlying mechanism of the illusion is located. We investigated whether there is a single common mechanism underlying the Ebbinghaus illusion in stimuli defined by different attributes. We used the traditional Ebbinghaus (Titchener) illusion figure: a target disk surrounded by smaller or larger inducer disks. The background and stimuli consisted of sine-wave gratings. We manipulated the luminance, contrast, and grating orientations of the target disk and inducer disks to create stimuli defined by each of these attributes. We then examined whether the illusion occurred in stimuli defined by each single attribute and in compound stimuli, in which the target and inducers were defined by different attributes. We found that the Ebbinghaus illusion occurred with the same strength in stimuli defined by all three attributes. We also found an asymmetry, such as the second-order inducers affected the first-order target less than they affected the second-order targets, but the first-order inducers affected all targets similarly. Our findings suggest that different attributes are likely to be integrated into a cue-invariant shape representation prone to the Ebbinghaus illusion. However, first-order and second order stimuli may differently contribute to the quantitative aspect of the illusion, resulting in the asymmetric illusion strength. PMID- 29758215 TI - Increased Long-term Dietary Fiber Intake Is Associated With a Decreased Risk of Fecal Incontinence in Older Women. AB - BACKGROUND & AIMS: Fiber supplements are frequently used as treatment for fecal incontinence (FI), but little is known about the role of dietary fiber in the prevention of FI. METHODS: We performed a prospective study to examine the association between long-term dietary fiber intake and risk of FI in 58,330 older women (mean age, 73 years) in the Nurses' Health Study who were free of FI in 2008. Energy-adjusted long-term dietary fiber intake was determined using food frequency questionnaires starting in 1984 and updated through 2006. We defined incident FI as at least 1 liquid or solid FI episode per month during the past year during 4 years of follow-up using self-administered biennial questionnaires. We used Cox proportional hazards models to calculate multivariable-adjusted hazard ratios and 95% CIs for FI according to fiber intake, adjusting for potential confounding factors. RESULTS: During 193,655 person-years of follow-up, we documented 7,056 incident cases of FI. Compared with women in the lowest quintile of fiber intake (13.5 g/day), women in the highest quintile (25 g/day) had an 18% decrease in risk of FI (multivariable hazard ratio, 0.82; 95% CI, 0.76 0.89). This decrease appeared to be greatest for risk of liquid stool FI, which was 31% lower in women with the highest intake of fiber compared with women with the lowest intake (multivariable hazard ratio, 0.69; 95% CI, 0.62-0.75). Risk of FI was not significantly associated with fiber source. CONCLUSIONS: In an analysis of data from almost 60,000 older women in the Nurses' Health Study, we found higher long-term intake of dietary fiber was associated with decreased risk of FI. Further studies are needed to determine the mechanisms that mediate this association. PMID- 29758216 TI - Molecular Background of Colorectal Tumors From Patients With Lynch Syndrome Associated With Germline Variants in PMS2. AB - BACKGROUND & AIMS: Germline variants in mismatch repair genes MLH1, MSH2 (EPCAM), MSH6, or PMS2 cause Lynch syndrome. Patients with these variants have an increased risk of developing colorectal cancers (CRCs) that differ from sporadic CRCs in genetic and histologic features. It has been a challenge to study CRCs associated with PMS2 variants (PMS2-associated CRCs) because these develop less frequently and in older patients than CRCs with variants in other mismatch repair genes. METHODS: We analyzed 20 CRCs associated with germline variants in PMS2, 22 sporadic CRCs, 18 CRCs with germline variants in MSH2, and 24 CRCs from patients with germline variants in MLH1. Tumor tissue blocks were collected from Dutch pathology departments in 2017. After extraction of tumor DNA, we used a platform designed to detect approximately 3,000 somatic hotspot variants in 55 genes (including KRAS, APC, CTNNB1, and TP53). Somatic variant frequencies were compared using the Fisher exact test. RESULTS: None of the PMS2-associated CRCs contained any somatic variants in the catenin-beta1 gene (CTNNB1), which encodes beta-catenin, whereas 14 of 24 MLH1-associated CRCs (58%) contained variants in CTNNB1. Half the PMS2-associated CRCs contained KRAS variants, but only 20% of these were in hotspots that encoded G12D or G13D. These hotspot variants occurred more frequently in CRCs associated with variants in MLH1 (37.5%; P = .44) and MSH2 (71.4%; P = .035) than in those associated with variants in PMS2. CONCLUSIONS: In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes. This might account for differences in development and less frequent occurrence. PMID- 29758218 TI - Mathematical model of hypertension-induced arterial remodeling: A chemo mechanical approach. AB - The development of chronic hypertension is a poorly described process involving many chemical and structural changes to the artery. Typically, mathematical models of this disease focus primarily on the mechanical aspects such as arterial geometry, elasticity, and tissue content, or alternatively on the chemical drivers of vasoactivity such as nitric oxide and reactive oxygen species. This paper presents a model that considers the powerful interaction between mechanical and biochemical drivers of hypertension and arterial remodeling. Based on biological processes thought to be involved in the development of hypertension, we have built a system of algebraic, differential, and integral equations. Endothelial dysfunction, which is known to limit vasodilation, is explicitly considered in the model and plays a vital role in the development of chronic hypertension. Numerical solutions to the system are consistent with available experimental data for normal and spontaneously-hypertensive rats. PMID- 29758219 TI - Prostate Specific Antigen Density as a Predictor of Clinically Significant Prostate Cancer When the Prostate Specific Antigen is in the Diagnostic Gray Zone: Defining the Optimum Cutoff Point Stratified by Race and Body Mass Index. AB - PURPOSE: We assessed the predictive value of prostate specific antigen density to detect clinically significant prostate cancer, defined as prostate cancer grade group 2 or greater, in a series of men undergoing prostate biopsy with prostate specific antigen 4 to 10 ng/ml. We sought to define an optimum cutoff point for prostate specific antigen density and assess how race and body mass index affects prostate specific antigen density performance. MATERIALS AND METHODS: We analyzed data on 2,162 men, of whom 56% were African American, with serum prostate specific antigen 4 to 10 ng/ml who underwent prostate biopsy. We compared the AUC between prostate specific antigen and prostate specific antigen density to predict clinically significant and any prostate cancer vs no cancer. We calculated the negative predictive value of prostate specific antigen density cutoff points ranging from 0.05 to 0.15 by every 0.01 step. We a priori defined the optimal cutoff point of prostate specific antigen density as a negative predictive value of 95% and tested whether the cutoff was sensitive to body mass index and race by comparing the negative predictive value across strata. RESULTS: Median prostate specific antigen was 5.6 ng/ml (IQR 4.8-7) and median prostate specific antigen density was 0.15 ng/ml/cc (IQR 0.1-0.22). Prostate specific antigen density improved the performance of prostate specific antigen to detect significant cancer (AUC 0.58 to 0.68) and any cancer (AUC 0.55 to 0.69, each p <0.001). We identified a prostate specific antigen density cutoff point of less than 0.08 ng/ml/cc with a 96% negative predictive value for grade group 2 or greater. This was largely unchanged among different races and body mass indexes. CONCLUSIONS: Regardless of race or body mass index men with prostate specific antigen density less than 0.08 were unlikely to harbor grade group 2 or greater disease when prostate specific antigen was 4 to 10 ng/ml. If validated, prostate specific antigen density is a simple inexpensive and available tool that can be used to identify men who can likely forego prostate biopsies, thus reducing the over detection and morbidity of unnecessary biopsies. PMID- 29758220 TI - Evaluation of an Aggressive Prostate Biopsy Strategy in Men Younger than 50 Years. AB - PURPOSE: Longitudinal cohort studies and guidelines demonstrate that prostate specific antigen 1 ng/ml or greater in younger patients confers an increased risk of delayed prostate cancer death. At our institution we have used an aggressive biopsy strategy in younger patients with prostate specific antigen 1 ng/ml or greater. Our objective was to determine the proportion of detected cancer and specifically clinically significant cancer by this strategy. MATERIALS AND METHODS: The prostate biopsy database at Princess Margaret Cancer Centre was queried for patients younger than 50 years who underwent a first prostate biopsy between 2000 and 2016. We included only patients who underwent prostate biopsy due to prostate specific antigen 1 ng/ml or greater and those with a suspicious digital rectal examination, a positive family history or a suspicious lesion on transrectal ultrasound. All clinical and pathological parameters were analyzed. Patients were stratified according to specific prostate specific antigen values. Multivariable logistic regression was performed to ascertain predictors of any prostate cancer diagnosis and of clinically significant prostate cancer. RESULTS: Of the 199 patients who met study inclusion criteria 37 (19%) were diagnosed with prostate cancer and 8 (22%) had a Gleason score of 7 or greater. Of those diagnosed with prostate cancer 25 (68%) had prostate specific antigen 1.5 ng/ml or greater and all men with a Gleason score of 7 or greater had prostate specific antigen 1.5 ng/ml or greater. Notably 19 patients (51%) had prostate cancer exceeding the Epstein criteria for active surveillance. Factors predicting prostate cancer included a positive family history, rising prostate specific antigen and lower prostate volume. CONCLUSIONS: Our results justify adopting an aggressive prostate biopsy strategy in men younger than 50 years with prostate specific antigen 1.5 ng/ml or greater while patients with prostate specific antigen less than 1.5 ng/ml are unlikely to have significant cancer. Special attention should be given to patients with a smaller prostate and a positive family history. PMID- 29758221 TI - Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac. AB - Striatal cholinergic interneurons provide modulation to striatal circuits involved in voluntary motor control and goal-directed behaviors through their autonomous tonic discharge and their firing "pause" responses to novel and rewarding environmental events. Striatal cholinergic interneuron hyperactivity was linked to the motor deficits associated with Parkinson's disease and the adverse effects of chronic antiparkinsonian therapy like l-DOPA-induced dyskinesia. Here we addressed whether Kv7 channels, which provide negative feedback to excitation in other neuron types, are involved in the control of striatal cholinergic interneuron tonic activity and response to excitatory inputs. We found that autonomous firing of striatal cholinergic interneurons is not regulated by Kv7 channels. In contrast, Kv7 channels limit the summation of excitatory postsynaptic potentials in cholinergic interneurons through a postsynaptic mechanism. Striatal cholinergic interneurons have a high reserve of Kv7 channels, as their opening using pharmacological tools completely silenced the tonic firing and markedly reduced their intrinsic excitability. A strong inhibition of striatal cholinergic interneurons was also observed in response to the anti-inflammatory drugs diclofenac and meclofenamic acid, however, this effect was independent of Kv7 channels. These data bring attention to new potential molecular targets and pharmacological tools to control striatal cholinergic interneuron activity in pathological conditions where they are believed to be hyperactive, including Parkinson's disease. PMID- 29758223 TI - Letter to the editor. PMID- 29758222 TI - Differentiation of sow and mouse ovarian granulosa cells exposed to zearalenone in vitro using RNA-seq gene expression. AB - Zearalenone (ZEA), a natural contaminant found in feed, has been shown to have a negative impact on domestic animal reproduction, particularly in pigs. There are species-specific differences in the ZEA-induced toxicity pattern. Here, we investigated the different biological effects of ZEA exposure on porcine and mouse granulosa cells, using RNA-seq analysis. We treated murine and porcine granulosa cells with 10 MUM and 30 MUM ZEA during 72 h of culturing, in vitro. The results showed that 10 MUM ZEA exposure significantly altered mitosis associated genes in porcine granulosa cells, while the same treatment significantly altered the steroidogenesis associated genes in mouse granulosa cells. Exposure to 30 MUM ZEA resulted in significantly up-regulated expression of inflammatory related genes in porcine granulosa cells as well as the cancer related genes in mouse granulosa cells. Similarly, 30 MUM ZEA exposure significantly decreased the expression of tumor suppressor factors in the mouse granulosa cells. Furthermore, immunofluorescence, RT-qPCR as well as western-blot analysis verified the different expression of related genes in ZEA exposed porcine and mouse granulosa cells. Collectively, these results illustrate the presence of species differences with regards to ZEA effects between porcine and mouse ovarian granulosa cells, in vitro. PMID- 29758224 TI - Humanised recombinant antibody fragments bind human pancreatic islet cells. AB - We describe here the humanisation of two mouse monoclonal antibodies that bind to surface markers on human pancreatic islet endocrine cells. Monoclonal antibodies produced by the HIC1-2B4 and HIC0-4F9 mouse hybridomas bind distinct surface molecules expressed on endocrine cells and have been validated for a number of experimental methods including immunohistochemistry and live cell sorting by flow cytometry. Variable region framework and first constant region domain sequences were replaced with that from compatible human antibody sequences, and the resulting recombinant antigen-binding fragments were cloned and expressed in mouse myeloma cells. ELISA, fluorescent immunohistochemistry, and flow cytometry were used to assess the specificity of the humanised antibody fragments. Purification and binding analyses indicated that human islet endocrine cell binding was retained in the humanised antibody fragments. These humanised, recombinant antibody fragments have a lower risk of eliciting adverse responses from a patient's immune system and, therefore, have highly improved clinical potential. Thus, they may be used to image, target or carry cargo specifically to islet cells in human patients. PMID- 29758225 TI - TRPV6 protects ER stress-induced apoptosis via ATF6alpha-TRPV6-JNK pathway in human embryonic stem cell-derived cardiomyocytes. AB - Human pluripotent stem cell-derived cardiomyocytes have potential applications in disease modeling and drug screening. Therefore, it is important to understand the mechanisms and signaling pathways underlying the survival and death of these cells. Endoplasmic reticulum (ER) stress is triggered by various cellular stresses that disturb protein folding in the ER. Cells cope with ER stress by activating the unfolded protein response (UPR), a homeostatic signaling network that orchestrates the recovery of ER function. In the present study, we hypothesized that ER stress may upregulate the expression of transient receptor potential channel TRPV6, which in turn serves to protect human embryonic stem cell-derived cardiomyocytes (hESC-CMs) from ER stress-induced apoptotic cell death. Indeed, we found that ER stress induced by thapsigargin and tunicamycin led to increased expression of TRPV6 via ATF6alpha signaling branch. siRNA mediated knockdown of TRPV6 aggravated ER stress-induced apoptotic cell death, whereas overexpression of TRPV6 attenuated ER stress-induced apoptosis in hESC CMs. Furthermore, the signaling pathway downstream of TRPV6 was MAPK-JNK. Taken together, these results provide strong evidence that, under ER stress, TRPV6 is upregulated to protect hESC-CMs from apoptotic cell death via ATF6alpha-TRPV6-JNK pathway. PMID- 29758226 TI - Phytophagous larvae occurring in Central and Southeastern European oak forests as a potential host of Entomophaga maimaiga (Entomophthorales: Entomophthoraceae) - A field study. AB - We evaluated the presence and impact of Entomophaga maimaiga on both target and non-target phytophagous larvae. All six study plots, with low gypsy moth population density, were situated in Central and Southeastern European oak forests and E. maimaiga had previously been reported from these plots. Totally, 45 of 4,045 (1.13%) collected non-target larvae died due to fungal infections. No non-target insect specimen was infected by E.maimaiga, although the presence of the pathogen could not be fully excluded in three cadavers. Out of 1,780L.dispar larvae collected, 15individuals (0.84%) were infected by E.maimaiga. PMID- 29758227 TI - Effects of feedback delay on learning from positive and negative feedback in patients with Parkinson's disease off medication. AB - Phasic dopamine (DA) signals conveyed from the substantia nigra to the striatum and the prefrontal cortex crucially affect learning from feedback, with DA bursts facilitating learning from positive feedback and DA dips facilitating learning from negative feedback. Consequently, diminished nigro-striatal dopamine levels as in unmedicated patients suffering from Parkinson's Disease (PD) have been shown to lead to a negative learning bias. Recent studies suggested a diminished striatal contribution to feedback processing when the outcome of an action is temporally delayed. This study investigated whether the bias towards negative feedback learning induced by a lack of DA in PD patients OFF medication is modulated by feedback delay. To this end, PD patients OFF medication and healthy controls completed a probabilistic selection task, in which feedback was given immediately (after 800 ms) or delayed (after 6800 ms). PD patients were impaired in immediate but not delayed feedback learning. However, differences in the preference for positive/negative learning between patients and controls were seen for both learning from immediate and delayed feedback, with evidence of stronger negative learning in patients than controls. A Bayesian analysis of the data supports the conclusion that feedback timing did not affect the learning bias in the patients. These results hint at reduced, but still relevant nigro-striatal contribution to feedback learning, when feedback is delayed. PMID- 29758228 TI - Differences in swallow physiology in patients with left and right hemispheric strokes. AB - BACKGROUND: We sought to determine the impact of lesion lateralization and lesion volume on swallow impairment on group-level by comparing patients with left and right hemisphere strokes and on patient-level by analyzing patients individually. METHODS: We performed a retrospective, observational, cross-sectional study of 46 patients with unilateral (22 left, 24 right), acute, first-ever, ischemic strokes who received a diffusion weighted MRI (DW-MRI) and modified barium swallow study (MBSS) during their acute hospital stay. We determined lesion side on the DW-MRI and measured swallow physiology using the Modified Barium Swallow Impairment Profile (MBSImPTM(c)), Penetration-Aspiration Scale (PAS), swallow timing, distance, area, and speed measures. We performed Pearson's Chi-Square and Wilcoxon Rank-Sum tests to compare patients with left and right hemisphere strokes, and Pearson or Spearman correlation, simple logistic regression, linear, and logistic multivariable regression modeling to assess the relationship between variables. RESULTS: At the group-level, there were no differences in MBSImP oral swallow impairment scores between patients with left and right hemisphere stroke. In adjusted analyses, patients with right hemisphere strokes showed significantly worse MBSImP pharyngeal total scores (p = 0.02), worse MBSImP component specific scores for laryngeal vestibular closure (Bonferroni adjusted alpha p <= 0.0029), and worse PAS scores (p = 0.03). Patients with right hemisphere strokes showed worse timing, distance, area, and speed measures. Lesion volume was significantly associated with MBSImP pharyngeal residue (p = 0.03) and pharyngeal total scores (p = 0.04). At the patient-level, 24% of patients (4 left, 7 right) showed opposite patterns of MBSImP oral and pharyngeal swallow impairment than seen at group-level. CONCLUSION: Our study showed differences in swallow physiology between patients with right and left unilateral strokes with patients with right hemisphere strokes showing worse pharyngeal impairment. Lesion lateralization seems to be a valuable marker for the severity of swallowing impairment at the group-level but less informative at the patient-level. PMID- 29758229 TI - Intraabdominal and Pelvic actinomycosis in association with posterior reversible encephalopathy syndrome (PRES): A case report. PMID- 29758230 TI - Vaccination with UV-inactivated nodavirus partly protects European sea bass against infection, while inducing few changes in immunity. AB - Developing viral vaccines through the ultraviolet (UV) inactivation of virus is promising technique since it is straightforward and economically affordable, while the resulting viruses are capable of eliciting an adequate antiviral immune response. Nodavirus (NNV) is a devastating virus that mainly affects European sea bass juveniles and larvae, causing serious economic losses in Mediterranean aquaculture. In this work, a potential vaccine consisting on UV-inactivated NNV (iNNV) was generated and administered to healthy juveniles of European sea bass to elucidate whether it triggers the immune response and improves their survival upon challenge. First, iNNV failed to replicate in cell cultures and its intraperitoneal administration to sea bass juveniles also failed to produce fish mortality and induction of the type I interferon (IFN) pathway, indicating that the NNV was efficiently inactivated. By contrast, iNNV administration induced significant serum non-specific antimicrobial activity as well as a specific antiviral activity and immunoglobulin M (IgM) titres against NNV. Interestingly, few changes were observed at transcriptional level in genes related to either innate or adaptive immunity, suggesting that iNNV could be modulating the immune response at protein or functional level. In addition, the iNNV vaccinated group showed improved survival, reaching a relative survival percentage of 57.9%. Moreover, challenged fish that had been vaccinated presented increased serum antibacterial, antiviral and IgM titres, as well as the higher transcription of mhc1a, ifn, isg15 and cd8a genes in brain, while in the head-kidney the transcription of mhc1a, mhc2b and cd8a was down-regulated and mx, isg15 and tcrb was up-regulated. Although the UV-inactivated vaccine against NNV showed promising results, more effort should be addressed to improving this prophylactic method by increasing our understanding of its action mechanisms, thus enabling the mortality rate of NNV to be further reduced. PMID- 29758232 TI - A review of brain insulin signaling in mood disorders: From biomarker to clinical target. AB - Patients with mood disorders are at increased risk for metabolic dysfunction. Co occurrence of the two conditions is typically associated with a more severe disease course and poorer treatment outcomes. The specific pathophysiological mechanisms underlying this bidirectional relationship between mood and metabolic dysfunction remains poorly understood. However, it is likely that impairment of metabolic processes within the brain play a critical role. The insulin signaling pathway mediates metabolic homeostasis and is important in the regulation of neurotrophic and synaptic plasticity processes, including those involved in neurodegenerative diseases like Alzheimer's. Thus, insulin signaling in the brain may serve to link metabolic function and mood. Central insulin signaling is mediated through locally secreted insulin and widespread insulin receptor expression. Here we review the preclinical and clinical data addressing the relationships between central insulin signaling, cellular metabolism, neurotrophic processes, and mood regulation, including key points of mechanistic overlap. These relationships have important implications for developing biomarker based diagnostics and precision medicine approaches to treat severe mood disorders. PMID- 29758231 TI - Infiltrating macrophages contribute to age-related neuroinflammation in C57/BL6 mice. AB - The recognized role of neuroinflammation in the age-related deterioration of neuronal function highlights the importance of understanding the factors that control microglial activation. Microglia, as the immune cells of the brain, are the arbiters of the inflammatory profile in the brain. Normally they are maintained in a quiescent state by means of ligand-receptor interactions with neurons, within a prevailing anti-inflammatory microenvironment. The evidence indicates that, as the ageing process continues, microglia become activated, shift towards an inflammatory phenotype and alter the milieu in the brain. Although there has been progress in identifying factors that contribute to age related microglial activation, our understanding remains incomplete. Here we report that there was an age-related increase in circulating inflammatory cytokines, accompanied by microglial activation. Neutrophils, and to a greater extent, macrophages, infiltrate the brain with age, perhaps as a result of increased chemokine expression in the brain, specifically CXCL1 and CCL2. We sought to determine whether macrophages might trigger microglial activation and the evidence shows that conditioned medium obtained from interferon-gamma (IFNgamma)-stimulated macrophages potently activated microglia. The data suggest that infiltrating macrophages may be one factor that contributes to age-related microglial activation. PMID- 29758234 TI - A validation of dynamic causal modelling for 7T fMRI. AB - BACKGROUND: There is growing interest in ultra-high field magnetic resonance imaging (MRI) in cognitive and clinical neuroscience studies. However, the benefits offered by higher field strength have not been evaluated in terms of effective connectivity and dynamic causal modelling (DCM). NEW METHOD: In this study, we address the validity of DCM for 7T functional MRI data at two levels. First, we evaluate the predictive validity of DCM estimates based upon 3T and 7T in terms of reproducibility. Second, we assess improvements in the efficiency of DCM estimates at 7T, in terms of the entropy of the posterior distribution over model parameters (i.e., information gain). RESULTS: Using empirical data recorded during fist-closing movements with 3T and 7T fMRI, we found a high reproducibility of average connectivity and condition-specific changes in connectivity - as quantified by the intra-class correlation coefficient (ICC = 0.862 and 0.936, respectively). Furthermore, we found that the posterior entropy of 7T parameter estimates was substantially less than that of 3T parameter estimates; suggesting the 7T data are more informative - and furnish more efficient estimates. COMPARED WITH EXISTING METHODS: In the framework of DCM, we treated field-dependent parameters for the BOLD signal model as free parameters, to accommodate fMRI data at 3T and 7T. In addition, we made the resting blood volume fraction a free parameter, because different brain regions can differ in their vascularization. CONCLUSIONS: In this paper, we showed DCM enables one to infer changes in effective connectivity from 7T data reliably and efficiently. PMID- 29758235 TI - Innovation and trends in the development and approval of antiviral medicines: 1987-2017 and beyond. AB - 2017 marked the 30th anniversary of the approval of zidovudine (AZT) as the first HIV/AIDS therapy. Since then, more than eighty antiviral drugs have received FDA approval, half of which treat HIV infection. Here, we provide a retrospective analysis of approved antiviral drugs, including therapeutics against other major chronic infections such as hepatitis B and C, and herpes viruses, over the last thirty years. During this time, only a few drugs were approved to treat acute viral infections, mainly influenza. Analysis of these approved antiviral drugs based on molecular class and mode of action shows that a large majority are small molecules and direct-acting agents as opposed to proteins, peptides, or oligonucleotides and host-targeting therapies. In addition, approvals of combination therapies accelerated over the last five years. We also provide a prospective study of future potential antiviral therapies, based on current clinical research pipelines across the pharmaceutical industry. Comparing past drug approvals with current clinical candidates hints at the future evolution in antiviral therapies and reveals how antiviral medicines are often discovered. Overall, this work helps forecast future trends and innovation in the field of antiviral research and development. PMID- 29758233 TI - Longitudinal assessment of ultrasound-guided complementary microRNA therapy of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second-leading cause of cancer related deaths worldwide and new strategies to efficiently treat HCC are critically needed. The aim of this study was to assess the longitudinal treatment effects of two complementary miRNAs (miRNA-122 and antimiR-21) encapsulated in biodegradable poly lactic-co-glycolic acid (PLGA) - poly ethylene glycol (PEG) nanoparticles (PLGA-PEG-NPs), administered by an ultrasound-guided and microbubble-mediated delivery approach in doxorubicin-resistant and non-resistant human HCC xenografts. Using in vitro assays, we show that repeated miRNA treatments resulted in gradual reduction of HCC cell proliferation and reversal of doxorubicin resistance. Optimized US parameters resulted in a 9-16 fold increase (p = 0.03) in miRNA delivery in vivo in HCC tumors after two US treatments compared to tumors without US treatment. Furthermore, when combined with doxorubicin (10 mg/kg), longitudinal miRNA delivery showed a significant inhibition of tumor growth in both resistant and non-resistant tumors compared to non-treated, and doxorubicin treated controls. We also found that ultrasound guided miRNA therapy was not only effective in inhibiting HCC tumor growth but also allowed lowering the dose of doxorubicin needed to induce apoptosis. In conclusion, the results of this study suggest that ultrasound-guided and MB mediated delivery of miRNA-122 and antimiR-21, when combined with doxorubicin, is a highly effective approach to treat resistant HCC while reducing doxorubicin doses needed for treating non-resistant HCC in longitudinal treatment experiments. Further refinement of this strategy could potentially lead to better treatment outcomes for patients with HCC. PMID- 29758236 TI - Identification of Compound-B, a novel anti-dengue virus agent targeting the non structural protein 4A. AB - Dengue virus (DENV) is the causative agent of dengue fever and dengue hemorrhagic fever/dengue shock syndrome. At present, no antiviral drugs are available for treatment DENV infections. In this study, a screening system based on a DENV infected cell-based assay identified a novel anti-DENV agent with a benzimidazole skeleton, named Compound-B, which demonstrated antiviral activity specific to four DENV serotypes (EC50: 1.32-4.12 MUM). Analysis of a single amino acid substitution of Compound-B-resistant DENV2 revealed that mutation C87S in the non structural protein 4A (NS4A) contributes to resistance to Compound-B. PMID- 29758238 TI - Electrophysiological correlates of timbre imagery and perception. AB - The primary objective of the present study was to verify whether the differences in imagined timbre are reflected by the event-related potentials (ERPs). It was verified the hypotheses that imagining of sounds, varying in spectral characteristics of timbre, influence the amplitude of the late positive component (LPC), associated with auditory imagery-related processes. It was also verified whether the manipulation of the perceived timbre corresponds to the amplitude fluctuations of the auditory evoked potentials (AEPs) N1 and P2. Also, it was expected that the amplitudes of the LPC, N1 and P2 components depend on musical expertise. Musicians and non-musicians took part in two experiments, each of which involved timbre manipulation in term of one parameter of the sound spectrum - spectral centroid or spectral irregularity. Each experiment consisted of auditory perception task followed by auditory imagery training and auditory imagery task. The present study showed that differences in perceived timbre associated with spectral centroid and spectral irregularity are reflected by fluctuations in the amplitude of the N1 and P2 potentials. Perceived differences in spectral centroid are sufficiently distinctive that generation of auditory images of sounds differing in this property induces changes in the amplitude of the late positive component (LPC), recorded during auditory imagery. This means that the LPC is sensitive to changes in the timbre of the imagined sound. Musicians are more accurate in performing auditory imagery task related to timbre than non-musicians. However, musical expertise does not affect the amplitude of the N1, P2 and LPC potentials. PMID- 29758237 TI - Rapid detection of hand, foot and mouth disease enterovirus genotypes by multiplex PCR. AB - Hand, foot and mouth disease (HFMD) is a pediatric disease associated with infection by enterovirus (EV) genotypes. The major HFMD EV pathogens are enterovirus A71 (EVA71) and coxsackievirus A16 (CVA16); however, recently, coxsackievirus A6 (CVA6) and coxsackievirus A10 (CVA10) have also emerged. EV genotypes cannot be distinguished on clinical grounds and a new methodology for the rapid detection of the four major HFMD EV genotypes is urgently required. In the present study, a multiplex real-time PCR assay was established for the simultaneous detection of CVA6, CVA10, CVA16 and EVA71. The specificity and sensitivity of the assay was determined on a validation panel of clinical samples, comprising cerebrospinal fluid (n = 51), blood (n = 39), feces (n = 58) and throat swabs (n = 29). The results showed that the multiplex real-time PCR exhibited high specificity, no cross-reactivity with other EV genotypes, lower limits of detection for CVA6, CVA10, CVA16 and EVA71 were 4 * 103, 4 * 102, 5 * 102, and 3 * 103 copies/MUL, respectively and had comparable sensitivity to singleplex assays testing clinical samples. The multiplex real-time PCR methodology established in this study can be employed for the rapid detection of the four most prevalent HFMD-associated EVs, for epidemiologic surveillance of circulating EV genotypes and for assessing treatment responses and vaccine studies. PMID- 29758239 TI - The use of MEMRI for monitoring central nervous system activity during intact insect walking. AB - BACKGROUND: Monitoring neuronal activity in the intact behaving animal is most desired in neuroethological research, yet it is rarely straightforward or even feasible. Here we present the use of manganese enhanced magnetic resonance imaging (MEMRI), a technique allowing monitoring the activity of an animal's nervous system during specific behavioral patterns. Using MEMRI we were able to show activity in different ganglia of the central nervous system of intact locusts during walking. RESULTS: We injected two groups of locusts with manganese, which serves as a magnetic contrast agent. One group was forced to walk on a treadmill for two hours, while the other was immobilized and served as a control. Subsequently, all animals were scanned in a T1 MRI protocol, and the accumulation of manganese in the neuronal tissues that were active during walking was demonstrated by comparing the scans of the two groups. Two neuronal sites showed significantly higher T1 signal in the walking locusts compared to the immobilized ones: the prothoracic ganglion, which locally controls the front legs, and the subesophageal ganglion, a head ganglion which takes part in initiation and maintenance of walking. CONCLUSION: MEMRI is a potent, non invasive technique for monitoring neuronal activity in intact locusts, and arthropods in general. Specifically, it provides a promising way for revealing the role of central and high-order neuronal structures in motor behaviors such as walking. PMID- 29758240 TI - Imidacloprid intensifies its impact on honeybee and bumblebee cellular immune response when challenged with LPS (lippopolysacharide) of Escherichia coli. AB - Insect hemocytes play an important role in insects' defense against environmental stressors as they are entirely dependent on their innate immune system for pathogen defense. In recent years a dramatic decline of pollinators has been reported in many countries. The drivers of this declines appear to be associated with pathogen infections like viruses, bacteria or fungi in combination with pesticide exposure. The aim of this study was thus to investigate the impact of imidacloprid, a neonicotinoid insecticide, on the cellular immune response of two pollinators (Apis mellifera and Bombus terrestris) during simultaneous immune activation with LPS (lipopolysaccharide) of Escherichia coli. For this purpose the phagocytosis capacity as well as the production of H2O2 and NO of larval hemocytes, exposed to five different imidacloprid concentrations in vitro, was measured. All used pesticide concentrations showed a weakening effect on phagocytosis with but also without LPS activation. Imidacloprid decreased H2O2 and increased NO production in honeybees. Immune activation by LPS clearly reinforced the effect of imidacloprid on the immune response of hemocytes in all three immune parameters tested. Bumblebee hemocytes appeared more sensitive to imidacloprid during phagocytosis assays while imidacloprid showed a greater impact on honeybee hemocytes during H2O2 and NO production. PMID- 29758241 TI - Targeting the CD73-adenosine axis in immuno-oncology. AB - The ectonucleotidases CD39 and CD73 are cell surface enzymes that catabolize the breakdown of extracellular ATP into adenosine. As such, they constitute critical components of the extracellular purinergic pathway and play important roles in maintaining tissue and immune homeostasis. With the coming of age of cancer immunotherapy, ectonucleotidases and adenosine receptors have emerged as novel therapeutic targets to enhance antitumor immune responses. With early-phase clinical trials showing promising results, it is becoming increasingly important to decipher the distinct mechanisms-of-action of adenosine-targeting agents, identify patients that will benefit from these agents and rationally develop novel synergistic combinations. Given the broad expression of ectonucleotidases and adenosine receptors, a better understanding of cell-specific roles will also be key for successful implementation of this new generation of immuno-oncology therapeutics. We here review the latest studies on the roles of CD73 and adenosine in cancer with a focus on cell-specific function. We also discuss ongoing clinical trials and future avenues for adenosine-targeting agents. PMID- 29758243 TI - Mechanisms of directed evolution of morphological structures and the problems of morphogenesis. AB - Morphogenesis mechanisms are considered from the point of view of complexity. It has been shown that the presence of long-range interactions between biologically important molecules is a necessary condition for the formation and stable operation of morphological structures. A quantum model of morphogenesis based on non-Archimedean analysis and the presence of long-range interactions between biologically important molecules has been constructed. This model shows that the evolution of morphological structures essentially depends on the availability of a priori information on these structures. Critical steps in evolution related to the most important morphological and behavioral findings have been analyzed; the results have shown that the implementation of such steps can only be explained within the framework of a partially directed evolution. Thus, the previously proposed model for a partially directed evolution is established for modeling the evolution of morphological structures. PMID- 29758242 TI - Diagnostic accuracy of nucleic acid amplification based assays for tuberculous meningitis: A meta-analysis. AB - BACKGROUND: Numerous in-house and commercial nucleic acid amplification tests (NAAT) have been evaluated using variable reference standards for diagnosis of TBM but their diagnostic potential is still not very clear. METHODS: We conducted a meta-analysis to assess the diagnostic accuracy of different NAAT based assays for diagnosing TBM against 43 data sets of confirmed TBM (n = 1066) and 61 data sets of suspected TBM (n = 3721) as two reference standards. The summary estimate of the sensitivity and the specificity were obtained using the bivariate model. QUADAS-2 tool was used to perform the Quality assessment for bias and applicability. Publication bias was assessed with Deeks' funnel plot. RESULTS: Studies with confirmed TBM had better summary estimates as compared to studies with clinically suspected TBM irrespective of NAAT and index tests used. Among in house assays, MPB as the gene target had best summary estimates in both confirmed [sensitivity:90%(83-95), specificity:97-%(87-99), DOR:247 (50-1221), AUC:99%(97 100), PLR:38.8-(6.6-133), NLR:0.11(0.05-0.18), I2 = 15%] and clinically suspected [sensitivity:69%(47-85), specificity:96%(90-98), DOR:62(16.8-232), AUC:94%(92 97), PLR:16.9(6.5-36.8), NLR:0.33(0.16-0.56), I2:15.3%] groups. GeneXpert revealed good diagnostic accuracy only in confirmed TBM group [sensitivity = 57%(38-74), specificity = 98%(89-100), DOR = 62(7-589), AUC = 87%(79-96), PLR = 33.2(3.8-128), NLR = 0.45(0.26-0.68), I2 = 0%]. CONCLUSIONS: This meta-analysis identified potential role of MPB gene among in-house assays and GeneXpert as commercial assay for diagnosing TBM. PMID- 29758245 TI - Validation and comparison of ELISA kits to measure interferon gamma responses in QuantiFERON cultural supernatants for diagnosis of tuberculosis. AB - Much effort has been made to reduce the cost of LTBI diagnosis with equivalent efficacy and efficiency of interferon-gamma release assay (IGRA). This study showed that repeatability, intermediate precision, and accuracy of the Bionote ELISA were comparable to QFT-ELISA. The Bionote-ELISA could provide the alternative method. PMID- 29758246 TI - Creation of deletion and insertion clonal complex 8 Staphylococcus aureus mutants using a common cloning vector. AB - Deletion and insertion clonal complex 8 Staphylococcus aureus mutants were created without using intermediate host S. aureus RN4220 or temperature-sensitive shuttle vectors. These mutants were created using a common cloning vector by passing the constructs through a modification host and recovering the electroporated cells in a large volume of medium. PMID- 29758247 TI - Individual behavioural predictors of amphetamine-induced emission of 50 kHz vocalization in rats. AB - Measurement of ultrasonic vocalizations (USVs) produced by adult rats represents a highly useful index of emotional arousal. The associations found between 50 kHz USV production and a variety of behavioural and pharmacological protocols increasingly suggests they serve as a marker of positive motivational states. This study used a powerful within-subjects design to investigate the relationships among individual differences in approach to a sweet-food reward, predisposition to emit 50 kHz USVs spontaneously, and 50 kHz USVs emission following acute systemic administration of amphetamine. Both approach motivation and predisposition to call were found to not correlate with each other but did predict 50 kHz USV response to acute amphetamine. These two behavioural phenotypes appear to represent dissociable predictors of acute amphetamine induced emission of 50 kHz USVs in a non-sensitization paradigm. In contrast to that, a measure of sucrose preference was not found to predict 50 kHz USV emission following amphetamine. Acute amphetamine was also found to increase average sound frequency of emitted USVs and selectively increase the proportion of Trill subtype 50 kHz USVs. Together, these data demonstrate that acute amphetamine-induced 50 kHz USVs in the adult rat represent more than just a univariate motivational state and may represent the product of dissociable subsystems of emotional behavior. PMID- 29758248 TI - Beneficial effect of etazolate on depression-like behavior and, learning, and memory impairment in a model of Parkinson's disease. AB - The aim of this study was to evaluate etazolate against depression-like behavior and, learning and memory impairment induced by 6- hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD). This aim was achieved through comparing 6-OHDA lesioned rats in the presence and absence of etazolate. The 6-OHDA was used to induce lesion as a model of PD. Etazolate was administered at a dose of 1 mg/kg/day for 14 days, starting 7 days after lesion induction. Apomorphine induced rotation test was used to evaluate 6-OHDA-induced motor deficits, tail suspension test was used to assess depression-like symptoms, and the radial arms water maze (RAWM) was used to evaluate special learning and memory functions. Antioxidant biomarkers and BDNF protein levels were assessed in the hippocampus. Results revealed that etazolate administration significantly improved 6-OHDA induced PD related symptoms including motor deficits, depression-like behavior and impairment of both short- and long- term memory. Moreover, etazolate significantly prevented 6-OHDA-induced reduction in oxidative stress biomarkers (GSH/GSSG ratio, GPx) and BDNF levels. In conclusion, motor dysfunction, depressive- like behavior, and learning and memory deficits in the 6-OHDA rat model of PD can be significantly prevented by etazolate. This prevention could be attributed to etazolate's ability to prevent reduction in antioxidative stress biomarkers and BDNF levels. PMID- 29758249 TI - Are laboratory studies on behavior of troglobitic species always trustful? A case study with an isopod from Brazil. AB - There is a huge lack of information regarding the natural history of subterranean species, particularly focusing on aspects of the behavioral ecology of Brazilian cave fauna. In the present work, we aimed to describe and evaluate the behavioral repertoire of Xangoniscus itacarambiensis (Isopoda, Styloniscidae) through observations in the field and laboratory and also by means of complementary experiments. Overall, we recorded 25 spontaneous behaviors. Besides describing the physical habitat, we recorded some intraspecific interactions, agonistic and territorial behaviors, as well as the amphibian habit. There was a direct relationship between the size of travertine dams where they live (measurements of length and width) and the mean number of individuals, although there was no significant correlation with the pool depth. Behaviors observed in the laboratory differed qualitatively and quantitatively from those observed in the field, with individuals more active in the latter. This scenario alerts about the significant behavioral alteration of such isopods when removed from their natural habitat, what must be considered in future behavioral studies including troglobites given their natural sensitivity to environmental changes. PMID- 29758250 TI - Mechanisms associated with the effects of urea on the micellar structure of sodium dodecyl sulphate in aqueous solutions. AB - We used simulations by Molecular Dynamics to characterize the mechanism whereby the variations in the urea concentration modifies the micellar structure of sodium dodecyl sulfate monomers in water. From a self-assembled micellar system, we observed that increasing urea concentration leads to a decrease in aggregation number. Likewise, when increasing urea concentration, the micelles increase their nonpolar surface exposed to solvent, while the polar surface exposed to solvent decreases. This rearrangement process of SDS micelles in presence of urea is mainly due to the fact that the ions of Na+ that stabilize the micellar structure increase its interaction with urea. In this process, the SDS hydrophilic head and Na+ ions increases its solvation by urea, destabilizing micellar structure and exponing the hydrophobic core to the solvent. PMID- 29758251 TI - Response to Aho Glele et al. PMID- 29758244 TI - Neural stem cell therapies and hypoxic-ischemic brain injury. AB - Hypoxic-ischemic brain injury is a significant cause of morbidity and mortality in the adult as well as in the neonate. Extensive pre-clinical studies have shown promising therapeutic effects of neural stem cell-based treatments for hypoxic ischemic brain injury. There are two major strategies of neural stem cell-based therapies: transplanting exogenous neural stem cells and boosting self-repair of endogenous neural stem cells. Neural stem cell transplantation has been proved to improve functional recovery after brain injury through multiple by-stander mechanisms (e.g., neuroprotection, immunomodulation), rather than simple cell replacement. Endogenous neural stem cells reside in certain neurogenic niches of the brain and response to brain injury. Many molecules (e.g., neurotrophic factors) can stimulate or enhance proliferation and differentiation of endogenous neural stem cells after injury. In this review, we first present an overview of neural stem cells during normal brain development and the effect of hypoxic ischemic injury on the activation and function of endogenous neural stem cells in the brain. We then summarize and discuss the current knowledge of strategies and mechanisms for neural stem cell-based therapies on brain hypoxic-ischemic injury, including neonatal hypoxic-ischemic brain injury and adult ischemic stroke. PMID- 29758252 TI - Depression-resistant Phenotype in Mice Overexpressing Regulator of G Protein Signaling 8 (RGS8). AB - Regulator of G protein signaling (RGS) proteins are negative regulators of heterotrimeric G proteins that act by accelerating Galpha-mediated GTPase activity to terminate G protein-coupled receptor-associated signaling. RGS8 is expressed in several brain regions involved with movement and mood. To investigate the role of RGS8 in vivo, we generated transgenic mice overexpressing brain RGS8 (RGS8tg). RGS8 gene and protein expressions were examined by real-time PCR and immunohistochemistry, respectively, and a significant increase in RGS8 protein was detected in the hippocampal CA1 region compared with wild-type mice (WT). We characterized the phenotypic traits, and found that RGS8tg showed decreased depressive-like behavior in the forced swimming test (FST). Previously, RGS8 was identified as a potent negative regulator of melanin-concentrating hormone receptor 1 (MCHR1), whose activation is mainly involved in energy homeostasis and emotional processing. Interestingly, acute oral administration of MCHR1 antagonist SNAP94847 did not have antidepressant-like effects on RGS8tg in the FST, but did show antidepressant effects on WT. In contrast, selective noradrenaline reuptake inhibitor desipramine had a significant effect on RGS8tg in the FST. MCHR1 is enriched in a subset of primary cilia, as sensory organelles that mediate extracellular signaling. Immunohistochemical analyses revealed significant elongation of MCHR1-positive cilia in the CA1 region of RGS8tg compared with WT. Taken together, these findings suggest that RGS8 participates in modulation of depression-like behavior through ciliary MCHR1 expressed in the CA1 region. The present study may support the possible modulation of RGS8 function in mood disorders. PMID- 29758253 TI - Responsive Neural Activities in the Primary Visual Cortex of Retina-Degenerated Rats. AB - To study the responsive neural activities in the primary visual cortex (V1) of retinal degeneration (RD) models, experiments involving the wild-type (WT) and RD rats were conducted. The neural responses in the V1 were recorded extracellularly, while a visual stimulus with varied light intensity was given to the subjects. First, the firing rate and its relationship with light intensity were compared between the WT and RD groups. Second, the mutual information (MI) between the visual stimulus and neural response was determined for every isolated unit to quantify the amount and efficiency of information transmission in the V1 for both the control and experimental groups. Third, the local field potential (LFP) signal was characterized and its power used to compute the MI and further evaluate the function change in the RD model regarding information transmission. Analysis of spiking activity showed that the RD group exhibited a relatively decreased firing rate, information amount and efficiency compared with the control group. However, the information transmission performance of the RD model was similar to that of the WT group in the context of LFP activity. Therefore, for the RD rats, the early stage of the visual system was impaired, while the later stage of the visual system, V1, was able to capture the information about the visual stimulus, especially at the population level. Thus, this pathway could be used to restore visual ability, such as by visual prostheses. PMID- 29758254 TI - GDNF family receptor alpha-1 in the catfish: Possible implication to brain dopaminergic activity. AB - Glial cell line-derived neurotrophic factor (GDNF)is a potent trophic factor that preferentially binds to GDNF family receptor alpha-1 (GFRalpha-1)by regulating dopaminergic (DA-ergic) neuronsin brain. Present study aimed to evaluate the significance of GFRalpha-1 expression during early brain development in catfish. Initially, the full-length cDNA of GFRalpha-1 was cloned from adult brain which showed high homology with other vertebrate counterparts. Quantitative PCR analysis of tissue distribution revealed ubiquitous expression of GFRalpha-1 in the tissues analyzed with high levels in female brain and ovary. Significant high expression was evident in brain at 75 and 100 days post hatch females than the respective age-match males. Expression of GFRalpha-1 was high in brain during the spawning phase when compared to other reproductive phases. Localization of GFRalpha-1 revealed its presence in preoptic area-hypothalamus which correlated well with the expression profile in discrete areas of brain in adult catfish. Transient silencing of GFRalpha-1through siRNA lowered expression levels of GFRalpha-1, which further down regulated the expression of certain brain-specific genes. Expression of GFRalpha-1 in brain declined significantly upon treatment with the 1-methyl-1,2,3,6-tetrahydropyridinecausing neurodegeneration which further correlated with catecholamines (CA), L-3,4-dihydroxyphenylalanine, DA and norepinephrine levels. Taken together, GFRalpha-1 plausibly entrains gonadotropin releasing hormone and gonadotropin axiseither directly or indirectly, at least by partially targeting CA-ergic activity. PMID- 29758255 TI - Do traditional techniques produce better conventional complete dentures than simplified techniques? A 10-year follow-up of a randomized clinical trial. AB - OBJECTIVES: The use of a simplified method (S) of fabricating complete dentures has been shown to be more cost-efficient than the traditional method (T), and there are no negative consequences that detract from the cost savings in the short term. However, it is not clear whether this remains constant over a decade. The objective of this study was to clarify patients' perspectives and determine any differences between the dentures fabricated with these two different techniques after a decade of use. MATERIAL AND METHODS: Edentate individuals participated in a randomized controlled clinical trial and completed a 6-month follow-up from 2001 to 2003 (T group n = 50; S group n = 54). For this 10-year follow-up, they were interviewed by telephone. The assessment included whether the denture was still in use or replaced, the condition of the dentures, patient satisfaction and oral health-related quality of life (OHRQoL). Between and within group differences and the factors that cause deterioration of oral health-related quality of life (OHRQoL) were determined. RESULTS: Among 54 responders (25 T and 29 S), 14T and 21S kept the original dentures. Both groups were similar in ratings of satisfaction and OHRQoL (maxilla T: 80.0 S: 86.0, p = 0.36; mandibular; T: 66.1 S: 72.3, p = 0.48; OHRQoL T: 111.1 S: 108.5, p = 0.46). Irrespective of fabrication method, discomfort, chewing difficulty and esthetics were the factors that deteriorate OHRQoL (adjusted r = 0.76, p < 0.001). CONCLUSION: The results indicate that the simplified method remains more cost efficient than the traditional method over a 10-year period. (IRB approval: A09 E71-12 B McGill University, trial registry: ClinicalTrial.org; NCT02289443). PMID- 29758257 TI - A mechanistic review on GNAO1-associated movement disorder. AB - Mutations in the GNAO1 gene cause a complex constellation of neurological disorders including epilepsy, developmental delay, and movement disorders. GNAO1 encodes Galphao, the alpha subunit of Go, a member of the Gi/o family of heterotrimeric G protein signal transducers. Go is the most abundant membrane protein in the mammalian central nervous system and plays major roles in synaptic neurotransmission and neurodevelopment. GNAO1 mutations were first reported in early infantile epileptic encephalopathy 17 (EIEE17) but are also associated with a more common syndrome termed neurodevelopmental disorder with involuntary movements (NEDIM). Here we review a mechanistic model in which loss-of-function (LOF) GNAO1 alleles cause epilepsy and gain-of-function (GOF) alleles are primarily associated with movement disorders. We also develop a signaling framework related to cyclic AMP (cAMP), synaptic vesicle release, and neural development and discuss gene mutations perturbing those mechanisms in a range of genetic movement disorders. Finally, we analyze clinical reports of patients carrying GNAO1 mutations with respect to their symptom onset and discuss pharmacological/surgical treatments in the context of our mechanistic model. PMID- 29758258 TI - Nuclear mRNA Surveillance Mechanisms: Function and Links to Human Disease. AB - Production of export-competent mRNAs involves transcription and a series of dynamic processing and modification events of pre-messenger RNAs in the nucleus. Mutations in the genes encoding the transcription and mRNP processing machinery and the complexities involved in the biogenesis events lead to the formation of aberrant messages. These faulty transcripts are promptly eliminated by the nuclear RNA exosome and its cofactors to safeguard the cells and organisms from genetic catastrophe. Mutations in the components of the core nuclear exosome and its cofactors lead to the tissue-specific dysfunction of exosomal activities, which are linked to diverse human diseases and disorders. In this article, we examine the structure and function of both the yeast and human RNA exosome complex and its cofactors, discuss the nature of the various altered amino acid residues implicated in these diseases with the speculative mechanisms of the mutation-induced disorders and project the frontier and prospective avenues of the future research in this field. PMID- 29758259 TI - Structural Basis for Polyamine Binding at the dCACHE Domain of the McpU Chemoreceptor from Pseudomonas putida. AB - Many bacteria can move chemotactically to a variety of compounds and the recognition of chemoeffectors by the chemoreceptor ligand binding domain (LBD) defines the specificity of response. Many chemoreceptors were found to recognize different amino and organic acids, but the McpU chemoreceptor from Pseudomonas putida was identified as the first chemoreceptor that bound specifically polyamines. We report here the three-dimensional structure of McpU-LBD in complex with putrescine at a resolution of 2.4 A, which fitted well a solution structure generated by small-angle X-ray scattering. Putrescine bound to a negatively charged pocket in the membrane distal module of McpU-LBD. Similarities exist in the binding of putrescine to McpU-LBD and taurine to the LBD of the Mlp37 chemoreceptor of Vibrio cholerae. In both structures, the primary amino group of the respective ligand is recognized by hydrogen bonds established by two aspartate and a tyrosine side chain. This feature may be used to predict the ligands of chemoreceptors with unknown function. Analytical ultracentrifugation revealed that McpU-LBD is monomeric in solution and that ligand binding does not alter this oligomeric state. This sensing mode thus differs from that of the well characterised four-helix bundle domains where ligands bind to two sites at the LBD dimer interface. Although there appear to be different sensing modes, results are discussed in the context of data, indicating that chemoreceptors employ the same mechanism of transmembrane signaling. This work enhances our understanding of CACHE domains, which are the most abundant sensor domains in bacterial chemoreceptors and sensor kinases. PMID- 29758256 TI - Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. AB - Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1 S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Calpha in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells. PMID- 29758260 TI - Quality Control of Membraneless Organelles. AB - The formation of membraneless organelles (MLOs) by phase separation has emerged as a new way of organizing the cytoplasm and nucleoplasm of cells. Examples of MLOs forming via phase separation are nucleoli in the nucleus and stress granules in the cytoplasm. The main components of these MLOs are macromolecules such as RNAs and proteins. In order to assemble by phase separation, these proteins and RNAs have to undergo many cooperative interactions. These cooperative interactions are supported by specific molecular features within phase-separating proteins, such as multivalency and the presence of disordered domains that promote weak and transient interactions. However, these features also predispose phase-separating proteins to aberrant behavior. Indeed, evidence is emerging for a strong link between phase-separating proteins, MLOs, and age-related diseases. In this review, we discuss recent progress in understanding the formation, properties, and functions of MLOs. We pay special attention to the emerging link between MLOs and age-related diseases, and we explain how changes in the composition and physical properties of MLOs promote their conversion into an aberrant state. Furthermore, we discuss the key role of the protein quality control machinery in regulating the properties and functions of MLOs and thus in preventing age-related diseases. PMID- 29758261 TI - Annotating Diseases Using Human Phenotype Ontology Improves Prediction of Disease Associated Long Non-coding RNAs. AB - Recently, many long non-coding RNAs (lncRNAs) have been identified and their biological function has been characterized; however, our understanding of their underlying molecular mechanisms related to disease is still limited. To overcome the limitation in experimentally identifying disease-lncRNA associations, computational methods have been proposed as a powerful tool to predict such associations. These methods are usually based on the similarities between diseases or lncRNAs since it was reported that similar diseases are associated with functionally similar lncRNAs. Therefore, prediction performance is highly dependent on how well the similarities can be captured. Previous studies have calculated the similarity between two diseases by mapping exactly each disease to a single Disease Ontology (DO) term, and then use a semantic similarity measure to calculate the similarity between them. However, the problem of this approach is that a disease can be described by more than one DO terms. Until now, there is no annotation database of DO terms for diseases except for genes. In contrast, Human Phenotype Ontology (HPO) is designed to fully annotate human disease phenotypes. Therefore, in this study, we constructed disease similarity networks/matrices using HPO instead of DO. Then, we used these networks/matrices as inputs of two representative machine learning-based and network-based ranking algorithms, that is, regularized least square and heterogeneous graph-based inference, respectively. The results showed that the prediction performance of the two algorithms on HPO-based is better than that on DO-based networks/matrices. In addition, our method can predict 11 novel cancer-associated lncRNAs, which are supported by literature evidence. PMID- 29758262 TI - S-adenosylhomocysteine Hydrolase Participates in DNA Methylation Inheritance. AB - DNA (cytosine-5) methyltransferase 1 (DNMT1) is essential for mammalian development and maintenance of DNA methylation following DNA replication in cells. The DNA methylation process generates S-adenosyl-l-homocysteine, a strong inhibitor of DNMT1. Here we report that S-adenosylhomocysteine hydrolase (SAHH/AHCY), the only mammalian enzyme capable of hydrolyzing S-adenosyl-l homocysteine binds to DNMT1 during DNA replication. SAHH enhances DNMT1 activity in vitro, and its overexpression in mammalian cells led to hypermethylation of the genome, whereas its inhibition by adenosine periodate or siRNA-mediated knockdown resulted in hypomethylation of the genome. Hypermethylation was consistent in both gene bodies and repetitive DNA elements leading to aberrant gene regulation. Cells overexpressing SAHH specifically up-regulated metabolic pathway genes and down-regulated PPAR and MAPK signaling pathways genes. Therefore, we suggest that alteration of SAHH level affects global DNA methylation levels and gene expression. PMID- 29758264 TI - Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice. AB - Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., beta amyloid (Abeta) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Abeta plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Abeta species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Abeta peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Abeta1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics. PMID- 29758266 TI - Alanine rich peptide from Populus trichocarpa inhibit growth of Staphylococcus aureus via targetting its extracellular domain of Sensor Histidine Kinase YycGex protein. AB - BACKGROUND: Due to growing concern towards microbial resistance, ongoing search for developing novel bioactive compounds such as peptides is on rise. The aim of this study was to evaluate antimicrobial effect of Populus trichocarpa extract, chemically identify the active peptide fraction and finds its target in Staphylococcus aureus. METHODS: In this study the active fraction of P. trichocarpa crude extract was purified and characterized using MS/MS. This peptide PT13 antimicrobial activity was confirmed by in-vitro agar based disk diffusion and in-vivo infection model of G. mellonella. The proteomic expression analysis of S. aureus under influence of PT13 was studied using LTQ-Orbitrap-MS in-solution digestion and identity of target protein was acquired with their quantified expression using label-free approach of Progenesis QI software. Docking study was performed with peptide PT13 and its target YycG protein using CABS-dock. RESULTS: The active fraction PT13 sequence was identified as KVPVAAAAAAAAAVVASSMVVAAAK, with 25 amino acid including 13 alanine having M/Z 2194.2469. PT13 was uniformly inhibited growth S. aureus SA91 and MIC was determined 16 MUg/mL for SA91 S. aureus strain. Sensor histidine kinase (YycG) was most significant target found differentially expressed under influence of PT13. G. mellonella larvae were killed rapidly due to S aureus infection, whereas death in protected group was insignificant in compare to control. The docking models showed ten docking models with RMSD value 1.89 for cluster 1 and RMSD value 3.95 for cluster 2 which is predicted to be high quality model. CONCLUSION: Alanine rich peptide could be useful in constructing as antimicrobial peptide for targeting extracellular Domain of Sensor Histidine Kinase YycG from S. aureus used in the study. PMID- 29758263 TI - PAGE4 and Conformational Switching: Insights from Molecular Dynamics Simulations and Implications for Prostate Cancer. AB - Prostate-associated gene 4 (PAGE4) is an intrinsically disordered protein implicated in prostate cancer. Thestress-response kinase homeodomain-interacting protein kinase 1 (HIPK1) phosphorylates two residues in PAGE4, serine 9 and threonine 51. Phosphorylation of these two residues facilitates the interaction of PAGE4 with activator protein-1 (AP-1) transcription factor complex to potentiate AP-1's activity. In contrast, hyperphosphorylation of PAGE4 by CDC like kinase 2 (CLK2) attenuates this interaction with AP-1. Small-angleX-ray scattering and single-molecule fluorescence resonance energy transfer measurements have shown that PAGE4 expands upon hyperphosphorylation and that this expansion is localized to its N-terminal half. To understand the interactions underlying this structural transition, we performed molecular dynamics simulations using Atomistic AWSEM, a multi-scale molecular model that combines atomistic and coarse-grained simulation approaches. Our simulations show that electrostatic interactions drive transient formation of an N-terminal loop, the destabilization of which accounts for the dramatic change in size upon hyperphosphorylation. Phosphorylation also changes the preference of secondary structure formation of the PAGE4 ensemble, which leads to a transition between states that display different degrees of disorder. Finally, we construct a mechanism-based mathematical model that allows us to capture the interactions ofdifferent phosphoforms of PAGE4 with AP-1 and its downstream target, the androgen receptor (AR)-a key therapeutic target in prostate cancer. Our model predicts intracellular oscillatory dynamics of HIPK1-PAGE4, CLK2-PAGE4, and AR activity, indicating phenotypic heterogeneity in an isogenic cell population. Thus, conformational switching of PAGE4 may potentially affect the efficiency of therapeutically targeting AR activity. PMID- 29758265 TI - Interactions between lysyl oxidases and ADAMTS proteins suggest a novel crosstalk between two extracellular matrix families. AB - The extracellular matrix (ECM) regulates numerous cellular events in addition to providing structural integrity. Among several protein and enzyme families implicated in functions of the ECM, the lysyl oxidases and ADAMTS proteins are known to participate in microfibril and elastic fiber formation as well as ECM associated signaling. A yeast two-hybrid screen to identify lysyl oxidase (LOX) binding proteins identified ADAMTSL4 as a potential interactor. We demonstrate here that several members of the LOX and ADAMTS families interact with one another. Upon investigating the interaction between LOX and ADAMTSL2 we found that the absence or inhibition of Lox affected ADAMTSL2 molecular forms and reduced its tissue levels. Thus, ADAMTSL2 stability and inter-molecular complexes may depend on the activity of lysyl oxidases. PMID- 29758267 TI - The functional architecture of axonal actin. AB - The cytoskeleton builds and supports the complex architecture of neurons. It orchestrates the specification, growth, and compartmentation of the axon: axon initial segment, axonal shaft, presynapses. The cytoskeleton must then maintain this intricate architecture for the whole life of its host, but also drive its adaptation to new network demands and changing physiological conditions. Microtubules are readily visible inside axon shafts by electron microscopy, whereas axonal actin study has long been focused on dynamic structures of the axon such as growth cones. Super-resolution microscopy and live-cell imaging have recently revealed new actin-based structures in mature axons: rings, hotspots and trails. This has caused renewed interest for axonal actin, with efforts underway to understand the precise organization and cellular functions of these assemblies. Actin is also present in presynapses, where its arrangement is still poorly defined, and its functions vigorously debated. Here we review the organization of axonal actin, focusing on recent advances and current questions in this rejuvenated field. PMID- 29758269 TI - G-quadruplex in animal development: Contribution to gene expression and genomic heterogeneity. AB - During animal development, gene expression is orchestrated by specific and highly evolutionarily conserved mechanisms that take place accurately, both at spatial and temporal levels. The last decades have provided compelling evidence showing that chromatin state plays essential roles in orchestrating most of the stages of development. The DNA molecule can adopt alternative structures different from the helical duplex architecture. G-rich DNA sequences can fold as intrastrand quadruple helix structures called G-quadruplexes or G4-DNA. G4 can also be formed in RNA molecules, such as mRNA, lncRNA and pre-miRNA. Emerging evidences suggest that G4s have crucial roles in a variety of biological processes, including transcription, recombination, replication, translation and chromosome stability. In this review, we have collected recent information gathered by various laboratories showing the important role of G4 DNA and RNA structures in several steps of animal development. PMID- 29758271 TI - An investigation of maternal food intake and maternal food talk as predictors of child food intake. AB - Though parental modeling is thought to play a critical role in promoting children's healthy eating, little research has examined maternal food intake and maternal food talk as independent predictors of children's food intake. The present study examines maternal food talk during a structured eating protocol, in which mothers and their children had the opportunity to eat a series of familiar and unfamiliar vegetables and desserts. Several aspects of maternal talk during the protocol were coded, including overall food talk, directives, pronoun use, and questions. This study analyzed the predictors of maternal food talk and whether maternal food talk and maternal food intake predicted children's food intake during the protocol. Higher maternal body mass index (BMI) predicted lower amounts of food talk, pronoun use, and questions. Higher child BMI z-scores predicted more first person pronouns and more wh-questions within maternal food talk. Mothers of older children used fewer directives, fewer second person pronouns, and fewer yes/no questions. However, maternal food talk (overall and specific types of food talk) did not predict children's food intake. Instead, the most robust predictor of children's food intake during this protocol was the amount of food that mothers ate while sitting with their children. These findings emphasize the importance of modeling healthy eating through action and have implications for designing interventions to provide parents with more effective tools to promote their children's healthy eating. PMID- 29758272 TI - Associations between attention-deficit/hyperactivity disorder symptoms and dietary habits in elementary school children. AB - OBJECTIVE: The aim of the present study was to investigate the associations between dietary habits and attention deficit/hyperactivity disorder (ADHD) symptoms in elementary school children. METHODS: The parents of 16,831 participating children assessed the ADHD symptoms of their children by responding to the Korean version of the ADHD rating scale (K-ARS). Parents also responded to the food habit questionnaire, which consists of 8 items regarding the eating pace, the frequency of overeating, and patterns of eating six types of food: fast food, soft drinks, instant noodles, fruit and vegetables, and milk. RESULTS: K ARS scores were positively associated with higher consumption of foods categorized as unhealthy, including fast food, soft drinks, and instant noodles, and negatively associated with higher consumption of fruit and vegetables categorized as healthy foods. K-ARS scores were also higher in the groups who overate more frequently and ate faster or slower compared to other family members. CONCLUSION: Our findings may provide useful clinical information for dietary interventions in children with ADHD. PMID- 29758270 TI - Collagen Gly missense mutations: Effect of residue identity on collagen structure and integrin binding. AB - Gly missense mutations in type I collagen, which replace a conserved Gly in the repeating (Gly-Xaa-Yaa)n sequence with a larger residue, are known to cause Osteogenesis Imperfecta (OI). The clinical consequences of such mutations range from mild to lethal, with more serious clinical severity associated with larger Gly replacement residues. Here, we investigate the influence of the identity of the residue replacing Gly within and adjacent to the integrin binding 502GFPGER507 sequence on triple-helix structure, stability and integrin binding using a recombinant bacterial collagen system. Recombinant collagens were constructed with Gly substituted by Ala, Ser or Val at four positions within the integrin binding region. All constructs formed a stable triple-helix structure with a small decrease in melting temperature. Trypsin was used to probe local disruption of the triple helix, and Gly to Val replacements made the triple helix trypsin sensitive at three of the four sites. Any mutation at Gly505, eliminated integrin binding, while decreased integrin binding affinity was observed in the replacement of Gly residues at Gly502 following the order Val > Ser > Ala. Molecular dynamics simulations indicated that all Gly replacements led to transient disruption of triple-helix interchain hydrogen bonds in the region of the Gly replacement. These computational and experimental results lend insight into the complex molecular basis of the varying clinical severity of OI. PMID- 29758273 TI - In silico experiment system for testing hypothesis on gene functions using three condition specific biological networks. AB - : Determining functions of a gene requires time consuming, expensive biological experiments. Scientists can speed up this experimental process if the literature information and biological networks can be adequately provided. In this paper, we present a web-based information system that can perform in silico experiments of computationally testing hypothesis on the function of a gene. A hypothesis that is specified in English by the user is converted to genes using a literature and knowledge mining system called BEST. Condition-specific TF, miRNA and PPI (protein-protein interaction) networks are automatically generated by projecting gene and miRNA expression data to template networks. Then, an in silico experiment is to test how well the target genes are connected from the knockout gene through the condition-specific networks. The test result visualizes path from the knockout gene to the target genes in the three networks. Statistical and information-theoretic scores are provided on the resulting web page to help scientists either accept or reject the hypothesis being tested. Our web-based system was extensively tested using three data sets, such as E2f1, Lrrk2, and Dicer1 knockout data sets. We were able to re-produce gene functions reported in the original research papers. In addition, we comprehensively tested with all disease names in MalaCards as hypothesis to show the effectiveness of our system. Our in silico experiment system can be very useful in suggesting biological mechanisms which can be further tested in vivo or in vitro. AVAILABILITY: http://biohealth.snu.ac.kr/software/insilico/. PMID- 29758274 TI - Rapid diversification and hybridization have shaped the dynamic history of the genus Elaenia. AB - Multi-locus data have proven invaluable in phylogenetic reconstruction and species delimitation. However, the mixed genetic signal from different loci can make inference of evolutionary history challenging and may produce incongruences depending on analytical and marker choice. Aside from incomplete lineage sorting (ILS) following diversification events that have had little time for deep differentiation, the most common causes of incongruent phylogenies are genetic introgression confounding a bifurcating evolutionary trajectory. In this study, we used multi-locus analytical approaches on sequence data of nine loci from 80 individuals of over 20 Neotropical Elaenia flycatcher species to examine the systematics, molecular phylogeny and species limits of this complex genus. Our results provide a robust phylogeny and estimates of species limits within Elaenia, but point to important cases of incongruences among phylogenies based on different analytical approaches. Simulations and estimates of divergence times provide reasonable explanations for the incongruent placement of some Elaenia taxa, pointing to multiple cases of both ILS and introgression within the genus. Molecular dating of major evolutionary events revealed intensive diversification during the Pleistocene, suggesting a central role of climate oscillations in the evolution of Elaenia flycatchers. PMID- 29758268 TI - Pathogenesis of Keratoconus: The intriguing therapeutic potential of Prolactin inducible protein. AB - Keratoconus (KC) is the most common ectatic corneal disease, with clinical findings that include discomfort, visual disturbance and possible blindness if left untreated. KC affects approximately 1:400 to 1:2000 people worldwide, including both males and females. The aetiology and onset of KC remains a puzzle and as a result, the ability to treat or reverse the disease is hampered. Sex hormones are known to play a role in the maintenance of the structure and integrity of the human cornea. Hormone levels have been reported to alter corneal thickness, curvature, and sensitivity during different times of menstrual cycle. Surprisingly, the role of sex hormones in corneal diseases and KC has been largely neglected. Prolactin-induced protein, known to be regulated by sex hormones, is a new KC biomarker that has been recently proposed. Studies herein discuss the role of sex hormones as a control mechanism for KC onset and progression and evidence supporting the view that prolactin-induced protein is an important hormonally regulated biomarker in KC is discussed. PMID- 29758275 TI - Employing hypothesis testing and data from multiple genomic compartments to resolve recalcitrant backbone nodes in Goodenia s.l. (Goodeniaceae). AB - Goodeniaceae is a primarily Australian flowering plant family with a complex taxonomy and evolutionary history. Previous phylogenetic analyses have successfully resolved the backbone topology of the largest clade in the family, Goodenia s.l., but have failed to clarify relationships within the species-rich and enigmatic Goodenia clade C, a prerequisite for taxonomic revision of the group. We used genome skimming to retrieve sequences for chloroplast, mitochondrial, and nuclear markers for 24 taxa representing Goodenia s.l., with a particular focus on Goodenia clade C. We performed extensive hypothesis tests to explore incongruence in clade C and evaluate statistical support for clades within this group, using datasets from all three genomic compartments. The mitochondrial dataset is comparable to the chloroplast dataset in providing resolution within Goodenia clade C, though backbone support values within this clade remain low. The hypothesis tests provided an additional, complementary means of evaluating support for clades. We propose that the major subclades of Goodenia clade C (C1-C3 + Verreauxia) are the result of a rapid radiation, and each represents a distinct lineage. PMID- 29758277 TI - First genetic evidence for the presence of the rumen fluke Paramphistomum epiclitum in Pakistan. AB - More than 70 species of the Superfamily Paramphistomoidea, have been identified in ruminants in different parts of the world. Most are pathogenic, causing amphistomosis. Adult flukes within this family have a predilection for the forestomach (rumen) or bile duct of the liver, where they may cause epithelial damage. Identification of adult Paramphistomum, Calicophoron, Gastrothylax and Fischoederius at the species level based on morphology requires specialised expertise, whereas molecular genetic marker analysis is more precise and transferable. In the present study, we performed molecular characterisation of twenty seven adult flukes collected from the forestomachs of buffalo, cattle and goats in the Punjab province of Pakistan. PCR and sequencing of the ITS-2 rDNA region revealed a single haplotype in all cases. Phylogenetic comparison of P. epiclitum ITS2-rDNA sequences with those from other Paramphistomum, Calicophoron, Gastrothylax and Fischoederius species was performed to assess within and between species variation and validate the use of ITS-2 rDNA as a robust species-specific marker for P. epiclitum identification. This work provides a validated species specific marker of P. epiclitum and the first report of this parasite species from Pakistan. The results of this study also have implications for the diagnosis and control of rumen flukes in the region and the need for accurate species identification to understand parasite distribution and population genetics. PMID- 29758276 TI - Age of Menarche in a Longitudinal US Cohort. AB - STUDY OBJECTIVE: Menarche is a critical milestone in a woman's life, and historically has been determined using several approaches. The goals of this study were to: (1) determine age at menarche from multiple reports of parents and adolescent participants in a prospective study; (2) examine factors affecting age at menarche; and (3) determine correlates of menarche and pubertal tempo. DESIGN: Longitudinal observational study. SETTING: Three sites of the Breast Cancer and the Environment Research Program. PARTICIPANTS: Girls enrolled at 6-8 years of age. INTERVENTIONS AND MAIN OUTCOME MEASURES: Parental and participant reported age of menarche, and tempo of puberty. RESULTS: There were 946 girls who were assigned an age of menarche. The correlation between parent and participant reports was high (Spearman R = 0.799, P < .001), and the difference was insignificant. Median age at menarche overall was 12.25 years. Compared with black participants, Hispanic girls were more likely to have menarche earlier, whereas white and Asian girls were more likely to have menarche later. Age of menarche was highly correlated with age of breast development (Spearman R = 0.547; P < .001), and inversely with body mass index (Spearman R = -0.403; P < .001). Tempo (interval of age of breast development to menarche) was slower in those with earlier breast development. CONCLUSION: Parental and adolescent reports of menarche are highly correlated. Earlier breast maturation was associated with slower tempo through puberty. Body mass index had a greater effect on age at menarche than did race and ethnicity. PMID- 29758278 TI - Prevalence of and risk factors associated with latent tuberculosis in Singapore: A cross-sectional survey. AB - OBJECTIVES: This first cross-sectional survey on latent tuberculosis infection (LTBI) in Singapore was performed by utilizing the QuantiFERON Gold In-tube (QFT GIT) assay to collect data on the prevalence of LTBI and to identify potential risk factors associated with LTBI. METHODS: Nationwide household addresses were selected randomly for enumeration, and Singaporeans or Permanent Residents aged 18-79 years were identified. One eligible member per household was selected using the Kish grid. Each participant answered a questionnaire assessing their medical history (including tuberculosis (TB)), socio-economic factors, and lifestyle factors. They also provided a blood specimen for the QFT-GIT assay. Participants with a positive QFT-GIT result were defined as having LTBI if they were asymptomatic. To identify independent risk factors, adjusted hazard ratios were obtained using the multivariable modified Breslow-Cox proportional hazards model. RESULTS: An overall QFT-GIT positivity rate of 12.7% was detected amongst 1682 Singapore residents. There was a wide variation in the positivity rate according to the participants' country of birth. Higher LTBI prevalence was also significantly associated with increasing age, lower educational and socio economic status, and alcohol use. CONCLUSIONS: Given the high prevalence of LTBI amongst foreign-born residents from regional countries, similar studies should be conducted amongst migrants in Singapore to improve national guidelines on screening and preventive treatment against LTBI. PMID- 29758279 TI - Potential role of genipin in cancer therapy. AB - Genipin, an aglycone derived from the iridoid glycoside, geniposide, is isolated and characterized from the extract of Gardenia jasminoides Ellis fruit (family Rubiaceae). It has long been used in traditional oriental medicine for the prevention and treatment of several inflammation driven diseases, including cancer. Genipin has been shown to have hepatoprotective activity acting as a potent antioxidant and inhibitor of mitochondrial uncoupling protein 2 (UCP2), and also reported to exert significant anticancer effects. It is an excellent crosslinking agent that helps to make novel sustained or delayed release nanoparticle formulations. In this review, we present the latest developments of genipin as an anticancer agent and briefly describe its diverse mechanism(s) of action. Several lines of evidence suggest that genipin is a potent inhibitor of UCP2, which functions as a tumor promoter in a variety of cancers, attenuates generation of reactive oxygen species and the expression of matrix metalloproteinase 2, as well as induces caspase-dependent apoptosis in vitro and in in vivo models. These finding suggests that genipin can serve as both a prominent anticancer agent as well as a potent crosslinking drug that may find useful application in several novel pharmaceutical formulations. PMID- 29758280 TI - Multi-Kinase Inhibitor with Anti-p38gamma Activity in Cutaneous T-Cell Lymphoma. AB - Current cutaneous T-cell lymphoma (CTCL) therapies are marked by an abbreviated response, subsequent drug resistance, and poor prognosis for patients with advanced disease. An understanding of molecular regulators involved in CTCL is needed to develop effective targeted therapies. One candidate regulator is p38gamma, a mitogen-activated protein kinase crucial for malignant T-cell activity and growth. p38gamma gene expression is selectively increased in CTCL patient samples and cell lines but not in healthy T cells. In addition, gene silencing of p38gamma reduced CTCL cell viability, showing a key role in CTCL pathogenesis. Screening p38gamma inhibitors is critical for understanding the mechanism of CTCL tumorigenesis and developing therapeutic applications. We prioritized a potent p38gamma inhibitor (F7, also known as PIK75) through a high throughput kinase inhibitor screen. At nanomolar concentrations, PIK75, a multiple kinase inhibitor, selectively killed CD4+ malignant CTCL cells but spared healthy CD4+ cells; induced significant reduction of tumor size in mouse xenografts; and effectively inhibited p38gamma enzymatic activity and phosphorylation of its substrate, DLGH1, in CTCL cells and mouse xenografts. Here, we report that PIK75 has a potential clinical application to serve as a scaffold molecule for the development of a more selective p38gamma inhibitor. PMID- 29758281 TI - Purinergic Molecules in the Epidermis. PMID- 29758284 TI - Intradermal Injection of Bone Marrow Mesenchymal Stromal Cells Corrects Recessive Dystrophic Epidermolysis Bullosa in a Xenograft Model. PMID- 29758282 TI - Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: A Multicenter Retrospective Study of 377 Adult Patients from the United States. AB - Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a rare, severe mucocutaneous reaction with few large cohorts reported. This multicenter retrospective study included patients with SJS/TEN seen by inpatient consultative dermatologists at 18 academic medical centers in the United States. A total of 377 adult patients with SJS/TEN between January 1, 2000 and June 1, 2015 were entered, including 260 of 377 (69%) from 2010 onward. The most frequent cause of SJS/TEN was medication reaction in 338 of 377 (89.7%), most often to trimethoprim/sulfamethoxazole (89/338; 26.3%). Most patients were managed in an intensive care (100/368; 27.2%) or burn unit (151/368; 41.0%). Most received pharmacologic therapy (266/376; 70.7%) versus supportive care alone (110/376; 29.3%)-typically corticosteroids (113/266; 42.5%), intravenous immunoglobulin (94/266; 35.3%), or both therapies (54/266; 20.3%). Based on day 1 SCORTEN predicted mortality, approximately 78 in-hospital deaths were expected (77.7/368; 21%), but the observed mortality of 54 patients (54/368; 14.7%) was significantly lower (standardized mortality ratio = 0.70; 95% confidence interval = 0.58-0.79). Stratified by therapy received, the standardized mortality ratio was lowest among those receiving both steroids and intravenous immunoglobulin (standardized mortality ratio = 0.52; 95% confidence interval 0.21-0.79). This large cohort provides contemporary information regarding US patients with SJS/TEN. Mortality, although substantial, was significantly lower than predicted. Although the precise role of pharmacotherapy remains unclear, co-administration of corticosteroids and intravenous immunoglobulin, among other therapies, may warrant further study. PMID- 29758283 TI - TGFbeta, Fibronectin and Integrin alpha5beta1 Promote Invasion in Basal Cell Carcinoma. AB - Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an aging population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have identified molecular mechanisms that explain the aggressiveness of high-risk infiltrative BCC, with a potential direct clinical impact. In this study, we first show that fibroblasts, transforming growth factor beta, and fibronectin are found preferentially in infiltrative human BCC. This allowed us to develop in vivo models for the study of infiltrative BCC, which in turn let us confirm the role of transforming growth factor-beta in inducing peritumoral fibronectin deposition and tumor infiltration. We then show that fibronectin promotes adhesion and migration of BCC cell lines through integrin alpha5beta1-mediated phosphorylation of focal adhesion kinase. Fittingly, both inhibition of integrin alpha5beta1 and phospho-focal adhesion kinase prevent fibronectin-induced migration of BCC cells in vitro as well as BCC infiltration in vivo. Altogether, our results open important insights into the pathogenesis of aggressive infiltrative BCC and identify integrin alpha5beta1 or focal adhesion kinase inhibition as promising strategies for the treatment of advanced BCC. PMID- 29758286 TI - A new definition of an acupuncture meridian. AB - This article provides a new definition of an acupuncture meridian. It suggests that a meridian consists of a distal tract of tissue that is affected by organ function. In the 1960's, Kim discovered the primo vascular system, and regarded the superficial primo vessels as equating to the meridians. Instead, this article suggests that the superficial primo vessels merely underlie the meridians, in that they enable their creation, which is why some meridians are said to occur along the paths of superficial primo vessels. But the meridians themselves do not have a dedicated anatomical structure; instead they are merely tracts of tissue whose normal function is impeded when the related abdominal organ is stressed. It is hypothesised that the organ information is communicated in electrical waves that may travel through the connective tissue sheaths of the superficial primo vessels. Hence the primo vessels serve as an inadvertent transport for this information, but the organ information is independent of the physiological purpose of the primo vascular system, as are the resultant meridians. PMID- 29758287 TI - Pseudomonas putida as a functional chassis for industrial biocatalysis: From native biochemistry to trans-metabolism. AB - The itinerary followed by Pseudomonas putida from being a soil-dweller and plant colonizer bacterium to become a flexible and engineer-able platform for metabolic engineering stems from its natural lifestyle, which is adapted to harsh environmental conditions and all sorts of physicochemical stresses. Over the years, these properties have been capitalized biotechnologically owing to the expanding wealth of genetic tools designed for deep-editing the P. putida genome. A suite of dedicated vectors inspired in the core tenets of synthetic biology have enabled to suppress many of the naturally-occurring undesirable traits native to this species while enhancing its many appealing properties, and also to import catalytic activities and attributes from other biological systems. Much of the biotechnological interest on P. putida stems from the distinct architecture of its central carbon metabolism. The native biochemistry is naturally geared to generate reductive currency [i.e., NAD(P)H] that makes this bacterium a phenomenal host for redox-intensive reactions. In some cases, genetic editing of the indigenous biochemical network of P. putida (cis-metabolism) has sufficed to obtain target compounds of industrial interest. Yet, the main value and promise of this species (in particular, strain KT2440) resides not only in its capacity to host heterologous pathways from other microorganisms, but also altogether artificial routes (trans-metabolism) for making complex, new-to-Nature molecules. A number of examples are presented for substantiating the worth of P. putida as one of the favorite workhorses for sustainable manufacturing of fine and bulk chemicals in the current times of the 4th Industrial Revolution. The potential of P. putida to extend its rich native biochemistry beyond existing boundaries is discussed and research bottlenecks to this end are also identified. These aspects include not just the innovative genetic design of new strains but also the incorporation of novel chemical elements into the extant biochemistry, as well as genomic stability and scaling-up issues. PMID- 29758285 TI - Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A. AB - Peeling skin syndromes form a large and heterogeneous group of inherited disorders characterized by superficial detachment of the epidermal cornified cell layers, often associated with inflammatory features. Here we report on a consanguineous family featuring noninflammatory peeling of the skin exacerbated by exposure to heat and mechanical stress. Whole exome sequencing revealed a homozygous nonsense mutation in FLG2, encoding filaggrin 2, which cosegregated with the disease phenotype in the family. The mutation was found to result in decreased FLG2 RNA levels as well as almost total absence of filaggrin 2 in the patient epidermis. Filaggrin 2 was found to be expressed throughout the cornified cell layers and to colocalize with corneodesmosin that plays a crucial role in maintaining cell-cell adhesion in this region of the epidermis. The absence of filaggrin 2 in the patient skin was associated with markedly decreased corneodesmosin expression, which may contribute to the peeling phenotype displayed by the patients. Accordingly, using the dispase dissociation assay, we showed that FLG2 downregulation interferes with keratinocyte cell-cell adhesion. Of particular interest, this effect was aggravated by temperature elevation, consistent with the clinical phenotype. Restoration of corneodesmosin levels by ectopic expression rescued cell-cell adhesion. Taken together, the present data suggest that filaggrin 2 is essential for normal cell-cell adhesion in the cornified cell layers. PMID- 29758288 TI - MicroRNAs in brown and beige fat. AB - Brown adipose tissue (BAT) dissipates energy as heat and its activity correlates with leanness in human adults. Understanding the mechanisms behind the activation of BAT and the process of "browning", i.e. the appearance of inducible brown adipocytes called beige or brite (brown-in-white) cells in white adipose tissue (WAT), is of great interest for developing novel therapies to combat obesity. MicroRNAs (miRNAs) are small transcriptional regulators that control gene expression in a variety of tissues, including WAT and BAT. Recently, miRNAs were reported to regulate browning. Nevertheless, further studies are needed to fully understand the miRNA networks that are involved in the control of brown and beige/brite adipocytes. Particularly, most miRNAs have so far been studied in mice, underlining the importance of additional human studies. In this review, we focus on the regulation of brown fat by miRNAs including their role in promoting or inhibiting the browning process. In recent years, RNA-based therapeutical approaches have entered clinical trials for treatment of other diseases, thus miRNAs could potentially be used to enhance brown and beige fat mass and activity as novel therapies against overweight and its complications. PMID- 29758289 TI - Exposure to a combination of formaldehyde and DINP aggravated asthma-like pathology through oxidative stress and NF-kappaB activation. AB - Several epidemiological and experimental studies indicate a positive association between exposure to formaldehyde or phthalates and allergic asthma. However, nothing is yet known about the effects of exposure to formaldehyde and phthalates together, nor the role of each on allergic asthma. Here, we investigated the effects of a combined exposure to formaldehyde and diisononyl phthalate (DINP) on asthma-like pathology in mice, and determined the underlying mechanisms implicated in NF-kappaB and ROS. Mice were exposed to formaldehyde and/or DINP and sensitization with OVA. The results showed that exposure to 1.0 mg/m3 formaldehyde or 20 mg/kg.d DINP slightly aggravated the airway wall remodeling, promoted the production of IgE and IgG1, and induced the occurrence of airway hyperresponsiveness (AHR). However, these pathological responses and AHR were greatly exacerbated by the combined exposure to formaldehyde and DINP. Administering melatonin to block oxidative stress, alleviated the pathological responses and AHR induced by formaldehyde and DINP, and inhibited the activation of the NF-kappaB and the secretion of TSLP. Blocking NF-kappaB with Dehydroxymethylepoxyquinimicin, inhibited the elevation of TSLP expression and Th2/Th17 cytokine secretion, and effectively alleviated the allergic asthma-like symptoms. The results suggested that exposure to both formaldehyde and DINP aggravated hypersensitivity asthma symptoms by promoting oxidative stress and activating NF-kappaB. These findings expand our understanding of how formaldehyde and DINP exposure affect the development of allergic asthma. PMID- 29758290 TI - Proteome response of dental pulp cells to exogenous FGF8. AB - : FGF8 specifies early tooth development by directing the migration of the early tooth founder cells to the site of tooth emergence. To date the effect of the FGF8 in adult dental pulp has not been studied. We have assessed the regenerative potential of FGF8 by evaluating changes in the proteome landscape of dental pulp following short- and long-term exposure to recombinant FGF8 protein. In addition, we carried out qRT PCR analysis to determine extracellular/adhesion gene marker expression and assessed cell proliferation and mineralization in response to FGF8 treatment. 2D and mass spectrometry data showed differential expression of proteins implicated in cytoskeleton/ECM remodeling and migration, cell proliferation and odontogenic differentiation as evidenced by the upregulation of gelsolin, moesin, LMNA, WDR1, PLOD2, COPS5 and downregulation of P4HB. qRT PCR showed downregulation of proteins involved in cell-matrix adhesion such as ADAMTS8, LAMB3 and ANOS1 and increased expression of the angiogenesis marker PECAM1. We have observed that, FGF8 treatment was able to boost dental pulp cell proliferation and to enhance dental pulp mineralization. Collectively, our data suggest that, FGF8 treatment could promote endogenous healing of the dental pulp via recruitment of dental pulp progenitors as well as by promoting their angiogenic and odontogenic differentiation. SIGNIFICANCE: Dental pulp cells (DP) have been studied extensively for the purposes of mineralized tissue repair, particularly for the reconstruction of hard and soft tissue maxillofacial defects. Canonical FGF signaling has been implicated throughout multiple stages of tooth development by regulating cell proliferation, differentiation, survival as well as cellular migration. FGF8 expression is indispensible for normal tooth development and particularly for the migration of early tooth progenitors to the sites of tooth emergence. The present study provides proteome and qRT PCR data with regard to the future application and biological relevance of FGF8 in dental regenerative medicine. AUTHORS WITH ORCID: Rozaliya Tsikandelova - 0000-0003-0178 3767 Zornitsa Mihaylova - 0000-0003-1748-4489 Sebastien Planchon - 0000-0002-0455 0574 Nikolay Ishkitiev - 0000-0002-4351-5579. PMID- 29758291 TI - Dr Elliot F. Ellis: Initiating personalized asthma management in children. PMID- 29758292 TI - Novel truncating PPM1D mutation in a patient with intellectual disability. AB - Truncating mutations in the last and penultimate exons of the PPM1D gene were recently described as a cause for mild to severe intellectual disability in fourteen patients. Feeding difficulties, periods of fever and vomiting as well as a high pain threshold were described as additional characteristic features and the disorder was subsequently termed "intellectual developmental disorder with gastrointestinal difficulties and high pain threshold (IDDGIP)" in the OMIM database (MIM # 617450). Here we report on an additional patient carrying a novel de novo truncating mutation NM_003620.3: c.1535del, p.(Asn512Ilefs*2) in the last exon of PPM1D. While the patient showed features overlapping with the reported phenotype, such as a short stature and small hands and feet, he also presented with additional features like cleft lip and palate and an aberrant right subclavian artery. Notably, the patient did not have any gastrointestinal difficulties or periods of fever, indicating variability of the phenotype of patients with PPM1D mutations. PMID- 29758294 TI - American Academy of Physical Medicine and Rehabilitation Position Statement on Opioid Prescribing. PMID- 29758293 TI - TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly. AB - Postnatal microcephaly comprises a heterogeneous group of neurodevelopmental disorders of varying severity, characterized by normal head size at birth, followed by a postnatal deceleration in head circumference of greater than 3 standard deviations (SD) below the mean. Many postnatal microcephaly syndromes are caused by mutations in genes known to be important for the regulation of gene expression in the developing forebrain. We studied a consanguineous Pakistani family with postnatal microcephaly, orofacial dyskinesia, spastic quadriplegia and, on MRI, cortical atrophy with myelination delay, suggestive of a FOXG1-like presentation. Using trio-based exome sequencing, we identified a homozygous missense mutation in the Transducin-like enhancer of split-1 (TLE1) gene, encoding for a non DNA-binding transcriptional corepressor, highly expressed in the postnatal brain. The regulation of the post-mitotic neural survival activity of TLE1 depends critically on an interaction with FOXG1, a gene shown to be involved in a postnatal microcephaly syndrome. Functional analysis on affected dermal fibroblasts showed a significant decrease in mitotic and proliferative index, indicating a lengthening of the cell cycle and a delay in mitosis, supporting that this gene could be a new candidate for postnatal microcephaly. PMID- 29758295 TI - Systematic bioinformatic approaches reveal novel gene expression signatures associated with acquired resistance to EGFR targeted therapy in lung cancer. AB - OBJECTIVES: Human non-small cell lung cancer (NSCLC) that harbors activating mutations in epidermal growth factor receptor (EGFR) initially responds to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib but eventually tumor cells acquire resistance. To date, several gene expression profiles have been reported in TKIs-resistant EGFR-mutant NSCLC. The objective of this study is to identify robust gene expression signatures, biological processes, and promising overcoming targets for TKIs-resistant EGFR mutant NSCLC. MATERIALS AND METHODS: Five publicly available microarray datasets were integrated by performing two network-based meta-analyses following by protein-protein interaction (PPI) network and gene set enrichment analysis. RESULTS AND CONCLUSION: According to our meta-analyses, 830 and 1286 genes were differentially expressed in the TKIs-resistant EGFR-mutant NSCLC cell lines compared to TKIs-sensitive EGFR-mutant NSCLC cell lines in the absence and presence of TKIs treatment, respectively. PPI network analysis identified ESR1 and ELAVL1 to be the most highly ranked hub genes involved in the NSCLC acquired TKI-resistance. Moreover, gene set enrichment analyses indicated that up regulated genes are mainly distributed in hallmarks "Glycolysis", some "E2F targets". Down-regulated genes mainly contribute to hallmarks "interferon alpha response", "interferon gamma response", and also "E2F targets". For the first time, this study has demonstrated several robust candidate genes and pathways of the NSCLC acquired TKI-resistance. Further experimental verifications are highly recommended to examine our findings. PMID- 29758296 TI - Isolation of the sex-determining gene Sex-lethal (Sxl) in Penaeus (Litopenaeus) vannamei (Boone, 1931) and characterization of its embryogenic, gametogenic, and tissue-specific expression. AB - The Pacific white shrimp Penaeus vannamei is the most cultured shrimp species around the world. Because females grow larger than males, the culture of 'only females' is of great interest, but knowledge on sex determination and differentiation is required for producing only females. In an effort to obtain information associated with reproduction in P. vannamei, transcriptomic data from female gonads was generated, and partial sequences of a transcript were identified as Sex-lethal (Sxl). Its characterization indicated that, differently from other penaeids in which this gene has been isolated, there are six isoforms of the Sxl transcript in P. vannamei (PvanSxl 1-6). These isoforms result from alternative splicing at three splice sites (SS1, SS2, SS3). The first splice-site is unique to P. vannamei, as it has not been reported for other Arthropod species; the second splice-site (SS2) is common among crustaceans, and the third splice-site (SS3) is also unique to P. vannamei and when spliced-out, it is always together with SS2. All isoforms are expressed during embryogenesis as well as gametogenesis of both genders. The two shorter isoforms, PvanSxl-5 and PvanSxl 6, which result from the splicing of SS2 and SS3, were found mostly expressed in adult testis, but PvanSxl-6 was also expressed in oocytes during gametogenesis. During oogenesis, the second largest isoform, PvanSxl-2, which splices-out only SS1, and PvanSxl-4 that splices-out SS1 and SS2 were highly expressed. These two isoforms were also highly expressed during embryonic development. In situ hybridization allowed pinpointing more specifically the cells where the PvanSxl transcripts were expressed. During embryogenesis, hybridization was observed from the one-cell stage embryo to late gastrula. In the female gonad in previtellogenesis, hybridization occurred in the nucleus of oocytes, whereas in secondary vitellogenesis the transcript also hybridized cytoplasmic granules and cortical crypts. Finally, in situ hybridization corroborated the expression of PvanSxl also in the male gonad during spermatogenesis, mostly occurring in the cytoplasm from spermatogonia and spermatocytes. PMID- 29758297 TI - Effect of negative pressure wound therapy on molecular markers in diabetic foot ulcers. AB - Diabetic foot ulcers are one of the most common complications of diabetes with high morbidity and mortality. Negative pressure wound therapy (NPWT) is one of the treatment modalities that facilitates the wound healing process; however, its molecular mechanism remains unclear. The aim of this study was to investigate the mechanism of action of NPWT in the treatment of diabetic foot ulcers via measuring the tissue expression of genes related to the wound healing process. The study included 40 patients with diabetic foot ulceration, 20 of them received NPWT and the other 20 were a control group treated with advanced moist therapy. Granulation tissue biopsies were obtained before and 10 days after treatment in both groups and subjected to real-time polymerase chain reaction to measure the mRNA expression of TGF-beta1, VEGF, TNF-alpha, IL-1beta, MMP-1, MMP-9 and TIMP-1 which are involved in the wound healing pathway. After 10 days of treatment with NPWT, the mRNA levels of IL-1beta, TNF-alpha, MMP-1, and MMP-9 were significantly downregulated, while the levels of VEGF, TGF-beta1 and TIMP-1 were significantly increased. Our study demonstrated that NPWT promotes wound healing in diabetic foot ulcers possibly by affecting growth factors, inflammatory cytokines, and matrix metalloproteinases. PMID- 29758298 TI - Transcriptome sequencing for identification of diapause-associated genes in fall webworm, Hyphantria cunea Drury. AB - Fall webworm, Hyphantria cunea Drury (Lepidoptera: Arctiidae) is extremely adaptable and highly invasive in China as a defoliator of ornamental and forest trees. Both voltinism and diapause strategies of fall webworm in China are variable, and this variability contributes to it invasiveness. Little is known about molecular regulation of diapause in fall webworm. To gain insight into possible mechanisms of diapause induction, high-throughput RNA-seq data were generated from non-diapause pupae (NDP) and diapause pupae (DP). A total of 58,151 unigenes were assembled and researched against nine public databases. In total, 29,013 up-regulated and 3451 down-regulated unigenes were differentially expressed by DP when compared with those of NDP. Genes encoding proteins such as UDP-glycosyl transferase (UGT), cytochrome P450 and Hsp70 were predicted to be involved in diapause. Moreover, GO function and KEGG pathway enrichments were performed on all differentially expressed genes (DEGs) and showed that cell cycle and insulin signaling pathways may be related to the diapause of the fall webworm. This study provides valuable information about the fall webworm transcriptome for future gene function research, especially as it relates to diapause. PMID- 29758299 TI - Autophagy regulates apoptosis by targeting NOXA for degradation. AB - Apoptosis and autophagy mutually regulate various cellular physiological and pathological processes. The crosstalk between autophagy and apoptosis is multifaceted and complicated. Elucidating the molecular mechanism of their crosstalk will advance the therapeutic applications of autophagy for treating cancer and other diseases. NOXA, a BH3-only member of the BCL-2 family, was reported to induce apoptosis and promote autophagy. Here, we report that autophagy regulates apoptosis by targeting NOXA for degradation. Inhibiting autophagy increases NOXA protein levels by extending the protein half-life. NOXA accumulation effectively suppresses tumor cell growth by inducing apoptosis, which is further enhanced when p53 is present. Mechanistically, NOXA is hijacked by p62 as autophagic cargo, and its three lysine residues at the C-terminus are necessary for NOXA degradation in lysosomes. Taken together, our study demonstrates that NOXA serves as a bridge in the crosstalk between autophagy and apoptosis and implies that autophagy inhibitors could be an effective therapy for cancer, especially wild-type p53-containing cancer. PMID- 29758300 TI - Alzheimer's disease and the autophagic-lysosomal system. AB - Age-related neurodegenerative diseases are of critical concern to the general population and research/medical community due to their health impact and socioeconomic consequences. A feature of most, if not all, neurodegenerative disorders is the presence of proteinopathies, in which misfolded or conformationally altered proteins drive disease progression and are often used as a primary neuropathological marker of disease. In particular, Alzheimer's disease (AD) is characterized by abnormal accumulation of protein aggregates, primarily extracellular plaques composed of the Abeta peptide and intracellular tangles comprised of the tau protein, both of which may indicate a primary defect in protein clearance. Protein degradation is a key cellular mechanism for protein homeostasis and is essential for cell survival but is disrupted in neurodegenerative diseases. Dysregulation in proteolytic pathways - mainly the autophagic-lysosomal system (A-LS) and the ubiquitin-proteasome system (UPS) - has been increasingly associated with proteinopathies in neurodegenerative diseases. Here we review the role of dysfunctional autophagy underlying AD related proteinopathy and discuss how to model this aspect of disease, as well as summarize recent advances in translational strategies for targeted A-LS dysfunction in AD. PMID- 29758301 TI - Lipid roles in hERG function and interactions with drugs. AB - Human-ether-a-go-go-related channel (hERG) is a voltage gated potassium channel (Kv11.1) abundantly expressed in heart and brain tissues. In addition to playing an important role in mediation of repolarizing K+ currents (IKr) in Action Potential (AP), hERG is notorious for its propensity to interact with various medications. The drug-induced block of K+ currents across hERG channel are strongly associated with dysrhythmic conditions collectively known as drug induced long-QT-syndrome. The recent availability of the high-resolution Cryo-EM structures for the hERG channel has provided unique opportunity to resolve structural mechanisms involved into the process of voltage-gating of hERG channels, map various roles played by components of ventricular and neuronal membranes and then to connect it to cellular pathways through which diverse chemical compounds might be affecting function of the channel. Specifically, lipids and lipid derivatives such as polyunsaturated fatty acids (PUFAs), ceramides and steroids have been shown to directly interact with the lipid facing amino acids in various Kv channels including hERG. In this review, possible lipophilic pathways of hERG activators and blockers, together with the existence of fenestration windows and effects of PUFAs, ceramides and steroids are explored throughout different sections. Finally, the interplay between long QT inducing drugs and phospholipidosis is briefly discussed. PMID- 29758302 TI - Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons. AB - Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 +/- 0.18 MUM), glycine (EC50 11.0 +/- 3.7 MUM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter screening of lead series compounds towards unwanted GABAA receptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist. PMID- 29758303 TI - Is protein structure enough? A review of the role of lipids in SLC6 transporter function. AB - SLC6 neurotransmitter transporters facilitate the Na+- and Cl--dependent uptake of amino acids and amino acid derivatives into cells. Disrupting transport leads to a range of neurological disorders. However, the SLC6 substrate transport mechanism is a topic of ongoing debate. Here, we review the prominent SLC6 substrate transport mechanisms through the lens of molecular dynamics simulations. SLC6 transporters are membrane proteins, yet their transport mechanism(s) have largely been studied without considering the impacts of synaptic lipid composition, or endogenous lipid modulators, on transporter structure and function. In this review, we highlight the importance of studying membrane transporters in an appropriate membrane model, and present opportunities for the community to glean understanding and insight into SLC6 transporter structure and function-in particular transport mechanism(s)-when both membrane lipids and endogenous lipid modulators are considered. PMID- 29758304 TI - Effects of behavioral counseling on cardiometabolic biomarkers: A longitudinal analysis of the Japanese national database. AB - In Japan, health insurers are obliged to conduct Specific Health Checkup (SHC) for middle-aged and elderly persons. High-risk persons are referred to Specific Health Guidance (SHG) to receive behavioral counseling based on individual action plans including targets for modification of daily energy balance through diet and physical activity. Using individual-level observational data, we examined the effects of diet and physical activity counseling on cardiometabolic biomarkers across the country. Subjects were 363,440 high-risk persons aged 40-64 who participated in intensive support in SHG for >=3 months between April 2008 and March 2012. We considered participants as receiving counseling on diet alone, physical activity alone, combined, or neither if they had targets for diet only, physical activity only, both, or neither, respectively. Biomarkers included body mass index, waist circumference, systolic and diastolic blood pressure, high density lipoprotein cholesterol, and hemoglobin A1c. Under the difference-in differences approach, we used multivariable linear regression on repeated measures of biomarkers at SHCs before and after SHG and estimated the effects of each counseling type as an interaction with time of SHC. Compared with neither counseling, diet and physical activity counseling, alone or combined, were significantly associated with additional improvements in biomarkers after SHG, for example, body mass index (men: 0.03-0.06 kg/m2, women: 0.10-0.15 kg/m2) and waist circumference (men: 0.16-0.29 cm, women: 0.43-0.47 cm) in both sexes and high-density lipoprotein cholesterol in men (0.13-0.29 mg/dL). Modest improvements in biomarkers were associated with diet and physical activity counseling, although effect sizes were small. PMID- 29758306 TI - Drug use among youth: National survey data support a common liability of all drug use. AB - The prevalence of substance use disorders in adults is higher if substance use is initiated during adolescence, underscoring the importance of youth substance use prevention. We examined whether the use of one substance by adolescents is associated with increased risk for using any other substance, regardless of use sequences. In 2017 we examined data from 17,000 youth aged 12-17 who participated in the 2014 National Survey on Drug Use and Health, a sample of nationally representative data on substance use among the U.S. civilian, noninstitutionalized population aged 12 or older. Descriptive analyses and multivariable logistic regression models were applied. After controlling for age, sex, and race/ethnicity, compared with youth without past-month marijuana use, youth with past-month marijuana use were 8.9 times more likely to report past month cigarette use, 5.6, 7.9 and 15.8 times more likely to report past-month alcohol use, binge use, or heavy use (respectively), and 9.9 times more likely to report past-month use of other illicit drugs. The prevalence of past-month use of cigarettes, marijuana, and other illicit drugs was significantly higher among past-month alcohol users compared with youth without past-month alcohol use, and increased as intensity of alcohol use rose. Among past-month cigarette smokers, the prevalence of marijuana, other illicit drugs, and alcohol use were each significantly higher than youth without past-month cigarette use. Youth marijuana use, cigarette smoking, or alcohol consumption is associated with other substance use. This finding has importance for youth prevention, supporting a message no use by youth of any substance. PMID- 29758305 TI - Maternal smoking during pregnancy and academic achievement of offspring over time: A registry data-based cohort study. AB - Few studies have assessed the cumulative impact of maternal smoking during pregnancy (MSDP) on scholastic outcomes over time. We examined the relations between MSDP and academic achievement in the 4th, 7th and 10th grades using registry data collected at birth, during the neonatal period, and at each grade level from the 2000, LIFECOURSE study birth cohort in Reykjavik, Iceland (N = 1151, girls = 49.3%). Latent growth modeling showed that MSDP influenced Icelandic achievement scores, standardized to a range from 0 to 60, at baseline (beta = -0.04), and over time (beta = -0.05). Likewise, MSDP was negatively associated with standardized mathematics scores at baseline (beta = -0.09) and continued to exert a negative impact on mathematics scores over time (beta = 0.08) after controlling for gender, income, cohabitation, and baseline mathematics and Icelandic achievement scores. Results provide evidence of the persistent negative impact of MSDP on academic achievement in offspring. Findings support the proposition that children whose mothers smoke during the first trimester of pregnancy are, on average, at greater risk for poor scholastic outcomes over time than children whose mothers do not smoke during their first trimester. To our knowledge, this is the first study using a longitudinal cohort design to assess whether the impacts of maternal smoking during pregnancy may persist over time. This study contributes to the current state of knowledge by providing an assessment that focuses on the impact of smoking during pregnancy on academic achievement from childhood into early adolescence. PMID- 29758308 TI - Synthesis and evaluation of acryloylated starch-g-poly (Acrylamide/Vinylmethacrylate/1-Vinyl-2-pyrrolidone) crosslinked terpolymer functionalized by dimethylphenylvinylsilane derivative as a novel polymer flooding agent. AB - Starch is a natural biopolymer that subjected to various chemical modifications through different industrial applications. Molecular structure of starch allow its grafting with different vinyl monomers in the presence of crosslinking agents to synthesize cross-linked hydrogels, which used in enhanced oil recovery (EOR) applications, water shutoff and drag reduction. Application of native starch in the field of petroleum reservoirs as a flooding agent suffer from some limitations concerned with microbial degradation, thermal and salinity resistance under harsh petroleum reservoir conditions. In the current research, we stated the synthesis of acryloylated starch then it's grafting with poly (Acrylamide/Vinylmethacrylate/1-Vinyl-2-pyrrolidone) terpolymer in presence of dimethylphenylvinylsilane through emulsification polymerization. Characterization and structure determination occur by different spectroscopic techniques as stated throughout the manuscript. Rheological and solution properties carried out as a function of shear rate, salinity and temperature at simulated reservoir conditions. Flooding tests carried out through linear-dimensional sandstone model at simulated reservoir conditions, and recovered oil amount calculated on volumetric basis. The obtained results indicate that the prepared starch-g terpolymer can tolerate to severe flooding conditions of high temperature and salinity, moreover it can increase recovery factor up to 49% of residual oil saturation so considered as a promised EOR candidate. PMID- 29758307 TI - Lactoferrin denaturation induced by anionic surfactants: The role of the ferric ion in the protein stabilization. AB - Here, investigation was made of the interaction between lactoferrin (Lf) and the anionic surfactants sodium dodecyl sulfate (SDS), sodium dodecylbenzene sulfonate (SDBS), and sodium decyl sulfate (DSS), using isothermal titration calorimetry, Nano differential scanning calorimetry (NanoDSC), and fluorescence spectroscopy. The Lf-surfactant interaction was enthalpically favorable (the integral enthalpy change ranged from -5.99 kJ mol-1, for SDS at pH 3.0, to -0.61 kJ mol-1, for DSS at pH 12.0) and promoted denaturation of the protein. The Lf denaturation efficiency followed the order DSS < SDS < SDBS. The adsorption capacity of the protein with respect to surfactant strongly depended on pH and the surfactant structure, reaching a maximum value of 505 SDBS molecules per gram of Lf at pH 3.0. The different efficiencies of the surfactants in denaturing Lf were attributed to the balance of hydrophobic and electrostatic interactions, which also depended on pH and the surfactant structure, highlighting the SDBS tryptophan residue specific interaction, where SDBS acted as a quencher of fluorescence. Interestingly, the NanoDSC and fluorescence measurements showed that the ferric ion bound to Lf increased its stability against denaturation induced by the surfactants. The results have important implications for understanding the influence of surfactants on structural changes in metalloproteins. PMID- 29758309 TI - Intrinsic structural versatility of the highly conserved 412-423 epitope of the Hepatitis C Virus E2 protein. AB - HCV infection is a major threaten for human health as it affects hundreds of million people worldwide. Here we investigated the conformational properties of the 412-423 fragment of the envelope E2 protein, one of the most immunogenic regions of the virus proteome whose characterization may provide interesting insights for anti-HCV vaccine development. The spectroscopic characterization of the polypeptide unravels its unexpected tendency to form amyloid-like aggregates. When kept in monomeric state, it shows a limited tendency to adopt regular secondary structure. Enhanced molecular dynamics simulations, starting from four distinct conformational states, highlight its structural versatility. Interestingly, all multiform conformational states of the polypeptide detected in crystallographic complexes with antibodies are present in the structural ensemble of all simulations. This observation corroborates the idea that known antibodies recognize this region through a conformational selection mechanism. Accordingly, the design of effective anti-HCV vaccines should consider the intrinsic flexibility of this region. The structural versatility of the 412-423 region is particularly puzzling if its remarkable sequence conservation is considered. It is likely that flexibility and sequence conservation are important features that endow this epitope with the ability to accomplish distinct functions such as immunity escape and interaction with host receptors. PMID- 29758310 TI - Chemical synthesis and characterization of chitosan/silver nanocomposites films and their potential antibacterial activity. AB - This study provides the optimum preparation parameters for functional chitosan silver nanocomposite (CSN) films with promising antibacterial efficacy though prepared with very low silver nitrate (AgNO3) concentration. Chitosan nano-silver composites were fabricated by In-situ chemical method utilizing the reducing ability of sodium borohydride (NaBH4) and afterward casted into films. Utilization of response surface methodology, NCSS, and SigmaPlot for the optimization of CSN and their predicted antibacterial efficacy assessment of the selected bacterial strains (standard and clinical) was the essential part of the study. The cumulative silver ions released from the CSN films was examined by AAS and was found pH dependent. The developed nanocomposite films exhibited strong antibacterial activity against ATCC strains of Gram-positive Staphylococcus aureus, Gram-negative bacteria (Pseudomonas aeruginosa) and clinically isolated strains of MRSA. The antibacterial activity CSN films were compared with three commercially available dressings (Aquacel Ag(r), Bactigras(r), and Kaltostat(r)) and Quench cream. Statistical analysis of the results indicated that the developed CSN films were equally or even more effective than commercial products. Thus the fabricated CSN films may act as a potential candidate to overcome the emerging antibiotic resistance particularly in hospital-acquired skin infections caused by MRSA. PMID- 29758311 TI - Over-expression of the poplar expansin gene PtoEXPA12 in tobacco plants enhanced cadmium accumulation. AB - As important cell wall proteins in plants, expansins are involved in a serious of abiotic stress resistance such as drought, heat, salt, even heavy metals. To understand the role of expansins in cadmium (Cd) stress, we analyzed the expression patterns of 36 expansin genes in Populus tomentosa. A Cd-induced expansin gene, PtoEXPA12, was identified, cloned, and transformed into tobacco plants. After treatment with Cd, the transgenic plants showed stronger symptoms of Cd toxicity as to the wild-type tobacco plants. Further physiological tests showed that the transformants had higher relative electrolyte leakage and superoxide dismutase activity, more malondialdehyde and H2O2 content, and lower chlorophyll content in Cd stress. Cd content measurement showed it is 1.40-2.07 fold higher and 1.29-1.38-fold higher separately in roots and shoots of transgenic plants than those in wild-type plants, while the transfer coefficient value kept invariably even decreased. Therefore, PtoEXPA12 was really involved in Cd uptake and accumulation, and led to Cd toxicity of cells. It would be a potentially applicable part in phytoremediation system. PMID- 29758312 TI - Protocatechuic acid methyl ester modulates fluoride induced pulmonary toxicity in rats. AB - We have found that protocatechuic acid methyl ester (PCAME) attenuates fluoride (F-) toxicity in lung epithelial cells (A549). However, this finding has to be confirmed with in vivo studies. Further, the effect of PCAME on F- induced pulmonary fibrosis and inflammation remains limited. Hence, the present study is aimed to determine the protective effect of PCAME against F- induced pulmonary toxicity in female albino Wistar rats. The animals were treated with sodium fluoride (NaF, 300 ppm in drinking water ad libitum) alone or in combination with PCAME (25 or 50 mg/kg bw/day by oral intubation) for 60 days and analyzed for changes in lung histology, oxidative stress, inflammation, apoptosis and fibrosis markers. PCAME supplementation prevented the F- induced changes in the above markers. Also, altered serum and bronchoalveolar lavage fluid markers and lung histoarchitecture were also restored by PCAME. F- induced modulations in oxidative stress markers, TUNEL positive cells and mRNA levels of inflammatory genes further normalized by PCAME in lung tissues. These results revealed that PCAME effectively attenuated the F- induced changes in the rat lungs by reducing cellular F- accumulation and enhancing antioxidants level. Thus PCAME can be used as a nutraceutical agent for F- toxicity. PMID- 29758313 TI - Flavonoids as protective agents against oxidative stress induced by gentamicin in systemic circulation. Potent protective activity and microbial synergism of luteolin. AB - The flavonoids effect on gentamicin (GEN)-induced oxidative stress (OS) in systemic circulation was evaluated in terms of reactive oxygen species (ROS) production, enzymatic antioxidant defenses superoxide dismutase (SOD) and catalase (CAT), and lipid peroxidation (LP) in vitro on human leukocytes and in vivo on rat whole blood. The inhibitory activity of ROS was ATS < QTS < isovitexin < vitexin < luteolin. Luteolin, the most active, showed more inhibition in ROS production than vitamin C (reference inhibitor) in mononuclear cells and a slightly lower protective behavior compared to this inhibitor in polymorphonuclear cells. In both cellular systems, luteolin tends to level SOD and CAT activities modified by GEN, reaching basal values and preventing LP. In Wistar rats, GEN plus luteolin can suppress ROS generation, collaborate with SOD and CAT and diminish LP produced by GEN at therapeutic doses. Finally, luteolin and antibiotic association was evaluated on the antimicrobial activity in S. aureus and E. coli showing a synergism between GEN and luteolin on S. aureus ATCC and an additive effect on E. coli ATCC. Therefore, simultaneous administration of luteolin and GEN could represent a potential therapeutic option capable of protecting the host against OS induced by GEN in the systemic circulation while enhancing the antibacterial activity of GEN. PMID- 29758314 TI - Realistic and aggregated exposure assessment of Korean men and women to color make-up products. PMID- 29758316 TI - Double limbal dermoid with Tessier's paramedian facial cleft. AB - We report the case of mandibulofacial dysostosis in a 9-year-old Indian boy presenting with unilateral double limbal dermoid in superotemporal and superonasal quadrants, high arched palate, and paramedian cleft in the right side of the nose with abnormal dentition. A multidisciplinary approach to treatment was advised. The dermoid cysts were excised surgically with a reconstruction of the ocular surface using multilayered amniotic membrane transplantation. PMID- 29758315 TI - Ameliorative role of ferulic acid against diabetes associated oxidative stress induced spleen damage. AB - Spleen, a secondary lymphoid organ, is the site of initiation of most of the immune responses. The present study is centered on the ameliorative role of ferulic acid against diabetic complications in the spleen of male Wistar rats. Induction of diabetes by STZ (at a dose of 50 mg kg-1 body wt, i.p.) reduced the spleen size, plasma insulin level, enhanced the blood glucose level and disrupted the intracellular antioxidant machineries along with the depletion of splenic white pulp. Induction of oxidative stress mediated inflammation and apoptosis (upregulation in the levels of inflammatory cytokines, translocation of NF KB in the nucleus, alteration in Bax/Bcl-2 ratio, release of cytochrome c from mitochondria, activation of caspase-9 and 3, PARP cleavage and DNA fragmentation) were evidenced from immunoblot analyses, DNA fragmentation and TUNEL assay. However, ferulic acid administration post diabetes induction, (at a dose of 50 mg kg-1 body wt, orally for eight weeks) could reverse such adverse effects. Therefore, ferulic acid, as a potential therapeutic agent may hold promise in evading oxidative stress mediated diabetic splenotoxicity in rats. PMID- 29758317 TI - Reply. PMID- 29758319 TI - Preface: Toward a new era of the Japanese Society for Neurochemistry. PMID- 29758318 TI - Proteome and behavioral alterations in phosphorylation-deficient mutant Collapsin Response Mediator Protein2 knock-in mice. AB - CRMP2, alternatively designated as DPYSL2, was the first CRMP family member to be identified as an intracellular molecule mediating the signaling of the axon guidance molecule Semaphorin 3A (Sema3A). In Sema3A signaling, cyclin-dependent kinase 5 (Cdk5) primarily phosphorylates CRMP2 at Ser522. Glycogen synthase kinase-3beta (GSK-3beta) subsequently phosphorylates the residues of Thr509 and Thr514 of CRMP2. Previous studies showed that CRMP2 is involved in pathogenesis of neurological disorders such as Alzheimer's disease. In Alzheimer's disease, hyper-phosphorylated forms of CRMP2 are accumulated in the paired helical filaments. To get insight into the possible involvement of the phosphorylation of CRMP2 in pathogenesis of neurological disorders, we previously created CRMP2 S522A knock-in (crmp2ki/ki) mice and demonstrated that the phosphorylation of CRMP2 at Ser522 is involved in normal dendrite patterning in cortical neurons. However, the behavioral impact and in vivo signaling network of the CRMP2 phosphorylation are not fully understood. In this study, we performed behavioral and proteomics analysis of crmp2ki/ki mice. The crmp2ki/ki mice appeared healthy and showed no obvious differences in physical characteristics compared to wild type mice, but they showed impaired emotional behavior, reduced sociality, and low sensitivity to pain stimulation. Through mass-spectrometry-based proteomic analysis, we found that 59 proteins were increased and 77 proteins were decreased in the prefrontal cortex of crmp2ki/ki mice. Notably, CRMP3, CRMP4, and CRMP5, the other CRMP family proteins, were increased in crmp2ki/ki mice. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses identified 14 pathways in increased total proteins and 13 pathways in decreased total proteins which are associated with the pathogenesis of Parkinson's, Alzheimer's, and Huntington's diseases. We also detected 20 pathways in increased phosphopeptides and 16 pathways in decreased phosphopeptides including "inflammatory mediator regulation of TRP channels" in crmp2ki/ki mice. Our study suggests that the phosphorylation of CRMP2 at Ser522 is involved in the signaling pathways that may be related to neuropsychiatric and neurodegenerative diseases and pain. PMID- 29758321 TI - Production of soluble bioactive mouse leukemia inhibitory factor from Escherichia coli using MBP tag. AB - Embryonic stem cells and induced pluripotent stem cells depend on one of cytokines called leukemia inhibitory factor (LIF) to retain their undifferentiated state and pluripotency. Nevertheless, further progresses of stem cell scientific investigation and its possible application are limited owing to the expense of commercial LIF. Here we introduced a simple, practical and high level expression of MBP-mouse LIF through Escherichia coli system which was bioactive. The mLIF cDNA was inserted into vector of pMAL-C2X in order to generate N-terminal MBP-mLIF recombinant proteins in the cytoplasm of Escherichia coli. MBP-mLIF as a soluble form was expressed. One-step purification through gravitational affinity chromatography was accomplished to acquire high purity (>92%) MBP-mLIF. The MBP-mLIF products specifically suppressed the growth of M1cells in a dose-dependent pattern. MBP-mLIF also was proved the ability to maintain the pluripotency of iPSCs. These outcomes revealed that the N-end MBP tags of the MBP-mLIF did not obstruct mLIF bioactivity. This method to generate recombinant MBP-mLIF is a simple, practical, economical and user-friendly protocol. PMID- 29758320 TI - Neoadjuvant crizotinib in ALK-rearranged inflammatory myofibroblastic tumor of the urinary bladder: A case report. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that involves various organs, but has a predilection for the urinary bladder in the genitourinary tract. Given that approximately half of all IMT cases have anaplastic lymphoma kinase (ALK) rearrangements, the ALK inhibitor crizotinib is suggested as a promising treatment for unresectable cases. No reports on neoadjuvant crizotinib therapy for locally advanced IMT of the bladder are available. PRESENTATION OF CASE: We report a case of a 17-year-old Japanese boy referred to our institution for painful urination and increased urinary frequency. He was diagnosed with ALK-positive IMT via transurethral resection of the bladder tumor. Computed tomography (CT) revealed a 5-cm mass and extramural invasion at the bladder dome. The diagnosis was locally advanced IMT of the bladder. We decided that partial cystectomy can be performed if neoadjuvant crizotinib therapy reduced the tumor size. After 2 months of administration, CT showed that the longest tumor diameter was reduced by 48%. Thus, we performed partial cystectomy, and the surgical margin was negative. No recurrence developed for over 1 year. DISCUSSION: IMT has intermediate malignant potential because its clinical course is relatively indolent with low risk of distant metastasis. As this patient is young and IMT of the bladder has good prognosis after surgical resection, bladder-preserving surgery is the most preferred approach. CONCLUSION: Neoadjuvant crizotinib therapy may be effective for large, locally advanced, and difficult to resect tumors. PMID- 29758322 TI - Endovascular Repair of an Inadvertent Right Vertebral Artery Rupture during Dialysis Catheter Insertion. AB - Central venous (CV) catheterization is not only an invaluable diagnostic modality but also an essential therapeutic tool for the treating physician, enabling rapid and reliable intravenous administration of drugs and fluids, providing venous access to patients undergoing long-term continuous or repeated intravenous treatment such as chemotherapy, or it can be used for hemodialysis in patients suffering from acute or chronic renal disease. On the other hand, CV catheterization can lead to a wide range of life-threatening complications for the patient especially if left untreated or become late-diagnosed. In particular, arterial injuries are among the most feared complications that require early clinical suspicion for prompt diagnosis and management. We report the case of a 79-year-old female dialysis patient who suffered from a vertebral artery (VA) injury complicated by a herald bleeding on the third postintervention day after an internal jugular vein dialysis catheter replacement. The patient initially presented neurological signs of a stroke and urgently treated endovascularly after immediate diagnosis of VA rupture was made. Imaging techniques are evidence based tools that help minimize these mechanical complications, including inadvertent arterial puncture and therefore should be practiced and taught in training programs to avoid the potentially devastating consequences of CV catheterization. PMID- 29758324 TI - Exertional Abdominal Pain as a Rare Presenting Manifestation of Chronic Mesenteric Ischemia from a Single Mesenteric Vessel Stenosis. AB - We present an atypical manifestation of chronic mesenteric ischemia in a patient with progressively worsening exertional abdominal pain. Imaging modalities revealed significant isolated stenosis of superior mesenteric artery (SMA). Successful angioplasty and stenting of SMA relieved patient's symptoms, thereby confirming the diagnosis of chronic mesenteric ischemia. Exertional abdominal pain may be a unique manifestation of this disease, but when it presents, clinicians should have acute clinical awareness of this diagnosis. PMID- 29758325 TI - High Glucose Upregulated Vascular Smooth Muscle Endothelin Subtype B Receptors via Inhibition of Autophagy in Rat Superior Mesenteric Arteries. AB - Autophagy plays an important role in cardiovascular diseases. High glucose (HG) upregulates endothelin subtype B (ETB) receptors in vascular smooth muscle cells (VSMCs). However, it is unclear as to whether autophagy is involved in HG-induced upregulation of ETB receptors in VSMCs. The present study was designed to examine the hypothesis that HG upregulates ETB receptors by inhibiting autophagy in VSMCs. We studied HG-treated rat superior mesenteric artery (SMA) without endothelium in the presence and absence of 5-aminoimidazole-4-carboxamide 1-beta D-ribofuranoside (AICAR), rapamycin, or MHY1485 for 24 hr. We measured contractile responses to sarafotoxin 6c (S6c) (an ETB receptor agonist) using a sensitive myograph. Levels of protein expression were determined using Western blotting. HG impaired autophagy and increased the levels of ETB receptor protein expression and ETB receptor-mediated contractile responses to S6c in SMA. However, these effects were reversed by AICAR (an agonist of adenosine monophosphate [AMP]-activated protein kinase [AMPK]) and rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]). However, MHY1485 (an agonist of mTOR) did not upregulate the AICAR-inhibited ETB receptor-mediated contractile responses or ETB receptor protein expression in the presence of HG. These data suggest that HG upregulated ETB receptors by inhibiting autophagy in VSMCs via AMPK and mTOR signaling pathways. PMID- 29758323 TI - Why Do Vascular Surgeons Get Sued? Analysis of Claims and Outcomes in Malpractice Litigation. AB - BACKGROUND: The objective of the study was to analyze causes and outcomes of malpractice claims against vascular surgeons in the United States. METHODS: Cases entered into the Westlaw database from January 1, 1999 to December 31, 2014 were reviewed. Search terms "vascular" and "surgeon" were used. Data were compiled on the allegation, subject matter, and outcome of each case. Additional data including demographics of the defendant were obtained from the U.S. News Health reports on practicing physicians. RESULTS: Of a total of 785 cases identified from the Westlaw database using the search terms "vascular" and "surgeon", 485 (61.8%) were identified where a vascular surgeon was the defendant or expert witness. Of these, 135 (27.8%) had a vascular surgeon identified as a defendant. Among these 135 cases, 88 (65.2%) were found for the defendant with 31 (23%) and 15 (11.1%) being found for the plaintiff or settled, respectively. Of the 31 cases found for the plaintiff, the median award was $750,000 and mean award was $1,830,000. Mean time from incident to verdict was 4.8 years. The most common procedures which led to litigation were open or endovascular peripheral revascularization (PR) (14.8%), carotid interventions (CIs) (11.85%), aortic interventions (AI) (11.1%), vascular trauma (9.63%), dialysis access (8.15%), and venous surgery (5.93%). The most common allegation was "failure to diagnose and treat" (48.9%), followed by complication of open surgery (31.85%) and negligent procedure (25.19%). The most common injuries reported were death (31.85%), major amputation (23.7%), neurovascular injury (14.8%), and bleeding (5.9%). CONCLUSIONS: Analysis of vascular surgery malpractice litigation in the Westlaw database revealed details regarding the subject matter and outcomes of these cases. Through this closed claims analysis, the most common procedures leading to litigation were found to be PR, CI, and AI and not thoracic outlet syndrome procedures as commonly believed. Furthermore, the most common allegations were a "failure to diagnose and treat" and "open surgical complication". Analysis of the salient features and outcomes in these cases can provide a framework for heightened awareness of issues which lead to malpractice claims and can ultimately improve patient care and safety. PMID- 29758327 TI - Oxidative Stress in Aortas of Patients with Advanced Occlusive and Aneurysmal Diseases. AB - BACKGROUND: Aortoiliac occlusive disease (AOD) and abdominal aortic aneurysm (AAA) are very important cardiovascular diseases that present different aspects of pathophysiology; however, oxidative stress and inflammatory response seem be relevant in both of them. Our objective was to evaluate oxidative damage and degree of inflammatory infiltrate in aortas of patients surgically treated for AOD and AAA. MATERIALS AND METHODS: Levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and myeloperoxidase (MPO) expression as well as nitrite levels and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in aortas of patients with AOD (n = 16) or AAA (n = 14), while the control group was formed by cadaveric organ donors (n = 10). We also analyzed the degree of inflammatory infiltrate in these aortas. RESULTS: There was an increase in ROS levels and NADPH oxidase activity in patients with AOD and AAA when compared with the control group, and the AOD group demonstrated higher ROS production and NADPH oxidase activity and also nitrite levels when compared with the AAA group (P < 0.001). On the other hand, an increase of SOD activity in the AOD group and CAT activity in the AAA group was observed. Inflammatory infiltrate and MPO expression were higher in the AOD group when compared with the control group (P < 0.05). CONCLUSIONS: Oxidative stress is relevant in both AOD and AAA, though AOD presented higher ROS levels and NADPH activity. Increased activities of antioxidant enzymes may be a compensatory phenomenon which occurs in aortas of patients with AOD and AAA. Perhaps, a relationship between oxidative stress and degree of inflammatory infiltrate may exist in the pathophysiology of AOD and AAA. PMID- 29758326 TI - Invited Commentary. PMID- 29758328 TI - Regulation of Yes-Associated Protein by Laminar Flow. AB - BACKGROUND: The cells lining the endothelium of blood vessels are recognized as playing critical roles in vascular health and disease. The mechanisms that regulate endothelial cells (ECs) proliferation and release of mediators remain poorly understood but represent a potential source of disease modulation. Actin cytoskeleton remodeling and cell shape have been suggested as key regulators of phosphorylation of yes-associated protein (YAP) which controls cellular growth and proliferation. Because different types of flow have been shown to affect cell shape and cytoskeleton differently, we hypothesized that the level of phosphorylated yes-associated protein (pYAP; serine 127) decreases in EC exposed to pulsatile uniform flow or steady laminar flow, whereas exposure to pulsatile disturbed flow causes an increase or no change. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to pulsatile uniform flow, pulsatile disturbed flow, or steady laminar flow and analyzed by immunoblotting. RESULTS: Exposure of HUVECs to steady laminar flow caused a significant decrease in the levels of pYAP (69.7 + 2.6%, P < 0.05), whereas total YAP levels remained nearly unchanged. Conversely, exposure to either pulsatile uniform or disturbed flow caused a significant decrease in the levels of both pYAP (63.2 + 10.9% and 69.8 + 11.9%, respectively; P < 0.05) and total YAP (57.1 + 17.8% and 58.4 + 16.3%, respectively; P < 0.05). Addition of MG132, a ubiquitin-proteasome system inhibitor, failed to significantly inhibit the decrease in the levels of total YAP in HUVECs exposed to either pulsatile uniform or disturbed flow. CONCLUSIONS: Flow causes a decrease in pYAP. The observed decrease in total YAP levels with pulsatile flow is due to degradation via a proteasome-independent mechanism. This may be a potential target for intervention for disease states such as atherosclerosis and intimal hyperplasia. PMID- 29758329 TI - Endovascular Treatment for a True Aneurysm of the Transplant Renal Artery using Noncovered Stent-Assisted Coil Embolization. AB - True degenerative aneurysms involving the donor renal artery after kidney transplantation are rather rare. The indications for operation and optimal therapy to combat this vascular complication are still not clear. Surgical revision has been used as a potential treatment: nonetheless, it has been associated with high risk of complications. In the present study, we report on a 31-year-old woman with a true aneurysm located at a transplant renal artery after transplantation which was successfully managed with stent-assisted coil embolization, resulting in occluded aneurysm sac and well-preserved renal function without any complication. We present technical details of this endovascular procedure, which may be useful for transplant renal artery aneurysm repair in high-risk surgical patients. PMID- 29758331 TI - Liver regeneration requires Yap1-TGFbeta-dependent epithelial-mesenchymal transition in hepatocytes. AB - BACKGROUND & AIMS: Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFbeta, since TGFbeta signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. METHODS: Wild-type mice underwent 70% partial hepatectomy (PH); TGFbeta expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24-72 h after PH. To determine the role of Yap1 in regulating TGFbeta signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1flox/flox mice. RESULTS: TGFbeta expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1, a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1alpha1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. CONCLUSION: Interactions between the TGFbeta and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFbeta-enriched microenvironment and regenerate injured livers. LAY SUMMARY: The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer. PMID- 29758332 TI - Reply to: "Real-world data on antiviral treatments for hepatitis C virus infections: Can we define intention to treat or per protocol analyses?" PMID- 29758330 TI - Human liver infiltrating gammadelta T cells are composed of clonally expanded circulating and tissue-resident populations. AB - BACKGROUND & AIMS: gammadelta T cells comprise a substantial proportion of tissue associated lymphocytes. However, our current understanding of human gammadelta T cells is primarily based on peripheral blood subsets, while the immunobiology of tissue-associated subsets remains largely unclear. Therefore, we aimed to elucidate the T cell receptor (TCR) diversity, immunophenotype and function of gammadelta T cells in the human liver. METHODS: We characterised the TCR repertoire, immunophenotype and function of human liver infiltrating gammadelta T cells, by TCR sequencing analysis, flow cytometry, in situ hybridisation and immunohistochemistry. We focussed on the predominant tissue-associated Vdelta2- gammadelta subset, which is implicated in liver immunopathology. RESULTS: Intrahepatic Vdelta2- gammadelta T cells were highly clonally focussed, with single expanded clonotypes featuring complex, private TCR rearrangements frequently dominating the compartment. Such T cells were predominantly CD27lo/- effector lymphocytes, whereas naive CD27hi, TCR-diverse populations present in matched blood were generally absent in the liver. Furthermore, while a CD45RAhi Vdelta2- gammadelta effector subset present in both liver and peripheral blood contained overlapping TCR clonotypes, the liver Vdelta2- gammadelta T cell pool also included a phenotypically distinct CD45RAlo effector compartment that was enriched for expression of the tissue tropism marker CD69, the hepatic homing chemokine receptors CXCR3 and CXCR6, and liver-restricted TCR clonotypes, suggestive of intrahepatic tissue residency. Liver infiltrating Vdelta2- gammadelta cells were capable of polyfunctional cytokine secretion, and unlike peripheral blood subsets, were responsive to both TCR and innate stimuli. CONCLUSION: These findings suggest that the ability of Vdelta2- gammadelta T cells to undergo clonotypic expansion and differentiation is crucial in permitting access to solid tissues, such as the liver, which results in functionally distinct peripheral and liver-resident memory gammadelta T cell subsets. They also highlight the inherent functional plasticity within the Vdelta2- gammadelta T cell compartment and provide information that could be used for the design of cellular therapies that suppress liver inflammation or combat liver cancer. LAY SUMMARY: gammadelta T cells are frequently enriched in many solid tissues, however the immunobiology of such tissue-associated subsets in humans has remained unclear. We show that intrahepatic gammadelta T cells are enriched for clonally expanded effector T cells, whereas naive gammadelta T cells are largely excluded. Moreover, whereas a distinct proportion of circulating T cell clonotypes was present in both the liver tissue and peripheral blood, a functionally and clonotypically distinct population of liver-resident gammadelta T cells was also evident. Our findings suggest that factors triggering gammadelta T cell clonal selection and differentiation, such as infection, can drive enrichment of gammadelta T cells into liver tissue, allowing the development of functionally distinct tissue-restricted memory populations specialised in local hepatic immunosurveillance. PMID- 29758333 TI - Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. AB - BACKGROUND & AIMS: Treatment with nucleos(t)ide analogues (NA) leads to hepatitis B virus (HBV) DNA suppression in most patients with chronic hepatitis B (CHB), but HBV surface antigen (HBsAg) loss rates are low. Upon NA discontinuation, HBV DNA can return rapidly with ensuing alanine aminotransferase flares and induction of cytokines. Several studies reported higher HBsAg loss rates after stopping therapy, but at present it is unclear if cell-mediated immune responses are altered after treatment discontinuation. The aim of this study was to characterise T cell responses during the early phase of virological relapse, following discontinuation of NA therapy in HBeAg-negative patients. METHODS: A total of 15 HBeAg-negative patients with CHB on long-term NA treatment were included in a prospective study and subjected to structured NA discontinuation. T cell responses were studied at the end of NA therapy and 4, 8 and 12 weeks thereafter. RESULTS: The T cell phenotype of patients with CHB on long-term NA therapy was markedly different compared to healthy individuals, but was only slightly altered after discontinuation of therapy. T cells from patients with HBsAg loss expressed low levels of KLRG1 and PD-1 at all time-points and high levels of Ki-67 and CD38 at week 12 after treatment cessation. In vitro peptide stimulated HBV-specific T cell responses were increased in several patients after NA cessation. Blocking of PD-L1 further enhanced HBV-specific T cell responses, especially after discontinuation of therapy. CONCLUSION: Relapse of active HBV replication after stopping therapy may trigger an immunological environment that enhances the responsiveness of HBV-specific T cells in vitro. Together with other immune interventions, this approach might be of interest for the development of novel therapeutic options to induce HBsAg loss in CHB. LAY SUMMARY: Relapse of hepatitis B virus replication after discontinuation of nucleos(t)ide analogue therapy in certain patients with chronic hepatitis B may alter the phenotype of T cells and enhance the responsiveness of hepatitis B virus-specific T cells to in vitro peptide stimulation. Blocking PD-L1 can further augment these hepatitis B virus-specific T cell responses. Interestingly, T cells of patients that subsequently achieve hepatitis B surface antigen loss are less exhausted at all time-points after stopping treatment and display a higher proliferative capacity 12-weeks after treatment discontinuation. These findings contribute to the understanding of the immunological events that occur during discontinuation of nucleos(t)ide analogue therapy. PMID- 29758334 TI - Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis. AB - BACKGROUND & AIMS: Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Herein, we examined whether Nrf2 (Nfe2l2) activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC). METHODS: We used wild-type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet. This experimental model causes massive fatty liver and steatohepatitis with fibrosis and enables identification of early stages of hepatocarcinogenesis. RESULTS: We found that Nrf2 activation takes place in early preneoplastic lesions identified by the marker glutathione S-transferase placental form (GSTP). Nrf2 missense mutations, known to disrupt the Keap1-Nrf2 binding, were present in 65.7% of GSTP positive foci. Nrf2KO rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of DENA-damaged hepatocytes. While Nrf2 genetic inactivation did not alter DENA-induced initiation, it led to increased liver injury and chronic compensatory hepatocyte regeneration when rats were fed a CMD diet. However, in spite of such a permissive environment, the livers of Nrf2KO rats did not display any preneoplastic lesion unlike those of WT rats. CONCLUSIONS: These results demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease: i) Nrf2 is activated at early steps of the tumorigenic process and ii) Nrf2 is mandatory for the clonal expansion of initiated cells, indicating that Nrf2 is critical in the onset of HCC. LAY SUMMARY: Dysregulation of the Keap1-Nrf2 molecular pathway has been observed in human tumors. In a nutritional model of hepatocarcinogenesis, the protein Nrf2 is frequently mutated/activated at early steps of the tumorigenic process. Herein, we show that Nrf2 is mandatory for the development of preneoplastic lesions. These results suggest that Nrf2 has a critical role in the onset of hepatocellular carcinoma. PMID- 29758335 TI - Normal on-treatment ALT during antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B. AB - BACKGROUND & AIMS: Recent studies reveal that the rate of normal on-treatment alanine aminotransferase (ALT) appears different for different nucleos(t)ide analogues (NAs); yet its clinical significance is unclear. We aimed to evaluate the impact of normal on-treatment ALT during antiviral treatment with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB). METHODS: A territory-wide cohort of patients with CHB who received ETV and/or TDF in 2005-2016 was identified. Serial on-treatment ALT levels were collected and analyzed. Normal on-treatment ALT (ALT-N) was defined as ALT <30 U/L in males and <19 U/L in females. The primary and secondary outcomes were composite hepatic events (including hepatocellular carcinoma) based on diagnostic codes. Patients with hepatic events before or during the first year of antiviral treatment or follow-up <1 year were excluded. RESULTS: A total of 21,182 patients with CHB (10,437 with and 10,745 without ALT-N at 12 months after antiviral treatment) were identified and followed for 4.0 +/- 1.7 years. Patients with and without ALT-N differed in baseline ALT (58 vs. 61 U/L), hepatitis B virus DNA (4.9 vs. 5.1 log10 IU/ml) and cirrhosis status (8.8% vs. 10.5%). A total of 627 (3.0%) patients developed composite hepatic events. Compared to no ALT-N, ALT-N at 3, 6, 9 and 12 months reduced the risk of hepatic events, after adjustment for baseline ALT and other important covariates, with adjusted hazard ratios (95% CI) of 0.61 (0.49-0.77), 0.55 (0.45-0.67), 0.54 (0.44-0.65) and 0.51 (0.42-0.61) respectively (all p <0.001). The cumulative incidence (95% CI) of composite hepatic events at six years was 3.51% (3.06%-4.02%) in ALT-N and 5.70% (5.15% 6.32%) in the no ALT-N group (p <0.001). CONCLUSIONS: Normal on-treatment ALT is associated with a lower risk of hepatic events in patients with CHB receiving NA treatment, translating into improved clinical outcomes in these patients. LAY SUMMARY: We investigated 21,182 patients with chronic hepatitis B receiving antiviral treatment. Alanine aminotransferase is a laboratory marker of liver function, with raised levels indicating liver dysfunction and in severe cases hepatitis. Normal on-treatment alanine aminotransferase during the first year of treatment in patients with CHB is associated with a lower risk of hepatic events. PMID- 29758336 TI - Hepatic manifestations of telomere biology disorders. AB - A 51-year-old Caucasian male was referred for evaluation of variceal bleeding. Laboratory tests were remarkable for mild thrombocytopenia and moderate alkaline phosphatase elevation. Synthetic liver function was well preserved. Abdominal computed tomography scan revealed moderate splenomegaly, gastric varices, and normal hepatic contour. A transjugular liver biopsy was performed revealing findings of nodular regenerative hyperplasia with no significant fibrosis or necroinflammatory activity. Hepatic venous pressure gradient was elevated at 31 mmHg, consistent with clinically significant portal hypertension. The clinical course was complicated by refractory gastric variceal bleeding requiring a surgical portosystemic shunt. Approximately seven years after the initial presentation, the patient developed progressive dyspnoea and a diagnosis of idiopathic pulmonary fibrosis was made. Contrast-enhanced echocardiogram was not suggestive of hepatopulmonary syndrome or portopulmonary hypertension. Given this new diagnosis a telomere biology disorder was suspected. A flow-fluorescence in situ hybridisation analysis for telomere length assessment revealed telomere lengths below the first percentile in both lymphocytes and granulocytes. Next generation sequencing analysis identified a heterozygous mutation involving the hTERT gene (Histidine983Threonine). The lung disease unfortunately progressed in the subsequent two years, leading to the patient's death nine years after his initial presentation with portal hypertension. During those nine years two brothers also developed idiopathic pulmonary fibrosis. The questions that arise from this case include. PMID- 29758337 TI - Model-free and model-based reward prediction errors in EEG. AB - Learning theorists posit two reinforcement learning systems: model-free and model based. Model-based learning incorporates knowledge about structure and contingencies in the world to assign candidate actions with an expected value. Model-free learning is ignorant of the world's structure; instead, actions hold a value based on prior reinforcement, with this value updated by expectancy violation in the form of a reward prediction error. Because they use such different learning mechanisms, it has been previously assumed that model-based and model-free learning are computationally dissociated in the brain. However, recent fMRI evidence suggests that the brain may compute reward prediction errors to both model-free and model-based estimates of value, signalling the possibility that these systems interact. Because of its poor temporal resolution, fMRI risks confounding reward prediction errors with other feedback-related neural activity. In the present study, EEG was used to show the presence of both model-based and model-free reward prediction errors and their place in a temporal sequence of events including state prediction errors and action value updates. This demonstration of model-based prediction errors questions a long-held assumption that model-free and model-based learning are dissociated in the brain. PMID- 29758338 TI - How do children fall asleep? A high-density EEG study of slow waves in the transition from wake to sleep. AB - INTRODUCTION: Slow waves, the hallmarks of non-rapid eye-movement (NREM) sleep, are thought to reflect maturational changes that occur in the cerebral cortex throughout childhood and adolescence. Recent work in adults has revealed evidence for two distinct synchronization processes involved in the generation of slow waves, which sequentially come into play in the transition to sleep. In order to understand how these two processes are affected by developmental changes, we compared slow waves between children and young adults in the falling asleep period. METHODS: The sleep onset period (starting 30s before end of alpha activity and ending at the first slow wave sequence) was extracted from 72 sleep onset high-density EEG recordings (128 electrodes) of 49 healthy subjects (age 8 25). Using an automatic slow wave detection algorithm, the number, amplitude and slope of slow waves were analyzed and compared between children (age 8-11) and young adults (age 20-25). RESULTS: Slow wave number and amplitude increased linearly in the falling asleep period in children, while in young adults, isolated high-amplitude slow waves (type I) dominated initially and numerous smaller slow waves (type II) with progressively increasing amplitude occurred later. Compared to young adults, children displayed faster increases in slow wave amplitude and number across the falling asleep period in central and posterior brain regions, respectively, and also showed larger slow waves during wakefulness immediately prior to sleep. CONCLUSIONS: Children do not display the two temporally dissociated slow wave synchronization processes in the falling asleep period observed in adults, suggesting that maturational factors underlie the temporal segregation of these two processes. Our findings provide novel perspectives for studying how sleep-related behaviors and dreaming differ between children and adults. PMID- 29758339 TI - Population-averaged atlas of the macroscale human structural connectome and its network topology. AB - A comprehensive map of the structural connectome in the human brain has been a coveted resource for understanding macroscopic brain networks. Here we report an expert-vetted, population-averaged atlas of the structural connectome derived from diffusion MRI data (N = 842). This was achieved by creating a high resolution template of diffusion patterns averaged across individual subjects and using tractography to generate 550,000 trajectories of representative white matter fascicles annotated by 80 anatomical labels. The trajectories were subsequently clustered and labeled by a team of experienced neuroanatomists in order to conform to prior neuroanatomical knowledge. A multi-level network topology was then described using whole-brain connectograms, with subdivisions of the association pathways showing small-worldness in intra-hemisphere connections, projection pathways showing hub structures at thalamus, putamen, and brainstem, and commissural pathways showing bridges connecting cerebral hemispheres to provide global efficiency. This atlas of the structural connectome provides representative organization of human brain white matter, complementary to traditional histologically-derived and voxel-based white matter atlases, allowing for better modeling and simulation of brain connectivity for future connectome studies. PMID- 29758341 TI - Effect of Zembrin(r) and four of its alkaloid constituents on electric excitability of the rat hippocampus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sceletium tortuosum (Mesembryanthemaceae), a succulent plant indigenous to South Africa. is consumed in the form of teas, decoctions and tinctures and is sometimes smoked and used as snuff. In recent years, Sceletium has received a great deal of commercial interest for relieving stress in healthy people, and for treating a broad range of psychological, psychiatric and inflammatory conditions. MATERIAL AND METHODS: The whole extract (Zembrin(r)) was tested ex vivo in the hippocampus slice preparation after one week of daily oral administration of 5 and 10 mg/kg. Four alkaloids - mesembrine, mesembranol, mesembrenol and mesembrenone - were tested directly in vitro. All four were also tested in the presence of different glutamate receptor agonists. RESULTS: Zembrin(r) ex vivo as well as all alkaloids in vitro attenuated the amplitude of the population spike during electric stimulation as single shock as well as theta burst stimulation. Only Mesembranol and Mesembrenol having a hydroxyl group at position C6 instead of carbonyl group as in mesembrine and mesembrenone acted by attenuation of AMPA receptor mediated transmission as documented for the whole extract. DISCUSSION: The current experimental series revealed a new physiological effect of Zembrin(r) on the electric activity of the hippocampus. Attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients. Administered doses of 5 and 10 mg/kg are in line with a dosage of 50 mg/subject as tested clinically. CONCLUSION: We have discovered a new structure activity relationship for Sceletium alkaloids. Since attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients), Mesembrenol and Mesembranol may serve as new chemical leads for the development of new drugs for the treatment of epilepsy. PMID- 29758342 TI - Next-generation sequencing in drug development: target identification and genetically stratified clinical trials. AB - Next-generation sequencing (NGS) enabled high-throughput analysis of genotype phenotype relationships on human populations, ushering in a new era of genetics informed drug development. The year 2017 was remarkable, with the first FDA approved gene therapy for cancer (KymriahTM) and for inherited diseases (LUXTURNATM), the first multiplex NGS panel for companion diagnostics (MSK IMPACTTM) and the first drug targeting a genetic signature rather than a disease (Keytruda(r)). We envision that population-scale NGS with paired electronic health records (EHRs) will become a routine measure in the drug development process for the identification of novel drug targets, and that genetically stratified clinical trials could be widely adopted to improve power in precision medicine-guided drug development. PMID- 29758340 TI - Traditional Mongolian medicine Eerdun Wurile improves stroke recovery through regulation of gene expression in rat brain. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Eerdun Wurile (EW) is one of the key Mongolian medicines for treatment of neurological and cardiological disorders. EW is ranked most regularly used Mongolian medicine in clinic. Components of EW which mainly originate from natural products are well defined and are unique to Mongolian medicine. AIM OF THE STUDY: Although the recipe of EW contains known neuroactive chemicals originated from plants, its mechanism of action has never been elucidated at molecular level. The objective of the present study is to explore the mechanism of neuroregenerative activity of EW by focusing on the regulation of gene expression in the brain of rat model of stroke. MATERIALS AND METHODS: Rat middle cerebral artery occlusion (MCAO) models were treated with EW for 15 days. Then, total RNAs from the cerebral cortex of rat MCAO models treated with either EW or control (saline) were extracted and analyzed by transcriptome sequencing. Differentially expressed genes were analyzed for their functions during the recovery of ischemic stroke. The expression level of significantly differentially expressed genes such as growth factors, microglia markers and secretive enzymes in the lesion was further validated by RT-qPCR and immunohistochemistry. RESULTS: Previously identified neuroactive compounds, such as geniposide (Yu et al., 2009), myristicin (Shin et al., 1988), costunolide (Okugawa et al., 1996), toosendanin (Shi and Chen, 1999) were detected in EW formulation. Bederson scale indicated that the treatment of rat MCAO models with EW showed significantly lowered neurological deficits (p < 0.01). The regional cerebral blood circulation was also remarkably higher in rat MCAO models treated with EW compared to the control group. A total of 186 genes were upregulated in the lesion of rat MCAO models treated with EW compared to control group. Among them, growth factors such as Igf1 (p < 0.05), Igf2 (p < 0.01), Grn (p < 0.01) were significantly upregulated in brain after treatment of rat MCAO models with EW. Meanwhile, greatly enhanced expression of microglia markers, as well as complementary components and secretive proteases were also detected. CONCLUSION: Our data collectively indicated that EW enhances expression of growth factors including Igf1 and Igf2 in neurons and microglia, and may stimulate microglia polarization in the brain. The consequences of such activity include stimulation of neuron growth, hydrolysis and clearance of cell debris at the lesion, as well as the angiogenesis. PMID- 29758343 TI - The effect of the composition of a fixed dose combination on bioequivalence results. AB - The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro-resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro-resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate-free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II). PMID- 29758344 TI - The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs. AB - Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations. PMID- 29758345 TI - New perspectives of starch: Synthesis and in vitro assessment of novel thiolated mucoadhesive derivatives. AB - AIM: The purpose of this study was to develop a novel thiolated starch polymer with improved mucoadhesive properties by conjugation of cysteamine to starch as a natural polymer of restricted mucoadhesive properties. METHODS: Aldehyde substructures were integrated into starch via oxidative cleavage of vicinal diols by increasing amounts of sodium periodate followed by covalent attachment of cysteamine to oxidized starch via reductive amination. Thiol groups were quantified via Ellman's reaction and their impact on mucoadhesion was analyzed by rheological investigations, the rotating cylinder method and tensile studies on porcine mucosa. RESULTS: The total amount of immobilized thiol groups revealed a correlation between degree of oxidation and thiolation. Modified starch demonstrated an up to 1.66-fold increase in water uptake in comparison to native starch. Modification of starch resulted in greatly improved cohesive properties and improvement in mucoadhesion. Rheological investigations revealed a 2- to 4 fold rise in viscosity of mucus. Tensile studies revealed a linear correlation between degree of oxidation/thiolation and enhancement of maximum detachment force and total work adhesion. CONCLUSION: In terms of these results, thiolated starch is a new, promising, polymer in the field of mucoadhesive drug delivery systems. PMID- 29758347 TI - Gene analysis: A rare gene disease of intellectual deficiency-Cohen syndrome. AB - Cohen syndrome is a rare, genetic, connective-tissue disorder, which is caused by mutations in the gene COH1 (VPS13B, Vacuolar Protein Sorting 13 Homolog B) at the chromosome 8q22. The disease is rare reported, which major clinical features include postnatal microcephaly, obesity, short stature, intellectual disability, progressive retinal dystrophy, intermittent neutropenia and many other unusual facial feature. We report four patients in China who were diagnosed with Cohen syndrome by genetic testing and clinical manifestations. At the same time, we review the related literature, and further expound the molecular mechanism of the disease, a variety of clinical manifestations, treatment and prognosis. PMID- 29758346 TI - Electro-responsive graphene oxide hydrogels for skin bandages: The outcome of gelatin and trypsin immobilization. AB - A free radical polymerization method was adopted for the fabrication of hybrid hydrogel films based on acrylamide and polyethylene glycol dimethacrylate as plasticizing and crosslinking agents, respectively, to be employed as smart skin bandages. Electro-sensitivity, biocompatibility and proteolytic properties were conferred to the final polymer networks by introducing graphene oxide (0.5% w/w), gelatin or trypsin (10% w/w) in the polymerization feed. The physical chemical and mechanical characterization of hybrid materials was performed by means of determination of protein content, Raman spectroscopy, thermogravimetric analysis and measurement of tensile strength. The evaluation of both water affinity and curcumin release profiles (analyzed by suitable mathematical modelling) upon application of an external electric stimulation in the 0-48 voltage range, confirmed the possibility to modulate the release kinetics. Proper proteolytic tests showed that the trypsin enzymatic activity was retained by 80% upon immobilization. Moreover, for all samples, we observed a viability higher than 94% in normal human fibroblast cells (MRC-5), while a reduction of methicillin resistant Staphylococcus aureus CFU mL-1 (90%) was obtained with curcumin loaded samples. PMID- 29758348 TI - Effect of prenatal stress on alpha5 GABAA receptor subunit gene expression in hippocampus and pilocarpine induced seizure in rats. AB - The GABAergic synapses go through structural and functional maturation during early brain development. Maternal stress alters GABAergic synapses in developing brain, which are associated with the pathophysiology of neuropsychiatric disorders in adults. The present study aimed to investigate the effect of prenatal restraint stress (PS) on pilocarpine-induced seizure and alpha5 subunit of gamma-amino butyric acid type A (GABAA) receptor expression in hippocampus. Pregnant Wistar rats were subjected to PS at gestational days 15-17 and the pups were examined for susceptibility to seizure and alpha5 subunit of GABAA receptor expression in hippocampus at postnatal days 14 and 21 (P14 and PND 21). Quantitative real-time PCR was used for evaluating the gene expression in the pups. Pilocarpine was injected intraperitoneally into the pups and seizure behaviors were recorded. The results showed that alpha5 subunit mRNA expression significantly increased in hippocampus at both the P14 and P21 in the stressed rats. However, alpha5 subunit level was greater at the P21 than at the P14 in both the groups. Latency of first tonic-clonic seizure significantly decreased in the PS group compared to the control pups. Number and duration of tonic-clonic seizures increased in the PS rats compared to the controls. PS led to an increase in total score of seizure at the P14 and P21. It can be concluded that PS increases the seizure susceptibility and GABAA receptor alpha5 subunit gene expression in offspring; it is likely that the mechanism of increased seizure susceptibility by PS, at least in part, can increase the GABAA receptor alpha5 subunit gene expression in hippocampus. PMID- 29758349 TI - Habitual aerobic exercise, gene APOA5 named rs662799 SNP and response of blood lipid and lipoprotein phenotypes among older Chinese adult. AB - BACKGROUND: The genetic component of dyslipidemia has been studied in adults but little in older population. It is remains unknown regarding influence and interaction of APOA5 gene single nucleotide polymorphism (SNP) and habitual aerobic exercise (HAE) on changes of blood lipids and lipoprotein phenotypes in older Chinese adults. METHODS: Four-hundred-twenty-three old Chinese individuals with HAE were divided into hyperlipidemia and normal groups. We genotyped polymorphic loci using matrix assisted laser desorption ionization time of flight mass spectrometry detection technology (MALDI-TOF). HAE level was assessed by International Physical Activity Questionnaire (IPAQ) scale. RESULTS: For three genotypes of rs662799 site, the AG + GG gene carriers presented higher risk of hyperlipidemia compared to the AA carriers, with the ratio of 1.676 (P = .018, 95% CI: 1.092-2.571) for the AG and 1.812 (P = .002, 95% CI: 1.247-2.632) for the GG, respectively. The rs662799 G allele was significantly associated with lower HDL-C but higher TG levels. In relation to different HAE levels, less interaction was observed between the AA carriers and different HAE levels on corresponding lipids changes. The AG + GG carriers with higher HAE levels had significantly lower TG responses compared to those with lower HAE levels (1.45 +/- 0.74 mmol/L vs. 1.86 +/- 1.15 mmol/L). CONCLUSIONS: Excess risk for low HDL-C and hyperlipidemia was associated with rs662799 genotype alleles of APOA5 SNPs in older Chinese adults. Interaction of gene-HAE and HAE levels may induce different responses of blood lipids and lipoprotein phenotypes. HAE levels have less influence on TG changes in the AA carriers; however, high HAE levels appeared to greatly impact TG responses in the AG + GG carriers. PMID- 29758350 TI - The true colours of the flatworm: Mechanisms of pigment biosynthesis and pigment cell lineage development in planarians. AB - Pigment cells serve a variety of important uses across the animal kingdom, and in many species can change and regenerate throughout the lifetime of the organism. The functions of these cells, as well as their origins in both embryonic development and adult regeneration, are not fully understood. Here, we review advances in the study of pigment cells in the freshwater planarian, a model system for stem cell biology and regeneration. Freshwater planarians produce at least three pigment types to generate brown eye and body colouration: melanin, porphyrin, and ommochrome. The body pigments of planarians are produced and contained by a specialized, highly dendritic cell type located in the subepidermal parenchymal space. This cell type is specifically ablated following intense light exposure, a characteristic which has been exploited to discover the gene expression and regeneration of planarian pigment cells. Regenerating pigment cells progress through an immature state marked by upregulation of pigment synthesis genes before differentiating into mature pigment cells; these two states are dynamically regulated in homeostasis to maintain constant body pigmentation. The transcription factors Albino, FoxF-1, and Ets-1, as well as an FGFR-like molecule, are required for proper maintenance of the pigment lineage in both regeneration and homeostasis. These discoveries set the stage for research into external signals that regulate the pigment lineage, as well as possible functions for pigment cells in planarians, including the extra-ocular light response. These insights will address outstanding questions about the evolutionarily-conserved biology of pigment cells. PMID- 29758351 TI - Development of microreactors with surface-immobilized biocatalysts for continuous transamination. AB - The industrial importance of optically pure compounds has thrown a spotlight on omega-transaminases that have shown a high potential for the synthesis of bioactive compounds with a chiral amine moiety. The implementation of biocatalysts in industrial processes relies strongly on fast and cost effective process development, including selection of a biocatalyst form and the strategy for its immobilization. Here, microscale reactors with selected surface immobilized amine-transaminase (ATA) in various forms are described as platforms for high-throughput process development. Wild type ATA (ATA-wt) from a crude cell extract, as well as Escherichia coli cells intracellularly overexpressing the enzyme, were immobilized on the surfaces of meander microchannels of disposable plastics by means of reactor surface silanization and glutaraldehyde bonding. In addition, a silicon/glass microchannel reactor was used for immobilization of an ATA-wt, genetically engineered to contain a silica-binding module (SBM) at the N terminus (N-SBM-ATA-wt), leading to immobilization on the non-modified inner microchannel surface. Microreactors with surface-immobilized biocatalysts were coupled with a quenching system and at-line HPLC analytics and evaluated based on continuous biotransformation, yielding acetophenone and l-alanine. E. coli cells and N-SBM-ATA-wt were efficiently immobilized and yielded a volumetric productivity of up to 14.42 g L-1 h-1, while ATA-wt small load resulted in two orders of magnitude lower productivity. The miniaturized reactors further enabled in-operando characterization of biocatalyst stability, crucial for successful transfer to a production scale. PMID- 29758353 TI - International assessment on quality and content of internet information on osteoarthritis. AB - OBJECTIVE: Osteoarthritis is one of the leading causes of global disability. Numerous studies have assessed the quality and content of online health information; however, how information content varies between multiple countries remains unknown. The primary objective of this study was to examine how the quality and content of online health information on osteoarthritis compares on an international scale. METHODS: Internet searches for the equivalent of "knee osteoarthritis treatment" were performed in ten countries around the world. For each country, the first ten websites were evaluated using a custom scoring form examining: website type; quality and reliability using the DISCERN and Health-on the-Net (HON) frameworks; and treatment content based on three international osteoarthritis treatment guidelines. Consistency of search results between countries speaking the same language was also assessed. RESULTS: Significant differences in all scoring metrics existed between countries speaking different languages. Western countries scored higher than more eastern countries, there were no differences between the United States and Mexico in any of the scoring metrics, and HON certified websites were of higher quality and reliability. Searches in different countries speaking the same language had at least 70% overlap. CONCLUSIONS: The quality of online health information on knee osteoarthritis varies significantly between countries speaking different languages. Differential access to quality, accurate, and safe health information online may represent a novel but important health inequality. Future efforts are needed to translate online health resources into additional languages. In the interim, patients may seek websites that display the HON seal. PMID- 29758352 TI - Prospective associations of C-reactive protein (CRP) levels and CRP genetic risk scores with risk of total knee and hip replacement for osteoarthritis in a diverse cohort. AB - OBJECTIVE: To examine associations of high-sensitivity C-reactive protein (CRP) levels and polygenic CRP genetic risk scores (GRS) with risk of end-stage hip or knee osteoarthritis (OA), defined as incident total hip (THR) or knee replacement (TKR) for OA. DESIGN: This study included a cohort of postmenopausal white, African American, and Hispanic women from the Women's Health Initiative. Women were followed from baseline to date of THR or TKR, death, or December 31, 2014. Medicare claims data identified THR and TKR. Hs-CRP and genotyping data were collected at baseline. Three CRP GRS were constructed: 1) a 4-SNP GRS comprised of genetic variants representing variation in the CRP gene among European populations; 2) a multilocus 18-SNP GRS of genetic variants significantly associated with CRP levels in a meta-analysis of genome-wide association studies; and 3) a 5-SNP GRS of genetic variants significantly associated with CRP levels among African American women. RESULTS: In analyses conducted separately among each race and ethnic group, there were no significant associations of ln hs-CRP with risk of THR or TKR, after adjusting for age, body mass index, lifestyle characteristics, chronic diseases, hormone therapy use, and non-steroidal anti inflammatory drug use. CRP GRS were not associated with risk of THR or TKR in any ethnic group. CONCLUSIONS: Serum levels of ln hs-CRP and genetically-predicted CRP levels were not associated with risk of THR or TKR for OA among a diverse cohort of women. PMID- 29758354 TI - ISAba1 and Tn6168 acquisition by natural transformation leads to third-generation cephalosporins resistance in Acinetobacter baumannii. AB - Acinetobacter baumannii has intrinsic beta-lactamase genes, namely ampC and blaOXA-51-like, which are only strongly expressed when the ISAba1 insertion sequence is upstream the 5' end of the genes. A second ampC gene has also been identified in some clinical A. baumannii strains. The increased expression of these genes leads to resistance to beta-lactams, including third-generation cephalosporins and/or carbapenems. The aim of this work was to assess the involvement of natural transformation in the transfer of chromosomal ampC associated mobile elements, and related changes in the resistance profile of recipient cells. Natural transformation assays with the naturally competent A. baumannii A118 clinical isolate as recipient cell and the multidrug resistant A. baumannii Ab51 clinical isolate as the source of donor DNA produced transformants. All tested transformants showed integration of the ISAba1 close to the ampC gene. In two transformants, the ISAba1 was acquired by transposition and inserted between the usual folE and the ampC genes. The remaining transformants acquired the ISAba1 adjacent to a second ampC gene, as part of Tn6168, likely by homologous recombination. Our study demonstrates that natural transformation can contribute to the widespread of beta-lactams resistance, and acquisition of non resistant determinants can lead to changes in the susceptibility profile of A. baumannii strains. PMID- 29758355 TI - Alcohol and Opioid Use in Chronic Pain: A Cross-Sectional Examination of Differences in Functioning Based on Misuse Status. AB - : Opioid misuse is regularly associated with disrupted functioning in those with chronic pain. Less work has examined whether alcohol misuse may also interfere with functioning. This study examined frequency of opioid and alcohol misuse in 131 individuals (61.1% female) prescribed opioids for the treatment of chronic pain. Participants completed an anonymous survey online, consisting of measures of pain, functioning, and opioid and alcohol misuse. Cut scores were used to categorize individuals according to substance misuse status. Individuals were categorized as follows: 35.9% (n = 47) were not misusing either opioids or alcohol, 22.9% (n = 30) were misusing both opioids and alcohol, 38.2% (n = 50) were misusing opioids alone, and only 3.0% (n = 4) were misusing alcohol alone. A multivariate analysis of variance was performed to examine differences in pain and functioning between groups (after excluding individuals in the alcohol misuse group due to the small sample size). Group comparisons indicated that individuals who were not misusing either substance were less disabled and distressed in comparison to those who were misusing opioids alone or both opioids and alcohol. No differences were indicated between the latter 2 groups. Overall, the observed frequency of opioid misuse was somewhat higher in comparison to previous work (approximately 1 out of every 3 participants), and misuse of both alcohol and opioids was common (approximately 1 out of every 5 participants). While these data are preliminary, they do suggest that issues of substance misuse in those with chronic pain extends beyond opioids alone. PERSPECTIVE: Opioid and alcohol misuse was examined in 131 individuals prescribed opioids for chronic pain. In total, 35.9% were not misusing either, 22.9% were misusing both, 38.2% were misusing opioids, and 3.1% were misusing alcohol. Individuals not misusing either were generally less disabled and distressed compared to those misusing opioids or both. PMID- 29758356 TI - The Influence of Placebo Analgesia Manipulations on Pain Report, the Nociceptive Flexion Reflex, and Autonomic Responses to Pain. AB - Expectations for pain relief and experience/conditioning are psychological factors that contribute to placebo analgesia, yet few studies have studied the physiological mechanisms underlying their effects. This study randomized 133 participants to 4 groups: an expectation only (E-only) group, a conditioning only (C-only) group, an expectation plus conditioning (E+C) group, and a natural history (NH) control group. Painful electric stimulations were delivered before and after an inert cream was applied to the site of stimulation. Pain-related outcomes (pain ratings, nociceptive flexion reflex [NFR], skin conductance response, and heart rate acceleration) were recorded after each stimulation. NFR (a measure of spinal nociception) assessed if placebo analgesia inhibited spinal processing of pain. E+C was the only manipulation that significantly inhibited pain and skin conductance response. Surprisingly, NFR was facilitated in the E+C and E-only groups. No effects were noted for C-only. Mediation analysis suggested 2 descending processes were engaged during E+C that influenced spinal nociception: 1) descending facilitation and 2) descending inhibition that was also responsible for pain reduction. These results suggest that E+C manipulations produce the strongest analgesia and have a complex influence on spinal nociception involving both inhibitory and facilitatory processes. PERSPECTIVE: This study assessed whether placebo analgesia manipulations that include expectations, conditioning, or both modulate the NFR (measure of spinal nociception). Only the manipulation that involved expectations and conditioning inhibited pain, but both expectation manipulations facilitated NFR. This suggests a complex modulation of spinal neurons by placebo manipulations. PMID- 29758357 TI - Pharmacopuncture With Scolopendra subspinipes Suppresses Mechanical Allodynia in Oxaliplatin-Induced Neuropathic Mice and Potentiates Clonidine-induced Anti allodynia Without Hypotension or Motor Impairment. AB - : Chemotherapy-induced neuropathic pain is a common dose-limiting side effect of anticancerdrugs but lacks an effective treatment strategy. Scolopendra subspinipes has been used in traditional medicine to treat chronic neuronal diseases. Moreover, pharmacopuncture with S subspinipes (SSP) produces potent analgesia in humans and experimental animals. In this study, we examined the effect of SSP into the ST36 acupoint on oxaliplatin-induced mechanical allodynia in mice. Acupoint treatment with SSP (0.5%/20 MUL) significantly decreased mechanical allodynia produced by a single oxaliplatin injection (10mg/kg i.p.), which was completely prevented by acupoint preinjection of lidocaine. Intrathecal treatment with yohimbine (25 MUg/5 MUL), an alpha2-adrenoceptor antagonist, prevented the anti-allodynic effect of SSP. In contrast, a high dose (0.1mg/kg i.p.) ofclonidine,an alpha2-adrenoceptor agonist, suppressed oxaliplatin-induced mechanical allodynia butproduced severe side effects including hypotension, bradycardia, and motor impairment. The combination of SSP with a lower dose of clonidine (0.03 mg/kg) produced a comparable analgesic effect without side effects. Collectively, our findings demonstrate that SSP produces an analgesic effect in oxaliplatin-induced pain via neuronal conduction at the acupoint and activation of spinal alpha2-adrenoceptors. Moreover, acombination of low-dose clonidine with SSP represents a novel and safe therapeutic strategy for chemotherapy-induced chronic pain. PERSPECTIVE: SSP can relieve oxaliplatin induced mechanical allodynia. Moreover, SSP potentiates clonidine-induced anti allodynia, allowing a lower dose of clonidine with no significant side effects. The combination of SSP and low-dose clonidine might provide a novel strategy for the management of chemotherapy-induced peripheral neuropathy. PMID- 29758358 TI - Lipidomic signature of serum from the rats exposed to alcohol for one year. AB - Alcohol abuse and its related diseases are the major risk factors for human health. Although the mechanism of alcohol-related disorders has been widely investigated, serum metabolites associated with long-term alcohol intake have not been well explored. In this study, we aimed to investigate the profiles of serum metabolites and lipid species of rats chronically exposed to alcohol, which may be involved in the pathogenesis of alcohol-associated disease. An 1H NMR-based metabolomics and Q-TOF/MS-based lipidomics approach were applied to investigate the profile of serum metabolites and lipid species of rats administrated daily with alcohol (12% vol/vol, 10 ml/kg per day, i.g.) for one year continuously. The rats administered with sterile water (10 ml/kg per day, i.g.) were used as control. We found that alcohol affected mostly the lipid species rather than small molecule metabolites in the serum of both female and male rats. Among the modified lipids, glycerophospholipid, sphingolipid and glycerolipids metabolism pathways were profoundly altered. The prominent changes in lipid profiles included diacylglycerol (DG), lysophosphatidylcholine (LysoPC), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE) and triacylglycerol (TG). Moreover, fatty-acyl profile of lipids and total degree of unsaturation of fatty acid were also significantly altered by alcohol. The modified lipidomic profile may help to understand the pathogenesis of alcohol-associated diseases and also be of value for clinical evaluation of alcohol abuse, alcohol-associated disease diagnosis. PMID- 29758361 TI - Bone accrual in oligo-amenorrheic athletes, eumenorrheic athletes and non athletes. AB - BACKGROUND: Mechanical loading improves bone mineral density (BMD) and strength while decreasing fracture risk. Cross-sectional studies show that exercise advantage is lost in oligo-amenorrheic athletes (OA). Longitudinal studies examining the opposing effects of exercise and hypogonadism on bone are lacking in adolescents/young adults. OBJECTIVE: Evaluate differences in bone accrual over 12 months in OA, eumenorrheic athletes (EA) and non-athletes (NA). We hypothesized that bone accrual would be lower in OA than EA and NA, with differences most pronounced at non-weight bearing trabecular sites. METHODS: 27 OA, 29 EA, and 22 NA, 14-25 years old, completed 12-months of the prospective study. Athletes were weight-bearing endurance athletes. Subjects were assessed for areal BMD and bone mineral content (BMC) using DXA at the femoral neck, total hip, lumbar spine and whole body (WB). Failure load (a strength estimate) at the distal radius and tibia was assessed using microfinite element analysis of data obtained via high resolution peripheral quantitative computed tomography (HRpQCT). The primary analysis was a comparison of changes in areal BMD, BMC, and failure load across groups over 12-months at the respective sites. RESULTS: Groups did not differ for baseline age, height or BMI. Percent body fat was lower in both OA and EA compared to NA. OA attained menarche later than EA and NA. Over the follow-up period, OA gained 1.9 +/- 2.7 kg of weight compared to 0.5 +/- 2.4 kg and 0.8 +/- 2.3 kg in EA and NA respectively (p = 0.09); 39% of OA resumed menses. Changes in BMD, BMD Z-scores, and tibial failure load over 12-months did not differ among groups. At follow up, EA had higher femoral neck, hip and WB BMD Z-scores than NA, and higher hip BMD Z-scores than OA (p < 0.05) after adjusting for covariates. At follow-up, radial failure load was lower in OA vs. NA, and tibial failure load lower in OA and NA vs. EA (p <= 0.04 for all). Change in weight and fat mass were associated with changes in BMD measures at multiple sites. CONCLUSION: Despite weight gain and menses recovery in many OA during follow-up, residual deficits persist without catch-up raising concerns for suboptimal peak bone mass acquisition. PMID- 29758360 TI - Single ingestion of di-(2-propylheptyl) phthalate (DPHP) by male volunteers: DPHP in blood and its metabolites in blood and urine. AB - Di-(2-propylheptyl) phthalate (DPHP) is used as a plasticizer for polyvinyl chloride products. A tolerable daily intake of DPHP of 0.2 mg/kg body weight has been derived from rat data. Because toxicokinetic data of DPHP in humans were not available, it was the aim of the present work to monitor DPHP and selected metabolites in blood and urine of 6 male volunteers over time following ingestion of a single DPHP dose (0.7 mg/kg body weight). Concentration-time courses in blood were obtained up to 24 h for DPHP, mono-(2-propylheptyl) phthalate (MPHP), mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP), and mono-(2-propyl-6 oxoheptyl) phthalate (oxo-MPHP); amounts excreted in urine were determined up to 46 h for MPHP, OH-MPHP, oxo-MPHP, and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). All curves were characterized by an invasion and an elimination phase the kinetic parameters of which were determined together with the areas under the concentration-time curves in blood (AUCs). AUCs were: DPHP > MPHP > oxo-MPHP > OH MPHP. The amounts excreted in urine were: oxo-MPHP > OH-MPHP> > cx-MPHP > MPHP. The AUCs of MPHP, oxo-MPHP, or OH-MPHP could be estimated well from the cumulative amounts of urinary OH-MPHP or oxo-MPHP excreted within 22 h after DPHP intake. Not considering possible differences in species-sensitivity towards unconjugated DPHP metabolites, it was concluded from a comparison of their AUCs in DPHP-exposed humans with corresponding earlier data in rats that there is no increased risk of adverse effects associated with the internal exposure of unconjugated DPHP metabolites in humans as compared to rats when receiving the same dose of DPHP per kg body weight. PMID- 29758362 TI - The anti-epileptic drugs valproate, carbamazepine and levetiracetam cause bone loss and modulate Wnt inhibitors in normal and ovariectomised rats. AB - Secondary osteoporosis is the major concern associated with long term intake of antiepileptic drugs (AEDs). Women are the vulnerable targets owing to post menopausal bone loss. In the present work, we evaluated the effect of 10 weeks of treatment with AED therapy (carbamazepine, CBZ, 75 mg/kg; sodium valproate, SVP, 300 mg/kg; levetiracetam, LTM, 150 mg/kg) on bone mineral density and microarchitecture at femoral epiphysis, lumbar vertebrae and proximal tibia of normal and ovariectomised Wistar rats. In addition, we measured serum levels of vitamin D, receptor activator of nuclear factor kappa beta-ligand (RANKL), procollagen type 1 amino-terminal propeptide (P1NP) and wnt inhibitors (sclerostin and DKK-1) following AED therapy. Micro-computed tomography analysis of bones revealed significant reduction in BMD at femur epiphysis and lumbar vertebrae with all the three AEDs evaluated. At proximal tibia, only CBZ showed a significant decline. The reduction in BMD was more pronounced in ovariectomised rats. AEDs also resulted in alteration of micro-CT parameters. These changes were accompanied by an increased serum RANKL with all AEDs while vitamin D levels were reduced only with CBZ treatment and P1NP levels were reduced with SVP and CBZ. Serum sclerostin levels were elevated following all AEDs in normal and ovariectomised rats except with CBZ in normal rats. However, increase in DKK-1 levels was observed with only LTM. Ovariectomy itself resulted in increased RANKL, sclerostin and DKK-1 and reduced vitamin D and P1NP levels. Significant differences were discernible between normal and ovariectomised rats treated with AEDs in all the parameters. However, while sclerostin increased further upon AEDs treatment, P1NP decreased with SVP and CBZ and serum DKK-1 levels showed a declining trend with all the three AEDs studied. We confirm adverse effects on bone following AEDs in female rats. Further, our results demonstrate for the first time that these effects are more pronounced in ovariectomised rats as compared to normal rats and that this could be related to estrogen deficiency which in turn enhances bone resorption via increased RANKL and reduces bone formation via increased sclerostin and reduced P1NP. Finally, our study demonstrated for the first time that AED treatment displayed changes in the serum levels of wnt inhibitors and hence modulation of wnt inhibitors might be partly involved in their adverse effects on bone. PMID- 29758359 TI - Probing flecainide block of INa using human pluripotent stem cell-derived ventricular cardiomyocytes adapted to automated patch-clamping and 2D monolayers. AB - Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are emerging tools for applications such as drug discovery and screening for pro-arrhythmogenicity and cardiotoxicity as leading causes for drug attrition. Understanding the electrophysiology (EP) of hPSC-CMs is essential but conventional manual patch clamping is highly laborious and low-throughput. Here we adapted hPSC-CMs derived from two human embryonic stem cell (hESC) lines, HES2 and H7, for a 16-channel automated planar-recording approach for single-cell EP characterization. Automated current- and voltage-clamping, with an overall success rate of 55.0 +/- 11.3%, indicated that 90% of hPSC-CMs displayed ventricular-like action potential (AP) and the ventricular cardiomyocytes (VCMs) derived from the two hESC lines expressed similar levels of INa, ICaL, Ikr and If and similarly lacked Ito and IK1. These well-characterized hPSC-VCMs could also be readily adapted for automated assays of pro-arrhythmic drug screening. As an example, we showed that flecainide (FLE) induced INa blockade, leftward steady-state inactivation shift, slowed recovery from inactivation in our hPSC-VCMs. Since single-cell EP assay is insufficient to predict drug-induced reentrant arrhythmias, hPSC-VCMs were further reassembled into 2D human ventricular cardiac monolayers (hvCMLs) for multi-cellular electrophysiological assessments. Indeed, FLE significantly slowed the conduction velocity while causing AP prolongation. Our RNA-seq data suggested that cell-cell interaction enhanced the maturity of hPSC-VCMs. Taken collectively, a combinatorial approach using single-cell EP and hvCMLs is needed to comprehensively assess drug-induced arrhythmogenicity. PMID- 29758363 TI - Different Surgical Approaches to 313 Cesarean Scar Pregnancies. AB - STUDY OBJECTIVE: To evaluate the efficacy of different surgical treatments for cesarean scar pregnancy (CSP). DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: Affiliated university hospitals. PATIENTS: Women (n = 313) with CSP. INTERVENTIONS: Dilation and curettage under ultrasound guidance (DCUS, n = 124), dilation and curettage with hysteroscopic guidance (DCH, n = 103), vaginal excision (n = 55), laparotomy (n = 12), and laparoscopy (n = 19). MEASUREMENTS AND MAIN RESULTS: Undetectable serum human chorionic gonadotropin (hCG) levels and thickness of the uterine scar were measured before and after surgery. Success rates of the 5 surgical treatments of CSP (DCUS, DCH, vaginal excision, laparotomy, and laparoscopy) ranged between 89% and 100%. Postoperative treatment was not needed in the vaginal and laparotomy groups, and vaginal treatment was associated with shorter operative time than laparotomy and laparoscopy and shorter time to undetectable hCG levels than DCUS and DCH. Serum hCG levels on day 3 after surgery were significantly lower than baseline levels in all groups of patients, but there was no significant difference between levels on days 3 and 5 postoperatively. Median scar thickness after surgery in the vaginal surgery, laparotomy, and laparoscopy groups was thicker than that in the DCUS and DCH groups. CONCLUSION: In certain circumstances, CSP can be treated simply by DCH or DCUS. However, time to undetectable hCG levels is prolonged compared with more invasive techniques. PMID- 29758364 TI - Effect of phototherapy on shear bond strength of resin cements to zirconia ceramics: A systematic review and meta-analysis of in-vitro studies. AB - BACKGROUND: The present study systematically reviewed the literature to investigate the effect of phototherapy on the shear bond strength (SBS) of resin cement to zirconia ceramic. METHODS: Electronic databases including MEDLINE (PubMed), ISI Web of Science, Scopus, ScIELO, LILACS and EMBASE until April 2018. The addressed focused question was: Does phototherapy increase the SBS of resin cement to zirconia ceramics?" RESULTS: A total of 8 in-vitro studies were included in the qualitative and quantitative analysis. The mean SBS for phototherapy ranged from 4.1 to 18.95 MPa while mean SBS for sandblasted zirconia composite specimens ranged from 3.98 to 23.35 MPa in the included studies. Qualitative analysis showed 3 studies favoured application of phototherapy in significantly increasing SBS, while 4 studies indicated sandblasting showed significantly greater SBS of resin cement to zirconia ceramics. Considering the effects of phototherapy, significant heterogeneity for SBS (Q value = 136.37, p<0.0001, I2 = 94.87%) was noticed among both the groups. The overall mean difference for SBS (SMD = -0.59, 95% CI = -1.99 to -0.80, p = 0.402) was not significant between phototherapy and sandblast (control) groups. CONCLUSION: Whether the effect of phototherapy on increasing the SBS of resin cement to zirconia ceramic is debatable. Further in-vitro studies should be performed in order to obtain strong conclusions. PMID- 29758365 TI - White matter pathways for prosodic structure building: A case study. AB - The relevance of left dorsal and ventral fiber pathways for syntactic and semantic comprehension is well established, while pathways for prosody are little explored. The present study examined linguistic prosodic structure building in a patient whose right arcuate/superior longitudinal fascicles and posterior corpus callosum were transiently compromised by a vasogenic peritumoral edema. Compared to ten matched healthy controls, the patient's ability to detect irregular prosodic structure significantly improved between pre- and post-surgical assessment. This recovery was accompanied by an increase in average fractional anisotropy (FA) in right dorsal and posterior transcallosal fiber tracts. Neither general cognitive abilities nor (non-prosodic) syntactic comprehension nor FA in right ventral and left dorsal fiber tracts showed a similar pre-post increase. Together, these findings suggest a contribution of right dorsal and inter hemispheric pathways to prosody perception, including the right-dorsal tracking and structuring of prosodic pitch contours that is transcallosally informed by concurrent syntactic information. PMID- 29758367 TI - Clinical and Neurosurgical Management of Cranial Machete Injuries: The Experience of a Tertiary Referral Center in Nicaragua. AB - BACKGROUND: The neurosurgical literature rarely describes managing open head injuries caused by machetes, although this is a common head injury in developing countries. We present our experience managing cranial machete injuries in Nicaragua over a 5-year period. METHODS: A retrospective chart review identified patients admitted to a neurosurgery service for cranial machete injury. RESULTS: Among 51 patients studied, the majority (n = 42, 82%) presented with mild neurologic deficits (Glasgow Coma Scale score >=14). Nondepressed skull fracture (25/37, 68%) was the most common injury identified on skull radiography, and pneumocephalus (15/29, 52%) was the most common injury identified with computed tomography. Overall, 38 patients (75%) underwent surgical intervention for 1 or more conditions, including laceration length >=10 cm (n = 20), open intracranial wound (n = 8), pneumocephalus (n = 7), cerebral contusion (n = 6), intracranial hemorrhage (n = 5), and depressed fracture (n = 5). All patients received aggressive antibiotic therapy. Patients without intracranial injury received a 7 day course of intravenous ceftriaxone, followed by a 10-day course of oral ciprofloxacin. Patients with violation of the dura received a 7- to 14-day course of intravenous metronidazole, ceftriaxone, and vancomycin, followed by a 10-day course of oral ciprofloxacin. Postoperative complications included a visible skull defect (n = 6), infection (n = 3), and unspecified neurologic (n = 2) and mixed (n = 1) complications. At discharge, most patients had only minimal disabilities (47/51, 92%). In-hospital mortality rate was zero. CONCLUSIONS: An aggressive approach to managing open head injury caused by machete yields good outcomes, with the majority of patients experiencing minimal disability at hospital discharge and a low rate of infection. PMID- 29758366 TI - Curcumin attenuates chronic intermittent hypoxia-induced brain injuries by inhibiting AQP4 and p38 MAPK pathway. AB - Chronic intermittent hypoxia (CIH) is one of the main features of obstructive sleep apnea (OSA), which is also commonly associated with neurocognitive impairments. The present study aimed to elucidate the beneficial effect of curcumin on CIH-induced brain injuries. Male balb/c mice (6 ~ 8 weeks) were exposed to normoxia or a pattern of CIH (8 h/day, cycles of 180 s each, hypoxia: 5% O2 for 50 s, reoxygenation: 21% O2 for 50 s) for 10 weeks, along with daily curcumin treatment (50, 100, or 200 mg/kg, intragastrically) or its vehicle. The results showed that CIH induced significant brain edema, as well as neuronal apoptosis and astrogliosis in the cerebral cortex, brainstem, and cerebellum regions of brain. In addition, increased astrocytic AQP4 expression and activation of p38 MAPK pathway were observed after CIH exposure. Curcumin dose dependently mitigated the brain edema and relevant cell alterations, showing a neuroprotective effect in CIH-induced brain injury. Together, these results suggest curcumin ameliorates the CIH-induced brain injuries, including brain edema, neuronal death and astrogliosis. The beneficial role of curcumin is mediated partially by regulating AQP4 and p38 MAPK pathway. PMID- 29758368 TI - Infections After Cranial Neurosurgery: Prospective Cohort of 103 Episodes Treated According to a Standardized Algorithm. AB - OBJECTIVE: The optimal surgical and antimicrobial treatment for intracranial infections after neurosurgery is unknown. We investigated the clinical, laboratory, and microbiological characteristics of intracranial infections after neurosurgery. In addition, treatment outcome in patients treated according to a standardized algorithm was evaluated. METHODS: Consecutive patients with extradural, intradural, and device-related infections after cranial neurosurgery were included prospectively. A standardized antimicrobial and surgical treatment regimen was applied. The probability of infection-free survival was estimated by using the Kaplan-Meier survival method. Survival curves between groups were compared by using log-rank Mantel-Cox test. RESULTS: Of 103 infections, 58 (56%) were extradural, 33 (32%) intradural, and 12 (12%) device-associated. Foreign material was involved in 98 infections (95%), including 78 bone flaps or fixation devices, 41 duraplasties, 17 external drains, and 15 functional devices. The median duration from primary surgery until infection diagnosis was 33 days (range, 6-1132 days). In total, 69 infections (67%) were monomicrobial, 26 (25%) polymicrobial, and 8 (8%) culture-negative. Ninety of 103 patients (90%) underwent surgical intervention, of whom foreign material was retained in 24 (23%). The probability of infection-free survival was 87% after 12 months (95% confidence interval 77%-93%). Nonadequate antimicrobial therapy was associated with treatment failure (5% vs. 70%, P < 0.001), which remained significant in the multiple logistic regression model (P = 0.01). CONCLUSIONS: Most (95%) intracranial infections were associated with foreign material and required surgical intervention and biofilm-active treatment. Via a standardized treatment approach, the infection-free survival after 12 months was good (87%), independent of the infection site or type of micro-organism. PMID- 29758370 TI - Revisiting the Role of Uninstrumented Posterior Lumbar Interbody Fusion. PMID- 29758369 TI - Intraoperative Active Bleeding in Endoscopic Surgery for Spontaneous Intracerebral Hemorrhage is Predicted by the Spot Sign. AB - BACKGROUND: Endoscopic evacuation of hematoma (EEH) has recently been applied to treat patients with spontaneous intracerebral hemorrhage (sICH). Intraoperative active bleeding (IAB), which is occasionally observed in EEH, might lead to greater blood loss, further brain damage, and more postoperative recurrent hemorrhage. However, no definite predictor of IAB has been established. Because the spot sign is associated with other hemorrhagic complications, we aimed to evaluate whether it predicts IAB. METHODS: We retrospectively assessed the incidence and risk factors of IAB, including the spot sign, in 127 sICH patients who underwent EEH within 6 hours after computed tomography angiography at our institution between June 2009 and December 2017. RESULTS: The study included 53 women and 74 men with an average age of 66.7 +/- 11.8 years. IAB occurred in 40 (31.5%) of the 127 patients, and it was more frequent in patients with the spot sign than in patients without it (14/24 [58.3%] vs. 26/103 [25.2%]; P = 0.003). Multivariable regression analyses suggested that the spot sign was an independent predictor of IAB (odds ratio [OR], 3.02; 95% confidence interval [CI], 1.10-8.30; P = 0.03). In addition, earlier surgery gradually increased the risk of IAB, and surgery within 4 hours of onset was an independent risk factor (OR, 4.34; 95% CI, 1.12-16.9; P = 0.03, referring to postonset 8 hours or more). CONCLUSIONS: The spot sign and early surgery were independent predictors of IAB in EEH for sICH. In patients with sICH and spot sign, complete treatment of IAB by electrocoagulation might be important for minimizing surgical complications. PMID- 29758372 TI - Percutaneous Endoscopic Lumbar Surgery via the Transfacet Approach for Lumbar Synovial Cyst. AB - BACKGROUND: There are currently no high-quality studies on the optimal therapeutic approach for juxtafacet cyst, as treatment guidelines have not been developed. Herein, a novel technique in which we used an endoscopic transfacet approach to treat a patient with symptomatic lumbar synovial cyst is presented. CASE DESCRIPTION: An 87-year-old man presented with severe dull pain in the right anterior thigh. Lumbar magnetic resonance imaging revealed disc extrusion over the central canal zone at the L2-L3 and L4-L5 levels and an ovoid lesion with a hyperintense center plus a hypointense rim on the T2-weighted image. The lesion was located over the medial side of the right juxtafacet region at the L2-L3 level, causing thecal sac compression. After the operation, the visual analog pain scale improved with a value of 0-1/10, and straight leg raise test was negative. Microscopically, cystic fibrous tissue with focal myxoid degeneration, fibrin exudate, and scant synovial-like lining was observed. These findings were consistent with clinical synovial cyst. Three months later, lumbar magnetic resonance imaging was performed, and no evidence of cyst was disclosed. Lumbar computed tomography revealed the upper part of left L2-L3 facet joint was removed. The patient did not report any radicular pain during the 6-month follow up period. CONCLUSIONS: Percutaneous endoscopic lumbar surgery could be a new option for the management of lumbar synovial cysts, especially when general anesthesia is not appropriate for the patient. PMID- 29758371 TI - Comparative Cost Analysis for the Surgical and Endovascular Treatment of Ruptured Intracranial Aneurysms in Taiwan: A Nationwide Population-Based Cohort Study. AB - OBJECTIVE: Using a database that enabled longitudinal follow-up, we assessed the cost, outcome, complications, and readmission rate of ruptured cerebral aneurysms repaired by surgical clipping and endovascular coiling. METHODS: This study was a retrospective review of data from a series of patients who underwent surgical clipping or endovascular coiling of ruptured cerebral aneurysms between 1996 and 2013. The medical records and hospital cost data were all examined. RESULTS: A total of 7690 and 1380 cases were treated with clipping and coiling, respectively. Patients treated with clipping had more comorbidities and were older. The average total cost for endovascular coiling was $13,974.3, whereas the average total cost for surgical clipping was $16,581.7. Perioperative (30-day) mortality was 10.7% in patients with coiled aneurysms, compared with 12.6% in those with clipped aneurysms (P = 0.045). After 1 year of follow-up, clipping was associated with a significantly longer length of hospital stay (P < 0.001) and significantly higher total hospital costs (P < 0.001). CONCLUSIONS: In Taiwan, the total hospital costs for the surgical clipping of cerebral aneurysms were higher than for endovascular coiling, and the surgical results were associated with significant complications. We suggest that the indications for coiling might need to be expanded from the current standards dictated by the guidelines in Taiwan. PMID- 29758373 TI - Ruptured Vertebral Artery Dissecting Aneurysm as a Risk Factor for Ocular Symptoms Accompanied with Subarachnoid Hemorrhage. AB - OBJECTIVE: Although ruptured vertebral artery dissecting aneurysms (VADAs) are often associated with ocular symptoms, such as abducent nerve palsy and Terson syndrome (TS), their frequency and risk factors in comparison with those associated with ruptured aneurysms in other locations have not been reported. METHODS: Three hundred forty-three patients with nontraumatic subarachnoid hemorrhage were treated in our hospital from April 2002 to May 2016, among which 35 (10.2%) had VADA as the origin of hemorrhage. They were analyzed retrospectively for risk factors of ocular symptoms. RESULTS: Of the 343 patients, 26 had eye movement disturbance (7.6%) and 22 had TS (6.4%). Both eye movement disturbance (14 patients; 40.0%; P < 0.0001) and TS (10 patients; 28.6%; P < 0.0001) occurred more frequently in the VADA than the non-VADA group. Abducent nerve palsy accounted for all eye movement disturbances associated with ruptured VADA, although it occurred in 6 of 12 affected patients with ruptured aneurysms in other locations. Of these patients, 4 improved within 3 months (28.6%) and 8 did so within 1 year (66.7%). Multivariate logistic regression analysis indicated that ruptured VADA is a risk factor for both eye movement disturbance and TS (P < 0.0001 and P = 0.0033; 95% confidence interval of odds ratio: 3.41-29.5 and 1.72-14.33, respectively). CONCLUSIONS: Eye movement disturbance and TS occurs more frequently in patients with ruptured VADA than with aneurysms in other locations. Early evaluation by an ophthalmologist is recommended in these patients. PMID- 29758376 TI - Ethylene signaling cross-talk with other hormones in Arabidopsis thaliana exposed to contrasting phosphate availability: Differential effects in roots, leaves and fruits. AB - Ethylene signaling plays a major role in the regulation of plant growth, but its cross-talk with other phytohormones is still poorly understood. Here, we investigated whether or not a defect in ethylene signaling, particularly in the ETHYLENE INSENSITIVE3 (EIN3) transcription factor, alters plant growth and influences the contents of other phytohormones. With this aim, a hormonal profiling approach using ultrahigh performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) was used to unravel organ-specific responses (in roots, leaves and fruits) in the ein3-1 mutant and wild-type A. thaliana plants exposed to contrasting phosphate (Pi) availability. A defect in ethylene signaling in the ein3-1 mutant increased the biomass of roots, leaves and fruits, both at 0.5 mM and 1 mM Pi, thus indicating the growth-inhibitory role of ethylene in all tested organs. The hormonal profiling in roots revealed a cross-talk between ethylene signaling and other phytohormones, as indicated by increases in the contents of auxin, gibberellins and the stress-related hormones, abscisic acid, salicylic acid and jasmonic acid. The ein3-1 mutant also showed increased cytokinin contents in leaves. Reduced Pi availability (from 1 mM to 0.5 mM Pi) affected fruit growth, but not root and leaf growth, thus indicating mild Pi deficiency. It is concluded that ethylene signaling plays a major role in the modulation of plant growth in A. thaliana and that the ein3-1 mutant is not only altered in ethylene signaling but in the contents of several phytohormones in an organ-specific manner, thus indicating a hormonal cross-talk. PMID- 29758377 TI - Global insights of protein responses to cold stress in plants: Signaling, defence, and degradation. AB - Cold stress (CS) as one of the unfavorable abiotic tensions proceeds different aspects of plant responses. These responses are generated through CS effects on crucial processes such as photosynthesis, energy metabolism, ROS homeostasis, membrane fluidity and cell wall architecture. As a tolerance response, plants apply proteins in various strategies such as transferring the message of cold entrance named as signaling, producing defensive and protective molecules against the stress and degrading some unfavorable or unnecessary proteins to produce other required ones. A change in one part of these networks can irritate alternations in others. These strategies as acclimation mechanisms are conducted through gene expression reprogramming to provide a new adjusted metabolic homeostasis dependent on the stress severity and duration and plant species. Investigating protein alterations in metabolic pathways and their role in adjusting cellular components from upstream to downstream levels can provide a profound knowledge of plants tolerance mechanism against the damaging effects of CS. In this review, we summarized the activity of some cold-responsive proteins from the perception phase to tolerance response against CS. PMID- 29758378 TI - Enhanced oxidative stress in the jasmonic acid-deficient tomato mutant def-1 exposed to NaCl stress. AB - Jasmonic acid (JA) has been mostly studied in responses to biotic stresses, such as herbivore attack and pathogenic infection. More recently, the involvement of JA in abiotic stresses including salinity was highlighted; yet, its role in salt stress remained unclear. In the current study, we compared the physiological and biochemical responses of wild-type (WT) tomato (Solanum lycopersicum) cv Castlemart and its JA-deficient mutant defenseless-1 (def-1) under salt stress to investigate the role of JA. Plant growth, photosynthetic pigment content, ion accumulation, oxidative stress-related parameters, proline accumulation and total phenolic compounds, in addition to both enzymatic and non-enzymatic antioxidant activities, were measured in both genotypes after 14 days of 100 mM NaCl treatment. Although we observed in both genotypes similar growth pattern and sodium, calcium and potassium levels in leaves under salt stress, def-1 plants exhibited a more pronounced decrease of nitrogen content in both leaves and roots and a slightly higher level of sodium in roots compared to WT plants. In addition, def-1 plants exposed to salt stress showed reactive oxygen species (ROS)-associated injury phenotypes. These oxidative stress symptoms in def-1 were associated with lower activity of both enzymatic antioxidants and non-enzymatic antioxidants. Furthermore, the levels of the non-enzymatic ROS scavengers proline and total phenolic compounds increased in both genotypes exposed to salt stress, with a higher amount of proline in the WT plants. Overall the results of this study suggest that endogenous JA mainly enhanced tomato salt tolerance by maintaining ROS homeostasis. PMID- 29758375 TI - Alterations in the microstructure of white matter in children and adolescents with Tourette syndrome measured using tract-based spatial statistics and probabilistic tractography. AB - Tourette syndrome (TS) is a neurodevelopmental disorder characterised by repetitive and intermittent motor and vocal tics. TS is thought to reflect fronto striatal dysfunction and the aetiology of the disorder has been linked to widespread alterations in the functional and structural integrity of the brain. The aim of this study was to assess white matter (WM) abnormalities in a large sample of young patients with TS in comparison to a sample of matched typically developing control individuals (CS) using diffusion MRI. The study included 35 patients with TS (3 females; mean age: 14.0 +/- 3.3) and 35 CS (3 females; mean age: 13.9 +/- 3.3). Diffusion MRI data was analysed using tract-based spatial statistics (TBSS) and probabilistic tractography. Patients with TS demonstrated both marked and widespread decreases in axial diffusivity (AD) together with altered WM connectivity. Moreover, we showed that tic severity and the frequency of premonitory urges (PU) were associated with increased connectivity between primary motor cortex (M1) and the caudate nuclei, and increased information transfer between M1 and the insula, respectively. This is to our knowledge the first study to employ both TBSS and probabilistic tractography in a sample of young patients with TS. Our results contribute to the limited existing literature demonstrating altered connectivity in TS and confirm previous results suggesting in particular, that altered insular function contributes to increased frequency of PU. PMID- 29758379 TI - A differential tolerance to mild salt stress conditions among six Italian rice genotypes does not rely on Na+ exclusion from shoots. AB - Rice is very sensitive to salt stress at the seedling level, with consequent poor crop establishment. A natural variability in susceptibility to moderate saline environments was found in a group of six Italian temperate japonica rice cultivars, and the physiological determinants for salt tolerance were investigated. Cation (Na+, K+ and Mg++) levels were determined in shoots from individual rice plantlets grown in the absence or in the presence of inhibitory, yet sublethal salt levels, and at increasing time after salt treatments. Significant variations were found among genotypes, but these were unrelated to the relative tolerance, which seems to result from neither mechanism(s) for reduced Na+ translocation to the aerial part, nor its increased retrieval from the xylem mediating Na+ exclusion from leaves. Accordingly, thiobarbituric acid reactive substance levels raised in leaf tissues of salt-treated seedlings, and osmo-induced proline accumulation was found in all genotypes. Data suggest that the difference in salt tolerance most likely depends on mechanisms for osmotic adjustment and/or antioxidative defence. PMID- 29758374 TI - Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. AB - The default mode network (DMN) comprises defined brain regions contributing to internally-directed thought processes. Reductions in task-induced deactivation in the DMN have been associated with increasing age and poorer executive task performance, but factors underlying these functional changes remain unclear. We investigated contributions of white matter (WM) microstructure, WM hyperintensities (WMH) and Alzheimer's pathology to age-related alterations in DMN function. Thirty-five cognitively normal older adults and 29 younger adults underwent working memory task fMRI and diffusion tensor imaging. In the older adults, we measured cerebrospinal fluid tau and Abeta42 (markers of AD pathology), and WMH on FLAIR imaging (marker of cerebrovascular disease). We identified a set of regions showing DMN deactivation and a set of inter connecting WM tracts (DMN-WM) common to both age groups. There were negative associations between DMN deactivation and task performance in older adults, consistent with previous studies. Decreased DMN deactivation was associated with AD pathology and WM microstructure but not with WMH volume. Mediation analyses showed that WM microstructure mediated declines in DMN deactivation associated with both aging and AD pathology. Together these results suggest that AD pathology may exert a "second-hit" on WM microstructure, over-and-above the effects of age, both contributing to diminished DMN deactivation in older adults. PMID- 29758380 TI - Predictors of positive drinking outcomes among youth receiving an alcohol brief intervention in the emergency department. AB - BACKGROUND: Reducing underage drinking is a public health priority given increased risk for injury and other consequences. Emergency department (ED) visits offer a potential "teachable moment" to initiate interventions among youth engaged in risky drinking. Given mixed findings for alcohol brief interventions (BIs), this paper examined baseline markers of BI response in order to inform future interventions. METHOD: We conducted secondary analyses of data from a randomized controlled trial of an alcohol BI delivered to youth in an ED. Among 475 participants (Mage = 18.6, SD = 1.4; 48.7% Female, 78.6% White/Caucasian) receiving a computer or therapist BI, we examined baseline characteristics (i.e., demographic, substance use, mood, risk/protective factors, and readiness to change) that predicted positive intervention response (i.e., BI responder) at 3 month follow-up using AUDIT-C scores (cut offs: <3 for ages 14-17; <4 for ages 18 20). RESULTS: Mediated logistic regression analysis (controlling for demographics) showed that greater readiness to change at baseline was positively related to BI response and baseline alcohol consumption was negatively related to BI response. Having a mentor was indirectly related to BI response via baseline alcohol consumption. Baseline readiness to change and alcohol consumption mediated the association between positive peer influences and BI response, whereas readiness to change mediated the relation between depression and BI response. CONCLUSION: Findings suggest that BI response is influenced by protective social factors, such as positive peers and mentors, and depression, via baseline alcohol severity indicators (i.e., readiness to change, consumption), thus providing clues for enhancing the content and dose of early interventions. PMID- 29758382 TI - Effects of exposure to BPF on development and sexual differentiation during early life stages of zebrafish (Danio rerio). AB - Bisphenol F (BPF) has become a predominant bisphenol contaminant in recent years. It has significant estrogenic properties in both in vivo and in vitro studies. We have previously studied the disrupting mechanisms of BPF on the hypothalamic pituitary-gonadal axis of adult zebrafish. However, the effects of BPF exposure on development and sexual differentiation of zebrafish embryos/larvae remain unclear. To determine the effects of BPF on the critical stage of sex differentiation in zebrafish, zebrafish embryos/larvae were exposed to 1, 10, 100, and 1000 MUg/L BPF from fertilization to 60 days post-fertilization (dpf). Developmental malformations were induced by exposure to BPF from 2 h post fertilization (hpf), with a LC50 of 10,030 MUg/L at 96 hpf and 9391 MUg/L at 120 hpf. Long-term exposure during sex differentiation tended to result in a female sex ratio bias. Histological analyses at 60 dpf indicated that the development of ovo-testes and immature ovaries was induced by 100 and 1000 MUg/L BPF. Homogenate testosterone levels decreased and 17beta-estradiol levels increased in zebrafish in a concentration-dependent manner. BPF exposure suppressed gene expression of double sex, Mab3-related transcription factor 1(dmrt1), fushi tarazu factor 1d (ff1d), sry-box containing gene 9a (sox9a) and anti-Mullerian hormone (amh); induced expression of the forkhead box L2 transcription factor (foxl2), leading to increased expression of aromatase (cyp19a1a), which promoted production of estrogens, and further caused phenotypic feminization of zebrafish. These results suggest that developmental exposure to BPF has adverse effects on sexual differentiation, and the results were useful for a BPF risk assessment. PMID- 29758384 TI - Disruption of SHP1/NMDA receptor signaling in spinal cord dorsal horn alleviated inflammatory pain. AB - Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors. SHP1 interacted with a membrane-proximal region within the cytoplasmic tail of GluN2A. This interaction was necessary to stimulate SHP1 activity and more importantly, restrict SHP1 signaling to specifically enhance the tyrosine phosphorylation of GluN2A during inflammatory pain. Electrophysiological and behavioral studies showed that SHP1 binding potentiated GluN2A currents and evoked GluN2A-dependent pain hypersensitivity. The siRNA-mediated knockdown of SHP1 or interference with SHP1/GluN2A interaction by a synthetic peptide alleviated inflammatory pain induced by either Complete Freund's Adjuvant or formalin. Our data implicated that SHP1 was a specific enhancer of GluN2A-mediated nociceptive synaptic transmission in spinal cord dorsal horn, and manipulation of SHP1 activity may serve as an effective strategy for the treatment of inflammatory pain. PMID- 29758381 TI - Exploring the role of low-frequency and rare exonic variants in alcohol and tobacco use. AB - BACKGROUND: Alcohol and tobacco use are heritable phenotypes. However, only a small number of common genetic variants have been identified, and common variants account for a modest proportion of the heritability. Therefore, this study aims to investigate the role of low-frequency and rare variants in alcohol and tobacco use. METHODS: We meta-analyzed ExomeChip association results from eight discovery cohorts and included 12,466 subjects and 7432 smokers in the analysis of alcohol consumption and tobacco use, respectively. The ExomeChip interrogates low frequency and rare exonic variants, and in addition a small pool of common variants. We investigated top variants in an independent sample in which ICD-9 diagnoses of "alcoholism" (N = 25,508) and "tobacco use disorder" (N = 27,068) had been assessed. In addition to the single variant analysis, we performed gene based, polygenic risk score (PRS), and pathway analyses. RESULTS: The meta analysis did not yield exome-wide significant results. When we jointly analyzed our top results with the independent sample, no low-frequency or rare variants reached significance for alcohol consumption or tobacco use. However, two common variants that were present on the ExomeChip, rs16969968 (p = 2.39 * 10-7) and rs8034191 (p = 6.31 * 10-7) located in CHRNA5 and AGPHD1 at 15q25.1, showed evidence for association with tobacco use. DISCUSSION: Low-frequency and rare exonic variants with large effects do not play a major role in alcohol and tobacco use, nor does the aggregate effect of ExomeChip variants. However, our results confirmed the role of the CHRNA5-CHRNA3-CHRNB4 cluster of nicotinic acetylcholine receptor subunit genes in tobacco use. PMID- 29758383 TI - Does size matter? Venom proteomic and functional comparison between night adder species (Viperidae: Causus) with short and long venom glands. AB - Night adders (Causus species within the Viperidae family) are amphibian specialists and a common source of snakebite in Africa. Some species are unique in that they have the longest venom glands of any viper, extending approximately 10% of the body length. Despite their potential medical importance and evolutionary novelty, their venom has received almost no research attention. In this study, venoms from a short-glanded species (C. lichtensteinii) and from a long-glanded species (C. rhombeatus) were compared using a series of proteomic and bioactivity testing techniques to investigate and compare the toxin composition and functioning of the venoms of these two species. Both C. rhombeatus and C. lichtensteinii were similar in overall venom composition and inhibition of blood coagulation through non-clotting proteolytic cleavage of fibrinogen. While the 1D gel profiles were very similar to each other in the toxin types present, 2D gel analyses revealed isoformic differences within each toxin classes. This variation was congruent with differential efficacy of South African Institute for Medical Research snake polyvalent antivenom, with C. lichtensteinii unaffected at the dose tested while C. rhombeatus was moderately but significantly neutralized. Despite the variation within toxin classes, the similarity in overall venom biochemistry suggests that the selection pressure for the evolution of long glands served to increase venom yield in order to subjugate proportionally large anurans as a unique form of niche partitioning, and is not linked to significant changes in venom function. These results not only contribute to the body of venom evolution knowledge but also highlight the limited clinical management outcomes for Causus envenomations. PMID- 29758385 TI - Evaluation of reinforcing and aversive effects of voluntary Delta9 tetrahydrocannabinol ingestion in rats. AB - Edible cannabis-infused products are an increasingly popular method of using cannabis in the United States. Yet, preclinical research to determine mechanisms underlying abuse of Delta9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, has focused primarily on the effects of parenteral administration. The purpose of this study was to examine the rewarding and aversive effects of oral THC in a novel rodent voluntary ingestion model. Adult male and female Sprague Dawley rats were given access to sucrose-sweetened solutions during daily sessions. A range of THC concentrations, each paired with a unique flavor previously tested alone, was introduced into these solutions for four-session exposure periods and drinking volumes were measured. Injected (i.p.) THC doses were also paired with unique flavors to compare the effects of route of THC administration on drinking. Introduction of THC into sucrose solutions dose dependently decreased drinking upon initial exposure, though drinking generally increased in subsequent sessions. By contrast, i.p. THC produced sustained dose dependent decreases in drinking in rats of both sexes. Subsequent exposure to paired flavors in the absence of THC resulted in further decreases in drinking, suggesting route-specific aversion. Additional testing using saccharin-sweetened solutions in a two-bottle choice paradigm was also conducted, with THC producing sustained dose-dependent decreases in drinking after initial exposure in rats of both sexes. Though self-administration of ingested THC was not demonstrated, evidence of route-specific THC aversion was observed, which suggests that certain routes and/or rates of THC administration may mitigate some of its aversive effects. PMID- 29758386 TI - The neurokinin-1 receptor mediates escalated alcohol intake induced by multiple drinking models. AB - We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures. PMID- 29758388 TI - Second language learners who are at-risk for reading disabilities: A growth mixture model study. AB - This one-year longitudinal study examined the developmental trajectories of English reading in Chinese children learning English as a second language (ESL) and identified cognitive profiles of children who are at risk for English reading disability. One hundred and eighty-four Chinese ESL children from eight Hong Kong kindergartens were measured four times during their last year of kindergarten for phonological awareness, letter knowledge, vocabulary and English word reading. Growth mixture modeling was applied to classify the children based on their growth trajectories in English word reading. Four subgroups of word reading growth were classified, namely high-achieving, fast-growth, slow-growth and low achieving groups. The cognitive-linguistic skills were compared across different groups with age, non-verbal intelligence and receptive vocabulary in L1 controlled. The results showed that low-achieving groups, who were expected to be at-risk for L2 reading disability, showed deficits in letter-name knowledge, phonemic awareness, and receptive and expressive vocabulary. Fast-growth and high achieving groups were not distinguishable on the measured cognitive-linguistic skills. Children in the low-growth groups were significantly weaker in phonemic awareness, receptive vocabulary and expressive vocabulary than children in the high-achieving group. Our findings identified specific cognitive-linguistic deficits that were associated with children who are at-risk for reading disability. Implications for the early identification of L2 reading disability were discussed. PMID- 29758387 TI - Exploring the impact of disability on self-determination measurement. AB - BACKGROUND: Self-determination is a psychological construct that applies to both the general population and to individuals with disabilities that can be self determined with adequate accommodations and opportunities. As the relevance of self-determination-related skills in life has been recently acknowledged, researchers have created a measure to assess self-determination in adolescents and young adults with and without disabilities. The Self-Determination Inventory: Student Report (Spanish interim version) is empirically being validated into Spanish. AIMS: As this scale is the first assessment addressed to all youth, further exploration of its psychometric properties is required to ensure the reliability of the self-determination measurement and gain further insight into the construct when applied to youth with and without disabilities. METHODS: More than 600 participants were asked to complete the scale. The impact of disability on the item response distributions across the dimensions of self-determination was explored. OUTCOMES: Differential item functioning (DIF) was found in only 5 of the scale's 45 items. Differences primary favored youth without disabilities. CONCLUSIONS: The weak presence of DIF across the items supports the instrument's psychometrical robustness when measuring self-determination in youth with and without disabilities and provides further understanding of the self-determination construct. Implications and future research directions are also discussed. PMID- 29758389 TI - Gallbladder perforation into the greater omentum following sleeve gastrectomy: A case report study. AB - INTRODUCTION: Obesity is considered a major risk factor for gallstone formation and is important due to its increasing prevalence worldwide. Many studies have reported an increased incidence of gallstone formation following bariatric surgery. This report documents a rare case of a complicated cholecystitis following sleeve gastrectomy and describes our management of the case and the management options for gallbladder disease in bariatric patients. PRESENTATION OF CASE: A 60-year-old male was diagnosed with asymptomatic cholelithiasis at the time of sleeve gastrectomy for obesity treatment. Two months after the procedure, he presented to the emergency department with symptoms of acute cholecystitis, which were initially managed conservatively. Six weeks later, he underwent a laparoscopic cholecystectomy. Intra-operative findings revealed a rare case of a complicated cholecystitis where the gallstone was half-eroded into the greater omentum. DISCUSSION: A notable proportion of bariatric patients develop symptomatic complicated cholecystitis following laparoscopic sleeve gastrectomy, compared to the normal population. Furthermore, complications develop quickly and technical difficulties are associated with subsequent surgeries. Thus, early cholecystectomy is justified. CONCLUSION: Patients with asymptomatic cholelithiasis, undergoing sleeve gastrectomy, may benefit from concomitant cholecystectomy. The question is yet controversial. This highlights the need for more clinical research in the field. PMID- 29758390 TI - Dried powder of corn stalk as a potential biosorbent for the removal of iodate from aqueous solution. AB - Removal of IO3- from environmental samples with low-cost methods and materials is very useful approach for especially large-scale applications. Corn stalk is highly abundant agriculture residual, which is employed as useful biosorbent in many studies. In the present work, dried powder of corn stalk is applied for the removal of IO3- under various conditions. The results indicate that the Kd is 49.73 ml g-1 under general conditions (m/V = 8 g L-1, t = 5 day, equilibrium pH = 7 +/- 0.3, T = 298 K and C0 = 15 mg L-1). The sorption kinetics follows the pseudo-second-order equation, and the isotherm is well described by the Langmuir model. The sorption reaction was non-spontaneous and endothermic. Hydroxyl and carbonyl groups of the corn stalk contribute to IO3- sorption by ion-exchange, electrostatic attraction and redox reactions. Spectroscopic analyses and the effect of equilibrium pH prove that corn stalk was not only removed IO3- from aqueous solution but also reduced IO3- into I2 and I-. These results demonstrate that corn stalk is a promising biosorbent for the environmental remediation of radioactive iodine pollution. PMID- 29758391 TI - The impact bias in self and others: Affective and empathic forecasting in individuals with social anxiety. AB - People tend to overestimate the intensity and duration of affect (i.e., impact bias) when making predictions about their own and others' responding, termed affective and empathic forecasting, respectively. Research links impact biases to clinical symptoms of affective disorders, but little work has been done to examine how social anxiety is related to affective and empathic forecasting biases. The current investigation included two studies examining these associations in independent samples of young adults with dimensionally distributed social anxiety symptoms. Study 1 (N = 100) examined the associations between social anxiety and affective and empathic forecasts in response to a series of novel hypothetical vignettes in which a second-person narrator (i.e., the self) elicited anger, disgust, or happiness from another person (i.e., the other). Study 2 utilized an innovative experimental paradigm involving N = 68 participant dyads. Overall, results supported the existence of affective and empathic forecasting biases. Further, symptoms of social anxiety were associated with the tendency to overestimate one's own and others' negative affect and underestimate others' positive affect. Such forecasting biases may help to explain the avoidance that is characteristic of individuals with social anxiety and could represent a fruitful target of cognitive behavioral intervention. PMID- 29758392 TI - Effects of mindfulness and psychoeducation on working memory in adult ADHD: A randomised, controlled fMRI study. AB - Adult attention-deficit/hyperactivity disorder (ADHD) is a serious mental disorder associated with impaired neurocognitive performance related to working memory function. Recent clinical trials have suggested that mindfulness is a promising intervention in adults with ADHD. We performed a randomised controlled clinical trial to investigate working memory (WM) with an n-back task in adults with ADHD during fMRI before and after an 8-week mindfulness intervention (MAP) compared with psychoeducation (PE). ADHD symptoms were assessed using the self- and observer-rated Conners Adult ADHD Rating Scales (CAARS). The complete pre post data of 21 MAP and 19 PE participants were analysed. We found no group difference in ADHD symptoms or task performance at the pre-measurement, but there was a significant decrease in ADHD symptoms and significant improvement in task performance in both groups at the post-measurement. Furthermore, we found a significant increase in task-related activation in the right parietal lobe, with no difference between groups. Exploratory two-sample paired t-tests revealed significant increased brain activation after MAP in the bilateral inferior parietal lobule, right posterior insula and right precuneus. A decrease in self rated 'Inattention/Memory Problems' after MAP compared to baseline was associated with stronger activation in parts of the left putamen, globus pallidus and thalamus. PMID- 29758393 TI - Phase I Trial of Brentuximab Vedotin for Steroid-Refractory Chronic Graft-versus Host Disease after Allogeneic Hematopoietic Cell Transplantation. AB - We conducted a phase I study of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30, for the treatment of steroid-refractory chronic graft versus-host disease (cGVHD). A modified 3 + 3 study design was used with the primary endpoint to determine the maximum tolerated dose of BV in this population. Escalating doses of BV were planned, starting with .6 mg/kg every 3 weeks (dose level 0) and increasing by .3 mg/kg per dose level. BV was administered in 21-day cycles for up to 16 cycles of therapy. Nineteen patients were enrolled on the study, with 2 withdrawing consent before dosing. The median number of cycles of therapy was 4 (range, 1 to 16). Reasons for stopping therapy prematurely included toxicities (n = 9), patient decision (n = 3), lack of response (n = 2), and death (n = 1). There were 2 dose-limiting toxicities observed: posterior reversible encephalopathy syndrome (cohort 4, grade 3) and sepsis (cohort 4, grade 4). The maximum tolerated dose was not reached because the trial was prematurely closed due to toxicity. Seven patients (41%) developed grade 3 or 4 adverse events that were attributed to therapy, including 4 patients who developed moderate or severe peripheral neuropathy that led to cessation of treatment in each case. According to National Institutes of Health cGVHD response criteria, 8 patients (47%) experienced a partial response, whereas 9 patients (53%) had a lack of response. There were no complete responses observed. Eleven patients (65%) were able to decrease their systemic corticosteroid dose by >=50% by 6 months after initiation of BV, including 3 patients who were able to stop corticosteroids completely. The median soluble CD30 level before therapy was 61.5 ng/mL (range, 7.8 to 474.9); however, we did not observe any association between soluble CD30 level and cGVHD severity at enrollment or clinical responses to BV. In conclusion, BV may have activity in treatment of steroid-refractory cGVHD, yet its use is limited by treatment-emergent toxicities, including peripheral neuropathy. Continued efforts to investigate targeted approaches to cGVHD that do not cause broad immunosuppression are needed. PMID- 29758395 TI - Self-reported nocturnal sleep duration and glycosylated hemoglobin A in the Study of Cardiovascular Risks in Adolescents (ERICA). AB - OBJECTIVE: At present, epidemiologic studies regarding the relationship between sleep duration and glucose metabolism in adolescents are scarce. The objective was to investigate the association between self-reported nocturnal sleep duration and glycosylated hemoglobin A in 12- to 17-year-old Brazilian adolescents. PATIENTS/METHODS: A school-based multicenter cross-sectional study was carried out in private and public schools from 273 municipalities with more than 100,000 inhabitants. The final sample comprised 24,923 adolescents. A self-administered questionnaire was used. Blood tests included glucose, insulin, glycosylated hemoglobin A and serum lipids. Age, sex, skin color, school type, body mass index (BMI), physical activity, and Brazilian regions were studied as possible effect modifiers and/or confounders using linear regression. RESULTS: A significant positive association was found between more than 12 h of nocturnal sleep and glycosylated hemoglobin A in two Brazilian regions: Southeast and South, even after adjustment for age, sex, skin color, and BMI (coefficients of 0.142 and 0.339, respectively). No association was found with nocturnal sleep duration <7 h. CONCLUSION: Notably, a significant positive relationship was found between more than 12 h of nocturnal sleep duration and glycosylated hemoglobin A in two Brazilian regions. The specific pubertal sleep curtailment can be a compensatory mechanism for dealing with the insulin resistance during adolescence. Those that escape from this regulatory strategy and sleep longer than the adequate duration, break down this balance and tend to damage their glucose metabolism. To our knowledge, this is the first large scale study, of the association between sleep duration and glucose metabolism in adolescents. PMID- 29758396 TI - Callous unemotional traits and the relationship between aggressive parenting practices and conduct problems in Singaporean families. AB - Research into parenting influences on child conduct problems in Asian countries has been limited compared to that conducted in Western countries, especially with regard to interplay between parenting and callous unemotional (CU) traits (e.g., lack of guilt and empathy). This study examined associations between dimensions of aggressive parenting practices (psychological aggression, mild and severe physical aggression), dimensions of child aggression (proactive, reactive), and child CU traits, in Singapore. Participants were children and adolescents with clinic-referred externalizing problems (N = 282; 87.6% boys), aged 7-16 years. Mild and severe parental physical aggression was found to be uniquely associated with children's proactive aggression, whereas parental psychological aggression was uniquely associated with both proactive and reactive aggression. Consistent with previous evidence regarding CU traits as moderators of the relationship between negative parenting and child conduct problems, physically aggressive parenting was found to be more strongly associated with children's proactive aggression among children with low levels of CU traits, than those with high CU traits. These findings support the need for ongoing research into CU traits in Asian cultures, focused on heterogeneous risk pathways to antisocial behavior and individual differences in response to family-based interventions. PMID- 29758397 TI - Discrimination between smiling faces: Human observers vs. automated face analysis. AB - This study investigated (a) how prototypical happy faces (with happy eyes and a smile) can be discriminated from blended expressions with a smile but non-happy eyes, depending on type and intensity of the eye expression; and (b) how smile discrimination differs for human perceivers versus automated face analysis, depending on affective valence and morphological facial features. Human observers categorized faces as happy or non-happy, or rated their valence. Automated analysis (FACET software) computed seven expressions (including joy/happiness) and 20 facial action units (AUs). Physical properties (low-level image statistics and visual saliency) of the face stimuli were controlled. Results revealed, first, that some blended expressions (especially, with angry eyes) had lower discrimination thresholds (i.e., they were identified as "non-happy" at lower non happy eye intensities) than others (especially, with neutral eyes). Second, discrimination sensitivity was better for human perceivers than for automated FACET analysis. As an additional finding, affective valence predicted human discrimination performance, whereas morphological AUs predicted FACET discrimination. FACET can be a valid tool for categorizing prototypical expressions, but is currently more limited than human observers for discrimination of blended expressions. Configural processing facilitates detection of in/congruence(s) across regions, and thus detection of non-genuine smiling faces (due to non-happy eyes). PMID- 29758394 TI - Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation. AB - Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). We characterized the incidence, risk factors, and long-term outcomes associated with TA-TMA by performing a comprehensive review of all adult patients (n = 1990) undergoing allogeneic HSCT at the Dana Farber Cancer Institute/Brigham and Women's Hospital between 2005 and 2013. Using the City of Hope criteria, we identified 258 patients (13%) with "definite" TMA and 508 patients (26%) with "probable" TMA. Mismatched donor transplantation (subdistribution hazard ratio [sHR], 1.79; 95% confidence interval [CI], 1.17 to 2.75; P = .007), sirolimus-containing graft versus-host disease prophylaxis (sHR, 1.73; 95% CI, 1.29 to 2.34; P < .001), myeloablative conditioning (sHR, 1.93, 95% CI, 1.38 to 2.68; P < .001), and high baseline lactate dehydrogenase (LDH) level (sHR, 1.64; 95% CI, 1.26 to 2.13; P < .001) were associated with definite TMA. Moreover, positive cytomegalovirus serostatus (sHR, 1.41; 95% CI, 1.16 to 1.71; P < .001), high and very high disease risk index (sHR, 1.48; 95% CI, 1.12 to 1.96, P = .007), and high baseline LDH level (sHR, 1.25; 95% CI, 1.05 to 1.49; P = .011) were associated with probable TMA. In multivariable analyses, definite and probable TMA were each independently associated with higher mortality (HR, 5.24; 95% CI, 4.43 to 6.20 and HR, 2.12; 95% CI, 1.84 to 2.44, respectively), and long-term kidney dysfunction (HR, 5.43; 95% CI, 4.61 to 6.40 and HR, 2.20; 95% CI, 1.92 to 2.51, respectively). Definite and probable TMA were also independently associated with an increased risk of nonrelapse mortality and shorter progression-free survival. Our findings indicate that TA-TMA is common following HSCT and is independently associated with increased risk of death and kidney dysfunction. PMID- 29758398 TI - Defining clogging potential for permeable concrete. AB - Permeable concrete is used to reduce urban flooding as it allows water to flow through normally impermeable infrastructure. It is prone to clogging by particulate matter and predicting the long-term performance of permeable concrete is challenging as there is currently no reliable means of characterising clogging potential. This paper reports on the performance of a range of laboratory prepared and commercial permeable concretes, close packed glass spheres and aggregate particles of varying size, exposed to different clogging methods to understand this phenomena. New methods were developed to study clogging and define clogging potential. The tests involved applying flowing water containing sand and/or clay in cycles, and measuring the change in permeability. Substantial permeability reductions were observed in all samples, particularly when exposed to sand and clay simultaneously. Three methods were used to define clogging potential based on measuring the initial permeability decay, half-life cycle and number of cycles to full clogging. We show for the first time strong linear correlations between these parameters for a wide range of samples, indicating their use for service-life prediction. PMID- 29758399 TI - Phosphorus solubility in basaltic glass: Limitations for phosphorus immobilization in glass and glass-ceramics. AB - The composition of sewage sludge from urban wastewater treatment plants is simulated using P-doped basalts. Electron microscopy analyses show that the solubility of P in the basaltic melt is limited by the formation of a liquid liquid immiscibility in the form of an aluminosilicate phase and a Ca-Mg-Fe-rich phosphate phase. The rheological behavior of these compositions is influenced by both phase separation and nanocrystallization. Upon a thermal treatment, the glasses will crystallize into a mixture of inosilicates and spinel-like phases at low P contents and into Ca-Mg-Fe phosphate at high P contents. Hardness measurements yield values between 5.41 and 7.66 GPa, inside the range of commercial glasses and glass-ceramics. Leaching affects mainly unstable Mg2+-PO43 complexes. PMID- 29758400 TI - A method to quantify and value floodplain sediment and nutrient retention ecosystem services. AB - Floodplains provide critical ecosystem services to local and downstream communities by retaining floodwaters, sediments, and nutrients. The dynamic nature of floodplains is such that these areas can both accumulate sediment and nutrients through deposition, and export material downstream through erosion. Therefore, estimating floodplain sediment and nutrient retention should consider the net flux of both depositional and erosive processes. An ecosystem services framework was used to quantify and value the sediment and nutrient ecosystem service provided by floodplains in the Difficult Run watershed, a small (151 km2) suburban watershed located in the Piedmont of Virginia (USA). A sediment balance was developed for Difficult Run and two nested watersheds. The balance included upland sediment delivery to streams, stream bank flux, floodplain flux, and stream load. Upland sediment delivery was estimated using geospatial datasets and a modified Revised Universal Soil Loss Equation. Predictive models were developed to extrapolate field measurements of the flux of sediment, sediment-bound nitrogen (N), and sediment-bound phosphorus (P) from stream banks and floodplains to 3232 delineated stream segments in the study area. A replacement cost approach was used to estimate the economic value of the sediment and nutrient retention ecosystem service based on estimated net stream bank and floodplain flux of sediment-bound N for all streams in the study area. Results indicated the net fluvial fluxes of sediment, sediment-bound N, and sediment-bound P were -10,439 Mg yr-1 (net export), 57,300 kg-N yr-1 (net trapping), and 98 kg-P yr-1(net trapping), respectively. For sediment, floodplain retention was offset by substantial losses from stream bank erosion, particularly in headwater catchments, resulting in a net export of sediment. Nutrient retention in the floodplain exceeded that lost through stream bank erosion resulting in net retention of nutrients (TN and TP). Using a conservative cost estimate of $12.69 (USD) per kilogram of nitrogen, derived from wastewater treatment costs, the estimated annual value for sediment and nutrient retention on Difficult Run floodplains was $727,226 +/- 194,220 USD/yr. Values and differences in floodplain nitrogen retention among stream reaches can be used to target areas for floodplain conservation and stream restoration. The methods presented are scalable and transferable to other areas if appropriate datasets are available for validation. PMID- 29758401 TI - Factors determining the exposure of dairy farmers to thoracic organic dust. AB - Bronchial respiratory diseases are more common in dairy farmers than in the general population, perhaps because the repeated inhalation of organic dust contributes to the development of these disorders. However, the factors determining the exposure of farmers to particles that can enter the lower bronchial tract and interact with it, i.e. the thoracic fraction of the inhalable dust, remain to be identified. We therefore measured the exposure of dairy farmers to thoracic organic dust and identified the farm features and tasks that increased exposure. We measured thoracic particles (n = 110) and farm characteristics and occupational tasks in 29 Brittany dairy farms. The mean (GM) (geometric standard deviation, GSD) concentration of thoracic dust in air inhaled by farmers was 0.24 mg/m3 (2.8) and the concentrations of endotoxins, Gram positive bacteria and fungi in the thoracic fraction were 128 EU/m3 (4.0), 960 CFU/m3 (6.3) and 690 CFU/m3 (5.4), respectively. Model-based estimates of the association between exposure, farm features and tasks indicated that manual grain and feed handling and mechanical bedding spreading significantly increased exposure to thoracic dust, endotoxins, bacteria and fungi. Exposure to bacteria and fungi was reduced by cowsheds divided into cubicles, whereas using automatic muck scrappers in alleyway and automatic milking tended to increase exposure to bacteria and endotoxins. Finally, exposure to endotoxin and fungi were reduced by warmer farm buildings and well-ventilated buildings having walls with large openings. In conclusions, major occupational tasks and specific farm features determine the exposure of Breton dairy farmers to thoracic organic dust. PMID- 29758403 TI - Progression of intrahisian atrioventricular block: Will this presage a renaissance of His-bundle studies? PMID- 29758402 TI - Lactation-related changes in tissue expression of PEDF in dairy cows. AB - Pigment epithelium-derived factor (PEDF) is evolving as metabolic regulatory protein. Albeit mostly considered in only pathological conditions related to excess energy intake resulting in obesity and insulin resistance, PEDF is likely to be involved in other physiological processes such as the homeorhetic adaptation of metabolism to lactation. We aimed to characterize the expression of PEDF and its association to the concomitant mobilization of body reserves during lactation in nonobese subjects. This mobilization is particularly distinct in dairy cows, and we therefore assessed the mRNA expression of PEDF and its putative receptors in different tissues in 2 trials with dairy cows fed with or without conjugated linoleic acids (CLAs). Conjugated linoleic acids depress milk fat synthesis and may thus reduce the drain of energy via milk. In pluriparous cows, the serum PEDF concentrations and the mRNA abundance in subcutaneous adipose tissue (scAT), as well as the hepatic and scAT mRNA abundance of the putative receptors, adipose triglyceride lipase, and laminin receptor 1, changed over time of sampling (day -21 until day 252 relative to calving). Conjugated linoleic acid treatment was associated with reduced PEDF concentrations in serum and lower PEDF mRNA abundance in scAT on day 21 postpartum. Comparing different tissues from primiparous cows, PEDF mRNA was highest in the liver, followed by scAT, visceral adipose tissue (AT), and mammary gland, and lowest in the muscle. Significant changes in PEDF expression with time of sampling were limited to AT in primiparous and pluriparous cows. Our data support a regulatory role for PEDF. The similarities between the time course of the serum concentrations of PEDF and its mRNA abundance in scAT may point to a regulatory role for AT rather than the liver for PEDF in dairy cows. PMID- 29758404 TI - Prospective blinded evaluation of a novel sensing methodology designed to reduce inappropriate shocks by the subcutaneous implantable cardioverter-defibrillator. AB - BACKGROUND: Most inappropriate shocks from the subcutaneous implantable cardioverter-defibrillator (S-ICD) are caused by cardiac oversensing. A novel sensing methodology, SMART Pass (SP; Boston Scientific Corporation, Natick, MA), aims to reduce cardiac oversensing. OBJECTIVE: The purpose of this study was to evaluate the effect of SP on shocks in ambulatory patients with S-ICD. METHODS: Patients implanted in 2015-2016 and enrolled in a remote patient monitoring system were included and followed for 1 year. Shocks were adjudicated by 3 independent blinded reviewers as appropriate or inappropriate. Shock incidence was calculated for patients with SP programmed enabled or disabled at implantation, censoring patients when SP programming changed or at the last transmission. The SP setting (enabled vs disabled) was modeled as a time dependent Cox regression variable. RESULTS: The cohort consisted of 1984 patients, and a total of 880 shocks were adjudicated. At implantation, SP was enabled in 655 patients (33%) and disabled in 1329 patients (67%). SP reduced the risk for the first inappropriate shock by 50% (P < .001) and the risk for all inappropriate shocks by 68% (P < .001) in multivariate analysis adjusted for age and device programming. The incidence of inappropriate shocks was 4.3% in the SP enabled arm vs 9.7% in the SP disabled arm. The incidence of appropriate shocks was similar (5.2% vs 6.6%; P = .18) along with the time to treat the first appropriate shock (17.4 seconds vs 16.7 seconds; P = .92) for SP enabled vs disabled, respectively. CONCLUSION: This prospective blinded evaluation of the SP filter demonstrates that enabling the SP filter results in a significant reduction of inappropriate shocks by the S-ICD without a negative effect on appropriate shocks. PMID- 29758406 TI - Molecular dynamics guided development of indole based dual inhibitors of EGFR (T790M) and c-MET. AB - Secondary acquired mutation in EGFR, i.e. EGFR T790M and amplification of c-MET form the two key components of resistant NSCLC. Thus, previously published pharmacophore models of EGFR T790M and c-MET were utilized to screen an in-house database. On the basis of fitness score, indole-pyrimidine scaffold was selected for further evaluation. Derivatives of indole-pyrimidine scaffold with variedly substituted aryl substitutions were sketched and then docked in both the targets. These docked complexes were then subjected to molecular dynamic simulations, to study the stability of the complexes and evaluate orientations of the designed molecules in the catalytic domain of the selected kinases. Afterwards, the complexes were subjected to MM-GBSA calculation, to study the effect of substitutions on binding affinity of double mutant EGFR towards these small molecules. Finally, the designed molecules were synthesized and evaluated for their inhibitory potential against both the kinases using in vitro experiments. Additionally, the compounds were also evaluated against EGFR (L858R) to determine their selectivity towards double mutant, resistant kinase [EGFR (T790M)]. Compound 7a and 7c were found to be possess nanomolar range inhibitory (IC50) potential against EGFR (T790M), 7 h showed good inhibitory potential against c MET with IC50 value of 0.101 uM. Overall, this work is one of the earliest report of compounds having significant dual inhibitory potential against secondary acquired EGFR and cMET, with IC50 values in nanomolar range. PMID- 29758405 TI - Accelerometer-based atrioventricular synchronous pacing with a ventricular leadless pacemaker: Results from the Micra atrioventricular feasibility studies. AB - BACKGROUND: Micra is a leadless pacemaker that is implanted in the right ventricle and provides rate response via a 3-axis accelerometer (ACC). Custom software was developed to detect atrial contraction using the ACC enabling atrioventricular (AV) synchronous pacing. OBJECTIVE: The purpose of this study was to sense atrial contractions from the Micra ACC signal and provide AV synchronous pacing. METHODS: The Micra Accelerometer Sensor Sub-Study (MASS) and MASS2 early feasibility studies showed intracardiac accelerations related to atrial contraction can be measured via ACC in the Micra leadless pacemaker. The Micra Atrial TRacking Using A Ventricular AccELerometer (MARVEL) study was a prospective multicenter study designed to characterize the closed-loop performance of an AV synchronous algorithm downloaded into previously implanted Micra devices. Atrioventricular synchrony (AVS) was measured during 30 minutes of rest and during VVI pacing. AVS was defined as a P wave visible on surface ECG followed by a ventricular event <300 ms. RESULTS: A total of 64 patients completed the MARVEL study procedure at 12 centers in 9 countries. Patients were implanted with a Micra for a median of 6.0 months (range 0-41.4). High-degree AV block was present in 33 patients, whereas 31 had predominantly intrinsic conduction during the study. Average AVS during AV algorithm pacing was 87.0% (95% confidence interval 81.8%-90.9%), 80.0% in high-degree block patients and 94.4% in patients with intrinsic conduction. AVS was significantly greater (P <.001) during AV algorithm pacing compared to VVI in high-degree block patients, whereas AVS was maintained in patients with intrinsic conduction. CONCLUSION: Accelerometer-based atrial sensing is feasible and significantly improves AVS in patients with AV block and a single-chamber leadless pacemaker implanted in the right ventricle. PMID- 29758407 TI - Synthesis and molecular docking of N,N'-disubstituted thiourea derivatives as novel aromatase inhibitors. AB - A three series of thioureas, monothiourea type I (4a-g), 1,4-bisthiourea type II (5a-h) and 1,3-bisthiourea type III (6a-h) were synthesized. Their aromatase inhibitory activities have been evaluated. Interestingly, eight thiourea derivatives (4e, 5f-h, 6d, 6f-h) exhibited the aromatase inhibitory activities with IC50 range of 0.6-10.2 MUM. The meta-bisthiourea bearing 4-NO2 group (6f) and 3,5-diCF3 groups (6h) were shown to be the most potent compounds with sub micromolar IC50 values of 0.8 and 0.6 MUM, respectively. Molecular docking also revealed that one of the thiourea moieties of these two compounds could mimic steroidal backbone of the natural androstenedione (ASD) via hydrophobic interactions with enzyme residues (Val370, Leu477, Thr310, and Phe221 for 6f, Val370, Leu477, Ser478, and Ile133 for 6h). This is the first time that the bisthioureas have been reported for their potential to be developed as aromatase inhibitors, in which the 4-NO2 and 3,5-diCF3 analogs have been highlighted as promising candidates. PMID- 29758408 TI - Abundant plasma protein depletion using ammonium sulfate precipitation and Protein A affinity chromatography. AB - Plasma is a highly valuable resource for biomarker research since it is easy obtainable and contains a high amount of information on patient health status. Although advancements in the field of proteomics enabled analysis of the plasma proteome, identification of low abundant proteins remains challenging due to high complexity and large dynamic range. In order to reduce the dynamic range of protein concentrations, a tandem depletion technique consisting of ammonium sulfate precipitation and Protein A affinity chromatography was developed. Using this method, 50% of albumin, together with other high abundant proteins such as alpha-1-antitrypsin, was depleted from the plasma sample at 20% to 40% ammonium sulfate saturation levels. In combination with immunoglobulin removal using a Protein A column, this technique delivered up to 40 new low- to medium abundance protein identifications when performing a shotgun mass spectrometry analysis. Compared to non-depleted plasma, 270 additional protein spots were observed during 2D-PAGE analysis. These results illustrate that this tandem depletion method is equivalent to commercial kits which are based on immune-affinity chromatography. Moreover, this method using Protein A immunoglobulin depletion was shown to be highly reproducible and a minimal amount of non-target proteins was depleted. The combination of ammonium sulfate precipitation and Protein A affinity chromatography offers a low cost, efficient, straightforward and reproducible alternative to commercial kits, with proteins remaining in native conformation, allowing protein activity and protein interaction studies. PMID- 29758409 TI - Tailoring metal oxide nanoparticle dispersions for inkjet printing. AB - There is a growing interest in science and industry for printed electronics. Printed electronics enable the production of large quantities of electronic components at low cost. Even though organic semiconductors are already widely used for printed components, inorganic materials may be advantageous due to their higher durability and superior device performance. Nevertheless, inorganic materials still remain difficult to print making the development of printable and functional inks a necessity. In this work we present the formulation, inkjet printing and processing of newly developed inks based on ethylene glycol as dispersion medium. Different metal oxide nanoparticles (ZnO, TiO2, CuO, SnO2 and In2O3) with high crystallinity and narrow size distribution were produced by chemical vapor synthesis. The particles were stabilized and the colloidal stability was evaluated by a combination of DLVO simulations and dynamic light scattering measurements. Measurements of rheological and interfacial properties, like viscosity and surface tension, are used to determine the printability on the basis of the inverse Ohnesorge number. Inks, developed in this work, have adjustable rheological properties as well as long-term stabilities without particle sedimentation over a period of several months. They are suitable for printing on different substrate materials like silicon and flexible polymeric substrates. PMID- 29758410 TI - Introducing double polar heads to highly fluorescent Thiazoles: Influence on supramolecular structures and photonic properties. AB - HYPOTHESIS: Supramolecular structures determine properties of optoelectronically active materials and can be tailored via the Langmuir-Blodgett (LB) technique. Interactions between dyes can cause high crystallinities of Langmuir monolayers, thus rendering retaining their integrity during the LB-deposition challenging. However, increasing degrees of freedom exclusively at the polar anchoring moieties of dyes might improve processability without perturbing the dye's optoelectronic properties nor the function-determining crystallinity of the layer. EXPERIMENTS: (Amphiphilic) thiazole dyes without, with a mono-polar, and with a double-polar anchor were synthesized, whereas the two constituting polar moieties of the latter derivate are separated by a flexible alkyl chain. The supramolecular structures and crystallinities of Langmuir and LB monolayers were characterized by means of LB isotherms, atomic force microscopy and polarization resolved fluorescence spectroscopy. FINDINGS: As compared to the mono-polar reference the introduction of a flexible double-polar head did not deteriorate UV vis absorption, emission or electrochemical properties of the thiazole but significantly extended the range of constant compressibility modulus, thus indicating improved processability of the Langmuir monolayers. Indeed, AFM studies revealed that the integrity of the monolayers could be retained during LB deposition. Additionally, also the underlying supramolecular structure of the chromophore moieties is largely identical to those obtained from the mono-polar reference thiazoles. PMID- 29758411 TI - EDS tomographic reconstruction regularized by total nuclear variation joined with HAADF-STEM tomography. AB - Energy-dispersive X-ray spectroscopy (EDS) tomography is an advanced technique to characterize compositional information for nanostructures in three dimensions (3D). However, the application is hindered by the poor image quality caused by the low signal-to-noise ratios and the limited number of tilts, which are fundamentally limited by the insufficient number of X-ray counts. In this paper, we explore how to make accurate EDS reconstructions from such data. We propose to augment EDS tomography by joining with it a more accurate high-angle annular dark field STEM (HAADF-STEM) tomographic reconstruction, for which usually a larger number of tilt images are feasible. This augmentation is realized through total nuclear variation (TNV) regularization, which encourages the joint EDS and HAADF reconstructions to have not only sparse gradients but also common edges and parallel (or antiparallel) gradients. Our experiments show that reconstruction images are more accurate compared to the non-regularized and the total variation regularized reconstructions, even when the number of tilts is small or the X-ray counts are low. PMID- 29758412 TI - Anti-inflammatory effect of the extracts from the branch of Taxillus yadoriki being parasitic in Neolitsea sericea in LPS-stimulated RAW264.7 cells. AB - Mistletoe has been used as the herbal medicine to treat hypertension, diabetes mellitus, inflammation, arthritis and viral infection. In this study, we evaluated the anti-inflammatory effect of extracts of branch from Taxillus yadoriki being parasitic in Neolitsea sericea (TY-NS-B) using in vitro model. TY NS-B significantly inhibited LPS-induced secretion of NO and PGE2 in RAW264.7 cells. TY-NS-B was also observed to inhibit LPS-mediated iNOS COX-2 expression. In addition, TY-NS-B attenuated production of inflammatory cytokines such as TNF alpha and IL-1beta induced by LPS. TY-NS-B blocked LPS-mediated inhibitor of IkappaB-alpha, and inhibited p65 translocation to the nucleus and NF-kappaB activation. Furthermore, TY-NS-B reduced the phosphorylation of MAPKs such as p38 and JNK, but not ERK1/2. In addition, TY-NS-B increased ATF3 expression and ATF3 knockdown by ATF3 siRNA attenuated TY-NS-B-mediated inhibition of pro inflammatory mediator expression. Collectively, our results suggest that TY-NS-B exerts potential anti-inflammatory effects by suppressing NF-kappaB and MAPK signaling activation, and increasing ATF3 expression. These findings indicate that TY-NS-B could be further developed as an anti-inflammatory drug. PMID- 29758413 TI - Physcion 8-O-beta-glucopyranoside inhibits clear-cell renal cell carcinoma bydownregulating hexokinase II and inhibiting glycolysis. AB - BACKGROUND: Clear-cell renal cell carcinoma (ccRCC) has the highest prevalence, approximately 80%, amongst all RCC cases. Therefore, the development of novel therapeutic agents against ccRCC is imperative. Our previous studies have shown that physcion 8-O-beta-glucopyranoside (PG), an anthraquinone extracted from Rumexjaponicus Houtt, exerted an anti-cancer effect in hepatocellular carcinoma cells. The present study was aimed to investigate a possible anti-neoplastic role of PG in ccRCC and the relevant underlying mechanism. MATERIALS AND METHODS: Two human ccRCC cell lines- RCC4 and ACHN- were used as in vitro models and treated with varying concentrations of PG. Cell Counting Kit-8 (CCK-8) assay was used to determine cell viability, and Annexin-V FITC/PI staining was used to analyze the percentage of apoptotic cells after PG treatment. Commercially available kits were used to measure the rates of glucose consumption and lactate production. Changes in mitochondrial membrane potential were examined by flow cytometry, and western blotting was performed to analyze the levels of various apoptosis markers. To examine the role of HK2 in the anti-tumor effect of PG, ccRCC cells were transfected with a vector overexpressing HK2. Moreover, a xenograft model was established to evaluate the therapeutic effect of PG in vivo. RESULTS: PG decreased viability in dose-dependent manner and induced apoptosis via the intrinsic pathway, along with inhibiting glycolysis in the ccRCC cell lines. Mechanistically, PG induced apoptosis and suppressed glycolysis by downregulating HK2. In vivo data also demonstrated that PG could exert an anti-tumor activity without any adverse side-effects. CONCLUSION: PG induced mitochondrial apoptosis and inhibited glycolysis in clear-cell renal cell carcinoma. Our findings provide preliminary experimental data that support further investigation of the therapeutic efficacy of PG in ccRCC. PMID- 29758414 TI - Role of PCSK9 in lipid metabolism and atherosclerosis. AB - Elevated plasma low-density lipoprotein cholesterol (LDL-C) is an important risk factor for cardiovascular diseases. Statins are the most widely used therapy for patients with hyperlipidemia. However, a significant residual cardiovascular risk remains in some patients even after maximally tolerated statin therapy. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a new pharmacologically therapeutic target for decreasing LDL-C. PCSK9 reduces LDL intake from circulation by enhancing LDLR degradation and preventing LDLR recirculation to the cell surface. Moreover, PCSK9 inhibitors have been approved for patients with either familial hypercholesterolemia or atherosclerotic cardiovascular disease, who require additional reduction of LDL-C. In addition, PCSK9 inhibition combined with statins has been used as a new approach to help reduce LDL-C levels in patients with either statin intolerance or unattainable LDL goal. This review will discuss the emerging anti-PCSK9 therapies in the regulation of cholesterol metabolism and atherosclerosis. PMID- 29758415 TI - Anti-tumor effects of propranolol: Adjuvant activity on a transplanted murine breast cancer model. AB - Propranolol (Pro), a non-specific beta-adrenergic blocking drug, competitively prevents the binding of catecholamines to receptors and suppresses cancer cells. The anti-tumor activity of propranolol has been proved in different kinds of cancers. In this study, we assessed the adjuvant activity of propranolol combined with a tumor vaccine model on the immunological parameters of breast tumor bearing mice. Breast tumor pieces were implanted into the flank of inbred BALB/C female mice from stock mice. Tumor-bearing mice were treated with tumor antigen lysate vaccine and propranolol/Vaccine (Pro/Vac) combination (as treatment groups), propranolol and PBS (as control groups) for 5 consecutive days, every 12 h. Moreover, all experimental groups received vaccine for three times with one week interval via s.c injection. After immunization courses, spleens of tumor bearing mice were removed and dissected, cell suspension was stimulated in vitro, and the cytokine levels in supernatant of splenocytes were measured via commercial ELISA kits. Compared with the vaccine group, immunization with tumor lysate in combination with propranolol significantly increased IL-2, IL-4, IL-12, IL-17, and IFN-gamma cytokines. Considering the suppression of tumor growth, propranolol seems to be a potent immunomodulator capable of inducing cellular immune responses against breast cancer. PMID- 29758416 TI - Drug targets for resistant malaria: Historic to future perspectives. AB - New antimalarial targets are the prime need for the discovery of potent drug candidates. In order to fulfill this objective, antimalarial drug researches are focusing on promising targets in order to develop new drug candidates. Basic metabolism and biochemical process in the malaria parasite, i.e. Plasmodium falciparum can play an indispensable role in the identification of these targets. But, the emergence of resistance to antimalarial drugs is an escalating comprehensive problem with the progress of antimalarial drug development. The development of resistance has highlighted the need for the search of novel antimalarial molecules. The pharmaceutical industries are committed to new drug development due to the global recognition of this life threatening resistance to the currently available antimalarial therapy. The recent developments in the understanding of parasite biology are exhilarating this resistance issue which is further being ignited by malaria genome project. With this background of information, this review was aimed to highlights and provides useful information on various present and promising treatment approaches for resistant malaria, new progresses, pursued by some innovative targets that have been explored till date. This review also discusses modern and futuristic multiple approaches to antimalarial drug discovery and development with pictorial presentations highlighting the various targets, that could be exploited for generating promising new drugs in the future for drug resistant malaria. PMID- 29758417 TI - Exploring the value of overseas biodiversity to Chinese netizens based on willingness to pay for the African elephants' protection. AB - For a long time, Chinese people have been considered to be concerned only with commercial interests but not ecological systems and biodiversity conservation, even though their trade and investment footprints are globalizing rapidly. This study intended to reveal the non-market valuation on the non-use value of African elephant to Chinese people. Taking the ban of ivory trade as the background, in this study, Chinese netizens' willingness to pay for African elephant conservation was investigated using the contingent valuation method. Four versions of questionnaires were designed and distinguished by offering different background information and payment vehicles (tax and donation). It was demonstrated that the differences in both given information and payment vehicles had no significant impacts on the estimated mean willingness to pay value. 53.36% of the respondents gave positive responses for the hypothetical projects of African elephant protection. The mean willingness to pay was 83.62 RMB (12.59 USD) and 158.58 RMB (23.88 USD) per year per household and the aggregated willingness to pay or benefits for the protection of African elephants from Chinese netizens were estimated to be 16.31 billion RMB (2.45 billion USD) and 30.92 billion RMB (4.65 billion USD) per year after grouping regression and benefit transfer adjustments, respectively. The current research shows that Chinese people, living thousands kilometers away from Africa, have a high public awareness for and valuation to the endangered elephants. PMID- 29758418 TI - Nutrient inputs and hydrology together determine biogeochemical status of the Loire River (France): Current situation and possible future scenarios. AB - The Grafs-Seneque/Riverstrahler model was implemented for the first time on the Loire River for the 2002-2014 period, to explore eutrophication after improvement of wastewater treatments. The model reproduced the interannual levels and seasonal trends of the major water quality variables. Although eutrophication has been impressively reduced in the drainage network, a eutrophication risk still exists at the coast, as shown by the N-ICEP indicator, pointing out an excess of nitrogen over silica and phosphorus. From maximum biomass exceeding 120 MUgChla l 1 in the 1980's, we observed decreasing maximum values from 80 to 30 MUgChla l-1 during the period studied. Several scenarios were explored. Regarding nutrient point sources, a low wastewater treatment scenario, similar to the situation in the 1980's, was elaborated, representing much greater pollution than the reference period (2002-2014). For diffuse sources, two agricultural scenarios were elaborated for reducing nitrogen, one with a strict application of the agricultural directives and another investigating the impact of radical structural changes in agriculture and the population's diet. Although reduced, a risk of eutrophication would remain, even with the most drastic scenario. In addition, a pristine scenario, with no human activity within the basin, was devised to assess water quality in a natural state. The impact of a change in hydrology on the Loire biogeochemical functioning was also explored according to the effect of climate change by the end of the 21st century. The EROS hydrological model was used to force Riverstrahler, considering the most pessimistic SRES A2 scenario run with the ARPEGE model. Nutrient fluxes all decreased due to a >50% reduction in the average annual discharge, overall reducing the risk of coastal eutrophication, but worsening the water quality status of the river network. The Riverstrahler model could be useful to help water managers contend with future threats in the Loire River, at the scale of its basin and at smaller nested scales. PMID- 29758419 TI - Seasonal ionomic and metabolic changes in Aleppo pines growing on mine tailings under Mediterranean semi-arid climate. AB - Aleppo pine is the most abundant conifer species in Mediterranean basin. Knowledge of adaptive mechanisms to cope with different environmental stresses simultaneously is necessary to improve its resilience to the predicted climatic changes and anthropogenic stressors, such as heavy metal/metal(loid)s (HMMs) pollution. Here, one year-old needles and rhizosphere soil samples from five mining and non-mining (NM) populations of Aleppo pines grown spontaneously in SE Spain were sampled in two consecutive years during spring and summer. Quantitative determination of a wide suite of edaphic, biochemical, and physiological parameters was performed, including soil physicochemical properties, ionome profile, foliar redox components, primary and secondary metabolites. Mining rhizosphere soils were characterized by elevated contents of HMMs, particularly lead and zinc, and low carbon, nitrogen and potassium levels. Multivariate data analysis based on needle ionome and antioxidative/oxidative parameters revealed a clear distinction between seasons irrespective of the population considered. Spring needles were characterized by higher levels of HMMs, sulfur, glutathione (GSH), proanthocyanidins (PAs), and soluble phenols (TPC), whereas reduced chlorophylls and increased levels of carotenoids, relative water content and K+, Na+ and Cl- typified summer needles. In general mining populations had higher levels of ascorbate, and TPC, and exhibited higher antioxidant activities than the NM population. This could contribute to prevent oxidative injury induced by HMMs. Taken together, results suggest that seasonal factors have a more marked effect on the metabolism of the Aleppo pine populations studied than that exerted by soil conditions. This effect could be mediated by water availability in surface soil layers. If this conclusion is right, predicted rainfall reduction and temperature increase in the Mediterranean basin associated to global climate change would lead to pine needle metabolism to express the summer pattern for more prolonged periods. This, in turn, could negatively affect the performance of Aleppo pine populations. PMID- 29758420 TI - Assessment of the impact of three pesticides on microbial dynamics and functions in a lab-to-field experimental approach. AB - The toxicity of pesticides on soil microorganisms is as an emerging area of concern. Novel and well-standardized tools could be now used to provide a robust assessment of the ecotoxicity of pesticides on soil microorganisms. We followed a tiered lab-to-field approach to assess the toxicity of three pesticides, widely used at EU level, (chlorpyrifos (CHL), isoproturon (IPU) and tebuconazole (TBZ)) on (i) the abundance of 11 microbial taxa and 8 functional microbial groups via q PCR and (ii) the activity of enzymes involved in biogeochemical cycles via fluorometric analysis. Correlation of microbial measurements with the concentration of pesticides, and their transformation products (TPs) in soil enabled the identification of the compounds driving the effects observed. At lab tests (*1, *2 and *10 the recommended dose), CHL and TBZ significantly reduced the relative abundance of ammonia-oxidizing bacteria (AOB) and archaea (AOA) which recovered by the end of the study, while all pesticides induced a persistent reduction in the relative abundance of sulfur-oxidizing bacteria (SOB). The two demethylated metabolites of IPU (MD-IPU and DD-IPU) adversely affected P-cycling enzymes and leucine aminopeptidase (Leu). At field tests (*1, *2 and *5 the recommended dose), a persistent reduction on the relative abundance of AOA was induced by all pesticides, but only CHL and its hydrolysis product 3,5,6 trichloro-2-pyridynol (TCP) soil levels were negatively correlated with AOA relative abundance. Our findings suggest that ammonia-oxidizing microorganisms constitute the most responsive microbial group to pesticides and could be potential candidates for inclusion in pesticide risk assessment. PMID- 29758421 TI - The effect of hypoxia and flow decrease in macroinvertebrate functional responses: A trait-based approach to multiple-stressors in mesocosms. AB - River ecosystems are most often subject to multiple co-occurring anthropogenic stressors. Mediterranean streams are particularly affected by water scarcity and organic loads that commonly lead to a simultaneous reduction in flow and increasing depletion of dissolved oxygen. In the present study, the single and combined effects of water scarcity (flow velocity reduction) and dissolved oxygen depletion were used to evaluate alterations of drifting macroinvertebrates on a channel mesocosm system, by employing a multiple trait-based approach. Our main findings confirmed that the impact of the two combined stressors can be implicated in alterations of ecosystem functions as result of the changes in proportions of biological traits. Overall, our results showed that, individually, flow velocity reduction and a severe oxygen depletion promoted a shift in community traits. In more detail, biological traits describing the dispersal of organisms and their respiration showed the strongest responses. The respiration mode responded to low flow with drift increase of gill breathers and decrease of individuals with tegument, whereas dispersal was clearly affected by the combination of stressors. Resistance through eggs was higher with the single effect of flow reduction, while swimmers' relative abundance increased in individuals that drift after exposure to the combination of stressors. Thus, while flow reduction alone is expected to specifically filter out the gill breathers and the egg producers, the combination of stressors will impact more drastically organism's dispersal and swimmers. Such changes in biological traits can result in variations in ecosystem functioning through, for example, local changes in biomass, secondary production, stream metabolism as well as resulting in biodiversity losses or alterations of its distribution patterns. PMID- 29758422 TI - Clonal expansion of environmentally-adapted Escherichia coli contributes to propagation of antibiotic resistance genes in beef cattle feedlots. AB - Livestock wastewater lagoons represent important environmental reservoirs of antibiotic resistance genes (ARGs), although factors contributing to their proliferation within these reservoirs remain poorly understood. Here, we characterized Escherichia coli from feedlot cattle feces and associated wastewater lagoons using CRISPR1 subtyping, and demonstrated that while generic E. coli were genetically diverse, populations were dominated by several 'feedlot adapted' CRISPR types (CTs) that were widely distributed throughout the feedlot. Moreover, E. coli bearing beta-lactamase genes, which confer reduced susceptibility to third-generation cephalosporin's, predominantly belonged to these feedlot-adapted CTs. Remarkably, the genomic region containing the CRISPR1 allele was more frequently subject to genetic exchange among wastewater isolates compared to fecal isolates, implicating this region in environmental adaptation. This allele is proximal to the mutS-rpoS-nlpD region, which is involved in regulating recombination barriers and adaptive stress responses. There were no loss-of-function mutS or rpoS mutations or beneficial accessory genes present within the mutS-rpoS-nlpD region that would account for increased environmental fitness among feedlot-adapted isolates. However, comparative sequence analysis revealed that protein sequences within this region were conserved among most feedlot-adapted CTs, but not transient fecal CTs, and did not reflect phylogenetic relatedness, implying that adaptation to wastewater environments may be associated with genetic variation related to stress resistance. Collectively, our findings suggest adaptation of E. coli to feedlot environments may contribute to propagation of ARGs in wastewater lagoons. PMID- 29758423 TI - Tracking enteric viruses in green vegetables from central Argentina: potential association with viral contamination of irrigation waters. AB - Consumption of green vegetable products is commonly viewed as a potential risk factor for infection with enteric viruses. The link between vegetable crops and fecally contaminated irrigation water establishes an environmental scenario that can result in a risk to human health. The aim of this work was to analyze the enteric viral quality in leafy green vegetables from Cordoba (Argentina) and its potential association with viral contamination of irrigation waters. During July December 2012, vegetables were collected from peri-urban green farms (n = 19) and its corresponding urban river irrigation waters (n = 12). Also, urban sewage samples (n = 6) were collected to analyze the viral variants circulating in the community. Viruses were eluted and concentrated by polyethylene glycol precipitation and then were subject to Reverse Transcription Polymerase Chain Reaction to assess the genome presence of norovirus, rotavirus and human astrovirus. The concentrates were also inoculated in HEp-2 (Human Epidermoid carcinoma strain #2) cells to monitor the occurrence of infective enterovirus. The frequency of detection of the viral groups in sewage, irrigation water and crops was: norovirus 100%, 67% and 58%, rotavirus 100%, 75% and 5%, astrovirus 83%, 75% and 32% and infective enterovirus 50%, 33% and 79%, respectively. A similar profile in sewage, irrigation water and green vegetables was observed for norovirus genogroups (I and II) distribution as well as for rotavirus and astrovirus G-types. These results provide the first data for Argentina pointing out that green leafy vegetables are contaminated with a broad range of enteric viruses and that the irrigation water would be a source of contamination. The presence of viral genomes and infective particles in food that in general suffer minimal treatment before consumption underlines that green crops can act as potential sources of enteric virus transmission. Public intervention in the use of the river waters as irrigation source is needed. PMID- 29758424 TI - Using strontium isotopes to evaluate the spatial variation of groundwater recharge. AB - Recharge of alluvial aquifers is a key component in understanding the interaction between floodplain vadose zone biogeochemistry and groundwater quality. The Rifle Site (a former U-mill tailings site) adjacent to the Colorado River is a well established field laboratory that has been used for over a decade for the study of biogeochemical processes in the vadose zone and aquifer. This site is considered an exemplar of both a riparian floodplain in a semiarid region and a post-remediation U-tailings site. In this paper we present Sr isotopic data for groundwater and vadose zone porewater samples collected in May and July 2013 to build a mixing model for the fractional contribution of vadose zone porewater (i.e. recharge) to the aquifer and its variation across the site. The vadose zone porewater contribution to the aquifer ranged systematically from 0% to 38% and appears to be controlled largely by the microtopography of the site. The area weighted average contribution across the site was 8% corresponding to a net recharge of 7.5 cm. Given a groundwater transport time across the site of ~1.5 to 3 years, this translates to a recharge rate between 5 and 2.5 cm/yr, and with the average precipitation to the site implies a loss from the vadose zone due to evapotranspiration of 83% to 92%, both ranges are in good agreement with previously published results by independent methods. A uranium isotopic (234U/238U activity ratios) mixing model for groundwater and surface water samples indicates that a ditch across the site is hydraulically connected to the aquifer and locally significantly affects groundwater. Groundwater samples with high U concentrations attributed to natural bio-reduced zones have 234U/238U activity ratios near 1, suggesting that the U currently being released to the aquifer originated from the former U-mill tailings. PMID- 29758426 TI - Two contrasted future scenarios for the French agro-food system. AB - Narratives of two prospective scenarios for the future of French agriculture were elaborated by pushing several trends already acting on the dynamics of the current system to their logical end. The first one pursues the opening and specialization characterizing the long-term evolution of the last 50 years of most French agricultural regions, while the second assumes a shift, already perceptible through weak signals, towards more autonomy at the farm and regional scales, a reconnection of crop and livestock farming and a more frugal human diet. A procedure is proposed to translate these qualitative narratives into a quantitative description of the corresponding nutrient fluxes using the GRAFS (Generalized Representation of Agro-Food Systems) methodology, thus allowing a comprehensive exploration of the agronomical and environmental performance of these two scenarios. The results show that the pursuit of the opening and specialization of French agriculture, even complying with regulations regarding reasoned fertilization, would result in considerable environmental burdens namely in terms of water pollution. The scenario generalizing organic farming practices, reconnection of crop and livestock farming systems and a demitarian human diet makes it possible to meet the future national food demand while still exporting significant amounts of cereals to the international market and ensuring better groundwater quality in most French regions. PMID- 29758425 TI - Blood cadmium determinants among males over forty living in Mexico City. AB - BACKGROUND: Mexico City has air, water and food pollution problems; however, human exposure to cadmium and its sources have not been described. OBJECTIVES: To determine the blood cadmium (BCd) level and its main exposure sources among males aged 40 years or older living in different areas of Mexico City. METHODS: After receiving informed consent, we interviewed 702 males aged >=40 years to collect data on their sociodemographic characteristics, lifetime occupation, smoking history, and dietary habits, using a validated questionnaire. The BCd level (MUg/L) was determined by atomic absorption spectrophotometry. RESULTS: The BCd mean level +/- SD was 2.61 +/- 0.82 MUg/L, and 20% of men reported a potential cadmium occupational exposure. After adjusting for age and other potential confounders, the main determinants of the BCd level were the current smoking status at interview, with low (beta<=8.5packs/year vs. non-smoker = 0.46; 95% CI: 0.28-0.64 MUg/L; p < 0.01) and high (beta> 8.5 packs/year vs. non-smoker = 0.71; 95% CI: 0.56-0.87 MUg/L; p < 0.01) smoking intensity, and living in the Center (betaCenter vs. South = 0.20; 95% CI: 0.02-0.37 MUg/L; p = 0.02) or West area of the city (betaWest vs. South = 0.40, 95% CI: 0.21-0.58 MUg/L; p < 0.001). Moreover, the potential dietary sources of BCd included: liver (betaYes vs. No = 0.13, 95% CI: 0.03-0.23 MUg/L; p = 0.01), "Chorizo" (beta>1-3servings/month vs. No = 0.14, 95% CI: 0.01-0.26 MUg/L; p < 0.001), sausage and ham. CONCLUSIONS: The BCd levels observed in this population are high and only similar to those observed in workers from a sanitary landfill area in Southern Thailand. Potential environmental Cd exposure sources, such as industrial activity and previous land use, in the West and Center areas of the city should be explored in detail, especially in vulnerable population groups, such as children. PMID- 29758427 TI - Quantitative assessment of soil productivity and predicted impacts of water erosion in the black soil region of northeastern China. AB - As Northeastern China is the country's most significant grain production base, soil productivity in this region has consistently attracted attention. National food security is threatened by an ongoing drain of soil nutrients and decline in soil productivity. Black soil is the key natural resource in this region of China, which is thus known as the "black soil region". It is necessary to study the impact of soil erosion on black soil and its productivity to protect this important resource and ensure its sustainable productivity. Through a field investigation and laboratory analysis, the physicochemical properties in 112 soil profiles from a typical black soil sub-region were measured to assess soil productivity using a soil productivity index (PI) model. The soil PI in the study area was relatively high and showed an increasing trend from southwest to northeast. PI values and their spatial distribution were affected by soil organic matter, soil clay content, soil thickness, slope and geomorphological position. Soil productivity and cluster analysis revealed that the southern and northwestern areas of the typical black soil sub-region under study were subject to the greatest risk. To maintain the region's soil productivity, it is vital to prevent the black soil layer, especially the topsoil, from being destroyed. PMID- 29758428 TI - Threats to coastal communities of Mahanadi delta due to imminent consequences of erosion - Present and near future. AB - Coastal erosion is a natural hazard which causes significant loss to properties as well as coastal habitats. Coastal districts of Mahanadi delta, one of the most populated deltas of the Indian subcontinent, are suffering from the ill effects of coastal erosion. An important amount of assets is being lost every year along with forced migration of huge portions of coastal communities due to erosion. An attempt has been made in this study to predict the future coastline of the Mahanadi Delta based on historical trends. Historical coastlines of the delta have been extracted using semi-automated Tasselled Cap technique from the LANDSAT satellite imageries of the year 1990, 1995, 2000, 2006 and 2010. Using Digital Shoreline Assessment System (DSAS) tool of USGS, the trend of the coastline has been assessed in the form of End Point Rate (EPR) and Linear Regression Rate (LRR). A hybrid methodology has been adopted using statistical (EPR) and trigonometric functions to predict the future positions of the coastlines of the years 2020, 2035 and 2050. The result showed that most of the coastline (~65%) is facing erosion at present. The predicted outcome shows that by the end of year 2050 the erosion scenario will worsen which in turn would lead to very high erosion risk for 30% of the total coastal mouzas (small administrative blocks). This study revealed the coastal erosion trend of Mahanadi delta and based on the predicted coastlines it can be inferred that the coastal communities in near future would be facing substantial threat due to erosion particularly in areas surrounding Puri (a renowned tourist pilgrimage) and Paradwip (one of the busiest ports and harbours of the country). PMID- 29758431 TI - A framework to investigate drivers of adaptation decisions in marine fishing: Evidence from urban, semi-urban and rural communities. AB - Traditional fishing livelihoods need to adapt to changing fish catch/populations, led by numerous anthropogenic, environmental and climatic stressors. The decision to adapt can be influenced by a variety of socio-economic and perceptual factors. However, adaptation decision-making in fishing communities has rarely been studied. Based on previous literature and focus group discussions with community, this study identifies few prominent adaptation responses in marine fishing and proposes credible factors driving decisions to adopt them. Further, a household survey is conducted, and the association of these drivers with various adaptation strategies is examined among fisherfolk of Maharashtra (India). This statistical analysis is based on 601 responses collected across three regional fishing groups: urban, semi-urban and rural. Regional segregation is done to understand variability in decision-making among groups which might be having different socio economic and perceptual attributes. The survey reveals that only few urban fishing households have been able to diversify into other livelihoods. While having economic capital increases the likelihood of adaptation among urban and semi-urban communities, rural fishermen are significantly driven by social capital. Perception of climate change affecting fish catch drives adoption of mechanized boats solely in urban region. But increasing number of extreme events affects decisions of semi-urban and rural fishermen. Further, rising pollution and trade competition is associated with adaptation responses in the urban and semi-urban community. Higher education might help fishermen choose convenient forms of adaptation. Also, cooperative membership and subsidies are critical in adaptation decisions. The framework and insights of the study suggest the importance of acknowledging differential decision-making of individuals and communities, for designing effective adaptation and capacity-building policies. PMID- 29758429 TI - Microbial ecology of two hot springs of Sikkim: Predominate population and geochemistry. AB - Northeastern regions of India are known for their floral and faunal biodiversity. Especially the state of Sikkim lies in the eastern Himalayan ecological hotspot region. The state harbors many sulfur rich hot springs which have therapeutic and spiritual values. However, these hot springs are yet to be explored for their microbial ecology. The development of neo generation techniques such as metagenomics has provided an opportunity for inclusive study of microbial community of different environment. The present study describes the microbial diversity in two hot springs of Sikkim that is Polok and Borong with the assist of culture dependent and culture independent approaches. The culture independent techniques used in this study were next generation sequencing (NGS) and Phospholipid Fatty Acid Analysis (PLFA). Having relatively distinct geochemistry both the hot springs are thermophilic environments with the temperature range of 50-77 degrees C and pH range of 5-8. Metagenomic data revealed the dominance of bacteria over archaea. The most abundant phyla were Proteobacteria and Bacteroidetes although other phyla were also present such as Acidobacteria, Nitrospirae, Firmicutes, Proteobacteria, Parcubacteria and Spirochaetes. The PLFA studies have shown the abundance of Gram Positive bacteria followed by Gram negative bacteria. The culture dependent technique was correlative with PLFA studies. Most abundant bacteria as isolated and identified were Gram-positive genus Geobacillus and Anoxybacillus. The genus Geobacillus has been reported for the first time in North-Eastern states of India. The Geobacillus species obtained from the concerned hot springs were Geobacillus toebii, Geobacillus lituanicus, Geobacillus Kaustophillus and the Anoxybacillus species includes Anoxybacillus gonensis and Anoxybacillus Caldiproteolyticus. The distribution of major genera and their statistical correlation analyses with the geochemistry of the springs predicted that the temperature, pH, alkalinity, Ca2+, Mg2+, Cl2+, and sulfur were main environmental variables influencing the microbial community composition and diversity. Also the piper diagram suggested that the water of both the hot springs are Ca-HCO3- type and can be predicted as shallow fresh ground waters. This study has provided an insight into the ecological interaction of the diverse microbial communities and associated physicochemical parameters, which will help in determining the future studies on different biogeochemical pathways in these hot springs. PMID- 29758430 TI - The extent and pathways of nitrogen loss in turfgrass systems: Age impacts. AB - Nitrogen loss from fertilized turf has been a concern for decades, with most research focused on inorganic (NO3-) leaching. The present work examined both inorganic and organic N species in leachate and soil N2O emissions from intact soil cores of a bermudagrass chronosequence (1, 15, 20, and 109 years old) collected in both winter and summer. Measurements of soil N2O emissions were made daily for 3 weeks, while leachate was sampled once a week. Four treatments were established to examine the impacts of fertilization and temperature: no N, low N at 30 kg N ha-1, and high N at 60 kg N ha-1, plus a combination of high N and temperature (13 degrees C in winter or 33 degrees C in summer compared to the standard 23 degrees C). Total reactive N loss generally showed a "cup" pattern of turf age, being lowest for the 20 years old. Averaged across all intact soil cores sampled in winter and summer, organic N leaching accounted for 51% of total reactive N loss, followed by inorganic N leaching at 41% and N2O-N efflux at 8%. Proportional loss among the fractions varied with grass age, season, and temperature and fertilization treatments. While high temperature enhanced total reactive N loss, it had little influence on the partitioning of loss among dissolved organic N, inorganic N and N2O-N when C availability was expected to be high in summer due to rhizodeposition and root turnover. This effect of temperature was perhaps due to higher microbial turnover in response to increased C availability in summer. However when C availability was low in winter, warming might mainly affect microbial growth efficiency and therefore partitioning of N. This work provides a new insight into the interactive controls of warming and substrate availability on dissolved organic N loss from turfgrass systems. PMID- 29758432 TI - Enhanced micropollutant biodegradation and assessment of nitrous oxide concentration reduction in wastewater treated by acclimatized sludge bioaugmentation. AB - This research investigated the micropollutant biodegradation and nitrous oxide (N2O) concentration reduction in high strength wastewater treated by two-stage activated sludge (AS) systems with (bioaugmented) and without (non-bioaugmented) acclimatized sludge bioaugmentation. The bioaugmented and non-bioaugmented systems were operated in parallel for 228 days, with three levels of concentrations of organics, nitrogen, and micropollutants in the influent: conditions 1 (low), 2 (moderate), and 3 (high). The results showed that, under condition 1, both systems efficiently removed the organic and nitrogen compounds. However, the bioaugmented system was more effective in the micropollutant biodegradation and N2O concentration reduction than the non-bioaugmented one. Under condition 2, the nitrogen and micropollutant biodegradation efficiency of the non-bioaugmented system slightly decreased, while the N2O concentration declined in the bioaugmented system. Under condition 3, the treatment performance and N2O concentration abatement were substantially lowered as the compounds concentration increased. Further analysis also showed that the acclimatized sludge bioaugmentation increased the bacterial diversity in the system. In essence, the acclimatized sludge bioaugmentation strategy was highly effective for the influent with low compounds concentration, achieving the organics and nitrogen removal efficiencies of 92-97%, relative to 71-97% of the non bioaugmented system. The micropollutant treatment efficiency of the bioaugmented system under condition 1 was 75-92%, indicating significant improvement in the treatment performance (p < 0.05), compared with 60-79% of the non-bioaugmented system. PMID- 29758433 TI - On the spatial relationship between ecosystem services and urbanization: A case study in Wuhan, China. AB - A clear understanding of the relationship between ecosystem services (ESs) and urbanization provides new insight into urban landscape planning and decision making. Although a considerable amount of literature has focused on this topic, few studies address the spatial interactions between ESs and urbanization, especially at the local scale. Various models and multisource data were integrated to estimate ESs and urbanization in Wuhan City, China. The bivariate Moran's I methods were employed to test and visualize the spatial correlations between ESs and urbanization. Spatial regression models were used to describe the spatial dependence of ESs on urbanization. Our results showed that all ESs have globally negative spatial correlations with urbanization, but focusing on local scale allowed spatial correlations to be categorized into four types: high ESs and high urbanization, high ESs and low urbanization, low ESs and high urbanization, and low ESs and low urbanization. Spatial regression models were identified as more suitable to measure the spatial dependence of ESs on urbanization, as they account for the effects of spatial autocorrelation. Among ESs, biodiversity conservation was the one most sensitive to increased urbanization, followed by outdoor recreation, water yield, grain productivity, carbon storage, and erosion prevention. The spatial exploration of the relationship between ESs and urbanization provides practical guidance for urban development planning and environmental protection. PMID- 29758435 TI - Possible impact of environmental policies in the recovery of a Ramsar wetland from trace metal contamination. AB - The Umia-Grove Intertidal Complex is located within the Ria of Arousa (NW Iberian Peninsula). Out of its significance for wintering shorebirds it has been included in the Ramsar List of Wetlands of International Importance as well as in international protection networks such as the European Natura 2000 and Important Bird and Biodiversity Areas-BirdLife International. In a sediment analysis conducted in the year 1999, the wetland was found to have been contaminated by potentially toxic trace metals, to wit: Cr, Cu, Ni, and Pb. Sediment samples retrieved in 2014 to make an updated assessment of the condition of the ecosystem showed evidence of the presence of selected trace elements, namely, Cd, Co, Cr, Cu, Ni, Pb, and Zn, within or slightly above the background ranges of local, regional, and general references. In the 15-year time frame between the two samplings there has been noticeable change in the relationship between nature and society as a consequence of the entry into force of a number of regulations aimed at avoiding the emission of contaminants; among others, the ban of Pb in gasoline, the deployment of wastewater treatment plants according to the European Water Framework Directive, and the limitation of the use of Cu pesticides. With the ensuing drop of human pressure, the self-purifying capacity of the ecosystem has effectively contributed to the wetland's recovery. Nevertheless, the application of a normalized enrichment factor to the more recent set of samples suggests the presence of relict low contamination by Cd, Cu, and Ni in localized areas. The compared analysis of the wetland condition in the two years is a sign of the success of the policies and regulations for environmental protection, but further work and more effectiveness are necessary in order to preserve threatened ecosystems of such importance as the Umia-Grove wetland. PMID- 29758434 TI - Potential agronomic and environmental properties of thermophilic anaerobically digested municipal sewage sludge measured by an unsupervised and a supervised chemometric approach. AB - Anaerobic digestion (AD) is the most widely used method of sewage sludge treatment (SS) before its agricultural use. AD achieves the required "sterilisation" of pathogens and is able to cover the energy required by the process, reducing pre-treatment costs, thanks to the production of biogas. The SS agronomic (fertilizer properties), environmental (pollutants contents) characteristics and nuisance to people (odours and pathogens) need to be evaluated together for the safe and useful deployment of SS in agriculture. To evaluate SS properties an unsupervised (Principal Component Analysis) and a supervised (K nearest neighbours) chemometric approach was applied to rank digested SS for agronomic and environmental properties in comparison with other organic matrices for which the agronomic and/or environmental properties are well known or expected. To do so, complete chemical, biological and "impact on people" characterization was carried out on SS ingestate (SS-ing.) and SS digestate (SS dig.) and another 10 biomasses. The SS-AD process enhanced the agronomic properties of sewage sludge and did not lead to a substantial concentration of pollutants because of the low degradation of organic matter. The best PCA performances were reached for amendment and fertilizer modules but the results found for the environment and nuisance to inhabitants were not satisfactory. The KNN approach proposed to evaluate the suitability of a biomass for agricultural purposes, represents a win-win approach as it allows one to avoid time-consuming and costly full field studies. PMID- 29758436 TI - N2O and CO2 emissions following repeated application of organic and mineral N fertiliser from a vegetable crop rotation. AB - Accounting for nitrogen (N) release from organic amendments (OA) can reduce the use of synthetic N-fertiliser, sustain crop production, and potentially reduce soil borne greenhouse gases (GHG) emissions. However, it is difficult to assess the GHG mitigation potential for OA as a substitute of N-fertiliser over the long term due to only part of the organic N added to soil is being released in the first year after application. High-resolution nitrous oxide (N2O) and carbon dioxide (CO2) emissions monitored from a horticultural crop rotation over 2.5 years from conventional urea application rates were compared to treatments receiving an annual application of raw and composted chicken manure combined with conventional and reduced N-fertiliser rates. The repeated application of composted manure did not increase annual N2O emissions while the application of raw manure resulted in N2O emissions up to 35.2 times higher than the zero N fertiliser treatment and up to 4.7 times higher than conventional N-fertiliser rate due to an increase in C and N availability following the repeated application of raw OA. The main factor driving N2O emissions was the incorporation of organic material accompanied by high soil moisture while the application of synthetic N-fertiliser induced only short-term N2O emission pulse. The average annual N2O emission factor calculated accounting for the total N applied including OA was equal to 0.27 +/- 0.17%, 3.7 times lower than the IPCC default value. Accounting for the estimated N release from OA only enabled a more realistic N2O emission factor to be defined for organically amended field that was equal to 0.48 +/- 0.3%. This study demonstrated that accounting for the N released from repeated application of composted rather than raw manure can be a viable pathway to reduce N2O emissions and maintain soil fertility. PMID- 29758437 TI - Flexible 3D Fe@VO2 core-shell mesh: A highly efficient and easy-recycling catalyst for the removal of organic dyes. AB - Nowadays, it is extremely urgent to search for efficient and effective catalysts for water purification due to the severe worldwide water-contamination crises. Here, 3D Fe@VO2 core-shell mesh, a highly efficient catalyst toward removal of organic dyes with excellent recycling ability in the dark is designed and developed for the first time. This novel core-shell structure is actually 304 stainless steel mesh coated by VO2, fabricated by an electrophoretic deposition method. In such a core-shell structure, Fe as the core allows much easier separation from the water, endowing the catalyst with a flexible property for easy recycling, while VO2 as the shell is highly efficient in degradation of organic dyes with the addition of H2O2. More intriguingly, the 3D Fe@VO2 core shell mesh exhibits favorable performance across a wide pH range. The 3D Fe@VO2 core-shell mesh can decompose organic dyes both in a light-free condition and under visible irradiation. The possible catalytic oxidation mechanism of Fe@VO2/H2O2 system is also proposed in this work. Considering its facile fabrication, remarkable catalytic efficiency across a wide pH range, and easy recycling characteristic, the 3D Fe@VO2 core-shell mesh is a newly developed high performance catalyst for addressing the universal water crises. PMID- 29758438 TI - Concentrations, fluxes and field calibration of passive water samplers for pesticides and hazard-based risk assessment. AB - Three passive sampler types including Chemcatcher(r) C18, polar organic chemical integrative sampler-hydrophilic-lipophilic balance (POCIS-HLB) and silicone rubber (SR) based on polydimethylsiloxane (PDMS) were evaluated for 124 legacy and current used pesticides at two sampling locations in southern Sweden over a period of 6 weeks and compared to time-proportional composite active sampling. In addition, an in situ calibration was performed resulting in median in situ sampling rates (RS, L day-1) of 0.01 for Chemcatcher(r) C18, 0.03 for POCIS-HLB, and 0.18 for SR, and median in situ passive sampler-water partition coefficients (log KPW, L kg-1) of 2.76 for Chemcatcher(r) C18, 3.87 for POCIS-HLB, and 2.64 for SR. Deisopropylatrazine D5 showed to be suitable as a performance reference compound (PRC) for SR. There was a good agreement between the pesticide concentrations using passive and active sampling. However, the three passive samplers detected 38 pesticides (including 9 priority substances from the EU Water Framework Directive (WFD) and 2 pyrethriods) which were not detected by the active sampler. The most frequently detected pesticides with a detection frequency of >90% for both sites were atrazine, 2,6-dichlorobenzamide, bentazone, chloridazon, isoproturon, and propiconazole. The annual average environmental quality standard (AA-EQS) for inland surface waters of the EU WFD and the risk quotient (RQ) of 1 was exceeded on a number of occasions indicating potential risk for the aquatic environment. PMID- 29758439 TI - Subgenual anterior cingulate-insula resting-state connectivity as a neural correlate to trait and state stress resilience. AB - Accumulating evidence indicates important roles of the subgenual anterior cingulate cortex and rostral limbic regions such as the anterior insula, in regulating stress-related affective responses and negative affect states in general. However, research is lacking in simultaneously assessing the inter relations between trait and state affective responses to stress, and the functional connectivity between the subgenual anterior cingulate and anterior insula. This preliminary research involved matched healthy participants with high (N = 10) and low (N = 10) self-reported trait stress resilience, and assessed their affective and subgenual anterior cingulate-anterior insula resting-state functional connectivity patterns before and after a psychosocial stress task. We found that while the low-resilience group displayed higher trait negative affect and perceived greater task-related stress, only the high-resilience group showed increase of negative affect, along with greater decrease of left subgenual anterior cingulate-right anterior insula connectivity, following stress induction. Moreover, the functional connectivity change mediated group difference in affect change following stress task. We speculate that the contingent increase of negative affect, and the associated temporary decoupling of subgenual anterior cingulate-insula circuitry, may represent a normative and adaptive stress response underpinned by adaptive and dynamic interplay between the default mode and salience networks. Such findings, if consolidated, have important implications for promoting stress resilience and reducing risk for stress-related affective disorders. PMID- 29758440 TI - Re-thinking the health benefits of outstations in remote Indigenous Australia. AB - The small, decentralised communities, known as outstations which satellite larger Indigenous Australian remote communities have often been conceptualised as places that are beneficial to health and well-being. This paper provides an exploration of the meaning of an outstation for one family and the benefits that this connection brings to them, which are expressed in a deep connection to the land, continuing relationships with ancestors and a safe refuge from the stresses of the larger community. We argue that the outstation provides a place for people to be in control of their lives and form hopes and plans for the future. These benefits are positioned in a context where the future liveability and sustainability of the outstation is both fragile and vulnerable. PMID- 29758441 TI - Does Enquiry Based Learning (EBL) impact on clinical practice? A qualitative exploration of midwifery graduates' perceptions. AB - OBJECTIVE: To elicit perceptions of midwifery graduates regarding the impact of Enquiry Based Learning (EBL) on their clinical practice. DESIGN: A qualitative approach utilising semi-structured interviews and content analysis. SETTING: A midwifery education provider in the Republic of Ireland. PARTICIPANTS: Purposive sampling was employed to recruit fourteen midwifery graduates, from a total of twenty eight, from two cohorts who had successfully completed a Higher Diploma in Midwifery programme. FINDINGS: Findings centred on the theme 'Effect of EBL on clinical practice', with positive perceptions of EBL reported in relation to its connexion to midwifery practice. CONCLUSIONS: Findings affirm the view that EBL augments linkage of theory to clinical practice in addition to linking clinical practice to theory. Consequently, competent practitioners are cultivated and an array of transferable skills developed, thus demonstrating the significant contribution of EBL in enriching clinical practice. PMID- 29758442 TI - Enhancing knowledge and skills through the delivery of a bespoke neonatal resuscitation training programme in a developing country. PMID- 29758444 TI - Yield of EEG monitoring in children with developmental disabilities is high. AB - PURPOSE: The purpose of this study was to investigate the yield of a 2-hour electroencephalography (EEG) monitoring (awake and sleep) in children with developmental disabilities and without any clinically apparent seizures. METHODS: In this retrospective study, I investigated all children below 9 years of age who had developmental disabilities and were referred to Shiraz Comprehensive Epilepsy center for electroencephalographic investigation from June 2017 until January 2018. Exclusion criteria included any past history of neonatal seizures, febrile or afebrile seizures, and parental suspicion for seizures. We systematically obtained a brief clinical history and performed a 2-hour, awake and asleep EEG monitoring for all patients. RESULTS: Thirty-two patients (23 males and 9 females) met all the inclusion and exclusion criteria; mean age (+/-standard deviation) was 4.1 (+/-2.1) years. Nineteen patients (59%) had an abnormal EEG: 15 patients (47%) had epileptiform discharges, and four children had abnormal background activity with no epileptiform discharges. CONCLUSION: Considering the high diagnostic yield of an awake and asleep EEG monitoring, as it was observed in the current study, this test on a screening basis can be reasonably justified in all children with developmental disabilities. PMID- 29758443 TI - Health care seeking behaviour during pregnancy, delivery and the postnatal period in Bangladesh: Assessing the compliance with WHO recommendations. AB - BACKGROUND: The World Health Organization (WHO) recommends four antenatal care (ANC) visits, delivery in a health facility and three postnatal care (PNC) visits for women to optimize the maternal health outcomes. OBJECTIVES: To examine the level and determinants of maternal health care seeking behaviour during pregnancy, delivery and the postnatal period, and assess the compliance with the WHO recommended levels of care in Bangladesh. DESIGN/SETTING: The study is based on secondary analysis of the data obtained from the 2014 Bangladesh Demographic and Health Survey (BDHS). The 2014 BDHS was a cross-sectional survey of a nationally representative sample of 17,863 ever-married women aged 15-49 years. The sample was selected following a two-stage stratified cluster sampling design. PARTICIPANTS: The dataset from a subsample of 4.627 ever-married women who had delivered their last birth within three years before the survey were included in the analysis to meet the objectives of the study. ANALYSIS: Descriptive statistics and multinomial logistic regression model were used for data analysis. FINDINGS: It has been observed that only 31% mothers had recommended four or more ANC visits, 37% births were delivered at health facilities, and 65% mothers received at least one PNC visit. Only 18.0% mothers received the WHO recommended optimal level of four or more ANC visits, births in a health facility and at least one PNC visit. Mothers aged less than 20 years, living in rural area, having no education and media exposure, multiparous, poor wealth status, husband with no education and husband's employment status appeared as significant predictors of optimal level maternal health care after adjusting for other factors. Mothers living in Sylhet, Chittagong and Barisal regions were less likely to receive the optimum level health care. KEY CONCLUSION: Utilization of maternal health care during pregnancy, delivery and the postnatal period among Bangladeshi women does not reflect the complete compliance with the WHO recommendations. Further studies are needed to identify the reasons for underutilization of optimum level maternal care practice in Bangladesh. IMPLICATION FOR PRACTICE: The findings underscore the need for targeted intervention for those groups of mothers who were identified as having lowest level of maternal care across the continuum of care. PMID- 29758445 TI - Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy. AB - BACKGROUND: Some studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated. OBJECTIVE: The objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE. METHODS: A group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected. RESULTS: One hundred sixty five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 +/- 17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100-600 mg), and the weight-adjusted dose was 5 mg/kg (3-6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h. Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found. CONCLUSIONS: In adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg. PMID- 29758446 TI - Improving staff response to seizures on the epilepsy monitoring unit with online EEG seizure detection algorithms. AB - OBJECTIVE: User safety and the quality of diagnostics on the epilepsy monitoring unit (EMU) depend on reaction to seizures. Online seizure detection might improve this. While good sensitivity and specificity is reported, the added value above staff response is unclear. We ascertained the added value of two electroencephalograph (EEG) seizure detection algorithms in terms of additional detected seizures or faster detection time. METHODS: EEG-video seizure recordings of people admitted to an EMU over one year were included, with a maximum of two seizures per subject. All recordings were retrospectively analyzed using Encevis EpiScan and BESA Epilepsy. Detection sensitivity and latency of the algorithms were compared to staff responses. False positive rates were estimated on 30 uninterrupted recordings (roughly 24 h per subject) of consecutive subjects admitted to the EMU. RESULTS: EEG-video recordings used included 188 seizures. The response rate of staff was 67%, of Encevis 67%, and of BESA Epilepsy 65%. Of the 62 seizures missed by staff, 66% were recognized by Encevis and 39% by BESA Epilepsy. The median latency was 31 s (staff), 10 s (Encevis), and 14 s (BESA Epilepsy). After correcting for walking time from the observation room to the subject, both algorithms detected faster than staff in 65% of detected seizures. The full recordings included 617 h of EEG. Encevis had a median false positive rate of 4.9 per 24 h and BESA Epilepsy of 2.1 per 24 h. CONCLUSIONS: EEG-video seizure detection algorithms may improve reaction to seizures by improving the total number of seizures detected and the speed of detection. The false positive rate is feasible for use in a clinical situation. Implementation of these algorithms might result in faster diagnostic testing and better observation during seizures. PMID- 29758447 TI - Experimental sharp force injuries to ribs: Multimodal morphological and geometric morphometric analyses using micro-CT, macro photography and SEM. AB - Tool marks on bones induced by knife blades can be analysed morphometrically in order to enable an allocation of the suspected "inflicting weapon" to the particular morphology of the bone lesions. Until now, geometric morphometrics has not been used to analyse the morphology of knife lesions on fleshed bones in detail. By using twelve experimental knives and a drop weight tower, stab/cut injuries were inflicted on untreated pig ribs. The morphology of the experimentally produced lesions was subsequently recorded with three imaging techniques (MUCT, macro photography and SEM) and analysed with different morphometric software (Amira, tps and Morpheus). Based on the measured distances between the walls of the kerf marks, which corresponded to the thickness of the blade, one could conclude to the respective blade thickness with a deviation of max. +/-0.35mm and match the injuries to the knives. With subsequent reanalysis after maceration, an average shrinkage factor up to 8.6% was observed. Among the three imaging techniques used in this study, MUCT was the most accurate and efficient technique, particularly because it represented the only non-destructive modality to document injuries without maceration, even though MUCT is more expensive and time-consuming as well as less accessible than a macro SLR-camera or a SEM. For optimal characterizations of the blades' and kerfs' shapes the software tps proofed to be the best choice. Accordingly, geometric morphometrics could serve as a tool in forensic investigations concerning kerf marks. PMID- 29758448 TI - Strong correlation between the self-model/other-model system and the anxiety/avoidance system assessing basic attachment dimensions. PMID- 29758449 TI - Comparison of comorbid depression between irritable bowel syndrome and inflammatory bowel disease: A meta-analysis of comparative studies. AB - BACKGROUND: The prevalence of comorbid depression is high in chronic gastrointestinal disorders, including irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). For these two disorders in particular, the findings have not been consistent. This meta-analysis systematically compares the rates and severity of comorbid depression between IBS and IBD patients. METHODS: A systematic literature search was conducted using PubMed, PsycINFO, Embase, Cochrane Library, Wan Fang, SinoMed, Chinese National Knowledge Infrastructure from their inception date to September 12, 2017 for comparative studies on IBS and IBD patients. Standardized mean differences (SMDs) and odds ratios (OR) of comorbid depression were calculated using random effect models. Data on comorbid anxiety in the included studies were also extracted and analyzed. RESULTS: Altogether, 22 studies with 1,244 IBS and 1,048 IBD patients were included. While there was no significant group difference in the prevalence of depression (10 studies, OR = 1.18, 95%CI: 0.87-1.60, P = 0.29), the IBS group had more severe depression (pooled SMD = 0.18, 95%CI: 0.04-0.33, P = 0.01) and anxiety than the IBD group (pooled SMD = 0.31, 95%CI: 0.14-0.49, P = 0.0006). Sixteen (72.7%) studies were assessed as 'high quality' using the Newcastle-Ottawa Scale (NOS). CONCLUSIONS: Although the prevalence of comorbid depression was similar between groups, IBS patients had more severe comorbid depressive and anxiety symptoms compared to IBD patients. Appropriate assessment and treatment of depressive and anxiety symptoms in these patient groups should be implemented. PMID- 29758450 TI - Comparison of traditional microbiological culture and 16S polymerase chain reaction analyses for identification of preoperative airway colonization for patients undergoing lung resection. AB - PURPOSE: Preoperative airway colonization is associated with increased risk of postoperative respiratory complications following lung resection. This study compares the rates of preoperative lower respiratory tract colonization identified by traditional culture and novel 16S polymerase chain reaction (PCR) tests. MATERIALS AND METHODS: Preoperative sputum and bronchoalveolar lavage (BAL) samples for 49 lung resection patients underwent culture and 16S PCR analyses. Rates of positive test results were determined and relationships between test results and suspected postoperative respiratory tract infection and hospital length of stay (LOS) were investigated. RESULTS: Preoperative BAL cultures were positive for 29 (59.2%) patients (population estimate 95%CI 45.2% 71.8%). 16S PCR tests were positive for 28 (57.1%) patients (population estimate 95%CI 43.3%-70.0%). 17 (34.7%) patients suffered suspected postoperative respiratory tract infection (population estimate 95%CI 22.9%-48.7%). Positive 16S PCR results tended to be associated with longer LOS (median 7.5 days vs 4.0 days for negative, p = 0.08) and increased risk of suspected postoperative respiratory tract infection (46.4% for positive vs 19.0% for negative, p = 0.07). CONCLUSIONS: Rates of colonization identified by culture and 16S PCR analyses of BAL samples were similar. Future research should attempt to clarify associations between airway colonization identified by 16S PCR and outcomes. 16S PCR may be useful when stratifying risk of postoperative respiratory complications. PMID- 29758451 TI - Diffusion effect on T2 relaxometry in triple-echo steady state free precession sequence. AB - PURPOSE: The purpose of this study is to evaluate the effect of diffusion on SSFP (Steady-state Free Precession) signals in triple-echo steady state (TESS) sequence and ultimately on the accuracy of T2 relaxometry. METHODS: The extended phase graph (EPG) algorithm was used to study the effect of diffusion on SSFP signals and T2 relaxometry. The simulation results were verified by a commercial phantom and in vivo studies. Based on the simulation results, a correction scheme was proposed to correct the estimated T2 values. RESULTS: T2 underestimation in TESS was evident in case of small flip angle and large unbalanced gradient moment on objects with large T2 and D values. The T2 underestimation mainly originated from the diffusion sensitivity of SSFP-echo. It was also observed that SSFP-FID (Free Induction Decay) signals increased with increasing diffusion weighting under some specific conditions. The proposed correction scheme corrected the T2 underestimation, which verified that the underestimation was due to the neglect of diffusion effect. For clinical practice of TESS in tissues with short T2 such as cartilage and muscle, the diffusion effect of TESS is negligible. CONCLUSION: The effect of diffusion cannot be neglected during TESS T2 quantification as it is the main source of T2 underestimation when small flip angle and large unbalanced gradient moment is used, especially for objects with large T2 and D values. PMID- 29758452 TI - Evaluation of machine learning algorithms for improved risk assessment for Down's syndrome. AB - Prenatal screening generates a great amount of data that is used for predicting risk of various disorders. Prenatal risk assessment is based on multiple clinical variables and overall performance is defined by how well the risk algorithm is optimized for the population in question. This article evaluates machine learning algorithms to improve performance of first trimester screening of Down syndrome. Machine learning algorithms pose an adaptive alternative to develop better risk assessment models using the existing clinical variables. Two real-world data sets were used to experiment with multiple classification algorithms. Implemented models were tested with a third, real-world, data set and performance was compared to a predicate method, a commercial risk assessment software. Best performing deep neural network model gave an area under the curve of 0.96 and detection rate of 78% with 1% false positive rate with the test data. Support vector machine model gave area under the curve of 0.95 and detection rate of 61% with 1% false positive rate with the same test data. When compared with the predicate method, the best support vector machine model was slightly inferior, but an optimized deep neural network model was able to give higher detection rates with same false positive rate or similar detection rate but with markedly lower false positive rate. This finding could further improve the first trimester screening for Down syndrome, by using existing clinical variables and a large training data derived from a specific population. PMID- 29758453 TI - Estimation and tracking of AP-diameter of the inferior vena cava in ultrasound images using a novel active circle algorithm. AB - Medical research suggests that the anterior-posterior (AP)-diameter of the inferior vena cava (IVC) and its associated temporal variation as imaged by bedside ultrasound is useful in guiding fluid resuscitation of the critically-ill patient. Unfortunately, indistinct edges and gaps in vessel walls are frequently present which impede accurate estimation of the IVC AP-diameter for both human operators and segmentation algorithms. The majority of research involving use of the IVC to guide fluid resuscitation involves manual measurement of the maximum and minimum AP-diameter as it varies over time. This effort proposes using a time varying circle fitted inside the typically ellipsoid IVC as an efficient, consistent and novel approach to tracking and approximating the AP-diameter even in the context of poor image quality. In this active-circle algorithm, a novel evolution functional is proposed and shown to be a useful tool for ultrasound image processing. The proposed algorithm is compared with an expert manual measurement, and state-of-the-art relevant algorithms. It is shown that the algorithm outperforms other techniques and performs very close to manual measurement. PMID- 29758454 TI - Biomechanical investigation on the influence of the regional material degeneration of an intervertebral disc in a lower lumbar spinal unit: A finite element study. AB - Intervertebral disc degeneration involves changes in its material properties that affect the mechanical functions of the spinal system. However, the alteration of the biomechanics of a spinal segment through specific material degradation in a specific region is poorly understood. In this study, the influence of the constitutive material degeneration of disc tissues on the mechanics of a lower lumbar spinal unit was examined using a three-dimensional nonlinear finite element model of the L4-L5 functional spinal unit. Different grades of disc degeneration were simulated by introducing a degeneration factor to the corresponding material properties to represent fibrous nucleus, increased fibre and ground substance laxity, increased fibre stiffness and total annular fracture along posterior and posterolateral regions. The model was loaded with an axial compression of 500 N and pure moments of up to 10 Nm to simulate extension, flexion, lateral bending and axial rotation. To validate the model, the spinal motion and intradiscal pressure of healthy and degenerated discs with existing in vitro data were compared. The disc with a fibrous nucleus and the presence of intradiscal pressure increase the spinal instability during flexion and axial rotation, and the absence of intradiscal pressure increases the spinal instability in all directions. Bulging displacement and shear strains in the disc with total fracture and ground substance laxity are high in all of the loading cases. Our study could provide useful information to enhance our understanding of the influence of each constitutive component of the intervertebral disc on the mechanics of the spinal segment. PMID- 29758455 TI - Deep neural networks for automatic detection of osteoporotic vertebral fractures on CT scans. AB - Osteoporotic vertebral fractures (OVFs) are prevalent in older adults and are associated with substantial personal suffering and socio-economic burden. Early diagnosis and treatment of OVFs are critical to prevent further fractures and morbidity. However, OVFs are often under-diagnosed and under-reported in computed tomography (CT) exams as they can be asymptomatic at an early stage. In this paper, we present and evaluate an automatic system that can detect incidental OVFs in chest, abdomen, and pelvis CT examinations at the level of practicing radiologists. Our OVF detection system leverages a deep convolutional neural network (CNN) to extract radiological features from each slice in a CT scan. These extracted features are processed through a feature aggregation module to make the final diagnosis for the full CT scan. In this work, we explored different methods for this feature aggregation, including the use of a long short term memory (LSTM) network. We trained and evaluated our system on 1432 CT scans, comprised of 10,546 two-dimensional (2D) images in sagittal view. Our system achieved an accuracy of 89.2% and an F1 score of 90.8% based on our evaluation on a held-out test set of 129 CT scans, which were established as reference standards through standard semiquantitative and quantitative methods. The results of our system matched the performance of practicing radiologists on this test set in real-world clinical circumstances. We expect the proposed system will assist and improve OVF diagnosis in clinical settings by pre-screening routine CT examinations and flagging suspicious cases prior to review by radiologists. PMID- 29758456 TI - GPER/Hippo-YAP signal is involved in Bisphenol S induced migration of triple negative breast cancer (TNBC) cells. AB - Nowadays, risk factors of triple-negative breast cancer (TNBC) metastasis are not well identified. Our present study reveals that an industrial chemical, bisphenol S (BPS), can promote the migration, but not the proliferation, of TNBC cells in vitro. BPS activates YAP, a key effector of Hippo pathway, by inhibiting its phosphorylation, which promotes YAP nuclear accumulation and up-regulates its downstream genes such as CTGF and ANKRD1. Inhibition of YAP blocks the BPS triggered cell migration and up-regulation of fibronectin (FN) and vimentin (Vim). BPS rapidly decreases the phosphorylation levels of LATS1 (Ser909) in TNBC cells, which regulates the activation and functions of YAP. Silencing LATS1/2 by siRNA increases BPS-induced dephosphorylation of YAP and extended the half-life of YAP protein. Inhibition of G protein-coupled estrogen receptor 1 (GPER) and its downstream PLCbeta/PKC signals attenuate the effects of BPS-induced YAP dephosphorylation and CTGF up-regulation. Targeted inhibition of GPER/YAP inhibits BPS-induced migration of TNBC cells. Collectively, we reveal that GPER/Hippo-YAP signal is involved in BPS-induced migration of TNBC cells. PMID- 29758457 TI - Progress and remaining challenges in high-throughput volume electron microscopy. AB - Recent advances in the effectiveness of the automatic extraction of neural circuits from volume electron microscopy data have made us more optimistic that the goal of reconstructing the nervous system of an entire adult mammal (or bird) brain can be achieved in the next decade. The progress on the data analysis side based mostly on variants of convolutional neural networks-has been particularly impressive, but improvements in the quality and spatial extent of published VEM datasets are substantial. Methodologically, the combination of hot-knife sample partitioning and ion milling stands out as a conceptual advance while the multi beam scanning electron microscope promises to remove the data-acquisition bottleneck. PMID- 29758460 TI - Assessment of the sensitivity of DQF/ZQF 2H NMR of D2O for studying modified nafion membranes at 20 degrees C and 80 degrees C. AB - Double and zero quantum filtered (ZQF/DQF) 2H NMR spectroscopy was used to study D2O in five different Nafion membranes, N117, N115, NR212, XL, and HP, in order to assess the effectiveness of the technique for monitoring differences in thickness, membrane reinforcement, and the addition of chemical stabilizers. Experiments were also carried out at 20 and 80 degrees C to understand if the ZQF/DQF technique could detect changes in the water environments and exchange dynamics as a function of temperature. For two of the membranes, significant decreases in the 1/T2 relaxation rates were observed at 80 degrees C. The two modified membranes showed changes in the quadrupolar couplings when heated, with the XL membranes showing a drop in the coupling and the HP membranes showing an increase in the coupling. No consistent variations could be associated with thickness, reinforcement or the addition of stabilizers. Overall the technique was able to detect some differences between the membranes but was limited by the variability in the observed NMR data. PMID- 29758458 TI - Effects of maternal nutrient restriction followed by realimentation during early and mid-gestation in beef cows. II. Placental development, umbilical blood flow, and uterine blood flow responses to diet alterations. AB - The objectives were to examine the effects of maternal nutrient restriction followed by realimentation during early to mid-gestation on placental development and uterine and umbilical hemodynamics in the beef cow. On day 30 of pregnancy, multiparous, non-lactating beef cows (620.5 +/- 11.3 kg) were assigned to 1 of 2 dietary treatments: control (C; 100% National Research Council [NRC] recommendations; n = 18) and restricted (R; 60% NRC; n = 30). On day 85, cows were slaughtered (C, n = 6; R, n = 6), remained on control (CC; n = 12) and restricted (RR; n = 12), or were realimented to control (RC; n = 11). On day 140, cows were slaughtered (CC, n = 6; RR, n = 6; RC, n = 5), remained on control (CCC, n = 6; RCC, n = 5), or were realimented to control (RRC, n = 6). On day 254, all remaining cows were slaughtered. Heart rate and umbilical and uterine hemodynamics [blood flow, resistance index (RI), and pulsatility index (PI)] were determined via Doppler ultrasonography. As expected umbilical blood flow increased and fetal heart rate decreased as gestation advanced. Umbilical PI in RRC cows was less (P = 0.01) compared to RCC and CCC. During late gestation, RCC cows had greater (P = 0.02) ipsilateral and total uterine blood flow vs. CCC and RRC. There was an increase in the number and weight of placentomes from R cows (P <= 0.02) compared to C cows (i.e. day 85). There were more placentomes (P = 0.03) in RR vs. CC and RC cows, but placentome weight was not affected (P = 0.18) by maternal dietary treatment at day 140. Maternal nutrient restriction during early to mid-gestation increased the weight (by day 85) and number (day 85 and 140) of placentomes, and did not reduce fetal weight compared to control cows. A longer realimentation period may enhance uterine blood flow and individual placentome size during later gestation, which may compensate for reduced nutrients experienced early in gestation. PMID- 29758461 TI - Anti-synchronization of complex-valued memristor-based delayed neural networks. AB - This paper investigates the anti-synchronization of complex-valued memristor based neural networks with time delays via designed external controllers. By constructing appropriate Lyapunov functions and using inequality technique, two different types of controllers are derived to guarantee the exponential anti synchronization of complex-valued memristor-based delayed neural networks. Compared with existing relevant results, the proposed results of this paper are more general and less conservative. In addition, the presented theoretical results are easy to be checked with the parameters of systems themselves. Finally, an example with numerical simulations illustrates the effectiveness of the obtained results. PMID- 29758459 TI - Arterial blood flow is the main source of testicular heat in bulls and higher ambient temperatures significantly increase testicular blood flow. AB - Two experiments were done in bulls to determine: total testicular blood flow, testis oxygenation and heat, and effects of ambient temperature on testicular temperatures and blood flow. In Experiment 1, arterial blood flow to testes and testicular oxygenation and heat were determined in Angus bulls (n = 8). Blood temperature and hemoglobin O2 saturation were both greater (P < 0.0001) in the testicular artery than in the testicular vein (39.2 +/- 0.2 vs 36.9 +/- 0.4 degrees C and 95.3 +/- 0.7 vs 42.0 +/- 5.8%, respectively; mean +/- SEM). Based on testicular blood flow of 12.4 +/- 1.1 mL/min and an arterial-venous temperature differential of 2.3 degrees C, blood contributed 28.3 +/- 5.1 cal/min of heat to the testis, whereas heat produced by testicular metabolism was estimated at 5.8 +/- 0.8 cal/min (based on O2 consumption of 1.2 +/- 0.2 mL/min). In Experiment 2, effects of three ambient temperatures (5, 15 and 35 degrees C) on testicular blood flow and temperatures were determined in 20 Angus bulls. At 35 versus 5 degrees C, there was greater testicular blood flow (8.2 +/- 0.9 versus 4.9 +/- 0.7 mL/min/100 g of testicular tissue, P < 0.05), and higher scrotal subcutaneous and intratesticular temperatures (P < 0.01). In conclusion, arterial blood flow was the main source of testicular heat, testes were close to hypoxia, and increased ambient temperature significantly increased scrotal subcutaneous and intratesticular temperatures, as well as testicular blood flow. These studies gave new insights into scrotal/testicular thermoregulation in bulls; they confirmed that testes are nearly hypoxic, but challenged the long standing paradigm that testicular blood flow does not increase when testes become warmer. PMID- 29758463 TI - The gamma ray detection threshold temperature of different superheated droplet detectors. AB - The response of superheated droplet detectors (SDD) loaded with four different active liquids, R-12 (CCl2F2), R-114 (C2Cl2F4), R-134a (C2H2F4) and R-610 (C4F10) have been studied to obtain the gamma ray detection threshold temperature (Tgamma) of the respective detectors. A 137Cs gamma ray source is used for this study. To obtain Tgamma from the experimental data a phenomenological model has been used. Result indicates that Tgamma maintains a linear relationship with the limit of superheat (Tlim) of different active liquids used in SDD. It indicates that the limit of superheat of a liquid can be used for the prediction of its gamma ray detection threshold temperature. PMID- 29758462 TI - Global stabilization analysis of inertial memristive recurrent neural networks with discrete and distributed delays. AB - This paper deals with the stabilization problem of memristive recurrent neural networks with inertial items, discrete delays, bounded and unbounded distributed delays. First, for inertial memristive recurrent neural networks (IMRNNs) with second-order derivatives of states, an appropriate variable substitution method is invoked to transfer IMRNNs into a first-order differential form. Then, based on nonsmooth analysis theory, several algebraic criteria are established for the global stabilizability of IMRNNs under proposed feedback control, where the cases with both bounded and unbounded distributed delays are successfully addressed. Finally, the theoretical results are illustrated via the numerical simulations. PMID- 29758464 TI - Modification of LSC spectra of 125I by high atomic number elements. AB - The 125I pulse-height spectra via a liquid scintillation counter (LSC) displayed notable variations. The counting efficiencies of higher and lower energy peaks increased and decreased, respectively, with the enhancement of the amount of high atomic numbered elements within the cocktails. This tendency was ascribed to the increasing probability of the interaction of photons with the scintillation cocktail. Moreover, it was noted that the shape of a 125I spectrum strongly depends on the amount of high atomic numbered elements. PMID- 29758465 TI - An experimental and DFT study of the packing and structure of dithenoylmethane monocarbonylphosphine Rhodium(I) complex [Rh((C4H3S)COCHCO(C4H3S))(CO)(PPh3)]. AB - [Rh((C4H3S)COCHCO(C4H3S))(CO)(PPh3)] crystals stack in one dimensional linear chains in the solid state, with slightly slipped pi-stacking of the thienyl groups of one molecule and the beta-diketonato backbone of a neighbouring molecule. The observed stacking is possible due to the near planar orientation of the two aromatic thienyl groups and the beta-diketonato backbone. The experimentally observed stacking and close intermolecular contacts are in agreement with theoretical QTAIM calculated intermolecular bond paths and intermolecular hydrogen bonds between neighbouring molecules. NBO calculations revealed donor - acceptor NBO interactions between the lone pair on rhodium of one molecule and (i) the empty antibonding orbital on C-H of the nearest thienyl group of a neighbouring molecule, as well as with the (ii) the empty antibonding orbital on two carbons of the nearest thienyl group to rhodium on the neighbouring molecule. PMID- 29758466 TI - Structural dynamics and quantum mechanical aspects of shikonin derivatives as CREBBP bromodomain inhibitors. AB - The Proteins involved in the chemical modification of lysine residues in histone, is currently being excessively focused as the therapeutic target for the treatment of cell related diseases like cancer. Among these proteins, the epigenetic reader, CREB-binding protein (CREBBP) bromodomain is one of the most prominent targets for effective anticancer drug design, which is responsible for the reorganization of acetylated histone lysine residues. Therefore, this study employed an integrative approach of structure based drug design, in combination with Molecular Dynamics (MD) and QM/MM study to identify as well as to describe the binding mechanism of two shikonin derivatives, acetylshikonin and propionylshikonin as inhibitors of CREBBP bromodomain. Here induced fit docking strategy was employed to explore the important intrinsic interactions of ligands with CREBBP bromodomain, consistently molecular dynamics simulation with two different methods and binding energy calculations by MM-GBSA and MM-PBSA were adopted to determine the stability of intermolecular interactions between protein and ligands. The results showed that both these derivatives made direct contacts with the important conserved residues of the active site, where propionylshikonin demonstrated stronger binding and stability than acetylshikonin, according to molecular dynamics simulation and binding free energy calculations. Further, QM/MM energy calculation was employed to study the chemical reactivity of the propionylshikonin and also to describe the mechanism of non bonded interactions between the propionylshikonin and CREBBP bromodomain. Though this study demands in vitro and in vivo experiments to evaluate the efficiency of the compound, these insights would assist to design more potent CREBBP bromodomain inhibitor, guiding the site of modification of propionylshikonin moiety for designing selective inhibitors. PMID- 29758467 TI - Ligation events influence ALG-2 dimerization. AB - ALG-2 dimerization was studied using Forster resonance-energy-transfer. D162C variants of ALG-2des23 were covalently modified with Alexa Fluor 488 and Alexa Fluor 647. When samples of the two labeled protein-preparations are combined, the sensitized emission from AF647 serves as a sensitive probe of dimer formation. At 25 degrees C, in the absence of divalent ions, the wild-type homodimer, DeltaGF122 homodimer, and heterodimer display dissociation constants of 7.1, 26, and 4.5 nM, respectively. At 35 degrees C, subunit interaction is weaker, indicating that dimer formation is exothermic. Binding of Mg2+ in the C-terminal EF-hand (EF5) dramatically enhances ALG-2 dimer stability. Although occupation of EF5 by Ca2+ likewise has a stabilizing effect, its direct influence on dimer stability would be negligible at cytosolic Ca2+ levels. However, dimer stability is substantially increased by the Ca2+-dependent binding of ALG-2 target peptides, suggesting that the occupation-status of the target-protein binding site is communicated to the dimer interface. Tween 20 is commonly used to improve ALG-2 solubility, the micelles ostensibly acting as target-protein surrogates. Paradoxically, however, the detergent markedly destabilizes ALG-2 dimers, particularly in the presence of Ca2+. PMID- 29758468 TI - Overcoming the stability, solubility and extraction challenges in reversed-phase UHPLC-MS/MS bioanalysis of a phosphate drug and its prodrug in blood lysate. AB - BMS-986104 is a S1P1R modulator drug candidate under development and has been evaluated in Phase I clinical trials. BMS-986104 functions as a prodrug and undergoes enzymatic transformations in vivo to form the pharmacologically active phosphate drug, BMS-986104-P. Here, we report approaches to overcome the stability, solubility and extraction challenges in developing a sensitive, accurate and rugged LC-MS/MS method for the simultaneous quantification of the phosphate drug and its prodrug in blood lysate. An effective stabilization strategy using a cocktail of phosphatase and kinase inhibitors was developed to ensure the stability of both analytes during sample collection, storage, and processing. A combination of surfactant (CHAPS) and weak base (Tris) was found to be able to effectively improve the solubilization of the phosphate drug. The blood lysate samples were extracted by protein precipitation followed by solid phase extraction using an Oasis HLB 96-well SPE plate. The method achieved acceptable matrix effect and recovery for the two analytes that have very different chemical properties. Stable-isotope labeled D6-BMS-986104 and D13-BMS 986104-P were utilized as the internal standards. Chromatographic separation was achieved using isocratic conditions on an Acquity UPLC BEH C18 analytical column. The two analytes and their internal standards were detected by positive ion electrospray tandem mass spectrometry. The calibration curves, which ranged from 2.00 to 2000 ng/mL for BMS-986104 and 4.00 to 4000 ng/mL for BMS-986104-P, were fitted to a 1/x2 weighted linear regression model. The intra-assay precision was within +/-5.0% CV, inter-assay precision was within +/-4.9% CV, and the assay accuracy was within +/-5.8% of the nominal values for both analytes in rat blood lysate. The method was validated and successfully applied to support multiple pre clinical toxicity studies. PMID- 29758469 TI - A facile and selective approach to the qualitative and quantitative analysis of triterpenoids and phenylpropanoids by UPLC/Q-TOF-MS/MS for the quality control of Ilex rotunda. AB - Ilex rotunda, in which triterpenoids and phenylpropanoids are major bioactive constituents, has been widely used in traditional Chinese medicines. In this study, a validated UPLC/Q-TOF-MS/MS method was developed to simultaneously identify and quantify the triterpenoids and phenylpropanoids in the stem bark, fruit, leaves, roots and stem xylem of this herbal medicine. A total of seventy triterpenoids and twelve phenylpropanoids were identified with the assistance of the modified mass defect filter and key product ion filter data processing strategies, and forty-eight of them were confirmed by reference substances. Meanwhile, the contents of twelve triterpenoids and three phenylpropanoids in the five plant parts were determined with good linearity (R2 >= 0.9993), precision (RSD <= 2.04%), repeatability (RSD <= 1.99%), stability (RSD <= 1.88%) and recovery (96.65-103.17% and RSD <= 3.54%). Furthermore, PCA and OPLS-DA methods were employed to visualize the relationships and discrimination of the forty-two stem bark samples from two origins based on the contents of fifteen analytes. Our findings may provide early scientific evidence for quality control and for elucidating the therapeutic principle of Ilex rotunda. PMID- 29758471 TI - The predictive specificity of psychological vulnerability markers for the course of affective disorders. AB - High scores on markers of psychological vulnerability have been associated with a worse course of affective disorders. However, little is known about the specificity of those associations in predicting the course of different depressive and anxiety disorders. We examined the impact of psychological vulnerability on the short- and long-term course of depressive and anxiety disorders. Participants from the Netherlands Study of Depression and Anxiety with a current diagnosis of depression or anxiety (n = 1256) were reassessed after 2 and 6 years. Diagnostic status and chronic duration (>85% of the time) of symptoms were the outcomes. Predictors were neuroticism, extraversion, locus of control, cognitive reactivity (rumination and hopelessness reactivity), worry and anxiety sensitivity. High neuroticism, low extraversion and external locus of control predicted chronicity of various affective disorders. Rumination, however, predicted chronicity of depressive but not anxiety disorders. Worry specifically predicted chronicity of GAD and anxiety sensitivity predicted chronicity of panic disorder and social anxiety disorder. These patterns were present both at short term and at long-term, without losing predictive accuracy. Psychological vulnerabilities that are theoretically specific to certain disorders indeed selectively predict the course of these disorders. General markers of vulnerability predicted the course of multiple affective disorders. This pattern of results supports the notion of specific as well as transdiagnostic predictors of the course of affective disorders and is consistent with hierarchical models of psychopathology. PMID- 29758472 TI - Contributions of depression and body mass index to body image. AB - Depression and body mass index (BMI) are known to be associated with body image, however, their independent or joint effects on body image in adults are largely unknown. Therefore, we studied associations of depression diagnosis, severity, and BMI with perceptual body size (PBS) and body image dissatisfaction (BID). Cross-sectional data from 882 remitted depressed patients, 242 currently depressed patients and 325 healthy controls from the Netherlands Study of Depression and Anxiety were used. Depressive disorders (DSM-IV based psychiatric interview), standardized self-reported depressive symptoms (Inventory of Depressive Symptomatology) and BMI were separately and simultaneously related to body image (the Stunkard Figure Rating scale) using linear regression analyses. Thereafter, interaction between depression and BMI was investigated. Analyses were adjusted for demographic and health variables. Higher BMI was associated with larger PBS (B = 1.13, p < .001) and with more BID (B = 0.61, p < .001). Independent of this, depression severity contributed to larger PBS (B = 0.07, p < .001), and both current (B = 0.21, p = .001) and remitted depression diagnosis (B = 0.12, p = .01) as well as depression severity (B = 0.11, p < .001) contributed to BID. There was no interaction effect between BMI and depression in predicting PBS and BID. In general, depression (current, remitted and severity) and higher BMI contribute independently to a larger body size perception as well as higher body image dissatisfaction. Efforts in treatment should be made to reduce body dissatisfaction in those suffering from depression and/or a high BMI, as BID can have long-lasting health consequences, such as development of anorexia and bulimia nervosa and an unhealthy lifestyle. PMID- 29758470 TI - Association between changes in heart rate variability during the anticipation of a stressful situation and the stress-induced cortisol response. AB - Vagal activity - reflecting the activation of stress regulatory mechanisms and prefrontal cortex activation - is thought to play an inhibitory role in the regulation of the hypothalamus-pituitary-adrenal axis. However, most studies investigating the association between stress-induced changes in heart rate variability (HRV, an index of cardiac vagal tone) and cortisol have shown a non significant relationship. It has been proposed that physiological changes observed during anticipation of a stressor allow individuals to make behavioral, cognitive, and physiological adjustments that are necessary to deal with the upcoming actual stressor. In this study, in a large sample of 171 healthy adults (96 men and 75 women; mean age = 29.98, SD = 11.07), we investigated whether the cortisol response to a laboratory-based stress task was related to anticipation induced or stress task-induced changes in HRV. As expected, regression analyses showed that a larger decrease in HRV during the anticipation of a stress task was related to higher stress task-induced cortisol increase, but not cortisol recovery. In line with prior research, the stress task-induced change in HRV was not significantly related to cortisol increase or recovery. Our results show for the first time that anticipatory HRV (reflecting differences in stress regulation and prefrontal activity before the encounter with the stressor) is important to understand the stress-induced cortisol increase. PMID- 29758473 TI - Genome-wide analysis of poplar SAUR gene family and expression profiles under cold, polyethylene glycol and indole-3-acetic acid treatments. AB - Small auxin-up RNA (SAUR) proteins play an important role in the regulation of plant growth and development. Here, we identified 105 SAUR genes and comprehensively analyzed them in Populus trichocarpa. Based on the phylogenetic relationships, the PtSAURs were classified into ten subfamilies. Of the 105 PtSAURs, 100 were randomly distributed along the nineteen chromosomes, while the remaining genes were located along unassigned scafoolds. These genes mainly evolved through segmental duplications. In total, 94 PtSAURs contained no introns, and each group had a similar conserved motif structure. A promoter analysis revealed various cis-elements related to growth, development and stress responses, and a synteny analysis established orthologous relationships among SAURs in Arabidopsis, rice, grape and poplar. The qRT-PCR and tissue expression analyses indicated that PtSAURs show different expression levels in various tissues in response to different treatments. PtSAUR53 was located on the nuclear and plasma membrane by conducting subcellular localization analysis. This study provides a comprehensive overview of poplar SAUR proteins and a foundation for further investigations for functional analysis of SAURs in poplar growth and development. At the same time, it will be valuable to further study the poplar SAUR genes to reveal their biological effects. PMID- 29758475 TI - Social isolation and loneliness in later life: A parallel convergent mixed methods case study of older adults and their residential contexts in the Minneapolis metropolitan area, USA. AB - Social isolation and loneliness are increasingly prevalent among older adults in the United States, with implications for morbidity and mortality risk. Little research to date has examined the complex person-place transactions that contribute to social well-being in later life. This study aimed to characterize personal and neighborhood contextual influences on social isolation and loneliness among older adults. Interviews were conducted with independent dwelling men and women (n = 124; mean age 71 years) in the Minneapolis metropolitan area (USA) from June to October, 2015. A convergent mixed-methods design was applied, whereby quantitative and qualitative approaches were used in parallel to gain simultaneous insights into statistical associations and in-depth individual perspectives. Logistic regression models predicted self-reported social isolation and loneliness, adjusted for age, gender, past occupation, race/ethnicity, living alone, street type, residential location, and residential density. Qualitative thematic analyses of interview transcripts probed individual experiences with social isolation and loneliness. The quantitative results suggested that African American adults, those with a higher socioeconomic status, those who did not live alone, and those who lived closer to the city center were less likely to report feeling socially isolated or lonely. The qualitative results identified and explained variation in outcomes within each of these factors. They provided insight on those who lived alone but did not report feeling lonely, finding that solitude was sought after and enjoyed by a portion of participants. Poor physical and mental health often resulted in reporting social isolation, particularly when coupled with poor weather or low-density neighborhoods. At the same time, poor health sometimes provided opportunities for valued social engagement with caregivers, family, and friends. The combination of group-level risk factors and in-depth personal insights provided by this mixed methodology may be useful to develop strategies that address social isolation and loneliness in older communities. PMID- 29758474 TI - Purification and characterization of two pathogenesis-related class 10 protein isoforms with ribonuclease activity from the fresh Angelica sinensis roots. AB - In this study, two pathogenesis-related (PR) class 10 protein isoforms, ASPR-1 and ASPR-2, were purified from fresh roots of the Chinese medicinal plant Angelica sinensis (A. sinensis) using 80% ammonium sulfate precipitation, Sephadex G50 gel filtration chromatography, and DEAE-Sepharose ion-exchange chromatography. The molecular masses of ASPR-1 and ASPR-2 were estimated to be 16.66 kDa and 16.46 kDa, respectively, using sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The isoforms are both glycoproteins containing glycosyl contents of 1.8% (ASPR-1) and 3.4% (ASPR-2). The two isoforms were predominantly present as monomers, but they partially dimerized in solution. The 15 N-terminal amino acids of ASPR-1 were determined to be GIQKTEVEAPSTVSA, with significant sequence homology to certain PR-10 proteins. ASPR-2 was also identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) analysis to be a PR-10 protein. The isoforms both exhibited ribonuclease (RNase) activity, with ASPR-2 having higher specific activity (128.85 U mg-1) than ASPR-1 (68.67 U mg-1). The isoforms had the same optimal temperature of 50 degrees C but different optimal pH values of 5.0 (ASPR 1) and 6.0 (ASPR-2). The RNase activities of the isoforms were both stable for 30 min at 50 degrees C, rapidly decreasing at higher or lower processing temperatures. However, ASPR-1 retained higher residual activity (89.4%-80.9%) than ASPR-2 (74.3%-67.9%) at temperatures from 40 degrees C to 60 degrees C. These results provide additional information to enrich the current knowledge of poorly annotated A. sinensis proteins. PMID- 29758477 TI - The effect of street-level greenery on walking behavior: Evidence from Hong Kong. AB - Accumulating evidence shows that urban greenspaces have great health benefits, but establishing a causal relationship is difficult. It is often hypothesized that walking and physical activity are mediators in the relationship between urban greenspaces and health outcomes. Furthermore, most urban greenspace physical activity studies have focused on parks rather than on landscaped streets, even though the latter are the most popular places for physical activity. The lack of research attention for landscaped streets is largely due to the fact that street greenery is difficult to measure, especially at eye level. Using readily available Google Street View images, we developed methods and tools to assess the availability of eye-level street greenery. A two-layered study was developed that 1) examined the association between urban greenspaces and the odds of walking (versus not walking) for 90,445 participants in the Hong Kong Travel Characteristics Survey and 2) carried out sensitivity analysis of the association between urban greenspaces and total walking time for a subset of 6770 participants. Multilevel regression models were developed to reveal the associations between street greenery and walking behaviors while controlling for sociodemographic characteristics and other activity-influencing built environment factors, taking into account the inherent clustering within the data. The results showed that both street greenery and the number of parks were associated with higher odds of walking; street greenery but not parks was associated with total walking time. Our results suggest that walking behavior is at least as strongly affected by eye-level street greenery as by parks. They also implicitly support the health benefits of urban greenspaces via walking and physical activity. With the large sample size, our findings pertain to the entire population of Hong Kong. Furthermore, the use of Google Street View is a sound and effective way to assess eye-level greenery, which may benefit further health studies. PMID- 29758478 TI - Mechanisms of value-learning in the guidance of spatial attention. AB - The role of associative reward learning in the guidance of feature-based attention is well established. The extent to which reward learning can modulate spatial attention has been much more controversial. At least one demonstration of a persistent spatial attention bias following space-based associative reward learning has been reported. At the same time, multiple other experiments have been published failing to demonstrate enduring attentional biases towards locations at which a target, if found, yields high reward. This is in spite of evidence that participants use reward structures to inform their decisions where to search, leading some to suggest that, unlike feature-based attention, spatial attention may be impervious to the influence of learning from reward structures. Here, we demonstrate a robust bias towards regions of a scene that participants were previously rewarded for selecting. This spatial bias relies on representations that are anchored to the configuration of objects within a scene. The observed bias appears to be driven specifically by reinforcement learning, and can be observed with equal strength following non-reward corrective feedback. The time course of the bias is consistent with a transient shift of attention, rather than a strategic search pattern, and is evident in eye movement patterns during free viewing. Taken together, our findings reconcile previously conflicting reports and offer an integrative account of how learning from feedback shapes the spatial attention system. PMID- 29758476 TI - Epistemic tensions between people living with asthma and healthcare professionals in clinical encounters. AB - RATIONALE: Asthma is a common respiratory condition with high prevalence rates globally. While there are effective treatments, asthma remains an important health concern as people continue to die from severe attacks. Improving the experiences of, and health outcomes for, people with asthma depends heavily on their interactions with healthcare professionals. Understanding negative clinical encounters will benefit people with asthma and healthcare providers. OBJECTIVE: To examine epistemic tensions in negative clinical encounters from a patient perspective, with an aim to better understand how patients respond to these tensions. Much of the scholarship on patient interactions with healthcare providers examines interpersonal or structural factors. Thus, focusing our analysis on tensions between lay and expert knowledge in negative clinical encounters provides a novel contribution to this body of scholarship. METHOD: As part of a larger qualitative study (n = 70) examining the lived experiences of people who have asthma or a child with asthma, semi-structured interviews with 17 participants who described having negative clinical encounters were analyzed for themes. RESULTS: Participants responded to epistemic tensions in two main ways: (1) by incorporating expert knowledge; and (2) by resisting/challenging expert knowledge. In both cases, participants also described feeling frustrated and uncertain about their or their child's clinical care. We analyze these responses by drawing on Lindstrom and Karlsson's (2016) conceptualization of epistemic tensions as arising from 3 characteristics of epistemic asymmetry: access, rights, and responsibility. CONCLUSION: Based on this study, (1) a patient's confidence in claiming epistemic access and asserting epistemic rights when epistemic tensions arise are related to the context and their own history of living with asthma; and (2), epistemic tensions can make visible the power relations in the patient-clinician relationship, which can lead to the exertion of biomedical authority, or the taking up of patient's lay knowledge. PMID- 29758479 TI - Move to learn: Integrating spatial information from multiple viewpoints. AB - Recalling a spatial layout from multiple orientations - spatial flexibility - is challenging, even when the global configuration can be viewed from a single vantage point, but more so when it must be viewed piecemeal. In the current study, we examined whether experiencing the transition between multiple viewpoints enhances spatial memory and flexible recall for a spatial configuration viewed simultaneously (Exp. 1) and sequentially (Exp. 2), whether the type of transition matters, and whether action provides an additional advantage over passive experience. In Experiment 1, participants viewed an array of dollhouse furniture from four viewpoints, but with all furniture simultaneously visible. In Experiment 2, participants viewed the same array piecemeal, from four partitioned viewpoints that allowed for viewing only a segment at a time. The transition between viewpoints involved rotation of the array or participant movement around it. Rotation and participant movement were passively experienced or actively generated. The control condition presented the dollhouse as a series of static views. Across both experiments, participant movement significantly enhanced spatial memory relative to array rotation or static views. However, in Exp. 2, there was a further advantage for actively walking around the array compared to being passively pushed. These findings suggest that movement around a stable environment is key to spatial memory and flexible recall, with action providing an additional boost to the integration of temporally segmented spatial events. Thus, spatial memory may be more flexible than prior data indicate, when studied under more natural acquisition conditions. PMID- 29758481 TI - Kaempferol alleviates palmitic acid-induced lipid stores, endoplasmic reticulum stress and pancreatic beta-cell dysfunction through AMPK/mTOR-mediated lipophagy. AB - Kaempferol, a natural flavonoid, has the beneficial effects of preserving pancreatic beta-cell mass and function, but its action on beta-cell lipid metabolism still remains elusive. Recently, autophagy has been reported to play a major role in lipid metabolism in various cell types, but its role in pancreatic beta-cell's lipid metabolism is rarely reported. Here, we investigated the role of kaempferol-induced autophagy in inhibition of lipid stores, ER stress and beta cell dysfunction in palmitic acid-challenged RIN-5F cells and isolated pancreatic islets. The lipid-lowering effect of kaempferol was determined by Oil Red O staining, triglyceride assay, BODIPY labeling, RT-PCR and immunoblot analysis of PLIN2 (the lipid droplet coat protein) expression. Further, the involvement of AMPK/mTOR-mediated lipophagy was established by pharmacological and genetic inhibitors of autophagy and AMPK. The co-localization studies of lipid droplets with autophagosomes/lysosomes by BODIPY-MDC-LysoTracker co-staining, LC3/BODIPY labeling and LC3/PLIN2 double immunolabeling further strengthened the findings. Kaempferol treatment exhibited decreased lipid stores and increased co localization of lipid droplets with autophagosomes and lysosomes in palmitic acid challenged beta-cells. Moreover, inhibition of autophagy led to decreased co localization and increased lipid droplets accumulation. Kaempferol-induced alleviation of ER stress and beta-cell dysfunctions was established by immunoblot analysis of CHOP-10 (a key mediator of cell death in response to ER stress) and insulin content/secretion analysis respectively. Together, these findings suggest that kaempferol prevents ectopic lipid accumulation and ER stress, thus restoring beta-cell function through AMPK-mediated lipophagy. The current data implies that kaempferol may be a potential therapeutic candidate to prevent obesity-linked diabetic complications. PMID- 29758480 TI - Analytical and clinical performance of progesterone receptor antibodies in breast cancer. AB - OBJECTIVE: Comparison of analytical and immunohistochemical performance of progesterone receptor (PR) antibodies with correlation to recurrence of invasive breast cancer treated with endocrine therapy. METHODS: The binding-affinity kinetics of PR clones 1E2, 1A6, 16 and 636 were compared using synthetic peptides derived from identified epitopes on a Biacore T200. A cohort of 351 cases (Hormone Receptor (HR)+/HER2-) were stained for PR expression with immunohistochemistry (IHC) and scored according to ASCO/CAP criteria. RESULTS: The stability of the antigen/antibody complex was greater for the 1E2 clone compared to 1A6, 16 and 636 clones. PR IHC on archival tissue resulted in 94.3% (299/317) concordance with clones. CONCLUSION: Clones evaluated in this study had a high level of concordance with IHC despite PR (1E2) demonstrating higher analytical binding properties than other clones. In a minority of cases (1.3% for 1E2 and 2.5% for 636) IHC results could convert estrogen receptor (ER)-/PR- to ER /PR+ tumors, making these patients potentially eligible for endocrine therapy. PMID- 29758482 TI - Pretreatment of wheat straw using basic ethanolamine-based deep eutectic solvents for improving enzymatic hydrolysis. AB - A series of ethanolamine based deep eutectic solvents (DESs), which have strong basicity, were firstly applied in wheat straw pretreatment. Typically, choline chloride: monoethanolamine (C:M) as the best solvent among these DESs can remove 71.4% lignin and reserve 93.7% cellulose (70 degrees C, L/S mass ratio of 20:1, 9 h), and improve the enzymatic hydrolysis of residue, i.e., 89.8% cellulose and 62.0% xylan conversion. The pretreatment capacity of C:M is comparable to other solvents while C:M has several advantages, e.g., lower cost with cheap materials and simpler preparation process, mild conditions and lower polysaccharide loss. The XRD, SEM and FT-IR results verified that the polysaccharide conversion and sugars yield were enhanced by the removal of lignin in the pretreatment process. The basic ethanolamine based DESs are promising solvents for industrial application of wheat straw pretreatment. PMID- 29758483 TI - Demonstrating the viability of halolipase production at a mechanically stirred tank biological reactor. AB - The definition of halophiles as "the coming stars of industrial biotechnology" in a recent review demands new research efforts for their efficient production at bioreactor scale. In this sense, the scarcity of information about halolipases production has furthered the research on the viability of Halomonas sp. LM1C culture in a mechanically stirred bioreactor. The operating conditions have been optimized by means of a Central Composite Face-Centered (CCFC) design. The operation at low aerations (0.25 vvm) and moderate agitation rates (583 rpm) led to activity levels near 8000 U/L, which clearly surpasses the typical values detected for other extremophilic enzymes. The process at optimum conditions has been kinetically characterized and the oxygen volumetric mass transfer coefficient (KLa) has been determined. PMID- 29758484 TI - Biological denitrification in marine aquaculture systems: A multiple electron donor microcosm study. AB - There is a lack of information on denitrification of saline wastewaters, such as those from marine recirculating aquaculture systems (RAS), ion exchange brines and wastewater in areas where sea water is used for toilet flushing. In this study, side-by-side microcosms were used to compare methanol, fish waste (FW), wood chips, elemental sulfur (S0) and a combination of wood chips and sulfur for saline wastewater denitrification. The highest denitrification rate was obtained with methanol (23.4 g N/(m3.d)), followed by FW (4.5 g N/(m3.d)), S0 (3.5 g N/(m3.d)), eucalyptus mulch (2.6 g N/(m3.d)), and eucalyptus mulch with sulfur (2.2 g N/(m3.d)). Significant differences were observed in denitrification rate for different wood species (pine > oak ? eucalyptus) due to differences in readily biodegradable organic carbon released. A pine wood-sulfur heterotrophic autotrophic denitrification (P-WSHAD) process provided a high denitrification rate (7.2-11.9 g N/(m3.d)), with lower alkalinity consumption and sulfate generation than sulfur alone. PMID- 29758485 TI - Isolation, characterization and strain selection of a Paenibacillus species for use as a probiotic to aid in ruminal methane mitigation, nitrate/nitrite detoxification and food safety. AB - The effects of dietary nitrate and Paenibacillus 79R4 (79R4), a denitrifying bacterium, when co-administered as a probiotic, on methane emissions, nitrate and nitrite-metabolizing capacity and fermentation characteristics were studied in vitro. Mixed populations of rumen microbes inoculated with 79R4 metabolized all levels of nitrite studied after 24 h in vitro incubation. Results from in vitro simulations resulted in up to 2 log10 colony forming unit reductions in E. coli O157:H7 and Campylobacter jejuni when these were co-cultured with 79R4. Nitrogen gas was the predominant final product of nitrite reduction by 79R4. When tested with nitrate-treated incubations of rumen microbes, 79R4 inoculation (provided to achieve 106 cells/mL rumen fluid volume) complemented the ruminal methane decreasing potential of nitrate (P < 0.05) while concurrently increasing fermentation efficiency and enhancing ruminal nitrate and nitrite-metabolizing activity (P < 0.05) compared to untreated and nitrate only-treated incubations. PMID- 29758487 TI - Maternal allergy as an isolated risk factor for early-onset preeclampsia: An epidemiological study. AB - Immunological mechanisms underlying the development of preeclampsia are well known, but no association to allergy has yet been demonstrated. The aim of this study was to assess the correlation between maternal pre-gestational allergy, and early-onset and late-onset preeclampsia, respectively. It was a retrospective cohort study including all women giving birth in the Norwegian cities of Stavanger (1996-2014) and Bergen (2009-2014). Pre-gestational asthma, allergy, other known risk factors for preeclampsia, maternal age and parity were obtained from the electronic medical record system. The main outcome variables were early onset and late-onset preeclampsia (before and after 34 completed weeks of gestation, respectively). We used multinomial logistic regression to estimate odds ratios (OR) with 95% confidence intervals (95% CI) for early and late-onset preeclampsia in women with pre-gestational allergy when compared to women without allergy, adjusting for covariates. Predicted probabilities for the outcomes were also calculated. Of the 110 064 included pregnancies, 2 799 developed late-onset preeclampsia (2.5%) and 348 developed early-onset preeclampsia (0.3%). Pre gestational allergy increased the risk of early-onset preeclampsia (OR 1.7, 95% CI 1.3-2.4), and reduced the risk of late-onset preeclampsia (OR 0.8, 95% CI 0.7 0.9). These findings add valuable information on preeclampsia as an immunological complication of pregnancy and corroborate the understanding of early- and late onset preeclampsia as two different entities. PMID- 29758488 TI - Genetic variants in dyf-7 validated by droplet digital PCR are not drivers for ivermectin resistance in Haemonchus contortus. AB - Resistance to ivermectin (IVM) in the nematode Haemonchus contortus in small ruminants is an increasing problem throughout the world. Access to molecular diagnostics will allow early detection of IVM resistance, which in turn can limit the spread of resistant isolates. One candidate gene which has recently been suggested as a marker for IVM resistance is that for dye-filling protein (dyf-7). In this study, we critically investigated the suitability of A141G and G153T single nucleotide polymorphisms (SNP) of dyf-7 as a marker in larval cultures collected from sheep farms in Sweden, involving several isolates for which resistance status had been characterised by the faecal egg count reduction test (FECRT). Initially, we designed dyf-7 primers from a worldwide collection of adult Haemonchus contortus DNA. With the sequence data, we created a haplotype network. We then optimised and used the same sets of primers and probes in a droplet digital PCR (ddPCR) assay for precise quantification of dyf-7 allele frequencies in pre- and post-anthelmintic treatment faecal larval cultures. The fractional abundance (FA) of the mutant SNP was within the range 7.8 and 31%. However, the FA was generally stable in samples collected from the same farms, even though they were obtained on different occasions up to 25 months apart. There was also no indication that the level of IVM resistance as measured by the faecal egg count reduction test was higher on farms with high FA. Furthermore, by comparing FA in samples from the same farms pre- and post-IVM treatment, we found no evidence of a correlation between dyf-7 and level of IVM resistance. Based on these results, dyf-7 is not a suitable marker for field testing of IVM resistance in H. contortus. PMID- 29758486 TI - Poly (I:C) and LPS induce distinct immune responses by ovarian stromal fibroblasts. AB - Despite its anatomical location, the ovary is a site of pathogen exposure in the human female reproductive tract (FRT). However, the role of ovarian stromal fibroblasts in immune protection is unclear. We generated a population of ovarian stromal fibroblasts derived from normal human ovaries that expressed the pattern recognition receptors TLR3, TLR4, RIG-I, & MDA5. Poly (I:C) and LPS, respective mimics of viral and bacterial infections, selectively upregulated antiviral gene expression and secretion of chemokines and antimicrobials. Poly (I:C) exclusively stimulated the expression of interferon (IFN) beta, IFNlambda1, and the IFN stimulated gene OAS2. Poly (I:C) also significantly increased secretion of elafin, CCL20, and RANTES, but had no effect on SDF-1alpha. In contrast, LPS had no effect on IFN or ISG expression but significantly increased secretion of RANTES and SDF-1alpha. Secretions from poly (I:C)-treated fibroblasts had both greater anti-HIV activity and induced higher levels of CD4 + T cell chemotaxis than those from LPS-treated cells. Our studies demonstrate a potential key role for ovarian fibroblasts in innate immune protection against incoming pathogens in the normal ovary. PMID- 29758490 TI - Lung cancer incidence trends in Uruguay 1990-2014: An age-period-cohort analysis. AB - BACKGROUND: Uruguay, a country with one of the highest lung cancer rates worldwide, initiated a series of comprehensive anti-smoking measures in 2005. We assess the tobacco control policies in the context of cohort-driven lung cancer incidence trends over a 25-year period, providing baseline predictions to 2035. METHODS: Using data from the National Cancer Registry of Uruguay, an age-period cohort analysis of trends 1990-2014 was performed. The NORDPRED package was used to predict the annual number of new cases of lung cancer and incidence rates up to 2035. RESULTS: In men, age-standardised (world) rates declined from a peak of 165.6 in 1995 to 103.1 by 2014, translating to a 70% reduction in the risk of lung cancer in men born in 1970 relative to the early-1940s. In females, rates increased steadily from 18.3 in 1991 to 30.0 by 2014, with successive increases in risk among generations of women born 1940-1960. There is however evidence of a decline in observed rates in women born recently. Extrapolations of the trends indicate an 8% reduction in the mean number of new lung cancer cases in men by 2035, but a 69% increase in women. CONCLUSION: Despite observed and predicted reductions in lung cancer incidence in Uruguayan men, rates among women are set to continue to increase, with a large rise in the annual number of female lung cancer diagnoses expected before 2035. There are signals of a diminishing risk among recent generations of women born after 1960. The current analysis provides important baseline information in assessing the future impact of the recent tobacco control initiatives in Uruguay. PMID- 29758489 TI - Fisetin inhibits the generation of inflammatory mediators in interleukin-1beta induced human lung epithelial cells by suppressing the NF-kappaB and ERK1/2 pathways. AB - Fisetin, a flavone that can be isolated from fruits and vegetables, has anti tumor and anti-oxidative properties and ameliorates airway hyperresponsiveness in asthmatic mice. This study investigated whether fisetin can suppress the expression of inflammatory mediators and intercellular adhesion molecule 1 (ICAM 1) in A549 human lung epithelial cells that were stimulated with interleukin 1beta (IL-1beta) to induce inflammatory responses. A549 cells were treated with fisetin (3-30 MUM) and then with IL-1beta. Fisetin significantly inhibited COX-2 expression and reduced prostaglandin E2 production, and it suppressed the levels of IL-8, CCL5, monocyte chemotactic protein 1, tumor necrosis factor alpha, and IL-6. Fisetin also significantly attenuated the expression of chemokine and inflammatory cytokine genes and decreased the expression of ICAM-1, which mediates THP-1 monocyte adhesion to inflammatory A549 cells. Fisetin decreased the translocation of nuclear transcription factor kappa-B (NF-kappaB) subunit p65 into the nucleus and inhibited the phosphorylation of proteins in the ERK1/2 pathway. Co-treatment of IL-1beta-stimulated A549 cells with ERK1/2 inhibitors plus fisetin reduced ICAM-1 expression. Furthermore, fisetin significantly increased the effects of the protective antioxidant pathway by promoting the expression of nuclear factor erythroid-2-related factor-2 and heme oxygenase 1. Taken together, these data suggest that fisetin has anti-inflammatory effects and that it suppresses the expression of chemokines, inflammatory cytokines, and ICAM 1 by suppressing the NF-kappaB and ERK1/2 signaling pathways in IL-1beta stimulated human lung epithelial A549 cells. PMID- 29758491 TI - Has cancer survival improved for older people as for younger people? New South Wales, 1980-2012. AB - BACKGROUND: Cancer survival has improved markedly in Australia for all ages but it is still lower in older patients. We hypothesize that the survival gap by age has increased. Our rationale is that treatment constraints in older people and potentially their limited participation in trials may have limited opportunities for survival gain. METHODS: Post-diagnostic five-year cancer-specific mortality rates were analysed by age group for cancers recorded on the NSW Cancer Registry. Live cases were censored on December 31st, 2012. Hazards ratios (HRs) were obtained from proportional hazards regression for 1990-99 and 2000-12 diagnostic periods, using 1980-89 as the reference, adjusting for socio-demographic factors, degree of cancer spread, and for all cancers combined, for cancer sites. RESULTS: Five-year mortality reduced by diagnostic period for all cancers collectively from 53% in 1980-89 to 33% in 2000-12, with decreases for separate cancer sites. Adjusted HRs (95% confidence intervals) were 0.78 (0.77, 0.80) for 1990-99 and 0.61 (0.58, 0.63) for 2000-12 for all cancers combined. The downward trend in HRs was smaller for the 80+ year age group, leading to significantly higher HRs of 0.83 (0.81, 0.87) and 0.73 (0.70, 0.76) for 1990-99 and 2000-12 respectively. Results were similar using competing risk regression and 5-year rather than 10 year age strata. CONCLUSION: The reduction in cancer mortality was smaller in older people, as seen in the USA. Research is needed to achieve the best trade offs between cancer control and harm avoidance in older people. Multidisciplinary teams have an important contribution to make. PMID- 29758493 TI - Spirituality, religiousness and coping in patients with schizophrenia: A cross sectional study in a tertiary care hospital. AB - Religion is a form of coping that helps individuals to deal with a wide variety of difficult life situations. But most of the research in this field has been in acute patients of schizophrenia. Also, most of the research on religion and schizophrenia has focused on religion and spirituality as coping mechanisms, and research evaluating the relationship between spirituality/religiousness and repertoire of other coping skills is sparse. Our objective was to evaluate the association between spirituality, religiousness and coping skills in patients with schizophrenia in remission. Hence, a total of 48 consecutive patients with schizophrenia were assessed on Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), WHO Quality of Life-Spirituality, Religiousness and Personal Belief scale (WHOQOL-SRPB) and Ways of Coping Checklist - Revised (WCC). Findings were described as patients who used more religiosity and spirituality as measured with WHO-SRPB domain score were better in their managing their stress as they used all the adaptive strategies like planful problem solving, positive reappraisal, distancing, self-controlling, seeking social support rather than maladaptive skills like confrontive coping and escape avoidance. A sound spiritual, religious, or personal belief system positively affects active and adaptive coping skills in patients with schizophrenia during remission, thus helping the individual to cope with illness related stressors. PMID- 29758492 TI - Review of methodological challenges in comparing the effectiveness of neoadjuvant chemotherapy versus primary debulking surgery for advanced ovarian cancer in the United States. AB - Randomized trials outside the U.S. have found non-inferior survival for neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced ovarian cancer (AOC). However, these trials reported lower overall survival and lower rates of optimal debulking than U.S. studies, leading to questions about generalizability to U.S. practice, where aggressive debulking is more common. Consequently, comparative effectiveness in the U.S. remains controversial. We reviewed U.S. comparative effectiveness studies of NACT versus PDS for AOC. Here we describe methodological challenges, compare results to trials outside the U.S., and make suggestions for future research. We identified U.S. studies published in 2010 or later that evaluated the comparative effectiveness of NACT versus PDS on survival in AOC through a PubMed search. Two independent reviewers abstracted data from eligible articles. Nine of 230 articles were eligible for review. Methodological challenges included unmeasured confounders, heterogeneous treatment effects, treatment variations over time, and inconsistent measurement of treatment and survival. Whereas some limitations were unavoidable, several limitations noted across studies were avoidable, including conditioning on mediating factors and immortal time introduced by measuring survival beginning from diagnosis. Without trials in the U.S., non-randomized studies are an important source of evidence for the ideal treatment for AOC. However, several methodological challenges exist when assessing the comparative effectiveness of NACT versus PDS in a non-randomized setting. Future observational studies must ensure that treatment is consistent throughout the study period and that treatment groups are comparable. Rapidly-evolving oncology data networks may allow for identification of treatment intent and other important confounders. PMID- 29758494 TI - Uncovering potential anti-neuroinflammatory components of Modified Wuziyanzong Prescription through a target-directed molecular docking fingerprint strategy. AB - Neuroinflammation is a main factor in the pathogenesis of neurodegenerative diseases, such as Alzheimer disease. Our previous studies indicated that the modified Wuziyanzong Prescription (MWP) can suppress neuroinflammatory responses via nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinases (MAPKs) signaling pathways. However, the anti-neuroinflammatory components of MWP remain unclear. Herein, a target-directed molecular docking fingerprint (TMDF) strategy, via integrating the chemical profiling and molecular docking approaches, was developed to identify the potential anti-neuroinflammatory components of MWP. First, as many as 120 possible structures, including 49 flavonoids, 28 phenylpropionic acids, 18 amides, 10 carotenoids, eight phenylethanoid glycosides, four lignans, two iridoids, and one triterpenoid were deduced by the source attribution and structural classification-assisted strategy. Then, their geometries were docked against five major targets of the NF kappaB and MAPKs signaling cascades, including p38-alpha, IKKbeta, ERK1, ERK2, and TRAF6. The docking results revealed diverse contributions of different components towards the protein targets. Collectively, prenylated flavonoids showed intensive or moderate anti-neuroinflammatory activities, while phenylpropanoids, amides, phenylethanoid glycosides, lignans, and triterpenoids exhibited moderate or weak anti-neuroinflammatory effects. The anti neuroinflammatory activities of four retrieved prenylated flavonoids were tested by Western blotting assay, and the results mostly agreed with those predicted by the docking method. These gained information demonstrates that the established TMDF strategy could be a rapid and feasible methodology to investigate the potential active components in herbal compound prescriptions. PMID- 29758496 TI - Cord blood concentrations of leptin, zinc-alpha2-glycoprotein, and adiponectin, and adiposity gain during the first 3 mo of life. AB - OBJECTIVES: Adipose tissue development starts in intrauterine life and cytokines are involved in this process. Therefore, understanding the role of cytokines in the fat mass gain of infants is crucial to prevent obesity later in life. Furthermore, recent evidence indicates a sex-specific link between cytokines and adipose tissue development. The objective of this study was to assess sex specific relationships of cord blood concentrations of the cytokines leptin, zinc alpha2-glycoprotein (ZAG), and adiponectin with infant adiposity during the first 3 mo of life. METHODS: This was a prospective cohort study of 104 mother-infant pairs that were selected from a maternity hospital in Sao Paulo, Brazil. Cord blood leptin, ZAG, and adiponectin were determined by enzyme-linked immunosorbent assays. The body composition of the infants was assessed monthly by air displacement plethysmography. A multiple linear regression analysis was conducted with the average fat mass gain from birth to the third month of life as the outcome and cord blood leptin, ZAG, and adiponectin as the variables of interest. RESULTS: Leptin was inversely associated with fat mass gain in the first 3 mo of life (P = 0.003; adjusted R2 = 0.09). There were inverse associations of leptin (P = 0.021), ZAG (P = 0.042), and maternal body mass index (P = 0.04) with fat mass gain in girls (adjusted R2 = 0.29) but fat mass gain in boys was positively associated with gestational age (P = 0.01; adjusted R2 = 0.15). CONCLUSIONS: The results of this study suggest that adiposity programming is sex-specific, which highlights the need to investigate the different metabolic mechanisms that are involved in adipogenesis. PMID- 29758495 TI - A rapid magnetic particle-based enzyme immunoassay for human cytomegalovirus glycoprotein B quantification. AB - Human cytomegalovirus (HCMV) is a herpes virus that can cause severe infections. Still, the available methods for its diagnostic have the main disadvantage of requiring long time to be performed. In this work, a simple magnetic particle based enzyme immunoassay (mpEIA) for the quantification of glycoprotein B of Human cytomegalovirus (gB-HCMV) in urine samples is proposed. The immunosensor scheme is based on the analyte protein gB-HCMV sandwiched between a primary monoclonal antibody, (MBs-PrG-mAb1), and a secondary anti-gB-HCMV antibody labelled with Horseradish peroxidase (Ab2-HRP) to allow spectrophotometric detection. The mpEIA analytical performance was tested in urine samples, showing a linear dependence between gB-HCMV concentration and the absorbance signal at 450 nm in a range of concentrations from 90 to 700 pg mL-1. The calculated detection limits for gB-HCMV were 90 +/- 2 pg mL-1 and the RSD was about 6.7% in urine samples. The immunosensor showed good selectivity against other viruses from Herpesviridae family, namely varicella zoster and Epstein Barr viruses. The recoveries of spiked human urine samples at 0.30-0.50 ng mL-1 concentration levels of gB-HCMV ranged between 91 to 105%. The proposed mpEIA method was validated following the guidelines of the European Medicines Agency (EMEA-2014), and allows rapid, successful and easy quantification of gB-HCMV in urine samples. PMID- 29758497 TI - Growth and recovery of zebrafish embryos after developmental exposure to raw and ozonated oil sands process-affected water. AB - Due to the increasing volume of oil sands process-affect water (OSPW) and its toxicity to aquatic organisms, it is important to fully understand its effects and study remediation processes that will enable its release to the environment. Ozone treatment is currently being considered as a tool to expedite remediation, as it is known to degrade toxic organic compounds present in OSPW. In this study, we aimed to measure the effects of OSPW exposure on the growth, development and recovery of zebrafish (Danio rerio) embryos. We also used ozone-treated OSPW to determine whether ozonation negated any effects of raw OSPW exposure. As biomarkers of exposure, we assessed the expression of genes involved in neurodevelopment (ngn1, neuroD), estrogenicity (vtg), oxidative stress (sod1), and biotransformation (cyp1a, cyp1b). Our study found that exposure to both raw and ozonated OSPW did not impair growth of zebrafish embryos, however, otoliths of exposed embryos were smaller than those of control embryos. The expression levels of both cyp1a and cyp1b were induced by raw OSPW exposure. However, after the exposure period, expression levels of these genes returned to control levels within two days of residence in clean water. We found no changes in the expression levels of ngn1, neuroD and vtg genes with exposure to treated or untreated OSPW. Overall, our study found that raw OSPW exposure did not have many negative effects on zebrafish embryos and embryos appeared to recover relatively quickly after exposure ended. Furthermore, ozone treatment decreased the induction of cyp1a and cyp1b. PMID- 29758498 TI - Accumulation, elimination and neuro-oxidative damage under lanthanum exposure in glass eels (Anguilla anguilla). AB - Rare earth elements (REEs) comprise elements from lanthanum to lutetium that together with yttrium and scandium are emergent contaminants of critical importance for numerous groundbreaking environmental technologies. Transfer to aquatic ecosystems is expected to increase, however, little information is known about their potential impacts in marine biota. Considering the endangered conservation status of the European eel (Anguilla anguilla) and the vulnerability of early fish life stages to contaminants, we exposed glass eels, through water, to an environmentally relevant concentration (120 ng.L-1) of lanthanum (La) for 7 days (plus 7 days of depuration). The aim was to study the accumulation and elimination of La in eel's body and subsequent quantification of acetylcholinesterase (AchE), lipid peroxidation and antioxidant enzymatic machinery. Accumulation peaked after 72 h-exposure to La, decreasing afterwards, even in continuous exposure. Accumulation was higher in the viscera, followed by the skinless body and ultimately in the head, possibly as a protective mechanism to cope with La neurotoxicity. A significant increase in AChE activity was observed in La-exposed glass eels, suggesting that La3+ may inhibit the binding of acetylcholine. A depression in lipid peroxidation was registered under La exposure, possibly indicating that La3+ may play physiological activities and functions as a free radical scavenger. Catalase activity was significantly inhibited in La-exposed glass eels after 72 h, indicating that the availability of La may induce physiological impairment. The quantification of Glutathione S Transferase activity revealed no differences between control and La-exposed organisms. Further investigation is needed towards understanding the biological effects of REEs. PMID- 29758499 TI - Interference of three herbicides on iron acquisition in maize plants. AB - The use of herbicides to control weed species could lead to environmental threats due to their persistence and accumulation in the ecosystems and cultivated fields. Nonetheless, the effect of these compounds on plant mineral nutrition in crops has been barely investigated. This study aimed at ascertaining the effect of three herbicides (S-metolachlor, metribuzin and terbuthylazine) on the capacity of maize to acquire iron (Fe). Interferences on plant growth and reductions on the Fe contents were found in the plants treated. Furthermore, root cell viability and functionality losses were ascertained following the treatments, which, in turn, decreased the amount of phytosiderophores (PSs) released by the roots. An investigation carried out in greater depth on root apices of treated plants using an FE-SEM (Scanning Electron Microscope) coupled with EDX (Energy Dispersive X-ray) indicated that the reductions on Fe content started in this part of the roots. Lastly, decreases were found also in copper (Cu+2), zinc (Zn+2) and manganese (Mn+2) content in root apices. PMID- 29758500 TI - Degradation of aniline by electrochemical activation of peroxydisulfate at MWCNT cathode: The proofed concept of nonradical oxidation process. AB - Enhanced elimination of aniline in aqueous solution was achieved by coupling electrosorption of aniline and electrochemical activation of peroxydisulfate (PDS) at multi-walled carbon nanotube (MWCNT) cathode, in which a synergistic effect occurred. It was found that PDS could be effectively activated under a small voltage at MWCNT cathode owing to the specific pore structures of MWCNTs. A nonradical oxidation pathway instead of radical-based oxidation was proposed from the cathodic activation of PDS, wherein PDS molecules with a modified electronic structure was suggested to be the principal reactive species. Meanwhile, the influences of various operation parameters such as electrode potential, PDS concentration, presence of chloride ions on the elimination efficiency, and the stability of MWCNT electrode were also attempted. Therefore, the electrochemical activation of PDS by MWCNT cathode is a promising energy-saving method for the treatment of organic pollutants in wastewater. PMID- 29758501 TI - Rolling-made gas diffusion electrode with carbon nanotube for electro-Fenton degradation of acetylsalicylic acid. AB - H2O2 production plays an important role in electro-Fenton process for pharmaceutical and personal care products (PPCPs) degradation. In this work, carbon nanotube (CNT) was attempted to make a gas diffusion electrode (GDE) by rolling method to achieve a high H2O2 production and current efficiency, and it was further used as electro-Fenton cathode for the degradation of acetylsalicylic acid (ASA) as one kind of PPCPs. The optimal amount of catalyst layer was 0.15 g CNT and 93.75 MUL PTFE, obtaining the production of H2O2 of 805 mg L-1 in 0.05 mM Na2SO4 solution at 100 mA after 180 min. The degradation of ASA by electro-Fenton on such a CNT-GDE cathode was studied, and some important parameters such as current, pH as well as the dosage of Fe2+ were optimized. The degradation ratio of ASA could achieve almost 100% after 10 min and the TOC removal ratio was 62% at 1 h under the condition of 100 mA and pH 3, showing a great potential for the treatment of PPCPs. PMID- 29758502 TI - Dual element (CCl) isotope approach to distinguish abiotic reactions of chlorinated methanes by Fe(0) and by Fe(II) on iron minerals at neutral and alkaline pH. AB - A dual element CCl isotopic study was performed for assessing chlorinated methanes (CMs) abiotic transformation reactions mediated by iron minerals and Fe(0) to further distinguish them in natural attenuation monitoring or when applying remediation strategies in polluted sites. Isotope fractionation was investigated during carbon tetrachloride (CT) and chloroform (CF) degradation in anoxic batch experiments with Fe(0), with FeCl2(aq), and with Fe-bearing minerals (magnetite, Mag and pyrite, Py) amended with FeCl2(aq), at two different pH values (7 and 12) representative of field and remediation conditions. At pH 7, only CT batches with Fe(0) and Py underwent degradation and CF accumulation evidenced hydrogenolysis. With Py, thiolytic reduction was revealed by CS2 yield and is a likely reason for different Lambda value (Deltadelta13C/Deltadelta37Cl) comparing with Fe(0) experiments at pH 7 (2.9 +/- 0.5 and 6.1 +/- 0.5, respectively). At pH 12, all CT experiments showed degradation to CF, again with significant differences in Lambda values between Fe(0) (5.8 +/- 0.4) and Fe bearing minerals (Mag, 2 +/- 1, and Py, 3.7 +/- 0.9), probably evidencing other parallel pathways (hydrolytic and thiolytic reduction). Variation of pH did not significantly affect the Lambda values of CT degradation by Fe(0) nor Py. CF degradation by Fe(0) at pH 12 showed a Lambda (8 +/- 1) similar to that reported at pH 7 (8 +/- 2), suggesting CF hydrogenolysis as the main reaction and that CF alkaline hydrolysis (13.0 +/- 0.8) was negligible. Our data establish a base for discerning the predominant or combined pathways of CMs natural attenuation or for assessing the effectiveness of remediation strategies using recycled minerals or Fe(0). PMID- 29758503 TI - MRI and PET/CT for evaluation of the pathological response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) has become an essential treatment for breast cancer. However, there is still no consensus on the best tool to evaluate pathological response to NAC. METHODS: Two reviewers systematically searched Cochrane, PubMed, EMBASE, Web of Science, and CBM (last updated in February 2017) for eligible articles. We independently screened and selected studies that conformed to the inclusion criteria and extracted the requisite data. Pooled sensitivity, specificity, and the area under the SROC curve were calculated to estimate the diagnostic accuracy of magnetic resonance imaging (MRI) and positron emission computed tomography (PET/CT). And the relative DOR (RDOR) was used to compare accuracy for levels of the covariable. RESULTS: Thirteen studies involving 575 patients who underwent MRI and 618 who underwent PET/CT were included in our analysis. The pooled sensitivity and specificity of MRI were 0.88 (95% CI: 0.78-0.94) and 0.69 (95% CI: 0.51-0.83), respectively. The corresponding values for PET/CT were 0.77 (95% CI: 0.58-0.90) and 0.78 (95% CI: 0.63-0.88), respectively. The area under the SROC curve for MRI and PET/CT were 0.88 and 0.84, respectively. And the RDOR = 1.44 (95% CI, 0.46-4.47 P = 0.83). CONCLUSION: MRI had a higher sensitivity and PET/CT had a higher specificity in predicting the pathologic response after NAC in patients with breast cancer. According to the area under the SROC curve and anatomic discriminative resolution, MRI is the more suitable recommendation for predicting the pathologic response after NAC. PMID- 29758504 TI - Patients' perspectives and experiences concerning barriers to accessing information about bilateral prophylactic mastectomy. AB - PURPOSE: To explore the barriers and experiences of accessing information for women who have received genetic risk assessment/testing results for breast cancer (BC) and are considering a bilateral prophylactic mastectomy (BPM) and, exploring participants' preferences concerning information and support needs. METHODS: A qualitative retrospective study guided by interpretative phenomenological analysis was utilised. Semi-structured interviews were conducted with forty-six women who were either considering BPM or had already undergone the surgery. RESULTS: Three themes identified barriers to accessing information; difficulties accessing information, inconsistent information and clinical focus/medicalized information. A fourth theme - preferences of information and support needs, identified three subthemes; these were, psychological support, clearly defined processes and photos of mastectomies/reconstruction surgeries. CONCLUSIONS: Barriers to accessing information appeared to be widespread. A lack of integrated services contributed to inconsistent information, and medicalized terminology/clinical focus of consultations further complicated understanding. Preferences for information include clearly defined processes, so women know the pathways after confirmation of familial BC risk. Clinical implications include a multidisciplinary team approach, and a protocol that reflects current practice. PMID- 29758505 TI - Functional exploration of extracellular polymeric substances (EPS) in the bioleaching of obsolete electric vehicle LiNixCoyMn1-x-yO2 Li-ion batteries. AB - As a fairly new concept, the recovery of valuable metals from urban mining by using bioleaching has become a hotspot. However, the function of extracellular polymeric substances (EPS) in the bioleaching of urban mining gains little attention. The current study used spent EV LIBs to represent urban mining products and systematically explored the function and role of EPS in the attachment of cells to the cathodes, formation of aggregates (cell-EPS-cathode), variation in the electrical and surface properties of the aggregates, concentration of both Fe2+ and Fe3+ surrounding the aggregates, electron transfer inside the aggregates and metals released from the aggregates. The results indicated that a strong adhesion of cells to the cathodes occurs mediated by EPS via both hydrophobic force as a main role and electrostatic force as a minor role. Second, the EPS not only adsorb Fe3+ but also more strongly adsorb Fe2+ to concentrate the Fe2+/Fe3+ cycle inside the aggregates, witnessing stronger reductive attack on the high valence state of metals as a contact reductive mechanism. Third, the retention or addition of EPS elevated the electronic potential and reduced the electronic resistance to lift the corrosion electric current, thereby boosting the electron transfer and metal dissolution. PMID- 29758506 TI - The association between menarche, intensity of training and passive joint ROM in young pre-professional female dancers: A longitudinal follow-up study. AB - OBJECTIVES: To determine the association between the status of menarche (yes/no), the intensity of training and the potential to improve passive joint range of motion (ROM) over a 12-month period of dance training. DESIGN: Prospective cohort study. SETTING: Dance studio. PARTICIPANTS: Fifty-nine female dancers aged 12.8 +/- 0.5. MAIN OUTCOME MEASURES: The dancers were asked about their dance intensity and screened for anthropometric parameters and passive joint ROM in Grades 7 and 8. RESULTS: Along the 12 months of dance training, we found significantly increased ankle-foot en-pointe, hip abduction, and hip external rotation (ER); significantly decreased hip internal rotation (IR); and significant increased hip ER:IR ratio. In Grade 7, 26 dancers (44.1%) reached menarche (Yes menarche); in Grade 8 an additional 23 dancers (39.0%) reached menarche (No/Yes menarche); and 10 dancers (16.9%) had not reached menarche (No menarche). MANOVA (mixed models) with repeated measures to compare joint ROM between the three menarche groups (Yes; No/Yes; No), with h/week dance practice as a co-variant, showed that hip ER, ankle-foot en-pointe, and ER:IR were significantly correlated with h/week in all three menarche groups. CONCLUSIONS: Most passive joint ROM can be improved over 12 months of dancing around the age onset of menarche. H/week of dance practice is a main factor contributing to improved hip ER, ankle-foot en-pointe and ER/IR ratio. PMID- 29758507 TI - Recovery practices in Division 1 collegiate athletes in North America. AB - OBJECTIVES: Establish current practice and attitudes towards recovery in a group of Division-1 Collegiate athletes from North America. DESIGN: A 16-item questionnaire was administered via custom software in an electronic format. PARTICIPANTS: 152 student athletes from a Division-1 Collegiate school across 3 sports (Basketball, American Football, Soccer). MAIN OUTCOME MEASURES: The approaches and attitudes to recovery in both training and competition. RESULTS: Sleep, cold water immersion (CWI) and nutrition were perceived to be the most effective modalities (88, 84 and 80% of the sample believed them to have a benefit respectively). Over half the sample did not believe in using compression for recovery. With regard to actual usage, CWI was the most used recovery modality and matched by athletes believing in, and using, the approach (65%). Only 24% of student athletes believed in, and used, sleep as a recovery modality despite it being rated and perceived as the most effective. CONCLUSIONS: Collectively, there is a discrepancy between perception and use of recovery modalities in Collegiate athletes. PMID- 29758508 TI - The efficacy of elastic therapeutic tape variations on measures of ankle function and performance. AB - OBJECTIVES: To investigate the effects of different variations of elastic therapeutic taping (ETT) on tests used to screen for ankle injury risk and function. DESIGN: Randomized crossover. SETTING: Laboratory. PARTICIPANTS: Twelve professional male soccer players completed three experimental trials: No tape (NT), RockTapeTM (RT), and KinesioTM Tape (KT) applied to the ankle complex. OUTCOME MEASURES: Clinical and functional ankle screening tests were used to assess the effects of ETT on measures of joint position sense, postural stability and ground reaction forces. RESULTS: KT (P = 0.04) and RT (P = 0.01) demonstrated significant improvements in end range joint position sense. When compared to NT, RT significantly (P = 0.02) improved mid-range joint position sense at 15 degrees , and time to complete a drop landing task. No significant differences were observed for measures of postural stability (P >= 0.12) nor ground reaction force variables (P >= 0.33). CONCLUSIONS: Results advocate the use of ETT for proprioceptive and functional tasks when applied to the ankles of healthy male soccer players. However, a greater number of practical and significant differences were observed when RT only was applied, indicating that practitioners may potentially advocate the use of RT for tasks requiring proprioception and functional performance. PMID- 29758509 TI - Potential health risks via consumption of six edible shellfish species collected from Piura - Peru. AB - Scallops and their potential predators were collected in Sechura Bay and in front of the Illescas Reserved Zone (north Peru), during El Nino-Southern Oscillation (ENSO) 2016, and analyzed for the metals chromium (Cr), manganese (Mn), iron (Fe), nickel (Ni), copper (Cu), zinc (Zn), arsenic (As), cadmium (Cd) and lead (Pb). This study showed that ~20% of the molluscs exceeded the maximum residual levels (MRLs) for human consumption in inorganic As, while ~30% of the crustaceans did. For Cd, around 10% and 40% of the molluscs and the crustaceans were above the MRLs, respectively. The cephalopod Octopus mimus exhibited As concentrations, but not Cd concentrations, that exceeded the MRLs. Cr, Ni, Cu, Zn and Pb in muscle exhibited generally concentrations below the MRLs. Integrated risk indices were estimated to determine if there is a health risk for consumption. Target hazard quotients (THQs) and total hazard indices (HIs) were mostly < 1, implying no human health risk. Provisional tolerable weekly intake (PTWI) for Cd was exceeded in Bursa ventricosa at Illescas Reserved Zone. Target cancer risks (TRs) for inorganic As were always higher than the threshold (1 * 10 6), therefore an actual cancer risk is present. PMID- 29758511 TI - Quantitative analysis of glycated albumin in serum based on ATR-FTIR spectrum combined with SiPLS and SVM. AB - A rapid quantitative analysis model for determining the glycated albumin (GA) content based on Attenuated total reflectance (ATR)-Fourier transform infrared spectroscopy (FTIR) combining with linear SiPLS and nonlinear SVM has been developed. Firstly, the real GA content in human serum was determined by GA enzymatic method, meanwhile, the ATR-FTIR spectra of serum samples from the population of health examination were obtained. The spectral data of the whole spectra mid-infrared region (4000-600 cm-1) and GA's characteristic region (1800 800 cm-1) were used as the research object of quantitative analysis. Secondly, several preprocessing steps including first derivative, second derivative, variable standardization and spectral normalization, were performed. Lastly, quantitative analysis regression models were established by using SiPLS and SVM respectively. The SiPLS modeling results are as follows: root mean square error of cross validation (RMSECVT) = 0.523 g/L, calibration coefficient (RC) = 0.937, Root Mean Square Error of Prediction (RMSEPT) = 0.787 g/L, and prediction coefficient (RP) = 0.938. The SVM modeling results are as follows: RMSECVT = 0.0048 g/L, RC = 0.998, RMSEPT = 0.442 g/L, and Rp = 0.916. The results indicated that the model performance was improved significantly after preprocessing and optimization of characteristic regions. While modeling performance of nonlinear SVM was considerably better than that of linear SiPLS. Hence, the quantitative analysis model for GA in human serum based on ATR-FTIR combined with SiPLS and SVM is effective. And it does not need sample preprocessing while being characterized by simple operations and high time efficiency, providing a rapid and accurate method for GA content determination. PMID- 29758512 TI - Conjugated ionic state and its distribution in perylene bisimide doped film: A characterization of Z-scanning in confocal Raman spectroscopy. AB - Ion-doped states are significant for improving the performance in organic semiconductor-based devices, which require clear characterization to understand their relationship with conductivity and charge transporting mechanisms. In this paper, Raman spectroscopy is used to track the evolution of a dianion-anion neutral mixture in a perylene bisimide (PBI)-doped film under air, with z scanning carried out in the confocal mode. The precise distribution for the different states along the film depth is realized within 3.5 MUm. The whole film is clearly divided into three regions: the ion-poor state, transition region and ion-rich state. The ion ratio and distribution are strongly related to the film conductivity and the onset voltage shift. Changes in the distribution of the ionic species during oxidation and electrode catalysis are clearly recorded by z scanning, which is beneficial for understanding the charge transfer properties as well as the mechanism underlying working devices. PMID- 29758510 TI - Assessing the chronic toxicity of nickel to a tropical marine gastropod and two crustaceans. AB - The mining and processing of nickel ores from tropical regions contributes 40% of the global supply. The potential impact of these activities on tropical marine ecosystems is poorly understood. Due to the lack of ecotoxicity data for tropical marine species, there is currently no available water quality guideline value for nickel that is specific to tropical species. In this study, we investigated the toxicity of nickel to three tropical marine invertebrates, the gastropod Nassarius dorsatus, the barnacle Amphibalanus amphitrite, and the copepod Acartia sinjiensis. All toxicity tests used chronic endpoints, namely larval growth, metamorphosis (transition from nauplii to cyprid larvae) and larval development for the snail, barnacle and copepod respectively. Toxicity tests were carried out under environmentally relevant conditions (i.e. 27-30?C, salinity 34-360/00, pH 8.1-8.4). Copper was also tested for quality assurance purposes and to allow for comparisons with previous studies. The copepod was the most sensitive species to nickel, with development inhibited by 10% (EC10) at 5.5 (5.0-6.0) ug Ni/L (95% confidence limits (CL)). Based on EC10 values, the gastropod and barnacle showed similar sensitivities to nickel with growth and metamorphosis inhibited by 10% at 64 (37-91) ug Ni/L and 67 (53-80) ug Ni/L, respectively. Based on existing data available in the literature, the copepod A. sinjiensis is so far the most sensitive tropical marine species to nickel. This study has provided high quality data which will contribute to the development of a water quality guideline value for nickel in tropical marine waters. A species sensitivity distribution of chronic nickel toxicity used the data generated in this paper supplemented by available literature data, comprising 12 species representing 6 taxonomic groups. A 5% hazard concentration (HC5) was determined as 8.2 ug/L Ni. PMID- 29758513 TI - New approach for determination of sulfadiazine in pharmaceutical preparations using 4(4-sulphophenylazo)pyrogallol: Kinetic spectrophotometric method. AB - A new trend describes the development and validation of a simple, sensitive and selective kinetic spectrophotometric methods for the determination of sulfadiazine in pharmaceutical formulations has been conducted. In this paper, sulfadiazine was derivatized as a new organic compound 4(4-sulphophenylazo) pyrogallol, 4-SPAP, by coupling pyrogallol with diazotized sulfadiazine in medium of controlled pH. 4-SPAP was characterized by techniques of FT-IR, H-NMR, GC Mass, TG and DSC thermal analysis methods. Solvatochromic behavior in solvents of various polarities was also investigated. The determination of sulfadiazine was accomplished by initial rate and fixed time methods. These methods were based on the reaction of the compound containing sulfadiazine, 4-SPAP, with Ca(II) to form colored product with a maximum absorbance at 520 nm. The two methods were adopted for constructing the calibration curves and examined for their suitability for the quantitation of sulfadiazine in pharmaceuticals. The limit of detection (LOD) and limit of quantification (LOQ) were found to be, by initial rate method, 0.35 and 1.05 MUg.mL-1and that by fixed time method were found to be 0.69 and 2.07 MUg.mL-1, respectively. The percent relative standard deviations (%RSD) for the results ranged from 1.04% to 1.76% and 0.85% to 1.42% for the initial rate and fixed time methods of the proposed kinetic spectrophotometric method, respectively. The existence of common excipients in the pharmaceutical formulation did not produce any significant interference. Statistical comparison was reported as indicated from the F- and t-test data of the proposed methods with that of reference method showing excellent agreement and indicating no significant difference in their accuracy and precision. PMID- 29758514 TI - An erythrosin B-based "turn on" fluorescent sensor for detecting perfluorooctane sulfonate and perfluorooctanoic acid in environmental water samples. AB - Because of the serious harm to animals and the environment associated with perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), a rapid, sensitive and low-cost method for detecting PFOS and PFOA is of great importance. In this paper, a novel sensing method has been proposed for the highly sensitive detection of PFOS and PFOA in environmental water samples based on the "turn-on" switch of erythrosine B (EB)-hexadecyltrimethylammonium bromide (CTAB) system. In pH 8.55 Britton-Robinson (BR) buffer, EB can react with CTAB by electrostatic attraction, resulting in a strong fluorescence quenching of EB. With a subsequent addition of the CTAB, a red-shift occurred (11 nm), followed by a significant increase in fluorescence at high surfactant concentrations. It was found that PFOS and PFOA can obviously enhance fluorescence intensity of EB-CTAB system. The enhanced fluorescence intensity is proportional to the concentration of PFOS and PFOA in the range of 0.05-10 MUM with detection limit of 12.8 nM and 11.8 nM (3sigma), respectively. The presented assay has been successfully applied to sensing PFOS and PFOA in real water samples with RSD <= 4.3% and 2.9%, respectively. PMID- 29758515 TI - Scavenging performance and antioxidant activity of gamma-alumina nanoparticles towards DPPH free radical: Spectroscopic and DFT-D studies. AB - The radical scavenging performance and antioxidant activity of gamma-alumina nanoparticles towards 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical were investigated by spectroscopic and computational methods. The radical scavenging ability of gamma-alumina nanoparticles in the media with different polarity (i.e. i-propanol and n-hexane) was evaluated by measuring the DPPH absorbance in UV-Vis absorption spectra. The structure and morphology of gamma-alumina nanoparticles before and after adsorption of DPPH were studied using XRD, FT-IR and UV-Vis spectroscopic techniques. The adsorption of DPPH free radical on the clean and hydrated gamma-alumina (1 1 0) surface was examined by dispersion corrected density functional theory (DFT-D) and natural bond orbital (NBO) calculations. Also, time-dependent density functional theory (TD-DFT) was used to predict the absorption spectra. The adsorption was occurred through the interaction of radical nitrogen N and NO2 groups of DPPH with the acidic and basic sites of gamma-alumina surface. The high potential for the adsorption of DPPH radical on gamma-alumina nanoparticles was investigated. Interaction of DPPH with Bronsted and Lewis acidic sites of gamma-alumina was more favored than Bronsted basic sites. The following order for the adsorption of DPPH over the different active sites of gamma-alumina was predicted: Bronsted base < Lewis acid < Bronsted acid. These results are of great significance for the environmental application of gamma-alumina nanoparticles in order to remove free radicals. PMID- 29758516 TI - Crash data modeling with a generalized estimator. AB - The investigation of relationships between traffic crashes and relevant factors is important in traffic safety management. Various methods have been developed for modeling crash data. In real world scenarios, crash data often display the characteristics of over-dispersion. However, on occasions, some crash datasets have exhibited under-dispersion, especially in cases where the data are conditioned upon the mean. The commonly used models (such as the Poisson and the NB regression models) have associated limitations to cope with various degrees of dispersion. In light of this, a generalized event count (GEC) model, which can be generally used to handle over-, equi-, and under-dispersed data, is proposed in this study. This model was first applied to case studies using data from Toronto, characterized by over-dispersion, and then to crash data from railway-highway crossings in Korea, characterized with under-dispersion. The results from the GEC model were compared with those from the Negative binomial and the hyper-Poisson models. The cases studies show that the proposed model provides good performance for crash data characterized with over- and under-dispersion. Moreover, the proposed model simplifies the modeling process and the prediction of crash data. PMID- 29758517 TI - Identification of chalcone-based antileishmanial agents targeting trypanothione reductase. AB - All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Furthermore, some drugs are associated with the emergence of drug resistance. Thus, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The present work highlights the use of natural derived products, i.e. chalcones, as potential source of antileishmanial agents. Thirty-one novel chalcone compounds have been synthesized and their activity has been evaluated against promastigotes of Leishmania donovani; 16 compounds resulted active against L. donovani in a range from 3.0 to 21.5 MUM, showing low toxicity against mammalian cells. Among these molecules, 6 and 16 showed good inhibitory activity on both promastigotes and intracellular amastigotes, coupled with an high selectivity index. Furthermore, compounds 6 and 16 inhibited the promastigote growth of other leishmanial species, including L. tropica, L. major and L. infantum. Finally, 6 and 16 interacted with high affinity with trypanothione reductase (TR), an essential enzyme for the leishmanial parasite and compound 6 inhibited TR with sub-micromolar potency. Thus, the effective inhibitory activity against Leishmania, the lack of toxicity on mammalian cells and the ability to block a crucial parasite's enzyme, highlight the potential for compound 6 to be optimized as novel drug candidate against leishmaniasis. PMID- 29758519 TI - Lanostane triterpenoids from Tricholoma pardinum with NO production inhibitory and cytotoxic activities. AB - Eight undescribed lanostane triterpenoids, pardinols A-H, along with one previously reported lanostane triterpenoid, namely saponaceol B, were isolated from the fruiting bodies of Tricholoma pardinum. Their structures and stereoconfigurations were established via combination of extensive spectroscopic analyses, alkaline methanolysis method and TDDFT/ECD calculations. Pardinols B and E-H exhibited certain inhibition activities of nitric oxide (NO) production with IC50 value ranging from 5.3 to 14.7 MUM, as well as cytotoxicities against human cancer cell-lines. PMID- 29758518 TI - Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer. AB - The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4 2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC. PMID- 29758521 TI - Bisindole alkaloids from Tabernaemontana corymbosa. AB - Continued study in bioactive monoterpenoid alkaloids led to the isolation of nine undescribed alkaloids, taberyunines A-I, together with 32 known ones from the aerial parts of Tabernaemontana corymbosa Roxb. ex Wall (Apocynaceae). Among the undescribed alkaloids, taberyunines A-G and H-I were assigned to Aspidosperma Aspidosperma and Vobasinyl-Ibogan type bisindoles, respectively. Their structures were determined by NMR spectra, MS data and X-ray diffraction. Taberyunine B showed significant cytotoxicity against three cancer cell lines. PMID- 29758520 TI - Probing the transcriptome of Aconitum carmichaelii reveals the candidate genes associated with the biosynthesis of the toxic aconitine-type C19-diterpenoid alkaloids. AB - Aconitum carmichaelii has long been used as a traditional Chinese medicine, and its processed lateral roots are known commonly as fuzi. Aconitine-type C19 diterpenoid alkaloids accumulating in the lateral roots are some of the main toxicants of this species, yet their biosynthesis remains largely unresolved. As a first step towards understanding the biosynthesis of aconitine-type C19 diterpenoid alkaloids, we performed de novo transcriptome assembly and analysis of rootstocks and leaf tissues of Aconitum carmichaelii by next-generation sequencing. A total of 525 unigene candidates were identified as involved in the formation of C19-diterpenoid alkaloids, including those encoding enzymes in the early steps of diterpenoid alkaloids scaffold biosynthetic pathway, such as ent copalyl diphosphate synthases, ent-kaurene synthases, kaurene oxidases, cyclases, and key aminotransferases. Furthermore, candidates responsible for decorating of diterpenoid alkaloid skeletons were discovered from transcriptome sequencing of fuzi, such as monooxygenases, methyltransferase, and BAHD acyltransferases. In addition, 645 differentially expressed genes encoding transcription factors potentially related to diterpenoid alkaloids accumulation underground were documented. Subsequent modular domain structure phylogenetics and differential expression analysis led to the identification of BAHD acyltransferases possibly involved in the formation of acetyl and benzoyl esters of diterpenoid alkaloids, associated with the acute toxicity of fuzi. The transcriptome data provide the foundation for future research into the molecular basis for aconitine-type C19 diterpenoid alkaloids biosynthesis in A. carmichaelii. PMID- 29758522 TI - Flavonoid alkaloids from Scutellaria moniliorrhiza with anti-inflammatory activities and inhibitory activities against aldose reductase. AB - Four undescribed flavonoid alkaloids, as two pairs of enantiomers, were initially isolated as a racemate from the whole plant of Scutellaria moniliorrhiza. By means of chiral HPLC, four isomers, named scumonilines A-D, were successfully separated, and their chemical structures including absolute configurations were established by mass as well as NMR spectroscopy and CD technique. In vitro, four flavonoid alkaloids showed anti-inflammatory activities, with IC50 values against the release of beta-glucuronidase from polymorphonuclear leukocytes of rats being in the range 5.16-5.85 MUMU. Moreover, four compounds were evaluated for their inhibitory activities against aldose reductase, and gave IC50 values in the range 2.29-3.03 MUMU. PMID- 29758523 TI - Glycosides of naphthohydroquinones and anthraquinones isolated from the aerial parts of Morinda parvifolia Bartl. ex DC (Rubiaceae) increase p53 mRNA expression in A2780 cells. AB - Eight previously undescribed naphthohydroquinone glycosides, namely morindaparvins H-O, together with four known anthraquinone glycosides were isolated from the n-BuOH extract of the aerial parts of Morinda parvifolia Bartl. ex DC (Rubiaceae). The structures of morindaparvins H-O were elucidated on the basis of spectroscopic analysis. To our knowledge, this is the first isolation of quinone glycosides from the plant M. parvifolia. The results showed that all 12 compounds at the concentration of 50 MUM significantly increased p53 mRNA expression in A2780 cells compared with the blank control group. PMID- 29758524 TI - Effect of DS-2969b, a novel GyrB inhibitor, on rat and monkey intestinal microbiota. AB - DS-2969b, a novel GyrB inhibitor, transiently and reversibly altered the counts of limited intestinal microbiota at around 10 MUg/g of faecal levels in rats and monkeys. Considering the high activity of DS-2969b against Clostridium difficile, 10 MUg/g of faecal levels would be sufficient for clearing C. difficile from the intestine. PMID- 29758525 TI - Concentrations and variability of organophosphate esters, halogenated flame retardants, and polybrominated diphenyl ethers in indoor and outdoor air in Stockholm, Sweden. AB - We investigated the concentrations and temporal variability of organophospate esters (OPEs), halogenated flame retardants (HFRs) and polybrominated diphenyl ethers (PBDEs) in indoor and outdoor urban air in Stockholm, Sweden over one year (2014-2015) period. The median concentrations of the three target chemical groups (OPEs, HFRs, PBDEs) were 1-2 orders of magnitude higher in indoor air than outdoor urban air. OPEs were the most abundant target FRs with median concentrations in indoor (Sigma10OPE = 340 000 pg/m3) and outdoor urban (Sigma10OPEs = 3100 pg/m3) air, being 3 orders of magnitude greater than for HFRs in indoor (Sigma15HFRs = 120 pg/m3) and outdoor urban (Sigma15HFRs = 1.6 pg/m3) air. In indoor air, PBDE concentrations (Sigma17PBDEs = 33 pg/m3) were lower than for the HFRs, but in outdoor urban air, concentrations (Sigma17PBDEs = 1.1 pg/m3) were similar to HFRs. The most abundant OPEs in both the indoor and outdoor urban air were tris(2-butoxyethyl)phosphate (TBOEP), tris(chloroisopropyl)phosphate (TCIPP), tris(2-chloroethyl)phosphate (TCEP), tri-n-butyl-phosphate (TnBP), triphenyl phosphate (TPhP) and tris(1,3-dichloroisopropyl)phosphate (TDCIPP). TCIPP in indoor air was found in the highest concentrations and showed the greatest temporal variability, which ranged from 85 000 to 1 900 000 pg/m3 during the one-year sampling period. We speculate that activities in the building, e.g. floor cleaning, polishing, construction, introduction of new electronics and changes in ventilation rate could explain its variation. Some OPEs (TnBP, TCEP, TCIPP, TDCIPP and TPhP), HFRs/PBDEs (pentabromotoluene, 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether, hexabromobenzene, BDE-28, -47, and -99) in outdoor urban air showed seasonality, with increased concentrations during the warm period (p < 0.05, Pearson's r ranged from -0.45 to -0.91). The observed seasonality for OPEs was probably due to changes in primary emission, and those for the HFRs and PBDEs was likely due to re-volatilization from contaminated surfaces. PMID- 29758526 TI - Cadmium dynamics in soil pore water and uptake by rice: Influences of soil applied selenite with different water managements. AB - Cadmium (Cd) in rice grains is a potential threat to human health. This study investigated the effects of selenite fertilisation (0 mg kg-1, 0.5 mg kg-1, and 1.0 mg kg-1) on soil solution Cd dynamics and rice uptake. Rice was grown in two Cd-contaminated soils in Jiangxi and Hunan Provinces under two different sets of conditions: aerobic and flooded. The experiments were conducted in pots. The plants were harvested at the seedling stage and at maturity to determine their Cd levels. Soil solutions were also extracted during the growing season to monitor Cd dynamics. The results showed that in the Jiangxi soil (pH 5.25), Cd concentrations in the soil solutions, seedlings, and mature rice plants were higher under aerobic than under flooded water management conditions. In the Hunan soil (pH 7.26), however, flooding decreased Cd levels in the rice seedlings but not in mature plants. Selenite additions to the Hunan soil decreased Cd concentrations in the soil solutions and in the mature rice plants. These effects were not observed for the solutions or the plants from Jiangxi soil amended with selenite. Relative to the control treatment, 0.5 mg kg-1 selenite decreased the rice grain Cd content by 45.2% and 67.7% under aerobic and flooding conditions, respectively. The results demonstrated that water management regimes affected rice Cd uptake more effectively in Jiangxi than in Hunan soil, whereas selenite addition was more effective in Hunan than in Jiangxi soil. Selenite addition was also more effective at reducing rice grain Cd levels when it was applied under flooding than under aerobic conditions. PMID- 29758527 TI - Removal, biotransformation and toxicity variations of climbazole by freshwater algae Scenedesmus obliquus. AB - Climbazole (CBZ) is an antibacterial and antifungal agent widely used in personal care products. In this study, we investigated the interactions between climbazole (CBZ) and freshwater microalgae Scenedesmus obliquus (S. obliquus). Dose-effect relationships between CBZ concentrations and growth inhibitions or chlorophyll a content were observed. After 12 days of incubation, the algae density and chlorophyll a content in 2 mg/L treatment group was 56.6% and 15.8% of those in the control group, respectively. Biotransformation was the predominant way to remove CBZ in the culture solution, whereas the contribution of bioaccumulation and bioadsorption were negligible. More than 88% of CBZ was removed by S. obliquus across all treatments after 12 days of incubation, and the biotransformation of CBZ followed the first order kinetic model with half-lives of approximately 4.5 days at different treatments. CBZ-alcohol (CBZ-OH) was the only biotransformation product identified in algal solution. Moreover, the toxicity of biotransformation products was much lower than its corresponding precursor compound (CBZ). The results of this study revealed that S. obliquus might have a great impact on the environmental fates of CBZ and could be further applied to remove organic pollutants in aquatic environment. PMID- 29758529 TI - The effect of naphthenic acids on physiological characteristics of the microalgae Phaeodactylum tricornutum and Platymonas helgolandica var. tsingtaoensis. AB - Naphthenic acids (NAs) account for 1-2% of crude oil and represent its main acidic component. However, the aquatoxic effects of NAs on marine phytoplankton and their ecological risks have remained largely unknown. Using the marine microalgae Phaeodactylum tricornutum and Platymonas helgolandica var. tsingtaoensis as the target, we studied the effects of NAs on their growth, cell morphology and physiological characteristics. The cell density decreased as the concentrations of NAs increased, indicating that they had an adverse effect on growth of the investigated algae in a concentration-dependent manner. Moreover, scanning electron microscopy revealed NAs exposure caused damage such as deformed cells, shrunken surface and ruptured cell structures. Exposure to NAs at higher concentrations for 48 h significantly increased the content of chlorophyll (Chl) a and b in P. tricornutum, but decreased their levels in P. helgolandica var. tsingtaoensis. NAs with concentrations no higher than 4 mg/L gradually enhanced the Chl fluorescence (ChlF) parameters and decreased the ChlF parameters at higher concentrations for the two marine microalgae. Additionally, NAs induced hormesis on photosynthetic efficiency of the two microalgae and also have the species difference in their aquatic toxicity. Overall, the results of this study provide a better understanding of the physiological responses of phytoplankton and will enable better risk assessments of NAs. PMID- 29758528 TI - Optimization of the NO photooxidation and the role of relative humidity. AB - Photocatalysis was recognised as a suitable process for the photoabatement of atmospheric pollutants. The photooxidation mechanism on TiO2 has been widely studied. However, recent studies demonstrated that the very often-assumed photooxidation intermediated by the hydroxyl radical cannot explain all the experimental observations. Indeed, this study contributes for a new understanding of NO photooxidation. First, the adsorption equilibrium isotherms of NO, NO2 and H2O on the photocatalyst, Aeroxide(r) P25 from Evonik Industries, were obtained. Also, the concentration of hydroxyl radicals was determined by photoluminescence. A comprehensive design of experiments was then followed; NO conversion and selectivity were obtained as a function of the relative humidity, irradiance, NO inlet concentration and residence time, following a response surface methodology (RSM). These results were then used to discuss the photooxidation mechanism of NO. PMID- 29758530 TI - Arbuscular mycorrhizal fungi alleviate boron toxicity in Puccinellia tenuiflora under the combined stresses of salt and drought. AB - To investigate the effect of arbuscular mycorrhizal fungi (AMF) on boron (B) toxicity in plants under the combined stresses of salt and drought, Puccinellia tenuiflora was grown in the soil with the inoculation of Funneliformis mosseae and Claroideoglomus etunicatum. After three weeks of treatment, the plants were harvested to determine mycorrhizal colonization rates, plant biomass, as well as tissue B, phosphorus, sodium, and potassium concentrations. The results show that the combined stresses reduced mycorrhizal colonization. Mycorrhizal inoculation significantly increased plant biomass while reduced shoot B concentrations. Mycorrhizal inoculation also slightly increased shoot phosphorus and potassium concentrations, and reduced shoot sodium concentrations. F. mosseae and C. etunicatum were able to alleviate the combined stresses of B, salt, and drought. The two fungal species and their combination showed no significant difference in the alleviation of B toxicity. It is inferred that AMF is able to alleviate B toxicity in P. tenuiflora by increasing biomass and reducing tissue B concentrations. The increase in plant phosphorus and potassium, as well as the decrease in sodium accumulation that induced by AMF, can help plant tolerate the combined stresses of salt and drought. Our findings suggest that F. mosseae and C. etunicatum are potential candidates for facilitating the phytoremediation of B contaminated soils with salt and drought stress. PMID- 29758531 TI - Capture, swallowing, and egestion of microplastics by a planktivorous juvenile fish. AB - Microplastics (<5 mm) have been found in many fish species, from most marine environments. However, the mechanisms underlying microplastic ingestion by fish are still unclear, although they are important to determine the pathway of microplastics along marine food webs. Here we conducted experiments in the laboratory to examine microplastic ingestion (capture and swallowing) and egestion by juveniles of the planktivorous palm ruff, Seriolella violacea (Centrolophidae). As expected, fish captured preferentially black microplastics, similar to food pellets, whereas microplastics of other colours (blue, translucent, and yellow) were mostly co-captured when floating close to food pellets. Microplastics captured without food were almost always spit out, and were only swallowed when they were mixed with food in the fish's mouth. Food probably produced a 'gustatory trap' that impeded the fish to discriminate and reject the microplastics. Most fish (93% of total) egested all the microplastics after 7 days, on average, and 49 days at most, substantially longer than food pellets (<2 days). No acute detrimental effects of microplastics on fish were observable, but potential sublethal effects of microplastics on the fish physiological and behavioural responses still need to be tested. This study highlights that visually-oriented planktivorous fish, many species of which are of commercial value and ecological importance within marine food webs, are susceptible to ingest microplastics resembling or floating close to their planktonic prey. PMID- 29758532 TI - Evaluation of the Nova Vet Meter for sheep-side monitoring of beta-hydroxybutyric acid (BHBA) and description of ewe BHBA during late gestation in three flocks from the Northeastern U.S. AB - Prevention of metabolic diseases in small ruminants may improve production efficiency and profitability, yet ewes carrying multiples or who are in poor body condition are at increased susceptibility to develop ketosis. This study evaluated the hand-held Nova Vet Meter to accurately detect beta-hydroxybutyric acid (BHBA) concentrations in ewes and determined the percentage of ewes at moderate (0.8 to 1.5 mmol/L BHBA) and greatest (>=1.6 mmol/L BHBA) risk to develop ketosis during late gestation. To validate the Nova Vet Meter, BHBA concentrations of 104 paired blood samples were measured using the Nova Vet Meter and gold-standard laboratory analysis. Receiver operating characteristics were calculated. The accuracy and sensitivity of detecting BHBA concentrations at 0.8 to 1.5 mmol/L were 94.2% and 97.3%, respectively. The accuracy and sensitivity of detecting BHBA concentrations >= 1.6 mmol/L were 98.0% and 50.0%, respectively. Ewe body weight (BW), body condition score (BCS), and BHBA of 117 ewes from three flocks were determined weekly during the four weeks before parturition. During the last three weeks of gestation >20% of ewes were identified with moderate risk to develop ketosis. During the last four weeks of gestation, ewes carrying triplets had reduced BCS (P = 0.0002) and increased BHBA concentrations (P < 0.0001) compared with singleton and twin pregnancies. Ewe BHBA did not correlate with lamb birth weight (R2 = 0.003; P = 0.41). In conclusion, the Nova Vet Meter is suitable for sheep-side BHBA monitoring between 0.8 and 1.5 mmol/L, but further testing is necessary to evaluate BHBA readings >=1.6 mmol/L. PMID- 29758534 TI - Investigations of the corneal epithelium in Veterinary Medicine: State of the art on corneal stem cells found in different mammalian species and their putative application. AB - The existence of progenitor cells that can readily differentiate into a specific cell type is a common cellular strategy for physiological tissue growth and repair mechanisms. In the mammalian cornea, many aspects regarding the nature and location of these cells are still unclear. In the human limbus (peripheral area of the cornea) progenitor cells have been found and characterized but in non human mammals, the picture is not so clear. In this review, we examine current knowledge about the morphology of limbus and the localization of corneal epithelial stem cells in all species studied so far, comparing data with humans. We have also explored different research directions in the veterinary field in order to discuss the: i) currently used protocols and ii) best range of treatments for ocular pathologies in which corneal stem cells are involved. PMID- 29758533 TI - Antimicrobial resistance, biofilm formation and virulence reveal Actinobacillus pleuropneumoniae strains' pathogenicity complexity. AB - Porcine pleuropneumonia is an important cause of lowered productivity and economic loss in the pig industry worldwide, associated primarily with Actinobacillus pleuropneumoniae infection. Its colonization and persistence within the upper respiratory tract of affected pigs depends upon interactions between a number of genetically controlled virulence factors, such as pore forming repeats-in-toxin exoproteins, biofilm formation, and antimicrobial resistance. This study investigated correlations between biofilm-forming capacity, antimicrobial resistance, and virulence of A. pleuropneumoniae obtained from clinical outbreaks of disease, using a Galleria mellonella alternative infection model. Results suggest that virulence is diverse amongst the 21 strains of A. pleuropneumoniae examined and biofilm formation correlated with genetic control of antimicrobial resistance. PMID- 29758535 TI - On farm intervention studies on reduction of boar taint prevalence: Feeding strategies, presence of gilts and time in lairage. AB - One of the challenges in the production of entire male pigs is the occurrence of boar taint. We separately tested the effect of 3 management strategies to reduce boar taint on respectively 2, 3, and 6 Flemish pig farms: 1) adapted feeding strategies, 2) presence of gilts in the compartment, and 3) varying lairage duration at the slaughterhouse. A commercialized feed concept resulted in a significant reduction of olfactory boar taint prevalence when fed for 2 weeks (T2W) compared to control (T-CON) (P = 0.030). For T2W and when fed for 3 weeks (T3W), androstenone (AND) (P = 0.002 for T2W, P = 0.029 for T3W) and skatole (SKA) (P < 0.001 for T2W and T3W) were significantly reduced compared to T-CON. Olfactory boar taint prevalence was significantly reduced when feeding 5% dried chicory roots (FI5%) (P = 0.032), but not for 3% dried chicory roots (FI3%) (P = 0.958). SKA concentration was significantly lower when feeding FI5% (P < 0.001) and when feeding FI3% (P = 0.034). Rearing entire male pigs separately from gilts and increasing lairage duration from <1 h to >3 h did not significantly affect boar taint. PMID- 29758536 TI - Characterization of SeseC_01411 as a surface protective antigen of Streptococcus equi ssp. zooepidemicus. AB - Streptococcus equi ssp. zooepidemicus (Streptococcus zooepidemicus, SEZ) is a commensal bacterium related to opportunistic infections of many species, including humans, dogs, cats, and pigs. SeseC_01411 has been proven to be immunogenic. However, its protective efficacy remained to be evaluated. In the present study, the purified recombinant SeseC_01411 could elicit a strong humoral antibody response and protect against lethal challenge with virulent SEZ in mice. Our finding confirmed that SeseC_01411 distributes on the surface of SEZ. In addition, the hyperimmune sera against SeseC_01411 could efficiently kill the bacteria in the phagocytosis test. The present study identified the immunogenic protein, SeseC_01411, as a novel surface protective antigen of SEZ. PMID- 29758537 TI - Biopolymers conjugated with magnetite as support materials for trypsin immobilization and protein digestion. AB - In the presented study synthesized magnetic nanoparticles were used as an inorganic precursor for the preparation of novel magnetite-lignin and magnetite chitin hybrid supports for enzyme immobilization. Effective synthesis of the hybrids was confirmed by Fourier transform infrared spectroscopy and powder X-ray diffraction analysis. The materials exhibited good thermal stability and surface areas of 4.3 and 5.6 m2/g respectively. The magnetite-lignin + trypsin and magnetite-chitin + trypsin systems were found to have good storage stability and reusability. After 20 days they retained over 75% and 90% respectively of their initial activity, and after 10 consecutive biocatalytic cycles retained over 60% and 80% respectively of their initial activity. The kinetic parameters of the free and immobilized enzyme were also comprehensively examined and compared. The results of peptide digestion tests confirmed the high proteolytic activity of the produced trypsin-based magnetic biocatalytic systems. PMID- 29758538 TI - Preparation and characterization of iron oxide magnetic nanoparticles functionalized by nisin. AB - Nisin is a known bacteriocin approved as a food additive for food preservation. It exhibits a wide spectrum antimicrobial activity against Gram-positive bacteria. Iron oxide magnetic nanoparticles were synthesized and characterized by X-ray diffraction method. A main part of iron oxide nanoparticles was found to be maghemite though a small quantity of magnetite could also be present. Magnetic nanoparticles were stabilized by citric, ascorbic, gallic or glucuronic acid coating. Stable iron oxide magnetic nanoparticles were functionalized by nisin using a simple and low cost adsorption method. Nisin loading was confirmed by FT IR spectra, thermogravimetric analysis, dynamic light scattering and atomic force microscopy methods. Nisin-loaded iron oxide magnetic nanoparticles were stable at least six weeks as judged by the measurements of zeta-potential and hydrodynamic diameter. The antimicrobial activity of nisin-loaded iron oxide magnetic nanoparticles was demonstrated toward Gram-positive bacteria. Functionalized nanoparticles could therefore find the application as antimicrobials in innovative and emerging technologies based on the magnetic field. PMID- 29758539 TI - Bulk and dispersed aqueous behaviour of an endogenous lipid, selachyl alcohol: Effect of Tween 80 and Pluronic F127 on nanostructure. AB - Tween 80 has been reported to provide a means of targeting drug nanocarriers to the blood- brain barrier. This study investigated the influence of addition of Tween 80 on the formation of different bulk and dispersed lyotropic liquid crystalline phases in selachyl alcohol-based systems. The effect of increasing concentrations of Tween 80 and Pluronic F127 (as a control) (0-25% w/w relative to SA) on the bulk phase behaviour and dispersions of selachyl alcohol (SA) were investigated using small angle X-ray scattering, dynamic light scattering, and cryogenic transmission electron microscopy. The addition of Tween 80 to SA bulk phase samples triggered concentration-dependent phase changes with the structure sequentially evolving from a reverse hexagonal phase (H2) to a mixed H2 and inverse bicontinuous cubic (V2) then a V2 phase alone. In contrast, the addition of Pluronic F127 resulted in a phase change from H2 phase to a mixed lamellar and H2 phase system. The mean particle size of internally structured particles was 125-190 nm with low polydispersity indices (0.1-0.2). Nanoparticles retained the bulk phase internal structure in the presence of Tween 80, whereas in the presence of Pluronic F127, the additional lamellar phase that formed in bulk phase systems was not observed. Cryo-TEM revealed the formation of cubosomes and hexosomes by SA in excess water in the presence of Tween 80 and Pluronic F127 respectively. In summary, it was shown that stabilisation of SA dispersions using Tween 80 resulted in a decrease in negative curvature leading to a change in internal structure from H2 to V2 phase. The studies provide the core understanding of particle structure to progress these structured lipid nanocarriers into delivery studies with Tween 80 as a mechanism to target the blood-brain barrier. PMID- 29758540 TI - Integrated antibacterial and antifouling surfaces via cross-linking chitosan-g eugenol/zwitterionic copolymer on electrospun membranes. AB - Integrated antibacterial and antifouling surfaces in favor of avoiding implant related infections are necessarily required for biomaterials when they contact with the body fluid. In this work, an antibacterial and antifouling membrane was developed via cross-linking chitosan-g-eugenol and the zwitterionic copolymer poly(sulfobetaine methylacrylate-co-2-aminoethyl methacrylate) on the electrospun polycarbonate urethane substrate using genipin as a cross-linker. Antibacterial assays demonstrated that the prepared membranes had efficient antibacterial activity with 92.8 +/- 2.5% and 95.2 +/- 1.3% growth inhibition rates against Escherichia coli and Staphylococcus aureus, respectively. The investigations on antifouling activity and hemocompatibility of the membranes showed significant resistances to bacterial attachment, non-specific protein adsorption and platelet adhesion, and presented lower hemolytic activity and good anticoagulant activity as well. Moreover, cell culture assays indicated that the prepared membranes exerted no obvious cytotoxicity with more than 80% of relative L929 fibroblast viability. Therefore, the membranes with integrated antibacterial and antifouling properties could be potentially applied in promising indwelling devices. PMID- 29758541 TI - Molecular interaction studies of some Co(III)-surfactants with the transport protein. AB - The present work describes the synthesis and the molecular interaction of two single-chain Co(III)-coordinated surfactant complexes with a plasma protein, human serum albumin by using various biophysical and in silico techniques. The experimental data reveals that like ordinary classical surfactants, our metallosurfactants also have the tendency to associate themselves and form micelles at critical micelle concentration. The thermodynamic parameters (DeltaH degrees , DeltaS degrees , and DeltaG degrees ) derived from the experiment demonstrates that the alkyl chain length and the head group of the Co(III) surfactant complexes played a vital role in the binding process. Both the physico chemical and computational docking results indicated that the Co(III)-surfactant complexes are stabilized by hydrogen bonding, hydrophobic and/or van der Waals forces. Thus, the data acquired herein for the interesting class of surfactant complexes will be of significance in metal-based drug discovery and developmental research. PMID- 29758542 TI - Fentanyl self-testing outside supervised injection settings to prevent opioid overdose: Do we know enough to promote it? AB - Since 2013, North America has experienced a sharp increase in unintentional fatal overdoses: fentanyl, and its analogues, are believed to be primarily responsible. Currently, the most practical means for people who use drugs (PWUD) to avoid or mitigate risk of fentanyl-related overdose is to use drugs in the presence of someone who is in possession of, and experienced using, naloxone. Self-test strips which detect fentanyl, and some of its analogues, have been developed for off-label use allowing PWUD to test their drugs prior to consumption. We review the evidence on the off-label sensitivity and specificity of fentanyl test strips, and query whether the accuracy of fentanyl test strips might be mediated according to situated practices of use. We draw attention to the weak research evidence informing the use of fentanyl self-testing strips. PMID- 29758543 TI - Magnesium sulfate versus esomeprazole impact on the neonates of preeclamptic rats. AB - OBJECTIVE: Preeclampsia represents a major complication of pregnancy, associated with greater maternal and fetal complications. We compared the effects of esomeprazole (a proton pump inhibitor) and magnesium sulfate (MgSO4) on the deleterious effects observed on the mother and neonates in experimentally induced preeclampsia in rats. STUDY DESIGN: Preeclampsia was induced in pregnant rats with NG-nitro-l-arginine methyl ester (L-NAME) starting from day 10-till end of pregnancy. Pregnant rats were divided into four groups: control pregnant; untreated preeclampsia; preeclamptic rats treated with MgSO4 and preeclamptic treated with esomeprazole. Treatment was started on day 14 and continued until end of pregnancy. Systolic blood pressure, gestation duration, the total number of pups/fetal resorption, pups birth weight, and histopathology examination of the pup's organs were recorded. RESULTS: In comparison with the L-NAME group, the MgSO4 and esomeprazole treatment reduced the values of systolic blood pressure; MgSO4 normalized gestational duration while esomeprazole prolonged it (post-term pregnancy); both restored number of delivered pups; with no statistical differences between the numbers of died pups between the four groups studied while with esomeprazole, out of 10 pregnant females, 2 of them had complete intrauterine fetal resorption; esomeprazole normalized birth weight and histological structure of fetal liver, kidney, and brain. On the other side, MgSO4 treatment gave rise to lower than normal birth weight and minimal tissue damage. CONCLUSION: Esomeprazole and MgSO4 improved systolic blood pressure, prevented preterm labor and restored numbers of pups delivered and fetal weight. Esomeprazole prolonged gestational period post-term with subsequent improving reproductive outcome. PMID- 29758546 TI - Chondrogenic properties of collagen type XI, a component of cartilage extracellular matrix. AB - Cartilage extracellular matrix (ECM) has been used for promoting tissue engineering. However, the exact effects of ECM on chondrogenesis and the acting mechanisms are not well understood. In this study, we investigated the chondrogenic effects of cartilage ECM on human mesenchymal stem cells (MSCs) and identified the contributing molecular components. To this end, a preparation of articular cartilage ECM was supplemented to pellets of chondrogenically differentiating MSCs, pellets of human chondrocytes, and bovine articular cartilage explants to evaluate the effects on cell proliferation and the production of cartilaginous matrix. Selective enzymatic digestion and screening of ECM components were conducted to identify matrix molecules with chondrogenic properties. Cartilage ECM promoted MSC proliferation, production of cartilaginous matrix, and maturity of chondrogenic differentiation, and inhibited the hypertrophic differentiation of MSC-derived chondrocytes. Selective digestion of ECM components revealed a contributory role of collagens in promoting chondrogenesis. The screening of various collagen subtypes revealed strong chondrogenic effect of collagen type XI. Finally, collagen XI was found to promote production and inhibit degradation of cartilage matrix in human articular chondrocyte pellets and bovine articular cartilage explants. Our results indicate that cartilage ECM promotes chondrogenesis and inhibits hypertrophic differentiation in MSCs. Collagen type XI is the ECM component that has the strongest effects on enhancing the production and inhibiting the degradation of cartilage matrix. PMID- 29758545 TI - Protection against UV-induced oxidative stress and DNA damage by Amazon moss extracts. AB - Amazon mosses, such as Holomitriopsis laevifolia and Leucobryum sp. are naturally exposed to high levels of solar ultraviolet (UV) radiation. Theoretically, under environmental stress conditions these mosses have developed protective chemical and metabolic strategies against UV damage, by way of biosynthesis of secondary metabolites, such as flavonoids. The present paper aimed to evaluate the free radical scavenging activity, and the photoprotective, mutagenic and photomutagenic potencies of the methanolic (ME), aqueous (AE), hydroalcoholic (HE), ethanolic (EE) extracts of H. laevifolia and Leucobryum sp. The phenolic contents were evaluated by spectrophotometry and by High-Performance Liquid Chromatography (HPLC). The present findings showed that the AE and HE of H. laevifolia and the AE of Leucobryum sp. presented the highest phenolic contents. The HPLC analysis indicated the presence mainly of phenolic and cinnamic acids, flavonols, flavones and flavanones. The AE and EE of H. laevifolia and the AE and HE of Leucobryum sp. efficiently scavenged the 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical. All extracts showed significant values of in vitro Sun Protection Factor alone, and HE of Leucobryum sp. showed a synergistic effect in association with benzophenone-3. None of the extracts induced mutagenicity in the auxotrophic strains for histidine of Salmonella typhimurium, and photomutagenicity of the TA102 and TA104 strains was not detected after exposure to UV-A radiation. Besides, all extracts showed photoprotective activity against UV-A radiation for the TA104 strain, including synergistic protection in association with BP-3. Thus, the constituents in H. Laevifolia and Leucobryum sp. could be good candidates for cosmetic and dermatological applications, particularly in association with synthetic UV filters, since the concentration of the filters in the final product could be reduced. PMID- 29758544 TI - Conduct and reporting of acceptability, attitudes, beliefs and experiences of pregnant women in randomised trials on diet and lifestyle interventions: A systematic review. AB - OBJECTIVE: To evaluate the conduct and reporting of views of pregnant women on the acceptability, attitudes, beliefs and their experiences in randomised trials on diet and lifestyle interventions. STUDY DESIGN: We undertook a systematic review of literature of randomised trials identified from our previous search in major electronic databases (until February 2017) without language restrictions. We included trials on diet and lifestyle interventions that reported acceptability, attitudes, beliefs and experiences of pregnant women. The quality of papers was evaluated using the Critical Skills Appraisal Programme (CASP) framework. Data were extracted for the following domains: acceptability, intention, behaviour, attitudes and factors influencing participation. The proportion of studies that reported the various components in each domain was reported in percentages. RESULTS: Of the 110 trials on diet and lifestyle in pregnancy, 24 reported on views of pregnant women. Acceptability of the provided information to the woman was reported in 84% (20/24), compared to 12% (3/24) on acceptability to partner or to family. Mother's intention to adhere to intervention in pregnancy was reported in 68% (17/24) of studies vs.only 16% (4/24) on family's intentions to support adherence. Changes in mother's behaviour were reported for consuming specific components of diet such as nuts (8%, 2/24), olive oil (12%, 3/24) and fruit (40%, 10/24) vs. 16% (4/24) of trials reporting changes in family's behaviour. While knowledge of food ingredients (72%, 18/24), and attitude to gestational weight gain were commonly reported (66%, 16/24) in over two-thirds of studies, only half assessed attitude to participation in research (45%, 11/24). All studies reported facilitators for uptake of intervention such as personalised support (100%, 24/24), with half (52%, 13/24) on beliefs about weight, and less than 10% (2/24) about baby's health. CONCLUSION: The focus on studies is mainly on the mother, and less on family. Further studies are needed with a holistic approach to ensure that such interventions when implemented are accepted by women and their families. PMID- 29758547 TI - Ultrasound assisted gene and photodynamic synergistic therapy with multifunctional FOXA1-siRNA loaded porphyrin microbubbles for enhancing therapeutic efficacy for breast cancer. AB - To improve the non-invasive therapeutic efficacy for ER positive breast cancer (ER+ BC), we fabricated a multifunctional FOXA1 loaded porphyrin microbubble to combine photodynamic therapy (PDT) and gene therapy of FOXA1 knockdown (KD) with ultrasound targeted microbubble destruction (UTMD) technology under the guidance of contrast enhanced ultrasound (CEUS). Cationic porphyrin microbubbles (CpMBs) were firstly fabricated from a porphyrin grafted lipid with two cationic amino groups (PGL-NH2) and fluorocarbon inert gas of C3F8. Porphyrin group in the CpMBs monolayer could be used as a photosensitizer for PDT, while amino groups could adsorb siRNA through electrostatic interaction for FOXA1 KD, which could inhibit the proliferation of estrogen-dependent ER+ BC. This system showed high photosensitizer and gene loading content. Moreover, CpMBs/siRNA can be converted into nanoparticles with low-frequency pulsed ultrasound (LFUS) exposure, which increase the transfection efficiency of siRNA (~4 fold) and the porphyrin uptake (~8 fold) in MCF-7 (a human breast cancer cell line, ER+) by sonoporation effect. In vivo, UTMD was performed under the guidance of CEUS, and the fluorescence intensity of CpMBs/siRNA at the tumour site reached a peak value at 6 h after injection and it was retained in the following 24 h. Furthermore, there was no tumour recurrence during the observation period (21 days) in the group of PDT combined with FXOA1 KD. Compared to the PDT or FOXA1 KD alone group, the combination of these two methods was much more efficient in inhibiting ER+ breast cancer, showing a good synergistic effect. CpMBs/siRNA combined with UTMD dramatically increased the local accumulation of porphyrin and siRNA through ultrasound-induced sonoporation effect under the guidance of CEUS, showing excellent therapeutic effect for estrogen-dependent ER+ breast cancer. PMID- 29758549 TI - EAFI: Examination of Anomalous Fantasy and Imagination. AB - The Examination of Anomalous Fantasy and Imagination (EAFI) is an instrument for a semistructured, phenomenological exploration of psychopathology of imagination. The EAFI provides a conceptual-descriptive framework to address such experiences. It consists of 16 main items, sometimes divided into subtypes. We suggest that the anomalies of imagination explored by the EAFI reflect an alteration in the structure of consciousness and belong to a fundamental, generative layer of psychopathology with relevance to differential diagnostic purposes. PMID- 29758548 TI - Stromal-Cell-Derived Factor (SDF) 1-Alpha Overexpression Promotes Bone Regeneration by Osteogenesis and Angiogenesis in Osteonecrosis of the Femoral Head. AB - BACKGROUND/AIMS: Osteonecrosis of the femoral head (ONFH) is a devastating orthopedic disease. Previous studies suggested that stromal-cell-derived factor (SDF)-1 was involved in osteogenesis and angiogenesis. However, whether SDF-1 potentiates the angiogenesis and osteogenesis of bone marrow-derived stromal stem cells (BMSCs) in ONFH is not clear. METHODS: BMSCs were transfected with green fluorescent protein (GFP) or the fusion gene encoding GFP and SDF-1alpha, and transgenic efficacy was monitored by immunofluorescence. The expression of SDF 1alpha, runt-related transcription factor 2 (Runx2, osteocalcin (OCN), and alkaline phosphatase (ALP) at the mRNA level was measured by real-time polymerase chain reactions (RT-PCR). The expression of SDF-1alpha, Runx2, OCN, and p-Smad1/5 were measured at the protein level by Western blot. Transwell migration assay and tube formation assay were utilized to detect the angiogenesis in vitro, whereas the in vivo angiogenesis was monitored by angiography. Immunohistological staining and micro-CT scanning were conducted to assess the histological changes in morphology. RESULTS: In vitro, SDF-1alpha overexpression in BMSCs promoted osteogenic differentiation and upregulated the expression of osteogenic-related proteins, such as ALP, Runx2, OCN, and p-Smadl/5. In the methylprednisolone induced ONFH rat model used in our investigation, the overexpression of SDF 1alpha in BMSCs promoted significantly more bone regeneration and the expression of OCN and Runx2 as compared with the effect of vehicle overexpression. Moreover, the morphology of ONFH was ameliorated after the transplantation of BMSCs with SDF-1alpha overexpression. Furthermore, SDF-1alpha overexpression in BMSCs significantly increased osteoblastic angiogenesis as indicated by the increased tube formation ability, CD31 expression, and vessel volume. CONCLUSION: SDF 1alpha overexpression in BMSCs promotes bone generation as indicated by osteogenesis and angiogenesis, suggesting SDF-1alpha may serve as a therapeutic drug target for ONFH treatment. PMID- 29758550 TI - MicroRNA-449a Inhibition Protects H9C2 Cells Against Hypoxia/Reoxygenation Induced Injury by Targeting the Notch-1 Signaling Pathway. AB - BACKGROUND/AIMS: The present study aimed to detect the expression of miR-449a and investigate the effect of miR-449a on cell injury in cardiomyocytes subjected to hypoxia/ reoxygenation (H/R) and its underlying mechanisms. METHODS: The expression of miR-449a was determined using reverse transcription-polymerase chain reaction in both neonatal rat ventricular myocytes and H9C2 cells. For gain of-function and loss-of-function studies, H9C2 cells were transfected with either miR-449a mimics or miR-449a inhibitor. The target gene of miR-449a was confirmed by a dual-luciferase reporter assay. Apoptosis was analyzed by both flow cytometry using Annexin V and propidium iodide and transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL). Necrosis was confirmed by the detection of lactate dehydrogenase release. The cell viability was measured using the methylthiotetrazole method. The protein levels of Notch-1, Notch-1 intracellular domain, hairy and enhancer of split-1 (Hes-1), and apoptosis-related genes were measured by Western blot analysis. RESULTS: MiR-449a was significantly upregulated in both neonatal rat ventricular myocytes and H9C2 cells subjected to H/R. However, H/R-induced cell apoptosis and necrosis were markedly reduced by miR-449a inhibition. By targeting Notch-1, miR-449a regulated the Notch-1/ Hes-1 signaling pathway. The blockade of the Notch signaling pathway partly abolished the protective effect of miR-449a suppression against H/R injury, whereas the overexpression of Notch-1 intracellular domain partly reversed the effect of miR-449a overexpression on H/R-induced cell injury. CONCLUSIONS: The present study suggested that miR-449a inhibition protected H9C2 cells against H/R-induced cell injury by targeting the Notch-1 signaling pathway, providing a novel insight into the molecular basis of myocardial ischemia reperfusion injury and a potential therapeutic target. PMID- 29758551 TI - Individual Negative Affective Trajectories Can Be Detected during Different Depressive Relapse Prevention Strategies. PMID- 29758552 TI - Downregulation of S100A4 Alleviates Cardiac Fibrosis via Wnt/beta -Catenin Pathway in Mice. AB - BACKGROUND/AIMS: Cardiac fibrosis is a pathological change leading to cardiac remodeling during the progression of myocardial ischemic diseases, and its therapeutic strategy remains to be explored. S100A4, a calcium-binding protein, participates in fibrotic diseases with an unclear mechanism. This study aimed to investigate the role of S100A4 in cardiac fibrosis. METHODS: Cardiac fibroblasts from neonatal C57BL/6 mouse hearts were isolated and cultured. Myocardial infarction was induced by ligating the left anterior descending coronary artery (LAD). The ligation was not performed in the sham group. A volume of 5*105pfu/g adenovirus or 5 uM/g ICG-001 was intramyocardially injected into five parts bordering the infarction zone or normal region. We used Western blotting, quantitative RT-PCR, immunofluorescence, immunohistochemistry and Masson's trichrome staining to explore the function of S100A4. RESULTS: We found significant increases of S100A4 level and cardiac fibrosis markers, and beta catenin signaling activation in vitro and in vivo. In addition, knockdown of S100A4 significantly reduced cardiac fibrosis and beta-catenin levels. Moreover, the expression of S100A4 decreased after ICG-001 inhibited beta-catenin signal pathway. CONCLUSION: Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/beta -catenin pathway in mice. S100A4 may be a therapeutic target of cardiac fibrosis. PMID- 29758554 TI - Psychosocial Distress in Bladder Cancer Stratified by Gender, Age, Treatment, and Tumour Stage. AB - OBJECTIVES: Cancer patients have to cope with anxieties -concerning their prognosis, potential recurrence/progression, and treatment-associated sequelae. Stress-related psychosocial factors influence survival and disease-related mortality in cancer patients. Despite improvements in diagnosis and treatment, bladder cancer (BC) remains characterized by high rates of recurrence and progression. We screened -pre-therapeutically the stress level of BC patients stratified by gender, disease state, treatment, and other factors by -self administered validated questionnaires to integrate them into psychosocial support as needed. METHODS: A cross-sectional analysis of distress and need of psychosocial care was done in 301 patients undergoing treatment for BC by 2 questionnaires (Distress Thermometer [DT] and Hornheider Screening Instrument). RESULTS: Of the 301 patients, 230 patients underwent transurethral resection for a first -diagnosis, 63 for recurrent disease, 37 had progressive disease, and 25 had advanced metastatic disease and eventually died of BC. The mean stress level in all patients was 4.6. Twenty-eight percent of the patients expressed a need for psychosocial support. In patients with progressive disease, significantly higher stress scores were seen as well as a higher need of psychosocial care (5.4 and 41%). CONCLUSIONS: The median DT-level of 4.6 indicates moderate psychosocial stress in BC patients. From a stress level of 5, the recommendations of a psycho oncological supervision are pronounced, so that our study showed that early systematic evaluation of psychosocial needs in BC patients is important. PMID- 29758553 TI - A Retrospective Cohort Study on Patients with Hidradenitis Suppurativa. AB - BACKGROUND: Hidradenitis suppurativa (HS) is one of the most distressing conditions observed in dermatology and has a substantial negative effect on the quality of life of affected persons. OBJECTIVES: The aim of this study was to evaluate different treatment strategies in patients with HS. METHODS: In a retrospective cohort, all patients with HS (July 2015 to March 2017) were reviewed. Collected data consisted of patients' demographics, clinical characteristics, psychosocial situation, and previous and current treatments. In addition, therapy response to the most recent prescribed treatments was assessed. RESULTS: 102 patients (38 females, 64 males; median age 37.5 years) were included in this study. 68.4% of patients had BMI >=25, and 76.5% of patients were current smokers. Hurley stages I, II, and III were detected in 13.5, 53.1, and 33.3% of patients, respectively. The most commonly administered treatments were surgery (67.6%), nonantibiotic topical therapies (72.5%), antibiotic topical therapies (55.9%), systemic antibiotics (88.2%), and biologics in 11.8% of the patients. 84.6% of the patients showed a response (27.5 and 47.1% partial and complete response, respectively) to the treatments. CONCLUSION: HS as a chronic, recurrent inflammatory skin disease is associated with smoking and obesity. Application of systemic antibiotics is the most frequent treatment strategy for this disease. However, surgical intervention seems to be the most effective treatment strategy. PMID- 29758555 TI - Secondary Prevention Three and Six Years after Stroke Using the French National Insurance Healthcare System Database. AB - BACKGROUND: Secondary prevention is inadequate in the first 2 years after stroke but what happens after that is less documented. The aim of this study was to assess the use and the adherence to preventive drugs 3 and 6 years after experiencing a transient ischemic attack (TIA) or an ischemic stroke (IS). METHODS: The population study was from the AVC69 cohort (IS or TIA admitted in an emergency or stroke unit in the Rhone area, France, for an IS or a TIA during a 7 month period). Medication use was defined as >=1 purchase during the studied year and adherence as Continuous Measure of Medication Acquisition >=0.8 using the French medical insurance health care funding database. RESULTS: The study population consisted of 210 patients at 3 years and 163 patients at 6 years. Medication use at 3 and 6 years was, respectively, 80.9 and 79.8% for antithrombotics, 69.1 and 66.3% for antihypertensives, 60.5 and 55.2% for statins and 48.6 and 46.6% for optimal treatment defined as the treatment achieved by the use of the 3 drugs. Adherence to each class was good at 3 years and tends to decrease at 6 years. CONCLUSIONS: More than one patient out of 2 do not use the optimal preventive treatment. PMID- 29758556 TI - Passive Hydrotherapy WATSU(r) for Rehabilitation of an Accident Survivor: A Prospective Case Report. AB - BACKGROUND: WaterShiatsu (WATSU) is a passive form of hydrotherapy in warm water (35 degrees C) that aims at relaxation, pain relief, and a sense of security. This case report focuses on a patient's experience of integrating WATSU into her rehabilitative care. CASE REPORT: A 52-year-old woman survived a severe motorcycle accident in which she sustained several fractures on the right side of her body, including ribs, the pelvis, and the femur. After discharge from stationary care, she independently scheduled 8 weekly WATSU sessions with an experienced WATSU therapist also trained in physiotherapy and psychosomatics. Quantitative and qualitative data obtained from the patient's diary and the therapist's notes is presented. RESULTS: The patient associated WATSU with physical and emotional release, reconciliation with her body, and trunk mobilization (followed by ameliorated breath). She ascribed WATSU lasting effects on her body image and reported continuous improvement by the Patient-Specific Functional Scale. The therapist employed WATSU to equalize awareness throughout the body and for careful mobilization. Due to complications (elevated inflammation markers), only 6 of 8 scheduled sessions were administered. CONCLUSIONS: WATSU was experienced as helpful in approaching a condition that the patient felt insufficiently covered by conventional physiotherapy alone. In early rehabilitation, additional medical/physiotherapeutic skills of contributing complementary therapists are advocated. PMID- 29758557 TI - A Phenomenological Approach to Psychopathology of Imagination: Development of a Descriptive Instrument - Examination of Anomalous Fantasy and Imagination. AB - This paper serves as an introduction to the Examination of Anomalous Fantasy and Imagination (EAFI) - a novel instrument for a semistructured, phenomenological exploration of psychopathology of imagination. We present an account of the phenomenology of imagination and proceed to a presentation of the disorders of imagination that are addressed in the EAFI. Furthermore, the interrater reliability of the EAFI was examined in a diagnostically heterogeneous sample of 20 in-patients. The interrater agreement ranged from 0.6 to 1.0, with an average kappa of 0.84. The internal consistency of the EAFI as measured by Cronbach's alpha was above 0.88. We suggest that the anomalies of imagination explored by the EAFI reflect an alteration of the structure of consciousness and belong to a fundamental, generative layer of psychopathology. These disorders may have relevance for differential diagnostic purposes, especially in first-contact, young patients. PMID- 29758558 TI - Mild Cognitive Impairment and Dementia Show Contrasting Associations with Risk of Cancer. AB - BACKGROUND: To investigate and to compare the relation between dementia and cancer with the association between mild cognitive impairment (MCI) and cancer. METHODS: A total of 13,207 persons from the Rotterdam Study were followed between 1990 and 2013 for the onset of dementia and cancer (sample 1). Between 2002 and 2005, a subset of 5,181 persons underwent extensive cognitive testing for MCI and subsequently were followed up for cancer until 2013 (sample 2). We used Cox proportional hazard models to determine the association between dementia and cancer, and MCI and cancer. RESULTS: In sample 1, 1,404 patients were diagnosed with dementia, and 2,316 developed cancer (63 among dementia cases). Dementia was associated with a decreased risk of cancer (hazard ratio [HR] 0.53; 95% CI 0.41 0.68). In sample 2, 513 persons were diagnosed with MCI and 670 persons developed cancer (81 among MCI cases). In contrast to individuals with dementia, those with MCI tended to have an increased risk of cancer (HR 1.25; 95% CI 0.99-1.58). CONCLUSIONS: We found that persons with MCI tended to have an increased risk of cancer, whereas those with dementia have a decreased risk. These findings call into question a biological explanation for the inverse link between dementia and cancer, thereby suggesting the presence of methodological bias. PMID- 29758559 TI - CircRNA-0004904, CircRNA-0001855, and PAPP-A: Potential Novel Biomarkers for the Prediction of Preeclampsia. AB - BACKGROUND/AIMS: Circular RNAs (circRNAs) are transcribed prevalently in the genome; however, their potential roles in multiple cardiovascular diseases, particularly preeclampsia (PE), are not yet well understood. This study investigated the expression profiles of circRNAs and explored circRNA-mediated pregnancy-associated plasma protein A (PAPP-A) expression as a potential biomarker for PE before 20 weeks of pregnancy. METHODS: A nested case-control two phase screening/validation study was performed in pregnant women before 20 weeks of gestation (before clinical diagnosis) at Guangzhou Women and Children's Medical Center from 2012 to 2015. In the screening phase, circRNA expression profiles of blood cells were assessed using a human circRNA microarray, which was designed to detect simultaneously 5396 circRNAs, in 5 patients with PE and 5 age- and gestational week-matched controls. In the validation phase, 18 circRNAs in blood cells predicted by bioinformatics tools were validated by quantitative reverse transcription PCR in a cohort of 60 patients (PE and age-, gestational week-, and sample storage time-matched controls). Then, we examined the involvement of circRNAs in PE-related pathways via interactions with miRNAs by multiple bioinformatics approaches. Bioinformatics analysis predicted that hsa_circ_0004904 and hsa_circ_0001855 miRNA sponges directly target PAPP-A. PAPP A was verified in the serum of the same cohort of patients using an enzyme-linked immunosorbent assay. Finally, we combined PAPP-A with circRNAs to create a novel preclinical diagnostic model for PE with logistic regression and evaluated the efficiency of this model with receiver operating curve analysis. RESULTS: Volcano plot analysis using various parameters showed that circRNAs were differentially expressed among both groups (P < 0.01, fold change > 2). In the screening phase, we found that 2178 circRNAs were differentially expressed between the control and PE groups, in which 884 circRNAs were downregulated and 1294 circRNAs were upregulated in the PE group compared with the control group. In the validation phase, two circRNAs, hsa_circ_0004904 and hsa_circ_0001855, were significantly upregulated in PE patients compared with healthy pregnant women (P < 0.05). PAPP A expression levels, related to the two circRNAs based on bioinformatics prediction, were increased in the PE group compared with the control group. The area under the curve of the combined model was 0.94 in the predicted PE subjects. CONCLUSIONS: This is the first study to report circRNA profiling in patients with PE prior to the onset of symptoms. Our data suggested that hsa_circ_0004904 and hsa_circ_0001855 combined with PAPP-A might be promising biomarkers for the detection of PE. Moreover, circRNAs may provide new insights into the potential mechanisms underlying the pathophysiology of PE. PMID- 29758560 TI - Prospective Randomized Trial Comparing Embryo Transfers of Cases with and without Catheter Rotation during Its Withdrawal. AB - OBJECTIVE: To compare embryo transfer (ET) technique based on catheter rotation during its withdrawal in cases with unexplained infertility in a prospective, randomized trial (NCT03097042). METHODS: Two hundred intracytoplasmic sperm injection (ICSI) patients undergoing ET with cleaving or blastocyst-stage fresh embryos were randomized into 2 groups: cases with (n = 100), and without (n = 100) catheter rotation during its withdrawal. Groups were matched for age and some clinical parameters. A soft catheter was used to transfer a single embryo with catheter rotation during its withdrawal in the study group and without rotation in the control. The use of a stiff catheter or tenaculum was not needed in any case. Groups were compared in terms of cycle characteristics and clinical pregnancy rates. RESULTS: Pregnancy rate was significantly higher in the study group (41 vs. 26%, p = 0.04). Clinical pregnancy rate was also significantly higher in the study group (39 vs. 25%, OR 1.9 [1.1-3.5], p = 0.05). On the other hand, the ongoing pregnancy rate was similar between the 2 groups (33 vs. 23%, p = 0.2). CONCLUSION: Catheter rotation during its withdrawal may be associated with increased pregnancy and clinical pregnancy rates; however, the difference in ongoing pregnancy rates did not reach statistical significance. PMID- 29758561 TI - Surgical Outcome and Hepatic Regeneration after Hepatic Resection for Hepatocellular Carcinoma in Elderly Patients. AB - INTRODUCTION: The rising proportion of elderly patients (aged 80 yearsor above) in our population means that more elderly patients are undergoing hepatectomy. METHODS: Five-hundred and thirty patients who underwent hepatectomy for hepatocellular carcinoma (HCC) were retrospectively analyzed with respect to their preoperative status and perioperative results, including remnant liver regeneration. The remnant liver volume was postoperatively measured with multidetector CT on postoperative day 7 and 1, 2, 5, and 12 months after surgery. An elderly group (aged 80 or older) was compared with a non-elderly group (aged less than 80 years). RESULTS: Underlying diseases of the cardiovascular system were significantly more common in the elderly group (57.8%, p = 0.0008). The postoperative incidence of Clavien-Dindo Grade IIIa or higher complications was 20.0% in the elderly group and 24.3% in the non-elderly group, and this difference was not significant. As for regeneration of the remnant liver after resection, this was not morphologically delayed compared to the non-elderly group. CONCLUSIONS: In this study, we have demonstrated that safe, radical hepatectomy, similar to procedures performed on non-elderly patients, can be performed on patients with HCC aged 80 and older with sufficient perioperative care. PMID- 29758562 TI - Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. AB - PurposeShort stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity.MethodsWe systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth.ResultsBy standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases.ConclusionA combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature. PMID- 29758567 TI - Synthesis and in vitro Evaluation of 2-heteroarylidene-1-tetralone Derivatives as Monoamine Oxidase Inhibitors. AB - The present study investigates the human monoamine oxidase (MAO) inhibition properties of a series of twelve 2-heteroarylidene-1-tetralone derivatives. Also included are related cyclohexylmethylidene, cyclopentylmethylidene and benzylidene substituted 1-tetralones. These compounds are related to the 2 benzylidene-1-indanone class of compounds which has previously been shown to inhibit the MAOs, with specificity for the MAO-B isoform. The target compounds were synthesised by the Claisen-Schmidt condensation between 7-methoxy-1 tetralone or 1-tetralone, and various aldehydes, under acid (hydrochloric acid) or base (potassium hydroxide) catalysis. The results of the MAO inhibition studies showed that the 2-heteroarylidene-1-tetralone and related derivatives are in most instances more selective inhibitors of the MAO-B isoform compared to MAO A. (2E)-2-Benzylidene-7-methoxy-3,4-dihydronaphthalen-1(2 H)-one (IC50=0.707 MUM) was found to be the most potent MAO-B inhibitor, while the most potent MAO-A inhibitor was (2E)-2-[(2-chloropyridin-3-yl)methylidene]-7-methoxy-3,4 dihydronaphthalen-1(2 H)-one (IC50=1.37 MUM). The effect of the heteroaromatic substituent on MAO-B inhibition activity, in decreasing order was found to be: cyclohexyl, phenyl>thiophene>pyridine, furane, pyrrole, cyclopentyl. This study concludes that, although some 2-heteroarylidene-1-tetralone derivatives are good potency MAO inhibitors, in general their inhibition potencies, particularly for MAO-B, are lower than structurally related chalcones and 1-indanone derivatives that were previously studied. PMID- 29758566 TI - Long-term Results for the BacJac Interspinous Device in Lumbar Spine Degenerative Disease. AB - OBJECTIVE: To evaluate the long-term results of using the BacJac interspinous device (Pioneer Surgical Technology Inc.) in a series of patients with degenerative lumbar spine disease. METHODS: Forty-one patients undergoing lumbar surgery with implantation of a BacJac device from 2009 to 2012 were enrolled in the present study. Patients were evaluated using the Oswestry Disability Scale (ODI). RESULTS: Although all patients showed a significant improvement of the ODI score immediately after surgery, only 41% of patients showed a satisfactory outcome. We observed worse results in the patients operated on at the L3-L4 level and in whom the device was implanted in a segment different from the one where surgical decompression had been performed. Weight gain in the months after surgery was also a poor outcome-influencing factor. CONCLUSIONS: This study confirms what is already suggested in the relevant literature regarding the long term inefficacy of the so-called dynamic stabilization devices. PMID- 29758563 TI - Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. AB - PurposeTo determine feasibility and utility of newborn screening for spinal muscular atrophy (SMA) in New York State.MethodsWe validated a multiplex TaqMan real-time quantitative polymerase chain reaction assay using dried blood spots for SMA. From January 2016 to January 2017, we offered, consented, and screened 3,826 newborns at three hospitals in New York City and tested newborns for the deletion in exon 7 of SMN1.ResultsNinety-three percent of parents opted in for SMA screening. Overall the SMA carrier frequency was 1.5%. We identified one newborn with a homozygous SMN1 deletion and two copies of SMN2, which strongly suggests the severe type 1 SMA phenotype. The infant was enrolled in the NURTURE clinical trial and was first treated with Spinraza at age 15 days. She is now age 12 months, meeting all developmental milestones, and free of any respiratory issues.ConclusionOur pilot study demonstrates the feasibility of population-based screening, the acceptance by families, and the benefit of newborn screening for SMA. We suggest that SMA be considered for addition to the national recommended uniform screening panel. PMID- 29758564 TI - Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. AB - PurposeMonogenic diabetes accounts for 1-2% of diabetes cases. It is often undiagnosed, which may lead to inappropriate treatment. This study was performed to estimate the prevalence of monogenic diabetes in a cohort of overweight/obese adolescents diagnosed with type 2 diabetes (T2D).MethodsSequencing using a custom monogenic diabetes gene panel was performed on a racially/ethnically diverse cohort of 488 overweight/obese adolescents with T2D in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. Associations between having a monogenic diabetes variant and clinical characteristics and time to treatment failure were analyzed.ResultsMore than 4% (22/488) had genetic variants causing monogenic diabetes (seven GCK, seven HNF4A, five HNF1A, two INS, and one KLF11). Patients with monogenic diabetes had a statistically, but not clinically, significant lower body mass index (BMI) z-score, lower fasting insulin, and higher fasting glucose. Most (6/7) patients with HNF4A variants rapidly failed TODAY treatment across study arms (hazard ratio = 5.03, P = 0.0002), while none with GCK variants failed treatment.ConclusionThe finding of 4.5% of patients with monogenic diabetes in an overweight/obese cohort of children and adolescents with T2D suggests that monogenic diabetes diagnosis should be considered in children and adolescents without diabetes-associated autoantibodies and maintained C-peptide, regardless of BMI, as it may direct appropriate clinical management. PMID- 29758568 TI - Social Media in Shoulder & Elbow Surgery: An Analysis of Twitter and Instagram. AB - Social media provide a unique method of analyzing outcomes and quality in medicine. The purpose of this observational study was to investigate the nature of social media content related to shoulder and elbow (S&E) surgery posted by patients, surgeons, and hospitals. A public search of Instagram for a two-year period yielded 1,177 patient-related posts. A categorical system assessed the perspective, timing, tone, and content of each post. Twitter accounts of 77 S&E specialists from the top five ranked U.S. News & World Report institutions were analyzed for activity and content. 5,246 Twitter and Instagram posts for the institutions were analyzed for frequency and content. Most patient-related posts were by patients (68%), postoperative (82%), positive (87%), and centered on return-to-play for Tommy John (34%), surgical site for shoulder arthroplasty (52%), and activities of daily living for rotator cuff repair (22%). 37% of surgeons had active accounts averaging 46 posts, 87% of which were practice advertisements. Hospitals averaged 273 posts over the 2-year period, focusing on education (38%) and community (18%). S&E patients share outcomes on social media in a positive tone with procedure-dependent emphases. Surgeons on social media use sites for practice augmentation. Hospitals often focused posts towards educating the community. PMID- 29758565 TI - Clinical and genetic analysis of a rare syndrome associated with neoteny. AB - PurposeWe describe a novel syndrome in seven female patients with extreme developmental delay and neoteny.MethodsAll patients in this study were female, aged 4 to 23 years, were well below the fifth percentile in height and weight, had failed to develop sexually, and lacked the use of language. Karyotype and array chromosome genomic hybridization analysis failed to identify large-scale structural variations. To further understand the underlying cause of disease in these patients, whole-genome sequencing was performed.ResultsIn five patients, coding de novo mutations (DNMs) were found in five different genes. These genes fell into similar functional categories of transcription regulation and chromatin modification. Comparison to a control population suggested that individuals with neotenic complex syndrome (NCS)-a name that we propose herein-could have an excess of rare inherited variants in genes associated with developmental delay and autism, although the difference was not significant.ConclusionWe describe an extreme form of developmental delay, with the defining characteristic of neoteny. In most patients we identified coding DNMs in a set of genes intolerant of haploinsufficiency; however, it is not clear whether these contributed to NCS. Rare inherited variants may also be associated with NCS, but more samples need to be analyzed to achieve statistical significance. PMID- 29758569 TI - Relation Between Iliopsoas Cross-sectional Area and Kicked Ball Speed in Soccer Players. AB - This study aimed to investigate the relationship between the maximal anatomical cross-sectional area (ACSA) of the iliopsoas muscle and ball speed in side-foot and instep kicks. The ACSA of the psoas major and iliacus was measured in 29 male collegiate soccer players by using magnetic resonance imaging. They performed maximal side-foot and instep kicks to a stationary ball. The kicked ball speed was measured with a high-speed camera. Ball speed in the side-foot and instep kicks was significantly correlated with body height (side-foot kick: r=0.650, P<0.001; instep kick: r=0.583, P<0.001). After adjustment for body height, the maximal ACSA of the psoas major was significantly correlated with ball speed in the side-foot kick (r=0.441, P=0.017), but not in the instep kick. The maximal ACSA of the iliacus was not correlated with ball speed in side-foot or instep kicks, even after adjustment for body height. Our results suggest that: 1) body height is a significant determinant of the ball speed in side-foot and instep kicks, and 2) for a given body height, the maximal ACSA of the dominant psoas major is a factor that affects the ball speed in side-foot kick. PMID- 29758570 TI - Acute Hip Abduction Fatigue on Lumbopelvic-Hip Complex Stability in Softball Players. AB - During an overhead throw, the gluteal muscle group stabilizes the lumbopelvic-hip complex (LPHC), leading to efficient energy transfer from the lower to upper extremity. It has been shown that LPHC instability can lead to throwing pathomechanics. The single leg squat has become a common assessment for LPHC stability, and could be used to determine the effects of fatigue on throwing athletes. The purpose of this study was to determine the effects of an acute abduction fatigue protocol on the LPHC of collegiate softball players via the single leg squat assessment of the leg ipsilateral to the throwing arm. Eighteen National Collegiate Athletic Association Division I softball players volunteered (20.5+/-1.9 years; 169.4+/-10.0 cm; 72.9+/-11.5 kg). Each participant performed a single leg squat on the leg ipsilateral to the throwing arm prior to and post side-lying hip abduction fatigue. LPHC and lower extremity kinematics were examined to determine potential effects of fatigue on LPHC stability. There were no significant main effects or interactions of LPHC or lower extremity kinematics during the single leg squat assessments across the fatigue protocol. Based on the current study, an acute bout of fatigue to the hip abductors does not affect LPHC stability in single leg squat execution. PMID- 29758571 TI - Effects of a 20-Min Nap Post Normal and Jet Lag Conditions on P300 Components in Athletes. AB - Post-lunch sleepiness belongs to biological rhythms. Athletes take a nap to counteract afternoon circadian nadir, in prevision of disturbed sleep. This study examined the effects of brief post-lunch nap on vigilance in young and healthy athletes. The P300 components, physiological and cognitive performances were assessed either after nap or rest, following a night of normal sleep (NSC) or simulated jet lag condition (5-h advance-JLC). P300 wave is the positive deflection at about 300 ms in response to a rare stimulus, representing higher information processing. P300 amplitude reflects the amount of attention allocated whereas P300 latency reflects time spent on stimulus classification. P300 amplitude was significantly increased (Fz:11.14+/-3.0vs9.05+/-3.2 uV; p<0.05) and P300 latency was shorter (Pz:327.16+/-18.0vs344.90+/-17.0 ms; p<0.01) after nap in NSC. These changes were accompanied by lower subjective sleepiness (19.7+/ 9.6vs27.5+/-16.5; p<0.05) and decrease in mean reaction times (MRT: divided attention, 645.1+/-74.2vs698+/-80.4 ms; p<0.05). In contrast, in JLC, only P300 amplitudes (Fz:10.30+/-3.1vs7.54+/-3.3 uV; p<0.01 and Cz: 11.48+/-3.1vs9.77+/-3.6 uV; p<0.05) increased but P300 latencies or MRT did not improve. These results indicated improvements in speed of stimulus evaluation time. Napping positively impacts on cognitive processing, especially when subjects are on normal sleep schedules. A nap should be planned for athletes whose performance requires speedy and accurate decisions. PMID- 29758572 TI - [Telephone Counseling for Pathological Gamblers as Immediate Access to the Health Care System: Acceptance and Use of The Mainzer Behavioral Addiction Helpline]. AB - OBJECTIVE: Despite extensive psychosocial consequences, just a small number of pathological gamblers participates in counseling or treatment. Telephone helplines should facilitate pathological gamblers' access to the health care system. There is a lack of research on the use and the effects of such facilities in Germany. The present research focuses on the question whether telephone helplines facilitate pathological gamblers' access to the health care system. METHOD: All first time calls due to a gambling problem received by the behavioral addiction helpline of the University Medical Center Mainz between 2013 and 2016 were analyzed by SPSS. RESULTS: Of the 773 calls analyzed, 89% were from male gamblers. 79.7% reported gambling in slot machine arcades as the primary problem. 66.6% received a referral for a diagnostic in-person assessment at the outpatient clinic for behavioral addiction of the University Medical Center Mainz. 80.4% made an appointment, of which 81.3% were kept. Men were more likely to keep the appointment. Only a few callers had found out about the behavioral addiction helpline by gambling providers. CONCLUSIONS: Telephone helplines facilitate pathological gamblers' access to the health care system.There is a deficit in the propagation of such an offer by gambling providers. Telephone helplines should be communicated more actively to problem gamblers in all gambling venues. PMID- 29758573 TI - [Assessment of Coding in German Diagnosis Related Groups System in Otorhinolaryngology]. AB - BACKGROUND: Prospective analysis of assessment reports in otorhinolaryngology for the period 01-03-2011 to 31-03-2017 by the Health Advisory Boards in Lower Saxony and Bremen, Germany in relation to coding in the G-DRG-System. MATERIAL AND METHODS: The assessment reports were documented using a standardized database system developed on the basis of the electronic data exchange (DTA) by the Health Advisory Board in Lower Saxony. In addition, the documentation of the assessment reports according to the G-DRG system was used for assessment. Furthermore, the assessment of a case was evaluated once again on the basis of the present assessment documents and presented as an example in detail. RESULTS: During the period from 01-03-2011 to 31-03-2017, a total of 27,424 cases of inpatient assessments of DRGs according to the G-DRG system were collected in the field of otorhinolaryngology. In 7,259 cases, the DRG was changed, and in 20,175 cases, the suspicion of a DRG-relevant coding error was not justified in the review; thus, a DRG change rate of 26% of the assessments was identified over the time period investigated. CONCLUSIONS: There were different kinds of coding errors. In order to improve the coding quality in otorhinolaryngology, in addition to the special consideration of the presented "hit list" by the otorhinolaryngology departments, there should be more intensive cooperation between hospitals and the Health Advisory Boards of the federal states. PMID- 29758574 TI - [Relationship Between The Use of Psychosomatic Rehabilitation and Regional Capacities for Medical and Psychotherapeutic Treatment of Mental Disorders in Westphalia]. AB - BACKGROUND: Regional disparities in mental health care are well known and become apparent in inadequate treatment capacities and long waiting time for psychotherapeutic treatment. Hence, the authors assume that there is a shift from curative to rehabilitative care. Accordingly, the purpose of this study was to analyze the relationship between regional treatment capacities and the use of psychosomatic rehabilitation on behalf of the German Statutory Pension Insurance Westphalia (i. e. DRV Westfalen) in 2013. METHODS: Regional data on medical and psychotherapeutic care within the purview of DRV Westfalen were drawn from public databases. Data on application and approval processes in psychosomatic rehabilitation as well as data on demographic and insurance-related traits, such as periods of insurance, were provided by DRV Westfalen for 2013. Logistic 2 level models were conducted. RESULTS: Regional data showed that poor medical care was associated with a significantly higher chance of applying for rehabilitation. The demographic and insurance-related traits of the applicants were significantly related both with the application for and approval of psychosomatic rehabilitation. Persons with a discontinuous work biography in 2013 had a higher chance for application for and approval of psychosomatic rehabilitation. No significant correlation of regional treatment capacities and the approval of applications for psychosomatic rehabilitation could be found. CONCLUSION: The results show that decisions on applications for psychosomatic rehabilitation basically depend on the personal health situation of the applicants. An increased application and approval rate in areas with poor medical care can be interpreted as compensatory means which indicate a need for improvement in regional care of mental disorders. PMID- 29758575 TI - [Descriptive Analysis of Health Economics of Intensive Home Care of Ventilated Patients]. AB - INTRODUCTION: Long-term ventilated patients in Germany receive intensive care mainly in the patients' home or in assisted-living facilities. There is a lack of knowledge about the nature and extent of resource use and costs associated with care of this small, heterogeneous but overall growing patient group. METHODS: A sub-study in the context of a research project SHAPE analyzed costs of 29 patients descriptively from a social perspective. Direct and indirect costs of intensive home care over a period of three months were recorded and analyzed retrospectively. Standardized recorded written self-reports from patients and relatives as well as information from the interviewing of nursing staff and from nursing documentation were the basis for this analysis. RESULTS: There was an average total cost of intensive home care for three months per patient of 61194 ? (95% CI 53 884-68 504) including hospital stays. The main costs were directly linked to outpatient medical and nursing care provided according to the Code of Social Law V and XI. Services provided by nursing home care service according to S 37(2) Code of Social Law V (65%) were the largest cost item. Approximately 13% of the total costs were attributable to indirect costs. CONCLUSIONS: Intensive home care for ventilated patients is resource-intensive and cost-intensive and has received little attention also from a health economics perspective. Valid information and transparency about the cost structures are required for an effective and economic design and management of the long-term care of this patient group. PMID- 29758576 TI - [Mental Health Stigma: An Influencing Factor in Healthcare Utilization by Veterans of the German Armed Forces]. AB - THEORETICAL BACKGROUND AND OBJECTIVE OF THE STUDY: Mental illness stigma is a barrier to healthcare utilization. This study is the first to research the connection between mental illness stigma and the use of healthcare by veterans of the German Armed Forces. An overview of perceived stigma components in this sample is provided that should help understand how these factors influence healthcare utilization. METHODS: 43 interviews with veterans of the German Armed Forces were conducted. The resulting data were analyzed in several coding steps. It was investigated whether the stigma experience of veterans of the German Armed Forces could be well illustrated by the theory-based stigmatization model of Link and Phelan. A set of hypotheses on stigma and healthcare utilization based on the data were developed. RESULTS: All stigma components according to the model of Link and Phelan were found in the sample. Internalized stigma, perceived public stigmatization, vocational disadvantage and social exclusion as well as feared misunderstanding of the military past in the civilian sector were reported as main stigma-relevant barriers to the use of healthcare. CONCLUSIONS: Recommendations for interventions are given to decrease mental illness stigma in this specific group of former soldiers. PMID- 29758577 TI - [Structure Parameters and Quality Outcomes of Ambulant Home-care]. AB - INTRODUCTION: So far, there are few data available on the changes of ambulant home-care in Germany over the last decades. Therefore, the aim of this research was to provide structure data on nursing personnel, funding, size, regional differences, and training needs of ambulant home-care services in Germany. In addition, a possible association between structure parameters and quality outcomes for pressure ulcer and malnutrition was investigated. METHODS: In 2015, a multicenter cross-sectional study was conducted in home-care services in Germany. Structure data from 99 randomly selected home-care services as well as data on pressure ulcers and malnutrition of 903 care-dependent clients were analyzed. The median (<98 clients) was used as a cut-off to differentiate between small and large home-care services. From a cut-off of 20,000 inhabitants, a region was considered urban. The average prevalence for decubitus and malnutrition (BMI<20 Kg/m2) were determined for each home-care service, and possible associations with structure parameters were analyzed using a multiple linear regression model. RESULTS: The proportion of registered nurses in non private (private) home-care services was 60.6% (52.3%). The proportion of employees with a 200- h basic qualification in nursing was higher in private (12.5 vs. 4.7%), small home-care services (14.0 vs. 5.8%) and in urban regions (11.5 vs 5.7%). In average, registered nurses working in small home-care services spent significantly more time per client than the ones working in large services (3.8 vs. 2.9 h/week). The highest need for further training was shown on the subjects of pain, medication and cognitive impairment. No statistically significant correlation could be found between the average decubitus prevalence and structure parameters. Only the association between malnutrition prevalence and the proportion of registered nurses was statistically significant. CONCLUSION: The present representative study provides structure data on nursing personnel, funding, size, regional differences, and training needs of ambulant home-care services in Germany that could be used as a baseline for further investigations. No statistically significant association could be found between structure and outcome quality parameters. There is a need for further training of nursing personnel on the subjects of medication, pain and cognitive impairment. PMID- 29758579 TI - [Simultaneous Cutaneous and Laryngeal Cryptococcosis]. PMID- 29758581 TI - [Managment of acute low back pain without trauma - an algorithm]. AB - BACKGROUND: Low back pain is a common problem for primary care providers, outpatient clinics and A&E departments. The predominant symptoms are those of so called "unspecific back pain", but serious pathologies can be concealed by the clinical signs. Especially less experienced colleagues have problems in treating these patients, as - despite the multitude of recommendations and guidelines - there is no generally accepted algorithm. METHODS: After a literature search (Medline/Cochrane), 158 articles were selected from 15,000 papers and classified according to their level of evidence. These were attuned to the clinical guidelines of the orthopaedic and pain-physician associations in Europe, North America and overseas and the experience of specialists at LMU Munich, in order to achieve consistency with literature recommendations, as well as feasibility in everyday clinical work and optimised with practical relevance. RESULTS: An algorithm was formed to provide the crucial differential diagnosis of lumbar back pain according to its clinical relevance and to provide a plan of action offering reasonable diagnostic and therapeutic steps. As a consequence of distinct binary decisions, low back patients should be treated at any given time according to the guidelines, with emergencies detected, unnecessary diagnostic testing and interventions averted and reasonable treatment initiated pursuant to the underlying pathology. CONCLUSION: In the context of the available evidence, a clinical algorithm has been developed that translates the complex diagnostic testing of acute low back pain into a transparent, structured and systematic guideline. PMID- 29758583 TI - Gender role conflict, emotional approach coping, self-compassion, and distress in prostate cancer patients: A model of direct and moderating effects. AB - OBJECTIVE: Gender role conflict or the negative consequences of male socialization may compromise men's adjustment to prostate cancer by shaping how patients perceive and cope with their illness. Given mixed findings regarding how gender role conflict interacts with emotional approach coping to regulate distress in prostate cancer patients, the present study examined the effects of emotional approach coping, when considered alongside self-compassion, the ability to be kind and understanding of oneself. METHOD: Ninety-two prostate cancer patients completed questionnaires measuring gender role conflict, emotional approach coping, self-compassion, and distress. A moderated mediation model was tested, where emotional approach coping mediated the path between gender role conflict and distress and self-compassion moderated paths between (1) gender role conflict and emotional approach coping, and (2) gender role conflict and distress. RESULTS: Results partially supported this model with all study variables predicting distress in the expected directions. Emotional approach coping did not mediate associations between gender role conflict and distress; however, self-compassion did moderate the pathway between these variables. CONCLUSION: Results indicated that higher levels of self-compassion might protect men from distress related to emasculating aspects of the cancer experience. Further investigation is required to understand how self-compassion interacts with emotionality and subsequently influences distress in prostate cancer patients. To better understand the effectiveness of emotional approach coping in reducing distress in prostate cancer patients, it is recommended that future research accounts for the receptiveness of social environments to men's emotional displays. PMID- 29758582 TI - [Relevance of MRI After Closed Reduction of Traumatic Hip Dislocation in Children]. AB - BACKGROUND: Traumatic hip dislocation in children and adolescents is a rare entity that typically results from high-energy trauma. After closed joint reduction, further treatment depends on the specific pattern of the lesion as identified using cross sectional imaging. The aim of this retrospective analysis was to evaluate relevant side effects after traumatic hip dislocation in children and adolescents in order to examine the need for focused diagnostics. PATIENTS/MATERIAL AND METHODS: This retrospective analysis covered 8 adolescents under 18 years suffering isolated traumatic hip joint dislocation between 2001 and 2017. In all patients, closed joint reduction was performed immediately after admission to the emergency room. In order to evaluate the complete extent of the injury, 5 patients received an MRI and 3 patients a CT scan following closed joint reduction. RESULTS: Two female and 6 male patients with a median age of 11 (range 5 - 16) years were included. In 2 cases, a free joint body was detected in the posterior joint gap in the posttraumatic CT scan after closed joint reduction. Interposition of the labrum into the joint gap was detected intraoperatively in both cases. In one patient who received posttraumatic MRI, labral interposition into the joint gap was observed after closed reduction. These findings were confirmed intraoperatively. In 4 other patients, no posttraumatic labral lesion was detected in the MRI after closed reduction. The reported side effects included ruptured anterior inferior iliac spine and ruptured femoral head ligament. CONCLUSION: MRI is gaining increasing importance following traumatic hip dislocation in children and adolescents. A missing chondral or osteochondral fragment in the CT scan does not exclude a labral lesion or interposition. Therefore, MRI following closed reduction is mandatory in any case. PMID- 29758584 TI - Inhibition of sympathetic sprouting in CCD rats by lacosamide. AB - BACKGROUND: Early hyperexcitability activity of injured nerve/neuron is critical for developing sympathetic nerve sprouting within dorsal root ganglia (DRG) since lacosamide (LCM), an anticonvulsant, inhibits Na+ channel. The present study tried to test the potential effect of LCM on inhibiting sympathetic sprouting in vivo. METHODS: Lacosamide (50 mg/kg) was daily injected intraperitoneally into rats subjected to chronic compression DRG (CCD), an animal model of neuropathic pain that exhibits sympathetic nerve sprouting, for the 1st 7 days after injury. Mechanical sensitivity was tested from day 3 to day 18 after injury, and then DRGs were removed off. Immunohistochemical staining for tyrosine hydroxylase (TH) was examined to observe sympathetic sprouting, and patch-clamp recording was performed to test the excitability and Na+ current of DRG neurons. RESULTS: Early systemic LCM treatment significantly reduced TH immunoreactivity density in injured DRG, lowered the excitability level of injured DRG neurons and increased paw withdrawal threshold. These effects on reducing sympathetic sprouting, inhibiting excitability and suppressing pain behaviour were observed 10 days after the end of early LCM injection. In vitro 100 MUmol/L LCM instantly reduced the excitability of CCD neurons via inhibiting Na+ current and reducing the amplitude of AP. CONCLUSIONS: All the findings suggest, for the first time, that early administration of LCM inhibited sympathetic sprouting and then alleviated neuropathic pain. SIGNIFICANCE: Early LCM administration inhibited sympathetic sprouting within DRG in CCD rats via reducing hyperexcitability of neurons. Early LCM administration suppressed neuropathic pain in CCD rats. PMID- 29758585 TI - Comparative study about the tensile strength and yielding mechanism of pacing lead among major manufacturers. AB - BACKGROUND: With extraction of cardiovascular implantable electronic devices (CIED) increasingly necessitated, various studies have contemplated to investigate clinical predictors for its success and complications. Intrinsic parameters of CIED leads have been studied less extensively and are the foci of this study. METHODS: Three major pacemaker manufacturers accepted invitation. Leads then underwent tensile test in vitro with their composite tensile strength (TS) compared. Mechanism of yielding, under tensile stress, was also observed among them. RESULTS: All pacing leads, participated in this study, surpassed requirement of European Standard EN 45502-2-1. Boston Scientific's FINELINE II STEROX 4456/52 cm (Boston Scientific Corp., St. Paul, MN, USA) and Medtronic's CAPSURE SENSE 4074/52 cm (Medtronic, Minneapolis, MN, USA) showed similar composite TS and both were stronger compared with St. Jude Medical's ISOFLEX OPTIM 1948/52 cm (P <0.001; St. Jude Medical, Sylmar, CA, USA). Despite a difference in the exact site, the Medtronic 4074 and St. Jude Medical 1948 yielded similarly in that their distal tip electrode remained connected with a flimsy inner coil to proximal portion of the lead after their composite TS was exceeded. Boston Scientific 4456's insulation tubing and coil wire broke almost simultaneously and separated completely from the tip electrode when it yielded. CONCLUSIONS: FINELINE II STEROX 4456/52 cm and CAPSURE SENSE 4074/52 cm showed stronger composite tensile strength than ISOFLEX OPTIM 1948/52 cm. FINELINE II STEROX 4456 was found more prone to complete severance. Limitations and precautions to translate these differences directly into real-life scenario are discussed. PMID- 29758578 TI - [CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. AB - Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa infection in order to give guidance for individual treatment options. PMID- 29758586 TI - Opioid intake prior to admission is not increased in elderly patients with low energy fractures: A case-control study in a German hospital population. AB - BACKGROUND: Recent studies revealed an increased prescription rate of opioids for elderly patients suffering bone fractures. To gain further insight, we conducted face-to-face interviews in the present study to compare the opioid intake between patients with low-energy fractures and patients suffering from internal diseases. METHODS: In this case-control study, 992 patients, aged 60 years and older, were enrolled between March 2014 and February 2015. The interview comprised a fall and medication history, comorbidities, mobility and other risk factors for fractures. Odds ratios (OR) and a multiple logistic regression model were calculated. RESULTS: The number of patients with pre-admission opioid intake in the last 12 months was comparable in the fracture (n = 399, 13.3%) and the control group (n = 593, 14.7% OR: 0.89, CI: 0.62-1.29). The number of patients with current opioid intake of short duration (<3 months) was similar in both groups (14% vs. 20%; OR: 0.66, CI: 0.23-1.93). Patients with opioid intake in the fracture group reported more frequently fatigue as an adverse event of opioid medication (58% vs. 30%; OR: 3.32, CI: 1.48-7.45). Patients with opioid intake showed more severe comorbidities and significantly decreased mobility compared to those without opioids. CONCLUSION: Elderly patients internalized due to low-energy fractures did not take opioids more frequently than patients with internal admission, for both short (<3 months) and longer duration intake. Patients with opioid intake were generally in poorer physical condition. The risk of fracture might increase in patients suffering from fatigue as a side effect of opioid medication. SIGNIFICANCE: This study is based on face-to-face interviews with patients, including details about side effects and fracture history, providing a more pronounced picture of the relation of opioid intake and risk of fracture. PMID- 29758587 TI - Regional vs. General Anesthesia for Total Knee and Hip Replacement: An Analysis of Postoperative Pain Perception from the International PAIN OUT Registry. AB - BACKGROUND: Total hip and knee replacements are common surgeries, and an optimal pain treatment is essential for early rehabilitation. Since data from randomized controlled trials on the use of regional anesthesia in joint replacements of the lower extremities are conflicting, we analyzed the international PAIN OUT registry for comparison of regional anesthesia vs. general anesthesia regarding pain and morphine consumption on the first postoperative day. METHODS: International Classification of Diseases-9 (ICD-9) codes were used to identify 2,346 cases of knee arthroplasty and 2,315 cases of hip arthroplasty between 2010 and 2016 from the PAIN OUT registry. Those were grouped according to anesthesia provided (general, regional, and a combination of both). On the first day after surgery, pain levels and opioid consumption were compared. Adjusted odds ratios (ORs [and 95% confidence intervals (CIs)]) were calculated with logistic regression, and propensity matching was used as a sensitivity analysis. RESULTS: After adjustment for confounders, regional anesthesia was associated with reduced opioid consumption (OR 0.20 [95% CI 0.13 to 0.30], P < 0.001) and less pain (OR 0.53 [95% CI 0.36 to 0.78], P = 0.001) than was general anesthesia in knee surgery. In hip surgery, regional anesthesia was only associated with reduced opioid consumption (OR 0.17 [95% CI 0.11 to 0.26], P < 0.001), whereas pain was comparable (OR 1.23 [95% CI 0.94 to 1.61], P = 0.1). Results from a propensity matched sensitivity analysis were similar. CONCLUSION: In total knee arthroplasty, regional anesthesia was associated with less pain and lower opioid consumption. In total hip arthroplasty, regional anesthesia was associated with lower opioid consumption, but not with reduced pain levels. PMID- 29758588 TI - Importance of disturbance history on net primary productivity in the world's most productive forests and implications for the global carbon cycle. AB - Analysis of growth and biomass turnover in natural forests of Eucalyptus regnans, the world's tallest angiosperm, reveals it is also the world's most productive forest type, with fire disturbance an important mediator of net primary productivity (NPP). A comprehensive empirical database was used to calculate the averaged temporal pattern of NPP from regeneration to 250 years age. NPP peaks at 23.1 +/- 3.8 (95% interquantile range) Mg C ha-1 year-1 at age 14 years, and declines gradually to about 9.2 +/- 0.8 Mg C ha-1 year-1 at 130 years, with an average NPP over 250 years of 11.4 +/- 1.1 Mg C ha-1 year-1 , a value similar to the most productive temperate and tropical forests around the world. We then applied the age-class distribution of E. regnans resulting from relatively recent historical fires to estimate current NPP for the forest estate. Values of NPP were 40% higher (13 Mg C ha-1 year-1 ) than if forests were assumed to be at maturity (9.2 Mg C ha-1 year-1 ). The empirically derived NPP time series for the E. regnans estate was then compared against predictions from 21 global circulation models, showing that none of them had the capacity to simulate a post disturbance peak in NPP, as found in E. regnans. The potential importance of disturbance impacts on NPP was further tested by applying a similar approach to the temperate forests of conterminous United States and of China. Allowing for the effects of disturbance, NPP summed across both regions was on average 11% (or 194 Tg C/year) greater than if all forests were assumed to be in a mature state. The results illustrate the importance of accounting for past disturbance history and growth stage when estimating forest primary productivity, with implications for carbon balance modelling at local to global scales. PMID- 29758589 TI - Spindle cell rhabdomyosarcoma of bone with FUS-TFCP2 fusion: confirmation of a very recently described rhabdomyosarcoma subtype. AB - AIMS: Rhabdomyosarcomas of bone are extremely rare, with fewer than 10 reported cases. A very rare subtype of spindle cell/sclerosing rhabdomyosarcoma harbouring a FUS-TFCP2 fusion and involving both soft tissue and bone locations has been reported very recently. We report only the fourth case of this unusual, clinically aggressive rhabdomyosarcoma. MATERIAL AND RESULTS: A previously well 72-year-old male presented with a destructive lesion of the mandible. Morphological and immunohistochemical study of a needle biopsy and the subsequent resection showed a spindle cell rhabdomyosarcoma. RNA-seq, RT-PCR and FISH confirmed the presence of the FUS-TFCP2 fusion. CONCLUSIONS: Spindle cell rhabdomyosarcomas carrying the FUS-TFCP2 fusion are very rare rhabdomyosarcoma variants with osseous predilection. The classification and differential diagnosis of this unusual molecular variant of spindle cell/sclerosing rhabdomyosarcoma are discussed. PMID- 29758590 TI - Interobserver variation in CD30 immunohistochemistry interpretation; consequences for patient selection for targeted treatment. AB - AIMS: CD30 immunohistochemistry (IHC) in malignant lymphoma is used for selection of patients in clinical trials using brentuximab vedotin, an antibody drug conjugate targeting the CD30 molecule. For reliable implementation in daily practice and meaningful selection of patients for clinical trials, information on technical variation and interobserver reproducibility of CD30 immunohistochemistry (IHC) staining is required. METHODS AND RESULTS: We conducted a three-round reproducibility assessment of CD30 scoring for categorised frequency and intensity, including a technical validation, a 'live polling' pre- and post-instruction scoring round and a web-based round including individual scoring with additional IHC information to mimic daily diagnostic practice. Agreement in all three scoring rounds was poor to fair (kappa = 0.12 0.35 for CD30-positive tumour cell percentage and kappa = 0.16-0.41 for staining intensity), even when allowing for one category of freedom in percentage of tumour cell positivity (kappa = 0.30-0.61). The first round with CD30 staining performed in five independent laboratories showed objective differences in staining intensity. In the second round, approximately half the pathologists changed their opinion on CD30 frequency after a discussion on potential pitfalls, highlighting hesitancy in decision-making. Using fictional cut-off points for percentage of tumour cell positivity, agreement was still suboptimal (kappa = 0.35-0.60). CONCLUSIONS: Lack of agreement in cases with heterogeneous expression is shown to influence patient eligibility for treatment with brentuximab vedotin, both in clinical practice and within the context of clinical trials, and limits the potential predictive value of the relative frequency of CD30-positive neoplastic cells for clinical response. PMID- 29758593 TI - Letter from Korea. PMID- 29758594 TI - PHOX2B is a reliable immunomarker in distinguishing peripheral neuroblastic tumours from CNS embryonal tumours. AB - AIMS: The PHOX2B gene regulates neuronal maturation in the brain stem nuclei associated with cardiorespiratory function and in the autonomic sympathetic and enteric nervous system. PHOX2B expression is a reliable immunomarker for peripheral neuroblastic tumours; however, no systematic evaluation of central nervous system (CNS) embryonal tumours was included in the studies. We encountered two cases in which the differential diagnosis included neuroblastoma and CNS embryonal tumour, and we hypothesised that PHOX2B immunostain would be helpful in establishing the diagnosis. METHODS AND RESULTS: PHOX2B immunostain was performed on 29 paediatric cases, with adequate controls: one retroperitoneal embryonal tumour in a child with retinoblastoma (index 1), one posterior fossa embryonal tumour in a child with a neuroblastoma (index 2), seven medulloblastomas, four atypical teratoid/rhabdoid tumours (ATRT), four retinoblastomas, six pineoblastomas, four embryonal tumours with multilayered rosettes (ETMR) and two CNS embryonal tumours, not elsewhere classified. Cell lineage immunomarkers (GFAP, OLIG2, synaptophysin, NeuN, CRX, PGP 9.5), immunosurrogates for molecular alterations (beta-catenin, INI1, Lin-28), array CGH and OncoPanel were performed as needed. Medulloblastomas, ATRTs, ETMRs, retinoblastomas and CNS embryonal tumours not elsewhere classified were essentially negative for PHOX2B. Two of six pineoblastomas had significant PHOX2B expression, while the rest were negative. Index 1 was negative for PHOX2B and PGP 9.5 and positive for CRX, consistent with retinoblastoma. Index 2 had diffuse PHOX2B expression, MYCN amplification and no copy number changes of medulloblastoma, in keeping with neuroblastoma. CONCLUSION: PHOX2B antibody is helpful in distinguishing between peripheral neuroblastic and CNS embryonal tumours, which are immunonegative, with the caveat that a subset of pineoblastomas has significant expression. PMID- 29758591 TI - Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats. AB - OBJECTIVE: Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury. METHODS: Three-week-old male Sprague-Dawley rats were fed a HF diet +/- the MR antagonist canrenoic acid (Canr) for 17 weeks. Control rats received normal chow (control NC). MCA structure was assessed by pressure myography. RESULTS: The MCAs from HF fed rats had smaller lumens and thicker walls when compared to arteries from control NC rats; Canr prevented the MCA remodeling associated with HF feeding. HF feeding increased the mRNA expression of markers of cell proliferation and vascular inflammation in cerebral arteries and Canr treatment prevented this. White mater injury was increased in the rats fed the HF diet and this was reduced by Canr treatment. The expression of doublecortin, a marker of new and immature neurons was reduced in HF fed rats, and MR antagonism normalized this. CONCLUSIONS: These data suggest that HF feeding leads to MR dependent remodeling of the MCA and this is associated with markers of dementia development. PMID- 29758592 TI - Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders. AB - BACKGROUND: Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES: To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA: We included RCTs, non RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS: We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS: We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding. PMID- 29758596 TI - Coupled harmonic oscillators and their quantum entanglement. AB - A system of two coupled quantum harmonic oscillators with the Hamiltonian H[over ]=1/2(1/m_{1}p[over ]_{1}^{2}+1/m_{2}p[over ]_{2}^{2}+Ax_{1}^{2}+Bx_{2}^{2}+Cx_{1}x_{2}) can be found in many applications of quantum and nonlinear physics, molecular chemistry, and biophysics. The stationary wave function of such a system is known, but its use for the analysis of quantum entanglement is complicated because of the complexity of computing the Schmidt modes. Moreover, there is no exact analytical solution to the nonstationary Schrodinger equation H[over ]Psi=ih?Psi/?t and Schmidt modes for such a dynamic system. In this paper we find a solution to the nonstationary Schrodinger equation; we also find in an analytical form a solution to the Schmidt mode for both stationary and dynamic problems. On the basis of the Schmidt modes, the quantum entanglement of the system under consideration is analyzed. It is shown that for certain parameters of the system, quantum entanglement can be very large. PMID- 29758595 TI - Crystallization in melts of short, semiflexible hard polymer chains: An interplay of entropies and dimensions. AB - What is the thermodynamic driving force for the crystallization of melts of semiflexible polymers? We try to answer this question by employing stochastic approximation Monte Carlo simulations to obtain the complete thermodynamic equilibrium information for a melt of short, semiflexible polymer chains with purely repulsive nonbonded interactions. The thermodynamics is obtained based on the density of states of our coarse-grained model, which varies by up to 5600 orders of magnitude. We show that our polymer melt undergoes a first-order crystallization transition upon increasing the chain stiffness at fixed density. This crystallization can be understood by the interplay of the maximization of different entropy contributions in different spatial dimensions. At sufficient stiffness and density, the three-dimensional orientational interactions drive the orientational ordering transition, which is accompanied by a two-dimensional translational ordering transition in the plane perpendicular to the chains resulting in a hexagonal crystal structure. While the three-dimensional ordering can be understood in terms of Onsager theory, the two-dimensional transition can be understood in terms of the liquid-hexatic transition of hard disks. Due to the domination of lateral two-dimensional translational entropy over the one dimensional translational entropy connected with columnar displacements, the chains form a lamellar phase. Based on this physical understanding, orientational ordering and translational ordering should be separable for polymer melts. A phenomenological theory based on this understanding predicts a qualitative phase diagram as a function of volume fraction and stiffness in good agreement with results from the literature. PMID- 29758597 TI - Comparison of six methods for the detection of causality in a bivariate time series. AB - In this comparative study, six causality detection methods were compared, namely, the Granger vector autoregressive test, the extended Granger test, the kernel version of the Granger test, the conditional mutual information (transfer entropy), the evaluation of cross mappings between state spaces, and an assessment of predictability improvement due to the use of mixed predictions. Seven test data sets were analyzed: linear coupling of autoregressive models, a unidirectional connection of two Henon systems, a unidirectional connection of chaotic systems of Rossler and Lorenz type and of two different Rossler systems, an example of bidirectionally connected two-species systems, a fishery model as an example of two correlated observables without a causal relationship, and an example of mediated causality. We tested not only 20000 points long clean time series but also noisy and short variants of the data. The standard and the extended Granger tests worked only for the autoregressive models. The remaining methods were more successful with the more complex test examples, although they differed considerably in their capability to reveal the presence and the direction of coupling and to distinguish causality from mere correlation. PMID- 29758599 TI - Quasibound states in a triple Gaussian potential. AB - We derive the transmission probabilities and delay times, and identify quasibound state structures in an open quantum system consisting of three Gaussian potential energy peaks, a system whose classical scattering dynamics we show to be chaotic. Such open quantum systems can serve as models for nanoscale quantum devices and their wave dynamics are similar to electromagnetic wave dynamics in optical microcavities. We use a quantum web to determine energy regimes for which the system exhibits the quantum manifestations of chaos, and we show that the classical scattering dynamics contains a significant amount of chaos. We also derive an exact expression for the non-Hermitian Hamiltonian whose eigenvalues give quasibound state energies and lifetimes of the system. PMID- 29758600 TI - Unified picture of strong-coupling stochastic thermodynamics and time reversals. AB - Strong-coupling statistical thermodynamics is formulated as the Hamiltonian dynamics of an observed system interacting with another unobserved system (a bath). It is shown that the entropy production functional of stochastic thermodynamics, defined as the log ratio of forward and backward system path probabilities, is in a one-to-one relation with the log ratios of the joint initial conditions of the system and the bath. A version of strong-coupling statistical thermodynamics where the system-bath interaction vanishes at the beginning and at the end of a process is, as is also weak-coupling stochastic thermodynamics, related to the bath initially in equilibrium by itself. The heat is then the change of bath energy over the process, and it is discussed when this heat is a functional of the system history alone. The version of strong-coupling statistical thermodynamics introduced by Seifert and Jarzynski is related to the bath initially in conditional equilibrium with respect to the system. This leads to heat as another functional of the system history which needs to be determined by thermodynamic integration. The log ratio of forward and backward system path probabilities in a stochastic process is finally related to log ratios of the initial conditions of a combined system and bath. It is shown that the entropy production formulas of stochastic processes under a general class of time reversals are given by the differences of bath energies in a larger underlying Hamiltonian system. The paper highlights the centrality of time reversal in stochastic thermodynamics, also in the case of strong coupling. PMID- 29758598 TI - Work probability distribution for a ferromagnet with long-ranged and short-ranged correlations. AB - Work fluctuations and work probability distributions are fundamentally different in systems with short-ranged versus long-ranged correlations. Specifically, in systems with long-ranged correlations the work distribution is extraordinarily broad compared to systems with short-ranged correlations. This difference profoundly affects the possible applicability of fluctuation theorems like the Jarzynski fluctuation theorem. The Heisenberg ferromagnet, well below its Curie temperature, is a system with long-ranged correlations in very low magnetic fields due to the presence of Goldstone modes. As the magnetic field is increased the correlations gradually become short ranged. Hence, such a ferromagnet is an ideal system for elucidating the changes of the work probability distribution as one goes from a domain with long-ranged correlations to a domain with short ranged correlations by tuning the magnetic field. A quantitative analysis of this crossover behavior of the work probability distribution and the associated fluctuations is presented. PMID- 29758601 TI - Long ligands reinforce biological adhesion under shear flow. AB - In this work, computer modeling has been used to show that longer ligands allow biological cells (e.g., blood platelets) to withstand stronger flows after their adhesion to solid walls. A mechanistic model of polymer-mediated ligand-receptor adhesion between a microparticle (cell) and a flat wall has been developed. The theoretical threshold between adherent and non-adherent regimes has been derived analytically and confirmed by simulations. These results lead to a deeper understanding of numerous biophysical processes, e.g., arterial thrombosis, and to the design of new biomimetic colloid-polymer systems. PMID- 29758602 TI - Response to a small external force and fluctuations of a passive particle in a one-dimensional diffusive environment. AB - We investigate the long-time behavior of a passive particle evolving in a one dimensional diffusive random environment, with diffusion constant D. We consider two cases: (a) The particle is pulled forward by a small external constant force and (b) there is no systematic bias. Theoretical arguments and numerical simulations provide evidence that the particle is eventually trapped by the environment. This is diagnosed in two ways: The asymptotic speed of the particle scales quadratically with the external force as it goes to zero, and the fluctuations scale diffusively in the unbiased environment, up to possible logarithmic corrections in both cases. Moreover, in the large D limit (homogenized regime), we find an important transient region giving rise to other, finite-size scalings, and we describe the crossover to the true asymptotic behavior. PMID- 29758603 TI - Quantifying fluctuations in reversible enzymatic cycles and clocks. AB - Biochemical reactions are fundamentally noisy at a molecular scale. This limits the precision of reaction networks, but it also allows fluctuation measurements that may reveal the structure and dynamics of the underlying biochemical network. Here, we study nonequilibrium reaction cycles, such as the mechanochemical cycle of molecular motors, the phosphorylation cycle of circadian clock proteins, or the transition state cycle of enzymes. Fluctuations in such cycles may be measured using either of two classical definitions of the randomness parameter, which we show to be equivalent in general microscopically reversible cycles. We define a stochastic period for reversible cycles and present analytical solutions for its moments. Furthermore, we associate the two forms of the randomness parameter with the thermodynamic uncertainty relation, which sets limits on the timing precision of the cycle in terms of thermodynamic quantities. Our results should prove useful also for the study of temporal fluctuations in more general networks. PMID- 29758604 TI - Catch bonding in the forced dissociation of a polymer endpoint. AB - Applying a force to certain supramolecular bonds may initially stabilize them, manifested by a lower dissociation rate. We show that this behavior, known as catch bonding and by now broadly reported in numerous biophysics bonds, is generically expected when either or both the trapping potential and the force applied to the bond possess some degree of nonlinearity. We enumerate possible scenarios and for each identify the possibility and, if applicable, the criterion for catch bonding to occur. The effect is robustly predicted by Kramers theory and Mean First Passage Time theory and confirmed in direct molecular dynamics simulation. Among the catch scenarios, one plays out essentially any time the force on the bond originates in a polymeric object, implying that some degree of catch bond behavior is to be expected in many settings relevant to polymer network mechanics or optical tweezer experiments. PMID- 29758605 TI - Origin of chaos near three-dimensional quantum vortices: A general Bohmian theory. AB - We provide a general theory for the structure of the quantum flow near three dimensional (3D) nodal lines, i.e., one-dimensional loci where the 3D wave function becomes equal to zero. In suitably defined coordinates (comoving with the nodal line) the generic structure of the flow implies the formation of 3D quantum vortices. We show that such vortices are accompanied by nearby invariant lines of the comoving quantum flow, called X lines, which are normally hyperbolic. Furthermore, the stable and unstable manifolds of the X lines produce chaotic scatterings of nearby quantum (Bohmian) trajectories, thus inducing an intricate form of the quantum current in the neighborhood of each 3D quantum vortex. Generic formulas describing the structure around 3D quantum vortices are provided, applicable to an arbitrary choice of 3D wave function. We also give specific numerical examples as well as a discussion of the physical consequences of chaos near 3D quantum vortices. PMID- 29758606 TI - Consistency properties of chaotic systems driven by time-delayed feedback. AB - Consistency refers to the property of an externally driven dynamical system to respond in similar ways to similar inputs. In a delay system, the delayed feedback can be considered as an external drive to the undelayed subsystem. We analyze the degree of consistency in a generic chaotic system with delayed feedback by means of the auxiliary system approach. In this scheme an identical copy of the nonlinear node is driven by exactly the same signal as the original, allowing us to verify complete consistency via complete synchronization. In the past, the phenomenon of synchronization in delay-coupled chaotic systems has been widely studied using correlation functions. Here, we analytically derive relationships between characteristic signatures of the correlation functions in such systems and unequivocally relate them to the degree of consistency. The analytical framework is illustrated and supported by numerical calculations of the logistic map with delayed feedback for different replica configurations. We further apply the formalism to time series from an experiment based on a semiconductor laser with a double fiber-optical feedback loop. The experiment constitutes a high-quality replica scheme for studying consistency of the delay driven laser and confirms the general theoretical results. PMID- 29758607 TI - Effect of shock waves on the statistics and scaling in compressible isotropic turbulence. AB - The statistics and scaling of compressible isotropic turbulence in the presence of large-scale shock waves are investigated by using numerical simulations at turbulent Mach number M_{t} ranging from 0.30 to 0.65. The spectra of the compressible velocity component, density, pressure, and temperature exhibit a k^{ 2} scaling at different turbulent Mach numbers. The scaling exponents for structure functions of the compressible velocity component and thermodynamic variables are close to 1 at high orders n>=3. The probability density functions of increments of the compressible velocity component and thermodynamic variables exhibit a power-law region with the exponent -2. Models for the conditional average of increments of the compressible velocity component and thermodynamic variables are developed based on the ideal shock relations and are verified by numerical simulations. The overall statistics of the compressible velocity component and thermodynamic variables are similar to one another at different turbulent Mach numbers. It is shown that the effect of shock waves on the compressible velocity spectrum and kinetic energy transfer is different from that of acoustic waves. PMID- 29758608 TI - Glass transition of soft colloids. AB - We explore the glassy dynamics of soft colloids using microgels and charged particles interacting by steric and screened Coulomb interactions, respectively. In the supercooled regime, the structural relaxation time tau_{alpha} of both systems grows steeply with volume fraction, reminiscent of the behavior of colloidal hard spheres. Computer simulations confirm that the growth of tau_{alpha} on approaching the glass transition is independent of particle softness. By contrast, softness becomes relevant at very large packing fractions when the system falls out of equilibrium. In this nonequilibrium regime, tau_{alpha} depends surprisingly weakly on packing fraction, and time correlation functions exhibit a compressed exponential decay consistent with stress-driven relaxation. The transition to this novel regime coincides with the onset of an anomalous decrease in local order with increasing density typical of ultrasoft systems. We propose that these peculiar dynamics results from the combination of the nonequilibrium aging dynamics expected in the glassy state and the tendency of colloids interacting through soft potentials to refluidize at high packing fractions. PMID- 29758609 TI - Experiments and characterization of low-frequency oscillations in a granular column. AB - The behavior of a vertically vibrated granular bed is reminiscent of a liquid in that it exhibits many phenomena such as convection and Faraday-like surface waves. However, when the lateral dimensions of the bed are confined such that a quasi-one-dimensional geometry is formed, the only phenomena that remain are bouncing bed and the granular Leidenfrost effect. This permits the observation of the granular Leidenfrost state for a wide range of energy injection parameters and more specifically allows for a thorough characterization of the low-frequency oscillation (LFO) that is present in this state. In both experiments and particle simulations we determine the LFO frequency from the power spectral density of the center-of-mass signal of the grains, varying the amplitude and frequency of the driving, the particle diameter, and the number of layers in the system. We thus find that the LFO frequency (i) is inversely proportional to the fast inertial timescale and (ii) decorrelates with a typical decay time proportional to the slow dissipative timescale in the system. The latter is consistent with the view that the LFO is driven by the inherent noise that is present in the granular Leidenfrost state with a low number of particles. PMID- 29758610 TI - Universality from disorder in the random-bond Blume-Capel model. AB - Using high-precision Monte Carlo simulations and finite-size scaling we study the effect of quenched disorder in the exchange couplings on the Blume-Capel model on the square lattice. The first-order transition for large crystal-field coupling is softened to become continuous, with a divergent correlation length. An analysis of the scaling of the correlation length as well as the susceptibility and specific heat reveals that it belongs to the universality class of the Ising model with additional logarithmic corrections which is also observed for the Ising model itself if coupled to weak disorder. While the leading scaling behavior of the disordered system is therefore identical between the second-order and first-order segments of the phase diagram of the pure model, the finite-size scaling in the ex-first-order regime is affected by strong transient effects with a crossover length scale L^{*}~32 for the chosen parameters. PMID- 29758611 TI - Transition from wakefield generation to soliton formation. AB - It is well known that when a short laser pulse propagates in an underdense plasma, it induces longitudinal plasma oscillations at the plasma frequency after the pulse, typically referred to as the wakefield. However, for plasma densities approaching the critical density, wakefield generation is suppressed, and instead the EM-pulse (electromagnetic pulse) undergoes nonlinear self-modulation. In this article we have studied the transition from the wakefield generation to formation of quasi-solitons as the plasma density is increased. For this purpose we have applied a one-dimensional relativistic cold fluid model, which has also been compared with particle-in-cell simulations. A key result is that the energy loss of the EM-pulse due to wakefield generation has its maximum for a plasma density of the order 10% of the critical density, but that wakefield generation is sharply suppressed when the density is increased further. PMID- 29758612 TI - Markov prior-based block-matching algorithm for superdimension reconstruction of porous media. AB - A superdimension reconstruction algorithm is used for the reconstruction of three dimensional (3D) structures of a porous medium based on a single two-dimensional image. The algorithm borrows the concepts of "blocks," "learning," and "dictionary" from learning-based superresolution reconstruction and applies them to the 3D reconstruction of a porous medium. In the neighborhood-matching process of the conventional superdimension reconstruction algorithm, the Euclidean distance is used as a criterion, although it may not really reflect the structural correlation between adjacent blocks in an actual situation. Hence, in this study, regular items are adopted as prior knowledge in the reconstruction process, and a Markov prior-based block-matching algorithm for superdimension reconstruction is developed for more accurate reconstruction. The algorithm simultaneously takes into consideration the probabilistic relationship between the already reconstructed blocks in three different perpendicular directions (x, y, and z) and the block to be reconstructed, and the maximum value of the probability product of the blocks to be reconstructed (as found in the dictionary for the three directions) is adopted as the basis for the final block selection. Using this approach, the problem of an imprecise spatial structure caused by a point simulation can be overcome. The problem of artifacts in the reconstructed structure is also addressed through the addition of hard data and by neighborhood matching. To verify the improved reconstruction accuracy of the proposed method, the statistical and morphological features of the results from the proposed method and traditional superdimension reconstruction method are compared with those of the target system. The proposed superdimension reconstruction algorithm is confirmed to enable a more accurate reconstruction of the target system while also eliminating artifacts. PMID- 29758613 TI - Soap-film flow induced by electric fields in asymmetric frames. AB - Net fluid flow of soap films induced by (ac or dc) electric fields in asymmetric frames is presented. Previous experiments of controllable soap film flow required the simultaneous use of an electrical current passing through the film and an external electric field or the use of nonuniform ac electric fields. Here a single voltage difference generates both the electrical current going through the film and the electric field that actuates on the charge induced on the film. The film is set into global motion due to the broken symmetry that appears by the use of asymmetric frames. If symmetric frames are used, the film flow is not steady but time dependent and irregular. Finally, we study numerically these film flows by employing the model of charge induction in ohmic liquids. PMID- 29758614 TI - General method to find the attractors of discrete dynamic models of biological systems. AB - Analyzing the long-term behaviors (attractors) of dynamic models of biological networks can provide valuable insight. We propose a general method that can find the attractors of multilevel discrete dynamical systems by extending a method that finds the attractors of a Boolean network model. The previous method is based on finding stable motifs, subgraphs whose nodes' states can stabilize on their own. We extend the framework from binary states to any finite discrete levels by creating a virtual node for each level of a multilevel node, and describing each virtual node with a quasi-Boolean function. We then create an expanded representation of the multilevel network, find multilevel stable motifs and oscillating motifs, and identify attractors by successive network reduction. In this way, we find both fixed point attractors and complex attractors. We implemented an algorithm, which we test and validate on representative synthetic networks and on published multilevel models of biological networks. Despite its primary motivation to analyze biological networks, our motif-based method is general and can be applied to any finite discrete dynamical system. PMID- 29758615 TI - Modeling the electrical properties of three-dimensional printed meshes with the theory of resistor lattices. AB - The electrical properties of conducting meshes are investigated numerically by solving the related Kirchhoff equations with the Lanczos algorithm. The method is directly inspired by the recursion technique widely used to study the electronic and vibrational spectra of solids. The method is demonstrated to be very efficient and fast when applied to resistor networks. It is used to calculate equivalent resistances between arbitrary pairs of nodes in simple resistive lattices. When the resistance fluctuates statistically from bond to bond, the method makes it possible to evaluate the fluctuations of the electrical properties of the network. It is also employed to assign an effective bulk resistivity to a discrete conducting three-dimensional mesh. PMID- 29758616 TI - Artificial light harvesting by dimerized Mobius ring. AB - We theoretically study artificial light harvesting by a Mobius ring. When the donors in the ring are dimerized, the energies of the donor ring are split into two subbands. Because of the nontrivial Mobius boundary condition, both the photon and acceptor are coupled to all collective-excitation modes in the donor ring. Therefore, the quantum dynamics in the light harvesting is subtly influenced by dimerization in the Mobius ring. It is discovered that energy transfer is more efficient in a dimerized ring than that in an equally spaced ring. This discovery is also confirmed by a calculation with the perturbation theory, which is equivalent to the Wigner-Weisskopf approximation. Our findings may be beneficial to the optimal design of artificial light harvesting. PMID- 29758618 TI - Analysis of timescale to consensus in voting dynamics with more than two options. AB - We generalize a binary majority-vote model on adaptive networks to its plurality vote counterpart and analyze the timescale to consensus when voters are given more than two options. When opinions are uniformly distributed in the population of voters in the initial state, we find that the timescale to consensus is shorter than the binary vote model from both numerical simulations and mathematical analysis using the master equation for the three-state plurality vote model. When intervention such as opinion conversion is allowed, as in the case of sudden change of mind of voter for any reason, the effort needed to push the fragmented three-opinion population in the thermodynamic limit to the consensus state, measured in minimal intervention cost, is less than that needed to push a polarized two-opinion population to the consensus state, when the degree (p) of homophily is less than 0.8. For a finite system, the fragmented three-opinion population will spontaneously reach the consensus state, with faster time to consensus, compared to polarized two-opinion population, for a broad range of p. PMID- 29758619 TI - Generative models for local network community detection. AB - Local network community detection aims to find a single community in a large network, while inspecting only a small part of that network around a given seed node. This is much cheaper than finding all communities in a network. Most methods for local community detection are formulated as ad hoc optimization problems. In this paper, we instead start from a generative model for networks with a community structure. By assuming that the network is uniform, we can approximate the structure of the unobserved parts of the network to obtain a method for local community detection. We apply this local approximation technique to two variants of the stochastic block model. This results in local community detection methods based on probabilistic models. Interestingly, in the limit, one of the proposed approximations corresponds to conductance, a popular metric in this field. Experiments on real and synthetic data sets show comparable or improved results compared to state-of-the-art local community detection algorithms. PMID- 29758620 TI - Accuracy of the microcanonical Lanczos method to compute real-frequency dynamical spectral functions of quantum models at finite temperatures. AB - We examine the accuracy of the microcanonical Lanczos method (MCLM) developed by Long et al. [Phys. Rev. B 68, 235106 (2003)PRBMDO0163 182910.1103/PhysRevB.68.235106] to compute dynamical spectral functions of interacting quantum models at finite temperatures. The MCLM is based on the microcanonical ensemble, which becomes exact in the thermodynamic limit. To apply the microcanonical ensemble at a fixed temperature, one has to find energy eigenstates with the energy eigenvalue corresponding to the internal energy in the canonical ensemble. Here, we propose to use thermal pure quantum state methods by Sugiura and Shimizu [Phys. Rev. Lett. 111, 010401 (2013)PRLTAO0031 900710.1103/PhysRevLett.111.010401] to obtain the internal energy. After obtaining the energy eigenstates using the Lanczos diagonalization method, dynamical quantities are computed via a continued fraction expansion, a standard procedure for Lanczos-based numerical methods. Using one-dimensional antiferromagnetic Heisenberg chains with S=1/2, we demonstrate that the proposed procedure is reasonably accurate, even for relatively small systems. PMID- 29758617 TI - Channel optimization of high-intensity laser beams in millimeter-scale plasmas. AB - Channeling experiments were performed at the OMEGA EP facility using relativistic intensity (>10^{18}W/cm^{2}) kilojoule laser pulses through large density scale length (~390-570 MUm) laser-produced plasmas, demonstrating the effects of the pulse's focal location and intensity as well as the plasma's temperature on the resulting channel formation. The results show deeper channeling when focused into hot plasmas and at lower densities, as expected. However, contrary to previous large-scale particle-in-cell studies, the results also indicate deeper penetration by short (10 ps), intense pulses compared to their longer-duration equivalents. This new observation has many implications for future laser-plasma research in the relativistic regime. PMID- 29758621 TI - Emergent structures in reaction-advection-diffusion systems on a sphere. AB - We demonstrate unusual effects due to the addition of advection into a two species reaction-diffusion system on the sphere. We find that advection introduces emergent behavior due to an interplay of the traditional Turing patterning mechanisms with the compact geometry of the sphere. Unidirectional advection within the Turing space of the reaction-diffusion system causes patterns to be generated at one point of the sphere, and transported to the antipodal point where they are destroyed. We illustrate these effects numerically and deduce conditions for Turing instabilities on local projections to understand the mechanisms behind these behaviors. We compare this behavior to planar advection which is shown to only transport patterns across the domain. Analogous transport results seem to hold for the sphere under azimuthal transport or away from the antipodal points in unidirectional flow regimes. PMID- 29758622 TI - Direct determination of forces between charged nanogels through coarse-grained simulations. AB - In this work, electrostatic forces between charged nanogels are explored through coarse-grained simulations. These simulations allow us to explicitly consider the complex topology of these nanoparticles and provide reliable force values to examine highly charged nanogels of a few tens of nanometers. The results obtained here clearly reveal that the electrostatic interactions between these nanoparticles are not governed by the net charge of the nanogel, which includes not only the charge of the polymer network but also the charge of ions inside. Thus two theoretical procedures for predicting effective charges are also proposed and investigated. Both provide predictions of the same order and capture the behavior found for the effective charge obtained from simulations. PMID- 29758623 TI - Pseudochemotaxis in inhomogeneous active Brownian systems. AB - We study dynamical properties of confined, self-propelled Brownian particles in an inhomogeneous activity profile. Using Brownian dynamics simulations, we calculate the probability to reach a fixed target and the mean first passage time to the target of an active particle. We show that both these quantities are strongly influenced by the inhomogeneous activity. When the activity is distributed such that high-activity zone is located between the target and the starting location, the target finding probability is increased and the passage time is decreased in comparison to a uniformly active system. Moreover, for a continuously distributed profile, the activity gradient results in a drift of active particle up the gradient bearing resemblance to chemotaxis. Integrating out the orientational degrees of freedom, we derive an approximate Fokker-Planck equation and show that the theoretical predictions are in very good agreement with the Brownian dynamics simulations. PMID- 29758624 TI - One-dimensional reduction of viscous jets. II. Applications. AB - In a companion paper [Phys. Rev. E 97, 043115 (2018)10.1103/PhysRevE.97.043115], a formalism allowing to describe viscous fibers as one-dimensional objects was developed. We apply it to the special case of a viscous fluid torus. This allows to highlight the differences with the basic viscous string model and with its viscous rod model extension. In particular, an elliptic deformation of the torus section appears because of surface tension effects, and this cannot be described by viscous string nor viscous rod models. Furthermore, we study the Rayleigh Plateau instability for periodic deformations around the perfect torus, and we show that the instability is not sufficient to lead to the torus breakup in several droplets before it collapses to a single spherical drop. Conversely, a rotating torus is dynamically attracted toward a stationary solution, around which the instability can develop freely and split the torus in multiple droplets. PMID- 29758625 TI - Shock-wave structure based on the Navier-Stokes-Fourier equations. AB - We use the Navier-Stokes-Fourier constitutive equations to study plane shock waves in dilute gases. It is shown that the experimental information on the normalized density profiles can be fit by using the so-called soft sphere model, in which the viscosity and thermal conductivity are proportional to a power of the temperature. PMID- 29758626 TI - Balancing selfishness and norm conformity can explain human behavior in large scale prisoner's dilemma games and can poise human groups near criticality. AB - Cooperation is central to the success of human societies as it is crucial for overcoming some of the most pressing social challenges of our time; still, how human cooperation is achieved and may persist is a main puzzle in the social and biological sciences. Recently, scholars have recognized the importance of social norms as solutions to major local and large-scale collective action problems, from the management of water resources to the reduction of smoking in public places to the change in fertility practices. Yet a well-founded model of the effect of social norms on human cooperation is still lacking. Using statistical physics techniques and integrating findings from cognitive and behavioral sciences, we present an analytically tractable model in which individuals base their decisions to cooperate both on the economic rewards they obtain and on the degree to which their action complies with social norms. Results from this parsimonious model are in agreement with observations in recent large-scale experiments with humans. We also find the phase diagram of the model and show that the experimental human group is poised near a critical point, a regime where recent work suggests living systems respond to changing external conditions in an efficient and coordinated manner. PMID- 29758627 TI - Time-fractional characterization of brine reaction and precipitation in porous media. AB - Brine reaction and precipitation in porous media sometimes occur in the presence of a strong fluid flowing field, which induces the mobilization of the precipitated salts and distorts their spatial distribution. It is interesting to investigate how the distribution responds to such mobilization. We view these precipitates as random walkers in the complex inner space of the porous media, where they make stochastic jumps among locations and possibly wait between successive transitions. In consideration of related experimental results, the waiting time of the precipitates at a particular position is allowed to range widely from short sojourn to permanent residence. Through the model of a continuous-time random walk, a class of time-fractional equations for the precipitate's concentration profile is derived, including that in the Riemann Liouville formalism and the Prabhakar formalism. The solutions to these equations show the general pattern of the precipitate's spatiotemporal evolution: a coupling of mass accumulation and mass transport. And the degree to which the mass is mobilized turns out to be monotonically correlated to the fractional exponent alpha. Moreover, to keep the completeness of the model, we further discuss how the interaction among the precipitates influences the precipitation process. In doing so, a time-fractional non-linear Fokker-Planck equation with source term is introduced and solved. It is shown that the interaction among the precipitates slightly perturbs their spatial distribution. This distribution is largely dominated by the brine reaction itself and the interaction between the precipitates and the porous media. PMID- 29758628 TI - Extreme learning machine for reduced order modeling of turbulent geophysical flows. AB - We investigate the application of artificial neural networks to stabilize proper orthogonal decomposition-based reduced order models for quasistationary geophysical turbulent flows. An extreme learning machine concept is introduced for computing an eddy-viscosity closure dynamically to incorporate the effects of the truncated modes. We consider a four-gyre wind-driven ocean circulation problem as our prototype setting to assess the performance of the proposed data driven approach. Our framework provides a significant reduction in computational time and effectively retains the dynamics of the full-order model during the forward simulation period beyond the training data set. Furthermore, we show that the method is robust for larger choices of time steps and can be used as an efficient and reliable tool for long time integration of general circulation models. PMID- 29758630 TI - Impact of spherical nanoparticles on nematic order parameters. AB - We study experimentally the impact of spherical nanoparticles on the orientational order parameters of a host nematic liquid crystal. We use spherical core-shell quantum dots that are surface functionalized to promote homeotropic anchoring on their interface with the liquid crystal host. We show experimentally that the orientational order may be strongly affected by the presence of spherical nanoparticles even at low concentrations. The orientational order of the composite system is probed by means of polarized micro-Raman spectroscopy and by optical birefringence measurements as function of temperature and concentration. Our data show that the orientational order depends on the concentration in a nonlinear way, and the existence of a crossover concentration chi_{c}~0.004pw. It separates two different regimes exhibiting pure-liquid crystal like (chichi_{c}), respectively. In the latter phase the degree of ordering is lower with respect to the pure-liquid crystal nematic phase. PMID- 29758629 TI - Physics of automated driving in framework of three-phase traffic theory. AB - We have revealed physical features of automated driving in the framework of the three-phase traffic theory for which there is no fixed time headway to the preceding vehicle. A comparison with the classical model approach to automated driving for which an automated driving vehicle tries to reach a fixed (desired or "optimal") time headway to the preceding vehicle has been made. It turns out that automated driving in the framework of the three-phase traffic theory can exhibit the following advantages in comparison with the classical model of automated driving: (i) The absence of string instability. (ii) Considerably smaller speed disturbances at road bottlenecks. (iii) Automated driving vehicles based on the three-phase theory can decrease the probability of traffic breakdown at the bottleneck in mixed traffic flow consisting of human driving and automated driving vehicles; on the contrary, even a single automated driving vehicle based on the classical approach can provoke traffic breakdown at the bottleneck in mixed traffic flow. PMID- 29758631 TI - Bifurcation structure of localized states in the Lugiato-Lefever equation with anomalous dispersion. AB - The origin, stability, and bifurcation structure of different types of bright localized structures described by the Lugiato-Lefever equation are studied. This mean field model describes the nonlinear dynamics of light circulating in fiber cavities and microresonators. In the case of anomalous group velocity dispersion and low values of the intracavity phase detuning these bright states are organized in a homoclinic snaking bifurcation structure. We describe how this bifurcation structure is destroyed when the detuning is increased across a critical value, and determine how a bifurcation structure known as foliated snaking emerges. PMID- 29758632 TI - 1/f noise in the intensity fluctuations of vertical-cavity surface-emitting lasers subject to parallel optical injection. AB - A first analysis of fluctuations of the light intensity of vertical-cavity surface-emitting lasers operating in a bistable regime reveals the presence of 1/f noise. In this regime the intensity fluctuates between two recently characterized states with residence times {tau_{1}} and {tau_{2}}. We identify three distinct processes. One of them presents a coherence enhancement phenomenon, and in the other two the distribution of residence times in one of the states follows either a power law P(tau_{1})~tau_{1}^{-2} or P(tau_{2})~tau_{2}^{-2}, and this is the cause of the 1/f shape in the spectral density of the intensity. The process at the coherence enhancement zone shows 1/f fluctuations in the light intensity and also in the time residence process. It is shown that the origin of these fluctuations is due to a power-law distribution in the time separation between pulses observed in the time residence series. PMID- 29758633 TI - Operator product expansion in Liouville field theory and Seiberg-type transitions in log-correlated random energy models. AB - We study transitions in log-correlated random energy models (logREMs) that are related to the violation of a Seiberg bound in Liouville field theory (LFT): the binding transition and the termination point transition (a.k.a., pre-freezing). By means of LFT-logREM mapping, replica symmetry breaking and traveling-wave equation techniques, we unify both transitions in a two-parameter diagram, which describes the free-energy large deviations of logREMs with a deterministic background log potential, or equivalently, the joint moments of the free energy and Gibbs measure in logREMs without background potential. Under the LFT-logREM mapping, the transitions correspond to the competition of discrete and continuous terms in a four-point correlation function. Our results provide a statistical interpretation of a peculiar nonlocality of the operator product expansion in LFT. The results are rederived by a traveling-wave equation calculation, which shows that the features of LFT responsible for the transitions are reproduced in a simple model of diffusion with absorption. We examine also the problem by a replica symmetry breaking analysis. It complements the previous methods and reveals a rich large deviation structure of the free energy of logREMs with a deterministic background log potential. Many results are verified in the integrable circular logREM, by a replica-Coulomb gas integral approach. The related problem of common length (overlap) distribution is also considered. We provide a traveling-wave equation derivation of the LFT predictions announced in a precedent work. PMID- 29758635 TI - Invasion waves in the biochemical warfare between living organisms. AB - Microorganisms and plants very commonly release toxic secondary chemical compounds (allelochemicals) that inhibit or kill sensitive strains or individuals from their own or other species. In this work we study a model that describes two species interacting through allelopathic suppression and competing for resources. Employing linear stability analysis, the conditions for coexistence or extinction of species in spatially homogeneous systems were determined. We found that the borders between the regimes of bistability, coexistence, and the extinction of the weaker by the stronger competitor, are altered by allelopathic interactions. In addition, traveling wave solutions for one species invasion were obtained considering the spatially explicit nature of the model. Our findings indicate that the minimum speed of the invasion wavefronts depends primarily on the competition coefficients and the parameters characterizing the species' functional responses to their allelochemicals. As a general rule, the species provided with the most effective chemical weapons dominates the population dynamics. Finally, we found a tristability at the coexistence region due to the combination of allelopathy and patchy population distributions in space. So, our model provides a distinct mechanism, independent of social behaviors, that produces such unexpected tristability impossible in classical competition models involving one-to-one individual interactions. PMID- 29758634 TI - Reduced-order model for inertial locomotion of a slender swimmer. AB - The inertial locomotion of an elongated model swimmer in a Newtonian fluid is quantified, wherein self-propulsion is achieved via steady tangential surface treadmilling. The swimmer has a length 2l and a circular cross section of longitudinal profile aR(z), where a is the characteristic width of the cross section, R(z) is a dimensionless shape function, and z is a dimensionless coordinate, normalized by l, along the centerline of the body. It is assumed that the swimmer is slender, epsilon=a/l?1. Hence, we utilize slender-body theory to analyze the Navier-Stokes equations that describe the flow around the swimmer. Therefrom, we compute an asymptotic approximation to the swimming speed, U, as U/u_{s}=1-beta[V(Re)-1/2?_{ 1}^{1}zlnR(z)dz]/ln(1/epsilon)+O[1/ln^{2}(1/epsilon)], where u_{s} is the characteristic speed of the surface treadmilling, Re is the Reynolds number based on the body length, and beta is a dimensionless parameter that differentiates between "pusher" (propelled from the rear, beta<0) and "puller" (propelled from the front, beta>0) -type swimmers. The function V(Re) increases monotonically with increasing Re; hence, fluid inertia causes an increase (decrease) in the swimming speed of a pusher (puller). Next, we demonstrate that the power expenditure of the swimmer increases monotonically with increasing Re. Further, the power expenditures of a puller and pusher with the same value of |beta| are equal. Therefore, pushers are superior in inertial locomotion as compared to pullers, in that they achieve a faster swimming speed for the same power expended. Finally, it is demonstrated that the flow structure predicted from our reduced-order model is consistent with that from direct numerical simulation of swimmers at intermediate Re. PMID- 29758636 TI - Emergent explosive synchronization in adaptive complex networks. AB - Adaptation plays a fundamental role in shaping the structure of a complex network and improving its functional fitting. Even when increasing the level of synchronization in a biological system is considered as the main driving force for adaptation, there is evidence of negative effects induced by excessive synchronization. This indicates that coherence alone cannot be enough to explain all the structural features observed in many real-world networks. In this work, we propose an adaptive network model where the dynamical evolution of the node states toward synchronization is coupled with an evolution of the link weights based on an anti-Hebbian adaptive rule, which accounts for the presence of inhibitory effects in the system. We found that the emergent networks spontaneously develop the structural conditions to sustain explosive synchronization. Our results can enlighten the shaping mechanisms at the heart of the structural and dynamical organization of some relevant biological systems, namely, brain networks, for which the emergence of explosive synchronization has been observed. PMID- 29758637 TI - Foam rheology at large deformation. AB - Large deformations are prone to cause irreversible changes in materials structure, generally leading to either material hardening or softening. Aqueous foam is a metastable disordered structure of densely packed gas bubbles. We report on the mechanical response of a foam layer subjected to quasistatic periodic shear at large amplitude. We observe that, upon increasing shear, the shear stress follows a universal curve that is nearly exponential and tends to an asymptotic stress value interpreted as the critical yield stress at which the foam structure is completely remodeled. Relevant trends of the foam mechanical response to cycling are mathematically reproduced through a simple law accounting for the amount of plastic deformation upon increasing stress. This view provides a natural interpretation to stress hardening in foams, demonstrating that plastic effects are present in this material even for minute deformation. PMID- 29758638 TI - Establishing the kinetics of ballistic-to-diffusive transition using directional statistics. AB - We establish the kinetics of ballistic-to-diffusive (BD) transition observed in two-dimensional random walk using directional statistics. Directional correlation is parameterized using the walker's turning angle distribution, which follows the commonly adopted wrapped Cauchy distribution (WCD) function. During the BD transition, the concentration factor (rho) governing the WCD shape is observed to decrease from its initial value. We next analytically derive the relationship between effective rho and time, which essentially quantifies the BD transition rate. The prediction of our kinetic expression agrees well with the empirical datasets obtained from correlated random walk simulation. We further connect our formulation with the conventionally used scaling relationship between the walker's mean-square displacement and time. PMID- 29758639 TI - Linear Rayleigh-Taylor instability in an accelerated Newtonian fluid with finite width. AB - The linear theory of Rayleigh-Taylor instability is developed for the case of a viscous fluid layer accelerated by a semi-infinite viscous fluid, considering that the top interface is a free surface. Effects of the surface tensions at both interfaces are taken into account. When viscous effects dominate on surface tensions, an interplay of two mechanisms determines opposite behaviors of the instability growth rate with the thickness of the heavy layer for an Atwood number A_{T}=1 and for sufficiently small values of A_{T}. In the former case, viscosity is a less effective stabilizing mechanism for the thinnest layers. However, the finite thickness of the heavy layer enhances its viscous effects that, in general, prevail on the viscous effects of the semi-infinite medium. PMID- 29758640 TI - Interface collisions. AB - We provide a theoretical framework to analyze the properties of frontal collisions of two growing interfaces considering different short-range interactions between them. Due to their roughness, the collision events spread in time and form rough domain boundaries, which defines collision interfaces in time and space. We show that statistical properties of such interfaces depend on the kinetics of the growing interfaces before collision, but are independent of the details of their interaction and of their fluctuations during the collision. Those properties exhibit dynamic scaling with exponents related to the growth kinetics, but their distributions may be nonuniversal. Our results are supported by simulations of lattice models with irreversible dynamics and local interactions. Relations to first passage processes are discussed and a possible application to grain-boundary formation in two-dimensional materials is suggested. PMID- 29758641 TI - Evaluation of temperature history of a spherical nanosystem irradiated with various short-pulse laser sources. AB - Spatiotemporal thermal response and characteristics of net entropy production rate of a gold nanosphere (radius: 50-200 nm), subjected to a short-pulse, femtosecond laser is reported. In order to correctly illustrate the temperature history of laser-metal interaction(s) at picoseconds transient with a comprehensive single temperature definition in macroscale and to further understand how the thermophysical response of the single-phase lag (SPL) and dual phase lag (DPL) frameworks (with various lag-ratios') differs, governing energy equations derived from these benchmark non-Fourier frameworks are numerically solved and thermodynamic assessment under both the classical irreversible thermodynamics (CIT) as well as extended irreversible thermodynamics (EIT) frameworks is subsequently carried out. Under the frameworks of SPL and DPL with small lag ratio, thermophysical anomalies such as temperature overshooting characterized by adverse temperature gradient is observed to violate the local thermodynamic equilibrium (LTE) hypothesis. The EIT framework, however, justifies the compatibility of overshooting of temperature with the second law of thermodynamics under a nonequilibrium paradigm. The DPL framework with higher lag ratio was however observed to remain free from temperature overshooting and finds suitable consistency with LTE hypothesis. In order to solve the dimensional non Fourier governing energy equation with volumetric laser-irradiation source term(s), the lattice Boltzmann method (LBM) is extended and a three-time level, fully implicit, second order accurate finite difference method (FDM) is illustrated. For all situations under observation, the LBM scheme is featured to be computationally superior to remaining FDM schemes. With detailed prediction of maximum temperature rise and the corresponding peaking time by all the numerical schemes, effects of the change of radius of the gold nanosphere, the magnitude of fluence of laser, and laser irradiation with multiple pulses on thermal energy transport and lagging behavior (if any) are further elucidated at different radial locations of the gold nanosphere. Last, efforts are further made to address the thermophysical characteristics when effective thermal conductivity (with temporal and size effects) is considered instead of the usual bulk thermal conductivity. PMID- 29758642 TI - Marangoni instability in a thin film heated from below: Effect of nonmonotonic dependence of surface tension on temperature. AB - We investigate Marangoni instability in a thin liquid film resting on a substrate of low thermal conductivity and separated from the surrounding gas phase by a deformable free surface. Considering a nonmonotonic variation of surface tension with temperature, here we analytically derive the neutral stability curve for the monotonic and oscillatory modes of instability (for both the long-wave and short wave perturbations) under the framework of linear stability analysis. For the long-wave instability, we derive a set of amplitude equations using the scaling k~(Bi)^{1/2}, where k is the wave number and Bi is the Biot number. Through this investigation, we demonstrate that for such a fluid layer upon heating from below, both monotonic and oscillatory instability can appear for a certain range of the dimensionless parameters, viz., Biot number (Bi), Galileo number (Ga), and inverse capillary number (Sigma). Moreover, we unveil, through this study, the influential role of the above-mentioned parameters on the stability of the system and identify the critical values of these parameters above which instability initiates in the liquid layer. PMID- 29758643 TI - Multiple scales in metapopulations of public goods producers. AB - Multiple scales in metapopulations can give rise to paradoxical behavior: in a conceptual model for a public goods game, the species associated with a fitness cost due to the public good production can be stabilized in the well-mixed limit due to the mere existence of these scales. The scales in this model involve a length scale corresponding to separate patches, coupled by mobility, and separate time scales for reproduction and interaction with a local environment. Contrary to the well-mixed high mobility limit, we find that for low mobilities, the interaction rate progressively stabilizes this species due to stochastic effects, and that the formation of spatial patterns is not crucial for this stabilization. PMID- 29758644 TI - Interplay of activation kinetics and the derivative conductance determines resonance properties of neurons. AB - In a neuron with hyperpolarization activated current (I_{h}), the correct input frequency leads to an enhancement of the output response. This behavior is known as resonance and is well described by the neuronal impedance. In a simple neuron model we derive equations for the neuron's resonance and we link its frequency and existence with the biophysical properties of I_{h}. For a small voltage change, the component of the ratio of current change to voltage change (dI/dV) due to the voltage-dependent conductance change (dg/dV) is known as derivative conductance (G_{h}^{Der}). We show that both G_{h}^{Der} and the current activation kinetics (characterized by the activation time constant tau_{h}) are mainly responsible for controlling the frequency and existence of resonance. The increment of both factors (G_{h}^{Der} and tau_{h}) greatly contributes to the appearance of resonance. We also demonstrate that resonance is voltage dependent due to the voltage dependence of G_{h}^{Der}. Our results have important implications and can be used to predict and explain resonance properties of neurons with the I_{h} current. PMID- 29758645 TI - Integral transforms of the quantum mechanical path integral: Hit function and path-averaged potential. AB - We introduce two integral transforms of the quantum mechanical transition kernel that represent physical information about the path integral. These transforms can be interpreted as probability distributions on particle trajectories measuring respectively the relative contribution to the path integral from paths crossing a given spatial point (the hit function) and the likelihood of values of the line integral of the potential along a path in the ensemble (the path-averaged potential). PMID- 29758646 TI - Contact angle hysteresis on doubly periodic smooth rough surfaces in Wenzel's regime: The role of the contact line depinning mechanism. AB - We report here on the contact angle hysteresis, appearing when a liquid meniscus is in contact with doubly sinusoidal wavelike patterned surfaces in Wenzel's wetting regime. Using the full capillary model we obtain numerically the contact angle hysteresis as a function of the surface roughness factor and the equilibrium contact angle for a block case and a kink case contact line depinning mechanism. We find that the dependencies of the contact angle hysteresis on the surface roughness factor are different for the different contact line depinning mechanisms. These dependencies are different also for the two types of rough surfaces we studied. The relations between advancing, receding, and equilibrium contact angles are investigated. A comparison with the existing asymptotical, numerical, and experimental results is carried out. PMID- 29758648 TI - Rheology of dilute cohesive granular gases. AB - Rheology of a dilute cohesive granular gas is theoretically and numerically studied. The flow curve between the shear viscosity and the shear rate is derived from the inelastic Boltzmann equation for particles having square-well potentials in a simple shear flow. It is found that (i) the stable uniformly sheared state only exists above a critical shear rate and (ii) the viscosity in the uniformly sheared flow is almost identical to that for uniformly sheared flow of hard core granular particles. Below the critical shear rate, clusters grow with time, in which the viscosity can be approximated by that for the hard-core fluids if we replace the diameter of the particle by the mean diameter of clusters. PMID- 29758647 TI - Transient response of nonideal ion-selective microchannel-nanochannel devices. AB - We report evidence of variation in ion selectivity of a fabricated microchannel nanochannel device resulting in the appearance of a distinct local maximum in the overlimiting chronopotentiometric response. In this system consisting of shallow microchannels joined by a nanochannel, viscous shear at the microchannel walls suppresses the electro-osmotic instability and prevents any associated contribution to the nonmonotonic response. Thus, this response is primarily electrodiffusive. Numerical simulations indicate that concentration polarization develops not only within the microchannel but also within the nanochannel itself, with a local voltage maximum in the chronopotentiometric response correlated with interfacial depletion and having the classic i^{-2} Sands time dependence. Furthermore, the occurrence of the local maxima is correlated with the change in selectivity due to internal concentration polarization. Understanding the transient nonideal permselective response is essential for obtaining fundamental insight and for optimizing efficient operation of practical fabricated nanofluidic and membrane devices. PMID- 29758649 TI - Framework for cascade size calculations on random networks. AB - We present a framework to calculate the cascade size evolution for a large class of cascade models on random network ensembles in the limit of infinite network size. Our method is exact and applies to network ensembles with almost arbitrary degree distribution, degree-degree correlations, and, in case of threshold models, for arbitrary threshold distribution. With our approach, we shift the perspective from the known branching process approximations to the iterative update of suitable probability distributions. Such distributions are key to capture cascade dynamics that involve possibly continuous quantities and that depend on the cascade history, e.g., if load is accumulated over time. As a proof of concept, we provide two examples: (a) Constant load models that cover many of the analytically tractable casacade models, and, as a highlight, (b) a fiber bundle model that was not tractable by branching process approximations before. Our derivations cover the whole cascade dynamics, not only their steady state. This allows us to include interventions in time or further model complexity in the analysis. PMID- 29758650 TI - Interactions of information transfer along separable causal paths. AB - Complex systems arise as a result of interdependences between multiple variables, whose causal interactions can be visualized in a time-series graph. Transfer entropy and information partitioning approaches have been used to characterize such dependences. However, these approaches capture net information transfer occurring through a multitude of pathways involved in the interaction and as a result mask our ability to discern the causal interaction within a subgraph of interest through specific pathways. We build on recent developments of momentary information transfer along causal paths proposed by Runge [Phys. Rev. E 92, 062829 (2015)PLEEE81539-375510.1103/PhysRevE.92.062829] to develop a framework for quantifying information partitioning along separable causal paths. Momentary information transfer along causal paths captures the amount of information transfer between any two variables lagged at two specific points in time. Our approach expands this concept to characterize the causal interaction in terms of synergistic, unique, and redundant information transfer through separable causal paths. Through a graphical model, we analyze the impact of the separable and nonseparable causal paths and the causality structure embedded in the graph as well as the noise effect on information partitioning by using synthetic data generated from two coupled logistic equation models. Our approach can provide a valuable reference for an autonomous information partitioning along separable causal paths which form a causal subgraph influencing a target. PMID- 29758651 TI - Characterizing granular networks using topological metrics. AB - We carry out a direct comparison of experimental and numerical realizations of the exact same granular system as it undergoes shear jamming. We adjust the numerical methods used to optimally represent the experimental settings and outcomes up to microscopic contact force dynamics. Measures presented here range from microscopic through mesoscopic to systemwide characteristics of the system. Topological properties of the mesoscopic force networks provide a key link between microscales and macroscales. We report two main findings: (1) The number of particles in the packing that have at least two contacts is a good predictor for the mechanical state of the system, regardless of strain history and packing density. All measures explored in both experiments and numerics, including stress tensor-derived measures and contact numbers depend in a universal manner on the fraction of nonrattler particles, f_{NR}. (2) The force network topology also tends to show this universality, yet the shape of the master curve depends much more on the details of the numerical simulations. In particular we show that adding force noise to the numerical data set can significantly alter the topological features in the data. We conclude that both f_{NR} and topological metrics are useful measures to consider when quantifying the state of a granular system. PMID- 29758652 TI - Alternative model of space-charge-limited thermionic current flow through a plasma. AB - It is widely assumed that thermionic current flow through a plasma is limited by a "space-charge-limited" (SCL) cathode sheath that consumes the hot cathode's negative bias and accelerates upstream ions into the cathode. Here, we formulate a fundamentally different current-limited mode. In the "inverse" mode, the potentials of both electrodes are above the plasma potential, so that the plasma ions are confined. The bias is consumed by the anode sheath. There is no potential gradient in the neutral plasma region from resistivity or presheath. The inverse cathode sheath pulls some thermoelectrons back to the cathode, thereby limiting the circuit current. Thermoelectrons entering the zero-field plasma region that undergo collisions may also be sent back to the cathode, further attenuating the circuit current. In planar geometry, the plasma density is shown to vary linearly across the electrode gap. A continuum kinetic planar plasma diode simulation model is set up to compare the properties of current modes with classical, conventional SCL, and inverse cathode sheaths. SCL modes can exist only if charge-exchange collisions are turned off in the potential well of the virtual cathode to prevent ion trapping. With the collisions, the current limited equilibrium must be inverse. Inverse operating modes should therefore be present or possible in many plasma devices that rely on hot cathodes. Evidence from past experiments is discussed. The inverse mode may offer opportunities to minimize sputtering and power consumption that were not previously explored due to the common assumption of SCL sheaths. PMID- 29758654 TI - Localization of multilayer networks by optimized single-layer rewiring. AB - We study localization properties of principal eigenvectors (PEVs) of multilayer networks (MNs). Starting with a multilayer network corresponding to a delocalized PEV, we rewire the network edges using an optimization technique such that the PEV of the rewired multilayer network becomes more localized. The framework allows us to scrutinize structural and spectral properties of the networks at various localization points during the rewiring process. We show that rewiring only one layer is enough to attain a MN having a highly localized PEV. Our investigation reveals that a single edge rewiring of the optimized MN can lead to the complete delocalization of a highly localized PEV. This sensitivity in the localization behavior of PEVs is accompanied with the second largest eigenvalue lying very close to the largest one. This observation opens an avenue to gain a deeper insight into the origin of PEV localization of networks. Furthermore, analysis of multilayer networks constructed using real-world social and biological data shows that the localization properties of these real-world multilayer networks are in good agreement with the simulation results for the model multilayer network. This paper is relevant to applications that require understanding propagation of perturbation in multilayer networks. PMID- 29758653 TI - Hidden long evolutionary memory in a model biochemical network. AB - We introduce a minimal model for the evolution of functional protein-interaction networks using a sequence-based mutational algorithm, and apply the model to study neutral drift in networks that yield oscillatory dynamics. Starting with a functional core module, random evolutionary drift increases network complexity even in the absence of specific selective pressures. Surprisingly, we uncover a hidden order in sequence space that gives rise to long-term evolutionary memory, implying strong constraints on network evolution due to the topology of accessible sequence space. PMID- 29758655 TI - Almost-dispersionless pulse transport in long quasiuniform spring-mass chains: A different kind of Newton's cradle. AB - Almost-dispersionless pulse transfer between the extremal masses of a uniform harmonic spring-mass chain of arbitrary length can be induced by suitably modifying two masses and their spring's elastic constant at both extrema of the chain. It is shown that a deviation (or a pulse) imposed to the first mass gives rise to a wave packet that, after a time of the order of the chain length, almost perfectly reproduces the same deviation (pulse) at the opposite end, with an amplitude loss that is as small as 1.3% in the infinite-length limit; such a dynamics can continue back and forth again for several times before dispersion cleared the effect. The underlying coherence mechanism is that the initial condition excites a bunch of normal modes with almost equal frequency spacing. This constitutes a possible mechanism for efficient energy transfer, e.g., in nanofabricated structures. PMID- 29758656 TI - Thermodynamic dislocation theory: Bauschinger effect. AB - The thermodynamic dislocation theory developed for nonuniform plastic deformations is used here to simulate the stress-strain curves for crystals subjected to antiplane shear-controlled load reversal. We show that the presence of the positive back stress during the load reversal reduces the magnitude of shear stress required to pull excess dislocations back to the center of the specimen. There, the excess dislocations of opposite signs meet and annihilate each other leading to the Bauschinger effect. PMID- 29758657 TI - One-dimensional reduction of viscous jets. I. Theory. AB - We build a general formalism to describe thin viscous jets as one-dimensional objects with an internal structure. We present in full generality the steps needed to describe the viscous jets around their central line, and we argue that the Taylor expansion of all fields around that line is conveniently expressed in terms of symmetric trace-free tensors living in the two dimensions of the fiber sections. We recover the standard results of axisymmetric jets and we report the first and second corrections to the lowest order description, also allowing for a rotational component around the axis of symmetry. When applied to generally curved fibers, the lowest order description corresponds to a viscous string model whose sections are circular. However, when including the first corrections, we find that curved jets generically develop elliptic sections. Several subtle effects imply that the first corrections cannot be described by a rod model since it amounts to selectively discard some corrections. However, in a fast rotating frame, we find that the dominant effects induced by inertial and Coriolis forces should be correctly described by rod models. For completeness, we also recover the constitutive relations for forces and torques in rod models and exhibit a missing term in the lowest order expression of viscous torque. Given that our method is based on tensors, the complexity of all computations has been beaten down by using an appropriate tensor algebra package such as xAct, allowing us to obtain a one-dimensional description of curved viscous jets with all the first order corrections consistently included. Finally, we find a description for straight fibers with elliptic sections as a special case of these results, and recover that ellipticity is dynamically damped by surface tension. An application to toroidal viscous fibers is presented in the companion paper [Pitrou, Phys. Rev. E 97, 043116 (2018)10.1103/PhysRevE.97.043116]. PMID- 29758658 TI - Electrostatic interaction between dissimilar colloids at fluid interfaces. AB - The electrostatic interaction between two nonidentical, moderately charged colloids situated in close proximity of each other at a fluid interface is studied. By resorting to a well-justified model system, this problem is analytically solved within the framework of linearized Poisson-Boltzmann density functional theory. The resulting interaction comprises a surface and a line part, both of which, as functions of the interparticle separation, show a rich behavior including monotonic as well as nonmonotonic variations. In almost all cases, these variations cannot be captured correctly by using the superposition approximation. Moreover, expressions for the surface tensions, the line tensions and the fluid-fluid interfacial tension, which are all independent of the interparticle separation, are obtained. Our results are expected to be particularly useful for emulsions stabilized by oppositely charged particles. PMID- 29758659 TI - Statistics of zero crossings in rough interfaces with fractional elasticity. AB - We study numerically the distribution of zero crossings in one-dimensional elastic interfaces described by an overdamped Langevin dynamics with periodic boundary conditions. We model the elastic forces with a Riesz-Feller fractional Laplacian of order z=1+2zeta, such that the interfaces spontaneously relax, with a dynamical exponent z, to a self-affine geometry with roughness exponent zeta. By continuously increasing from zeta=-1/2 (macroscopically flat interface described by independent Ornstein-Uhlenbeck processes [Phys. Rev. 36, 823 (1930)PHRVAO0031-899X10.1103/PhysRev.36.823]) to zeta=3/2 (super-rough Mullins Herring interface), three different regimes are identified: (I) -1/21. The effect on P(l) of short-scale smoothening is also analyzed numerically and analytically. A tight relation between the mean interval, the mean width of the interface, and the density of zeros is also reported. The results drawn from our analysis of rough interfaces subject to particular boundary conditions or constraints, along with discretization effects, are relevant for the practical analysis of zeros in interface imaging experiments or in numerical analysis. PMID- 29758660 TI - Mechanical transduction via a single soft polymer. AB - Molecular machines from biology and nanotechnology often depend on soft structures to perform mechanical functions, but the underlying mechanisms and advantages or disadvantages over rigid structures are not fully understood. We report here a rigorous study of mechanical transduction along a single soft polymer based on exact solutions to the realistic three-dimensional wormlike chain model and augmented with analytical relations derived from simpler polymer models. The results reveal surprisingly that a soft polymer with vanishingly small persistence length below a single chemical bond still transduces biased displacement and mechanical work up to practically significant amounts. This "soft" approach possesses unique advantages over the conventional wisdom of rigidity-based transduction, and potentially leads to a unified mechanism for effective allosterylike transduction and relay of mechanical actions, information, control, and molecules from one position to another in molecular devices and motors. This study also identifies an entropy limit unique to the soft transduction, and thereby suggests a possibility of detecting higher efficiency for kinesin motor and mutants in future experiments. PMID- 29758661 TI - Symmetry- and input-cluster synchronization in networks. AB - We study cluster synchronization in networks and show that the stability of all possible cluster synchronization patterns depends on a small set of Lyapunov exponents. Our approach can be applied to clusters corresponding to both orbital partitions of the network nodes (symmetry-cluster synchronization) and equitable partitions of the network nodes (input-cluster synchronization). Our results are verified experimentally in networks of coupled optoelectronic oscillators. PMID- 29758663 TI - Emergence of collective propulsion through cell-cell adhesion. AB - The mechanisms driving the collective movement of cells remain poorly understood. To contribute toward resolving this mystery, a model was formulated to theoretically explore the possible functions of polarized cell-cell adhesion in collective cell migration. The model consists of an amoeba cell with polarized cell-cell adhesion, which is controlled by positive feedback with cell motion. This model cell has no persistent propulsion and therefore exhibits a simple random walk when in isolation. However, at high density, these cells acquire collective propulsion and form ordered movement. This result suggests that cell cell adhesion has a potential function, which induces collective propulsion with persistence. PMID- 29758662 TI - Brownian dynamics of self-regulated particles with additional degrees of freedom: Symmetry breaking and homochirality. AB - We consider the Brownian motion of a collection of particles each with an additional degree of freedom. The degree of freedom of a particle (or, in general, a molecule) can assume distinct values corresponding to certain states or conformations. The time evolution of the additional degree of freedom of a particle is guided by those of its neighbors as well as the temperature of the system. We show that the local averaging over these degrees of freedom results in emergence of a collective order in the dynamics in the form of selection or dominance of one of the isomers leading to a symmetry-broken state. Our statistical model captures the basic features of homochirality, e.g., autocatalysis and chiral inhibition. PMID- 29758664 TI - Stabilization of dynamics of oscillatory systems by nonautonomous perturbation. AB - Synchronization and stability under periodic oscillatory driving are well understood, but little is known about the effects of aperiodic driving, despite its abundance in nature. Here, we consider oscillators subject to driving with slowly varying frequency, and investigate both short-term and long-term stability properties. For a phase oscillator, we find that, counterintuitively, such variation is guaranteed to enlarge the Arnold tongue in parameter space. Using analytical and numerical methods that provide information on time-variable dynamical properties, we find that the growth of the Arnold tongue is specifically due to the growth of a region of intermittent synchronization where trajectories alternate between short-term stability and short-term neutral stability, giving rise to stability on average. We also present examples of higher-dimensional nonlinear oscillators where a similar stabilization phenomenon is numerically observed. Our findings help support the case that in general, deterministic nonautonomous perturbation is a very good candidate for stabilizing complex dynamics. PMID- 29758665 TI - Dynamic conductivity and partial ionization in dense fluid hydrogen. AB - A theoretical description for optical conduction experiments in dense fluid hydrogen is presented. Different quantum statistical approaches are used to describe the mechanism of electronic transport in hydrogen's high-temperature dense phase. We show that at the onset of the metallic transition, optical conduction could be described by a strong rise in atomic polarizability, due to increased ionization, whereas in the highly degenerate limit, the Ziman weak scattering model better accounts for the observed saturation of reflectance. The inclusion of effects of partial ionization in the highly degenerate region provides great agreement with experimental results. Hydrogen's fluid metallic state is revealed to be a partially ionized free-electron plasma. Our results provide some of the first theoretical transport models that are experimentally benchmarked, as well as an important guide for future studies. PMID- 29758666 TI - System identification of propagating wave segments in excitable media and its application to advanced control. AB - The present paper proposes a scheme for controlling wave segments in excitable media. This scheme consists of two phases: in the first phase, a simple mathematical model for wave segments is derived using only the time series data of input and output signals for the media; in the second phase, the model derived in the first phase is used in an advanced control technique. We demonstrate with numerical simulations of the Oregonator model that this scheme performs better than a conventional control scheme. PMID- 29758667 TI - Husimi-cactus approximation study on the diluted spin ice. AB - We investigate dilution effects on the classical spin-ice materials such as Ho_{2}Ti_{2}O_{7} and Dy_{2}Ti_{2}O_{7}. In particular, we derive a formula of the thermodynamic quantities as functions of the temperature and a nonmagnetic ion concentration based on a Husimi-cactus approximation. We find that the formula predicts a dilution-induced crossover from the cooperative to the conventional paramagnets in a ground state, and that it also reproduces the "generalized Pauling's entropy" given by Ke et al. To verify the formula from a numerical viewpoint, we compare these results with Monte Carlo simulation calculation data, and then find good agreement for all parameter values. PMID- 29758668 TI - Gene regulatory and signaling networks exhibit distinct topological distributions of motifs. AB - The biological processes of cellular decision making and differentiation involve a plethora of signaling pathways and gene regulatory circuits. These networks in turn exhibit a multitude of motifs playing crucial parts in regulating network activity. Here we compare the topological placement of motifs in gene regulatory and signaling networks and observe that it suggests different evolutionary strategies in motif distribution for distinct cellular subnetworks. PMID- 29758669 TI - Classical nucleation theory in the phase-field crystal model. AB - A full understanding of polycrystalline materials requires studying the process of nucleation, a thermally activated phase transition that typically occurs at atomistic scales. The numerical modeling of this process is problematic for traditional numerical techniques: commonly used phase-field methods' resolution does not extend to the atomic scales at which nucleation takes places, while atomistic methods such as molecular dynamics are incapable of scaling to the mesoscale regime where late-stage growth and structure formation takes place following earlier nucleation. Consequently, it is of interest to examine nucleation in the more recently proposed phase-field crystal (PFC) model, which attempts to bridge the atomic and mesoscale regimes in microstructure simulations. In this work, we numerically calculate homogeneous liquid-to-solid nucleation rates and incubation times in the simplest version of the PFC model, for various parameter choices. We show that the model naturally exhibits qualitative agreement with the predictions of classical nucleation theory (CNT) despite a lack of some explicit atomistic features presumed in CNT. We also examine the early appearance of lattice structure in nucleating grains, finding disagreement with some basic assumptions of CNT. We then argue that a quantitatively correct nucleation theory for the PFC model would require extending CNT to a multivariable theory. PMID- 29758671 TI - Fluctuation relation for heat exchange in Markovian open quantum systems. AB - A fluctuation relation for the heat exchange of an open quantum system under a thermalizing Markovian dynamics is derived. We show that the probability that the system absorbs an amount of heat from its bath, at a given time interval, divided by the probability of the reverse process (releasing the same amount of heat to the bath) is given by an exponential factor which depends on the amount of heat and the difference between the temperatures of the system and the bath. Interestingly, this relation is akin to the standard form of the fluctuation relation (for forward-backward dynamics). We also argue that the probability of the violation of the second law of thermodynamics in the form of the Clausius statement (i.e., net heat transfer from a cold system to its hot bath) drops exponentially with both the amount of heat and the temperature differences of the baths. PMID- 29758670 TI - Ion-ion dynamic structure factor, acoustic modes, and equation of state of two temperature warm dense aluminum. AB - The ion-ion dynamical structure factor and the equation of state of warm dense aluminum in a two-temperature quasiequilibrium state, with the electron temperature higher than the ion temperature, are investigated using molecular dynamics simulations based on ion-ion pair potentials constructed from a neutral pseudoatom model. Such pair potentials based on density functional theory are parameter-free and depend directly on the electron temperature and indirectly on the ion temperature, enabling efficient computation of two-temperature properties. Comparison with ab initio simulations and with other average-atom calculations for equilibrium aluminum shows good agreement, justifying a study of quasiequilibrium situations. Analyzing the van Hove function, we find that ion ion correlations vanish in a time significantly smaller than the electron-ion relaxation time so that dynamical properties have a physical meaning for the quasiequilibrium state. A significant increase in the speed of sound is predicted from the modification of the dispersion relation of the ion acoustic mode as the electron temperature is increased. The two-temperature equation of state including the free energy, internal energy, and pressure is also presented. PMID- 29758672 TI - Generation of intermittent gravitocapillary waves via parametric forcing. AB - We report on the generation of an intermittent wave field driven by a horizontally moving wave maker interacting with Faraday waves. The spectrum of the local gravitocapillary surface wave fluctuations displays a power law in frequency for a wide range of forcing parameters. We compute the probability density function of the local surface height increments, which show that they change strongly across time scales. The structure functions of these increments are shown to display power laws as a function of the time lag, with exponents that are nonlinear functions of the order of the structure function. We argue that the origin of this scale-invariant intermittent spectrum is the Faraday wave pattern breakup due to its advection by the propagating gravity waves. Finally, some interpretations are proposed to explain the appearance of this intermittent spectrum. PMID- 29758673 TI - Pushing the limits of Monte Carlo simulations for the three-dimensional Ising model. AB - While the three-dimensional Ising model has defied analytic solution, various numerical methods like Monte Carlo, Monte Carlo renormalization group, and series expansion have provided precise information about the phase transition. Using Monte Carlo simulation that employs the Wolff cluster flipping algorithm with both 32-bit and 53-bit random number generators and data analysis with histogram reweighting and quadruple precision arithmetic, we have investigated the critical behavior of the simple cubic Ising Model, with lattice sizes ranging from 16^{3} to 1024^{3}. By analyzing data with cross correlations between various thermodynamic quantities obtained from the same data pool, e.g., logarithmic derivatives of magnetization and derivatives of magnetization cumulants, we have obtained the critical inverse temperature K_{c}=0.221654626(5) and the critical exponent of the correlation length nu=0.629912(86) with precision that exceeds all previous Monte Carlo estimates. PMID- 29758674 TI - Heterogeneous update mechanisms in evolutionary games: Mixing innovative and imitative dynamics. AB - Innovation and evolution are two processes of paramount relevance for social and biological systems. In general, the former allows the introduction of elements of novelty, while the latter is responsible for the motion of a system in its phase space. Often, these processes are strongly related, since an innovation can trigger the evolution, and the latter can provide the optimal conditions for the emergence of innovations. Both processes can be studied by using the framework of evolutionary game theory, where evolution constitutes an intrinsic mechanism. At the same time, the concept of innovation requires an opportune mathematical representation. Notably, innovation can be modeled as a strategy, or it can constitute the underlying mechanism that allows agents to change strategy. Here, we analyze the second case, investigating the behavior of a heterogeneous population, composed of imitative and innovative agents. Imitative agents change strategy only by imitating that of their neighbors, whereas innovative ones change strategy without the need for a copying source. The proposed model is analyzed by means of analytical calculations and numerical simulations in different topologies. Remarkably, results indicate that the mixing of mechanisms can be detrimental to cooperation near phase transitions. In those regions, the spatial reciprocity from imitative mechanisms is destroyed by innovative agents, leading to the downfall of cooperation. Our investigation sheds some light on the complex dynamics emerging from the heterogeneity of strategy revision methods, highlighting the role of innovation in evolutionary games. PMID- 29758675 TI - Electrically modulated capillary filling imbibition of nematic liquid crystals. AB - The flow of nematic liquid crystals (NLCs) in the presence of an electric field is typically characterized by the variation in its rheological properties due to transition in its molecular arrangements. Here, we bring out a nontrivial interplay of a consequent alteration in the resistive viscous effects and driving electrocapillary interactions, toward maneuvering the capillary filling dynamics over miniaturized scales. Considering a dynamic interplay of the relevant bulk and interfacial forces acting in tandem, our results converge nicely to previously reported experimental data. Finally, we attempt a scaling analysis to bring forth further insight to the reported observations. Our analysis paves the way for the development of microfluidic strategies with previously unexplored paradigms of interaction between electrical and fluidic phenomenon, providing with an augmented controllability on capillary filling as compared to tthose reported to be achievable by the existing strategies. This, in turn, holds utilitarian scopes in improved designs of functional capillarities in electro optical systems, electrorheological utilities, electrokinetic flow control, as well as in interfacing and imaging systems for biomedical microdevices. PMID- 29758676 TI - Spectral control of high harmonics from relativistic plasmas using bicircular fields. AB - We introduce two-color counterrotating circularly polarized laser fields as a way to spectrally control high harmonic generation (HHG) from relativistic plasma mirrors. Through particle-in-cell simulations, we show that only a selected group of harmonic orders can appear owing to the symmetry of the laser fields and the related conservation laws. By adjusting the intensity ratio of the two driving field components, we demonstrate the overall HHG efficiency, the relative intensity of allowed neighboring harmonic orders, and that the polarization state of the harmonic source can be tuned. The HHG efficiency of this scheme can be as high as that driven by a linearly polarized laser field. PMID- 29758677 TI - Escape time, relaxation, and sticky states of a softened Henon-Heiles model: Low frequency vibrational mode effects and glass relaxation. AB - Here we study the relaxation of a chain consisting of three masses joined by nonlinear springs and periodic conditions when the stiffness is weakened. This system, when expressed in their normal coordinates, yields a softened Henon Heiles system. By reducing the stiffness of one low-frequency vibrational mode, a faster relaxation is enabled. This is due to a reduction of the energy barrier heights along the softened normal mode as well as for a widening of the opening channels of the energy landscape in configurational space. The relaxation is for the most part exponential, and can be explained by a simple flux equation. Yet, for some initial conditions the relaxation follows as a power law, and in many cases there is a regime change from exponential to power-law decay. We pinpoint the initial conditions for the power-law decay, finding two regions of sticky states. For such states, quasiperiodic orbits are found since almost for all components of the initial momentum orientation, the system is trapped inside two pockets of configurational space. The softened Henon-Heiles model presented here is intended as the simplest model in order to understand the interplay of rigidity, nonlinear interactions and relaxation for nonequilibrium systems such as glass-forming melts or soft matter. Our softened system can be applied to model beta relaxation in glasses and suggest that local reorientational jumps can have an exponential and a nonexponential contribution for relaxation, the latter due to asymmetric molecules sticking in cages for certain orientations. PMID- 29758678 TI - Solvent coarsening around colloids driven by temperature gradients. AB - Using mesoscopic numerical simulations and analytical theory, we investigate the coarsening of the solvent structure around a colloidal particle emerging after a temperature quench of the colloid surface. Qualitative differences in the coarsening mechanisms are found, depending on the composition of the binary liquid mixture forming the solvent and on the adsorption preferences of the colloid. For an adsorptionwise neutral colloid, the phase next to its surface alternates as a function of time. This behavior sets in on the scale of the relaxation time of the solvent and is absent for colloids with strong adsorption preferences. A Janus colloid, with a small temperature difference between its two hemispheres, reveals an asymmetric structure formation and surface enrichment around it, even if the solvent is within its one-phase region and if the temperature of the colloid is above the critical demixing temperature T_{c} of the solvent. Our phenomenological model turns out to capture recent experimental findings according to which, upon laser illumination of a Janus colloid and due to the ensuing temperature gradient between its two hemispheres, the surrounding binary liquid mixture develops a concentration gradient. PMID- 29758679 TI - Role of sufficient statistics in stochastic thermodynamics and its implication to sensory adaptation. AB - A sufficient statistic is a significant concept in statistics, which means a probability variable that has sufficient information required for an inference task. We investigate the roles of sufficient statistics and related quantities in stochastic thermodynamics. Specifically, we prove that for general continuous time bipartite networks, the existence of a sufficient statistic implies that an informational quantity called the sensory capacity takes the maximum. Since the maximal sensory capacity imposes a constraint that the energetic efficiency cannot exceed one-half, our result implies that the existence of a sufficient statistic is inevitably accompanied by energetic dissipation. We also show that, in a particular parameter region of linear Langevin systems there exists the optimal noise intensity at which the sensory capacity, the information thermodynamic efficiency, and the total entropy production are optimized at the same time. We apply our general result to a model of sensory adaptation of E. coli and find that the sensory capacity is nearly maximal with experimentally realistic parameters. PMID- 29758680 TI - Effects of monoclinic symmetry on the properties of biaxial liquid crystals. AB - Tilted smectic liquid crystal phases such as the smectic-C phase seen in calamitic liquid crystals are usually treated using the assumption of biaxial orthorhombic symmetry. However, the smectic-C phase has monoclinic symmetry, thereby allowing disassociation of the principal optic and dielectric axes based on symmetry and invariance principles. This is demonstrated here by comparing optical and dielectric measurements for two materials with highly first-order direct transitions from nematic to smectic-C phases. The results show a high difference between the orientations of the principal axes sets, which is interpreted as the existence of two distinct cone angles for optical and dielectric frequencies. Both materials exhibit an increasing degree of monoclinic behavior with decreasing temperature. Due to fast switching speeds, ferroelectric smectic-C* materials are important for fast modulators and LCoS devices, where the dielectric biaxiality influences device operation. PMID- 29758681 TI - Logarithmic speed-up of relaxation in A-B annihilation with exclusion. AB - We show that the decay of the density of active particles in the reaction A+B->0 in one dimension, with exclusion interaction, results in logarithmic corrections to the expected power law decay, when the starting initial condition (i.c.) is periodic. It is well known that the late-time density of surviving particles goes as t^{-1/4} with random initial conditions, and as t^{-1/2} with alternating initial conditions (ABABAB?). We show that the decay for periodic i.c.'s made of longer blocks (A^{n}B^{n}A^{n}B^{n}?) do not show a pure power-law decay when n is even. By means of first-passage Monte Carlo simulations, and a mapping to a q state coarsening model which can be solved in the independent interval approximation (IIA), we show that the late-time decay of the density of surviving particles goes as t^{-1/2}[ln(t)]^{-1} for n even, but as t^{-1/2} when n is odd. We relate this kinetic symmetry breaking in the Glauber Ising model. We also see a very slow crossover from a t^{-1/2}[ln(t)]^{-1} regime to eventual t^{-1/2} behavior for i.c.'s made of mixtures of odd- and even-length blocks. PMID- 29758682 TI - Evaluation of the path integral for flow through random porous media. AB - We present a path integral formulation of Darcy's equation in one dimension with random permeability described by a correlated multivariate lognormal distribution. This path integral is evaluated with the Markov chain Monte Carlo method to obtain pressure distributions, which are shown to agree with the solutions of the corresponding stochastic differential equation for Dirichlet and Neumann boundary conditions. The extension of our approach to flow through random media in two and three dimensions is discussed. PMID- 29758683 TI - Markovian robots: Minimal navigation strategies for active particles. AB - We explore minimal navigation strategies for active particles in complex, dynamical, external fields, introducing a class of autonomous, self-propelled particles which we call Markovian robots (MR). These machines are equipped with a navigation control system (NCS) that triggers random changes in the direction of self-propulsion of the robots. The internal state of the NCS is described by a Boolean variable that adopts two values. The temporal dynamics of this Boolean variable is dictated by a closed Markov chain-ensuring the absence of fixed points in the dynamics-with transition rates that may depend exclusively on the instantaneous, local value of the external field. Importantly, the NCS does not store past measurements of this value in continuous, internal variables. We show that despite the strong constraints, it is possible to conceive closed Markov chain motifs that lead to nontrivial motility behaviors of the MR in one, two, and three dimensions. By analytically reducing the complexity of the NCS dynamics, we obtain an effective description of the long-time motility behavior of the MR that allows us to identify the minimum requirements in the design of NCS motifs and transition rates to perform complex navigation tasks such as adaptive gradient following, detection of minima or maxima, or selection of a desired value in a dynamical, external field. We put these ideas in practice by assembling a robot that operates by the proposed minimalistic NCS to evaluate the robustness of MR, providing a proof of concept that is possible to navigate through complex information landscapes with such a simple NCS whose internal state can be stored in one bit. These ideas may prove useful for the engineering of miniaturized robots. PMID- 29758685 TI - Effect of self-deflection on a totally asymmetric simple exclusion process with functions of site assignments. AB - This study proposes a model of a totally asymmetric simple exclusion process on a single-channel lane with functions of site assignments along the pit lane. The system model attempts to insert a new particle to the leftmost site at a certain probability by randomly selecting one of the empty sites in the pit lane, and reserving it for the particle. Thereafter, the particle is directed to stop at the site only once during its travel. Recently, the system was determined to show a self-deflection effect, in which the site usage distribution biases spontaneously toward the leftmost site, and the throughput becomes maximum when the site usage distribution is slightly biased to the rightmost site. Our exact analysis describes this deflection effect and show a good agreement with simulations. PMID- 29758684 TI - Persistence of non-Markovian Gaussian stationary processes in discrete time. AB - The persistence of a stochastic variable is the probability that it does not cross a given level during a fixed time interval. Although persistence is a simple concept to understand, it is in general hard to calculate. Here we consider zero mean Gaussian stationary processes in discrete time n. Few results are known for the persistence P_{0}(n) in discrete time, except the large time behavior which is characterized by the nontrivial constant theta through P_{0}(n)~theta^{n}. Using a modified version of the independent interval approximation (IIA) that we developed before, we are able to calculate P_{0}(n) analytically in z-transform space in terms of the autocorrelation function A(n). If A(n)->0 as n->infinity, we extract theta numerically, while if A(n)=0, for finite n>N, we find theta exactly (within the IIA). We apply our results to three special cases: the nearest-neighbor-correlated "first order moving average process", where A(n)=0 for n>1, the double exponential-correlated "second order autoregressive process", where A(n)=c_{1}lambda_{1}^{n}+c_{2}lambda_{2}^{n}, and power-law-correlated variables, where A(n)~n^{-MU}. Apart from the power-law case when MU<5, we find excellent agreement with simulations. PMID- 29758686 TI - Testing ground for fluctuation theorems: The one-dimensional Ising model. AB - In this paper we determine the nonequilibrium magnetic work performed on a Ising model and relate it to the fluctuation theorem derived some years ago by Jarzynski. The basic idea behind this theorem is the relationship connecting the free energy difference between two thermodynamic states of a system and the average work performed by an external agent, in a finite time, through nonequilibrium paths between the same thermodynamic states. We test the validity of this theorem by considering the one-dimensional Ising model where the free energy is exactly determined as a function of temperature and magnetic field. We have found that the Jarzynski theorem remains valid for all the values of the rate of variation of the magnetic field applied to the system. We have also determined the probability distribution function for the work performed on the system for the forward and reverse processes and verified that predictions based on the Crooks relation are equally correct. We also propose a method to calculate the lag between the current state of the system and that of the equilibrium based on macroscopic variables. We have shown that the lag increases with the sweeping rate of the field at its final value for the reverse process, while it decreases in the case of the forward process. The lag increases linearly with the size of the chain and with a slope decreasing with the inverse of the rate of variation of the field. PMID- 29758687 TI - Dynamical patterns in nematic active matter on a sphere. AB - Using simulations of self-propelled agents with short-range repulsion and nematic alignment, we explore the dynamical phases of a dense active nematic confined to the surface of a sphere. We map the nonequilibrium phase diagram as a function of curvature, alignment strength, and activity. Our model reproduces several phases seen in recent experiments on active microtubule bundles confined the surfaces of vesicles. At low driving, we recover the equilibrium nematic ground state with four +1/2 defects. As the driving is increased, geodesic forces drive the transition to a polar band wrapping around an equator, with large empty spherical caps corresponding to two +1 defects at the poles. Upon further increasing activity, the bands fold onto themselves, and the system eventually transitions to a turbulent state marked by the proliferation of pairs of topological defects. We highlight the key role of the nematic persistence length in controlling pattern formation in these confined systems with positive Gaussian curvature. PMID- 29758688 TI - Choice of no-slip curved boundary condition for lattice Boltzmann simulations of high-Reynolds-number flows. AB - Various curved no-slip boundary conditions available in literature improve the accuracy of lattice Boltzmann simulations compared to the traditional staircase approximation of curved geometries. Usually, the required unknown distribution functions emerging from the solid nodes are computed based on the known distribution functions using interpolation or extrapolation schemes. On using such curved boundary schemes, there will be mass loss or gain at each time step during the simulations, especially apparent at high Reynolds numbers, which is called mass leakage. Such an issue becomes severe in periodic flows, where the mass leakage accumulation would affect the computed flow fields over time. In this paper, we examine mass leakage of the most well-known curved boundary treatments for high-Reynolds-number flows. Apart from the existing schemes, we also test different forced mass conservation schemes and a constant density scheme. The capability of each scheme is investigated and, finally, recommendations for choosing a proper boundary condition scheme are given for stable and accurate simulations. PMID- 29758689 TI - Dynamics of deformation and pinch-off of a migrating compound droplet in a tube. AB - A computational fluid dynamic investigation has been carried out to study the dynamics of a moving compound droplet inside a tube. The motions associated with such a droplet is uncovered by solving the axisymmetric Navier-Stokes equations in which the spatiotemporal evolution of a pair of twin-deformable interfaces has been tracked employing the volume-of-fluid approach. The deformations at the interfaces and their subsequent dynamics are found to be stimulated by the subtle interplay between the capillary and viscous forces. The simulations uncover that when a compound drop composed of concentric inner and outer interfaces migrates inside a tube, initially in the unsteady domain of evolution, the inner drop shifts away from the concentric position to reach a morphology of constant eccentricity at the steady state. The coupled motions of the droplets in the unsteady regime causes a continuous deformation of the inner and outer interfaces to obtain a configuration with a (an) prolate (oblate) shaped outer (inner) interface. The magnitudes of capillary number and viscosity ratio are found to have significant influence on the temporal evolution of the interfacial deformations as well as the eccentricity of the droplets. Further, the simulations uncover that, following the asymmetric deformation of the interfaces, the migrating compound droplet can undergo an uncommon breakup stimulated by a rather irregular pinch-off of the outer shell. The breakup is found to initiate with the thinning of the outer shell followed by the pinch-off. Interestingly, the kinetics of the thinning of outer shell is found to follow two distinct power law regimes-a swiftly thinning stage at the onset followed by a rate limiting stage before pinch-off, which eventually leads to the uncommon breakup of the migrating compound droplets. PMID- 29758690 TI - Phase-space interference in extensive and nonextensive quantum heat engines. AB - Quantum interference is at the heart of what sets the quantum and classical worlds apart. We demonstrate that quantum interference effects involving a many body working medium is responsible for genuinely nonclassical features in the performance of a quantum heat engine. The features with which quantum interference manifests itself in the work output of the engine depends strongly on the extensive nature of the working medium. While identifying the class of work substances that optimize the performance of the engine, our results shed light on the optimal size of such media of quantum workers to maximize the work output and efficiency of quantum energy machines. PMID- 29758691 TI - Self-avoiding walk on a square lattice with correlated vacancies. AB - The self-avoiding walk on the square site-diluted correlated percolation lattice is considered. The Ising model is employed to realize the spatial correlations of the metric space. As a well-accepted result, the (generalized) Flory's mean-field relation is tested to measure the effect of correlation. After exploring a perturbative Fokker-Planck-like equation, we apply an enriched Rosenbluth Monte Carlo method to study the problem. To be more precise, the winding angle analysis is also performed from which the diffusivity parameter of Schramm-Loewner evolution theory (kappa) is extracted. We find that at the critical Ising (host) system, the exponents are in agreement with Flory's approximation. For the off critical Ising system, we find also a behavior for the fractal dimension of the walker trace in terms of the correlation length of the Ising system xi(T), i.e., D_{F}^{SAW}(T)-D_{F}^{SAW}(T_{c})~1/sqrt[xi(T)]. PMID- 29758692 TI - Breathing multichimera states in nonlocally coupled phase oscillators. AB - Chimera states for the one-dimensional array of nonlocally coupled phase oscillators in the continuum limit are assumed to be stationary states in most studies, but a few studies report the existence of breathing chimera states. We focus on multichimera states with two coherent and incoherent regions and numerically demonstrate that breathing multichimera states, whose global order parameter oscillates temporally, can appear. Moreover, we show that the system exhibits a Hopf bifurcation from a stationary multichimera to a breathing one by the linear stability analysis for the stationary multichimera. PMID- 29758693 TI - Phase separation of self-propelled ballistic particles. AB - Self-propelled particles phase-separate into coexisting dense and dilute regions above a critical density. The statistical nature of their stochastic motion lends itself to various theories that predict the onset of phase separation. However, these theories are ill-equipped to describe such behavior when noise becomes negligible. To overcome this limitation, we present a predictive model that relies on two density-dependent timescales: tau_{F}, the mean time particles spend between collisions; and tau_{C}, the mean lifetime of a collision. We show that only when tau_{F}0 via confinement to a sphere of finite radius. In some parameter regime, the gas thus enclosed undergoes a discontinuous transition between distinct density profiles. For the free energy needed to identify the equilibrium state we introduce a construction of gravitational self-energy that works in all D for the lattice gas. The decay rate of the density profile of an open cluster is shown to transform via a stretched exponential for 1infinity}=0.7476(1) and p_{c,k->infinity}=0.0033(9) being the limit values for large k-mer sizes. p_{j,k} is always greater than p_{c,k}, and consequently, the percolation phase transition occurs for all values of k. In the case of inverse percolation, the process starts with an initial configuration where all lattice bonds are occupied and, given that periodic boundary conditions are used, the opposite sides of the lattice are connected by nearest-neighbor occupied bonds. Then, the system is diluted by randomly removing linear bond k-mers from the lattice. The central idea here is based on finding the maximum concentration of occupied bonds (minimum concentration of empty bonds) for which connectivity disappears. This particular value of concentration is called the inverse percolation threshold p_{c,k}^{i}, and determines a geometrical phase transition in the system. On the other hand, the inverse jamming coverage p_{j,k}^{i} is the coverage of the limit state, in which no more objects can be removed from the lattice due to the absence of linear clusters of nearest-neighbor bonds of appropriate size. It is easy to understand that p_{j,k}^{i}=1-p_{j,k}. The obtained results for p_{c,k}^{i} show that the inverse percolation threshold is a decreasing function of k in the range 1<=k<=18. For k>18, all jammed configurations are percolating states, and consequently, there is no nonpercolating phase. In other words, the lattice remains connected even when the highest allowed concentration of removed bonds p_{j,k}^{i} is reached. In terms of network attacks, this striking behavior indicates that random attacks on single nodes (k=1) are much more effective than correlated attacks on groups of close nodes (large k's). Finally, the accurate determination of critical exponents reveals that standard and inverse bond percolation models on square lattices belong to the same universality class as the random percolation, regardless of the size k considered. PMID- 29758717 TI - Biaxial potential of surface-stabilized ferroelectric liquid crystals. AB - A biaxial surface potential Phi_{s} of smectic-C^{*} surface-stabilized ferroelectric liquid crystals (SSFLCs) is introduced in this paper to explain the experimentally observed electric-field dependence of polarization P[over ]_{cell}(E), in particular the shape of the static hysteresis loops. Our potential consists of three independent parts. The first nonpolar part Phi_{n} describes the deviation of the prime director n (which is the most probable orientation of the long molecular axes) from the easy alignment axis R, which is located in the boundary surface plane. It is introduced in the same manner as the uniaxial Rapini potential. The second part Phi_{p} of the potential is a polar term associated with the presence of the polar axis in a FLC. The third part Phi_{m} relates to the inherent FLC biaxiality, which has not been taken into consideration previously. The Phi_{m} part takes into account the deviations of the secondary director m (which is the most probable orientation of the short molecular axes) from the normal to the boundary surface. The overall surface potential Phi_{s}, which is a sum of Phi_{n},Phi_{p}, and Phi_{m}, allows one to model the conditions when either one, two, or three minima of the SSFLC cell free energy are realized depending on the biaxiality extent. A monodomain or polydomain structure, as well as the bistability or monostability of SSFLC cells, depends on the number of free-energy minima, as confirmed experimentally. In this paper, we analyze the biaxiality impact on the FLC alignment. We also answer the question of whether the bistable or monostable structure can be formed in an SSFLC cell. Our approach is essentially based on a consideration of the biaxial surface potential, while the uniaxial surface potential cannot adequately describe the experimental observations in the FLC. PMID- 29758719 TI - Theory of time-averaged neutral dynamics with environmental stochasticity. AB - Competition is the main driver of population dynamics, which shapes the genetic composition of populations and the assembly of ecological communities. Neutral models assume that all the individuals are equivalent and that the dynamics is governed by demographic (shot) noise, with a steady state species abundance distribution (SAD) that reflects a mutation-extinction equilibrium. Recently, many empirical and theoretical studies emphasized the importance of environmental variations that affect coherently the relative fitness of entire populations. Here we consider two generic time-averaged neutral models; in both the relative fitness of each species fluctuates independently in time but its mean is zero. The first (model A) describes a system with local competition and linear fitness dependence of the birth-death rates, while in the second (model B) the competition is global and the fitness dependence is nonlinear. Due to this nonlinearity, model B admits a noise-induced stabilization mechanism that facilitates the invasion of new mutants. A self-consistent mean-field approach is used to reduce the multispecies problem to two-species dynamics, and the large-N asymptotics of the emerging set of Fokker-Planck equations is presented and solved. Our analytic expressions are shown to fit the SADs obtained from extensive Monte Carlo simulations and from numerical solutions of the corresponding master equations. PMID- 29758720 TI - Characteristic time scales for diffusion processes through layers and across interfaces. AB - This paper presents a simple tool for characterizing the time scale for continuum diffusion processes through layered heterogeneous media. This mathematical problem is motivated by several practical applications such as heat transport in composite materials, flow in layered aquifers, and drug diffusion through the layers of the skin. In such processes, the physical properties of the medium vary across layers and internal boundary conditions apply at the interfaces between adjacent layers. To characterize the time scale, we use the concept of mean action time, which provides the mean time scale at each position in the medium by utilizing the fact that the transition of the transient solution of the underlying partial differential equation model, from initial state to steady state, can be represented as a cumulative distribution function of time. Using this concept, we define the characteristic time scale for a multilayer diffusion process as the maximum value of the mean action time across the layered medium. For given initial conditions and internal and external boundary conditions, this approach leads to simple algebraic expressions for characterizing the time scale that depend on the physical and geometrical properties of the medium, such as the diffusivities and lengths of the layers. Numerical examples demonstrate that these expressions provide useful insight into explaining how the parameters in the model affect the time it takes for a multilayer diffusion process to reach steady state. PMID- 29758721 TI - Diffusion-advection within dynamic biological gaps driven by structural motion. AB - To study the significance of advection in the transport of solutes, or particles, within thin biological gaps (channels), we examine theoretically the process driven by stochastic fluid flow caused by random thermal structural motion, and we compare it with transport via diffusion. The model geometry chosen resembles the synaptic cleft; this choice is motivated by the cleft's readily modeled structure, which allows for well-defined mechanical and physical features that control the advection process. Our analysis defines a Peclet-like number, A^{D}, that quantifies the ratio of time scales of advection versus diffusion. Another parameter, A^{M}, is also defined by the analysis that quantifies the full potential extent of advection in the absence of diffusion. These parameters provide a clear and compact description of the interplay among the well-defined structural, geometric, and physical properties vis-a[over ]-vis the advection versus diffusion process. For example, it is found that A^{D}~1/R^{2}, where R is the cleft diameter and hence diffusion distance. This curious, and perhaps unexpected, result follows from the dependence of structural motion that drives fluid flow on R. A^{M}, on the other hand, is directly related (essentially proportional to) the energetic input into structural motion, and thereby to fluid flow, as well as to the mechanical stiffness of the cleftlike structure. Our model analysis thus provides unambiguous insight into the prospect of competition of advection versus diffusion within biological gaplike structures. The importance of the random, versus a regular, nature of structural motion and of the resulting transient nature of advection under random motion is made clear in our analysis. Further, by quantifying the effects of geometric and physical properties on the competition between advection and diffusion, our results clearly demonstrate the important role that metabolic energy (ATP) plays in this competitive process. PMID- 29758722 TI - Symmetries and synchronization in multilayer random networks. AB - In the light of the recently proposed scenario of asymmetry-induced synchronization (AISync), in which dynamical uniformity and consensus in a distributed system would demand certain asymmetries in the underlying network, we investigate here the influence of some regularities in the interlayer connection patterns on the synchronization properties of multilayer random networks. More specifically, by considering a Stuart-Landau model of complex oscillators with random frequencies, we report for multilayer networks a dynamical behavior that could be also classified as a manifestation of AISync. We show, namely, that the presence of certain symmetries in the interlayer connection pattern tends to diminish the synchronization capability of the whole network or, in other words, asymmetries in the interlayer connections would enhance synchronization in such structured networks. Our results might help the understanding not only of the AISync mechanism itself but also its possible role in the determination of the interlayer connection pattern of multilayer and other structured networks with optimal synchronization properties. PMID- 29758723 TI - Quantum gas in the fast forward scheme of adiabatically expanding cavities: Force and equation of state. AB - With use of the scheme of fast forward which realizes quasistatic or adiabatic dynamics in shortened timescale, we investigate a thermally isolated ideal quantum gas confined in a rapidly dilating one-dimensional (1D) cavity with the time-dependent size L=L(t). In the fast-forward variants of equation of states, i.e., Bernoulli's formula and Poisson's adiabatic equation, the force or 1D analog of pressure can be expressed as a function of the velocity (L[over ]) and acceleration (L[over ]) of L besides rapidly changing state variables like effective temperature (T) and L itself. The force is now a sum of nonadiabatic (NAD) and adiabatic contributions with the former caused by particles moving synchronously with kinetics of L and the latter by ideal bulk particles insensitive to such a kinetics. The ratio of NAD and adiabatic contributions does not depend on the particle number (N) in the case of the soft-wall confinement, whereas such a ratio is controllable in the case of hard-wall confinement. We also reveal the condition when the NAD contribution overwhelms the adiabatic one and thoroughly changes the standard form of the equilibrium equation of states. PMID- 29758724 TI - Nonlinear oscillatory rarefied gas flow inside a rectangular cavity. AB - The nonlinear oscillation of rarefied gas flow inside a two-dimensional rectangular cavity is investigated on the basis of the Shakhov kinetic equation. The gas dynamics, heat transfer, and damping force are studied numerically via the discrete unified gas-kinetic scheme for a wide range of parameters, including gas rarefaction, cavity aspect ratio, and oscillation frequency. Contrary to the linear oscillation where the velocity, temperature, and heat flux are symmetrical and oscillate with the same frequency as the oscillating lid, flow properties in nonlinear oscillatory cases turn out to be asymmetrical, and second-harmonic oscillation of the temperature field is observed. As a consequence, the amplitude of the shear stress near the top-right corner of the cavity could be several times larger than that at the top-left corner, while the temperature at the top right corner could be significantly higher than the wall temperature in nearly the whole oscillation period. For the linear oscillation with the frequency over a critical value, and for the nonlinear oscillation, the heat transfer from the hot to cold region dominates inside the cavity, which is contrary to the anti Fourier heat transfer in a low-speed rarefied lid-driven cavity flow. The damping force exerted on the oscillating lid is studied in detail, and the scaling laws are developed to describe the dependency of the resonance and antiresonance frequencies (corresponding to the damping force at a local maximum and minimum, respectively) on the reciprocal aspect ratio from the near hydrodynamic to highly rarefied regimes. These findings could be useful in the design of the micro electro-mechanical devices operating in the nonlinear-flow regime. PMID- 29758725 TI - Onset of density-driven instabilities in fractured aquifers. AB - Linear stability analysis is conducted to study the onset of density-driven convection involved in solubility trapping of CO_{2} in fractured aquifers. The effect of physical properties of a fracture network on the stability of a diffusive boundary layer in a saturated fractured porous media is investigated using the dual porosity concept. Linear stability analysis results show that both fracture interporosity flow and fracture storativity play an important role in the stability behavior of the system. It is shown that a diffusive boundary layer under the gravity field in fractured porous media with lower fracture storativity and/or higher fracture interporosity flow coefficient is more stable. We present scaling relations for the onset of convective instability in fractured aquifers with single and variable matrix block size distribution. These findings improve our understanding of density-driven flow in fractured aquifers and are important in the estimation of potential storage capacity, risk assessment, and storage site characterization and screening. PMID- 29758726 TI - Efficiency at maximum power of a laser quantum heat engine enhanced by noise induced coherence. AB - Quantum coherence has been demonstrated in various systems including organic solar cells and solid state devices. In this article, we report the lower and upper bounds for the performance of quantum heat engines determined by the efficiency at maximum power. Our prediction based on the canonical three-level Scovil and Schulz-Dubois maser model strongly depends on the ratio of system-bath couplings for the hot and cold baths and recovers the theoretical bounds established previously for the Carnot engine. Further, introducing a fourth level to the maser model can enhance the maximal power and its efficiency, thus demonstrating the importance of quantum coherence in the thermodynamics and operation of the heat engines beyond the classical limit. PMID- 29758728 TI - Amphibian sacculus and the forced Kuramoto model with intrinsic noise and frequency dispersion. AB - The amphibian sacculus (AS) is an end organ that specializes in the detection of low-frequency auditory and vestibular signals. In this paper, we propose a model for the AS in the form of an array of phase oscillators with long-range coupling, subject to a steady load that suppresses spontaneous oscillations. The array is exposed to significant levels of frequency dispersion and intrinsic noise. We show that such an array can be a sensitive and robust subthreshold detector of low-frequency stimuli, though without significant frequency selectivity. The effects of intrinsic noise and frequency dispersion are contrasted. Intermediate levels of intrinsic noise greatly enhance the sensitivity through stochastic resonance. Frequency dispersion, on the other hand, only degrades detection sensitivity. However, frequency dispersion can play a useful role in terms of the suppression of spontaneous activity. As a model for the AS, the array parameters are such that the system is poised near a saddle-node bifurcation on an invariant circle. However, by a change of array parameters, the same system also can be poised near an emergent Andronov-Hopf bifurcation and thereby function as a frequency-selective detector. PMID- 29758727 TI - Defect transitions in nematic liquid-crystal capillary bridges. AB - We use experiment and computational modeling to understand the defect structure and director configuration in a nematic liquid crystal capillary bridge confined between two parallel plates. We find that tuning of the aspect ratio of the bridge drives a transition between a ring defect and a point defect. This transition exhibits hysteresis, due to the metastability of the point-defect structure. In addition, we see that the shape of the capillary-bridge surface determines whether the defect is hyperbolic or radial, with waistlike bridges containing hyperbolic defects and barrel-like bridges containing radial defects. PMID- 29758729 TI - Neural field theory of perceptual echo and implications for estimating brain connectivity. AB - Neural field theory is used to predict and analyze the phenomenon of perceptual echo in which random input stimuli at one location are correlated with electroencephalographic responses at other locations. It is shown that this echo correlation (EC) yields an estimate of the transfer function from the stimulated point to other locations. Modal analysis then explains the observed spatiotemporal structure of visually driven EC and the dominance of the alpha frequency; two eigenmodes of similar amplitude dominate the response, leading to temporal beating and a line of low correlation that runs from the crown of the head toward the ears. These effects result from mode splitting and symmetry breaking caused by interhemispheric coupling and cortical folding. It is shown how eigenmodes obtained from functional magnetic resonance imaging experiments can be combined with temporal dynamics from EC or other evoked responses to estimate the spatiotemporal transfer function between any two points and hence their effective connectivity. PMID- 29758730 TI - Two-point active microrheology in a viscous medium exploiting a motional resonance excited in dual-trap optical tweezers. AB - Two-point microrheology measurements from widely separated colloidal particles approach the bulk viscosity of the host medium more reliably than corresponding single-point measurements. In addition, active microrheology offers the advantage of enhanced signal to noise over passive techniques. Recently, we reported the observation of a motional resonance induced in a probe particle in dual-trap optical tweezers when the control particle was driven externally [Paul et al., Phys. Rev. E 96, 050102(R) (2017)2470-004510.1103/PhysRevE.96.050102]. We now demonstrate that the amplitude and phase characteristics of the motional resonance can be used as a sensitive tool for active two-point microrheology to measure the viscosity of a viscous fluid. Thus, we measure the viscosity of viscous liquids from both the amplitude and phase response of the resonance, and demonstrate that the zero crossing of the phase response of the probe particle with respect to the external drive is superior compared to the amplitude response in measuring viscosity at large particle separations. We compare our viscosity measurements with those using a commercial rheometer and obtain an agreement ~1%. The method can be extended to viscoelastic material where the frequency dependence of the resonance may provide further accuracy for active microrheological measurements. PMID- 29758731 TI - Combining phase-field crystal methods with a Cahn-Hilliard model for binary alloys. AB - Diffusion-induced phase transitions typically change the lattice symmetry of the host material. In battery electrodes, for example, Li ions (diffusing species) are inserted between layers in a crystalline electrode material (host). This diffusion induces lattice distortions and defect formations in the electrode. The structural changes to the lattice symmetry affect the host material's properties. Here, we propose a 2D theoretical framework that couples a Cahn-Hilliard (CH) model, which describes the composition field of a diffusing species, with a phase field crystal (PFC) model, which describes the host-material lattice symmetry. We couple the two continuum models via coordinate transformation coefficients. We introduce the transformation coefficients in the PFC method to describe affine lattice deformations. These transformation coefficients are modeled as functions of the composition field. Using this coupled approach, we explore the effects of coarse-grained lattice symmetry and distortions on a diffusion-induced phase transition process. In this paper, we demonstrate the working of the CH-PFC model through three representative examples: First, we describe base cases with hexagonal and square symmetries for two composition fields. Next, we illustrate how the CH-PFC method interpolates lattice symmetry across a diffuse phase boundary. Finally, we compute a Cahn-Hilliard type of diffusion and model the accompanying changes to lattice symmetry during a phase transition process. PMID- 29758732 TI - Non-Gaussian diffusion in static disordered media. AB - Non-Gaussian diffusion is commonly considered as a result of fluctuating diffusivity, which is correlated in time or in space or both. In this work, we investigate the non-Gaussian diffusion in static disordered media via a quenched trap model, where the diffusivity is spatially correlated. Several unique effects due to quenched disorder are reported. We analytically estimate the diffusion coefficient D_{dis} and its fluctuation over samples of finite size. We show a mechanism of population splitting in the non-Gaussian diffusion. It results in a sharp peak in the distribution of displacement P(x,t) around x=0, that has frequently been observed in experiments. We examine the fidelity of the coarse grained diffusion map, which is reconstructed from particle trajectories. Finally, we propose a procedure to estimate the correlation length in static disordered environments, where the information stored in the sample-to-sample fluctuation has been utilized. PMID- 29758733 TI - Role of short periodic orbits in quantum maps with continuous openings. AB - We apply a recently developed semiclassical theory of short periodic orbits to the continuously open quantum tribaker map. In this paradigmatic system the trajectories are partially bounced back according to continuous reflectivity functions. This is relevant in many situations that include optical microresonators and more complicated boundary conditions. In a perturbative regime, the shortest periodic orbits belonging to the classical repeller of the open map-a cantor set given by a region of exactly zero reflectivity-prove to be extremely robust in supporting a set of long-lived resonances of the continuously open quantum maps. Moreover, for steplike functions a significant reduction in the number needed is obtained, similarly to the completely open situation. This happens despite a strong change in the spectral properties when compared to the discontinuous reflectivity case. In order to give a more realistic interpretation of these results we compare with a Fresnel-type reflectivity function. PMID- 29758734 TI - Mechanical instability and percolation of deformable particles through porous networks. AB - The transport of micron-sized particles such as bacteria, cells, or synthetic lipid vesicles through porous spaces is a process relevant to drug delivery, separation systems, or sensors, to cite a few examples. Often, the motion of these particles depends on their ability to squeeze through small constrictions, making their capacity to deform an important factor for their permeation. However, it is still unclear how the mechanical behavior of these particles affects collective transport through porous networks. To address this issue, we present a method to reconcile the pore-scale mechanics of the particles with the Darcy scale to understand the motion of a deformable particle through a porous network. We first show that particle transport is governed by a mechanical instability occurring at the pore scale, which leads to a binary permeation response on each pore. Then, using the principles of directed bond percolation, we are able to link this microscopic behavior to the probability of permeating through a random porous network. We show that this instability, together with network uniformity, are key to understanding the nonlinear permeation of particles at a given pressure gradient. The results are then summarized by a phase diagram that predicts three distinct permeation regimes based on particle properties and the randomness of the pore network. PMID- 29758735 TI - Simple waves in a two-component Bose-Einstein condensate. AB - We study the dynamics of so-called simple waves in a two-component Bose-Einstein condensate. The evolution of the condensate is described by Gross-Pitaevskii equations which can be reduced for these simple wave solutions to a system of ordinary differential equations which coincide with those derived by Ovsyannikov for the two-layer fluid dynamics. We solve the Ovsyannikov system for two typical situations of large and small difference between interspecies and intraspecies nonlinear interaction constants. Our analytic results are confirmed by numerical simulations. PMID- 29758736 TI - Full melting of a two-dimensional complex plasma crystal triggered by localized pulsed laser heating. AB - The full melting of a two-dimensional plasma crystal was induced in a principally stable monolayer by localized laser stimulation. Two distinct behaviors of the crystal after laser stimulation were observed depending on the amount of injected energy: (i) below a well-defined threshold, the laser melted area recrystallized; (ii) above the threshold, it expanded outwards in a similar fashion to mode coupling instability-induced melting, rapidly destroying the crystalline order of the whole complex plasma monolayer. The reported experimental observations are due to the fluid mode-coupling instability, which can pump energy into the particle monolayer at a rate surpassing the heat transport and damping rates in the energetic localized melted spot, resulting in its further growth. This behavior exhibits remarkable similarities with impulsive spot heating in ordinary reactive matter. PMID- 29758737 TI - Structural stability of interaction networks against negative external fields. AB - We explore structural stability of weighted and unweighted networks of positively interacting agents against a negative external field. We study how the agents support the activity of each other to confront the negative field, which suppresses the activity of agents and can lead to collapse of the whole network. The competition between the interactions and the field shape the structure of stable states of the system. In unweighted networks (uniform interactions) the stable states have the structure of k-cores of the interaction network. The interplay between the topology and the distribution of weights (heterogeneous interactions) impacts strongly the structural stability against a negative field, especially in the case of fat-tailed distributions of weights. We show that apart from critical slowing down there is also a critical change in the system structure that precedes the network collapse. The change can serve as an early warning of the critical transition. To characterize changes of network structure we develop a method based on statistical analysis of the k-core organization and so-called "corona" clusters belonging to the k-cores. PMID- 29758738 TI - Open quantum maps from complex scaling of kicked scattering systems. AB - We derive open quantum maps from periodically kicked scattering systems and discuss the computation of their resonance spectra in terms of theoretically grounded methods, such as complex scaling and sufficiently weak absorbing potentials. In contrast, we also show that current implementations of open quantum maps, based on strong absorptive or even projective openings, fail to produce the resonance spectra of kicked scattering systems. This comparison pinpoints flaws in current implementations of open quantum maps, namely, the inability to separate resonance eigenvalues from the continuum as well as the presence of diffraction effects due to strong absorption. The reported deviations from the true resonance spectra appear, even if the openings do not affect the classical trapped set, and become appreciable for shorter-lived resonances, e.g., those associated with chaotic orbits. This makes the open quantum maps, which we derive in this paper, a valuable alternative for future explorations of quantum chaotic scattering systems, for example, in the context of the fractal Weyl law. The results are illustrated for a quantum map model whose classical dynamics exhibits key features of ionization and a trapped set which is organized by a topological horseshoe. PMID- 29758739 TI - Revealing the microstructure of the giant component in random graph ensembles. AB - The microstructure of the giant component of the Erdos-Renyi network and other configuration model networks is analyzed using generating function methods. While configuration model networks are uncorrelated, the giant component exhibits a degree distribution which is different from the overall degree distribution of the network and includes degree-degree correlations of all orders. We present exact analytical results for the degree distributions as well as higher-order degree-degree correlations on the giant components of configuration model networks. We show that the degree-degree correlations are essential for the integrity of the giant component, in the sense that the degree distribution alone cannot guarantee that it will consist of a single connected component. To demonstrate the importance and broad applicability of these results, we apply them to the study of the distribution of shortest path lengths on the giant component, percolation on the giant component, and spectra of sparse matrices defined on the giant component. We show that by using the degree distribution on the giant component one obtains high quality results for these properties, which can be further improved by taking the degree-degree correlations into account. This suggests that many existing methods, currently used for the analysis of the whole network, can be adapted in a straightforward fashion to yield results conditioned on the giant component. PMID- 29758740 TI - Duality and the universality class of the three-state Potts antiferromagnet on plane quadrangulations. AB - We provide a criterion based on graph duality to predict whether the three-state Potts antiferromagnet on a plane quadrangulation has a zero- or finite temperature critical point, and its universality class. The former case occurs for quadrangulations of self-dual type, and the zero-temperature critical point has central charge c=1. The latter case occurs for quadrangulations of non-self dual type, and the critical point belongs to the universality class of the three state Potts ferromagnet. We have tested this criterion against high-precision computations on four lattices of each type, with very good agreement. We have also found that the Wang-Swendsen-Kotecky algorithm has no critical slowing-down in the former case, and critical slowing-down in the latter. PMID- 29758741 TI - Two order parameters for the Kuramoto model on complex networks. AB - We investigate the behavior of two different order parameters for the Kuramoto model in the desynchronized phase. Since the primary role of the order parameter is to distinguish different phases, we focus on the ability to discern the desynchronized phase from the synchronized one on complex networks with the size N. From the exact derivation of the difference between two order parameters, Delta, on a star network, we find that these order parameters disagree in the desynchronized phase. We also show that the hub plays an important role and provide an analytic conjecture on the condition that the two order parameters agree with each other as N->infinity. The conjecture is numerically confirmed. PMID- 29758742 TI - Stable target opinion through power-law bias in information exchange. AB - We study a model of binary decision making when a certain population of agents is initially seeded with two different opinions, "+" and "-," with fractions p_{1} and p_{2}, respectively, p_{1}+p_{2}=1. Individuals can reverse their initial opinion only once based on this information exchange. We study this model on a completely connected network, where any pair of agents can exchange information, and a two-dimensional square lattice with periodic boundary conditions, where information exchange is possible only between the nearest neighbors. We propose a model in which each agent maintains two counters of opposite opinions and accepts opinions of other agents with a power-law bias until a threshold is reached, when they fix their final opinion. Our model is inspired by the study of negativity bias and positive-negative asymmetry, which has been known in the psychology literature for a long time. Our model can achieve a stable intermediate mix of positive and negative opinions in a population. In particular, we show that it is possible to achieve close to any fraction p_{3}, 0<=p_{3}<=1, of "-" opinion starting from an initial fraction p_{1} of "-" opinion by applying a bias through adjusting the power-law exponent of p_{3}. PMID- 29758743 TI - Uncertainty dimension and basin entropy in relativistic chaotic scattering. AB - Chaotic scattering is an important topic in nonlinear dynamics and chaos with applications in several fields in physics and engineering. The study of this phenomenon in relativistic systems has received little attention as compared to the Newtonian case. Here we focus our work on the study of some relevant characteristics of the exit basin topology in the relativistic Henon-Heiles system: the uncertainty dimension, the Wada property, and the basin entropy. Our main findings for the uncertainty dimension show two different behaviors insofar as we change the relativistic parameter beta, in which a crossover behavior is uncovered. This crossover point is related with the disappearance of KAM islands in phase space, which happens for velocity values above the ultrarelativistic limit, v>0.1c. This result is supported by numerical simulations and by qualitative analysis, which are in good agreement. On the other hand, the computation of the exit basins in the phase space suggests the existence of Wada basins for a range of beta<0.625. We also studied the evolution of the exit basins in a quantitative manner by computing the basin entropy, which shows a maximum value for beta~0.2. This last quantity is related to the uncertainty in the prediction of the final fate of the system. Finally, our work is relevant in galactic dynamics, and it also has important implications in other topics in physics such as as in the Stormer problem, among others. PMID- 29758744 TI - Load response of shape-changing microswimmers scales with their swimming efficiency. AB - External forces acting on a microswimmer can feed back on its self-propulsion mechanism. We discuss this load response for a generic microswimmer that swims by cyclic shape changes. We show that the change in cycle frequency is proportional to the Lighthill efficiency of self-propulsion. As a specific example, we consider Najafi's three-sphere swimmer. The force-velocity relation of a microswimmer implies a correction for a formal superposition principle for active and passive motion. PMID- 29758745 TI - Bursting endemic bubbles in an adaptive network. AB - The spread of an infectious disease is known to change people's behavior, which in turn affects the spread of disease. Adaptive network models that account for both epidemic and behavioral change have found oscillations, but in an extremely narrow region of the parameter space, which contrasts with intuition and available data. In this paper we propose a simple susceptible-infected susceptible epidemic model on an adaptive network with time-delayed rewiring, and show that oscillatory solutions are now present in a wide region of the parameter space. Altering the transmission or rewiring rates reveals the presence of an endemic bubble-an enclosed region of the parameter space where oscillations are observed. PMID- 29758746 TI - Decrease of Fisher information and the information geometry of evolution equations for quantum mechanical probability amplitudes. AB - The relevance of the concept of Fisher information is increasing in both statistical physics and quantum computing. From a statistical mechanical standpoint, the application of Fisher information in the kinetic theory of gases is characterized by its decrease along the solutions of the Boltzmann equation for Maxwellian molecules in the two-dimensional case. From a quantum mechanical standpoint, the output state in Grover's quantum search algorithm follows a geodesic path obtained from the Fubini-Study metric on the manifold of Hilbert space rays. Additionally, Grover's algorithm is specified by constant Fisher information. In this paper, we present an information geometric characterization of the oscillatory or monotonic behavior of statistically parametrized squared probability amplitudes originating from special functional forms of the Fisher information function: constant, exponential decay, and power-law decay. Furthermore, for each case, we compute both the computational speed and the availability loss of the corresponding physical processes by exploiting a convenient Riemannian geometrization of useful thermodynamical concepts. Finally, we briefly comment on the possibility of using the proposed methods of information geometry to help identify a suitable trade-off between speed and thermodynamic efficiency in quantum search algorithms. PMID- 29758747 TI - Spontaneous repulsion in the A+B->0 reaction on coupled networks. AB - We study the transient dynamics of an A+B->0 process on a pair of randomly coupled networks, where reactants are initially separated. We find that, for sufficiently small fractions q of cross couplings, the concentration of A (or B) particles decays linearly in a first stage and crosses over to a second linear decrease at a mixing time t_{x}. By numerical and analytical arguments, we show that for symmetric and homogeneous structures t_{x}?(/q)log(/q) where is the mean degree of both networks. Being this behavior is in marked contrast with a purely diffusive process, where the mixing time would go simply like /q, we identify the logarithmic slowing down in t_{x} to be the result of a spontaneous mechanism of repulsion between the reactants A and B due to the interactions taking place at the networks' interface. We show numerically how this spontaneous repulsion effect depends on the topology of the underlying networks. PMID- 29758748 TI - Magnetic field generation by pointwise zero-helicity three-dimensional steady flow of an incompressible electrically conducting fluid. AB - We introduce six families of three-dimensional space-periodic steady solenoidal flows, whose kinetic helicity density is zero at any point. Four families are analytically defined. Flows in four families have zero helicity spectrum. Sample flows from five families are used to demonstrate numerically that neither zero kinetic helicity density nor zero helicity spectrum prohibit generation of large scale magnetic field by the two most prominent dynamo mechanisms: the magnetic alpha-effect and negative eddy diffusivity. Our computations also attest that such flows often generate small-scale field for sufficiently small magnetic molecular diffusivity. These findings indicate that kinetic helicity and helicity spectrum are not the quantities controlling the dynamo properties of a flow regardless of whether scale separation is present or not. PMID- 29758749 TI - Role of atomic spin-mechanical coupling in the problem of a magnetic biocompass. AB - It is a well established notion that animals can detect the Earth's magnetic field, while the biophysical origin of such magnetoreception is still elusive. Recently, a magnetic receptor Drosophila CG8198 (MagR) with a rodlike protein complex is reported [S. Qin et al., Nat. Mater. 15, 217 (2016)10.1038/nmat4484] to act like a compass needle to guide the magnetic orientation of animals. This view, however, is challenged [M. Meister, Elife 5, e17210 (2016)10.7554/eLife.17210] by arguing that thermal fluctuations beat the Zeeman coupling of the proteins's magnetic moment with the rather weak geomagnetic field (~25-65 MUT). In this work, we show that the spin-mechanical interaction at the atomic scale gives rise to a high blocking temperature which allows a good alignment of the protein's magnetic moment with the Earth's magnetic field at room temperature. Our results provide a promising route to resolve the debate on the thermal behaviors of MagR, and may stimulate a broad interest in spin mechanical couplings down to atomistic levels. PMID- 29758751 TI - fcc-bcc phase transition in plasma crystals using time-resolved measurements. AB - Three-dimensional plasma crystals are often described as Yukawa systems for which a phase transition between the crystal structures fcc and bcc has been predicted. However, experimental investigations of this transition are missing. We use a fast scanning video camera to record the crystallization process of 70 000 microparticles and investigate the existence of the fcc-bcc phase transition at neutral gas pressures of 30, 40, and 50 Pa. To analyze the crystal, robust phase diagrams with the help of a machine learning algorithm are calculated. This work shows that the phase transition can be investigated experimentally and makes a comparison with numerical results of Yukawa systems. The phase transition is analyzed in dependence on the screening parameter and structural order. We suggest that the transition is an effect of gravitational compression of the plasma crystal. Experimental investigations of the fcc-bcc phase transition will provide an opportunity to estimate the coupling strength Gamma by comparison with numerical results of Yukawa systems. PMID- 29758750 TI - Multimodal transport and dispersion of organelles in narrow tubular cells. AB - Intracellular components explore the cytoplasm via active motor-driven transport in conjunction with passive diffusion. We model the motion of organelles in narrow tubular cells using analytical techniques and numerical simulations to study the efficiency of different transport modes in achieving various cellular objectives. Our model describes length and time scales over which each transport mode dominates organelle motion, along with various metrics to quantify exploration of intracellular space. For organelles that search for a specific target, we obtain the average capture time for given transport parameters and show that diffusion and active motion contribute to target capture in the biologically relevant regime. Because many organelles have been found to tether to microtubules when not engaged in active motion, we study the interplay between immobilization due to tethering and increased probability of active transport. We derive parameter-dependent conditions under which tethering enhances long-range transport and improves the target capture time. These results shed light on the optimization of intracellular transport machinery and provide experimentally testable predictions for the effects of transport regulation mechanisms such as tethering. PMID- 29758752 TI - Formation of dominant mode by evolution in biological systems. AB - A reduction in high-dimensional phenotypic states to a few degrees of freedom is essential to understand biological systems. Here, we show evolutionary robustness causes such reduction which restricts possible phenotypic changes in response to a variety of environmental conditions. First, global protein expression changes in Escherichia coli after various environmental perturbations were shown to be proportional across components, across different types of environmental conditions. To examine if such dimension reduction is a result of evolution, we analyzed a cell model-with a huge number of components, that reproduces itself via a catalytic reaction network-and confirmed that common proportionality in the concentrations of all components is shaped through evolutionary processes. We found that the changes in concentration across all components in response to environmental and evolutionary changes are constrained to the changes along a one dimensional major axis, within a huge-dimensional state space. On the basis of these observations, we propose a theory in which such constraints in phenotypic changes are achieved both by evolutionary robustness and plasticity and formulate this proposition in terms of dynamical systems. Accordingly, broad experimental and numerical results on phenotypic changes caused by evolution and adaptation are coherently explained. PMID- 29758753 TI - When fast and slow interfaces grow together: Connection to the half-space problem of the Kardar-Parisi-Zhang class. AB - We study height fluctuations of interfaces in the (1+1)-dimensional Kardar-Parisi Zhang (KPZ) class, growing at different speeds in the left half and the right half of space. Carrying out simulations of the discrete polynuclear growth model with two different growth rates, combined with the standard setting for the droplet, flat, and stationary geometries, we find that the fluctuation properties at and near the boundary are described by the KPZ half-space problem developed in the theoretical literature. In particular, in the droplet case, the distribution at the boundary is given by the largest-eigenvalue distribution of random matrices in the Gaussian symplectic ensemble, often called the GSE Tracy-Widom distribution. We also characterize crossover from the full-space statistics to the half-space one, which arises when the difference between the two growth speeds is small. PMID- 29758754 TI - From near to eternity: Spin-glass planting, tiling puzzles, and constraint satisfaction problems. AB - We present a methodology for generating Ising Hamiltonians of tunable complexity and with a priori known ground states based on a decomposition of the model graph into edge-disjoint subgraphs. The idea is illustrated with a spin-glass model defined on a cubic lattice, where subproblems, whose couplers are restricted to the two values {-1,+1}, are specified on unit cubes and are parametrized by their local degeneracy. The construction is shown to be equivalent to a type of three dimensional constraint-satisfaction problem known as the tiling puzzle. By varying the proportions of subproblem types, the Hamiltonian can span a dramatic range of typical computational complexity, from fairly easy to many orders of magnitude more difficult than prototypical bimodal and Gaussian spin glasses in three space dimensions. We corroborate this behavior via experiments with different algorithms and discuss generalizations and extensions to different types of graphs. PMID- 29758755 TI - Electrostatic bending response of a charged helix. AB - We explore the electrostatic bending response of a chain of charged particles confined on a finite helical filament. We analyze how the energy difference DeltaE between the bent and the unbent helical chain scales with the length of the helical segment and the radius of curvature and identify features that are not captured by the standard notion of the bending rigidity, normally used as a measure of bending tendency in the linear response regime. Using DeltaE to characterize the bending response of the helical chain we identify two regimes with qualitatively different bending behaviors for the ground state configuration: the regime of small and the regime of large radius-to-pitch ratio, respectively. Within the former regime, DeltaE changes smoothly with the variation of the system parameters. Of particular interest are its oscillations with the number of charged particles encountered for commensurate fillings which yield length-dependent oscillations in the preferred bending direction of the helical chain. We show that the origin of these oscillations is the nonuniformity of the charge distribution caused by the long-range character of the Coulomb interactions and the finite length of the helix. In the second regime of large values of the radius-to-pitch ratio, sudden changes in the ground state structure of the charges occur as the system parameters vary, leading to complex and discontinuous variations in the ground state bending response DeltaE. PMID- 29758756 TI - Resilience of networks to environmental stress: From regular to random networks. AB - Despite the huge interest in network resilience to stress, most of the studies have concentrated on internal stress damaging network structure (e.g., node removals). Here we study how networks respond to environmental stress deteriorating their external conditions. We show that, when regular networks gradually disintegrate as environmental stress increases, disordered networks can suddenly collapse at critical stress with hysteresis and vulnerability to perturbations. We demonstrate that this difference results from a trade-off between node resilience and network resilience to environmental stress. The nodes in the disordered networks can suppress their collapses due to the small-world topology of the networks but eventually collapse all together in return. Our findings indicate that some real networks can be highly resilient against environmental stress to a threshold yet extremely vulnerable to the stress above the threshold because of their small-world topology. PMID- 29758757 TI - Electrohydrodynamic channeling effects in narrow fractures and pores. AB - In low-permeability rock, fluid and mineral transport occur in pores and fracture apertures at the scale of micrometers and below. At this scale, the presence of surface charge, and a resultant electrical double layer, may considerably alter transport properties. However, due to the inherent nonlinearity of the governing equations, numerical and theoretical studies of the coupling between electric double layers and flow have mostly been limited to two-dimensional or axisymmetric geometries. Here, we present comprehensive three-dimensional simulations of electrohydrodynamic flow in an idealized fracture geometry consisting of a sinusoidally undulated bottom surface and a flat top surface. We investigate the effects of varying the amplitude and the Debye length (relative to the fracture aperture) and quantify their impact on flow channeling. The results indicate that channeling can be significantly increased in the plane of flow. Local flow in the narrow regions can be slowed down by up to 5% compared to the same geometry without charge, for the highest amplitude considered. This indicates that electrohydrodynamics may have consequences for transport phenomena and surface growth in geophysical systems. PMID- 29758758 TI - Transition from homogeneous to inhomogeneous limit cycles: Effect of local filtering in coupled oscillators. AB - We report an interesting symmetry-breaking transition in coupled identical oscillators, namely, the continuous transition from homogeneous to inhomogeneous limit cycle oscillations. The observed transition is the oscillatory analog of the Turing-type symmetry-breaking transition from amplitude death (i.e., stable homogeneous steady state) to oscillation death (i.e., stable inhomogeneous steady state). This novel transition occurs in the parametric zone of occurrence of rhythmogenesis and oscillation death as a consequence of the presence of local filtering in the coupling path. We consider paradigmatic oscillators, such as Stuart-Landau and van der Pol oscillators, under mean-field coupling with low pass or all-pass filtered self-feedback and through a rigorous bifurcation analysis we explore the genesis of this transition. Further, we experimentally demonstrate the observed transition, which establishes its robustness in the presence of parameter fluctuations and noise. PMID- 29758759 TI - Calculation of gyrotropy coefficients in media with low-pitch helical structures. AB - Chiral smectic liquid crystals are known for their huge optical activity due to the precession of the anisotropic dielectric tensor around the helicoidal axis. For an oblique direction of the propagating wave, the helix acts as a grating which splits an incident beam in different directions as long as the pitch is not too small with respect to the light wavelength. When the pitch of the helix is smaller than the wavelength, the effect of the helix is a renormalization of the gyrotropic coefficients (g_{?} and g_{?}) of the resulting uniaxial medium. We report here on a method to compute these coefficients in that limit. Resolution of the Maxwell equations, using a perturbative approach, gives expressions for g_{?} and g_{?} as a power development of the ratio (p/lambda). The various terms of these developments coincide with the approximate expressions of these coefficients known in the literature. PMID- 29758761 TI - Appearance of deterministic mixing behavior from ensembles of fluctuating hydrodynamics simulations of the Richtmyer-Meshkov instability. AB - We obtain numerical solutions of the two-fluid fluctuating compressible Navier Stokes (FCNS) equations, which consistently account for thermal fluctuations from meso- to macroscales, in order to study the effect of such fluctuations on the mixing behavior in the Richtmyer-Meshkov instability (RMI). The numerical method used was successfully verified in two stages: for the deterministic fluxes by comparison against air-SF_{6} RMI experiment, and for the stochastic terms by comparison against the direct simulation Monte Carlo results for He-Ar RMI. We present results from fluctuating hydrodynamic RMI simulations for three He-Ar systems having length scales with decreasing order of magnitude that span from macroscopic to mesoscopic, with different levels of thermal fluctuations characterized by a nondimensional Boltzmann number (Bo). For a multidimensional FCNS system on a regular Cartesian grid, when using a discretization of a space time stochastic flux Z(x,t) of the form Z(x,t)->1/sqrt[h?t]N(ih,nDeltat) for spatial interval h, time interval Deltat, h, and Gaussian noise N should be greater than h_{0}, with h_{0} corresponding to a cell volume that contains a sufficient number of molecules of the fluid such that the fluctuations are physically meaningful and produce the right equilibrium spectrum. For the mesoscale RMI systems simulated, it was desirable to use a cell size smaller than this limit in order to resolve the viscous shock. This was achieved by using a modified regularization of the noise term via Z(x,t) >1/sqrt[?tmax(h^{3},h_{0}^{3})]N(ih,nDeltat), with h_{0}=xih?hLJ} between the set of nonisomorphic sticky-hard-sphere clusters M_{SHS} and the sets of local energy minima M_{LJ} of the (m,n)-Lennard Jones potential V_{mn}^{LJ}(r)=E/n-m[mr^{-n}-nr^{-m}] is established. The number of nonisomorphic stable clusters depends strongly and nontrivially on both m and n and increases exponentially with increasing cluster size N for N?10. While the map from M_{SHS}->M_{SHS->LJ} is noninjective and nonsurjective, the number of Lennard-Jones structures missing from the map is relatively small for cluster sizes up to N=13, and most of the missing structures correspond to energetically unfavorable minima even for fairly low (m,n). Furthermore, even the softest Lennard-Jones potential predicts that the coordination of 13 spheres around a central sphere is problematic (the Gregory-Newton problem). A more realistic extended Lennard-Jones potential chosen from coupled-cluster calculations for a rare gas dimer leads to a substantial increase in the number of nonisomorphic clusters, even though the potential curve is very similar to a (6,12)-Lennard Jones potential. PMID- 29758766 TI - Bak-Sneppen model: Local equilibrium and critical value. AB - The Bak-Sneppen (BS) model is a very simple model that exhibits all the richness of self-organized criticality theory. At the thermodynamic limit, the BS model converges to a situation where all particles have a fitness that is uniformly distributed between a critical value p_{c} and 1. The p_{c} value is unknown, as are the variables that influence and determine this value. Here we study the BS model in the case in which the lowest fitness particle interacts with an arbitrary even number of m nearest neighbors. We show that p_{c} verifies a simple local equilibrium relation. Based on this relation, we can determine bounds for p_{c} of the BS model and exact results for some BS-like models. Finally, we show how transformations of the original BS model can be done without altering the model's complex dynamics. PMID- 29758767 TI - Neural network approach to time-dependent dividing surfaces in classical reaction dynamics. AB - In a dynamical system, the transition between reactants and products is typically mediated by an energy barrier whose properties determine the corresponding pathways and rates. The latter is the flux through a dividing surface (DS) between the two corresponding regions, and it is exact only if it is free of recrossings. For time-independent barriers, the DS can be attached to the top of the corresponding saddle point of the potential energy surface, and in time dependent systems, the DS is a moving object. The precise determination of these direct reaction rates, e.g., using transition state theory, requires the actual construction of a DS for a given saddle geometry, which is in general a demanding methodical and computational task, especially in high-dimensional systems. In this paper, we demonstrate how such time-dependent, global, and recrossing-free DSs can be constructed using neural networks. In our approach, the neural network uses the bath coordinates and time as input, and it is trained in a way that its output provides the position of the DS along the reaction coordinate. An advantage of this procedure is that, once the neural network is trained, the complete information about the dynamical phase space separation is stored in the network's parameters, and a precise distinction between reactants and products can be made for all possible system configurations, all times, and with little computational effort. We demonstrate this general method for two- and three dimensional systems and explain its straightforward extension to even more degrees of freedom. PMID- 29758768 TI - Detachment dynamics of colloidal spheres with adhesive interactions. AB - Escape of colloidal-size particles from various kinds of solids, such as aggregates and surfaces, occurs in a wide variety of settings of both fundamental and applied scientific interest. In this paper an exact solution for the detachment of adhesive spheres from each other by means of diffusion is presented. The solution takes into account repeated detachment and reattachment events in the course of time on the way toward the permanently separated state. For strongly adhesive spheres this state is approached in an exponential manner essentially regardless of how the bound state is specified. The analytical solution is shown to capture semiquantitatively the escape from more realistic potential wells using a mapping procedure whereby equality of second virial coefficients is imposed. PMID- 29758769 TI - Modulation of dynamic modes by interplay between positive and negative feedback loops in gene regulatory networks. AB - A positive and a negative feedback loop can induce bistability and oscillation, respectively, in biological networks. Nevertheless, they are frequently interlinked to perform more elaborate functions in many gene regulatory networks. Coupled positive and negative feedback loops may exhibit either oscillation or bistability depending on the intensity of the stimulus in some particular networks. It is less understood how the transition between the two dynamic modes is modulated by the positive and negative feedback loops. We developed an abstract model of such systems, largely based on the core p53 pathway, to explore the mechanism for the transformation of dynamic behaviors. Our results show that enhancing the positive feedback may promote or suppress oscillations depending on the strength of both feedback loops. We found that the system oscillates with low amplitudes in response to a moderate stimulus and switches to the on state upon a strong stimulus. When the positive feedback is activated much later than the negative one in response to a strong stimulus, the system exhibits long-term oscillations before switching to the on state. We explain this intriguing phenomenon using quasistatic approximation. Moreover, early switching to the on state may occur when the system starts from a steady state in the absence of stimuli. The interplay between the positive and negative feedback plays a key role in the transitions between oscillation and bistability. Of note, our conclusions should be applicable only to some specific gene regulatory networks, especially the p53 network, in which both oscillation and bistability exist in response to a certain type of stimulus. Our work also underscores the significance of transient dynamics in determining cellular outcome. PMID- 29758770 TI - Chaos and Anderson-like localization in polydisperse granular chains. AB - We investigate the dynamics of highly polydisperse finite granular chains. From the spatiospectral properties of small vibrations, we identify which particular single-particle displacements lead to energy localization. Then, we address a fundamental question: Do granular nonlinearities and the resulting chaotic dynamics destroy this energy localization? Our numerical simulations show that for moderate nonlinearities, the overall system behaves chaotically, and spreading of energy occurs. However, long-lasting chaotic energy localization is observed for particular single-particle excitations in the presence of the nonsmooth nonlinearities. On the other hand, for sufficiently strong nonlinearities, the granular chain reaches energy equipartition. In this case, an equilibrium chaotic state is reached independent of the initial position excitation. PMID- 29758771 TI - General propagation lattice Boltzmann model for nonlinear advection-diffusion equations. AB - In this paper, a general propagation lattice Boltzmann model is proposed for nonlinear advection-diffusion equations (NADEs), and the Chapman-Enskog analysis shows that the NADEs with variable coefficients can be recovered correctly from the present model. We also perform some simulations of the linear advection diffusion equation, nonlinear heat conduction equation, NADEs with anisotropic diffusion, and variable coefficients to test the present model, and find that the numerical results agree well with the corresponding analytical solutions. Moreover, it is also shown that by properly adjusting the two free parameters introduced into the propagation step, the present model could be more stable and more accurate than the standard lattice Bhatnagar-Gross-Krook model. PMID- 29758773 TI - Whole-genome sequencing: not yet making the clinical grade. PMID- 29758774 TI - Legal aspects of biobanking as key issues for personalized medicine and translational exploitation. AB - This perspective article provides an overview on selected legal aspects of biobanking. It discusses these issues with a focus on public biobanks in a university setting and the specific challenges posed by personalized medicine. We conclude that any decisions as to the design of the regulatory environment should follow a process that takes account of the values, hopes and concerns of all stakeholders involved. In particular, we stress the importance of a careful planning of consent obligations combining traditional legal methods with an adequate institutional setup. In order to enhance the translational exploitation of biobanks, we further emphasize the pressing need to carefully consider a great variety of strategies and policy choices relating to intellectual property rights. PMID- 29758775 TI - Personalizing busulfan therapy for children undergoing hematopoietic stem cell transplantation. PMID- 29758776 TI - The future of genomic testing in primary care: the changing face of personalized medicine. AB - Primary care is recognized worldwide as a key component for improving health outcomes in the population. At the same time, healthcare systems are rapidly changing with increasing expectations from technological advances. Genomics is a major driver in changing how medicine is being practiced; however, the importance for primary care has been under-appreciated. Strategically implementing genomics in a way that accounts for the unique characteristics of the primary care context is essential. In this perspective, we present important areas that we believe are critical in consideration of both the future of genomic medicine and primary healthcare delivery. PMID- 29758777 TI - Public attitudes toward genetic risk testing and its role in healthcare. AB - Developments in genomics continue to increase the number of disorders for which genetic testing is available, whether in the primary healthcare system, through direct-to-consumer testing, or as part of expanded newborn screening panels. This paper reviews a robust literature on public attitudes toward genetics and genetic testing. In general, attitudes are positive about genetic research and new genomic technologies, with majorities indicating an interest in genetic testing. However, complex beliefs comprise the public's thinking about genetics. Attitudes are driven by beliefs about the type of genetic research, the personal and clinical utility of tests, and the area of genetics in which testing is applied. Limitations of current research are noted and suggestions made for future research. PMID- 29758778 TI - Creating policy frameworks for public health genomics to benefit developing countries. AB - Unprecedented advances in life sciences, as exemplified by the revolution in genomics, are yet to translate into effective public health interventions to benefit the health of populations living in the developing world. The developing countries continue to bear the major burden of disease globally, both infectious and chronic diseases, and they could clearly benefit from genomics being harnessed and used to address the greatest public health problems in addition to benefits for the health of individuals. For this to happen, we need to understand what are the major challenges or bottlenecks to be overcome and, informed by these priorities, create an effective, inclusive, equitable and sustainable policy framework within which knowledge translation into improved health outcomes of underprivileged populations can take place. PMID- 29758781 TI - Company Profile: Multiple Myeloma Research Foundation. AB - The role of nonprofit organizations in drug development has evolved from a primary emphasis on grant funding to a driving force that is advancing scientific development and leading cutting edge research. The Multiple Myeloma Research Foundation (MMRF) is a leader in this field, and has recognized that despite recent advances, multiple myeloma patients' responses to today's treatments are variable and unpredictable, often based on the patient's molecular profile. The MMRF believes all patients would benefit from the creation of new, personalized treatment approaches and is working to make this vision a reality with its ambitious Personalized Medicine Initiative. Most recently, MMRF launched the CoMMpassSM (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) study to collect and analyze tissue samples and genetic information from approximately 1000 multiple myeloma patients over the next 5 years. The study is designed to tailor next-generation personalized multiple myeloma treatments. PMID- 29758779 TI - Challenges for the implementation of high-throughput testing and liquid biopsies in personalized medicine cancer trials. AB - During recent decades, major advances in the comprehension of biology and in biotechnologies have paved the way for what is commonly named personalized medicine. For cancer therapy, personalized medicine represents a paradigm shift in which patient treatment is based on biology in addition to histology and tumor location. Here, we report the major personalized medicine trials in oncology that are either based on molecular alterations from tumor tissue or from circulating blood markers. We next review important challenges facing the implementation of personalized medicine in daily clinical practice, including tumor heterogeneity, reliability of high-throughput technologies, the key role of bioinformatics and the assessment of biomarkers and synthetic models, in order to use big data in actual cancer biology. PMID- 29758782 TI - Institutional Profile: Center for Connected Health. AB - The Center for Connected Health, a division of Partners HealthCare (MA, USA), is working to create a new model for healthcare delivery, by developing programs and innovative strategies to move care from the hospital or doctor's office into the day-to-day lives of patients. Our technology-enabled and patient-centric connected health initiatives are engaging patients, providers and the connected health community to improve quality and access to care. Many patients 'graduate' from these connect programs empowered and equipped to better manage their own health; and these programs are being successfully integrated across the Partners' network of hospitals and implemented by major employers. Our focus is to innovate, accelerate and operate connected health initiatives to transform healthcare delivery in an era plagued with a rising prevalence of chronic diseases. PMID- 29758783 TI - Pathologists and the third wave of medical genomics. PMID- 29758784 TI - Direct-to-consumer genetic testing: regulating offer or use? PMID- 29758788 TI - Genomic pathology: a disruptive innovation. PMID- 29758785 TI - Will gene-environment interactions explain differential antidepressant response? PMID- 29758789 TI - Interview: An evolving career in personalized medicine: an interview with Dr Paul Billings. AB - Paul Billings speaks to Tarryn Greenberg, Managing Commissioning Editor Board certified internist and clinical geneticist Dr Paul R Billings serves as Chief Medical Officer of Life Technologies Corporation, a new position aimed at improving patient care through expanding the use of medically relevant genomic technologies in clinical settings. Dr Billings brings extensive expertise and healthcare experience in the areas of genomics and molecular medicine. Most recently, he served as Director and Chief Scientific Officer of the Genomic Medicine Institute at El Camino Hospital (CA, USA), the largest community hospital in the Silicon Valley. He was a member of the US Department of Health and Human Services Secretary's Advisory Committee on Genetics, Health and Society. He currently serves on the Scientific Advisory Board of the US FDA, the Genomic Medicine Advisory Committee at the Department of Veterans Affairs and the IOM Roundtable on Genomics. Dr Billings has had a distinguished career as a physician and researcher. He has been a founder or chief executive officer of companies involved in genetic and diagnostic medicine, including GeneSage, Omicia and CELLective Dx Corporation. Previously, he was Senior Vice President for corporate development at Laboratory Corporation of America Holdings (LabCorp). He has held academic appointments at some of the most prestigious universities in the USA, including Harvard Medical School, UC San Francisco (CA, USA), Stanford University School of Medicine (CA, USA) and UC Berkeley (CA, USA), and has served as a physician at a number of prominent medical centers. He is the author of nearly 200 publications and books on experimental and clinical medicine. His work on genetic discrimination was instrumental in the creation and passage of the federal Genetic Information Non-Discrimination Act of 2008. Dr Billings holds an MD from Harvard Medical School (MA, USA) and a PhD in immunology, also from Harvard University. Dr Billings is a long time Board Member and has previously served as Board Chair, of the Council for Responsible Genetics. PMID- 29758790 TI - TRIG on TRACK: educating pathology residents in genomic medicine. AB - Genomic technologies are dramatically changing the practice of medicine. Next generation sequencing has allowed prognostic stratification of cancer patients, personalized drug therapy and the identification of genetic risk factors for a multitude of diseases. As the physicians who oversee tissue- and laboratory-based diagnostic testing, pathologists must understand and utilize this new technology for the benefit of patients; however, only a minority of pathology residency programs currently provide training in genomics. In response to this urgent need, the Training Residents in Genomics (TRIG) Working Group has made significant progress towards creating, implementing, evaluating and disseminating a national curriculum in genomic pathology. Although presented in the context of pathology training, the approach described in this review can serve as model for education in genomic medicine of students, trainees or professionals in other areas of healthcare. PMID- 29758791 TI - Between hype and hope: whole-genome sequencing in clinical medicine. PMID- 29758792 TI - Mapping genes for oligodendroglioma. PMID- 29758794 TI - Interview: A perspective on personalized medicine: Dr David Korn. AB - David Korn speaks to Tarryn Greenberg, Managing Commissioning Editor David Korn (BA, scl, MD, cl; Harvard University, MA, USA) stepped down from his position as Harvard University's inaugural Vice-Provost for Research on June 30, 2011. He is presently Consultant in Pathology and member of the medical staff at the Massachusetts General Hospital, Boston, MA, USA and Professor of Pathology at Harvard Medical School. Dr Korn has been a member of the editorial boards of the American Journal of Pathology, The Journal of Biological Chemistry, and Human Pathology, and for many years was an Associate Editor of the latter. He has sat on many societies, councils and boards. He has written many scientific articles, ranging from bacteriophage biochemistry and genetics to the biochemistry and molecular biology of DNA replication in human cells. During the past two decades his work, writings and lectures have focused on issues of academic values and integrity, research integrity, and health and science policy, and he is presently regarded as a national authority on matters of financial conflicts of interest in academic research. PMID- 29758795 TI - Modernizing US regulatory and reimbursement policy to support continued innovation in genomic pathology. AB - The pace of technical and scientific advancement for genomics-based technologies has outstripped the ability of the US regulatory bodies to keep abreast of the emerging paradigms, resulting in regulatory pronouncements that often appear dated and payment systems that are misaligned. Over burdensome evidentiary requirements, encroachment of federal regulators into the practice of laboratory medicine, and failure to align public health objectives with pay or valuation sufficient to support professional pathology services and necessary capital investment threaten to stifle continued innovation in genomic-based diagnostic tools. Nevertheless, the US FDA is committed to improving regulatory science and to increased stakeholder participation in policy-making, and serious efforts to address coding and test value are underway. Moreover, federal legislation will be debated in the coming months that, if enacted, could clarify authorities and institute meaningful regulatory and reimbursement paradigms better suited to molecular testing. This review explores these dynamic policy issues and their implications for genomic pathology as the foundation of personalized medicine. PMID- 29758797 TI - Deriving clinical action from whole-genome analysis. PMID- 29758796 TI - Association between endothelin type A receptor haplotypes and mortality in coronary heart disease. AB - AIMS: The endothelin type A receptor, encoded by EDNRA, mediates the effects of endothelin-1 to promote vasoconstriction, vascular cell growth, adhesion, fibrosis and thrombosis. We investigated the association between EDNRA haplotype and cardiovascular outcomes in patients with coronary artery disease. METHODS: Coronary disease patients (n = 1007) were genotyped for the His323His (rs5333) variant and one tag SNP from each of the major EDNRA haplotype blocks (rs6537484, rs1568136, rs5335 and rs10003447). EDNRA haplotype associations with clinical history, natriuretic peptides cardiac function and cardiovascular outcomes were tested over a median 3.8 years. RESULTS: Univariate analysis identified a 'low risk' EDNRA haplotype associated with later age of Type 2 diabetes onset (p = 0.004) smaller BMI (p = 0.021), and reduced mortality (log rank p = 0.001). Cox proportional hazards analysis including established cardiovascular risk factors revealed an independent association between haplotype and mortality (p < 0.0001). CONCLUSION: These data highlight the potential importance of the endothelin system, and in particular EDNRA in coronary disease. PMID- 29758799 TI - Circulating nucleosomes: a new addition to the personalized medicine toolkit. AB - Dr Stefan Holdenrieder is senior physician at the Institute of Clinical Chemistry and Clinical Pharmacology of the University Hospital Bonn, Germany. He is an expert in the field of circulating tumor biomarkers and particularly circulating nucleosomes. He has conducted numerous clinical studies concerning the biomarker based detection and monitoring of cancer diseases and has published more than 90 papers in recognized international journals. PMID- 29758798 TI - The business value and cost-effectiveness of genomic medicine. AB - Genomic medicine offers the promise of more effective diagnosis and treatment of human diseases. Genome sequencing early in the course of disease may enable more timely and informed intervention, with reduced healthcare costs and improved long term outcomes. However, genomic medicine strains current models for demonstrating value, challenging efforts to achieve fair payment for services delivered, both for laboratory diagnostics and for use of molecular information in clinical management. Current models of healthcare reform stipulate that care must be delivered at equal or lower cost, with better patient and population outcomes. To achieve demonstrated value, genomic medicine must overcome many uncertainties: the clinical relevance of genomic variation; potential variation in technical performance and/or computational analysis; management of massive information sets; and must have available clinical interventions that can be informed by genomic analysis, so as to attain more favorable cost management of healthcare delivery and demonstrate improvements in cost-effectiveness. PMID- 29758800 TI - An assessment of clinician and researcher needs for support in the era of genomic medicine. AB - AIM: To assess clinicians' and researchers' past, current and anticipated future use of next-generation sequencing (NGS) and anticipated needs for support. Materials & methods: A web-based survey was conducted at Boston Children's Hospital. RESULTS: Many clinicians anticipate that they will use exome/genome sequencing (44.8%) and/or candidate gene panels (50%) within the next year. Researcher respondents anticipate the need for exome/genome sequencing (48.0%) and candidate gene panels (31.8%). Few respondents (13.6%) said that they felt 'Completely Ready' or 'Pretty Much Ready' to incorporate NGS into their clinical practice or research. CONCLUSION: Researchers and clinicians anticipate increased utilization of NGS. Respondents indicated varying degrees of need for a diverse list of support services, ranking interpretation and clinical correlation support as the most needed services. PMID- 29758801 TI - Overcoming immune system evasion by personalized immunotherapy. PMID- 29758802 TI - Benefits and burdens of newborn screening: public understanding and decision making. AB - In this article we review the literature regarding the public understanding of the potential benefits and burdens of expanded newborn bloodspot screening. We draw attention to broadened notions of benefit that go beyond early identification of asymptomatic individuals and interventions to reduce morbidity or mortality, and include benefits gained by families through knowledge that may facilitate life choices, as well as gains generated by avoiding diagnostic delays. We also reflect on burdens such as increasing false-positive results and parental anxiety, together with risks of overdiagnosis when the natural history of a condition is poorly understood. We conclude that expanded notions of benefit and burden bring with them implications for parental consent and confidentiality and the secondary use of bloodspots. PMID- 29758803 TI - Targeted next-generation sequencing: the clinician's stethoscope for genetic disorders. AB - Genetic biomarkers are crucial for diagnosis, guiding of treatments and estimation of prognosis. In the past, clinical genetic diagnostics was limited by the sequencing information gained from selected exons and single genes. For genetically heterogeneous diseases, such as cardiomyopathies, where underlying mutations in more than 1000 exons are known, a Sanger-based comprehensive test would have been extremely expensive and labor intensive. Next-generation sequencing has overcome these problems in terms of costs, speed and throughput. In this review we discuss available methods for targeted next-generation sequencing that ease the introduction of this technology into routine clinical application. We further provide results of a study we have performed to compare two state-of-the-art methods for their enrichment efficiency and detection accuracy of variants in a clinical setting. PMID- 29758806 TI - Metabolomics for the future of personalized medicine through information and communication technologies. PMID- 29758807 TI - A revolution in healthcare: challenges and opportunities for personalized medicine. PMID- 29758808 TI - Chromosomal microarrays: influential players in the diagnosis of developmental disorders. PMID- 29758810 TI - Ethical considerations for biobanking: should individual research results be shared with relatives? PMID- 29758811 TI - Research Highlights: Pulling out novel COPD genes from the 'gray zone' of genome wide association studies. PMID- 29758812 TI - Personalized medicine in rare diseases. PMID- 29758813 TI - Discovery of new treatments in the context of delivering personalized medicine. PMID- 29758814 TI - The rocky road to personalized medicine: computational and statistical challenges. PMID- 29758815 TI - Predictive medicine and biomarkers: the case of rare diseases. PMID- 29758816 TI - Personalized medicine: renewing the social science research agenda. PMID- 29758817 TI - Company Profile: HistoRx: tissue-based diagnostic solutions for personalized medicine. AB - The mission of HistoRx (CT, USA) is to develop and commercialize clinically actionable immunohistochemical (IHC) biomarker assays with the distinctive characteristic of being as quantitative, objective and standardized as the measurement of glucose in blood. In clinical laboratory practice, serum glucose measurement is expected to give the same result regardless of the laboratory or operator performing the test, and the same should be true for tissue-based IHC tests in anatomical pathology. By offering such improvements to standard IHC analysis using reproducible AQUA(r) assays, patients will benefit from standardized results for determination of appropriate targeted therapeutic drug treatment. PMID- 29758818 TI - Enabling personalized medicine in Europe: a look at the European Commission's funding activities in the field of personalized medicine research. AB - The potential benefits that personalized medicine approaches can bring to healthcare are discussed with much interest throughout the EU. This novel approach is based on a better understanding of the molecular mechanisms of health and disease and it has now begun to show results. There is, however, a long way to go before the area is fully exploited. This special report reviews the European Commission's funding activities related to personalized medicine research. Although the specific focus on personalized medicine is relatively new, the European Commission has already committed significant funding to research in enabling technologies relevant to the field, as well as to specific disease areas for their application. A stocktaking exercise which started in 2010 has helped identify immediate and future challenges in personalized medicine research. The outcome of this exercise, summarized below, will contribute to developing a vision for future research funding at the EU level. PMID- 29758819 TI - Public health perspective: from personalized medicine to personal health. PMID- 29758820 TI - Opinion leaders' views on issues in personalized medicine. PMID- 29758821 TI - How can evolutionary medicine inform future personalized medicine? PMID- 29758822 TI - The need for education in personalized medicine. PMID- 29758823 TI - There is nothing 'incidental' about unrelated findings. PMID- 29758825 TI - Scaling crowdsourced health studies: the emergence of a new form of contract research organization. AB - Accessing crowdsourced cohorts for health studies is a significant emerging opportunity that could have a positive impact on public health research, particularly as outcomes shift to the personalized, preventive medicine of the future. Health social networks have grown to become some of the largest aggregate patient registries and offer cost and efficiency benefits for study recruitment and operation by both traditional researchers and citizen scientists. Here, a model is proposed for extending crowdsourced studies beyond small-group experimentation to large-scale intervention-based research studies that are professionally run and scientifically rigorous, in effect creating a new form of contract research organization. PMID- 29758824 TI - Gender-based differences in hemostatic responses. AB - AIM: Recent reports indicate increased mortality in women owing to cardiovascular diseases necessitating more gender-based studies. It is hypothesized that women have variable hemostatic responses to anticoagulant drugs. MATERIALS & METHODS: The hemostatic responses in healthy males (n = 10) and females (n = 10) were evaluated by performing various assays in the presence of anticoagulant drugs. Citrated whole blood from healthy volunteers (n = 20) was supplemented with rivaroxaban (final concentration [FC] = 0.3 ug/ml) and enoxaparin (FC =5 ug/ml). RESULTS: Differences between males and females were noted in the whole blood activated partial thromboplastin time (p = 0.0442) and Heptest(r) (p = 0.0345) assays in the saline control values. In the plasma system, rivaroxaban at a FC of 0.3 ug/ml and enoxaparin at 5 ug/ml showed a gender-based difference in the Heptest (p = 0.0423). Females showed faster fibrin formation than males. In the plasma system, plasminogen activator inhibitor-1 and domain-dimer assays (American Diagnostica, CT, USA) were performed with domain-dimer showing differences (p = 0.035). In the von Willebrand factor multimers, only band 5 showed differences (p = 0.032). Gender-based differences were observed. CONCLUSION: Careful adjustment of the dosages of anticoagulant drugs may be necessary to avoid bleeding or thrombosis. PMID- 29758826 TI - Ascertainment and critical assessment of the views of the general public and healthcare professionals on nutrigenomics in Greece. AB - AIM: The aim of this study was to understand the general public's and healthcare professionals' views on nutrigenomics. PATIENTS & METHODS: We designed a cross sectional survey of healthcare professionals (n = 87) and the general public (n = 1504) in the three largest cities in Greece (Athens, Thessaloniki and Patras). RESULTS: Our data revealed that only 11.5% of respondents from the general public had been advised to take a genetic test in order to explore the relationship between their genes and their nutritional status. Although 80.5% of healthcare professionals would have been willing to recommend their patients/clients to undergo nutrigenomic analysis to correlate their genetic profile with their diet, only 17.2% of respondents had actually done so. In general, the general public was opposed to direct-access nutrigenomics testing. CONCLUSION: The application of genomic information in the context of nutritional choice requires the continuing education of healthcare professionals and the dissemination of accurate and reliable information to the general public. PMID- 29758827 TI - Personalized medicine: a competitor or an upgrade of evidence-based medicine? AB - Evidence-based medicine is a method of healthcare decision-making that intends to combine the most reliable scientific information with individual expertise and patient preferences in order to offer the optimal diagnostic and therapeutic option for the patient. In recent years, the term personalized medicine has been introduced to represent an approach considering differences among individual patients. In modern medicine the most important sources of evidence are clinical trials using epidemiological methods, and molecular biological and genetic methods characterizing individual patients. Responses to a certain therapeutic intervention differ among patients for several reasons. Identifying benefits and harms of an intervention can be handled by two approaches. The first is a statistical approach using the rule of large numbers, resulting in statistically meaningful conclusions. The other approach is personalized: the conclusions are valid for individual patients or subgroups identified by well-defined markers. Whether the evidence is statistical deriving from a large number of clinical observations or personalized based on molecular studies - it should be scientifically sound to apply in clinical practice. Confronting evidence-based medicine with personalized medicine would be justified only if the former is misinterpreted and restricted only to the use of randomized trials and their systematic reviews. The practice of personalized medicine is also based on evidence, and in many instances evidence from molecular research is also statistical in nature. Regarding healthcare decision about an individual patient, whether using evidence from randomized trials or from molecular studies of biomarkers, we have to base our decisions on reliable, good quality evidence. Evidence from molecular and genetic medicine thus improves the armament of evidence-based medicine, and this upgrade yields a more reliable support for our decisions in everyday practice. PMID- 29758830 TI - Impact of the new EGF receptor and ALK testing guideline on personalized lung cancer medicine. PMID- 29758831 TI - New oral anticoagulant drugs: real-world data. PMID- 29758832 TI - Epigenetics and personalized medicine: prospects and ethical issues. AB - As scientific knowledge about gene-environment interactions and the role of epigenetic factors in gene expression grows, new possibilities for personalized medicine may be opened up. In particular, the associations that have been demonstrated between epigenetic markers and certain diseases are an exciting development for personalized medicine. These advances also create new ethical challenges, regarding causal and moral responsibility, due to unique characteristics of how epigenetic effects regulate gene expression, are established and may change over the course of a person's life. This article examines the ethical implications of integrating epigenetic knowledge into personalized medicine. PMID- 29758833 TI - Pathology-supported genetic testing directed at shared disease pathways for optimized health in later life. AB - Several chronic, noncommunicable diseases share common genetic risk factors. These include cardiovascular disease and several neurological and psychiatric disorders, as well as some forms of cancer. Clinical compartmentalization and the challenges of translational research have delayed the implementation of personalized medicine. To overcome these limitations, a pathology-supported genetic testing service has been established to enable the incorporation of genomics into a universally accepted body of knowledge. An online questionnaire is used to obtain information on personal and family medical conditions, medication use/side effects, lifestyle factors and pathology test results relevant to the genetic analysis performed. Validation studies from multidisciplinary sources and the expanding GknowmixTM database are applied to determine whether the clinical characteristics of the patient match the test results. With this approach, a set of common functional polymorphisms at critical control points within key biological pathways can be studied to determine current or future clinical relevance across diagnostic boundaries. PMID- 29758835 TI - Research Highlights: New insights into prostate cancer susceptibility. PMID- 29758834 TI - Challenges for implementing next-generation sequencing-based genome diagnostics: it's also the people, not just the machines. AB - The scope of next-generation DNA sequencing (NGS) is transitioning from research to diagnostics (and beyond), but the conditions for routine clinical application have not been clearly defined. Technological limitations for sequencing a patient's DNA fast and affordably are rapidly disappearing. At the same time, more and more is known about the role of DNA variation in disease susceptibility, disease development and response to treatment. Consequently, more and more pediatricians, cardiologists and other medical specialists would like to apply NGS-based diagnostics. The standard, comprehensive and easy-to-handle genetic test these specialists are looking for, however, is not yet available. Molecular diagnostic laboratories have started to implement NGS into their routine workflows, but are also becoming increasingly aware that the context in which they operate is changing. It becomes apparent that the major challenges are not in the technology, but rather in anticipating the changing scope and scale. Developing the infrastructure to sustainably perform NGS-based diagnostics in a changing technological, clinical and societal context is therefore more relevant than defining minimal performance criteria or standard analysis pipelines. Implementing NGS-based diagnostics comes with novel applications, emerging service models and reconfiguration of professional roles, and should thus be considered in the context of future healthcare. Here, we present the key elements for transition of NGS from research to diagnostics. PMID- 29758837 TI - Clinical trials for precision oncology using next-generation sequencing. AB - The demonstrated genomic heterogeneity of human cancers is having major impacts on the development and evaluation of cancer therapeutics and molecular diagnostics. Many new cancer drugs target somatic alterations in tumors and are being developed with companion diagnostics. Oncology drug development and practice are likely to become increasingly stratified and utilize the enrichment Phase III trial paradigm. Although this paradigm includes an increasing number of successes, single-agent molecularly targeted treatment of metastatic disease will generally provide limited patient benefit. More substantial gains will require better understanding of crosstalk among signaling pathways, ability to combine drugs and use of drugs at initial diagnosis. Early phase discovery clinical trials in which patients will have genome-wide tumor characterization at diagnosis and at critical retreatment points will provide data sets for learning how to effectively match therapeutics to genomic alterations. However, moving tumor genomics to clinical oncology entails many practical challenges. We review some of these challenges and the clinical studies that are being undertaken to translate genomics to clinical oncology. PMID- 29758838 TI - Tissue microarrays: leaping the gap between research and clinical adoption. AB - The use of tissue microarrays (TMAs) in the preclinical and translational research settings has become ubiquitous as they allow for high-throughput in situ biomarker analysis of hundreds of patient samples, with time and cost efficiency. Coupled with advanced imaging and image-analysis technologies that allow for objective and standardized biomarker expression assessment, TMAs have become critical tools for the development and validation of clinically meaningful biomarker diagnostic assays. However, their diagnostic use in the clinical laboratory setting is limited due to the need for conventional whole-section tissue assessment used for routine diagnostic purposes. In this article, after reviewing TMA basics and their translational and clinical research applications, we will focus on the use of TMAs for robust assay development and quality control in the clinical laboratory setting, as well as provide insights into how TMAs may serve well in the clinical setting as assay performance and quantification controls. PMID- 29758836 TI - Oncology health professionals' attitudes toward treatment-focused genetic testing for women newly diagnosed with breast cancer. AB - AIM: This study explored the attitudes of oncology health professionals towards treatment-focused genetic testing (TFGT) for women newly diagnosed with breast cancer. MATERIALS & METHODS: Members of several relevant medical organizations in Australia and New Zealand were invited via email to participate in an online survey. RESULTS: A total of 149 respondents, including 40 surgeons, 46 oncologists and 63 breast care nurses, completed the online questionnaire. The majority of respondents believed that TFGT was useful for patient care (87.3%) and valuable for the treatment and management of breast cancer (90.6%). In multivariable analyses, breast care nurses were significantly more likely to agree that TFGT was useful for patient care and the treatment and management of breast cancer compared with oncologists and surgeons (beta = 0.30; 95% CI: 0.01 0.60; p = 0.045). Participants also agreed that TFGT has an impact on treatment decision-making (96.0%), uptake of bilateral mastectomy (98.7%) and uptake of risk-reducing salpingo-oophorectomy (98.0%) in women newly diagnosed with breast cancer. A slight preference towards surgeons (49.7%) as the best health professional to make the initial offer of TFGT was observed and the majority of respondents suggested the best time to offer TFGT was shortly after diagnosis, when the treatment plan is discussed. CONCLUSION: The findings suggest health professionals have positive attitudes towards TFGT. Future training programs focusing on teamwork models and guidelines specifying health professionals' roles in regards to TFGT and follow-up management may be of benefit. PMID- 29758841 TI - Personalized medicine for radiation therapy. PMID- 29758842 TI - Impact of chromosomal translocation and genomic instability on personalized medicine. PMID- 29758843 TI - Research Highlights: Highlights from the latest articles in chronic obstructive pulmonary disease genetics. PMID- 29758844 TI - Harnessing massively parallel DNA sequencing for the personalization of cancer management. AB - In order to properly diagnose and classify tumors and select the most appropriate therapies for patients, one must accurately and efficiently identify oncogenic mutations in key cancer-associated genes. Massively parallel DNA sequencing technology has the potential to dramatically enhance the field of molecular diagnostics. For increasingly lower costs, one can interrogate all clinically relevant genes for mutations, copy number alterations and structural rearrangements, with high detection sensitivity in heterogeneous tissue. Advances in exon capture, molecular barcoding and profiling of formalin-fixed paraffin embedded specimens have further established the clinical potential of massively parallel sequencing. This article discusses promising strategies for DNA sequencing as a clinical tool and also the challenges in its implementation in the clinical arena. PMID- 29758845 TI - Willingness-to-pay and preferences for warfarin pharmacogenetic testing in Chinese warfarin patients and the Chinese general public. AB - AIM: Genetic factors have been found to affect warfarin maintenance dose and a key factor for the successful clinical implementation of warfarin pharmacogenetic testing (WPGT) is economic sustainability. We aimed to estimate the willingness to-pay (WTP) and preferences for WPGT in Singaporean Chinese subjects. Methods & subjects: A total of 197 warfarin patients and 187 members of the public completed a questionnaire. The discrete choice methodology was used and the choice model was estimated using hierarchical Bayes. Marginal WTP, attribute importance and WTP for three hypothetical WPGTs were calculated from the estimated utilities. RESULTS: Both patients and the public placed most emphasis on side effects, followed by cost, number of International Normalized Ratio tests and 'nature of test'. WTP for WPGT ranged from S$160 to S$730. CONCLUSION: WPGTs are likely to be economically sustainable. PMID- 29758846 TI - Combination of Pyrosequencing(r) and Sanger sequencing reveals alleged novel mutation in exon 18 of EGFR. AB - BACKGROUND: EGFR sequencing is crucial for therapeutic decisions in treatment regimens of lung cancer patients. Several mutations have been identified in the past, of which some were confirmed as activating or resistance mutations by in vitro phenotyping. In this study, novel mutations of so far unknown relevance were identified by a combination of Sanger and Pyrosequencing(r). MATERIALS & METHODS: Formalin-fixed paraffin-embedded lung biopsies from 20 randomly selected patients suffering from non-small-cell lung cancer with previous external EGFR mutation analyses were reanalyzed by Sanger sequencing according to a previous study, and Pyrosequencing with the EGFR Pyro Kit (Qiagen, Hilden, Germany). Sensitivity and specificity were determined in comparison with the results of an external supplier for all relevant mutations in exons 18, 19, 20 and 21. RESULTS: Our analyses revealed that Pyrosequencing is faster and more sensitive for the common mutations compared with Sanger sequencing and the results of the external supplier. A new mutation, c.2160delC, in exon 18 in 40% of patients leading to a frameshift was identified. Another two frameshift mutations were detected in exon 18 in 10% of patients; c.2168delT in combination with c.2160delC, and c.2163insG alone. CONCLUSION: Divergences regarding the detection of the common mutations could be traced back to inhomogeneous or insufficient tumor material. Surprisingly, none of the newly identified mutations have been previously described, although they occurred in total in up to 40% of randomly selected cases. A possible explanation may be that commercial assays did not cover these deletions that are located nearby but not in the known mutation hotspot of exon 18, or that Sanger sequencing produced serious artifacts. PMID- 29758847 TI - How to spend your acquisitions budget in 2013 for advancing in personalized medicine. PMID- 29758848 TI - An economic model to value companion diagnostics in non-small-cell lung cancer. AB - AIM: An economic model was used to evaluate the potential economic impact and cost-effectiveness of companion diagnostic testing for patients with non-small cell lung cancer (NSCLC). MATERIALS & METHODS: A decision analysis model examined alternative patient management strategies for patients with advanced NSCLC who were not amenable to surgical treatment. A review of the literature provided the variables used to develop a timely base case and sensitivity analysis. A potential future scenario was also modeled. The model includes three options: conventional treatment (CT), new treatment (NT) and companion diagnostic (CD) strategy. RESULTS: In the base case analysis based upon current data, the cost per life-year saved for CT, NT option and CD was US$43,367, US$47,394 and US$47,779, respectively. The cost per life-year saved for CT, NT option and CD in a potential future scenario with more expensive, effective targeted therapy was US$47,748, US$69,255 and US$66,369, respectively. CONCLUSION: In the future scenario, CDs have an incremental cost-effectiveness of US$56,829 per life-year saved when compared with NT as a first-line treatment. This is one demonstration of how CDs may be a cost-effective option for the treatment of patients with advanced NSCLC when the NT is extremely expensive but the outcome is significantly improved. PMID- 29758849 TI - Taking measure of personalized medicine: the proteome. AB - Good medicine begins, by and large, with measurements. For medicine to become truly personalized, it is critical that the right measurements are made and interpreted. Although genomics holds great promise for deepening our understanding of biology, we believe that a perhaps more critical and transformative measurement for medicine is proteomics, which has lagged behind genomics for largely technological reasons. Proteins uniquely provide a real time, clinically relevant measure of individual patients. We describe here an entirely new proteomics technology that makes the measure of proteins from biological samples as straightforward as measuring genes, and list some of the applications that have already been performed. PMID- 29758850 TI - Metabolomics as a tool for personalizing medicine: 2012 update. AB - Numerous factors in conjunction with an individual's genetic make up will determine predisposition to disease, adverse or beneficial effects of drug treatment or therapy, and disease progression. A major limitation of current clinical measures is that the disease phenotype, which is comprised of the genotype and other environmental factors, is underestimated. Rather, each disease is treated similarly even though the disease process is highly complex. Methods that evaluate the interaction of genotype and environmental factors would likely be a better indicator of patients' response to medical treatments. The omics technologies, specifically metabolomics, will play a major role in the movement towards personalized medicine. Metabolomics is phenotype driven and should provide better clinical biomarkers. Furthermore, recent studies have shown that associations between genetic variants and downstream metabolite changes can provide a unique description of an individual's genotype and phenotype, which will further enhance the movement towards personalized medicine. PMID- 29758851 TI - Concepts for the translation of genome-based innovations into public health: a comprehensive overview. AB - Recent vast and rapid development of genome-related sciences is followed by the development of different assessment techniques or attempts to adapt the existing ones. The aim of this article is to give an overview of existing concepts for the assessment and translation of innovations into healthcare, applying a descriptive analysis of their present use by public health specialists and policy makers. The international literature review identified eight concepts including Health Technology Assessment, analytic validity, clinical validity, clinical utility, ethical, legal and social implications, Public Health Wheel and others. This study gives an overview of these concepts (including the level of current use) applying a descriptive analysis of their present use by public health specialists and policy makers. Despite the heterogeneity of the analyzed concepts and difference in use in everyday healthcare practice, the cross-integration of these concepts is important in order to improve translation speed and quality. Finally, some recommendations are made regarding the most applicable translational concepts. PMID- 29758852 TI - Erratum to Bacteria attachment to surfaces - AFM force spectroscopy and physicochemical analyses [J. Colloid Interf. Sci. 364 (2011) 213-218]. PMID- 29758853 TI - Ozone from fireworks: Chemical processes or measurement interference? AB - Fireworks have been identified as one ozone source by photolyzing NO2 or O2 and are believed to potentially be important for the nighttime ozone during firework events. In this study, we conducted both lab and field experiments to test two types of fireworks with low and high energy with the goal to distinguish whether the visible ozone signal during firework displays is real. The results suggest that previous understanding of the ozone formation mechanism during fireworks is misunderstood. Ultraviolet ray (UV)-based ozone monitors are interfered by aerosols and some specific VOCs. High-energy fireworks emit high concentrations of particular matters and low VOCs that the artificial ozone can be easily removed by an aerosol filter. Low-energy fireworks emit large amounts of VOCs mostly from the combustion of the cardboard from fireworks that largely interferes with the ozone monitor. Benzene and phenol might be major contributors to the artificial ozone signal. We further checked the nighttime ozone concentration in Jinan and Beijing, China, during Chinese New Year, a period with intense fireworks. A signal of 3-8ppbv ozone was detected and positively correlated to NO and SO2, suggesting a considerable influence of these chemicals in interfering with ambient ozone monitoring. PMID- 29758854 TI - Bioelectrochemically assisted anaerobic digestion system for biogas upgrading and enhanced methane production. AB - The objective of this study was to evaluate the effect of biofilm and external voltage on the performance and microbial community composition of batch-fed, combined anaerobic digestion-bioelectrochemical cell (AD-BEC) systems under different operational conditions. A dextrin/peptone mixture was fed at a range of organic loading rates (0.34 to 1.37g COD/L-d). The hybrid system with both suspended biomass and biofilm without any external potential application achieved a substantially higher initial soluble COD consumption (53.7+/-2.3% vs. 39.7+/ 3.7) and methane (CH4) production (331 vs. 225mL) within one day of feeding than the conventional AD system (suspended biomass only). Compared to the conventional AD system, the hybrid systems had higher resilience to shock organic loadings. A range of external potential (0.5 to 2.0V vs. Ag/AgCl) was applied to AD-BEC reactors, developed with two different start-up procedures. A potential of 2.0V resulted in water electrolysis leading to a higher CH4 production rate (105 vs. 84mL/L-d) and biogas CH4 content (88.5+/-1.4 vs. 64.5+/-1.9%) in the AD-BEC reactor (closed vs. open circuit condition, respectively). Application of external potential enriched putative exoelectrogens at the anode biofilm and hydrogenotrophic methanogens at the cathode biofilm, which may have contributed to the observed enhanced CH4 production in the AD-BEC system. A phylotype related to Methanobacterium formicicum, a hydrogenotrophic methanogen, dominated the archaeal community in the AD-BEC cathode biofilm. PMID- 29758855 TI - Ratios of greenhouse gas emissions observed over the Yellow Sea and the East China Sea. AB - During a cruise of the survey vessel Dongfanghong II on the Yellow Sea and the East China Sea in the spring of 2017 we performed accurate measurements of the mole fractions of carbon dioxide (CO2), methane (CH4), carbon monoxide (CO) and nitrous oxide (N2O) using two types of Cavity Ring-Down Spectrometers (CRDS). The spatial variations of the mole fraction of the four trace gases were very similar. The emission sources of these gases were divided into several regions by using the NOAA HYSPLIT model. Then we analyzed the variations of the ratios of the mole fraction enhancements between every pair of trace gases downwind of these source areas. The ratios showed that the distributions of these trace gases over the Yellow Sea and the East China Sea in the spring were mainly caused by the emissions from Eastern China. The much higher enhancement ratio of DeltaCO/DeltaCO2 and the lower ratio of DeltaCH4/DeltaCO observed in the air parcels from big cities like Beijing and Shanghai indicated high CO emission from the cities during our time of observation. Compared with the values of NOAA's Marine Boundary Layer (MBL), the ratios of the averages in the air coming from the Northern sector (Russia) were on average closer to the MBL, and the air that stayed over the Yellow Sea and the East China Sea was a mixture of emissions from wide regional areas. The highly variable N2O data of the air from Qingdao and Shanghai showed much more fluctuation. PMID- 29758856 TI - Relative contributions of wind and water erosion to total soil loss and its effect on soil properties in sloping croplands of the Chinese Loess Plateau. AB - Wind and water erosion are two dominant types of erosion that lead to soil and nutrient losses. Wind and water erosion may occur simultaneously to varying extents in semi-arid regions. The contributions of wind and water erosion to total erosion and their effects on soil quality, however, remains elusive. We used cesium-137 (137Cs) inventories to estimate the total soil erosion and used the Revised Universal Soil Loss Equation (RUSLE) to quantify water erosion in sloping croplands. Wind erosion was estimated from the subtraction of the two. We also used 137Cs inventories to calculate total soil erosion and validate the relationships of the soil quality and erosion at different slope aspects and positions. The results showed that wind erosion (1460tkm-2a-1) on northwest facing slope was responsible for approximately 39.7% of the total soil loss, and water erosion (2216tkm-2a-1) accounted for approximately 60.3%. The erosion rates were 58.8% higher on northwest- than on southeast-facing slopes. Northwest-facing slopes had lower soil organic carbon, total nitrogen, clay, and silt contents than southeast-facing slopes, and thus, the 137Cs inventories were lower, and the total soil erosions were higher on the northwest-facing slopes. The variations in soil physicochemical properties were related to total soil erosion. The lowest 137Cs inventories and nutrient contents were recorded at the upper positions on the northwest-facing slopes due to the successive occurrence of more severe wind and water erosion at the same site. The results indicated that wind and water could accelerate the spatial variability of erosion rate and soil properties and cause serious decreases in the nutrient contents in sloping fields. Our research could help researchers develop soil strategies to reduce soil erosion according to the dominant erosion type when it occurs in a hilly agricultural area. PMID- 29758857 TI - Herbivory induced non-local responses of the clonal invader Carpobrotus edulis are not mediated by clonal integration. AB - The anthropogenic displacement of species around the world results in new environmental situations where native and exotic species coexist. Exotic plants have to face native herbivores, and interactions between introduced plants and native herbivores seem to play an important role in the invasiveness of some exotic plant species. We studied the role of clonal integration in induce morphological, physiological, and biochemical responses in the clonal invader Carpobrotus edulis against the attack of the native snail Theba pisana. Our results demonstrated the presence of labour division mediated by physiological integration, with a significant increase of photosynthesis potential (both at morphological and physiological) in un-attacked integrated ramets. This response could be especially important under herbivory, as the negative impact of T. pisana on the photosynthetic structures of attacked C. edulis ramets could be buffered by transferring the dependence of photosynthetic activity to the un attacked ramets. Our results also showed a constitutive resistance in un-attacked apical ramets, showing a similar amount of defence compounds to those exhibited in the basal branches attacked by snails. Results reported a non-local compensatory response, which there was an increase of total biomass in apical ramets when their basal ramets were attacked by the herbivore. We interpret this result as a compensatory response, with these apical ramets increasing shoot biomass to compensate for the biomass loss due to a potential attack from herbivores. However, this non-local response was not mediated by physiological integration but probably due to belowground communication, with the presence of alarm signals released by root exudates. We conclude that the attack of this snail is not enough to be a possible biological control due to the compensatory response to this snail by C. edulis, favouring their expansion. Future studies should focus on unravelling the role of belowground communication in the defensive responses of C. edulis. PMID- 29758858 TI - Treated and untreated wastewater effluents alter river sediment bacterial communities involved in nitrogen and sulphur cycling. AB - Studying the dynamics of nitrogen and sulphur cycling bacteria in river surface sediments is essential to better understand their contribution to global biogeochemical cycles. Evaporitic rocks settled at the headwater of the Deba River catchment (northern Spain) lead to high values of sulphate concentration in its waters. Besides, the discharge of effluents from untreated and treated residual (urban and industrial) wastewaters increases the concentration of metals, nutrients and organic compounds in its mid- and low-water courses. The aim of this study was to assess the impact of anthropogenic contamination from untreated and treated residual and industrial wastewaters on the structure and function of bacterial communities present in surface sediments of the Deba River catchment. The application of a quantitative functional approach (qPCR) based on denitrification genes (nir: nirS+nirK; and nosZ), together with a 16S rRNA gene metabarcoding structural analysis, revealed (i) the high relevance of the sulphur cycle at headwater surface sediments (as reflected by the abundance of members of the Syntrophobacterales order, and the Sulfuricurvum and Thiobacillus genera) and (ii) the predominance of sulphide-driven autotrophic denitrification over heterotrophic denitrification. Incomplete heterotrophic denitrification appeared to be predominant in surface sediments strongly impacted by treated and untreated effluents, as reflected by the lower values of the nosZ/nir ratio, thus favouring N2O emissions. Understanding nitrogen and sulphur cycling pathways has profound implications for the management of river ecosystems, since this knowledge can help us determine whether a specific river is acting or not as a source of greenhouse gases (i.e., N2O). PMID- 29758859 TI - Food web contaminant dynamics of a large Atlantic Slope river: Implications for common and imperiled species. AB - Persistent and bioaccumulative contaminants often reach concentrations that threaten aquatic life by causing alterations in organism behavior and development, disruption of biological processes, reproductive abnormalities, and mortality. The objectives of this research were to determine the aquatic food web structure and trophic transfer and accumulation of contaminants within a riverine ecosystem and identify potential stressors to the health of an imperiled fish, the robust redhorse (Moxostoma robustum) and other species of conservation concern in a large Atlantic Slope (USA) river. Trophic position was determined for food web taxa by stable isotope analyses of representative producers, consumers, and organic matter of the Yadkin-Pee Dee River of North Carolina and South Carolina. Contaminant analyses were performed on water, sediment, organic matter, and aquatic biota to assess the prevalence and accumulation of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), current use pesticides (CUPs), polycyclic aromatic hydrocarbons (PAHs), and selected metals. Contaminants were prevalent in the environment and food web components of the river. PCBs were detected in 32% of biotic samples (mean 0.24MUg/g dry weight [DW], range 0.01-3.33MUg/g DW), and DDTs (legacy OCPs and metabolites) were detected in 90% (mean 0.014MUg/g DW, range 0.0004-0.29MUg/g DW). The trace metals manganese and cadmium exceeded published threshold effect concentrations in sediment (460 and 0.99MUg/g DW, respectively). Mercury was detected in all food web samples exhibiting a mean of 0.61MUg/g DW and range 0.006-2.35MUg/g DW (mean 0.13MUg/g wet weight [WW], range 0.001-0.6MUg/g WW). Concentrations exceeded the 0.2MUg/g WW aquatic life criterion for mercury in 38% of fish samples. Fish trophic magnification factors (TMFs; range 0.33-3.75) indicated that contaminant accumulation occurred from both water and dietary sources. The combination of analytical approaches applied here provides new insight into contaminant dynamics with conservation implications. PMID- 29758860 TI - High nitrogen isotope fractionation of nitrate during denitrification in four forest soils and its implications for denitrification rate estimates. AB - Denitrification is a major process contributing to the removal of nitrogen (N) from ecosystems, but its rate is difficult to quantify. The natural abundance of isotopes can be used to identify the occurrence of denitrification and has recently been used to quantify denitrification rates at the ecosystem level. However, the technique requires an understanding of the isotopic enrichment factor associated with denitrification, which few studies have investigated in forest soils. Here, soils collected from two tropical and two temperate forests in China were incubated under anaerobic or aerobic laboratory conditions for two weeks to determine the N and oxygen (O) isotope enrichment factors during denitrification. We found that at room temperature (20 degrees C), NO3- was reduced at a rate of 0.17 to 0.35MUgNg-1h-1, accompanied by the isotope fractionation of N (15epsilon) and O (18epsilon) of 310/00 to 650/00 (48.3+/ 2.00/00 on average) and 110/00 to 390/00 (18.9+/-1.70/00 on average), respectively. The N isotope effects were, unexpectedly, much higher than reported in the literature for heterotrophic denitrification (typically ranging from 50/00 to 300/00) and in other environmental settings (e.g., groundwater, marine sediments and agricultural soils). In addition, the ratios of Deltadelta18O:Deltadelta15N ranged from 0.28 to 0.60 (0.38+/-0.02 on average), which were lower than the canonical ratios of 0.5 to 1 for denitrification reported in other terrestrial and freshwater systems. We suggest that the isotope effects of denitrification for soils may vary greatly among regions and soil types and that gaseous N losses may have been overestimated for terrestrial ecosystems in previous studies in which lower fractionation factors were applied. PMID- 29758861 TI - Advancing towards functional environmental flows for temperate floodplain rivers. AB - Abstraction, diversion, and storage of flow alter rivers worldwide. In this context, minimum flow regulations are applied to mitigate adverse impacts and to protect affected river reaches from environmental deterioration. Mostly, however, only selected instream criteria are considered, neglecting the floodplain as an indispensable part of the fluvial ecosystem. Based on essential functions and processes of unimpaired temperate floodplain rivers, we identify fundamental principles to which we must adhere to determine truly ecologically-relevant environmental flows. Literature reveals that the natural flow regime and its seasonal components are primary drivers for functions and processes of abiotic and biotic elements such as morphology, water quality, floodplain, groundwater, riparian vegetation, fish, macroinvertebrates, and amphibians, thus preserving the integrity of floodplain river ecosystems. Based on the relationship between key flow regime elements and associated environmental components within as well as adjacent to the river, we formulate a process-oriented functional floodplain flow (ff-flow) approach which offers a holistic conceptual framework for environmental flow assessment in temperate floodplain river systems. The ff-flow approach underlines the importance of emulating the natural flow regime with its seasonal variability, flow magnitude, frequency, event duration, and rise and fall of the hydrograph. We conclude that the ecological principles presented in the ff-flow approach ensure the protection of floodplain rivers impacted by flow regulation by establishing ecologically relevant environmental flows and guiding flow restoration measures. PMID- 29758862 TI - Catalytic co-pyrolysis of cellulose and polypropylene over all-silica mesoporous catalyst MCM-41 and Al-MCM-41. AB - Fast pyrolysis is one of the most economical and efficient technologies to convert biomass to bio-oil and valuable chemical products. Co-pyrolysis with hydrogen rich materials such as plastics over zeolite catalysts is one of the significant solutions to various problems of bio-oil such as high oxygen content, low heat value and high acid content. This paper studied pyrolysis of cellulose and polypropylene (PP) separately and co-pyrolysis of cellulose and PP over MCM 41 and Al-MCM-41. The pyrolysis over different heating rates (10K/min, 20K/min, 30K/min) was studied by Thermogravimetry Analysis (TGA) and kinetic parameters were obtained by Coats-Redfern method and isoconversion method. TG and DTG data shows that the two catalysts advance the pyrolysis reaction of PP significantly and reduce its peak temperature of DTG curve from 458 degrees C to 341 degrees C. The activation energy of pyrolysis of PP also has a remarkable reduction over the two catalysts. Py-GC/MS method was used to obtain the product distribution of pyrolysis of cellulose and PP separately and co-pyrolysis of cellulose and PP over MCM-41 and Al-MCM-41 at constant temperature of 650 degrees C. Experiment results proved that co-pyrolysis with PP bring significant changes to the product distribution of cellulose. Oxygenated compounds such as furans are decreased, while yields of olefins and aromatics increase greatly. The yield of furans increases with the catalysis of MCM-41 as for the pyrolysis of cellulose and co pyrolysis, while the yield of olefins and aromatics both experience significant growth over Al-MCM-41, which can be explained by the abundant acid centers in Al MCM-41. PMID- 29758863 TI - Particle size differentiation explains flow regulation controls on sediment sorting in the water-level fluctuation zone of the Three Gorges Reservoir, China. AB - The Three Gorges Dam has significantly interrupted fluvial continuity and modified the mass transfer regime along river continuums. Flow regulation following regular dam operations drives dramatic hydrological regime shifts, which facilitates sediment dispersal in the water-level fluctuation zone over episodic inundation periods. How flow regulation modulates sediment redistribution, however, remains unclear. In this study, we depict absolute particle size composition of suspended sediment and sink sediment in the water level fluctuation zone, and these are interpreted in the context of flow regulation controls on sediment sorting. Multiple sampling strategies were applied at different spatial and temporal scales, to overcome limitations of labour and cost input in a large-scale field study and to collect representative samples. The results revealed a longitudinal fining trend and seasonal variability in particle size composition for suspended sediment. Sink sediment collected from the water-level fluctuation zone during a single summer flood event displayed a similar longitudinal fining trend, reflecting preferential settling of coarser fractions in the backwater reaches where flow velocity declines sharply. Surface sediment demonstrated a laterally coarsening trend with increasing elevations along a slope profile. Flooding duration, frequency and timing represent key factors in determining the elevation-dependent variations in the magnitude of sedimentation and its source inputs. Relatively longer flooding duration and frequent intermediate summer floods with high suspended sediment flux are responsible for high sedimentation rates in the lower portions with distal upstream source inputs, while low sedimentation rates in the upper portions are principally associated with water impoundment and sediment produced from local bank erosion. Vertical particle size variability was observed along a sedimentary core profile, which most likely reflects seasonal differences in source supply with contrasting particle size characteristics. We conclude that absolute particle size differentiation explains flow regulation controls on sediment sorting in the water-level fluctuation zone of the Three Gorges Reservoir. PMID- 29758864 TI - Analysis of the environmental behavior of farmers for non-point source pollution control and management in a water source protection area in China. AB - The environmental behavior of farmers plays an important role in exploring the causes of non-point source pollution and taking scientific control and management measures. Based on the theory of planned behavior (TPB), the present study investigated the environmental behavior of farmers in the Water Source Area of the Middle Route of the South-to-North Water Diversion Project in China. Results showed that TPB could explain farmers' environmental behavior (SMC=0.26) and intention (SMC=0.36) well. Furthermore, the farmers' attitude towards behavior (AB), subjective norm (SN), and perceived behavioral control (PBC) positively and significantly influenced their environmental intention; their environmental intention further impacted their behavior. SN was proved to be the main key factor indirectly influencing the farmers' environmental behavior, while PBC had no significant and direct effect. Moreover, environmental knowledge following as a moderator, gender and age was used as control variables to conduct the environmental knowledge on TPB construct moderated mediation analysis. It demonstrated that gender had a significant controlling effect on environmental behavior; that is, males engage in more environmentally friendly behaviors. However, age showed a significant negative controlling effect on pro environmental intention and an opposite effect on pro-environmental behavior. In addition, environmental knowledge could negatively moderate the relationship between PBC and environmental intention. PBC had a greater impact on the environmental intention of farmers with poor environmental knowledge, compared to those with plenty environmental knowledge. Altogether, the present study could provide a theoretical basis for non-point source pollution control and management. PMID- 29758865 TI - Risk assessment and source analysis of soil heavy metal pollution from lower reaches of Yellow River irrigation in China. AB - The level of concentration of heavy metal in soil is detrimental to soil quality. The Heigangkou-Liuyuankou irrigation area in the lower-reach of Yellow River irrigation, as home to a large population and a major site to agricultural production, is vulnerable to heavy metal pollution. This study examined soil quality in Heigangkou-Liuyuankou irrigation areas of Kaifeng, China. Pollution in soil and potential risks introduced by heavy metal accumulation were assessed using Nemerow, Geoaccumulation, and Hakanson's ecological risk indices. Statistics and Geographic Information Systems (GIS) were used to model and present the spatiotemporal changes of the pollution sources and factors affecting the levels of pollution. The heavy metals found in the sampled soil are Cr, Ni, Cu, Zn, Cd, Pb, As, and Hg. Among them, Cd is more concentrated than the others. The southwestern region of the studied area confronts the most serious heavy metal pollution. There exist spatial disparities of low concentrations of different heavy metals in the study area. Hg and Cd are found to pose the highest potential ecological risks. However, their risk levels are not the same across the study area. Levels concentration of Ni, Cu, Zn, Cd, Pb, As, and Hg in soil are highly correlated. In combination, they post an additional threat to the ecological environment. Transportation, rural settlements, and water bodies are found to be the major sources of Cr, Ni, Cu, Zn, Cd, Pb, and Hg pollution in the soil; among the major sources, transportation is the most significant factor. PMID- 29758866 TI - Estimation of human-origin estrone and 17beta-estradiol concentrations in the Han River, Seoul, South Korea and its uncertainty-based ecological risk characterization. AB - Estrogens originated from humans can reach ambient water and possibly cause significant ecological risks. In this study, the quantities of human-origin estrone (E1) and 17beta-estradiol (E2) in the influent and effluent of four sewer treatment plants (STPs) in Seoul, South Korea were estimated using a demographic model. A Monte Carlo simulation was used to assess the quantitative uncertainty of estimated E1 and E2 concentrations. Mean concentrations of E1 and E2 estimated for STP influents ranged from 29.5 to 38.4 and 7.5 to 9.7ng/L, respectively. Meanwhile, mean concentrations of E1 and E2 estimated for STP effluents were 4.9 to 6.6 and 0.28 to 0.36ng/L, respectively. These estimated values are similar to measured data as reported in the literatures within the range of uncertainty based on the Monte Carlo simulation. The hazard quotient (HQ) value in the main stem of the Han River was calculated to be far less than 1 because of the dilution effect of the Han River's abundant flow, indicating that most of the Han River ecosystem will not be influenced by these endogenous estrogens. With a 95% cumulative probability, HQ values in the main stem of the Han River for the Jungrang, Nanji, Tanchun, and Seonam STPs were less than 0.18, 0.07, 0.08, and 0.15, respectively. Nevertheless, HQ values >1 were observed in the vicinity of the STP outlets when using the numerical modeling. Our results show that the endocrine disruption potential of E1 and E2 around STP outlets in the main stem of the Han River must be monitored carefully. PMID- 29758867 TI - Stable sulfur isotope ratios and chemical compositions of fine aerosols (PM2.5) in Beijing, China. AB - Pervasive particulate pollution has been observed over large areas of the North China Plain. The high level of sulfate, a major component in fine particles, is pronounced during heavy pollution periods. Being different from source apportionments by atmospheric chemistry-transport model and receptor modeling methods, here we utilize sulfur isotopes to discern the potential emission sources. Sixty-five daily PM2.5 samples were collected at an urban site in Beijing between September 2013 and July 2014. Inorganic ions, organic/elemental carbon and stable sulfur isotopes of sulfate were analyzed. The "fingerprint" characteristics of stable sulfur isotopic composition, together with trajectory clustering modeled by HYSPLIT-4 (HYbrid Single-Particle Lagrangian Integrated Trajectory) and FLEXPART ("FLEXible PARTicle dispersion model"), was employed to identify potential aerosol sources in Beijing. Results exhibited a distinctive seasonality with sulfate, nitrate, ammonium, organic matter, and element carbon being the dominant species of PM2.5. Elevated concentrations of chloride with high organic matter were found in autumn and winter as a result of enhanced fossil fuel (mainly coal) combustion. The delta34S values of the Beijing aerosols ranged from 2.80/00 to 9.90/00 with an average of 6.0 +/- 1.80/00, further indicating that the major sulfur source was direct coal burning emission. Owing to the changing patterns between oxidation pathways of S(IV) in different seasons, delta34S values varied with a winter maximum (8.2 +/- 1.10/00) and a summer minimum (4.9 +/- 1.90/00). The results of trajectory clustering and FLEXPART demonstrated that higher concentrations of sulfate with lower sulfur isotope ratios (4.6 +/- 0.80/00) were associated with air masses from the south or east, whereas lower sulfate concentrations with heavier sulfur isotope ratios (6.7 +/- 1.60/00) were observed when the air masses were mainly from the north or northwest. These results suggested that the fine aerosol pollution in Beijing, especially sulfate pollution, was mainly due to coal combustion sources from regional and local regions. PMID- 29758868 TI - Environmental incidents in China: Lessons from 2006 to 2015. AB - Environmental incidents are among the most significant environmental challenges in China. Hundreds of environmental incidents occur every year, endangering human health and ecosystems. In this paper, we conducted an analytical study of environmental incidents from 2006 to 2015 in China. We first examined the spatiotemporal characteristics of the total 5213 incidents based on the statistical data collected from the China Statistical Yearbook on Environment. We then examined the characteristics of the sources of risk, causes of harm and resulting damage of environmental incidents based on first-hand data from 1369 cases collected by the Ministry of Environmental Protection (MEP) of China, which obtains detailed incident information. The results show that (1) there was a significant downward trend in the overall number of environmental incidents between 2006 and 2015, and developed eastern regions were high incidence areas; (2) hazardous chemicals were the main risk stressors; (3) production safety accidents and traffic accidents were the two major causes, and (4) most of these incidents resulted in polluted water and air. This paper is the first to provide a longitudinal analysis of the full scope of environmental incidents across the different regions of China, which has useful implications for policy-making and environmental management. PMID- 29758869 TI - Food preference and ecotoxicological tests with millipedes in litter contaminated with mercury. AB - Worldwide, various guidelines and directives for human health and the environment aim to reduce anthropogenic mercury (Hg) emission. Forest ecosystems are natural sinks of this element, transferring it from the atmosphere to litter and soil. Millipedes play an important role in litter/soil and may be negatively affected by contamination. As a pioneering contribution to ecotoxicological test guidelines with millipedes in litter, the present study evaluated food preference of millipedes and mercury toxicity, to prevent interference of food types in toxicity responses. Four food preference tests were performed with Trigoniulus corallinus and Rhinocricus padbergi in relation to leaf morphology, leaf fragmentation level and palatability/nutritional quality. Ecotoxicological effects on these animals were evaluated with increasing concentrations of HgCl2 spiked in litter. In both species, Hg concentrations were measured in repugnatorial glands, casts, exoskeleton and gut. In 28day trials, high bioaccumulation factors (BAF) of Hg were found in gut (= 56), exoskeleton (= 49) and casts (= 39) of R. padbergi. BAFs in the gut, exoskeleton and casts of T. corallinus were lower: 52, 45 and 32, respectively. Mortality tests indicated higher sensitivity of T. corallinus to Hg, compared with R. padbergi. Regarding leaf morphology, lanceolate, linear, obovate and ovate leaf shapes and entire margin were preferred by both species. Although higher biomass gain for both species was observed by ingestion of smaller fragmentation stages, T. corallinus preferred more fragmented leaves while R. padbergi consumed more leaves with lower fragmentation level. Both species preferred and grew better in cellulose rich litter with lower lignin content corresponding to the mixed litter, over single species leaves of Myrceugenia scutellata and Inga edulis. Therefore, future ecological tests with millipedes should consider the use of entire leaves with less irregular shapes, and higher cellulose and lower lignin contents, to provide ideal conditions for millipede growth and activity. PMID- 29758870 TI - Effect of the micro-flocculation stage on the flocculation/sedimentation process: The role of shear rate. AB - Dynamic analysis on the variation of particle size distribution (PSD) and the fractal characteristics of PSD (Df) were investigated to better understand the continuous procedure of the floc growth and optimize the control of flocculation process. It was found that the flocculation process could be divided into three stages, i.e., the micro-flocculation stage, the growth stage and the steady (or breakage) stage. As the stage which is crucial to the morphology of micro-flocs (the building blocks of large flocs), the micro-flocculation stage plays an important role on flocculation/sedimentation process. The results showed that an increase in shear rate (11s-11 half-life), indicating the potential impact of this chemical on microbial communities in aquatic systems. PMID- 29758873 TI - Lost but can't be neglected: Huge quantities of small microplastics hide in the South China Sea. AB - Large quantities of microplastics with small particle sizes were found in the South China Sea (SCS). The abundances of microplastics in seawater were 0.045+/ 0.093and 2569+/-1770particles/m3 according to the bongo net and pumping sampling methods, respectively. Smaller-size fractions (size<0.3mm) contributed 92% of the number of microplastics to the total load. Continental slope is the largest reservoir of microplastics with an inventory of 295tons. 21 polymer types were found in the samples using the micro Fourier Transform Infrared Spectroscopy (FTIR), among which alkyds (22.5%) and polycaprolactone (PCL) (20.9%) accounted for almost half of the total polymer content. Lighter plastics would not only concentrate upon the coastal area, being more likely to drift further into open seas with ocean currents. The distribution characteristics showed that it was mainly controlled by terrestrial input of the Pearl River. This study, as the first report from SCS on microplastics in water for its distribution and influence factors, provided impetus for further research on the transportation fate and the behavior of this emerging pollutant from coastal zone to the open oceans. PMID- 29758872 TI - Enhanced photoelectrochemical degradation of Ibuprofen and generation of hydrogen via BiOI-deposited TiO2 nanotube arrays. AB - This study employed BiOI-deposited TiO2 nanotube arrays (BiOI-TNTAs) electrode in a photoelectrochemical (PEC) system to oxidize Ibuprofen and generate hydrogen in the anodic and cathodic chamber, respectively. FESEM results revealed the diameter of TiO2 nanotubes was 90-110nm. According to the XRD analysis, the BiOI TNTAs were dominated by the anatase phase and tetragonal structure of BiOI. XPS results confirmed the coexistence of BiOI in the BiOI-TNTAs associated with Bi (33.76%) and I (8.81%). UV-vis absorption spectra illustrated BiOI-TNTAs exhibit strong absorptions in the visible light region. The PEC method showed the best degradation efficiency for Ibuprofen is a rate constant of 3.21*10-2min-1. The results of the Nyquist plot revealed the recombination of photogenerated electron hole pairs was inhibited as the bias potential was applied. Furthermore, the Bode plot demonstrated the lifetime (tauel) of photoexcited electrons of BiOI-TNTAs was 1.8 and 4.1 times longer than that of BiOI-Ti and TNTAs, respectively. In the cathodic chamber, the amount of hydrogen generation reached 219.94MUM/cm2 after 3h of reaction time. PMID- 29758874 TI - Contribution of biotic and abiotic factors in the natural attenuation of sulfamethoxazole: A path analysis approach. AB - Sulfamethoxazole (SMX) is a sulfonamide antibiotic, widely used as curative and preventive drug for human, animal, and aquaculture bacterial infections. Its residues have been ubiquitously detected in the surface waters and sediments. In the present study, SMX dissipation and kinetics was studied in the natural water samples from Jiulong River under simulated complex natural conditions as well as conditions to mimic various biotic and abiotic environmental conditions in isolation. Structural equation modeling (SEM) by employing partial least square technique in path coefficient analysis was used to investigate the direct and indirect contributions of different environmental factors in the natural attenuation of SMX. The model explained 81% of the variability in natural attenuation as a dependent variable under the influence of sole effects of direct photo-degradation, indirect photo-degradation, hydrolysis, microbial degradation and bacterial degradation. The results of SEM suggested that the direct and indirect photo-degradation were the major pathways in the SMX natural attenuation. However, other biotic and abiotic factors also play a mediatory role during the natural attenuation and other processes. Furthermore, the potential transformation products of SMX were identified and their toxicity was evaluated. PMID- 29758875 TI - Thifluzamide affects lipid metabolism in zebrafish (Danio reio). AB - Thifluzamide, a succinate dehydrogenase inhibitor (SDHI) fungicide, has been widely used in rice fields throughout the world and causes hepatotoxicity in zebrafish (Danio reio). This study was conducted to investigate the effect of thifluzamide on lipid metabolism in zebrafish after exposure to a control or, 0.019, 0.19, or 1.90mg/L thifluzamide for 28days. Following exposure, pathological changes in the liver were evaluated. Total cholesterol (TCHO) level, and triglyceride (TG) levels as well as hepatic lipase (HL), lipoprotein lipase (LPL), fatty acid synthetase (FAS) and carnitine palmitoyltransferase (CPT-I) activities were measured. In addition, the expression levels of genes related to lipid metabolism were quantified. No obvious accumulation of lipid droplets was detected in the liver following any of the thifluzamide treatments. TCHO and TG levels were significantly decreased. FAS activity was markedly decreased, and CPT I activity was significantly increased in the 0.19 and 1.90mg/L groups. However, no apparent changes in HL and LPL activities were observed in any of the treatment groups. Additionally, the expression of genes related to lipid metabolism showed corresponding changes. The results suggest that altered gene expression and enzyme activities might be responsible for the changes in lipid metabolism, as evidenced by the decreased TCHO and TG levels. Overall, thifluzamide altered lipid metabolism and led to events that might contribute to developmental toxicity in exposed zebrafish. PMID- 29758876 TI - Selection of passerine birds as bio-sentinel of persistent organic pollutants in terrestrial environment. AB - A broad suite of persistent organic pollutants (POPs), including polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and dichlorodiphenyltrichloroethane (DDT) and its metabolites, were analyzed in pectoral muscle of eight terrestrial passerine bird species from an extensive e waste recycling site in South China. Concentrations of PCBs, PBDEs, and DDTs in bird samples ranged from 1260-279,000, 121-14,200, and 31-7910ng/g lipid weight, respectively. Insectivorous birds had significantly higher levels of PCBs, PBDEs, and DDTs than those in granivorous birds. Concentrations of POPs in resident insectivorous birds were significantly greater than those in migrant insectivorous birds. PCBs were the predominant pollutants in all bird species from the e-waste site, followed by PBDEs and DDTs, indicating that PCBs were mainly derived from e-wastes. The granivorous birds had higher proportions of hepta-CBs in total PCBs and higher proportions of octa- to deca-BDEs in total PBDEs compared with the insectivorous birds. The various dietary sources, migration behavior, and possible biotransformation were suspected as reasons of the distinct profiles of POPs in different bird species. The delta15N values were significantly and positively correlated with concentrations of POPs in resident insectivorous birds, but not in other passerine bird species, suggesting the influence of trophic levels on bioaccumulation of POPs in resident insectivorous birds. The resident insectivorous birds seem to be promising bio-sentinel of POPs in terrestrial environment around the e-waste sites. PMID- 29758877 TI - The role of ppargamma in embryonic development of Xenopus tropicalis under triphenyltin-induced teratogenicity. AB - Evidence has shown that triphenyltin (TPT) triggers severe malformations in Xenopus tropicalis embryos, partly due to activation of PPARgamma (peroxisome proliferator activated receptor gamma) protein. In the present study, we investigated how abundance of ppargamma and TPT exposure interact and affect X. tropicalis embryonic development. We observed ppargamma expression signals appeared in the neural crest and neural fold, as well as in the brain, eyes and spinal cord organs. Both ppargamma overexpression and its Morpholino (MO) knockdown inhibited pax6 (paired box 6) expression, a marker of eye development, and significantly up- and down-regulated lipid and glucose homeostasis related genes, such as lpl (lipoprotein lipase), slc2a4 (solute carrier family 2 (facilitated glucose transporter), member 4) and pck1 (phosphoenolpyruvate carboxykinase 1, cytosolic), thus inducing eye phenotypes. Overexpression of ppargamma induced small eye phenotype, while ppargamma MO induced small eye plus turbid eye lens microencephaly and enlarged trunk. In contrast, 5-20MUgSn/L (stannum/L) TPT exposure reversed some impacts induced by ppargamma overexpression, i.e., no small eye, up-regulation of pax6 and down-regulation of ppargamma, lpl, slc2a4 and pck1. Meanwhile, microinjection of ppargamma MO combined with exposure to 20MUgSn/L TPT caused 85% mortality. In brief, our work clearly indicates that ppargamma is essential to eye development and inhibition of its expression combined with TPT exposure can be extremely harmful to X. tropicalis embryo. PMID- 29758878 TI - The influence of relative humidity on the heterogeneous oxidation of sulfur dioxide by ozone on calcium carbonate particles. AB - Heterogeneous reactions of SO2 and O3 with CaCO3 particles were investigated at a series of relative humidity (RH, 1% to 90%) and 298K using a diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). The uptake coefficients of SO2 on CaCO3 at different RHs were obtained for the first time. Our results proved that high RH could substantially promote the formation of sulfate, for which the highest concentration (80% RH and reaction time of 200min) and highest formation rate in stable stage (85% RH) were 14 times and 43 times that at 1% RH, respectively. The surface products, increment of concentration and formation rate of sulfate changed with RH which were due to the surface adsorbed water (SAW) on the particles. SAW could increase the reactive sites on the particles and thus accelerate the conversion of SO2 into sulfite, and sulfite could be oxidized rapidly. Liquid-like water layers formed on the particle surface could enhance the ion mobility and promote the aggregation of CaSO4 hydrates, which could expose more reactive sites and result in additional adsorption of SO2. Piecewise equations of uptake coefficient with RH were given and could be referred by model simulation. The results are of importance in understanding the explosive growth of sulfate during severe haze episodes accompanied with high RH. PMID- 29758879 TI - Inhibition of element sulfur and calcium oxide on the formation of PCDD/Fs during co-combustion experiment of municipal solid waste. AB - In order to investigate the effect of element sulfur (S) and calcium oxide (CaO) on the formation of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) during municipal solid waste (MSW) combustion process, MSW was incinerated with S or CaO in a laboratory-scale incinerator and heated in the flow of N2-O2 gas mixture at 800 degrees C. It can be concluded that 25% of oxygen concentration is the best condition for the following inhibitors experiments through a series of oxygen variation experiments. With adding S and CaO in MSW incineration, seventeen kinds of 2, 3, 7, 8-substituted PCDD/Fs congeners were analysed with high-resolution chromatography and mass spectrometry method. The results show that S and CaO obviously suppress PCDD/Fs formation. Comparing inhibition effect of S with that of CaO, the inhibitory effect of S on HpCDD/Fs formation was most remarkable, of around 88.1%; while CaO could inhibit the formation of HxCDD/Fs more evidently than sulfur and the inhibition was 85.1%. PCDFs were the main components of dioxins produced from MSW incineration in the experiments, and S and CaO were unable to change the dominating generation route of PCDD/Fs. S and CaO could mainly consume chlorine sources or weaken the chlorination in the PCDD/Fs formation process to restrain the PCDFs formation, but the inhibition mechanisms were different. In addition, some dioxins or precursors might be decomposed by S and CaO. PMID- 29758880 TI - Comparing grey water versus tap water and coal ash versus perlite on growth of two plant species on green roofs. AB - Green roofs provide important ecosystem services in urban areas. In Mediterranean and other semi-arid climate regions, most perennial plants on green roofs need to be irrigated during the dry season. However, the use of freshwater in such regions is scarce. Therefore, the possibility of using grey water should be examined. Coal ash, produced primarily from the burning of coal in power plants, constitutes an environmental contaminant that should be disposed. One option is to use ash as a growing substrate for plants. Here, we compare the effects of irrigating with grey- versus tap-water and using ash versus perlite as growing substrates in green roofs. The study was conducted in northern Israel in a Mediterranean climate. The design was full factorial with three factors: water type (grey or tap-water)*substrate-type (coal ash vs perlite)*plant species (Phyla nodiflora, Convolvulus mauritanicus or no-plant). The development of plants and the quality of drainage water along the season, as well as quality of the used substrates were monitored. Both plant species developed well under all the experimental conditions with no effect of water type or substrate type. Under all treatments, both plant species enhanced electrical conductivity (EC) and chemical oxygen demand (COD) of the drainage water. In the summer, EC and COD reached levels that are unacceptable in water and are intended to be reused for irrigation. We conclude that irrigating with grey water and using coal ash as a growth substrate can both be implemented in green roofs. The drainage from tap water as well as from grey water can be further used for irrigating the roof, but for that, COD and EC levels must be lowered by adding a sufficient amount of tap water before reusing. PMID- 29758881 TI - Water footprint and economic water productivity of Italian wines with appellation of origin: Managing sustainability through an integrated approach. AB - In the agribusiness wine is certainly a very interesting sector to analyze. The specific aim of this work is to assess water efficiency and economic water productivity for the Italian wines with Appellation of Origin (AO). This assessment could represent a potential management instrument to improve production performances from a more integrated perspective, pursuing new market trends. The study is related to Italy, the first worldwide producer, and analyzes the available data of AO wines, which globally have specific features, being strictly connected with the territory and its background. The results show the top and bottom five AO wines in terms of crop water use and economic water productivity and their trends during the period 2011-2015, based on average annual change rates. Results of this study are relevant for the wine sector since they can guide decision makers on vine variety selection in the context of micro- and macro-level sustainability of water resource use. PMID- 29758882 TI - Responses of stream microbes to multiple anthropogenic stressors in a mesocosm study. AB - Stream ecosystems are affected by multiple anthropogenic stressors worldwide. Even though effects of many single stressors are comparatively well studied, the effects of multiple stressors are difficult to predict. In particular bacteria and protists, which are responsible for the majority of ecosystem respiration and element flows, are infrequently studied with respect to multiple stressors responses. We conducted a stream mesocosm experiment to characterize the responses of single and multiple stressors on microbiota. Two functionally important stream habitats, leaf litter and benthic phototrophic rock biofilms, were exposed to three stressors in a full factorial design: fine sediment deposition, increased chloride concentration (salinization) and reduced flow velocity. We analyzed the microbial composition in the two habitat types of the mesocosms using an amplicon sequencing approach. Community analysis on different taxonomic levels as well as principle component analyses (PCoAs) based on realtive abundances of operational taxonomic units (OTUs) showed treatment specific shifts in the eukaryotic biofilm community. Analysis of variance (ANOVA) revealed that Bacillariophyta responded positively salinity and sediment increase, while the relative read abundance of chlorophyte taxa decreased. The combined effects of multiple stressors were mainly antagonistic. Therefore, the community composition in multiply stressed environments resembled the composition of the unstressed control community in terms of OTU occurrence and relative abundances. PMID- 29758883 TI - Challenges in coupling LTER with environmental assessments: An insight from potential and reality of the Chinese Ecological Research Network in servicing environment assessments. AB - Environmental assessments estimate, evaluate and predict the consequences of natural processes and human activities on the environment. Long-term ecosystem observation and research networks (LTERs) are potentially valuable infrastructure to support environmental assessments. However, very few environmental assessments have successfully incorporated them. In this study, we try to reveal the current status of coupling LTERs with environmental assessments and look at the challenges involved in improving this coupling through exploring the role that Chinese Ecological Research Network (CERN), the LTER of China, currently plays in regional environment assessments. A review of official protocols and standards, regional assessments and CERN researches related to ecosystems and environment shows that there is great potential for coupling CERN with environment assessments. However in practice, CERN does not currently play the expected role. Remote sensing and irregular inventory data are still the main data sources currently used in regional assessments. Several causes led to the present situation: (1) insufficient cross-site research and failure to scale up site level variables to the regional scale; (2) data barriers resulting from incompatible protocols and low data usability due to lack of data assimilation and scaling; and (3) absence of indicators relevant to human activities in existing monitoring protocols. For these reasons, enhancing cross-site monitoring and research, data assimilation and scaling up are critical steps required to improve coupling of LTER with environmental assessments. Site-focused long-term monitoring should be combined with wide-scale ground surveys and remote sensing to establish an effective connection between different environmental monitoring platforms for regional assessments. It is also necessary to revise the current monitoring protocols to include human activities and their impacts on the ecosystem, or change the LTERs into Long-Term Socio-Ecological Research (LTSER) networks. PMID- 29758884 TI - The impact of urban open space and 'lift-up' building design on building intake fraction and daily pollutant exposure in idealized urban models. AB - Sustainable urban design is an effective way to improve urban ventilation and reduce vehicular pollutant exposure to urban residents. This paper investigated the impacts of urban open space and 'lift-up' building design on vehicular CO (carbon monoxide) exposure in typical three-dimensional (3D) urban canopy layer (UCL) models under neutral atmospheric conditions. The building intake fraction (IF) represents the fraction of total vehicular pollutant emissions inhaled by residents when they stay at home. The building daily CO exposure (Et) means the extent of human beings' contact with CO within one day indoor at home. Computational fluid dynamics (CFD) simulations integrating with these two concepts were performed to solve turbulent flow and assess vehicular CO exposure to urban residents. CFD technique with the standard k-epsilon model was successfully validated by wind tunnel data. The initial numerical UCL model consists of 5-row and 5-column (5*5) cubic buildings (building height H=street width W=30m) with four approaching wind directions (theta=0 degrees , 15 degrees , 30 degrees , 45 degrees ). In Group I, one of the 25 building models is removed to attain urban open space settings. In Group II, the first floor (Lift-up1), or second floor (Lift-up2), or third floor (Lift-up3) of all buildings is elevated respectively to create wind pathways through buildings. Compared to the initial case, urban open space can slightly or significantly reduce pollutant exposure for urban residents. As theta=30 degrees and 45 degrees , open space settings are more effective to reduce pollutant exposure than theta=0 degrees and 15 degrees .The pollutant dilution near or surrounding open space and in its adjacent downstream regions is usually enhanced. Lift-up1 and Lift-up2 experience much greater pollutant exposure reduction in all wind directions than Lift-up3 and open space. Although further investigations are still required to provide practical guidelines, this study is one of the first attempts for reducing urban pollutant exposure by improving urban design. PMID- 29758885 TI - Impact of anthropogenic climate change and human activities on environment and ecosystem services in arid regions. AB - The implications of anthropogenic climate change, human activities and land use change (LUC) on the environment and ecosystem services in the coastal regions of Saudi Arabia were analyzed. Earth observations data was used to drive land use categories between 1970 and 2014. Next, a Markov-CA model was developed to characterize the dynamic of LUC between 2014 and 2100 and their impacts on regions' climate and environment. Non-parametric change point and trend detection algorithms were applied to temperature, precipitation and greenhouse gases data to investigate the presence of anthropogenic climate change. Lastly, climate models were used to project future climate change between 2014 and 2100. The analysis of LUC revealed that between 1970 and 2014, built up areas experienced the greatest growth during the study period, leading to a significant monotonic trend. Urban areas increased by 2349.61km2 between 1970 and 2014, an average increase of >53.4km2/yr. The projected LUC between 2014 and 2100 indicate a continued increase in urban areas and irrigated cropland. Human alteration of land use from natural vegetation and forests to other uses after 1970, resulted in a loss, degradation, and fragmentation, all of which usually have devastating effects on the biodiversity of the region. Resulting in a statistically significant change point in temperature anomaly after 1968 with a warming trend of 0.24 degrees C/decade and a downward trend in precipitation anomaly of 12.2mm/decade. Total greenhouse gas emissions including all anthropogenic sources showed a statistically significant positive trend of 78,090Kt/decade after 1991. This is reflected in the future projection of temperature anomaly between 1900 and 2100 with a future warming trend of 0.19 degrees C/decade. In conclusion, human activities, industrial revelation, deforestation, land use transformation and increase in greenhouse gases had significant implications on the environment and ecosystem services of the study area. PMID- 29758886 TI - Carrier flies of multidrug-resistant Escherichia coli as potential dissemination agent in dairy farm environment. AB - The life cycle of synanthropic flies and their behavior, allows them to serve as mechanical vectors of several pathogens. Given that flies can carry multidrug resistant (MDR) bacteria, this study aimed to investigate the spread of genes of antimicrobial resistance in Escherichia coli isolated from flies collected in two dairy farms in Brazil. Besides antimicrobial resistance determinants, the presence of virulence genes related to bovine colibacillosis was also assessed. Of 94 flies collected, Musca domestica was the most frequently found in the two farms. We isolated 198 E. coli strains (farm A=135 and farm B=63), and >30% were MDR E. coli. We found an association between blaTEM and phenotypical resistance to ampicillin, or chloramphenicol, or tetracycline; and blaCTX-M and resistance to cefoperazone. A high frequency (86%) of phylogenetic group B1 among MDR strains and the lack of association between multidrug resistance and virulence factors suggest that antimicrobial resistance possibly is associated with the commensal bacteria. Clonal relatedness of MDR E. coli performed by Pulsed-Field Gel Electrophoresis showed wide genomic diversity. Different flies can carry clones, but with distinct antimicrobial resistance pattern. Sanger sequencing showed that the same class 1 integron arrangement is displayed by apparently unrelated strains, carried by different flies. Our conjugation results indicate class 1 integron transfer associated with tetracycline resistance. We report for the first time, in Brazil, that MDR E. coli is carried by flies in the milking environment. Therefore, flies can act as carriers for MDR strains and contribute to dissemination routes of antimicrobial resistance. PMID- 29758887 TI - Arsenic-rich shallow groundwater in sandy aquifer systems buffered by rising carbonate waters: A geochemical case study from Mannar Island, Sri Lanka. AB - Major ion, trace elements, and stable isotope analyses were performed on groundwater samples collected from Mannar Island in the northern Indian Ocean. Arsenic concentrations up to 34MUg/L have been observed in groundwater samples from the island. In addition, 23% of extensively used shallow drinking water wells showed higher arsenic contents than the recommended value by the World Health Organization (10MUg/L). Groundwater in the island showed pH values between 6.9 and 8.9 and was dominated by Na+, K+, Ca2+, Mg2+, HCO3-, Cl- and SO42-. The delta18OH2O and delta2HH2O composition of most groundwater plotted very close to the local meteoric waterline, however, some wells showed enriched isotope compositions that are most likely due to evaporation. Sea water intrusion in this island was likely of minor importance as indicated by the major ion composition. An approximated mass balance calculation using chloride concentrations indicated that out of the 35 investigated wells only 6 near-shore wells were influenced by sea water intrusion up to about 15%. Even though this is a sandy aquifer, groundwaters were characterized with higher contents of dissolved inorganic carbon (DIC) (2.11-10.9mmol/L). The corresponding delta13CDIC values varied from 19.40/00 to -6.50/00. Except for a few samples with values approaching -200/00, these isotope values are more typical for carbonate dissolution and equilibration of CO2 in the aquifer. This study shows that the underlying carbonate system may buffer the aqueous geochemistry of the groundwater on the island. The high arsenic content in groundwater may have been mobilized through reductive dissolution of Fe-Mn oxides and oxy-hydroxides that are coated on sandy aquifer materials. The lower content of DOC (0.2-1.5mmol/L) provides evidence for the restricted formation of pyrite in the aquifer. PMID- 29758888 TI - Filter-based measurement of light absorption by brown carbon in PM2.5 in a megacity in South China. AB - Carbonaceous aerosols represent an important nexus between air pollution and climate change. Here we collected filter-based PM2.5 samples during summer and autumn in 2015 at one urban and two rural sites in Guangzhou, a megacity in southern China, and got the light absorption by black carbon (BC) and brown carbon (BrC) resolved with a DRI Model 2015 multi-wavelength thermal/optical carbon analyzer apart from determining the organic carbon (OC) and elemental carbon (EC) contents. On average BrC contributed 12-15% of the measured absorption at 405nm (LA405) during summer and 15-19% during autumn with significant increase in the LA405 by BrC at the rural sites. Carbonaceous aerosols, identified as total carbon (TC), yielded average mass absorption efficiency at 405nm (MAE405) that were approximately 45% higher in autumn than in summer, an 83% increase was noted in the average MAE405 for OC, compared with an increase of only 14% in the average MAE405 for EC. The LA405 by BrC showed a good correlation (p<0.001) with the ratios of secondary OC to PM2.5 in summer. However, this correlation was poor (p>0.1) in autumn, implying greater secondary formation of BrC in summer. The correlations between levoglucosan (a marker of biomass burning) and the LA405 by BrC were significant during autumn but insignificant during summer, suggesting that the observed increase in the LA405 by BrC during autumn in rural areas was largely related to biomass burning. The measurements of light absorption at 550nm presented in this study indicated that the use of the IMPROVE algorithm with an MAE value of 10m2/g for EC to approximate light absorption may be appropriate in areas not strongly affected by fossil fuel combustion; however, this practice would underestimate the absorption of light by PM2.5 in areas heavily affected by vehicle exhausts and coal burning. PMID- 29758889 TI - Controlled induction of denitrification in Pseudomonas aureofaciens: A simplified denitrifier method for dual isotope analysis in NO3. PMID- 29758890 TI - The extent of tebuconazole leaching from unpainted and painted softwood. AB - Exposure to water and high air humidity may affect the preservation of wood products as many preservatives are water-soluble and thus likely to leach. In this study, depletion of a common fungicide, tebuconazole (TAZ), from treated wood was investigated using a 14C-labeled tracer. The wood species and treatment technique were chosen to be representative of products such as windows and doors; specifically, ponderosa pine was dip treated with a solvent-based, metal-free formulation. The impact of different aqueous settings including high air humidity, and either simulated continuous or intermittent rain was evaluated over a period of two months. Along with the exposure type, the effect of end-grain sealing on TAZ loss was explored. Despite the exposure of treated wood to laboratory-simulated harsh environmental conditions, more than 60% of the originally sorbed TAZ remained in the wood under all scenarios. While high air humidity did not lead to TAZ depletion, simulated continuous rain led to a TAZ leaching mainly from the end grain. TAZ leaching was found to be higher for unpainted wood, where up to 40% of the originally sorbed TAZ was prone to depletion from an end grain. End-grain sealing with water-based primer and paint led to a substantial two-fold reduction of TAZ leaching. Unexpectedly, wood exposure to intermittent rain caused additional TAZ loss that could not be explained only by water leaching. PMID- 29758891 TI - Benzo[a]pyrene degradation and bioaccumulation in soil-plant system under artificial contamination. AB - The involvement of benzo[a]pyrene (BaP) one of the most toxic polycyclic aromatic hydrocarbons (PAHs) in the soil-plant system causes its potential carcinogenicity and mutagenicity for human health. The aim of this article is benzo[a]pyrene (BaP) degradation and bioaccumulation in soil-plant system under artificial contamination in model experiment with Haplic Chernozem and that spiked with various doses of BaP (20, 200, 400 and 800MUgkg-1) equivalent to 1, 10, 20 and 40 levels of maximal permissible concentrations (MPC) planted with spring barley (Hordeum sativum distichum). The experimental soil samples were planted every spring and incubated outdoor during 4years. The express-method of subcritical water extraction was used for BaP extraction from samples. It was established the values of BaP period of semi-degradation in soil (T50, y) contaminated with 10, 20 and 40MPC deviated from 1.4 to 1.8years, while these values in low contaminated soils deviated from 2.9 to 5.4years. It was found the BaP concentrations in plants depended on initial BaP contamination and reduced simultaneously with diminish of BaP concentration in the related spiked samples. Growing of spring barley in the BaP spiked soils lead to BaP accumulation in plants. The bioaccumulation factors for BaP in roots and vegetative part of barley plants (BAFr and BAFv respectively) fluctuated within 0.035-0.065 and 0.015-0.025 respectively at the 1st season and then reduced about twice to the 4th season. Meantime those values in control soils vice-versa increased twice from 0.03 and 0.01 respectively. PMID- 29758892 TI - Transport of sediment borne contaminants in a Mediterranean river during a high flow event. PMID- 29758894 TI - Environmental and economic analysis of power generation in a thermophilic biogas plant. AB - This paper investigates the environmental and economic performance of the power production from biogas using Life Cycle Assessment, Life Cycle Costing and Cost Benefit Analysis methodologies. The analysis is based on a commercial thermophilic biogas plant located in Spain where is installed a Combined Heat and Power system that produces electricity that is sold to the grid. Power generation has been assumed as the only function of the biogas system, expanding the system boundaries to include the additional function related to the end-of-life management of the biowastes. Thus environmental burdens from the conventional management of residues were calculated separately and subtracted. The base scenario involves using agri-food waste, sewage sludge and pig/cow manure as substrates. This situation is compared against an alternative scenario where the production of synthetic fertilizer is surrogated by the digestate. The results have shown that the most impacting activities in all impacts categories of power production are primarily attributable to the operation and maintenance of the biogas plant except for water resource depletion and climate change. The avoided emissions associated with the conventional management of pig/cow manure more than offset GHG emissions of the biogas system resulting in a negative impact value of -73.9gCO2eq/kWh in the base case scenario. The normalized results show that local impact categories such as primarily human toxicity, fresh water ecotoxicity and particulate matter are the most significantly affected by the biogas system while global impact categories as climate change and ozone depletion are less severely affected. The operation and maintenance phase is also shown to be the largest contributor after the life cycle cost analysis, followed by the construction and dismantling of the biogas plant and the profitability of the project is primarily related to the income obtained from the management of the biowastes used as substrates. PMID- 29758893 TI - Future changes in Yuan River ecohydrology: Individual and cumulative impacts of climates change and cascade hydropower development on runoff and aquatic habitat quality. AB - The eco-hydrological system in southwestern China is undergoing great changes in recent decades owing to climate change and extensive cascading hydropower exploitation. With a growing recognition that multiple drivers often interact in complex and nonadditive ways, the purpose of this study is to predict the potential future changes in streamflow and fish habitat quality in the Yuan River and quantify the individual and cumulative effect of cascade damming and climate change. The bias corrected and spatial downscaled Coupled Model Intercomparison Project Phase 5 (CMIP5) General Circulation Model (GCM) projections are employed to drive the Soil and Water Assessment Tool (SWAT) hydrological model and to simulate and predict runoff responses under diverse scenarios. Physical habitat simulation model is established to quantify the relationship between river hydrology and fish habitat, and the relative change rate is used to assess the individual and combined effects of cascade damming and climate change. Mean annual temperature, precipitation and runoff in 2015-2100 show an increasing trend compared with that in 1951-2010, with a particularly pronounced difference between dry and wet years. The ecological habitat quality is improved under cascade hydropower development since that ecological requirement has been incorporated in the reservoir operation policy. As for middle reach, the runoff change from January to August is determined mainly by damming, and climate change influence becomes more pronounced in dry seasons from September to December. Cascade development has an effect on runoff of lower reach only in dry seasons due to the limited regulation capacity of reservoirs, and climate changes have an effect on runoff in wet seasons. Climate changes have a less significant effect on fish habitat quality in middle reach than damming, but a more significant effect in lower reach. In addition, the effect of climate changes on fish habitat quality in lower reach is high in dry seasons but low in flood seasons. PMID- 29758895 TI - Chemical speciation, including polycyclic aromatic hydrocarbons (PAHs), and toxicity of particles emitted from meat cooking operations. AB - We assessed the chemical properties and oxidative stress of particulate matter (PM) emissions from underfired charbroiled meat operations with and without the use of aftertreatment control technologies. Cooking emissions concentrations showed a strong dependence on the control technology utilized, with all emission rates showing decreases with the control technologies compared to the baseline testing. The organic acids profile was dominated by the saturated nonanoic, myristic, palmitic, and stearic acids, and the unsaturated oleic, elaidic, and palmitoleic acids. Cholesterol was also found in relatively high concentrations. Lower and medium-weight polycyclic aromatic hydrocarbons (PAHs) were the dominant species for all cooking experiments. Heavier PAHs were also detected in high concentrations, especially in the particle-phase. For the nitrated PAH emissions (nitro-PAHs), low molecular weight compounds dominated the cooking emissions. Under the present experimental conditions, the heterocyclic aromatic amines (HAAs) showed very low concentrations, which suggests these species are rarely formed in meat cooking PM. The most efficient control technology for reducing the majority of the toxic pollutants was the electrostatic precipitator, which resulted in total emissions reductions on the order of 95%, 79%, 90%, 96%, 90%, and 94%, respectively, for particle-phase PAHs, gas-phase PAHs, particle-phase nitro-PAHs, gas-phase nitro-PAHs, particle-phase HAAs, and gas-phase HAAs compared to the baseline testing. Our experiment showed that cooking aerosol contained higher levels of prooxidants in the particle-phase and the corresponding vapors contained higher levels of electrophiles. Overall, the use of control technologies reduced the redox and electrophilic activities of cooking PM. PMID- 29758896 TI - Evaluation and uncertainty estimation of the impact of air quality modelling on crop yields and premature deaths using a multi-model ensemble. AB - This study promotes the critical use of air pollution modelling results for health and agriculture impacts, with the primary goal of providing more reliable estimates to decision makers. To date, the accuracy of air quality (AQ) models and the effects of model-to-model result variability (which we will refer to as model uncertainty) on impact assessment studies have been often ignored, thus undermining the robustness of the information used in the decision making process and the confidence in the results obtained. A suite of twelve PM2.5 and ozone concentration fields produced by regional-scale chemistry transport Air Quality (AQ) models during the third phase of the Air Quality Model Evaluation International Initiative (AQMEII) has been used to calculate the impact of air pollution on premature deaths and crop yields. An innovative technique is applied to bias-adjust the models to available observations. The model results for ozone and PM2.5 are combined in a multi-model (MM) ensemble, which is used to estimate the damage and economic cost to human health and crop yields, as well as the associated uncertainties. The MM ensemble quantifies directly the uncertainty introduced by AQ models into the air pollution impact assessment chain, while the indirect use of experimental information through a bias adjustment, reduces the uncertainty in the ozone and PM2.5 fields and subsequently the uncertainty of the final impact assessment and cost valuation. The analysis over the European countries analysed in this study shows a mean number of premature deaths due to exposure to PM2.5 and ozone of approximately 370,000 (inter-quantile range between 260,000 and 415,000) and a relative yield loss of approximately 7% to 9% (depending on the exposure metrics used, for wheat and maize together). Furthermore, the results indicate that a reduction in the uncertainty of the modelled ozone by 61% and by 80% (depending on the aggregation metric used) and by 46% for PM2.5, produces a reduction in the uncertainty in premature mortality and crop loss of >60%, and of an equivalent percentage in the final uncertainty of cost valuation, providing decision makers with more accurate estimations for more targeted interventions. PMID- 29758897 TI - The association between ambient PM2.5 exposure and the risk of preterm birth in China: A retrospective cohort study. AB - BACKGROUND: The relationship between PM2.5 exposure and preterm birth remains unclear. OBJECTIVES: To explore the effect of exposure to PM2.5 on preterm birth in China. METHODS: The birth outcomes of 426,246 pregnant women enrolled between January 2014 and December 2014 in NFPCP (National Free Pre-pregnancy Checkups Project) were collected, and their individual PM2.5 exposure values were estimated from the China National Environmental Monitoring Centre. The time of gestational exposure to PM2.5 was divided into four periods (the first trimester, the second trimester, the third trimester and the entire pregnancy). The average concentration and the corresponding quartiles of PM2.5 were calculated in these periods by the daily average PM2.5 data. Cox proportional hazards regression was used and he effects of maternal age, education level, occupation, second-hand smoking, alcohol use, pre-pregnancy BMI, baby's sex, number of previous pregnancies, coastal areas and season of conception were adjusted for. RESULTS: A total of 426,246 singleton births were included, among which 35,261 (8.3%) were preterm birth. Effect of each 10MUg/m3 increase of PM2.5 on preterm birth was most significant during the third trimester (HR, 1.06; 95%CI, 1.06-1.07), and also significant during the first trimester (HR, 1.04; 95%CI, 1.03-1.04), the second trimester (HR, 1.02; 95%CI, 1.02-1.02) and the entire pregnancy (HR, 1.06; 95%CI, 1.05-1.06). Compared with the lowest quartile of PM2.5, other quartiles increased the risk of preterm birth, and were most significant during the third trimester (HR, 1.87; 95%CI, 1.69-2.06). Subgroup analysis showed that compared with other subgroups, women who were older than 30years, had low education level, worked as farmers, had male baby, had previous pregnancies, not live in coastal areas and pregnant in winter were more sensitive to PM2.5 exposure. CONCLUSIONS: Ambient PM2.5 exposure during pregnancy played an important role in the pregnancy process and increased the risk of preterm birth. PMID- 29758898 TI - Characterization of iron oxide nanoparticle films at the air-water interface in Arctic tundra waters. AB - Massive amounts of organic carbon have accumulated in Arctic permafrost and soils due to anoxic and low temperature conditions that limit aerobic microbial respiration. Alternative electron acceptors are thus required for microbes to degrade organic carbon in these soils. Iron or iron oxides have been recognized to play an important role in carbon cycle processes in Arctic soils, although the exact form and role as an electron acceptor or donor remain poorly understood. Here, Arctic biofilms collected during the summers of 2016 and 2017 from tundra surface waters on the Seward Peninsula of western Alaska were characterized with a suite of microscopic and spectroscopic methods. We hypothesized that these films contain redox-active minerals bound to biological polymers. The major components of the films were found to be iron oxide nanoparticle aggregates associated with extracellular polymeric substances. The observed mineral phases varied between films collected in different years with magnetite (Fe2+Fe23+O4) nanoparticles (<5nm) predominantly identified in the 2016 films, while for films collected in 2017 ferrihydrite-like amorphous iron oxyhydroxides were found. While the exact formation mechanism of these Artic iron oxide films remains to be explored, the presence of magnetite and other iron oxide/oxyhydroxide nanoparticles at the air-water interface may represent a previously unknown source of electron acceptors for continual anaerobic microbial respiration of organic carbon within poorly drained Arctic tundra. PMID- 29758899 TI - Evaluating land ecological security and examining its relationships with driving factors using GIS and generalized additive model. AB - Land ecological security (LES) refers to the environmental health and sustainability of the land resources and ecosystems, which are substantially affected by biophysical and socio-economic factors. We assess the spatiotemporal patterns of LES in Ningbo city on the southeast coast of China from 1975 to 2015 and explore the effects of driving factors. Expert evaluation is used to estimate the LES score for each 2*2km grid and map the patterns by Kriging. Five levels of LES are used: very secure, secure, neutral, insecure and very insecure. A generalized additive model (GAM) captures the relationships between LES and driving factors, and identifies the dominant factors. Our results show that the Ningbo LES has been deteriorating since 1975, and it is now very insecure in Ningbo city center and the central area of the satellite city Cixi. The dominant factors affecting LES are distances to city center (Dcity), district center (Ddistrict) and road networks (Droads), and the moving window built-up area (Dndbi). Among these, Dndbi is most important as inferred by the highest explained deviance of the GAM. This study improves our understanding of the spatiotemporal patterns of LES in Ningbo and how LES changes. As a result, it provides insight to help local governments optimize land-use configuration, potentially improving the environment and ecosystems and creating a more environmentally friendly city. PMID- 29758900 TI - How to describe organic contamination in soils: A model comparison for chlorinated solvent concentrations at industrial site scale. AB - The heavy-tailed distribution of the data of organic pollution in soils can raise specific problems in estimating and mapping the concentrations. Some high values often highly impact the sample variogram and extend the pollution hot-spots on the estimation maps. Non-linear geostatistical models, such as the anamorphosed Gaussian model, have been proposed in the 70's. They allow a consistent estimate of the concentrations and the probability that the concentrations exceed a cut off. These well-founded methods are rarely used by environmental consultants, mainly because of time constraints and because the hypotheses of the models are not always satisfied. To estimate the concentrations, an empirical method widely used by environmental consultants consists of truncating the high values to gain robustness in the variogram analysis. The truncation value is arbitrary, even if it has a strong influence on the estimates of the concentrations. Proposed to handle heavy-tailed distributions of ore grades, the top-cut model (Rivoirard et al., 2013) justifies the use of truncated values but corrects the underestimation of the mean caused by truncation. In this model, the decomposition of the variable into three components (the truncated value, a weighted indicator at the top-cut threshold and a residual) makes the variographic study more robust and guides choosing the top-cut threshold. In the case of a chlorinated solvent contamination, a detailed comparison between several estimation methods is performed: ordinary kriging, kriging after truncation of the highest concentrations and estimation within the top-cut model, with structured or pure nugget residual. A sensitivity study to the top-cut threshold is realized. The results of two implementations of the cross-validation are compared. The top-cut model with nugget residual appears to be robust, even if the hypotheses of the model are not perfectly satisfied. PMID- 29758901 TI - Pharmaceutical residues are widespread in Baltic Sea coastal and offshore waters Screening for pharmaceuticals and modelling of environmental concentrations of carbamazepine. AB - The consumption of pharmaceuticals worldwide coupled with modest removal efficiencies of sewage treatment plants have resulted in the presence of pharmaceuticals in aquatic systems globally. In this study, we investigated the environmental concentrations of a selection of 93 pharmaceuticals in 43 locations in the Baltic Sea and Skagerrak. The Baltic Sea is vulnerable to anthropogenic activities due to a long turnover time and a sensitive ecosystem in the brackish water. Thirty-nine of 93 pharmaceuticals were detected in at least one sample, with concentrations ranging between 0.01 and 80 ng/L. One of the pharmaceuticals investigated, the anti-epileptic drug carbamazepine, was widespread in coastal and offshore seawaters (present in 37 of 43 samples). In order to predict concentrations of pharmaceuticals in the sub-basins of the Baltic Sea, a mass balance-based grey box model was set up and the persistent, widely used carbamazepine was selected as the model substance. The model was based on hydrological and meteorological sub-basin characteristics, removal data from smaller watersheds and wastewater treatment plants, and statistics relating to population, consumption and excretion rate of carbamazepine in humans. The grey box model predicted average environmental concentrations of carbamazepine in sub basins with no significant difference from the measured concentrations, amounting to 0.57-3.2 ng/L depending on sub-basin location. In the Baltic Sea, the removal rate of carbamazepine in seawater was estimated to be 6.2 10-9 s-1 based on a calculated half-life time of 3.5 years at 10 degrees C, which demonstrates the long response time of the environment to measures phasing out persistent or slowly degradable substances such as carbamazepine. Sampling, analysis and grey box modelling were all valuable in describing the presence and removal of carbamazepine in the Baltic Sea. PMID- 29758902 TI - Organic carbon source and salinity shape sediment bacterial composition in two China marginal seas and their major tributaries. AB - Marginal sea sediments receive organic substrates of different origins, but whether and to what extent sediment microbial communities are reflective of the different sources of organic substrates remain unclear. To address these questions, sediment samples were collected in two connected China marginal seas, i.e., Bohai Sea and Yellow Sea, and their two major tributaries (Yellow River and Liao River). Sediment bacterial community composition (BCC) was examined using 16S rRNA gene pyrosequencing. In addition, physicochemical variables that describe environmental conditions and sediment features were measured. Our results revealed that BCCs changed with salinity and organic carbon (OC) content. Members of Gaiellaceae and Comamonadaceae showed a rapid decrease as salinity and phytoplankton-derived OC increased, while Piscirickettsiaceae and Desulfobulbaceae exhibited an opposite distribution pattern. Differences of riverine vs. marginal sea sediment BCCs could be mostly explained by salinity. However, within the marginal seas, sediment BCC variations were mainly explained by OC-related variables, including terrestrial-derived fatty acids (Terr_FA), phytoplankton-derived polyunsaturated fatty acids (Phyto_PUFA), stable carbon isotopes (delta13C), and carbon to nitrogen ratio (C/N). In addition to environmental variables, network analysis suggested that interactions among individual bacterial taxa might be important in shaping sediment BCCs in the studied areas. PMID- 29758903 TI - Potential impact of climate change on groundwater resources in the Central Huai Luang Basin, Northeast Thailand. AB - The Central Huai Luang Basin is one of the important rice producing areas of Udon Thani Province in Northeastern Thailand. The basin is underlain by the rock salt layers of the Maha Sarakham Formation and is the source of saline groundwater and soil salinity. The regional and local groundwater flow systems are the major mechanisms responsible for spreading saline groundwater and saline soils in this basin. Climate change may have an impact on groundwater recharge, on water table depth and the consequences of waterlogging, and on the distribution of soil salinity in this basin. Six future climate conditions from the SEACAM and CanESM2 models were downscaled to investigate the potential impact of future climate conditions on groundwater quantity and quality in this basin. The potential impact was investigated by using a set of numerical models, namely HELP3 and SEAWAT, to estimate the groundwater recharge and flow and the salt transport of groundwater simulation, respectively. The results revealed that within next 30years (2045), the future average annual temperature is projected to increase by 3.1 degrees C and 2.2 degrees C under SEACAM and CanESM2 models, respectively, while the future precipitation is projected to decrease by 20.85% under SEACAM and increase by 18.35% under the CanESM2. Groundwater recharge is projected to increase under the CanESM2 model and to slightly decrease under the SEACAM model. Moreover, for all future climate conditions, the depths of the groundwater water table are projected to continuously increase. The results showed the impact of climate change on salinity distribution for both the deep and shallow groundwater systems. The salinity distribution areas are projected to increase by about 8.08% and 56.92% in the deep and shallow groundwater systems, respectively. The waterlogging areas are also projected to expand by about 63.65% from the baseline period. PMID- 29758904 TI - Selected organohalogenated flame retardants in Egyptian indoor and outdoor environments: Levels, sources and implications for human exposure. AB - There is scant information on the presence of the polybrominated diphenyl ethers (PBDEs) and other alternative flame-retardants (NFRs) in Africa. Hence, to investigate their levels, sources, and human exposure scenarios, elevated fine dust (EFD) samples from apartments (n = 12), working places (n = 9) and cars (n = 12), floor dust (FD) samples (n = 5) and outdoor dust samples (n = 21) were collected from Alexandria, Egypt, during 2014. Gaseous concentrations were estimated using low density polyethylene sheets (n = 33 and 21 for indoor and outdoor sites, respectively). Indoor gaseous and dust PBDE (7.0-300 pg/m3; 4.0 770 ng/g), and NFR (0.40-48 pg/m3; 0.50-8.5 ng/g) concentrations were significantly higher (p = 0.004-0.02) than outdoor concentrations (PBDEs: 3.0-41 pg/m3, 1.5-195 ng/g; NFRs: 0.20-13 pg/m3, 0.50-4.0 ng/g). Median PBDE concentration in cars (210 ng/g) was higher than in apartments and working places (130 ng/g respectively). PBDE concentrations in FD were 7.0-14-folds lower than EFD concentrations. Outdoor PBDE concentrations were significantly higher (p < 0.01) at residential-industrial places with older buildings. All samples were dominated by BDE-47 and 99. HBB, BTBPE and DDC-CO were the most abundant NFRs in EFD samples. Profiles of PBDE and NFR in FD closely matched those of outdoor dust, indicating a possible carryover from the outdoor environment. Although factors such as number of electronics, construction year and floor type significantly correlated with the majority of PBDE congeners and some NFRs in apartments and working places, sources were not clearly identified for NFRs. Significant log-linear relationships were obtained between theoretical and calculated dust-air partitioning coefficients for all samples indicating an equilibrium state between dust and vapor. Low possibility of occurrence of adverse health effects was concluded, with the inhalation pathway (for adults) and dust ingestion (for children) acting as the most important exposure routes. PMID- 29758906 TI - Does drought always cause economic losses in agriculture? An empirical investigation on the distributive effects of drought events in some areas of Southern Europe. AB - Studies on the impacts of drought usually make the implicit assumption that there will always be a negative effect on the environment, the economy and society. However, other approaches, based for example on the framework provided by the consumer surplus theory, try to focus on the distributive effects of drought. In this paper, in the wake of such approaches, we address the question of the distributive effects of drought on agriculture, exploring and studying in depth the characteristics, the signs and the magnitude of the socio-economic impacts of droughts on specific significant agricultural areas in Europe. According to our estimations, essentially based on the analysis of trends and changes in production and prices, we found that drought events can create not only "losers", but also "winners". Some social groups (for example, some categories of farmers) can even "win", while others "lose" (for example, final consumers). These findings apparently introduce questions of social justice in the evaluation of the impacts of climate change. PMID- 29758905 TI - Spatial and temporal distribution of microplastics in water and sediments of a freshwater system (Antua River, Portugal). AB - Microplastics (particles with a size<5mm), one of the most emerging aquatic pollutants, are of particular concern since they can reach high densities and interact with biotic and abiotic environment. The occurrence of microplastics in freshwater systems is less understood than in marine environment. Hence, the present study aims to provide new insights into microplastics abundances and distribution in Antua River (Portugal) by applying the isolation method of wet peroxide oxidation with addition of zinc chloride to water and sediment samples collected in March and October 2016, in three sampling sites. The abundance of microplastics in water ranged from 5 to 8.3mgm-3 or 58-193itemsm-3 in March and from 5.8-51.7mgm-3 or 71-1265itemsm-3 in October. In sediments, the abundance ranged from 13.5-52.7mgkg-1 or 100-629itemskg-1 in March and from 2.6-71.4mgkg-1 or 18-514itemskg-1 in October. The water and sediment samples with the greatest abundances were from Sao Joao da Madeira and Aguincheira, respectively. Spatio temporal distribution showed different pattern according to methodological approaches, seasonal and hydrodynamic conditions and the proximity to urban/industry areas. Analysis of plastics by Fourier transform infrared spectroscopy underline polyethylene and polypropylene as the most common polymer types identified in this work. The low medium high oxidation ratio was 56:22:22 (%) in March and 61:31:8 (%) in October. Foams and fibers were the most abundant type in Sao Joao da Madeira, while fibers and fragments were the most abundant in Aguincheira and Estarreja in water and sediment samples, respectively. This study emphasizes the importance of rivers as carriage systems of microplastics. Further studies should be performed to identify point sources in order to mitigate the microplastics contamination in aquatic systems. PMID- 29758907 TI - Dual carbon isotopes (14C and 13C) and optical properties of WSOC and HULIS-C during winter in Guangzhou, China. AB - Water-soluble brown carbon (ws-BrC) exerts an important influence on climate change, but its emission sources and optical properties remain poorly understood. In this study, we isolated two ws-BrC proxies, water-soluble organic carbon (WSOC) and humic-like substance carbon (HULIS-C), from particulate matter collected in Guangzhou, China, during December 2012 for the measurement of dual carbon isotopes (14C and 13C) and light absorption. The mass absorption efficiencies of WSOC and HULIS-C at 365nm were 0.81+/-0.16 and 1.33+/-0.21m2g-1C, respectively. The 14C results showed that two-thirds of WSOC and HULIS-C were derived from non-fossil sources (e.g., biomass burning and biogenic emission), and the remaining third was derived from fossil sources. The delta13C values of WSOC and HULIS-C were -23.7+/-1.20/00 and -24.2+/-0.90/00, respectively, underlining the limited influences of C4 plants and natural gas on ws-BrC. Fitting the data to a multiple linear regression, we further concluded that approximately 80% and 10% of the light absorption at 365nm was due to non-fossil and fossil carbon, respectively. Non-fossil sources of ws-BrC, such as the burning of agricultural residue, were responsible for the light absorption recorded in Guangzhou. PMID- 29758908 TI - Spatial relationships among cereal yields and selected soil physical and chemical properties. AB - Sandy soils occupy large area in Poland (about 50%) and in the world. This study aimed at determining spatial relationships of cereal yields and the selected soil physical and chemical properties in three study years (2001-2003) on low productive sandy Podzol soil (Podlasie, Poland). The yields and soil properties in plough and subsoil layers were determined at 72-150 points. The test crops were: wheat, wheat and barley mixture and oats. To explore the spatial relationship between cereal yields and each soil property spatial statistics was used. The best fitting models were adjusted to empirical semivariance and cross semivariance, which were used to draw maps using kriging. Majority of the soil properties and crop yields exhibited low and medium variability (coefficient of variation 5-70%). The effective ranges of the spatial dependence (the distance at which data are autocorrelated) for yields and all soil properties were 24.3-58.5m and 10.5-373m, respectively. Nugget to sill ratios showed that crop yields and soil properties were strongly spatially dependent except bulk density. Majority of the pairs in cross-semivariograms exhibited strong spatial interdependence. The ranges of the spatial dependence varied in plough layer between 54.6m for yield*pH up to 2433m for yield*silt content. Corresponding ranges in subsoil were 24.8m for crop yield*clay content in 2003 and 1404m for yield*bulk density. Kriging maps allowed separating sub-field area with the lowest yield and soil cation exchange capacity, organic carbon content and pH. This area had lighter color on the aerial photograph due to high content of the sand and low content of soil organic carbon. The results will help farmers at identifying sub-field areas for applying localized management practices to improve these soil properties and further spatial studies in larger scale. PMID- 29758909 TI - Water resources conservation and nitrogen pollution reduction under global food trade and agricultural intensification. AB - Global food trade entails virtual flows of agricultural resources and pollution across countries. Here we performed a global-scale assessment of impacts of international food trade on blue water use, total water use, and nitrogen (N) inputs and on N losses in maize, rice, and wheat production. We simulated baseline conditions for the year 2000 and explored the impacts of an agricultural intensification scenario, in which low-input countries increase N and irrigation inputs to a greater extent than high-input countries. We combined a crop model with the Global Trade Analysis Project model. Results show that food exports generally occurred from regions with lower water and N use intensities, defined here as water and N uses in relation to crop yields, to regions with higher resources use intensities. Globally, food trade thus conserved a large amount of water resources and N applications, and also substantially reduced N losses. The trade-related conservation in blue water use reached 85km3y-1, accounting for more than half of total blue water use for producing the three crops. Food exported from the USA contributed the largest proportion of global water and N conservation as well as N loss reduction, but also led to substantial export associated N losses in the country itself. Under the intensification scenario, the converging water and N use intensities across countries result in a more balanced world; crop trade will generally decrease, and global water resources conservation and N pollution reduction associated with the trade will reduce accordingly. The study provides useful information to understand the implications of agricultural intensification for international crop trade, crop water use and N pollution patterns in the world. PMID- 29758910 TI - Assessing the effect of chlorinated hydrocarbon degradation in aquitards on plume persistence due to back-diffusion. AB - This modeling study aims to investigate how reactive processes in aquitards impact plume persistence in adjacent aquifers. For that purpose the migration of a trichloroethene (TCE) plume in an aquifer originating from dense non-aqueous phase liquid (DNAPL) source dissolution and back-diffusion from an underlying reactive aquitard was simulated in a 2D-numerical model. Two aquitard degradation scenarios were modeled considering one-step degradation from TCE to cis dichloroethene (cDCE): a uniform (constant degradation with aquitard depth) and a non-uniform scenario (decreasing degradation with aquitard depth) and were compared with a no-degradation scenario. In the no-degradation scenario, a long term TCE tailing above the Maximum Contaminant Level (MCL) caused by back diffusion after source removal was observed. In contrast, in the aquitard degradation scenarios, TCE back-diffusion periods were shorter, whereby the extent of back-diffusion reduction depended on the aquitard degradation depth and the rate. For high degradation rates (half-life: 30-80days), an aquitard degradation depth greater than 65cm prevented TCE plume persistence after source removal but generated a long-term tailing above the MCL for the produced cDCE. For slow degradation rates (half-life: <200days), TCE was only partially degraded after source removal, independent of the aquitard degradation depth, leading to a long-term dual contamination of the aquifer by cDCE and TCE. A sudden enrichment of 13C in TCE and cDCE was observed after source removal in the uniform and non uniform degradation scenarios that was distinct from delta13C patterns observed when aquifer degradation occurs (continuous enrichment of 13C along the plume axis) and for when there is absence of degradation (no change of isotope ratios). This demonstrates that delta13C measurements in the aquifer can be used as a diagnostic tool to demonstrate aquitard degradation, which simplifies the identification of reactive processes in aquitards, as aquifers are usually easier to monitor than aquitards. PMID- 29758911 TI - A hybrid land-water-environment model for identification of ecological effect and risk under uncertain meteorological precipitation in an agroforestry ecosystem. AB - In this study, a hybrid land-water-environment (LWE) model is developed for identifying ecological effect and risk under uncertain precipitation in an agroforestry ecosystem. A simulation-based fuzzy-stochastic programming with risk analysis (SFSR) method is used into LWE model to reflect the meteorological impacts; meanwhile, it also can quantify artificial fuzziness (e.g., risk attitude of policymaker) and natural vagueness (e.g., ecological function) in decision-making. The developed LWE model with SFSR method is applied to a practical agroforestry ecosystem in China. Results of optimized planting scale, irrigative water schedule, pollution mitigation scheme, and system benefit under changed rainfall, precise risk-adoption and vague ecological function are obtained; meanwhile their corresponding ecological effects and risks are analyzed. It found that current LWE plans could generate massive water deficits (e.g., 23.22*106m3 in crop irrigation and 26.32*106m3 in forest protection at highest) due to over-cultivation and excessive pollution discharges (e.g., the highest excessive TP and TN discharges would reach 460.64 and 15.30*103 ton) due to irrational fertilization, which would increase regional ecological risks. In addition, fifteen scenarios associated with withdrawing cultivation and recovering forest based on regional environment heterogeneity (such as soil types) have been discussed to adjust current agriculture-environment policies. It found that, the excessive pollution discharges (TN and TP) could be reduced 12.95% and 18.32% at highest through ecological expansions, which would generate higher system benefits than that without withdrawing farmland and recovering forest. All above can facilitate local policymakers to modulate a comprehensive LWE with more sustainable and robust manners, achieving regional harmony between socio-economy and eco-environment. PMID- 29758912 TI - Evaluation of soil quality along two revegetation chronosequences on the Loess Hilly Region of China. AB - Vegetation restoration has been widely implemented to control soil degradation, reduce soil erosion, and improve soil quality. It is vital to understand the mechanisms affecting soil quality in soil restoration processes and to determine an appropriate recover pattern for soil restoration. Thus, a soil quality index was developed using integrated approach to assess soil quality after vegetation restoration in this study. Soil samples were collected from two restoration pathways (afforestation by Robinia pseudoacacia L. and natural recovery of abandoned farmland) with ages sequence of 0, 17,27 and 42years old at two soil depths (0-10 and 10-20cm) to measure soil physicochemical and biological properties on the Loess Hilly Region of China, China. The results showed that soil quality index (SQI) was developed based on microbial biomass carbon (MBC), fine particles (FP), and total phosphorus (TP). The MBC, which had the fastest increase rate than TP and FP, had the highest contribution to the final SQI and these contributions increased with recovery age. The MBC values were higher in Robinia pseudoacacia L. than in abandoned land sites at all recovery ages with greater increases along with restoration age. The SQI values significantly increased with increasing restoration age up to 27years (P<0.05). After 27years, SQI values for the AL sites remained stable, while SQI values for RP sites continually improved with increasing restoration age. In addition, SQI values were higher for RP sites than for AL sites for all restoration ages. PMID- 29758913 TI - Roles of MnO2 on performance, sludge characteristics and microbial community in anammox system. AB - The long-term impacts of MnO2 on performance, sludge characteristics and microbial community of biogranule-based anaerobic ammonium oxidation (anammox) process were evaluated in an up-flow anaerobic sludge blanket reactor. It was found that the total nitrogen removal efficiency of reactor was fluctuated between 90%-93% at 1-200mgL-1 MnO2. Notably, the specific anammox activity was increased to maximum value of 657.3+/-10.6mgTNg-1VSSd-1 at 50mgL-1 MnO2 and then slightly decreased, but still higher than that achieved at 0-15mgL-1 MnO2, which had similar variation trends to the content of heme c and extracellular polymeric substances in anammox granules. High throughput sequencing indicated that MnO2 could improve the microbial richness and diversity of anammox granules and Candidatus Kuenenia was always the dominant species, and its abundance continued to increase to 21.3% at the end of operational experiment. Therefore, MnO2 could be applied to enhance the anammox process and the optimal influent MnO2 concentration was lower than 50mgL-1 in view of the reactor performance and cost issues. PMID- 29758914 TI - Hermetia illucens as a new and promising species for use in entomoremediation. AB - This study investigated the use of Hermetia illucens (black soldier fly - BSF) larvae as a new species for use in entomoremediation. The H. illucens larvae effectively reduced the dry mass of polluted corn leaves by an average of 49% after 36days for both Cd and Zn (50mg.kg-1), which is a better result than that, which can be obtained by one of the standard proposed pretreatments for biomass polluted after phytoextraction: composting. The presence of heavy metals did not significantly affect the dry mass utilization efficiency. Based on this, we proposed the use of H. illucens as a new post-harvest management method of phytoextraction-polluted biomass. Cadmium mostly accumulates in the puparium, while Zn accumulates in the adults. The high Cd content in the puparium further creates possibility of its application in the metal recovery process. It is also proposed that the general definition of entomoremediation be expanded. PMID- 29758915 TI - Dissolved organic matter release in overlying water and bacterial community shifts in biofilm during the decomposition of Myriophyllum verticillatum. AB - This study investigated the alterations in biomass, nutrients and dissolved organic matter concentration in overlying water and determined the bacterial 16S rRNA gene in biofilms attached to plant residual during the decomposition of Myriophyllum verticillatum. The 55-day decomposition experimental results show that plant decay process can be well described by the exponential model, with the average decomposition rate of 0.037d-1. Total organic carbon, total nitrogen, and organic nitrogen concentrations increased significantly in overlying water during decomposition compared to control within 35d. Results from excitation emission matrix-parallel factor analysis showed humic acid-like and tyrosine acid-like substances might originate from plant degradation processes. Tyrosine acid-like substances had an obvious correlation to organic nitrogen and total nitrogen (p<0.01). Decomposition rates were positively related to pH, total organic carbon, oxidation-reduction potential and dissolved oxygen but negatively related to temperature in overlying water. Microbe densities attached to plant residues increased with decomposition process. The most dominant phylum was Bacteroidetes (>46%) at 7d, Chlorobi (20%-44%) or Proteobacteria (25%-34%) at 21d and Chlorobi (>40%) at 55d. In microbes attached to plant residues, sugar- and polysaccharides degrading genus including Bacteroides, Blvii28, Fibrobacter, and Treponema dominated at 7d while Chlorobaculum, Rhodobacter, Methanobacterium, Thiobaca, Methanospirillum and Methanosarcina at 21d and 55d. These results gain the insight into the dissolved organic matter release and bacterial community shifts during submerged macrophytes decomposition. PMID- 29758916 TI - Assessing the cold temperature effect on hospital visit by allergic rhinitis in Seoul, Korea. AB - The association between temperature and health outcome has been studied in worldwide. However, studies for mild diseases such as AR, with high prevalence and considerable economic burden, are lacking compared to other relatively severe respiratory diseases. We aimed to assess the trend of hospital visit by AR and estimate the cold temperature effect on hospital visit by allergic rhinitis in Seoul, Korea, 2003-2011. We fitted generalized additive model with quasi-poisson distribution, controlling for humidity, long-term trend, day of week, national holiday, and influenza epidemic. We estimated the cumulative cold temperature effect (10%, -1.7 degrees C) referent to 7.9 degrees C for the considered lag periods using distributed lag non-linear model: vary from the day of hospital visit to 10days before. Stratified analysis by season was also conducted. To adjust for possible confounding effect of air pollutants, we additionally adjusted for PM10, O3 and NO2 respectively. Hospital visit counts and rates per 1,000,000 show increasing trend especially in elderly population (over 65years). Hospital visit rate is higher in children population (age<13years). Statistically significant cold temperature effects were found in the total (1.094(95%CI: 1.037, 1.153)), male (1.100 (95%CI: 1.010, 1.163)), female (1.088 (95%CI: 1.059, 1.170)) and adult (1.113 (95%CI: 1.059, 1.170)) population with consideration of 3-day lag period. In the stratified analysis by the season, the strongest effect was shown in the autumn (Sep-Nov) season. Confounding effects by air pollutants were not found. In this study, we found significant increasing trend of hospital visit by AR. This study provides suggestive evidence of cold temperature effect on hospital visit by AR. To reduce the growing burden of AR, it is important to find possible related environmental risk factors. More studies should be conducted for better understanding of temperature effect on AR. PMID- 29758917 TI - Source and path identification of metals pollution in a mining area by PMF and rare earth element patterns in road dust. AB - To better assess pollution and offer efficient protection for local residents, it is necessary to both conduct an exhaustive investigation into pollution levels and quantify its contributing sources and paths. As it is the biggest light rare earth element (REE) reserve in the world, Bayan Obo deposit releases large amounts of heavy metals into the surrounding environment. In this study, road dust from zones located at different distances to the mining area was collected and sieved using seven sizes. This allowed for subsequent analysis of size dependent influences of mining activities. A receptor model was used to quantitatively assess mine contributions. REE distribution patterns and other REE parameters were compared with those in airborne particulates and the surrounding soil to analyze pollution paths. Results showed that 27 metals were rated as moderately to extremely polluted (290/min), lactate above 1.5 mmol/L, age above 80 years; HR 2.43 95% CI 1.50-3.92; p < 0.001). Parameters of microvascular perfusion were associated neither with BUN nor mortality. CONCLUSIONS: BUN is associated with hospital mortality and a combination of BUN and clinical signs might constitute a powerful but easy-to-use tool for risk stratification in critically ill patients and help improve their outcome. BUN was not associated with parameters of microcirculation which were not associated with mortality. PMID- 29758936 TI - Evaluation of integrated color-coded perfusion analysis for contrast-enhanced ultrasound (CEUS) after percutaneous interventions for malignant liver lesions: First results. AB - BACKGROUND: With the rising number of percutaneous ablation therapies in malignant liver lesions there is a need of reliable diagnostics after the intervention to differentiate between reactive changes and tumor. PURPOSE: To assess the success of percutaneous ablation therapies for malignant liver lesions using CEUS with perfusion analysis. MATERIAL AND METHODS: Retrospective analysis of perfusion analysis for 67 patients with 94 malignant liver lesions, treated with ablation therapies. The lesions were 70 hepatocellular carcinomas (HCC), 18 metastases, 4 cholangiocellular carcinomas (CCC), 2 lesions remained unclear. CEUS was performed after bolus injection of 1.6-2.4 ml of sulfur-hexafluoride microbubbles. The perfusion analysis was calculated using Peak, TTP, mTT and AUC with integrated software during the late arterial to early portal-venous phase for approximately 9 sec (5-15 sec). For the evaluation of the success after percutaneous treatment the perfusion results were compared to the follow-up control after 6 months with CT and MRI and CEUS. RESULTS: Perfusion analyses after percutaneous treatment of malignant liver lesions showed highly significant perfusion differences when comparing the center to the surrounding tissue and the margins (p<0.0001) for Peak and also for AUC. 62 lesions were successfully treated, meaning there was no local recurrence after 6 months. In cases of residual tumor CEUS showed a nodular marginal enhancement, the corresponding perfusion analyses showed nodular red and yellow pseudo-color shades. CONCLUSIONS: Using CEUS and perfusion analysis, a critical analysis of post ablation defects in malignant liver lesions is possible. With the help of pseudo colors, remaining tumor-vascularization can be detected. PMID- 29758937 TI - The controversial origin of pericytes during angiogenesis - Implications for cell based therapeutic angiogenesis and cell-based therapies. AB - Pericytes reside within the basement membrane of small vessels and are often in direct cellular contact with endothelial cells, fulfilling important functions during blood vessel formation and homeostasis. Recently, these pericytes have been also identified as mesenchymal stem cells. Mesenchymal stem cells, and especially their specialized subpopulation of pericytes, represent promising candidates for therapeutic angiogenesis applications, and have already been widely applied in pre-clinical and clinical trials. However, cell-based therapies of ischemic diseases (especially of myocardial infarction) have not resulted in significant long-term improvement. Interestingly, pericytes from a hematopoietic origin were observed in embryonic skin and a pericyte sub-population expressing leukocyte and monocyte markers was described during adult angiogenesis in vivo. Since mesenchymal stem cells do not express hematopoietic markers, the latter cell type might represent an alternative pericyte population relevant to angiogenesis. Therefore, we sourced blood-derived angiogenic cells (BDACs) from monocytes that closely resembled hematopoietic pericytes, which had only been observed in vivo thus far. BDACs displayed many pericytic features and exhibited enhanced revascularization and functional tissue regeneration in a pre-clinical model of critical limb ischemia. Comparison between BDACs and mesenchymal pericytes indicated that BDACs (while resembling hematopoietic pericytes) enhanced early stages of angiogenesis, such as endothelial cell sprouting. In contrast, mesenchymal pericytes were responsible for blood vessel maturation and homeostasis, while reducing endothelial sprouting.Since the formation of new blood vessels is crucial during therapeutic angiogenesis or during integration of implants into the host tissue, hematopoietic pericytes (and therefore BDACs) might offer an advantageous addition or even an alternative for cell-based therapies. PMID- 29758939 TI - Higher Blood Vitamin C Levels are Associated with Reduction of Apolipoprotein E E4-related Risks of Cognitive Decline in Women: The Nakajima Study. AB - BACKGROUND: Antioxidants like vitamins C and E may minimize the risk for Alzheimer's disease. OBJECTIVE: We examined whether vitamins C and E modify the apolipoprotein E (APOE) E4-related risks for developing cognitive decline. METHODS: We conducted a population-based prospective study including Japanese residents aged 65 years from Nakajima, Japan. The participants received an evaluation of cognitive function and underwent blood tests including tests for vitamins C and E levels and APOE phenotypes. The APOE E4-by-gender-by-vitamin C or E interactions on developing cognitive decline were analyzed. RESULTS: Of 606 participants with normal cognitive function determined using a baseline survey (2007-2008), 349 completed the follow up survey between 2014 and 2016. In women with APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin C concentration tertile [multivariate OR 0.10 (95% CI 0.01-0.93)] compared with the lowest tertile. In men without APOE E4, significantly reduced risk for cognitive decline was observed for the highest blood vitamin E concentration tertile [multivariate OR 0.19 (0.05-0.74)] as compared with the lowest tertile. CONCLUSION: Our results demonstrate significant beneficial effects of vitamins C and E in reducing the risk of cognitive decline in women with APOE E4 and men without APOE E4, respectively. PMID- 29758940 TI - Self-Reported Physical Activity is Associated with Tau Burden Measured by Positron Emission Tomography. AB - Numerous animal studies have reported exercise reduces the accumulation of Alzheimer's disease pathology, including amyloid-beta (Abeta) and tau. Furthermore, we previously reported a relationship between higher levels of physical activity (PA) and lower brain Abeta burden in a human population. The recent advent of tau positron emission tomography (PET) tracers enables us to extend our investigations into the evaluation of the relationship between PA and brain tau burden. Utilizing data from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we have examined the cross-sectional relationship between habitual PA and PET-quantified tau burden. Forty-three cognitively healthy older adults were categorized into low-moderate PA (LMPA; n = 16) or high PA (HPA; n = 27), based on self-reported PA levels. Tau PET imaging with the AV1451 tracer was conducted on all participants. The LMPA group had significantly higher neocortical tau burden (presented as a z-score; 1.22+/-1.98), compared to the HPA group (z-score: - 0.28+/-1.18). The difference between the LMPA and HPA groups was also evident when examining regional tau burden in the temporoparietal cortex and the prefrontal cortex. Our results suggest an association between self reported PA level and brain tau burden. Future longitudinal and interventional studies utilizing larger samples sizes are vital to further investigate the nature of the relationship between tau and PA. PMID- 29758941 TI - From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer's Disease. AB - The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer's disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years. PMID- 29758938 TI - Influence of Lewy Pathology on Alzheimer's Disease Phenotype: A Retrospective Clinico-Pathological Study. AB - BACKGROUND: Studies have shown the frequent coexistence of Lewy pathology (LP) in Alzheimer's Disease (AD). OBJECTIVE: The aim of this study was to determine the influence of LP on the clinical and cognitive phenotype in a cohort of patients with a neuropathological diagnosis of AD. METHODS: We reviewed neuropathologically proven AD cases, reaching Braak stages V and VI in the brain banks of Lille and Paris between 1993 and 2016, and classified them according to LP extension (amygdala, brainstem, limbic, or neocortical). We then searched patient files for all available clinical and neuropsychiatric features and neuropsychological data. RESULTS: Thirty-three subjects were selected for this study, among which 16 were devoid of LP and 17 presented AD with concomitant LP. The latter were stratified into two subgroups according to LP distribution: 7 were AD with amygdala LP and 10 were AD with 'classical' (brainstem, limbic or neocortical) LP. When analyzing the incidence of each clinical feature at any point during the disease course, we found no significant difference in symptom frequency between the three groups. However, fluctuations appeared significantly earlier in patients with classical LP (2+/-3.5 years) than in patients without LP (7+/-1.7 years) or with amygdala LP (8+/-2.8 years; p < 0.01). There was no significant difference in cognitive profiles. CONCLUSION: Our findings suggest that the influence of LP on the clinical phenotype of AD is subtle. Core features of dementia with Lewy bodies do not allow clinical diagnosis of a concomitant LP on a patient-to-patient basis. PMID- 29758942 TI - Lost in Translation? Finding Our Way To Effective Alzheimer's Disease Therapies. AB - Efforts over the past two decades to develop effective disease-modifying treatments for Alzheimer's disease have been disappointing, while parallel efforts in another chronic neurologic disease, multiple sclerosis, have been remarkably productive. In an effort to advance development of therapeutics for Alzheimer's disease, these two fields are contrasted in terms of the utility of animal models, definition of study populations, and utility of biomarkers. Possible solutions are suggested, and the review concludes with description of some active peer-reviewed, publicly funded clinical studies which address some of the identified weaknesses in past clinical trials for age-related dementia. PMID- 29758944 TI - The Conundrum of GSK3 Inhibitors: Is it the Dawn of a New Beginning? AB - Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer's disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials. However, the conundrum of what happened to the fate of the AstraZeneca's GSK3 inhibitors and the undertaking to find a therapeutic that could control glycogen metabolism and aberrant tau hyperphosphorylation in the brain, and rescue synaptic dysfunction has largely been untold. AstraZeneca was in the forefront of GSK3 drug discovery research with six GSK3 drug candidates, one of which progressed up to Phase II clinical trials in the quest to untangle the tau hypothesis for AD. Analysis of key toxicity issues, serendipitous findings and efficacy, and biomarker considerations in relation to safety margins have limited the potential of small molecule therapeutics as a way forward. To guide future innovation of this important target, we reveal the roller coaster journey comprising of two decades of preclinical and clinical GSK3 drug discovery at AstraZeneca; the understanding of which could lead to improved GSK3 therapies for disease. These learnings in combination with advances in achieving kinase selectivity, different modes of action as well as the recent discovery of novel conjugated peptide technology targeting specific tissues have potentially provided a venue for scientific innovation and a new beginning for GSK3 drug discovery. PMID- 29758943 TI - Novel Key Players in the Development of Tau Neuropathology: Focus on the 5 Lipoxygenase. AB - Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5 lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies. PMID- 29758945 TI - A 10-Year Follow-Up of Adiposity and Dementia in Swedish Adults Aged 70 Years and Older. AB - BACKGROUND: Adiposity measured in mid- or late-life and estimated using anthropometric measures such as body mass index (BMI) and waist-to-hip ratio (WHR), or metabolic markers such as blood leptin and adiponectin levels, is associated with late-onset dementia risk. However, during later life, this association may reverse and aging- and dementia-related processes may differentially affect adiposity measures. OBJECTIVE: We explored associations of concurrent BMI, WHR, and blood leptin and high molecular weight adiponectin levels with dementia occurrence. METHODS: 924 Swedish community-dwelling elderly without dementia, aged 70 years and older, systematically-sampled by birth day and birth year population-based in the Gothenburg city region of Sweden. The Gothenburg Birth Cohort Studies are designed for evaluating risk and protective factors for dementia. All dementias diagnosed after age 70 for 10 years were identified. Multivariable logistic regression models were used to predict dementia occurrence between 2000-2005, 2005-2010, and 2000-2010 after excluding prevalent baseline (year 2000) dementias. Baseline levels of BMI, WHR, leptin, and adiponectin were used. RESULTS: Within 5 years of baseline, low BMI (<20 kg/m2) was associated with higher odds of dementia compared to those in the healthy BMI category (>= 20-24.9 kg/m2). Compared to the lowest quartile, leptin levels in the second quartile were associated with lower odds of dementia in women (p < 0.05). CONCLUSION: In late-life, anthropometric and metabolic adiposity measures appear to be differentially associated with dementia risk. While BMI and leptin levels are highly positively correlated, our results show that their association with dementia at age >=70 years, is asynchronous. These data suggest that with aging, the complexity of the adiposity exposure may increase and suggests metabolic dysregulation. Additional studies are needed to better understand this complexity. PMID- 29758947 TI - Phenomenological Characteristics of Future Thinking in Alzheimer's Disease. AB - This study investigates phenomenological reliving of future thinking in Alzheimer's disease (AD) patients and matched controls. All participants were asked to imagine in detail a future event, and afterward, were asked to rate phenomenological characteristics of their future thinking. As compared to controls, AD participants showed poor rating for reliving, travel in time, visual imagery, auditory imagery, language, and spatiotemporal specificity. However, no significant differences were observed between both groups in emotion and importance of future thinking. Results also showed lower rating for visual imagery relative to remaining phenomenological features in AD participants compared to controls; conversely, these participants showed higher ratings for emotion and importance of future thinking. AD seems to compromise some phenomenological characteristics of future thinking, especially, visual imagery; however, other phenomenological characteristics, such as emotion, seem to be relatively preserved in these populations. By highlighting the phenomenological experience of future thinking in AD, our paper opens a unique window into the conscious experience of the future in AD patients. PMID- 29758946 TI - Gut Microbiota is Altered in Patients with Alzheimer's Disease. AB - Previous studies suggest that gut microbiota is associated with neuropsychiatric disorders, such as Parkinson's disease, amyotrophic lateral sclerosis, and depression. However, whether the composition and diversity of gut microbiota is altered in patients with Alzheimer's disease (AD) remains largely unknown. In the present study, we collected fecal samples from 43 AD patients and 43 age- and gender-matched cognitively normal controls. 16S ribosomal RNA sequencing technique was used to analyze the microbiota composition in feces. The composition of gut microbiota was different between the two groups. Several bacteria taxa in AD patients were different from those in controls at taxonomic levels, such as Bacteroides, Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales. Our findings suggest that gut microbiota is altered in AD patients and may be involved in the pathogenesis of AD. PMID- 29758948 TI - Argyrophilic Grain Pathology in Frontotemporal Lobar Degeneration: Demographic, Clinical, Neuropathological, and Genetic Features. AB - Frontotemporal lobar degeneration (FTLD) is a clinically, pathologically, and genetically heterogeneous group of disorders that affect the frontal and temporal lobes of the brain. FTLD classification distinguishes three main neuropathological groups: FTLD-tau, FTLD-TDP, and FTLD-FUS. As a four-repeat tauopathy, argyrophilic grain disease (AGD) is included in the FTLD-tau group. AGD may also appear in association with other neuropathological disorders. We describe the demographic, clinical, neuropathological, and genetic characteristics of a series of FTLD cases presenting with AGD. For this purpose, a clinico-pathological study of 71 autopsy-confirmed FTLD cases from different tissue banks was performed. AGD was found in 52.1% of FTLD cases. The presence of AGD increased with the increasing age (up to 88.9% in cases older than 80 years; p < 0.001) and was associated with higher ages at onset (p < 0.001) and death (p < 0.001). In AGD cases, progressive supranuclear palsy (PSP) was the most frequent clinical diagnosis (29.7%) and gait disturbance was the most common symptom (64.5%); behavioral and language symptoms were less frequent as compared with non-AGD cases (p = 0.055; p = 0.012). PSP was the most frequent neuropathological diagnosis among cases with AGD (32.4%). This group also showed less brain atrophy (p = 0.094) and higher prevalence of Alzheimer (p = 0.002) and vascular pathology (p = 0.047) as compared to the non-AGD group. We also observed that H1/H1 genotype was overrepresented in AGD cases (p = 0.018) and that there was no association with any specific APOE allele. A subanalysis of PSP cases according to the AGD status was carried out, yielding no significant differences. PMID- 29758949 TI - Patient Engagement: The Fundacio ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research. PMID- 29758950 TI - Simulated medication errors: A means of evaluating healthcare professionals' knowledge and understanding of medication safety. AB - OBJECTIVE: To determine multi-disciplinary perceptions of the clinical significance of medication errors (MEs), the responsible health professional(s), the contributing factors and potential preventive strategies. METHODS: The five simulated ME cases represented errors from five wards at a children's hospital in Australia. Pre-determined answers for each case were developed through consensus among the researchers. The root cause analysis (RCA) was undertaken via a questionnaire disseminated to physicians, nurses and pharmacists at the study hospital to seek their opinions on the ME cases. Agreement model between the participants and pre-determined responses regarding the contributing factors was conducted using general estimating equation (GEE) analysis. RESULTS: Of the 111 RCA questionnaires distributed, 25 were returned. The majority (93%) of respondents rated the significance of the MEs as either 'moderate' or 'life threatening'. Furthermore, they correctly identified two contributing factors relevant to all cases: dismissal of policies/procedures or guidelines (90%) and human resources issues (87%). GEE analysis revealed varied agreement patterns across the contributing factors. Suggested prevention strategies focused on policy and procedures, staffing and supervision, and communication. CONCLUSION: Simulated case studies had potential use to seek front-line healthcare professionals' understanding of the clinical significance and contributing factors to MEs, along with preventive measures. PMID- 29758951 TI - SSRI and SNRI withdrawal symptoms reported on an internet forum. AB - BACKGROUND: Antidepressant withdrawal symptoms are well-recognised, but their potential duration remains uncertain. OBJECTIVE: We aimed to describe the characteristics of withdrawal associated with two popular classes of antidepressants, including duration. METHODS: We analysed the content of a sample of posts on an antidepressant withdrawal website. We compared the characteristics of withdrawal associated with SSRIs and SNRIs, including time of onset, duration and nature of symptoms. RESULTS: 110 posts about SSRI withdrawal, and 63 concerning SNRI withdrawal, were analysed. The mean duration of withdrawal symptoms was significantly longer with SSRIs than SNRIs: 90.5 weeks (standard deviation, SD, 150.0) and 50.8 weeks (SD 76.0) respectively; p = 0.043). Neurological symptoms, such as 'brain zaps,' were more common among SNRI users (p = 0.023). Psychosexual/genitourinary symptoms may be more common among SSRI users (p = 0.054). LIMITATIONS: The website aims to help people with antidepressant withdrawal, and is therefore likely to attract people who have difficulties. Length of prior use of antidepressants was long, with a mean of 252.2 weeks (SD 250.8). CONCLUSIONS: People accessing antidepressant withdrawal websites report experiencing protracted withdrawal symptoms. There are some differences in the characteristics of withdrawal associated with different classes of antidepressants. PMID- 29758952 TI - Knowledge and attitudes of patients in primary care on off-label treatment. AB - OBJECTIVE: To examine primary care patients' knowledge and attitudes on off-label treatment. METHODS: In 47 primary care offices in Osijek-Baranja County, 1300 patients were given questionnaires about their knowledge and attitudes on off label treatment. Questionnaires were completed voluntarily and anonymously. RESULTS: Majority of patients (96.3%) had no knowledge about off-label treatment, and upon having it explained, 42.3% would not accept such treatment under any circumstances, while 54.5% would never accept such treatment for their children. Patients place more trust in primary care doctors than in hospital doctors; 69.6% of patients strongly believe that primary care doctors would not expose them to off-label treatment while only 41.2% of them think the same in relation to hospital doctors. In case of serious consequences following off-label therapy 49.9% of patients would sue doctors who prescribed it. CONCLUSION: Patients in primary care possess limited knowledge about off-label treatment. Most patients do not wish to be exposed to such treatment, and are particularly reluctant to have their children exposed to it. In case of serious side effects, half of the patients would sue doctors who had prescribed the off-label therapy. PMID- 29758953 TI - Electroacupunture contributes to recovery of neurological deficits in experimental stroke by activating astrocytes. AB - BACKGROUND: Neurological deficits is one of the most prevalent clinical manifestation after stroke. The effects of astrocytes activated by electroacupunture (EA) after stroke on the neurological recovery in middle cerebral artery occlusion (MCAO) rats was not clear and definite. OBJECTIVE: Our previous study showed that treatment with EA for 7 days contributed to the activation of astrocytes in MCAO rats. The purposes of this study were to 1) confirm the effects of EA for 14 days on activation of astrocytes in MCAO rats, and 2) test the relationships between activation of astrocytes and neurological functional recovery induced by EA in MCAO rats. METHODS: All rats were randomly divided into five groups: naive control group, sham control control group, MCAO, MCAO/EAn, MCAO/EAd (n = 8, for each group). Rats in MCAO/EAn group received EA treatment at acupoints of Neiguan (PC06). MCAO/EAd group received EA stimulus at acupoints of Diji (SP08). The primary indicators were locomotor recovery, histopathology, immunohistochemistry, RT-PCR and Western blot. RESULTS: The neurological deficit and histopathological improvements and activation of astrocytes were observed after EA treatment at acupoints PC06. Parametric correlation analyses revealed a cubic correlation relationship between activation of astrocytes and neurological recovery of MCAO rats treated with EA. CONCLUSION: EA treatment at the acupoints of Neiguan involved in the regulation of activation of astrocytes, which our data suggested has a cubic correlation relationship with the neurological recovery of MCAO rats. PMID- 29758955 TI - Fetal heart rate monitoring device using condenser microphone sensor: Validation and comparison to standard devices. AB - BACKGROUND: Fetal heart rate (FHR) monitoring device is highly demanded to assess the fetus health condition in home environments. Conventional standard devices such as ultrasonography and cardiotocography are expensive, bulky and uncomfortable and consequently not suitable for long-term monitoring. Herein, we report a device that can be used to measure fetal heart rate in clinical and home environments. METHODS: The proposed device measures and displays the FHR on a screen liquid crystal display (LCD). The device consists of hardware that comprises condenser microphone sensor, signal conditioning, microcontroller and LCD, and software that involves the algorithm used for processing the conditioned fetal heart signal prior to FHR display. The device's performance is validated based on analysis of variance (ANOVA) test. RESULTS: FHR data was recorded from 22 pregnant women during the 17th to 37th week of gestation using the developed device and two standard devices; AngelSounds and Electronic Stethoscope. The results show that F-value (1.5) is less than F????????, (3.1) and p-value (p> 0.05). Accordingly, there is no significant difference between the mean readings of the developed and existing devices. Hence, the developed device can be used for monitoring FHR in clinical and home environments. PMID- 29758956 TI - Prediction of human gait trajectories during the SSP using a neuromusculoskeletal modeling: A challenge for parametric optimization. AB - The parametric optimization techniques have been widely employed to predict human gait trajectories; however, their applications to reveal the other aspects of gait are questionable. The aim of this study is to investigate whether or not the gait prediction model is able to justify the movement trajectories for the higher average velocities. A planar, seven-segment model with sixteen muscle groups was used to represent human neuro-musculoskeletal dynamics. At first, the joint angles, ground reaction forces (GRFs) and muscle activations were predicted and validated for normal average velocity (1.55 m/s) in the single support phase (SSP) by minimizing energy expenditure, which is subject to the non-linear constraints of the gait. The unconstrained system dynamics of extended inverse dynamics (USDEID) approach was used to estimate muscle activations. Then by scaling time and applying the same procedure, the movement trajectories were predicted for higher average velocities (from 2.07 m/s to 4.07 m/s) and compared to the pattern of movement with fast walking speed. The comparison indicated a high level of compatibility between the experimental and predicted results, except for the vertical position of the center of gravity (COG). It was concluded that the gait prediction model can be effectively used to predict gait trajectories for higher average velocities. PMID- 29758957 TI - Non-invasive continuous blood pressure measurement based on mean impact value method, BP neural network, and genetic algorithm. AB - BACKGROUND: Non-invasive continuous blood pressure monitoring can provide an important reference and guidance for doctors wishing to analyze the physiological and pathological status of patients and to prevent and diagnose cardiovascular diseases in the clinical setting. Therefore, it is very important to explore a more accurate method of non-invasive continuous blood pressure measurement. OBJECTIVE: To address the shortcomings of existing blood pressure measurement models based on pulse wave transit time or pulse wave parameters, a new method of non-invasive continuous blood pressure measurement - the GA-MIV-BP neural network model - is presented. METHOD: The mean impact value (MIV) method is used to select the factors that greatly influence blood pressure from the extracted pulse wave transit time and pulse wave parameters. These factors are used as inputs, and the actual blood pressure values as outputs, to train the BP neural network model. The individual parameters are then optimized using a genetic algorithm (GA) to establish the GA-MIV-BP neural network model. RESULTS: Bland-Altman consistency analysis indicated that the measured and predicted blood pressure values were consistent and interchangeable. CONCLUSIONS: Therefore, this algorithm is of great significance to promote the clinical application of a non invasive continuous blood pressure monitoring method. PMID- 29758958 TI - The non-contact biometric identified bio signal measurement sensor and algorithms. AB - In these days, wearable devices have been developed for effectively measuring biological data. However, these devices have tissue allege and noise problem. To solve these problems, biometric measurement based on a non-contact method, such as face image sequencing is developed. This makes it possible to measure biometric data without any operation and side effects. However, it is impossible for a remote center to identify the person whose data are measured by the novel methods. In this paper, we propose the novel non-contact heart rate and blood pressure imaging system, Deep Health Eye. This system has authentication process at the same time as measuring bio signals, through non-contact method. In the future, this system can be convenient home bio signal monitoring system by combined with smart mirror. PMID- 29758954 TI - The use of transcranial magnetic stimulation to evaluate cortical excitability of lower limb musculature: Challenges and opportunities. AB - Neuroplasticity is a fundamental yet relatively unexplored process that can impact rehabilitation of lower extremity (LE) movements. Transcranial magnetic stimulation (TMS) has gained widespread application as a non-invasive brain stimulation technique for evaluating neuroplasticity of the corticospinal pathway. However, a majority of TMS studies have been performed on hand muscles, with a paucity of TMS investigations focused on LE muscles. This perspective review paper proposes that there are unique methodological challenges associated with using TMS to evaluate corticospinal excitability of lower limb muscles. The challenges include: (1) the deeper location of the LE motor homunculus; (2) difficulty with targeting individual LE muscles during TMS; and (3) differences in corticospinal circuity controlling upper and lower limb muscles. We encourage future investigations that modify traditional methodological approaches to help address these challenges. Systematic TMS investigations are needed to determine the extent of overlap in corticomotor maps for different LE muscles. A simple, yet informative methodological solution involves simultaneous recordings from multiple LE muscles, which will provide the added benefit of observing how other relevant muscles co-vary in their responses during targeted TMS assessment directed toward a specific muscle. Furthermore, conventionally used TMS methods (e.g., determination of hot spot location and motor threshold) may need to be modified for TMS studies involving LE muscles. Additional investigations are necessary to determine the influence of testing posture as well as activation state of adjacent and distant LE muscles on TMS-elicited responses. An understanding of these challenges and solutions specific to LE TMS will improve the ability of neurorehabilitation clinicians to interpret TMS literature, and forge novel future directions for neuroscience research focused on elucidating neuroplasticity processes underlying locomotion and gait training. PMID- 29758959 TI - Dense deconvolution net: Multi path fusion and dense deconvolution for high resolution skin lesion segmentation. AB - BACKGROUND: Dermoscopy imaging has been a routine examination approach for skin lesion diagnosis. Accurate segmentation is the first step for automatic dermoscopy image assessment. OBJECTIVE: The main challenges for skin lesion segmentation are numerous variations in viewpoint and scale of skin lesion region. METHODS: To handle these challenges, we propose a novel skin lesion segmentation network via a very deep dense deconvolution network based on dermoscopic images. Specifically, the deep dense layer and generic multi-path Deep RefineNet are combined to improve the segmentation performance. The deep representation of all available layers is aggregated to form the global feature maps using skip connection. Also, the dense deconvolution layer is leveraged to capture diverse appearance features via the contextual information. Finally, we apply the dense deconvolution layer to smooth segmentation maps and obtain final high-resolution output. RESULTS: Our proposed method shows the superiority over the state-of-the-art approaches based on the public available 2016 and 2017 skin lesion challenge dataset and achieves the accuracy of 96.0% and 93.9%, which obtained a 6.0% and 1.2% increase over the traditional method, respectively. CONCLUSIONS: By utilizing Dense Deconvolution Net, the average time for processing one testing images with our proposed framework was 0.253 s. PMID- 29758960 TI - Biomechanical investigation of orthodontic treatment planning based on orthodontic force measurement and finite element method before implementation: A case study. AB - BACKGROUND: Orthodontic treatment planning (OTP) is primarily depended on clinical experiences of orthodontists at present, while equivocal OTP would increase the possibility of treatment failure. OBJECTIVE: The objective was to investigate a methodology for quantitatively evaluating OTP, using theoretical analyses, orthodontic forces measurement (OFM) and finite element method (FEM). METHODS: An OTP was theoretically designed based on a clinical case and forces on incisors in OTP were measured on a specialized platform. Further, FEM simulations were performed on the designed OTP and control group. At last, an 18-month tracking was carried out to observe treatment effects of the designed OTP. RESULTS: The moving tendencies of incisors were in keeping with ideal treatment from the designed OTP through FEM; the maximal hydrostatic stress and logarithmic strain in periodontal ligament (PDL) decreased by 26.81% and 32.60% compared to the control group. Clinical feedback indicated that a controllable correction of incisors was realized after 18 months, which was in accord with the FEM result and root/bone resorption by reason of stress/strain reduction on PDL did not occur. CONCLUSIONS: Biomechanical responses of periodontium can be quantitatively estimated using OTM and FEM. This study provided an alternative technological mean for the predictability and optimization of clinical OTP. PMID- 29758961 TI - Exploration of genetics commonness between bladder cancer and breast cancer based on a silcio analysis on disease subtypes. AB - BACKGROUND AND OBJECTIVE: Muscle-invasive bladder cancers (MIBCs) are heterogeneous cancers and can be grouped into basal-like and luminal subtypes that are highly reminiscent of those found in breast cancer. Like basal-like breast cancers, basal-like MIBCs are associated with advanced stage and metastatic disease. However, the biological and clinical significance of molecular subtypes of MIBCs remain unclear. Therefore, we implemented a serious of bioinformatics methods to explore genetic similarities between bladder and breast cancers. METHODS AND RESULTS: In the current study, by the application of multiple levels data analysis including random forest analysis, PPI and transcription factor regulation network construction, Gene Ontology (GO) and KEGG pathway enrichment analysis, we explored the genetics commonness between MIBC and breast cancers from the molecular heterogeneity based on the disease subtypes. CONCLUSIONS: Our study identified some basal-related and luminal-related genes shared by two cancers. These studies can help shed light on the potential relationships between MIBC and breast cancer as a whole. PMID- 29758962 TI - Association between serum magnesium and common complications of diabetes mellitus. AB - BACKGROUND: Magnesium ion, as important cation in the human body, involved in various enzymatic reactions, glucose transport and insulin release. Now diabetes mellitus and diabetic complications have become important public health problems around the world. OBJECTIVE: This paper explores the association between concentration levels of serum magnesium and common complications and comorbidities of diabetes mellitus and other biochemical indexes. METHODS: There are 1217 eligible patients selected from 14,317 cases of diabetic hospitalization patients from January 2010 to December 2011. Random forest algorithm was applied to assess the importance of various biochemical indexes and to perform diabetic complications prediction. RESULTS: The research results showed that low concentration of serum magnesium and four common diabetic complications - diabetic retinopathy, diabetic nephropathy, diabetic neuropathy and diabetic macroangiopathy - exists association, but no obvious correlation with other comorbidities like hypertension. CONCLUSIONS: The specific factors of four common diabetic complications were selected from the biochemical indexes to provide a reference direction for further research. PMID- 29758963 TI - Force control of wire driving lower limb rehabilitation robot. AB - BACKGROUND: To solve the technical problems associated with the research on lower limb rehabilitation robot in terms of configuration design, human-machine compatibility, lightweight, and multimodel rehabilitation. OBJECTIVE: This study introduced a parallel wire driving lower limb rehabilitation robot. The robot featured modular design, reconfiguration, multimodel, and good human-machine compatibility. METHODS: The dynamics model of the wire driving module (WDM) was built based on which a multiple feedback loop controller (including a forward controller and a surplus force compensator) was designed. RESULTS: The experimental results showed that the WDM could load force accurately and reliably during the loading procedure. CONCLUSIONS: The machinery and control system of the WDM met the design request. PMID- 29758965 TI - Laser parameters for efficient biomedical stimulation: A study to increase cognitive response rate. AB - BACKGROUND: The laser is able to irradiate the exact amount of stimulation to an area by a non contact method, and has the advantage of being able to stimulate the local target area. OBJECTIVE: This study examined an efficient method of laser tactile stimulation using laser parameter combinations. METHODS: The laser parameters that could cause an increase in the cognitive response rate of human subjects were examined without increasing the amount of total laser energy. RESULTS: As a result, the appropriate matching parameters such as duty ratio, pulse frequency, and exposure time of laser pulses showed a dominant influence in effectively increasing the tactile response rate of subjects with limited amount of total laser energy. CONCLUSIONS: This study can be applied to neurophysiology, cognitive research, and clinical laser application. PMID- 29758964 TI - The effect of sitting posture on the loads at cervico-thoracic and lumbosacral joints. AB - BACKGROUND: The sitting in an awkward posture for a prolonged time may lead to spinal or musculoskeletal disease. It is important to investigate the joint loads at spine while sitting. OBJECTIVE: The purpose of this study was to investigate the joint moment and antero-posterior (AP) reaction force at cervico-thoracic and lumbosacral joint for various sitting postures. METHODS: Twenty healthy males participated in this study. Six sitting postures were defined from three spinal curvatures (slump, flat, and lordosis) and two arm postures (arms-on-chest and arms-forward). Kinematic and kinetic data were measured in six sitting postures from which joint moment and AP reaction force were calculated by inverse dynamics. RESULTS: In the cervico-thoracic joint, joint moment and AP reaction force were greater in slump than the flat and lordosis postures (p< 0.001) and also in arms-forward posture compared to arms-on-chest posture. In the lumbosacral joint, joint moment and AP reaction force were greater in slump than flat and lordotic posture (p< 0.001) but there was no difference between different arm postures. The joint loads (moment and AP reaction force) at the cervico-thoriacic joint were closely related to the head flexion angle (r> 0.86) while those at the lumbosacral joint were correlated to the trunk flexion angle (r> 0.77). In slump posture, the joint moments were close to or over the extreme of the daily life such as sit-to-stand and walking. Consequently, if the slump is continued for a long time, it may cause pain and diseases at the cervico-thoracic and lumbosacral joints. CONCLUSIONS: The results of the study indicated that the lordosis or flat would be better spinal postures. Also, keeping arms close to body would be desirable to reduce joint loads. PMID- 29758966 TI - Comparison of gait patterns in elderly fallers and non-fallers. AB - Gait is associated with an important risk factor of falls in the elderly. It is important to find differences of quantitative gait variables between fallers and non-fallers. The aim of this study was to investigate gait patterns in elderly fallers and non-fallers. Thirty-eight fallers and 38 non-fallers of similar age and height participated in this study. Subjects walked across the GaitRite walkway at self-selected comfortable speeds. Spatio-temporal gait variables were measured to characterize gait patterns. Kinetic variables were derived from normalized vertical ground reaction force (GRF). Independent t-tests were performed to compare the fallers with the non-fallers. The fallers walked more slowly with shorter steps and more variable step times than the non-fallers (p< 0.05). The fallers showed a longer stance phase with increased double-limb support than the non-fallers (p< 0.05). The times to reach maximal weight acceptance and mid-stance of the fallers were significantly longer than those of the non-fallers (p< 0.05). These results suggest that spatio-temporal variables and GRF variables would be useful for distinguishing prospective fallers from non fallers among the elderly. PMID- 29758967 TI - Multi-subject subspace alignment for non-stationary EEG-based emotion recognition. AB - Emotion recognition based on EEG signals is a critical component in Human-Machine collaborative environments and psychiatric health diagnoses. However, EEG patterns have been found to vary across subjects due to user fatigue, different electrode placements, and varying impedances, etc. This problem renders the performance of EEG-based emotion recognition highly specific to subjects, requiring time-consuming individual calibration sessions to adapt an emotion recognition system to new subjects. Recently, domain adaptation (DA) strategies have achieved a great deal success in dealing with inter-subject adaptation. However, most of them can only adapt one subject to another subject, which limits their applicability in real-world scenarios. To alleviate this issue, a novel unsupervised DA strategy called Multi-Subject Subspace Alignment (MSSA) is proposed in this paper, which takes advantage of subspace alignment solution and multi-subject information in a unified framework to build personalized models without user-specific labeled data. Experiments on a public EEG dataset known as SEED verify the effectiveness and superiority of MSSA over other state of the art methods for dealing with multi-subject scenarios. PMID- 29758968 TI - Temperature dependent of viscoelasticity measurement on fat emulsion phantom using acoustic radiation force elasticity imaging method. AB - During the past two decades, tissue elasticity has been extensively studied and has been used in clinical disease diagnosis. But biological soft tissues are viscoelastic in nature. Therefore, they should be simultaneously characterized in terms of elasticity and viscosity. In addition, the mechanical properties of soft tissues are temperature dependent. However, how the temperature influences the shear wave dispersion and the viscoelasticity of soft tissue are still unclear. The aim of this study is to compare viscoelasticity of fat emulsion phantom with different temperature using acoustic radiation force elasticity imaging method. In our experiment, we produced four proportions of ultrasonic phantom by adding fat emulsion gelatin. Through adjusting the component of the fat emulsion, we change the viscoelasticity of the ultrasonic phantom. We used verasonics system to gather data and voigt model to fit the elasticity and viscosity value of the ultrasonic phantom we made. The influence of temperature to the ultrasonic phantom also measured in our study. The results show that the addition of fat emulsion to the phantom can increase the viscosity of the phantom, and the shear wave phase velocity decreases gradually at each frequency with the temperature increases, which provides a new material for the production of viscoelastic phantom. PMID- 29758969 TI - Human emotion classification based on multiple physiological signals by wearable system. AB - BACKGROUND: Human emotion classification is traditionally achieved using multi channel electroencephalogram (EEG) signal, which requires costly equipment and complex classification algorithms. OBJECTIVE: The experiments can be implemented in the laboratory environment equipped with high-performance computers for the online analysis; this will hinder the usability in practical applications. METHODS: Considering that other physiological signals are also associated with emotional changes, this paper proposes to use a wearable, wireless system to acquire a single-channel electroencephalogram signal, respiration, electrocardiogram (ECG) signal, and body postures to explore the relationship between these signals and the human emotions. RESULTS AND CONCLUSIONS: Compared with traditional emotion classification method, the presented method was able to extract a small number of key features associated with human emotions from multiple physiological signals, where the algorithm complexity was greatly reduced when incorporated with the support vector machine classification. The proposed method can support an embedded on-line analysis and may enhance the usability of emotion classification. PMID- 29758970 TI - Effects of an intra-ventricular assist device on the stroke volume of failing ventricle: Analysis of a mock circulatory system. AB - BACKGROUND: A novel intra-ventricular assist device (iVAD) was established as a new pulsatile assist device to address various disadvantages, such as bulky configuration and reduced arterial pulsatility, observed in conventional ventricular assist devices. OBJECTIVE: Analyzed the native left ventricular stroke volume (SV) after iVAD support in vitro. METHODS: The SV of iVAD was examined in a home-designed mock circulatory system (MCS) at different heart rates and drive pressures and the SV of a failure ventricle was examined with iVAD at 75, 90, 120 bpm and 120-180 mmHg drive pressure after iVAD support. Data pertaining to native left ventricular SV before and after iVAD support were compared. RESULTS: The native ventricular SV was improved by iVAD when its drive pressure (DP) was slightly greater than that of the mock system. Conversely, the native ventricular SV was decreased when DP was much greater than that (150 mmHg) of MCS. A high DP had a significant effect on SV. CONCLUSIONS: The proposed device improved the dysfunctional native left ventricular SV when DP of iVAD was slightly greater than that of MCS. However, iVAD reduced the SV when the drive pressure was greater than that of MCS. PMID- 29758971 TI - Effects of DanceSport on walking balance and standing balance among the elderly. AB - BACKGROUND: Dancesport is a popular activity among older adults who look for fun and fitness in Korea. Studies reported positive sociological and psychological effects of dancesport. But, little studies were performed to evaluate the effects of dancesport on balance performances. OBJECTIVE: The objective of the present study was to evaluate the effects of dancesport for 15 weeks on walking balance and standing balance of older adults. METHODS: Older adults regularly participated in the dancesport program 3 times a week for 15 weeks. The program included Rumba, Cha-cha-cha, and Jive. They exercised the prescribed dancesport at intermediate level for 50-60 mins for each time. A total 22 reflective markers were placed on the anatomical landmarks and 8 cameras were used to measure 3-D positions of participants. Also, center of pressure (COP) data were measured to analyze standing balance using a ground reaction board at 1200 Hz for 30 seconds. One-way analysis of variance (ANOVA) was performed to test the effects of 15 weeks of dancesport on walking balance and standing balance. RESULTS: The results suggested that, after 15 weeks of dancesport participation, older adults' walking balance (48.3 +/- 20.3 cm2 vs 38.2 +/- 18.2 cm2) and standing balance (COP area: 189.4 +/- 85.4 mm2 vs 103.5 +/- 55.4mm2, COP distance: 84.2 +/- 34.4 cm vs 76.5 +/- 21.4 cm) were significantly improved. CONCLUSION: Performing dancesport would require moving center of mass rapidly and frequently while maintaining posture. This may result in improving walking balance and standing balance in the present study. The study concluded that dancesport would be an effective exercise method in enhancing postural stability of older adults. PMID- 29758972 TI - Development of capacitive sensor for automatically measuring tumbler water level with FEA simulation. AB - BACKGROUND: Drinking water has several advantages that have already been established, such as improving blood circulation, reducing acid in the stomach, etc. However, due to people not noticing the amount of water they consume every time they drink, most people drink less water than the recommended daily allowance. OBJECTIVE: In this paper, a capacitive sensor for developing an automatic tumbler to measure water level is proposed. Different than in previous studies, the proposed capacitive sensor was separated into two sets: the main sensor for measuring the water level in the tumbler, and the reference sensor for measuring the incremental level unit. METHODS: In order to confirm the feasibility of the proposed idea, and to optimize the shape of the sensor, a 3D model of the capacitive sensor with the tumbler was designed and subjected to Finite Element Analysis (FEA) simulation. According to the simulation results, the electrodes were made of copper and assembled in a tumbler manufactured by a 3D printer. The tumbler was filled with water and was subjected to experiments in order to assess the sensor's performance. RESULTS: The comparison of experimental results to the simulation results shows that the measured capacitance value of the capacitive sensor changed linearly as the water level varied. This proves that the proposed sensor can accurately measure the water level in the tumbler. Additionally, by use of the curve fitting method, a compensation algorithm was found to match the actual level with the measured level. CONCLUSIONS: The experimental results proved that the proposed capacitive sensor is able to measure the actual water level in the tumbler accurately. A digital control part with micro-processor will be designed and fixed on the bottom of the tumbler for developing a smart tumbler. PMID- 29758974 TI - Emotion recognition from multichannel EEG signals using K-nearest neighbor classification. AB - BACKGROUND: Many studies have been done on the emotion recognition based on multi channel electroencephalogram (EEG) signals. OBJECTIVE: This paper explores the influence of the emotion recognition accuracy of EEG signals in different frequency bands and different number of channels. METHODS: We classified the emotional states in the valence and arousal dimensions using different combinations of EEG channels. Firstly, DEAP default preprocessed data were normalized. Next, EEG signals were divided into four frequency bands using discrete wavelet transform, and entropy and energy were calculated as features of K-nearest neighbor Classifier. RESULTS: The classification accuracies of the 10, 14, 18 and 32 EEG channels based on the Gamma frequency band were 89.54%, 92.28%, 93.72% and 95.70% in the valence dimension and 89.81%, 92.24%, 93.69% and 95.69% in the arousal dimension. As the number of channels increases, the classification accuracy of emotional states also increases, the classification accuracy of the gamma frequency band is greater than that of the beta frequency band followed by the alpha and theta frequency bands. CONCLUSIONS: This paper provided better frequency bands and channels reference for emotion recognition based on EEG. PMID- 29758973 TI - The pulmonary damage caused by smoking: A longitudinal study. AB - BACKGROUND: Smoking for a long period is known to cause several harms to the human body, chiefly associated with serious pulmonary damage. OBJECTIVE: The purpose of this study was to evaluate the difference in the pulmonary damage between current smokers and ex-smokers, through measuring the bronchial parameters and the extent of emphysema, in order to further illustrate the harm of smoking and the need to stop smoking. METHODS: Using the FACT-Digital lung TM software quantitatively analysis of CT images, including the WT, WA%, LD, LV, PD, and %LAA-950 was performed. The percentage of low attenuation areas less than 950 Hounsfield units (%LAA-950) was defined as the extent of emphysema. The longitudinal data in the two consecutive years of these current smoker group and ex-smoker group were compared by paired t-test. RESULTS: The LV, %LAA-950, WT and WA% of current smokers increased more rapidly each year than that of ex-smokers. The PD and LD of current smokers declined more rapidly each year than that of ex smokers. CONCLUSIONS: This study shows that pulmonary damage caused by smoking related to the smoking status, can be measured. Smoking cessation has a positive role in alleviating the progress of pulmonary damage. PMID- 29758977 TI - Evaluation of plantar pressures in people with hallux valgus using principal component analysis. AB - BACKGROUND: Foot deformities are serious problems in the elderly as they increase the risk of falling. OBJECTIVE: This study aimed to examine the relationship between foot plantar pressure during gait and hallux valgus (HV). METHODS: Foot pressure data were recorded using an F-scan II system. We analyzed the entire waveform of plantar pressure during gait from 37 healthy adults using principle component analysis (PCA), conducted using a 370 * 357 matrix of time-normalized plantar data of 7 areas during gait (5 gait trials * 2 (both feet) of 37 participants * 51 data points * 7 plantar areas). Two-way (plantar pressure * presence or absence of HV) analyses of variance were conducted on the principal component scores (PCSs) of principal component vectors (PCVs) 1 through 5, each of which exhibited more than 5% variance. RESULTS: The PCA clarified that the 2nd, 3rd, and 5th PCVs (PCV 2, 3, and 5) were related to HV (p< 0.01). These PCVs exhibit a significant interaction between plantar pressure area and HV presence. CONCLUSIONS: The larger plantar pressure of the HV group around the hallux area during walking compared with the non-HV group is a dominant difference in plantar pressure features due to HV. PMID- 29758975 TI - Design of liver functional reserve monitor based on three-wavelength from red light to IR. AB - BACKGROUND: The preoperative evaluation of liver functional reserve is very important to determine the excision of liver lobe for the patients with liver cancer. There already exist many effective evaluation methods, but these ones have many disadvantages such as large trauma, complicated process and so on. OBJECTIVE: Therefore, it is essential to develop a fast, accurate and simple detection method of liver functional reserve for the practical application in the clinical engineering field. METHODS: According to the principle of spectrophotometry, this paper proposes a detection method of liver functional reserve based on three-wavelength from red light to infrared light (IR), in which the artery pulse, the vein pulse and the move of tissue are taken into account. RESULTS: By using photoelectric sensor technology and excreting experiment of indocyanine green, a minimally invasive, fast and simple testing equipment is designed in this paper. CONCLUSIONS: The testing result shows this equipment can greatly reduce the interference from human body and ambient, realize continuous and real-time detection of arterial degree of blood oxygen saturation and liver functional reserve. PMID- 29758978 TI - Analysis of foot kinematics wearing high heels using the Oxford foot model. AB - Wearing high heels is thought to lead to various foot disorders and injuries such as metatarsal pain, Achilles tendon tension, plantar fasciitis and Haglund malformation. However, there is little available information explaining the specific mechanisms and reasons why wearing high heels causes foot deformity. Therefore, the purpose of this study was to investigate the foot kinematics of high heel wearers and compare any differences with barefoot individuals using the Oxford Foot Model (OFM). Fifteen healthy women aged 20-25 years were measured while walking barefoot and when wearing high heels. The peak value of angular motion for the hallux with respect to the forefoot, the forefoot with respect to the hind foot, and the hind foot with respect to the tibia were all analyzed. Compared to the barefoot, participants wearing high heels demonstrated larger hallux dorsiflexion (22.55?+/- 1.62? VS 26.6?+/- 2.33? for the barefoot; P= 0.001), and less hallux plantarflexion during the initial stance phase (-4.86?+/- 2.32? VS -8.68?+/- 1.13?; P< 0.001). There were also greater forefoot adduction (16.15?+/- 1.37? VS 13.18?+/- 0.79?; P< 0.001), but no significant differences were found in forefoot abduction between the two conditions. The hind foot demonstrated a larger dorsiflexion in the horizontal plane (16.59?+/- 1.69? VS 12.08?+/- 0.9?; P< 0.001), greater internal rotation (16.72?+/- 0.48? VS 7.97?+/- 0.55?; P< 0.001), and decreased peak hind foot extension rotation (-5.49?+/- 0.69? VS -10.73?+/- 0.42?; P= 0.001). These findings complement existing kinematic evidence that wearing high heels can lead to foot deformities and injuries. PMID- 29758979 TI - Developmental screening tool: Accuracy and feasibility of non-invasive anaemia estimation. AB - Anaemia is predicted as one of the serious communal health issue in the world. The deficiency exists most common among children and women. A substantial issue prevails in providing quality healthcare services to rural communities, which remains a challenge to health service providers throughout the world. Traditionally physician and health workers recognized anaemia from certain clinical findings, such as pallor of the conjunctivae, nail beds, lips, tongue, and oral mucosa. Confirmation of anaemic condition through physical examination of Dorsum of a tongue or lower bulbar conjunctiva is a subjective analysis. Invasive methods have a possibility to spread infection through the needle. The existing non-invasive techniques need costly equipment and qualified technicians. Growing developments in science and technologies play an important role in medicine. This proposal introduces a new non-invasive diagnostic tool correlating the hemoglobin with conjunctiva pallor colour scores and classification using neural networks. In this study, the eye images were obtained using a mobile camera were processed using the HSI model, which estimates different colour scores of the selected region. These scores were correlated with laboratory haemoglobin value. Feedforward neural network and Elman neural network were used for classifying anaemic and non-anaemic cases. This proposed tool will be useful for the health workers to identify the mass screening of anaemia in rural areas. PMID- 29758982 TI - Melatonin Antagonizes Jasmonate-Triggered Anthocyanin Biosynthesis in Arabidopsis thaliana. AB - As a plant-specific flavonoid type metabolite, anthocyanin is an important plant sourced nutrition. Although the anthocyanin biosynthesis pathway has been revealed, how to modulate anthocyanin production by endogenous molecules is still elusive. Here, we investigated the role of melatonin in anthocyanin biosynthesis in the reference plant Arabidopsis thaliana and found that melatonin suppresses anthocyanin synthesis. Moreover, melatonin was able to significantly inhibit jasmonate-stimulated anthocyanin production. Unexpectedly, melatonin could not repress the jasmonate-triggered JAZ protein degradation that is a key event for relaying jasmonate signaling. The expression of jasmonate-induced marker genes or other jasmonate-related phenotypes were not discernibly changed in the presence of melatonin. These results indicate that the antagonization of jasmonate-induced anthocyanin synthesis by melatonin does not occur through the abrogation of jasmonate signaling. Furthermore, we found that melatonin does not trigger anthocyanin catabolism. Finally, we supplied anthocyanin biosynthesis precursors to examine their roles in anthocyanin biosynthesis and found that melatonin most likely acts before the dihydrokaempferol production step. Our work illustrates that melatonin plays a negative role in the induction of anthocyanin biosynthesis and sheds new light on the role of melatonin in plant cell metabolism. PMID- 29758980 TI - Metabolomics for the Effect of Biotin and Nicotinamide on Transition Dairy Cows. AB - The objective of this study was to evaluate alterations in serum metabolites of transition dairy cows affected by biotin (BIO) and nicotinamide (NAM) supplementation. A total of 40 multiparous Holsteins were paired and assigned randomly within a block to one of the following four treatments: control (T0), 30 mg/day BIO (TB), 45 g/day NAM (TN), and 30 mg/day BIO + 45 g/day NAM (TB+N). Supplemental BIO and NAM were drenched on cows from 14 days before the expected calving date. Gas chromatography time-of-flight/mass spectrometry was used to analyze serum samples collected from eight cows in every groups at 14 days after calving. In comparison to T0, TB, TN, and TB+N had higher serum glucose concentrations, while non-esterified fatty acid in TN and TB+N and triglyceride in TB+N were lower. Adenosine 5'-triphosphate was significantly increased in TB+N. Both TN and TB+N had higher glutathione and lower reactive oxygen species. Moreover, TB significantly increased inosine and guanosine concentrations, decreased beta-alanine, etc. Certain fatty acid concentrations (including linoleic acid, oleic acid, etc.) were significantly decreased in both TN and TB+N. Some amino acid derivatives (spermidine in TN, putrescine and 4 hydroxyphenylethanol in TB+N, and guanidinosuccinic acid in both TN and TB+N) were affected. Correlation network analysis revealed that the metabolites altered by NAM supplementation were more complicated than those by BIO supplementation. These findings showed that both BIO and NAM supplementation enhanced amino acid metabolism and NAM supplementation altered biosynthesis of unsaturated fatty acid metabolism. The improved oxidative status and glutathione metabolism further indicated the effect of NAM on oxidative stress alleviation. PMID- 29758983 TI - Intertwining Roles of the Disperse Phase Properties during Emulsification. AB - The combined effect of viscosity ratio, interfacial tension, and disperse phase density on the process of droplet formation during emulsification was evaluated. For that aim, emulsification by ultrasonication of oil/water systems with viscosity ratios between 1 and 600, with and without surfactant was performed. The time evolution of the average droplet size was estimated by dynamic light scattering measurements. For viscosity ratios between 1 and 200 in the presence of surfactant, our results partly reproduce those of the intriguing U-type reported in the literature. Beyond that range, the droplet size decreases, as the viscosity ratio rises. For surfactant-free systems, the size is slightly affected by the increase in viscosity. This complex scenario is analyzed in terms of both the individual and intertwined roles of interfacial tension, viscosity, and density ratios: (1) if the interfacial tension dominates, the droplet rupturing process is independent of its internal properties, and inversely, (2) if the interfacial tension is low, the internal properties play a major role in the rupturing of the droplet. Finally, we identified a scenario in which the retarded addition of surfactant leads to emulsions with a stability similar to those with the surfactant added at the beginning, saving energy and time. PMID- 29758984 TI - Inhibition of Methylglyoxal-Induced Histone H1 Nepsilon-Carboxymethyllysine Formation by (+)-Catechin. AB - Reactive dicarbonyl species (RCS) such as methylglyoxal (MGO) and glyoxal (GO) are common intermediates in protein damage, leading to the formation of advanced glycation end products (AGEs) through nonenzymatic glycation. (+)-Catechin, a natural plant extract from tea, has been evaluated for its ability in trapping GO and MGO. However, (+)-catechin is also reported to have both antioxidant ability and pro-oxidant properties. Until now, whether (+)-catechin can inhibit the formation of nonenzymatic glycation and the mechanism of the inhibition in nucleoprotein nonenzymatic glycation is still unclear. In the present study, histone H1 and MGO were used to establish an in vitro (100 mM phosphate buffer solution (PBS), pH 7.4, 37 degrees C) protein glycation model to study the trapping ability of (+)-catechin. Our data show that MGO caused dose-dependent protein damage, and the content of MGO-induced Schiff base formation was inhibited by (+)-catechin when the molecular ratio of catechin:MGO was 1:6. The formation of Nepsilon-carboxymethyllysine (CML) was reduced significantly when the ratio of (+)-catechin and MGO was 1:1, which was similar to the inhibition effect of aminoguanidine (AG). The formation of CML under in vitro conditions can be inhibited by low concentration (12.5-100 MUM) of (+)-catechin but not with high concentration (200-800 MUM) of (+)-catechin. The reason is that the high concentration of (+)-catechin did not inhibit CML formations due to H2O2 produced by (+)-catechin. In the presence of catalase, catechin can inhibit MGO-induced CML formation. In conclusion, the trapping ability of (+)-catechin may be more effective at the early stage of nonenzymatic glycation. However, a high concentration (200-800 MUM) of (+)-catechin may not inhibit the formation of CML because it induced the increase of H2O2 formation. PMID- 29758981 TI - Human Cytochrome CYP17A1: The Structural Basis for Compromised Lyase Activity with 17-Hydroxyprogesterone. AB - The multifunctional enzyme, cytochrome P450 (CYP17A1), plays a crucial role in the production of androgens, catalyzing two key reactions on pregnenolone (PREG) and progesterone (PROG), the first being a 17-hydroxylation to generate 17-OH PREG and 17-OH PROG, with roughly equal efficiencies. The second is a C-C bond scission or "lyase" reaction in which the C17-C20 bond is cleaved, leading to the eventual production of powerful androgens, whose involvement in the proliferation of prostate cancer has generated intense interest in developing inhibitors of CYP17A1. For humans, the significance of the C-C bond cleavage of 17-OH PROG is lessened, because it is about 50 times less efficient than for 17-OH PREG in terms of kcat/Km. Recognizing the need to clarify relevant reaction mechanisms involved with such transformations, we first report studies of solvent isotope effects, results of which are consistent with a Compound I mediated PROG hydroxylase activity, yet exclude this intermediate as a participant in the formation of androstenedione (AD) via the lyase reaction. This finding is also supported by a combination of cryoreduction and resonance Raman spectroscopy that traps and structurally characterizes the key hemiketal reaction intermediates. Adding to a previous study of PREG and 17-OH PREG metabolism, the current work provides definitive evidence for a more facile protonation of the initially formed ferric peroxo-intermediate for 17-OH PROG-bound CYP17A1, compared to the complex with 17-OH PREG. Importantly, Raman characterization also reveals an H bonding interaction with the terminal oxygen of the peroxo fragment, rather than with the proximal oxygen, as is present for 17-OH PREG. These factors would favor a diminished lyase activity of the sample with 17-OH PROG relative to the complex with 17-OH PREG, thereby providing a convincing structural explanation for the dramatic differences in activity for these lyase substrates in humans. PMID- 29758985 TI - Ultrasonic Pretreatment Combined with Dry-State Glycation Reduced the Immunoglobulin E/Immunoglobulin G-Binding Ability of alpha-Lactalbumin Revealed by High-Resolution Mass Spectrometry. AB - Bovine alpha-lactalbumin (alpha-LA) is one of major food allergens in cow's milk. The present work sought to research the effects of ultrasonic pretreatment combined with dry heating-induced glycation between alpha-LA and galactose on the immunoglobulin E (IgE)/immunoglobulin G (IgG)-binding ability and glycation extent of alpha-LA, determined by inhibition enzyme-linked immunosorbent assay and high-resolution mass spectrometry, respectively. The IgE/IgG-binding ability of glycated alpha-LA was significantly decreased as a result of ultrasonic pretreatment, while the average molecular weight, incorporation ratio (IR) value, location and number of glycation sites, and degree of substitution per peptide (DSP) value were elevated. When the mixtures of alpha-LA and galactose were pretreated by ultrasonication at 150 W/cm2, glycated alpha-LA possesses seven glycation sites, the highest IR and DSP values, and the lowest IgE/IgG-binding ability. Therefore, the decrease in the IgE/IgG-binding ability of alpha-LA depends upon not only the shielding effect of the linear epitope found to be caused by the glycation of K13, K16, K58, K93, and K98 sites but also the intensified glycation extent, which reflected in the increase of the IR value, the number of glycation sites, and the DSP value. Moreover, allergenic proteins and monosaccharides pretreated by ultrasonication and then followed by dry-state glycation were revealed as a promising way of achieving lower allergenicity of proteins in food processing. PMID- 29758986 TI - Perfluoroalkyl Acids (PFAAs) in Serum from 2-4-Month-Old Infants: Influence of Maternal Serum Concentration, Gestational Age, Breast-Feeding, and Contaminated Drinking Water. AB - Little is known about factors influencing infant perfluorinated alkyl acid (PFAA) concentrations. Associations between serum PFAA concentrations in 2-4-month-old infants ( n = 101) and determinants were investigated by multiple linear regression and general linear model analysis. In exclusively breast-fed infants, maternal serum PFAA concentrations 3 weeks after delivery explained 13% (perfluoroundecanoic acid, PFUnDA) to 73% (perfluorohexanesulfonate, PFHxS) of infant PFAA concentration variation. Median infant/maternal ratios decreased with increasing PFAA carbon chain length from 2.8 for perfluoroheptanoic acid and perfluorooctanoic acid (PFOA) to 0.53 for PFUnDA and from 1.2 to 0.69 for PFHxS and perfluorooctanesulfonate (PFOS). Infant PFOA, perfluorononanoic acid (PFNA), and PFOS levels increased 0.7-1.2% per day of gestational age. Bottle-fed infants had mean concentrations of PFAAs 2 times lower than and a mean percentage of branched (%br) PFOS isomers 1.3 times higher than those of exclusively breast-fed infants. PFOA, PFNA, and PFHxS levels increased 8-11% per week of exclusive breast-feeding. Infants living in an area receiving PFAA-contaminated drinking water had 3-fold higher mean perfluorobutanesulfonate (PFBS) and PFHxS concentrations and higher mean %br PFHxS. Prenatal PFAA exposure and postnatal PFAA exposure significantly contribute to infant PFAA serum concentrations, depending on PFAA carbon chain length. Moderately PFBS- and PFHxS-contaminated drinking water is an important indirect exposure source. PMID- 29758987 TI - Coassembly of Mixed Weakley-Type Polyoxometalates to Novel Nanoflowers with Tunable Fluorescence for the Detection of Toluene. AB - In this work, three-dimensional nanoflowers with tunable fluorescent properties constructed with mixed Weakley-type polyoxometalates (POMs, Na9[LnW10O36].32H2O, Ln = Eu, Tb, abbreviated to LnW10) and tetraethylenepentamine (TEPA) have been successfully prepared through a facile ionic self-assembly (ISA) method. The shape and petal size of the nanoflower as well as its fluorescent behaviors can be tuned through varying the ratio of EuW10/TbW10. The varied-temperature emission behaviors at 80-260 K show that the fluorescent intensity of both Tb3+ and Eu3+ decreased with the increase in temperature, which makes them potential luminescent ratiometric thermometers. Moreover, after being mixed with polydimethylsiloxane (PDMS), the as-formed hybrid films showed stable fluorescence along with good transparency. The robustness of the hybrid films was also demonstrated by corrosion resistance upon treatment with strong acid and alkali and thus can be used as a sensor to detect toluene circularly. Our results provide a new avenue to the facile construction of fluorescent composites and demonstrate that the POM complexes can be further used in supramolecular chemistry and nanomaterials. PMID- 29758988 TI - Creating Functional Interfaces with Biological Circuits. PMID- 29758989 TI - The Double Hazard of Bleeding and Thrombosis in Hemostasis From a Clinical Point of View: A Global Assessment by Rotational Thromboelastometry (ROTEM). AB - Hemostasis is a complex dynamic process involving bleeding and thrombosis as two end-points. Conventional coagulation tests which are measured in plasma examine only isolated portions of the coagulation cascade, thereby giving no information on important interactions essential to the clinical evaluation of hemostatic function. Thromboelastography (TEG), originally described in 1948 has improved over the decades and become a valuable tool of coagulation testing because of the limitations of standard coagulation tests. TEG is a technique that provides data about the entire coagulation system, from the beginning of clot formation to fibrinolysis, involving both cellular and plasma components of hemostasis. Rotational thromboelastometry (ROTEM) which evolved from TEG technology overcome several limitations of classical TEG while maintaining a good correlation with conventional TEG determination. ROTEM analyses are useful for rapid assessment of global clotting function in various clinical situations including liver transplantation, cardiac surgery, obstetrics, trauma, hemophilia and idiopathic thrombocytopenic purpura. ROTEM has been also reported to be useful in identifying various hypercoagulable conditions including major surgery, malignancy, Behcet's disease and apheresis. Further developments in ROTEM based transfusion strategies may also reduce transfusion requirements and improve clinical outcomes by optimizing the administration of blood components. This is a literature review of ROTEM including its technique, interpretation and specially clinical applications in different scenarios of bleeding and thrombotic disorders. PMID- 29758990 TI - The Uncanny: A Biopsychosocial Perspective. AB - A biopsychosocial model provides a framework for a contemporary understanding of paranormal phenomena. From this perspective, paranormal beliefs and experiences are best understood by identifying biological, psychological, and sociocultural explanatory factors. Treatment recommendations are provided. PMID- 29758991 TI - The Rational Unconscious: Implications for Mental Illness and Psychotherapy. AB - Rational and reality-congruent unconscious processes facilitate adaptive functioning and have implications for mental illness and psychotherapy. With this knowledge, psychotherapists can more effectively guide interventions to improve mental health. PMID- 29758993 TI - Lower In-Hospital Ventricular Tachyarrhythmia in Patients With Acute Myocardial Infarction Receiving Prior Statin Therapy. AB - We evaluated whether prior statin therapy reduces in-hospital ventricular tachycardia/ventricular fibrillation (VT/VF) in percutaneous coronary intervention (PCI) patients with acute myocardial infarction (MI). Among the 1177 patients from the Acute Myocardial Infarction Registry-National Institutes of Health (KAMIR-NIH), 823 (70%) patients received prior statin therapy. Prior statin therapy was associated with a reduced risk of VT/VF events in both adjusted propensity score analysis (odds ratio [OR] 0.414, 95% confidence interval [CI], 0.198-0.865, P = .019) and adjusted inverse probability of treatment weight analysis (OR 0.463, 95% CI, 0.216-0.994, P = .048). The risk of in-hospital death did not differ significantly between those with or without prior statin therapy (hazard ratio [HR] 0.416, 95% CI, 0.112-1.548, P = .191). Major adverse cardiac events occurred in 116 (8.9%) patients during follow-up. Prior statin therapy was associated with a lower risk of major adverse cardiac events during the follow-up period (HR 0.486, 95% CI, 0.243-0.974, P = .042); however, this was mainly driven by reduced noncardiac death. Prior statin therapy might reduce the incidence of serious cardiac tachyarrhythmia, such as VT/VF, in patients with MI undergoing PCI. However, the reduction in VT/VF due to prior statin therapy did not improve short- and long-term clinical outcomes. PMID- 29758992 TI - Risk-Based Data Monitoring: Quality Control in Central Nervous System (CNS) Clinical Trials. AB - Monitoring the quality of clinical trial efficacy outcome data has received increased attention in the past decade, with regulatory guidance encouraging it to be conducted proactively, and remotely. However, the methods utilized to develop and implement risk-based data monitoring (RBDM) programs vary, and there is a dearth of published material to guide these processes in the context of central nervous system (CNS) trials. We reviewed regulatory guidance published within the past 6 years, generic white papers, and studies applying RBDM to data from CNS clinical trials. Methodologic considerations and system requirements necessary to establish an effective, real-time risk-based monitoring platform in CNS trials are presented. Key RBDM terms are defined in the context of CNS trial data, such as "critical data," "risk indicators," "noninformative data," and "mitigation of risk." Additionally, potential benefits of, and challenges associated with implementation of data quality monitoring are highlighted. Application of methodological and system requirement considerations to real-time monitoring of clinical ratings in CNS trials has the potential to minimize risk and enhance the quality of clinical trial data. PMID- 29758994 TI - Structural and Functional Connectivity Underlying Gray Matter Covariance: Impact of Developmental Insult. AB - Structural covariance networks (SCNs) may offer unique insights into the developmental impact of childhood maltreatment (CM) because they are thought to reflect coordinated maturation of distinct gray matter regions. T1-weighted magnetic resonance images were acquired from 121 young people with emerging mental illness. Diffusion-weighted and resting-state functional imaging was also acquired from a random subset of participants (n = 62). Ten study-specific SCNs were identified using a whole-brain gray matter independent component analysis. The effects of CM and age on average gray matter density and the expression of each SCN were calculated. CM was linked to age-related decreases in gray matter density across an SCN that overlapped with the default mode network (DMN) and frontoparietal network. Resting-state functional connectivity (rsFC) and structural connectivity were calculated in the study-specific SCN and across the whole brain. Gray matter covariance was significantly correlated with rsFC across the SCN, and rsFC fully mediated the relationship between gray matter covariance and structural connectivity in the nonmaltreated group. A unique association of gray matter covariance with structural connectivity was detected among individuals with a history of CM. Perturbation of gray matter development across the DMN and frontoparietal network following CM may have significant implications for mental well-being, given the networks' roles in self-referential activity. Cross-modal comparisons suggest that reduced gray matter following CM could arise from deficient functional activity earlier in life. PMID- 29758995 TI - Diagnostic accuracy of dual-source and 320-row computed tomography angiography in detecting coronary in-stent restenosis: a systematic review and meta-analysis. AB - Background Dual-source and 320-row computed tomography angiography (CTA) are increasingly used in diagnosing coronary in-stent restenosis (CISR). Purpose We sought to perform this meta-analysis to evaluate the diagnostic accuracy of dual source computed tomography angiography (DSCTA) and 320-row CTA in detecting CISR when compared to invasive coronary angiography. Material and Methods Five scientific databases (PubMed, Embase, Scopus, The Cochrane Library, and Web of Science) were searched for research studies in which DSCTA and/or 320-row CTA were used as diagnostic tools for CISR, as recently as October 2017. Study inclusion, data extraction, systematic review, pooled meta-analysis, and subgroup analysis were conducted by two researchers independently. Results Thirteen studies with 1384 assessable stents on DSCTA and five studies including 622 assessable stents on 320-row CTA were finally included. The sensitivity, specificity, and area under the curve (AUC) of DSCTA in diagnosing CISR were 0.92 (0.87-0.96), 0.91 (0.87-0.94), and 0.97 (0.95-0.98), respectively, and they were 0.91 (0.82-0.96), 0.95 (0.88-0.98), and 0.96 (0.94-0.97) for 320-row CTA. Subgroup analysis result suggested that DSTCA performed significantly better in CISR detection when the stent diameter was >= 3 mm compared to stent diameter < 3 mm: 0.98 (0.97-0.99) vs. 0.82 (0.79-0.86) with P < 0.05. Conclusion Our meta analysis indicated both DSCTA and 320-row CTA had high diagnostic accuracy in detecting CISR and may serve as alternatives for further patient evaluation with CISR, especially for stent diameters >= 3 mm. PMID- 29758997 TI - Cholesterol and inflammation: The lesser the better in atherothrombosis. PMID- 29758996 TI - Patterns of malignant non-mass enhancement on 3-T breast MRI help predict invasiveness: using the BI-RADS lexicon fifth edition. AB - Background Non-mass enhancements (NME) with invasive components account for 10 42% of total malignant NMEs. The factors associated with invasiveness on magnetic resonance imaging (MRI) could be useful for clinical assessment and treatment. Purpose To evaluate the clinical significances of the distributions and internal enhancement patterns (IEP) of malignant NMEs on 3-T breast MRI. Material and Methods A total of 448 consecutive women with newly diagnosed breast cancer that had undergone preoperative MRI and surgery between February 2013 and March 2016 were identified. After exclusions, 72 malignant NMEs without a mass in 72 women (mean age = 51.5 years) were included. Two readers independently assessed distributions and IEPs of NME, according to the Breast Imaging Reporting and Data System lexicon fifth edition. Collected data included the presence of invasion and histopathologic factors. Results A clustered ring IEP was significantly associated with invasive cancer (75.0%, P = 0.001, Reader1; 72.9%, P < 0.001, Reader 2), absence of necrosis (79.0%, P < 0.001; 72.1%, P < 0.001, respectively), and high Ki-67 expression (74.2%, P = 0.048; 74.2%, P = 0.003, respectively). A clumped IEP was related to ductal carcinoma in situ (33.3%, P = 0.025; 50.0%, P = 0.001, respectively), absence of lymph node metastasis (24.1%, P = 0.029; 31.5%, P = 0.030, respectively), and presence of necrosis (34.5%, P = 0.003; 44.8%, P = 0.001, respectively). Conclusion The presence of a clustered ring IEP in patients with breast cancer was found to be significantly associated with invasive breast cancer and high Ki-67 expression. PMID- 29758999 TI - Movement Disorders Associated With Antipsychotic Medication in People With Schizophrenia: An Overview of Cochrane Reviews and Meta-Analysis. AB - Movement disorders associated with antipsychotic medications are relatively common, stigmatising, and potentially disabling. Their prevalence in people with psychosis who are prescribed second-generation antipsychotics (SGAs) is uncertain, as is their level of recognition by clinicinas. We conducted meta analyses of randomised controlled trials included in the Cochrane Database of Systematic Reviews on schizophrenia and schizophrenia-like psychoses to estimate the prevalence of new-onset dystonia, akathisia, parkinsonism, and tremor with SGAs (amisulpride, asenapine, aripiprazole, clozapine, olanzapine, paliperidone, quetiapine, risperidone, L-sulpiride, and ziprasidone) approved in Canada and the UK, comparing them with haloperidol and chlorpromazine. We used a random effects model because of the heterogeneity between-studies in drug dosage and method of ascertainment of movement disorders. Our systematic search yielded 37 Cochrane systematic reviews (28 for SGAs), which generated 316 informative randomised controlled trials (243 for SGAs). With respect to SGAs, prevalence estimates ranged from 1.4% (quetiapine) to 15.3% (L-sulpiride) for dystonia, 3.3% (paliperidone) to 16.4% (L-sulpiride) for akathisia, 2.4% (asenapine) to 29.3% (L sulpiride) for parkinsonism, and 0.2% (clozapine) to 28.2% (L-sulpiride) for tremor. Prevalence estimates were not influenced by treatment duration, the use of a flexible or fixed dosing scheme, or whether studies used validated instruments for the screening/rating of movement disorders. Overall, we found high overlap on the prevalence of new-onset movement disorders across different SGAs precribed for established psychoses. Variations in prevalence figures across antipsychotic medications were observed for the different movement disorders. Differences in pharmacological properties, such as for the dopamine D2 R association rate and serotonin 5-HT2A antagonism, could contribute to this variation. PMID- 29758998 TI - High Levels of Soluble Triggering Receptor Expressed on Myeloid Cells-Like Transcript (TLT)-1 Are Associated With Acute Respiratory Distress Syndrome. AB - We have previously demonstrated that elevated levels of soluble triggering receptor expressed on myeloid cells-like transcript 1 (sTLT-1) modulate sepsis induced inflammation and positively correlate with disseminated intravascular coagulation (DIC). Here, we evaluate the clinical implications of plasma sTLT-1 in acute respiratory distress syndrome (ARDS), which is common in sepsis patients. Soluble TLT-1 levels in the plasma of ARDS patients (n = 20) were determined by slot blot analysis and were compared with clinical parameters to identify significant associations. For comparisons to ARDS, we also measured sTLT 1 levels in matched healthy controls (n = 20). Of the 20 plasma samples evaluated from patients with ARDS, 60% were diagnosed with sepsis and 40% were diagnosed with septic shock. The white blood cells (WBCs) of patients with ARDS were found to be significantly elevated over healthy controls with a mean of 13 k/uL over 6.2 k/uL, respectively. The mean plasma levels of sTLT-1 were 148.4 pg/mL +/- 16.52 in the patient cohort and 92.45 pg/mL +/- 17.12 in the control group ( P = .02). No statistically significant correlations were found between plasma levels of sTLT-1 and WBCs, sepsis, septic shock or acute physiologic, and chronic health evaluation II scores. A statistically significant inverse correlation (r2 = .25, P < .05) was found between plasma sTLT-1 and peripheral platelet counts in patients with ARDS. Increased levels of sTLT-1 in ARDS patients suggest that TLT 1 may mediate the pathobiology of ARDS. Moreover, our data are the first to demonstrate a specific platelet marker in the development of ARDS due to sepsis. PMID- 29759000 TI - Biological Sex Differences in Depression: A Systematic Review. AB - Depression is the leading cause of disability worldwide, and its prevalence is 2 times higher in women than in men. There is, however, a lack of data on sex specific pathophysiology of this disorder. The purpose of this systematic review is to identify the biological sex differences found in major depressive disorder (MDD) in studies published in the last 10 years. We conducted a literature search using the Medline, PsycInfo, PubMed, and Web of Science databases, selecting English-language studies that included physiological measures compared by sex in addition to MDD. We identified 20 relevant studies, which consisted primarily of mixed methodology and samples. The reported physiological measures comprised a variety of serum biomarkers, gene mRNA expression, and brain activity. Findings suggest different biological patterns in those with MDD depending on sex. Specifically, women presented higher levels of inflammatory, neurotrophic, and serotonergic markers and a stronger correlation between levels of some inflammatory and neurotrophic factors and the severity of symptoms. This review provides information about possible different biological patterns for women and men with depressive disorder and may have important implications for treatment. Future research should include homogeneous samples; make comparisons based on sex, control sex hormone fluctuations and pharmacological treatment; and use consistent criteria for evaluating psychobiological changes in MDD. PMID- 29759001 TI - Betwixt and Between Well and Sick in Cervical Precancer: Canadian Women's Experiences of Recurring HPV Infections and HPV Vaccination. AB - Background This research fuses the experiences of a precancer diagnosis with the decision-making surrounding a vaccine that can protect against human papillomavirus strains that women may not have been exposed to. The interviewee cohort is of note as half the women were in their 30s and 40s and 75% were over the age of 26. These groupings are often overlooked in media discourses and narrative research surrounding human papillomavirus and the human papillomavirus vaccine. Purpose Womens' diagnoses and treatment experiences, including colposcopies, biopsies, and Loop Electrosurgical Excision Procedures, are chronicled to highlight a liminal, precancerous state-one in which they are not deemed healthy, but nor have they been diagnosed with cancer. These are emotion filled experiences that are ridden with anxiety and fear, but also ones that are structured with self-care strategies to contain human papillomavirus infections and the risk of cervical cancer. Methods Twenty women who attended Sunnybrook Health Sciences Centre's human papillomavirus vaccination clinic were interviewed and their narratives were documented and analyzed to determine their experiences surrounding human papillomavirus infections and precancer as well as their motivations for human papillomavirus vaccination. Results The decision to undergo human papillomavirus vaccination was a self-care strategy that accompanied treatment procedures and was a means to reduce cervical cancer risk. While encouraged with the human papillomavirus vaccine's potential to curb cervical cancer, they had a tempered view of the vaccine and its effectiveness in their cases, given their medical histories. Conclusions The research provides an in depth accounting of an often overlooked grouping in human papillomavirus and human papillomavirus vaccination research and media discourse which, generally, focuses upon middle-school-aged girls and university-/college-aged women. In addition, the research provides recommendations for practice for cervical precancer diagnoses going forward. PMID- 29759003 TI - Mothers' History of Child Sexual Abuse and Child Behavior Problems: The Mediating Role of Mothers' Helpless State of Mind. AB - This investigation evaluated a theoretically specified model of associations among mothers' history of child sexual abuse (CSA), a helpless state of mind (SOM) with regard to the mother-child relationship, and increased behavior problems in the next generation. Moreover, we evaluated the moderating influence of child gender on predicted relations between mothers' CSA severity and helpless SOM (i.e., moderated mediation). Participants were 225 biological mother preschooler dyads (48% female; 46.4% Latinx) drawn from an ongoing, longitudinal study of representation and regulation in child development. Mothers' history of CSA was assessed when their children were 4 years old and emerged as a prominent risk factor in this diverse, high-risk community sample with 40% of mothers reporting contact-based sexual abuse prior to age 18. Mediation analyses revealed a significant indirect pathway from a continuous rating of mothers' CSA severity to increased externalizing behavior problems from ages 4 to 8 in the next generation via mothers' helpless SOM at age 6. Further, this indirect path was significant for mother-daughter dyads, but not for mother-son dyads. This investigation contributes to the neophyte literature on intergenerational CSA effects by revealing the impact of a mother's CSA history on her SOM regarding the mother-child relationship, particularly when parenting daughters. Clinical interventions that enhance survivors' awareness of and reflection on their SOM regarding the parent-child relationship may attenuate intergenerational CSA effects on child adaptation. PMID- 29759004 TI - Is There a Delay in Diagnosis of Duchenne Muscular Dystrophy Among Preterm-Born Males? AB - The objective of this study was to investigate whether males who were born preterm took longer to receive a Duchenne muscular dystrophy diagnosis than term males. Data for males with Duchenne muscular dystrophy identified through a population-based surveillance system were analyzed using a Kaplan-Meier estimator. The first signs and symptoms were noted at a median age of 2 years in both groups. Median age when first signs and symptoms prompted medical evaluation was 2.59 years among preterm and 4.01 years among term males. Median age at definitive diagnosis was 4.25 years and 4.92 years for preterm and term males, respectively. Neither difference was statistically significant. Preterm males tended to be seen for their initial medical evaluation earlier than term males, though they were not diagnosed significantly earlier. It may take clinicians longer after the initial evaluation of preterm males to arrive at a Duchenne muscular dystrophy diagnosis. PMID- 29759005 TI - IDO-expressing Fibroblasts Suppress the Development of Imiquimod-induced Psoriasis-like Dermatitis. AB - Psoriasis is a chronic skin condition whose pathogenesis is reported to be due to the activation of the interleukin-23/interleukin-17 (IL-23/IL-17) pathway. Here, we report that indoleamine 2,3-dioxygenase (IDO)-expressing fibroblasts reduce the activity of this pathway in activated immune cells. The findings showed that intralesional injection of IDO-expressing fibroblasts in imiquimod-induced psoriasis-like dermatitis on the back and ear (Pso. ear group) in mice significantly improves the clinical lesional appearance by reducing the number of skin-infiltrated IL-17+ CD4+ T cells (1.9% +/- 0.3% vs. 6.9% +/- 0.6%, n = 3, P value < 0.01), IL-17+ gammadelta+ T cells (2.8% +/- 0.3% vs. 11.6% +/- 1.2%, n = 3, P value < 0.01), IL-23+ activated dendritic cells (7.6% +/- 0.9% vs. 14.0% +/- 0.5%, n = 3, P < 0.01), macrophages (4.3% +/- 0.1% vs. 11.3% +/- 1.0%, n = 3, P value < 0.01), and granulocytes (2.5% +/- 0.4% vs. 4.5% +/- 0.3%, n = 3, P value < 0.01) as compared to untreated psoriatic mice. This finding suggests that IDO expressing fibroblasts, and to a lesser extent, non-IDO primary fibroblasts suppress the psoriatic-like symptoms by inhibiting the infiltration of key immune cells involved in the development of psoriasis. PMID- 29759007 TI - Contemporary Trends Emerging in Epigenomics and Metabolism. AB - Diabetes is the disease of our time. It is a complex disorder. It is increasingly appreciated that genetic factors cannot fully explain susceptibility to diabetes and its complications. For almost a decade, the epigenetics field has grown tremendously becoming an alternative but integral component of how we interpret gene regulation. Some consider the field an epiphenomenon with an evidence base awaiting critical testing. The advent of experimental tools combined with the development of research methods has brought with the field technological advancements that allow scientists to assess ideas that have not yet been tested critically. If there was ever a time not to give up on epigenetics, then that time would be now. Under the seeming disorder of more than 3 billion base pairs, the human genome works successfully with order. It is a complex order. Instructed by a chemical code that is largely uncharted in metabolic disease, developmental studies have clearly shown that code exclusivity is key to unlocking the genetic blueprint. Central to this chemical code are specific modifications to DNA and RNA, histones and nonhistone proteins: these tiny chemical marks that have wide ranging functions. Robustness is key, and these marks are written to be precisely read and accurately erased. PMID- 29759006 TI - Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice. AB - Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1beta blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels >2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1beta activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1beta blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1beta blockade. In addition, IL-1beta blockade has only been studied in patients with C-reactive protein >2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1beta pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1beta blockade extends to other anti inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis. PMID- 29759009 TI - Implementation of Policy, Systems, and Environmental Community-Based Interventions for Cardiovascular Health Through a National Not-for-Profit: A Multiple Case Study. AB - INTRODUCTION: In 2014, the Centers for Disease Control and Prevention funded the American Heart Association to implement policy, systems, and environment-focused strategies targeting access to healthy food and beverages, physical activity, and smoke-free environments. METHOD: To understand factors affecting implementation and variations in success across sites, evaluators conducted a multiple case study. Based on past literature, community sites were categorized as capacity building or implementation-ready, for comparison. A sample of six communities were selected using a systematic selection tool. Through site visits, evaluators conducted interviews with program staff and community partners and assessed action plans. RESULTS: Evaluators identified important implications for nationally coordinated community-based prevention programming. Differences in implementation varied by the communities' readiness, with the most notable differences in how they planned activities and defined success. Existing partner relationships (or lack thereof) played a significant role, regardless of the American Heart Association's existing presence within the communities, in the progression of initiatives and the differences observed among phases. Last, goals in capacity-building sites were tied to organizational goals while goals in implementation-ready sites were more incremental with increased community influence and buy-in. DISCUSSION: Using national organizations as a mechanism to carry out large-scale community-based prevention work is a viable option that provides coordinated, wide-scale implementation without sacrificing a community's priorities or input. In funding future initiatives, the presence of relationships and the time needed to cultivate such relationships should be accounted for in the planning and implementation processes, as well as both local and national expectations. PMID- 29759008 TI - Thin Slices of Athletes' Nonverbal Behavior Give Away Game Location: Testing the Territoriality Hypothesis of the Home Game Advantage. AB - The present research investigated whether perceivers could detect who is playing at home or away in soccer matches based on thin slices of professional (Experiment 1) and amateur (Experiment 3) athletes' nonverbal behavior prior to the match and whether perceivers rated athletes playing at home relatively higher on behavioral dimensions (Experiments 2 and 3) linked to territoriality. In Experiment 1 ( N = 80), participants watched short videos depicting soccer players prior to a UEFA Champions League match and rated whether athletes were more likely to be playing at home or away. In Experiment 2 (two groups N = 102 and N = 101), perceivers rated these videos in terms of assertiveness, dominance, and aggression. In Experiment 3, we replicated the procedure of Experiments 1 and 2 with different stimulus material from amateur soccer ( N = 112). Participants could significantly differentiate between home playing and away playing athletes (Experiment 1: d = 0.44 and Experiment 3: d = 1.07). Experiments 2 and 3 showed that perceivers rated professional and amateur soccer players higher on assertiveness ( d = 0.34-0.63), dominance ( d = 0.20-0.55), and aggression ( d = 0.16-0.49) when playing at home compared to playing away. Findings are supportive of evolutionary accounts of nonverbal behavior, ecological approaches to person perception, and the thin slices of behavior hypothesis by demonstrating that humans change their nonverbal behavior depending on game location. We discuss the relevance of the present findings for the home advantage in sports. PMID- 29759010 TI - The Associations Between Social Rank Uncertainty, Machiavellianism, and Dominance: From a Life History Perspective. AB - This study used the life history (LH) theory to investigate how environmental cues are associated with Machiavellianism. A total of 252 undergraduate students completed self-report measures of social rank uncertainty, Machiavellianism, fast LH strategy, and dominance. The results indicated that Machiavellianism was related to a fast LH strategy. Furthermore, a fast LH strategy mediated an association between social rank uncertainty and Machiavellianism. Finally, Machiavellianism was positively associated with dominance. These findings may enhance our understanding of the evolutionary origin of Machiavellianism. PMID- 29759011 TI - Preservation technique of the piriformis tendon is superior to reattachment technique in terms of contiguity and muscle atrophy: using magnetic resonance imaging. AB - PURPOSE: The preservation technique of the piriformis tendon during the posterolateral approach in total hip arthroplasty (THA) is reportedly superior to the reattachment technique in terms of dislocation. However, the long-term effects of preservation of the piriformis tendon during THA remain unknown. In this study, we evaluated the contiguity of the piriformis/conjoined tendon and atrophy of the piriformis/internal obturator muscle during a long-term postoperative follow-up using magnetic resonance imaging (MRI). METHODS: We retrospectively evaluated 48 patients with available MRI. The 48 patients were classified into a P group ( n = 29), in which the piriformis tendon was preserved, and an R group ( n = 19), in which the piriformis was reattached after sectioning. The mean follow-up duration was 45.9 months. The contiguity of the piriformis/conjoined tendon and atrophy of the piriformis/internal obturator muscle were evaluated in all patients. RESULTS: The piriformis tendon remained attached to the greater trochanter in all P-group patients and 68.4% of R-group patients. The mean piriformis muscle atrophy ratios were 15.9% +/- 21.1% in the P group and 41.6% +/- 19.1% in the R group ( p < 0.001). The conjoined tendon repair remained intact in 72.4% of P-group patients and 36.8% of R-group patients ( p < 0.05). The mean internal obturator muscle atrophy ratio was 31.4% +/- 26.2% in the P group and 50.4% +/- 19.1% in the R group ( p < 0.05). No postoperative pulmonary embolism, wound infection, deep infection, or hip dislocation occurred. CONCLUSIONS: In our study, we suggest that the preservation technique of the piriformis tendon is superior to the reattachment technique in terms of contiguity and muscle atrophy. PMID- 29759012 TI - Using the Replicating Effective Programs Framework to Adapt a Heart Health Intervention. AB - Heart disease is the leading cause of death in the United States. African Americans and people of low socioeconomic status suffer disproportionately from heart disease-related morbidity and mortality. In Detroit, Michigan, a primarily African American and low-income urban area, heart disease mortality is at twice the national rate. Despite evidence for the effectiveness of self-management support interventions in reducing chronic disease burden for older adults, few are adapted for communities most in need. This article describes the process of adapting Take PRIDE, an evidence-based heart disease self-management intervention, for older adults in Detroit via the Replicating Effective Programs (REP) framework. Working within a community-academic partnership, we found REP useful in facilitating the identification of diverse stakeholders, core versus adaptable elements of the intervention and barriers to implementation. We also made several modifications to the REP framework in order to better fit our project needs. Overall, we found REP to be an effective, flexible tool that allowed us to successfully adapt a disease-management intervention for this setting. Processes, lessons learned, and recommendations offered in this article may help researchers and practitioners working to expand access to self management support for populations most affected by chronic disease. PMID- 29759013 TI - Adapting to a Shifting Health Care Landscape: Illinois Breast and Cervical Cancer Program Lead Agencies' Perspectives. AB - Understanding how safety net programs adapt to systemic health care changes is pivotal for creating feasible recommendations for policy implementation. This study characterizes perspectives of Lead Agency (LA) coordinators of the Illinois Breast and Cervical Cancer Program (IBCCP) in response to sociopolitical changes at state and national levels. Our cross-sectional study included 29 semistructured telephone interviews between December 2015 and January 2016. Respondents indicated some changes in the priority population served, changes in referrals and clinical services, and, a continued commitment to IBCCP. Our findings suggest that IBCCP and other safety net programs will need to be flexible to meet the ongoing needs of historically vulnerable populations in a complex, shifting environment. Implications for public health practice and policy include the need to ensure that program personnel are aware of evidence-based strategies to reach different priority populations and are kept abreast of organizational and system changes that may affect referral patterns as well as the need to educate health care providers working with safety net programs about changes in the delivery and coordination of services. PMID- 29759014 TI - Simplified and Yet Turing Universal Spiking Neural P Systems with Communication on Request. AB - Spiking neural P systems are a class of third generation neural networks belonging to the framework of membrane computing. Spiking neural P systems with communication on request (SNQ P systems) are a type of spiking neural P system where the spikes are requested from neighboring neurons. SNQ P systems have previously been proved to be universal (computationally equivalent to Turing machines) when two types of spikes are considered. This paper studies a simplified version of SNQ P systems, i.e. SNQ P systems with one type of spike. It is proved that one type of spike is enough to guarantee the Turing universality of SNQ P systems. Theoretical results are shown in the cases of the SNQ P system used in both generating and accepting modes. Furthermore, the influence of the number of unbounded neurons (the number of spikes in a neuron is not bounded) on the computation power of SNQ P systems with one type of spike is investigated. It is found that SNQ P systems functioning as number generating devices with one type of spike and four unbounded neurons are Turing universal. PMID- 29759015 TI - Morphologic and Immunohistochemical Characteristics of Anorectal Melanoma. AB - Anorectal melanoma is a rare aggressive disease. Due to its rarity and considerable histologic and immunohistochemical variabilities, misdiagnosis as lymphoma, carcinoma, sarcoma, and/or gastrointestinal stromal tumor is not uncommon, particularly in amelanotic cases. We reviewed histologic features and immunohistochemical stains of 19 anorectal melanoma cases. Histopathologic features were evaluated including junctional activity, melanin pigment, and morphologic features. Immunohistochemical stains were performed using Sox10, S100 protein, HMB-45, melan-A, CD56, and cytokeratins. Epithelioid histopathologic morphology was observed in 63.2% of the cases followed by 47.4% of the cases with spindle-cell, 26.3% with lymphoma-like, and 26.3% with pleomorphic morphologies. Junctional melanocytic activity was seen in almost half of the cases. Melanin pigment was absent (amelanotic) in nearly 40% of the cases. Immunohistochemically, diffuse positive expression of Sox10, S100 protein, melan A, and HMB-45 was seen in 100%, 40%, 53.3%, and 38.5% of the cases, respectively. Cytokeratins were negative and CD56 was positive in 2 cases. These findings indicate that anorectal melanomas often show one or combined histolopathologic features without presence of melanin pigment and absence of junctional melanocytic activity. Anorectal melanoma should be kept in mind in the differential diagnosis of malignant neoplasms of anorectal region with epithelioid, spindle-cell, lymphoma-like, and pleomorphic morphologies. Sox10 immunohistochemistry stain can be used as a first-line screening tool to avoid extensive or unnecessary workups and/or potential misdiagnosis. PMID- 29759016 TI - Improving the sensitivity of miniature linear ion trap mass spectrometer by a DC voltage applied on the eject electrodes. AB - A miniaturized linear ion trap mass spectrometer with continuous atmospheric pressure interface has been built in our lab. Significant extension in mass range and reduction in power consumption have been realized by the supplemental alternating current frequency scan mode. However, relatively poor sensitivity has been witnessed, which is directly dominated by the detection efficiency of the ion detector. Theoretical analysis has been implemented to find ways to improve the detection efficiency. The results show that enhanced sensitivity can be obtained by applying a direct current voltage on the pair of electrodes in eject direction. Experiments show that the sensitivity has been improved by more than one time due to the application of direct current voltage. With this design, this homemade miniature linear ion trap mass spectrometer can be used to analyze more rarefied samples, especially to on-site chemical analysis and space application. PMID- 29759017 TI - Aggression and Helping as Responses to Same-Sex and Opposite-Sex Rejection in Men and Women. AB - Research shows that interpersonal rejection increases aggression and decreases helping toward the rejecter. Based on the assumptions of the evolutionary approach, it was hypothesized that aggression would be higher and helping would be lower after rejection by a same-sex rather than an opposite-sex other. Moreover, it was predicted that the effect for aggression would be stronger in men, and the effect for helping would be stronger in women. Participants ( N = 100) were rejected or accepted by a same- or opposite-sex person, and later aggression and helping were measured using the tangram Help-Hurt task. The major finding was that same-sex rejection resulted in more aggression and less helping than opposite-sex rejection, but the rejectee's sex did not moderate the effect. Instead, men were more aggressive and less helping independently of condition. Along with the sexual exchange theory, more negative behavior in same-sex rejection could be interpreted as raised in-group sexual competitive tendencies, whereas less negative behavior in opposite-sex rejection could result from the motivation to exchange resources between men and women. PMID- 29759018 TI - Accelerating Pediatric Cancer Drug Development: Challenges and Opportunities for Pediatric Master Protocols. AB - Although outcomes for children with cancer have significantly improved over the past 40 years, there has been little progress in the treatment of some pediatric cancers, particularly when advanced. Additionally, clinical trial options and availability are often insufficient. Improved genomic and immunologic understanding of pediatric cancers, combined with innovative clinical trial designs, may provide an enhanced opportunity to study childhood cancers. Master protocols, which incorporate the use of precision medicine approaches, coupled with the ability to quickly assess the safety and effectiveness of new therapies, have the potential to accelerate early-phase clinical testing of novel therapeutics and which may result in more rapid approval of new drugs for children with cancer. Designing and conducting master protocols for children requires addressing similar principles and requirements as traditional adult oncology trials, but there are also unique considerations for master protocols conducted in children with cancer. The purpose of this paper is to define the key challenges and opportunities associated with this approach in order to ensure that master protocols can be adapted to benefit children and adolescents and ensure that adequate data are captured to advance, in parallel, the clinical development of investigational agents for children with cancer. PMID- 29759019 TI - Reported Adverse Drug Reactions During the Use of Corticosteroids in a Tertiary Care Hospital. AB - BACKGROUND: Corticosteroids have been used in numerous medical conditions. Studying the pattern and causality of adverse drug reactions (ADRs) helps us gain greater insight into their prevention, detection, assessment, and treatment. This reduces cost of health care and increases compliance. The study aimed to evaluate the ADRs reported in patients receiving corticosteroids for age, type of reaction, duration of steroid therapy, treatment prescribed for the ADR, and causal relationship of the ADR with the prescribed steroid. METHODS: ADRs observed in the patients admitted to the hospital wards and reported from October 1, 2015, to January 1, 2016, were studied for age, type of reaction, seriousness of the reaction, duration of steroid therapy, and treatment prescribed for the ADR. Causality assessment was done using the WHO-UMC scale. RESULTS: A total of 59 ADRs were reported. More than three-fourths (76.6%) were adults. The gastrointestinal system was the most common organ system affected (45.8%), followed by the cardiovascular system (18.6%). The other ADRs affected the psychiatric, dermatologic, musculoskeletal, endocrine, metabolic, and nervous systems. In addition, 3.4% of the ADRs were serious causing disability and prolongation of hospitalization respectively. More than half (57.4%) of the patients were on long-term steroids. Most (91.5%) of the ADRs showed a possible causal relationship, whereas 6.8% showed a probable causal relationship with the prescribed steroid. The causal relationship of one ADR with the prescribed steroid seemed unlikely. CONCLUSION: The decision to initiate corticosteroids requires careful consideration of relative risks and benefits in each patient. Strategies such as low-dose and alternate day therapy may reduce the incidence of adverse effects. PMID- 29759020 TI - Corrigendum. AB - ISFM Consensus Guidelines on the Diagnosis and Management of Hypertension in Cats Samantha S Taylor, Andrew H Sparkes, Katherine Briscoe, Jenny Carter, Salva Cervantes Sala, Rosanne E Jepson, Brice S Reynolds and Brian A Scansen J Feline Med Surg 2017; 19: 288-303 Readers should note that the version of the guidelines that appeared in print in March 2017 and online until May 2018 has been amended. The version now appearing online is the correct one. For information, the following amendment has been made to the original published version. In Table 6 on page 299 the unit for esmolol should have been MUg/kg/min and not mg/kg/min, as stated. The 'Suggested dose' column entry for esmolol has therefore been amended to '50-100 MUg/kg/min CRI'. PMID- 29759021 TI - Alginate Ototoxicity in the Mouse Model. AB - Objective To determine whether alginate exposure to the round window of the mouse causes any measurable ototoxicity. Study Design Prospective animal study. Setting Basic science laboratory affiliated with a tertiary care university medical center. Subjects and Methods After Institutional Animal Care and Use Committee approval, 5 adult mice were obtained and underwent bullostomy and round window niche application of alginate. Auditory brainstem response (ABR) tests were completed at baseline prior to the procedure and also 5, 14, and 30 days postprocedure. Results were compared. At termination of procedure, the mice were sacrificed with harvest of the cochleae, which were viewed under histologic section. Results There were no significant increases in ABR thresholds in any of the test animals at all test periods after alginate exposure compared to baseline. There were also no observable behavioral changes after the procedure to indicate vestibular dysfunction. Cochlear sectioning revealed no evidence of histologic damage. Conclusion Exposure of alginate to the round window does not cause any obvious ototoxicity in the mouse model. Further clinical trials will be needed to elucidate the effect of alginate in the human middle ear. PMID- 29759022 TI - Compassion-focused therapy for trauma in people with intellectual disabilities: A conceptual review. AB - Trauma exposure and post-traumatic stress disorder are more prevalent in people with intellectual disabilities (PWID) than in the general population, yet the evidence base for trauma interventions in this population is sparse. Compassion focused therapy (CFT) may be particularly well-suited to PWID for a number of reasons, including its adaptability to different developmental levels. PWID are more likely to have issues with self-relating (e.g. shame and self-criticism) and attachment than the general population, two issues that are compounded by trauma and which CFT explicitly seeks to address. Furthermore, compassion-focused approaches emphasize cultivating a sense of safeness while empowering people to make behavioural changes; this is particularly pertinent to PWID who have been traumatized and may feel unsafe and disempowered. An overview of CFT and its application to trauma are given, as well as some case studies using CFT with PWID. PMID- 29759023 TI - Embodied Neoliberalism: Epidemiology and the Lived Experience of Consumer Debt. AB - A growing set of epidemiological data links personal financial debt to negative mental and physical health outcomes. These findings point to debt as a potentially significant socioeconomic determinant of population health, especially given rising rates of household and consumer debt in industrialized nations. However, the political and economic contexts in which rising consumer debt is embedded and the ways in which it is experienced in everyday life are underexplored in this epidemiological literature. This gap leaves open questions about how best to situate and understand debt as a health determinant with both psychosocial and neo-material attributes. In this article, we discuss findings from a qualitative study of personal debt experience in Boston, Massachusetts. Participants' debt narratives highlight the powerful feelings of shame, guilt, and personal responsibility that debt engenders. The findings point to the influence of neoliberal ideology in shaping emotional responses to debt and suggest that these responses may be important pathways through which debt affects health. We discuss our findings within the broader landscape of American neoliberal economic policy and its role in shaping trends of consumer debt burden. PMID- 29759024 TI - Subcutaneous Emphysema and Pneumomediastinum after Eustachian Tube Balloon Dilation. PMID- 29759025 TI - Impact of Infant Supraglottoplasty on Quality of Life. AB - Objectives The objective of the present study is to examine the impact of supraglottoplasty on the quality of life (QOL) of caregivers and infants with severe laryngomalacia and moderate laryngomalacia with feeding difficulties. Study Design Prospective cohort study. Setting Tertiary children's hospital. Subjects and Methods Thirty-nine infants who underwent supraglottoplasty were examined. The primary caregiver answered the 47-item short form of the Infant and Toddler Quality of Life Questionnaire-47 pre- and postoperatively; the subsection scores were compared. A 1-way analysis of variance was performed to analyze the effect of age and sex. A comparison was made between our cohort and a general population of healthy children. Results The average age at surgery was 4.0 months, and 53% of the patients were male. There was significant postoperative improvement in overall health, physical ability, growth and development, bodily pain, temperament, emotional impact on the caregiver, impact on caregiver's time, and family cohesion scores ( P < .05). The same subscale scores remained significantly improved postoperatively after age and sex were controlled. Preoperative QOL scores were significantly worse than those of the general population in nearly all categories. Postoperative physical ability ( P = .009) and temperament ( P = .011) QOL scores were higher than the those of the general population. Scores for growth and development ( P = .132), bodily pain ( P = .481), and family cohesion ( P = .717) were equivalent to those of the general population. Conclusion QOL was significantly improved after supraglottoplasty for infants with severe laryngomalacia and moderate laryngomalacia with feeding difficulties. After supraglottoplasty, QOL was similar to that of the general infant population in most categories. PMID- 29759027 TI - Upper limb congenital muscular hypertrophy and aberrant muscle syndrome in children. AB - : Congenital muscle hypertrophy of the upper limb is a very rare condition with unknown aetiology. This descriptive observational and retrospective series included eight children followed by a multidisciplinary team from 2005 to 2017. The diagnosis was based on a cluster of clinical and radiological characteristics after elimination of differential diagnoses. Patients were categorized according to: anomalies of the wrist, anomalies of long fingers of intrinsic or extrinsic origin; and anomalies of the thumb with or without first web space contracture. Treatment begins in young children with hand orthoses to limit muscle contraction and joint malposition. The purpose of surgical treatment was to release contractures and to restore muscle balance through, in the main, finger intrinsic releases and first web releases. At the 2-year follow-up, we found that limited surgical procedures improved finger, thumb and wrist positions. We conclude that muscle hypertrophy is the main cause of deformity and that selective releases of contracted musculo-tendinous units and skin lengthening are effective. LEVEL OF EVIDENCE: IV. PMID- 29759026 TI - Efficacy of Oligodendrocyte Progenitor Cell Transplantation in Rat Models with Traumatic Thoracic Spinal Cord Injury: A Systematic Review and Meta-Analysis. AB - Spinal cord injury (SCI) is a devastating disease that results in severe motor, sensory, and autonomic dysfunction, for which there are currently no available treatments. Subsequent to the primary mechanical damage, progressive secondary damage further exacerbates the functional deficit. Demyelination may play an important role in the pathogenesis of SCI. Oligodendrocyte progenitor cells (OPCs) are considered a candidate cellular treatment approach for SCI attributable to their unique potential. Here, we conducted a systematic review and meta-analysis to assess the efficacy of OPC transplantation in rat models with traumatic thoracic SCI, and 17 studies (20 experiments, 402 rats) were identified. The Basso, Beattie, Bresnahan (BBB) locomotor rating score, latency and amplitude of motor evoked potential (MEP), percentage of myelinated axons, and cavity size were used as outcome measurements. The pooled results of the meta analysis in different subgroups (based on cell dose or sex) both suggested that the BBB score of the OPC group was significantly improved compared to that of the control group 2, 4, and 8 weeks after transplantation. Whereas the amplitude of MEP was not significantly different, the latency of MEP was significantly shorter compared to that of the control group 4 weeks after transplantation. The percentage of myelinated axons increased significantly in the OPC group compared to that of the control group after OPC transplantation. Area measurements across groups revealed a significant reduction in cavity size in the OPC-treated groups compared to the control group. In conclusion, OPC transplantation provided considerable beneficial effects after traumatic SCI. PMID- 29759028 TI - Reciprocal Predictive Accuracy of Sinonasal Symptom Severity, Nasal Endoscopy, and Frequency of Past Chronic Rhinosinusitis Exacerbations. AB - Objective We sought to determine whether chronic rhinosinusitis (CRS) symptom severity, endoscopic exam findings, and acute exacerbation of CRS (AECRS) frequency-all important and distinct clinical manifestations of CRS-would be predictive of each other and, therefore, inform when further assessment of each other metric should be pursued. Study Design Cross-sectional cohort study. Setting Tertiary academic rhinology clinic. Subjects and Methods In total, 241 patients with CRS were prospectively recruited and completed the 22-item Sinonasal Outcome Test (SNOT-22) to reflect CRS symptom severity. AECRS frequency was assessed using the number of sinus infections as well as CRS-related antibiotics and CRS-related oral corticosteroids used in the past 3 months. An endoscopy score was calculated for each patient. Results SNOT-22 score and AECRS were predictive of each other while AECRS and endoscopy score were not predictive of each other. SNOT-22 score could be used to predict having had, in the past 3 months, at least 1 sinus infection (area under the curve [AUC] = 0.727; P < .001), at least 1 CRS-related antibiotic used (AUC = 0.691; P < .001), or at least 1 CRS-related oral corticosteroid course used (AUC = 0.655; P < .001). Having a SNOT-22 score >=30 could be predicted by reporting at least 1 sinus infection (AUC = 0.634; P < .001), CRS-related antibiotics (AUC = 0.614; P < .001), or CRS-related oral corticosteroids (AUC = 0.616; P < .001) in the past 3 months. These relationships held for patients with and without nasal polyps. Conclusion The predictive power of CRS outcome measures reflecting symptomatology, AECRS frequency, and endoscopic findings may be of clinical utility in situations where time or resources are limited to perform an ideally full assessment of patients with CRS. PMID- 29759029 TI - Burnout in Otolaryngology-Head and Neck Surgery: A Single Academic Center Experience. AB - Burnout in modern medicine is becoming more recognized and researched. The objective in this study is to evaluate burnout in a tertiary care academic institution and compare results among faculty, trainees, and advanced practice practitioners (APPs) in a cross-sectional survey using the Maslach Burnout Inventory. Fifty-two surveys were distributed; 44 participants completed the survey (85%): 25 staff physicians (57%), 14 resident physicians (32%), and 5 nurse practitioners (11%). Staff physicians had low emotional exhaustion, moderate depersonalization, and low result for reduced personal accomplishments; trainees reported low emotional exhaustion, high depersonalization, and moderate reduced personal accomplishment; and nurse practitioners reported moderate on all 3 dimensions. There is overall low burnout in this tertiary care academic center of otolaryngologist providers and no difference in rates among the different groups (trainees, APPs, staff). Measures addressing specific deficiencies among dimensions of burnout would be helpful to prevent disintegration of physician satisfaction into burnout. PMID- 29759030 TI - Development of Human-Derived Cell Culture Lines for Recurrent Respiratory Papillomatosis. AB - Recurrent respiratory papillomatosis (RRP) is mainly caused by human papillomavirus (HPV) 6 and 11. While various adjuvant therapies have been reported, no effective therapy has been documented to universally "cure" this disease. In the era of precision medicine, it would be valuable to identify effective intervention based on drug sensitivity testing and/or molecular analysis. It is essential to be able to successfully carry out in vitro culture and expand tumor cells directly from patients to accomplish this goal. Here we report the result of successful culture of HPV-infected cell lines (success rate 70%, 9/13) that express the E6/E7 RNA transcript, using pathologic tissue biopsies from patients treated at our institution. The availability of such a system would enable ex vivo therapeutic testing and disease modeling. PMID- 29759031 TI - Problems with polypills. PMID- 29759032 TI - TIM-3-Expressing Mast Cells Are Present in Chronic Rhinosinusitis with Nasal Polyps. AB - Objectives To identify whether TIM-3 expression is present in the mast cell population within nasal polyps and to determine its correlation with clinical severity in patients with chronic rhinosinusitis with nasal polyposis. Study Design Basic science, translational study. Setting Nasal polyp tissue collected from patients seen at a tertiary care hospital (2015-2016). Subjects and Methods Nasal polyp tissue obtained during functional endoscopic sinus surgery (n = 24) was enzymatically digested into epithelial and stromal fractions. Viable mast cells expressing TIM-3 were identified using flow cytometry for the following: CD45, Live/Dead, c-kit, FcepsilonR1, TIM-3. Disease severity was assessed using the Sino-Nasal Outcome Test, Lund-Mackay staging system, Lund-Kennedy staging system, and complete blood counts. Results Mast cells were found in both the epithelial and stromal layers of polyps, with a greater %TIM-3+ mast cells in the epithelial layer compared with that of the stromal layer ( P = .001). As the percentage of mast cells increased, there was a comparative worsening in endoscopic severity after comparing pre- and postoperative LK scores (rho = 0.455, P = .029). In a subgroup of patients with concomitant asthma, increased epithelial %TIM-3+ mast cells also correlated with worsening endoscopic appearance postoperatively (rho = 0.866, P = .001, n = 11). Oral corticosteroid treatment did not change the viability of mast cells nor their influence on the increased postoperative endoscopic disease severity (rho = -0.544, P = .020, n = 18). Conclusion Viable mast cells were found to be present in polyps with increased TIM-3 expression at the epithelial layer. This suggests that TIM-3 may play a role in chronic inflammation in CRSwNP via mast cell activation. PMID- 29759033 TI - Thyroid Incidentalomas Detected on 18F-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography: Malignant Risk Stratification and Management Plan. AB - OBJECTIVE: The aims of this study were to stratify the risk of malignancy in thyroid incidentalomas detected on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) using ultrasound features according to guidelines for thyroid nodules and to develop a subsequent management plan. METHODS: From a historical cohort of 96,942 consecutive patients who underwent 18F-FDG PET/CT between October 2008 and September 2015, 1342 patients with 1364 nodules underwent ultrasound evaluation for focal uptake in thyroid gland, with a final diagnosis made for 877 patients with 907 nodules, which were included in this study. Ultrasound images were retrospectively reviewed, and they were stratified according to the American Thyroid Association and Korean Thyroid Image Reporting and Data System guidelines. The calculated malignancy risks were compared with the estimated risks suggested by the guidelines. RESULTS: The overall malignancy risk of thyroid incidentalomas detected on 18F-FDG PET/CT was 54.7%. When stratified according to the American Thyroid Association guidelines, the malignancy risks of thyroid incidentalomas with high and intermediate suspicion (93.2% and 45.2%, respectively) were higher than those indicated in the guidelines. The malignancy risks of thyroid incidentalomas with low and very low suspicion (8.1% and 0%, respectively) were within the guideline ranges. These findings were also noted when thyroid incidentalomas were stratified according to the Korean Thyroid Image Reporting and Data System, and in a subgroup of nodules >1 cm. CONCLUSIONS: Ultrasound examinations can be used to stratify the malignancy risk of thyroid incidentalomas detected on 18F-FDG PET/CT. The risk of malignancy did not increase in thyroid incidentalomas with low and very low suspicion, indicating that only selective biopsies may be needed in these categories of thyroid incidentalomas. PMID- 29759034 TI - Motives, Offending Behavior, and Gender Differences in Murder Perpetrators With or Without Psychosis. AB - Little is known whether differences exist in motivation and reactive/instrumental offense behaviors between murder offenders with and without psychotic disorder. To contribute to better prevention strategies, the aim of this study was to investigate offense characteristics in murder offenders with a psychotic, nonpsychotic or no psychiatric diagnosis, and whether these factors differ according to sex. This data study examined the population of murder offenders between 1997 and 2005 ( N = 435) in Victoria, Australia. Apparent motive for murder was allocated to one of six classifications. Assignations of reactive versus instrumental offense categories, co-offending, victim-offender relationship were determined by review of case material. Mental health service usage and prevalence of mental illnesses were identified through data with the statewide register of contacts with the public mental health system. Of the 435 offenders, 43 (9.9%) had been diagnosed with a psychotic illness. Gender differences between and within offenders with and without a psychotic disorder were analyzed. Murder offenders with a psychotic disorder were 3.19 (95% confidence interval [CI] = [1.27, 8.03]) times more likely to be motivated by revenge than nonpsychotic offenders and those with no diagnosis (odds ratio [OR] = 2.46, 95% CI = [1.10, 5.53]). The diagnostic groups did not differ on premeditation of their offenses or prior convictions. Perpetrators with psychotic illness were significantly more likely to kill family members and others known to them. It appears that for the psychotic disorder group, the perception of having been wronged in some way is a potential risk marker for planning and committing a serious offense. Care should be taken to improve adherence and access to care to avoid possible future serious violence especially in female patients with a high burden of mental illness like schizophrenia or severe mood disorders. PMID- 29759035 TI - A Novel Missense Mutation in the SLC5A5 Gene in a Sudanese Family with Congenital Hypothyroidism. AB - Thyroid hormone synthesis requires the presence of iodide. The sodium-iodide symporter (NIS) is a glycoprotein that mediates the active uptake of iodide from the blood stream into the thyroid grand. NIS defects due to SLC5A5 gene mutations are known to cause congenital hypothyroidism (CH). The proposita is a 28-year-old female whose origin is North Sudan where neonatal screening for CH is not available. She presented with severe constipation and a goiter at the age of 40 days. Laboratory testing confirmed CH, and she was started on levothyroxine. Presumably due to the delayed treatment, the patient developed mental retardation. Her younger sister presented with a goiter, tongue protrusion, and umbilical hernia, and the youngest brother was also diagnosed with CH based on a thyrotropin level >100 MUIU/mL at the age of 22 days and 8 days, respectively. The two siblings were treated with levothyroxine and had normal development. Their consanguineous parents had no history of thyroid disorders. Whole-exome sequencing was performed on the proposita. This identified a novel homozygous missense mutation in the SLC5A5 gene-c.1042T>G, p.Y348D-which was subsequently confirmed by Sanger sequencing. All affected children were homozygous for the same mutation, and their unaffected mother was heterozygous. The NIS protein is composed of 13 transmembrane segments (TMS), an extracellular amino-terminus, and an intracellular carboxy-terminus. The mutation is located in the TMS IX, which has the most beta-OH group-containing amino acids (serine and threonine), which is implicated in Na+ binding and translocation. In conclusion, a novel homozygous missense mutation in the SLC5A5 gene was identified in this Sudanese family with CH. The mutation is located in the TMS IX of the NIS protein, which is essential for NIS function. Low iodine intake in Sudan is considered to affect the severity of hypothyroidism in patients. PMID- 29759036 TI - The association between occupational lead exposure and serum levels of selected soluble receptors. AB - The present study was designed to evaluate soluble receptors as potential targets for lead (Pb). Analyses included the serum levels of soluble Vascular Endothelial Growth Factor Receptors 2 (sVEGFR-2), soluble Epidermal Growth Factor Receptor (sEGFR), soluble Human Epidermal Growth Factor 2 (sHER-2/neu), and soluble Interleukin 6 Receptors (sIL-6R) in the groups of chronically and subchronically occupationally exposed workers. The first group consisted of 56 male workers chronically exposed to Pb. The second group (control) comprised 24 male administrative workers. The third group included 36 male workers exposed to Pb for 40 +/- 3 days. Examined subjects were employed in the Pb-zinc works to perform periodic maintenance of blast furnaces and production lines. The serum levels of sHER-2/neu and sIL-6R were significantly lower in the group of workers chronically exposed to Pb compared to control values by 45% ( p < 0.05) and 44% ( p < 0.05), respectively. The values of sVEGFR-2 and sEGFR decreased after a subchronic exposure to Pb compared to baseline by 14% ( p < 0.05) and 21% ( p < 0.05), respectively. At the same time, the levels of sIL-6R also decreased by 14% ( p < 0.05). Results of the present study indicated that both chronic and subchronic occupational Pb exposures resulted in decreased levels of several soluble receptors (sVEGFR-2, sEGFR, sHER-2/neu, and sIL-6R), probably due to Pb induced modulations of the transcription factors and metalloprotease activities, that are necessary for soluble receptor synthesis. PMID- 29759037 TI - Deep head and neck infections: outcome following empirical therapy with early generation antibiotics. AB - In order to study the bacteriological profile, antibiotic sensitivity and outcome following empirical therapy with early generation antibiotics in patients with deep head and neck infection, a retrospective review of 42 patients admitted for drainage and intravenous antibiotic therapy was performed. Ludwig's angina was the commonest infection, with the most common organisms isolated being Group F beta-haemolytic (15%) and non-haemolytic (12.5%) streptococcus. All streptococci and anaerobic gram-positive cocci were susceptible to penicillin. S. aureus isolates were oxacillin-sensitive and enterococcus isolates were ampicillin sensitive. All 42 patients received empirical therapy with either intravenous penicillin or its derivatives. In only three patients was a change of antibiotic required based on culture and sensitivity results. Early generation antibiotics appear ideal as empirical therapy for deep head and neck infection. PMID- 29759040 TI - Continuous catheter-infused local anesthetic for lower extremity revascularization. PMID- 29759039 TI - Common femoral artery endarterectomy in the age of endovascular therapy. AB - OBJECTIVES: Common femoral artery endarterectomy (CFE) is the standard treatment for common femoral artery occlusive disease. We aim to assess the medium term outcomes of CFE with or without further concomitant procedures. DESIGN: A retrospective observational study. METHODS: All patients who underwent either isolated CFE (ICFE), CFE with angioplasty for occlusive arterial disease (CFEA) or concomitant CFE with endovascular aortic aneurysm repair (CFEE) were included. Patient demographics follow up, clinical improvement, types of CFE closure, patency rates, and survival-free amputation were noted. RESULTS: From 2002 to 2015, 1512 patients were referred with a diagnosis of critical limb ischemia. Of those, 1134 required revascularization. Sixty-one patients underwent 66 CFE. Ten limbs underwent an ICFE, 35 had CFEA, and 21 underwent CFEE. Demographics were comparable in all groups. Twenty-seven were closed primarily, while 39 required patch closure (12 venous, 8 Dacron, 19 biological). Technical success was 100% in ICFEs, 94% in CFEA, and 100% for CFEE ( p = 0.274). Immediate clinical success was 100% in both CFE and CFEE, but was 85.7% in CFEA ( p = 0.035). Immediate hemodynamic success was similar in all three groups ( p = 0.73). Sustained hemodynamic success was 30% in ICFE, 54.3% in CFEA, and 23.8% in CFEE ( p = 0.056). At two years, the primary patency was 90% in ICFE, 74.3% in CFEA, and 100% in CFEE ( p = 0.049). Primary-assisted patency was 90% in ICFE, 82.9% in CFEA, and 100% in CFEE ( p = 0.17). Secondary patency was 90% in ICFE, 94.3% in CFEA, and 100% in CFEE ( p = 0.409). Re-intervention was required in 26.9% of primary closures, versus 12.8% with patch closures ( p = 0.279). Amputation-free survival was 100% in ICFE, 80% in CFEA, and 100% in CFEE ( p = 0.056). CONCLUSION: CFE is a reliable and dependable procedure, even in the absence of good distal runoff. PMID- 29759041 TI - Naming the Unspeakable Harm of Street Harassment: A Survey-Based Examination of Disclosure Practices. AB - Street harassment may be considered an "unspeakable" harm on account of the routine silencing and trivialization of victims' experiences. Disclosing street harassment is vital in making its harms visible and in working to transform social and cultural attitudes. Despite a recent resurgence of interest in street harassment via online activist groups, there is scant research on disclosure practices. Drawing on findings from an online, mixed-methods survey with 292 participants who have experienced street harassment, I examine disclosure practices using an intersectional lens. I argue that disclosure is an epistemological process, through which a limited and partial understanding of street harassment is produced. PMID- 29759042 TI - Melatonin prevents and ameliorates lead-induced gonadotoxicity through antioxidative and hormonal mechanisms. AB - We investigated the effects of melatonin on sperm parameters and some biochemical markers in lead-exposed male Wistar rats. Lead (50 mg/kg bw/day) and/or melatonin (4 mg/kg or 10 mg/kg bw/day) was administered for 4 weeks, while 2-week lead exposure was preceded by or followed by 2-week treatment with both doses of melatonin in other groups. Lead reduced glutathione, catalase, adjusted testes weight, semen parameters but did not change malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase, and total antioxidant capacity. Though independent of prolactin, lead-induced gonadotoxicity was both centrally and peripherally mediated, as it reduced gonadotropin-releasing hormone and testosterone levels, while gonadotropin levels did not change significantly probably due to negative feedback by elevated estradiol. However, pre-, simultaneous, or posttreatment of lead-exposed rats with melatonin reduced MDA, SOD, and estradiol but dose-dependently increased other parameters. Conclusively, lead causes male gonadotoxicity through oxidative stress and endocrine mechanisms, and these could be dose-dependently prevented and ameliorated by melatonin. PMID- 29759044 TI - Relationship Between Auditory Context and Visual Distance Perception: Effect of Musical Expertise in the Ability to Translate Reverberation Cues Into Room-Size Perception. AB - In a recently published work by our group [ Scientific Reports, 7, 7189 (2017)], we performed experiments of visual distance perception in two dark rooms with extremely different reverberation times: one anechoic ( T ~ 0.12 s) and the other reverberant ( T ~ 4 s). The perceived distance of the targets was systematically greater in the reverberant room when contrasted to the anechoic chamber. Participants also provided auditorily perceived room-size ratings which were greater for the reverberant room. Our hypothesis was that distance estimates are affected by room size, resulting in farther responses for the room perceived larger. Of much importance to the task was the subjects' ability to infer room size from reverberation. In this article, we report a postanalysis showing that participants having musical expertise were better able to extract and translate reverberation cues into room-size information than nonmusicians. However, the degree to which musical expertise affects visual distance estimates remains unclear. PMID- 29759045 TI - Neuropathological Developments in Sudden Infant Death Syndrome. AB - A wide variety of neuropathological abnormalities have been investigated in infants who have died of sudden infant death syndrome (SIDS). Issues which detracted from early studies included failure to use uniform definitions of SIDS and lack of appropriately matched control populations. Development of the triple risk model focused attention on the concept of an inherent susceptibility to unexpected death in certain infants, with research demonstrating a role for the neurotransmitter serotonin within the brainstem. However, it now appears that neuropathological abnormalities in SIDS infants are more complex than a simple serotonergic deficiency in certain medullary nuclei but instead could involve failure of an integrated network of neurochemical transmitters in a variety of subcortical locations. The following overview examines recent research developments looking particularly at the potential role of the peptide neurotransmitter substance P and its neurokinin-1 receptor in multiple nuclei within the brainstem, asymmetry and microdysgenesis of the hippocampus, and decreased orexin levels within dorsomedial, perifornical, and lateral levels in the hypothalamus. Whether such research will lead to identifiable biomarker for infants at risk of SIDS is yet to be established. Use of standardized and consistent methods of classifying and categorizing infant deaths will be pivotal in generating reproducible research results. PMID- 29759046 TI - Classification of Preterm Birth With Placental Correlates. AB - Premature birth lacks a widely accepted classification that unites features of the clinical presentation with placental pathology. To further explore associations between the clinical categories of preterm birth and placental histology, 109 infants with gestational age <34 weeks and birth weight <2000 g were selected and, based on electronic records, were classified into preterm birth categories of preterm labor, prelabor premature rupture of membranes, preeclampsia, indicated preterm birth for maternal factors (other than preeclampsia), indicated preterm birth for fetal factors, and the clinical diagnosis of abruption. Corresponding placentas were analyzed for gross and microscopic variables, with findings grouped into categories of amniotic fluid infection, lymphocytic inflammation, maternal vascular malperfusion, and fetal vascular malperfusion. Placental features of maternal vascular malperfusion were pervasive in all preterm birth categories and were commonly associated with amniotic fluid infection and lymphocytic inflammation. Features of maternal vascular malperfusion were significantly associated with preterm birth due to preeclampsia, and amniotic fluid infection was highly associated with prelabor preterm rupture of membranes. Findings of lymphocytic inflammation were significantly increased in cases of abruption. Laminar decidual necrosis was present in all cases of abruption. Placentas from multiple gestations had significantly less histologic findings compared to singletons. Given that 75% of placentas demonstrated at least 1 feature of maternal vascular malperfusion despite different clinical presentations, seemingly different pathologies such as ascending amniotic fluid infection or lymphocytic inflammation may be mechanistically related to processes established early in pregnancy. The concept of "uterine ischemia" may be too simplistic to account for all of the changes attributed to maternal vascular malperfusion in the preterm placenta. PMID- 29759043 TI - Electrochemotherapy of Spinal Metastases Using Transpedicular Approach-A Numerical Feasibility Study. AB - Vertebral column is the most frequent site for bone metastases. It has been demonstrated in previous studies that bone metastases can be efficiently treated by electrochemotherapy. We developed a novel approach to treat spinal metastases, that is, transpedicular approach that combines electrochemotherapy with already established technologies for insertion of fixation screws in spinal surgery. In the transpedicular approach, needle electrodes are inserted into the vertebral body through pedicles and placed around the tumor. The main goal of our study was to numerically investigate the feasibility of the proposed treatment approach. Three clinical cases were used in this study-1 with a tumor completely contained within the vertebral body and 2 with tumors spread also to the pedicles and spinal canal. Anatomically accurate numerical models were built for all 3 cases, and numerical computations of electric field distribution in tumor and surrounding tissue were performed to determine the treatment outcome. Complete coverage of tumor volume with sufficiently high electric field is a prerequisite for successful electrochemotherapy. Close to 100% tumor coverage was obtained in all 3 cases studied. Two cases exhibited tumor coverage of >99%, while the coverage in the third case was 98.88%. Tumor tissue that remained untreated was positioned on the margin of the tumor volume. We also evaluated hypothetical damage to spinal cord and nerves. Only 1 case, which featured a tumor grown into the spinal canal, exhibited potential risk of neural damage. Our study shows that the proposed transpedicular approach to treat spinal metastases is feasible and safe if the majority of tumor volume is contained within the vertebral body. In cases where the spinal cord and nerves are contained within the margin of the tumor volume, a successful and safe treatment is still possible, but special attention needs to be given to evaluation of potential neural damage. PMID- 29759047 TI - Histological predictors of renal outcome in lupus nephritis: the importance of tubulointerstitial lesions and scoring of glomerular lesions. AB - Introduction Lupus nephritis (LN) affects nearly 60% of patients with systemic lupus erythematosus and up to 30% of them will progress to end-stage renal disease (ESRD), despite receiving aggressive immunosuppressive therapy. The prognostic value of ISN/RPS classification is controversial. Therefore, we aimed to identify clinical and pathological predictors of outcome in LN patients independent of this classification. Material and methods Thirty-seven patients with LN who underwent percutaneous kidney biopsy between 1997 and 2016 were included in this study. Twenty clinical and twenty histological variables were tested for their association with a composite end-point of doubling of serum creatinine, ESRD and death. Univariate and multivariate Cox proportional hazard regression analysis were performed to identify independent predictors of outcome. Results During a median follow-up period of 48 months (IQR: 17.5-120 months), 21.6% of patients reached the composite end-point. The overall survival rate of our cohort was 89% at one year, 86% at five years, 74% at 10 years and 64% at 20 years. Patients with Class IV LN showed the worst prognosis with 44% survival at 10 years, while those who additionally showed crescents and global sclerosis on kidney biopsy had an even lower survival of 21% and 0% at 10 years, respectively. After multivariate adjustment, we identified estimated glomerular filtration rate at baseline (HR, 0.91 per ml/min /1.73 m2; 95% CI, 0.84 to 0.99), 24-hour proteinuria at baseline (HR, 2.04 per g/d; 95% CI, 1.19 to 3.5), crescents (HR, 1.068 per %; 95% CI, 1.003 to 1.091), global sclerosis (HR, 1.036 per %; 95% CI, 0.984 to 1.091), presence of adhesions (HR, 9.2; 95% CI, 1.38 to 61.2) and tubulitis (HR, 13.1; 95% CI; 1.3 to 131) as independent predictors of outcome in our cohort of LN. Conclusions Our study identified glomerular (crescents, global sclerosis, adhesions) and tubulointerstitial (tubulitis) lesions, in addition to clinical variables (renal function, 24-hour proteinuria), as important predictors of renal outcome, independent of the ISN/RPS classification. We suggest that the ISN/RPS classification could be improved by a quantitative assessment of glomeruli with active and chronic lesions and by a greater emphasis given to tubulointerstitial lesions. PMID- 29759048 TI - Evaluation of ATG5 polymorphisms in Italian patients with systemic lupus erythematosus: contribution to disease susceptibility and clinical phenotypes. AB - Systemic lupus erythematosus (SLE) is a common heterogeneous autoimmune disease that is caused by the involvement both of genetic and environmental factors. There is evidence that autophagy is involved in several aspects of SLE pathogenesis. In particular, polymorphisms in the ATG5 gene have been observed to be associated with disease susceptibility. Our aim was to verify if ATG5 polymorphisms are involved in the susceptibility to disease and its clinical phenotypes in an Italian cohort of SLE patients. This study involved 315 SLE patients and 265 healthy controls. Three polymorphisms in the ATG5 gene (rs573775, rs6568431 and rs2245214) were investigated by allelic discrimination assay. A case-control association study, a genotype/phenotype correlation analysis and a haplotype study were performed. Moreover, an expression study was conducted in peripheral blood mononuclear cells from 15 SLE patients to verify a possible effect of the three SNPs on the expression of ATG5. Among the three investigated SNPs, only the rs573775 SNP was significantly associated with disease susceptibility with the variant allele conferring a higher risk of developing SLE (OR = 1.50, p = 0.018 and OR = 1.48, p = 0.007 at the genotypic and allelic level, respectively). The variant allele of rs6568431 SNP was more present in patients with anemia (OR = 1.86, p = 0.009) and renal involvement (OR = 1.63, p = 0.06), while the variant allele of rs2245214 SNP was significantly associated with a higher risk of producing anti-DNA autoantibodies (OR = 1.66, p = 0.04). Carriers of the rs6568431 variant allele showed higher messenger RNA levels compared to the carriers of the wild-type allele, suggesting also a potential variant allele dose-dependent effect on gene expression. In conclusion, our study confirms a role for ATG5 polymorphisms both in disease susceptibility and in the modulation of clinical phenotypes in an Italian SLE cohort. These results further suggest that genetic variations in autophagy genes could play a role in autoimmune diseases susceptibility and are worth further investigation. PMID- 29759049 TI - Klinefelter's syndrome with lupus encephalitis and retroperitoneal teratoma. AB - We report a case of a middle-aged male who presented with pyrexia of unknown origin, oral ulcers, rash and bicytopenia. His past medical history included unexplained proteinuria, infertility and joint pain. Initial workup showed a large retroperitoneal soft tissue mass, which has appeared stable for 10 years. He subsequently developed neuropsychiatric symptoms with imaging findings of meningoencephalitis. Concurrent investigations showed elevated ANA, anti-double stranded DNA (dsDNA) and ESR levels, as well as low complement levels. Bone marrow aspirate samples revealed karyotype of chromosome 47, XXY. The unifying diagnosis was therefore Klinefelter's syndrome (KS) with retroperitoneal teratoma and systemic lupus erythematosus (SLE), with manifestations of cytopenias, myositis, serositis, cutaneous vasculitis, encephalitis and nephritis. Upon commencing immunosuppressive therapy, there was dramatic improvement in his mental state and resolution of imaging findings. This case illustrates that males with KS may develop severe SLE manifestations; hence, increased diagnostic vigilance of KS in males with SLE is important in order to recognize effects of hypogonadism and other associations with KS such as retroperitoneal teratoma. PMID- 29759050 TI - European Board of Hand Surgery Diploma Examination 2017 (19-20th June, 2017, Budapest, Hungary). PMID- 29759051 TI - Clinical decision making in hand surgery. PMID- 29759052 TI - Hand surgery in Belgium. PMID- 29759054 TI - Successfully Navigating Multiple Electronic Health Records When Using Telepsychiatry: The NC-STeP Experience. AB - Telepsychiatry is a viable option for providing psychiatric care to those who are currently underserved or who lack access to services, but barriers to its widespread utilization remain. Use of different electronic health record systems (EHRs) by various health care systems is one such barrier. Utilization of different EHRs makes it difficult for providers to review patient data and to document clinical encounters. This column describes a Web portal developed by the North Carolina Statewide Telepsychiatry Program that connects participating hospital emergency departments and remote psychiatric providers, allowing them to share secure electronic health information regarding patient encounters across different EHRs. PMID- 29759053 TI - Histopathologic and Immunohistochemistry Findings in Feline Renal Cell Carcinoma. AB - The biological behavior and immunohistochemical features of feline renal cell carcinoma (RCC) have not been well characterized. In the present study, immunohistochemical examinations were performed in 12 feline cases of RCC. The RCC consisted of solid ( n = 2), solid-tubular ( n = 2), tubular ( n = 3), papillary ( n = 2), tubulopapillary ( n = 2), and sarcomatoid ( n = 1) type lesions. Of the cases with RCC, 1 developed metastatic disease and 6 cases had no evidence of recurrence at 80 to 2292 days after surgery. One papillary-type tumor had cuboidal cells with scant cytoplasm and monomorphic nuclei, and the other had pseudostratified columnar cells with abundant cytoplasm. Immunohistochemistry revealed that the tumor cells in most cases were positive for cytokeratin (CK)7, CK20, KIT, and CD10, with the exception of cases of the solid type with clear cytoplasm (solid anaplastic), papillary type with columnar cells, and sarcomatoid types. A small number of tumor cells in the solid anaplastic and in the sarcomatoid types were positive for aquaporin-1. Increased expression of N cadherin and Twist along with nuclear accumulation of beta-catenin were observed in the sarcomatoid type. These results indicated that CK, KIT, and CD10 are relatively strongly expressed in most feline RCC. The solid anaplastic RCC exhibited CD10 expression with the absence of distal tubule marker expression. Although immunohistochemistry profiles were relatively consistent with those described in human RCC, the histopathologic features were different from those seen in humans. Epithelial-mesenchymal transition (EMT) marker expression in the current cases may suggest the involvement of an EMT-like mechanism in the development of sarcomatoid RCC in cats. PMID- 29759055 TI - Results of a Coordinated Specialty Care Program for Early Psychosis and Predictors of Outcomes. AB - OBJECTIVE: This study prospectively evaluated outcomes of OnTrackNY, a statewide coordinated specialty care (CSC) program for treatment of early psychosis in community settings, as well as predictors of outcomes. METHODS: The sample included 325 individuals ages 16-30 with recent-onset nonaffective psychosis who were enrolled in OnTrackNY and who had at least one three-month follow-up. Clinicians provided data at baseline and quarterly up to one year. Domains assessed included demographic and clinical characteristics, social and occupational functioning, medications, suicidality and violence, hospitalization, and time to intervention. Primary outcomes included the symptoms, occupational functioning, and social functioning scales of the Global Assessment of Functioning (GAF), as adapted by the U.S. Department of Veterans Affairs Mental Illness Research, Education and Clinical Center; education and employment status; and psychiatric hospitalization rate. RESULTS: Education and employment rates increased from 40% to 80% by six months, hospitalization rates decreased from 70% to 10% by three months, and improvement in GAF scores continued for 12 months. Female gender, non-Hispanic white race-ethnicity, and more education at baseline predicted better education and employment status at follow-up. CONCLUSIONS: Individuals with early psychosis receiving CSC achieved significant improvements in education and employment and experienced a decrease in hospitalization rate. Demographic variables and baseline education predicted education and employment outcomes. CSC teams should make particular effort to support the occupational goals of individuals at increased risk of not engaging in work or school, including male participants and participants from racial and ethnic minority groups. PMID- 29759056 TI - Housing and Employment Outcomes for Mental Health Self-Direction Participants. AB - OBJECTIVE: In self-direction, participants control individual budgets, allocating service dollars according to needs and preferences within program parameters to meet self-defined recovery goals. Mental health self-direction is associated with enhanced wellness and recovery outcomes at lower or similar cost than traditional service arrangements. This study compared outcomes of housing independence and employment between individuals who participated in self-direction and those who did not. METHODS: This quasi-experimental study involved administrative data from 271 self-directing participants. Using coarsened exact matching with observed demographic, diagnostic, and other characteristics, the authors constructed a comparison group of non-self-directing individuals (N=1,099). The likelihood of achieving positive outcomes between first and last assessments during the approximately four-year study period was compared for self-directing and non-self directing individuals. RESULTS: Self-directing participants were more likely than nonparticipants to increase days worked for pay or maintain days worked at 20 or more days in the past 30 days (number needed to treat [NNT]=18; small effect size) and maintain or attain independent housing (NNT=16; small effect size), when analyses controlled, to the extent possible, for observed individual characteristics. CONCLUSIONS: Based on data from the nation's largest and longest standing program of its kind, results suggest that mental health self-direction is associated with modest improvements or maintenance of positive outcomes in employment and housing independence. This research adds to the literature examining self-direction in the context of mental health and begins to fill the need for a greater understanding of self-direction's relationship to outcomes of interest to service users and families, providers, and system administrators. PMID- 29759057 TI - Comparing Costs of Traditional and Specialty Probation for People With Serious Mental Illness. AB - OBJECTIVE: Specialty mental health probation reduces the likelihood of rearrest for people with mental illness, who are overrepresented in the justice system. This study tested whether specialty probation was associated with lower costs than traditional probation during the two years after placement in probation. METHODS: A longitudinal, matched study compared costs of behavioral health care and criminal justice contacts among 359 probationers with mental illness at prototypic specialty or traditional agencies. Compared with traditional officers, specialty officers supervised smaller caseloads, established better relationships with supervisees, and participated more in treatment. Participants and officers were interviewed, and administrative databases were integrated to capture service use and criminal justice contacts. Unit costs were attached to these data to estimate costs incurred by each participant over two years. Cost differences were estimated by using machine-learning algorithms combined with targeted maximum likelihood estimation (TMLE), a double-robust estimator that accounts for associations between confounders and both treatment assignment and outcomes. RESULTS: Specialty probation cost $11,826 (p<.001) less per participant than traditional probation, with overall savings of about 51%. Specialty and traditional probation did not differ in criminal justice costs because the additional costs for supervision of specialty caseloads were offset by reduced recidivism. However, for behavioral health care, specialty probation cost an estimated $14,049 (p<.001) less per client than traditional probation. Greater outpatient costs were more than offset by reduced emergency, inpatient, and residential costs. CONCLUSIONS: Well-implemented specialty probation yielded substantial savings-and should be considered in justice reform efforts for people with mental illness. PMID- 29759059 TI - Developmental Programming and Polycystic Ovarian Syndrome. PMID- 29759058 TI - Impact of Medical Homes on Expenditures and Utilization for Beneficiaries With Behavioral Health Conditions. AB - OBJECTIVE: Individuals with behavioral health conditions may benefit from enhanced care management provided by a patient-centered medical home (PCMH). In late 2011 and early 2012 Medicare began participating in PCMH initiatives in eight states through the Multi-Payer Advanced Primary Care Practice (MAPCP) demonstration. This study examined how the initiatives addressed the needs of patients with behavioral health conditions and the impacts of the demonstration on expenditures and utilization for this population. METHODS: Semistructured interviews provided insight into states' approaches to improving care, and multivariate difference-in-difference regressions of Medicare and Medicaid claims data were used to model changes in utilization and expenditures, comparing Medicare and Medicaid beneficiaries with behavioral health conditions in MAPCP demonstration practices with similar beneficiaries in non-PCMH primary care practices. Utilization included inpatient admissions and emergency department visits for all causes and for behavioral health conditions and outpatient visits for behavioral health conditions. Expenditure outcomes included expenditures for all services and those with a principal diagnosis of a behavioral health condition. RESULTS: Practices reported screening more patients for behavioral health conditions, linking patients to community-based behavioral health resources, and hiring behavioral health specialists to provide care. Several states embarked on unique initiatives to improve access to behavioral health services. However, few significant associations were found between participation in the MAPCP demonstration and utilization and expenditures for behavioral health services. CONCLUSIONS: Even though PCMHs made concerted efforts to improve access to care for their patients with behavioral health conditions, few substantial changes in patterns of care were noted. PMID- 29759060 TI - Correction to: Overweight adolescents' views on physical activity - experiences of participants in an internet-based intervention: a qualitative study. AB - Correction to: BMC Public Health (2018) 18: 448. https://doi.org/10.1186/s12889 018-5324-x . In the original version of this article [1], published on 4 April 2018, there was 1 incorrect author family name. The redundant affiliation (5) has also been removed. The original article has been updated. PMID- 29759061 TI - Role of ultrasound guided transversus abdominis plane block as a component of multimodal analgesic regimen for lower segment caesarean section: a randomized double blind clinical study. AB - BACKGROUND: While opioids are the mainstay for post-operative analgesia after lower segment caesarean section, they are associated with various untoward effects. Ultrasound guided transversus abdominis plane (TAP) block has been postulated to provide effective analgesia for caesarean section. We evaluated the analgesic efficacy of this block for post caesarean analgesia in a randomised controlled trial. METHODS: One hundred thirty-nine mothers undergoing caesarean delivery were randomised to receive TAP block with either 20 ml 0.375% ropivacaine or 20 ml saline after obtaining informed consent. All the subjects received a standard spinal anaesthetic and diclofenac was administered for post operative pain. Breakthrough pain was treated with tramadol. Post-operatively, all the subjects were assessed at 0, 2, 4, 6, 8, 10, 12, 18 & 24 h. The primary outcome was the time to first analgesic request. The secondary measures of outcome were pain, nausea, sedation, number of doses of tramadol administered and satisfaction with the pain management. RESULTS: The median (interquartile range) time to first analgesic request was prolonged in the TAP group compared to the control group (p < 0.0001); 11 h (8,12) and 4 h (2.5,6) respectively. The median (interquartile range) number of doses of tramadol consumed in the TAP group was 0 (0,1) compared to 2 (1,2) in the control group (p < 0.0001). At all points in the study, pain scores both at rest and on movement were lower in the study group (p < 0.0001). Maternal satisfaction with pain relief was also higher in the study group (p 0.0002). One subject in the TAP group had convulsions following injection of local anaesthetic solution. She was managed conservatively with supportive treatment following which she recovered. CONCLUSION: TAP block reduces pain, prolongs the duration of analgesia and decreases supplemental opioid consumption when used for multimodal analgesia for pain relief after caesarean section. However, the risk of local anaesthetic systemic toxicity remains unknown with this block. Hence larger safety trials and measures to limit this complication need to be ascertained. TRIAL REGISTRATION: The trial was registered with the Clinical Trial Registry of India ( CTRI/2017/03/008194 ) on 23/03/2017 (trial registered retrospectively). PMID- 29759063 TI - Discontinuation of the PACE Plus trial: problems in patient recruitment in general practice. AB - BACKGROUND: The PACE Plus trial was a multi-center, double-blinded, superiority randomized controlled trial (RCT) conducted in patients from Dutch general practice to investigate the efficacy of paracetamol and NSAIDs in acute non specific low back pain (LBP). Because insufficient numbers of patients could be recruited (only four out of the required 800 patients could be recruited over a period of 6 months), the trial was prematurely terminated in February 2017, 6 months after the start of recruitment. This article aims to transparently communicate the discontinuation of PACE Plus and to make recommendations for future studies. METHODS: General Practitioners (GPs) from 36 participating practices received a one-question survey in which they were asked to give the three most important factors that in their opinion contributed to failure of patient recruitment. RESULTS: GPs of 33 out of 36 (92%) participating practices sent a response. A total of 81 factors were reported. These have been categorized into patient factors (26 out of 81 comments, 32%), GP factors (39 out of 81 comments, 48%) and research factors (16 out of 81 comments, 20%). DISCUSSION: Patient recruitment in the PACE Plus trial may have failed due to inefficient medication distribution, recruitment of incident rather than prevalent cases, a design that was too complicated, adequate self-management of LBP, patient expectations different from the trial's scope and lack of time of participating GPs. Substantial differences in design may explain why the preceding PACE trial did manage to successfully complete patient recruitment. CONCLUSION: Although the PACE Plus trial was terminated as a result of insufficient patient inclusion, the research questions addressed in this trial remain relevant but unanswered. We hope that lessons learned from the discontinuation of PACE Plus and corresponding recommendations may be helpful in the design of upcoming research projects in LBP in general practice. TRIAL REGISTRATION: Dutch Trial Registration NTR6089, registered September 14th 2016. PMID- 29759062 TI - Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury. AB - BACKGROUND: Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae. Preserving or rescuing BBB integrity and homeostasis therefore represents a translational research area of high therapeutic potential. METHODS: Induction of general and localized BBB disruption in mice was carried out using systemic administration of LPS and focal photothrombotic ischemic insult, respectively, in the presence and absence of the monoacylglycerol lipase (MAGL) inhibitor, CPD-4645. The effects of CPD-4645 treatment were assessed by gene expression analysis performed on neurovascular enriched brain fractions, cytokine and inflammatory mediator measurement, and functional assessment of BBB permeability. The mechanism of action of CPD-4645 was studied pharmacologically using inverse agonists/antagonists of the cannabinoid receptors CB1 and CB2. RESULTS: Here, we demonstrate that the neurovasculature exhibits a unique transcriptional signature following inflammatory insults, and pharmacological inhibition of MAGL using a newly characterized inhibitor rescues the transcriptional profile of brain vasculature and restores its functional homeostasis. This pronounced effect of MAGL inhibition on blood-brain barrier permeability is evident following both systemic inflammatory and localized ischemic insults. Mechanistically, the protective effects of the MAGL inhibitor are partially mediated by cannabinoid receptor signaling in the ischemic brain insult. CONCLUSIONS: Our results support considering MAGL inhibitors as potential therapeutics for BBB dysfunction and cerebral edema associated with inflammatory brain insults. PMID- 29759064 TI - Propolis ethanolic extracts reduce adenosine diphosphate induced platelet aggregation determined on whole blood. AB - BACKGROUND: Propolis is a well-known bee product containing more than 2000 identified compounds. It has many beneficial effects on human health that include antibacterial, antiviral, anticancer and hepatoprotective justifying its use as a dietary supplement. Platelet aggregation plays crucial role in thrombus formation that can cause stroke or heart attacks. As cardiovascular diseases, including those caused by thrombus formation, are related to 50% of deaths of Western population, the objective of this study was to determine antiaggregatory activity of propolis on platelet aggregation on the whole blood samples. METHODS: Twenty one propolis samples from Southeast Europe were characterized by spectrophotometric methods to determine content of the total flavonoids and phenolic acids. High performance liquid chromatography coupled with diode array detection was used to identify and quantify individual polyphenols. Platelet aggregation was tested by impedance aggregometry on the whole blood samples of ten healthy volunteers. RESULTS: The mean content of total polyphenols was 136.14 mg/g and ranged from 59.23 to 277.39 mg/g. Content of total flavonoids ranged between 6.83 and 55.44 mg/g with the mean value of 19.28 mg/g. Percentage of total phenolic acids was in the range 8.79 to 45.67% (mean 26.63%). Minimal antiaggregatory concentration, representing the lowest concentration of propolis extract sample that can cause statistically significant reduction of aggregation, ranged from 5 MUM to 10.4 mM. Samples of propolis with lower content of luteolin and higher content of pinocembrin-7-methyleter showed better antiplatelet activity i.e. lower values of minimal antiaggregatory concentration. CONCLUSIONS: This is the first study that shows antiaggregatory potential of propolis ethanolic extracts on the whole blood samples in the low micromolar concentrations suggesting that propolis supplementation may influence platelet aggregation and consequently thrombus formation. Further in vivo studies are needed to confirm the beneficial effects in prevention of cardiovascular diseases. PMID- 29759066 TI - Prevalence and comorbidity of osteoporosis- a cross-sectional analysis on 10,660 adults aged 50 years and older in Germany. AB - BACKGROUND: Knowledge on prevalence of osteoporosis stratifying for socioeconomic background is insufficient in Germany. Little is known in Europe about other diseases that go along with it although these aspects are important for implementing effective public health strategies. METHODS: This cross-sectional analysis was based on the national telephone survey "German Health Update" (GEDA 2012) performed in 2012/2013. GEDA 2012 provides information on self-reported diseases and sociodemographic characteristics for nearly 20,000 adults. Descriptive statistical analysis and multiple logistic regression were used to examine the association between osteoporosis and age, sex, other diseases and education defined by ISCED. Analyses were limited to participants aged 50 years and older. RESULTS: Overall, 8.7% of the 10,660 participants aged 50+ years had osteoporosis (men 4.7%, women 12.2%). More than 95% of the adults with osteoporosis had at least one coexisting disease. The odds for arthrosis (OR 3.3, 95% CI 2.6-4.1), arthritis (OR 3.0, 95% CI 2.2-4.2), chronic low back pain (OR 2.8, 95% CI 2.3-3.5), depression (OR 2.3, 95% CI 1.7-3.1) and chronic heart failure (OR 2.3, 95% CI 1.6-3.1), respectively, were greater for adults with osteoporosis. Education showed no significant association with osteoporosis. CONCLUSIONS: There was no clear evidence of socioeconomic differences regarding osteoporosis for adults in Germany. However, clinicians need to be aware that multimorbidity is very common in adults with osteoporosis. Health care interventions for osteoporosis could be improved by offering preventive care for other diseases that go along with it. Over- or under-diagnosis in different socioeconomic levels has to be further explored. PMID- 29759065 TI - High-resolution mapping of traffic related air pollution with Google street view cars and incidence of cardiovascular events within neighborhoods in Oakland, CA. AB - BACKGROUND: Some studies have linked long-term exposure to traffic related air pollutants (TRAP) with adverse cardiovascular health outcomes; however, previous studies have not linked highly variable concentrations of TRAP measured at street level within neighborhoods to cardiovascular health outcomes. METHODS: Long-term pollutant concentrations for nitrogen dioxide [NO2], nitric oxide [NO], and black carbon [BC] were obtained by street-level mobile monitoring on 30 m road segments and linked to residential addresses of 41,869 adults living in Oakland during 2010 to 2015. We fit Cox proportional hazard models to estimate the relationship between air pollution exposures and time to first cardiovascular event. Secondary analyses examined effect modification by diabetes and age. RESULTS: Long-term pollutant concentrations [mean, (standard deviation; SD)] for NO2, NO and BC were 9.9 ppb (SD 3.8), 4.9 ppb (SD 3.8), and 0.36 MUg/m3 (0.17) respectively. A one SD increase in NO2, NO and BC, was associated with a change in risk of a cardiovascular event of 3% (95% confidence interval [CI] -6% to 12%), 3% (95% CI 5% to 12%), and - 1% (95% CI -8% to 7%), respectively. Among the elderly (>=65 yrs), we found an increased risk of a cardiovascular event of 12% for NO2 (95% CI: 2%, 24%), 12% for NO (95% CI: 3%, 22%), and 7% for BC (95% CI: -3%, 17%) per one SD increase. We found no effect modification by diabetes. CONCLUSIONS: Street level differences in long-term exposure to TRAP were associated with higher risk of cardiovascular events among the elderly, indicating that within-neighborhood differences in TRAP are important to cardiovascular health. Associations among the general population were consistent with results found in previous studies, though not statistically significant. PMID- 29759068 TI - Childhood retinol-binding protein 4 (RBP4) levels predicting the 10-year risk of insulin resistance and metabolic syndrome: the BCAMS study. AB - BACKGROUND: Elevated retinol-binding protein 4 (RBP4) levels may contribute to the development of metabolic abnormalities, but prospective studies evaluating the association between childhood RBP4 levels and metabolic syndrome (MS) in adulthood are lacking. We investigated whether RBP4 levels during childhood predict cardiometabolic risk at 10-year follow-up. METHODS: The relationships between RBP4 levels, the established adipokines (leptin and adiponectin) and the components of MS were examined in 3445 school-aged children recruited in 2004 for the Beijing Child and Adolescent Metabolic Syndrome study. In 2015, 352 of these individuals completed an in-depth follow-up examination. RESULTS: Participants with higher childhood RBP4 levels had adverse cardiometabolic profiles at follow up. Those with incident or persistent MS had higher baseline RBP4 levels than those who never exhibited the elements of MS. Moreover, baseline RBP4 predicted hyperglycemia (OR per SD increase = 1.48, P = 0.009), elevated triglyceride (OR = 1.54, P < 0.001), elevated blood pressures (OR = 1.46, P = 0.015), MS (OR = 1.68, P = 0.002) and insulin resistance (OR = 1.44, P = 0.015) in the 10-year follow-up phase, independent of baseline BMI. Significant improvements were seen for the net reclassification improvement and integrated discrimination index after adding childhood RBP4 levels into the risk models using conventional cardiometabolic risk factors in predicting MS at follow-up (P < 0.05). Leptin and adiponectin demonstrated the expected associations with metabolic disorders. CONCLUSIONS: Childhood RBP4 serves as a risk factor for subsequent development of MS and its components, independent of pediatric obesity. Incorporating childhood RBP4 into conventional cardiometabolic risk assessment models significantly improves the prediction of MS. PMID- 29759067 TI - Small RNA profiling of low biomass samples: identification and removal of contaminants. AB - BACKGROUND: Sequencing-based analyses of low-biomass samples are known to be prone to misinterpretation due to the potential presence of contaminating molecules derived from laboratory reagents and environments. DNA contamination has been previously reported, yet contamination with RNA is usually considered to be very unlikely due to its inherent instability. Small RNAs (sRNAs) identified in tissues and bodily fluids, such as blood plasma, have implications for physiology and pathology, and therefore the potential to act as disease biomarkers. Thus, the possibility for RNA contaminants demands careful evaluation. RESULTS: Herein, we report on the presence of small RNA (sRNA) contaminants in widely used microRNA extraction kits and propose an approach for their depletion. We sequenced sRNAs extracted from human plasma samples and detected important levels of non-human (exogenous) sequences whose source could be traced to the microRNA extraction columns through a careful qPCR-based analysis of several laboratory reagents. Furthermore, we also detected the presence of artefactual sequences related to these contaminants in a range of published datasets, thereby arguing in particular for a re-evaluation of reports suggesting the presence of exogenous RNAs of microbial and dietary origin in blood plasma. To avoid artefacts in future experiments, we also devise several protocols for the removal of contaminant RNAs, define minimal amounts of starting material for artefact-free analyses, and confirm the reduction of contaminant levels for identification of bona fide sequences using 'ultra-clean' extraction kits. CONCLUSION: This is the first report on the presence of RNA molecules as contaminants in RNA extraction kits. The described protocols should be applied in the future to avoid confounding sRNA studies. PMID- 29759069 TI - Guillain-Barre syndrome risk among individuals infected with Zika virus: a multi country assessment. AB - BACKGROUND: Countries with ongoing outbreaks of Zika virus have observed a notable rise in reported cases of Guillain-Barre syndrome (GBS), with mounting evidence of a causal link between Zika virus infection and the neurological syndrome. However, the risk of GBS following a Zika virus infection is not well characterized. In this work, we used data from 11 locations with publicly available data to estimate the risk of GBS following an infection with Zika virus, as well as the location-specific incidence of infection and the number of suspect GBS cases reported per infection. METHODS: We built a mathematical inference framework utilizing data from 11 locations that had reported suspect Zika and GBS cases, two with completed outbreaks prior to 2015 (French Polynesia and Yap) and nine others in the Americas covering partial outbreaks and where transmission was ongoing as of early 2017. RESULTS: We estimated that 2.0 (95% credible interval 0.5-4.5) reported GBS cases may occur per 10,000 Zika virus infections. The frequency of reported suspect Zika cases varied substantially and was highly uncertain, with a mean of 0.11 (95% credible interval 0.01-0.24) suspect cases reported per infection. CONCLUSIONS: These estimates can help efforts to prepare for the GBS cases that may occur during Zika epidemics and highlight the need to better understand the relationship between infection and the reported incidence of clinical disease. PMID- 29759070 TI - Identifying frailty in primary care: a qualitative description of family physicians' gestalt impressions of their older adult patients. AB - BACKGROUND: Many tools exist to guide family physicians' impressions about frailty status of older adults, but no single tool, instrument, or set of criteria has emerged as most useful. The role of physicians' subjective impressions in frailty decisions has not been studied. This study explores how family physicians conceptualize frailty, and the factors that they consider when making subjective decisions about patients' frailty statuses. METHODS: Descriptive qualitative study of family physicians who practice in a large urban academic family medicine center as they participated in one-on-one "think-aloud" interviews about the frailty status of their patients aged 80 years and over. Of 23 eligible family physicians, 18 shared their impressions about the frailty status of their older adult patients and the factors influencing their decisions. Interviews were audio-recorded, transcribed, and thematically analyzed. RESULTS: Four themes were identified, the first of which described how physicians conceptualized frailty as a spectrum and dynamic in nature, but also struggled to conceptualize it without a formal definition in place. The remaining three themes described factors considered before determining patients' frailty statuses: physical characteristics (age, weight, medical conditions), functional characteristics (physical, cognitive, social) and living conditions (level of independence, availability of supports, physical environment). CONCLUSIONS: Family physicians viewed frailty as multifactorial, dynamic, and inclusive of functional and environmental factors. This conceptualization can be useful to make comprehensive and flexible evaluations of frailty status in conjunction with more objective frailty tools. PMID- 29759071 TI - Metformin attenuates triglyceride accumulation in HepG2 cells through decreasing stearyl-coenzyme A desaturase 1 expression. AB - BACKGROUND: The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased worldwide. Metformin decreases triglyceride (TG) accumulation in hepatocytes in vivo and in vitro. Stearyl-coenzyme A desaturase 1 (SCD1) knockout mice also show decreased liver TG accumulation; however, whether SCD1 plays a role in the effect of metformin on TG accumulation is unknown. Therefore, the aim of this study was to investigate whether SCD1 mediated the effect of metformin on TG accumulation. METHODS: HepG2 and AML12 cells were exposed to high glucose and high insulin with or without metformin. An adenovirus was used for the SCD1 knockdown and overexpression. The triglyceride level in cells was detected. The expression of related genes was detected by Western blot and quantitative real time PCR. A dual-luciferase reporter assay was used to determine the effect of metformin on the transcriptional activity of the SCD1 promoter. RESULTS: Metformin decreased TG accumulation to normal level in HepG2 cells exposed to high glucose and high insulin. The expression of SCD1 and fatty acid synthetase (FAS) was also decreased to normal level by metformin. Knockdown of SCD1 mimicked the effect of metformin on decreasing TG levels in AML12 cells, and the overexpression of SCD1 attenuated the effect of metformin on decreasing TG accumulation in HepG2 cells. The dual-luciferase reporter assay showed that the transcriptional activity of the SCD1 promoter (- 550/+ 199) after metformin treatment was 2-fold lower compared to control group in HepG2 cells. Additionally, the phosphorylation of AMPK after metformin treatment was 2-fold higher, and the expression of sterol regulatory element-binding protein-1c (SREBP 1c) after metformin treatment was about 2-fold lower compared to high glucose and high insulin group in HepG2 cells. CONCLUSIONS: Together, these results reveal that metformin reduces TG accumulation in HepG2 cells via inhibiting the expression of SCD1. PMID- 29759073 TI - Laparoscopic splenectomy for solitary splenic metastasis in a patient with ovarian cancer with a long disease-free interval: a case report. AB - BACKGROUND: In general, splenic metastasis of epithelial ovarian cancer is considered a terminal stage resulting in widespread metastasis. Solitary splenic metastasis of epithelial ovarian cancer is rare in patients with post-treatment ovarian cancer with long disease-free intervals. CASE PRESENTATION: We report a case of a 62-year-old Japanese woman who presented with elevated serum cancer antigen 125 due to a solitary splenic metastasis of ovarian cancer. She underwent primary open cytoreduction including resection of the right ovarian cancer and postoperative chemotherapy, followed by secondary open cytoreduction and additional postoperative chemotherapy. The disease-free interval was more than 5 years after the additional postoperative chemotherapy. She did not complain of any symptoms and there were no abnormal findings except for elevated cancer antigen 125. However, computed tomography and magnetic resonance imaging revealed a tumor of 6.5 * 4.5 cm in her spleen, and 18F-fluorodeoxyglucose positron emission tomography-computed tomography showed no other metastatic lesions. Laparoscopic splenectomy was performed as tertiary cytoreduction with a diagnosis of a solitary splenic metastasis. Her elevated cancer antigen 125 immediately decreased to within the normal range after the splenectomy. On microscopic examination, the tumor was grade 3 endometrioid adenocarcinoma localized in the spleen, consistent with the previous grade 3 endometrioid adenocarcinoma ovarian cancer. CONCLUSIONS: Elevated cancer antigen 125 is useful for early detection of metastasis of ovarian cancer. Computed tomography, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography-computed tomography are useful to evaluate whether splenic metastasis of ovarian cancer is solitary, and laparoscopic splenectomy is safe and feasible for a solitary splenic metastasis. PMID- 29759072 TI - CHAT gene polymorphism rs3810950 is associated with the risk of Alzheimer's disease in the Czech population. AB - BACKGROUND: Cholinergic hypothesis of Alzheimer's disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer's disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer's aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before. METHODS: We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer's disease in a group of 1186 persons; 759 patients with Alzheimer's disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function. RESULTS: The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p < 0.002) thus demonstrating that the rs3810950 polymorphism can have a modest but statistically significant effect on the risk of AD in the Czech population. Furthermore, the molecular modelling indicated that the polymorphism is likely to be associated with significant variations in the tertiary structure of the protein molecule which may impact its enzyme activity. CONCLUSIONS: Our findings are consistent with the results of the meta-analytical studies of the relationship between rs3810950 polymorphism and AD and provide further material evidence for a direct (primary) involvement of cholinergic mechanisms in the etiopathogenesis of AD, particularly as a factor in cognitive decline and perturbed conscious awareness commonly observed in patients with AD. PMID- 29759074 TI - Dengue fever complicated with Guillain-Barre syndrome: a case report and review of the literature. AB - BACKGROUND: Dengue is an arboviral infection classically presenting with fever, arthralgia, headache, and rashes. It is hyperendemic in Sri Lanka and has a major impact on health. Neurological complications of dengue fever are rare but have been reported in the literature. CASE PRESENTATION: A 60-year-old Sri Lankan man presented with a history of fever, arthralgia, and generalized malaise of 2 days duration. A diagnosis of dengue was confirmed with leukopenia, thrombocytopenia, and positive NS1 antigen done on day 2 without evidence of hemoconcentration. On admission, our patient had weakness of the bilateral lower limbs, which progressed in an ascending pattern involving both upper limbs and neck muscles, requiring assisted ventilation. Electromyography confirmed a demyelinating polyneuropathy and cerebrospinal fluid showed albumincytological dissociation. He was treated with intravenous immunoglobulins and made an uneventful recovery. Subsequently, his immunoglobulin M test result for dengue virus was positive. CONCLUSIONS: Guillain-Barre syndrome is a rare but possible neurological sequel following dengue fever. In regions where dengue is hyperendemic, screening for dengue illness may be important in patients presenting with acute flaccid paralysis. PMID- 29759075 TI - Metabolic profiles in community-acquired pneumonia: developing assessment tools for disease severity. AB - BACKGROUND: This study aimed to determine whether community-acquired pneumonia (CAP) had a metabolic profile and whether this profile can be used for disease severity assessment. METHODS: A total of 175 individuals including 119 CAP patients and 56 controls were enrolled and divided into two cohorts. Serum samples from a discovery cohort (n = 102, including 38 non-severe CAP, 30 severe CAP, and 34 age and sex-matched controls) were determined by untargeted ultra high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) based metabolomics. Selected differential metabolites between CAP patients versus controls, and between the severe CAP group versus non-severe CAP group, were confirmed by targeted mass spectrometry assays in a validation cohort (n = 73, including 32 non-severe CAP, 19 severe CAP and 22 controls). Pearson's correlation analysis was performed to assess relationships between the identified metabolites and clinical severity of CAP. The area under the curve (AUC), sensitivity and specificity of the metabolites for predicting the severity of CAP were also investigated. RESULTS: The metabolic signature was markedly different between CAP patients and controls. Fifteen metabolites were found to be significantly dysregulated in CAP patients, which were mainly mapped to the metabolic pathways of sphingolipid, arginine, pyruvate and inositol phosphate. The alternation trends of five metabolites among the three groups including sphinganine, p-Cresol sulfate, dehydroepiandrosterone sulfate (DHEA-S), lactate and L-arginine in the validation cohort were consistent with those in the discovery cohort. Significantly lower concentrations of sphinganine, p-Cresol sulfate and DHEA-S were observed in CAP patients than in controls (p < 0.05). Serum lactate and sphinganine levels were positively correlated with confusion, urea level, respiratory rate, blood pressure, and age > 65 years (CURB-65), pneumonia severity index (PSI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, while DHEA-S inversely correlated with the three scoring systems. Combining lactate, sphinganine and DHEA-S as a metabolite panel for discriminating severe CAP from non-severe CAP exhibited a better AUC of 0.911 (95% confidence interval 0.825-0.998) than CURB-65, PSI and APACHE II scores. CONCLUSIONS: This study demonstrates that serum metabolomics approaches based on the LC-MS/MS platform can be applied as a tool to reveal metabolic changes during CAP and establish a metabolite signature related to disease severity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03093220 . Registered retrospectively on 28 March 2017. PMID- 29759077 TI - Regulating pharmaceutical companies' financial largesse. AB - Nissanholtz-Gannot and Yenkellevich (NGY) explore the impact of a 2010 amendment to the Israeli National Health Insurance Law that requires annual reporting of payments from pharmaceutical companies (PCs) to doctors and healthcare organizations. The amendment was adopted to ensure transparency and to facilitate appropriate regulation of interest conflicts. To learn whether the amendment was having the desired effects, NGY interviewed multiple representatives of an assortment of stakeholders. They found broad agreement among the respondents that financial relationships between PCs and physicians should be transparent. But they also discovered that ignorance of the 2010 amendment was widespread, especially among physicians, and that knowledgeable respondents thought loopholes rendered the law ineffective. Lastly, NGY found that the improvement in the transparency culture has more to do with pressure put by international and non Israeli national actors on the multi-national PCs operating in Israel than with the Israeli new law.In this short paper we critically review NGY's study. We are much less optimistic than they are about the situation in Israel. For example, we show that the new law has not increased transparency vis-a-vis the patients as virtually all reports to the government specify only the institutions receiving them and not individual physicians' names. We are skeptical of the effectiveness of self-regulation or government regulation. Instead, we propose some ways to increase patients' oversight, such as facilitation of class actions to enforce fiduciary duties and disclosures, as well as structuring co-payments for drugs in ways which will signal to the patients their relative efficacy. PMID- 29759076 TI - Threats of Zika virus transmission for Asia and its Hindu-Kush Himalayan region. AB - Asia and its Hindu Kush Himalayan (HKH) region is particularly vulnerable to environmental change, especially climate and land use changes further influenced by rapid population growth, high level of poverty and unsustainable development. Asia has been a hotspot of dengue fever and chikungunya mainly due to its dense human population, unplanned urbanization and poverty. In an urban cycle, dengue virus (DENV) and chikungunya virus (CHIKV) are transmitted by Aedes aegypti and Ae. albopictus mosquitoes which are also competent vectors of Zika virus (ZIKV). Over the last decade, DENV and CHIKV transmissions by Ae. aegypti have extended to the Himalayan countries of Bhutan and Nepal and ZIKV could follow in the footsteps of these viruses in the HKH region. The already established distribution of human-biting Aedes mosquito vectors and a naive population with lack of immunity against ZIKV places the HKH region at a higher risk of ZIKV. Some of the countries in the HKH region have already reported ZIKV cases. We have documented an increasing threat of ZIKV in Asia and its HKH region because of the high abundance and wide distribution of human-biting mosquito vectors, climate change, poverty, report of indigenous cases in the region, increasing numbers of imported cases and a naive population with lack of immunity against ZIKV. An outbreak anywhere is potentially a threat everywhere. Therefore, in order to ensure international health security, all efforts to prevent, detect, and respond to ZIKV ought to be intensified now in Asia and its HKH region. To prepare for possible ZIKV outbreaks, Asia and the HKH region can also learn from the success stories and strategies adopted by other regions and countries in preventing ZIKV and associated complications. The future control strategies for DENV, CHIKV and ZIKV should be considered in tandem with the threat to human well-being that is posed by other emerging and re-emerging vector-borne and zoonotic diseases, and by the continuing urgent need to strengthen public primary healthcare systems in the region. PMID- 29759079 TI - S-allylcysteine suppresses ovarian cancer cell proliferation by DNA methylation through DNMT1. AB - BACKGROUND: The anti-tumor effects of S-allylcysteine (SAC), a water-soluble garlic derivative, on human ovarian cancer cells have been previous studied in vitro and in vivo models but the precise epigenetic molecular mechanisms are still unclear. This study aimed to investigate the epigenetic mechanism of SAC. METHODS: Human epithelial ovarian cancer cell line A2780 was selected. Cell proliferation and cell cycle was analyzed. DNA methylation, DNA methyltransferase (DNMT) activity, tumor suppressor gene expressions, as well as protein expression were analyzed. RESULTS: SAC could inhibit the proliferation of A2780 cells in dose- and time-dependent manners (the IC50 was 16.25 mmol/L and 5.25 mmol/L at 48 h and 72 h). Treatment of A2780 cells with SAC resulted in G1/S phase arrest. SAC treatment decreased global DNA methylation levels in A2780 cells in a dose dependent manner. SAC decreased the levels of 5-methylcytosine, DNMT activity, messenger RNA (mRNA) and protein levels of DNMT1. Additionally, SAC treatment resulted in re-expression of the mRNA and proteins of silenced tumor suppressor gene CDKN1A accompany with reduced cell division control 2 expression. CONCLUSION: Our data indicated the potential therapeutic effects of SAC on the human ovarian carcinoma cell line A2780 in vitro. The epigenetic mechanism of action of SAC may have important implications for epigenetic therapy. PMID- 29759080 TI - Zika virus crosses an in vitro human blood brain barrier model. AB - Zika virus (ZIKV) is a flavivirus that is highly neurotropic causing congenital abnormalities and neurological damage to the central nervous systems (CNS). In this study, we used a human induced pluripotent stem cell (iPSC)-derived blood brain barrier (BBB) model to demonstrate that ZIKV can infect brain endothelial cells (i-BECs) without compromising the BBB barrier integrity or permeability. Although no disruption to the BBB was observed post-infection, ZIKV particles were released on the abluminal side of the BBB model and infected underlying iPSC derived neural progenitor cells (i-NPs). AXL, a putative ZIKV cellular entry receptor, was also highly expressed in ZIKV-susceptible i-BEC and i-NPs. This iPSC-derived BBB model can help elucidate the mechanism by which ZIKV can infect BECs, cross the BBB and gain access to the CNS. PMID- 29759081 TI - Comparative study of the paraspinal muscles after OVF between the insufficient union and sufficient union using MRI. AB - BACKGROUND: Identification of poor prognostic factors for OVF is important but has not yet been clearly established. Despite paraspinal muscles could play an important role in the etiology of OVF, what influence time-dependent changes in paraspinal muscles have after OVF, and the impact on conservative treatments for patients who have an OVF remain largely unknown. The purposes of this study were to (1) evaluate time-dependent changes of the paraspinal musculature using MRI after injury in patients with osteoporotic vertebral fractures (OVFs), and (2) compare paraspinal muscles between conservatively treated patients with OVF who have successful union and those failed to conservative treatment. METHODS: A total of 115 consecutive patients who had sustained a recent OVF injury in the thoracolumbar region were assessed for eligibility using medical records and all required data were available from 90 patients who had been followed up for at least 6 months. Patients who needed to undergo surgery and patients who were diagnosed as having insufficient union after 6 months of follow-up were assigned to a group with insufficient union. Lumbar trunk parameters, relative cross sectional area (rCSA) and proportion of fat infiltration (FI%) were calculated from MRI. To evaluate the time-dependent changes in the paraspinal muscle in patients after OVF injury, correlations between the timing of MRI and rCSA, FI% were determined. To clarify the impact of paraspinal muscles on the outcome of conservative treatments of patients with OVF, we compared rCSA between the groups. RESULTS: Sixty-five patients were assigned to a group with insufficient union and 25 patients were assigned to a group with successful union. FI% of the multifidus and erector spinae in the group with insufficient union were significantly greater than in the group with union. The timing of MRI in relation to initial injury was significantly correlated with FI% of the multifidus and erector spinae. rCSA of the erector spinae was significantly larger in the group with successful union than in the group with insufficient union. CONCLUSIONS: These findings indicated a time-dependent increase of fatty degeneration of the multifidus and erector muscles, but no change in the rCSA and larger rCSAs of spinal erectors may play a role in successful union in patients with OVF. PMID- 29759078 TI - Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis. AB - BACKGROUND: Microglial activation contributes to the neuropathology associated with chronic alcohol exposure and withdrawal, including the expression of inflammatory and anti-inflammatory genes. In the current study, we examined the transcriptome of primary rat microglial cells following incubation with alcohol alone, or alcohol together with a robust inflammatory stimulus. METHODS: Primary microglia were prepared from mixed rat glial cultures. Cells were incubated with 75 mM ethanol alone or with proinflammatory cytokines ("TII": IL1beta, IFNgamma, and TNFalpha). Isolated mRNA was used for RNAseq analysis and qPCR. Effects of alcohol on phagocytosis were determined by uptake of oligomeric amyloid beta. RESULTS: Alcohol induced nitrite production in control cells and increased nitrite production in cells co-treated with TII. RNAseq analysis of microglia exposed for 24 h to alcohol identified 312 differentially expressed mRNAs ("Alc DEs"), with changes confirmed by qPCR analysis. Gene ontology analysis identified phagosome as one of the highest-ranking KEGG pathways including transcripts regulating phagocytosis. Alcohol also increased several complement-related mRNAs that have roles in phagocytosis, including C1qa, b, and c; C3; and C3aR1. RNAseq analysis identified over 3000 differentially expressed mRNAs in microglia following overnight incubation with TII; and comparison to the group of Alc-DEs revealed 87 mRNAs modulated by alcohol but not by TII, including C1qa, b, and c. Consistent with observed changes in phagocytosis-related mRNAs, the uptake of amyloid beta1-42, by primary microglia, was reduced by alcohol. CONCLUSIONS: Our results define alterations that occur to microglial gene expression following alcohol exposure and suggest that alcohol effects on phagocytosis could contribute to the development of Alzheimer's disease. PMID- 29759083 TI - Hypertrophic osteoarthropathy mimicking a reactive arthritis: a case report and review of the literature. AB - BACKGROUND: Hypertrophic osteoarthropathy (HOA) is a syndrome characterized by abnormal proliferation of skin and periosteal tissues of the extremities. It can be a rare hereditary disease (pachydermoperiostosis) or can be secondary to various diseases, though mostly lung malignancies. Here, we report an unusual clinical presentation of HOA. CASE PRESENTATION: A 77-year-old man presented with fever, diarrhea, and an oligoarthritis involving the left knee and the ankles. Since left knee synovial fluid aspiration revealed an aseptic synovitis and Clostridium Difficile toxin was detectable in stool samples, a reactive arthritis secondary to a Clostridium Difficile induced colitis was initially suspected. However, the presence of a worsened digital clubbing and the lack of a good clinical response to steroid therapy led us to perform a radionuclide bone scanning, which revealed HOA. This turned out to be associated with a lepidic predominant lung adenocarcinoma, which was clinically and radiologically difficult to distinguish from a relapse of pneumonia. CONCLUSION: Consistent with the literature, HOA tends to have a variable clinical presentation, mimicking that of various rheumatic diseases. This clinical case shows that HOA can present as a presumptive acute reactive arthritis, and it highlights the importance of patient's follow-up in the differential diagnosis of inflammatory arthritis, especially when a worsened digital clubbing is present. PMID- 29759082 TI - Barriers to identifying eating disorders in pregnancy and in the postnatal period: a qualitative approach. AB - BACKGROUND: Eating Disorders (ED) are mental health disorders that typically effect women of childbearing age and are associated with adverse maternal and infant outcomes. UK healthcare guidance recommends routine enquiry for current and past mental illness in antenatal and postnatal care for all women, and that pregnant women with a known ED are offered enhanced monitoring and support. Midwives and health visitors are ideally placed to identify and support women with ED as they are often the primary point of contact during the antenatal and postnatal periods. However, research on the barriers to identifying ED in the perinatal period is limited. This study aimed to understand the barriers to disclosure and identification of ED in pregnancy and postnatally as perceived by women with past or current ED, and midwives and health visitors working in the UK National Health Service. METHODS: Two studies were undertaken: mixed-measures survey of pregnant and postnatal women with current or past ED; focus groups with student and qualified midwives and health visitors. RESULTS: Five themes emerged on the barriers to disclosure in pregnancy as perceived by women: stigma, lack of opportunity, preference for self-management, current ED symptomatology and illness awareness. Four themes were identified on the barriers to identification of ED in pregnancy and in the postnatal period as perceived by health professionals: system constraints, recognition of role, personal attitudes, and stigma and taboo. CONCLUSIONS: Several barriers to the identification of ED during and after pregnancy were described, the main factors were stigma and poor professional training. Perinatal mental health is becoming increasingly prioritised within national policy initiatives; however, ED continue to be neglected and increased awareness is needed. Similarly, clinical guidance aimed at responding to the rising prevalence of obesity focus on changing nutrition but not on assessing for the presence of ED behaviours that might be affecting nutrition. Improving education and training for health professionals may contribute to reducing stigma and increase confidence in identifying ED. The barriers identified in this research need to be addressed if recognition and response to women with ED during the perinatal period is to improve. PMID- 29759086 TI - Comprehensive nationwide analysis of mother-to-child HIV transmission in Finland from 1983 to 2013. AB - HIV-positive children are still born in Europe despite low mother-to-child transmission (MTCT) rates. We aimed to clarify the remaining barriers to the prevention of MTCT. By combining the national registers, we identified all women living with HIV delivering at least one child during 1983-2013. Of the 212 women delivering after HIV diagnosis, 46% were diagnosed during the pregnancy. In multivariate analysis, age >30 years (P = 0.001), sexual transmission (P = 0.012), living outside of the metropolitan area (P = 0.001) and Eastern European origin (P = 0.043) were risk factors for missed diagnosis before pregnancy. The proportion of immigrants increased from 18% before 1999 to 75% during 2011-2013 (P < 0.001). They were diagnosed during the pregnancy equally to natives and achieved similar, good treatment results. No MTCT occurred when the mother was diagnosed before the delivery. In addition, 12 women had delivered in 2 years prior their HIV diagnosis, most before implementation of the national screening of pregnant women. Three of these children were infected, the last one in 2000. Our data demonstrate that complete elimination of MTCT is feasible in a high income, low-prevalence country. This requires ongoing universal screening in early pregnancy and easy access to antiretroviral therapy to all HIV-positive people. PMID- 29759087 TI - Antechiniella septentrionalis n. sp. (Spirurida: Acuariidae), a new intestinal nematode parasite of the tundra vole Microtus oeconomus (Pallas) (Rodentia: Muridae) in the north-east of Russia. AB - Antechiniella septentrionalis n. sp. (Spirurida: Acuariidae) is described from the duodenum of a tundra vole, Microtus oeconomus (Pallas), collected in the Magadan region in the north-east part of Russia. It differs from A. suffodiax (Beveridge & Barker, 1975) and A. sertatum Smales, 1991 mainly in having a larger number of postcloacal papillae (5-6 pairs vs 4 pairs), a differently shaped left spicule, the disposition of precloacal papillae in two rows vs one, and oblong vs oval eggs. Other differences include the different disposition of ovaries in A. septentrionalis n. sp and A. suffodiax and the different structure of deirids in A. septentrionalis n. sp. and A. sertatum. The new species was characterized molecularly (partial sequences for 18S rRNA, 28S rRNA and cox1 mtDNA). The phylogenetic analyses performed showed the affinity of the new species to the members of the Acuariidae and other spirurid nematodes. PMID- 29759085 TI - Telepathology consultation for frozen section diagnosis in China. AB - BACKGROUND: Telepathology (TP) provides remote pathology services for primary diagnosis practices, including intraoperative consultation of surgical pathology; it has not been widely implemented in China. In this study, the results of an implementation were reported, which lasted for two and a half years, and demonstrated the experience of the diagnosis of the intraoperative frozen sections by using TP consultation platform of Southern Medical University and Guangzhou Huayin Medical Laboratory Center (SMU-HUAYIN TP) in China. METHODS: The SMU-HUAYIN TP consultation platform connects 71 participating basic hospitals and 11 senior pathologists. Nanfang Hospital is a high-level hospital located in a large city in China. This retrospective study summarizes the experience and results of TP for frozen section diagnosis by comparing the data of the platform and Nanfang Hospital over a period of 2.5 years from January 2015 to June 2017. RESULTS: A total of 5233 cases were submitted to the platform, including 1019 cases in 2015, 2320 cases in 2016, and 1894 cases in 2017. The most common cases were breast (30.42%), followed by thyroid (29.05%) and gynecological (24.86%). Average turn-around time (TAT) of the cases from the platform in 2015 and 2016 was controlled within 30 min. In most TP cases (90.31%) and cases from Nanfang Hospital (86.14%), a definitive diagnosis was provided. The coincidence rate was 99.77% in the TP cases and 99.35% in the cases from Nanfang Hospital. The false positive and false negative rates of TP cases were 0.04 and 0.19%, respectively and no significant difference was found among different senior pathologists (P = 0.974, P = 0.989, P > 0.05). Similarly, there was no significant difference between TP cases and cases from Nanfang Hospital that were diagnosed by the same senior pathologist (P > 0.05). CONCLUSIONS: Our results indicate that TP in frozen section diagnosis could improve patient care and solve the problem of unevenly distributed pathology resources in China. We believe that in the near future, TP in frozen section diagnosis will become an important component of telemedicine and will play a significant role in health care reform in China. PMID- 29759088 TI - MATERNAL EDUCATIONAL ATTAINMENT AND SEX RATIO AT BIRTH BY RACE IN THE UNITED STATES, 2007-2015. AB - SummaryMany factors influence the male:female birth ratio (number of male births divided by total births, M/T). Studies have suggested that this ratio may be positively correlated with the education levels of mothers. This study assessed the effect of maternal education on M/T in the US population overall and by racial group. Number of live births by sex of the child, maternal educational level reached and race were obtained from the Centres for Disease Control (CDC Wonder) for the period 2007-2015. The total study sample comprised 28,268,183 live births. Overall, for the four available recorded racial groups (Asian/Pacific Islander, White, American Indian/Alaska Native and Black/African American), M/T rose significantly with increasing education levels (p<0.0001). When analysed by race, this relationship was only found for White births (p<0.0001). The M/T of Black births rose with increasing maternal education level up to associate degree level (p=ns), then fell significantly with higher levels of education (chi 2=4.5, p=0.03). No significant trends were present for Asian/Pacific Islander or American Indian/Alaska Native births. Socioeconomic indicators are generally indicators of better condition and in this study educational attainment was overall found to be positively correlated with M/T, supporting the Trivers-Willard hypothesis. PMID- 29759084 TI - Sex differences in associations between maternal deprivation and alterations in hippocampal calcium-binding proteins and cognitive functions in rats. AB - BACKGROUND AND OBJECTIVE: Adverse early-life experiences have been suggested as one of the key contributors to neurodevelopmental disorders, such that these experiences influence brain development, cognitive ability and mental health. Previous studies indicated that hippocampal levels of the calcium-binding proteins calretinin (CALR) and calbindin-D28k (CALB) changed in response to maternal deprivation (MD), a model for adverse early-life experiences. We investigated the effects of MD on hippocampal CALR and CALB protein levels and cognitive behaviors, and explored whether these effects were sex-related. METHODS: From postnatal day 2 (PND-2) to PND-14, rat pups in the MD group were separated from their mothers for 3 h/day for comparison with pups raised normally (control). To determine hippocampal CALR and CALB levels, fluorescent immunostaining of hippocampal sections and Western blot analysis of hippocampal tissues were employed at various timepoints (PND-21, -25, -30, -35 and -40). Behavioral and cognitive changes were determined by open field test (PND-21) and Morris water maze (PND-25). RESULTS: Western blot analysis showed changes in the hippocampal CALR and CALB levels in both male and female MD groups, compared with controls. The open field test showed reduced exploration only in male MD groups but not female MD groups. The Morris water maze tests indicated that MD caused spatial memory impairment both in male and female rats, but there was a sex difference in CALR and CALB levels. CONCLUSIONS: Male rats are relatively more vulnerable to MD stress than female rats, but both male and female rats demonstrate spatial learning impairment after exposure to MD stress. Sex difference in CALR and CALB levels may reveal the different mechanisms behind the behavioral observations. PMID- 29759089 TI - Thrombocytopenia in bacteraemia and association with bacterial species. AB - Thrombocytopenia is common in patients with invasive bacterial infections. Bacteria can activate platelets, but it is unclear if this affects platelet count. The aim of this study was to examine whether bacteraemia with Staphylococcus aureus, which readily activate human platelets, was more likely to be complicated by thrombocytopenia than bacteraemia with Escherichia coli or Streptococcus pneumoniae with different abilities to activate platelets.We compared information from 600 adult patients with community-acquired bacteraemia with S. aureus (n = 140), E. coli (n = 420) and S. pneumoniae (n = 40) in Southern Sweden, 2012, linking information on positive blood cultures from microbiological databases and medical charts. The proportion of patients with thrombocytopenia (platelet count <150 * 109/ml) was calculated. Logistic regression was used to estimate the odds ratios (OR) for thrombocytopenia according to bacterial species adjusted for confounders.The proportion of thrombocytopenia was 29% in S. aureus, 28% in E. coli and 20% in S. pneumonia bacteraemia (P = 0.50), corresponding to an OR of 1.2 (95% confidence interval 0.7-1.9) for thrombocytopenia for S. aureus as compared with E. coli or S. pneumoniae, adjusted for confounders.This study indicates that platelet activation by bacteria is not a major causative mechanism in sepsis-associated thrombocytopenia. PMID- 29759090 TI - Perceived Discrimination and Emotional Reactions in People with Different Types of Disabilities: A Qualitative Approach. AB - The purpose of this study is to assess the discourse of people with disabilities regarding their perception of discrimination and stigma. Semi-structured interviews were conducted with ten adults with physical disabilities, ten with hearing impairments and seven with visual impairments. The agreement between the coders showed an excellent reliability for all three groups, with kappa coefficients between .82 and .96. Differences were assessed between the three groups regarding the types of discrimination they experienced and their most frequent emotional responses. People with physical disabilities mainly reported being stared at, undervalued, and subtly discriminated at work, whereas people with hearing impairments mainly reported encountering barriers in leisure activities, and people with visual impairments spoke of a lack of equal opportunities, mockery and/or bullying, and overprotection. Regarding their emotional reactions, people with physical disabilities mainly reported feeling anxious and depressed, whereas people with hearing impairments reported feeling helpless, and people with visual impairments reported feeling anger and self pity. Findings are relevant to guide future research and interventions on the stigma of disability. PMID- 29759091 TI - Developmental and Gender Differences in the Production of the Past Tense in Spanish Children. AB - This study investigates gender differences in children's linguistic development of Spanish past tense verbs. Two groups of 30 children, each consisting of 15 girls and 15 boys, were studied: Preschool children (5 years old) and 1st grade (7 years old). Participants carried out an elicitation task where a verbal change from present to past tense was required. Frequency and regularity variables were introduced as experimental factors to study differences between gender and age. The results showed that morphological rules were more successfully applied in 1st grade than in preschool children. Youngest participants showed a greatest influence of lexical variables, such as verb frequency and produced more omission and repetition errors. Gender differences only appeared in the oldest children, with girls being more affected by verb frequency and regularity. Girls also demonstrated a broader vocabulary than boys as shown by the qualitative analyses. PMID- 29759093 TI - Validation of a novel image-weighed technique for monitoring food intake and estimation of portion size in hospital settings: a pilot study. AB - OBJECTIVE: Optimal nutrition for hospital patients is crucial and routine monitoring of patients' nutrient intake is imperative. However, personalised monitoring and customised intervention using traditional methods is challenging and labour-intensive, consequently it is often neglected in hospital settings. The present pilot study aimed to examine the reliability and validity of the Dietary Intake Monitoring System (DIMS) against the weighed food method (WFM). DESIGN: The DIMS 2.0 is composed of an integrated digital camera, weighing scale, radio-frequency identification sensor and WIFI connection for real-time image and weight dietary data acquisition and analysis. The DIMS equipment was used to collect data for a paired set of meals both before and after meal consumption at lunchtime. SETTING: Odense University Hospital, Denmark. SUBJECTS: Photos and weights of seventeen patient meals were captured. RESULTS: The results showed a significant correlation between DIMS and WFM for energy (r=0.99, P<0.01) and protein intake (r=0.98, P<0.01). Intraclass correlation coefficients (ICC) revealed a high degree of agreement among the four non-trained assessors for estimates of portion size of each food item before (0.88, P<0.01) and after consumption (0.99, P<0.01). The ICC for energy and protein intake were 0.99 (P<0.01) and 0.99 (P<0.01), respectively. Bland-Altman plots revealed no systematic bias. CONCLUSIONS: Considering the huge benefits associated with routine monitoring, technological advances have made it possible to develop a novel, easy-to-use DIMS that, according to the findings, is a valid alternative for use in hospital settings. PMID- 29759094 TI - ABSTRACTS SCANDINAVIAN COLLEGE OF NEUROPSYCHOPHARMACOLOGY SCNP 59th Annual Meeting, 11 - 13 April, 2018 Aarhus, Denmark. PMID- 29759092 TI - Cardiac function in children with premature ventricular contractions: the effect of omega-3 polyunsaturated fatty acid supplementation. AB - BACKGROUND: Premature ventricular contractions are accepted as benign in structurally normal hearts. However, reversible cardiomyopathy can sometimes develop. Omega-3 polyunsaturated fatty acids have anti-arrhythmic properties in animals and humans.AimWe evaluated left ventricular function in children with premature ventricular contractions with normal cardiac anatomy and assessed the impact of omega-3 fatty acid supplementation on left ventricular function in a prospective trial. METHODS: A total of 25 patients with premature ventricular contraction, with more than 2% premature ventricular contractions on 24-hour Holter electrocardiography, and 30 healthy patients were included into study. All patients underwent electrocardiography, left ventricular M-mode echocardiography, and myocardial performance index testing. Patients with premature ventricular contraction were given omega-3 fatty acids at a dose of 1 g/day for 3 months, and control echocardiography and 24-hour Holter electrocardiography were performed. Neither placebo nor omega-3 fatty acids were given to the control group. RESULTS: Compared with the values of the control group, the patients with premature ventricular contraction had significantly lower fractional shortening. The myocardial performance index decreased markedly in the patient groups. The mean heart rate and mean premature ventricular contraction percentage of Group 2 significantly decreased in comparison with their baseline values after the omega 3 supplementation. CONCLUSION: In conclusion, premature ventricular contractions can lead to systolic cardiac dysfunction in children. Omega-3 supplementation may improve cardiac function in children with premature ventricular contractions. This is the first study conducted in children to investigate the possible role of omega-3 fatty acid supplementation on treatment of premature ventricular contractions. PMID- 29759096 TI - Australian consumers' views towards an environmentally sustainable eating pattern. AB - OBJECTIVE: The present qualitative study aimed to gain an in-depth understanding of participants' attitudes, knowledge, perceived effectiveness (a person's belief that his/her behaviour can contribute to environmental preservation) and behaviours relating to a sustainable eating pattern. DESIGN: One-to-one interviews (either face-to-face or by telephone) were conducted following a structured interview schedule, audio-recorded, transcribed verbatim and analysed using inductive thematic analysis in NVivo 10. SETTING: Victorian (Australia) adult participants recruited via online advertisements, flyers on community advertisement boards and letterbox drops. SUBJECTS: Twenty-four participants (mean age 40 years, range 19-69 years; thirteen female, eleven male) were interviewed. RESULTS: Participants reported that environmental impact was not an important influence on their food choice. Participants displayed limited knowledge about a sustainable eating pattern, with most unaware of the environmental impact of food-related behaviours. Most participants believed sustainable eating would be only slightly beneficial to the environment. Participants reported undertaking limited sustainable food behaviours currently and were more willing to undertake a food behaviour if they perceived additional benefits, such as promoting health or supporting the local community. CONCLUSIONS: The study suggests consumers need further information about a sustainable eating pattern and the environmental impact of food choice. The findings highlight some of the barriers that will need to be addressed when promoting this kind of eating pattern and that a range of interventions will be necessary. PMID- 29759095 TI - Giant left ventricular rhabdomyoma treated successfully with everolimus: case report and review of literature. AB - : IntroductionIntracardiac rhabdomyomas can cause severe ventricular dysfunction and outflow tract obstruction.Case reportA term newborn infant with antenatal diagnosis of giant left ventricle rhabdomyoma presented with cardiac failure and duct-dependent systemic circulation after birth. She was treated successfully with everolimus, showing decrease in tumour size and improvement in left ventricular ejection fraction.DiscussionTumour regression rate was 0.32 cm2/day and improved to 0.80 cm2/day with the use of everolimus. Herein we report a newborn with inoperable giant left ventricular cardiac rhabdomyoma and significant regression of the tumour. To our knowledge, this is the largest left ventricular rhabdomyoma reported. A review of the literature was undertaken for comparison. CONCLUSION: Everolimus has proven to be efficacious in size reduction of cardiac rhabdomyomas in cases when surgical resection is not possible. PMID- 29759097 TI - The effect of proportional v. value pricing on fountain drink purchases: results from a field experiment. AB - OBJECTIVE: Reducing sugar-sweetened beverage consumption is a public health priority, yet finding an effective and acceptable policy intervention is challenging. One strategy is to use proportional pricing (a consistent price per fluid ounce) instead of the typical value-priced approach where large beverages offer better value. The purpose of the present study was to evaluate whether proportional pricing affects the purchasing of fountain beverages at a university cinema concession stand. DESIGN: Four price strategies for beverages were evaluated over ten weekends of film screenings. We manipulated two factors: the price structure (value pricing v. proportional pricing) and the provision of information about the price per fluid ounce (labels v. no labels). The key outcomes were the number and size of beverages purchased. We analysed data using regression analyses, with standard errors clustered by film and controlling for the day and time of purchase. SETTING: A university cinema concession stand in Minnesota, USA, in spring 2015. SUBJECTS: University students. RESULTS: Over the study period (360 beverages purchased) there were no significant effects of the proportional pricing treatment. Pairing a label with the standard value pricing increased the likelihood of purchasing large drinks but the label did not affect purchasing when paired with proportional pricing. CONCLUSIONS: Proportional prices did not significantly affect the size of beverages purchased by students at a university cinema, but adding a price-per-ounce label increased large drink purchases when drinks were value-priced. More work is needed to address whether pricing and labelling strategies might promote healthier beverage purchases. PMID- 29759098 TI - Psychological Flexibility as a Moderator of the Relationships between Job Demands and Resources and Occupational Well-being. AB - The aim of this study was to identify the relations of job demands (work overload) and job resources (social support and autonomy) with subjective job well-being (job satisfaction, positive affects, negative affects), as well as the moderating role of personal resources (psychological flexibility at work) in such relationships. The sample consisted of 4,867 Brazilian workers, of both sexes, with ages ranging from 18 to 67 years. Structural equation modelling showed that the work overload was negatively associated with job satisfaction (beta = -.06; p < .001) and positively with negative affects (beta = .24; p < .001); autonomy was positively associated with satisfaction (beta = .08; p < .001) and negative affects (beta = .08; p < .001); social support was positively associated with satisfaction (beta = .17; p < .001) and positive affects (beta = .20; p < .001), and negatively with negative affects (beta = -.21; p < .001); psychological flexibility moderated the relationships of overload with satisfaction (beta = .04; p < .05) and negative affects (beta = .08; p < .001); autonomy with positive affects (beta = -.06; p < .001) and social support with negative affects (beta = .08; p < .001). These results are discussed from perspective of a job demands resources theory, especially with respect to the relevance of personal resources for the promotion of occupational well-being. PMID- 29759099 TI - Procedural sedation by advanced care paramedics for emergency gastrointestinal endoscopy. AB - CLINICIAN'S CAPSULE What is known about the topic? Advanced care paramedics (ACPs) in our emergency department (ED) successfully perform procedural sedation and analgesia (PSA) for several procedures, including orthopedic manipulations. What did this study ask? How does the novel practice of ACP-led ED PSA for upper gastrointestinal (UGI) endoscopy compare to that for orthopedic procedures? What did this study find? Adverse events occurred more frequently during UGI endoscopy sedations than orthopedic sedations (41.0% v. 17.5%), with hypotension occurring most often. Why does this study matter to clinicians? ACP-led ED PSA may be expanded to include UGI endoscopy when the risk of hemodynamic compromise is taken into account. PMID- 29759100 TI - Development and validation of the Child Three-Factor Eating Questionnaire (CTFEQr17). AB - OBJECTIVE: To develop and validate a child and adolescent version of the Three Factor Eating Questionnaire (CTFEQr17) and to assess its psychometric properties and factor structure. We also examined associations between the CTFEQr17 and BMI and food preferences. DESIGN: A two-phase approach was utilized, employing both qualitative and quantitative methodologies. SETTING: Primary and secondary schools, UK. SUBJECTS: In phase 1, seventy-six children (thirty-nine boys; mean age 12.3 (sd 1.4) years) were interviewed to ascertain their understanding of the original TFEQr21 and to develop accessible and understandable items to create the CTFEQr17. In phase 2, 433 children (230 boys; mean age 12.0 (sd 1.7) years) completed the CTFEQr17 and a food preference questionnaire, a sub-sample (n 253; 131 boys) had their height and weight measured, and forty-five children (twenty three boys) were interviewed to determine their understanding of the CTFEQr17. RESULTS: The CTFEQr17 showed good internal consistency (Cronbach's alpha=0.85) and the three-factor structure was retained: cognitive restraint (CR), uncontrolled eating (UE) and emotional eating (EE). Qualitative data demonstrated a high level of understanding of the questionnaire (95 %). High CR was found to be significantly associated with a higher body weight, BMI and BMI percentile. High UE and EE scores were related to a preference for high-fat savoury and high fat sweet foods. The relationships between CTFEQr17, anthropometry and food preferences were stronger for girls than boys. CONCLUSIONS: The CTFEQr17 is a psychometrically sound questionnaire for use in children and adolescents, and associated with anthropometric and food preference measures. PMID- 29759101 TI - Effect of the Health Tourism weight loss programme on body composition and health outcomes in healthy and excess-weight adults. AB - Excess weight loss while minimising fat-free mass (FFM) loss is important for health. Travel is a particular period at risk for weight gain and for which the effects of a short-term intensive weight loss programme have not been studied. Therefore, we studied the effect of a novel, 1-week supervised health travel programme combining high volume, low-to-moderate intensity exercise and energy intake restriction on weight, body composition and health outcomes in adults. Weight was also monitored for 12 weeks after the programme. In all, thirty-six subjects (nineteen men, seventeen women) consisting of sixteen excess-weight (BMI: 27.1 (sd 1.7) kg/m2) and twenty healthy-weight (BMI: 22.3 (sd 1.8) kg/m2) individuals participated. Subjects performed 1 h of slow-paced intermittent jogging three times per d and other leisure activities, whereas consuming only provided foods without water restriction. Body mass significantly decreased from pre- to post-intervention in excess-weight and healthy-weight individuals (-3.5 (sd 1.5) and -3.5 (sd 1.3) %, respectively; P<0.001 for both), and losses were maintained at 12 weeks post-intervention in both groups (-6.3 (sd 3.8) and -1.7 (sd 4.0) %, respectively; P<0.01 for both). Fat mass also significantly decreased in both groups (excess weight: -9.2 (sd 4.6) %: healthy weight: -13.4 (sd 9.0) %; P<0.01 for both), whereas FFM was maintained. Similar improvements were observed for blood biochemistry and pressure in both groups. This short-term weight loss intervention yielded favourable outcomes in both excess- and healthy-weight adults, particularly a 3.5 % weight loss with no significant change to FFM. In addition, participants maintained weight loss for at least 12 weeks. Of multiple programme choices, the Health Tourism weight loss programme's results indicate that it is a viable option. PMID- 29759103 TI - Dietary taste patterns by sex and weight status in the Netherlands. AB - Taste is a key driver of food choice and intake. Taste preferences are widely studied, unlike the diet's taste profile. This study assessed dietary taste patterns in the Netherlands by sex, BMI, age and education. A taste database, containing 476 foods' taste values, was combined with 2-d 24-h recalls in two study populations. The percentage of energy intake from six taste clusters was assessed in the Dutch National Food Consumption Survey (DNFCS 2007-2010; n 1351) and in an independent observational study: the Nutrition Questionnaires plus (NQplus) study (2011-2013; n 944). Dietary taste patterns were similar across study populations. Men consumed relatively more energy from 'salt, umami and fat' (DNFCS; 24 % energy, NQplus study; 23 %)- and 'bitter' (7 %)-tasting foods compared with women (21 %, P<0.001, 22 %, P=0.005; 3 %, P<0.001, 4 %, P<0.001, respectively). Women consumed more % energy from 'sweet and fat' (15 %)- and 'sweet and sour' (13 %, 12 %, respectively)-tasting foods compared with men (12 %, P<0.001, 13 %, P=0.001; 10 %, P<0.001). Obese individuals consumed more % energy from 'salt, umami and fat'- and less from 'sweet and fat'-tasting foods than normal-weight individuals ('salt, umami and fat', men; obese both studies 26 %, normal-weight DNFCS 23 %, P=0.037, NQplus 22 %, P=0.001, women; obese 23 %, 24 %, normal weight 20 %, P=0.004, P=0.011, respectively, 'sweet and fat', men; obese 11 %, 10 %, normal weight 13 %, P<0.05, 14 %, P<0.01, women; obese 14 %, 15 %, normal weight 16 %, P=0.12, P=0.99). In conclusion, our taste database can be used to deepen our understanding of the role of taste in dietary intake in the Netherlands by sex, BMI, age and education. PMID- 29759102 TI - Fruit and vegetable consumption and risk of depression: accumulative evidence from an updated systematic review and meta-analysis of epidemiological studies. AB - Findings from observational studies investigating the association between fruit and vegetable consumption and risk of depression were inconsistent. We conducted a systematic review and meta-analysis to summarise available data on the association between fruit and vegetable intake and depression. A systematic literature search of relevant reports published in Medline/PubMed, ISI (Web of Science), SCOPUS and Google Scholar until Oct 2017 was conducted. Data from 27 publications (sixteen cross-sectional, nine cohort and two case-control studies) on fruit, vegetables and/or total fruit and vegetable consumption in relation to depression were included in the systematic review. A total of eighteen studies that reported relative risks (RR), hazard ratios or OR for the relationship were included in the meta-analysis. The pooled RR for depression in the highest v. the lowest category of fruit intake was 0.83 (95 % CI 0.71, 0.98) in cohort studies and 0.76 (95 % CI 0.63, 0.92) in cross-sectional studies. Consumption of vegetables was also associated with a 14 % lower risk of depression (overall RR=0.86; 95 % CI 0.75, 0.98) in cohort studies and a 25 % lower risk of depression (overall RR=0.75; 95 % CI 0.62, 0.91) in cross-sectional studies. Moreover, an inverse significant association was observed between intake of total fruit and vegetables and risk of depression (overall RR=0.80; 95 % CI 0.65, 0.98) in cross-sectional studies. In a non-linear dose-response association, we failed to find any significant association between fruit or vegetable intake and risk of depression (fruit (cross-sectional studies): P non-linearty=0.12; vegetables (cross-sectional studies): P non-linearty<0.001; (cohort studies) P non linearty=0.97). Meta-regression of included observational studies revealed an inverse linear association between fruit or vegetable intake and risk of depression, such that every 100-g increased intake of fruit was associated with a 3 % reduced risk of depression in cohort studies (RR=0.97; 95 % CI 0.95, 0.99). With regard to vegetable consumption, every 100-g increase in intake was associated with a 3 % reduced risk of depression in cohort studies (RR=0.97; 95 % CI 0.95, 0.98) and 5 % reduced odds in cross-sectional studies (RR=0.95; 95 % CI 0.91, 0.98). This meta-analysis of observational studies provides further evidence that fruit and vegetable intake was protectively associated with depression. This finding supports the current recommendation of increasing fruit and vegetable intake to improve mental health. PMID- 29759104 TI - Delayed postprandial TAG peak after intake of SFA compared with PUFA in subjects with and without familial hypercholesterolaemia: a randomised controlled trial. AB - Postprandial hypertriacylglycerolaemia is associated with an increased risk of developing CVD. How fat quality influences postprandial lipid response is scarcely explored in subjects with familial hypercholesterolaemia (FH). The aim of this study was to investigate the postprandial response of TAG and lipid sub classes after consumption of high-fat meals with different fat quality in subjects with FH compared with normolipidaemic controls. A randomised controlled double-blind cross-over study with two meals and two groups was performed. A total of thirteen hypercholesterolaemic subjects with FH who discontinued lipid lowering treatment 4 weeks before and during the study, and fourteen normolipidaemic controls, were included. Subjects were aged 18-30 years and had a BMI of 18.5-30.0 kg/m2. Each meal consisted of a muffin containing 60 g (70 E%) of fat, either mainly SFA (40 E%) or PUFA (40 E%), eaten in a random order with a wash-out period of 3-5 weeks between the meals. Blood samples were collected at baseline (fasting) and 2, 4 and 6 h after intake of the meals. In both FH and control subjects, the level of TAG and the largest VLDL sub-classes peaked at 2 h after intake of PUFA and at 4 h after intake of SFA. No significant differences were found in TAG levels between meals or between groups (0.25<=P<=0.72). The distinct TAG peaks may reflect differences in the postprandial lipid metabolism after intake of fatty acids with different chain lengths and degrees of saturation. The clinical impact of these findings remains to be determined. PMID- 29759105 TI - The glycaemic index and insulinaemic index of commercially available breakfast and snack foods in an Asian population. AB - A low-glycaemic-index (GI) breakfast has been shown to lower blood glucose levels throughout the day. A wide variety of breakfast foods are consumed, but their GI values are largely unknown, hence limiting consumers' ability to select healthier options. This study investigated the GI values of ten common breakfast (five Asian and five Western) foods in this region using a randomised, cross-over study design. Participants arrived after an overnight fast, and fasting blood sample was taken before participants consumed test foods. Next, blood samples were taken at fixed intervals for 180 min. Glycaemic and insulinaemic responses to test foods were calculated as incremental AUC over 120 min, which were subsequently reported as glycaemic and insulinaemic indices. In all, nineteen healthy men (nine Chinese and ten Indians) aged 24.7 (sem 0.4) years with a BMI of 21.7 (sem 0.4) kg/m2 completed the study. Asian breakfast foods were of medium (white bun filled with red bean paste=58 (sem 4); Chinese steamed white bun=58 (sem 3)) to high GI (rice idli=85 (sem 4); rice dosa=76 (sem 5); upma=71 (sem 6)), whereas Western breakfast foods were all of low GI (whole-grain biscuit=54 (sem 5); whole grain biscuit filled with peanut butter=44 (sem 3); whole-grain oat muesli=55 (sem 4); whole-grain oat protein granola=51 (sem 4); whole-grain protein cereal=49 (sem 3)). The GI of test foods negatively correlated with protein (r s 0.366), fat (r s -0.268) and dietary fibre (r s -0.422) (all P<0.001). GI values from this study contribute to the worldwide GI database, and may assist healthcare professionals in recommending low-GI breakfast to assist in lower daily glycaemia among Asians who are susceptible to type 2 diabetes mellitus. PMID- 29759106 TI - Stage-specific feed intake restriction differentially regulates placental traits and proteome of goats. AB - A total of twenty-four healthy twin-bearing Liuyang black goats were allocated to two trials. In Trial 1, twelve goats received either the control diet (CG, n 6, 100 % feed) or restricted diet (RG, n 6, 60 % feed of CG) from gestation days 26 to 65 after synchronisation. In Trial 2, the remaining goats were randomly and equally divided into two treatments: CG and RG from days 95 to 125 of gestation. Placental traits, fetal weight, serum parameters, nitric oxide (NO), angiogenesis gene expression and cotyledon proteome were measured at the end of each trial. In early pregnancy, the total and relative weights of placenta, uterine caruncle and cotyledon, as well as fetus, were increased (P<0.05) in RG. The NO content in maternal serum was also increased (P<0.05) in RG. In all, fifty differentially expressed proteins were identified in cotyledon. The up-regulated proteins are related to proliferation and fission of trophoblast cell and the placenta angiogenesis. During the late pregnancy trial, placental weight was increased (P<0.05) in RG, but weight of the fetus was decreased (P<0.05). The capillary density in the cotyledon was also decreased (P<0.01). A total of fifty-eight proteins were differentially expressed in cotyledon. The up-regulated proteins in RG are related to placenta formation, blood flow regulation and embryonic development. These results indicated that feed intake restriction during gestation influenced the placental and fetal development in a stage-dependent manner. These findings have important implications for developing novel nutrient management strategies in goat production. PMID- 29759107 TI - Inulin supplementation reduces the negative effect of a high-fat diet rich in SFA on bone health of growing pigs. AB - Consumption of a high-fat diet, rich in SFA, causes deterioration of bone properties. Some studies suggest that feeding inulin to animals may increase mineral absorption and positively affect bone quality; however, these studies have been carried out only on rodents fed a standard diet. The primary objective of this study was to determine the effect of inulin on bone health of pigs (using it as an animal model for humans) fed a high-fat diet rich in SFA, having an unbalanced ratio of lysine:metabolisable energy. It was hypothesised that inulin reduces the negative effects of such a diet on bone health. At 50 d of age, twenty-one pigs were randomly allotted to three groups: the control (C) group fed a standard diet, and two experimental (T and TI) groups fed a high-fat diet rich in SFA. Moreover, TI pigs consumed an extra inulin supply (7 % of daily feed intake). After 10 weeks, whole-body bone mineral content (P=0.0054) and bone mineral density (P=0.0322) were higher in pigs of groups TI and C compared with those of group T. Femur bone mineral density was highest in pigs in group C, lower in group TI and lowest in group T (P=0.001). Femurs of pigs in groups TI and C had similar, but higher, maximum strength compared with femurs of pigs in group T (P=0.0082). In conclusion, consumption of a high-fat diet rich in SFA adversely affected bone health, but inulin supplementation in such a diet diminishes this negative effect. PMID- 29759108 TI - A Western dietary pattern is prospectively associated with cardio-metabolic traits and incidence of the metabolic syndrome. AB - The aim of this study was to derive dietary patterns associated with cardio metabolic traits and to examine whether these predict prospective changes in these traits and incidence of the metabolic syndrome (iMetS). Subjects from the Malmo Diet and Cancer Study cardiovascular cohort without cardio-metabolic disease and related drug treatments at baseline (n 4071; aged 45-67 years, 40 % men) were included. We applied reduced rank regression on thirty-eight foods to derive patterns that explain variation in response variables measured at baseline (waist circumference, TAG, HDL- and LDL-cholesterol, systolic and diastolic blood pressure, fasting glucose and insulin). Patterns were examined in relation to change in cardio-metabolic traits and iMetS in subjects who were re-examined after 16.7 years (n 2704). Two dietary patterns ('Western' and 'Drinker') were retained and explained 3.2 % of the variation in response variables. The 'Western' dietary pattern was inversely associated with HDL-cholesterol and positively with all other response variables (both at baseline and follow-up), but there was no association with LDL at follow-up. After adjustment for potential confounders, the 'Western' dietary pattern was associated with higher risk of iMetS (hazard ratio Q4 v. Q1: 1.47; 95 % CI 1.23, 1.77; P trend=1.5*10 5). The 'Drinker' dietary pattern primarily explained variation in HDL and was not associated with iMetS. In conclusion, this study supports current food-based dietary guidelines suggesting that a 'Western' dietary pattern with high intakes of sugar-sweetened beverages and red and processed meats and low intakes of wine, cheese, vegetables and high-fibre foods is associated with detrimental effects on cardio-metabolic health. PMID- 29759109 TI - Hypocholesterolaemic effect of whole-grain highland hull-less barley in rats fed a high-fat diet. AB - Whole-grain highland hull-less barley (WHLB) contains high amounts of bioactive compounds that potentially exhibit cholesterol-lowering effects. This study investigated the hypocholesterolaemic effect of WHLB. A total of seventy-two male Sprague-Dawley rats were divided into four groups and were fed with the normal control diet, high-fat diet (HFD) and HFD containing low or high dose (10 or 48.95 %) of WHLB. High dose of WHLB significantly decreased the organ indexes of liver and abdominal fat and lipid levels of plasma and liver in HFD rats. The lipid regulation effect of WHLB, which was reconfirmed through hepatocyte morphologic observation, was accompanied by a large excretion of bile acids in the small intestinal contents and the faeces. Real-time PCR analyses, which were further reconfirmed through Western blot analyses, revealed that a high dose of WHLB significantly enhanced the hepatic expressions of AMP-activated protein kinase alpha, cholesterol 7alpha-hydroxylase, LDL receptor, liver X receptor, and PPARalpha and decreased the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase. It also enhanced the ileal expression of farnesoid X receptor and resulted in the decrease of expression of apical sodium-dependent bile acid transporter. WHLB exhibited hypocholesterolaemic effects mainly by inhibiting cholesterol synthesis, cholesterol accumulation in peripheral tissue, and bile acid reabsorption and by stimulating bile acid synthesis. PMID- 29759110 TI - Effects of a multi-component nutritional telemonitoring intervention on nutritional status, diet quality, physical functioning and quality of life of community-dwelling older adults. AB - This study aimed to evaluate the effects of an intervention including nutritional telemonitoring, nutrition education, and follow-up by a nurse on nutritional status, diet quality, appetite, physical functioning and quality of life of Dutch community-dwelling elderly. We used a parallel arm pre-test post-test design with 214 older adults (average age 80 years) who were allocated to the intervention group (n 97) or control group (n 107), based on the municipality. The intervention group received a 6-month intervention including telemonitoring measurements, nutrition education and follow-up by a nurse. Effect measurements took place at baseline, after 4.5 months, and at the end of the study. The intervention improved nutritional status of participants at risk of undernutrition (beta (T1)=2.55; 95 % CI 1.41, 3.68; beta (T2)=1.77; 95 % CI 0.60, 2.94) and scores for compliance with Dutch guidelines for the intake of vegetables (beta=1.27; 95 % CI 0.49, 2.05), fruit (beta=1.24; 95 % CI 0.60, 1.88), dietary fibre (beta=1.13; 95 % CI 0.70, 1.57), protein (beta=1.20; 95 % CI 0.15, 2.24) and physical activity (beta=2.13; 95 % CI 0.98, 3.29). The intervention did not have an effect on body weight, appetite, physical functioning and quality of life. In conclusion, this intervention leads to improved nutritional status in older adults at risk of undernutrition, and to improved diet quality and physical activity levels of community-dwelling elderly. Future studies with a longer duration should focus on older adults at higher risk of undernutrition than this study population to investigate whether the impact of the intervention on nutritional and functional outcomes can be improved. PMID- 29759111 TI - A dietary pattern rich in animal organ, seafood and processed meat products is associated with newly diagnosed hyperuricaemia in Chinese adults: a propensity score-matched case-control study. AB - Previous studies have indicated that some food items and nutrients are associated with uric acid metabolism in humans. However, little is known about the role of dietary patterns in hyperuricaemia. We designed this case-control study to evaluate the associations between dietary patterns and newly diagnosed hyperuricaemia in Chinese adults. A total of 1422 cases and 1422 controls were generated from 14 538 participants using the 1:1 ratio propensity score matching methods. Dietary intake was assessed using a validated self-administered FFQ. Dietary patterns were derived by factor analysis. Hyperuricaemia was defined as concentrations of serum uric acid higher than 7 mg/dl (416.5 MUmol/l) for men and 6 mg/dl (357 MUmol/l) for women. Three dietary patterns were derived by factor analysis: sweet pattern; vegetable pattern; animal foods pattern. The animal foods pattern characterised by higher intake of an animal organ, seafood and processed meat products was associated with higher prevalence of newly diagnosed hyperuricaemia (P for trend<0.01) after adjustment. Compared with the participants in the lowest quartile of the animal foods pattern, the OR of newly diagnosed hyperuricaemia in the highest quartile was 1.50 (95 % CI 1.20, 1.87). The other two dietary patterns were not associated with the prevalence of newly diagnosed hyperuricaemia after adjustment. In conclusion, a diet rich in animal organ, seafood and processed meat products is associated with higher prevalence of newly diagnosed hyperuricaemia in a Chinese population. Further cohort studies and randomised controlled trials are required to clarify these findings. PMID- 29759112 TI - Remodelling of mitochondria during spermiogenesis of Chinese soft-shelled turtle (Pelodiscus sinensis). AB - Mitochondria are vital cellular organelles that have the ability to change their shape under different conditions, such as in response to stress, disease, changes in metabolic rate, energy requirements and apoptosis. In the present study, we observed remodelling of mitochondria during spermiogenesis and its relationship with mitochondria-associated granules (MAG). At the beginning of spermiogenesis, mitochondria are characterised by their round shape. As spermiogenesis progresses, the round-shaped mitochondria change into elongated and then swollen mitochondria, subsequently forming a crescent-like shape and finally developing into onion-like shaped mitochondria. We also noted changes in mitochondrial size, location and patterns of cristae at different stages of spermiogenesis. Significant differences (P<0.0001) were found in the size of the different-shaped mitochondria. In early spermatids transitioning to the granular nucleus stage, the size of the mitochondria decreased, but increased subsequently during spermiogenesis. Changes in size and morphological variations were achieved through marked mitochondrial fusion. We also observed a non-membranous structure (MAG) closely associated with mitochondria that may stimulate or control fusion during mitochondrial remodelling. The end product of this sophisticated remodelling process in turtle spermatozoa is an onion-like mitochondrion. The acquisition of this kind of mitochondrial configuration is one strategy for long term sperm storage in turtles. PMID- 29759115 TI - Fired Up, Ready to Go-- Pediatric and Adolescent Gynecology. PMID- 29759114 TI - Ribozyme-catalysed RNA synthesis using triplet building blocks. AB - RNA-catalyzed RNA replication is widely believed to have supported a primordial biology. However, RNA catalysis is dependent upon RNA folding, and this yields structures that can block replication of such RNAs. To address this apparent paradox, we have re-examined the building blocks used for RNA replication. We report RNA-catalysed RNA synthesis on structured templates when using trinucleotide triphosphates (triplets) as substrates, catalysed by a general and accurate triplet polymerase ribozyme that emerged from in vitro evolution as a mutualistic RNA heterodimer. The triplets cooperatively invaded and unraveled even highly stable RNA secondary structures, and support non-canonical primer free and bidirectional modes of RNA synthesis and replication. Triplet substrates thus resolve a central incongruity of RNA replication, and here allow the ribozyme to synthesise its own catalytic subunit '+' and '-' strands in segments and assemble them into a new active ribozyme. PMID- 29759117 TI - Current Evidence-Based Understanding of the Epidemiology, Prevention, and Treatment of Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common atrial arrhythmia in adults worldwide. As medical advancements continue to contribute to an ever-increasing aging population, the burden of atrial fibrillation on the modern health care system continues to increase. Therapies are also evolving, for treatment of the arrhythmia itself, and stroke risk mitigation. Internists and cardiologists alike are, in most instances, the frontline contact for AF patients, and would benefit from remaining facile in their understanding of care options. To continue to deliver high-quality care to this expanding patient group, an updated, concise review for the clinician is prudent. This article provides a comprehensive summary of the current epidemiology and pathophysiology of AF, as well as contemporary procedural therapeutic options. PMID- 29759118 TI - Approach to Patients with Suspected Rheumatic Disease. AB - Patients with rheumatic disease may present with a myriad of symptoms, from joint pain and rashes to more subtle findings, such as dry eyes and dry mouth. In this article, the authors review in detail the common presenting symptoms of rheumatic disease along with key features in the history and physical examination to help distinguish these from other disease processes. PMID- 29759119 TI - A Primer on Rheumatologic Laboratory Tests: What They Mean and When to Order Them. AB - Rheumatologic laboratory tests are frequently ordered by primary care physicians in patients who complain of joint pain. Clinicians should keep in mind the pretest probability of a rheumatologic disorder before ordering any test because laboratory tests in rheumatology are not diagnostic of any particular disease. Any rheumatologic laboratory test result should only be used to further refine the diagnosis, and it should not replace a thorough history and physical examination. In this article, the authors discuss the diagnostic utility of the commonly ordered rheumatologic laboratory tests based on their sensitivity, specificity, and likelihood ratios. PMID- 29759120 TI - Practical Pearls About Current Rheumatic Medications. AB - New and existing rheumatic disease is frequently encountered in the primary care setting. The number of medications used to treat various rheumatic conditions continues to increase. Some medications have very specific indications, whereas others have increasing off-label uses. Regardless of the indication, the medications used in rheumatology have variable dosing recommendations, significant side effects, recommended monitoring parameters, and potential medication interactions. Clinicians need to be aware of the potential uses as well as possible pitfalls associated with medications used in rheumatology. PMID- 29759113 TI - Distinct roles of ATM and ATR in the regulation of ARP8 phosphorylation to prevent chromosome translocations. AB - Chromosomal translocations are hallmarks of various types of cancers and leukemias. However, the molecular mechanisms of chromosome translocations remain largely unknown. The ataxia-telangiectasia mutated (ATM) protein, a DNA damage signaling regulator, facilitates DNA repair to prevent chromosome abnormalities. Previously, we showed that ATM deficiency led to the 11q23 chromosome translocation, the most frequent chromosome abnormalities in secondary leukemia. Here, we show that ARP8, a subunit of the INO80 chromatin remodeling complex, is phosphorylated after etoposide treatment. The etoposide-induced phosphorylation of ARP8 is regulated by ATM and ATR, and attenuates its interaction with INO80. The ATM-regulated phosphorylation of ARP8 reduces the excessive loading of INO80 and RAD51 onto the breakpoint cluster region. These findings suggest that the phosphorylation of ARP8, regulated by ATM, plays an important role in maintaining the fidelity of DNA repair to prevent the etoposide-induced 11q23 abnormalities. PMID- 29759121 TI - Diagnosis and Treatment of Gout and Pseudogout for Everyday Practice. AB - Gout and pseudogout are crystalline arthropathies commonly seen in primary care. It is important to understand their pathophysiology to facilitate recognition and appropriate treatment. Prompt gouty arthritis treatment relieves short-term suffering. Long-term treatment with urate-lowering therapy prevents recurrent attacks and is generally well-tolerated though flare risk is increased during treatment initiation. When anti-inflammatory medications are prescribed, the flare risk is low. Pseudogout acute treatment is similar to acute gouty arthritis treatment. There is no standard regimen for long-term chronic therapies of pseudogout. This article enhances the recognition and treatment of these diseases in the primary care setting. PMID- 29759122 TI - Early Diagnosis and Treatment of Rheumatoid Arthritis. AB - Rheumatoid arthritis is the most common inflammatory arthritis, and a significant cause of morbidity and mortality. Primary care providers should be able to distinguish the clinical presentation of rheumatoid arthritis from osteoarthritis, because the treatment and outcomes differ greatly between these 2 common forms of arthritis. This article provides a current overview of our understanding of rheumatoid arthritis, with an emphasis on early diagnosis and approaches to treatment. PMID- 29759123 TI - Systemic Lupus Erythematosus for Primary Care. AB - Systemic lupus erythematosus is a chronic autoimmune condition with variable organ system involvement; manifestations can range from mild to potentially life threatening. Early diagnosis is important, as progression of disease can be halted. Diagnosis is made by review of signs and symptoms, imaging, and serology. PMID- 29759124 TI - The Seronegative Spondyloarthropathies. AB - The seronegative spondyloarthropathies are a group of five diseases characterized by inflammatory oligoarticular arthritis, enthesitis, and axial involvement. They have an increased incidence of the HLA-B27 gene. They are commonly associated with extra-articular features including involvement of the skin, eyes, and gastrointestinal tract. Early recognition and referral are key to limit disability, and comanagement with primary care and rheumatology offers the best outcomes. PMID- 29759125 TI - Common Soft Tissue Musculoskeletal Pain Disorders. AB - Soft tissue musculoskeletal pain disorders are common in the primary care setting. Early recognition and diagnosis of these syndromes minimizes patient pain and disability. This article gives a brief overview of the most common soft tissue musculoskeletal pain syndromes. The authors used a regional approach to organize the material, as providers will encounter these syndromes with complaints of pain referring to an anatomic location. The covered disorders include myofascial pain syndrome, rotator cuff tendinopathy, bicipital tendinopathy, subacromial bursitis, olecranon bursitis, epicondylitis, De Quervain disease, trigger finger, trochanteric bursitis, knee bursitis, pes anserine bursitis, Baker cyst, plantar fasciitis, and Achilles tendinopathy. PMID- 29759126 TI - Primary Care Vasculitis: Polymyalgia Rheumatica and Giant Cell Arteritis. AB - Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are related inflammatory diseases of adults aged 50 years or older. The diagnosis of PMR is based on morning stiffness, proximal shoulder and pelvic girdle pain, and functional impairment. GCA is characterized by headache, jaw claudication, and visual disturbances. Constitutional symptoms and elevated inflammatory markers are common to both conditions. Temporal artery biopsy remains the gold standard for diagnosis of GCA. Glucocorticoids are the cornerstone of therapy, with tapering regimens individualized to the patient. Prompt diagnosis and treatment are essential to avert vision loss in GCA. Tocilizumab increases remission rates in GCA. PMID- 29759128 TI - Autoimmunity Mimics: Infection and Malignancy. AB - Musculoskeletal rheumatic syndromes are commonly encountered in the primary care setting. A plethora of commonly encountered and rare infectious agents can produce osteoarticular and soft tissue manifestations. Likewise, malignancies may manifest rheumatic symptoms via direct tumor invasion or paraneoplastic effects. Awareness of these diseases and their clinical risk factors should result in improved screening and earlier recognition and intervention, leading to improved long-term outcomes and overall patient care. PMID- 29759127 TI - Fibromyalgia in Primary Care. AB - Fibromyalgia is a common disorder and has substantial impact on quality of life. The cause remains unknown, but current evidence points to multifactorial involvement of pain processing. Clinical diagnosis is aided by evidence-based diagnostic criteria with subscores for widespread pain and symptom severity. Nonpharmacologic treatments, including cognitive behavioral therapy, sleep hygiene, and regular aerobic exercise, form the cornerstone of management. Pharmacologic intervention is an important adjunct, but benefit is variable. There is no cure for fibromyalgia at this time, but persistence and patience in management may lead to a satisfactory lifestyle. PMID- 29759131 TI - Rheumatic Diseases: Beyond the Musculoskeletal System. PMID- 29759129 TI - Approach to Osteoarthritis Management for the Primary Care Provider. AB - Osteoarthritis is the most common joint disease in the world today. Patients will present for evaluation and treatment to primary care providers on a regular basis. A general understanding of its pathogenesis, risk factors, diagnosis, and treatment is imperative. The goal of this article was to provide the primary care provider with a primer on osteoarthritis care and management. PMID- 29759133 TI - Polygenic Risk Scores: What Are They Good For? PMID- 29759132 TI - The Gamma-Aminobutyric Acid B Receptor in Depression and Reward. AB - The metabotropic gamma-aminobutyric acid B (GABAB) receptor was the first described obligate G protein-coupled receptor heterodimer and continues to set the stage for discoveries in G protein-coupled receptor signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABAB receptors in depression, reward, and the convergence of these domains in anhedonia, a shared symptom of major depressive disorder and withdrawal from drugs of abuse. GABAB receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABAB receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABAB1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABAB receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABAB receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABAB receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABAB1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement is more reliably attenuated by GABAB receptor activation. Separation of desirable and undesirable side effects of agonists is achievable with positive allosteric modulators, which are poised to enter clinical studies for drug abuse. GABAB1 isoforms are key to understanding the neurobiology of anhedonia, whereas allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression. PMID- 29759134 TI - Behavioural alterations and morphological changes are attenuated by the lack of TRPA1 receptors in the cuprizone-induced demyelination model in mice. AB - We have recently reported that the Transient Receptor Potential Ankyrin 1 (TRPA1) receptor deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. The aim of the present study was to gather additional data on the role of TRPA1 by investigating the time course of behavioural alterations and morphological changes in cuprizone-treated TRPA1 receptor gene-deficient mice. Demyelination was induced by feeding male wild-type (WT) and TRPA1 gene-deleted (TRPA1 KO) mice with 0.2% cuprizone for 6 weeks. Behavioural tests were performed once per week to follow cuprizone-induced functional changes. Mechanonociceptive thresholds were investigated by a dynamic plantar aesthesiometer and von Frey filaments. Motor performance was assessed by accelerating RotaRod and horizontal grid tests. For the study of spontaneous activity, the open field test was used. The time course of corpus callosum demyelination was also followed weekly by magnetic resonance imaging (MRI). Histological analysis of myelin loss was performed with Luxol Fast Blue (LFB) staining at week 3 and electron microscopy (EM) at week 6. Astrocyte and microglia accumulation at week 3 was assessed by immunohistochemistry (IHC). Cuprizone treatment induced no changes in mechanonociception or motor performance. In the open arena, cuprizone-treated mice spent more time with locomotion, their mean velocity was significantly higher and the distance they travelled was longer than untreated mice. No statistical difference was detected between WT and TRPA1 KO mice in these parameters. On the other hand, significantly increased rearing behaviour was induced in WT mice compared to TRPA1 KO animals. Morphological changes detected with MRI, LFB, IHC and EM analysis revealed reduced damage of the myelin and attenuated accumulation of astrocytes and microglia in cuprizone-treated TRPA1 KO animals, at each examined time point. Our recent data further suggest that inhibition of TRPA1 receptors could be a promising therapeutic approach to limit central nervous system damage in demyelinating diseases. PMID- 29759135 TI - The levels of soluble forms of CD21 and CD83 in multiple sclerosis. AB - Multiple Sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) in which immune system plays a crucial role in progression of the disease. An enormous amount of research has been shown that immune mediators such as cytokines and chemokines are the culprits of MS propagation suggesting that modulation of such molecules may pave the path to hinder the disease development. It has been shown that both CD21 and CD83 contribute to the resolution of inflammation occurred in MS. CD21 and CD83 have also been ascribed to Epstein Barr virus (EBV) infection (the prime suspect of MS causality) and the levels of vitamin D, respectively. Hence, in this study, we measured the serum concentrations of soluble forms of CD21 and CD83 in 255 patients with MS divided into two groups who were receiving interferon-beta (185 MS patients) and fingolimod (70 MS patients) in comparison to 384 healthy individuals. The levels of EBV titers including anti-VCA IgM, anti-VCA IgG and anti-EBNA-1 IgG were also measured. The results showed that the concentration of soluble CD21 (sCD21) was markedly decreased in serum samples of MS patients with respect of controls. Contrarily, the level of soluble CD83 (sCD83) was elevated in MS patients compared to healthy individuals. In addition, the levels of sCD21 and sCD83 were correlated with the titers of EBV. The data showed the significant association between the expanded disability status scale (EDSS) and the levels of both sCD21 and sCD83. It seems that both sCD21 and sCD83 might be good candidate for disease monitoring and can be considered potential biomarkers for the disease activity. PMID- 29759136 TI - Characterization of sleep-pattern and neuro-immune-endocrine markers at 24 hour post-injection of a single low dose of lipopolysaccharide in male Wistar rats. AB - The long-term effect of immune system activation by a low dose of lipopolysaccharide on neuro-immune-endocrine regulation is unclear. Sleep, neurotransmitter concentrations, TNF-alpha, and corticosterone levels were evaluated in male Wistar rats implanted with conventional sleep recordings. In this work, we found that REM sleep was reduced in the first 4 h post-injection, without affecting the total sleep time, while adrenaline concentration was reduced in the hippocampus at 24 h post-injection of LPS. Our results demonstrated that, although the acute immune response was not evident 24 h after the injection of LPS, it was able to promote the reduction of AD in the hippocampus, which may explain in part the depressive behavior reported in rodents following LPS administration. PMID- 29759137 TI - Low amounts of bisecting glycans characterize cerebrospinal fluid-borne IgG. AB - Immunoglobulin G (IgG) harbors a conserved N-glycosylation site which is important for its effector functions. Changes in glycosylation of IgG occur in many autoimmune diseases but also in physiological conditions. Therefore, the glycosylation pattern of serum IgG is well characterized. However, limited data is available on the glycosylation pattern of IgG in cerebrospinal fluid (CSF) compared to serum. Here, we report significantly reduced levels of bisected glycans in CSF IgG. Galactosylation and sialylation of IgG4 also differed significantly. Therefore, we propose a common mechanism mediating glycosylation changes of IgG at the transition from serum to CSF in steady state conditions. PMID- 29759138 TI - Impact of imipramine on proteome of rat primary glial cells. AB - Microglia and astrocytes, two types of glial cells are known to be important targets for antidepressant drugs. Here we used a comprehensive proteomic analysis to examine the effect of imipramine on rat primary mixed glial culture. The two dimensional differential gel electrophoresis method allowed us to identify 62 proteins that were altered by imipramine. Functional analysis revealed that imipramine influenced the level of proteins involved in oxidative stress; in particular, it elevated the level of glutathione transferases. Imipramine upregulated proteins related to glycolysis but down-regulated many mitochondrial proteins including enzymes involved in oxidative phosphorylation. Mitochondrial dysfunction, especially decrease of mitochondrial membrane potential can be counted as a side effect triggered by imipramine. Imipramine induced lowering of chaperone level and alterations suggesting impaired protein synthesis could be associated with increased apoptosis. One of the most pronounced effect of imipramine is the reduction of vimentin level, this protein is engaged in majority of biological processes which were found to be affected by imipramine. Many imipramine regulated proteins, including chaperones, cathepsins and annexins are involved in immune responses. Additionally, imipramine influenced proteins associated with phagocytosis and cell migration. Overall these findings indicate that imipramine produces complex effect on glial cells, primarily on microglia and suggest their transition towards a more quiescent, metabolically less demanding phenotype. PMID- 29759140 TI - The involvement of neuroinflammation and necroptosis in the hippocampus during vascular dementia. AB - The prevalence of vascular dementia is increasing at an alarming rate. The Confirmation of the clinical diagnosis of vascular dementia depends on post mortem examination of the brain. In our study, we investigated the vascular disease and neuroinflammation during vascular dementia. Our results showed a beta amyloid deposits, neovascularization, neuronal hypertrophy and neuroinflammation in the hippocampus tissue. Interestingly, the neuroinflammation was characterized by a higher expression of TNF-alpha, IL-1beta, TGF-beta and iNOS which are TLR4/RelA pathway dependent. Finally, the finding of necroptosis by impaired blood supply and inflammation state suggests that the cognitive impairment was caused by vascular disease and neuroinflammation. PMID- 29759141 TI - Elevated plasma macrophage migration inhibitor factor as a risk factor for the development of post-stroke depression in ischemic stroke. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity and inflammatory responses, has been reported to link to the pathophysiology of cardiovascular disease and depression. The aim of this study was to test the possible association between plasma MIF and the development of post-stroke depression (PSD) in Chinese patients with acute ischemic stroke (AIS). METHODS: The first-ever AIS patients who were hospitalized at Affiliated Hospital of Weifang Medical College during the period from November 2015 to September 2017 were included. Neurological and neuropsychological evaluations were conducted at the 3-month follow-up. Plasma concentrations of MIF were tested by Quantikine Human MIF Immunoassay. Plasma levels of homocysteine (HCY), C reactive protein (CRP) and Interleukin 6 (IL-6) were also tested. Results were expressed as percentages for categorical variables and as medians (Interquartile range-IQR) for the continuous variables. RESULTS: Finally, 333 stroke patients were included, and 95 out of those patients (28.5%) were classified as major depression. In the patients with major depression, plasma levels of MIF were higher compared with those in patients free-depression [27.3(IQR, 23.5-34.9) ng/ml vs. 20.9(IQR, 17.0-24.8) ng/ml; Z = 8.369, P < 0.001]. For each 1unit increase of MIF, the unadjusted and adjusted risk of PSD increased by 18% (odds ratios [OR]: 1.18; 95% confidence interval [CI], 1.13-1.23, P < 0.001) and 11% (1.11; 1.02-1.16, P = 0.001), respectively. In a multivariate model using the elevated levels of MIF (>=median) vs. normal (8 fold; p < 0.001) compared to the untreated, activated cells. Furthermore, TQ treatment significantly (P < 0.0001) reduced the expression of inflammatory cytokines, IL-2 = 38%, IL-4 = 19%, IL-6 = 83%, IL-10 = 237%, and IL-17a = 29%, in the activated microglia compared to the untreated, activated which expression levels were significantly elevated compared to the control microglia: IL-2 = 127%, IL-4 = 151%, IL-6 = 670%, IL-10 = 133%, IL-17a = 127%. Upon assessing the gene expression of NFkappaB signaling targets, this study also demonstrated that TQ treatment of activated microglia resulted in >7 fold down-regulation of several NFkappaB signaling targets genes, including interleukin 6 (IL6), complement factor B (CFB), chemokine (CC motif) ligand 3 (CXCL3), chemokine (CC) motif ligand 5 (CCL5) compared to the untreated, activated microglia. This modulation in gene expression counteracts the >10-fold upregulation of these same genes observed in the activated microglia compared to the controls. Our results show that TQ treatment of LPS/IFNgamma-activated BV-2 microglial cells induce a significant increase in expression of neuroprotective proteins, a significant decrease in expression inflammatory cytokines, and a decrease in the expression of signaling target genes of the NFkappaB pathway. Our findings are the first to show that TQ treatment increased the expression of these neuroprotective proteins (biliverdin reductase-A, 3-mercaptopyruvate sulfurtransferase, glutaredoxin-3, and mitochondrial lon protease) in the activated BV-2 microglial cells. Additionally, our results indicate that TQ treatment decreased the activation of the NFkappaB signaling pathway, which plays a key role in neuroinflammation. In conclusion, our results demonstrate that TQ treatment reduces the inflammatory response and modulates the expression of specific proteins and genes and hence potentially reduce neuroinflammation and neurodegeneration driven by microglial activation. PMID- 29759152 TI - Minimal Residual Disease Detection by Flow Cytometry in Multiple Myeloma: Why and How? AB - The outlook for myeloma patients has steadily improved with the introduction of newer drug combinations in recent years. Unlike older therapies that largely achieved only modest levels of neoplastic clone reduction, the newer drug combinations have led to deeper suppression of myeloma clones in most patients. Frequently the neoplastic clones become undetectable with traditional disease evaluation approaches. Recent studies using ultrasensitive disease monitoring have demonstrated that patients with disease undetectable by traditional techniques show wide heterogeneity in disease levels varying by several orders of magnitude. Moreover, measurement of the depth of disease suppression even at very low level has emerged as the most powerful prognostication tool in myeloma. Minimal (or measurable) residual disease (MRD) evaluation has also been proposed as a relevant tool in assessment of drug efficacy and in selection of further therapeutic options. In the face of the robust MRD measurement utility data, it has become critical to develop widely applicable disease monitoring techniques that can be applied to more patients in a variety of clinical setting. Both DNA based and flow cytometry-based approaches have been successfully developed for this purpose achieving sensitivity approaching 1 neoplastic cell in a million. This review article focuses on the theoretical and practical aspects and challenges of deep MRD monitoring in myeloma by flow cytometry. Challenges of flow cytometric disease monitoring in the era of antigen-directed therapy are also discussed. PMID- 29759150 TI - Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease. AB - The presence or absence of minimal residual disease (MRD) in patients with multiple myeloma (MM) has emerged as a useful marker to determine the depth of remission. MRD negativity as an endpoint has been shown to be associated with improved progression-free survival in many studies. MRD detection is therefore part of numerous clinical trial protocols for MM. At the present time, two methodologies are most widely accepted for MRD detection: (1) multicolor flow cytometry and (2) next-generation sequencing-based clonotype detection. While both of those methodologies enable accurate quantification of MRD in the bone marrow (BM), with sensitivity as low as 10-5 to 10-6, there are several limitations to these methods. First, these approaches reveal the presence or absence of MRD but provide limited molecular information about MM. More comprehensive characterization of MM cells at the MRD stage may identify molecular mechanisms of drug resistance. Second, MRD detection in the BM is typically performed at one time point only, but more frequent detection may define the duration of the MRD status and thus refine its prognostic value. Third, less-invasive approaches that avoid the discomfort and risk associated with BM biopsy would be highly desirable, especially in elderly or frail patients. "Liquid biopsy" for the detection and characterization of circulating MM cells may address these issues. Although MRD detection in the peripheral blood at the same sensitivity as in the BM may be challenging, the identification of patients who do not achieve MRD negativity might reduce the need for BM biopsies. Here, we give an overview of approaches that have been described to detect and characterize MM cells when they occur at very low frequencies in the peripheral blood or in the BM, emphasizing recently described next-generation sequencing approaches for more comprehensive characterization of circulating MM cells. PMID- 29759153 TI - Mass spectrometry methods for detecting monoclonal immunoglobulins in multiple myeloma minimal residual disease. AB - Mass spectrometry methods that can detect low levels of monoclonal immunoglobulin in serum have recently been developed. These assays are based on the principle that each immunoglobulin has a unique amino acid sequence and therefore, has a unique mass. This mass can be used as a surrogate marker in order to monitor a patient's disease over time and at low levels. Here, we explain these methods, discuss their advantages and disadvantages and how they may be used to monitor monoclonal immunoglobulins for minimal residual disease detection in multiple myeloma. PMID- 29759154 TI - MRD Testing in Multiple Myeloma: The Main Future Driver for Modern Tailored Treatment. AB - The past decade, several highly efficacious drugs have been approved for the treatment of multiple myeloma. Many of these newer drugs are less toxic than older chemotherapy drugs. Using modern combination therapy in newly diagnosed multiple myeloma patients, high proportions of newly diagnosed multiple myeloma patients obtain minimal residual disease (MRD) negativity and MRD testing has rapidly become an integral part of clinical trials focusing on patients in this setting. Only recently, MRD negativity was reported in clinical trials focusing on older newly diagnosed multiple myeloma patients (ie, nontransplant candidates), as well as studies focusing on patients with relapsed or refractory multiple myeloma. In the past, deeper responses were rarely seen in these patient categories due to inferior therapies and lack of MRD assays. The reason for the rapidly increased interest in MRD testing in all types of clinical trials is the fact that MRD negativity is closely correlated with longer progression-free survival which has been documented in recent meta-analyses. Consequently, MRD negativity has the potential to soon become a regulatory surrogate end-point for drug approval. This review dissects and discusses current data on MRD in multiple myeloma, it outlines new hypotheses, which can be tested in future clinical studies, and it discusses opportunities and future avenues for translational research. The goal of this article is to stimulate critical analysis of our current treatment landscape and development of future translational research involving MRD testing. PMID- 29759155 TI - In the expanding arena of endoscopic management for Barrett's neoplasia, how should we fit in endoscopic submucosal dissection? PMID- 29759156 TI - POEM: the sun rises in the East.... PMID- 29759157 TI - Per-oral endoscopic myotomy short-term outcomes are good-but the long-term results are what count. PMID- 29759158 TI - EUS-FNA giving way to fine-needle biopsy: Is it time to retire your old trusted needles? PMID- 29759159 TI - Pancreatic cancer screening in high-risk individuals: Ready for prime time? PMID- 29759160 TI - Guidewire caliber is not important when controlled by high-caliber operators. PMID- 29759161 TI - Outcome analysis in Crohn's disease using endomicroscopy: How important and reliable is in vivo analysis of microscopic changes? PMID- 29759162 TI - Small and diminutive hyperplastic polyps in the proximal colon: Are they innocent or guilty of a crime? PMID- 29759163 TI - Response. PMID- 29759164 TI - Effective endoscopic treatment for intraluminal duodenal diverticulum. PMID- 29759165 TI - A novel method to prevent catheter dysfunction during spray cryotherapy. PMID- 29759166 TI - Response. PMID- 29759167 TI - Terminology for vascular lesions of the GI tract. PMID- 29759168 TI - Response. PMID- 29759169 TI - The silence of the LAMS. PMID- 29759170 TI - Pancreas cyst fluid viscocity assesment in the diagnosis of mucinous cyts. PMID- 29759171 TI - Response. PMID- 29759173 TI - Erratum. PMID- 29759172 TI - Response. PMID- 29759174 TI - A highly selective fluorescent probe for cyanide ion and its detection mechanism from theoretical calculations. AB - A new cyanide probe has been prepared by one-step synthesis and evaluated by UV vis and fluorescent method. This probe is combined by a fluorene part and a hemicyanine group through a conjugated linker, which is found to show rapid response, high selectivity and sensitivity for cyanide anions with significant dual colorimetric and fluorescent signal changes in aqueous solution. An intramolecular charge transfer (ICT) effect plays a key role in the CN- sensing properties, and the details of this mechanism are further supported by DFT and TD DFT calculations. The theoretical study shows that the introduction of CN- twists the original plane structure and blocks the ICT process in the whole molecule, which brings about the absorption blue-shift and the fluorescence quenching. PMID- 29759175 TI - Gold nanoparticle aggregation: Colorimetric detection of the interactions between avidin and biotin. AB - This paper reported a novel colorimetric assay strategy for avidin and biotin interactions based on terminal protection of the biotinylated single-stranded DNA and the surface plasmon resonance adsorption of gold nanoparticles (AuNPs). In this assay, it was firstly found that biotin-ssDNA specifically bound to the target protein avidin with strong affinity could be protected from hydrolysis by exonuclease I (Exo I). Furthermore, a colorimetric strategy was designed for the detection of avidin and biotin interactions. In the process, in the presence of avidin, the interaction of avidin and biotin protected the digestion of Exo I towards the biotin-ssDNA. The biotin-ssDNA with negatively charged would attach to the surface of AuNPs with positively charge in high salt solution through electrostatic interactions, which prevented AuNPs to aggregate. With the increased addition of avidin, the absorbance of AuNPs in 520 nm increased gradually and the color showed gradually wine red. By taking advantage of terminal protection, the developed strategy could offer high sensitivity for detecting small molecule-protein interactions. The results revealed that the developed strategy was highly sensitive for detecting avidin in the concentration ranging from 0.01 to 0.2 MUg/mL with the detection limit of 4 * 10-3 MUg/mL.The developed assay also showed highly specific, cost-efficient and convenient. Moreover, this strategy only required labeling the small molecule on a single stranded DNA, circumventing protein modifications that might be harmful for activity. In view of these advantages, this new colorimetric method could have potential to become a universal, sensitive, and selective platform for detection of small molecule-protein interactions. PMID- 29759177 TI - Highly sensitive detection of hepatitis C virus DNA by using a one-donor-four acceptors FRET probe. AB - Sensitive detection of Hepatitis C virus (HCV) DNA is critical to treat and prevent the propagation of hepatitis C diseases. Herein a FRET probe of One-Donor Multi-Acceptors (D-mA) assembly is designed through the formation of triple-helix DNA structure, which can greatly reduce the background of FRET system so as to greatly increase the detection sensitivity of hepatitis C virus DNA with the limit of detection (3sigma) being 24.57 nmol/L, making the detection of clinic samples successful and showing that the newly developed FRET probe of D-mA assembly could be applied for the early diagnosis and treatment of hepatitis C disease. PMID- 29759176 TI - Carbon nanosphere-based fluorescence aptasensor for targeted detection of breast cancer cell MCF-7. AB - In this work, carbon nanosphere (CNS)-based fluorescence "turn off/on" aptasensor was developed for targeted detection of breast cancer cell MCF-7 by conjugation with FAM (a dye)-labeled mucin1 (MUC1) aptamer P0 (P0-FAM), which can recognize MUC1 protein overexpressed on the surface of MCF-7. Different from other carbon based fluorescence quenching materials, CNSs prepared by the carbonization of glucose not only have the high fluorescence quenching efficiency (98.8%), but also possess negligible cytotoxicity (in the concentration range of 0-1 mg/mL, which is 10 times higher than that of traditional carbon nanotubes or graphene oxide (0-100 ug/mL)). As for the detection of the mimic of the tumor antigen MUC1, the resulting fluorescence intensity increases nearly linearly in the range of 0-6 MUM with the limit of detection (LOD) of 25 nM. PMID- 29759178 TI - One-pot synthesis of the stable CdZnTeS quantum dots for the rapid and sensitive detection of copper-activated enzyme. AB - Galactose oxidase is a copper-activated enzyme and have a vital role in metabolism of galactose. Much of the work is focused on determining the amount of galactose in the blood rather than measuring the amount of galactose oxidase to urge the galactosemia patients to restrict milk intake. Here, a simple and effective method was developed for Cu2+ and copper-activated enzyme detection based on homogenous alloyed CdZnTeS quantum dots (QDs). Meso- 2,3 dimercaptosuccinic acid (DMSA) was used as the reducing agent for preparing QDs and the highest quantum yield of CdZnTeS QDs was 69.4%. In addition, the as prepared CdZnTeS QDs show superior fluorescence properties, such as good photo /chemical stability. The DMSA was the surface ligand of the QDs, containing abundant -SH and -COOH, thus the surface ligands have a high affinity with Cu2+. Therefore, this developed probe can be applied for Cu2+ and galactose oxidase detection and shows a good sensitivity in the buffer. Then, this probe was successfully used for Cu2+ and galactose oxidase detection in real samples with the satisfactory results. The proposed fluorescence quenching strategy gives a new and simple insight for enzyme assay without the enzyme-catalyzed reaction. PMID- 29759179 TI - N-doped carbon nanotubes-reinforced hollow fiber solid-phase microextraction coupled with high performance liquid chromatography for the determination of phytohormones in tomatoes. AB - A N-doped carbon nanotubes-reinforced hollow fiber solid-phase microextraction (N doped CNTs-HF-SPME) method was developed for determination of two naphthalene derived phytohormones, 1-naphthalene acetic acid (NAA) and 2-naphthoxyacetic acid (2-NOA), at trace levels in tomatoes. N-doped CNTs were dispersed in ultrapure water with the assistance of surfactant, and then immobilized into the pores of hollow fiber by capillary forces and sonification. The resultant N-doped CNTs-HF was wetted with 1-octanol, subsequently immersed into the tomato samples to extract the target analytes under a magnetic stirring, and then desorbed with methanol by sonication prior to chromatographic analysis. Compared with CNTs, the surface hydrophilicity of N-doped CNTs was improved owing to the doping of nitrogen atoms, and a uniform dispersion was formed, thus greatly simplifying the preparation process and reducing waste of materials. In addition, N-doped CNTs-HF exhibits a more effective extraction performance for NAA and 2-NOA on account of the introduction of Lewis-basic nitrogen. It is worth to mention that owing to the clean-up function of HF, there are not any complicated sample pretreatment procedures prior to the microextraction. To achieve the highest extraction efficiency, important microextraction parameters including the length and the concentration level of N-doped CNTs in surfactant solution, extraction time, desorption conditions such as the type and volume of solvents, pH value, stirring rate and volume of the donor phase were thoroughly investigated and optimized. Under the optimal conditions, the method showed 165- and 123-fold enrichment factors of NAA and 2-NOA, good inter-fiber repeatability and batch-to-batch reproducibility, good linearity with correlation coefficients higher than 0.9990, low limits of detection and quantification (at ng g-1 levels), and satisfactory recoveries in the range of 83.10-108.32% at three spiked levels. The proposed method taking advantages of both excellent adsorption performance of N-doped CNTs and the clean-up function of HF, was a simple, green, efficient and cost effective enrichment procedure for the determination of trace NAA and 2-NOA in tomatoes. PMID- 29759180 TI - Aligner-mediated cleavage-triggered exponential amplification for sensitive detection of nucleic acids. AB - Exponential amplification reaction (EXPAR), as a simple and high sensitive method, holds great promise in nucleic acids detection. One major challenge in EXPAR is the generation of trigger DNA with a definite 3'-end, which now relies on fingerprinting technology. However, the requirement of different endonucleases for varying target sequences and two head-to-head recognition sites in double stranded DNA, as well as the confinement of trigger DNA's 3'-end to be near/within the recognition site, usually subject EXPAR to compromised universality and/or repeated matching of reaction conditions. Herein, we report a simple and universal method for high sensitive detection of nucleic acids, termed aligner-mediated cleavage-triggered exponential amplification (AMCEA). The aligner-mediated cleavage (AMC) needs only one nicking endonuclease and can make a break at any site of choice in a programmable way. Thus, the 3'-end of target DNA can be easily redefined as required, a key step for initiating the amplification reaction. This capability endows the proposed AMCEA with excellent universality and simplicity. Moreover, it is sensitive and specific, with a detection limit at amol level, a broad dynamic range of 5~6 orders of magnitude and the ability to distinguish single nucleotide mutation. Experiments performed with human serum indicate that AMCEA is compatible with the complex biological sample, and thus has the potentials for practical applications. PMID- 29759181 TI - Ultrasensitive detection of thiophenol based on a water-soluble pyrenyl probe. AB - We report a simple pyrene-based fluorescent probe, sodium 8-(2,4 dinitrophenoxy)pyrene-1,3,6-trisulfonate (HPTS-DNP), for the ultrasensitive and visual detection of thiophenol in 100% aqueous media. The sensing mechanism of this method is based on nucleophilic aromatic substitution on HPTS-DNP caused by thiophenol to afford a highly fluorescent product, 8-hydroxypyrene-1,3,6 trisulfonic acid trisodium salt (HPTS). The extremely low fluorescence background of HPTS-DNP and high quantum yield of HPTS ensure the superior sensing performance toward thiophenol, including rapid responses, off-on detection mode and excellent sensitivity. The detection limit is as low as 0.49 nmol L-1 according to the measurements with a spectrofluorimeter. This probe also features good selectivity (response ratio of thiophenol to interferents >30), precision (2.93%) and accuracy (102%). This approach could be applied for monitoring the thiophenol concentrations in environmental water samples. HPTS-DNP also showed good cell permeation capacity and low cellular cytotoxicity, indicating further application in bioimaging studies. PMID- 29759182 TI - Development of a new analytical tool for assessing the mutagen 2-methyl-1,4 dinitro-pyrrole in meat products by LC-ESI-MS/MS. AB - The use of sorbate and nitrite in meat processing may lead to the formation of 2 methyl-1,4-dinitro-pyrrole (DNMP), a mutagenic compound. This work was aimed at developing and validating an analytical method for the quantitation of DNMP by liquid chromatography-tandem mass spectrometry. Full validation was performed in accordance to Commission Decision 2002/657/EC and method applicability was checked in several samples of meat products. A simple procedure, with low temperature partitioning solid-liquid extraction, was developed. The nitrosation during the extraction was monitored by the N-nitroso-DL-pipecolic acid content. Chromatographic separation was achieved in 8 min with di-isopropyl-3-aminopropyl silane bound to hydroxylated silica as stationary phase. Samples of bacon and cooked sausage yielded the highest concentrations of DNMP (68 +/- 3 and 50 +/- 3 MUg kg-1, respectively). The developed method proved to be a reliable, selective, and sensitive tool for DNMP measurements in meat products. PMID- 29759184 TI - Application of a webcam camera as a cost-effective sensor with image processing for dual electrochemical - colorimetric detection system. AB - A webcam camera as an alternative cost-effective colorimetric sensor for the simple dual electrochemical - colorimetric detection system is proposed. Performance test of the system was investigated through electrochemical and colorimetric behaviors of redox reactions of potassium ferrocyanide complex. Image processing with two color systems, RGB and HSV, was applied together with various electrochemical techniques. Color responses obtained from the webcam correlated with electrochemical signals in various electrochemical techniques. The results from the proposed dual detection system agreed well with those obtained using conventional UV-vis spectroelectrochemical system reported previously. The application of proposed system was demonstrated for studying the redox reaction of catechin and electrochemical - colorimetric behaviors of Fe(II) and Fe(III) mixture. PMID- 29759183 TI - Evaluation of thrombin inhibitory activity of catechins by online capillary electrophoresis-based immobilized enzyme microreactor and molecular docking. AB - An online capillary electrophoresis (CE)-based thrombin (THR) immobilized enzyme microreactor (IMER) method was established to screen THR inhibitors in this study. S-2366 was used as chromogenic substrate for determination of THR activity and other kinetic constants. After continuously run for 50 times, the prepared IMER could still remain 89% of the initial immobilized enzyme activity. The Michaelis-Menten constant (Km) of immobilized THR was measured as 0.514 mmol/L and the half-maximal inhibitory concentration (IC50) and inhibition constant (Ki) of argatroban on THR were determined as 78.07 and 26.53 nmol/L, respectively, which indicated that CE-based THR IMER was successfully established and could be applied to screen THR inhibitors. Then the prepared IMER was used to investigate the inhibitory potency on THR of four main catechins in green tea including epicatechin (EC), epigallocatechin (EGC), epicatechin gallate (ECG), and epigallocatechin gallate (EGCG). The results showed that ECG and EGCG had good THR inhibition activity and their inhibition rates at concentration of 200 MUmol/L were 53.2 +/- 3.8% and 55.8 +/- 2.6%, respectively, which was in consistent with the results of microplate reader assay. Additionally, molecular docking results showed that the benzopyran groups of ECG and EGCG were inserted into the THR active pocket and interacted with residues LYS60F, TRP60D, TRY60A, IEU99, GLY216, HIS57 and SER195, but EC and EGC did not. Therefore, the developed CE-based THR IMER is reliable method for measuring THR inhibitory activity of natural inhibitors. PMID- 29759186 TI - Affinity capture surface carboxyl-functionalized MoS2 sheets to enhance the sensitivity of surface plasmon resonance immunosensors. AB - The development of functionalized molybdenum disulfide (MoS2) has led to a new trend in the biosensing field, owing to its high sensitivity and bio-affinity characteristics with regards to the simple synthesis of carboxyl-functionalized MoS2 nanocomposites. In this study, we used monochloroacetic acid (MCA) to successfully modify carboxyl-MoS2. The efficiency of this MCA modification method showed a higher -COOH group content of 30.1%, mainly due to chlorine atoms occupying the MoS2 sulfur vacancy to allow for the formation of a strong bonding effect. This then enhanced the surface area of -COOH and improved the formation of covalent bonds between proteins. We demonstrated that MoS2-COOH-based surface plasmon resonance (SPR) chips can provide excellent sensitivity and high affinity for immunoassay biomolecules detected in a low sample volume of 20 MUl. With respect to the shifts of the SPR angles of the chips, the high binding affinity at a BSA concentration of 14.5 nM for a MoS2-COOH chip, a MoS2 chip and a traditional SPR chip are 4.69 m degrees , 2.49 m degrees and 1.53 m degrees , respectively. In addition, the MoS2-COOH chip could amplify the SPR angle response by 3.1 folds and enhance the high association rate of ka by 212 folds compared to MoS2 and traditional SPR chips. The results thus obtained revealed that the overall affinity binding value, KA, of the MoS2-COOH chip can be significantly enhanced by up to ~ 6.5 folds that of the MoS2 chip. In summary, the excellent binding affinity, biocompatible and high sensitivity suggest the potential of the clinical application of this MoS2-COOH-based SPR chip detection method for in vitro diagnostic and point-of-care testing devices. PMID- 29759187 TI - Synthesis of penetrable poly(methacrylic acid-co-ethylene glycol dimethacrylate) microsphere and its HPLC application in protein separation. AB - In the present study, the narrow-dispersed penetrable poly(methacrylic acid-co ethylene glycol dimethacrylate) (poly(MAA-co-EDMA)) microspheres were successfully synthesized based on the sacrificial support method. The poly(MAA-co EDMA) microspheres mirrored the porous structure of the sacrificial support, i.e. penetrable silica, characteristic of copious mesopores and throughpores. In addition, they possessed large surface area, adjustable hydrophobicity and the cation-exchange ability. Owing to their multi functionalities, they were applied as chromatographic stationary phase to separate proteins in different separation modes, including reversed phase, hydrophobic interaction and weak cation exchange. Moreover, thanks to their throughpores, fast separation at low column backpressure could be achieved in these three modes. Both protein recovery and column stability were satisfactory. The penetrable poly(MAA-co-EDMA) microspheres were potential stationary phase matrix for fast protein separation. PMID- 29759185 TI - A fast sample processing strategy for large-scale profiling of human urine phosphoproteome by mass spectrometry. AB - Liquid biopsies using body fluids have gained much attention in recent years due to their multiple advantages in clinical diagnosis, such as less/non-invasive collection, suitability for longitudinal disease monitoring, and better representation of tumor heterogeneity. As an attractive choice for liquid biopsy, urine proteins and their post-translational modifications (PTMs) have the potential to offer significant insights into physiological variations and pathological changes in the human body. However, due to the intrinsically large variability of urine proteins and their PTMs among different individuals, there is a high demand for strategies for high-throughput analysis of a large number of samples to obtain a comprehensive view and a reliable reference interval of the urine proteome. In this work, we proposed a new urine phosphoproteome sample processing strategy that combines fast protein extraction, efficient multiple immobilized-proteases digestion, and tandemly connected centrifugal tips device based facile phosphopeptide enrichment & fractionation. This strategy is capable of paralleled sample processing with an approximate five-fold reduction in processing time and is therefore particularly suitable for handling a large number of urine samples. Totally, we identified 4196 phosphosites in human urine proteins by mass spectrometry in replicated tests, a number which is dozens of times larger than those previously reported. Therefore, this strategy may have great potential in urine-based phosphoprotein biomarker screening and drug response studies. PMID- 29759188 TI - The facile approaches to asymmetric modification of glassy biconical microchannel wall with silver, copper or gold. AB - The modification of inner surface has significant influence in the properties of the nano or microchannel based on various materials, especially for the ionic current rectification (ICR) that arises from the selective interaction between ions in solution and the inner surface. Herein, we demonstrate a simple strategy to asymmetrically modify the inner wall of a glassy biconical microchannel with silver, copper or gold by means of silver mirror reaction and polydopamine platform, respectively. And the bidirectional ionic current rectification phenomena were observed in all of the modified biconical microchannels. All of the modification methods are simple, facile and low-cost, and can be applied in the modification of other glassy pipettes. PMID- 29759189 TI - Characterization of an array of honeys of different types and botanical origins through fluorescence emission based on LEDs. AB - A set of 10 honeys comprising a diverse range of botanical origins have been successfully characterized through fluorescence spectroscopy using inexpensive light-emitting diodes (LEDs) as light sources. It has been proven that each LED honey combination tested originates a unique emission spectrum, which enables the authentication of every honey, being able to correctly label it with its botanical origin. Furthermore, the analysis was backed up by a mathematical analysis based on partial least square models which led to a correct classification rate of each type of honey of over 95%. Finally, the same approach was followed to analyze rice syrup, which is a common honey adulterant that is challenging to identify when mixed with honey. A LED-dependent and unique fluorescence spectrum was found for the syrup, which presumably qualifies this approach for the design of uncomplicated, fast, and cost-effective quality control and adulteration assessing tools for different types of honey. PMID- 29759190 TI - Simultaneous voltammetry detection of dopamine and uric acid in human serum and urine with a poly(procaterol hydrochloride) modified glassy carbon electrode. AB - In the present study, procaterol hydrochloride (ProH) was successfully electropolymerized onto a glass carbon electrode (GCE) with simply cyclic voltammetry scans to construct a poly(procaterol hydrochloride) (p-ProH) membrane modified electrode. Compared with the bare GCE, much higher oxidation peak current responses and better peak potentials separation could be obtained for the simultaneous oxidation of dopamine (DA) and uric acid (UA), owning to the excellent electrocatalytic ability of the p-ProH membrane. And it's based on that a square wave voltammetry (SWV) method was developed to selective and simultaneous measurement of DA and UA. Under the optimum conditions, the linear dependence of oxidation peak current on analyte concentrations were found to be 1.0-100 MUmol/L and 2-100 MUmol/L, giving detection limits of 0.3 MUmol/L and 0.5 MUmol/L for DA and UA, separately. The as prepared modified electrode shows simplicity in construction with the merits of good reproducibility, high stability, passable selectivity and nice sensitivity. Finally, the proposed p ProH membrane modified electrode was successfully devoted to the detection of DA and UA in biological fluids such as human serum and urine with acceptable results. PMID- 29759191 TI - Comparative evaluation of seven commercial products for human serum enrichment/depletion by shotgun proteomics. AB - Seven commercial products for human serum depletion/enrichment were tested and compared by shotgun proteomics. Methods were based on four different capturing agents: antibodies (Qproteome Albumin/IgG Depletion kit, ProteoPrep Immunoaffinity Albumin and IgG Depletion Kit, Top 2 Abundant Protein Depletion Spin Columns, and Top 12 Abundant Protein Depletion Spin Columns), specific ligands (Albumin/IgG Removal), mixture of antibodies and ligands (Albumin and IgG Depletion SpinTrap), and combinatorial peptide ligand libraries (ProteoMiner beads), respectively. All procedures, to a greater or lesser extent, allowed an increase of identified proteins. ProteoMiner beads provided the highest number of proteins; Albumin and IgG Depletion SpinTrap and ProteoPrep Immunoaffinity Albumin and IgG Depletion Kit resulted the most efficient in albumin removal; Top 2 and Top 12 Abundant Protein Depletion Spin Columns decreased the overall immunoglobulin levels more than other procedures, whereas specifically gamma immunoglobulins were mostly removed by Albumin and IgG Depletion SpinTrap, ProteoPrep Immunoaffinity Albumin and IgG Depletion Kit, and Top 2 Abundant Protein Depletion Spin Columns. Albumin/IgG Removal, a resin bound to a mixture of protein A and Cibacron Blue, behaved less efficiently than the other products. PMID- 29759192 TI - The polystyrene-divinylbenzene stationary phase hybridized with oxidized nanodiamonds for liquid chromatography. AB - A novel polystyrene-divinylbenzene microspheres hybridized with oxidized nanodiamonds (PS-DVB-OND) was synthesized by the method of seed swelling and polymerization. The oxidized nanodiamonds (OND) were characterized by Fourier transform infrared (FTIR) spectra, X-ray phtoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), X-ray diffraction (XRD). PS-DVB-OND particles were characterized by scanning electron microscopy (SEM) and transmission electron microscope (TEM). The result suggested that OND were successfully embedded into the polymer microspheres with the diameter of 6 +/- 2 um. Compared to polystyrene-divinylbenzene (PS-DVB) microspheres, PS-DVB-OND microspheres could tolerate higher pressure. The PS-DVB-OND microspheres were used as stationary phase of reversed-phase liquid chromatography directly and anion exchangers after further quaternized with methylamine and 1,4-butanediol diglycidyl ether. Reversed-phase liquid chromatographic performance of PS-DVB-OND beads was investigated through separating six benzenes such as toluene, benzaldehyde, phenol, benzoic acid, 1,4-hydroquinone and methyl p hydroxybenzoate. Inorganic anions such as F-, Cl-, NO2-, Br-, NO3-, HPO42- and SO42-, were baseline separated on the anion exchangers of PS-DVB-OND microspheres. The result suggested that the prepared PS-DVB-OND microspheres have the potential as liquid chromatographic stationary phase under high pressure and extremely pH conditions. PMID- 29759193 TI - Highly sensitive detection and mutational analysis of lung cancer circulating tumor cells using integrated combined immunomagnetic beads with a droplet digital PCR chip. AB - Circulating tumor cells (CTCs) have become an important biomarker for liquid biopsy to monitor tumor progression and indicate response to therapies. Many epithelial cellular adhesion molecule (EpCAM) dependent CTC isolation methods have been developed, which have a limitation for low EpCAM expressed tumor cells. In an effort to overcome these drawbacks, we developed combined immunomagnetic beads (EpCAM, Mucin1 and epidermal growth factor receptor) to sensitively isolate CTCs for immunofluorescence analysis and genetic characterization. With this combined immunomagnetic beads, 93.35% H446 cells from spiked blood sample can be recovered. We were able to detect CTCs in 127 among 143 patients included in the study (88.8%). Some CTC clusters were captured with the combined magnetic beads system. In 17 of them, CTCs after chemotherapy significantly decreased compared to that before chemotherapy (4.42 (+/- 3.94) vs. 12 (+/- 7)/mL, P = 0.002). For subsequent genetic characterization of CTCs, 2 of 6 samples, using a droplet digital PCR (ddPCR) chip, have detectable EGFR L858R mutation in the cells enriched with the combined immunomagnetic beads. In conclusion, this method integrating the combined immunomagnetic beads and the ddPCR chip for CTCs detection can be of potential application in terms of diagnosis, therapeutic evaluation and personalized medicine in lung cancer. PMID- 29759194 TI - Solid-phase microextraction of volatile organic compounds in headspace of PM induced MRC-5 cell lines. AB - The exploration of volatile organic compounds (VOCs) produced by cell lines may be a powerful and non-invasive tool for the study of the health risk of human exposure to atmospheric particulate matter (PM). In this work, we developed a sensitive solid phase microextraction-gas chromatography-mass spectrometry method (SPME-GC-MS) to analyze VOCs in breathed gas of PM2.5-induced human embryonic fibroblast cell line (MRC-5). A novel graphene oxide/polyaniline/polydopamine (GO/PANI/PDA) coating was prepared on a stainless steel wire via electrochemical deposition and self-polymerization for the first time. The GO/PANI/PDA coating exhibited high extraction efficiency, good thermal stability (> 380 C), excellent mechanical stability as well as long service time (> 150 times). Parameters that may affect the results were optimized systematically. Under the optimal conditions, VOCs including benzene series, aldehydes and alkane were detected with low limit of detection (0.2-2.0 MUg L-1) and good correlation (correlation coefficients above 0.9922). The relative standard deviations of within-day and between-day were 1.1-8.4% and 0.2-11.2%, respectively. Satisfactory recoveries of 82-117% indicated good repeatability of the method. The method has been successfully applied for the determination of target VOCs in the headspace gas of PM2.5-induced MRC-5 cell. And it is expected to provide an alternative tool for the study of cytotoxicology of atmospheric particulates. PMID- 29759195 TI - Simultaneous competitive and sandwich formats multiplexed immunoassays based on ICP-MS detection. AB - Inductively Coupled Plasma Mass Spectrometry (ICP-MS) based immunoassay method has been proposed in multiple immunoassays but has not been used in competitive and sandwich formats immunoassay simultaneously. The two immunoassays were usually conducted separately in clinical field depending on the size and the amount of binding sites of targets. We proposed an immunoassay method based on magnetic beads and ICP-MS detection that could be suitable for both small and large molecules. The functionalized magnetic beads were added to capture the immune complex after immune reaction. In this way, thyrotropin and free thyroid hormone can be captured, separated and then detected according to the elemental tags by ICP-MS simultaneously. The new method was evaluated by comparing the results with time resolved fluorescence immunoassays (TRFIA). The dynamic ranges of TSH and FT4 were 0.16-105 mU/L and 3.5-65 pmol/L, respectively. The limits of detections were 0.06 mU/L for TSH and 1.59 pmol/L for FT4. And the relative standard deviations (RSD) of TSH and FT4 were 4.64% at 2.5 mU/L and 1.87% at 5.85 pmol/L. This immunoassay method enables the determination of small and large biomolecules simultaneously via competitive and sandwich immunoassay formats. PMID- 29759197 TI - Ratiometric fluorescent detection of chromium(VI) in real samples based on dual emissive carbon dots. AB - As we know, hexavalent chromium (Cr(VI)) was usually used as an additive to improve the color fastness during the printing and dyeing process, and thus posing tremendous threat to our health and living quality. In this work, the dual emissive carbon dots (DECDs) were synthesized through hydrothermal treatment of m aminophenol and oxalic acid. The obtained DECDs not only exhibited dual emission fluorescence peaks (430 nm, 510 nm) under the single excitation wavelength of 380 nm, but also possessed good water solubility and excellent fluorescence stability. A ratiometric fluorescent method for the determination of Cr(VI) was developed using the DECDs as a probe. Under the optimal conditions, a linear range was obtained from 2 to 300 MUM with a limit of detection of 0.4 MUM. Furthermore, the proposed ratiometric fluorescent method was applied to the analysis of Cr(VI) in textile, steel, industrial wastewater and chromium residue samples with satisfactory recoveries (88.4-106.8%). PMID- 29759198 TI - Colorimetric determination of uranyl (UO22+) in seawater via DNAzyme-modulated photosensitization. AB - Various DNA-modulated photosensitization schemes have been reported for various applications, but DNAzyme has not yet been included. Here, we found the DNAzyme with metal ion as cofactor could also be efficient in modulation of photosensitization process. The UO22+-specific DNAzyme can switch between double strand DNA (dsDNA) and single strand DNA (ssDNA) upon UO22+ cleavage, which can regulate the photosensitization process of SYBR Green I. Coupling with photosensitization-induced chromogenic reaction (TMB oxidation), a simple colorimetric sensor for UO22+ was developed accordingly. To increase the visual resolution of the proposed assay, a background color was supplied. Compared with the previous DNAzyme-based UO22+ sensors, the proposed assay featured label-free and simple. Besides, the tolerance for high salinity of this assay is appealing. The proposed assay offered a detection limit of 0.08 MUg/L with UV-vis detection and 0.5 MUg/L with the naked eye. With the proposed colorimetric assay, UO22+ levels in the range of 0.7-1.2 MUg/L (2.9-5.0 nM) were identified in high salinity seawater samples, with spike-recoveries ranging from 93% to 104%. PMID- 29759196 TI - Label-free sensitive luminescence biosensor for immunoglobulin G based on Ag6Au6 ethisterone cluster-estrogen receptor alpha aggregation and graphene. AB - A specific and label-free "on-off-on" luminescence biosensor based on a novel heterometallic cluster [Ag6Au6(ethisterone)12]-estrogen receptor alpha (Ag6Au6Eth ERalpha) aggregation utilizing graphene oxide (GO) as a quencher to lead a small background signal was firstly constructed to detect immunoglobulin G (IgG) with a simple process and high selectivity. The efficient photoluminescent (PL) Ag6Au6Eth-ERalpha aggregation is strongly quenched by GO. In the presence of IgG, the PL of this system will be restored, and perceivable by human eyes under UV lamp excitation (365 nm). The quenching mechanism of GO on Ag6Au6Eth-ERalpha and enhancement mechanism of IgG on Ag6Au6Eth-ERalpha-GO were investigated in detail. Under the optimum conditions, the biosensor for high sensitive IgG detection expressed a wider linear range of 0.0078-10 ng/mL and a lower detection limit of 0.65 pg/mL with good stability and repeatability, which provided a new approach for label-free IgG detection. PMID- 29759199 TI - Determination and speciation of ultratrace arsenic and chromium species using aluminium oxide supported on graphene oxide. AB - Alumina supported on graphene oxide (Al2O3/GO) nanocomposite as new nanosorbent in dispersive micro-solid phase extraction (DMSPE) for As(V) and Cr(III) preconcentration is described. The crucial issue of the study is synthesis of novel nanocomposite suitable for sorption of selected species of arsenic and chromium. Al2O3/GO demonstrates selectivity toward arsenates in the presence of arsenites at pH 5 and chromium(III) ions in the presence of chromate anions at pH 6. The Al2O3/GO nanocomposite was characterized by scanning electron microscopy (SEM) transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and the Raman spectroscopy. The maximum adsorption capacity calculated based on the Langmuir adsorption model were 43.9 mg g-1 and 53.9 mg g-1 for As(V) and Cr(III), respectively. The nanocomposite was used as solid sorbent in preconcentration of As(V) and Cr(III)_ions from water samples and their determination using energy dispersive X-ray fluorescence spectrometry (EDXRF). The As(V) and Cr(III) ions can be quantitatively preconcentrated from 25 to 100 mL aqueous samples within 5 min using DMSPE procedure and 1 mg of Al2O3/GO. The nanocomposite was also used for preparation of Al2O3/GO membrane. Then, As(V) and Cr(III)_ions can be retained under flow condition by passing analyzed solution through Al2O3/GO membrane. Under the optimized conditions, As(V) and Cr(III) ions can be determined with very good recovery (92-108%), precision (RSD 2.7-4.0%) and excellent limit of detection (0.02 ng mL-1 As and 0.11 ng mL-1 Cr). The accuracy of the method was studied by analyzing certified reference materials (NIST 1640a) and spiked real water samples. PMID- 29759200 TI - Rapid colorimetric lactoferrin-based sandwich immunoassay on cotton swabs for the detection of foodborne pathogenic bacteria. AB - Cotton swab is the conventional swabbing tool that is usually applied for collecting pathogens from contaminated surfaces, followed by cells lysis and DNA extraction before subjecting to genetic analysis. However, such an approach is time consuming as it involves several steps and requires highly trained personnel to perform the experiment. In this study, we developed a new cotton swab-based detection system that involved integrating bacterial collection, preconcentration and detection on Q-tips. The platform is based on a sandwich assay that can detect different pathogens visually by color changes. Lactoferrin-immobilized cotton is used as a general capturing tool to collect various pathogens from surfaces. The presence of particular bacteria is then detected by immersing the cotton in antibodies attached to different colored nanobeads. The target cell is captured between the lactoferrin and specific antibody-conjugated beads which results in certain color development. The effectiveness of this simply fabricated sensor was demonstrated using Salmonella typhimurium, Salmonella enteritidis, Staphylococcus aureus and Campylobacter jejuni. The intensity of the color on the cotton surfaces increased with increasing the concentration of the pathogenic bacteria. The detection limit was as low as 10 cfu/ml for Salmonella typhimurium and Campylobacter jejuni, 100 cfu/ml for Salmonella enteritidis and 100 cfu/ml for Staphylococcus aureus on chicken meat surface. Moreover, this method showed high selectivity and was further confirmed by loop-mediated isothermal amplification (LAMP). The simplicity and the low cost of this colorimetric sensor renders it applicable to a wide range of other pathogens on different surfaces. PMID- 29759201 TI - Specific detection of stable single nucleobase mismatch using SU-8 coated silicon nanowires platform. AB - Novel microarray platform for single nucleotide polymorphisms (SNPs) detection has been developed using silicon nanowires (SiNWs) as support and two different surface modification methods for attaining the necessary functional groups. Accordingly, we compared the detection specificity and stability over time of the probes printed on SiNWs modified with (3-aminopropyl)triethoxysilane (APTES) and glutaraldehyde (GAD), or coated with a simpler procedure using epoxy-based SU-8 photoresist. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX) were used for comparative characterization of the unmodified and coated SiNWs. The hybridization efficiency was assessed by comprehensive statistical analysis of the acquired data from confocal fluorescence scanning of the manufactured biochips. The high detection specificity between the hybridized probes containing different mismatch types was demonstrated on SU-8 coating by one way ANOVA test (adjusted p value *** < .0001). The stability over time of the probes tethered on SiNWs coated with SU-8 was evaluated after 1, 4, 8 and 21 days of probe incubation, revealing values for coefficient of variation (CV) between 2.4% and 5.6%. The signal-to-both-standard-deviations ratio measured for SU-8 coated SiNWs platform was similar to the commercial support, while the APTES-GAD coated SiNWs exhibited the highest values. PMID- 29759202 TI - A new extraction phase based on a polymer inclusion membrane for the detection of chlorpyrifos, diazinon and cyprodinil in natural water samples. AB - A simple and effective method for the detection of three pesticides (chlorpyrifos, diazinon and cyprodinil) is developed using a polymer inclusion membrane (PIM) prior to gas chromatography and mass spectrometry detection (GC MS). Analytes are extracted from natural water samples using a 3 cm2 PIM made of the polymer, cellulose triacetate (CTA), and the plasticizer, nitrophenyl octyl ether (NPOE). Addition of the plasticizer to the CTA matrix is found to be necessary for the extraction of pesticides. After extraction, analytes are recovered from the membrane with 1 mL of acetonitrile and injected into the GC-MS system. The main factors affecting the extraction efficiency are evaluated, including membrane composition, stirring mode, extraction and elution time. Ultrasonic assisted elution of the extracted pesticides is accomplished after 15 min of contact. The PIM-assisted extraction method makes it possible for pesticides to be determined in the range of 50-1000 ng L-1 with good linearity (coefficient of determination >=0.995) and suitable recoveries (85-119%) and precision (<21%, n = 3) using 100 mL of a water sample. This methodology is shown to be suitable for the detection of chlorpyrifos in local river waters. PMID- 29759203 TI - Stability of proton-bound clusters of alkyl alcohols, aldehydes and ketones in Ion Mobility Spectrometry. AB - Significant substances in emerging applications of ion mobility spectrometry such as breath analysis for clinical diagnostics and headspace analysis for food purity include low molar mass alcohols, ketones, aldehydes and esters which produce mobility spectra containing protonated monomers and proton-bound dimers. Spectra for all n- alcohols, aldehydes and ketones from carbon number three to eight exhibited protonated monomers and proton-bound dimers with ion drift times of 6.5-13.3 ms at ambient pressure and from 35 degrees to 80 degrees C in nitrogen. Only n-alcohols from 1-pentanol to 1-octanol produced proton-bound trimers which were sufficiently stable to be observed at these temperatures and drift times of 12.8-16.3 ms. Polar functional groups were protected in compact structures in ab initio models for proton-bound dimers of alcohols, ketones and aldehydes. Only alcohols formed a V-shaped arrangement for proton-bound trimers strengthening ion stability and lifetime. In contrast, models for proton-bound trimers of aldehydes and ketones showed association of the third neutral through weak, non-specific, long-range interactions consistent with ion dissociation in the ion mobility drift tube before arriving at the detector. Collision cross sections derived from reduced mobility coefficients in nitrogen gas atmosphere support the predicted ion structures and approximate degrees of hydration. PMID- 29759204 TI - Internal standard-based SERS aptasensor for ultrasensitive quantitative detection of Ag+ ion. AB - A ratiometric surface-enhanced Raman scattering (SERS) aptasensor based on internal standard (IS) methods was proposed for the ultrasensitive and reproducible quantitative detection of silver ion (Ag+) with Au@Ag core-shell nanoparticle (Au@Ag NP) substrate. In principle, the thiolated 5'-Rox C containing labeled aptamer probe (Rox-aptamer) is firstly immobilized on the SERS substrate surface and then hybridizes with the complementary DNA (cDNA) to form a rigid double-stranded DNA (dsDNA), in which the Rox Raman labels is used to produce the Raman signal. Furthermore, the pyridine is employed as an IS element to provide the ratiometric determination of target. In the presence of Ag+, the Rox-aptamer is turned into the cytosine (C)-Ag+-C mediated hairpin structure, which remarkably reduces the distance between the Rox labels and the Au@Ag NP surface responsible for a measurable 'turn-on' signal change of Rox. This IS based ratiometric SERS aptasensor exhibits a limit of detection of 50 pM for Ag+ with a linear detection range from 0.1 to 100 nM and the shortcoming of irreproducibility of SERS signal could be overcome. The proposed method provides a simple, robust, and rapid approach for the sensitive and reproducible quantitative detection of Ag+, and it could also be used for the detection of other metal ions which exhibits specific interactions with natural or synthetic bases. PMID- 29759205 TI - Green synthesis of carbon dots functionalized silver nanoparticles for the colorimetric detection of phoxim. AB - In this work, Lycii Fructus as raw materials for green synthesis of fluorescent carbon dots (CDs) reduce AgNO3. The CDs-AgNPs were synthesized by one-step method. CDs were applied to stabilize AgNPs due to abundant functional groups on the surface of CDs. In presence of phoxim, the dispersed CDs-AgNPs get aggregated and the absorption peak with red shift from 400 nm to 525 nm, resulting in the color changed from yellow to red. Under optimized conditions, the absorbance ratio at A525 nm/A400 nm was related linearly to the concentrations of phoxim in the range of 0.1-100 MUM. The detection limit was calculated to 0.04 MUM, which is lower than maximum residue limits of phoxim in samples in China. The colorimetric sensor was successfully utilized to monitoring phoxim in environmental and fruit samples with good recoveries ranges from 87% to 110.0%. These results showed the sensor had a promising application prospect in real samples. PMID- 29759206 TI - Sequential injection system with in-line solid phase extraction and soil mini column for determination of zinc and copper in soil leachates. AB - A sequential injection (SI) system equipped with in-line solid phase extraction column and in-line soil mini-column is proposed for determination of zinc and copper in soil leachates. The spectrophotometric determination (560 nm) is based on the reaction of both analytes with 1-(2-Pyridylazo)-2-naphthol (PAN). Zinc is determined after retaining copper on a cationic resin (Chelex100) whereas copper is determined from the difference of the absorbance measured for both analytes, introduced into the system with the use of a different channel, and zinc absorbance. The influence of several potential interferences was studied. Using the developed method, zinc and copper were determined within the concentration ranges of 0.005-0.300 and 0.011-0.200 mg L-1, and with a relative standard deviation lower than 6.0% and 5.1%, respectively. The detection limits are 1.4 and 3.0 ug/L for determination of zinc and copper, respectively. The developed SI method was verified by the determination of both analytes in synthetic and certified reference materials of water samples, and applied to the determination of the analytes in rain water and soil leachates from laboratory scale soil core column and in-line soil mini-column. PMID- 29759207 TI - In vivo monitoring of nicotine biosynthesis in tobacco leaves by low-temperature plasma mass spectrometry. AB - Low-temperature plasma (LTP) is capable of ionizing a broad range of organic molecules at ambient conditions. The coupling of LTP to a mass analyzer delivers chemical profiles from delicate objects. To investigate the suitability of LTP ionization for mass spectrometry (MS) based in vivo studies, we monitored the auxin-regulated nicotine biosynthesis in tobacco (Nicotiana tabacum) and evaluated possible biological effects. The measured nicotine concentrations in different experiments were comparable to literature data obtained with conventional methods. The observed compounds suggest the rupture of trichomes, and cell damage was observed on the spots exposed to LTP. However, the lesions only affected a negligible proportion of the leaf surface area and no systemic reaction was noted. Thus, our study provides the proof-of-concept for measuring the biosynthetic activity of plant surfaces in vivo. PMID- 29759208 TI - Polarity tuned perphenylcarbamoylated cyclodextrin separation materials for achiral and chiral differentiation. AB - Phenylcarbamoyls are known to remarkably accentuate cyclodextrin's enantioselectivities. In this work, by inducing electron-donating methoxyl or electron-withdrawing bromine/trifluoromethyl moieties, three novel cyclodextrin enantioseparation materials including per(4-trifluoromethoxy) phenylcarbamoylated beta-CD CSP (CSP1), per(4-bromo)phenylcarbamoylated-beta-CD CSP (CSP2) and per(4 methoxy)phenylcarbamoylated-beta-CD CSP (CSP3) were prepared via thiol-ene click chemistry. The polarity tuning decorations are found to significantly influence the CSPs' achiral and chiral separation performance. The three CSPs can easily separate toluene, 1,2-xylene and 1,3,5-trimethylbenzene with the strongest retention on CSP3. In reversed-phase mode, the three CSPs exhibited completely different enantioseparation ability towards specific isoxazolines and flavonoids. 4'-hydroxyflavanone was separated on CSP1 with a resolution of 9.24 while 6 methoxyflavanone was best separated on CSP2 (Rs = 9.98). CSP3 exhibited the strongest differentiation ability towards 4NPh-2Py (Rs = 9.69). The comparison study may provide some insight into the design of functional cyclodextrin materials. PMID- 29759209 TI - Fabrication of RGO-NiCo2O4 nanorods composite from deep eutectic solvents for nonenzymatic amperometric sensing of glucose. AB - A novel reduced graphene oxide supported nickel cobaltate nanorods composite (RGO NiCo2O4) was prepared by a simple ionothermal method in deep eutectic solvents for the first time. Electrochemical results demonstrated that the obtained nanocomposite modified glassy carbon electrode exhibited excellent electrocatalytic performance towards the oxidation of glucose with a wide double linear range from 1 MUM to 25 mM and a low detection limit of 0.35 MUM (S/N = 3). NiCo2O4 nanorods with many small interconnected nanoparticles provided many electrocatalytic active sites, while RGO with large surface area offered good electrical conductivity. The synergistic effect between NiCo2O4 nanorods and RGO contributed to the enhanced sensing ability of the hybrid nanostructure. This sensitive glucose sensor can be also used for the practical detection of glucose in human serum. PMID- 29759210 TI - Smart bi-metallic perovskite nanofibers as selective and reusable sensors of nano level concentrations of non-steroidal anti-inflammatory drugs. AB - A strategy for trace-level carbon-based electrochemical sensors is investigated via exploring the interesting properties of BaNb2O6 nanofibers (NFs). Utilizing adsorptive stripping square wave voltammetry (ASSWV), an electrochemical sensing platform was developed based on BaNb2O6 nanofibers-modified carbon paste electrode (CPE) for the sensitive detection of lornoxicam (LOR). Different techniques were used to characterize the fabricated BaNb2O6 perovskite NFs. The obtained data show the feasibility to electro-oxidize LOR and paracetamol (PAR) on the surface of the fabricated sensor. The amount of nanofiber and testing conditions were optimized using response surface methodology and ASSWV technique. The optimized BaNb2O6/CPE sensor exhibits low detection limit of 6.39 * 10-10 mol L-1, even in the presence of the co-formulated drug paracetamol (PAR). The sensor was successfully applied for biological applications. PMID- 29759211 TI - Triplex DNA formation-mediated strand displacement reaction for highly sensitive fluorescent detection of melamine. AB - Since melamine is a strong hazard to human health, the development of new methods for highly sensitive detection of melamine is highly desirable. Herein, a novel fluorescent biosensing strategy was designed for sensitive and selective melamine assay based on the recognition ability of abasic (AP) site in triplex towards melamine and signal amplification by Mg2+-dependent DNAzyme. In this strategy, the melamine-induced formation of triplex DNA was employed to trigger the strand displacement reaction (SDR). The SDR process converted the specific target recognition into the release and activation of Mg2+-dependent DNAzyme, which could catalyze the cleavage of fluorophore/quencher labeled DNA substrate (FQ), resulting in a significantly increased fluorescent signal. Under the optimal conditions, the fluorescent signal has a linear relationship with the logarithm of the melamine concentration in a wide range of 0.005-50 MUM. The detection limit was estimated to be 0.9 nM (0.1ppb), which is sufficiently sensitive for practical application. Furthermore, this strategy exhibits high selectivity against other potential interfering substances, and the practical application of this strategy for milk samples reveals that the proposed strategy works well for melamine assay in real samples. Therefore, this strategy presents a new method for the sensitive melamine assay and holds great promise for sensing applications in the environment and the food safety field. PMID- 29759212 TI - A colorimetric and turn-on NIR fluorescent probe based on xanthene system for sensitive detection of thiophenol and its application in bioimaging. AB - Developing fluorescent probes for specific detection of extremely toxic thiophenols is pretty significant in the field of environment, chemistry and biology. We report herein a turn-on red fluorescent xanthene-based probe (RD Probe) for detecting thiophenol with high selectivity over other analytes including aliphatic thiols. The probe could play the part of a "naked eye"colorimetric indicator toward thiophenol. Moreover, the relative fluorescence intensity at 653 nm displayed good linearity with the concentration of thiophenol ranging from 0 to 6 MUM, and the limit of detection for thiophenol could be as low as 15 nM. Furthermore, the practicability of RD-Probe has been successfully proved through the quantitative thiophenol detection in real water samples and fluorescence bioimaging of thiophenol in HeLa cells. PMID- 29759213 TI - Evaporative fluorophore labeling of carbohydrates via reductive amination. AB - As analytical glycomics became to prominence, newer and more efficient sample preparation methods are being developed. Albeit, numerous reductive amination based carbohydrate labeling protocols have been reported in the literature, the preferred way to conduct the reaction is in closed vials. Here we report on a novel evaporative labeling protocol with the great advantage of continuously concentrating the reagents during the tagging reaction, therefore accommodating to reach the optimal reagent concentrations for a wide range of glycan structures in a complex mixture. The optimized conditions of the evaporative labeling process minimized sialylation loss, otherwise representing a major issue in reductive amination based carbohydrate tagging. In addition, complete and uniform dispersion of dry samples was obtained by supplementing the low volume labeling mixtures (several microliters) with the addition of extra solvent (e.g., THF). Evaporative labeling is an automation-friendly glycan labeling method, suitable for standard open 96 well plate format operation. PMID- 29759214 TI - Improving thermal control of capillary electrophoresis with mass spectrometry and capacitively coupled contactless conductivity detection by using 3D printed cartridges. AB - A 3D-printed cartridge was developed to improve the interface between a capillary electrophoresis instrument and a mass spectrometer. The thermostated airflow from the CE was guided to the entrance of the electrospray source keeping as much as possible the silica capillary in a proper Joule-heating dissipation environment. Hollow 3D-printed walls made of ABS covered by a 0.2 mm thick copper foil on the inner side were used. The cartridge also allows including up to two capacitively coupled contactless conductivity detectors (C4Ds). Experiments about the separation of monoethyl carbonate (a thermally unstable species) shows that the peak area obtained with the original cartridge is only 21% of the value obtained with the 3D-printed cartridge, which demonstrates the improvement in heat dissipation. PMID- 29759215 TI - Study of chromium species release from metal implants in blood and joint effusion: Utilization of HPLC-ICP-MS. AB - The objective of this study was to develop and validate a novel analytical procedure for determination of total chromium and Cr(III) and Cr(VI) species released from metal implants into whole blood and joint effusion. Firstly, the ion-pair chromatographic method employing reversed-phase high-performance liquid chromatography inductively coupled plasma mass spectrometry (ICP-MS) for analysis of species was developed. Secondly, all samples, protein and low molecular fractions were analyzed for their total chromium content using ICP-MS. This new measurement procedure was validated by the following parameters: limit of detection (0.13 MUg L-1 for Cr(III), 0.14 MUg L-1 for Cr(VI)), linearity of calibration, trueness (recovery 84-92%), intermediate precision (RSD < 5%). We determined statistically significantly higher chromium levels in joint effusion samples obtained from patients in comparison with a control group. On the other hand, no relevant difference among the concentrations of both species and total chromium in blood was observed. Our results show that the majority of chromium is present in the trivalent form and bound to proteins. This speciation study is rare in the field of speciation analysis in clinical samples. It is characterized by very fast and simple sample preparation without any changes in distribution or stability of both Cr forms and efficient simultaneous analysis of Cr species. PMID- 29759217 TI - Complexing porous polymer monoliths for online solid-phase extraction of metals in sequential injection analysis with electrochemical detection. AB - A monolithic column affording complexing groups was synthesized for automated solid-phase extraction of potentially toxic metal ions in a low-pressure sequential injection analyzer. Poly(glycidyl methacrylate-co-ethylene dimethacrylate) monoliths were synthesized by free-radical polymerization in the coffins of fused silica-lined stainless-steel tubes (2.10 mm i.d. * 5-6 cm length). High permeability (4.33 * 10-13 m2) was achieved for monoliths polymerized for 24 h at 60 degrees C from a mixture of 30 wt% glycidyl methacrylate, 10 wt% ethylene glycol dimethacrylate, 35 wt% n-propanol, 20 wt% 1,4 butanediol and 5 wt% water. Azobisisobutyronitrile (1 wt% with respect to the monomers) initiated the free-radical polymerization. These generic columns were modified with iminodiacetate to create complexing functionalities on the polymer surface, being further used for online solid-phase extraction of Cu2+, Pb2+ and Cd2+ from natural, tap and drinking waters prior to their determination by stripping chronopotentiometry. The high permeability of the column allowed the loading, washing, eluting and reconditioning steps to be made at flow rate of 10 uL s-1. The limits of detection and quantification achieved by processing 1500 uL of sample were 0.51 and 1.7 ug L-1 for Cu2+, 1.4 and 4.7 ug L-1 for Pb2+, and 1.2 and 3.8 ug L-1 for Cd2+, respectively. Recoveries were between 75.5% and 117%, obtained by quantification via external calibration curves, thus eliminating the need for the laborious standard addition strategies. PMID- 29759216 TI - Geometric search: A new approach for fitting PARAFAC2 models on GC-MS data. AB - PARAFAC2 is a powerful decomposition method which is ideally suited for modeling gas chromatography-mass spectrometry (GC-MS) data. However, the most widely used fitting algorithms (alternating least squares, ALS) are very slow which hinders use of the model. In this paper, an iterative method called geometric search is proposed to fit the PARAFAC2 model. This method models the PARAFAC2 loading parameters as geometric sequences with offsets during the ALS iterations. It extrapolates the optimal parameters from prior iterations to accelerate ALS convergence process. The performance of this method was evaluated by simulated datasets and two GC-MS datasets of wine and tobacco samples. This geometric search method proved an efficient way to fit PARAFAC2 models, compared with a standard ALS algorithm and two widely used line search algorithms in terms of convergence speed and fitting quality. PMID- 29759218 TI - A thiazolo[4,5-b]pyridine-based fluorescent probe for detection of zinc ions and application for in vitro and in vivo bioimaging. AB - 2-HPTP, a novel thiazolo [4, 5-b] pyridine-based Zn2+ selective fluorescent probe has been synthesized and investigated. This probe exhibited a high selectivity towards Zn2+ over other biologically essential cations such as Na+, K+, Ca2+, or Mg2+. 2-HPTP formed a 1:1 complex with Zn2+ and showed a fluorescent enhancement with a long emission wavelength red-shift (85 nm) upon complex formation with Zn2+. The detection limit and association constant were calculated as 3.48 * 10-7 M and 2.40 * 106 M-1 by a fluorescence titration experiment. Furthermore, the live cell imaging experiment showed that 2-HPTP was membrane permeable and photostable, and hence, could be used to monitor the concentration changes of intracellular Zn2+. The co-staining experiments in the cells demonstrated that 2 HPTP possessed high lysosomal selectivity in living cells. Finally, using the nematode C. elegans as an experimental model, we established that 2-HPTP could be successful in imaging Zn2+ concentration changes in living tissues. Therefore, this molecule should be useful for studies on the biological functions of Zn2+. PMID- 29759220 TI - Determination of perchlorate from tea leaves using quaternary ammonium modified magnetic carboxyl-carbon nanotubes followed by liquid chromatography-tandem quadrupole mass spectrometry. AB - The novel quaternary ammonium modified magnetic carboxyl-carbon nanotubes (QA-Mag CCNTs) have been synthesised and characterized. QA-Mag-CCNTs were applied in magnetic dispersive solid phase extraction (Mag-dSPE) for preconcentration of perchlorate from tea leaves prior to liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS) analysis. The Mag-dSPE procedure for preconcentration of perchlorate succeed in overcoming the flaw (containing target analyte randomly) of commercially available SPE cartridge. Under optimal conditions, the results showed higher extraction efficiency of QA-Mag-CCNTs, with recoveries between 85.2% and 107%. And the satisfactory precision with inter-day and intra-day RSD values were lower than 8.0%. Furthermore, QA-Mag-CCNTs were evaluated for reuse up to 20 times. The limit of quantification (LOQ) for perchlorate was 8.21 ng kg 1. The developed method was successfully applied in tea leaves for food-safety risk monitoring in Zhejiang province, China. The results showed the concentrations of perchlorate in 229 out of 240 collected samples were in the range of 0.082-988 MUg kg-1. It was confirmed that QA-Mag-CCNTs were highly effective materials used for preconcentration of perchlorate. PMID- 29759221 TI - Simultaneous determination of total dissolved nitrogen and total dissolved phosphorus in natural waters with an on-line UV and thermal digestion. AB - A flow injection method combined with an on-line UV and thermal digestion for simultaneous determination of total dissolved nitrogen (TDN) and total dissolved phosphorus (TDP) in natural waters was established in this study. A novel flow manifold made the proposed system compact and automatic. The conversion rates of various nitrogen and phosphorus compounds to their nitrate and phosphate forms with different digestion models and different concentrations were well investigated using the flow injection technique. The reagent concentrations for colorimetric analysis were optimized based on a univariate experimental design. The detection limits were 0.8 MUmol L-1 and 0.2 MUmol L-1, and linear analytical ranges were up to 300 MUmol L-1 and 25 MUmol L-1 for TDN and TDP, respectively. The sample throughput was ~ 5 h-1. The recovery of spiked natural water samples varied from 86.8% to 102.6% for TDN and 88.0% to 102.0% for TDP. The present approach was successfully applied for the determination of TDN and TDP in natural water samples and was found to have good agreement with reference methods. The outcomes of present study indicated that the proposed method is suitable for routine analysis as well as for potential on-line monitoring. PMID- 29759219 TI - Electrochemical detection of microcystin-LR based on its deleterious effect on DNA. AB - This work reveals the deleterious effect of microcystin-LR (MC-LR) on the conformation of DNA and develops an electrochemical biosensor for detection of MC LR. The biosensor is prepared by physically immobilizing calf thymus DNA (ctDNA) on gold electrode. In the presence of MC-LR, the conformation change of immobilized ctDNA decreases the electron transfer impedance, thus enhances the amperometric response. The proposed method shows a linear range of 4-512 ng/L and a detection limit of 1.4 ng/L, which is 700-fold lower than the guideline level suggested by the World Health Organization. The detection results are in good agreement with those from the conventional HPLC method. This biosensor possesses good stability against other components in natural water sample, and has been used for detection of MC-LR in local water bodies, indicating its application promise. PMID- 29759222 TI - A high-performance chiral selector derived from chitosan (p-methylbenzylurea) for efficient enantiomer separation. AB - N-Methoxycarbonyl chitosan was prepared by selectively modifying the amino group at the 2-position of chitosan with methyl chloroformate, which was further functionalized with p-methylbenzylamine to produce chitosan (p-methylbenzylurea). Then, the hydroxyl groups at the 3- and 6-positions of the glucose skeleton were modified with various phenyl isocyanates, affording a series of chitosan 3,6 bis(arylcarbamate)-2-(p-methylbenzylurea)s, which were characterized and proposed as chiral selectors for enantiomer separation. Nineteen racemates, most of which are drugs or intermediates for drugs, were selected as the model analytes to evaluate the enantioseparation performance. The structure-performance relationship of the chiral selectors was investigated in detail. It was found that the methyl-substituted chiral selectors possessed more preferable enantioseparation performance compared with the chloro-substituted ones, and the chiral selectors containing a methyl substituent at the 4-position of the benzene ring showed the best chiral recognition and separation ability with 17 racemates being recognized and 13 racemates being baseline separated. The prepared chiral separation materials derived from these chiral selectors exhibited favorable solvent tolerance towards ethyl acetate, acetone, chloroform and a low proportion of tetrahydrofuran in normal phase. To sum up, this work provided a useful reference for the design and preparation of high-performance chiral separation materials for efficient enantiomer separation. PMID- 29759223 TI - Effects of hydrophilic monomers on sorptive properties of divinylbenzene-based reversed phase sorbents. AB - Solid phase extraction (SPE) has been extensively used as a pretreatment method. In SPE methods, commercially available reversed phase type sorbents, which consist of macroporus styrene-divinylbenzene or copolymers including divinylbenzene (DVB) and hydrophilic monomers, have been applied to a variety of samples. The later sorbents are called hydrophilic lipophilic balanced (HLB) type sorbents. Hydrophilic monomers in hydrophilic lipophilic balanced type sorbents contribute to the increase in retention of polar compounds, because hydrophilic monomers improve the wettability and increase the interaction with polar compounds as analytes. In this study, three different methacrylate monomers (ethylene glycol dimethacrylate (EGDMA), glycerol dimethacrylate (GDMA) and trimethylolpropane trimethacrylate (TMPTMA)), which are expected to improve the retention of polar compounds, were chosen, and DVB-based copolymetric sorbents including the three monomers were newly synthesized. Among them, the sorbents including GDMA or TMPTMA gave higher recoveries to polar compounds such as uridine and adenine than that including EGDMA. The optimization studies of hydrophilic lipophilic balance, inert diluent and the purity of DVB improved the sorptive abilities of the sorbents. The developed sorbents have higher recoveries for variety of polar compounds (cytosine, uracil, cytidine, uridine, 2' deoxycytidine, 2'-deoxyguanosine, adenine, thymidine, adenosine and 2' deoxyadenosine) than commercially available hydrophilic lipophilic balanced type sorbents, while the recoveries for theophylline were comparable between the proposed sorbents and the commercial sorbents. PMID- 29759225 TI - CeO2-CB nanocomposite as a novel SALDI substrate for enhancing the detection sensitivity of pharmaceutical drug molecules in beverage samples. AB - SALDI-MS analysis of pharmaceutical drug molecules (amitriptyline, imipramine and promazine) using carbon-based substrates, namely, activated charcoal (AC), carbon nanotubes (CNTs), carbon black (CB), graphene (rGO), graphene oxide (GO) and graphite, was explored and compared with the conventional organic matrix of MALDI. CB exhibited superior performance with respect to the other substrates in terms of detection sensitivity. Despite the effectiveness of CB to detect all drug molecules, it demonstrated a number of background signals, which may be an issue for the analysis of other molecules in the future. Therefore, for the first time, a CeO2-CB nanocomposite was synthesized and applied as a novel SALDI substrate to minimize the background signals and stabilize CB when exposed to high laser power. The nanocomposite was characterized using XRD, TEM, FTIR, UV Vis and N2 sorpometry. The spectrum obtained using the novel nanocomposite in the absence of the drug molecules showed minimal background signals compared to CB. Additionally, the CeO2-CB nanocomposite enhanced the detection sensitivity of the drug molecules with a limit of detection (LOD) of 100 ng/mL. This active substrate nanocomposite was further applied for the analysis of drug-spiked beverages without sample pretreatment or extraction, mimicking cases encountered by forensic toxicologists. All of the drugs and/or their adducts were detected in the drug-spiked beverage samples. PMID- 29759226 TI - A novel electrochemiluminescence resonance energy transfer system of luminol graphene quantum dot composite and its application in H2O2 detection. AB - Luminol-nitrogen doped graphene quantum dot (luminol-NGQDs) nanocomposite was synthesized and a novel electrochemiluminescence resonance energy transfer (ECL RET) process occurred between luminol as the donor and NGQDs as the acceptor in the composite. This ECL-RET effect helped luminol-NGQDs composite produced an anodic ECL signal without coreactants. The ECL-RET mechanism was also studied based on the fluorescence spectra, the ultraviolet-visible absorption spectra and the electrochemiluminescence (ECL) spectra. Based on the significant sensitization effect of hydrogen peroxide on luminol-NGQDs ECL signal, an ECL method for the sensitive determination of hydrogen peroxide was established and then applied to the detection of hydrogen peroxide in water samples. PMID- 29759224 TI - Enhancing the peroxidase-like activity of ficin via heme binding and colorimetric detection for uric acid. AB - Ficin, a classical sulfhydryl protease, was found to possess intrinsic peroxidase like activity. In this paper, we have put forward a novel strategy to improving the peroxidase-like activity of ficin through binding heme. Heme-ficin complexes were successfully obtained by simple one-step syntheticism. The results demonstrated that the catalytic activity and efficiency of heme-ficin complexes were about 1.7 times and 3 times higher than those of native ficin, respectively. Taking advantages of the high peroxidase-like activity, the heme-ficin complexes were used for colorimetric determination of uric acid with a low detection limit of 0.25 MUM. Based on the excellent selectivity and sensitivity, we detected the concentration of uric acid in human serum successfully. On the basis of these findings, the heme-ficin complexes are promising for wide applications in various fields. Thus we not only optimized the peroxidase-like activity of the ficin, but also established a new strategy for development of artificial enzyme mimics by mimicking the architecture of the active site in horseradish peroxidase. PMID- 29759227 TI - A novel electrochemical sensor for detecting hyperin with a nanocomposite of ZrO2 SDS-SWCNTs as decoration. AB - A novel high-sensitive electrochemical sensor with glassy carbon electrode (GCE) as support for hyperin determination is successfully designed and constructed, and the well-shaped nano-meter modified material is synthesized via a one-step and facile route. Functionalized with surfactant sodium dodecyl sulfate (SDS), Single-Walled Carbon Nanotubes (SWCNTs) are synchronously grafted with ZrO2 nanoparticles to develop into the as-prepared nano-composite (ZrO2-SDS-SWCNTs). Compared to the previous reports related with hyperin detection, the linear range gets wider and detection limit (LOD) becomes lower with the aid of this novel nano-composite modified glassy carbon electrode (ZrO2-SDS-SWCNTs/GCE). The crystalline phases and functionalization of the preparation process has been investigated by X-ray diffraction (XRD) and Fourier transform infrared (FT-IR) instrument analysis, respectively, and the micro-morphology of related modified materials is also visibly characterized by scanning electron microscope (SEM) and transmission electron microscope (TEM). In addition, electrochemical properties of the modified materials are comparably explored by means of impedance spectroscopy (EIS) and cyclic voltammograms (CV). According to the established calibration curve under optimized condition, the peak current (Differential pulse voltammetry (DPV) signal) keeps a linear relationship with hyperin concentration in the ranges of 1.0 * 10-9 - 3.0 * 10-7 mol L-1, meanwhile detection limit reaches as low as 5 * 10-10 mol L-1 (S/N = 3). As for practical applications, the proposed sensor has also worked well on sensitive hyperin determination in real species Abelmoschus manihot. PMID- 29759228 TI - A magnetic hydrazine-functionalized dendrimer embedded with TiO2 as a novel affinity probe for the selective enrichment of low-abundance phosphopeptides from biological samples. AB - Dendrimers exhibit tunable terminal functionality and bio-friendly nature, making them of being promising materials for applications in the field of separation and enrichment. In this work, we prepared magnetic hydrazide-functionalized poly amidoamine (PAMAM) dendrimer embedded with TiO2 for the enrichment of phosphopeptides. The novel affinity probe possessed superparamagnetism, realizing its rapid separation from sample solution. Electrostatic attraction and hydrogen bonding existed between PAMAM and phosphopeptides while Lewis acid-base interaction was originated between TiO2 and the targets. The combined synergistic strength of multiple binding interactions contributed to the highly selective enrichment of phosphopeptides. The specificity for the capture of phosphopeptides was reflected in quantities as low as 1:1000 mass ratio of phosphopeptides to non phosphopeptides. The detection limit of beta-casein digests was low to 0.4 fmol, indicating the high sensitivity of the developed method. Fifteen and four phosphopeptides could be selectively captured from non-fat milk digests and human serum samples, which further confirmed the great potential of the affinity probe in the extraction of low-abundance phosphopeptides from real complex biological samples. PMID- 29759229 TI - Evaluation of polar organic chemical integrative and hollow fibre samplers for the determination of a wide variety of organic polar compounds in seawater. AB - The calibration of two passive samplers for the determination of 20 emerging organic compounds in seawater is described in this work: i) a new version of polar organic chemical integrative sampler (POCIS) containing 100 mg of mixed mode anion exchanger (Strata X-AW) and 100 mg of polymeric HLB (Plexa) sorbent materials and using a highly porous Nylon membrane (30-MUm pore size) and ii) polyethersulfone (PES) hollow fibre. Among the studied contaminants, herbicides, hormones, life style products (stimulants and artificial sweeteners), industrial chemicals (corrosion inhibitor and fluorinated compounds), personal care products and several pharmaceuticals were included. In the case of POCIS, both the sorbents and the Nylon membranes were extracted and analysed independently. The calibration set up consisted on a continuous-flow tank that was fed with a continuous flow of seawater (2 L/h) and a stock mixture of contaminants (20 mL/h), assuring a nominal concentration of ~ 600 ng/L (each analyte) in the tank. The uptake was linear in POCIS sorbent and Nylon membranes but exponential for PES hollow fibres. Furthermore, the highest sampling rates (Rs) values were obtained in POCIS sorbent (between 2.7 for acetaminophen and 491 mL/day for perfluoro-n-octanoic acid, PFOA) followed by Nylon membranes (between 3.6 for OBT and 50 mL/day for telmisartan) and the lowest were those from PES fibres (between 1.7 for bezafibrate and 157 mL/day for butylparaben). Additionally, five deuterated compounds ([2H5]-atrazine, [2H3]-amitriptyline, [2H7]-irbesartan, [2H3]-ketoprofen and [2H9]-progesterone) were studied as candidates for performance reference compounds (PRCs) in both POCIS and PES, and though [2H5] atrazine, [2H9]-progesterone and [2H3]-amitriptyline showed acceptable results in the case of POCIS, only [2H5]-atrazine provided a good validation. In the case of PES fibres, the PRC corrections did not provide acceptable results due to a low dissipation of the PRCs. Finally, POCIS were deployed in two sites of the low part of the estuary of Bilbao (northern Spain) from where water samples were also taken and analysed. As a result, in addition to the overall good agreement between the passive and active samplings, passive samplers allowed the determination of several compounds that were below the detection limits in the active sampling. PMID- 29759231 TI - A high throughput metabolomics method and its application in female serum samples in a normal menstrual cycle based on liquid chromatography-mass spectrometry. AB - Periodical changes of steroid hormones have a great impact on the homeostasis of the female. However, there are few studies concerning the metabolome changes during the cycle. To study the periodic metabolic changes, a female cohort was enrolled with time-series serum samples collected during a menstrual cycle. To meet the requirement of the large-scale sample analysis, a high throughput metabolomics method was established by using an efficient sample preparation on a 96 well filter plate and a rapid LC condition in 12 min, which reduces about 70% of the samples preprocessing time and 60% analysis time. Evaluation of metabolite coverage and separation performances reflected that the method was robust for the large-scale metabolomics study. Using this method, we found that 12.6% of total detected ions including lipids, amino acids, citric acid, and so on were significantly changed during a menstrual cycle. Some metabolites were found periodically changed, which is similar to hormones (estrone and progesterone) during the cycle. These results show the novel high throughput method can be applied in large-scale metabolomics studies. PMID- 29759230 TI - A novel near-infrared fluorescent probe for highly selective detection of cysteine and its application in living cells. AB - A novel red-emitting fluorescent probe (DDNA) for cysteine has been rationally designed and synthesized, which exhibited a low limit of detection to Cys (0.26 MUM) as well as a favorable large stokes shift (lambdaEm-lambdaEx = 128 nm). This novel fluorophore (HDM), which features a large pi-conjugation system and typical intramolecular charge transfer (ICT) process, has a long emission wavelength at 631 nm. Besides that, as a turn-on fluorescent probe, it shows high selectivity and sensitivity for Cys over other metal ions and amino acids including the similar structured homocysteine (Hcy) and glutathione (GSH). Finally, the probe DDNA was successfully applied to bioimage intracellular Cys in Hela cells with low cytotoxicity. PMID- 29759232 TI - Synthesis-identification integration: One-pot hydrothermal preparation of fluorescent nitrogen-doped carbon nanodots for differentiating nucleobases with the aid of multivariate chemometrics analysis. AB - Most of the conventional multidimensional differential sensors currently need at least two-step fabrication, namely synthesis of probe(s) and identification of multiple analytes by mixing of analytes with probe(s), and were conducted using multiple sensing elements or several devices. In the study, we chose five different nucleobases (adenine, cytosine, guanine, thymine, and uracil) as model analytes, and found that under hydrothermal conditions, sodium citrate could react directly with various nucleobases to yield different nitrogen-doped carbon nanodots (CDs). The CDs synthesized from different nucleobases exhibited different fluorescent properties, leading to their respective characteristic fluorescence spectra. Hence, we combined the fluorescence spectra of the CDs with advanced chemometrics like principle component analysis (PCA), hierarchical cluster analysis (HCA), K-nearest neighbor (KNN) and soft independent modeling of class analogy (SIMCA), to present a conceptually novel "synthesis-identification integration" strategy to construct a multidimensional differential sensor for nucleobase discrimination. Single-wavelength excitation fluorescence spectral data, single-wavelength emission fluorescence spectral data, and fluorescence Excitation-Emission Matrices (EEMs) of the CDs were respectively used as input data of the differential sensor. The results showed that the discrimination ability of the multidimensional differential sensor with EEM data set as input data was superior to those with single-wavelength excitation/emission fluorescence data set, suggesting that increasing the number of the data input could improve the discrimination power. Two supervised pattern recognition methods, namely KNN and SIMCA, correctly identified the five nucleobases with a classification accuracy of 100%. The proposed "synthesis-identification integration" strategy together with a multidimensional array of experimental data holds great promise in the construction of differential sensors. PMID- 29759233 TI - Critical review of dog detection and the influences of physiology, training, and analytical methodologies. AB - Detection dogs serve a plethora of roles within modern society, and are relied upon to identify threats such as explosives and narcotics. Despite their importance, research and training regarding detection dogs has involved ambiguity. This is partially due to the fact that the assessment of effectiveness regarding detection dogs continues to be entrenched within a traditional, non scientific understanding. Furthermore, the capabilities of detection dogs are also based on their olfactory physiology and training methodologies, both of which are hampered by knowledge gaps. Additionally, the future of detection dogs is strongly influenced by welfare and social implications. Most importantly however, is the emergence of progressively inexpensive and efficacious analytical methodologies including gas chromatography related techniques, "e-noses", and capillary electrophoresis. These analytical methodologies provide both an alternative and assistor for the detection dog industry, however the interrelationship between these two detection paradigms requires clarification. These factors, when considering their relative contributions, illustrate a need to address research gaps, formalise the detection dog industry and research process, as well as take into consideration analytical methodologies and their influence on the future status of detection dogs. This review offers an integrated assessment of the factors involved in order to determine the current and future status of detection dogs. PMID- 29759234 TI - Label free aptasensor for ochratoxin A detection using polythiophene-3-carboxylic acid. AB - This work demonstrates the development of electrochemical aptasensor using ochratoxin A (OTA) aptamers. Different aptamer coupling strategies were tested using polythiophene-carboxylic acid (PT3C) and polypyrrole-3-carboxylic acid (PP3C). The best sensitivity was recorded by polythiophene-3-carboxylic acid (PT3C) on screen-printed carbon electrode (SPCE) to attain the direct detection of OTA. The quantification of OTA was achieved by using electrochemical impedance spectroscopy. A good dynamic range 0.125-2.5 ng ml-1 was obtained for OTA with limit of detection (LOD) 0.125 ng ml-1 and Limit of quantification (LOQ) 0.3 ng ml-1 respectively. The good reproducibility was recorded with RSD% of 3.68. The obtained straight line equation was y = 0.4061 * + 1.03, r = 0.99. For real sample applications, the developed aptasensors were demonstrated in coffee samples. The aptasensor displayed good recovery values in the range 88-89%, thus exhibited the effectiveness of proposed aptasensor for such complex matrices. PMID- 29759235 TI - Rapid microbiological methods (RMMs) for evaluating the activity of cephalosporin antibiotics employing triphenyltetrazolium chloride. AB - Agar diffusion method has been used to evaluate antimicrobial activity since the discovery of penicillin. Nevertheless, little progress has occurred in reducing the time required to determine growth inhibition zones. The aim of this work was to develop, optimize and validate rapid microbiological methods (RMMs) for cephalosporin antibiotics using triphenyltetrazolium chloride (TTC) to reduce the incubation time of the assays. Through a factorial design in which the inoculum suspension, incubation time, and percentage of the TTC solution were varied, it was possible to validate the RMMs for cefazolin, cefuroxime, ceftriaxone, and cefepime. The validated conditions employed 5 mL of MHA medium inoculated with 2% of Staphylococcus aureus suspension, incubation time of 5 h and 30 min at 37 +/- 1 degrees C and the addition of 0.3% TTC solution in 1% agar, cefazolin and cefuroxime in concentrations from 15 to 60 ug mL-1, ceftriaxone and cefepime in concentrations from 20 to 80 ug mL-1. The methods were selective, linear (for standard and sample curves, respectively), accurate, precise, robust and rugged. The results found by the RMMs were statistically similar to those found by conventional microbiological methods, but the advantages of the former decreased the incubation time from 22 h to 5 h and 30 min. Therefore, RMMs can be used in the evaluation and quantification of cephalosporin antibiotics, ensuring their quality, safety, and therapeutic efficacy. PMID- 29759236 TI - Rapid synthesis of three-dimensional sulfur-doped porous graphene via solid-state microwave irradiation for protein removal in plasma sample pretreatment. AB - In this work, we prepared three-dimensional sulfur-doped porous graphene (3D-SPG) via solid-state microwave method and first introduced it to plasma sample pretreatment as adsorbent for the removal of proteins. The efficient heating effect of solid-state microwave irradiation endowed the as-prepared 3D-SPG with large specific surface area, porous structures and sulfur-doped conjugated pi electron surface, thus producing an outstanding adsorbent for proteins adsorption. The adsorption behavior of 3D-SPG towards proteins was explored using bovine serum albumin (BSA) as the model protein and several kinetic models and isotherm models were employed to describe the adsorption process. The results indicated that BSA was adsorbed onto 3D-SPG in a monolayer manner with high adsorption capacity, and chemisorption and intraparticle diffusion was the rate controlling step in proteins adsorption process. By applying 3D-SPG as adsorbent to remove proteins in real rat plasma, we found that 3D-SPG solid phase extraction (SPE) gained exceedingly high protein removal efficiency compared with other plasma pretreatment methods, suggesting that 3D-SPG SPE could effectively prevent the deterioration of column performance and decrease the interference caused by matrix effect in the follow-up analysis. Furthermore, in comparison with the tandem mass spectra results between 3D-SPG SPE and methanol precipitation, 3D-SPG SPE demonstrated the ability to extract the protein-binding metabolites which usually could not be extracted by methanol precipitation. This ability made 3D-SPG SPE of great value in untargeted metabolomics profiling, because 3D-SPG SPE could be a complementary method to methanol precipitation to improve the coverage of metabolites. PMID- 29759237 TI - Evaluation of the activity of beta-glucosidase immobilized on polydimethylsiloxane (PDMS) with a microfluidic flow injection analyzer with embedded optical fibers. AB - beta-glucosidase from almonds was immobilized on a polydimethylsiloxane (PDMS) microdevice by covalent chain using 3-aminopropyltrietoxysilane and glutaraldehyde. Enzymatic activity was evaluated using p-nitro-phenyl-beta-D glucopyranoside dissolved in a 0.01 M pH 5.0 phosphate solution at 45 degrees C measuring the reaction product (p-nitrophenol) at 410 nm. The microdevice consisted of two parts: the one part where the enzymatic reaction was carried out and a second part where pH was adjusted at 10, with NaOH. The reaction product was measured at the microchip exit using two optical fibers which were aligned facing each other with a gap of 7 mm, between both tips using guides located perpendicular to the flow outlet. A water bath was used to carry out the enzymatic reaction on the microdevice at 45 degrees C. The enzymatic surface of the PDMS microdevice was 1.15 cm2 and the immobilized beta-glucosidase amount on the microdevice was of 1.17 ug/cm2. The calculated kinetics parameters were: Km 2.5 mM; Vmax 2.2 mM/min; Kcat 908.3/min and Kcat/Km 363.3/mM min. The immobilized enzyme is very stable decreasing only 5% the first 15 days; on the 30th day, the activity was 69%, regarding the initial activity. PMID- 29759238 TI - Ion mobility spectrometer with orthogonal X-Ray source for increased sensitivity. AB - Ion mobility spectrometers (IMS) are compact devices for extremely sensitive detection of proton and electron affine volatile compounds down to low pptv concentrations within less than a second. The measuring principle requires ionization of the target analyte. Most IMS employ radioactive electron sources, such as 63Ni or 3H. These radioactive materials suffer from legal restrictions limiting the fields of application. Furthermore, the electron emission has a predetermined intensity and cannot be controlled or disabled. In a previous work, we replaced the axially mounted 3H source of our ion mobility spectrometer with a commercially available X-ray source operated at low acceleration voltage of 4.5 kV to be applicable in most application without legal restrictions. However, the high penetration depth of the radiation together with the statistical behavior of the X-ray ionization process led to an increase of Fano noise and thus a limited signal-to-noise ratio. Therefore, the X-ray source is now mounted orthogonal to the drift tube in order to avoid Fano noise. Here, we compare the analytical performance of this orthogonal setup with the axially mounted X-ray source. The noise level is significantly reduced. This improves the signal-to-noise ratio from 700 with the axially placed source to more than 3000 with the orthogonally placed source, while the resolving power still remains at R = 100. Furthermore, typical limits of detection for some model substances in the low pptv range in positive and negative ion mode are given. PMID- 29759239 TI - Single-hole hollow molecularly imprinted polymer embedded carbon dot for fast detection of tetracycline in honey. AB - It is difficult to detect tetracycline (TC) in honey sample by using carbon dots (CDs) because the autofluorescence of the matrix of honey sample overlaps with the fluorescence emission spectrum of the large majority of CDs. Herein, single hole hollow molecularly imprinted polymers embedded carbon dots (HMIP@CD) was prepared via microwave-assisted method. TC in diluted honey sample was adsorbed by the HMIP@CD within 3 min, after which the HMIP@CD absorbed with TC was separated by centrifugation from honey sample and redispersed into phosphate buffer solution. The autofluorescence of honey that interferes with the fluorescence signal of HMIP@CD was avoided. The method exhibited an excellent linearity within 10-200 MUg L-1 and a low detection limit of 3.1 MUg L-1. At three spiking levels of TC, the recoveries ranged from 93% to 105% with precisions below 1.6%. This method provides an effective strategy for detecting analyte in complex matrix with autofluorescence interference. PMID- 29759240 TI - Reduced graphene oxide-ZnO nanocomposite based electrochemical sensor for sensitive and selective monitoring of 8-hydroxy-2'-deoxyguanosine. AB - Developing reliable and feasible electrochemical sensors for the detection of 8 hydroxy-2'-deoxyguanosine (8-OHdG) is important because the urinary level of 8 OHdG is related to cancer disease. Moreover, the co-existed uric acid (UA) as an interference severe affects the sensitive detection of 8-OHdG. Herein, sensitive monitoring of 8-OHdG was conducted using a nanocomposite of reduced graphene oxide (rGO) and ZnO nanoparticles (ZnO@rGO) as the sensing material. This nanocomposite was prepared via in-situ reduction of GO with Zn powders. Compared with those obtained on the unmodified glassy carbon electrode (GCE) and GO modified GCE (GO/GCE) the oxidation signals of 8-OHdG are significantly enhanced on the ZnO@rGO nanocomposite coated GCE (ZnO@rGO/GCE). Moreover, uricase has been employed successfully to eliminate the interferences of UA. A large amount of UA did not affect the oxidation signals of trace level of 8-OHdG. The linear range for the detection of 8-OHdG using ZnO@rGO/GCE was from 5.0 to 5000.0 nM. The detection limit was 1.25 nM calculated from a three-signal-to-noise ratio. The developed monitoring system is sensitive and selective for the determination of 8 OHdG and thus useful in practical applications, such as for the monitoring of 8 OHdG in the clinic urine samples. PMID- 29759241 TI - In Silico investigation of a post liquid chromatographic membrane extractor. AB - Recently, a vapor permeable membrane was coupled to ion exclusion chromatography for the selective removal of volatile fatty acids. The volatile components are isolated from the acidic chromatographic eluent flowing through the lumen of the membrane tube and isolated in the annular portion of a surrounding extractant jacket flow where they are measured conductometrically. The extractor dimensions and extractant flow rate must be balanced to maintain chromatographic efficiency and improve sensitivity. The extraction process has been simulated by a series of repeated transfers between two flowing streams using experimentally measured permeation rates. Five n-alkyl carboxylic acids (formic-pentanoic acid) separated by ion exclusion are used as the test suite for generating and validating the model. The dependence of the peak broadening and concentration factor upon the various parameters, particularly the length, have been reduced to simple empirical formulas which may be used for optimization. PMID- 29759242 TI - A fluorescence probe acted on Site I binding for Human Serum Albumin. AB - A sensitive turn-on probe XYQ, has been developed for the monitoring of HSA species with highly selective and instantaneous response to real- urine sample and living cells imaging. Furthermore, the fluorescence probe acted on Site I and discrimination of HSA from BSA. PMID- 29759243 TI - Polymer brushes-containing coordination polymer networks on monolith for rapid solid phase extraction of multi-class drug residues in meat samples. AB - A new solid phase extraction sorbent, based on poly(methacrylic acid) brushes containing coordination polymer networks on monolith, was in-situ synthesized in a commercial syringe filter via surface grafting. Extraction of twenty model analytes, including nine sulfonamides, eight steroid hormones, and three quinolones, could be efficiently achieved by the monolithic hybrid filter due to multi-interactions. Through simple filtering steps, fast extraction (60 s of adsorption and 60 s of desorption) could be achieved. Furthermore, the monolithic hybrid filter was used to analyze the model compounds in chicken meat samples in combination with ultra-performance liquid chromatography-tandem mass spectrometry. Compared with other adsorption sorbents in reported literatures, the proposed monolithic hybrid filter allowed for shorter purification time, simplified sample pretreatment procedure, and comparable LODs and LOQs of 0.1-3 MUg kg-1 and 0.4-10 MUg kg-1, respectively. The recoveries for all analytes ranged from 83.9% to 103% with inter-day relative standard deviation lower than 10%. The results demonstrated that the developed analytical method was highly efficient and operationally convenient, and had a great potential for high throughput analysis of multi-residues. PMID- 29759244 TI - A single nanoparticle-based real-time monitoring of biocatalytic progress and detection of hydrogen peroxide. AB - This paper reported a new method to observe the catalytic progress of the natural horseradish peroxidase (HRP) in-situ on single gold nanoparticles (GNPs) by the combination of dark field imaging and plasmonic resonance scattering spectra. The produced single HRP-GNP exhibited localized catalytic property toward H2O2 Diaminobenzidine (DAB), which could be used to detect the concentration of H2O2 in micro/nanospace. The linear range for H2O2 sensing was from 0.01 MUM to 5 MUM with a detection limit of 10 nM. The new design strategy could be applied for a broader bioanalysis situation by substituting the HRP with other specified biocatalyst. PMID- 29759245 TI - Separation and preconcentration of actinides from concentrated nitric acid by extraction chromatography in microsystems. AB - An original method of monolith impregnation in microsystem for the analysis of radionuclides in nitric acid is reported. Three microcolumns made of monolith poly(AMA-co-EDMA) were impregnated in COC microsystems. The robustness of the microsystems in nitric acid media until 8 M was demonstrated. High exchange capacity and affinity for tetravalent and hexavalent actinides in concentrated nitric media were obtained. The retention characteristics of the microcolumns impregnated by TBP, TBP-CMPO and DAAP were compared with those of the equivalent commercial particulate resins TBPTM, TRUTM and UTEVATM respectively. The separation of U, Th and Eu was validated in a classical microsystem and a procedure is proposed in a centrifugal microsystem. PMID- 29759246 TI - A novel strategy for retention prediction of nucleic acids with their sequence information in ion-pair reversed phase liquid chromatography. AB - In this work, retention behaviors of oligonucleotides and double-stranded deoxyribonucleic acids (dsDNAs) have been investigated in ion-pair reversed-phase liquid chromatography (IP-RPLC). We demonstrated that classic linear solvent strength (LSS) model is applicable for describing isocratic retention of oligonucleotides and dsDNAs, which indicated that nucleic acids share the similar retention mechanism as other common small molecules in IP-RPLC. The separation of nucleic acids in IP-RPLC is driven by both hydrophobic and electrostatic interactions. We defined the parameter lnkw/S obtained from LSS model in IP-RPLC as chromatographic hydrophobic and electrostatic interaction index (CHEI). CHEI of a nucleic acid has been revealed to correlate well with its gradient retention time. Notably, we proposed a strategy for retention prediction based on CHEI and base sequence information of nucleic acids. Corresponding to base locus, each base sequence is converted to a featured locus vector consisting of zeros and ones. CHEI prediction models were established by support vector regression (SVR) algorithm with locus vectors. Predicted CHEI values have been applied to predict retention times under desired gradient elution runs. This protocol is easy to grasp and worth pursuing further development for more precise retention prediction performance of nucleic acids in IP-RPLC. PMID- 29759247 TI - Study of sample preparation for determination of endocannabinoids and analogous compounds in human serum by LC-MS/MS in MRM mode. AB - Endocannabinoids are lipids with a key role in physiological processes such as the immune response or the metabolism. This involvement explains their association to pathologies such as cancer, obesity or multiple sclerosis. The determination of endocannabinoids constitutes a challenge for clinical laboratories due to the variety of biological matrices and the wide range of concentrations at which they can be found. This research deals with the comparison of three sample preparation strategies (viz., on-line SPE, off-line SPE for interferents removal, and protein precipitation) for subsequent LC-MS/MS analysis of 14 endocannabinoids and analogous compounds in serum. As a result, the on-line coupling between SPE and LC-MS/MS is proposed as the best approach for this determination. The proposed method allows full automation of the overall process, shortening of the analysis time, and avoidance of errors associated with sample preparation steps. The improvement in sensitivity and selectivity thus achieved allows obtaining quantification limits at the pg mL-1 level, which makes possible the application of the method for clinical studies. PMID- 29759248 TI - Qualitative and quantitative analysis of human nails to find correlation between nutrients and vitamin D deficiency using LIBS and ICP-AES. AB - In this work, we analysed human fingernails of people who suffer from vitamin D deficiency using the laser-induced breakdown spectroscopy(LIBS) and inductively coupled plasma atomic emission spectroscopy (ICP-AES)techniques. The measurements have been conducted on 71 nail samples collected randomly from volunteers of different genders and ages ranged between 20 and 50 years. The main aim of this study is to find the correlation between vitamin D deficiency and the intensity of some dominated lines in the LIBS spectra. A LIBS spectrum consists of dominant lines of fifteen elements including calcium, magnesium, sodium, potassium, titanium, iron, chloride, sulphur, copper, chromium, zinc, nitrogen, phosphor, and oxygen. By recording the spectrum in specific ranges and focusing on calcium, magnesium, sodium, and potassium, we found a correlation between the intensity of the potassium (K) lines at (766.5 and 769.9 nm)and vitamin D level in both age groups (20 and 25 years old), with weak correlation for the calcium (Ca), magnesium (Mg), and sodium (Na) lines. To verify the validity of the LIBS results, we analysed the nail samples with ICP, a standard analytical technique. The elements detected with our LIBS technique are in a good agreement with those identified by ICP-AES. From the health and physiological perspectives, the LIBS system, which is used for spectral analysis in this work, is appropriate for diagnostic purposes such as to find the correlation between vitamin D deficiency and potassium content, especially for hypertensive patients who simultaneously take potassium-based medication and vitamin D supplement. PMID- 29759249 TI - In-line carbon nanofiber reinforced hollow fiber-mediated liquid phase microextraction using a 3D printed extraction platform as a front end to liquid chromatography for automatic sample preparation and analysis: A proof of concept study. AB - A novel concept for automation of nanostructured hollow-fiber supported microextraction, combining the principles of liquid-phase microextraction (LPME) and sorbent microextraction synergically, using mesofluidic platforms is proposed herein for the first time, and demonstrated with the determination of acidic drugs (namely, ketoprofen, ibuprofen, diclofenac and naproxen) in urine as a proof-of-concept applicability. Dispersed carbon nanofibers (CNF) are immobilized in the pores of a single-stranded polypropylene hollow fiber (CNF@HF) membrane, which is thereafter accommodated in a stereolithographic 3D-printed extraction chamber without glued components for ease of assembly. The analytical method involves continuous-flow extraction of the acidic drugs from a flowing stream donor (pH 1.7) into an alkaline stagnant acceptor (20 mmol L-1 NaOH) containing 10% MeOH (v/v) across a dihexyl ether impregnated CNF@HF membrane. The flow setup features entire automation of the microextraction process including regeneration of the organic film and on-line injection of the analyte-laden acceptor phase after downstream neutralization into a liquid chromatograph (LC) for reversed phase core-shell column-based separation. Using a 12-cm long CNF@HF and a sample volume of 6.4 mL, linear dynamic ranges of ketoprofen, naproxen, diclofenac and ibuprofen, taken as models of non-steroidal anti-inflammatory drugs, spanned from ca. 5-15 ug L-1 to 500 ug L-1 with enhancement factors of 43-97 (against a direct injection of 10 uL standards into LC), and limits of detection from 1.6 to 4.3 ug L-1. Relative recoveries in real urine samples ranged from 97% to 105%, thus demonstrating the reliability of the automatic CNF@HF-LPME method for in-line matrix clean-up and determination of drugs in urine at therapeutically relevant concentrations. PMID- 29759251 TI - Using of aerodynamic droplet breakup for mass-spectrometric analysis. AB - The method of ionization by aerodynamic droplet breakup is considered for applications in mass spectrometric analysis. It is assumed that Aerodynamic Breakup Droplet Ionization (ABDI) occurs in a tube linking the region of atmospheric pressure to the area of weak vacuum. The possibility of ionization of solutions of organic compounds and organometallic complexes is shown. As test compounds were chosen: heroin (as an example of organic compounds) and organometallic complexes of ruthenium and copper, dissolved in water or acetonitrile. The quality of the ABDI spectra depends on the analyte. In general, the analytes ionized by the ABDI method show a great propensity to form dimers and trimers. ABDI system can be easily installed on any mass spectrometer with inlet at atmospheric pressure and used as an additional method. Since compounds prone to degradation in ESI analysis are better suited for ABDI analysis, this seems useful. PMID- 29759250 TI - Metal chelation dual-template epitope imprinting polymer via distillation precipitation polymerization for recognition of porcine serum albumin. AB - A novel dual-template epitope imprinting polymer coated on magnetic carbon nanotubes (MCNTs@D-EMIP) was successfully prepared for specific recognition of porcine serum albumin (PSA) via dual-template epitope imprinting, metal chelation imprinting and distillation-precipitation polymerization (DPP). C-terminal peptides and N-terminal peptides of PSA were selected as templates simultaneously, and zinc acrylate and ethylene glycol dimethacrylate (EGDMA) were used as functional monomer and cross-linker, respectively. The epitope templates were immobilized by metal chelation and six-membered ring formed with zinc acrylate. Finally, MCNTs@D-EMIP was synthesized by DPP in only 30 min, which was much shorter than those of other polymerization methods. The prepared MCNTs@D EMIP displayed specific recognition ability toward PSA and its adsorption amount and imprinting factor were 45.05 mg g-1 and 4.50, which were much higher than those of single template epitope imprinting polymers. Besides, high-performance liquid chromatography (HPLC) analysis of PSA in porcine blood serum real sample indicated that the specificity was not affected by other competitive proteins, which forcefully stated that the MCNTs@D-EMIP had potential to be applied in bio separation area. In addition, the results of cross-reactivity experiment proved that this strategy had generality to prepare dual-template epitope imprinting polymer for recognition of target protein. In summary, this study provided an efficient protocol to recognize target protein in complex sample via dual template epitope imprinting approach, metal chelation imprinting and distillation precipitation polymerization. PMID- 29759252 TI - Simultaneous determination of quercetin and its metabolites in rat plasma by using ultra-high performance liquid chromatography tandem mass spectrometry. AB - Fast, selective, and sensitive ultra-high performance liquid chromatography method with tandem mass spectrometry detection for the determination of quercetin and its metabolites with various physico-chemical properties such as molecular weight, lipophilicity, and acid-base properties has been developed. These compounds included small hydrophilic phenolic acids and more lipophilic metabolites with preserved flavonoid structure in small amount of rat plasma. The developed method enables selective separation of phenolic acids and a pair of isomers tamarixetin and isorhamnetin with satisfactory peak shapes and a high sensitivity using mass spectrometry detection. In addition, two sample preparation procedures including protein precipitation and microextraction in packed sorbent (MEPS) were optimized. The sample acidification included in protein precipitation as well as optimizing of MEPS sorbents and elution solvents improved isolation of quercetin and related compounds from rat plasma. Finally, both methods developed for sample preparation were fully validated to demonstrate sufficient accuracy and precision and acceptable matrix effects. Both sample preparation approaches combined with mass spectrometry-based quantification allowed the simultaneous determination of quercetin and its metabolites from a small amount of biological samples of only 50 MUL. Due to the fast and non selective parallel sample preparation, the protein precipitation was eventually applied to plasma samples derived from pharmacokinetic studies. PMID- 29759254 TI - Protein separation using a novel silica-based RPLC/IEC mixed-mode stationary phase modified with N-methylimidazolium ionic liquid. AB - Ionic liquids (ILs) immobilized on silica as a novel high-performance liquid chromatography (HPLC) stationary phase have attracted considerable attentions. However, it has not been applied to protein separation. In this paper, N methylimidazolium IL-modified silica-based stationary phase (SilprMim) was prepared and investigated as a novel multi-interaction stationary phase with positive charges for protein separation. The results indicate that all of the basic proteins tested cannot be adsorbed on this novel stationary phase, whereas all of the acidic proteins tested can be retained, and the baseline separation of eight kinds of acidic protein standards can be achieved when being performed under reversed phase/ion-exchange chromatography (RPLC/IEC) mode. Compared with commonly used commercial C4 column, the novel stationary phase can show good selectivity and resolution to acidic proteins. The effects of acetonitrile and salt concentration, pH as well as the ligand structure on protein separation were investigated in detail. In addition, the mix-mode retention mechanism of proteins on the SilprMim column was also discussed using stoichiometric displacement theory for retention in LC (SDT-R). The result shows that the protein retention can be controlled mainly by the electrostatic and hydrophobic interactions between the proteins and the stationary phase. As a result, with such characteristics of multi-interaction mechanism and multi-modal separation, not only the selectivity to the acidic proteins can be enhanced, but also a better resolution can be achieved. The result demonstrates that the SilprMim mixed-mode chromatography (MMC) column has a promising application in the separation and analysis of acidic proteins from the complex samples. PMID- 29759253 TI - Development of electrochemically controlled packed-in-tube solid phase microextraction method for sensitive analysis of acidic drugs in biological samples. AB - In the present research, for the first time, a novel "packed-in-tube" configuration has been applied to electrochemically controlled in-tube solid phase microextraction, followed by high performance liquid chromatography. In order to prepare a mini packed column, small beads of stainless steel were first placed into the stainless steel column. Then, a nanostructured polypyrrole film was prepared on the internal surface of a stainless steel tube and the surface of stainless steel particles through a facile in-situ electrodeposition method. Filling the column with tiny particles of stainless steel effectively reduces the dead volume of the extraction tube and increases the extraction phase volume. The column was used for separation and preconcentration of diclofenac and mefenamic acid as model analytes from biological samples. Several important factors affecting extraction efficiency, such as extraction and desorption times, flow rates of the sample solution and eluent, and extraction and desorption voltages were investigated and optimized. This method showed good linearity for the drugs in the range of 0.3-200.0 MUg L-1, 1.1-200.0 MUg L-1, and 1.8-200.0 MUg L-1 with coefficients of determination better than 0.9986, 0.9973, and 0.9973 in water, urine, and plasma samples, respectively. Intra- and inter-assay precisions (RSD%, n = 3) were in the range of 2.6-4.8% and 2.9-5.1, respectively, at three concentration levels of 10, 25, and 75 ug L-1. In addition, the limits of detection were in the range of 0.02-0.04 MUg L-1. The validated method was successfully applied to the analysis of diclofenac and mefenamic acid in some biological samples. Finally, it is concluded that this method can be a general and reliable alternative to the analysis of ionic compounds in biological matrices. PMID- 29759256 TI - Moving Our Attention from Keyboards to Patients: A Way Forward for Improving Professional Fulfillment and Health Care Value. PMID- 29759255 TI - Rapid separation of zirconium using microvolume anion-exchange cartridge for 93Zr determination with isotope dilution ICP-MS. AB - Estimating the risks associated with radiation from long-lived fission products (LLFP) in radioactive waste is essential to ensure the long-term safety of potential disposal sites. In this study, the amount of 93Zr, a LLFP, was determined by ICP-MS after separating Zr from a spent nuclear fuel solution using a microvolume anion-exchange cartridge (TEDA cartridge). Zirconium in 9.4 M HCl was stably retained on the TEDA cartridge and readily eluted with 0.75 mL of a mixed solution of 9.4 M HCl and 0.01 M HF. The time taken to complete the Zr separation was 1.2 min. Almost all the other elements initially present in the spent nuclear fuel sample were removed, leading to accurate measurement of all six Zr isotopes (90Zr, 91Zr, 92Zr, 93Zr, 94Zr, and 96Zr). This demonstrated that the TEDA cartridge allowed highly selective separation of Zr regardless of its small bed volume of 0.08 cm3. The concentrations of these isotopes were determined by an isotope-dilution method using a natural Zr standard that has a different isotopic composition from that of the spent nuclear fuel sample. The amount of 93Zr in an initial spent nuclear fuel pellet was 1081 +/- 79 ng per mg of 238U. The measured concentrations of all Zr isotopes, as well as the isotopic composition, were consistent with values predicted using a burnup calculation code. PMID- 29759257 TI - Developing a Medical Scribe Program at an Academic Hospital: The Hennepin County Medical Center Experience. AB - BACKGROUND: Medical scribes are frequently incorporated into the patient care model to improve provider efficiency and enable providers to refocus their attention to the patient rather than the electronic health record (EHR). The medical scribe program was based on four pillars (objectives): (1) provider satisfaction, (2) standardized documentation, (3) documentation components for risk adjustment, and (4) revenue enhancement. METHODS: The medical scribe program was deployed in nine non-resident-supported clinics (internal medicine, ophthalmology, orthopedics, hematology/oncology, urology), with the medical scribes (who have no clinical duties) supporting both physicians and advanced practice providers (nurse practitioners and physician assistants). This paper describes a prospective quasi-experimental study conducted at an academic, inner city, hospital-based clinic system, RESULTS: A pre-post analysis showed positive results; of the 51 providers, 44 responded to the survey pre and 41 responded post. Respondents in the post-scribe group felt that a scribe was valuable (90.2%), that documentation time at the office improved (75.0% poor or marginal pre-scribe, vs. 24% post; p <0.0001), and that time spent on the EHR at home declined (63.6% with excessive or moderately high home EHR time pre vs. 31.7% post; p = 0.003). More providers felt satisfied with their role in clinic with the use of scribes, and more providers felt that with scribes they could listen sufficiently to patients (p <0.05). CONCLUSION: Scribe support was well received across the institution in multiple clinical settings. Benefits for providers were seen in documentation time and ability to listen to patients. Scribes appear to be an effective intervention for improving clinician work life. PMID- 29759258 TI - Improving Maternal Safety at Scale with the Mentor Model of Collaborative Improvement. AB - BACKGROUND: Obstetric safety bundles, consisting of action steps shown to improve outcomes, have been developed to address the most common and preventable causes of maternal morbidity and mortality. Implementing these best practices across all birthing facilities remains an important and challenging clinical and public health priority. METHODS: The California Maternal Quality Care Collaborative (CMQCC) developed an innovative external mentor model for large-scale collaborative improvement in which participating organizations were subdivided into small teams of six to eight hospitals, led by a paired dyad of physician and nurse leaders. The mentor model preserves the active sharing that enhances improvement across a large group of facilities working on the same project while enabling individualized attention to teams. The mentor model was tested by implementing the obstetric hemorrhage safety bundle (which consists of 17 key practices in four domains) in multiple California hospitals. RESULTS: A total of 126 hospitals were engaged to simultaneously implement the safety bundle. The adoption rates for the recommended practices in the four action domains were (1) Readiness, 78.9%; (2) Recognition and Prevention, 76.5%; (3) Response, 63.1%; and (4) Reporting and Systems Learning, 58.7%. Mentors (31/40) and participating teams (48 responses from 39/126 hospitals) provided feedback in an exit survey. Among the respondents, 64.5% of mentors and 72.9% of participants agreed that compared to a traditional collaborative structure, the mentor model was better suited for quality improvement at scale. CONCLUSION: The mentor model was successful in providing individualized support to teams and enabled implementation of the hemorrhage safety bundle across a diverse group of 126 hospitals. PMID- 29759259 TI - 1,300 Days and Counting: A Risk Model Approach to Preventing Retained Foreign Objects (RFOs). AB - BACKGROUND: A retained foreign object (RFO) is a devastating surgical complication that typically results in additional surgeries, increased length of stay, and risk of infections and is potentially fatal. Memorial Sloan Kettering Cancer Center (MSKCC) convened a multidisciplinary task force to undertake an improvement initiative to reduce the frequency of RFO incidents. METHODS: A needs assessment was undertaken using focus group interviews, review of past RFOs, and operating room (OR) observations, and a comprehensive intervention plan was initiated. Items at risk of retention were reclassified and new tracking sheets were developed. A probabilistic risk model was developed based on aviation industry methodology, an RFO risk projection, and the retention risk classification of surgical items. Training initiatives were launched to shift organizational culture and staff behaviors toward greater awareness of RFO risk and proactive prevention. RESULTS: Since the implementation of our task force's recommendations on March 24, 2014, there have been no RFO incidents at our institution to this day. The last RFO occurred in August 2013-more than 1,300 days ago (as of March 28, 2017). The RFO incident frequency was reduced from 1.69 per year to a risk model estimate of 1 in 22 years. Ongoing training maintains the staff's behavioral changes as well as the improved OR and organizational culture. CONCLUSION: Implementation of a multidisciplinary approach to preventing RFOs was successful at MSKCC. The use of an RFO risk model enabled the creation of a robust system for RFO prevention. Support from leadership, participation by all stakeholders, education, training, and cooperation from frontline staff are all important contributors to RFO prevention success. PMID- 29759260 TI - A Call to Bridge Across Silos during Care Transitions. AB - BACKGROUND: Older adults with complex medical conditions are vulnerable during care transitions. Poor care transitions can lead to poor patient outcomes and frequent readmissions to the hospital. FACTORS CONTRIBUTING TO SUBOPTIMAL CARE TRANSITIONS: Key factors related to ineffective care transitions, which can lead to suboptimal patient outcomes, include poor cross-site communication and collaboration; lack of awareness of patient wishes, abilities, and goals of care; and incomplete medication reconciliation. Fundamental elements for effective care transitions put forth by The Joint Commission for effective care transitions include interdisciplinary coordination and collaboration of patient care in care transitions, shared accountability by all clinicians involved in care transitions, and provision of appropriate support and follow-up after discharge. REVIEW OF FOUR EXISTING MODELS OF CARE TRANSITIONS: Consideration of four existing care transitions models representing different health care settings-Care Transitions Intervention(r) Guided Care, Interventions to Reduce Acute Care Transfers (INTERACT(r)), Home Health Model of Care Transitions-revealed that they are important but limited in their impact on transitions across health care settings. PROPOSAL OF THE INTEGRATED CARE TRANSITIONS APPROACH: An innovative approach, Integrated Care Transitions Approach (ICTA), is proposed that incorporates the best practices of the four models discussed in this article and factors identified as essential for an effective care transition while addressing limitations of existing transitional care models. ICTA's four key characteristics and seven key elements are unique and stem from factors that help achieve effective care transitions. PMID- 29759261 TI - Deriving a Framework for a Systems Approach to Agitated Patient Care in the Emergency Department. AB - BACKGROUND: The rising agitated patient population presenting to the emergency department (ED) has caused increasing safety threats for health care workers and patients. Development of evidence-based strategies has been limited by the lack of a structured framework to examine agitated patient care in the ED. In this study, a systems approach from the patient safety literature was used to derive a comprehensive theoretical framework for addressing ED patient agitation. METHODS: A mixed-methods approach was used with ED staff members at an academic site and a community site of a regional health care network. Participants consisted of resident and attending physicians, physician assistants/nurse practitioners, nurses, technicians, and security officers. After a simulated agitated patient encounter to prime participants, uniprofessional and interprofessional focus groups were conducted, followed by a structured thematic analysis using a grounded theory approach. Quantitative data consisted of surveys of violence exposure and attitudes toward patient aggression and management. RESULTS: Data saturation was reached with 57 participants. Violence exposure was higher for technicians, nurses, and officers. Conflicting priorities and management challenges occurred due to four main interconnected elements: perceived complex patient motivations; a patient care paradox between professional duty and personal safety; discordant interprofessional dynamics mitigated by respect and trust; and logistical challenges impeding care delivery and long-term outcomes. CONCLUSION: Using a systems approach, five interconnected levels of ED agitated patient care delivery were identified: patient, staff, team, ED microsystem, and health care macrosystem. These care dimensions were synthesized to form a novel patient safety-based framework that can help guide future research, practice, and policy. PMID- 29759262 TI - Focus on the Quadruple Aim: Development of a Resiliency Center to Promote Faculty and Staff Wellness Initiatives. AB - DEFINING THE PROBLEM: A growing body of evidence highlights the need for wellness programs to support health care professionals. Although much of the existing literature centers on practicing physicians and physician trainees, there is growing awareness that these challenges are not unique to physicians and affect all members of the health care team. Traumatic and stressful events will always be a part of health care; how these events are addressed on a personal and team level is essential to the success of a health care system. A Resiliency Center was developed on the basis of the specific concerns and strengths of local stakeholders to support the well-being of employees at University of Utah Health. INITIAL APPROACH: The initial approach to evaluating and supporting faculty wellness began concurrent with planning for the Resiliency Center in 2016. Stakeholders were brought together by leaders in Health Sciences to propose a Resiliency Center. Initial data gathering was performed with several survey tools, including the American Medical Association's Mini Z. PLANNED INITIATIVES: The Resiliency Center, which is housed in the Office of Wellness and Integrative Health, is intended to serve as an overarching structure to help coordinate the faculty and staff wellness initiatives currently in existence and fill identified gaps. The four pillars of the Center are wellness initiatives, communication skills training, peer support, and an on-site Employee Assistance Program. NEXT STEPS: The current focus is on program development and outreach, with plans to measure the impact of the Center. PMID- 29759264 TI - The Association between the Electronic Health Record and Patient-Reported Receipt of Tobacco Cessation Care in Hospitalized Veterans. PMID- 29759263 TI - A Bedside Computerized Decision-Support Tool for Intravenous Insulin Infusion Management in Critically Ill Patients. AB - Intravenous (IV) insulin infusions using a validated protocol are the recommended method for blood glucose control in critically ill patients. Computerized decision-support tools improve quality over manual paper-based protocols. However, nonproprietary computerized tools targeting the recommended blood glucose range of 140-180 mg/dL are not readily available. A bedside computerized decision-support tool was developed at a US Department of Veterans Affairs health system to assist the nursing staff with the management of patients requiring IV insulin infusion. Initial evaluation showed that the tool was useful in the safe and effective management of an IV insulin infusion protocol for blood glucose control targeting the updated blood glucose range. PMID- 29759265 TI - Sleep-Wake Neurochemistry. AB - The regulated alternations between wakefulness and sleep states reflect complex behavioral processes, orchestrated by distinct neurochemical changes in brain parenchyma. No single neurotransmitter or neuromodulator controls the sleep-wake states in isolation. Rather, fine-tuned interactions within organized neuronal circuits regulate waking and sleep states and drive their transitions. Structural or functional dysregulation and medications interfering with these ensembles can lead to sleep-wake disorders and exert wanted or unwanted pharmacological actions on sleep-wake states. Knowledge of the neurochemical bases of sleep-wake states, which will be discussed in this article, provides the conceptual framework for understanding pharmacological effects on sleep and wake. PMID- 29759266 TI - Drug-Induced Insomnia and Excessive Sleepiness. AB - Psychotropic and nonpsychotropic drugs, which may induce or aggravate insomnia and/or daytime sleepiness, are discussed. These central nervous system effects are possible from the interactions of a drug with any of the many neurotransmitters or receptors that are involved in sleep and wakefulness. Multiple interactions between disease, sleep, comorbid sleep disorders, and direct or indirect influences of pharmacologic agents are possible. Awareness of these effects is important to adapt treatment and reach optimal results for every patient. Besides the importance for health and quality of life, effects on sleep or waking function can be a potential source of noncompliance. PMID- 29759267 TI - Drug-Induced Sleep-Disordered Breathing and Ventilatory Impairment. AB - This article describes current knowledge about drug entities that have the potential to induce, aggravate, or modify sleep-disordered breathing. The drug effects on sleep-disordered breathing may vary by patient age, gender, and comorbidity. In general, the clinical relevance of drug-induced sleep-disordered breathing is increasing in sleep medicine and the evidence in the field is growing in parallel. PMID- 29759268 TI - Prescription Drugs Used in Insomnia. AB - The scope of this article is to review the effects on sleep of prescription drugs that are commonly prescribed for chronic insomnia in adults. The following groups are discussed: benzodiazepines and its receptor agonists, the dual orexin receptor antagonist suvorexant, melatonin and its receptor agonists, sedating antidepressants, and antipsychotics. Together with the neurobiologic and pharmacologic properties of these drugs, clinical effects are described, including subjective and objective effects on sleep duration, continuity, and architecture. Medical prescription information is given when available. Recently published American and European guidelines for the treatment of insomnia serve as reference frame. PMID- 29759269 TI - Drugs Used in Narcolepsy and Other Hypersomnias. AB - Narcolepsy and idiopathic hypersomnia cannot be cured; all available treatments are symptomatic. It is of paramount importance for patients, and their relatives, to be informed about the consequences of these chronic diseases and to become ready to accept the consequences of the diagnosis before starting any treatment. This facilitates the implementation of behavioral modifications and the proper use of medication to decrease the disease burden. A supportive social environment (eg, family members, friends, employer, colleagues, and patient support groups) is instrumental. Current treatment options are discussed with a focus on pharmacologic treatment, including future directions. PMID- 29759270 TI - Drugs Used in Parasomnia. AB - Patient education and behavioral management represent the first treatment approaches to the patient with parasomnia, especially in case of disorders of arousal (DOA). A pharmacologic treatment of DOA may be useful when episodes are frequent and persist despite resolution of predisposing factors, are associated with a high risk of injury, or cause significant impairment, such as excessive sleepiness. Approved drugs for DOA are still lacking. The most commonly used medications are benzodiazepines and antidepressants. The pharmacologic treatment of rapid eye movement sleep behavior disorder is symptomatic, and the most commonly used drugs are clonazepam and melatonin. PMID- 29759271 TI - Drug Therapy in Obstructive Sleep Apnea. AB - There are several reasons to develop a pharmacologic remedy in obstructive sleep apnea (OSA); but so far, there is no generally effective drug available. Previous attempts to find a drug in OSA therapy were serendipity driven in small pilot trials. There is growing literature on phenotyping pathophysiologic mechanisms of OSA that may be exploited in strategic drug development programs. The current review addresses potential pitfalls encountered in previous studies and highlights several drug candidates under development in the field. PMID- 29759272 TI - Pharmacologic and Nonpharmacologic Treatment of Restless Legs Syndrome. AB - This article provides an updated practical guide for the treatment of primary restless legs syndrome (RLS). Articles that appeared after the American Academy of Neurology guideline search were reviewed according to the same evidence rating schedule. We found limited evidence for nonpharmacologic treatment options. In moderate to severe primary RLS, pharmacologic options may be considered, including iron suppletion, an alpha2delta ligand, a dopamine agonist, a combination of an alpha2delta ligand and a dopamine agonist, or oxycodone/naloxone. This article includes treatment options in case of augmentation. PMID- 29759273 TI - Drugs Used in Circadian Sleep-Wake Rhythm Disturbances. AB - This article focuses on melatonin and other melatonin receptor agonists, and specifically their circadian phase shifting and sleep-enhancing properties. The circadian system and circadian rhythm sleep-wake disorders are briefly reviewed, followed by a summary of the circadian phase shifting, sleep-enhancing properties, and possible safety concerns associated with melatonin and other melatonin receptor agonists. The recommended use of melatonin, including dose and timing, in the latest American Academy of Sleep Medicine Clinical Practice Guidelines for the treatment of intrinsic circadian rhythm disorders is also reviewed. Lastly, the practical aspects of treatment and consideration of clinical treatment outcomes are discussed. PMID- 29759274 TI - Pharmacologic Treatment of Sleep Disorders in Pregnancy. AB - Pregnancy often predisposes women to new-onset sleep disturbances, as well as exacerbations of preexisting sleep disorders. The goals of treating perinatal sleep disorders include the promotion of restorative sleep and the benefits it brings to both mother and fetus. The prescribing of any sleep aid in pregnancy must include consideration of the risks and benefits for both the patient and her fetus. Although data on the perinatal use of sleep aids is limited, there may be effects on fetal development, timing and duration of delivery, and postnatal outcomes. PMID- 29759275 TI - Sleep-Related Drug Therapy in Special Conditions: Children. AB - Sleep disorders in children may lead to neurodevelopmental and neurocognitive deficits; it is important to diagnose and treat them properly. Apart from the existing challenges in diagnosis, another drawback is that few therapies are currently approved. In this article, a comprehensive summary of the most common pediatric sleep disorders, along with the various pharmacologic and nonpharmacologic approaches for their management, is presented. Special attention has been paid to the currently available treatment options for pediatric insomnia, obstructive sleep apnea, parasomnias, narcolepsy, and restless legs syndrome, and comparisons are made with the corresponding treatment options for sleep disorders in adults. PMID- 29759276 TI - Hypnotic Discontinuation in Chronic Insomnia. AB - Patients with chronic insomnia are commonly prescribed hypnotic medications. The long-term effects of chronic hypnotics are not known and discontinuation is encouraged but often difficult to achieve. A gradual taper is preferred to abrupt cessation to avoid rebound insomnia and withdrawal symptoms. Written information provided to the patient about medication discontinuation may be helpful. Cognitive behavioral therapy or behavioral therapies alone can improve hypnotic discontinuation outcomes. There is limited evidence for adjunct medications to assist in hypnotic cessation for insomnia. PMID- 29759277 TI - Effects of Chronic Opioid Use on Sleep and Wake. AB - Chronic use of opioids negatively affects sleep on 2 levels: sleep architecture and breathing. Patients suffer from a variety of daytime sequelae. There may be a bidirectional relationship between poor sleep quality, sleep-disordered breathing, and daytime function. Opioids are a potential cause of incident depression. The best therapeutic option is withdrawal of opioids, which proves difficult. Positive airway pressure devices are considered first-line treatment for sleep-related breathing disorders. New generation positive pressure servo ventilators are increasingly popular as a treatment option for opioid-induced sleep-disordered breathing. Treatments to improve sleep quality, sleep-related breathing disorders, and quality of life in patients who use opioids chronically are discussed. PMID- 29759278 TI - Medications and Their Effects on Sleep and Wake. PMID- 29759279 TI - Measuring Clinical Productivity. AB - Productivity measurements have been used to evaluate and compare physicians and physician practices. Anesthesiology is unique in that factors outside anesthesiologist control impact opportunity for revenue generation and make comparisons between providers and facilities challenging. This article uses data from the multicenter University of Pittsburgh Physicians Department of Anesthesiology to demonstrate factors influencing productivity opportunity by surgical facility, between department divisions and subspecialties within multispecialty divisions, and by individuals within divisions. The complexities of benchmarking anesthesiology productivity are demonstrated, and the potential value of creating a productivity profile for facilities and groups is illustrated. PMID- 29759280 TI - Overlapping Surgery: A Case Study in Operating Room Throughput and Efficiency. AB - A keystone of operating room (OR) management is proper OR allocation to optimize access, safety, efficiency, and throughput. Access is important to surgeons, and overlapping surgery may increase patient access to surgeons with specialized skill sets and facilitate the training of medical students, residents, and fellows. Overlapping surgery is commonly performed in academic medical centers, although recent public scrutiny has raised debate about its safety, necessitating monitoring. This article introduces a system to monitor overlapping surgery, providing a surgeon-specific Key Performance Indicator, and discusses overlapping surgery as an approach toward OR management goals of efficiency and throughput. PMID- 29759281 TI - Measuring Quality for Individual Anesthesia Clinicians. AB - A robust quality management system (QMS) will provide value to patients, providers, and hospitals or systems by focusing on system performance. The QMS must remain independent of provider-specific measures used for privileging. Some outcome measures may be used to assess system performance; they must not be used to assess individual provider performance. All anesthesia providers, especially leaders, must be guardians of an organization's safety culture. PMID- 29759282 TI - Challenges in Outcome Reporting. AB - Although measuring outcomes is an integral part of medical quality improvement, large-scale outcome reporting efforts face several challenges. Among these are difficulties in establishing consensus definitions for outcome measurement; classifying gray outcomes, such as postoperative respiratory failure; and adequately adjusting for patient comorbidities and severity of illness. Unintended consequences of outcome reporting can also distort care in undesirable ways, and clinician reluctance to care for high-risk patients may occur with reporting programs. Ultimately, clinicians need not compare outcomes to improve and should recognize that even outcomes that cannot be precisely quantitated can still be improved. PMID- 29759283 TI - Quality Reporting: Understanding National Priorities, Identifying Local Applicability. AB - Since the 1990s, the use of quality measures in healthcare has grown exponentially. Practices must maintain current knowledge of measures that affect their clinicians locally and understand how assessment of these medical professionals affects the priorities and quality activities of practices and facilities. Because quality measures are increasingly used by hospital administrators, health plans, and payers, practices are being asked to shoulder the additional burdens of collecting and reporting data to various entities. Part of the solution to this increased burden often includes contracting with vendors and outside experts, as well as identifying effective local physician and practice champions. PMID- 29759284 TI - Quality and the Health System: Becoming a High Reliability Organization. AB - Since the publication of "To Err is Human" in 1999, substantial efforts have been made within the health care industry to improve quality and patient safety. Although improvements have been made, recent estimates continue to indicate the need for a marked change in approach. In this article, the authors discuss the concepts and characteristics of high reliability organizations, safety culture, and clinical microsystems. The health care delivery system must move beyond current quality and patient safety approaches and fully engage in these new concepts to transform health care system performance. PMID- 29759285 TI - Value Proposition and Anesthesiology. AB - Health care in general and anesthesia in particular have seen dramatic changes in the economic landscape. It is vital if anesthesia groups wish to survive and prosper in this new environment to understand the changes occurring in health care and be flexible and proactive in taking on these challenges. More than ever anesthesia groups must be good corporate citizens and seek ways in which to enhance their value to the organization, whether in the operating room or out of operating room locations, and be a proactive partner with the hospital. PMID- 29759286 TI - Bundled Payments and Hidden Costs. AB - In a fee-for-service environment, anesthesiologists are paid for the volume of services billed, with little relation to the cost of delivering the services. In bundled payments, anesthesiologists are paid a set fee for an episode of care inclusive of all the anesthesia, pain medicine, and related services for the surgical episode and a period of time after the initial procedure to cover complications and redo procedures. When calculating a bundled payment, all the services typically used by a patient must be counted when calculating both the costs and expected payment. PMID- 29759287 TI - Comprehensive Preoperative Assessment and Global Optimization. AB - To successfully deliver greater perioperative value-based care and to effectively contribute to sustained and meaningful perioperative population health management, the scope of existing preoperative management and its associated services and care provider skills must be expanded. New models of preoperative management are needed, which rely extensively on continuously evolving evidence based best practice, as well as telemedicine and telehealth, including mobile technologies and connectivity. Along with conventional comorbidity optimization, prehabilitation can effectively promote enhanced postoperative recovery. This article focuses on the opportunities and mechanisms for delivering value-based, comprehensive preoperative assessment and global optimization of the surgical patient. PMID- 29759288 TI - Perioperative Surgical Home for the Patient with Chronic Pain. AB - The management of acute pain for the phenotypically different patient who suffers from chronic pain is challenging. The care of these patients is expensive and siloed. The physician-led, multidisciplinary, patient-centric, care coordination framework of the perioperative surgical home is an optimal vehicle for the management of these patients. The engagement of physician anesthesiologists in the optimization, in-hospital management, and postdischarge care of the patient with chronic pain will lead to improved outcomes, reduced health care expenditures, and improve the health of this challenging population. PMID- 29759289 TI - Comprehensive Acute Pain Management in the Perioperative Surgical Home. AB - The careful coordination of care throughout the perioperative continuum offered by the perioperative surgical home (PSH) is important in the treatment of postoperative pain. Physician anesthesiologists have expertise in acute pain management, pharmacology, and regional and neuraxial anesthetic techniques, making them ideal leaders for managing perioperative analgesia within the PSH. Severe postoperative pain is one of many patient- and surgery-specific factors in the development of chronic postsurgical pain. Delivering adequate perioperative analgesia is important to avoid this development, to decrease perioperative morbidity, and to improve patient satisfaction. PMID- 29759291 TI - Integrating Academic and Private Practices: Challenges and Opportunities. AB - As health care reform shifts toward value over volume, academic medical centers, known for highly specialized, high-cost care, will suffer from erosion of their traditional funding sources. Academic medical centers have undertaken mergers and partnerships with community medical centers, to maintain a more diversified, cost effective, and competitive presence in their markets. These consolidations have seen varying results. Cultural factors are frequently cited as a cause of dysfunction and disintegration. Anesthesiology groups integrating academic and private practice physicians are likely to face many of the same challenges. Appropriate attention to culture and other key issues may help realize numerous benefits. PMID- 29759294 TI - Mortality Risk Stratification in Small Patient Cohorts: The Post-Fontan Heart Transplantation Paradigm. PMID- 29759290 TI - Anesthesiology's Future with Specialists in Population Health. AB - In population health medicine, often it is not primary care, but rather the specialists' care teams that are responsible for the most overall spending for health care. Engaging specialists in population health medicine is a prerequisite to be successful in improving the quality of care by reducing complications, unnecessary utilization, avoidable Emergency Department visits/readmissions, and total cost of care. Creating patient-centric, physician-lead, interdisciplinary care teams to redesign the delivery of care across the continuum of the episode of care (eg, shadow bundle) is a successful approach to commercial or Centers for Medicare and Medicaid Services value-based payments. PMID- 29759296 TI - What We Have Learned From the Ocular Hypertension Treatment Study. PMID- 29759295 TI - Effect of Acute Kidney Injury After Percutaneous Mitral Valve Repair on Outcome. AB - Limited data exist on the occurrence of acute kidney injury (AKI) associated with percutaneous mitral valve repair (PMVR). The objectives of the present study were (1) to assess the prevalence of AKI after MitraClip (Abbott Vascular, Santa Clara, California) implantation, (2) to analyze the predictive factors of AKI, and (3) to evaluate the prognostic value of AKI after PMVR with a view to optimizing the management of high-risk patients. A total of 206 patients (serum creatinine [SCr] 1.3 +/- 0.6 mg/dl, estimated glomerular filtration rate 55 +/- 24 ml/min) who underwent PMVR were included. AKI was defined as an increase in SCr by >=0.3 mg/dl within 48 hours or an increase in SCr by >=1.5 times baseline. AKI was assessed during the first 5 days after MitraClip implantation. The incidence of AKI after MitraClip was 18% and none of the patients required dialysis. Age, logistic EuroSCORE, baseline renal function, N-terminal pro-B-type natriuretic peptide levels, serum glycated hemoglobin A1c, serum C-reactive protein, diuretic usage, and elevated right atrial pressure were the risk factors of AKI. Incidence of AKI was associated with poor outcome. Short-term mortality was increased (30-day mortality rate AKI vs no AKI: 18% vs 1%; p <0.001). Likewise, Kaplan-Meier analysis and log-rank test confirmed reduced long-term survival of patients with AKI (1-year all-cause mortality of patients with AKI vs patients with no AKI: 34% vs 13 %; p <0.001). In conclusion, every fifth patient experienced AKI after MitraClip implantation, which was associated with increased short-term mortality and a more than threefold increase in the risk of death 1 year after PMVR. PMID- 29759297 TI - Isolated hypoglossal palsy, a rare complication of Epstein-Barr virus infection. PMID- 29759298 TI - Unusual presentation of a previously undescribed variant of the neck venous drainage system. PMID- 29759299 TI - Behavior of squamous cell carcinoma of the floor of the mouth. Is supraomohyoid neck dissection sufficiently safe to manage clinically N0 patients? AB - AIM: The main aim of the present report is to study the behavior of SCC of the floor of the mouth. MATERIALS AND METHOD: A retrospective analysis was conducted using the records of patients diagnosed with squamous cell carcinoma of the floor of the mouth between 2000 and 2012 in the HUVN. Ninety-three patients with squamous cell carcinoma of the floor of the mouth treated with tumourectomy and selective neck dissection were included in the study. The pattern of distribution of cervical metastases and numerous histological features such as T-stage, N stage, surgical margins, tumor thickness, ECS (extracapsular spread) and vascular invasion were analyzed. RESULTS: Level I was the most affected level, followed by Level II. T stage, tumor thickness, and surgical margins showed a strong relationship with the risk of developing a local or cervical failure at follow up. Overall survival was 52.7%. T stage, tumor thickness, N stage, recurrence, extracapsular spread, and vascular invasion were also associated with a poor prognosis. CONCLUSIONS: SCC of the floor of the mouth is an aggressive disease even at early stages. Due to the low rate of positive nodes observed at level IV and V in clinically N0 patients, supraomohyoid neck dissection might be considered sufficiently safe in this group. PMID- 29759301 TI - Pneumothorax: Immediate ultrasound diagnosis in the critical patient. PMID- 29759300 TI - Decreased contractile response of peripheral arterioles to serotonin after CPB in patients with diabetes. AB - BACKGROUND: Regulation of coronary vasomotor tone by serotonin is significantly changed after cardioplegic arrest and reperfusion. The current study investigates whether cardiopulmonary bypass may also affect peripheral arteriolar response to serotonin in patients with or without diabetes. METHODS: Human peripheral microvessels (90-180 um diameter) were dissected from harvested skeletal muscle tissues from diabetic and non-diabetic patients before and after cardiopulmonary bypass and cardiac surgery (n = 8/group). In vitro contractile response to serotonin was assessed by videomicroscopy in the presence or absence of serotonin alone (10-9-10-5M) or combined with the selective serotonin 1B receptor (5-HT1B) antagonist, SB224289 (10-6M). 5-HT1A/1B protein expression in the skeletal muscle was measured by Western-blot and immunohistochemistry. RESULTS: There were no significant differences in contractile response of peripheral arterioles to serotonin (10-5M) pre-cardiopulmonary bypass between diabetic and non-diabetic patients. After cardiopulmonary bypass, contractile response to serotonin was significantly impaired in both diabetic and non-diabetic patients compared to their pre-cardiopulmonary bypass counterparts (P < .05). This effect was more pronounced in diabetic patients than non-diabetic patients (P < .05 versus non diabetic). The contractile response to serotonin was significantly inhibited by the 5-HT1B antagonist in both diabetic and non-diabetic vessels (P < .05 versus serotonin alone). There were no significant differences in the expression/distribution of 5-HT1A/1B between non-diabetic and diabetic groups or between pre- versus post- cardiopulmonary bypass vessels. CONCLUSIONS: Cardiopulmonary bypass is associated with decreased contractile response of peripheral arterioles to serotonin and this effect was exaggerated in the presence of diabetes. Serotonin-induced contractile response of the peripheral arterioles was via 5-HT1B in both diabetic and non-diabetic patients. PMID- 29759302 TI - Difficult airway management and neuromuscular blockade. PMID- 29759303 TI - Anesthesia technique and quality of recovery after laparoscopic cholecystectomy: Case closed? PMID- 29759304 TI - [Tools to assess the impact on health of public health programmes and community interventions from an equity perspective]. AB - It is essential to develop a comprehensive approach to institutionally promoted interventions to assess their impact on health from the perspective of the social determinants of health and equity. Simple, adapted tools must be developed to carry out these assessments. The aim of this paper is to present two tools to assess the impact of programmes and community-based interventions on the social determinants of health. The first tool is intended to assess health programmes through interviews and analysis of information provided by the assessment team. The second tool, by means of online assessments of community-based interventions, also enables a report on inequality issues that includes recommendations for improvement. In addition to reducing health-related social inequities, the implementation of these tools can also help to improve the efficiency of public health interventions. PMID- 29759305 TI - [Multilevel analysis of the technical efficiency of hospitals in the Spanish National Health System by property and type of management]. AB - OBJECTIVE: To analyze technical efficiency by type of property and management of general hospitals in the Spanish National Health System (2010-2012) and identify hospital and regional explanatory variables. METHOD: 230 hospitals were analyzed combining data envelopment analysis and fixed effects multilevel linear models. Data envelopment analysis measured overall, technical and scale efficiency, and the analysis of explanatory factors was performed using multilevel models. RESULTS: The average rate of overall technical efficiency of hospitals without legal personality is lower than hospitals with legal personality (0.691 and 0.876 in 2012). There is a significant variability in efficiency under variable returns (TE) by direct, indirect and mixed forms of management. The 29% of the variability in TE es attributable to the Region. Legal personality increased the TE of the hospitals by 11.14 points. On the other hand, most of the forms of management (different to those of the traditional hospitals) increased TE in varying percentages. At regional level, according to the model considered, insularity and average annual income per household are explanatory variables of TE. DISCUSSION: Having legal personality favours technical efficiency. The regulatory and management framework of hospitals, more than public or private ownership, seem to explain technical efficiency. Regional characteristics explain the variability in TE. PMID- 29759306 TI - Level of understanding of Alzheimer disease among caregivers and the general population. AB - INTRODUCTION: Understanding of Alzheimer disease is fundamental for early diagnosis and to reduce caregiver burden. The objective of this study is to evaluate the degree of understanding of Alzheimer disease among informal caregivers and different segments of the general population through the Alzheimer's Disease Knowledge Scale. PATIENTS AND METHODS: We assessed the knowledge of caregivers in different follow-up periods (less than one year, between 1 and 5 years, and over 5 years since diagnosis) and individuals from the general population. Alzheimer's Disease Knowledge Scale scores were grouped into different items: life impact, risk factors, symptoms, diagnosis, treatment, disease progression, and caregiving. RESULTS: A total of 419 people (215 caregivers and 204 individuals from the general population) were included in the study. No significant differences were found between groups for overall Alzheimer's Disease Knowledge Scale score (19.1 vs. 18.8, P = .9). There is a scarce knowledge of disease risk factors (49.3%) or the care needed (51.2%), while symptoms (78.6%) and course of the disease (77.2%) were the best understood aspects. Older caregiver age was correlated with worse Alzheimer's Disease Knowledge Scale scores overall and for life impact, symptoms, treatment, and disease progression (P < .05). Time since diagnosis improved caregivers' knowledge of Alzheimer disease symptoms (P = .00) and diagnosis (P = .05). CONCLUSION: Assessing the degree of understanding of Alzheimer disease is essential to the development of health education strategies both in the general population and among caregivers. PMID- 29759307 TI - [The importance of abdominal ultrasound in the management of tumors/pelvics in primary care]. PMID- 29759308 TI - The Value of Adjuvant Radiotherapy in Cutaneous Squamous Cell Carcinoma: A Review. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in humans and its incidence is rising. Although surgery is the treatment of choice for cSCC, postoperative adjuvant radiotherapy has an important role in local and locorregional disease control. In this review, we analyze the value of postoperative radiotherapy in the management of high-risk cSCC (in particular, cases with perineural invasion), cSCC with positive surgical margins, and locally advanced cSCC (with parotid gland and/or lymph node metastasis). PMID- 29759309 TI - Efficacy of stem cells in maxillary sinus floor augmentation: systematic review and meta-analysis. AB - The aim of this review was to test the hypothesis of no difference in the efficacy of bone regeneration when using stem cells in maxillary sinus floor augmentation surgery in comparison to other grafts. Nine randomized clinical trials and one follow-up study involving human subjects were identified through a search of the PubMed/MEDLINE, Scopus, Cochrane, and Web of Science databases, supplemented by a hand search. No significant difference between groups was found for the implant survival rate, increase in bone height, marginal bone loss following implant placement, or new bone formation. With regard to the residual bone graft, an effect favouring the graft group at 3-4months (P=0.001) and favouring the stem cell group at 6months (P=0.01) was found. Analyses of the subgroup in which the BMAC system extraction method was used in combination with Bio-Oss, revealed no difference in new bone formation; however, the results for residual bone graft at 3months favoured the control graft (Bio-Oss) (P=0.01), but at 6months favoured the stem cells (Bio-Oss+BMAC system) (P=0.01). Based on all findings, the use of stem cells does not contribute significantly to greater implant survival rates or the efficacy of bone regeneration following sinus lift procedures. PMID- 29759310 TI - Flavanols are potential anti-obesity agents, a systematic review and meta analysis of controlled clinical trials. AB - BACKGROUND: The anti-obesity potential of flavonoids has been shown by animal and human studies. In this meta-analysis, we systematically reviewed controlled clinical trials and quantified the effects of flavonoids and flavonoid subclasses on obesity-related anthropometric measures. METHODS AND RESULTS: PubMed, EMBASE, Scopus, Web of Science, and ProQuest databases were searched to identify trials examining the effect of flavonoids on body mass index (BMI), waist circumference, and body fat percentage. Fifty eight trials passed the eligibility process. Analysis endpoints were calculated as the mean difference between baseline and post-treatment. Flavonoids were in subclasses of flavanols, flavonols, isoflavones, flavanones, anthocyanins, and proanthocyanidins. They were mostly in the form of supplements and dosages varying from 40 to 1300 mg/day. Among flavonoid subclasses, flavanols showed potential for decreasing BMI, in the overall population (mean difference (MD) = -0.28 kg/m2, P = 0.04; n = 21) and in the subgroups of Asians (MD = -0.42 kg/m2; P = 0.046; n = 13), ages < 50 years (MD = -0.50 kg/m2; P = 0.008; n = 14), BMI >= 25 kg/m2 (MD = -0.30 kg/m2; P = 0.049; n = 15), and at doses >= 500 mg/day (MD = -0.36 kg/m2; P = 0.049; n = 12). Isoflavones also decreased BMI of non-Asian populations (MD = -0.26 kg/m2; P = 0.035; n = 13) and doses >= 75 mg/day (MD = -0.34 kg/m2; P = 0.027; n = 8). In the overall assessment, flavanols also decreased waist circumference (MD = -0.60 cm; P = 0.02; n = 18) but had no significant effect on body fat percentage. The available trials did not reveal significant effects from flavonols, flavanones, and anthocyanins on the specified anthropometric measures. CONCLUSIONS: Overall results of this meta-analysis showed that flavanols have potential against obesity. PMID- 29759311 TI - Quadripolar Leads in Cardiac Resynchronization Therapy. AB - Despite the benefit of cardiac resynchronization therapy (CRT) in patients with heart failure and conduction delay, a considerable number of patients do not respond substantially. Left ventricular lead position is an important factor in response, restricted by the patient's specific anatomy and local pathophysiology. Quadripolar leads could enhance response to CRT, offering 4 pacing locations along the distal end of the lead. Several quadripolar leads are available, all with different shapes and electrode spacing. Electrodes can be positioned in an ideal pacing location, determined by delayed mechanical or electrical activation, and away from phrenic nerve stimulation, high pacing thresholds, and fibrosis. Implantation is safe, with comparable or even lower complication rates compared with standard bipolar leads. Studies on biventricular pacing with quadripolar leads show apparent variations in acute hemodynamic response between pacing configurations, implying a patient-specific response. Pacing with an optimal pacing vector of a quadripolar lead benefits acute hemodynamic response. Multipoint pacing, pacing the left ventricle with 2 of 4 electrodes, could further enhance response. However, larger trials are needed to confirm these results, and results on long-term outcome of CRT with quadripolar leads and the benefit of multipoint pacing are warranted. We conclude that quadripolar leads are an important improvement in the treatment of heart failure patients with CRT. PMID- 29759313 TI - Should All Patients Be Started on Antiarrhythmic Drugs After Atrial Fibrillation Ablation? PMID- 29759312 TI - Effect of Antiarrhythmic Drug Initiation on Readmission After Catheter Ablation for Atrial Fibrillation. AB - OBJECTIVES: This study sought to evaluate the impact on antiarrhythmic drug (AAD) initiation on the risk of readmission after catheter ablation for atrial fibrillation (AF) among patients not already treated with an AAD. BACKGROUND: Hospital readmission, a commonly tracked indicator of quality and efficiency of care delivery, occurs in about 15% patients within 90 days of undergoing catheter ablation for AF. METHODS: Using a large national administrative claims database, we identified all atrial fibrillation patients (>=18 years of age) who underwent catheter ablation between January 2005 and December 2013 (n = 7,442). We identified the subset of patients who had not been on an AAD in the 90 days before ablation (n = 2,542) and, among those, the patients in whom an AAD was initiated at discharge following the ablation (n = 519). RESULTS: The readmission rate was significantly lower among patients who were initiated on an AAD compared with those who were not (11.6% vs. 16.2%, p = 0.009). The association persisted after adjustment for age, sex, Charlson index, and CHADS2 score (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.56 to 0.97; p = 0.03). In unadjusted time to event analysis, amiodarone (HR: 0.55, 95% CI: 0.32 to 0.94; p = 0.039) was associated with the greatest reduction in readmission whereas dronedarone, Class II agents, and Class IC agents had no statistically significant effect on readmission. AADs were discontinued in 44.5% of patients at 3 months. CONCLUSIONS: Initiation of an AAD at discharge of catheter ablation is associated with a significant reduction in readmission within 90 days. Routine initiation of an AAD after catheter ablation may reduce healthcare utilization in the periablation period; however, the high rate of medication discontinuation may suggest that side effects or inefficacy may limit long-term AAD use post ablation. PMID- 29759314 TI - Mechanistic Comparison of "Nearly Missed" Versus "On-Target" Rotor Ablation. AB - OBJECTIVES: This study used advanced optical mapping techniques to examine atrial fibrillation (AF) dynamics before and after 2 distinct electrogram-based ablation strategies: complex fractionated atrial electrograms (CFAEs) and DFmax/rotor ablation. BACKGROUND: Among the electrogram analytical features proposed to unravel the atrial regions that perpetuate AF, CFAEs, highest dominant frequency sites (DFmax), and, more recently, phase analysis-enabled rotor mapping have received the largest attention. Still, the mechanisms by which these approaches modulate AF dynamics and lead to AF termination are unknown. METHODS: In Langendorff-perfused sheep hearts, AF was maintained by the continuous perfusion of acetylcholine and high-resolution endocardial-epicardial optical videos were recorded from the left atrial free wall and the posterior left atrium. Then, DFmax/rotor regions (n = 7), or CFAE regions harboring the highest wavebreak density (HWD) (n = 5), were targeted with a 4F ablation catheter (5 to 15 W, 30 to 60 s/point). Thereafter, we examined the changes in AF dynamics and whether AF terminated. RESULTS: DFmax/rotor point ablation resulted in a significant decrease in DFmax values. In 2 animals AF terminated, whereas in the remaining 5 animals the post-ablation DFmax domain remained in the vicinity of its pre ablation location. However, after HWD/CFAEs density ablation, DFmax values did not change, AF did not terminate, and post-ablation DFmax domains relocated from the left atrial free wall to the pulmonary vein-posterior left atrium region. In another group of hearts (n = 12), we observed that upon a progressive increase in acetylcholine concentration-mimicking the acute electrophysiological changes occurring after ablation-3-dimensional rotors drifted from one atrial region to another along large gradients of myocardial thickness. CONCLUSIONS: "On-target" DFmax/rotor ablation leads to the annihilation of the fibrillation-driving rotor. This translates into large decreases in AF frequency or AF termination. In contrast, "nearly missed" HWD/CFAEs ablation spares the fibrillation-driving rotor, and set the stage for rotor drift along large myocardial thickness gradients. PMID- 29759315 TI - Targeting Atrial Fibrillation Rotors: Does Being Close Count? PMID- 29759316 TI - Atrial Fibrillation or Flutter During Pregnancy in Patients With Structural Heart Disease: Data From the ROPAC (Registry on Pregnancy and Cardiac Disease). AB - OBJECTIVES: Atrial fibrillation (AF)/atrial flutter (AFL) during pregnancy in these women is associated with adverse outcome of pregnancy. BACKGROUND: The incidence, timing, and consequences of AF or AFL during pregnancy in patients with heart disease are not well known. METHODS: Between January 2008 to June 2011, 60 hospitals in 28 countries prospectively enrolled 1,321 pregnant women with congenital heart disease, valvular heart disease, ischemic heart disease, or cardiomyopathy in the ROPAC (Registry of Pregnancy and Cardiac Disease). We studied the incidence, onset, and predictors of AF/AFL during pregnancy and assessed the pregnancy outcome. An overview of the existing literature is provided. RESULTS: Seventeen women (1.3%) developed AF/AFL during pregnancy, mainly in the second trimester (61.5%). Univariable analysis identified the following pre-pregnancy risk factors for AF/AFL in pregnancy: AF/AFL before pregnancy (odds ratio [OR]: 7.1, 95% confidence interval [CI]: 1.5 to 32.8); mitral valvular heart disease (OR: 6.9, 95% CI: 2.6 to 18.3); beta-blocker use (OR: 3.3, 95% CI: 1.2 to 9.0); and left-sided lesions (OR: 2.9, 95% CI: 1.0 to 8.3). Maternal mortality was higher in women with than in women without AF/AFL (11.8% vs. 0.9%; p = 0.01), although heart failure was not seen more often. Low birth weight (<2,500 g) occurred more often in women with than in women without AF/AFL (35% vs. 14%; p = 0.02). CONCLUSIONS: AF/AFL occurs in 1.3% of pregnant patients with structural heart disease with a peak at the end of the second trimester. AF/AFL during pregnancy in cardiac patients is associated with unfavorable maternal outcome and also has an impact on fetal birth weight. PMID- 29759317 TI - Atrial Fibrillation and Atrial Flutter in Pregnant Women With Heart Disease: Contributions From the ROPAC Investigators. PMID- 29759318 TI - Pre-Clinical Investigation of a Low-Intensity Collimated Ultrasound System for Pulmonary Vein Isolation in a Porcine Model. AB - OBJECTIVES: The purpose of this study was to assess the feasibility of pulmonary vein (PV) isolation using low-intensity collimated ultrasound. BACKGROUND: Contemporary approaches to PV isolation are limited by the technical complexity of mapping and ablation. We describe a novel approach to left atrial anatomic rendering and PV isolation that aims to overcome some of these limitations by using low-intensity collimated ultrasound (LICU) system, which allows for near real-time geometry creation and automated ablation in a porcine model. METHODS: Twenty swine were anesthetized, and the LICU ablation catheter was placed in the left atrium via percutaneous transseptal access. Ultrasound M-mode-based anatomies of the inferior PVs were successfully created, and ablation was performed under automatic robotic control along a user-defined lesion path. One animal was excluded because of device failure. RESULTS: All target PVs in the 19 remaining animals were isolated acutely, requiring a mean of 1.6 applications. Ten animals were sacrificed acutely, and the remaining 9 survived for 35 +/- 11 days. Of these 9, 1 animal was excluded from analysis because the index lasso position could not be reliably recreated. PVs in 5 of 8 animals remained isolated at sacrifice. Of the 77 total histological sections, 62 lesions (80.5%) were noted to be transmural. Lesions were homogeneous and characterized by coagulative necrosis and fibrous tissue. The mean myocardial thickness was 2.66 +/- 1.80 mm, and the mean lesion depth was 4.28 +/- 1.97 mm. No extra cardiac or collateral lesions were noted. CONCLUSIONS: This study demonstrates the safety and efficacy of a novel noncontact ultrasound mapping and ablation system to produce continuous transmural lesions that can isolate PVs in a porcine model. PMID- 29759320 TI - Call "the Cleaners": How to Treat Drug-Induced Torsades de Pointes. PMID- 29759319 TI - Mexiletine Prevents Recurrent Torsades de Pointes in Acquired Long QT Syndrome Refractory to Conventional Measures. AB - OBJECTIVES: The purpose of this study was to examine the role of mexiletine, a late sodium current (INa-L) blocker, in acute termination of torsades de pointes (TdP) refractory to conventional therapy in acquired long QT syndromes (LQTS). BACKGROUND: Long QT interval can predispose to TdP and is therefore associated with significant mortality. Currently, there is no available pharmacotherapy to target directly the ionic basis of most LQTS for the acute termination of TdP. Earlier evidence highlighted the role of INa-L in the pathophysiology of long QT and TdP, particularly in patients with congenital LQTS. METHODS: Twelve patients with TdP caused by acquired LQTS were treated with mexiletine after failure of conventional treatment including discontinuation of QT-prolonging drugs, intravenous administration of magnesium, and correction of serum electrolyte abnormalities. RESULTS: No recurrence of TdP occurred within 2 h after initiation of treatment with mexiletine in all 12 patients. Macro T-wave alternans accompanied by QT prolongation, an electrocardiographic precursor of TdP that was seen in 3 patients, was also abolished by mexiletine. Treatment with mexiletine shortened the QTc interval from 599 +/- 27 ms to 514 +/- 16 ms (p = 0.001). The interval from the peak to the end of the T-wave (Tp-e interval) decreased from 145 +/- 18 ms to 106 +/- 9 ms (p = 0.005). The Tp-e/QT ratio decreased from 0.27 +/- 0.02 to 0.23 +/- 0.018 (p = 0.01). Mexiletine had no significant effect on QRS complex duration. CONCLUSIONS: INa-L blockade with mexiletine may be an effective treatment approach to terminate refractory TdP from several acquired causes of LQTS. PMID- 29759322 TI - The Leadless Cardiac Pacemaker: Conductive Communication. PMID- 29759321 TI - Age-Related Differences in Presentation, Treatment, and Outcome of Patients With Atrial Fibrillation in Europe: The EORP-AF General Pilot Registry (EURObservational Research Programme-Atrial Fibrillation). AB - OBJECTIVES: This study sought to compare age-related differences in presentation, treatment, and outcome of atrial fibrillation (AF) in a wide cohort of European subjects. BACKGROUND: AF is the most common sustained arrhythmia in the elderly. METHODS: We evaluated all patients enrolled in the EORP-AF (EURObservational Research Programme-Atrial Fibrillation) General Pilot Registry in 70 centers of 9 European countries. RESULTS: Among 3,119 subjects, 1,051 (33.7%) were age >=75 years. Permanent AF was significantly more common in the elderly, who had a higher prevalence of hypertension, valvular diseases, chronic heart failure, coronary artery disease, renal failure, chronic obstructive pulmonary disease, and prior hemorrhagic event or a transient ischemic attack. Common diagnostic tests were underused in older subjects. Despite their higher stroke risk, the use of oral anticoagulants was significantly lower in the elderly (76.7% vs. 82.8%; p = 0.0012), whereas aspirin and clopidogrel alone or in combination were more often prescribed. Rate control was the management of choice in the older group, with electrical cardioversion and catheter ablation performed less frequently than in the younger age group. Antiarrhythmic drugs were significantly less prescribed in the elderly (29.8% vs. 41.7%; p < 0.0001). At the 1-year follow-up, mortality (11.5% vs. 3.7%; p < 0.0001) and the composite of stroke/transient ischemic attack, systemic thromboembolism, and/or death (13.6% vs. 4.9%; p < 0.0001) were significantly higher in the >=75 years of age cohort. CONCLUSIONS: In older patients, AF is more often associated with comorbidities. Rate control is the preferred therapeutic approach. Despite a higher CHA2DS2-VASc score, the use of oral anticoagulation is suboptimal. In elderly subjects, the rate of adverse events is higher at follow-up. PMID- 29759323 TI - Breaking New Paths: Late-Breaking Clinical Trials From HRS and EUROPACE CARDIOSTIM 2015. PMID- 29759326 TI - Audio Summary. PMID- 29759327 TI - Immunotherapy-responsive childhood neurodegeneration with systemic and central nervous system inflammation. AB - Subacute neuroregression in association with raised neopterin and overexpression of interferon stimulated genes (ISGs) could indicate a type 1 interferonopathy. Here we describe a novel immunotherapy-responsive, clinico-immunological and imaging phenotype with evidence of innate immune activation. Three children (patient 1: 22-month-old boy; patient 2: 5-year-old girl; patient 3: 4-year-old girl) presented with asymmetric bilateral mixed dystonia and spasticity, regression in language (expressive more than receptive) and bulbar symptoms with no evidence of seizures. Symptoms evolved over several weeks to months. Brain MRI changes mimicked cerebral atrophy, initially asymmetric. CSF revealed raised neopterins. Blood RNA assay showed abnormal overexpression of ISGs and transient raised alanine aminotransferase (ALT). Importantly, all three children were treated with intravenous methylprednisolone and immunoglobulin with significant and sustained improvement in their motor and language function, and normalisation of imaging. Immune-mediated encephalitis can masquerade as subacute neuroregression. PMID- 29759328 TI - A novel applicator design for intracavitary brachytherapy of the nasopharynx: Simulated reconstruction, image-guided adaptive brachytherapy planning, and dosimetry. AB - PURPOSE: In nasopharyngeal cancer, brachytherapy is given as boost in primary treatment or as salvage for recurrent or persistent disease. The Rotterdam nasopharyngeal applicator (RNA) allows for suboptimal reduction of soft palate radiation dose, based on image-guided brachytherapy plans. Building on the RNA, we propose a novel design, the Benavides nasopharyngeal applicator (BNA). METHODS AND MATERIALS: The virtual BNA was reconstructed on two cases (one T1, one T2) previously treated with intracavitary brachytherapy using the RNA. Dose was prescribed to the high-risk clinical target volumes (CTVs) and optimization was such that high-risk CTV D90 >= 100% of prescribed dose (PD), intermediate-risk CTV D90 >= 75% PD, and soft palate D2cc <= 120% PD. The optimized RNA and BNA image-guided brachytherapy plans were compared in terms of CTV coverage and organs-at-risk sparing. RESULTS: Optimization objectives were more easily met with the BNA. For the T1 case, all three planning objectives were easily achieved in both the RNA and BNA, but with 18-19% lower soft palate doses with the BNA. For the T2 case, the CTV planning objectives were achieved in both the RNA and BNA, but the soft palate constraint was only achieved with the BNA, with 38-41% lower soft palate doses. CONCLUSIONS: Compared to the RNA, the BNA permits easier optimization and improves therapeutic ratio by a significant reduction of soft palate doses, based on simulation using a proposed system for CTV/organs-at-risk delineation, prescription, and optimization for image-guided adaptive brachytherapy. Clinical piloting using a prototype is necessary to evaluate its feasibility and utility. PMID- 29759329 TI - Comparison of dosimetric and clinical outcomes between short- and long-channel cylinder applicators for vaginal brachytherapy in intermediate- and high-risk endometrial cancer. AB - PURPOSE: Vaginal brachytherapy (VBT) using a cylinder applicator is a standard treatment of intermediate- and high-risk endometrial cancer. We conducted a retrospective study of the dosimetric and clinical outcomes at our institution with 2 single-channel applicators in patients receiving VBT. METHODS AND MATERIALS: One hundred thirty-six patients with endometrial cancer treated from 2006 to 2016 receiving VBT after definitive surgery were evaluated. Two cylinders were used with the distal dwell position 7.1-12.8 mm from the apex varying by diameter (short channel), and 3.2 mm from the apex (long channel). We prescribed 18-26 Gy in 3-4 fractions at 0.5 cm depth. Measurements of the distance from the apex to the prescription isodose line were taken from CT imaging. Student's t test and the Wilcoxon rank-sum test were used with corrections for multiple comparisons. RESULTS: Patients had International Federation of Gynecology and Obstetrics 2009 Stage I-II disease (70 Stage IA, 58 Stage IB, 9 Stage II). Mean cylinder apex dose was 95.2% and 154.7% of prescription (p < 0.001), and mean distance from apex to the prescription isodose line was 0.54 mm and 3.5 mm (p < 0.001) for the short- and long-channel cylinders, respectively. There were no significant differences in any toxicity between cylinders. Four patients (2.9%) had vaginal recurrence, all of whom were treated with the short-channel cylinder. Cylinder type was not associated with vaginal recurrence (p = 0.27). CONCLUSIONS: A cylinder applicator with a distal dwell position closer to the apex results in higher doses to the vaginal cuff and increased D2cc to the bladder. All four recurrences were in the short-channel cylinder. Additional investigation into applicator design and impact on patient outcomes in larger cohorts with sufficient followup is warranted. PMID- 29759330 TI - [WHO classification of head and neck tumours 2017: Main novelties and update of diagnostic methods]. AB - The publication of the new WHO classification of head and neck tumours in 2017 brought major modifications. Especially, a new chapter is dedicated to the oropharynx, focusing on the description of squamous cell carcinoma induced by the virus Human Papilloma Virus (HPV), and new entities of tumors are described in nasal cavities and sinuses. In this article are presented the novelties and main changes of this new classification, as well as the updates of the diagnostic methods (immunohistochemistry, cytogenetics or molecular biology). PMID- 29759333 TI - Clinical Electrophysiology: A New Member of the Family. PMID- 29759331 TI - Prognostic Value of Pretreatment FDG-PET Parameters in High-dose Image-guided Radiotherapy for Oligometastatic Non-Small-cell Lung Cancer. AB - BACKGROUND: Emerging data support aggressive local treatment of oligometastatic non-small-cell lung cancer (NSCLC) patients. We sought to determine whether the metabolic burden of disease found by fluorodeoxyglucose positron emission tomography at the time of high-dose radiotherapy (RT) for oligometastatic NSCLC can serve as a prognostic biomarker. MATERIALS AND METHODS: We conducted a retrospective cohort study of 67 RT treatment courses in 55 patients with oligometastatic NSCLC who had undergone high-dose RT to all sites of active disease at our institution. The metabolic tumor volume, total lesion glycolysis (TLG), and maximum standardized uptake value of all lesions were measured on the pretreatment fluorodeoxyglucose positron emission tomography scans. Cox regression analysis was used to assess the influence of imaging and clinical factors on overall survival (OS). RESULTS: On univariate analysis, a greater metabolic tumor volume and TLG were predictive of shorter OS (hazard ratio of death, 2.42 and 2.14, respectively; P = .009 and P = .004, respectively). The effects remained significant on multivariate analysis. Neither the maximum standardized uptake value nor the number of lesions was significantly associated with OS. Patients within the highest quartile of TLG values (> 86.8 units) had a shorter median OS than those within the lower 3 quartiles (12.4 vs. 30.1 months; log-rank P = .014). CONCLUSION: The metabolic tumor burden was prognostic of OS and might help to better select oligometastatic NSCLC patients for locally ablative therapy. PMID- 29759332 TI - SUNSET: Stereotactic Radiation for Ultracentral Non-Small-Cell Lung Cancer-A Safety and Efficacy Trial. AB - BACKGROUND: Lung stereotactic body radiotherapy (SBRT) is considered a standard curative treatment for medically inoperable early stage non-small-cell lung cancer (NSCLC). Patients with ultracentral tumors (signifying tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, or pulmonary artery) may be at higher risk of serious toxicities such as bronchial stricture and collapse, esophageal strictures, tracheal-esophageal fistula, and hemorrhage. The primary objective of the study is to determine the maximum tolerated dose of radiotherapy for ultracentral NSCLC. METHODS: This multicenter phase 1 dose-escalation study will use a time-to-event continual reassessment method (TITE-CRM). Accrual will start at level 1 (60 Gy in 8 fractions delivered daily). The model will use all available information from previously accrued patients to assign the highest dose with a predicted risk of grade 3-5 toxicity of 30% or less. All patients with newly diagnosed stage T1-3 N0M0 NSCLC (International Union Against Cancer, 8th edition) with tumor size <= 6 cm and meeting the criteria for ultracentral location (ie, tumors whose planning target volume touches or overlaps the central bronchial tree, esophagus, pulmonary vein, or pulmonary artery) will be eligible for this study. DISCUSSION: It is important to identify a safe dose-fractionation regimen for treating ultracentral tumors with SBRT. In addition, the data from this study may be informative in guiding future studies on the use of SBRT in treating malignancies within the mediastinum-for example, for salvage treatment of mediastinal lymph nodes for recurrent NSCLC or mediastinal oligometastases. PMID- 29759335 TI - Is Human Long-Standing Persistent Atrial Fibrillation More Stable Than Assumed? PMID- 29759334 TI - Temporal Stability of Rotors and Atrial Activation Patterns in Persistent Human Atrial Fibrillation: A High-Density Epicardial Mapping Study of Prolonged Recordings. AB - OBJECTIVES: This study aimed to determine the spatiotemporal stability of rotors and other atrial activation patterns over 10 min in longstanding, persistent AF, along with the relationship of rotors to short cycle-length (CL) activity. BACKGROUND: The prevalence, stability, and mechanistic importance of rotors in human atrial fibrillation (AF) remain unclear. METHODS: Epicardial mapping was performed in 10 patients undergoing cardiac surgery, with bipolar electrograms recorded over 10 min using a triangular plaque (area: 6.75 cm2; 117 bipoles; spacing: 2.5 mm) applied to the left atrial posterior wall (n = 9) and the right atrial free wall (n = 4). Activations were identified throughout 6 discrete 10-s segments of AF spanning 10 min, and dynamic activation mapping was performed. The distributions of 4,557 generated activation patterns within each mapped region were compared between the 6 segments. RESULTS: The dominant activation pattern was the simultaneous presence of multiple narrow wave fronts (26%). Twelve percent of activations represented transient rotors, seen in 85% of mapped regions with a median duration of 3 rotations. A total of 87% were centered on an area of short CL activity (<100 ms), although such activity had a positive predictive value for rotors of only 0.12. The distribution of activation patterns and wave-front directionality were highly stable over time, with a single dominant pattern within a 10-s AF segment recurring across all 6 segments in 62% of mapped regions. CONCLUSIONS: In patients with longstanding, persistent AF, activation patterns are spatiotemporally stable over 10 min. Transient rotors can be demonstrated in the majority of mapped regions, are spatiotemporally associated with short CL activity, and, when recurrent, demonstrate anatomical determinism. PMID- 29759337 TI - If Some Primary Prevention Implantable Cardioverter-Defibrillator Implants Are Futile, Can We Identify Them A Priori? PMID- 29759336 TI - Prediction of Nonarrhythmic Mortality in Primary Prevention Implantable Cardioverter-Defibrillator Patients With Ischemic and Nonischemic Cardiomyopathy. AB - OBJECTIVES: The objective of this study was to investigate the feasibility of identifying heart failure patients who are less likely to benefit from implantable cardioverter-defibrillator (ICD) therapy among those eligible for primary prevention ICDs. BACKGROUND: The cost-effectiveness of ICDs in primary prevention may be improved dramatically. METHODS: Using a cause-of-death analysis approach, we evaluated the discriminative and predictive values of a risk score with regard to overall mortality and specific causes of death by examining 2,485 patients enrolled in the French Primary Prevention ICD program (2002 to 2012). The risk score included points for New York Heart Association functional class III or greater, age >70 years, QRS duration >120 ms, atrial fibrillation, and glomerular filtration rate <60 ml/min. Sensitivity analyses were performed for ischemic and nonischemic cardiomyopathy, as well as for patients undergoing cardiac resynchronization therapy. RESULTS: After a mean follow-up of 3.0 +/- 2.1 years, the overall mortality rate was 5.9 per 100 patient-years (95% confidence interval: 5.4 to 6.5), which increased with the number of risk factors (0 to 5, respectively), as follows: 2.5, 2.9, 4.8, 9.0, 12.3, and 14.8 per 100 patient years (p < 0.001). The higher mortality rate among patients with the highest scores resulted from an increase in nonarrhythmic mortality (from 2.1 to 14.8 per 100 patient-years, p < 0.001), whereas the occurrence of appropriate ICD therapies did not change significantly across the categories. The C statistic testing of the score was observed to be highly similar for patients with ischemic cardiomyopathy (0.685) and nonischemic cardiomyopathy (0.658) and those receiving cardiac resynchronization therapy (0.678). CONCLUSIONS: Our findings suggest the feasibility of and interest in identifying patients eligible for primary prevention ICD implantation who are at significant risk of nonarrhythmic death in the real-world setting. PMID- 29759338 TI - Effect of Obstructive Sleep Apnea Treatment on Atrial Fibrillation Recurrence: A Meta-Analysis. AB - OBJECTIVES: This study aimed to evaluate the cumulative effect of treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) on atrial fibrillation (AF) recurrence. BACKGROUND: OSA is a known predictor for onset and recurrence of AF. The effect of treatment with CPAP on AF recurrence has been evaluated in small studies with varied outcomes. METHODS: We searched MEDLINE, EMBASE, CINAHL, Google Scholar, Cochrane Database of Systematic Reviews, and Cochrane Trials Register for relevant studies. Evaluation of AF recurrence in CPAP users and nonusers in patients with OSA was the primary outcome evaluated in this study. The secondary outcome was evaluation of AF recurrence in CPAP users and nonusers after pulmonary vein isolation (PVI). RESULTS: Seven prospective cohort studies with a total of 1,087 patients met the inclusion criteria. Across all patient groups, the use of CPAP was associated with a significant reduction in AF recurrence (relative risk: 0.58, 95% confidence interval: 0.51 to 0.67; heterogeneity chi-square p = 0.91, I2 = 0%). The beneficial effect of CPAP use was statistically significant in both groups of patients: those who underwent catheter ablation with PVI and those who did not undergo ablation and were managed medically. No other study covariates had any significant association with these outcomes of AF reduction. CONCLUSIONS: The use of CPAP is associated with significant reduction in recurrence of AF in patients with OSA. This effect remains consistent and similar across patient populations irrespective of whether they undergo PVI. PMID- 29759340 TI - Catheter Ablation for Ventricular Tachycardia in the Elderly: Safe and Efficacious? PMID- 29759339 TI - Safety and Efficacy of Catheter Ablation for Ventricular Tachycardia in Elderly Patients With Structural Heart Disease. AB - OBJECTIVES: This study sought to determine the safety and efficacy of ventricular tachycardia (VT) ablation in elderly patients with structural heart disease. BACKGROUND: As patients with cardiomyopathy live longer, the number of elderly patients with VT is increasing. Catheter ablation is an effective treatment for VT; however, outcomes may differ among elderly patients. METHODS: We studied 238 consecutive patients with ischemic or nonischemic cardiomyopathies who underwent catheter ablation for VT refractory to antiarrhythmic medications. Patients were divided into 3 age groups (Group A, <65 years; Group B, 65 to 75 years; and Group C, >75 years). RESULTS: Compared with Groups A and B, patients in Group C were more likely to have ischemic cardiomyopathy, lower left ventricular ejection fraction, longer mean VT cycle length, and less likely to undergo epicardial ablation. Acute procedural success, complications, 28-day survival, and 1-year VT free survival rates were similar across groups (p = 0.9, 0.3, 0.3, and 0.9, respectively). As expected, Group C patients had worse survival in long-term follow-up (p < 0.001). CONCLUSIONS: VT ablation can be performed in elderly patients with structural heart disease with similar efficacy and complication rates as in younger patients. VT ablation should not be withheld for older age alone. PMID- 29759341 TI - Long QT Syndrome and Sports Participation: Oil and Water or an Acceptable and Manageable Combination? PMID- 29759342 TI - Prognostic Significance of Heart Rate Variability Among Patients Treated With Cardiac Resynchronization Therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). AB - OBJECTIVES: This study sought to evaluate the prognostic value of heart rate variability (HRV) for death or heart failure in patients with mildly symptomatic heart failure undergoing cardiac resynchronization therapy with a defibrillator (CRT-D). BACKGROUND: There are limited data regarding the prognostic value of HRV as a means of identifying high-risk patients treated with CRT-D. METHODS: We analyzed the relationship between pre-implant time-domain (SD of all normal-to normal RR intervals [SDNN], SDs of averaged 5-min normal-to-normal RR intervals, root mean square of successive differences, and mean of the SDs of all normal-to normal RR intervals for all 5-min segments of the entire recording), and frequency-domain (low-frequency power, very-low-frequency power [VLF], high frequency power, low-frequency power/low-frequency power ratio) HRV parameters, and the end point of death or heart failure and death alone. Study subjects include 719 patients in normal sinus rhythm enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy); outcomes of CRT-D patients with low HRV (lower tertile) were compared with CRT-D patients with preserved HRV (2 upper tertiles) and with patients receiving implantable cardioverter-defibrillators only. RESULTS: During a mean 3.4 +/- 0.9 years of follow-up, 124 patients reached the primary end point of death or heart failure, and 47 died. In multivariate analysis, low SDNN (<=93 ms) was associated with significantly higher risk of death or heart failure (hazard ratio [HR] 1.63 [95% confidence interval (CI): 1.12 to 2.36]; p = 0.010) and mortality (HR 2.10 [95% CI: 1.14 to 3.87]; p = 0.017) compared with higher SDNN (>93 ms). Similarly, low VLF (<=179 ms2) was associated with an increased risk of death or heart failure (HR 2.14 [95% CI: 1.46 to 3.13]; p < 0.001) and death alone (HR 2.49 [95% CI: 1.35 to 4.57]; p = 0.003). There was no significant difference in outcome between low HRV patients treated with CRT-D and patients receiving an implantable cardioverter-defibrillator only. CONCLUSIONS: Our findings indicate that autonomic dysfunction (quantified by low SDNN and low VLF) identified patients with no benefit or limited benefit from cardiac resynchronization therapy. Pre implant HRV analysis might help in optimizing qualifications for this treatment. PMID- 29759343 TI - Refining Patient Selection for Cardiac Resynchronization Therapy: A Place for Heart Rate Variability? PMID- 29759344 TI - Right Precordial T-Wave Inversion in Healthy Endurance Athletes Can Be Explained by Lateral Displacement of the Cardiac Apex. AB - OBJECTIVES: The objective of this study was to test the hypothesis that T-wave inversion in the right precordial leads (TWIV2-3) reflects lateral displacement of the heart such that the surface electrocardiographic (ECG) leads overlie a greater proportion of the right ventricle (RV). BACKGROUND: TWIV2-3 on ECG is more frequently observed among endurance athletes (EAs) than in the general population, the underlying mechanism for which is unclear. METHODS: Sixty-eight EAs and 41 nonathletic control subjects underwent ECG and cardiac magnetic resonance imaging (CMRI). In addition to standard measurements of biventricular function and volume, novel measurements of cardiac displacement and orientation were analyzed from horizontal long-axis images. These included RV wall thickness in diastole (RVd), cardiac-to-hemithorax area ratio (CHTx%), percentage of circumferential displacement of the RV apex toward the axilla (%LatD), and the angle of interventricular septum with respect to the thoracic midline (?septal). RESULTS: All cardiac volume, RVd, CHTx%, %LatD, and ?septal values were greater in EAs than in controls. Compared to EAs without TWIV2-3, EAs with TWIV2-3 (n = 26) did not have greater RV wall thickness or cardiac volumes (RVd = 4.9 vs. 4.8 mm, p = 0.695; LVEDV = 231 vs. 229 ml, p = 0.856; RVEDV = 257 vs. 254 mL, p = 0.746), but all measurements of cardiac displacement toward the axilla were greater (%LatD = 45.6% vs. 37.9%, respectively, p < 0.0001; ?septal = 54.23 degrees vs. 48.63 degrees , respectively, p = 0.001; and CHTx% = 46.3% vs. 41.9%, respectively, p = 0.048). CONCLUSIONS: In healthy EAs, TWIV2-3 is associated with displacement of the RV toward the left axilla rather than RV dilatation or hypertrophy. TWIV2-3 may be explained by the position of the RV relative to that of the surface ECG leads. PMID- 29759345 TI - Can Right Precordial T-Wave Inversion in Healthy Endurance Athletes Be Explained? PMID- 29759349 TI - Building a Foundation of Training: Community Collaboration to Make Cardiovascular Care Work. PMID- 29759346 TI - Measured Lead Parameters and Electrogram Sensing Over Time in Patients With Cardiac Sarcoidosis and an Implanted Cardiac-Defibrillator. AB - OBJECTIVES: The study sought to characterize the performance of implanted leads among a cohort of patients with cardiac sarcoidosis (CS) and implantable cardiac defibrillators (ICDs). BACKGROUND: An ICD is indicated for some patients with CS for the prevention of sudden cardiac death. CS can lead to myocardial inflammation and scar that may interfere with lead performance. METHODS: We performed a case-control study within the cohort of patients at the University of Colorado Hospital with CS and an ICD (n = 48) compared with randomly selected controls (n = 117) who had other indications for an ICD. We compared the measured lead parameters at the time of routine interrogation to assess the differences between groups over time. The mean duration of follow-up was 51 months. Survival analysis was performed by the method of Kaplan and Meier and by Cox proportional hazards regression. RESULTS: There was no significant difference in measured lead impedance, capture thresholds, or sensed electrograms at implantation between the CS and control groups. There were no significant differences between the mean parameters between groups over the follow-up period. However, patients with CS have a high incidence of significant (>50%) drop in measured electrograms (16 of 46 [33%] CS patients vs. 4 of 117 [3.4%] controls; hazard ratio: 10.49, 95% confidence interval: 3.47 to 31.67). As a result of alterations in lead parameters, 2 patients (4.3%) required lead revision, and 6 patients (13%) required ICD testing to ensure adequate detection of induced ventricular fibrillation. CONCLUSIONS: Reductions over time in ICD sensing of P- and/or R wave electrograms are common in patients with CS. Although further investigation is needed to determine the mechanism of these changes, these findings suggest that patients with CS who have an ICD should be closely monitored for clinically relevant changes in P- and R-wave amplitudes. PMID- 29759350 TI - Poor oral health in patients with schizophrenia: A systematic review and meta analysis. AB - Increased rates of comorbid physical illness have been commonly reported in patients with schizophrenia. However, there are fewer data on dental disease in these patients. We systematically evaluated existing data on the oral health survey of schizophrenia patients through meta-analysis. Using the available databases, we performed a systematic search to identify the studies examining the oral health in schizophrenia patients from January 1997 to June 2017, based on the inclusion and exclusion criteria. Two investigators extracted the related data independently. The meta-analysis was performed by using the RevMan 5.3 software after data extraction and quality assessment. We compared the oral health results between the schizophrenia patients and the general population, including the following measures: the mean number of decayed, missing and filled teeth (DMFT). Eight studies comprising 2640 patients with schizophrenia and 19,698 healthy controls were included in the meta-analysis. The patients with schizophrenia had significantly higher scores of dental caries (mean difference [MD] = 7.77, 95% confidence interval [CI] = 3.27 to 12.27), missing teeth (MD = 7.61, 95% CI = 3.44 to 11.77), and decayed teeth (MD = 3.44, 95% CI = 2.06 to 4.82) compared to controls (all p < 0.01). By contrast, the schizophrenia patients had fewer score of filled teeth (MD = -3.06, 95% CI, -4.82 to -1.30) than the controls (p < 0.01), indicating decreased access to dental care. Our systematic review suggests that patients with schizophrenia have worse oral health than the general population, but have received less dental care services. Hence, the oral health services should be taken into account in the patients with schizophrenia. PMID- 29759352 TI - A Systematic Review on the Progression of Paroxysmal to Persistent Atrial Fibrillation: Shedding New Light on the Effects of Catheter Ablation. AB - The progression from paroxysmal atrial fibrillation (AF) to persistent or long term persistent forms has recently gained increasing attention. A growing amount of data has shown a significant morbidity and mortality associated with the transition. The aim of our systematic review was to assess the evidence regarding AF progression rates with different management approaches. Electronic databases were searched by using text words and relevant indexing to capture data on AF progression. Studies that considered progression from paroxysmal AF to a persistent or permanent form were included. The papers collected were divided into 2 groups: 1) general population studies (with almost exclusively medical therapy); and 2) studies that consider progression of AF subsequent to AF ablation. Twenty-one studies were included in the first group and 8 in the second group. In the first group, percentage of AF progression at 1 year ranged from 10% to 20%. Studies that included a longer follow-up detected a higher percentage of progression (from 50% to 77% after 12 years). In patients treated with catheter ablation, the percentage of progression was significantly lower (from 2.4% to 2.7% at 5 years' follow-up). The percentage of progression after catheter ablation did not change according to duration of follow-up. AF ablation is associated with significantly reduced progression to persistent forms compared with studies in the general population. Prevention of long-term AF progression may be a clinically relevant outcome after AF ablation. Further research is required to determine whether delaying progression of AF by catheter ablation reduces morbidity and mortality. PMID- 29759351 TI - Dysbindin-1 contributes to prefrontal cortical dendritic arbor pathology in schizophrenia. AB - Deep layer III pyramidal cells in the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia and bipolar disorder previously were shown to exhibit dendritic arbor pathology. This study sought to determine whether MARCKS, its regulatory protein dysbindin-1, and two proteins, identified using microarray data, CDC42BPA and ARHGEF6, were associated with dendritic arbor pathology in the DLPFC from schizophrenia and bipolar disorder subjects. Using western blotting, relative protein expression was assessed in the DLPFC (BA 46) grey matter from subjects with schizophrenia (n = 19), bipolar disorder (n = 17) and unaffected control subjects (n = 19). Protein expression data were then correlated with dendritic parameter data obtained previously. MARCKS and dysbindin-1a expression levels did not differ among the three groups. Dysbindin-1b expression was 26% higher in schizophrenia subjects (p = 0.01) and correlated inversely with basilar dendrite length (r = -0.31, p = 0.048) and the number of spines per basilar dendrite (r = -0.31, p = 0.048), but not with dendritic spine density (r = -0.16, p = 0.32). The protein expression of CDC42BPA was 33% higher in schizophrenia subjects (p = 0.03) but, did not correlate with any dendritic parameter (p > 0.05). ARHGEF6 87 kDa isoform expression did not differ among the groups. CDC42BPA expression was not altered in frontal cortex from rats chronically administered haloperidol or clozapine. Dysbindin-1b appears to play a role in dendritic arbor pathology observed previously in the DLPFC in schizophrenia. PMID- 29759354 TI - Idiopathic Premature Ventricular Contraction Ablation: Prime Time or Second Line? PMID- 29759353 TI - Multicenter Outcomes for Catheter Ablation of Idiopathic Premature Ventricular Complexes. AB - OBJECTIVES: This study reports multicenter outcomes and complications for catheter ablation of premature ventricular complexes (PVCs) and investigates predictors of procedural success, as well as development of PVC-induced cardiomyopathy. BACKGROUND: Catheter ablation of frequent idiopathic PVCs is used to eliminate symptoms and treat PVC-induced cardiomyopathy. Large-scale multicenter outcomes and complication rates have not been reported. METHODS: This retrospective cohort study included 1,185 patients (55% female; mean age 52 +/- 15 years; mean ejection fraction 55 +/- 10%; mean PVC burden 20 +/- 13%) who underwent catheter ablation for idiopathic PVCs at 8 centers between 2004 and 2013. The following factors were evaluated: patient demographics, procedural characteristics, complication rates, and clinical outcomes. RESULTS: Acute procedural success was achieved in 84% of patients. In centers at which patients were followed up routinely with post-ablation Holter monitoring, continued success at clinical follow-up without use of antiarrhythmic drugs was 71%. Including the use of antiarrhythmic medications, the success rate at a mean of 1.9 years of follow-up was 85%. In a multivariate analysis, the significant predictors of acute success were PVC location and number of distinct PVC configurations (p < 0.03). The only significant predictor of continued success at clinical follow-up was a right ventricular outflow tract PVC location (p < 0.01). In 245 patients (21%) with PVC-induced cardiomyopathy, the mean ejection fraction improved from 38% to 50% (p < 0.01) after ablation. Independent predictors for development of PVC-induced cardiomyopathy were male gender, PVC burden, lack of symptoms, and epicardial PVC origin (p < 0.05). The overall complication rate was 5.2% (2.4% major complications and 2.8% minor complications), and complications were most commonly related to vascular access (2.8%). There was no procedure related mortality. CONCLUSIONS: Catheter ablation of frequent PVCs is a low-risk and often effective treatment strategy to eliminate PVCs and associated symptoms. In patients with PVC-induced cardiomyopathy, cardiac function is frequently restored after successful ablation. PMID- 29759356 TI - Catheter Ablation for Paroxysmal Atrial Fibrillation: Triggers and Thoughts Provoked by Adenosine. PMID- 29759355 TI - Adenosine-Provoked Atrial Fibrillation Originating From Non-Pulmonary Vein Foci: The Clinical Significance and Outcome After Catheter Ablation. AB - OBJECTIVES: The goal of this study was to systematically investigate the incidence and clinical significance of non-pulmonary vein (PV) foci revealed by adenosine/adenosine triphosphate (ATP) testing during atrial fibrillation (AF) ablation. BACKGROUND: ATP is reported to provoke AF. METHODS: A total of 464 patients with consecutive paroxysmal AF undergoing ATP testing after PV antrum isolation were included. RESULTS: AF originating from non-PV foci was provoked in 26 (5.6%) total patients during first (n = 20) or repeat (n = 8) ablation procedures. Dormant PV conduction was also revealed by ATP testing in 6 patients. Non-PV foci were located in the superior vena cava (SVC) (i.e., the SVC group) and atria (i.e., the atria group) in 10 and 18 (9 each in the right and left atria) patients, respectively. In the multivariable analysis, being female was the sole independent predictor of ATP-provoked AF originating from non-PV foci (hazard ratio [HR]: 2.52 [95% confidence interval (CI): 1.069 to 5.929]; p = 0.034). After additional ablation targeting non-PV foci, freedom from recurrent AF after the last procedure was similar between the SVC group and patients without ATP-provoked AF but was significantly lower in the atria group than in others (p = 0.0008). Atria group membership (HR: 3.725 [95% CI: 1.692 to 8.199]; p = 0.001) and being female (HR: 1.538 [95% CI: 1.189 to 1.989]; p = 0.001) were significant independent predictors associated with recurrence after the last procedure in the multivariable Cox regression model. CONCLUSIONS: ATP provoked AF originating from non-PV foci under isoproterenol in 5.6% of patients undergoing paroxysmal AF ablation. ATP testing might be useful for identifying and eliminating AF originating from the SVC. The atria group was associated with a poor outcome after the last procedure despite efforts to eliminate non-PV foci. PMID- 29759357 TI - Obesity and the Risk of Incident, Post-Operative, and Post-Ablation Atrial Fibrillation: A Meta-Analysis of 626,603 Individuals in 51 Studies. AB - OBJECTIVES: The purpose of this study was to quantify the magnitude of association between incremental increases in body mass index (BMI) and the development of incident, post-operative, and post-ablation atrial fibrillation (AF). BACKGROUND: Obesity has been estimated to account for one-fifth of all AF and approximately 60% of recent increases in population AF incidence. From a public health perspective, obesity, therefore, is a modifiable risk factor that could be profitably targeted. METHODS: A systematic review and meta-analysis was conducted. Medline and EMBASE databases were searched for observational studies reporting data on the association between obesity and incident, post-operative, and post-ablation AF. Studies were included if they reported or provided data allowing calculation of risk estimates. RESULTS: Data from 51 studies including 626,603 individuals contributed to this analysis. There were 29% (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.23 to 1.36) and 19% (OR: 1.19, 95% CI: 1.13 to 1.26) greater excess risks of incident AF for every 5-U BMI increase in cohort and case-control studies, respectively. Similarly, there were 10% (OR: 1.10, 95% CI: 1.04 to 1.17) and 13% (OR: 1.13, 95% CI: 1.06 to 1.22) greater excess risks of post-operative and post-ablation AF for every 5-U increase in BMI, respectively. CONCLUSIONS: Incremental increases in BMI are associated with a significant excess risk of AF in different clinical settings. For every 5-U increase in BMI, there were 10% to 29% greater excess risks of incident, post operative, and post-ablation AF. By providing a comprehensive and reliable quantification of the relationship between incremental increases in obesity and AF across different clinical settings, our findings highlight the potential for even moderate reductions in population body mass indexes to have a significant effect in mitigating the rising burden of AF. PMID- 29759359 TI - Ablation for Persistent Atrial Fibrillation: Pulmonary Vein Isolation Plus What? PMID- 29759358 TI - Left Atrial Appendage Ligation and Ablation for Persistent Atrial Fibrillation: The LAALA-AF Registry. AB - OBJECTIVES: This study was intended to evaluate the impact of adding the left atrial appendage (LAA) closure system (LARIAT) procedure to conventional atrial fibrillation (AF) ablation in patients with persistent AF. BACKGROUND: Percutaneous endoepicardial LARIAT may result in both mechanical and electrical exclusion of the LAA and aid in improving the outcomes of catheter ablation by eradicating the LAA triggers and altering the substrate. METHODS: We performed a prospective observational study of patients with persistent AF referred for AF ablation. Patients underwent LAA ligation with LARIAT procedure before undergoing AF ablation (LARIAT group). Age- and sex-matched persistent AF patients undergoing AF ablation during the same time frame were included in the control group (ablation-only group). RESULTS: A total of 138 patients were included in the study, with 69 patients in the LARIAT group. The mean age of the population was 67 +/- 10 years, with 96 (70%) men. Left atrial (LA) size, CHADS2, CHADSVasc, and HAS-BLED scores were higher in the LARIAT group when compared with the ablation-only group. There were no differences in the type of lesions during AF ablation between the groups. The primary outcome of freedom from AF at 1 year off antiarrhythmic therapy after 1 ablation procedure was higher in the LARIAT group (45 [65%] vs. 27 [39%]; p = 0.002). More patients in the ablation-only group underwent repeat ablation because of AF recurrence (11 [16%] vs. 23 [33%]; p = 0.018). CONCLUSIONS: In patients with persistent AF, addition of LAA ligation with the LARIAT device to conventional ablation appears to improve the success rate of AF ablation. PMID- 29759361 TI - Triggers, Substrate, and Hypertension in Atrial Fibrillation: How Does It All Add Up? PMID- 29759362 TI - Gadolinium Augmentation of Myocardial Tissue Heating During Radiofrequency Ablation. AB - OBJECTIVES: This study hypothesized that a metal already commonly used in medical procedures, gadolinium (Gd), will augment radiofrequency (RF) thermal injury and affect cardiac ablation lesions. BACKGROUND: Enhancement of RF ablation using metallic particles has been proposed for ablation of tumors. METHODS: A series of ablation lesions were delivered at variable power using an ex vivo model. Tissue temperatures and lesion characteristics were analyzed. Ablation in a porcine in vivo model after direct needle injection of the myocardium with Gd or after systemic administration of Gd encased in heat sensitive liposomes was also performed and compared to control values. RESULTS: Ablation after Gd infiltration of myocardial tissue resulted in significantly larger lesions at both low- and high-power settings. Larger impedance changes were observed during ablation of Gd treated myocardium. In vivo ablation using a force-sensing irrigated tip catheter resulted in enhanced lesion sizes after Gd injection without a higher incidence of steam pops or perforation. Systemic administration of liposomal Gd with local release by RF heating did not result in larger ablation sizes. CONCLUSIONS: Gd can be used to enhance RF ablation lesions. In both ex vivo studies with a 4-mm ablation catheter under power control and in vivo findings with an irrigated tip catheter, ablation of myocardium infiltrated with Gd resulted in larger lesions, with altered RF electrical and thermal characteristics. More research is needed to refine the potential for Gd facilitation of RF ablation. The use of systemic heat-sensitive liposomes containing Gd with targeted release by RF heating did not affect lesion size. PMID- 29759363 TI - After the Fire and Ice Age, Are We Entering the Metal Age? PMID- 29759360 TI - Impact of Uncontrolled Hypertension on Atrial Fibrillation Ablation Outcome. AB - OBJECTIVES: The goal of this study was to evaluate the impact of hypertension on the outcome of atrial fibrillation (AF) ablation. BACKGROUND: Hypertension is a well-known independent risk factor for incident AF. METHODS: A total of 531 consecutive patients undergoing AF ablation were enrolled in this study and divided into 3 groups: patients with uncontrolled hypertension despite medical treatment (group I, n = 160), patients with controlled hypertension (group II, n = 192), and patients without hypertension (group III, n = 179). Pulmonary vein (PV) antrum and posterior wall isolation was always performed, and non-PV triggers were identified during isoproterenol infusion. All patients underwent extensive follow-up. RESULTS: Three groups differed in terms of left atrial (LA) size, non-PV triggers, and moderate/severe LA scar. Non-PV triggers were present in 94 (58.8%), 64 (33.3%), and 50 (27.9%) patients in groups I, II, and III, respectively (p < 0.001). After 19 +/- 7.7 months of follow-up, 65 (40.6%), 54 (28.1%), and 46 (25.7%) patients in groups I, II, and III had recurrences (log rank test, p = 0.003). Among patients in group I who underwent additional non-PV trigger ablation, freedom from AF/atrial tachycardia was 69.8%, which was similar to groups II and III procedural success (log-rank p = 0.7). After adjusting for confounders, uncontrolled hypertension (group I) (hazard ratio [HR]: 1.52, p = 0.045), non-PV triggers (HR: 1.85, p < 0.001), and nonparoxysmal AF (HR: 1.64, p = 0.002) demonstrated significant association with arrhythmia recurrence. CONCLUSIONS: Controlled hypertension does not affect the AF ablation outcome when compared with patients without hypertension. By contrast, uncontrolled hypertension confers higher AF recurrence risk and requires more extensive ablation. PMID- 29759365 TI - Shifting Ventricular Fibrillation Drive Mechanism as Time Progresses: Evidence From Explanted Human Hearts. PMID- 29759364 TI - Mechanisms of Long-Duration Ventricular Fibrillation in Human Hearts and Experimental Validation in Canine Purkinje Fibers. AB - OBJECTIVES: This study sought to determine the characteristics of human LDVF, particularly as it contrasts with short-duration VF (SDVF), and evaluate the role of Purkinje fibers in its maintenance. BACKGROUND: The electrophysiological mechanisms of long-duration ventricular fibrillation (LDVF) have not been studied in the human heart. METHODS: VF was induced in 12 human Langendorff hearts, and the hearts were examined from initiation to LDVF (10 min). Endocardial, epicardial, and transmural plunge needle mapping were performed on the hearts. Simulated LDVF was studied in canine hearts to determine the potential role of Purkinje fiber automaticity. RESULTS: The mean age at transplant was 48 +/- 20 years, and the mean ejection fraction was <20%. The mean cycle length of local activation times on the endocardium was 252 +/- 66 ms in SDVF and 441 +/- 80 ms in LDVF (p = 0.0002). On the endocardium and the epicardium in LDVF, cycle length was 441 +/- 80 ms and 590 +/- 88 ms, respectively (p = 0.0002). No endocardial to epicardial activation frequency gradient was seen in SDVF. Simultaneous transmural needle activation was most common in SDVF, whereas endocardial to epicardial activation was most common in LDVF (47.7% and 38.8% of activations, respectively [p = 0.031]). Re-entry was less common in LDVF, and over time, wave break (i.e., nontransmural propagation of wave fronts) developed. Isochronal maps of the left ventricular endocardium in LDVF identified Purkinje potentials as preceding and predominating endocardial activations. In explanted canine heart preparations, rapid pacing led to spontaneous Purkinje fiber activity that was dependent on pacing rate and duration. CONCLUSIONS: LDVF in human hearts is characterized by focal endocardial activity with mid-myocardial wave break and not by re-entry. This arrhythmia is modulated by rapid activations in early VF that lead to spontaneous Purkinje fiber activity. PMID- 29759367 TI - Atrial Fibrillation and Thrombogenesis: Innocent Bystander or Guilty Accomplice? PMID- 29759368 TI - Pulmonary Vein Stenosis After Laser Balloon Ablation for Atrial Fibrillation. PMID- 29759369 TI - The Issue of Focus. PMID- 29759370 TI - Correction. PMID- 29759366 TI - Thrombogenic Risk in Patients With Atrial Fibrillation: Importance of Comorbid Conditions and Intracardiac Changes. AB - OBJECTIVES: This study sought to determine the differences between the prothrombotic properties and chamber characteristics in patients with lone atrial fibrillation (AF) and those with AF and comorbidities. BACKGROUND: Thromboembolic risk is increased in patients with AF; however, whether this is due to AF per se or its comorbidities remains unclear. METHODS: A total of 87 patients undergoing ablation were prospectively recruited for the study, including 30 patients with lone AF, 30 patients with AF and comorbidities in sinus rhythm, and 27 patients with left-sided accessory pathways as controls. Blood samples were obtained from the left atrium (LA), right atrium (RA), and femoral vein (FV) after transseptal puncture. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric-dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS: Platelet activation in the LA was significantly elevated compared to that in the FV in patients with lone AF and those with AF and comorbidities compared with that in the FV (p < 0.05 respectively). Thrombin generation was significantly elevated in the LA compared with RA in AF patients (p < 0.05). There were no significant differences in P-selectin, TAT, and sCD40L among the 3 groups. However, there was a significant stepwise increase in endothelial dysfunction measured by ADMA from controls to lone AF and then to patients with AF and comorbidities (p < 0.001 between the 2 groups). CONCLUSIONS: Patients with lone AF and those with AF and comorbidities had a greater propensity for atrial thrombogenesis than controls. Prothrombotic risk is greatest in those with comorbid conditions, in whom enhanced thrombogenesis occurs predominantly through increase in endothelial dysfunction. PMID- 29759373 TI - Random Motion of Chromatin Is Influenced by Lamin A Interconnections. AB - Using fluorescence correlation spectroscopy in single-plane illumination microscopy, we investigated the dynamics of chromatin in interphase mouse adult fibroblast cell nuclei under the influence of the intermediate filament protein lamin A. We find that 1) lamin A-eGFP and histone H2A-mRFP show significant comobility, indicating that their motions are clearly interconnected in the nucleus, and 2) that the random motion of histones H2A within the chromatin network is subdiffusive, i.e., the effective diffusion coefficient decreases for slow timescales. Knocking out lamin A changes the diffusion back to normal. Thus, lamin A influences the dynamics of the entire chromatin network. Our conclusion is that lamin A plays a central role in determining the viscoelasticity of the chromatin network and helping to maintain local ordering of interphase chromosomes. PMID- 29759375 TI - Massive Buttock Necrosis Following Aortobifemoral Bypass Surgery. PMID- 29759374 TI - Dependence of Chromatosome Structure on Linker Histone Sequence and Posttranslational Modification. AB - Linker histone (LH) proteins play a key role in higher-order structuring of chromatin for the packing of DNA in eukaryotic cells and in the regulation of genomic function. The common fruit fly (Drosophila melanogaster) has a single somatic isoform of the LH (H1). It is thus a useful model organism for investigating the effects of the LH on nucleosome compaction and the structure of the chromatosome, the complex formed by binding of an LH to a nucleosome. The structural and mechanistic details of how LH proteins bind to nucleosomes are debated. Here, we apply Brownian dynamics simulations to compare the nucleosome binding of the globular domain of D. melanogaster H1 (gH1) and the corresponding chicken (Gallus gallus) LH isoform, gH5, to identify residues in the LH that critically affect the structure of the chromatosome. Moreover, we investigate the effects of posttranslational modifications on the gH1 binding mode. We find that certain single-point mutations and posttranslational modifications of the LH proteins can significantly affect chromatosome structure. These findings indicate that even subtle differences in LH sequence can significantly shift the chromatosome structural ensemble and thus have implications for chromatin structure and transcriptional regulation. PMID- 29759376 TI - The Pac-Man Sign. PMID- 29759377 TI - Diagnostic DIVA tests accompanying the Disabled Infectious Single Animal (DISA) vaccine platform for African horse sickness. AB - African Horse Sickness Virus (AHSV) (Orbivirus genus, Reoviridae family) causes high mortality in naive domestic horses with enormous economic and socio emotional impact. There are nine AHSV serotypes showing limited cross neutralization. AHSV is transmitted by competent species of Culicoides biting midges. AHS is a serious threat beyond the African continent as endemic Culicoides species in moderate climates transmit the closely related prototype bluetongue virus. There is a desperate need for safe and efficacious vaccines, while DIVA (Differentiating Infected from Vaccinated) vaccines would accelerate control of AHS. Previously, we have shown that highly virulent AHSV with an in frame deletion of 77 amino acids (aa) in NS3/NS3a is completely safe, does not cause viremia and shows protective capacity. This deletion mutant is a promising DISA (Disabled Infectious Single Animal) vaccine platform, since exchange of serotype specific virus proteins has been shown for all nine serotypes. Here, we show that a prototype NS3 competitive ELISA is DIVA compliant to AHS DISA vaccine platforms. Epitope mapping of NS3/NS3a shows that more research is needed to evaluate this prototype serological DIVA assay regarding sensitivity and specificity, in particular for AHSVs expressing antigenically different NS3/NS3a proteins. Further, an experimental panAHSV PCR test targeting genome segment 10 is developed that detects reference AHSV strains, whereas AHS DISA vaccine platforms were not detected. This DIVA PCR test completely guarantees genetic DIVA based on in silico and in vitro validation, although test validation regarding diagnostic sensitivity and specificity has not been performed yet. In conclusion, the prototype NS3 cELISA and the PCR test described here enable serological and genetic DIVA accompanying AHS DISA vaccine platforms. PMID- 29759378 TI - Recombinant M. bovis BCG expressing the PLD protein promotes survival in mice challenged with a C. pseudotuberculosis virulent strain. AB - The aim of this study was to evaluate the survival of mice inoculated with M. bovis BCG Pasteur recombinant expressing the PLD protein and challenged with a C. pseudotuberculosis virulent strain. Four groups were immunized with a sterile 0.9% saline solution (G1), 106 CFU of M. bovis BCG Pasteur (G2), 106 CFU of M. bovis BCG/pld (G3) or 106 CFU of M. bovis BCG/pld with a booster with rPLD (G4) and challenged with 104 CFU of C. pseudotuberculosis MIC-6 strain. The highest survival rate of 88% was observed in G4, followed by 77% in G3 and 66% in G2. A significant statistical difference was observed in the levels of cytokines IFN gamma and IL-10 in vaccinated groups (G3 and G4) when compared with the control group (G1) (p < 0.05). The results seem promising as the recombinant vaccine elicited a cellular immune response and provided significant survival after a high virulent challenge. PMID- 29759379 TI - Simultaneous surface display and cargo loading of encapsulin nanocompartments and their use for rational vaccine design. AB - In the past decades protein nanoparticles have successfully been used for vaccine applications. Their particulate nature and dense repetitive subunit organization makes them perfect carriers for antigen surface display and confers high immunogenicity. Nanoparticles have emerged as excellent candidates for vectorization of biological and immunostimulating molecules. Nanoparticles and biomolecular nanostructures such as ferritins or virus like particles have been used as diagnostic and therapeutic delivery systems, in vaccine development, as nanoreactors, etc. Recently, a new class of bacterial protein compartment has been discovered referred to as encapsulin nanocompartment. These compartments have been used for targeted diagnostics, as therapeutic delivery systems and as nanoreactors. Their biological origin makes them conveniently biocompatible and allows genetic functionalization. The aim of our study was to implement encapsulin nanocompartements for simultaneous epitope surface display and heterologous protein loading for rational vaccine design. For this proof-of concept-study, we produced Thermotoga maritima encapsulin nanoparticles in E. coli. We demonstrated the ability of simultaneous display in our system by inserting Matrix protein 2 ectodomain (M2e) of influenza A virus at the nanoparticle surface and by packaging of a fluorescent reporter protein (GFP) into the internal cavity. Characterization of the nanoparticles by electronic microscopy confirmed homogenously shaped particles of 24 nm diameter in average. The results further show that engineering of the particle surface improved the loading capacity of the heterologous reporter protein suggesting that surface display may induce a critical elastic deformation resulting in improved stiffness. In Balb/c mice, nanoparticle immunization elicited antibody responses against both the surface epitope and the loaded cargo protein. These results confirm the potential of encapsulin nanocompartments for customized vaccine design and antigen delivery. PMID- 29759382 TI - Cardiac Electrophysiology Procedures, Known Unknowns, and Unknown Unknowns: The Potential of Magnetic Resonance Guidance. PMID- 29759380 TI - Impact of a clinical interventions bundle on uptake of HPV vaccine at an OB/GYN clinic. AB - INTRODUCTION: HPV vaccine uptake is lowest among young adults. Little is known about the most effective way to decrease missed opportunities (MO) and increase uptake of the vaccine in this vulnerable population. OBJECTIVES: To determine the impact of a clinical intervention bundle on the rate of MO and uptake of the vaccine among young adult women. METHODS: From 2/2014 to 7/2015, an intervention bundle (designating physician and nurse champions, pre-screening patients' charts, empowering nurses to recommend immunization, providing no-cost vaccinations, placing prompts in clinic note templates, eliminating requirement for pre-vaccination pregnancy test) was implemented at an urban, hospital-based OB/GYN clinic. Medical records were reviewed for all vaccine-eligible (non pregnant, 11-26 years) women seen between 2/2013 and 9/2016. Impact of the bundled interventions on the monthly rates of MO and vaccine uptake was estimated by analyzing immunization trends with an interrupted time-series model using counterfactual comparison groups in order to control for pre-existing trends. RESULTS: There were 6,463 vaccine-eligible visits during our study period. The prevalence of women who had both completed and initiated the series was significantly higher, 20.3% and 29.7% respectively, in the last month, compared to their counterfactuals (p < 0.01). In the last study month, the rate of MO was significantly lower than its counterfactual (19.73 per 100 encounters lower, p < 0.01). Hispanic women had attributable reductions in their rates of MO that were twice that of White women. Statistically significant attributable reductions were also seen among Spanish speakers, publicly insured, and uninsured women. CONCLUSIONS: Implementation of this intervention bundle effectively reduced the monthly rate of MO and increased the prevalence of women who had initiated and completed the HPV vaccine series. The reduction of MO was most drastic among Hispanic, publicly insured and uninsured women compared to White and privately insured. PMID- 29759383 TI - Safety and Efficacy of Exercise Training in Patients With an Implantable Cardioverter-Defibrillator: A Meta-Analysis. AB - OBJECTIVES: In this study, the authors performed a meta-analysis of currently available comparative prospective studies to assess the efficacy and safety of exercise training in heart failure (HF) patients with implantable cardioverter defibrillators (ICD). BACKGROUND: ICDs have been shown to improve survival in patients with HF. However, many patients with ICDs experience fear of shocks and avoid physical activity. Few data exist for efficacy and safety of exercise training in HF patients with ICDs. METHODS: Prospective parallel arm trials with control and exercise training groups that evaluated the efficacy of exercise training in patients with ICDs were included in the meta-analysis. Outcomes of interest were difference in the change in cardiorespiratory fitness (CRF) (ml/kg/min) between exercise and control group and the likelihood of ICD shocks among exercise training compared with that among control participants on follow up. RESULTS: We included study level data from 6 trials (5 randomized controlled trials and 1 nonrandomized controlled trial). In the pooled analysis, ICD patients undergoing exercise training had significant improvement in CRF (weighted mean difference: 1.98 ml/kg/min; 95% confidence interval [CI]: 0.58 to 3.38). The likelihood of ICD shocks on follow-up was also significantly lower among exercise training than among control participants (pooled odds ratio: 0.47; 95% CI: 0.24 to 0.91). CONCLUSIONS: Among patients with HF and ICD implantation, exercise training was associated with significant improvement in CRF and lower likelihood of ICD shocks. PMID- 29759384 TI - No Further Question: Cardiac Rehabilitation Benefits Patients With Implantable Cardioverter Defibrillators: Insurers, Are You Listening? PMID- 29759381 TI - Genomic evidence that the live Chlamydia abortus vaccine strain 1B is not attenuated and has the potential to cause disease. AB - BACKGROUND: The live, temperature-attenuated vaccine strain 1B of Chlamydia abortus, the aetiological agent of ovine enzootic abortion (OEA), has been implicated in cases of vaccine breakdown. The aim of this study was to understand the nature of this attenuation through sequencing of the vaccine parent strain (AB7) and the derived mutant strains 1B and 1H, as well as to clarify the role of the vaccine strain in causing disease through comparative whole genome analysis. METHODS: Whole genome sequencing was performed on: vaccine parent strain AB7; N methyl-N'-nitro-N-nitrosoguanidine (NTG)-induced temperature attenuated mutant strain 1B grown from the commercial live vaccines Cevac Chlamydia and Enzovax; strain 1H a reverted NTG mutant; and 5 strains isolated from cases of OEA originating from animals from the original vaccine safety trial (2 strains) or from vaccinated ewes or ewes exposed to vaccinated animals (3 strains). RESULTS: We confirmed that AB7 is in a different lineage from the reference strain S26/3. The genome of vaccine strain 1B contains ten single nucleotide polymorphisms (SNPs) created by the NTG treatment, which are identical to those found in strain 1H. The strains from OEA cases also cluster phylogenetically very tightly with these vaccine strains. CONCLUSIONS: The results show that C. abortus vaccine strain 1B has an identical genome sequence to the non-attenuated "reverted mutant" strain 1H. Thus, the protection of the 1B vaccine is unlikely to be due to the NTG induced SNPs and is more likely caused by the administration of high doses of C. abortus elementary bodies that stimulate protective immunity. Vaccine identical strains were also isolated from cases of disease, as well as strains which had acquired 1-3 SNPs, including an animal that had not been vaccinated with either of the commercial live OEA vaccines, indicating that the 1B vaccine strain may be circulating and causing disease. PMID- 29759385 TI - The Impact of First Procedure Success Rate on the Economics of Atrial Fibrillation Ablation. AB - OBJECTIVES: The purpose of this study was to compare health care costs associated with repeat ablation of atrial fibrillation (AF) with health care costs associated with a successful first procedure. BACKGROUND: Catheter ablation has become established as a rhythm control strategy for symptomatic paroxysmal and persistent AF. The economic impact of ablation is not completely understood, and it may be affected by repeat procedures performed for recurrent AF. METHODS: The source of data was the MarketScan (Truven Health, Ann Arbor, Michigan) administrative claims dataset from April 2008 to March 2013, including U.S. patients with private and Medicare supplemental insurance. Patients who underwent an outpatient atrial ablation procedure and a diagnosis of AF were identified. Total health care cost was calculated for 1 year before and after the ablation. Patients were categorized as having undergone a repeat ablation if an additional ablation was performed in the following year. RESULTS: Of 12,027 patients included in the study, repeat ablation was performed in 2,066 (17.2%) within 1 year. Patients with repeat ablation had higher rates of emergency department visits (43.4% vs. 32.2%; < 0.001) and subsequent hospitalization (35.6% vs. 21.5%; p < 0.001), after excluding hospitalizations for the repeat procedure. Total medical cost was higher for patients with repeat ablation ($52,821 vs. $13,412; p < 0.001), and it remained 46% higher even after excluding the cost associated with additional ablations ($19,621 vs. $13,412; p < 0.001). CONCLUSIONS: Health care costs are significantly higher for patients with a repeat ablation for AF than for patients with only a single ablation procedure, even though both groups have similar baseline characteristics. The increased costs persist even after excluding the cost of the repeat ablation itself. These results emphasize the economic benefit of procedural success in AF ablation. PMID- 29759386 TI - Burden of Cardiac Arrhythmias in Patients With Anthracycline-Related Cardiomyopathy. AB - OBJECTIVES: The objective of this study was to determine the incidence of arrhythmias and device (internal cardiac defibrillator/cardiac resynchronization therapy defibrillator) therapies in patients with a diagnosis of cardiomyopathy and anthracycline exposure. BACKGROUND: The burden of arrhythmias in adult cancer survivors with anthracycline-related cardiomyopathy has not been studied, but might have important implications for clinical management and outcomes. METHODS: Retrospective cohort study of all patients with left ventricular dysfunction (LVD) who underwent internal cardiac defibrillator/cardiac resynchronization therapy defibrillator implantation at the Mayo Clinic from 1990 to 2012. Ninety five patients were cancer survivors (on average, 5 years), 23 of which had anthracycline-related cardiomyopathy (CA-ACM) and 72 of which had non anthracycline-related cardiomyopathy (CA-NACM). A second control group of 68 noncancer patients with ischemic heart disease-related LVD or dilated cardiomyopathy (ischemic heart disease [IHD]/DCM) was age- and gender-matched to patients with CA-ACM. All patients were followed for arrhythmias and appropriate ICD therapies, total mortality, heart transplantation, and left ventricular ejection fraction. RESULTS: More than 5.5 +/- 3.0 years after device implantation, nonsustained ventricular tachycardia was the most common arrhythmia in patients with CA-ACM followed by atrial fibrillation and sustained ventricular tachycardia or fibrillation (73.9%, 56.6%, and 30.4%, respectively), which was not significantly different from CA-NACM and IHD/DCM. The 5-year rate of ICD therapies was 19.9% in the CA-ACM group versus 22.1% in the CA-NACM group and 32.6% in the IHD/DCM group (p = NS for both). Device therapy-free, heart transplantation-free, and/or overall survival as well as cardiac function dynamics over time were not different in patients with CA-ACM than in patients with CA-NACM and IHD/DCM. CONCLUSIONS: This study indicates that the burden of arrhythmia in patients with anthracycline-related cardiomyopathy is not different from cancer and non-cancer patients with IHD-related LVD or DCM. PMID- 29759387 TI - Cardiovascular Outcomes in Anthracycline-Related Cardiomyopathy: When a p Value of >0.05 Is a Good Outcome! PMID- 29759388 TI - Complications in Catheter Ablation of Atrial Fibrillation in 3,000 Consecutive Procedures: Balloon Versus Radiofrequency Current Ablation. AB - OBJECTIVES: The aim of this study was to identify predictors of cardiac tamponade (CT) during atrial fibrillation (AF) ablation using different technologies and strategies. BACKGROUND: The major cause of death during catheter ablation of AF is related to CT. The risk for CT may be linked to different procedural steps (transseptal puncture, catheter manipulation during left atrial and pulmonary vein mapping and ablation). METHODS: All AF ablation procedures undertaken from May 2010 to July 2015 at a single center were included. Two ablation groups were defined: group A, radiofrequency current, and group B, balloon. Group A was divided into groups A1 (pulmonary vein isolation [PVI] only) and A2 (PVI plus additional ablation). In group A, 2 transseptal punctures were performed, followed by wide-area circumferential point-by-point PVI (group A1) within a 3 dimensional left atrial map and complex fractionated atrial electrograms and/or linear lesions (group A2). In group B, 1 transseptal puncture by balloon-based PVI (cryoballoon, laser balloon). All episodes of CT were analyzed. RESULTS: In total, 3,000 AF ablation procedures were performed, 2,125 in group A (group A1, n = 1,559; group A2, n = 566) and 875 in group B (cryoballoon, n = 589; laser balloon, n = 286). The rate of CT was 1.1% (32 of 3,000) and was significantly lower in group B than in group A: 0.1% (1 of 875) versus 1.5% (31 of 2,125) (p = 0.001). The reduced CT risk remained if PVI only (group B vs. group A1) was compared: 0.8% (13 of 1,559) versus 0.1% (1 of 875) (p = 0.024). The greatest CT risk was seen in group A2: 3.2% (18 of 566). Radiofrequency current ablation beyond PVI was a predictor of CT. CONCLUSIONS: The risk for CT in patients undergoing AF ablation at a single high-volume center was decreased with the use of balloon catheters. Extensive radiofrequency current ablation beyond PVI leads to an increased perforation risk. PMID- 29759389 TI - Noninvasive Predictors of Ventricular Arrhythmias in Patients With Tetralogy of Fallot Undergoing Pulmonary Valve Replacement. AB - OBJECTIVES: This study sought to test the hypothesis that a vectorcardiographic parameter, the QRS vector magnitude (QRSVm), can risk stratify those patients at risk for sustained spontaneous ventricular arrhythmias (VAs) or ventricular arrhythmia inducibility (VAI) in a large cohort of patients with tetralogy of Fallot (TOF). BACKGROUND: Patients with TOF have an increased risk of VAs, but predicting those at risk can often be challenging. METHODS: Blinded retrospective analyses of 177 TOF patients undergoing pulmonary valve replacement (PVR) between 1997 and 2015 were performed. VAI was evaluated by programmed electrical stimulation in 48 patients. QRS intervals and QRSVm voltage measurements were assessed from resting 12-lead electrocardiograms, and risk of VA was determined. Clinical characteristics, including imaging and cardiac catheterizations, were used for other modality comparisons. RESULTS: Sustained spontaneous VA occurred in 12 patients and inducible VA in 18 patients. Age and QRSVm were significant univariate predictors of VA. QRSVm was the only independent predictor of VAI (p < 0.001). Using a root mean square QRS value of 1.24 mV, the positive and negative predictive values were 47.9% and 97.8%, respectively, for spontaneous sustained VA. For VAI, using a QRSVm cutoff of 1.31 mV, positive and negative predictive values were 63.0% and 95.3%, respectively. CONCLUSIONS: In TOF patients undergoing PVR, older age was associated with increased spontaneous VA risk. Lower QRSVm predicted spontaneous VA or VAI risk with high negative predictive values. QRSVm is the only independent predictor of VAI. These clinical features may help further risk stratify TOF patients requiring therapies to prevent sudden death. PMID- 29759390 TI - QRS Vector Magnitude as a Predictor of Ventricular Arrhythmias in Tetralogy of Fallot: Does it Add Up? PMID- 29759391 TI - Outcomes of In-Hospital Cardiopulmonary Resuscitation in Morbidly Obese Patients. AB - OBJECTIVES: This study sought to assess the impact of morbid obesity on outcomes in patients with in-hospital cardiac arrest (IHCA). BACKGROUND: Obesity is associated with increased risk of out-of-hospital cardiac arrest; however, little is known about survival of morbidly obese patients with IHCA. METHODS: Using the Nationwide Inpatient Sample database from 2001 to 2008, we identified adult patients undergoing resuscitation for IHCA, including those with morbid obesity (body mass index >=40 kg/m2) by using International Classification of Diseases 9th edition codes and clinical outcomes. Outcomes including in-hospital mortality, length of stay, and discharge dispositions were identified. Logistic regression model was used to examine the independent association of morbid obesity with mortality. RESULTS: Of 1,293,071 IHCA cases, 27,469 cases (2.1%) were morbidly obese. The overall mortality was significantly higher for the morbidly obese group than for the nonobese group experiencing in-hospital non ventricular fibrillation (non-VF) (77% vs. 73%, respectively; p = 0.006) or VF (65% vs. 58%, respectively; p = 0.01) arrest particularly if cardiac arrest happened late (>7 days) after hospitalization. Discharge to home was significantly lower in the morbidly obese group (21% vs. 31%, respectively; p = 0.04). After we adjusted for baseline variables, morbid obesity remained an independent predictor of increased mortality. Other independent predictors of mortality were age and severe sepsis for non-VF and VF group and venous thromboembolism, cirrhosis, stroke, malignancy, and rheumatologic conditions for non-VF group. CONCLUSIONS: The overall mortality of morbidly obese patients after IHCA is worse than that for nonobese patients, especially if IHCA occurs after 7 days of hospitalization and survivors are more likely to be transferred to a skilled nursing facility. PMID- 29759392 TI - Cardiac Tumor Lysis-Induced Ventricular Arrhythmia? PMID- 29759393 TI - Mapping Signatures of Ventricular Ectopic Activity of Endocavitary Origin. PMID- 29759394 TI - Device-Related Thrombus Formation With the Amplatzer Amulet LAA Device: Optimal Implantation = Optimal Results. PMID- 29759395 TI - Reply: Device-Related Thrombus Formation With the Amplatzer Amulet LAA Device: Optimal Implantation = Optimal Results. PMID- 29759396 TI - Left Atrial Appendage Occlusion With the Amulet Device: Incomplete Occlusion, Thrombus Formation and the Importance of Intraprocedural Echocardiography. PMID- 29759397 TI - Reply: Left Atrial Appendage Occlusion With the Amulet Device: Incomplete Occlusion, Thrombus Formation, and the Importance of Intraprocedural Echocardiography. PMID- 29759398 TI - Development, Preclinical Validation, and Clinical Translation of a Cardiac Magnetic Resonance - Electrophysiology System With Active Catheter Tracking for Ablation of Cardiac Arrhythmia. AB - OBJECTIVES: This study sought to develop an actively tracked cardiac magnetic resonance-guided electrophysiology (CMR-EP) system and perform first-in-human clinical ablation procedures. BACKGROUND: CMR-EP offers high-resolution anatomy, arrhythmia substrate, and ablation lesion visualization in the absence of ionizing radiation. Implementation of active tracking, where catheter position is continuously transmitted in a manner analogous to electroanatomic mapping (EAM), is crucial for CMR-EP to take the step from theoretical technology to practical clinical tool. METHODS: The setup integrated a clinical 1.5-T scanner, an EP recording and ablation system, and a real-time image guidance platform with components undergoing ex vivo validation. The full system was assessed using a preclinical study (5 pigs), including mapping and ablation with histological validation. For the clinical study, 10 human subjects with typical atrial flutter (age 62 +/- 15 years) underwent MR-guided cavotricuspid isthmus (CTI) ablation. RESULTS: The components of the CMR-EP system were safe (magnetically induced torque, radiofrequency heating) and effective in the CMR environment (location precision). Targeted radiofrequency ablation was performed in all animals and 9 (90%) humans. Seven patients had CTI ablation completed using CMR guidance alone; 2 patients required completion under fluoroscopy, with 2 late flutter recurrences. Acute and chronic CMR imaging demonstrated efficacious lesion formation, verified with histology in animals. Anatomic shape of the CTI was an independent predictor of procedural success. CONCLUSIONS: CMR-EP using active catheter tracking is safe and feasible. The CMR-EP setup provides an effective workflow and has the potential to change the way in which ablation procedures may be performed. PMID- 29759399 TI - Left Atrial Appendage Ligation in Nonvalvular Atrial Fibrillation Patients at High Risk for Embolic Events With Ineligibility for Oral Anticoagulation: Initial Report of Clinical Outcomes. AB - OBJECTIVES: This study sought to assess long-term clinical outcomes in adults with nonvalvular atrial fibrillation (AF) who are ineligible for oral anticoagulation therapy and underwent left atrial appendage (LAA) ligation with the Lariat device. BACKGROUND: LAA exclusion has been used to prevent thrombus formation within the LAA in AF patients and is believed to decrease the risk of cardioembolic events. METHODS: LAA ligation with the Lariat device was performed in 139 patients with nonvalvular AF. LAA closure was verified during the procedure by LA angiography and transesophageal echocardiography. A follow-up transesophageal echocardiography was performed at 30 to 45 days post-procedure. After the procedure, patients received aspirin only, clopidogrel only, aspirin plus clopidogrel, or no antithrombotic drugs. Patients did not receive transition oral anticoagulation therapy post-LAA ligation. Patients were followed for LAA closure and adverse events, including stroke, systemic events, and death. RESULTS: Acute closure was accomplished in 138 of 139 treated patients (99%). In 1 patient, a posterior lobe was partially closed. At the day-30 to day-45 transesophageal echocardiography (n = 127), 114 (90%) had complete LAA closure, and 13 (10%) had a 2- to 4-mm leak. There were no leaks >=5 mm. The periprocedural adverse event rate was 11.5%, including 2 cardiac perforations and 1 death due to pulmonary embolus. Over a mean follow-up of 2.9 +/- 1.1 years, the event rate for the composite endpoint of stroke and systemic embolism was 1.0% per year (n = 4). The combined stroke, embolism, and death of any cause event rate was 2.8% (n = 11) per year. CONCLUSIONS: The findings from this analysis of post-procedure event rates suggest that LAA ligation with the Lariat device effectively closes the LAA and may be a beneficial approach to reduce the risk of embolic events in AF patients ineligible to oral anticoagulation therapy. However, future randomized clinical trials are needed to verify these results and to determine device and procedural safety. PMID- 29759400 TI - Percutaneous Left Atrial Appendage Closure Using the Lariat: To Close, or Not to Close, That Is the Question. PMID- 29759401 TI - Left Atrial Appendage Eccentricity and Irregularity Are Associated With Residual Leaks After Percutaneous Closure. AB - OBJECTIVES: Predictors of residual leak following percutaneous LAA closure were evaluated. BACKGROUND: Left atrial appendage (LAA) closure aims to exclude this structure from the circulation, typically using a circular occluder. A noncircular orifice is frequently encountered however, and fibrous remodeling of the LAA in atrial fibrillation may restrict orifice deformation. Noncircularity may thus be implicated in the occurrence of residual leak despite an appropriately oversized device. METHODS: Pre-procedural multislice computerized tomography was used to quantify LAA orifice eccentricity and irregularity. Univariate predictors of residual leak were identified with respect to the orifice, device, and relevant clinical variables, with the nature of any correlations then further evaluated. RESULTS: Eccentricity and irregularity indexes of the orifice in 31 individuals were correlated with residual leak even where the device was appropriately oversized. An eccentricity index of 0.15 predicted a residual leak with 85% sensitivity and 59% specificity. An irregularity index of 0.05 predicted a significant residual leak >=3 mm with 100% sensitivity and 86% specificity. Orifice size, device size, degree of device oversize, left atrial volume, and pulmonary artery pressure were not predictors of residual leak. CONCLUSIONS: Eccentricity and irregularity of the LAA orifice are implicated in residual leak after percutaneous closure even where there is appropriate device over-size. Irregularity index in particular is a novel predictor of residual leak, supporting a closer consideration of orifice morphology before closure. PMID- 29759402 TI - Ablation for Atrial Fibrillation Combined With Left Atrial Appendage Closure. AB - OBJECTIVES: The study sought to determine long-term clinical effects of combining catheter ablation (CA) and left atrial appendage (LAA) occlusion (LAAO) in a single procedure. BACKGROUND: CA relieves symptoms in atrial fibrillation (AF), but freedom from AF is not assured. Thus, oral anticoagulation (OAC) remains necessary in high stroke risk patients. LAAO has proved a viable alternative for preventing thromboembolic complications. METHODS: Symptomatic patients with drug refractory AF (CHADS2 >=1) and indications for LAAO were included. Transesophageal echocardiography was performed to assess LAA size/anatomy/thrombus. After CA, LAAO was performed using the Watchman device (Atritech, Inc., Plymouth, Minnesota, Minnesota). At 3 months, OAC was switched to aspirin/clopidogrel if LAAO criteria were met. RESULTS: From September 2009 to October 2013, 62 patients (22 female, 64 +/- 8 years of age, CHADS2 2.5) underwent combined procedures. Indications for LAAO included history of stroke despite OAC (29.0%), contraindications for OAC (24.2%), high stroke risk (24.2%), and miscellaneous reasons (22.6%). LAAO resulted in complete acute closure in all, with a median number of 1 device. After a median follow-up of 38 (range: 25 to 45) months, 95% of the patients met the criteria for successful sealing and 78% could discontinue OAC, while recurrence of AF was documented in 42%. During long-term follow-up, 3 ischemic strokes were observed with an annual stroke risk of 1.7%, which is lower than the expected annual risk of 6.5%. CONCLUSIONS: LAAO combined with CA for AF can be performed successfully and safely in a single procedure, with a lower than expected stroke rate. Further studies are necessary to determine which patients benefit most from the combined therapy. PMID- 29759403 TI - Treatment of Atrial and Ventricular Arrhythmias Through Autonomic Modulation. AB - This paper reviews the contribution of autonomic nervous system (ANS) modulation in the treatment of arrhythmias. Both the atria and ventricles are innervated by an extensive network of nerve fibers of parasympathetic and sympathetic origin. Both the parasympathetic and sympathetic nervous system exert arrhythmogenic electrophysiological effects on atrial and pulmonary vein myocardium, while in the ventricle the sympathetic nervous system plays a more dominant role in arrhythmogenesis. Identification of ANS activity is possible with nuclear imaging. This technique may provide further insight in mechanisms and treatment targets. Additionally, the myocardial effects of the intrinsic ANS can be identified through stimulation of the ganglionic plexuses. These can be ablated for the treatment of atrial fibrillation. New (non-) invasive treatment options targeting the extrinsic cardiac ANS, such as low-level tragus stimulation and renal denervation, provide interesting future treatment possibilities both for atrial fibrillation and ventricular arrhythmias. However, the first randomized trials have yet to be performed. Future clinical studies on modifying the ANS may not only improve the outcome of ablation therapy but may also advance our understanding of the manner in which the ANS interacts with the myocardium to modify arrhythmogenic triggers and substrate. PMID- 29759405 TI - Can Cryoablation Improve the Outcome of Catheter Ablation of Ventricular Arrhythmias Originating From the Papillary Muscles? PMID- 29759404 TI - Cryoablation for Ventricular Arrhythmias Arising From the Papillary Muscles of the Left Ventricle Guided by Intracardiac Echocardiography and Image Integration. AB - OBJECTIVES: This case series reports outcomes and complications of catheter cryoablation at the papillary muscles (PM) of the left ventricle (LV). BACKGROUND: Catheter radiofrequency ablation is an effective treatment for ventricular arrhythmias (VAs) arising from the PM of the LV. The use of cryoablation at PMs has not been described. METHODS: Ten patients (70% men; median age: 38 years [range: 34 to 45 years]) with drug-refractory premature ventricular contractions or ventricular tachycardia underwent catheter cryoablation. VAs were localized using 3-dimensional (3D) mapping, multidetector computed tomography, and intracardiac echocardiography, with arrhythmia foci being mapped at either the anterolateral PM or posteromedial papillary muscle (PMPM) of the LV. Focal ablation, up to 240 s with freeze-thaw-freeze cycles was performed using an 8-mm cryoablation catheter via a transmitral approach. RESULTS: Termination of ventricular arrhythmia was observed in all 10 patients during ablation. Median follow-up was 6 months after ablation. The PMPM had higher prevalence of clinical arrhythmias (100% PMPM VAs vs. 10% anterolateral PM VAs). The PM base was the most frequent site of origin of the arrhythmias (60% of patients). Pace-mapping showed >=11/12 match in all treated PM at the site of effective lesion. All VAs arising from the base of the PM showed Purkinje potentials. There were no post-procedure complications. VA recurred in 1 patient. CONCLUSIONS: Cryoablation for arrhythmias arising from the PMs of the LV can be performed, and is a safe and effective alternative energy source for ablation. PMID- 29759407 TI - Complete Heart Block Complicating ST-Segment Elevation Myocardial Infarction Has Not Gone Away. PMID- 29759406 TI - Complete Heart Block Complicating ST-Segment Elevation Myocardial Infarction: Temporal Trends and Association With In-Hospital Outcomes. AB - OBJECTIVES: The purpose of this study was to determine the association of complete heart block (CHB) with outcomes and to examine temporal trends in the incidence and outcomes of CHB complicating ST-segment elevation myocardial infarction (STEMI). BACKGROUND: There are limited data available on the incidence and outcomes of CHB in STEMI patients who undergo contemporary management. METHODS: We used the 2003 to 2012 National Inpatient Sample databases to identify all patients age >=18 years hospitalized with STEMI. Patients with a concomitant diagnosis of CHB were then identified. Multivariable logistic regression was used to analyze the association of CHB with outcomes and to examine the temporal trends in incidence and outcomes of CHB complicating STEMI. RESULTS: Of 2,273,853 patients with STEMI, 49,882 (2.2%) had CHB. The incidence of CHB increased from 2.1% in 2003 to 2.3% in 2012 (adjusted odds ratio [OR] per year: 1.02; 95% confidence interval [CI]: 1.02 to 1.03). STEMI patients with CHB had higher in hospital mortality than those without CHB (20.4% vs. 8.7%; adjusted OR: 2.47; 95% CI: 2.41 to 2.53). The higher mortality associated with CHB was independent of the location of STEMI; however, the magnitude of this association was greatest in patients with anterior STEMI. In patients with CHB complicating STEMI, although permanent pacemaker implantation rates declined (adjusted OR per year: 0.96; 95% CI: 0.95 to 0.97), in-hospital mortality remained unchanged during the study period (adjusted OR per year: 1.00; 95% CI: 0.99 to 1.01). CONCLUSIONS: The incidence of CHB complicating STEMI has increased slightly over the last decade, although the absolute incidence remains quite low. CHB remains associated with higher in-hospital mortality in STEMI patients even in the current era of prompt reperfusion therapy. In patients with CHB complicating STEMI, there was no change in risk-adjusted in-hospital mortality during the study period. PMID- 29759409 TI - Genetics, Exercise, and Early-Onset Arrhythmogenic Right Ventricular Cardiomyopathy. PMID- 29759408 TI - Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy in the Pediatric Population: Clinical Characterization and Comparison With Adult-Onset Disease. AB - OBJECTIVES: The aims of this study were to determine the clinical characteristics and outcomes of pediatric-onset arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and to compare these with those of adult-onset ARVD/C. BACKGROUND: Improved early detection and increased awareness of ARVD/C have led to a growing group of pediatric patients seeking management recommendations. Prior studies have mainly included adults with ARVD/C; however, clinical features and outcomes may differ in pediatric subjects. METHODS: Among 502 subjects fulfilling task force criteria for ARVD/C, we identified 75 (15%) with pediatric-onset disease (diagnosis at <18 years of age or probands presenting symptomatically at <18 years of age). Clinical characteristics and outcomes (sustained ventricular tachycardia, cardiac transplantation, and death) were compared between pediatric and adult patients. RESULTS: Pediatric patients presented at 15.3 +/- 2.4 years of age. Most pediatric patients were male (55%) and ARVD/C-associated mutation carriers (80%). One-fourth of pediatric patients presented with sudden cardiac death (15%) or resuscitated sudden cardiac arrest (11%). Compared with adults, pediatric patients were disproportionately mutation carriers (p = 0.002) but not more often male (p = 0.696) or probands (p = 0.371). Pediatric patients were more likely to present with sudden cardiac death (p = 0.003), whereas adults more often presented with sustained ventricular tachycardia (p = 0.017). There were no other phenotypic differences between the groups. During 8.4 +/- 7.5 years of follow-up, survival free from sustained ventricular tachycardia (p = 0.359), cardiac transplantation (p = 0.523), and death (p = 0.359) was similar between pediatric and adult patients. CONCLUSIONS: Pediatric patients with ARVD/C are typically male mutation carriers presenting in adolescence. Pediatric patients disproportionately present with sudden cardiac death. However, once diagnosed, clinical characteristics and outcomes are similar between pediatric and adult patients. PMID- 29759410 TI - Percutaneous Retrieval of Implanted Leadless Pacemakers: Feasibility at 2.5 Years Post-Implantation in an In Vivo Ovine Model. AB - OBJECTIVES: This in vivo ovine study describes the feasibility and safety of retrieving implanted leadless pacemakers (LPs). BACKGROUND: Although LPs have been shown to be removable soon after implantation, there are no data on the feasibility of removing chronically implanted LPs. METHODS: This study was performed in 2 phases. In the mid-term cohort, 10 chronically (5.3 months) implanted animals underwent retrieval, followed by: 1) immediate necropsy in 5; and 2) in the remaining 5, reimplantation of a new LP followed by necropsy at 6 weeks. In the long-term cohort, 8 additional sheep underwent retrieval at 2.3 +/- 0.1 years followed by necropsy. Retrieval was performed using either a single or triple loop snare. All 18 LPs (100%) were successfully retrieved. The time from retrieval catheter insertion to retrieval was 2:35 +/- 01:11 and 3:04 +/- 01:13 minutes in the mid-term and long-term study groups, respectively. RESULTS: There were no significant differences in retrieval times using either snare. Intracardiac echocardiography was used pre- and post-retrieval to confirm the absence of pericardial effusion in all 8 sheep. On necropsy, there was no evidence of pericardial bleeding or perforation. Only minor tissue disruption and hemorrhage was noted at the implant site after retrieval. Histology demonstrated fibrous connective tissue at the contact sites of endocardium and LP can and at the helix. There was no evidence of pulmonary thromboembolism. CONCLUSIONS: We demonstrate the feasibility and safety of percutaneous, catheter-based retrieval in chronic LP implants of a maximum duration of approximately 2.5 years. PMID- 29759411 TI - Electrophysiologic Insights Into Site of Atrioventricular Block: Lessons From Permanent His Bundle Pacing. AB - OBJECTIVES: This study sought to report the feasibility of permanent His bundle pacing (HBP) in patients with advanced atrioventricular block (AVB) and electrophysiological observations into site of block in patients with infranodal AVB. BACKGROUND: HBP is a physiological alternative to right ventricular pacing. Historic studies have reported a low incidence of intra-His AVB. Recent studies of permanent HBP reported limited success in patients with infranodal AVB. METHODS: Consecutive patients with advanced AVB underwent permanent HBP using Medtronic 3830 lead (Minneapolis, Minnesota) and a fixed-shaped catheter (C315 His). The HB was mapped using unipolar recording from the lead tip or by pace mapping. Success of HBP, type of AVB, and pacing outcomes were documented. Patients were followed at 2 weeks, 2 months, and then yearly. RESULTS: A total of 100 patients with advanced AVB (age 75 +/- 12 years; male 62%; AV nodal 46%; infranodal 54%) underwent permanent HBP. HBP was successful in 84 patients (84%; AV nodal 93%, infranodal 76%). Mean procedure time was 71 +/- 21 min, mean fluoroscopy time was 11 +/- 6 min. Baseline QRS duration was 122 +/- 27 ms; paced QRSd was 124 +/- 22 ms. The HB pacing threshold at implant, 2 weeks, 2 months, and last follow-up (19 +/- 12 months; range: 6 to 46 months) was 1.3 +/- 0.9 V, 1.6 +/- 1.0 V, 1.6 +/- 1.1 V, and 1.7 +/- 1.0 V at 0.5 ms, respectively. Five patients required lead revision. CONCLUSIONS: Permanent HBP was successful in 84% of unselected patients with AVB. His-Purkinje conduction could be normalized in 76% of patients with infranodal block, suggesting intra-His block. Incidence of infra-His AVB was low (24%) in this series. Routine HBP in patients with AVB is feasible and safe for at least up to 18 months. PMID- 29759413 TI - His Bundle Pacing: A New Promise in Heart Failure Therapy? PMID- 29759412 TI - Atrioventricular Optimized Direct His Bundle Pacing Improves Acute Hemodynamic Function in Patients With Heart Failure and PR Interval Prolongation Without Left Bundle Branch Block. AB - OBJECTIVES: The purpose of this study was to investigate whether heart failure patients with narrow QRS duration (or right bundle branch block) but with long PR interval gain acute hemodynamic benefit from atrioventricular (AV) optimization. We tested this with biventricular pacing and (to deliver pure AV shortening) direct His bundle pacing. BACKGROUND: Benefits of pacing for heart failure have previously been indicated by acute hemodynamic studies and verified in outcome studies. A new target for pacing in heart failure may be PR interval prolongation, which is associated with 58% higher mortality regardless of QRS duration. METHODS: We enrolled 16 consecutive patients with systolic heart failure, PR interval prolongation (mean, 254 +/- 62 ms) and narrow QRS duration (n = 13; mean QRS duration: 119 +/- 17 ms) or right bundle branch block (n = 3; mean, QRS duration: 156 +/- 18 ms). We successfully delivered temporary direct His bundle pacing in 14 patients and temporary biventricular pacing in 14 participants. We performed AV optimization using invasive systolic blood pressure obtaining parabolic responses (mean R2: 0.90 for His, and 0.85 for biventricular pacing). RESULTS: The mean increment in systolic BP compared with intrinsic ventricular conduction was 4.1 mm Hg (95% confidence interval [CI]: +1.9 to +6.2 mm Hg for His and 4.3 mm Hg [95% CI: +2.0 to +6.5 mm Hg] for biventricular pacing. QRS duration lengthened with biventricular pacing (change = +22 ms [95% CI: +18 to +25 ms]) but not with His pacing (change = +0.5 ms [95% CI: -2.6 to +3.6 ms). CONCLUSIONS: AV-optimized pacing improves acute hemodynamic function in patients with heart failure and long PR interval without left bundle branch block. That it can be achieved by single-site His pacing shows that its mechanism is AV shortening. The improvement is ~60% of the effect size previously reported for biventricular pacing in left bundle branch block. Randomized, blinded trials are warranted to test for long-term beneficial effects. PMID- 29759414 TI - Termination of Persistent Perimitral Atrial Flutter by Selective Contrast Injection Into the Vein of Marshall. PMID- 29759415 TI - Left Atrial Appendage Occlusion in the Spotlight. PMID- 29759417 TI - Audio Summary. PMID- 29759418 TI - A clone-directed approach may improve diagnosis and treatment of proliferative glomerulonephritis with monoclonal immunoglobulin deposits. AB - The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID. PMID- 29759419 TI - Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy. AB - IgA nephropathy (IgAN) is a disease associated with activation of the complement system. But the factors influencing complement activation in IgAN are not fully understood. Complement factor H (FH) is an essential negative regulator of complement C3 activation. Complement factor H-related protein (FHR)-5 shares high sequence similarity with factor H. However, unlike factor H, on binding to activated C3 it enables further activation to proceed. Previously, we reported the contribution of rare variants of the CFHR5 gene to IgAN susceptibility. Here we compared circulating levels of FHR-5 in 1126 patients with IgAN and regular follow-up with those of 153 unrelated healthy individuals to explore the relationship of FHR-5 levels with IgAN development and progression. Circulating FHR-5 levels were significantly elevated in patients with IgAN compared to healthy individuals (median 4.55 [interquartile range 3.58 to 5.85] MUg/ml vs 3.19 [interquartile range 2.55 to 3.92] MUg/ml). Higher circulating FHR-5 levels were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease (hazard ratio, per standard deviation increment of natural square root transformed FHR-5 of 1.226; 95% confidence interval: 1.106-1.359). Thus, the circulating FHR-5 level is an independent risk factor for IgAN progression. PMID- 29759420 TI - Lysyl oxidase like-2 contributes to renal fibrosis in Col4alpha3/Alport mice. AB - Lysyl oxidase like-2 (LOXL2) is an amine oxidase with both intracellular and extracellular functions. Extracellularly, LOXL2 promotes collagen and elastin crosslinking, whereas intracellularly, LOXL2 has been reported to modify histone H3, stabilize SNAIL, and reduce cell polarity. Although LOXL2 promotes liver and lung fibrosis, little is known regarding its role in renal fibrosis. Here we determine whether LOXL2 influences kidney disease in COL4A3 (-/-) Alport mice. These mice were treated with a small molecule inhibitor selective for LOXL2 or with vehicle and assessed for glomerular sclerosis and fibrosis, albuminuria, blood urea nitrogen, lifespan, pro-fibrotic gene expression and ultrastructure of the glomerular basement membrane. Laminin alpha2 deposition in the glomerular basement membrane and mesangial filopodial invasion of the glomerular capillaries were also assessed. LOXL2 inhibition significantly reduced interstitial fibrosis and mRNA expression of MMP-2, MMP-9, TGF-beta1, and TNF-alpha. LOXL2 inhibitor treatment also reduced glomerulosclerosis, expression of MMP-10, MMP-12, and MCP 1 mRNA in glomeruli, and decreased albuminuria and blood urea nitrogen. Mesangial filopodial invasion of the capillary tufts was blunted, as was laminin alpha2 deposition in the glomerular basement membrane, and glomerular basement membrane ultrastructure was normalized. There was no effect on lifespan. Thus, LOXL2 plays an important role in promoting both glomerular and interstitial pathogenesis associated with Alport syndrome in mice. Other etiologies of chronic kidney disease are implicated with our observations. PMID- 29759421 TI - Prevalence and distribution of hepatitis C virus genotypes in Galicia during the period 2000-2015. AB - INTRODUCTION: We present the largest study conducted in Galicia on the prevalence and distribution of HCV genotypes/subtypes. METHODS: Retrospective study collecting the total number of patients chronically infected by HCV between 2000.01.01 to 2015.12.31 in 3of the main health areas: Santiago, Pontevedra and Vigo. RESULTS: We collected a total of 4469 patients. The median age was 50 years (IQR 57-45), 72,3% were men, 0,4% were coinfected with another genotype, 20,6% were coinfected with HIV and 35.2% with HBV. The main route of transmission was parenteral (83,1%), followed by unknown (15,3%), sexual (1,4%) and vertical (0,2%). The distribution of genotypes was: 62,9% HCV-1 (29,2% HCV-1a and 31,9% HCV-1b), 3,4% HCV-2, 21,0% HCV-3, 12,6% HCV-4 and 0,1% HCV-5. CONCLUSION: The distribution of genotypes in Galicia shows significant differences with respect to that observed in Spain. This distribution varies with age, gender, coinfection with HIV and/or HBV, and within geographical areas. PMID- 29759424 TI - Lung Ultrasound Findings Undetectable by Chest Radiography in Children with Community-Acquired Pneumonia. AB - The purpose of our study was to evaluate any differences between lung ultrasonography and chest radiography (CR) images in children with a diagnosis of community-acquired pneumonia (CAP) and, if there are any, to analyze the reasons and possible clinical implications. We reviewed the medical records of patients admitted to the pediatric ward from January 2014 to December 2016 and selected only cases discharged with a diagnosis of CAP who had undergone performed lung ultrasound (LUS) and CR within 24 h of each other. All radiologic and sonographic images of the selected cases were examined blindly by a senior radiologist and a skilled sonographer, respectively, with respect to number, position and size of lung injuries. Of the 47 cases of pneumonia, 28 lung lesions spotted by LUS were undetected by CR. Compared with CR, LUS detects more cases of pneumonia, a greater number of cases of double pneumonia and minimal pleural effusions. LUS should be considered the first-line imaging tool for CAP. PMID- 29759425 TI - Simultaneous Evaluation of Thermal and Non-Thermal Effects of High-Intensity Focused Ultrasound on a Tissue-Mimicking Phantom. AB - Physiologically relevant phantoms with high reliability are essential for extending the therapeutic applications of high-intensity therapeutic ultrasound. Here we describe a tissue-mimicking phantom capable of quantifying temperature changes and observing non-thermal phenomena by high-intensity therapeutic ultrasound. Using polydiacetylene liposomes, we fabricated agar-based polydiacetylene hydrogel phantoms (PHPs) that not only respond to temperature, but also have acoustic properties similar to those of human liver tissue. The color of PHPs changed from blue to red depending on the temperature in the range 40 degrees C-70 degrees C, where the red/blue ratio of PHP had a good linearity of 99.06% for the temperature changes. Furthermore, repeated high-intensity focused ultrasound led to histotripsy on the PHP with liquefied and damaged areas measuring 0.7 and 4.0 cm2, respectively, at the signal generator amplitude setting voltage of 80 mV. Our results indicate not only the usability of the thermochromic phantom, but also its potential for evaluating non-thermal phenomena in various high-intensity focused ultrasound therapies. PMID- 29759422 TI - Executive summary of the GeSIDA/National AIDS Plan consensus document on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2018). AB - This update to the document on antiretroviral therapy (ART) in adults, which has been prepared jointly by GeSIDA and the Spanish National AIDS Plan for the last two decades, supersedes the document published in 2017.1 The update provides physicians treating HIV-1-infected adults with evidence-based recommendations to guide their therapeutic decisions. The main difference with respect to the previous document concerns recommended initial ART regimens, only three of which are maintained as preferential. All three include dolutegravir or raltegravir, together with emtricitabine/tenofovir alafenamide or abacavir/lamivudine. Other differences concern the section on switching ART in patients with suppressed viral replication, which now includes new two- and three-drug regimens, and the antiretroviral drugs recommended for pregnant women and patients with tuberculosis. A recommendation has also been added for patients who present with acute HIV infection after pre-exposure prophylaxis. PMID- 29759423 TI - Hepatitis C prevalence among the migrant population in Spain: A systematic review and meta-analysis. AB - INTRODUCTION: Spain, which has one of the largest migrant populations in Europe, has committed to eliminating the hepatitis C virus (HCV). The aim of this study was to estimate the prevalence of HCV among migrant groups in Spain, a country of 46 million people, with an estimated HCV-antibody prevalence of 1.7%. METHODS: Studies on HCV and migration in Spain were identified by systematically searching three databases from the first records to 30 November 2017, and consulting experts at the Ministry of Health and in the 17 Spanish autonomous communities. A meta-analysis was conducted to determine pooled HCV prevalence for the general migrant population. Prevalences were also calculated for high-risk migrant populations and populations who had undergone hospital screening, stratified by region of origin. RESULTS: Out of 243 studies identified, 26 met the eligibility criteria. The meta-analysis of the general migrant population found HCV antibody prevalence to be 1.6%. Migrants originating from European countries, including those at high or moderate risk for HCV, had the highest pooled prevalence (7.1%). In the general migrant population, prevalence was highest among sub-Saharan African migrants (3.1%) and lowest among Latin American migrants (0.2%). CONCLUSION: Based on the limited available data, the prevalence among the general migrant population was found to be the same as the general Spanish population. Further research is needed to more accurately determine HCV prevalence for the overall migrant population and specific migrant subpopulations with a higher risk in the country as a whole and in each of Spain's 17 autonomous communities. PMID- 29759426 TI - Development of Nonpulmonary Vein Foci Increases Risk of Atrial Fibrillation Recurrence After Pulmonary Vein Isolation. AB - OBJECTIVES: The aim of this paper was to clarify the impact of nonpulmonary vein foci (NPVF) on atrial fibrillation (AF) recurrence after pulmonary vein (PV) isolation. BACKGROUND: NPVF are considered contributing factors for the recurrence of AF after PV isolation, but their exact role remains unclear. METHODS: We retrospectively reviewed 216 patients (paroxysmal AF, n = 172; persistent AF, n = 44) who underwent a second electrophysiological study 6 months after the original PV isolation. Patients with AF recurrence underwent additional ablation procedures for reconnected PV and NPVF. NPVF were detected in the control group and with drug infusion (isoproterenol or isoproterenol with adenosine triphosphate) during the first and second procedure. NPVF detected for the first time in the second session were defined as newly developed, and their effect on AF recurrence after the second procedure was investigated, along with the predictive factors for NPVF development. RESULTS: Patients with AF recurrence after the first session had a significantly higher reconnected PV (91.5% vs. 68.2% in patients without recurrence). NPVF were detected in 20 and 54 patients in the first and second sessions, respectively. Patients with newly developed NPVF had a significantly higher AF recurrence (24.1% vs. 7.4% in patients without newly developed NPVF). Newly developed NPVF and AF recurrence after the first session were independent predictors for AF recurrence after the second procedure, whereas AF history and NPVF in the first session were independent predictors for newly developed NPVF. CONCLUSIONS: NPVF detection and ablation may represent important therapeutic options to prevent AF recurrence, especially in patients who require repeated procedures. PMID- 29759427 TI - Sorting Out the Significance of Nonpulmonary Vein Triggers. PMID- 29759428 TI - Atrial Fibrillation and Pulmonary Venous Electrical Conduction Recovery After Full Surgical Resection and Anastomosis of the Pulmonary Veins: Insights From Follow-Up and Ablation Procedures in Lung Transplant Recipients. AB - OBJECTIVES: The authors report their experience with atrial fibrillation (AF) rates and ablation findings in lung transplant recipients. BACKGROUND: Pulmonary venous (PV) conduction recovery accounts for most failed atrial fibrillation (AF) catheter ablation procedures. Lung transplantation involves full surgical resection and replacement of the recipient's PVs with donor's PVs, which may represent the ultimate PV ablation. METHODS: They followed 755 consecutive lung transplant recipients categorized based on transplant status (unilateral vs. bilateral) and pre-transplant AF. RESULTS: In patients without pre-transplant AF (n = 704), late AF (beyond 6 months after transplant) occurred in 2.5% and 3.3% of unilateral or bilateral lung transplants, respectively. In patients with pre transplant AF (n = 51), AF recurred in 19.4% and 25.0% of bilateral and unilateral transplants, respectively. In a subset of patients who underwent left atrial ablations after transplant for recurrent refractory AF (n = 8), PV conduction recovery across the surgical anastomoses lines was observed in 22 of 26 previously disconnected PVs. Conduction recovery was observed in >=1 vein in all but 1 patient. Re-isolation of the veins with additional substrate modification/flutter ablations successfully restored and maintained sinus rhythm in 7 of 8 patients. CONCLUSIONS: In lung transplant recipients who undergo full surgical resection of the PVs, a prior history of AF was associated with late AF, regardless of whether patients underwent single or bilateral lung transplantation. PV conduction recovery still occurred and was observed in most patients who underwent left atrial ablation procedures for recurrent AF. PMID- 29759429 TI - Defining Blanking Period Post-Pulmonary Vein Antrum Isolation. AB - OBJECTIVES: This study sought to determine the exact period after pulmonary vein antrum isolation (PVI) during which early recurrence of atrial tachyarrhythmia (ERAT) does not predict late arrhythmia recurrence (LR), in order to better define the blanking period. BACKGROUND: Recurrence of atrial fibrillation after PVI is not uncommon. The first 3 months after PVI have been commonly treated as a blanking period, during which ERAT is not thought to predict LR after PVI; however, recent studies have shown that ERAT does predict LR. METHODS: Baseline and follow-up data for 636 patients (mean age: 61.4 +/- 10.6 years; 67.1% male; 59% paroxysmal atrial fibrillation; 31.4% ERAT) who underwent PVI between 2010 and 2014 were included. Recurrences were monitored by electrocardiography and Holter monitoring at 1-, 3-, 6-, 9-, and 12-month intervals post-procedure. Receiver-operating characteristic curve analysis was used to define the blanking period after PVI. RESULTS: Overall, 51%, 76%, and 92% of patients who had ERAT in the first, second, and third month post-PVI, respectively, also experienced LR (p = 0.001). Using a logistic regression model, those manifesting ERAT during the first, second, and third month post-PVI were 4.22, 9.03, and 19.43 (p = 0.001) times more likely to experience LR, respectively, compared to those without ERAT. Furthermore, receiver-operating characteristic analysis revealed that 23 days post-PVI is the optimal cutoff date for the blanking period, with area under the curve of 0.7, sensitivity of 69.2%, and specificity of 61.2%. CONCLUSIONS: The likelihood of experiencing LR progressively rises with ERAT after the first month post-PVI. Blanking period after PVI should be limited to the first 23 days clinically and in future studies. PMID- 29759430 TI - Early Recurrences of Atrial Tachyarrhythmias After Ablation of Atrial Fibrillation: How Long Do We Have to Be Blind? PMID- 29759431 TI - Anatomic Parameters Predicting Procedural Difficulty and Balloon Temperature Predicting Successful Applications in Individual Pulmonary Veins During 28-mm Second-Generation Cryoballoon Ablation. AB - OBJECTIVES: This study sought to identify anatomic parameters predicting procedural difficulty in achieving pulmonary vein isolation (PVI) and in procedural predictors of successful applications during second-generation cryoballoon (CB) ablation. BACKGROUND: PV anatomies vary and influence the procedural difficulty during CB PVI. METHODS: In total, 408 initial freezes among 110 patients undergoing PVI for paroxysmal atrial fibrillation using 28-mm second generation CBs with single 3-min freeze techniques were included. The anatomic parameters were obtained from pre-procedural cardiac computed tomography. The nadir balloon temperature and temperature at the start of the plateau phase were recorded during each freeze. RESULTS: Acute PVI was achieved by initial applications in 335 pulmonary veins (PVs) (82.1%) and touch-up was required in 13 (3.2%). A multivariate analysis revealed that a thinner left lateral ridge (<4.7 mm), higher ovality (>50.5%), and longer PV ostium-bifurcation distance (>26.1 mm) required multiple applications for a successful left superior PVI. Older age (>68 years), and shorter PV ostium-bifurcation distance (<10.4 mm) required multiple applications for a successful right superior and right inferior PVI, respectively. Shorter PVTLs were also associated with requiring touch-up of the RIPV. Balloon temperatures were lower for successful than failed PVI applications. Successful PVIs were predicted using the nadir balloon temperature at 33.0 +/- 2.6 s, 33.0 +/- 2.5 s, 33.6 +/- 2.5 s, and 33.0 +/- 2.5 s from the initiation of freezes with positive predictive values of 87.7%, 88.5%, 98.5%, and 81.6% using cutoff temperatures of -34 degrees C, -33 degrees C, -37 degrees C, and -33 degrees C in the left superior, left inferior, right superior, and right inferior PVs, respectively. CONCLUSIONS: The anatomic information might predict procedural difficulty and the balloon temperature a successful PVI during the early CB ablation freezing phase. PMID- 29759432 TI - Incidence of Pulmonary Vein Stenosis After Radiofrequency Catheter Ablation of Atrial Fibrillation. AB - OBJECTIVES: This study aimed to determine incidence of pulmonary vein stenosis (PVS) and evaluate PVS-related symptoms. BACKGROUND: The real-life incidence of PVS after radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is unknown. METHODS: All patients who underwent RFCA of AF from 2005 to 2016 with routine pre- and post-ablation screening by magnetic resonance imaging or computed tomography were included. Primary ablation strategy was PV antrum isolation alone in all patients. PVS, defined as a significant reduction in the superoinferior or anteroposterior PV diameter, was classified as mild (30% to 50%), moderate (50% to 70%), or severe (>70%). RESULTS: Sufficient quality imaging of the PV anatomy before ablation and during follow-up (mean 6 +/- 4 months) was performed in 976 patients (76.4% men, 59.1% paroxysmal AF). Of these patients, 306 (31.4%) showed mild stenosis, 42 (4.3%) revealed moderate stenosis, and 7 (0.7%) had a severe stenosis in at least 1 PV. Incidence of PVS fluctuated over the past decade. All severe PVS cases were likely caused by ablations being performed inside the PVs. Only 1 (0.1%) patient reported PVS-related symptoms of severe dyspnea during follow-up. Computed tomography revealed a subtotal occlusion of the left inferior PV and a severe stenosis of the left superior PV, requiring stenting. CONCLUSIONS: Although mild PVS was frequently observed after RFCA in this large cohort, incidence of severe PVS was <1% and incidence of symptomatic PVS necessitating intervention was negligible. Based on these findings, it seems appropriate to only screen for PVS in patients with suggestive symptoms. PMID- 29759433 TI - Pulmonary Vein Stenosis Following Radiofrequency Ablation of Atrial Fibrillation: Has It Become a Clinically Negligible Complication? PMID- 29759435 TI - Temporal Trends in and Factors Associated With Use of Single- Versus Dual-Coil Implantable Cardioverter-Defibrillator Leads: Data From the NCDR ICD Registry. AB - OBJECTIVES: This analysis evaluated temporal trends and factors associated with the use of dual-coil implantable cardioverter-defibrillator (ICD) leads. BACKGROUND: Data suggest that dual-coil ICD leads are not associated with lower mortality and can be more difficult to extract than single-coil leads. METHODS: A total of 435,772 patients at 1,690 hospitals underwent ICD lead insertion in the National Cardiovascular Data Registry's ICD Registry between April 2010 and December 2015. Hospitals were classified into 3 pre-specified groups (low, decreasing, or high use) based on the frequency of dual-coil lead use. RESULTS: Nationally, the use of dual-coil leads has decreased over time, from 87% of ICD leads in early 2010 to 55% at the end of 2015. Hospitals in the low-use (n = 292) or decreasing-use (n = 561) group had more ICDs inserted by electrophysiologists compared to the high-use (n = 837) group (90% or 80% vs 46%; p < 0.001 for both) and more extractions performed (median 7 or 11 vs 2; p < 0.001 for both). Despite statistical differences, there were no clinically significant differences in patient characteristics across all 3 groups. CONCLUSIONS: Although the use of dual-coil ICD leads has decreased over time, it continues to represent the majority of insertions in the United States. Hospital-level factors, but not patient factors, were associated with use of dual-coil ICD leads. Whether decreasing dual-coil ICD lead use has improved patient outcomes remains unknown and should be examined in large, multicenter, contemporaneous patient groups. PMID- 29759434 TI - Pulmonary Vein Re-Isolation as a Routine Strategy Regardless of Symptoms: The PRESSURE Randomized Controlled Trial. AB - OBJECTIVES: The goal of this study was to determine whether a strategy of early re-isolation of pulmonary vein (PV) reconnection in all patients, regardless of symptoms, would reduce the recurrence of atrial fibrillation (AF) and improve quality of life. BACKGROUND: Lasting pulmonary vein isolation (PVI) remains elusive. PV reconnection is strongly linked to the recurrence of arrhythmia. METHODS: A total of 80 patients with paroxysmal AF were randomized 1:1 after contact force-guided PVI to receive either standard care or undergo a repeat electrophysiology study after 2 months regardless of symptoms (repeat study). At the initial procedure, PVI was demonstrated by entrance/exit block and adenosine administration after a minimum 20-min wait. At the repeat study, all sites of PV reconnection were re-ablated. Patients recorded electrocardiograms daily and whenever symptomatic for 12 months using a handheld monitor. Recurrence was defined as >=30 s of atrial tachyarrhythmia (AT) after a 3-month blanking period. The Atrial Fibrillation Effect on Quality-of-Life Questionnaire was completed at baseline and at 6 and 12 months. RESULTS: All 40 patients randomized to repeat study attended for this after 62 +/- 6 days, of whom 25 (62.5%) had reconnection of 41 (26%) PVs. There were no complications related to these procedures. Subjects recorded a total of 32,203 electrocardiograms (380 [335 to 447] per patient) during 12.6 (12.2 to 13.2) months of follow-up. AT recurrence was significantly lower for the repeat study group (17.5% vs. 42.5%; p = 0.03), as was AT burden (p = 0.03). Scores on the Atrial Fibrillation Effect on Quality-of Life Questionnaire were higher in the repeat study group at 6 months (p < 0.001) and 12 months (p = 0.02). CONCLUSIONS: A strategy of routine repeat assessment with re-isolation of PV reconnection improved freedom from AT recurrence, AT burden, and quality of life compared with current standard care. (The Effect of Early Repeat Atrial Fibrillation [AF] on AF Recurrence [PRESSURE]; NCT01942408). PMID- 29759436 TI - Single- and Dual-Coil Defibrillator Leads: The Electrophysiology Social Network in Action. PMID- 29759437 TI - Cleaning and Sterilization of Used Cardiac Implantable Electronic Devices With Process Validation: The Next Hurdle in Device Recycling. AB - OBJECTIVES: This study sought to develop a validated, reproducible sterilization protocol, which could be used in the reprocessing of cardiac implantable electronic devices (CIEDs). BACKGROUND: Access to cardiac CIED therapy in high income and in low- and middle-income countries varies greatly. CIED reuse may reduce this disparity. METHODS: A cleaning and sterilization protocol was developed that includes washing CIEDs in an enzymatic detergent, screw cap and set screw replacement, brushing, inspection, and sterilization in ethylene oxide. Validation testing was performed to assure compliance with accepted standards. RESULTS: With cleaning, the total mean bioburden for each of 3 batches of 10 randomly chosen devices was reduced from 754 to 10.1 colony-forming units. After sterilization with ethylene oxide, with 3 half-cycle and 3 full-cycle processes, none of the 90 biological indicator testers exhibited growth after 7 days. Through cleaning and sterilization, protein and hemoglobin concentrations were reduced from 99.2 to 1.42 MUg/cm2 and from 21.4 to 1.03 MUg/cm2, respectively. Mean total organic carbon residual was 1.44 parts per million (range 0.36 to 2.9 parts per million). Endotoxin concentration was not detectable at the threshold of <0.03 endotoxin units/ml or <3.0 endotoxin units/device. Cytotoxicity and intracutaneous reactivity tests met the standards set by the Association for Advancement of Medical Instrumentation and the International Organization for Standardization. CONCLUSIONS: CIEDs can be cleaned and sterilized according to a standardized protocol achieving a 12-log reduction of inoculated product, resulting in sterility assurance level of 10-6. PMID- 29759439 TI - High-Density Electroanatomical Mapping to Identify Point of Epicardial to Endocardial Breakthrough in Perimitral Flutter. PMID- 29759438 TI - Atrial-Esophageal Fistula Development After Atrial Fibrillation Ablation. PMID- 29759440 TI - Puncture of the Closed Coronary Sinus Ostium in a Patient With Coronary Sinus Atresia. PMID- 29759442 TI - Tracheal stab wound with entrance and exit orifices. PMID- 29759443 TI - Optimizing Implantable Cardioverter-Defibrillator Remote Monitoring: A Practical Guide. AB - Remote monitoring (RM) receives a Class I: Level of Evidence: A recommendation for the follow-up of patients with implantable cardioverter-defibrillators, positioning the technology as standard of care. RM is often seen and sold as a plug-and-play technology, whereas fundamental differences exist in the philosophy and conception of the 5 main RM systems. The capabilities and limitations of the different RM systems need to be understood and taken into account when the decision is made to remotely manage an individual patient. The purpose of this review is to provide to the cardiologist practical information about RM systems' specificities with respect to the different technical and clinical alerts. Clinically based indications and programming suggestions are provided. PMID- 29759445 TI - Pre-Ablation Transesophageal Echocardiography in the Era of Minimally Interrupted or Uninterrupted Anticoagulation: Performance Does Not Guarantee Future Results. PMID- 29759444 TI - Trends in Transesophageal Echocardiography Use, Findings, and Clinical Outcomes in the Era of Minimally Interrupted Anticoagulation for Atrial Fibrillation Ablation. AB - OBJECTIVES: This study assessed trends in transesophageal echocardiography (TEE) use, rate of left atrial appendage (LAA) thrombus detection, and incidence of periprocedural cerebrovascular accident (CVA) since transitioning to a strategy of uninterrupted warfarin or briefly interrupted novel oral anticoagulant therapy in 2010. BACKGROUND: TEE is routinely performed before ablation for atrial fibrillation (AF) to ensure absence of LAA thrombus. METHODS: Patients with AF ablation presenting between January 2010 and September 2015 at Johns Hopkins Hospital were enrolled in an AF ablation registry; TEE and ablation outcomes were retrospectively analyzed. Presence of LAA thrombus, dense spontaneous echo contrast (SEC), or patent foramen ovale (PFO) were recorded. CVA incidence from procedure onset to 30 days post-procedure was evaluated using electronic medical record review. RESULTS: Pre-procedure TEE was performed in 646 of 1,224 AF ablation cases (52.8%). There was a decline in pre-procedure TEE use from 86% in 2010 to 42% in 2015 (p < 0.001). CVA incidence was 4/1,224 (0.33%) cases, and did not change during the study period. TEE findings included LAA thrombus (n = 6; 0.93%), PFO (n = 23; 3.6%), and dense spontaneous echo contrast (n = 99; 15.3%). Both SEC and LAA thrombus were associated with persistent AF, higher CHA2DS2VASC score, increased LA size, reduced LAA flow velocity, and decreased left ventricular ejection fraction. PFO was not associated with prior AF ablation, and SEC was not associated with increased CVA incidence. CONCLUSIONS: CVA is a rare complication of AF ablation in patients with minimally interrupted anticoagulation. Pre-ablation TEE may be reasonably avoided in patients without high-risk features. PMID- 29759446 TI - Comparative Effectiveness of Hybrid Ablation Versus Endocardial Catheter Ablation Alone in Patients With Persistent Atrial Fibrillation. AB - OBJECTIVES: The outcomes of hybrid ablation versus endocardial catheter ablation alone were evaluated in patients with persistent and long-standing persistent atrial fibrillation (AF). BACKGROUND: Variable outcomes exist following endocardial catheter ablation in medically refractory patients with persistent AF. A hybrid epicardial-endocardial approach has emerged as an alternative to endocardial ablation. METHODS: In 133 consecutive patients, 69 received endocardial ablation alone (pulmonary vein isolation and radiofrequency catheter ablation [endo group]) and 64 received endocardial catheter ablation and epicardial ablation (hybrid group). Recurrence was defined as any arrhythmia following the 3-month blanking period. RESULTS: Patients were followed for a median of 16 months. The hybrid and endo groups were similar in age (61 +/- 10 years vs. 62 +/- 8 years), body mass index (35 +/- 6 kg/m2 vs. 35 +/- 7 kg/m2), CHA2D2-VASc score (2 +/- 1 vs. 2 +/- 1), and ejection fraction (54 +/- 11% vs. 53 +/- 8%). The hybrid group had longer AF duration (median [interquartile range (IQR)] (12 months [IQR: 8 to 28 months] vs. 7 months [IQR: 5 to 12 months]; p < 0.001) and more previous ablations (58% vs. 25%; p < 0.001). Both groups had similar antiarrhythmic drug use at follow-up (55% vs. 48%). The hybrid group was less likely to have recurrence (37% vs. 58%; p = 0.013) and repeat ablation (9% vs. 26%; p = 0.012), and had an AF-free survival of 72% versus 51% (p = 0.01). CONCLUSIONS: Among patients with persistent AF, hybrid ablation is associated with less AF recurrence and fewer re-do ablations. Prospective large-scale randomized trials are needed to validate these results. PMID- 29759447 TI - Hybrid Ablation for Atrial Fibrillation: Better or Just Different? PMID- 29759448 TI - Repolarization Versus Depolarization Defects in Brugada Syndrome: A Tale of 2 Different Electrophysiologic Settings? PMID- 29759441 TI - Nuclear organization mediates cancer-compromised genetic and epigenetic control. AB - Nuclear organization is functionally linked to genetic and epigenetic regulation of gene expression for biological control and is modified in cancer. Nuclear organization supports cell growth and phenotypic properties of normal and cancer cells by facilitating physiologically responsive interactions of chromosomes, genes and regulatory complexes at dynamic three-dimensional microenvironments. We will review nuclear structure/function relationships that include: 1. Epigenetic bookmarking of genes by phenotypic transcription factors to control fidelity and plasticity of gene expression as cells enter and exit mitosis; 2. Contributions of chromatin remodeling to breast cancer nuclear morphology, metabolism and effectiveness of chemotherapy; 3. Relationships between fidelity of nuclear organization and metastasis of breast cancer to bone; 4. Dynamic modifications of higher-order inter- and intra-chromosomal interactions in breast cancer cells; 5. Coordinate control of cell growth and phenotype by tissue-specific transcription factors; 6. Oncofetal epigenetic control by bivalent histone modifications that are functionally related to sustaining the stem cell phenotype; and 7. Noncoding RNA-mediated regulation in the onset and progression of breast cancer. The discovery of components to nuclear organization that are functionally related to cancer and compromise gene expression have the potential for translation to innovative cancer diagnosis and targeted therapy. PMID- 29759449 TI - Management of Tamponade Complicating Catheter Ablation for Atrial Fibrillation: Early Removal of Pericardial Drains Is Safe and Effective and Reduces Analgesic Requirements and Hospital Stay Compared to Conventional Delayed Removal. AB - OBJECTIVES: This study reports on the safety of early removal of pericardial drains after cardiac tamponade complicating atrial fibrillation catheter ablation (AFCA) procedures, the need for repeat pericardiocentesis, major adverse outcomes, as well as length of stay, and the need for opiate analgesia. BACKGROUND: Tamponade from AFCA is traditionally managed by pericardiocentesis with delayed removal of the drain (typically 12 to 24 h later) in case of re bleeding. A drain in situ often causes severe pain but ongoing blood loss is rare. Our institution adopted the practice of early removal of drains before leaving the laboratory if bleeding has stopped. METHODS: The authors performed a retrospective descriptive analysis of 43 cases of tamponade complicating AFCA from 2006 to 2015, comparing patients in whom the drain was removed early (group early removal [ER]; n = 25) versus traditional delayed removal (group delayed removal [DR]; n = 18). RESULTS: The groups were similar with respect to clinical/demographic characteristics, proportions of first-time versus re-do and pulmonary vein isolation versus pulmonary vein isolation + additional ablation. There were no deaths. No ER patients required drain re-insertion before discharge. The length of stay was shorter in the ER group (3 days; range 1 to 9 days) than in the DR group (4 days; range 2 to 60 days). The requirement for opiate analgesia was less in the ER group (8%) than in the DR group (72%). CONCLUSIONS: Early removal of pericardial drains after tamponade complicating AFCA procedures appears to be safe and effective, with re-insertion not required in this cohort. The traditional practice of leaving drains in situ for 12 to 24 h may result in more patient discomfort and longer hospitalization. PMID- 29759450 TI - T-Wave Morphology Analysis in Congenital Long QT Syndrome Discriminates Patients From Healthy Individuals. AB - OBJECTIVES: This study aims to assess the capability of T-wave analysis to: 1) identify genotype-positive long QT syndrome (LQTS) patients; 2) identify LQTS patients with borderline or normal QTc interval (<=460 ms); and 3) classify LQTS subtype. BACKGROUND: LQTS often presents with a nondiagnostic electrocardiogram (ECG). T-wave abnormalities may be the only marker of this potentially lethal arrhythmia syndrome. METHODS: ECGs taken at rest in 108 patients (43 with LQTS1, 20 with LQTS2, and 45 control subjects) were evaluated for T-wave flatness, asymmetry, and notching, which produces a morphology combination score (MCS) of the 3 features (MCS = 1.6 * flatness + asymmetry + notch) using QT Guard Plus Software (GE Healthcare, Milwaukee, Wisconsin). To assess for heterogeneity of repolarization, the principal component analysis ratio 2 (PCA-2) was calculated. RESULTS: Mean QTc intervals were 486 +/- 50 ms (LQTS1), 479 +/- 36 ms (LQTS2), and 418 +/- 24 ms (control subjects) (p < 0.05). MCS and PCA-2 differed between LQTS patients and control subjects (MCS: 117.8 +/- 57.4 vs. 71.9 +/- 16.2; p < 0.001; PCA-2: 20.2 +/- 10.4% vs. 14.6 +/- 5.5%; p < 0.001), LQTS1 and LQTS2 patients (MCS: 96.3 +/- 28.7 vs. 164 +/- 75.2; p < 0.001; PCA-2: 17.8 +/- 8.3% vs. 25 +/- 12.6%; p < 0.001), and between LQTS patients with borderline or normal QTc intervals (n = 17) and control subjects (MCS: 105.7 +/- 49.9 vs. 71.9 +/- 16.2; p < 0.001; PCA-2: 18.1 +/- 7.2% vs. 14.6 +/- 5.5%; p < 0.001). T-wave metrics were consistent across multiple ECGs from individual patients based on the average intraclass correlation coefficient (MCS: 0.96; PCA-2: 0.86). CONCLUSIONS: Automated T-wave morphology analysis accurately discriminates patients with pathogenic LQTS mutations from control subjects and between the 2 most common LQTS subtypes. Mutation carriers without baseline QTc prolongation were also identified. This may be a useful tool for screening families of LQTS patients, particularly when the QTc interval is subthreshold and genetic testing is unavailable. PMID- 29759451 TI - T-Wave Morphology in LQTS Patients: Challenges and Hopes. PMID- 29759453 TI - The Dynamic Substrate for Atrial Fibrillation: Can We Identify It and Is It of Clinical Importance? PMID- 29759452 TI - High Remission Rates in Vasovagal Syncope: Systematic Review and Meta-Analysis of Observational and Randomized Studies. AB - OBJECTIVES: The aims of this study were to quantify the degree of improvement in vasovagal syncope after assessment and to identify predictive factors. BACKGROUND: No treatments for vasovagal syncope have been proved effective, but patients in all prospective studies appear to show a reduction in the likelihood of fainting. METHODS: A systematic review and meta-analysis was performed of studies published from 1993 through 2013. Inclusion criteria were: 1) vasovagal syncope frequency in the preceding 1 to 2 years; and 2) the proportion of subjects with syncope in at least the first follow-up year. Random-effects methods were used. RESULTS: Of 338 screened studies, 17 were analyzed, with a mean of 112 subjects (range 9 to 511 subjects). In the preceding epoch, 97% of subjects fainted, with 2.6 +/- 1.0 syncopal spells per year. In the follow-up year, the proportion of patients with >=1 syncope recurrence was 677 of 1,912 (35.4%), and in the meta-analysis, the proportion of subjects fainting was only 0.44 (95% confidence interval: 0.41 to 0.46; p < 0.001). Subjects in larger studies were less likely to faint than those in randomized trials (relative risk: 0.35 vs. 0.55; p = 0.004). The probabilities of >=1 syncope recurrence in the observational versus randomized studies were 0.30 (95% confidence interval: 0.24 to 0.37) and 0.54 (95% confidence interval: 0.46 to 0.62), respectively (p < 0.001). None of the degree of blinding, type of intervention, age, sex, and number of recent faints predicted the probability of syncope recurrence. Heterogeneity was very high in all analyses (I2 = 60% to 96%). CONCLUSIONS: The spontaneous remission rate in highly symptomatic syncope patients is high, and remission occurs in all types of studies. Improvement was more likely in larger and observational studies. PMID- 29759454 TI - Determinants of Subcutaneous Implantable Cardioverter-Defibrillator Efficacy: A Computer Modeling Study. AB - OBJECTIVES: This study determined the impact of subcutaneous implantable cardioverter-defibrillator (S-ICD) coil and generator position on defibrillation threshold (DFT). BACKGROUND: S-ICD implantation can occasionally result in unacceptably high DFT. Implant position characteristics associated with high DFTs in S-ICD patients have not been fully elucidated. METHODS: A 3.8-million-element computer model built from magnetic resonance images was used to simulate the electric fields that occur during defibrillation. Generator positions were tested from posterior to anterior in 4-cm increments. The left parasternal coil was tested with 0, 5, and 10 mm of underlying subcutaneous fat and the generator with 20 mm of underlying fat. The estimated DFT for the S-ICD was defined as the energy delivered when producing an electric field of 4 volts/cm in at least 95% of the ventricular myocardium. RESULTS: Estimated DFTs were 22, 29, 64, and 135 joules for posterior, standard (lateral), mid-anterior, and anterior generator locations, respectively. Defibrillation thresholds were 29, 58, and 95 joules with 0, 5, and 10 mm subcoil fat, respectively, and 45 joules with 20 mm subgenerator fat. Combining anterior generator position with subcoil fat resulted in a very high DFT (379 joules). Shock impedance increased with both subcoil and subgenerator fat but was minimally affected by anterior/posterior generator position. CONCLUSIONS: The model suggests that an S-ICD implantation strategy involving posterior generator location and coil and generator directly over the fascia without underlying fat is likely to markedly lower DFTs with the S-ICD and assist in troubleshooting of patients with unacceptably high DFTs. PMID- 29759455 TI - Catheter Ablation of the Left Posterior Fascicle for Bundle Branch Re-Entrant Ventricular Tachycardia With Right Bundle Branch Block Morphology: A Stepwise Approach. PMID- 29759456 TI - Coronary Vasospasm After Isolation of Left Atrial Appendage Using a Second Generation Cryoballoon. PMID- 29759458 TI - Labeling and Drug Safety Communication Approaches to Loperamide Abuse. PMID- 29759457 TI - Multimodality Imaging to Guide Stenting of an Occluded Pulmonary Vein Following Atrial Fibrillation Ablation. PMID- 29759459 TI - Reply: Labeling and Drug Safety of Loperamide: Time for a Proactive Approach? PMID- 29759460 TI - Mark Josephson: Reflections. PMID- 29759461 TI - Substrate Mapping for Ventricular Tachycardia: Assumptions and Misconceptions. AB - Substrate mapping was developed to treat poorly tolerated infarct-related ventricular tachycardias (VTs). This concept was based on 30-year-old data derived from surgical and percutaneous mapping during sinus rhythm and VT that demonstrated specific electrograms (EGMs) that characterized the "arrhythmogenic substrate" of VT. Electrogram characteristics of the arrhythmogenic VT substrate during sinus rhythm included low-voltage, fractionation, long duration, split signals, and isolated late potentials as well as EGMs demonstrating adjacent early and late activation. Introduction of electroanatomical mapping (EAM) systems during the mid-1990s has allowed investigators to record electrograms in 3 dimensions and to identify sites assumed to represent the central common pathway ("isthmus") during re-entrant VTs. However, several important assumptions and misconceptions make currently used "substrate mapping" techniques inaccurate. These include: 1) re-entrant circuits are produced by fixed barriers of immutable "inexcitable" scar; 2) low voltage amplitude (<=0.5 mV) implies dense "inexcitable" scar; 3) isthmuses identified in patients with tolerated VTs using entrainment mapping are both valid and provide an accurate depiction of isthmuses in less hemodynamically tolerated VTs; and 4) current mapping tools and methods can delineate specific electrophysiologic features that will determine the barriers forming channels during re-entrant VTs. None of these assumptions has been validated and recent experimental and human data using higher resolution mapping with very small electrodes cast doubt on their validity. These data call for re-evaluation of substrate-mapping techniques to characterize the arrhythmogenic substrate of post-infarction VT. Standardization of recording techniques including electrode size, interelectrode spacing, tissue contact, catheter orientation, and wavefront activation must be taken into consideration. PMID- 29759463 TI - Prognostic Value of Scar Imaging for Substrate Ablation of Ventricular Tachycardia: Fact or Fiction? PMID- 29759462 TI - Scar Extension Measured by Magnetic Resonance-Based Signal Intensity Mapping Predicts Ventricular Tachycardia Recurrence After Substrate Ablation in Patients With Previous Myocardial Infarction. AB - OBJECTIVES: The aim of this study was to determine if noninvasive measurement of scar by contrast-enhanced magnetic resonance imaging (MRI)-based signal intensity (SI) mapping predicts ventricular tachycardia (VT) recurrence after endocardial ablation. BACKGROUND: Scar extension on voltage mapping predicts VT recurrence after ablation procedures. METHODS: A total of 46 consecutive patients with previous myocardial infarction (87% men, mean age 68 +/- 9 years, mean left ventricular ejection fraction 36 +/- 10%) who underwent VT substrate ablation before the implantation of a cardioverter-defibrillator were included. Before ablation, contrast-enhanced MRI was performed, and areas of endocardial and epicardial scarring and heterogeneous tissue were measured; averaged subendocardial and subepicardial signal intensities were projected onto 3 dimensional endocardial and epicardial shells in which dense scar, heterogeneous tissue, and normal tissue were differentiated. RESULTS: During a mean follow-up period of 32 +/- 24 months 17 patients (37%) had VT recurrence. Patients with recurrence had larger scar and heterogeneous tissue areas on SI maps in both endocardium (81 +/- 27 cm2 vs. 48 +/- 21 cm2 [p = 0.001] and 53 +/- 21 cm2 vs. 30 +/- 15 cm2 [p = 0.001], respectively) and epicardium (76 +/- 28 cm2 vs. 51 +/- 29 cm2 [p = 0.032] and 59 +/- 25 cm2 vs. 37 +/- 19 cm2 [p = 0.008]). In the multivariate analysis, MRI endocardial scar extension was the only independent predictor of VT recurrence (hazard ratio: 1.310 [per 10 cm2]; 95% confidence interval: 1.051 to 1.632; p = 0.034). Freedom from VT recurrence was higher in patients with small endocardial scars by MRI (<65 cm2) than in those with larger scars (>=65 cm2) (85% vs. 20%, log-rank p = 0.018). CONCLUSIONS: Pre-procedure endocardial scar extension assessment by contrast-enhanced MRI predicts VT recurrence after endocardial substrate ablation. This information may be useful to select patients for ablation procedures. PMID- 29759466 TI - Sudden Cardiac Death and Chronic Obstructive Pulmonary Disease: Evidence, Mechanisms, and Therapeutic Implications. PMID- 29759464 TI - Verapamil-Sensitive Upper Septal Idiopathic Left Ventricular Tachycardia: Prevalence, Mechanism, and Electrophysiological Characteristics. AB - OBJECTIVES: This study sought to demonstrate the prevalence, mechanism, and electrocardiographic and electrophysiological characteristics of upper septal idiopathic left fascicular ventricular tachycardia (US-ILVT). BACKGROUND: ILVT is classified into left anterior and posterior types with no clear data about US ILVT. METHODS: Among 193 ILVT patients, we identified 12 patients (6.2%; age 41 +/- 22 years, 7 men) with US-ILVT. RESULTS: Of 12 patients with US-ILVT, 6 patients (50%) had previous history of radiofrequency catheter ablation for common ILVT. Sustained VT (cycle length: 349 +/- 53 ms) was seen in all patients with a QRS interval slightly wider (104 +/- 18 ms) than that during sinus rhythm (90 +/- 19 ms). The VT exhibited an identical QRS configuration as sinus rhythm in 6 (50%) and incomplete right bundle branch block configuration in another 6. His-ventricular interval during VT was always shorter than that during sinus rhythm (27 +/- 5 ms vs. 47 +/- 10 ms). Purkinje potentials were activated in a reverse direction to that of common ILVT; namely, the diastolic potential (P1) was activated retrogradely but the pre-systolic potential (P2) was activated antegradely. At the left upper-middle ventricular septum, P1 potential was recorded during VT, preceding the QRS by 54 +/- 20 ms. Radiofrequency catheter ablation at that site eliminated the VT with no recurrence during a 58 +/- 35 months of follow-up. CONCLUSIONS: US-ILVT is an identifiable VT that shares common criteria with ILVT and has a narrow QRS interval. Some US-ILVT cases appeared after common ILVT ablation. It is a reverse type of common ILVT (orthodromic form) with baseline morphological abnormalities that might provide a potential substrate for such VT. PMID- 29759465 TI - Chronic Obstructive Pulmonary Disease and Risk of Sudden Cardiac Death. AB - OBJECTIVES: The purpose of this study was to determine whether chronic obstructive pulmonary disease (COPD) is associated with sudden cardiac death (SCD) in the community. BACKGROUND: COPD is linked to cardiovascular mortality; an association with SCD has not been systematically investigated in the general population. METHODS: In the Oregon Sudden Unexpected Death Study (approximately 1 million population), adult SCD case subjects were compared with geographic control subjects with coronary artery disease. Detailed clinical and electrocardiographic risk marker information was obtained from medical records. The association of COPD with SCD in the overall population and in a propensity score-matched dataset was assessed with logistic models. RESULTS: SCD case subjects (n = 728; age 69.9 +/- 13.7 years) were more likely than control subjects (n = 548; age 67.2 +/- 11.3 years) to have left ventricular ejection fraction <=35% (27.5% vs. 12.0%; p < 0.0001), COPD (30.8% vs. 12.8%, p < 0.0001), diabetes mellitus (47.7% vs. 31.8%; p < 0.0001), use short-acting beta-2 agonist agents (SBAs) (22.3% vs. 12.6%; p < 0.0001), and less likely to use beta-blockers (60.6% vs. 66.4%; p = 0.03). In multivariable analysis, COPD was significantly associated with SCD (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.4 to 3.5; p < 0.001). There was no significant interaction between COPD and medications, but an interaction was identified between SBAs and beta-blockers (p = 0.04); SBAs were strongly associated with SCD in subjects not taking beta blockers (OR: 3.3; 95% CI: 1.4 to 7.7; p = 0.005) but not in those taking beta blockers (OR: 1.3; 95% CI: 0.7 to 2.3; p = 0.39). The COPD-SCD association was maintained in a propensity score-matched analysis. CONCLUSIONS: COPD is associated with SCD risk in the community independent of medications, electrocardiographic risk markers, and left ventricular ejection fraction. Among other mechanisms, pro-arrhythmogenic right ventricular remodeling and systemic inflammation warrant further investigation. PMID- 29759467 TI - Low-Level Electrical Stimulation of Aortic Root Ventricular Ganglionated Plexi Attenuates Autonomic Nervous System-Mediated Atrial Fibrillation. AB - OBJECTIVES: This study investigated the effect of electrical stimulation of aortic root ventricular ganglionated plexi (GP) on atrial fibrillation (AF) inducibility. BACKGROUND: The ventricular GP are interconnected with atrial GP to govern heart function, although the effect of ventricular GP modification on control of AF remains unknown. METHODS: Effective refractory periods (ERPs) of test pulmonary veins (PVs) were measured at baseline and during high-level (HL ES) and low-level (LL-ES) electrical stimulation of the aortic root GP. The arrhythmogenic threshold of acetylcholine and isoproterenol was determined at baseline and during HL-ES and LL-ES. Moreover, AF was induced at PVs by programmed electrical stimulation after HL-ES or LL-ES. Immunohistochemistry staining was performed to examine the autonomic activity from aortic root GP to the PVs. RESULTS: Compared with the baseline group, HL-ES of aortic root GP significantly shortened atrial ERP (95 +/- 13 ms vs. 122 +/- 9 ms) and PV ERP (104 +/- 11 ms vs. 131 +/- 12 ms); decreased the threshold concentration of AF by both acetylcholine (1.3 +/- 0.2 MUmol/l vs. 3.2 +/- 0.3 MUmol/l) and isoproterenol (0.3 +/- 0.1 MUmol/l vs. 1.3 +/- 0.2 MUmol/l); and increased the AF inducing rate from PVs (90% vs. 30%). In contrast, LL-ES of the GP prevented the shortening of ERP and PV ERP to 125 +/- 10 ms and 133 +/- 11 ms, respectively; increased threshold levels of acetylcholine and isoproterenol to 5.7 +/- 0.4 MUmol/l and 3.2 +/- 0.3 MUmol/l; and decreased the AF-inducing rate to 5%. We also found that the biotinylated dextran amine-containing varicose fibers projected directly from the aortic root GP to the left PVs. CONCLUSIONS: These findings suggest that autonomic innervations of left PVs partly originated from aortic root ventricular GP. Moreover, LL-ES of aortic root ventricular GP suppressed AF inducibility and arose from PVs mediated by the autonomic nervous system. PMID- 29759468 TI - Electrophysiological Predictors of Transplantation and Left Ventricular Assist Device-Free Survival in Patients With Nonischemic Cardiomyopathy Undergoing Ventricular Tachycardia Ablation. AB - OBJECTIVES: This study sought to identify predictors of transplantation/left ventricular assist device (LVAD)-free survival among patients with left ventricular nonischemic cardiomyopathy (NICM) and ventricular tachycardia (VT). BACKGROUND: Outcomes vary widely among these patients. METHODS: The derivation cohort consisted of patients with NICM undergoing VT ablation from 2007 to 2011. Scar percentage was defined as the area of low voltage divided by total surface area. Cox proportional hazard modeling was performed to identify predictors of shorter time to the primary endpoint of death, transplantation, or LVAD. A risk score was created using beta regression coefficients. The risk score was then validated in a separate cohort of patients undergoing ablation from 2004 to 2007. RESULTS: Of 100 patients with NICM undergoing VT ablation, 41 experienced an endpoint during 1.2 years mean follow-up. In multivariate modeling, VT storm, wider native QRS duration, greater endocardial/epicardial bipolar scar percentage, and lower left ventricular ejection fraction (LVEF) identified worse transplantation/LVAD-free survival. The risk score = (VT storm * 83) + (greater of endocardial/epicardial bipolar scar percentage * 4) + (QRS duration) - (LVEF * 3). A score >180 identified patients at high risk for the endpoint, whereas a score <100 identified low risk. Among the 50-patient validation cohort, the high risk group again had worse transplantation/LVAD-free survival during a mean 3.0 years of follow-up (<10% vs. 50% for intermediate and >80% for low, p < 0.001). CONCLUSIONS: Wider native QRS duration, greater bipolar scar percentage, VT storm, and lower LVEF are potent predictors of time to death, transplantation, or LVAD. By combining these variables into an "electrophysiological risk score," patient risk can be refined. PMID- 29759469 TI - Prediction of Major Clinical Endpoints in Nonischemic Cardiomyopathy: Through the Eye of the Electrophysiologist. PMID- 29759470 TI - Utility of a Novel Rapid High-Resolution Mapping System in the Catheter Ablation of Arrhythmias: An Initial Human Experience of Mapping the Atria and the Left Ventricle. AB - OBJECTIVES: This study sought to assess the clinical efficacy, safety, and clinical utility of a novel electroanatomical mapping system. BACKGROUND: A new mapping system capable of rapidly acquiring detailed maps based on automatic annotation of thousands of points was recently released for clinical use. This is the first description of its utility in humans. METHODS: The first consecutive 20 cases (7 atrial tachycardia, 8 atrial fibrillation, 3 ventricular tachycardia, and 2 ventricular ectopic beat ablations) were analyzed. The system uses a bidirectional deflectable basket catheter with 64 closely spaced mini-electrodes. It automatically accepts and annotates electrograms when a number of predefined criteria are met. RESULTS: Thirty right atrial maps were acquired in 11 (4 to 15) min, consisting of 7,220 (3,467 to 10,947) points, 22 left atrial maps in 11 (6 to 19) min, consisting of 7,818 (4,379 to 12,262) points and 10 left ventricular maps in 37 (14 to 43) min, consisting of 8,709 (2,605 to 15,514) points. The mini basket catheter could reach all areas of interest without deflectable sheaths. No embolic events, bleeding complications, or endocardial structure damage were observed. Correction of the automatic annotation was performed in 0.02% of points in 4 of 62 maps. The system revealed re-entry circuits of atrial tachyarrhythmias, identified gaps on linear lesions, and identified and correctly annotated the clinical ventricular ectopic beats and channels of slow conduction within ventricular scar. CONCLUSIONS: The novel automatic mapping system was rapid, safe, and efficacious in mapping a variety of cardiac arrhythmias in humans. Further clinical research is needed to optimize its use in the ablation of complex arrhythmias. PMID- 29759472 TI - Is Good Contact Enough for Atrial Fibrillation Ablation? PMID- 29759473 TI - Use of Transesophageal Echocardiography to Improve the Safety of Transvenous Lead Extraction. AB - OBJECTIVES: The aim of this study was to evaluate the utility of transesophageal echocardiography (TEE) during transvenous lead extraction (TLE) involving both conventional and laser lead removal. BACKGROUND: TLE carries a small but measurable risk of serious adverse events. Few studies have examined the potential benefit of continuous monitoring with TEE during this procedure. METHODS: Continuous TEE monitoring was performed in 100 consecutive patients (67% male; average age, 57 +/- 17 years) who underwent TLE in the past 5 years. Lead extraction was attempted for 193 leads. The average time since lead implant was 78 +/- 55 months (range, 1.4 to 274.4 months). Indications for extraction were device endocarditis (n = 28), lead fracture (n = 28), recalled lead (n = 21), pocket infection (n = 17), and other (n = 6). RESULTS: Complete success occurred in 181 leads (94%), partial success in 4 leads (2%), and failure in 8 leads (4%). Eighty patients required laser lead extraction (80%). Major complications included 1 right ventricular and 2 right atrial/superior vena cava lacerations, which were detected and localized within 1 to 2 min with the use of TEE and resulted in prompt surgical repair. There was 1 upper gastrointestinal bleed caused by the TEE probe. TEE prevented premature termination and unnecessary surgery in 4 patients with hypotension but no intracardiac abnormalities seen on TEE. In-hospital mortality rate was 0%. In total, TEE provided immediately useful clinical information in 7 patients (7%). CONCLUSIONS: Continuous monitoring with TEE facilitates prompt diagnosis and treatment of intracardiac damage and prevents premature termination of cases with hypotension but no abnormalities on TEE. PMID- 29759474 TI - Transesophageal Echocardiography Monitoring During Lead Extraction Procedures: Sound Advice. PMID- 29759471 TI - The Effect of Contact Force in Atrial Radiofrequency Ablation: Electroanatomical, Cardiovascular Magnetic Resonance, and Histological Assessment in a Chronic Porcine Model. AB - OBJECTIVES: This study sought to determine the effect of contact force (CF) on atrial lesion size, quality, and transmurality by using a chronic porcine model of radiofrequency ablation. BACKGROUND: CF is a major determinant of ventricular lesion formation, but uncertainty exists regarding the most appropriate CF parameters to safely achieve permanent, transmural lesions in the atria. METHODS: Intercaval linear ablation (30 W, 42 degrees C, 17 ml/min irrigation) was performed in 8 Gottingen minipigs by using a force-sensing catheter with CF >20 g (high force) or <10 g (low force) at alternate ends of the line, separated by an intentional gap. Voltage mapping and cardiovascular magnetic resonance (CMR) imaging were performed pre-ablation, immediately after ablation, and at 2 months' post-procedure. Lesions were sectioned orthogonal to the axis of ablation to assess transmurality. RESULTS: Mean CF was 22.6 +/- 11.4 g and 7.8 +/- 4.0 g in the high and low CF regions. Acute tissue edema was greater with high CF, both caudally (7.0 mm vs. 4.6 mm; p = 0.016) and cranially (6.9 mm vs. 4.6 mm; p = 0.038). There was no difference in chronic lesion size (voltage mapping) or volume (late gadolinium enhancement CMR) between high and low CF regions. There was no difference in scar density (assessed by low-voltage criteria and late gadolinium enhancement signal intensity) or histological transmurality between high and low CF regions. CONCLUSIONS: Although high CF (>20 g) resulted in more acute tissue edema than low CF (<10 g), chronically there was no difference in lesion size, quality, or transmurality. Appropriate CF targets for atrial ablation may be lower than previously thought. PMID- 29759476 TI - Cryoballoon Pulmonary Vein Isolation After Lung Lobectomy. PMID- 29759475 TI - Simplified Method for Vagal Effect Evaluation in Cardiac Ablation and Electrophysiological Procedures. AB - OBJECTIVES: The aim of this study is to show a simplified reversible approach to investigate and confirm vagal denervation at any time during the ablation procedure without autonomic residual effect. BACKGROUND: Parasympathetic denervation has been increasingly applied in ablation procedures such as in vagal related atrial fibrillation and cardioneuroablation. This method proposes an easy way to study the vagal effect and to confirm its elimination following parasympathetic denervation through vagal stimulation (VS) by an electrophysiological catheter placed in the internal jugular vein. METHODS: A prospective controlled study including 64 patients without significant cardiopathy (48 male [75.0%], age 46.4 +/- 16.4 years) who had a well-defined RF ablation indication for symptomatic arrhythmias, comprising a "denervation group" (DG), with indication for ablation with parasympathetic denervation (vagal related atrial fibrillation or severe cardioinhibitory syncope) and a "control group" (CG), with ablation indication without parasympathetic denervation (accessory pathway or ventricular arrhythmia). By using a neurostimulator, both groups underwent non simultaneous bilateral VS (8 to 12 s, frequency: 30 Hz, pulse width: 50 MUs, amplitude: 0.5 to 1 V/kg up to 70 V) through the internal jugular vein pre- and post-ablation. RESULTS: Significant cardioinhibition was achieved pre-ablation in all cases (pause of 11.5 +/- 1.9 s in DG vs. 11.4 +/- 2.1 s in CG; p = 0.79). Eight patients (12.5%) presented catheter progression difficulty in 1 jugular vein (2 right, 6 left); however, the contralateral VS was adequate for cardioinhibition. After ablation, the cardioinhibition was reproduced only in CG (pause of 11.2 +/- 2.2 s) as in DG it was entirely eliminated. There was no significant difference between pre- and post-ablation cardioinhibition in CG (p = 0.84). There was no complication (follow-up 8.8 +/- 5 months). CONCLUSIONS: The vagal stimulation was feasible, easy, and reliable, and showed no complications. It may be repeated during the procedure to control the denervation degree without residual effect. It could be a suitable tool for vagal denervation confirmation or autonomic tests during electrophysiological studies. Ablation without parasympathetic denervation did not change the vagal response. PMID- 29759477 TI - Electrophysiology and Health Care Reform: Expanding Our Value Proposition. PMID- 29759480 TI - Audio Summary. PMID- 29759481 TI - Author's reply. PMID- 29759482 TI - The Tumor Microenvironment: A Druggable Target for Metastatic Disease? PMID- 29759483 TI - Induction of the Immunoproteasome Subunit Lmp7 Links Proteostasis and Immunity in alpha-Synuclein Aggregation Disorders. AB - Accumulation of aggregated alpha-synuclein into Lewy bodies is thought to contribute to the onset and progression of dopaminergic neuron degeneration in Parkinson's disease (PD) and related disorders. Although protein aggregation is associated with perturbation of proteostasis, how alpha-synuclein aggregation affects the brain proteome and signaling remains uncertain. In a mouse model of alpha-synuclein aggregation, 6% of 6215 proteins and 1.6% of 8183 phosphopeptides changed in abundance, indicating conservation of proteostasis and phosphorylation signaling. The proteomic analysis confirmed changes in abundance of proteins that regulate dopamine synthesis and transport, synaptic activity and integrity, and unearthed changes in mRNA binding, processing and protein translation. Phosphorylation signaling changes centered on axonal and synaptic cytoskeletal organization and structural integrity. Proteostatic responses included a significant increase in the levels of Lmp7, a component of the immunoproteasome. Increased Lmp7 levels and activity were also quantified in postmortem human brains with PD and dementia with Lewy bodies. Functionally, the immunoproteasome degrades alpha-synuclein aggregates and generates potentially antigenic peptides. Expression and activity of the immunoproteasome may represent testable targets to induce adaptive responses that maintain proteome integrity and modulate immune responses in protein aggregation disorders. PMID- 29759484 TI - Runt-Related Transcription Factor 1 (RUNX1) Promotes TGF-beta-Induced Renal Tubular Epithelial-to-Mesenchymal Transition (EMT) and Renal Fibrosis through the PI3K Subunit p110delta. AB - Renal fibrosis is widely considered a common mechanism leading to end-stage renal failure. Epithelial-to-mesenchymal transition (EMT) plays important roles in the pathogenesis of renal fibrosis. Runt-related transcription factor 1(RUNX1) plays a vital role in hematopoiesis via Endothelial-to-Hematopoietic Transition (EHT), a process that is conceptually similar to EMT, but its role in EMT and renal fibrosis is unclear. Here, we demonstrate that RUNX1 is overexpressed in the processes of TGF-beta-induced partial EMT and renal fibrosis and that the expression level of RUNX1 is SMAD3-dependent. Knockdown of RUNX1 attenuated both TGF-beta-induced phenotypic changes and the expression levels of EMT marker genes in renal tubular epithelial cells (RTECs). In addition, overexpression of RUNX1 promoted the expression of EMT marker genes in renal tubular epithelial cells. Moreover, RUNX1 promoted TGF-beta-induced partial EMT by increasing transcription of the PI3K subunit p110delta, which mediated Akt activation. Specific deletion of Runx1 in mouse RTECs attenuated renal fibrosis, which was induced by both unilateral ureteral obstruction (UUO) and folic acid (FA) treatment. These findings suggest that RUNX1 is a potential target for preventing renal fibrosis. PMID- 29759487 TI - Clinical examination of proton pencil beam scanning on a moving anthropomorphic lung phantom. AB - The objective of this study was to examine the use of proton pencil beam scanning for the treatment of moving lung tumors. A single-field uniform dose proton pencil beam scanning (PBS) plan was generated for the standard thorax phantom designed by the Imaging and Radiation Oncology Core (IROC) Houston QA Center. Robust optimization, including range and setup uncertainties as well as volumetric repainting, was used for the plan. Patient-specific quality assurance (QA) measurements were performed using both a water tank and a custom heterogeneous QA phantom. A custom moving phantom was used to find the optimal number of volumetric repainting. Both analytical and Monte Carlo (MC) algorithms were used for dose calculation and their accuracies were compared with actual measurements. A single ionization chamber, a 2-dimensional ionization chamber array, thermoluminescent dosimeters (TLDs), and films were used for dose measurements. The optimal number of volumetric repainting was found to be 4 times in our system. The mean dose overestimations on a moving target by analytical and MC algorithms based on a time-averaged computed tomography (CT) image of the phantom were found to be 4.8% and 2.4%, respectively. The mean gamma indexes for analytical and MC algorithms were 91% and 96%, respectively. The MC dose algorithm calculation was found to have a better agreement with measurements compared with the analytical algorithm. When treating moving lung tumors using proton PBS, the techniques of robust optimization, volumetric repainting, and MC dose calculation were found effective. Extra care needs to be taken when an analytical dose calculation algorithm is used. PMID- 29759485 TI - Roles of Alternative RNA Splicing of the Bif-1 Gene by SRRM4 During the Development of Treatment-induced Neuroendocrine Prostate Cancer. AB - Treatment-induced neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that becomes more prevalent when hormonal therapy, chemotherapy, or radiation therapy is applied to patients with metastatic prostate adenocarcinoma (AdPC). How AdPC cells survive these anti cancer therapies and progress into t-NEPC remains unclear. By comparing the whole transcriptomes between AdPC and t-NEPC, we identified Bif-1, an apoptosis associated gene, which undergoes alternative RNA splicing in t-NEPC. We found that while Bif-1a is the predominant variant of the Bif-1 gene in AdPC, two neural-specific variants, Bif-1b and Bif-1c, are highly expressed in t-NEPC patients, patient derived xenografts, and cell models. The neural-specific RNA splicing factor, SRRM4, promotes Bif-1b and Bif-1c splicing, and the expression of SRRM4 in tumors is strongly associated with Bif-1b/-1c levels. Furthermore, we showed that Bif-1a is pro-apoptotic, while Bif-1b and Bif-1c are anti-apoptotic in PCa cells under camptothecin and UV light irritation treatments. Taken together, our data indicate that SRRM4 regulates alternative RNA splicing of the Bif-1 gene that enables PCa cells resistant to apoptotic stimuli under anti cancer therapies, and may contribute to AdPC progression into t-NEPC. PMID- 29759488 TI - Neuromuscular Disorders and the Role of the Clinical Electrophysiologist. AB - Cardiac involvement is common and may be the presenting or predominant manifestation in a variety of neuromuscular disorders, most notably the inherited muscle disorders, or muscular dystrophies. Cardiac manifestations of the neuromuscular disorders result from pathological involvement of the myocardium and the cardiac conduction system, with resulting cardiomyopathy or rhythm disturbances including supraventricular arrhythmias, life-threatening ventricular arrhythmias, and sudden cardiac death. Many of these neuromuscular disorders are rare and may be unrecognized by even experienced specialists in internal and cardiovascular medicine. Furthermore, the initial cardiac manifestations in these patients are often asymptomatic. The goal of this investigation is to review the scope of cardiac conduction defects and rhythm disturbances in these disorders and to propose some practical recommendations for arrhythmia monitoring and management of these patients. PMID- 29759489 TI - Ablation Index and Surround Flow Catheter Irrigation: Impedance-Based Appraisal in Clinical Ablation. AB - OBJECTIVES: This study sought to assess the impact of ablation power and catheter irrigation during clinical radiofrequency ablation using impedance drop. BACKGROUND: In preclinical studies, ablation power and catheter irrigation are determinants of ablation efficacy. METHODS: Static 30-s left atrial ablations were delivered in patients undergoing their first atrial fibrillation ablation. Impedance drop during ablation (as a measure of efficacy) was compared using the following: the force time integral (FTI); the FTI-P (a cumulative multiple FTI and ablation power), and ablation index (AI), a weighted algorithm including contact force, power, and duration. Comparison was also made between a conventionally irrigated (SmartTouch [ST]) versus surround flow (STSF) contact force-sensing catheter. RESULTS: We analyzed 1,013 ablations. For both catheters, the Spearman correlation was higher between impedance drop and AI (rho = 0.89 ST, 0.84 STSF) than FTI-P (rho = 0.71 ST, 0.53 STSF) or FTI (rho = 0.77 ST, 0.52 STSF); p < 0.0005 for each. STSF ablations had lower minimum catheter tip temperatures (25 degrees C [interquartile range (IQR): 25 degrees C to 27 degrees C] vs. 35 degrees C [IQR: 34 degrees C to 36 degrees C]; p < 0.005), and lesser impedance drop per FTI or AI (p < 0.005 for both). For STSF, impedance drop plateaued sooner than for ST with respect to FTI (184g.s vs. 463g.s) and AI (370 AI vs. 430 AI). CONCLUSIONS: AI is a more complete ablation descriptor than is FTI or FTI-P, reflected by a stronger correlation with impedance drop. STSF ablations have lower impedance drop per AI or FTI than ST ablations do, suggesting different targets should be used if ablating guided by impedance drop with STSF. With ST, ablation beyond 430 AI provides minimal additional biophysical efficacy, suggesting an upper limit to use for clinical ablation. PMID- 29759486 TI - Inhibition of HDACs-EphA2 Signaling Axis with WW437 Demonstrates Promising Preclinical Antitumor Activity in Breast Cancer. AB - Histone deacetylase inhibitors (HDACi) are small molecules targeting epigenetic enzymes approved for hematologic neoplasms, which have also demonstrated clinical activities in solid tumors. In our present study, we screened our internal compound library and discovered a novel HDACi, WW437, with potent anti-breast cancer ability in vitro and in vivo. WW437 significantly inhibited phosphorylated EphA2 and EphA2 expression. Further study demonstrated WW437 blocked HDACs-EphA2 signaling axis in breast cancer. In parallel, we found that EphA2 expression positively correlates with breast cancer progression; and combined use of WW437 and an EphA2 inhibitor (ALW-II-41-27) exerted more remarkable effect on breast cancer growth than either drug alone. Our findings suggested inhibition of HDACs EphA2 signaling axis with WW437 alone or in combination with other agents may be a promising therapeutic strategy for advanced breast cancer. PMID- 29759490 TI - Cooking a Quality Radiofrequency Ablation Lesion: How Difficult Can That Be? PMID- 29759491 TI - Chamber-Specific Radiofrequency Lesion Dimension Estimation Using Novel Catheter Based Tissue Interface Temperature Sensing: A Preclinical Assessment. AB - OBJECTIVES: This study sought to compare a novel lesion dimension estimation approach to actual measurements of lesion dimensions on necropsy in porcine atria and ventricles. BACKGROUND: An irrigated-tip, force-sensing radiofrequency catheter with 6 temperature (tip-tissue interface) sensors allows for assessment of lesion dimensions based on estimated tissue temperature. Lesion dimension assessment has not been attempted previously in atrial tissue. METHODS: Ablations were performed using this catheter in all chambers. Irrigated radiofrequency was delivered using 20 to 50 W for durations that ranged from 15 to 90 s with contact force ranging from 5 to 45 g to replicate a wide spectrum of clinical conditions. All swine were then sacrificed and lesions were identified and photographed. Three independent observers made offline measurements, which were then averaged to obtain lesion width and depth for comparison with estimated dimensions based on interface tissue temperature. RESULTS: In 9 swine, 54 atrial and 61 ventricular lesions were assessed. In the atria, the mean difference between the measured and estimated depth and width was 0.9 +/- 0.74 mm and 1.2 +/- 0.9 mm, respectively. Eighty percent of all lesions had a difference of <=1.7 mm for depth and <=1.74 mm for width. In the ventricle, the mean difference between the measured and estimated depth and width was 0.75 +/- 0.6 mm and 1.66 +/- 1.1 mm, respectively. Eighty percent of all lesions had a difference of <=1.1 mm ventricular depth and <=2.6 mm for width. CONCLUSIONS: Estimation of lesion dimensions can be achieved with clinically relevant accuracy using unique temperature signatures. These data have important implications for understanding the adequacy of lesion overlap and assessment of transmurality. PMID- 29759493 TI - Can We Produce Deeper Radiofrequency Lesions? PMID- 29759492 TI - Radiofrequency Ablation Using an Open Irrigated Electrode Cooled With Half-Normal Saline. AB - OBJECTIVES: This study evaluated the use of half-normal saline (HNS) as the radiofrequency ablation (RFA) cooling irrigant. BACKGROUND: Some instances of ventricular arrhythmia may originate deep within myocardium and can be refractory to standard ablation using open irrigated RFA. Recent data suggest that deeper ablation lesions can be created by decreasing the irrigant ionic concentration delivered through open irrigated RFA than by using normal saline (NS). METHODS: Bovine myocardium was placed in a circulating saline bath. Two RFA catheters were oriented across from each other, with myocardium in between. Sequential unipolar HNS-irrigated RFA was performed and compared to bipolar ablation by using NS or HNS. Unipolar HNS ablation of the ventricles in a porcine model was performed and compared to ablation using NS. RESULTS: Sequential ex vivo unipolar RFA with HNS produced larger lesions than sequential unipolar RFA with NS and produced lesions of similar size to those created with bipolar RFA using NS. Ex vivo bipolar RFA using HNS created the largest lesions. In vivo unipolar HNS ablation in porcine endocardium created larger lesion volumes, 152.9 +/- 29.2 MUl, compared to 94.7 +/- 33.4 MUl for unipolar ablation using NS. CONCLUSIONS: By decreasing ionic concentration and charge density in RFA using HNS instead of NS irrigant, larger ablation lesions can be created and are similar in size to lesions created using bipolar ablation. This may be a useful ablation strategy for deep myocardial circuits refractory to standard ablation. Further studies are needed to evaluate this novel RFA strategy. PMID- 29759494 TI - Impact of Lowering Irrigation Flow Rate on Atrial Lesion Formation in Thin Atrial Tissue: Preliminary Observations From Experimental and Clinical Studies. AB - OBJECTIVES: The authors sought to investigate the effect of low irrigation flow rate on lesion characteristics and ablation outcomes in a clinicopathological study. BACKGROUND: Irrigated ablation produces deeper lesions compared with nonirrigated ablation, which may not be desirable in the thin-walled posterior left atrium (LA), where collateral esophageal injury is possible. METHODS: Lesions were placed on the smooth posterior right atrium in 20 swine and posterior LA in 60 patients at a maximum power of 20 to 25 W with either: 1) power-controlled ablation at an irrigation flow rate of 17 ml/min (high-flow group 10 swine; n = 40) or 2) temperature-controlled ablation at an irrigation flow rate of 2 ml/min (low-flow group 10 swine; n = 20). Safety and efficacy was also compared in 326 patients undergoing AF ablation using high-flow (n = 160) or low-flow settings (n = 166) for posterior LA ablation. RESULTS: Low-flow, compared with high-flow, lesions in swine had a higher incidence of lesions with: impedance fall >=10 Omega, loss of pace capture, electrograms characteristic of transmural lesions, and visible lesions on anatomic inspection (p < 0.05 for all). Low-flow lesions had a maximal diameter at the endocardial surface, whereas high-flow lesions had a maximal diameter at the epicardial surface. In humans, impedance, pace capture, and transmurality data also strongly favored low-flow lesions. There was no difference in acute pulmonary vein isolation, complications, or 12-month arrhythmia-free survival between the groups. CONCLUSIONS: Low-flow irrigated ablation provides favorable lesion characteristics for posterior LA ablation without increasing the risk of adverse events. PMID- 29759495 TI - In Vitro Validation of the Lesion Size Index to Predict Lesion Width and Depth After Irrigated Radiofrequency Ablation in a Porcine Model. AB - OBJECTIVES: In an in vitro model, the authors tested the hypotheses that: 1) lesion dimensions correlate with lesion size index (LSI); and 2) LSI could predict lesion dimensions better than power, contact force (CF), and force-time integral (FTI). BACKGROUND: When performing radiofrequency (RF) catheter ablation for cardiac arrhythmias, reliable predictors of lesion quality are lacking. The LSI is a multiparametric index incorporating time, power, CF, and impedance recorded during ablation. METHODS: RF lesions were created on porcine myocardial slabs by using an open-tip irrigated catheter capable of real-time monitoring of catheter-tissue CF. Initially, 3 power settings of 20, 25, and 30 W were used with a fixed CF of 10 g. A fixed power of 20 W was then set with a CF of 20 and 30 g, thereby yielding a total of 5 ablation groups. In each group, LSI values of 5, 6, 7, and 8 were targeted. Sixty RF lesions were created by using 20 ablation protocols (3 lesions for each protocol). RESULTS: Lesion width and depth were not correlated with power or CF, but the results significantly correlated with FTI (p < 0.01) and LSI (p < 0.0001). Four steam pops occurred with power set at 30 W; no pops were noted with 20 or 25 W even when high LSI values were targeted. CONCLUSIONS: In this in vitro model, FTI and LSI predicted RF lesion dimensions, whereas power and CF did not. The LSI predictive value was higher than that of FTI. Steam pops occurred only using high ablation power levels, regardless of the targeted LSI. PMID- 29759496 TI - J Waves for Predicting Cardiac Events in Hypertrophic Cardiomyopathy. AB - OBJECTIVES: This study sought to investigate whether the presence of J waves was associated with cardiac events in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: It has been uncertain whether the presence of J waves predicts life-threatening cardiac events in patients with HCM. METHODS: This study evaluated consecutive 338 patients with HCM (207 men; age 61 +/- 17 years of age). A J-wave was defined as J-point elevation >0.1 mV in at least 2 contiguous inferior and/or lateral leads. Cardiac events were defined as sudden cardiac death, ventricular fibrillation or sustained ventricular tachycardia, or appropriate implantable cardiac defibrillator therapy. The study also investigated whether adding the J-wave in a conventional risk model improved a prediction of cardiac events. RESULTS: J waves were seen in 46 (13.6%) patients at registration. Cardiac events occurred in 31 patients (9.2%) during median follow-up of 4.9 years (interquartile range: 2.6 to 7.1 years). In a Cox proportional hazards model, the presence of J waves was significantly associated with cardiac events (adjusted hazard ratio: 4.01; 95% confidence interval [CI]: 1.78 to 9.05; p = 0.001). Compared with the conventional risk model, the model using J waves in addition to conventional risks better predicted cardiac events (net reclassification improvement, 0.55; 95% CI: 0.20 to 0.90; p = 0.002). CONCLUSIONS: The presence of J waves was significantly associated with cardiac events in HCM. Adding J waves to conventional cardiac risk factors improved prediction of cardiac events. Further confirmatory studies are needed before considering J-point elevation as a marker of risk for use in making management decisions regarding risk in patients with HCM. PMID- 29759497 TI - J Point Elevation in Hypertrophic Cardiomyopathy: Riding a New Wave in Risk Stratification? PMID- 29759499 TI - Prevention of Atrioesophageal Fistula After Catheter Ablation: If the Esophagus Cannot Stand the Heat (Cold), Can It Be Moved to the Sidelines? PMID- 29759498 TI - The Extent of Mechanical Esophageal Deviation to Avoid Esophageal Heating During Catheter Ablation of Atrial Fibrillation. AB - OBJECTIVES: This study sought to determine the extent of lateral esophageal displacement required during mechanical esophageal deviation (MED) and to eliminate luminal esophageal temperature elevation (LETElev) during pulmonary vein (PV) isolation. BACKGROUND: MED is a conceptually attractive strategy of minimizing esophageal injury while allowing uninterrupted energy delivery along the posterior left atrium during PV isolation. METHODS: MED was performed using a malleable metal stylet within a plastic tube placed within the esophagus. Barium was instilled to characterize the trailing esophageal edge. For each MED attempt, the MEDEffective, defined as the distance from the trailing esophageal edge-to ablation line, was correlated to occurrences of LETElev. RESULTS: In 114 consecutive patients/221 PV pairs undergoing MED (age 62.1 +/- 11 years, 75% men, 62%/38% paroxysmal/persistent AF), esophageal stretching invariably occurred such that the esophageal edge trailed behind the plastic tube. MEDEffective distances of 0 mm to 10 mm, 10 mm to 15 mm, 15 mm to 20 mm or >20 mm were achieved in 60 (27.1%), 64 (29%), 48 (21.7%), and 49 (22.2%) attempts, respectively. Overall, LET elevation >38 degrees C occurred in 81 of 221 (36.7%) PV pairs. The incidence of LETElev among the 4 groups was 73.3%, 35.9%, 25%, and 4.1%, respectively. MEDEffective distances were 9.1 +/- 6.5 mm and 18 +/- 7.6 mm in patients with and without LETElev, respectively (p < 0.0001). Three patients (2.6%) experienced clinically significant MED-related trauma, albeit only with a stiffer stylet. CONCLUSIONS: Mechanical esophageal deviation >20 mm from the PV ablation line prevents significant esophageal heating during PV isolation, but this level of displacement was difficult to safely achieve with this off-the-shelf mechanical stylet approach. PMID- 29759501 TI - Assessment of Atrial Fibrillation-Specific Symptoms Before and 2 Years After Atrial Fibrillation Ablation: Do Patients and Physicians Differ in Their Perception of Symptom Relief? AB - OBJECTIVES: The aim of this study was to evaluate patient-reported and physician assessed atrial fibrillation (AF)-related symptoms after AF ablation. BACKGROUND: Success of AF ablation is usually defined as freedom from AF, although symptom relief is often patients' desire. METHODS: Symptom relief was assessed as perceived by patients using the short, validated, AF-specific symptom questionnaire AF6 and as classified by physicians using the European Heart Rhythm Association (EHRA) classification at baseline and 6, 12, and 24 months after AF ablation. Recurrence of arrhythmia was documented by continuous electrocardiographic monitoring. RESULTS: In total, 54 patients completed the 24 month follow-up. All 6 items on the AF6, AF6 sum score, and EHRA class improved significantly over time. The greatest improvement was seen during the first 6 months after ablation, but AF6 scores showed continued improvement up to 12 months, in contrast to EHRA class. There was a low correlation between AF6 score and EHRA class, but the predictive ability was low. Both AF6 scores and EHRA class were significantly correlated with AF burden at all times after ablation. A change of >9 points in AF6 sum score corresponded to a meaningful reduction in symptom severity. CONCLUSION: Patient-reported and physician-assessed outcomes were both useful in assessing symptom relief after AF ablation, although patient reported outcomes were more sensitive tools. There was also a discrepancy between patient-reported and physician-assessed outcomes after ablation. Freedom from AF and a low AF burden most often resulted in a reduction of symptoms, but symptom relief also occurred despite little effect on the arrhythmia. PMID- 29759502 TI - Symptoms and Quality of Life After Atrial Fibrillation Ablation: Two Different Concepts. PMID- 29759500 TI - Antibacterial Envelope Is Associated With Low Infection Rates After Implantable Cardioverter-Defibrillator and Cardiac Resynchronization Therapy Device Replacement: Results of the Citadel and Centurion Studies. AB - OBJECTIVES: This study sought to determine whether the nonabsorbable TYRX Antibacterial Envelope (TYRX) reduces major cardiovascular implantable electronic device (CIED) infections 12 months after implant. BACKGROUND: TYRX is a monofilament polypropylene mesh impregnated with minocycline and rifampin specifically designed to hold a CIED in place and elute antimicrobials over time. There are limited data on its ability to reduce CIED infections. METHODS: We prospectively enrolled patients who underwent generator replacement with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy device (CRT), treated with TYRX. The primary endpoints were major CIED infection and CIED mechanical complications. Given the differences in infection rates among ICD and CRT patients, 3 different control populations were used: a published benchmark rate for ICD patients, and both site-matched and comorbidity-matched controls groups for CRT patients. RESULTS: Overall, a major CIED infection occurred in 5 of 1,129 patients treated with TYRX (0.4%; 95% confidence interval: 0.0% to 0.9%), significantly lower than the 12-month benchmark rate of 2.2% (p = 0.0023). Among the TYRX-treated CRT cohort, the major CIED infection rate was 0.7% compared with an infection rate of 1.0% and 1.3% (p = 0.38 and p = 0.02) in site-matched and comorbidity-matched control groups, respectively. Among the ICD group, the 12-month infection rate was 0.2% compared with the published benchmark of 2.2% (p = 0.0052). The most common CIED mechanical complication in study patients was pocket hematoma, which occurred in 18 of the 1,129 patients (1.6%; 95% confidence interval: 0.8 to 2.5), which is comparable with a published rate of 1.6%. CONCLUSIONS: Use of TYRX was associated with a lower major CIED infection rate. (TYRXTM Envelope for Prevention of Infection Following Replacement With a CRT or ICD; [Centurion]; NCT01043861/NCT01043705). PMID- 29759503 TI - Benefit of Implantable Cardioverter-Defibrillator Generator Replacement in a Primary Prevention Population-Based Cohort. AB - OBJECTIVES: This study investigated the benefit of an implantable cardioverter defibrillator (ICD) generator replacement in patients who did not have an ongoing theoretical indication for ICD therapy at time of replacement. BACKGROUND: Primary prevention ICD therapy is known to reduce mortality in patients with cardiomyopathy and reduced left ventricular systolic function. The data describing outcomes after generator replacement are limited. METHODS: This was a retrospective cohort study following patients implanted with primary prevention ICD therapy from 2002 until 2015 who subsequently received a generator replacement. Patients with an ongoing theoretical indication for ICD therapy were defined as either left ventricular ejection fraction <=35% or having had prior appropriate ICD therapy. Outcomes were mortality, appropriate ICD therapy and shock, inappropriate shock, and device and lead complications. RESULTS: A total of 614 patients were identified; 173 (28.2%) underwent a generator replacement and were followed for a mean of 2.9 years after replacement; 144 (83.2%) had an ongoing theoretical indication. Patients with no ongoing theoretical indication (n = 29, 16.7%) had lower mortality (hazard ratio [HR]: 0.39, 95% confidence interval [CI]: 0.15-1.00; p = 0.0495), appropriate shock rate (HR: 0.29, 95% CI: 0.09 to 0.96; p = 0.04), and appropriate ICD therapy rate (HR: 0.30, 95% CI: 0.12 to 0.77; p = 0.012) when compared with patients with ongoing theoretical indication. In the entire cohort, there were low rates of inappropriate shock (4.0%), device complication (5.1%), and lead complication (2.3%). CONCLUSIONS: In patients with primary prevention ICD therapy who underwent generator replacement, improved left ventricular ejection fraction and lack of prior appropriate ICD therapy at time of replacement were associated with a lower risk of mortality and incident ventricular arrhythmia. PMID- 29759504 TI - Generator Replacement in Primary Prevention ICD Patients: Is it Time to Develop Guideline Recommendations? PMID- 29759505 TI - Right Ventricular Subepicardial Hematoma Following Ventricular Tachycardia Ablation. PMID- 29759506 TI - Occlusion of the Left Hepatic Vein Facilitates Difficult Cavotricuspid Isthmus Ablation. PMID- 29759507 TI - Left Diaphragmatic Hemiparesis: An Unexpected Complication of Transvenous Lead Extraction. PMID- 29759509 TI - The coronary calcium paradox: Yet another step towards the differentiation between stable and rupture-prone coronary plaques? PMID- 29759508 TI - Estimating Cancer Risk Associated With Ionizing Radiation Exposure During Atrial Fibrillation Ablation. PMID- 29759511 TI - Stents in saphenous vein grafts. PMID- 29759510 TI - Predicting morbidity after robotic partial nephrectomy: The effect of tumor, environment, and patient-related factors. AB - PURPOSE: To investigate the effect of tumor and nontumor related parameters on perioperative outcomes of robotic partial nephrectomy (RPN). PATIENTS AND METHODS: Patients who underwent RPN for a localized renal tumor at 2 institutions between June 2010 and November 2016 were reviewed. RENAL and Mayo adhesive probability (MAP) scores were calculated and information on comorbid conditions including ASA score, performance status, Charlson's comorbidity index (CCI), and history of cardiovascular disease was collected. Correlations between each variable and warm ischemia time, estimated blood loss (EBL), operative time, change in estimated glomerular filtration rate, and length of hospital stay were assessed. Logistic regression analyses were performed to identify the best predictors of overall complications, major complications, risk of conversion, and Trifecta achievement. RESULTS: A total of 500 patients were included. RENAL score was found to have a statistically significant (P<0.05) correlation with warm ischemia time, EBL, and change in estimated glomerular filtration rate. MAP score showed significant association (P<0.05) with operative time and EBL. CCI had a significant correlation (P<0.05) with length of hospital stay and postoperative complications. In multivariable analyses, MAP score as a continuous variable (OR = 7.66; P<0.001) and MAP risk group stratification (OR = 3.29; P = 0.005) were independent predictors of the risk of conversion. Major complications were significantly associated with the cardiovascular disease in both univariable (OR = 2.35; P = 0.01) and multivariable analysis (OR = 4.52, P = 0.01). Finally, the MAP score as a continuous variable was an independent factor of Trifecta achievement (OR = 0.56; P = 0.04). CONCLUSION: Patients related factors were the most important determinants of postoperative complications after RPN. RENAL and MAP scores had some influence on intraoperative parameters. PMID- 29759513 TI - The Current State and Future Potential of Pediatric and Congenital Electrophysiology. AB - Pediatric electrophysiologists specialize in the diagnosis and treatment of rhythm abnormalities in pediatric, congenital heart disease, and inherited arrhythmia syndrome patients. The field originated out of the unique knowledge base that rhythm management in young patients required. In the 1970s, pediatric electrophysiology was recognized as a distinct cardiac subspecialty and it has evolved rapidly since that time. Despite the considerable growth in personnel, technology, and complexity that the field has undergone, further opportunities to progress pediatric electrophysiology exist. In this review, we highlight some of the clinical focus of pediatric and adult congenital electrophysiologists to date and identify areas within this specialty where the pediatric and congenital electrophysiology community could come together in order to drive improvements in rhythm management for patients. PMID- 29759515 TI - CARTOFINDER: Can it "Find" Rotors in Atrial Fibrillation? PMID- 29759514 TI - Identification of Repetitive Activation Patterns Using Novel Computational Analysis of Multielectrode Recordings During Atrial Fibrillation and Flutter in Humans. AB - OBJECTIVES: The purpose of this study was to assess computational analysis of 64 electrode basket catheter (BC) recordings of atrial fibrillation (AF) and atrial flutter using novel software, CARTOFINDER (CF). BACKGROUND: Repetitive patterns have been recorded during AF and reported to be an important mechanism of AF. CF was used to identify rotational repetitive activation patterns (RAPs) in the right (RA) and left atrium (LA). METHODS: To assess for presence of RAPs, multiple 1-min BC maps of the RA and LA were obtained before and after radiofrequency ablation (RFA) around the pulmonary veins in 14 patients undergoing AF ablation. Validation of the CF algorithm was based on analysis of BC recordings of the cavotricuspid isthmus flutter. RESULTS: There were 2.9 rotational RAPs per patient (1.3 RA; 1.6 LA). No RAPs were noted in 2 patients. RFA was delivered on top of (n = 10), within 5 mm (n = 5), or distant (n = 10) from any RAP. Reproducibility of the BC to identify the same RAP was 82%. Post pulmonary vein (PV) isolation, there was a 45% reduction in RAP versus pre-RFA. CF was validated by 4 electrophysiologists blindly reviewing 32 RA CF maps. Electrophysiologists correctly categorized presence/absence of RAP in 122 of 128 maps (95%). CONCLUSIONS: CF is novel software incorporated into CARTO that identifies rotational RAP in the RA and LA with 82% reproducibility. PV RFA results in 45% reduction of RAP, suggesting that RFA beyond PV isolation is required to eliminate the bulk of RAP. Electrophysiologists who were first-time users of CF could readily identify RAPs. PMID- 29759516 TI - High-Resolution Mapping of Ventricular Scar: Evaluation of a Novel Integrated Multielectrode Mapping and Ablation Catheter. AB - OBJECTIVES: This study sought to evaluate an investigational catheter that incorporates 3 microelectrodes embedded along the circumference of a standard 3.5 mm open-irrigated catheter. BACKGROUND: Mapping resolution is influenced by both electrode size and interelectrode spacing. Multielectrode mapping catheters enhance mapping resolution within scar compared with standard ablation catheters; however, this requires the use of 2 separate catheters for mapping and ablation. METHODS: Six swine with healed infarction and 2 healthy controls underwent mapping of the left ventricle using a THERMOCOOL SMARTTOUCH SF catheter with 3 additional microelectrodes (0.167 mm2) along its circumference (Qdot, Biosense Webster, Diamond Bar, California). Mapping resolution in healthy and scarred tissue was compared between the standard electrodes and microelectrodes using electrogram characteristics, cardiac magnetic resonance, and histology. RESULTS: In healthy myocardium, bipolar voltage amplitude was similar between the standard electrodes and microelectrodes, with a fifth percentile of 1.19 and 1.30 mV, respectively. In healed infarction, the area of low bipolar voltage (defined as <1.5 mV) was smaller with microelectrodes (16.8 cm2 vs. 25.3 cm2; p = 0.033). Specifically, the microelectrodes detected zones of increased bipolar voltage amplitude, with normal electrogram characteristics occurring at the end of or after the QRS, consistent with channels of preserved subendocardium. Identification of surviving subendocardium by the microelectrodes was consistent with cardiac magnetic resonance and histology. The microelectrodes also improved distinction between near-field and far-field electrograms, with more precise identification of scar border zones. CONCLUSIONS: This novel catheter combines high-resolution mapping and radiofrequency ablation with an open-irrigated, tissue contact-sensing technology. It improves scar mapping resolution while limiting the need for and cost associated with the use of a separate mapping catheter. PMID- 29759517 TI - In Vivo Validation of Electrocardiographic Imaging. AB - OBJECTIVES: The purpose of this study was to evaluate the accuracy of noninvasive reconstructions of epicardial potentials, electrograms, activation and recovery isochrones, and beat origins by simultaneously performing electrocardiographic imaging (ECGI) and invasive epicardial electrography in intact animals. BACKGROUND: Noninvasive imaging of electrical potentials at the epicardium, known as ECGI, is increasingly applied in patients to assess normal and abnormal cardiac electrical activity. METHODS: Body-surface potentials and epicardial potentials were recorded in normal anesthetized dogs. Computed tomography scanning provided a torso-heart geometry that was used to reconstruct epicardial potentials from body-surface potentials. RESULTS: Electrogram reconstructions attained a moderate accuracy compared with epicardial recordings (median correlation coefficient: 0.71), but with considerable variation (interquartile range: 0.36 to 0.86). This variation could be explained by a spatial mismatch (overall resolution was <20 mm) that was most apparent in regions with electrographic transition. More accurate derivation of activation times (Pearson R: 0.82), recovery times (R: 0.73), and the origin of paced beats (median error: 10 mm; interquartile range: 7 to 17 mm) was achieved by a spatiotemporal approach that incorporates the characteristics of the respective electrogram and neighboring electrograms. Reconstruction of beats from repeated single-site pacing showed a stable localization of origin. Cardiac motion, currently ignored in ECGI, correlates negatively with reconstruction accuracy. CONCLUSIONS: ECGI shows a decent median accuracy, but variability in electrogram reconstruction can be sizable. At present, therefore, clinical interpretations of ECGI should not be made on the basis of single electrograms only. Incorporating local spatiotemporal characteristics allows for accurate reconstruction of epicardial activation and recovery patterns, and beat origin localization to a 10-mm precision. Even more reliable interpretations are expected when the influences of cardiac motion are accounted for in ECGI. PMID- 29759518 TI - Benefit of the Wearable Cardioverter-Defibrillator in Protecting Patients After Implantable-Cardioverter Defibrillator Explant: Results From the National Registry. AB - OBJECTIVES: This study reports on the time course of reimplantation and benefits of the wearable cardioverter-defibrillator (WCD) in patients post implantable cardioverter-defibrillator (ICD) explantation. BACKGROUND: The WCD is used to treat patients at high risk for ventricular tachycardia (VT) and ventricular fibrillation (VF), including patients with ICD-related infections who undergo device removal and cannot be immediately reimplanted. METHODS: This retrospective study included consecutive patients from 2002 to 2014 who underwent ICD removal because of device-related infection and were prescribed a WCD. WCD-stored electrocardiograms were reviewed. Event outcome was assessed through either the manufacturer WCD registry or the Social Security death index search. RESULTS: A total of 8,058 patients (mean age 62 +/- 14 years, 75% male) were included in the analysis. Median time to reimplantation of an ICD was 50 days (interquartile range: 24 to 83 days). While wearing the WCD, 334 patients (4%) experienced 406 VT/VF events, of which 348 events were treated. Shocks were averted in 54 events by conscious patients. The overall 24-h survival, both treated and nontreated, was 93% (312 of 334). VT/VF occurrence was the highest in the initial weeks after ICD removal (0.9%, 0.7%, and 0.7% per week for weeks 1, 2, and 3, respectively). The 12-month cumulative event rate was 10%. For all patients, the 30-day post event survival was 81%. An ICD was reimplanted in 80% of patients. CONCLUSIONS: The risk of VT/VF reaches 4% during the first 2 months and 10% at 1 year after ICD removal. WCD demonstrated a high efficacy for protecting patients from VT/VF. Clinicians may use the WCD as an ICD alternative when reimplantation is medically delayed. PMID- 29759519 TI - Mitigating Post-Extraction Risk: Is it Worth the inVESTment? PMID- 29759512 TI - Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double blind, randomised trial. AB - BACKGROUND: Few studies have examined the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure compared with bare-metal stents (BMS) in patients undergoing stenting of de-novo SVG lesions. We assessed the risks and benefits of the use of DES versus BMS in de novo SVG lesions. METHODS: Patients were recruited to our double-blind, randomised controlled trial from 25 US Department of Veterans Affairs centres. Eligible participants were aged at least 18 years and had at least one significant de-novo SVG lesion (50-99% stenosis of a 2.25-4.5 mm diameter SVG) requiring percutaneous coronary intervention with intent to use embolic protection devices. Enrolled patients were randomly assigned, in a 1:1 ratio, by phone randomisation system to receive a DES or BMS. Randomisation was stratified by presence or absence of diabetes and number of target SVG lesions requiring percutaneous coronary intervention (one or two or more) within each participating site by use of an adaptive scheme intended to balance the two stent type groups on marginal totals for the stratification factors. Patients, referring physicians, study coordinators, and outcome assessors were masked to group allocation. The primary endpoint was the 12-month incidence of target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. The DIVA trial is registered with ClinicalTrials.gov, number NCT01121224. FINDINGS: Between Jan 1, 2012, and Dec 31, 2015, 599 patients were randomly assigned to the stent groups, and the data for 597 patients were used. The patients' mean age was 68.6 (SD 7.6) years, and 595 (>99%) patients were men. The two stent groups were similar for most baseline characteristics. At 12 months, the incidence of target vessel failure was 17% (51 of 292) in the DES group versus 19% (58 of 305) in the BMS group (adjusted hazard ratio 0.92, 95% CI 0.63-1.34, p=0.70). Between-group differences in the components of the primary endpoint, serious adverse events, or stent thrombosis were not significant. Enrolment was stopped before the revised target sample size of 762 patients was reached. INTERPRETATION: In patients undergoing stenting of de-novo SVG lesions, no significant differences in outcomes between those receiving DES and BMS during 12 months of follow-up were found. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower-cost BMS can be used in SVG lesions without compromising either safety or efficacy. FUNDING: US Department of Veterans Affairs Cooperative Studies Program. PMID- 29759520 TI - Ablation of Inappropriate Sinus Tachycardia: A Systematic Review of the Literature. AB - OBJECTIVES: The goal of this study was to describe short- and long-term outcomes in all patients referred for inappropriate sinus tachycardia ablation, along with the potential complications of the intervention. BACKGROUND: Sinus node (SN) ablation/modification has been proposed for patients refractory to pharmacological therapy. However, available data derive from limited series. METHODS: The electronic databases MEDLINE, Embase, CINAHL, Cochrane, and Scopus were systematically searched (January 1, 1995-December 31, 2015). Studies were screened according to predefined inclusion and exclusion criteria. RESULTS: A total of 153 patients were included. Their mean age was 35.18 +/- 10.02 years, and 139 (90.8%) were female. All patients had failed to respond to maximum tolerated doses of pharmacological therapy (3.5 +/- 2.4 drugs). Mean baseline heart rates averaged 101.3 +/- 16.4 beats/min according to electrocardiography and 104.5 +/- 13.5 beats/min according to 24-h Holter monitoring. Two electrophysiological strategies were used, SN ablation and SN modification, with the latter being used more. Procedural acute success (using variably defined pre determined endpoints) was 88.9%. Consistently, all groups reported high-output pacing from the ablation catheter to confirm absence of phrenic nerve stimulation before radiofrequency delivery. Need of pericardial access varied between 0% and 76.9%. Thirteen patients (8.5%) experienced severe procedural complications, and 15 patients (9.8%) required implantation of a pacemaker. At a mean follow-up interval of 28.1 +/- 12.6 months, 86.4% of patients demonstrated successful outcomes. The symptomatic recurrence rate was 19.6%, and 29.8% of patients continued to receive antiarrhythmic drug therapy after procedural intervention. CONCLUSIONS: Inappropriate sinus tachycardia ablation/modification achieves acute success in the vast majority of patients. Complications are fairly common and diverse. However, symptomatic relief decreases substantially over longer follow up periods, with a corresponding high recurrence rate. PMID- 29759521 TI - Utility of Pre-Induction Ventriculoatrial Response to Adenosine in the Diagnosis of Orthodromic Reciprocating Tachycardia. AB - OBJECTIVES: This study sought to evaluate the utility of ventriculoatrial (VA) conduction patterns in response to adenosine in predicting inducibility of orthodromic reciprocating tachycardia (ORT). BACKGROUND: Adenosine is known to consistently block atrioventricular (AV) nodal conduction. We hypothesized that persistent VA conduction despite administration of adenosine would have a high predictive value for identifying the presence of a retrograde accessory pathway (AP) and associated ORT. METHODS: A total of 168 patients undergoing electrophysiological study for supraventricular tachycardia (SVT) had assessment of VA conduction during ventricular pacing and adenosine administration. Standard pacing maneuvers were then used for induction and diagnosis of the SVT mechanism. RESULTS: Absence of VA block to adenosine (doses up to 24 mg) had 88% sensitivity and 91% specificity for identifying ORT (positive predictive value 76%, negative predictive value 96%). Four patients with adenosine-induced VA block and inducible ORT had decremental APs. Adenosine caused VA block in 6 patients with eccentric VA activation due to atypical AV nodal conduction, and concentric VA conduction persisted in all 12 patients with a septal AP. Adenosine unmasked free wall APs in 10 patients by blocking AV nodal conduction, shifting VA activation from concentric to eccentric. CONCLUSIONS: The response of VA conduction to adenosine is a highly sensitive and specific method for detecting retrograde AP conduction and inducible ORT. Adenosine-induced VA block rules out inducible ORT due to a nondecremental AP. In cases of VA fusion, adenosine-induced block of AV nodal conduction can delineate the location of the AP atrial insertion site. PMID- 29759523 TI - Discovery of a Gene Responsible for Sudden Cardiac Death. PMID- 29759524 TI - ICD Utilization: Can We Select the Right Patients? PMID- 29759522 TI - Bundle Branch Re-Entrant Ventricular Tachycardia: Novel Genetic Mechanisms in a Life-Threatening Arrhythmia. AB - OBJECTIVES: This study sought to investigate for an underlying genetic etiology in cases of apparent idiopathic bundle branch re-entrant ventricular tachycardia (BBRVT). BACKGROUND: BBRVT is a life-threatening arrhythmia occurring secondary to macro-re-entry within the His-Purkinje system. Although classically associated with dilated cardiomyopathy, BBRVT may also occur in the setting of isolated, unexplained conduction system disease. METHODS: Cases of BBRVT with normal biventricular size and function were recruited from 6 North American centers. Enrollment required a clinically documented wide complex tachycardia and BBRVT proven during invasive electrophysiology study. Study participants were screened for mutations within genes associated with cardiac conduction system disease. Pathogenicity of identified mutations was evaluated using in silico phylogenetic and physicochemical analyses and in vitro biophysical studies. RESULTS: Among 6 cases of idiopathic BBRVT, each presented with hemodynamic compromise and 2 suffered cardiac arrests requiring resuscitation. Putative culprit mutations were identified in 3 of 6 cases, including 2 in SCN5A (Ala1905Gly [novel] and c.4719C>T [splice site mutation]) and 1 in LMNA (Leu327Val [novel]). Biophysical analysis of mutant Ala1905Gly Nav1.5 channels in tsA201 cells revealed significantly reduced peak current density and positive shifts in the voltage dependence of activation, consistent with a loss-of-function. The SCN5A c.4719C>T splice site mutation has previously been reported as disease-causing in 3 cases of Brugada syndrome, whereas the novel LMNA Leu327Val mutation was associated with a classic laminopathy phenotype. Following catheter ablation, BBRVT was noninducible in all cases and none experienced a clinical recurrence during follow-up. CONCLUSIONS: Our investigation into apparent idiopathic BBRVT has identified the first genetic culprits for this life-threatening arrhythmia, providing further insight into its underlying pathophysiology and emphasizing a potential role for genetic testing in this condition. Our findings also highlight BBRVT as a novel genetic etiology of unexplained sudden cardiac death that can be cured with catheter ablation. PMID- 29759525 TI - Factors Associated With Cardiac Electrophysiologist Assessment and Catheter Ablation Procedures in Patients With Atrial Fibrillation. AB - OBJECTIVES: This study sought to determine factors associated with cardiac electrophysiologist assessment and atrial fibrillation (AF) ablation in patients with new-onset AF. BACKGROUND: Factors driving variation in the use of AF ablation have not been well described. METHODS: All individuals with new-onset AF in Ontario, Canada, between January 1, 2010, and December 31, 2012, were identified. Survival analysis accounting for the competing risk of death was used to evaluate the association between clinical and nonclinical factors and receipt of an electrophysiologist assessment. Factors associated with AF ablation were then determined in the subgroup of patients who received an electrophysiologist assessment. RESULTS: A total of 22,032 patients with new-onset AF were identified, 8,161 (37%) of whom received an electrophysiology assessment. Prior cardiologist care was associated with electrophysiologist assessment (hazard ratio [HR]: 1.57; p < 0.0001). Rural residence was associated with a decreased incidence of electrophysiology assessment (HR: 0.80; p < 0.0001). A total of 424 (5.2%) patients receiving an electrophysiologist assessment had an AF ablation. Recurrent AF emergency department (ED) visits between the index ED visit and the initial electrophysiologist assessment (HR for >=2 ED visits: 4.22; p < 0.0001) and rural residence (HR: 1.50; p = 0.002) were both associated with AF ablation. Cardiovascular comorbidities were associated with a decreased incidence of AF ablation. CONCLUSIONS: Rural patients with AF have a lower incidence of electrophysiologist assessment but paradoxically a higher incidence of AF ablation compared with their urban counterparts. Clinical factors such as recurrent ED visits for AF and cardiovascular comorbidities are the most important factors associated with of AF ablation. PMID- 29759526 TI - External Cardioversion of Supraventricular Tachycardia in Omphalo-Thoracopagus Conjoined Twins. PMID- 29759527 TI - Idiopathic Ventricular Fibrillation Ablation Facilitated by PENTARAY Mapping of the Moderator Band. PMID- 29759528 TI - Artificial Intelligence and the Practice of Radiology: An Alternative View. PMID- 29759529 TI - Tailoring Radiology Resident Education Using Aggregated Missed-Cases Data. PMID- 29759530 TI - Emerging glycobiology tools: A renaissance in accessibility. AB - The glycobiology of the immune response is a topic that has garnered increased attention due to a number of key discoveries surrounding IgG function, the specificity of some broadly neutralizing anti-HIV antibodies, cancer immunoregulation by galectin molecules and others. This review is the opening article in a Special Edition of Cellular Immunology focused on glycoimmunology, and has the goal of setting the context for these articles by providing a mini review of how glycans impact immunity. We also focus on some of the technological and methodological advances in the field of glycobiology that are being deployed to lower the barrier of entry into the glycosciences, and to more fully interrogate the glycome and its function. PMID- 29759531 TI - Biphasic anaphylaxis: A review of the literature and implications for emergency management. AB - BACKGROUND: The biphasic reaction is a feared complication of anaphylaxis management in the emergency department (ED). The traditional recommended ED observation time is 4-6 h after complete resolution of symptoms for every anaphylaxis patient. However, there has been great controversy regarding whether this standard of care is evidence-based. METHODS: Articles were selected using a PubMed, MEDLINE search for the keywords "biphasic anaphylaxis", yielding 155 articles. Articles were filtered by English language, and the keyword biphasic in the title. Case reports and case series were excluded, narrowing to 33 articles. Then, articles were filtered by relevance to the ED setting, and studies conducted in outpatient clinic settings were excluded, narrowing the search to 16 articles. All remaining articles were reviewed and findings were discussed. RESULTS: The reported mean time to onset between the resolution of initial anaphylaxis and biphasic reaction ranges widely by study from 1 to 72 h with the majority of studies reporting the mean time to onset >8 h. A delay between anaphylaxis symptom onset and administration of epinephrine of 60-190 min was reported to correlate with biphasic anaphylaxis in three studies. Anaphylaxis requiring >1 dose of epinephrine to achieve symptom resolution was also reported to correlate with biphasic reactions in two studies. No definitive conclusions about the role of corticosteroids in preventing biphasic reactions can be made at this time however; a couple small studies have shown that they may decrease the incidence of biphasic reactions. Additional risk factors correlated with biphasic reaction vary widely between studies and the generalizability of these risk factors is questionable. CONCLUSIONS: There is a need for further research to identify true risk factors associated with biphasic anaphylaxis and to clearly define the role of corticosteroids in biphasic reactions. However, given the low incidence and rare mortality of biphasic reactions, patients who receive epinephrine within one hour of symptom onset and who respond to epinephrine with rapid and complete symptom resolution can probably be discharged from the ED with careful return precautions and education without the need for prolonged observation. PMID- 29759532 TI - Therapeutic Approaches to Atrial Fibrillation Ablation Targeting Atrial Fibrosis. AB - Atrial fibrosis is the fundamental histopathologic finding in atrial fibrillation (AF) patients and an important predictor of ablation failure beyond pulmonary vein isolation. There is wide variation in the extent and localization of left atrial fibrosis in patients with paroxysmal and nonparoxysmal AF. Box isolation of fibrotic areas is an effective rhythm control concept in patients with paroxysmal AF despite durable pulmonary vein isolation, and this strategy has recently been implemented successfully in initial AF ablation procedures in addition to pulmonary vein isolation for patients with nonparoxysmal AF. In contrast, the time for "empirical" lines or other nonindividualized substrate modifications seems over. PMID- 29759533 TI - 12-Lead Electrocardiogram to Localize Region of Abnormal Electroanatomic Substrate in Arrhythmogenic Right Ventricular Cardiomyopathy. AB - OBJECTIVES: The purpose of this study was to evaluate the relationship between electrocardiogram (ECG) QRS fragmentation (fQRS) and right ventricular (RV) endocardial (ENDO) and epicardial (EPI) electroanatomic substrate abnormalities in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: fQRS is frequently observed in patients with ARVC and reflects delayed conduction due to RV fibrosis. METHODS: A total of 30 consecutive patients met the task force criteria for ARVC (19 men, mean age 41.1 +/- 14.3 years) presenting for ventricular tachycardia ablation with detailed RV ENDO and EPI electroanatomic maps were included. Of these, 25 patients had depolarization abnormalities (fragmentation during and/or immediately after the QRS complex [fQRS]) in >=2 contiguous ECG leads. Inferior (II, III, aVF) fQRS was identified in 23 patients, anterior (V1 to V3) in 15 patients, and basal superior (I/aVR) in 11 patients. The surface area and anatomic distribution of ENDO and EPI bipolar low-voltage regions (ENDO <=1.5 mV, <0.5 mV "dense scar"/EPI <=1.0 mV) and degree of isolated late potential activity consistent with a marked substrate abnormality were compared to the location of region-specific fQRS. RESULTS: In fQRS patients, ENDO very low bipolar voltage area (27.4 +/- 24.9 cm2 [median 19 cm2] vs. 5.8 +/- 5.4 cm2 [median 5 cm2]; p = 0.02) and EPI late potential percentage (22.6 +/- 9.6% [median 24%] vs. 6.8 +/- 3.9% [median 8%]; p = 0.002) were significantly larger than in patients without fQRS. Overall, ENDO and EPI bipolar low voltage area and late potential density increased as the number of fQRS ECG regions (0 to 3) increased. Inferior fQRS most frequently identified EPI inferior substrate (82% sensitivity, 100% specificity), anterior fQRS identified RV EPI mid-free wall substrate (55% sensitivity, 100% specificity), and basal superior fQRS identified ENDO (45.8% sensitivity, 100% specificity) and EPI (52% sensitivity, 100% specificity) RV outflow tract substrate abnormalities. CONCLUSIONS: The extent and distribution of RV voltage substrate abnormalities can be predicted by region-specific ECG depolarization changes in patients with ARVC and ventricular tachycardia. PMID- 29759534 TI - Still an Important Tool: The Role of the 12-Lead ECG to Localize Abnormal Electroanatomic Substrate in Arrhythmogenic Right Ventricular Cardiomyopathy. PMID- 29759535 TI - Utility of Conventional Electrocardiographic Criteria in Patients With Idiopathic Ventricular Tachycardia. AB - OBJECTIVES: This study sought to determine the ability of conventional electrocardiographic (ECG) criteria to correctly differentiate idiopathic ventricular tachycardia (VT) from supraventricular tachycardia (SVT) with aberrancy. BACKGROUND: Previously reported VT ECG criteria were developed from cohorts of patients with structural heart disease and have not been applied to patients with idiopathic VT. METHODS: ECGs of 115 idiopathic VTs, 101 post myocardial infarction (MI) VTs, and 111 wide QRS SVTs were analyzed using standard criteria. VT was diagnosed in patients when at least 1 criterion was met, SVT when no criteria were met, and indeterminate when there were conflicting criteria. RESULTS: Standard ECG criteria more frequently diagnosed VT in the post MI group than the idiopathic group (95% vs. 82%, respectively; p < 0.01). Diagnosis in only 12 of the 111 SVT patients (11%) met the criteria for VT. All patients in the idiopathic VT group with right branch bundle block morphology who did not meet VT criteria demonstrated an rsR' pattern in V1 (consistent with SVT). Among idiopathic VT patients, Purkinje-associated VT had the lowest sensitivity for correct VT diagnosis in 13 of 23 patients (57%), septal sites of origin were correctly diagnosed in only 56 of 76 patients (74%), whereas nonseptal sites had a high sensitivity in 35 of 35 patients (100%; p < 0.005). CONCLUSIONS: Conventional ECG criteria have reduced sensitivity to distinguish VT from SVT with aberrancy in patients with idiopathic VT. This is most pronounced in VT originating from septal sites, particularly Purkinje sites and the septal outflow tract regions. Clinicians should be aware that application of conventional ECG criteria in idiopathic VT may underdiagnose VT. PMID- 29759536 TI - Value of a Posterior Electrocardiographic Lead for Localization of Ventricular Outflow Tract Arrhythmias: The V4/V8 Ratio. AB - OBJECTIVES: This study sought to prospectively evaluate the value of a dedicated electrocardiographic posterior lead to create an anteroposterior ratio to localize premature ventricular complexes (PVCs) between the right ventricular outflow tract and left ventricular outflow tract for catheter ablation. BACKGROUND: The anteroposterior relationship between the right and left outflow tract has not been explored for electrocardiographic localization of ventricular arrhythmia. METHODS: Standard V5 and V6 leads were placed posteriorly and ablation was performed with activation mapping. The site of successful ablation was correlated with the ratio of the R-wave in V4 to the R-wave in V8. Normalization of the V4/V8 ratio to a V4/V8 index was achieved by dividing the V4/V8 ratio by sinus V4/V8. After determination of optimal cutoffs, comparison with V2 transition ratio and V2S/V3R was subsequently performed using receiver operating characteristic curves in a prospective validation cohort. RESULTS: A total of 134 patients underwent ablation of PVCs with 2 modified posterior leads. PVCs successfully ablated from the left side had a statistically significantly higher V4/V8 ratio compared with right-sided PVCs (11.7 +/- 10.6 vs. 2.3 +/- 2.4, p < 0.001). At a cutoff of >3, the V4/V8 ratio had a sensitivity of 88% with a specificity of 77% for left-sided locations. At a cutoff of >2.28, the V4/V8 index had a sensitivity of 67% with a specificity of 98%. In the prospective validation cohort (n = 40), the V4/V8 ratio exhibited the highest sensitivity of 75% with a negative predictive value of 89% compared with the V4/V8 index, V2 transition ratio, and V2S/V3R. The V4/V8 index had the highest specificity of 96% with positive predictive value of 89% compared to the other predictive ratios. When analyzing cases with a V3 transition, the V4/V8 index demonstrated 100% specificity and positive predictive value. CONCLUSIONS: A simple modification of V5 to V8 posteriorly may provide incremental diagnostic value for localizing PVCs arising from the outflow tracts. Normalizing PVC localization criteria to the sinus rhythm results in the highest specificity when compared with other validated criteria. PMID- 29759537 TI - Real-Time Localization of Ventricular Tachycardia Origin From the 12-Lead Electrocardiogram. AB - OBJECTIVES: The aim of this study was to develop rapid computational methods for identifying the site of origin of ventricular activation from the 12-lead electrocardiogram. BACKGROUND: Catheter ablation of ventricular tachycardia in patients with structural heart disease frequently relies on a substrate-based approach, which may use pace mapping guided by body-surface electrocardiography to identify culprit exit sites. METHODS: Patients undergoing ablation of scar related VT (n = 38) had 12-lead electrocardiograms recorded during pacing at left ventricular endocardial sites (n = 1,012) identified on 3-dimensional electroanatomic maps and registered to a generic left ventricular endocardial surface divided into 16 segments and tessellated into 238 triangles; electrocardiographic data were reduced for each lead to 1 variable, consisting of QRS time integral. Two methods for estimating the origin of activation were developed: 1) a discrete method, estimating segment of activation origin using template matching; and 2) a continuous method, using population-based multiple linear regression to estimate triangle of activation origin. A variant of the latter method was derived, using patient-specific multiple linear regression. RESULTS: The optimal QRS time integral included the first 120 ms of the QRS interval. The mean localization error of population-based regressions was 12 +/- 8 mm. Patient-specific regressions can achieve localization accuracy better than 5 mm when at least 10 training-set pacing sites are used; this accuracy further increases with each added pacing site. CONCLUSIONS: Computational intraprocedure methods can automatically identify the segment and site of left ventricular activation using novel algorithms, with accuracy within <10 mm. PMID- 29759538 TI - Computer-Assisted Mapping in Electrophysiology: Are the Machines Taking Over? PMID- 29759539 TI - Do Myofibroblasts Represent a Hidden Factor for Impaired Conduction and Tachyarrhythmia in Post-Myocardial Infarction? PMID- 29759540 TI - Incidence, Predictors, and Outcomes of Early Atrial Arrhythmias After Lung Transplant: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study sought to determine the incidence, predictors, and prognostic implications of early post-lung transplant atrial arrhythmias (AAs). BACKGROUND: Although frequently encountered, the prognostic implications of early AAs after lung transplant remain uncertain. METHODS: A systematic review of MEDLINE and the Cochrane Library was conducted for all studies that reported early post-lung transplant AAs. Random-effects DerSimonian-Laird risk ratios (RRs) were calculated for categorical variables and standardized mean difference (SMD) for continuous variables. RESULTS: A total of 12 studies with 3,203 patients (mean age 57 +/- 3 years; 52% males) were included. The incidence of early post-lung transplant AAs during hospitalization was 26.6% at mean follow-up duration of 6.7 days. Predictors of post-lung transplant AAs included advanced age (SMD: 0.50; 95% confidence interval [CI]: 0.35 to 0.64), male gender (RR: 1.37; 95% CI: 1.28 to 1.47), history of smoking (RR: 1.23; 95% CI: 1.05 to 1.46), hypertension (RR: 1.35; 95% CI: 1.13 to 1.59), hyperlipidemia (RR: 1.39; 95% CI: 1.18 to 1.63), coronary artery disease (RR: 1.40; 95% CI: 1.12 to 1.7), left atrial diameter (SMD: 0.25; 95% CI: 0.07 to 0.44), and restrictive lung disease (RR: 1.34; 95% CI: 1.13 to 1.59). Post-lung transplant AAs were associated with increased all-cause mortality (adjusted RR: 1.63; 95% CI: 1.22 to 2.19) at mean follow-up of 27.8 months and length of hospital stay (36.5 +/- 16.5 days vs. 26.1 +/- 14.3 days; p < 0.001). CONCLUSIONS: Early AAs post-lung transplant are associated with increased mortality and length of hospital stay. Advanced age, male sex, smoking, hypertension, hyperlipidemia, coronary artery disease, increased left atrial diameter, and restrictive lung disease are independent predictors of early AAs in post-lung transplant patients. PMID- 29759542 TI - A New QT Interval Correction Formulae to Adjust for Increases in Heart Rate. AB - OBJECTIVES: This study sought to develop a formula from a large population-based study that best fit the QT-heart rate (HR) relationship independent of the standard mathematical relationships. BACKGROUND: Attempts to adjust or correct for the impact of HR on the QT interval (QTc) have applied various mathematical equations to electrocardiographic (ECG) data rather than allowing the data to determine the form of the relationship. METHODS: A spline correction function was developed using the ECG data from NHANES (National Health and Nutrition Examination Surveys) II and III. The magnitude of linear, quadratic, and cubic trends in the relationship between HR and each QTc was quantified using an F statistic with differences between QTcs compared using a permutation procedure. RESULTS: The effect of HR on QT was obliterated by the spline QT for both men and women. The cross-validated spline QTc was superior (i.e., flatter) to 6 other formulae, including ones proposed previously. In ECGs from the clinic with HRs faster than 70 beats/min, the QTcs from different formulae were significantly (p < 0.0001) different from one another. Individual values suggest the use of the longest and shortest QTc intervals as developed originally. The new QTc and its population percentile ranking can be provided for clinical ECGs. CONCLUSIONS: A new QTc formula was developed which eliminates the relationship between QT and HR. At faster HRs, the 2 most commonly used QTcs provide numerical values at the extremes of QTc. Compared to existing formulae, the new formula had the best performance. PMID- 29759544 TI - Beyond Calming of the Storm: Long-Term Outcomes in Scar-Related Ventricular Tachycardia. PMID- 29759543 TI - Long-Term Outcomes of Catheter Ablation of Electrical Storm in Nonischemic Dilated Cardiomyopathy Compared With Ischemic Cardiomyopathy. AB - OBJECTIVES: The goal of this study was to determine the long-term outcomes of catheter ablation (CA) of electrical storm in patients with nonischemic dilated cardiomyopathy (NIDCM) compared with patients with ischemic cardiomyopathy (ICM). BACKGROUND: CA of ventricular tachycardia (VT) electrical storm has been shown to improve VT-free survival in patients with ICM. Data on the outcomes of CA of electrical storm in patients with NIDCM are insufficient. METHODS: The study included 267 consecutive patients with NIDCM (n = 71; ejection fraction 32 +/- 14%) and ICM (n = 196; ejection fraction 28 +/- 12%). Endo-epicardial CA was performed in 59 (22%) patients. CA was guided by activation and entrainment mapping for tolerated VT and pacemapping/targeting of abnormal substrate for unmappable VT. RESULTS: After a median follow-up of 45 (25th to 75th percentile: 9 to 71) months and 1 (25th to 75th percentile: 1 to 8) procedures, 76 (29%) patients died, 25 (9%) underwent heart transplantation, 87 (33%) experienced VT recurrence, and 13 (5%) had recurrence of electrical storm. Overall VT-free survival was 54% at 60 months (48% in NIDCM and 54% in ICM; p = 0.128). Patients with VT recurrence experienced a median of 2 (1 to 10) VT episodes in the 5 (1 to 14) months after the procedure. Death/transplantation-free survival was 62% at 60 months (53% in NIDCM and 64% in ICM; p = 0.067). Persistent inducibility of any VT with cycle length >=250 ms at programmed stimulation at the end of the procedure was the only independent predictor of VT recurrence. Low ejection fraction, New York Heart Association functional class, and VT recurrence over follow-up independently predicted death/transplantation. CONCLUSIONS: CA of electrical storm was similarly effective in patients with NIDCM compared with patients with ICM, with elimination of electrical storm in 95% of cases and achievement of complete VT control at long-term follow-up in most patients. PMID- 29759545 TI - Sequential Inappropriate Subcutaneous Implantable Cardioverter-Defibrillator Shocks: Pro-Arrhythmia Followed by Failure to Rescue. PMID- 29759541 TI - The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome. AB - OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 +/- 23.8 ms and 313.2 +/- 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of IKr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed IKr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS. PMID- 29759546 TI - Subcutaneous Implantable Cardioverter-Defibrillator and Arrhythmogenic Right Ventricular Cardiomyopathy: The Importance of Repeat ECG Screening During Exercise Test. PMID- 29759547 TI - Extensive Endothelialization or Thrombus Related to New-Generation Left Atrial Appendage Occluders. PMID- 29759548 TI - Differences Between the Effects of ICDs in Patients Awaiting Heart Transplantation With Pulsatile-Flow and Continuous-Flow LVADs. PMID- 29759549 TI - Reply: Differences Between the Effects of ICDs in Patients Awaiting Heart Transplantation With Pulsatile-Flow and Continuous-Flow LVADs. PMID- 29759551 TI - Genomics and pharmacogenomics of pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukaemia (ALL) is a prevalent form of pediatric cancer that accounts for 70-80% of all leukemias. Genome-based analysis, exome sequencing, transcriptomics and proteomics have provided insight into genetic classification of ALL and helped identify novel subtypes of the disease. B and T cell-based ALL are two well-characterized genomic subtypes, significantly marked by bone marrow disorders, along with mutations in trisomy 21 and T53. The other ALLs include Early T-cell precursor ALL, Philadelphia chromosome-like ALL, Down syndrome associated ALL and Relapsed ALL. Chromosomal number forms a basis of classification, such as, hypodiploid ALL, near-haploid, low-hypodiploid, high hypodiploid and hypodiploid-ALL. Advances in therapies targeting ALL have been noteworthy, with significant pre-clinical and clinical studies on drug pharmacokinetics and pharmacodynamics. Methotrexate and 6-mercaptopurine are leading drugs with best demonstrated efficacies against childhood ALL. The drugs in combination, following dose titration, have also been used for maintenance therapy. Methotrexate-polyglutamate is a key metabolite that specifically targets the disease pathogenesis, and 6-thioguanine nucleotides, derived from 6 mercaptopurine, impede replication and transcription processes, inducing cytotoxicity. Additionally, glucocorticoids, asparaginase, anthracycline, vincristine and cytarabine that trans-repress gene expression, deprives cells of asparagine, triggers cell cycle arrest, influences cytochrome-P450 polymorphism and inhibits DNA polymerase, respectively, have been used in chemotherapy in ALL patients. Overall, this review covers the progress in genome technology related to different sub-types of ALL and pharmacokinetics and pharmacodynamics of its medications. It also enlightens adverse effects of current drugs, and emphasizes the necessity of genome-wide association studies for restricting childhood ALL. PMID- 29759550 TI - Sarcoma-The standard-bearer in cancer discovery. AB - Sarcoma is a rare tumor type that occurs most frequently in connective tissue. Despite its uncommon occurrence, sarcoma research has provided the means for groundbreaking research that has advanced our understanding of general cancer mechanisms. It is through sarcoma research that the pioneering efforts of cancer immunotherapy were explored, that we understand the inherent genetic nature of cancer mutations, and that we appreciate the subclassification of general cancer types to make more accurate prognoses. This review explores the brief history of sarcoma research and what sarcomas can still teach us about the future of cancer research, especially in regard to novel immunotherapy targets, the role of epigenetics in disease progression and chemoresistance, and the benefits of more focused clinical trials. PMID- 29759552 TI - The emerging co-regulatory role of long noncoding RNAs in epithelial-mesenchymal transition and the Warburg effect in aggressive tumors. AB - Malignant tumor cells have several unique characteristics, and their ability to undergo epithelial-mesenchymal transition (EMT) is a molecular gateway to invasive behavior. Rapid proliferation and increased invasiveness during EMT enhance aberrant glucose metabolism in tumor cells. Meanwhile, aerobic glycolysis provides energy, biosynthesis precursors, and an appropriate microenvironment to facilitate EMT. Reciprocal crosstalk between the processes synergistically contributes to malignant cancer behaviors, but the regulatory mechanisms underlying this interaction remain unclear. Long non-coding RNAs (lncRNAs) are a recently recognized class of RNAs involved in multiple physiological and pathological tumor activities. Increasing evidence indicates that lncRNAs play overlapping roles in both EMT and cancer metabolism. In this review, we describe the lncRNAs reportedly involved in the two biological processes and explore the detailed mechanisms that could help elucidate this co-regulatory network and provide a theoretical basis for clinical management of EMT-related malignant phenotypes. PMID- 29759553 TI - The role of heme iron molecules derived from red and processed meat in the pathogenesis of colorectal carcinoma. AB - Emerging evidence that heme iron in red meat is a risk factor for colorectal carcinogenesis is a topic that has received recent scrutiny. This review aims to summarise the mechanism of colorectal carcinogenesis by heme contained in red and processed meat. Heme iron can induce cytotoxicity by 'cytotoxic heme factor' and promote surface epithelial cell apoptosis and compensatory epithelial hyperplasia. Heme, induces peroxidation of lipids, leading to free radical formation and generation of DNA adducts in colorectal epithelial cells. In addition, heme catalyses the formation of N-nitroso-compounds, which in turn results in the initiation of colorectal carcinogenesis. Emerging data suggest that intestinal dysbiosis can promote carcinogenic properties of heme. Heme induces multiple genetic alterations by regulating WNT signalling pathway and causing mutations in major colon cancer genes such as APC, TP53 and KRAS. However, a balanced diet containing green vegetables, olive oil and calcium may reduce the carcinogenic effects of heme. PMID- 29759554 TI - The identification and isolation of CTCs: A biological Rubik's cube. AB - Liquid biopsy represents an alternative to conventional biopsies for the evaluation of tumors mainly due to its easy sampling. One of the main applications is the enumeration of Circulating Tumor Cells (CTCs) to evaluate tumor progression or response to treatment. The analysis of the functional characteristics of CTCs could give us much more information about their role in order to establish a more personalized treatment for the patients. The major issue that has to be solved is the isolation of the CTC population. Multiple protocols have been developed, however none of them has demonstrated to be the definitive one. In fact, a combination of these techniques has often been performed in order to obtain a purer and viable population of CTCs. In this review we have summarized for the first time the different combinatorial approaches used in the last years to optimize the isolation of CTCs and their limitations. PMID- 29759555 TI - Prognostic and predictive factors in patients with brain metastases from solid tumors: A review of published nomograms. AB - OBJECTIVE: To review published nomograms that predict endpoints such as overall survival (OS) or risk of intracranial relapse in patients with brain metastases from solid tumors. METHODS: The methods and results of nomogram studies identified by a systematic search were extracted and compared, stratified by endpoint predicted by the respective nomograms. In particular, validation strategies (external/internal), concordance indices (cut-off 0.75) and comparisons to older models were analyzed. RESULTS: Six publications reported on prediction of OS. Most of these analyses focused on one particular primary tumor site, e.g., breast cancer or hepatocellular carcinoma, while the largest study included different primary tumor sites. The median number of patients was 244. Three of six studies included external validation cohorts. With few exceptions, concordance indices <0.75 were reported. In all studies reporting this endpoint, the nomogram outperformed older prognostic scores. Two nomograms focused on development of new brain metastases after radiosurgery (one externally validated), one on survival free from salvage whole brain radiotherapy (WBRT) after radiosurgery, and one on neurologic and non-neurologic death in patients receiving radiosurgery after WBRT failure. All concordance indices of these 4 nomograms were <0.70. CONCLUSION: Taking into account concordance indices and comparisons to older prognostic models, the most promising, externally validated nomograms are the breast cancer and the non-small cell lung cancer nomogram predicting OS, and the distant brain failure after radiosurgery nomogram. Additional validation studies as well as continuous monitoring of the models' performance appear necessary to ensure their clinical applicability in the present era of rapidly changing treatment paradigms. PMID- 29759556 TI - Radiological evaluation of response to immunotherapy in brain tumors: Where are we now and where are we going? PMID- 29759557 TI - Organization, quality and cost of oncological home-hospitalization: A systematic review. AB - BACKGROUND: Home-hospitalization might be a patient-centred approach facing the increasing burden of cancer on societies. This systematic review assessed how oncological home-hospitalization has been organized and to what extent its quality and costs were evaluated. RESULTS: Twenty-four papers describing parenteral cancer drug administration to adult patients in their homes were included. Most papers concluded oncological home-hospitalization had no significant effect on patient-reported quality of life (7/8 = 88%), but large majority of patients were satisfied (12/13, 92%) and preferred home treatment (7/8, 88%). No safety risks were associated with home-hospitalization (10/10, 100%). The cost of home-hospitalization was found beneficial in five trials (5/9, 56%); others reported no financial impact (2/9, 22%) or additional costs (2/9, 22%). CONCLUSION: Despite heterogeneity, majority of reported models for oncological home-hospitalization demonstrated that this is a safe, equivalent and acceptable alternative to ambulatory hospital care. More well-designed trials are needed to evaluate its economic impact. PMID- 29759559 TI - Clinical importance of DNA repair in sporadic colorectal cancer. AB - Colorectal cancer (CRC) is the third major cause of cancer-related deaths worldwide. However, despite the scientific efforts to provide a molecular classification to improve CRC clinical practice management, prognosis and therapeutic decision are still strongly dependent on the TNM staging system. Mismatch repair system deficiencies can occur in many organs, but it is mainly a hallmark of CRC influencing clinical outcomes and response to therapy. This review will discuss the effect of the modulation of other DNA repair pathways (direct, excision and double strand break repairs) in the clinical and pathological aspects of colorectal cancer and its potential as prognostic and predictive biomarkers. PMID- 29759560 TI - Cardiotoxic effects of chemotherapy: A review of both cytotoxic and molecular targeted oncology therapies and their effect on the cardiovascular system. AB - Cardiotoxic effects of chemotherapy and targeted drugs are ubiquitous and challenging in the field of oncology therapeutics. The broad spectrum of toxicities ranging from ischemic, hypertensive, cardiomyopathic, and arrhythmic complications can present as a significant challenge for clinicians treating cancer patients. If early diagnosis and intervention of cardiotoxic complications is missed, this can lead to delay or abrogation of planned treatment, which can potentially culminate to significant morbidity due to not only the cardiotoxic complications but also the progression of cancer. Hence, full knowledge of cardiovascular complications of chemotherapeutic agents, essential diagnostics tests to order, and appropriate management is paramount to oncologist, oncology pharmacists, and scientific clinical investigators. The aforementioned is particularly true in the current oncology era of plenteous early clinical trials studying several pathway/molecular-targeting agents with an increased cardiotoxic potential and the rapid expedited approval of those drugs by the FDA. Herein, we present a review discussing cardiotoxic effects of drugs and guidelines for management of the toxicities to assist the medical field in general managing patients with cancer. PMID- 29759561 TI - Going the distance: Are we losing patients along the multiple myeloma treatment pathway? AB - Despite data suggesting that individuals with multiple myeloma can benefit from receiving several lines of therapy, and guidelines recommending treatment after relapse, a recent European patient chart review found that only 61% of patients receive second-line treatment. The review found that factors such as old age and previous adverse events lead to physicians deciding not to treat after relapse. However, given the large number of regimens available, treatment can be tailored to individual patients' needs and supportive care measures can help with the management of adverse effects. If approved therapies are not suitable for a patient, guidelines recommend registration in a clinical trial, yet only 7% of patients in the review were participating in such studies. A need for better education on the range of treatments available and their risk-benefit profiles is suggested. Access to new drugs should be examined to maximise the number of patients benefitting from them. PMID- 29759558 TI - The influence of genetic variation on late toxicities in childhood cancer survivors: A review. AB - INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration. PMID- 29759562 TI - Investigational agents to enhance the efficacy of chemotherapy or radiation in pancreatic cancer. AB - Pancreatic cancer (PC) continues to be a fatal malignancy. With standard treatments having modest impact, alternative courses of actions are being investigated such as enhancing the efficacy of standard treatment through sensitization of PC cells to chemotherapy or radiation. This review emphasizes investigational agents that increase the responses to chemotherapy or radiation in PC models. Our group has extensively investigated on Curcumin (Cur), analogs (EF31, UBS109, and L49H37), nanoparticles and a small molecule Tolfenamic acid (TA) for enhancing therapeutic efficacy in both in vitro and in vivo assays. Cur has a low level of toxicity and promising anti-cancer activity, however, its clinical development has been limited by low bioavailability. Cur analogs and nanoparticles were synthesized to improve Cur's efficacy and bioavailability. These compounds were found to be effective in enhancing the therapeutic effects of chemotherapy in pre-clinical models. Small molecules such as NSAIDs have also been tested for the anti-cancer activity and induction of response of chemotherapy and radiation. Interest in TA, a NSAID, has recently increased due to promising preclinical data demonstrating its anti-cancer properties with minimum toxicity. TA also synergistically increased the response of XRT in PC cells and in an orthotropic mouse model. With strong preclinical evidence, research aimed at developing less toxic therapies for PC using Cur analogues or TA is ready for translation into clinical testing. PMID- 29759563 TI - Targeting the tumor promoting effects of adenosine in chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a hematological malignancy which is characterized by progressive accumulation of functionally deficient B cells in blood, bone marrow, and lymphatic tissue. The tumor microenvironment (TME) appears to play a critical role in genesis and progression of CLL. High levels of extracellular adenosine (ADO) are detected in CLL as a consequence of expression of ecto-enzymes, such as CD39 and CD73. Extracellular ADO exhibits a broad range of effects on cell cycle control, immunoregulation, angiogenesis and cytokine regulation through both direct and indirect mechanisms. In this review, we focused on the multiple functions and related mechanisms of ADO signaling in CLL generation and progression. PMID- 29759564 TI - Biological aspects of chondrosarcoma: Leaps and hurdles. AB - Chondrosarcomas are characterized by their chemo- and radioresistance leading to a therapeutic surgical approach which remains the only available treatment with a 10-year survival between 30% and 80% depending on the grade. Non-surgical treatments are under investigation and rely on an accurate biological understanding of drug resistance mechanisms. Novel targeted therapy which represents a new relevant therapeutic approach will open new treatment options by targeting several pathways responsible for processes of proliferation and invasion. Survival pathways such as PI3K, AKT, mTOR and VEGF have been shown to be involved in proliferation of chondrosarcoma cells and antiapoptotic proteins may also play a relevant role. Other proteins such as p53 or COX2 have been identified as potential new targets. This review provides an insight into the biological substantial treatment challenges of CHS and focuses on improving our understanding of CH biology through an overview of major signaling pathways that could represent targets for new therapeutic approaches. PMID- 29759565 TI - Glucocorticoids as an adjunct to oncologic treatment in solid malignancies - Not an innocent bystander. AB - Glucocorticoids are steroidal hormones which exert their action via genomic and non-genomic mechanisms. In the clinical setting, glucocorticoids are utilized for their anti-inflammatory, anti-allergenic and immunomodulatory effects and for their well-established, pro-apoptotic effects on hematological malignancies. In the treatment of solid tumors, glucocorticoids serve primarily for alleviation of tumor- and treatment-related symptoms and in most cases are not considered to have a direct effect on tumor growth and spread. However, significant pre clinical data suggest that glucocorticoids have diverse effects on tumor progression, both pro- and anti- tumorigenic. In contrast, the clinical data regarding the pro- and anti-tumorigenic effects of glucocorticoids on solid tumors is scarce, and summarized in this review. The following review presents the suggested glucocorticoids mechanism of action and the effects of glucocorticoids on tumor cells, on the tumor microenvironment and on tumor response to cytotoxic therapy, in the pre-clinical and clinical settings. PMID- 29759566 TI - Role of bevacizumab in uterine leiomyosarcoma. AB - In the recent years, angiogenetic inhibitors have emerged for the treatment of several malignancies. In particular, bevacizumab has proved to be effective in many types of cancers (including sarcoma), but the limitations of antiangiogenic therapy have been shown in practice. Here, we sought to review the current evidence on the role and efficacy of bevacizumab in patients affected by uterine leiomyosarcoma. On April 2017, Literature was searched in order to identify studies reporting outcomes of patients affected either by early stage or advanced/recurred uterine leiomyosarcoma undergoing treatment with bevacizumab, alone or in combination with other chemotherapeutic regimens. Searching the literature data of 69 patients affected by metastatic, unresectable uterine leiomyosarcoma were retrieved; on the contrary, no data regarding the use of bevacizumab in patients with early-stage uterine leiomyosarcoma was published. Current evidence suggested that the addiction of bevacizumab to standard treatment modality does not increase grade 3 or worse toxicity (assessed by CTCAE). Pooled data regarding response rate suggested that 35%, 28%, 26% and 11% of patients experienced objective cure (complete + partial response), stable disease, progressive disease and unknown response, respectively. Data from the only one randomized controlled trial suggested that objective cure rate does not differ from standard chemotherapy treatment, thus limiting the indication to add bevacizumab in patients affected by metastatic, unresectable uterine leiomyosarcoma. The current evidence does not justify the use of bevacizumab into clinical practice. Further randomized studies testing the role of bevacizumab are warranted. PMID- 29759567 TI - EpCAM duality becomes this molecule in a new Dr. Jekyll and Mr. Hyde tale. AB - EpCAM, known as an epithelial cell adhesion molecule, plays an essential role in cell adhesion, migration, metastasis and cell signalling. Rather than acting as an apoptosis antagonist, it induces cellular proliferation that impacts the cell cycle, and as a signalling transducer it uses and enhances the Wnt pathway, which is significantly relevant in cell renewal and cancer. EpCAM has become a marker of circulating tumour cells (CTCs) in lung cancer due to its specificity, and its high and stable expression level. Recent findings have allowed us to relearn and discover EpCAM again as a CSCs marker by demonstrating its role in human epithelial cancer progression. In line with this, the focus of attention on EpCAM has become an appealing therapeutic target, although the literature shows a clear controversy in information about its clinical significance. Despite this contradictory fact, solid evidence has demonstrated its dual role as a molecule with oncogenic and tumour suppressor properties, in which the microenvironment is influential. Therefore, its dual role appears to be both tissue- and tumour- dependent. In this review, we summarised the novel and updated insights in the EpCAM field by simplifying the understanding of the biological role of this fascinating molecule, and by showing the promising therapeutic tools that have been developed by various approaches which use antibodies and vaccines for different cancer types for the clear purpose of improving patient outcome. PMID- 29759568 TI - Positron emission tomography and computed tomographic (PET/CT) imaging for radiation therapy planning in anal cancer: A systematic review and meta-analysis. AB - To improve the accuracy of chemoradiation therapy in anal cancer patients PET/CT is frequently used in the planning of radiation therapy. A systematic review was performed to assess impact on survival, quality of life, symptom score, change in target definition and treatment intention. Systematic literature searches were conducted in Medline, EMBASE, the Cochrane Library, and Centre for Reviews and Dissemination. Ten cross-sectional studies were identified. No data were available on survival or quality of life. The summary estimate of the proportion of patients in which PET/CT had an impact on the target definition, was 23% (95% CI 16;33). The corresponding summary estimate of a change in treatment intent from curative to palliative was 3% (95% CI 2;6). Almost one in four patients had a change in target definition, which supports the use of PET/CT in radiation therapy planning, but the consequence regarding survival and quality of life is still uncertain. PMID- 29759569 TI - Genetic alterations crossing the borders of distinct hematopoetic lineages and solid tumors: Diagnostic challenges in the era of high-throughput sequencing in hemato-oncology. AB - Owing to the introduction of next-generation sequencing (NGS) new challenges for diagnostic algorithms and the interpretation of the results for therapeutic decision making in hemato-oncology have arisen. Recurrent somatic mutations crossing the borders between different hematological entities and solid neoplasms have been detected. In analogy to mutant TP53, the same mutation type may occur in myeloid, B- or T-lymphatic malignancies or solid neoplasms. At the same time, a certain mutation can show different prognostic outcomes in different entities and co-existence of certain mutations may change the prognostic relevance. These insights may spark the investigation of targeted therapies with the same substances across different disease entities. This review article summarizes mutations that can emerge in different hematologic and solid malignancies and summarizes other obstacles in the era of modern molecular diagnostics, such as the phenomenon of "clonal hematopoiesis of indeterminate potential" being difficult to interpret in the individual patient. PMID- 29759570 TI - Re-irradiation as salvage treatment in recurrent glioblastoma: A comprehensive literature review to provide practical answers to frequently asked questions. AB - The primary aim of this review is to provide practical recommendations in terms of fractionation, dose, constraints and selection criteria to be used in the daily clinical routine. Based on the analysis of the literature reviewed, in order to keep the risk of severe side effects <=3,5%, patients should be stratified according to the target volume. Thus, patients should be treated with different fractionation and total EQD2 (<12.5 ml: EQD2 < 65 Gy with radiosurgery; >12.5 ml and <35 ml: EQD2 < 50 Gy with hypofractionated stereotactic radiotherapy; >35 ml and <50 ml: EQD2 < 36 Gy with conventionally fractionated radiotherapy). Concurrent approaches with temozolomide or bevacizumab do not seem to improve the outcomes of reirradiation and may lead to a higher risk of toxicity but these findings need to be confirmed in prospective series. PMID- 29759571 TI - Prediction models for endometrial cancer for the general population or symptomatic women: A systematic review. AB - OBJECTIVE: To provide an overview of prediction models for the risk of developing endometrial cancer in women of the general population or for the presence of endometrial cancer in symptomatic women. METHODS: We systematically searched the Embase and Pubmed database until September 2017 for relevant publications. We included studies describing the development, the external validation, or the updating of a multivariable model for predicting endometrial cancer in the general population or symptomatic women. RESULTS: Out of 2756 references screened, 14 studies were included. We found two prediction models for developing endometrial cancer in the general population (risk models) and one extension. Eight studies described the development of models for symptomatic women (diagnostic models), one comparison of the performance of two diagnostic models and two external validation. Sample size varied from 60 (10 with cancer) to 201,811 (855 with cancer) women. The age of the women was included as a predictor in almost all models. The risk models included epidemiological variables related to the reproductive history of women, hormone use, BMI, and smoking history. The diagnostic models also included clinical predictors, such as endometrial thickness and recurrent bleeding. The concordance statistic (c), assessing the discriminative ability, varied from 0.68 to 0.77 in the risk models and from 0.73 to 0.957 in the diagnostic models. Methodological information was often limited, especially on the handling of missing data, and the selection of predictors. One risk model and four diagnostic models were externally validated. CONCLUSIONS: Only a few models have been developed to predict endometrial cancer in asymptomatic or symptomatic women. The usefulness of most models is unclear considering methodological shortcomings and lack of external validation. Future research should focus on external validation and extension with new predictors or biomarkers, such as genetic and epigenetic markers. PMID- 29759573 TI - Early Arrhythmic Risk Assessment in Idiopathic Cardiomyopathy: A Tincture of Time Can Be the Wrong Medicine. PMID- 29759572 TI - Early Arrhythmic Events in Idiopathic Dilated Cardiomyopathy. AB - OBJECTIVES: The study sought to provide an insight into the prevalence, characterization and possible reliable indicators of early sudden cardiac death/malignant ventricular arrhythmias (SCD/MVAs) in a large cohort of dilated cardiomyopathy (DCM). BACKGROUND: DCM generally affects young individuals and is characterized by an unpredictable prognosis with a non-negligible risk of SCD/MVAs, particularly in early stages of disease. METHODS: From 1988 to 2014, 952 patients with DCM were consecutively included in the Heart Muscle Disease Registry of Trieste. RESULTS: Globally, 20 patients (2.1% of the overall population) experienced SCD/MVAs within the first 6 months after enrollment (primary endpoint). At baseline they showed a worse functional class (New York Heart Association functional class III to IV 42% vs. 22%, p = 0.038), a longer QRS complex duration (127 +/- 41 ms vs. 108 +/- 33 ms; p = 0.013) and a larger indexed left ventricular end-systolic volume (LVESVI) (82 +/- 49 ml/m2 vs. 67 +/- 34 ml/m2; p = 0.049), as compared to patients without early SCD/MVAs. Beta blockers were less tolerated (59% vs. 83% in patients with no early SCD/MVAs; p = 0.008), mostly due to hemodynamic intolerance. At multivariate analysis, LVESVI (odds ratio [OR]: 1.012; 95% confidence interval [CI]: 1.000 to 1.024; p = 0.043) and QRS complex duration (OR: 1.017; 95% CI: 1.003 to 1.030; p = 0.015) were independently associated with the primary endpoint, whereas beta-blockers demonstrated a protective effect (OR: 0.169, CI: 0.048 to 0.593; p = 0.006). CONCLUSIONS: Patients with DCM present a significant risk of major arrhythmic events in the first phase of the disease. Baseline LVESVI, QRS duration, and intolerance to beta-blocker therapy might be useful tools in the arrhythmic early risk assessment. PMID- 29759574 TI - Potentially Lethal Ventricular Arrhythmias and Heart Failure in Arrhythmogenic Right Ventricular Cardiomyopathy: What Are the Differences Between Men and Women? AB - OBJECTIVES: The aim of this study was to assess sex-related differences in sporadic cases of arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Previous studies have suggested male predominance in ARVC. However, the impact of sex on the heterogeneous clinical profile and prognosis of ARVC were not fully recognized. METHODS: The study population included 110 patients with ARVC who fulfilled the revised Task Force criteria (median age 48 years [interquartile range (IQR): 36 to 57 years]). All patients were sporadic cases without family history of ARVC. Male patients had a 3:1 predominance (75%). Ninety-seven patients (88%) were considered to have "definite" ARVC based on revised Task Force criteria. RESULTS: At the initial evaluation, there were no significant sex-related differences in age, 12-lead electrocardiogram findings, late potentials by signal-averaged electrocardiogram, left ventricular ejection fraction, or right ventricular ejection fraction. During a median follow-up of 10.0 years (IQR: 5.2 to 15.6 years), 18 patients died from cardiac causes. Kaplan Meier analysis, considering patients' lives since birth, revealed that male patients had a significantly higher risk of ventricular tachycardia/ventricular fibrillation than did female patients (56% vs. 90%, p = 0.02), whereas female patients had a significantly higher risk of heart failure (HF) death or heart transplantation (22% vs. 5%, p = 0.002). On multivariate Cox regression analysis, female sex was an independent risk factor for HF death or heart transplantation due to HF (hazard ratio: 6.29, 95% confidence interval: 1.29 to 40.2; p = 0.02). CONCLUSIONS: Among patients with sporadic ARVC, men had a significantly higher risk of ventricular tachycardia/ventricular fibrillation, whereas women had a significantly higher risk of HF death or heart transplantation due to HF. PMID- 29759575 TI - Men and Women in Arrhythmogenic Right Ventricular Cardiomyopathy. PMID- 29759576 TI - Time Dependence of Ventricular Tachyarrhythmias After Myocardial Infarction: A MADIT-CRT Substudy. AB - OBJECTIVES: The purpose of this study was to assess the relationship between the time since a myocardial infarction (MI) and the risk of ventricular tachyarrhythmic events (VTEs) in patients with left ventricular dysfunction and mild symptoms of heart failure. BACKGROUND: Patients with left ventricular dysfunction after MI are at high risk for VTEs. METHODS: Ventricular tachycardia (VT), ventricular fibrillation (VF), or death as a function of time since MI was assessed in 693 patients enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy). Patients were categorized as those with a period of <3 years since an MI (lowest quartile, n = 172) versus those with a period of >=3 years since an MI (n = 521). Risk of VT/VF or death was compared. RESULTS: Cumulative probability of VT/VF or death was significantly higher among patients in the highest quartile of time since an MI compared with those in the lowest quartile (41% vs. 22%, p = 0.015). Multivariate analysis showed that in patients with left bundle branch block (LBBB), those with a period of >=3 years since an MI had a significantly higher risk of VT/VF or death (hazard ratio: 2.33; 95% confidence interval: 1.43 to 3.80; p = 0.001) and a higher risk of VT/VF (hazard ratio: 3.18; 95% confidence interval: 1.71 to 5.90; p < 0.001) compared with patients with a period of <3 years since an MI. These findings were consistent when the time since an MI was analyzed in a continuous fashion. A significant relationship between the time since an MI and outcomes was not observed in patients with non-LBBB. CONCLUSIONS: Among post-MI patients with left ventricular dysfunction and LBBB, the risk of VTEs is directly related to the time since an MI occurred. (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271). PMID- 29759577 TI - Chatty Cells: Not Cardiac Regeneration, But Segregation for Rhythm Preservation? PMID- 29759578 TI - The Ventricular Ectopic QRS Interval: A Potential Marker for Ventricular Arrhythmia in Ischemic Heart Disease. AB - OBJECTIVES: The purpose of this study was to determine the potential value of a novel marker for the severity of structural heart disease and the risk of arrhythmia. BACKGROUND: The ventricular ectopic QRS interval (VEQSI) has been shown to identify structural heart disease and predict mortality in an unselected population. In ischemic heart disease (IHD), risk stratification for sudden death is imperfect. We hypothesized that VEQSI would identify patients with prior myocardial infarction (MI) compared with healthy subjects and distinguish IHD patients who have suffered life-threatening events from those without prior significant ventricular arrhythmia. METHODS: The 12-lead Holter recordings from 189 patients with previous MI were analyzed: 38 with prior ventricular tachycardia/ventricular fibrillation (MI-VT/VF) (66 +/- 9 years; 92% male); 151 without prior significant ventricular arrhythmia (MI-no VT/VF) (64 +/- 11 years; 74% male). These were compared with 60 healthy controls (62 +/- 7 years; 70% male). All ventricular ectopic beats were reviewed and maximal VEQSI duration (VESQI max) was recorded as the duration of the longest ventricular ectopic beat. RESULTS: VEQSI max was longer in post-MI patients compared with normal controls (185 +/- 26 ms vs. 164 +/- 16 ms; p < 0.001) and in MI-VT/VF patients with prior life-threatening events compared with MI-no VT/VF patients without prior life threatening events (214 +/- 20 ms vs. 177 +/- 22 ms; p < 0.001). Multivariate analysis established VEQSI max as the strongest independent marker for prior serious ventricular arrhythmia. VEQSI max >198 ms had 86% sensitivity, 85% specificity, 62% positive predictive value, and 96% negative predictive value for identifying patients with prior life-threatening events (odds ratio: 37.4; 95% confidence interval: 13.0 to 107.5). CONCLUSIONS: VEQSI max >198 ms distinguishes post-MI patients with prior life-threatening events from those without prior significant ventricular arrhythmia. This may be a useful additional index for risk stratification in IHD. PMID- 29759579 TI - Clinical and Electrophysiological Characteristics of Incessant Atrioventricular Nodal Re-Entrant Tachycardia. AB - OBJECTIVES: This study investigated clinical and electrophysiological findings in patients with incessant atrioventricular nodal reentrant tachycardia (AVNRT). BACKGROUND: AVNRT is the most frequent cause of paroxysmal supraventricular tachycardia (SVT) and, rarely, incessant SVT. There are a few case reports describing incessant AVNRT. METHODS: Among 342 patients treated using ablation for AVNRT, we identified 8 patients with incessant AVNRT (2.3%). We describe the clinical and electrophysiological features of patients with incessant AVNRT and compare them with those of patients with paroxysmal AVNRT (n = 334). RESULTS: This study population consisted of 5 men and 3 women with incessant AVNRT. Patients with incessant AVNRT presented more frequently with the fast-slow form than those with paroxysmal AVNRT (63% vs. 14%, respectively, p < 0.001). The ejection fraction in patients with incessant AVNRT was significantly lower than that in patients with paroxysmal AVNRT (49 +/- 12% vs. 60 +/- 8%, p = 0.03). The H-V interval in patients with incessant AVNRT was significantly longer than that in patients with paroxysmal AVNRT. A large circuit path length is inferred by spontaneous tachycardia induction in response to slight changes in sinus rate or random premature beats, suggesting that slight changes in rate produce changes in atrial or nodal refractoriness and provoke SVT. Catheter ablation in the conventional slow pathway region was successful in eliminating SVT. CONCLUSIONS: AVNRT can rarely present as incessant SVT, mimicking permanent junctional reciprocating tachycardia, and can be associated with tachycardia-associated cardiomyopathy. Catheter ablation in the slow pathway region leads to long-term success. PMID- 29759580 TI - Incessant Atrioventricular Nodal Re-Entrant Tachycardia: What's So Different? PMID- 29759581 TI - Algorithm-Based Screening May Improve Patient Selection for the Subcutaneous Implantable Defibrillator. AB - OBJECTIVES: The study sought to describe the concept of algorithm-based screening with an external subcutaneous implantable cardioverter-defibrillator (S-ICD) to evaluate sensing using the rhythm discrimination algorithm of the device. BACKGROUND: In a proportion of patients, screening for S-ICD therapy with the dedicated screening tool results in false negative and false positive results. METHODS: Both patients who failed the standard screening and who passed with abnormal baseline ECGs were screened with an external S-ICD to evaluate sensing at rest and during exercise in all 3 sensing vectors (algorithm-based screening). Patients with adequate sensing were implanted with an S-ICD. Follow-up data regarding (in)appropriate shocks was collected. RESULTS: Algorithm-based screening was performed in 15 patients. Group 1 consists of 8 who failed standard screening and Group 2 consists of 7 who passed and had abnormal ECGs. Six of 8 who failed standard screening in all sensing vectors demonstrated adequate sensing with the external S-ICD and were implanted with an S-ICD. Of these 6 implanted patients in Group 1, 1 inappropriate shock was observed duration median of 17 months' follow-up and 2 episodes of ventricular fibrillation were successfully treated. Of the 7 patients in Group 2, who passed standard screening, 2 demonstrated inadequate sensing during additional screening with the external S-ICD. No appropriate or inappropriate shocks were observed in Group 2 during 10 months' follow-up. CONCLUSIONS: Algorithm-based screening with the external S-ICD may improve patient selection and reduce the number of false positive and false negative screening results of the standard screening method. PMID- 29759584 TI - Soluble CD40 Ligand in Atrial Fibrillation: Time and Other Confounding Factors. PMID- 29759582 TI - Outcomes in Patients With Congenital Heart Disease Receiving the Subcutaneous Implantable-Cardioverter Defibrillator: Results From a Pooled Analysis From the IDE Study and the EFFORTLESS S-ICD Registry. AB - OBJECTIVES: This study was conceived to determine the safety and efficacy of the subcutaneous implantable cardioverter-defibrillator (S-ICD) in patients with congenital heart disease (CHD). BACKGROUND: The S-ICD is a treatment option for patients with CHD in which a transvenous device is contraindicated due to anatomic considerations. However, efficacy in this group has not been determined. METHODS: A pooled analysis of 865 patients in the EFFORTLESS (Evaluation of Factors Affecting the Clinical Outcome and Cost-Effectiveness) registry (an international observational database) and a U.S. Investigational Device Exemption study were reviewed. RESULTS: Nineteen CHD patients versus 846 non-CHD patients with a median follow-up of 567 days and 639 days, respectively, were included. There were no deaths and no appropriate shocks for ventricular tachycardia/ventricular fibrillation in the CHD cohort, versus 26 deaths (3.1%, p = 0.42) and 111 appropriate shocks in 59 patients (7.1%) in the non-CHD cohort (p = 0.23). There were similar complication rates for the CHD versus non-CHD groups (10.5 vs. 9.6% [p = 0.89]), with inappropriate shocks for T-wave oversensing as the only complication in the CHD group (n = 2). The rate of inappropriate shocks was similar for both groups (10.5% vs. 10.9% [p = 0.96]). Successful defibrillation testing at 80J was comparable for the CHD versus non-CHD groups (100% vs. 98.5%). CONCLUSIONS: The overall analysis of the CHD cohort from the pooled data of the Investigational Device Exemption study and the EFFORTLESS registry shows that the S-ICD is a safe option in CHD patients deemed to be at high risk for sudden cardiac death who do not have pacing indications. Further research to accurately define sudden cardiac death risk in the diverse anatomic substrates of CHD patients is warranted. PMID- 29759583 TI - Association of Soluble CD40 Ligand With Duration of Atrial Fibrillation and With Intensity of Spontaneous Echocardiographic Contrast. AB - OBJECTIVES: The authors tested the hypothesis that the inflammatory response of nonvalvular atrial fibrillation (NVAF) is associated with elevated soluble CD40 ligand (sCD40L). BACKGROUND: NVAF is generally believed to be an inflammatory disease process. sCD40L represents a sensitive in vivo indicator of platelet activation and may serve as an "inflammatory and thrombotic thermometer." METHODS: Plasma sCD40L was measured using enzyme-linked immunoadsorbent assay in 109 NVAF cases (60.9 +/- 15 years of age; 26% women) and 48 normal sinus rhythm (NSR) controls (62.3 +/- 15 years of age; 44% women). Patients were separated by arrhythmia duration of <1 month (n = 21), 1 to 12 months (n = 18), and >12 months (n = 70). RESULTS: Median sCD40L level was significantly higher in NVAF cases than in NSR controls (321 pg/ml vs. 238 pg/ml, respectively; p = 0.029). This difference was driven by higher levels in patients with NVAF duration for <1 month (552 pg/ml) and 1 to 12 months (328 pg/ml). NVAF patients with arrhythmia duration for over 1 year had sCD40L levels not significantly different from those of NSR controls. An sCD40L concentration of 552 pg/ml distinguished NVAF patients with dysrhythmia duration of <1 month (area under the curve [AUC] of 0.72; p = 0.0010) or duration for <=12 months (AUC: 0.69; p = 0.0003) from NSR controls. Circulating sCD40L levels were also significantly higher among patients with mild spontaneous echocardiogram contrast (SEC) (p = 0.0378) and those with moderate SEC (p = 0.007) compared with NSR controls. CONCLUSIONS: sCD40L levels are significantly higher in NVAF patients than in NSR controls but only for up to 1 year after development of dysrhythmia. An sCD40L concentration of 552 pg/ml can help to assess development or recurrence of asymptomatic NVAF. PMID- 29759585 TI - MICRA Leadless Pacemaker on Autopsy. PMID- 29759586 TI - The Small Cardiac Vein as an Unrecognized Substrate for Atrial Tachycardia. PMID- 29759588 TI - Seeking Balance: Risk, ICDs, and Nonischemic Cardiomyopathy. PMID- 29759587 TI - T-Wave Alternans in a Hypothermic Patient Leading to Unstable Ventricular Tachycardia. PMID- 29759589 TI - Ultrasound-guided subacromial-subdeltoid bursa corticosteroid injections: a study of short- and long-term outcomes. AB - AIM: To assess shoulder pain and disability in patients undergoing corticosteroid injection into the subacromial-subdeltoid (SA-SD) bursa under ultrasound guidance, evaluating both short and long-term outcomes. MATERIALS AND METHODS: In this prospective, longitudinal, analytical study 376 patients referred for SA-SD bursa injection during a 6 month period were asked to complete a questionnaire assessing shoulder pain and disability in the form of the Shoulder Pain and Disability Index (SPADI). Patients were reassessed at 6 weeks and 12 months post injection. Data were collated and analysed based on the diagnosis made at ultrasound. RESULTS: Almost two-thirds (63.6%) of patients irrespective of the underlying diagnosis showed improvement in pain and disability 6 weeks after injection, but this figure decreased significantly after 12 months to 27.3%. There was no significant difference in outcome between patients with a rotator cuff tendon tear and without a tear at 6 weeks; however, there was a difference between these two groups at 12 months with significantly fewer patients with a tear receiving benefit. CONCLUSION: The pattern of good short-term, but poorer long-term outcomes from SA-SD bursa injection is in line with previous studies; however, this study provides additional information on the effect of the underlying diagnosis on the potential outcome, specifically the presence or absence of a rotator cuff tendon tear. PMID- 29759590 TI - Reasons for (non)participation in supplemental population-based MRI breast screening for women with extremely dense breasts. AB - AIM: To determine the willingness of women with extremely dense breasts to undergo breast cancer screening with magnetic resonance imaging (MRI) in a research setting, and to examine reasons for women to participate or not. MATERIALS AND METHODS: Between 2011 and 2015, 8,061 women (50-75 years) were invited for supplemental MRI as part of the Dense Tissue and Early Breast Neoplasm Screening (DENSE) trial (ClinicalTrials.gov Identifier: NCT01315015), after a negative screening mammography in the national population-based mammography screening programme. Demographics of participants and non participants were compared. All invitees were asked to report reasons for (non)participation. Ethical approval was obtained. Participants provided written informed consent. RESULTS: Of the 8,061 invitees, 66% answered that they were interested, and 59% eventually participated. Participants were on average 54 years old (interquartile range: 51-59 years), comparable to women with extremely dense breasts in the population-based screening programme (55 years). Women with higher socio-economic status (SES) were more often interested in participation than women with lower SES (68% versus 59%, p<0.001). The most frequently stated reasons for non-participation were "MRI-related inconveniences and/or self reported contraindications to MRI" (27%) and "anxiety regarding the result of supplemental screening" (21%). "Expected personal health benefit" (68%) and "contribution to science" (43%) were the most frequent reasons for participation. CONCLUSION: Of women invited for MRI because of extremely dense breasts, 59% participated. Common reasons for non-participation were "MRI-related inconveniences" and "anxiety regarding the result of supplemental screening". In case of future implementation, availability of precise evidence on benefits and harms might reduce this anxiety. PMID- 29759591 TI - Corrigendum to "Prevalence of dyslipidemia and achievement of low-density lipoprotein cholesterol targets in Chinese adults: A nationally representative survey of 163,641 adults" [Int. J. Cardiol. 260 (2018) 196-203]. PMID- 29759592 TI - CCDC115-CDG: A new rare and misleading inherited cause of liver disease. AB - Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115 CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed. PMID- 29759594 TI - Liquid chromatography-mass spectrometry-based metabolomics and lipidomics reveal toxicological mechanisms of bisphenol F in breast cancer xenografts. AB - Bisphenol F (BPF) is a major alternative to bisphenol (BPA) and has been widely used. Although BPA exposure is known to generate various toxic effects, toxicity of BPF remains under-explored. A comprehensive method involving mass spectrometry (MS)-based global lipidomics and metabolomics, and matrix-assisted laser desorption/ionization-mass spectrometry (MALDI)- MS imaging (MSI) was used to study toxic effects of BPF and the underlying mechanisms on tumor metastasis related tissues (liver and kidney) in breast cancer xenografts. Our results demonstrated that BPF exposure disturbed the metabolome and lipidome of liver and kidney. Exposure induced reprogramming of the glutathione (GSH) biosynthesis and glycolytic metabolism by activating glycine, serine, cysteine, glutamine, lactate and pyruvate in liver and kidney tissues. It also perturbed the biosynthesis and degradation of glycerophospholipids (GPs) and glycerolipids (GLs), resulting in abnormality of membrane homeostasis and cellular functions in kidney tissues. Moreover, spatial distribution and profile of metabolites changed across renal cortex and medulla regions after BPF treatment. Levels of phosphatidylethanolamines (PE) and triacylglycerols (TAG) increased in renal medulla and pelvis, while the levels of phosphatidylcholines (PC) and phosphatidylinositols (PI) increased in cortex and pelvis. These observations offer a deeper understanding of critical role of metabolites and lipid reprogramming in BPF-induced biological effects. PMID- 29759593 TI - Electrodialytic 2-compartment cells for emerging organic contaminants removal from effluent. AB - The present work discusses the efficiency of the electrodialytic (ED) process to remove emerging organic contaminants (EOCs) from effluent. The ED process was carried out in a cell of two-compartments (2 C-cell) with effluent in either the anode or cathode compartment, separated from the electrolyte compartment through an anion or a cation exchange membrane (AEM and CEM, respectively). As effluent destination might be soil irrigation, and having in mind the nutrient recycling, phosphorus was also monitored in the process. The ED removals showed to be dependent of EOCs characteristics and cell design. Removals were higher when using an AEM (60-72%) than a CEM (8-63%), except for caffeine when the effluent was placed in the cathode, that did not show any removal. When using an AEM with the effluent placed in the anode compartment, all the EOCs (including caffeine) were removed between 57-72%, mainly through electrodegradation phenomena. Regarding phosphorus, a polarity switch may be done to a 2 C-cell with a AEM, depending on the effluent final use. This technology is still in its first steps and, in both cases, further optimization of ED parameters is needed. Still, this technological innovation and cross-cutting research envisages the promotion of economic, social and environmental benefits. PMID- 29759595 TI - HER2-Positive Lobular Versus Ductal Carcinoma of the Breast: Pattern of First Recurrence and Molecular Insights. AB - BACKGROUND: Infiltrating lobular carcinoma (ILC) represents about 10% of breast cancer and rarely shows overexpression of human epidermal growth factor receptor 2 (HER2). We compared biological and clinical characteristics of HER2-positive ILC versus HER2-positive infiltrating ductal carcinoma (IDC). PATIENTS AND METHODS: We retrospectively analyzed the data of 328 patients with HER2-positive pure ductal or lobular breast carcinoma, comparing clinical and biological data at diagnosis as well as outcome between the 2 histologies. A gene-mutation analysis was performed in a subset of patients. RESULTS: Two hundred ninety-one patients (88.7%) had IDC and 37 patients (11.3%) ILC. ILC resulted more frequently in multicenter (24.3% vs. 6.5%, P < .0001) and node-positive (54.1% vs. 45%, P = .013) disease of lower proliferative activity (Mib1 < 20%: 51.4% vs. 22.3%, P < .0001) and lower histologic grade (grade 3: 32.4% vs. 57.4%, P = .038). Disease recurred in 57 patients (17.4%) and involved the bone in 40% of ILC patients (vs. 17% of IDC patients) and the viscera in 30% of ILC patients (vs. 59.6% of IDC patients). No difference in the recurrence rate between the 2 histologies was observed in patients treated with adjuvant trastuzumab (12.5% of ILC patients and 8.3% of IDC patients). Exploratory molecular analysis revealed a higher frequency of mutations in ILC, with more cases of multiple mutations. CONCLUSION: HER2-positive ILC shows different biological behavior than IDC, with a possible higher mutation load. Despite lower proliferation activity and estrogen receptor expression in ILC breast cancer, trastuzumab is clearly an effective therapy for this histologic subtype. PMID- 29759596 TI - Implementing an educational program to improve critical care nurses' enteral nutritional support. AB - BACKGROUND: Although international nutrition societies recommend enteral nutrition guidelines for patients in intensive care units (ICUs), large gaps exist between these recommendations and actual clinical practice. Education programs designed to improve nurses' knowledge about enteral nutrition are therefore required. In Korea, there are no educational intervention studies about evidence-based guidelines of enteral nutrition for critically ill patients. OBJECTIVES: We aimed to evaluate the effects of an education program to improve critical care nurses' perceptions, knowledge, and practices towards providing enteral nutritional support for ICU patients. METHODS: A quasi-experimental, one group study with a pre- and post-test design was conducted from March to April 2015. Nurses (N = 205) were recruited from nine ICUs from four tertiary hospitals in South Korea. The education program comprised two sessions of didactic lectures. Data were collected before (pre-test) and 1 month after (post-test) the education program using questionnaires that addressed nurses' perceptions, knowledge, and practices relating to providing enteral nutritional support for ICU patients. RESULTS: After the program, nurses showed a significant improvement in their perceptions and knowledge of enteral nutrition for ICU patients. There was a significant improvement in inspecting nostrils daily, flushing the feeding tube before administration, providing medication that needs to be crushed correctly, changing feeding sets, and adjusting feeding schedules. CONCLUSIONS: The findings indicate that an enteral nutrition education program could be an effective strategy to increase critical care nurses' support for the critically ill. This education program can be incorporated into hospital education or in service training for critical care nurses to strengthen their perceptions and knowledge of nutritional support in the ICU. This may improve the clinical outcomes of ICU patients. PMID- 29759597 TI - Performance and robustness of optimal fractional fuzzy PID controllers for pitch control of a wind turbine using chaotic optimization algorithms. AB - The most studied controller for pitch control of wind turbines is proportional integral-derivative (PID) controller. However, due to uncertainties in wind turbine modeling and wind speed profiles, the need for more effective controllers is inevitable. On the other hand, the parameters of PID controller usually are unknown and should be selected by the designer which is neither a straightforward task nor optimal. To cope with these drawbacks, in this paper, two advanced controllers called fuzzy PID (FPID) and fractional-order fuzzy PID (FOFPID) are proposed to improve the pitch control performance. Meanwhile, to find the parameters of the controllers the chaotic evolutionary optimization methods are used. Using evolutionary optimization methods not only gives us the unknown parameters of the controllers but also guarantees the optimality based on the chosen objective function. To improve the performance of the evolutionary algorithms chaotic maps are used. All the optimization procedures are applied to the 2-mass model of 5-MW wind turbine model. The proposed optimal controllers are validated using simulator FAST developed by NREL. Simulation results demonstrate that the FOFPID controller can reach to better performance and robustness while guaranteeing fewer fatigue damages in different wind speeds in comparison to FPID, fractional-order PID (FOPID) and gain-scheduling PID (GSPID) controllers. PMID- 29759598 TI - Molecular and Cellular Mechanisms of Atrial Fibrosis in Atrial Fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Atrial fibrosis has emerged as an important pathophysiological contributor and has been linked to AF recurrences, resistance to therapy and complications. Here, the author reviews the molecular and cellular mechanisms that control atrial fibrosis. It is important to note that not all tissue fibrosis is identical. For example, reactive (interstitial) fibrosis increases the amount of collagen between cardiac muscle bundles without fundamentally altering muscle bundle architecture. Replacement (reparative) fibrosis replaces dead cardiomyocytes with extracellular matrix tissue and fibroblasts, preserving tissue integrity at the expense of muscle bundle continuity. Replacement fibrosis may be much more disruptive to electric conduction and more difficult to reverse than reactive fibrosis. The author reviews the complex signaling systems that cause fibrosis, including those connected to connective tissue growth factor, angiotensin-II, platelet-derived growth factor, and transforming growth factor-beta. The author then considers the molecular constitution of fibrous tissue, including the production and maturation of collagen and the roles of important extracellular matrix proteins such as fibronectin, tenascin-C, and thrombospodin-1. The author then discusses the evolving evidence for an important role of Ca2+ entry in the profibrotic activation of fibroblasts, along with evidence that dysregulation of Ca2+-transporting transient potential receptor channels and inward rectifier K+ channels in AF fibroblasts is profibrotic. Finally, the author reviews the evidence for micro-ribonucleic acid involvement in atrial fibrotic signaling and AF promotion. It is hoped that an improved understanding of the mechanisms controlling atrial fibrosis will open up new opportunities for AF prevention and management. PMID- 29759600 TI - Risk Factor Modification in Atrial Fibrillation: Saving Dollars and Making Sense. PMID- 29759599 TI - Cost-Effectiveness and Clinical Effectiveness of the Risk Factor Management Clinic in Atrial Fibrillation: The CENT Study. AB - BACKGROUND: Atrial fibrillation (AF) imposes a substantial cost burden on the healthcare system. Weight and risk factor management (RFM) reduces AF burden and improves the outcomes of AF ablation. OBJECTIVES: This study sought to evaluate the cost and clinical effectiveness of integrating RFM into the overall management of AF. METHODS: Of 1,415 consecutive patients with symptomatic AF, 825 patients had body mass index >=27 kg/m2. After screening for exclusion criteria, the final cohort comprised 355 patients: 208 patients who opted for RFM and 147 control subjects and were followed by 3 to 6 monthly clinic review, 7-day Holter monitoring, and AF Symptom Score. A decision analytical model calculated the incremental cost-effectiveness ratios of cost per unit of global well-being gained and unit of AF burden reduced. RESULTS: There were no differences in baseline characteristics or follow-up duration (p = NS). Arrhythmia-free survival was better in the RFM compared with control subjects (Kaplan-Meier: 79% vs. 44%; p < 0.001). At follow-up, RFM group had less unplanned specialist visits (0.19 +/ 0.40 vs. 1.94 +/- 2.00; p < 0.001), hospitalizations (0.74 +/- 1.3 vs. 1.05 +/- 1.60; p = 0.03), cardioversions (0.89 +/- 1.50 vs. 1.51 +/- 2.30; p = 0.002), emergency presentations (0.18 +/- 0.50 vs. 0.76 +/- 1.20; p < 0.001), and ablation procedures (0.60 +/- 0.69 vs. 0.72 +/- 0.86; p = 0.03). Antihypertensive (0.53 +/- 0.70 vs. 0.78 +/- 0.60; p = 0.04) and antiarrhythmic (0.26 +/- 0.50 vs. 0.91 +/- 0.60; p = 0.003) use declined in RFM. The RFM group had an increase of 0.1930 quality-adjusted life years and a cost saving of $12,094 (incremental cost effectiveness ratios of $62,653 saved per quality-adjusted life years gained). CONCLUSIONS: A structured physician-directed RFM program is clinically effective and cost saving. PMID- 29759602 TI - Left Atrial Hypertension in Atrial Fibrillation: Dealing With the Pressure. PMID- 29759601 TI - Resting and Exercise-Induced Left Atrial Hypertension in Patients With Atrial Fibrillation: The Causes and Implications for Catheter Ablation. AB - OBJECTIVES: The aim of this paper was to investigate the prevalence of resting and exercise-induced left atrial hypertension (LAH) in patients with nonvalvular atrial fibrillation (AF), association of the LAH with other cardiac abnormalities, and its implications for AF catheter ablation. BACKGROUND: The clinical role of LAH in patients with established AF is largely unknown. METHODS: Patients scheduled for catheter ablation of AF (n = 240; age 60 +/- 10 years; 67% men, 62% paroxysmal AF) underwent detailed echocardiography, assessment of quality of life (QoL), left atrial (LA) voltage mapping, and measurement of the LA pressure at rest and during isometric handgrip exercise. After ablation they were followed for AF recurrence for 16 +/- 6 months. RESULTS: Resting and exercise-induced LAH (mean LA pressure >15 mm Hg) occurred in 15% and 34% of the patients, respectively. Both the patients with resting and exercise-induced LAH had typical features of latent heart failure with preserved ejection fraction associated with advanced LA structural and functional remodeling. AF recurred after ablation in 45% of the patients. LAH was an independent risk factor for arrhythmia recurrence (hazard ratio: 1.7, 95% confidence interval: 1.2 to 2.2). The patients with LAH had worse baseline QoL, but they benefited significantly more from a successful ablation than the patients without LAH. CONCLUSIONS: Presence of either resting or exercise-induced LAH identified AF patients with a distinct clinical profile, extensive LA substrate, and different clinical response to catheter ablation. Stratification of AF patients based on the LA exercise hemodynamics could help in the future to tailor the ablation strategy. PMID- 29759603 TI - Sudden Cardiac Death: Pharmacotherapy and Proarrhythmic Drugs: A Nationwide Cohort Study in Denmark. AB - OBJECTIVES: This study sought to describe the use of pharmacotherapy in a nationwide cohort of young patients with sudden cardiac death (SCD). BACKGROUND: Several drugs have been associated with an increased risk of SCD and sudden arrhythmic death syndrome (SADS). It remains unclear how pharmacotherapy may contribute to the overall burden of SCD in the general population. METHODS: This was a nationwide study that included all deaths that occurred between 2000 and 2009 and between 2007 and 2009 in people age 1 to 35 years and 36 to 49 years, respectively. Two physicians identified all SCDs through review of death certificates. Autopsy reports were collected. Pharmacotherapy prescribed within 90 days before SCD was identified in the Danish Registry of Medicinal Product Statistics. RESULTS: We identified 1,363 SCDs; median age was 38 years (interquartile range: 29 to 45 years), and 72% (n = 975) were men. Autopsy was performed in 55%. Overall, 58% of SCD cases (n = 786) received at least 1 drug within 90 days before death. The most common drugs were analgesic drugs (n = 239; 18%), antihypertensive drugs (n = 234; 17%), and antibiotic drugs (n = 218; 16%). After multivariable adjustment, prescription of "brugadogenic" drugs or >1 QT prolonging drug was associated with an increased risk of SADS compared with explained SCD (odds ratio: 2.16 [95% confidence interval: 1.12 to 4.17] and 2.91 [95% confidence interval: 1.46 to 5.81], respectively). CONCLUSIONS: Pharmacotherapy was identified in 58% of the SCD cases. After multivariable adjustment, there was a 2- and 3-fold increased risk of SADS compared with explained SCD in patients receiving brugadogenic drugs or >1 QT-prolonging drug, respectively. Identification of high-risk patients is warranted to lower the burden of SCD. PMID- 29759605 TI - Tying Ourselves in Knots to Avoid Ventricular Pacing in Sick Sinus Syndrome: Does it Matter? PMID- 29759604 TI - Atrioventricular Interval Extension Is Highly Efficient in Preventing Unnecessary Right Ventricular Pacing in Sinus Node Disease: A Randomized Cross-Over Study Versus Dual- to Atrial Single-Chamber Mode Switch. AB - OBJECTIVES: This study sought to compare the Intrinsic Rhythm Support (IRSplus) and Ventricular Pace Suppress (VpS) in terms of right ventricular pacing percentage (VP %), mean atrioventricular interval (MAVI), atrial fibrillation, and cardiac volumes. BACKGROUND: Modern pacemakers are provided with algorithms for reducing unnecessary ventricular pacing. These may be classified as: periodic search for intrinsic atrioventricular (AV) conduction prolonging the AV delay accordingly; or DDD-ADI mode switch. The IRSplus and VpS algorithms belong to the former and latter classes, respectively. METHODS: Patients with sick sinus dysfunction without evidence of II/III degree AV block were 1:1 randomized to 6 month periods of either IRSplus or VpS, and then crossed over. Subsequent follow ups were at the 12th month after randomization for device data retrieving, and at the 18th month with the same device programming for echocardiographic assessment. RESULTS: A total of 230 patients (62% males, median age 75 years [interquartile range: 69 to 79 years]) were enrolled. At a linear mixed-model analysis with order of treatment and investigational sites as nested random effects, differences in VP% and MAVI reached statistical significance: VP% was 1% (0% to 11%) during IRSplus and 3% (0% to 26%) during VpS (p = 0.029); MAVI was 225 ms (198 to 253 ms) during IRSplus and 214 ms (188 to 240 ms) during VpS (p = 0.014). No differences were observed in atrial fibrillation burden and incidence, ejection fraction, and cardiac volumes. CONCLUSIONS: Both IRSplus and VpS algorithms ensured VP% <=3% in most patients with sinus node dysfunction and preserved AV conduction. The IRSplus was slightly more efficient in reducing VP% at the expense of a small MAVI increase, with statistical but clinically insignificant differences. (Ventricular Pace Suppression Versus Intrinsic Rhythm Support Study; NCT01528657). PMID- 29759606 TI - Factors Predicting Arrhythmia-Related Symptoms and Health-Related Quality of Life in Patients Referred for Radiofrequency Ablation of Atrial Fibrillation: An Observational Study (the SMURF Study). AB - OBJECTIVES: The purpose of this study was to correlate the arrhythmia-related symptoms and health-related quality of life (HRQoL) in patients with atrial fibrillation (AF) who are eligible for radiofrequency ablation (RFA) with a number of objective indicators. BACKGROUND: Although the clinical consequences of AF have been studied extensively, the variation in the symptoms of patients with AF and HRQoL remains under-researched. METHODS: We studied 192 patients eligible for RFA of AF referred to the University Hospital, Linkoping, Sweden, between January 2012 and April 2014. The ASTA (Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia) symptom scale was used to assess arrhythmia-related symptoms in the patients. The ASTA HRQoL scale and the short-form 36 (SF-36) physical and mental components summaries (PCS and MCS) were used to express disease-specific and overall HRQoL of the patients, respectively. RESULTS: Anxiety, low-grade inflammation, and left atrial dilatation significantly predicted arrhythmia-related symptoms (R2 = 0.313; p < 0.001). Depression was the most important predictor of arrhythmia-specific HRQoL (standardized beta: 0 .406), and the produced model explained a significant proportion of the variation in arrhythmia-specific HRQoL (R2 = 0.513; p < 0.001). The most important predictor of PCS was obesity (body mass index >30 kg/m2) (standardized beta: 0.301), whereas the most important predictor of MCS was anxiety (standardized beta: -0.437). CONCLUSIONS: Anxiety, depression, and low-grade inflammation were the factors that predicted both arrhythmia-related symptoms and HRQoL in patients with AF. Obesity was the most significant predictor of patient general physical status. These factors need to be addressed in patients with AF to improve management of their disease. Intensive risk factor modification can be of great importance. (Reasons for Variations in Health Related Quality of Life and Symptom Burden in Patients With Atrial Fibrillation [SMURF]; NCT01553045). PMID- 29759608 TI - Amiodarone for Suppression of Ventricular Tachycardia: When Less Is More. PMID- 29759607 TI - Amiodarone Discontinuation or Dose Reduction Following Catheter Ablation for Ventricular Tachycardia in Structural Heart Disease. AB - OBJECTIVES: This study sought to examine long-term outcomes in patients with structural heart disease in whom amiodarone was reduced/discontinued after ventricular tachycardia (VT) ablation. BACKGROUND: VT in patients with structural heart disease increases morbidity and mortality. Amiodarone can decrease VT burden, but long-term use may result in organ toxicities and possibly increased mortality. Catheter ablation can also decrease VT burden. Whether amiodarone can be safely reduced/discontinued following ablation remains unknown. METHODS: We studied consecutive patients undergoing VT ablation from 2008 to 2011, typically followed by noninvasive programmed stimulation several days later. Patients were divided into 3 groups by amiodarone use: group A-amiodarone reduced/discontinued following ablation; group B-amiodarone not reduced; group C-not on amiodarone at time of ablation. Baseline characteristics and outcomes were compared between groups. RESULTS: Overall, 231 patients (90% male; mean age: 63.4 +/- 12.9 years; 53.7% ischemic cardiomyopathy) were included (group A: 99 patients; group B: 29 patients; group C: 103 patients). Group B patients were older with more advanced heart failure. Group A patients less frequently had inducible VT at the end of ablation or noninvasive programmed stimulation. In follow-up, 1-year VT-free survival was similar between groups (p = 0.10). Mortality was highest in group B (p < 0.001). Higher amiodarone dose after ablation (hazard ratio: 1.23; 95% confidence interval: 1.03 to 1.47; p = 0.02) was independently associated with shorter time to death. CONCLUSIONS: After successful VT ablation, as confirmed by noninducibility at the end of ablation and noninvasive programmed stimulation, amiodarone may be safely reduced/discontinued without an unacceptable increase in VT recurrence. Reduction/discontinuation of amiodarone should be considered an important goal of VT ablation. PMID- 29759610 TI - Effect of Different Cutpoints for Defining Success Post-Catheter Ablation for Persistent Atrial Fibrillation: A Substudy of the STAR AF II Trial. PMID- 29759611 TI - A Fibrillating Left Atrial Appendage During Sinus Rhythm. PMID- 29759609 TI - Coronary Vein Exit and Carbon Dioxide Insufflation to Facilitate Subxiphoid Epicardial Access for Ventricular Mapping and Ablation: First Experience. AB - OBJECTIVES: This study assessed the feasibility of intentional coronary venous perforation and exit with subsequent pericardial carbon dioxide (CO2) insufflation as a novel method for assisting subxiphoid pericardial puncture in the setting of epicardial mapping and ablation for ventricular tachycardia. The technique required that coronary venous perforation would not lead to significant bleeding. BACKGROUND: Widespread adoption of first-line endoepicardial ventricular tachycardia ablation has not been taken up because of the risk of lacerating coronary vessels and puncturing the right ventricle with direct subxiphoid puncture. METHODS: A lateral branch of the coronary sinus was subselected using a diagnostic JR4 coronary catheter inside a steerable sheath, via femoral access, and a distal branch then perforated intentionally using a high tip load 0.014-inch angioplasty wire. Either a microcatheter or over-the wire balloon was then passed over this into the pericardial space, allowing up to 150 ml of pericardial CO2 insufflation, which allowed direct visualization of subxiphoid anterior pericardial access using a microneedle technique. RESULTS: Intentional coronary vein exit was achieved in all 12 patients. In 1 patient, this confirmed widespread pericardial adhesions and therefore only endocardial VT ablation was undertaken. The other patients underwent successful pericardial CO2 insufflation and subxiphoid access allowing epicardial ventricular mapping and ablation. The immediate pericardial aspirate was dry or contained serous fluid in all but 1 patient. CONCLUSIONS: We report the first human transcoronary vein exit procedure. Coronary vein exit and subsequent percutaneous subxiphoid anterior access using a microneedle puncture after CO2 pericardial insufflation can be achieved reliably and safely. PMID- 29759612 TI - Percutaneous Pericardiocentesis for Epicardial Ventricular Tachycardia Ablation With the Anterior Approach Not Passing Through the Abdominal Cavity. PMID- 29759613 TI - Threading the Eye of a Needle: Successful Implantation of Defibrillator Leads Through a Stent Strut After Treatment for Complex Superior Vena Cava Obstruction. PMID- 29759614 TI - Fibrosis and Atrial Fibrillation. PMID- 29759615 TI - Enhancing Response in the Cardiac Resynchronization Therapy Patient: The 3B Perspective-Bench, Bits, and Bedside. AB - Cardiac resynchronization therapy (CRT) is an established nonpharmacological treatment for patients with heart failure (HF), reduced left ventricular (LV) ejection fraction, and a wide QRS complex. Although the therapy was developed 30 years ago and approved by the Food and Drug Administration in 2001, attempts to improve it have never stopped. Such improvements have been facilitated by combining knowledge from bench (basic science), bits (computer modeling), and bedside (clinical studies); these issues are addressed in the present review. Improvements include better patient selection, positioning of the LV lead, pacing from multiple sites, and optimization of atrioventricular and ventriculo ventricular intervals. Overall, patterns of electrocardiographic and echocardiographic (strain) signals appear to be more useful for patient selection than timing intervals (QRS duration, time-to-peak shortening). Quadripolar leads have significantly improved CRT outcome due to increased electrical and mechanical lead performance (avoiding phrenic nerve stimulation and improving lead stability), but also thanks to the flexibility offered by the novel leads to avoid in-scar pacing. The benefit of multiple site stimulation over optimal conventional biventricular pacing seems small and is awaiting evidence from large trials. There is rapidly growing interest in merging imaging information to guide positioning of the LV lead in late activated regions without scar and in LV lead positions other than the epicardial coronary veins (LV endocardium, His bundle, LV septum). All these developments look promising but await further clinical validation. Finally, computer modeling is rapidly becoming important in understanding the substrate for CRT, in improving and assisting patient selection, as well as in guiding therapy planning. PMID- 29759617 TI - Focal Sources: Another Potentially Important Target for Persistent Atrial Fibrillation? PMID- 29759616 TI - Spatial Relationships of Complex Fractionated Atrial Electrograms and Continuous Electrical Activity to Focal Electrical Sources: Implications for Substrate Ablation in Human Atrial Fibrillation. AB - OBJECTIVES: This study sought to evaluate the spatial relationships of focal electrical sources (FSs) to complex fractionated atrial electrograms (CFAE) and continuous electrical activity (CEA). BACKGROUND: Fractionated atrial electrograms have been associated with atrial fibrillation (AF) drivers in computational studies and represent ablation targets in the management of persistent AF. METHODS: We included a subset of 66 patients (age: 63 [56, 67] years, 69% persistent AF) with electroanatomic data from the SELECT AF (Selective complex fractionated atrial electrograms targeting for atrial fibrillation) randomized control trial that compared the efficacy of CFAE with CEA ablation in AF patients undergoing pulmonary vein antral ablation. Focal sources were identified based on bipolar electrogram periodicity and QS unipolar electrogram morphology. RESULTS: A total of 77 FSs (median: 1 [1st quartile, 3rd quartile: 1, 2] per patient) were identified most commonly in the pulmonary vein antrum and left atrial appendage. The proportions of FSs inside CFAE and CEA regions were similar (13% vs. 1.3%, respectively; p = 0.13). Focal sources were more likely to be on the border zone of CFAEs than in CEAs (49% vs. 7.8%, respectively; p = 0.012). Following ablation, 53% of patients had >=1 unablated extrapulmonary vein FS. The median number of unablated FS was higher in patients with AF recurrence post ablation than in patients without (median: 1 [0, 1] vs. 0 [0, 1], respectively; p = 0.026). CONCLUSIONS: One-half of the FSs detected during AF localized to the border of CFAE areas, whereas most of the FSs were found outside CEA areas. CFAE or CEA ablation leaves a number of FS unablated, which is associated with AF recurrence. These findings suggest that many CFAEs may arise from passive wave propagation, remote from FS, which may limit their therapeutic efficacy in AF substrate modification. PMID- 29759618 TI - Real-World Evaluation of Magnetic Resonance Imaging in Patients With a Magnetic Resonance Imaging Conditional Pacemaker System: Results of 4-Year Prospective Follow-Up in 2,629 Patients. AB - OBJECTIVES: This global, multicenter, prospective study, initiated to meet U.S. Food and Drug Administration condition-of-approval requirements, evaluated the safety and efficacy of the Medtronic magnetic resonance imaging (MRI)-conditional pacing system when used in an MRI environment in routine clinical practice. The primary endpoint was MRI-related complications. The secondary endpoint was the cumulative change in pacing capture threshold (PCT) for patients undergoing multiple MRI scans. BACKGROUND: Large-scale, real-world evaluation of MRI in patients implanted with an MRI-conditional pacing system remains limited, with few published data for patients who undergo multiple MRI scans. METHODS: Patients were enrolled and followed up prospectively from the time of implantation. Evaluation of the pacemaker function was performed before and after MRI. The MRI related complication-free rate was evaluated. Changes in electrical performance after each scan and cumulative changes over multiple scans were analyzed. RESULTS: In 81 centers, 2,629 patients were implanted with a complete SureScan pacing system (41.8% women, age 70.2 +/- 12.5 years). A total of 526 patients (28.5%) received 872 clinically indicated MRI scans, including 58 thoracic scans. No MRI-related complications occurred during or after MRI, meeting the primary objective. Six (1%) MRI-related observations (atrial fibrillation, PCT increase, and chest symptoms) were reported. A total of 171 patients (32.5%) underwent 2 or more scans with no cumulative increase in PCT. CONCLUSIONS: This report constitutes the largest longitudinal MRI experience in patients implanted with an MRI-conditional pacing system. Results support the safety profile of the SureScan system and demonstrate for the first time that patients may safely undergo multiple MRI scans. (SureScan Post-Approval Study; NCT01299675). PMID- 29759619 TI - Catheter Ablation for Cardiac Arrhythmias: Utilization and In-Hospital Complications, 2000 to 2013. AB - OBJECTIVES: This study sought to investigate the utilization of and in-hospital complications in patients undergoing catheter ablation in the United States from 2000 to 2013 by using the National Inpatient Sample and Nationwide Inpatient Sample. BACKGROUND: Catheter ablation has become a mainstay in the treatment of a wide range of cardiac arrhythmias. METHODS: This study identified patients 18 years of age and older who underwent inpatient catheter ablation from 2000 to 2013 and had 1 primary diagnosis of any of the following arrhythmias: atrial fibrillation, atrial flutter, supraventricular tachycardia, or ventricular tachycardia. RESULTS: An estimated total of 519,951 (95% confidence interval: 475,702 to 564,200) inpatient ablations were performed in the United States between 2000 and 2013. The median age was 62 years (interquartile range: 51 to 72 years), and 59.3% of the patients were male. The following parameters showed increasing trends during the study period: annual volume of ablations, number of hospitals performing ablations, mean age and comorbidity index of patients, rate of >=1 complication, and length of stay (p < 0.001 for each). Substantial proportions (27.5%) of inpatient ablation procedures were performed in low-volume hospitals and were associated with an increased risk for complications (odds ratio: 1.26; 95% confidence interval: 1.12 to 1.42; p < 0.001). Older age, greater numbers of comorbidities, and complex ablations for atrial fibrillation and ventricular tachycardia were independent predictors of in-hospital complications and in-hospital mortality. In addition, female sex and lower hospital volumes were independent predictors of complications. CONCLUSIONS: From 2000 to 2013, there was a substantial increase in the annual number of in hospital catheter ablation procedures, as well as the rate of periprocedural complications nationwide. Low-volume centers had a significantly higher rate of complications. PMID- 29759620 TI - Boldly Going Where Few Have Gone Before: The Voyages of Cardiac Catheter Ablation. PMID- 29759621 TI - Analyses of the Mode of Termination During Diagnostic Ventricular Pacing to Differentiate the Mechanisms of Supraventricular Tachycardias. AB - OBJECTIVES: The goal of this study was to determine the diagnostic yield of analyzing the mode of termination during ventricular overdrive pacing (VOP) to differentiate the mechanisms of supraventricular tachycardias (SVTs). BACKGROUND: The majority of the diagnostic criteria for VOP rely on successful entrainment, but termination of SVTs is common during VOP. METHODS: We studied 225 SVTs with a 1:1 atrioventricular relationship, including 34 atrial tachycardias, 67 orthodromic reciprocating tachycardias (ORTs) (including 4 ORTs using accessory pathways [APs] with decremental properties), and 124 atrioventricular nodal re entrant tachycardias. The total pacing prematurity (TPP) needed to reset or terminate the SVT was calculated by using a simplified method, and the post pacing interval minus the tachycardia cycle length (PPI - TCL) was predicted from the TPP. RESULTS: VOP terminated 87 SVTs (39%). No atrial tachycardias were terminated by VOP in this study. SVT termination occurred after (n = 71) or before (n = 16) atrial resetting. The predicted PPI - TCL was highly correlated with the measured PPI - TCL (r = 0.96; p < 0.001). The TPP had diagnostic accuracy equivalent to the predicted PPI - TCL. The TPP was measurable irrespective of the termination mode and correctly diagnosed ORTs with decremental APs. All ORTs using septal APs and no atrioventricular nodal re entrant tachycardias had a TPP <125 ms. Considering other criteria evaluable in terminated SVTs, a combined criteria of a TPP <125 ms and atrial capture/termination within the fusion period were specific for ORTs using free wall APs, except for left anterolateral/lateral sites. CONCLUSIONS: The termination analyses were useful for differential diagnoses of SVTs terminated during VOP. PMID- 29759623 TI - Pulmonary Vein Isolation With a Pace Capture-Guided Approach: Durable or Debatable? PMID- 29759622 TI - 5-Year Outcome of Pulmonary Vein Isolation by Loss of Pace Capture on the Ablation Line Versus Electrical Circumferential Pulmonary Vein Isolation. AB - OBJECTIVES: This study sought to compare long-term arrhythmia-free survival between electrical circumferential pulmonary vein isolation (PVI) and PVI with the endpoint of unexcitability along the ablation line. BACKGROUND: PVI is the standard ablation strategy of paroxysmal atrial fibrillation, although arrhythmia recurrence in long-term follow-up (FU) is high. The endpoint of unexcitability along the ablation line results in decreased arrhythmia recurrence compared to electrical PVI in 1-year FU. METHODS: Seventy-four consecutive patients (age 62.5 +/- 10.6 years; 70.3% male) with de novo paroxysmal atrial fibrillation who were initially included in our randomized trial and underwent catheter ablation at our institution were analyzed. Patients who were randomized to either a conventional group (PVI, guided by circumferential catheter signals) or a pace-guided group (PG, anatomical ablation line encircling, ablation until loss of pace capture at 10 V, 2-ms pulse width on the ablation line) underwent long-term FU. The primary endpoint was recurrence of any atrial fibrillation or atrial tachycardia after a blanking period of 3 months. RESULTS: Sixty-nine patients completed a mean FU period of 5.14 +/- 0.98 years. Arrhythmia-free survival without antiarrhythmic drug therapy was significantly higher in the PG group (71.05% vs. 25.81%, p = 0.002). Furthermore, multiple procedure success (1.29 +/- 0.61 procedures in PG vs. 1.97 +/- 1.06 procedures in conventional group, p < 0.001) was higher in the PG group compared to the conventional group (89.47% vs. 58.06%, p = 0.005). CONCLUSIONS: The endpoint of unexcitability along the PVI line improves success rates, resulting in a significant reduction of exposure to invasive procedures in 5-year FU. PMID- 29759624 TI - Long Detection Programming in Single-Chamber Defibrillators Reduces Unnecessary Therapies and Mortality: The ADVANCE III Trial. AB - OBJECTIVES: This study sought to evaluate the effects of programming a long detection in single-chamber (VVI) implantable cardioverter-defibrillators (ICDs) in the multicenter prospective ADVANCE III (Avoid DeliVering TherApies for Non sustained Arrhythmias in ICD PatiEnts III) trial. BACKGROUND: Programming strategies may reduce unnecessary ICD shocks and their adverse effects but to date have been described only for dual-chamber ICDs. METHODS: A total of 545 subjects (85% male; atrial fibrillation 25%, left ventricular ejection fraction 31%, ischemic etiology 68%, secondary prevention indications 32%) receiving a VVI ICD were randomized to long detection (30 of 40 intervals) or standard programming (18 of 24 intervals) based on device type, atrial fibrillation history, and indication. In both arms, antitachycardia pacing (ATP) therapy during charging was programmed for episodes with cycle length 320 to 200 ms and shock only for cycle length <200 ms. Wavelet and stability functions enabled. Therapies delivered were compared using a negative binomial regression model. RESULTS: A total of 267 patients were randomized to long detection and 278 to the control group. Median follow-up was 12 months. One hundred twelve therapies (shocks and ATP) occurred in the long detection arm versus 257 in the control arm, for a 48% reduction with 30 of 40 intervals (95% confidence interval [CI]: 0.36 to 0.76; p = 0.002). In the long detection arm, overall shocks were reduced by 40% compared to the control arm (48 vs. 24; 95% CI: 0.38 to 0.94; p = 0.026) and appropriate shocks by 51% (34 vs. 74; 95% CI: 0.26 to 0.94; p = 0.033). Syncopal events did not differ between arms, but survival improved in the long detection arm. CONCLUSIONS: Among patients implanted with a VVI ICD, programming with the long detection interval significantly reduced appropriate therapies, shocks, and all-cause mortality. (Avoid DeliVering TherApies for Non-sustained Arrhythmias in ICD PatiEnts III [ADVANCEIII]; NCT00617175). PMID- 29759625 TI - Post-Extrasystolic Potentiation as a Predictor of Recovery of Left Ventricular Dysfunction After Radiofrequency Catheter Ablation. AB - OBJECTIVES: This study hypothesizes that post-extrasystolic potentiation reflects left ventricle contractile reserve and therefore may predict an improvement of premature ventricular contraction (PVC)-induced cardiomyopathy after PVC ablation. BACKGROUND: Post-extrasystolic potentiation is a physiologic phenomenon of blood pressure accentuation after a PVC beat. METHODS: We performed a retrospective study of patients with a PVC burden of >=10% PVC/24 h and left ventricular ejection fraction (LVEF) of <50% who underwent successful ablation between January 1, 2009, to June 30, 2015. Subjects were classified as having reversible (a final LVEF >=50%) or irreversible (final LVEF <50%) LV dysfunction on a follow-up echocardiogram. A reference (control) group with >=10% PVC but normal LV function was also identified. RESULTS: Sixty-one patients (age 68 +/- 11 years, 98% male) were studied: 30 with preserved and 31 with reduced LVEF. During median follow-up of 9.4 months, the LVEF of 17 of 31 reduced EF patients improved (reversible) but 14 did not (irreversible). The post-PVC beat systolic blood pressure (SBP) (mm Hg) increase ranged from 12.1 in control subjects (LVEF >50%) to 11.5 in reversible patients to 5 in irreversible patients. In multivariate analysis, the independent predictors of reversible LV function were post-PVC SBP rise (odds ratio [OR]: 4.61; 95% confidence interval [CI]: 1.45 to 15.83 per 5-mm Hg increase; p < 0.001), post-PVC pulse pressure change (OR: 5.2; 95% CI: 2.3 to 18.6 per 5-mm Hg increase; p < 0.001), and PVC QRS duration (OR: 2.78; 95% CI: 1.63 to 10.94 per 10-ms increase; p < 0.001). CONCLUSIONS: In patients with LV dysfunction and frequent PVC, post-PVC SBP accentuation may be a marker for subsequent recovery of LVEF after ablation in presumed PVC-induced cardiomyopathy. PMID- 29759626 TI - Post-Extrasystolic Potentiation for Individualizing Care of Premature Ventricular Contraction-Induced Cardiomyopathy. PMID- 29759627 TI - Complications and Health Care Costs Associated With Transvenous Cardiac Pacemakers in a Nationwide Assessment. AB - OBJECTIVES: The aim of this study was to retrospectively characterize transvenous pacemaker (TVP) complications and associated health care costs in a large-scale U.S. patient cohort. BACKGROUND: TVP complications have previously been shown to affect more than 1 in 10 patients but may be underestimated. Pacemakers are widely implanted across community and urban hospitals by operators of varying specialization and experience. METHODS: Truven Health MarketScan databases track U.S. health care claims and encounters of private or Medicare supplemental insurance. Patients implanted with de dual- and single-chamber TVPs between April 2010 and March 2014 and over 1 year of pre-implantation MarketScan enrollment were identified. International Classification of Diseases-Ninth Revision and Current Procedural Terminology codes were used to extract relevant comorbidities and complications. Incremental adjusted cost analysis was performed for acute complications, defined as those occurring within 30 days of implantation. RESULTS: Among 72,701 TVP implantations (mean age 75 +/- 12 years, 55% men, 13% single chamber) with 1.5 +/- 1.1 years of follow-up, acute complications (0 to 1 month) occurred in 7.7% of single- and 9.1% of dual-chamber TVPs and long-term complications (1 to 36 months) in 6.4% and 5.9% of single- and dual-chamber TVPs, respectively. The net 3-year event rates were approximately 15% and 16%. The incidence and incremental cost of complications are considerable. Most common acute complications include thoracic trauma (3.71%, $70,114), leads requiring revision (3.51%, $9,296), and infection (1.15%, $80,247). Long-term complications are attributed to leads (2.84%), infection (2.42%), and pocket (0.96%). CONCLUSIONS: Claims data suggest that TVP complications are more common than previously reported, affecting nearly 1 in 6 patients by 3 years and contributing to considerable incremental U.S. health care cost. PMID- 29759628 TI - The Price of Imperfection: Complications and Costs Associated With Transvenous Pacemaker Implantation. PMID- 29759630 TI - Clockwork and Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia. PMID- 29759629 TI - Circadian Variation of Ventricular Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia. AB - OBJECTIVES: The aim of this paper was to investigate whether ventricular arrhythmias in children with catecholaminergic polymorphic ventricular tachycardia (CPVT) show circadian patterns. BACKGROUND: Circadian arrhythmic patterns have been established in long QT, Brugada, and early repolarization, but have not been investigated in CPVT. METHODS: This is a multicenter, retrospective review of pediatric CPVT patients, age <21 years at diagnosis. Timing of ventricular tachycardia (VT >=3 beats) was assessed during 24-h continuous monitoring (Holter, implantable loop recorder, implantable cardioverter defibrillator) and by eliminating sleep hours, in addition to sporadic exercise stress tests. Morning was defined as 6:00 am to 11:59 am, afternoon 12:00 pm to 5:59 pm, and evening 6:00 pm to 11:59 pm. Distribution of VT events was compared by time of day, day of week, age, and sex. RESULTS: Eighty patients (53% male), 61% with an ICD, experienced 423 VT events during a median follow-up time of 6 years (interquartile range: 2 to 10 years). When compared to morning hours, VT was more likely to occur in the afternoon (odds ratio [OR]: 2.54; 95% confidence interval [CI]: 1.69 to 3.83) or evening hours (OR: 2.91; 95% CI: 1.82 to 4.67). The predominance of afternoon/evening events persisted regardless of age, gender, or day of the week. Among 50 patients who underwent exercise stress tests, VT was significantly more likely to occur in the afternoon (OR: 3.00; 95% CI: 1.39 to 6.48). CONCLUSIONS: In pediatric CPVT patients, ventricular arrhythmias are more likely to occur in the afternoon and evening hours. Because children's activity levels peak in both the morning and afternoon, the lack of arrhythmias in the morning hours raises questions whether factors other than adrenergic stimulation influence arrhythmia induction in pediatric patients with CPVT. PMID- 29759631 TI - Idiopathic Lead Migration: Concept and Variants of an Uncommon Cause of Cardiac Implantable Electronic Device Dysfunction. AB - OBJECTIVES: This cumulative case study was performed to properly address the possible mechanisms, forms, and consequences of "twiddler's," "reel," and "ratchet" syndromes. BACKGROUND: Twiddler's, reel, and ratchet syndromes are rare entities responsible for lead displacement of cardiac implantable electronic devices (CIED). METHODS: From 2007 to 2012, 1,472 CIED were implanted at our center. Eighty-nine cases were reviewed for failure of pacing circuit integrity. Only 9 met the inclusion criteria for idiopathic lead migration (ILM) and were grouped as ILM (twiddler) or ILM (reel). For a pooled analysis of cases, a review of the literature from 1990 to 2012 was performed, and the authors identified 78 cases from 64 publications. RESULTS: The study population consisted of 87 cases (45 women; median age, 66 years; 46 with ILM [twiddler] and 41 with ILM [reel]). Migration affected only 1 lead in 65% of 46 devices with more than 1 lead. None of the previously reported risk factors-manual manipulation of the device, elderly age, obesity, oversized pocket, and psychiatric history-correlated with the risk of ILM. CONCLUSIONS: Neither manual manipulation of the device nor the other traditional risk factors reported in the literature for ILM syndrome correlated with the risk of ILM. PMID- 29759632 TI - Catheter Ablation of Brugada Syndrome: Importance of Repeated Administration of Ajmaline to Unmask the Entire Epicardial Substrate. PMID- 29759633 TI - Transseptal Delivery of a Leadless Left Ventricular Endocardial Pacing Electrode. PMID- 29759634 TI - An Unexpected Intermittent Repetitive Audible Alert Just After Replacement of an Implantable Cardioverter-Defibrillator. PMID- 29759635 TI - Nonsustained Ventricular Tachycardia at the Time of Implantation Predicts Appropriate Therapies on Rapid Ventricular Arrhythmia in Primary Prevention Patients With Nonischemic Cardiomyopathy: Results From the Very-High-Rate Registry. PMID- 29759636 TI - Are Rotors Markers of Substrate or a Mechanism of Perpetuation of Atrial Fibrillation?: Rotor Ablation in AF: Many Unanswered Questions. PMID- 29759637 TI - Reply: Are Rotors Markers of Substrate or a Mechanism of Perpetuation of Atrial Fibrillation? Increasing Data for Rotational Drivers of Human AF. PMID- 29759638 TI - A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature. AB - Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. PMID- 29759639 TI - Uniparental disomy unveils a novel recessive mutation in POMT2. AB - Mutations in POMT2 are most commonly associated with Walker-Warburg syndrome and Muscle-Eye-Brain disease, but can also cause limb girdle muscular dystrophy (LGMD2N). We report a case of LGMD due to a novel mutation in POMT2 unmasked by uniparental isodisomy. The patient experienced proximal muscle weakness from three years of age with minimal progression. She developed progressive contractures and underwent unilateral Achilles tenotomy. By age 11, she had borderline low left ventricular ejection fraction and mild restrictive lung disease. Muscle biopsy showed mild dystrophic changes with selective reduction in alpha-dystroglycan immunostaining. Sequencing of POMT2 showed a novel homozygous c.1502A>C variant that was predicted to be probably pathogenic. Fibroblast complementation studies showed lack of functional glycosylation rescued by wild type POMT2 expression. Chromosomal microarray showed a single 15 Mb copy number neutral loss of heterozygosity on chromosome 14 encompassing POMT2. RNAseq verified homozygosity at this locus. Together, our findings indicate maternal uniparental isodisomy causing LGMD2N. PMID- 29759641 TI - Impact of antimicrobial wipes compared with hypochlorite solution on environmental surface contamination in a health care setting: A double-crossover study. AB - OBJECTIVE: Antimicrobial wipes are increasingly used in health care settings. This study evaluates, in a clinical setting, the efficacy of sporicidal wipes versus a cloth soaked in a 1,000 ppm chlorine solution. INTERVENTION: A double crossover study was performed on 2 different surgical and cardiovascular wards in a 1,000-bed teaching hospital over 29 weeks. The intervention period that consisted of surface decontamination with the preimpregnated wipe or cloth soaked in chlorine followed a 5-week baseline assessment of microbial bioburden on surfaces. Environmental samples from 11 surfaces were analyzed weekly for their microbial content. RESULTS: A total of 1,566 environmental samples and 1,591 ATP swabs were analyzed during the trial. Overall, there were significant differences in the recovery of total aerobic bacteria (P < .001), total anaerobic bacteria (P < .001), and ATP measurement (P < .001) between wards and between the different parts of the crossover study. Generally, the use of wipes produced the largest reduction in the total aerobic and anaerobic counts when compared with the baseline data or the use of 1,000 ppm chlorine. Collectively, the introduction of training plus daily wipe disinfection significantly reduced multidrug-resistant organisms recovered from surfaces. Reversion to using 1,000 ppm chlorine resulted in the number of sites positive for multidrug-resistant organisms rising again. CONCLUSIONS: This double-crossover study is the first controlled field trial comparison of using preimpregnated wipes versus cotton cloth dipped into a bucket of hypochlorite to decrease surface microbial bioburden. The results demonstrate the superiority of the preimpregnated wipes in significantly decreasing microbial bioburden from high-touch surfaces. PMID- 29759640 TI - Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. AB - BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). METHODS: The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. RESULTS: Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). CONCLUSION: The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2 mediated angiogenesis pathway predicted the prognosis of patients with ICC. PMID- 29759642 TI - Covering the instrument table decreases bacterial bioburden: An evaluation of environmental quality indicators. AB - BACKGROUND: Covering the instrument table during surgery may decrease contamination. We hypothesized that (1) covering the instrument table in an operating room (OR) during static periods of nonuse and dynamic periods of active use would dramatically decrease the bacterial bioburden on the table, and (2) the use of sterile plastic table covers would be equivalent to sterile impervious paper covers in reducing the bioburden in a dynamic environment. METHODS: Bacterial contamination of the instrument table was evaluated by settle plates in static and dynamic ORs. Airborne particulate and bacterial contaminants were sampled throughout the room. Tested groups included instrument tables covered with sterile impervious paper covers, sterile plastic covers, or no covers. RESULTS: Covering the instrument table during static and dynamic operating room conditions resulted in a significantly decreased bacterial load on the instrument table. No differences were seen between paper and plastic covers. CONCLUSIONS: A significant decrease in bacterial bioburden on the instrument table when the table was covered during static and dynamic periods was observed, suggesting the utility for covering the instrument table during periods of nonuse and during active surgeries. PMID- 29759644 TI - Academy of Nutrition and Dietetics Evidence-Based Practice Guideline for the Management of Heart Failure in Adults. PMID- 29759645 TI - Complementary enantioselectivity profiles of chiral cinchonan carbamate selectors with distinct carbamate residues and their implementation in enantioselective two dimensional high-performance liquid chromatography of amino acids. AB - A cardinal requirement for effective 2D-HPLC separations is sufficient complementarity in the retention profiles of first and second dimension separations. It is shown that retention and enantioselectivity of chiral selectors derived from cinchona alkaloids can be conveniently modulated by structural variation of the carbamate residue of the quinine/quinidine carbamate ligand of such chiral stationary phases (CSP). A variety of aliphatic and aromatic residues have been tested in comparison to non-carbamoylated quinine CSP. Various measures of orthogonality have been utilized to derive the CSP that is most complementary to the tert-butylcarbamoylated quinine CSP (tBuCQN CSP), which is commercially available as Chiralpak QN-AX column. It turned out that O-9 (2,6-diisopropylphenylcarbamoyl)-modified quinine is most promising in this respect. Its implementation as a complementary CSP for the separation of amino acids derivatized with Sanger's reagent (2,4-dinitrophenylated amino acids) in the first dimension combined with a tBuCQN CSP in the second dimension revealed successful enantiomer separations in a comprehensive chiral*chiral 2D-HPLC setup. However, the degree of complementarity could be greatly enhanced when simultaneously the absolute configurations were exchanged from quinine to quinidine in the chiral selector of the first dimension separation resulting in opposite elution orders of the enantiomers in the two dimensions. The advantage of such a chiral*chiral over achiral*chiral 2D-HPLC setup, amongst others, is the perfect compatibility of the mobile phase because in both dimensions the identical eluent can be used. PMID- 29759646 TI - Quantification of 38 dietary polyphenols in plasma by differential isotope labelling and liquid chromatography electrospray ionization tandem mass spectrometry. AB - Polyphenols constitute one of the most complex classes of phytochemicals in the human diet and have been suggested to play a role in the prevention of chronic diseases such as cardiovascular diseases, diabetes and cancers. However, evidence from epidemiological studies is still needed to better understand their role in disease prevention. To do so, robust methods for the accurate measurement of these molecules in large series of samples are needed. We report here the development of a highly-sensitive method based on differential isotope labelling with 13C- and 12C-dansyl chloride for the analysis of 38 structurally diverse polyphenols in 50 MUL plasma by tandem mass spectrometry with limits of quantification varying between 0.11 to 44 nmol/L. Full validation of the method was achieved for 37 compounds out of the 38 tested. The method showed intra- and inter-batch coefficients of variations of 2.3-9.0% and 2.8-20.3% respectively depending on polyphenols when applied to 1163 plasma samples from the European Prospective Investigation on Cancer and Nutrition (EPIC) study. For the first time this method allowed to quantify with high accuracy and reproducibility a large selection of compounds representative of the main classes of dietary polyphenols in low volumes of plasma. PMID- 29759643 TI - Oncoplastic breast surgery for the management of ductal carcinoma in situ (DCIS): is it oncologically safe? A retrospective cohort analysis. AB - BACKGROUND: Few data exist in literature regarding oncoplastic surgery (ONC) and ductal carcinoma in situ (DCIS). The role of ONC in the treatment of DCIS has not been elucidated yet: no case-control study has yet been published on the issue and no long-term oncologic results are reported. METHODS: Using the European Institute of Oncology (IEO) institutional breast cancer data base we investigated the oncologic safety of ONC for DCIS comparing a consecutive series of 44 patients who have underwent ONC followed by external irradiation for DCIS (Group A-study group) with 375 patients who received conservation alone followed by external irradiation for DCIS (Group B control group) in the same period. We excluded patients presenting with secondary tumors or local relapses and those requiring re-excision or completion mastectomy for positive margins. Primary endpoints were disease-free survival (DFS) and ipsilateral breast tumor recurrence (IBTR) within the study group and comparison with the control group. RESULTS: Events rates and death rates were similar in the two groups. The average annual rate of invasive IBTR in group A and B was 1.6% and 1.0% respectively. No difference in the rate of lymphnode metastasis, distant metastasis, contralateral breast cancer, other primary cancer or death was observed across the two groups. CONCLUSIONS: Our findings suggest the safety of ONC and irradiation for the management of DCIS extending the indications for conservation in DCIS patients otherwise treated with mastectomy. It provides the best available evidence supporting ONC as a valid treatment option for the management of DCIS. PMID- 29759647 TI - Fundamental aspects of field-amplified electrokinetic injection of cations for enantioselective capillary electrophoresis with sulfated cyclodextrins as selectors. AB - Head-column field-amplified sample stacking of cations from a low conductivity sample followed by enantiomeric separation using negatively charged chiral selectors was studied experimentally and with computer simulation. Aspects investigated include the direct electrokinetic injection of the analytes into the background electrolyte, the use of a selector free buffer plug, the contribution of complexation within the buffer plug and the application of an additional water plug between sample and buffer plug. Attention was paid for changes of ionic strength which is known to have a significant impact on complexation and thus effective mobility. Racemic methadone was selected as a model compound, randomly substituted sulfated beta-cyclodextrin as chiral selector and phosphate buffers (pH 6.3) for the background electrolyte and the buffer plug. Results confirm that the buffer plug is providing a spacer between cationic analytes and the negatively charged selector during electrokinetic injection. Simulation predicts the required length and composition of the plug for a given injection time to avoid an interference with the selector. A short water plug added between the low conductivity sample and a high conductivity buffer plug is demonstrated to provide best conditions to achieve high sensitivity in enantioselective drug assays with sulfated cyclodextrins as selectors. PMID- 29759648 TI - Synthesis of magnetic mesoporous metal-organic framework-5 for the effective enrichment of malachite green and crystal violet in fish samples. AB - A novel, magnetic and mesoporous Fe3O4@PEI-MOF-5 material was synthesized for the effective enrichment of malachite green (MG) and crystal violet (CV) in fish samples. The Fe3O4@PEI-MOF-5 material was prepared by a facile two-step solvothermal approach in which Fe3O4@PEI and MOF-5 were connected through chemical bonds. Characterization of the newly synthesized Fe3O4@PEI-MOF-5 material was performed by Fourier transform infrared spectroscopy, X-ray diffractometry, vibrating sample magnetometry, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis and X-ray photoelectron spectroscopy. This new material was determined to have high magnetization and chemical stability, a large surface area and a distinctive morphology. An effective enrichment and detection method for MG and CV was subsequently developed by combining the Fe3O4@PEI-MOF-5 material with ultra-high performance liquid chromatography-tandem mass spectrometry. The linearity ranges of this approach for MG and CV were 1-500ng/mL and 0.25-500ng/mL, respectively, with correlation coefficients (R2) of 0.999. The limits of detection (LODs) of the method for MG and CV were 0.30ng/mL and 0.08ng/mL, respectively, indicating that the Fe3O4@PEI-MOF-5 material had good adsorption properties for MG and CV. Fe3O4@PEI-MOF-5 can be expected to also provide efficient enrichment of MG and CV in other complex matrices. PMID- 29759650 TI - Direct current dielectrophoretic manipulation of the ionic liquid droplets in water. AB - The ionic liquids (ILs) as the environmentally benign solvents show great potentials in microemulsion carrier systems and have been widely used in the biochemical and pharmaceutical fields. In the work, the ionic liquid-in-water microemulsions were fabricated by using two kinds of hydrophobic ionic liquid, 1 Butyl-3-methylimidazolium hexafluorophosphate [Bmim][PF6] and 1-Hexyl-3 methylimidazolium hexafluorophosphate [Hmim][PF6] with Tween 20. The ionic liquid droplets in water experience the dielectrophoretic (DEP) forces induced by applying electrical field via a nano-orifice and a micron orifice on the opposite channel walls of a microchannel. The dielectrophoretic behaviors of the ionic liquid-in-water emulsion droplets were investigated under direct current (DC) electric field. The positive and negative DEP behaviors of the ionic liquid-in water droplets varying with the electrical conductivity of the suspending medium were investigated and two kinds of the ionic liquid droplets of similar sizes were separated by their different DEP behaviors. In addition, the separation of the ionic liquid-in-water droplets by size was conducted. This paper, for the first time to our knowledge, presents the DC-DEP manipulation of the ionic liquid in-water emulsion droplets by size and by type. This method provides a platform to manipulate the ionic liquid droplets individually. PMID- 29759649 TI - Using pattern recognition entropy to select mass chromatograms to prepare total ion current chromatograms from raw liquid chromatography-mass spectrometry data. AB - The total ion current chromatogram (TICC) obtained by liquid-chromatography-mass spectrometry (LC-MS) is often extremely complex and 'noisy' in appearance, particularly when an electrospray ionization source is used. Accordingly, meaningful qualitative and quantitative information can be obtained in LC-MS by data mining processes. Here, one or more higher-quality mass chromatograms can be identified/extracted/isolated and combined to form a TICC, wherein much of the background mass noise is eliminated, and quantitative data for chromatographic peaks can be obtained. Pattern Recognition Entropy (PRE) is a new application of Shannon's statistical concept of entropy. PRE is both a pattern recognition tool and a summary statistic that can be used to identify information-containing mass chromatograms, where higher quality data (higher signal-to-noise mass chromatograms) usually have lower PRE values. Reduced TICCs are obtained by first calculating the PRE values of the component mass chromatograms. A plot of PRE value vs. m/z for the mass chromatograms is then generated, and the resulting band of PRE values is fit to a piecewise spline polynomial. The distribution of the differences between the individual PRE values and the spline fit is then used to select 'good' mass chromatograms. For the data set considered herein, best results were obtained with a threshold of 0.5 standard deviations below the average value (value of the spline). PRE reduces the number of component mass chromatograms significantly (by an order of magnitude) and at the same time preserves most of the chemical information that is collectively in them. It can also distinguish between mass chromatograms of chemically similar species. PRE is arguably a less computationally intensive alternative to the widely used CODA algorithm for variable reduction. It produces reduced TICCs of comparable if not higher quality, and it requires only a single user input for variable selection. Reduced TICCs generated by PRE can be smoothed to further improve their signal-to noise ratios. PMID- 29759652 TI - The severity of denture stomatitis as related to risk factors and different Candida spp. AB - OBJECTIVES: 1) To select patients with Candida-related denture stomatitis (DS) and to study possible risk factors associated with DS, 2) to evaluate the severity of DS according to Newton's classification, and 3) to investigate the association between the presence of non-albicans Candida spp. (NAC) or mixed Candida spp. and the severity of DS. STUDY DESIGN: Eighty-two patients with Candida-positive DS have undergone 1) filling in the interview questionnaire, 2) clinical examination, and 3) microbiologic examination. RESULTS: A total of 113 Candida spp. isolates were obtained from Candida-positive DS patients: C. albicans (as a single species) in 47/82 (57%) patients (study group A [SG_A]) and NAC/mixed Candida spp. in 35/82 (43%) patients (SG_B). Univariate logistic regression analysis showed that older age, longer age of the mandibular denture, and ex-smoker status were associated with SG_A. A multivariate model revealed no significant predictor of DS severity. Patients from SG_A were 3 times as likely to have DS type I, while patients from SG_B were 4.9 times as likely to have DS type III. CONCLUSIONS: Our results show the association between type III of DS (by Newton's classification) and the presence of NAC or mixed Candida spp. in denture wearers. PMID- 29759651 TI - Unilateral pyramidal cataract. PMID- 29759654 TI - Letter comments on EJC published paper: 'No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer study'. PMID- 29759653 TI - Kinematics and kinetics of the shoe during human slips. AB - This paper quantified the heel kinematics and kinetics during human slips with the goal of guiding available coefficient of friction (ACOF) testing methods for footwear and flooring. These values were then compared to the testing parameters recommended for measuring shoe-floor ACOF. Kinematic and kinetic data of thirty nine subjects who experienced a slip incident were pooled from four similar human slipping studies for this secondary analysis. Vertical ground reaction force (VGRF), center of pressure (COP), shoe-floor angle, side-slip angle, sliding speed and contact time were quantified at slip start (SS) and at the time of peak sliding speed (PSS). Statistical comparisons were used to test if any discrepancies exist between the state of slipping foot and current ACOF testing parameters. The main findings were that the VGRF (26.7 %BW, 179.4 N), shoe-floor angle (22.1 degrees ) and contact time (0.02 s) at SS were significantly different from the recommended ACOF testing parameters. Instead, the testing parameters are mostly consistent with the state of the shoe at PSS. We argue that changing the footwear testing parameters to conditions at SS is more appropriate for relating ACOF to conditions of actual slips, including lower vertical forces, larger shoe-floor angles and shorter contact duration. PMID- 29759655 TI - Re: No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer Study. PMID- 29759656 TI - Well-Being among Emergency Medicine Resident Physicians: Results from the ABEM Longitudinal Study of Emergency Medicine Residents. AB - BACKGROUND: The Longitudinal Study of Emergency Medicine Residents (LSEMR) conducted by the American Board of Emergency Medicine queries a randomized cohort of emergency medicine (EM) residents. It is designed to identify residents' perceptions of their training, sources of stress, well-being level, and career choice satisfaction over time. OBJECTIVES: This study utilizes LSEMR to identify resident well-being levels, career satisfaction, factors producing stress, and whether a specific cohort is more stressed than the overall respondent group. METHODS: Data from five longitudinal cohorts were analyzed using descriptive statistics to assess stressors, career satisfaction, and self-reported resident well-being. Participants' answers were reported on a 5-point Likert scale. RESULTS: There were 766 residents who completed the survey in five cohorts. Respondents were 30 years old (median 29), male (66%), and predominantly White (79%). The most frequently encountered problems included "time devoted to documentation and bureaucratic issues," "knowing enough," and "crowding in the emergency department." In contrast, the least frequently reported problems included "gender discrimination," "EMS support," "minority discrimination," and "other residents." Respondents thought being an EM resident was fun and would select EM again. Less than 20% indicated they had seriously considered transferring to another EM program. Resident reports of health concerns changed over time, with fewer residents reporting they were exceptionally healthy in 2016. CONCLUSIONS: Residents are, overall, happy with their career choice. However, concern was expressed regarding continued well-being in training. Sources of stress in training are identified. Strategies should be developed to decrease identified stressors and increase well-being among EM residents. PMID- 29759657 TI - No Radiographic Safe Margin Found in the "Easy IJ" Internal Jugular Vein Procedure. AB - BACKGROUND: The Easy IJ procedure involves placement of a 4.8-cm intravenous catheter into the internal jugular (IJ) vein using ultrasound guidance. It is not known whether this needle length has the potential to cause a pneumothorax. OBJECTIVE: The objective of this study was to determine if a radiographic "safe margin" exists. We hypothesized that an average margin of >=2 cm would exist between the catheter tip and the pleura. METHODS: Operators used a central approach to the IJ vein. We reviewed radiographic images taken immediately after the Easy IJ procedure. Using digital software, we measured the distance from the catheter tip to the closest point of the pleura and from the catheter tip to the level of the lung apex. We defined distances exceeding the margin of safety either passing the pleura or ending inferior to the apex-as negative for the purpose of calculating an average. We used the t distribution to calculate 95% confidence intervals (CIs) for average values. RESULTS: Radiographs showing the catheter tip were available from 62 patients. The mean needle-to-pleura distance was -0.1 cm (95% CI -0.7 to 0.5 cm). The mean vertical distance to the apex was 0.2 cm (95% CI -0.8 to 0.3 cm), with a standard deviation of 2.25 cm. CONCLUSION: Radiographic analysis failed to show a margin of safety for the Easy IJ procedure. Postprocedure imaging may still be necessary to exclude pneumothorax. PMID- 29759658 TI - Three cases of food protein-induced enterocolitis syndrome caused by egg yolk. PMID- 29759659 TI - The global development and clinical efficacy of sublingual tablet immunotherapy for allergic diseases. AB - Allergy immunotherapy (AIT) is a treatment option for respiratory allergy that is complementary to pharmacotherapy, with a distinct mechanism of action. Alternative methods to subcutaneous administration of AIT that enable patients to safely self-administer AIT is considered an unmet clinical need. The sublingual immunotherapy tablet (SLIT-tablet) is an orally disintegrating pharmaceutical formulation (oral lyophilisate) containing standardized allergens. SLIT-tablets have been developed for sublingual immunotherapy (SLIT) of cedar-pollen, grass pollen, ragweed-pollen, tree-pollen, and house dust mite allergies. It is a once daily tablet treatment to be self-administered after the first dose has been provided under the supervision of a physician with experience in the diagnosis and treatment of allergic diseases. Once the first dose is adequately tolerated, subsequent doses may be self-administered. SLIT-tablets have proven efficacy for allergic rhinitis (AR) with and without conjunctivitis (C) and allergic asthma (AA) in adults, children, and poly-sensitized allergic patients. Meta-analyses indicate that SLIT-tablets have superior or similar efficacy compared with anti allergic pharmacotherapies for seasonal AR and superior efficacy for perennial AR. SLIT-tablets have also demonstrated clinically relevant improvements of asthma, with significant reductions in the following: daily inhaled corticosteroid use, risk of asthma exacerbations, and asthma symptoms. SLIT tablets are generally well tolerated, with a low risk of systemic allergic reactions. The most common treatment-related adverse events are mild-moderate oral reactions. Current evidence supports SLIT-tablets to be considered as an alternative or add-on treatment to pharmacotherapy for AR/C and asthma. Future SLIT developments may include early intervention to prevent the development or progression of allergic disease in children. PMID- 29759660 TI - Extensive serum biomarker analysis in patients with nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is a fast-growing cancer characterized by high occurrences of nodal and distant metastases and poor prognosis. It is therefore important to identify new serum biomarkers for the early diagnosis and prognostic prediction of this disease. The present study identifies biomarkers in NPC patient serum using a solid-phase antibody array detecting the expression profiles of 174 cytokines in a single experiment. ELISA was performed to validate the array results. The levels of TIMP-2, SELL, CCL24, MMP-1, MMP-3, IGF-I and IL 8 were significantly higher in serum from NPC patients, while the levels of MSP alpha and HCC-4 were lower. Furthermore, the validation results were identical to those obtained from the antibody array. These results indicate that these cytokines might serve as novel biomarkers for the diagnosis and prognostic prediction of NPC. PMID- 29759661 TI - Integrity of the Urethral Sphincter Complex, Nerve-sparing, and Long-term Continence Status after Robotic-assisted Radical Prostatectomy. AB - BACKGROUND: The applicability of the sphincter complex integral theory to robotic assisted radical prostatectomy (RARP) is unclear, with little known about the long-term effect of sphincter complex integrity on continence. OBJECTIVE: To determine whether the preoperative anatomical and functional features of the sphincter complex and the degree of nerve-sparing affect long-term continence after RARP. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 529 patients who underwent RARP at a single tertiary center. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Anatomical factors, including membranous urethral length (MUL) and pelvic diaphragm length (PDL), were assessed using sagittal views of preoperative magnetic resonance imaging. MUL was defined as the distance from the posterior prostate apex to the urethra level at the penile bulb, and PDL was defined as the length of the urethra that met the planes created by the pelvic floor muscles. Functional parameters including maximum urethral closure pressure (MUCP) and functional urethral length were evaluated using preoperative measurements of the urethral pressure profiles. The degree of nerve-sparing was stratified as bilateral, unilateral, or none. Continence (pad-free status) was assessed according to anatomical and functional factors and nerve-sparing. We used binary logistic regression to assess factors predicting continence return 12 mo after RARP. RESULTS AND LIMITATIONS: Continence return rates 1, 3, 6, and 12 mo after RARP were 39.7%, 66.0%, 80.2%, and 87.0%, respectively. Continence return rates at 12 mo differed significantly in patients with MUL >=11.7mm (91.9%) and <11.7mm (79.9%), PDL >=9.9mm (96.7%) and <9.9mm (74.5%), and MUCP >=66 cmH2O (89.7%) and <66 cmH2O (79.4%). The continence return rate was significantly higher in patients with bilateral (93.0%) than in patients with unilateral (78.1%) or no (76.7%) nerve-sparing. Multivariate analysis showed that PDL (odds ratio [OR]=2.187 per mm), MUCP (OR=1.037 per cmH2O), and bilateral nerve-sparing (OR=3.671) were independently associated with continence return 12 mo after RALP. CONCLUSIONS: The anatomical length and static pressure of the sphincter complex affected continence after RARP. Bilateral nerve-sparing was independently associated with long-term continence. PATIENT SUMMARY: Predisposing length and static pressure of the urinary sphincter affect continence after robotic-assisted radical prostatectomy. Nerve bundle preservation during surgery enhances postoperative return of continence. PMID- 29759662 TI - Nandrolone decanoate and physical activity affect quadriceps in peripubertal rats. AB - Anabolic androgenic steroids (AASs) are synthetic analogs of testosterone often used by athletes to increase the skeletal muscle mass. Our goal was to examine the effects of physical activity and physical activity combined with supraphysiological doses of nandrolone on functional morphology of the quadriceps muscle. The study included 32 peripubertal Wistar rats, divided into 4 groups: control (T-N-), nandrolone (T-N+), physical activity (T+N-) and physical activity plus nandrolone (T+N+) groups. The T+N- and T+N+ group swam for 4 weeks, 1 h/day, 5 days/week. The T-N+ and T+N+ groups received nandolone decanoate (20 mg/kg b.w.) once per week, subcutaneously. Subsequently, the rats were sacrificed and muscle specimens were prepared for the processing. Tissue sections were histochemically and immunohistochemically stained, while the image analysis was used for quantification. Longitudinal diameter of quadriceps muscle cells was increased for 21% in T-N+, for 57% in T+N- and for 64% in T+N+ group while cross section muscle cell area was increased in T-N+ for 19%, in T+N- for 47% and in T+N+ group for 59%, compared to the control. Collagen fibers covered area was increased in T-N+ group for 36%, in T+N- for 109% and in T+N+ group for 159%, compared to the control. Erythrocyte depots were decreased in T-N+ group and increased in T+N- and T+N+ group, in comparison with T-N-. VEGF depots were increased in all treated groups. Chronic administration of supraphysiological doses of AASs alone or in combination with physical activity induces hypertrophy and significant changes in the quadriceps muscle tissue structure. PMID- 29759663 TI - Cellular Physiology and Clinical Manifestations of Fascicular Arrhythmias in Normal Hearts. AB - Fascicular ventricular arrhythmias represent a spectrum of ventricular tachycardias dependent on the specialized conduction system. Although they are more common in structurally abnormal hearts, there is an increasing body of literature describing their role in normal hearts. In this review, the authors present data from both basic and clinical research that explore the current understanding of idiopathic fascicular ventricular arrhythmias. Evaluation of the cellular electrophysiology of the Purkinje cells shows clear evidence of enhanced automaticity and triggered activity as potential mechanisms of arrhythmias. Perhaps more importantly, heterogeneity in conduction system velocity and refractoriness of the left ventricular conduction system in animal models are in line with clinical descriptions of re-entrant fascicular arrhythmias in humans. Further advances in our understanding of the conduction system will help bridge the current gap between basic science and clinical fascicular arrhythmias. PMID- 29759664 TI - Angiographic Efficacy of the Atriclip Left Atrial Appendage Exclusion Device Placed by Minimally Invasive Thoracoscopic Approach. AB - OBJECTIVES: This study sought to assess long-term left atrial appendage (LAA) closure efficacy of the Atriclip applied via totally thoracoscopic (TT) approach with computed tomographic angiography. BACKGROUND: LAA closure is associated with a low risk for atrial fibrillation-related embolic stroke. The Atriclip exclusion device allows epicardial LAA closure, avoiding the need for post-operative oral anticoagulation. Previous data with Atriclip during open chest procedures show a high efficacy rate of closure >95%. METHODS: Three-dimensional volumetric 2-phase computed tomographic angiography >=90 days post-implantation was independently assessed by chest radiology for complete LAA closure on all consented subjects identified retrospectively as having had a TT-placed Atriclip at Vanderbilt University Medical Center from June 13, 2011, to October 6, 2015. RESULTS: Complete LAA closure (defined by complete exclusion of the LAA with no exposed trabeculations, and clip within 1 cm from the left circumflex artery) was found in 61 of 65 subjects (93.9%). Four cases had incomplete closure (6.2%). Two clips were placed too distally, leaving a large stump with exposed trabeculae. Two clips failed to address a secondary LAA lobe. No major complications were associated with TT placement of the Atriclip. Follow-up over 183 patient-years revealed 1 stroke in a patient with complete LAA closure and no thrombus (hypertensive cerebrovascular accident). CONCLUSIONS: Angiographic LAA closure efficacy with a TT-placed Atriclip is high (93.9%). The clinical significance of a remnant stump is unknown. Confirmation of complete LAA occlusion should be made before cessation of systemic anticoagulation. PMID- 29759665 TI - Thoracoscopic Left Atrial Appendage Occlusion: We Can Do It, Now Should We? PMID- 29759666 TI - Patients With Atrial Fibrillation Who Are Not on Anticoagulant Treatment Due to Increased Bleeding Risk Are Common and Have a High Risk of Stroke. AB - OBJECTIVES: This study sought to determine how many patients with atrial fibrillation (AF) are not treated with oral anticoagulants (OAC) due to a high risk of bleeding and to characterize their risk of ischemic stroke in a real world setting. BACKGROUND: AF is associated with a 5-fold increased risk of ischemic stroke. OAC reduce the risk of stroke in patients with AF who do not have an increased bleeding risk, but no comparably effective treatment exists for patients with contraindications to OAC. METHODS: We analyzed administrative claims data from individuals with commercial and Medicare supplemental health insurance in the United States. We selected patients with AF and a documented contraindication to OAC who were not treated with OAC. The primary endpoint was the occurrence of ischemic stroke, as calculated per patient year. RESULTS: We identified 1,300,643 patients with AF claims, of which 43,248 had a contraindication event and remained OAC naive for at least 1 year or died in hospital. More than 80% of the patients had a CHA2DS2-VASc score of >1. The incidence of ischemic stroke was 4.1% in the overall OAC naive cohort and was more common with increasing CHA2DS2/CHA2DS2-VASc score. Hemorrhagic stroke occurred in 3.6%. For patients with previous intracranial bleeding, the incidences of ischemic and hemorrhagic stroke were 12.2% and 20.3%, respectively. CONCLUSIONS: Patients with AF who are not treated with OAC due to increased bleeding risk are common. These patients are at considerable risk of both ischemic and hemorrhagic events. A novel approach to stroke prophylaxis in this population is needed. PMID- 29759667 TI - Patients With Atrial Fibrillation: Switching Emphasis From Stroke Prevention to Stroke and Hemorrhage Prevention. PMID- 29759668 TI - Incidence, Characteristics, and Clinical Course of Device-Related Thrombus After Watchman Left Atrial Appendage Occlusion Device Implantation in Atrial Fibrillation Patients. AB - OBJECTIVES: This study investigated characteristics and clinical impact of device related thrombus formation after Watchman device implantation in atrial fibrillation (AF) patients. BACKGROUND: Left atrial appendage occlusion using the Watchman device is an effective alternative to anticoagulation for stroke prevention in AF patients. However, device-related thrombus formation remains an important concern after Watchman implantation. METHODS: From 2006 to 2014, 119 consecutive AF patients underwent Watchman implantation. Transesophageal echocardiographic (TEE) follow-up was scheduled at 45 days, at 6 months, and at 12 months after the procedure. The incidence, characteristics, and clinical course of device-related thrombus formation detected by TEE were assessed. RESULTS: Follow-up TEE identified thrombus formation on the Watchman device in 4 patients (3.4%). The prevalence of chronic AF was 100% in patients with thrombus, which was higher than that for patients without thrombus (40.0%). Deployed device size was numerically larger in patients with thrombus (29.3 +/- 3.8 mm vs. 25.7 +/- 3.2 mm, respectively). All patients with thrombus discontinued any of the anticoagulant/antiplatelet therapy which was required under the study protocol. After restarting or continuing warfarin and aspirin therapy, complete resolution of the thrombus was achieved in all patients at subsequent follow-up TEE. Warfarin therapy was discontinued within 6 months for all cases, and there was no thrombus recurrence. The mean follow-up duration was 1,456 +/- 546 days, with no death, stroke, or systemic embolization events in patients with thrombus. CONCLUSIONS: AF burden, device size, and anticoagulant/antiplatelet regimens can be associated with device-related thrombus after Watchman device implantation. Short-term warfarin therapy was effective, and the clinical outcomes were favorable. PMID- 29759669 TI - Watchman Device-Related Thrombus: Defeating the Purpose of the Device? PMID- 29759670 TI - Systemic Octreotide Therapy in Prevention of Gastrointestinal Bleeds Related to Arteriovenous Malformations and Obscure Etiology in Atrial Fibrillation. AB - OBJECTIVES: The present study describes the use of octreotide (OCT) in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) who have gastrointestinal (GI) bleeding related to arteriovenous malformations (AVMs), as well as its effect on OAC tolerance and subsequent rebleeding. BACKGROUND: AVMs cause significant GI bleeding, especially in patients with AF who are receiving OAC for stroke prevention. OCT has been shown to minimize recurrent GI bleeds related to AVMs. METHODS: In a multicenter, observational study, 38 AF patients with contraindications to OAC because of AVM-related GI bleeding were started on 100 MUg of subcutaneous OCT twice daily. OAC was resumed in all patients within 48 h. Incidence of recurrent GI bleeds was calculated, and hemoglobin levels were recorded at enrollment and at 3 and 6 months' follow-up. RESULTS: After a median follow-up of 8 months, 36 patients (mean age 69 +/- 8.0 years; mean CHA2DS2-VASc score 3 +/- 1 and mean HAS-BLED score 3 +/- 1) were available for analysis. All were able to successfully resume OAC, and 28 of 36 (78%) remained on OAC at the conclusion of the study, whereas 8 underwent left atrial appendage closure with subsequent OAC discontinuation. No systemic thromboembolic events occurred in follow-up. Of the 28 patients who continued receiving OAC, 19 (68%) were free of recurrent GI bleed, 4 had minor GI bleeds, 4 required transfusion, and 1 required colectomy for GI bleeding. Mean hemoglobin levels in all patients receiving OAC were significantly higher at 3- and 6-month follow-up than at baseline (p < 0.001). CONCLUSIONS: Subcutaneous OCT therapy is an attractive option in AF patients receiving OAC who have AVM-related GI bleeds. It allows successful reinitiation of OAC as a bridge to left atrial appendage exclusion or short-term relief from bleeding. PMID- 29759671 TI - Yield and Pitfalls of Ajmaline Testing in the Evaluation of Unexplained Cardiac Arrest and Sudden Unexplained Death: Single-Center Experience With 482 Families. AB - OBJECTIVES: This study evaluated the yield of ajmaline testing and assessed the occurrence of confounding responses in a large cohort of families with unexplained cardiac arrest (UCA) or sudden unexplained death (SUD). BACKGROUND: Ajmaline testing to diagnose Brugada syndrome (BrS) is routinely used in the evaluation of SUD and UCA, but its yield, limitations, and appropriate dosing have not been studied in a large cohort. METHODS: We assessed ajmaline test response and genetic testing results in 637 individuals from 482 families who underwent ajmaline testing for SUD or UCA. RESULTS: Overall, 89 individuals (14%) from 88 families (18%) had a positive ajmaline test result. SCN5A mutations were identified in 9 of 86 ajmaline-positive cases (10%). SCN5A mutation carriers had positive test results at significantly lower ajmaline doses than noncarriers (0.75 [range: 0.64 to 0.98] mg/kg vs. 1.03 [range: 0.95 to 1.14] mg/kg, respectively; p < 0.01). In 7 of 88 families (8%), it was concluded that the positive ajmaline response was a confounder, either in the presence of an alternative genetic diagnosis accounting for UCA/SUD (5 cases) or noncosegregation of positive ajmaline response and arrhythmia (2 cases). The rate of confounding responses was significantly higher in positive ajmaline responses obtained at >1 mg/kg than in those obtained at <=1 mg/kg (7 of 48 vs. 0 of 41 individuals; Fisher's exact test: p = 0.014). CONCLUSIONS: In line with previous, smaller studies, a positive ajmaline response was observed in a large proportion of UCA/SUD families. Importantly, our data emphasize the potential for confounding possibly false-positive ajmaline responses in this population, particularly at high doses, which could possibly lead to a misdiagnosis. Clinicians should consider all alternative causes in UCA/SUD and avoid ajmaline doses >1 mg/kg. PMID- 29759672 TI - Read My Lips: A Positive Ajmaline Test Does Not Always Mean You Have Brugada Syndrome. PMID- 29759673 TI - Characterization of Ventricular Tachycardia After Left Ventricular Assist Device Implantation as Destination Therapy: A Single-Center Ablation Experience. AB - OBJECTIVES: This study sought to report mechanisms of ventricular tachycardia (VT) and outcomes of VT ablation in patients with a left ventricular assist device (LVAD) as destination therapy. BACKGROUND: Continuous flow LVAD implantation plays a growing role in the management of end-stage heart failure, and VT is common. There are limited reports of VT ablation in patients with a destination LVAD. METHODS: Patients with a continuous-flow LVAD referred for VT ablation from 2010 to 2016 were analyzed retrospectively. Baseline patient characteristics, procedural data, and clinical follow-up were evaluated. Arrhythmia-free survival was assessed. RESULTS: Twenty-one patients (90% male, 62 +/- 10 years) underwent catheter ablation of VT at a median of 191 days (interquartile range: 55 to 403 days) after LVAD implantation (15 HeartMate II, 6 HeartWare HVAD). Five patients (24%) had termination (n = 4) or slowing (n = 1) of VT with ablation near the apical inflow cannula, and 3 (14%) had bundle-branch re-entry. Freedom from recurrent VT among surviving patients was 64% at 1 year, with overall survival 67% at 1 year for patients without arrhythmia recurrence and 29% for patients with recurrence (p = 0.049). One patient had suspected pump thrombosis within 30 days of the ablation procedure, with no other major acute complications. CONCLUSIONS: In this relatively large, single-center experience of VT ablation in destination LVAD, freedom from recurrent VT and implantable cardioverter-defibrillator shocks was associated with improved 1-year survival. Bundle branch re-entry was more prevalent than anticipated, and cannula-adjacent VT was less common. This challenging population remains at risk for late pump thrombosis and mortality. PMID- 29759674 TI - Population-Based Evaluation of Major Adverse Events After Catheter Ablation for Atrial Fibrillation. AB - OBJECTIVES: The purpose of this study was to evaluate the safety and incidence of periprocedural adverse events (AEs) among patients who underwent catheter ablation (CA) for atrial fibrillation (AF) in Quebec and Ontario, Canada. BACKGROUND: CA is evolving into the mainstay therapy for patients with symptomatic AF refractory to antiarrhythmic medication. However, the safety of CA at the population level over time requires further evaluation. METHODS: A population-based cohort was constructed using administrative databases of all patients who underwent CA between 1999 and 2014 in Quebec and Ontario, Canada. Incidence and predictors of AEs were assessed within 30 days of CA. Major AEs included all-cause mortality, cerebrovascular accident (CVA) including transient ischemic attack, pericardial effusion requiring drainage (PERD), vascular AEs, hemorrhage/hematoma, and pulmonary embolism. RESULTS: Of 6,388 patients who had a CA (mean age 57.3 years; mean CHA2DS2-VASc 1.1 +/- 1.4; 27.6% female), 221 (3.5%) patients developed major AEs within 30 days of index CA. Hemorrhage/hematoma was the most frequent (1.4%), followed by PERD (1.0%) and CVA (0.6%). PERD was more likely to occur post-discharge than during the index CA (p < 0.05). CVA decreased by more than 50% in patients with recent compared with remote CA (p < 0.05). Compared with index CA, the incidence of PERD and hemorrhage/hematoma was greater at first repeat CA (p < 0.05 for both). CONCLUSIONS: CA is a relatively safe procedure with low incidence of major AEs. The incidence of procedure-related CVA appeared to decline significantly over time. Incidence of PERD remained relatively stable and was more likely to be diagnosed after discharge and following repeat CA. PMID- 29759675 TI - Risk of Catheter Ablation for Atrial Fibrillation. PMID- 29759676 TI - Outcomes Associated With Electrical Cardioversion for Atrial Fibrillation When Performed Autonomously by an Advanced Practice Provider. AB - OBJECTIVES: This study sought to determine the feasibility, safety, and efficacy of elective electrical cardioversion (CV) for atrial fibrillation (AF) when performed autonomously by a trained advanced practice provider (APP) using a guideline-directed protocol. BACKGROUND: APPs have emerged as an integral part of the cardiovascular team. METHODS: A licensed advanced practice nurse-clinical nurse specialist was trained and obtained credentials to perform CVs. The advanced practice nurse performed 415 CVs autonomously (APP group) in a noninvasive procedure room with an electrophysiologist (EP) immediately available in an adjacent electrophysiology laboratory. The APP performed a history and physical examination, obtained informed consent, reviewed each patient with the supervising EP, and performed the CV. An anesthesiologist administered sedation. Outcomes were compared with 387 CVs performed by an MD when the APP was not available (MD group). Patient satisfaction scores were compared before and after the APP-directed CVs were performed. RESULTS: The proportion of patients discharged in sinus rhythm was the same in the APP group as it was in the MD group (95% vs. 96%, respectively; p = 0.49). There were 4 adverse events in the CVs performed by the APP: 1 transient ischemic attack and 3 occurrences of bradycardia requiring atropine or other medication. There was 1 adverse event in the MD group, which was hypotension requiring vasopressor initiation. Patient satisfaction scores were stable after initiation of APP-driven cardioversions. CONCLUSIONS: With appropriate clinical training, an APP can safely perform CVs autonomously, using a protocol that includes a guideline-directed procedural checklist and physician supervision, with excellent patient satisfaction and outcomes. PMID- 29759677 TI - The Expanding Role of Nurses in Electrophysiology Practice. PMID- 29759678 TI - Feasibility of Imaging Inflammation in the Left Atrium Post AF Ablation Using PET Technology. PMID- 29759679 TI - Left Atrial Thrombus After Left Atrial Appendage Ligation With the LARIAT Device. PMID- 29759680 TI - Esophageal Damage During Epicardial Ventricular Tachycardia Ablation. PMID- 29759681 TI - Initial Experience With Non-Vitamin K Antagonist Oral Anticoagulants for Short Term Anticoagulation After Left Atrial Appendage Closure Device. PMID- 29759682 TI - Mortality reductions from marginal increases in public spending on health. AB - There is limited empirical evidence of the nature of any relationship between health spending and health outcomes in Australia. We address this by estimating the elasticity of health outcomes with respect to public healthcare spending using an instrumental variable (IV) approach to account for endogeneity of healthcare spending to health outcomes. Results suggest that, based on the conditional mean, a 1% increase in public health spending was associated with a 2.2% (p < 0.05) reduction in the number of standardised Years of Life Lost (YLL). Sensitivity analyses and robustness checks supported this conclusion. Further exploration using IV quantile regression indicated that marginal returns on public health spending were significantly greater for areas with poorer health outcomes compared to areas with better health outcomes. On average, marginal increases in public health spending reduce YLL, but areas with poorer health outcomes have the greatest potential to benefit from the same marginal increase in public health spending compared to areas with better health outcomes. Understanding the relationship between health spending and outcomes and how this differs according to baseline health outcomes can help meet dual policy objectives to improve the productivity of the healthcare system and reduce inequity. PMID- 29759683 TI - SBRT for pancreatic cancer: In regard of Bohoudi et al. PMID- 29759685 TI - Evaluation of the small-aperture intracorneal inlay: Three-year results from the cohort of the U.S. Food and Drug Administration clinical trial. AB - PURPOSE: To evaluate the safety and effectiveness of the Kamra small-aperture intracorneal inlay. SETTING: Centers in North America, Europe, Asia, and Australia. DESIGN: Prospective clinical trial. METHODS: Patients with emmetropic presbyopia had intracorneal implantation of the inlay in the nondominant eye. RESULTS: The study comprised 507 patients with emmetropic presbyopia who were aged 45 to 60 years old. The implanted eyes exhibited 3.5 diopters of defocus range above 20/40, with 363 (87.1%) of 417 patients and 391 (93.8%) of 417 patients having 20/40 or better monocular and binocular uncorrected near visual acuity (UNVA) at 36 months, respectively. Patients implanted via a femtosecond laser pocket procedure using a spot/line setting of 6 MUm * 6 MUm demonstrated further improved near vision, with 131 (90.3%) of 145 patients and 137 (94.5%) of 145 of patients having 20/40 or better monocular and binocular UNVA, respectively. Uncorrected distance visual acuity 20/25 or better was maintained in 135 (93.1%) of 145 of implanted eyes and 100% (145) of 145 of implanted eyes binocularly at 36 months. Less than 1.5% of eyes had a loss of 2 or more lines of corrected distance visual acuity for 3 months or more at any time after surgery. Forty-four inlays (8.7%) were removed from the full cohort over 3 years. The removal rate was significantly less in the 6 * 6 pocket group (3.0% for visual complaints) and further reduced with deeper implantation (0%). Less than 1.0% of the patients reported severe glare or halos postoperatively. CONCLUSION: The small-aperture corneal inlay was found to be safe and effective, improving near vision both monocularly and binocularly with minimal effect on distance visual acuity. PMID- 29759688 TI - Lead Abandonment or Lead Extraction?: Weighing the Risks. PMID- 29759686 TI - Molecular Mechanisms Governing Embryonic Differentiation of Pituitary Somatotropes. AB - Pituitary somatotropes secrete growth hormone (GH), which is essential for normal growth and metabolism. Somatotrope defects result in GH deficiency (GHD), leading to short stature in childhood and increased cardiovascular morbidity and mortality in adulthood. Current hormone replacement therapies fail to recapitulate normal pulsatile GH secretion. Stem cell therapies could overcome this problem but are dependent on a thorough understanding of somatotrope differentiation. Although several transcription factors, signaling pathways, and hormones that regulate this process have been identified, the mechanisms of action are not well understood. The purpose of this review is to highlight the known players in somatotrope differentiation while emphasizing the need to better understand these pathways to serve patients with GHD. PMID- 29759687 TI - Cardiac Implantable Electronic Device Infections: Added Complexity and Suboptimal Outcomes With Previously Abandoned Leads. AB - OBJECTIVES: This study sought to assess the impact of previously abandoned leads on the clinical management of cardiac device infections, notably transvenous lead extraction and subsequent clinical course. BACKGROUND: The population of patients with cardiac implantable electronic devices continues to grow with a disproportionate increase in device infections, which are invariably life threatening. A potentially complicating issue is the widely practiced strategy of device lead abandonment at the time of system revision, change, or upgrade, which is affecting an increasing number of patients. METHODS: The study assessed the impact of previously abandoned leads in a prospectively maintained registry of consecutive patients undergoing percutaneous extraction of infected cardiac devices at the Cleveland Clinic between August 1996 and September 2012. The primary clinical endpoint was complete procedural and clinical success defined as the successful removal of the device and all lead material from the vascular space, in the absence of a major complication. RESULTS: Of 1,386 patients with infected cardiac devices, 323 (23.3%) had previously abandoned leads. Failure to achieve the primary endpoint occurred more frequently in patients with abandoned leads (13.0% vs. 3.7%; p < 0.0001). This was primarily due to retention of lead material (11.5% vs. 2.9%; p < 0.0001), which was associated with poor clinical outcomes including higher rates of 1-month mortality (7.4% vs. 3.5% in those without lead remnants). Lead extraction procedures in patients with previously abandoned leads were longer (p < 0.0001), with longer fluoroscopy times (p < 0.0001), and more likely to require specialized extraction tools (94.4% vs. 81.8%; p < 0.0001) or adjunctive rescue femoral workstations (14.9% vs. 2.9%; p < 0.0001). Procedural complications occurred more frequently in patients with previously abandoned leads (11.5% vs. 5.6%; p = 0.0003), which was true for both major (3.7% vs. 1.4%; p = 0.009) and minor complications (7.7% vs. 4.4%; p = 0.02). CONCLUSIONS: Previously abandoned leads complicate the management of cardiac device infections, leading to worse clinical outcomes. PMID- 29759689 TI - Comparison of Single-Coil and Dual-Coil Implantable Defibrillators: A Meta Analysis. AB - OBJECTIVES: The purpose of this investigation was to conduct a meta-analysis of studies comparing defibrillation threshold (DFT) and outcomes with single-coil and dual-coil implantable cardioverter-defibrillator (ICD) systems. BACKGROUND: Use of dual-coil rather than single-coil defibrillator leads may lower the DFT with a transvenous ICD system; however, dual-coil ICDs may have higher lead related complications. METHODS: Sixteen studies, each with more than 10 human subjects, that compared single-coil and dual-coil ICD systems were included for the final analysis after a comprehensive publication search using predefined search terms and additional search from cross-references. A test of heterogeneity, pooling, and meta-analysis of the data from the studies were performed using R statistical software. A random effects model was used for meta analysis. RESULTS: Data pooled from 14 studies analyzed for difference in DFT showed an estimated difference in mean DFTs between single-coil and dual-coil ICDs of 0.81 J (95% confidence interval [CI]: 0.31 to 1.30 J), thus favoring dual coil ICDs. However, pooled data from 5 studies revealed no difference in first shock efficacy for dual-coil ICDs compared with single-coil ICDs (estimated overall odds ratio: 0.94; 95% CI: 0.49 to 1.78; p = 0.85). The all-cause mortality rate analyzed from 4 studies was lower in patients with single-coil ICDs (estimated hazard ratio: 0.91; 95% CI: 0.83 to 0.99). CONCLUSIONS: There was a marginal difference in the defibrillation threshold of transvenous ICDs between single-coil and dual-coil lead systems. However, first-shock efficacy was no different between the 2 groups, and patients with single-coil ICDs had favorable all-cause mortality rates on the basis of data from nonrandomized studies. Potential risks and benefits of single-coil and dual-coil ICD leads should be carefully weighed. PMID- 29759691 TI - Secondary Prevention: A Blast From the Past. PMID- 29759692 TI - Impact of Implantable Cardioverter-Defibrillators on Waitlist Mortality Among Patients Awaiting Heart Transplantation: An UNOS/OPTN Analysis. AB - OBJECTIVES: This study sought to assess the impact of implantable cardioverter defibrillators (ICDs) on waitlist mortality in patients listed for heart transplantation (HT). BACKGROUND: The impact of ICDs on preventing sudden cardiac death in patients awaiting HT has not been studied in large multicenter cohorts. Furthermore, whether ICDs benefit patients with a left ventricular assist device (LVAD) is unknown. METHODS: Adults (age >=18 years) listed for first-time HT in the United States between January 1, 1999, and September 30, 2014, were retrospectively identified from the United Network for Organ Sharing registry. The primary predictor variable was the presence of an ICD at the time of listing. Primary outcome variable was all-cause waitlist mortality. RESULTS: Data on 32,599 patients (mean age 53 +/- 12 years, 77% male, 70% Caucasian) were analyzed. During median follow-up of 154 days, 3,638 patients (11%) died on the waitlist (9% in ICD group vs. 15% in no-ICD group; p < 0.0001), whereas 63% underwent HT. Having an ICD at listing was associated with an adjusted 13% relative reduction in mortality (hazard ratio: 0.87; 95% confidence interval: 0.80 to 0.94). In the subgroup of patients with LVAD (n = 9,478), having an ICD was associated with an adjusted 19% relative reduction in mortality (hazard ratio: 0.81; 95% confidence interval: 0.70 to 0.94). CONCLUSIONS: ICD use was associated with improved survival on the HT waitlist in patients with or without LVADs. These findings strengthen the current guideline recommendations of using ICDs in nonhospitalized patients awaiting HT and provide new insight into the effectiveness of ICDs on survival in LVAD-supported patients. PMID- 29759684 TI - How aging impacts the encoding of binaural cues and the perception of auditory space. AB - Over the years, the effect of aging on auditory function has been investigated in animal models and humans in an effort to characterize age-related changes in both perception and physiology. Here, we review how aging may impact neural encoding and processing of binaural and spatial cues in human listeners with a focus on recent work by the authors as well as others. Age-related declines in monaural temporal processing, as estimated from measures of gap detection and temporal fine structure discrimination, have been associated with poorer performance on binaural tasks that require precise temporal processing. In lateralization and localization tasks, as well as in the detection of signals in noise, marked age related changes have been demonstrated in both behavioral and electrophysiological measures and have been attributed to declines in neural synchrony and reduced central inhibition with advancing age. Evidence for such mechanisms, however, are influenced by the task (passive vs. attending) and the stimulus paradigm (e.g., static vs. continuous with dynamic change). That is, cortical auditory evoked potentials (CAEP) measured in response to static interaural time differences (ITDs) are larger in older versus younger listeners, consistent with reduced inhibition, while continuous stimuli with dynamic ITD changes lead to smaller responses in older compared to younger adults, suggestive of poorer neural synchrony. Additionally, the distribution of cortical activity is broader and less asymmetric in older than younger adults, consistent with the hemispheric asymmetry reduction in older adults model of cognitive aging. When older listeners attend to selected target locations in the free field, their CAEP components (N1, P2, P3) are again consistently smaller relative to younger listeners, and the reduced asymmetry in the distribution of cortical activity is maintained. As this research matures, proper neural biomarkers for changes in spatial hearing can provide objective evidence of impairment and targets for remediation. Future research should focus on the development and evaluation of effective approaches for remediating these spatial processing deficits associated with aging and hearing loss. PMID- 29759690 TI - Survival After Secondary Prevention Implantable Cardioverter-Defibrillator Placement: An Analysis From the NCDR ICD Registry. AB - OBJECTIVES: This study sought to define the characteristics and risks of death of patients receiving a physician-designated secondary prevention implantable cardioverter-defibrillator (ICD) in contemporary clinical practice. BACKGROUND: Data on utilization and outcomes of ICDs for the secondary prevention of sudden cardiac death (SCD) are limited. METHODS: Patients enrolled in the National Cardiovascular Data Registry's (NCDR) ICD Registry from 2006 to 2009 with a physician-designated secondary prevention indication for ICD implantation were identified and linked to the Social Security Death Master File. Those patients with a history either of tachycardic arrest or sustained ventricular tachycardia (SCD/VT) or of syncope without SCD/VT were included. Kaplan-Meier survival analysis was used to assess mortality. Cox proportional hazards survival modeling was used to assess the risk of death in these groups, adjusting for patient characteristics. RESULTS: In the study cohort of 46,685 patients (mean age 66 +/- 14 years, 73.5% male, 85% white), 78% had SCD/VT and 22% had syncope. Overall mortality was 10.4% at 1 year and 16.4% at 2 years. Compared with patients having SCD/VT, the adjusted hazard of death at 1 year was lower in the patients having syncope (hazard ratio: 0.89; 95% confidence interval: 0.83 to 0.96) but was not significantly different by 2 years (hazard ratio: 0.96; 95% confidence interval: 0.90 to 1.01). CONCLUSIONS: Nearly 9 of 10 patients receiving a secondary prevention ICD in clinical practice are alive 1 year after implantation. The risk of death varies by indication and is highest among patients who survive SCD or sustained VT in the first year after device implantation. PMID- 29759693 TI - Trends in Cardiac Tamponade Among Recipients of Permanent Pacemakers in the United States: From 2008 to 2012. AB - OBJECTIVES: The aim of this study was to describe the trends and predictors of cardiac tamponade among permanent pacemaker (PPM) recipients in the United States between 2008 and 2012. BACKGROUND: Limited data exist regarding the burden, trend, and predictors of tamponade in patients following PPM implantation. METHODS: The National (Nationwide) Inpatient Sample database was used to identify PPM implantations between 2008 and 2012. RESULTS: Among 922,549 patients who received PPM devices between 2008 and 2012, cardiac tamponade occurred in 2,595 patients (0.28%). Overall, in-hospital cardiac tamponade rates increased by 35% among recipients of PPMs. The incidence rate steadily increased from 0.26% in 2008 to 0.35% in 2012 (p < 0.0001). Although the mean age (p = 0.28) and sex distribution (p = 0.25) did not change over the years, the rate of in-hospital mortality increased among patients who developed tamponade from 2008 to 2012 (p = 0.014). After multivariate adjustment for patient and hospital characteristics, female sex (odds ratio [OR]: 1.23; 95% confidence interval [CI]: 1.04 to 1.54; p = 0.011), dual-chamber pacemakers (OR: 1.68; 95% CI: 1.17 to 2.41; p < 0.004), and chronic liver disease (OR: 3.18; 95% CI: 1.92 to 5.64; p < 0.001) were found to be independently associated with a greater odds of cardiac tamponade. Conversely, hypertension (OR: 0.71; 95% CI: 0.45 to 0.94; p = 0.021) and atrial fibrillation (OR: 0.78; 95% CI; 0.61 to 0.96; p = 0.002) were associated with lower odds of tamponade. CONCLUSIONS: The burden of cardiac tamponade associated with PPM implantation has steadily increased in the United States. Specific patient factors were identified that could predict the risk for developing tamponade among PPM recipients. PMID- 29759694 TI - Cardiac Tamponade From Permanent Pacemaker Implantation: Is the Pressure Building? PMID- 29759695 TI - Increased Incidence of Ventricular Arrhythmias in Patients With Advanced Cancer and Implantable Cardioverter-Defibrillators. AB - OBJECTIVES: This study evaluated the incidence of ventricular arrhythmia and implantable cardioverter-defibrillator (ICD) therapies in patients with a diagnosis of cancer. BACKGROUND: Cardiac disease and cancer are prevalent conditions and share common predisposing factors. No studies have assessed the impact of cancer on the burden of ventricular arrhythmia in patients with cancer and ICDs. METHODS: Retrospective study of patients with an ICD and cancer who were followed from January 2007 to June 2015. Rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) before and after patients' cancers were diagnosed were evaluated by searching device data collection systems. Rates were adjusted for length of follow-up and compared using the Wilcoxon test, and times to first therapy following diagnosis (stages I to III vs. IV) were compared using Kaplan-Meier curves and log-rank test. RESULTS: Among 1,598 patients with an ICD, 209 patients (13.1%) had a pathological diagnosis of malignancy; and in 102 patients (6.4%), malignancy was diagnosed following device insertion. After the diagnosis of cancer, 32% of patients experienced VT/VF over 23.2 +/- 23.6 months, and the frequency of arrhythmic events was significantly increased after the diagnosis (1.19 +/- 0.32 vs. 0.12 +/- 0.21 episodes per month, respectively; p = 0.03). The incidence of VT/VF was markedly higher in patients with stage IV cancer than in those with earlier stages (p = 0.03). In this group, the incidence of VT/VF was 41.2%, with an average of 7.2 +/- 18.5 events per patient, all of whom received ICD shocks. The rate of ICD deactivation in stage IV patients was 35.3%. Inappropriate therapies occurred in 13.7%, and atrial fibrillation was the most frequent cause. CONCLUSIONS: One-third of patients who had received ICDs developed ventricular arrhythmia after a diagnosis of cancer. The incidence was significantly higher in those with advanced metastatic disease. Findings underscore the need to discuss ICD management as part of end-of-life care. PMID- 29759697 TI - Aging in Brugada Syndrome: What About Risks? PMID- 29759696 TI - Clinical Characteristics and Long-Term Prognosis of Senior Patients With Brugada Syndrome. AB - OBJECTIVES: This study investigated clinical characteristics and prognosis of Brugada syndrome (BrS) in patients older than 60 years of age during a long-term follow-up period. BACKGROUND: Clinical characteristics and prognosis of senior patients with BrS have not been clearly elucidated. METHODS: A total of 181 patients with BrS were divided into 2 groups by age at the time of diagnosis: the younger group was <60 years of age (n = 123), and the senior group was >=60 years of age (n = 58). RESULTS: Mean ages were 42.7 +/- 11 years and 68.6 +/- 7.1 years, respectively. Prevalence of spontaneous type 1 electrocardiogram (ECG) was lower in the senior group (22 of 58; 37.9%) than in the younger group (64 of 123; 51.9%) (p = 0.027). Among various ECG parameters, the senior group had a lower incidence of prolonged r-J intervals in V2 >=90 ms than the younger group (34 of 58; 58.6% vs. 90 of 123; 73.1%, p = 0.049) and day-to-day variation of Brugada ECG patterns (3 of 58; 5.2% vs. 23 of 123; 18.7%, p = 0.032). During a mean follow-up period of 7.6 +/- 5.8 years, no senior patients experienced documented fatal ventricular arrhythmias, but 11 younger patients did. Kaplan-Meier analysis revealed a better prognosis in the senior group than in the younger group (log rank, p = 0.011). CONCLUSIONS: Senior BrS patients, >=60 years of age, had a better prognosis than those <60 years of age. Implantable cardioverter defibrillator insertion for senior patients with BrS needs careful consideration. PMID- 29759698 TI - Thrombus Formation After Left Atrial Appendage Occlusion With the Amplatzer Amulet Device. AB - OBJECTIVES: This study sought to define the ideal post-procedural anticoagulant regime and to systematically study the incidence of device-related thrombus. BACKGROUND: Left atrial appendage occlusion (LAAo) is an alternative to life-long oral anticoagulation in selected patients with atrial fibrillation. METHODS: This study included 24 atrial fibrillation patients (ages 79 +/- 8 years; 75% male, CHA2DS2VASc [Congestive Heart Failure, Hypertension, Age >=75 Years, Diabetes Mellitus, Previous Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years. Sex] score: 4.3 +/- 1.5, HAS-BLED [Hypertension, Abnormal Renal and Liver Function, Stroke, Bleeding, Labile International Normalized Ratio, Elderly, Drugs or Alcohol] score: 3.6 +/- 0.8) after LAAo with the use of the Amplatzer Amulet system. Dual antiplatelet therapy for 3 months was prescribed in 95.6% of the cases. RESULTS: Transesophageal echocardiography identified a high rate of device adherent thrombi (16.7%, n = 4 of 23) after a mean of 11.0 +/- 8.2 weeks. Thrombus formation occurred under dual antiplatelet therapy (3 of 4) or clopidogrel monotherapy (1 of 4). When compared with patients without thrombi, echocardiography showed higher degrees of spontaneous echo contrast grades within the LAA (3.0 +/- 1.0 vs. 1.3 +/- 1.1), lower LAA peak emptying velocities (17.5 +/- 5.0 cm/s vs. 48.3 +/- 21.1 cm/s), and decreased left ventricular function (39 +/- 10% vs. 50 +/- 13%) in patients with device-related thrombus. All thrombi were observed within the untrabeculated region of the LAA ostium between the left upper pulmonary vein ridge and the occluder disc, indicating suboptimal LAA occlusion. CONCLUSIONS: Device-related thrombus is a frequent finding after LAAo with the Amplatzer Amulet device (St. Jude Medical, St. Paul, Minnesota). Our results emphasize the need for an optimized post-LAAo anticoagulation regimen, a revised implantation strategy, and possibly modified patient selection criteria. PMID- 29759699 TI - Virchow's Triad and Failure to "Pacify" the Left Atrial Appendage. PMID- 29759701 TI - An Extreme Example of Subclavian Crush. PMID- 29759700 TI - Where Is the Lead?: An Unusual Progression of Lead Fracture. PMID- 29759702 TI - For Whom the Bell Tolls. PMID- 29759703 TI - Clinical EP in 2017 and Beyond: Adapting to Payment Reform. PMID- 29759704 TI - Patients With Cardiac Rhythm Management Devices: How True Is the Need for Magnetic Resonance Imaging? PMID- 29759705 TI - Can We Identify the Extra-Pulmonary Vein Substrate in Paroxysmal Atrial Fibrillation Using Incremental Atrial Pacing? PMID- 29759706 TI - The Human Left Atrial Venous Circulation as a Vascular Route for Atrial Pharmacological Therapies: Effects of Ethanol Infusion. AB - OBJECTIVES: This study catalogued the human venous left atrium (LA) circulation system and the ablative effects of ethanol in different branches. BACKGROUND: Vascular routes to target the LA could have significant therapeutic potential. Beyond the vein of Marshall (VOM), the fluoroscopic LA venous anatomy has not been described. METHODS: Patients undergoing ethanol infusion in the VOM as adjunctive therapy to atrial fibrillation (AF) catheter ablation were included in this study. Balloon occlusion venograms of the VOM and other LA veins were obtained in 218 patients. RESULTS: Sequentially from the coronary sinus (CS) ostium, LA veins included: 1) proximal septal vein draining the inferior septum; 2) inferior LA vein in the annular inferior LA; 3) VOM; 4) LA appendage vein; and 4) anterior LA vein. Additionally, venous sinuses not connected to the CS included roof veins and posterior wall veins, which drained into the right and left atria, respectively. Venous connections between LA veins through capillaries and with pulmonary veins were abundant. Extracardiac collateral vessels were present in 38 patients (17.4%). Ethanol infusion in LA veins led to tissue ablation in their corresponding regions. CONCLUSIONS: The atrial venous anatomy is amenable to selective cannulation. Consistent anatomical patterns are present. Targeting atrial tissues through atrial veins can be used for therapeutic purposes. PMID- 29759707 TI - Left Atrial Venous Anatomy: A Map for Future AF Therapies. PMID- 29759708 TI - Intra-Atrial Right Coronary Artery and its Ablation Implications. AB - OBJECTIVES: The study examined the frequency in which a right coronary artery (RCA) anomaly resulting in intra-atrialization of the vessel might increase risk of RCA damage during routine radiofrequency ablation in the right atrium even with low power or temperature. BACKGROUND: Right coronary artery (RCA) injury with endocardial RF ablation of the right atrium is a rare complication. METHODS: This prospective observational study comprised an analysis of coronary artery anatomies in 331 patients who underwent autopsies at our institution from 2005 to 2014. The presence of intra-atrial RCA including the number and length of intra atrial RCA segments with accompanying atherosclerosis and coronary anomalies were evaluated. RESULTS: The authors report a case series of 6 of 331 (1.8%) patients in whom autopsies showed evidence of an intra-atrial RCA. The patients were all men (average 69 +/- 12 years of age). They observed 3 variations of the intra atrial RCA course. In 2 similar variations, the RCA entered the anterolateral aspect of the right atrium, returning to its normal distribution to supply the distal RCA (case 4 of 6) and the atrioventricular nodal artery (case 1 of 6). In the sixth case, the atrialized artery was an anterior branch of the RCA, in which the artery similarly coursed across the pectinate muscles, extending to the region of the anterior crista terminalis, before diving into the muscle. CONCLUSIONS: The prevalence and variants of the intra-atrial RCA have not been reported before. In the presence of an intra-atrial artery, RCA damage may occur due to direct injury rather than collateral injury due to transmural extension of an ablation lesion. PMID- 29759709 TI - Clusters, Gaps, and Randomness: Vasovagal Syncope Recurrence Patterns. AB - OBJECTIVES: This study elucidated the temporal recurrence patterns of syncope in patients with frequent vasovagal syncope (VVS). BACKGROUND: Understanding the temporal distribution of fainting spells in syncope patients may illuminate biological processes and inform decision making. METHODS: Patients from the POST 2 (Prevention of Syncope Trial 2) were included; all had VVS and fainted >=4 times in the study year, providing >=3 interevent intervals (IEIs). Only fainting spells separated by >=1 day were included. IEI distributions were analyzed using Poisson modeling and cumulative sum distributions. RESULTS: Twenty-four patients (5 males, 19 females; mean 33 years of age) had a total of 286 syncopal events and 262 IEIs, with a median 6 IEI. They resembled excluded subjects in age and sex but fainted more often in their lives (median: 57 vs. 13 fainting spells, respectively; p < 0.0001) and in the previous year (median: 23 vs. 3 fainting spells, respectively; p < 0.0001). Subjects had a median IEI duration of 8 (interquartile range: 4 to 19) days. The IEI distributions were fit well by Poisson models with a median r2 of 0.94 (95% confidence interval: 0.91 to 0.97). The patients' Poisson rate constant frequencies were 7 to 263 fainting spells/year with a median rate of 19 fainting spells/year. The modal syncope frequency was 10 to 15 fainting spells per year. Seven patients had biexponential distributions, and many patients fainted in clusters. CONCLUSIONS: Patients with frequent VVS have fainting spells that occur randomly in time. Clusters of syncope occur, and in this population, there is a central tendency to 10 to 15 fainting spells per year. This provides a quantitative measure of frequency and predictability that may afford individualized treatment goals. PMID- 29759710 TI - Vasovagal Syncope: Down on Your Luck? PMID- 29759711 TI - Cardio-Neuromodulation: The Right-Sided Approach. PMID- 29759712 TI - Hyperkalemia-Induced Brugada Phenocopy. PMID- 29759713 TI - The Sinister Mammary Hematoma: Extreme Pacing Lead Perforation Into the Breast. PMID- 29759714 TI - Effects of Catheter Ablation Targeting the Trigger Beats in Inherited Catecholaminergic Polymorphic Ventricular Tachycardia. PMID- 29759715 TI - The Nonischemic Cardiomyopathy Defibrillator Conundrum: Is a Meta-Analysis Enough? PMID- 29759716 TI - Atrial Fibrillation in Athletes: A Lesson in the Virtue of Moderation. AB - Although the cardiovascular benefits of moderate exercise are well established, there is growing epidemiological support for the notion that high-intensity endurance athletics increases the risk of atrial fibrillation (AF). There are many gaps in evidence related to epidemiology and mechanisms of AF in endurance athletes. The proposed pathophysiological mechanisms include alterations of autonomic tone, electrical remodeling, anatomical remodeling, fibrosis, and inflammation. Clinical management of the athlete with AF often includes a period of decreased frequency, intensity, and duration of exercise with assessment for improvement in AF recurrence. Based on symptoms, a strategy of rate or rhythm control should be selected; however, due to side effects and intolerance of medications, ablation may be a preferred approach. The risks and benefits of anticoagulation for stroke prevention must be carefully assessed in the athlete with AF. All patients should be encouraged to be physically active with moderation; however, men should be advised of the higher risk of AF with long term, high-intensity endurance training. PMID- 29759717 TI - Low-Level Vagus Nerve Stimulation Suppresses Post-Operative Atrial Fibrillation and Inflammation: A Randomized Study. AB - OBJECTIVES: This study sought to examine the efficacy of low-level vagus nerve stimulation (LLVNS) in suppressing post-operative atrial fibrillation (POAF) and inflammatory cytokines in patients undergoing cardiac surgery. BACKGROUND: POAF often complicates cardiac surgery. METHODS: Patients undergoing cardiac surgery were randomized to active or sham LLVNS. In all patients, a bipolar wire was sutured to the vagus nerve pre-ganglionic fibers alongside the lateral aspect of the superior vena cava. High-frequency (20 Hz) stimulation, 50% below the threshold for slowing the heart rate, was delivered for 72 h in the LLVNS group. The development of POAF was monitored continuously during the entire hospital stay by use of telemetry. Blood was collected on arrival in the intensive care unit and at 24 and 72 h for measurement of inflammatory cytokines. Patients were followed up within 1 month after cardiac surgery. RESULTS: A total of 54 patients were randomized to either active LLVNS (n = 26) or sham control (n = 28). The baseline characteristics of the patients were balanced in the 2 groups. POAF occurred in 3 patients (12%) in the LLVNS group and 10 patients (36%) in the control group (hazard ratio: 0.28; 95% confidence interval: 0.10 to 0.85; p = 0.027). None of the patients developed any complications as a result of wire placement. At 72 h, serum tumor necrosis factor-alpha and interleukin-6 levels were significantly lower in the LLVNS group than in the control group. CONCLUSIONS: These data suggest that LLVNS suppresses POAF and attenuates inflammation in patients undergoing cardiac surgery. Further studies are warranted. PMID- 29759718 TI - Vagal Neuromodulation for Atrial Arrhythmias. PMID- 29759719 TI - Atrial Ganglionated Plexus Modification: A Novel Approach to Treat Symptomatic Sinus Bradycardia. AB - OBJECTIVES: This study sought to determine if anatomic atrial ganglionated plexus (GP) ablation leads to long-term sinus rate (SR) increase and improves quality of life in patients with symptomatic sinus bradycardia (SB). BACKGROUND: Atrial GP ablation has been demonstrated to increase SR in our previous study. Atrial GP ablation may also be effective in treating patients with symptomatic SB. METHODS: Sixty-two patients with symptomatic SB were recruited: Group A included patients <50 years of age (n = 40); Group B included patients >=50 years of age (n = 22). All patients underwent anatomic ablation of the main atrial GP, and 24-h Holter monitoring and quality-of-life assessment were performed during 1 year of follow up. Quality of life was accessed by the Medical Outcomes Study Short-Form 36 Health Survey. RESULTS: Although SR markedly increased in all patients after GP ablation, the increase was significantly greater in patients <50 years of age than in patients >=50 years of age (19.3 +/- 9.9 beats/min vs. 10.8 +/- 5.4 beats/min; p = 0.001). The right anterior GP and the GP at the junction of the aorta and superior vena cava made the greatest contributions to SR increase among all GP. The mean and minimal SR increased significantly after ablation and remained elevated for 12 months only in Group A patients. Although symptoms and quality of life improved in all patients, 5 of the 8 domains of the Medical Outcomes Study Short-Form 36 Health Survey did not show obvious improvements in patients of Group B at 12 months. CONCLUSIONS: Anatomic atrial GP ablation effectively increased SR and improved quality of life in patients <50 years of age with symptomatic SB. PMID- 29759720 TI - Ablation of Atrial Gangionated Plexi to Treat Symptomatic Sinus Bradycardia. PMID- 29759722 TI - New Insights Into an Old Arrhythmia: High-Resolution Mapping Demonstrates Conduction and Substrate Variability in Right Atrial Macro-Re-Entrant Tachycardia. AB - OBJECTIVES: Using high-resolution 3-dimensional (3D) mapping, the aim of this study was to further characterize right atrial macro-re-entrant tachycardias and answer unresolved questions in the understanding of this arrhythmia. BACKGROUND: Despite advances in understanding of the mechanisms of right atrial macro-re entrant tachycardias, many questions lack definitive answers. The advent of high resolution 3D mapping provides an opportunity to gain further insights into the nature of these common circuits. METHODS: A total of 25 patients with right atrial macro-re-entrant tachycardia were studied. High-resolution 3D mapping (Rhythmia mapping system, Boston Scientific, Natick, Massachusetts) was performed. Regional voltage and conduction velocity were determined. Maps were analyzed to characterize wave front propagation patterns in all atrial regions. The relationship between substrate and conduction was evaluated. RESULTS: A total of 42 right atrial macro-re-entrant circuits were observed. The most common location of the posterior line of block was the posteromedial right atrium (73%). This line of block continued superiorly into the superior vena cava, taking an oblique course to finish on the anterior superior vena cava aspect in 73%. Conduction delay at the crista terminalis was less common (23%). Conduction slowing or block was seen at the limbus of the fossa ovalis (73%) and Eustachian ridge (77%). Highly variable and localized areas of slow conduction were also observed in the inferior septum (45%), superior septum (27%), anterosuperior right atrium (23%), and lateral right atrium (23%). Localized conduction slowing was seen in the cavotricuspid isthmus in 50% of patients, but there was no generalized conduction slowing in this isthmus. The voltage in regions of slow conduction was significantly lower compared with areas of normal conduction velocity (p < 0.001). Conduction channels were observed in 55% of patients. CONCLUSIONS: High-resolution 3D mapping has provided new insights into the nature of right atrial macro-re-entrant tachycardias. Variable regions of abnormal atrial substrate were associated with conduction slowing and block. Individual variation in propagation patterns was observed in association with this variable substrate. (Mapping of Atrial Arrhythmias Using High Spatial Resolution Mapping Catheters and the Rhythmia Mapping System; ACTRN12615000544572). PMID- 29759721 TI - Efficacy of Implantable Cardioverter-Defibrillator Therapy in Patients With Nonischemic Cardiomyopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: This study sought to evaluate the efficacy of implantable cardioverter-defibrillator (ICD) therapy with or without cardiac resynchronization therapy (CRT) in patients with nonischemic cardiomyopathy (NICM). BACKGROUND: The effect of ICD on mortality of patients with NICM and left ventricular ejection fraction <=35% has recently been questioned. Prior randomized controlled trials (RCTs) evaluating ICD efficacy in patients with NICM have yielded conflicting results. Furthermore, whether ICD therapy benefits NICM patients with concomitant CRT is unknown. METHODS: Relevant RCTs published between 2000 and 2016 were identified. Patients with ischemic cardiomyopathy were excluded. Study sample was stratified into CRT and non-CRT groups. The efficacy of having a defibrillator in each group was compared using random effects meta analysis techniques. RESULTS: Six RCTs (N = 3,544) were included. Among the 2,347 patients who did not have CRT, ICD use was associated with a 24% reduction in mortality (relative risk [RR]: 0.76; 95% confidence interval [CI]: 0.63 to 0.91; p = 0.003). However, among the 1,197 patients with CRT, having a CRT defibrillator was not associated with a statistically significant reduction in mortality (RR: 0.74; 95% CI: 0.46 to 1.16; p = 0.19) compared to CRT-pacemaker. Subgroup analysis in non-CRT patients showed that ICD use reduced sudden cardiac death by 73% (RR: 0.27; 95% CI: 0.15 to 0.50; p < 0.001) compared to medical therapy. CONCLUSIONS: Compared to medical therapy, ICD use significantly improved survival among patients with NICM and ejection fraction <=35%. Although CRT defibrillator was not associated with a statistically significant mortality benefit compared to CRT-pacemaker, the apparent lack of power in this analysis warrants further investigation. PMID- 29759723 TI - Typical Flutter Rewritten: From Textbooks to Ultra-High-Definition Mapping. PMID- 29759725 TI - Anti-allergic inflammatory components from Sanguisorba officinalis L. AB - Sanguisorba officinalis L. was well known as a traditional herbal medicine to treat inflammation and allergic skin diseases. The aim of this research was to indentify compounds with anti-allergic inflammatory property. Twenty-five compounds (1-25) were isolated from S. officinalis including two new compounds (1 and 8), and their chemical structures were identified by NMR and ESIMS analysis. Consequently, the anti-allergic inflammatory activities of these isolates were investigated by inhibiting beta-hexosaminidase and IL-4 production in PMA/A23187 stimulated RBL-2H3 cells. Compounds 6, 8, 13, 17-18 and 25 significantly inhibited beta-hexosaminidase release and IL-4 production. Additionally, compounds 8, 17 and 25 effectively suppressed the activation of NF-kappaB and NF kappaB p65 translocation into the nucleus. Anti-inflammatory effects of isolated compounds were evaluated in LPS-stimulated RAW264.7 macrophages, and they showed dramatic inhibition on LPS-induced overproduction of nitric oxide (NO) and TNF alpha. Consistently, the protein levels of iNOS and COX-2 were remarkably decreased by the single compounds 8, 13 and 25. These results showed that compounds 8, 13 and 25 from S. officinalis may have a therapeutic potential for allergic inflammatory diseases. PMID- 29759724 TI - Diagnostic Value of MRI in Patients With Implanted Pacemakers and Implantable Cardioverter-Defibrillators Across a Cross Population: Does the Benefit Justify the Risk? A Proof of Concept Study. AB - OBJECTIVES: The objective of this study was to assess the diagnostic usefulness of thoracic and nonthoracic magnetic resonance imaging (MRI) imaging in patients with implantable cardiac devices (permanent pacemaker or implantable cardioverter defibrillators [ICDs]) to determine if there was a substantial benefit to patients with regard to diagnosis and/or management. BACKGROUND: MRI is infrequently performed on patients with conventional pacemakers or ICDs. Multiple studies have documented the safety of MRI scans in patients with implanted devices, yet the diagnostic value of this approach has not been established. METHODS: Evaluation data were acquired in 136 patients with implanted cardiac devices who underwent MRIs during a 10-year period at a single institution. Specific criteria were followed for all patients to objectively define if the diagnosis by MRI enhanced patient care; 4 questions were answered after scan interpretation by both MRI technologists and MRI physicians who performed the scan. 1) Did the primary diagnosis change? 2) Did the MRI provide additional information to the existing diagnosis? 3) Was the pre-MRI (tentative) diagnosis confirmed? 4) Did patient management change? If "Yes" was answered to any of the preceding questions, the MRI scan was considered to be of value to patient diagnosis and/or therapy. RESULTS: In 97% (n = 132) of patients, MR added value to patient diagnosis and management. In 49% (n = 67) of patients, MRI added additional valuable information to the primary diagnosis, and in 30% (n = 41) of patients, MRI changed the principle diagnosis and subsequent management of the patient. No safety issues were encountered, and no adverse effects of undergoing the MRI scan were noted in any patient. CONCLUSIONS: MRI in patients with implanted pacemakers and defibrillators added value to patient diagnosis and management, which justified the risk of the procedure. PMID- 29759727 TI - Valproic acid induces three novel cytotoxic secondary metabolites in Diaporthe sp., an endophytic fungus from Datura inoxia Mill. AB - Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (1-4) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 1-3 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC50 of 20 and 32 uM respectively and against PC-3 with an IC50 of 14 and 18 uM respectively. Moreover, compound 1 displayed significant DPPH scavenging activity with EC50 of 10.3 uM using ascorbic acid as a positive control. PMID- 29759726 TI - N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity. AB - Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-kappaB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties. PMID- 29759728 TI - Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity. AB - KU-596 is a second-generation C-terminal heat shock protein 90 KDa (Hsp90) modulator based on the natural product, novobiocin. KU-596 has been shown to induce Hsp70 levels and manifest neuroprotective activity through induction of the heat shock response. A ring-constrained analog of KU-596 was designed and synthesized to probe its binding orientation and ability to induce Hsp70 levels. Compound 2 was found to exhibit comparable or increased activity compared to KU 596, which is under clinical investigation for the treatment of neuropathy. PMID- 29759730 TI - Citrate chemistry and biology for biomaterials design. AB - Leveraging the multifunctional nature of citrate in chemistry and inspired by its important role in biological tissues, a class of highly versatile and functional citrate-based materials (CBBs) has been developed via facile and cost-effective polycondensation. CBBs exhibiting tunable mechanical properties and degradation rates, together with excellent biocompatibility and processability, have been successfully applied in vitro and in vivo for applications ranging from soft to hard tissue regeneration, as well as for nanomedicine designs. We summarize in the review, chemistry considerations for CBBs design to tune polymer properties and to introduce functionality with a focus on the most recent advances, biological functions of citrate in native tissues with the new notion of degradation products as cell modulator highlighted, and the applications of CBBs in wound healing, nanomedicine, orthopedic, cardiovascular, nerve and bladder tissue engineering. Given the expansive evidence for citrate's potential in biology and biomaterial science outlined in this review, it is expected that citrate based materials will continue to play an important role in regenerative engineering. PMID- 29759729 TI - Recyclable magnetic nanoparticles grafted with antimicrobial metallopolymer antibiotic bioconjugates. AB - Over-prescription and improper use of antibiotics has led to the emergence of bacterial resistance, posing a major threat to public health. There has been significant interest in the development of alternative therapies and agents to combat antibiotic resistance. We report the preparation of recyclable magnetic iron oxide nanoparticles grafted with charged cobaltocenium-containing metallopolymers by surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization. beta-Lactam antibiotics were then conjugated with metallopolymers to enhance their vitality against both Gram-positive and Gram negative bacteria. The enhanced antibacterial activity was a result of synergy of antimicrobial segments that facilitate the inhibition of hydrolysis of antibiotics and local enhancement of antibiotic concentration on a nanoparticle surface. These magnetic nanoparticles can be recycled numerous times without losing the initial antimicrobial potency. Studies suggested negligible toxicity of metallopolymer-grafted nanoparticles to red blood cells and minimal tendency to induce resistance in bacteria. PMID- 29759732 TI - Thoracoscopic off-pump closure of a large left circumflex coronary artery fistula: A novel minimally invasive approach. PMID- 29759733 TI - "All-inclusive" guidelines on bicuspid aortic valve-related aortopathy. PMID- 29759731 TI - Intrafibrillar, bone-mimetic collagen mineralization regulates breast cancer cell adhesion and migration. AB - Bone metastasis is a leading cause of death in patients with breast cancer, but the underlying mechanisms are poorly understood. While much work focuses on the molecular and cellular events that drive breast cancer bone metastasis, it is mostly unclear what role bone extracellular matrix (ECM) properties play in this process. Bone ECM primarily consists of mineralized collagen fibrils, which are composed of non-stoichiometric carbonated apatite (HA) and collagen type I. Reduced bone mineral content is epidemiologically linked with increased risk of bone metastasis. Yet elucidating the potential functional impact of collagen mineralization on breast cancer cells has remained challenging because of a lack of model systems that allow studying tumor cell behavior as a function of physiological, intrafibrillar collagen mineralization. Here, we have developed cell culture substrates composed of mineralized collagen type I fibrils using a polymer-induced liquid-precursor (PILP) process. Intrafibrillar HA decreased breast cancer cell adhesion forces and accordingly reduced collagen fiber alignment relative to cells cultured on control collagen. The resulting mineral mediated changes in collagen network characteristics and mechanosignaling correlated with increased cell motility, but inhibited directed migration of breast cancer cells. These results suggest that physiological mineralization of collagen fibrils reduces tumor cell adhesion with potential functional consequences on skeletal homing of disseminated tumor cells in early stages of breast cancer metastasis. PMID- 29759734 TI - Lymphangiography and thoracic duct embolization following unsuccessful thoracic duct ligation: Imaging findings and outcomes. AB - OBJECTIVE: To summarize the imaging findings and outcomes of thoracic duct (TD) embolization (TDE) performed in patients with chylous leaks persisting after TD ligation (TDL). MATERIALS AND METHODS: In this review of 50 patients (30 males and 20 females; median age, 54 years) referred for TDE following unsuccessful surgical TDL, records were reviewed for lymphangiographic findings, technical success of TDE, and outcome of TDE. Comparisons between groups were performed using the Fisher exact test. RESULTS: The causes of chylothorax were traumatic in 39 patients (78%) and nontraumatic in 11 (22%). Lymphangiography identified missed TDL in 30 patients (60%) and complete TDL in 15 patients (30%); however, in 12 of these 15 patients, collaterals around the ligation site supplying the leak could be identified. Incomplete ligation was observed in 4 patients (8%). In 1 patient (2%), a second TD was identified circumventing a complete ligation of the main TD. TDE was performed in 49 patients, and TD disruption was performed in 1 patient. Resolution of the chylous leak occurred in 45 patients (90%). There were 3 minor complications that resulted in no clinical sequela. CONCLUSIONS: TDE produced cessation of chylous leak in the majority of the patients with persistent chylothorax after surgical TDL. Missed ligation is the most common finding on lymphangiography in patients with failed TDL. These findings support the use of image-guided closure of TD leaks. PMID- 29759736 TI - Balancing risk versus reward in isolated repair of severe tricuspid regurgitation. PMID- 29759735 TI - Preoperative serum ST2 level predicts acute kidney injury after adult cardiac surgery. AB - OBJECTIVE: The purpose of this study was to evaluate the relationship between preoperative levels of serum soluble ST2 (ST2) and acute kidney injury (AKI) after cardiac surgery. Previous research has shown that biomarkers facilitate the prediction of AKI and other complications after cardiac surgery. METHODS: Preoperative ST2 proteins were measured in 1498 patients undergoing isolated coronary artery bypass graft surgery at 8 hospitals participating in the Northern New England Biomarker Study from 2004 to 2007. AKI severity was defined using the Acute Kidney Injury Network (AKIN) definition. Preoperative ST2 levels were measured using multiplex assays. Ordered logistic regression was used to examine the relationship between ST2 levels and levels of AKI severity. RESULTS: Participants in this study showed a significant association between elevated preoperative ST2 levels and acute kidney risk. Before adjustment, the odds of patients developing AKIN stage 2 or 3, compared with AKIN stage 1, are 2.43 times higher (95% confidence interval, 1.86-3.16; P < .001) for patients in the highest tercile of preoperative ST2. After adjustment, patients in the highest tercile of preoperative ST2 had significantly greater odds of developing AKIN stage 2 or 3 AKI (odds ratio, 1.99; 95% confidence interval, 1.50-2.65; P < .001) compared with patients with AKIN stage 1. CONCLUSIONS: Preoperative ST2 levels are associated with postoperative AKI risk and can be used to identify patients at higher risk of developing AKI after cardiac surgery. PMID- 29759738 TI - An ugly nose and a Nazi father: Bad premise for a cardiac rheumatic disorder. PMID- 29759737 TI - Long-term outcome of cryopreserved allograft for aortic valve replacement. AB - OBJECTIVE: The most efficient surgical approach to severe aortic valve disease in the young adult is still debated: cryopreserved aortic allograft offers excellent hemodynamic and avoid anticoagulation, but long-term durability is influenced by structural valve deterioration (SVD). This study aimed to describe long-term results of aortic allografts and to identify factors influencing long-term durability. METHODS: From January 1993 to August 2010, 210 patients underwent aortic allograft replacement via the free-hand subcoronary implantation technique (N = 55) or root replacement with coronary reimplantation (N = 155). Clinic and echocardiographic follow-up was updated to April 2016. RESULTS: Overall mortality and cardiac mortality occurred in 80 (38.1%) and 64 (30.5%) patients, respectively. Reoperation was required in 69 cases (32.8%), whereas SVD required reoperation in 57 cases (27.1%). No early endocarditis occurred, whereas late endocarditis occurred in 4 patients. The free-hand technique seems to be associated with improved left ventricular remodeling compared with the root replacement technique, and smaller allograft size represents a predictor of reoperation independently on the surgical technique used. In the overall population, there were 44 women of childbearing age, and 37 patients remained pregnant during the follow-up of the study. No differences were found in the clinical outcomes among women who had children and who did not. CONCLUSIONS: Cryopreserved allograft is a valid option, especially in complex infective endocarditis and in women of childbearing age. A careful choice of allograft size and implantation technique can reduce the risk of SVD. PMID- 29759739 TI - Aortic valve bypass surgery in severe aortic valve stenosis: Insights from cardiac and brain magnetic resonance imaging. AB - OBJECTIVE: To investigate and describe the distribution of aortic and cerebral blood flow (CBF) in patients with severe valvular aortic stenosis (AS) before and after aortic valve bypass (AVB) surgery. METHODS: We enrolled 10 consecutive patients who underwent AVB surgery for severe AS. Cardiovascular magnetic resonance imaging (CMR) and brain magnetic resonance imaging were performed as baseline before surgery and twice after surgery. Quantitative flow measurements were obtained using 1.5-T magnetic resonance imaging (MRI) scanner phase-contrast images of the ascending aorta, descending thoracic aorta (3 cm proximally and distally from the conduit-to-aorta anastomosis), and ventricular outflow portion of the conduit. The evaluation of CBF was performed using 3.0-T MRI scanner arterial spin labeling (ASL) through sequences acquired at the gray matter, dorsal default-mode network, and sensorimotor levels. RESULTS: Conduit flow, expressed as the percentage of total antegrade flow through the conduit, was 63.5 +/- 8% and 67.8 +/- 7% on early and mid-term postoperative CMR, respectively (P < .05). Retrograde perfusion from the level of the conduit insertion in the descending thoracic aorta toward the aortic arch accounted for 6.9% of total cardiac output and 11% of total conduit flow. We did not observe any significant reduction in left ventricular stroke volume at postoperative evaluation compared with preoperative evaluation (P = .435). No differences were observed between preoperative and postoperative CBF at the gray matter, dorsal default-mode network, and sensorimotor levels (P = .394). CONCLUSIONS: After AVB surgery in patients with severe AS, cardiac output is split between the native left ventricular outflow tract and the apico-aortic bypass, with two-thirds of the total antegrade flow passing through the latter and one-third passing through the former. In our experience, CBF assessment confirms that the flow redistribution does not jeopardize cerebral blood supply. PMID- 29759740 TI - Endoscopic vacuum sponge therapy for an infant with an esophageal leak. PMID- 29759742 TI - Chronotropic Incompetency During Exercise Testing: A Risk Marker for Future Atrial Fibrillation? PMID- 29759741 TI - Outcomes of repeat mitral valve replacement in patients with prior mitral surgery: A benchmark for transcatheter approaches. AB - OBJECTIVES: With the emergence of transcatheter mitral valve-in-valve/ring replacement for deteriorated bioprostheses or failed repair, comparative clinical benchmarks for surgical repeat mitral valve replacement (re-MVR) are needed. We present in-hospital and survival outcomes of a 24-year experience with re-MVR. METHODS: From January 1992 to June 2015, 520 adult patients underwent re-MVR; 273 had undergone prior mitral valve repair (pMVP) and 247 had undergone prior MVR (pMVR). A benchmark cohort of isolated re-MVR was defined based on potential eligibility for transcatheter mitral valve-in-valve/ring replacement, resulting in 73 pMVPs with previous annuloplasty rings and 74 pMVRs with previous bioprosthetic valves for comparison. RESULTS: For the entire cohort, mean age was 64 +/- 12 years for pMVP patients and 63 +/- 15 years for pMVR patients (P = .281), which was similar for the benchmark cohort. Overall operative mortality was 14 out of 273 (5%) for pMVP versus 23 out of 247 (9%) for pMVR (P = .087). There were 3 operative deaths (4.1%) in both groups of the benchmark cohort (P = 1.0). For the benchmark cohort, median time to reoperation was 9.8 years for pMVP and 9.1 years for pMVR. Cox proportional hazard analysis showed that chronic kidney disease (hazard ratio [HR], 2.47; 95% CI, 1.77-3.44), endocarditis (HR, 1.49; 95% CI, 1.07-2.07), pMVR (HR, 1.45; 95% CI, 1.12-1.89), early reoperation <= 1 year (HR, 1.49; 95% CI, 1.02-2.17), and age (HR, 1.04/y; 95% CI, 1.03-1.05) were associated with decreased survival after re-MVR. CONCLUSIONS: A re-MVR is a high-risk operation, but in carefully selected patients such as our benchmark population, it can be performed with acceptable results. Patients undergoing pMVP also have better long-term survival compared with patients undergoing pMVR. These results will serve as a benchmark for transcatheter mitral valve-in-valve/ring replacement. PMID- 29759743 TI - Hierarchical Schema for Identifying Focal Electrical Sources During Human Atrial Fibrillation: Implications for Catheter-Based Atrial Substrate Ablation. AB - OBJECTIVES: The study sought to localize focal sources (FS) during atrial fibrillation (AF) using periodic component analysis (PiCA) and QS unipolar electrogram (EGM) morphology based on the assumption that periodic activation with centrifugal propagation is inherent to a FS. BACKGROUND: The localization of FS maintaining AF remains challenging, due to limitations in conventional time frequency domain analysis. This is relevant to identifying targets for AF substrate ablation. METHODS: In 41 patients (age 56 +/- 9 years, 76% persistent AF), bipolar EGMs were recorded in the left atrium (LA) during AF with a roving 20-pole catheter. Bipolar EGMs with periodicity were determined using PiCA. FS were defined as periodic sites with predominantly QS unipolar EGM morphology. RESULTS: For each patient, 456 +/- 109 bipolar EGMs were recorded, of which 261 +/- 15 (60%) demonstrated periodicity. FS were identified in 63% of patients (pulmonary vein [PV] 1.5 +/- 1.5; extra-PV 2.6 +/- 2.3). After PV antral ablation and follow-up of 14 +/- 9 months, 37% of patients had symptomatic AF recurrence. Mean global LA periodicity cycle length was shorter in patients with AF recurrence compared to those without (143 +/- 20 ms vs. 154 +/- 9 ms; p = 0.02). Among 12 (29%) patients with FS exclusively in the PV, only 1 (8%) had AF recurrence. AF recurrence was significantly higher (50%; p = 0.01) in 14 (34%) patients with extra-PV FS. CONCLUSIONS: Our novel hierarchical analysis schema, incorporating PiCA and unipolar EGM morphology, detected a small number of FS in patients with predominantly persistent AF. FS in the PV was associated with successful PV antral ablation. Further prospective studies are required to determine whether these FS maintain AF and represent ablation targets. PMID- 29759745 TI - New Strategies to Improve Rhythm Outcome of Catheter Ablation of Persistent and Longstanding Persistent Atrial Fibrillation: Hunting Rotors and Focal Sources. PMID- 29759744 TI - Benefits of Atrial Substrate Modification Guided by Electrogram Similarity and Phase Mapping Techniques to Eliminate Rotors and Focal Sources Versus Conventional Defragmentation in Persistent Atrial Fibrillation. AB - OBJECTIVES: This prospective study compared the efficacy of atrial substrate modification guided by a nonlinear phase mapping technique with that of conventional substrate ablation. BACKGROUND: The optimal ablation strategy for persistent atrial fibrillation (AF) was unknown. METHODS: In phase 1 study, we applied a cellular automation technique to simulate the electrical wave propagation to improve the phase mapping algorithm, involving analysis of high similarity electrogram regions. In addition, we defined rotors and focal AF sources, using the physical parameters of the divergence and curvature forces. In phase 2 study, we enrolled 68 patients with persistent AF undergoing substrate modification into 2 groups, group-1 (n = 34) underwent similarity index (SI) and phase mapping techniques; group-2 (n = 34) received complex fractionated atrial electrogram ablation with commercially available software. Group-1 received real time waveform similarity measurements in which a phase mapping algorithm was applied to localize the sources. We evaluated the single-procedure freedom from AF. RESULTS: In group-1, we identified an average of 2.6 +/- 0.89 SI regions per chamber. These regions involved rotors and focal sources in 65% and 77% of patients in group-1, respectively. Group-1 patients had shorter ablation procedure times, higher termination rates, and significant reduction in AF recurrence compared to group-2 and a trend toward benefit for all atrial arrhythmias. Multivariate analysis showed that substrate mapping using nonlinear similarity and phase mapping was the independent predictor of freedom from AF recurrence (hazard ratio: 0.26; 95% confidence interval: 0.09 to 0.74; p = 0.01). CONCLUSIONS: Our study showed that for persistent AF ablation, a specified substrate modification guided by nonlinear phase mapping could eliminate localized re-entry and non-pulmonary focal sources after pulmonary vein isolation. PMID- 29759746 TI - Incidence of Atrial Fibrillation After Atrial Flutter Ablation. AB - OBJECTIVES: This study was conceived to perform a comprehensive systematic review and meta-analysis of the available evidence to compute the incidence of atrial fibrillation (AF) after successful atrial flutter (AFL) catheter ablation, defined by targeting for bidirectional block, using different types of follow-up modalities and durations. BACKGROUND: Cavotricuspid-isthmus dependent AFL is usually initiated by short bursts of AF. The incidence of AF after AFL ablation is variable. We evaluated the variation in the reported incidence of AF depending on the type and duration of follow-up, and AF incidence in patients with prior AF versus no prior AF. METHODS: A systematic review and meta-analysis of published studies between January 1996 and April 2015 and abstracts in the last 2 years describing patients who underwent AFL ablation and the subsequent incidence of AF was performed. RESULTS: Forty-eight studies were included (n = 8,257, ablation success rate: 96%, 79% male). Incidence of new-onset AF correlated with follow-up duration (29% for a weighted mean follow-up duration of 30 months). New-onset AF incidence with <2 years follow-up was 12.4% among group 1 (electrocardiogram and symptoms-driven evaluation, n = 759), 19% for group 2 (outpatient Holter monitoring for 1 day to 7 days/year, n = 315), and 45% for group 3 (>7 days/year Holter monitoring or by implanted cardiac devices, n = 178). Mean follow-up duration was 15.3 months, 18.5 months, and 16.3 months, respectively. In patients with and without prior AF, the incidence for AF after AFL ablation was 35.3% during mean follow-up duration of 29.7 months. In studies with <2 years follow-up duration, AF incidence was 54% in patients with prior AF versus 13.9% without prior AF (odds ratio: 7.43, 95% confidence interval: 4.96 to 11.11; p < 0.00001). In studies with >2 years follow-up duration, AF incidence was 51.3% in patients with prior AF versus 26.2% without prior AF (odds ratio: 2.93, 95% confidence interval: 2.42 to 3.56; p < 0.00001). CONCLUSIONS: The incidence of AF after AFL ablation is high especially in patients with prior AF when compared to those without prior AF. The detection of AF in patients without prior AF significantly increases with more frequent monitoring and/or longer follow-up duration. PMID- 29759748 TI - Contact Force-Guided Pulmonary Vein Isolation: The Quest for Perfection Continues. PMID- 29759747 TI - Relationship Between Catheter Stability and 12-Month Success After Pulmonary Vein Isolation: A Subanalysis of the SMART-AF Trial. AB - OBJECTIVES: This study sought to assess the correlation between catheter and tissue contact force (CF) stability and 12-month clinical success for atrial fibrillation (AF) ablation. BACKGROUND: The SMART-AF (Thermocool Smarttouch Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation) multicenter trial provided a robust dataset of AF ablation procedures, using the CF sensing ablation catheter. METHODS: CF and CF stability were correlated with 12-month success for drug-refractory symptomatic AF ablation. CF stability was assessed by stability of ablation parameters (CF, time, location stability) over 3-dimensional electroanatomic maps of pulmonary veins (PVs) using a new proprietary software module and the percentage of time within investigator selected CF ranges. Available data for potential "PV gaps" were retrospectively identified when stability criteria were not met and were correlated with 12-month success. RESULTS: Average CF categories of 0 to 10, 10 to 20, and >20 g were associated with 12-month success rates of 90%, 70%, and 70%, respectively; thus, higher average CF did not correlate with treatment success. An exploratory univariate analysis showed significantly higher success rates with a CF of 6.5 to 10.3 g than with <6.5 g (odds ratio: 2.95; 95% confidence interval: 1.13 to 7.72; p = 0.028) but a CF >10 g did not improve success. When stable CF was applied >=73% of the time within the preselected CF range, success improved. A receiver operating characteristic curve analysis revealed that PV gaps exceeding 10.6-mm distance significantly correlated with 12-month failure. CONCLUSIONS: In the SMART-AF trial, CF stability with sufficient CF was most predictive of optimal 12 month success. (Thermocool Smarttouch Catheter for the Treatment of Symptomatic Paroxysmal Atrial Fibrillation [SMART-AF]; NCT01385202). PMID- 29759749 TI - Exercise Capacity Correlates With Left Atrial Structural Remodeling as Detected by Late Gadolinium-Enhanced Cardiac Magnetic Resonance in Patients With Atrial Fibrillation. AB - OBJECTIVES: This study hypothesized that left atrial structural remodeling (LA TR) correlates with exercise capacity (EC) in a cohort of patients with atrial fibrillation (AF). BACKGROUND: Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) imaging provides a method of assessing LA-TR in patients with AF. METHODS: A total of 145 patients (32% female, mean age 63.4 +/- 11.6 years of age) with AF (66 paroxysmal, 71 persistent, 8 long-standing persistent) presenting for catheter ablation were included in the study. All patients underwent LGE-CMR imaging as well as maximal exercise test using the Bruce protocol prior to catheter ablation of AF. EC was quantified by minutes of exercise and metabolic equivalent (MET) level achieved. LA-TR was quantified from LGE-CMR imaging and classified according to the Utah classification of LA structural remodeling (Utah stage I: <10% LA wall enhancement; Utah II: 10% to <20%; Utah III: 20% to <30%; and Utah IV: >30%). AF recurrence was assessed at 1 year from the date of ablation. RESULTS: The average duration of exercise was 8 +/- 3 min, and the mean MET achieved was 9.7 +/- 3.2. METs achieved were inversely correlated with LA-TR (R2 = 0.061; p = 0.003). The duration of exercise was also inversely correlated with LA-TR (R2 = 0.071; p = 0.001). Both EC and LA TR were associated with AF recurrence post ablation in univariate analysis, but only LA-TR and age were independently predictive of recurrence in multivariate analysis (p = 0.001). For every additional minute on the treadmill, subjects were 13% more likely to be free of AF 1 year post ablation (p = 0.047). CONCLUSIONS: EC is inversely associated with LA-TR in patients with AF and is predictive of freedom from AF post-ablation. PMID- 29759750 TI - Exercise Capacity and Atrial Remodeling in Atrial Fibrillation: Who's on First? PMID- 29759751 TI - Recurrence of Atrial Arrhythmias Despite Persistent Pulmonary Vein Isolation After Catheter Ablation for Atrial Fibrillation: A Case Series. AB - OBJECTIVES: The aim of this study was to categorize arrhythmia mechanisms and to summarize ablation strategies in patients with persistent pulmonary vein isolation (PVI) at the time of redo procedures. BACKGROUND: Persistent PVI is more frequently seen in patients undergoing redo procedures for recurrent atrial arrhythmias after catheter ablation for atrial fibrillation (AF). METHODS: Consecutive patients who underwent their first AF ablation procedures at Brigham and Women's Hospital were screened and included if they had persistent isolation of all pulmonary veins at the time of redo procedures. RESULTS: Of 300 consecutive patients undergoing first AF ablation procedures, redo procedures were performed in 63 (21%), and 26 patients (9%) had persistent PVI. Of those, 11 had recurred with AF and 15 with organized atrial tachycardia (AT). During the index procedure, linear ablation was performed in 46% of patients with recurrent AF and 93% with recurrent organized AT (p = 0.020). At the time of last follow up, 2 of 10 patients (20%) in the AF group and 10 of 15 patients (67%) in AT group were in sinus rhythm, without class I or III antiarrhythmic drugs (p = 0.022). CONCLUSIONS: Patients with recurrence of atrial arrhythmia despite persistent PVI frequently present with organized AT. Linear ablation during the index procedure is associated with recurrence of organized AT. Recurrence rates after redo procedures were higher if patients had recurrent AF after the index procedure, and these patients often presented with AF again. Patients with recurrent AF despite persistent PVI may represent a population with lower success rates of catheter ablation. PMID- 29759753 TI - Electrogram Fractionation-Guided Ablation for Persistent Atrial Fibrillation: Toward More Specificity for Identifying the Arrhythmogenic Sources. PMID- 29759752 TI - Electrogram Fractionation-Guided Ablation in the Left Atrium Decreases the Frequency of Activation in the Pulmonary Veins and Leads to Atrial Fibrillation Termination: Pulmonary Vein Modulation Rather Than Isolation. AB - OBJECTIVES: This study sought to evaluate the impact of a complex fractionated atrial electrogram (CFAE)-guided ablation strategy on atrial fibrillation (AF) dynamics in patients with persistent AF. BACKGROUND: It is still unclear whether complete pulmonary vein isolation (PVI) is required or if the ablation of well delineated pulmonary vein (PV) subregions could achieve similar outcomes in persistent AF. METHODS: CFAE-guided ablations were performed in 76 patients (65.2 +/- 10 years of age) with persistent AF. In 47 patients, we measured mean PVs and left atrial appendage (LAA) cycle length (CL) values (PV-CL and LAA-CL), before ablation and before AF termination. We defined "active" PVs as PV-CL <= LAA-CL, "rapid fires" as PV-CL <=80% of LAA-CL, and "PV-LAA CL gradient" as a significant CL difference between the 2 regions. RESULTS: AF termination (sinus rhythm [SR] or atrial tachycardia [AT] conversion) occurred in 92% and SR conversion in 75%. The radiofrequency time for AF termination and total radiofrequency time were 26 +/- 25 min and 61.1 +/- 21.6 min, respectively. Thirty of 47 patients had active PV (with 19 PV "rapid fires"). Ablation significantly increased median CL, both at PVs and LAA from 188 ms (interquartile range [IQR]: 161 to 210 ms) to 227.5 ms (IQR: 200 to 256 ms) (p < 0.0001) and from 197 ms (IQR: 168 to 220 ms) to 224 ms (IQR: 193 to 250 ms) (p < 0001), respectively. After ablation, PV-LAA CL gradients were withdrawn and all PV "rapid fires" were extinguished (without PVI). After 17.2 +/- 10 months of follow-up and 1.61 +/- 0.75 procedures, 86.3% and 73% of the patients were free from AF and from any arrhythmia (AF/AT), respectively. CONCLUSIONS: CFAE-guided ablation leads to a large decrease in PV frequency of activation, preceding AF termination. A PV modulation approach, rather than complete PVI, may be preferable for persistent AF. PMID- 29759754 TI - A High Baseline Electrographic Organization Level Is Predictive of Successful Termination of Persistent Atrial Fibrillation by Catheter Ablation. AB - OBJECTIVES: This study sought to investigate whether the level of organization of electrocardiographic (ECG) signals based on novel indexes is predictive of persistent atrial fibrillation (pAF) termination by catheter ablation (CA). BACKGROUND: Whether the level of ECG organization in pAF is correlated with the restoration of sinus rhythm by CA remains unknown. METHODS: Thirty consecutive patients who underwent stepwise CA for pAF (sustained duration 19 +/- 11 months) were included in the study (derivation cohort). ECG lead V6 was placed on the patients' back (V6b) to improve left atrial (LA) recording. Two novel ECG indexes were computed using an adaptive harmonic frequency tracking scheme: 1) the adaptive organization index (AOI), which quantifies the cyclicity of AF harmonic oscillations; and 2) the adaptive phase index (API), which quantifies the phase coupling between the harmonic components. Index cutoff values predictive of procedural AF termination were then tested on a validation cohort of 8 consecutive patients. RESULTS: In the derivation cohort, CA terminated AF in 21 patients within the LA (70%; left-terminated [LT] group), whereas CA did not terminate AF in 9 patients (30%; non-left-terminated [NLT] group). LT patients displayed a higher ECG organization level at baseline than the NLT patients, with the best separation achieved by AOI and API computed on lead V1 (area under the curve [AUC] = 0.94 and AUC = 0.88, respectively; p < 0.05) and API on lead V6b (AUC = 0.83; p < 0.05). Similar results were obtained for both AOI and API in the validation cohort. CONCLUSIONS: Patients in whom pAF terminated within the LA exhibited a higher level of atrial ECG organization, which was suggestive of a limited number of LA drivers than that of patients in whom the pAF could not be terminated by CA. PMID- 29759756 TI - Coronary Sinus Stenosis as Collateral Damage of Radiofrequency Ablation in Patients With Atrial Fibrillation. PMID- 29759755 TI - Total Anomalous Coronary Venous Return: Strategic Planning in Atrial Fibrillation Ablation. PMID- 29759757 TI - Atrial Fibrillation: Keeping Sight of the Big Picture. PMID- 29759758 TI - Should We Use Drugs to Decrease Drug-Induced QT Prolongation? PMID- 29759760 TI - Glass Half Empty? PMID- 29759759 TI - Discontinuation of Dofetilide From QT Prolongation and Ventricular Tachycardia in the Real World. AB - OBJECTIVES: The purpose of this study was to determine the incidence and correlates of QT prolongation or ventricular tachycardia (VT) resulting in discontinuation of dofetilide in a real-world setting. BACKGROUND: Dofetilide is a class III antiarrhythmic agent approved for achieving and maintaining sinus rhythm in patients with symptomatic atrial fibrillation. Because of a risk of QT prolongation and VT, patients starting dofetilide need to be hospitalized for 3 days to closely monitor telemetry and electrocardiography. In large clinical trials, <3% of patients had to discontinue dofetilide because of QT prolongation, but data from real-world experience are lacking. METHODS: We examined 114 consecutive patients with atrial fibrillation who were hospitalized for starting dofetilide at the Minneapolis Veterans Affairs Health Care System from 2011 to 2014. RESULTS: The mean age of the patients was 64 +/- 8 years. Dofetilide was discontinued in 22 (19%) patients because of QT prolongation (17%) or VT (2%). A total of 32 (28%) patients were taking other QT-prolonging drugs. Of these, 10 (31%) had to discontinue dofetilide versus 12 (15%) of the 82 patients who were not taking any other QT-prolonging drugs (p = 0.04). Patients who were taking concomitant QT-prolonging drugs were 1.9 times more likely to discontinue dofetilide (95% confidence interval: 1.1 to 3.4; p = 0.04) compared with those who were not taking any other QT-prolonging drugs. CONCLUSIONS: The incidence of QT prolongation or VT that lead to discontinuation of dofetilide is remarkably higher in the real-world setting than in clinical trials. Concomitant use of other QT-prolonging drugs was associated with discontinuation of dofetilide. PMID- 29759761 TI - Potent Inhibition of hERG Channels by the Over-the-Counter Antidiarrheal Agent Loperamide. AB - OBJECTIVES: The aim of this study was to determine the in vitro electrophysiological properties of loperamide. The authors' hypothesis was that loperamide is a potent blocker of the current carried by the human ether-a-go-go related gene (hERG) potassium channel. BACKGROUND: Loperamide is a peripherally acting MU-opioid agonist available worldwide as an over-the-counter treatment for diarrhea. Like most opioids, it is not currently known to be proarrhythmic. Recent cases of torsade de pointes in association with high-dose loperamide raise concern given its structural similarity to methadone, another synthetic opioid with an established arrhythmia risk. METHODS: Effects of loperamide on blockade of the hERG potassium channel ion current were assessed in Chinese Hamster Ovary (CHO) cells stably expressing hERG to elucidate current amplitude and kinetics. The concentration required to produce 50% inhibition of hERG current was assessed from the amplitude of tail currents and the impact on action potential duration was assessed in isolated swine ventricular cardiomyocytes. RESULTS: The 50% inhibitory concentration for loperamide inhibition of hERG ionic tail currents was approximately 40 nmol/l. In current-voltage measurements, loperamide reduced steady and tail currents and shifted the current activation to more negative potentials. Loperamide (10 nmol/l) also increased the action potential duration, assessed at 90% of repolarization, in ventricular myocytes by 16.4 +/- 1.7% (n = 6; p < 0.004). The maximum rate of rise of phase 0 of the action potential, however, was not significantly altered at any tested concentration of loperamide. CONCLUSIONS: Loperamide is a potent hERG channel blocker. It significantly prolongs the action potential duration and suggests a causal association between loperamide and recent clinical cases of torsade de pointes. PMID- 29759762 TI - An Emerging Malignant Arrhythmia Epidemic Due to Loperamide Abuse: Underlying Mechanisms and Clinical Relevance. PMID- 29759764 TI - Left Ventricular Endocardial Stimulation in Patients With a Poor Response to Cardiac Resynchronization Therapy: What Is Next? PMID- 29759763 TI - Atrial Fibrillation in Patients With Left Ventricular Assist Devices: Incidence, Predictors, and Clinical Outcomes. AB - OBJECTIVES: This study sought to determine the prevalence of atrial fibrillation (AF) and its association with cardiac outcomes in patients with left ventricular assist devices (LVADs). BACKGROUND: LVADs are pivotal treatments for end-stage heart failure and a critical bridge to heart transplantation. METHODS: Medical records of 249 consecutive patients who received an LVAD at Columbia University Medical Center were reviewed. Patient demographics, clinical variables, medications, and outcomes were recorded. Descriptive statistics were generated, and multivariable logistic regression was performed to assess the independent association of clinical variables with the presence of AF. RESULTS: Overall, AF was documented in 80 patients (32%) following LVAD placement. Before LVAD placement, 182 patients had no history of AF, whereas 67 patients had documented AF. Among these 67 patients, 56 (84%) continued to have AF following LVAD placement; 24 patients without a history of AF (13%) developed AF after LVAD placement. Patients manifesting AF after LVAD placement were more likely to have had AF before LVAD insertion (p < 0.001). There were no significant differences in risk of stroke or death for patients with AF before or following LVAD insertion. CONCLUSIONS: AF is common in patients with LVADs, with 32% manifesting AF after placement of their LVAD, including 13% without a prior documented history of AF. The presence of AF was not associated with increased risk of death or stroke. PMID- 29759765 TI - The Role of the Baroreflex in Tilt Table Testing: Outcome and Type of Response. AB - OBJECTIVES: The purpose of this study was to better understand the role of the baroreflex in tilt-induced vasovagal syncope (VVS). BACKGROUND: The role of the baroreflex in tilt-induced VVS remains controversial. The authors hypothesized that: 1) patients with positive tilt table test (TTT) results have greater baroreflex gain (BRG) compared with patients with negative TTT results; and 2) patients with tilt-induced asystole have greater BRG compared with patients without asystole. METHODS: Using the sequence method, BRG measurements were obtained in 438 consecutive patients undergoing TTT. Two hundred sixty-eight patients (61%) had positive TTT results (mean age 50 +/- 21 years; 34% men), and 170 patients (39%) had negative TTT results (mean age 48 +/- 21 years; 35% men). RESULTS: Mean BRG was significantly higher in patients with positive TTT results compared with those with negative TTT results (12.9 +/- 6.0 ms/mm Hg vs. 11.5 +/- 6.0 ms/mm Hg; p = 0.01). Among the 268 patients with positive TTT results, 23 (9%) had more than 3 s of asystole (mean age 37 +/- 17; 30% men), and 245 patients had a mixed vasodepressor or cardioinhibitory response without asystole (mean age 51 +/- 17 years; 34% men). Mean BRG was greater in patients with tilt induced asystole (>3 s) compared with patients without asystole (15.3 +/- 5.9 ms/mm Hg vs. 12.7 +/- 5.9 ms/mm Hg; p = 0.03). CONCLUSIONS: The results of this study demonstrate that baseline BRG was higher in patients with positive TTT results compared with those with negative TTT results, with greater values noted in patients with tilt-induced asystole (>3 s) compared with those without asystole. PMID- 29759767 TI - Long-Term Results of Triventricular Versus Biventricular Pacing in Heart Failure: A Propensity-Matched Comparison. AB - OBJECTIVES: The goal of this study was to assess the impact of triventricular pacing (Tri-V) on long-term survival. BACKGROUND: Biventricular pacing (Bi-V) is an important adjunctive treatment in advanced heart failure, but almost one-third of patients experience no improvement with this therapy and are labeled as nonresponders. Adding a third ventricular lead (Tri-V) has been shown to be feasible and provides favorable acute results when assessed by using echocardiographic, hemodynamic, and clinical endpoints. However, the long-term effects of Tri-V pacing and how it affects long-term survival remains unknown. METHODS: This single-center, propensity score-matched cohort study compared 34 patients with advanced heart failure who underwent implantation with Tri-V devices versus 34 control subjects treated with Bi-V pacing. Clinical outcomes during a median of 2,478 days (IQR: 1,183 to 3,214 days) were compared. RESULTS: Tri-V-treated patients compared with Bi-V-treated patients presented with a trend for shorter battery longevity (time to box change, 1,758 +/- 360 days vs. 1,993 +/- 408 days; p = 0.072). Incidence of lead dislodgement (Tri-V vs. Bi-V, 0.86 vs. 1.10 per 100 patient-years; p = 0.742), device-related infection (Tri-V vs. Bi-V, 1.83 vs. 1.76 per 100 patient-years; p = 0.996), and refractory phrenic nerve capture (Tri-V vs. Bi-V, 0.48 vs. 1.84 per 100 patient-years; p = 0.341) was comparable in the 2 groups. Episodes of ventricular arrhythmia requiring implantable cardioverter-defibrillator intervention occurred more frequently in the Bi-V group versus the Tri-V group (6.55 vs. 16.88 per 100 patient-years; adjusted hazard ratio: 0.31; 95% confidence interval: 0.14 to 0.66; p = 0.002). Lower all-cause mortality and heart transplant was observed in the Tri-V group compared with the Bi-V group (6.99 vs. 11.92 per 100 patient-years; adjusted hazard ratio: 0.44; 95% confidence interval: 0.23 to 0.85; p = 0.015). CONCLUSIONS: Tri-V displayed a similar safety profile compared with Bi-V and was associated with potential benefits regarding long-term survival and ventricular arrhythmia burden. PMID- 29759768 TI - Triventricular Pacing: A Nice Concept to Be Proven. PMID- 29759766 TI - Blunted Chronotropic Response to Hypotension in Cough Syncope. AB - OBJECTIVES: This study compared hemodynamic and chronotropic responses to cough in cough syncope (CS) patients to those in control subjects. BACKGROUND: Cough syncope is an uncommon form of situational fainting variously attributed to both reflex and mechanical causes. We hypothesized that if baroreflex responses contribute to CS, post-cough hypotension should be associated with cardioinhibition comparable to that observed in other reflex faints. METHODS: The study population consisted of 8 CS patients (group 1), 21 patients with vasovagal syncope (group 2), and 6 patients with nonvertiginous "lightheadedness" (group 3). Testing with patients seated included volitional coughing that achieved a transient blood pressure (BP) of >=200 mm Hg. Beat-to-beat blood pressure (systolic blood pressure [SBP]) before cough, minimum cough-induced SBP and heart rate (HR) (beats/min) after cough, and HR change during cough-induced hypotension were recorded, along with SBP recovery time from SBP nadir after cough. RESULTS: Compared to controls, cough-induced SBP drop was greater in CS patients (CS patients: -48 +/- 13.1 mm Hg vs. -29 +/- 11.2 mm Hg for group 2 controls; p = 0.005; or -25 +/- 10 mm Hg in group 3 controls; p = 0.02), and recovery time was longer (CS: 46 +/- 19 s vs. 11 +/- 3.6 s in group 1 controls; p = 0.002; or 12 +/ 5 s in group 3 controls; p = 0.01). Furthermore, despite greater induced hypotension, post-cough chronotropic response was less in CS patients (+15% above baseline rate) than in either group 2 (+31% above baseline rate; p < 0.001) or group 3 (+28%; p = 0.01) controls. CONCLUSIONS: In CS patients, post-cough chronotropic response is blunted compared to that in controls despite greater cough-induced hypotension favoring baroreflex cardioinhibition contribution to the pathophysiology of cough syncope. PMID- 29759769 TI - Protection of Critical Structures During Radiofrequency Ablation of Adjacent Myocardial Tissue Using Catheter Tips Partially Insulated With Thermally Conductive Material. AB - OBJECTIVES: This study sought to determine whether partially insulated focused ablation (PIFA) catheters can minimize risk of injury to critical structures, such as the phrenic nerve and atrioventricular (AV) node, during ablation of adjacent myocardial tissue. BACKGROUND: PIFA catheters using thermally conductive materials may have differential radiofrequency (RF) heating properties allowing for tailored RF application with more precision. METHODS: Open-irrigated, 4- and 8-mm RF ablation catheter tips were insulated partially by coating one-half of their surfaces with a layer of vinyl, silicone, vinyl-silicone, polyurethane, or a composite of aluminum oxide/boron nitride (AOBN). These coated catheters or corresponding noninsulated catheters were positioned with 10 g of force on viable bovine myocardial tissue during RF application in an ex vivo setup. Tip temperatures, power, and lesion volumes were compared. The most effective coating, AOBN, was modified further by adding fenestrations to aid in passive cooling. PIFA catheters with fenestrated AOBN coating were then tested in an in vivo porcine model to target myocardial tissue adjacent to the AV node and the phrenic nerve. RESULTS: PIFA catheters all demonstrated higher tip temperatures, although silicone- and AOBN-catheters demonstrated this to a lesser degree. Significant differences in lesion volumes and temperature-limited powers were noted between control, silicone, and AOBN tips. Steam pops were significantly higher for silicone but not AOBN. In contrast with non-PIFA catheters, injuries to the phrenic nerve and AV node during in vivo ablations with AOBN insulation positioned over these structures were reduced significantly. CONCLUSIONS: RF ablation using catheter tips partially coated with a thermally conductive insulation material such as AOBN results in larger ablation lesion volumes without temperature limitations. Partial insulation of the catheter tip will protect adjacent critical structures during RF ablation. PMID- 29759770 TI - Ibrutinib, an Approved Tyrosine Kinase Inhibitor as a Potential Cause of Recurrent Polymorphic Ventricular Tachycardia. PMID- 29759772 TI - Harmful Effects of Monophasic Cathodal Pacing. PMID- 29759773 TI - The Year in JACC: Clinical Electrophysiology. PMID- 29759771 TI - Novel Electrophysiology Signal Recording System Enables Specific Visualization of the Purkinje Network and Other High-Frequency Signals. PMID- 29759774 TI - Assessment of Left Atrial Fibrosis by Late Gadolinium Enhancement Magnetic Resonance Imaging: Methodology and Clinical Implications. AB - Recently, studies using late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) to identify structural changes of atrial tissue have contributed significantly to understanding the pathophysiology and progression of atrial fibrillation (AF). Moreover, imaging of atrial fibrosis using MRI has evolved to be a tool to improve clinical outcome of AF ablation procedures by allowing a patient-specific individualized management approach. LGE-MRI has been shown to predict AF ablation outcome based on pre-procedural imaging to define the extent of atrial fibrosis. The results of the ongoing DECAAF II (Delayed-Enhancement MRI Determinant of Successful Radiofrequency Catheter Ablation of Atrial Fibrillation) trial might extend ablation strategies from pulmonary vein isolation alone to a substrate-based approach. Furthermore, an improved understanding of the underlying mechanisms of atrial structural remodeling is crucial in order to reduce the occurrence of AF-associated complications (e.g., ischemic stroke and heart failure). This review article provides current methodology of atrial fibrosis imaging using LGE-MRI and delineates actual clinical implications and future directions for this imaging approach. PMID- 29759776 TI - It Is Time for a Wake-Up Call: How to Use the Best-In-Class Technology for the Most Challenging CRT Patients. PMID- 29759777 TI - The Impact of the PR Interval in Patients Receiving Cardiac Resynchronization Therapy: Results From the REVERSE Study. AB - OBJECTIVES: This study sought to evaluate the impact of baseline PR interval on cardiac resynchronization therapy (CRT) outcomes in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) study. BACKGROUND: The baseline electrocardiogram has important prognostic value to determine response to CRT. Specifically, QRS duration and morphology are strong predictors of response and outcomes; however, the prognostic importance of the PR interval is less clear. METHODS: REVERSE was a double-blinded, randomized study of CRT in mild heart failure (HF). The primary endpoint was the analysis of patients in sinus rhythm (n = 582) of the time-to-first HF hospitalization or death during the 2-year randomized period of the trial. In addition, the long term impact of PR interval was assessed in the cohort actively on CRT during the pre-planned 5-year follow-up. Subjects were analyzed by PR interval, grouped by the median (180 ms) in 20-ms bins or as a continuous variable depending on the analysis performed. Secondary endpoints included the clinical composite score and echocardiographic measures of reverse remodeling. RESULTS: During the randomized phase of the study, CRT had similar effectiveness for both PR <180 ms (hazard ratio [HR]: 0.34) and PR >180 ms (HR: 0.57) subgroups (interaction p = 0.33). Similar results were observed when PR interval was grouped in 20-ms bins or treated as a continuous variable. In multivariable analysis of the long-term follow-up, left bundle branch block morphology, New York Heart Association functional class, HF etiology, and QRS duration, but not PR interval, predicted HF hospitalization or death. CONCLUSIONS: Baseline PR interval does not affect clinical outcomes or reverse remodeling with CRT in mild HF. (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction [REVERSE]; NCT00271154). PMID- 29759775 TI - Real-Time X-MRI-Guided Left Ventricular Lead Implantation for Targeted Delivery of Cardiac Resynchronization Therapy. AB - OBJECTIVES: This study sought to test the feasibility of a purpose-built, integrated software platform to process, analyze, and overlay cardiac magnetic resonance (CMR) data in real time within a combined cardiac catheter laboratory and magnetic resonance imaging scanner suite (X-MRI) to guide left ventricular (LV) lead implantation. BACKGROUND: Suboptimal LV lead position is a major determinant of poor cardiac resynchronization therapy (CRT) response, and the optimal site is highly patient specific. Pacing myocardial scar is associated with poorer outcomes; conversely, targeting latest mechanical activation (LMA) may improve them. METHODS: Fourteen patients (age 74 +/- 5.1 years; New York Heart Association functional class: 2.7 +/- 0.4; 86% ischemic with ejection fraction 27 +/- 7.6%; QRSd: 157 +/- 19 ms) underwent CMR followed by immediate CRT implantation using derived scar and dyssynchrony data, overlaid onto fluoroscopy in an X-MRI suite. Rapid LV segmentation enabled detailed scar quantification, identification of LMA segments, and selection of myocardial targets. At coronary venography, the CMR-derived 3-dimensional shell was fused, enabling identification of viable venous targets subtended by target segments for LV lead placement. RESULTS: The platform was successful in all 14 patients, of whom 10 (71%) were paced in pre-procedurally defined target segments. Pacing in CMR-defined target segments (out of scar) showed a significant decrease in the LV capture threshold (mean difference: 2.4 [1.5 to 3.2]; p < 0.001) and shorter paced QRS duration (mean difference: 25 [15 to 34]; p < 0.001) compared with pacing in areas of CMR determined scar. In 5 (36%) patients with extensive scar in the posterolateral wall, CMR guidance enabled successful lead delivery in an alternative anatomically favorable site. Radiation dose and implant times were similar to historical controls (p = NS). CONCLUSIONS: Real-time CMR-guided LV lead placement is feasible and achievable in a single clinical setting and may prove helpful to preferentially select sites for LV lead placement. PMID- 29759778 TI - Does First Degree AV Block Have Importance in Patients Considered for Cardiac Resynchronization Therapy?: Giving It the Third Degree. PMID- 29759779 TI - 16 Years of Cardiac Resynchronization Pacing Among Congenital Heart Disease Patients: Direct Contractility (dP/dt-max) Screening When the Guidelines Do Not Apply. AB - OBJECTIVES: The purpose of this study was to use direct cardiac resynchronization therapy (CRT)-paced contractility (dP/dt-max) response as a pre-implantation evaluation among patients with congenital heart disease (CHD) and follow clinical parameters and contractility indexes after CRT implantation. BACKGROUND: Patients with CHD often develop early heart failure with few therapeutic options, leading to heart transplantation (HT). Unfortunately, guidelines for CRT do not apply, and function evaluations by cardiac ultrasound are often inaccurate among CHD anatomies. Therefore, which CHD patients would benefit from CRT remains an enigma. METHODS: From 1999 to 2015, 103 CHD patients with New York Heart Association (NYHA) functional class II to IV were listed for HT; 40 patients on optimal medical therapy were referred for paced contractility response cardiac catheterization before CRT consideration. If dP/dt-max improved >=15% from baseline, these "responders" were given the option of CRT with continued follow up after implantation. RESULTS: Of 40 patients studied, 26 (65%) (age 22 +/- 8.2 years; 9 of 26 [35%] single or systemic right ventricle; 17 of 26 [65%] with pacemakers) met criteria for possible hemodynamic benefit and underwent CRT implantation. All 26 patients improved in NYHA functional classification: 5 of 26 patients (19%) were later relisted for HT (4 to 144 months, mean 55 months) after CRT implantation, whereas 21 of 26 (81%) continued with improved NYHA functional class (12 to 112 months, mean 44 months) later. A repeat dP/dt-max study following long-term CRT showed stable function or continued contractility improvement. CONCLUSIONS: Heart failure is common among CHD patients, and therapies are limited. CRT guidelines do not address clinical and anatomic issues of CHD. Short-term paced contractility response testing identifies those CHD patients who are likely to respond to CRT regardless of anatomy. PMID- 29759780 TI - Screening for Optimal Cardiac Resynchronization Therapy Indication in Congenital Heart Disease. PMID- 29759781 TI - Sex-Specific Response to Cardiac Resynchronization Therapy: Effect of Left Ventricular Size and QRS Duration in Left Bundle Branch Block. AB - OBJECTIVES: In this study, the authors sought to assess the impact of body and heart size on sex-specific cardiac resynchronization therapy (CRT) response rate, according to QRS duration (QRSd) as a continuum. BACKGROUND: Effects of CRT differ between sexes for any given QRSd. METHODS: New York Heart Association functional class III/IV patients with nonischemic cardiomyopathy and "true" left bundle branch block (LBBB) were evaluated. Left ventricular mass (LVM) and end diastolic volume were measured echocardiographically. Positive response was defined by left ventricular ejection fraction (LVEF) improvement post-CRT. RESULTS: Among 130 patients (LVEF 19 +/- 7.1%; QRSd 165 +/- 20 ms; 55% female), CRT improved LVEF to 32 +/- 14% (p < 0.001) during a median 2 years follow-up. Positive responses occurred in 103 of 130 (79%) (78% when QRSd <150 ms vs. 80% when QRSd >=150 ms; p = 0.8). Body surface area (BSA), QRSd, and LVM were lower in women, but QRSd/LVM ratio greater (p < 0.0001). Sexes did not differ for pharmacotherapy and comorbidities, but female CRT response was greater: 90% (65 of 72) versus 66% (38 of 58) in males (p < 0.001). With QRSd as a continuum, the overall CRT-response relationship showed a progressive increase to plateau between 150 and 170 ms, then a decrease. Sex-specific differences were conspicuous: among females, a peak effect was observed between 135 and 150 ms, thereafter a decline, with the male response rate lower, but with a gradual increase as QRSd lengthened. Sex-specific differences were unaltered by BSA, but resolved with integration of LVM or end-diastolic volume. CONCLUSIONS: Sex differences in the QRSd-response relationship among CRT patients with LBBB were unexplained by application of strict LBBB criteria or by BSA, but resolved by QRSd normalization for heart size using LV mass or volume. PMID- 29759783 TI - Regional Left Ventricular Electrical Activation and Peak Myocardial Contraction in Cardiac Resynchronization Therapy: The Importance of Being in the Right Place at the Right Time? PMID- 29759782 TI - Regional Left Ventricular Electrical Activation and Peak Contraction Are Closely Related in Candidates for Cardiac Resynchronization Therapy. AB - OBJECTIVES: This study determined the relationship between the timing of left ventricular (LV) electrical activation and peak contraction at potential LV pacing locations in candidates for cardiac resynchronization therapy (CRT). BACKGROUND: Targeting the LV lead to the region of latest electrical activation or the segment of latest peak contraction has both been shown to improve CRT response. Whether these regions correspond within CRT patients is uncertain. METHODS: Twenty-eight consecutive CRT candidates underwent intraprocedural coronary venous electroanatomic mapping using EnSite NavX. Peak contraction time of the mapped LV regions was determined using longitudinal strain derived from speckle tracking echocardiography. Electrical activation and peak contraction times were correlated on a per patient basis, and the regions of latest electrical activation and latest peak contraction were compared. RESULTS: Successful measurements by both techniques allowed analysis in 23 of 28 patients. There was a strong positive correlation between electrical activation and peak contraction times within each patient (R2 = 0.85 +/- 0.09). However, the magnitude of the electrical activation-peak contraction relationship varied greatly among patients (slope of regression line: 4.05 +/- 3.23). The regions of latest electrical activation and latest peak contraction corresponded in 19 of 23 (83%) patients and were adjacent in 4 patients. CONCLUSIONS: There is a close relationship between the timing of LV electrical activation and peak contraction in CRT candidates. This finding suggests that a strategy of determining the latest activated LV region based on speckle tracking echocardiography corresponds to that based on intracardiac measurements of electrical activation. PMID- 29759784 TI - Atrial Tachycardias After Surgical Atrial Fibrillation Ablation: Clinical Characteristics, Electrophysiological Mechanisms, and Ablation Outcomes From a Large, Multicenter Study. AB - OBJECTIVES: The clinical characteristics, electrophysiological mechanisms, and ablation outcomes of post-surgical atrial fibrillation ablation (SAFA) atrial tachycardias (ATs) have not been studied in a large, multicenter cohort. BACKGROUND: ATs are often seen following SAFA. METHODS: Analysis was performed on 137 patients (age, 62 +/- 10 years; 74% male) who underwent catheter ablation for symptomatic post-SAFA AT from 2004 to 2013 at 3 high-volume institutions in the United States. RESULTS: A total of 137 patients had 149 ATs that were mapped; 103 (69%) had a left atrial (LA) origin and 46 (31%) had a right atrial origin. Of the 149, a total of 44 (30%) had a focal mechanism, with 29 (66%) having an LA origin, with 53% localized to LA posterior wall. Of the 105 re-entrant ATs, 74 (71%) were of LA origin. The predominant circuits were cavotricuspid isthmus (n = 25), perimitral (n = 19), LA roof (n = 17), left pulmonary veins (n = 13), right pulmonary vein/LA septum (n = 12), and LA appendage (n = 7). A total of 93% of patients had >=1 pulmonary vein reconnection requiring reisolation. Catheter ablation resulted in termination and noninducibility of 97% of right atrial and 93% of LA ATs. Over a 12-month follow-up, 80% of patients were free of any AT or AF. CONCLUSIONS: In this large multicenter cohort of post-SAFA ATs, most were of LA origin, with macro-re-entry being the most common arrhythmia mechanism. Wide variability in location of AT circuits was seen in both right atrial and LA and likely reflects underlying arrhythmogenic substrate and differences in modified SAFA techniques. Catheter ablation was highly successful in eliminating the culprit AT with favorable long-term outcomes. PMID- 29759786 TI - The Value Proposition of Remote Catheter Navigation: Efficient Tools Versus Expensive Toys. PMID- 29759785 TI - Manual Versus Robotic Catheter Ablation for the Treatment of Atrial Fibrillation: The Man and Machine Trial. AB - OBJECTIVES: Circumferential pulmonary vein isolation (CPVI) using irrigated radiofrequency is the most frequently used ablation technique for the treatment of atrial fibrillation worldwide. BACKGROUND: To date, no large randomized multicenter trials have evaluated the efficacy and safety of CPVI using robotic navigation (RN) systems compared with the current gold standard of manual ablation (MN). METHODS: In this prospective, international multicenter noninferiority trial, 258 patients with paroxysmal or persistent atrial fibrillation were randomized for CPVI using either RN (RN group, n = 131) or manual ablation (MN group, n = 127). In all patients, CPVI was performed using irrigated radiofrequency ablation in combination with a 3-dimensional mapping system. The primary endpoint was the absence of atrial arrhythmia recurrence on or off antiarrhythmic drugs during a 12-month follow-up period. Secondary endpoints were the evaluation of periprocedural complications and procedural data such as procedure time, fluoroscopy time, and incidence of esophageal injury. RESULTS: Baseline characteristics were comparable between the RN group and MN group. Procedure time was significantly shorter in the MN group (129.3 +/- 43.1 min vs. 140.9 +/- 36.5 min; p = 0.026). 247 patients completed the 12-month follow-up (RN group, n = 123; MN group, n = 124). Recurrence rate was comparable between the RN and MN groups (n = 29 of 123 [23.6%] vs. 25 of 124 [20.2%]). The incidence of procedure-related major complications did not differ significantly between ablation arms (RN group, n = 8 [6.1%] vs. MN group, n = 6 [4.7%]; p = 0.62). One patient from the RN group developed a fatal atrioesophageal fistula. CONCLUSIONS: This study demonstrated that robotic ablation is noninferior to the current gold standard of manual ablation for CPVI with respect to success and complication rates. Procedure times were significantly longer in the RN group. (Alster Man and Machine: Comparison of Manual and Mechanical Remote Robotic Catheter Ablation for Drug-Refractory Atrial Fibrillation; NCT00982475). PMID- 29759787 TI - Nationwide Longitudinal Follow-Up of Riata Leads Under Advisory at 3 Annual Screenings: Report From the Netherlands Heart Rhythm Association Device Advisory Committee. AB - OBJECTIVES: This study sought to determine prospectively the rate of conductor externalization (CE), and whether this was associated with electrical failure. BACKGROUND: The Riata family of defibrillator leads was placed under U.S. Food and Drug Administration advisory as of November 28, 2011 because of high rates of CE. METHODS: A nationwide cohort established in 2012 of 1,029 patients with recalled Riata leads with 147 CE were followed until death, lead discontinuation, or 3 annual screenings with fluoroscopy and device interrogation. RESULTS: Follow up of 882 patients with normal baseline fluoroscopy revealed incident overt CE in 95 leads (11%) after median risk time of 2.9 years, yielding an incidence rate of 4.9 (95% confidence interval [CI]: 3.9 to 5.9) per 100 patient-years. The incidence rate was significantly higher in 8-F Riata leads than in 7-F Riata ST leads (7.0 vs. 3.2 per 100 patient-years; p < 0.001). Electrical follow-up demonstrated electrical abnormality in 77 leads, resulting in an incidence rate of 4.0 (95% CI: 3.2 to 5.0) per 100 patient-years. The incidence rate of electrical abnormalities was not different between leads without CE and those with CE (3.9 vs. 5.2 per 100 patient-years; p = 0.39). CONCLUSIONS: The development of CE is progressive in nature with an incidence rate of new CE of 4.9 per 100 patient-years, with a higher rate for 8-F Riata leads than for 7-F Riata ST leads. Despite the high rate of structural failure, no association between development of CE and electrical failure was observed. PMID- 29759788 TI - Novel Extravascular Defibrillation Configuration With a Coil in the Substernal Space: The ASD Clinical Study. AB - OBJECTIVES: This study assessed the defibrillation efficacy of the substernal lateral electrode configuration. BACKGROUND: Subcutaneous implantable cardioverter-defibrillators (ICDs) are regarded as alternatives to transvenous ICDs in certain subjects. However, substantially higher shock energy of up to 80 J may be required. Proposed is a new defibrillation method of placing the shock coil into the substernal space. METHODS: This prospective, nonrandomized, feasibility study was conducted in subjects scheduled for midline sternotomy or implant of ICD. A blunted end tunneling tool was used to insert a defibrillation lead behind the sternum using a percutaneous subxiphoid approach. A skin patch electrode was placed on the left mid-axillary line at the fourth to fifth intercostal space. After ventricular fibrillation induction, a single 35-J shock was delivered between the lead and skin patch. RESULTS: Sixteen subjects (12 males, 4 females; mean age: 61.6 +/- 11.8 years) were enrolled. The mean lead placement time was 11.1 +/- 6.6 min. Of the 14 subjects with successfully induced ventricular fibrillation episodes, 13 subjects (92.9%) had successful defibrillation. The 1 failure was associated with high and lateral shock coil placement. Mean ventricular fibrillation duration was 18.4 +/- 5.6 s with a shock impedance of 98.1 +/- 19.3 ohms. Of the 11 subjects with coil-patch electrograms, the average R-wave amplitude during sinus rhythm was 3.0 +/- 1.4 mV. CONCLUSIONS: These preliminary data demonstrate that substernal defibrillation is feasible and successful defibrillation can be achieved with the shock energy available in current transvenous ICDs. This may open new alternatives to extravascular ICD therapy. PMID- 29759789 TI - Brugada Pattern With a Concurrent Accessory Pathway. PMID- 29759790 TI - Ablation of a Unique Focal Ventricular Tachycardia in Repaired Truncus Arteriosus. PMID- 29759791 TI - An Oscillating Mass Attached to a Pacemaker Lead: Thrombus or Vegetation? A Fishing Story. PMID- 29759793 TI - Cardiac Oncology: An Unexplored Frontier in Electrophysiologists. PMID- 29759792 TI - A Meta-Analysis of Randomized Trials Comparing the Safety and Efficacy of Intraoperative Defibrillation Testing With No Defibrillation Testing on ICD Implantation. PMID- 29759794 TI - Effectiveness of cross-linked enzyme aggregates of cellulolytic enzymes in hydrolyzing wheat straw. AB - Development of industrially potent cellulolytic enzymes is one of the greatest challenges faced in lignocellulosic feed-stock based bio-refining. In the current work cross-linked enzyme aggregates (CLEAs) of commercial cellulase mix were successfully prepared and their performance to be used as potential industrial enzymes in terms of stability and wheat straw hydrolysis was evaluated. The CLEAs were more stable compared to native enzymes with half-lives being 2.30-, 1.56-, 3.07- and 1.67-fold higher at 70 degrees C for filter paper activity (FPA), endoglucanase, beta-glucosidase and xylanase, respectively. CLEAs retained 77.4% of endoglucanase and 85.9% of xylanase activity after five cycles of hydrolysis of soluble substrates such as carboxymethyl cellulose and xylan, respectively. A maximum saccharification yield of 31.8% by soluble enzymes and 32.9% by CLEAs were obtained when alkali-pretreated wheat straw was subjected to hydrolysis. On repeated batch hydrolysis for five consecutive cycles of 24 h each, the CLEAs showed an overall higher saccharification yield of 43.3% compared to 31.8% with soluble enzymes. PMID- 29759795 TI - Children and Firearms: A Public Health Crisis. PMID- 29759796 TI - Factors Associated With Anthropometric Indicators of Nutritional Status in Children With Chronic Kidney Disease Undergoing Peritoneal Dialysis, Hemodialysis, and After Kidney Transplant. AB - OBJECTIVE: The objective of the study was to demonstrate that there are differences in the factors associated with anthropometric indicators of nutritional status, with particular emphasis on arm indicators, in children with end-stage kidney disease undergoing peritoneal dialysis (PD), hemodialysis (HD), and after kidney transplant (KT). METHODS: An analytical cross-sectional study of consecutive cases included 130 children and adolescents with end-stage kidney disease undergoing substitutive treatment: 49 patients who underwent KT, 33 undergoing PD, and 47 undergoing HD. Socioeconomic data were obtained from all the 3 groups; anthropometric indicators of nutritional status were calculated. Student's t-test and analysis of variance were used for parametric variables. Chi square test, Mann-Whitney U test, Kruskal-Wallis test, and odds ratio (OR) were used for nonparametric variables. RESULTS: The number of parents living as couples was higher for patients who underwent KT (OR = 3.5 [95% confidence interval {CI} 1.34-9.0]) and undergoing PD (OR = 3.0 [95% CI 1.06-8.8]) than those undergoing HD. The number of mothers who worked outside the home was higher for patients who underwent KT and undergoing PD than the mothers of patients undergoing HD (OR = 13.7 [95% CI: 4.56-41.05]; OR = 15.4 [CI 95% 4.8-49], respectively). Family income was higher for patients who underwent KT and undergoing PD (P = .019, P = .093, respectively). More than 40% of patients in all the 3 groups had growth impairment. Body mass index, mid-upper arm circumference, tricipital and subscapular skinfolds, total arm area, and arm fat area were affected in HD and PD groups (9 to 40%), while of the patients who underwent KT, 36.7% were overweight or obese. More than 50% of patients who underwent KT and undergoing HD and PD had involvement in the arm muscular area. CONCLUSIONS: Socioeconomic conditions are more influential for children in the HD program. The nutritional status of children after KT improves; however, not all anthropometric indicators are fully recovered. Children after KT are up to 9 times more likely to be overweight or obese. PMID- 29759797 TI - Our Surgical Experience: Open Versus Endoscopic Carpal Tunnel Surgery. AB - Carpal tunnel release is one of the most common hand operations in the United States and every year approximately 500,000 patients undergo surgical release. In this article, we examine the argument for endoscopic carpal tunnel release versus open carpal tunnel release, as well as some of the literature on anatomical variants in the median nerve at the wrist. We further describe the experience of several surgeons in a large academic practice. The goals of this article are to describe key anatomic findings and to present several cases that have persuaded us to favor offering patients open carpal tunnel release. PMID- 29759798 TI - An Acute Nocardia Infection in a Pediatric Hand. AB - Nocardia species are aerobic gram-positive filamentous organisms that may cause cutaneous or pulmonary disease in humans. Primary cutaneous nocardiosis may manifest as an acute superficial pyogenic infection that can mimic more common organisms such as Staphylococcus or Streptococcus. Acute pyogenic Nocardia infection of the pediatric hand is a rare manifestation of this condition. We present a 17-month-old boy who presented with an acute abscess formation on his left fourth and fifth digits that was found to be secondary to Nocardia brasiliensis. PMID- 29759799 TI - Novel non-ATP competitive small molecules targeting the CK2 alpha/beta interface. AB - Increased CK2 levels are prevalent in many cancers. Combined with the critical role CK2 plays in many cell-signaling pathways, this makes it a prime target for down regulation to fight tumour growth. Herein, we report a fragment-based approach to inhibiting the interaction between CK2alpha and CK2beta at the alpha beta interface of the holoenzyme. A fragment, CAM187, with an IC50 of 44 MUM and a molecular weight of only 257 gmol-1 has been identified as the most promising compound. Importantly, the lead fragment only bound at the interface and was not observed in the ATP binding site of the protein when co-crystallised with CK2alpha. The fragment-like molecules discovered in this study represent unique scaffolds to CK2 inhibition and leave room for further optimisation. PMID- 29759800 TI - [Hypertensive crisis and anticholinergic toxidrome secondary to accidental consumption of datura stramonium in two children]. AB - OBJECTIVE: To identify a hypertensive clinical form of atropine or anticholinergic toxidrome secondary to accidental consumption of Datura seeds. PATIENTS AND METHODS: We report two cases of Datura intoxication in two children who presented marked anticholinergic syndrome whose diagnosis was made by the anamnesis and the clinic. RESULT: Patient 1: A 5-year-old boy, returns home agitated with balance disorders. He was admitted to pediatric resuscitation unit. His Glasgow score was 11/15. The child made inconsistent remarks. The neurological examination revealed mydriasis. Hemodynamically, the blood pressure was 145/91mmHg, the heart rate was 145 bpm. The rest of the examination noted a temperature of 37.5 degrees , a bladder globe. Standard biological tests were normal. ECG found sinus tachycardia. Urine analysis revealed a positive alkaloid reaction with the presence of atropine. The evolution was favorable after 48hours. Patient 2: 45-month-old boy admitted to a state of severe agitation of toxic origin. The clinical examination showed a central and peripheral anticholinergic symptomatology with severe hallucinations, severe hypertension, and a heart rate at 190 bpm. The rest of the examination found erythema in the thorax and upper limbs, bilateral mydriasis. The toxicological report confirmed the presence of alkaloids. The evolution was favorable. CONCLUSION: Hypertension crisis and other anticholinergic clinical signs of Datura stramonium intoxication achieve favorable outcomes in children. PMID- 29759801 TI - [Evaluation of the prescription of furosemide in persons aged 75years and older in a geriatric acute-care unit]. AB - INTRODUCTION: Furosemide is very often prescribed in France. It may cause important adverse effects especially in elderly persons. In order to limit its misuse and excessive expenditure for health insurance organizations, the European Society of Cardiology drafted strict guidelines for its prescription. We conducted a study in this population to determine the rate of prescription of furosemide in elderly persons outside the guidelines. METHOD: This was a prospective, single-centre, observational study bearing on elderly persons aged 75years and more admitted to a geriatric acute-care unit over a period of 6months. The prevalence of furosemide prescription and the proportion of prescriptions outside guidelines were calculated. The sociodemographic and medical characteristics of patients treated with furosemide were studied as were the modalities of furosemide prescription. RESULTS: In the 818 patients hospitalized during the period of the study, 267 were taking furosemide at admission (32.6%). Among these prescriptions, 69.2% were outside the guidelines. Arterial hypertension was the leading indication for furosemide (38.2%), followed by chronic heart failure (24.3%). CONCLUSION: This study confirmed the high prevalence of furosemide prescription and its misuse. Furosemide is often re prescribed with no medical re-evaluation. PMID- 29759802 TI - Combined chemoradiation vs radiation therapy alone in stage-II nasopharyngeal carcinoma: A meta-analysis of the published literature. AB - The aim of this meta-analysis was to evaluate the efficacy and toxicity of adding chemotherapy to radiotherapy (RT) in the treatment of stage-II nasopharyngeal carcinoma (NPC). We searched Pubmed, Cochrane Library, Embase, China National Knowledge Internet, China Biology Medicine, VIP, and Wanfang database for studies of the RT with or without chemotherapy in patients with stage-II NPC that were published in any language. Analyses were carried out using RevMan 5.3 software. The relative risk was used to evaluate the data, the I2 test was used to compare heterogeneity, sensitivity analysis was used to evaluate the stability and reliability of the results. There were 16 studies with 3038 patients that were included in this analysis. Risk ratios (RR) of 1.04 (95% CI: 1.01-1.06), 1.05 (95% CI: 1.00-1.10), 1.05 (95% CI: 1.02-1.07), and 1.00 (95% CI: 0.97-1.03) were observed for overall survival (OS), progression-free survival (PFS), locoregional failure-free survival (LRFS), and distant metastasis-free survival (DMFS). Subgroup analysis showed that compared with conventional RT alone, chemoradiation (CRT) could significantly improve OS (RR = 1.09, 95% CI: 1.03-1.15), PFS (RR = 1.20, 95% CI: 1.08-1.35), and LRFS (RR = 1.09, 95% CI: 1.04-1.14), but did not significantly improve the rate of DMFS (RR = 1.03, 95% CI: 0.94-1.12). However, compared with intensity modulated radiation therapy alone, CRT did not significantly improve the rate of OS (RR = 1.01, 95% CI: 0.99-1.03), PFS (RR = 0.99, 95% CI: 0.95-1.03), LRFS (RR = 1.02, 95% CI: 0.99-1.05), and DMFS (RR = 0.99, 95% CI: 0.96-1.01). Compared with conventional RT alone, CRT could significantly improve patients' prognoses in terms of OS, PFS, and LRFS for stage II NPC, but not DMFS, and CRT can provide greater benefits from concurrent chemotherapy than neoadjuvant chemotherapy. With intensity modulated radiation therapy, the stage-II NPC patients did not benefit from the addition of chemotherapy. PMID- 29759803 TI - Reticulocyte hemoglobin content (MCHr) in the assessment of iron deficient erythropoiesis in inflammatory bowel disease. AB - BACKGROUND: In conditions associated with inflammation, biochemical parameters alone could be inadequate for assessing iron status. We investigated the potential utility of mean reticulocyte hemoglobin content (MCHr) in the assessment of the erythropoiesis status in inflammatory bowel disease (IBD). METHODS: We recruited 124 anemic outpatients with IBD. Serum iron, transferrin and ferritin were tested. Complete blood counts were performed on a CELL-DYN Sapphire analyzer (Abbott Diagnostics). Differences among groups were assessed using analysis of variance, considering P < 0.05 to be significant. Receiver operating characteristic analysis was used to assess the diagnostic performance of MCHr for detecting iron deficient erythropoiesis. The reference used as an indicator of insufficient iron availability was transferrin saturation <20%. RESULTS: Overall, 47.6% of the patients had iron deficiency anemia (IDA) and 31.5% anemia of chronic disease (ACD), while the others (20.9%) had mixed anemia. Patients with ACD or mixed anemia showed functional iron deficiency: normal or high ferritin and low MCHr. The area under curve was 0.858 (95% CI 0.742-0.942), considering a cut off 30.3 pg, the sensitivity was 82.2%, specificity 83.3%. CONCLUSIONS: MCHr provides information on iron availability in IBD patients. It is a reliable test to assess iron supply for erythropoiesis. PMID- 29759804 TI - Urinary tract infection by aerococcus sanguinicola. An emerging opportunistic pathogen. AB - Elderly patients with underlying urological disease have a greater risk of urinary tract infections due to uncommon pathogens. The disease caused by Aerococcus has been underestimated, but mass spectrometry could be a simple method for identifying this pathogen. In this study, we report 2 cases of urinary tract infection by Aerococcus sanguinicola. A descriptive clinical microbiological study was conducted on the presence of A. sanguinicola causing urinary tract infections. The presence of A. sanguinicola occurred in elderly patients with previous urological disease and a significant count in urine obtained through bladder catheterisation. Correct identification was achieved through mass spectrometry, and the clinical outcome of administering amoxicillin and cefuroxime was satisfactory. In this study, we also report the pathogenic capacity of A. sanguinicola. When there is a significant number of alpha haemolytic microorganisms in the urine cultures, A. sanguinicola should be ruled out before reporting a result as urogenital microbiota. PMID- 29759805 TI - Corrigendum to 'Reactivation of BK polyomavirus during pregnancy, vertical transmission, and clinical significance: A meta-analysis' [J. Clin. Virol. 102 (2018) 56-62]. PMID- 29759806 TI - Integration of post-acute care and hospice care in adult day services. PMID- 29759807 TI - Predicting patterns of disaster-related resiliency among older adult Typhoon Haiyan survivors. AB - Reported natural disasters are steadily increasing, yet there is limited previous research explicitly exploring the predictors of disaster resiliency among older people from typhoon-hit provinces. This study examined the relationships between life satisfaction, attitude, spirituality and locus of control towards resiliency among older adult Typhoon Haiyan survivors. A descriptive correlational design was conducted among these survivors in the Eastern Philippines. Standard multiple linear regression analysis was used in the study. The findings indicated that spirituality and attitude were significant predictors of the survivors' resiliency. The spirituality and positive attitudes of the older adults were associated with disaster resiliency among the typhoon survivors. Thus, the findings suggest the need for nurse gerontologists to promote spirituality and encourage positive attitudes among older adults. PMID- 29759808 TI - Implementation of a clinical nursing pathway for percutaneous coronary intervention: A prospective study. AB - This study is to evaluate the effect of a clinical nursing pathway (CNP) on the clinical outcomes of the transradial approach for emergency percutaneous coronary intervention (PCI). A total of 118 subjects diagnosed with acute myocardial infarction (AMI) were enrolled in the study. They were randomly divided into a control group receiving conventional nursing and a clinical nursing pathway group. The differences in door-to-balloon time, length of hospital stay, hospitalization cost, postoperative complications, and patient satisfaction with nursing care between the two groups were determined and analyzed statistically. Results indicated that the clinical nursing pathway is a more cost-effective care strategy for transradial PCI in the setting of AMI resulting in a reduced door-to balloon time, less post-operative complications, and improved patient satisfaction. PMID- 29759809 TI - What will you put in your shadow/memory box? PMID- 29759811 TI - Linking spatial grids of the old and new excavations at Zhoukoudian Locality 1, China. PMID- 29759810 TI - Move it before it's too late: helping older adults accept less residential burden and more assistance. PMID- 29759812 TI - Reduced-dose dasatinib in chronic-phase CML. PMID- 29759813 TI - Chemoradiotherapy for pancreatic adenocarcinoma. PMID- 29759814 TI - Painful fingernails in a patient with chronic fibrosing pulmonary aspergillosis. PMID- 29759815 TI - Dysphagia in an elderly patient. PMID- 29759816 TI - Actin Remodeling in Regulated Exocytosis: Toward a Mesoscopic View. AB - Cellular communication relies on fusion of secretory vesicles with the plasma membrane, following dynamic events that change the micro- and nanoscale environment of the approaching vesicles in the vicinity of docking sites. Visualization of fine cortical actin network structures and their interactions with vesicle and plasma membrane has recently been facilitated by the development of new imaging technologies. Consequently, a greater understanding is emerging of the role of the cortical actin network on controlling secretory vesicles as they undergo docking, priming, and fusion in exocytic hot spots. In this review, we propose a mechanistic framework underpinning the mesoscopic properties of the cortical actin and discuss how molecular coupling of these pleiotropic effects orchestrate every single step of regulated exocytosis. PMID- 29759817 TI - Enhancer Logic and Mechanics in Development and Disease. AB - Enhancers are distally located genomic cis-regulatory elements that integrate spatiotemporal cues to coordinate gene expression in a tissue-specific manner during metazoan development. Enhancer function depends on a combination of bound transcription factors and cofactors that regulate local chromatin structure, as well as on the topological interactions that are necessary for their activity. Numerous genome-wide studies concur that the vast majority of disease-associated variations occur within non-coding genomic sequences, in other words the 'cis regulome', and this underscores their relevance for human health. Advances in DNA sequencing and genome-editing technologies have dramatically expanded our ability to identify enhancers and investigate their properties in vivo, revealing an extraordinary level of interconnectivity underlying cis-regulatory networks. We discuss here these recently developed methodologies, as well as emerging trends and remaining questions in the field of enhancer biology, and how perturbation of enhancer activities/functions results in enhanceropathies. PMID- 29759818 TI - Biodiesels from microbial oils: Opportunity and challenges. AB - Although biodiesel has been extensively explored as an important renewable energy source, the raw materials-associated cost poses a serious challenge on its large scale commercial production. The first and second generations of biodiesel are mainly produced from usable raw materials, e.g. edible oils, crops etc. Such a situation inevitably imposes higher demands on land and water usage, which in turn compromise future food and water supply. Obviously, there is an urgent need to explore alternative feedstock, e.g. microbial oils which can be produced by many types of microorganisms including microalgae, fungi and bacteria with the advantages of small footprint, high lipid content and efficient uptake of carbon dioxide. Therefore, this review offers a comprehensive picture of microbial oil based technology for biodiesel production. The perspectives and directions forward are also outlined for future biodiesel production and commercialization. PMID- 29759819 TI - Problematic effects of antibiotics on anaerobic treatment of swine wastewater. AB - Swine wastewaters with high levels of organic pollutants and antibiotics have become serious environmental concerns. Anaerobic technology is a feasible option for swine wastewater treatment due to its advantage in low costs and bioenergy production. However, antibiotics in swine wastewater have problematic effects on micro-organisms, and the stability and performance of anaerobic processes. Thus, this paper critically reviews impacts of antibiotics on pH, COD removal efficiencies, biogas and methane productions as well as the accumulation of volatile fatty acids (VFAs) in the anaerobic processes. Meanwhile, impacts on the structure of bacteria and methanogens in anaerobic processes are also discussed comprehensively. Furthermore, to better understand the effect of antibiotics on anaerobic processes, detailed information about antimicrobial mechanisms of antibiotics and microbial functions in anaerobic processes is also summarized. Future research on deeper knowledge of the effect of antibiotics on anaerobic processes are suggested to reduce their adverse environmental impacts. PMID- 29759821 TI - Using Multilevel Modeling to Examine Blunted Neural Responses to Reward in Major Depression. AB - BACKGROUND: Major depressive disorder (MDD) is a pernicious disorder characterized by deficits in reward processing. A better understanding of these deficits may help to elucidate the underlying pathophysiology and guide treatment development. METHODS: This study assessed reward positivity and feedback negativity event-related potentials and their difference scores elicited in response to monetary gains and losses among 100 young adults (52 with MDD). Multilevel modeling was used to assess individual- and trial-level change in neural responses over time. RESULTS: Trial-level analyses indicated that a diagnosis of MDD and depressive symptom severity significantly moderated the trajectory of reward positivity, with individuals with higher symptoms of depression demonstrating less sensitivity to rewards over time. CONCLUSIONS: These results provide further support for reward dysfunction in MDD and highlight important individual differences in the trajectory of neural responses to reward. Future studies are warranted to investigate reward sensitivity over time to elucidate important individual- and trial-level differences in reward processing. PMID- 29759820 TI - Clustered Regularly Interspaced Short Palindromic Repeats-Based Genome Surgery for the Treatment of Autosomal Dominant Retinitis Pigmentosa. AB - PURPOSE: To develop a universal gene therapy to overcome the genetic heterogeneity in retinitis pigmentosa (RP) resulting from mutations in rhodopsin (RHO). DESIGN: Experimental study for a combination gene therapy that uses both gene ablation and gene replacement. PARTICIPANTS: This study included 2 kinds of human RHO mutation knock-in mouse models: RhoP23H and RhoD190N. In total, 23 RhoP23H/P23H, 43 RhoP23H/+, and 31 RhoD190N/+ mice were used for analysis. METHODS: This study involved gene therapy using dual adeno-associated viruses (AAVs) that (1) destroy expression of the endogenous Rho gene in a mutation independent manner via an improved clustered regularly interspaced short palindromic repeats-based gene deletion and (2) enable expression of wild-type protein via exogenous cDNA. MAIN OUTCOME MEASURES: Electroretinographic and histologic analysis. RESULTS: The thickness of the outer nuclear layer (ONL) after the subretinal injection of combination ablate-and-replace gene therapy was approximately 17% to 36% more than the ONL thickness resulting from gene replacement-only therapy at 3 months after AAV injection. Furthermore, electroretinography results demonstrated that the a and b waves of both RhoP23H and RhoD190N disease models were preserved more significantly using ablate-and replace gene therapy (P < 0.001), but not by gene replacement monotherapy. CONCLUSIONS: As a proof of concept, our results suggest that the ablate-and replace strategy can ameliorate disease progression as measured by photoreceptor structure and function for both of the human mutation knock-in models. These results demonstrate the potency of the ablate-and-replace strategy to treat RP caused by different Rho mutations. Furthermore, because ablate-and-replace treatment is mutation independent, this strategy may be used to treat a wide array of dominant diseases in ophthalmology and other fields. Clinical trials using ablate-and-replace gene therapy would allow researchers to determine if this strategy provides any benefits for patients with diseases of interest. PMID- 29759823 TI - Self-rated health and wellbeing among school-aged children with and without special educational needs: Differences between mainstream and special schools. AB - BACKGROUND: Studies among students with special educational needs (SEN) in separate special schools (SSS) and mainstream schools (MS) are particularly applicable to educational attainment and social participation. However, indicators of health and wellbeing have rarely been considered. AIMS: This study investigates two related topics: first, health and wellbeing differences between students with SEN in special schools (SSS) and students without SEN in regular schools, and second, the rarely considered question whether health and wellbeing among students with SEN differ between school settings (i.e. MS vs. SSS). METHODS AND PROCEDURES: Bivariate and multilevel analyses are applied with data from the German National Educational Panel Study (NEPS) with 5267 students (grade 7). OUTCOMES AND RESULTS: After having controlled for background characteristics, students in SSS report higher likelihoods of poor self-rated health compared to students in higher track schools. Self-rated health of students with SEN does not significantly differ between MS vs. SSS. For life satisfaction, students with SEN show higher likelihoods of low life satisfaction when attending MS. CONCLUSIONS AND IMPLICATIONS: Teachers in inclusive settings are encouraged to establish class work and teaching that support a real change from class placement to inclusive culture in order to suitably support students with SEN. PMID- 29759824 TI - The use of cardiac CT as a roadmap for resolving coronary stent dislodgement. PMID- 29759822 TI - Multivariate Relationships Between Cognition and Brain Anatomy Across the Psychosis Spectrum. AB - BACKGROUND: Cognitive and structural brain abnormalities range from mild to severe in psychosis. The relation of specific cognitive functions to specific brain structures across the psychosis spectrum is less certain. METHODS: Participants (n = 678) with bipolar, schizoaffective, or schizophrenia psychoses and healthy control subjects were recruited via the Bipolar-Schizophrenia Network for Intermediate Phenotypes. The Schizo-Bipolar Scale was used to create a psychosis continuum (from purely affective to purely nonaffective). Canonical correlation between 14 cognitive measures and structural brain measures (gray matter volume, cortical thickness, cortical surface area, and local gyrification indices) for 68 neocortical regions yielded constructs that defined shared cognition-brain structure relationships. Canonical discriminant analysis was used to integrate these constructs and efficiently summarize cognition-brain structure relationships across the psychosis continuum. RESULTS: General cognition was associated with larger gray matter volumes and thicker cortices but smaller cortical surface area in frontoparietal regions. Working memory was associated with larger volume and surface area in frontotemporal regions. Faster response speed was associated with thicker frontal cortices. Constructs that captured general cognitive ability and working memory and their relationship to cortical volumes primarily defined an ordered psychosis spectrum (purely affective, least abnormal through purely nonaffective, and most abnormal). A construct that captured general cognitive ability and its relationship to cortical surface area differentiated purely affective cases from other groups. CONCLUSIONS: General cognition and working memory with cortical volume deviations characterized more nonaffective psychoses. Alternatively, affective psychosis cases with general cognitive deficits had deviations in cortical surface area, perhaps accounting for heterogeneous findings across previous studies. PMID- 29759825 TI - Beyond "Move More": Feeling the Rhythms of physical activity in mid and later life. AB - The last two decades have seen growing unease regarding the negative health consequences of increasing levels of physical inactivity, both in the UK and further afield. Public health initiatives and interventions aimed at increasing levels of physical activity have, therefore, become somewhat commonplace. Within the current context of demographic change, with growing numbers of older adults and evidence that inactivity increases with age, these initiatives hold particular relevance to mid and later-life adults. Yet despite their prevalence, the policy gains from such promotional efforts have typically been modest at best, demonstrating the limits to decontextualized health messages that encourage people to 'sit less', 'move more' or 'move faster'. In this paper, we draw on the concept of rhythm, to provide an original contribution in response to recent calls to rethink existing approaches to physical activity in mid-life and beyond. We draw from three qualitative data sets from separate studies exploring health, wellbeing and ageing (two in the context of chronic health conditions and sensory impairments). Inspired by facet methodology, we advance knowledge by providing 'flashes of insight' into the subtle patterns and tempos that frame physical activity in mid and later life. In doing so, we offer alternative insight into how people avail themselves to, and experience motion and stillness during these life stages. That alternative, as we also note, has an important role to play in the development of appropriate, relatable health messages regarding movement that recognises 'expertise by experience'. PMID- 29759826 TI - Framework design and pontics of fiber-reinforced composite fixed dental prostheses - An overview. AB - PURPOSE: Fiber-reinforced composite (FRC) fixed dental prostheses (FDPs) have shown good performance in clinical applications due to their good mechanical properties and minimally invasive approach. However, typical failure patterns of FRC FDPs are often localized at the pontic site. That reflects the structural considerations at the framework and pontic location that need to be examined when creating these kinds of prostheses. STUDY SELECTION: Peer-reviewed articles and other scientific literature were reviewed for providing up-to-date information on how pontics of FRC FDPs can be made. A thorough literature search was done using PubMed and Google Scholar. Two individuals did an assessment of the articles in order to include those related to pontics and framework design of FRC FDPs. The search terms used were "fiber-reinforced dental prosthesis" and "Pontics of fiber reinforced dental prosthesis". RESULTS: These findings indicate that a cross sectional fiber design, substructure and thicker pontics made of a variety of materials might reduce failures at the pontic site. CONCLUSIONS: The thickness of pontics of FRC FDPs interrelated with the vertical positioning of the FRC framework influences the load-bearing capacities of prostheses of these kinds. The understanding of the factors involved in the fabrication of pontics of FRC FDPs may overcome the drawbacks identified in these prostheses, thus extending their longevity. PMID- 29759828 TI - Subcutaneous Versus Transvenous Implantable Defibrillator Therapy: Achilles' Last Stand? PMID- 29759827 TI - Subcutaneous Versus Transvenous Implantable Defibrillator Therapy: A Meta Analysis of Case-Control Studies. AB - OBJECTIVES: This study aims to conduct a meta-analysis comparing efficacy and safety outcomes between subcutaneous implantable cardioverter-defibrillator (S ICD) and transvenous implantable cardioverter-defibrillator (TV-ICD). BACKGROUND: The S-ICD was developed to minimize complications related to the conventional TV ICD. Direct comparison of clinical outcomes between the 2 devices has been limited by varying patient characteristics and definitions of complications with no randomized trials completed comparing these systems. METHODS: Studies in the PubMed and Embase databases and secondary referencing sources were systematically reviewed. Studies meeting criteria were included in the meta-analysis. Baseline characteristics and outcome data of the S-ICD and TV-ICD groups were appraised and analyzed. A random-effects model was used to derive odds ratio (OR) with 95% confidence interval (CI). RESULTS: Five studies met inclusion criteria. Baseline characteristics were similar between the S-ICD and TV-ICD groups. Fewer lead complications occurred in the S-ICD group compared to the TV-ICD group (OR: 0.13; 95% CI: 0.05 to 0.38). The infection rate was similar between the S-ICD and TV ICD groups (OR: 0.75; 95% CI: 0.30 to 1.89). There were no differences in system or device failures between groups (OR: 1.13; 95% CI: 0.43 to 3.02). Overall, inappropriate therapy (T-wave oversensing, supraventricular tachycardia, episodes of inappropriate sensing) was similar between the 2 groups (OR: 0.87; 95% CI: 0.51 to 1.49). However, the nature of inappropriate therapy was different between the S-ICD and TV-ICD groups. Both devices appear to perform equally well with respect to appropriate shocks. CONCLUSIONS: S-ICD reduced lead-related complications but was similar to TV-ICD with regard to non-lead-related complications, including inappropriate therapy. These results support the concept that S-ICD is a safe and effective alternative to TV-ICD in appropriate patients. PMID- 29759829 TI - Acute and 3-Month Performance of a Communicating Leadless Antitachycardia Pacemaker and Subcutaneous Implantable Defibrillator. AB - OBJECTIVES: The primary objective was to assess the acute and 3-month performance of the modular antitachycardia pacing (ATP)-enabled leadless pacemaker (LP) and subcutaneous implantable cardioverter-defibrillator (S-ICD) system, particularly device-device communication and ATP delivery. BACKGROUND: Transvenous pacemakers and implantable cardioverter-defibrillators (ICDs) have considerable rates of lead complications. We examined the next step in multicomponent leadless cardiac rhythm management: feasibility of pacing (including ATP) by a LP, commanded by an implanted S-ICD through wireless, intrabody, device-device communication. METHODS: The combined modular cardiac rhythm management therapy system of the LP and S-ICD prototypes was evaluated in 3 animal models (ovine, porcine, and canine) both in acute and chronic (90 days) experiments. LP performance, S-ICD to LP communication, S-ICD and LP rhythm discrimination, and ATP delivery triggered by the S-ICD were tested. RESULTS: The LP and S-ICD were successfully implanted in 98% of the animals (39 of 40). Of the 39 animals, 23 were followed up for 90 days post-implant. LP performance was adequate and exhibited appropriate VVI behavior during the 90 days of follow-up in all tested animals. Unidirectional communication between the S-ICD and LP was successful in 99% (398 of 401) of attempts, resulting in 100% ATP delivery by the LP (10 beats at 81% of the coupling interval). Adequate S-ICD sensing was observed during normal sinus rhythm, LP pacing, and ventricular tachycardia/ventricular fibrillation. CONCLUSIONS: This study presents the preclinical acute and chronic performance of the combined function of an ATP-enabled LP and S-ICD. Appropriate VVI functionality, successful wireless device-device communication, and ATP delivery were demonstrated by the LP. Clinical studies on safety and performance are needed. PMID- 29759830 TI - Long-Term Experience With the Subcutaneous Implantable Cardioverter-Defibrillator in Teenagers and Young Adults. AB - OBJECTIVES: This study sought to examine the use of the subcutaneous implantable cardioverter-defibrillator (S-ICD) in teenagers and young adults. BACKGROUND: The S-ICD is an important advance in device therapy for the prevention of sudden cardiac death. Although guidelines recommend S-ICD use, long-term data are still limited, especially in subgroups. Therefore, this study analyzed teenagers and young adults <26 years of age with S-ICD in our large single-center S-ICD registry. METHODS: Between July 2010 and December 2016, 147 S-ICD systems were inserted at our institution. Thirty-one patients were included in the study; 13 were teenagers (<20 years of age), and 18 were young adults (20 to 26 years of age). The patients were compared with an age-matched control group with transvenous ICDs. RESULTS: Primary prevention of sudden cardiac death was the indication in 13 patients (41.9%). Ventricular arrhythmias were adequately terminated in 8 patients (25.8%). In 5 patients (16.1%), oversensing resulting in at least 1 inappropriate shock was observed. All inappropriate shocks occurred in teenagers. Younger age was an independent predictor of inappropriate shocks in S ICD (hazard ratio: 0.56; 95% confidence interval: 0.34 to 0.92; p < 0.05). No ineffective shocks were observed in a median follow-up of 25.7 +/- 20.2 months. CONCLUSIONS: Young patients may be suitable candidates for S-ICD because of the high number of lead failures with transvenous systems expected in these patients during their lifetime. In the present study, S-ICD therapy was safe and feasible in teenagers and young adults. However, episodes of inappropriate shocks may occur, but rates of inappropriate shocks were comparable to those in patients with transvenous ICDs. PMID- 29759831 TI - Sustaining and Disruptive Innovation in Clinical Electrophysiology: The Subcutaneous Implantable Cardioverter-Defibrillator in the Young. PMID- 29759833 TI - Cardiac Resynchronization Therapy With Multipoint Left Ventricular Lead Pacing. PMID- 29759832 TI - Safety and Efficacy of Multipoint Pacing in Cardiac Resynchronization Therapy: The MultiPoint Pacing Trial. AB - OBJECTIVES: The MultiPoint Pacing (MPP) trial assessed the safety and efficacy of pacing 2 left ventricular sites with a quadripolar lead in patients with heart failure indicated for a CRT-D device. BACKGROUND: Cardiac resynchronization therapy nonresponse is a complex problem where stimulation of multiple left ventricular sites may be a solution. METHODS: Enrolled patients were indicated for a CRT-D system. Bi-ventricular (Bi-V) pacing was activated at implant. Three months later, clinical response was assessed and the patient was randomized (1:1) to receive Bi-V pacing or MPP. Patients were followed for 6 months post randomization and clinical response was again assessed. RESULTS: The CRT-D system was successfully implanted in 455 of 469 attempted implants (97%). A total of 381 patients were randomized to Bi-V or MPP at 3 months. The primary safety endpoint was met with freedom from system-related complications of 93.2%. The primary efficacy endpoint of the noninferiority comparison of nonresponder rates between the 2 arms was met. Patients randomized to MPP arm and programmed to pace from anatomically distant poles (MPP-AS) responded to therapy at significantly higher rates than MultiPoint pacing-other programmed settings (MPP-Other). Within this group, 87% were responders at 9 months, 100% designated as nonresponders at 3 months converted to responders at 9 months, and 54% experienced an incremental response compared to MPP-Other. Also within MPP-AS, 92% of patients with de novo CRT-D implant were classified as responders compared with patients with MPP Other. CONCLUSIONS: MPP is safe and effective for treating heart failure. The study met the pre-specified hypothesis that response to MPP is noninferior to Bi V pacing with a quadripolar left ventricular lead. (MultiPoint Pacing IDE Study [MPP IDE]; NCT01786993). PMID- 29759834 TI - Utility of Frailty Assessment for Elderly Patients Undergoing Cardiac Resynchronization Therapy. AB - OBJECTIVES: The aim of this study was to evaluate the impact of frailty in the elderly on response to cardiac resynchronization therapy (CRT). BACKGROUND: CRT has been shown to improve symptoms and outcome of patients with congestive heart failure (HF) and impaired left ventricular ejection fraction (LVEF). The impact of frailty on the results of CRT is unknown. METHODS: Frailty defined as <14 of 17 points using the ONCODAGE (Outil de depistage geriatrique en oncologie) G8 score was assessed before device implantation in candidates for CRT who were >70 years of age. The primary endpoint was the response to CRT, defined as an improvement of >5% of the LVEF and the absence of hospitalization for HF or cardiovascular death at 9 months. RESULTS: Ninety-two of 151 included patients (61%) were frail, and 89 (59%) were responders. Frailty was more frequent in nonresponders: 45 of 62 (73%) versus 47 of 89 (53%) (p = 0.014) and was identified as an independent predictor of nonresponse to CRT (R = 0.30; 95% confidence interval: 0.02 to 0.59; p = 0.039). Frailty was associated with a higher cumulative probability of hospitalization for HF (log-rank p = 0.032) and of all-cause death (log-rank p = 0.033). A G8 score <10.25 correlated with hospitalization for HF or death at 9 months (area under the curve: 0.75; 95% confidence interval: 0.63 to 0.87; cutoff <10.25; 77% sensitivity, 63% specificity). CONCLUSIONS: Frailty is as an independent predictor of nonresponse to CRT. Frail patients implanted with CRT devices have a higher risk of hospitalization for HF and mortality. Routine comprehensive geriatric assessment at the time of screening for device therapy should be recommended to optimize management. (Frailty Score Assessment for Elderly Patients Undergoing Cardiac Resynchronization Therapy [FRAILTY]; NCT02369419). PMID- 29759835 TI - Hemodynamic Support in Ventricular Tachycardia Ablation: An International VT Ablation Center Collaborative Group Study. AB - OBJECTIVES: This study sought to evaluate the clinical outcomes of patients receiving hemodynamic support (HS) during ventricular tacchycardia (VT) ablation. BACKGROUND: There are limited real-world data evaluating its effect of HS in ablation outcomes. METHODS: An analysis of 1,655 patients from the International VT Ablation Center Collaborative group was performed. A total of 105 patients received HS with percutaneous ventricular assist device. RESULTS: Patients in the HS group had lower left ventricular ejection fraction (LVEF), higher New York Heart Association (NYHA) functional class, and more implantable cardioverter defibrillator (ICD) shocks, VT storm, and antiarrhythmic drug use (all p < 0.05). The HS group also required significantly longer fluoroscopy, procedure, and total lesion time. Acute procedural success (71.8% vs. 73.7%; p = 0.04) was significantly lower and complications (12.5% vs. 6.5%; p = 0.03) and 1-year mortality (34.7% vs. 9.3%; p < 0.001) were significantly higher in the HS group. Multivariate Cox regression analysis demonstrated HS as an independent predictor of mortality (hazard ratio: 5.01; 95% confidence interval: 3.44 to 7.20; p < 0.001). There was no significant difference in VT recurrence between groups. In a subgroup analysis including LVEF <=20% and NYHA functional class III to IV patients, acute procedural success (74.0% vs. 70.5%; p = 0.8), complications (15.6% vs. 7.8%; p = 0.2), VT recurrence (30.2% vs. 38.1%; p = 0.44), and 1-year mortality (40.0% vs. 28.8%; p = 0.2) were no different between the HS and no-HS groups. CONCLUSIONS: Patients requiring HS were sicker with multiple comorbidities and, as expected, had a significantly higher 1-year mortality than did those patients in the no-HS group. In patients with LVEF <=20% and NYHA functional class III to IV, there was also no significant difference in clinical outcomes when compared with no HS. Further studies are needed to systematically evaluate patients undergoing VT ablation receiving HS. PMID- 29759836 TI - Ventricular Tachycardia Ablation: Should We Be Impelled to Do More? PMID- 29759837 TI - Clinical Features and Sites of Ablation for Patients With Incessant Supraventricular Tachycardia From Concealed Nodofascicular and Nodoventricular Tachycardias. AB - OBJECTIVES: This study sought to describe the clinical features and sites of successful ablation for incessant nodofascicular (NF) and nodoventricular (NV) tachycardias. BACKGROUND: Incessant supraventricular tachycardias have been associated with tachycardia-induced cardiomyopathies and have been previously attributed to permanent junctional reciprocating tachycardias, atrial tachycardias, and atrioventricular nodal re-entrant tachycardias. Incessant concealed NF and NV tachycardias have not been described previously. METHODS: Three cases of incessant concealed NF and NV re-entrant tachycardias were identified from 2 centers. RESULTS: The authors describe 3 cases with incessant supraventricular tachycardia resulting from NV (2 cases) and NF (1 case) pathways. Atrioventricular nodal re-entrant tachycardia was excluded by His synchronous premature ventricular complexes that either delayed or terminated the tachycardia. Ventricular pacing showed constant and progressive fusion in cases 1 and 3. In 2 cases, there was spontaneous initiation with a 1:2 response (cases 1 and 3); the presence of retrograde longitudinal dissociation or marked decremental pathway conduction in cases 1 and 3 sustains these tachycardias. The NV pathway was successfully ablated in the slow pathway region in case 3 and at the right bundle branch in case 1. The NF pathway was successfully ablated within the proximal coronary sinus in case 2. CONCLUSIONS: This is the first report of incessant supraventricular tachycardia using concealed NF or NV pathways. These tachycardias demonstrated spontaneous initiation from sinus rhythm with a 1:2 response and retrograde longitudinal dissociation or marked decremental pathway conduction. Successful ablation was achieved at either right-sided sites or within the coronary sinus. PMID- 29759838 TI - Detection of Subclinical Atrial Fibrillation in High-Risk Patients Using an Insertable Cardiac Monitor. AB - OBJECTIVES: The study sought to determine the incidence of subclinical atrial fibrillation (AF) in high-risk patients and to compare the effect of continuous versus intermittent monitoring. BACKGROUND: AF often occurs in a subclinical form, which makes it difficult to detect. The authors do not know the incidence of subclinical AF among patients >=65 years of age with hypertension and diabetes mellitus. This group of patients has increased risk of developing AF and in addition a high thromboembolic risk, if AF is present. METHODS: A total of 82 outpatients >=65 years of age (median age 71.3 years [interquartile range [IQR]: 67.4 to 75.1 years]) with hypertension and diabetes mellitus, and no history of AF or any other cardiovascular disease, were consecutively included. All patients received an insertable cardiac monitor (ICM) and were followed for a median of 588 days (IQR: 453 to 712 days). We compared continuous monitoring with 72-h Holter monitoring 1 month after ICM insertion. The primary endpoint was AF >=2 min for the ICM and AF >=30 s for the Holter monitoring. RESULTS: During follow up 17 (20.7%) patients were found to have subclinical AF detected by ICM with a median time to first detected episode of 91 days (IQR: 41 to 251 days) from inclusion. Only 2 (2.4%) patients also had AF episodes on the 72-h Holter monitoring. All detected episodes were completely asymptomatic. CONCLUSIONS: The incidence of subclinical AF in this group of patients was surprisingly high. Continuous monitoring with ICM detected significantly more AF episodes than 72-h Holter monitoring. (Detection of Subclinical Atrial Fibrillation in High Risk Patients Using Implantable Loop Recorder; NCT02041832). PMID- 29759840 TI - Twisting and Turning to Find an Explanation for Torsades de Pointes. PMID- 29759839 TI - Short-Lasting Episodes of Torsade de Pointes in the Chronic Atrioventricular Block Dog Model Have a Focal Mechanism, While Longer-Lasting Episodes Are Maintained by Re-Entry. AB - OBJECTIVES: This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. BACKGROUND: The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the initiation and the perpetuation of TdP. METHODS: In 5 TdP-sensitive chronic atrioventricular block dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10 s. Software was developed to automatically detect activation times and to create 3 dimensional visualizations of the arrhythmia. For each episode of ectopic activity (ranging from 2 beats to NT episodes), a novel methodology was created to construct directed graphs of the wave propagation and detect re-entry loops by using an iterative depth-first-search algorithm. RESULTS: Depending on the TdP definition (number of consecutive ectopic beats), we analyzed 29 to 54 TdP: 29 were longer than 5 beats. In the total group, 9 were NT and 45 were self terminating. Initiation and termination were always based on focal activity. Re entry becomes more important in the longer-lasting episodes (>14 beats), whereas in all NT TdP, re-entry was the last active mechanism. During re-entry, excitation fronts were constantly present in the heart, while during focal TdP, there was always a silent interval between 2 consecutive waves (142 ms) during which excitation fronts were absent. Interbeat intervals were significantly smaller for re-entry episodes-220 versus 310 ms in focal. Electrograms recorded in particular areas during NT TdP episodes had significantly smaller amplitude (0.38) than during focal episodes (0.59). CONCLUSIONS: TdP can be driven by focal activity as well as by re-entry depending on the duration of the episode. NT episodes are always maintained by re-entry, which can be identified in local unipolar electrograms by shorter interbeat intervals and smaller deflection amplitude. PMID- 29759842 TI - Temporal Relationship of Asystole to Onset of Transient Loss of Consciousness in Tilt-Induced Reflex Syncope. AB - OBJECTIVES: The purpose of this study was to investigate the relationship between the onset of asystole and transient loss of consciousness (TLOC) in tilt-induced reflex syncope and estimate how often asystole was the principal cause of TLOC. BACKGROUND: The presence of asystole in vasovagal syncope (VVS) may prompt physicians to consider pacemaker therapy for syncope prevention, but the benefit of pacing is limited in VVS. METHODS: We evaluated electrocardiography, electroencephalography, blood pressure, and clinical findings during tilt-table tests. Inclusion required TLOC (video), electroencephalographic slowing, accelerating blood pressure decrease, and an RR interval >=3 s. We excluded cases with nitroglycerin provocation. Asystole after onset of TLOC (group A) or within 3 s before TLOC (group B) was unlikely to cause TLOC, but an earlier start of asystole (group C) could be the cause of TLOC. RESULTS: In one-third of 35 cases (groups A [n = 9] and B [n = 3]), asystole was unlikely to be the primary cause of TLOC. The median of the mean arterial pressure at the onset of asystole was higher when asystole occurred early (45.5 mm Hg, group C) than when it occurred late (32.0 mm Hg, groups A and B), which suggests that vasodepression was not prominent at the start of asystole in early asystole, further suggesting that early asystole was the prime mechanism of syncope. CONCLUSIONS: In one-third of cases of tilt-induced asystolic reflex syncope, asystole occurred too late to have been the primary cause of TLOC. Reliance on electrocardiography data only is likely to overestimate the importance of asystole. PMID- 29759841 TI - Prolonged Ventricular Conduction and Repolarization During Right Ventricular Stimulation Predicts Ventricular Arrhythmias and Death in Patients With Cardiomyopathy. AB - OBJECTIVES: The goal of this study was to evaluate whether prolonged ventricular conduction (paced QRS) and repolarization (paced QTc) times observed during ventricular stimulation predict ventricular arrhythmic events and death. BACKGROUND: Abnormal ventricular conduction and repolarization can predispose patients to ventricular arrhythmias. METHODS: Consecutive patients with left ventricular dysfunction (ejection fraction <50%) undergoing electrophysiology studies from January 2002 until May 2014 were identified at Mayo Clinic (Rochester, Minnesota). Patients were followed up until December 2014 for occurrence of ventricular arrhythmias and death. RESULTS: Among the 501 patients included (mean age 65 years; mean left ventricular ejection fraction 33.1%), longer paced ventricular conduction was associated with longer baseline QRS duration, longer QT interval, and lower ejection fraction. On multivariable analysis, longer paced QRS duration was associated with higher risk of ventricular arrhythmia (hazard ratio [HR]: 1.11 per 10-ms increase; 95% confidence interval [CI]: 1.07 to 1.16; p < 0.001) and all-cause death or arrhythmia (HR: 1.09; 95% CI: 1.09 to 1.13; p < 0.001). A paced QRS duration >190 ms was associated with a 3.6 times higher risk of ventricular arrhythmia (HR: 3.6; 95% CI: 2.35 to 5.53; p < 0.001) and a 2.1 times higher risk of death or arrhythmia (HR: 2.12; 95% CI: 1.53 to 2.95; p < 0.001), independent of left ventricular function or baseline QRS duration. Longer QTc interval during ventricular pacing was associated with a higher risk of ventricular arrhythmia (HR: 1.03 per 10-ms increase; 95% CI: 1.02 to 1.12; p < 0.001) independent of paced QRS duration. CONCLUSIONS: Longer paced QRS duration and paced QTc interval predict ventricular arrhythmias in patients with cardiomyopathy. Ventricular conduction and repolarization prolongation during right ventricular pacing can determine the risk of ventricular arrhythmias. PMID- 29759844 TI - Novel Electrophysiology Signal Recording System Improves Signal Acquisition and Appreciation of Catheter Contact Force. PMID- 29759843 TI - Asystole and Loss of Consciousness. PMID- 29759845 TI - Electroanatomic Characterization of a "No Access" Hypoplastic Left Ventricle. PMID- 29759846 TI - Balloon Dilation of an Inferior Vena Cava Filter to Implant a Leadless Pacemaker. PMID- 29759847 TI - Nocturnal Premature Ventricular Contraction Burden as a Marker of Disease Severity in Arrhythmogenic Right Ventricular Cardiomyopathy. PMID- 29759848 TI - The health care system is making 'too much noise' to provide family-centred care in neonatal intensive care units: Perspectives of health care providers and hospital administrators. AB - AIM: To describe the perspectives of health care providers and hospital administrators on their experiences of providing care for infants in Level II neonatal intensive care units and their families. RESEARCH METHODS: We conducted 36 qualitative interviews with neonatal health care providers and hospital administrators and analysed data using a descriptive interpretive approach. SETTING: 10 Level II Neonatal Intensive Care Units in a single, integrated health care system in one Canadian province. FINDINGS: Three major themes emerged: (1) providing family-centred care, (2) working amidst health care system challenges, and (3) recommending improvements to the health care system. The overarching theme was that the health care system was making 'too much noise' for health care providers and hospital administrators to provide family-centred care in ways that would benefit infants and their families. Recommended improvements included: refining staffing models, enhancing professional development, providing tools to deliver consistent care, recognising parental capacity to be involved in care, strengthening continuity of care, supporting families to be with their infant, and designing family-friendly environments. CONCLUSION: When implementing family centred care initiatives, health care providers and hospital administrators need to consider the complexity of providing care in Level II Neonatal Intensive Care Units, and recognise that health care system changes may be necessary to optimise implementation. PMID- 29759850 TI - Differences in Prehospital Patient Assessments for Pediatric Versus Adult Patients. AB - OBJECTIVE: To evaluate whether completion of vital signs assessments in pediatric transports by emergency medical services (EMS) differs by patient age. STUDY DESIGN: We reviewed records by 20 agencies in a regional EMS system in Southwestern Pennsylvania between April 1, 2013 and December 31, 2016. We abstracted demographics, vital signs (systolic blood pressure, heart rate, respiratory rate), clinical, and transport characteristics. We categorized age as neonates (<=30 days), infants (1 month to <1 year), toddler (1 to <2 years), early childhood (2 to <6 years), middle childhood (6 to <12 years), adolescent (12 to <18 years), and adult (>=18 years). We used unadjusted and adjusted logistic regression to test if age group was associated with vital signs documentation, reporting of Glasgow Coma Scale and pain scale after trauma, and recording of oxygen saturation and breath sounds in respiratory complaints, using adults as the reference group. RESULTS: In total, 371 746 cases (21 883 pediatric, 5.9%) were included. In adjusted analysis, most pediatric categories had reduced odds of complete vitals documentation (percent, OR, 95% CI): neonates (49.6%, 0.02, 0.02-0.03), infants (68.2%, 0.04, 0.03-0.04), toddlers (78.1%, 0.07, 0.06-0.07), early childhood (87.4%, 0.13, 0.12-0.15), and middle childhood (95.3%, 0.54, 0.46-0.63). Pain score documentation was lower in children after trauma (OR 0.80, 95%CI 0.76-0.85), and oxygen saturation documentation was lower in children with respiratory complaints (OR 0.20, 95%CI 0.18-0.25). CONCLUSIONS: Pediatric patients were at increased risk of lacking vital signs documentation during prehospital care. This represents a critical area for education and quality improvement. PMID- 29759851 TI - The Role of Adiposity in the Association between Muscular Fitness and Cardiovascular Disease. AB - OBJECTIVES: To test the associations of muscular fitness and body mass index (BMI), individually and combined, with clustered cardiovascular disease risk factors in children and adolescents and to analyze the mediator role of BMI in the association between muscular fitness and clustered cardiovascular disease risk factors. STUDY DESIGN: In total, 239 children (113 girls) and 270 adolescents (128 girls) participated in this cross-sectional study. Height and weight were assessed, and BMI was calculated. A cardiovascular disease risk factors index (CVDRF-I) was created from the combination of the following variables: waist circumference, systolic blood pressure, triglycerides, high density lipoprotein cholesterol, and glucose. Handgrip strength/weight and standing long jump tests were used to assess muscular fitness. A muscular fitness index was computed from the combination of both tests. RESULTS: Muscular fitness index was associated with CVDRF-I in children of both sexes and adolescent boys; however, these associations disappeared after accounting for BMI. BMI was associated with CVDRF-I in both children and adolescents, even after adjusting for muscular fitness (all P < .001). In male and female children and in adolescent boys, the association between muscular fitness and CVDRF-I was mediated by BMI (all P < .001). Because there was no association between muscular fitness and CVDRF-I in adolescent girls, the mediation hypothesis was discarded. CONCLUSIONS: BMI is an independent predictor of CVDRF-I in children and adolescents of both sexes. Conversely, the effect of muscular fitness on CVDRF-I seems to be fully mediated by BMI levels in male and female children and in adolescent boys. PMID- 29759852 TI - Practice guidelines for the management of adult community-acquired urinary tract infections. PMID- 29759853 TI - [Periodic electrocardiographic monitoring of the QT interval in patients on SSRI treatment]. PMID- 29759849 TI - Methicillin-Resistant Staphylococcus aureus: The Effects Are More Than Skin Deep. AB - OBJECTIVES: To assess the psychosocial effects of a methicillin-resistant Staphylococcus aureus (MRSA) diagnosis on the households of children with MRSA skin and soft tissue infection (SSTI). STUDY DESIGN: We constructed and administered an interview to the primary caregiver within the home of a child with a history of MRSA SSTI. RESULTS: Seventy-six households were enrolled. Survey responses were analyzed and grouped into 4 themes: health behavior changes, disclosure, social interactions, and knowledge/awareness. The most common theme was disclosure; 91% of participants reported sharing their child's MRSA diagnosis with someone outside of the household. Forty-two percent of respondents reported a change in the manner in which household contacts interacted as a result of the index patient's MRSA diagnosis, including isolating the index patient from other children in the household. Many households reported adopting enhanced personal hygiene behaviors and environmental cleaning routines. Thirty-eight percent of participating households reported altering how they interact with people outside of their home, largely to avoid spreading MRSA to vulnerable individuals. In addition, many participants perceived that others regarded them with caution, especially at daycare, whereas other affected households were excluded from family gatherings. CONCLUSION: Primary caregivers of children with MRSA SSTI reported changing their health behaviors, altering their interactions with people outside of their home, and feeling isolated by others in response to their child's MRSA diagnosis. The findings of our study highlight a need for community interventions and education to prevent the negative psychosocial repercussions associated with MRSA. PMID- 29759854 TI - A meta-analysis of reduced leaflet motion for surgical and transcatheter aortic valves: Relationship to cerebrovascular events and valve degeneration. AB - BACKGROUND: Reduced leaflet motion (RLM) of transcatheter aortic valves (TAV) is observed in up to 4% of cases with similar frequency in surgical valves, with an overall incidence that differs based on prosthesis type and size. This phenomenon likely represents subclinical leaflet thrombosis. Herein we sought to analyze the existing reported literature to assess whether or not RLM is associated with subsequent valve degeneration or cerebrovascular events. METHODS AND RESULTS: We searched PubMed, and EMBASE (2008-2017) to identify relevant studies. Studies with <1-year follow-up, studies not evaluating RLM, and/or clinical outcomes were excluded. Our co-primary endpoints were the incidence of cerebrovascular events (stroke and/or transient ischemic attack-TIA) or structural valvular degeneration defined as moderate or greater regurgitation and/or a mean gradient >=20 mm Hg. The literature search yielded 30 potential studies. Of these, six observational studies with a total population of 1704 patients met our selection criteria. RLM was associated with an increased risk of stroke or TIA (adjusted OR 2.60, 95% CI 1.56 to 4.34, p = 0.004). At one year, RLM was associated with an increased risk of structural valve degeneration (adjusted OR 2.51, 95% CI 1.47 to 4.30, p = 0.006). The association between RLM and clinical endpoints remained even after limiting analysis to transcatheter aortic valve replacement (TAVR) patients only. CONCLUSIONS: In patients with bio prosthetic aortic valve, presence of RLM is associated with increased risk of stroke or TIA as well as structural valvular degeneration. These findings support ongoing surveillance efforts and evaluation of pharmacotherapies to address RLM in effort to minimize subsequent clinical events. PMID- 29759855 TI - Response to Letter to the Editor on "Impact of Operative Time on Adverse Events Following Primary Total Joint Arthroplasty". PMID- 29759856 TI - Malnutrition and the Development of Periprosthetic Joint Infection in Patients Undergoing Primary Elective Total Joint Arthroplasty. AB - BACKGROUND: Although an abundance of literature exists linking malnutrition with infectious complications in surgical patients, there is little specifically examining the link between malnutrition and periprosthetic joint infection (PJI). This study evaluated the relationship between abnormal nutritional parameters and development of PJI in patients undergoing primary total joint arthroplasty (TJA). METHODS: We retrospectively reviewed TJA patients from 2000 to 2016 with preoperative nutritional screening at a single institution. Any development of PJI at 2 years was assessed as the primary outcome. The Musculoskeletal Infection society criteria were used to define PJI. The association between the aforementioned nutritional markers and PJI was evaluated in a bivariate analysis followed by multivariate logistic regression. Performance for markers was assessed using receiver operator characteristic curves. Sensitivity and specificity were also compared. RESULTS: Multivariate analysis demonstrated that low albumin (adjusted odds ratio [OR], 4.69; 95% confidence interval [CI], 2.428 9.085; P < .001) and low hemoglobin (adjusted OR, 2.718; 95% CI, 1.100-2.718; P = .018) were significantly associated with PJI. Albumin had the highest specificity and (95% CI, 97.8%-98.4%) and positive predictive value compared to all other markers. Platelet-to-white blood cell ratio had the highest sensitivity (95% CI, 29.5%-40.3%). The area under the curve was greatest for albumin (0.61; 95% CI, 0.55-0.67) followed by hemoglobin (0.57; 95% CI, 0.51-0.63), platelets (0.56; 95% CI, 0.50-0.62), and platelet-to-white blood cell ratio (0.54; 95% CI, 0.49-0.60). CONCLUSION: The most valuable predictor of PJI following primary TJA, among nutritional parameters examined, was preoperative albumin with a very high specificity and positive predictive value. PMID- 29759858 TI - Left Atrial Appendage: Embryology, Anatomy, Physiology, Arrhythmia and Therapeutic Intervention. AB - Known for the pathological connection to atrial fibrillation (AF), the left atrial appendage (LAA) is the most common source of thromboembolism in patients with AF and may be an arrhythmogenic source for the maintenance of AF. Potential interventions of the LAA for stroke prevention have recently been developed through better understanding its anatomy and physiology. Occlusion of the LAA is an alternative to the use of life-long anticoagulation in selected nonvalvular AF cases. The PROTECT-AF (The WATCHMAN LAA Closure Device for Embolic PROTECTion in Patients with Atrial Fibrillation) and PREVAIL (Randomized Trial of LAA Closure vs. Warfarin for Stroke/Thromboembolic Prevention in Patients with Non-valvular Atrial Fibrillation) randomized controlled trials demonstrated that LAA exclusion using the Watchman percutaneous device is not inferior to warfarin. However, the appendage is structurally complex and has considerable morphological variations among individuals, and it can be challenging to generalize the device for all patients. Continued technological developments including occlusion/ligation through epicardial, endocardial, or surgical approaches, as well as operator expertise regarding LAA anatomy, physiology, and pathophysiology, should improve interventional outcomes. Furthermore, the optimal strategy for re-entrant tachyarrhythmias arising from LAA remains unknown. Whereas an observational study suggested that LAA isolation was more effective than focal ablation, LAA isolation may be associated with significant impairments in LAA contractility, predisposing individuals to a risk of thrombosis. PMID- 29759859 TI - A Possible Role for Pacing the Left Ventricular Septum in Cardiac Resynchronization Therapy. AB - OBJECTIVES: The purpose of this study was to investigate whether stimulation at the left ventricular (LV) septum (LVs), alone or in combination with another site, could be an alternative way to apply cardiac resynchronization therapy (CRT) that avoids the coronary sinus and phrenic nerve stimulation and may create more physiological sequence of activation. BACKGROUND: In CRT, biventricular pacing is commonly performed from the right ventricle (RV) and the epicardium of the LV lateral wall (LVlat). In the left bundle branch block (LBBB), half of the electrical delay occurs due to impulse conduction across the septum. METHODS: Experiments were performed in 13 dogs with LBBB, 7 of them with chronic myocardial infarction (LBBB + MI). Pacing leads were positioned in the right atrium, RV, LVs, and at the LVlat epicardium. LV pump function was measured using conductance catheter and synchrony of electrical activation of the ventricles using epicardial mapping and from surface electrocardiogram. In 12 CRT patients, LV pump function was measured during temporary RV + LVs pacing and compared to RV + LVlat and RV + LVlat endo pacing. RESULTS: In the animals, electrical and hemodynamic benefits of LVs and RV + LVs pacing were comparable to those during conventional biventricular pacing and were comparable in LBBB and LBBB + MI hearts. Dispersion of repolarization was reduced by LVs stimulation, but not by LVlat pacing. In patients, hemodynamic benefits of RV + LVs, RV + LVlat and RV + LVlat endo pacing were similar. CONCLUSIONS: The use of the LVs as LV pacing site in CRT improves synchronization and acute hemodynamics comparably to conventional biventricular pacing in dyssynchronous canines and in patients. In addition, LVs stimulation may reduce dispersion of repolarization compared to epicardial pacing. PMID- 29759860 TI - Left Ventricular Endocardial Pacing for Cardiac Resynchronization Therapy: Wavefront of the Future? PMID- 29759857 TI - Multiple-Dose Intravenous Tranexamic Acid Further Reduces Hidden Blood Loss After Total Hip Arthroplasty: A Randomized Controlled Trial. AB - BACKGROUND: The most appropriate dose of tranexamic acid in total hip arthroplasty (THA) has not been decided. This study was conducted to evaluate the clinical effects of multiple-dose intravenous tranexamic acid (IV-TXA) in THA. METHODS: One hundred fifty patients were randomized to receive one dose of IV-TXA before incision, followed by 2 doses of IV-TXA (group A), or 3 doses of IV-TXA (group B), or 4 doses of IV-TXA (group C) at 3-hour intervals. The primary outcome was hidden blood loss (HBL). Other outcome measurements such as total blood loss, maximum hemoglobin (Hb) drop, postoperative lowest Hb level, fibrinolysis parameter (D-dimer), inflammatory factor (interleukin-6), transfusion rate, length of stay, and complications were also compared. RESULTS: The mean HBL, total blood loss, and maximum Hb drop were significantly lower in group C than in groups B and A. Such differences were also detected between groups B and A. The postoperative lowest Hb level was significantly higher in group C. D-dimer and interleukin-6 in group C were significantly lower than in groups B and A at 24 and 48 hours postoperatively. Such differences were also significant between groups B and A. There was no significant difference in length of stay among groups. No patient underwent blood transfusion during hospitalization. No episodes of deep venous thrombosis or pulmonary embolism occurred in all cases. CONCLUSION: The 5-dose IV-TXA regimen can further diminish HBL, decrease maximum Hb drop, provide additional fibrinolysis control, and ameliorate postoperative inflammatory response following THA. PMID- 29759861 TI - Reduced Mortality Associated With Quadripolar Compared to Bipolar Left Ventricular Leads in Cardiac Resynchronization Therapy. AB - OBJECTIVES: The study sought to compare survival, lead deactivation, and lead replacement with quadripolar versus bipolar leads using a retrospective cohort of patients with newly implanted cardiac resynchronization therapy (CRT) systems. BACKGROUND: In CRT, quadripolar left ventricular (LV) leads offer alternative pacing sites and vectors not available with bipolar LV leads, which may improve the effectiveness of the therapy. METHODS: Using nationwide data from device implant registration records of a single manufacturer, we identified patients with a de novo cardiac resynchronization therapy with defibrillation (CRT-D) implanted between November 30, 2011, and May 31, 2013. Patients were followed for up to 24 months. The primary predictor was LV lead type (quadripolar Quartet [St. Jude Medical, St. Paul, Minnesota] LV lead or bipolar LV lead). The primary outcome was death and the secondary outcomes were LV lead replacement and deactivation. RESULTS: Among 23,570 patients (69.5 +/- 11.1 years of age; 28% female; median follow-up time 1.14 years), 18,406 had quadripolar and 5,164 had bipolar LV leads. The quadripolar and bipolar groups had 5.04 and 6.45 deaths per 100 patient-years, respectively (p < 0.001). After multivariate adjustment, the quadripolar lead was associated with a lower risk of deactivation (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.46 to 0.84; p = 0.002), replacement (HR: 0.67; 95% CI: 0.55 to 0.83; p < 0.001), and death (HR: 0.77; 95% CI: 0.69 to 0.86; p < 0.001). CONCLUSIONS: In this observational study of CRT-D devices, use of a quadripolar, compared to a bipolar LV lead, was associated with a reduction in LV lead deactivation, replacement, and mortality. PMID- 29759862 TI - Improved Survival Using a Quadripolar Cardiac Resynchronization Lead: Truth, Fiction-or Something in Between? PMID- 29759863 TI - Interventricular Electrical Delay Is Predictive of Response to Cardiac Resynchronization Therapy. AB - OBJECTIVES: This study was conceived to evaluate the relationship between interventricular electrical delay, as measured by the right ventricle-left ventricle (RV-LV) interval, and outcomes in a prospectively designed substudy of the SMART-AV (SMARTDELAY determined AV Optimization) trial. BACKGROUND: Despite the well-documented benefit of cardiac resynchronization therapy (CRT), the nonresponder rate remains an important clinical problem. Implanting LV leads by traditional anatomic criteria has limited impact on outcomes. However, pacing at sites with late electrical activation improves CRT response rates. Thus, we hypothesized that interventricular electrical delay is associated with improved CRT outcomes. METHODS: This was a multicenter study of patients with advanced heart failure undergoing CRT implantation. In 419 subjects, the unpaced RV-LV interval was measured in sinus rhythm. LV volumes and ejection fraction were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. RESULTS: When separated by quartiles based on interventricular delay, the magnitudes of LV volumes, ejection fraction and the QOL measure increased significantly with prolongation of RV-LV delay (p < 0.05). The LV end systolic volume response rate increased progressively from 30% to 75% (p < 0.001), and the QOL response rate increased from 50% to 65% (p = 0.08). Patients in the highest quartile of RV-LV had a 5.98-fold increase (p < 0.001) in their odds of a reverse remodeling response, with female sex, ischemic etiology, and baseline LV end-systolic volume being the other independent predictors of response. CONCLUSIONS: Baseline interventricular delay is a potent independent predictor of remodeling and QOL responses with CRT. PMID- 29759865 TI - Is Our Health Care System Equipped for the Changing Heart Failure Demographics? PMID- 29759864 TI - Predictors and Risk of Ventricular Tachyarrhythmias or Death in Black and White Cardiac Patients: A MADIT-CRT Trial Substudy. AB - OBJECTIVES: The study sought to analyze the risk of ventricular tachyarrhythmia (VTA) or death in black and white subjects implanted with implantable cardioverter-defibrillators (ICDs) or defibrillator and combined cardiac resynchronization therapy (CRT-D) in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy) trial. BACKGROUND: There are limited data on ethnic differences in the risk for VTA in mildly symptomatic heart failure patients with left ventricular dysfunction. METHODS: The risk for first VTA (>=180 beats/min) or death was evaluated in black (n = 139) versus white (n = 1,638) patients enrolled in the MADIT-CRT trial using Kaplan-Meier survival analyses and Cox proportional hazards regression models after adjustment for relevant clinical covariates. Multivariate analysis was used to identify race-specific risk factors for VTA. RESULTS: At 4 years of follow-up, the cumulative probability for a first VTA or death was significantly higher among black patients (42%) as compared with whites (34%; log-rank p value for the overall difference during follow-up = 0.01). Multivariate analysis confirmed significantly higher risk of VTA or death (hazard ratio: 1.60; 95% confidence interval: 1.18 to 2.17; p = 0.002), and higher risk of VTA alone (hazard ratio: 1.71; 95% confidence interval: 1.22 to 2.41; p = 0.002) in blacks compared to whites. The findings were similar in both ICD and CRT-D implanted patients, with no significant race-to-treatment-interaction (interaction p values >0.05). Independent risk factors for VTA among blacks included increased systolic blood pressure values and larger cardiac volumes. CONCLUSIONS: In the MADIT-CRT trial, black patients had a significantly higher rate of ventricular tachyarrhythmias or death compared to whites, with either an implanted ICD or CRT-D. (MADIT-CRT: Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy [MADIT-CRT], NCT00180271; Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy Post Approval Registry [MADIT CRT PAR], NCT01294449; MADIT-CRT LONG-TERM INTERNATIONAL FOLLOW-UP REGISTRY EUROPE, NCT02060110). PMID- 29759867 TI - New Parameter for Detecting Isthmus Location in Ventricular Tachycardia Caused by a Re-Entrant Circuit. PMID- 29759866 TI - Simultaneous Amplitude Frequency Electrogram Transformation (SAFE-T) Mapping to Identify Ventricular Tachycardia Arrhythmogenic Potentials in Sinus Rhythm. AB - OBJECTIVES: This study sought to develop a novel automated technique, simultaneous amplitude frequency electrogram transformation (SAFE-T), to identify ventricular tachycardia (VT) isthmuses by analysis of sinus rhythm arrhythmogenic potentials (AP). BACKGROUND: Substrate ablation is useful for patients with scar related hemodynamically unstable VT; however, the accuracy of different approaches remains inadequate, varying from targeting late potentials to full scar homogenization. METHODS: High-density ventricular mapping was performed in 3 groups: 1) 18 normal heart control subjects; 2) 10 ischemic patients; and 3) 8 nonischemic VT patients. In VT patients, isthmus sites were characterized using entrainment responses. Sinus rhythm right ventricle/left ventricle endocardial and epicardial electrograms underwent Hilbert-Huang spectral analysis and were displayed as 3-dimensional SAFE-T maps. AP and their relation to the VT isthmus sites were studied. RESULTS: AP were defined by a cutoff value of 3.08 Hz mV using normal heart control subjects. Receiver-operating characteristics showed that VT isthmus sites were best identified using SAFE-T mapping (p < 0.001) as compared with bipolar and unipolar scar and late potential mapping with an optimal cutoff value of 3.09 Hz mV, allowing identification of 100% of the 34 mapped VT isthmuses, compared with 68% using late potentials. There was no significant difference between sinus rhythm and paced SAFE-T values. Abnormal SAFE-T areas involved about one-quarter of the scar total area. CONCLUSIONS: Automated electrogram analysis using 3-dimensional SAFE-T mapping allows rapid and objective identification of AP that reliably detect VT isthmuses. The results suggest that SAFE-T mapping is good alternative strategy to late potential mapping in identifying VT isthmuses and allows reduced ablation as compared to scar homogenization. PMID- 29759869 TI - Pulmonary Vein Reconnection in Patients With and Without Atrial Fibrillation Recurrence After Ablation. PMID- 29759868 TI - Relationship Between Pulmonary Vein Reconnection and Atrial Fibrillation Recurrence: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study systematically reviewed the prevalence of pulmonary vein (PV) reconnection in subjects with and without AF recurrence and assessed the relationship between PV reconnection and freedom from atrial fibrillation (AF). BACKGROUND: Pulmonary vein reconnection is frequently observed in patients experiencing recurrent AF post catheter ablation. However, its prevalence in AF free patients has not been well studied. METHODS: An electronic search was performed for studies describing PV electrical conduction in subjects with and without AF recurrence post PV isolation (PVI). RESULTS: Eleven of 5,665 articles met selection criteria. A total of 683 subjects were included in the meta analysis; 379 had AF recurrence, and 304 were AF-free. Among patients with AF recurrence, 324 of 379 patients (85.5%) had at least 1 pulmonary vein reconnected. Among AF-free patients, 178 of 304 patients (58.6%) had at least 1 PV electrically reconnected, and 126 of 304 (41.4%) had durable PVI. The relative risk (RR) of recurrent AF was significantly lower with durable PVI than with PV reconnection (RR: 0.57; 95% confidence interval [CI]: 0.37 to 0.86; p = 0.008). Analysis of 7 studies including exclusively paroxysmal AF patients (n = 470) showed RR of 0.69 (95% CI: 0.45 to 1.05; p = 0.09). CONCLUSIONS: This meta analysis shows that durable PVI is associated with a lower risk of AF recurrence after catheter ablation. However, the association was modest, and PV electrical reconnection is common, affecting 58% of AF-free patients. Analysis of studies that included exclusively patients with paroxysmal AF showed a weaker relationship. Additional research is warranted to better understand the mechanism(s) of benefit of catheter ablation for AF and investigate whether PVI should be the primary goal. PMID- 29759870 TI - Incidence of Thromboembolic Complications Within 30 Days of Electrical Cardioversion Performed Within 48 Hours of Atrial Fibrillation Onset. AB - OBJECTIVES: This study sought to compare the risk of thromboembolism after cardioversion within 48 h of atrial fibrillation (AF) onset in patients therapeutically versus not therapeutically anticoagulated. BACKGROUND: Although guidelines do not mandate anticoagulation for cardioversion within 48 h of AF onset, risk of thromboembolism in this group has been understudied. METHODS: Patients undergoing cardioversion within 48 h after AF onset were identified from a prospectively collected database and retrospectively reviewed to determine anticoagulation status and major thromboembolic events within 30 days of cardioversion. RESULTS: Among 567 cardioversions in 484 patients without therapeutic anticoagulation (mean CHA2DS2-VASc score, 2.3 +/- 1.7), 6 had neurological events (1.06%), all in patients on aspirin alone. Among 898 cardioversions in 709 patients on therapeutic anticoagulation (mean CHA2DS2-VASc score, 2.6 +/- 1.7; p = 0.017), 2 neurological events occurred (0.22%; OR: 4.8; p = 0.03), both off anticoagulation at the time of stroke. No thromboembolic events occurred in patients with CHA2DS2-VASc score <2 (p = 0.06) or in patients with postoperative AF. CONCLUSIONS: In patients with acute-onset AF, odds of thromboembolic complications were almost 5 times higher in patients without therapeutic anticoagulation at the time of cardioversion. However, no events occurred in post-operative patients and in those with CHA2DS2-VASc scores of <2, supporting the utility of accurate assessment of AF onset and risk stratification in determining the need for anticoagulation for cardioversion of AF <48 h in duration. PMID- 29759871 TI - Anticoagulation for Cardioversion of Acute Onset Atrial Fibrillation: Time to Revise Guidelines? PMID- 29759873 TI - Cardiac Implantable Electronic Device Infection: Rise of Resistant Pathogens. PMID- 29759872 TI - Microbiology of Cardiac Implantable Electronic Device Infections. AB - OBJECTIVES: This study reports a high-volume tertiary care center experience with the microbiology of cardiac implantable electronic devices (CIED) infections with assessment of temporal trends and profiles of late versus early infections. BACKGROUND: The rates of CIED infections have been increasing. With changing demographics, patient and device characteristics, prophylactic measures, and the wide use of broad-spectrum antibiotics, there is need for updated contemporary data on the microbiology of CIED infections. METHODS: The study included 816 consecutive patients with confirmed CIED infections who underwent transvenous lead extraction at our institution between the years 2000 and 2011. Blood cultures were obtained in addition of pocket swabs, pocket capsule, and leads. RESULTS: Staphylococcal species remained the most common pathogens in CIED infections (68.4%), especially coagulase-negative species (37.6%). Methicillin resistant staphylococci were the pathogens in 33.8% of all CIED infections and accounted for 49.4% of all staphylococcal infections. Gram-negative pathogens were identified in 8.9% of cases, whereas 13.2% were with negative cultures. CIED infections related to streptococci (2.5%), enterococci (4.2%), anaerobes (1.6%), fungi (0.9%), and mycobacteria species (0.2%) were less common. Of pocket infections, 49.5% occurred more than 1 year after pocket manipulation, and 53.6% of these were related to coagulase-negative staphylococci. In contrast, most endovascular infections were related to Staphylococcus aureus. The proportions of culture negative infections have increased (p < 0.0001). CONCLUSIONS: The study provides contemporary data on the microbiology of CIED infections. The rates of methicillin resistance seem to be greater than those reported from the preceding decade. PMID- 29759875 TI - Preventing Phrenic Nerve Injury During Second Generation Cryoballoon Ablation: What Will it Take? PMID- 29759874 TI - Prevalence and Pre-Procedural Predictors Associated With Right Phrenic Nerve Injury in Electromyography-Guided, Second-Generation Cryoballoon Ablation: Single Large Balloon and Single 3-Minute Freeze Techniques. AB - OBJECTIVES: This study aimed to evaluate the incidence and pre-procedural predictors of right phrenic nerve injury (PNI) in electromyography-guided, second generation cryoballoon (CB) ablation. BACKGROUND: Second-generation CBs perform better pulmonary vein isolation (PVI) than first-generation CBs; however, right PNI remains a concern. METHODS: One hundred consecutive patients with paroxysmal atrial fibrillation who underwent cryoablation were prospectively enrolled. Contrast-enhanced cardiac multidetector computed tomography (MDCT) was obtained pre-procedurally. PVI was performed with one 28-mm second-generation balloon using a 3-min freeze technique under electromyography guidance. RESULTS: In all, 377 of 392 (96.2%) PVs were isolated using a CB. In 9 (9.0%) patients, right PNI was observed during the ablation of the right superior PV (RSPV). All events occurred during freezing, except for 1 that occurred during thawing. Right peri cardiophrenic bundles (RPCBs) were identified at the level of the RSPV on MDCT in 97 patients. In the logistic regression analysis, the distance from the RSPV ostium to the RPCBs (hazard ratio: 0.263; 95% confidence interval [CI]: 0.110 to 0.630; p = 0.003) was the sole predictor of PNI. The optimal cutoff point for the distance for predicting right PNI was 12.4 mm (sensitivity 96.6%, specificity 88.9%) with an area under the curve of 0.968 (95% CI: 0.922 to 1.000). The PNI resolved spontaneously within 1 day and 2 months in 6 and 2 patients, respectively, and at 8 months in the remaining patient, with delayed recognition of an electromyography decrease. CONCLUSIONS: Persistent right PNI is a rare complication during electromyography-guided, second-generation CB ablation. Electromyography should be monitored even during the thawing time. Pre-procedural MDCT might be useful for risk stratification of right PNI. PMID- 29759877 TI - Pseudoaneurysm Development After Ablation for Atrial Tachycardia in a Patient With Single-Ventricle Anatomy. PMID- 29759876 TI - Patient Activity Decreases and Mortality Increases After the Onset of Persistent Atrial Fibrillation in Patients With Implantable Cardioverter-Defibrillators. AB - OBJECTIVES: The study sought to determine the effect of persistent atrial fibrillation (AF) on device-measured activity and mortality. BACKGROUND: Patients with AF often complain of fatigue, which may be reflected in patient activity. Daily activity can be objectively measured by implanted devices. METHODS: We retrospectively studied patients (n = 266, 88% male, 69 +/- 10 years of age) from the deidentified Medtronic CareLink database with persistent AF (>=28 consecutive days with >=23 h of AF/day), dual-chamber implantable cardioverter-defibrillators (ICDs) capable of monitoring daily activity and AF burden, no AF between months 1 and 6 post-implant, and >=1 year of data. RESULTS: The first persistent AF episode occurred 980 +/- 534 days after implant and lasted a median of 87 days (interquartile range: 49 to 161 days). Average daily activity over a week just prior (baseline) to the first persistent AF episode was compared to each of the 4 weeks during the AF episode and to each of the weeks following termination of the persistent AF episode. Daily activity decreased significantly from the baseline week (135 min/day) compared to each of the 4 consecutive weeks after AF onset (8%, 11%, 14%, and 17% decrease, p < 0.001). Mortality at 4 years was increased in patients with persistent AF compared to a matched group with no persistent AF (20.6% vs. 8.6%, p < 0.01). CONCLUSIONS: Patients with ICDs have a significant reduction in activity following the onset of persistent AF and a significant increase in mortality when compared to a matched group without persistent AF. Objective measures of activity may more accurately reflect the impact of persistent AF on patients' functional status. PMID- 29759878 TI - High-Density Biventricular Activation Mapping During Intraseptal Ventricular Tachycardia: Successful Ablation Using Bipolar Radiofrequency. PMID- 29759880 TI - Resynchronizing the Heart and Remodeling Healthcare. PMID- 29759879 TI - Cryoballoon Isolation of the Superior Vena Cava. PMID- 29759882 TI - Dermatomyositis. PMID- 29759881 TI - Spanish urological schools (1880-1970). AB - INTRODUCTION AND OBJECTIVES: We researched the start of urological specialisation in Spain, from the end of the 19th century to the institution of the education system (resident medical intern) to learn about the centres and individuals who created the urological teaching units and training schools in which the first Spanish urologists specialised their training. MATERIAL AND METHODS: We extracted the references from books on the history of urology, from periodic urological publications and from the posters on history submitted to the congresses of the Spanish Urological Association and filled in the data and dates with the Historical Dictionary of Spanish Urologists. RESULT: There are 30 urological specialization centres, 8 with official accreditation recognised by the corresponding ministry but whose official status is unknown. These centres are in the urology departments of large Spanish hospitals, university clinic hospitals and in private schools directed by notable urologists. There are 14 main centres, corresponding chronologically to the following cities: Madrid, Barcelona, Santiago de Compostela, Seville, Las Palmas of Gran Canaria, Cadiz, Santander, Valencia, Granada, Bilbao, San Sebastian, Oviedo, Zaragoza and Salamanca. CONCLUSION: Urological training in Spain from the end of the 19th century to the first half of the 20th century was well-established, both in officially accredited centres and in the urology departments of the main hospitals, in university clinic hospitals and in private schools and clinics. The training was directed by experienced urologists who ensured proper teaching and training, a method that persisted until the institution of the resident medical intern system in 1970. PMID- 29759883 TI - Minimally invasive plate osteosynthesis for tibial derotation osteotomies in children with cerebral palsy. AB - OBJECTIVE: Tibial derotation osteotomy can be used in the treatment of rotational deformities in case of ineffective conservative management. Our aim was to evaluate the results of the patients who underwent minimal invasive plate osteosynthesis for tibial derotation osteotomies. METHODS: Total of 16 patients (17 procedures) were included in this study. Mean age was 11.5 (3-25) years. We clinically assessed the tibial torsion by measuring the thigh-foot angle (TFA). No immobilization was used postoperatively and range of motion exercises were begun immediately. The patient was allowed weight-bearing activity, as tolerated, when callus formation was seen on the radiographs, at approximately three to four weeks after surgery. RESULTS: The mean follow-up time was 27.5 months. Mean preoperative and follow up TFA were 27 degrees of internal rotation and 3.74 degrees of external rotation, respectively. A mean of 22.3 degrees improvement was achieved postoperatively. There was only one wound detachment, which was accepted as a complication and healed with local wound care. CONCLUSIONS: The recurrence risk and correction loss can be decreased with plate-screw fixation. Minimal invasive surgery would also decrease the risk of wound complications. LEVEL OF EVIDENCE: Level IV, Therapeutic study. PMID- 29759884 TI - Assessment of induced CYP3A activity in pregnant women using 4beta hydroxycholesterol: Cholesterol ratio as an appropriate metabolic marker. AB - AIMS: This study was aimed at evaluating changes in CYP3A activity following and during pregnancy by analyzing metabolic markers for CYP3A activity, which can help avoid unnecessary drug exposure and invasive sampling. METHODS: Forty-eight pregnant women and 25 non-pregnant women were enrolled in this study. Plasma and urine samples were collected from the pregnant women during each trimester and from the non-pregnant women for evaluation of metabolic markers for CYP3A activity. Metabolic markers for CYP3A activity were measured using GC-MS. RESULTS: An increased 4beta-hydroxycholesterol/cholesterol ratio, consistent with high CYP3A activity, was observed in pregnant women compared with that in non pregnant women; however, no differences were observed among trimesters. No significant differences were observed in urinary markers. CONCLUSIONS: We observed an increase in the activity of CYP3A following but not during pregnancy when measured using the 4beta-hydroxycholesterol/cholesterol ratio. In addition, based on our results, we suggest that the plasma 4beta hydroxycholesterol/cholesterol ratio be used to measure CYP3A activity in pregnant women. PMID- 29759887 TI - Very sensitive alpha-Al2O3:C polycrystals for thermoluminescent dosimetry. AB - New materials have been widely investigated for ionizing radiation dosimetry for medical procedures. Carbon-doped alumina (alpha-Al2O3:C) have been reported to be excellent thermoluminescent (TL) and optically stimulated luminescence (OSL) radiation dosimeters. In the present study, we have synthetized nano and micro sized alpha-Al2O3:C polycrystals, doped with different percentages of carbon atoms aiming to compare their efficiency as TL dosimeters. The dosimetric characteristics for X ray and gamma fields were investigated. Samples doped with different amounts of carbon atoms were sintered under different atmosphere conditions, at temperatures ranging from 1300 degrees C to 1750 degrees C. Among the investigated samples, the micro-sized alumina doped with 0.01% of carbon and sintered at 1700 degrees C under reducing atmosphere, has presented a very high TL output. The main TL peak is centered at 250 degrees C and has a linear behavior with photon dose in the dose range of 0.02-to-5000 mGy, with correlation coefficient very close to one (0.99991). Samples produced by using nanosized alumina have shown much lower TL output when compared to the samples with microsized alumina. The micro-sized alumina obtained by the methodology used in this work is a suitable candidate to be explored for application in X and Gamma radiation dosimetry. PMID- 29759886 TI - Oocyte retrieval difficulties in women with ovarian endometriomas. AB - RESEARCH QUESTION: What are the frequency, characteristics and consequences of technical diffiiculties encountered by physicians when carrying out oocyte retrieval in women with ovarian endometriomas? DESIGN: We prospectively recruited women undergoing IVF and compared technical difficulties between women with (n = 56) and without (n = 227) endometriomas. RESULTS: In exposed women, the cyst had to be transfixed in eight cases (14%, 95% CI 7 to 25%) and accidental contamination of the follicular fluid with the endometrioma content was recorded in nine women (16%, 95% CI 8 to 27%). Moreover, follicular aspiration was more frequently incomplete (OR 3.6, 95% CI 1.4 to 9.6). In contrast, the retrievals were not deemed to be more technically difficult by the physicians and the rate of oocytes retrieved per developed follicle did not differ. No pelvic infections or cyst ruptures were recorded (0%, 95% CI 0 to 5%). CONCLUSIONS: Oocyte retrieval in women with ovarian endometriomas is more problematic but the magnitude of these increased difficulties is modest. PMID- 29759888 TI - Comparison of simulated and experimental values of self-absorption correction factors for a fast and credible adjust in efficiency curve of gamma spectroscopy. AB - Self-absorption correction factors are fundamental in spectroscopy to correct the efficiency of the samples detection whose density is different from the radioactive standard. Mathematical simulations have been widespread as a tool to facilitate the procedure of correction factors calculation. In this paper, LabSOCS was used to calculate the self-absorption correction factor for some geometries and the values found were compared to those obtained in MCNP and experimental values. The percentage deviations found for the self-absorption correction factor calculated by LabSOCS were below 1.6% when compared to experimental values. Deviations were below 1.9% in the curve extrapolation of the experimental procedure found in literature. Results obtained show that the deviations increase proportionally to the difference between the density values of the radioactive standard and the sample. High percentage deviations were also noticed in simulations whose samples had high densities, complex geometries and low energy gamma-rays. PMID- 29759885 TI - Terfenadone is a strong inhibitor of CYP2J2 present in the human liver and intestinal microsomes. AB - Cytochrome P450 2J2 (CYP2J2) is involved in the metabolism of drugs, including albendazole, astemizole, ebastine, and endogenous substrates. In a previous study, we used recombinant CYP2J2 and determined whether danazol, hydroxyebastine, telmisartan, and terfenadone inhibited CYP2J2 by using four representative CYP2J2 substrates, namely albendazole, astemizole, ebastine, and terfenadine. In this study, we evaluated the inhibitory potential of these four chemicals on human liver and intestinal microsomes, which are commonly used in a reaction phenotyping study. Among the four CYP2J2 inhibitors tested, terfenadone was strongest inhibitor of CYP2J2-mediated metabolism of albendazole, astemizole, and terfenadine with IC50 values of 0.31, 0.15, and 2.11 MUM, respectively, in human liver microsomes (HLMs). In addition, terfenadone had strong inhibitory effect on the metabolism of the abovementioned drugs in human intestinal microsomes (HIMs), with IC50 values of 0.43, 0.08 and 1.07 MUM, respectively. Danazol, weakly inhibited CYP2J2-mediated metabolism of albendazole and astemizole with IC50 values of 13.8 and 18.3 MUM, respectively in HLMs, whereas it strongly inhibited the CYP2J2-mediated ebastine hydroxylase activity in HLMs and HIMs (IC50 = 1.93-1.95 MUM). Our data suggest that terfenadone may be used as a general CYP2J2 inhibitor in reaction phenotyping study using HLMs and HIMs regardless of the substrate used. PMID- 29759889 TI - Social Learning Strategies: Bridge-Building between Fields. AB - While social learning is widespread, indiscriminate copying of others is rarely beneficial. Theory suggests that individuals should be selective in what, when, and whom they copy, by following 'social learning strategies' (SLSs). The SLS concept has stimulated extensive experimental work, integrated theory, and empirical findings, and created impetus to the social learning and cultural evolution fields. However, the SLS concept needs updating to accommodate recent findings that individuals switch between strategies flexibly, that multiple strategies are deployed simultaneously, and that there is no one-to-one correspondence between psychological heuristics deployed and resulting population level patterns. The field would also benefit from the simultaneous study of mechanism and function. SLSs provide a useful vehicle for bridge-building between cognitive psychology, neuroscience, and evolutionary biology. PMID- 29759890 TI - Distribution and absence of generalized lesions in mice following single dose intramuscular inoculation of the vaccine candidate MVA-MERS-S. AB - Modified Vaccinia Virus Ankara (MVA) is a highly attenuated and replication deficient virus serving as vaccine against infectious diseases. Here, we assessed the in vivo distribution of a recombinant MVA candidate vaccine against the Middle Eastern Respiratory Syndrome (MVA-MERS-S) in mice. Intramuscularly inoculated mice were necropsied at different time points and examined by histology, immunohistochemistry and real-time PCR. We detected inflammation and myonecrosis at the parenteral site and hyperplasia of the draining lymph nodes. MVA-MERS-S did not result in detectable lesions in tissues peripheral to the parenteral site and draining lymph nodes. Real-time PCR analysis of >240 tissue samples detected MVA-DNA predominantly at the injection site and in the draining lymph nodes, and suggested continuous clearance of the candidate vaccine during the observation period. Levels of parenteral site inflammation and hyperplasia of draining lymph nodes were considered in line with immunological responses to vaccine inoculation. PMID- 29759891 TI - The putative role of oxidative stress and inflammation in the pathophysiology of sleep dysfunction across neuropsychiatric disorders: Focus on chronic fatigue syndrome, bipolar disorder and multiple sclerosis. AB - Sleep and circadian abnormalities are prevalent and burdensome manifestations of diverse neuro-immune diseases, and may aggravate the course of several neuropsychiatric disorders. The underlying pathophysiology of sleep abnormalities across neuropsychiatric disorders remains unclear, and may involve the inter-play of several clinical variables and mechanistic pathways. In this review, we propose a heuristic framework in which reciprocal interactions of immune, oxidative and nitrosative stress, and mitochondrial pathways may drive sleep abnormalities across potentially neuroprogressive disorders. Specifically, it is proposed that systemic inflammation may activate microglial cells and astrocytes in brain regions involved in sleep and circadian regulation. Activated glial cells may secrete pro-inflammatory cytokines (for example, interleukin-1 beta and tumour necrosis factor alpha), nitric oxide and gliotransmitters, which may influence the expression of key circadian regulators (e.g., the Circadian Locomotor Output Cycles Kaput (CLOCK) gene). Furthermore, sleep disruption may further aggravate oxidative and nitrosative, peripheral immune activation, and (neuro) inflammation across these disorders in a vicious pathophysiological loop. This review will focus on chronic fatigue syndrome, bipolar disorder, and multiple sclerosis as exemplars of neuro-immune disorders. We conclude that novel therapeutic targets exploring immune and oxidative & nitrosative pathways (p.e. melatonin and molecular hydrogen) hold promise in alleviating sleep and circadian dysfunction in these disorders. PMID- 29759893 TI - The left main stem: The barometer of coronary artery disease severity? PMID- 29759894 TI - About the twists and turns: Relationship of coronary artery geometry and atherosclerosis. PMID- 29759892 TI - The marginalisation of dreams in clinical psychological practice. AB - The longstanding human interest in dreams has led to a significant body of psychological and philosophical discourse, including research. Recently, however, dreams have been relegated to the periphery of clinical psychological practice. This is potentially problematic as clients continue to bring dreams to therapy and many psychologists lack the confidence or competence to respond effectively to dream material. Building on the structural, professional and research cultures surrounding psychology using a cultural-historical activity theory framework, we argue the marginalisation of dreams is due to cultural-historical factors. These factors include the political and economic context in which psychology developed; psychology's early attempts to differentiate from psychoanalysis by identifying with behaviourism and the natural sciences; and a discipline-specific definition of what constitutes evidence-based practice. These factors led to professional discourses within which dreams are seen as of little clinical or therapeutic value, or that dream work is only for long-term therapy and requires extensive therapist training. However, there are diverse models of dream work consistent with most theoretical orientations within contemporary psychological practice. We conclude with recommendations on how to rebuild clinical confidence and competence in the use of dream material within the current professional environment. PMID- 29759895 TI - Cardiovascular computed tomographic angiography: Entering into the 5th stage. PMID- 29759896 TI - Aortic calcification and the risk for paravalvular regurgitation after TAVI: The importance of focusing on reliable outcomes and appropriate variables. PMID- 29759897 TI - In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2016-17 season: Comparison with the 2010-11 to 2015-16 seasons. AB - To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) in the viruses epidemic in the 2016-17 Japanese influenza season, we measured the 50% inhibitory concentration (IC50) of these NAIs for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2015-16 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 276 virus isolates, 6 A (H1N1)pdm09 (2.2%), 249 A (H3N2) (90.2%), and 21 B (7.6%), had the IC50 measured for the four NAIs. B isolates included 11 (52.4%), 9 (42.9%), and one (4.8%) of the Victoria, Yamagata, and undetermined strains, respectively. No A (H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2016-17 season. No isolate with highly reduced sensitivity to the four NAIs have been found for A (H3N2) or B from the 2010-11 to 2016-17 seasons. No significant trend of increase or decrease was found in the geometric mean IC50s of the four NAIs during the seven studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained and that any change in the effectiveness of these NAIs would be minute. Common usage of NAIs for patient treatment has not been a driving force in the selection of NAI resistant viruses. PMID- 29759898 TI - Risk factors for human papillomavirus detection in urine samples of heterosexual men visiting urological clinics in Japan. AB - OBJECTIVE: The present study aimed to investigate human papillomavirus (HPV) prevalence and identify risk factors for HPV detection in urine samples among heterosexual men attending urological clinics. MATERIALS AND METHODS: Spot urine samples including initial stream were collected from 845 participants, and the cell pellets were preserved into liquid-based cytological solution. After DNA extraction from each sample, HPV-DNA amplification and genotyping were performed using Luminex multiplex polymerase chain reaction. Participants completed a questionnaire on their age, education, smoking status, sexuality, age of sexual debut, marital status, and present history of sexually transmitted infections. RESULTS: Data from 803 patients were included in the analysis. Overall HPV and high-risk (HR)HPV prevalence in urine samples were 6.2% and 3.1%, respectively. HPV and HR-HPV prevalences were the highest in men with urethritis, and were significantly higher than those without urethritis. HPV detection was the most common in men aged 40-49 years, although significant detection differences were not age-related. Urethritis was an independent risk factor for HPV detection from urine samples, with an odds ratio (OR) of 4.548 (95%CI; 1.802-11.476) (p = 0.001). On the other hand, a sub-analysis excluding men with urethritis demonstrated that prostate cancer was a significant risk factor for HPV detection, with OR of 2.844 (95%CI; 1.046-7.732) (p = 0.0410), whereas was not a significant risk for HR-HPV detection in urine samples. CONCLUSION: Prostate cancer may represent a risk factor for HPV detection in the urine of men without urethritis. REGISTRATION OF CLINICAL TRIALS: The authors did not register to Clinical Trial because this is observational and cross-sectional study. PMID- 29759899 TI - Integrated diversity analysis of the microbial community in a reverse osmosis system from a Brazilian oil refinery. AB - Oil refineries are known for the large volume of water used in their processes, as well as the amount of wastewater generated at the end of the production chain. Due to strict environmental regulations, the recycling of water has now become a viable alternative for refineries. Among the many methods available to treat wastewater for reuse, the use of membranes in reverse osmosis systems stands out due to several economic and environmental benefits. However, these systems are vulnerable to contamination and deposition of microorganisms, mainly because of the feedwater quality. In this study, the microbial diversity of feedwater and reverse osmosis membranes was investigated using a combination of culture dependent and culture-independent methods in order to characterize the microorganisms colonizing and deteriorating the membranes. In total, 37 bacterial isolates, 17 filamentous fungi and approximately 400 clones were obtained and analyzed. Among the bacterial genera identified, the most represented were Sphingobium, Acidovorax, Microbacterium, Rhizobium and Shinella. The results revealed genera that acted as candidate key players in initial biofilm formation in membrane systems, and provided important information concerning the microbial ecology of oligotrophic aquatic systems. PMID- 29759900 TI - Detection of the type III secretion system and its phylogenetic and symbiotic characterization in peanut bradyrhizobia isolated from Guangdong Province, China. AB - The distribution of rhcRST and rhcJ-C1 fragments located in different loci of the type III secretion system (T3SS) gene cluster in the peanut-nodulating bradyrhizobia isolated from Guangdong Province, China was investigated by PCR based sequencing. T3SS was detected in approximately one-third of the peanut bradyrhizobial strains and the T3SS-harboring strains belonging to different Bradyrhizobium genomic species. Diverse T3SS groups corresponding to different symbiotic gene types were defined among the 23 T3SS-harboring strains. The same or similar T3SS genes were detected in different genospecies, indicating that interspecies horizontal transfer of symbiotic genes had occurred in the Bradyrhizobium genus. PMID- 29759901 TI - New data on resynchronization, ablation, anticoagulation, an assist device and athletes' electrocardiograms: A mosaic of updates. PMID- 29759902 TI - Peri-anaesthetic mortality and nonfatal gastrointestinal complications in pet rabbits: a retrospective study on 210 cases. AB - OBJECTIVE: The aim of this study was to determine the incidence and the associated risk factors of peri-anaesthetic mortality and gastrointestinal complications in pet rabbits. STUDY DESIGN: Retrospective cohort study. ANIMALS: A total of 185 pet rabbits admitted to the Exotic Referal Service of Beaumont Sainsbury's Animal Hospital over the period 2009-2016. METHODS: The clinical records of the rabbits were obtained from the database. To evaluate the incidence of peri-anaesthetic mortality, three possible outcomes were considered: alive, dead or euthanized within the 72 hours following the anaesthetic event. Food intake and stool production during the first 72 hours following the anaesthetic event were evaluated to investigate the occurrence of gastrointestinal complications. Thereafter, various hypothesized risk factors, including administration of alpha-2 agonists, body weight, American Society of Anaesthesiologists classification and endotracheal intubation were tested against peri-anaesthetic mortality and gastrointestinal complications, with both univariate and multivariate binary logistic regression. RESULTS: Twenty-five out of 185 rabbits underwent two anaesthetic events; therefore, data from 210 cases were used. Of these 210 cases, six died during sedation or general anaesthesia and four (one of which euthanized) died during the first 72 postoperative hours, accounting for an actual mortality rate equal to 4.8% (95% confidence interval, 0.025-0.086). Peri-anaesthetic gastrointestinal complications developed in 77 (38%) out of the 204 anaesthetic events whose outcome was not intraoperative death (95% confidence interval, 0.314-0.446). Species-specific risk factors could not be identified for peri-anaesthetic mortality; however, the odds for post anaesthetic gastrointestinal complications increased significantly with body weight (p = 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Our findings confirm that rabbits continue to have a higher incidence of peri-anaesthetic mortality than dogs and cats, and highlight a high risk for nonfatal peri-anaesthetic gastrointestinal complications in this species. PMID- 29759903 TI - Potential Adverse Drug Events and Nephrotoxicity Related to Prophylaxis With Omeprazole for Digestive Disorders: A Prospective Cohort Study. AB - PURPOSE: The purpose of this study was to assess whether prophylaxis for digestive disorders with omeprazole is a risk factor for adverse drug events (ADEs) and kidney impairment. METHODS: This was a 9-month, prospective, double blinded cohort study performed in a Brazilian public hospital. All inpatients 18 years or older admitted during the period of data collection were divided into 2 cohorts. The first group comprised 200 patients receiving prophylaxis for digestive disorders with omeprazole. A total of 54 inpatients who received treatment with omeprazole and whose indication was not approved by the Brazilian Sanitary Agency and the US Food and Drug Administration were excluded. The second group comprised 219 inpatients without a prescription for omeprazole. Follow-up was performed until discharge and included assessment of medical records, medical prescriptions, laboratory data, and pharmaceutical anamnesis. The primary end point was kidney impairment. The variables monitored were kidney function (serum creatinine and urea levels as well as glomerular filtration rate), hepatic function (alanine aminotransferase and aspartate aminotransferase levels), pharmacotherapy, magnesium levels, and imputation of ADEs. With the aid of algorithms of World Health Organization and the National Coordinating Council for Medication Error Reporting and Prevention, we assessed the causality of adverse drug reactions (ADRs) and the seriousness of medication errors (ADEs), respectively. FINDINGS: Prophylaxis for digestive disorders with omeprazole (P = 0.019) and sex (P = 0.010) were considered risk factors for increased serum creatinine level via multivariate logistic regression even with concomitant use of nephrotoxic drugs (P = 0.252). Six ADEs related to omeprazole were identified: 2 ADRs (1 possible and 1 definite), 2 medication errors (nonserious), 1 therapeutic failure, and 1 drug-drug interaction. IMPLICATIONS: Prophylaxis for digestive disorders with omeprazole and male sex may contribute to the development of kidney impairment because both result in increased serum creatinine levels. Therefore, pharmacotherapeutic follow-up of male patients diagnosed with kidney disorders should be considered to identify potential drug drug interactions early. This follow-up can prevent worsening clinical conditions and/or contraindicate prophylactic use of omeprazole. ClinicalTrials.gov identifier: NCT02278432. PMID- 29759904 TI - Ultrasound for the diagnosis of pyogenic flexor tenosynovitis. AB - The usefulness of ultrasound for making the diagnosis of pyogenic flexor tenosynovitis (PFTS) has been demonstrated. The primary goal of this study was to show that the diameter of the flexor sheath near the A2 pulley was larger when PFTS was present compared to the healthy contralateral finger. The secondary goal was to determine the reproducibility of these ultrasound measurements. Our series included 20 patients (12 men and 8 women) operated due to PFTS. The average age was 41.7 years old. The average diameter of the digital sheath measured near the A2 pulley on transverse and longitudinal ultrasound sections was 5.01mm (transverse 5mm, longitudinal 5.03mm) on infected fingers, and 4.17mm on healthy contralateral fingers. Reproducibility, as measured by the intraclass coefficient between transverse and longitudinal values, was 0.910 for infected fingers and 0.928 for contralateral fingers, thus was excellent. Our hypothesis was confirmed. A unilateral increase of more than 20% in diameter of the flexor sheath measured in transverse or longitudinal ultrasound sections near the pulley A2 contributes to the surgical indication when a patient presents with PFTS. PMID- 29759905 TI - Analysis of 4063 complications of shoulder arthroplasty reported to the US Food and Drug Administration from 2012 to 2016. AB - BACKGROUND: Most of the literature on shoulder arthroplasty failure comes from high-volume centers. These reports tend to exclude the experience of community orthopedic surgeons, who perform most of the shoulder joint replacements. METHODS: We analyzed the failure reports mandated by the US Food and Drug Administration for all hospitals. Each reported event from 2012 to 2016 was characterized by implant, failure mode, and year of surgery. RESULTS: For the 1673 anatomic arthroplasties, the most common failure modes were glenoid component failure (20.4%), rotator cuff/subscapularis tear (15.4%), pain/stiffness (12.9%), dislocation/instability (11.8%), infection (9%), and humeral component loosening (5.1%). For the 2390 reverse arthroplasties, the most common failure modes were dislocation/instability (32%), infection (13.8%), glenosphere-baseplate dissociation (12.2%), failed/loosened baseplate (10.4%), humeral component dissociation/tray fracture (5.5%), difficulty inserting the baseplate (4.8%), and difficulty inserting the glenosphere (4.2%). Although the percentage distribution among the different failure modes was relatively consistent over the years of this study, the percentage distribution of these failure modes differed substantially among different implant manufacturers. CONCLUSIONS: The Food and Drug Administration database reveals modes of shoulder arthroplasty failure that are not emphasized in the published literature, such as rotator cuff tear, infection, and postoperative pain/stiffness for anatomic total shoulder arthroplasty and implant dissociation and baseplate failure for reverse shoulder arthroplasty. Knowledge of these failure modes may help inform surgical technique and implant design in ways that will lower the risk of implant failure in the future. PMID- 29759906 TI - Determining glenoid component version after total shoulder arthroplasty. AB - BACKGROUND: Glenoid component loosening after total shoulder arthroplasty (TSA) may occur if retroversion is not corrected to <10 degrees . However, accurately measuring postoperative glenoid component version has been difficult without postoperative computed tomography (CT), adding cost and radiation exposure outside of the standard radiographic follow-up. We present a new method to assess glenoid component version after TSA using only routine preoperative CT and postoperative radiographs (x-rays). METHODS: Preoperative glenoid version was measured using established methods with an axillary x-ray, 2-dimensional CT, and Glenosys software (Imascap, Plouzane, France). Postoperative glenoid component version and inclination were measured for 61 TSA patients using Mimics software (Materialise, Leuven, Belgium) with preoperative CT and postoperative x-rays. Four patients also had postoperative CTs. Glenoid implantation and imaging were performed on 14 cadavers, allowing validation of results against the gold standard postoperative CT glenoid retroversion measurement. RESULTS: Compared with the gold standard, retroversion and inclination measurement error was 2 degrees +/- 1 degrees and 2 degrees +/- 1 degrees , respectively. Average postoperative version correction was 6 degrees +/- 7 degrees , with 35 of 61 patients (57%) corrected to <10 degrees of retroversion. Correlation between preoperative version measurement methods was good to very good, except on the axillary x-ray. Patients not corrected to <10 degrees of retroversion had significantly higher preoperative retroversion (14 degrees +/- 6 degrees ) than those corrected to <10 degrees (6 degrees +/- 7 degrees ; P < .00001). CONCLUSIONS: Glenoid component retroversion after TSA can be accurately measured with a method using only routine preoperative CT and postoperative x-rays, validated to within 1.9 degrees of the gold standard postoperative CT measurement. Future studies using this method may correlate glenoid retroversion correction with glenoid component longevity to help optimize shoulder arthroplasty outcomes. PMID- 29759907 TI - Mechanical and imaging evaluation of the effect of sutures on tendons: tape sutures are protective to suture pulling through tendon. AB - BACKGROUND: High-strength sutures, including #2 and tape-type, are popular when performing arthroscopic rotator cuff repair. Although the most common mechanism of anatomic failure of rotator cuff repair is suture pulling through tendon, the effect of sutures on the suture-tendon interface has rarely been investigated. We evaluated the effect of commercially available modern high-strength standard #2 and tape-type sutures on tendon. METHODS: Isolated sutures (FiberTape, #2 FiberWire [Arthrex Inc., Naples, FL, USA], Ultratape, and #2 Ultrabraid [Smith & Nephew, Andover, MA, USA]) and suture-tendon constructs using sheep infraspinatus tendons were evaluated using mechanical testing and imaging (microcomputed tomography) techniques. RESULTS: For the 4 suture-tendon constructs evaluated, maximum and residual displacements were all less than 3 mm. Whether evaluating isolated sutures or suture-tendon constructs, tape-type sutures had smaller displacements than standard #2 sutures when products from the same company were compared. On initial suture passing and after mechanical testing, hole volume was larger in constructs with tape-type rather than standard #2 sutures comparing within the same company. Collectively, constructs with larger hole volumes after mechanical testing had stiffer sutures. The percentage difference in hole volume was larger for standard #2 than tape-type sutures: FiberWire (43%), Ultrabraid (17%), FiberTape (11%), and Ultratape (9%). CONCLUSIONS: Tape-type sutures created larger final holes than standard #2 sutures from the same company. When initially passed through the tendon, tape-type sutures produced larger holes than standard #2 sutures; however, standard #2 sutures enlarged their initially smaller holes more and displaced more than tape-type sutures during cyclic loading, which suggests that tape-type sutures may be protective to suture pulling through tendon. PMID- 29759908 TI - Including management criteria for hazardous drugs in the drug procurement process. PMID- 29759909 TI - The Predictive Value of Arteriogenic Erectile Dysfunction for Coronary Artery Disease in Men. AB - BACKGROUND: Erectile dysfunction (ED) is assumed to be connected with vascular disease caused by endothelial dysfunction, and characterized by the incapability of the smooth muscle cells lining the arterioles to relax, therefore, inhibit vasodilatation. AIM: To assess the predictive value of arteriogenic ED for coronary artery disease in men above the age of 40 years. METHODS: 75 Patients reporting arteriogenic ED and 25 men with normal erectile function were enrolled in the study. Both patients and controls were subjected to the following investigations: lipid profile, fasting blood sugar, body mass index (BMI), waist circumference, penile duplex study, stress electrocardiography (ECG) test, International Index of Erectile Function (IIEF) Type 5 (Arabic version), and cardiovascular (CV) 10-year risk assessment using Framingham and Prospective Cardiovascular Munster (PROCAM) scoring systems. OUTCOMES: We compare between the study groups regarding the interpretation of exercise testing. RESULTS: We observed significant increase in the mean value of age, systolic blood pressure, BMI, weight, height, and waist circumference in the cases; significant prevalence of obesity and overweight in the cases (P < .001); significant increase in the mean value of total cholesterol, triglycerides (TG), and low-density lipoprotein; and decrease in mean value of high-density lipoprotein in the cases (P < .001). Additionally, there was high incidence of positive stress ECG in the cases (25.3%) vs that in controls (12%), and significant difference between patients with positive stress ECG test and those with negative stress ECG test regarding their lipid profile, age, BMI, and waist circumference with higher values in positive stress ECG for total cholesterol, TG, and low-density lipoprotein, and lower value for high-density lipoprotein (P < .001). According to PROCAM and Framingham scoring systems 10-year risk assessment, there was a high significant difference between the cases and control groups with a higher score in cases than the control group with 30.7% of cases having >= 30% risk of developing coronary heart disease, and significant positive correlations between CV risk and BMI, and negative correlations with IIEF-5 cases (P < .001). CLINICAL TRANSLATION: Ischemic heart disease events were higher in men with documented arteriogenic ED than those without ED. CONCLUSIONS: All items of metabolic syndrome were investigated and analyzed and we evaluated our groups using both PROCAM and Framingham scoring system. An exercise ECG is suggested before starting treatment of vasculogenic ED at least in patients with CV risk factors. Azab SS, Hosni HED, El Far TA, et al. The Predictive Value of Arteriogenic Erectile Dysfunction for Coronary Artery Disease in Men. J Sex Med 2018;15:880-887. PMID- 29759910 TI - Genetic parameters, predictions, and rankings for semen production traits in a Thailand multi-breed dairy population using genomic-polygenic and polygenic models. AB - The objectives were to compare estimates of variance components, genetic parameters, prediction accuracies, and rankings of bulls for semen volume (VOL), number of sperm (NS), and motility (MOT) using genomic-polygenic (GPRM) and polygenic repeatability models (PRM). The dataset comprised 13,535 VOL, 12,773 NS, and 12,660 MOT from 131 bulls collected from 2001 to 2017 in the Semen Production and Dairy Genetic Evaluation Center of the Dairy Farming Promotion Organization of Thailand. Genotypic data encompassed 76,519 actual and imputed SNP from 72 animals. The three-trait GPRM and PRM included the fixed effects of contemporary group, ejaculate order, age of bull, ambient temperature, and heterosis. Random effects were animal additive genetic, permanent environmental, and residual. Variance components and genetic parameters were estimated using AIREMLF90. GPRM heritabilities were slightly greater than PRM for MOT (0.27 compared with 0.24), and slightly less for VOL (0.11 compared with 0.12), and NS (0.17 compared with 0.19). Repeatabilities were slightly less for GPRM than PRM (0.44 compared with 0.45 for MOT, 0.26 compared with 0.28 for NS, and 0.20 compared with 0.21 for VOL). Additive genetic correlations were high between NS and MOT (GPRM: 0.76, PRM: 0.78), moderate between VOL and NS (GPRM: 0.43, PRM: 0.55), and near zero between VOL and MOT (GPRM: -0.13, PRM: 0.04). Rank correlations between GPRM and PRM estimated breeding values (EBV) were high for all traits. The similarity between GPRM and PRM results suggested that SNP data from the small number of genotyped animals had a minimal impact on genetic predictions in this population. PMID- 29759911 TI - Management of otitis media with effusion in children. Societe francaise d'ORL et de chirurgie cervico-faciale clinical practice guidelines. AB - The Societe francaise d'ORL et de chirurgie cervico-faciale clinical practice guidelines concern the management of otitis media with effusion (OME) in children under the age of 12 years. They are based on extensive review of MEDLINE and Cochrane Library publications in English or French from 1996 to 2016 concerning the methods of diagnosis and assessment of otitis media with effusion, as well as the efficacy of tympanostomy tubes and medical and surgical treatments of OME. PMID- 29759912 TI - A call to action in hematologic disorders: A report from the ASH scientific workshop on hematology and aging. PMID- 29759915 TI - Social interaction anxiety and personality traits predicting engagement in health risk sexual behaviors. AB - Individuals with social interaction anxiety, a facet of social anxiety disorder, withdraw from or avoid social encounters and generally avoid risks. However, a subset engages in health risk sexual behavior (HRSB). Because sensation seeking, emotion dysregulation, and impulsivity predict engagement in HRSB among adolescents and young adults, the present study hypothesized that latent classes of social interaction anxiety and these personality traits would differentially predict likelihood of engagement in HRSB. Finite mixture modeling was used to discern four classes: two low social interaction anxiety classes distinguished by facets of emotion dysregulation, positive urgency, and negative urgency (Low SIAS High Urgency and Low SIAS Low Urgency) and two high social interaction anxiety classes distinguished by positive urgency, negative urgency, risk seeking, and facets of emotion dysregulation (High SIAS High Urgency and High SIAS Low Urgency). HRSB were entered into the model as auxiliary distal outcomes. Of importance to this study were findings that the High SIAS High Urgency class was more likely to engage in most identified HRSB than the High SIAS Low Urgency class. This study extends previous findings on the heterogeneity of social interaction anxiety by identifying the effects of social interaction anxiety and personality on engagement in HRSB. PMID- 29759913 TI - Improving implementation of psychological interventions to older adult patients with cancer: Convening older adults, caregivers, providers, researchers. AB - INTRODUCTION: Older adults with cancer (OACs) are a large and growing population. Psychological distress is prevalent in this population yet few OACs receive evidence-based psychological care. The purpose of this project was to identify barriers and strategies for the implementation of psychological interventions to OACs from the perspective of OACs, OAC caregivers, researchers, clinicians, and advocacy organization members. METHODS: The Cornell Research-to-Practice (RTP) Consensus Workshop Model was used to organize and convene a consensus conference. The one-day conference consisted of small and large group discussions regarding barriers, facilitators, and strategies for the implementation of psychological interventions targeting OACs. A half-day roundtable meeting was subsequently conducted to organize data generated at the conference. De-identified transcriptions of the small group discussions were uploaded into NVivo 11 software and qualitatively analyzed using standard methods. RESULTS: Thirty-five participants attended the consensus conference from across stakeholder groups. Three themes related to implementation barriers were identified: lack of knowledge about psychological interventions in patients and providers; personal and social factors associated with being an OAC; and institutional-level factors. Themes related to implementation strategies focused on increasing awareness, tailoring interventions for older adults, and modifying institutional-level factors. DISCUSSION: Effective implementation of psychological interventions to OACs is complex and barriers exist across multiple levels of care. However, this project indicates that implementation can be improved in various ways that include all members of the healthcare system. Further clarification of implementation strategies and rigorous evaluation of their effectiveness is vital to improving care and care outcomes of OACs. PMID- 29759914 TI - Symptom cluster of emotional distress, fatigue and cognitive difficulties among young and older breast cancer survivors: The mediating role of subjective stress. AB - OBJECTIVES: To examine the nature of the symptom cluster of emotional distress, fatigue, and cognitive difficulties in young and older breast cancer survivors (BCS); To assess the mediating role of subjective stress and coping strategies (emotional control and meaning-focused coping) in the association between age and symptom cluster. MATERIALS AND METHODS: Participants were 170 BCS, stages I-III, 1-12 months post-chemotherapy, filled-out the Fatigue, Emotional Control, Meaning focused Coping, Emotional Distress and the Cognitive Difficulties Questionnaires. Statistical analyses included tests for difference between-groups Pearson correlations and Structural Equation Modeling for the assessment of the study model. RESULTS: Older BCS (aged 60-82) reported lower levels of emotional distress (M = 0.87, SD = 0.87), fatigue (M = 3.85, SD = 2.38), and cognitive difficulties (M = 1.17, SD = 1.07) compared to the younger BCS (aged 24-59) (emotional distress M = 1.17, SD = 0.85, fatigue M = 5.02, SD = 2.32, and cognitive difficulties M = 1.66, SD = 1.23, p < .01-,05). The older survivors reported lower levels of subjective stress and used more emotional control strategies compared to the younger BCS. The empirical model had good fit indices (chi2 = 27.60, p = 0.20, chi2/df = 1.26; CFI = 0.98; TLI = 0.98; NFI = 0.95; RMSEA = 0.04 (90% CI = 0.00, 10) and showed that subjective stress, but not coping strategies, mediated the effect of age on symptom cluster severity. CONCLUSIONS: Lower levels of subjective stress, but not coping strategies, mediated the association of age with the symptom cluster of emotional distress, fatigue and cognitive difficulties. Further research is needed to explore differences in subjective stress by age. PMID- 29759916 TI - Occupational dust and cigarette smoke exposure might link rheumatoid arthritis to COPD. PMID- 29759917 TI - Mica pneumoconiosis: a neglected occupational lung disease. PMID- 29759919 TI - Does Pepsin Play a Role in Etiology of Laryngeal Nodules? AB - OBJECTIVES: Vocal fold nodules (VFNs) are benign disorders affecting the superficial lamina propria of the true vocal folds. The etiology of VFNs still remains unclear but laryngeal trauma caused by vocal abuse, tobacco, alcohol, and laryngopharyngeal reflux (LPR) plays a crucial role on the pathogenesis. The aim of this study was to assess the presence of pepsin in formalin-fixed, paraffin embedded (FEPE) specimens of VFNs to evaluate the role of LPR as a risk factor for VFNs. MATERIALS AND METHODS: A total of 28 pathology specimens of patients suffering from VFNs who had undergone laser microsurgery under general anesthesia were evaluated. The specimens were maintained in paraffin blocks in the pathology department. Western blot (WB) and enzyme-linked immunosorbent assay (ELISA) analyses were used to measure pepsin enzyme levels in the VFNs tissue specimens. Signs of LPR were assessed according to the reflux finding score. RESULTS: The mean reflux finding score of the patients was 13.6 +/- 2.89 (8-21). According to WB and ELISA analyses, pepsin was detected with both the WB the ELISA tests in positive controls, but there was no pepsin enzyme in any of the 28 laryngeal FEPE VFNs specimens. CONCLUSION: The pepsin enzyme was not detected in any of the FEPE VFNs specimens, and it is concluded that further studies are needed to reveal the role of pepsin in the etiology of VFNs. PMID- 29759921 TI - A Comparison of Voice Activity and Participation Profiles Among Etiological Groups. AB - OBJECTIVES: The purpose of this study was to determine whether patients with functional voice disorders show voice activity and participation profiles different from those of the organic and neurogenic groups. METHODS: The Korean Version of the Voice Activity and Participation Profile (K-VAPP) was administered to 200 participants (150 patients with functional, organic, and neurogenic voice disorders, 50 for each etiological group, 50 controls without vocal complaint). The K-VAPP subscale scores of the etiological groups were compared, controlling for age, professional use of voice, and severity of voice disorder measured by overall severity of the Consensus Auditory-Perceptual Evaluation of Voice (CAPE V). RESULTS: Results of a one-way analysis of variance indicated significant differences in the overall severity across groups (neurogenic > functional = organic > control). Among four groups, the organic group showed higher mean Z scores of the K-VAPP than the control group, and the functional group showed higher mean Z-scores of the K-VAPP than the organic group. Compared with the neurogenic group, the functional group showed lower mean Z-scores for total score, Activity Limitation Score, SUB3, and SUB5. A comparison among three etiological groups showed that the functional group did not show higher scores than the organic group. On the contrary, the functional group showed a lower total score, Participation Restriction Score, and score for subsection 3 (effect on daily communication) than the neurogenic group. CONCLUSIONS: Psychometric assessment of voice disorders using the K-VAPP could provide clinicians with baseline information that is applicable to various voice disorders. Further studies pertaining to the follow-up of voice disorders with various etiologies are needed to extend its clinical usefulness. PMID- 29759922 TI - Treatment with ribavirin of acute hepatitis and severe renal damage in an immunocompetent patient. PMID- 29759923 TI - Madelung's disease in a patient with advanced hepatocellular carcinoma. PMID- 29759920 TI - Dysphonia, Perceived Control, and Psychosocial Distress: A Qualitative Study. AB - OBJECTIVES: The purpose of this qualitative study was to examine relationships between psychological factors, particularly perceived control, and voice symptoms in adults seeking treatment for a voice problem. METHODS: Semistructured interviews of adult patients with a clinical diagnosis of muscle tension dysphonia were conducted and transcribed. Follow-up interviews were conducted as needed for further information or clarification. A multidisciplinary team analyzed interview content using inductive techniques. Common themes and subthemes were identified. A conceptual model was developed describing the association between voice symptoms, psychological factors, precipitants of ongoing voice symptoms, and perceived control. RESULTS: Thematic saturation was reached after 23 interviews. No participants reported a direct psychological cause for their voice problem, although half described significant life events preceding voice problem onset (eg, miscarriage and other health events, interpersonal conflicts, and family members' illnesses, injuries, and deaths). Participants described psychological influences on voice symptoms that led to rapid exacerbation of their voice symptoms. Participants described the helpfulness of speech therapy and sometimes also challenges of applying techniques in daily life. They also discussed personal coping strategies that included behavioral (eg, avoiding triggers and seeking social support) and psychological (eg, mind-body awareness and emotion regulation) components. Voice related perceived control was associated with adaptive emotional and behavioral responses, which appeared to facilitate symptom improvement. CONCLUSIONS: In this qualitative pilot study, participant narratives suggested that psychological factors and emotions influence voice symptoms, facilitating development of a preliminary conceptual model of how adaptive and maladaptive responses develop and how they influence vocal function. PMID- 29759924 TI - Resources used in the treatment of perianal Crohn's disease and the results in a real-life cohort. AB - OBJECTIVE: To study the multidisciplinary management of patients with Crohn's disease (CD) and perianal disease (perianal Crohn's disease, PCD), as well as to analyse a possible relationship between the recurrence of perianal symptoms, the type of fistula and the treatment used. PATIENTS AND METHODS: Descriptive, retrospective study of patients with PCD who were treated in the Inflammatory Bowel Disease Unit. Epidemiological, clinical, diagnostic and therapeutic variables were collected, as well as clinical outcome and response to treatment. RESULTS: Of the 300 patients who attended the outpatient clinic at a university hospital, 65 had PCD. Sixteen simple fistulas (24.6%) and 49 complex fistulas (75.4%) were diagnosed. The most commonly used diagnostic technique was the endoanal ultrasound (45%). Antibiotics were used in 77.4% of patients, and 70% needed anti-TNF therapy to manage the PCD. Surgery was performed on 75.4% of the patients overall. PCD recurred in 41.5% of cases, requiring a change of the biological drugs administered and/or surgery. Complex fistulas were more likely to require surgery (P=.012) and recurrence of PCD was also more common with complex fistulas (P=.036). CONCLUSION: Management of PCD must be multidisciplinary and combined. Most patients with complex PCD require treatment based on biological drugs. Despite therapy, remission of perianal symptoms is not achieved in a percentage of patients, supporting the need to develop new therapies for refractory cases. PMID- 29759925 TI - Metronidazole in the prevention of antibiotic-associated diarrhoea and Clostridium difficile infection in high-risk hospitalised patients. AB - BACKGROUND: In-hospital diarrhoea has a high impact on morbidity and mortality rates among hospitalised patients. Chemoprophylaxis with antibiotics in selected patients could be a cost-effective tool for prevention. METHODS: A prospective randomised, open-label study was conducted in a tertiary hospital in Mexico City, selecting patients at high risk of acquiring in-hospital diarrhoea and assigning them to a group taking metronidazole 500mg orally every eight hours for seven days or an observation group. The primary endpoint was the presence of antibiotic associated diarrhoea and Clostridium difficile (C. difficile) infection during the seven days of evaluation. The study was approved by the institutional ethics committee. Registration number (11.2017) of 14 March 2017. RESULTS: Of the 116 patients who met the inclusion criteria, 96 were analysed, 41 in the intervention group and 55 in the observation group: 4.9% of patients in the intervention group and 16.4% in the observation group developed antibiotic-associated diarrhoea (odds ratio [OR] 0.26 (0.05-1.29); p =.109). 0% of patients in the intervention group and 9.1% in the observation group developed C. difficile infection (odds ratio [OR] 0.91 (0.84-0.99); p =.069). CONCLUSIONS: Metronidazole prophylaxis did not result in a reduction in antibiotic-associated diarrhoea. It could, however, be an effective measure for preventing C. difficile infection in selected high risk patients. This was the first prospective study designed for this purpose. New studies that involve a larger number of patients are required in the future. PMID- 29759927 TI - Incidence of Nonunion of the Hallux Interphalangeal Joint Arthrodesis: A Systematic Review. AB - Hallux interphalangeal joint arthrodesis is an effective procedure to treat pain and provide stability and is often performed for intrinsic pain to the hallux interphalangeal joint. Additionally, this procedure is typically used in concert with the Jones tenosuspension. Although this as an accepted technique, the available data are scant, and questions remain regarding nonunion rates and contributory factors to poor healing. A systematic review of the reported data were undertaken to determine the rate of nonunion for hallux interphalangeal joint arthrodesis. Seven studies involving 313 hallux interphalangeal joint arthrodeses met the inclusion criteria. The nonunion rate was 28.3% at a weighted mean follow-up period of 8.4 months. The overall complication rate was 33.0%. Considering the increased rate of complications and nonunion rate for this commonly used procedure, additional prospective comparative analyses are needed regarding this topic to identify important patient demographic data and determine superior fixation constructs. PMID- 29759918 TI - Potential immunotherapies for traumatic brain and spinal cord injury. AB - Traumatic injury of the central nervous system (CNS) including brain and spinal cord remains a leading cause of morbidity and disability in the world. Delineating the mechanisms underlying the secondary and persistent injury versus the primary and transient injury has been drawing extensive attention for study during the past few decades. The sterile neuroinflammation during the secondary phase of injury has been frequently identified substrate underlying CNS injury, but as of now, no conclusive studies have determined whether this is a beneficial or detrimental role in the context of repair. Recent pioneering studies have demonstrated the key roles for the innate and adaptive immune responses in regulating sterile neuroinflammation and CNS repair. Some promising immunotherapeutic strategies have been recently developed for the treatment of CNS injury. This review updates the recent progress on elucidating the roles of the innate and adaptive immune responses in the context of CNS injury, the development and characterization of potential immunotherapeutics, as well as outstanding questions in this field. PMID- 29759926 TI - Drug Repurposing for Viral Infectious Diseases: How Far Are We? AB - Despite the recent advances in controlling some viral pathogens, most viral infections still lack specific treatment. Indeed, the need for effective therapeutic strategies to combat 'old', emergent, and re-emergent viruses is not paralleled by the approval of new antivirals. In the past years, drug repurposing combined with innovative approaches for drug validation, and with appropriate animal models, significantly contributed to the identification of new antiviral molecules and targets for therapeutic intervention. In this review, we describe the main strategies of drug repurposing in antiviral discovery, discuss the most promising candidates that could be repurposed to treat viral infections, and analyze the possible caveats of this trendy strategy of drug discovery. PMID- 29759928 TI - Bdnf variant is associated with milder motor symptom severity in early-stage Parkinson's disease. AB - INTRODUCTION: Parkinson's disease (PD) progression is heterogeneous. Variants in PD-related genes may alter disease progression or severity. We examined if the single nucleotide variant rs6265 in the gene Bdnf alters clinical phenotype in early-stage, unmedicated PD. METHODS: A retrospective analysis was conducted using data collected in the Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism (DATATOP) study. DNA samples (n = 217) were genotyped for the Bdnf rs6265 variant, and the primary endpoint was time to initiate levodopa. The Parkinson's Progression Markers Initiative (PPMI) was used for validation (n = 383). RESULTS: The primary endpoint of time to initiate levodopa was associated with a delay in subjects with two copies of the rs6265 minor (Met66) allele (HR: 4.9; 95% CI: 1.3-18.8). Secondary endpoints were not different among genotypes. PPMI subjects with two Met66 alleles demonstrated significantly lower total and part III Movement Disorder Society - United Parkinson's Disease Rating Scale (MDS UPDRS) scores at baseline, as well as more tremor-related symptoms, but not a delay in initiation of maintenance pharmacotherapy. CONCLUSIONS: Data from two distinct, unmedicated, early-stage PD cohorts suggest that carrying two copies of the rs6265 Met66 allele (~4% of the population) is associated with less severity in motor symptoms and potentially a slower rate of progression. PMID- 29759929 TI - Entacapone and prostate cancer in Parkinson's disease patients: A large Veterans Affairs healthcare system study. AB - BACKGROUND: An increased incidence of prostate cancer was observed in Parkinson's disease (PD) patients treated with entacapone during a pre-approval randomized clinical trial; the relation has not been robustly investigated in the U.S. ambulatory setting. OBJECTIVE: To investigate whether entacapone is associated with prostate cancer and to assess whether the associations are correlated with advanced disease at the time of cancer diagnosis. METHODS: Using data from the Department of Veterans Affairs healthcare system, new-user cohorts were created of PD patients treated with add-on entacapone or add-on dopamine agonist/monoamine oxidase B inhibitors between January 2000 and December 2014. Patients were followed on-treatment for occurrence of prostate cancer, identified via linkage to the VA cancer registry. RESULTS: Mean follow-up time was 3.1 and 4.0 years in the entacapone and control cohort, respectively. There were 17,666 subjects meeting study criteria (mean age, 74 (SD 8.6) years); the entacapone treated group comprised 5,257 subjects. Twenty-three prostate cancer cases occurred in the entacapone cohort and ninety-seven in the control cohort. The overall incidence of prostate cancer was 1.8 per 1,000 person-years of risk. There was no difference in risk of prostate cancer between the cohorts for increased duration of entacapone intake (adjusted HR: 1.08; 95% confidence interval: 0.46-2.51 for cumulative exposure of >=2 years). Time since starting drug therapy and cumulative dose (mg) also do not suggest a difference in prostate cancer risk between cohorts. CONCLUSIONS: Prolonged therapy with entacapone was not associated with increased prostate cancer incidence; however, findings suggest a higher severity of prostate cancer. PMID- 29759930 TI - Diagnostic criteria for camptocormia in Parkinson's disease: A consensus-based proposal. AB - INTRODUCTION: Camptocormia is defined as an involuntary, marked flexion of the thoracolumbar spine appearing during standing or walking and resolving in the supine position or when leaning against a wall. However, there is no established agreement on the minimum degree of forward flexion needed to diagnose camptocormia. Likewise, the current definition does not categorize camptocormia on the basis of the bending fulcrum. METHODS: We performed a survey among movement disorders experts to identify camptocormia using images of patients with variable degrees and types of forward trunk flexion by fulcrum (upper and lower fulcra). We tested the subsequently generated diagnostic criteria in a sample of 131 consecutive patients referred for evaluation of postural abnormalities. RESULTS: Experts reached full consensus on lower camptocormia (L1-Sacrum, hip flexion) with a bending angle >=30 degrees and upper camptocormia (C7 to T12-L1) with a bending angle >=45 degrees . This definition detected camptocormia in 9/131 consecutive PD patients (2 upper/7 lower) but excluded camptocormia in 71 patients considered to have camptocormia by the referring neurologist. CONCLUSIONS: Camptocormia can be defined as "an involuntary flexion of the spine appearing during standing or walking and resolving in the supine position of at least 30 degrees at the lumbar fulcrum (L1-Sacrum, hip flexion, i.e. lower camptocormia) and/or at least 45 degrees at the thoracic fulcrum (C7 to T12-L1, i.e. upper camptocormia)". Strict criteria for camptocormia are met by 7% of patients with abnormal posture. The ascertainment of upper and lower camptocormia subtypes could improve the validity of epidemiological studies and assist future therapeutic trials. PMID- 29759931 TI - President's Message. PMID- 29759932 TI - Examining the link between placental pathology, growth restriction, and stillbirth. AB - Stillbirth, often defined as death of a fetus >=20 weeks of gestation, is emotionally devastating for families and caregivers. It is often associated with fetal growth restriction (FGR). Indeed, FGR or small-for-gestational age fetus (SGA) is a major risk factor for stillbirth. In rare cases, this is due to genetic abnormalities or infections. However, in most cases, it is linked to placental insufficiency. This may be due to abnormal placental development or placental damage, thereby resulting in decreased blood flow, oxygen, and nutrients to the fetus. Several placental histological abnormalities are associated with stillbirth, FGR, or both. Most involve vascular abnormalities but some are inflammatory lesions. This paper reviews evidence regarding the relationships between placental function and pathology, FGR, and stillbirth. Issues with clinical relevance, knowledge gaps, and areas for further research are highlighted. PMID- 29759933 TI - Trauma and fear in Australian midwives. AB - BACKGROUND: Relatively little is known about the extent of trauma and birth related fear in midwives and how this might affect practice. AIM: (1) Determine prevalence of birth related trauma and fear in midwives and associations with midwives' confidence to advise women during pregnancy of their birth options and to provide care in labour. (2) Describe midwives' experiences of birth related trauma and/or fear. METHOD: A mixed methods design. A convenience sample of midwives (n=249) completed an anonymous online survey. Descriptive and inferential statistics were used to analyse the quantitative data. Latent content analysis was used to extrapolate meaning from the 170 midwives who wrote about their experiences of personal and/or professional trauma. RESULTS: The majority of midwives (93.6%) reported professional (n=199, 85.4%) and/or personal (n=97, 41.6%) traumatic birth experiences. Eight percent (n=20) reported being highly fearful of birth. Trauma was not associated with practice concerns but fear was. Midwives categorised as having 'high fear' reported more practice concerns (Med 23.5, n=20) than midwives with 'low fear' (Med 8, n=212) (U=1396, z=-3.79, p<0.001, r=0.24). Reasons for personal trauma included experiencing assault, intervention and stillbirth. Professional trauma related to both witnessing and experiencing disrespectful care and subsequently feeling complicit in the provision of poor care. Feeling unsupported in the workplace and fearing litigation intensified trauma. CONCLUSION: High fear was associated with lower confidence to support childbearing women. Fear and trauma in midwives warrants further investigation to better understand the impact on professional practice. PMID- 29759934 TI - Parasite Collections: Overlooked Resources for Integrative Research and Conservation. AB - Parasite natural history collections form vital scientific infrastructure that play a substantial role in increasing awareness of the importance of parasites to ecosystems, conservation assessments, science, and society. These collections support novel investigations that integrate across taxa, time, and space, and should be cultivated to advance organismal-based science. Promoting and supporting parasite collections will ensure their ongoing stability and accessibility. PMID- 29759935 TI - Applied anatomy of round window and adjacent structures of tympanum related to cochlear implantation. AB - INTRODUCTION: Various aspects of the round window anatomy and anatomy of posterior tympanum have relevant implications for designing cochlear implant electrodes and visualizing the round window through facial recess. Preoperative information about possible anatomical variations of the round window and its relationships to the adjacent neurovascular structures can help reduce complications in cochlear implant surgery. OBJECTIVE: The present study was undertaken to assess the common variations in round window anatomy and the relationships to structures of the tympanum that may be relevant for cochlear implant surgery. METHODS: Thirty-five normal wet human cadaveric temporal bones were studied by dissection for anatomy of round window and its relation to facial nerve, carotid canal, jugular fossa and other structures of posterior tympanum. The dissected bones were photographed by a digital camera of 18 megapixels, which were then imported to a computer to determine various parameters using ScopyDoc 8.0.0.22 version software, after proper calibration and at 1* magnification. RESULTS: When the round window niche is placed posteriorly and inferiorly, the distance between round window and vertical facial nerve decreases, whereas that with horizontal facial nerve increases. In such cases, the distance between oval window and round window also increases. Maximum height of the round window in our study ranged from 0.51-1.27mm (mean of 0.69+/-0.25mm). Maximum width of round window ranged from 0.51 to 2.04mm (mean of 1.16+/-0.47mm). Average minimum distance between round window and carotid canal was 3.71+/-0.88mm (range of 2.79 5.34mm) and that between round window and jugular fossa was 2.47+/-0.9mm (range of 1.24-4.3mm). CONCLUSION: The distances from the round window to the oval window and facial nerve are important parameters in identifying a difficult round window niche. Modification of the electrode may be a better option than drilling off the round window margins for insertion of cochlear implant electrodes. PMID- 29759936 TI - In vitro antioxidant, antilipoxygenase and antimicrobial activities of extracts from seven climbing plants belonging to the Bignoniaceae. AB - OBJECTIVES: This study aimed to evaluate the in vitro antioxidant capacity, to determine the anti-inflammatory effect due to lipoxygenase inhibition and to test the antimicrobial activity of ethanolic extracts from leaves of seven climbing species belonging to the Bignoniaceae family. These species are Adenocalymma marginatum (Cham.) DC., Amphilophium vauthieri DC., Cuspidaria convoluta (Vell.) A. H. Gentry, Dolichandra dentata (K. Schum.) L. G. Lohmann, Fridericia caudigera (S. Moore) L. G. Lohmann, Fridericia chica (Bonpl.) L. G. Lohmann and Tanaecium selloi (Spreng.) L. G. Lohmann. METHODS: The antioxidant activity was evaluated using three methods, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and ferric reducing antioxidant power. Lipoxygenase-inhibiting activity was assayed spectrophotometrically; the result was expressed as percent inhibition. The antimicrobial activity was assessed using the agar disk diffusion method. Minimal inhibitory concentration (MIC) and minimal bactericidal/fungicidal concentration were also determined for each extract against 12 pathogenic bacterial strains of Staphylococcus aureus and seven fungal strains of the Candida genus. The identification of the major compounds present in the most promising extract was established by high performance liquid chromatography-tandem mass spectrometry. RESULTS: C. convoluta, F. caudigera, and F. chica exhibited the best antioxidant activity by scavenging DPPH and ABTS+ radicals and reducing Fe3+ ion. These extracts showed a notable inhibition of lipoxygenase. F. caudigera was found to have the lower MIC value against S. aureus strains and six Candida species. The extracts of F. caudigera and C. convoluta were active even against methicillin-resistant S. aureus. C. convoluta had higher total phenol content, better antioxidant activity and superior anti-inflammatory and antimicrobial activity. The main phenolic compounds found in this extract were coumaric and hydroxybenzoic acid derivatives and glycosylated and nonglycosylated flavones. CONCLUSION: Most of the extracts exhibited antioxidant activity as well as in vitro inhibition of lipoxygenase. The excellent antimicrobial activity of T. selloi and F. chica supports their use in traditional medicine as antiseptic agents. The extracts of F. caudigera and C. convoluta, both with notable biological activities in this study, could be used as herbal remedies for skin care. In addition, this study provides, for the first time, information about phenolic compounds present in C. convoluta. PMID- 29759937 TI - Identification of Epigenetic Regulators of DUX4-fl for Targeted Therapy of Facioscapulohumeral Muscular Dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic de repression of the disease locus, leading to pathogenic misexpression of the DUX4 gene in skeletal muscle. While the factors and pathways involved in normal repression of the FSHD locus in healthy cells have been well characterized, very little is known about those responsible for the aberrant activation of DUX4-fl in FSHD myocytes. Reasoning that DUX4-fl activators might represent useful targets for small molecule inhibition, we performed a highly targeted, candidate-based screen of epigenetic regulators in primary FSHD myocytes. We confirmed several of the strongest and most specific candidates (ASH1L, BRD2, KDM4C, and SMARCA5) in skeletal myocytes from two other unrelated FSHD1 patients, and we showed that knockdown led to reduced levels of DUX4-fl and DUX4-FL target genes, as well as altered chromatin at the D4Z4 locus. As a second mode of validation, targeting the CRISPR/dCas9-KRAB transcriptional repressor to the promoters of several candidates also led to reduced levels of DUX4-fl. Furthermore, these candidates can be repressed by different methods in skeletal myocytes without major effects on certain critical muscle genes. Our results demonstrate that expression of DUX4 fl is regulated by multiple epigenetic pathways, and they indicate viable, druggable candidates for therapeutic target development. PMID- 29759938 TI - Differentiation Therapy by Epigenetic Reconditioning Exerts Antitumor Effects on Liver Cancer Cells. AB - Primary liver tumors are mainly represented by hepatocellular carcinoma (HCC), one of the most aggressive and resistant forms of cancer. Liver tumorigenesis is characterized by an accumulation of epigenetic abnormalities, leading to gene extinction and loss of hepatocyte differentiation. The aim of this work was to investigate the feasibility of converting liver cancer cells toward a less aggressive and differentiated phenotype using a process called epigenetic reconditioning. Here, we showed that an epigenetic regimen with non-cytotoxic doses of the demethylating compound 5-azacytidine (5-AZA) promoted an anti-cancer response by inhibiting HCC cell tumorigenicity. Furthermore, epigenetic reconditioning improved sorafenib response. Remarkably, epigenetic treatment was associated with a significant restoration of differentiation, as attested by the increased expression of characteristic hepatocyte markers in reconditioned cells. In particular, we showed that reexpression of these epigenetically silenced liver genes following 5-AZA treatment or after knockdown of DNA methyltransferase 1 (DNMT1) was the result of regional CpG demethylation. Lastly, we confirmed the efficacy of HCC differentiation therapy by epigenetic reconditioning using an in vivo tumor growth model. In summary, this work demonstrates that epigenetic reconditioning using the demethylating compound 5-AZA shows therapeutic significance for liver cancer and is potentially attractive for the treatment of solid tumors. PMID- 29759939 TI - Preventive Effect of Cilostazol on Pneumonia in Patients with Acute Cerebral Infarction. AB - BACKGROUND: The antiplatelet drug cilostazol decreases the risk of ischemic stroke recurrence in patients with chronic cerebral infarction. Additionally, cilostazol reduces the occurrence of pneumonia in these patients. The purpose of this study was to investigate whether cilostazol is effective for preventing pneumonia in patients with acute cerebral infarction. MATERIALS AND METHODS: A total of 199 consecutive Japanese patients with noncardioembolic acute cerebral infarction, who visited our hospital from January 2010 to April 2016, were retrospectively assessed by using medical records. We compared changes in the occurrence of pneumonia between cilostazol (n = 127) and noncilostazol (n = 72) groups. RESULTS: A total of 76% of patients in the cilostazol group were not administered other antiplatelet drugs. The median duration until cilostazol administration was 5 days (interquartile range = 2-8 days) after the onset of cerebral infarction. A total of 8.0% of the cohort was accompanied by pneumonia. The incidence of pneumonia in the cilostazol group was significantly lower than that in the noncilostazol group (4.7% versus 13.9%, P = .02). Within 30 days after acute cerebral infarction, the presence of neurological deterioration in the cilostazol group tended to be lower compared with the noncilostazol group, but this difference was not significant (5.5% versus 12.5%, P = .08). CONCLUSIONS: These findings suggest that cilostazol is effective for preventing pneumonia in patients with acute cerebral infarction. PMID- 29759940 TI - A Correlational Study on Cerebral Microbleeds and Carotid Atherosclerosis in Patients with Ischemic Stroke. AB - PURPOSE: This study aimed to investigate the correlation between cerebral microbleeds and carotid atherosclerosis in patients with ischemic stroke. SUBJECTS AND METHODS: Patients with ischemic stroke treated in a hospital in China from 2016 to 2017 were enrolled in the study. Based on the results from susceptibility-weighted imaging, the patients were divided into cerebral microbleed and noncerebral microbleed groups. The degree of carotid atherosclerosis was assessed with carotid intima-media thickness (CIMB) and Crouse score of carotid plaque. The details of patients' demographic information, cerebrovascular disease-related risk factors, carotid atherosclerosis indices, cerebral microbleed distribution, and grading were recorded, compared, and analyzed. RESULTS: Logistic regression analysis of the 198 patients showed that CIMB and Crouse score were significantly correlated with the occurrence of cerebral microbleeds. The CIMB thickening group (P = .03) and the plaque group (P = .01) were more susceptible to cerebral microbleeds. In the distribution of cerebral microbleed sites, Crouse scores were the highest in the mixed group and showed a statistically significant difference (P < .01). As the degree of carotid atherosclerosis increased, the average number of cerebral microbleeds also increased (P < .01). The receiver operating characteristic curve analysis of the carotid atherosclerosis indices showed a statistically significant difference. The CIMB value combined with the Crouse score was the best indicator (P < .01). CONCLUSION: In patients with ischemic stroke, cerebral microbleeds are closely related to carotid atherosclerosis. Active control of carotid atherosclerosis is important to prevent cerebral microbleeds in patients with ischemic stroke. PMID- 29759941 TI - Differences in and Determinants of Prehospital Delay Times among Stroke Patients 1994 Versus 2012. AB - OBJECTIVES: Prehospital delay is a challenge for stroke treatment and the delivery of time-critical treatments. Few studies have examined secular trends in prehospital delay, and results vary. This study investigates how prehospital delay among Norwegian stroke patients has changed over the last 2 decades. METHODS: We compared time from symptom onset to admission in 2 cohorts of stroke patients admitted to Akershus University Hospital, Norway, in 1994 (n = 550) and 2012 (n = 522), and constructed predictive models for arrival within 3 hours for each cohort. RESULTS: More patients arrived within 3 hours of symptom onset in 2012 compared to 1994 (proportion, 47.1% versus 19.3%, P < .001), also after adjusting for age, sex, and baseline differences; odds ratio (OR) was 5.14 (95% confidence interval [CI] 3.69-7.15). Stroke severity was the only predictor examined that was independently associated with early arrival during both periods. For patients with moderate strokes the overall OR was 2.06 (95% CI 1.41 3.00) and for severe strokes 4.52 (95% CI 2.97-6.87), compared to those with mild strokes. In the 1994 cohort additional predictors of early arrival were living with others and not being admitted from nursing home. CONCLUSIONS: Prehospital delay in Norway has decreased considerably over the last 2 decades and since the availability of time-critical treatments. However, there is still an urgent need to reduce the number of delayed admissions as a large proportion of patients continue to arrive too late to benefit from these treatments. Patients with severer strokes were predicted to have earlier arrival. PMID- 29759944 TI - Testing assumptions on prefrontal transcranial direct current stimulation: Comparison of electrode montages using multimodal fMRI. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) has been widely applied in cognitive neurosciences and advocated as a therapeutic intervention, e.g. in major depressive disorder. Although several targets and protocols have been suggested, comparative studies of tDCS parameters, particularly electrode montages and their cortical targets, are still lacking. OBJECTIVE: This study investigated a priori hypotheses on specific effects of prefrontal-tDCS montages by using multimodal functional magnetic resonance imaging (fMRI) in healthy participants. METHODS: 28 healthy male participants underwent three common active-tDCS montages and sham tDCS in a pseudo-randomized order, comprising a total of 112 tDCS-fMRI sessions. Active tDCS was applied at 2 mA for 20 min. Before and after tDCS, a resting-state fMRI (RS fMRI) was recorded, followed by a task fMRI with a delayed-response working memory (DWM) task for assessing cognitive control over emotionally negative or neutral distractors. RESULTS: After tDCS with a cathode-F3/anode-F4 montage, RS fMRI connectivity decreased in a medial part of the left PFC. Also, after the same stimulation condition, regional brain activity during DWM retrieval decreased more in this area after negative than after neutral distraction, and responses to the DWM task were faster, independent of distractor type. CONCLUSION: The current study does not confirm our a priori hypotheses on direction and localization of polarity-dependent tDCS effects using common bipolar electrode montages over PFC regions, but it provides evidence for montage specific effects on multimodal neurophysiological and behavioral outcome measures. Systematic research on the actual targets and the respective dose response relationships of prefrontal tDCS is warranted. PMID- 29759945 TI - Diagnosis of local hepatic tuberculosis through next-generation sequencing: Smarter, faster and better. AB - BACKGROUND: A 45-year-old man who complained of continuous fever and multiple hepatic masses was admitted to our hospital. Repeated MRI manifestations were similar while each radiological report suggested contradictory diagnosis pointing to infections or malignances respectively. Pathologic examination of the liver tissue showed no direct evidence of either infections or tumor. We performed next generation sequencing on the liver tissue and peripheral blood to further investigate the possible etiology. METHODS: High throughput sequencing was performed on the liver lesion tissues using BGISEQ-100 platform, and data was mapped to the Microbial Genome Databases after filtering low quality data and human reads. RESULTS: We identified a total of 299 sequencing reads of Mycobacterium tuberculosis (M. tuberculosis) complex sequences from the liver tissue, including 8, 229 of 4,424,435 of the M. tuberculosis nucleotide sequences, and Mycobacterium africanum, Mycobacterium bovis, and Mycobacterium canettii were also detected due to the 99.9% identical rate among these strains. No specific Mycobacterial tuberculosis nucleotide sequence was detected in the sample of peripheral blood. Patient's symptom quickly recovered after anti tuberculosis treatment and repeated Ziehl-Neelsen staining of the liver tissue finally identified small numbers of positive bacillus. CONCLUSIONS: The diagnosis of this patient was difficult to establish before the next-generation sequencing because of contradictive radiological results and negative pathological findings. More sensitive diagnostic methods are urgently needed. This is the first case reporting hepatic tuberculosis confirmed by the next-generation sequencing, and marks the promising potential of the application of the next-generation sequencing in the diagnosis of hepatic lesions with unknown etiology. PMID- 29759943 TI - Randomized controlled trial of home-based 4-week tDCS in chronic minimally conscious state. AB - BACKGROUND: Patients with chronic disorders of consciousness face a significant lack of treatment options. OBJECTIVE: We aimed at investigating the feasibility and the behavioral effects of home-based transcranial direct current stimulation (tDCS), applied by relatives or caregivers, in chronic patients in minimally conscious state (MCS). METHODS: Each participant received, in a randomized order, 20 sessions of active and 20 sessions of sham tDCS applied over the prefrontal cortex for 4 weeks; separated by 8 weeks of washout. Level of consciousness was assessed using the Coma Recovery Scale-Revised before the first stimulation (baseline), at the end of the 20 tDCS sessions (direct effects) and 8 weeks after the end of each stimulation period (long-term effects). Reported adverse events and data relative to the adherence (i.e., amount of sessions effectively received) were collected as well. RESULTS: Twenty-seven patients completed the study and 22 patients received at least 80% of the stimulation sessions. All patients tolerated tDCS well, no severe adverse events were noticed after real stimulation and the overall adherence (i.e., total duration of stimulation) was good. A moderate effect size (0.47 and 0.53, for modified intention to treat and per protocol analysis, respectively) was observed at the end of the 4 weeks of tDCS in favor of the active treatment. CONCLUSIONS: We demonstrated that home based tDCS can be used adequately outside a research facility or hospital by patients' relatives or caregivers. In addition, 4 weeks of tDCS moderately improved the recovery of signs of consciousness in chronic MCS patients. PMID- 29759942 TI - TMS evoked N100 reflects local GABA and glutamate balance. AB - BACKGROUND: Animal studies suggest that synchronized electrical activities in the brain are regulated by the primary inhibitory and excitatory neurotransmitters gamma-aminobutyric acid (GABA) and glutamate, respectively. Identifying direct evidence that this same basic chemical-electrical neuroscience principle operates in the human brains is critical for translation of neuroscience to pathological research. OBJECTIVE/HYPOTHESIS: We hypothesize that the background neurochemical concentrations may affect the cortical excitability probed by transcranial magnetic stimulation (TMS). METHODS: We used TMS with simultaneous evoked potential recording to probe the cortical excitability and determined how background frontal cortical GABA and glutamate levels measured using magnetic resonance spectroscopy (MRS) modulate frontal electrical activities. RESULTS: We found that TMS-evoked N100 reflects a balance between GABA-inhibitory and glutamate-excitatory levels. About 46% of individual variances in frontal N100 can be explained by their glutamate/GABA ratio (r = -0.68, p = 0.001). Both glutamate (r = -0.51, p = 0.019) and GABA (r = 0.55, p = 0.01) significantly contributed to this relationship but in opposite directions. CONCLUSION: The current finding encourages additional mechanistic studies to develop TMS evoked N100 as a potential electrophysiological biomarker for translating the known inhibitory GABAergic vs. excitatory glutamatergic chemical-electrical principle from animal brain studies to human brain studies. PMID- 29759946 TI - Assessment of structural and hemodynamic performance of vascular stents modelled as periodic lattices. AB - This work considers vascular stents with tubular geometry assumed to follow a periodic arrangement of repeating unit cells. Structural and hemodynamic metrics are presented to assess alternative stent geometries, each defined by the topology of the unit cell. Structural metrics include foreshortening, elastic recoil and radial stiffness, whereas hemodynamic performance is described by a wall shear stress index quantifying the impact of in-stent restenosis. A representative volume element (RVE) modelling approach is used, and results are compared to those obtained from full simulations of entire stents. We demonstrate that the RVE approach can be used to quantify the impact of the topology of the repeating unit on the structural and hemodynamic properties of a stent, and thus support clinicians in making proper choices among alternative stent geometries. PMID- 29759947 TI - A simplified method to account for wall motion in patient-specific blood flow simulations of aortic dissection: Comparison with fluid-structure interaction. AB - Aortic dissection (AD) is a complex and highly patient-specific vascular condition difficult to treat. Computational fluid dynamics (CFD) can aid the medical management of this pathology, yet its modelling and simulation are challenging. One aspect usually disregarded when modelling AD is the motion of the vessel wall, which has been shown to significantly impact simulation results. Fluid-structure interaction (FSI) methods are difficult to implement and are subject to assumptions regarding the mechanical properties of the vessel wall, which cannot be retrieved non-invasively. This paper presents a simplified 'moving-boundary method' (MBM) to account for the motion of the vessel wall in type-B AD CFD simulations, which can be tuned with non-invasive clinical images (e.g. 2D cine-MRI). The method is firstly validated against the 1D solution of flow through an elastic straight tube; it is then applied to a type-B AD case study and the results are compared to a state-of-the-art, full FSI simulation. Results show that the proposed method can capture the main effects due to the wall motion on the flow field: the average relative difference between flow and pressure waves obtained with the FSI and MBM simulations was less than 1.8% and 1.3%, respectively and the wall shear stress indices were found to have a similar distribution. Moreover, compared to FSI, MBM has the advantage to be less computationally expensive (requiring half of the time of an FSI simulation) and easier to implement, which are important requirements for clinical translation. PMID- 29759948 TI - Measuring relative positions and orientations of the tibia with respect to the femur using one-channel 3D-tracked A-mode ultrasound tracking system: A cadaveric study. AB - The purpose of this study is to investigate the technical feasibility of measuring relative positions and orientations of the tibia with respect to the femur in an in-vitro experiment by using a 3D-tracked A-mode ultrasound system and to determine its accuracy of angular and translational measurements. As A mode ultrasound is capable of detecting bone surface through soft tissue in a non invasive manner, the combination of a single A-mode ultrasound transducer with an optical motion tracking system provides the possibility for digitizing the 3D locations of bony points at different anatomical regions on the thigh and the shank. After measuring bony points over a large area of both the femur and tibia, the bone models of the femur and tibia that were segmented from CT or MRI images were registered to the corresponding bony points. Then the relative position of the tibia with respect to the femur could be obtained and the angular and translational components could also be measured. A cadaveric experiment was conducted to assess its accuracy compared to the reference measurement obtained by optical markers fixed to intra-cortical bone pins placed in the femur and tibia. The results showed that the ultrasound system could achieve 0.49 +/- 0.83 degrees , 0.85 +/- 1.86 degrees and 1.85 +/- 2.78 degrees (mean +/- standard deviation) errors for Flexion-Extension, Adduction-Abduction and External Internal rotations, respectively, and -2.22 +/- 3.62 mm, -2.80 +/- 2.35 mm and 1.44 +/- 2.90 mm errors for Anterior-Posterior, Proximal-Distal and Lateral Medial translations, respectively. It was concluded that this technique is feasible and facilitates the integration of arrays of A-mode ultrasound transducers with an optical motion tracking system for non-invasive dynamic tibiofemoral kinematics measurement. PMID- 29759950 TI - Wrist to forearm ratio as a median nerve shear wave elastography test in carpal tunnel syndrome diagnosis. PMID- 29759951 TI - Immediate and long-term results of unsintered hydroxyapatite and poly L-lactide composite sheets for orbital wall fracture reconstruction. AB - INTRODUCTION: Bone defect reconstruction in orbital wall fractures with absorbable alloplastic such as the unsintered hydroxyapatite and poly L-lactide composite (u-HA/PLLA) system is gaining popularity. The u-HA/PLLA material has osteoconductive and osteosynthetic properties. However, quantitative, long-term outcome data after the use of u-HA/PLLA for orbital wall fractures are lacking. PATIENTS AND METHODS: We retrospectively analyzed 115 patients who underwent surgical repair of orbital wall fractures with a u-HA/PLLA sheet from 2011 to 2016. A chart review was performed, and the time-dependent changes at fracture sites were assessed by imaging. The immediate postoperative and the latest follow up bony orbital volumes of the affected side were compared. RESULTS: Seventy patients were eligible for this study (mean age, 44.6 +/- 22.1 years; 48 men and 22 women; mean follow-up period, 29.7 +/- 12.8 months). Except for one case of hematoma, there were no postoperative wound complications. Of the 70 patients, 10 had postoperative diplopia and 2 had enophthalmos; these conditions were presumably caused by the extension and severity of the fracture. Satisfactory reduction in the entire orbital wall, without pathological changes, was demonstrated. There were no significant differences in the mean bony orbital volumes of the affected side immediately after surgery (24.774 +/- 3.092 cm3) and at the latest follow-up (24.749 +/- 3.205 cm3) (p = 0.756). CONCLUSION: The u HA/PLLA sheet is useful for orbital wall fracture reconstruction because of its desirable handling characteristics, initial mechanical strength, long-term maintenance of structural stability, radiopacity, and few associated complications. Future randomized controlled trials need to be performed to compare u-HA/PLLA with other conventional materials. PMID- 29759949 TI - The Glycoscience of Immunity. AB - Carbohydrates, or glycans, are as integral to biology as nucleic acids and proteins. In immunology, glycans are well known to drive diverse functions ranging from glycosaminoglycan-mediated chemokine presentation and selectin dependent leukocyte trafficking to the discrimination of self and non-self through the recognition of sialic acids by Siglec (sialic acid-binding Ig-like lectin) receptors. In recent years, a number of key immunological discoveries are driving a renewed and burgeoning appreciation for the importance of glycans. In this review, we highlight these findings which collectively help to define and refine our knowledge of the function and impact of glycans within the immune response. PMID- 29759952 TI - Head and Neck Anatomy: Effect of Focussed Near-Peer Teaching on Anatomical Confidence in Undergraduate Medical Students. AB - OBJECTIVES: To assess the effect of near-peer head and neck anatomy teaching on undergraduates and to quantify the benefit from a focussed teaching course. Near peer teaching involves colleagues within close seniority and age proximity teaching one another on a specified topic. DESIGN: Small group teaching sessions were delivered to medical students on 3 key areas of ENT anatomy. Participants were given a precourse and postcourse questionnaire to determine the benefit attained from the course. SETTING: An undergraduate anatomy course taking place at the University of Birmingham Medical School. PARTICIPANTS: A total of 30 medical students: 15 preclinical (years 1-2) and 15 clinical (years 3-5) medical students participated from a single institution. RESULTS: A total of 71% of students expressed inadequate teaching of head and neck anatomy in undergraduate curriculum. All students (n = 30) expressed benefit from the course, however the patterns of learning differed: preclinical students showed a significant improvement in both their ability to name anatomical structures and their application (p < 0.05). CONCLUSIONS: Near-peer learning provides benefit to all medical undergraduates in the context of teaching anatomy which may make it a valuable teaching tool for the future of medical education. PMID- 29759953 TI - Acceptability of a Mobile Phone App for Measuring Time Use in Breast Cancer Survivors (Life in a Day): Mixed-Methods Study. AB - BACKGROUND: Advancements in mobile technology allow innovative data collection techniques such as measuring time use (ie, how individuals structure their time) for the purpose of improving health behavior change interventions. OBJECTIVE: The aim of this study was to examine the acceptability of a 5-day trial of the Life in a Day mobile phone app measuring time use in breast cancer survivors to advance technology-based measurement of time use. METHODS: Acceptability data were collected from participants (N=40; 100% response rate) using a self administered survey after 5 days of Life in a Day use. RESULTS: Overall, participants had a mean age of 55 years (SD 8) and completed 16 years of school (SD 2). Participants generally agreed that learning to use Life in a Day was easy (83%, 33/40) and would prefer to log activities using Life in a Day over paper and-pencil diary (73%, 29/40). A slight majority felt that completing Life in a Day for 5 consecutive days was not too much (60%, 24/40) or overly time-consuming (68%, 27/40). Life in a Day was rated as easy to read (88%, 35/40) and navigate (70%, 32/40). Participants also agreed that it was easy to log activities using the activity timer at the start and end of an activity (90%, 35/39). Only 13% (5/40) downloaded the app on their personal phone, whereas 63% (19/30) of the remaining participants would have preferred to use their personal phone. Overall, 77% (30/39) of participants felt that the Life in a Day app was good or very good. Those who agreed that it was easy to edit activities were significantly more likely to be younger when compared with those who disagreed (mean 53 vs 58 years, P=.04). Similarly, those who agreed that it was easy to remember to log activities were more likely to be younger (mean 52 vs 60 years, P<.001). Qualitative coding of 2 open-ended survey items yielded 3 common themes for Life in a Day improvement (ie, convenience, user interface, and reminders). CONCLUSIONS: A mobile phone app is an acceptable time-use measurement modality. Improving convenience, user interface, and memory prompts while addressing the needs of older participants is needed to enhance app utility. TRIAL REGISTRATION: ClinicalTrials.gov NCT00929617; https://clinicaltrials.gov/ct2/show/NCT00929617 (Archived by WebCite at http://www.webcitation.org/6z2bZ4P7X). PMID- 29759955 TI - Translation, Cross-Cultural Adaptation, and Validation of the Malay Version of the System Usability Scale Questionnaire for the Assessment of Mobile Apps. AB - BACKGROUND: A mobile app is a programmed system designed to be used by a target user on a mobile device. The usability of such a system refers not only to the extent to which product can be used to achieve the task that it was designed for, but also its effectiveness and efficiency, as well as user satisfaction. The System Usability Scale is one of the most commonly used questionnaires used to assess the usability of a system. The original 10-item version of System Usability Scale was developed in English and thus needs to be adapted into local languages to assess the usability of a mobile apps developed in other languages. OBJECTIVE: The aim of this study is to translate and validate (with cross cultural adaptation) the English System Usability Scale questionnaire into Malay, the main language spoken in Malaysia. The development of a translated version will allow the usability of mobile apps to be assessed in Malay. METHODS: Forward and backward translation of the questionnaire was conducted by groups of Malay native speakers who spoke English as their second language. The final version was obtained after reconciliation and cross-cultural adaptation. The content of the Malay System Usability Scale questionnaire for mobile apps was validated by 10 experts in mobile app development. The efficacy of the questionnaire was further probed by testing the face validity on 10 mobile phone users, followed by reliability testing involving 54 mobile phone users. RESULTS: The content validity index was determined to be 0.91, indicating good relevancy of the 10 items used to assess the usability of a mobile app. Calculation of the face validity index resulted in a value of 0.94, therefore indicating that the questionnaire was easily understood by the users. Reliability testing showed a Cronbach alpha value of .85 (95% CI 0.79-0.91) indicating that the translated System Usability Scale questionnaire is a reliable tool for the assessment of usability of a mobile app. CONCLUSIONS: The Malay System Usability Scale questionnaire is a valid and reliable tool to assess the usability of mobile app in Malaysia. PMID- 29759956 TI - Too Important to Ignore: Leveraging Digital Technology to Improve Chronic Illness Management Among Black Men. AB - Health disparities associated with chronic illness experiences of black men demonstrate widespread, systematic failures to meet an urgent need. Well established social and behavioral determinants that have led to health disparities among black men include racism, discrimination, and stress. While advocacy work that includes community-engagement and tailoring health promotion strategies have shown local impact, evidence shows the gaps are increasing. We suspect that failure to reduce current disparities may be due to conventional public health interventions and programs; therefore, we submit that innovative interventions, ones that embrace digital technologies and their ability to harness naturally occurring social networks within groups, like black men, have particular importance and deserve attention. This commentary characterizes the current literature on chronic illness among black men as well as health interventions that use digital technology, to build a case for expanding research in this area to reduce the overwhelming burden of chronic illness among black men. PMID- 29759954 TI - Identifying National Availability of Abortion Care and Distance From Major US Cities: Systematic Online Search. AB - BACKGROUND: Abortion is a common medical procedure, yet its availability has become more limited across the United States over the past decade. Women who do not know where to go for abortion care may use the internet to find abortion facility information, and there appears to be more online searches for abortion in states with more restrictive abortion laws. While previous studies have examined the distances women must travel to reach an abortion provider, to our knowledge no studies have used a systematic online search to document the geographic locations and services of abortion facilities. OBJECTIVE: The objective of our study was to describe abortion facilities and services available in the United States from the perspective of a potential patient searching online and to identify US cities where people must travel the farthest to obtain abortion care. METHODS: In early 2017, we conducted a systematic online search for abortion facilities in every state and the largest cities in each state. We recorded facility locations, types of abortion services available, and facility gestational limits. We then summarized the frequencies by region and state. If the online information was incomplete or unclear, we called the facility using a mystery shopper method, which simulates the perspective of patients calling for services. We also calculated distance to the closest abortion facility from all US cities with populations of 50,000 or more. RESULTS: We identified 780 facilities through our online search, with the fewest in the Midwest and South. Over 30% (236/780, 30.3%) of all facilities advertised the provision of medication abortion services only; this proportion was close to 40% in the Northeast (89/233, 38.2%) and West (104/262, 39.7%). The lowest gestational limit at which services were provided was 12 weeks in Wyoming; the highest was 28 weeks in New Mexico. People in 27 US cities must travel over 100 miles (160 km) to reach an abortion facility; the state with the largest number of such cities is Texas (n=10). CONCLUSIONS: Online searches can provide detailed information about the location of abortion facilities and the types of services they provide. However, these facilities are not evenly distributed geographically, and many large US cities do not have an abortion facility. Long distances can push women to seek abortion in later gestations when care is even more limited. PMID- 29759958 TI - Data Access and Usage Practices Across a Cohort of Researchers at a Large Tertiary Pediatric Hospital: Qualitative Survey Study. AB - BACKGROUND: Health and health-related data collected as part of clinical care is a foundational component of quality improvement and research. While the importance of these data is widely recognized, there are many challenges faced by researchers attempting to use such data. It is crucial to acknowledge and identify barriers to improve data sharing and access practices and ultimately optimize research capacity. OBJECTIVE: To better understand the current state, explore opportunities, and identify barriers, an environmental scan of investigators at BC Children's Hospital Research Institute (BCCHR) was conducted to elucidate current local practices around data access and usage. METHODS: The Clinical and Community Data, Analytics and Informatics group at BCCHR comprises over 40 investigators with diverse expertise and interest in data who share a common goal of facilitating data collection, usage, and access across the community. Semistructured interviews with 35 of these researchers were conducted, and data were summarized qualitatively. A total impact score, considering both frequency with which a problem occurs and the impact of the problem, was calculated for each item to prioritize and rank barriers. RESULTS: Three main themes for barriers emerged: the lengthy turnaround time before data access (18/35, 51%), inconsistent and opaque data access processes (16/35, 46%), and the inability to link data (15/35, 43%) effectively. Less frequent themes included quality and usability of data, ethics and privacy review barriers, lack of awareness of data sources, and efforts required duplicating data extraction and linkage. The two main opportunities for improvement were data access facilitation (14/32, 44%) and migration toward a single data platform (10/32, 31%). CONCLUSIONS: By identifying the current state and needs of the data community onsite, this study enables us to focus our resources on combating the challenges having the greatest impact on researchers. The current state parallels that of the national landscape. By ensuring protection of privacy while achieving efficient data access, research institutions will be able to maximize their research capacity, a crucial step towards achieving the ultimate and shared goal between all stakeholders-to better health outcomes. PMID- 29759957 TI - A Mobile Health Intervention to Reduce Pain and Improve Health (MORPH) in Older Adults With Obesity: Protocol for the MORPH Trial. AB - BACKGROUND: Chronic pain is a complex, age-related health issue that affects both physical functioning and quality of life. Because the impact of chronic pain is worsened by obesity and inactivity, nonpharmacological interventions that promote movement, reduce sitting, and aid in weight loss are needed to help manage pain symptoms among older adults with chronic pain. OBJECTIVE: The Mobile Intervention to Reduce Pain and Improve Health (MORPH) pilot trial aims to develop and test the feasibility and acceptability of a novel, patient-centered intervention to reduce chronic pain and improve physical functioning in older adults, leveraging the combination of telecoaching and individually adaptive mHealth tools to decrease both body mass and sedentary behavior. METHODS: MORPH comprises 2 phases, including a 1-year iterative development phase, and a 1-year pilot randomized controlled trial (RCT). During the development phase, representative participants will engage in one-on-one structured interviews and a 1-week field test. The resulting feedback will be used to guide the development of the finalized MORPH intervention package. During the second phase, the finalized intervention will be tested in a pilot RCT (N=30) in which older adult participants with chronic pain and obesity will be assigned to receive the 12 week MORPH intervention or to a waitlist control. Primary outcomes include self reported pain symptoms and physical function. RESULTS: Phase 1 recruitment is ongoing as of December 2017. CONCLUSIONS: The MORPH intervention brings together a strong body of evidence using group-based behavioral intervention designs with contemporary mHealth principles, allowing for intervention when and where it matters the most. Given the ubiquity of smartphone devices and the popularity of consumer activity and weight monitors, the results of this study may serve to inform the development of scalable, socially driven behavioral pain management interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03377634; https://clinicaltrials.gov/ct2/show/NCT03377634 (Archived by WebCite at http://www.webcitation.org/6yj0J5Pan). REGISTERED REPORT IDENTIFIER: RR1 10.2196/9712. PMID- 29759960 TI - Temporal Associations Between Social Activity and Mood, Fatigue, and Pain in Older Adults With HIV: An Ecological Momentary Assessment Study. AB - BACKGROUND: Social isolation is associated with an increased risk for mental and physical health problems, especially among older persons living with HIV (PLWH). Thus, there is a need to better understand real-time temporal associations between social activity and mood- and health-related factors in this population to inform possible future interventions. OBJECTIVE: This study aims to examine real-time relationships between social activity and mood, fatigue, and pain in a sample of older PLWH. METHODS: A total of 20 older PLWH, recruited from the University of California, San Diego HIV Neurobehavioral Research Program in 2016, completed smartphone-based ecological momentary assessment (EMA) surveys 5 times per day for 1 week. Participants reported their current social activity (alone vs not alone and number of social interactions) and levels of mood (sadness, happiness, and stress), fatigue, and pain. Mixed-effects regression models were used to analyze concurrent and lagged associations among social activity, mood, fatigue, and pain. RESULTS: Participants (mean age 58.8, SD 4.3 years) reported being alone 63% of the time, on average, (SD 31.5%) during waking hours. Being alone was related to lower concurrent happiness (beta=-.300; 95% CI -.525 to .079; P=.008). In lagged analyses, social activity predicted higher levels of fatigue later in the day (beta=-1.089; 95% CI -1.780 to -0.396; P=.002), and higher pain levels predicted being alone in the morning with a reduced likelihood of being alone as the day progressed (odds ratio 0.945, 95% CI 0.901-0.992; P=.02). CONCLUSIONS: The use of EMA elucidated a high rate of time spent alone among older PLWH. Promoting social activity despite the presence of pain or fatigue may improve happiness and psychological well-being in this population. PMID- 29759962 TI - Containing health myths in the age of viral misinformation. PMID- 29759963 TI - The Genetic Non-Discrimination Act: critical for promoting health and science in Canada. PMID- 29759959 TI - Health Care Professionals' Attitudes Toward, and Experiences of Using, a Culture Sensitive Smartphone App for Women with Gestational Diabetes Mellitus: Qualitative Study. AB - BACKGROUND: The increasing prevalence of gestational diabetes mellitus (GDM) among women of different ethnic backgrounds provides new challenges for health care professionals, who often find it difficult to provide information about the management of this disease to such individuals. Mobile health (mHealth) may act as a useful tool for blood sugar control and care process enhancement. However, little is known about health care professionals' experiences and attitudes toward the use of mHealth for women with GDM. OBJECTIVE: The aim of this study was to explore how health care professionals perceived the provision of care to pregnant women who managed their GDM using the culture-sensitive Pregnant+ app in a randomized controlled trial. METHODS: Individual interviews with 9 health care professionals providing care for women with GDM were conducted. Braun and Clark's method of thematic content analysis inspired the analysis. This study included health care professionals who were primarily responsible for providing care to participants with GDM in the Pregnant+ randomized controlled trial at 5 diabetes outpatient clinics in Oslo, Norway. RESULTS: Health care professionals perceived mHealth, particularly the Pregnant+ app, as an appropriate tool for the care of women with GDM, who were described as individuals comprising a heterogeneous, motivated group that could be easily approached with health-related information. Some participants reported challenges with respect to provision of advice to women with different food cultures. The advantages of the Pregnant+ app included provision of information that women could access at home, the information provided being perceived as trustworthy by health care professionals, the culture sensitivity of the app, and the convenience for women to register blood sugar levels. Technical problems, particularly those associated with the automatic transfer of blood glucose measurements, were identified as the main barrier to the use of the Pregnant+ app. Strict inclusion criteria and the inclusion of participants who could not speak Norwegian were the main challenges in the recruitment process for the randomized controlled trial. CONCLUSIONS: The findings of this study suggest that mHealth is a useful tool to enhance the care provided by health care professionals to women with GDM. Future mobile apps for the management of GDM should be developed by a trustworthy source and in cooperation with health care professionals. They should also be culture sensitive and should not exhibit technical problems. PMID- 29759964 TI - Risk of fragility fracture among patients with gout and the effect of urate lowering therapy. AB - BACKGROUND: Previous studies that quantified the risk of fracture among patients with gout and assessed the potential effect of urate-lowering therapy have provided conflicting results. Our study aims to provide better estimates of risk by minimizing the effect of selection bias and confounding on the observed association. METHODS: We used data from the Clinical Practice Research Datalink, which records primary care consultations of patients from across the United Kingdom. We identified patients with incident gout from 1990 to 2004 and followed them up until 2015. Each patient with gout was individually matched to 4 controls on age, sex and general practice. We calculated absolute rate of fracture and hazard ratios (HRs) using Cox regression models. Among patients with gout, we assessed the impact of urate-lowering therapy on fracture, and used landmark analysis and propensity score matching to account for immortal time bias and confounding by indication. RESULTS: We identified 31 781 patients with incident gout matched to 122 961 controls. The absolute rate of fracture was similar in both cases and controls (absolute rate = 53 and 55 per 10 000 person-years, respectively) corresponding to an HR of 0.97 (95% confidence interval 0.92-1.02). Our finding remained unchanged when we stratified our analysis by age and sex. We did not observe statistically significant differences in the risk of fracture among those prescribed urate-lowering therapy within 1 and 3 years after gout diagnosis. INTERPRETATION: Overall, gout was not associated with an increased risk of fracture. Urate-lowering drugs prescribed early during the course of disease had neither adverse nor beneficial effect on the long-term risk of fracture. PMID- 29759966 TI - Malignant intertrigo. PMID- 29759965 TI - Screening for impaired vision in community-dwelling adults aged 65 years and older in primary care settings. PMID- 29759967 TI - Cytisine for smoking cessation. PMID- 29759968 TI - Failure to monitor or prevent unintended pregnancy is the key intergenerational problem, not the pregnancy outcome. PMID- 29759961 TI - The Roles of Xenobiotic Receptors: Beyond Chemical Disposition. AB - Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development. PMID- 29759970 TI - Patients seeking more involvement at medical meetings. PMID- 29759969 TI - The authors respond to "Failure to monitor or prevent unintended pregnancy is the key intergenerational problem, not the pregnancy outcome". PMID- 29759971 TI - Making the best of Canada's worsening residency mismatch. PMID- 29759972 TI - Outdated contract for rural doctors is affecting patient care. PMID- 29759975 TI - Restoring the switch for cancer cell death: Targeting the apoptosis signaling pathway. AB - PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new. The pharmacologic restoration of apoptotic functions, either by blocking the action of antiapoptotic proteins/regulators (e.g., through investigational therapies such as inhibitors of apoptosis proteins, SMAC [second mitochondria-derived activator of caspases] mimetics, MDM2 [murine double minute 2] antagonists) or by inducing apoptosis (e.g., through investigational agonistic monoclonal antibodies or fusion proteins), holds robust potential for cancer pharmacotherapy. Notably, BH domain 3 (BH3) mimetics, a new class of small molecules that block the action antiapoptotic proteins, are touted a success for apoptosis-based targeted therapy. Venetoclax, a synthetic peptide that belongs to this class of BH3 mimetics, is currently approved by the Food and Drug Administration for the treatment of relapsed/refractory chronic lymphocytic leukemia in patients with 17p deletion as a single agent. This agent has been increasingly used either alone or as part of combination therapy for diverse hematologic malignancies in clinical trials. CONCLUSION: Advances in the understanding of molecular mechanisms of apoptosis have given rise to more refined targeted therapies for diverse malignancies, with the goal to improve survival outcome while sparing treatment-related toxicities. PMID- 29759974 TI - Ceramide Transporter CERT Is Involved in Muscle Insulin Signaling Defects Under Lipotoxic Conditions. AB - One main mechanism of insulin resistance (IR), a key feature of type 2 diabetes, is the accumulation of saturated fatty acids (FAs) in the muscles of obese patients with type 2 diabetes. Understanding the mechanism that underlies lipid induced IR is an important challenge. Saturated FAs are metabolized into lipid derivatives called ceramides, and their accumulation plays a central role in the development of muscle IR. Ceramides are produced in the endoplasmic reticulum (ER) and transported to the Golgi apparatus through a transporter called CERT, where they are converted into various sphingolipid species. We show that CERT protein expression is reduced in all IR models studied because of a caspase dependent cleavage. Inhibiting CERT activity in vitro potentiates the deleterious action of lipotoxicity on insulin signaling, whereas overexpression of CERT in vitro or in vivo decreases muscle ceramide content and improves insulin signaling. In addition, inhibition of caspase activity prevents ceramide-induced insulin signaling defects in C2C12 muscle cells. Altogether, these results demonstrate the importance of physiological ER-to-Golgi ceramide traffic to preserve muscle cell insulin signaling and identify CERT as a major actor in this process. PMID- 29759977 TI - Correction: Non-centrosomal epidermal microtubules act in parallel to LET 502/ROCK to promote C. elegans elongation (doi:10.1242/dev.126615). PMID- 29759973 TI - Enhanced Glucose Control Following Vertical Sleeve Gastrectomy Does Not Require a beta-Cell Glucagon-Like Peptide 1 Receptor. AB - Bariatric surgeries, including vertical sleeve gastrectomy (VSG), resolve diabetes in 40-50% of patients. Studies examining the molecular mechanisms underlying this effect have centered on the role of the insulinotropic glucagon like peptide 1 (GLP-1), in great part because of the ~10-fold rise in its circulating levels after surgery. However, there is currently debate over the role of direct beta-cell signaling by GLP-1 to mediate improved glucose tolerance following surgery. In order to assess the importance of beta-cell GLP-1 receptor (GLP-1R) for improving glucose control after VSG, a mouse model of this procedure was developed and combined with a genetically modified mouse line allowing an inducible, beta-cell-specific Glp1r knockdown (Glp1rbeta-cell-ko). Mice with VSG lost ~20% of body weight over 30 days compared with sham-operated controls and had a ~60% improvement in glucose tolerance. Isolated islets from VSG mice had significantly greater insulin responses to glucose than controls. Glp1r knockdown in beta-cells caused glucose intolerance in diet-induced obese mice compared with obese controls, but VSG improved glycemic profiles to similar levels during oral and intraperitoneal glucose challenges in Glp1rbeta-cell-ko and Glp1rWT mice. Therefore, even though the beta-cell GLP-1R seems to be important for maintaining glucose tolerance in obese mice, in these experiments it is dispensable for the improvement in glucose tolerance after VSG. Moreover, the metabolic physiology activated by VSG can overcome the deficits in glucose regulation caused by lack of beta-cell GLP-1 signaling in obesity. PMID- 29759976 TI - Missed opportunities for prevention of vertical HIV transmission in Canada, 1997 2016: a surveillance study. AB - BACKGROUND: Vertical HIV transmission has declined in Canada, but missed opportunities for prevention continue to occur. We sought to determine the adequacy, and changes over time in adequacy, of uptake of maternal and neonatal antiretroviral therapy for the prevention of vertical HIV transmission, and to determine the vertical transmission rate over time and according to adequacy of antenatal antiretroviral therapy during the combination antiretroviral therapy era in Canada. METHODS: The Canadian Perinatal HIV Surveillance Program collects data annually through retrospective chart review concerning HIV-infected women and their infants. We determined receipt of adequate antiretroviral treatment (antenatal combination antiretroviral treatment for >= 4 wk, intrapartum intravenous zidovudine treatment and 4-6 wk of infant oral zidovudine treatment) and predictors of inadequate antenatal combination antiretroviral therapy (none or < 4 wk) in Canada in 1997-2016. RESULTS: We identified 3785 mother-infant pairs. Uptake of 4 weeks or more of antenatal combination antiretroviral therapy increased over time across all provinces/territories and regardless of maternal race/ethnicity or risk category (p < 0.001). During 2011-2016, 92 women (6.5%) received no or less than 4 weeks of antenatal combination antiretroviral therapy, 146 women (10.7%) received no intrapartum zidovudine treatment, and 43 infants (3.1%) received less than 4 weeks of zidovudine treatment. In multivariate analysis restricted to 2011-2016, higher uptake of adequate antenatal combination antiretroviral therapy was seen among black women than among Indigenous (odds ratio [OR] 2.99, 95% confidence interval [CI] 1.23-7.26) or white (OR 1.87, 95% CI 0.99-1.27) women and in British Columbia/Yukon Territory than in Alberta (OR 3.31, 95% CI 1.06-10.32), Ontario (OR 3.16, 95% CI 1.08-9.26) or Quebec (OR 3.44, 95% CI 1.09-10.84). Among the 14 vertical HIV transmission events during 2011 2016 (vertical transmission rate 1.0%), maternal HIV infection was diagnosed before the onset of labour in 5 cases, and only 2 women received adequate antenatal combination antiretroviral therapy. INTERPRETATION: Efforts to improve timely access to care, HIV screening and treatment for all women, combined with enhanced resources targeting populations at increased risk for HIV infection, will be needed if vertical HIV transmission is to be eliminated in Canada. PMID- 29759979 TI - Margaret McCartney: Can we now talk openly about the risks of screening? PMID- 29759980 TI - Understanding axon guidance: are we nearly there yet? AB - During nervous system development, neurons extend axons to reach their targets and form functional circuits. The faulty assembly or disintegration of such circuits results in disorders of the nervous system. Thus, understanding the molecular mechanisms that guide axons and lead to neural circuit formation is of interest not only to developmental neuroscientists but also for a better comprehension of neural disorders. Recent studies have demonstrated how crosstalk between different families of guidance receptors can regulate axonal navigation at choice points, and how changes in growth cone behaviour at intermediate targets require changes in the surface expression of receptors. These changes can be achieved by a variety of mechanisms, including transcription, translation, protein-protein interactions, and the specific trafficking of proteins and mRNAs. Here, I review these axon guidance mechanisms, highlighting the most recent advances in the field that challenge the textbook model of axon guidance. PMID- 29759981 TI - Abeta1-42 triggers the generation of a retrograde signaling complex from sentinel mRNAs in axons. AB - Neurons frequently encounter neurodegenerative signals first in their periphery. For example, exposure of axons to oligomeric Abeta1-42 is sufficient to induce changes in the neuronal cell body that ultimately lead to degeneration. Currently, it is unclear how the information about the neurodegenerative insult is transmitted to the soma. Here, we find that the translation of pre-localized but normally silenced sentinel mRNAs in axons is induced within minutes of Abeta1 42 addition in a Ca2+-dependent manner. This immediate protein synthesis following Abeta1-42 exposure generates a retrograde signaling complex including vimentin. Inhibition of the immediate protein synthesis, knock-down of axonal vimentin synthesis, or inhibition of dynein-dependent transport to the soma prevented the normal cell body response to Abeta1-42 These results establish that CNS axons react to neurodegenerative insults via the local translation of sentinel mRNAs encoding components of a retrograde signaling complex that transmit the information about the event to the neuronal soma. PMID- 29759982 TI - Expression variation and covariation impair analog and enable binary signaling control. AB - Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. Such high variation is beneficial for population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here, we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5-15%, compatible with accurate single cell transmission. Focusing on bimodal ERK signaling, we show that variation and covariation in MEK and ERK expression improves controllability of the percentage of activated cells, demonstrating how variation and covariation in expression enables population-level control of binary cell-fate decisions. Together, our study argues for a control principle whereby low expression variation enables accurate control of analog single-cell signaling, while increased variation, covariation, and numbers of pathway components are required to widen the stimulus range over which external inputs regulate binary cell activation to enable precise control of the fraction of activated cells in a population. PMID- 29759985 TI - What interests should be disclosed to journals? PMID- 29759978 TI - The developmental origin of brain tumours: a cellular and molecular framework. AB - The development of the nervous system relies on the coordinated regulation of stem cell self-renewal and differentiation. The discovery that brain tumours contain a subpopulation of cells with stem/progenitor characteristics that are capable of sustaining tumour growth has emphasized the importance of understanding the cellular dynamics and the molecular pathways regulating neural stem cell behaviour. By focusing on recent work on glioma and medulloblastoma, we review how lineage tracing contributed to dissecting the embryonic origin of brain tumours and how lineage-specific mechanisms that regulate stem cell behaviour in the embryo may be subverted in cancer to achieve uncontrolled proliferation and suppression of differentiation. PMID- 29759983 TI - High-throughput discovery of functional disordered regions: investigation of transactivation domains. AB - Over 40% of proteins in any eukaryotic genome encode intrinsically disordered regions (IDRs) that do not adopt defined tertiary structures. Certain IDRs perform critical functions, but discovering them is non-trivial as the biological context determines their function. We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality conferring patterns in their protein sequence are inferred through statistical learning. Using yeast HSF1 transcription factor-based assay, we discovered IDRs that function as transactivation domains (TADs) by screening a random sequence library and a designed library consisting of variants of 13 diverse TADs. Using machine learning, we find that segments devoid of positively charged residues but with redundant short sequence patterns of negatively charged and aromatic residues are a generic feature for TAD functionality. We anticipate that investigating defined sequence libraries using IDR-Screen for specific functions can facilitate discovering novel and functional regions of the disordered proteome as well as understand the impact of natural and disease variants in disordered segments. PMID- 29759986 TI - Trends in Cannabis and Cigarette Use Among Parents With Children at Home: 2002 to 2015. AB - BACKGROUND: In this study, we investigated trends in cannabis use among parents with children at home in the United States and estimated changes in prevalence of any cannabis use and daily cannabis use among parents who identified as cigarette smokers and nonsmokers with children in the home from 2002 to 2015. METHODS: The National Survey on Drug Use and Health is an annual, nationally representative, cross-sectional study conducted in the United States. Using logistic regression models, associations between cigarette smoking and any past-month and daily past month cannabis use among parents with children in the home from 2002 to 2015 were estimated. Moderation of these associations by demographics and trends over time was examined. RESULTS: Past-month cannabis use among parents with children in the home increased from 4.9% in 2002 to 6.8% in 2015, whereas cigarette smoking declined from 27.6% to 20.2%. Cannabis use increased from 11.0% in 2002 to 17.4% in 2015 among cigarette-smoking parents and from 2.4% to 4.0% among non-cigarette smoking parents (P value for trends <.0001). Cannabis use was nearly 4 times more common among cigarette smokers versus nonsmokers (17.4% vs 4.0%; adjusted odds ratio = 3.88 [3.16-4.75]), as was daily cannabis use (4.6% vs 0.8%; adjusted odds ratio = 3.70 [2.46-5.55]). The overall percentage of parents who used either cigarettes and/or cannabis decreased from 29.7% in 2002 to 23.5% in 2015. CONCLUSIONS: Efforts to decrease secondhand smoke exposure via cigarette smoking cessation may be complicated by increases in cannabis use. Educating parents about secondhand cannabis smoke exposure should be integrated into public education programs on secondhand tobacco smoke exposure. PMID- 29759987 TI - Parental Desensitization to Gun Violence in PG-13 Movies. AB - : : media-1vid110.1542/5745216462001PEDS-VA_2017-3491Video Abstract OBJECTIVE: To assess effects of justified versus unjustified screen violence on parents' willingness to allow children to view films that contain extensive gun violence. METHODS: A national US sample of 610 parents with at least 1 child between ages 6 and 17 was randomly assigned to view a series of four 90-second video clips from popular films depicting violent gun use under either justified or unjustified conditions. Graphic consequences were removed to mimic the violence common in PG 13 movies. Parents reported their perceived justification for the violence, their emotional reaction while viewing it, the minimum age they would consider appropriate for viewing the film, and whether they would allow their own child to view it. Predictors included experimental condition, viewing order, child age, and recent moviegoing. Growth curve modeling determined the effects of the predictors on both intercepts and slopes of viewing order. RESULTS: Parents were less emotionally upset and more accepting of child viewing for justified than unjustified gun violence, with perceptions of justification better predictors of parental restriction than emotion. Nevertheless, with the exception of parents with extensive moviegoing habits, parents viewed justified violence as appropriate for adolescents starting at age 15, older than the PG-13 rating suggests. CONCLUSIONS: Parents are less restrictive of child viewing of gun violence in PG-13 movies when it features characters whose weapon use is seen as justified. The apparent acceptance of rising gun violence in PG-13 movies may be partly attributable to the perception that the violence in those films is justified. PMID- 29759984 TI - NDF, a nucleosome-destabilizing factor that facilitates transcription through nucleosomes. AB - Our understanding of transcription by RNA polymerase II (Pol II) is limited by our knowledge of the factors that mediate this critically important process. Here we describe the identification of NDF, a nucleosome-destabilizing factor that facilitates Pol II transcription in chromatin. NDF has a PWWP motif, interacts with nucleosomes near the dyad, destabilizes nucleosomes in an ATP-independent manner, and facilitates transcription by Pol II through nucleosomes in a purified and defined transcription system as well as in cell nuclei. Upon transcriptional induction, NDF is recruited to the transcribed regions of thousands of genes and colocalizes with a subset of H3K36me3-enriched regions. Notably, the recruitment of NDF to gene bodies is accompanied by an increase in the transcript levels of many of the NDF-enriched genes. In addition, the global loss of NDF results in a decrease in the RNA levels of many genes. In humans, NDF is present at high levels in all tested tissue types, is essential in stem cells, and is frequently overexpressed in breast cancer. These findings indicate that NDF is a nucleosome destabilizing factor that is recruited to gene bodies during transcriptional activation and facilitates Pol II transcription through nucleosomes. PMID- 29759988 TI - Transient Telomerase Inhibition with Imetelstat Impacts DNA Damage Signals and Cell-Cycle Kinetics. AB - Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear chromosomes and contributes to proper telomere-loop (T-loop) formation. Formation of the T-loop, an obligate step before cell division can proceed, requires the generation of a 3'-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, it is discovered that telomerase activity is critical for efficient cell-cycle progression using transient chemical inhibition by the telomerase inhibitor, imetelstat. Telomerase inhibition changed cell cycle kinetics and increased the proportion of cells in G2-phase, suggesting delayed clearance through this checkpoint. Investigating the possible contribution of unstructured telomere ends to these cell-cycle distribution changes, it was observed that imetelstat treatment induced gammaH2AX DNA damage foci in a subset of telomerase-positive cells but not telomerase-negative primary human fibroblasts. Chromatin-immunoprecipitation with gammaH2AX antibodies demonstrated imetelstat treatment-dependent enrichment of this DNA damage marker at telomeres. Notably, the effects of telomerase inhibition on cell cycle profile alterations were abrogated by pharmacological inhibition of the DNA-damage-repair transducer, ATM. Also, imetelstat potentiation of etoposide, a DNA-damaging drug that acts preferentially during S-G2 phases of the cell cycle, depends on functional ATM signaling. Thus, telomerase inhibition delays the removal of ATM-dependent DNA damage signals from telomeres in telomerase-positive cancer cells and interferes with cell cycle progression through G2Implications: This study demonstrates that telomerase activity directly facilitates the progression of the cell cycle through modulation of transient telomere dysfunction signals. Mol Cancer Res; 16(8); 1215-25. (c)2018 AACR. PMID- 29759989 TI - Novel Regulation of Integrin Trafficking by Rab11-FIP5 in Aggressive Prostate Cancer. AB - The laminin-binding integrins, alpha3beta1 and alpha6beta1, are needed for tumor metastasis and their surface expression is regulated by endocytic recycling. beta1 integrins share the Rab11 recycling machinery, but the trafficking of alpha3beta1 and alpha6beta1 are distinct by an unknown mechanism. Using a mouse PDX tumor model containing human metastatic prostate cancer, Rab11 family interacting protein 5 (Rab11-FIP5) was identified as a lead candidate for alpha6beta1 trafficking. Rab11-FIP5 and its membrane-binding domain were required for alpha6beta1 recycling, without affecting the other laminin-binding integrin (i.e., alpha3beta1) or unrelated membrane receptors like CD44, transferrin receptor, or E-cadherin. Depletion of Rab11-FIP5 resulted in the intracellular accumulation of alpha6beta1 in the Rab11 recycling compartment, loss of cell migration on laminin, and an unexpected loss of alpha6beta1 recycling in cell cell locations. Taken together, these data demonstrate that alpha6beta1 is distinct from alpha3beta1 via Rab11-FIP5 recycling and recycles in an unexpected cell-cell location.Implications: Rab11-FIP5-dependent alpha6beta1 integrin recycling may be selectively targeted to limit migration of prostate cancer cells into laminin-rich tissues. Mol Cancer Res; 16(8); 1319-31. (c)2018 AACR. PMID- 29759991 TI - What's happening in Neurology(r). PMID- 29759992 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29759993 TI - What's happening in Neurology(r)Genetics. PMID- 29759990 TI - Epigenetic Targeting of Adipocytes Inhibits High-Grade Serous Ovarian Cancer Cell Migration and Invasion. AB - Ovarian cancer (OC) cells frequently metastasize to the omentum, and adipocytes play a significant role in ovarian tumor progression. Therapeutic interventions targeting aberrant DNA methylation in ovarian tumors have shown promise in the clinic, but the effects of epigenetic therapy on the tumor microenvironment are understudied. Here, we examined the effect of adipocytes on OC cell behavior in culture and impact of targeting DNA methylation in adipocytes on OC metastasis. The presence of adipocytes increased OC cell migration and invasion, and proximal and direct coculture of adipocytes increased OC proliferation alone or after treatment with carboplatin. Treatment of adipocytes with hypomethylating agent guadecitabine decreased migration and invasion of OC cells toward adipocytes. Subcellular protein fractionation of adipocytes treated with guadecitabine revealed decreased DNA methyltransferase 1 (DNMT1) levels even in the presence of DNA synthesis inhibitor, aphidicolin. Methyl-Capture- and RNA-sequencing analysis of guadecitabine-treated adipocytes revealed derepression of tumor-suppressor genes and epithelial-mesenchymal transition inhibitors. SUSD2, a secreted tumor suppressor downregulated by promoter CpG island methylation in adipocytes, was upregulated after guadecitabine treatment, and recombinant SUSD2 decreased OC cell migration and invasion. Integrated analysis of the methylomic and transcriptomic data identified pathways associated with inhibition of matrix metalloproteases and fatty acid alpha-oxidation, suggesting a possible mechanism of how epigenetic therapy of adipocytes decreases metastasis. In conclusion, the effect of DNMT inhibitor on fully differentiated adipocytes suggests that hypomethylating agents may affect the tumor microenvironment to decrease cancer cell metastasis.Implications: Epigenetic targeting of tumor microenvironment can affect metastatic behavior of ovarian cancer cells. Mol Cancer Res; 16(8); 1226 40. (c)2018 AACR. PMID- 29759994 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29759995 TI - Lymphoplasmacyte-rich meningioma involving the whole intracranial dura mater. PMID- 29759996 TI - Pearls & Oy-sters: Relapse of anti-NMDA receptor encephalitis after prior first- and second-line immunotherapy. PMID- 29759997 TI - Editors' note: Olfaction and incident Parkinson disease in US white and black older adults. PMID- 29759999 TI - Author response: Olfaction and incident Parkinson disease in US white and black older adults. PMID- 29759998 TI - Reader response: Olfaction and incident Parkinson disease in US white and black older adults. PMID- 29760000 TI - Editors' note: Teaching Video NeuroImages: Palsy of conjugate horizontal gaze and face due to isolated abducens nuclear infarction. PMID- 29760001 TI - Reader response: Teaching Video NeuroImages: Palsy of conjugate horizontal gaze and face due to isolated abducens nuclear infarction. PMID- 29760002 TI - Author response: Teaching Video NeuroImages: Palsy of conjugate horizontal gaze and face due to isolated abducens nuclear infarction. PMID- 29760003 TI - Teaching Video NeuroImages: Palsy of conjugate horizontal gaze and face due to isolated abducens nuclear infarction. PMID- 29760004 TI - Clinical Reasoning: A 77-year-old man presenting with episodic expressive aphasia. PMID- 29760005 TI - Clinical Reasoning: Progressive cognitive decline, cerebellar ataxia, recurrent myoclonus, and epilepsy. PMID- 29760006 TI - Teaching Video NeuroImages: Figure 8 head-shaking stereotypy in rhombencephalosynapsis. PMID- 29760007 TI - Eradicating Polio. PMID- 29760008 TI - Acute small bowel obstruction in a child with a strict raw vegan diet. PMID- 29760010 TI - Home oximetry to screen for obstructive sleep apnoea in Down syndrome. AB - OBJECTIVE: Children with Down syndrome are at high risk of obstructive sleep apnoea (OSA) and screening is recommended. Diagnosis of OSA should be confirmed with multichannel sleep studies. We aimed to determine whether home pulse oximetry (HPO) discriminates children at high risk of OSA, who need further diagnostic multichannel sleep studies. DESIGN: Cross-sectional prospective study in a training sample recruited through three UK centres. Validation sample used single-centre retrospective analysis of clinical data. PATIENTS: Children with Down syndrome aged 0.5-6 years. INTERVENTION: Diagnostic multichannel sleep study and HPO. MAIN OUTCOME MEASURES: Sensitivity and specificity of HPO to predict moderate-to-severe OSA. RESULTS: 161/202 children with Down syndrome met quality criteria for inclusion and 25 had OSA. In this training sample, the best HPO parameter predictors of OSA were the delta 12 s index >0.555 (sensitivity 92%, specificity 65%) and 3% oxyhaemoglobin (SpO2) desaturation index (3% ODI)>6.15 dips/hour (sensitivity 92%, specificity 63%). Combining variables (delta 12 s index, 3% ODI, mean and minimum SpO2) achieved sensitivity of 96% but reduced specificity to 52%. All predictors retained or improved sensitivity in a clinical validation sample of 50 children with variable loss of specificity, best overall was the delta 12 s index, a measure of baseline SpO2 variability (sensitivity 92%; specificity 63%). CONCLUSIONS: HPO screening could halve the number of children with Down syndrome needing multichannel sleep studies and reduce the burden on children, families and health services alike. This approach offers a practical universal screening approach for OSA in Down syndrome that is accessible to the non-specialist paediatrician. PMID- 29760011 TI - Preserving oral history: 50 years of paediatric nephrology in Europe. PMID- 29760009 TI - Randomised controlled trial of a theory-based behavioural intervention to reduce formula milk intake. AB - OBJECTIVE: To assess the efficacy of a theory-based behavioural intervention to prevent rapid weight gain in formula milk-fed infants. DESIGN: In this single (assessor) blind, randomised controlled trial, 669 healthy full-term infants receiving formula milk within 14 weeks of birth were individually randomised to intervention (n=340) or attention-matched control (n=329) groups. The intervention aimed to reduce formula milk intakes, and promote responsive feeding and growth monitoring to prevent rapid weight gain (>=+0.67 SD scores (SDS)). It was delivered to mothers by trained facilitators up to infant age 6 months through three face-to-face contacts, two telephone contacts and written materials. RESULTS: Retention was 93% (622) at 6 months, 88% (586) at 12 months and 94% attended >=4/5 sessions. The intervention strengthened maternal attitudes to following infant feeding recommendations, reduced reported milk intakes at ages 3 (-14%; intervention vs control infants), 4 (-12%), 5 (-9%) and 6 (-7%) months, slowed initial infant weight gain from baseline to 6 months (mean change 0.32 vs 0.42 SDS, baseline-adjusted difference (intervention vs control) -0.08 (95% CI -0.17 to -0.004) SDS), but had no effect on the primary outcome of weight gain to 12 months (baseline-adjusted difference -0.04 (-0.17, 0.10) SDS). By 12 months, 40.3% of infants in the intervention group and 45.9% in the control group showed rapid weight gain (OR 0.84, 95% CI 0.59 to 1.17). CONCLUSIONS: Despite reducing milk intakes and initial weight gain, the intervention did not alter the high prevalence of rapid weight gain to age 12 months suggesting the need for sustained intervention. TRIAL REGISTRATION NUMBER: ISRCTN20814693. PMID- 29760014 TI - Hospitals as anchor institutions: how the NHS can act beyond healthcare to support communities. PMID- 29760012 TI - Agreement between core laboratory and study investigators for imaging scores in a thrombectomy trial. AB - PURPOSE: We aimed to assess the agreement between study investigators and the core laboratory (core lab) of a thrombectomy trial for imaging scores. METHODS: The Alberta Stroke Program Early CT Score (ASPECTS), the European Collaborative Acute Stroke Study (ECASS) hemorrhagic transformation (HT) classification, and the Thrombolysis In Cerebral Infarction (TICI) scores as recorded by study investigators were compared with the core lab scores in order to assess interrater agreement, using Cohen's unweighted and weighted kappa statistics. RESULTS: There were frequent discrepancies between study sites and core lab for all the scores. Agreement for ASPECTS and ECASS HT classification was less than substantial, with disagreement occurring in more than one-third of cases. Agreement was higher on MRI-based scores than on CT, and was improved after dichotomization on both CT and MRI. Agreement for TICI scores was moderate (with disagreement occurring in more than 25% of patients), and went above the substantial level (less than 10% disagreement) after dichotomization (TICI 0/1/2a vs 2b/3). CONCLUSION: Discrepancies between scores assessed by the imaging core lab and those reported by study sites occurred in a significant proportion of patients. Disagreement in the assessment of ASPECTS and day 1 HT scores was more frequent on CT than on MRI. The agreement for the dichotomized TICI score (the trial's primary outcome) was substantial, with less than 10% of disagreement between study sites and core lab. TRIAL REGISTRATION NUMBER: NCT02523261, Post results. PMID- 29760013 TI - Severity of cerebral vasospasm associated with development of collaterals following aneurysmal subarachnoid hemorrhage. AB - INTRODUCTION: Cerebral collateral circulation has been studied extensively in ischemic stroke where it has been shown to be a predictor of reperfusion, final infarct size, and outcome. Little is known about the significance of the collaterals in the setting of aneurysmal subarachnoid hemorrhage (aSAH). We sought to evaluate the effect of cerebral vasospasm on the development of cerebral collaterals following aneurysmal subarachnoid hemorrhage and the effects of the latter on delayed cerebral ischemia (DCI). METHODS: We retrospectively evaluated 64 aSAH patients with evidence of DCI between day 5 and 7, enrolled in a prospectively maintained observational cohort study. Angiograms were evaluated by four blinded neurointerventionalists. We compared good collateral grades to poor collateral grades, additionally we compared enrolled individuals with any collaterals versus patients who had no collaterals. RESULTS: Inter-rater reliability for collateral grades was substantial (weighted kappa 0.632). Mild vasospasm was more frequent in patients with poor collateral grades compared with patients with good collateral grades (32% vs 4% P=0.012). There was no difference between the collateral groups with regards to DCI, functional, or cognitive outcome. Patients adjudicated to have any collaterals were more likely to have severe vasospasm (62% vs 33% P=0.023) and less likely to have mild vasospasm (37% vs 9% P=0.007). In a multivariable model, vasospasm severity remained associated with collateral status, while aneurysm location was not. CONCLUSIONS: The severity of vasospasm following aSAH was associated with the development of collaterals. There was no difference between collateral grades with regards to DCI or outcome. PMID- 29760017 TI - Correction. PMID- 29760015 TI - Novel genomic findings in multiple myeloma identified through routine diagnostic sequencing. AB - AIMS: Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. METHODS: A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline. RESULTS: At least one mutation was found in 69 (80%) patients. Frequently mutated genes included TP53 (36%), KRAS (22.1%), NRAS (15.1%), FAM46C/DIS3 (8.1%) and TET2/FGFR3 (5.8%), including multiple mutations not previously described in myeloma. Importantly we observed TP53 mutations in the absence of a 17 p deletion in 8% of the cohort, highlighting the need for sequencing-based assessment in addition to cytogenetics to identify these high-risk patients. Multiple novel copy number changes and immunoglobulin heavy chain translocations are also discussed. CONCLUSIONS: Our results demonstrate that many clinically relevant genomic findings remain in multiple myeloma which have not yet been identified through large-scale sequencing efforts, and provide important mechanistic insights into plasma cell pathobiology. PMID- 29760016 TI - Diabetes-Induced Cardiomyocyte Passive Stiffening Is Caused by Impaired Insulin Dependent Titin Modification and Can Be Modulated by Neuregulin-1. AB - RATIONALE: Increased titin-dependent cardiomyocyte tension is a hallmark of heart failure with preserved ejection fraction associated with type-2 diabetes mellitus. However, the insulin-related signaling pathways that modify titin-based cardiomyocyte tension, thereby contributing to modulation of diastolic function, are largely unknown. OBJECTIVE: We aimed to determine how impaired insulin signaling affects titin expression and phosphorylation and thus increases passive cardiomyocyte tension, and whether metformin or neuregulin-1 (NRG-1) can correct disturbed titin modifications and increased titin-based stiffness. METHODS AND RESULTS: We used cardiac biopsies from human diabetic (n=23) and nondiabetic patients (n=19), cultured rat cardiomyocytes, left ventricular tissue from apolipoprotein E-deficient mice with streptozotocin-induced diabetes mellitus (n=12-22), and ZSF1 (obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid) rats (n=5-6) and analyzed insulin-dependent signaling pathways that modulate titin phosphorylation. Titin-based passive tension was measured using permeabilized cardiomyocytes. In human diabetic hearts, we detected titin hypophosphorylation at S4099 and hyperphosphorylation at S11878, suggesting altered activity of protein kinases; cardiomyocyte passive tension was significantly increased. When applied to cultured cardiomyocytes, insulin and metformin increased titin phosphorylation at S4010, S4099, and S11878 via enhanced ERK1/2 (extracellular signal regulated kinase 1/2) and PKCalpha (protein kinase Calpha) activity; NRG-1 application enhanced ERK1/2 activity but reduced PKCalpha activity. In apolipoprotein E-deficient mice, chronic treatment of streptozotocin-induced diabetes mellitus with NRG-1 corrected titin phosphorylation via increased PKG (protein kinase G) and ERK1/2 activity and reduced PKCalpha activity, which reversed the diabetes mellitus-associated changes in titin-based passive tension. Acute application of NRG-1 to obese ZSF1 rats with type-2 diabetes mellitus reduced end-diastolic pressure. CONCLUSIONS: Mechanistically, we found that impaired cGMP-PKG signaling and elevated PKCalpha activity are key modulators of titin-based cardiomyocyte stiffening in diabetic hearts. We conclude that by restoring normal kinase activities of PKG, ERK1/2, and PKCalpha, and by reducing cardiomyocyte passive tension, chronic NRG-1 application is a promising approach to modulate titin properties in heart failure with preserved ejection fraction associated with type-2 diabetes mellitus. PMID- 29760018 TI - Forces for Integration. PMID- 29760019 TI - Innovations in Primary Care: Garage Tinkerers and Great Deeds. PMID- 29760021 TI - Call for Papers: Learning From Practice Transformation. PMID- 29760020 TI - White Privilege in Health Care: Following Recognition With Action. PMID- 29760022 TI - Burnout and Scope of Practice in New Family Physicians. AB - PURPOSE: Family physicians report some of the highest levels of burnout, but no published work has considered whether burnout is correlated with the broad scope of care that family physicians may provide. We examined the associations between family physician scope of practice and self-reported burnout. METHODS: Secondary analysis of the 2016 National Family Medicine Graduate Survey respondents who provided outpatient continuity care (N = 1,617). We used bivariate analyses and logistic regression to compare self-report of burnout and measures of scope of practice including: inpatient medicine, obstetrics, pediatric ambulatory care, number of procedures and/or clinical content areas, and providing care outside the principal practice site. RESULTS: Forty-two percent of respondents reported feeling burned out from their work once a week or more. In bivariate analysis, elements of scope of practice associated with higher burnout rates included providing more procedures/clinical content areas (mean procedures/clinical areas: 7.49 vs 7.02; P = .02) and working in more settings than the principal practice site (1+ additional settings: 57.6% vs 48.4%: P = .001); specifically in the hospital (31.4% vs 24.2%; P = .002) and patient homes (3.3% vs 1.5%; P = .02). In adjusted analysis, practice characteristics significantly associated with lower odds of burnout were practicing inpatient medicine (OR = 0.70; 95% CI, 0.56-0.87; P = .0017) and obstetrics (OR = 0.64; 95% CI, 0.47-0.88; P = .0058). CONCLUSIONS: Early career family physicians who provide a broader scope of practice, specifically, inpatient medicine, obstetrics, or home visits, reported significantly lower rates of burnout. Our findings suggest that comprehensiveness is associated with less burnout, which is critical in the context of improving access to good quality, affordable care while maintaining physician wellness. PMID- 29760023 TI - Improving Prediction of Dementia in Primary Care. AB - PURPOSE: The Mini-Mental State Examination (MMSE) is one of the most widely used instruments to screen for cognitive deficits; however, this instrument alone is not sensitive enough to detect early symptoms of dementia. We aimed to investigate whether additionally using the Visual Association Test (VAT) improves the predictive value of the MMSE score for development of dementia. METHODS: Analyses were based on data from 2,690 primary care patients aged 70 to 78 years who participated in the Prevention of Dementia by Intensive Vascular Care (preDIVA) trial. We assessed change in the 30-point MMSE score over 2 years and the VAT score at 2 years-dichotomized as perfect (6 points) or imperfect (<=5 points)-and evaluated the predictive values of these tests for a diagnosis of dementia in the subsequent 4 to 6 years. Data were analyzed with logistic regression analysis. RESULTS: Patients having a decline of 2 points or more in total MMSE score over 2 years had an odds ratio of 3.55 (95% CI, 2.51-5.00) for developing dementia. Patients having the same decline in MMSE score plus an imperfect VAT score had an odds ratio of 9.55 (95% CI, 5.89-15.41) for developing dementia. A 1-point decline in MMSE score increased odds of dementia only when the VAT score was imperfect. Dementia risk for patients with a 2- or 3-point decrease in MMSE score and a perfect VAT score did not differ significantly from the average risk of the cohort as a whole. CONCLUSIONS: Administering the VAT in patients with a small decline on the MMSE over a 2-year period has substantial incremental value for identifying those at elevated risk for developing dementia. This simple test may help distinguish older adults who need further cognitive examination from those in whom a watchful waiting policy is justified. PMID- 29760024 TI - An Updated Analysis of Direct-to-Consumer Television Advertisements for Prescription Drugs. AB - PURPOSE: In 2015, the American Medical Association called for a ban of direct-to consumer advertising (DTCA) for prescription drugs. Yet, the pharmaceutical industry spends more than ever on broadcast advertisements, with national health care costs largely driven by drug spending. An evaluation of these ads is critical, as these advertisements can impact the frequency which patients ask their doctors about medications. METHODS: A content analysis of prime-time direct to-consumer ads was conducted across 4 major cable television networks. The ad content (n = 61) was coded for factual claims made regarding target conditions, appeals used, portrayal of medications, and lifestyle characteristics shown. RESULTS: We found a substantial decrease in the percentage of ads that conveyed information about the conditions being targeted, such as risk factors (16%) and prevalence (16%). Positive emotional appeals (94%) continued to be emphasized; yet there was decreased use of negative emotional appeals (51%), pointing to an overall more positive portrayal of a patient's experience with a medication. The lifestyles portrayed in the sample largely featured how products can enable more recreational activities (69%) and fewer ads (7%) presented alternatives to product use. CONCLUSIONS: Direct-to-consumer advertising continued to promote prescription drugs above educating the population. Improvement in the educational value of DTCA is likely to require regulatory action rather than reliance on self regulation by the pharmaceutical industry. PMID- 29760025 TI - Association of the Social Determinants of Health With Quality of Primary Care. AB - PURPOSE: In primary care, there is increasing recognition of the difficulty of treating patients' immediate health concerns when their overall well-being is shaped by underlying social determinants of health. We assessed the association of social complexity factors with the quality of care patients received in primary care settings. METHODS: Eleven social complexity factors were defined using administrative data on poverty, mental health, newcomer status, and justice system involvement from the Manitoba Population Research Data Repository. We measured the distribution of these factors among primary care patients who made at least 3 visits during 2010-2013 to clinicians in Manitoba, Canada. Using generalized linear mixed modeling, we measured 26 primary care indicators to compare the quality of care received by patients with 0 to 5 or more social complexity factors. RESULTS: Among 626,264 primary care patients, 54% were living with at least 1 social complexity factor, and 4% were living with 5 or more. Social complexity factors were strongly associated with poorer outcomes with respect to primary care indicators for prevention (eg, breast cancer screening; odds ratio [OR] = 0.77; 99% CI, 0.73-0.81), chronic disease management (eg, diabetes management; OR = 0.86; 99% CI, 0.79-0.92), geriatric care (eg, benzodiazepine prescriptions; OR = 1.63; 99% CI, 1.48-1.80), and use of health services (eg, ambulatory visits; OR = 1.09; 99% CI, 1.08-1.09). CONCLUSIONS: Linking health and social data demonstrates how social determinants are associated with primary care service provision. Our findings provide insight into the social needs of primary care populations, and may support the development of focused interventions to address social complexity in primary care. PMID- 29760029 TI - Free Children's Visits and General Practice Attendance. AB - PURPOSE: In July 2015, all children aged younger than 6 years gained free access to daytime and out-of-hours general practice services in the Republic of Ireland. Although 30% previously had free access, 70% did not. METHODS: To examine subsequent changes in service use, we retrospectively analyzed anonymized visitation data from 8 general practices in North Dublin providing daytime service and their local out-of-hours service, comparing the 1 year before and the 1 year after introduction of free care. RESULTS: In the year after granting of free general practice care for children younger than 6 years, 9.4% more children attended the daytime services and 20.1% more children were seen in the out-of hours services. Annual number of visits by patients increased by 28.7% for daytime services and by 25.7% for out-of-hours services, translating to 6,682 more visits overall. Average visitation rate for children this age increased from 2.77 visits per year to 3.25 visits per year for daytime services, but changed little for out-of-hours services, from 1.52 visits per year to 1.59 visits per year. CONCLUSIONS: Offering free childhood general practice services led to a dramatic increase in visits. This increase has implications for future health care service planning in mixed public and privately funded systems. PMID- 29760028 TI - Roles and Functions of Community Health Workers in Primary Care. AB - Community health workers have potential to enhance primary care access and quality, but remain underutilized. To provide guidance on their integration, we characterized roles and functions of community health workers in primary care through a literature review and synthesis. Analysis of 30 studies identified 12 functions (ie, care coordination, health coaching, social support, health assessment, resource linking, case management, medication management, remote care, follow-up, administration, health education, and literacy support) and 3 prominent roles representing clusters of functions: clinical services, community resource connections, and health education and coaching. We discuss implications for community health worker training and clinical support in primary care. PMID- 29760027 TI - Case Management in Primary Care for Frequent Users of Health Care Services: A Mixed Methods Study. AB - PURPOSE: This study aimed to evaluate the effects of the V1SAGES case management intervention (Vulnerable Patients in Primary Care: Nurse Case Management and Self management Support) for frequent users of health care services with chronic disease and complex care needs on psychological distress and patient activation. METHODS: We used a 2-phase sequential mixed methods design. The first phase was a pragmatic randomized controlled trial with intention-to-treat analysis that measured the effects of the intervention compared with usual care on psychological distress and patient activation before and after 6 months. The second phase had a qualitative descriptive design and entailed thematic analysis of in-depth interviews (25 patients, 6 case management nurses, 9 health managers) and focus groups (8 patients' spouses, 21 family physicians) to understand stakeholders' perceived effects of the intervention on patients. RESULTS: A total of 247 patients were randomized into the intervention group (n = 126) or the control group (n = 121). Compared with usual care, the intervention reduced psychological distress (odds ratio = 0.43; 95% CI, 0.19-0.95, P = .04), but did not have any significant effect on patient activation (P = .43). Qualitative results suggested that patients and their spouses benefitted from the case management intervention, gaining a sense of security, and stakeholders noted better patient self-management of health. CONCLUSIONS: Together, our study's quantitative and qualitative results suggest that case management reduces psychological distress, making patients and caregivers feel more secure, whereas impact on self-management is unclear. Case management is a promising avenue to improve outcomes among frequent users of health care with complex needs. PMID- 29760026 TI - Care Transitions From Patient and Caregiver Perspectives. AB - PURPOSE: Despite concerted actions to streamline care transitions, the journey from hospital to home remains hazardous for patients and caregivers. Remarkably little is known about the patient and caregiver experience during care transitions, the services they need, or the outcomes they value. The aims of this study were to (1) describe patient and caregiver experiences during care transitions and (2) characterize patient and caregiver desired outcomes of care transitions and the health services associated with them. METHODS: We interviewed 138 patients and 110 family caregivers recruited from 6 health networks across the United States. We conducted 34 homogenous focus groups (103 patients, 65 caregivers) and 80 key informant interviews (35 patients, 45 caregivers). Audio recordings were transcribed and analyzed using principles of grounded theory to identify themes and the relationship between them. RESULTS: Patients and caregivers identified 3 desired outcomes of care transition services: (1) to feel cared for and cared about by medical providers, (2) to have unambiguous accountability from the health care system, and (3) to feel prepared and capable of implementing care plans. Five care transition services or provider behaviors were linked to achieving these outcomes: (1) using empathic language and gestures, (2) anticipating the patient's needs to support self-care at home, (3) collaborative discharge planning, (4) providing actionable information, and (5) providing uninterrupted care with minimal handoffs. CONCLUSIONS: Clear accountability, care continuity, and caring attitudes across the care continuum are important outcomes for patients and caregivers. When these outcomes are achieved, care is perceived as excellent and trustworthy. Otherwise, the care transition is experienced as transactional and unsafe, and leaves patients and caregivers feeling abandoned by the health care system. PMID- 29760031 TI - Creating a Centralized Infrastructure to Facilitate Medical Education Research. AB - PURPOSE: Building research capacity and increasing scholarly productivity are identified needs of the specialty of family medicine. The Accreditation Council for Graduate Medical Education (ACGME) has increased the scholarly requirements for residency programs, placing even more pressure on faculty to be productive in the scholarly realm. The Council of Academic Family Medicine Educational Research Alliance (CERA) was created by volunteer members of the specialty with shared interests in overcoming barriers and increasing scholarly production. METHODS: CERA has developed the infrastructure and expertise to regularly conduct omnibus surveys of key family medicine educational leaders. Proposals are centrally collected and competitively chosen. The omnibus survey process includes collaboration with experienced mentors, centralized institutional review board clearance, pilot testing, and centralized data collection. The survey results are disseminated back to research teams for presentation and publication of the findings. RESULTS: To date, over 115 research teams have had their projects included in CERA omnibus surveys. Projects have been led by research teams from across the country and with a wide variety of research experience. This collaborative work has resulted in more than 75 scientific presentations and over 55 peer-reviewed papers in the medical literature. The raw data are now available online and serve as a repository for future secondary analysis and as an educational resource. CONCLUSIONS: The CERA infrastructure has allowed a large number of research teams to conduct meaningful scholarship at a fraction of the typical cost in terms of time and energy. CERA has expanded family medicine research by removing barriers for teams with limited experience or resources. PMID- 29760030 TI - Nurse Practitioner-Physician Comanagement: A Theoretical Model to Alleviate Primary Care Strain. AB - PURPOSE: Various models of care delivery have been investigated to meet the increasing demands in primary care. One proposed model is comanagement of patients by more than 1 primary care clinician. Comanagement has been investigated in acute care with surgical teams and in outpatient settings with primary care physicians and specialists. Because nurse practitioners are increasingly managing patient care as independent clinicians, our study objective was to propose a model of nurse practitioner-physician comanagement. METHODS: We conducted a literature search using the following key words: comanagement; primary care; nurse practitioner OR advanced practice nurse. From 156 studies, we extracted information about nurse practitioner-physician comanagement antecedents, attributes, and consequences. A systematic review of the findings helped determine effects of nurse practitioner-physician comanagement on patient care. Then, we performed 26 interviews with nurse practitioners and physicians to obtain their perspectives on nurse practitioner-physician comanagement. Results were compiled to create our conceptual nurse practitioner-physician comanagement model. RESULTS: Our model of nurse practitioner-physician comanagement has 3 elements: effective communication; mutual respect and trust; and clinical alignment/shared philosophy of care. Interviews indicated that successful comanagement can alleviate individual workload, prevent burnout, improve patient care quality, and lead to increased patient access to care. Legal and organizational barriers, however, inhibit the ability of nurse practitioners to practice autonomously or with equal care management resources as primary care physicians. CONCLUSIONS: Future research should focus on developing instruments to measure and further assess nurse practitioner-physician comanagement in the primary care practice setting. PMID- 29760032 TI - White Privilege in a White Coat: How Racism Shaped my Medical Education. AB - In this essay, I reflect on some of the ways racial privilege influenced my experience as a white physician in training. While white Americans often think of "racism" as a social construct primarily affecting people of color, "racism" is a system of both racial disadvantage as well as reciprocal racial advantage. Medical professionals are increasingly aware of how social determinants of health lead to important health disparities, however white physicians seldom ask how their own racial privilege reinforces a white supremacist culture and what effects this may have on our patients' health. Drawing attention to the powerful legacy of racial discrimination in medical institutions, I call on other white physicians to name their privilege in order to dismantle the systems that propagate racism in our profession. PMID- 29760033 TI - The Mid-Career Demon. AB - For several months I have been trying to tag a greyness that has shaded my doctoring. I was not burned out but uncovered the desert experience of mind and soul known as acedia, which is called the noonday demon because it vexes those in the mid-stages of life. Grappling with the noonday demon has upended all of my assumptions about the workings of hope in the practice of medicine. For me, hope is no longer the anticipation of a positive outcome, or the warm feeling associated with the validation of a correct diagnosis, or the conclusion of successful treatment. I am beginning to realize that hope is the pulse of caregiving beating in me-and in the heart of every physician-which first stirs when I am with a patient, and then propels me forward in all of my doctoring. PMID- 29760035 TI - The Patient Profile: Improving Treatment Adherence. PMID- 29760034 TI - Physician Burnout: Resilience Training is Only Part of the Solution. AB - Physicians and physician trainees are among the highest-risk groups for burnout and suicide, and those in primary care are among the hardest hit. Many health systems have turned to resilience training as a solution, but there is an ongoing debate about whether that is the right approach. This article distinguishes between unavoidable occupational suffering (inherent in the physician's role) and avoidable occupational suffering (systems failures that can be prevented). Resilience training may be helpful in addressing unavoidable suffering, but it is the wrong treatment for the organizational pathologies that lead to avoidable suffering- and may even compound the harm doctors experience. To address avoidable suffering, health systems would be better served by engaging doctors in the co-design of work systems that promote better mental health outcomes. PMID- 29760043 TI - HER2 Amplification in Tumors Activates PI3K/Akt Signaling Independent of HER3. AB - Current evidence suggests that HER2-driven tumorigenesis requires HER3. This is likely due to the unique ability of HER3 to activate PI3K/Akt pathway signaling, which is not directly accessible to HER2. By genetic elimination of HER3 or shRNA knockdown of HER3 in HER2-amplified cancer cells, we find residual HER2-driven activation of PI3K/Akt pathway signaling that is driven by HER2 through direct and indirect mechanisms. Indirect mechanisms involved second messenger pathways, including Ras or Grb2. Direct binding of HER2 to PI3K occurred through p-Tyr1139, which has a weak affinity for PI3K but becomes significant at very high expression and phosphorylation. Mutation of Y1139 impaired the tumorigenic competency of HER2. Total elimination of HER3 expression in HCC1569 HER2 amplified cancer cells significantly impaired tumorigenicity only transiently, overcome by subsequent increases in HER2 expression and phosphorylation with binding and activation of PI3K. In contrast to activation of oncogenes by mutation, activation by overexpression was quantitative in nature: weak intrinsic activities were strengthened by overexpression, with additional gains observed through further increases in expression. Collectively, these data show that progressive functional gains by HER2 can increase its repertoire of activities such as the activation of PI3K and overcome its dependency on HER3.Significance: The intrinsic ability of HER2 to activate PI3K correlates with increased HER2 expression and can supplant the dependency upon HER3 for growth in HER2-amplified cancers. Cancer Res; 78(13); 3645-58. (c)2018 AACR. PMID- 29760044 TI - NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model. AB - Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line-derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709-17. (c)2018 AACR. PMID- 29760045 TI - GFPT2-Expressing Cancer-Associated Fibroblasts Mediate Metabolic Reprogramming in Human Lung Adenocarcinoma. AB - Metabolic reprogramming of the tumor microenvironment is recognized as a cancer hallmark. To identify new molecular processes associated with tumor metabolism, we analyzed the transcriptome of bulk and flow-sorted human primary non-small cell lung cancer (NSCLC) together with 18FDG-PET scans, which provide a clinical measure of glucose uptake. Tumors with higher glucose uptake were functionally enriched for molecular processes associated with invasion in adenocarcinoma and cell growth in squamous cell carcinoma (SCC). Next, we identified genes correlated to glucose uptake that were predominately overexpressed in a single cell-type comprising the tumor microenvironment. For SCC, most of these genes were expressed by malignant cells, whereas in adenocarcinoma, they were predominately expressed by stromal cells, particularly cancer-associated fibroblasts (CAF). Among these adenocarcinoma genes correlated to glucose uptake, we focused on glutamine-fructose-6-phosphate transaminase 2 (GFPT2), which codes for the glutamine-fructose-6-phosphate aminotransferase 2 (GFAT2), a rate limiting enzyme of the hexosamine biosynthesis pathway (HBP), which is responsible for glycosylation. GFPT2 was predictive of glucose uptake independent of GLUT1, the primary glucose transporter, and was prognostically significant at both gene and protein level. We confirmed that normal fibroblasts transformed to CAF-like cells, following TGFbeta treatment, upregulated HBP genes, including GFPT2, with less change in genes driving glycolysis, pentose phosphate pathway, and TCA cycle. Our work provides new evidence of histology-specific tumor stromal properties associated with glucose uptake in NSCLC and identifies GFPT2 as a critical regulator of tumor metabolic reprogramming in adenocarcinoma.Significance: These findings implicate the hexosamine biosynthesis pathway as a potential new therapeutic target in lung adenocarcinoma. Cancer Res; 78(13); 3445-57. (c)2018 AACR. PMID- 29760046 TI - Dual HDAC and PI3K Inhibition Abrogates NFkappaB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas. AB - Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFkappaB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFkappaB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFkappaB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. (c)2018 AACR. PMID- 29760047 TI - Nanoparticles That Reshape the Tumor Milieu Create a Therapeutic Window for Effective T-cell Therapy in Solid Malignancies. AB - A major obstacle to the success rate of chimeric antigen receptor (CAR-) T-cell therapy against solid tumors is the microenvironment antagonistic to T cells that solid tumors create. Conventional checkpoint blockade can silence lymphocyte antisurvival pathways activated by tumors, but because they are systemic, these treatments disrupt immune homeostasis and induce autoimmune side effects. Thus, new technologies are required to remodel the tumor milieu without causing systemic toxicities. Here, we demonstrate that targeted nanocarriers that deliver a combination of immune-modulatory agents can remove protumor cell populations and simultaneously stimulate antitumor effector cells. We administered repeated infusions of lipid nanoparticles coated with the tumor-targeting peptide iRGD and loaded with a combination of a PI3K inhibitor to inhibit immune-suppressive tumor cells and an alpha-GalCer agonist of therapeutic T cells to synergistically sway the tumor microenvironment of solid tumors from suppressive to stimulatory. This treatment created a therapeutic window of 2 weeks, enabling tumor-specific CAR-T cells to home to the lesion, undergo robust expansion, and trigger tumor regression. CAR-T cells administered outside this therapeutic window had no curative effect. The lipid nanoparticles we used are easy to manufacture in substantial amounts, and we demonstrate that repeated infusions of them are safe. Our technology may therefore provide a practical and low-cost strategy to potentiate many cancer immunotherapies used to treat solid tumors, including T cell therapy, vaccines, and BITE platforms.Significance: A new nanotechnology approach can promote T-cell therapy for solid tumors. Cancer Res; 78(13); 3718 30. (c)2018 AACR. PMID- 29760048 TI - Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. AB - Of the three RAS oncoproteins, only HRAS is delocalized and inactivated by farnesyltransferase inhibitors (FTI), an approach yet to be exploited clinically. In this study, we treat mice bearing Hras-driven poorly differentiated and anaplastic thyroid cancers (Tpo-Cre/HrasG12V/p53flox/flox ) with the FTI tipifarnib. Treatment caused sustained tumor regression and increased survival; however, early and late resistance was observed. Adaptive reactivation of RAS MAPK signaling was abrogated in vitro by selective RTK (i.e., EGFR, FGFR) inhibitors, but responses were ineffective in vivo, whereas combination of tipifarnib with the MEK inhibitor AZD6244 improved outcomes. A subset of tumor bearing mice treated with tipifarnib developed acquired resistance. Whole-exome sequencing of resistant tumors identified a Nf1 nonsense mutation and an activating mutation in Gnas at high allelic frequency, supporting the on-target effects of the drug. Cell lines modified with these genetic lesions recapitulated tipifarnib resistance in vivo This study demonstrates the feasibility of targeting Ras membrane association in cancers in vivo and predicts combination therapies that confer additional benefit.Significance: Tipifarnib effectively inhibits oncogenic HRAS-driven tumorigenesis and abrogating adaptive signaling improves responses. NF1 and GNAS mutations drive acquired resistance to Hras inhibition, supporting the on-target effects of the drug. Cancer Res; 78(16); 4642-57. (c)2018 AACR. PMID- 29760051 TI - Approach to classify, separate, and enrich objects in groups using ensemble sorting. AB - The sorting of objects into groups is a fundamental operation, critical in the preparation and purification of populations of cells, crystals, beads, or droplets, necessary for research and applications in biology, chemistry, and materials science. Most of the efforts exploring such purification have focused on two areas: the degree of separation and the measurement precision required for effective separation. Conventionally, achieving good separation ultimately requires that the objects are considered one by one (which can be both slow and expensive), and the ability to measure the sorted objects by increasing sensitivity as well as reducing sorting errors. Here we present an approach to sorting that addresses both critical limitations with a scheme that allows us to approach the theoretical limit for the accuracy of sorting decisions. Rather than sorting individual objects, we sort the objects in ensembles, via a set of registers which are then in turn sorted themselves into a second symmetric set of registers in a lossless manner. By repeating this process, we can arrive at high sorting purity with a low set of constraints. We demonstrate both the theory behind this idea and identify the critical parameters (ensemble population and sorting time), and show the utility and robustness of our method with simulations and experimental systems spanning several orders of scale, sorting populations of macroscopic beads and microfluidic droplets. Our method is general in nature and simplifies the sorting process, and thus stands to enhance many different areas of science, such as purification, enrichment of rare objects, and separation of dynamic populations. PMID- 29760049 TI - Insulin suppresses the production of fibroblast growth factor 23 (FGF23). AB - Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1-dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans. PMID- 29760050 TI - Ultrafast nonthermal heating of water initiated by an X-ray Free-Electron Laser. AB - The bright ultrafast pulses of X-ray Free-Electron Lasers allow investigation into the structure of matter under extreme conditions. We have used single pulses to ionize and probe water as it undergoes a phase transition from liquid to plasma. We report changes in the structure of liquid water on a femtosecond time scale when irradiated by single 6.86 keV X-ray pulses of more than 106 J/cm2 These observations are supported by simulations based on molecular dynamics and plasma dynamics of a water system that is rapidly ionized and driven out of equilibrium. This exotic ionic and disordered state with the density of a liquid is suggested to be structurally different from a neutral thermally disordered state. PMID- 29760052 TI - Spatial mutation patterns as markers of early colorectal tumor cell mobility. AB - A growing body of evidence suggests that a subset of human cancers grows as single clonal expansions. In such a nearly neutral evolution scenario, it is possible to infer the early ancestral tree of a full-grown tumor. We hypothesized that early tree reconstruction can provide insights into the mobility phenotypes of tumor cells during their first few cell divisions. We explored this hypothesis by means of a computational multiscale model of tumor expansion incorporating the glandular structure of colorectal tumors. After calibrating the model to multiregional and single gland data from 19 human colorectal tumors using approximate Bayesian computation, we examined the role of early tumor cell mobility in shaping the private mutation patterns of the final tumor. The simulations showed that early cell mixing in the first tumor gland can result in side-variegated patterns where the same private mutations could be detected on opposite tumor sides. In contrast, absence of early mixing led to nonvariegated, sectional mutation patterns. These results suggest that the patterns of detectable private mutations in colorectal tumors may be a marker of early cell movement and hence the invasive and metastatic potential of the tumor at the start of the growth. In alignment with our hypothesis, we found evidence of early abnormal cell movement in 9 of 15 invasive colorectal carcinomas ("born to be bad"), but in none of 4 benign adenomas. If validated with a larger dataset, the private mutation patterns may be used for outcome prediction among screen detected lesions with unknown invasive potential. PMID- 29760054 TI - Placebo treatment facilitates social trust and approach behavior. AB - Placebo effect refers to beneficial changes induced by the use of inert treatment, such as placebo-induced relief of physical pain and attenuation of negative affect. To date, we know little about whether placebo treatment could facilitate social functioning, a crucial aspect for well-being of a social species. In the present study, we develop and validate a paradigm to induce placebo effects on social trust and approach behavior (social placebo effect), and show robust evidence that placebo treatment promotes trust in others and increases preference for a closer interpersonal distance. We further examine placebo effects in real-life social interaction and show that placebo treatment makes single, but not pair-bonded, males keep closer to an attractive first-met female and perceive less social anxiety in the female. Finally, we show evidence that the effects of placebo treatment on social trust and approach behavior can be as strong as the effect of intranasal administration of oxytocin, a neuropeptide known for its function in facilitating social cognition and behavior. The finding of the social placebo effect extends our understanding of placebo effects on improvement of physical, mental, and social well-being and suggests clinical potentials in the treatment of social dysfunction. PMID- 29760053 TI - Size-tagged preferred ends in maternal plasma DNA shed light on the production mechanism and show utility in noninvasive prenatal testing. AB - Cell-free DNA in human plasma is nonrandomly fragmented and reflects genomewide nucleosomal organization. Previous studies had demonstrated tissue-specific preferred end sites in plasma DNA of pregnant women. In this study, we performed integrative analysis of preferred end sites with the size characteristics of plasma DNA fragments. We mined the preferred end sites in short and long plasma DNA molecules separately and found that these "size-tagged" ends showed improved accuracy in fetal DNA fraction estimation and enhanced noninvasive fetal trisomy 21 testing. Further analysis revealed that the fetal and maternal preferred ends were generated from different locations within the nucleosomal structure. Hence, fetal DNA was frequently cut within the nucleosome core while maternal DNA was mostly cut within the linker region. We further demonstrated that the nucleosome accessibility in placental cells was higher than that for white blood cells, which might explain the difference in the cutting positions and the shortness of fetal DNA in maternal plasma. Interestingly, short and long size-tagged ends were also observable in the plasma of nonpregnant healthy subjects and demonstrated size differences similar to those in the pregnant samples. Because the nonpregnant samples did not contain fetal DNA, the data suggested that the interrelationship of preferred DNA ends, chromatin accessibility, and plasma DNA size profile is likely a general one, extending beyond the context of pregnancy. Plasma DNA fragment end patterns have thus shed light on production mechanisms and show utility in future developments in plasma DNA-based noninvasive molecular diagnostics. PMID- 29760056 TI - Effects of the hippopotamus on the chemistry and ecology of a changing watershed. AB - Cross-boundary transfers of nutrients can profoundly shape the ecology of recipient systems. The common hippopotamus, Hippopotamus amphibius, is a significant vector of such subsidies from terrestrial to river ecosystems. We compared river pools with high and low densities of H. amphibius to determine how H. amphibius subsidies shape the chemistry and ecology of aquatic communities. Our study watershed, like many in sub-Saharan Africa, has been severely impacted by anthropogenic water abstraction reducing dry-season flow to zero. We conducted observations for multiple years over wet and dry seasons to identify how hydrological variability influences the impacts of H. amphibius During the wet season, when the river was flowing, we detected no differences in water chemistry and nutrient parameters between pools with high and low densities of H. amphibius Likewise, the diversity and abundance of fish and aquatic insect communities were indistinguishable. During the dry season, however, high-density H. amphibius pools differed drastically in almost all measured attributes of water chemistry and exhibited depressed fish and insect diversity and fish abundance compared with low-density H. amphibius pools. Scaled up to the entire watershed, we estimate that H. amphibius in this hydrologically altered watershed reduces dry season fish abundance and indices of gamma-level diversity by 41% and 16%, respectively, but appears to promote aquatic invertebrate diversity. Widespread human-driven shifts in hydrology appear to redefine the role of H. amphibius, altering their influence on ecosystem diversity and functioning in a fashion that may be more severe than presently appreciated. PMID- 29760057 TI - Weak Galilean invariance as a selection principle for coarse-grained diffusive models. AB - How does the mathematical description of a system change in different reference frames? Galilei first addressed this fundamental question by formulating the famous principle of Galilean invariance. It prescribes that the equations of motion of closed systems remain the same in different inertial frames related by Galilean transformations, thus imposing strong constraints on the dynamical rules. However, real world systems are often described by coarse-grained models integrating complex internal and external interactions indistinguishably as friction and stochastic forces. Since Galilean invariance is then violated, there is seemingly no alternative principle to assess a priori the physical consistency of a given stochastic model in different inertial frames. Here, starting from the Kac-Zwanzig Hamiltonian model generating Brownian motion, we show how Galilean invariance is broken during the coarse-graining procedure when deriving stochastic equations. Our analysis leads to a set of rules characterizing systems in different inertial frames that have to be satisfied by general stochastic models, which we call "weak Galilean invariance." Several well-known stochastic processes are invariant in these terms, except the continuous-time random walk for which we derive the correct invariant description. Our results are particularly relevant for the modeling of biological systems, as they provide a theoretical principle to select physically consistent stochastic models before a validation against experimental data. PMID- 29760055 TI - Chemokine C-C motif ligand 33 is a key regulator of teleost fish barbel development. AB - Barbels are important sensory organs in teleosts, reptiles, and amphibians. The majority of ~4,000 catfish species, such as the channel catfish (Ictalurus punctatus), possess abundant whisker-like barbels. However, barbel-less catfish, such as the bottlenose catfish (Ageneiosus marmoratus), do exist. Barbeled catfish and barbel-less catfish are ideal natural models for determination of the genomic basis for barbel development. In this work, we generated and annotated the genome sequences of the bottlenose catfish, conducted comparative and subtractive analyses using genome and transcriptome datasets, and identified differentially expressed genes during barbel regeneration. Here, we report that chemokine C-C motif ligand 33 (ccl33), as a key regulator of barbel development and regeneration. It is present in barbeled fish but absent in barbel-less fish. The ccl33 genes are differentially expressed during barbel regeneration in a timing concordant with the timing of barbel regeneration. Knockout of ccl33 genes in the zebrafish (Danio rerio) resulted in various phenotypes, including complete loss of barbels, reduced barbel sizes, and curly barbels, suggesting that ccl33 is a key regulator of barbel development. Expression analysis indicated that paralogs of the ccl33 gene have both shared and specific expression patterns, most notably expressed highly in various parts of the head, such as the eye, brain, and mouth areas, supporting its role for barbel development. PMID- 29760058 TI - Amazonia is the primary source of Neotropical biodiversity. AB - The American tropics (the Neotropics) are the most species-rich realm on Earth, and for centuries, scientists have attempted to understand the origins and evolution of their biodiversity. It is now clear that different regions and taxonomic groups have responded differently to geological and climatic changes. However, we still lack a basic understanding of how Neotropical biodiversity was assembled over evolutionary timescales. Here we infer the timing and origin of the living biota in all major Neotropical regions by performing a cross-taxonomic biogeographic analysis based on 4,450 species from six major clades across the tree of life (angiosperms, birds, ferns, frogs, mammals, and squamates), and integrate >1.3 million species occurrences with large-scale phylogenies. We report an unprecedented level of biotic interchange among all Neotropical regions, totaling 4,525 dispersal events. About half of these events involved transitions between major environmental types, with a predominant directionality from forested to open biomes. For all taxonomic groups surveyed here, Amazonia is the primary source of Neotropical diversity, providing >2,800 lineages to other regions. Most of these dispersal events were to Mesoamerica (~1,500 lineages), followed by dispersals into open regions of northern South America and the Cerrado and Chaco biomes. Biotic interchange has taken place for >60 million years and generally increased toward the present. The total amount of time lineages spend in a region appears to be the strongest predictor of migration events. These results demonstrate the complex origin of tropical ecosystems and the key role of biotic interchange for the assembly of regional biotas. PMID- 29760059 TI - Nouns slow down speech across structurally and culturally diverse languages. AB - By force of nature, every bit of spoken language is produced at a particular speed. However, this speed is not constant-speakers regularly speed up and slow down. Variation in speech rate is influenced by a complex combination of factors, including the frequency and predictability of words, their information status, and their position within an utterance. Here, we use speech rate as an index of word-planning effort and focus on the time window during which speakers prepare the production of words from the two major lexical classes, nouns and verbs. We show that, when naturalistic speech is sampled from languages all over the world, there is a robust cross-linguistic tendency for slower speech before nouns compared with verbs, both in terms of slower articulation and more pauses. We attribute this slowdown effect to the increased amount of planning that nouns require compared with verbs. Unlike verbs, nouns can typically only be used when they represent new or unexpected information; otherwise, they have to be replaced by pronouns or be omitted. These conditions on noun use appear to outweigh potential advantages stemming from differences in internal complexity between nouns and verbs. Our findings suggest that, beneath the staggering diversity of grammatical structures and cultural settings, there are robust universals of language processing that are intimately tied to how speakers manage referential information when they communicate with one another. PMID- 29760062 TI - Correction for Ishikawa et al., Ion-beam irradiation, gene identification, and marker-assisted breeding in the development of low-cadmium rice. PMID- 29760061 TI - Methylglucosylation of aromatic amino and phenolic moieties of drug-like biosynthons by combinatorial biosynthesis. AB - Glycosylation is a prominent strategy to optimize the pharmacokinetic and pharmacodynamic properties of drug-like small-molecule scaffolds by modulating their solubility, stability, bioavailability, and bioactivity. Glycosyltransferases applicable for "sugarcoating" various small-molecule acceptors have been isolated and characterized from plants and bacteria, but remained cryptic from filamentous fungi until recently, despite the frequent use of some fungi for whole-cell biocatalytic glycosylations. Here, we use bioinformatic and genomic tools combined with heterologous expression to identify a glycosyltransferase-methyltransferase (GT-MT) gene pair that encodes a methylglucosylation functional module in the ascomycetous fungus Beauveria bassiana The GT is the founding member of a family nonorthologous to characterized fungal enzymes. Using combinatorial biosynthetic and biocatalytic platforms, we reveal that this GT is a promiscuous enzyme that efficiently modifies a broad range of drug-like substrates, including polyketides, anthraquinones, flavonoids, and naphthalenes. It yields both O- and N-glucosides with remarkable regio- and stereospecificity, a spectrum not demonstrated for other characterized fungal enzymes. These glucosides are faithfully processed by the dedicated MT to afford 4-O-methylglucosides. The resulting "unnatural products" show increased solubility, while representative polyketide methylglucosides also display increased stability against glycoside hydrolysis. Upon methylglucosidation, specific polyketides were found to attain cancer cell line-specific antiproliferative or matrix attachment inhibitory activities. These findings will guide genome mining for fungal GTs with novel substrate and product specificities, and empower the efficient combinatorial biosynthesis of a broad range of natural and unnatural glycosides in total biosynthetic or biocatalytic formats. PMID- 29760063 TI - Elastic coupling power stroke mechanism of the F1-ATPase molecular motor. AB - The angular velocity profile of the 120 degrees F1-ATPase power stroke was resolved as a function of temperature from 16.3 to 44.6 degrees C using a DeltaMUATP = -31.25 kBT at a time resolution of 10 MUs. Angular velocities during the first 60 degrees of the power stroke (phase 1) varied inversely with temperature, resulting in negative activation energies with a parabolic dependence. This is direct evidence that phase 1 rotation derives from elastic energy (spring constant, kappa = 50 kBT.rad-2). Phase 2 of the power stroke had an enthalpic component indicating that additional energy input occurred to enable the gamma-subunit to overcome energy stored by the spring after rotating beyond its 34 degrees equilibrium position. The correlation between the probability distribution of ATP binding to the empty catalytic site and the negative Ea values of the power stroke during phase 1 suggests that this additional energy is derived from the binding of ATP to the empty catalytic site. A second torsion spring (kappa = 150 kBT.rad-2; equilibrium position, 90 degrees ) was also evident that mitigated the enthalpic cost of phase 2 rotation. The maximum DeltaG? was 22.6 kBT, and maximum efficiency was 72%. An elastic coupling mechanism is proposed that uses the coiled-coil domain of the gamma-subunit rotor as a torsion spring during phase 1, and then as a crankshaft driven by ATP binding-dependent conformational changes during phase 2 to drive the power stroke. PMID- 29760060 TI - Corticoinsular circuits encode subjective value expectation and violation for effortful goal-directed behavior. AB - We are presented with choices each day about how to invest our effort to achieve our goals. Critically, these decisions must frequently be made under conditions of incomplete information, where either the effort required or possible reward to be gained is uncertain. Such choices therefore require the development of potential value estimates to guide effortful goal-directed behavior. To date, however, the neural mechanisms for this expectation process are unknown. Here, we used computational fMRI during an effort-based decision-making task where trial wise information about effort costs and reward magnitudes was presented separately over time, thereby allowing us to model distinct effort/reward computations as choice-relevant information unfolded. We found that ventromedial prefrontal cortex (vmPFC) encoded expected subjective value. Further, activity in dorsal anterior cingulate (dACC) and anterior insula (aI) reflected both effort discounting as well as a subjective value prediction error signal derived from trial history. While prior studies have identified these regions as being involved in effort-based decision making, these data demonstrate their specific role in the formation and maintenance of subjective value estimates as relevant information becomes available. PMID- 29760064 TI - Helical rotation of the diaphanous-related formin mDia1 generates actin filaments resistant to cofilin. AB - The complex interplay between actin regulatory proteins facilitates the formation of diverse cellular actin structures. Formin homology proteins (formins) play an essential role in the formation of actin stress fibers and yeast actin cables, to which the major actin depolymerizing factor cofilin barely associates. In vitro, F-actin decorated with cofilin exhibits a marked increase in the filament twist. On the other hand, a mammalian formin mDia1 rotates along the long-pitch actin helix during processive actin elongation (helical rotation). Helical rotation may impose torsional force on F-actin in the opposite direction of the cofilin induced twisting. Here, we show that helical rotation of mDia1 converts F-actin resistant to cofilin both in vivo and in vitro. F-actin assembled by mDia1 without rotational freedom became more resistant to the severing and binding activities of cofilin than freely rotatable F-actin. Electron micrographic analysis revealed untwisting of the long-pitch helix of F-actin elongating from mDia1 on tethering of both mDia1 and the pointed end side of the filament. In cells, single molecules of mDia1DeltaC63, an activated mutant containing N terminal regulatory domains, showed tethering to cell structures more frequently than autoinhibited wild-type mDia1 and mDia1 devoid of N-terminal domains. Overexpression of mDia1DeltaC63 induced the formation of F-actin, which has prolonged lifetime and accelerates dissociation of cofilin. Helical rotation of formins may thus serve as an F-actin stabilizing mechanism by which a barbed end bound molecule can enhance the stability of a filament over a long range. PMID- 29760065 TI - Temperature regulates NF-kappaB dynamics and function through timing of A20 transcription. AB - NF-kappaB signaling plays a pivotal role in control of the inflammatory response. We investigated how the dynamics and function of NF-kappaB were affected by temperature within the mammalian physiological range (34 degrees C to 40 degrees C). An increase in temperature led to an increase in NF-kappaB nuclear/cytoplasmic oscillation frequency following Tumor Necrosis Factor alpha (TNFalpha) stimulation. Mathematical modeling suggested that this temperature sensitivity might be due to an A20-dependent mechanism, and A20 silencing removed the sensitivity to increased temperature. The timing of the early response of a key set of NF-kappaB target genes showed strong temperature dependence. The cytokine-induced expression of many (but not all) later genes was insensitive to temperature change (suggesting that they might be functionally temperature compensated). Moreover, a set of temperature- and TNFalpha-regulated genes were implicated in NF-kappaB cross-talk with key cell-fate-controlling pathways. In conclusion, NF-kappaB dynamics and target gene expression are modulated by temperature and can accurately transmit multidimensional information to control inflammation. PMID- 29760066 TI - Socioeconomic status moderates age-related differences in the brain's functional network organization and anatomy across the adult lifespan. AB - An individual's environmental surroundings interact with the development and maturation of their brain. An important aspect of an individual's environment is his or her socioeconomic status (SES), which estimates access to material resources and social prestige. Previous characterizations of the relation between SES and the brain have primarily focused on earlier or later epochs of the lifespan (i.e., childhood, older age). We broaden this work to examine the relationship between SES and the brain across a wide range of human adulthood (20 89 years), including individuals from the less studied middle-age range. SES, defined by education attainment and occupational socioeconomic characteristics, moderates previously reported age-related differences in the brain's functional network organization and whole-brain cortical structure. Across middle age (35-64 years), lower SES is associated with reduced resting-state system segregation (a measure of effective functional network organization). A similar but less robust relationship exists between SES and age with respect to brain anatomy: Lower SES is associated with reduced cortical gray matter thickness in middle age. Conversely, younger and older adulthood do not exhibit consistent SES-related difference in the brain measures. The SES-brain relationships persist after controlling for measures of physical and mental health, cognitive ability, and participant demographics. Critically, an individual's childhood SES cannot account for the relationship between their current SES and functional network organization. These findings provide evidence that SES relates to the brain's functional network organization and anatomy across adult middle age, and that higher SES may be a protective factor against age-related brain decline. PMID- 29760070 TI - Pacing of Paleozoic macroevolutionary rates by Milankovitch grand cycles. AB - Periodic fluctuations in past biodiversity, speciation, and extinction have been proposed, with extremely long periods ranging from 26 to 62 million years, although forcing mechanisms remain speculative. In contrast, well-understood periodic Milankovitch climate forcing represents a viable driver for macroevolutionary fluctuations, although little evidence for such fluctuation exists except during the Late Cenozoic. The reality, magnitude, and drivers of periodic fluctuations in macroevolutionary rates are of interest given long standing debate surrounding the relative roles of intrinsic biotic interactions vs. extrinsic environmental factors as drivers of biodiversity change. Here, we show that, over a time span of 60 million years, between 9 and 16% of the variance in biological turnover (i.e., speciation probability plus species extinction probability) in a major Early Paleozoic zooplankton group, the graptoloids, can be explained by long-period astronomical cycles (Milankovitch "grand cycles") associated with Earth's orbital eccentricity (2.6 million years) and obliquity (1.3 million years). These grand cycles modulate climate variability, alternating times of relative stability in the environment with times of maximum volatility. We infer that these cycles influenced graptolite speciation and extinction through climate-driven changes to oceanic circulation and structure. Our results confirm the existence of Milankovitch grand cycles in the Early Paleozoic Era and show that known processes related to the mechanics of the Solar System were shaping marine macroevolutionary rates comparatively early in the history of complex life. We present an application of hidden Markov models to macroevolutionary time series and protocols for the evaluation of statistical significance in spectral analysis. PMID- 29760067 TI - Sequencing-based counting and size profiling of plasma Epstein-Barr virus DNA enhance population screening of nasopharyngeal carcinoma. AB - Circulating tumor-derived DNA testing for cancer screening has recently been demonstrated in a prospective study on identification of nasopharyngeal carcinoma (NPC) among 20,174 asymptomatic individuals. Plasma EBV DNA, a marker for NPC, was detected using real-time PCR. While plasma EBV DNA was persistently detectable in 97.1% of the NPCs identified, ~5% of the general population had transiently detectable plasma EBV DNA. We hypothesized that EBV DNA in plasma of subjects with or without NPC may have different molecular characteristics. We performed target-capture sequencing of plasma EBV DNA and identified differences in the abundance and size profiles of EBV DNA molecules within plasma of NPC and non-NPC subjects. NPC patients had significantly higher amounts of plasma EBV DNA, which showed longer fragment lengths. Cutoff values were established from an exploratory dataset and tested in a validation sample set. Adopting an algorithm that required a sample to concurrently pass cutoffs for EBV DNA counting and size measurements, NPCs were detected at a positive predictive value (PPV) of 19.6%. This represented superior performance compared with the PPV of 11.0% in the prospective screening study, which required participants with an initially detectable plasma EBV DNA result to be retested within 4 weeks. The observed differences in the molecular nature of EBV DNA molecules in plasma of subjects with or without NPC were successfully translated into a sequencing-based test that had a high PPV for NPC screening and achievable through single time-point testing. PMID- 29760069 TI - Heterometallic Ru-Pt metallacycle for two-photon photodynamic therapy. AB - As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru-Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy. PMID- 29760068 TI - Endocast morphology of Homo naledi from the Dinaledi Chamber, South Africa. AB - Hominin cranial remains from the Dinaledi Chamber, South Africa, represent multiple individuals of the species Homo naledi This species exhibits a small endocranial volume comparable to Australopithecus, combined with several aspects of external cranial anatomy similar to larger-brained species of Homo such as Homo habilis and Homo erectus Here, we describe the endocast anatomy of this recently discovered species. Despite the small size of the H. naledi endocasts, they share several aspects of structure in common with other species of Homo, not found in other hominins or great apes, notably in the organization of the inferior frontal and lateral orbital gyri. The presence of such structural innovations in a small-brained hominin may have relevance to behavioral evolution within the genus Homo. PMID- 29760071 TI - PRDM1 silences stem cell-related genes and inhibits proliferation of human colon tumor organoids. AB - PRDM1 is a tumor suppressor that plays an important role in B and T cell lymphomas. Our previous studies demonstrated that PRDM1beta is a p53-response gene in human colorectal cancer cells. However, the function of PRDM1beta in colorectal cancer cells and colon tumor organoids is not clear. Here we show that PRDM1beta is a p53-response gene in human colon organoids and that low PRDM1 expression predicts poor survival in colon cancer patients. We engineered PRDM1 knockouts and overexpression clones in RKO cells and characterized the PRDM1 dependent transcript landscapes, revealing that both the alpha and beta transcript isoforms repress MYC-response genes and stem cell-related genes. Finally, we show that forced expression of PRDM1 in human colon cancer organoids prevents the formation and growth of colon tumor organoids in vitro. These results suggest that p53 may exert tumor-suppressive effects in part through a PRDM1-dependent silencing of stem cell genes, depleting the size of the normal intestinal stem cell compartment in response to DNA damage. PMID- 29760072 TI - Estrogen receptor beta controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage. AB - Injury to the enteric nervous system (ENS) can cause several gastrointestinal (GI) disorders including achalasia, irritable bowel syndrome, and gastroparesis. Recently, a subpopulation of enteric glial cells with neuronal stem/progenitor properties (ENSCs) has been identified in the adult ENS. ENSCs have the ability of reconstituting the enteric neuronal pool after damage of the myenteric plexus. Since the estrogen receptor beta (ERbeta) is expressed in enteric glial cells and neurons, we investigated whether a selective ERbeta agonist, LY3201, can influence neuronal and glial cell differentiation. Myenteric ganglia from the murine muscularis externa were isolated and cultured in either glial cell medium or neuronal medium. In glial cell medium, the number of glial progenitor cells (Sox10+) was increased by fourfold in the presence of LY3201. In the neuronal medium supplemented with an antimitotic agent to block glial cell proliferation, LY3201 elicited a 2.7-fold increase in the number of neurons (neurofilament+ or HuC/D+). In addition, the effect of LY3201 was evaluated in vivo in two murine models of enteric neuronal damage and loss, namely, high-fat diet and topical application of the cationic detergent benzalkonium chloride (BAC) on the intestinal serosa, respectively. In both models, treatment with LY3201 significantly increased the recovery of neurons after damage. Thus, LY3201 was able to stimulate glial-to-neuron cell differentiation in vitro and promoted neurogenesis in the damaged myenteric plexus in vivo. Overall, our study suggests that selective ERbeta agonists may represent a therapeutic tool to treat patients suffering from GI disorders, caused by excessive neuronal/glial cell damage. PMID- 29760075 TI - Additive-free carbon nanotube dispersions, pastes, gels, and doughs in cresols. AB - Cresols are a group of naturally occurring and massively produced methylphenols with broad use in the chemical industry. Here, we report that m-cresol and its liquid mixtures with other isomers are surprisingly good solvents for processing carbon nanotubes. They can disperse carbon nanotubes of various types at unprecedentedly high concentrations of tens of weight percent, without the need for any dispersing agent or additive. Cresols interact with carbon nanotubes by charge transfer through the phenolic hydroxyl proton and can be removed after processing by evaporation or washing, without altering the surface of carbon nanotubes. Cresol solvents render carbon nanotubes polymer-like rheological and viscoelastic properties and processability. As the concentration of nanotubes increases, a continuous transition of four states can be observed, including dilute dispersion, thick paste, free-standing gel, and eventually a kneadable, playdough-like material. As demonstrated with a few proofs of concept, cresols make powders of agglomerated carbon nanotubes immediately usable by a broad array of material-processing techniques to create desirable structures and form factors and make their polymer composites. PMID- 29760076 TI - High-temperature superconductivity using a model of hydrogen bonds. AB - Recently, there has been much interest in high-temperature superconductors and more recently in hydrogen-based superconductors. This work offers a simple model that explains the behavior of the superconducting gap based on naive BCS (Bardeen Cooper-Schrieffer) theory and reproduces most effects seen in experiments, including the isotope effect and [Formula: see text] enhancement as a function of pressure. We show that this is due to a combination of the factors appearing in the gap equation: the matrix element between the proton states and the level splitting of the proton. PMID- 29760073 TI - Regulation of myeloid cell phagocytosis by LRRK2 via WAVE2 complex stabilization is altered in Parkinson's disease. AB - Leucine-rich repeat kinase 2 (LRRK2) has been implicated in both familial and sporadic Parkinson's disease (PD), yet its pathogenic role remains unclear. A previous screen in Drosophila identified Scar/WAVE (Wiskott-Aldrich syndrome protein-family verproline) proteins as potential genetic interactors of LRRK2 Here, we provide evidence that LRRK2 modulates the phagocytic response of myeloid cells via specific modulation of the actin-cytoskeletal regulator, WAVE2. We demonstrate that macrophages and microglia from LRRK2-G2019S PD patients and mice display a WAVE2-mediated increase in phagocytic response, respectively. Lrrk2 loss results in the opposite effect. LRRK2 binds and phosphorylates Wave2 at Thr470, stabilizing and preventing its proteasomal degradation. Finally, we show that Wave2 also mediates Lrrk2-G2019S-induced dopaminergic neuronal death in both macrophage-midbrain cocultures and in vivo. Taken together, a LRRK2-WAVE2 pathway, which modulates the phagocytic response in mice and human leukocytes, may define an important role for altered immune function in PD. PMID- 29760074 TI - AtPep3 is a hormone-like peptide that plays a role in the salinity stress tolerance of plants. AB - Peptides encoded by small coding genes play an important role in plant development, acting in a similar manner as phytohormones. Few hormone-like peptides, however, have been shown to play a role in abiotic stress tolerance. In the current study, 17 Arabidopsis genes coding for small peptides were found to be up-regulated in response to salinity stress. To identify peptides leading salinity stress tolerance, we generated transgenic Arabidopsis plants overexpressing these small coding genes and assessed survivability and root growth under salinity stress conditions. Results indicated that 4 of the 17 overexpressed genes increased salinity stress tolerance. Further studies focused on AtPROPEP3, which was the most highly up-regulated gene under salinity stress. Treatment of plants with synthetic peptides encoded by AtPROPEP3 revealed that a C-terminal peptide fragment (AtPep3) inhibited the salt-induced bleaching of chlorophyll in seedlings. Conversely, knockdown AtPROPEP3 transgenic plants exhibited a hypersensitive phenotype under salinity stress, which was complemented by the AtPep3 peptide. This functional AtPep3 peptide region overlaps with an AtPep3 elicitor peptide that is related to the immune response of plants. Functional analyses with a receptor mutant of AtPep3 revealed that AtPep3 was recognized by the PEPR1 receptor and that it functions to increase salinity stress tolerance in plants. Collectively, these data indicate that AtPep3 plays a significant role in both salinity stress tolerance and immune response in Arabidopsis. PMID- 29760077 TI - Conformations of peptoids in nanosheets result from the interplay of backbone energetics and intermolecular interactions. AB - The conformations adopted by the molecular constituents of a supramolecular assembly influence its large-scale order. At the same time, the interactions made in assemblies by molecules can influence their conformations. Here we study this interplay in extended flat nanosheets made from nonnatural sequence-specific peptoid polymers. Nanosheets exist because individual polymers can be linear and untwisted, by virtue of polymer backbone elements adopting alternating rotational states whose twists oppose and cancel. Using molecular dynamics and quantum mechanical simulations, together with experimental data, we explore the design space of flat nanostructures built from peptoids. We show that several sets of peptoid backbone conformations are consistent with their being linear, but the specific combination observed in experiment is determined by a combination of backbone energetics and the interactions made within the nanosheet. Our results provide a molecular model of the peptoid nanosheet consistent with all available experimental data and show that its structure results from a combination of intra and intermolecular interactions. PMID- 29760080 TI - Uncertainty in long-run forecasts of quantities such as per capita gross domestic product. PMID- 29760078 TI - Chaperone AMPylation modulates aggregation and toxicity of neurodegenerative disease-associated polypeptides. AB - Proteostasis is critical to maintain organismal viability, a process counteracted by aging-dependent protein aggregation. Chaperones of the heat shock protein (HSP) family help control proteostasis by reducing the burden of unfolded proteins. They also oversee the formation of protein aggregates. Here, we explore how AMPylation, a posttranslational protein modification that has emerged as a powerful modulator of HSP70 activity, influences the dynamics of protein aggregation. We find that adjustments of cellular AMPylation levels in Caenorhabditis elegans directly affect aggregation properties and associated toxicity of amyloid-beta (Abeta), of a polyglutamine (polyQ)-extended polypeptide, and of alpha-synuclein (alpha-syn). Expression of a constitutively active C. elegans AMPylase FIC-1(E274G) under its own promoter expedites aggregation of Abeta and alpha-syn, and drastically reduces their toxicity. A deficiency in AMPylation decreases the cellular tolerance for aggregation-prone polyQ proteins and alters their aggregation behavior. Overexpression of FIC 1(E274G) interferes with cell survival and larval development, underscoring the need for tight control of AMPylase activity in vivo. We thus define a link between HSP70 AMPylation and the dynamics of protein aggregation in neurodegenerative disease models. Our results are consistent with a cytoprotective, rather than a cytotoxic, role for such protein aggregates. PMID- 29760083 TI - The role of the permanent wilting point in controlling the spatial distribution of precipitation. AB - Convection-permitting simulations on an idealized land planet are performed to understand whether soil moisture acts to support or impede the organization of convection. Initially, shallow circulations driven by differential radiative cooling induce a self-aggregation of the convection into a single band, as has become familiar from simulations over idealized sea surfaces. With time, however, the drying of the nonprecipitating region induces a reversal of the shallow circulation, drawing the flow at low levels from the precipitating to the nonprecipitating region. This causes the precipitating convection to move over the dry soils and reverses the polarity of the circulation. The precipitation replenishes these soils with moisture at the expense of the formerly wet soils which dry, until the process repeats itself. On longer timescales, this acts to homogenize the precipitation field. By analyzing the strength of the shallow circulations, the surface budget with its effects on the boundary layer properties, and the shape of the soil moisture resistance function, we demonstrate that the soil has to dry out significantly, for the here-tested resistance formulations below 15% of its water availability, to be able to alter the precipitation distribution. We expect such a process to broaden the distribution of precipitation over tropical land. This expectation is supported by observations which show that in drier years the monsoon rains move farther inland over Africa. PMID- 29760079 TI - Selection and environmental adaptation along a path to speciation in the Tibetan frog Nanorana parkeri. AB - Tibetan frogs, Nanorana parkeri, are differentiated genetically but not morphologically along geographical and elevational gradients in a challenging environment, presenting a unique opportunity to investigate processes leading to speciation. Analyses of whole genomes of 63 frogs reveal population structuring and historical demography, characterized by highly restricted gene flow in a narrow geographic zone lying between matrilines West (W) and East (E). A population found only along a single tributary of the Yalu Zangbu River has the mitogenome only of E, whereas nuclear genes of W comprise 89-95% of the nuclear genome. Selection accounts for 579 broadly scattered, highly divergent regions (HDRs) of the genome, which involve 365 genes. These genes fall into 51 gene ontology (GO) functional classes, 14 of which are likely to be important in driving reproductive isolation. GO enrichment analyses of E reveal many overrepresented functional categories associated with adaptation to high elevations, including blood circulation, response to hypoxia, and UV radiation. Four genes, including DNAJC8 in the brain, TNNC1 and ADORA1 in the heart, and LAMB3 in the lung, differ in levels of expression between low- and high-elevation populations. High-altitude adaptation plays an important role in maintaining and driving continuing divergence and reproductive isolation. Use of total genomes enabled recognition of selection and adaptation in and between populations, as well as documentation of evolution along a stepped cline toward speciation. PMID- 29760082 TI - A cytokine network involving IL-36gamma, IL-23, and IL-22 promotes antimicrobial defense and recovery from intestinal barrier damage. AB - The gut epithelium acts to separate host immune cells from unrestricted interactions with the microbiota and other environmental stimuli. In response to epithelial damage or dysfunction, immune cells are activated to produce interleukin (IL)-22, which is involved in repair and protection of barrier surfaces. However, the specific pathways leading to IL-22 and associated antimicrobial peptide (AMP) production in response to intestinal tissue damage remain incompletely understood. Here, we define a critical IL-36/IL-23/IL-22 cytokine network that is instrumental for AMP production and host defense. Using a murine model of intestinal damage and repair, we show that IL-36gamma is a potent inducer of IL-23 both in vitro and in vivo. IL-36gamma-induced IL-23 required Notch2-dependent (CD11b+CD103+) dendritic cells (DCs), but not Batf3 dependent (CD11b-CD103+) DCs or CSF1R-dependent macrophages. The intracellular signaling cascade linking IL-36 receptor (IL-36R) to IL-23 production by DCs involved MyD88 and the NF-kappaB subunits c-Rel and p50. Consistent with in vitro observations, IL-36R- and IL-36gamma-deficient mice exhibited dramatically reduced IL-23, IL-22, and AMP levels, and consequently failed to recover from acute intestinal damage. Interestingly, impaired recovery of mice deficient in IL 36R or IL-36gamma could be rescued by treatment with exogenous IL-23. This recovery was accompanied by a restoration of IL-22 and AMP expression in the colon. Collectively, these data define a cytokine network involving IL-36gamma, IL-23, and IL-22 that is activated in response to intestinal barrier damage and involved in providing critical host defense. PMID- 29760081 TI - The genome-wide rate and spectrum of spontaneous mutations differ between haploid and diploid yeast. AB - By altering the dynamics of DNA replication and repair, alternative ploidy states may experience different rates and types of new mutations, leading to divergent evolutionary outcomes. We report a direct comparison of the genome-wide spectrum of spontaneous mutations arising in haploids and diploids following a mutation accumulation experiment in the budding yeast Saccharomyces cerevisiae Characterizing the number, types, locations, and effects of thousands of mutations revealed that haploids were more prone to single-nucleotide mutations (SNMs) and mitochondrial mutations, while larger structural changes were more common in diploids. Mutations were more likely to be detrimental in diploids, even after accounting for the large impact of structural changes, contrary to the prediction that mutations would have weaker effects, due to masking, in diploids. Haploidy is expected to reduce the opportunity for conservative DNA repair involving homologous chromosomes, increasing the insertion-deletion rate, but we found little support for this idea. Instead, haploids were more susceptible to SNMs in late-replicating genomic regions, resulting in a ploidy difference in the spectrum of substitutions. In diploids, we detect mutation rate variation among chromosomes in association with centromere location, a finding that is supported by published polymorphism data. Diploids are not simply doubled haploids; instead, our results predict that the spectrum of spontaneous mutations will substantially shape the dynamics of genome evolution in haploid and diploid populations. PMID- 29760084 TI - Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. AB - Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela. PMID- 29760085 TI - MDA-9/Syntenin regulates protective autophagy in anoikis-resistant glioma stem cells. AB - Glioma stem cells (GSCs) comprise a small subpopulation of glioblastoma multiforme cells that contribute to therapy resistance, poor prognosis, and tumor recurrence. Protective autophagy promotes resistance of GSCs to anoikis, a form of programmed cell death occurring when anchorage-dependent cells detach from the extracellular matrix. In nonadherent conditions, GSCs display protective autophagy and anoikis-resistance, which correlates with expression of melanoma differentiation associated gene-9/Syntenin (MDA-9) (syndecan binding protein; SDCBP). When MDA-9 is suppressed, GSCs undergo autophagic death supporting the hypothesis that MDA-9 regulates protective autophagy in GSCs under anoikis conditions. MDA-9 maintains protective autophagy through phosphorylation of BCL2 and by suppressing high levels of autophagy through EGFR signaling. MDA-9 promotes these changes by modifying FAK and PKC signaling. Gain-of-function and loss-of-function genetic approaches demonstrate that MDA-9 regulates pEGFR and pBCL2 expression through FAK and pPKC. EGFR signaling inhibits autophagy markers (ATG5, Lamp1, LC3B), helping to maintain protective autophagy, and along with pBCL2 maintain survival of GSCs. In the absence of MDA-9, this protective mechanism is deregulated; EGFR no longer maintains protective autophagy, leading to highly elevated and sustained levels of autophagy and consequently decreased cell survival. In addition, pBCL2 is down-regulated in the absence of MDA-9, leading to cell death in GSCs under conditions of anoikis. Our studies confirm a functional link between MDA-9 expression and protective autophagy in GSCs and show that inhibition of MDA-9 reverses protective autophagy and induces anoikis and cell death in GSCs. PMID- 29760086 TI - Mapping the functional anatomy of Orai1 transmembrane domains for CRAC channel gating. AB - Store-operated Orai1 channels are activated through a unique inside-out mechanism involving binding of the endoplasmic reticulum Ca2+ sensor STIM1 to cytoplasmic sites on Orai1. Although atomic-level details of Orai structure, including the pore and putative ligand binding domains, are resolved, how the gating signal is communicated to the pore and opens the gate is unknown. To address this issue, we used scanning mutagenesis to identify 15 residues in transmembrane domains (TMs) 1-4 whose perturbation activates Orai1 channels independently of STIM1. Cysteine accessibility analysis and molecular-dynamics simulations indicated that constitutive activation of the most robust variant, H134S, arises from a pore conformational change that opens a hydrophobic gate to augment pore hydration, similar to gating evoked by STIM1. Mutational analysis of this locus suggests that H134 acts as steric brake to stabilize the closed state of the channel. In addition, atomic packing analysis revealed distinct functional contacts between the TM1 pore helix and the surrounding TM2/3 helices, including one set mediated by a cluster of interdigitating hydrophobic residues and another by alternative ridges of polar and hydrophobic residues. Perturbing these contacts via mutagenesis destabilizes STIM1-mediated Orai1 channel gating, indicating that these bridges between TM1 and the surrounding TM2/3 ring are critical for conveying the gating signal to the pore. These findings help develop a framework for understanding the global conformational changes and allosteric interactions between topologically distinct domains that are essential for activation of Orai1 channels. PMID- 29760087 TI - Pseudomonas aeruginosa transcriptome during human infection. AB - Laboratory experiments have uncovered many basic aspects of bacterial physiology and behavior. After the past century of mostly in vitro experiments, we now have detailed knowledge of bacterial behavior in standard laboratory conditions, but only a superficial understanding of bacterial functions and behaviors during human infection. It is well-known that the growth and behavior of bacteria are largely dictated by their environment, but how bacterial physiology differs in laboratory models compared with human infections is not known. To address this question, we compared the transcriptome of Pseudomonas aeruginosa during human infection to that of P. aeruginosa in a variety of laboratory conditions. Several pathways, including the bacterium's primary quorum sensing system, had significantly lower expression in human infections than in many laboratory conditions. On the other hand, multiple genes known to confer antibiotic resistance had substantially higher expression in human infection than in laboratory conditions, potentially explaining why antibiotic resistance assays in the clinical laboratory frequently underestimate resistance in patients. Using a standard machine learning technique known as support vector machines, we identified a set of genes whose expression reliably distinguished in vitro conditions from human infections. Finally, we used these support vector machines with binary classification to force P. aeruginosa mouse infection transcriptomes to be classified as human or in vitro. Determining what differentiates our current models from clinical infections is important to better understand bacterial infections and will be necessary to create model systems that more accurately capture the biology of infection. PMID- 29760088 TI - Lead pollution recorded in Greenland ice indicates European emissions tracked plagues, wars, and imperial expansion during antiquity. AB - Lead pollution in Arctic ice reflects midlatitude emissions from ancient lead silver mining and smelting. The few reported measurements have been extrapolated to infer the performance of ancient economies, including comparisons of economic productivity and growth during the Roman Republican and Imperial periods. These studies were based on sparse sampling and inaccurate dating, limiting understanding of trends and specific linkages. Here we show, using a precisely dated record of estimated lead emissions between 1100 BCE and 800 CE derived from subannually resolved measurements in Greenland ice and detailed atmospheric transport modeling, that annual European lead emissions closely varied with historical events, including imperial expansion, wars, and major plagues. Emissions rose coeval with Phoenician expansion, accelerated during expanded Carthaginian and Roman mining primarily in the Iberian Peninsula, and reached a maximum under the Roman Empire. Emissions fluctuated synchronously with wars and political instability particularly during the Roman Republic, and plunged coincident with two major plagues in the second and third centuries, remaining low for >500 years. Bullion in silver coinage declined in parallel, reflecting the importance of lead-silver mining in ancient economies. Our results indicate sustained economic growth during the first two centuries of the Roman Empire, terminated by the second-century Antonine plague. PMID- 29760089 TI - Uncertainty in forecasts of long-run economic growth. AB - Forecasts of long-run economic growth are critical inputs into policy decisions being made today on the economy and the environment. Despite its importance, there is a sparse literature on long-run forecasts of economic growth and the uncertainty in such forecasts. This study presents comprehensive probabilistic long-run projections of global and regional per-capita economic growth rates, comparing estimates from an expert survey and a low-frequency econometric approach. Our primary results suggest a median 2010-2100 global growth rate in per-capita gross domestic product of 2.1% per year, with a standard deviation (SD) of 1.1 percentage points, indicating substantially higher uncertainty than is implied in existing forecasts. The larger range of growth rates implies a greater likelihood of extreme climate change outcomes than is currently assumed and has important implications for social insurance programs in the United States. PMID- 29760090 TI - Why we need to look beyond the glass transition temperature to characterize the dynamics of thin supported polymer films. AB - There is significant variation in the reported magnitude and even the sign of [Formula: see text] shifts in thin polymer films with nominally the same chemistry, film thickness, and supporting substrate. The implicit assumption is that methods used to estimate [Formula: see text] in bulk materials are relevant for inferring dynamic changes in thin films. To test the validity of this assumption, we perform molecular simulations of a coarse-grained polymer melt supported on an attractive substrate. As observed in many experiments, we find that [Formula: see text] based on thermodynamic criteria (temperature dependence of film height or enthalpy) decreases with decreasing film thickness, regardless of the polymer-substrate interaction strength epsilon. In contrast, we find that [Formula: see text] based on a dynamic criterion (relaxation of the dynamic structure factor) also decreases with decreasing thickness when epsilon is relatively weak, but [Formula: see text] increases when epsilon exceeds the polymer-polymer interaction strength. We show that these qualitatively different trends in [Formula: see text] reflect differing sensitivities to the mobility gradient across the film. Apparently, the slowly relaxing polymer segments in the substrate region make the largest contribution to the shift of [Formula: see text] in the dynamic measurement, but this part of the film contributes less to the thermodynamic estimate of [Formula: see text] Our results emphasize the limitations of using [Formula: see text] to infer changes in the dynamics of polymer thin films. However, we show that the thermodynamic and dynamic estimates of [Formula: see text] can be combined to predict local changes in [Formula: see text] near the substrate, providing a simple method to infer information about the mobility gradient. PMID- 29760091 TI - High-capacity rechargeable batteries based on deeply cyclable lithium metal anodes. AB - Discovering new chemistry and materials to enable rechargeable batteries with higher capacity and energy density is of paramount importance. While Li metal is the ultimate choice of a battery anode, its low efficiency is still yet to be overcome. Many strategies have been developed to improve the reversibility and cycle life of Li metal electrodes. However, almost all of the results are limited to shallow cycling conditions (e.g., 1 mAh cm-2) and thus inefficient utilization (<1%). Here we achieve Li metal electrodes that can be deeply cycled at high capacities of 10 and 20 mAh cm-2 with average Coulombic efficiency >98% in a commercial LiPF6/carbonate electrolyte. The high performance is enabled by slow release of LiNO3 into the electrolyte and its subsequent decomposition to form a Li3N and lithium oxynitrides (LiN x Oy)-containing protective layer which renders reversible, dendrite-free, and highly dense Li metal deposition. Using the developed Li metal electrodes, we construct a Li-MoS3 full cell with the anode and cathode materials in a close-to-stoichiometric amount ratio. In terms of both capacity and energy, normalized to either the electrode area or the total mass of the electrode materials, our cell significantly outperforms other laboratory scale battery cells as well as the state-of-the-art Li ion batteries on the market. PMID- 29760092 TI - Noncatalytic chalcone isomerase-fold proteins in Humulus lupulus are auxiliary components in prenylated flavonoid biosynthesis. AB - Xanthohumol (XN) and demethylxanthohumol (DMX) are specialized prenylated chalconoids with multiple pharmaceutical applications that accumulate to high levels in the glandular trichomes of hops (Humulus lupulus L.). Although all structural enzymes in the XN pathway have been functionally identified, biochemical mechanisms underlying highly efficient production of XN have not been fully resolved. In this study, we characterized two noncatalytic chalcone isomerase (CHI)-like proteins (designated as HlCHIL1 and HlCHIL2) using engineered yeast harboring all genes required for DMX production. HlCHIL2 increased DMX production by 2.3-fold, whereas HlCHIL1 significantly decreased DMX production by 30%. We show that CHIL2 is part of an active DMX biosynthetic metabolon in hop glandular trichomes that encompasses a chalcone synthase (CHS) and a membrane-bound prenyltransferase, and that type IV CHI-fold proteins of representative land plants contain conserved function to bind with CHS and enhance its activity. Binding assays and structural docking uncover a function of HlCHIL1 to bind DMX and naringenin chalcone to stabilize the ring-open configuration of these chalconoids. This study reveals the role of two HlCHILs in DMX biosynthesis in hops, and provides insight into their evolutionary development from the ancestral fatty acid-binding CHI-fold proteins to specialized auxiliary proteins supporting flavonoid biosynthesis in plants. PMID- 29760093 TI - Transhemispheric ecosystem disservices of pink salmon in a Pacific Ocean macrosystem. AB - Pink salmon (Oncorhynchus gorbuscha) in the North Pacific Ocean have flourished since the 1970s, with growth in wild populations augmented by rising hatchery production. As their abundance has grown, so too has evidence that they are having important effects on other species and on ocean ecosystems. In alternating years of high abundance, they can initiate pelagic trophic cascades in the northern North Pacific Ocean and Bering Sea and depress the availability of common prey resources of other species of salmon, resident seabirds, and other pelagic species. We now propose that the geographic scale of ecosystem disservices of pink salmon is far greater due to a 15,000-kilometer transhemispheric teleconnection in a Pacific Ocean macrosystem maintained by short-tailed shearwaters (Ardenna tenuirostris), seabirds that migrate annually between their nesting grounds in the South Pacific Ocean and wintering grounds in the North Pacific Ocean. Over this century, the frequency and magnitude of mass mortalities of shearwaters as they arrive in Australia, and their abundance and productivity, have been related to the abundance of pink salmon. This has influenced human social, economic, and cultural traditions there, and has the potential to alter the role shearwaters play in insular terrestrial ecology. We can view the unique biennial pulses of pink salmon as a large, replicated, natural experiment that offers basin-scale opportunities to better learn how these ecosystems function. By exploring trophic interaction chains driven by pink salmon, we may achieve a deeper conservation conscientiousness for these northern open oceans. PMID- 29760095 TI - Volatile biomarkers of symptomatic and asymptomatic malaria infection in humans. AB - Malaria remains among the world's deadliest diseases, and control efforts depend critically on the availability of effective diagnostic tools, particularly for the identification of asymptomatic infections, which play a key role in disease persistence and may account for most instances of transmission but often evade detection by current screening methods. Research on humans and in animal models has shown that infection by malaria parasites elicits changes in host odors that influence vector attraction, suggesting that such changes might yield robust biomarkers of infection status. Here we present findings based on extensive collections of skin volatiles from human populations with high rates of malaria infection in Kenya. We report broad and consistent effects of malaria infection on human volatile profiles, as well as significant divergence in the effects of symptomatic and asymptomatic infections. Furthermore, predictive models based on machine learning algorithms reliably determined infection status based on volatile biomarkers. Critically, our models identified asymptomatic infections with 100% sensitivity, even in the case of low-level infections not detectable by microscopy, far exceeding the performance of currently available rapid diagnostic tests in this regard. We also identified a set of individual compounds that emerged as consistently important predictors of infection status. These findings suggest that volatile biomarkers may have significant potential for the development of a robust, noninvasive screening method for detecting malaria infections under field conditions. PMID- 29760094 TI - Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum. AB - The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR. PMID- 29760096 TI - An operando X-ray diffraction study of chloroaluminate anion-graphite intercalation in aluminum batteries. AB - We investigated rechargeable aluminum (Al) batteries composed of an Al negative electrode, a graphite positive electrode, and an ionic liquid (IL) electrolyte at temperatures down to -40 degrees C. The reversible battery discharge capacity at low temperatures could be superior to that at room temperature. In situ/operando electrochemical and synchrotron X-ray diffraction experiments combined with theoretical modeling revealed stable AlCl4-/graphite intercalation up to stage 3 at low temperatures, whereas intercalation was reversible up to stage 4 at room temperature (RT). The higher-degree anion/graphite intercalation at low temperatures affords rechargeable Al battery with higher discharge voltage (up to 2.5 V, a record for Al battery) and energy density. A remarkable cycle life of >20,000 cycles at a rate of 6C (10 minutes charge time) was achievable for Al battery operating at low temperatures, corresponding to a >50-year battery life if charged/discharged once daily. PMID- 29760097 TI - The glycolipid GM1 reshapes asymmetric biomembranes and giant vesicles by curvature generation. AB - The ganglioside GM1 is present in neuronal membranes at elevated concentrations with an asymmetric spatial distribution. It is known to generate curvature and can be expected to strongly influence the neuron morphology. To elucidate these effects, we prepared giant vesicles with GM1 predominantly present in one leaflet of the membrane, mimicking the asymmetric GM1 distribution in neuronal membranes. Based on pulling inward and outward tubes, we developed a technique that allowed the direct measurement of the membrane spontaneous curvature. Using vesicle electroporation and fluorescence intensity analysis, we were able to quantify the GM1 asymmetry across the membrane and to subsequently estimate the local curvature generated by the molecule in the bilayer. Molecular-dynamics simulations confirm the experimentally determined dependence of the membrane spontaneous curvature as a function of GM1 asymmetry. GM1 plays a crucial role in connection with receptor proteins. Our results on curvature generation of GM1 point to an additional important role of this ganglioside, namely in shaping neuronal membranes. PMID- 29760098 TI - Cochlear amplification and tuning depend on the cellular arrangement within the organ of Corti. AB - The field of cochlear mechanics has been undergoing a revolution due to recent findings made possible by advancements in measurement techniques. While it has long been assumed that basilar-membrane (BM) motion is the most important determinant of sound transduction by the inner hair cells (IHCs), it turns out that other parts of the sensory epithelium closer to the IHCs, such as the reticular lamina (RL), move with significantly greater amplitude for weaker sounds. It has not been established how these findings are related to the complex cytoarchitecture of the organ of Corti between the BM and RL, which is composed of a lattice of asymmetric Y-shaped elements, each consisting of a basally slanted outer hair cell (OHC), an apically slanted phalangeal process (PhP), and a supporting Deiters' cell (DC). Here, a computational model of the mouse cochlea supports the hypothesis that the OHC micromotors require this Y-shaped geometry for their contribution to the exquisite sensitivity and frequency selectivity of the mammalian cochlea. By varying only the OHC gain parameter, the model can reproduce measurements of BM and RL gain and tuning for a variety of input sound levels. Malformations such as reversing the orientations of the OHCs and PhPs or removing the PhPs altogether greatly reduce the effectiveness of the OHC motors. These results imply that the DCs and PhPs must be properly accounted for in emerging OHC regeneration therapies. PMID- 29760099 TI - Hydrogel delivery of lysostaphin eliminates orthopedic implant infection by Staphylococcus aureus and supports fracture healing. AB - Orthopedic implant infections are a significant clinical problem, with current therapies limited to surgical debridement and systemic antibiotic regimens. Lysostaphin is a bacteriolytic enzyme with high antistaphylococcal activity. We engineered a lysostaphin-delivering injectable PEG hydrogel to treat Staphylococcus aureus infections in bone fractures. The injectable hydrogel formulation adheres to exposed tissue and fracture surfaces, ensuring efficient, local delivery of lysostaphin. Lysostaphin encapsulation within this synthetic hydrogel maintained enzyme stability and activity. Lysostaphin-delivering hydrogels exhibited enhanced antibiofilm activity compared with soluble lysostaphin. Lysostaphin-delivering hydrogels eradicated S. aureus infection and outperformed prophylactic antibiotic and soluble lysostaphin therapy in a murine model of femur fracture. Analysis of the local inflammatory response to infections treated with lysostaphin-delivering hydrogels revealed indistinguishable differences in cytokine secretion profiles compared with uninfected fractures, demonstrating clearance of bacteria and associated inflammation. Importantly, infected fractures treated with lysostaphin-delivering hydrogels fully healed by 5 wk with bone formation and mechanical properties equivalent to those of uninfected fractures, whereas fractures treated without the hydrogel carrier were equivalent to untreated infections. Finally, lysostaphin-delivering hydrogels eliminate methicillin-resistant S. aureus infections, supporting this therapy as an alternative to antibiotics. These results indicate that lysostaphin-delivering hydrogels effectively eliminate orthopedic S. aureus infections while simultaneously supporting fracture repair. PMID- 29760100 TI - Functional organization of intrinsic and feedback presynaptic inputs in the primary visual cortex. AB - In the primary visual cortex (V1) of many mammalian species, neurons are spatially organized according to their preferred orientation into a highly ordered map. However, whether and how the various presynaptic inputs to V1 neurons are organized relative to the neuronal orientation map remain unclear. To address this issue, we constructed genetically encoded calcium indicators targeting axon boutons in two colors and used them to map the organization of axon boutons of V1 intrinsic and V2-V1 feedback projections in tree shrews. Both connections are spatially organized into maps according to the preferred orientations of axon boutons. Dual-color calcium imaging showed that V1 intrinsic inputs are precisely aligned to the orientation map of V1 cell bodies, while the V2-V1 feedback projections are aligned to the V1 map with less accuracy. Nonselective integration of intrinsic presynaptic inputs around the dendritic tree is sufficient to reproduce cell body orientation preference. These results indicate that a precisely aligned map of intrinsic inputs could reinforce the neuronal map in V1, a principle that may be prevalent for brain areas with function maps. PMID- 29760101 TI - Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein. AB - The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member alpha1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases. PMID- 29760104 TI - Correction for Xu et al., Drought delays development of the sorghum root microbiome and enriches for monoderm bacteria. PMID- 29760103 TI - Comprehensive phylogeny of ray-finned fishes (Actinopterygii) based on transcriptomic and genomic data. AB - Our understanding of phylogenetic relationships among bony fishes has been transformed by analysis of a small number of genes, but uncertainty remains around critical nodes. Genome-scale inferences so far have sampled a limited number of taxa and genes. Here we leveraged 144 genomes and 159 transcriptomes to investigate fish evolution with an unparalleled scale of data: >0.5 Mb from 1,105 orthologous exon sequences from 303 species, representing 66 out of 72 ray-finned fish orders. We apply phylogenetic tests designed to trace the effect of whole genome duplication events on gene trees and find paralogy-free loci using a bioinformatics approach. Genome-wide data support the structure of the fish phylogeny, and hypothesis-testing procedures appropriate for phylogenomic datasets using explicit gene genealogy interrogation settle some long-standing uncertainties, such as the branching order at the base of the teleosts and among early euteleosts, and the sister lineage to the acanthomorph and percomorph radiations. Comprehensive fossil calibrations date the origin of all major fish lineages before the end of the Cretaceous. PMID- 29760107 TI - RCPCH's Russell Viner: "The NHS does not prioritise children's health". PMID- 29760105 TI - Triplets, birthweight, and handedness. AB - The mechanisms behind handedness formation in humans are still poorly understood. Very low birthweight is associated with higher odds of left-handedness, but whether this is due to low birthweight itself or premature birth is unknown. Handedness has also been linked to development, but the role of birthweight behind this association is unclear. Knowing that birthweight is lower in multiple births, triplets being about 1.5 kg lighter in comparison with singletons, and that multiples have a higher prevalence of left-handedness than singletons, we studied the association between birthweight and handedness in two large samples consisting exclusively of triplets from Japan (n = 1,305) and the Netherlands (n = 947). In both samples, left-handers had significantly lower birthweight (Japanese mean = 1,599 g [95% confidence interval (CI): 1,526-1,672 g]; Dutch mean = 1,794 g [95% CI: 1,709-1,879 g]) compared with right-handers (Japanese mean = 1,727 g [95% CI: 1,699-1,755 g]; Dutch mean = 1,903 g [95% CI: 1,867-1,938 g]). Within-family and between-family analyses both suggested that left handedness is associated with lower birthweight, also when fully controlling for gestational age. Left-handers also had significantly delayed motor development and smaller infant head circumference compared with right-handers, but these associations diluted and became nonsignificant when controlling for birthweight. Our study in triplets provides evidence for the link between low birthweight and left-handedness. Our results also suggest that developmental differences between left- and right-handers are due to a shared etiology associated with low birthweight. PMID- 29760102 TI - Broad receptor engagement of an emerging global coronavirus may potentiate its diverse cross-species transmissibility. AB - Porcine deltacoronavirus (PDCoV), identified in 2012, is a common enteropathogen of swine with worldwide distribution. The source and evolutionary history of this virus is, however, unknown. PDCoV belongs to the Deltacoronavirus genus that comprises predominantly avian CoV. Phylogenetic analysis suggests that PDCoV originated relatively recently from a host-switching event between birds and mammals. Insight into receptor engagement by PDCoV may shed light into such an exceptional phenomenon. Here we report that PDCoV employs host aminopeptidase N (APN) as an entry receptor and interacts with APN via domain B of its spike (S) protein. Infection of porcine cells with PDCoV was drastically reduced by APN knockout and rescued after reconstitution of APN expression. In addition, we observed that PDCoV efficiently infects cells of unusual broad species range, including human and chicken. Accordingly, PDCoV S was found to target the phylogenetically conserved catalytic domain of APN. Moreover, transient expression of porcine, feline, human, and chicken APN renders cells susceptible to PDCoV infection. Binding of PDCoV to an interspecies conserved site on APN may facilitate direct transmission of PDCoV to nonreservoir species, including humans, potentially reflecting the mechanism that enabled a virus, ancestral to PDCoV, to breach the species barrier between birds and mammals. The APN cell surface protein is also used by several members of the Alphacoronavirus genus. Hence, our data constitute the second identification of CoVs from different genera that use the same receptor, implying that CoV receptor selection is subjected to specific restrictions that are still poorly understood. PMID- 29760108 TI - Anatomy of a glacial meltwater discharge event in an Antarctic cove. AB - Glacial meltwater discharge from Antarctica is a key influence on the marine environment, impacting ocean circulation, sea level and productivity of the pelagic and benthic ecosystems. The responses elicited depend strongly on the characteristics of the meltwater releases, including timing, spatial structure and geochemical composition. Here we use isotopic tracers to reveal the time varying pattern of meltwater during a discharge event from the Fourcade Glacier into Potter Cove, northern Antarctic Peninsula. The discharge is strongly dependent on local air temperature, and accumulates into an extremely thin, buoyant layer at the surface. This layer showed evidence of elevated turbidity, and responded rapidly to changes in atmospherically driven circulation to generate a strongly pulsed outflow from the cove to the broader ocean. These characteristics contrast with those further south along the Peninsula, where strong glacial frontal ablation is driven oceanographically by intrusions of warm deep waters from offshore. The Fourcade Glacier switched very recently to being land-terminating; if retreat rates elsewhere along the Peninsula remain high and glacier termini progress strongly landward, the structure and impact of the freshwater discharges are likely to increasingly resemble the patterns elucidated here.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760106 TI - Metabolic regulation of chromatin modifications and gene expression. AB - Dynamic regulation of gene expression in response to changing local conditions is critical for the survival of all organisms. In metazoans, coherent regulation of gene expression programs underlies the development of functionally distinct cell lineages. The cooperation between transcription factors and the chromatin landscape enables precise control of gene expression in response to cell intrinsic and cell-extrinsic signals. Many of the chemical modifications that decorate DNA and histones are adducts derived from intermediates of cellular metabolic pathways. In addition, several of the enzymes that can remove these marks use metabolites as part of their enzymatic reaction. These observations have led to the hypothesis that fluctuations in metabolite levels influence the deposition and removal of chromatin modifications. In this review, we consider the emerging evidence that cellular metabolic activity contributes to gene expression and cell fate decisions through metabolite-dependent effects on chromatin organization. PMID- 29760109 TI - Shelf-ocean exchange and hydrography west of the Antarctic Peninsula: a review. AB - The West Antarctic Peninsula (WAP) is a highly productive marine ecosystem where extended periods of change have been observed in the form of glacier retreat, reduction of sea-ice cover and shifts in marine populations, among others. The physical environment on the shelf is known to be strongly influenced by the Antarctic Circumpolar Current flowing along the shelf slope and carrying warm, nutrient-rich water, by cold waters flooding into the northern Bransfield Strait from the Weddell Sea, by an extensive network of glaciers and ice shelves, and by strong seasonal to inter-annual variability in sea-ice formation and air-sea interactions, with significant modulation by climate modes like El Nino-Southern Oscillation and the Southern Annular Mode. However, significant gaps have remained in understanding the exchange processes between the open ocean and the shelf, the pathways and fate of oceanic water intrusions, the shelf heat and salt budgets, and the long-term evolution of the shelf properties and circulation. Here, we review how recent advances in long-term monitoring programmes, process studies and newly developed numerical models have helped bridge these gaps and set future research challenges for the WAP system.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760110 TI - Variability in summer surface residence time within a West Antarctic Peninsula biological hotspot. AB - Palmer Deep canyon along the central West Antarctic Peninsula is known to have higher phytoplankton biomass than the surrounding non-canyon regions, but the circulation mechanisms that transport and locally concentrate phytoplankton and Antarctic krill, potentially increasing prey availability to upper-trophic-level predators such as penguins and cetaceans, are currently unknown. We deployed a three-site high-frequency radar network that provided hourly surface circulation maps over the Palmer Deep hotspot. A series of particle release experiments were used to estimate surface residence time and connectivity across the canyon. The majority of residence times fell between 1.0 and 3.5 days, with a mean of 2 days and a maximum of 5 days. We found a highly significant negative relationship between wind speed and residence time. Our residence time analysis indicates that the elevated phytoplankton biomass over the central canyon is transported into and out of the hotspot on time scales much shorter than the observed phytoplankton growth rate, suggesting that the canyon may not act as an incubator of phytoplankton productivity as previously suggested. It may instead serve more as a conveyor belt of phytoplankton biomass produced elsewhere, continually replenishing the phytoplankton biomass for the local Antarctic krill community, which in turn supports numerous top predators.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760111 TI - A simplified method to estimate the run-off in Periglacial Creeks: a case study of King George Islands, Antarctic Peninsula. AB - Although the relationship between surface air temperature and glacial discharge has been studied in the Northern Hemisphere for at least a century, similar studies for Antarctica remain scarce and only for the past four decades. This data scarcity is due to the extreme meteorological conditions and terrain inaccessibility. As a result, the contribution of glacial discharge in Antarctica to global sea-level rise is still attached with great uncertainties, especially from partly glaciated hydrological basins as can be found in the Antarctic Peninsula. In this paper, we propose a simplified model based on the Monte Carlo method and Fourier analysis for estimating discharge in partly glaciated and periglacial hydrological catchments with a summer melt period. Our model offers the advantage of scarce data requirements and quick recognition of periglacial environments. Discharge was found to be highly correlated with surface air temperature for the partially glaciated hydrological catchments on Potter Peninsula, King George Island (Isla 25 Mayo). The model is simple to implement and requires few variables to make most versatile simulations. We have obtained a monthly simulated maximum flow estimates between 0.74 and 1.07 m3 s-1 for two creeks (South and North Potter) with a very good fit to field observations. The glacial mean monthly discharge during summer months was estimated to 0.44+/-0.02 m3 s-1 for South Potter Creek and 0.55+/-0.02 m3 s-1 for North Potter Creek.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760112 TI - Macronutrient and carbon supply, uptake and cycling across the Antarctic Peninsula shelf during summer. AB - The West Antarctic Peninsula shelf is a region of high seasonal primary production which supports a large and productive food web, where macronutrients and inorganic carbon are sourced primarily from intrusions of warm saline Circumpolar Deep Water. We examined the cross-shelf modification of this water mass during mid-summer 2015 to understand the supply of nutrients and carbon to the productive surface ocean, and their subsequent uptake and cycling. We show that nitrate, phosphate, silicic acid and inorganic carbon are progressively enriched in subsurface waters across the shelf, contrary to cross-shelf reductions in heat, salinity and density. We use nutrient stoichiometric and isotopic approaches to invoke remineralization of organic matter, including nitrification below the euphotic surface layer, and dissolution of biogenic silica in deeper waters and potentially shelf sediment porewaters, as the primary drivers of cross-shelf enrichments. Regenerated nitrate and phosphate account for a significant proportion of the total pools of these nutrients in the upper ocean, with implications for the seasonal carbon sink. Understanding nutrient and carbon dynamics in this region now will inform predictions of future biogeochemical changes in the context of substantial variability and ongoing changes in the physical environment.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760113 TI - Impact of sea-ice melt on dimethyl sulfide (sulfoniopropionate) inventories in surface waters of Marguerite Bay, West Antarctic Peninsula. AB - The Southern Ocean is a hotspot of the climate-relevant organic sulfur compound dimethyl sulfide (DMS). Spatial and temporal variability in DMS concentration is higher than in any other oceanic region, especially in the marginal ice zone. During a one-week expedition across the continental shelf of the West Antarctic Peninsula (WAP), from the shelf break into Marguerite Bay, in January 2015, spatial heterogeneity of DMS and its precursor dimethyl sulfoniopropionate (DMSP) was studied and linked with environmental conditions, including sea-ice melt events. Concentrations of sulfur compounds, particulate organic carbon (POC) and chlorophyll a in the surface waters varied by a factor of 5-6 over the entire transect. DMS and DMSP concentrations were an order of magnitude higher than currently inferred in climatologies for the WAP region. Particulate DMSP concentrations were correlated most strongly with POC and the abundance of haptophyte algae within the phytoplankton community, which, in turn, was linked with sea-ice melt. The strong sea-ice signal in the distribution of DMS(P) implies that DMS(P) production is likely to decrease with ongoing reductions in sea-ice cover along the WAP. This has implications for feedback processes on the region's climate system.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760114 TI - A 'shallow bathtub ring' of local sedimentary iron input maintains the Palmer Deep biological hotspot on the West Antarctic Peninsula shelf. AB - Palmer Deep (PD) is one of several regional hotspots of biological productivity along the inner shelf of the West Antarctic Peninsula. The proximity of hotspots to shelf-crossing deep troughs has led to the 'canyon hypothesis', which proposes that circumpolar deep water flowing shoreward along the canyons is upwelled on the inner shelf, carrying nutrients including iron (Fe) to surface waters, maintaining phytoplankton blooms. We present here full-depth profiles of dissolved and particulate Fe and manganese (Mn) from eight stations around PD, sampled in January and early February of 2015 and 2016, allowing the first detailed evaluation of Fe sources to the area's euphotic zone. We show that upwelling of deep water does not control Fe flux to the surface; instead, shallow sediment-sourced Fe inputs are transported horizontally from surrounding coastlines, creating strong vertical gradients of dissolved Fe within the upper 100 m that supply this limiting nutrient to the local ecosystem. The supply of bioavailable Fe is, therefore, not significantly related to the canyon transport of deep water. Near shore time-series samples reveal that local glacial meltwater appears to be an important Mn source but, surprisingly, is not a large direct Fe input to this biological hotspot.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760115 TI - Evidences of strong sources of DFe and DMn in Ryder Bay, Western Antarctic Peninsula. AB - The spatial distribution, biogeochemical cycling and external sources of dissolved iron and dissolved manganese (DFe and DMn) were investigated in Ryder Bay, a small coastal embayment of the West Antarctic Peninsula, during Austral summer (2013 and 2014). Dissolved concentrations were measured throughout the water column at 11 stations within Ryder Bay. The concentration ranges of DFe and DMn were large, between 0.58 and 32.7 nM, and between 0.18 and 26.2 nM, respectively, exhibiting strong gradients from the surface to the bottom. Surface concentrations of DFe and DMn were higher than concentrations reported for the Southern Ocean and coastal Antarctic waters, and extremely high concentrations were detected in deep water. Glacial meltwater and shallow sediments are likely to be the main sources of DFe and DMn in the euphotic zone, while lateral advection associated with local sediment resuspension and vertical mixing are significant sources for intermediate and deep waters. During summer, vertical mixing of intermediate and deep waters and sediment resuspension occurring from Marguerite Trough to Ryder Bay are thought to be amplified by a series of overflows at the sills, enhancing the input of Fe and Mn from bottom sediment and increasing their concentrations up to the euphotic layer.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760116 TI - Changes in the upper ocean mixed layer and phytoplankton productivity along the West Antarctic Peninsula. AB - The West Antarctic Peninsula (WAP) has experienced significant change over the last 50 years. Using a 24 year spatial time series collected by the Palmer Long Term Ecological Research programme, we assessed long-term patterns in the sea ice, upper mixed layer depth (MLD) and phytoplankton productivity. The number of sea ice days steadily declined from the 1980s until a recent reversal that began in 2008. Results show regional differences between the northern and southern regions sampled during regional ship surveys conducted each austral summer. In the southern WAP, upper ocean MLD has shallowed by a factor of 2. Associated with the shallower mixed layer is enhanced phytoplankton carbon fixation. In the north, significant interannual variability resulted in the mixed layer showing no trended change over time and there was no significant increase in the phytoplankton productivity. Associated with the recent increases in sea ice there has been an increase in the photosynthetic efficiency (chlorophyll a-normalized carbon fixation) in the northern and southern regions of the WAP. We hypothesize the increase in sea ice results in increased micronutrient delivery to the continental shelf which in turn leads to enhanced photosynthetic performance.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760117 TI - Inter-decadal variability of phytoplankton biomass along the coastal West Antarctic Peninsula. AB - The West Antarctic Peninsula (WAP) is a climatically sensitive region where periods of strong warming have caused significant changes in the marine ecosystem and food-web processes. Tight coupling between phytoplankton and higher trophic levels implies that the coastal WAP is a bottom-up controlled system, where changes in phytoplankton dynamics may largely impact other food-web components. Here, we analysed the inter-decadal time series of year-round chlorophyll-a (Chl) collected from three stations along the coastal WAP: Carlini Station at Potter Cove (PC) on King George Island, Palmer Station on Anvers Island and Rothera Station on Adelaide Island. There were trends towards increased phytoplankton biomass at Carlini Station (PC) and Palmer Station, while phytoplankton biomass declined significantly at Rothera Station over the studied period. The impacts of two relevant climate modes to the WAP, the El Nino-Southern Oscillation and the Southern Annular Mode, on winter and spring phytoplankton biomass appear to be different among the three sampling stations, suggesting an important role of local-scale forcing than large-scale forcing on phytoplankton dynamics at each station. The inter-annual variability of seasonal bloom progression derived from considering all three stations together captured ecologically meaningful, seasonally co-occurring bloom patterns which were primarily constrained by water column stability strength. Our findings highlight a coupled link between phytoplankton and physical and climate dynamics along the coastal WAP, which may improve our understanding of overall WAP food-web responses to climate change and variability.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760119 TI - Spring-summer net community production, new production, particle export and related water column biogeochemical processes in the marginal sea ice zone of the Western Antarctic Peninsula 2012-2014. AB - New production (New P, the rate of net primary production (NPP) supported by exogenously supplied limiting nutrients) and net community production (NCP, gross primary production not consumed by community respiration) are closely related but mechanistically distinct processes. They set the carbon balance in the upper ocean and define an upper limit for export from the system. The relationships, relative magnitudes and variability of New P (from 15NO3- uptake), O2 : argon based NCP and sinking particle export (based on the 238U : 234Th disequilibrium) are increasingly well documented but still not clearly understood. This is especially true in remote regions such as polar marginal ice zones. Here we present a 3-year dataset of simultaneous measurements made at approximately 50 stations along the Western Antarctic Peninsula (WAP) continental shelf in midsummer (January) 2012-2014. Net seasonal-scale changes in water column inventories (0-150 m) of nitrate and iodide were also estimated at the same stations. The average daily rates based on inventory changes exceeded the shorter term rate measurements. A major uncertainty in the relative magnitude of the inventory estimates is specifying the start of the growing season following sea ice retreat. New P and NCP(O2) did not differ significantly. New P and NCP(O2) were significantly greater than sinking particle export from thorium-234. We suggest this is a persistent and systematic imbalance and that other processes such as vertical mixing and advection of suspended particles are important export pathways.This article is part of the theme issue 'The marine system of the west Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760118 TI - Icebergs, sea ice, blue carbon and Antarctic climate feedbacks. AB - Sea ice, including icebergs, has a complex relationship with the carbon held within animals (blue carbon) in the polar regions. Sea-ice losses around West Antarctica's continental shelf generate longer phytoplankton blooms but also make it a hotspot for coastal iceberg disturbance. This matters because in polar regions ice scour limits blue carbon storage ecosystem services, which work as a powerful negative feedback on climate change (less sea ice increases phytoplankton blooms, benthic growth, seabed carbon and sequestration). This resets benthic biota succession (maintaining regional biodiversity) and also fertilizes the ocean with nutrients, generating phytoplankton blooms, which cascade carbon capture into seabed storage and burial by benthos. Small icebergs scour coastal shallows, whereas giant icebergs ground deeper, offshore. Significant benthic communities establish where ice shelves have disintegrated (giant icebergs calving), and rapidly grow to accumulate blue carbon storage. When 5000 km2 giant icebergs calve, we estimate that they generate approximately 106 tonnes of immobilized zoobenthic carbon per year (t C yr-1). However, their collisions with the seabed crush and recycle vast benthic communities, costing an estimated 4 * 104 t C yr-1 We calculate that giant iceberg formation (ice shelf disintegration) has a net potential of approximately 106 t C yr-1 sequestration benefits as well as more widely known negative impacts.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760120 TI - Benthic meltwater fjord habitats formed by rapid glacier recession on King George Island, Antarctica. AB - The coasts of the West Antarctic Peninsula are strongly influenced by glacier meltwater discharge. The spatial structure and biogeochemical composition of inshore habitats are shaped by large quantities of terrigenous particulate material deposited in the vicinity of the coast, which impacts the pelagic and benthic ecosystems. We used a multitude of geochemical and environmental variables to identify the radius extension of the meltwater impact from the Fourcade Glacier into the fjord system of Potter Cove, King George Island. The k means cluster algorithm, canonical correspondence analysis, variance analysis and Tukey's post hoc multiple comparison tests were applied to define and cluster coastal meltwater habitats. A minimum of 10 clusters were needed to classify the 8 km2 study area into meltwater fjord habitats (MFHs), fjord habitats and marine habitats. Strontium content in surface sediments is the main geochemical indicator for lithogenic creek discharge in Potter Cove. Furthermore, bathymetry, glacier distance and geomorphic positioning are the essential habitats explaining variables. The mean and maximum MFH extent amounted to 1 km and 2 km, respectively. Extrapolation of the identified meltwater impact ranges to King George Island coastlines, which are presently ice-covered bays and fjord areas, indicated an overall coverage of 200-400 km2 MFH, underpinning the importance of better understanding the biology and biogeochemistry in terrestrial marine transition zones.This article is part of the theme issue 'The marine system of the West Antarctic Peninsula: status and strategy for progress in a region of rapid change'. PMID- 29760121 TI - The marine system of the West Antarctic Peninsula: status and strategy for progress. PMID- 29760122 TI - Perturbations in mitochondrial dynamics by p66Shc lead to renal tubular oxidative injury in human diabetic nephropathy. AB - Renal tubular injury is increasingly being recognized as an early characteristic of diabetic nephropathy (DN). Mitochondrial dynamic alterations and redox protein p66Shc-mediated oxidative stress are both critical for ensuing diabetic tubular cell injury and apoptosis; whether these two processes are interlinked remains unclear. In the present study, we observed changes in mitochondrial morphology and expression of associated proteins in tubules of patients with DN. We demonstrated mitochondrial fragmentation as an important pathogenic feature of tubular cell injury that is linked to oxidative stress and p66Shc up-regulation. In renal proximal tubular cells, alterations in mitochondrial dynamics and expression of fission-fusion proteins were observed under high glucose (HG) ambience, along with p66Shc Ser36 phosphorylation. Gene ablation of p66Shc alleviated HG-induced mitochondrial fragmentation, down-regulated Fis1 and reduced p66Shc-Fis1 binding, increased Mfn1 expression, and disrupted interactions between Mfn1 and proapoptotic Bak. Overexpression of p66Shc exacerbated these changes, whereas overexpression of dominant-negative p66Shc Ser36 mutant had a marginal effect under HG, indicating that p66Shc phosphorylation as a prerequisite in the modulation of mitochondrial dynamics. Disrupted mitochondrial dynamics and enhanced Mfn1-Bak interactions modulated by p66Shc led to loss of mitochondrial voltage potential, cytochrome C release, excessive ROS generation, and apoptosis. Taken together, these results link p66Shc to mitochondrial dynamic alterations in the pathogenesis of DN and unveil a novel mechanism by which p66Shc mediates HG-induced mitochondrial fragmentation and proapoptotic signaling that results in oxidative injury and apoptosis in the tubular compartment in human diabetic nephropathy. PMID- 29760123 TI - Diabetes-Attributable Nursing Home Costs for Each U.S. State. AB - OBJECTIVE: To estimate the diabetes-attributable nursing home costs for each state. RESEARCH DESIGN AND METHODS: We used a diabetes-attributable fraction (AF) approach to estimate nursing home costs attributable to diabetes (in 2013 dollars) in aggregate and per person with diabetes in each state. We calculated the AFs as the difference in diabetes prevalence between nursing homes and the community. We used the Centers for Medicare & Medicaid Services 2013-2015 Minimum Data Set to estimate the prevalence of diabetes in nursing homes and to adjust for the intensity of care among people with diabetes in nursing homes. Community prevalence was estimated using the Behavioral Risk Factor Surveillance System (BRFSS). State nursing home expenditures were from the 2013 State Health Expenditure Accounts. RESULTS: The fraction of total nursing home expenditures attributable to diabetes ranged from 12.3% (Illinois) to 22.5% (Washington, DC; median AF of 15.6%, New Jersey). The median AF was highest in the 19-64 years age group and lowest in the 85 years or older age-group. Nationally, diabetes attributable nursing home costs were $18.6 billion. State-level diabetes attributable costs ranged from $21 million in Alaska to $2.0 billion in California. Diabetes-attributable nursing home costs per person ranged from $374 in New Mexico to $1,610 in Washington, DC (median of $799 in Maine). CONCLUSIONS: Our estimates provide state policymakers with an improved understanding of the economic burden of diabetes in each state's nursing homes. These estimates could serve as critical inputs for planning and evaluating diabetes prevention and management interventions that can keep people healthier and living longer in their communities. PMID- 29760124 TI - In Vitro Activity of Ceftazidime-Avibactam against Clinical Isolates of Enterobacteriaceae and Pseudomonas aeruginosa Collected in Asia-Pacific Countries: Results from the INFORM Global Surveillance Program, 2012 to 2015. AB - The in vitro activities of ceftazidime-avibactam and comparators against 9,149 isolates of Enterobacteriaceae and 2,038 isolates of Pseudomonas aeruginosa collected by 42 medical centers in nine countries in the Asia-Pacific region from 2012 to 2015 were determined as part of the International Network for Optimal Resistance Monitoring (INFORM) global surveillance program. Antimicrobial susceptibility testing was conducted by Clinical and Laboratory Standards Institute (CLSI) broth microdilution, and isolate subset analysis was performed on the basis of the resistant phenotypes and beta-lactamase content. Ceftazidime avibactam demonstrated potent in vitro activity (MIC, <=8 MUg/ml) against all Enterobacteriaceae tested (99.0% susceptible) and was the most active against isolates that were metallo-beta-lactamase (MBL) negative (99.8% susceptible). Against P. aeruginosa, 92.6% of all isolates and 96.1% of MBL-negative isolates were susceptible to ceftazidime-avibactam (MIC, <=8 MUg/ml). The rates of susceptibility to ceftazidime-avibactam ranged from 97.0% (Philippines) to 100% (Hong Kong, South Korea) for Enterobacteriaceae and from 83.1% (Thailand) to 100% (Hong Kong) among P. aeruginosa isolates, with lower susceptibilities being observed in countries where MBLs were more frequently encountered (Philippines, Thailand). Ceftazidime-avibactam inhibited 97.2 to 100% of Enterobacteriaceae isolates, per country, that carried serine beta-lactamases, including extended spectrum beta-lactamases, AmpC cephalosporinases, and carbapenemases (KPC, GES, OXA-48-like). It also inhibited 91.3% of P. aeruginosa isolates that were carbapenem nonsusceptible in which no acquired beta-lactamase was detected. Among MBL-negative Enterobacteriaceae isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 96.1, 87.7, 100, and 98.8% of isolates, respectively, and among MBL-negative P. aeruginosa isolates that were ceftazidime nonsusceptible, meropenem nonsusceptible, colistin resistant, and multidrug resistant, ceftazidime-avibactam inhibited 79.6, 83.6, 83.3, and 68.2% of isolates, respectively. Overall, clinical isolates of Enterobacteriaceae and P. aeruginosa collected in nine Asia-Pacific countries from 2012 to 2015 were highly susceptible to ceftazidime-avibactam. PMID- 29760125 TI - Characterization of the Anti-Hepatitis C Virus Activity of New Nonpeptidic Small Molecule Cyclophilin Inhibitors with the Potential for Broad Anti-Flaviviridae Activity. AB - Although members of the Flaviviridae display high incidence, morbidity, and mortality rates, the development of specific antiviral drugs for each virus is unlikely. Cyclophilins, a family of host peptidyl-prolyl cis-trans isomerases (PPIases), play a pivotal role in the life cycles of many viruses and therefore represent an attractive target for broad-spectrum antiviral development. We report here the pangenotypic anti-hepatitis C virus (HCV) activity of a small molecule cyclophilin inhibitor (SMCypI). Mechanistic and modeling studies revealed that the SMCypI bound to cyclophilin A in competition with cyclosporine (CsA), inhibited its PPIase activity, and disrupted the CypA-nonstructural protein 5A (NS5A) interaction. Resistance selection showed that the lead SMCypI hardly selected amino acid substitutions conferring low-level or no resistance in vitro Interestingly, the SMCypI selected D320E and Y321H substitutions, located in domain II of the NS5A protein. These substitutions were previously associated with low-level resistance to cyclophilin inhibitors such as alisporivir. Finally, the SMCypI inhibited the replication of other members of the Flaviviridae family with higher 50% effective concentrations (EC50s) than for HCV. Thus, because of its chemical plasticity and simplicity of synthesis, our new family of SMCypIs represents a promising new class of drugs with the potential for broad-spectrum anti-Flaviviridae activity as well as an invaluable tool to explore the role of cyclophilins in viral life cycles. PMID- 29760127 TI - In Vitro Activity of Clofazimine against Nontuberculous Mycobacteria Isolated in Beijing, China. AB - Due to the natural resistance of nontuberculous mycobacteria (NTM) to many antibiotics, the treatment of diseases caused by NTM is often long-term but unsuccessful. The main goal of this study was to evaluate the in vitro susceptibilities to clofazimine of 209 isolates consisting of different NTM species isolated in Beijing, China. Furthermore, 47 reference strains were also tested, including 30 rapidly growing mycobacterium (RGM) species and 17 slowly growing mycobacterium (SGM) species. The potential molecular mechanism contributing to clofazimine resistance of NTM was investigated as well. Clofazimine exhibited excellent activity against both reference strains and clinical isolates of different SGM species, and most of the strains had MICs far below 1 MUg/ml. Although the majority of the clinical isolates of Mycobacterium abscessus and Mycobacterium fortuitum had MICs higher than 2 MUg/ml, 17 out of the 30 reference strains of different RGM species had MICs below 1 MUg/ml in vitro According to the MIC distributions, the tentative epidemiological cutoff (ECOFF) values for Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium intracellulare were defined at 0.5 MUg/ml, 1 MUg/ml, and 2 MUg/ml, respectively. Intriguingly, single-direction cross-resistance between bedaquiline- and clofazimine (Cfz)-resistant isolates was observed among the tested NTM species. This study demonstrates that clofazimine had strong activity against most SGM species in vitro, as well as some RGM species. The data provide important insights into the possible clinical application of Cfz to treat NTM infections. PMID- 29760128 TI - Nitric Oxide-Releasing Macromolecule Exhibits Broad-Spectrum Antifungal Activity and Utility as a Topical Treatment for Superficial Fungal Infections. AB - Cutaneous and superficial fungal infections affecting the skin, nails, and hair of humans are caused primarily by dermatophytes of the genera Trichophyton and Epidermophyton or by yeasts of the genera Candida and Malassezia. Onychomycosis is a common fungal infection of the nail that frequently coexists with tinea pedis, the most prevalent mycotic skin infection. Efficacy rates for current topical onychomycosis therapies are hampered by low drug penetration across the nail plate, which is theoretically obviated with nitric oxide (NO)-based topical therapies. The Nitricil technology platform is comprised of polysiloxane-based macromolecules that stably release therapeutic levels of NO. In the reported studies, NVN1000, the lead candidate of the platform, was assessed for its spectrum of in vitro activity against a broad range of filamentous fungi and yeast species commonly associated with cutaneous fungal infections. Time-kill assays demonstrated that NVN1000 exhibited fungicidal activity as early as 4 h. Additionally, the penetration of several unique NVN1000 NO-releasing drug product formulations (gel, cream, and lacquer) was evaluated following a single topical application in an in vitro infected human nail assay, with all formulations showing similar inhibition of fungal growth. Repeated topical application in this model demonstrated that a lower-strength dose of NO could achieve the same efficacy as a higher-strength dose after 7 days. Together, these in vitro results demonstrate that NO-releasing treatments rapidly penetrate the nail plate and eradicate the fungal infection, representing promising novel topical therapies for the treatment of onychomycosis and other cutaneous fungal infections. PMID- 29760126 TI - Efficacy, Biodistribution, and Nephrotoxicity of Experimental Amphotericin B Deoxycholate Formulations for Pulmonary Aspergillosis. AB - An experimental micellar formulation of 1:1.5 amphotericin B-sodium deoxycholate (AMB:DCH 1:1.5) was obtained and characterized to determine its aggregation state and particle size. The biodistribution, nephrotoxicity, and efficacy against pulmonary aspergillosis in a murine model were studied and compared to the liposomal commercial formulation of amphotericin B after intravenous administration. The administration of 5 mg/kg AMB:DCH 1:1.5 presented 2.8-fold higher lung concentrations (18.125 +/- 3.985 MUg/g after 6 daily doses) and lower kidney exposure (0.391 +/- 0.167 MUg/g) than liposomal commercial amphotericin B (6.567 +/- 1.536 and 5.374 +/- 1.157 MUg/g in lungs and kidneys, respectively). The different biodistribution of AMB:DCH micelle systems compared to liposomal commercial amphotericin B was attributed to their different morphologies and particle sizes. The efficacy study has shown that both drugs administered at 5 mg/kg produced similar survival percentages and reductions of fungal burden. A slightly lower nephrotoxicity, associated with amphotericin B, was observed with AMB:DCH 1:1.5 than the one induced by the liposomal commercial formulation. However, AMB:DCH 1:1.5 reached higher AMB concentrations in lungs, which could represent a therapeutic advantage over liposomal commercial amphotericin B-based treatment of pulmonary aspergillosis. These results are encouraging to explore the usefulness of AMB:DCH 1:1.5 against this disease. PMID- 29760129 TI - Pharmacokinetic Changes during Pregnancy According to Genetic Variants: a Prospective Study in HIV-Infected Patients Receiving Atazanavir-Ritonavir. AB - Atazanavir-ritonavir concentrations change over time during pregnancy in HIV positive patients; the impact of genetic variants is unknown. Twenty patients were enrolled in this study; plasma and intracellular concentrations of antiretrovirals were measured, in addition to single-nucleotide polymorphisms in transport-related genes. Linear logistic regression showed that genetic variants in organic-anion-transporter-1B1- and pregnane-X-receptor-encoding genes affected third-trimester atazanavir exposure. In this prospective study, genetic variants partially explained the observed interpatient variability in third-trimester exposure to antiretrovirals. PMID- 29760130 TI - Clinical, Radiological, and Microbiological Characteristics of Mycobacterium simiae Infection in 97 Patients. AB - Mycobacterium simiae is a rare species of slow-growing nontuberculous mycobacteria (NTM). From 2002 to 2017, we conducted a retrospective study that included all patients with NTM-positive respiratory samples detected in two university hospitals of the French overseas department of Reunion Island. We recorded the prevalence of M. simiae in this cohort, as well as the clinical, radiological, and microbiological features of patients with at least 1 sample positive for M. simiae In our cohort, 97 patients (15.1%) were positive for M. simiae Twenty-one patients (21.6%) met the American Thoracic Society (ATS) criteria for infection. M. simiae infection was associated with bronchiectasis, micronodular lesions, and weight loss. Antibiotic susceptibility testing was performed for 60 patients, and the isolates were found to have low susceptibility to antibiotics, except for amikacin, fluoroquinolones, and clarithromycin. Treatment failed for 4 of the 8 patients treated for M. simiae infection. Here, we describe a specific cluster corresponding to a large cohort of patients with M. simiae, a rare nontuberculous mycobacterium associated with low pathogenicity and poor susceptibility to antibiotics. PMID- 29760131 TI - Identification and Characterization of Salmonella enterica Serotype Newport Isolates with Decreased Susceptibility to Ciprofloxacin in the United States. AB - Nontyphoidal Salmonella (NTS) causes an estimated 1.2 million illnesses, 23,000 hospitalizations, and 450 deaths each year in the United States. Decreased susceptibility to ciprofloxacin (DSC) has historically been associated with chromosomal mutations of the quinolone resistance determining region (QRDR), but plasmid-mediated quinolone resistance (PMQR) genes are increasing. To investigate DSC among Salmonella enterica serotype Newport strains, we examined 40 isolates from 1996 to 2016 with DSC. Thirty isolates (71%) contained the PMQR gene qnrB and eight isolates (19%) contained a QRDR. PMID- 29760132 TI - A Multimodal Imaging Approach Enables In Vivo Assessment of Antifungal Treatment in a Mouse Model of Invasive Pulmonary Aspergillosis. AB - Aspergillus fumigatus causes life-threatening lung infections in immunocompromised patients. Mouse models are extensively used in research to assess the in vivo efficacies of antifungals. In recent years, there has been an increasing interest in the use of noninvasive imaging techniques to evaluate experimental infections. However, single imaging modalities have limitations concerning the type of information they can provide. In this study, magnetic resonance imaging and bioluminescence imaging were combined to obtain longitudinal information on the extent of developing lesions and fungal load in a leukopenic mouse model of invasive pulmonary aspergillosis (IPA). This multimodal imaging approach was used to assess changes occurring within lungs of infected mice receiving voriconazole treatment starting at different time points after infection. The results showed that IPA development depends on the inoculum size used to infect animals and that disease can be successfully prevented or treated by initiating intervention during early stages of infection. Furthermore, we demonstrated that a reduction in fungal load is not necessarily associated with the disappearance of lesions on anatomical lung images, especially when antifungal treatment coincides with immune recovery. In conclusion, multimodal imaging allows an investigation of different aspects of disease progression or recovery by providing complementary information on dynamic processes, which are highly useful for assessing the efficacy of (novel) therapeutic compounds in a time- and labor-efficient manner. PMID- 29760134 TI - OXA-72-Mediated Carbapenem Resistance in Sequence Type 1 Multidrug (Colistin) Resistant Acinetobacter baumannii Associated with Urinary Tract Infection in a Dog from Serbia. PMID- 29760133 TI - Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults. AB - There are limited data on the pharmacokinetic and safety profiles of artesunate amodiaquine in human immnunodeficiency virus-infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC0-28) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults (n = 6/arm) received half the standard adult treatment regimen of artesunate amodiaquine. In step 2, another cohort (n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC0-28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir boosted lopinavir arm had 51% lower desethylamodiaquine AUC0-28, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng . h/ml (P < 0.001). No significant differences in AUC0-28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity. PMID- 29760135 TI - In Vitro Activity of Imipenem-Relebactam against Clinical Isolates of Gram Negative Bacilli Isolated in Hospital Laboratories in the United States as Part of the SMART 2016 Program. AB - Relebactam is a non-beta-lactam, bicyclic diazabicyclooctane beta-lactamase inhibitor of class A and class C beta-lactamases, including Klebsiella pneumoniae carbapenemases (KPCs). It is in phase 3 clinical development in combination with imipenem/cilastatin. The in vitro activities of imipenem-relebactam, imipenem, and comparators were determined using the Clinical and Laboratory Standards Institute (CLSI) reference broth microdilution method for isolates of Enterobacteriaceae (n = 3,419) and Pseudomonas aeruginosa (n = 896) collected in 2016 by 21 U.S. hospital laboratories participating in the SMART (Study for Monitoring Antimicrobial Resistance Trends) global surveillance program. Relebactam was tested at a fixed concentration of 4 MUg/ml. Imipenem-relebactam MICs were interpreted using CLSI breakpoints for imipenem. Rates of susceptibility to imipenem-relebactam and imipenem for non ProteeaeEnterobacteriaceae (n = 3,143) and P. aeruginosa were 99.1% (3,115/3,143) and 95.9% (3,013/3,143) and were 94.4% (846/896) and 74.7% (669/896), respectively. Relebactam restored imipenem susceptibility to 78.5% (102/130) of imipenem-nonsusceptible non-ProteeaeEnterobacteriaceae and to 78.0% (177/227) of imipenem-nonsusceptible P. aeruginosa isolates. Susceptibility to imipenem relebactam was 98.2% (444/452) and 82.2% (217/264) for multidrug-resistant (MDR) non-ProteeaeEnterobacteriaceae and MDR P. aeruginosa, respectively. Given the ability of relebactam to restore susceptibility to imipenem in nonsusceptible isolates of both non-ProteeaeEnterobacteriaceae and P. aeruginosa and to demonstrate potent activity against current MDR isolates of both non ProteeaeEnterobacteriaceae and P. aeruginosa, further development of imipenem relebactam appears warranted. PMID- 29760136 TI - Aztreonam-Avibactam Combination Restores Susceptibility of Aztreonam in Dual Carbapenemase-Producing Enterobacteriaceae. PMID- 29760137 TI - Identification and Characterization of Conjugative Plasmids That Encode Ciprofloxacin Resistance in Salmonella. AB - This study aimed to characterize novel conjugative plasmids that encode transferable ciprofloxacin resistance in Salmonella In this study, 157 nonduplicated Salmonella isolates were recovered from food products, of which 55 were found to be resistant to ciprofloxacin. Interestingly, 37 of the 55 CiprSalmonella isolates (67%) did not harbor any mutations in the quinolone resistance-determining regions (QRDR). Six Salmonella isolates were shown to carry two novel types of conjugative plasmids that could transfer the ciprofloxacin resistance phenotype to Escherichia coli J53 (azithromycin resistant [Azir]). The first type of conjugative plasmid belonged to the ~110-kb IncFIB-type conjugative plasmids carrying qnrB-bearing and aac(6')-Ib-cr-bearing mobile elements. Transfer of the plasmid between E. coli and Salmonella could confer a ciprofloxacin MIC of 1 to 2 MUg/ml. The second type of conjugative plasmid belonged to ~240-kb IncH1/IncF plasmids carrying a single PMQR gene, qnrS Importantly, this type of conjugative ciprofloxacin resistance plasmid could be detected in clinical Salmonella isolates. The dissemination of these conjugative plasmids that confer ciprofloxacin resistance poses serious challenges to public health and Salmonella infection control. PMID- 29760138 TI - Colocation of the Polymyxin Resistance Gene mcr-1 and a Variant of mcr-3 on a Plasmid in an Escherichia coli Isolate from a Chicken Farm. AB - A colistin-resistant Escherichia coli isolate from a commercial poultry farm in China carried two colistin resistance genes, mcr-1 and variant of mcr-3, in an IncP plasmid. The variant of the mcr-3 gene, named mcr-3.11, encoded two amino acid substitutions compared with the mcr-3 gene. A novel genetic structure, ISKpn40-mcr-3-dgkA-ISKpn40, might be the key element mediating the translocation of mcr-3 through the formation of a circular form. The mcr-1 and mcr-3 genes, which are colocated on a plasmid, might pose a huge threat to public health. PMID- 29760139 TI - ClpA and HtpX Proteases Are Involved in Intrinsic Aminoglycoside Resistance of Stenotrophomonas maltophilia and Are Potential Aminoglycoside Adjuvant Targets. AB - The linkage of the protease-chaperon system, SmeYZ pump, and aminoglycoside resistance was assessed in Stenotrophomonas maltophilia The clpA, clpS, clpP, and htpX genes were upregulated in response to kanamycin exposure. Of these, clpA and htpX were the primary determinants responsible for intrinsic aminoglycoside (AG) resistance. Inactivation of clpA and htpX compromised protease-mediated intrinsic aminoglycoside resistance and weakened SmeYZ pump-mediated aminoglycoside resistance, signifying HtpX and ClpA as potential AG adjuvant targets for treatment of S. maltophilia infections. PMID- 29760140 TI - Evolution of Antibiotic Resistance in Biofilm and Planktonic Pseudomonas aeruginosa Populations Exposed to Subinhibitory Levels of Ciprofloxacin. AB - The opportunistic Gram-negative pathogen Pseudomonas aeruginosa, known for its intrinsic and acquired antibiotic resistance, has a notorious ability to form biofilms, which often facilitate chronic infections. The evolutionary paths to antibiotic resistance have mainly been investigated in planktonic cultures and are less studied in biofilms. We experimentally evolved P. aeruginosa PAO1 colony biofilms and stationary-phase planktonic cultures for seven passages in the presence of subinhibitory levels (0.1 mg/liter) of ciprofloxacin (CIP) and performed a genotypic (whole-bacterial population sequencing) and phenotypic assessment of the populations. We observed a higher proportion of CIP resistance in the CIP-evolved biofilm populations than in planktonic populations exposed to the same drug concentrations. However, the MICs of ciprofloxacin were lower in CIP-resistant isolates selected from the biofilm population than the MICs of CIP resistant isolates from the planktonic cultures. We found common evolutionary trajectories between the different lineages, with mutations in known CIP resistance determinants as well as growth condition-dependent adaptations. We observed a general trend toward a reduction in type IV-pilus-dependent motility (twitching) in CIP-evolved populations and a loss of virulence-associated traits in the populations evolved in the absence of antibiotic. In conclusion, our data indicate that biofilms facilitate the development of low-level mutational resistance, probably due to the lower effective drug exposure than in planktonic cultures. These results provide a framework for the selection process of resistant variants and the evolutionary mechanisms involved under the two different growth conditions. PMID- 29760141 TI - Influence of Inoculum Effect on the Efficacy of Daptomycin Monotherapy and in Combination with beta-Lactams against Daptomycin-Susceptible Enterococcus faecium Harboring LiaSR Substitutions. AB - Enterococcus faecium isolates that harbor LiaFSR substitutions but are phenotypically susceptible to daptomycin (DAP) by current breakpoints are problematic, since predisposition to resistance may lead to therapeutic failure. Using a simulated endocardial vegetation (SEV) pharmacokinetic/pharmacodynamic (PK/PD) model, we investigated DAP regimens (6, 8, and 10 mg/kg of body weight/day) as monotherapy and in combination with ampicillin (AMP), ceftaroline (CPT), or ertapenem (ERT) against E. faecium HOU503, a DAP-susceptible strain that harbors common LiaS and LiaR substitutions found in clinical isolates (T120S and W73C, respectively). Of interest, the efficacy of DAP monotherapy, at any dose regimen, was dependent on the size of the inoculum. At an inoculum of ~109 CFU/g, DAP doses of 6 to 8 mg/kg/day were not effective and led to significant regrowth with emergence of resistant derivatives. In contrast, at an inoculum of ~107 CFU/g, marked reductions in bacterial counts were observed with DAP at 6 mg/kg/day, with no resistance. The inoculum effect was confirmed in a rat model using humanized DAP exposures. Combinations of DAP with AMP, CPT, or ERT demonstrated enhanced eradication and reduced potential for resistance, allowing de-escalation of the DAP dose. Persistence of the LiaRS substitutions was identified in DAP-resistant isolates recovered from the SEV model and in DAP resistant derivatives of an initially DAP-susceptible clinical isolate of E. faecium (HOU668) harboring LiaSR substitutions that was recovered from a patient with a recurrent bloodstream infection. Our results provide novel data for the use of DAP monotherapy and combinations for recalcitrant E. faecium infections and pave the way for testing these approaches in humans. PMID- 29760142 TI - In Vitro and In Vivo Activity of Peptidomimetic Compounds That Target the Periodontal Pathogen Porphyromonas gingivalis. AB - The interaction of the periodontal pathogen Porphyromonas gingivalis with oral streptococci is important for initial colonization of the oral cavity by P. gingivalis and is mediated by a discrete motif of the streptococcal antigen I/II protein. A synthetic peptide encompassing this motif functions as a potent inhibitor of P. gingivalis adherence, but the use of peptides as topically applied therapeutic agents in the oral cavity has limitations arising from the relatively high cost of peptide synthesis and their susceptibility to degradation by proteases expressed by oral organisms. In this study, we demonstrate the in vitro and in vivo activity of five small-molecule mimetic compounds of the streptococcal peptide. Using a three-species biofilm model, all five compounds were shown to effectively inhibit the incorporation of P. gingivalis into in vitro biofilms and exhibited 50% inhibitory concentrations (IC50s) of 10 to 20 MUM. Four of the five compounds also significantly reduced maxillary alveolar bone resorption induced by P. gingivalis infection in a mouse model of periodontitis. All of the compounds were nontoxic toward a human telomerase immortalized gingival keratinocyte cell line. Three compounds exhibited slight toxicity against the murine macrophage J774A.1 cell line at the highest concentration tested. Compound PCP-III-201 was nontoxic to both cell lines and the most potent inhibitor of P. gingivalis virulence and thus may represent a novel potential therapeutic agent that targets P. gingivalis by preventing its colonization of the oral cavity. PMID- 29760143 TI - Developmental Sensitivity in Schistosoma mansoni to Puromycin To Establish Drug Selection of Transgenic Schistosomes. AB - Schistosomiasis is considered the most important disease caused by helminth parasites, in terms of morbidity and mortality. Tools to facilitate gain- and loss-of-function approaches can be expected to precipitate the discovery of novel interventions, and drug selection of transgenic schistosomes would facilitate the establishment of stable lines of engineered parasites. Sensitivity of developmental stages of schistosomes to the aminonucleoside antibiotic puromycin was investigated. For the schistosomulum and sporocyst stages, viability was quantified by fluorescence microscopy following dual staining with fluorescein diacetate and propidium iodine. By 6 days in culture, the 50% lethal concentration (LC50) for schistosomula was 19 MUg/ml whereas the sporocysts were 45-fold more resilient. Puromycin potently inhibited the development of in vitro laid eggs (LC50, 68 ng/ml) but was less effective against liver eggs (LC50, 387 MUg/ml). Toxicity for adult stages was evaluated using the xCELLigence-based, real-time motility assay (xWORM), which revealed LC50s after 48 h of 4.9 and 17.3 MUg/ml for male and female schistosomes, respectively. Also, schistosomula transduced with pseudotyped retrovirus encoding the puromycin resistance marker were partially rescued when cultured in the presence of the antibiotic. Together, these findings will facilitate selection on puromycin of transgenic schistosomes and the enrichment of cultures of transgenic eggs and sporocysts to facilitate the establishment of schistosome transgenic lines. Streamlining schistosome transgenesis with drug selection will open new avenues to understand parasite biology and hopefully lead to new interventions for this neglected tropical disease. PMID- 29760144 TI - Personalizing Polymyxin B Dosing Using an Adaptive Feedback Control Algorithm. AB - Polymyxin B is used as an antibiotic of last resort for patients with multidrug resistant Gram-negative bacterial infections; however, it carries a significant risk of nephrotoxicity. Herein we present a polymyxin B therapeutic window based on target area under the concentration-time curve (AUC) values and an adaptive feedback control algorithm (algorithm) which allows for the personalization of polymyxin B dosing. The upper bound of this therapeutic window was determined through a pharmacometric meta-analysis of polymyxin B nephrotoxicity data, and the lower bound was derived from murine thigh infection pharmacokinetic (PK)/pharmacodynamic (PD) studies. A previously developed polymyxin B population pharmacokinetic model was used as the backbone for the algorithm. Monte Carlo simulations (MCS) were performed to evaluate the performance of the algorithm using different sparse PK sampling strategies. The results of the nephrotoxicity meta-analysis showed that nephrotoxicity rate was significantly correlated with polymyxin B exposure. Based on this analysis and previously reported murine PK/PD studies, the target AUC0-24 (AUC from 0 to 24 h) window was determined to be 50 to 100 mg . h/liter. MCS showed that with standard polymyxin B dosing without adaptive feedback control, only 71% of simulated subjects achieved AUC values within this window. Using a single PK sample collected at 24 h and the algorithm, personalized dosing regimens could be computed, which resulted in >95% of simulated subjects achieving AUC0-24 values within the target window. Target attainment further increased when more samples were used. Our algorithm increases the probability of target attainment by using as few as one pharmacokinetic sample and enables precise, personalized dosing in a vulnerable patient population. PMID- 29760145 TI - In Vitro Activity of Imipenem-Relebactam and Ceftolozane-Tazobactam against Resistant Gram-Negative Bacilli. AB - Understanding which antimicrobial agents are likely to be active against Gram negative bacilli can guide selection of antimicrobials for empirical therapy as mechanistic rapid diagnostics are adopted. In this study, we determined the MICs of a novel beta-lactam-beta-lactamase inhibitor combination, imipenem-relebactam, along with ceftolozane-tazobactam, imipenem, ertapenem, meropenem, ceftriaxone, and cefepime, against 282 drug-resistant isolates of Gram-negative bacilli. For isolates harboring blaKPC (n = 110), the addition of relebactam to imipenem lowered the MIC50/MIC90 from 16/>128 MUg/ml for imipenem alone to 0.25/1 MUg/ml. For isolates harboring blaCTX-M (n = 48), the MIC50/MIC90 of ceftolozane tazobactam were 0.5/16 MUg/ml (83% susceptible). For isolates harboring blaCMY-2 (n = 17), the MIC50/MIC90 of ceftolozane-tazobactam were 4/8 MUg/ml (47% susceptible). Imipenem-relebactam was active against most KPC-producing (but not NDM- or IMP-producing) Enterobacteriaceae and is an encouraging addition to the present antibiotic repertoire. PMID- 29760146 TI - Copper Acyl Salicylate Has Potential as an Anti-Cryptococcus Antifungal Agent. AB - The in vitro antifungal activity of aspirin against cryptococcal cells has been reported. However, the unwanted effects of aspirin may limit its clinical application. Conceivably, a derivative of aspirin could overcome this challenge. Toward this end, this study considered the usage of an aspirinate-metal complex, namely, copper acyl salicylate (CAS), as an anti-Cryptococcus antifungal agent. Additionally, the study examined the effects of this compound on macrophage function. The in vitro susceptibility results revealed that cryptococcal cells were vulnerable (in a dose-dependent manner) to CAS, which might have effected growth inhibition by damaging cryptococcal cell membranes. Interestingly, when CAS was used in combination with fluconazole or amphotericin B, synergism was observed. Furthermore, CAS did not negatively affect the growth or metabolic activity of macrophages; rather, it sensitized those immune cells to produce interferon gamma and interleukin 6, which, in turn, might have aided in the phagocytosis of cryptococcal cells. Compared to our aspirin data, CAS was noted to be more effective in killing cryptococcal cells (based on susceptibility results) and less toxic toward macrophages (based on growth inhibition results). Taking these findings together, it is reasonable to conclude that CAS may be a better anti-Cryptococcus drug that could deliver better therapeutic outcomes, compared to aspirin. PMID- 29760147 TI - Rifabutin Acts in Synergy and Is Bactericidal with Frontline Mycobacterium abscessus Antibiotics Clarithromycin and Tigecycline, Suggesting a Potent Treatment Combination. AB - Mycobacterium abscessus is a rapidly emerging mycobacterial pathogen causing dangerous pulmonary infections. Because these bacteria are intrinsically multidrug resistant, treatment options are limited and have questionable efficacy. The current treatment regimen relies on a combination of antibiotics, including clarithromycin paired with amikacin and either imipenem or cefoxitin. Tigecycline may be added when triple therapy is ineffective. We initially screened a library containing the majority of clinically available antibiotics for anti-M. abscessus activity. The screen identified rifabutin, which was then investigated for its interactions with M. abscessus antibiotics used in drug regimens. Combination of rifabutin with either clarithromycin or tigecycline generated synergistic anti-M. abscessus activity, dropping the rifabutin MIC below concentrations found in the lung. Importantly, these combinations generated bactericidal activity. The triple combination of clarithromycin, tigecycline, and rifabutin was also synergistic, and clinically relevant concentrations had a sterilizing effect on M. abscessus cultures. We suggest that combinations including rifabutin should be further investigated for treatment of M. abscessus pulmonary infections. PMID- 29760148 TI - Bacterial Silver Resistance Gained by Cooperative Interspecies Redox Behavior. AB - Silver has emerged as an important therapeutic option for wound infections in recent years due to its broad-spectrum antimicrobial activity. The silver cation (Ag+), but not the bulk metal (Ag0), is highly toxic for most microorganisms, although resistance due to genetic modification or horizontal gene transfer does occur. Pseudomonas aeruginosa, however, achieves silver resistance by producing the redox-active metabolite pyocyanin that reduces Ag+ to nontoxic Ag0 Pyocyanin also possesses broad-spectrum antimicrobial activity. Many microbial species reduce pyocyanin, which reduces molecular oxygen to antimicrobial hydrogen peroxide. In this study, it was hypothesized that both Ag+ and oxygen would act as competing terminal electron acceptors for pyocyanin, thus acting as a universal microbial protectant from Ag+ while avoiding hydrogen peroxide formation. Escherichia coli and Staphylococcus aureus efficiently reduced pyocyanin and generated hydrogen peroxide, while Ag+ markedly reduced the amount of hydrogen peroxide produced. Although unable to reduce directly Ag+ to Ag0 on their own, E. coli and S. aureus did so when pyocyanin was present, resulting in increased survival when exposed to Ag+ Coincubation experiments with either E. coli or S. aureus with P. aeruginosa demonstrated increased survival for those species to Ag+, but only if pyocyanin was present. These data demonstrate that microorganisms that display no intrinsic silver resistance may survive and proliferate under potentially toxic conditions, provided their environment contains a suitable redox-active metabolite-producing bacterium. Chronic wounds are often polymicrobial in nature, with pyocyanin-producing P. aeruginosa bacteria frequently being present; therefore, redox-based silver resistance may compromise treatment efforts. PMID- 29760150 TI - Anatomic Gene Expression Atlas Fuels Glioblastoma Discovery. AB - The Ivy Glioblastoma Atlas provides detailed information about genes expressed in different anatomic regions of human brain tumors. Researchers are already drawing upon the resource to identify novel therapeutic targets for this deadly cancer. PMID- 29760149 TI - Digital clinical encounters. PMID- 29760151 TI - Salt Intake and Immunity. PMID- 29760153 TI - Do Maternal Air Pollution Exposures Have Long-Lasting Influences on Child Blood Pressure? PMID- 29760152 TI - 20-HETE: Hypertension and Beyond. PMID- 29760155 TI - Association of circulating CXCL10 and CXCL11 with systemic sclerosis. PMID- 29760154 TI - Maternal Exposure to Ambient Particulate Matter <=2.5 um During Pregnancy and the Risk for High Blood Pressure in Childhood. AB - Exposure to ambient air pollution has been associated with greater risk of elevated blood pressure (BP) in adults and children. Recent evidence suggests that air pollution exposure in pregnancy may also portend increased risk for the next generation; however, few studies have examined this relationship. We conducted a prospective study of 1293 mothers in the Boston Birth Cohort (enrolled 1998-2012) and their children who had follow-up visits between 3 and 9 years of age and complete exposure and outcome data. Our primary exposure, ambient particulate matter <=2.5 um (PM2.5) concentration during pregnancy, was estimated by matching mother's residential address to the US Environmental Protection Agency's air quality monitors. We defined our primary outcome child systolic BP (SBP) percentile according to US reference (Fourth Report) and classified elevated BP as SBP >=90th percentile. Our multivariable-adjusted cubic spline showed a sharp increase in offspring SBP percentile and risk for elevated BP when third-trimester PM2.5 concentration was >=13 MUg/m3 The highest versus lowest tertile of third-trimester PM2.5 exposure was associated with a 4.85 (95% confidence interval: 1.38-8.37) percentile increase in child SBP or a 1.61 (95% confidence interval: 1.13-2.30) times higher risk of child elevated BP. A 5 MUg/m3 increment in PM2.5 during the third trimester was associated with a 3.49 (95% confidence interval: 0.71-6.26) percentile increase in child SBP or a 1.47 (95% confidence interval: 1.17-1.85) times higher risk of elevated BP. Our findings suggest that exposure to ambient PM2.5 during the third trimester of pregnancy is associated with elevated BP in children, ages 3 to 9 years. PMID- 29760156 TI - Improved survival with renal transplantation for end-stage renal disease due to granulomatosis with polyangiitis: data from the United States Renal Data System. AB - BACKGROUND: Renal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to granulomatosis with polyangiitis (GPA) is unknown. METHODS: We identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure. RESULTS: During the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06-0.16). DISCUSSION: Renal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population. PMID- 29760157 TI - Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. AB - OBJECTIVE: Emerging evidence supports a role for epigenetic regulation in the pathogenesis of scleroderma (SSc). We aimed to assess the role of methyl-CpG binding protein 2 (MeCP2), a key epigenetic regulator, in fibroblast activation and fibrosis in SSc. METHODS: Dermal fibroblasts were isolated from patients with diffuse cutaneous SSc (dcSSc) and from healthy controls. MeCP2 expression was measured by qPCR and western blot. Myofibroblast differentiation was evaluated by gel contraction assay in vitro. Fibroblast proliferation was analysed by ki67 immunofluorescence staining. A wound healing assay in vitro was used to determine fibroblast migration rates. RNA-seq was performed with and without MeCP2 knockdown in dcSSc to identify MeCP2-regulated genes. The expression of MeCP2 and its targets were modulated by siRNA or plasmid. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-MeCP2 antibody was performed to assess MeCP2 binding sites within MeCP2-regulated genes. RESULTS: Elevated expression of MeCP2 was detected in dcSSc fibroblasts compared with normal fibroblasts. Overexpressing MeCP2 in normal fibroblasts suppressed myofibroblast differentiation, fibroblast proliferation and fibroblast migration. RNA-seq in MeCP2-deficient dcSSc fibroblasts identified MeCP2-regulated genes involved in fibrosis, including PLAU, NID2 and ADA. Plasminogen activator urokinase (PLAU) overexpression in dcSSc fibroblasts reduced myofibroblast differentiation and fibroblast migration, while nidogen-2 (NID2) knockdown promoted myofibroblast differentiation and fibroblast migration. Adenosine deaminase (ADA) depletion in dcSSc fibroblasts inhibited cell migration rates. Taken together, antifibrotic effects of MeCP2 were mediated, at least partly, through modulating PLAU, NID2 and ADA. ChIP-seq further showed that MeCP2 directly binds regulatory sequences in NID2 and PLAU gene loci. CONCLUSIONS: This study demonstrates a novel role for MeCP2 in skin fibrosis and identifies MeCP2-regulated genes associated with fibroblast migration, myofibroblast differentiation and extracellular matrix degradation, which can be potentially targeted for therapy in SSc. PMID- 29760158 TI - Checkpoint inhibitor-induced polymyalgia rheumatica controlled by cobimetinib, a MEK 1/2 inhibitor. PMID- 29760160 TI - Development of a novel clinical staging model for cirrhosis using the Nationwide Inpatient Sample. AB - Scoring systems such as Model for End-stage Liver Disease (MELD) and Child-Pugh are often used by clinicians to determine prognosis in patients with cirrhosis. Since clinical complications are important in determining cirrhosis outcomes, our goal was to use these to develop a novel prognostic staging model. Data from the Nationwide Inpatient Sample (NIS), years 2003-2011, were queried for records of patients over the age of 18 with cirrhosis excluding patients with prior or inpatient liver transplantation. The primary outcome was inpatient mortality with focus on cirrhosis-related complications: non-bleeding esophageal varices, variceal hemorrhage, ascites, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS). Of 59 862 903 hospitalizations, 824 783 (1.4%) with cirrhosis were identified. Overall mortality was 7% with two-thirds (66%) of deaths occurring in patients with a decompensating event, defined as variceal hemorrhage, ascites, HE, SBP, and/or HRS. Overall mortality rates decreased from 2003 to 2011 (9.0-6.0%), in both compensated and decompensated groups. Mortality was higher in patients with variceal haemorrhage (OR 1.56; p<0.05), HE (OR 1.75; p<0.05), SBP (OR 2.64; p<0.05) and HRS (OR 9.10; p<0.05) compared with patients with no complications. HRS had the highest mortality, whether alone or in combination with another event such as HE (OR 12.40; p<0.05) or SBP (OR 12.64; p<0.05). Cirrhosis inpatient outcomes are related to the severity of liver disease, with more severe complications such as HE, SBP, and HRS having the most significant effect on inpatient mortality, and are utilised in this novel four-stage clinical model. PMID- 29760159 TI - Inadequate response to treat-to-target methotrexate therapy in patients with new onset rheumatoid arthritis: development and validation of clinical predictors. AB - OBJECTIVE: To identify and validate clinical baseline predictors associated with inadequate response (IR) to methotrexate (MTX) therapy in newly diagnosed patients with rheumatoid arthritis (RA). METHODS: In U-Act-Early, 108 disease modifying antirheumatic drug (DMARD)-naive patients with RA were randomised to initiate MTX therapy and treated to target until sustained remission (disease activity score assessing 28 joints (DAS28) <2.6 with four or less swollen joints for >=24 weeks) was achieved. If no remission, hydroxychloroquine was added to the treatment regimen (ie, 'MTX+') and replaced by tocilizumab if the target still was not reached thereafter. Regression analyses were performed to identify clinical predictors for IR, defined as needing addition of a biological DMARD, to 'MTX+'. Data from the treatment in the Rotterdam Early Arthritis Cohort were used for external validation of the prediction model. RESULTS: Within 1 year, 56/108 (52%) patients in U-Act-Early showed IR to 'MTX+'. DAS28 (adjusted OR (ORadj) 2.1, 95% CI 1.4 to 3.2), current smoking (ORadj 3.02, 95% CI 1.1 to 8.0) and alcohol consumption (ORadj 0.4, 95% CI 0.1 to 0.9) were identified as baseline predictors. The area under the receiver operator characteristic curve (AUROC) of the prediction model was 0.75 (95% CI 0.66 to 0.84); the positive (PPV) and negative predictive value (NPV) were 65% and 80%, respectively. When applying the model to the validation cohort, the AUROC slightly decreased to 0.67 (95% CI 0.55 to 0.79) and the PPV and NPV to 54% and 80%, respectively. CONCLUSION: Higher DAS28, current smoking and no alcohol consumption are predictive factors for IR to step-up 'MTX+' in DMARD-naive patients with new-onset RA. TRIAL REGISTRATION: NCT01034137; Post-results, ISRCTN26791028; Post-results. PMID- 29760163 TI - ? Safinamide for Parkinson's disease. AB - ? Safinamide (Xadago - Zambon S.p.A) is a monoamine-oxidase B (MAO-B) inhibitor licensed as add-on therapy for people with idiopathic Parkinson's disease who are experiencing motor fluctuations with levodopa.1 Currently there is no cure for Parkinson's disease and drugs are used to reduce motor symptoms and improve daily activities.2,3 Here, we review the evidence for this MAO-B inhibitor. PMID- 29760161 TI - CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. AB - HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene-expression patterns within confined chromatin domains for normal development. Here, we used targeted pooled CRISPR-Cas9-knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci. We discovered that the CTCF binding site located between HOXA7 and HOXA9 genes (CBS7/9) is critical for establishing and maintaining aberrant HOXA9-HOXA13 gene expression in AML. Disruption of the CBS7/9 boundary resulted in spreading of repressive H3K27me3 into the posterior active HOXA chromatin domain that subsequently impaired enhancer/promoter chromatin accessibility and disrupted ectopic long-range interactions among the posterior HOXA genes. Consistent with the role of the CBS7/9 boundary in HOXA locus chromatin organization, attenuation of the CBS7/9 boundary function reduced posterior HOXA gene expression and altered myeloid specific transcriptome profiles important for pathogenesis of myeloid malignancies. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies. PMID- 29760162 TI - Unrelated cord blood transplantation in patients with idiopathic refractory severe aplastic anemia: a nationwide phase 2 study. AB - Outcomes remain poor for refractory severe aplastic anemia (SAA) patients. Alternative donor transplantation may be considered, but results from previous studies are not encouraging. We conducted a prospective nationwide phase 2 study to assess unrelated cord blood (CB) transplantation (CBT) efficacy and safety in refractory SAA patients (Aplastic Anemia and Cord Blood Transplantation protocol). To demonstrate a significant difference in 1-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients and therefore included 26 (median age, 16 years). Eligibility criteria required 1 or 2 unrelated CB units, containing separately or together >4 * 107 frozen nucleated cells (NCs) per kilogram of recipient body weight. Conditioning regimen comprised fludarabine (FLU), cyclophosphamide (CY), antithymocyte globulin (ATG), and 2-Gy total body irradiation (TBI). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively. Twenty-three patients were alive at 1 year, with an 88.5% overall survival (OS) rate, differing significantly from the expected 20% (P < .0001; 84% OS at 2 years). CBT with units containing >=4 * 107 frozen NCs per kilogram is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors. This trial was registered at www.clinicaltrials.gov as #NCT01343953. PMID- 29760164 TI - ? Bezlotoxumab for prevention of recurrence of Clostridium difficile infection. AB - Clostridium difficile infection is a significant cause of infectious diarrhoea and is associated with considerable morbidity and mortality.1,2 Management of Clostridium difficile infection often requires treatment with antibiotics (metronidazole, vancomycin or fidaxomicin) alongside supportive care to manage hydration, electrolytes and nutrition. However, the risk of recurrence is approximately 20%.2 Here, we review the evidence for bezlotoxumab (? Zinplava - Merck Sharp & Dohme Limited), a monoclonal antibody licensed for the prevention of recurrence of Clostridium difficile in adults who are at high risk of recurrence. PMID- 29760165 TI - The impact of transcription on metabolism in prostate and breast cancers. AB - Metabolic dysregulation is regarded as an important driver in cancer development and progression. The impact of transcriptional changes on metabolism has been intensively studied in hormone-dependent cancers, and in particular, in prostate and breast cancer. These cancers have strong similarities in the function of important transcriptional drivers, such as the oestrogen and androgen receptors, at the level of dietary risk and epidemiology, genetics and therapeutically. In this review, we will focus on the function of these nuclear hormone receptors and their downstream impact on metabolism, with a particular focus on lipid metabolism. We go on to discuss how lipid metabolism remains dysregulated as the cancers progress. We conclude by discussing the opportunities that this presents for drug repurposing, imaging and the development and testing of new therapeutics and treatment combinations. PMID- 29760167 TI - Factors associated with pain and osteoarthritis at the hip and knee in Great Britain's Olympians: a cross-sectional study. AB - BACKGROUND: Knowledge of the epidemiology and potentially modifiable factors associated with musculoskeletal disease is an important first step in injury prevention among elite athletes. AIM: This study investigated the prevalence and factors associated with pain and osteoarthritis (OA) at the hip and knee in Great Britain's (GB) Olympians aged 40 and older. METHODS: This is a cross-sectional study. A survey was distributed to 2742 GB Olympians living in 30 countries. Of the 714 (26.0%) who responded, 605 were eligible for analysis (ie, aged 40 and older). RESULTS: The prevalence of hip and knee pain was 22.4% and 26.1%, and of hip and knee OA was 11.1% and 14.2%, respectively. Using a multivariable model, injury was associated with OA at the hip (adjusted OR (aOR) 10.85; 95% CI 3.80 to 30.96) and knee (aOR 4.92; 95% CI 2.58 to 9.38), and pain at the hip (aOR 5.55; 95% CI 1.83 to 16.86) and knee (aOR 2.65; 95% CI 1.57 to 4.46). Widespread pain was associated with pain at the hip (aOR 7.63; 95% CI 1.84 to 31.72) and knee (aOR 4.77; 95% CI 1.58 to 14.41). Older age, obesity, knee malalignment, comorbidities, hypermobility and weight-bearing exercise were associated with hip and knee OA and/or pain. CONCLUSIONS: This study detected an association between several factors and hip and knee pain/OA in retired GB Olympic athletes. These associations require further substantiation in retired athletes from other National Olympic Committees, and through comparison with the general population. Longitudinal follow-up is needed to investigate the factors associated with the onset and progression of OA/pain, and to determine if modulation of such factors can reduce the prevalence of pain and OA in this population. PMID- 29760166 TI - The role of IL-1B in breast cancer bone metastasis. AB - Approximately 75% of patients with late-stage breast cancer will develop bone metastasis. This condition is currently considered incurable and patients' life expectancy is limited to 2-3 years following diagnosis of bone involvement. Interleukin (IL)-1B is a pro-inflammatory cytokine whose expression in primary tumours has been identified as a potential biomarker for predicting breast cancer patients at increased risk for developing bone metastasis. In this review, we discuss how IL-1B from both the tumour cells and the tumour microenvironment influence growth of primary breast tumours, dissemination into the bone metastatic niche and proliferation into overt metastases. Recent evidence indicates that targeting IL-1B signalling may provide promising new treatments that can hold tumour cells in a dormant state within bone thus preventing formation of overt bone metastases. PMID- 29760170 TI - Trump promises to reduce drug prices but drops campaign promises. PMID- 29760171 TI - The NHS at 80? How it might look in 2028. PMID- 29760169 TI - Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus. AB - OBJECTIVE: The initial colonisation of the human microbiota and the impact of maternal health on neonatal microbiota at birth remain largely unknown. The aim of our study is to investigate the possible dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus (GDM) and to estimate the potential risks of the microbial shift to neonates. DESIGN: Pregnant women and neonates suffering from GDM were enrolled and 581 maternal (oral, intestinal and vaginal) and 248 neonatal (oral, pharyngeal, meconium and amniotic fluid) samples were collected. To avoid vaginal bacteria contaminations, the included neonates were predominantly delivered by C-section, with their samples collected within seconds of delivery. RESULTS: Numerous and diverse bacterial taxa were identified from the neonatal samples, and the samples from different neonatal body sites were grouped into distinct clusters. The microbiota of pregnant women and neonates was remarkably altered in GDM, with a strong correlation between certain discriminatory bacteria and the oral glucose tolerance test. Microbes varying by the same trend across the maternal and neonatal microbiota were observed, revealing the intergenerational concordance of microbial variation associated with GDM. Furthermore, lower evenness but more depletion of KEGG orthologues and higher abundance of some viruses (eg, herpesvirus and mastadenovirus) were observed in the meconium microbiota of neonates associated with GDM. CONCLUSION: GDM can alter the microbiota of both pregnant women and neonates at birth, which sheds light on another form of inheritance and highlights the importance of understanding the formation of early-life microbiome. PMID- 29760168 TI - Do highly physically active workers die early? A systematic review with meta analysis of data from 193 696 participants. AB - OBJECTIVE: Recent evidence suggests the existence of a physical activity paradox, with beneficial health outcomes associated with leisure time physical activity, but detrimental health outcomes for those engaging in high level occupational physical activity. This is the first quantitative systematic review of evidence regarding the association between occupational physical activity and all-cause mortality. DESIGN: Systematic review with meta-analysis. DATA SOURCE: A literature search was performed in electronic databases PubMed, Embase, CINAHL, PsycINFO and Cochrane. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We screened for peer reviewed articles from prospective studies assessing the association of occupational physical activity with all-cause mortality. A meta-analysis assessed the association of high (compared with low) level occupational physical activity with all-cause mortality, estimating pooled hazard ratios (HR) (with 95% CI). RESULTS: 2490 unique articles were screened and 33 (from 26 studies) were included. Data from 17 studies (with 193 696 participants) were used in a meta analysis, showing that men with high level occupational physical activity had an 18% increased risk of early mortality compared with those engaging in low level occupational physical activity (HR 1.18, 95% CI 1.05 to 1.34). No such association was observed among women, for whom instead a tendency for an inverse association was found (HR 0.90, 95% CI 0.80 to 1.01). CONCLUSIONS: The results of this review indicate detrimental health consequences associated with high level occupational physical activity in men, even when adjusting for relevant factors (such as leisure time physical activity). These findings suggest that research and physical activity guidelines may differentiate between occupational and leisure time physical activity. PMID- 29760172 TI - Development of a bar code-based exposure assessment method to evaluate occupational exposure to disinfectants and cleaning products: a pilot study. AB - OBJECTIVE: Healthcare workers are highly exposed to various types of disinfectants and cleaning products. Assessment of exposure to these products remains a challenge. We aimed to investigate the feasibility of a method, based on a smartphone application and bar codes, to improve occupational exposure assessment among hospital/cleaning workers in epidemiological studies. METHODS: A database of disinfectants and cleaning products used in French hospitals, including their names, bar codes and composition, was developed using several sources: ProdHyBase (a database of disinfectants managed by hospital hygiene experts), and specific regulatory agencies and industrial websites. A smartphone application has been created to scan bar codes of products and fill a short questionnaire. The application was tested in a French hospital. The ease of use and the ability to record information through this new approach were estimated. RESULTS: The method was tested in a French hospital (7 units, 14 participants). Through the application, 126 records (one record referred to one product entered by one participant/unit) were registered, majority of which were liquids (55.5%) or sprays (23.8%); 20.6% were used to clean surfaces and 15.9% to clean toilets. Workers used mostly products with alcohol and quaternary ammonium compounds (>90% with weekly use), followed by hypochlorite bleach and hydrogen peroxide (28.6%). For most records, information was available on the name (93.7%) and bar code (77.0%). Information on product compounds was available for all products and recorded in the database. CONCLUSION: This innovative and easy-to-use method could help to improve the assessment of occupational exposure to disinfectants/cleaning products in epidemiological studies. PMID- 29760173 TI - Dual impact of organisational change on subsequent exit from work unit and sickness absence: a longitudinal study among public healthcare employees. AB - OBJECTIVES: We investigated work-unit exit, total and long-term sickness absence following organisational change among public healthcare employees. METHODS: The study population comprised employees from the Capital Region of Denmark (n=14 388). Data on reorganisation at the work-unit level (merger, demerger, relocation, change of management, employee layoff or budget cut) between July and December 2013 were obtained via surveys distributed to the managers of each work unit. Individual-level data on work-unit exit, total and long-term sickness absence (>=29 days) in 2014 were obtained from company registries. For exposure to any, each type or number of reorganisations (1, 2 or >=3), the HRs and 95% CIs for subsequent work-unit exit were estimated by Cox regression, and the risk for total and long-term sickness absence were estimated by zero-inflated Poisson regression. RESULTS: Reorganisation was associated with subsequent work-unit exit (HR 1.10, 95% CI 1.01 to 1.19) in the year after reorganisation. This association was specifically important for exposure to >=3 types of changes (HR 1.52, 95% CI 1.30 to 1.79), merger (HR 1.29, 95% CI 1.12 to 1.49), demerger (HR 1.41, 95% CI 1.16 to 1.71) or change of management (HR 1.24, 95% CI 1.11 to 1.38). Among the employees remaining in the work unit, reorganisation was also associated with more events of long-term sickness absence (OR 1.15, 95% CI 1.00 to 1.33), which was particularly important for merger (OR 1.31, 95% CI 1.00 to 1.72) and employee layoff (OR 1.31, 95% CI 1.08 to 1.59). CONCLUSIONS: Specific types of reorganisation seem to have a dual impact on subsequent work-unit exit and sickness absence in the year after change. PMID- 29760174 TI - SNT-1 Functions as the Ca2+ Sensor for Tonic and Evoked Neurotransmitter Release in Caenorhabditis Elegans. AB - Synaptotagmin-1 (Syt1) binds Ca2+ through its tandem C2 domains (C2A and C2B) and triggers Ca2+-dependent neurotransmitter release. Here, we show that snt-1, the homolog of mammalian Syt1, functions as the Ca2+ sensor for both tonic and evoked neurotransmitter release at the Caenorhabditis elegans neuromuscular junction. Mutations that disrupt Ca2+ binding in double C2 domains of SNT-1 significantly impaired tonic release, whereas disrupting Ca2+ binding in a single C2 domain had no effect, indicating that the Ca2+ binding of the two C2 domains is functionally redundant for tonic release. Stimulus-evoked release was significantly reduced in snt-1 mutants, with prolonged release latency as well as faster rise and decay kinetics. Unlike tonic release, evoked release was triggered by Ca2+ binding solely to the C2B domain. Moreover, we showed that SNT-1 plays an essential role in the priming process in different subpopulations of synaptic vesicles with tight or loose coupling to Ca2+ entry.SIGNIFICANCE STATEMENT We showed that SNT-1 in Caenorhabditis elegans regulates evoked neurotransmitter release through Ca2+ binding to its C2B domain in a similar way to Syt1 in the mouse CNS and the fly neuromuscular junction. However, the largely decreased tonic release in snt-1 mutants argues SNT-1 has a clamping function. Indeed, Ca2+-binding mutations in the C2 domains in SNT-1 significantly reduced the frequency of the miniature EPSC, indicating that SNT-1 also acts as a Ca2+ sensor for tonic release. Therefore, revealing the differential mechanisms between invertebrates and vertebrates will provide significant insights into our understanding how synaptic vesicle fusion is regulated. PMID- 29760175 TI - Modulation of Receptor Protein Tyrosine Phosphatase Sigma Increases Chondroitin Sulfate Proteoglycan Degradation through Cathepsin B Secretion to Enhance Axon Outgrowth. AB - Severed axon tips reform growth cones following spinal cord injury that fail to regenerate, in part, because they become embedded within an inhibitory extracellular matrix. Chondroitin sulfate proteoglycans (CSPGs) are the major axon inhibitory matrix component that is increased within the lesion scar and in perineuronal nets around deafferented neurons. We have recently developed a novel peptide modulator (intracellular sigma peptide) of the cognate receptor of CSPGs, protein tyrosine phosphatase sigma (RPTPsigma), which has been shown to markedly improve sensorimotor function, micturition, and coordinated locomotor behavior in spinal cord contused rats. However, the mechanism(s) underlying how modulation of RPTPsigma mediates axon outgrowth through inhibitory CSPGs remain unclear. Here, we describe how intracellular sigma peptide modulation of RPTPsigma induces enhanced protease Cathepsin B activity. Using DRG neurons from female Sprague Dawley rats cultured on an aggrecan/laminin spot assay and a combination of biochemical techniques, we provide evidence suggesting that modulation of RPTPsigma regulates secretion of proteases that, in turn, relieves CSPG inhibition through its digestion to allow axon migration though proteoglycan barriers. Understanding the mechanisms underlying RPTPsigma modulation elucidates how axon regeneration is impaired by proteoglycans but can then be facilitated following injury.SIGNIFICANCE STATEMENT Following spinal cord injury, chondroitin sulfate proteoglycans (CSPGs) upregulate and potently inhibit axon regeneration and functional recovery. Protein tyrosine phosphatase sigma (RPTPsigma) has been identified as a critical cognate receptor of CSPGs. We have previously characterized a synthetic peptide (intracellular sigma peptide) that targets the regulatory intracellular domain of the receptor to allow axons to regenerate despite the presence of CSPGs. Here, we have found that one important mechanism by which peptide modulation of the receptor enhances axon outgrowth is through secretion of a protease, Cathepsin B, which enables digestion of CSPGs. This work links protease secretion to the CSPG receptor RPTPsigma for the first time with implications for understanding the molecular mechanisms underlying neural regeneration and plasticity. PMID- 29760176 TI - Postnatal Ablation of Synaptic Retinoic Acid Signaling Impairs Cortical Information Processing and Sensory Discrimination in Mice. AB - Retinoic acid (RA) and its receptors (RARs) are well established essential transcriptional regulators during embryonic development. Recent findings in cultured neurons identified an independent and critical post-transcriptional role of RA and RARalpha in the homeostatic regulation of excitatory and inhibitory synaptic transmission in mature neurons. However, the functional relevance of synaptic RA signaling in vivo has not been established. Here, using somatosensory cortex as a model system and the RARalpha conditional knock-out mouse as a tool, we applied multiple genetic manipulations to delete RARalpha postnatally in specific populations of cortical neurons, and asked whether synaptic RA signaling observed in cultured neurons is involved in cortical information processing in vivo Indeed, conditional ablation of RARalpha in mice via a CaMKIIalpha-Cre or a layer 5-Cre driver line or via somatosensory cortex-specific viral expression of Cre-recombinase impaired whisker-dependent texture discrimination, suggesting a critical requirement of RARalpha expression in L5 pyramidal neurons of somatosensory cortex for normal tactile sensory processing. Transcranial two photon imaging revealed a significant increase in dendritic spine elimination on apical dendrites of somatosensory cortical layer 5 pyramidal neurons in these mice. Interestingly, the enhancement of spine elimination is whisker experience dependent as whisker trimming rescued the spine elimination phenotype. Additionally, experiencing an enriched environment improved texture discrimination in RARalpha-deficient mice and reduced excessive spine pruning. Thus, RA signaling is essential for normal experience-dependent cortical circuit remodeling and sensory processing.SIGNIFICANCE STATEMENT The importance of synaptic RA signaling has been demonstrated in in vitro studies. However, whether RA signaling mediated by RARalpha contributes to neural circuit functions in vivo remains largely unknown. In this study, using a RARalpha conditional knock-out mouse, we performed multiple regional/cell-type-specific manipulation of RARalpha expression in the postnatal brain, and show that RARalpha signaling contributes to normal whisker-dependent texture discrimination as well as regulating spine dynamics of apical dendrites from layer (L5) pyramidal neurons in S1. Deletion of RARalpha in excitatory neurons in the forebrain induces elevated spine elimination and impaired sensory discrimination. Our study provides novel insights into the role of RARalpha signaling in cortical processing and experience-dependent spine maturation. PMID- 29760178 TI - Region- and Activity-Dependent Regulation of Extracellular Glutamate. AB - Transporter-mediated glutamate uptake plays an essential role in shaping synaptic neurotransmission. The rapid removal of synaptically released glutamate ensures the high temporal dynamics characteristic of fast excitatory chemical neurotransmission and prevents the overexcitation of extrasynaptic NMDA receptors that have been implicated in synaptic plasticity impairments and cell death. Despite clear regional differences in plasticity and excitotoxic thresholds, few studies have compared extracellular glutamate dynamics across different brain regions and in response to a range of neural activity including plasticity inducing stimuli. Here, we used the rapid extracellular fluorescent glutamate sensor iGluSnFR (intensity-based glutamate-sensing fluorescent reporter) and high speed imaging (205 frames per second) to quantify relative differences in glutamate clearance rates over a wide range of presynaptic activity in situ in the hippocampus, cortex, and striatum of male C57/BL6NCrl mice. We found that the hippocampus was significantly more efficient than the cortex and striatum at clearing synaptically released glutamate and that this efficiency could be attributed, at least in part, to faster glutamate diffusion away from the release site. In addition, we found that pharmacological inhibition of GLT-1, the brain's most abundant glutamate transporter, slowed clearance rates to only a fraction (~20-25%) of the effect induced by nonselective transporter blockade, regardless of the brain region and the duration of presynaptic activity. In all, our data reveal clear regional differences in glutamate dynamics after neural activity and suggest that non-GLT-1 transporters can make a large contribution to the rate of glutamate clearance in the hippocampus, cortex, and striatum.SIGNIFICANCE STATEMENT Glutamate is the brain's most abundant neurotransmitter, and although essential for rapid cell-cell communication, too much glutamate can negatively impact cellular health. Extracellular glutamate levels are tightly regulated by membrane-bound transporters that rapidly remove the glutamate that is released during neural activity, thereby shaping both the spatial and temporal dynamics of excitatory neurotransmission. Using high-speed imaging of an optical sensor of extracellular glutamate, we show that glutamate dynamics vary widely from one brain region to the next and are highly dependent on the duration of synaptic activity. Our data demonstrate the heterogeneous nature of glutamate regulation in the brain and suggest that such regional differences can dramatically affect both the localization and duration of postsynaptic receptor activation during synaptic neurotransmission. PMID- 29760177 TI - Epigenetic Promoter DNA Methylation of miR-124 Promotes HIV-1 Tat-Mediated Microglial Activation via MECP2-STAT3 Axis. AB - The present study demonstrates HIV-1 Tat-mediated epigenetic downregulation of microglial miR-124 and its association with microglial activation. Exposure of mouse primary microglia isolated from newborn pups of either sex to HIV-1 Tat resulted in decreased expression of primary miR-124-1, primary miR-124-2 as well as the mature miR-124. In parallel, HIV-1 Tat exposure to mouse primary microglial cells resulted in increased expression of DNA methylation enzymes, such as DNMT1, DNMT3A, and DNMT3B, which were also accompanied by increased global DNA methylation. Bisulfite-converted genomic DNA sequencing in the HIV-1 Tat-exposed mouse primary microglial cells further confirmed increased DNA methylation of the primary miR-124-1 and primary miR-124-2 promoters. Bioinformatic analyses identified MECP2 as a novel 3'-UTR target of miR-124. This was further validated in mouse primary microglial cells wherein HIV-1 Tat mediated downregulation of miR-124 resulted in increased expression of MECP2, leading in turn to further repression of miR-124 via the feedback loop. In addition to MECP2, miR-124 also modulated the levels of STAT3 through its binding to the 3'-UTR, leading to microglial activation. Luciferase assays and Ago2 immunoprecipitation determined the direct binding between miR-124 and 3'-UTR of both MECP2 and STAT3. Gene silencing of MECP2 and DNMT1 and overexpression of miR 124 blocked HIV-1 Tat-mediated downregulation of miR-124 and microglial activation. In vitro findings were also confirmed in the basal ganglia of SIV infected rhesus macaques (both sexes). In summary, our findings demonstrate a novel mechanism of HIV-1 Tat-mediated activation of microglia via downregulation of miR-124, leading ultimately to increased MECP2 and STAT3 signaling.SIGNIFICANCE STATEMENT Despite the effectiveness of combination antiretroviral therapy in controlling viremia, the CNS continues to harbor viral reservoirs. The persistence of low-level virus replication leads to the accumulation of early viral proteins, including HIV-1 Tat protein. Understanding the epigenetic/molecular mechanism(s) by which viral proteins, such as HIV-1 Tat, can activate microglia is thus of paramount importance. This study demonstrated that HIV-1 Tat-mediated DNA methylation of the miR-124 promoter leads to its downregulation with a concomitant upregulation of the MECP2-STAT3-IL6, resulting in microglial activation. These findings reveal an unexplored epigenetic/molecular mechanism(s) underlying HIV-1 Tat-mediated microglial activation, thereby providing a potential target for the development of therapeutics aimed at ameliorating microglial activation and neuroinflammation in the context of HIV-1 infection. PMID- 29760179 TI - Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice. AB - Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice (N = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either ad libitum or only during the light phase [Zeitgeber time (ZT) 0 12] or dark phase (ZT12-24) for 8 weeks. A subgroup of mice from all conditions (n = 8/condition) were placed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were dampened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.SIGNIFICANCE STATEMENT Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity. PMID- 29760180 TI - The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions. AB - Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use. PMID- 29760181 TI - Corticosterone Signaling and a Lateral Habenula-Ventral Tegmental Area Circuit Modulate Compulsive Self-Injurious Behavior in a Rat Model. AB - Self-injurious behavior (SIB) is commonly observed in patients with neuropsychiatric disorders, as well as in nonclinical populations with stress related mental-health problems. However, the exact circuitry mechanisms underlying SIB have remained poorly understood. Here, with bilateral injection of muscimol into the entopeduncular nucleus (EP), we established a rat model of SIB. Following the muscimol injection, the male rats exhibited in a dose-dependent manner stereotypic self-biting behavior that lasted for hours and often resulted in wounds of various severities. The SIB was associated with an elevated level of serum corticosterone and could be exacerbated by enhancing the corticosterone signaling and, conversely, alleviated by inhibiting the corticosterone signaling. Activity mapping using c-fos immunostaining, combined with connectivity mapping using herpes simplex virus-based anterograde tracing from the EP and pseudorabies virus-based retrograde tracing from the masseter muscle, revealed the potential involvement of many brain areas in SIB. In particular, the lateral habenula (LHb) and the ventral tegmental area (VTA), the two connected brain areas involved in stress response and reward processing, showed a significant increase in neuronal activation during SIB. Furthermore, suppressing the LHb activity or modulating the GABAergic transmission in the VTA could significantly reduce the occurrence of SIB. These results demonstrate the importance of stress hormone signaling and the LHb-VTA circuit in modulating SIB resulting from EP malfunction, and suggest potential targets for therapeutic intervention of SIB and related disorders.SIGNIFICANCE STATEMENT Self-injurious behavior (SIB) occurs in ~4% of the general population, with substantially higher occurrence among adolescents and patients of neuropsychiatric disorders. Stress has been linked to the occurrence of SIB, yet the underlying mechanisms have remained unclear. Using a rat model of SIB induced by disruption of activity in the entopeduncular nucleus (EP), we found that the behavior is regulated by stress and linked to corticosterone signaling. Viral tracing and c-fos immunostaining revealed the involvement of various subcortical areas, especially the EP-lateral habenula (LHb)-ventral tegmental area (VTA) circuit, in SIB. Furthermore, regulating activity in the LHb or the VTA alleviates SIB. These results may have implications in the development of new strategies for treating SIB. PMID- 29760183 TI - Neural Mechanisms Underlying Individual Differences in Control-Averse Behavior. AB - When another person tries to control one's decisions, some people might comply, but many will feel the urge to act against that control. This control aversion can lead to suboptimal decisions and it affects social interactions in many societal domains. To date, however, it has been unclear what drives individual differences in control-averse behavior. Here, we address this issue by measuring brain activity with fMRI while healthy female and male human participants made choices that were either free or controlled by another person, with real consequences to both interaction partners. In addition, we assessed the participants' affects, social cognitions, and motivations via self-reports. Our results indicate that the social cognitions perceived distrust and lack of understanding for the other person play a key role in explaining control aversion at the behavioral level. At the neural level, we find that control-averse behavior can be explained by functional connectivity between the inferior parietal lobule and the dorsolateral prefrontal cortex, brain regions commonly associated with attention reorientation and cognitive control. Further analyses reveal that the individual strength of functional connectivity complements and partially mediates the self-reported social cognitions in explaining individual differences in control-averse behavior. These findings therefore provide valuable contributions to a more comprehensive model of control aversion.SIGNIFICANCE STATEMENT Control aversion is a prevalent phenomenon in our society. When someone tries to control their decisions, many people tend to act against the control. This can lead to suboptimal decisions such as noncompliance to medical treatments or disobeying the law. The degree to which individuals engage in control-averse behavior, however, varies significantly. Understanding the proximal mechanisms that underlie individual differences in control-averse behavior has potential policy implications, for example, when designing policies aimed at increasing compliance with vaccination recommendations, and is therefore a highly relevant research goal. Here, we identify a neural mechanism between parietal and prefrontal brain regions that can explain individual differences in control averse behavior. This mechanism provides novel insights into control aversion beyond what is accessible through self-reports. PMID- 29760182 TI - Alternating Modulation of Subthalamic Nucleus Beta Oscillations during Stepping. AB - Gait disturbances in Parkinson's disease are commonly refractory to current treatment options and majorly impair patient's quality of life. Auditory cues facilitate gait and prevent motor blocks. We investigated how neural dynamics in the human subthalamic nucleus of Parkinsons's disease patients (14 male, 2 female) vary during stepping and whether rhythmic auditory cues enhance the observed modulation. Oscillations in the beta band were suppressed after ipsilateral heel strikes, when the contralateral foot had to be raised, and reappeared after contralateral heel strikes, when the contralateral foot rested on the floor. The timing of this 20-30 Hz beta modulation was clearly distinct between the left and right subthalamic nucleus, and was alternating within each stepping cycle. This modulation was similar, whether stepping movements were made while sitting, standing, or during gait, confirming the utility of the stepping in place paradigm. During stepping in place, beta modulation increased with auditory cues that assisted patients in timing their steps more regularly. Our results suggest a link between the degree of power modulation within high beta frequency bands and stepping performance. These findings raise the possibility that alternating deep brain stimulation patterns may be superior to constant stimulation for improving parkinsonian gait.SIGNIFICANCE STATEMENT Gait disturbances in Parkinson's disease majorly reduce patients' quality of life and are often refractory to current treatment options. We investigated how neural activity in the subthalamic nucleus of patients who received deep brain stimulation surgery covaries with the stepping cycle. 20-30 Hz beta activity was modulated relative to each step, alternating between the left and right STN. The stepping performance of patients improved when auditory cues were provided, which went along with enhanced beta modulation. This raises the possibility that alternating stimulation patterns may also enhance beta modulation and may be more beneficial for gait control than continuous stimulation, which needs to be tested in future studies. PMID- 29760184 TI - Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration. AB - Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb+, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression. PMID- 29760185 TI - Stability of an aggregation-prone partially folded state of human profilin-1 correlates with aggregation propensity. AB - A set of missense mutations in the gene encoding profilin-1 has been linked to the onset of familial forms of ALS (fALS), also known as Lou Gehrig's disease. The pathogenic potential of these mutations is linked to the formation of intracellular inclusions of the mutant proteins and correlates with the mutation induced destabilization of its native, fully folded state. However, the mechanism by which these mutations promote misfolding and self-assembly is yet unclear. Here, using temperature-jump and stopped-flow kinetic measurements, we show that, during refolding, WT profilin-1 transiently populates a partially folded (PF) state endowed with hydrophobic clusters exposed to the solvent and with no detectable secondary structure. We observed that this conformational state is marginally stable at neutral pH but becomes significantly populated at mildly acidic pH. Interestingly, the fALS-associated mutations did not cause a change in the refolding mechanism of profilin-1, but induced a stabilization of the PF state. In the presence of preformed profilin-1 aggregates, the PF state, unlike the unfolded and folded states, could interact with these aggregates via nonspecific hydrophobic interactions and also increase thioflavin-T fluorescence, revealing its amyloidogenic potential. Moreover, in the variants tested, we found a correlation between conformational stability of PF and aggregation propensity, defining this conformational state as an aggregation-prone folding intermediate. In conclusion, our findings indicate that mutation-induced stabilization of a partially folded state can enhance profilin-1 aggregation and thereby contribute to the pathogenicity of the mutations. PMID- 29760186 TI - Hypertrophic cardiomyopathy mutations increase myofilament Ca2+ buffering, alter intracellular Ca2+ handling, and stimulate Ca2+-dependent signaling. AB - Mutations in thin filament regulatory proteins that cause hypertrophic cardiomyopathy (HCM) increase myofilament Ca2+ sensitivity. Mouse models exhibit increased Ca2+ buffering and arrhythmias, and we hypothesized that these changes are primary effects of the mutations (independent of compensatory changes) and that increased Ca2+ buffering and altered Ca2+ handling contribute to HCM pathogenesis via activation of Ca2+-dependent signaling. Here, we determined the primary effects of HCM mutations on intracellular Ca2+ handling and Ca2+ dependent signaling in a model system possessing Ca2+-handling mechanisms and contractile protein isoforms closely mirroring the human environment in the absence of potentially confounding remodeling. Using adenovirus, we expressed HCM causing variants of human troponin-T, troponin-I, and alpha-tropomyosin (R92Q, R145G, and D175N, respectively) in isolated guinea pig left ventricular cardiomyocytes. After 48 h, each variant had localized to the I-band and comprised ~50% of the total protein. HCM mutations significantly lowered the Kd of Ca2+ binding, resulting in higher Ca2+ buffering of mutant cardiomyocytes. We observed increased diastolic [Ca2+] and slowed Ca2+ reuptake, coupled with a significant decrease in basal sarcomere length and slowed relaxation. HCM mutant cells had higher sodium/calcium exchanger activity, sarcoplasmic reticulum Ca2+ load, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) activity driven by Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of phospholamban. The ryanodine receptor (RyR) leak/load relationship was also increased, driven by CaMKII-mediated RyR phosphorylation. Altered Ca2+ homeostasis also increased signaling via both calcineurin/NFAT and extracellular signal-regulated kinase pathways. Altered myofilament Ca2+ buffering is the primary initiator of signaling cascades, indicating that directly targeting myofilament Ca2+ sensitivity provides an attractive therapeutic approach in HCM. PMID- 29760187 TI - Lipopolysaccharide (LPS)-binding protein stimulates CD14-dependent Toll-like receptor 4 internalization and LPS-induced TBK1-IKKepsilon-IRF3 axis activation. AB - Toll-like receptor 4 (TLR4) is an indispensable immune receptor for lipopolysaccharide (LPS), a major component of the Gram-negative bacterial cell wall. Following LPS stimulation, TLR4 transmits the signal from the cell surface and becomes internalized in an endosome. However, the spatial regulation of TLR4 signaling is not fully understood. Here, we investigated the mechanisms of LPS induced TLR4 internalization and clarified the roles of the extracellular LPS binding molecules, LPS-binding protein (LBP), and glycerophosphatidylinositol anchored protein (CD14). LPS stimulation of CD14-expressing cells induced TLR4 internalization in the presence of serum, and an inhibitory anti-LBP mAb blocked its internalization. Addition of LBP to serum-free cultures restored LPS-induced TLR4 internalization to comparable levels of serum. The secretory form of the CD14 (sCD14) induced internalization but required a much higher concentration than LBP. An inhibitory anti-sCD14 mAb was ineffective for serum-mediated internalization. LBP lacking the domain for LPS transfer to CD14 and a CD14 mutant with reduced LPS binding both attenuated TLR4 internalization. Accordingly, LBP is an essential serum molecule for TLR4 internalization, and its LPS transfer to membrane-anchored CD14 (mCD14) is a prerequisite. LBP induced the LPS-stimulated phosphorylation of TBK1, IKKepsilon, and IRF3, leading to IFN-beta expression. However, LPS-stimulated late activation of NF-kappaB or necroptosis were not affected. Collectively, our results indicate that LBP controls LPS induced TLR4 internalization, which induces TLR adaptor molecule 1 (TRIF) dependent activation of the TBK1-IKKepsilon-IRF3-IFN-beta pathway. In summary, we showed that LBP-mediated LPS transfer to mCD14 is required for serum-dependent TLR4 internalization and activation of the TRIF pathway. PMID- 29760188 TI - Depression in type 1 diabetes was associated with high levels of circulating galectin-3. AB - OBJECTIVE: Neuroinflammatory responses are implicated in depression. The aim was to explore whether depression in patients with type 1 diabetes (T1D) was associated with high circulating galectin-3, controlling for metabolic variables, s-creatinine, life style factors, medication and cardiovascular complications. DESIGN: Cross-sectional. METHODS: Participants were T1D patients (n = 283, 56% men, age 18-59 years, diabetes duration >=1 year). Depression was assessed by Hospital Anxiety and Depression Scale-depression subscale. Blood samples, anthropometrics and blood pressure were collected, and supplemented with data from medical records and the Swedish National Diabetes Registry. Galectin-3 >=2.562 ug/l, corresponding to the 85th percentile, was defined as high galectin 3. RESULTS: Median (quartile1, quartile3) galectin-3 (ug/l) was 1.3 (0.8, 2.9) for the 30 depressed patients, and 0.9 (0.5, 1.6) for the 253 non-depressed, P = 0.009. Depression was associated with high galectin-3 in all the 283 patients (adjusted odds ratio (AOR) 3.5), in the 161 men (AOR 3.4), and in the 122 women (AOR 3.9). HbA1c, s-lipids, s-creatinine, blood pressure, obesity, smoking, physical inactivity, cardiovascular complications and drugs (antihypertensive, lipid lowering, oral antidiabetic drugs and antidepressants) were not associated with high galectin-3. CONCLUSIONS: This is the first study to show an association between depression and galectin-3. Depression was the only explored parameter associated with high circulating galectin-3 levels in 283 T1D patients. High galectin-3 levels might contribute to the increased risk for Alzheimer's disease, cardiovascular and all-cause mortality observed in persons with depression. Potentially, in the future, treatment targeting galactin-3 might improve the prognosis for patients with high galectin-3 levels. PMID- 29760189 TI - Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study. AB - Recent studies have shown a significant increase in the temporal trend of medullary thyroid carcinoma (MTC) incidence. However, it remains unknown to which extent sporadic medullary thyroid carcinoma (SMTC) and hereditary MTC (HMTC) affect the MTC incidence over time. We conducted a nationwide retrospective study using previously described RET and MTC cohorts combined with review of medical records, pedigree comparison and relevant nationwide registries. The study included 474 MTC patients diagnosed in Denmark between 1960 and 2014. In the nationwide period from 1997 to 2014, we recorded a mean age-standardized incidence of all MTC, SMTC and HMTC of 0.19, 0.13 and 0.06 per 100,000 per year, respectively. The average annual percentage change in incidence for all MTC, SMTC and HMTC were 1.0 (P = 0.542), 2.8 (P = 0.125) and -3.1 (P = 0.324), respectively. The corresponding figures for point prevalence at January 1, 2015 were 3.8, 2.5 and 1.3 per 100,000, respectively. The average annual percentage change in prevalence from 1998 to 2015 for all MTC, SMTC and HMTC was 2.8 (P < 0.001), 3.8 (P < 0.001) and 1.5 (P = 0.010), respectively. We found no significant change in the incidence of all MTC, SMTC and HMTC possibly due to our small sample size. However, due to an increasing trend in the incidence of all MTC and opposing trends of SMTC (increasing) and HMTC (decreasing) incidence, it seems plausible that an increase for all MTC seen by others may be driven by the SMTC group rather than the HMTC group. PMID- 29760190 TI - Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity. AB - Tick-borne encephalitis virus (TBEV) is one of the flaviviruses that targets the CNS and causes encephalitis in humans. The mechanism of TBEV that causes CNS destruction remains unclear. It has been reported that RANTES-mediated migration of human blood monocytes and T lymphocytes is specifically induced in the brain of mice infected with TBEV, which causes ensuing neuroinflammation and may contribute to brain destruction. However, the viral components responsible for RANTES induction and the underlying mechanisms remain to be fully addressed. In this study, we demonstrate that the NS5, but not other viral proteins of TBEV, induces RANTES production in human glioblastoma cell lines and primary astrocytes. TBEV NS5 appears to activate the IFN regulatory factor 3 (IRF-3) signaling pathway in a manner dependent on RIG-I/MDA5, which leads to the nuclear translocation of IRF-3 to bind with RANTES promoter. Further studies reveal that the activity of RNA-dependent RNA polymerase (RdRP) but not the RNA cap methyltransferase is critical for TBEV NS5-induced RANTES expression, and this is likely due to RdRP-mediated synthesis of dsRNA. Additional data indicate that the residues at K359, D361, and D664 of TBEV NS5 are critical for RdRP activity and RANTES induction. Of note, NS5s from other flaviviruses, including Japanese encephalitis virus, West Nile virus, Zika virus, and dengue virus, can also induce RANTES expression, suggesting the significance of NS5-induced RANTES expression in flavivirus pathogenesis. Our findings provide a foundation for further understanding how flaviviruses cause neuroinflammation and a potential viral target for intervention. PMID- 29760192 TI - Circadian Rhythms Influence the Severity of Sepsis in Mice via a TLR2-Dependent, Leukocyte-Intrinsic Mechanism. AB - Circadian rhythms coordinate an organism's activities and biological processes to the optimal time in the 24-h daylight cycle. We previously demonstrated that male C57BL/6 mice develop sepsis more rapidly when the disease is induced in the nighttime versus the daytime. In this report, we elucidate the mechanism of this diurnal difference. Sepsis was induced via cecal ligation and puncture (CLP) at zeitgeber time (ZT)-19 (2 am) or ZT-7 (2 pm). Like the males used in our prior study, female C57BL/6 mice had a worse outcome when CLP was induced at ZT-19 versus ZT-7, and these effects persisted when we pooled the data from both sexes. In contrast, mice with a mutated Period 2 (Per2) gene had a similar outcome when CLP was induced at ZT-19 versus ZT-7. Bone marrow chimeras reconstituted with C57BL/6 immune cells exhibited a worse outcome when sepsis was induced at ZT-19 versus ZT-7, whereas chimeras with Per2-mutated immune cells did not. Next, murine macrophages were subjected to serum shock to synchronize circadian rhythms and exposed to bacteria cultured from the mouse cecum at 4-h intervals for 48 h. We observed that IL-6 production oscillated with a 24-h period in C57BL/6 cells exposed to cecal bacteria. Interestingly, we observed a similar pattern when cells were exposed to the TLR2 agonist lipoteichoic acid. Furthermore, TLR2 knockout mice exhibited a similar sepsis phenotype when CLP was induced at ZT-19 versus ZT-7. Together, these data suggest that circadian rhythms in immune cells mediate diurnal variations in murine sepsis severity via a TLR2-dependent mechanism. PMID- 29760191 TI - Effects of Influenza on Alveolar Macrophage Viability Are Dependent on Mouse Genetic Strain. AB - Secondary bacterial coinfections following influenza virus pose a serious threat to human health. Therefore, it is of significant clinical relevance to understand the immunological causes of this increased susceptibility. Influenza-induced alterations in alveolar macrophages (AMs) have been shown to be a major underlying cause of the increased susceptibility to bacterial superinfection. However, the mechanisms responsible for this remain under debate, specifically in terms of whether AMs are depleted in response to influenza infection or are maintained postinfection, but with disrupted phagocytic activity. The data presented in this article resolves this issue by showing that either mechanism can differentially occur in individual mouse strains. BALB/c mice exhibited a dramatic IFN-gamma-dependent reduction in levels of AMs following infection with influenza A, whereas AM levels in C57BL/6 mice were maintained throughout the course of influenza infection, although the cells displayed an altered phenotype, namely an upregulation in CD11b expression. These strain differences were observed regardless of whether infection was performed with low or high doses of influenza virus. Furthermore, infection with either the H1N1 A/California/04/2009 (CA04) or H1N1 A/PR8/1934 (PR8) virus strain yielded similar results. Regardless of AM viability, both BALB/c and C57BL/6 mice showed a high level of susceptibility to postinfluenza bacterial infection. These findings resolve the apparent inconsistencies in the literature, identify mouse strain-dependent differences in the AM response to influenza infection, and ultimately may facilitate translation of the mouse model to clinical application. PMID- 29760193 TI - Expression of the Atypical Chemokine Receptor ACKR4 Identifies a Novel Population of Intestinal Submucosal Fibroblasts That Preferentially Expresses Endothelial Cell Regulators. AB - Atypical chemokine receptors (ACKRs) are expressed by discrete populations of stromal cells at specific anatomical locations where they control leukocyte migration by scavenging or transporting chemokines. ACKR4 is an atypical receptor for CCL19, CCL21, and CCL25. In skin, ACKR4 plays indispensable roles in regulating CCR7-dependent APC migration, and there is a paucity of migratory APCs in the skin-draining lymph nodes of Ackr4-deficient mice under steady-state and inflammatory conditions. This is caused by loss of ACKR4-mediated CCL19/21 scavenging by keratinocytes and lymphatic endothelial cells. In contrast, we show in this study that Ackr4 deficiency does not affect dendritic cell abundance in the small intestine and mesenteric lymph nodes, at steady state or after R848 induced mobilization. Moreover, Ackr4 expression is largely restricted to mesenchymal cells in the intestine, where it identifies a previously uncharacterized population of fibroblasts residing exclusively in the submucosa. Compared with related Ackr4- mesenchymal cells, these Ackr4+ fibroblasts have elevated expression of genes encoding endothelial cell regulators and lie in close proximity to submucosal blood and lymphatic vessels. We also provide evidence that Ackr4+ fibroblasts form physical interactions with lymphatic endothelial cells, and engage in molecular interactions with these cells via the VEGFD/VEGFR3 and CCL21/ACKR4 pathways. Thus, intestinal submucosal fibroblasts in mice are a distinct population of intestinal mesenchymal cells that can be identified by their expression of Ackr4 and have transcriptional and anatomical properties that strongly suggest roles in endothelial cell regulation. PMID- 29760194 TI - Differential Roles of LTbetaR in Endothelial Cell Subsets for Lymph Node Organogenesis and Maturation. AB - Cellular cross-talk mediated by lymphotoxin alphabeta-lymphotoxin beta receptor (LTbetaR) signaling plays a critical role in lymph node (LN) development. Although the major role of LTbetaR signaling has long been considered to occur in mesenchymal lymphoid tissue organizer cells, a recent study using a VE cadherincreLtbrfl/fl mouse model suggested that endothelial LTbetaR signaling contributes to the formation of LNs. However, the detailed roles of LTbetaR in different endothelial cells (ECs) in LN development remain unknown. Using various cre transgenic mouse models (Tekcre , a strain targeting ECs, and Lyve1cre , mainly targeting lymphatic ECs), we observed that specific LTbetaR ablation in Tekcre+ or Lyve1cre+ cells is not required for LN formation. Moreover, double-cre mediated LTbetaR depletion does not interrupt LN formation. Nevertheless, TekcreLtbrfl/fl mice exhibit reduced lymphoid tissue inducer cell accumulation at the LN anlagen and impaired LN maturation. Interestingly, a subset of ECs (VE cadherin+Tekcre-low/neg ECs) was found to be enriched in transcripts related to hematopoietic cell recruitment and transendothelial migration, resembling LN high ECs in adult animals. Furthermore, endothelial Tek was observed to negatively regulate hematopoietic cell transmigration. Taken together, our data suggest that although Tekcre+ endothelial LTbetaR is required for the accumulation of hematopoietic cells and full LN maturation, LTbetaR in VE-cadherin+Tekcre-low/neg ECs in embryos might represent a critical portal-determining factor for LN formation. PMID- 29760195 TI - Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease. AB - Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and alpha motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR deficient mouse strain can potentially be used as a motor neuron disease model. PMID- 29760196 TI - Perinodal Adipose Tissue Participates in Immune Protection through a Lymphatic Vessel-Independent Route. AB - Lymphatic vessels remove and transport excess interstitial fluid to lymph nodes (LNs) for fluid balance and immune protection. LNs are typically surrounded by perinodal adipose tissue (PAT). However, PAT is a blood vessel-rich but lymphatic rare tissue; therefore, how excess fluid in PAT is removed remains unclear. Using C57BL/6 mice, fluorescent dye tracing and transmission electron microscopy results suggest that fluid in PAT can travel to the LN via collagen I+ channels (PAT-LN conduits), merge into a collagen-rich space between the PAT and LN capsule (PAT-LN sinus), and may enter the LN via the LN capsule-associated conduits. This newly identified route of fluid flow allows fluid to enter the draining LN even when the afferent lymphatic vessels are blocked, indicating that fluid trafficking in PAT-LN conduits is not dependent on functional lymphatic vessels. Similar to lymphatic vessels, PAT-LN conduits can deliver Ags to the LN for immune protection. Additionally, Staphylococcus aureus from intradermal or i.v. infection may use PAT-LN conduits to infect PAT and stimulate PAT immune protection. Our studies revealed a new route of material exchange between PAT and the LN. Ag accumulation and bacterial infection in PAT demonstrate that PAT not only provides energy and regulatory factors, but can also directly participate in immune protection, indicating a new immune function of PAT for host immunity. PMID- 29760197 TI - GLUCOSAMINE INOSITOLPHOSPHORYLCERAMIDE TRANSFERASE1 (GINT1) Is a GlcNAc Containing Glycosylinositol Phosphorylceramide Glycosyltransferase. AB - Glycosylinositol phosphorylceramides (GIPCs), which have a ceramide core linked to a glycan headgroup of varying structures, are the major sphingolipids in the plant plasma membrane. Recently, we identified the major biosynthetic genes for GIPC glycosylation in Arabidopsis (Arabidopsis thaliana) and demonstrated that the glycan headgroup is essential for plant viability. However, the function of GIPCs and the significance of their structural variation are poorly understood. Here, we characterized the Arabidopsis glycosyltransferase GLUCOSAMINE INOSITOLPHOSPHORYLCERAMIDE TRANSFERASE1 (GINT1) and showed that it is responsible for the glycosylation of a subgroup of GIPCs found in seeds and pollen that contain GlcNAc and GlcN [collectively GlcN(Ac)]. In Arabidopsis gint1 plants, loss of the GlcN(Ac) GIPCs did not affect vegetative growth, although seed germination was less sensitive to abiotic stress than in wild-type plants. However, in rice, where GlcN(Ac) containing GIPCs are the major GIPC subgroup in vegetative tissue, loss of GINT1 was seedling lethal. Furthermore, we could produce, de novo, "rice-like" GlcN(Ac) GIPCs in Arabidopsis leaves, which allowed us to test the function of different sugars in the GIPC headgroup. This study describes a monocot GIPC biosynthetic enzyme and shows that its Arabidopsis homolog has the same biochemical function. We also identify a possible role for GIPCs in maintaining cell-cell adhesion. PMID- 29760198 TI - Cellulose Synthase Stoichiometry in Aspen Differs from Arabidopsis and Norway Spruce. AB - Cellulose is synthesized at the plasma membrane by cellulose synthase complexes (CSCs) containing cellulose synthases (CESAs). Genetic analysis and CESA isoform quantification indicate that cellulose in the secondary cell walls of Arabidopsis (Arabidopsis thaliana) is synthesized by isoforms CESA4, CESA7, and CESA8 in equimolar amounts. Here, we used quantitative proteomics to investigate whether the CSC model based on Arabidopsis secondary cell wall CESA stoichiometry can be applied to the angiosperm tree aspen (Populus tremula) and the gymnosperm tree Norway spruce (Picea abies). In the developing xylem of aspen, the secondary cell wall CESA stoichiometry was 3:2:1 for PtCESA8a/b:PtCESA4:PtCESA7a/b, while in Norway spruce, the stoichiometry was 1:1:1, as observed previously in Arabidopsis. Furthermore, in aspen tension wood, the secondary cell wall CESA stoichiometry changed to 8:3:1 for PtCESA8a/b:PtCESA4:PtCESA7a/b. PtCESA8b represented 73% of the total secondary cell wall CESA pool, and quantitative polymerase chain reaction analysis of CESA transcripts in cryosectioned tension wood revealed increased PtCESA8b expression during the formation of the cellulose enriched gelatinous layer, while the transcripts of PtCESA4, PtCESA7a/b, and PtCESA8a decreased. A wide-angle x-ray scattering analysis showed that the shift in CESA stoichiometry in tension wood coincided with an increase in crystalline cellulose microfibril diameter, suggesting that the CSC CESA composition influences microfibril properties. The aspen CESA stoichiometry results raise the possibility of alternative CSC models and suggest that homomeric PtCESA8b complexes are responsible for cellulose biosynthesis in the gelatinous layer in tension wood. PMID- 29760199 TI - The NAC Transcription Factor SlNAP2 Regulates Leaf Senescence and Fruit Yield in Tomato. AB - Leaf senescence is an essential physiological process in plants that supports the recycling of nitrogen and other nutrients to support the growth of developing organs, including young leaves, seeds, and fruits. Thus, the regulation of senescence is crucial for evolutionary success in wild populations and for increasing yield in crops. Here, we describe the influence of a NAC transcription factor, SlNAP2 (Solanum lycopersicum NAC-like, activated by Apetala3/Pistillata), that controls both leaf senescence and fruit yield in tomato (S. lycopersicum). SlNAP2 expression increases during age-dependent and dark-induced leaf senescence. We demonstrate that SlNAP2 activates SlSAG113 (S. lycopersicum SENESCENCE-ASSOCIATED GENE113), a homolog of Arabidopsis (Arabidopsis thaliana) SAG113, chlorophyll degradation genes such as SlSGR1 (S. lycopersicum senescence inducible chloroplast stay-green protein 1) and SlPAO (S. lycopersicum pheide a oxygenase), and other downstream targets by directly binding to their promoters, thereby promoting leaf senescence. Furthermore, SlNAP2 directly controls the expression of genes important for abscisic acid (ABA) biosynthesis, S. lycopersicum 9-cis-epoxycarotenoid dioxygenase 1 (SlNCED1); transport, S. lycopersicum ABC transporter G family member 40 (SlABCG40); and degradation, S. lycopersicum ABA 8'-hydroxylase (SlCYP707A2), indicating that SlNAP2 has a complex role in establishing ABA homeostasis during leaf senescence. Inhibiting SlNAP2 expression in transgenic tomato plants impedes leaf senescence but enhances fruit yield and sugar content likely due to prolonged leaf photosynthesis in aging tomato plants. Our data indicate that SlNAP2 has a central role in controlling leaf senescence and fruit yield in tomato. PMID- 29760200 TI - The Protein Arginine Methyltransferase PRMT-5 Regulates SER-2 Tyramine Receptor Mediated Behaviors in Caenorhabditis elegans. AB - G protein-coupled receptors are 7-pass transmembrane receptors that couple to heterotrimeric G proteins to mediate cellular responses to a diverse array of stimuli. Understanding the mechanisms that regulate G protein-coupled receptors is crucial to manipulating their signaling for therapeutic benefit. One key regulatory mechanism that contributes to the functional diversity of many signaling proteins is post-translational modification. Whereas phosphorylation remains the best studied of such modifications, arginine methylation by protein arginine methyltransferases is emerging as a key regulator of protein function. We previously published the first functional evidence that arginine methylation of G protein-coupled receptors modulates their signaling. We report here a third receptor that is regulated by arginine methylation, the Caenorhabditis elegans SER-2 tyramine receptor. We show that arginines within a putative methylation motif in the third intracellular loop of SER-2 are methylated by PRMT5 in vitro Our data also suggest that this modification enhances SER-2 signaling in vivo to modulate animal behavior. The identification of a third G protein-coupled receptor to be functionally regulated by arginine methylation suggests that this post-translational modification may be utilized to regulate signaling through a broad array of G protein-coupled receptors. PMID- 29760201 TI - A High-Resolution Genetic Map for the Laboratory Rat. AB - An accurate and high-resolution genetic map is critical for mapping complex traits, yet the resolution of the current rat genetic map is far lower than human and mouse, and has not been updated since the original Jensen-Seaman map in 2004. For the first time, we have refined the rat genetic map to sub-centimorgan (cM) resolution (<0.02 cM) by using 95,769 genetic markers and 870 informative meioses from a cohort of 528 heterogeneous stock (HS) rats. Global recombination rates in the revised sex-averaged map (0.66 cM/Mb) did not differ compared to the historical map (0.65 cM/Mb); however, substantial refinement was made to the localization of highly recombinant regions within the revised map. Also for the first time, sex-specific rat genetic maps were generated, which revealed both genomewide and fine-scale variation in recombination rates between male and female rats. Reanalysis of multiple quantitative trait loci (QTL) using the historical and refined rat genetic maps demonstrated marked changes to QTL localization, shape, and effect size. As a resource to the rat research community, we have provided revised centimorgan positions for all physical positions within the rat genome and commonly used genetic markers for trait mapping, including 44,828 SSLP markers and the RATDIV genotyping array. Collectively, this study provides a substantial improvement to the rat genetic map and an unprecedented resource for analysis of complex traits and recombination in the rat. PMID- 29760202 TI - Survey of Human Chromosome 21 Gene Expression Effects on Early Development in Danio rerio. AB - Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS), one of the most genetically complex conditions compatible with human survival. Assessment of the physiological consequences of dosage-driven overexpression of individual Hsa21 genes during early embryogenesis and the resulting contributions to DS pathology in mammals are not tractable in a systematic way. A recent study looked at loss-of-function of a subset of Caenorhabditis elegans orthologs of Hsa21 genes and identified ten candidates with behavioral phenotypes, but the equivalent over-expression experiment has not been done. We turned to zebrafish as a developmental model and, using a number of surrogate phenotypes, we screened Hsa21 genes for effects on early embyrogenesis. We prepared a library of 164 cDNAs of conserved protein coding genes, injected mRNA into early embryos and evaluated up to 5 days post-fertilization (dpf). Twenty-four genes produced a gross morphological phenotype, 11 of which could be reproduced reliably. Seven of these gave a phenotype consistent with down regulation of the sonic hedgehog (Shh) pathway; two showed defects indicative of defective neural crest migration; one resulted consistently in pericardial edema; and one was embryonic lethal. Combinatorial injections of multiple Hsa21 genes revealed both additive and compensatory effects, supporting the notion that complex genetic relationships underlie end phenotypes of trisomy that produce DS. Together, our data suggest that this system is useful in the genetic dissection of dosage-sensitive gene effects on early development and can inform the contribution of both individual loci and their combinatorial effects to phenotypes relevant to the etiopathology of DS. PMID- 29760204 TI - Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients. AB - The noninferiority of direct oral factor Xa (FXa) inhibitors (rivaroxaban, apixaban, and edoxaban) in treatment of atrial fibrillation were demonstrated compared with warfarin by several large clinical trials; however, subsequent meta analyses reported a higher risk of major bleeding with rivaroxaban than with the other FXa inhibitors. In the present study, we first estimated the changes of prothrombin time (PT) in 5 randomized trials based on reported population pharmacokinetic and pharmacodynamic models and then carried out a model-based meta-analysis to obtain models describing the relationship between PT changes and the event rates of ischemic stroke/systemic embolism (SE) and of major bleeding. By using the models, we simulated the optimal therapeutic doses for each FXa inhibitor. It was suggested that dose reduction of rivaroxaban from the current 20 mg/d to 10 mg/d would decrease patient deaths from major bleeding (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.64-0.74) with little increase in those for ischemic stroke/SE (HR, 1.11; 95% CI, 1.07-1.20). The overall decrease in the mortality caused by both events was estimated as 5.81 per 10 000 patient-years (95% CI, 3.92-8.16), with an HR of 0.87 (95% CI, 0.83-0.91). For apixaban and edoxaban, no distinct change in the overall mortality was simulated by dose modification. This study suggested that the current dose of rivaroxaban might be excessive and would need to be reduced to decrease the excess risk of major bleeding. PMID- 29760205 TI - Abnormal plasma clot formation and fibrinolysis reveal bleeding tendency in patients with partial factor XI deficiency. AB - Individuals with factor XI (FXI) deficiency have a variable bleeding risk that cannot be predicted from plasma FXI antigen or activity. This limitation can result in under- or overtreatment of patients and risk of bleeding or thrombosis. Previously, plasma clot fibrinolysis assays showed sensitivity to bleeding tendency in a small cohort of patients with severe FXI deficiency. Here, we determined the ability of plasma clot formation, structure, and fibrinolysis assays to predict bleeding tendency in a larger, independent cohort of patients with severe and partial FXI deficiency. Patients were characterized as nonbleeders or bleeders based on bleeding after tonsillectomy and/or dental extraction before diagnosis of FXI deficiency. Blood was collected in the absence or presence of the contact pathway inhibitor corn trypsin inhibitor (CTI). Clotting was triggered in platelet-poor plasma with tissue factor, CaCl2, and phospholipids in the absence and presence of thrombomodulin or tissue plasminogen activator. Clot formation and fibrinolysis were assessed by turbidity and confocal microscopy. CTI-treated plasmas from bleeders showed significantly reduced clot formation and decreased resistance to fibrinolysis compared with plasmas from controls or nonbleeders. Differences were enhanced in the presence of CTI. A model that combines activated partial thromboplastin time with the rate of clot formation and area under the curve in fibrinolysis assays identifies most FXI-deficient bleeders. These results show assays with CTI-treated platelet-poor plasma reveal clotting and clot stability deficiencies that are highly associated with bleeding tendency. Turbidity-based fibrinolysis assays may have clinical utility for predicting bleeding risk in patients with severe or partial FXI deficiency. PMID- 29760206 TI - Alternative Oxidase Activity Reduces Stress in Vibrio fischeri Cells Exposed to Nitric Oxide. AB - Alternative oxidase (Aox) is a non-energy-conserving respiratory oxidase found in certain eukaryotes and bacteria, whose role in physiology is not entirely clear. Using the genetically tractable bacterium Vibrio fischeri as a model organism, I have identified a role for Aox to reduce levels of stress in cells exposed to oxygen and nitric oxide (NO). In V. fischeri lacking the NO-detoxifying enzyme flavohemoglobin (Hmp), deletion of aox in cells grown in the presence of oxygen and NO results in alterations to the transcriptome that include increases in transcripts mapping to stress-related genes. Using fluorescence-based reporters, I identified corresponding increases in intracellular reactive oxygen species and decreases in membrane integrity in cells lacking aox Under these growth conditions, activity of Aox is linked to a decrease in NADH levels, indicating coupling of Aox activity with NADH dehydrogenase activity. Taken together, these results suggest that Aox functions to indirectly limit production of ferrous iron and damaging hydroxyl radicals, effectively reducing cellular stress during NO exposure.IMPORTANCE Unlike typical respiratory oxidases, alternative oxidase (Aox) does not directly contribute to energy conservation, and its activity would presumably reduce the efficiency of respiration and associated ATP production. Aox has been identified in certain bacteria, a majority of which are marine associated. The presence of Aox in these bacteria poses the interesting question of how Aox function benefits bacterial growth and survival in the ocean. Using the genetically tractable marine bacterium Vibrio fischeri, I have identified a role for Aox in reduction of stress under conditions where electron flux through the aerobic respiratory pathway is inhibited. These results suggest that Aox activity could positively impact longer-term bacterial fitness and survival under stressful environmental conditions. PMID- 29760203 TI - A Dense Linkage Map of Lake Victoria Cichlids Improved the Pundamilia Genome Assembly and Revealed a Major QTL for Sex-Determination. AB - Genetic linkage maps are essential for comparative genomics, high quality genome sequence assembly and fine scale quantitative trait locus (QTL) mapping. In the present study we identified and genotyped markers via restriction-site associated DNA (RAD) sequencing and constructed a genetic linkage map based on 1,597 SNP markers of an interspecific F2 cross of two closely related Lake Victoria cichlids (Pundamilia pundamilia and P sp. 'red head'). The SNP markers were distributed on 22 linkage groups and the total map size was 1,594 cM with an average marker distance of 1.01 cM. This high-resolution genetic linkage map was used to anchor the scaffolds of the Pundamilia genome and estimate recombination rates along the genome. Via QTL mapping we identified a major QTL for sex in a ~1.9 Mb region on Pun-LG10, which is homologous to Oreochromis niloticus LG 23 (Ore-LG23) and includes a well-known vertebrate sex-determination gene (amh). PMID- 29760207 TI - Association of Mycobacterium Proteins with Lipid Droplets. AB - Mycobacterium tuberculosis is a global pathogen of significant medical importance. A key aspect of its life cycle is the ability to enter into an altered physiological state of nonreplicating persistence during latency and resist elimination by the host immune system. One mechanism by which M. tuberculosis facilitates its survival during latency is by producing and metabolizing intracytoplasmic lipid droplets (LDs). LDs are quasi-organelles consisting of a neutral lipid core such as triacylglycerol surrounded by a phospholipid monolayer and proteins. We previously reported that PspA (phage shock protein A) associates with LDs produced in Mycobacterium In particular, the loss or overproduction of PspA alters LD homeostasis in Mycobacterium smegmatis and attenuates the survival of M. tuberculosis during nonreplicating persistence. Here, M. tuberculosis PspA (PspAMtb) and a DeltapspA M. smegmatis mutant were used as model systems to investigate the mechanism by which PspA associates with LDs and determine if other Mycobacterium proteins associate with LDs using a mechanism similar to that for PspA. Through this work, we established that the amphipathic helix present in the first alpha-helical domain (H1) of PspA is both necessary and sufficient for the targeting of this protein to LDs. Furthermore, we identified other Mycobacterium proteins that also possess amphipathic helices similar to PspA H1, including a subset that localize to LDs. Altogether, our results indicate that amphipathic helices may be an important mechanism by which proteins target LDs in prokaryotes.IMPORTANCEMycobacterium spp. are one of the few prokaryotes known to produce lipid droplets (LDs), and their production has been linked to aspects of persistent infection by M. tuberculosis Unfortunately, little is known about LD production in these organisms, including how LDs are formed, their function, or the identity of proteins that associate with them. In this study, an established M. tuberculosis LD protein and a surrogate Mycobacterium host were used as model systems to study the interactions between proteins and LDs in bacteria. Through these studies, we identified a commonly occurring protein motif that is able to facilitate the association of proteins to LDs in prokaryotes. PMID- 29760208 TI - RpoN-Dependent Direct Regulation of Quorum Sensing and the Type VI Secretion System in Pseudomonas aeruginosa PAO1. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen of humans, particularly those with cystic fibrosis. As a global regulator, RpoN controls a group of virulence-related factors and quorum-sensing (QS) genes in P. aeruginosa To gain further insights into the direct targets of RpoN in vivo, the present study focused on identifying the direct targets of RpoN regulation in QS and the type VI secretion system (T6SS). We performed chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) that identified 1,068 binding sites of RpoN, mostly including metabolic genes, a group of genes in QS (lasI, rhlI, and pqsR) and the T6SS (hcpA and hcpB). The direct targets of RpoN have been verified by electrophoretic mobility shifts assays (EMSA), lux reporter assay, reverse transcription-quantitative PCR, and phenotypic detection. The DeltarpoN::Tc mutant resulted in the reduced production of pyocyanin, motility, and proteolytic activity. However, the production of rhamnolipids and biofilm formation were higher in the DeltarpoN::Tc mutant than in the wild type. In summary, the results indicated that RpoN had direct and profound effects on QS and the T6SS.IMPORTANCE As a global regulator, RpoN controls a wide range of biological pathways, including virulence in P. aeruginosa PAO1. This work shows that RpoN plays critical and global roles in the regulation of bacterial pathogenicity and fitness. ChIP-seq provided a useful database to characterize additional functions and targets of RpoN in the future. The functional characterization of RpoN-mediated regulation will improve the current understanding of the regulatory network of quorum sensing and virulence in P. aeruginosa and other bacteria. PMID- 29760209 TI - Complex control of a genomic island governing biofilm and rugose colony development in Vibrio vulnificus. AB - V. vulnificus is a potent opportunistic human pathogen that contaminates the human food-chain by asymptomatically colonizing seafood. Expression of the 9-gene brp exopolysaccharide locus mediates surface adherence and is controlled by the secondary signaling molecule c-di-GMP and the regulator BrpT. Here, we show that c-di-GMP and BrpT also regulate the expression of an adjacent 5-gene cluster that includes the cabABC operon, brpT and another VpsT-like transcriptional regulator, brpS The expression of the 14 genes spanning the region increased with elevated intracellular c -di-GMP levels in a BrpT-dependent manner, save brpS, which was positively regulated by c-di-GMP and repressed by BrpT. BrpS repressed brpA expression and was required for rugose colony development. Mutation of its consensus WFSA c-di-GMP binding motif blocked these activities, suggesting that BrpS function is dependent on binding c-di-GMP. BrpT specifically bound the cabA, brpT and brpS promoters and binding sites homologous to the V. cholerae VpsT binding site were identified upstream of brpA and brpT. Transcription was initiated distal to brpA, and a conserved RfaH-recruiting ops element and a potential Rho utilization (rut) terminator site were identified within the 100 bp leader region, suggesting integration of early termination and operon polarity suppression into the regulation of brp transcription. The GC content and codon usage of the 16 kb brp region was 5.5% lower relative to the flanking DNA, suggesting its recent assimilation via horizontal transfer. Thus, architecturally, the brp region can be considered as an acquired biofilm and rugosity island that is subject to complex regulation.Significance statement Biofilm and rugose colony formation are developmental programs that underpin the evolution of V. vulnificus as a potent opportunistic human pathogen and successful environmental organism. Better understanding of the regulatory pathways governing theses phenotypes promote the development and implementation of strategies to mitigate food-chain contamination by this pathogen. c-di-GMP signaling is central to both pathways. We show that the molecule orchestrates the expression of 14 genes clustered in a 16 Kb segment of the genome that govern biofilm and rugose colony development. This region exhibits the hallmarks of horizontal transfer, suggesting complex regulatory control of a recently assimilated genetic island governing the colonization response of V. vulnificus. PMID- 29760210 TI - The State of the Union Is Strong: a Review of ASM's 6th Conference on Cell-Cell Communication in Bacteria. AB - The 6th American Society for Microbiology Conference on Cell-Cell Communication in Bacteria convened from 16 to 19 October 2017 in Athens, GA. In this minireview, we highlight some of the research presented at that meeting that addresses central questions emerging in the field, including the following questions. How are cell-cell communication circuits designed to generate responses? Where are bacteria communicating? Finally, why are bacteria engaging in such behaviors? PMID- 29760212 TI - Model of Persistent Salmonella Infection: Salmonella enterica Serovar Pullorum Modulates the Immune Response of the Chicken from a Th17-Type Response towards a Th2-Type Response. AB - Salmonella enterica infection affects a wide range of animals and humans, and a small number of serovars cause typhoid-like infections, one characteristic of which is persistent infection in convalescents. Avian-specific S. enterica serovar Pullorum produces systemic disease in young chickens, which is followed by a carrier state in convalescent birds, leading to infection of the ovary at sexual maturity and vertical transmission. However, the immunological basis of persistent infection remains unclear. S. enterica serovar Enteritidis is taxonomically closely related but does not show this characteristic. Differences in the immune responses between S Pullorum and S Enteritidis were compared by using Salmonella-infected chicken monocyte-derived macrophages (chMDMs) and CD4+ T lymphocytes that had been cocultured with infected chMDMs or chicken splenocytes in vitro and also in 2-day-old chickens in vivo In comparison with S Enteritidis, S Pullorum-infected chMDMs showed reduced mRNA expression levels of interleukin-12alpha (IL-12alpha) and IL-18 and stimulated the proliferation of Th2 lymphocytes, with reduced expression of gamma interferon (IFN-gamma) and IL 17 and increased expression levels of IL-4 and IL-13 There was little evidence of clonal anergy or immune suppression induced by S Pullorum in vitro. S Pullorum also increased the levels of expression of IL-4 and decreased the levels of IFN gamma in the spleen and cecal tonsil of infected birds. This suggests that S Pullorum is able to modulate host immunity from a dominant IFN-gamma-producing Th17 response toward a Th2 response, which may promote persistent infection in chickens. S Pullorum in chickens is presented as a good model of the typhoid group to study persistent infection. PMID- 29760213 TI - Changes in IgA Protease Expression Are Conferred by Changes in Genomes during Persistent Infection by Nontypeable Haemophilus influenzae in Chronic Obstructive Pulmonary Disease. AB - Nontypeable Haemophilus influenzae (NTHi) is an exclusively human pathobiont that plays a critical role in the course and pathogenesis of chronic obstructive pulmonary disease (COPD). NTHi causes acute exacerbations of COPD and also causes persistent infection of the lower airways. NTHi expresses four IgA protease variants (A1, A2, B1, and B2) that play different roles in virulence. Expression of IgA proteases varies among NTHi strains, but little is known about the frequency and mechanisms by which NTHi modulates IgA protease expression during infection in COPD. To assess expression of IgA protease during natural infection in COPD, we studied IgA protease expression by 101 persistent strains (median duration of persistence, 161 days; range, 2 to 1,422 days) collected longitudinally from patients enrolled in a 20-year study of COPD upon initial acquisition and immediately before clearance from the host. Upon acquisition, 89 (88%) expressed IgA protease. A total of 16 of 101 (16%) strains of NTHi altered expression of IgA protease during persistence. Indels and slipped-strand mispairing of mononucleotide repeats conferred changes in expression of igaA1, igaA2, and igaB1 Strains with igaB2 underwent frequent changes in expression of IgA protease B2 during persistence, mediated by slipped-strand mispairing of a 7 nucleotide repeat, TCAAAAT, within the open reading frame of igaB2 We conclude that changes in iga gene sequences result in changes in expression of IgA proteases by NTHi during persistent infection in the respiratory tract of patients with COPD. PMID- 29760211 TI - Updates to Clostridium difficile Spore Germination. AB - Germination of Clostridium difficile spores is a crucial early requirement for colonization of the gastrointestinal tract. Likewise, C. difficile cannot cause disease pathologies unless its spores germinate into metabolically active, toxin producing cells. Recent advances in our understanding of C. difficile spore germination mechanisms indicate that this process is both complex and unique. This review defines unique aspects of the germination pathways of C. difficile and compares them to those of two other well-studied organisms, Bacillus anthracis and Clostridium perfringensC. difficile germination is unique, as C. difficile does not contain any orthologs of the traditional GerA-type germinant receptor complexes and is the only known sporeformer to require bile salts in order to germinate. While recent advances describing C. difficile germination mechanisms have been made on several fronts, major gaps in our understanding of C. difficile germination signaling remain. This review provides an updated, in depth summary of advances in understanding of C. difficile germination and potential avenues for the development of therapeutics, and discusses the major discrepancies between current models of germination and areas of ongoing investigation. PMID- 29760214 TI - YopN Is Required for Efficient Effector Translocation and Virulence in Yersinia pseudotuberculosis. AB - Type III secretion systems (T3SSs) are used by various Gram-negative pathogens to subvert the host defense by a host cell contact-dependent mechanism to secrete and translocate virulence effectors. While the effectors differ between pathogens and determine the pathogenic life style, the overall mechanism of secretion and translocation is conserved. T3SSs are regulated at multiple levels, and some secreted substrates have also been shown to function in regulation. In Yersinia, one of the substrates, YopN, has long been known to function in the host cell contact-dependent regulation of the T3SS. Prior to contact, through its interaction with TyeA, YopN blocks secretion. Upon cell contact, TyeA dissociates from YopN, which is secreted by the T3SS, resulting in the induction of the system. YopN has also been shown to be translocated into target cells by a T3SS dependent mechanism. However, no intracellular function has yet been assigned to YopN. The regulatory role of YopN involves the N-terminal and C-terminal parts, while less is known about the role of the central region of YopN. Here, we constructed different in-frame deletion mutants within the central region. The deletion of amino acids 76 to 181 resulted in an unaltered regulation of Yop expression and secretion but triggered reduced YopE and YopH translocation within the first 30 min after infection. As a consequence, this deletion mutant lost its ability to block phagocytosis by macrophages. In conclusion, we were able to differentiate the function of YopN in translocation and virulence from its function in regulation. PMID- 29760215 TI - Specific Binding to Differentially Expressed Human Carcinoembryonic Antigen Related Cell Adhesion Molecules Determines the Outcome of Neisseria gonorrhoeae Infections along the Female Reproductive Tract. AB - The gonococcal Opa proteins are an antigenically variable family of surface adhesins that bind human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM3, CEACAM5, and/or CEACAM6, cell surface glycoproteins that are differentially expressed on a broad spectrum of human cells and tissues. While they are presumed to be important for infection, the significance of various Opa-CEACAM-mediated cellular interactions in the context of the genital tract has remained unclear. Here, we observed that CEACAM1 and CEACAM5 are differentially expressed on epithelia lining the upper and lower portions of the human female genital tract, respectively. Using transgenic mouse lines expressing human CEACAMs in a manner that reflects this differential pattern, we considered the impact of Opa-CEACAM interactions during uncomplicated lower genital tract infections versus during pelvic inflammatory disease. Our results demonstrate that Opa-CEACAM5 binding on vaginal epithelia facilitates the long-term colonization of the lower genital tract, while Opa protein binding to CEACAM1 on uterine epithelia enhances gonococcal association and penetration into these tissues. While these Opa-dependent interactions with CEACAM-expressing epithelial surfaces promote infection, Opa binding by neutrophil-expressed CEACAMs counterbalances this by facilitating more effective gonococcal clearance. Furthermore, during uterine infections, CEACAM-dependent tissue invasion aggravates disease pathology by increasing the acute inflammatory response. Together, these findings demonstrate that the outcome of infection is determined by both the cell type-specific expression of human CEACAMs and the CEACAM specificity of the Opa variants expressed, which combine to determine the level of gonococcal association with the genital mucosa versus the extent of CEACAM dependent inflammation and gonococcal clearance by neutrophils. PMID- 29760217 TI - Temporal Manipulation of Mitochondrial Function by Virulent Francisella tularensis To Limit Inflammation and Control Cell Death. AB - Francisella tularensis subsp. tularensis is a highly pathogenic intracellular bacterium that suppresses host inflammation by impairing the metabolic shift from oxidative phosphorylation to glycolysis. Decreased mitochondrial metabolism is central to initiating a metabolic shift to glycolysis and regulating inflammation, but F. tularensis subsp. tularensis manipulation of host mitochondrial function has not been explored. We demonstrate, using extracellular flux analysis, that F. tularensis subsp. tularensis infection initially improves host macrophage mitochondrial bioenergetics in a capsule-dependent manner. Enhancement of mitochondrial function by F. tularensis subsp. tularensis allowed for modest replication and inhibition of apoptosis early after infection. However, using live cell imaging, we found that F. tularensis subsp. tularensis facilitated the loss of mitochondrial function at later time points during infection in a capsule-independent fashion. This loss of function was paired with oncosis and rapid bacterial replication. Inhibition of oncosis reduced intracellular bacterial numbers, underscoring the requirement for this process during F. tularensis subsp. tularensis infection. These findings establish that temporal mitochondrial manipulation by F. tularensis subsp. tularensis is critical for maintenance of a noninflammatory environment and subsequently aids in optimal replication and dissemination of this pathogenic organism. PMID- 29760216 TI - Plasmodium falciparum MSP3 Exists in a Complex on the Merozoite Surface and Generates Antibody Response during Natural Infection. AB - Plasmodium falciparum merozoite surface protein 3 (MSP3) is an abundantly expressed secreted merozoite surface protein and a leading malaria vaccine candidate antigen. However, it is unclear how MSP3 is retained on the surface of merozoites without a glycosylphosphatidylinositol (GPI) anchor or a transmembrane domain. In the present study, we identified an MSP3-associated network on the Plasmodium merozoite surface by immunoprecipitation of Plasmodium merozoite lysate using antibody to the N terminus of MSP3 (anti-MSP3N) followed by mass spectrometry analysis. The results suggested the association of MSP3 with other merozoite surface proteins: MSP1, MSP6, MSP7, RAP2, and SERA5. Protein-protein interaction studies by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) analysis showed that MSP3 complex consists of MSP1, MSP6, and MSP7 proteins. Immunological characterization of MSP3 revealed that MSP3N is strongly recognized by hyperimmune serum from African and Asian populations. Furthermore, we demonstrate that human antibodies, affinity purified against recombinant MSP3N (rMSP3N), promote opsonic phagocytosis of merozoites in cooperation with monocytes. At nonphysiological concentrations, anti-MSP3N antibodies inhibited the growth of P. falciparum in vitro Together, the data suggest that MSP3 and especially its N-terminal region containing known B/T cell epitopes are targets of naturally acquired immunity against malaria and also comprise an important candidate for a multisubunit malaria vaccine. PMID- 29760218 TI - Validation of an Expanded Carrier Screen that Optimizes Sensitivity via Full-Exon Sequencing and Panel-wide Copy Number Variant Identification. AB - BACKGROUND: By identifying pathogenic variants across hundreds of genes, expanded carrier screening (ECS) enables prospective parents to assess the risk of transmitting an autosomal recessive or X-linked condition. Detection of at-risk couples depends on the number of conditions tested, the prevalence of the respective diseases, and the screen's analytical sensitivity for identifying disease-causing variants. Disease-level analytical sensitivity is often <100% in ECS tests because copy number variants (CNVs) are typically not interrogated because of their technical complexity. METHODS: We present an analytical validation and preliminary clinical characterization of a 235-gene sequencing based ECS with full coverage across coding regions, targeted assessment of pathogenic noncoding variants, panel-wide CNV calling, and specialized assays for technically challenging genes. Next-generation sequencing, customized bioinformatics, and expert manual call review were used to identify single nucleotide variants, short insertions and deletions, and CNVs for all genes except FMR1 and those whose low disease incidence or high technical complexity precluded novel variant identification or interpretation. RESULTS: Screening of 36859 patients' blood or saliva samples revealed the substantial impact on fetal disease-risk detection attributable to novel CNVs (9.19% of risk) and technically challenging conditions (20.2% of risk), such as congenital adrenal hyperplasia. Of the 7498 couples screened, 335 were identified as at risk for an affected pregnancy, underscoring the clinical importance of the test. Validation of our ECS demonstrated >99% analytical sensitivity and >99% analytical specificity. CONCLUSIONS: Validated high-fidelity identification of different variant types especially for diseases with complicated molecular genetics-maximizes at-risk couple detection. PMID- 29760219 TI - Detectable High-Sensitivity Cardiac Troponin within the Population Reference Interval Conveys High 5-Year Cardiovascular Risk: An Observational Study. AB - BACKGROUND: Increased cardiac troponin I or T detected by high-sensitivity assays (hs-cTnI or hs-cTnT) confers an increased risk of adverse prognosis. We determined whether patients presenting with putatively normal, detectable cTn concentrations [> limit of detection and < upper reference limit (URL)] have increased risk of major adverse cardiovascular events (MACE) or all-cause mortality. METHODS: A prospective 5-year follow-up of patients recruited in the emergency department with possible acute coronary syndrome (ACS) and cTn concentrations measured with hs-cTnI (Abbott) and hs-cTnT (Roche) assays. Cox regression models were generated with adjustment for covariates in those without MACE on presentation. Hazard ratios (HRs) for hs-cTn were calculated relative to the HRs at the median concentration. RESULTS: Of 1113 patients, 836 were without presentation MACE. Of these, 138 incurred a MACE and 169 died during a median 5.8 year follow-up. HRs for MACE at the URLs were 2.3 (95% CI, 1.7-3.2) for hs-cTnI and 1.8 (95% CI, 1.3-2.4) for hs-cTnT. Corresponding HRs for mortality were 1.7 (95% CI, 1.2-2.2) for hs-cTnI and 2.3 (95 % CI, 1.7-3.1) for hs-cTnT. The HR for MACE increased with increasing hs-cTn concentration similarly for both assays, but the HR for mortality increased at approximately twice the rate for hs-cTnT than hs-cTnI. Patients with hs-cTnI >=10 ng/L or hs-cTnT >=16 ng/L had the same percentage of MACE at 5-year follow-up (33%) as patients with presentation MACE. CONCLUSIONS: Many patients with ACS ruled out and putatively normal but detectable hs-cTnI concentrations are at similar long-term risk as those with MACE. hs-cTnT concentrations are more strongly associated with 5-year mortality than hs-cTnI. PMID- 29760220 TI - Quantifying Atherogenic Lipoproteins: Current and Future Challenges in the Era of Personalized Medicine and Very Low Concentrations of LDL Cholesterol. A Consensus Statement from EAS and EFLM. AB - BACKGROUND: The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein quantification for cardiovascular risk management. CONTENT: We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (a) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (b) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (c) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle targeted treatment reduces the number of cardiovascular events and healthcare related costs than treatment targeted to LDL cholesterol. SUMMARY: Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels. PMID- 29760222 TI - ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy. AB - Purpose: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF- and/or RAS-mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS-mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as observed with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. Here, we aimed to model the mechanism of resistance to ERK inhibitors.Experimental Design: We tested five structurally different ATP-competitive ERK inhibitors representing three different scaffolds on BRAF/RAS-mutant cancer cell lines of different tissue types to generate resistant lines. We have used in vitro modeling, structural biology, and genomic analysis to understand the development of resistance to ERK inhibitors and the mechanisms leading to it.Results: We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitors, ERBB receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK inhibitor resistance.Conclusions: These findings suggest that combination therapy with MEK or ERBB receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Clin Cancer Res; 24(16); 4044-55. (c)2018 AACR. PMID- 29760221 TI - Development and Validation of a Prostate Cancer Genomic Signature that Predicts Early ADT Treatment Response Following Radical Prostatectomy. AB - Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT.Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT-treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling-related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis.Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035).Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908-16. (c)2018 AACR. PMID- 29760224 TI - Natriuretic Peptide-Guided Heart Failure Therapy After the GUIDE-IT Study. PMID- 29760225 TI - Oxygen After Cardiac Arrest: Enough Is Enough? PMID- 29760223 TI - Genomic Heterogeneity and the Small Renal Mass. AB - Purpose: Tumor heterogeneity may represent a barrier to preoperative genomic characterization by needle biopsy in clear cell renal cell carcinoma (ccRCC). The extent of heterogeneity in small renal tumors remains unknown. Therefore, we set out to evaluate heterogeneity in resected large and small renal tumors.Experimental Design: We conducted a study from 2013 to 2016 that evaluated 47 consecutive ccRCC tumors resected during radical or partial nephrectomy. Cases were designated as small (<4 cm) and large (>7 cm) tumors. Each tumor had three regions sampled. Copy-number variation (CNV) was assessed and gene expression analysis was performed to characterize the clear-cell A and B (ccA/ccB) profile and the cell-cycle progression (CCP) score. Genomic heterogeneity between three regions was evaluated using CNV subclonal events, regional expression profiles, and correlation between gene expression.Results: Twenty-three small and 24 large tumors were analyzed. Total CNVs and subclonal CNVs events were less frequent in small tumors (P < 0.001). Significant gene expression heterogeneity was observed for both CCP scores and ccA/ccB classifications. Larger tumors had more variance in CCP scores (P = 0.026). The distribution of ccA/ccB differed between small and large tumors with mixed ccA/ccB tumors occurring more frequently in the larger tumors (P = 0.024). Analysis of five mixed tumors (with both ccA/ccB regions) demonstrated the more aggressive ccB phenotype had greater CNV events (P = 0.014).Conclusions: Small renal tumors have much less genomic complexity and fewer subclonal events. Pretreatment genomic characterization with single-needle biopsy in small tumors may be useful to assess biologic potential and may influence therapy. Clin Cancer Res; 24(17); 4137-44. (c)2018 AACR. PMID- 29760226 TI - Accounting for Nonadherence. PMID- 29760228 TI - Effect of Liraglutide on Cardiovascular Events in Patients With Type 2 Diabetes Mellitus and Polyvascular Disease: Results of the LEADER Trial. PMID- 29760229 TI - Letter by Romeo et al Regarding Article, "Immediate and Midterm Cardiac Remodeling After Surgical Pulmonary Valve Replacement in Adults With Repaired Tetralogy of Fallot: A Prospective Cardiovascular Magnetic Resonance and Clinical Study". PMID- 29760230 TI - Response by Heng et al to Letter Regarding Article, "Immediate and Midterm Cardiac Remodeling After Surgical Pulmonary Valve Replacement in Adults With Repaired Tetralogy of Fallot: A Prospective Cardiovascular Magnetic Resonance and Clinical Study". PMID- 29760231 TI - Letter by Adabag et al Regarding Article, "Age and Outcomes of Primary Prevention Implantable Cardioverter-Defibrillators in Patients With Nonischemic Systolic Heart Failure". PMID- 29760232 TI - Response by Elming et al to Letter Regarding Article, "Age and Outcomes of Primary Prevention Implantable Cardioverter-Defibrillators in Patients With Nonischemic Systolic Heart Failure". PMID- 29760227 TI - Socioeconomic Status and Cardiovascular Outcomes: Challenges and Interventions. AB - Socioeconomic status (SES) has a measurable and significant effect on cardiovascular health. Biological, behavioral, and psychosocial risk factors prevalent in disadvantaged individuals accentuate the link between SES and cardiovascular disease (CVD). Four measures have been consistently associated with CVD in high-income countries: income level, educational attainment, employment status, and neighborhood socioeconomic factors. In addition, disparities based on sex have been shown in several studies. Interventions targeting patients with low SES have predominantly focused on modification of traditional CVD risk factors. Promising approaches are emerging that can be implemented on an individual, community, or population basis to reduce disparities in outcomes. Structured physical activity has demonstrated effectiveness in low-SES populations, and geomapping may be used to identify targets for large-scale programs. Task shifting, the redistribution of healthcare management from physician to nonphysician providers in an effort to improve access to health care, may have a role in select areas. Integration of SES into the traditional CVD risk prediction models may allow improved management of individuals with high risk, but cultural and regional differences in SES make generalized implementation challenging. Future research is required to better understand the underlying mechanisms of CVD risk that affect individuals of low SES and to determine effective interventions for patients with high risk. We review the current state of knowledge on the impact of SES on the incidence, treatment, and outcomes of CVD in high-income societies and suggest future research directions aimed at the elimination of these adverse factors, and the integration of measures of SES into the customization of cardiovascular treatment. PMID- 29760233 TI - Letter by Koshy et al Regarding Article, "Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study". PMID- 29760234 TI - Response by Halcox and Wareham to Letter Regarding Article, "Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study". PMID- 29760235 TI - Letter by Koh Regarding Article, "Day-to-Day Blood Pressure Variability and Risk of Dementia in a General Japanese Elderly Population: The Hisayama Study". PMID- 29760236 TI - Anti-sigma factor YlaD regulates transcriptional activity of sigma factor YlaC and sporulation via manganese-dependent redox-sensing molecular switch in Bacillus subtilis. AB - YlaD, a membrane-anchored anti-sigma (sigma) factor of Bacillus subtilis, contains a HX3CXXC motif that functions as a redox-sensing domain and belongs to one of the zinc (Zn)-co-ordinated anti-sigma factor families. Despite previously showing that the YlaC transcription is controlled by YlaD, experimental evidence of how the YlaC-YlaD interaction is affected by active cysteines and/or metal ions is lacking. Here, we showed that the P yla promoter is autoregulated solely by YlaC. Moreover, reduced YlaD contained Zn and iron, while oxidized YlaD did not. Cysteine substitution in YlaD led to changes in its secondary structure; Cys3 had important structural functions in YlaD, and its mutation caused dissociation from YlaC, indicating the essential requirement of a HX3CXXC motif for regulating interactions of YlaC with YlaD. Analyses of the far-UV CD spectrum and metal content revealed that the addition of Mn ions to Zn-YlaD changed its secondary structure and that iron was substituted for manganese (Mn). The ylaC gene expression using betaGlu activity from P yla :gusA was observed at the late exponential and early-stationary phase, and the ylaC-overexpressing mutant constitutively expressed gene transcripts of clpP and sigH, an important alternative sigma factor regulated by ClpXP. Collectively, our data demonstrated that YlaD senses redox changes and elicits increase in Mn ion concentrations and that, in turn, YlaD-mediated transcriptional activity of YlaC regulates sporulation initiation under oxidative stress and Mn-substituted conditions by regulating clpP gene transcripts. This is the first report of the involvement of oxidative stress-responsive B. subtilis extracytoplasmic function sigma factors during sporulation via a Mn-dependent redox-sensing molecular switch. PMID- 29760237 TI - Identification of a Wells-Dawson polyoxometalate-based AP-2gamma inhibitor with pro-apoptotic activity. AB - AP-2 gamma (AP-2gamma) is a transcription factor that plays pivotal roles in breast cancer biology. To search for small molecule inhibitors of AP-2gamma, we performed a high-throughput fluorescence anisotropy screen and identified a polyoxometalate compound with Wells-Dawson structure K6[P2Mo18O62] (Dawson-POM) that blocks the DNA-binding activity of AP-2gamma. We showed that this blocking activity is due to the direct binding of Dawson-POM to AP-2gamma. We also provided evidence to show that Dawson-POM decreases AP-2gamma-dependent transcription similar to silencing the gene. Finally, we demonstrated that Dawson POM contains anti-proliferative and pro-apoptotic effects in breast cancer cells. In summary, we identified the first small molecule inhibitor of AP-2gamma and showed Dawson-POM-mediated inhibition of AP-2gamma as a potential avenue for cancer therapy. PMID- 29760240 TI - Cochrane Corner: drug-eluting stents versus bare-metal stents for acute coronary syndrome. PMID- 29760239 TI - Dietary Acrylamide Intake and Risk of Renal Cell Carcinoma in Two Large Prospective Cohorts. AB - Background: Accumulating evidence suggests that dietary acrylamide intake is not associated with the risk of most cancers in humans. However, a meta-analysis of five epidemiologic studies found a suggestion of an increased risk of kidney cancer with higher dietary acrylamide intake.Methods: We investigated this association in the prospective Health Professionals Follow-up Study (HPFS; 1986 2014) and Nurses' Health Study (NHS; 1980-2014) cohorts. Dietary acrylamide intake was calculated on the basis of 46 acrylamide-containing foods reported on food frequency questionnaires completed every 4 years. The associations with the incidence of total and fatal renal cell carcinoma (RCC; n = 292/84 HPFS, n = 337/87 NHS) during more than two decades of follow-up were assessed using Cox proportional hazards models adjusting for potential confounders.Results: There was no association between cumulative average or baseline acrylamide intake and the risk of total or fatal RCC risk in men or women. Acrylamide intake was also not associated with RCC risk among never-smokers, nor was it associated with the risk of clear cell RCC.Conclusions: Dietary acrylamide was not associated with risk of RCC in two long-term prospective cohorts with repeated measures of dietary intake.Impact: This analysis of RCC adds to the body of evidence that dietary acrylamide is not an important cancer risk factor in humans. Cancer Epidemiol Biomarkers Prev; 27(8); 979-82. (c)2018 AACR. PMID- 29760238 TI - Structural and ligand-binding analysis of the YAP-binding domain of transcription factor TEAD4. AB - The oncoprotein YAP (Yes-associated protein) requires the TEAD family of transcription factors for the up-regulation of genes important for cell proliferation. Disrupting YAP-TEAD interaction is an attractive strategy for cancer therapy. Targeting TEADs using small molecules that either bind to the YAP binding pocket or the palmitate-binding pocket is proposed to disrupt the YAP TEAD interaction. There is a need for methodologies to facilitate robust and reliable identification of compounds that occupy either YAP-binding pocket or palmitate-binding pocket. Here, using NMR spectroscopy, we validated compounds that bind to these pockets and also identify the residues in mouse TEAD4 (mTEAD4) that interact with these compounds. Flufenamic acid (FA) was used as a positive control for validation of palmitate-binding pocket-occupying compounds by NMR. Furthermore, we identify a hit from a fragment screen and show that it occupies a site close to YAP-binding pocket on the TEAD surface. Our results also indicate that purified mTEAD4 can catalyze autopalmitoylation. NMR studies on mTEAD4 revealed that exchanges exist in TEAD as NMR signal broadening was observed for residues close to the palmitoylation site. Mutating the palmitoylated cysteine (C360S mutant) abolished palmitoylation, while no significant changes in the NMR spectrum were observed for the mutant which still binds to YAP. We also show that FA inhibits TEAD autopalmitoylation. Our studies highlight the utility of NMR spectroscopy in identifying small molecules that bind to TEAD pockets and reinforce the notion that both palmitate-binding pocket and YAP-binding pocket are targetable. PMID- 29760241 TI - Cochrane corner: adenosine versus intravenous calcium channel antagonists for supraventricular tachycardia. PMID- 29760242 TI - Cochrane corner: text messaging to improve adherence to drugs for secondary prevention of cardiovascular disease. PMID- 29760243 TI - Underutilisation of public access defibrillation is related to retrieval distance and time-dependent availability. AB - INTRODUCTION: Public access defibrillation doubles the chances of neurologically intact survival following out-of-hospital cardiac arrest (OHCA). Although there are increasing numbers of defibrillators (automated external defibrillator (AEDs)) available in the community, they are used infrequently, despite often being available. We aimed to match OHCAs with known AED locations in order to understand AED availability, the effects of reduced AED availability at night and the operational radius at which they can be effectively retrieved. METHODS: All emergency calls to South Central Ambulance Service from April 2014 to April 2016 were screened to identify cardiac arrests. Each was mapped to the nearest AED, according to the time of day. Mapping software was used to calculate the actual walking distance for a bystander between each OHCA and respective AED, when travelling at a brisk walking speed (4 mph). RESULTS: 4012 cardiac arrests were identified and mapped to one of 2076 AEDs. All AEDs were available during daytime hours, but only 713 at night (34.3%). 5.91% of cardiac arrests were within a retrieval (walking) radius of 100 m during the day, falling to 1.59% out-of hours. Distances to rural AEDs were greater than in urban areas (P<0.0001). An AED could potentially have been retrieved prior to actual ambulance arrival in 25.3% cases. CONCLUSION: Existing AEDs are underused; 36.4% of OHCAs are located within 500 m of an AED. Although more AEDs will improve availability, greater use can be made of existing AEDs, particularly by ensuring they are all available on a 24/7 basis. PMID- 29760244 TI - Early use of mineralocorticoid receptor antagonists in ST-elevation myocardial infarction: is it ever too early? PMID- 29760245 TI - Management of percutaneous coronary intervention complications. PMID- 29760246 TI - The hidden curriculum and continuing professional development for family physicians. PMID- 29760247 TI - ? PMID- 29760248 TI - Debating the opioid guidelines: corrections. PMID- 29760250 TI - Correction. PMID- 29760249 TI - Debating the opioid guidelines: context. PMID- 29760252 TI - Choosing Wisely in primary care: Moving from recommendations to implementation. PMID- 29760251 TI - Teach your parents and providers well: Call for refocus on the health of trans and gender-diverse children. PMID- 29760254 TI - Learning narrative-based medicine skills: Narrative-based medicine 3. AB - OBJECTIVE: To raise awareness of narrative-based medicine (NBM) as a valuable approach to the consultation, which, if practised more widely by GPs, would convey considerable benefits to both patient and doctor. SOURCES OF INFORMATION: While this article draws on the perspectives of 2 of NBM's key proponents, Rita Charon and John Launer, it also presents the author's perspective on the usefulness of the arts. MAIN MESSAGE: This article presents some practical ways in which GPs can start using the skills of NBM and methods for developing those skills further. This will include methods for broadening awareness, learning to decipher meanings, and developing reflective skills. In particular, the arts are a powerful means for gaining these skills, in addition to stimulating the imagination and promoting creativity. CONCLUSION: Technological advances in medicine give strength to the notion that medicine is primarily a science. In the face of this, it can be forgotten that medicine is also an art. Narrative-based medicine is the means by which the art of medicine can be practised. PMID- 29760255 TI - Choosing guidelines to use in your practice. PMID- 29760253 TI - Deprescribing benzodiazepine receptor agonists: Evidence-based clinical practice guideline. AB - OBJECTIVE: To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper and stop benzodiazepine receptor agonists (BZRAs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes. METHODS: The overall team comprised 8 clinicians (1 family physician, 2 psychiatrists, 1 clinical psychologist, 1 clinical pharmacologist, 2 clinical pharmacists, and 1 geriatrician) and a methodologist; members disclosed conflicts of interest. For guideline development, a systematic process was used, including the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Evidence was generated by conducting a systematic review of BZRA deprescribing trials for insomnia, as well as performing a review of reviews of the harms of continued BZRA use and narrative syntheses of patient preferences and resource implications. This evidence and GRADE quality of evidence ratings were used to generate recommendations. The team refined guideline content and recommendations through consensus and synthesized clinical considerations to address front-line clinician questions. The draft guideline was reviewed by clinicians and stakeholders. RECOMMENDATIONS: We recommend that deprescribing (tapering slowly) of BZRAs be offered to elderly adults (>= 65 years) who take BZRAs, regardless of duration of use, and suggest that deprescribing (tapering slowly) be offered to adults aged 18 to 64 who have used BZRAs for more than 4 weeks. These recommendations apply to patients who use BZRAs to treat insomnia on its own (primary insomnia) or comorbid insomnia where potential underlying comorbidities are effectively managed. This guideline does not apply to those with other sleep disorders or untreated anxiety, depression, or other physical or mental health conditions that might be causing or aggravating insomnia. CONCLUSION: Benzodiazepine receptor agonists are associated with harms, and therapeutic effects might be short term. Tapering BZRAs improves cessation rates compared with usual care without serious harms. Patients might be more amenable to deprescribing conversations if they understand the rationale (potential for harm), are involved in developing the tapering plan, and are offered behavioural advice. This guideline provides recommendations for making decisions about when and how to reduce and stop BZRAs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients. PMID- 29760256 TI - Red-eared zebra diagnosis: Case of relapsing polychondritis. PMID- 29760257 TI - Choosing Wisely Canada recommendations. PMID- 29760258 TI - Antipsychotics for agitation in dementia. PMID- 29760259 TI - Biotin interference: Underrecognized patient safety risk in laboratory testing. PMID- 29760261 TI - What's happening in your waiting room? PMID- 29760262 TI - Advance care planning in family medicine training. PMID- 29760260 TI - Older patient engagement in advance care planning in Canadian primary care practices: Results of a multisite survey. AB - OBJECTIVE: To assess primary care patients' engagement in advance care planning (ACP) and predictors of engagement. DESIGN: Cross-sectional survey using a revised version of a validated questionnaire. SETTING: Alberta, Ontario, and British Columbia. PARTICIPANTS: Convenience sample of 20 family practices that provided a consecutive sample of 810 patients aged 50 years and older. MAIN OUTCOME MEASURES: Engagement in ACP activities, and sociodemographic and health related predictors of having engaged in ACP activities. RESULTS: Patients had a mean age of 66 years (55.6% women). Two-thirds of patients (68.5%; 555) had thought about the kinds of medical treatments they would want or not want if they were sick and in hospital, 52.8% (n = 428) had talked with someone about what they would want, 32.0% (n = 259) had written down their wishes, 50.4% (n = 408) had named someone to be their substitute decision maker, and 23.0% (n = 186) had engaged in all 4 key ACP activities. Of those patients who had talked to someone about medical treatments wanted or not, 17.5% (n = 75) had talked to their family doctors. Age (adjusted odds ratio per 10-year category of 1.55; 95% CI 1.26 to 1.90; P < .001) was significantly associated with having engaged in all ACP activities. CONCLUSION: Many patients have engaged in some ACP activities, but few have discussed ACP with their family physicians. Strategies should be implemented in primary care to reduce the barriers to discussing ACP. PMID- 29760263 TI - Flawed health care system, strong family physicians. PMID- 29760264 TI - ? PMID- 29760265 TI - ? PMID- 29760266 TI - The reality of urban FPs. PMID- 29760267 TI - ? PMID- 29760268 TI - ? PMID- 29760270 TI - ? PMID- 29760271 TI - ? PMID- 29760273 TI - What influences success in family medicine maternity care education programs? Qualitative exploration. AB - OBJECTIVE: To ascertain how program leaders in family medicine characterize success in family medicine maternity care education and determine which factors influence the success of training programs. DESIGN: Qualitative research using semistructured telephone interviews. SETTING: Purposive sample of 6 family medicine programs from 5 Canadian provinces. PARTICIPANTS: Eighteen departmental leaders and program directors. METHODS: Semistructured telephone interviews were conducted with program leaders in family medicine maternity care. Departmental leaders identified maternity care programs deemed to be "successful." Interviews were audiorecorded and transcribed verbatim. Team members conducted thematic analysis. MAIN FINDINGS: Participants considered their education programs to be successful in family medicine maternity care if residents achieved competency in intrapartum care, if graduates planned to include intrapartum care in their practices, and if their education programs were able to recruit and retain family medicine maternity care faculty. Five key factors were deemed to be critical to a program's success in family medicine maternity care: adequate clinical exposure, the presence of strong family medicine role models, a family medicine-friendly hospital environment, support for the education program from multiple sources, and a dedicated and supportive community of family medicine maternity care providers. CONCLUSION: Training programs wishing to achieve greater success in family medicine maternity care education should employ a multifaceted strategy that considers all 5 of the interdependent factors uncovered in our research. By paying particular attention to the informal processes that connect these factors, program leaders can preserve the possibility that family medicine residents will graduate with the competence and confidence to practise full-scope maternity care. PMID- 29760274 TI - ? PMID- 29760269 TI - ? PMID- 29760272 TI - Physical activity assessment and counseling in Quebec family medicine groups. AB - OBJECTIVE: To determine how often primary health care providers (PHCPs) in family medicine groups (FMGs) assess physical activity (PA) levels, provide PA counseling (PAC), and refer patients to exercise professionals; to describe patients' PA levels, physical fitness, and satisfaction regarding their PA management in FMGs; to describe available PA materials in FMGs and PHCPs' PAC self-efficacy and PA knowledge; and to identify characteristics of patients and PHCPs that determine the assessment of PA and PAC provided by PHCPs. DESIGN: Cross-sectional study using questionnaires and a medical chart audit. SETTING: Ten FMGs within the Integrated University Health Network of the Centre hospitalier universitaire de Sherbrooke in Quebec. PARTICIPANTS: Forty FPs, 24 nurses, and 439 patients. MAIN OUTCOME MEASURES: Assessment of PA level and PAC provided by PHCPs. RESULTS: Overall, 51.9% of the patients had had their PA level assessed during the past 18 months, but only 21.6% received PAC from at least 1 of the PHCPs. Similar percentages were found among the inactive (n = 244) and more active (n = 195) patients. The median PAC self-efficacy score of PHCPs was 70.2% (interquartile range 52.0% to 84.7%) and the median PA knowledge score was 45.8% (interquartile range 41.7% to 54.2%), with no significant differences between nurses and FPs. In multivariate analysis, 34% of the variance in PAC provided was explained by assessment of PA level, overweight or obese status, type 2 diabetes or prediabetes, less FP experience, lower patient annual family income, more nurse encounters, and a higher patient physical component summary of quality of life. CONCLUSION: The rates of assessment of PA and provision of PAC in Quebec FMGs were low, even though most of the patients were inactive. Initiatives to support PHCPs and more resources to assess PA levels and provide PAC should be implemented. PMID- 29760276 TI - Early Blood-Brain Barrier Disruption in Ischemic Stroke Initiates Multifocally Around Capillaries/Venules. AB - BACKGROUND AND PURPOSE: Detection and localization of the early phase of blood brain barrier disruption (BBBD) in vivo during cerebral ischemia/reperfusion injury remain a major challenge but may be a relevant outcome parameter in stroke. METHODS: We studied early BBBD in mice after transient middle cerebral artery occlusion by multimodal, high-field (9.4T) in vivo magnetic resonance imaging, including the contrast agent gadofluorineM as an albumin-binding tracer. GadofluorineM contrast-enhanced magnetic resonance imaging was performed to determine BBBD at 2, 6, and 24 hours after reperfusion. BBBD was confirmed and localized along the microvascular tree by using fluorescent gadofluorineM and immunofluorescence stainings (cluster of differentiation 31, ephrin type-B receptor 4, alpha smooth muscle actin, ionized calcium binding adaptor molecule 1). RESULTS: GadofluorineM contrast-enhanced magnetic resonance imaging revealed a multifocal spatial distribution of early BBBD and its close association with the microvasculature at a resolution of 40 MUm. GadofluorineM leakage was closely associated with ephrin type-B receptor 4-positive but not alpha smooth muscle actin-positive vessels. The multifocal pattern of early BBBD (already at 2 hours after reperfusion) thus occurred in the distal capillary and venular microvascular bed. These multifocal zones showed distinct imaging signs indicative of early vasogenic edema. The total volume of multifocal early BBBD accurately predicted infarct size at 24 hours after reperfusion. CONCLUSIONS: Early BBBD in focal cerebral ischemia initiates multifocally in the distal capillary and venular bed of the cerebral microvasculature. It is closely associated with perimicrovascular vasogenic edema and microglial activation and predicts the extent of final infarction. PMID- 29760275 TI - Targeting Reperfusion Injury in the Age of Mechanical Thrombectomy. PMID- 29760277 TI - Patent Foramen Ovale Closure Versus Medical Therapy for Cryptogenic Ischemic Stroke: A Topical Review. PMID- 29760279 TI - Histone H3K27 methylation modulates the dynamics of FANCD2 on chromatin to facilitate NHEJ and genome stability. AB - Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper. PMID- 29760278 TI - Imaging Endophenotypes of Stroke as a Target for Genetic Studies. PMID- 29760280 TI - Monoubiquitination of Cancer Stem Cell Marker CD133 at Lysine 848 Regulates Its Secretion and Promotes Cell Migration. AB - CD133, a widely known marker of cancer stem cells, was recently found in extracellular vesicles. However, the mechanisms underlying CD133 translocation to the extracellular space remain largely unknown. Here we report that CD133 is monoubiquitinated. Ubiquitination occurs primarily on complex glycosylated CD133. The lysine 848 residue at the intracellular carboxyl terminus is one of the sites for CD133 ubiquitination. The K848R mutation does not affect CD133 degradation by the lysosomal pathway but significantly reduces CD133 secretion by inhibiting the interaction between CD133 and tumor susceptibility gene 101 (Tsg101). Furthermore, knockdown of the E3 ubiquitin protein ligase Nedd4 largely impairs CD133 ubiquitination and vesicle secretion. Importantly, CD133-containing vesicles are taken up by recipient cells, consequently promoting cell migration. The K848R mutation reduces cell migration induced by CD133. Taken together, our findings show that monoubiquitination contributes to CD133 vesicle secretion and promotes recipient cell migration. These findings provide a clue to the mechanisms of CD133 secretion and cancer stem cell microenvironment interactional effects. PMID- 29760281 TI - The RAG-2 Inhibitory Domain Gates Accessibility Of The V(D)J Recombinase To Chromatin. AB - Accessibility of antigen receptor loci to RAG is correlated with the presence of H3K4me3, which binds to a plant homeodomain (PHD) in the RAG-2 subunit and promotes V(D)J recombination. A point mutation in the PHD, W453A, eliminates binding of H3K4me3 and impairs recombination. The debilitating effect of the W453A mutation is ameliorated by second-site mutations that locate an inhibitory domain in the interval from 352 through 405 of RAG-2. Disruption of the inhibitory domain stimulates V(D)J recombination within extrachromosomal substrates and at endogenous antigen receptor loci. Association of RAG-1 and RAG 2 with chromatin at the IgH locus in B cell progenitors is dependent on recognition of H3K4me3 by the PHD. Strikingly, disruption of the inhibitory domain permits association of RAG with the IgH locus in the absence of H3K4me3 binding. Thus, the inhibitory domain acts as a gate that prohibits RAG from accessing the IgH locus unless RAG-2 is engaged by H3K4me3. PMID- 29760283 TI - Correction for Liu et al., "Merkel Cell Polyomavirus Infection of Animal Dermal Fibroblasts". PMID- 29760282 TI - The Caenorhabditis elegans Ortholog of TDP-43 Regulates the Chromatin Localization of the Heterochromatin Protein 1 Homolog HPL-2. AB - TDP-1 is the Caenorhabditis elegans ortholog of mammalian TDP-43, which is strongly implicated in the etiology of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We discovered that deletion of the tdp-1 gene results in enhanced nuclear RNA interference (RNAi). As nuclear RNAi in C. elegans involves chromatin changes moderated by HPL-2, a homolog of heterochromatin protein 1 (HP1), we investigated the interaction of TDP-1 and HPL 2. We found that TDP-1 and HPL-2 interact directly and that loss of TDP-1 dramatically alters the chromatin association of HPL-2. We showed previously that deletion of the tdp-1 gene results in transcriptional alterations and the accumulation of double-stranded RNA (dsRNA). These molecular changes are replicated in an hpl-2 deletion strain, consistent with HPL-2 acting in consort with TDP-1 to modulate these aspects of RNA metabolism. Our observations identify novel mechanisms by which HP1 homologs can be recruited to chromatin and by which nuclear depletion of human TDP-43 may lead to changes in RNA metabolism that are relevant to disease. PMID- 29760285 TI - Occurrence of Incomplete Endothelialization Causing Residual Permeability After Left Atrial Appendage Closure. AB - AIMS: Percutaneous left atrial appendage (LAA) occlusion is occasionally incomplete, with residual permeability of the LAA on cardiac computed tomography. The cause for this is unclear. Our objective was to determine if residual permeability was related to incomplete endothelialization. METHODS: A total of 35 consecutive patients contraindicated for anticoagulant therapy admitted for LAA occlusion were included; 12 patients received a Watchman device (Boston Scientific) and 23 patients received an Amplatzer Cardiac Plug (St. Jude Medical). Incomplete endothelialization was defined as residual permeability on cardiac computed tomography without peridevice leak on transesophageal echocardiography at follow-up. RESULTS: Five patients did not receive cardiac computed tomography. After 10 +/- 6 months of follow-up, residual permeability of the LAA (at least partial) was recorded on cardiac computed tomography in 21 of 30 patients (70%). Seven of 30 patients presented with a peridevice leak on transesophageal echocardiography. Among the remaining 23 patients, 14 (61%) presented with incomplete endothelialization and 9 (39%) presented with complete endothelialization. There was no statistical difference between the patients presenting with complete vs incomplete endothelialization. CONCLUSION: We found that incomplete endothelialization, defined as residual permeability on cardiac computed tomography without peridevice leak on transesophageal echocardiography, occurred in 61% of the patients after 10 +/- 6 months of percutaneous LAA closure. Predisposing factors and appropriate monitoring of LAA patients remain to be determined in larger cohorts. PMID- 29760286 TI - Comparison of the FemoSeal Vascular Closure Device With Manual Compression After Femoral Artery Puncture - Post-hoc Analysis of a Large-Scale, Randomized Clinical Trial. AB - OBJECTIVES: To assess the safety and efficacy of arteriotomy closure with the intravascular FemoSeal vascular closure device (VCD; St. Jude Medical) compared to manual compression in patients undergoing diagnostic cardiac catheterization via the common femoral artery. BACKGROUND: There is limited evidence on the performance of individual contemporary VCDs compared to manual compression. METHODS: This is a subanalysis of 3018 patients who underwent transfemoral diagnostic coronary angiography and were randomly assigned to arteriotomy closure with either the intravascular FemoSeal VCD or manual compression within the investigator-initiated, large-scale, randomized, multicenter, open-label ISAR CLOSURE trial. Primary endpoint was the composite of access-site related vascular complications at 30 days. Secondary endpoints were time to hemostasis and repeat manual compression. RESULTS: Vascular access-site complications were lower in patients assigned to the FemoSeal VCD compared to manual compression (6.0% vs 7.9%; P=.04), driven by a lower incidence of hematomas in the FemoSeal group (4.3% vs 6.8%; P<.01). Pseudoaneurysm rates were comparable in both groups (1.5% vs 1.5%; P=.88). Time to hemostasis was significantly shortened with the FemoSeal VCD compared to manual compression (0.5 min [IQR, 0.2-1.0 min] vs 10 min [IQR, 10 15 min]; P<.001). However, repeat manual compression was increased with the FemoSeal VCD (1.5% vs 0.7%; P=.03). CONCLUSION: In patients undergoing transfemoral diagnostic coronary angiography, the use of the FemoSeal VCD is associated with shortened time to hemostasis and a reduction in vascular access site complications driven by fewer hematomas when compared to manual compression. PMID- 29760284 TI - Unprotected Left Main Coronary Artery Disease: Outcomes of Treatment With Second Generation Drug-Eluting Stents - Insight From the FAILS-2 Study. AB - OBJECTIVE: To evaluate the outcome of patients undergoing PCI for unprotected left main coronary artery (ULMCA) disease with different drug-eluting stent (DES) types. BACKGROUND: Published literature suggests that second-generation DES options have differing vascular responses and outcomes, but there is a paucity of data in real-life patients in the LM setting. METHODS: This is a retrospective, multicenter study, including patients treated with a second-generation DES for ULMCA disease between 2007 and 2015. The primary endpoint was target-lesion revascularization (TLR). Secondary endpoints were major adverse cardiac events, myocardial infarction (MI), and stent thrombosis (ST). RESULTS: A total of 1209 patients were enrolled; 840 patients (69.5%) received an everolimus-eluting stent (EES), 133 patients (11.0%) received a zotarolimus-eluting stent (ZES), and 236 patients (19.5%) received a biodegradable polymer, biolimus-eluting stent (BP BES). During a mean follow-up of 722 +/- 640 days, TLR occurred in 47 patients (3.8%). At univariate analysis, EES patients had a lower TLR rate (3.6% vs 4.5% in ZES vs 4.2% in BP-BES), which was statistically significant at multivariate analysis (hazard ratio, 0.50; 95% confidence interval, 0.27-0.93; P=.03). No differences in major adverse cardiac events, death, MI, or ST were observed between groups. CONCLUSION: The safety profile of the stents used was comparable over the follow-up period. However, EES patients had lower restenosis rates, with a reduced need for repeat PCI. PMID- 29760287 TI - [Multi-Organ Distribution of Alpha-Synuclein Pathology in Dementia with Lewy Bodies]. AB - In Parkinson's disease and dementia with Lewy bodies, neuronal alpha-synuclein aggregates (Lewy bodies and Lewy neurites) are distributed throughout the nervous system, including the brain, spinal cord, sympathetic ganglia, enteric nervous system, cardiac and pelvic plexuses, submandibular gland, adrenal medulla, and skin. Lewy bodies also occur in 10-20% of neurologically asymptomatic individuals older than 60 years. These cases are called incidental Lewy body disease (ILBD). In ILBD, Lewy bodies can be found in the brain, spinal cord, sympathetic ganglia, visceral autonomic nervous system and skin. In addition, neuronal loss in the substantia nigra is observed in ILBD. Thus, ILBD represents pre-symptomatic Parkinson's disease and/or dementia with Lewy bodies. The pathological process of Lewy body disease may affect the peripheral and central nervous systems at the same time. PMID- 29760288 TI - [Neuropathologic Subtypes of Frontotemporal Lobar Degeneration]. AB - Frontotemporal lobar degeneration (FTLD) is a heterogeneous disease entity encompassing a wide variety of histopathological features and genetic backgrounds. The last two decades have seen the discovery of causative genes and the identification of relevant proteins. The current histopathological classification is based on the major types of protein deposition in the brain, and most FTLD cases can be placed into one of three pathological subgroups: FTLD tau, FTLD-TDP, and FTLD-FUS. Further sub-classification within each subgroup is based on the morphology of neuronal and glial inclusions and lesion distribution. Affected patients, including some from the same subgroups, show considerable heterogeneity in their clinical presentations, suggesting that the subgroups represent a variety of well-defined clinical syndromes, including variants of frontotemporal dementia (behavioral variant frontotemporal dementia, progressive non-fluent aphasia, and semantic dementia) and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, and supranuclear palsy syndrome). On the other hand, patients with MAPT mutations always show the FTLD-tau phenotype, whereas patients with progranulin, C9orf72, VCP or TARDBP usually present the FTLD-TDP phenotype. In this review, we describe the histopathologic features of the main FTLD subtypes and summarize the clinical presentations and genetic characteristics of affected patients. PMID- 29760289 TI - [Neurocognitive Disorders Other Than Alzheimer Disease: Vascular Dementia]. AB - Vascular dementia involves several mechanism of pathogenesis. Cerebral small vessel diseases play a central role in vascular dementia, including sporadic cerebral small vessel diseases, cerebral autosomal-dominant or autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CARASIL), cerebral amyloid angiopathy, and amyloid beta-related angiitis. Although these diseases have different pathomechanisms, chronic white matter hypoperfusion contributes to development of neuronal dysfunction as a common pathway in vascular dementia. Vascular dementia also may affect the cognitive decline observed in neurodegenerative diseases such as Alzheimer's disease. PMID- 29760290 TI - [Senile Dementia of the Neurofibrillary Tangle Type (SD-NFT)]. AB - A subset of older individuals with dementia have neurofibrillary tangles (NFTs) in the medial temporal lobe and show absence of amyloid beta-protein (Abeta) deposition in the brain. In 1996, the author's group reported senile dementia of the NFT type (SD-NFT) as a disease entity characterized by these pathological features as well as late-onset dementia in older subjects. In 2014, it was proposed that this pathological condition, irrespective of the presence of cognitive impairment, should be referred to as primary age-related tauopathy (PART). SD-NFT is a dementing disease caused by severe PART pathology. This article reviews features of SD-NFT, relationships among PART, cognitive impairment, and Alzheimer's disease (AD) pathogenesis; and PART/SD-NFT as a background of SNAP [suspected non-AD pathophysiology] in the differential diagnosis of AD. PMID- 29760291 TI - [2016 WHO Classification of Tumors of CNS: A Paradigm Shift from Histologic to Molecular Classification]. AB - With the recent development in molecular genetics, the WHO classification of CNS tumors was revised in 2016. The new WHO classification made a paradigm shift from traditional histologic classification to molecular classification. In particular, integrated diagnoses that combined morphologic and molecular information were introduced for diffuse gliomas and embryonal tumors. The new classification is expected to result in more accurate diagnosis, appropriate therapeutic strategy, precise prediction of prognosis, etc. Practical efforts have already been started at the clinical sites to adapt to the new classification. PMID- 29760292 TI - [Targeting Transcellular Transport of alpha-Synuclein for Developing Disease Modifying Therapies for Synucleinopathy]. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder and it is characterized by progressive physical disability along with a variety of non-motor symptoms. Drugs that replenish dopamine can partly alleviate the motor symptoms; however, they do not cure the disease itself. Therefore, there is an urgent need for disease modifying therapies that would delay or prevent neurodegeneration. Increasing evidence suggests that alpha-synuclein, a key molecule in PD, is secreted into the extracellular environment and can be transported from cell-to-cell, thereby affecting the physiological state of the neighboring cells in a prion-like manner. Given the potential role of extracellular alpha-synuclein as the cause of disease progression, its prion-like propagation is a promising target for developing disease-modifying therapies for PD and other synucleinopathies. PMID- 29760293 TI - [Safety of Dual Antiplatelet Therapy with Argatroban in Patients with Acute Ischemic Stroke]. AB - To prevent early neurological worsening or recurrence in stroke patients with intracranial arterial stenosis or branch atheromatous disease, aggressive antithrombotic therapy, such as dual antiplatelet therapy (DAPT) with or without anticoagulant therapy, is warranted. Such an aggressive antithrombotic therapy, however, may increase the bleeding risk. We studied the risks of DAPT with the anticoagulant argatroban in patients with acute ischemic stroke or transient ischemic attack (TIA). Between October 2011 and September 2015, 341 patients with stroke or TIA, who received DAPT with argatroban within 48 hours after onset, were retrospectively studied. The endpoint was any bleeding event during hospitalization or 30 days after admission. Median duration of DAPT was 12 days, and 66% of the patients received intravenous heparin (median duration, 5 days) following argatroban. No symptomatic intracerebral hemorrhages were observed, while severe, moderate, and mild extracranial hemorrhages occured in one (0.3%), three (0.9%), and four (1.2%) patients, respectively. In conclusion, DAPT with argatroban can be safely administered to patients with acute ischemic stroke or TIA. (Received July 24, 2017; Accepted January 15, 2018; Published May 1, 2018). PMID- 29760294 TI - Breath profiles of children on ketogenic therapy. AB - Ketogenic diets (KDs) were initially introduced to clinical practices as alimentary approaches with the aim to control drug-resistant epilepsies. Over the decades, a large and growing body of research has addressed the antiseizure effect of various KDs, and worked out KD-based dietary regimens, including their acting factors and modes of action. KDs have also appeared in weight loss therapies. Therapy control, particularly at initiation, happens through regular blood analysis and control of urine ketone levels. However, there is a lack of fast, reliable, and preferably non-invasive methods to accomplish this. The detection of exhaled breath constituents may offer a solution. The exhaled breath contains hundreds of volatile organic compounds (VOCs), which can be modified by diet. VOC detection technology has resulted in low-cost sensors that can facilitate the self-monitoring of patients in the future if reliable breath markers are available. Therefore, it is of interest to investigate the composition of exhaled breath in children on KDs. Twenty-two pediatric patients between 4 and 18 years of age were recruited in this study. Eleven of them received a KD and suffered from epilepsy, with the exception of one child, who was admitted to a weight-reduction therapy. The control group involved 11 patients with neurological disorders but not on KD. Breath volatiles were analyzed using gas chromatography mass spectrometry (GC-MS) after preconcentration of the analytes on needle traps (NTs). We found that the breath concentrations of a number of VOCs, namely acetaldehyde, acetone, 2-methylfuran, methyl-vinyl-ketone, and 2-pentanone were significantly elevated in the breath of children on a KD in comparison to their control counterparts. Interestingly, breath ethanol was lower in patients on a KD than in non-KD patients. Association studies revealed an interrelationship among (i) lipid parameters and ketone bodies, (ii) methacrolein, methyl-vinyl-ketone, and high-density lipoprotein, as well as (iii) methyl-vinyl-ketone, acetone, and 2-pentanone, thus raising the possibility of a common metabolic source. The duration of diet was positively and negatively associated with breath acetone and breath ethanol, respectively. Some of the changes were linked to beta-oxidation, but there are uncertainties in regard to metabolic sources of other metabolites. Lipid peroxidation and alteration of intestinal microbial composition may also be involved in the changes of VOC profiles during KD. Since lipids used for metabolism during KD originate from external sources, the processes occurring cannot simply be compared to and deduced from changes appearing in starvation; however, lipid mobilization is also evident in starvation. To find reliable and sensitive VOC markers that are linked to the respective ketogenic regimen, further investigations are needed to reveal the metabolic background. PMID- 29760295 TI - Cognitive function assessment should be included in preoperative evaluation. PMID- 29760296 TI - Hydroxytyrosol and olive leaf extract exert cardioprotective effects by inhibiting GRP78 and CHOP expression. AB - Myocardial infarction triggers massive biochemical changes, even cardiac cell death. Endoplasmic reticulum stress is involved in the pathology of myocardial infarction-mediated apoptosis. In the present study, myocardial cell line H9c2 cells were treated with cobalt chloride (CoCl2) to induce hypoxia. Isoproterenol was used for two successive days to induce myocardial infarction in SD rats. The cardioprotective effect of olive leaf extract (OLE) and its main constituent hydroxytyrosol and the underlying mechanisms were evaluated. The results showed that hydroxytyrosol markedly protected H9c2 cells against CoCl2-induced apoptosis. Hydroxytyrosol could reduce the mRNA and protein expression of GRP78 and CHOP induced by CoCl2 in vitro. In vivo, the decreased ejection fraction and fractional shortening, increased heart weight/body ratio, the formation of infarction, disordered cardiac muscle fibers and infiltration of inflammatory cells induced by isoproterenol could be significantly ameliorated by pretreatment with OLE for a month. Similarly, OLE could also reverse the increase of GRP78 and CHOP expression induced by isoproterenol. Therefore, OLE and hydroxytyrosol exert a cardioprotective effect through endoplasmic reticulum stress, which could be a new target for the prevention and treatment of cardiovascular diseases. PMID- 29760297 TI - Follicular hyperandrogenism and insulin resistance in polycystic ovary syndrome patients with normal circulating testosterone levels. AB - Polycystic ovary syndrome (PCOS) is a common reproductive disease with high heterogeneity. The role of excess androgen in PCOS etiology remains disputed, since around 20%-50% of PCOS women do not display hyperandrogenemia. The microenvironment of the ovary critically influences follicular development. In the present study, we assessed the role of androgen in PCOS by investigating whether excessive follicular fluid androgen was present in PCOS patients with normal serum androgen levels and influenced by follicular fluid insulin resistance (IR). Follicular fluid samples of 105 women with PCOS and 105 controls were collected. Levels of steroid hormones, glucose and insulin in the follicular fluid were examined and compared with data from serum biochemistry tests. We found that 64.9% (63/97) of PCOS patients with normal serum androgen levels displayed abnormally high follicular fluid androgen level. The follicular fluid androgen level was positively correlated with follicular fluid IR within a certain range and follicular fluid estrogen-to-testosterone (E2/T) ratio was significantly reduced in these patients. These results indicated that there existed a subgroup of PCOS patients who displayed excessive follicular fluid androgen and IR despite their normal circulating testosterone (T) levels. Our study highlights the importance of ovary hyperandrogenism and IR in the etiology of PCOS. PMID- 29760299 TI - Exploring the public-private and company size differences in employees' work characteristics and burnout: data analysis of a nationwide survey in Taiwan. AB - Distinct differences exist between public-private sector organizations with respect to the market environment and operational objectives; furthermore, among private sector businesses, organizational structures and work conditions often vary between large- and small-sized companies. Despite these obvious structural distinctions, however, sectoral differences in employees' psychosocial risks and burnout status in national level have rarely been systematically investigated. Based on 2013 national employee survey data, 15,000 full-time employees were studied. Sector types were classified into "public," "private enterprise-large (LE)," and "private enterprise-small and medium (SME);" based on the definition of SMEs by Taiwan Ministry of Economic Affairs, and the associations of sector types with self-reported burnout status (measured by the Chinese version of Copenhagen Burnout Inventory) were examined, taking into account other work characteristics and job instability indicators. Significantly longer working hours and higher perceived job insecurity were found among private sector employees than their public sector counterparts. With further consideration of company size, greater dissatisfaction of job control and career prospect were found among SME employees than the other two sector type workers. This study explores the pattern of public-private differences in work conditions and employees' stress-related problems to have policy implications for supporting mechanism for disadvantaged workers in private sectors. PMID- 29760298 TI - A Newly Designed Primer Revealed High Phylogenetic Diversity of Endozoicomonas in Coral Reefs. AB - Endozoicomonas bacteria are commonly regarded as having a potentially symbiotic relationship with their coral hosts. However, their diversity and phylogeny in samples collected from various sources remain unclear. Therefore, we designed an Endozoicomonas-specific primer paired with a bacterial universal primer to detect the 16S ribosomal RNA (rRNA) genes of this taxon and conducted an in-depth investigation of the Endozoicomonas community structure in reef-building corals. The primer had high specificity in the V3-V4 region (95.6%) and its sensitivity was high, particularly when Endozoicomonas was rare in samples (e.g., in seawater, which had a higher alpha diversity of Endozoicomonas than corals). In coral samples, predominant V3-V4 ribotypes had greater divergence than predominant V1-V2 ribotypes, and were grouped into at least 9 novel clades in a phylogenetic tree, indicating Endozoicomonas had high phylogenetic diversity. Divergence within this genus was potentially higher than that among 7 outgroup genera based on the phylogenetic distances of partial 16S rDNA sequences, suggesting that the taxonomy of this genus needs to be revised. In conclusion, dominant Endozoicomonas populations had variable phylogenies; furthermore, the newly designed primers may be useful molecular tools for the reliable detection of the Endozoicomonas community in marine environments. PMID- 29760300 TI - Workaholism and negative work-related incidents among nurses. AB - The present study comprised 1,781 nurses who participated in an investigation about working conditions, sleep, and health. They answered a questionnaire about age, sex, marital status, children living at home, work hours per week, number of night shifts last year, and total sleep duration and that also included a validated instrument assessing workaholism. In addition, they were asked to report on eight items concerning negative work-related incidents (dozed off at work, dozed while driving, harmed or nearly harmed self, harmed or nearly harmed patients/others, and harmed or nearly harmed equipment). Logistic regression analyses identified several predictors of these specific incidents: Low age (dozed at work, harmed and nearly harmed self, harmed and nearly harmed equipment), male sex (harmed and nearly harmed self, nearly harmed equipment), not living with children (harmed patients/others), low percentage of full-time equivalent (nearly harmed self and harmed patients/others), number of night shifts last year (dozed off at work and while driving, nearly harmed patients/others) and sleep duration (inversely related to dozed off at work and while driving, nearly harmed self). However, the most consistent predictor of negative work-related incidents was workaholism which was positively and significantly associated with all the eight incidents. PMID- 29760301 TI - Relationship between concealment of emotions at work and musculoskeletal symptoms: results from the third Korean working conditions survey. AB - In this study, we explored the relationship between concealing emotions at work and musculoskeletal symptoms in Korean workers using data from a national, population-based survey. Data were obtained from the third Korean Working Conditions Survey in 2011. We investigated the prevalence of three musculoskeletal symptoms ("back pain", "pain in the upper extremities", and "pain in the lower extremities"). Multiple logistic regression analysis was also performed to determine odds ratios (ORs) for musculoskeletal symptoms according to concealing emotions at work, adjusting for socioeconomic factors. In both sexes, the emotion-concealing group showed a significantly higher prevalence of "pain in the upper extremities" and "pain in the lower extremities" than the non emotion-concealing group. For back pain, male-but not female-workers who concealed their emotions showed a higher prevalence than their non-emotion concealing counterparts; the difference was statistically significant. Adjusted ORs for musculoskeletal symptoms (excluding "back pain" for female workers) in the emotion-concealing group were significantly higher. Our study suggests that concealment of emotions is closely associated with musculoskeletal symptoms, and the work environment should operate in consideration not only of the physical health work condition of workers but also of their emotional efforts including concealing emotion at work. PMID- 29760302 TI - Smoking, alcohol consumption, and risks for biliary tract cancer and intrahepatic bile duct cancer. AB - BACKGROUND: Smoking and alcohol are established risk factors for several types of cancer, but the effects on biliary cancers comprising biliary tract cancer (BTC) and intrahepatic bile duct cancer (IHBDC) have been inconclusive. METHODS: In this population-based prospective cohort study in Japan, we investigated the association of smoking and alcohol consumption with the risks of BTC and its subtypes, and IHBDC incidence in men and women. Furthermore, the association of smoking stratified by drinking status was investigated. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazard model. RESULTS: A total of 48,367 men and 54,776 women aged 40-69 years were enrolled between 1990 and 1994 and followed up for 846,417 person-years in men and 1,021,330 person-years in women until 2012, during which 246 BTC and 80 IHBDC male cases and 227 BTC and 60 IHBDC female cases were identified. In men, smoking was significantly associated with an increased risk of IHBDC (HR = 2.25 [95% CI, 1.19-4.25] for current smokers with >=30 pack-years), and the risk was enhanced among regular drinkers (HR = 3.48 [95% CI, 1.41-8.61]). A non significant increase of IHBDC risk associated with alcohol was observed. Neither smoking nor alcohol consumption was associated with BTC risk. In women, the association of smoking and alcohol consumption with IHBDC and BTC was unclear because current smokers and regular drinkers were very few. CONCLUSION: Our findings suggest that smoking increases IHBDC risk in men, especially among regular drinkers. PMID- 29760303 TI - MiR-140-3p is Involved in In-Stent Restenosis by Targeting C-Myb and BCL-2 in Peripheral Artery Disease. AB - AIM: In-Stent Restenosis (ISR) is the major reason for recurrent ischemia and amputation after endovascular treatment of Peripheral Artery Disease (PAD). Our previous study demonstrated that miR-140-3p is significantly down-regulated in PAD arteries. However, expression and function of miR-140-3p in ISR of human PAD are currently unclear.The aim of this study is to determine the miR-140-3p expression and its regulative role in ISR of PAD. METHODS: The RNA level was determined by quantitative real-time polymerase chain Reaction (qRT-PCR) and in situ hybridization. Primary cultured ASMCs were isolated from human femoral arterial of the healthy donors or ISR patients. Cell proliferation was determined by Edu incorporation and CCK-8 assay. Apoptosis was determined by Annexin-V/PI Double-Staining assay and TUNEL assay. A rat carotid artery balloon angioplasty model was used to investigate the effect of miR-140-3p on restenosis. RESULTS: MiR-140-3p was significantly down-regulated in PAD and ISR arteries than normal arteries. Primary cultured ISR ASMCs exhibited elevated proliferation and down regulated miR-140-3p than normal ASMCs. Transfection of miR-140-3p mimic attenuated PDGF-BB-induced proliferation in cultured ASMCs and induced apoptosis. Luciferase reporter assay indicated that miR-140-3p transfection significantly down-regulated C-Myb and BCL-2 in ISR ASMCs by targeting to their 3'-UTRs. MiR 140-3p transfection induced anti-proliferation and apoptosis in ASMCs, which were ameliorated by over-expression of C-Myb or BCL-2. Moreover, the animal study showed that miR-140-3p can reduce restenosis following angioplasty via targeting C-Myb and BCL-2. CONCLUSIONS: The result suggests that miR-140-3p regulates ASMC function via targeting C-Myb and BCL-2 in the process of ISR in PAD. The novel findings may offer a hopeful therapeutic target for human PAD. PMID- 29760304 TI - Metyrapone-responsive ectopic ACTH-secreting pheochromocytoma with a vicious cycle via a glucocorticoid-driven positive-feedback mechanism. AB - In ectopic ACTH-secreting pheochromocytoma, combined ACTH-driven hypercortisolemia and hypercatecholaminemia are serious conditions, which can be fatal if not diagnosed and managed appropriately, especially when glucocorticoid driven positive feedback is suggested with a high ACTH/cortisol ratio. A 46-year old man presented with headache, rapid weight loss, hyperhidrosis, severe hypertension and hyperglycemia without typical Cushingoid appearance. Endocrinological examinations demonstrated elevated plasma and urine catecholamines, serum cortisol and plasma ACTH. Moreover, his ACTH/cortisol ratio and catecholamine levels were extremely high, suggesting catecholamine-dominant ACTH-secreting pheochromocytoma. Computed tomography revealed a large right adrenal tumor. 18F-FDG positron emission tomography showed uptake in the area of the adrenal tumor, while 123I-metaiodobenzylguanidine scintigraphy showed no accumulation. His plasma ACTH level paradoxically became elevated after a dexamethasone suppression test. After metyrapone administration, not only serum cortisol but also plasma ACTH levels were exponentially decreased almost in parallel, suggesting a glucocorticoid-driven positive-feedback regulation in this rapidly exacerbated ectopic ACTH-producing pheochromocytoma. Interestingly enough, plasma catecholamine levels were also decreased by metyrapone, although they remained extremely high. He became severely dehydrated due to hypoadrenalism requiring hydrocortisone supplementation. His clinical signs and symptoms were improved, and right adrenalectomy was performed uneventfully, resulting in complete remission of pheochromocytoma and Cushing's syndrome. A glucocorticoid driven positive-feedback regulation in this ectopic ACTH-secreting pheochromocytoma created a vicious cycle with rapid exacerbation of both hypercortisolemia and hypercatecholaminemia with extremely elevated plasma ACTH level. Metyrapone was clinically effective to stop this vicious cycle; nonetheless, great care must be taken to avoid hypoadrenalism especially when hypercatecholaminemia remained. PMID- 29760305 TI - Enhancement of Warfarin Anticoagulant Reaction in Patients with Repeated Oral Tolvaptan Administration. AB - The pharmacokinetics and pharmacodynamics of warfarin remained unaffected by tolvaptan during clinical trials. However, tolvaptan prolonged the prothrombin time-international normalized ratio (PT-INR) level of patients with cardiovascular disease taking warfarin. Tolvaptan was prescribed to 576 patients from December 2010 to December 2015. Of these patients, 37 underwent anticoagulant therapy. We investigated PT-INR fluctuation immediately before tolvaptan therapy was initiated. PT-INR remained unchanged in the control group and in groups administered with less than 7.5 mg/d tolvaptan, whereas it was significantly increased (p=0.03) in the group administered with more than 7.5 mg/d tolvaptan. This result indicates the possibility that tolvaptan affects the pharmacodynamics of warfarin in vivo. However, further research is necessary to clarify the mechanism of this phenomenon. PMID- 29760307 TI - Identification of urinary biomarkers for the prediction of gestational diabetes mellitus in early second trimester of young gravidae based on iTRAQ quantitative proteomics. AB - Gestational Diabetes Mellitus (GDM) has brought great harm to maternal and fetus. Up to now, only a few plasma biomarkers for its early diagnosis have been reported; nevertheless, there is no report about identification of urinary biomarkers for prediction of GDM. Thus, it is necessary to correct this deficiency. In our study, urine samples were collected from 889 healthy young gravidae at the early second trimester (15 to 20 weeks), 69 of whom were subsequently diagnosed with GDM at 24 to 28 weeks. iTRAQ (the isobaric tags for relative and absolute quantification) quantitative proteomics was conducted on sixteen GDM (trial group) and an equal number of matched healthy young gravidae (control group). Validation was performed in 40 cases of each group by ELISA. A total of 1,901 proteins were identified in this study, including 119 significantly differential proteins (fold change ?1.2 or ?0.83 and p < 0.05). Compared with control group, 83 differential proteins were increased and 36 proteins were decreased in GDM group. The validation for expression of CD59 and IL1RA showed significant difference and the area under the receiver operating characteristic curve was 0.729 and 0.899, respectively (p < 0.05). The two candidate protein biomarkers (CD59 and IL1RA) in urine could be an early, noninvasive diagnostic predictors of young pravidae with GDM, and IL1RA is stronger diagnostic power than CD59. PMID- 29760309 TI - Overwhelming Suppression of Neointimal Coverage on High-Resolution Coronary Angioscopy After Paclitaxel-Coated Balloon Angioplasty for In-Stent Restenosis of Cobalt-Chrome Everolimus-Eluting Stent. PMID- 29760308 TI - Cardiovascular Outcome and Mortality in Patients Undergoing Endovascular Treatment for Symptomatic Peripheral Artery Disease - Short-Term Results of the Toma-Code Registry. AB - BACKGROUND: The present study was performed to clarify whether the preoperative clinical symptoms for endovascular therapy (EVT) can predict post-EVT death and cardiovascular prognosis in Japanese patients with peripheral artery disease (PAD), including acute disease.Methods and Results:The TOkyo taMA peripheral vascular intervention research COmraDE (Toma-Code) Registry is a Japanese prospective cohort of 2,321 consecutive patients with PAD treated with EVT, in 34 hospitals in the Kanto and Koshin'etsu regions, from August 2014 to August 2016. In total, 2,173 symptomatic patients were followed up for a median of 10.4 months, including 1,370 with claudication, 719 with critical limb ischemia (CLI), and 84 with acute limb ischemia (ALI) for EVT. The all-cause death rates per 100 person-years for claudication, CLI and ALI were 3.5, 26.2, and 24.5, respectively. Similarly, major adverse cardiac and cerebrovascular events (MACCE) rates per 100 person-years for claudication, CLI, ALI, and others were 5.2, 31.2, and 29.7, respectively. After adjusting for the predictors of all-cause death and MACCE, namely, age, body mass index <18, diabetes mellitus, dialysis, cerebrovascular disease, and low left ventricular ejection fraction, it was determined that the preoperative indication for EVT was strongly associated with all-cause death and MACCE. CONCLUSIONS: The preoperative clinical symptoms for EVT can predict the prognosis in patients with PAD undergoing EVT. PMID- 29760306 TI - Necessity for a Significant Maintenance Dosage Reduction of Voriconazole in Patients with Severe Liver Cirrhosis (Child-Pugh Class C). AB - Therapeutic drug monitoring for voriconazole, an antifungal agent, is essential for maximizing efficacy and preventing toxicity. The aim of this study was to elucidate the optimal maintenance dose of voriconazole in patients with severe liver cirrhosis (Child-Pugh class C) by reviewing the plasma trough concentrations obtained by therapeutic drug monitoring and daily doses of voriconazole. We retrospectively evaluated 6 patients with Child-Pugh class C cirrhosis who received oral voriconazole treatment and were liver transplant recipients or were awaiting liver transplantation. We compared their voriconazole trough concentrations and daily maintenance doses to those of patients who did not have liver cirrhosis (n=56). We found that plasma voriconazole trough concentrations in all patients with Child-Pugh class C were almost within therapeutic range, and the median plasma trough concentration at steady state was not significantly different from that of patients who did not have liver cirrhosis. In addition, the median daily maintenance dose of voriconazole was significantly lower (2.13 mg/kg/d) than that of the control patients (6.27 mg/kg/d), suggesting that trough voriconazole concentrations are elevated in Child-Pugh class C patients. Thus, we conclude that oral voriconazole maintenance doses in patients with Child-Pugh class C should be reduced to approximately one third that of patients with normal liver function, with the follow-up dose adjusted by therapeutic drug monitoring. PMID- 29760310 TI - Cannon Sounds. PMID- 29760312 TI - Change in Cerebral Blood Flow after Palliative Percutaneous Angioplasty and Timing of Second Stage Carotid Artery Stenting in Staged Angioplasty. AB - The purpose of this study is to elucidate the hemodynamic changes after palliative angioplasty and the timing of second stage carotid artery stenting (CAS) in staged angioplasty for patients with severe hemodynamically compromised carotid artery stenosis. Among consecutive 111 patients with carotid artery stenosis, chronological changes in the cerebral blood flow of all 11 hemodynamically compromised patients treated with CAS were evaluated with single photon emission computed tomogram (SPECT) in each stage of the treatment. Ten of these 11 patients underwent staged angioplasty and one was treated with single stage CAS. All the 10 patients who underwent staged angioplasty showed improved cerebral vascular reactivity (CVR) on SPECT after the first stage palliative angioplasty. Only one patient treated with staged angioplasty with 4-week interval before the CAS showed restenosis of the lesion. Cerebral hyperperfusion syndrome (CHS) was not observed in nine of 10 patients with staged angioplasty. One patient of staged angioplasty (who presented restenosis at the time of elective CAS) and another patient in whom we could not apply staged angioplasty (for his renal dysfunction) showed CHS after CAS. In conclusion, restoration of CVR could be achieved within a few days following palliative angioplasty, and 1-2 week interval is enough for staged angioplasty. PMID- 29760311 TI - Postoperative Subdural Air Collection Is a Risk Factor for Chronic Subdural Hematoma after Surgical Clipping of Cerebral Aneurysms. AB - The precise mechanism of the development of chronic subdural hematoma (CSDH) as a postoperative complication after aneurysmal clipping remains unclear. The purpose of this study was to identify the independent risk factors for CSDH after craniotomy for aneurysmal clipping and to elucidate the relationship between CSDH and subdural air (SDA) collection immediately after surgery. The medical records and radiologic data of 344 patients who underwent surgical clipping of unruptured aneurysms from July 2010 to July 2016 were retrospectively evaluated. Patient characteristics, aneurysm characteristics, and operation data were statistically analyzed to reveal their relationships with CSDH development. Among the 344 patients, 46 (13.4%) developed CSDH and 13 (3.8%) required subsequent burr-hole surgery for evacuation and irrigation. Multivariate analyses showed that advanced age (P < 0.0001), male sex (P = 0.035), and surgical clipping of multiple aneurysms (P = 0.037) were independent preoperative predictors of CSDH development. Advanced age (P = 0.0005) and postoperative SDA after clipping surgery (P < 0.0001) were independent postoperative predictors of CSDH development. Postoperative SDA and CSDH were not associated with the individual surgeon or operation time. Postoperative severe SDA was significantly associated with the ipsilateral development of CSDH, irrespective of the side of craniotomy. Postoperative SDA is an independent risk factor for CSDH after surgical clipping of unruptured aneurysms and is as important as advanced age, male sex, and surgical clipping of multiple aneurysms in predicting CSDH. PMID- 29760313 TI - Detection of Sirtuin-1 protein expression in peripheral blood leukocytes in dogs. AB - Sirtuin-1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase with a large number of protein substrates. It has attracted a lot of attention in association with extending lifespan. The objective of this study was to enable the evaluation of SIRT1 expression in peripheral blood mononuclear cells (PBMCs) from dogs by flow cytometry. Three transcript variants were amplified from PBMCs by reverse transcription PCR and the nucleotide sequences were analyzed. On the basis of deduced amino acid sequence, a monoclonal antibody against human SIRT1, 1F3, was selected to detect canine SIRT1. Canine SIRT1 in peripheral blood mononuclear cells was successfully detected by western blotting using this antibody. Intracellular canine SIRT1 was also detected in permeabilized 293T cells transfected with a canine SIRT1 expression plasmid by flow cytometry using this antibody. SIRT1 was detected in all leukocyte subsets including lymphocytes, granulocytes and monocytes. The expression level was markedly different among individual dogs. These results indicated that the method applied in this study is useful for evaluating canine SIRT1 levels in PBMCs from dogs. PMID- 29760314 TI - The Neuroprotective and antioxidative effects of submicron and blended Lycium barbarum in experimental retinal degeneration in rats. AB - The object is to determine the neuroprotective and antioxidative effects of submicron and blended Lycium barbarum (LB) on retinal degeneration as evaluated by ERG, retinal histopathology and assays of antioxidant (total GSH) and peroxidant (MDA) in the retina. A rat model of light-induced retinal degeneration was used to assess the protective effect of different forms of Lycium barbarum (LB) on retinal degeneration. Rats were divided into four experimental groups, normal control, light-induced untreated, submicron LB and blended LB treated. The rats of submicron and blended groups were treated with 250 mg/kg LB orally once daily for 54 days, followed by induction of retinal degeneration. Retinal function was assessed by electroretinography (ERG). Enzyme-linked immunosorbent assay of the retina lysates was measured for the levels of antioxidants, reduced glutathione and glutathione disulfide, and peroxidants, malondialdehyde, in the retina. The ERG results showed a protective effect in LB treated groups with a greater effect observed in submicron LB treated group than the blended LB treated group. There were higher levels of GSH plus GSSG and lower MDA in submicron LB treated group than other groups. In conclusion, LB provided protective and antioxidative effects on the rat retina with light-induced retinal degeneration. Submicron LB protected degenerative retina better than blended LB. LB is effective against oxidative stress in the degenerative retina. PMID- 29760317 TI - Seismic imaging of mantle wedge corner flow and arc magmatism. AB - I reviewed studies on the inhomogeneous seismic structure of the mantle wedge in subduction zones, in relation to corner flow and its implications for arc magmatism. Seismic studies in Tohoku clearly imaged the descending flow portion of the corner flow as a thin seismic low-velocity layer right above the slab. Slab-derived H2O is fixed to the layer as hydrous minerals, which are brought down by the slab and eventually decompose. The released H2O rises and encounters the ascending flow, formed to fill the gap caused by the descending flow. The combination of H2O addition and adiabatic decompression causes partial melting within the ascending flow. For many subduction zones, seismic tomography has distinctly imaged the ascending flow of the corner flow as a seismic low-velocity and/or high-attenuation layer in the mantle wedge inclined nearly parallel to the slab. These observations indicate that the volcanic front in subduction zones is formed both by the ascending flow and the addition of slab-derived H2O. PMID- 29760316 TI - Unique sex determination system in the silkworm, Bombyx mori: current status and beyond. AB - The silkworm Bombyx mori has been used for silk production for over 5,000 years. In addition to its contribution to sericulture, B. mori has played an important role in the field of genetics. Classical genetic studies revealed that a gene(s) with a strong feminizing activity is located on the W chromosome, but this W linked feminizing gene, called Feminizer (Fem), had not been cloned despite more than 80 years of study. In 2014, we discovered that Fem is a precursor of a single W chromosome-derived PIWI-interacting RNA (piRNA). Fem-derived piRNA binds to PIWI protein, and this complex then cleaves the mRNA of the Z-linked Masculinizer (Masc) gene, which encodes a protein required for both masculinization and dosage compensation. These findings showed that the piRNA mediated interaction between the two sex chromosomes is the primary signal for the sex determination cascade in B. mori. In this review, we summarize the history, current status, and perspective of studies on sex determination and related topics in B. mori. PMID- 29760315 TI - Structural differences in the brain between wild and laboratory rats (Rattus norvegicus): Potential contribution to wariness. AB - Wild animals typically exhibit defensive behaviors in response to a wider range and/or a weaker intensity of stimuli compared with domestic animals. However, little is known about the neural mechanisms underlying "wariness" in wild animals. Wild rats are one of the most accessible wild animals for experimental research. Laboratory rats are a domesticated form of wild rat, belonging to the same species, and are therefore considered suitable control animals for wild rats. Based on these factors, we analyzed structural differences in the brain between wild and laboratory rats to elucidate the neural mechanisms underlying wariness. We examined wild rats trapped in Tokyo, and weight-matched laboratory rats. We then prepared brain sections and compared the basolateral complex of the amygdala (BLA), the bed nucleus of the stria terminalis (BNST), the main olfactory bulb and the accessory olfactory bulb. The results revealed that wild rats exhibited larger BLA, BNST and caudal part of the accessory olfactory bulb compared with laboratory rats. These results suggest that the BLA, BNST, and vomeronasal system potentially contribute to wariness in wild rats. PMID- 29760319 TI - Hepatic Eosinophilic Abscess Associated with Sigmoid Colon Cancer. AB - The clinical course of hepatic eosinophilic abscess (HEA) induced by malignant tumors is not well-known; however, it is considered to be a benign hepatic lesion. HEA is difficult to diagnose by imaging alone and a pathological examination is generally needed, particularly in patients with malignant tumors, because the radiological findings can be similar to those of metastasis. We report a case of multiple HEAs with eosinophilia and sigmoid colon cancer that was difficult to diagnose without a pathological examination. After the resection of the sigmoid colon cancer, the patient's eosinophilia was quickly ameliorated and the HEAs disappeared within 6 months. PMID- 29760318 TI - Efficacy and Safety of Switching from Insulin Glargine 100 U/mL to the Same Dose of Glargine 300 U/mL in Japanese Type 1 and 2 Diabetes Patients: A Retrospective Analysis. AB - Objective Insulin glargine [300 U/mL (Gla-300)] achieved better glycemic control and reduced the risk of hypoglycemia in comparison to glargine [100 U/mL; (Gla 100)] in phase 3 trials. This is the first study to retrospectively evaluate the efficacy and safety of Gla-300 in Japanese type 1 and 2 diabetes patients in a routine clinical setting. Methods We analyzed 20 type 1 diabetes patients and 62 type 2 diabetes patients who switched from Gla-100 to the same dose of Gla-300. Sixty type 2 diabetes patients who continued the use of Gla-100 during the study were included as controls. Results At three months after switching, the HbA1c levels were decreased in the patients with type 1 diabetes, but not to a significant extent. In the type 2 diabetes patients, the HbA1c levels were significantly decreased after switching (p<0.01). In contrast, there was no change in the HbA1c levels of the type 2 diabetes patients who continued the use of Gla-100 over the same period. The BMI values of the type 1 diabetes patients tended to decrease (p=0.06) and there was a significant decrease in the BMI values of the type 2 diabetes patients (p<0.05). There was no change in the BMI values of the type 2 diabetes patients who continued the use of Gla-100. The rates of hypoglycemia and adverse events did not change during the follow-up period. Conclusion In the clinical setting, switching from Gla-100 to the same dose of Gla-300 had a favorable effect on glycemic control and body weight control in Japanese type 1 and type 2 diabetes patients, without any increase in adverse events; however, a prospective study should be performed to confirm these findings. PMID- 29760321 TI - Geographic Access to Cancer Treatment in Japan: Results From a Combined Dataset of the Patient Survey and the Survey of Medical Institutions in 2011. AB - BACKGROUND: There has been no nationwide analysis of travel time for hospital admission in Japan. Factors associated with travel time are also unknown. This study aimed to describe the distribution of travel time for hospital admission of cancer patients and identify underlying factors. METHODS: The individual data from the Patient Survey in 2011 were linked to those from the Survey of Medical Institutions in the same year, and GIS data were used to calculate driving travel time between the addresses of medical institutions and the population centers of municipalities where patients lived. Proportions of patients with travel time exceeding versus not exceeding 45 minutes were calculated. To analyze the data with consideration of both individual factors of patients and geographical characteristics of areas where patients lived, multilevel logistic model analysis was performed. RESULTS: The analysis included 50,845 cancer inpatients. The majority of the cancer patients (approximately 80%) were admitted to hospitals located less than a 45-minute drive from their residences. The travel time tended to be longer for younger patients. The proportion of patients with travel time >=45 minutes was lower among those with stomach or colorectal cancer (approximately 15%) than those with cervical cancer or leukemia (approximately 30%). The lack of designated cancer care hospitals in the secondary healthcare service areas was significantly associated with travel time. CONCLUSIONS: Selection of hospitals by cancer inpatients is affected by age, cancer sites, and availability of designated cancer care hospitals in the secondary healthcare service areas where patients live. PMID- 29760320 TI - Breast Cancer Incidence Trends and Projections in Northeastern Thailand. AB - BACKGROUND: The northeast has the lowest incidence of breast cancer of all regions in Thailand, although national rates are increasing. The heterogeneity in subnational trends necessitates a comprehensive evaluation of breast cancer incidence trends and projections to provide evidence for future region-specific strategies that may be employed to attenuate this growing burden. METHODS: Joinpoint regression and age-period-cohort modeling were used to describe trends from 1988-2012. Data was projected from three separate models to provide a range of estimates of incidence to the year 2030 by age group. RESULTS: Age standardized rates (ASRs) increased significantly for all women from 1995-2012 by 4.5% per year. Rates for women below age 50 increased by 5.1% per year, while women age 50 years and older increased by 6% per year from 1988-2012. Projected rates show that women age 50 years and older have the largest projected increase in ASRs by 2030 compared to younger women and all women combined. CONCLUSIONS: Breast cancer trends in Khon Kaen are presently lower than other regions but are expected to increase and become comparable to other regions by 2030, particularly for women ages 50 years and older. PMID- 29760323 TI - ERRATUM. PMID- 29760322 TI - Effect of dietary difructose anhydride III supplementation on bone mineral density and calcium metabolism in late-lactation dairy cows. AB - The aim of the present study was to examine the effect of 28 days of dietary difructose anhydride (DFA) III supplementation on calcium (Ca) metabolism in late lactation dairy cows. Twenty-four multiparous pregnant Holstein cows were divided into two groups. The DFA group was fed total mixed ration (TMR) supplemented with 40 g of DFA III, and the control group was fed TMR only. The replenishment of bone Ca reserves was evaluated by measuring bone mineral density (BMD) and blood biochemical bone markers. Serum Ca concentrations, urinary Ca-to-creatinine (Cre) (Ca/Cre) ratios, and milk Ca concentrations were also analyzed. The BMD of the 4th caudal vertebra in the DFA group was higher than in the control group on day 28. With respect to bone markers, the ratios of undercarboxylated osteocalcin (ucOC) to osteocalcin (OC) in the DFA group were significantly lower than those in the control group on days 21 and 28. Milk Ca concentrations in the DFA group were also higher than those in the control group on days 14, 21, and 28, whereas serum Ca concentrations and urinary Ca/Cre ratios were unchanged in both groups. These results suggest that dietary supplementation with DFA III increased BMD and decreased serum ucOC/OC ratios in late-lactation dairy cows; this indicates that the replenishment of bone Ca reserves may be enhanced by dietary DFA III supplementation. PMID- 29760324 TI - Endoconduit for Transcatheter Aortic Valve Implantation. AB - Access challenges are sometimes encountered in patients who require transcatheter aortic valve implantation (TAVI). Transapical (TA) access is a well-established alternative, but it is more invasive than the standard transfemoral (TF) access techniques. We adopted the iliac endoconduit technique to perform TF TAVI in a patient with small-caliber, heavily calcified iliac arteries. This technique could provide an adequate access route for TAVI that is minimally invasive, even for patients with prohibitory iliac anatomy. PMID- 29760325 TI - Role of Computed Tomography in Planning the Appropriate X-Ray Gantry for Quantitative Aortography of Post-transcatheter Aortic Valve Implantation Regurgitation. AB - BACKGROUND: The clinical robustness of contrast-videodensitometric (VD) assessment of aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) has been demonstrated. Correct acquisition of aortic root angiography for VD assessment, however, is hampered by the opacified descending aorta and by individual anatomic peculiarities. The aim of this study was to use preprocedural multi-slice computed tomography (MSCT) to optimize the angiographic projection in order to improve the feasibility of VD assessment.Methods and Results:In 92 consecutive patients, post-TAVI AR (i.e., left ventricular outflow tract [LVOT] AR) was assessed on aortic root angiograms using VD software. The patients were divided into 2 groups: The first group of 54 patients was investigated prior to the introduction of the standardized acquisition protocol; the second group of 38 consecutive patients after implementation of the standardized acquisition protocol, involving MSCT planning of the optimal angiographic projection. Optimal projection planning has dramatically improved the feasibility of VD assessment from 57.4% prior to the standardized acquisition protocol, to 100% after the protocol was implemented. In 69 analyzable aortograms (69/92; 75%), LVOT-AR ranged from 3% to 28% with a median of 12%. Inter-observer agreement was high (mean difference+/-SD, 1+/-2%), and the 2 observers' measurements were highly correlated (r=0.94, P<0.0001). CONCLUSIONS: Introduction of computed tomography-guided angiographic image acquisition has significantly improved the analyzability of the angiographic VD assessment of post-TAVI AR. PMID- 29760326 TI - Appropriate Use of Urinary Catheter in Acute Heart Failure Patients. PMID- 29760327 TI - Effects of beta-Sitosteryl Sulfate on the Hydration Behavior of Dipalmitoylphosphatidylcholine. AB - We investigated the hydration behavior of dipalmitoylphosphatidylcholine (DPPC) bilayers containing sodium beta-sitosteryl sulfate (PSO4). PSO4 was found to enhance hydration in the headgroup region of DPPC bilayers. Therefore, with the incorporation of PSO4 into DPPC membranes, the amount of water required to reach the fully hydrated state was enhanced as indicated by the constant values of the main phase transition temperature (Tm) and the bilayer repeat distance (d). For example, with the addition of 20 mol% of PSO4, the saturation point was shifted to ~70 wt% water compared to ~40 wt% for pure DPPC and 47 wt% for DPPC cholesterol. The effectiveness of PSO4 in fluidizing the membrane and enhancing its hydration state can be useful in the pharmaceutical and cosmetic industries. PMID- 29760328 TI - Dynamics of Polymorphic Transformations in Palm Oil, Palm Stearin and Palm Kernel Oil Characterized by Coupled Powder XRD-DSC. AB - The in situ polymorphic forms and thermal transitions of refined, bleached and deodorized palm oil (RBDPO), palm stearin (RBDPS) and palm kernel oil (RBDPKO) were investigated using coupled X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Results indicated that the DSC onset crystallisation temperature of RBDPO was at 22.6 degrees C, with a single reflection at 4.2A started to appear from 23.4 to 17.1 degrees C, and were followed by two prominent exothermic peaks at 20.1 degrees C and 8.5 degrees C respectively. Further cooling to -40 degrees C leads to the further formation of a beta'polymorph. Upon heating, a of beta'->betatransformation was observed between 32.1 to 40.8 degrees C, before the sample was completely melted at 43.0 degrees C. The crystallization onset temperature of RBDPS was 44.1 degrees C, with the appearance of the alpha polymorph at the same temperature as the appearance of the first sharp DSC exothermic peak. This quickly changed from alpha->beta' in the range 25 to 21.7 degrees C, along with the formation of a small beta peak at -40 degrees C. Upon heating, a small XRD peak for the beta polymorph was observed between 32.2 to 36.0 degrees C, becoming a mixture of (beta'+ beta) between 44.0 to 52.5 degrees C. Only the beta polymorph survived further heating to 59.8 degrees C. For RBDPKO, the crystallization onset temperature was 11.6 degrees C, with the formation of a single sharp exothermic peak at 6.5 degrees C corresponding to the beta' polymorphic form until the temperature reached -40 degrees C. No transformation of the polymorphic form was observed during the melting process of RBDPKO, before being completely melted at 33.2 degrees C. This work has demonstrated the detailed dynamics of polymorphic transformations of PKO and PS, two commercially important hardstocks used widely by industry and will contribute to a greater understanding of their crystallization and melting dynamics. PMID- 29760329 TI - Delivery of Curcumin Using Skim Milk or Oil in Water Emulsions: Effect of the Matrices on Cellular Uptake. AB - To enhance the curcumin delivery in a variety of food grade matrices namely spray dried ethanolic curcumin in fresh skim milk (Spray dried Cu-SM), a fresh mixture of ethanolic curcumin and skim milk (Fresh Cu-SM) a powder mixture of curcumin and skim milk powder (Powder Cu-SMP) and oil in water emulsion (Emulsion) were studied. The cellular uptake of curcumin from the respective matrices was studied on Caco-2 cell monolayers. Spray dried Cu-SM showed higher encapsulation efficiency compared to a corresponding Powder Cu-SMP and an oil-in-water emulsion (40% oil) bearing curcumin. Furthermore, ethanolic administration of curcumin in spray dried form enhanced the cellular uptake of curcumin considerably higher than non-ethanolic samples (approx. 4 times). Overall, milk protein based vectors were found to perform better than emulsion samples. These findings highlighted the fact that curcumin uptake may be tailored by fine tuning of curcumin delivery vehicles which highlights possible application of powders as functional foods. PMID- 29760330 TI - Variations in Volatile Oil Yield and Composition of "Xin-yi" (Magnolia biondii Pamp. Flower Buds) at Different Growth Stages. AB - Dried flower buds of Magnolia biondii Pamp. are the main ingredient in "Xin-yi" in China, and the volatile oils of M. biondii flower buds are the principal medicinal component. Gas chromatographymass spectrometry (GC-MS) and microscopic techniques were employed to detect the volatile yields of M. biondii flowers at various growth stages. The volatile oil yields of M. biondii flowers differed significantly at different growth stages and were closely related to flower dry weight, oil cell density and degree of oil accumulation. In February 2016, flower buds had the highest dry weight, the maximum percentage of oil cells at the oil saturation stage and the highest density of oil cells, which coincided with the highest oil yield. In March 2016, flower buds had a lower dry weight, a higher percentage of oil cells at the oil-degrading stage and the lowest oil cell density, resulting in decreased oil yields. The total amounts of the major medicinal components in the M. biondii flower also showed regular changes at different growth stages. In January and February of 2016, M. biondii flowers had a higher dry weight, volatile oil yield and total content of medicinal ingredients, which was the best time for harvesting high-quality medicinal components. Our study reveals that volatile oil content and chemical composition are closely related to the growth stage of M. biondii flower buds. The results provide a scientific morphology and composition index for evaluating the medicinal value and harvesting of high-quality M. biondii medicinal herbs. PMID- 29760331 TI - Some Strategies for Utilization of Rice Bran Functional Lipids and Phytochemicals. AB - Rice bran contains a great amount of functional lipids and phytochemicals including gamma-oryzanols, tocotrienols, and tocopherols. However, utilization of those compounds is limited and needs some proven guidelines for better implementation. We introduce some effective strategies for the utilization of rice functional lipids, including an introduction of pigmented rice varieties for better bioactive compounds, biofortification of rice tocotrienols, plasma technology for improving rice phytochemicals, supercritical CO2 extraction of high quality rice bran oil, and an example on the development of tocotrienol fortified foods. PMID- 29760332 TI - Dry Thermotropic Glycolipid Self-Assembly:A Review. AB - Also recognized as carbohydrate liquid crystals, glycolipids are amphiphiles whose basic unit comprises of a sugar group attached to an alkyl chain. Glycolipids are amphitropic, which means these materials form liquid crystal self assemblies when dry (thermotropic) as well as when dissolved in solvents (lyotropic/surfactants) such as water. Many glycolipids are also naturally derived since these can be found in cell membranes. Their membrane and surfactant functions are largely understood through their lyotropic properties. While glycolipids are expected to play major roles as eco-friendly surfactants in the global surfactant market, their usefulness as thermotropic liquid crystal material is, to date, unknown, due to relatively lack of research performed and data reported in the literature. Understandably since glycolipids are hygroscopic with many hydroxy groups, removing the last trace water is very challenging. In recent time, with careful lyophilization and more consistent characterization technique, some researchers have attempted serious studies into "dry" or anhydrous glycolipids. Motivated by possible developments of novel thermotropic applications, some results from these studies also provide surprising new understanding to support conventional wisdom of the lyotropic systems. Here we review the dry state of glycosides, a family of glycolipids whose sugar headgroup is linked to the lipid chain via a glycosidic oxygen linker. The structure property relationship of both linear and anhydrous Guerbet glycosides will be examined. In particular, how the variation of sugar stereochemistry (e.g. anomer vs. epimer), the chain length and chain branching affect the formation of thermotropic liquid crystals phases, which not only located under equilibrium but also far from equilibrium conditions (glassy phase) are scrutinized. The dry glycolipid assembly has been subjected to electric and magnetic fields and the results show interesting behaviors including a possible transient current generation. PMID- 29760333 TI - Binary Phase Behavior of Saturated-Unsaturated Mixed-Acid Triacylglycerols-A Review. AB - Most natural lipids contain a complex mixture of individual triacylglycerols (TAGs). An in-depth knowledge of the mixing behavior of TAGs is necessary for the rational design and engineering of food materials. The binary phase diagram of TAGs is a simplified model that can be explored to help foster an understanding of the phase behavior of complex fats and oils. This article reviews recent research on the binary phase behavior of saturated-unsaturated mixed-acid TAGs, with special emphasis on the stearicunsaturated and palmitic-unsaturated diacid TAGs. The occurrence of polymorphic forms and mutual solubility of TAG mixtures are strongly related to the glycerol conformation of the saturated-oleic diacid TAGs; it appears to be most influenced by the chain-length mismatch in saturated elaidic diacid TAGs. In addition, the polymorphism of pure enantiomers and racemic mixture of chiral TAGs was also reviewed, while the effect of chirality on mixing behavior was discussed. PMID- 29760334 TI - Roles of Sodium Dodecyl Sulfate on Tetrahydrofuran-Assisted Methane Hydrate Formation. AB - Sodium dodecyl sulfate (SDS) markedly improved tetrahydrofuran (THF) - assisted methane hydrate formation. Firstly, methane hydrate formation with different THF amount, 1, 3, and 5.56 mol%, was studied. SDS with 1, 4, and 8 mM was then investigated for its roles on the methane hydrate formation with and without THF. The experiments were conducted in a quiescent condition in a fixed volume crystallizer at 8 MPa and 4 degrees C. The results showed that almost all studied THF and SDS concentrations enhanced the methane hydrate formation kinetics and methane consumption compared to that without the promoters, except 1 mol% THF. Although, with 1 mol% THF, there were no hydrates formed for 48 hours, the addition of just 1 mM SDS surprisingly promoted the hydrate formation with a significant increased in the kinetics. This prompts the use of methane hydrate technology for natural gas storage application with minimal promoters. PMID- 29760335 TI - Phosphine Induced Dimerization of Propargyl Alcohols Leading to Allyl Propargyl Ethers. AB - A facile method for synthesizing allyl propargyl ethers (APEs) was developed based on the dimerization of propargyl alcohols. The reaction proceeded via an oxaphosphetane intermediate, which was generated without the use of a strong base, thus making this process a pseudo-Wittig reaction under mild reaction conditions. A wide variety of functional groups, including formyl and pyridyl groups were tolerated, thus yielding the corresponding functionalized APEs, which are otherwise not readily prepared via conventional methods. Moreover, a cross reaction was found to occur when the reaction was conducted in the presence of alcohols that were more acidic than propargyl alcohol, which suggests that the proton transfer from the intermediately formed betaine to the second alcohol is crucial for undergoing the dimerization. PMID- 29760336 TI - Enhanced Physical Stability of Mixed Ion Pair Amphiphile/Double-chained Cationic Surfactant Vesicles in the Presence of Cholesterol. AB - In this study, a pseudodouble-chained ion pair amphiphile (IPA), hexadecyltrimethylammoniumdodecylsulfate (HTMA-DS), and dialkyldimethylammonium bromide (DXDAB) with different chain lengths were used as the main materials to fabricate positively charged catanionic vesicles with various mole fractions of cholesterol. The effects of cholesterol and DXDAB alkyl chain length on physical stability of the catanionic vesicles were then investigated by size, zeta potential, and Fourier transform infrared analyses. With the presence of cholesterol in the mixed HTMA-DS/DXDAB vesicles or with increasing the DXDAB content in the presence of a proper amount of cholesterol, the physical stability of the catanionic vesicles could be enhanced. The spacing effect of cholesterol would reduce the counterion binding tendency at the charged vesicle surfaces, resulting in a more pronounced charge character of the catanionic vesicles. Furthermore, cholesterol-induced disordered structure contributed to the flexibility of the vesicular bilayers. Thus the physical stability of the vesicles was improved by adding cholesterol. With increasing the hydrocarbon chain length of DXDAB, cholesterol located toward the middle of the bilayers, enhancing the effects of cholesterol on charge and molecular packing characteristics of the vesicles. This led to a more pronounced stability enhancement effect on the vesicles with a longer alkyl chain length of DXDAB. The results suggested that the presence of cholesterol in the HTMA-DS/DXDAB catanionic vesicles could enhance vesicle stability through adjusting intra vesicle and/or inter-vesicle interactions. In addition, the stability enhancement effect was more pronounced in the systems with a long DXDAB alkyl chain. The findings will be useful for developing new formulas of catanionic vesicles as drug delivery carriers. PMID- 29760337 TI - Adsorption Behavior of TBPS in the Process of Cu Electrodeposition on an Au Film. AB - The adsorption behavior of an Cu electroplating additive, 3,3 thiobis-(1 propanesulfonic acid sodium salt) (TBPS) in a process of Cu deposition onto a single crystalline Au(111) surface is studied by an in-situ Surface-Enhanced Infrared Absorption Spectroscopy (SEIRAS). The SEIRAS spectra of the TBPS adlayer on a Cu film is investigated first and compared to that on an Au film. These results are utilized to evaluate the characteristics of TBPS adlayer on the electrode surface during the Cu deposition and stripping processes. The results show that the SEIRAS spectra of TBPS adsorbed on the Cu film resembles closely to that on the Au film, and the most pronounced peaks are symmetric S-O (ss-SO) and asymmetric S-O (as-SO) stretching modes. However, the as-SO band is sharper with a higher intensity on the Cu film. Since the ss-SO and as-SO peaks correspond to the molecular with upright and lie-down orientations, respectively, it implies that the TBPS molecules have higher ratio of lie-down orientation on the Cu film. In the Cu electrodeposition process, the cyclic voltammetry (CV) result shows that the presence of the TBPS in the HClO4 solution can decrease the inhibition effect of HClO4 to the Cu deposition. For the spectra measured at various potential during cathodic and anodic sweeping, an obvious change of the spectra occurs at ca. 0.6 V, the initiation of Cu underpotential deposition (Cu-UPD). For potentials higher and lower than 0.6 V, the spectra are similar, respectively, to those measured for the Au and Cu films. This result indicates that the TBPS molecules originally adsorbing on the Au film transfer to the surface of deposited Cu layer. This inference is also confirmed by the variation in wavenumber and peak intensity of ss-SO and as-SO peaks during the potential sweeping. PMID- 29760338 TI - Septic pulmonary emboli as a complication of peripheral venous cannula insertion. AB - Septic pulmonary emboli can occur as a complication of many diseases, most common being right sided infective endocarditis. Septic emboli through a peripheral venous cannula are rarely reported in literature though central venous catheter is commonly implicated. We describe a case of widespread cellulitis and septic pulmonary emboli as a complication of peripheral venous cannulation. PMID- 29760339 TI - The potential antifibrotic impact of apocynin and alpha-lipoic acid in concanavalin A-induced liver fibrosis in rats: Role of NADPH oxidases 1 and 4. AB - Liver fibrosis results from chronic inflammation that precipitates excessive accumulation of extracellular matrix. Oxidative stress is involved in its pathogenesis. This study aimed to elucidate the potential antifibrotic effect of the NADPH oxidase (NOX) inhibitor, apocynin against concanavalin A (ConA)-induced immunological model of liver fibrosis, and to investigate the ability of the antioxidant, alpha-lipoic acid (alpha-LA) to potentiate this effect. Rats were treated with apocynin and/or alpha-LA for six weeks. Hepatotoxicity indices, oxidative stress, insulin, NOXs, inflammatory and liver fibrosis markers were assessed. Treatment of animals with apocynin and alpha-LA significantly ameliorated the changes in liver functions and histopathological architecture induced by ConA. Liver fibrosis induced by ConA was evident where alpha-smooth muscle actin and transforming growth factor- beta1 were elevated, which was further confirmed by Masson's trichrome stain and increased hydroxyproline. Co treatment with apocynin and alpha-LA significantly reduced their expression. Besides, apocynin and alpha-LA significantly ameliorated oxidative stress injury evoked by ConA, as evidenced by enhancing reduced glutathione content, antioxidant enzymes activities and decreasing lipid peroxides. ConA induced a significant elevation in serum insulin level and inflammatory markers; tumor necrosis factor-alpha, interleukin-6 and nuclear factor kappa b. Furthermore, the mRNA tissue expression of NOXs 1 and 4 was found to be elevated in the ConA group. All these elevations were significantly reduced by apocynin and alpha-LA co-treatment. These findings indicate that using apocynin and alpha-LA in combination possess marked antifibrotic effects, and that NOX enzymes are partially involved in the pathogenesis of ConA-induced liver fibrosis. PMID- 29760340 TI - Effect of CYP2C9, VKORC1, CYP4F2, and GGCX gene variants and patient characteristics on acenocoumarol maintenance dose: Proposal for a dosing algorithm for Moroccan patients. AB - We investigated the impact of non-genetics factors, and single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP4F2, and GGCX on acenocoumarol dosage in Moroccan adult's patients, in order to develop an algorithm to predict acenocoumarol dose for Moroccan patients. Our study consisted of 217 Moroccan patients taking a maintenance dose of acenocoumarol for various indications. The patients were genotyped for VKORC1 -1639 G>A, VKORC1 1173 C>T, CYP2C9*2, CYP2C9*3, CYP4F2 1347 G>A and GGCX 12970 C>G SNPs. The statistical analysis was performed using the SPSS software. The age and SNPs in VKORC1 and CYP2C9 were significantly associated with the weekly acenocoumarol dose requirement (p = 0.023, p = 0.0001 and p = 0.001 respectively). There was no association found between the weekly acenocoumarol dose and the CYP4F2 or GGCX variants (p-value > 0.05). Non-parametric analysis confirmed the accumulate effect of variant alleles at VKORC1 -1639 G>A, VKORC1 1173 C>T and CYP2C9 SNPs on the acenocoumarol dose requirement. With 90.24% less dose required for one patient carrying homozygote variant at VKORC1 -1173 (TT) and CYP2C9 *x/*x haplotype. The multiple linear regression analysis showed that mutation in VKORC1 -1639, VKORC1 1173 SNPs, or in CYP2C9 haplotype reduces the mean acenocoumarol weekly dose to 25.4%, 23.4% and 6.2%, respectively. The R2 for multiple regression analysis final model was found to be 35.9%. In this work we were able to establish the factors influencing interindividual sensitivity to the anticoagulant therapy that can help physicians to predict optimal dose requirement for long term therapy. PMID- 29760342 TI - 1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of C. elegans by down-regulating PAK1 at nM levels. AB - PAK1 (RAC/CDC42-activated kinase 1) is the major oncogenic/ageing kinase, and its dysfunction extends the healthy lifespan of C. elegans by activating HSP16 gene. 15K is a highly cell-permeable 1,2,3-triazolyl ester of ketorolac that down regulates both PAK1 and its down-stream COX-2 in R- and S-forms, respectively. 15K is 500-5,000 times more potent than ketorolac, an old pain-killer, inhibiting the growth of cancer cell lines with IC50 ranging 5-24 nM. Scores of natural and synthetic PAK1-blockers have been shown to extend the lifespan of small animals such as C. elegans, but none of them has been effective at nM levels. Thus, we examined in vivo effect of 15K at nM levels on the survival rate of C. elegans with or without heat-shock. Like the PAK1-deficient mutant, 15K (at 50 nM) treated worm significantly lives longer, is far more heat-resistant and less productive (fertile) than the non-treated counterpart, with an increased expression of HSP16 gene. 15K has been proven to be among the most potent anti cancerous and longevity-promoting PAK1-blockers, and therefore has a potential to treat a variety of solid tumours without severe side effect. PMID- 29760341 TI - Estimation of lactic acid bacterial cell number by DNA quantification. AB - Lactic acid bacteria are provided by fermented foods, beverages, medicines, and supplements. Because the beneficial effects of medicines and supplements containing functional lactic acid bacteria are related to the bacterial cell number, it is important to establish a simple method for estimating the total number of lactic acid bacterial cells in the products for quality control. Almost all of the lactic acid bacteria in the products are dead, however, making it difficult to estimate the total number of lactic acid bacterial cells in the products using a standard colony-counting method. Here we estimated the total lactic acid bacterial cell number in samples containing dead bacteria by quantifying the DNA. The number of viable Enterococcus faecalis 0831-07 cells decreased to less than 1 * 10-8 by 15 min of heat treatment at 80 degrees C. The amount of extracted DNA from heat-treated cells was 78% that of non-heated cells. The number of viable Lactobacillus paraplantarum 11-1 cells decreased to 1 * 10-4 after 4 days culture. The amount of extracted DNA of the long-cultured cells, however, was maintained at 97%. These results suggest that cell number of lactic acid bacteria killed by heat-treatment or long-term culture can be estimated by DNA quantification. PMID- 29760344 TI - Is There Any Clinical Significance of the Acute Antral Lesion Size After Pulmonary Vein Isolation Using Different Balloon Technologies or Ablation Energy? PMID- 29760345 TI - Identification of Pathogenic Mutations for Dilated Cardiomyopathy Accompanied With Unicuspid Aortic Valve. PMID- 29760343 TI - Acute effect of ivabradine on heart rate and myocardial oxygen consumption in dogs with asymptomatic mitral valve degeneration. AB - Degenerative mitral valve disease (DMVD) is a common cardiac disease in geriatric dogs characterized by the degeneration of the mitral valve, leading to decreased cardiac output and activation of the sympathetic and renin-angiotensin aldosterone system. This disease results in an increased resting heart rate (HR) and myocardial oxygen consumption (MVO2). A recent publication demonstrated that dogs with asymptomatic DMVD had a significantly higher HR and systemic blood pressure (BP) than age-matched control dogs. This higher HR will eventually contribute to increased MVO2. This study aimed to determine the effects of a single oral dose of ivabradine on the HR, MVO2 as assessed by the rate-pressure product, and BP in dogs with asymptomatic DMVD. Seven beagles with naturally occurring DMVD were instrumented by the Holter recorder and an oscillometric device to measure electrocardiogram and BP for 24 and 12 h, respectively. Each dog was randomly subjected to receive either placebo or ivabradine (0.5, 1.0 and 2.0 mg/kg). The results revealed that oral administration of ivabradine significantly decreased the HR and rate-pressure product in a dose-dependent manner without adverse effects. The highest dose of 2.0 mg/kg significantly reduced systolic and mean BP. Therefore, the findings imply that a single oral ivabradine administration at a dose of 1.0 mg/kg is suitable for dogs with asymptomatic DMVD to reduce the HR and MVO2 without marked effects on BP. This may potentially make ivabradine promising for management of an elevated HR in DMVD dogs. PMID- 29760346 TI - Effect of Sitagliptin on Coronary Flow Reserve Assessed by Magnetic Resonance Imaging in Type 2 Diabetic Patients With Coronary Artery Disease. AB - BACKGROUND: The present study was conducted to assess the cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP4i) on coronary flow reserve (CFR), left ventricular (LV) function and endothelial function of the peripheral artery by comparison with those of alpha-glucosidase inhibitors (alphaGI) in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD).Methods and Results:We randomly assigned 30 patients with T2DM and CAD to receive either sitagliptin or voglibose, and 28 patients (age 69+/-9 years, 75% male, hemoglobin A1c [HbA1c] 6.62+/-0.48%) completed the study (14 in each group). CFR and LV function, assessed by cardiac magnetic resonance imaging, and endothelial function, assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT), were measured at baseline and 24 weeks after treatment. Clinical and laboratory parameters, including HbA1c level, plasma active glucagon-like peptide-1 concentrations, and biomarkers of inflammation, were unchanged in both groups after 24 weeks of treatment. CFR were unchanged in both the alphaGI group (3.01+/ 0.98 at baseline and 3.06+/-0.8 after treatment, P=NS) and the DPP4i group (4.29+/-2.04 at baseline and 3.63+/-1.31 after treatment, P=NS), with no interaction effect. LV functional parameters and the reactive hyperemia index also remained unchanged after the 24-week treatment. CONCLUSIONS: DPP4i did not improve CFR, LV function or endothelial function of the peripheral artery in patients with relatively well-controlled T2DM and CAD. PMID- 29760347 TI - Identification of Pathogenic Mutations for Dilated Cardiomyopathy Accompanied With Unicuspid Aortic Valve - Reply. PMID- 29760348 TI - What Causes Pulmonary Arterial Hypertension in Down Syndrome With Congenital Heart Disease? PMID- 29760350 TI - Identification of Chlamydia pneumoniae candidate genes that interact with human apoptotic factor caspase-9. AB - Chlamydia pneumoniae is an obligate intracellular pathogen responsible for respiratory diseases, including pneumonia and bronchitis, and is highly involved in chronic diseases, including atherosclerosis, asthma, and Alzheimer's disease. We previously showed that the host apoptotic factor caspase-9 played a crucial role for chlamydial multiplication and host apoptosis inhibition by chlamydial infection. To identify chlamydial genes interacting with human caspase-9, yeast two-hybrid screening was performed and 5 chlamydial genes, including Cpj0838 and pmpG were isolated from the C. pneumoniae genomic library. Pull-down experiments showed that caspase-9 physically bound to the Cpj0838 product and chlamydial cells, which contain PmpG proteins. This study could provide a clue to understanding host-Chlamydia interactions, especially the apoptosis repression by Chlamydia infection. PMID- 29760349 TI - Identification of novel potential acetate-oxidizing bacteria in an acetate-fed methanogenic chemostat based on DNA stable isotope probing. AB - Acetate is a significant intermediate of anaerobic fermentation. There are two pathways for converting acetate to CH4 and CO2: acetoclastic methanogenesis by acetoclastic methanogens, and syntrophic acetate oxidation by acetate-oxidizing bacteria (AOB) and hydrogenotrophic methanogens. Detailed investigations of syntrophic acetate-oxidizing bacteria (SAOB) should contribute to the elucidation of the microbial mechanisms of methanogenesis. In this study, we investigated the major phylogenetic groups of acetate-utilizing bacteria (AUB) in a mesophilic methanogenic chemostat fed with acetate as the sole carbon source by using DNA stable isotope probing (SIP) technology. The results indicated that acetoclastic methanogenesis and acetate oxidization/hydrogenotrophic methanogenesis coexisted in the mesophilic chemostat fed with acetate, operated at a dilution rate of 0.1 d-1. OTU Ace13(9-17) (KU869530), Ace13(9-4) (KU667241), and Ace13(9-23) (KU667236), assigned to the phyla Firmicutes and Bacteroidetes, were probably potential SAOB in the chemostat, which needs further investigation. Species in the phyla Proteobacteria, Deferribacteres, Acidobacteria, Spirochaetes and Actinobacteria were probably capable of utilizing acetate for their growth. Methanoculleus was likely to be the preferred hydrogenotrophic methanogen for syntrophy with AOB in the chemostat. PMID- 29760352 TI - Time-Dependent Changes in Local and Serum Levels of Inflammatory Cytokines as Markers for Incised Wound Aging of Skeletal Muscles. AB - Wound age estimation is an important research field in forensic pathology. The expression levels of cytokines in the incised skeletal muscle were analyzed using a mouse model to explore the applicability for wound aging. A 5-mm long incisional wound was made at the biceps femoris muscle, and the muscle and serum were sampled at 6, 12, 24 and 48 hours after injury. Using a multiplex bead-based immunoassay, we measured the tissue levels of nine cytokines (IL-1beta, IL-6, IL 7, CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10), which are all involved in the pathways of inflammatory response and tissue injury. Immunoassay of post-injury muscle samples revealed significant increases in the levels of six cytokines, except for CCL3, CCL4 and IL-7, at 6 hours after injury. The elevated tissue levels of these six cytokines were maintained during 48 hours after injury, although the levels of IL-6 and CXCL1 were significantly decreased at 12 hours. In case of CCL3, its tissue levels were increased only at 12 hours. By contrast, CCL4 and IL-7 levels were increased only at 48 hours. Moreover, serum levels of most cytokines, except for CXCL1, remained unchanged during 24 hours after injury, followed by significant increases at 48 hours. Serum CXCL1 levels were increased at 6 hours and then decreased to the basal levels. Thus, the significant increase in the muscle levels of CXCL1 and IL-7 was observed at 6 and 48 hours after injury, respectively. Measuring muscle CXCL1 and IL-7 levels is helpful for estimating incised wound aging. PMID- 29760353 TI - Direct and Indirect Harassment Experiences and Burnout among Academic Faculty in Japan. AB - The purpose of this study is three-fold: (1) to compare harassment (sexual, gender, and academic harassment both directly and indirectly experienced - i.e. "directly harassed" and "have seen or heard of someone who experienced harassment", respectively) experienced by males and females, (2) to investigate whether such experiences correlate with burnout, and (3) to explore whether social support might mitigate any such relationship between harassment and burnout. This cross-sectional study was conducted at a private university in Japan in February 2014 and is based on a work-life balance survey obtained from 330 academic faculty members. We investigated the association between each of the six subcategories of harassment (direct and indirect forms of each of the three types) and burnout using general linear regression models; we then evaluated interactions between harassment and social support in these models. The prevalence of direct and indirect experiences of harassment was higher in females than in males for all three types of harassment. Males showed higher burnout scores if they had direct experiences of harassment. There were significant interactions between social support and the direct experience of harassment; high social support mitigated the effect size of direct harassment on burnout among males. Females showed higher burnout scores if they had indirect experiences of harassment. However, the same buffering effect of social support on burnout as observed in males was not observed in females. Direct harassment experiences increased the risk of burnout in males, and indirect harassment experiences increased burnout in females. PMID- 29760351 TI - Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats. AB - Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-alpha, IL-1beta and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease. PMID- 29760354 TI - Development of health technology assessment in China: New challenges. AB - Health technology assessment (HTA) is a field of scientific policy research that adopts multidisciplinary approaches to conduct systematic evaluation of health technologies and inform decision making. Although achievements have been made by HTA activities among academics, providers, and policy makers, development of the field of HTA in China is fragmented and not yet formally integrated in health policy making processes. All stakeholders need to make more efforts to strengthen HTA knowledge translation and facilitate a decision making process that is based on evidence including HTA findings. This article reviews how the field of HTA has developed in China, analyzes what factors have been influencing China's HTA development, and proposes policy recommendations. PMID- 29760355 TI - Interventions integrating non-communicable disease prevention and reproductive, maternal, newborn, and child health: A systematic review. AB - Reproductive, maternal, newborn, and child health (RMNCH) care services could be critical entry points for preventing non-communicable diseases in women and children. In high-income countries, non-communicable diseases screening has been integrated into both the medical and public health systems. To integrate these services in low- and middle-income countries, it is necessary to closely examine its effectiveness and feasibility. In this systematic review, we evaluated the effectiveness of integrating gestational and non-gestational non-communicable diseases interventions and RMNCH care among women and children in low- and middle income countries. This systematic review included randomized and quasi-randomized controlled trials published from 2000 to 2015. Participants included reproductive age women, children < 5 years old, and RMNCH care providers. The included interventions comprised packaged care/services that integrated RMNCH services with non-communicable disease care. The outcomes were maternal and/or infant mortality and complications, as well as health care service coverage. We analyzed six studies from 7,949 retrieved articles. Yoga exercise (p < 0.01) and nutritional improvements (p < 0.05) were effective in reducing gestational hypertension and diabetes. Additionally, integrating cervical cancer and RMNCH services was useful for identifying potential cervical cancer cases. Interventions that integrate non-communicable disease care/screening and RMNCH care may positively impact the health of women and children in low- and middle income countries. However, as primary evidence is scarce, further research on the effectiveness of integrating non-communicable disease prevention and RMNCH care is warranted. (Review Registration: PROSPERO International prospective register of systematic reviews (CRD42015023425).). PMID- 29760356 TI - The impact of parental migration on injuries among left behind young people aged 10 years to 24 years in Botswana. AB - There has been little evidence of the relationship between children and absence of parents in Botswana literature; and it is still the case that absence of parents increases the risk of injuries to their children. The aim of this study is to investigate the impact of parental migration among left behind young people aged 10 years to 24 years in Botswana and examine patterns of injuries from immigrant families. This is a population-based crosssection from which a dataset was created by compiling data from two different sources for the period of 2010 to 2015. All the variables were transformed into natural logarithms so as to avoid outliers and normalize the variables. All statistical modeling was carried out using Statistical Analysis System version 6.1. Left behind young people were associated with higher risk of injuries especially in motor vehicle accidents 391(40%), fire 264 (27%), and burns 162 (16%) except for drowning, machinery and poisoning. Parental migration is the most important issue in the total number of injuries. Correlation coefficient shows that non-left behind, the greater the chance to be classified under the poisoning cases (r = 0.888) and is lower compared to the left behind (r = 0.471). This study shows clearly that injuries take an insufficiently high toll on children's health and on society. Additionally, if parental migration trends continue, Botswana's burden of injuries are expected to rise in the next 10 years. PMID- 29760357 TI - Intimate partner violence victimization and HIV infection among men who have sex with men in Shanghai, China. AB - Intimate partner violence (IPV) and its association with HIV infection among men who have sex men (MSM) in China are not understood. In this study, 732 MSM recruited from Shanghai, China between March and August 2015 were administered with a questionnaire survey and HIV blood testing. IPV victimization was measured by 25 forced-choice items capturing lifetime experience of physical, sexual, psychological, deprivation or neglect, and other forms of violence. Of them, 179 (24.3%) reported having experienced at least one type of IPV victimization. In separate multivariable analyses, sexual violence was associated with age over 35 years (AOR = 0.26, 95% CI: 0.07-1.02), ever had male-to-male commercial sex (AOR = 2.53, 95%CI: 1.19-5.39), and diagnosis of a sexually transmitted infection (STI) (AOR = 2.14, 95%CI: 0.98-4.66). Both psychological violence (AOR = 2.53, 95%CI: 1.25-5.12)and deprivation or neglect violence (AOR = 1.75, 95%CI: 1.14 2.68) were associated with ever had sex with a casual male partner(s). Having experienced at least one type of IPV victimization was significantly associated with ever had sex with a causal partner(s) (AOR = 1.72, 95%CI: 1.15-2.57) and ever had a diagnosis of a STI (AOR = 1.80, 95% CI: 1.12-2.88). HIV infection was marginally associated with having experienced any form of IPV victimization. IPV victimization is common among MSM, especially young MSM, in China, although its association with HIV infection is not conclusive in our sample. Nonetheless, our findings highlight the importance of the needs of individualized IPV interventions for certain target risk groups of MSM. PMID- 29760358 TI - A reliable grading system for prediction of hematoma expansion in intracerebral hemorrhage in the basal ganglia. AB - Hematoma expansion (HE) is an independent predictor of poor outcome and secondary neurological deterioration in intracerebral hemorrhage (ICH) and is associated with high morbidity and mortality. Noncontrast computed tomography (NCCT) may identify the sites of active extravasation. Therefore, we have attempted to (1) devise a reliable and easy-to-use prediction score to predict the risk of HE in ICH and (2) validate the accuracy of this grading system and perform an independent analysis of HE predictors. We included patients in whom an intracerebral hemorrhage (ICH) occurred in the basal ganglia between Jan. 2015 and Jan. 2018. These patients had undergone a baseline CT scan at Qinghai Provincial People's Hospital within 24 hours after the onset of ICH symptoms. Two observers independently assessed the presence of the island sign, blend sign, or swirl sign on an NCCT scan during patient selection. Patients underwent a baseline NCCT scan and 24-hour NCCT follow-up for analysis of HE. The accuracy of this grading system was assessed. Independent predictors of HE were identified using multivariable regression. Of 266 patients with ICH, 61 (22.93%) presented with the island sign, 63 (23.68%) presented with the blend sign, and 50 (18.80%) presented with the swirl sign. The overall incidence of HE was 37.22% (99/266). Of 125 patients (46.99%) who underwent a baseline CT scan within 6 hours of onset, 141 (53.01%) underwent a scan in 6-24 hours. Multivariable logistic regression analysis identified the hematoma volume (OR, 0.974; P = 0.042), intraventricular hemorrhage (IVH) extension (OR, 3.225; P = 0.003), time from onset to the baseline CT scan (OR, 0.986; P < 0.001), and anticoagulant use or an international normalized ratio (INR) > 1.5 (OR, 3.362; P = 0.006) as closely associated with HE. In conclusion, the grading system demonstrated reliable accuracy at predicting HE. The grading system demonstrated acceptable accuracy in an independent single-institution study. The role of the grading system in predicting HE and poor outcome in patients with ICH is significant. NCCT imaging markers may serve as key markers for HE prediction. PMID- 29760359 TI - A simple and economical method of gas chromatography-mass spectrometry to determine the presence of 6 pesticides in human plasma and its clinical application in patients with acute poisoning. AB - An economical, rapid, and sensitive method of gas chromatography-mass spectrometry (GC-MS) was developed and validated to determine the presence of six pesticides (dichlorvos, acetochlor, atrazine, chlorpyrifos, alpha-endosulfan, and beta-endosulfan) in human plasma. The pesticides were extracted with acetonitrile and concentrated using anhydrous sodium sulfate. Then, the target compounds were analyzed and quantified with GC-MS using borneol as an internal standard. Separation was performed on a HP-5MS capillary column (30 m * 0.25 mm * 0.25 um) with temperature programming. Detection was accomplished under electro-spray ionization (ESI) in selected ion monitoring (SIM) mode. Under optimized conditions, satisfactory linear ranges of 0.05-10 MUg/mL were obtained for all of the analyzed pesticides. The linear correlation coefficients were greater than 0.99. The average recovery was between 86.8 and 106.5%. The inter- and intra-day precision ranged from 1.7-14.5% and 4.2-13.8%, respectively. Dichlorvos was unstable in plasma both at room temperature and when frozen. The other five pesticides were stable after storage at - 20 degrees C for 17 days and two freeze thaw cycles. Thirty-five plasma samples from 15 patients with acute self poisoning were analyzed using this method. Dichlorvos was found in 13 plasma samples with a mean concentration of 0.289 MUg/mL, and atrazine was found in 6 with a mean concentration of 0.261 MUg/mL. Acetochlor was found in one plasma sample (0.153 MUg/mL). This method is simple, reliable and cost-effective. It takes little time and does not waste solvents, and it can be used to routinely detect six pesticides in patients with acute poisoning. PMID- 29760360 TI - Performing laparoscopic surgery - Perspectives of young Chinese hepatobiliary surgeons. AB - Laparoscopic liver resection (LLR) has garnered attention as a new form of liver surgery. In China, many hepatobiliary surgeons are now encouraging the examination and assessment of LLC in order to improve its outcomes, and several young hepatobiliary surgeons recently shared their clinical experiences and the results of their research in presentations at the Akamon Forum as part of the 118th Annual Congress of the Japan Surgical Society, which was held April 5-7, 2018 in Tokyo, Japan. In China, LLR has gradually improved over the past 20 years, including both expanded indications and improved surgical approaches. However, China is a vast country, and the level of medical care varies nationwide. Medical facilities that can perform advanced laparoscopic techniques are currently limited to those in large cities. Moreover, additional clinical studies of the long-term oncological outcomes of LLR need to be performed in the future. PMID- 29760361 TI - [Current status and future prospects of nursing education in Japan]. AB - The Bachelor of Nursing program is being held at 255 universities in 2017. There are various initiatives universities to meet the needs of society, nurturing high quality nurses, but securing the level of education is one of the tasks. The Ministry of Education, Culture, Sports, Science and Technology established a nursing education model core curriculum for solving the problem. Each university is expected that the curriculum will be built with reference to this model core curriculum for quality assurance of education. PMID- 29760362 TI - [Pharmacology education in nursing: what should be taught and how? - from Western to Chinese medicine]. AB - Doctors give prescriptions after considering the medical conditions of patients. Pharmacists check the prescription and give information about the effects of the drugs to the patients, including their side effects. Nurses observe patients to determine the effects and side effects of the administered drugs, and then report these to doctors. Each specialist plays a role, allowing medication to be completed. However, in order to fully attain the effects of a drug, we need to consider the method of its administration. For example, it is difficult to attain the effects of laxatives for a person who eats irregularly; however, they are uniformly administered. Pharmacology education in nursing focuses on the mechanism of drugs and the way of maintaining their therapeutic effects and safeness, based on the viewpoint of "curing". Furthermore, nursing science focuses on the differences in efficacy depending on the characteristics of a patient, and also on the side effects of drugs, based on the viewpoint of "caring". However, education where care and cure are integrated needs to be provided, so that nurses can acquire applied skills to consider individual patient's bodies, lives, and psychological situations comprehensively, and then suggest the optimal method of administration. Also, there is Eastern medicine as well as Western medicine. Administration of Chinese medicine should be related to the patient's lifestyle. Nurses have to learn how each medicine is related to the patient's lifestyle, and what aspects in the patient they have to focus on. PMID- 29760363 TI - [Education of physiology in nursing school: common issues and measures with pharmacology]. AB - Anatomy, physiology or pharmacology is the important subject in nursing education. Nursing education is established in a law since 1951. Although the law is revised many times according to social situation, the subjects like physiology have been positioned as a basic specialized subject in the law now. Physiology is educated at 1st grade in most nursing school. However, there are some problems in educating physiology. First, academic ability in nursing students tend to decline recently. For example, there are some students who cannot solve simple arithmetic. They cannot calculate how much volume (mL) they have to aspirate injection solution to the syringe, when a doctor orders an injection medicine. Thus, there are increasing number of students who are not good at calculation. Second, they do not learn the technical term exactly. There are many names of pharmaceutical drug they must learn in pharmacology, some of which have similar names of pharmaceutical drug. If students do not learn them exactly, there is the possibility of causing a medical accident. Third, students learn something or an events from restricted one side. Therefore, they cannot answer the question they are asked from a different point of view. Furthermore, student cannot relate the knowledge they have learned with other knowledge. It seems that it must be important to have students understand how to utilize the knowledge in physiology or pharmacology in nursing practice at an early stage. PMID- 29760364 TI - [Pharmacology education in nursing based on the Patient-oriented Pharmacology: Personal drug (P-Drug) and integrated Drug (iDrug)]. AB - The installation of nursing colleges/universities has rapidly increased from the late 1990s, there are 255 institutions in Japan as of 2017. Pharmacology and clinical pharmacology education in undergraduate and postgraduate nursing colleges/universities is highly important, however, the lack of human resources involved in pharmacology education due to the rapid increase of nursing colleges/universities cannot be denied. The Ministry of Education, Culture, Sports, Science and Technology of Japan established a "nursing education model core curriculum" for quality assurance of education at nursing colleges/universities. To meet the needs of a new phase of nursing education, re examination of curriculum of nursing Pharmacology education is necessary. In this manuscript, we would like to propose a novel concept "integrated drug (iDrug)" based on "Patient-oriented Pharmacology" for nursing Pharmacology education to maintain high level of safety medication. PMID- 29760365 TI - [Analysis of astrocytic function using Ca2+ imaging]. AB - Accumulating evidence shows astrocytic contribution to brain function and diseases, however, the function of astrocytes remains to be uncovered. Dynamic changes in the intracellular Ca2+ level in astrocytes are one of the outstanding indexes of ongoing astrocytic activity. Therefore, we tried to uncover astrocytic function using approaches combined with Ca2+ imaging. We showed that astrocytes promote neuronal growth and survival after injury via Ca2+-dependent regulation of a cell adhesion protein, N-cadherin. Furthermore, we developed a method for the monitoring of astrocytic Ca2+ signals in living mouse brain, and found a previously unidentified pattern of spontaneous Ca2+ signals, which are preferably displayed in astrocytic fine processes. These findings and methods are promising to provide further information of astrocytic function, which can contribute to development of pharmacology. PMID- 29760366 TI - [Contribution of chimeric mice with a humanized liver to the evaluation of pharmacology, toxicity, and pharmacokinetics in drug discovery and development]. AB - To develop new drugs with high efficacy and safety, it is important to predict the pharmacological, toxicological, and pharmacokinetic profiles of drug candidates in humans. Chimeric mice with a humanized liver are mice in which human hepatocytes have been transplanted, such that mouse liver cells are replaced with human hepatocytes; these mice have been used as prediction models. Studies performed thus far indicate that chimeric mice with a humanized liver can be used for the prediction of human-specific metabolite formation and plasma concentration-time curves for several drugs. Furthermore, studies advocate the utility of chimeric mice with a humanized liver for modelling drug-induced hepatotoxicity and disease such as hepatitis virus infection in safety and pharmacological evaluations respectively. Taken together, these findings indicate that chimeric mice with a humanized liver can be used to evaluate the relationship between pharmacokinetics, toxicity, and efficacy; the contribution by active metabolites may also be assessed. In recent years, new and improved animal models have been developed to overcome the disadvantages of chimeric mice with a humanized liver. It is expected that their usefulness for optimization of drug candidates and translational research in drug discovery and development will further increase. PMID- 29760367 TI - [Pharmacological action and clinical outcome of newly developed NSAIDs patch, "LOQOA(r) tape"]. AB - Topical non-steroidal anti-inflammatory drugs (NSAIDs) patches are indispensable for the treatment of musculoskeletal diseases, while they are considered less effective than oral NSAIDs. LOQOA(r) tape is a tape-type patch containing esflurbiprofen (SFP) as a major active ingredient with potent cyclooxygenase inhibition and sufficient skin permeability. SFP patch (SFPP) showed higher percutaneous absorption rate, rapid pain relief, and potent anti-inflammatory efficacy comparing with existing NSAIDs patches in rat. SFPP showed dramatically higher synovial fluid and tissue concentration on SFP than that of flurbiprofen (FP) patch after single application to knee osteoarthritis (OA) patients. On the other hand, clinical dosage of SFPP was determined as not more than two patches a day from the estimation of systemic exposure to SFP of SFPP and oral FP. SFPP showed statistically significant differences in pain relief and all the other efficacy end points compared to inactive placebo or FP patch in knee OA patients. Efficacy on OA other than knee joint was also observed. In long-term study of SFPP, using up to two patches a day, a total of 201 patients was included and 161 patients achieved 52-week application. Among drug-related side effects, skin reaction at the application sites was observed in 46.8% and discontinued in 4.3%. Although gastro-intestinal reaction and abnormal changes in laboratory tests related to kidney function were observed as systemic drug-related side effects, most of them were mild in severity. SFPP, the new generation NSAIDs patch, would be one of effective options for the treatment of symptomatic OA patients. PMID- 29760368 TI - Digitizing the direct laryngoscopy experience: the economic way!! PMID- 29760369 TI - Ketamine with Propofol for Endoscopic Procedures. PMID- 29760370 TI - Using eye tracking technology to compare the effectiveness of malignant hyperthermia cognitive aid design. AB - BACKGROUND: Malignant hyperthermia is a rare but potentially fatal complication of anesthesia, and several different cognitive aids designed to facilitate a timely and accurate response to this crisis currently exist. Eye tracking technology can measure voluntary and involuntary eye movements, gaze fixation within an area of interest, and speed of visual response and has been used to a limited extent in anesthesiology. METHODS: With eye tracking technology, we compared the accessibility of five malignant hyperthermia cognitive aids by collecting gaze data from twelve volunteer participants. Recordings were reviewed and annotated to measure the time required for participants to locate objects on the cognitive aid to provide an answer; cumulative time to answer was the primary outcome. RESULTS: For the primary outcome, there were differences detected between cumulative time to answer survival curves (P < 0.001). Participants demonstrated the shortest cumulative time to answer when viewing the Society for Pediatric Anesthesia (SPA) cognitive aid compared to four other publicly available cognitive aids for malignant hyperthermia, and this outcome was not influenced by the anesthesiologists' years of experience. CONCLUSIONS: This is the first study to utilize eye tracking technology in a comparative evaluation of cognitive aid design, and our experience suggests that there may be additional applications of eye tracking technology in healthcare and medical education. Potentially advantageous design features of the SPA cognitive aid include a single page, linear layout, and simple typescript with minimal use of single color blocking. PMID- 29760371 TI - Under-Reported Aspects of Platinum Drug Pharmacology. AB - Platinum drugs remain the backbone of many antineoplastic regimens. Among the numerous chemical or pharmacological effects of platinum drugs, some aspects tend to be under-reported. Thus, this perspective paper intends to stress some neglected properties of platinum drugs: first, the physico-chemical characteristics (aquation reaction kinetics) that determine site-specific toxicity; second, the impact on RNA molecules. Knowledge of the 'RNA world' has dramatically changed our understanding of cellular and molecular biology. The inherent RNA-crosslinking properties should make platinum-based drugs interact with coding and non-coding RNAs. Third, we will discuss the impact on the immune system, which is now recognized to substantially contribute to chemotherapy efficacy. Together, platinum drugs are in fact old drugs, but are worth re focusing on. Many aspects are still mysterious but can pave the way to new drugs or an improved application of the already existing compounds. PMID- 29760373 TI - Comprehensive Assessment of the Psychological Burden for Students in Physical Education Classes in Chinese Universities. AB - BACKGROUND Physical education (PE) is part of the curriculum in Chinese universities. The psychological burden, or anxiety levels, for students in PE classes, can result from several factors, including teaching content, teaching environment, and the organization of the teaching methods. The aim of this study was to assess the psychological burden on students in PE classes in Chinese universities. MATERIAL AND METHODS The study included 400 students (200 men and 200 women) from a Chinese university, who participated in PE classes. The distribution of the levels of psychological burden associated with PE was assessed using subjective measurements and a fuzzy comprehensive evaluation method that to provide an integrated framework combining the results of judgments made at multiple stages of the evaluation process. RESULTS Of the 400 study participants who attended PE classes, 61.5% of male students and 47.5% of female students coped well or very well when dealing with the perceived psychological burden; 33.5% of male students and 42.5% of female students reported a medium level of psychological burden. Few students reported a high level of psychological burden associated with PE classes. The average psychological burden in female students was greater than for male students who participated in PE classes. CONCLUSIONS The combination of subjective measurement of the psychological burden associated with PE classes by university students in China, combined with a fuzzy comprehensive evaluation method showed that female university students might require more support than male students to overcome any psychological burden associated with PE classes. PMID- 29760372 TI - A Review of Induction with Rabbit Antithymocyte Globulin in Pediatric Heart Transplant Recipients. AB - Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin(r)) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable. PMID- 29760374 TI - Overview of Cerebral Edema During Correction of Hyperglycemic Crises. AB - BACKGROUND Hyperglycemic crises can cause severe neurologic impairment. One of the most dreaded consequences of hyperglycemic crises is cerebral edema, a rare complication seen during the treatment of hyperglycemic crises resulting from overly-aggressive fluid resuscitation and rapid correction of hyperglycemia and hyperosmolarity. CASE REPORT We present a case of profound hyperglycemic crisis with blood glucose greater than 2000 mg/dL, complicated by the development of new neurologic deficits after rapid correction of hyperglycemia. Brain imaging failed to reveal a diagnosis of cerebral edema or other acute intracranial process. However, the deficits did not resolve by the time of discharge, raising concern that the neurologic impairment may have been the consequence of overly-aggressive treatment of the hyperglycemic crisis. CONCLUSIONS Neurologic status must be monitored closely, with frequent re-examination, in patients who present with hyperglycemic crises. Care should be taken to prevent over-correction of hyperglycemia and hyperosmolarity following initial fluid resuscitation of these patients to prevent cerebral edema or other significant neurologic impairment. PMID- 29760375 TI - Effect of Ankle Range of Motion (ROM) and Lower-Extremity Muscle Strength on Static Balance Control Ability in Young Adults: A Regression Analysis. AB - BACKGROUND The purpose of this study was to investigate the effect of ankle ROM and lower-extremity muscle strength on static balance control ability in young adults. MATERIAL AND METHODS This study was conducted with 65 young adults, but 10 young adults dropped out during the measurement, so 55 young adults (male: 19, female: 36) completed the study. Postural sway (length and velocity) was measured with eyes open and closed, and ankle ROM (AROM and PROM of dorsiflexion and plantarflexion) and lower-extremity muscle strength (flexor and extensor of hip, knee, and ankle joint) were measured. Pearson correlation coefficient was used to examine the correlation between variables and static balance ability. Simple linear regression analysis and multiple linear regression analysis were used to examine the effect of variables on static balance ability. RESULTS In correlation analysis, plantarflexion ROM (AROM and PROM) and lower-extremity muscle strength (except hip extensor) were significantly correlated with postural sway (p<0.05). In simple correlation analysis, all variables that passed the correlation analysis procedure had significant influence (p<0.05). In multiple linear regression analysis, plantar flexion PROM with eyes open significantly influenced sway length (B=0.681) and sway velocity (B=0.011). CONCLUSIONS Lower-extremity muscle strength and ankle plantarflexion ROM influenced static balance control ability, with ankle plantarflexion PROM showing the greatest influence. Therefore, both contractile structures and non-contractile structures should be of interest when considering static balance control ability improvement. PMID- 29760376 TI - The novel 19q13 KRAB zinc-finger tumour suppressor ZNF382 is frequently methylated in oesophageal squamous cell carcinoma and antagonises Wnt/beta catenin signalling. AB - Zinc finger proteins (ZFPs) are the largest transcription factor family in mammals. About one-third of ZFPs are Kruppel-associated box domain (KRAB)-ZFPs and involved in the regulation of cell differentiation/proliferation/apoptosis and neoplastic transformation. We recently identified ZNF382 as a novel KRAB-ZFP epigenetically inactivated in multiple cancers due to frequent promoter CpG methylation. However, its epigenetic alterations, biological functions/mechanism and clinical significance in oesophageal squamous cell carcinoma (ESCC) are still unknown. Here, we demonstrate that ZNF382 expression was suppressed in ESCC due to aberrant promoter methylation, but highly expressed in normal oesophagus tissues. ZNF382 promoter methylation is correlated with ESCC differentiation levels. Restoration of ZNF382 expression in silenced ESCC cells suppressed tumour cell proliferation and metastasis through inducing cell apoptosis. Importantly, ZNF382 suppressed Wnt/beta-catenin signalling and downstream target gene expression, likely through binding directly to FZD1 and DVL2 promoters. In summary, our findings demonstrate that ZNF382 functions as a bona fide tumour suppressor inhibiting ESCC pathogenesis through inhibiting the Wnt/beta-catenin signalling pathway. PMID- 29760377 TI - Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation. AB - The assembly of prereplicative complex (pre-RC) during G1 phase must be tightly controlled to sustain cell proliferation and maintain genomic stability. Mechanisms to prevent pre-RC formation in G2/M and S phases are well appreciated, whereas how cells ensure efficient pre-RC assembly during G1 is less clear. Here we report that cyclin K regulates pre-RC formation. We find that cyclin K expression positively correlates with cell proliferation, and knockdown of cyclin K or its cognate kinase CDK12 prevents the assembly of pre-RC in G1 phase. Mechanistically we uncover that cyclin K promotes pre-RC assembly by restricting cyclin E1 activity in G1. We identify a cyclin K-dependent, novel phosphorylation site in cyclin E1 that disrupts its interaction with CDK2. Importantly, this antagonistic relationship is largely recapitulated in cyclin E1-overexpressing tumors. We discuss the implications of our findings in light of recent reports linking cyclin K and CDK12 to human tumorigenesis. PMID- 29760378 TI - The ginsenoside PPD exerts anti-endometriosis effects by suppressing estrogen receptor-mediated inhibition of endometrial stromal cell autophagy and NK cell cytotoxicity. AB - Endometriosis (EMS) is an estrogen-dependent gynecological disease with a low autophagy level of ectopic endometrial stromal cells (eESCs). Impaired NK cell cytotoxic activity is involved in the clearance obstruction of the ectopic endometrial tissue in the abdominopelvic cavity. Protopanaxadiol (PPD) and protopanaxatriol (PPT) are two metabolites of ginsenosides, which have profound biological functions, such as anti-cancer activities. However, the role and mechanism of ginsenosides and metabolites in endometriosis are completely unknown. Here, we found that the compounds PPD, PPT, ginsenoside-Rg3 (G-Rg3), ginsenoside-Rh2 (G-Rh2), and esculentoside A (EsA) led to significant decreases in the viability of eESCs, particularly PPD (IC50 = 30.64 uM). In vitro and in vivo experiments showed that PPD promoted the expression of progesterone receptor (PR) and downregulated the expression of estrogen receptor alpha (ERalpha) in eESCs. Treatment with PPD obviously induced the autophagy of eESCs and reversed the inhibitory effect of estrogen on eESC autophagy. In addition, eESCs pretreated with PPD enhanced the cytotoxic activity of NK cells in response to eESCs. PPD decreased the numbers and suppressed the growth of ectopic lesions in a mouse EMS model. These results suggest that PPD plays a role in anti-EMS activation, possibly by restricting estrogen-mediated autophagy regulation and enhancing the cytotoxicity of NK cells. This result provides a scientific basis for potential therapeutic strategies to treat EMS by PPD or further structural modification. PMID- 29760379 TI - Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration. AB - Autophagy, interacting with actin cytoskeleton and the NO-dependent pathway, may affect the phenotype and function of endothelial cells. Moreover, caveolin-1 (Cav 1), as a structure protein in liver sinusoidal endothelial cells (LSECs), is closely related to autophagy. Hence, we aim to explore the role of autophagic degradation of Cav-1 in LSECs defenestration. In vivo, we found the increase of autophagy in liver sinusoidal endothelium in human fibrotic liver. Furthermore, autophagy, degradation of Cav-1, and actin filament (F-actin) remodeling were triggered during the process of CCl4-induced LSECs defenestration; in contrast, autophagy inhibitor 3MA diminished the degradation of Cav-1 to maintain fenestrae and relieve CCl4-induced fibrosis. In vitro, during LSECs defenestration, the NO dependent pathway was down-regulated through the reduction of the PI3K-AKT-MTOR pathway and initiation of autophagic degradation of Cav-1; while, these effects were aggravated by starvation. However, VEGF inhibited autophagic degradation of Cav-1 and F-actin remodeling to maintain LSECs fenestrae via activating the PI3K AKT-MTOR pathway. Additionally, inhibiting autophagy, such as 3MA, bafilomycin, or ATG5-siRNA, could attenuate the depletion of Cav-1 and F-actin remodeling to maintain LSECs fenestrae and improve the NO-dependent pathway; in turn, eNOS siRNA and L-NAME, for blocking the NO-dependent pathway, could elevate autophagic degradation of Cav-1 to aggravate defenestration. Finally, overexpressed Cav-1 rescued rapamycin-induced autophagic degradation of Cav-1 to maintain LSECs fenestrae; whereas knockdown of Cav-1 facilitated defenestration due to the activation of the AMPK-dependent autophagy. Consequently, autophagic degradation of Cav-1 promotes LSECs defenestration via inhibiting the NO-dependent pathway and F-actin remodeling. PMID- 29760380 TI - A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo. AB - Pentose phosphate pathway (PPP) is a major glucose metabolism pathway, which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here we demonstrate that the natural molecule polydatin inhibits glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP. Polydatin blocks G6PD causing accumulation of reactive oxygen species and strong increase of endoplasmic reticulum stress. These effects are followed by cell cycle block in S phase, an about 50% of apoptosis, and 60% inhibition of invasion in vitro. Accordingly, in an orthotopic metastatic model of tongue cancer, 100 mg/kg polydatin induced an about 30% tumor size reduction with an about 80% inhibition of lymph node metastases and 50% reduction of lymph node size (p < 0.005). Polydatin is not toxic in animals up to a dose of 200 mg/kg and a phase II clinical trial shows that it is also well tolerated in humans (40 mg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread. PMID- 29760381 TI - The extent of liver injury determines hepatocyte fate toward senescence or cancer. AB - It is well known that induction of hepatocyte senescence could inhibit the development of hepatocellular carcinoma (HCC). Until now, it is still unclear how the degree of liver injury dictates hepatocyte senescence and carcinogenesis. In this study, we investigated whether the severity of injury determines cell fate decisions between hepatocyte senescence and carcinogenesis. After testing of different degrees of liver injury, we found that hepatocyte senescence is strongly induced in the setting of severe acute liver injury. Longer-term, moderate liver injury, on the contrary did not result into hepatocyte senescence, but led to a significant incidence of HCC instead. In addition, carcinogenesis was significantly reduced by the induction of severe acute injury after chronic moderate liver injury. Meanwhile, immune surveillance, especially the activations of macrophages, was activated after re-induction of senescence by severe acute liver injury. We conclude that severe acute liver injury leads to hepatocyte senescence along with activating immune surveillance and a low incidence of HCC, whereas chronic moderate injury allows hepatocytes to proliferate rather than to enter into senescence, and correlates with a high incidence of HCC. This study improves our understanding in hepatocyte cell fate decisions and suggests a potential clinical strategy to induce senescence to treat HCC. PMID- 29760384 TI - Instability of the Northeast Greenland Ice Stream over the last 45,000 years. AB - The sensitivity of the Northeast Greenland Ice Stream (NEGIS) to prolonged warm periods is largely unknown and geological records documenting such long-term changes are needed to place current observations in perspective. Here we use cosmogenic surface exposure and radiocarbon ages to determine the magnitude of NEGIS margin fluctuations over the last 45 kyr (thousand years). We find that the NEGIS experienced slow early Holocene ice-margin retreat of 30-40 m a-1, likely as a result of the buttressing effect of sea-ice or shelf-ice. The NEGIS was ~20 70 km behind its present ice-extent ~41-26 ka and ~7.8-1.2 ka; both periods of high orbital precession index and/or summer temperatures within the projected warming for the end of this century. We show that the NEGIS was smaller than present for approximately half of the last ~45 kyr and is susceptible to subtle changes in climate, which has implications for future stability of this ice stream. PMID- 29760383 TI - Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. AB - Metastatic uveal melanoma is a deadly disease with no proven standard of care. Here we present a metastatic uveal melanoma patient with an exceptional high sensitivity to a PD-1 inhibitor associated with outlier CpG>TpG mutation burden, MBD4 germline deleterious mutation, and somatic MBD4 inactivation in the tumor. We identify additional tumors in The Cancer Genome Atlas (TCGA) cohorts with similar hypermutator profiles in patients carrying germline deleterious MBD4 mutations and somatic loss of heterozygosity. This MBD4-related hypermutator phenotype may explain unexpected responses to immune checkpoint inhibitors. PMID- 29760387 TI - Publisher Correction: Laser-accelerated particle beams for stress testing of materials. AB - The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 3 in which all panels, with the exception of the bottom-left 'Ti' panel, were blank. The HTML has been updated to include a corrected version of the Supplementary Information. PMID- 29760385 TI - The rise of South-South trade and its effect on global CO2 emissions. AB - Economic globalization and concomitant growth in international trade since the late 1990s have profoundly reorganized global production activities and related CO2 emissions. Here we show trade among developing nations (i.e., South-South trade) has more than doubled between 2004 and 2011, which reflects a new phase of globalization. Some production activities are relocating from China and India to other developing countries, particularly raw materials and intermediate goods production in energy-intensive sectors. In turn, the growth of CO2 emissions embodied in Chinese exports has slowed or reversed, while the emissions embodied in exports from less-developed regions such as Vietnam and Bangladesh have surged. Although China's emissions may be peaking, ever more complex supply chains are distributing energy-intensive industries and their CO2 emissions throughout the global South. This trend may seriously undermine international efforts to reduce global emissions that increasingly rely on rallying voluntary contributions of more, smaller, and less-developed nations. PMID- 29760386 TI - Rapid labelling and covalent inhibition of intracellular native proteins using ligand-directed N-acyl-N-alkyl sulfonamide. AB - Selective modification of native proteins in live cells is one of the central challenges in recent chemical biology. As a unique bioorthogonal approach, ligand directed chemistry recently emerged, but the slow kinetics limits its scope. Here we successfully overcome this obstacle using N-acyl-N-alkyl sulfonamide as a reactive group. Quantitative kinetic analyses reveal that ligand-directed N-acyl N-alkyl sulfonamide chemistry allows for rapid modification of a lysine residue proximal to the ligand binding site of a target protein, with a rate constant of ~104 M-1 s-1, comparable to the fastest bioorthogonal chemistry. Despite some off target reactions, this method can selectively label both intracellular and membrane-bound endogenous proteins. Moreover, the unique reactivity of N-acyl-N alkyl sulfonamide enables the rational design of a lysine-targeted covalent inhibitor that shows durable suppression of the activity of Hsp90 in cancer cells. This work provides possibilities to extend the covalent inhibition approach that is currently being reassessed in drug discovery. PMID- 29760382 TI - Vaccine-elicited receptor-binding site antibodies neutralize two New World hemorrhagic fever arenaviruses. AB - While five arenaviruses cause human hemorrhagic fevers in the Western Hemisphere, only Junin virus (JUNV) has a vaccine. The GP1 subunit of their envelope glycoprotein binds transferrin receptor 1 (TfR1) using a surface that substantially varies in sequence among the viruses. As such, receptor-mimicking antibodies described to date are type-specific and lack the usual breadth associated with this mode of neutralization. Here we isolate, from the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross neutralize Machupo virus with varying efficiency. Structures of GP1-Fab complexes explain the basis for efficient cross-neutralization, which involves avoiding receptor mimicry and targeting a conserved epitope within the receptor-binding site (RBS). The viral RBS, despite its extensive sequence diversity, is therefore a target for cross-reactive antibodies with activity against New World arenaviruses of public health concern. PMID- 29760388 TI - Cell of origin and mutation pattern define three clinically distinct classes of sebaceous carcinoma. AB - Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC (p = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers. PMID- 29760389 TI - Aurora A-dependent CENP-A phosphorylation at inner centromeres protects bioriented chromosomes against cohesion fatigue. AB - Sustained spindle tension applied to sister centromeres during mitosis eventually leads to uncoordinated loss of sister chromatid cohesion, a phenomenon known as "cohesion fatigue." We report that Aurora A-dependent phosphorylation of serine 7 of the centromere histone variant CENP-A (p-CENP-AS7) protects bioriented chromosomes against cohesion fatigue. Expression of a non-phosphorylatable version of CENP-A (CENP-AS7A) weakens sister chromatid cohesion only when sister centromeres are under tension, providing the first evidence of a regulated mechanism involved in protection against passive cohesion loss. Consistent with this observation, p-CENP-AS7 is detected at the inner centromere where it forms a discrete domain. The depletion or inhibition of Aurora A phenocopies the expression of CENP-AS7A and we show that Aurora A is recruited to centromeres in a Bub1-dependent manner. We propose that Aurora A-dependent phosphorylation of CENP-A at the inner centromere protects chromosomes against tension-induced cohesion fatigue until the last kinetochore is attached to spindle microtubules. PMID- 29760391 TI - Asynchronous evolution of interdependent nest characters across the avian phylogeny. AB - Nest building is a widespread behavior among birds that reflects their adaptation to the environment and evolutionary history. However, it remains unclear how nests evolve and how their evolution relates to the bird phylogeny. Here, by examining the evolution of three nest characters-structure, site, and attachment across all bird families, we reveal that nest characters did not change synchronically across the avian phylogeny but had disparate evolutionary trajectories. Nest structure shows stronger phylogenetic signal than nest site, while nest attachment has little variation. Nevertheless, the three characters evolved interdependently. For example, the ability of birds to explore new nest sites might depend on the emergence of novel nest structure and/or attachment. Our results also reveal labile nest characters in passerines compared with other birds. This study provides important insights into avian nest evolution and suggests potential associations between nest diversification and the adaptive radiations that generated modern bird lineages. PMID- 29760393 TI - Tuning of the Hanle effect from EIT to EIA using spatially separated probe and control beams. AB - We demonstrate a technique for continuous tuning of the Hanle effect from electromagnetically induced transparency (EIT) to electromagnetically induced absorption (EIA) by changing the polarization ellipticity of a control beam. In contrast to previous work in this field, we use spatially separated probe and control beams. The experiments are done using magnetic sublevels of the Fg = 4 -> Fe = 5 closed hyperfine transition in the 852 nm D2 line of 133Cs. The atoms are contained in a room temperature vapor cell with anti-relaxation (paraffin) coating on the walls. The paraffin coating is necessary for the atomic coherence to be transported between the beams. The experimental results are supported by a density-matrix analysis of the system, which also explains the observed amplitude and zero-crossing of the resonances. Such continuous tuning of the sign of a resonance has important applications in quantum memory and other precision measurements. PMID- 29760390 TI - Olfactory bulb acetylcholine release dishabituates odor responses and reinstates odor investigation. AB - Habituation and dishabituation modulate the neural resources and behavioral significance allocated to incoming stimuli across the sensory systems. We characterize these processes in the mouse olfactory bulb (OB) and uncover a role for OB acetylcholine (ACh) in physiological and behavioral olfactory dishabituation. We use calcium imaging in both awake and anesthetized mice to determine the time course and magnitude of OB glomerular habituation during a prolonged odor presentation. In addition, we develop a novel behavioral investigation paradigm to determine how prolonged odor input affects odor salience. We find that manipulating OB ACh release during prolonged odor presentations using electrical or optogenetic stimulation rapidly modulates habituated glomerular odor responses and odor salience, causing mice to suddenly investigate a previously ignored odor. To demonstrate the ethological validity of this effect, we show that changing the visual context can lead to dishabituation of odor investigation behavior, which is blocked by cholinergic antagonists in the OB. PMID- 29760394 TI - Controlling evanescent waves using silicon photonic all-dielectric metamaterials for dense integration. AB - Ultra-compact, densely integrated optical components manufactured on a CMOS foundry platform are highly desirable for optical information processing and electronic-photonic co-integration. However, the large spatial extent of evanescent waves arising from nanoscale confinement, ubiquitous in silicon photonic devices, causes significant cross-talk and scattering loss. Here, we demonstrate that anisotropic all-dielectric metamaterials open a new degree of freedom in total internal reflection to shorten the decay length of evanescent waves. We experimentally show the reduction of cross-talk by greater than 30 times and the bending loss by greater than 3 times in densely integrated, ultra compact photonic circuit blocks. Our prototype all-dielectric metamaterial waveguide achieves a low propagation loss of approximately 3.7+/-1.0 dB/cm, comparable to those of silicon strip waveguides. Our approach marks a departure from interference-based confinement as in photonic crystals or slot waveguides, which utilize nanoscale field enhancement. Its ability to suppress evanescent waves without substantially increasing the propagation loss shall pave the way for all-dielectric metamaterial-based dense integration. PMID- 29760396 TI - Correlating Photoluminescence and Structural Properties of Uncapped and GaAs Capped Epitaxial InGaAs Quantum Dots. AB - The understanding of the correlation between structural and photoluminescence (PL) properties of self-assembled semiconductor quantum dots (QDs), particularly InGaAs QDs grown on (001) GaAs substrates, is crucial for both fundamental research and optoelectronic device applications. So far structural and PL properties have been probed from two different epitaxial layers, namely top capped and buried layers respectively. Here, we report for the first time both structural and PL measurements from an uncapped layer of InGaAs QDs to correlate directly composition, strain and shape of QDs with the optical properties. Synchrotron X-ray scattering measurements show migration of In atom from the apex of QDs giving systematic reduction of height and enlargement of QDs base in the capping process. The optical transitions show systematic reduction in the energy of ground state and the first excited state transition lines with increase in capping but the energy of the second excited state line remain unchanged. We also found that the excitons are confined at the base region of these elliptically shaped QDs showing an interesting volume-dependent confinement energy scaling of 0.3 instead of 0.67 expected for spherical dots. The presented method will help us tuning the growth of QDs to achieve desired optical properties. PMID- 29760395 TI - Silver nanoparticles promote the emergence of heterogeneic human neutrophil sub populations. AB - Neutrophil surveillance is central to nanoparticle clearance. Silver nanoparticles (AgNP) have numerous uses, however conflicting evidence exists as to their impact on neutrophils and whether they trigger damaging inflammation. Neutrophil's importance in innate defence and regulating immune networks mean it's essential we understand AgNP's impact on neutrophil function. Human neutrophil viability following AgNP or Ag Bulk treatment was analysed by flow cytometry and AnV/PI staining. Whilst AgNP exposure did not increase the total number of apoptotic neutrophils, the number of late apoptotic neutrophils was increased, suggesting AgNP increase transit through apoptosis. Mature (CD16bright/CD62Lbright), immature (CD16dim/CD62Lbright) and apoptotic (CD16dim/CD62Ldim) neutrophil populations were evident within isolated neutrophil preparations. AgNP exposure significantly reduced CD62L staining of CD16bright/CD62Lbright neutrophils, and increased CD16 staining of CD16dim/CD62Lbright populations, suggesting AgNPs trigger neutrophil activation and maturation, respectively. AgNP exposure dramatically increased IL-8, yet not classical pro-inflammatory cytokine release, suggesting AgNP triggers neutrophil activation, without pro-inflammation or damaging, necrotic cell death. For the first time, we show AgNPs differentially affect distinct sub-populations of circulating human neutrophils; activating mature neutrophils with the emergence of CD16bright/CD62Ldim neutrophils. This may stimulate particle clearance without harmful inflammation, challenging previous assumptions that silver nanomaterials induce neutrophil toxicity and damaging inflammatory responses. PMID- 29760392 TI - Author Correction: Susceptible genes and disease mechanisms identified in frontotemporal dementia and frontotemporal dementia with Amyotrophic Lateral Sclerosis by DNA-methylation and GWAS. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29760397 TI - Automatic anatomical classification of esophagogastroduodenoscopy images using deep convolutional neural networks. AB - The use of convolutional neural networks (CNNs) has dramatically advanced our ability to recognize images with machine learning methods. We aimed to construct a CNN that could recognize the anatomical location of esophagogastroduodenoscopy (EGD) images in an appropriate manner. A CNN-based diagnostic program was constructed based on GoogLeNet architecture, and was trained with 27,335 EGD images that were categorized into four major anatomical locations (larynx, esophagus, stomach and duodenum) and three subsequent sub-classifications for stomach images (upper, middle, and lower regions). The performance of the CNN was evaluated in an independent validation set of 17,081 EGD images by drawing receiver operating characteristics (ROC) curves and calculating the area under the curves (AUCs). ROC curves showed high performance of the trained CNN to classify the anatomical location of EGD images with AUCs of 1.00 for larynx and esophagus images, and 0.99 for stomach and duodenum images. Furthermore, the trained CNN could recognize specific anatomical locations within the stomach, with AUCs of 0.99 for the upper, middle, and lower stomach. In conclusion, the trained CNN showed robust performance in its ability to recognize the anatomical location of EGD images, highlighting its significant potential for future application as a computer-aided EGD diagnostic system. PMID- 29760398 TI - Urban sparrows respond to a sexually selected trait with increased aggression in noise. AB - Animals modify acoustic communication signals in response to noise pollution, but consequences of these modifications are unknown. Vocalizations that transmit best in noise may not be those that best signal male quality, leading to potential conflict between selection pressures. For example, slow paced, narrow bandwidth songs transmit better in noise but are less effective in mate choice and competition than fast paced, wide bandwidth songs. We test the hypothesis that noise affects response to song pace and bandwidth in the context of competition using white-crowned sparrows (Zonotrichia leucophrys). We measure male response to song variation along a gradient of ambient noise levels in San Francisco, CA. We find that males discriminate between wide and narrow bandwidth songs but not between slow and fast paced songs. These findings are biologically relevant because songs in noisy areas tend to have narrow bandwidths. Therefore, this song phenotype potentially increases transmission distance in noise, but elicits weaker responses from competitors. Further, we find that males respond more strongly to stimuli in noisier conditions, supporting the 'urban anger' hypothesis. We suggest that noise affects male responsiveness to song, possibly leading to more territorial conflict in urban areas. PMID- 29760399 TI - Publisher Correction: Non-tuberculous Mycobacteria isolated from Pulmonary samples in sub-Saharan Africa - A Systematic Review and Meta Analyses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29760400 TI - Sex-related differences in vision are heterogeneous. AB - Despite well-established sex differences for cognition, audition, and somatosensation, few studies have investigated whether there are also sex differences in visual perception. We report the results of fifteen perceptual measures (such as visual acuity, visual backward masking, contrast detection threshold or motion detection) for a cohort of over 800 participants. On six of the fifteen tests, males significantly outperformed females. On no test did females significantly outperform males. Given this heterogeneity of the sex effects, it is unlikely that the sex differences are due to any single mechanism. A practical consequence of the results is that it is important to control for sex in vision research, and that findings of sex differences for cognitive measures using visually based tasks should confirm that their results cannot be explained by baseline sex differences in visual perception. PMID- 29760401 TI - Belief state representation in the dopamine system. AB - Learning to predict future outcomes is critical for driving appropriate behaviors. Reinforcement learning (RL) models have successfully accounted for such learning, relying on reward prediction errors (RPEs) signaled by midbrain dopamine neurons. It has been proposed that when sensory data provide only ambiguous information about which state an animal is in, it can predict reward based on a set of probabilities assigned to hypothetical states (called the belief state). Here we examine how dopamine RPEs and subsequent learning are regulated under state uncertainty. Mice are first trained in a task with two potential states defined by different reward amounts. During testing, intermediate-sized rewards are given in rare trials. Dopamine activity is a non monotonic function of reward size, consistent with RL models operating on belief states. Furthermore, the magnitude of dopamine responses quantitatively predicts changes in behavior. These results establish the critical role of state inference in RL. PMID- 29760402 TI - Roles of Enhancer RNAs in RANKL-induced Osteoclast Differentiation Identified by Genome-wide Cap-analysis of Gene Expression using CRISPR/Cas9. AB - Bidirectional transcription has been proposed to play a role associated with enhancer activity. Transcripts called enhancer RNAs (eRNAs) play important roles in gene regulation; however, their roles in osteoclasts are unknown. To analyse eRNAs in osteoclasts comprehensively, we used cap-analysis of gene expression (CAGE) to detect adjacent transcription start sites (TSSs) that were distant from promoters for protein-coding gene expression. When comparing bidirectional TSSs between osteoclast precursors and osteoclasts, we found that bidirectional TSSs were located in the 5'-flanking regions of the Nrp2 and Dcstamp genes. We also detected bidirectional TSSs in the intron region of the Nfatc1 gene. To investigate the role of bidirectional transcription in osteoclasts, we performed loss of function analyses using the CRISPR/Cas9 system. Targeted deletion of the DNA regions between the bidirectional TSSs led to decreased expression of the bidirectional transcripts, as well as the protein-coding RNAs of Nrp2, Dcstamp, and Nfatc1, suggesting that these transcripts act as eRNAs. Furthermore, osteoclast differentiation was impaired by targeted deletion of bidirectional eRNA regions. The combined results show that eRNAs play important roles in osteoclastogenic gene regulation, and may therefore provide novel insights to elucidate the transcriptional mechanisms that control osteoclast differentiation. PMID- 29760403 TI - Correlation between ultrasound-diagnosed non-alcoholic fatty liver and periodontal condition in a cross-sectional study in Japan. AB - This cross-sectional study investigated the relationship between periodontal condition and ultrasound-diagnosed non-alcoholic fatty liver disease (NAFLD) in a Japanese oral health check population. A total of 1226 consecutive participant were enrolled in the study. Abdominal ultrasonography was applied to diagnose NAFLD. Of the study participants, 339 (27.7%) had ultrasonography-diagnosed NAFLD. The participants with NAFLD had a significantly higher prevalence of probing pocket depth (PPD) >= 4 mm (86.7%) than those without NAFLD (72.9%) (p < 0.05). After adjusting for gender, age, Brinkman index, regular exercise habits, body mass index, number of teeth present, presence of periodontitis, blood pressure, and serum parameters, there was a statistically significant difference in the adjusted odds ratios of having PPD >= 4 mm for NAFLD (Odds ratio = 1.881, 95% confidence interval 1.184-2.987, p < 0.01). Having PPD >= 4 mm may be a risk factor for ultrasound-diagnosed NAFLD in this cross-sectional study of a Japanese oral health check population. PMID- 29760404 TI - Indirect excitons in van der Waals heterostructures at room temperature. AB - Indirect excitons (IXs) are explored both for studying quantum Bose gases in semiconductor materials and for the development of excitonic devices. IXs were extensively studied in III-V and II-VI semiconductor heterostructures where IX range of existence has been limited to low temperatures. Here, we present the observation of IXs at room temperature in van der Waals transition metal dichalcogenide (TMD) heterostructures. This is achieved in TMD heterostructures based on monolayers of MoS2 separated by atomically thin hexagonal boron nitride. The IXs we realize in the TMD heterostructure have lifetimes orders of magnitude longer than lifetimes of direct excitons in single-layer TMD and their energy is gate controlled. The realization of IXs at room temperature establishes the TMD heterostructures as a material platform both for a field of high-temperature quantum Bose gases of IXs and for a field of high-temperature excitonic devices. PMID- 29760405 TI - ARID1A mutation sensitizes most ovarian clear cell carcinomas to BET inhibitors. AB - Current treatment for advanced stage ovarian clear cell cancer is severely hampered by a lack of effective systemic therapy options, leading to a poor outlook for these patients. Sequencing studies revealed that ARID1A is mutated in over 50% of ovarian clear cell carcinomas. To search for a rational approach to target ovarian clear cell cancers with ARID1A mutations, we performed kinome centered lethality screens in a large panel of ovarian clear cell carcinoma cell lines. Using the largest OCCC cell line panel established to date, we show here that BRD2 inhibition is predominantly lethal in ARID1A mutated ovarian clear cell cancer cells. Importantly, small molecule inhibitors of the BET (bromodomain and extra terminal domain) family of proteins, to which BRD2 belongs, specifically inhibit proliferation of ARID1A mutated cell lines, both in vitro and in ovarian clear cell cancer xenografts and patient-derived xenograft models. BET inhibitors cause a reduction in the expression of multiple SWI/SNF members including ARID1B, providing a potential explanation for the observed lethal interaction with ARID1A loss. Our data indicate that BET inhibition may represent a novel treatment strategy for a subset of ARID1A mutated ovarian clear cell carcinomas. PMID- 29760407 TI - Comparison of intensity, phase retardation, and local birefringence images for filtering blebs using polarization-sensitive optical coherence tomography. AB - Polarization-sensitive optical coherence tomography (PS-OCT) allows the recording of depth-resolved polarimetric measurements. It has been reported that phase retardation and local birefringence images can noninvasively detect fibrotic area in blebs after glaucoma surgery. Evaluation of scar fibrosis in blebs is important not only for predicting bleb function, but also for planning revision trabeculectomy. Herein, we characterize the intensity, phase retardation, and local birefringence images of blebs using PS-OCT. A total of 85 blebs from 85 patients who had undergone trabeculectomy were examined. Both phase retardation and local birefringence images detected fibrotic changes in blebs after glaucoma surgery. Phase retardation images detected slight fibrotic change during the early stage after surgery, whereas local birefringence images showed localized fibrotic tissue. There are two main patterns of local birefringence image changes in blebs: plate-like birefringence changes and diffuse changes. The area of plate like birefringence change was significantly larger in poorly functioning blebs and is thus correlated with bleb function. These data suggest that the plate-like fibrotic change evaluation by PS-OCT may be useful not only for noninvasive evaluation of fibrotic scar tissue in blebs, but also for developing strategies for revision trabeculectomy. PMID- 29760408 TI - Electron Information in Single- and Dual-Frequency Capacitive Discharges at Atmospheric Pressure. AB - Determining the electron properties of weakly ionized gases, particularly in a high electron-neutral collisional condition, is a nontrivial task; thus, the mechanisms underlying the electron characteristics and electron heating structure in radio-frequency (rf) collisional discharges remain unclear. Here, we report the electrical characteristics and electron information in single-frequency (4.52 MHz and 13.56 MHz) and dual-frequency (a combination of 4.52 MHz and 13.56 MHz) capacitive discharges within the abnormal alpha-mode regime at atmospheric pressure. A continuum radiation-based electron diagnostic method is employed to estimate the electron density (ne) and temperature (Te). Our experimental observations reveal that time-averaged ne (7.7-14 * 1011 cm-3) and Te (1.75-2.5 eV) can be independently controlled in dual-frequency discharge, whereas such control is nontrivial in single-frequency discharge, which shows a linear increase in ne and little to no change in Te with increases in the rf input power. Furthermore, the two-dimensional spatiotemporal evolution of neutral bremsstrahlung and associated electron heating structures is demonstrated. These results reveal that a symmetric structure in electron heating becomes asymmetric (via a local suppression of electron temperature) as two-frequency power is simultaneously introduced. PMID- 29760406 TI - LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling. AB - ABSTACT: Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistically, PVT1 binds with KLF5 and increases its stability via BAP1, which upregulates beta-catenin signaling, resulting in enhanced TNBC tumorigenesis. PVT1, KLF5, and beta-catenin were also revealed to be co-expressed in clinical TNBC samples. Our findings uncover a new singaling pathway to mediate TNBC, and provide PVT1 as a new target for improving treatment of TNBC. PMID- 29760409 TI - Histone deacetylase inhibitor MS-275 restores social and synaptic function in a Shank3-deficient mouse model of autism. AB - Autism is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors. Genetic screening has identified synaptic, transcriptional, and chromatin genes disrupted in autistic patients. Haploinsufficiency of Shank3, which encodes a scaffold protein at glutamatergic synapses, is causally linked to autism. Using a Shank3-deficient mouse model that exhibits prominent autism-like phenotypes, we have found that histone acetylation in the prefrontal cortex (PFC) is abnormally low, which can be reversed by MS-275 (also known as Entinostat, SNDX-275), a class I histone deacetylase (HDAC) inhibitor that is selectively potent in PFC. A brief (3-day) treatment with MS-275 (i.p.) led to the sustained (11 days) rescue of autistic social preference deficits in Shank3-deficient mice, without altering locomotion, motor coordination, anxiety, or the increased grooming. MS-275 treatment also rescued the diminished NMDAR surface expression and NMDAR function induced by Shank3 deficiency. Moreover, F-actin at synapses was restored and the transcription of actin regulators was elevated by MS-275 treatment of Shank3-deficient mice, which may contribute to the recovery of actin based NMDAR synaptic delivery. Taken together, these results suggest that MS-275 treatment could normalize the aberrant epigenetic regulation of genes, leading to the amelioration of synaptic and social deficits associated with autism. PMID- 29760410 TI - Motivational changes that develop in a mouse model of inflammation-induced depression are independent of indoleamine 2,3 dioxygenase. AB - Despite years of research, our understanding of the mechanisms by which inflammation induces depression is still limited. As clinical data points to a strong association between depression and motivational alterations, we sought to (1) characterize the motivational changes that are associated with inflammation in mice, and (2) determine if they depend on inflammation-induced activation of indoleamine 2,3 dioxygenase-1 (IDO1). Lipopolysaccharide (LPS)-treated or spared nerve injured (SNI) wild type (WT) and Ido1-/- mice underwent behavioral tests of antidepressant activity (e.g., forced swim test) and motivated behavior, including assessment of (1) reward expectancy using a food-related anticipatory activity task, (2) willingness to work for reward using a progressive ratio schedule of food reinforcement, (3) effort allocation using a concurrent choice task, and (4) ability to associate environmental cues with reward using conditioned place preference. LPS- and SNI-induced deficits in behavioral tests of antidepressant activity in WT but not Ido1-/- mice. Further, LPS decreased food related-anticipatory activity, reduced performance in the progressive ratio task, and shifted effort toward the preferred reward in the concurrent choice task. These effects were observed in both WT and Ido1-/- mice. Finally, SNI mice developed a conditioned place preference based on relief from pain in an IDO1 independent manner. These findings demonstrate that the motivational effects of inflammation do not require IDO1. Further, they indicate that the motivational component of inflammation-induced depression is mechanistically distinct from that measured by behavioral tests of antidepressant activity. PMID- 29760411 TI - Paenialvin A-D, four peptide antibiotics produced by Paenibacillus alvei DSM 29. AB - Four peptide antibiotics, named paenialvin A-D, were isolated from Paenibacillus alvei DSM 29. Mass spectrum analysis determined the molecular masses of paenialvin A-D to be 1891, 1875, 1877, and 1923 Da, respectively. Tandem mass spectra and nuclear magnetic resonance (NMR) were used to elucidate their chemical structures. Paenialvin A-D showed antimicrobial activity against most strains that were tested, including methicillin-resistant Staphalococcus aureus, Staphylococcus aureus, Bacillus subtilis, Loktanella hongkongensis, Escherichia coli, and Pseudomonas aeruginosa. In particular, the minimum inhibitory concentration of paenialvins against Staphalococcus aureus reached 0.8-3.2 MUg/mL. Although they were cytotoxic against HeLa cells at a concentration of 50 MUg/mL, the lack of hemolysis by paenialvins confirmed that they are potential candidates for anti-tumor drugs. PMID- 29760412 TI - A paradox of epidemics between the state and parameter spaces. AB - It is recently revealed from amounts of real data of recurrent epidemics that there is a phenomenon of hysteresis loop in the state space. To understand it, an indirect investigation from the parameter space has been given to qualitatively explain its mechanism but a more convincing study to quantitatively explain the phenomenon directly from the state space is still missing. We here study this phenomenon directly from the state space and find that there is a positive correlation between the size of outbreak and the size of hysteresis loop, implying that the hysteresis is a nature feature of epidemic outbreak in real case. Moreover, we surprisingly find a paradox on the dependence of the size of hysteresis loop on the two parameters of the infectious rate increment and the transient time, i.e. contradictory behaviors between the two spaces, when the evolutionary time of epidemics is long enough. That is, with the increase of the infectious rate increment, the size of hysteresis loop will decrease in the state space but increase in the parameter space. While with the increase of the transient time, the size of hysteresis loop will increase in the state space but decrease in the parameter space. Furthermore, we find that this paradox will disappear when the evolutionary time of epidemics is limited in a fixed period. Some theoretical analysis are presented to both the paradox and other numerical results. PMID- 29760413 TI - Enrichment-triggered prodrug activation demonstrated through mitochondria targeted delivery of doxorubicin and carbon monoxide. AB - Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two 'click and release' systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer. PMID- 29760414 TI - Fragment-derived inhibitors of human N-myristoyltransferase block capsid assembly and replication of the common cold virus. AB - Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections. PMID- 29760416 TI - Author Correction: Interface-induced spontaneous positive and conventional negative exchange bias effects in bilayer La0.7Sr0.3MnO3/Eu0.45 Sr0.55 MnO3 heterostructures. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760415 TI - RBM24 stabilizes hepatitis B virus pregenomic RNA but inhibits core protein translation by targeting the terminal redundancy sequence. AB - The terminal redundancy (TR) sequence of the 3.5-kb hepatitis B virus (HBV) RNA contains sites that govern many crucial functions in the viral life cycle, including polyadenylation, translation, RNA packaging, and DNA synthesis. In the present study, RNA-binding motif protein 24 (RBM24) is shown to be involved in the modulation of HBV replication by targeting the TR of HBV RNA. In HBV transfected hepatoma cell lines, both knockdown and overexpression of RBM24 led to decreased HBV replication and transcription. Ectopic expression of RBM24 inhibited HBV replication, which was partly restored by knockdown of RBM24, indicating that a proper level of RBM24 was required for HBV replication. The regulation of RBM24 of HBV replication and translation was achieved by the interaction between the RNA-binding domains of RBM24 and both the 5' and 3' TR of 3.5-kb RNA. RBM24 interacted with the 5' TR of HBV pregenomic RNA (pgRNA) to block 80S ribosome assembly on HBV pgRNA and thus inhibited core protein translation, whereas the interaction between RBM24 and the 3' TR enhanced the stability of HBV RNA. Finally, the regulatory function of RBM24 on HBV replication was further confirmed in a HBV infection model. In conclusion, the present study demonstrates the dual functions of RBM24 by interacting with different TRs of viral RNA and reveals that RBM24 is an important host gene for HBV replication. PMID- 29760418 TI - Silicon-chip-based mid-infrared dual-comb spectroscopy. AB - The development of a spectroscopy device on a chip that could realize real-time fingerprinting with label-free and high-throughput detection of trace molecules represents one of the big challenges in sensing. Dual-comb spectroscopy (DCS) in the mid-infrared is a powerful technique offering high acquisition rates and signal-to-noise ratios through use of only a single detector with no moving parts. Here, we present a nanophotonic silicon-on-insulator platform designed for mid-infrared (mid-IR) DCS. A single continuous-wave low-power pump source generates two mutually coherent mode-locked frequency combs spanning from 2.6 to 4.1 MUm in two silicon microresonators. A proof-of-principle experiment of vibrational absorption DCS in the liquid phase is achieved acquiring spectra of acetone spanning from 2900 to 3100 nm at 127-GHz (4.2-cm-1) resolution. These results represent a significant step towards a broadband, mid-IR spectroscopy instrument on a chip for liquid/condensed matter phase studies. PMID- 29760417 TI - NDRG3 lowers the metastatic potential in prostate cancer as a feedback controller of hypoxia-inducible factors. AB - Expression of hypoxia-inducible factors (HIFs) and N-myc downstream-regulated gene 3 (NDRG3) are oxygen-dependently regulated by prolyl hydroxylase domain (PHD) enzymes. Little is known about the role of NDRG3 in the cellular adaptation to hypoxia, whereas the roles of HIFs are well understood. In this study, we investigated how NDRG3 affects the hypoxic response in prostate cancer cells. Compared with HIF-1alpha, hypoxic induction of NDRG3 was observed at a later phase. NDRG3 reduced hypoxic expression of HIF-1alpha by inhibiting AKT-driven translation of HIF1A mRNA. In addition, NDRG3 functionally inhibited HIF-1 by dissociating the coactivator p300 from HIF-1alpha. Accordingly, NDRG3 may fine tune the HIF-1 signaling pathway to cope with long-term hypoxia. Of the diverse effects of HIF-1alpha on cancer progression, hypoxia-induced cell migration was investigated. In transwell chambers, NDRG3 negatively regulated the migration and invasion of prostate cancer cells under hypoxia. An informatics analysis using Gene Expression Omnibus (GEO) revealed that NDRG3 downregulation is associated with prostate cancer metastasis and high expression of HIF-1 downstream genes. In cancer tissue arrays, NDRG3 expression was lower in prostate cancer tissues with a Gleason score of 8 or greater and was inversely correlated with HIF-1alpha expression. Therefore, NDRG3 may have an anti-metastatic function in prostate cancer under a hypoxic microenvironment. PMID- 29760419 TI - PLGA nanoparticles co-delivering MDR1 and BCL2 siRNA for overcoming resistance of paclitaxel and cisplatin in recurrent or advanced ovarian cancer. AB - The inherent or acquired resistance to paclitaxel and cisplatin, which are commonly used chemotherapeutic agents for ovarian cancer treatment, remains an important issue in chemotherapy of multidrug resistant ovarian cancer. Currently, it is still challenging to deal with the recurrent or advanced stage ovarian cancer. When drug efflux and anti-apoptotic pathways are highly interdependent and also involved in developing the resistance of multidrug resistant ovarian cancer, simultaneous inhibition of both pathways represents the potential targets to enhance the efficacy of chemotherapy. Here, we introduce PLGA nanoparticles system as a "dual RNAi delivery system" to contain both MDR1 and BCL2 siRNA, which is designed for simultaneous inhibition of drug efflux and cell death defense pathways. In the present studies, siRNA-loaded PLGA nanoparticles efficiently elicit the simultaneous suppression of both genes, which consequently shows more enhanced drug-sensitivity than sole suppression of drug efflux or anti apoptosis in the resistant ovarian cancer cells, owing to the interdependence of both pathways. Our siRNA-loaded PLGA nanoparticles for co-delivering MDR1 and BCL2 siRNA provide an efficient combination therapy strategy to overcome the chemoresistance of paclitaxel and cisplatin on the paclitaxel-resistant SKOV3-TR and cisplatin-resistant A2780-CP20 ovarian cancer respectively. PMID- 29760420 TI - Engineering modular intracellular protein sensor-actuator devices. AB - Understanding and reshaping cellular behaviors with synthetic gene networks requires the ability to sense and respond to changes in the intracellular environment. Intracellular proteins are involved in almost all cellular processes, and thus can provide important information about changes in cellular conditions such as infections, mutations, or disease states. Here we report the design of a modular platform for intrabody-based protein sensing-actuation devices with transcriptional output triggered by detection of intracellular proteins in mammalian cells. We demonstrate reporter activation response (fluorescence, apoptotic gene) to proteins involved in hepatitis C virus (HCV) infection, human immunodeficiency virus (HIV) infection, and Huntington's disease, and show sensor-based interference with HIV-1 downregulation of HLA-I in infected T cells. Our method provides a means to link varying cellular conditions with robust control of cellular behavior for scientific and therapeutic applications. PMID- 29760423 TI - Simultaneous Amelioratation of Colitis and Liver Injury in Mice by Bifidobacterium longum LC67 and Lactobacillus plantarum LC27. AB - Disturbances in the gut microbiota composition are associated with chronic inflammatory diseases of the intestine and the liver. In a preliminary study, Lactobacillus plantarum LC27 and Bifidobacterium longum LC67 could inhibit Escherichia coli growth and lipopolysaccharide-induced NF-kappaB activation linked to gut inflammation. Here, we investigated their effects on 2,4,6 trinitrobenzesulfonic acid (TNBS)-induced colitis and liver damage in mice. First, oral administration of LC27 or LC67 (1 * 109 CFU/mouse) inhibited TNBS induced colon shortening [F(5,30) = 100.66, P < 0.05] and myeloperoxidase activity [F(5,30) = 56.48, P < 0.05]. These probiotics restored TNBS-induced disturbance of gut microbiota, leading to the suppression of Proteobacteria to Bacteroidetes ratio and fecal and blood lipopolysaccharide levels. Second, LC27 and LC67 inhibited TNBS-induced NF-kappaB activation, reversed TNBS-suppressed tight junction protein expression, and restored Th17/Treg balance. Also, treatment with LC27 or LC67 significantly decreased TNBS-induced alanine transaminase [ALT, F(5,30) = 3.50, P < 0.05] and aspartate transaminase [AST, F(5,30) = 12.81, P < 0.05] levels in the blood, as well as t-butylhydroperoxide induced ALT and AST levels. Finally, the mixture of LC27 and LC67 (0.5 * 109 CFU/mouse, respectively) synergistically attenuated TNBS- or t-butylhydroperoxide induced colitis and liver damage. The capability of LC27 and LC67 to reverse TNBS mediated microbiota shift and damage signals suggests that these probiotics may synergistically attenuate colitis and liver injury by alleviating gut microbiota imbalance. PMID- 29760425 TI - The Spinal Cord Ability Ruler (SCAR): combining aspects of two widely-used outcome measures into one. PMID- 29760422 TI - Sculpting and fusing biomimetic vesicle networks using optical tweezers. AB - Constructing higher-order vesicle assemblies has discipline-spanning potential from responsive soft-matter materials to artificial cell networks in synthetic biology. This potential is ultimately derived from the ability to compartmentalise and order chemical species in space. To unlock such applications, spatial organisation of vesicles in relation to one another must be controlled, and techniques to deliver cargo to compartments developed. Herein, we use optical tweezers to assemble, reconfigure and dismantle networks of cell sized vesicles that, in different experimental scenarios, we engineer to exhibit several interesting properties. Vesicles are connected through double-bilayer junctions formed via electrostatically controlled adhesion. Chemically distinct vesicles are linked across length scales, from several nanometres to hundreds of micrometres, by axon-like tethers. In the former regime, patterning membranes with proteins and nanoparticles facilitates material exchange between compartments and enables laser-triggered vesicle merging. This allows us to mix and dilute content, and to initiate protein expression by delivering biomolecular reaction components. PMID- 29760426 TI - Author Correction: Grain and starch granule morphology in superior and inferior kernels of maize in response to nitrogen. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29760421 TI - Roadblocks and resolutions in eukaryotic translation. AB - During protein synthesis, ribosomes encounter many roadblocks, the outcomes of which are largely determined by substrate availability, amino acid features and reaction kinetics. Prolonged ribosome stalling is likely to be resolved by ribosome rescue or quality control pathways, whereas shorter stalling is likely to be resolved by ongoing productive translation. How ribosome function is affected by such hindrances can therefore have a profound impact on the translational output (yield) of a particular mRNA. In this Review, we focus on these roadblocks and the resumption of normal translation elongation rather than on alternative fates wherein the stalled ribosome triggers degradation of the mRNA and the incomplete protein product. We discuss the fundamental stages of the translation process in eukaryotes, from elongation through ribosome recycling, with particular attention to recent discoveries of the complexity of the genetic code and regulatory elements that control gene expression, including ribosome stalling during elongation, the role of mRNA context in translation termination and mechanisms of ribosome rescue that resemble recycling. PMID- 29760424 TI - Parental haplotype-specific single-cell transcriptomics reveal incomplete epigenetic reprogramming in human female germ cells. AB - In contrast to mouse, human female germ cells develop asynchronously. Germ cells transition to meiosis, erase genomic imprints, and reactivate the X chromosome. It is unknown if these events all appear asynchronously, and how they relate to each other. Here we combine exome sequencing of human fetal and maternal tissues with single-cell RNA-sequencing of five donors. We reconstruct full parental haplotypes and quantify changes in parental allele-specific expression, genome wide. First we distinguish primordial germ cells (PGC), pre-meiotic, and meiotic transcriptional stages. Next we demonstrate that germ cells from various stages monoallelically express imprinted genes and confirm this by methylation patterns. Finally, we show that roughly 30% of the PGCs are still reactivating their inactive X chromosome and that this is related to transcriptional stage rather than fetal age. Altogether, we uncover the complexity and cell-to-cell heterogeneity of transcriptional and epigenetic remodeling in female human germ cells. PMID- 29760427 TI - Author Correction: Zika Virus in Salivary Glands of Five Different Species of Wild-Caught Mosquitoes from Mexico. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760430 TI - Physical mechanism of spring and early summer drought over North America associated with the boreal warming. AB - Drought during the early vegetation growing season (spring through early summer) is a severe natural hazard in the large cropland over North America. Given the recent increasing severity of climate change manifested as surface warming, there has been a growing interest in how warming affects drought and the prospect of drought. Here we show the impact of boreal warming on the spring and early summer drought over North America using Cyclostationary Empirical Orthogonal Function analysis. Northern Hemispheric warming, the leading mode of the surface air temperature variability, has led to a decrease in precipitation, evaporation and moisture transport over the central plain of North America. From a quantitative assessment of atmospheric water budget, precipitation has decreased more than evaporation and moisture transport, resulting in increased (decreased) moisture in the lower troposphere (land surface). Despite the increased moisture content, relative humidity has decreased due to the increased saturation specific humidity arising from the lower-tropospheric warming. The anomaly patterns of the soil moisture and Palmer Drought Severity Index resemble that of the anomalous relative humidity. Results of the present study suggest a credible insight that drought in the main cropland will intensify if the anthropogenic warming continues, exacerbating vulnerability of drought. PMID- 29760428 TI - Generation and characterisation of a parkin-Pacrg knockout mouse line and a Pacrg knockout mouse line. AB - Mutations in PARK2 (parkin) can result in Parkinson's disease (PD). Parkin shares a bidirectional promoter with parkin coregulated gene (PACRG) and the transcriptional start sites are separated by only ~200 bp. Bidirectionally regulated genes have been shown to function in common biological pathways. Mice lacking parkin have largely failed to recapitulate the dopaminergic neuronal loss and movement impairments seen in individuals with parkin-mediated PD. We aimed to investigate the function of PACRG and test the hypothesis that parkin and PACRG function in a common pathway by generating and characterizing two novel knockout mouse lines harbouring loss of both parkin and Pacrg or Pacrg alone. Successful modification of the targeted allele was confirmed at the genomic, transcriptional and steady state protein levels for both genes. At 18-20 months of age, there were no significant differences in the behaviour of parental and mutant lines when assessed by openfield, rotarod and balance beam. Subsequent neuropathological examination suggested there was no gross abnormality of the dopaminergic system in the substantia nigra and no significant difference in the number of dopaminergic neurons in either knockout model compared to wildtype mice. PMID- 29760431 TI - Evidence that UBASH3 is a causal gene for type 1 diabetes. PMID- 29760429 TI - Novel canine circovirus strains from Thailand: Evidence for genetic recombination. AB - Canine circoviruses (CanineCV's), belonging to the genus Circovirus of the Circoviridae family, were detected by next generation sequencing in samples from Thai dogs with respiratory symptoms. Genetic characterization and phylogenetic analysis of nearly complete CanineCV genomes suggested that natural recombination had occurred among different lineages of CanineCV's. Similarity plot and bootscaning analyses indicated that American and Chinese viruses had served as major and minor parental viruses, respectively. Positions of recombination breakpoints were estimated using maximum-likelihood frameworks with statistical significant testing. The putative recombination event was located in the Replicase gene, intersecting with open reading frame-3. Analysis of nucleotide changes confirmed the origin of the recombination event. This is the first description of naturally occurring recombinant CanineCV's that have resulted in the circulation of newly emerging CanineCV lineages. PMID- 29760432 TI - Microcephaly, short stature, and limb abnormality disorder due to novel autosomal biallelic DONSON mutations in two German siblings. AB - Recently, variants in DONSON have been reported to cause different disorders of the microcephalic primordial dwarfism spectrum. Using whole-exome sequencing, we identified two novel, compound heterozygous DONSON variants in a pair of siblings, one of whom was previously diagnosed with Fanconi anemia. This occurred because the present cases exhibited clinical findings in addition to those of the microcephalic primordial dwarfism disorder, including severe limb malformations. These findings suggest that the DONSON and Fanconi anemia proteins could have supplementary roles in developmental processes as they have in the maintenance of genomic integrity, resulting in related disease phenotypes. PMID- 29760434 TI - Multimerized IgG1 Fc molecule as an anti-inflammatory agent. PMID- 29760435 TI - Biomarkers as drug development tools: discovery, validation, qualification and use. AB - The 21st Century Cures Act, approved in the USA in December 2016, has encouraged the establishment of the national Precision Medicine Initiative and the augmentation of efforts to address disease prevention, diagnosis and treatment on the basis of a molecular understanding of disease. The Act adopts into law the formal process, developed by the FDA, of qualification of drug development tools, including biomarkers and clinical outcome assessments, to increase the efficiency of clinical trials and encourage an era of molecular medicine. The FDA and European Medicines Agency (EMA) have developed similar processes for the qualification of biomarkers intended for use as companion diagnostics or for development and regulatory approval of a drug or therapeutic. Biomarkers that are used exclusively for the diagnosis, monitoring or stratification of patients in clinical trials are not subject to regulatory approval, although their qualification can facilitate the conduct of a trial. In this Review, the salient features of biomarker discovery, analytical validation, clinical qualification and utilization are described in order to provide an understanding of the process of biomarker development and, through this understanding, convey an appreciation of their potential advantages and limitations. PMID- 29760436 TI - Fyn-ding a target for OA therapy. PMID- 29760433 TI - Diagnostic value of ultrasound features and sex of fetuses in female patients with papillary thyroid microcarcinoma. AB - Little work has been done on the prediction of papillary thyroid microcarcinoma in female patients who have given birth to children, which may be different from other people. We performed a retrospective review of female patients who underwent thyroidectomy, aiming at identifying special predictors of papillary thyroid microcarcinoma in female patients who have given birth to children. Univariate analysis was used to identify potential covariates for the prediction of papillary thyroid microcarcinoma. Multivariable logistic regression analysis was used to identify independent predictors and construct a regression model based on a training cohort (246 patients) and then the regression model was validated using an independent cohort (80 patients). We found that having not more than one boy, taller-than-wide shape, poorly defined margin, marked hypoechogenicity, and microcalcification were independent risk factors for the papillary thyroid microcarcinoma in multivariate analyses. The combined predictive formula had a high predictive effect for papillary thyroid microcarcinoma (AUC = 0.938 for training cohort and 0.929 for validation cohort, respectively). The combined predictive formula has clinical value in the prognosis of papillary thyroid microcarcinoma and it may be simple and effective to ask fertility condition of patients to increase the US diagnosis accuracy of papillary thyroid microcarcinoma. PMID- 29760439 TI - The Nagoya Protocol could backfire on the Global South. PMID- 29760437 TI - CD82 hypomethylation is essential for tuberculosis pathogenesis via regulation of RUNX1-Rab5/22. AB - The tumor suppressor gene CD82/KAI1 is a member of the tetraspanin superfamily and organizes various membrane-based processes. Mycobacterium tuberculosis (MTB) persists in host macrophages by interfering with phagolysosome biogenesis and inflammatory responses, but the role of CD82 in controlling the intracellular survival of pathogenic mycobacteria within macrophages remains poorly understood. In this study, we demonstrated that the virulent MTB strain H37Rv (MTB Rv) induced CD82 promoter hypomethylation, resulting in CD82 expression. Targeting of the runt-related transcription factor 1 (RUNX1) by CD82 is essential for phagosome arrest via interacting with Rab5/22. This arrest is required for the intracellular growth of MTB in vitro and in vivo, but not for that of MTB H37Ra (MTB Ra) in macrophages. In addition, knockdown or knockout of CD82 or RUNX1 increased antibacterial host defense via phagolysosome biogenesis, inflammatory cytokine production, and subsequent antimicrobial activity both in vitro and in vivo. Notably, the levels of CD82 and RUNX1 in granulomas were elevated in tuberculosis (TB) patients, indicating that CD82 and RUNX1 have clinical significance in human TB. Our findings identify a previously unrecognized role of CD82 hypomethylation in the regulation of phagosome maturation, enhanced intracellular survival, and the innate host immune response to MTB. Thus, the CD82-RUNX1-Rab5/22 axis may be a previously unrecognized virulence mechanism of MTB pathogenesis. PMID- 29760440 TI - Plant spectral diversity integrates functional and phylogenetic components of biodiversity and predicts ecosystem function. AB - Biodiversity promotes ecosystem function as a consequence of functional differences among organisms that enable resource partitioning and facilitation. As the need for biodiversity assessments increases in the face of accelerated global change, novel approaches that are rapid, repeatable and scalable are critical, especially in ecosystems for which information about species identity and the number of species is difficult to acquire. Here, we present 'spectral diversity'-a spectroscopic index of the variability of electromagnetic radiation reflected from plants measured in the visible, near-infrared and short-wave infrared regions (400-2,400 nm). Using data collected from the Cedar Creek biodiversity experiment (Minnesota, USA), we provide evidence that the dissimilarity of species' leaf spectra increases with functional dissimilarity and evolutionary divergence time. Spectral diversity at the leaf level explains 51% of total variation in productivity-a proportion comparable to taxonomic (47%), functional (51%) or phylogenetic diversity (48%)-and performs similarly when calculated from high-resolution canopy image spectra. Spectral diversity is an emerging dimension of plant biodiversity that integrates trait variation within and across species even in the absence of taxonomic, functional, phylogenetic or abundance information, and has the potential to transform biodiversity assessment because of its scalability to remote sensing. PMID- 29760441 TI - Origin and maintenance of chemical diversity in a species-rich tropical tree lineage. AB - Plant secondary metabolites play important ecological and evolutionary roles, most notably in the deterrence of natural enemies. The classical theory explaining the evolution of plant chemical diversity is that new defences arise through a pairwise co-evolutionary arms race between plants and their specialized natural enemies. However, plant species are bombarded by dozens of different herbivore taxa from disparate phylogenetic lineages that span a wide range of feeding strategies and have distinctive physiological constraints that interact differently with particular plant metabolites. How do plant defence chemicals evolve under such multiple and potentially contrasting selective pressures imposed by diverse herbivore communities? To tackle this question, we exhaustively characterized the chemical diversity and insect herbivore fauna from 31 sympatric species of Amazonian Protieae (Burseraceae) trees. Using a combination of phylogenetic, metabolomic and statistical learning tools, we show that secondary metabolites that were associated with repelling herbivores (1) were more frequent across the Protieae phylogeny and (2) were found in average higher abundance than other compounds. Our findings suggest that generalist herbivores can play an important role in shaping plant chemical diversity and support the hypothesis that chemical diversity can also arise from the cumulative outcome of multiple diffuse interactions. PMID- 29760438 TI - Structural basis of actin monomer re-charging by cyclase-associated protein. AB - Actin polymerization powers key cellular processes, including motility, morphogenesis, and endocytosis. The actin turnover cycle depends critically on "re-charging" of ADP-actin monomers with ATP, but whether this reaction requires dedicated proteins in cells, and the underlying mechanism, have remained elusive. Here we report that nucleotide exchange catalyzed by the ubiquitous cytoskeletal regulator cyclase-associated protein (CAP) is critical for actin-based processes in vivo. We determine the structure of the CAP-actin complex, which reveals that nucleotide exchange occurs in a compact, sandwich-like complex formed between the dimeric actin-binding domain of CAP and two ADP-actin monomers. In the crystal structure, the C-terminal tail of CAP associates with the nucleotide-sensing region of actin, and this interaction is required for rapid re-charging of actin by both yeast and mammalian CAPs. These data uncover the conserved structural basis and biological role of protein-catalyzed re-charging of actin monomers. PMID- 29760443 TI - Stepwise heating in Stille polycondensation toward no batch-to-batch variations in polymer solar cell performance. AB - For a given pi-conjugated polymer, the batch-to-batch variations in molecular weight (Mw) and polydispersity index (D) can lead to inconsistent process dependent material properties and consequent performance variations in the device application. Using a stepwise-heating protocol in the Stille polycondensation in conjunction with optimized processing, we obtained an ultrahigh-quality PTB7 polymer having high Mw and very narrow D. The resulting ultrahigh-quality polymer based solar cells demonstrate up to 9.97% power conversion efficiencies (PCEs), which is over 24% enhancement from the control devices fabricated with commercially available PTB7. Moreover, we observe almost negligible batch-to batch variations in the overall PCE values from ultrahigh-quality polymer-based devices. The proposed stepwise polymerization demonstrates a facile and effective strategy for synthesizing high-quality semiconducting polymers that can significantly improve device yield in polymer-based solar cells, an important factor for the commercialization of organic solar cells, by mitigating device-to device variations. PMID- 29760444 TI - Minerals in the pre-settled coral Stylophora pistillata crystallize via protein and ion changes. AB - Aragonite skeletons in corals are key contributors to the storage of atmospheric CO2 worldwide. Hence, understanding coral biomineralization/calcification processes is crucial for evaluating and predicting the effect of environmental factors on this process. While coral biomineralization studies have focused on adult corals, the exact stage at which corals initiate mineralization remains enigmatic. Here, we show that minerals are first precipitated as amorphous calcium carbonate and small aragonite crystallites, in the pre-settled larva, which then evolve into the more mature aragonitic fibers characteristic of the stony coral skeleton. The process is accompanied by modulation of proteins and ions within these minerals. These findings may indicate an underlying bimodal regulation tactic adopted by the animal, with important ramification to its resilience or vulnerability toward a changing environment. PMID- 29760447 TI - The role of platelets in acute kidney injury. AB - Acute kidney injury (AKI), a major public health problem associated with high mortality and increased risk of progression towards end-stage renal disease, is characterized by the activation of intra-renal haemostatic and inflammatory processes. Platelets, which are present in high numbers in the circulation and can rapidly release a broad spectrum of bioactive mediators, are important acute modulators of inflammation and haemostasis, as they are the first cells to arrive at sites of acute injury, where they interact with endothelial cells and leukocytes. Diminished control of platelet reactivity by endothelial cells and/or an increased release of platelet-activating mediators can lead to uncontrolled platelet activation in AKI. As increased platelet sequestration and increased expression levels of the markers P-selectin, thromboxane A2, CC-chemokine ligand 5 and platelet factor 4 on platelets have been reported in kidneys following AKI, platelet activation likely plays a part in AKI pathology. Results from animal models and some clinical studies highlight the potential of antiplatelet therapies in the preservation of renal function in the context of AKI, but as current strategies also affect other cell types and non-platelet-derived mediators, additional studies are required to further elucidate the extent of platelet contribution to the pathology of AKI and to determine the best therapeutic approach by which to specifically target related pathogenic pathways. PMID- 29760446 TI - Allatostatin C modulates nociception and immunity in Drosophila. AB - Bacterial induced inflammatory responses cause pain through direct activation of nociceptive neurons, and the ablation of these neurons leads to increased immune infiltration. In this study, we investigated nociceptive-immune interactions in Drosophila and the role these interactions play during pathogenic bacterial infection. After bacterial infection, we found robust upregulation of ligand gated ion channels and allatostatin receptors involved in nociception, which potentially leads to hyperalgesia. We further found that Allatostatin-C Receptor 2 (AstC-R2) plays a crucial role in host survival during infection with the pathogenic bacterium Photorhabdus luminescens. Upon examination of immune signaling in AstC-R2 deficient mutants, we demonstrated that Allatostatin-C Receptor 2 specifically inhibits the Immune deficiency pathway, and knockdown of AstC-R2 leads to overproduction of antimicrobial peptides related to this pathway and decreased host survival. This study provides mechanistic insights into the importance of microbe-nociceptor interactions during bacterial challenge. We posit that Allatostatin C is an immunosuppressive substance released by nociceptors or Drosophila hemocytes that dampens IMD signaling in order to either prevent immunopathology or to reduce unnecessary metabolic cost after microbial stimulation. AstC-R2 also acts to dampen thermal nociception in the absence of infection, suggesting an intrinsic neuronal role in mediating these processes during homeostatic conditions. Further examination into the signaling mechanisms by which Allatostatin-C alters immunity and nociception in Drosophila may reveal conserved pathways which can be utilized towards therapeutically targeting inflammatory pain and chronic inflammation. PMID- 29760445 TI - Elevated prenatal anti-Mullerian hormone reprograms the fetus and induces polycystic ovary syndrome in adulthood. AB - Polycystic ovary syndrome (PCOS) is the main cause of female infertility worldwide and corresponds with a high degree of comorbidities and economic burden. How PCOS is passed on from one generation to the next is not clear, but it may be a developmental condition. Most women with PCOS exhibit higher levels of circulating luteinizing hormone, suggestive of heightened gonadotropin releasing hormone (GnRH) release, and anti-Mullerian hormone (AMH) as compared to healthy women. Excess AMH in utero may affect the development of the female fetus. However, as AMH levels drop during pregnancy in women with normal fertility, it was unclear whether their levels were also elevated in pregnant women with PCOS. Here we measured AMH in a cohort of pregnant women with PCOS and control pregnant women and found that AMH is significantly more elevated in the former group versus the latter. To determine whether the elevation of AMH during pregnancy in women with PCOS is a bystander effect or a driver of the condition in the offspring, we modeled our clinical findings by treating pregnant mice with AMH and followed the neuroendocrine phenotype of their female progeny postnatally. This treatment resulted in maternal neuroendocrine-driven testosterone excess and diminished placental metabolism of testosterone to estradiol, resulting in a masculinization of the exposed female fetus and a PCOS like reproductive and neuroendocrine phenotype in adulthood. We found that the affected females had persistently hyperactivated GnRH neurons and that GnRH antagonist treatment in the adult female offspring restored their neuroendocrine phenotype to a normal state. These findings highlight a critical role for excess prenatal AMH exposure and subsequent aberrant GnRH receptor signaling in the neuroendocrine dysfunctions of PCOS, while offering a new potential therapeutic avenue to treat the condition during adulthood. PMID- 29760448 TI - The gut microbiota and the brain-gut-kidney axis in hypertension and chronic kidney disease. AB - Crosstalk between the gut microbiota and the host has attracted considerable attention owing to its involvement in diverse diseases. Chronic kidney disease (CKD) is commonly associated with hypertension and is characterized by immune dysregulation, metabolic disorder and sympathetic activation, which are all linked to gut dysbiosis and altered host-microbiota crosstalk. In this Review, we discuss the complex interplay between the brain, the gut, the microbiota and the kidney in CKD and hypertension and explain our brain-gut-kidney axis hypothesis for the pathogenesis of these diseases. Consideration of the role of the brain gut-kidney axis in the maintenance of normal homeostasis and of dysregulation of this axis in CKD and hypertension could lead to the identification of novel therapeutic targets. In addition, the discovery of unique microbial communities and their associated metabolites and the elucidation of brain-gut-kidney signalling are likely to fill fundamental knowledge gaps leading to innovative research, clinical trials and treatments for CKD and hypertension. PMID- 29760449 TI - Aurora kinase A (AURKA) interaction with Wnt and Ras-MAPK signalling pathways in colorectal cancer. AB - Hyperactivation of Wnt and Ras-MAPK signalling are common events in development of colorectal adenomas. Further progression from adenoma-to-carcinoma is frequently associated with 20q gain and overexpression of Aurora kinase A (AURKA). Interestingly, AURKA has been shown to further enhance Wnt and Ras-MAPK signalling. However, the molecular details of these interactions in driving colorectal carcinogenesis remain poorly understood. Here we first performed differential expression analysis (DEA) of AURKA knockdown in two colorectal cancer (CRC) cell lines with 20q gain and AURKA overexpression. Next, using an exact algorithm, Heinz, we computed the largest connected protein-protein interaction (PPI) network module of significantly deregulated genes in the two CRC cell lines. The DEA and the Heinz analyses suggest 20 Wnt and Ras-MAPK signalling genes being deregulated by AURKA, whereof beta-catenin and KRAS occurred in both cell lines. Finally, shortest path analysis over the PPI network revealed eight 'connecting genes' between AURKA and these Wnt and Ras-MAPK signalling genes, of which UBE2D1, DICER1, CDK6 and RACGAP1 occurred in both cell lines. This study, first, confirms that AURKA influences deregulation of Wnt and Ras-MAPK signalling genes, and second, suggests mechanisms in CRC cell lines describing these interactions. PMID- 29760442 TI - Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. AB - Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = 0.62, P = 5.30 * 10-5) but not between CCT and primary open-angle glaucoma (r = 0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation. PMID- 29760454 TI - Publisher Correction: High power surface emitting terahertz laser with hybrid second- and fourth-order Bragg gratings. AB - The original PDF version of this Article contained an error in Equation 1. The 'Lambda' was missing from the denominator. This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication. PMID- 29760450 TI - Caveolin-3 differentially orchestrates cholinergic and serotonergic constriction of murine airways. AB - The mechanisms of controlling airway smooth muscle (ASM) tone are of utmost clinical importance as inappropriate constriction is a hallmark in asthma and chronic obstructive pulmonary disease. Receptors for acetylcholine and serotonin, two relevant mediators in this context, appear to be incorporated in specialized, cholesterol-rich domains of the plasma membrane, termed caveolae due to their invaginated shape. The structural protein caveolin-1 partly accounts for anchoring of these receptors. We here determined the role of the other major caveolar protein, caveolin-3 (cav-3), in orchestrating cholinergic and serotonergic ASM responses, utilizing newly generated cav-3 deficient mice. Cav-3 deficiency fully abrogated serotonin-induced constriction of extrapulmonary airways in organ baths while leaving intrapulmonary airways unaffected, as assessed in precision cut lung slices. The selective expression of cav-3 in tracheal, but not intrapulmonary bronchial epithelial cells, revealed by immunohistochemistry, might explain the differential effects of cav-3 deficiency on serotonergic ASM constriction. The cholinergic response of extrapulmonary airways was not altered, whereas a considerable increase was observed in cav-3-/- intrapulmonary bronchi. Thus, cav-3 differentially organizes serotonergic and cholinergic signaling in ASM through mechanisms that are specific for airways of certain caliber and anatomical position. This may allow for selective and site specific intervention in hyperreactive states. PMID- 29760451 TI - The electron distribution in the "activated" state of cytochrome c oxidase. AB - Cytochrome c oxidase catalyzes reduction of O2 to H2O at a catalytic site that is composed of a copper ion and heme group. The reaction is linked to translocation of four protons across the membrane for each O2 reduced to water. The free energy associated with electron transfer to the catalytic site is unequal for the four electron-transfer events. Most notably, the free energy associated with reduction of the catalytic site in the oxidized cytochrome c oxidase (state O) is not sufficient for proton pumping across the energized membrane. Yet, this electron transfer is mechanistically linked to proton pumping. To resolve this apparent discrepancy, a high-energy oxidized state (denoted O H ) was postulated and suggested to be populated only during catalytic turnover. The difference between states O and O H was suggested to be manifested in an elevated midpoint potential of CuB in the latter. This proposal predicts that one-electron reduction of cytochrome c oxidase after its oxidation would yield re-reduction of essentially only CuB. Here, we investigated this process and found ~5% and ~6% reduction of heme a3 and CuB, respectively, i.e. the apparent redox potentials for heme a3 and CuB are lower than that of heme a. PMID- 29760452 TI - Quantifying compressive forces between living cell layers and within tissues using elastic round microgels. AB - Increasing evidence shows that mechanical stresses are critical in regulating cell functions, fate, and diseases. However, no methods exist that can quantify isotropic compressive stresses. Here we describe fluorescent nanoparticle labeled, monodisperse elastic microspheres made of Arg-Gly-Asp-conjugated alginate hydrogels (elastic round microgels, ERMGs). We generate 3D displacements and calculate strains and tractions exerted on an ERMG. Average compressive tractions on an ERMG are 570 Pa within cell layers and 360 Pa in tumor repopulating cell (TRC) colonies grown in 400-Pa matrices. 3D compressive tractions on a 1.4-kPa ERMG are applied by surrounding cells via endogenous actomyosin forces but not via mature focal adhesions. Compressive stresses are substantially heterogeneous on ERMGs within a uniform cell colony and do not increase with TRC colony sizes. Early-stage zebrafish embryos generate spatial and temporal differences in local normal and shear stresses. This ERMG method could be useful for quantifying stresses in vitro and in vivo. PMID- 29760456 TI - Segregation mediated heterogeneous structure in a metastable beta titanium alloy with a superior combination of strength and ductility. AB - In beta titanium alloys, the beta stabilizers segregate easily and considerable effort has been devoted to alleviate/eliminate the segregation. In this work, instead of addressing the segregation problems, the segregation was utilized to develop a novel microstructure consisting of a nanometre-grained duplex (alpha+beta) structure and micrometre scale beta phase with superior mechanical properties. An as-cast Ti-9Mo-6W alloy exhibited segregation of Mo and W at the tens of micrometre scale. This was subjected to cold rolling and flash annealing at 820 oC for 2 and 5 mins. The solidification segregation of Mo and W leads to a locally different microstructure after cold rolling (i.e., nanostructured beta phase in the regions rich in Mo and W and plate-like martensite and beta phase in regions relatively poor in Mo and W), which play a decisive role in the formation of the heterogeneous microstructure. Tensile tests showed that this alloy exhibited a superior combination of high yield strength (692 MPa), high tensile strength (1115 MPa), high work hardening rate and large uniform elongation (33.5%). More importantly, the new technique proposed in this work could be potentially applicable to other alloy systems with segregation problems. PMID- 29760455 TI - Substrate sequence selectivity of APOBEC3A implicates intra-DNA interactions. AB - The APOBEC3 (A3) family of human cytidine deaminases is renowned for providing a first line of defense against many exogenous and endogenous retroviruses. However, the ability of these proteins to deaminate deoxycytidines in ssDNA makes A3s a double-edged sword. When overexpressed, A3s can mutate endogenous genomic DNA resulting in a variety of cancers. Although the sequence context for mutating DNA varies among A3s, the mechanism for substrate sequence specificity is not well understood. To characterize substrate specificity of A3A, a systematic approach was used to quantify the affinity for substrate as a function of sequence context, length, secondary structure, and solution pH. We identified the A3A ssDNA binding motif as (T/C)TC(A/G), which correlated with enzymatic activity. We also validated that A3A binds RNA in a sequence specific manner. A3A bound tighter to substrate binding motif within a hairpin loop compared to linear oligonucleotide, suggesting A3A affinity is modulated by substrate structure. Based on these findings and previously published A3A-ssDNA co-crystal structures, we propose a new model with intra-DNA interactions for the molecular mechanism underlying A3A sequence preference. Overall, the sequence and structural preferences identified for A3A leads to a new paradigm for identifying A3A's involvement in mutation of endogenous or exogenous DNA. PMID- 29760453 TI - Evolutionary instability of CUG-Leu in the genetic code of budding yeasts. AB - The genetic code used in nuclear genes is almost universal, but here we report that it changed three times in parallel during the evolution of budding yeasts. All three changes were reassignments of the codon CUG, which is translated as serine (in 2 yeast clades), alanine (1 clade), or the 'universal' leucine (2 clades). The newly discovered Ser2 clade is in the final stages of a genetic code transition. Most species in this clade have genes for both a novel tRNASer(CAG) and an ancestral tRNALeu(CAG) to read CUG, but only tRNASer(CAG) is used in standard growth conditions. The coexistence of these alloacceptor tRNA genes indicates that the genetic code transition occurred via an ambiguous translation phase. We propose that the three parallel reassignments of CUG were not driven by natural selection in favor of their effects on the proteome, but by selection to eliminate the ancestral tRNALeu(CAG). PMID- 29760458 TI - Hyperglycemia does not affect tissue repair responses in shear stress-induced atherosclerotic plaques in ApoE-/- mice. AB - The mechanisms responsible for macrovascular complications in diabetes remain to be fully understood. Recent studies have identified impaired vascular repair as a possible cause of plaque vulnerability in diabetes. This notion is supported by observations of a reduced content of fibrous proteins and smooth muscle cell mitogens in carotid endarterectomy from diabetic patients along with findings of decreased circulating levels of endothelial progenitor cells. In the present study we used a diabetic mouse model to characterize how hyperglycemia affects arterial repair responses. We induced atherosclerotic plaque formation in ApoE deficient (ApoE-/-) and heterozygous glucokinase knockout ApoE-deficient mice (ApoE-/- GK+/-) mice with a shear stress-modifying cast. There were no differences in cholesterol or triglyceride levels between the ApoE-/- and ApoE-/- GK+/- mice. Hyperglycemia did not affect the size of the formed atherosclerotic plaques, and no effects were seen on activation of cell proliferation, smooth muscle cell content or on the expression and localization of collagen, elastin and several other extracellular matrix proteins. The present study demonstrates that hyperglycemia per se has no significant effects on tissue repair processes in injured mouse carotid arteries, suggesting that other mechanisms are involved in diabetic plaque vulnerability. PMID- 29760460 TI - Seasonal blood pressure variation: implications for cardiovascular risk stratification. AB - Long-term blood pressure variations contribute to an increased risk of cardiovascular events during cold season, requiring personalized management of antihypertensive medications in a single patient, and can influence the results of clinical trials and epidemiological surveys in population studies. In addition to blood pressure values, which guide the stratification of cardiovascular risk, other cardiovascular risk factor levels also tend to be higher in the winter months and lower in the summer months. The resultant estimation of individual cardiovascular risk may thus vary depending on the season. At the patient level, only a low value in the winter should thus be considered a true measure of low cardiovascular risk, whereas low values measured in the summer do not indicate a low risk in the winter. Likewise, estimations of cardiovascular risk in population studies may vary according to the period of the year. Efforts should thus be directed at considering the potential influence of seasonal variations in establishing "normal" and "high-risk" assessment at both the patient and population levels, integrating such data into clinical practice. PMID- 29760457 TI - Global genetic differentiation of complex traits shaped by natural selection in humans. AB - There are mean differences in complex traits among global human populations. We hypothesize that part of the phenotypic differentiation is due to natural selection. To address this hypothesis, we assess the differentiation in allele frequencies of trait-associated SNPs among African, Eastern Asian, and European populations for ten complex traits using data of large sample size (up to ~405,000). We show that SNPs associated with height ([Formula: see text]), waist to-hip ratio ([Formula: see text]), and schizophrenia ([Formula: see text]) are significantly more differentiated among populations than matched "control" SNPs, suggesting that these trait-associated SNPs have undergone natural selection. We further find that SNPs associated with height ([Formula: see text]) and schizophrenia ([Formula: see text]) show significantly higher variance in linkage disequilibrium (LD) scores across populations than control SNPs. Our results support the hypothesis that natural selection has shaped the genetic differentiation of complex traits, such as height and schizophrenia, among worldwide populations. PMID- 29760461 TI - Arterial stiffness, not systolic blood pressure, increases with age in native Papuan populations. AB - Systolic blood pressure (SBP) and arterial stiffness are closely related and may behave reciprocally as cause or effect, interacting in a vicious cycle. Both SBP and arterial stiffness increase with age in populations in most developed countries. However, the age-related increase in SBP appears to be absent in indigenous populations, partially because of their lifelong low-sodium and high potassium diets, whereas age-related arterial stiffening in these populations remains to be determined. We performed a field survey of the indigenous population of Soroba, a small village located in the central highlands of Papua, Indonesia. Blood pressure levels and brachial-ankle pulse wave velocity (baPWV) were measured using an automatic device. A total of 125 native Papuans 16-75 years of age (59% women) were included in this study. SBP and pulse pressure were not correlated with age. However, diastolic and mean arterial pressure levels increased with age. The prevalence of hypertension was 5% (n = 6; all women), and baPWV significantly increased with age. Compared with participants 45 years of age and older, those younger than 45 years had a higher body mass index (BMI) and spot urine sodium-to-potassium ratio but lower baPWV; however, SBP was not different between these age groups. Multivariate linear regression analysis revealed that SBP was independently associated with baPWV, sex and BMI but not with age; baPWV was independently associated with SBP, age, BMI, sex and heart rate. SBP and baPWV were closely related, but the age-related changes in these measurements differed in this highland Papuan population. PMID- 29760459 TI - GATA4-dependent regulation of the secretory phenotype via MCP-1 underlies lamin A mediated human mesenchymal stem cell aging. AB - Defects in the nuclear lamina occur during physiological aging and as. result of premature aging disorders. Aging is also accompanied by an increase in transcription of genes encoding cytokines and chemokines,. phenomenon known as the senescence-associated secretory phenotype (SASP). Progerin and prelamin. trigger premature senescence and loss of function of human mesenchymal stem cells (hMSCs), but little is known about how defects in nuclear lamin. regulate SASP. Here, we show that both progerin overexpression and ZMPSTE24 depletion induce paracrine senescence, especially through the expression of monocyte chemoattractant protein-1 (MCP-1), in hMSCs. Importantly, we identified that GATA4 is. mediator regulating MCP-1 expression in response to prelamin. or progerin in hMSCs. Co-immunoprecipitation revealed that GATA4 expression is maintained due to impaired p62-mediated degradation in progerin-expressing hMSCs. Furthermore, depletion of GATA4 abrogated SASP-dependent senescence through suppression of NF-KB and MCP-1 in hMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin. proteins trigger paracrine senescence through. GATA4-dependent pathway in hMSCs. This molecular link between defective lamin. and GATA4 can provide insights into physiological aging and pathological aging disorders. PMID- 29760462 TI - Distinct mechanisms coordinate transcription and translation under carbon and nitrogen starvation in Escherichia coli. AB - Bacteria adapt to environmental stress by producing proteins that provide stress protection. However, stress can severely perturb the kinetics of gene expression, disrupting protein production. Here, we characterized how Escherichia coli mitigates such perturbations under nutrient stress through the kinetic coordination of transcription and translation. We observed that, when translation became limiting under nitrogen starvation, transcription elongation slowed accordingly. This slowdown was mediated by (p)ppGpp, the alarmone whose primary role is thought to be promoter regulation. This kinetic coordination by (p)ppGpp was critical for the robust synthesis of gene products. Surprisingly, under carbon starvation, (p)ppGpp was dispensable for robust synthesis. Characterization of the underlying kinetics revealed that under carbon starvation, transcription became limiting, and translation aided transcription elongation. This mechanism naturally coordinated transcription with translation, alleviating the need for (p)ppGpp as a mediator. These contrasting mechanisms for coordination resulted in the condition-dependent effects of (p)ppGpp on global protein synthesis and starvation survival. Our findings reveal a kinetic aspect of gene expression plasticity, establishing (p)ppGpp as a condition-dependent global effector of gene expression. PMID- 29760463 TI - Marsarchaeota are an aerobic archaeal lineage abundant in geothermal iron oxide microbial mats. AB - The discovery of archaeal lineages is critical to our understanding of the universal tree of life and evolutionary history of the Earth. Geochemically diverse thermal environments in Yellowstone National Park provide unprecedented opportunities for studying archaea in habitats that may represent analogues of early Earth. Here, we report the discovery and characterization of a phylum-level archaeal lineage proposed and herein referred to as the 'Marsarchaeota', after the red planet. The Marsarchaeota contains at least two major subgroups prevalent in acidic, microaerobic geothermal Fe(III) oxide microbial mats across a temperature range from ~50-80 degrees C. Metagenomics, single-cell sequencing, enrichment culturing and in situ transcriptional analyses reveal their biogeochemical role as facultative aerobic chemoorganotrophs that may also mediate the reduction of Fe(III). Phylogenomic analyses of replicate assemblies corresponding to two groups of Marsarchaeota indicate that they branch between the Crenarchaeota and all other major archaeal lineages. Transcriptomic analyses of several Fe(III) oxide mat communities reveal that these organisms were actively transcribing two different terminal oxidase complexes in situ and genes comprising an F420-dependent butanal catabolism. The broad distribution of Marsarchaeota in geothermal, microaerobic Fe(III) oxide mats suggests that similar habitat types probably played an important role in the evolution of archaea. PMID- 29760465 TI - Neural encoding and production of functional morphemes in the posterior temporal lobe. AB - Morphemes are the smallest meaning-carrying units in human language, and are among the most basic building blocks through which humans express specific ideas and concepts. By using time-resolved cortical stimulations, neural recordings, and focal lesion evaluations, we show that inhibition of a small cortical area within the left dominant posterior-superior temporal lobe selectively impairs the ability to produce appropriate functional morphemes but does not distinctly affect semantic and lexical retrieval, comprehension, or articulation. Additionally, neural recordings within this area reveal the localized encoding of morphological properties and their planned production prior to speech onset. Finally, small lesions localized to the gray matter in this area result in a selective functional morpheme-production deficit. Collectively, these findings reveal a detailed division of linguistic labor within the posterior-superior temporal lobe and suggest that functional morpheme processing constitutes an operationally discrete step in the series of computations essential to language production. PMID- 29760468 TI - The effect of hydration number on the interfacial transport of sodium ions. AB - Ion hydration and transport at interfaces are relevant to a wide range of applied fields and natural processes1-5. Interfacial effects are particularly profound in confined geometries such as nanometre-sized channels6-8, where the mechanisms of ion transport in bulk solutions may not apply9,10. To correlate atomic structure with the transport properties of hydrated ions, both the interfacial inhomogeneity and the complex competing interactions among ions, water and surfaces require detailed molecular-level characterization. Here we constructed individual sodium ion (Na+) hydrates on a NaCl(001) surface by progressively attaching single water molecules (one to five) to the Na+ ion using a combined scanning tunnelling microscopy and noncontact atomic force microscopy system. We found that the Na+ ion hydrated with three water molecules diffuses orders of magnitude more quickly than other ion hydrates. Ab initio calculations revealed that such high ion mobility arises from the existence of a metastable state, in which the three water molecules around the Na+ ion can rotate collectively with a rather small energy barrier. This scenario would apply even at room temperature according to our classical molecular dynamics simulations. Our work suggests that anomalously high diffusion rates for specific hydration numbers of ions are generally determined by the degree of symmetry match between the hydrates and the surface lattice. PMID- 29760464 TI - CO2-sensitive tRNA modification associated with human mitochondrial disease. AB - It has been generally thought that tRNA modifications are stable and static, and their frequencies are rarely regulated. N6-threonylcarbamoyladenosine (t6A) occurs at position 37 of five mitochondrial (mt-)tRNA species. We show that YRDC and OSGEPL1 are responsible for t6A37 formation, utilizing L-threonine, ATP, and CO2/bicarbonate as substrates. OSGEPL1-knockout cells exhibit respiratory defects and reduced mitochondrial translation. We find low level of t6A37 in mutant mt tRNA isolated from the MERRF-like patient's cells, indicating that lack of t6A37 results in pathological consequences. Kinetic measurements of t6A37 formation reveal that the Km value of CO2/bicarbonate is extremely high (31 mM), suggesting that CO2/bicarbonate is a rate-limiting factor for t6A37 formation. Consistent with this, we observe a low frequency of t6A37 in mt-tRNAs isolated from human cells cultured without bicarbonate. These findings indicate that t6A37 is regulated by sensing intracellular CO2/bicarbonate concentration, implying that mitochondrial translation is modulated in a codon-specific manner under physiological conditions. PMID- 29760467 TI - The Oral Microbiome Bank of China. AB - The human microbiome project (HMP) promoted further understanding of human oral microbes. However, research on the human oral microbiota has not made as much progress as research on the gut microbiota. Currently, the causal relationship between the oral microbiota and oral diseases remains unclear, and little is known about the link between the oral microbiota and human systemic diseases. To further understand the contribution of the oral microbiota in oral diseases and systemic diseases, a Human Oral Microbiome Database (HOMD) was established in the US. The HOMD includes 619 taxa in 13 phyla, and most of the microorganisms are from American populations. Due to individual differences in the microbiome, the HOMD does not reflect the Chinese oral microbial status. Herein, we established a new oral microbiome database-the Oral Microbiome Bank of China (OMBC, http://www.sklod.org/ombc ). Currently, the OMBC includes information on 289 bacterial strains and 720 clinical samples from the Chinese population, along with lab and clinical information. The OMBC is the first curated description of a Chinese-associated microbiome; it provides tools for use in investigating the role of the oral microbiome in health and diseases, and will give the community abundant data and strain information for future oral microbial studies. PMID- 29760469 TI - Frequent pauses in Escherichia coli flagella elongation revealed by single cell real-time fluorescence imaging. AB - The bacterial flagellum is a large extracellular protein organelle that extrudes from the cell surface. The flagellar filament is assembled from tens of thousands of flagellin subunits that are exported through the flagellar type III secretion system. Here, we measure the growth of Escherichia coli flagella in real time and find that, although the growth rate displays large variations at similar lengths, it decays on average as flagella lengthen. By tracking single flagella, we show that the large variations in growth rate occur as a result of frequent pauses. Furthermore, different flagella on the same cell show variable growth rates with correlation. Our observations are consistent with an injection-diffusion model, and we propose that an insufficient cytoplasmic flagellin supply is responsible for the pauses in flagellar growth in E. coli. PMID- 29760466 TI - Two-photon imaging of neuronal activity in motor cortex of marmosets during upper limb movement tasks. AB - Two-photon imaging in behaving animals has revealed neuronal activities related to behavioral and cognitive function at single-cell resolution. However, marmosets have posed a challenge due to limited success in training on motor tasks. Here we report the development of protocols to train head-fixed common marmosets to perform upper-limb movement tasks and simultaneously perform two photon imaging. After 2-5 months of training sessions, head-fixed marmosets can control a manipulandum to move a cursor to a target on a screen. We conduct two photon calcium imaging of layer 2/3 neurons in the motor cortex during this motor task performance, and detect task-relevant activity from multiple neurons at cellular and subcellular resolutions. In a two-target reaching task, some neurons show direction-selective activity over the training days. In a short-term force field adaptation task, some neurons change their activity when the force field is on. Two-photon calcium imaging in behaving marmosets may become a fundamental technique for determining the spatial organization of the cortical dynamics underlying action and cognition. PMID- 29760470 TI - Breast cancer associated germline structural variants harboring small noncoding RNAs impact post-transcriptional gene regulation. AB - Copy Number Variants (CNVs) are a class of structural variations of DNA. Germline CNVs are known to confer disease susceptibility, but their role in breast cancer warrants further investigations. We hypothesized that breast cancer associated germline CNVs contribute to disease risk through gene dosage or other post transcriptional regulatory mechanisms, possibly through tissue specific expression of CNV-embedded small-noncoding RNAs (CNV-sncRNAs). Our objectives are to identify breast cancer associated CNVs using a genome wide association study (GWAS), identify sncRNA genes embedded within CNVs, confirm breast tissue (tumor and normal) expression of the sncRNAs, correlate their expression with germline copy status and identify pathways influenced by the genes regulated by sncRNAs. We used an association study design and accessed germline CNV data generated on Affymetrix Human SNP 6.0 array in 686 (in-house data) and 495 (TCGA data) subjects served as discovery and validation cohorts. We identified 1812 breast cancer associated CNVs harboring miRNAs (n = 38), piRNAs (n = 9865), snoRNAs (n = 71) and tRNAs (n = 12) genes. A subset of CNV-sncRNAs expressed in breast tissue, also showed correlation with germline copy status. We identified targets potentially regulated by miRNAs and snoRNAs. In summary, we demonstrate the potential impact of embedded CNV-sncRNAs on expression and regulation of down stream targets. PMID- 29760471 TI - Bioinspired detoxification of blood: The efficient removal of anthrax toxin protective antigen using an extracorporeal macroporous adsorbent device. AB - Whilst various remedial human monoclonal antibodies have been developed to treat the potentially life-threatening systemic complications associated with anthrax infection, an optimal and universally effective administration route has yet to be established. In the later stages of infection when antibody administration by injection is more likely to fail one possible route to improve outcome is via the use of an antibody-bound, adsorbent haemoperfusion device. We report here the development of an adsorbent macroporous polymer column containing immobilised B. anthracis exotoxin-specific antibodies, PANG (a non-glycosylated, version of a plant-produced human monoclonal antibody) and Valortim (a fully human monoclonal N-linked glycosylated antibody), for removal of anthrax protective antigen (PA) from freshly frozen human plasma and human whole blood. In addition, we have demonstrated that continuous extracorporeal blood recirculation through a Valortim-bound haemoperfusion column significantly reduced the blood plasma concentration of anthrax PA over 2 hours using an in vivo PA rat infusion model. This work provides proof-of-concept evidence to support the development of such alternative detoxification platforms. PMID- 29760472 TI - Author Correction: SMARCA2-regulated host cell factors are required for MxA restriction of influenza A viruses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29760473 TI - Environmental suitability models predict population density, performance and body condition for microendemic salamanders. AB - Species can show strong variation of local abundance across their ranges. Recent analyses suggested that variation in abundance can be related to environmental suitability, as the highest abundances are often observed in populations living in the most suitable areas. However, there is limited information on the mechanisms through which variation in environmental suitability determines abundance. We analysed populations of the microendemic salamander Hydromantes flavus, and tested several hypotheses on potential relationships linking environmental suitability to population parameters. For multiple populations across the whole species range, we assessed suitability using species distribution models, and measured density, activity level, food intake and body condition index. In high-suitability sites, the density of salamanders was up to 30-times higher than in the least suitable ones. Variation in activity levels and population performance can explain such variation of abundance. In high suitability sites, salamanders were active close to the surface, and showed a low frequency of empty stomachs. Furthermore, when taking into account seasonal variation, body condition was better in the most suitable sites. Our results show that the strong relationship between environmental suitability and population abundance can be mediated by the variation of parameters strongly linked to individual performance and fitness. PMID- 29760475 TI - Computed tomography for evaluating right ventricle and pulmonary artery in pediatric tetralogy of Fallot: correlation with post-operative pulmonary regurgitation. AB - Pulmonary regurgitation (PR) is the most common complication after tetralogy of Fallot (TOF) surgical repair, and long-term PR might result in cardiovascular events. The aim of this study was to assess the influence of pre-operative right ventricle (RV) and pulmonary artery (PA) parameters assessed by dual-source computed tomography on post-operative PR. A total of 41 TOF patients who underwent trans-valve surgical repair were retrospectively recruited. The RV and PA parameters evaluated by pre-operative DSCT were compared between the PR and non-PR groups. Our result revealed that the PA parameters (McGoon ratio, Nakata index, and LPA diameter) and RV parameters (RV length diameter and RV short diameter) all showed significant differences between the two groups (all p < 0.05). There was a significant correlation between PR and LPA diameter (r = 0.361), McGoon ratio (r = 0.413), and Nakata index (r = 0.482). Receiver operating characteristic analysis also revealed a moderate sensitivity and specificity of LPA (66.33%; 82.60%), McGoon ratio (83.33%, 56.52%), and Nakata index (83.33%; 60.87%) for predicting the occurrence of PR. This study indicated that these pre-operative indices calculated by DSCT are associated with post operative PR and that these pre-operative PA and RV parameters may serve as novel predictors of the risk of PR. PMID- 29760478 TI - On the relationship between the specific heat enhancement of salt-based nanofluids and the ionic exchange capacity of nanoparticles. AB - Nanoparticles have been used in thermal applications to increase the specific heat of the molten salts used in Concentrated Solar Power plants for thermal energy storage. Although several mechanisms for abnormal enhancement have been proposed, they are still being investigated and more research is necessary. However, this nanoparticle-salt interaction can also be found in chemical applications in which nanoparticles have proved suitable to be used as an adsorbent for nitrate removal given their high specific surface, reactivity and ionic exchange capacity. In this work, the ionic exchange capacity mechanism for the nanoparticles functionalization phenomenon was evaluated. The ionic exchange capacity of silica and alumina nanoparticles dispersed in lithium, sodium and potassium nitrates was measured. Fourier-transform infrared spectroscopy tests confirmed the adsorption of nitrate ions on the nanoparticle surface. A relationship between the ionic exchange capacity of nanoparticles and the specific heat enhancement of doped molten salts was proposed for the first time. PMID- 29760476 TI - Self-organizing layers from complex molecular anions. AB - The formation of traditional ionic materials occurs principally via joint accumulation of both anions and cations. Herein, we describe a previously unreported phenomenon by which macroscopic liquid-like thin layers with tunable self-organization properties form through accumulation of stable complex ions of one polarity on surfaces. Using a series of highly stable molecular anions we demonstrate a strong influence of the internal charge distribution of the molecular ions, which is usually shielded by counterions, on the properties of the layers. Detailed characterization reveals that the intrinsically unstable layers of anions on surfaces are stabilized by simultaneous accumulation of neutral molecules from the background environment. Different phases, self organization mechanisms and optical properties are observed depending on the molecular properties of the deposited anions, the underlying surface and the coadsorbed neutral molecules. This demonstrates rational control of the macroscopic properties (morphology and size of the formed structures) of the newly discovered anion-based layers. PMID- 29760481 TI - Protein intake in hospitalized older people with and without increased risk of malnutrition. AB - A protein intake of >=1.2 grams per kg body weight (g/kg) is recommended for ill older adults. In a cross-sectional study, we investigated if this recommendation was met by 62 hospitalized adults of 65 years and older in a Dutch hospital. We compared protein intake between two subgroups based on the risk of malnutrition and the prescribed diet: a low risk group (n = 31) receiving a standard hospital diet and a medium/high risk group (n = 31) receiving a protein-enriched diet. A 24h-recall was performed to calculate protein intake per patient. Protein intake was on average 1.2 g/kg in the medium/high risk group and 0.9 g/kg in the low risk group. Seventeen patients reached a protein intake of >=1.2 g/kg. Fifteen patients had a protein intake below 0.8 g/kg. It seems sensible to consider providing a protein-enriched diet to all older hospitalized adults, regardless of their risk of malnutrition. PMID- 29760482 TI - Glycemic impact of non-nutritive sweeteners: a systematic review and meta analysis of randomized controlled trials. AB - BACKGROUND/OBJECTIVES: Nonnutritive sweeteners (NNSs) are zero- or low-calorie alternatives to nutritive sweeteners, such as table sugars. A systematic review and meta-analysis of randomized controlled trials was conducted to quantitatively synthesize existing scientific evidence on the glycemic impact of NNSs. SUBJECTS/METHODS: PubMed and Web of Science databases were searched. Two authors screened the titles and abstracts of candidate publications. The third author was consulted to resolve discrepancies. Twenty-nine randomized controlled trials, with a total of 741 participants, were included and their quality assessed. NNSs under examination included aspartame, saccharin, steviosides, and sucralose. The review followed the PRISMA guidelines. RESULTS: Meta-analysis was performed to estimate and track the trajectory of blood glucose concentrations over time after NNS consumption, and to test differential effects by type of NNS and participants' age, weight, and disease status. In comparison with the baseline, NNS consumption was not found to increase blood glucose level, and its concentration gradually declined over the course of observation following NNS consumption. The glycemic impact of NNS consumption did not differ by type of NNS but to some extent varied by participants' age, body weight, and diabetic status. CONCLUSIONS: NNS consumption was not found to elevate blood glucose level. Future studies are warranted to assess the health implications of frequent and chronic NNS consumption and elucidate the underlying biological mechanisms. PMID- 29760480 TI - Low energy cost for cultured pearl formation in grafted chimeric Pinctada margaritifera. AB - The pearl oyster is one of the rare animal models that support two distinct genomes, through the surgical graft process operated for culture pearl production. This grafted organism is assimilated to a chimera whose physiological functioning remains poorly known. The question of the energy expenditure comparison between chimera and non-chimera animals arises. To answer this question, grafted and non-grafted pearl oysters were evaluated for their energetic needs by the indirect calorimetry method. This method made it possible to measure the energy expenditure based on the respiration rate (RR) measurement, reflecting the basal metabolism. The results showed that the RR values for grafted and non-grafted pearl oysters were not significantly different (p < 0.05). The estimated cost of pearl calcification including CaCO3 and proteins synthesis was 0.237 +/- 0.064 J h-1, representing 0.64% of the total energy expenditure of grafted pearl oysters. This study made it possible, for the first time, to see the energy cost of cultured pearl formation in P. margaritifera and the little impact in the energetic metabolism of the chimera organism. PMID- 29760477 TI - Functional interplay between E2F7 and ribosomal rRNA gene transcription regulates protein synthesis. AB - A prerequisite for protein synthesis is the transcription of ribosomal rRNA genes by RNA polymerase I (Pol I), which controls ribosome biogenesis. UBF (upstream binding factor) is one of the main Pol I transcription factors located in the nucleolus that activates rRNA gene transcription. E2F7 is an atypical E2F family member that acts as a transcriptional repressor of E2F target genes, and thereby contributes to cell cycle arrest. Here, we describe an unexpected role for E2F7 in regulating rRNA gene transcription. We have found that E2F7 localises to the perinucleolar region, and further that E2F7 is able to exert repressive effects on Pol I transcription. At the mechanistic level, this is achieved in part by E2F7 hindering UBF recruitment to the rRNA gene promoter region, and thereby reducing rRNA gene transcription, which in turn compromises global protein synthesis. Our results expand the target gene repertoire influenced by E2F7 to include Pol I-regulated genes, and more generally suggest a mechanism mediated by effects on Pol I transcription where E2F7 links cell cycle arrest with protein synthesis. PMID- 29760479 TI - Immunoprofiling of Chlamydia trachomatis using whole-proteome microarrays generated by on-chip in situ expression. AB - Using Chlamydia trachomatis (Ct) as a complex model organism, we describe a method to generate bacterial whole-proteome microarrays using cell-free, on-chip protein expression. Expression constructs were generated by two successive PCRs directly from bacterial genomic DNA. Bacterial proteins expressed on microarrays display antigenic epitopes, thereby providing an efficient method for immunoprofiling of patients and allowing de novo identification of disease related serum antibodies. Through comparison of antibody reactivity patterns, we newly identified antigens recognized by known Ct-seropositive samples, and antigens reacting only with samples from cervical cancer (CxCa) patients. Large scale validation experiments using high-throughput suspension bead array serology confirmed their significance as markers for either general Ct infection or CxCa, supporting an association of Ct infection with CxCa. In conclusion, we introduce a method for generation of fast and efficient proteome immunoassays which can be easily adapted for other microorganisms in all areas of infection research. PMID- 29760483 TI - Structure and crystallography of foliated and chalk shell microstructures of the oyster Magallana: the same materials grown under different conditions. AB - Oyster shells are mainly composed of layers of foliated microstructure and lenses of chalk, a highly porous, apparently poorly organized and mechanically weak material. We performed a structural and crystallographic study of both materials, paying attention to the transitions between them. The morphology and crystallography of the laths comprising both microstructures are similar. The main differences were, in general, crystallographic orientation and texture. Whereas the foliated microstructure has a moderate sheet texture, with a defined 001 maximum, the chalk has a much weaker sheet texture, with a defined 011 maximum. This is striking because of the much more disorganized aspect of the chalk. We hypothesize that part of the unanticipated order is inherited from the foliated microstructure by means of, possibly, [Formula: see text] twinning. Growth line distribution suggests that during chalk formation, the mantle separates from the previous shell several times faster than for the foliated material. A shortage of structural material causes the chalk to become highly porous and allows crystals to reorient at a high angle to the mantle surface, with which they continue to keep contact. In conclusion, both materials are structurally similar and the differences in orientation and aspect simply result from differences in growth conditions. PMID- 29760474 TI - Structural basis for the recognition of complex-type N-glycans by Endoglycosidase S. AB - Endoglycosidase S (EndoS) is a bacterial endo-beta-N-acetylglucosaminidase that specifically catalyzes the hydrolysis of the beta-1,4 linkage between the first two N-acetylglucosamine residues of the biantennary complex-type N-linked glycans of IgG Fc regions. It is used for the chemoenzymatic synthesis of homogeneously glycosylated antibodies with improved therapeutic properties, but the molecular basis for its substrate specificity is unknown. Here, we report the crystal structure of the full-length EndoS in complex with its oligosaccharide G2 product. The glycoside hydrolase domain contains two well-defined asymmetric grooves that accommodate the complex-type N-linked glycan antennae near the active site. Several loops shape the glycan binding site, thereby governing the strict substrate specificity of EndoS. Comparing the arrangement of these loops within EndoS and related endoglycosidases, reveals distinct-binding site architectures that correlate with the respective glycan specificities, providing a basis for the bioengineering of endoglycosidases to tailor the chemoenzymatic synthesis of monoclonal antibodies. PMID- 29760486 TI - Long-lost data reveal astronauts' mark on the Moon. PMID- 29760485 TI - Clinical Application of Genome and Exome Sequencing as a Diagnostic Tool for Pediatric Patients: a Scoping Review of the Literature. AB - PURPOSE: Availability of clinical genomic sequencing (CGS) has generated questions about the value of genome and exome sequencing as a diagnostic tool. Analysis of reported CGS application can inform uptake and direct further research. This scoping literature review aims to synthesize evidence on the clinical and economic impact of CGS. METHODS: PubMed, Embase, and Cochrane were searched for peer-reviewed articles published between 2009 and 2017 on diagnostic CGS for infant and pediatric patients. Articles were classified according to sample size and whether economic evaluation was a primary research objective. Data on patient characteristics, clinical setting, and outcomes were extracted and narratively synthesized. RESULTS: Of 171 included articles, 131 were case reports, 40 were aggregate analyses, and 4 had a primary economic evaluation aim. Diagnostic yield was the only consistently reported outcome. Median diagnostic yield in aggregate analyses was 33.2% but varied by broad clinical categories and test type. CONCLUSION: Reported CGS use has rapidly increased and spans diverse clinical settings and patient phenotypes. Economic evaluations support the cost saving potential of diagnostic CGS. Multidisciplinary implementation research, including more robust outcome measurement and economic evaluation, is needed to demonstrate clinical utility and cost-effectiveness of CGS. PMID- 29760487 TI - Holiday trips spell trouble for the future of life on Earth. PMID- 29760488 TI - Mutant mice hold back the years. PMID- 29760484 TI - Top-down descending facilitation of spinal sensory excitatory transmission from the anterior cingulate cortex. AB - Spinal sensory transmission is under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain. Descending modulation from the brainstem rostral ventromedial medulla (RVM) has been the most studied, whereas little is known about direct corticospinal modulation. Here, we found that stimulation in the anterior cingulate cortex (ACC) potentiated spinal excitatory synaptic transmission and this modulation is independent of the RVM. Peripheral nerve injury enhanced the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury. Finally, using optogenetics, we showed that selective activation of ACC-spinal cord projecting neurons caused behavioral pain sensitization, while inhibiting the projection induced analgesic effects. Our results provide strong evidence that ACC stimulation facilitates spinal sensory excitatory transmission by a RVM independent manner, and that such top-down facilitation may contribute to the process of chronic neuropathic pain. PMID- 29760489 TI - Gymnastic feats help DNA 'walker' set speed record. PMID- 29760491 TI - Flesh-eating bacteria thrive on pain. PMID- 29760490 TI - Bloody battles as birds maul European bats. PMID- 29760492 TI - DNA points to a frog-killer's birthplace. PMID- 29760495 TI - A map for fatal brain tumour may aid cures. PMID- 29760496 TI - An unexpected twist in 'crystallized' time. PMID- 29760497 TI - Author Correction: White Matter and Gray Matter Segmentation in 4D Computed Tomography. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760499 TI - Hepatic stellate cells secrete Ccl5 to induce hepatocyte steatosis. AB - Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of disease severity, starting from pure steatosis, leading to fatty inflammation labeled as non-alcoholic steatohepatitis (NASH), and finally fibrosis leading to cirrhosis. Activated hepatic stellate cells (HSCs) are known to contribute to fibrosis, but less is known about their function during NAFLD's early stages prior to fibrosis. We developed an ex vivo assay that cocultures primary HSCs from mouse models of liver disease with healthy hepatocytes to study their interaction. Our data indicate that chemokine Ccl5 is one of the HSC-secreted mediators in early NASH in humans and in mice fed with choline-deficient, L-amino acid defined, high fat diet. Furthermore, Ccl5 directly induces steatosis and pro-inflammatory factors in healthy hepatocytes through the receptor Ccr5. Although Ccl5 is already known to be secreted by many liver cell types including HSCs and its pro-fibrotic role well characterized, its pro-steatotic action has not been recognized until now. Similarly, the function of HSCs in fibrogenesis is widely accepted, but their pro steatotic role has been unclear. Our result suggests that in early NASH, HSCs secrete Ccl5 which contributes to a broad array of mechanisms by which hepatic steatosis and inflammation are achieved. PMID- 29760500 TI - Author Correction: The Mobility Enhancement of Indium Gallium Zinc Oxide Transistors via Low-temperature Crystallization using a Tantalum Catalytic Layer. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760498 TI - Hierarchical mechanism of amino acid sensing by the T-box riboswitch. AB - In Gram-positive bacteria, T-box riboswitches control gene expression to maintain the cellular pools of aminoacylated tRNAs essential for protein biosynthesis. Co transcriptional binding of an uncharged tRNA to the riboswitch stabilizes an antiterminator, allowing transcription read-through, whereas an aminoacylated tRNA does not. Recent structural studies have resolved two contact points between tRNA and Stem-I in the 5' half of the T-box riboswitch, but little is known about the mechanism empowering transcriptional control by a small, distal aminoacyl modification. Using single-molecule fluorescence microscopy, we have probed the kinetic and structural underpinnings of tRNA binding to a glycyl T-box riboswitch. We observe a two-step mechanism where fast, dynamic recruitment of tRNA by Stem-I is followed by ultra-stable anchoring by the downstream antiterminator, but only without aminoacylation. Our results support a hierarchical sensing mechanism wherein dynamic global binding of the tRNA body is followed by localized readout of its aminoacylation status by snap-lock-based trapping. PMID- 29760502 TI - Infant colic: mechanisms and management. AB - Infant colic is a commonly reported phenomenon of excessive crying in infancy with an enigmatic and distressing character. Despite its frequent occurrence, little agreement has been reached on the definition, pathogenesis or the optimal management strategy for infant colic. This Review aims to delineate the definitional entanglement with the Rome IV criteria, which were published in 2016, as the leading, most recent diagnostic criteria. Moreover, neurogenic, gastrointestinal, microbial and psychosocial factors that might contribute to the pathophysiology of infant colic are explored. This Review underlines that a comprehensive medical history and physical examination in the absence of alarm symptoms serve as guidance for the clinician to a positive diagnosis. It also highlights that an important aspect of the management of infant colic is parental education and reassurance. Management strategies, including behavioural, dietary, pharmacological and alternative interventions, are also discussed. Owing to a lack of large, high-quality randomized controlled trials, none of these therapies are strongly recommended. Finally, the behavioural and somatic sequelae of infant colic into childhood are summarized. PMID- 29760503 TI - Author Correction: Dynamic Changes of Genome-Wide DNA Methylation during Soybean Seed Development. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760505 TI - Low-value approvals and high prices might incentivize ineffective drug development. PMID- 29760501 TI - Habitual coffee consumption and cognitive function: a Mendelian randomization meta-analysis in up to 415,530 participants. AB - Coffee's long-term effect on cognitive function remains unclear with studies suggesting both benefits and adverse effects. We used Mendelian randomization to investigate the causal relationship between habitual coffee consumption and cognitive function in mid- to later life. This included up to 415,530 participants and 300,760 coffee drinkers from 10 meta-analysed European ancestry cohorts. In each cohort, composite cognitive scores that capture global cognition and memory were computed using available tests. A genetic score derived using CYP1A1/2 (rs2472297) and AHR (rs6968865) was chosen as a proxy for habitual coffee consumption. Null associations were observed when examining the associations of the genetic score with global and memory cognition (beta = 0.0007, 95% C.I. -0.009 to 0.008, P = 0.87; beta = -0.001, 95% C.I. -0.005 to 0.002, P = 0.51, respectively), with high consistency between studies (Pheterogeneity > 0.4 for both). Domain specific analyses using available cognitive measures in the UK Biobank also did not support effects by habitual coffee intake for reaction time, pairs matching, reasoning or prospective memory (P >= 0.05 for all). Despite the power to detect very small effects, our meta analysis provided no evidence for causal long-term effects of habitual coffee consumption on global cognition or memory. PMID- 29760504 TI - Beliefs about others' intentions determine whether cooperation is the faster choice. AB - Is collaboration the fast choice for humans? Past studies proposed that cooperation is a behavioural default, based on Response Times (RT) findings. Here we contend that the individual's reckoning of the immediate social environment shapes her predisposition to cooperate and, hence, response latencies. In a social dilemma game, we manipulate the beliefs about the partner's intentions to cooperate and show that they act as a switch that determines cooperation and defection RTs; when the partner's intention to cooperate is perceived as high, cooperation choices are speeded up, while defection is slowed down. Importantly, this social context effect holds across varying expected payoffs, indicating that it modulates behaviour regardless of choices' similarity in monetary terms. Moreover, this pattern is moderated by individual variability in social preferences: Among conditional cooperators, high cooperation beliefs speed up cooperation responses and slow down defection. Among free-riders, defection is always faster and more likely than cooperation, while high cooperation beliefs slow down all decisions. These results shed new light on the conflict of choices account of response latencies, as well as on the intuitive cooperation hypothesis, and can help to correctly interpret and reconcile previous, apparently contradictory results, by considering the role of context in social dilemmas. PMID- 29760506 TI - Only the best CAR T cells. PMID- 29760508 TI - Reigning in RIG-I. PMID- 29760507 TI - GBR membrane of novel poly (butylene succinate-co-glycolate) co-polyester co polymer for periodontal application. AB - In periodontics, osteoconductive biodegradable guided bone regeneration (GBR) membranes with acceptable physico-mechanical properties are required to fix alveolar bone defects. The objectives of the present study were to produce and characterize a novel co-polyester-poly (butylene succinate-co-glycolate) (PBSGL), and fabricate a PBSGL membrane by electrospinning. We then aimed to evaluate the in vitro effect of the glycolate ratio on the biocompatibility and osteogenic differentiation of mesenchymal stem cells (MSCs), and evaluate in vivo bone regeneration using these membranes in rabbit calvarial defects by histology. Increasing the glycolate ratio of electrospun PBSGL membranes resulted in better cell attachment, greater cell metabolic activity, and enhanced osteogenic potential at both transcriptional and translational levels. Histologic and histomorphometric evaluations revealed further that bone defects covered with fibers of higher glycolate ratios showed more bone formation, with no adverse inflammatory response. These results suggest that novel PBSGL electrospun nanofibers show great promise as GBR membranes for bone regeneration. PMID- 29760509 TI - The role of metal/oxide interfaces for long-range metal particle activation during CO oxidation. PMID- 29760510 TI - Electron-phonon interaction in efficient perovskite blue emitters. AB - Low-dimensional perovskites have-in view of their high radiative recombination rates-shown great promise in achieving high luminescence brightness and colour saturation. Here we investigate the effect of electron-phonon interactions on the luminescence of single crystals of two-dimensional perovskites, showing that reducing these interactions can lead to bright blue emission in two-dimensional perovskites. Resonance Raman spectra and deformation potential analysis show that strong electron-phonon interactions result in fast non-radiative decay, and that this lowers the photoluminescence quantum yield (PLQY). Neutron scattering, solid state NMR measurements of spin-lattice relaxation, density functional theory simulations and experimental atomic displacement measurements reveal that molecular motion is slowest, and rigidity greatest, in the brightest emitter. By varying the molecular configuration of the ligands, we show that a PLQY up to 79% and linewidth of 20 nm can be reached by controlling crystal rigidity and electron-phonon interactions. Designing crystal structures with electron-phonon interactions in mind offers a previously underexplored avenue to improve optoelectronic materials' performance. PMID- 29760511 TI - Author Correction: Adherence to diet recommendations and risk of abdominal aortic aneurysm in the Malmo Diet and Cancer Study. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760512 TI - Author Correction: High-temperature operation of electrical injection type-II (GaIn)As/Ga(AsSb)/(GaIn)As "W"-quantum well lasers emitting at 1.3 um. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760513 TI - Author Correction: Fetal cardiac cine magnetic resonance imaging in utero. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760515 TI - Author Correction: Analysis of mutations in pncA reveals non-overlapping patterns among various lineages of Mycobacterium tuberculosis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760514 TI - Publisher Correction: Evolution of chalcone isomerase from a noncatalytic ancestor. AB - In the version of this article originally published, the number for the equal contributions footnote was missing for Miriam Kaltenbach and Jason R. Burke in the author list. The error has been corrected in the PDF and print versions of this article. PMID- 29760518 TI - Theory of Single-Impact Atomic Force Spectroscopy in liquids with material contrast. AB - Scanning probe microscopy has enabled nanoscale mapping of mechanical properties in important technological materials, such as tissues, biomaterials, polymers, nanointerfaces of composite materials, to name only a few. To improve and widen the measurement of nanoscale mechanical properties, a number of methods have been proposed to overcome the widely used force-displacement mode, that is inherently slow and limited to a quasi-static regime, mainly using multiple sinusoidal excitations of the sample base or of the cantilever. Here, a different approach is put forward. It exploits the unique capabilities of the wavelet transform analysis to harness the information encoded in a short duration spectroscopy experiment. It is based on an impulsive excitation of the cantilever and a single impact of the tip with the sample. It performs well in highly damped environments, which are often seen as problematic in other standard dynamic methods. Our results are very promising in terms of viscoelastic property discrimination. Their potential is oriented (but not limited) to samples that demand imaging in liquid native environments and also to highly vulnerable samples whose compositional mapping cannot be obtained through standard tapping imaging techniques. PMID- 29760519 TI - Author Correction: Magnetism and high magnetic-field-induced stability of alloy carbides in Fe-based materials. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760517 TI - Author Correction: Heart Failure Phenotypes Induced by Knockdown of DAPIT in Zebrafish: A New Insight into Mechanism of Dilated Cardiomyopathy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29760521 TI - Robotic assembly of artificial nanomaterials. PMID- 29760520 TI - Author Correction: Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29760516 TI - MicroRNA and transcriptome analysis in periocular Sebaceous Gland Carcinoma. AB - Sebaceous gland carcinoma (SGC) is a rare, but life-threatening condition with a predilection for the periocular region. Eyelid SGC can be broadly categorised into two subtypes, namely either nodular or pagetoid with the latter being more aggressive and requiring radical excision to save life. We have identified key altered microRNAs (miRNA) involved in SGC shared by both subtypes, hsa-miR-34a-5p and hsa-miR-16-5p. However, their gene targets BCL2 and MYC were differentially expressed with both overexpressed in pagetoid but unchanged in nodular suggesting different modes of action of these two miRNAs on BCL/MYC expression. Hsa-miR-150p is nodular-specifically overexpressed, and its target ZEB1 was significantly downregulated in nodular SGC suggesting a tumour suppressor role. Invasive pagetoid subtype demonstrated specific overexpression of hsa-miR-205 and downregulation of hsa-miR-199a. Correspondingly, miRNA gene targets, EZH2 (by hsa miR-205) and CD44 (by hsa-miR-199a), were both overexpressed in pagetoid SGC. CD44 has been identified as a potential cancer stem cell marker in head and neck squamous cell carcinoma and its overexpression in pagetoid cells represents a novel treatment target. Aberrant miRNAs and their gene targets have been identified in both SGC subtypes, paving the way for better molecular understanding of these tumours and identifying new treatment targets. PMID- 29760523 TI - Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. AB - Checkpoint immunotherapy that inhibits tumour immune evasion has demonstrated significant clinical success. However, the therapeutic response is limited to certain patient populations, and immunotoxicity as well as autoimmunity have compromised the therapeutic benefits. Here, we report on an inherently therapeutic fucoidan-dextran-based magnetic nanomedicine (IO@FuDex3) conjugated with a checkpoint inhibitor (anti-PD-L1) and T-cell activators (anti-CD3 and anti CD28). IO@FuDex3 can repair the immunosuppressive tumour microenvironment by reinvigorating tumour-infiltrating lymphocytes, while targeting the nanomedicine via magnetic navigation to the tumour to minimize off-target effects. Treatment that combines IO@FuDex3 and magnetic navigation reduces the occurrence of adverse events and extends the median survival from 32 to 63 days with less than 1 per cent dose compared with soluble anti-PD-L1. Thus, we demonstrate the potential of integrating anti-PD-L1 and T-cell activators as a form of inherently therapeutic nanomedicine to augment the therapeutic index of combination checkpoint immunotherapy. PMID- 29760524 TI - What does dopamine mean? AB - Dopamine is a critical modulator of both learning and motivation. This presents a problem: how can target cells know whether increased dopamine is a signal to learn or to move? It is often presumed that motivation involves slow ('tonic') dopamine changes, while fast ('phasic') dopamine fluctuations convey reward prediction errors for learning. Yet recent studies have shown that dopamine conveys motivational value and promotes movement even on subsecond timescales. Here I describe an alternative account of how dopamine regulates ongoing behavior. Dopamine release related to motivation is rapidly and locally sculpted by receptors on dopamine terminals, independently from dopamine cell firing. Target neurons abruptly switch between learning and performance modes, with striatal cholinergic interneurons providing one candidate switch mechanism. The behavioral impact of dopamine varies by subregion, but in each case dopamine provides a dynamic estimate of whether it is worth expending a limited internal resource, such as energy, attention, or time. PMID- 29760526 TI - Synaptic homeostasis: quality vs. quantity. PMID- 29760522 TI - Carbon nanotube bundles with tensile strength over 80 GPa. AB - Carbon nanotubes (CNTs) are one of the strongest known materials. When assembled into fibres, however, their strength becomes impaired by defects, impurities, random orientations and discontinuous lengths. Fabricating CNT fibres with strength reaching that of a single CNT has been an enduring challenge. Here, we demonstrate the fabrication of CNT bundles (CNTBs) that are centimetres long with tensile strength over 80 GPa using ultralong defect-free CNTs. The tensile strength of CNTBs is controlled by the Daniels effect owing to the non-uniformity of the initial strains in the components. We propose a synchronous tightening and relaxing strategy to release these non-uniform initial strains. The fabricated CNTBs, consisting of a large number of components with parallel alignment, defect free structures, continuous lengths and uniform initial strains, exhibit a tensile strength of 80 GPa (corresponding to an engineering tensile strength of 43 GPa), which is far higher than that of any other strong fibre. PMID- 29760527 TI - Prefrontal cortex as a meta-reinforcement learning system. AB - Over the past 20 years, neuroscience research on reward-based learning has converged on a canonical model, under which the neurotransmitter dopamine 'stamps in' associations between situations, actions and rewards by modulating the strength of synaptic connections between neurons. However, a growing number of recent findings have placed this standard model under strain. We now draw on recent advances in artificial intelligence to introduce a new theory of reward based learning. Here, the dopamine system trains another part of the brain, the prefrontal cortex, to operate as its own free-standing learning system. This new perspective accommodates the findings that motivated the standard model, but also deals gracefully with a wider range of observations, providing a fresh foundation for future research. PMID- 29760525 TI - Two distinct mechanisms for experience-dependent homeostasis. AB - Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling. Nevertheless, NMDA-receptor-independent changes in mEPSC amplitude consistent with synaptic scaling could be induced by extreme reductions of activity. Therefore, two distinct mechanisms operate within different ranges of neuronal activity to homeostatically regulate synaptic strength. PMID- 29760530 TI - Let K-Ras activate its own inhibitor. PMID- 29760528 TI - LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells. AB - The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4 was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype-phenotype annotated database identified novel mutation in atypical adMD. PMID- 29760529 TI - De novo nonsense mutation in WHSC1 (NSD2) in patient with intellectual disability and dysmorphic features. AB - Intellectual disability is the most common developmental disorder caused by chromosomal aberrations as well as single-nucleotide variants (SNVs) and small insertions/deletions (indels). Here we report identification of a novel, probably pathogenic mutation in the WHSC1 gene in a patient case with phenotype overlapping the features of Wolf-Hirschhorn syndrome. Deletions involving WHSC1 (Wolf-Hirschhorn syndrome candidate 1 gene) were described earlier in patients with Wolf-Hirschhorn syndrome. However, to our knowledge, single-point mutations in WHSC1 associated with any intellectual deficiency syndromes have not been reported. Using whole exome sequencing, we found a de novo nonsense mutation in WHSC1 (c.3412C>T, p.Arg1138Ter, NM_001042424.2) in patient with syndromic intellectual disability. This finding is challenging regarding a possible causative role of WHSC1 in intellectual disability syndromes, specifically Wolf Hirschhorn syndrome. From the clinical standpoint, our finding suggests that next generation sequencing along with chromosome microarray analysis (CMA) might be useful in genetic testing for patients with intellectual disability and dysmorphic features. PMID- 29760531 TI - The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. AB - Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRASG12C, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small molecules can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable. PMID- 29760534 TI - Retrieval of aerosol optical properties using MERIS observations: Algorithm and some first results. AB - The MEdium Resolution Imaging Spectrometer (MERIS) instrument on board ESA Envisat made measurements from 2002 to 2012. Although MERIS was limited in spectral coverage, accurate Aerosol Optical Thickness (AOT) from MERIS data are retrieved by using appropriate additional information. We introduce a new AOT retrieval algorithm for MERIS over land surfaces, referred to as eXtensible Bremen AErosol Retrieval (XBAER). XBAER is similar to the "dark-target" (DT) retrieval algorithm used for Moderate-resolution Imaging Spectroradiometer (MODIS), in that it uses a lookup table (LUT) to match to satellite-observed reflectance and derive the AOT. Instead of a global parameterization of surface spectral reflectance, XBAER uses a set of spectral coefficients to prescribe surface properties. In this manner, XBAER is not limited to dark surfaces (vegetation) and retrieves AOT over bright surface (desert, semiarid, and urban areas). Preliminary validation of the MERIS-derived AOT and the ground-based Aerosol Robotic Network (AERONET) measurements yield good agreement, the resulting regression equation is y = (0.92 * +/- 0.07) + (0.05 +/- 0.01) and Pearson correlation coefficient of R = 0.78. Global monthly means of AOT have been compared from XBAER, MODIS and other satellite-derived datasets. PMID- 29760533 TI - Cross-specificity of protective human antibodies against Klebsiella pneumoniae LPS O-antigen. AB - Humoral immune responses to microbial polysaccharide surface antigens can prevent bacterial infection but are typically strain specific and fail to mediate broad protection against different serotypes. Here we describe a panel of affinity matured monoclonal human antibodies from peripheral blood immunoglobulin M positive (IgM+) and IgA+ memory B cells and clonally related intestinal plasmablasts, directed against the lipopolysaccharide (LPS) O-antigen of Klebsiella pneumoniae, an opportunistic pathogen and major cause of antibiotic resistant nosocomial infections. The antibodies showed distinct patterns of in vivo cross-specificity and protection against different clinically relevant K. pneumoniae serotypes. However, cross-specificity was not limited to K. pneumoniae, as K. pneumoniae-specific antibodies recognized diverse intestinal microbes and neutralized not only K. pneumoniae LPS but also non-K. pneumoniae LPS. Our data suggest that the recognition of minimal glycan epitopes abundantly expressed on microbial surfaces might serve as an efficient humoral immunological mechanism to control invading pathogens and the large diversity of the human microbiota with a limited set of cross-specific antibodies. PMID- 29760535 TI - An evaluation of gravity waves and gravity wave sources in the Southern Hemisphere in a 7 km global climate simulation. AB - In this study, gravity waves (GWs) in the high-resolution GEOS-5 Nature Run are first evaluated with respect to satellite and other model results. Southern Hemisphere winter sources of non-orographic GWs in the model are then investigated by linking measures of tropospheric non-orographic gravity wave generation tied to precipitation and frontogenesis with absolute gravity wave momentum flux in the lower stratosphere. Finally, non-orographic GW momentum flux is compared to orographic gravity wave momentum flux and compared to previous estimates. The results show that the global patterns in GW amplitude, horizontal wavelength, and propagation direction are realistic compared to observations. However, as in other global models, the amplitudes are weaker and horizontal wavelengths longer than observed. The global patterns in absolute GW momentum flux also agree well with previous model and observational estimates. The evaluation of model non-orographic GW sources in the Southern Hemisphere winter shows that strong intermittent precipitation (greater than 10 mm h-1) is associated with GW momentum flux over the South Pacific, whereas frontogenesis and less intermittent, lower precipitation rates (less than 10 mm h-1) are associated with GW momentum flux near 60 degrees S. In the model, orographic GWs contribute almost exclusively to a peak in zonal mean momentum flux between 70 and 75 degrees S, while non-orographic waves dominate at 60 degrees S, and non orographic GWs contribute a third to a peak in zonal mean momentum flux between 25 and 30 degrees S. PMID- 29760532 TI - Apoptotic cell-induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans. AB - The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance. PMID- 29760536 TI - A Method for C2 Acylation of 1,3-Indandiones. AB - The 1,3-indandione scaffold is an important structural motif used in the preparation of a large number of industrial chemical and pharmaceutical compounds. However, few approaches allow for the direct C2 acylation on these building blocks. A method was developed using DMAP and EDCI, which is mild in reactivity, covers a diverse range of carboxylic acid acylating agents, is compatible with electron releasing and withdrawing substituents on the 1,3 indandione partner, and performs well in a polar aprotic solvent (for solubility reasons) This method cleanly afforded twenty five different products in yields of 32-96%. PMID- 29760537 TI - Bench-Scale Test Facility for Evaluating the Performance of Thermal Imagers for Fire Service Applications. AB - A bench-scale facility was developed for the evaluation of thermal imaging cameras. Smoke obscuration conditions in the optical smoke cell were characterized by measuring laser light transmittance through the cell. Measurements showed that the laser transmittance along the axial direction of the optical smoke cell was relatively uniform in the upper and lower halves of the cell for various smoke obscuration conditions. The thermal sensitivity of thermal imagers was investigated using the Michelson Contrast (CM) as a performance metric for a bar target viewed through the smoke-filled cell for different background thermal conditions. The results of the study indicate that the optical smoke cell can be utilized as a well-controlled and effective bench-scale test apparatus to evaluate aspects of the performance of thermal imagers for fire service applications. PMID- 29760538 TI - Gastrointestinal stromal tumors: A multidisciplinary challenge. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors located in the alimentary tract. Its usual manifestation is gastrointestinal bleeding. However, small asymptomatic lesions are frequently detected as incidental finding. Characteristically, most GISTs (> 95%) are positive for the KIT protein (CD117) by IHC staining and approximately 80%-90% of GISTs carry a mutation in the c-KIT or PDGFRA genes. Mutational analysis should be performed when planning adjuvant and neoadjuvant therapy, due to its possible resistance to conventional treatment. The arise of tyrosine kinase inhibitor has supposed a revolution in GISTs treatment being useful as adjuvant, neoadjuvant or recurrence disease treatment. That is why a multidisciplinary approach to this disease is required. The correct characterization of the tumor at diagnosis (the diagnosis of recurrences and the evaluation of the response to treatment with tyrosine kinase inhibitors) is fundamental for facing these tumors and requires specialized Endoscopist, Radiologists and Nuclear Medicine Physician. Surgery is the only potentially curative treatment for suspected resectable GIST. In the case of high risk GISTs, surgery plus adjuvant Imatinib-Mesylate for 3 years is the standard treatment. Neoadjuvant imatinib-mesylate should be considered to shrink the tumor in case of locally advanced primary or recurrence disease, unresectable or potentially resectable metastasic tumors, and potentially resectable disease in complex anatomic locations to decrease the related morbidity. In the case of Metastatic GIST under Neoadjuvant treatment, when there are complete response, stable disease or limited disease progression, complete cytoreductive surgery could be a therapeutic option if feasible. PMID- 29760539 TI - New therapeutic options opened by the molecular classification of gastric cancer. AB - Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC. PMID- 29760542 TI - Mouse models for investigating the underlying mechanisms of nonalcoholic steatohepatitis-derived hepatocellular carcinoma. AB - As the incidence of hepatocellular carcinoma (HCC) caused by infection with the hepatotropic viruses hepatitis B and hepatitis C decreases, greater attention has become focused on HCC caused by nonalcoholic steatohepatitis (NASH), an advanced form of nonalcoholic fatty liver disease which has shown increasing prevalence in correspondence with the overall increase in metabolic syndrome over the recent decades. Several clinical population studies have shown a positive relationship between NASH and HCC, while also providing initial insights into the underlying mechanisms of HCC development from NASH. Research into the pathological progression of NASH to HCC has advanced by use of several beneficial rodent models. In this review, we summarize the established mouse models for preclinical research of NASH-associated HCC and discuss the underlying hepatic mechanisms of NASH-related tumorigenesis identified to date that could lead to new targets for treatment and prevention. PMID- 29760541 TI - Laparoscopic gastrojejunostomy for gastric outlet obstruction in patients with unresectable hepatopancreatobiliary cancers: A personal series and systematic review of the literature. AB - The major symptoms of advanced hepatopancreatic-biliary cancer are biliary obstruction, pain and gastric outlet obstruction (GOO). For obstructive jaundice, surgical treatment should de consider in recurrent stent complications. The role of surgery for pain relief is marginal nowadays. On the last, there is no consensus for treatment of malignant GOO. Endoscopic duodenal stents are associated with shorter length of stay and faster relief to oral intake with more recurrent symptoms. Surgical gastrojejunostomy shows better long-term results and lower re-intervention rates, but there are limited data about laparoscopic approach. We performed a systematic review of the literature, according PRISMA guidelines, to search for articles on laparoscopic gastrojejunostomy for malignant GOO treatment. We also report our personal series, from 2009 to 2017. A review of the literature suggests that there is no standardized surgical technique either standardized outcomes to report. Most of the studies are case series, so level of evidence is low. Decision-making must consider medical condition, nutritional status, quality of life and life expectancy. Evaluation of the patient and multidisciplinary expertise are required to select appropriate approach. Given the limited studies and the difficulty to perform prospective controlled trials, no study can answer all the complexities of malignant GOO and more outcome data is needed. PMID- 29760540 TI - Ambiguous roles of innate lymphoid cells in chronic development of liver diseases. AB - Innate lymphoid cells (ILCs) are defined as a distinct arm of innate immunity. According to their profile of secreted cytokines and lineage-specific transcriptional factors, ILCs can be categorized into the following three groups: group 1 ILCs (including natural killer (NK) cells and ILC1s) are dependent on T bet and can produce interferon-gamma; group 2 ILCs (ILC2s) are dependent on GATA3 and can produce type 2 cytokines, including interleukin (IL)-5 and IL-13; and, group 3 ILCs (including lymphoid tissue-like cells and ILC3s) are dependent on RORgammat and can produce IL-22 and IL-17. Collaborative with adaptive immunity, ILCs are highly reactive innate effectors that promptly orchestrate immunity, inflammation and tissue repair. Dysregulation of ILCs might result in inflammatory disorders. Evidence regarding the function of intrahepatic ILCs is emerging from longitudinal studies of inflammatory liver diseases wherein they exert both physiological and pathological functions, including immune homeostasis, defenses and surveillance. Their overall effect on the liver depends on the balance of their proinflammatory and antiinflammatory populations, specific microenvironment and stages of immune responses. Here, we review the current data about ILCs in chronic liver disease progression, to reveal their roles in different stages as well as to discuss their therapeutic potency as intervention targets. PMID- 29760543 TI - Microbiota modification by probiotic supplementation reduces colitis associated colon cancer in mice. AB - AIM: To investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer (CAC). METHODS: C57BL/6 mice received an intraperitoneal injection of azoxymethane (10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water (5% w/v). Probiotic group received daily a mixture of Lactobacillus acidophilus, Lactobacillus rhamnosus and Bifidobacterium bifidum. Microbiota composition was assessed by 16S rRNA Illumina HiSeq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR (Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two sided. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software GraphPad Prism 5.0. The project was approved by the institutional review board committee. RESULTS: At day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size (< 2 mm) (P < 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera Lactobacillus, Bifidobacterium, Allobaculum, Clostridium XI and Clostridium XVIII increased in the probiotic group (P < 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p IKK and TNF-alpha and increased IL-10 expression in the colon. CONCLUSION: Our results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC. PMID- 29760544 TI - Ischemia/reperfusion injury in porcine intestine - Viability assessment. AB - AIM: To investigate viability assessment of segmental small bowel ischemia/reperfusion in a porcine model. METHODS: In 15 pigs, five or six 30-cm segments of jejunum were simultaneously made ischemic by clamping the mesenteric arteries and veins for 1 to 16 h. Reperfusion was initiated after different intervals of ischemia (1-8 h) and subsequently monitored for 5-15 h. The intestinal segments were regularly photographed and assessed visually and by palpation. Intraluminal lactate and glycerol concentrations were measured by microdialysis, and samples were collected for light microscopy and transmission electron microscopy. The histological changes were described and graded. RESULTS: Using light microscopy, the jejunum was considered as viable until 6 h of ischemia, while with transmission electron microscopy the ischemic muscularis propria was considered viable until 5 h of ischemia. However, following >= 1 h of reperfusion, only segments that had been ischemic for <= 3 h appeared viable, suggesting a possible upper limit for viability in the porcine mesenteric occlusion model. Although intraluminal microdialysis allowed us to closely monitor the onset and duration of ischemia and the onset of reperfusion, we were unable to find sufficient level of association between tissue viability and metabolic markers to conclude that microdialysis is clinically relevant for viability assessment. Evaluation of color and motility appears to be poor indicators of intestinal viability. CONCLUSION: Three hours of total ischemia of the small bowel followed by reperfusion appears to be the upper limit for viability in this porcine mesenteric ischemia model. PMID- 29760545 TI - Quantitative assessment of hepatic fibrosis in chronic hepatitis B and C: T1 mapping on Gd-EOB-DTPA-enhanced liver magnetic resonance imaging. AB - AIM: To assess the accuracy of Look-Locker on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for staging liver fibrosis in chronic hepatitis B/C (CHB/C). METHODS: We prospectively included 109 patients with CHB or CHC who underwent a 3.0-Tesla MRI examination, including T1-weighted and Look-Locker sequences for T1 mapping. Hepatocyte fractions (HeF) and relaxation time reduction rate (RE) were measured for staging liver fibrosis. A receiver operating characteristic analysis using the area under the receiver operating characteristic curve (AUC) was used to compare the diagnostic performance in predicting liver fibrosis between HeF and RE. RESULTS: A total of 73 patients had both pathological results and MRI information. The number of patients in each fibrosis stage was evaluated semiquantitatively according to the METAVIR scoring system: F0, n = 23 (31.5%); F1, n = 19 (26.0%); F2, n = 13 (17.8%); F3, n = 6 (8.2%), and F4, n = 12 (16.4%). HeF by EOB enhancement imaging was significantly correlated with fibrosis stage (r = -0.808, P < 0.05). AUC values for diagnosis of any (>= F1), significant (>= F2) or advanced (>= F3) fibrosis, and cirrhosis (F4) using HeF were 0.837 (0.733 0.913), 0.890 (0.795-0.951), 0.957 (0.881-0.990), and 0.957 (0.882-0.991), respectively. HeF measurement was more accurate than use of RE in establishing liver fibrosis staging, suggesting that calculation of HeF is a superior noninvasive liver fibrosis staging method. CONCLUSION: A T1 mapping-based HeF method is an efficient diagnostic tool for the staging of liver fibrosis. PMID- 29760548 TI - Silver nanoparticles induced alterations in multiple cellular targets, which are critical for drug susceptibilities and pathogenicity in fungal pathogen (Candida albicans). AB - Purpose: A significant increase in the incidence of fungal infections and drug resistance has been observed in the past decades due to limited availability of broad-spectrum antifungal drugs. Nanomedicines have shown significant antimicrobial potential against various drug-resistant microbes. Silver nanoparticles (AgNps) are known for their antimicrobial properties and lower host toxicity; however, for clinical applications, evaluation of their impact at cellular and molecular levels is essential. The present study aims to understand the cellular and molecular mechanisms of AgNp-induced toxicity in a common fungal pathogen, Candida albicans. Methods: AgNps were synthesized by chemical reduction method and characterized using UV-visible spectroscopy, X-ray powder diffraction, transmission electron microscopy, scanning electron microscopy-energy dispersive X-ray spectroscopy, energy dispersive X-ray fluorescence, and zeta potential. The anti-Candida activity of AgNps was assessed by broth microdilution and spot assays. Effects of AgNps on cellular and molecular targets were assessed by monitoring the intracellular reactive oxygen species (ROS) production in the absence and presence of natural antioxidant, changes in surface morphology, cellular ultrastructure, membrane microenvironment, membrane fluidity, membrane ergosterol, and fatty acids. Results: Spherical AgNps (10-30 nm) showed minimum inhibitory concentration (minimum concentration required to inhibit the growth of 90% of organisms) at 40 MUg/mL. Our results demonstrated that AgNps induced dose dependent intracellular ROS which exerted antifungal effects; however, even scavenging ROS by antioxidant could not offer protection from AgNp mediated killing. Treatment with AgNps altered surface morphology, cellular ultrastructure, membrane microenvironment, membrane fluidity, ergosterol content, and fatty acid composition, especially oleic acid. Conclusion: To summarize, AgNps affected multiple cellular targets crucial for drug resistance and pathogenicity in the fungal cells. The study revealed new cellular targets of AgNps which include fatty acids like oleic acid, vital for hyphal morphogenesis (a pathogenic trait of Candida). Yeast to hypha transition being pivotal for virulence and biofilm formation, targeting virulence might emerge as a new paradigm for developing nano silver-based therapy for clinical applications in fungal therapeutics. PMID- 29760547 TI - Comparison of the effects of deferasirox, deferoxamine, and combination of deferasirox and deferoxamine on an aplastic anemia mouse model complicated with iron overload. AB - Background and aim: Iron overload is commonly observed during the course of aplastic anemia (AA), which is believed to aggravate hematopoiesis, cause multiple organ dysfunction, lead to disease progression, and impair quality of life. Deferasirox (DFX) and deferoxamine (DFO) are among the most common iron chelation agents available in the clinical setting. The aim of this study was to investigate if the combination therapy with DFX and DFO is superior in hematopoietic recovery and iron chelation. Methods: Briefly, we developed a composite mouse model with AA and iron overload that was consequently treated with DFX, DFO, or with a combination of both agents. The changes in peripheral hemogram, marrow apoptosis, and its related protein expressions were compared during the process of iron chelation, while the iron depositions in liver and bone marrow and its regulator were also detected. Results: The obtained results showed that compared to DFX, DFO has a better effect in protecting the bone marrow from apoptosis-induced failure. The combination of DFO and DFX accelerated the chelation of iron, while their efficiency on further hemogram improvement appeared limited. Conclusion: To sum up, our data suggest that single treatment with DFO may be a better choice for improving the hematopoiesis during the gradual chelation treatment irrespective of the convenience of oral DFX, while the combination treatment should be considered for urgent reduction of the iron burden. PMID- 29760546 TI - Thiopurines are negatively associated with anthropometric parameters in pediatric Crohn's disease. AB - AIM: To determine the distribution of anthropometric parameter (AP)-z-scores and characterize associations between medications/serum biomarkers and AP-z-scores in pediatric Crohn's disease (CD). METHODS: CD patients [< chronological age (CA) 21 years] were enrolled in a cross-sectional study. Descriptive statistics were generated for participants' demographic characteristics and key variables of interest. Paired t-tests were used to compare AP-z-scores calculated based on CA (CA z-scores) and bone age (BA) (BA z-scores) for interpretation of AP's. Linear regression was utilized to examine associations between medications and serum biomarkers with AP-z-scores calculated based on CA (n = 82) and BA (n = 49). We reported regression coefficients as well as their corresponding p-values and 95% confidence intervals. RESULTS: Mean CA at the time of the study visit was 15.3 +/ 3.5 (SD; range = 4.8-20.7) years. Mean triceps skinfold (P = 0.039), subscapular skinfold (P = 0.002) and mid-arm circumference (MAC) (P = 0.001) BA z-scores were higher than corresponding CA z-scores. Medications were positively associated with subscapular skinfold [adalimumab (P = 0.018) and methotrexate (P = 0.027)] and BMI CA z-scores [adalimumab (P = 0.029)]. Azathioprine/6-mercaptopurine were negatively associated with MAC (P = 0.045), subscapular skinfold (P = 0.014), weight (P = 0.002) and BMI (P = 0.013) CA z-scores. ESR, CRP, and WBC count were negatively associated, while albumin and IGF-1 BA z-scores were positively associated, with specific AP z-scores (P < 0.05). Mean height CA z-scores were higher in females, not males, treated with infliximab (P = 0.038). Hemoglobin (P = 0.018) was positively associated, while platelets (P = 0.005), ESR (P = 0.003) and CRP (P = 0.039) were negatively associated with height CA z-scores in males, not females. CONCLUSION: Our results suggest poor efficacy of thiopurines and a possible sex difference in statural growth response to infliximab in pediatric CD. Prospective longitudinal studies are required. PMID- 29760549 TI - Nanostructured Ag+-substituted fluorhydroxyapatite-TiO2 coatings for enhanced bactericidal effects and osteoinductivity of Ti for biomedical applications. AB - Background: Poor mechanical properties, undesirable fast dissolution rate, and lack of antibacterial activity limit the application of hydroxyapatite (HA) as an implant coating material. To overcome these limitations, a hybrid coating of Ag+ substituted fluorhydroxyapatite and titania nanotube (TNT) was prepared. Methods: The incorporation of silver into the HA-TiO2 hybrid coating improves its antimicrobial properties. The addition of F as a second binary element increases the structural stability of the coating. The TNT/F-and-Ag-substituted HA (FAgHA) bilayer coating on the Ti substrate was confirmed by X-ray diffraction, scanning electron microscope, energy-dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). Results: The results indicate that the FAgHA/TNT nanocomposite coating has a dense and uniform morphology with a nano rod-like structure. The solubility measurement result shows that the substitution of F- ions into the AgHA structure has a positive effect on the dissolution resistance of HA. The adhesion strength of FAgHA/TNT has significantly increased because of the interlocking of the roughened surface with nano-rod-like particles that entered into the voids of the TiO2 nanotubes. Compared with that of the bare Ti, the corrosion current density of FAgHA/TNT-coated Ti substrate decreased from 3.71 to 0.18 MUA, and its corrosion resistance increased by almost two orders of magnitude. Moreover, despite pure HA, the FAgHA killed all viable Staphylococcus aureus after 24 hours of incubation. Although the fabricated FAgHA/TNT coating is hydrophobic, it induced deposition of the typical spherical apatite when immersed in a simulated body fluid (SBF); the osteoblasts spread very well on the surface of the coating. In addition, in vitro cell culture tests demonstrated cell viability and alkaline phosphatase (ALP) similar to pure HA, which indicated good cytocompatibility. Interestingly, compared with bare Ti, FAgHA/TNT-coated Ti surface was innocent for cell vitality and even more beneficial for cell osteogenesis in vitro. Conclusion: Enhancing the osseointegration and preventing infection in implants, the FAgHA/TNT-coated Ti makes implants more successful. PMID- 29760550 TI - Synergistic antifungal effect of chitosan-stabilized selenium nanoparticles synthesized by pulsed laser ablation in liquids against Candida albicans biofilms. AB - Background: Candida albicans is a major opportunistic fungal pathogen. One of the most important virulence factors that contribute to the pathogenesis of candidiasis is its ability to form biofilms. A key characteristic of Candida biofilms is their resistance to antifungal agents. Due to significant morbidity and mortality rates related to biofilm-associated drug resistance, there is an urgency to develop novel nanotechnology-based approaches preventing biofilm related infections. Methods: In this study, we report, for the first time, the synthesis of selenium nanoparticles by irradiating selenium pellets by nanosecond pulsed laser ablation in liquid chitosan as a capping agent. Synergy of the fungicidal effect of selenium nanoparticles and chitosan was quantified by the combination index theorem of Chou-Talalay. Results: This drug combination resulted in a potent fungicidal effect against a preformed C. albicans biofilm in a dose-response manner. By advanced electron microscopy techniques, we documented the adhesive and permeabilizing properties of chitosan, therefore allowing selenium nanoparticles to enter as the cell wall of the yeast became disrupted and distorted. Most importantly, we demonstrated a potent quantitative synergistic effect when compounds such as selenium and chitosan are combined. Conclusion: These chitosan-stabilized selenium nanoparticles could be used for ex vivo applications such as sterilizers for surfaces and biomedical devices. PMID- 29760552 TI - Patients receiving chiropractic care in a neurorehabilitation hospital: a descriptive study. AB - Objectives: Individuals rehabilitating from complex neurological injury require a multidisciplinary approach, which typically does not include chiropractic care. This study describes inpatients receiving multidisciplinary rehabilitation including chiropractic care for brain injury, spinal cord injury (SCI), stroke, and other complex neurological conditions. Design: Chiropractic services were integrated into Crotched Mountain Specialty Hospital (CMSH) through this project. Patient characteristics and chiropractic care data were collected to describe those receiving care and the interventions during the first 15 months when chiropractic services were available. Setting: CMSH, a 62-bed subacute multidisciplinary rehabilitation, skilled nursing facility located in Greenfield, New Hampshire, USA. Results: Patient mean (SD) age (n=27) was 42.8 (13) years, ranging from 20 to 64 years. Males (n=18, 67%) and those of white race/ethnicity (n=23, 85%) comprised the majority. Brain injury (n=20) was the most common admitting condition caused by trauma (n=9), hemorrhage (n=7), infarction (n=2), and general anoxia (n=2). Three patients were admitted for cervical SCI, 1 for ankylosing spondylitis, 1 for traumatic polyarthropathy, and 2 for respiratory failure with encephalopathy. Other common comorbid diagnoses potentially complicating the treatment and recovery process included myospasm (n=13), depression (n=11), anxiety (n=10), dysphagia (n=8), substance abuse (n=8), and candidiasis (n=7). Chiropractic procedures employed, by visit (n=641), included manual myofascial therapies (93%), mechanical percussion (83%), manual muscle stretching (75%), and thrust manipulation (65%) to address patients with spinal related pain (n=15, 54%), joint or regional stiffness (n= 14, 50%), and extremity pain (n=13, 46%). Care often required adapting to participant limitations or conditions. Such adaptations not commonly encountered in outpatient settings where chiropractic care is usually delivered included the need for lift assistance, wheelchair dependence, contractures, impaired speech, quadriplegia/paraplegia, and the presence of feeding tubes and urinary catheters. Conclusion: Patients suffered significant functional limitations and comorbidity resulting in modifications to the typical delivery of chiropractic care. Chiropractic services focused on relieving musculoskeletal pain and stiffness. PMID- 29760553 TI - A favorable outcome of advanced dermatofibrosarcoma protuberans under treatment with sunitinib after imatinib failure. AB - While traditional cytotoxic agents play a limited role in advanced dermatofibrosarcoma protuberans (DFSP), the treatment of sunitinib for patients with advanced DFSP after imatinib failure is not well defined. The objective of this case report was to analyze the relationship between molecular mechanisms and clinical outcomes of sunitinib treatment in patients with advanced DFSP after imatinib failure. In this case report, a 37-year-old man suffered from advanced DFSP progression after surgical operation, microwave ablation, and chemotherapy. The immunohistochemistry in this patient revealed abundant expression of platelet derived growth factor receptor-beta on tumor cells, which is one of the drug targets of sunitinib. The nucleotide sequence analysis revealed COL1A1-PDGFB fusion transcripts in this patient. Thus, we treated the patient with sunitinib, a multi-targeted tyrosine kinase inhibitor, after imatinib failure. After treatment with sunitinib, the patient exhibited a partial response and 9 months' progression-free survival without significant adverse drug effects. In our case, the patient with advanced DFSP experienced a favorable outcome in 9-months' progression-free survival and a significant improvement of quality of life without serious side effects after sunitinib treatment. Therefore, sunitinib could serve as another treatment option for patients with advanced DFSP. PMID- 29760554 TI - The CXCL12 rs1801157 polymorphism and risk of colorectal cancer: a meta-analysis. AB - Background: The CXCL12 rs1801157 polymorphism is putatively associated with the risk of malignancy. However, research results are inconsistent regarding particular cancers, especially colorectal cancer (CRC). Methods: We conducted a meta-analysis via a comprehensive literature search of the databases PubMed and Embase. Odds ratios and their corresponding 95% confidence intervals were extracted to assess comprehensively the association between the CXCL12 rs1801157 polymorphism and the risk of CRC. Results: According to the following models, the correlation between the presence of the CXCL12 rs1801157 polymorphism and the risk of CRC was not statistically significant: allelic (G cf. A), heterozygous (GG cf. GA), homozygous (GG cf. AA), dominant (GG cf. GA+AA), or recessive (AA cf. GA+GG) for pooled calculating. However, in subgroup analysis, elevated risk of CRC was found in the non-Caucasian group in four genetic models, while no connection was found in the Caucasian group. The sensitivity analysis confirmed that the result of the Caucasian group was stable and analyzed the heterogeneity of the non-Caucasian group. Conclusion: This meta-analysis suggested that the CXCL12 rs1801157 polymorphism did not significantly confer a risk of CRC among Caucasians but may among non-Caucasians. These results warrant confirmation and further studies of different ethnic populations. PMID- 29760555 TI - Comprehensive analysis of a long noncoding RNA-associated competing endogenous RNA network in colorectal cancer. AB - Purpose: This study was aimed to develop a lncRNA-associated competing endogenous RNA (ceRNA) network to provide further understanding of the ceRNA regulatory mechanism and pathogenesis in colorectal cancer (CRC). Patients and methods: Expression profiles of mRNAs, lncRNAs, and miRNAs, and clinical information for CRC patients were obtained from The Cancer Genome Atlas. The differentially expressed mRNAs, lncRNAs, and miRNAs (referred to as "DEmRNAs", "DElncRNAs", and "DEmiRNAs", respectively) were screened out between 539 CRC samples and 11 normal samples. The interactions between DElncRNAs and DEmiRNAs were predicted by miRcode. The DEmRNAs targeted by the DEmiRNAs were retrieved according to TargetScan, miRTar-Base, and miRDB. The lncRNA-miRNA-mRNA ceRNA network was constructed based on the DEmiRNA-DElncRNA and DEmiRNA-DEmRNA interactions. Functional enrichment analysis revealed the biological processes and pathways of DEmRNAs involved in the development of CRC. Key lncRNAs were further analyzed for their associations with overall survival and clinical features of CRC patients. Results: A total of 1,767 DEmRNAs, 608 DElncRNAs, and 283 DEmiRNAs were identified as CRC-specific RNAs. Three hundred eighty-two DEmiRNA-DElncRNA interactions and 68 DEmiRNA-DEmRNA interactions were recognized according to the relevant databases. The lncRNA-miRNA-mRNA ceRNA network was constructed using 25 DEmiRNAs, 52 DEmRNAs, and 64 DElncRNAs. Two DElncRNAs, five DEmiRNAs, and six DEmRNAs were demonstrated to be related to the prognosis of CRC patients. Four DElncRNAs were found to be associated with clinical features. Twenty-eight Gene Ontology terms and 10 Kyoto Encyclopedia of Genes and Genomes pathways were found to be significantly enriched by the DEmRNAs in the ceRNA network. Conclusion: Our results showed cancer-specific mRNA, lncRNA, and miRNA expression patterns and enabled us to construct an lncRNA-associated ceRNA network that provided new insights into the molecular mechanisms of CRC. Key RNA transcripts related to the overall survival and clinical features were also found with promising potential as biomarkers for diagnosis, survival prediction, and classification of CRC. PMID- 29760551 TI - Nanoparticle-mediated drug delivery to treat infections in the female reproductive tract: evaluation of experimental systems and the potential for mathematical modeling. AB - A variety of drug-delivery platforms have been employed to deliver therapeutic agents across cervicovaginal mucus (CVM) and the vaginal mucosa, offering the capability to increase the longevity and retention of active agents to treat infections of the female reproductive tract (FRT). Nanoparticles (NPs) have been shown to improve retention, diffusion, and cell-specific targeting via specific surface modifications, relative to other delivery platforms. In particular, polymeric NPs represent a promising option that has shown improved distribution through the CVM. These NPs are typically fabricated from nontoxic, non inflammatory, US Food and Drug Administration-approved polymers that improve biocompatibility. This review summarizes recent experimental studies that have evaluated NP transport in the FRT, and highlights research areas that more thoroughly and efficiently inform polymeric NP design, including mathematical modeling. An overview of the in vitro, ex vivo, and in vivo NP studies conducted to date - whereby transport parameters are determined, extrapolated, and validated - is presented first. The impact of different NP design features on transport through the FRT is summarized, and gaps that exist due to the limitations of iterative experimentation alone are identified. The potential of mathematical modeling to complement the characterization and evaluation of diffusion and transport of delivery vehicles and active agents through the CVM and mucosa is discussed. Lastly, potential advancements combining experimental and mathematical knowledge are suggested to inform next-generation NP designs, such that infections in the FRT may be more effectively treated. PMID- 29760556 TI - Rechallenge of oxaliplatin-containing regimens in the third- or later-line therapy for patients with heavily treated metastatic colorectal cancer. AB - Purpose: The third- or later-line therapy available often yield poor survival benefit in patients metastatic colorectal cancer (mCRC). The retrospective study aimed to evaluate efficacy of rechallenge of oxaliplatin-containing regimens. Patients and methods: Patients with mCRC who progressed from fluoropyrimidine, oxaliplatin, and irinotecan in the first- and second-line chemotherapy, were treated by reexposure to oxaliplatin-containing regimen. Patients treated by anti epidermal growth factor receptor (EGFR) antibodies with irinotecan were included in the control arm. Results: Ninety-five and 29 patients were treated with either oxaliplatin reexposure or anti-EGFR antibodies with irinotecan, respectively, as the third- or later-line therapy. The median time to treatment failure (TTF) and overall survival (OS) was 3.77 and 12.17 months in the oxaliplatin arm, with 4.77 months of TTF and 11.37 months of OS in the control arm; there was no significance between the 2 arms (p>0.05). Oxaliplatin reexposure resulted in 6.3% objective response rate with no complete response, 6 partial response, 39 stable disease, and 37 progressive disease. The disease control rate was 47.4% (45/95). The multivariate analysis found that patients who achieved disease control by oxaliplatin reexposure had a superior TTF (6.13 vs 1.7 months, p<0.001) and OS (15.73 vs 6.27 months, p<0.001) compared with those presenting with progressive disease. Conclusion: This study showed that rechallenge of oxaliplatin-containing chemotherapy in the third- or later-line therapy may lead to tumor control and improved survival in mCRC patients, which was equivalent to that of anti-EGFR antibodies with irinotecan. Clinical significance: Rechallenge of oxaliplatin containing regimens in the third- or later-line of therapy is a common practice, despite few evidence available. The present study found that rechallenge of oxaliplatin-containing regimens produced equivalent tumor control and survival benefit to that of anti-EGFR antibodies with irinotecan in mCRC. PMID- 29760558 TI - Pretreatment hematologic markers as prognostic predictors of gastroenteropancreatic neuroendocrine tumors: a systematic review and meta analysis. AB - Background: Systemic inflammation can be reflected by peripheral hematologic parameters and combined index like the lymphocyte count, neutrophil count, platelet count, neutrophil-to-lymphocyte (NLR), and platelet-to-lymphocyte ratio (PLR). This systematic review and meta-analysis aimed to summarize the association between the hematologic markers and prognosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: A computerized systematic search of PubMed, Embase, and Web of Science was conducted up to August 2016. Studies evaluating prognosis value of hematologic parameters in patients with GEP-NETs were retrieved. For meta-analysis, hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and synthesized using Review Manager software. Results: We identified eight retrospective cohort studies comprising a total of 724 cases. The majority of included studies focused on pancreatic neuroendocrine tumors (PNETs). The prognostic values of NLR, PLR, and platelet count were reported in six studies, two studies, and one study, respectively. All the parameters were associated with prognostic outcomes in patients with GEP-NETs. A high NLR was significantly associated with poor prognosis in GEP-NETs (pooled HR 3.05, 95% CI 1.96-4.76, I2 = 0%, P < 0.00001 for overall survival (OS); pooled HR 3.30, 95% CI 2.04-5.32, I2 = 0%, P < 0.00001 for recurrence-free survival [RFS]). In PNETs, pooled-analyses also showed significant superiority of a low NLR on OS (pooled HR 4.21, 95% CI 1.95-9.13, I2 = 0%, P = 0.0003) and RFS (pooled HR 5.37, 95% CI 2.14-13.47, I2 = 0%, P = 0.003). Conclusions: These findings suggest that the elevated NLR could be an adverse prognosis factor for GEP-NETs. The conclusion should be mainly limited to PNETs as the majority of included cases were PNET patients. The prognostic value of other hematologic parameters deserves further investigation. We recommend that further studies should use a continuous NLR variable and adopt a prospective and matched study design. PMID- 29760559 TI - Smoking and outcomes in kidney transplant recipients: a post hoc survival analysis of the FAVORIT trial. AB - Background: Tobacco use remains an international health problem with between 10% and 40% of adults currently using tobacco. Given the rising number of patients either awaiting or having received a kidney transplant and the absence of smoking cessation as the criterion for transplantation in guidelines, we explored the association between smoking status and clinical outcomes in kidney transplant recipients. Patients and methods: In this post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplant trial, the associations between smoking status, defined as never having smoked, formerly or currently smoking, and both all-cause mortality and graft survival were assessed using Cox proportional hazards models. Fatal events were centrally adjudicated into prespecified categories: all-cause, cardiovascular and non-cardiovascular causes. Graft loss was defined as return to dialysis or retransplantation. Clinical Trials URL: http://www.clinicaltrials.gov/show/NCT00064753. Results: Among 4110 transplant recipients, there were 451 current smokers and 1611 former smokers. The mortality rate per 100 patient-years was 4.0 (71 deaths) for smokers, 3.5 (226 deaths) for former smokers and 2.4 (116 deaths) for never smokers. Hazard ratio for mortality for current smokers was 1.70 (CI=1.26-2.29, p=0.001) and for former smokers was 1.21 (0.98-1.50, p=0.08) with 1.0 representing never smokers. As the number of cardiovascular deaths was similar in each group (all p>0.3), the differences between groups was driven by non-cardiovascular death rates. Current smokers (2.39; 1.62-3.61, p<0.001) and former smokers (1.50; 1.12-2.01, p=0.007) had increased hazard of non-cardiovascular death. Kidney allograft failure was more likely in current smokers than in either former or never smokers (3.5, 2.1 and 2.0 per 100 patient-years, p<0.001, adjusted hazard ratio 1.49 and 1.05, respectively). Conclusion: Continued smoking was associated with >100% increased risk of non-cardiovascular death, 70% greater risk of all-cause mortality and a 50% greater risk of graft loss, a risk not seen in former smokers. These findings confirm previous non-adjudicated observations that smoking is associated with adverse clinical outcomes and suggest that more emphasis should be placed on smoking cessation prior to kidney transplantation. PMID- 29760560 TI - Spinal anesthesia instead of general anesthesia for infants undergoing tendon Achilles lengthening. AB - Spinal anesthesia (SA) has been used relatively sparingly in the pediatric population, as it is typically reserved for patients in whom the perceived risk of general anesthesia is high due to comorbid conditions. Recently, concern has been expressed regarding the potential long-term neurocognitive effects of general anesthesia during the early stages of life. In view of this, our center has developed a program in which SA may be used as the sole agent for applicable surgical procedures. While this approach in children is commonly used for urologic or abdominal surgical procedures, there have been a limited number of reports of its use for orthopedic procedures in this population. We present the use of SA for 6 infants undergoing tendon Achilles lengthening, review the use of SA in orthopedic surgery, describe our protocols and dosing regimens, and discuss the potential adverse effects related to this technique. PMID- 29760557 TI - UCA1 promotes cell proliferation and invasion and inhibits apoptosis through regulation of the miR129-SOX4 pathway in renal cell carcinoma. AB - Background: Renal cell carcinoma (RCC) is the most common cancer in kidney malignancies. UCA1 has been identified as an oncogenic lncRNA in multiple cancers, including RCC. However, the underlying molecular mechanism of UCA1 involved in RCC progression is far from being addressed. Methods: Reverse transcription quantitative polymerase chain reaction (RT-qPCR) assays were used to measure expressions of UCA1, miR129, and SOX4 mRNA. Western blot assays were employed to detect SOX4 protein expression. Cell proliferation, invasion, and apoptosis were assessed by CCK-8, Matrigel invasion, and annexin-fluorescein isothiocyanate (FITC) apoptosis-detection assays, respectively. The interaction between UCA1 and miR129 was demonstrated by luciferase, RNA pull-down, and RNA immunoprecipitation (RIP) assays. Luciferase assays were also used to explore whether UCA1 was able to act as a molecular sponge of miR129 to affect the interplay of miR129 and SOX4. Results: UCA1 expression was upregulated in RCC tissue and cells, and higher UCA1 expression was associated with advanced pathogenic status and poor prognosis of RCC patients. UCA1 knockdown suppressed proliferation and invasion and induced apoptosis in RCC cells. UCA1 inhibited miR129 expression by direct interaction in RCC cells. miR129 overexpression inhibited cell proliferation and invasion and promoted apoptosis. Moreover, miR129 downregulation abrogated UCA1 knockdown-mediated antiproliferation, anti invasion, and proapoptosis effects in RCC cells. Furthermore, UCA1 acted as a ceRNA of miR129 to enhance target-gene SOX4 expression in RCC cells. Conclusion: UCA1 promoted cell proliferation and invasion and inhibited apoptosis by regulating SOX4 via miR129 in RCC, offering a promising therapeutic target and prognosis marker for RCC patients. PMID- 29760561 TI - An Efficient System for Gene Perturbation in Embryonic Hippocampal Progenitors Using Ex Vivo Electroporation Followed by In Vitro Dissociated Cell Culture. AB - We established an efficient cell culture assay that permits combinatorial genetic perturbations in hippocampal progenitors to examine cell-autonomous mechanisms of fate specification. The procedure begins with ex vivo electroporation of isolated, intact embryonic brains, in a manner similar to in utero electroporation but with greatly improved access and targeting. The electroporated region is then dissected and transiently maintained in organotypic explant culture, followed by dissociation and plating of cells on coverslips for in vitro culture. This assay recapitulates data obtained in vivo with respect to the neuron-glia cell fate switch and can be effectively used to test intrinsic or extrinsic factors that regulate this process. The advantages of this ex vivo procedure over in utero electroporation include the fact that distinct combinations of perturbative reagents can be introduced in different embryos from a single litter, and issues related to embryonic lethality of transgenic animals can be circumvented. PMID- 29760562 TI - Tau: A Common Denominator and Therapeutic Target for Neurodegenerative Disorders. AB - There is compelling evidence that a number of neurodegenerative diseases share common pathogenic mechanisms. Better understanding these mechanisms will allow us to develop new therapeutic strategies. This commentary follows up on our recent findings that tau pathology can be found in healthy fetal tissue transplanted into the brain of patients with either Huntington or Parkinson disease. We will examine how tau appears to be shared in a number of different conditions and how its expression relates to cognitive decline and disease progression. We will further review pathogenic mechanisms and especially the relevance of the possible prion-like behavior of tau. We will conclude by discussing how all this work opens up novel therapeutic approaches to treating the cognitive impairments related to neurodegenerative diseases using a common strategy. PMID- 29760564 TI - Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection. AB - Background and objective: Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. Methods: Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients. Results: Serum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P<0.001) and the levels from asymptomatic HBV carrier status, chronic hepatitis, liver cirrhosis to HCC were progressively increased. Serum sTim-3 levels were closely associated with the severity of liver function abnormalities. Importantly, serum sTim-3 levels were independently associated with HCC risk (OR, 4.310; 95% CI, 2.141-8.676, P<0.001) in comparison to non-HCC diseases in chronic HBV infection and significantly associated with the overall survival of HCC patients, with a level >3000 pg/mL being related to shorter overall survival than a level <=3000 pg/mL (P=0.019). Conclusion: Serum sTim-3 is involved in disease progression and HCC development in chronic HBV infection and its quantitative determination may be potentially used as a marker for monitoring the disease progression and predicting the HCC prognosis in chronic HBV infection. PMID- 29760563 TI - Durvalumab: a potential maintenance therapy in surgery-ineligible non-small-cell lung cancer. AB - Lung cancer is the most common cancer worldwide and the most common cause of cancer-related death. Non-small-cell lung cancer comprises ~87% of newly diagnosed cases of lung cancer, and nearly one-third of these patients have stage III disease. Despite improvements in the treatment of stage IV lung cancer, particularly with the introduction and dissemination of checkpoint inhibitors, very little progress has been made in the treatment of stage III lung cancer. In this article, we discuss the general staging criteria and treatment options for stage III lung cancer. We review how concurrent radiation and chemotherapy can have immunomodulatory effects, supporting the rationale for incorporating immunotherapy into existing treatment paradigms. Finally, we discuss the results of the PACIFIC trial and implications for the treatment of stage III lung cancer. In the PACIFIC trial, adding durvalumab as a maintenance therapy following the completion of chemoradiotherapy improved progression-free survival in patients with locally advanced unresectable stage III lung cancer. On the strength of these results, durvalumab has been approved by the US Food and Drug Administration for use in this setting, representing the first advance in the treatment of stage III lung cancer in nearly a decade. PMID- 29760565 TI - Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways associated with TP53 expression status in HBV-related hepatocellular carcinoma. AB - Background: The aim of this investigation was to identify candidate single nucleotide polymorphisms (SNPs) and molecular pathways associated with tumor protein p53 (TP53) expression status in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), clarify their potential mechanisms, and generate SNP-to-gene to pathway hypothesis. Materials and methods: Identify candidate Causal SNPs and Pathways (ICSNPathway) was used to perform pathway analysis based on the results of our previous genome-wide association study of TP53 expression status in 387 HBV-related HCC patients. Results: Through the ICSNPathway analysis, we identified 18 candidate SNPs and 10 candidate pathways that are associated with TP53 expression status in HBV-related HCC. The strongest mechanism involved the modulation of major histocompatibility complex, class II, DP beta 1 (human leukocyte antigen [HLA]-DPB1-rs1042153), major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1-rs1130399, HLA-DQB1 rs1049056, HLA-DQB1-rs1049059, and HLA-DQB1-rs1049060), and major histocompatibility complex, class II, DR beta 1 (HLA-DRB1-rs35445101). SNPs consequently affected regulatory roles in all the candidate pathways except hematopoietic cell lineage pathways. Association analysis using the GSE14520 data set, Gene Multiple Association Network Integration Algorithm, and Search Tool for the Retrieval of Interacting Genes/Proteins suggests that all genes of the candidate SNPs were associated with TP53. Survival analysis showed that the collagen type VI alpha 3 chain (COL6A3) rs111231885 and COL6A3-rs113155945 and COL6A3 block 4 CC haplotypes with TP53 negative status may have protective effects in HBV-related HCC patients after hepatectomy. Conclusion: Our pathway analysis identified 18 candidate SNPs and 10 candidate pathways that were associated with TP53 expression status in HBV-related HCC. Among these candidate SNPs, the genetic variation of COL6A3 may be a potential prognostic biomarker of HBV-related HCC. PMID- 29760566 TI - ITGA7 functions as a tumor suppressor and regulates migration and invasion in breast cancer. AB - Background: Breast cancer is the most common malignancy in women and the underlying mechanism of breast cancer cell metastasis is still far from uncover. Integrin subunit alpha 7 (ITGA7) is a functioning protein. It has been detected in many malignancies. But the function of ITGA7 in breast cancer is not clear. Our aim is to explore ITGA7 expression and its role in breast cancer. Methods: Real-time PCR was performed to determine ITGA7 expression in BC tissues and normal adjacent tissues. The specific functions of ITGA7 in breast cancer cell lines (MDA-MB-231 and BT-549) transfected with small interfering RNA were determined through migration, invasion assays. Western blot assays were performed to determine the expression of c-met and vimentin. Results: ITGA7 was down regulated in breast cancer tissues compared to the adjacent normal tissues (T:N =7.68+/-27.38: 41.01+/- 31.47, P<0.001) and this observation was consistent with the TCGA cohort (T:N =4.51+/-0.45:5.40+/-0.61, P<0.0001). In vitro experiments showed that knocking down ITGA7 significantly inhibited the migration and invasion of the breast cancer cell lines (MDA-MB-231 and BT-549). Meanwhile, knockdown of ITGA7 promoted c-met and vimentin expression, which may induce invasion and migration. Conclusion: ITGA7 plays an important tumorigenic function and acts as a suppress gene in breast cancer. Our findings indicate that ITGA7 was the gene associated with breast cancer. PMID- 29760567 TI - MiR-497-5p, miR-195-5p and miR-455-3p function as tumor suppressors by targeting hTERT in melanoma A375 cells. AB - Background: hTERT gene plays an important role in melanoma, although the specific mechanism involved is unclear. The aim of this study was to screen and identify the relative miRNAs with the regulation of hTERT in melanoma. Materials and methods: Quantitative real-time polymerase chain reaction (q-PCR) and immunohistochemistry were performed to detect hTERT mRNA and protein expression in 36 formalin-fixed paraffin-embedded melanoma tissues and 36 age- and sex matched pigmented nevi cases, respectively. Bioinformatics analysis and custom miRNA polymerase chain reaction array were determined for predicting, screening and verifying miRNAs with the regulation of the hTERT gene. To investigate the biological functions, miRNAs mimics or inhibitors were transfected into melanoma A375 cells. The relative expression of miR-497-5p, miR-195-5p, miR-455-3p and hTERT mRNA was determined by q-PCR. The protein expression of hTERT was detected by Western blot. 3-(4,5-Dimethylthiazolyl-2-yl)-2,5-biphenyl tetrazolium bromide and flow cytometry were employed to detect cell proliferation ability, cell apoptosis and cell cycle. Transwell and wound healing assays were used to observe cell invasion and migration abilities. A direct target gene of miRNAs was analyzed by a dual luciferase reporter activity assay. Results: MiR-497-5p, miR 195-5p, miR-455-3p were significantly downregulated, while hTERT was upregulated in melanoma tissues. hTERT expression level was inversely correlated with miR-497 5p, miR-195-5p and miR-455-3p. Overexpression of miR-497-5p, miR-195-5p and miR 455-3p inhibited A375 cell proliferation, migration and invasion, arrested the cell cycle, induced cell apoptosis and decreased hTERT expression at both mRNA and protein levels. Suppression of miR-497-5p, miR-195-5p and miR-455-3p partially reversed the inhibitory effects. Finally, hTERT was identified as a direct target of miR-497-5p, miR-195-5p and miR-455-3p. Conclusions: MiR-497-5p, miR-195-5p and miR-455-3p act as tumor suppressors by targeting hTERT in melanoma A375 cells. Therefore, miR-497-5p, miR-195-5p and miR-455-3p could be potential targeted therapeutic choice for melanoma. PMID- 29760569 TI - Concomitant use of opioid medications with triptans or serotonergic antidepressants in US office-based physician visits. AB - Background: Opioids are not recommended for routine treatment of migraine because their benefits are outweighed by risks of medication overuse headache and abuse/dependence. A March 2016 US Food and Drug Administration (FDA) safety communication warned of the risk of serotonin syndrome from using opioids concomitantly with 5-hydroxytryptamine receptor agonists (triptans) or serotonergic antidepressants: selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Epidemiological information about co-prescribing of these medications is limited. The objective of this study was to estimate the nationwide prevalence of co-prescribing of an opioid with a serotonergic antidepressant and/or triptan in US office-based physician visits made by 1) all patients and 2) patients diagnosed with migraine. Methods: National Ambulatory Medical Care Survey (NAMCS) data were obtained for 2013 and 2014. Physician office visits that included the new or continued prescribing of >=1 opioid medication with a triptan or an SSRI/SNRI were identified. Co prescribed opioids were stratified by agent to determine the proportion of co prescriptions with opioids posing a higher risk of serotonergic agonism (meperidine, tapentadol, and tramadol). Results: Of an annualized mean 903.6 million office-based physician visits in 2013-2014, 17.7 million (2.0% of all US visits) resulted in the prescribing of >=1 opioid medication with a triptan or an SSRI/SNRI. Opioid-SSRI/SNRI was co-prescribed in 16,044,721 visits, while opioid triptan was co-prescribed in 1,622,827 visits. One-fifth of opioid co-prescribing was attributable to higher-risk opioids, predominantly tramadol (18.6% of opioid SSRI/SNRI, 21.8% of opioid-triptan). Of 7,672,193 visits for patients diagnosed with migraine, 16.3% included opioid prescribing and 2.0% included co-prescribed opioid-triptan. Conclusion: During a period approximately 2 years prior to an FDA warning about the risk of serotonin syndrome from opioid-SSRI/SNRI or opioid triptan co-prescribing, use of these combinations was common in the USA. Studies on prescribing patterns following the March 2016 warning, and on the risk of serotonin syndrome associated with these co-prescriptions, are needed. PMID- 29760568 TI - Co-existence of BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma is associated with tumor aggressiveness, but not with lymph node metastasis. AB - Background: Mutations of BRAFV600E and TERT promoters are associated with thyroid cancer development. This study further investigated association of these mutations with clinicopathological characteristics from patients with papillary thyroid carcinoma (PTC). Methods: Tumor tissues from 342 PTC patients were obtained for DNA extraction and polymerase chain reaction amplification to detect the BRAFV600E mutation using amplification-refractory mutation system-polymerase chain reaction. TERT promoter mutations were assessed using Sanger DNA sequencing. The association of these gene mutations with clinicopathological characteristics was then statistically analyzed. Results: Two hundred and seventy of 342 (78.9%) PTC patients harbored the BRAFV600E mutation, which was associated with older age male patients. Moreover, TERT promoter mutations occurred in 12 of 342 (3.5 %) PTC patients, all of whom also had the BRAF mutation. One hundred thirty-three patients with papillary thyroid microcarcinoma (PTMC) had no TERT mutations. Statistically, the coexistence of BRAF and TERT promoter mutations were significantly associated with older age, larger tumor size, extrathyroidal extension, and advanced tumor stage, but not with central lymph node metastasis, lateral lymph node metastasis, numbers of lymph node metastasis >5, and numbers of involved/harvested lymph nodes (No. of LNs involved or harvested). The multivariate analyses showed older age (odds ratio [OR], 2.194; 95% CI: 1.117 4.311; p=0.023), larger tumor size (OR, 4.100; 95% CI: 2.257-7.450; p<0.001), and multiplicity (OR, 2.240; 95% CI: 1.309-3.831; p=0.003) were all independent predictors for high prevalence of extrathyroidal extension. However, there was no statistical association with any clinicopathological characteristics except for Hashimoto thyroiditis in PTMC. Conclusion: The current study demonstrated that the coexistence of BRAF and TERT promoter mutations were associated with the PTC aggressiveness, although these mutations were not associated with PTC lymph node metastasis or with PTMC. PMID- 29760571 TI - Multiple extrafoveal macular holes following internal limiting membrane peeling. AB - Objective: Internal limiting membrane (ILM) peeling has been the standard of treatment for macular holes. Besides, causing retinal nerve fiber layer surface abnormality, postoperative extrafoveal multiple retinal holes is a rare phenomenon following ILM peeling. We report an unusual complication of eight extrafoveal macular holes occurring following ILM peeling. Case presentation: A 60-year-old male presented with complaints of decreased and distorted vision in the right eye. He was diagnosed as having epiretinal membrane with lamellar macular hole. He underwent 23G pars plana vitrectomy, brilliant blue assisted ILM peeling and fluid gas exchange. Intraoperatively, ILM was found to be adherent to the underlying neurosensory retina. One month after cataract surgery, he underwent YAG capsulotomy in the right eye. He complained of visual distortion. His fundus evaluation in the right eye showed multiple (eight) extrafoveal retinal holes temporal to the macula clustered together. Conclusion: This case demonstrated that peeling of ILM, especially when it is adherent to the underlying neurosensory retina, may cause unwanted mechanical trauma to the inner retina. Glial apoptosis and neuronal degeneration may presumably play a role in delayed appearance of multiple (eight) extrafoveal macular holes, which has not been reported earlier. PMID- 29760570 TI - Plasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma. AB - Purpose: To evaluate the efficacy and safety of plasma rich in growth factors (PRGF) eye drops in patients with glaucoma with secondary ocular surface disorders (OSDs) due to surgeries and topical hypotensive drugs use. Materials and methods: A retrospective case-series study design was used including six patients (eight eyes) diagnosed with glaucoma who received surgical (nonpenetrating deep sclerectomy and/or trabeculectomy) and medical treatments (hypotensive eye drops) to control intraocular pressure (IOP) and who developed secondary OSDs, unresponsive to conventional treatments. Patients were treated with PRGF eye drops (four times a day). Outcome measures were ocular surface disease index (OSDI), best-corrected visual acuity (BCVA, in logarithm of the minimum angle of resolution), visual analog scale (VAS), frequency and severity of symptoms, and IOP. The safety of the treatment was also evaluated. Results: Six patients (seven eyes with open-angle glaucoma and one eye with uveitic glaucoma) treated with PRGF eye drops were evaluated. Mean age was 71 years (SD=7.2, range 58-79 years). Five were female and one was male. The mean treatment time was 21.8 weeks (SD=9.0, range 12-36 weeks). The mean time to reach closure of the corneal ulcer was 14.5 (SD=5.5) weeks. A statistical significant reduction in OSDI scale (50.6%), VAS frequency (53.1%), VAS severity (42.0%), and a 41.8% improvement in BCVA were observed (p<0.05). IOP also decreased by 16.6% (p=0.010). Only one of the six patients reported itching in both eyes as an adverse event (AE); however, the patient continued with the PRGF eye drops until the end of therapy; the remaining patients did not report any AEs during the follow-up period. Conclusions: In patients with glaucoma and secondary OSDs refractive to conventional treatments, the treatment with PRGF eye drops could be considered a possible therapeutic option, because it demonstrates an improvement in the signs and symptoms of the ocular surface, as well as a better control of the IOP. This is an initial research work that can open doors for future research to confirm these findings. PMID- 29760572 TI - Breath-powered sumatriptan dry nasal powder: an intranasal medication delivery system for acute treatment of migraine. AB - There is a need for fast-acting, non-oral medication options for migraine because some attacks develop rapidly and some are accompanied by nausea, vomiting, and gastroparesis, which can hinder oral medication uptake and absorption. The most commonly prescribed migraine medications are oral triptans, with sumatriptan as the most common. However, oral triptans are associated with adverse events (AEs) of atypical sensations that may be problematic for patients. Subcutaneous (SC) injectable sumatriptan and conventional liquid triptan nasal spray formulations are also available, but the frequency of atypical sensations is the highest with SC sumatriptan, and the intense bitter taste of conventional liquid triptan nasal spray discourages use. AVP-825 (ONZETRA(r) Xsail(r)) is an intranasal medication delivery system containing 22 mg sumatriptan nasal powder that is now available in the USA for the acute treatment of migraine with or without aura in adults. The objective of this review is to summarize the development of AVP-825, which utilizes unique features of nasal anatomy to achieve efficient absorption and reduced systemic exposure. Literature searches for "sumatriptan nasal powder", "AVP-825", and "sumatriptan intranasal" were conducted. Review articles and pharmacokinetic, Phase II and Phase III studies were evaluated. AVP-825 demonstrates an earlier onset of efficacy and lower rate of atypical sensations than the oral standard of care, which can be attributed to its fast absorption and low systemic exposure. AEs of abnormal taste are predominantly mild. These results confirm the initial design concept for AVP-825, which aligned pharmacokinetics, anatomy, and drug presentation in a novel device to achieve optimal outcomes for the acute treatment of migraine. PMID- 29760573 TI - Does courtesy bias affect how clients report on objective and subjective measures of family planning service quality? A comparison between facility- and home-based interviews. AB - Purpose: Despite a general understanding that exit interviews being conducted at service providers' facilities may influence clients' responses favorably to health professionals, there is very little evidence available that demonstrates the extent to which this problem exists. This study aimed at assessing and comparing clients' perceptions of the quality of family planning services and their satisfaction levels between facility- and home-based interviews. Methods: A cross-sectional survey was conducted among clients receiving family planning services across three service delivery channels - nongovernmental organization (NGO) clinics, social franchise (SF) centers, and outreach camps. The survey took place from December 2015 to January 2016 in 70 districts across all four provinces of Pakistan. A total of 2,807 clients were interviewed, of whom 1,404 clients were interviewed at health facilities after receiving services and 1,403 were interviewed at their homes within 3 days of method uptake. Results: Overall, we found no significant differences between the characteristics of study participants interviewed at health facilities or at home. The findings suggested that experiences reported in exit surveys at facilities were strongly biased positively. This was true for both experiential (service quality) and perception based (satisfaction) questions in the context of SF centers, while at NGO clinics the interview location only affected clients' responses regarding service quality. However, in outreach settings, clients are more likely to share bad experiences in exit interviews than in home-based interviews on objectively asked questions (service quality). Conclusion: Our study indicates signs of courtesy bias and possibly the Hawthorne effect in exit interviews. Program implementers could opt for home-based interviews for women receiving services at NGO clinics or SF center, whereas exit interviews could be used in outreach settings. PMID- 29760574 TI - Seasonal variations in body composition, maximal oxygen uptake, and gas exchange threshold in cross-country skiers. AB - Introduction: In order to ensure that athletes achieve their highest performance levels during competitive seasons, monitoring their long-term performance data is crucial for understanding the impact of ongoing training programs and evaluating training strategies. The present study was thus designed to investigate the variations in body composition, maximal oxygen uptake (VO2max), and gas exchange threshold values of cross-country skiers across training phases throughout a season. Materials and methods: In total, 15 athletes who participate in international cross-country ski competitions voluntarily took part in this study. The athletes underwent incremental treadmill running tests at 3 different time points over a period of 1 year. The first measurements were obtained in July, during the first preparation period; the second measurements were obtained in October, during the second preparation period; and the third measurements were obtained in February, during the competition period. Body weight, body mass index (BMI), body fat (%), as well as VO2max values and gas exchange threshold, measured using V-slope method during the incremental running tests, were assessed at all 3 time points. The collected data were analyzed using SPSS 20 package software. Significant differences between the measurements were assessed using Friedman's twoway variance analysis with a post hoc option. Results: The athletes' body weights and BMI measurements at the third point were significantly lower compared with the results of the second measurement (p<0.001). Moreover, the incremental running test time was significantly higher at the third measurement, compared with both the first (p<0.05) and the second (p<0.01) measurements. Similarly, the running speed during the test was significantly higher at the third measurement time point compared with the first measurement time point (p<0.05). Body fat (%), time to reach the gas exchange threshold, running speed at the gas exchange threshold, VO2max, amount of oxygen consumed at gas exchange threshold level (VO2GET), maximal heart rate (HRmax), and heart rate at gas exchange threshold level (HRGET) values did not significantly differ between the measurement time points (p>0.05). Conclusion: VO2max and gas exchange threshold values recorded during the third measurements, the timing of which coincided with the competitive season of the cross-country skiers, did not significantly change, but their incremental running test time and running speed significantly increased while their body weight and BMI significantly decreased. These results indicate that the cross-country skiers developed a tolerance for high-intensity exercise and reached their highest level of athletic performance during the competitive season. PMID- 29760576 TI - Trends of Gallbladder Cancer in Jordan Over 2 Decades: Where Are We? AB - Background and Study Aims: The prevalence of gallbladder cancer (GBC) varies between different parts of the world. This study is a review of literature and an update of a previously published study conducted in our university and aims to reassess the incidence of GBC over the past 2 decades. Patients and Methods: We conducted a retrospective study between 2002 and 2016. Data regarding demographics, clinical presentation, risk factors, histopathology, investigations, and treatments were obtained. A diagnosis of GBC established during surgery or primarily detected in the surgical specimen was classified as incidental. Results: Of 11 391 cholecystectomies performed, 31 cases (0.27%) of GBC were found. The mean age of patients with GBC was 68 years (43-103 years), 74% were women. The annual incidence of GBC was 0.2/100 000 (men: 0.1/100 000; women: 0.3/100 000). Biliary colic and acute cholecystitis were the main presentations. Diagnosis of GBC was "incidental" in 67% of cases. About 75% of patients with GBC had gallstones, 13% had polyps, and 3% had porcelain gallbladder. Adenocarcinoma was the dominant (87%) histologic type. Conclusions: The GBC rate in our region, similar to others parts of the world, is still low and has not changed over the past 2 decades. This study consolidates the previously published recommendations regarding the high index of suspicion of GBC in elderly with cholelithiasis. PMID- 29760577 TI - Perceptions of Acute Malnutrition and Its Management in Infants Under 6 Months of Age: A Qualitative Study in Rural Bangladesh. AB - Background: World Health Organization guidelines advise community-based care (CBC) for "uncomplicated" severe acute malnutrition (SAM) infants <6 months old (u6m), whereas current national protocols refer to inpatient care. Our aim was to inform and shape future management strategies by understanding caregivers' and different stakeholders' perceptions on malnutrition among infants u6m on barriers/facilitators to future CBC. Methods: The methods used in this study are as follows: in-depth interviews and focus group discussions (FGDs) in southern Bangladesh, thematic analysis of transcripts, and sample size by data saturation. Results: We conducted 5 FGDs with 29 caregivers, 4 with 29 health care workers, 4 key informant interviews each with community leaders and health supervisors. Five themes emerged. 1) Identification of SAM infants and care-seeking behavior: malnutrition was not noticed until severe, caregivers focused on clinical symptoms. Both allopathic and traditional healers were consulted. (2) Perceived causes of infant malnutrition: underlying illness, poor feeding practices, poverty, and local superstitions. (3) Views and preferences on treatment: hospitals and doctors were perceived as offering the best treatment, health care workers were also important, and respondents highlighted the need care of the caregiver/mother along with the infant. (4) Perceived benefits and risks of CBC: lower cost and greater accessibility were appreciated but worried about quality. (5) Community networks: wider family and social support networks were considered important aspects of care. Conclusions: There is considerable potential for CBC but needs to be better and earlier identification of at-risk infants, strengthening of health systems to avoid community options being perceived as "second best," engagement with families and communities to tackle "upstream" determinants of SAM, and care for mother-infant pairs. PMID- 29760578 TI - Development and Evaluation of the PROMIS(r) Pediatric Positive Affect Item Bank, Child-Report and Parent-Proxy Editions. AB - Objective: The purpose of this study is to describe the psychometric evaluation and item response theory calibration of the PROMIS Pediatric Positive Affect item bank, child-report and parent-proxy editions. Methods: The initial item pool comprising 53 items, previously developed using qualitative methods, was administered to 1,874 children 8-17 years old and 909 parents of children 5-17 years old. Analyses included descriptive statistics, reliability, factor analysis, differential item functioning, and construct validity. A total of 14 items were deleted, because of poor psychometric performance, and an 8-item short form constructed from the remaining 39 items was administered to a national sample of 1,004 children 8-17 years old, and 1,306 parents of children 5-17 years old. The combined sample was used in item response theory (IRT) calibration analyses. Results: The final item bank appeared unidimensional, the items appeared locally independent, and the items were free from differential item functioning. The scales showed excellent reliability and convergent and discriminant validity. Positive affect decreased with children's age and was lower for those with a special health care need. After IRT calibration, we found that 4 and 8 item short forms had a high degree of precision (reliability) across a wide range of the latent trait (>4 SD units). Conclusion: The PROMIS Pediatric Positive Affect item bank and its short forms provide an efficient, precise, and valid assessment of positive affect in children and youth. PMID- 29760575 TI - The development of human visual cortex and clinical implications. AB - The primary visual cortex (V1) is the first cortical area that processes visual information. Normal development of V1 depends on binocular vision during the critical period, and age-related losses of vision are linked with neurobiological changes in V1. Animal studies have provided important details about the neurobiological mechanisms in V1 that support normal vision or are changed by visual diseases. There is very little information, however, about those neurobiological mechanisms in human V1. That lack of information has hampered the translation of biologically inspired treatments from preclinical models to effective clinical treatments. We have studied human V1 to characterize the expression of neurobiological mechanisms that regulate visual perception and neuroplasticity. We have identified five stages of development for human V1 that start in infancy and continue across the life span. Here, we describe these stages, compare them with visual and anatomical milestones, and discuss implications for translating treatments for visual disorders that depend on neuroplasticity of V1 function. PMID- 29760579 TI - The effect of transcutaneous neuromuscular electrical stimulation on laryngeal vestibule closure timing in swallowing. AB - Background: The purpose of this study was to investigate the effect of transcutaneous neuromuscular electrical stimulation (NMES) on the timing of laryngeal vestibule closure during the pharyngeal stage of swallowing in healthy adults. The theoretical framework proposed that NMES applied to these muscles would present a perturbation to laryngeal vestibular closure reaction time (the amount of time for the laryngeal vestibule to close once the swallowing reflex has been triggered) by providing an antagonistic force to the direction of vestibule closure. Methods: Nine healthy adults (2 males, 7 females) received ten consecutive stimulations applied to the submandibular hyolaryngeal muscles while performing dry swallows. Laryngeal vestibule closure reaction time (LVCrt) and the laryngeal vestibule closure duration (LVCd) were measured from videoflouroscopic images pre-stimulation and post-stimulation. Results: Results indicated a significant effect of stimulation on LVCrt but not LVCd. LVCrt was significantly reduced (timing was faster) during swallows immediately after stimulation compared to pre-stimulation. Conclusions: Findings from this study support the supposition that laryngeal muscles respond to perturbations via adaptation learning, which might be used for rehabilitation of neuromuscular swallowing impairment. This pilot study supports the need for further research. PMID- 29760581 TI - Educational program for middle-level public health nurses to develop new health services regarding community health needs: protocol for a randomized controlled trial. AB - Background: Developing health services is a key strategy for improving the community health provided by public health nurses. However, an effective educational program for improving their skills in planning such services has not been developed. To describe our program and its evaluation protocol for the education of middle-level public health nurses to improve their skills in developing new health services to fulfil community health needs in Japan. Methods: In this randomized control trial, eligible participants in Japan will be randomly allocated to an intervention group and a control wait-list group. We will provide 8 modules of web-based learning for public health nurses from July to October 2018. To ensure fairness of educational opportunity, the wait-list group will participate in the same program as the intervention group after collection of follow-up data of the intervention group. The primary outcomes will be evaluated using the scale of competency measurement of creativity for public health nurses at baseline, immediately after the intervention. Secondary outcomes will be knowledge and performance regarding program development of public health nurses. Discussion: This study will enable the analysis of the effects of the educational program on public health nurses for improving their competency to develop new health services for fulfilling community health needs and enriching health care systems. Trial registration: We registered our study protocol to the University hospital Medical Information Network- Clinical Trials Registry approved by International Committee of Medical Journal Editors (No. UMIN000032176, April, 2018). PMID- 29760580 TI - Sinonasal adenoid cystic carcinoma-role of on-site FNAC: a case report. AB - Background: Adenoid cystic carcinoma (ACC), a rare tumor of epithelial cell origin, commonly arises from the major salivary glands. Uncommonly it may be found outside the salivary glands and it's especially rare in the nasal cavity. Case presentation: A 71-year female had complaints of swelling at the base of nose, Fine needle aspiration (FNA) from the swelling revealed features of adenoid cystic carcinoma; cell block & IHC for CD-117 was positive. Conclusions: Sino nasal ACC (SNACC) continues to pose diagnostic and therapeutic challenges to clinicians. Due to its rarity & vague presentation, early diagnosis requires a high index of suspicion. FNA can be used as an invaluable diagnostic tool in the evaluation of these lesions. Since it's incidence in sinonasal region is rare; our attempt to report this case will heighten the physician's awareness of this disease, helping further treatment. PMID- 29760582 TI - Registered nurses' and older people's experiences of participation in nutritional care in nursing homes: a descriptive qualitative study. AB - Background: The evaluation and treatment of older people's nutritional care is generally viewed as a low priority by nurses. However, given that eating and drinking are fundamental human activities, the support and enhancement of an optimal nutritional status should be regarded as a vital part of nursing. Registered nurses must therefore be viewed as having an important role in assessing and evaluating the nutritional needs of older people as well as the ability to intervene in cases of malnutrition. This study aimed to illuminate the experience of participating in nutritional care from the perspectives of older people and registered nurses. A further aim is to illuminate the latter's experience of nutritional care per se. Methods: A qualitative, descriptive design was adopted. Data were collected through semi-structured interviews (n = 12) with eight registered nurses and four older persons (mean age 85.7 years) in a city in the southern part of Sweden. The subsequent analysis was conducted by content analysis. Result: The analysis reflected three themes: 'participation in nutritional care equals information', 'nutritional care out of remit and competence' and 'nutritional care more than just choosing a flavour'. They were interpreted to illuminate the experience of participation in nutritional care from the perspective of older people and RNs, and the latter's experience of nutritional care in particular per se. Conclusions: Our findings indicate that a paternalistic attitude in care as well as asymmetry in the nurse-patient relationship are still common characteristics of modern clinical nursing practice for older people. Considering that participation should be central to nursing care, and despite the RN's awareness of the importance of involving the older persons in their nutritional care this was not reflected in reality. Strategies to involve older persons in their nutritional care in a nursing home context need to take into account that for this population participation might not always be experienced as an important part of nursing care. PMID- 29760583 TI - LncRNA PVT1 promotes the growth of HPV positive and negative cervical squamous cell carcinoma by inhibiting TGF-beta1. AB - Background: Our study aimed to investigate the role of lncRNA PVT1 in cervical squamous cell carcinoma. Materials and methods: A total of 156 patients with cervical squamous cell carcinoma were enrolled in this study and human papillomavirus (HPV) infection was detected by highly sensitive PCR techniques. Serum levels of PVT1 in patients infected with different HPVs and healthy controls was detected by qRT-PCR and compared. Serum levels of PVT1 were also compared among patients with different sizes of tumor. ROC curve analysis was performed to evaluate the diagnostic values of serum for cervical squamous cell carcinoma. Survival curves were plotted by Kaplan-Meier method and compared to evaluate the prognostic values of serum PVT1 for this disease. Effects of PVT1 siRNA silencing and overexpression on proliferation of cervical squamous cell carcinoma cells were explored by CCK-8 assay. Western blot was performed to detect the expression of TGF-beta1 after PVT1 siRNA silencing and overexpression. Results: No significant differences in serum levels of PVT1 were detected among patients infected with different HPVs and HPV-negative patients. However, serum levels of PVT1 were significantly higher in all patient groups than in healthy control group. Serum level of PVT1 increased with the increased sizes of primary tumor. Serum PVT1 accurately predicted the disease and its prognosis. PVT1 siRNA silencing inhibited the proliferation of cancer cells and reduced the expression of TGF-beta1, while PVT1 overexpression played an opposite role. Conclusion: LncRNA PVT1 promotes the growth HPV positive and negative cervical squamous cell carcinoma by inhibiting TGF-beta1. PMID- 29760585 TI - miR-93-5p enhance lacrimal gland adenoid cystic carcinoma cell tumorigenesis by targeting BRMS1L. AB - Background: Lacrimal adenoid cystic carcinoma (LACC) is one of the most common malignancies that affects lacrimal gland. MicroRNAs are known to play a crucial role as oncogenes or tumor suppressors. Specifically, miR-93 has been reported to play a crucial role in colorectal, breast, pancreatic, lung cancer and hepatocellular carcinoma. However, the role of miR-93 in LACC and the potential molecular mechanisms involved remain unknown. Therefore, we took the challenge to determine the involvement of miR-93 in the LACC by targeting BRMS1L. Method: A total of 5 adenoid cystic carcinoma (ACC) of lacrimal gland patient tissues and their plasma were examined. Three normal lacrimal glands and three normal serums were collected as a control group. After surgical resection, the specimens were preserved in liquid nitrogen and stored at - 80 degrees C until RNA extraction. Afterwards, LACC cells with miR-93-5p overexpression were subjected to qRT-PCR and western blot for epithelial-mesenchymal transition (EMT) markers levels. Ability of LACC cell migration, invasion, proliferation and apoptosis was examined by wounded healing, transwell, CCK-8 and apoptosis assays. Afterwards, TargetScan was used to predict putative targets of miR-93-5p. Then, the examination was performed whether miR-93-5p targets BRMS1L by the use of luciferase reporter assays and western blotting. Finally, immunohistochemical staining was sone and all the images were taken using a microscope (Nikon, Tokyo). Results: Our results showed that miR-93 was overexpressed in tissues and plasma of LACC patients compared to healthy controls. MiR-93 downregulated E cadherin expression while increasing N-cadherin expression and significantly inhibited luciferase activity. Furthermore, western blotting results confirmed that miR-93-5p could inhibit BRMS1L expression. The BRMS1L staining in LACC tissues was weaker than in normal controls. In addition, miR-93-5p revealed a reverse correlation with the expression of BRMS1L. In addition, significant upregulation of E-cadherin and downregulation of N-cadherin were found when LACC cells were transfected with BRMS1L. Finally, miR-93-5p significantly enhanced TOP/FOP luciferase activity. Upregulation of BRMS1L reduced TOP/FOP luciferase activity while further overexpression of miR-93-5p could not rescue Wnt signaling activity. Conclusions: Our findings report that miR-93 promotes LACC cell migration, invasion, and proliferation via targeting downregulation of BRMS1L through regulation of Wnt signaling pathway. PMID- 29760584 TI - LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models. AB - Background: Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. Methods: We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. Results: Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. Conclusion: LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted. PMID- 29760586 TI - Atorvastatin and diacerein reduce insulin resistance and increase disease tolerance in rats with sepsis. AB - Background: Sepsis is one of the leading causes of death among hospitalized patients. At the onset of this condition, there is an over-production of pro inflammatory mediators that contribute to organ failure and death. The excess production of pro-inflammatory mediators also impairs insulin signaling, which may be a pathophysiological tissue marker of proinflammatory cytokine action before organ failure. Statins and diacerein have pleiotropic effects, such as the blockage of inflammatory signaling pathways, suggesting that these drugs may be an attractive therapeutic or prophylactic strategy against sepsis. The aim of the present study was to investigate whether a statin or diacerein can improve insulin signaling, disease tolerance and survival in sepsis by inhibiting inflammatory pathways. Methods: We investigated the effect of these drugs on survival, tissue insulin signaling and inflammatory pathways in the liver and muscle of rats with sepsis induced by cecal ligation and puncture (CLP). Results: The results showed that administration of medications, with anti-inflammatory ability, to septic animals increased survival and improved disease tolerance and insulin resistance in the liver and muscle. The treatment also attenuated ER stress, NF-kappaB, JNK activation and restored glucose-6-phosphatase (G6Pase) levels in the liver. Conclusions: Our results indicate that atorvastatin and diacerein treatment can modulate inflammatory pathways and, in parallel, attenuate insulin resistance in sepsis. Since these two drugs have safety profiles and minimal side effects, we suggest that these drugs may be alternative therapies for the prevention or therapies for the treatment of insulin resistance in sepsis, which could potentially reduce mortality in patients with sepsis. PMID- 29760587 TI - The role of adipokines in skeletal muscle inflammation and insulin sensitivity. AB - Background: There is currently an unmet clinical need to develop better pharmacological treatments to improve glucose handling in Type II Diabetes patients with obesity. To this end, determining the effect of obesity-associated adipokines on skeletal muscle insulin sensitivity has emerged as an important area of drug discovery research. This review draws together the data on the functional role of adipokines on skeletal muscle insulin signalling, highlights several understudied novel adipokines and provides a perspective on the direction of future research. Main body: The adipokines leptin, resistin, visfatin and adiponectin have all been shown to affect skeletal muscle insulin sensitivity by impacting on the activity of components within insulin signalling pathways, affecting GLUT4 translocation and modulating insulin-mediated skeletal muscle glucose uptake. Furthermore, proteomic analysis of the adipose tissue secretome has recently identified several novel adipokines including vaspin, chemerin and pref-1 that are associated with obesity and insulin resistance in humans and functionally impact on insulin signalling pathways. However, predominantly, these functional findings are the result of studies in rodents, with in vitro studies utilising either rat L6 or murine C2C12 myoblasts and/or myotubes. Despite the methodology to isolate and culture human myoblasts and to differentiate them into myotubes being established, the use of human muscle in vitro models for the functional validation of adipokines on skeletal muscle insulin sensitivity is limited. Conclusion: Understanding the mechanism of action and function of adipokines in mediating insulin sensitivity in skeletal muscle may lead to the development of novel therapeutics for patients with type 2 diabetes. However, to date, studies conducted in human skeletal muscle cells and tissues are limited. Such human in vitro studies should be prioritised in order to reduce the risk of candidate drugs failing in the clinic due to the assumption that rodent skeletal muscle target validation studies will to translate to human. PMID- 29760590 TI - Evaluation of high-grade astrocytoma recurrence patterns after radiotherapy in the era of temozolomide: A single institution experience. AB - Aim: Evaluating the recurrence patterns of high-grade astrocytomas in patients who were treated with radiotherapy (RT) plus temozolomide (TMZ). Background: The current literature suggests that reducing the margins added to the CTV does not significantly change the risk of recurrence and overall survival; thus, we decided to analyze our data and to examine the possibility of changing the adopted margins. Materials and methods: From February 2008 till September 2013, 55 patients were treated for high-grade astrocytomas, 20 patients who had been confirmed to have recurrence were selected for the present study. Post-operative MRI was superimposed on the planning CT images in order to correlate the anatomical structures with the treatment targets. Recurrences were defined according to the Response Assessment Criteria for Glioblastoma. The mean margins of the PTVinitial and PTVboost were 1.2 cm and 1.4 cm, respectively. The analysis of the percentage of the recurrence volume (Volrec) within the 100% isodose surface was based on the following criteria: (I) Central: >95% of the Volrec; (II) In-field: 81-95% of the Volrec; (III) Marginal: 20-80% of the Volrec; and (IV) Outside: <20% of the Volrec. Results: Of the 20 patients, 13 presented with central recurrences, 3 with in-field recurrences, 2 with marginal recurrences and 2 with outside recurrences. Therefore, the lower Volrec within 100% of the prescribed dose was considered in the classification. Conclusions: Of the selected patients, 80% had >=81-95% of the Volrec within 100% of the prescribed dose and predominantly had central or in-field recurrences. These results are comparable with those from the literature. PMID- 29760591 TI - CyberKnife Stereotactic Radiosurgery in brain metastases: A report from Latin America with literature review. AB - Background and aim: Stereotactic radiosurgery is increasingly being employed for the treatment of brain metastases, both as an adjuvant to surgical resection, and also as a primary treatment modality. The aim of this study is to evaluate overall survival and local control in patients with brain metastases treated with CyberKnife Stereotactic Radiosurgery (CKRS), due to the lack of evidence reported in Latin America. Materials and methods: We performed a retrospective chart review from October 2011 to January 2017 of 49 patients with 152 brain metastases. Clinical and prognostic factors were further analyzed by independent analysis. Kaplan-Meier curves were constructed for overall survival and local control. The median follow-up period was 12 months (range, 1-37 months). Results: The median age was 61 years (range, 27-85 years) and Karnofsky performance status >70 in 96% of the patients. The median overall survival rate was 15.5 months (95% confidence interval [CI], 10.23-24.3 months). Overall 3-month, 6-month and 1-year local control rates were 98% (95% CI, 85-99%), 96% (95% CI, 82-99%), and 90% (94% IC, 76-96%), respectively. Local failure (LF) was observed in 6 patients (18 lesions). No late complications, such as radiation necrosis, were observed during the follow-up period. Conclusions: CKRS achieves excellent overall survival and local control rates with low toxicity in patients with brain metastases. PMID- 29760593 TI - Dosimetric effect of limited aperture multileaf collimator on VMAT plan quality: A study of prostate and head-and-neck cancers. AB - Aim: The aim of study was to evaluate the dosimetric effect of collimator rotation on VMAT plan quality, when using limited aperture multileaf collimator of Elekta Beam ModulatorTM providing a maximum aperture of 21 cm * 16 cm. Background: The increased use of VMAT technique to deliver IMRT from conventional to very specialized treatments present a challenge in plan optimization. In this study VMAT plans were optimized for prostate and head and neck cancers using Elekta Beam-ModulatorTM, whereas previous studies were reported for conventional Linac aperture. Materials and methods: VMAT plans for nine of each prostate and head-and-neck cancer patients were produced using the 6 MV photon beam for Elekta SynergyS(r) Linac using Pinnacle3 treatment planning system. Single arc, dual arc and two combined independent-single arcs were optimized for collimator angles (C) 0 degrees , 90 degrees and 0 degrees -90 degrees (0 degrees -90 degrees ; i.e. the first-arc was assigned C0 degrees and second-arc was assigned C90 degrees ). A treatment plan comparison was performed among C0 degrees , C90 degrees and C(0 degrees -90 degrees ) for single-arc dual-arc and two independent-single-arcs VMAT techniques to evaluate the influence of extreme collimator rotations (C0 degrees and 90 degrees ) on VMAT plan quality. Plan evaluation criteria included the target coverage, conformity index, homogeneity index and doses to organs at risk. A 'two-sided student t-test' (p <= 0.05) was used to determine if there was a significant difference in dose volume indices of plans. Results: For both prostate and head-and-neck, plan quality at collimator angles C0 degrees and C(0 degrees -90 degrees ) was clinically acceptable for all VMAT-techniques, except SA for head-and-neck. Poorer target coverage, higher normal tissue doses and significant p-values were observed for collimator angle 90 degrees when compared with C0 degrees and C(0 degrees -90 degrees ). Conclusions: A collimator rotation of 0 degrees provided significantly better target coverage and sparing of organs-at-risk than a collimator rotation of 90 degrees for all VMAT techniques. PMID- 29760589 TI - Tumor microenvironment - Unknown niche with powerful therapeutic potential. AB - Head and neck squamous cell carcinomas (HNSCC) are in a group of cancers that are the most resistant to treatment. The survival rate of HNSCC patients has been still very low since last 20 years. The existence of relationship between oncogenic and surrounding cells is probably the reason for a poor response to treatment. Fibroblasts are an important element of tumor stroma which increases tumor cells ability to proliferate. Another highly resistance, tumorigenic and metastatic cell population in tumor microenvironment are cancer initiating cells (CICs). The population of cancer initiating cells can be found regardless of differentiation status of cancer and they seem to be crucial for HNSCC development. In this review, we describe the current state of knowledge about HNSCC biological and physiological tumor microenvironment. PMID- 29760594 TI - Uncertainty in positioning ion chamber at reference depth for various water phantoms. AB - Background: Uncertainty in the calibration of high-energy radiation sources is dependent on user and equipment type. Aim: We evaluated the uncertainty in the positioning of a cylindrical chamber at a reference depth for reference dosimetry of high-energy photon beams and the resulting uncertainty in the chamber readings for 6- and 10-MV photon beams. The aim was to investigate major contributions to the positioning uncertainty to reduce the uncertainty in calibration for external photon beam radiotherapy. Materials and methods: The following phantoms were used: DoseView 1D, WP1D, 1D SCANNER, and QWP-07 as one-dimensional (1D) phantoms for a vertical-beam geometry; GRI-7632 as a phantom for a fixed waterproofing sleeve; and PTW type 41023 and QWP-04 as 1D phantoms for a horizontal-beam geometry. The uncertainties were analyzed as per the Guide to the Expression of Uncertainty in Measurement. Results: The positioning and resultant uncertainties in chamber readings ranged from 0.22 to 0.35 mm and 0.12-0.25%, respectively, among the phantoms (using a coverage factor k = 1 in both cases). The major contributions to positioning uncertainty are: definition of the origin for phantoms among users for the 1D phantoms for a vertical-beam geometry, water level adjustment among users for the phantom for a fixed waterproofing sleeve, phantom window deformation, and non-water material of the window for the 1D phantoms for a horizontal-beam geometry. Conclusion: The positioning and resultant uncertainties in chamber readings exhibited minor differences among the seven phantoms. The major components of these uncertainties differed among the phantom types investigated. PMID- 29760588 TI - In vitro gentamicin exposure alters caveolae protein profile in cochlear spiral ligament pericytes. AB - Background: The aminoglycoside antibiotic gentamicin is an ototoxic drug and has been used experimentally to investigate cochlear damage induced by noise.We have investigated the changes in the protein profile associated with caveolae in gentamicin treated and untreated spiral ligament (SL) pericytes, specialized cells in the blood labyrinth barrier of the inner ear microvasculature. Pericytes from various microvascular beds express caveolae, protein and cholesterol rich microdomains, which can undergo endocytosis and transcytosis to transport small molecules in and out the cells. A different protein profile in transport specialized caveolae may induce pathological changes affecting the integrity of the blood labyrinth barrier and ultimately contributing to hearing loss. Method: Caveolae isolation from treated and untreated cells is achieved through ultracentrifugation of the lysates in discontinuous gradients. Mass spectrometry (LC-MS/MS) analysis identifies the proteins in the two groups. Proteins segregating with caveolae isolated from untreated SL pericytes are then compared to caveolae isolated from SL pericytes treated with the gentamicin for 24 h. Data are analyzed using bioinformatic tools. Results: The caveolae proteome in gentamicin treated cells shows that 40% of total proteins are uniquely associated with caveolae during the treatment, and 15% of the proteins normally associated with caveolae in untreated cell are suppressed. Bioinformatic analysis of the data shows a decreased expression of proteins involved in genetic information processing, and an increase in proteins involved in metabolism, vesicular transport and signal transduction in gentamicin treated cells. Several Rab GTPases proteins, ubiquitous transporters, uniquely segregate with caveolae and are significantly enriched in gentamicin treated cells. Conclusion: We report that gentamicin exposure modifies protein profile of caveolae from SL pericytes. We identified a pool of proteins which are uniquely segregating with caveolae during the treatment, mainly participating in metabolic and biosynthetic pathways, in transport pathways and in genetic information processing. Finally, we show for the first time proteins associated with caveolae SL pericytes linked to nonsyndromic hearing loss. PMID- 29760592 TI - 4D modeling in a gimbaled linear accelerator by using gold anchor markers. AB - Purpose: The purpose of this study was to verify whether the dynamic tumor tracking (DTT) feature of a Vero4DRT system performs with 10-mm-long and 0.28 mm diameter gold anchor markers. Methods: Gold anchor markers with a length of 10 mm and a diameter of 0.28 mm were used. Gold anchor markers were injected with short and long types into bolus material. These markers were sandwiched by a Tough Water (TW) phantom in the bolus material. For the investigation of 4-dimensional (4D) modeling feasibility under various phantom thicknesses, the TW phantom was added at 2 cm intervals (in upper and lower each by 1 cm). A programmable respiratory motion table was used to simulate breathing-induced organ motion, with an amplitude of 30 mm and a breathing cycle of 3 s. X-ray imaging parameters of 80 kV and 125 kV (320 mA and 5 ms) were used. The least detection error of the fiducial marker was defined as the 4D-modeling limitation. Results: The 4D modeling process was attempted using short and long marker types and its limitation with the short and long types was with phantom thicknesses of 6 and 10 cm at 80 kV and 125 kV, respectively. However, the loss in detectability of the gold anchor because of 4D-modeling errors was found to be approximately 6% (2/31) with a phantom thickness of 2 cm under 125 kV. 4D-modeling could be performed except under the described conditions. Conclusions: This work showed that a 10-mm long gold anchor marker in short and long types can be used with DTT for short water equivalent path length site, such as lung cancer patients, in the Vero4DRT system. PMID- 29760596 TI - 11C-methionine positron emission tomography for target delineation of recurrent glioblastoma in re-irradiation planning. AB - Aim: To define the optimal margin on MRI scans in the re-radiation planning of recurrent glioblastoma using methionine positron emission tomography (MET-PET). Background: It would be very useful if the optimal margin on MRI to cover the uptake area on MET-PET is known. Materials and Methods: CT, MRI, and MET-PET were performed separately over the course of 2 weeks. Among the MRI scans, we used the contrast-enhanced T1-weighted images (Gd-MRI) and T2-weighted images (T2-MRI). The Gd-MRI-based clinical target volume (CTV) (CTV-Gd) and the T2-MRI-based CTV (CTV-T2) were defined as the contrast-enhanced area on Gd-MRI and the high intensity area on T2-MRI, respectively. We defined CTV x mm (x = 5, 10, 15, 20) as x mm outside the CTV. MET-PET-based CTV (CTV-MPET) was defined as the area of accumulation of MET-PET. We calculated the sensitivity and specificity of CTV-Gd and CTV-T2 following comparison with CTV-MPET, which served as the gold standard in this study. Results: The sensitivity of CTV-T2 5 mm (98%) was significantly higher than CTV-T2 (87%), and there was no significant difference in the sensitivity between CTV-T2 5 mm and CTV T2 10, 15, or 20 mm. The sensitivity of CTV-Gd 20 mm (97%) was lower than that of CTV-T2 5 mm (98%). Conclusions: A margin of at least 5 mm around the high intensity area on T2-MRI is necessary in the target volume delineation of recurrent glioblastoma for the coverage of MET PET findings in re-radiation therapy planning. PMID- 29760595 TI - Application of induced pluripotency in cancer studies. AB - As soon as induced pluripotent stem cells (iPSCs) reprogramming of somatic cells were developed, the discovery attracted the attention of scientists, offering new perspectives for personalized medicine and providing a powerful platform for drug testing. The technology was almost immediately applied to cancer studies. As presented in this review, direct reprogramming of cancer cells with enforced expression of pluripotency factors have several basic purposes, all of which aim to explain the complex nature of cancer development and progression, therapy resistance and relapse, and ultimately lead to the development of novel anti cancer therapies. Here, we briefly present recent advances in reprogramming methodologies as well as commonalities between cell reprogramming and carcinogenesis and discuss recent outcomes from the implementation of induced pluripotency into cancer research. PMID- 29760597 TI - Application of an incident taxonomy for radiation therapy: Analysis of five years of data from three integrated cancer centres. AB - Aim: To develop and apply a clinical incident taxonomy for radiation therapy. Background: Capturing clinical incident information that focuses on near-miss events is critical for achieving higher levels of safety and reliability. Methods and materials: A clinical incident taxonomy for radiation therapy was established; coding categories were prescription, consent, simulation, voluming, dosimetry, treatment, bolus, shielding, imaging, quality assurance and coordination of care. The taxonomy was applied to all clinical incidents occurring at three integrated cancer centres for the years 2011-2015. Incidents were managed locally, audited and feedback disseminated to all centres. Results: Across the five years the total incident rate (per 100 courses) was 8.54; the radiotherapy-specific coded rate was 6.71. The rate of true adverse events (unintended treatment and potential patient harm) was 1.06. Adverse events, where no harm was identified, occurred at a rate of 2.76 per 100 courses. Despite workload increases, overall and actual rates both exhibited downward trends over the 5-year period. The taxonomy captured previously unidentified quality assurance failures; centre-specific issues that contributed to variations in incident trends were also identified. Conclusions: The application of a taxonomy developed for radiation therapy enhances incident investigation and facilitates strategic interventions. The practice appears to be effective in our institution and contributes to the safety culture. The ratio of near miss to actual incidents could serve as a possible measure of incident reporting culture and could be incorporated into large scale incident reporting systems. PMID- 29760599 TI - Vascular Erectile Dysfunction and Subclinical Cardiovascular Disease. AB - Purpose of review: We review the recent literature on the hypothesized temporal relationship between subclinical cardiovascular disease (CVD), vascular erectile dysfunction (ED), and clinical CVD. In addition, we combine emerging research with expert consensus guidelines such as The Princeton Consensus III to provide a preventive cardiologist's perspective toward an ideal approach to evaluating and managing CVD and ED risk in patients. Recent findings: Development of ED was found to occur during the progression from subclinical CVD to clinical CVD. A strong association was observed between subclinical CVD as assessed by coronary artery calcium (CAC) and carotid plaque and subsequent ED, providing evidence for the role of subclinical CVD in predicting ED. ED is also identified as a substantial independent risk factor for overt clinical CVD, and ED symptoms may precede CVD symptoms by 2-3 years. Summary: Given the body of evidence on the relationship between subclinical CVD, ED, and clinical CVD we recommend that all men with vascular ED should undergo cardiovascular risk assessment. We further recommend using CAC scores for advanced risk assessment in patients at low intermediate to intermediate risk (5-20% CVD risk), with risk driving subsequent lifestyle and pharmacologic treatment decisions. PMID- 29760598 TI - Predictors of chemoradiation related febrile neutropenia prophylaxis in older adults - Experience from a limited resource setting. AB - Aim: To identify risk factors that lower efficacy of antibiotic prophylaxis of febrile neutropenia among older patients on chemoradiation. Background: Audit of institutional data showed that older adults are at higher risk of febrile neutropenia during chemoradiation. In limited resource settings widespread use of Granulocyte-Colony Stimulating Factor (G-CSF) is not economically feasible and antibiotics are used commonly. Despite compliance with antibiotics, prophylaxis is inadequate in many patients owing to patient and tumor related factors. Materials and methods: Data from records of 219 older patients receiving antibiotic prophylaxis during chemoradiation were studied. Baseline assessment data and predisposing factors for febrile neutropenia were recorded. All patients received prophylactic fluoroquinolones. Incidence of febrile neutropenia and association with predisposing factors at baseline was analyzed by multiple logistic regression. Results: 38.4% developed febrile neutropenia despite compliance. Multiple logistic regression revealed geriatric assessment (G8) score and tumor stage to be significant predictors of febrile neutropenia while on antibiotics (p < 0.0001). Odds ratios for two significant predictors G8 score and tumor stage, respectively, were 2.9 (95% CI 1.8036-4.6815) and 2.7 (95% CI 1.7501 4.1318). Correlation between these two significant predictors was found to be low in our cohort (Spearman's coefficient of rank correlation (rho) - 0.431, p < 0.0001). Conclusion: G8 score and tumor burden are significant predictors of efficacy of antibiotic prophylaxis among older adults receiving chemoradiation. In older patients having poor G8 scores and advanced tumors, antibiotic prophylaxis is unsuitable. Interestingly, co-morbidities and poor performance status did not impact efficacy of antibiotic prophylaxis among our elderly patients. PMID- 29760600 TI - Comprehensive proteome analysis of nasal lavage samples after controlled exposure to welding nanoparticles shows an induced acute phase and a nuclear receptor, LXR/RXR, activation that influence the status of the extracellular matrix. AB - Background: Epidemiological studies have shown that many welders experience respiratory symptoms. During the welding process a large number of airborne nanosized particles are generated, which might be inhaled and deposited in the respiratory tract. Knowledge of the underlying mechanisms behind observed symptoms is still partly lacking, although inflammation is suggested to play a central role. The aim of this study was to investigate the effects of welding fume particle exposure on the proteome expression level in welders suffering from respiratory symptoms, and changes in protein mediators in nasal lavage samples were analyzed. Such mediators will be helpful to clarify the pathomechanisms behind welding fume particle-induced effects. Methods: In an exposure chamber, 11 welders with work-related symptoms in the lower airways during the last month were exposed to mild-steel welding fume particles (1 mg/m3) and to filtered air, respectively, in a double-blind manner. Nasal lavage samples were collected before, immediately after, and the day after exposure. The proteins in the nasal lavage were analyzed with two different mass spectrometry approaches, label-free discovery shotgun LC-MS/MS and a targeted selected reaction monitoring LC-MS/MS analyzing 130 proteins and four in vivo peptide degradation products. Results: The analysis revealed 30 significantly changed proteins that were associated with two main pathways; activation of acute phase response signaling and activation of LXR/RXR, which is a nuclear receptor family involved in lipid signaling. Connective tissue proteins and proteins controlling the degradation of such tissues, including two different matrix metalloprotease proteins, MMP8 and MMP9, were among the significantly changed enzymes and were identified as important key players in the pathways. Conclusion: Exposure to mild-steel welding fume particles causes measurable changes on the proteome level in nasal lavage matrix in exposed welders, although no clinical symptoms were manifested. The results suggested that the exposure causes an immediate effect on the proteome level involving acute phase proteins and mediators regulating lipid signaling. Proteases involved in maintaining the balance between the formation and degradation of extracellular matrix proteins are important key proteins in the induced effects. PMID- 29760601 TI - Tumor Cell-Accelerated Senescence Is Associated With DNA-PKcs Status and Telomere Dysfunction Induced by Radiation. AB - Whether telomere structure integrity is related to radiosensitivity is not well investigated thus far. In this study, we investigated the relation between telomere instability and radiation-induced accelerated senescence. Partial knockdown of DNA-dependent catalytic subunit of protein kinase (DNA-PKcs) in human breast cancer cell line MCF-7 was established by small interfering RNA. Radiosensitivity of control and DNA-PKcs knockdown MCF-7 cells was analyzed by clonogenetic assay. Cell growth was measured by real-time cell electronic sensing. Senescence and apoptosis were evaluated by beta-galactosidase histochemical staining and fluorescence-activated cell sorting, respectively. DNA damage was determined by long polymerase chain reaction (PCR). Telomere length and integrity were analyzed by real-time PCR and cytogenetic assay, respectively. DNA-PKcs knockdown MCF-7 cells were more sensitive to X-irradiation than control cells. Further investigation revealed that accelerated senescence is more pronounced than apoptosis in cells after radiation, particularly in DNA-PKcs knockdown cells. The cytogenetic assay and kinetics of DNA damage repair revealed that the role of telomere end-capping in DNA-PKcs, rather than DNA damage repair, was more relevant to radiosensitivity. To our knowledge, this is the first study to show that DNA-PKcs plays an important role in radiation-induced accelerated senescence via maintenance of telomere integrity in MCF-7 cells. These results could be useful for future understanding of the radiation-induced genome instability and its consequences. PMID- 29760604 TI - Tuning the optical properties of poly(o-phenylenediamine-co-pyrrole) via template mediated copolymerization. AB - Tailoring of conjugated monomers via copolymerization is a facile method to obtain tunable spectral, morphological and optical properties. To investigate the effect of copolymerization of pyrrole with o-phenylenediamine on the optoelectronic properties of the synthesized copolymers, the present work reports the synthesis of copolymers of o-phenylenediamine with pyrrole with varying mol ratios via chemical polymerization in methylene blue (MB) medium. Copolymerization was confirmed by Fourier transform infrared spectroscopy and ultraviolet-visible studies. Ultraviolet-visible spectroscopy revealed variation in the optical properties with the change in the monomer ratio. Fluorescence studies showed that the copolymer containing 80% poly(o-phenylenediamine) revealed highest quantum yield among all the copolymers. The emission color could therefore be tuned by careful selection of narrow band co-monomers, which could help in designing tunable fluorescence emitting materials for potential application in OLED devices. PMID- 29760602 TI - Sodium Valproate Inhibits Small Cell Lung Cancer Tumor Growth on the Chicken Embryo Chorioallantoic Membrane and Reduces the p53 and EZH2 Expression. AB - The study aims to test the effect of different sodium valproate (NaVP) doses on small cell lung cancer NCI-H146 cells tumor in chicken embryo chorioallantoic membrane (CAM) model. Xenografts were investigated in the following groups: nontreated control and 5 groups treated with different NaVP doses (2, 3, 4, 6, and 8 mmol/L). Invasion of tumors into CAM in the nontreated group reached 76%. Tumors treated with 8 mmol/L NaVP doses significantly differed in tumor invasion frequency from the control and those treated with 2 mmol/L (P < .01). The calculated probability of 50% tumor noninvasion into CAM was when tumors were treated with 4 mmol/L of NaVP. Number of p53-positive cells in tumors was significantly reduced when treated with NaVP doses from 3 to 8 mmol/L as compared with control; number of EZH2-positive cells in control significantly differed from all NaVP-treated groups. No differences in p53- and EZH2-positive cell numbers were found among 4, 6, and 8 mmol/L NaVP-treated groups. Invaded tumors had an increased N-cadherin and reduced E-cadherin expression. The results indicate the increasing NaVP dose to be able to inhibit tumors progression. Expression of p53 and EZH2 may be promising target markers of therapeutic efficacy evaluation. PMID- 29760605 TI - National Trend of Uroflowmetry, Urodynamic Study and Cystoscopy Considering the Change in the Population Structure in Korea from 2010 to 2015. AB - Background: Although lower urinary tract symptoms (LUTS) show a higher prevalence with age, few studies have reported the trend of these examination tools including uroflowmetry, urodynamic study and cystoscopy. Methods: We evaluated the trend of performance of uroflowmetry, urodynamic study and cystoscopy by using National Health Insurance Data from 2010 to 2015. Primary outcome findings included cumulative number of patients per year, cumulative age-standardized patient rate per year and per age group, and correlation between the number of patients per year and the percentage of population per year in each age group. Results: The overall trend for frequency of uroflowmetry and cystoscopy showed an increasing pattern (P < 0.001, respectively) while the trend for frequency of urodynamic study showed a decreasing pattern (P < 0.001). After age standardization, the overall trend showed similar results. Correlation between the number of patients per year and the percentage of population per year showed a positive correlation in the 50s age group and the above 70s age group (P = 0.003 and < 0.01, respectively) on uroflowmetry and in the above 70s age group (P < 0.01) on cystoscopy. Urodynamic study showed negative correlations in the 50s age group and the above 60s age group (P = 0.001 and 0.01, respectively). Conclusion: National trend for frequency of uroflowmetry, urodynamic study and cystoscopy showed a different trend. The increasing trend of uroflowmetry and cystoscopy was related with growth of the aged population. However, urodynamic study showed a decreasing trend regardless of the age group. PMID- 29760606 TI - Influence of Major Coping Strategies on Treatment Non-adherence and Severity of Comorbid Conditions in Hemodialysis Patients. AB - Background: Non-adherence and comorbidities are prevalent among hemodialysis patients and are associated with increased mortality and financial burden. We aimed to investigate the influence of major coping strategies (CSs) on non adherence and comorbidities in hemodialysis patients. Methods: A total of 49 patients were enrolled. We collected participant data including CS measured by a Korean version of the ways of coping questionnaire (K-WCQ), comorbidities measured by age-adjusted Charlson comorbidity index (CCI), and adherence measured by the 8-item Morisky medication adherence scale (MMAS-8). Results: Regarding major CS, 61.2% of participants reported use of support-seeking CS (SUP group), 14.3% reported use of problem-focused CS (PRO group), and 24.5% reported use of hopeful-thinking CS (HOP group). The mean MMAS-8 score was higher in the PRO group than in the HOP group (P = 0.024). The mean CCI score was lower in the PRO group than in the HOP group (P = 0.017). In the HOP group, the severity of somatic symptoms was positively correlated with the scores for the emotion focused CS subscale (r = 0.39, P = 0.029) and the hopeful-thinking CS subscale (r = 0.38, P = 0.036) of the K-WCQ. The level of life satisfaction positively correlated with the score for the problem-focused CS subscale in the HOP group (r = 0.40, P = 0.027). Conclusion: We should pay more attention to the CSs of hemodialysis patients and provide interventions that promote problem-focused CSs, especially for nonadherent patients with high comorbidity rates who mainly use a hopeful-thinking CS. PMID- 29760603 TI - Relationship Between Aerobic Capacity With Oxidative Stress and Inflammation Biomarkers in the Blood of Older Mexican Urban-Dwelling Population. AB - The maximal oxygen uptake (VO2max) constitutes an indicator of an organism's capacity to integrate oxygen into the metabolism to obtaining energy. The aim of this study was to determine the relationship between VO2max and oxidative stress (OxS) and chronic inflammation in the elderly individuals. A cross-sectional and exploratory study was conducted in a sample of 52 older persons. We measured plasma lipid peroxides (LPO), red blood cell glutathione peroxidase, red blood cell superoxide dismutase, and total antioxidant status. The interleukin 10 and tumor necrosis factor-alpha (TNF-alpha) were measured in serum by ELISA. The VO2max was determined by the Rockport aerobic test, and the energy expenditure (caloric expenditure and metabolic equivalence unit (MET) per day) was measured by a 3-day activity record. We observed a positive correlation between VO2 max with IL-10, MET/day*day-1 and kcal*day-1 (r = 0.31, P < .05, r = 0.44, P < .01, and r = 0.29, P < .05, respectively), and a negative correlation with the body mass index, TNF-alpha, and LPO (r = -0.27, P < .05, r = -0.29, P < .05, and r = 0.40, P < .01 respectively). Our findings suggest that there is an inverse relationship between the aerobic capacity and the OxS and chronic inflammation biomarkers in the blood in older Mexican adults. PMID- 29760607 TI - Association between BMI for Obesity and Distress about Appearance in Korean Adolescents. AB - Background: Previous research has related obesity to body dissatisfaction and low self-esteem. This study aimed to evaluate this relation between obesity and distress about appearance. Methods: We performed a cross-sectional study using data from the Korea Youth Risk Behavior Web-based Survey for 288,390 participants assessed from 2009 to 2012. The participants were categorized according to body mass index; obese, overweight, healthy weight, and underweight. The relation between obesity and distress was analyzed using simple and multiple logistic regression with complex sampling adjusted for age, sex, region of residence, economic level, parental education level, alcohol consumption, and smoking habits as confounders. Results: The adjusted odds ratio (AOR) was higher for participants with obesity (AOR for healthy weight = 1.15 [95% confidence interval {CI}, 1.08-1.22]; AOR for overweight = 1.85 [95% CI, 1.72-1.98]; AOR for obese = 2.45 [95% CI, 2.27-2.64]; reference = underweight, P < 0.001). In males, healthy weight was associated with an AOR below 1 (AOR for healthy weight = 0.92 [95% CI, 0.85-0.99]; AOR for overweight = 1.26 [95% CI, 1.14-1.38]; AOR for obese = 1.66 [95% CI, 1.50-1.84], P < 0.001). In females, higher AORs were associated with obesity (AOR for healthy weight = 1.44 [95% CI, 1.33-1.57]; AOR for overweight = 2.71 [95% CI, 2.45-2.99]; AOR for obese = 3.71 [95% CI, 3.32-4.14], P < 0.001). Conclusion: Obesity is related to distress about appearance, and the relation is stronger in girls than in boys. PMID- 29760608 TI - Calf Circumference as a Simple Screening Marker for Diagnosing Sarcopenia in Older Korean Adults: the Korean Frailty and Aging Cohort Study (KFACS). AB - Background: The purpose of this study was to explore the optimal cut-off point of calf circumference (CC) as a simple proxy marker of appendicular skeletal muscle mass (ASM) and sarcopenia in the Korean elderly and to test the criterion-related validity of CC by analyzing its relationships with the physical function. Methods: The participants were 657 adults aged 70 to 84 years who had completed both dual energy X-ray absorptiometry (DXA) and physical function test in the first baseline year of the Korean Frailty and Aging Cohort Study. Results: ASM and skeletal muscle mass index (SMI) were correlated positively with CC (male, ASM, r = 0.55 and SMI, r = 0.54; female, ASM, r = 0.55 and SMI, r = 0.42; all P < 0.001). Testing the validity of CC as a proxy marker for low muscle mass, an area under the curve (AUC) of 0.81 for males and 0.72 for females were found and their optimal cut-off values of CC were 35 cm for males and 33 cm for females. In addition, CC-based low muscle groups were correlated with physical functions even after adjusting for age and body mass index. Also, the cut-off value of CC for sarcopenia was 32 cm (AUC; male, 0.82 and female, 0.72). Conclusion: The optimal cut-off values of CC for low MM are 35 cm for males and 33 cm for females. Lower CC based on these cut-off values is related with poor physical function. CC may be also a good indicator of sarcopenia in Korean elderly. PMID- 29760610 TI - The structure and function of the epidermal barrier in patients with atopic dermatitis - treatment options. Part two. AB - Atopic dermatitis (AD) is a chronic and recurrent disease induced by underlying defects of the epidermal barrier and immunological disorders, typical of atopic diseases. The genetic and immunological mechanisms (outlined in the previous paper) affecting the dysfunction of the barrier are intensified by environmental factors, e.g. airborne and food allergens, infections and stress. For this reason, proper skin care, which prevents further damage and restores the epidermal barrier is of such importance in the field of AD therapy. Appropriate therapy is based on emollients which, coupled with anti-inflammatory and antipruritic treatment, should be used as the first-line therapy. The aim of the present paper is to outline the effects of the abovementioned factors on the dysfunction of the epidermal barrier as well as to emphasize the importance of proper atopic skin care in maintaining the integrity of the barrier and preventing exacerbation of the disease. PMID- 29760609 TI - Identification of potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma. AB - Background: This study aimed to identify potential crucial genes and construction of microRNA-mRNA negative regulatory networks in osteosarcoma by comprehensive bioinformatics analysis. Methods: Data of gene expression profiles (GSE28424) and miRNA expression profiles (GSE28423) were downloaded from GEO database. The differentially expressed genes (DEGs) and miRNAs (DEMIs) were obtained by R Bioconductor packages. Functional and enrichment analyses of selected genes were performed using DAVID database. Protein-protein interaction (PPI) network was constructed by STRING and visualized in Cytoscape. The relationships among the DEGs and module in PPI network were analyzed by plug-in NetworkAnalyzer and MCODE seperately. Through the TargetScan and comparing target genes with DEGs, the miRNA-mRNA regulation network was established. Results: Totally 346 DEGs and 90 DEMIs were found to be differentially expressed. These DEGs were enriched in biological processes and KEGG pathway of inflammatory immune response. 25 genes in the PPI network were selected as hub genes. Top 10 hub genes were TYROBP, HLA DRA, VWF, PPBP, SERPING1, HLA-DPA1, SERPINA1, KIF20A, FERMT3, HLA-E. PPI network of DEGs followed a pattern of power law network and met the characteristics of small-world network. MCODE analysis identified 4 clusters and the most significant cluster consisted of 11 nodes and 55 edges. SEPP1, CKS2, TCAP, BPI were identified as the seed genes in their own clusters, respectively. The miRNA mRNA regulation network which was composed of 89 pairs was established. MiR-210 had the highest connectivity with 12 target genes. Among the predicted target of MiR-96, HLA-DPA1 and TYROBP were the hub genes. Conclusion: Our study indicated possible differentially expressed genes and miRNA, and microRNA-mRNA negative regulatory networks in osteosarcoma by bioinformatics analysis, which may provide novel insights for unraveling pathogenesis of osteosarcoma. PMID- 29760612 TI - Trends in folic acid supplementation during pregnancy - the effect on allergy development in children. AB - Introduction: The results of some previous studies suggested that maternal folate supplementation during pregnancy may contribute to allergy development in offspring. Aim: This study was performed to examine the influence of maternal folic acid intake prior to and during pregnancy on the development of various types of allergy in children taking into account the timing and dosage of supplemented folate. Material and methods: The retrospective study was performed between 2010 and 2014 in 307 child-mother pairs (203 allergic children and 104 children without allergy symptoms, aged 2-72 months). Allergy diagnosis was based on medical history, physical examination, positive results of allergic tests: specific IgE and/or skin prick tests and double-blind, placebo-controlled food challenge. The data concerning maternal folate supplementation prior to and during pregnancy were obtained based on a questionnaire. Results: Mothers of allergic children used to take folic acid more frequently in the preconception period (42.9%), in the 1st (94.1%) and the 2nd/3rd (81.3%) trimester of pregnancy than mothers of the healthy ones (30.8%, 82.7% and 55.8%, respectively) (p < 0.05). Maternal intake of folate in a dosage higher than recommended (> 0.4 mg/day) was more often observed in the group of allergic subjects, especially in children with combined sensitization to food and inhalant allergens, than in the control group (p < 0.05). Conclusions: Our results suggest an impact of maternal folic acid supplementation prior to and during pregnancy on allergy development in children. Further observations are required to establish the role of folate in fetal epigenetic modifications. PMID- 29760613 TI - Latex immunotherapy: evidence of effectiveness. AB - Introduction: The only etiological and decisive therapy, able to influence the natural history of latex allergy is the specific desensitization. Aim: To verify the clinical efficacy and immunological changes determined by latex sublingual immunotherapy in allergic patients who underwent this treatment for at least 3 years. Material and methods: We enrolled 76 patients (16 males and 60 females, mean age 34 years old) with evidence of a natural rubber latex allergy. To assess the effectiveness of the immunotherapy we performed a latex skin prick test, specific IgE and IgG4 and challenge tests before and after at least 3 years of desensitization. Results: We observed a reduction in the mean diameter of the wheal area at the skin prick test and a decrease in latex specific IgE while no significant changes of latex IgG4 values were found. Moreover a reduction of symptoms and scores at the provocation tests were remarked. Conclusions: Although the primary prevention (which still remains the gold standard treatment for patients suffering from the latex allergy) sublingual immunotherapy can be offered with efficacy in addition to symptomatic treatment to selected patients. PMID- 29760611 TI - Clinicopathologic retrospective analysis of blastic plasmacytoid dendritic cell neoplasms. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is one of the aggressive rare hematopoietic malignancies with predilection to the skin, primarily found in adults. The precise incidence of BPDCN is difficult to estimate due to constantly changing nomenclature and lack of precise defining criteria prior to the 2008 WHO classification system. There are not many cases described in the literature, what makes the diagnostic process challenging. Skin lesions such as erythematous infiltrates and nodules are usually the first manifestation of the disease. Therefore, in doubtful diagnostic cases, dermatologists should perform histopathological and immunohistochemistry examinations along with hematological and oncological cooperation, as early diagnosis and appropriate treatment is essential for improvement of the disease course. This analysis, despite the small number of patients may provide useful information on the clinical and histopathological features of this rare malignancy. PMID- 29760614 TI - Eradication of Helicobacter pylori, as add-on therapy, has a significant, but temporary influence on recovery in chronic idiopathic urticaria: a placebo controlled, double blind trial in the Polish population. AB - Introduction: The infectious factor like Helicobacter pylori (HP) has been thought to trigger the vicious circle of chronic idiopathic urticaria (CIU), therefore its eradication could modify the course of the disease. Aim: To reveal the influence of HP eradication on CIU clinical course. Material and methods: Sixty-four CIU patients, receiving fexofenadine, as the basic treatment, took part in the research, divided into 3 groups: HP patients treated by eradication, HP patients receiving placebo, and patients without bacteria. Gastroscopy, urease test and histopathology were done to detect HP. Patients with HP were randomized and received eradication treatment or placebo. The efficacy of eradication was checked after 6 weeks by means of another gastroscopy, urease test and histopathology. In the 6th week and in the 4th and 6th month after eradication, the symptoms were evaluated basing on the score symptom scale. Results: Helicobacter pylori did not occur more frequently in CIU patients than in the healthy population. A statistically significant clinical improvement of CIU symptoms was observed in the 6th week after eradication as compared to the group receiving placebo (p = 0.02) and patients who were not infected (p = 0.02). Further observation in the eradicated patients group revealed the rebound phenomenon - worsening of the clinical state (p = 0.001), which in the 4th month did not differ from the patients not infected or patients receiving placebo. Conclusions: Although HP occurs as frequently in CIU patients as in the healthy population, eradication, added to basic antihistaminic treatment, has a significant influence on CIU patients' recovery parallel to the reduction of stomach inflammation features. PMID- 29760615 TI - Stress, itch and quality of life in chronic urticaria females. AB - Introduction: Chronic urticaria (CU) belongs to a group of psychodermatological disorders, thus stress can play a significant role in this dermatosis onset and/or exacerbation. On the other hand, the disease itself accompanied by itch, may be a source of distress and could worsen patients' quality of life (QoL). Aim: The first goal of our study was to compare stress intensity between CU subjects and the control group. The second aim was to investigate the relationships between disease-related parameters (CU severity, itch) and psychological variables (stress and QoL) in CU patients. Material and methods: Forty-six female patients with CU participated in our study. Thirty-three healthy females constituted a control group. The following methods were applied: Urticaria Activity Score (UAS), Itch Severity Evaluation Questionnaire, Visual analogue scale (VAS), Social Readjustment Rating Scale (SRRS) and the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL). Results: Chronic urticaria patients demonstrated a significantly higher stress level in comparison to the control group (z = 2.699; p < 0.001). Regarding the total pruritus score, all CU Q2oL dimensions were affected, except for subscale swelling/mental status. The strongest link was revealed between global itch and QoL subscale embarrassment (r = 0.51, p < 0.001). There were also statistically significant correlations between stress (VAS scale and SRRS) and QoL (all at least p < 0.05).Conclusions: Taking into account the significant pruritus contribution to QoL impairment, it would be worth employing itch-coping trainings in the CU group. As a consequence, feeling of self-control and self-efficacy could be enhanced, thus resulting in the well-being improvement. PMID- 29760616 TI - High frequency of primary hereditary ichthyoses in the North-East region of Cairo, Egypt. AB - Introduction: Inherited ichthyoses are caused by mutations in various genes important for keratinocyte differentiation and epidermal barrier function. Although ichthyoses are rare disorders, they require costly long-term medical management, and thus there is a need for efficient preventive and therapeutic strategies. Aim: We performed a retrospective study to determine the frequency, types, clinical presentation and associated genomic errors of primary hereditary ichthyoses in Egyptian patients and their relatives consulting the Genetics Clinic, Pediatric Hospital, Ain Shams University. Material and methods: The outpatient log books of patients between January 2000 and December 2014 were reviewed, and diagnosis of new patients was confirmed through examination by a dermatologist. All epidemiologic, demographic, and clinical data were extracted and recorded in especially designed data collection forms. Results: The occurrence rate of primary hereditary ichthyoses in our study was 25.7% of genodermatosis patients attending the genetics clinics and 1 per 2359 patients attending the Pediatric Hospital. The commonest type of ichthyosis in our study was Lamellar ichthyosis (38%), followed by congenital ichthyosiform erythroderma (26.8%). Consanguineous marriage was reported among the parents of 79% of patients and positive family history was reported in 72% of patients. Conclusions: To the best of our knowledge, this preliminary study is the first report on the clinico-epidemiological features of primary hereditary ichthyoses in Egypt. The high rate of prenatal consanguinity among parents of our patients may account for the high frequency of these genodermatoses in Egypt. This highlights the importance of genetic counselling and prenatal diagnosis in Egypt. PMID- 29760619 TI - ADAMTS13 deficiency and immunological abnormalities in patients with systemic sclerosis. AB - Introduction: Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disorder characterized by immunological deviations and generalized microvascular damage. Aim: To determine the serum level of the von Willebrand factor cleaving protease (ADAMTS13) in 39 SSc patients and healthy controls. Material and methods: ADAMTS13 serum level was determined in 39 SSc patients and 11 healthy controls. Complete history of the patients was recorded and thorough clinical, rheumatological, and dermatological examinations were performed. Results: The serum levels of ADAMTS13 were significantly lower in SSc than in normal controls (455.47 +/-128 vs. 702.01 +/-142 ng/ml, p < 0.00001). However significant correlations among serum ADAMTS 13 levels and organ changes were not found in SSc patients. Conclusions: We demonstrate a decreased serum level of ADAMTS13 in SSc patients, which may contribute to the vessel microangiopathy observed in systemic sclerosis. PMID- 29760618 TI - Demodex spp. as a possible aetiopathogenic factor of acne and relation with acne severity and type. AB - Introduction: Acne is a very common skin disease in adolescents and young adults, but it also affects adults. However, its aetiology is not yet fully understood. Demodex appears to be associated with multiple skin disorders, but controversy persists. Some reports indicate a connection between acne vulgaris and demodicosis. Aim: To confirm the association between Demodex infestation and acne vulgaris. Material and methods: A total of 108 patients were enrolled in the acne group. Acne severity was calculated as GASS and acne type (adolescent and post adolescent) was recorded. An age-sex matched healthy control group comprising 65 individuals were included in the study. Dermatological examinations were performed and an SSSB was used to determine the presence of Demodex. Results: In our study, Demodex positivity was seen in 46 (42.6%) patients in the acne group and 8 (12.3%) in the control group; this difference was statistically significant (p < 0.001). A multivariate Backward Step-By-Step Logistic Regression analysis identified the most effective factors for acne development such as Demodex positivity (OR = 5.565, 95% CI: 2.384-12.99 and p < 0.001) and age under 25 years (OR = 2.3 and 95% CI: 1.183-4.473 and p = 0.014). Alcohol consumption was related to Demodex positivity (p = 0.019) in post adolescent acne. Conclusions: Our study is the first one to evaluate acne severity, acne type and the relationship to Demodex prevalence. We suggest that Demodex infestation should be considered when the classical therapies are ineffective especially in cases of post adolescent acne. PMID- 29760617 TI - ROC analysis of selected matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in psoriatic patients. AB - Introduction: Psoriasis is a common, chronic inflammatory disease characterised by typical scaly skin lesions. The role of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in the pathogenesis and development of this condition have been repeatedly emphasised in available literature. Aim: ROC analysis of selected MMPs (MMP-2, MMP-3, MMP-9, MMP-12, TIMP-2) and TIMPs (TIMP 2, TIMP-3) in psoriasis patients. The area under the ROC curve (AUC) indicates the clinical usefulness of a biomarker and its diagnostic power. Material and methods: Plasma samples of 49 patients suffering from plaque psoriasis and 40 healthy volunteers were evaluated. Concentrations of MMPs and TIMPs were determined using the enzyme-linked immunosorbent assay (ELISA) while Psoriasis Area and Severity Index (PASI) was used to define disease advancement. Results: In the total psoriasis patients group, the largest area under the ROC curve was obtained for TIMP-3. After the division of the total group based on disease severity, the highest AUC of all tested parameters was observed for patients with mild disease severity and subgroup Ia for TIMP-3, for subgroup Ib for MMP-12, and for individuals with moderate disease severity for MMP-2. The combined analysis of all tested parameters showed an increase in AUC values in the total group examined as well as in all groups of disease severity. Conclusions: These results indicate the usefulness and high diagnostic power of TIMP-3 in early detection of psoriasis. Additionally, the combination of all tested parameters appeared to be a valuable biomarker panel for the analysed disease. PMID- 29760620 TI - Anti-endothelial cell antibodies do not correlate with disease activity in systemic sclerosis. AB - Introduction: Anti-endothelial cell antibodies (AECA) recognize endothelial cell proteins and are thought to play an important role in vascular damage observed in systemic scleroderma (SSc) and many other autoimmune diseases. In SSc, AECA were found to be more common in patients with pulmonary hypertension, digital ulcers and nailfold capillaroscopic changes. Until now, there have been no studies examining the association between AECA positivity with the activity and duration of the disease. Aim: To evaluate associations between the presence of AECA in sera of patients with SSc and internal organs involvement as well as disease activity. Material and methods: Sera of 58 patients with SSc (50 with localized subtype and 8 with diffuse subtype) were examined for AECA presence using an indirect immunofluorescence technique. Several clinical and laboratory features were also evaluated as well as disease activity and disease duration. Results: A significant association between positive AECA and a subtype of SSc (p = 0.021) was found, as well as between presence of digital ulcers and digital scars (p = 0.001), calcinosis (p = 0.02), acroosteolysis (p = 0.028) and a nearly significant association between AECA and lung fibrosis (p = 0.47). No association between disease duration, disease activity and AECA (p = 1.000 and 0.191, respectively) was present. Conclusions: Anti-endothelial cell antibodies are not associated with the activity of SSc. Digital ulcers, calcinosis and acroosteolysis are more common among AECA-positive patients suggesting that the presence of AECA might be an indicator of vascular complications development in SSc. Positive AECA among patients with lung fibrosis indicate their possible role in the development of lung disease. Further prospective studies including a greater number of patients are required. PMID- 29760621 TI - Disease severity and prophylactic measures in patients with cutaneous lupus erythematosus: results of a worldwide questionnaire-based study. AB - Introduction: Due to a wide array of dermatologic manifestations, assessment of disease severity in cutaneous lupus erythematosus (CLE) remains challenging. Given a need for some standardization in this field, we conducted a worldwide questionnaire-based study among physicians experienced in CLE management. Aim: We asked about CLE assessment, their prophylactic measures advised to patients, and treatment recommendations. Material and methods: A total of 83 completed questionnaires were received. Participating physicians recommended assessing disease severity at each patient's visit (39.1%), monthly (4.9%) or at least every third month (17.3%). Almost half of the responding physicians (47.0%) waited 2-3 months before identifying a specific treatment option as not effective. Results: The vast part of the participants informed their patients about of the risks of sun exposure and advised adequate preventive measures. Smoking was less frequently a matter of discussion between physicians and their patients. Recommendations for the timing of CLE severity assessment likely depends on disease severity and the type of therapeutic intervention. Conclusions: Proper patient education about effective prophylactic measures should be included during routine CLE patient consultations. PMID- 29760622 TI - Skin and mucous membranes' manifestations of dermatological diseases within the genital area in females. AB - Introduction: Lichen sclerosus et atrophicus (LSA) and an inversed type of psoriasis belong to a group of benign dermatoses usually located within the region of female external genitalia. The most common subjective symptoms reported by patients are itching, pain and changes in the color and structure of the skin. Aim: This paper presents 3 cases of patients suffering from selected dermatoses located within the external female genitalia treated at the Department of Dermatology, Poznan University of Medical Sciences. Case reports: Case 1. A 78 year-old patient admitted to the Department of Dermatology diagnosed with l ichen sclerosus and atrophic as well as scleroderma, which had already been confirmed by histopathological examination in 2014. Laboratory tests demonstrated an increased level of glycemia, elevated ESR and lymphopenia. In the treatment of TFX (Thymus factor X) therapy (immunomodulating treatment), vitamins A + E containing cream and Protopic 0.1% ointment twice daily were recommended. Case 2. A patient aged 49 was admitted to the Department of Dermatology due to exacerbation of skin inflammation in the course of psoriasis. She presented with severe erythematous and papular lesions covered with silvery scales, with the highest intensity within the palmar surfaces of both hands, in the folds of under the breasts, groins, and therefore, the clinical picture was characteristic of inversed psoriasis (psoriasis inversa). Case 3. A 20-year-old patient admitted to the Department of Dermatology in order to proceed with the treatment of a diffuse type of scleroderma. Clinical diagnosis has been already confirmed by the skin biopsy (typical histological features of scleroderma), however exclusion of other dermatoses such as LSA was not possible. Conclusions: While analyzing the available scientific reports, the physician in charge must adjust therapeutic options individually, taking into account the clinical condition of the patient in case of dermatological diseases within the female genital region. PMID- 29760624 TI - Lipoid proteinosis: a first report of mutation Val10Gly in the signal peptide of the ECM1 gene. PMID- 29760623 TI - Importance of sonography of the skin and subcutaneous tissue in the early diagnosis of melanoma in-transit metastasis with the presentation of two cases. PMID- 29760625 TI - Pyoderma gangrenosum with its subtype affecting oral mucosa pyostomatitis vegetans following skin melanoma surgical excision in a patient with ulcerative colitis: a case report. PMID- 29760626 TI - Toxic epidermal necrolysis in an 8-year-old girl successfully treated with cyclosporin A, intravenous immunoglobulin and plasma exchange. PMID- 29760627 TI - A desensitization protocol for delayed allergy to cytarabine: analysis of two cases. PMID- 29760628 TI - Hirudotherapy - a rare cause of pseudolymphoma. PMID- 29760630 TI - Editorial. PMID- 29760629 TI - Plane warts on the back of the hand successfully treated with oral isotretinoin. PMID- 29760631 TI - New Aspects in the Immuno-Pathogenesis of Autoimmunity. PMID- 29760632 TI - Genetics of Autoimmune Disease. PMID- 29760633 TI - Autoimmune Aspects of Pregnancy and Infertility. PMID- 29760634 TI - Apoptosis and Autoimmunity. PMID- 29760635 TI - Celiac Disease - General and Laboratory Aspects. PMID- 29760636 TI - Laboratory Standards in Diagnosis and Therapy Monitoring of Rheumatoid Arthritis. PMID- 29760637 TI - Laboratory Standard in the Diagnosis and Therapy Monitoring of Autoimmune Disease: Vasculitis. PMID- 29760639 TI - Laboratory Standards in the Diagnosis and Therapy Monitoring of Systemic Lupus Erythematosus. PMID- 29760640 TI - The Quality Assurance and Organization of Autoantibody Laboratory. PMID- 29760638 TI - Theory, Targets and Therapy in Rheumatic Diseases. PMID- 29760641 TI - Statistical Management of Autoimmune Diseases Data. PMID- 29760642 TI - Guidelines for Antinuclear Antibody Testing. PMID- 29760643 TI - Combining Polygenic Hazard Score With Volumetric MRI and Cognitive Measures Improves Prediction of Progression From Mild Cognitive Impairment to Alzheimer's Disease. AB - Improved prediction of progression to Alzheimer's Disease (AD) among older individuals with mild cognitive impairment (MCI) is of high clinical and societal importance. We recently developed a polygenic hazard score (PHS) that predicted age of AD onset above and beyond APOE. Here, we used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to further explore the potential clinical utility of PHS for predicting AD development in older adults with MCI. We examined the predictive value of PHS alone and in combination with baseline structural magnetic resonance imaging (MRI) data on performance on the Mini Mental State Exam (MMSE). In survival analyses, PHS significantly predicted time to progression from MCI to AD over 120 months (p = 1.07e-5), and PHS was significantly more predictive than APOE alone (p = 0.015). Combining PHS with baseline brain atrophy score and/or MMSE score significantly improved prediction compared to models without PHS (three-factor model p = 4.28e-17). Prediction model accuracies, sensitivities and area under the curve were also improved by including PHS in the model, compared to only using atrophy score and MMSE. Further, using linear mixed-effect modeling, PHS improved the prediction of change in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score and MMSE over 36 months in patients with MCI at baseline, beyond both APOE and baseline levels of brain atrophy. These results illustrate the potential clinical utility of PHS for assessment of risk for AD progression among individuals with MCI both alone, or in conjunction with clinical measures of prodromal disease including measures of cognitive function and regional brain atrophy. PMID- 29760645 TI - Systems Analysis of Human Visuo-Myoelectric Control Facilitated by Anodal Transcranial Direct Current Stimulation in Healthy Humans. AB - Induction of neuroplasticity by transcranial direct current stimulation (tDCS) applied to the primary motor cortex facilitates motor learning of the upper extremities in healthy humans. The impact of tDCS on lower limb functions has not been studied extensively so far. In this study, we applied a system identification approach to investigate the impact of anodal transcranial direct current stimulation of the leg area of the motor cortex via the human visuo myoelectric controller. The visuo-myoelectric reaching task (VMT) involves ballistic muscle contraction after a visual cue. We applied a black box approach using a linear ARX (Auto-regressive with eXogenous input) model for a visuomotor myoelectric reaching task. We found that a 20th order finite impulse response (FIR) model captured the TARGET (single input)-CURSOR (single output) dynamics during a VMT. The 20th order FIR model was investigated based on gain/phase margin analysis, which showed a significant (p < 0.01) effect of anodal tDCS on the gain margin of the VMT system. Also, response latency and the corticomuscular coherence (CMC) time delay were affected (p < 0.05) by anodal tDCS when compared to sham tDCS. Furthermore, gray box simulation results from a Simplified Spinal Like Controller (SSLC) model demonstrated that the input-output function for motor evoked potentials (MEP) played an essential role in increasing muscle activation levels and response time improvement post-tDCS when compared to pre tDCS baseline performance. This computational approach can be used to simulate the behavior of the neuromuscular controller during VMT to elucidate the effects of adjuvant treatment with tDCS. PMID- 29760644 TI - An Algorithm for Preclinical Diagnosis of Alzheimer's Disease. AB - Almost all Alzheimer's disease (AD) therapeutic trials have failed in recent years. One of the main reasons for failure is due to designing the disease modifying clinical trials at the advanced stage of the disease when irreversible brain damage has already occurred. Diagnosis of the preclinical stage of AD and therapeutic intervention at this phase, with a perfect target, are key points to slowing the progression of the disease. Various AD biomarkers hold enormous promise for identifying individuals with preclinical AD and predicting the development of AD dementia in the future, but no single AD biomarker has the capability to distinguish the AD preclinical stage. A combination of complimentary AD biomarkers in cerebrospinal fluid (Abeta42, tau, and phosphor tau), non-invasive neuroimaging, and genetic evidence of AD can detect preclinical AD in the in-vivo ante mortem brain. Neuroimaging studies have examined region-specific cerebral blood flow (CBF) and microstructural changes in the preclinical AD brain. Functional MRI (fMRI), diffusion tensor imaging (DTI) MRI, arterial spin labeling (ASL) MRI, and advanced PET have potential application in preclinical AD diagnosis. A well-validated simple framework for diagnosis of preclinical AD is urgently needed. This article proposes a comprehensive preclinical AD diagnostic algorithm based on neuroimaging, CSF biomarkers, and genetic markers. PMID- 29760646 TI - DGCR8 Promotes Neural Progenitor Expansion and Represses Neurogenesis in the Mouse Embryonic Neocortex. AB - DGCR8 and DROSHA are the minimal functional core of the Microprocessor complex essential for biogenesis of canonical microRNAs and for the processing of other RNAs. Conditional deletion of Dgcr8 and Drosha in the murine telencephalon indicated that these proteins exert crucial functions in corticogenesis. The identification of mechanisms of DGCR8- or DROSHA-dependent regulation of gene expression in conditional knockout mice are often complicated by massive apoptosis. Here, to investigate DGCR8 functions on amplification/differentiation of neural progenitors cells (NPCs) in corticogenesis, we overexpress Dgcr8 in the mouse telencephalon, by in utero electroporation (IUEp). We find that DGCR8 promotes the expansion of NPC pools and represses neurogenesis, in absence of apoptosis, thus overcoming the usual limitations of Dgcr8 knockout-based approach. Interestingly, DGCR8 selectively promotes basal progenitor amplification at later developmental stages, entailing intriguing implications for neocortical expansion in evolution. Finally, despite a 3- to 5-fold increase of DGCR8 level in the mouse telencephalon, the composition, target preference and function of the DROSHA-dependent Microprocessor complex remain unaltered. Thus, we propose that DGCR8-dependent modulation of gene expression in corticogenesis is more complex than previously known, and possibly DROSHA-independent. PMID- 29760647 TI - Discrimination and Recognition of Phantom Finger Sensation Through Transcutaneous Electrical Nerve Stimulation. AB - Tactile sensory feedback would make a significant contribution to the state-of the-art prosthetic hands for achieving dexterous manipulation over objects. Phantom finger sensation, also called referred sensation of lost fingers, can be noninvasively evoked by transcutaneous electrical nerve stimulation (TENS) of the phantom finger territories (PFTs) near the stump for upper-limb amputees. As such, intuitive sensations pertaining to lost fingers could be non-invasively generated. However, the encoding of stimulation parameters into tactile sensations that can be intuitively interpreted by the users remains a significant challenge. Further, how discriminative such artificial tactile sensation with TENS of the PFTs is still unknown. In this study, we systematically characterized the tactile discrimination across different phantom fingers on the stump skin by TENS among six subjects. Charge-balanced and biphasic stimulating current pulses were adopted. The pulse amplitude (PA), the pulse frequency (PF) and the pulse width (PW) were modulated to evaluate the detection threshold, perceived touch intensity, and the just-noticeable difference (JND) of the phantom finger sensation. Particularly, the recognition of phantom fingers under simultaneous stimulation was assessed. The psychophysical experiments revealed that subjects could discern fine variations of stimuli with comfortable sensation of phantom fingers including D1 (phantom thumb), D2 (phantom index finger), D3 (Phantom middle finger), and D5 (Phantom pinky finger). With respect to PA, PF, and PW modulations, the detection thresholds across the four phantom fingers were achieved by the method of constant stimuli based on a two-alternative forced choice (2AFC) paradigm. For each modulation, the perceived intensity, which was indexed by skin indentations on the contralateral intact finger pulp, reinforced gradually with enhancing stimuli within lower-intensity range. Particularly, the curve of the indentation depth vs. PF almost reached a plateau with PF more than 200 Hz. Moreover, the performance of phantom finger recognition deteriorated with the increasing number of phantom fingers under simultaneous TENS. For one, two and four stimulating channels, the corresponding recognition rate of an individual PFT were respective 85.83, 67.67, and 46.44%. The results of the present work would provide direct guidelines regarding the optimization of stimulating strategies to deliver artificial tactile sensation by TENS for clinical applications. PMID- 29760649 TI - Brain Region-Dependent Rejection of Neural Precursor Cell Transplants. AB - The concept of CNS as an immune-privileged site has been challenged by the occurrence of immune surveillance and allogeneic graft rejection in the brain. Here we examined whether the immune response to allogeneic neural grafts is determined by the site of implantation in the CNS. Dramatic regional differences were observed between immune responses to allogeneic neural precursor/stem cell (NPC) grafts in the striatum vs. the hippocampus. Striatal grafts were heavily infiltrated with IBA-1+ microglia/macrophages and CD3+ T cells and completely rejected. In contrast, hippocampal grafts exhibited milder IBA-1+ cell infiltration, were not penetrated efficiently by CD3+ cells, and survived efficiently for at least 2 months. To evaluate whether the hippocampal protective effect is universal, astrocytes were then transplanted. Allogeneic astrocyte grafts elicited a vigorous rejection process from the hippocampus. CD200, a major immune-inhibitory signal, plays an important role in protecting grafts from rejection. Indeed, CD200 knock out NPC grafts were rejected more efficiently than wild type NPCs from the striatum. However, lack of CD200 expression did not elicit NPC graft rejection from the hippocampus. In conclusion, the hippocampus has partial immune-privilege properties that are restricted to NPCs and are CD200 independent. The unique hippocampal milieu may be protective for allogeneic NPC grafts, through host-graft interactions enabling sustained immune-regulatory properties of transplanted NPCs. These findings have implications for providing adequate immunosuppression in clinical translation of cell therapy. PMID- 29760648 TI - Profile of Arachidonic Acid-Derived Inflammatory Markers and Its Modulation by Nitro-Oleic Acid in an Inherited Model of Amyotrophic Lateral Sclerosis. AB - The lack of current treatments for amyotrophic lateral sclerosis (ALS) highlights the need of a comprehensive understanding of the biological mechanisms of the disease. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected as a screening tool to identify treatment response. Herein, we focus on (a) detection of arachidonic acid (AA) metabolization products by lipoxygenase (LOX) and prostaglandin endoperoxide H synthase in SOD1G93A mice and (b) evaluate its response to the electrophilic nitro-oleic acid (NO2-OA). Regarding LOX-derived products, a significant increase in 12-hydroxyeicosatetraenoic acid (12-HETE) levels was detected in SOD1G93A mice both in plasma and brain whereas no changes were observed in age-matched non-Tg mice at the onset of motor symptoms (90 days-old). In addition, 15 hydroxyeicosatetraenoic acid (15-HETE) levels were greater in SOD1G93A brains compared to non-Tg. Prostaglandin levels were also increased at day 90 in plasma from SOD1G93A compared to non-Tg being similar in both types of animals at later stages of the disease. Administration of NO2-OA 16 mg/kg, subcutaneously (s/c) three times a week to SOD1G93A female mice, lowered the observed increase in brain 12-HETE levels compared to the non-nitrated fatty acid condition, and modified many others inflammatory markers. In addition, NO2-OA significantly improved grip strength and rotarod performance compared to vehicle or OA treated animals. These beneficial effects were associated with increased hemeoxygenase 1 (HO-1) expression in the spinal cord of treated mice co-localized with reactive astrocytes. Furthermore, significant levels of NO2-OA were detected in brain and spinal cord from NO2-OA -treated mice indicating that nitro-fatty acids (NFA) cross brain-blood barrier and reach the central nervous system to induce neuroprotective actions. In summary, we demonstrate that LOX-derived oxidation products correlate with disease progression. Overall, we are proposing that key inflammatory mediators of AA-derived pathways may be useful as novel footprints of ALS onset and progression as well as NO2-OA as a promising therapeutic compound. PMID- 29760650 TI - Characterization of Wnt and Notch-Responsive Lgr5+ Hair Cell Progenitors in the Striolar Region of the Neonatal Mouse Utricle. AB - Dysfunctions in hearing and balance are largely connected with hair cell (HC) loss. Although regeneration of HCs in the adult cochlea does not occur, there is still limited capacity for HC regeneration in the mammalian utricle from a distinct population of supporting cells (SCs). In response to HC damage, these Lgr5+ SCs, especially those in the striolar region, can regenerate HCs. In this study, we isolated Lgr5+ SCs and Plp1+ SCs (which originate from the striolar and extrastriolar regions, respectively) from transgenic mice by flow cytometry so as to compare the properties of these two subsets of SCs. We found that the Lgr5+ progenitors had greater proliferation and HC regeneration ability than the Plp1+ SCs and that the Lgr5+ progenitors responded more strongly to Wnt and Notch signaling than Plp1+ SCs. We then compared the gene expression profiles of the two populations by RNA-Seq and identified several genes that were significantly differentially expressed between the two populations, including genes involved in the cell cycle, transcription and cell signaling pathways. Targeting these genes and pathways might be a potential way to activate HC regeneration. PMID- 29760652 TI - Cadherins Interact With Synaptic Organizers to Promote Synaptic Differentiation. AB - Classical cadherins, a set of ~20 related recognition and signaling molecules, have been implicated in many aspects of neural development, including the formation and remodeling of synapses. Mechanisms underlying some of these steps have been studied by expressing N-cadherin (cdh2), a Type 1 cadherin, in heterologous cells, but analysis is complicated because widely used lines express cdh2 endogenously. We used CRISPR-mediated gene editing to generate a Human embryonic kidney (HEK)293 variant lacking Cdh2, then compared the behavior of rodent cortical and hippocampal neurons co-cultured with parental, cdh2 mutant and cdh2-rescued 293 lines. The comparison demonstrated that Cdh2 promotes neurite branching and that it is required for three synaptic organizers, neurologin1 (NLGL1), leucine-rich repeat transmembrane protein 2 (LRRtm2), and Cell Adhesion Molecule 1 (Cadm1/SynCAM) to stimulate presynaptic differentiation, assayed by clustering of synaptic vesicles at sites of neurite-293 cell contact. Similarly, Cdh2 is required for a presynaptic organizing molecule, Neurexin1beta, to promote postsynaptic differentiation in dendrites. We also show that another Type I cadherin, Cdh4, and a Type II cadherin, Cdh6, can substitute for Cdh2 in these assays. Finally, we provide evidence that the effects of cadherins require homophilic interactions between neurites and the heterologous cells. Together, these results indicate that classical cadherins act together with synaptic organizers to promote synaptic differentiation, perhaps in part by strengthening the intracellular adhesion required for the organizers to act efficiently. We propose that cadherins promote high affinity contacts between appropriate partners, which then enable synaptic differentiation. PMID- 29760653 TI - CK2 Phosphorylating I2PP2A/SET Mediates Tau Pathology and Cognitive Impairment. AB - Casein kinase 2 (CK2) is highly activated in Alzheimer disease (AD) and is associated with neurofibrillary tangles formation. Phosphorylated SET, a potent PP2A inhibitor, mediates tau hyperphosphorylation in AD. However, whether CK2 phosphorylates SET and regulates tau pathological phosphorylation in AD remains unclear. Here, we show that CK2 phosphorylating SET at Ser9 induced tau hyperphosphorylation in AD. We found that either Abeta treatment or tau overexpression stimulated CK2 activation leading to SET Ser9 hyperphosphorylation in neurons and animal models, while inhibition of CK2 by TBB abolished this event. Overexpression of CK2 in mouse hippocampus via virus injection induced cognitive deficit associated with SET Ser9 hyperphosphorylation. Injection of SET Ser9 phosphorylation mimetic mutant induced tau pathology and behavior impairments. Conversely co-injection of non-phosphorylated SET S9A with CK2 abolished the CK2 overexpression-induced AD pathology and cognitive deficit. Together, our data demonstrate that CK2 phosphorylates SET at Ser9 leading to SET cytoplasmic translocation and inhibition of PP2A resulting in tau pathology and cognitive impairments. PMID- 29760651 TI - Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene. AB - The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the fragile X mental retardation (FMR1) gene. FMR1 alleles with more than 200 CGG repeats bear chromosomal fragility when cells experience folate deficiency. CGG repeats were reported to be able to form secondary structures, such as hairpins, in vitro. When such secondary structures are formed, repeats can lead to replication fork stalling even in the absence of any additional perturbation. Indeed, it was recently shown that the replication forks stall at the endogenous FMR1 locus in unaffected and FXS cells, suggesting the formation of secondary repeat structures at the FMR1 gene in vivo. If not dealt with properly replication fork stalling can lead to polymerase slippage and repeat expansion as well as fragile site expression. Despite the presence of repeat structures at the FMR1 locus, chromosomal fragility is only expressed under replicative stress suggesting the existence of potential molecular mechanisms that help the replication fork progress through these repeat regions. DNA helicases are known to aid replication forks progress through repetitive DNA sequences. Yet, the identity of the DNA helicase(s) responsible for unwinding the CGG repeats at FMR1 locus is not known. We found that the human DNA helicase B (HDHB) may provide an answer for this question. We used chromatin-immunoprecipitation assay to study the FMR1 region and common fragile sites (CFS), and asked whether HDHB localizes at replication forks stalled at repetitive regions even in unperturbed cells. HDHB was strongly enriched in S-phase at the repetitive DNA at CFS and FMR1 gene but not in the flanking regions. Taken together, these results suggest that HDHB functions in preventing or repairing stalled replication forks that arise in repeat-rich regions even in unperturbed cells. Furthermore, we discuss the importance and potential role of HDHB and other helicases in the resolution of secondary CGG repeat structures. PMID- 29760654 TI - Failure to Replicate the Association Between Fractional Anisotropy and the Serotonin Transporter Gene (5-HTTLPR, rs25531). AB - Recent work underlines the importance of alterations in white matter (e.g., measured by fractional anisotropy (FA)) as a neural vulnerability marker for psychiatric disorders. In this context, the uncinate fasciculus (UF), which connects the limbic system with prefrontal areas, has repeatedly been linked to psychiatric disorders, fear processing, and anxiety-related traits. Individual differences in FA may partly be genetically determined. Variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) is a particularly promising candidate in this context, which has been linked to psychiatric disorders as well as to limbic and prefrontal reactivity. However, findings on the association between the 5-HTTLPR and FA within the UF-tract have been heterogeneous. The present study investigated this relationship and extended previous work by considering different genetic classification approaches as well as sex effects in a human sample (n = 114). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. As a main result, we did not find any significant relationship between the 5-HTTLPR and FA in the UF-tract although power analyses showed an adequate power. In addition, genotype effects were neither found when different classification approaches were used nor when analyses were carried out in males or females only. The present findings suggest that the association of the 5-HTTLPR and FA seems to be a more labile phenomenon than previously assumed. Possible explanations and limitations are discussed. PMID- 29760655 TI - Neural Codes for One's Own Position and Direction in a Real-World "Vista" Environment. AB - Humans, like animals, rely on an accurate knowledge of one's spatial position and facing direction to keep orientated in the surrounding space. Although previous neuroimaging studies demonstrated that scene-selective regions (the parahippocampal place area or PPA, the occipital place area or OPA and the retrosplenial complex or RSC), and the hippocampus (HC) are implicated in coding position and facing direction within small-(room-sized) and large-scale navigational environments, little is known about how these regions represent these spatial quantities in a large open-field environment. Here, we used functional magnetic resonance imaging (fMRI) in humans to explore the neural codes of these navigationally-relevant information while participants viewed images which varied for position and facing direction within a familiar, real world circular square. We observed neural adaptation for repeated directions in the HC, even if no navigational task was required. Further, we found that the amount of knowledge of the environment interacts with the PPA selectivity in encoding positions: individuals who needed more time to memorize positions in the square during a preliminary training task showed less neural attenuation in this scene-selective region. We also observed adaptation effects, which reflect the real distances between consecutive positions, in scene-selective regions but not in the HC. When examining the multi-voxel patterns of activity we observed that scene-responsive regions and the HC encoded both spatial information and that the RSC classification accuracy for positions was higher in individuals scoring higher to a self-reported questionnaire of spatial abilities. Our findings provide new insight into how the human brain represents a real, large-scale "vista" space, demonstrating the presence of neural codes for position and direction in both scene-selective and hippocampal regions, and revealing the existence, in the former regions, of a map-like spatial representation reflecting real-world distance between consecutive positions. PMID- 29760656 TI - A Fast Contour Detection Model Inspired by Biological Mechanisms in Primary Vision System. AB - Compared to computer vision systems, the human visual system is more fast and accurate. It is well accepted that V1 neurons can well encode contour information. There are plenty of computational models about contour detection based on the mechanism of the V1 neurons. Multiple-cue inhibition operator is one well-known model, which is based on the mechanism of V1 neurons' non-classical receptive fields. However, this model is time-consuming and noisy. To solve these two problems, we propose an improved model which integrates some additional other mechanisms of the primary vision system. Firstly, based on the knowledge that the salient contours only occupy a small portion of the whole image, the prior filtering is introduced to decrease the running time. Secondly, based on the physiological finding that nearby neurons often have highly correlated responses and thus include redundant information, we adopt the uniform samplings to speed up the algorithm. Thirdly, sparse coding is introduced to suppress the unwanted noises. Finally, to validate the performance, we test it on Berkeley Segmentation Data Set. The results show that the improved model can decrease running time as well as keep the accuracy of the contour detection. PMID- 29760658 TI - High Plasma Exposure of Statins Associated With Increased Risk of Contrast Induced Acute Kidney Injury in Chinese Patients With Coronary Artery Disease. AB - The role of statins in reducing the incidence of contrast-induced acute kidney injury (CI-AKI) remains controversial. We sought to evaluate the association between CI-AKI and high plasma exposure of statins in coronary artery disease (CAD) patients undergoing coronary angiography (CAG). This association was first evaluated in 1,219 patients with CAD receiving atorvastatin (AT) therapy and validated in 635 patients receiving rosuvastatin (RST) therapy. The plasma concentrations of statins were quantified using validated UPLC-MS/MS methods and CI-AKI incidence was assessed during the first 48 h postoperatively. Among all participants (n = 1,854), AKI occurred in 57 of 1219 (4.7%) in the AT cohort and 30 of 635 (4.7%) in the RST cohort. High plasma AT-all exposure was associated with increased risk of CI-AKI (odds ratio [OR]: 2.265; 95% confidence interval [CI]: 1.609-3.187; p < 0.0001). Plasma AT-all concentration in the CI-AKI group (22.40 +/- 24.63 ng/mL) was 2.6-fold higher than that in the control group (8.60 +/- 9.65 ng/mL). High plasma RST exposure also significantly increased the risk of CI-AKI (OR: 2.281; 95% CI: 1.441-3.612; p = 0.0004). We further divided patients into two subgroups for each statin according to baseline renal function, and association between high plasma statin exposure and CI-AKI still remained highly significant in both subgroups. This study suggests for the first time that high plasma exposure of statins may significantly increase the risk of CI-AKI. Statins should be used with greater caution in CAD patients undergoing CAG to reduce the occurrence of CI-AKI. PMID- 29760659 TI - Long-Term Efficacy of Maintenance Therapy for Multiple Myeloma: A Quantitative Synthesis of 22 Randomized Controlled Trials. AB - We aimed to quantitatively synthesize data from randomized controlled trials (RCTs) concerning maintenance for multiple myeloma (MM). We searched electronic literature databases and conference proceedings to identify relevant RCTs. We selected eligible RCTs using predefined selection criteria. We conducted meta analysis comparing maintenance containing new agents and conventional maintenance, and subgroup analysis by transplantation status and mainstay agent as well. We performed trial sequential analysis (TSA) to determine adequacy of sample size for overall and subgroup meta-analyses. We performed network meta analysis (NMA) to compare and rank included regimens. A total of 22 RCTs involving 9,968 MM patients and 15 regimens were included, the overall quality of which was adequate. Significant heterogeneity was detected for progression-free survival (PFS) but not overall survival (OS). Meta-analyses showed that maintenance containing new agents significantly improved PFS but not OS [PFS: Hazard Ratio (HR) = 0.59, 95% Confidence Interval (CI) = 0.54 to 0.64; OS: HR = 0.93, 95% CI = 0.87 to 1.00], compared with controls. Subgroup analyses revealed lenalidomide (Len)-based therapies better than thalidomide-based ones (HR = 0.50 and 0.66, respectively; P = 0.001). NMA revealed that most of the maintenance regimens containing new agents were significantly better than simple observation in terms of PFS but not OS. Len single agent was the most effective, considering PFS and OS both. We concluded that conventional maintenance has very limited effect. Maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS. Maintenance with Len may have the largest survival benefits. Emerging strategies may further change the landscape of maintenance of MM. PMID- 29760660 TI - Ophiopogonin D', a Natural Product From Radix Ophiopogonis, Induces in Vitro and in Vivo RIPK1-Dependent and Caspase-Independent Apoptotic Death in Androgen Independent Human Prostate Cancer Cells. AB - Objective: The purpose of this study was to evaluate the anticancer effects of Ophiopogonin D' (OPD', a natural product extracted from a traditional Chinese medicine (Radix Ophiopogonis) against androgen-independent prostate cancer cells and to explore the underlying molecular mechanism(s) of action. Methods: The CCK 8 assay was used to assess the viability of prostate cancer cells. The cell morphology was examined by an ultrastructural analysis via transmission electron microscopy. Cells in apoptosis (early and late stages) were detected using an Annexin V-FITC/propidium iodide kit with a FACSCaliber flow cytometer. JC-1, a cationic lipophilic probe, was employed to measure the mitochondrial membrane potential (MMP) of PC3 cells. Changes in the protein expression of RIPK1, C RIPK1, caspase 8, cleaved-caspase 8, Bim, Bid, caspase 10, and cleaved-caspase 10 were evaluated by Western blotting. The mRNA expression of Bim was examined by quantitative real-time reverse transcription polymerase chain reaction. Z-VAD-FMK (a caspase inhibitor) and necrostatin-1 (a specific inhibitor of RIPK1) were utilized to determine whether the cell death was mediated by RIPK1 or caspases. PC3 and DU145 xenograft models in BALB/c nude mice were used to evaluate the anticancer activity of OPD' in vivo. Results: OPD' was shown to exert potent anti tumor activity against PC3 cells. It induced apoptosis via a RIPK1-related pathway, increased the protein expression levels of RIPK1 and Bim, and decreased the levels of cleaved-RIPK1, caspase 8, cleaved-caspase 8, Bid, caspase 10, and cleaved-caspase 10. OPD' also increased the mRNA expression of Bim. The protein expression of Bim was decreased when cells were pre-treated with necrostatin-1. Treatment with OPD' inhibited the growth of PC3 and DU145 xenograft tumors in BALB/c nude mice. Conclusion: OPD' significantly inhibited the in vitro and in vivo growth of prostate cells via RIPK1, suggesting that OPD' may be developed as a potential anti-prostate cancer agent. PMID- 29760661 TI - A Semantic Transformation Methodology for the Secondary Use of Observational Healthcare Data in Postmarketing Safety Studies. AB - Background: Utilization of the available observational healthcare datasets is key to complement and strengthen the postmarketing safety studies. Use of common data models (CDM) is the predominant approach in order to enable large scale systematic analyses on disparate data models and vocabularies. Current CDM transformation practices depend on proprietarily developed Extract-Transform-Load (ETL) procedures, which require knowledge both on the semantics and technical characteristics of the source datasets and target CDM. Purpose: In this study, our aim is to develop a modular but coordinated transformation approach in order to separate semantic and technical steps of transformation processes, which do not have a strict separation in traditional ETL approaches. Such an approach would discretize the operations to extract data from source electronic health record systems, alignment of the source, and target models on the semantic level and the operations to populate target common data repositories. Approach: In order to separate the activities that are required to transform heterogeneous data sources to a target CDM, we introduce a semantic transformation approach composed of three steps: (1) transformation of source datasets to Resource Description Framework (RDF) format, (2) application of semantic conversion rules to get the data as instances of ontological model of the target CDM, and (3) population of repositories, which comply with the specifications of the CDM, by processing the RDF instances from step 2. The proposed approach has been implemented on real healthcare settings where Observational Medical Outcomes Partnership (OMOP) CDM has been chosen as the common data model and a comprehensive comparative analysis between the native and transformed data has been conducted. Results: Health records of ~1 million patients have been successfully transformed to an OMOP CDM based database from the source database. Descriptive statistics obtained from the source and target databases present analogous and consistent results. Discussion and Conclusion: Our method goes beyond the traditional ETL approaches by being more declarative and rigorous. Declarative because the use of RDF based mapping rules makes each mapping more transparent and understandable to humans while retaining logic-based computability. Rigorous because the mappings would be based on computer readable semantics which are amenable to validation through logic-based inference methods. PMID- 29760663 TI - Suppression of Urinary Voiding by Conditional High Frequency Stimulation of the Pelvic Nerve in Conscious Rats. AB - Female Wistar rats were instrumented to record bladder pressure and to stimulate the left pelvic nerve. Repeated voids were induced by continuous infusion of saline into the bladder (11.2 ml/h) via a T-piece in the line to the bladder catheter. In each animal tested (n = 6) high frequency pelvic nerve stimulation (1-3 kHz, 1-2 mA sinusoidal waveform for 60 s) applied within 2 s of the onset of a sharp rise in bladder pressure signaling an imminent void was able to inhibit micturition. Voiding was modulated in three ways: (1) Suppression of voiding (four rats, n = 13 trials). No fluid output or a very small volume of fluid expelled (<15% of the volume expected based on the mean of the previous 2 or 3 voids). Voiding suppressed for the entirety of the stimulation period (60 s) and resumed within 37 s of stopping stimulation. (2) Void deferred (four rats, n = 6 trials). The imminent void was suppressed (no fluid expelled) but a void occurred later in the stimulation period (12-44 s, mean 24.5 +/- 5.2 s after the onset of the stimulation). (3) Reduction in voided volume (five rats, n = 20 trials). Voiding took place but the volume of fluid voided was 15-80% (range 21.8-77.8%, mean 45.3 +/- 3.6%) of the volume expected from the mean of the preceding two or three voids. Spontaneous voiding resumed within 5 min of stopping stimulation. Stimulation during the filling phase in between voids had no effect. The experiments demonstrate that conditional high frequency stimulation of the pelvic nerve started at the onset of an imminent void can inhibit voiding. The effect was rapidly reversible and was not accompanied by any adverse behavioral side effects. PMID- 29760665 TI - Left Ventricular Trabeculations Decrease the Wall Shear Stress and Increase the Intra-Ventricular Pressure Drop in CFD Simulations. AB - The aim of the present study is to characterize the hemodynamics of left ventricular (LV) geometries to examine the impact of trabeculae and papillary muscles (PMs) on blood flow using high performance computing (HPC). Five pairs of detailed and smoothed LV endocardium models were reconstructed from high resolution magnetic resonance images (MRI) of ex-vivo human hearts. The detailed model of one LV pair is characterized only by the PMs and few big trabeculae, to represent state of art level of endocardial detail. The other four detailed models obtained include instead endocardial structures measuring >=1 mm2 in cross sectional area. The geometrical characterizations were done using computational fluid dynamics (CFD) simulations with rigid walls and both constant and transient flow inputs on the detailed and smoothed models for comparison. These simulations do not represent a clinical or physiological scenario, but a characterization of the interaction of endocardial structures with blood flow. Steady flow simulations were employed to quantify the pressure drop between the inlet and the outlet of the LVs and the wall shear stress (WSS). Coherent structures were analyzed using the Q-criterion for both constant and transient flow inputs. Our results show that trabeculae and PMs increase the intra-ventricular pressure drop, reduce the WSS and disrupt the dominant single vortex, usually present in the smoothed-endocardium models, generating secondary small vortices. Given that obtaining high resolution anatomical detail is challenging in-vivo, we propose that the effect of trabeculations can be incorporated into smoothed ventricular geometries by adding a porous layer along the LV endocardial wall. Results show that a porous layer of a thickness of 1.2.10-2 m with a porosity of 20 kg/m2 on the smoothed-endocardium ventricle models approximates the pressure drops, vorticities and WSS observed in the detailed models. PMID- 29760664 TI - Reduced Renal Mass, Salt-Sensitive Hypertension Is Resistant to Renal Denervation. AB - Aim: Activation of the sympathetic nervous system is common in resistant hypertension (RHT) and also in chronic kidney disease (CKD), a prevalent condition among resistant hypertensives. However, renal nerve ablation lowers blood pressure (BP) only in some patients with RHT. The influence of loss of nephrons per se on the antihypertensive response to renal denervation (RDNx) is unclear and was the focus of this study. Methods: Systemic hemodynamics and sympathetically mediated low frequency oscillations of systolic BP were determined continuously from telemetrically acquired BP recordings in rats before and after surgical excision of ~80% of renal mass and subsequent RDNx. Results: After reduction of renal mass, rats fed a high salt (HS) diet showed sustained increases in mean arterial pressure (108 +/- 3 mmHg to 128 +/- 2 mmHg) and suppression of estimated sympathetic activity (~15%), responses that did not occur with HS before renal ablation. After denervation of the remnant kidney, arterial pressure fell (to 104 +/- 4 mmHg), estimated sympathetic activity and heart rate (HR) increased concomitantly, but these changes gradually returned to pre-denervation levels over 2 weeks of follow up. Subsequently, sympathoinhibition with clonidine did not alter arterial pressure while significantly suppressing estimated sympathetic activity and HR. Conclusion: These results indicate that RDNx does not chronically lower arterial pressure in this model of salt-sensitive hypertension associated with substantial nephron loss, but without ischemia and increased sympathetic activity, thus providing further insight into conditions likely to impact the antihypertensive response to renal-specific sympathoinhibition in subjects with CKD. PMID- 29760666 TI - Candyflipping and Other Combinations: Identifying Drug-Drug Combinations from an Online Forum. AB - Novel psychoactive substances (NPS) refer to synthetic compounds or derivatives of more widely known substances of abuse that have emerged over the last two decades. Case reports suggest that users combine substances to achieve desired psychotropic experiences while reducing dysphoria and unpleasant somatic effects. However, the pattern of combining NPS has not been studied on a large scale. Here, we show that posts discussing NPS describe combining nootropics with sedative-hypnotics and stimulants with plant hallucinogens or psychiatric medications. Discussions that mention sedative-hypnotics most commonly also mention hallucinogens and stimulants. We analyzed 20 years of publicly available posts from Lycaeum, an Internet forum dedicated to sharing information about psychoactive substance use. We used techniques from natural language processing and machine learning to identify NPS and correlate patterns of co-mentions of substances across posts. We found that conversations mentioning synthetic hallucinogens tended to divide into those mentioning hallucinogens derived from amphetamine and those derived from ergot. Conversations that mentioned synthetic hallucinogens tended not to mention plant hallucinogens. Conversations that mention bath salts commonly mention sedative-hypnotics or nootropics while more canonical stimulants are discussed with plant hallucinogens and psychiatric medications. All types of substances are frequently compared to MDMA, DMT, cocaine, or atropine when trying to describe their effects. Our results provide the largest analysis to date of online descriptions of patterns of polysubstance use and further demonstrate the utility of social media in learning about trends in substance use. We anticipate this work to lead to a more detailed analysis of the knowledge contained online about the patterns of usage and effects of novel psychoactive substances. PMID- 29760662 TI - Targeting Renin-Angiotensin System Against Alzheimer's Disease. AB - Renin Angiotensin System (RAS) is a hormonal system that regulates blood pressure and fluid balance through a coordinated action of renal, cardiovascular, and central nervous systems. In addition to its hemodynamic regulatory role, RAS involves in many brain activities, including memory acquisition and consolidation. This review has summarized the involvement of RAS in the pathology of Alzheimer's disease (AD), and the outcomes of treatment with RAS inhibitors. We have discussed the effect of brain RAS in the amyloid plaque (Abeta) deposition, oxidative stress, neuroinflammation, and vascular pathology which are directly and indirectly associated with AD. Angiotensin II (AngII) via AT1 receptor is reported to increase brain Abeta level via different mechanisms including increasing amyloid precursor protein (APP) mRNA, beta-secretase activity, and presenilin expression. Similarly, it was associated with tau phosphorylation, and reactive oxygen species generation. However, these effects are counterbalanced by Ang II mediated AT2 signaling. The protective effect observed with angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) could be as the result of inhibition of Ang II signaling. ARBs also offer additional benefit by shifting the effect of Ang II toward AT2 receptor. To conclude, targeting RAS in the brain may benefit patients with AD though it still requires further in depth understanding. PMID- 29760668 TI - Implicit Motives as Determinants of Networking Behaviors. AB - In today's world of work, networking behaviors are an important and viable strategy to enhance success in work and career domains. Concerning personality as an antecedent of networking behaviors, prior studies have exclusively relied on trait perspectives that focus on how people feel, think, and act. Adopting a motivational perspective on personality, we enlarge this focus and argue that beyond traits predominantly tapping social content, motives shed further light on instrumental aspects of networking - or why people network. We use McClelland's implicit motives framework of need for power (nPow), need for achievement (nAch), and need for affiliation (nAff) to examine instrumental determinants of networking. Using a facet theoretical approach to networking behaviors, we predict differential relations of these three motives with facets of (1) internal vs. external networking and (2) building, maintaining, and using contacts. We conducted an online study, in which we temporally separate measures (N = 539 employed individuals) to examine our hypotheses. Using multivariate latent regression, we show that nAch is related to networking in general. In line with theoretical differences between networking facets, we find that nAff is positively related to building contacts, whereas nPow is positively related to using internal contacts. In sum, this study shows that networking is not only driven by social factors (i.e., nAff), but instead the achievement motive is the most important driver of networking behaviors. PMID- 29760667 TI - A DRD2/ANNK1-COMT Interaction, Consisting of Functional Variants, Confers Risk of Post-traumatic Stress Disorder in Traumatized Chinese. AB - Objective: Post-traumatic stress disorder (PTSD) is a trauma- and stress-related psychiatric syndrome that occurs after exposure to extraordinary stressors. The neurotransmitter dopamine (DA) plays important roles in neurobiological processes like reward and stress, and a link between PTSD and the dopaminergic system has been reported. Thus, the investigation of an association between PTSD and gene gene interaction (epistasis) within dopaminergic genes could uncover the genetic basis of dopamine-related PTSD symptomatology and contribute to precision medicine. Methods: We genotyped seven single nucleotide polymorphisms (SNPs) of three dopaminergic genes DRD2/ANNK1 (rs1800497 and rs1801028), COMT (rs6269, rs4633, rs4818 and rs4680) and DBH (rs1611115), in a Chinese predominantly adult cohort that had been exposed to an earthquake (156 PTSD cases and 978 controls). Results: Statistical genetics analysis identified a DRD2/ANNK1-COMT interaction (rs1800497 * rs6269), which is associated with PTSD diagnosis (Pinteraction = 0.0008055 and Pcorrected = 0.0169155). Single-variant and haplotype-based subset analyses showed that rs1800497 modulates the association directions of both the rs6269 G allele and the rs6269-rs4633-rs4818-rs4680 haplotype G-C-G-G. The interaction (rs1800497 * rs6269) was replicated in a Chinese young female cohort (32 cases and 581 controls, Pinteraction = 0.01329). Conclusions: Rs1800497 is related to the DA receptor D2 density and rs6269-rs4633-rs4818-rs4680 haplotypes affect the catechol O-methyltransferase level and enzyme activity. Thus, the interaction was inferred to be at protein-protein and DA activity level. The genotype combinations of the two SNPs indicate a potential origin of DA homeostasis abnormalities in PTSD development. PMID- 29760657 TI - Purkinje Cell Signaling Deficits in Animal Models of Ataxia. AB - Purkinje cell (PC) dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction. Mutations affecting Na+ channels (NaV1.1, NaV1.6, NaVbeta4, Fgf14 or Rer1) reduce the firing rate of PCs, mainly via an impairment of the Na+ resurgent current. Mutations that reduce Kv3 currents limit the firing rate frequency range. Mutations of Kv1 channels act mainly on inhibitory interneurons, generating excessive GABAergic signaling onto PCs, resulting in episodic ataxia. Kv4.3 mutations are responsible for a complex syndrome with several neurologic dysfunctions including ataxia. Mutations of either Cav or BK channels have similar consequences, consisting in a disruption of the firing pattern of PCs, with loss of precision, leading to ataxia. Another category of pathogenic mechanisms of ataxia regards alterations of synaptic signals arriving at the PC. At the parallel fiber (PF)-PC synapse, mutations of glutamate delta-2 (GluD2) or its ligand Crbl1 are responsible for the loss of synaptic contacts, abolishment of long-term depression (LTD) and motor deficits. At the same synapse, a correct function of metabotropic glutamate receptor 1 (mGlu1) receptors is necessary to avoid ataxia. Failure of climbing fiber (CF) maturation and establishment of PC mono-innervation occurs in a great number of mutant mice, including mGlu1 and its transduction pathway, GluD2, semaphorins and their receptors. All these models have in common the alteration of PC output signals, due to a variety of mechanisms affecting incoming synaptic signals or the way they are processed by the repertoire of ionic channels responsible for intrinsic membrane properties. Although the PC is a final common pathway of ataxia, the link between specific firing alterations and neurologic symptoms has not yet been systematically studied and the alterations of the cerebellar contribution to motor signals are still unknown. PMID- 29760669 TI - Ontological Constraints in Children's Inductive Inferences: Evidence From a Comparison of Inferences Within Animals and Vehicles. AB - There is a lively debate concerning the role of conceptual and perceptual information in young children's inductive inferences. While most studies focus on the role of basic level categories in induction the present research contributes to the debate by asking whether children's inductions are guided by ontological constraints. Two studies use a novel inductive paradigm to test whether young children have an expectation that all animals share internal commonalities that do not extend to perceptually similar inanimates. The results show that children make category-consistent responses when asked to project an internal feature from an animal to either a dissimilar animal or a similar toy replica. However, the children do not have a universal preference for category-consistent responses in an analogous task involving vehicles and vehicle toy replicas. The results also show the role of context and individual factors in inferences. Children's early reliance on ontological commitments in induction cannot be explained by perceptual similarity or by children's sensitivity to the authenticity of objects. PMID- 29760670 TI - Validating the Copenhagen Psychosocial Questionnaire (COPSOQ-II) Using Set-ESEM: Identifying Psychosocial Risk Factors in a Sample of School Principals. AB - School principals world-wide report high levels of strain and attrition resulting in a shortage of qualified principals. It is thus crucial to identify psychosocial risk factors that reflect principals' occupational wellbeing. For this purpose, we used the Copenhagen Psychosocial Questionnaire (COPSOQ-II), a widely used self-report measure covering multiple psychosocial factors identified by leading occupational stress theories. We evaluated the COPSOQ-II regarding factor structure and longitudinal, discriminant, and convergent validity using latent structural equation modeling in a large sample of Australian school principals (N = 2,049). Results reveal that confirmatory factor analysis produced marginally acceptable model fit. A novel approach we call set exploratory structural equation modeling (set-ESEM), where cross-loadings were only allowed within a priori defined sets of factors, fit well, and was more parsimonious than a full ESEM. Further multitrait-multimethod models based on the set-ESEM confirm the importance of a principal's psychosocial risk factors; Stressors and depression were related to demands and ill-being, while confidence and autonomy were related to wellbeing. We also show that working in the private sector was beneficial for showing a low psychosocial risk, while other demographics have little effects. Finally, we identify five latent risk profiles (high risk to no risk) of school principals based on all psychosocial factors. Overall the research presented here closes the theory application gap of a strong multi dimensional measure of psychosocial risk-factors. PMID- 29760671 TI - Emotion in Stories: Facial EMG Evidence for Both Mental Simulation and Moral Evaluation. AB - Facial electromyography research shows that corrugator supercilii ("frowning muscle") activity tracks the emotional valence of linguistic stimuli. Grounded or embodied accounts of language processing take such activity to reflect the simulation or "reenactment" of emotion, as part of the retrieval of word meaning (e.g., of "furious") and/or of building a situation model (e.g., for "Mark is furious"). However, the same muscle also expresses our primary emotional evaluation of things we encounter. Language-driven affective simulation can easily be at odds with the reader's affective evaluation of what language describes (e.g., when we like Mark being furious). To examine what happens in such cases, we independently manipulated simulation valence and moral evaluative valence in short narratives. Participants first read about characters behaving in a morally laudable or objectionable fashion: this immediately led to corrugator activity reflecting positive or negative affect. Next, and critically, a positive or negative event befell these same characters. Here, the corrugator response did not track the valence of the event, but reflected both simulation and moral evaluation. This highlights the importance of unpacking coarse notions of affective meaning in language processing research into components that reflect simulation and evaluation. Our results also call for a re-evaluation of the interpretation of corrugator EMG, as well as other affect-related facial muscles and other peripheral physiological measures, as unequivocal indicators of simulation. Research should explore how such measures behave in richer and more ecologically valid language processing, such as narrative; refining our understanding of simulation within a framework of grounded language comprehension. PMID- 29760673 TI - Three-Week Inpatient Treatment of Obsessive-Compulsive Disorder: A 6-Month Follow Up Study. AB - Background: Specialized inpatient or residential treatment might be an alternative treatment approach for patients with obsessive-compulsive disorder (OCD) that do not respond satisfactorily to the standard outpatient treatment formats. Method: The aim of this open trial was to investigate the 6-month effectiveness of a 3-week inpatient treatment of OCD, where exposure with response prevention (ERP) was the main treatment intervention. The sample consisted of 187 adult patients with OCD, all with previous treatment attempts for OCD. Results: The sample showed significant reductions in symptoms of OCD and depression. The effect sizes were large for obsessive-compulsive symptoms and moderate to large for depressive symptoms. At discharge, 79.7% of the intent-to treat (ITT) group were classified as treatment responders (>=35% reduction in Y BOCS scores). However, some participants experienced relapse, as 61.5% of the ITT group were classified as treatment responders at 6-month follow-up. Antidepressant use appeared not to influence the outcome. Only pre-treatment levels of obsessive-compulsive symptoms emerged as a significant predictor of relapse. Conclusion: The 3-week inpatient programme produced similar treatment effects as previous inpatient and residential studies of longer duration (2 - 3 months). The results suggest that patients with severe OCD can be treated efficiently using this brief inpatient format. However, better relapse prevention interventions are needed. PMID- 29760672 TI - Analysis of Tonguing and Blowing Actions During Clarinet Performance. AB - Articulation on the clarinet is achieved by a combination of precise actions taking place inside the player's mouth. With the aim to analyse the effects of tonguing and blowing actions during playing, several physical variables are measured and parameters related to articulation are studied. Mouth pressure, mouthpiece pressure and reed displacement are recorded in an experiment with clarinet players to evaluate the influence of the player's actions on the selected parameters and on the sound. The results show that different combinations of tongue and blowing actions are used during performance. Portato and legato playing show constant blowing throughout the musical phrase, which varies according to the dynamic level. In portato, short tongue-reed interaction is used homogeneously among players and playing conditions. In staccato playing, where the tongue-reed contact is longer, the mouth pressure is reduced significantly between notes. Such a mouth-pressure decrease might be used to stop the note in slow staccato playing. It is hereby shown that when the note is stopped by the action of the tongue both the attack and release transients are shorter compared to the case where the vibration of the reed is stopped by a decrease of mouth pressure. PMID- 29760674 TI - Validation of a Spanish Questionnaire on Mobile Phone Abuse. AB - Mobile phone addiction has attracted much attention recently and is showing similarity to other substance use disorders. Because no studies on mobile phone addiction had yet been conducted in Spain, we developed and validated a questionnaire (Cuestionario de Abuso del Telefono Movil, ATeMo) to measure mobile phone abuse among young adults in Spanish. The ATeMo questionnaire was designed based on relevant DSM-5 diagnostic criteria and included craving as a diagnostic symptom. Using stratified sampling, the ATeMo questionnaire was administered to 856 students (mean age 21, 62% women). The MULTICAGE questionnaire was administered to assess history of drug abuse and addiction. Using confirmatory factor analysis, we found evidence for the construct validity of the following factors: Craving, Loss of Control, Negative Life Consequences, and Withdrawal Syndrome, and their association with a second order factor related to mobile phone abuse. The four ATeMO factors were also associated with alcoholism, internet use, and compulsive buying. Important gender differences were found that should be considered when studying mobile phone addictions. The ATeMo is a valid and reliable instrument that can be used in further research on mobile phone abuse. PMID- 29760675 TI - Feigning Amnesia Moderately Impairs Memory for a Mock Crime Video. AB - Previous studies showed that feigning amnesia for a crime impairs actual memory for the target event. Lack of rehearsal has been proposed as an explanation for this memory-undermining effect of feigning. The aim of the present study was to replicate and extend previous research adopting a mock crime video instead of a narrative story. We showed participants a video of a violent crime. Next, they were requested to imagine that they had committed this offense and to either feign amnesia or confess the crime. A third condition was included: Participants in the delayed test-only control condition did not receive any instruction. On subsequent recall tests, participants in all three conditions were instructed to report as much information as possible about the offense. On the free recall test, feigning amnesia impaired memory for the video clip, but participants who were asked to feign crime-related amnesia outperformed controls. However, no differences between simulators and confessors were found on both correct cued recollection or on distortion and commission rates. We also explored whether inner speech might modulate memory for the crime. Inner speech traits were not found to be related to the simulating amnesia effect. Theoretical and practical implications of our results are discussed. PMID- 29760676 TI - Helsinki Stroke Model Is Transferrable With "Real-World" Resources and Reduced Stroke Thrombolysis Delay to 34 min in Christchurch. AB - Background: Christchurch hospital is a tertiary hospital in New Zealand supported by five general neurologists with after-hours services provided mainly by onsite non-neurology medical residents. We assessed the transferrability and impact of the Helsinki Stroke model on stroke thrombolysis door-to-needle time (DNT) in Christchurch hospital. Methods: Key components of the Helsinki Stroke model were implemented first in 2015 with introduction of patient pre-notification and thrombolysis by the computed tomography (CT) suite, followed by implementation of direct transfer to CT on ambulance stretcher in May 2017. Data from the prospective thrombolysis registry which began in 2012 were analyzed for the impact of these interventions on median DNT. Results: Between May and December 2017, 46 patients were treated with alteplase, 25 (54%) patients were treated in hours (08:00-17:00 non-public holiday weekdays) and 21 (46%) patients were treated after-hours. The in-hours, after-hours, and overall median (interquartile range) DNTs were 34 (28-43), 47 (38-60), and 40 (30-51) minutes. The corresponding times in 2012-2014 prior to interventions were 87 (68-106), 86 (72 116), and 87 (71-112) minutes, representing median DNT reduction of 53, 39, and 47 minutes, respectively (p-values <0.01). The interventions also resulted in significant reductions in the overall median door-to-CT time (from 49 to 19 min), CT-to-needle time (32 to 20 min) and onset-to-needle time (168 to 120 min). Conclusion: The Helsinki stroke model is transferrable with real-world resources and reduced stroke DNT in Christchurch by over 50%. PMID- 29760677 TI - One-Week Exposure to a Free-Choice High-Fat High-Sugar Diet Does Not Interfere With the Lipopolysaccharide-Induced Acute Phase Response in the Hypothalamus of Male Rats. AB - Obesity has been associated with increased susceptibility to infection in humans and rodents. Obesity is also associated with low-grade hypothalamic inflammation that depends not only on body weight but also on diet. In the present study, we investigated if the bacterial endotoxin [lipopolysaccharide (LPS)]-induced acute phase response is aggravated in rats on a 1-week free-choice high-fat high-sugar (fcHFHS) diet and explained by diet-induced hypothalamic inflammation. Male Wistar rats were on an fcHFHS diet or chow for 1 week and afterwards intraperitoneally injected with LPS or saline. Hypothalamic inflammatory intermediates and plasma cytokines were measured after LPS. Both LPS and the fcHFHS diet altered hypothalamic Nfkbia mRNA and nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (NFKBIA) protein levels, whereas Il1beta, Il6, and Tnfalpha mRNA expression was solely induced upon LPS. We observed an interaction in hypothalamic Nfkbia and suppressor of cytokine signaling (SOCS) 3 mRNA upon LPS; both were higher in rats on a fcHFHS diet compared with chow animals. Despite this, plasma cytokine levels between fcHFHS diet-fed and chow-fed rats were similar after LPS administration. Consuming a fcHFHS diet but not LPS injections increased hypothalamic Atf4 (a cellular stress marker) mRNA expression, whereas Tlr4 mRNA was decreased only upon LPS. Our study does not support a role for diet-induced mild hypothalamic inflammation in the increased susceptibility to infection despite altered Nfkbia and Socs3 mRNA expression after the diet. Additional factors, related to increased fat mass, might be involved. PMID- 29760678 TI - Controversial Role of Kisspeptins/KiSS-1R Signaling System in Tumor Development. AB - KiSS-1 was first described as a metastasis suppressor gene in malignant melanoma. KiSS-1 encodes a 145 amino-acid residue peptide that is further processed, producing the 54 amino acid metastin and shorter peptides collectively named kisspeptins (KPs). KPs bind and activate KiSS-1R (GPR54). Although the KPs system has been extensively studied for its role in endocrinology of reproductive axis in mammals, its role in cancer is still controversial. Experimental evidences show that KP system exerts an anti-metastatic effect by the regulation of cellular migration and invasion in several cancer types. However, the role of KPs/KiSS-1R is very complex. Genomic studies suggest that KiSS-1/KiSS-1R expression might be different in the various stages of tumor development. Furthermore, overexpression of KiSS-1R has been reported to elicit drug resistance in triple negative breast cancer. In this review, we focused on multiple functions exerted by the KPs/KiSS-1R system in regulating tumor progression. PMID- 29760679 TI - Hematocrit Values Predict Carotid Intimal-Media Thickness in Obese Patients With Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study. AB - Background: Literature data suggest with some criticism that full-fledged cardiovascular (CV) events (acute or chronic) are likely predicted by blood components, which are reported to be associated with the presence/severity of non alcoholic fatty liver disease (NAFLD). This study was aimed at determining which marker(s) derived from blood count, such as white blood cells, neutrophils, neutrophil/lymphocyte ratio, platelet count, hemoglobin, mean corpuscular volume, hematocrit values were associated with ear or subclinical atherosclerosis, in obese patients of various classes suffering from NAFLD. Methods: One hundred consecutive obese patients presenting NAFLD at ultrasound, with low prevalence of co-morbidities and no history or instrumental features of CV diseases, underwent carotid intima-media thickness (IMT) assessment by Doppler ultrasonography. All of them were studied taking into account anthropometric parameters, the metabolic profile, and inflammatory markers. Results: White blood cells and neutrophil count showed no statistical association with IMT, which was predicted by the amount of visceral adiposity, as appreciated by ultrasonography. After adjusting for visceral adiposity and smoking status, only age and hematocrit contextually predicted early atherosclerosis, evaluated as IMT. Visceral adiposity was a confounding factor in foreseeing IMT. Conclusion: Hematocrit values along with the patient's age suggest an initial atherosclerosis, evaluated as IMT, and if this finding is confirmed in larger cohorts, could be added to other canonical CV risk factors. Inferences can be enhanced by future prospective studies that aim to identify the relationships between incident cardio-metabolic cases and this hematologic parameter. PMID- 29760682 TI - Daily Gene Expression Rhythms in Rat White Adipose Tissue Do Not Differ Between Subcutaneous and Intra-Abdominal Depots. AB - White adipose tissue (WAT) is present in different depots throughout the body. Although all depots are exposed to systemic humoral signals, they are not functionally identical. Studies in clock gene knockout animals and in shift workers suggest that daily rhythmicity may play an important role in lipid metabolism. Differences in rhythmicity between fat depots might explain differences in depot function; therefore, we measured mRNA expression of clock genes and metabolic genes on a 3-h interval over a 24-h period in the subcutaneous inguinal depot and in the intra-abdominal perirenal, epididymal, and mesenteric depots of male Wistar rats. We analyzed rhythmicity using CircWave software. Additionally, we measured plasma concentrations of glucose, insulin, corticosterone, and leptin. The clock genes (Bmal1/Per2/Cry1/Cry2/RevErbalpha/DBP) showed robust daily gene expression rhythms, which did not vary between WAT depots. Metabolic gene expression rhythms (SREBP1c/PPARalpha/PPARgamma/FAS/LPL/Glut4/HSL/CPT1b/leptin/visfatin/resistin) were more variable between depots. However, no distinct differences between intra abdominal and subcutaneous rhythms were found. Concluding, specific fat depots are not associated with differences in clock gene expression rhythms and, therefore, do not provide a likely explanation for the differences in metabolic function between different fat depots. PMID- 29760680 TI - Disruption in Thyroid Signaling Pathway: A Mechanism for the Effect of Endocrine Disrupting Chemicals on Child Neurodevelopment. AB - Thyroid hormones are crucial in normal brain development. Transient and mild thyroid hormone insufficiency in pregnancy is also associated with impaired neurodevelopment in the offspring (e.g., 3-4 IQ score loss in association with maternal free thyroxine in the lowest fifth percentile). While inadequate iodine intake remains the most common underlying cause of mild thyroid hormone insufficiency in vulnerable populations including pregnant women, other factors such as exposure to environmental contaminants have recently attracted increasing attention, in particular in interaction with iodine deficiency. Endocrine disrupting chemicals (EDCs) are natural and synthetic substances with ubiquitous exposure in children and adults including pregnant women. EDCs interfere, temporarily or permanently, with hormonal signaling pathways in the endocrine system by binding to hormone receptors and modifying gene expression. Other mechanisms involve alterations in production, metabolism, and transfer of hormones. Experimental studies have shown that exposures to EDCs affect various brain processes such as neurogenesis, neural differentiation and migration, as well as neural connectivity. Neuroimaging studies confirm brain morphological abnormalities (e.g., cortical thinning) consistent with neurodevelopmental impairments as a result of EDC exposures at standard use levels. In this review, we provide an overview of present findings from toxicological and human studies on the anti-thyroid effect of EDCs with a specific attention to fetal and early childhood exposure. This brief overview highlights the need for additional multidisciplinary studies with a focus on thyroid disruption as an underlying mechanism for developmental neurotoxicity of EDC, which can provide insight into modifiable risk factors of developmental delays in children. PMID- 29760683 TI - Evaluation of Primers Targeting the Diazotroph Functional Gene and Development of NifMAP - A Bioinformatics Pipeline for Analyzing nifH Amplicon Data. AB - Diazotrophic microorganisms introduce biologically available nitrogen (N) to the global N cycle through the activity of the nitrogenase enzyme. The genetically conserved dinitrogenase reductase (nifH) gene is phylogenetically distributed across four clusters (I-IV) and is widely used as a marker gene for N2 fixation, permitting investigators to study the genetic diversity of diazotrophs in nature and target potential participants in N2 fixation. To date there have been limited, standardized pipelines for analyzing the nifH functional gene, which is in stark contrast to the 16S rRNA gene. Here we present a bioinformatics pipeline for processing nifH amplicon datasets - NifMAP ("NifH MiSeq Illumina Amplicon Analysis Pipeline"), which as a novel aspect uses Hidden-Markov Models to filter out homologous genes to nifH. By using this pipeline, we evaluated the broadly inclusive primer pairs (Ueda19F-R6, IGK3-DVV, and F2-R6) that target the nifH gene. To evaluate any systematic biases, the nifH gene was amplified with the aforementioned primer pairs in a diverse collection of environmental samples (soils, rhizosphere and roots samples, biological soil crusts and estuarine samples), in addition to a nifH mock community consisting of six phylogenetically diverse members. We noted that all primer pairs co-amplified nifH homologs to varying degrees; up to 90% of the amplicons were nifH homologs with IGK3-DVV in some samples (rhizosphere and roots from tall oat-grass). In regards to specificity, we observed some degree of bias across the primer pairs. For example, primer pair F2-R6 discriminated against cyanobacteria (amongst others), yet captured many sequences from subclusters IIIE and IIIL-N. These aforementioned subclusters were largely missing by the primer pair IGK3-DVV, which also tended to discriminate against Alphaproteobacteria, but amplified sequences within clusters IIIC (affiliated with Clostridia) and clusters IVB and IVC. Primer pair Ueda19F-R6 exhibited the least bias and successfully captured diazotrophs in cluster I and subclusters IIIE, IIIL, IIIM, and IIIN, but tended to discriminate against Firmicutes and subcluster IIIC. Taken together, our newly established bioinformatics pipeline, NifMAP, along with our systematic evaluations of nifH primer pairs permit more robust, high-throughput investigations of diazotrophs in diverse environments. PMID- 29760684 TI - Bioprospecting Deep-Sea Actinobacteria for Novel Anti-infective Natural Products. AB - The global prevalence of drug resistance has created an urgent need for the discovery of novel anti-infective drugs. The major source of antibiotics in current clinical practice is terrestrial actinobacteria; the less-exploited deep sea actinobacteria may serve as an unprecedented source of novel natural products. In this study, we evaluated 50 actinobacteria strains derived from diverse deep water sponges and environmental niches for their anti-microbial activities against a panel of pathogens including Candida albicans, Clostridium difficile, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa. More than half of the tested strains (27) were identified as active in at least one assay. The rare earth salt lanthanum chloride (LaCl3) was shown to be as an effective elicitor. Among the 27 strains, the anti microbial activity of 15 were induced or enhanced by the addition of LaCl3. This part of study focused on one strain R818, in which potent antifungal activity was induced by the addition of LaCl3. We found that the LaCl3-activated metabolites in R818 are likely antimycin-type compounds. One of them, compound 1, has been purified. Spectroscopic analyses including HR-MS and 1D NMR indicated that this compound is urauchimycin D. The antifungal activity of compound 1 was confirmed with a minimal inhibitory concentration (MIC) of 25 MUg/mL; the purified compound also showed a moderate activity against C. difficile. Additional notable strains are: strain N217 which showed both antifungal and antibacterial (including P. aeruginosa) activities and strain M864 which showed potent activity against C. difficile with an MIC value (0.125 MUg/mL) lower than those of vancomycin and metronidazole. Our preliminary studies show that deep-sea actinobacteria is a promising source of anti-infective natural products. PMID- 29760681 TI - Sex Steroids, Adult Neurogenesis, and Inflammation in CNS Homeostasis, Degeneration, and Repair. AB - Sex steroidal hormones coordinate the development and maintenance of tissue architecture in many organs, including the central nervous systems (CNS). Within the CNS, sex steroids regulate the morphology, physiology, and behavior of a wide variety of neural cells including, but not limited to, neurons, glia, endothelial cells, and immune cells. Sex steroids spatially and temporally control distinct molecular networks, that, in turn modulate neural activity, synaptic plasticity, growth factor expression and function, nutrient exchange, cellular proliferation, and apoptosis. Over the last several decades, it has become increasingly evident that sex steroids, often in conjunction with neuroinflammation, have profound impact on the occurrence and severity of neuropsychiatric and neurodegenerative disorders. Here, I review the foundational discoveries that established the regulatory role of sex steroids in the CNS and highlight recent advances toward elucidating the complex interaction between sex steroids, neuroinflammation, and CNS regeneration through adult neurogenesis. The majority of recent work has focused on neuroinflammatory responses following acute physical damage, chronic degeneration, or pharmacological insult. Few studies directly assess the role of immune cells in regulating adult neurogenesis under healthy, homeostatic conditions. As such, I also introduce tractable, non-traditional models for examining the role of neuroimmune cells in natural neuronal turnover, seasonal plasticity of neural circuits, and extreme CNS regeneration. PMID- 29760686 TI - The Transcriptional Regulator TFB-RF1 Activates Transcription of a Putative ABC Transporter in Pyrococcus furiosus. AB - Transcription factor B recruiting factor 1 (TFB-RF1; PF1088) is a transcription regulator which activates transcription on archaeal promoters containing weak TFB recognition elements (BRE) by recruiting TFB to the promoter. The mechanism of activation is described in detail, but nothing is known about the biological function of this protein in Pyrococcus furiosus. The protein is located in an operon structure together with the hypothetical gene pf1089 and western blot as well as end-point RT-PCR experiments revealed an extremely low expression rate of both proteins. Furthermore, conditions to induce the expression of the operon are not known. By introducing an additional copy of tfb-RF1 using a Pyrococcus shuttle vector we could circumvent the lacking expression of both proteins under standard growth conditions as indicated by western blot as well as end-point RT PCR experiments. A ChIP-seq experiment revealed an additional binding site of TFB RF1 in the upstream region of the pf1011/1012 operon, beside the expected target of the pf1089/tfb-RF1 region. This operon codes for a putative ABC transporter which is most-related to a multidrug export system and in vitro analysis using gel shift assays, DNase I footprinting and in vitro transcription confirmed the activator function of TFB-RF1 on the corresponding promoter. These findings are also in agreement with in vivo data, as RT-qPCR experiments also indicate transcriptional activation of both operons. Taken together, the overexpression strategy of tfb-RF1 enabled the identification of an additional operon of the TFB RF1 regulon which indicates a transport-related function and provides a promising starting position to decipher the physiological function of the TFB-RF1 gene regulatory network in P. furiosus. PMID- 29760687 TI - Molecular Characterization of Clostridium difficile Isolates in China From 2010 to 2015. AB - Clostridium difficile infection (CDI) has become a worldwide public health problem causing high mortality and a large disease burden. Molecular typing and analysis is important for surveillance and infection control of CDI. However, molecular characterization of C. difficile across China is extremely rare. Here, we report on the toxin profiles, molecular subtyping with multilocus sequence typing (MLST) and PCR ribotyping, and epidemiological characteristics of 199 C. difficile isolates collected between 2010 through 2015 from 13 participating centers across China. We identified 35 STs and 27 ribotypes (RTs) among the 199 C. difficile isolates: ST35 (15.58%), ST3 (15.08%), ST37 (12.06%), and RT017 (14.07%), RT001 (12.06%), RT012 (11.56%) are the most prevalent. One isolate with ST1 and 8 isolates with ST 11 were identified. We identified a new ST in this study, denoted ST332. The toxin profile tcdA+tcdB+tcdC+tcdR+tcdE+CDT- (65.83%) was the predominant profile. Furthermore, 11 isolates with positive binary toxin genes were discovered. According to the PCR ribotyping, one isolate with RT 027, and 6 isolates with RT 078 were confirmed. The epidemiological characteristics of C. difficile in China shows geographical differences, and both the toxin profile and molecular types exhibit great diversity across the different areas. PMID- 29760685 TI - Phylogeny Trumps Chemotaxonomy: A Case Study Involving Turicella otitidis. AB - The genus Turicella was proposed to harbor clinical strains isolated from middle ear fluids of patients with otitis media. 16S rRNA phylogeny showed that it belonged to the mycolic acid-containing actinobacteria, currently classified in the order Corynebacteriales, and was closely related to the genus Corynebacterium. A new genus was proposed for the organisms as unlike corynebacteria they lacked mycolic acids and had different menaquinones. Here, we carried out large-scale comparative genomics on representative strains of the genera Corynebacterium and Turicella to check if this chemotaxonomic classification is justified. Three genes that are known to play an essential role in mycolic acid biosynthesis were absent in Turicella and two other mycolate-less Corynebacterium spp., explaining the lack of mycolic acids resulted from the deletion of genes and does not confer any phylogenetic context. Polyphasic phylogenetic analyses using 16S rRNA, bacterial core genes and genes responsible for synthesizing menaquinones unequivocally indicate that Turicella is a true member of the genus Corynebacterium. Here, we demonstrate that menaquinone and mycolic acid that have been used as critical taxonomic markers should be interpreted carefully, particularly when genome-based taxonomy is readily available. Based on the phylogenetic analysis, we propose to reclassify Turicella otitidis as Corynebacterium otitidis comb. nov. PMID- 29760689 TI - Trichoderma Biofertilizer Links to Altered Soil Chemistry, Altered Microbial Communities, and Improved Grassland Biomass. AB - In grasslands, forage and livestock production results in soil nutrient deficits as grasslands typically receive no nutrient inputs, leading to a loss of grassland biomass. The application of mature compost has been shown to effectively increase grassland nutrient availability. However, research on fertilization regime influence and potential microbial ecological regulation mechanisms are rarely conducted in grassland soil. We conducted a two-year experiment in meadow steppe grasslands, focusing on above- and belowground consequences of organic or Trichoderma biofertilizer applications and potential soil microbial ecological mechanisms underlying soil chemistry and microbial community responses. Grassland biomass significantly (p = 0.019) increased following amendment with 9,000 kg ha-1 of Trichoderma biofertilizer (composted cattle manure + inoculum) compared with other assessed organic or biofertilizer rates, except for BOF3000 (fertilized with 3,000 kg ha-1 biofertilizer). This rate of Trichoderma biofertilizer treatment increased soil antifungal compounds that may suppress pathogenic fungi, potentially partially responsible for improved grassland biomass. Nonmetric multidimensional scaling (NMDS) revealed soil chemistry and fungal communities were all separated by different fertilization regime. Trichoderma biofertilizer (9,000 kg ha-1) increased relative abundances of Archaeorhizomyces and Trichoderma while decreasing Ophiosphaerella. Trichoderma can improve grassland biomass, while Ophiosphaerella has the opposite effect as it may secrete metabolites causing grass necrosis. Correlations between soil properties and microbial genera showed plant-available phosphorus may influence grassland biomass by increasing Archaeorhizomyces and Trichoderma while reducing Ophiosphaerella. According to our structural equation modeling (SEM), Trichoderma abundance was the primary contributor to aboveground grassland biomass. Our results suggest Trichoderma biofertilizer could be an important tool for management of soils and ultimately grassland plant biomass. PMID- 29760688 TI - Dissecting the Acid Stress Response of Rhizobium tropici CIAT 899. AB - Rhizobium tropici CIAT899 is a nodule-forming alpha-proteobacterium displaying intrinsic resistance to several abiotic stress conditions such as low pH and high temperatures, which are common in tropical environments. It is a good competitor for Phaseolus vulgaris (common bean) nodule occupancy at low pH values, however little is known about the genetic and physiological basis of the tolerance to acidic conditions. To identify genes in R. tropici involved in pH stress response we combined two different approaches: (1) A Tn5 mutant library of R. tropici CIAT899 was screened and 26 acid-sensitive mutants were identified. For 17 of these mutants, the transposon insertion sites could be identified. (2) We also studied the transcriptomes of cells grown under different pH conditions using RNA Seq. RNA was extracted from cells grown for several generations in minimal medium at 6.8 or 4.5 (adapted cells). In addition, we acid-shocked cells pre-grown at pH 6.8 for 45 min at pH 4.5. Of the 6,289 protein-coding genes annotated in the genome of R. tropici CIAT 899, 383 were differentially expressed under acidic conditions (pH 4.5) vs. control condition (pH 6.8). Three hundred and fifty one genes were induced and 32 genes were repressed; only 11 genes were induced upon acid shock. The acid stress response of R. tropici CIAT899 is versatile: we found genes encoding response regulators and membrane transporters, enzymes involved in amino acid and carbohydrate metabolism and proton extrusion, in addition to several hypothetical genes. Our findings enhance our understanding of the core genes that are important during the acid stress response in R. tropici. PMID- 29760690 TI - Two New Lytic Bacteriophages of the Myoviridae Family Against Carbapenem Resistant Acinetobacter baumannii. AB - Two lytic bacteriophages, WCHABP1 and WCHABP12, were recovered from hospital sewage and were able to infect 9 and 12 out of 18 carbapenem-resistant Acinetobacter baumannii clinical strains, which belonged to different clones. Electron microscopy scan showed that both bacteriophages had the similar morphology as those of the Myoviridae family. Whole genomic sequencing revealed 45.4- or 45.8-kb genome with a 37.6% GC content for WCHABP1 and WCHABP12, both of which showed significant DNA sequence similarity with bacteriophages of the Ap22virus genus within the Myoviridae family. Taxonomic analysis was therefore performed following the proposal approved by the International Committee on Taxonomy of Viruses, which confirmed that WCHABP1 and WCHABP12 represented two new species of the Ap22virus genus. No tRNAs but 88 and 89 open reading frames (ORFs) were predicted for the two bacteriophages, among which 22 and 21 had known function and encoded proteins for morphogenesis, packaging, lysis, and nucleiotide metabolism. The C-terminal amino acids of the large unit of fiber tail proteins varied between the bacteriophages, which may explain their different host ranges. For most lytic bacteriophages, a set of holin and endolysin are required for lysis. However, no known holin-encoding genes were identified in WCHABP1 and WCHABP12, suggesting that they may use alternative, yet to-be-identified, novel holins for host cell membrane lysis. To test the efficacy of the bacteriophages in protecting against A. baumannii infection, a Galleria mellonella larva model was used. Only <20% G. mellonella larvae survived at 96 h after being infected by carbapenem-resistant A. baumannii strains, from which the two bacteriophages were recovered. With the administration of WCHABP1 and WCHABP12, the survival of larvae increased to 75%, while the treatment of polymyxin B only slightly increased the survival rate to 25%. The isolation of two new lytic bacteriophages in this study could expand our sight on Acinetobacter bacteriophages and may offer new potential therapeutic alternatives against A. baumannii. PMID- 29760692 TI - IL17/IL17RA as a Novel Signaling Axis Driving Mesenchymal Stem Cell Therapeutic Function in Experimental Autoimmune Encephalomyelitis. AB - The therapeutic effect of mesenchymal stem cells (MSCs) in multiple sclerosis (MS) and the experimental autoimmune encephalomyelitis (EAE) model has been well described. This effect is, in part, mediated through the inhibition of IL17 producing cells and the generation of regulatory T cells. While proinflammatory cytokines such as IFNgamma, TNFalpha, and IL1beta have been shown to enhance MSCs immunosuppressive function, the role of IL17 remains poorly elucidated. The aim of this study was, therefore, to investigate the role of the IL17/IL17R pathway on MSCs immunoregulatory effects focusing on Th17 cell generation in vitro and on Th17-mediated EAE pathogenesis in vivo. In vitro, we showed that the immunosuppressive effect of MSCs on Th17 cell proliferation and differentiation is partially dependent on IL17RA expression. This was associated with a reduced expression level of MSCs immunosuppressive mediators such as VCAM1, ICAM1, and PD L1 in IL17RA-/- MSCs as compared to wild-type (WT) MSCs. In the EAE model, we demonstrated that while WT MSCs significantly reduced the clinical scores of the disease, IL17RA-/- MSCs injected mice exhibited a clinical worsening of the disease. The disability of IL17RA-/- MSCs to reduce the progression of the disease paralleled the inability of these cells to reduce the frequency of Th17 cells in the draining lymph node of the mice as compared to WT MSCs. Moreover, we showed that the therapeutic effect of MSCs was correlated with the generation of classical Treg bearing the CD4+CD25+Foxp3+ signature in an IL17RA-dependent manner. Our findings reveal a novel role of IL17RA on MSCs immunosuppressive and therapeutic potential in EAE and suggest that the modulation of IL17RA in MSCs could represent a novel method to enhance their therapeutic effect in MS. PMID- 29760693 TI - Treatment Intensification in HIV-Infected Patients Is Associated With Reduced Frequencies of Regulatory T Cells. AB - In untreated HIV infection, the efficacy of T cell responses decreases over the disease course, resulting in disease progression. The reasons for this development are not completely understood. However, immunosuppressive cells are supposedly crucially involved. Treatment strategies to avoid the induction of these cells preserve immune functions and are therefore the object of intense research efforts. In this study, we assessed the effect of treatment intensification [=5-drug antiretroviral therapy (ART)] on the development of suppressive cell subsets. The New Era (NE) study recruited patients with primary HIV infection (PHI) or chronically HIV-infected patients with conventional ART (CHI) and applied an intensified 5-drug regimen containing maraviroc and raltegravir for several years. We compared the frequencies of the immune suppressive cells, namely, the myeloid-derived suppressor cells (MDSCs), regulatory B cells (Bregs), and regulatory T cells (Tregs), of the treatment intensification patients to the control groups, especially to the patients with conventional 3-drug ART, and analyzed the Gag/Nef-specific CD8 T cell responses. There were no differences between PHI and CHI in the NE population (p > 0.11) for any of the studied cell types. Polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC), monocytic myeloid-derived suppressor cell (M-MDSC), and the Breg frequencies were comparable to those of patients with a 3-drug ART. However, the Treg levels were significantly lower in the NE patients than those in 3ART treated individuals and other control groups (p <= 0.0033). The Gag/Nef-specific CD8 T cell response was broader (p = 0.0134) with a higher magnitude (p = 0.026) in the NE population than that in the patients with conventional ART. However, we did not find a correlation between the frequency of the immune suppressive cells and the interferon-gamma+ CD8 T cell response. In the treatment intensification subjects, the frequencies of the immune suppressive cells were comparable or lower than those of the conventional ART-treated subjects, with surprisingly broad HIV-specific CD8 T cell responses, suggesting a preservation of immune function with the applied treatment regimen. Interestingly, these effects were seen in both treatment intensification subpopulations and were not attributed to the start of treatment in primary infection. PMID- 29760691 TI - Extracellular Vesicle Heterogeneity: Subpopulations, Isolation Techniques, and Diverse Functions in Cancer Progression. AB - Cells release membrane enclosed nano-sized vesicles termed extracellular vesicles (EVs) that function as mediators of intercellular communication by transferring biological information between cells. Tumor-derived EVs have emerged as important mediators in cancer development and progression, mainly through transfer of their bioactive content which can include oncoproteins, oncogenes, chemokine receptors, as well as soluble factors, transcripts of proteins and miRNAs involved in angiogenesis or inflammation. This transfer has been shown to influence the metastatic behavior of primary tumors. Moreover, tumor-derived EVs have been shown to influence distant cellular niches, establishing favorable microenvironments that support growth of disseminated cancer cells upon their arrival at these pre-metastatic niches. It is generally accepted that cells release a number of major EV populations with distinct biophysical properties and biological functions. Exosomes, microvesicles, and apoptotic bodies are EV populations most widely studied and characterized. They are discriminated based primarily on their intracellular origin. However, increasing evidence suggests that even within these EV populations various subpopulations may exist. This heterogeneity introduces an extra level of complexity in the study of EV biology and function. For example, EV subpopulations could have unique roles in the intricate biological processes underlying cancer biology. Here, we discuss current knowledge regarding the role of subpopulations of EVs in cancer development and progression and highlight the relevance of EV heterogeneity. The position of tetraspanins and integrins therein will be highlighted. Since addressing EV heterogeneity has become essential for the EV field, current and novel techniques for isolating EV subpopulations will also be discussed. Further dissection of EV heterogeneity will advance our understanding of the critical roles of EVs in health and disease. PMID- 29760694 TI - Dissemination of Orientia tsutsugamushi, a Causative Agent of Scrub Typhus, and Immunological Responses in the Humanized DRAGA Mouse. AB - Scrub typhus is caused by Orientia tsutsugamushi, an obligated intracellular bacterium that affects over one million people per year. Several mouse models have been used to study its pathogenesis, disease immunology, and for testing vaccine candidates. However, due to the intrinsic differences between the immune systems in mouse and human, these mouse models could not faithfully mimic the pathology and immunological responses developed by human patients, limiting their value in both basic and translational studies. In this study, we have tested for the first time, a new humanized mouse model through footpad inoculation of O. tsutsugamushi in DRAGA (HLA-A2.HLA-DR4.Rag1KO.IL2RgammacKO.NOD) mice with their human immune system reconstituted by infusion of HLA-matched human hematopoietic stem cells from umbilical cord blood. Upon infection, Orientia disseminated into various organs of DRAGA mice resulted in lethality in a dose-dependent manner, while all C3H/HeJ mice infected by the same route survived. Tissue-specific lesions associated with inflammation and/or necroses were observed in multiple organs of infected DRAGA mice. Consistent with the intracellular nature of Orientia, strong Th1, but subdued Th2 responses were elicited as reflected by the human cytokine profiles in sera from infected mice. Interestingly, the percentage of both activated and regulatory (CD4+FOXP3+) human T cells were elevated in spleen tissues of infected mice. After immunization with irradiated whole cell Orientia, humanized DRAGA mice showed a significant activation of human T cells as evidenced by increased number of human CD4+ and CD8+ T cells. Specific human IgM and IgG antibodies were developed after repetitive immunization. The humanized DRAGA mouse model represents a new pre-clinical model for studying Orientia-human interactions and also for testing vaccines and novel therapeutics for scrub typhus. PMID- 29760696 TI - Podosomes, But Not the Maturation Status, Determine the Protease-Dependent 3D Migration in Human Dendritic Cells. AB - Dendritic cells (DC) are professional Antigen-Presenting Cells scattered throughout antigen-exposed tissues and draining lymph nodes, and survey the body for pathogens. Their ability to migrate through tissues, a 3D environment, is essential for an effective immune response. Upon infection, recognition of Pathogen-Associated Molecular Patterns (PAMP) by Toll-like receptors (TLR) triggers DC maturation. Mature DC (mDC) essentially use the protease-independent, ROCK-dependent amoeboid mode in vivo, or in collagen matrices in vitro. However, the mechanisms of 3D migration used by human immature DC (iDC) are still poorly characterized. Here, we reveal that human monocyte-derived DC are able to use two migration modes in 3D. In porous matrices of fibrillar collagen I, iDC adopted the amoeboid migration mode. In dense matrices of gelled collagen I or Matrigel, iDC used the protease-dependent, ROCK-independent mesenchymal migration mode. Upon TLR4 activation by LPS, mDC-LPS lose the capacity to form podosomes and degrade the matrix along with impaired mesenchymal migration. TLR2 activation by Pam3CSK4 resulted in DC maturation, podosome maintenance, and efficient mesenchymal migration. Under all these conditions, when DC used the mesenchymal mode in dense matrices, they formed 3D podosomes at the tip of cell protrusions. Using PGE2, known to disrupt podosomes in DC, we observed that the cells remained in an immature status and the mesenchymal migration mode was abolished. We also observed that, while CCL5 (attractant of iDC) enhanced both amoeboid and mesenchymal migration of iDC, CCL19 and CCL21 (attractants of mDC) only enhanced mDC-LPS amoeboid migration without triggering mesenchymal migration. Finally, we examined the migration of iDC in tumor cell spheroids, a tissue-like 3D environment. We observed that iDC infiltrated spheroids of tumor cells using both migration modes. Altogether, these results demonstrate that human DC adopt the mesenchymal mode to migrate in 3D dense environments, which relies on their capacity to form podosomes independent of their maturation status, paving the way of further investigations on in vivo DC migration in dense tissues and its regulation during infections. PMID- 29760695 TI - Group 2 Innate Lymphoid Cells in Pulmonary Immunity and Tissue Homeostasis. AB - Group 2 innate lymphoid cells (ILC2) represent an evolutionary rather old but only recently identified member of the family of innate lymphoid cells and have received much attention since their detailed description in 2010. They can orchestrate innate as well as adaptive immune responses as they interact with and influence several immune and non-immune cell populations. Moreover, ILC2 are able to rapidly secrete large amounts of type 2 cytokines that can contribute to protective but also detrimental host immune responses depending on timing, location, and physiological context. Interestingly, ILC2, despite their scarcity, are the dominant innate lymphoid cell population in the lung, indicating a key role as first responders and amplifiers upon immune challenge at this site. In addition, the recently described tissue residency of ILC2 further underlines the importance of their respective microenvironment. In this review, we provide an overview of lung physiology including a description of the most prominent pulmonary resident cells together with a review of known and potential ILC2 interactions within this unique environment. We will further outline recent observations regarding pulmonary ILC2 during immune challenge including respiratory infections and discuss different models and approaches to study ILC2 biology in the lung. PMID- 29760697 TI - Hookworm Secreted Extracellular Vesicles Interact With Host Cells and Prevent Inducible Colitis in Mice. AB - Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an immunoregulatory environment. Indeed, hookworms are such potent suppressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite-host interactions have been highlighted. Here, we analyze EVs from the rodent parasite Nippostrongylus brasiliensis, which has been used as a model for human hookworm infection. N. brasiliensis EVs (Nb-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of Nb-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from N. brasiliensis but not those from the whipworm Trichuris muris or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1beta, IFNgamma, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in Nb-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non infectious diseases resulting from a dysregulated immune system, such as IBD. PMID- 29760698 TI - Mechanisms of Cryptococcus neoformans-Mediated Host Damage. AB - Cryptococcus neoformans is not usually considered a cytotoxic fungal pathogen but there is considerable evidence that this microbe can damage host cells and tissues. In this essay, we review the evidence that C. neoformans damages host cells and note that the mechanisms involved are diverse. We consider C. neoformans-mediated host damage at the molecular, cellular, tissue, and organism level. Direct mechanisms of cytotoxicity include lytic exocytosis, organelle dysfunction, phagolysosomal membrane damage, and cytoskeletal alterations. Cytotoxicity contributes to pathogenesis by interfering with immune effector cell function and disrupting endothelial barriers thus allowing dissemination. When C. neoformans-mediated and immune-mediated host damage is sufficient to affect homeostasis, cryptococcosis occurs at the organism level. PMID- 29760700 TI - Bacillus Calmette-Guerin-Induced Trained Immunity Is Not Protective for Experimental Influenza A/Anhui/1/2013 (H7N9) Infection in Mice. AB - Avian influenza A of the subtype H7N9 has been responsible for almost 1,600 confirmed human infections and more than 600 deaths since its first outbreak in 2013. Although sustained human-to-human transmission has not been reported yet, further adaptations to humans in the viral genome could potentially lead to an influenza pandemic, which may have severe consequences due to the absence of pre existent immunity to this strain at population level. Currently there is no influenza A (H7N9) vaccine available. Therefore, in case of a pandemic outbreak, alternative preventive approaches are needed, ideally even independent of the type of influenza virus outbreak. Bacillus Calmette-Guerin (BCG) is known to induce strong heterologous immunological effects, and it has been shown that BCG protects against non-related infection challenges in several mouse models. BCG immunization of mice as well as human induces trained innate immune responses, resulting in increased cytokine responses upon subsequent ex vivo peripheral blood mononuclear cell restimulation. We investigated whether BCG (Statens Serum Institut-Denmark)-induced trained immunity may protect against a lethal avian influenza A/Anhui/1/2013 (H7N9) challenge. Here, we show that isolated splenocytes as well as peritoneal macrophages of BCG-immunized BALB/c mice displayed a trained immunity phenotype resulting in increased innate cytokine responses upon ex vivo restimulation. However, after H7N9 infection, no significant differences were found between the BCG immunized and the vehicle control group at the level of survival, weight loss, pulmonary influenza A nucleoprotein staining, or histopathology. In conclusion, BCG-induced trained immunity did not result in protection in an oseltamivir-sensitive influenza A/Anhui/1/2013 (H7N9) challenge mouse model. PMID- 29760699 TI - Tetraspanin CD9: A Key Regulator of Cell Adhesion in the Immune System. AB - The tetraspanin CD9 is expressed by all the major subsets of leukocytes (B cells, CD4+ T cells, CD8+ T cells, natural killer cells, granulocytes, monocytes and macrophages, and immature and mature dendritic cells) and also at a high level by endothelial cells. As a typical member of the tetraspanin superfamily, a prominent feature of CD9 is its propensity to engage in a multitude of interactions with other tetraspanins as well as with different transmembrane and intracellular proteins within the context of defined membranal domains termed tetraspanin-enriched microdomains (TEMs). Through these associations, CD9 influences many cellular activities in the different subtypes of leukocytes and in endothelial cells, including intracellular signaling, proliferation, activation, survival, migration, invasion, adhesion, and diapedesis. Several excellent reviews have already covered the topic of how tetraspanins, including CD9, regulate these cellular processes in the different cells of the immune system. In this mini-review, however, we will focus particularly on describing and discussing the regulatory effects exerted by CD9 on different adhesion molecules that play pivotal roles in the physiology of leukocytes and endothelial cells, with a particular emphasis in the regulation of adhesion molecules of the integrin and immunoglobulin superfamilies. PMID- 29760701 TI - Human Gingiva-Derived Mesenchymal Stem Cells Modulate Monocytes/Macrophages and Alleviate Atherosclerosis. AB - Atherosclerosis is the major cause of cardiovascular diseases. Current evidences indicate that inflammation is involved in the pathogenesis of atherosclerosis. Human gingiva-derived mesenchymal stem cells (GMSC) have shown anti-inflammatory and immunomodulatory effects on autoimmune and inflammatory diseases. However, the function of GMSC in controlling atherosclerosis is far from clear. The present study is aimed to elucidate the role of GMSC in atherosclerosis, examining the inhibition of GMSC on macrophage foam cell formation, and further determining whether GMSC could affect the polarization and activation of macrophages under different conditions. The results show that infusion of GMSC to AopE-/- mice significantly reduced the frequency of inflammatory monocytes/macrophages and decreased the plaque size and lipid deposition. Additionally, GMSC treatment markedly inhibited macrophage foam cell formation and reduced inflammatory macrophage activation, converting inflammatory macrophages to anti-inflammatory macrophages in vitro. Thus, our study has revealed a significant role of GMSC on modulating inflammatory monocytes/macrophages and alleviating atherosclerosis. PMID- 29760703 TI - The Increased Endogenous Sulfur Dioxide Acts as a Compensatory Mechanism for the Downregulated Endogenous Hydrogen Sulfide Pathway in the Endothelial Cell Inflammation. AB - Endogenous hydrogen sulfide (H2S) and sulfur dioxide (SO2) are regarded as important regulators to control endothelial cell function and protect endothelial cell against various injuries. In our present study, we aimed to investigate the effect of endogenous H2S on the SO2 generation in the endothelial cells and explore its significance in the endothelial inflammation in vitro and in vivo. The human umbilical vein endothelial cell (HUVEC) line (EA.hy926), primary HUVECs, primary rat pulmonary artery endothelial cells (RPAECs), and purified aspartate aminotransferase (AAT) protein from pig heart were used for in vitro experiments. A rat model of monocrotaline (MCT)-induced pulmonary vascular inflammation was used for in vivo experiments. We found that endogenous H2S deficiency caused by cystathionine-gamma-lyase (CSE) knockdown increased endogenous SO2 level in endothelial cells and enhanced the enzymatic activity of AAT, a major SO2 synthesis enzyme, without affecting the expressions of AAT1 and AAT2. While H2S donor could reverse the CSE knockdown-induced increase in the endogenous SO2 level and AAT activity. Moreover, H2S donor directly inhibited the activity of purified AAT protein, which was reversed by a thiol reductant DTT. Mechanistically, H2S donor sulfhydrated the purified AAT1/2 protein and rescued the decrease in the sulfhydration of AAT1/2 protein in the CSE knockdown endothelial cells. Furthermore, an AAT inhibitor l-aspartate-beta-hydroxamate (HDX), which blocked the upregulation of endogenous SO2/AAT generation induced by CSE knockdown, aggravated CSE knockdown-activated nuclear factor-kappaB pathway in the endothelial cells and its downstream inflammatory factors including ICAM 1, TNF-alpha, and IL-6. In in vivo experiment, H2S donor restored the deficiency of endogenous H2S production induced by MCT, and reversed the upregulation of endogenous SO2/AAT pathway via sulfhydrating AAT1 and AAT2. In accordance with the results of the in vitro experiment, HDX exacerbated the pulmonary vascular inflammation induced by the broken endogenous H2S production in MCT-treated rat. In conclusion, for the first time, the present study showed that H2S inhibited endogenous SO2 generation by inactivating AAT via the sulfhydration of AAT1/2; and the increased endogenous SO2 generation might play a compensatory role when H2S/CSE pathway was downregulated, thereby exerting protective effects in endothelial inflammatory responses in vitro and in vivo. PMID- 29760704 TI - Exploring the Immunomodulatory Moonlighting Activities of Acute Phase Proteins for Tolerogenic Dendritic Cell Generation. AB - The acute phase response is generated by an overwhelming immune-inflammatory process against infection or tissue damage, and represents the initial response of the organism in an attempt to return to homeostasis. It is mediated by acute phase proteins (APPs), an assortment of highly conserved plasma reactants of seemingly different functions that, however, share a common protective role from injury. Recent studies have suggested a crosstalk between several APPs and the mononuclear phagocyte system (MPS) in the resolution of inflammation, to restore tissue integrity and function. In fact, monocyte-derived dendritic cells (Mo DCs), an integral component of the MPS, play a fundamental role both in the regulation of antigen-specific adaptive responses and in the development of immunologic memory and tolerance, particularly in inflammatory settings. Due to their high plasticity, Mo-DCs can be modeled in vitro toward a tolerogenic phenotype for the treatment of aberrant immune-inflammatory conditions such as autoimmune diseases and allotransplantation, with the phenotypic outcome of these cells depending on the immunomodulatory agent employed. Yet, recent immunotherapy trials have emphasized the drawbacks and challenges facing tolerogenic Mo-DC generation for clinical use, such as reduced therapeutic efficacy and limited in vivo stability of the tolerogenic activity. In this review, we will underline the potential relevance and advantages of APPs for tolerogenic DC production with respect to currently employed immunomodulatory/immunosuppressant compounds. A further understanding of the mechanisms of action underlying the moonlighting immunomodulatory activities exhibited by several APPs over DCs could lead to more efficacious, safe, and stable protocols for precision tolerogenic immunotherapy. PMID- 29760706 TI - Complement-Opsonized HIV-1 Alters Cross Talk Between Dendritic Cells and Natural Killer (NK) Cells to Inhibit NK Killing and to Upregulate PD-1, CXCR3, and CCR4 on T Cells. AB - Dendritic cells (DCs), natural killer (NK) cells, and T cells play critical roles during primary HIV-1 exposure at the mucosa, where the viral particles become coated with complement fragments and mucosa-associated antibodies. The microenvironment together with subsequent interactions between these cells and HIV at the mucosal site of infection will determine the quality of immune response that ensues adaptive activation. Here, we investigated how complement and immunoglobulin opsonization influences the responses triggered in DCs and NK cells, how this affects their cross talk, and what T cell phenotypes are induced to expand following the interaction. Our results showed that DCs exposed to complement-opsonized HIV (C-HIV) were less mature and had a poor ability to trigger IFN-driven NK cell activation. In addition, when the DCs were exposed to C-HIV, the cytotolytic potentials of both NK cells and CD8 T cells were markedly suppressed. The expression of PD-1 as well as co-expression of negative immune checkpoints TIM-3 and LAG-3 on PD-1 positive cells were increased on both CD4 as well as CD8 T cells upon interaction with and priming by NK-DC cross talk cultures exposed to C-HIV. In addition, stimulation by NK-DC cross talk cultures exposed to C-HIV led to the upregulation of CD38, CXCR3, and CCR4 on T cells. Together, the immune modulation induced during the presence of complement on viral surfaces is likely to favor HIV establishment, dissemination, and viral pathogenesis. PMID- 29760702 TI - Emerging Concepts in Immune Thrombocytopenia. AB - Immune thrombocytopenia (ITP) is an autoimmune disease defined by low platelet counts which presents with an increased bleeding risk. Several genetic risk factors (e.g., polymorphisms in immunity-related genes) predispose to ITP. Autoantibodies and cytotoxic CD8+ T cells (Tc) mediate the anti-platelet response leading to thrombocytopenia. Both effector arms enhance platelet clearance through phagocytosis by splenic macrophages or dendritic cells and by induction of apoptosis. Meanwhile, platelet production is inhibited by CD8+ Tc targeting megakaryocytes in the bone marrow. CD4+ T helper cells are important for B cell differentiation into autoantibody secreting plasma cells. Regulatory Tc are essential to secure immune tolerance, and reduced levels have been implicated in the development of ITP. Both Fcgamma-receptor-dependent and -independent pathways are involved in the etiology of ITP. In this review, we present a simplified model for the pathogenesis of ITP, in which exposure of platelet surface antigens and a loss of tolerance are required for development of chronic anti-platelet responses. We also suggest that infections may comprise an important trigger for the development of auto-immunity against platelets in ITP. Post-translational modification of autoantigens has been firmly implicated in the development of autoimmune disorders like rheumatoid arthritis and type 1 diabetes. Based on these findings, we propose that post-translational modifications of platelet antigens may also contribute to the pathogenesis of ITP. PMID- 29760705 TI - Induction of Cytotoxic T-Lymphocyte Responses Upon Subcutaneous Administration of a Subunit Vaccine Adjuvanted With an Emulsion Containing the Toll-Like Receptor 3 Ligand Poly(I:C). AB - There is an unmet medical need for new subunit vaccines that induce cytotoxic T lymphocyte (CTL) responses to prevent infection with a number of pathogens. However, stimulation of CTL responses via clinically acceptable subcutaneous (s.c.) and intramuscular (i.m.) injection is challenging. Recently, we designed a liposomal adjuvant [cationic adjuvant formulation (CAF)09] composed of the cationic lipid dimethyldioctadecylammonium (DDA) bromide, a synthetic monomycoloyl glycerol analog and polyinosinic:polycytidylic acid, which induce strong CTL responses to peptide and protein antigens after intraperitoneal administration. By contrast, CAF09 does not stimulate CTL responses upon s.c. or i.m. injection because the vaccine forms a depot that remains at the injection site. Hence, we engineered a series of nanoemulsions (CAF24a-c) based on the active components of CAF09. The oil phase consisted of biodegradable squalane, and the surface charge was varied systematically by replacing DDA with zwitterionic distearoylphosphoethanolamine. We hypothesized that the nanoemulsions drain to the lymph nodes to a larger extent than CAF09, upon s.c. co-administration with the model antigen chicken egg ovalbumin (OVA). This results in an increased dose fraction that reaches the draining lymph nodes (dLNs) and subsequently activates cross-presenting dendritic cells (DCs), which can prime CTL responses. Indeed, the nanoemulsions induced antigen-specific CD8+ T-cell responses, which were significantly higher than those stimulated by OVA adjuvanted with CAF09. We explain this by the observed rapid localization of CAF24a in the dLNs and the subsequent association with conventional DCs, which promotes induction of CTL responses. Uptake of CAF24a was not specific for DCs, because CAF24a was also detected with B cells and macrophages. No measurable dose fraction of CAF09 was detected in the dLNs within the study period, and CAF09 formed a depot at the site of injection. Importantly, s.c. vaccination with OVA adjuvanted with CAF24a induced significant levels of specific lysis of antigen pulsed splenocytes were induced after, which was not observed for OVA adjuvanted with CAF09. Thus, CAF24a is a promising adjuvant for induction of CTL responses upon s.c. and i.m. immunization, and it offers interesting perspectives for the design of vaccines against pathogens for which CTL responses are required to prevent infection. PMID- 29760708 TI - Dual TLR2/9 Recognition of Herpes Simplex Virus Infection Is Required for Recruitment and Activation of Monocytes and NK Cells and Restriction of Viral Dissemination to the Central Nervous System. AB - The importance of TLR2 and TLR9 in the recognition of infection with herpes simplex virus (HSV) and HSV-caused diseases has been described, but some discrepancies remain concerning the benefits of these responses. Moreover, the impact of TLR2/9 on innate and adaptive immune responses within relevant mucosal tissues has not been elucidated using natural mucosal infection model of HSV. Here, we demonstrate that dual TLR2/9 recognition is essential to provide resistance against mucosal infection with HSV via an intravaginal route. Dual TLR2/9 ablation resulted in the highly enhanced mortality with exacerbated symptoms of encephalitis compared with TLR2 or TLR9 deficiency alone, coinciding with highly increased viral load in central nervous system tissues. TLR2 appeared to play a minor role in providing resistance against mucosal infection with HSV, since TLR2-ablated mice showed higher survival rate compared with TLR9-ablated mice. Also, the high mortality in dual TLR2/9-ablated mice was closely associated with the reduction in early monocyte and NK cell infiltration in the vaginal tract (VT), which was likely to correlate with low expression of cytokines and CCR2 ligands (CCL2 and CCL7). More interestingly, our data revealed that dual TLR2/9 recognition of HSV infection plays an important role in the functional maturation of TNF-alpha and iNOS-producing dendritic cells (Tip-DCs) from monocytes as well as NK cell activation in VT. TLR2/9-dependent maturation of Tip DCs from monocytes appeared to specifically present cognate Ag, which effectively provided functional effector CD4+ and CD8+ T cells specific for HSV Ag in VT and its draining lymph nodes. TLR2/9 expressed in monocytes was likely to directly facilitate Tip-DC-like features after HSV infection. Also, dual TLR2/9 recognition of HSV infection directly activated NK cells without the aid of dendritic cells through activation of p38 MAPK pathway. Taken together, these results indicate that dual TLR2/9 recognition plays a critical role in providing resistance against mucosal infection with HSV, which may involve a direct regulation of Tip-DCs and NK cells in VT. Therefore, our data provide a more detailed understanding of TLR2/9 role in conferring antiviral immunity within relevant mucosal tissues after mucosal infection with HSV. PMID- 29760707 TI - The Yin and Yang of Tyrosine Kinase Inhibition During Experimental Polymicrobial Sepsis. AB - Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-alpha-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side. PMID- 29760709 TI - Protein Kinase Serine/Threonine Kinase 24 Positively Regulates Interleukin 17 Induced Inflammation by Promoting IKK Complex Activation. AB - Interleukin 17 (IL-17) is a key inflammatory cytokine that plays a critical role in tissue inflammation and autoimmune diseases. However, its signaling remains poorly understood. In this study, we identified serine/threonine kinase 24 (Stk24) as a positive modulator of IL-17-mediated signaling and inflammation. Stk24 deficiency or knockdown markedly inhibited IL-17-induced phosphorylation of NF-kappaB and impaired IL-17-induced chemokines and cytokines expression. Stk24 overexpression greatly enhanced IL-17-induced NF-kappaB activation and expression of chemokines and cytokines in a kinase activity-independent manner. The IL-17 induced inflammatory response was significantly reduced in Stk24-deficient mice. In addition, the severity of experimental autoimmune encephalomyelitis was markedly reduced in mice with a deficiency of Stk24 in non-hematopoietic cells. We further demonstrated that Stk24 directly interacts with TAK1 and IKKbeta and promotes the formation of TAK1/IKK complexes, leading to enhanced IKKbeta/NF kappaB activation and downstream cytokines and chemokines induction. Collectively, our findings suggest that Stk24 plays an important role in controlling IL-17-triggered inflammation and autoimmune diseases and provides new insight into the therapeutic targets of IL-17-mediated inflammatory disease. PMID- 29760710 TI - Ionizing Radiation Induces Morphological Changes and Immunological Modulation of Jurkat Cells. AB - Impairment or stimulation of the immune system by ionizing radiation (IR) impacts on immune surveillance of tumor cells and non-malignant cells and can either foster therapy response or side effects/toxicities of radiation therapy. For a better understanding of the mechanisms by which IR modulates T-cell activation and alters functional properties of these immune cells, we exposed human immortalized Jurkat cells and peripheral blood lymphocytes (PBL) to X-ray doses between 0.1 and 5 Gy. This resulted in cellular responses, which are typically observed also in naive T-lymphocytes in response of T-cell receptor immune stimulation or mitogens. These responses include oscillations of cytosolic Ca2+, an upregulation of CD25 surface expression, interleukin-2 and interferon-gamma synthesis, elevated expression of Ca2+ sensitive K+ channels and an increase in cell diameter. The latter was sensitive to inhibition by the immunosuppressant cyclosporine A, Ca2+ buffer BAPTA-AM, and the CDK1-inhibitor RO3306, indicating the involvement of Ca2+-dependent immune activation and radiation-induced cell cycle arrest. Furthermore, on a functional level, Jurkat and PBL cell adhesion to endothelial cells was increased upon radiation exposure and was highly dependent on an upregulation of integrin beta-1 expression and clustering. In conclusion, we here report that IR impacts on immune activation and functional properties of T-lymphocytes that may have implications in both toxic effects and treatment response to combined radiation and immune therapy in cancer patients. PMID- 29760711 TI - Selective Modulation of TNF-TNFRs Signaling: Insights for Multiple Sclerosis Treatment. AB - Autoimmunity develops when self-tolerance mechanisms are failing to protect healthy tissue. A sustained reaction to self is generated, which includes the generation of effector cells and molecules that destroy tissues. A way to restore this intrinsic tolerance is through immune modulation that aims at refurbishing this immunologically naive or unresponsive state, thereby decreasing the aberrant immune reaction taking place. One major cytokine has been shown to play a pivotal role in several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS): tumor necrosis factor alpha (TNFalpha) modulates the induction and maintenance of an inflammatory process and it comes in two variants, soluble TNF (solTNF) and transmembrane bound TNF (tmTNF). tmTNF signals via TNFR1 and TNFR2, whereas solTNF signals mainly via TNFR1. TNFR1 is widely expressed and promotes mainly inflammation and apoptosis. Conversely, TNFR2 is restricted mainly to immune and endothelial cells and it is known to activate the pro-survival PI3K-Akt/PKB signaling pathway and to sustain regulatory T cells function. Anti-TNFalpha therapies are successfully used to treat diseases such as RA, colitis, and psoriasis. However, clinical studies with a non-selective inhibitor of TNFalpha in MS patients had to be halted due to exacerbation of clinical symptoms. One possible explanation for this failure is the non selectivity of the treatment, which avoids TNFR2 stimulation and its immune and tissue protective properties. Thus, a receptor-selective modulation of TNFalpha signal pathways provides a novel therapeutic concept that might lead to new insights in MS pathology with major implications for its effective treatment. PMID- 29760713 TI - Human Leukocyte Antigen-Class I Alleles and the Autoreactive T Cell Response in Psoriasis Pathogenesis. AB - Psoriasis is a complex immune-mediated inflammatory skin disease characterized by T-cell-driven epidermal hyperplasia. It occurs on a strong genetic predisposition. The human leukocyte antigen (HLA)-class I allele HLA-C*06:02 on psoriasis susceptibility locus 1 (PSORS1 on 6p21.3) is the main psoriasis risk gene. Other HLA-class I alleles encoding HLA molecules presenting overlapping peptide repertoires show associations with psoriasis as well. Outside the major histocompatibility complex region, genome-wide association studies identified more than 60 psoriasis-associated common gene variants exerting only modest individual effects. They mainly refer to innate immune activation and the interleukin-23/Th/c17 pathway. Given their strong risk association, explaining the role of the HLA-risk alleles is essential for elucidating psoriasis pathogenesis. Psoriasis lesions develop upon epidermal infiltration, activation, and expansion of CD8+ T cells. The unbiased analysis of a paradigmatic Valpha3S1/Vbeta13S1-T-cell receptor from a pathogenic epidermal CD8+ T-cell clone of an HLA-C*06:02+ psoriasis patient had revealed that HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation, and it identified a peptide form ADAMTS-like protein 5 as an HLA-C*06:02-presented melanocyte autoantigen. These data demonstrate that psoriasis is an autoimmune disease, where the predisposing HLA-class I alleles promote organ-specific inflammation through facilitating a T-cell response against a particular skin specific cell population. This review discusses the role of HLA-class I alleles in the pathogenic psoriatic T-cell immune response. It concludes that as a principle of T-cell driven HLA-associated inflammatory diseases proinflammatory traits promote autoimmunity in the context of certain HLA molecules that present particular autoantigens. PMID- 29760712 TI - The Function of MicroRNAs in B-Cell Development, Lymphoma, and Their Potential in Clinical Practice. AB - B-cell formation, development, and differentiation are complex processes regulated by several mechanisms. Recently, there has been growing evidence indicating that microRNAs (miRNAs) are important for normal B-cell lineage development. miRNAs are small non-coding RNA molecules, about 20-22 nucleotide in length, that play an important role in regulating gene expression. They pair with specific messenger RNAs (mRNAs), resulting in mRNAs translational repression or degradation. Here, we review current research about the function of miRNAs in the aspects of B-cell physiology and pathology. We start by introducing the process of miRNA biogenesis. We will then focus on the role of miRNAs during B-cell lineage commitment and development in the bone marrow, followed by a discussion of miRNAs' role in subsequent peripheral B-cell activation, proliferation, and final differentiation (including B-cell central tolerance and autoimmunity). We list and describe several examples to illustrate miRNAs' role in the development of B-cell lymphoma, both as oncogenes and tumor suppressor genes. Finally, we delineate the potential value of miRNAs in diagnosing B-cell lymphoma, predicting clinical outcomes, and modulating the efficiency of anticancer treatments. Despite the vast amount of research conducted on miRNAs in recent years, it is still necessary to increase and further strengthen studies on miRNAs and their targets to promote a better understanding on B-cell development and as a result, construct more effective treatments against B-cell disease. PMID- 29760714 TI - Fine Mapping and Candidate Gene Identification for Wax Biosynthesis Locus, BoWax1 in Brassica oleracea L. var. capitata. AB - Cuticular waxes play important roles in plant protection against various biotic and abiotic environmental stresses. The cuticular wax covering gives normal cabbage a glaucous appearance, but the appearance of waxless mutant is glossy green. Based on the present study, inheritance of the glossy green character of mutant HUAYOU2 follows a simple recessive pattern. Genetic analysis of an F2 population comprising 808 recessive individuals derived from HUAYOU2 (P1, maternal parent) and M36 (P2, paternal parent) revealed that a single recessive locus, BoWax1 (Brassica oleracea Wax 1), controls glossy green trait in B. oleracea. This locus was mapped to a region of 158.5 kb on chromosome C01. Based on nucleotide sequence analysis, Bol013612 was identified as the candidate gene for BoWax1. Sequencing results demonstrated that there is a deletion mutation of two nucleotides in the cDNA of Bol013612 of HUAYOU2, which may account for its glossy green trait. These results lay the foundation for functional analysis of BoWax1 and may accelerate research on wax metabolism in cabbage. PMID- 29760715 TI - Higher Temperature at Lower Elevation Sites Fails to Promote Acclimation or Adaptation to Heat Stress During Pollen Germination. AB - High temperatures associated with climate change are expected to be detrimental for aspects of plant reproduction, such as pollen viability. We hypothesized that (1) higher peak temperatures predicted with climate change would have a minimal effect on pollen viability, while high temperatures during pollen germination would negatively affect pollen viability, (2) high temperatures during pollen dispersal would facilitate acclimation to high temperatures during pollen germination, and (3) pollen from populations at sites with warmer average temperatures would be better adapted to high temperature peaks. We tested these hypotheses in Pinus edulis, a species with demonstrated sensitivity to climate change, using populations along an elevational gradient. We tested for acclimation to high temperatures by measuring pollen viability during dispersal and germination stages in pollen subjected to 30, 35, and 40 degrees C in a factorial design. We also characterized pollen phenology and measured pollen heat tolerance using trees from nine sites along a 200 m elevational gradient that varied 4 degrees C in temperature. We demonstrated that this gradient is biologically meaningful by evaluating variation in vegetation composition and P. edulis performance. Male reproduction was negatively affected by high temperatures, with stronger effects during pollen germination than pollen dispersal. Populations along the elevational gradient varied in pollen phenology, vegetation composition, plant water stress, nutrient availability, and plant growth. In contrast to our hypothesis, pollen viability was highest in pinyons from mid-elevation sites rather than from lower elevation sites. We found no evidence of acclimation or adaptation of pollen to high temperatures. Maximal plant performance as measured by growth did not occur at the same elevation as maximal pollen viability. These results indicate that periods of high temperature negatively affected sexual reproduction, such that even high pollen production may not result in successful fertilization due to low germination. Acquired thermotolerance might not limit these impacts, but pinyon could avoid heat stress by phenological adjustment of pollen development. Higher pollen viability at the core of the distribution could be explained by an optimal combination of biotic and abiotic environmental factors. The disconnect between measures of growth and pollen production suggests that vigor metrics may not accurately estimate reproduction. PMID- 29760716 TI - Metabolomic Fingerprints of Individual Algal Cells Using the Single-Probe Mass Spectrometry Technique. AB - Traditional approaches for the assessment of physiological responses of microbes in the environment rely on bulk filtration techniques that obscure differences among populations as well as among individual cells. Here, were report on the development on a novel micro-scale sampling device, referred to as the "Single probe," which allows direct extraction of metabolites from living, individual phytoplankton cells for mass spectrometry (MS) analysis. The Single-probe is composed of dual-bore quartz tubing which is pulled using a laser pipette puller and fused to a silica capillary and a nano-ESI. For this study, we applied Single probe MS technology to the marine dinoflagellate Scrippsiella trochoidea, assaying cells grown under different illumination levels and under nitrogen (N) limiting conditions as a proof of concept for the technology. In both experiments, significant differences in the cellular metabolome of individual cells could readily be identified, though the vast majority of detected metabolites could not be assigned to KEGG pathways. Using the same approach, significant changes in cellular lipid complements were observed, with individual lipids being both up- and down-regulated under light vs. dark conditions. Conversely, lipid content increased across the board under N limitation, consistent with an adjustment of Redfield stoichiometry to reflect higher C:N and C:P ratios. Overall, these data suggest that the Single-probe MS technique has the potential to allow for near in situ metabolomic analysis of individual phytoplankton cells, opening the door to targeted analyses that minimize cell manipulation and sampling artifacts, while preserving metabolic variability at the cellular level. PMID- 29760718 TI - Multiplexed Nanopore Sequencing of HLA-B Locus in Maori and Pacific Island Samples. AB - The human leukocyte antigen (HLA) system encodes the human major histocompatibility complex (MHC). HLA-B is the most polymorphic gene in the MHC class I region and many HLA-B alleles have been associated with adverse drug reactions (ADRs) and disease susceptibility. The frequency of such HLA-B alleles varies by ethnicity, and therefore it is important to understand the prevalence of such alleles in different population groups. Research into HLA involvement in ADRs would be facilitated by improved methods for genotyping key HLA-B alleles. Here, we describe an approach to HLA-B typing using next generation sequencing (NGS) on the MinIONTM nanopore sequencer, combined with data analysis with the SeqNext-HLA software package. The nanopore sequencer offers the advantages of long-read capability and single molecule reads, which can facilitate effective haplotyping. We developed this method using reference samples as well as individuals of New Zealand Maori or Pacific Island descent, because HLA-B diversity in these populations is not well understood. We demonstrate here that nanopore sequencing of barcoded, pooled, 943 bp polymerase chain reaction (PCR) amplicons of 49 DNA samples generated ample read depth for all samples. HLA-B alleles were assigned to all samples at high-resolution with very little ambiguity. Our method is a scaleable and efficient approach for genotyping HLA-B and potentially any other HLA locus. Finally, we report our findings on HLA-B genotypes of this cohort, which adds to our understanding of HLA-B allele frequencies among Maori and Pacific Island people. PMID- 29760717 TI - Reduced Neuronal Transcription of Escargot, the Drosophila Gene Encoding a Snail Type Transcription Factor, Promotes Longevity. AB - In recent years, several genes involved in complex neuron specification networks have been shown to control life span. However, information on these genes is scattered, and studies to discover new neuronal genes and gene cascades contributing to life span control are needed, especially because of the recognized role of the nervous system in governing homeostasis, aging, and longevity. Previously, we demonstrated that several genes that encode RNA polymerase II transcription factors and that are involved in the development of the nervous system affect life span in Drosophila melanogaster. Among other genes, escargot (esg) was demonstrated to be causally associated with an increase in the life span of male flies. Here, we present new data on the role of esg in life span control. We show that esg affects the life spans of both mated and unmated males and females to varying degrees. By analyzing the survival and locomotion of the esg mutants, we demonstrate that esg is involved in the control of aging. We show that increased longevity is caused by decreased esg transcription. In particular, we demonstrate that esg knockdown in the nervous system increased life span, directly establishing the involvement of the neuronal esg function in life span control. Our data invite attention to the mechanisms regulating the esg transcription rate, which is changed by insertions of DNA fragments of different sizes downstream of the structural part of the gene, indicating the direction of further research. Our data agree with the previously made suggestion that alterations in gene expression during development might affect adult lifespan, due to epigenetic patterns inherited in cell lineages or predetermined during the development of the structural and functional properties of the nervous system. PMID- 29760720 TI - The Long-Term Outcome Comparison of Different Time-Delayed Kallikrein Treatments in a Mouse Cerebral Ischemic Model. AB - Delayed administration of kallikrein after cerebral infarction can improve neurological function. However, the appropriate kallkrein treatment time after ischemic stroke has not been illuminated. In this study, we compared the long term outcome among three kallikrein therapeutic regimens starting at different time points following mouse cerebral ischemia. Furthermore, the protective mechanisms involving neurogenesis, angiogenesis, and AKT-GSK3beta-VEGF signaling pathway were analyzed. Human tissue kallikrein was injected through the tail vein daily starting at 8 h, 24 h, or 36 h after right middle cerebral artery occlusion (MCAO) until the 28th day. Three therapeutic regimens all protected against neurological dysfunction, but kallikrein treatment starting at 8 h after MCAO had the best efficacy. Additionally, kallikrein treatment at 8 h after MCAO significantly enhanced cell proliferation including neural stem cell and induced differentiation of neural stem cell into mature neuron. Kallikrein treatment starting at 8 h also promoted more angiogenesis than other two treatment regimens, which was associated with AKT-GSK3beta-VEGF signaling pathway. Thus, we confirm that three delayed kallikrein treatments provide protection against cerebral infarction and furthermore suggest that kallikrein treatment starting at 8 h had a better effect than that at 24 h and 36 h. These findings provide the experimental data contributing to better clinical application of exogenous kallikrein. PMID- 29760719 TI - IFNalpha-Expressing Amniotic Fluid-Derived Mesenchymal Stem Cells Migrate to and Suppress HeLa Cell-Derived Tumors in a Mouse Model. AB - Background: Immunotherapy for cervical cancer with type I interferon (IFN) is limited because of the cytotoxicity that accompanies the high doses that are administered. In this study, we investigated the utilization of amniotic fluid derived mesenchymal stem cells (AF-MSCs) as a means for delivering IFNalpha to local tumor sites for the suppression of cervical cancer in a mouse model using HeLa cell xenografts. Methods: The tumor tropism ability of AF-MSCs and AF-MSCs genetically modified to overexpress IFNalpha (IFNalpha-AF-MSCs) was examined through Transwell in vitro and through fluorescent images and immunohistochemistry in a mouse model. Tumor size and tumor apoptosis were observed to evaluate the efficacy of the targeting therapy. Mechanistically, tumor cell apoptosis was detected by cytometry and TUNEL, and oncogenic proteins c-Myc, p53, and Bcl-2 as well as microvessel density were detected by immunohistochemistry. Results: In this model, intravenously injected AF-MSCs selectively migrated to the tumor sites, participated in tumor construction, and promoted tumor growth. After being genetically modified to overexpress IFNalpha, the IFNalpha-AF-MSCs maintained their tumor tropism but could significantly suppress tumor growth. The restrictive efficacy of IFNalpha-AF-MSCs was associated with the suppression of angiogenesis, inhibition of tumor cell proliferation, and induction of apoptosis in tumor cells. Neither AF-MSCs nor IFNalpha-AF-MSCs trigger tumor formation. Conclusions: IFNalpha-AF-MSC-based therapy is feasible and shows potential for treating cervical cancer, suggesting that AF-MSCs may be promising vehicles for delivering targeted anticancer therapy. PMID- 29760721 TI - Decreased Count and Dysfunction of Circulating EPCs in Postmenopausal Hypercholesterolemic Females via Reducing NO Production. AB - Endothelial progenitor cells (EPCs) contribute to the endogenous endothelial repair program during hypercholesterolemia. EPC count and migratory and proliferative capacities remain unchanged in the premenopausal female with hypercholesterolemia. However, the changes of count and activity of circulating EPCs in the hypercholesterolemic postmenopausal females are unknown. Here, we find that the migratory and proliferative capacities of circulating EPCs were decreased in patients with hypercholesterolemia versus normocholesterolemia. No significant differences were found between postmenopausal females and age-matched males. NO production showed positive correlation with the activity and count of circulating EPCs in patients with hypercholesterolemia. Flow-mediated dilatation (FMD) is directly interrelated with EPC counts and function. Our findings reveal that decreased EPC count and endothelial dysfunction lead to less NO production in hypercholesterolemic postmenopausal females. Maintaining the EPC numbers and activity might be emerging as a potential therapeutic strategy to reduce the risk of cardiovascular injury in elder women. PMID- 29760723 TI - Applications of Mesenchymal Stem Cells in Sinus Lift Augmentation as a Dental Implant Technology. AB - The potential application of stem cell biology in human dentistry is a new and emerging field of research. The objective of the current review was to study the efficiency of mesenchymal stem cells (MSCs) in sinus lift augmentation (SLA). A literature review was performed in PubMed Central using MeSH keywords such as sinus lift, MSCs, dental implants, and augmentation. The searches involved full text papers written in English, published in the past 10 years (2007-2017). The review included in vitro and in vivo studies on the use of MSCs in SLA. Electronic searching provided 45 titles, and among them, 8 papers were chosen as suitable based on the inclusion requirements of this review. The reviewed studies have revealed the potential of MSCs in SLA. According to these papers, stem cell therapy combined with different biomaterials may considerably improve bone regeneration in previous steps of dental implantation and may veritably lead to efficient clinical usages in the recent future. However, the identification of an ideal source of stem cells as well as long-term studies is vital to assess the success rate of this technology. Further clinical trials are also needed to approve the potential of MSCs in SLA. PMID- 29760722 TI - MicroRNA-126 Priming Enhances Functions of Endothelial Progenitor Cells under Physiological and Hypoxic Conditions and Their Therapeutic Efficacy in Cerebral Ischemic Damage. AB - Endothelial progenitor cells (EPCs) have shown the potential for treating ischemic stroke (IS), while microRNA-126 (miR-126) is reported to have beneficial effects on endothelial function and angiogenesis. In this study, we investigated the effects of miR-126 overexpression on EPCs and explore the efficacy of miR-126 primed EPCs (EPCmiR-126) in treating IS. The effects of miR-126 overexpression on EPC proliferation, migratory, tube formation capacity, reactive oxygen species (ROS) production, and nitric oxide (NO) generation were determined. In in vivo study, the effects of EPCmiR-126 on the cerebral blood flow (CBF), neurological deficit score (NDS), infarct volume, cerebral microvascular density (cMVD), and angiogenesis were determined. Moreover, the levels of circulating EPCs (cEPCs) and their contained miR-126 were measured. We found (1) miR-126 overexpression promoted the proliferation, migration, and tube formation abilities of EPCs; decreased ROS; and increased NO production of EPCs via activation of PI3K/Akt/eNOS pathway; (2) EPCmiR-126 was more effective than EPCs in attenuating infarct volume and NDS and enhancing cMVD, CBF, and angiogenesis; and (3) infusion of EPCmiR-126 increased the number and the level of miR-126 in cEPCs. Our data indicate that miR-126 overexpression enhanced the function of EPCs in vitro and in vivo. PMID- 29760726 TI - Brain Injury and Stem Cell Replacement. PMID- 29760725 TI - The Effects of Hyperacute Serum on the Elements of the Human Subchondral Bone Marrow Niche. AB - Mesenchymal stem cells (MSCs) are widely used in laboratory experiments as well as in human cell therapy. Their culture requires animal sera like fetal calf serum (FCS) as essential supplementation; however, animal sera pose a risk for clinical applications. Human blood derivatives, for example, platelet-rich plasma (PRP) releasates, are potential replacements of FCS; however, it is unclear which serum variant has the best effect on the given cell or tissue type. Additionally, blood derivatives are commonly used in musculoskeletal diseases like osteoarthritis (OA) or osteonecrosis as "proliferative agents" for the topical MSC pool. Hyperacute serum (HAS), a new serum derivative, has been designed to approximate the natural coagulation cascade with a single-step, additive-free preparation method. We investigated the effects of HAS on monolayer MSC cultures and in their natural niche, in 3D subchondral bone and marrow explants. Viability measurements, RT-qPCR evaluation for gene expression and flow cytometry for cell surface marker analysis were performed to compare the effects of FCS-, PRP-, or HAS-supplemented culture media. Monolayer MSCs showed significantly higher metabolic activity following 5 days' incubation in HAS, and osteoblast-specific mRNA expression was markedly increased, while cells also retained their MSC specific cell surface markers. A similar effect was observed on bone and marrow explants, which was further confirmed with confocal microscopy analysis. Moreover, markedly higher bone marrow preservation was observed with histology in case of HAS supplementation compared to FCS. These findings indicate possible application of HAS in regenerative solutions of skeletal diseases like OA or osteonecrosis. PMID- 29760727 TI - Expanded CD133+ Cells from Human Umbilical Cord Blood Improved Heart Function in Rats after Severe Myocardial Infarction. AB - Pharmacological approaches are partially effective in limiting infarct size. Cell therapies using a cell population enriched with endothelial progenitor cells (EPCs) CD133+ have opened new perspectives for the treatment of ischemic areas after infarction. This preclinical study evaluated the effect of intramyocardial transplantation of purified or expanded human umbilical cord blood-derived CD133+ cells on the recovery of rats following acute myocardial infarction (AMI). Histology studies, electrocardiogram, and fluorescence in situ hybridization (FISH) were used to evaluate heart recovery. Purified CD133+ cells, enriched in endothelial progenitor cells, when expanded in vitro acquired an endothelial-like cell phenotype expressing CD31 and von Willebrand factor (vWF). The group of infarcted rats that received expanded CD133+ cells had a more significant recovery of contraction performance and less heart remodeling than the group that received purified CD133+ cells. Either purified or expanded CD133+ cells were able to induce neovascularization in the infarcted myocardium in an equivalent manner. Few human cells were detected in the infarcted myocardium of the rats 28 days after transplantation suggesting that the effects observed might be related primarily to paracrine activity. Although both cell populations ameliorated the infarcted heart and are suitable for regeneration of the vascular system, expanded CD133+ cells are more beneficial and promising candidates for vascular regeneration. PMID- 29760724 TI - Adult Neural Stem Cells: Basic Research and Production Strategies for Neurorestorative Therapy. AB - Over many decades, constructing genetically and phenotypically stable lines of neural stem cells (NSC) for clinical purposes with the aim of restoring irreversibly lost functions of nervous tissue has been one of the major goals for multiple research groups. The unique ability of stem cells to maintain their own pluripotent state even in the adult body has made them into the choice object of study. With the development of the technology for induced pluripotent stem cells (iPSCs) and direct transdifferentiation of somatic cells into the desired cell type, the initial research approaches based on the use of allogeneic NSCs from embryonic or fetal nervous tissue are gradually becoming a thing of the past. This review deals with basic molecular mechanisms for maintaining the pluripotent state of embryonic/induced stem and reprogrammed somatic cells, as well as with currently existing reprogramming strategies. The focus is on performing direct reprogramming while bypassing the stage of iPSCs which is known for genetic instability and an increased risk of tumorigenesis. A detailed description of various protocols for obtaining reprogrammed neural cells used in the therapy of the nervous system pathology is also provided. PMID- 29760728 TI - Mesenchymal Stromal Cells Cultured in Serum from Heart Failure Patients Are More Resistant to Simulated Chronic and Acute Stress. AB - Despite regulatory issues surrounding the use of animal-derived cell culture supplements, most clinical cardiac cell therapy trials using mesenchymal stromal cells (MSCs) still rely on fetal bovine serum (FBS) for cell expansion before transplantation. We sought to investigate the effect of human serum from heart failure patients (HFS) on cord blood MSCs (CB-MSCs) during short-term culture under regular conditions and during simulated acute and chronic stress. Cell survival, proliferation, metabolic activity, and apoptosis were quantified, and gene expression profiles of selected apoptosis and cell cycle regulators were determined. Compared to FBS, HFS and serum from healthy donors (CS) showed similar effects by substantially increasing cell survival during chronic and acute stress and by increasing cell yields 5 days after acute stress. Shortly after the termination of acute stress, both HFS and CS resulted in a marked decrease in apoptotic cells. Transcriptome analysis suggested a decrease in TNF mediated induction of caspases and decreased activation of mitochondrial apoptosis. Our data confirm that human serum from both healthy donors and heart failure patients results in increased cell yields and increased resistance to cellular stress signals. Therefore, we consider autologous serum a valid alternative to FBS in cell-based therapies addressing severe heart disease. PMID- 29760729 TI - Ceramic Hollow Fibre Constructs for Continuous Perfusion and Cell Harvest from 3D Hematopoietic Organoids. AB - Tissue vasculature efficiently distributes nutrients, removes metabolites, and possesses selective cellular permeability for tissue growth and function. Engineered tissue models have been limited by small volumes, low cell densities, and invasive cell extraction due to ineffective nutrient diffusion and cell biomaterial attachment. Herein, we describe the fabrication and testing of ceramic hollow fibre membranes (HFs) able to separate red blood cells (RBCs) and mononuclear cells (MNCs) and be incorporated into 3D tissue models to improve nutrient and metabolite exchange. These HFs filtered RBCs from human umbilical cord blood (CB) suspensions of 20% RBCs to produce 90% RBC filtrate suspensions. When incorporated within 5 mL of 3D collagen-coated polyurethane porous scaffold, medium-perfused HFs maintained nontoxic glucose, lactate, pH levels, and higher cell densities over 21 days of culture in comparison to nonperfused 0.125 mL scaffolds. This hollow fibre bioreactor (HFBR) required a smaller per-cell medium requirement and operated at cell densities > 10-fold higher than current 2D methods whilst allowing for continuous cell harvest through HFs. Herein, we propose HFs to improve 3D cell culture nutrient and metabolite diffusion, increase culture volume and cell density, and continuously harvest products for translational cell therapy biomanufacturing protocols. PMID- 29760730 TI - Current Progress and Challenges for Skeletal Muscle Differentiation from Human Pluripotent Stem Cells Using Transgene-Free Approaches. AB - Neuromuscular diseases are caused by functional defects of skeletal muscles, directly via muscle pathology or indirectly via disruption of the nervous system. Extensive studies have been performed to improve the outcomes of therapies; however, effective treatment strategies have not been fully established for any major neuromuscular disease. Human pluripotent stem cells have a great capacity to differentiate into myogenic progenitors and skeletal myocytes for use in treating and modeling neuromuscular diseases. Recent advances have allowed the creation of patient-derived stem cells, which can be used as a unique platform for comprehensive study of disease mechanisms, in vitro drug screening, and potential new cell-based therapies. In the last decade, a number of methods have been developed to derive skeletal muscle cells from human pluripotent stem cells. By controlling the process of myogenesis using transcription factors and signaling molecules, human pluripotent stem cells can be directed to differentiate into cell types observed during muscle development. In this review, we highlight signaling pathways relevant to the formation of muscle tissue during embryonic development. We then summarize current methods to differentiate human pluripotent stem cells toward the myogenic lineage, specifically focusing on transgene-free approaches. Lastly, we discuss existing challenges for deriving skeletal myocytes and myogenic progenitors from human pluripotent stem cells. PMID- 29760733 TI - Ex Vivo and In Vivo Stem Cells-Based Tissue Engineering Strategies for Their Use in Regenerative Medicine. PMID- 29760731 TI - Recovery of Donor Hematopoiesis after Graft Failure and Second Hematopoietic Stem Cell Transplantation with Intraosseous Administration of Mesenchymal Stromal Cells. AB - Multipotent mesenchymal stromal cells (MSCs) participate in the formation of bone marrow niches for hematopoietic stem cells. Donor MSCs can serve as a source of recovery for niches in patients with graft failure (GF) after allogeneic bone marrow (BM) transplantation. Since only few MSCs reach the BM after intravenous injection, MSCs were implanted into the iliac spine. For 8 patients with GF after allo-BMT, another hematopoietic stem cell transplantation with simultaneous implantation of MSCs from their respective donors into cancellous bone was performed. BM was aspirated from the iliac crest of these patients at 1-2, 4-5, and 9 months after the intraosseous injection of donor MSCs. Patients' MSCs were cultivated, and chimerism was determined. In 6 out of 8 patients, donor hematopoiesis was restored. Donor cells (9.4 +/- 3.3%) were detected among MSCs. Thus, implanted MSCs remain localized at the site of administration and do not lose the ability to proliferate. These results suggest that MSCs could participate in the restoration of niches for donor hematopoietic cells or have an immunomodulatory effect, preventing repeated rejection of the graft. Perhaps, intraosseous implantation of MSCs contributes to the success of the second transplantation of hematopoietic stem cells and patient survival. PMID- 29760732 TI - Comparative Study on In Vitro Culture of Mouse Bone Marrow Mesenchymal Stem Cells. AB - In vitro culture of mesenchymal stem cells (MSCs) from mouse bone marrow (BM) has been hampered because of the low yield of MSCs during isolation and the contamination of hematopoietic cells during expansion. The lack of specific mouse BM-MSC markers increases the difficulty. Several techniques have been reported to improve the purity and in vitro growth of mouse BM-MSCs. However, systematic report on comparison of characteristics in primary BM-MSCs between different culture conditions is rare. Here, we studied the effects of oxygen concentrations and initial medium replacement intervals, along with cell passages, on mouse BM MSCs isolated with differential adhesion method. BM-MSCs exhibited elevated proliferative and clonogenic abilities in 5% oxygen compared with 10% and 21% oxygen, as well as a better expression of the MSC marker Sca-1. Adipogenic and osteogenetic differentiation of BM-MSCs can be observed in both 21% and 5% oxygen. Adipogenic differentiation appeared stronger under normoxia conditions. BM-MSCs showed increased proliferative capacity and adipogenic/osteogenetic differentiation potential when initial medium replacement interval was 4 days compared with 1 day. As passage number increased, cells were more MSC-like in morphology and in expression of surface markers (positive for CD29, CD44, and Sca 1 and negative for CD11b, CD19, and CD45). These data provide new insight into optimizing the culture method and understanding the biological characteristics of mouse BM-MSCs during in vitro expansion. PMID- 29760735 TI - Stem Cells for Cartilage Regeneration: A Roadmap to the Clinic. PMID- 29760734 TI - Dexamethasone-Activated MSCs Release MVs for Stimulating Osteogenic Response. AB - The extracellular microvesicles (MVs) are attracting much attention because they are found to be the key paracrine mediator participating in tissue regeneration. Dexamethasone (DXM) is widely accepted as an important regulator in tailoring the differentiation potential of mesenchymal stem cells (MSCs). However, the effect of DXM on the paracrine signaling of MSCs remains unknown. To this point, we aimed to explore the role of DXM in regulating the paracrine activity of MSCs through evaluating the release and function of MSC-MVs, based on their physicochemical characteristics and support on osteogenic response. Results showed that DXM had no evident impact on the release of MSC-MVs but played a pivotal role in regulating the function of MSC-MVs. MVs obtained from the DXM stimulated MSCs (DXM-MVs) increased MC3T3 cell proliferation and migration and upregulated Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and osteopontin (OPN) expression. The repair efficiency of DXM-MVs for femur defects was further investigated in an established rat model. It was found that DXM-MVs accelerated the healing process of bone formation in the defect area. Thus, we conclude that using DXM as stimuli to obtain functional MSCs-MVs could become a valuable tool for promoting bone regeneration. PMID- 29760736 TI - Comparison of Immunological Characteristics of Mesenchymal Stem Cells from the Periodontal Ligament, Umbilical Cord, and Adipose Tissue. AB - Mesenchymal stem cells (MSCs) are of therapeutic importance in the fields of regenerative medicine and immunological diseases. Accordingly, studies evaluating MSCs for clinical applications are increasing. In this study, we characterized MSCs from the periodontal ligament, umbilical cord (UC-MSCs), and adipose tissue, which were relatively easy to obtain with limited ethical concerns regarding their acquisition, and compared their immunological characteristics. Among MSCs isolated from the three different tissues, UC-MSCs grew the fastest in vitro. The three types of MSCs were shown to inhibit proliferation of activated peripheral blood mononuclear cells (PBMCs) to a similar degree, via the indoleamine 2,3 dioxygenase and cyclooxygenase-2 pathways. They were also shown to inhibit the proliferation of PBMCs using HLA-G, which was most prominent in UC-MSCs. Unlike the other two types of MSCs, UC-MSCs showed minimal expression of HLA-DR after activation, suggesting that they pose minimal risk of initiating an allogeneic immune response when administered in vivo. These characteristics, the ease of collection, and the minimal ethical concerns regarding their use suggest UC-MSCs to be suitable MSC therapeutic candidates. PMID- 29760737 TI - Injection Laryngoplasty Using Autologous Fat Enriched with Adipose-Derived Regenerative Stem Cells: A Safe Therapeutic Option for the Functional Reconstruction of the Glottal Gap after Unilateral Vocal Fold Paralysis. AB - Background: Paralysis of one vocal fold leads to glottal gap and vocal fold insufficiency that has significant impact upon a patient's quality of life. Fillers have been tested to perform intracordal injections, but they do not provide perdurable results. Early data suggest that enriching fat grafts with adipose-derived regenerative cells (ADRCs) promote angiogenesis and modulate the immune response, improving graft survival. The aim of this study is to propose ADRC-enriched adipose tissue grafts as effective filler for the paralyzed vocal fold to use it for functional reconstruction of the glottal gap. Method: This is the first phase I-IIA clinical trial (phase I/IIA clinical trial, unicentric, randomized, controlled, and two parallel groups), to evaluate the safety of a new therapy with ADRC-enriched fat grafting (ADRC: group I) for laryngoplasty after unilateral vocal fold paralysis. Control group patients received centrifuged autologous fat (CAF: group II) grafts. Overall mean age is 52.49 +/- 16.60 years. Group I (ADRC): 7 patients (3 males and 4 females), 52.28 +/- 20.95 year. Group II (CAF): 7 patients (3 males and 4 females), 52.71 +/- 12.59 year. Results: VHI 10 test showed that preoperative mean score was 24.21 +/- 8.28. Postoperative mean score was 6.71 +/- 6.75. Preoperative result in group I was 21.14 +/- 3.58 and postoperative result was 3.14 +/- 3.53. Preoperative result for group II was 27.29 +/- 10.66. Postoperative score in group II was 10.29 +/- 7.52. Wilcoxon and the Student t-tests showed that the patient's self-perception of posttreatment improvement is larger when ADRCs are used. Comparing pre- and posttreatment voice quality analysis, group I showed a p = 0.053. Group II showed a p = 0.007. There would be no significant differentiation between pre- and posttreatment results. This is true for group II and limited for group I. Conclusions: This prospective trial demonstrates the safety and efficacy of the treatment of glottal gap defects utilizing ADRC-enriched fat grafts. This trial is registered with NCT02904824. PMID- 29760739 TI - Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients. AB - Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT. PMID- 29760738 TI - Dental Mesenchymal Stem/Stromal Cells and Their Exosomes. AB - Stem cells derived from human dental pulp tissue (DP-MSC) differ from the other mesenchymal stem cells prepared from bone marrow or adipose tissue due to their embryonic origin from the neural crest and are of special interest because of their neurotropic character. Furthermore, the therapeutic potential of DP-MSCs is realized through paracrine action of extracellularly released components, for which exosomes play an important role. In this review, we intend to explore the properties of these cells with an emphasis on exosomes. The therapeutic applicability of these cells and exosomes in dental practice, neurodegenerative diseases, and many other difficultly treatable diseases, like myocardial infarction, focal cerebral ischemia, acute lung or brain injury, acute respiratory distress syndrome, acute inflammation, and several others is concisely covered. The use of cellular exosomes as an important diagnostic marker and indicator of targeted cancer therapies is also discussed, while the importance of stem cells from human exfoliated deciduous teeth as a source of evolutionally young cells for future regenerative therapies is stressed. We conclude that exosomes derived from these cells are potent therapeutic tools for regenerative medicine in the near future as clinical administration of DP-MSC conditioned medium and/or exosomes is safer and more practical than stem cells. PMID- 29760741 TI - Establishing a Surgical Procedure for Rhesus Epiretinal Scaffold Implantation with HiPSC-Derived Retinal Progenitors. AB - Background: To develop an effective surgical procedure for cellular scaffold epiretinal implantation in rhesus, facilitating subsequent epiretinal stem cell transplantation. Methods: Retinal progenitors were seeded onto a poly(lactic-co glycolic) acid (PLGA) scaffold. First, the cellular scaffolds were delivered by 18G catheter or retinal forceps into rabbit epiretinal space (n = 50). Then, the cell survival rate was evaluated by Cell Counting Kit-8 (CCK-8). Second, three methods of scaffold fixation, including adhesion after gas-liquid exchange (n = 1), tamponade by hydrogel (n = 1), and fixation by retinal tacks (n = 4), were performed in rhesus monkeys. After one month, fundus photography and SD-OCT were performed to assess the outcomes, and histological examination was performed to evaluate proliferation. Results: The cell survival rate was significantly higher in the catheter group. Follow-up examination showed that retinal tack fixation was the only method to maintain the scaffolds attached to host retina for at least 3 weeks, which is the minimal time required for cell integration. Histological staining demonstrated slight glial fibrillary acidic protein (GFAP) accumulation in the retinal tack insertion area. Conclusions: The established surgical procedure offers a new insight into research of epiretinal cell replacement therapy in rhesus eyes. The successful delivery and long-term fixation provide a prerequisite for cell migration and integration. PMID- 29760740 TI - Current Progress in the Rejuvenation of Aging Stem/Progenitor Cells for Improving the Therapeutic Effectiveness of Myocardial Repair. AB - Ischemic heart disease affects a majority of people, especially elderly patients. Recent studies have utilized autologous adult stem/progenitor cells as a treatment option to heal cardiac tissue after myocardial infarction. However, donor cells from aging patients are more likely to be in a senescent stage. Rejuvenation is required to reverse the damage levied by aging and promote a youthful phenotype. This review aims to discuss current strategies that are effective in rejuvenating aging cardiac stem cells and represent novel therapeutic methods to treat the aging heart. Recent literature mainly focuses on three approaches that aim to reverse cardiac aging: genetic modification, pharmaceutical administration, and optimization of extracellular factors. In vitro genetic modification can be used to overexpress or knock down certain genes and allow for reversal of the aging phenotype. Pharmaceutical administration is another approach that allows for manipulation of signaling pathways related to cell proliferation and cell senescence. Since the stem cell niche can contribute to the age-related decline in stem cell function, rejuvenation strategies also include optimization of extracellular factors. Overall, improving the intrinsic properties of aging stem cells as well as the surrounding environment allows these cells to adopt a phenotype similar to their younger counterparts. PMID- 29760742 TI - Correlation between Therapeutic Efficacy of CD34+ Cell Treatment and Directed In Vivo Angiogenesis in Patients with End-Stage Diffuse Coronary Artery Disease. AB - Background: This study was aimed at testing the association between the therapeutic efficacy of CD34+ cell treatment in patients with end-stage diffuse coronary artery disease as reflected in angiographic grading and results of directed in vivo angiogenesis assay (DIVAA) on their isolated peripheral blood mononuclear cell- (PBMC-) derived endothelial progenitor cells (EPCs). Methods: Angiographic grades (0: <5%; 1: 5-35%; 2: 35-75%; 3: >75%) which presented the improvement of vessel density pre- and post-CD34+ treatment were given to 30 patients with end-stage diffuse coronary artery disease having received CD34+ cell treatment. The patients were categorized into low-score group (angiographic grade 0 or 1, n = 12) and high-score group (angiographic grade 2 or 3, n = 18). The percentages of circulating EPCs with KDR+/CD34+/CD45-, CD133+/CD34+/CD45-, and CD34+ were determined in each patient using flow cytometry. PBMC-derived EPCs from all patients were subjected to DIVAA through a 14-day implantation in nude mice. The DIVAA ratio (i.e., mean fluorescent units in angioreactors with EPCs/mean fluorescent units in angioreactors without EPCs) was obtained for each animal with implanted EPCs from each patient. Results and Conclusions: The number of EPCs showed no significant difference among the two groups. The DIVAA ratio in the high-score group was significantly higher than that in the low-score group (p = 0.0178). Logistic regression revealed a significant association between the DIVAA ratio and angiographic grading (OR 3.12, 95% CI: 1.14-8.55, p = 0.027). The area under the ROC curve (AUC) was 0.8519 (p = 0.0013). We proposed that DIVAA may be a reliable tool for assessing coronary vascularization after CD34+ cell treatment. PMID- 29760744 TI - Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway. AB - Background: Post-infarction cardiac injury is closely associated with cardiac remodeling and heart dysfunction. Mammalian STE20-like kinase 1 (Mst1), a regulator of cellular apoptosis, is involved in cardiac remodeling in post infarction heart, but the mechanisms remain poorly defined. We aimed to explore the role of Mst1 in regulating chronic post-infarction cardiac injury, with a focus on mitochondrial homoeostasis. Methods: Wild-type (WT) and Mst1-knockout mice were as the cardiac myocardial infarction model. Cardiac fibrosis, myocardial inflammation response, heart dysfunction and cardiomyocyte death were measured in vivo using immunohistochemistry, immunofluorescence, western blot, qPCR and TUNEL assays. Cardiomyocytes were isolated from WT and Mst1-knockout mice, and a chronic hypoxia model was used to induce damage. Mitochondrial function was determined via JC1 staining, ROS measurement, cyt-c leakage detection and mitochondrial apoptotic pathways analysis. Mitochondrial fission was observed using immunofluorescence. A pathway activator and inhibitor were applied to establish the signaling pathways involved in regulating mitochondrial homeostasis. Results: Our study demonstrated that Mst1 expression was significantly upregulated in the heart post-infarction. Activated Mst1 induced cardiac fibrosis, an excessive inflammatory response, and cardiomyocyte death, whereas the genetic ablation of Mst1 protected the myocardium against chronic post-infarction injury. Function assays showed that upregulation of Mst1 activity contributed to JNK pathway activation, which led to Drp1 migration from the cytoplasm onto the surface of the mitochondria, indicative of mitochondrial fission activation. Excessive mitochondrial fission caused mitochondrial fragmentation, resulting in mitochondrial potential collapse, ROS overproduction, mitochondrial pro-apoptotic leakage into the cytoplasm, and the initiation of caspase-9-mediated mitochondrial apoptosis. By contrast, Mst1 deletion helped to maintain mitochondrial structure and function, sending pro-survival signals to the cardiomyocytes. Conclusions: Our results identify Mst1 as a malefactor in the development of post-infarction cardiac injury and that it acts through the JNK Drp1-mitochondrial fission pathway. PMID- 29760743 TI - Crosstalk between the Warburg effect, redox regulation and autophagy induction in tumourigenesis. AB - Tumourigenic tissue uses modified metabolic signalling pathways in order to support hyperproliferation and survival. Cancer-associated aerobic glycolysis resulting in lactic acid production was described nearly 100 years ago. Furthermore, increased reactive oxygen species (ROS) and lactate quantities increase metabolic, survival and proliferation signalling, resulting in increased tumourigenesis. In order to maintain redox balance, the cell possesses innate antioxidant defence systems such as superoxide dismutase, catalase and glutathione. Several stimuli including cells deprived of nutrients or failure of antioxidant systems result in oxidative stress and cell death induction. Among the cell death machinery is autophagy, a compensatory mechanism whereby energy is produced from damaged and/or redundant organelles and proteins, which prevents the accumulation of waste products, thereby maintaining homeostasis. Furthermore, autophagy is maintained by several pathways including phosphoinositol 3 kinases, the mitogen-activated protein kinase family, hypoxia-inducible factor, avian myelocytomatosis viral oncogene homolog and protein kinase receptor-like endoplasmic reticulum kinase. The persistent potential of cancer metabolism, redox regulation and the crosstalk with autophagy in scientific investigation pertains to its ability to uncover essential aspects of tumourigenic transformation. This may result in clinical translational possibilities to exploit tumourigenic oxidative status and autophagy to advance our capabilities to diagnose, monitor and treat cancer. PMID- 29760745 TI - Diagnostic value of decoy receptor 3 combined with procalcitonin and soluble urokinase-type plasminogen activator receptor for sepsis. AB - The levels of decoy receptor 3 (DcR3), soluble urokinase type plasminogen activator receptor (suPAR) and procalcitonin (PCT) are significantly increased in sepsis. We investigated the diagnostic value of DcR3 combined with suPAR and PCT in sepsis. Patients with sepsis, non-infectious systemic inflammatory response comprehensive syndrome (SIRS) and healthy controls were recruited according to the diagnostic standard. We measured DcR3, suPAR, PCT, interleukin-6 (IL-6) and C reactive protein (CRP), and the diagnostic value was evaluated by receiver operating characteristics (ROC) curves. In our analysis, serum DcR3, suPAR and PCT levels of the sepsis group were significantly higher than those of the SIRS and control groups. However, IL-6, CRP and WBC showed no significant difference between the SIRS group and the sepsis group. The serum DcR3 level was positively correlated with the serum suPAR level (r = 0.37, p = 0.0022) and PCT level (r = 0.37, p = 0.0021). Using DcR3, suPAR and PCT to distinguish SIRS from sepsis, the area under the curve (AUC) values were 0.892, 0.778 and 0.692. When DcR3, suPAR and PCT combined were used for diagnosis of sepsis, the AUC was 0.933, at a cut off point of 0.342. This combination improved the sensitivity and specificity of diagnosis of sepsis, suggesting that use of the combination of three indexes enhanced the efficiency of sepsis diagnosis. PMID- 29760746 TI - MicroRNA-495 inhibits the high glucose-induced inflammation, differentiation and extracellular matrix accumulation of cardiac fibroblasts through downregulation of NOD1. AB - Background: MicroRNAs (miRNAs) have physiological and pathophysiological functions that are involved in the regulation of cardiac fibrosis. This study aimed to investigate the effects of miR-495 on high glucose-induced cardiac fibrosis in human cardiac fibroblasts (CFs) and to establish the mechanism underlying these effects. Methods: Human CFs were transfected with an miR-495 inhibitor or mimic and incubated with high glucose. The levels of NOD1 and miR 495 were then determined via quantitative RT-PCR. Pro-inflammatory cytokine levels, cell differentiation and extracellular matrix accumulation were respectively detected using ELISA, quantitative RT-PCR and western blot assays. The luciferase reporter assay, quantitative RT-PCR and western blot were used to explore whether NOD1 was a target of miR-495. The effects of miR-495 on the NF kappaB and TGF-beta1/Smad signaling pathways were also detected via western blot. Results: Our results show that high glucose can significantly increase the expression of NOD1 in a time-dependent manner. Upregulation of miR-495 significantly alleviated the high glucose-induced increases in cell differentiation and collagen accumulation of CFs. Moreover, the bioinformatics analysis predicted that NOD1 was a potential target gene for miR-495. The luciferase reporter assay showed that miR-495 can directly target NOD1. The introduction of miR-495 could significantly inhibit the high glucose-activated NF kappaB and TGF-beta1/Smad signaling pathways. Conclusion: Upregulation of miR-495 ameliorates the high glucose-induced inflammatory, cell differentiation and extracellular matrix accumulation of human CFs by modulating both the NF-kappaB and TGF-beta1/Smad signaling pathways through downregulation of NOD1 expression. These results provide further evidence for the protective effect of miR-495 overexpression in cases of high glucose-induced cardiac fibrosis. PMID- 29760748 TI - Evaluation of Immunohistochemistry-Equivocal (2+) HER2 Gene Status in Invasive Breast Cancer by Silver DNA in Situ Hybridization (SISH) and its Association with Clinicopathological Variables. AB - Background and Objective: Determination of HER2 gene is crucial in breast carcinoma management and prognosis, as HER2 alterations are linked to a shorter disease-free period, overall survival and resistance to tamoxifen anti-estrogen therapy and other chemotherapy regimens, regardless of the nodal or hormone receptor status. This study aimed to estimate HER2 gene status of infiltrative mammary cancer cases with immunohistochemically equivocal (2+) score using Silver DNA in Situ Hybridization (SISH) technique and to investigate its association with clinicopathological variables. Methods: The study included 52 formalin-fixed paraffin embedded tissue blocks from female patients with invasive breast carcinoma with score of 2+ (equivocal) HER2 immunohistochemistry. All cases were studied by silver DNA in situ hybridization technique (SISH) for the determination of the amplified HER2 DNA. Results: The SISH technique showed that HER2 gene was not amplified in 33 cases out of 52 (63.5%); while the rest of 19 cases (36.5%) revealed amplified gene status. According to age, HER2 gene status reported non-significant difference in the age groups between cases with amplified and non-amplified gene status (P=0.173). There was a significant negative association between positive Estrogen (ER) and Progesterone (PR) status and HER2 gene amplification (P= 0.002 and 0.017, respectively). Conclusion: More than half of breast carcinoma cases with equivocal HER2 immunoreactivity showed non-amplified gene status; this needs to be considered by oncologists in their management planning of breast cancer. Amplified HER2 gene is significantly associated with negative ER and PR status that affects patients' management protocols and future outcome of the disease. PMID- 29760747 TI - Malignant Colorectal Polyps; Pathological Consideration (A review). AB - Background: Routine screening colonoscopy is on the rise and pathologists have to deal with the ever larger numbers of excised colonic polyps. It is very important to optimize the patients' individual treatment and further surveillance. Pathologists play a critical role in management, as most of the clinical decisions concerning colonic polyp management are based on pathologic findings. One of the most important clinical issues in colonic adenomas is the diagnosis of malignancy and reporting its different aspects by the pathologist. The histologic type and the extent of carcinoma within a malignant polyp have considerable impact on the decisions of gastroenterologists and surgeons for further management. Therefore, the most recent literature regarding the diagnosis and reporting of the different features of malignant polyps was reviewed. Data Acquisition: There is growing literature regarding the different pathologic features and reporting of malignant colonic polyps, and in this review, published articles that are listed on Google Scholar and Pub Med are discussed. Conclusion: Diagnosis of malignant colon polyp requires the presence of tumor cells that are penetrating beyond the muscular mucosa into submucosa (pT1). As well as establishing a diagnosis of malignant polyp, it is very important to report the size of the invasive component, the presence or absence of lymphovascular invasion, the degree of tumor differentiation and the distance of the carcinoma from the line of resection. Other important features that may be reported include: the presence or absence of tumor budding, the depth of tumor cell penetration into the submucosa, and results of immunohistochemistry for mismatch repair proteins and BRAF. PMID- 29760749 TI - Aggressive Fibromatosis, Clinicopathologic Findings of 25 Cases; A Single-Center Experience and Review of the Literature. AB - Background: Aggressive fibromatosis is a rare benign tumor with no potential for metastasis; however, its aggressive nature causes treatment failure and episodes of recurrence. There is no report from Iran about the treatment of this tumor, and all published articles are single-case reports, therefore in this study, we report our experience from two of the largest referral centers of the South of Iran. Methods: During five years (2007-2011), among more than 20000 surgical pathology specimens, 25 cases of fibromatosis were identified. Clinicopathologic findings were recorded for all of the cases, and follow up history according to the patients' charts and direct contact by phone call were extracted. Results: There were 25 cases of fibromatosis, with female predominance, especially in the reproductive ages. All of the tumors had been located in the abdominal area, lower extremity, and head and neck area. Twenty-three cases had been operated for surgical excision. Fifteen cases had at least one episode of recurrence, mostly located in the abdominal area. No death or metastasis occurred. Conclusion: Clinicopathologic findings of desmoid tumor in Iran are very similar to other countries, however, there is still much controversy about the method of treatment for fibromatosis, and there are many challenges for patients, regarding multiple episodes of recurrence and the infiltrative aggressive nature of fibromatosis. PMID- 29760750 TI - Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC PCR) Genotyping of Escherichia coli Strains Isolated from Different Animal Stool Specimens. AB - Background: Escherichia coli is a commensal-pathogenic organism, which includes a wide range of strains. Despite several advanced molecular-genomic technologies for detecting and identifying different strains of E. coli, Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR) technique is a quick, sharp and cost effective fingerprint method. The major purpose of the present study was to determine the distribution of ERICs within E. coli strains isolated from different healthy animal stool specimens including hens, sheep, and cows, as an appropriate and quick molecular-genomic tool. Methods: The animal stool samples were obtained during 1 year (October 2012 to October 2013), from animal husbandries around Tehran and Alborz provinces, Iran. After screening processes, the E. coli bacteria were isolated and cultured via standard microbiological methods. The DNA molecules of E. coli bacteria were harvested and Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC PCR) was applied for bacterial molecular genotyping. The ERIC-PCR products were run on 1% gel electrophoresis. The final images regarding gel electrophoresis banding patterns were used for dendrogram generation via the GelClust software. Results: Of 120 isolated samples, 115 different strains were recognized as E. coli. The fingerprint patterns involved 380 to 3280 bp bands. The predominant bands included 2900 bp, 1200 bp, and 1200 bp in stool samples of hens, sheep, and cows, respectively. The highest frequencies and diversities were seen among E. coli strains isolated from hens and sheep stool samples. Conclusion: The DNA profiles were clearly detectable via specific fingerprint patterns. The ERIC-PCR seemed to be a good approach for molecular typing of E. coli strains isolated from different animal sources. PMID- 29760751 TI - Cervical Cancer and Genital Infections: Assessment of Performance and Validation in Human Papillomavirus Genotyping Assays in Iran, its Neighbouring Countries and Persian Gulf Area. AB - Background: The accuracy of diagnostic assays in Human Papillomavirus (HPV) genital infection and cervical cancer has remained a clinical challenge in diagnosis. Evidence indicates that a large proportion of cervical cancer can be prevented through organized care for HPV and testing. Countries with low per capita income, such as Iran and its neighbours, have no national organized program for cervical cancer screening and vaccination. The aim of this study was to review recent published papers in this region for evaluating the efficacy of released data regarding HPV genotyping system in genital infections and cervical cancer. Methods: Investigating various medical search engines retrieved 46 reports, mostly after 2010, consisting of either home brew protocols or commercial technologies in this field. Results: Summarized results demonstrated that except a few cases, all reports were limited studies performed in confined populations focusing on attending patients at clinics for regular checkups. In the present study, 52.8% of papers were from Iran and the rest belonged to other countries. The rate of HPV infection was reported in the range of 0.62% to 25% in the normal population, while it varied from 18.75% to 100% in females with cervical cancer. In HPV genotyping surveys, only 26.1 % (12/46) of reports had validated and World Health Organization (WHO) proficient procedures. Also, multiple infections were not mentioned in 56.52% (25/46) of researches. Conclusions: Employing reliable genotyping methods is the best way for regular screening of cervical cancer related to HPV and precancerous diseases in females of these areas. The focus of most surveys was to come up with the best national policies for establishing a preventive program in Iran and Persian Gulf area. PMID- 29760754 TI - Comparison of P53 Intensity, Frequency and Size in Normal Skin Periphery of Squamous Cell Carcinoma, Basal Cell Carcinoma And Melanocytic Nevus in Persian Skin Type. AB - Background: Non-Melanoma Skin Cancer (NMSC), the most prevalent types being Squamous Cell Carcinoma (SCC) and Basal Cell Carcinoma (BCC), is the most common type of malignancy in human beings. These neoplasms are more frequent in the elderly and fair skinned people and mainly occur on sun-exposed sites of the body. Ultraviolet B (UVB) has a well-known effect in induction and promotion of growth of these cancers. The p53 tumor suppressor gene is believed to be an early target in UV-induced skin carcinogenesis. Aggregates of keratinocytes with p53 protein overexpression are frequently identified in normal human skin and are more prevalent in chronically sun-exposed skin, and have been proposed to play a role in skin cancer pathogenesis. The aim of this study was to clarify the potential role of P53 in the development of NMSC. Methods: Immunohistochemical evaluation of p53 expression in peri-lesional skin of 90 cases of SCC, BCC and melanocytic nevi was performed. Results: The well-delineated compact type of p53 clone, but not the strong dispersed type, was significantly more predominant in SCCs in comparison with BCCs and melanocytic nevi (P value=0.001). The size of p53 clones was also significantly greater in SCCs compared to the BCCs (P=0.003) and melanocytic nevi (P=0.001). There was no significant difference between these neoplasms regarding the frequency of P53 clones (P=0.86). Conclusion: This study suggests the possible relationship of epidermal p53 clones with the pathogenesis of SCC. PMID- 29760753 TI - Investigation of Efflux-Mediated Tetracycline Resistance in Shigella Isolates Using the Inhibitor and Real Time Polymerase Chain Reaction Method. AB - Background: Shigella spp. are gram negative bacteria, which are of global public health importance. The growing of multidrug-resistant Shigella isolates are a major problem around the world. Methods: Overall, 50 isolates of Shigella spp. from children diarrheic stools were studied. The isolates were identified and confirmed using biochemical, serological and molecular methods (ipaH, wbgZ and rfc genes). Antimicrobial susceptibility test was done according to the Clinical and Laboratory Standards Institute (CLSI) guidelines against minocycline, tetracycline, doxycycline, ampicillin, streptomycin, trimethoprim sulfamethoxazole, nalidixic acid, norfloxacin, ciprofloxacin and levofloxacin. Also, the role of efflux pump in defense of Shigella against tetracycline was investigated by Minimum Inhibitory Concentration (MIC) with and without an efflux pump inhibitor. Detection of tetA, tetB, tetC and tetD genes in Shigella was evaluated by conventional Polymerase Chain Reaction (PCR) and real time PCR. Results: Molecular identification revealed a prevalence of 14% for Shigella flexneri and 86% for Shigella sonnei. Minimum Inhibitory Concentration (MIC) of 90% of resistant isolates was changed in the presence CCCP. Results of conventional PCR exhibited that 66% of isolates were positive for tetA, while according to real time PCR method, 90% of isolates carried tetA. Positive results for tetB were 12% and 18% by conventional and real time PCR methods, respectively. No positive results were detected for tetC and tetD. Also, tetB was detected only in S. flexneri while tetA was detected in both S. flexneri and S. sonnei. Conclusion: It seems that efflux-mediated tetracycline resistance to tetracycline in S. flexneri can be related to tetB, however resistance in S. sonnei can be related to the expression of tetA. PMID- 29760752 TI - Immunohistochemical and Electron Microscopic Study of the Inhibitory Effects of Olive Oil Polyphenol on Dexamethasone-Induced Apoptosis. AB - Background: There is accumulating evidence that a polyphenol present in olive oil, oleuropein, has antioxidant, anti-inflammatory and anti-apoptotic effects. This study aimed at determining the anti-apoptotic effect of Oleuropein (Ole) on dexamethasone-induced apoptosis of mouse thymocytes. Method: Mice were randomly divided to four groups as follow: Dexamethasone (Dex)-treated group (20 mg/kg; single dose), Ole-treated group (20 mg/kg per day), Dex plus Ole-treated group, and vehicle group. Sections of thymus were taken 16 hours after dexamethasone injection and studied for histopathological and immunohistochemistry assessment. Result: Further characteristics of degeneration in thymocytes were observed in the Dex group compared with the Dex plus Ole group. Compared with the Dex group (10.94+/-3.35), positive staining for Bax in thymocytes decreased in Dex plus Ole group (2.64+/-1.26), but remained higher than the Ole (0.65+/-0.30) and vehicle (0.67+/-0.29) groups. Compared with the Dex group (2.94+/-0.42), positive staining for Bcl-2 in thymocytes increased in Dex plus Ole group (12.24+/-1.84) yet was lower than the Ole (14.94+/-1.54) and vehicle (18.93+/-3.54) groups. Conclusion: Our results suggest that dexamethasone-induced apoptosis is subsided by oleuropein. PMID- 29760755 TI - Fluorescent in Situ Hybridization and Real-Time Quantitative Polymerase Chain Reaction to Evaluate HER-2/neu Status in Breast Cancer. AB - Background: Breast cancer remains the most common and second lethal cancer in females. HER-2/neu is one of the most important amplified oncogene in breast cancer. The amplification of HER-2 is correlated with decreased survival, metastasis, and early recurrence. The amplification of HER-2/neu gene and synthesis of the protein are reported in 10%-34% of breast cancer cases associated with tumor size, advanced tumor stage, high-grade tumor, young age at diagnosis, absence of steroid hormone receptor, and lymph node involvement. Methods: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods are options to evaluate HER-2 expression. The current study aimed at identifying the correlation between FISH and real-time polymerase chain reaction (PCR) in measuring HER-2 expression. Results: The study investigated the performance of the real-time PCR as measured against FISH method in IHC +2 borderline cases. In a total of 120 IHC 2+ samples, 58.3% were negative and 41.6% positive for HER-2 gene, confirmed by FISH as a gold standard method. The real time PCR ratio was <1.8 for a majority (82.8%) of the tumor samples with unamplified HER-2 gene by FISH as a gold standard assay. Conclusion: Despite the fact that real-time PCR is a promising method to evaluate HER-2 over expression and a supplementary array to FISH, according to the results of the present study it cannot be utilized instead of gold standard techniques; therefore, additional studies should be carried out to appraise the value of this method to evaluate HER-2 over expression. PMID- 29760756 TI - Alpha-Synuclein Expression in Acute Erythroleukaemia, Acute Megakaryoblastic Leukemia, and Normal Counterparts in Bone Marrow. AB - Background: Alpha-synuclein is a member of synuclein family of proteins with unidentified function localized in the cytoplasm, mitochondria of neurons, and presynaptic nerve endings. Although it is found in the Lewy bodies in synucleinopathies and in Alzheimer's disease, the protein could also be considered as a novel marker in diagnosis of diseases related to the hematopoietic system. Methods: The current study evaluated alpha-synuclein expression in bone marrow sections obtained from 9 patients with acute myeloblastic leukemia (AML)-M6, 2 patients with AML-M7, and 56 patients with other forms of AML by immunohistochemical (IHC) analysis. Results: Seven out of 9 cases with erythroleukemia (66.7%) and 1 of the 2 cases with M7 (50%) were positive. In contrast; the blasts in 2 out of 56 AML cases with non-M6/M7 (3.6%) showed positive staining. Accordingly, alpha-synuclein was positive in normal erythroid precursors and megakaryocytes (if existing) in these cases; while, it was negative in lymphoid and myeloid precursors. Conclusion: Alpha-synuclein expression in non-neoplastic and neoplastic erythroid cells and megakaryocytes could be used as a complementary and useful marker for distinction between AML M6/M7 and other types of AML. PMID- 29760757 TI - Inhibitory Activities of Platelet-Rich and Platelet-Poor Plasma on the Growth of Pathogenic Bacteria. AB - Background: The utility and efficacy of novel materials in tissue regeneration and antimicrobial therapy are contingent upon the employment of either blood derivatives rich in platelets or platelet-poor-plasma (PPP). This effect is largely mediated by the increased or decreased concentration of platelets in the plasma. The current study aimed to analyze and evaluate the impact of platelet rich (PRP) or PPP on inhibiting the growth of human pathogenic bacteria and compare their effects with those of chloramphenicol and penicillin. Methods: In the current comparative study, PRP-1 was generated using 1-step blood centrifugation method; whereas, for PRP-2 and PPP the 2-step centrifugation protocol was used. The antimicrobial activity of PRP-1, 2, and PPP were tested on Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa, Streptococcus agalactiae, Staphylococcus epidermidis, Shigella sp. and Serratia sp. Well diffusion and serial micro-dilution methods were used for this purpose. Chloramphenicol and penicillin susceptibility were tested using the disk diffusion method. Results: While whole blood (WB) and PPP had no discernible impact on the growth parameters of any of the bacteria tested in the current study, PRP-1 reduced the growth rate of a few selected strains. In addition, while PRP-2 clearly inhibited the growth of Shigella sp., E. coli, S. aureus, S. agalactiae, and S. epidermidis, it had no impact on the growth of K. pneumoniae, P. aeruginosa, and Serratia sp. Conclusion: It can be claimed that there is a strong correlation between the concentration of platelets and the antibacterial activity of PRP. PMID- 29760758 TI - Upper Normal Limit of Thyroid-Stimulating Hormone and Metabolic Syndrome in Iranian Patients with Obesity. AB - Background: The current study aimed at evaluating the association between thyroid stimulating hormone (TSH) level in upper normal limits with metabolic syndrome, modifiable risk factor for cardiovascular disease, and its components according to Adult Treatment Panel III of National Cholesterol Education Program. Methods: The current cross sectional study recruited 82 patients with euthyroid overweight or obesity. They all had body mass index (BMI) higher than 25 kg/m2. The patients were categorized in 2 groups: Group 1 (patients with metabolic syndrome) and Group 2 (patients with non-metabolic syndrome). Demographic features and anthropometric indices were all appraised by a trained examiner. Metabolic syndrome components, BMI, age, gender, C-reactive protein (CRP), and thyroid function test (TFT) were assessed and compared. Results: Age, triglyceride level, waist circumference, hypertension frequency, BMI and CRP were significantly higher in group 1. The most prevalent metabolic syndrome criterion was low level of serum high density lipoprotein (HDL). Patients with metabolic syndrome had greater TSH level, but it was not statistically significant (P-value=0.636). Euthyroid patients with TSH levels in the range of 3.88-5 mIU/L had 5.89 (95% confidence interval (CI) = 1.02 to 17.64) times higher risk of developing metabolic syndrome than other TSH values. After age adjustment, the relationship between the upper quartile of TSH level and the metabolic syndrome became insignificant (OR=2.97, 95% CI=0.51 to 17.2). Conclusion: TSH in upper normal limits was statistically correlated with metabolic syndrome. However, after adjustment for age, it became insignificant. Relationship between thyroid hormones and metabolic syndrome may be confounded by other important cardiovascular risk factors in euthyroid patients. PMID- 29760759 TI - How does temperature affect functional kleptoplasty? Comparing populations of the solar-powered sister-species Elysia timida Risso, 1818 and Elysia cornigera Nuttall, 1989 (Gastropoda: Sacoglossa). AB - Background: Despite widespread interest in solar-powered sea slugs (Sacoglossa: Gastropoda), relatively little is know about how they actually perform functional kleptoplasty. Sister-taxa Elysia timida and E. cornigera provide an ideal model system for investigating this phenomenon, since they feed on the same algal genus and only E. timida is capable of long-term kleptoplasty. Recent research has explored factors regarding functional kleptoplasty in E. timida, including their starvation longevity, digestive activity, autophagal response and photosynthetic efficiency under two different temperature conditions (18 degrees C and 21 degrees C). These studies revealed the trends E. timida displays regarding each factor during starvation as well as influences temperature has on some aspects of functional kleptoplasty. This study examines E. cornigera regarding each of these factors in an attempt to elucidate differences between each species that could explain their differing kleptoplastic abilities. Since both species naturally occur in 25 degrees C seawater (E. timida peak summer temperature, E. cornigera low winter temperature), each species was acclimatized to 25 degrees C to facilitate comparison and determine if these species exhibit physiological differences to starvation when under the same environmental conditions. Results: When comparing the different E. timida temperature treatments, it becomes clear that increased temperatures compromise E. timida's kleptoplastic abilities. Specimens acclimatized to 25 degrees C revealed shorter starvation longevities surviving an average 42.4 days compared to the 95.9 day average observed in specimens exposed to 18 degrees C. Each temperature treatment displayed a significantly different decrease throughout the starvation period in both, the rate of photosynthetic efficiency and in the decreasing functional kleptoplast abundance. Lysosomal abundances are assessed here as indicators of different aspects of metabolic activity, which could be correlated to temperature. E. cornigera, also acclimatized to 25 degrees C did not display significantly similar patterns as any of the E. timida temperature treatments, having fewer incorporated kleptoplasts, a higher lysosomal response to starvation, a faster decrease in photosynthetic efficiency and a lower starvation longevity. Conclusions: These results confirm that each species has different physiological reactions to starvation and kleptoplast retention, even under the same conditions. While temperature affects aspects of functional kleptoplasty, it is likely not responsible for the differences in kleptoplastic abilities seen in these species. PMID- 29760760 TI - Differences in the reliance on cuticular hydrocarbons as sexual signaling and species discrimination cues in parasitoid wasps. AB - Background: Cuticular hydrocarbons (CHC) have been documented to play crucial roles as species- and sex-specific cues in the chemical communication systems of a wide variety of insects. However, whether they are sufficient by themselves as the sole cue triggering sexual behavior as well as preference of con- over heterospecific mating partners is rarely assessed. We conducted behavioral assays in three representative species of parasitoid wasps (Hymenoptera: Pteromalidae) to determine their reliance on CHC as species-specific sexual signaling cues. Results: We found a surprising degree of either unspecific or insufficient sexual signaling when CHC are singled out as recognition cues. Most strikingly, the cosmopolitan species Nasonia vitripennis, expected to experience enhanced selection pressure to discriminate against other co-occurring parasitoids, did not discriminate against CHC of a partially sympatric species from another genus, Trichomalopsis sarcophagae. Focusing on the latter species, in turn, it became apparent that CHC are even insufficient as the sole cue triggering conspecific sexual behavior, hinting at the requirement of additional, synergistic sexual cues particularly important in this species. Finally, in the phylogenetically and chemically most divergent species Muscidifurax uniraptor, we intriguingly found both CHC-based sexual signaling as well as species discrimination behavior intact although this species is naturally parthenogenetic with sexual reproduction only occurring under laboratory conditions. Conclusions: Our findings implicate a discrepancy in the reliance on and specificity of CHC as sexual cues in our tested parasitioid wasps. CHC profiles were not sufficient for unambiguous discrimination and preference behavior, as demonstrated by clear cross-attraction between some of our tested wasp genera. Moreover, we could show that only in T. sarcophagae, additional behavioral cues need to be present for triggering natural mating behavior, hinting at an interesting shift in signaling hierarchy in this particular species. This demonstrates the importance of integrating multiple, potentially complementary signaling modalities in future studies for a better understanding of their individual contributions to natural sexual communication behavior. PMID- 29760762 TI - Prevalence of postpartum depression and interventions utilized for its management. AB - Introduction: Postpartum depression is a mood disorder that affects approximately 10-15% of adult mothers yearly. This study sought to determine the prevalence of postpartum depression and interventions utilized for its management in a Health facility in Ghana. Methods: A descriptive cross-sectional study design using a quantitative approach was used for the study. The study population included mothers and healthcare workers. Simple random sampling technique was used to select 257 mothers, while a convenience sampling technique was used to select 56 health workers for the study. A Patient Health Questionnaire was used to screen for depression and a structured questionnaire comprising closed-ended questions was used to collect primary data on the interventions for the management of postpartum depression. Data were analyzed using statistical software SPSS version 16.0. Results: Postpartum depression was prevalent among 7% of all mothers selected. The severity ranged from minimal depression to severe depression. Psychosocial support proved to be the most effective intervention (p = 0.001) that has been used by the healthcare workers to reduce depressive symptoms. Conclusion: Postpartum depression is prevalent among mothers although at a lower rate and psychosocial support has been the most effective intervention in its management. Postpartum depression may affect socialization behaviors in children and the mother, and it may lead to thoughts of failure leading to deeper depression. Frequent screening exercises for postpartum depression should be organized by authorities of the hospitals in conjunction with the Ministry of Health. PMID- 29760761 TI - A randomized trial of the effects of flaxseed to manage constipation, weight, glycemia, and lipids in constipated patients with type 2 diabetes. AB - Background: To compare the effects of baked flaxseed versus those who received a placebo on constipation symptom scores, weight, glycemic and lipid control in constipated patients with type 2 diabetes (T2D). Methods: In a single-blinded, randomized controlled trial, 53 constipated patients with T2D with body mass index (BMI) 20.5-48.9 kg/m2 received either 10 g of flaxseed pre-mixed in cookies twice per day or placebo cookies for 12 weeks. The constipation symptom scores, BMI, fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and lipid profile were determined at the beginning and end of 4, 8, and 12-week period. Constipation was evaluated with a stool diary (ROME III). Results: After the 12 week intervention, constipation symptom scores (2.46), weight (- 3.8 kg), BMI (- 1.5 kg/m2), FPG (- 26.7 mg/dl), cholesterol (- 37.3 mg/dl), triglycerides (- 10.4 mg/dl), LDLC (- 21.0 mg/dl), HDLC (4.7 mg/dl), cholesterol/ HDLC ratio (- 1.4 mg/dl) significantly decreased from baseline in the flaxseed group (all P-values < 0.05). The differences of absolute change of constipation symptom scores (2.46 vs. 0.41), weight (- 3.8 vs. 0.0 kg), BMI (- 1.5 vs.-0.1 kg/m2), FPG (- 26.7 vs. 1.9 mg/dl), >HbA1c (- 0.8 vs. 1.0%), cholesterol (- 37.3 vs. -10.4 mg/dl), LDLC ( 21.0 vs. -4.3 mg/dl), and HDLC (4.7 vs. -4.4 mg/dl) between the flaxseed and placebo groups were statistically significant (all P-values < 0.05). The compliance was good and no adverse effects were observed. Conclusion: In constipated patients with T2D, flaxseed cookies used as a snack may be a useful tool for decreasing constipation symptoms, weight, glycemic and lipid levels. Trial registration: irct.ir: IRCT20110416006202N2. PMID- 29760763 TI - An open-label, flexible dose adaptive study evaluating the efficacy of vortioxetine in subjects with panic disorder. AB - Background: Despite the current treatments available for panic disorder (PD), as many as one-third of patients have persistent and treatment-resistant panic attacks. Vortioxetine is an approved medicine for major depressive disorder and has been shown to have anxiolytic properties. The purpose of this study was to evaluate its efficacy and safety in an adult population with a diagnosis of PD. Methods: The study design was open label with flexible dose strategies (5, 10, or 20 mg) with a treatment period of 10 weeks. 27 male and female subjects aged between 18 and 60 years, who met DSM-IV criteria for PD with or without agoraphobia, or who had a Panic Disorder Severity Scale (PDSS) score > 8 at baseline were enrolled. Statistical significance was established by the Student's T test. Results: A statistically significant decrease in the occurrence of panic attacks was measured with the PDSS with vortioxetine. In addition, a moderate improvement in the quality of life and no significant side effects were observed using the Quality-of-Life Scale and Monitoring of Side Effects Scale, respectively. Conclusions: These results provide some support for the use of vortioxetine in the management of panic disorder.Trial registration ClinicalTrials.gov ID#: NCT02395510. Registered March 23, 2015, https://clinicaltrials.gov/ct2/show/NCT02395510. PMID- 29760764 TI - Human Brain Organoids on a Chip Reveal the Physics of Folding. AB - Human brain wrinkling has been implicated in neurodevelopmental disorders and yet its origins remain unknown. Polymer gel models suggest that wrinkling emerges spontaneously due to compression forces arising during differential swelling, but these ideas have not been tested in a living system. Here, we report the appearance of surface wrinkles during the in vitro development and self organization of human brain organoids in a micro-fabricated compartment that supports in situ imaging over a timescale of weeks. We observe the emergence of convolutions at a critical cell density and maximal nuclear strain, which are indicative of a mechanical instability. We identify two opposing forces contributing to differential growth: cytoskeletal contraction at the organoid core and cell-cycle-dependent nuclear expansion at the organoid perimeter. The wrinkling wavelength exhibits linear scaling with tissue thickness, consistent with balanced bending and stretching energies. Lissencephalic (smooth brain) organoids display reduced convolutions, modified scaling and a reduced elastic modulus. Although the mechanism here does not include the neuronal migration seen in in vivo, it models the physics of the folding brain remarkably well. Our on chip approach offers a means for studying the emergent properties of organoid development, with implications for the embryonic human brain. PMID- 29760765 TI - An improved method for Agrobacterium rhizogenes-mediated transformation of tomato suitable for the study of arbuscular mycorrhizal symbiosis. AB - Background: Solanum lycopersicum, an economically important crop grown worldwide, has been used as a model for the study of arbuscular mycorrhizal (AM) symbiosis in non-legume plants for several years and several cDNA array hybridization studies have revealed specific transcriptomic profiles of mycorrhizal tomato roots. However, a method to easily screen candidate genes which could play an important role during tomato mycorrhization is required. Results: We have developed an optimized procedure for composite tomato plant obtaining achieved through Agrobacterium rhizogenes-mediated transformation. This protocol involves the unusual in vitro culture of composite plants between two filter papers placed on the culture media. In addition, we show that DsRed is an appropriate molecular marker for the precise selection of cotransformed tomato hairy roots. S. lycopersicum composite plant hairy roots appear to be colonized by the AM fungus Rhizophagus irregularis in a manner similar to that of normal roots, and a modified construct useful for localizing the expression of promoters putatively associated with mycorrhization was developed and tested. Conclusions: In this study, we present an easy, fast and low-cost procedure to study AM symbiosis in tomato roots. PMID- 29760766 TI - Holistic and component plant phenotyping using temporal image sequence. AB - Background: Image-based plant phenotyping facilitates the extraction of traits noninvasively by analyzing large number of plants in a relatively short period of time. It has the potential to compute advanced phenotypes by considering the whole plant as a single object (holistic phenotypes) or as individual components, i.e., leaves and the stem (component phenotypes), to investigate the biophysical characteristics of the plants. The emergence timing, total number of leaves present at any point of time and the growth of individual leaves during vegetative stage life cycle of the maize plants are significant phenotypic expressions that best contribute to assess the plant vigor. However, image-based automated solution to this novel problem is yet to be explored. Results: A set of new holistic and component phenotypes are introduced in this paper. To compute the component phenotypes, it is essential to detect the individual leaves and the stem. Thus, the paper introduces a novel method to reliably detect the leaves and the stem of the maize plants by analyzing 2-dimensional visible light image sequences captured from the side using a graph based approach. The total number of leaves are counted and the length of each leaf is measured for all images in the sequence to monitor leaf growth. To evaluate the performance of the proposed algorithm, we introduce University of Nebraska-Lincoln Component Plant Phenotyping Dataset (UNL-CPPD) and provide ground truth to facilitate new algorithm development and uniform comparison. The temporal variation of the component phenotypes regulated by genotypes and environment (i.e., greenhouse) are experimentally demonstrated for the maize plants on UNL-CPPD. Statistical models are applied to analyze the greenhouse environment impact and demonstrate the genetic regulation of the temporal variation of the holistic phenotypes on the public dataset called Panicoid Phenomap-1. Conclusion: The central contribution of the paper is a novel computer vision based algorithm for automated detection of individual leaves and the stem to compute new component phenotypes along with a public release of a benchmark dataset, i.e., UNL-CPPD. Detailed experimental analyses are performed to demonstrate the temporal variation of the holistic and component phenotypes in maize regulated by environment and genetic variation with a discussion on their significance in the context of plant science. PMID- 29760768 TI - Mechanisms of change for interventions aimed at improving the wellbeing, mental health and resilience of children and adolescents affected by war and armed conflict: a systematic review of reviews. AB - Despite increasing research and clinical interest in delivering psychosocial interventions for children affected by war, little research has been conducted on the underlying mechanisms of change associated with these interventions. This review aimed to identify these processes in order to inform existing interventions and highlight research gaps. A systematic review of reviews was conducted drawing from academic databases (PubMed, PILOTS, Cochrane Library for Systematic Reviews) and field resources (e.g. Medecins Sans Frontieres and the Psychosocial Centre of the International Federation of Red Cross and Red Crescent Societies), with extracted data analysed using Thematic Content Analysis. Thirteen reviews of psychosocial or psychological interventions for children and adolescents (< 25 years old) affected by war, armed conflict or political violence were identified, covering over 30 countries worldwide. Qualitative analysis identified 16 mechanisms of change, one of which was an adverse mechanism. Themes included protection from harm, play, community and family capacity building, strengthening relationships with caregivers, improved emotional regulation, therapeutic rapport, trauma processing, and cognitive restructuring; with the adverse mechanism relating to the pathologising of normal reactions. However, only 4 mechanisms were supported by strong empirical evidence, with only moderate or poor quality evidence supporting the other mechanisms. The poor quality of supporting evidence limits what can be inferred from this review's findings, but serves to highlight clinically informed mechanisms of change for existing and widely used non-specialist interventions in the field, which urgently need rigorous scientific testing to inform their continued practice. PMID- 29760769 TI - Family assessment conversations as a tool to support families affected by parental mental illness: a retrospective review of electronic patient journals. AB - Background: Previous research has shown a link between parental mental illness and adverse development in their offspring. In Norway, it is mandatory for health professionals to identify if patients in adult mental health services have children, and subsequently to provide support for the children. An important tool to detect if families are affected by parental mental illness and to assess if there is a need for further intervention is the Family Assessment Conversation. Family Assessment Conversations is potentially a powerful tool for communication with families affected by parental mental illness because it facilitates early identification of children at risk of various adversities due to the family situation. Additionally the tool may initiate processes that enable children and parents to cope with the situation when a parent becomes seriously ill. Little is however known about how the mental health practitioners use the family assessment form in conversations, and to what extent they record relevant information in the electronic patient journals. Methods: The main aim of the study was to provide information about the existing practice within mental health services for adults in terms of parental mental illness and family assessment conversations. The project is a retrospective journal review. The data base consists of relevant journal data from 734 patients aged 20-60 years admitted. In total, 159 recordings of family assessment conversations were discovered. Results: The main result in this study was that many of the questions in the family assessment form lacked documented responses and assessments from the healthcare professionals. Only 17% of the participants had been assessed with the total family assessment form. Additionally, there was a lack of documentation about whether or not the children had been informed in a large proportion of the assessment forms (31%). A total of 55% say that the child has not been informed. This implies that there is still a long way to go in order to make sure that children of parents with a mental illness are given relevant information and support. Conclusions: The documentation and family assessment frequency is low and reflects the challenges healthcare professionals and patient experience when the child's situation becomes the topic of assessment. There is a need to further investigate the challenges of changing the mental health systems to incorporate the children and families of patients. More research should promote knowledge on what may facilitate family assessment dialogue. PMID- 29760767 TI - Survival after cancer diagnosis in a cohort of HIV-positive individuals in Latin America. AB - Background: This study aimed to evaluate trends and predictors of survival after cancer diagnosis in persons living with HIV in the Caribbean, Central, and South America network for HIV epidemiology cohort. Methods: Demographic, cancer, and HIV-related data from HIV-positive adults diagnosed with cancer <= 1 year before or any time after HIV diagnosis from January 1, 2000-June 30, 2015 were retrospectively collected. Cancer cases were classified as AIDS-defining cancers (ADC) and non-AIDS-defining cancers (NADC). The association of mortality with cancer- and HIV-related factors was assessed using Kaplan-Meier curves and Cox proportional hazards models stratified by clinic site and cancer type. Results: Among 15,869 patients, 783 had an eligible cancer diagnosis; 82% were male and median age at cancer diagnosis was 39 years (interquartile range [IQR]: 32-47). Patients were from Brazil (36.5%), Argentina (19.9%), Chile (19.7%), Mexico (19.3%), and Honduras (4.6%). A total of 564 ADC and 219 NADC were diagnosed. Patients with NADC had similar survival probabilities as those with ADC at one year (81% vs. 79%) but lower survival at five years (60% vs. 69%). In the adjusted analysis, risk of mortality increased with detectable viral load (adjusted hazard ratio [aHR] = 1.63, p = 0.02), age (aHR = 1.02 per year, p = 0.002) and time between HIV and cancer diagnoses (aHR = 1.03 per year, p = 0.01). Conclusion: ADC remain the most frequent cancers in the region. Overall mortality was related to detectable viral load and age. Longer-term survival was lower after diagnosis of NADC than for ADC, which may be due to factors unrelated to HIV. PMID- 29760770 TI - Mental health literacy: knowledge of depression among undergraduate students in Hanoi, Vietnam. AB - Background: Mental health literacy (MHL) refers to an individuals' knowledge and beliefs about mental disorders that aid their recognition, management, and prevention. This study aims to investigate the MHL of depression among public health and sociology undergraduate students in Hanoi, Vietnam. Methods: A cross sectional survey was carried out from May to September 2015. Data was collected using an anonymous, self-administered questionnaire distributed to 350 undergraduate students (213 public health majors; 137 sociology majors). Questions about MHL of depression were adapted from the Australian National Survey of Mental Health Literacy and Stigma. Question topics included recognition of depression, help-seeking intentions, first-aid support, and knowledge about interventions to help people with depression. Chi squared tests were conducted to compare proportional statistics across groups for multiple measures. Results: With regard to recognition of mental disorders, 32.0% of the respondents used the accurate label "depression" for the vignette. Among those who correctly identified depression, 82.1% would seek help. The corresponding statistic was 81.1% from those who did not recognize depression. Both groups would seek help from counselor, psychologist, family members, and close friends. First-aid support suggested by the respondents in both groups were informal sources (to listen to her problem in an understanding way, to encourage her to be more physically active, etc.). The interventions considered most helpful by the respondents were self-help strategies such as learning how to relax, getting physically active, doing exercise early in the morning, and reading a self-help book. Joining a group of individuals with similar problems was chosen to be a helpful intervention among those who did not recognize depression (p < 0.001), but those who correctly identify depression believed that people with depression should be admitted to hospital for psychiatric treatment (p < 0.05). Conclusion: There is a need for education about MHL of depression among undergraduate students in Vietnam. The training can focus on symptoms of depression, appropriate help-seeking intentions, and first-aid support relevant to the Vietnamese context. PMID- 29760771 TI - Systematic review: cultural adaptation and feasibility of screening for autism in non-English speaking countries. AB - Background: Screening children for autism has gained wider acceptance within clinical practice, and early intervention has improved outcomes. Increasingly, adapting an existing screening instrument is a common, fast method to create a usable screening tool, especially for countries with limited resources and/or expertise. However, concerns have been raised regarding adaptation adequacy and the feasibility of screening across cultural groups. This study systematically examined the levels of cultural adaptation and feasibility aspects considered when screening for autism in non-English speaking countries to build upon the sparse knowledge that exists on this topic in the literature. Methods: Nineteen studies, obtained from five electronic databases, were examined. PRISMA guidance was used for this review. The Ecological Validity Framework model, and Bowen Recommendations for Feasibility were adopted to extract relevant data, which was synthesised narratively. Results: Cultural adaptation within the included studies mostly involved language translation with little information offered to enable conclusions on how the processes were guided and maintained. Few cultural adjustments involved modifying screening methods; clarifying difficult concepts and changing instrument content were employed to address the core values, competence, beliefs, and norms of the adapted culture. However, less attention was given to adapt the screening goals within the context of cultural values, and customs or to consider interactional match between the clients and assessors. The review also highlighted an acceptable level of practicality to screen for autism but did not encourage integrating autism screening within routine practice or beyond the study context for different cultures. Conclusion: Concurring with previous literature, we agree that knowledge on cultural adaptation for autism screening instruments is limited and not sufficiently documented to establish adaptation levels (process and/or contents), and prove adequacy. However, this review provides an infrastructure to improve future adaptation processes. Integrating autism screening as routine medical practice is not encouraged and warrants further feasibility studies to minimize wasted resources and improve screening effectiveness in various health care systems. PMID- 29760772 TI - Engineering a palette of eukaryotic chromoproteins for bacterial synthetic biology. AB - Background: Coral reefs are colored by eukaryotic chromoproteins (CPs) that are homologous to green fluorescent protein. CPs differ from fluorescent proteins (FPs) by intensely absorbing visible light to give strong colors in ambient light. This endows CPs with certain advantages over FPs, such as instrument-free detection uncomplicated by ultra-violet light damage or background fluorescence, efficient Forster resonance energy transfer (FRET) quenching, and photoacoustic imaging. Thus, CPs have found utility as genetic markers and in teaching, and are attractive for potential cell biosensor applications in the field. Most near-term applications of CPs require expression in a different domain of life: bacteria. However, it is unclear which of the eukaryotic CP genes might be suitable and how best to assay them. Results: Here, taking advantage of codon optimization programs in 12 cases, we engineered 14 CP sequences (meffRed, eforRed, asPink, spisPink, scOrange, fwYellow, amilGFP, amajLime, cjBlue, meffBlue, aeBlue, amilCP, tsPurple and gfasPurple) into a palette of Escherichia coli BioBrick plasmids. BioBricks comply with synthetic biology's most widely used, simplified, cloning standard. Differences in color intensities, maturation times and fitness costs of expression were compared under the same conditions, and visible readout of gene expression was quantitated. A surprisingly large variation in cellular fitness costs was found, resulting in loss of color in some overnight liquid cultures of certain high-copy-plasmid-borne CPs, and cautioning the use of multiple CPs as markers in competition assays. We solved these two problems by integrating pairs of these genes into the chromosome and by engineering versions of the same CP with very different colors. Conclusion: Availability of 14 engineered CP genes compared in E. coli, together with chromosomal mutants suitable for competition assays, should simplify and expand CP study and applications. There was no single plasmid-borne CP that combined all of the most desirable features of intense color, fast maturation and low fitness cost, so this study should help direct future engineering efforts. PMID- 29760774 TI - Rich biotin content in lignocellulose biomass plays the key role in determining cellulosic glutamic acid accumulation by Corynebacterium glutamicum. AB - Background: Lignocellulose is one of the most promising alternative feedstocks for glutamic acid production as commodity building block chemical, but the efforts by the dominant industrial fermentation strain Corynebacterium glutamicum failed for accumulating glutamic acid using lignocellulose feedstock. Results: We identified the existence of surprisingly high biotin concentration in corn stover hydrolysate as the determining factor for the failure of glutamic acid accumulation by Corynebacterium glutamicum. Under excessive biotin content, induction by penicillin resulted in 41.7 +/- 0.1 g/L of glutamic acid with the yield of 0.50 g glutamic acid/g glucose. Our further investigation revealed that corn stover contained 353 +/- 16 MUg of biotin per kg dry solids, approximately one order of magnitude greater than the biotin in corn grain. Most of the biotin remained stable during the biorefining chain and the rich biotin content in corn stover hydrolysate almost completely blocked the glutamic acid accumulation. This rich biotin existence was found to be a common phenomenon in the wide range of lignocellulose biomass and this may be the key reason why the previous studies failed in cellulosic glutamic acid fermentation from lignocellulose biomass. The extended recording of the complete members of all eight vitamin B compounds in lignocellulose biomass further reveals that the major vitamin B members were also under the high concentration levels even after harsh pretreatment. Conclusions: The high content of biotin in wide range of lignocellulose biomass feedstocks and the corresponding hydrolysates was discovered and it was found to be the key factor in determining the cellulosic glutamic acid accumulation. The highly reserved biotin and the high content of their other vitamin B compounds in biorefining process might act as the potential nutrients to biorefining fermentations. This study creates a new insight that lignocellulose biorefining not only generates inhibitors, but also keeps nutrients for cellulosic fermentations. PMID- 29760773 TI - High-oleate yeast oil without polyunsaturated fatty acids. AB - Background: Oleate-enriched triacylglycerides are well-suited for lubricant applications that require high oxidative stability. Fatty acid carbon chain length and degree of desaturation are key determinants of triacylglyceride properties and the ability to manipulate fatty acid composition in living organisms is critical to developing a source of bio-based oil tailored to meet specific application requirements. Results: We sought to engineer the oleaginous yeast Yarrowia lipolytica for production of high-oleate triacylglyceride oil. We studied the effect of deletions and overexpressions in the fatty acid and triacylglyceride synthesis pathways to identify modifications that increase oleate levels. Oleic acid accumulation in triacylglycerides was promoted by exchanging the native ?9 fatty acid desaturase and glycerol-3-phosphate acyltransferase with heterologous enzymes, as well as deletion of the Delta12 fatty acid desaturase and expression of a fatty acid elongase. By combining these engineering steps, we eliminated polyunsaturated fatty acids and created a Y. lipolytica strain that accumulates triglycerides with > 90% oleate content. Conclusions: High-oleate content and lack of polyunsaturates distinguish this triacylglyceride oil from plant and algal derived oils. Its composition renders the oil suitable for applications that require high oxidative stability and further demonstrates the potential of Y. lipolytica as a producer of tailored lipid profiles. PMID- 29760775 TI - A downstream box fusion allows stable accumulation of a bacterial cellulase in Chlamydomonas reinhardtii chloroplasts. AB - Background: We investigated strategies to improve foreign protein accumulation in the chloroplasts of the model algae Chlamydomonas reinhardtii and tested the outcome in both standard culture conditions as well as one pertinent to algal biofuel production. The downstream box (DB) of the TetC or NPTII genes, the first 15 codons following the start codon, was N-terminally fused to the coding region of cel6A, an endoglucanase from Thermobifida fusca. We also employed a chimeric regulatory element, consisting of the 16S rRNA promoter and the atpA 5'UTR, previously reported to enhance protein expression, to regulate the expression of the TetC-cel6A gene. We further investigated the accumulation of TetC-Cel6A under N-deplete growth conditions. Results: Both of the DB fusions improved intracellular accumulation of Cel6A in transplastomic C. reinhardtii strains though the TetC DB was much more effective than the NPTII DB. Furthermore, using the chimeric regulatory element, the TetC-Cel6A protein accumulation displayed a significant increase to 0.3% total soluble protein (TSP), whereas NPTII-Cel6A remained too low to quantify. Comparable levels of TetC- and NPTII-cel6A transcripts were observed, which suggests that factors other than transcript abundance mediate the greater TetC-Cel6A accumulation. The TetC-Cel6A accumulation was stable regardless of the growth stage, and the transplastomic strain growth rate was not altered. When transplastomic cells were suspended in N deplete medium, cellular levels of TetC-Cel6A increased over time along with TSP, and were greater than those in cells suspended in N-replete medium. Conclusions: The DB fusion holds great value as a tool to enhance foreign protein accumulation in C. reinhardtii chloroplasts and its influence is related to translation or other post-transcriptional processes. Our results also suggest that transplastomic protein production can be compatible with algal biofuel production strategies. Cells displayed a consistent accumulation of recombinant protein throughout the growth phase and nitrogen starvation, a strategy used to induce lipid production in algae, led to higher cellular heterologous protein content. The latter result is contrary to what might have been expected a priori and is an important result for the development of future algal biofuel systems, which will likely require co-products for economic sustainability. PMID- 29760776 TI - Integrated in situ gas stripping-salting-out process for high-titer acetone butanol-ethanol production from sweet sorghum bagasse. AB - Background: The production of biobutanol from renewable biomass resources is attractive. The energy-intensive separation process and low-titer solvents production are the key constraints on the economy-feasible acetone-butanol ethanol (ABE) production by fermentation. To decrease energy consumption and increase the solvents concentration, a novel two-stage gas stripping-salting-out system was established for effective ABE separation from the fermentation broth using sweet sorghum bagasse as feedstock. Results: The ABE condensate (143.6 g/L) after gas stripping, the first-stage separation, was recovered and introduced to salting-out process as the second-stage. K4P2O7 and K2HPO4 were used, respectively. The effect of saturated salt solution temperature on final ABE concentration was also investigated. The results showed high ABE recovery (99.32%) and ABE concentration (747.58 g/L) when adding saturated K4P2O7 solution at 323.15 K and 3.0 of salting-out factor. On this condition, the energy requirement of the downstream distillation process was 3.72 MJ/kg of ABE. Conclusions: High-titer cellulosic ABE production was separated from the fermentation broth by the novel two-stage gas stripping-salting-out process. The process was effective, which reduced the downstream process energy requirement significantly. PMID- 29760777 TI - A Pseudomonas putida efflux pump acts on short-chain alcohols. AB - Background: The microbial production of biofuels is complicated by a tradeoff between yield and toxicity of many fuels. Efflux pumps enable bacteria to tolerate toxic substances by their removal from the cells while bypassing the periplasm. Their use for the microbial production of biofuels can help to improve cell survival, product recovery, and productivity. However, no native efflux pump is known to act on the class of short-chain alcohols, important next-generation biofuels, and it was considered unlikely that such an efflux pump exists. Results: We report that controlled expression of the RND-type efflux pump TtgABC from Pseudomonas putida DOT-T1E strongly improved cell survival in highly toxic levels of the next-generation biofuels n-butanol, isobutanol, isoprenol, and isopentanol. GC-FID measurements indicated active efflux of n-butanol when the pump is expressed. Conversely, pump expression did not lead to faster growth in media supplemented with low concentrations of n-butanol and isopentanol. Conclusions: TtgABC is the first native efflux pump shown to act on multiple short-chain alcohols. Its controlled expression can be used to improve cell survival and increase production of biofuels as an orthogonal approach to metabolic engineering. Together with the increased interest in P. putida for metabolic engineering due to its flexible metabolism, high native tolerance to toxic substances, and various applications of engineering its metabolism, our findings endorse the strain as an excellent biocatalyst for the high-yield production of next-generation biofuels. PMID- 29760778 TI - Loss of DMRT1 gene in a Mos 45,XY,-9[8]/46,XY,r(9)[29]/47,XY,+idic r(9)* 2[1]/46,XY,idic r(9)[1]/46,XY[1] female presenting with short stature. AB - Background: A 46,XY sex reversal syndrome is characterized by discordant genetic and phenotypic sex, leading to normal external female genitalia, undeveloped gonads and presence of Mullerian structures in an otherwise 46,XY individual. Chromosome 9pter aberrations, such as ring chromosome have been reported to cause 46,XY disorders of sex development (DSD), due to involvement of DMRT1 gene located at the 9p24.3 region. Case presentation: This study presents a unique case of a 12-year-old female with mos 46,XY, (r)9[31]/45,XY,-9[9] karyotype, presenting with intellectual disability and short stature, mimicking Turner syndrome. Re-karyotyping was performed using standard GTL-banding technique. Further cytogenetic study using standard metaphase fluorescent in situ hybridization (FISH) technique was applied to cultured lymphocytes from peripheral blood, hybridized using green control probe specific to 9q21 loci, and red DMRT1 probe specific to 9p24.3 loci. Cytogenetics and FISH analysis revealed mos 45,XY,-9[8]/46,XY,r(9)[29]/47,XY,+idic r(9)* 2[1]/46,XY,idic r(9)[1]/46,XY[1] and haploinsufficiency of DMRT1 gene in most cells. CGH array revealed a deletion around 1.25 Mb at 9p24.3 loci [arr 9p24.3(204,193-1,457,665)* 1] and three duplications around 13 Mb [9p24.3p22.3(1,477,660-14,506,754)* 3] near the breakage point that formed the ring chromosome 9. Conclusions: The clinical presentation of the subject that mimics Turner syndrome highlights the importance of cytogenetic analysis to detect the possibility of ring chromosome 9. Sex reversal due to haploinsufficiency of DMRT1 gene in ring chromosome 9 structures is exceedingly rare with only a handful of cases ever reported. This finding further highlights the importance of DMRT1 gene in sex determination and differentiation in males. More research is required to pinpoint the exact mechanism that underlies sex reversal caused by DMRT1 haploinsufficiency. PMID- 29760779 TI - A boy with developmental delay and mosaic supernumerary inv dup(5)(p15.33p15.1) leading to distal 5p tetrasomy - case report and review of the literature. AB - Background: With only 11 patients reported, 5p tetrasomy belongs to rare postnatal findings. Most cases are due to small supernumerary marker chromosomes (sSMCs) or isochromosomes. The patients share common but unspecific symptoms such as developmental delay, seizures, ventriculomegaly, hypotonia, and fifth finger clinodactyly. Simple interstitial duplications leading to trisomies of parts of 5p are much more frequent and better described. Duplications encompassing 5p13.2 cause a defined syndrome with macrocephaly, distinct facial phenotype, heart defects, talipes equinovarus, feeding difficulties, respiratory distress and anomalies of the central nervous system, developmental delay and hypotonia. Case presentation: We present a boy with dysmorphic features, developmental delay, intellectual disability and congenital anomalies, and a mosaic sSMC inv dup(5)(p15.33p15.1). He is the fourth and the oldest reported patient with distal 5p tetrasomy. His level of mosaicism was significantly different in lymphocytes (13.2%) and buccal cells (64.7%). The amplification in our patient is smaller than that in the three previously published patients but the only phenotype difference is the absence of seizures in our patient. Conclusions: Our observations indicate that for the assessment of prognosis, especially with respect to intellectual functioning, the level of mosaicism could be more important than the extent of amplification and the number of extra copies. Evaluation of the phenotypical effect of rare chromosomal aberrations is challenging and each additional case is valuable for refinement of the genotype phenotype correlation. Moreover, our patient demonstrates that if the phenotype is severe and if the level of sSMC mosaicism is low in lymphocytes, other tissues should be tested. PMID- 29760782 TI - An improved method for inducing prometaphase chromosomes in plants. AB - Background: Detailed karyotyping using metaphase chromosomes in melon (Cucumis melo L.) remains a challenge because of their small chromosome sizes and poor stainability. Prometaphase chromosomes, which are two times longer and loosely condensed, provide a significantly better resolution for fluorescence in situ hybridization (FISH) than metaphase chromosomes. However, suitable method for acquiring prometaphase chromosomes in melon have been poorly investigated. Results: In this study, a modified Carnoy's solution II (MC II) [6:3:1 (v/v) ethanol: acetic acid: chloroform] was used as a pretreatment solution to obtain prometaphase chromosomes. We demonstrated that the prometaphase chromosomes obtained using the MC II method are excellent for karyotyping and FISH analysis. We also observed that a combination of MC II and the modified air dry (ADI) method provides a satisfactory meiotic pachytene chromosome preparation with reduced cytoplasmic background and clear chromatin spreads. Moreover, we demonstrated that pachytene and prometaphase chromosomes of melon and Abelia * grandiflora generate significantly better FISH images when prepared using the method described. We confirmed, for the first time, that Abelia * grandiflora has pairs of both strong and weak 45S ribosomal DNA signals on the short arms of their metaphase chromosomes. Conclusion: The MC II and ADI method are simple and effective for acquiring prometaphase and pachytene chromosomes with reduced cytoplasm background in plants. Our methods provide high-resolution FISH images that can help accelerate molecular cytogenetic research in plants. PMID- 29760780 TI - Derivative chromosomes involving 5p large rearranged segments went unnoticed with the use of conventional cytogenetics. AB - Background: In countries where comparative genomic hybridization arrays (aCGH) and next generation sequencing are not widely available due to accessibility and economic constraints, conventional 400-500-band karyotyping is the first-line choice for the etiological diagnosis of patients with congenital malformations and intellectual disability. Conventional karyotype analysis can rule out chromosomal alterations greater than 10 Mb. However, some large structural abnormalities, such as derivative chromosomes, may go undetected when the analysis is performed at less than a 550-band resolution and the size and banding pattern of the interchanged segments are similar. Derivatives frequently originate from inter-chromosomal exchanges and sometimes are inherited from a parent who carries a reciprocal translocation. Case presentation: We present two cases with derivative chromosomes involving a 9.1 Mb 5p deletion/14.8 Mb 10p duplication in the first patient and a 19.9 Mb 5p deletion/ 18.5 Mb 9p duplication in the second patient. These long chromosomal imbalances were ascertained by aCGH but not by conventional cytogenetics. Both patients presented with a deletion of the Cri du chat syndrome region and a duplication of another genomic region. Each patient had a unique clinical picture, and although they presented some features of Cri du chat syndrome, the phenotype did not conclusively point towards this diagnosis, although a chromosomopathy was suspected. Conclusions: These cases highlight the fundamental role of the clinical suspicion in guiding the approach for the etiological diagnosis of patients. Molecular cytogenetics techniques, such as aCGH, should be considered when the clinician suspects the presence of a chromosomal imbalance in spite of a normal karyotype. PMID- 29760783 TI - Minor digestive symptoms and their impact in the general population: a cluster analysis approach. AB - Background: The classification and treatment of patients who do not meet the criteria for a functional gastrointestinal (GI) disorder has not been well established. This study aimed to record the prevalence of minor digestive symptoms (MDSs) in the general population attempting to divide them into symptom clusters as well as trying to assess their impact and the way sufferers cope with them. Methods: Following face-to-face interviews, a web-based, self-administered questionnaire was designed to capture a range of GI sensations using 34 questions and 12 images depicting abdominal symptoms. A randomly selected sample of 1515 women and 409 men representing the general population in France was studied. Cluster analysis was used to identify groups of respondents with naturally co occurring symptoms. Data were also collected on other factors such as exacerbating and relieving strategies. Results: MDSs were reported at least every 2 months in 66.5% of women and 47.7% of men. A total of 11 symptom clusters were identified: constipation-like, flatulence, abdominal pressure, abdominal swelling, acid reflux, diarrhoea-like, intestinal heaviness, intestinal pain, gurgling, burning and gastric pain. Despite being minor, these problems had a major impact on vitality and self-image as well as emotional, social and physical well-being. Respondents considered lifestyle, food and disordered function as the main factors responsible for MDSs. Physical measures and dietary modification were the most frequent strategies adopted to obtain relief. Conclusions: MDSs are common and improved methods of recognition are needed so that better management strategies can be developed for individuals with these symptoms. The definition of symptom clusters may offer one way of achieving this goal. PMID- 29760784 TI - Practical guidance for the management of iron deficiency in patients with inflammatory bowel disease. AB - Iron deficiency or iron deficiency anemia (IDA) are some of the most common systemic complications of inflammatory bowel diseases (IBD). Symptoms such as fatigue, reduced ability to concentrate and reduced exercise tolerance can mimic common symptoms of IBD and can therefore easily be overseen. Furthermore, clinicians tend to see mild to moderate anemia as an inevitable accompaniment of IBD that is sufficiently explained by the underlying disease and does not require further workup. But in contrast to these clinical routines, current guidelines recommend that any degree of anemia in patients with IBD should be further evaluated and treated. Multiple studies have shown that anemia is a main factor for decreased quality of life (QoL) in patients with IBD. Correction of anemia, however, can significantly improve the QoL of patients with IBD. It is therefore recommended that every patient with IBD is regularly screened for iron deficiency and anemia. If detected, appropriate workup and treatment should be initiated. Over the last years, a number of new diagnostic tools and treatment options have been developed. Multiple studies have demonstrated the safety of newer formulations of intravenous iron in patients with IBD and have compared oral and intravenous iron in various situations. Treatment recommendations have changed and new evidence-based guidelines were developed. However, to date these guidelines are still not widely implemented in clinical practice. The aim of this review is to draw attention to the need for treatment for every level of anemia in patients with IBD and to provide some practical guidance for screening, diagnostics, treatment and follow up of IDA in patients with IBD following current international guidelines. PMID- 29760785 TI - Monitoring Crohn's disease activity: endoscopy, fecal markers and computed tomography enterography. AB - Background: The treatment goal of Crohn's disease (CD) has moved towards achieving mucosal healing, resolution of transmural inflammation, and normalization of biomarkers. The purpose of this study was to evaluate how well computed tomography enterography (CTE) and fecal calprotectin (FC) correlated with endoscopic activity in newly diagnosed patients with CD and after 1 year of therapy. Methods: Consecutive patients with newly diagnosed CD were evaluated by endoscopy, CTE, and FC at diagnosis and 12 months after beginning immunosuppression. Endoscopic severity was assessed using the Simplified Endoscopic Score for Crohn's Disease (SES-CD). Biomarkers, clinical indexes, and FC were recorded on the day of ileocolonoscopy at diagnosis and 1 year after diagnosis. We adapted a CTE score for disease activity based on radiological signs of inflammation (i.e. mural thickness, mural hyperenhancement, mesenteric fat proliferation, mesenteric fat densification, comb sign, presence of strictures, fistulas, abscesses, ascites, and lymphadenopathy). Correlations between endoscopy, CTE, and FC were assessed using Spearman's rank correlation. Results: A total of 29 patients (48% women; median age 30 (24.5-35.5) years) were included in this prospective cohort. CTE findings significantly correlated with endoscopic findings. Endoscopic remission (ER) at 1-year follow up significantly correlated with improvement in mural hyperenhancement (p = 0.004), mesenteric fat densification (p = 0.001), comb sign (p = 0.004), and strictures (p = 0.008) in CTE. None of the CTE findings improved in patients without ER. FC correlated with SES-CD (rs = 0.696, p < 0.001) and with CTE features of inflammation (rs = 0.596, p < 0.001). A cut-off of 100 ug/g predicted ER with 92% sensitivity, 65% specificity, and 83% accuracy (area under curve 0.878, p < 0.001). Conclusions: CTE findings and FC levels correlated with endoscopic activity in CD both at diagnosis and at 1-year follow up. These two noninvasive markers of disease activity may be used as an alternative to endoscopy to monitor disease response to therapy. PMID- 29760781 TI - Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems. AB - Background: In the past 15 years, impressive progress has been made to understand the molecular mechanism behind aneuploidy, largely due to the effort of using various -omics approaches to study model systems (e.g. yeast and mouse models) and patient samples, as well as the new realization that chromosome alteration mediated genome instability plays the key role in cancer. As the molecular characterization of the causes and effects of aneuploidy progresses, the search for the general mechanism of how aneuploidy contributes to cancer becomes increasingly challenging: since aneuploidy can be linked to diverse molecular pathways (in regards to both cause and effect), the chances of it being cancerous is highly context-dependent, making it more difficult to study than individual molecular mechanisms. When so many genomic and environmental factors can be linked to aneuploidy, and most of them not commonly shared among patients, the practical value of characterizing additional genetic/epigenetic factors contributing to aneuploidy decreases. Results: Based on the fact that cancer typically represents a complex adaptive system, where there is no linear relationship between lower-level agents (such as each individual gene mutation) and emergent properties (such as cancer phenotypes), we call for a new strategy based on the evolutionary mechanism of aneuploidy in cancer, rather than continuous analysis of various individual molecular mechanisms. To illustrate our viewpoint, we have briefly reviewed both the progress and challenges in this field, suggesting the incorporation of an evolutionary-based mechanism to unify diverse molecular mechanisms. To further clarify this rationale, we will discuss some key concepts of the genome theory of cancer evolution, including system inheritance, fuzzy inheritance, and cancer as a newly emergent cellular system. Conclusion: Illustrating how aneuploidy impacts system inheritance, fuzzy inheritance and the emergence of new systems is of great importance. Such synthesis encourages efforts to apply the principles/approaches of complex adaptive systems to ultimately understand aneuploidy in cancer. PMID- 29760788 TI - The effectiveness of stress management training on blood glucose control in patients with type 2 diabetes. AB - Background: Type 2 diabetes is a chronic disease that is expanding at an alarming rate in the world. Research on individuals with type 2 diabetes showed that stressful life events cause problems in the effective management and control of diabetes. This study aimed at investigating the effect of a stress management intervention on blood glucose control in individuals with type 2 diabetes referred to Zarandeh clinic, Iran. Methods: In this experimental study, 230 individuals with type 2 diabetes (179 female and 51 male) were enrolled and assigned to experimental (n = 115) and control (n = 115) groups. A valid and reliable multi-part questionnaire including demographics, Perceived Stress Scale, Coping Inventory for Stressful Situations, Coping Self-Efficacy Scale, and multidimensional scale of perceived social support was used to for data collection. The experimental group received a training program, developed based on the social cognitive theory and with an emphasis on improving self-efficacy and perceived social support, during eight sessions of one and a half hours. Control group received only standard care. Data were analyzed using SPSS 15 applying the t test, paired t-tests, Pearson correlation coefficient, and Chi square analysis. The significance level was considered at 0.05. Results: Before the intervention, the mean perceived stress scores of the experimental and control groups were 33.9 +/- 4.6 and 35 +/- 6.5, respectively, and no significant difference was observed (p > 0.05). However, after the intervention, the mean perceived stress score of the experimental group (26.7 +/- 4.7) was significantly less than that of the control group (34.5 +/- 7) (p = 0.001). Before the intervention, the mean scores of HbA1c in the experimental and control groups were 8.52 +/- 1 and 8.42 +/- 1.2, respectively, and there was no significant difference between the two groups. However, after the intervention, the results showed a significant decrease in glycosylated hemoglobin levels in the experimental group (p <= 0.05). Moreover, after the intervention, the result showed a significant difference between the mean scores of all aspects of Coping Inventory for Stressful Situations, coping self-efficacy, and perceived social support in the two groups (p < 0.05). Conclusion: Our results suggested that the theory-based stress management intervention based on social cognitive theory may help to decrease stress and increase coping self-efficacy, stress management, perceived social support, and lead to a reduction in the glycosylated hemoglobin levels among patients with diabetes. PMID- 29760786 TI - Ultrasound criteria for risk stratification of thyroid nodules in the previously iodine deficient area of Austria - a single centre, retrospective analysis. AB - Background: We aimed to study the validity of six published ultrasound criteria for risk stratification of thyroid nodules in the former severely iodine deficient population of Austria. Methods: Retrospective, single centre, observer blinded study design. All patients with a history of thyroidectomy due to nodules seen in the centre between 2004 and 2014 with preoperative in-house sonography and documented postoperative histology were analyzed (n = 195). A board of five experienced thyroidologists evaluated the images of 45 papillary carcinomas, 8 follicular carcinomas, and 142 benign nodules regarding the following criteria: mild hypoechogenicity, marked hypoechogenicity, microlobulated or irregular margins, microcalcifications, taller than wide shape, missing thin halo. Results: All criteria but mild hypoechogenicity were significantly more frequent in thyroid cancer than in benign nodules. The number of positive criteria was significantly higher in cancer (2.79 +/- 1.35) than in benign nodules (1.73 +/- 1.18; p < 0.001). Thus, with a cut-off of two or more positive criteria, a sensitivity of 85% and a specificity of 45% were reached to predict malignancy in this sample of thyroid nodules. As expected, the findings were even more pronounced in papillary cancer only (2.98 +/- 1.32 vs. 1.73 +/- 1.18, p < 0.001). The six ultrasound criteria could not identify follicular cancer. Conclusion: Our findings support the recently published EU-TIRADS score. Apart from mild hypoechogenicity, the analyzed ultrasound criteria can be applied for risk stratification of thyroid nodules in the previously severely iodine deficient population of Austria. PMID- 29760787 TI - Inverted Rearfoot posture in subjects with coexisting patellofemoral osteoarthritis in medial knee osteoarthritis: an exploratory study. AB - Background: While abnormal rearfoot posture and its relationship to patellofemoral (PF) pain has been thoroughly discussed in the literature, its relationship to patellofemoral osteoarthritis (PFOA) has not been determined. This study aimed to examine whether rearfoot posture is associated with a higher prevalence of radiographic PFOA in a compartment-specific manner in patients with medial tibiofemoral osteoarthritis (TFOA). Methods: Participants from orthopedic clinics (n = 68, age 56-90 years, 75.0% female), diagnosed with radiographic medial TFOA (Kellgren/Lawrence [K/L] grade >= 2) were included in this study. The presence of PFOA and static rearfoot posture were evaluated using a radiographic skyline view and a footprint automatic measurement apparatus, respectively. The relationship between rearfoot posture and PFOA was examined using analysis of covariance and propensity score-adjusted logistic regression analysis. Results: On average, patients with coexisting PFOA and medial TFOA (n = 39) had an inverted calcaneus 3.1 degrees greater than those with isolated medial TFOA (n = 29). Increased calcaneus inverted angle was significantly associated with a higher probability of the presence of medial PFOA (odds ratio: 1.180, 95% confidence interval: [1.005, 1.439]; p = 0.043). Calcaneus inverted angle was not associated with higher odds of lateral PFOA presence based on the adjusted values. Conclusions: The presence of an inverted rearfoot was associated with PFOA. Although these findings do not clearly indicate a biomechanical link between rearfoot posture and PFOA, this study shed light on the potential relationship between altered rearfoot posture and PFOA, as can be seen between rearfoot abnormality and PF pain. PMID- 29760789 TI - Higher cardiometabolic risk in idiopathic versus autoimmune type 1 diabetes: a retrospective analysis. AB - Background: Idiopathic type 1 diabetes mellitus (IDM) is characterized by an onset with insulinopenia and ketoacidosis with negative beta-cell autoimmunity markers and lack of association with HLA. The aim of the study is to compare the clinical and metabolic parameters, the macro and microvascular complications, the adipose tissue dysfunction and the insulin secretion and sensitivity indexes in patients with IDM and autoimmune type 1 diabetes mellitus (ADM) at clinical onset. Methods: Thirty patients with IDM and 30 with ADM, matched for age and gender, were retrospectively analyzed. BMI, waist circumference, lipids, glycemia, HbA1c, insulin requirement, glutamic oxaloacetic and glutamic pyruvic transaminases (GOT and GPT), glucagon stimulated c-peptide (GSC-pep) test levels, M value during hyperinsulinemic euglycemic clamp and Visceral Adiposity Index (VAI) were obtained from our database. Results: Patients with IDM showed a significantly higher BMI (p 0.012), WC (p 0.07), VAI (p 0.004), LDL-cholesterol (p 0.027), GOT (p 0.005), GPT (p 0.001), M value (p 0.006) and GSC-pep peak (p 0.036), with concomitant lower HDL-cholesterol (p < 0.001), than patients with ADM. In addition, patients with IDM showed a more marked familial history for diabetes (p 0.005) and a higher percentage of hepatic steatosis (p 0.001), visceral obesity (p 0.032) and hypercholesterolemia (p 0.007) compared to patients with ADM. Conclusions: Patients with IDM show many metabolic complications at onset, such as visceral obesity, hepatic steatosis and hypercholesterolemia and a higher cardiometabolic risk, than patients with ADM, similarly to patients with type 2 diabetes at onset. PMID- 29760790 TI - Anticancer Properties of Fenofibrate: A Repurposing Use. AB - Cancer is a leading cause of death throughout the world, and cancer therapy remains a big medical challenge in terms of both its therapeutic efficacy and safety. Therefore, to find out a safe anticancer drug has been long goal for oncologist and medical scientists. Among clinically used medicines with no or little toxicity, fenofibrate is a drug of the fibrate class that plays an important role in lowering the levels of serum cholesterol and triglycerides while elevating the levels of high-density lipoproteins. Recently, several studies have implied that fenofibrate may exert anticancer effects via a variety of pathways involved in apoptosis, cell-cycle arrest, invasion, and migration. Given the great potential that fenofibrate may have anticancer effects, this review was to investigate all published works which directly or indirectly support the anticancer activity of fenofibrate. These studies provide evidence that fenofibrate exerted antitumor effects in several human cancer cell lines, such as breast, liver, glioma, prostate, pancreas, and lung cancer cell lines. Among these studies some have further confirmed the possibility and efficacy of fenofibrate anticancer in xenograft mouse models. In the last part of this review, we also discuss the potential mechanisms of action of fenofibrate based on the available information. Overall, we may repurpose fenofibrate as an anticancer drug in cancer treatment, which urgently need further and comprehensively investigated. PMID- 29760793 TI - Hepatitis B Virus Infection Predicts Better Survival In Patients With Colorectal Liver-only Metastases Undergoing Liver Resection. AB - Objective: Hepatitis B virus (HBV) infection has been shown to decrease the risk of liver metastasis in patients with non-metastatic colorectal cancer (CRC). However, the prognostic value of HBV infection in long-term survival of patients with colorectal liver-only metastases (CRLM) after liver resection has not yet been evaluated. This study aims to explore the association between HBV infection and survival in CRLM patients. Methods: A total of 289 CRLM patients undergoing liver resection were recruited at our center from September 1999 to August 2015. Patients were divided into an HBV infection group and a non-HBV infection group. Progression-free survival (PFS) and overall survival (OS) related to HBV infection were analyzed using both Kaplan-Meier and multivariate Cox regression methods. Results: HBV infection was found in 12.1 %(35/289) of patients. Of these patients, 31.4 %(11/35) had chronic hepatitis B (CHB), 42.9 % (15/35) were inactive hepatitis B surface antigen (HBsAg) carriers (IC) and 25.7 % (9/35) did not undergo HBV DNA detection. HBV infection was associated with more liver metastases (P = 0.025) and larger-sized liver metastases (P = 0.049). The 3-year OS and PFS rates in the HBV infection group were higher than those in the HBV non infected group (OS: 75.0 % vs 64.8 %, P = 0.031; PFS: 55.9 % vs 39.6 %, P = 0.034). In multivariate Cox analysis, HBV infection was identified as an independent factor for better 3-year OS (hazard ratio (HR), 0.446; 95 %confidence interval (CI), 0.206-0.966; P = 0.041) but not an independent factor for 3-year PFS. Conclusions: HBV-infected CRLM patients survived longer than non-infected patients. In clinical work, therapeutic regimens and follow-up for HBsAg-positive patients may be different from that for HBsAg-negative patients, even though objective prospective studies are still needed. PMID- 29760791 TI - Serum VEGF levels in the early diagnosis and severity assessment of non-small cell lung cancer. AB - Background: Effective biomarkers are essential to the differential diagnosis and severity assessment of non-small cell lung cancer (NSCLC). This study explored the use of the serum vascular endothelial growth factor (VEGF) levels as a biomarker with the aim of achieving better management of NSCLC. Methods: Serum VEGF levels were assayed via enzyme-linked immunosorbent assay in 180 patients with NSCLC, 136 patients with benign pulmonary nodules, and 119 healthy controls. We additionally detected the serum concentration of three traditional biomarkers carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and cytokeratin 19 fragments (Cyfra 21-1)-to comparatively evaluate the efficiency and diagnostic value of VEGF in patients with NSCLC. We further evaluated the relationship between serum VEGF levels and clinicopathologic parameters. VEGF levels were compared between pro- and post-surgical patients using the Wilcoxon matched-pairs signed-rank test. DNA was isolated from the primary tumors. EGFR mutations were detected by Scorpions amplification refractory mutation system (ARMS). Results: Patients with NSCLC had significantly higher serum concentration of VEGF, compared to those with benign pulmonary nodules and healthy controls (P <0.0001). As a diagnostic biomarker of NSCLC, VEGF had area under the curve values of 0.824 and 0.839, sensitivities of 75.0% and 75.0%, and specificities of 93.3% and 95.6% when compared with healthy people and patients with benign pulmonary nodules, respectively; notably, these values were greater than those of CA125, Cyfra 21-1 and CEA. Furthermore, a model in which VEGF was combined with CEA, CA125, and Cyfra 21-1 was more effective for NSCLC diagnosis than VEGF alone (sensitivity, 85.0% and 84.4; specificity, 90.0% and 91.9% vs. healthy controls and patients with benign pulmonary nodules, respectively). When use to identify early-stage NSCLC, VEGF showed a better diagnostic efficacy than other biomarkers. The pro surgical VEGF levels were significantly higher than those measured 25-30 days after surgery. Moreover, VEGF concentration differed significantly among cases according to TNM stages and malignant grades (P <0.0001). EGFR mutations and the size of benign pulmonary nodules did not affect the level of serum VEGF significantly. Conclusion: The serum VEGF levels exhibited relatively high sensitivity and specificity for NSCLC, and may therefore be a useful diagnostic biomarker. Furthermore, the serum VEGF levels could be used to assess prognosis and curative effects. PMID- 29760792 TI - The Emerging Role of Circular RNAs in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) ranks the third leading cause of cancer death in the world and has a notably low survival rate. Circular RNAs (circRNAs) are newly classed non-coding RNA (ncRNA) members that are capable of regulating gene expression at transcription or post-transcription levels. Recent studies demonstrate that some circRNAs are differentially expressed in HCC, and the deregulation of these circRNAs is associated with the clinical pathological and prognostic significance. They also play essential roles in HCC progression, and contribute to cell proliferation, migration, invasion and metastasis by targeting different microRNAs (miRNAs) and protein-coding genes. In this review, we concentrate on recent progress of some important circRNAs in HCC, with an emphasis on their deregulation, functions and regulatory mechanisms, and discuss their potential utility as diagnostic and/or prognostic biomarkers or therapeutic targets for HCC. PMID- 29760795 TI - Capable Infection of Hepatitis B Virus in Diffuse Large B-cell Lymphoma. AB - Background: Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma (NHL). It is strongly correlated to the host immunity and infection status. Aim: This study tested the hypothesis that hepatitis B virus (HBV) infection is also associated with DLBCL. Methods: Clinical analysis of the correlation between DLBCL and HBV infection, detection of HBV in situ of DLBCL tissue, and biological experiments that determined whether HBV infects B lymphocytes were conducted. Results: Our long-term clinical data showed that the positive rate of serum HBV was significantly increased in DLBCL patients (23.6%) compared to that in the general Chinese population (7.2%, P<0.001), especially in advanced stage lymphoma patients (P=0.003). In addition, HBV could infect B lymphocytes in vitro and the HBV antigen and nucleic acid could be detected intracellularly. Hepatitis B x protein (HBx) was also strongly expressed in tissues from DLBCL patients that were serum HBV surface antigen (HBsAg) positive. These patients responded less well to therapy with an odds ratio (OR) of 3.04. Conclusions: HBV can infect B lymphocytes. It might be related to the development of DLBCL and may also impact the efficacy of treatment. PMID- 29760794 TI - Yangyin Fuzheng Decoction enhances anti-tumor efficacy of cisplatin on lung cancer. AB - Traditional Chinese medicine has been widely used in cancer treatment in China. Yangyin Fuzheng Decoction is a traditional Chinese compound medicine, composed of 12 traditional Chinese herbs. This study aimed to investigate anti-tumor activity and the underlying mechanisms of Yangyin Fuzheng Decoction combined with cisplatin in the treatment of lung cancer. We established lung cancer model in C57BL/6 mice injected with mouse Lewis lung cancer cells. Our results demonstrated that Yangyin Fuzheng Decoction treatment increased necrotic area in tumor tissue, and significantly enhanced the recruitment of inflammatory cells into the tumor. In addition, Yangyin Fuzheng Decoction treatment enhanced the anti-tumor efficacy of cisplatin and partially recovered mouse body weight loss caused by cisplatin treatment. Mechanistically, we found that Yangyin Fuzheng Decoction upregulated the expression of pro-apoptotic proteins p53 and Bax and suppressed the expression of anti-apoptotic protein Bcl-2. Combined treatment of Yangyin Fuzheng Decoction and cisplatin further increased p53 and Bax levels and suppressed Bcl-2 level. Taken together, these data suggest that Yangyin Fuzheng Decoction could synergistically enhance the apoptotic signaling in cancer cells during chemotherapy. In addition, it has health improving and immune response enhancing effects. Yangyin Fuzheng Decoction could be a promising adjunct agent for lung cancer chemotherapy. PMID- 29760796 TI - B cell lymphoma with different metabolic characteristics show distinct sensitivities to metabolic inhibitors. AB - Purpose: Cancer cells exhibit profound alterations in their metabolism (abnormal glucose and glutamine metabolism). Targeting cancer metabolism is a promising therapeutic strategy. Lymphoma can be classified into many different types and it is very complicated. Therefore, in this paper, we want to know whether the B cell lymphoma cells with different metabolic characteristics have distinct sensitivities to metabolic inhibitors. Methods: We classified 9 B cell lymphoma cell lines into different metabolic subtypes according to the dependency on glutamine and glucose. Then we detected the OCR, ECAR, glucose consumption and lactate production, mitochondrial content and growth rate. And we also determined the IC50 of these 9 cell lines to metabolic inhibitors. Results: According to the dependency on glutamine and glucose, we successfully classified three distinct metabolic subtypes in B cell lymphoma cell lines, one subtype was defined glutamine and glucose equally utilized subtype (GLN=Glu), whereas the other two subtypes were GLN-addicted and Glu-dependent. And these three subtypes showed striking differences in glucose and glutamine utilization, glycolysis and mitochondrial function, and proliferation rate. GLN-addicted and Glu-dependence subtypes also showed differences in cell sensitivity to inhibitors of glutamine and glycolysis metabolism, respectively. However, GLN=Glu subtype seems minimal sensitive to glycolytic and glutaminolytic inhibitors, and with high proliferation rate. Conclusions: The cells rely more on glucose/gltamine have a stronger sensitivity to glucose/glutamine depletion or glycolysis/ glutaminolysis inhibition and a lessened sensitivity to glutaminolysis/glycolysis inhibitors. To target tumor metabolism based on metabolic characteristics may provide a new therapeutic strategy for the treatment of B cell lymphoma. PMID- 29760797 TI - LMO1 super-enhancer polymorphism rs2168101 G>T correlates with decreased neuroblastoma risk in Chinese children. AB - Neuroblastoma is one of the most frequently occurring childhood cancers. The rs2168101 G>T polymorphism observed in the LMO1 gene is located at a conserved GATA transcription factor binding motif. This polymorphism was reported to be significantly associated with neuroblastoma susceptibility. However, whether this and other functional polymorphisms can affect neuroblastoma risk of Chinese children remains unknown. We conducted a two-center hospital-based case-control study with a total of 374 cases and 812 controls to assess the role of five LMO1 gene polymorphisms in the neuroblastoma risk. We confirmed that rs2168101 G>T was significantly associated with decreased neuroblastoma risk for both northern and southern Chinese children and the combined subjects [GT vs. GG: adjusted odds ratio (OR)=0.57, 95% confidence interval (CI)=0.44-0.74, P<0.0001; TT vs. GG: adjusted OR=0.29, 95% CI=0.15-0.56, P=0.0002; GT/TT vs. GG: adjusted OR=0.53, 95% CI=0.41-0.68, P<0.0001; and TT vs. GT/GG: adjusted OR=0.36, 95% CI=0.19-0.69, P=0.002] after adjustment for age and gender. This association was further confirmed by performing a stratifying analysis and a false-positive report probability analysis. Similar results were observed for the rs3750952 G>C polymorphism. In summary, the current study confirmed that the potentially functional LMO1 rs2168101 G>T and rs3750952 G>C polymorphisms were associated with neuroblastoma susceptibility. This research requires further validation with larger sample sizes and inclusion of different ethnicities. PMID- 29760798 TI - A Multicenter Retrospective Comparison of Sequential versus Sandwich Chemoradiotherapy for Stage IE-IIE Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type. AB - Background: Chemotherapy and radiotherapy are critical for treating early-stage extranodal natural killer/T-cell lymphoma, nasal type (ENKTL); however, the optimal therapy sequence remains unclear. Therefore, we performed this study to compare the efficacy of L-asparaginase/pegaspargase-based sequential versus sandwich chemoradiotherapy for patients newly diagnosed with stage IE-IIE ENKTL. Methods: Patients were categorized into sequential (N = 111) and sandwich (N = 104) groups. Chemotherapy regimens included GELOX, SMILE, and VLP. The median radiotherapy dose was 55.0 Gy (range, 40.0-63.0 Gy). Adverse events, treatment responses, and survival outcomes were analyzed. Results: Patients' clinical characteristics were largely comparable between the 2 groups; however, the sandwich group comprised a larger number of Ann Arbor stage IIE patients. Local invasion was the most significant predictor of overall survival (OS); local invasion and Ann Arbor stage were significant predictors of progression-free survival (PFS). There were no significant differences in the complete response rate (85.6% vs. 89.4%, p = 0.396), 3-year OS (77.5% vs. 80.8%, p = 0.636), or 3 year PFS rates (74.8% vs. 76.9%, p = 0.806) in the sequential vs. sandwich groups, respectively. The incidence of grade 3/4 hematological toxicities was higher in the sandwich group than in the sequential group (27.9% vs. 15.3%, respectively, p = 0.025). The response rates and survival outcomes in stage IE and IIE patients did not differ between sequential and sandwich groups. Conclusions: In the era of L-asparaginase/pegaspargase, both sequential and sandwich chemoradiotherapy are safe and similarly effective in patients with newly diagnosed stage IE-IIE ENKTL. PMID- 29760799 TI - Hepatotoxicity in Advanced Lung Adenocarcinoma: A Retrospective Study of 2108 Cases. AB - The study aimed to identify the risk factors and frequency of hepatotoxicity in patients with advanced lung adenocarcinoma. Liver function tests were documented in 2108 patients with advanced (IIIB/IV) lung adenocarcinoma at a single institution who received first line platinum-based doublet chemotherapy. Hepatotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Risk factors for hepatotoxicity were assessed using logistic regression analysis. Differences in hepatotoxicity between pemetrexed and non-pemetrexed regimens were evaluated after propensity score matching. After accounting for hepatic dysfunction during the first-line treatment, 892 patients receiving beyond first-line treatment were included in the subsequent analyses. Hepatotoxicity in beyond first-line treatment was compared between patients having epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy alone. In the first-line analysis, 316 (15.0%) patients developed liver dysfunction. Younger age (Odds Ratio [OR] 2.398, 95% Confidence Interval [95% CI] 1.755-3.275), pretreatment liver impairment (OR 2.285, 95% CI 1.622-3.220), and pemetrexed-contained chemotherapy (OR 1.835, 95% CI 1.408-2.393) were risk factors of hepatotoxicity (all P<0.001). Significant differences were observed for patients with all grades of hepatotoxicity while no differences were found concerning grade 3/4 hepatotoxicity between 844 pemetrexed and 844 non-pemetrexed regimen matched cases (P<0.0001 and P=0.4220, respectively). After first-line treatment, the presence of hepatitis virus (OR 2.905, 95% CI 1.487-5.675; P=0.002) and TKI therapy (OR 2.621, 95% CI 1.809 3.798; P<0.001) were additionally associated with increased hepatotoxicity. Patients with advanced lung adenocarcinoma with younger age, pretreatment liver injury, and presence of hepatitis virus were at high risk for hepatotoxicity following chemotherapy. Pemetrexed-contained chemotherapy and TKIs should be used cautiously in patients who are susceptible to liver damage. PMID- 29760800 TI - Risk of immune-related colitis with PD-1/PD-L1 inhibitors vs chemotherapy in solid tumors: systems assessment. AB - Background: We performed a meta-analysis to evaluate the risk of immune-related colitis associated with PD1/PD-L1 inhibitors as compared to chemotherapy in solid tumor patients. Methods: Eligible studies were identified through a comprehensive search of multiple databases and included solid tumor patients in randomized controlled trials (RCTs) with PD-1/PD-L1 inhibitors. The data was analyzed by Stata version 12.0 software. Results: After exclusion of ineligible studies, 11 clinical trials were considered eligible for the meta-analysis, including 5751 patients. Compared with chemotherapy, the risk ratios (RRs) of all-grade colitis were significant for the PD-1 inhibitor subgroup (RR 2.69, 95% confidence interval (CI): 1.15-6.29, p=0.023), and for pembrolizumab subgroup (RR 3.17, 95% CI: 1.08-9.37, p=0.037), but not for nivolumab treatment and PD-L1 inhibitor (atezolizumab) treatment (RR 2.05, 95% CI: 0.52-8.13, p=0.305; RR 4.75,95% CI: 0.56-40.50, p=0.154, respectively). The RR of all-grade colitis was significant for PD-1/PD-L1 inhibitor in NSCLC (RR 4.34, 95% CI: 1.37-13.82, p=0.013), and not significant in melanoma (RR 2.11, 95% CI: 0.54-8.34, p=0.285). Moreover, the RRs of all-grade diarrhea were significant for the PD-1 inhibitor subgroup (RR 0.61, 95% CI: 0.44-0.83, p=0.002), for the nivolumab subgroup (RR 0.54, 95% CI: 0.34 0.87, p=0.012), and for atezolizumab subgroup (RR 0.48, 95% CI: 0.25-0.89, p=0.021). The RR of high-grade diarrhea was significant for atezolizumab subgroup (RR 0.34, 95% CI: 0.12-0.94, p=0.037). Conclusions: Our meta-analysis demonstrates that compared with chemotherapy, pembrolizumab may result in a higher risk of all-grade immune-mediated colitis. PD-1/PD-L1 inhibitor treatment in NSCLC patients, but not in melanoma patients, increases the risk of all-grade colitis incidence. PMID- 29760801 TI - Diagnostic and prognostic value of microRNA-628 for cancers. AB - Background: Many studies manifested miRNA-628 (miR-628) was deregulated in various cancers, indicating that miR-628 might serve as a novel biomarker of cancer diagnosis and prognosis, but it's role was still uncertain. This study aimed to evaluate the value of miR-628 in various cancers for diagnosis and prognosis, as well as its predictive power in combination biomarkers. Materials and Methods: A literature search was performed using Medline (via PubMed), Embase, Web of Science databases, and Ovid platform up to November 2017. Meta analysis was performed to provide summative outcomes. Quality assessment of each included study was performed. Results: Twelve articles with 20 studies were included in our meta-analysis, including 8 articles with 15 studies for diagnostic meta-analysis and 4 articles with 5 studies for prognostic meta analysis. For the diagnostic meta-analysis of miR-628 alone, the overall pooled results for sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic (SROC) curve (AUC) were 0.81 (95% CI: 0.62-0.91), 0.72 (95% CI: 0.48-0.88), 2.90 (95% CI: 1.50-5.40), 0.27 (95% CI: 0.14-0.50), 11.0 (95% CI: 4.00-25.00), and 0.84 (95% CI: 0.80-0.87), respectively. For the diagnostic meta-analysis of miR-628-related combination biomarkers, the above six parameters were 0.89 (95% CI: 0.84-0.92), 0.93 (95% CI: 0.82-0.97), 12.30 (95% CI: 4.70-32.50), 0.12 (95% CI: 0.08-0.19), and 100.00 (95% CI: 28.00-354.00), 0.93 (95% CI: 0.90-0.95), respectively. For the prognostic meta-analysis, patients with lower miR-628 had significant shorter overall survival than high expression of miR-628 (HR = 1.553, 95% CI: 1.041-2.318, z = 2.16, P = 0.031). Conclusions: This study confirms that miR-628 may be a promising biomarker for cancer diagnosis and prognosis. Expertly, microRNAs combination biomarkers could be a new alternative for clinical application. PMID- 29760802 TI - The Efficacy and Late Toxicities of Computed Tomography-based Brachytherapy with Intracavitary and Interstitial Technique in Advanced Cervical Cancer. AB - Purpose: To report the efficacy and late side effects(LSEs) of CT-based image guided brachytherapy for the treatment of cervical cancer. Materials: Between 2008 and 2014, 100 patients with FIGO stage IIB-IVA cervical carcinoma were analyzed. The patients received pelvic irradiation (45-50 Gy in 25 fractions) with concurrent chemotherapy, whereas the mean prescribed EBRT dose, including initial and boost doses to positive lymph nodes, ranged from 54 to 64 Gy. Afterwards, intracavitary(IC) or combined intracavitary/interstitial(IC/IS) brachytherapy was performed using a CT-based procedure with prescribed doses of 6 or 8 Gy in 3-7 fractions. Results: The median follow-up time was 46 months. The 5 year local control, distant metastasis-free survival, and overall survival rates were 88.9%, 81.8%, 77.9%, respectively. IC/IS brachytherapy improved the HR-CTV D90 compared with IC (p<0.01). Seven patients (7.0%) had grade 2 bladder LSEs and none had grade 3/4 bladder LSEs. There was no significant relationship between bladder LSEs and the dose-volume histogram (p>0.05 for all). Thirty-seven patients (37%) had grade 2 rectal LSEs, 3(3%) had grade 3 rectal LSE. The rectum D1cc, D2cc, and D5cc values were significantly higher in patients with grades 2/3 rectal toxicity than in those with grades 0/1 (p<0.05 for all). There was no grade 2 and above small bowel LSEs. Conclusions: CT-based brachytherapy planning can achieve excellent local control with acceptable morbidity. HR-CTV D90 can increase in the IC/IS group compared with the IC group. The D1cc, D2cc, and D5cc all showed excellent predictive values for rectal LSEs. PMID- 29760803 TI - Effectiveness of Cetuximab in Combination with Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A 1:2 Propensity Score-matched Analysis. AB - Background: This study aimed to compare concurrent chemoradiotherapy (CCRT) plus cetuximab (C) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma(NPC). Methods: A total of 682 locoregionally advanced NPC patients who had undergone chemoradiotherapy with or without cetuximab were included. Propensity score-matching method was used to match patients. Progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between the two treatment arms. Results: After matching, 225 patients were identified for the analysis. Compared to CCRT, CCRT plus C was associated with significantly improved 3-year PFS (83.7% vs 71.9%, P = 0.036), LRFS (98.6% vs 90.2%, P = 0.034) but not OS (91.4% vs 85.4%, P = 0.117). Among patients with T4 and/or N3 category, CCRT plus C significantly prolonged 3-year PFS (81.0% vs 61.4%, P = 0.022) and increased 3-year OS (88.0% vs 77.9%, P = 0.086). No significant differences were observed between CCRT plus C and CCRT alone groups with regard to 3-year PFS, OS, LRFS and DMFS rates in stage III patients. Acute oral and oropharyngeal mucositis during radiotherapy were more common in the CCRT plus C than that in CCRT, but late toxicities were comparable. Conclusions: This study reveals that patients with locoregionally advanced NPC could benefit from the addition of cetuximab to CCRT, and this therapeutic gain mainly originated from T4 and/or N3 subgroup although suffering more acute moderate to severe toxicities. PMID- 29760805 TI - Preoperative SCC-Ag and thrombocytosis as predictive markers for pelvic lymphatic metastasis of squamous cervical cancer in early FIGO stage. AB - Objectives: To explore the clinical significance of squamous cell carcinoma antigen (SCC-Ag) and thrombocytosis to predict pelvic lymphatic metastasis (PLM) of squamous cervical cancer (SCC) in International Federation of Gynecology and Obstetrics (FIGO) stages IA-IIA. Methods: A retrospective clinicopathologic review of 782 patients of a primary cohort in three Chinese hospitals from 2010 to 2015, and 407 patients of a validation cohort in another institution from 2015 to 2017. A receiver operating characteristic curve was used to determine the optimal SCC-Ag threshold to predict PLM in the groups. Univariate and multivariate logistic analyses for PLM were performed to assess differences in outcome. Results: In the primary and validation cohort, 15.6% (122/782) and 25.3% (103/407) patients were classified into the thrombocytosis group (platelet count >300 * 109/L), respectively. Optimal cutoff values of SCC-Ag for predicting PLM of the thrombocytosis group and the normal group were 3.26 ng/mL (AUC 0.754; sensitivity 73.08%; specificity 72.92%; P = 0.000) and 4.58 ng/mL (AUC 0.706; sensitivity 53.26%; specificity 83.98%; P = 0.000), respectively, in the primary cohort, and 1.55 ng/mL (AUC 0.705; sensitivity 79.31%; specificity 55.41%; P = 0.000) and 1.75 ng/mL (AUC 0.655; sensitivity 69.57%; specificity 64.26%; P = 0.000), respectively, in the validation cohort. In multivariate logistic analysis, preoperative SCC-Ag over 3.26 ng/mL and lymphovascular space involvement were the significant predictors of PLM for SCC in FIGO stages IA-IIA. Conclusions: Preoperative SCC-Ag alone or combined with thrombocytosis might be used as predictive markers for PLM before initial treatment in early stage SCC. PMID- 29760804 TI - Association between Fusobacterium nucleatum and colorectal cancer: Progress and future directions. AB - The initiation and progression of colorectal cancer (CRC) involves genetic and epigenetic alterations influenced by dietary and environmental factors. Increasing evidence has linked the intestinal microbiota and colorectal cancer. More recently, Fusobacterium nucleatum (Fn), an opportunistic commensal anaerobe in the oral cavity, has been associated with CRC. Several research teams have reported an overabundance of Fn in human CRC and have elucidated the possible mechanisms by which Fn is involved in colorectal carcinogenesis in vitro and in mouse models. However, the mechanisms by which Fn promotes colorectal carcinogenesis remain unclear. To provide new perspectives for early diagnosis, the identification of high risk populations and treatment for colorectal cancer, this review will summarize the relative research progresses regarding the relationship between Fn and colorectal cancer. PMID- 29760806 TI - Surgical management of periampullary adenocarcinoma: defining an optimal prognostic lymph node stratification schema. AB - Background: Lymph node (LN) metastasis is a strong predictor of unfavorable prognosis for patients with periampullary adenocarcinoma after surgical resection. We sought to assess the prognostic performance of several LN staging systems, including American Joint Committee on Cancer (AJCC)/ International Union Against Cancer (7th edition) N stage, the total number of LN (TLN), the number of metastatic LN (MLN), the lymph node ratio (LNR) and the log odds of MLNs (LODDS), in patients with periampullary adenocarcinoma after surgical resection and identify the optional LN staging system to accurately stratify patients with different prognoses. Methods: We retrospectively analyzed 205 patients with periampullary adenocarcinoma after surgical resection. The predictive effects of several LN staging systems on overall survival (OS) and progression free survival (PFS) for all included patients and patients with more than 12 TLNs examined were evaluated and compared using the time-dependent receive operating characteristic (ROC) curve and decision curve analysis (DCA), respectively. Results: Eighty-nine patients (43.4%) had LN metastasis and their survival was not significantly decreased compared with patients without LN metastasis. LODDS and LNR were able to stratify patients into various subgroups with significant differences of both OS and PFS. When assessed using ROC curve and DCA, LODDS outperformed LNR and other LN staging systems in predicting OS and PFS. In addition, when analyzed in patients with more than 12 TLNs examined, LODDS had a higher value of area under ROC curve (AUC) and showed better performance of DCA. Conclusion: LODDS performs better than other LN staging systems in predicting OS and PFS for patients with periampullary adenocarcinoma after surgical resection. Adequate LN dissection is necessary for curative surgery, as well as to achieve a more accurate staging of the disease and a more precise prediction of survival for these patients. PMID- 29760807 TI - Quality Control of Next-generation Sequencing-based In vitro Diagnostic Test for Onco-relevant Mutations Using Multiplex Reference Materials in Plasma. AB - Background: Widespread clinical implementation of next-generation sequencing (NGS)-based cancer in vitro diagnostic tests (IVDs) highlighted the urgency to establish reference materials which could provide full control of the process from nucleic acid extraction to test report generation. The formalin-fixed, paraffin-embedded (FFPE) tissue and blood plasma containing circulating tumor deoxyribonucleic acid (ctDNA) were mostly used for clinically detecting onco relevant mutations. Methods: We respectively developed multiplex FFPE and plasma reference materials covering three clinically onco-relevant mutations within the epidermal growth factor receptor (EGFR) gene at serial allelic frequencies. All reference materials were quantified and validated via droplet digital polymerase chain reaction (ddPCR), and then were distributed to eight domestic manufacturers for the collaborative evaluation of the performance of several domestic NGS-based cancer IVDs covering four major NGS platforms (NextSeq, HiSeq, Ion Proton and BGISEQ). Results: All expected mutations except one at extremely low allelic frequencies were detected, despite some differences in coefficient of variation (CV) which increased with the decrease of allelic frequency (CVs ranging from 18% to 106%). It was worth noting that the CV value seemed to correlate with a particular mutation as well. The repeatability of determination of different mutations was L858R>T790M>19del. Conclusions: The results indicated our reference materials would be pivotal for quality control of NGS-based cancer IVDs and would guide the further development of reference materials covering more onco-relevant mutations. PMID- 29760808 TI - PIASy antagonizes Ras-driven NSCLC survival by promoting GATA2 SUMOylation. AB - GATA2 regulated transcriptional network has been validated requisite for RAS oncogene-driven non-small cell lung cancer (NSCLC). GATA2 has been reported as a SUMOylated protein. In endothelial cells, its transcriptional activity is attenuated by SUMO-2 conjugation, which is specifically catalyzed by its E3 ligase PIASy. In this study, we found a decreased expression of PIASy in RAS mutant NSCLC cell lines and specimens with RAS mutations. Forced expression of PIASy in NSCLC cells inhibits their viability in vitro, as well as tumorigenesis and growth in vivo. Mechanistically, we demonstrated overexpression of PIASy in A549 cells altered the regulated transcriptional network of GATA2, including proteasome, IL-1-signaling, and Rho-signaling pathways. Forced expression of PIASy resulted in the accumulated SUMOylation of GATA2, attenuating its transcriptional activity in A549 cells. These results collectively suggest that PIASy plays an antagonistic role in RAS-driven NSCLC survival, by enhancing the SUMOylation of GATA2 and inhibiting its transcriptional activity. PMID- 29760809 TI - The latest exploration of staging and prognostic classification for pancreatic neuroendocrine tumors: a large population-based study. AB - Background: A modified European Neuroendocrine Tumor Society (mENETS) staging system has been confirmed to be more suitable for pancreatic neuroendocrine tumors (pNETs) when compared to the American Joint Committee on Cancer (AJCC) or the European Neuroendocrine Tumor Society (ENETS) systems in the last few years. However, the importance of N stage has been recently published with several significant updates. Methods: SEER registry (n = 2,209) was used to evaluate the application of the AJCC 7th staging system, ENETS staging system, mENETS staging system and reformed ENETS (rENETS) staging system in this study. Results: For the ENETS staging system, patients with stage I disease had a similar prognosis to patients with stage II disease (P=0.154), and patients with stage IIIA and stage IIIB diseases showed adverse prognostic potential. The proportion of patients with stage III diseases using AJCC 7th staging system was extremely lower than those with mENETS staging system or rENETS staging system (3.6%, 23.0% and 23.7%, respectively). Furthermore, the hazard ratio of death for patients with stage II or III disease using rENETS staging system was slightly higher than that of mENETS staging system. Besides, survival curves were better separated by rENETS staging system. A prognostic nomogram for overall survival (OS) was formulated to obtain superior discriminatory abilities. Conclusions: The rENETS staging system has superior distribution in proportion than the AJCC 7th, ENETS or mENETS staging system, and one more accurate and advanced predictive model will be achieved via the incorporation to be adopted in clinical practice. PMID- 29760810 TI - DNA methylation and socioeconomic status in a Mexican-American birth cohort. AB - Background: Maternal social environmental stressors during pregnancy are associated with adverse birth and child developmental outcomes, and epigenetics has been proposed as a possible mechanism for such relationships. Methods: In a Mexican-American birth cohort of 241 maternal-infant pairs, cord blood samples were measured for repeat element DNA methylation (LINE-1 and Alu). Linear mixed effects regression was used to model associations between indicators of the social environment (low household income and education, neighborhood-level characteristics) and repeat element methylation. Results from a dietary questionnaire were also used to assess the interaction between maternal diet quality and the social environment on markers of repeat element DNA methylation. Results: After adjusting for confounders, living in the most impoverished neighborhoods was associated with higher cord blood LINE-1 methylation (beta = 0.78, 95%CI 0.06, 1.50, p = 0.03). No other neighborhood-, household-, or individual-level socioeconomic indicators were significantly associated with repeat element methylation. We observed a statistical trend showing that positive association between neighborhood poverty and LINE-1 methylation was strongest in cord blood of infants whose mothers reported better diet quality during pregnancy (pinteraction = 0.12). Conclusion: Our findings indicate a small yet unexpected positive association between neighborhood-level poverty during pregnancy and methylation of repetitive element DNA in infant cord blood and that this association is possibly modified by diet quality during pregnancy. However, our null findings for other adverse SES indicators do not provide strong evidence for an adverse association between early-life socioeconomic environment and repeat element DNA methylation in infants. PMID- 29760811 TI - Global DNA methylation changes spanning puberty are near predicted estrogen responsive genes and enriched for genes involved in endocrine and immune processes. AB - Background: The changes that occur during puberty have been implicated in susceptibility to a wide range of diseases later in life, many of which are characterized by sex-specific differences in prevalence. Both genetic and environmental factors have been associated with the onset or delay of puberty, and recent evidence has suggested a role for epigenetic changes in the initiation of puberty as well. Objective: To identify global DNA methylation changes that arise across the window of puberty in girls and boys. Methods: Genome-wide DNA methylation levels were measured using the Infinium 450K array. We focused our studies on peripheral blood mononuclear cells (PBMCs) from 30 girls and 25 boys pre- and post-puberty (8 and 14 years, respectively), in whom puberty status was confirmed by Tanner staging. Results: Our study revealed 347 differentially methylated probes (DMPs) in females and 50 DMPs in males between the ages of 8 and 14 years (FDR 5%). The female DMPs were in or near 312 unique genes, which were over-represented for having high affinity estrogen response elements (permutation P < 2.0 * 10-6), suggesting that some of the effects of estrogen signaling in puberty are modified through epigenetic mechanisms. Ingenuity Pathway Analysis (IPA) of the 312 genes near female puberty DMPs revealed significant networks enriched for immune and inflammatory responses as well as reproductive hormone signaling. Finally, analysis of gene expression in the female PBMCs collected at 14 years revealed modules of correlated transcripts that were enriched for immune and reproductive system functions, and include genes that are responsive to estrogen and androgen receptor signaling. The male DMPs were in or near 48 unique genes, which were enriched for adrenaline and noradrenaline biosynthesis (Enrichr P = 0.021), with no significant networks identified. Additionally, no modules were identified using post-puberty gene expression levels in males. Conclusion: Epigenetic changes spanning the window of puberty in females may be responsive to or modify hormonal changes that occur during this time and potentially contribute to sex-specific differences in immune mediated and endocrine diseases later in life. PMID- 29760812 TI - Effects of Glucan and Vitamin D Supplementation on Obesity and Lipid Metabolism in Diabetic Retinopathy. AB - Background: Diabetes mellitus is a chronic disease manifested by an increase of blood glucose. Objective: To evaluate the effects of glucan and vitamin D supplementation in patients with diabetic retinopathy. Method: We evaluated the effects of 3-month supplementation with glucan and vitamin D in 54 patients with diabetic retinopathy. We measured levels of vitamin D, cholesterol, HDL cholesterol, and triglycerides. Results: The supplementation strongly decreased the cholesterol levels and improved the levels of HDL cholesterol. In addition, vitamin D levels were strongly improved, but still not at optimal values. Conclusion: From our data, we concluded that glucan and vitamin D supplementation strongly influence lipid metabolism and have positive effects on human health. PMID- 29760814 TI - Short Exposures to an Extremely Low-Frequency Magnetic Field (ELF MF) Enhance Protein but not mRNA Alkaline Phosphatase Expression in Human Osteosarcoma Cells. AB - Background: Among electromagnetic fields treatments used in orthopedics, extremely low-frequency magnetic fields (ELF MF) need more detailed information about the molecular mechanisms of their effects and exposure conditions. Objective: Evaluation of the effects of an ELF MF exposure system, recently introduced among current clinical treatments for fracture healing and other bone diseases, on Alkaline Phosphatase (ALP) activity and expression in a human osteosarcoma cell line (SaOS-2), as marker typically associated to osteogenesis and bone tissue regeneration. Method: Cells were exposed to the ELF MF physical stimulus (75 Hz, 1.5 mT) for 1h. Cell viability, enzymatic activity, protein and mRNA expression of alkaline phosphatase were then measured at different times after exposure (0, 4 and 24 h). Results: Data demonstrate that this signal is active on an osteogenic process already one hour after exposure. Treatment was, in fact, capable, even after an exposure shorter than those commonly used in clinical applications, to significantly up-regulate alkaline phosphatase enzymatic activity. This regulation is produced essentially through an increase of ALP protein level, without changes of its mRNA concentration, while assessed magnetic field did not affect cell growth and viability and did not produce temperature variations. Conclusion: Tested low-frequency magnetic field affects cellular ALP expression with a posttranslational mechanism, without the involvement of regulations at gene transcription and mRNA level. This molecular effect is likely produced even within treated tissues during therapies with this signal and may be implicated in the induction of observed effects in treated patients. PMID- 29760816 TI - Management of Cervically Fractured Central Incisors: A Multidisciplinary Approach. AB - Introduction: Fracture of tooth structure at or below the gingival margin compromises rehabilitation and hampers esthetics and function. Management: Management of such cases by a post-core and crown restoration, or periodontal surgery or orthodontic extrusion alone may not always suffice in attaining a good result. Case Report: A multi-disciplinary approach which includes all of the above mentioned procedures helps in long term success. Conclusion: Careful case evaluation, treatment planning and meticulous attention to detail are the keys to the best treatment outcome. PMID- 29760815 TI - Long-Term Effects of Acute Myeloid Leukemia Treatment on the Oral System in a Pediatric Patient. AB - Introduction: Acute Myeloid Leukemia (AML) in pediatric patients is a serious disease, although, for the subgroup of patients who receive proper treatment, a long-term survival rate above 50% is typical. The cycles of chemo- and radiotherapy used to treat AML can impair dental development. Case Report: Herein, we describe the oral condition of a 25-year-old male patient treated for AML with chemo- and radiotherapy from 5 to 7 years of age; his AML has remained in remission for the past 18 years. He had lost only one permanent tooth, but the remaining teeth demonstrated serious deformations and radicular hypoplasia. Two teeth required immediate extraction and subsequent replacement by implant supported crowns. We found that the decayed, missing, filled teeth (DMFT) index was not representative of the real oral condition. Here, we report the full case and provide a brief review of the literature. Conclusion: Antitumor treatment of pediatric leukemia can induce total impairment of dental development and function. These adverse effects may become clinically evident many years after the resolution of cancer, and can be significantly detrimental to the patient's quality of life. PMID- 29760818 TI - Short-Term Crossover Study on the Effect of Orthogonalized Deep-Grooved Posterior Artificial Teeth on the Masticatory Efficiency of Complete Denture Wearers. AB - Background: Mastication has been regarded to play an important role in achieving quality daily life for the elderly. On the occlusal surface of posterior artificial teeth, parallel grooves of 1 mm depth and 1 mm width with an inter groove distance of 2 mm have been found to significantly improve masticatory efficiency on a mechanical simulator. Materials and Methods: In the present study, the effect of the grooved design on masticatory efficiency in edentulous subjects using a short-term crossover trial was evaluated. Six edentulous participants, 1 male and 5 females, were assigned into two groups. One received duplicated complete dentures with grooved molars first, and the other received duplicated complete dentures with conventional molars first. The design of the teeth was crossover after evaluating masticatory efficiency. Raw carrot, raw lettuce and mixed foodstuffs were used to evaluate masticatory efficiency. Subjects were instructed to masticate 20 strokes and arbitrary strokes until they felt like swallowing. Results: The number of masticatory strokes taken was significantly smaller using the grooved design (p<.05). Masticatory efficiency analysis revealed that the grooved design achieved significantly higher masticatory efficiency at 20 masticatory strokes for raw carrot and mixed foodstuffs (p<.05). Conclusion: Results show that compared with conventional lingualized occlusion, the grooved design accomplishes higher masticatory efficiency in vivo. Considering the distinction of this design that it can be applied to any existing denture occlusion, the design might help improve the dietary life of the elderly. PMID- 29760817 TI - Telescopic Denture. AB - Aim: This article explains the concept of telescopic denture. Procedure: It describes the different types of telescopic attachment (or double crown), and provides an overview of the advantages and the disadvantages of this type of prosthodontic treatment. Conclusion: The indications and the clinical applications of telescopic denture are discussed. PMID- 29760819 TI - Antibacterial and Anti-inflammatory Potential of Morus alba Stem Extract. AB - Background: Periodontitis, a chronic inflammatory disease, is the leading cause of tooth loss in adults. Evidence for the anti inflammatory activity of M. alba Stem Extract (MSE) in periodontal disease is limited. Objective: The study aimed to investigate the inhibitory effect of MSE on the growth of periodontopathic bacteria and expression of interleukin (IL)-6 and IL-8 in Porphyromonas gingivalis Lipopolysaccharide (LPS)-stimulated human Periodontal Ligament (hPDL) fibroblasts. Methods: The antimicrobial activities of MSE were tested against P. gingivalis and Actinobacillus actinomycetemcomitans by the disk diffusion, the minimum inhibitory concentration and the minimal bactericidal concentration methods. Cytotoxicity of P. gingivalis LPS and MSE on hPDL fibroblasts was determined by MTS assay. The expression of cytokines (IL-6 and IL-8) mRNA and proteins in hPDL fibroblasts was measured using the reverse transcription-qPCR and enzyme-linked immunosorbent assay, respectively. Results: MSE exhibited antibacterial activities against P. gingivalis and A. actinomycetemcomitans with the zones of inhibition of 10.00 +/- 0.33 mm and 17.33 +/- 0.58 mm, respectively. MIC and MBC values for MSE against P. gingivalis were 62.5 MUg/ml. The MIC and MBC values against A. actinomycetemcomitans were 250 MUg/mL and 500 MUg/ml, respectively. P. gingivalis LPS was shown to mediate the expression of pro inflammatory cytokines in hPDL fibroblasts. However, treatment with MSE concentrations of 2.5 and 5.0 MUg/ml significantly suppressed P. gingivalis LPS induced IL-6 and IL-8 mRNA and protein expression (p< 0.05). Conclusion: The present study demonstrates that MSE has antibacterial activity against two putative periodontal pathogens. MSE suppressed IL-6 and IL-8 expression in P. gingivalis LPS-stimulated hPDL fibroblasts, indicating a possible anti inflammatory effect. Thus, it is a potential adjunctive agent for the treatment of periodontitis. PMID- 29760820 TI - Comparison of Changes in Incisors Position in Cases Treated with Damon Self Ligating and Conventional Fixed Appliances. AB - Objective: This study aimed to compare the changes in maxillary and mandibular incisors position in cases treated with Damon self-ligating and conventional fixed appliances. Methods: The sample comprised 51 patients with Class I malocclusion, mild to moderate crowding, treated without extractions, divided into 2 groups: Group 1 consisted of 20 patients treated with Damon self-ligating appliance, with a mean initial age of 15.00 years, treated for a mean period of 2.01 years; and Group 2 comprised 31 patients treated with conventional fixed appliances, with a mean initial age of 14.98 years, treated for a mean period of 1.81 years. The initial and final cephalograms of each patient were measured. The intergroup comparisons were performed with independent t or Mann-Whitney tests. Results: Both groups showed a mild protrusion and a buccal inclination of the maxillary and mandibular incisors, with no statistically significant difference between them. Conclusion: The changes in maxillary and mandibular incisors position were similar between the groups treated with Damon self-ligating and conventional fixed appliances. PMID- 29760813 TI - Protective and Restorative Effects of Nutrients and Phytochemicals. AB - Intoroduction: Dietary intake fundamentally provides reintegration of energy and essential nutrients to human organisms. However, its qualitative and quantitative composition strongly affects individual's health, possibly being either a preventive or a risk factor. It was shown that nutritional status resulting from long-term exposition to specific diet formulations can outstandingly reduce incidences of most common and most important diseases of the developed world, such as cardiovascular and neoplastic diseases. Diet formulations result from different food combinations which bring specific nutrient molecules. Numerous molecules, mostly but not exclusively from vegetal foods, have been characterized among nutritional components as being particularly responsible for diet capabilities to exert risk reduction. These "bioactive nutrients" are able to produce effects which go beyond basic reintegration tasks, i.e. energetic and/or structural, but are specifically pharmacologically active within pathophysiological pathways related to many diseases, being able to selectively affect processes such as cell proliferation, apoptosis, inflammation, differentiation, angiogenesis, DNA repair and carcinogens activation. Conclusion: The present review was aimed to know the molecular mechanisms and pathways of activity of bioactive molecules; which will firstly allow search for optimal food composition and intake, and then use them as possible therapeutical targets and/or diagnostics. Also, the present review discussed the therapeutic effect of both nutrients and phytochemicals. PMID- 29760821 TI - A Mini Review of Using the Oralift Appliance and a Pilot Study to See if 3D Imaging Techniques Could Improve Outcomes. AB - Background: Occlusal appliances of various designs have been described in the literature. They usually have to be worn for substantial periods including night time to have the desired effect for which they are designed. The Oralift(r) appliance has been designed to address the signs of facial ageing and to help stop parafunctional habits. The appliance is based on the principles of the pivot appliance and is worn for very short periods, never at night and not even every day. The maximum usage recommended is two hours every third day. Objective: This is a review of five patients who have been treated with Oralift(r) with the aim of assessing whether the visual changes seen by wearing the appliance can be quantified by changes in volume as measured by 3D Imaging, and if this quantification could be useful in improving the outcomes for each patient. Methods: The patients were fitted with the appliances in general practice, and 2D images were taken before, during and after treatment. Afterwards, the patient attended King's College London, to have 3D imaging. Results: 3D imaging has been proved far superior to standardized 2D photography in assessing the changes taking place on the face, and helped quantify the volume changes. Conclusion: To further improve the outcome for each patient, the 3D imaging should be done before the visit to the practitioner or ideally by the practitioner so that the results could be assessed, and the treatment adjusted accordingly. The implication of the volume changes requires a much larger study. PMID- 29760822 TI - Influence of Lateral Cephalometric Radiographs on Orthodontic Treatment Planning of Class II Patients. AB - Background: Lateral Cephalometric Radiographs (LCR) are a common decision-making aid in orthodontic treatment planning and are routinely used in clinical practice. The aim of this present study was to test the null hypothesis that LCR evaluation does not alter specific components of orthodontic treatment planning in Class II patients. Materials and Methods: Records of 75 patients, who had been treated at the Department of Orthodontics, Centre of Dental Medicine, University of Zurich comprised the study material. Inclusion criteria were: (1) adolescents between the age of 12-15, (2) permanent dentition with Class II buccal segment relationship (3) absence of craniofacial and dento-alveolar malformations. Fifteen orthodontists from the dental faculties of Istanbul University, Istanbul and Ege University, Izmir filled out Likert-type linear scale questionnaires without knowing that they would repeat the same procedure with and without LCRs at two different time points. Equivalence and clinical relevance were assessed using (%95 CI) Wilcoxon signed rank tests. Results: Extraction decision did not differ between groups (p=0.68). Preference of functional appliance use (p=0.006) and inter-maxillary fixed functional appliance (p=0.043) was different among groups. Conclusion: LCR evaluation has minor influence on treatment planning procedure of Class II patients. It might be beneficial to consider its prescription not in a routine manner but as a supplementary tool considering possible reduction of radiation exposure. PMID- 29760823 TI - Comment on "Xerostomia and Salivary Gland Hypofunction in Patients with Oral Lichen Planus Before and After Treatment with Topical Corticosteroids". PMID- 29760826 TI - Best Prophylactic Strategy in Groups at Risk of Intraoperative Floppy Iris Syndrome Development: Comparison Between Atropine Instillation and Adrenaline Intracameral Injection. AB - Background: Intraoperative Floppy Iris Syndrome (IFIS) is an important cause of surgical complications and iris defects in patients undergoing phacoemulsification that were treated with selective subtype alpha1A receptor antagonists for a long period of time. To date, no definitive preventive strategy has emerged, yet. The need of prophylaxis is dictated by the high prevalence of males affected by benign prostatic hyperplasia undergoing cataract surgery. Objective: To identify the best prophylactic strategy in groups at risk of IFIS development by comparing two mydriatic treatments in course of phacoemulsification surgery. Methods: 81 eyes of 81 patients in treatment with Tamsulosin were enrolled in the study. 43 eyes were treated with atropine sulfate 1% while 38 eyes received an injection of mydriatic solution containing epinephrine in the anterior chamber. All phacoemulsifications were videotaped in order to assess the occurrence of IFIS and the severity of the syndrome. Results: The treatment group showed a statistically significant reduction (p = 0.0115) of floppy iris syndrome incidence, from 86.05% (37/43) of the atropine group to 60.53% (23/38). The analysis showed a reduction of IFIS mild form only, whereas the incidence of severe forms remained unchanged. Conclusions: We believe that IFIS may arise through two different mechanisms: pharmacological antagonism and anatomical modifications. Patients suffering from mild forms of the disease showed a statistically significant reduction of IFIS incidence after intraoperative prophylaxis due to epinephrine's ability to displace Tamsulosin, resulting in the increase of iris tone when the disease is caused mainly by receptorial antagonism. On the contrary, prophylaxis does not deliver any valuable result in case of severe forms where the anatomical variations play a major role. PMID- 29760825 TI - A Current Approach to Halitosis and Oral Malodor- A Mini Review. AB - Background: Halitosis, in other words, oral malodor is an important multifactorial health problem affecting the psychological and social life of individuals and is the most common reason for referral to dentists after dental caries and periodontal diseases. Objective: The objective of this review was to present and discuss conventional and recently introduced information about the types, causes, detection and treatment methods of halitosis. Methods: An expanded literature review was conducted which targeted all articles published in peer reviewed journals relating to the topic of halitosis. Only articles written in Turkish and English languages were considered. The review itself began with a search of relevant subject headings such as 'halitosis, oral malodor, volatile sulfur compounds in PubMed/Medline, Scopus, Google Scholar and Tubitak Ulakbim databases. A hand search of references was also performed. Results: When search results are combined, the total number of relevant literature was found to be 4646 abstracts and 978 full-text articles. Abstracts, editorial letters were not included and about half of full-text articles were not related to dental practice. Among the remaining 124 full-text articles, duplicated articles and articles written other than Turkish and English languages were removed and 54 full-text articles were used for this review. Discussion: According to the reviewed articles, both conventional and new methods were introduced in the management of halitosis. However, conventional methods seem to be more effective and widely used in the diagnosis and treatment of halitosis. Conclusion: As being first line professionals, dentists must analyze and treat oral problems which may be responsible for the patient's malodor, and should inform the patient about halitosis causes and oral hygiene procedures (tooth flossing, tongue cleaning, appropriate mouthwash and toothpaste selection and use) and if the problem persists, they should consult to a medical specialist. PMID- 29760824 TI - The Impact of Orthodontic Bands on the Marginal Periodontium of Maxillary First Molars: A Retrospective Cross-Sectional Radiographic Analysis. AB - Aim: Available information on the effect of orthodontic treatment on crestal alveolar bone levels measured in radiographs is contradictory. The aim of this study was to compare the alveolar bone level and periodontal ligament space of banded upper first molars to untreated controls. Materials and Methods: This retrospective cross-sectional radiographic study investigated alveolar bone levels of upper first molars of an orthodontic test group and an untreated control group of comparable age (15-16.25 years), using existing bitewing radiographs.Eighty-six individuals were included in each group. Three parameters were measured mesially and distally on both sides of the patient as follows: I) Alveolar Bone Level (ABL): measured as the distance between the cemento-enamel junction and the alveolar crest, II) the Periodontal Ligament Space (PLS): measured as the most coronal distance between the alveolar crest and the tooth surface, and III) angle between the lines (alveolar crests mesial and distal) and (cemento-enamel junction mesial and distal). Results: The mean duration of the orthodontic treatment in the test group was 2.5 years. The periodontal ligament space was statistically significantly wider on mesial areas of right molars (mean 0.2 mm, p<0.01), but there was no statistically significant difference found in the three other areas (distal part of the right molar, mesial and distal parts of the left molar). There was a statistically significant mean alveolar bone loss in the right and left mesial areas, respectively accounting for 0.3 mm (p<0.001) and 0.2 mm (p<0.01). No statistically significant alveolar bone loss was measured on the distal surfaces of the upper molars. The angle was wider on both sides for the test group (right p<0.001 and left p<0.05). Conclusions: A significant alveolar bone loss on the mesial tooth surface of upper first molars after orthodontic treatment was found with concurrent different levelling angles in the test group. On all other sites, no statistically significant changes were found. There was some minimal statistical significant alveolar bone loss after finishing treatment in patients who had orthodontic bands placed on their maxillary 1st molars, but no clinical significance was found. PMID- 29760827 TI - Transcriptome Analysis of Orbital Adipose Tissue in Active Thyroid Eye Disease Using Next Generation RNA Sequencing Technology. AB - Objective: This study utilized Next Generation Sequencing (NGS) to identify differentially expressed transcripts in orbital adipose tissue from patients with active Thyroid Eye Disease (TED) versus healthy controls. Method: This prospective, case-control study enrolled three patients with severe, active thyroid eye disease undergoing orbital decompression, and three healthy controls undergoing routine eyelid surgery with removal of orbital fat. RNA Sequencing (RNA-Seq) was performed on freshly obtained orbital adipose tissue from study patients to analyze the transcriptome. Bioinformatics analysis was performed to determine pathways and processes enriched for the differential expression profile. Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) was performed to validate the differential expression of selected genes identified by RNA-Seq. Results: RNA-Seq identified 328 differentially expressed genes associated with active thyroid eye disease, many of which were responsible for mediating inflammation, cytokine signaling, adipogenesis, IGF-1 signaling, and glycosaminoglycan binding. The IL-5 and chemokine signaling pathways were highly enriched, and very-low-density-lipoprotein receptor activity and statin medications were implicated as having a potential role in TED. Conclusion: This study is the first to use RNA-Seq technology to elucidate differential gene expression associated with active, severe TED. This study suggests a transcriptional basis for the role of statins in modulating differentially expressed genes that mediate the pathogenesis of thyroid eye disease. Furthermore, the identification of genes with altered levels of expression in active, severe TED may inform the molecular pathways central to this clinical phenotype and guide the development of novel therapeutic agents. PMID- 29760829 TI - Challenges in recruiting African-American women for a breast cancer genetics study. AB - Background: African-American women, especially in the southern United States, are underrepresented in cancer genetics research. A study was designed to address this issue by investigating the germline mutation rate in African-American women in Arkansas with a personal and/or family history of breast cancer. Women were tested for these mutations using a large panel of breast cancer susceptibility genes. In this analysis, we discuss the challenges encountered in recruiting African-American women from an existing biorepository to participate in this study. Methods: We attempted to contact 965 African-American women with a personal and/or family history of breast cancer who participated in Spit for the Cure (SFTC) between 2007 and 2013 and provided consent to be recontacted. The SFTC participants were invited by telephone and email to participate in the genetic study. Enrollment required completion of a phone interview to obtain a family and medical history and return of a signed consent form. Results: Among eligible SFTC participants, 39.6% (382/965) were able to be contacted with the phone numbers and email addresses they provided. Of these, 174 (45.5%) completed a phone interview and returned a signed consent form. Others were not able to be contacted (n = 583), declined to participate (n = 57), did not keep phone interview appointments (n = 82), completed the phone interview but never returned a signed consent (n = 54), were deceased (n = 13), or were too confused to consent to participate (n = 2). Conclusions: Recruiting African-American women into our breast cancer genetics study proved challenging primarily due to difficulty establishing contact with potential participants. Given their prior participation in breast cancer research, we anticipated that this would be a highly motivated population. Indeed, when we were able to contact SFTC participants, only 14.9% declined to participate in our study. Innovative communication, retention, and recruitment strategies are needed in future studies to address the recruitment challenges we faced. PMID- 29760828 TI - Periodontal Infectogenomics. AB - Periodontal diseases are chronic infectious disease in which the pathogenic bacteria initiate the host immune response leading to the destruction of tooth supporting tissue and eventually result in the tooth loss. It has multifactorial etiological factors including local, systemic, environmental and genetic factors. The effect of genetic factors on periodontal disease is already under extensive research and has explained the role of polymorphisms of immune mediators affecting disease response. The role genetic factors in pathogens colonisation is emerged as a new field of research as "infectogenomics". It is a rapidly evolving and high-priority research area now days. It further elaborates the role of genetic factors in disease pathogenesis and help in the treatment, control and early prevention of infection. The aim of this review is to summarise the contemporary evidence available in the field of periodontal infectogenomics to draw some valuable conclusions to further elaborate its role in disease pathogenesis and its application in the clinical practice. This will open up opportunity for more extensive research in this field. PMID- 29760830 TI - Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews. AB - Background: Patients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system. Methods: We used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist. Results: Twenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result. Conclusion: The maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations. PMID- 29760831 TI - Current Status of Organ Preservation in Carcinoma Larynx. AB - Organ preservation in carcinoma larynx is a long debated topic. There are multiple organ preserving approaches in the management of carcinoma larynx depending on various factors. Radical radiotherapy (RT) and conservation laryngeal surgery have shown equivalent results in early laryngeal cancer. Concurrent chemoradiation (CTRT) is the standard treatment in stage III and IV laryngeal cancer with intact cartilage and functional larynx. Patients with cartilage destruction or dysfunctional larynx are not the candidates for organ preservation. This systematic review is aimed at discussing the evolution of different organ preserving approaches, their efficacy, impact on voice quality, their pitfalls and future directions. PMID- 29760832 TI - Impact of Provider Volume on Outcomes of Patients With Hodgkin Lymphoma. AB - Background: While the provider volume-outcome relationship has been established for many complex surgeries and invasive procedures, the provider volume impact on outcomes for Hodgkin lymphoma (HL) is less certain. We hypothesized that high volume providers (HVPs) may have superior outcomes compared with low-volume providers (LVPs). Methods: We performed a chart-based, retrospective review of all patients receiving adriamycin, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for HL at the West Cancer Center from January 2010 to June 2015. Patients were divided into HVP (> 3 inpatient chemotherapy (CT)/month (m)) versus LVP (< 3 CT per m) groups. Of 95 patients identified, 93 received at least one dose of ABVD, 21 treated by HVP and 72 by LVP. Patient characteristics were well balanced between groups. Results: HVPs were less likely to prescribe dose delays (odds ratio (OR): 0.32; confidence interval (CI): 0.16 - 0.65; P = 0.0007) and to hold doses for afebrile neutropenia (OR: 0.05; CI: 0.00 - 0.85; P = 0.0006). HVP delivered significantly fewer prophylactic growth factors (0% of doses vs. 42%, OR: 0.00; CI < 0.00 - 0.06; P < 0.0001). Both event-free survival (EFS) (HR: 6.68; CI: 1.10 - 7.63; P = 0.0321) and overall survival (OS) (HR: 3.68; CI: 1.11 - 12.22; P = 0.032) were significantly inferior in the patients treated by LVP. Conclusions: In this study, patients with HL treated by LVP had inferior outcomes compared with those treated by HVP. HVPs were less likely to prescribe dose delays, hold doses for afebrile neutropenia or administer growth factor prophylaxis. These observations need to be confirmed in alternative datasets. PMID- 29760833 TI - Synchronous Presence of EGFR, ALK Driver Mutations Along With PD L1 Overexpression in a Resected Early Stage Non-Small Cell Lung Cancer: A Case Report and Review of Literature. AB - Treatment of lung cancer has been revolutionized with development of drugs that target key driver mutations and immune checkpoints. Until recently, it was believed that these driver mutations are mutually exclusive. However, few reports have emerged citing the presence of both mutations either synchronously or metachronously. We describe a case report of lung adenocarcinoma harboring two driver mutations in the same tumor cells as well as exhibiting high PDL1 expression. We further discuss the possible association of these driver mutations with PDL1 expression. PMID- 29760834 TI - A Case Series of Two Patients Presenting With Pericardial Effusion as First Manifestation of Non-Small Cell Lung Cancer With BRAF Mutation and Expression Of PD-L1. AB - Lung cancer is the number one cause of cancer-related deaths in the United States. Involvement of pericardium occurs once cancer has progressed to stage IV which can cause massive effusion in the pericardial sac. This can lead to cardiac tamponade which can be fatal very quickly if untreated. The following is a two patient case series in which both patients presented with large pericardial effusion. The first patient sought medical attention due to new onset palpitations and was found to have hemorrhagic pericardial effusion and pulmonary embolism (PE). The second patient presented with shortness of breath. Investigations revealed that she had pericardial and pleural effusions along with multiple metastases throughout the body. Both patients ended up with a diagnosis of non-small cell lung cancer (NSCLC) with BRAF mutation. One patient had V600E mutation; other patient had a variant p.D594N mutation. Both patients also had expression of PD-L1. PMID- 29760835 TI - Cutaneous Mucormycosis Following a Bullous Pemphigoid Flare in a Chronic Lymphocytic Leukemia Patient on Ibrutinib. AB - While the recent development of novel therapeutics in oncology, such as small molecule kinase inhibitors (SMKIs), has enabled our ability to target disease specific molecular pathways, the prolonged impact of these agents on the immune system and infectious risk remains to be seen. We present a 68-year-old male with refractory chronic lymphocytic leukemia (CLL) on ibrutinib monotherapy for 3 years who developed extensive cutaneous mucormycosis following a severe bullous pemphigoid (BP) flare. He received amphotericin B for 4 weeks and was continued on posaconazole with resolution of his mucormycosis infection. Consistent with a growing evidence of literature identifying opportunistic fungal infections in patients on ibrutinib therapy, providers should be cognizant of medical comorbidities that may predispose to such infections and explore methods of prevention before starting ibrutinib and other SMKIs. PMID- 29760836 TI - Concomitant ATM Mutations Identified by Next Generation Sequencing in a Patient With New-Onset Acute Myeloid Leukemia Following Imatinib Treatment for Chronic Myeloid Leukemia. PMID- 29760837 TI - Solvation of Carbon Nanoparticles in Water/Alcohol Mixtures: Using Molecular Simulation To Probe Energetics, Structure, and Dynamics. AB - Molecular dynamics simulations were used to examine the solvation behavior of buckminsterfullerene and single-walled carbon nanotubes (SWCNT) in a range of water/alcohol solvent compositions at 1 atm and 300 K. Results indicate that the alcohols assume the role of pseudosurfactants by shielding the nanotube from the more unfavorable interactions with polar water molecules. This is evident in both the free energies of transfer (DeltaDeltaGwater->xOH = -68.1 kJ/mol and -86.5 kJ/mol for C60 in methanol and ethanol; DeltaDeltaGwater->xOH = -345.6 kJ/mol and -421.2 kJ/mol for the (6,5)-SWCNT in methanol and ethanol) and the composition of the solvation shell at intermediate alcohol concentrations. Additionally, we have observed the retardation of both the translational and rotational dynamics of molecules near the nanoparticle surface through use of time correlation functions. A 3-fold increase in the residence times of the alcohol molecules within the solvation shells at low concentrations further reveals their surfactant-like behavior. Such interactions are important when considering the complex molecular environment present in many schemes used for nanoparticle purification techniques. PMID- 29760838 TI - Comparing Quick Sequential Organ Failure Assessment Scores to End-tidal Carbon Dioxide as Mortality Predictors in Prehospital Patients with Suspected Sepsis. AB - Introduction: Early identification of sepsis significantly improves outcomes, suggesting a role for prehospital screening. An end-tidal carbon dioxide (ETCO2) value <= 25 mmHg predicts mortality and severe sepsis when used as part of a prehospital screening tool. Recently, the Quick Sequential Organ Failure Assessment (qSOFA) score was also derived as a tool for predicting poor outcomes in potentially septic patients. Methods: We conducted a retrospective cohort study among patients transported by emergency medical services to compare the use of ETCO2 <= 25 mmHg with qSOFA score of >= 2 as a predictor of mortality or diagnosis of severe sepsis in prehospital patients with suspected sepsis. Results: By comparison of receiver operator characteristic curves, ETCO2 had a higher discriminatory power to predict mortality, sepsis, and severe sepsis than qSOFA. Conclusion: Both non-invasive measures were easily obtainable by prehospital personnel, with ETCO2 performing slightly better as an outcome predictor. PMID- 29760839 TI - Severely Elevated Blood Pressure and Early Mortality in Children with Traumatic Brain Injuries: The Neglected End of the Spectrum. AB - Introduction: In adults with traumatic brain injuries (TBI), hypotension and hypertension at presentation are associated with mortality. The effect of age adjusted blood pressure in children with TBI has been insufficiently studied. We sought to determine if age-adjusted hypertension in children with severe TBI is associated with mortality. Methods: This was a retrospective analysis of the Department of Defense Trauma Registry (DoDTR) between 2001 and 2013. We included for analysis patients <18 years with severe TBI defined as Abbreviated Injury Severity (AIS) scores of the head >=3. We defined hypertension as moderate for systolic blood pressures (SBP) between the 95th and 99th percentile for age and gender and severe if greater than the 99th percentile. Hypotension was defined as SBP <90 mmHg for children >10 years or < 70mmHg + (2 * age) for children <=10 years. We performed multivariable logistic regression and Cox regression to determine if BP categories were associated with mortality. Results: Of 4,990 children included in the DoDTR, 740 met criteria for analysis. Fifty patients (6.8%) were hypotensive upon arrival to the ED, 385 (52.0%) were normotensive, 115 (15.5%) had moderate hypertension, and 190 (25.7%) had severe hypertension. When compared to normotensive patients, moderate and severe hypertension patients had similar Injury Severity Scores, similar AIS head scores, and similar frequencies of neurosurgical procedures. Multivariable logistic regression demonstrated that hypotension (odd ratio [OR] 2.85, 95 confidence interval [CI] 1.26-6.47) and severe hypertension (OR 2.58, 95 CI 1.32-5.03) were associated with increased 24-hour mortality. Neither hypotension (Hazard ratio (HR) 1.52, 95 CI 0.74-3.11) nor severe hypertension (HR 1.65, 95 CI 0.65-2.30) was associated with time to mortality. Conclusion: Pediatric age-adjusted hypertension is frequent after severe TBI. Severe hypertension is strongly associated with 24 hour mortality. Pediatric age-adjusted blood pressure needs to be further evaluated as a critical marker of early mortality. PMID- 29760841 TI - Modification of Daly's Do-it-yourself, Ultrasound-guided Pericardiocentesis Model for Added External Realism. PMID- 29760840 TI - Clinical Ultrasound Is Safe and Highly Specific for Acute Appendicitis in Moderate to High Pre-test Probability Patients. AB - Introduction: Clinical ultrasound (CUS) is highly specific for the diagnosis of acute appendicitis but is operator-dependent. The goal of this study was to determine if a heterogeneous group of emergency physicians (EP) could diagnose acute appendicitis on CUS in patients with a moderate to high pre-test probability. Methods: This was a prospective, observational study of a convenience sample of adult and pediatric patients with suspected appendicitis. Sonographers received a structured, 20-minute CUS training on appendicitis prior to patient enrollment. The presence of a dilated (>6 mm diameter), non compressible, blind-ending tubular structure was considered a positive study. Non visualization or indeterminate studies were considered negative. We collected pre test probability of acute appendicitis based on a 10-point visual analog scale (moderate to high was defined as >3), and confidence in CUS interpretation. The primary objective was measured by comparing CUS findings to surgical pathology and one week follow-up. Results: We enrolled 105 patients; 76 had moderate to high pre-test probability. Of these, 24 were children. The rate of appendicitis was 36.8% in those with moderate to high pre-test probability. CUS were recorded by 33 different EPs. The sensitivity, specificity, and positive and negative likelihood ratios of EP-performed CUS in patients with moderate to high pre-test probability were 42.8% (95% confidence interval [CI] [25-62.5%]), 97.9% (95% CI [87.5-99.8%]), 20.7 (95% CI [2.8-149.9]) and 0.58 (95% CI [0.42-0.8]), respectively. The 16 false negative scans were all interpreted as indeterminate. There was one false positive CUS diagnosis; however, the sonographer reported low confidence of 2/10. Conclusion: A heterogeneous group of EP sonographers can safely identify acute appendicitis with high specificity in patients with moderate to high pre-test probability. This data adds support for surgical consultation without further imaging beyond CUS in the appropriate clinical setting. PMID- 29760842 TI - Appropriateness of Extremity Magnetic Resonance Imaging Examinations in an Academic Emergency Department Observation Unit. AB - Introduction: Emergency departments (ED) and hospitals face increasing challenges related to capacity, throughput, and stewardship of limited resources while maintaining high quality. Appropriate utilization of extremity magnetic resonance imaging (MRI) examinations within the emergency setting is not well known. Therefore, this study aimed to determine indications for and appropriateness of MRI of the extremities for musculoskeletal conditions in the ED observation unit (EDOU). Methods: We conducted this institutional review board-approved, retrospective study in a large, quaternary care academic center and Level I trauma center. An institutional database was queried retrospectively to identify all adult patients undergoing an extremity MRI while in the EDOU during the two year study period from October 2013 through September 2015. We compared clinical history with the American College of Radiology (ACR) Appropriateness Criteria(r) for musculoskeletal indications. The primary outcome was appropriateness of musculoskeletal MRI exams of the extremities; examinations with an ACR Criteria score of seven or higher were deemed appropriate. Secondary measures included MRI utilization and imaging findings. Results: During the study period, 22,713 patients were evaluated in the EDOU. Of those patients, 4,409 had at least one MRI performed, and 88 MRIs met inclusion criteria as musculoskeletal extremity examinations (2% of all patients undergoing an MRI exam in the EDOU during the study period). The most common exams were foot (27, 31%); knee (26, 30%); leg/femur (10, 11%); and shoulder (10, 11%). The most common indications were suspected infection (42, 48%) and acute trauma (23, 26%). Fifty-six percent of exams were performed with intravenous contrast; and 83% (73) of all MRIs were deemed appropriate based on ACR Criteria. The most common reason for inappropriate imaging was lack of performance of radiographs prior to MRI. Conclusion: The majority of musculoskeletal extremity MRI examinations performed in the EDOU were appropriate based on ACR Appropriateness Criteria. However, the optimal timing and most-appropriate site for performance of many clinically appropriate musculoskeletal extremity MRIs performed in the EDOU remains unclear. Potential deferral to the outpatient setting may be a preferred population health management strategy. PMID- 29760844 TI - Even the Thinnest Salami Contains Some Meat. PMID- 29760843 TI - Multicenter Study of Albuterol Use Among Infants Hospitalized with Bronchiolitis. AB - Introduction: Although bronchiolitis is a common reason for infant hospitalization, significant heterogeneity persists in its management. The American Academy of Pediatrics currently recommends that inhaled albuterol not be used in routine care of children with bronchiolitis. Our objective was to identify factors associated with pre-admission (e.g., emergency department or primary care) use of albuterol among infants hospitalized for bronchiolitis. Methods: We analyzed data from a 17-center observational study of 1,016 infants (age <1 year) hospitalized with bronchiolitis between 2011-2014. Pre-admission albuterol use was ascertained by chart review, and data were available for 1,008 (99%) infants. We used multivariable logistic regression to identify infant characteristics independently associated with pre-admission albuterol use. Results: Half of the infants (n=508) received at least one albuterol treatment before admission. Across the 17 hospitals, pre-admission albuterol use ranged from 23-84%. In adjusted analysis, independent predictors of albuterol use were the following: age >=2 months (age 2.0-5.9 months [odds ratio (OR) 2.09, 95% confidence interval (CI) {1.45-3.01}] and age 6.0-11.9 months [OR 2.89, 95% CI {1.99-4.19}]); prior use of a bronchodilator (OR 1.89, 95% CI [1.24-2.90]); and presence of wheezing documented in pre-admission chart (OR 3.94, 95% CI [2.61 5.93]). By contrast, albuterol use was less likely among those with >=7 days since the start of breathing problem (OR 0.66, 95% CI [0.44-1.00]) and parent reported fever (OR 0.75, 95% CI [0.58-0.96]). Conclusion: Variation in pre admission albuterol use suggests that local practice had a strong influence on use, but that patient characteristics also influenced the decision. While we agree with current guidelines in recommending against albuterol for all infants with bronchiolitis, our understanding of possible subgroups of responders may improve through investigation of infants with the identified characteristics. PMID- 29760846 TI - In the U.S. "Healthcare" Is Now Strictly a Business Term. PMID- 29760845 TI - Ruling out Pulmonary Embolism in Patients with High Pretest Probability. AB - Introduction: The American College of Emergency Physicians guidelines recommend more aggressive workup beyond imaging alone in patients with a high pretest probability (PTP) of pulmonary embolism (PE). However, the ability of multiple tests to safely rule out PE in high PTP patients is not known. We sought to measure the ability of negative computed tomography pulmonary angiography (CTPA) along with negative D-dimer to rule out PE in these high-risk patients. Methods: We analyzed data from a previous prospective observational study conducted in 12 emergency departments (ED). Wells score criteria were entered by providers before final PE testing. PE was diagnosed by imaging on the index ED visit, or within 45 days, demonstrating either PE or deep vein thrombosis (DVT), or if the patient died of PE during the 45-day, follow-up period. Testing threshold was set at 1.8%. Results: A total of 7,940 patients were enrolled and tested for PE, and 257 had high PTP (Wells >6). Sixteen of these high-risk patients had negative CTPA and negative D-dimer, of whom two were positive for PE (12.5% [95% confidence interval {2.2%-40.0%}]). One of these patients had a DVT on CT venogram and the other was diagnosed at follow-up. Conclusion: Our analysis suggests that in patients with high PTP of PE, neither negative CTPA by itself nor a negative CTPA plus a negative D-dimer are sufficient to rule out PE. More aggressive workup strategies may be required for these patients. PMID- 29760847 TI - Decreased Nursing Staffing Adversely Affects Emergency Department Throughput Metrics. AB - Introduction: The effect of nurse staffing on emergency department (ED) efficiency remains a significant area of interest to administrators, physicians, and nurses. We believe that decreased nursing staffing adversely affects key ED throughput metrics. Methods: We conducted a retrospective observational review of our electronic medical record database from 1/1/2015 to 12/31/2015 at a high volume, urban public hospital. We report nursing hours, door-to-discharge length of stay (LOS) and door-to-admit LOS, and percentage of patients who left without being seen (LWBS). ED nursing hours per day was examined across quartiles with the effect evaluated using analysis of covariance and controlled for total daily ED volume, hospital occupancy and ED admission rate. Results: From 1/1/15 12/31/15, 105,887 patients presented to the ED with a range of 336 to 580 nursing hours per day with a median of 464.7. Independent of daily ED volume, hospital occupancy and ED admission rate, days in the lowest quartile of nursing hours experienced a 28.2-minute increase per patient in door-to-discharge LOS compared to days in the highest quartile of nursing hours. Door-to-admit LOS showed no significant change across quartiles. There was also an increase of nine patients per day who left without being seen by a provider in the lowest quartile of nursing hours compared to the highest quartile. Conclusion: Lower nursing hours contribute to a statistically significant increase in door-to-discharge LOS and number of LWBS patients, independent of daily ED volume, hospital occupancy and ED admission rate. Consideration of the impact of nursing staffing is needed to optimize throughput metrics for our urban, safety-net hospital. PMID- 29760848 TI - Code Help: Can This Unique State Regulatory Intervention Improve Emergency Department Crowding? AB - Introduction: Emergency department (ED) crowding adversely affects multiple facets of high-quality care. The Commonwealth of Massachusetts mandates specific, hospital action plans to reduce ED boarding via a mechanism termed "Code Help." Because implementation appears inconsistent even when hospital conditions should have triggered its activation, we hypothesized that compliance with the Code Help policy would be associated with reduction in ED boarding time and total ED length of stay (LOS) for admitted patients, compared to patients seen when the Code Help policy was not followed. Methods: This was a retrospective analysis of data collected from electronic, patient-care, timestamp events and from a prospective Code Help registry for consecutive adult patients admitted from the ED at a single academic center during a 15-month period. For each patient, we determined whether the concurrent hospital status complied with the Code Help policy or violated it at the time of admission decision. We then compared ED boarding time and overall ED LOS for patients cared for during periods of Code Help policy compliance and during periods of Code Help policy violation, both with reference to patients cared for during normal operations. Results: Of 89,587 adult patients who presented to the ED during the study period, 24,017 (26.8%) were admitted to an acute care or critical care bed. Boarding time ranged from zero to 67 hours 30 minutes (median 4 hours 31 minutes). Total ED LOS for admitted patients ranged from 11 minutes to 85 hours 25 minutes (median nine hours). Patients admitted during periods of Code Help policy violation experienced significantly longer boarding times (median 20 minutes longer) and total ED LOS (median 46 minutes longer), compared to patients admitted under normal operations. However, patients admitted during Code Help policy compliance did not experience a significant increase in either metric, compared to normal operations. Conclusion: In this single-center experience, implementation of the Massachusetts Code Help regulation was associated with reduced ED boarding time and ED LOS when the policy was consistently followed, but there were adverse effects on both metrics during violations of the policy. PMID- 29760849 TI - Acute Pulmonary Embolism in Emergency Department Patients Despite Therapeutic Anticoagulation. AB - Introduction: Emergency department (ED) patients with acute pulmonary embolism (PE) despite therapeutic anticoagulation at the time of diagnosis are uncommonly encountered and present a diagnostic and management challenge. Their characterization and outcomes are poorly described. We sought to describe the prevalence and characteristics of therapeutically anticoagulated patients among a population of patients with acute PE in a community setting and to describe treatment changes and 30-day outcomes. Methods: From a large retrospective cohort of adults with acute, objectively-confirmed PE across 21 EDs between 01/2013 and 04/2015, we identified patients who arrived on direct oral or injectable anticoagulants, or warfarin with an initial ED international normalized ratio (INR) value >=2.0. Patients were excluded from the larger cohort if they had received a diagnosis of venous thromboembolism (VTE) in the prior 30 days. We gathered demographic and clinical variables from electronic health records and structured manual chart review. We report discharge anticoagulation regimens and major 30-day adverse outcomes. Results: Among 2,996 PE patients, 36 (1.2%) met study criteria. Mean age was 63 years. Eleven patients (31%) had active cancer and 25 (69%) were high risk on the PE Severity Index (Classes III-V), comparable to the larger cohort (p>0.1). Reasons for pre-arrival anticoagulation were VTE treatment or prevention (n=21), and atrial fibrillation or flutter (n=15). All patients arrived on warfarin and one was also on enoxaparin: 32 had a therapeutic INR (2.0-3.0) and four had a supratherapeutic INR (>3.0). Fifteen patients (42%) had at least one subtherapeutic INR (<2.0) in the 14 days preceding their diagnostic visit. Two patients died during hospitalization. Of the 34 ultimately discharged, 22 underwent a change in anticoagulation drug or dosing, 19 of whom received injectables, either to replace or to supplement warfarin. Four patients also received inferior vena cava filters. Thirty-day outcomes included one major hemorrhage and one additional death. No patients experienced recurrent or worsening VTE. Conclusion: We found a low prevalence of therapeutic anticoagulation at the time of acute PE diagnosis. Most patients with breakthrough PE underwent a change in therapy, though management varied widely. Subtherapeutic anticoagulation levels in the preceding weeks were common and support the importance of anticoagulation adherence. PMID- 29760850 TI - Predictors of Short-Term Outcomes after Syncope: A Systematic Review and Meta Analysis. AB - Introduction: We performed a systematic review and meta-analysis to identify predictors of serious clinical outcomes after an acute-care evaluation for syncope. Methods: We identified studies that assessed for predictors of short term (<=30 days) serious clinical events after an emergency department (ED) visit for syncope. We performed a MEDLINE search (January 1, 1990 - July 1, 2017) and reviewed reference lists of retrieved articles. The primary outcome was the occurrence of a serious clinical event (composite of mortality, arrhythmia, ischemic or structural heart disease, major bleed, or neurovascular event) within 30 days. We estimated the sensitivity, specificity, and likelihood ratio of findings for the primary outcome. We created summary estimates of association on a variable-by-variable basis using a Bayesian random-effects model. Results: We reviewed 2,773 unique articles; 17 met inclusion criteria. The clinical findings most predictive of a short-term, serious event were the following: 1) An elevated blood urea nitrogen level (positive likelihood ratio [LR+]: 2.86, 95% confidence interval [CI] [1.15, 5.42]); 2); history of congestive heart failure (LR+: 2.65, 95%CI [1.69, 3.91]); 3) initial low blood pressure in the ED (LR+: 2.62, 95%CI [1.12, 4.9]); 4) history of arrhythmia (LR+: 2.32, 95%CI [1.31, 3.62]); and 5) an abnormal troponin value (LR+: 2.49, 95%CI [1.36, 4.1]). Younger age was associated with lower risk (LR-: 0.44, 95%CI [0.25, 0.68]). An abnormal electrocardiogram was mildly predictive of increased risk (LR+ 1.79, 95%CI [1.14, 2.63]). Conclusion: We identified specific risk factors that may aid clinical judgment and that should be considered in the development of future risk prediction tools for serious clinical events after an ED visit for syncope. PMID- 29760851 TI - Isolated Hand Palsy in National Institutes of Health Stroke Scale (NIHSS): Is It Useful? PMID- 29760853 TI - Emergency Physicians at War. AB - Operation Enduring Freedom (OEF-A) in Afghanistan and Operation Iraqi Freedom (OIF) represent the first major, sustained wars in which emergency physicians (EPs) fully participated as an integrated part of the military's health system. EPs proved invaluable in the deployments, and they frequently used the full spectrum of trauma and medical care skills. The roles EPs served expanded over the years of the conflicts and demonstrated the unique skill set of emergency medicine (EM) training. EPs supported elite special operations units, served in medical command positions, and developed and staffed flying intensive care units. EPs have brought their combat experience home to civilian practice. This narrative review summarizes the history, contributions, and lessons learned by EPs during OEF-A/OIF and describes changes to daily clinical practice of EM derived from the combat environment. PMID- 29760854 TI - Peritoneal Dialysis in Austere Environments: An Emergent Approach to Renal Failure Management. AB - Peritoneal dialysis (PD) is a means of renal replacement therapy (RRT) that can be performed in remote settings with limited resources, including regions that lack electrical power. PD is a mainstay of end-stage renal disease (ESRD) therapy worldwide, and the ease of initiation and maintenance has enabled it to flourish in both resource-limited and resource-abundant settings. In natural disaster scenarios, military conflicts, and other austere areas, PD may be the only available life-saving measure for acute kidney injury (AKI) or ESRD. PD in austere environments is not without challenges, including catheter placement, availability of dialysate, and medical complications related to the procedure itself. However, when hemodialysis is unavailable, PD can be performed using generally available medical supplies including sterile tubing and intravenous fluids. Amidst the ever-increasing global burden of ESRD and AKI, the ability to perform PD is essential for many medical facilities. PMID- 29760855 TI - The Opioid Crisis in America: Too much, too little, too late. PMID- 29760852 TI - Altered Mental Status: Current Evidence-based Recommendations for Prehospital Care. AB - Introduction: In the United States emergency medical services (EMS) protocols vary widely across jurisdictions. We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of a patient with an acute change in mental status and to compare these recommendations against the current protocols used by the 33 EMS agencies in the State of California. Methods: We performed a literature review of the current evidence in the prehospital treatment of a patient with altered mental status (AMS) and augmented this review with guidelines from various national and international societies to create our evidence-based recommendations. We then compared the AMS protocols of each of the 33 EMS agencies for consistency with these recommendations. The specific protocol components that we analyzed were patient assessment, point-of care tests, supplemental oxygen, use of standardized scoring, evaluating for causes of AMS, blood glucose evaluation, toxicological treatment, and pediatric evaluation and management. Results: Protocols across 33 EMS agencies in California varied widely. All protocols call for a blood glucose check, 21 (64%) suggest treating adults at <60mg/dL, and half allow for the use of dextrose 10%. All the protocols recommend naloxone for signs of opioid overdose, but only 13 (39%) give specific parameters. Half the agencies (52%) recommend considering other toxicological causes of AMS, often by using the mnemonic AEIOU TIPS. Eight (24%) recommend a 12-lead electrocardiogram; others simply suggest cardiac monitoring. Fourteen (42%) advise supplemental oxygen as needed; only seven (21%) give specific parameters. In terms of considering various etiologies of AMS, 25 (76%) give instructions to consider trauma, 20 (61%) to consider stroke, and 18 (55%) to consider seizure. Twenty-three (70%) of the agencies have separate pediatric AMS protocols; others include pediatric considerations within the adult protocol. Conclusion: Protocols for patients with AMS vary widely across the State of California. The evidence-based recommendations that we present for the prehospital diagnosis and treatment of this condition may be useful for EMS medical directors tasked with creating and revising these protocols. PMID- 29760856 TI - Continuous Intravenous Sub-Dissociative Dose Ketamine Infusion for Managing Pain in the Emergency Department. AB - Introduction: Our objective was to describe dosing, duration, and pre- and post infusion analgesic administration of continuous intravenous sub-dissociative dose ketamine (SDK) infusion for managing a variety of painful conditions in the emergency department (ED). Methods: We conducted a retrospective chart review of patients aged 18 and older presenting to the ED with acute and chronic painful conditions who received continuous SDK infusion in the ED for a period over six years (2010-2016). Primary data analyses included dosing and duration of infusion, rates of pre- and post-infusion analgesic administration, and final diagnoses. Secondary data included pre- and post-infusion pain scores and rates of side effects. Results: A total of 104 patients were enrolled in the study. Average dosing of SDK infusion was 11.26 mg/hr, and the mean duration of infusion was 135.87 minutes. There was a 38% increase in patients not requiring post infusion analgesia. The average decrease in pain score was 5.04. There were 12 reported adverse effects, with nausea being the most prevalent. Conclusion: Continuous intravenous SDK infusion has a role in controlling pain of various etiologies in the ED with a potential to reduce the need for co-analgesics or rescue analgesic administration. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this modality across a wide range of pain syndromes and different age groups in the ED. PMID- 29760857 TI - Retrospective Chart Review of Synthetic Cannabinoid Intoxication with Toxicologic Analysis. AB - Introduction: Use of synthetic cannabinoids (SC) has recently emerged as a new drug epidemic. Our emergency departments (EDs) received a surge of SC users presenting with lethargy and bradycardia, contrasting prior reports of SC-induced tachycardia and agitation. Our goal was to describe these novel presentations and characterize the compounds. Methods: We present a case series of patients with SC intoxication who presented to our toxicology service covering two tertiary care EDs between 2/11/2015 and 6/23/2015. A retrospective chart review recorded initial vital signs, chief complaint and clinical course. Urine, blood and xenobiotic samples were analyzed using either liquid chromatography/mass spectrometry or gas chromatography/mass spectrometry. We compared resulting spectra against databases containing numerous SCs or metabolites and scored based on a reference comparison. Results: Between 2/11/2015 and 6/23/2015, we identified 141 visits. Males comprised 139 visits (age range 21-68 years; median 35, interquartile range 20). Sixty-eight percent presented with lethargy or loss of consciousness. Hypotension (SBP <90 mmHg) and bradycardia (HR<60 bpm) were seen in 10% and 24% of visits, respectively. While most patients were discharged after observation, three were admitted to the intensive care unit and seven to telemetry. Admissions were for vital sign instability, bradycardia requiring pacing, prolonged sedation and respiratory failure requiring mechanical ventilation.Laboratory analysis revealed SC in the XLR-11 family in 18/36 drug, 9/12 blood, and 23/31 urine samples. Carboxamide indazole derivative (CID) family compounds were detected in 13/36 drug samples, 21/31 urine samples, but no blood samples; 11/31 drug samples contained both XLR-11 and CID. Other compounds detected included PB-22 and nicotine. No JWH compounds, opiates, imidazoline receptor agonists, benzodiazepines or other sedative-hypnotics were detected. Conclusion: Unlike their predecessors, novel SC may be associated with significant central nervous system depression and bradycardia. While prior reports indicated that SC mostly contained JWH compounds, none were detected in these samples. The most commonly identified compounds in this series were CID and alkyl SC derivatives, such as INACA compounds and XLR-11. These tend to be full agonists at the cannabinoid receptor and are presumably more potent. The lack of other depressants suggests that the clinical findings are due to the combination of these compounds and not coingestants or adulterants. SC intoxication should be considered for patients with undifferentiated psychomotor depression and bradycardia. PMID- 29760858 TI - Occult Suicidality and Psychiatric Disease Among Emergency Department Patients with Low-acuity Chief Complaints. AB - Introduction: Patients presenting to emergency departments (ED) are often screened for suicidality, even when their chief complaint does not involve mental health concerns. Patient receptiveness to ED-based mental health screening and intervention is unknown, particularly among patients with low-acuity chief complaints, who often prioritize rapid evaluation and discharge. Methods: This cross-sectional study included adults with low-acuity chief complaints presenting to an urban, academic ED in the Northeastern United States during daytime and evening hours, from 2015 to 2016. Participants completed validated mental health screening instruments, including the Suicide Behaviors Questionnaire-Revised and the Patient Health Questionnaire-4. Participants were also asked to rate the importance of addressing mental health concerns during their ED visit. Results: We approached 1,688 patients, and 816 (48.4%) consented to participate in the study. Of these, 27% screened positive for anxiety and 25% screened positive for depression. Even among patients with no prior depression history, 17% were at high risk of depression. Eleven percent of participants were at high risk for suicidal behavior, including 5% of those with no reported history of depression or bipolar disorder. Thirty-five percent of patients at risk for suicide and 53% of those at high risk of depression thought it was important or very important to address these issues during the ED visit. Conclusion: Symptoms of mental health disorders were common among this group of ED patients presenting with low-acuity chief complaints. Patients often desired to address these mental health concerns as part of their ED visit. PMID- 29760860 TI - Effect of an Educational Intervention on Medical Student Scripting and Patient Satisfaction: A Randomized Trial. AB - Introduction: Effective communication between clinicians and patients has been shown to improve patient outcomes, reduce malpractice liability, and is now being tied to reimbursement. Use of a communication strategy known as "scripting" has been suggested to improve patient satisfaction in multiple hospital settings, but the frequency with which medical students use this strategy and whether this affects patient perception of medical student care is unknown. Our objective was to measure the use of targeted communication skills after an educational intervention as well as to further clarify the relationship between communication element usage and patient satisfaction. Methods: Medical students were block randomized into the control or intervention group. Those in the intervention group received refresher training in scripted communication. Those in the control group received no instruction or other intervention related to communication. Use of six explicit communication behaviors were recorded by trained study observers: 1) acknowledging the patient by name, 2) introducing themselves as medical students, 3) explaining their role in the patient's care, 4) explaining the care plan, 5) providing an estimated duration of time to be spent in the emergency department (ED), and 6) notifying the patient that another provider would also be seeing them. Patients then completed a survey regarding their satisfaction with the medical student encounter. Results: We observed 474 medical student-patient encounters in the ED (231 in the control group and 243 in the intervention group). We were unable to detect a statistically significant difference in communication element use between the intervention and control groups. One of the communication elements, explaining steps in the care plan, was positively associated with patient perception of the medical student's overall communication skills. Otherwise, there was no statistically significant association between element use and patient satisfaction. Conclusion: We were unable to demonstrate any improvement in student use of communication elements or in patient satisfaction after refresher training in scripted communication. Furthermore, there was little variation in patient satisfaction based on the use of scripted communication elements. Effective communication with patients in the ED is complicated and requires further investigation on how to provide this skill set. PMID- 29760859 TI - Substance Use in Pregnant Women Using the Emergency Department: Undertested And Overlooked? AB - Introduction: The objective was to determine if pregnant women visiting the emergency department (ED) are tested for substance use as frequently as non pregnant women. Methods: We captured all ED visits over a six-year period (2010 2016) from a single community hospital and identified women of childbearing age, defined for our study as 11-50 years old. We collected demographic data including age in years, ethnicity, body mass index, marital status, disposition, last encounter department, method of arrival, and day of week. An independent binary variable was created based on whether the woman was tested for alcohol or drugs (amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opioids) during her visit. We then compared rates of testing for substance use by pregnancy status. Results: We identified 61,222 ED visits by women of childbearing age (range 11-50, mean 30.5, standard deviation 9.6) over a six-year period from 2010 2016. Of the 57,360 non-pregnant women, 4.14% were tested compared to 1.04% of the 3,862 pregnant women tested with a relative risk of 0.25 (p<0.001, 95% confidence interval [CI] [0.183-0.341]). The most highly tested chief complaints for all women - psychiatric or substance use concerns - showed pregnant women were still 37% and 54% less likely to be tested, respectively (risk ratio [RR] 0.46, 95% CI [0.19-1.13]; RR 0.63, 95% CI [0.41-0.96]). Beyond pregnancy status, we found no significant interaction between patient demographics and substance use testing. Conclusion: Pregnant women presenting to the ED were 75% less likely to be tested for drug or alcohol use than non-pregnant women. Our study showed only pregnancy status as a statistically significant variable in drug- and alcohol-screening rates when pregnant and non-pregnant patient chief complaints and demographics were compared. Increased attention to the screening of pregnant women for substance use may be necessary to provide adequate care and intervention to this population. PMID- 29760861 TI - Scholarly Tracks in Emergency Medicine Residency Programs Are Associated with Increased Choice of Academic Career. AB - Introduction: Career preparation in residency training is not standardized. Scholarly tracks have emerged in emergency medicine (EM) residencies to allow specialized training in an area of focus. The characteristics of these tracks and their value and impact on resident career choice are unknown. We aim to describe the current state of scholarly tracks in residency training programs and their association with pursuit of an academic career. Methods: Program leaders at EM training programs completed an online survey consisting of multiple-choice items with free-text option. Additionally, participants completed a matrix of dropdown items identifying the immediately chosen post-residency position and applicable track of each member of their graduating class. Descriptive statistics were calculated and reported for multiple-choice items. We performed comparative statistics using chi-squared and Wilcoxon rank-sum tests. Free-text responses were analyzed using a thematic approach. Results: 113/157(72%) programs participated, 51 with and 62 without tracks. Tracks were more common in four-year programs (odds ratio [OR]=4.8;[2.0-11.9]) and larger programs (chi-sq, p=0.001). Perceived benefits of tracks from programs with them included advanced training (46/50; 92%), career guidance (44/50; 88%), mentorship (44/50; 88%), and preparation for an academic career (40/50; 80%). Residents often participated in a single track (37/50; 74%) usually during their later residency years. Programs with tracks were more likely to graduate residents to an academic career, OR 1.8;[1.3-2.4]. Conclusion: This study describes the current characteristics and perceptions of scholarly tracks in EM residencies. Scholarly tracks are associated with an academic position immediately following residency. The results of this study may inform the development and use of scholarly tracks in residency training programs. PMID- 29760862 TI - Free Open Access Medical Education (FOAM) in Emergency Medicine: The Global Distribution of Users in 2016. AB - Introduction: Free open-access medical education (FOAM) is a collection of interactive online medical education resources-free and accessible to students, physicians and other learners. This novel approach to medical education has the potential to reach learners across the globe; however, the extent of its global uptake is unknown. Methods: This descriptive report evaluates the 2016 web analytics data from a convenience sample of FOAM blogs and websites with a focus on emergency medicine (EM) and critical care. The number of times a site was accessed, or "sessions", was categorized by country of access, cross-referenced with World Bank data for population and income level, and then analyzed using simple descriptive statistics and geographic mapping. Results: We analyzed 12 FOAM blogs published from six countries, with a total reported volume of approximately 18.7 million sessions worldwide in 2016. High-income countries accounted for 73.7% of population-weighted FOAM blog and website sessions in 2016, while upper-middle income countries, lower-middle income countries and low income countries accounted for 17.5%, 8.5% and 0.3%, respectively. Conclusion: FOAM, while largely used in high-income countries, is used in low- and middle income countries as well. The potential to provide free, online training resources for EM in places where formal training is limited is significant and thus is prime for further investigation. PMID- 29760863 TI - Implementation of an Emergency Medicine Research Associates Program: Sharing 20 Years of Experience. AB - Introduction: The use of research associates (RA) programs to facilitate study enrollment in the emergency department was initiated during the mid-1990s. The University of Rochester Medical Center (URMC) was an early adopting site for this model, which has experienced considerable growth and development over the past 20 years. Methods: Our goal was to detail the Emergency Department Research Associates (EDRA) program processes developed at the URMC that has led to our program's sustainability and productivity. These processes, and the lessons learned during their development, can assist institutions seeking to establish an RA program or refine an existing program. Results: Defined procedures for selecting, training, and monitoring EDRAs have been created and refined with the goal of maximizing study enrollment and minimizing protocol deviations. Our EDRA program functions as a paid service center for investigators, and our EDRAs engage in a variety of study-related activities including screening and enrolling patients, administering surveys, collecting bio-specimens, and making follow-up calls. Over the past two years, our program has averaged 222 enrollments/month (standard deviation = 79.93), gathering roughly 25 participants per study per month. Conclusion: Our EDRA model has consistently resulted in some of the highest number of enrollments across a variety of recently funded, multi-center studies. Maintaining a high-quality EDRA program requires continual investment on the part of the leadership team, though the benefits to investigators within and outside the department outweigh these costs. PMID- 29760864 TI - 3 for the Price of 1: Teaching Chest Pain Risk Stratification in a Multidisciplinary, Problem-based Learning Workshop. AB - Introduction: Chest pain is a common chief complaint among patients presenting to health systems and often leads to complex and intensive evaluations. While these patients are often cared for by a multidisciplinary team (primary care, emergency medicine, and cardiology), medical students usually learn about the care of these patients in a fragmented, single-specialty paradigm. The present and future care of patients with chest pain is multidisciplinary, and the education of medical students on the subject should be as well. Our objective was to evaluate the effectiveness of a multidisciplinary, problem-based learning workshop to teach third-year medical students about risk assessment for patients presenting with chest pain, specifically focusing on acute coronary syndromes. Methods: To create an educational experience consistent with multidisciplinary team-based care, we designed a multidisciplinary, problem-based learning workshop to provide medical students with an understanding of how patients with chest pain are cared for in a systems-based manner to improve outcomes. Participants included third-year medical students (n=219) at a single, tertiary care, academic medical center. Knowledge acquisition was tested in a pre-/post-retention test study design. Results: Following the workshop, students achieved a 19.7% (95% confidence interval [CI] [17.3-22.2%]) absolute increase in scores on post-testing as compared to pre-testing. In addition, students maintained an 11.1% (95% CI [7.2 15.0%]) increase on a retention test vs. the pre-test. Conclusion: A multidisciplinary, problem-based learning workshop is an effective method of producing lasting gains in student knowledge about chest pain risk stratification. PMID- 29760865 TI - The Uphill Battle of Performing Education Scholarship: Barriers Educators and Education Researchers Face. AB - Introduction: Educators and education researchers report that their scholarship is limited by lack of time, funding, mentorship, expertise, and reward. This study aims to evaluate these groups' perceptions regarding barriers to scholarship and potential strategies for success. Methods: Core emergency medicine (EM) educators and education researchers completed an online survey consisting of multiple-choice, 10-point Likert scale, and free-response items in 2015. Descriptive statistics were reported. We used qualitative analysis applying a thematic approach to free-response items. Results: A total of 204 educators and 42 education researchers participated. Education researchers were highly productive: 19/42 reported more than 20 peer-reviewed education scholarship publications on their curricula vitae. In contrast, 68/197 educators reported no education publications within five years. Only a minority, 61/197 had formal research training compared to 25/42 education researchers. Barriers to performing research for both groups were lack of time, competing demands, lack of support, lack of funding, and challenges achieving scientifically rigorous methods and publication. The most common motivators identified were dissemination of knowledge, support of evidence-based practices, and promotion. Respondents advised those who seek greater education research involvement to pursue mentorship, formal research training, collaboration, and rigorous methodological standards. Conclusion: The most commonly cited barriers were lack of time and competing demands. Stakeholders were motivated by the desire to disseminate knowledge, support evidence-based practices, and achieve promotion. Suggested strategies for success included formal training, mentorship, and collaboration. This information may inform interventions to support educators in their scholarly pursuits and improve the overall quality of education research in EM. PMID- 29760866 TI - Short genome report of cellulose-producing commensal Escherichia coli 1094. AB - Bacterial surface colonization and biofilm formation often rely on the production of an extracellular polymeric matrix that mediates cell-cell and cell-surface contacts. In Escherichia coli and many Betaproteobacteria and Gammaproteobacteria cellulose is often the main component of the extracellular matrix. Here we report the complete genome sequence of the cellulose producing strain E. coli 1094 and compare it with five other closely related genomes within E. coli phylogenetic group A. We present a comparative analysis of the regions encoding genes responsible for cellulose biosynthesis and discuss the changes that could have led to the loss of this important adaptive advantage in several E. coli strains. Data deposition: The annotated genome sequence has been deposited at the European Nucleotide Archive under the accession number PRJEB21000. PMID- 29760867 TI - Knowledge and training in paediatric medical traumatic stress and trauma-informed care among emergency medical professionals in low- and middle-income countries. AB - Background: Provision of psychosocial care, in particular trauma-informed care, in the immediate aftermath of paediatric injury is a recommended strategy to minimize the risk of paediatric medical traumatic stress. Objective: To examine the knowledge of paediatric medical traumatic stress and perspectives on providing trauma-informed care among emergency staff working in low- and middle income countries (LMICs). Method: Training status, knowledge of paediatric medical traumatic stress, attitudes towards incorporating psychosocial care and barriers experienced were assessed using an online self-report questionnaire. Respondents included 320 emergency staff from 58 LMICs. Data analyses included descriptive statistics, t-tests and multiple regression. Results: Participating emergency staff working in LMICs had a low level of knowledge of paediatric medical traumatic stress. Ninety-one percent of respondents had not received any training or education in paediatric medical traumatic stress, or trauma-informed care for injured children, while 94% of respondents indicated they wanted training in this area. Conclusions: There appears to be a need for training and education of emergency staff in LMICs regarding paediatric medical traumatic stress and trauma-informed care, in particular among staff working in comparatively lower income countries. PMID- 29760868 TI - Non-medical use of prescription drugs by young men: impact of potentially traumatic events and of social-environmental stressors. AB - Background: Non-medical use of prescription drugs (NMUPD) is an increasing phenomenon associated with physical and psychological consequences. This study investigated the effects of distinct forms of stress on NMUPD. Methods: Data from 5308 young adult men from the Swiss cohort study on substance use risk factors (C SURF) were analysed regarding NMUPD of sleeping pills, tranquilizers, opioid analgesics, psychostimulants, and antidepressants. Various forms of stress (discrete, potentially traumatic events, recent and long-lasting social environmental stressors) during the period preceding the NMUPD assessment were measured. Backward log-binomial regression was performed and risk ratios (RR) were calculated. Results: NMUPD was significantly associated with the cumulative number of potentially traumatic events (e.g. for opioid analgesics, RR = 1.92, p < .001), with problems within the family (e.g. for sleeping pills, RR = 2.45, p < .001), and the peer group (e.g. for tranquilizer use, RR = 2.34, p < .01). Factors describing family functioning in childhood showed very few significant associations. Sexual assault by acquaintances was associated only with use of sleeping pills (RR = 2.91, p p <.01); physical assault by acquaintances was not associated with NMUPD. Physical (e.g. for psychostimulants, RR = 2.01, p < .001) or sexual assaults (e.g. for antidepressants, RR = 4.64, p < .001) perpetrated outside the family context did show associations with several drug categories. Conclusion: NMUPD appears to be more consistently associated with discrete and potentially traumatic events and with recent social-environmental stressors than with long-lasting stressors due to family functioning during childhood and youth. Physical and sexual assaults perpetrated by strangers showed more associations with NMUPD than those perpetrated by a family member. PMID- 29760870 TI - A multicenter phase II study of Q3 week or weekly paclitaxel in combination with bevacizumab for the treatment of metastatic or unresectable angiosarcoma. AB - Paclitaxel (P) and bevacizumab (B) are agents that provide clinical benefit in advanced angiosarcoma (AS). The objective of this study was to assess the efficacy and safety of P-B in two different scheduled regimens. Patients were to receive P 200mg/m2 IV with B 15mg/kg IV every 21 days (Regimen A) or P 90mg/m2 IV weekly D1, 8, 15 with B 15mg/kg IV D1 of a 28 day cycle (Regimen B) x6 cycles. Maintenance B followed at a dose of 15 mg/kg intravenously once every 21 days. The primary end point was 4 month non-progression rate (NPR). A total of 16 patients were enrolled. 4 month NPR was 62.5% with median overall survival 16 months and median progression free survival 5.06 months. 11 patients made it to cycle 3 and were evaluable for response with 1 CR (9%), 4 PR (36%), 2 SD (18%), and 6 PD (36%). There were ten grade 3 toxicities and four grade 4 toxicities. The breakdown between the two regimens revealed comparable efficacy and safety. Paclitaxel and Bevacizumab is an active regimen in angiosarcoma. Q3 week and weekly paclitaxel appear similar in efficacy and safety. PMID- 29760869 TI - Metabolic alterations in urine extracellular vesicles are associated to prostate cancer pathogenesis and progression. AB - Urine contains extracellular vesicles (EVs) that concentrate molecules and protect them from degradation. Thus, isolation and characterisation of urinary EVs could increase the efficiency of biomarker discovery. We have previously identified proteins and RNAs with differential abundance in urinary EVs from prostate cancer (PCa) patients compared to benign prostate hyperplasia (BPH). Here, we focused on the analysis of the metabolites contained in urinary EVs collected from patients with PCa and BPH. Targeted metabolomics analysis of EVs was performed by ultra-high-performance liquid chromatography-mass spectrometry. The correlation between metabolites and clinical parameters was studied, and metabolites with differential abundance in PCa urinary EVs were detected and mapped into cellular pathways. We detected 248 metabolites belonging to different chemical families including amino acids and various lipid species. Among these metabolites, 76 exhibited significant differential abundance between PCa and BPH. Interestingly, urine EVs recapitulated many of the metabolic alterations reported in PCa, including phosphathidylcholines, acyl carnitines, citrate and kynurenine. Importantly, we found elevated levels of the steroid hormone, 3beta-hydroxyandros 5-en-17-one-3-sulphate (dehydroepiandrosterone sulphate) in PCa urinary EVs, in line with the potential elevation of androgen synthesis in this type of cancer. This work supports urinary EVs as a non-invasive source to infer metabolic changes in PCa. PMID- 29760871 TI - Presacral myelolipoma as a possible parasymptom of cancer: A case report. AB - Presacral myelolipomas are rare, benign, asymptomatic tumors composed of mature adipose tissue and hematopoietic elements. Presacral myelolipomas can occur in patients with a medical history of malignancy, steroid use, and/or endocrine disorders including diabetes mellitus. A 65-year-old man with no specific medical history experienced temporal abdominal pain without bowel symptoms that lasted a few hours. By the time he visited a hospital, the pain had diminished. Computed tomography failed to detect any abnormality in the abdominal or pelvic organs that would have caused the abdominal pain but revealed a lesion 4 cm in diameter in the frontal sacrum. Magnetic resonance imaging showed that the lesion contained fat elements with a high signal intensity on T1- and T2-weighted images, which was decreased on fat-suppression T2-weighted images. Computed tomography-guided biopsy and imaging allowed a diagnosis of presacral myelolipoma. After 3 months, hematochezia was observed, and follow-up examination revealed rectal carcinoma with multiple lung metastases. He died due to spread of the cancer despite chemotherapy, 6 months after the cancer was found. Considering the possible association between presacral myelolipoma and cancer, presacral myelolipoma might be a cancer parasymptom. Checking for possible malignancy may therefore be warranted in patients with presacral myelolipoma, especially in those without diabetes mellitus. PMID- 29760872 TI - Giant morphea-form basal cell carcinoma of the umbilicus: Successful debulking with vismodegib. AB - Basal cell carcinoma of the umbilicus is very rare. The nodular subtype is the main representative. Giant basal cell carcinomas represent around 1% of all basal cell carcinomas. The hedgehog pathway inhibitor vismodegib is indicated for advanced basal cell carcinoma and CD56-negative immunostaining seems indicative for successful treatment. A 54-year-old man presented a 10 cm * 14 cm large and 4.5 cm deep morphea-form basal cell carcinoma with faint immunohistochemical CD56 expression arising from the umbilicus. A sequential treatment was initiated with debulking using vismodegib 150 mg per day for 4 months, followed by reconstructive surgery. To the best of our knowledge, this is the first report of a giant basal cell carcinoma of the morphea-form type of the umbilicus. The sequential treatment plan reduces the duration of vismodegib inherent adverse effects and significantly reduces the tumor mass prior to surgery. Besides increasing adherence to vismodegib treatment, this approach facilitates the surgical technique and improves cosmetic outcome. PMID- 29760873 TI - Early morphea simulating patch-stage mycosis fungoides in two cases. AB - Morphea is a skin disorder characterized by thickening of dermis and subcutaneous tissues and loss of adnexal structures. In the early inflammatory stage of morphea, diagnostic histological findings are absent and this may lead to confusion with other inflammatory dermatoses such as mycosis fungoides (MF). We report two cases of early stage morphea mimicking patchstage of MF. Histopathologic examination of biopsies obtained early in the disease course revealed lymphocytic epidermotropism arranged in small pautrier-like collections as well as linear arrangements in dermal- epidermal junction. Additional biopsies were performed which revealed replacement of subcutaneous fat with closely packed thick collagen bundles under eccrine glands. This report points toward the fact that early stage morphea can simulate MF. Therefore additional evaluation is sometimes required for definite diagnosis. PMID- 29760874 TI - A Bayesian Model of the Memory Colour Effect. AB - According to the memory colour effect, the colour of a colour-diagnostic object is not perceived independently of the object itself. Instead, it has been shown through an achromatic adjustment method that colour-diagnostic objects still appear slightly in their typical colour, even when they are colourimetrically grey. Bayesian models provide a promising approach to capture the effect of prior knowledge on colour perception and to link these effects to more general effects of cue integration. Here, we model memory colour effects using prior knowledge about typical colours as priors for the grey adjustments in a Bayesian model. This simple model does not involve any fitting of free parameters. The Bayesian model roughly captured the magnitude of the measured memory colour effect for photographs of objects. To some extent, the model predicted observed differences in memory colour effects across objects. The model could not account for the differences in memory colour effects across different levels of realism in the object images. The Bayesian model provides a particularly simple account of memory colour effects, capturing some of the multiple sources of variation of these effects. PMID- 29760875 TI - Glycogen synthase kinase 3 promotes multicellular development over unicellular encystation in encysting Dictyostelia. AB - Background: Glycogen synthase kinase 3 (GSK3) regulates many cell fate decisions in animal development. In multicellular structures of the group 4 dictyostelid Dictyostelium discoideum, GSK3 promotes spore over stalk-like differentiation. We investigated whether, similar to other sporulation-inducing genes such as cAMP dependent protein kinase (PKA), this role of GSK3 is derived from an ancestral role in encystation of unicellular amoebas. Results: We deleted GSK3 in Polysphondylium pallidum, a group 2 dictyostelid which has retained encystation as an alternative survival strategy. Loss of GSK3 inhibited cytokinesis of cells in suspension, as also occurs in D. discoideum, but did not affect spore or stalk differentiation in P. pallidum. However, gsk3- amoebas entered into encystation under conditions that in wild type favour aggregation and fruiting body formation. The gsk3- cells were hypersensitive to osmolytes, which are known to promote encystation, and to cyst-inducing factors that are secreted during starvation. GSK3 was not itself regulated by these factors, but inhibited their effects. Conclusions: Our data show that GSK3 has a deeply conserved role in controlling cytokinesis, but not spore differentiation in Dictyostelia. Instead, in P. pallidum, one of many Dictyostelia that like their solitary ancestors can still encyst to survive starvation, GSK3 promotes multicellular development into fruiting bodies over unicellular encystment. PMID- 29760876 TI - RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune responses. AB - Background: As an important danger signal, the presence of DNA in cytoplasm triggers potent immune responses. Cyclic GMP-AMP synthase (cGAS) is a recently characterized key sensor for cytoplasmic DNA. The engagement of cGAS with DNA leads to the synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which binds and activates the downstream adaptor protein STING to promote type I interferon production. Although cGAS has been shown to play a pivotal role in innate immunity, the exact regulation of cGAS activation is not fully understood. Results: We report that an E3 ubiquitin ligase, RING finger protein that interacts with C kinase (RINCK, also known as tripartite motif protein 41, TRIM41), is critical for cGAS activation by mediating the monoubiquitination of cGAS. Using CRISPR/Cas9, we generated RINCK-deletion cells and showed that the deficiency of RINCK resulted in dampened interferon production in response to cytosolic DNA. Consistently, the RINCK-deletion cells also exhibited insufficient interferon production upon herpes simplex virus 1, a DNA virus, infection. As a result, the viral load in RINCK-deficient cells was significantly higher than that in wild-type cells. We also found that RINCK deficiency inhibited the up stream signaling of DNA-triggered interferon production pathway, which was reflected by the phosphorylation of the TANK-binding kinase 1 and the interferon regulatory factor 3. Interestingly, we found that RINCK binds to cGAS and promotes the monoubiquitination of cGAS, thereby positively regulating the cGAS mediated cGAMP synthesis. Conclusions: Our study reveals that monoubiquitination is an important regulation for cGAS activation and uncovers a critical role of RINCK in the cGAS-mediated innate immunity. PMID- 29760877 TI - An EAACI task force report: recognising the potential of the primary care physician in the diagnosis and management of drug hypersensitivity. AB - Adverse drug reactions include drug hypersensitivity reactions (DHRs), which can be immunologically mediated (allergy) or non-immunologically mediated. The high number of DHRs that are unconfirmed and often self-reported is a frequent problem in daily clinical practice, with considerable impact on future prescription choices and patient health. It is important to distinguish between hypersensitivity and non-hypersensitivity reactions by adopting a structured diagnostic approach to confirm or discard the suspected drug, not only to avoid life-threatening reactions, but also to reduce the frequent over-diagnosis of DHRs. Primary care physicians are often the first point of contact for the sufferer of a reaction, as such they have a key role in deciding whether to discard the diagnosis or send the patient for further investigation. In this review, we highlight the importance of diagnosing DHRs, analysing in detail the role of primary care physicians. We describe the common patterns of DHRs and signs of its progression, as well as the indications and contraindications for referring the patient to an allergist. The diagnostic process is described and the possible tests are discussed, which often depend on the drug involved and the type of DHR suspected. We also describe recommendations regarding the avoidance of medication suspected to have caused the reaction and the use of alternatives. PMID- 29760879 TI - Smell the change: On the potential of gas-chromatographic ion mobility spectrometry in ecosystem monitoring. AB - Plant volatile organic compounds (pVOCs) are being recognized as an important factor in plant-environment interactions. Both the type and amount of the emissions appear to be heavily affected by climate change. A range of studies therefore has been directed toward understanding pVOC emissions, mostly under laboratory conditions (branch/leaf enclosure). However, there is a lack of rapid, sensitive, and selective analytical methods, and therefore, only little is known about VOC emissions under natural, outdoor conditions. An increased sensitivity and the identification of taxon-specific patterns could turn VOC analysis into a powerful tool for the monitoring of atmospheric chemistry, ecosystems, and biodiversity, with far-reaching relevance to the impact of climate change on pVOCs and vice versa. This study for the first time investigates the potential of ion mobility spectrometry coupled to gas-chromatographic preseparation (GC-IMS) to dramatically increase sensitivity and selectivity for continuous monitoring of pVOCs and to discriminate contributing plant taxa and their phenology. Leaf volatiles were analyzed for nine different common herbaceous plants from Germany. Each plant turned out to have a characteristic metabolite pattern. pVOC patterns in the field would thus reflect the composition of the vegetation, but also phenology (with herbaceous and deciduous plants contributing according to season). The technique investigated here simultaneously enables the identification and quantification of substances characteristic for environmental pollution such as industrial and traffic emissions or pesticides. GC-IMS thus has an enormous potential to provide a broad range of data on ecosystem function. This approach with near-continues measurements in the real plant communities could provide crucial insights on pVOC-level emissions and their relation to climate and phenology and thus provide a sound basis for modeling climate change scenarios including pVOC emissions. PMID- 29760878 TI - Chiropractic treatment including instrument-assisted manipulation for non specific dizziness and neck pain in community-dwelling older people: a feasibility randomised sham-controlled trial. AB - Background: Dizziness in older people is a risk factor for falls. Neck pain is associated with dizziness and responds favourably to neck manipulation. However, it is unknown if chiropractic intervention including instrument-assisted manipulation of the neck in older people with neck pain can also improve dizziness. Methods: This parallel two-arm pilot trial was conducted in Melbourne, Australia over nine months (October 2015 to June 2016). Participants aged 65-85 years, with self-reported chronic neck pain and dizziness, were recruited from the general public through advertisements in local community newspapers and via Facebook. Participants were randomised using a permuted block method to one of two groups: 1) Activator IITM-instrument-assisted cervical and thoracic spine manipulation plus a combination of: light massage; mobilisation; range of motion exercises; and home advice about the application of heat, or 2) Sham-Activator IITM-instrument-assisted manipulation (set to zero impulse) plus gentle touch of cervical and thoracic spinal regions. Participants were blinded to group allocation. The interventions were delivered weekly for four weeks. Assessments were conducted one week pre- and post-intervention. Clinical outcomes were assessed blindly and included: dizziness (dizziness handicap inventory [DHI]); neck pain (neck disability index [NDI]); self-reported concerns of falling; mood; physical function; and treatment satisfaction. Feasibility outcomes included recruitment rates, compliance with intervention and outcome assessment, study location, success of blinding, costs and harms. Results: Out of 162 enquiries, 24 participants were screened as eligible and randomised to either the chiropractic (n = 13) or sham (n = 11) intervention group. Compliance was satisfactory with only two participants lost to follow up; thus, post-intervention data for 12 chiropractic intervention and 10 sham intervention participants were analysed. Blinding was similar between groups. Mild harms of increased spinal pain or headaches were reported by 6 participants. Costs amounted to AUD$2635 per participant. The data showed a trend favouring the chiropractic group in terms of clinically-significant improvements in both NDI and DHI scores. Sample sizes of n = 150 or n = 222 for dizziness or neck pain disability as the primary outcome measure, respectively, would be needed for a fully powered trial. Conclusions: Recruitment of participants in this setting was difficult and expensive. However, a larger trial may be feasible at a specialised dizziness clinic within a rehabilitation setting. Compliance was acceptable and the outcome measures used were well accepted and responsive. Trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12613000653763. Registered 13 June 2013.Trial funding: Foundation for Chiropractic Research and Postgraduate Education (Denmark). PMID- 29760880 TI - Diversity and distribution of parasitic angiosperms in China. AB - Parasitic plants are an important component of vegetation worldwide, but their diversity and distribution in China have not been systematically reported. This study aimed to (1) explore floral characteristics of China's parasitic plants, (2) map spatial distribution of diversity of these species, and (3) explore factors influencing the distribution pattern. We compiled a nationwide species list of parasitic plants in China, and for each species, we recorded its phylogeny, endemism, and life form (e.g., herb vs. shrub; hemiparasite vs. holoparasite). Species richness and area-corrected species richness were calculated for 28 provinces, covering 98.89% of China's terrestrial area. Regression analyses were performed to determine relationships between provincial area-corrected species richness of parasitic plants and provincial total species richness (including nonparasitic plants) and physical settings (altitude, midlongitude, and midlatitude). A total of 678 species of parasitic angiosperms are recorded in China, 63.13% of which are endemic. Of the total, 59.73% (405 species) are perennials, followed by shrubs/subshrubs (14.75%) and vines (1.47%). About 76.11% (516 species) are of root hemiparasites, higher than that of stem parasites (100, 14.75%), root holoparasites (9.00%), and endophytic parasites (0.15%). A significant positive relationship is found between the area-corrected species richness and the total species richness, which has been previously demonstrated to increase with decreasing longitude and latitude. Moreover, more parasitic species are found in the southwest high-altitude areas than low areas. Consistently, the area-corrected species richness increases with increasing altitude, decreasing latitude, and decreasing longitude, as indicated by regression analyses. China is rich in parasitic flora with a high proportion of endemic species. Perennials and root hemiparasites are the dominant types. The spatial distribution of parasitic plants is largely heterogeneous, with more species living in southwest China, similar to the distribution pattern of Chinese angiosperms. The positive relationship between parasitic and nonparasitic plant species richness should be addressed in the future. PMID- 29760881 TI - Upwelling and eddies affect connectivity among local populations of the goldeye rockfish, Sebastes thompsoni (Pisces, Scorpaenoidei). AB - The goldeye rockfish, Sebastes thompsoni, commercial rockfish catch in the Northwest Pacific Ocean, may influence its population structure. To clarify the population genetic structure of Korean S. thompsoni and its degree of hybridization with the most close species, Sebastes joyneri, we analyzed a mitochondrial (mt) DNA control region and eleven polymorphic microsatellite (ms) loci. S. joyneri individuals were clearly distinguished from S. thompsoni by the mtDNA control region and ms loci results, with single interspecific hybridization between two species suggesting no impact on genetic structure of S. thompsoni. Analysis of mtDNA revealed no population structure within S. thompsoni, suggesting the survival of a single population in southern refugia during the glacial period. The ms loci results, in contrast, showed two genetically distinct clusters within S. thompsoni: One was predominant throughout Korean coasts (from the Yellow Sea, via the Korea Strait to the East Sea); the other was predominant at Dokdo Island in the East Sea; and both occurred in similar ratios at Wangdolcho Reef in the East Sea. A possible factor that restricts gene flow between Korean coastal and offshore populations in the East Sea may be related to the complex oceanic current patterns such as eddies and upwelling, which represent impermeable barriers to population connectivity for this species. Our findings highlight that these two populations might be representative of two separate stock within Korean waters and maintain their geographically related genetic structure. PMID- 29760882 TI - The thermal dependency of locomotor performance evolves rapidly within an invasive species. AB - Biological invasions can stimulate rapid shifts in organismal performance, via both plasticity and adaptation. We can distinguish between these two proximate mechanisms by rearing offspring from populations under identical conditions and measuring their locomotor abilities in standardized trials. We collected adult cane toads (Rhinella marina) from invasive populations that inhabit regions of Australia with different climatic conditions. We bred those toads and raised their offspring under common-garden conditions before testing their locomotor performance. At high (but not low) temperatures, offspring of individuals from a hotter location (northwestern Australia) outperformed offspring of conspecifics from a cooler location (northeastern Australia). This disparity indicates that, within less than 100 years, thermal performance in cane toads has adapted to the novel abiotic challenges that cane toads have encountered during their invasion of tropical Australia. PMID- 29760883 TI - Resource diversity and provenance underpin spatial patterns in functional diversity across native and exotic species. AB - Functional diversity metrics are increasingly used to augment or replace taxonomic diversity metrics to deliver more mechanistic insights into community structure and function. Metrics used to describe landscape structure and characteristics share many of the same limitations as taxonomy-based metrics, particularly their reliance on anthropogenically defined typologies with little consideration of structure, management, or function. However, the development of alternative metrics to describe landscape characteristics has been limited. Here, we extend the functional diversity framework to characterize landscapes based on the diversity of resources available across habitats present. We then examine the influence of resource diversity and provenance on the functional diversities of native and exotic avian communities in New Zealand. Invasive species are increasingly prevalent and considered a global threat to ecosystem function, but the characteristics of and interactions between sympatric native and exotic communities remain unresolved. Understanding their comparative responses to environmental change and the mechanisms underpinning them is of growing importance in predicting community dynamics and changing ecosystem function. We use (i) matrices of resource use (species) and resource availability (habitats) and (ii) occurrence data for 62 native and 25 exotic species and 19 native and 13 exotic habitats in 2015 10 * 10 km quadrats to examine the relationship between native and exotic avian and landscape functional diversity. The numbers of species in, and functional diversities of, native and exotic communities were positively related. Each community displayed evidence of environmental filtering, but it was significantly stronger for exotic species. Less environmental filtering occurred in landscapes providing a more diverse combination of resources, with resource provenance also an influential factor. Landscape functional diversity explained a greater proportion of variance in native and exotic community characteristics than the number of habitat types present. Resource diversity and provenance should be explicitly accounted for when characterizing landscape structure and change as they offer additional mechanistic understanding of the links between environmental filtering and community structure. Manipulating resource diversity through the design and implementation of management actions could prove a powerful tool for the delivery of conservation objectives, be they to protect native species, control exotic species, or maintain ecosystem service provision. PMID- 29760884 TI - Habitat constraints on carotenoid-based coloration in a small euryhaline teleost. AB - Display of bright and striking color patterns is a widespread way of communication in many animal species. Carotenoid-based coloration accounts for most of the bright yellow, orange, and red displays in invertebrates, fish, amphibians, reptiles, and birds, being widely considered a signal of individual health. This type of coloration is under the influence of several factors, such as sexual selection, predator pressure, pigment availability, and light transmission. Fish offer numerous examples of visual communication by means of color patterns. We used a small cyprinodontid fish, Aphanius fasciatus (Valenciennes, 1821), as a model species to assess habitat constraints on the color display in male caudal fin. Populations from natural and open/closed artificial habitats were tested for differences in the pigmentation of caudal fins. The most important factors explaining the intensity of coloration were the habitat type and the chlorophyll concentration in the sediment, followed by water turbidity; yellow fins were observed in natural habitats with low chlorophyll concentration and high water turbidity, while orange fins occurred in artificial habitats with high chlorophyll concentration and low turbidity. Furthermore, A. fasciatus in artificial habitats showed a higher somatic and a lower reproductive allotment with respect to natural habitats, according to the existing literature on the species. Furthermore, in closed artificial habitats, where the most intense reddish coloration of caudal fins was observed, a trade-off between somatic growth and the coloration intensity of a carotenoid-based sexual ornament has been observed; in these populations, intensity of caudal fin coloration was negatively related to the somatic allotment. Results of this study suggested how both the pigmentation of male's caudal fin and the life history strategies of the species are constrained by habitat characteristics. PMID- 29760885 TI - Areas of high conservation value at risk by plant invaders in Georgia under climate change. AB - Invasive alien plants (IAP) are a threat to biodiversity worldwide. Understanding and anticipating invasions allow for more efficient management. In this regard, predicting potential invasion risks by IAPs is essential to support conservation planning into areas of high conservation value (AHCV) such as sites exhibiting exceptional botanical richness, assemblage of rare, and threatened and/or endemic plant species. Here, we identified AHCV in Georgia, a country showing high plant richness, and assessed the susceptibility of these areas to colonization by IAPs under present and future climatic conditions. We used actual protected areas and areas of high plant endemism (identified using occurrences of 114 Georgian endemic plant species) as proxies for AHCV. Then, we assessed present and future potential distribution of 27 IAPs using species distribution models under four climate change scenarios and stacked single-species potential distribution into a consensus map representing IAPs richness. We evaluated present and future invasion risks in AHCV using IAPs richness as a metric of susceptibility. We show that the actual protected areas cover only 9.4% of the areas of high plant endemism in Georgia. IAPs are presently located at lower elevations around the large urban centers and in western Georgia. We predict a shift of IAPs toward eastern Georgia and higher altitudes and an increased susceptibility of AHCV to IAPs under future climate change. Our study provides a good baseline for decision makers and stakeholders on where and how resources should be invested in the most efficient way to protect Georgia's high plant richness from IAPs. PMID- 29760886 TI - Geographic variation in body size and its relationship with environmental gradients in the Oriental Garden Lizard, Calotes versicolor. AB - Patterns of geographic variation in body size are predicted to evolve as adaptations to local environmental gradients. However, many of these clinal patterns in body size, such as Bergmann's rule, are controversial and require further investigation into ectotherms such as reptiles on a regional scale. To examine the environmental variables (temperature, precipitation, topography and primary productivity) that shaped patterns of geographic variation in body size in the reptile Calotes versicolor, we sampled 180 adult specimens (91 males and 89 females) at 40 locations across the species range in China. The MANOVA results suggest significant sexual size dimorphism in C. versicolor (F23,124 = 11.32, p < .001). Our results showed that C. versicolor failed to fit the Bergmann's rule. We found that the most important predictors of variation in body size of C. versicolor differed for males and females, but mechanisms related to heat balance and water availability hypotheses were involved in both sexes. Temperature seasonality, precipitation of the driest month, precipitation seasonality, and precipitation of the driest quarter were the most important predictors of variation in body size in males, whereas mean precipitation of the warmest quarter, mean temperature of the wettest quarter, precipitation seasonality, and precipitation of the wettest month were most important for body size variation in females. The discrepancy between patterns of association between the sexes suggested that different selection pressures may be acting in males and females. PMID- 29760887 TI - Distribution of alien animal species richness in the Czech Republic. AB - Biogeographical barriers formed by natural forces over billions of years have been substantially disrupted by human activity, particularly in recent centuries. In response to these anthropogenic changes, global homogenization of biota is observed at an ever-increasing rate, causing environmental and economic losses as well as emerging health risks. Identifying factors underlying alien species richness is essential for prevention of future introductions and subsequent spread. In this study, we examined the effects of environmental and human-related factors on distribution of alien animal species richness in the Czech Republic (Central Europe). We compiled a set of maps showing the level of invasion of six categories of alien animal species in each of 628 grid cells (ca. 12.0 * 11.1 km) covering the Czech Republic. Relationships between alien species richness and 12 variables characterizing climatic conditions, topography, land cover, and human population size were calculated using the generalized least squares method. Species richness of all alien species, of invertebrates, and of terrestrial species showed the strongest positive relationship with mean annual temperature, while the number of black and grey (proposed prominent invaders) and aquatic species was most closely related to the presence of large rivers. Alien vertebrates showed a strong negative relationship with annual precipitation. The highest alien animal species richness was found in and near large population centers and in agricultural landscapes in warm and dry lowlands. The gateways for alien aquatic species are rather large rivers over sport fishing and aquaculture import. Compiled maps create a powerful visual communication tool, useful in development of programs to prevent future introductions. PMID- 29760888 TI - Adaptive phenotypic plasticity in a clonal invader. AB - Organisms featuring wide trait variability and occurring in a wide range of habitats, such as the ovoviviparous New Zealand freshwater snail Potamopyrgus antipodarum, are ideal models to study adaptation. Since the mid-19th century, P. antipodarum, characterized by extremely variable shell morphology, has successfully invaded aquatic areas on four continents. Because these obligately and wholly asexual invasive populations harbor low genetic diversity compared to mixed sexual/asexual populations in the native range, we hypothesized that (1) this phenotypic variation in the invasive range might be adaptive with respect to colonization of novel habitats, and (2) that at least some of the variation might be caused by phenotypic plasticity. We surveyed 425 snails from 21 localities across northwest Europe to attempt to disentangle genetic and environmental effects on shell morphology. We analyzed brood size as proxy for fitness and shell geometric morphometrics, while controlling for genetic background. Our survey revealed 10 SNP genotypes nested into two mtDNA haplotypes and indicated that mainly lineage drove variation in shell shape but not size. Physicochemical parameters affected both shell shape and size and the interaction of these traits with brood size. In particular, stronger stream flow rates were associated with larger shells. Our measurements of brood size suggested that relatively larger slender snails with relatively large apertures were better adapted to strong flow than counterparts with broader shells and relatively small apertures. In conclusion, the apparent potential to modify shell morphology plays likely a key role in the invasive success of P. antipodarum; the two main components of shell morphology, namely shape and size, being differentially controlled, the former mainly genetically and the latter predominantly by phenotypic plasticity. PMID- 29760889 TI - Measuring inferential importance of taxa using taxon influence indices. AB - Assessing the importance of different taxa for inferring evolutionary history is a critical, but underutilized, aspect of systematics. Quantifying the importance of all taxa within a dataset provides an empirical measurement that can establish a ranking of extant taxa for ecological study and/or quantify the relative importance of newly announced or redescribed specimens to enable the disentangling of novelty and inferential influence. Here, we illustrate the use of taxon influence indices through analysis of both molecular and morphological datasets, introducing a modified Bayesian approach to the taxon influence index that accounts for model and topological uncertainty. Quantification of taxon influence using the Bayesian approach produced clear rankings for both dataset types. Bayesian taxon rankings differed from maximum likelihood (ML)-derived rankings from a mitogenomic dataset, and the highest ranking taxa exhibited the largest interquartile range in influence estimate, suggesting variance in the estimate must be taken into account when the ranking of taxa is the feature of interest. Application of the Bayesian taxon influence index to a recent morphological analysis of the Tully Monster (Tullimonstrum) reveals that it exhibits consistently low inferential importance across two recent treatments of the taxon with alternative character codings. These results lend support to the idea that taxon influence indices may be robust to character coding and therefore effective for morphological analyses. These results underscore a need for the development of approaches to, and application of, taxon influence analyses both for the purpose of establishing robust rankings for future inquiry and for explicitly quantifying the importance of individual taxa. Quantifying the importance of individual taxa refocuses debates in morphological studies from questions of character choice/significance and taxon sampling to explicitly analytical techniques, and guides discussion of the context of new discoveries. PMID- 29760891 TI - High midday temperature stress has stronger effects on biomass than on photosynthesis: A mesocosm experiment on four tropical seagrass species. AB - The effect of repeated midday temperature stress on the photosynthetic performance and biomass production of seagrass was studied in a mesocosm setup with four common tropical species, including Thalassia hemprichii, Cymodocea serrulata, Enhalus acoroides, and Thalassodendron ciliatum. To mimic natural conditions during low tides, the plants were exposed to temperature spikes of different maximal temperatures, that is, ambient (29-33 degrees C), 34, 36, 40, and 45 degrees C, during three midday hours for seven consecutive days. At temperatures of up to 36 degrees C, all species could maintain full photosynthetic rates (measured as the electron transport rate, ETR) throughout the experiment without displaying any obvious photosynthetic stress responses (measured as declining maximal quantum yield, Fv/Fm). All species except T. ciliatum could also withstand 40 degrees C, and only at 45 degrees C did all species display significantly lower photosynthetic rates and declining Fv/Fm. Biomass estimation, however, revealed a different pattern, where significant losses of both above- and belowground seagrass biomass occurred in all species at both 40 and 45 degrees C (except for C. serrulata in the 40 degrees C treatment). Biomass losses were clearly higher in the shoots than in the belowground root rhizome complex. The findings indicate that, although tropical seagrasses presently can cope with high midday temperature stress, a few degrees increase in maximum daily temperature could cause significant losses in seagrass biomass and productivity. PMID- 29760890 TI - Diel movement of brown trout, Salmo trutta, is reduced in dense populations with high site fidelity. AB - The movement of individuals within preferred areas is reduced by a high availability of food and information about its distribution, while high number of competitors promotes increased movement. Experienced animals use information about social and physical environment to improve resources exploitation, tended to maintain positions within the preferred areas and reuse the environment that is often referred to as site fidelity. In this study, radio-telemetry was used to observe the movements of 98 adult brown trout, Salmo trutta, in oligotrophic streams with different population densities; to determine subpopulation site fidelity, 5,195 conspecifics from 14 subpopulations were individually tagged during spring and autumn. During a 7-year-long field study, we tested the hypothesis that brown trout individuals from subpopulations with high site fidelity would display lower movement. The hypothesis was supported, and reduced movement was further related to high subpopulation density in association with high slope indicating the physical environment-influenced movement. The probability of contact between individuals increased with subpopulation site fidelity and subpopulation density. No influence of food abundance on brown trout movement was found. Furthermore, increased body size predicted higher movement (and vice versa). The least movement occurred during the day and during the full moons. Our study tended to show that individuals reused preferred areas and needed less movement to exploit available resources. PMID- 29760892 TI - Effects of female preference intensity on the permissiveness of sexual trait polymorphisms. AB - Recent developments in sexual selection theory suggest that on their own, mate preferences can promote the maintenance of sexual trait diversity. However, how mate preferences constrain the permissiveness of sexual trait diversity in different environmental regimes remains an open question. Here, we examine how a range of mate choice parameters affect the permissiveness of sexual trait polymorphism under several selection regimes. We use the null model of sexual selection and show that environments with strong assortative mating significantly increase the permissiveness of sexual trait polymorphism. We show that for a given change in mate choice parameters, the permissiveness of polymorphism changes more in environments with strong natural selection on sexual traits than in environments with weak selection. Sets of nearly stable polymorphic populations with weak assortative mating are more likely to show accidental divergence in sexual traits than sets of populations with strong assortative mating. The permissiveness of sexual trait polymorphism critically depends upon particular combinations of natural selection and mate choice parameters. PMID- 29760893 TI - High levels of polyandry, but limited evidence for multiple paternity, in wild populations of the western rock lobster (Panulirus cygnus). AB - Polyandry, where multiple mating by females results in the temporal and spatial overlap of ejaculates from two or more males, is taxonomically widespread and occurs in varying frequencies within and among species. In decapods (crabs, lobsters, crayfish, and prawns), rates of polyandry are likely to be variable, but the extent to which patterns of multiple paternity reflect multiple mating, and thus are shaped by postmating processes that bias fertilization toward one or a subset of mated males, is unclear. Here, we use microsatellite markers to examine the frequency of multiple mating (the presence of spermatophores from two or more males) and patterns of paternity in wild populations of western rock lobster (Panulirus cygnus). Our data confirm that >45% of females had attached spermatophores arising from at least two males (i.e., confirming polyandry), but we found very limited evidence for multiple paternity; among 24 clutches sampled in this study, only two arose from fertilizations by two or more males. Single inferred paternal genotypes accounted for all remaining progeny genotypes in each clutch, including several instances when the mother had been shown to mate with two or more males. These findings highlight the need for further work to understand whether polyandry is adaptive and to uncover the mechanisms underlying postmating paternity biases in this system. PMID- 29760894 TI - Bioclimatic and altitudinal variables influence the potential distribution of canine parvovirus type 2 worldwide. AB - Canine parvovirus type 2 (CPV-2) is extremely contagious and causes high rate of morbidity to many wild carnivores. It has three variants (CPV-2a, CPV-2b, and CPV 2c) that are distributed worldwide with different frequencies and levels of genetic and antigenic variability. The disease poses a threat to the healthy survival and reproduction of wildlife. The research on the relationship between CPV-2 epidemic and environmental variables is lacking. To fill this research gap, we used maximum entropy (MaxEnt) approach with principal component analysis (PCA) to evaluate the relation between CPV-2 and environmental variables and to create a world risk map for this disease. According to the PCA results, 18 environmental variables were selected from 68 variables for subsequent analyses. MaxEnt showed that annual mean temperature, isothermality, altitude, November precipitation, maximum temperature of warmest month, and precipitation of warmest quarter were the six most important variables associated with CPV-2 distribution, with a total of 77.7% percent contribution. The risk of this disease between 18 degrees N and 47 degrees N was high, especially in the east of China and the United States. These results support further prediction of risk factors for this virus to help secure the health and sustainable survival of wild carnivores. PMID- 29760895 TI - Can species-specific prey responses to chemical cues explain prey susceptibility to predation? AB - The perception of danger represents an essential ability of prey for gaining an informational advantage over their natural enemies. Especially in complex environments or at night, animals strongly rely on chemoreception to avoid predators. The ability to recognize danger by chemical cues and subsequent adaptive responses to predation threats should generally increase prey survival. Recent findings suggest that European catfish (Silurus glanis) introduction induce changes in fish community and we tested whether the direction of change can be attributed to differences in chemical cue perception. We tested behavioral response to chemical cues using three species of freshwater fish common in European water: rudd (Scardinius erythrophthalmus), roach (Rutilus rutilus), and perch (Perca fluviatilis). Further, we conducted a prey selectivity experiment to evaluate the prey preferences of the European catfish. Roach exhibited the strongest reaction to chemical cues, rudd decreased use of refuge and perch did not alter any behavior in the experiment. These findings suggest that chemical cue perception might be behind community data change and we encourage collecting more community data of tested prey species before and after European catfish introduction to test the hypothesis. We conclude that used prey species can be used as a model species to verify whether chemical cue perception enhances prey survival. PMID- 29760896 TI - Shell morphology and color of the subtidal whelk Buccinum undatum exhibit fine scaled spatial patterns. AB - Geographical patterns in morphology can be the result of divergence among populations due to neutral or selective changes and/or phenotypic plasticity in response to different environments. Marine gastropods are ideal subjects on which to explore these patterns, by virtue of the remarkable intraspecific variation in life-history traits and morphology often observed across relatively small spatial scales. The ubiquitous N-Atlantic common whelk (Buccinum undatum) is well known for spatial variation in life-history traits and morphology. Previous studies on genetic population structure have revealed that it exhibits significant differentiation across geographic distances. Within Breidafjordur Bay, a large and shallow bay in W-Iceland, genetic differentiation was demonstrated between whelks from sites separated by just 20 km. Here, we extended our previous studies on the common whelk in Breidafjordur Bay by quantifying phenotypic variation in shell morphology and color throughout the Bay. We sought to test whether trait differentiation is dependent on geographic distance and/or environmental variability. Whelk in Breidafjordur Bay displayed fine-scale patterns of spatial variation in shape, thickness, and color diversity. Differentiation increased with increasing distance between populations, indicating that population connectivity is limited. Both shape and color varied along a gradient from the inner part of the bay in the east to the outer part in the west. Whelk shells in the innermost part of Breidafjordur Bay were thick with an elongate shell, round aperture, and low color diversity, whereas in the outer part of the bay the shells were thinner, rounder, with a more elongate aperture and richer color diversity. Significant site-specific difference in shell traits of the common whelk in correlation with environmental variables indicates the presence of local ecotypes and limited demographic connectivity. PMID- 29760897 TI - Bison body size and climate change. AB - The relationship between body size and temperature of mammals is poorly resolved, especially for large keystone species such as bison (Bison bison). Bison are well represented in the fossil record across North America, which provides an opportunity to relate body size to climate within a species. We measured the length of a leg bone (calcaneal tuber, DstL) in 849 specimens from 60 localities that were dated by stratigraphy and 14C decay. We estimated body mass (M) as M = (DstL/11.49)3. Average annual temperature was estimated from delta18O values in the ice cores from Greenland. Calcaneal tuber length of Bison declined over the last 40,000 years, that is, average body mass was 37% larger (910 +/- 50 kg) than today (665 +/- 21 kg). Average annual temperature has warmed by 6 degrees C since the Last Glacial Maximum (~24-18 kya) and is predicted to further increase by 4 degrees C by the end of the 21st century. If body size continues to linearly respond to global temperature, Bison body mass will likely decline by an additional 46%, to 357 +/- 54 kg, with an increase of 4 degrees C globally. The rate of mass loss is 41 +/- 10 kg per degrees C increase in global temperature. Changes in body size of Bison may be a result of migration, disease, or human harvest but those effects are likely to be local and short-term and not likely to persist over the long time scale of the fossil record. The strong correspondence between body size of bison and air temperature is more likely the result of persistent effects on the ability to grow and the consequences of sustaining a large body mass in a warming environment. Continuing rises in global temperature will likely depress body sizes of bison, and perhaps other large grazers, without human intervention. PMID- 29760898 TI - Difference in plasticity of resting metabolic rate - the proximate explanation to different niche breadth in sympatric Ficedula flycatchers. AB - Variation in relative fitness of competing recently formed species across heterogeneous environments promotes coexistence. However, the physiological traits mediating such variation in relative fitness have rarely been identified. Resting metabolic rate (RMR) is tightly associated with life history strategies, thermoregulation, diet use, and inhabited latitude and could therefore moderate differences in fitness responses to fluctuations in local environments, particularly when species have adapted to different climates in allopatry. We work in a long-term study of collared (Ficedula albicollis) and pied flycatchers (Ficedula hypoleuca) in a recent hybrid zone located on the Swedish island of Oland in the Baltic Sea. Here, we explore whether differences in RMR match changes in relative performance of growing flycatcher nestlings across environmental conditions using an experimental approach. The fitness of pied flycatchers has previously been shown to be less sensitive to the mismatch between the peak in food abundance and nestling growth among late breeders. Here, we find that pied flycatcher nestlings have lower RMR in response to higher ambient temperatures (associated with low food availability). We also find that experimentally relaxed nestling competition is associated with an increased RMR in this species. In contrast, collared flycatcher nestlings did not vary their RMR in response to these environmental factors. Our results suggest that a more flexible nestling RMR in pied flycatchers is responsible for the better adaptation of pied flycatchers to the typical seasonal changes in food availability experienced in this hybrid zone. Generally, subtle physiological differences that have evolved when species were in allopatry may play an important role to patterns of competition, coexistence, or displacements between closely related species in secondary contact. PMID- 29760899 TI - Plant community responses to increased precipitation and belowground litter addition: Evidence from a 5-year semiarid grassland experiment. AB - Global climate change is predicted to stimulate primary production and consequently increases litter inputs. Changing precipitation regimes together with enhanced litter inputs may affect plant community composition and structure, with consequent influence on diversity and ecosystem functioning. Responses of plant community to increased precipitation and belowground litter addition were examined lasting 5 years in a semiarid temperate grassland of northeastern China. Increased precipitation enhanced community species richness and abundance of annuals by 16.8% and 44%, but litter addition suppressed them by 25% and 54.5% after 5 years, respectively. During the study period, perennial rhizome grasses and forbs had consistent negative relationship under ambient plots, whereas positive relationship between the two functional groups was found under litter addition plots after 5 years. In addition, increased precipitation and litter addition showed significant interaction on community composition, because litter addition significantly increased biomass and abundance of rhizome grasses under increased precipitation plots but had no effect under ambient precipitation levels. Our findings emphasize the importance of water availability in modulating the responses of plants community to potentially enhanced litter inputs in the semiarid temperate grassland. PMID- 29760900 TI - Personality and performance are affected by age and early life parameters in a small primate. AB - A whole suite of parameters is likely to influence the behavior and performance of individuals as adults, including correlations between phenotypic traits or an individual's developmental context. Here, we ask the question whether behavior and physical performance traits are correlated and how early life parameters such as birth weight, litter size, and growth can influence these traits as measured during adulthood. We studied 486 captive gray mouse lemurs (Microcebus murinus) and measured two behavioral traits and two performance traits potentially involved in two functions: exploration behavior with pull strength and agitation score with bite force. We checked for the existence of behavioral consistency in behaviors and explored correlations between behavior, performance, morphology. We analyzed the effect of birth weight, growth, and litter size, while controlling for age, sex, and body weight. Behavior and performance were not correlated with one another, but were both influenced by age. Growth rate had a positive effect on adult morphology, and birth weight significantly affected emergence latency and bite force. Grip strength was not directly affected by early life traits, but bite performance and exploration behavior were impacted by birth weight. This study shows how early life parameters impact personality and performance. PMID- 29760901 TI - Survival of the feces: Does a nematode lungworm adaptively manipulate the behavior of its cane toad host? AB - Parasites can enhance their fitness by modifying the behavior of their hosts in ways that increase rates of production and transmission of parasite larvae. We used an antihelminthic drug to experimentally alter infections of lungworms (Rhabdias pseudosphaerocephala) in cane toads (Rhinella marina). We then compared subsequent behaviors of dewormed toads versus toads that retained infections. Both in the laboratory and in the field, the presence of parasites induced hosts to select higher body temperatures (thereby increasing rates of lungworm egg production), to defecate in moister sites, and to produce feces with higher moisture content (thereby enhancing survival of larvae shed in feces). Because those behavioral modifications enhance rather than decrease parasite fitness, they are likely to have arisen as adaptive manipulations of host behavior rather than as host adaptations to combat infection or as nonadaptive consequences of infection on host physiology. However, the mechanisms by which lungworms alter cane toad thermal preference and defecation are not known. Although many examples of host manipulation by parasites involve intermediate hosts facilitating their own demise, our findings indicate that manipulation of definitive hosts can be as subtle as when and where to defecate. PMID- 29760902 TI - Exploring the evolution of multicellularity in Saccharomyces cerevisiae under bacteria environment: An experimental phylogenetics approach. AB - There have been over 25 independent unicellular to multicellular evolutionary transitions, which have been transformational in the complexity of life. All of these transitions likely occurred in communities numerically dominated by unicellular organisms, mostly bacteria. Hence, it is reasonable to expect that bacteria were involved in generating the ecological conditions that promoted the stability and proliferation of the first multicellular forms as protective units. In this study, we addressed this problem by analyzing the occurrence of multicellularity in an experimental phylogeny of yeasts (Sacharomyces cerevisiae) a model organism that is unicellular but can generate multicellular clusters under some conditions. We exposed a single ancestral population to periodic divergences, coevolving with a cocktail of environmental bacteria that were inoculated to the environment of the ancestor, and compared to a control (no bacteria). We quantified culturable microorganisms to the level of genera, finding up to 20 taxa (all bacteria) that competed with the yeasts during diversification. After 600 generations of coevolution, the yeasts produced two types of multicellular clusters: clonal and aggregative. Whereas clonal clusters were present in both treatments, aggregative clusters were only present under the bacteria treatment and showed significant phylogenetic signal. However, clonal clusters showed different properties if bacteria were present as follows: They were more abundant and significantly smaller than in the control. These results indicate that bacteria are important modulators of the occurrence of multicellularity, providing support to the idea that they generated the ecological conditions-promoting multicellularity. PMID- 29760903 TI - Function-related Drivers of Skull Morphometric Variation and Sexual Size Dimorphism in a Subterranean Rodent, Plateau Zokor (Eospalax baileyi). AB - Sexual dimorphism is prevalent in most living organisms. The difference in size between sexes of a given species is generally known as sexual size dimorphism (SSD). The magnitude of the SSD is determined by Rensch's rule where size dimorphism increases with increasing body size when the male is the larger sex and decreases with increasing average body size when the female is the larger sex. The unique underground environment that zokors (Eospalax baileyi) live under in the severe habitat of the Qinghai-Tibetan Plateau (QTP) could create SSD selection pressures that may or may not be supported by Rensch's rule, making this scientific question worthy of investigation. In this study, we investigated the individual variation between sexes in body size and SSD of plateau zokors using measurements of 19 morphological traits. We also investigated the evolutionary mechanisms underlying SSD in plateau zokors. Moreover, we applied Rensch's rule to all extant zokor species. Our results showed male-biased SSD in plateau zokors: The body- and head-related measurements were greater in males than in females. Linear regression analysis between body length, body weight, and carcass weight showed significant relationships with some traits such as skull length, lower incisor length, and tympanic bulla width, which might support our prediction that males have faster growth rates than females. Further, the SSD pattern corroborated the assumption of Rensch's rule in plateau zokors but not in the other zokor species. Our findings suggest that the natural underground habitat and behavioral differences between sexes can generate selection pressures on male traits and contribute to the evolution of SSD in plateau zokors. PMID- 29760904 TI - Low acclimation capacity of narrow-ranging thermal specialists exposes susceptibility to global climate change. AB - Thermal acclimation is hypothesized to offer a selective advantage in seasonal habitats and may underlie disparities in geographic range size among closely related species with similar ecologies. Understanding this relationship is also critical for identifying species that are more sensitive to warming climates. Here, we study North American plethodontid salamanders to investigate whether acclimation ability is associated with species' latitudinal extents and the thermal range of the environments they inhabit. We quantified variation in thermal physiology by measuring standard metabolic rate (SMR) at different test and acclimation temperatures for 16 species of salamanders with varying latitudinal extents. A phylogenetically-controlled Markov chain Monte Carlo generalized linear mixed model (MCMCglmm) was then employed to determine whether there are differences in SMR between wide- and narrow-ranging species at different acclimation temperatures. In addition, we tested for a relationship between the acclimation ability of species and the environmental temperature ranges they inhabit. Further, we investigated if there is a trade-off between critical thermal maximum (CTMax) and thermal acclimation ability. MCMCglmm results show a significant difference in acclimation ability between wide and narrow-ranging temperate salamanders. Salamanders with wide latitudinal distributions maintain or slightly increase SMR when subjected to higher test and acclimation temperatures, whereas several narrow-ranging species show significant metabolic depression. We also found significant, positive relationships between acclimation ability and environmental thermal range, and between acclimation ability and CTMax. Wide-ranging salamander species exhibit a greater capacity for thermal acclimation than narrow-ranging species, suggesting that selection for acclimation ability may have been a key factor enabling geographic expansion into areas with greater thermal variability. Further, given that narrow-ranging salamanders are found to have both poor acclimation ability and lower tolerance to warm temperatures, they are likely to be more susceptible to environmental warming associated with anthropogenic climate change. PMID- 29760906 TI - ShapeRotator: An R tool for standardized rigid rotations of articulated three dimensional structures with application for geometric morphometrics. AB - The quantification of complex morphological patterns typically involves comprehensive shape and size analyses, usually obtained by gathering morphological data from all the structures that capture the phenotypic diversity of an organism or object. Articulated structures are a critical component of overall phenotypic diversity, but data gathered from these structures are difficult to incorporate into modern analyses because of the complexities associated with jointly quantifying 3D shape in multiple structures. While there are existing methods for analyzing shape variation in articulated structures in two-dimensional (2D) space, these methods do not work in 3D, a rapidly growing area of capability and research. Here, we describe a simple geometric rigid rotation approach that removes the effect of random translation and rotation, enabling the morphological analysis of 3D articulated structures. Our method is based on Cartesian coordinates in 3D space, so it can be applied to any morphometric problem that also uses 3D coordinates (e.g., spherical harmonics). We demonstrate the method by applying it to a landmark-based dataset for analyzing shape variation using geometric morphometrics. We have developed an R tool (ShapeRotator) so that the method can be easily implemented in the commonly used R package geomorph and MorphoJ software. This method will be a valuable tool for 3D morphological analyses in articulated structures by allowing an exhaustive examination of shape and size diversity. PMID- 29760905 TI - Roads to isolation: Similar genomic history patterns in two species of freshwater crabs with contrasting environmental tolerances and range sizes. AB - Freshwater species often show high levels of endemism and risk of extinction owing to their limited dispersal abilities. This is exemplified by the stenotopic freshwater crab, Johora singaporensis which is one of the world's 100 most threatened species, and currently inhabits less than 0.01 km2 of five low order hill streams within the highly urbanized island city-state of Singapore. We compared populations of J. singaporensis with that of the non-threatened, widespread, abundant, and eurytopic freshwater crab, Parathelphusa maculata, and found surprisingly high congruence between their population genomic histories. Based on 2,617 and 2,470 genome-wide SNPs mined via the double-digest restriction associated DNA sequencing method for ~90 individuals of J. singaporensis and P. maculata, respectively, the populations are strongly isolated (FST = 0.146 0.371), have low genetic diversity for both species (also for COI), and show signatures of recent genetic bottlenecks. The most genetically isolated populations for both species are separated from other populations by one of the oldest roads in Singapore. These results suggest that anthropogenic developments may have impacted stream-dependent species in a uniform manner, regardless of ubiquity, habitat preference, or dispersal modes of the species. While signs of inbreeding were not detected for the critically endangered species, the genetic distinctiveness and low diversity of the populations call for genetic rescue and connecting corridors between the remaining fragments of the natural habitat. PMID- 29760907 TI - Assessing the impacts of imperfect detection on estimates of diversity and community structure through multispecies occupancy modeling. AB - Detecting all species in a given survey is challenging, regardless of sampling effort. This issue, more commonly known as imperfect detection, can have negative impacts on data quality and interpretation, most notably leading to false absences for rare or difficult-to-detect species. It is important that this issue be addressed, as estimates of species richness are critical to many areas of ecological research and management. In this study, we set out to determine the impacts of imperfect detection, and decisions about thresholds for inclusion in occupancy, on estimates of species richness and community structure. We collected data from a stream fish assemblage in Algonquin Provincial Park to be used as a representation of ecological communities. We then used multispecies occupancy modeling to estimate species-specific occurrence probabilities while accounting for imperfect detection, thus creating a more informed dataset. This dataset was then compared to the original to see where differences occurred. In our analyses, we demonstrated that imperfect detection can lead to large changes in estimates of species richness at the site level and summarized differences in the community structure and sampling locations, represented through correspondence analyses. PMID- 29760908 TI - Do the fluorescent red eyes of the marine fish Tripterygion delaisi stand out? In situ and in vivo measurements at two depths. AB - Since the discovery of red fluorescence in fish, much effort has been invested to elucidate its potential functions, one of them being signaling. This implies that the combination of red fluorescence and reflection should generate a visible contrast against the background. Here, we present in vivo iris radiance measurements of Tripterygion delaisi under natural light conditions at 5 and 20 m depth. We also measured substrate radiance of shaded and exposed foraging sites at those depths. To assess the visual contrast of the red iris against these substrates, we used the receptor noise model for chromatic contrasts and Michelson contrast for achromatic calculations. At 20 m depth, T. delaisi iris radiance generated strong achromatic contrasts against substrate radiance, regardless of exposure, and despite substrate fluorescence. Given that downwelling light above 600 nm is negligible at this depth, we can attribute this effect to iris fluorescence. Contrasts were weaker in 5 m. Yet, the pooled radiance caused by red reflection and fluorescence still exceeded substrate radiance for all substrates under shaded conditions and all but Jania rubens and Padina pavonia under exposed conditions. Due to the negative effects of anesthesia on iris fluorescence, these estimates are conservative. We conclude that the requirements to create visual brightness contrasts are fulfilled for a wide range of conditions in the natural environment of T. delaisi. PMID- 29760909 TI - Changes in intestinal microbiota across an altitudinal gradient in the lizard Phrynocephalus vlangalii. AB - High altitude is an important driving force in animal evolution. However, the effect of altitude on gut microbial communities in reptiles has not been examined in detail. Here, we investigated the intestinal microbiota of three populations of the lizard Phrynocephalus vlangalii living at different altitudes using 16S rRNA gene sequencing. Bacteroidetes, Firmicutes, and Proteobacteria were the most abundant phyla. Bacteroides, Odoribacter, and Parabacteroides were the most abundant genera. Significant differences in the intestinal microbiota composition were found among the three populations from different altitudes. The proportions of Verrucomicrobia and Akkermansia decreased, whereas Bacteroides increased significantly with altitude. Greater abundance of Bacteroides at higher altitude led to the fractional increase in the phylum Bacteroides relative to other phyla. Hypoxia may be the main factor that caused intestinal microbiota variation in P. vlangalii along the altitude gradient. Overall, our study suggested that the community composition and structure of intestinal microbiota of the lizard P. vlangalii varied along altitudes, and such differences likely play a certain role in highland adaptation. Our findings warrant a further study that would determine whether ambient and body temperatures play a key role in the modulation of intestinal microbiota in reptiles. PMID- 29760911 TI - Strong associations between plant genotypes and bacterial communities in a natural salt marsh. AB - Although microbial communities have been shown to vary among plant genotypes in a number of experiments in terrestrial ecosystems, relatively little is known about this relationship under natural conditions and outside of select model systems. We reasoned that a salt marsh ecosystem, which is characterized by twice-daily flooding by tides, would serve as a particularly conservative test of the strength of plant-microbial associations, given the high degree of abiotic regulation of microbial community assembly resulting from alternating periods of inundation and exposure. Within a salt marsh in the northeastern United States, we characterized genotypes of the foundational plant Spartina alterniflora using microsatellite markers, and bacterial metagenomes within marsh soil based on pyrosequencing. We found significant differences in bacterial community composition and diversity between bulk and rhizosphere soil, and that the structure of rhizosphere communities varied depending on the growth form of, and genetic variation within, the foundational plant S. alterniflora. Our results indicate that there are strong plant-microbial associations within a natural salt marsh, thereby contributing to a growing body of evidence for a relationship between plant genotypes and microbial communities from terrestrial ecosystems and suggest that principles of community genetics apply to this wetland type. PMID- 29760910 TI - The influence of diet and environment on the gut microbial community of field crickets. AB - The extent to which diet and environment influence gut community membership (presence or absence of taxa) and structure (individual taxon abundance) is the subject of growing interest in microbiome research. Here, we examined the gut bacterial communities of three cricket groups: (1) wild caught field crickets, (2) laboratory-reared crickets fed cat chow, and (3) laboratory-reared crickets fed chemically defined diets. We found that both environment and diet greatly altered the structure of the gut bacterial community. Wild crickets had greater gut microbial diversity and higher Firmicutes to Bacteroidetes ratios, in contrast to laboratory-reared crickets. Predictive metagenomes revealed that laboratory-reared crickets were significantly enriched in amino acid degradation pathways, while wild crickets had a higher relative abundance of peptidases that would aid in amino acid release. Although wild and laboratory animals differ greatly in their bacterial communities, we show that the community proportional membership remains stable from Phylum to Family taxonomic levels regardless of differences in environment and diet, suggesting that endogenous factors, such as host genetics, have greater control in shaping gut community membership. PMID- 29760912 TI - Continuous increase of vancomycin resistance in enterococci causing nosocomial infections in Germany - 10 years of surveillance. AB - Background: Enterococci are frequent pathogens causing nosocomial infections in Germany. Infections due to strains with vancomycin resistance are high when compared with other European states. Therefore, the study aimed to describe the recent progression of nosocomial infections due to vancomycin-resistant enterococci (VRE) in Germany. Methods: We analyzed data from two components of the German national nosocomial infection surveillance system for the period 2007 2016. For primary bloodstream infections (BSIs) and urinary tract infections (UTIs) we used data from intensive care units and for surgical site infections (SSIs) data from surgical departments. In a sensitivity analysis, we considered only data from participants that participated continuously from 2007 to 2016 ("core group"). We calculated proportions of VRE among all nosocomial enterococcal infections with 95% confidence intervals (95% CIs) and trends over time. A multivariable logistic regression was used to compare occurrence of VRE proportions among German federal states. Results: Enterococcal infections from 857 ICUs and 1119 surgical departments were analyzed. On ICUs, the proportion of vancomycin resistance in enterococci causing nosocomial infections significantly increased for BSIs from 5.9 to 16.7% and for UTIs from 2.9 to 9.9%; for surgical site infections, the proportion of VRE increased from 0.9 to 5.2% (P < 0.001 for all). In the core group, the increase of VRE was more pronounced in ICUs (BSIs: 5.5 to 21.6%; UTIs: 2 to 11.2%) but was not seen in surgical departments (SSIs: 1.5 to 2.8%). Compared with the most populous German federal state North Rhine Westphalia, enterococcal infections in Hesse (Odds Ratio (OR) 2.3, 95% CI 1.7 3.1), Saxony (OR 2.5, 95% CI 1.8-3.5) and Thuringia (OR 1.9, 95% CI 1.4-2.6) were more likely to be caused by vancomycin-resistant strains. Conclusion: In Germany, the proportion of VRE in nosocomial infection due to enterococci is still increasing. It remains unclear, why a large variation in the proportion of VRE exists between German federal states. PMID- 29760913 TI - Evaluation of a modified Cheatham-Platinum stent for the treatment of aortic coarctation by finite element modelling. AB - Objectives: Stent implantation for the treatment of aortic coarctation has become a standard approach for the management of older children and adults. Criteria for optimal stent design and construction remain undefined. This study used computational modelling to compare the performance of two generations of the Cheatham-Platinum stent (NuMED, Hopkinton, NY, USA) deployed in aortic coarctation using finite element analysis. Design: Three-dimensional models of both stents, reverse engineered from microCT scans, were implanted in the aortic model of one representative patient. They were virtually expanded in the vessel with a 16 mm balloon and a pressure of 2 atm. Results: The conventional stent foreshortened to 96.5% of its initial length, whereas the new stent to 99.2% of its initial length. Diameters in 15 slices across the conventional stent were 11.6-15 mm (median 14.2 mm) and slightly higher across the new stent: 10.7-15.3 mm (median 14.5 mm) (p= 0.021). Apposition to the vessel wall was similar: conventional stent 31.1% and new stent 28.6% of total stent area. Conclusions: The new design Cheatham-Platinum stent showed similar deployment results compared to the conventional design. The new stent design showed slightly higher expansion, using the same delivery balloon. Patient-specific computational models can be used for virtual implantation of new aortic stents and promise to inform subsequent in vivo trials. PMID- 29760915 TI - Onsite production of medical air: is purity a problem? AB - Introduction: Medical air (MA) is widely used in hospitals, often manufactured onsite by compressing external ambient air and supplied through a local network piping system. Onsite production gives rise to a risk of impurities that are governed by the same pharmacopoeia purity standards applicable to commercially produced MA. The question to be addressed in this paper is how to assess if a lack of purity poses a medical problem? Methods: The MA produced onsite at a major Canadian hospital was monitored for carbon dioxide (CO2) and other impurity gases at high frequency (one per minute) over a two-month period. Results: The average CO2 concentration was 255 ppm. The United States Pharmacopeia (USP) threshold of 500 ppm was exceeded during 1% of the total study period, and the average while exceeding the threshold was 526 ppm. The maximum concentration was 634 ppm. Discussion and conclusion: To our knowledge, there is only one study that evaluated the effects suffered by respiratory patients of elevated nitric oxide in MA; thus, it is not clear what are the medical bases for the thresholds stated in the USP. To perform a Quality Risk Assessment, the threshold and the time above threshold should be considered in determining the frequency of sampling and analysis, and operating methods required to ensure the quality of MA entering the pipeline meets the clinical, regulatory, and patient safety standards. In conclusion, because the USP does not provide impurity thresholds for specific patients nor time above thresholds, there is a need for the medical community to determine these quantities before it can be known if the purity of MA is a problem. PMID- 29760916 TI - Treatment outcome reporting in anorexia nervosa: time for a paradigm shift? PMID- 29760914 TI - Gas stunning with CO2 affected meat color, lipid peroxidation, oxidative stress, and gene expression of mitogen-activated protein kinases, glutathione S transferases, and Cu/Zn-superoxide dismutase in the skeletal muscles of broilers. AB - Background: Meat color and lipid peroxidation are important traits related to meat quality. CO2 concentration is a critical factor that can affect meat quality in the commercial use of gas stunning (GS). However, the effect and mechanism of CO2 stunning on meat color and lipid peroxidation during long-term storage remain poorly studied. We aimed to study the effects of GS methods, especially CO2 concentration, on meat color and meat lipid peroxidation in broilers during long term storage at 4 degrees C and to explore the potential mechanism of meat color change via lipid peroxidation and the inner lipid peroxide scavenging system. Methods: Eighteen broilers were sacrificed after exposure to one of the following gas mixtures for 90 s: 40% CO2 + 21% O2 + 39% N2 (G40%), 79% CO2 + 21% O2 (G79%), or no stunning (0% CO2, control). Meat color, serum variables, enzyme activities, and the gene expression of mitogen-activated protein kinase (MAPK), nuclear factor-erythroid 2-related factor 2 (Nrf2), glutathione S-transferase (GST) and superoxide dismutase (SOD) were determined. Results: The concentrations of serum triiodothyronine (T3, P = 0.03) and the ratio of serum free triiodothyronine/free thyroxine (FT3/FT4, P < 0.01) were decreased, whereas levels of serum cortisol (P < 0.01) were increased in the 40% CO2 group compared with the control group. Additionally, the thiobarbituric acid-reactive substances (TBARS) 3 d (P < 0.01) and TBARS 6 d (P = 0.01) in breast meat and the TBARS 3 d in thigh meat (P < 0.01) were increased in the 40% CO2 group compared with the control group. Serum T3 was negatively correlated with TBARS6 d both in the breast and thigh meat (r = - 0.63, P < 0.01 and r = - 0.47, P = 0.05 respectively). T3/T4 was negatively correlated with TBARS6 d in the breast meat and in the thigh meat (r = - 0.57, P = 0.01; and r = - 0.53, P = 0.03 respectively). Compared with the control group, Lightness (L*) 1 d (P = 0.03) and L*9 d (P < 0.01) were increased, whereas total chromatic aberration (E*) 1 d (P = 0.05) and E*3 d (P < 0.01) were decreased in the breast meat of both the G40% and G79% groups. The values of yellowness (b*) 3 d (P = 0.01), b*6 d (P < 0.01) and E*6 d (P < 0.01) in the thigh meat were lower in both the G40% and G79% groups than in the control group. In the breast muscle, the mRNA levels of c-Jun N-terminal kinase 2 (JNK2, P = 0.03), GSTT1 (P = 0.04), and SOD1 (P = 0.05) were decreased, and the mRNA levels of JNK1 (P = 0.07), Nrf2 (P = 0.09), and GSTA3 (P = 0.06) were slightly lower in both the G40% and G79% groups compared with the control group. However, among these genes, only the mRNA level of JNK1 was decreased in the G40% group compared with the control group and the G79% group (P = 0.03) in the thigh muscle. Conclusions: Compared with the control group, meat color quality in the breast meat was decreased, and the expression of genes in the MAPK/Nrf2/ARE (antioxidant responsive element) antioxidant pathway in breast muscle was partly suppressed by GS of both 40% and 79% CO2. However, oxidative stress and meat lipid peroxidation during storage were aggravated by GS with 40% CO2 compared to GS with 79% CO2 and no GS. PMID- 29760917 TI - Factors associated with glycemic status and ability to adapt to changing demands in people with and without type 2 diabetes mellitus: A cross-sectional study. AB - Objectives: Type 2 diabetes mellitus studies focus on metabolic indicators and different self-reported lifestyle or care behaviors. Self-reported instruments involve conscious process therefore responses might not reflect reality. Meanwhile implicit responses involve automatic, unconscious processes underlying social judgments and behavior. No studies have explored the combined influence of both metabolic indicators and implicit responses on lifestyle practices in type 2 diabetes mellitus patients. The purpose was to investigate the explained variance of socio-demographic, metabolic, anthropometric, clinical, psychosocial, cognitive, and lifestyle variables on glycemic status and on the ability to adapt to changing demands in people with and without type 2 diabetes mellitus in Monterrey, Mexico. Methods: Adults with (n = 30, mean age 46.90 years old, 33.33% male) and without (n = 32, mean age: 41.69 years old, 21.87% male) type 2 diabetes mellitus were studied. Glycemic status was assessed using Bio-Rad D-10 Hemoglobin A1c Program, which uses ion-exchange high-performance chromatography. Stroop 2 test was used to assess the ability to changing demands. Results: In participants with type 2 diabetes mellitus, less years of education, negative self-actualization, and higher levels of cholesterol and triglycerides explained more than 50% of the variance in glycemic status. In participants without type 2 diabetes mellitus, the variance (38.7%) was explained by total cholesterol, metabolic syndrome, high-density lipoprotein, and self-actualization scores; the latter in opposite direction. The ability to adapt to changing demands was explained by total cholesterol, malondialdehyde, insulin resistance, and triglycerides. In participants without type 2 diabetes mellitus, the contributing variables were metabolic syndrome and nutrition scores. Conclusion: Results showed significant effect on at least one of the following variables (socio demographic, metabolic, or lifestyle subscale) on glycemic status in people with and without type 2 diabetes mellitus. The ability to adapt to changing demands was explained by metabolic variables but only in participants without type 2 diabetes mellitus. Preference for unhealthy behaviors (implicit or automatic responses) outweighs healthy lifestyle practices in people with and without type 2 diabetes mellitus. PMID- 29760918 TI - Patient reported adverse events among epileptic patients taking antiepileptic drugs. AB - Objective: The aim of this study was to assess patient reported adverse events and associated factors among epileptic patients taking antiepileptic drugs on follow-up at University of Gondar Referral Hospital. Methods: Cross-sectional study was done on 354 adult epileptic patients. Patients who were on antiepileptic drugs for epilepsy treatment for less than a year, those who were below 18 years old, patients with incomplete information on the chart and those who were involuntary or uncooperative were excluded from the study. Data were entered in to SPSS version 20.0 for analysis. Bivariate and multivariate binary logistic regression analysis was done to see factors associated with antiepileptic drugs adverse effect. Level of statistical significance was declared at p <= 0.05. Result: Generalized tonic clonic seizure was the most common (86.2%) type of epilepsy. A total of 79 adverse events were reported. The most frequently encountered adverse events were fatigue (5.08%), gastrointestinal disturbance (4.24%) and sedation/depression (4.24%). Adverse drug effect of antiepileptic drugs was significantly associated with illiterate educational status, increased number of antiepileptic drugs, no seizure during last follow-up and last year, and 1-5 seizures for the last year. Conclusion: About one-sixth of epileptic patients reported adverse drug effects. Adverse drug effects were more commonly seen in patients with low educational status, increased number of antiepileptic drugs, absence of seizure during last follow-up and last year, and 1-5 seizures for the last year. So clinicians should give emphasis for patients with these characteristics to counsel on how to minimize or prevent adverse drug events from antiepileptic drugs or giving reassurance about it if it is minor. PMID- 29760919 TI - Anatomy of the posterior and middle ethmoidal arteries via computed tomography. AB - Objective: The aim of this study is to investigate the anatomy of the posterior and middle ethmoidal arteries from the viewpoint of an endoscopic sinus surgeon. Methods: Based on 100 computed tomography images, the anatomical position of the posterior ethmoidal artery in relation to the posterior ethmoid cells was classified into five types. The presence of the posterior and middle ethmoidal arteries, their distance from the skull base, and their length exposed in the ethmoid cells were measured. The association of patients' age and sex, presence of the middle ethmoidal artery, and anatomical type of the posterior ethmoidal artery with the posterior ethmoidal artery distance from the ethmoid roof was analyzed. Results: The posterior ethmoidal artery's position, relative to the ethmoid cell walls, was most often near the first wall, anterior to the optic canal (92.5%). The posterior ethmoidal artery's distance from the skull base ranged from 0 to 6.4 mm (mean: 1.2 mm). Older age, longer length of the posterior ethmoidal artery exposed in the ethmoid cells, and absence of the middle ethmoidal artery were positively associated with a longer posterior ethmoidal artery distance from the skull base. Conclusion: Attention should be paid to the posterior and middle ethmoidal arteries. PMID- 29760921 TI - Giant peritoneal loose body in a patient with end-stage renal disease. AB - A 72-year-old male with end-stage renal disease underwent a computed tomography scan to assess renal function. An oval-shaped mass, 50 mm * 60 mm in size, was discovered incidentally in his recto-vesical pouch. Because it was suspected to be a teratoma, which could be an impediment for future renal transplantation, surgery was performed. It revealed a giant peritoneal loose body, a rare entity, that has not been reported before in patients with renal chronic insufficiency. PMID- 29760920 TI - Serum lipidomics of bovine paratuberculosis: Disruption of choline-containing glycerophospholipids and sphingolipids. AB - Objectives: Bovine paratuberculosis is a devastating infection with Mycobacterium avium subspecies paratuberculosis that ultimately results in death from malnutrition. While the infection is characterized by a long (2-4 years) subclinical phase with immune activation, ultimately host defense mechanisms fail and the bacteria spread from the small intestine to other organs. Since both the gastrointestinal tract and liver are essential for the biosynthesis of structural glycerophospholipids, we investigated the circulating levels of these lipids in field infections and experimentally infected cattle. Methods: Serum lipidomics of control and M. avium subspecies paratuberculosis-infected cattle were performed utilizing high-resolution mass spectrometry. Results: In M. avium subspecies paratuberculosis-positive cattle, demonstrating clinical signs, we monitored large decreases in the levels of circulating phosphocholine-containing lipids. These included phosphatidylcholines, choline plasmalogens, and sphingomyelins. Next, we monitored the time course of these lipid alterations in experimentally infected calves and found that altered lipid levels were only detected in cattle with clinical signs of infection. Conclusions: Our data indicate that altered availability of choline-containing lipids occurs late in the disease process and is most likely a result of malnutrition and altered biosynthetic capacities of the liver and gastrointestinal tract. Alterations in the bioavailability of these critical structural lipids presumably contributes to the demise of M. avium subspecies paratuberculosis-infected cattle. In light of increasing concern that M. avium subspecies paratuberculosis may be a zoonotic bacterium that contributes to the development of Crohn's disease and multiple sclerosis, our data also have human clinical relevance. PMID- 29760922 TI - Long-term results of intravitreal bevacizumab and dexamethasone for the treatment of punctate inner choroidopathy associated with choroidal neovascularization: A case series. AB - Introduction: To present a case series of three female patients with punctate inner choroidopathy. We report the outcomes after an essentially long follow-up period of up to 14 years and provide evidence of the effectiveness of intravitreal injections of bevacizumab and dexamethasone 0.7 mg in punctate inner choroidopathy patients with choroidal neovascular membrane formation. Case series presentation: This is a retrospective case series of three female patients with punctate inner choroidopathy who were treated with intravitreal injections anti vascular endothelial growth factor agent (bevacizumab, 1.25 mg/0.05 mL). Two patients also received intravitreal dexamethasone 0.7 mg. Once a choroidal neovascular membrane developed, the outcome was poor with a best-corrected visual acuity of 6/60 or counting fingers in the affected eyes. The patients were followed up for 5, 14 and 8 years. Conclusion: The use of dexamethasone 0.7 mg in punctate inner choroidopathy yielded encouraging results and long periods of stability. When choroidal neovascular membrane complicates the primary disease, the prognosis is unfavourable, especially if the macula integrity has already been considerably affected. On the contrary, aggressive early therapy and continued monthly monitoring can prevent severe fibrosis, as showed in previous reports. Further larger-scale studies are needed to evaluate the efficacy of intravitreal dexamethasone 0.7 mg and bevacizumab as an alternative treatment in non-infectious uveitis. PMID- 29760923 TI - Finger drop sign-Characteristic pattern of distal weakness in Guillain-Barre Syndrome: A case report and review of the literature. AB - Guillain-Barre Syndrome is an acquired acute autoimmune polyradiculoneuropathy that commonly presents with limb weakness and occasional cranial nerve, respiratory and autonomic involvement. Although the classic description of Guillain-Barre Syndrome is that of a demyelinating neuropathy with ascending weakness, predominant bilateral finger drop as presenting feature has rarely been reported. A characteristic pattern of weakness involving the extensor components of the fingers known as "finger drop sign" has been first described to be specific in acute motor axonal neuropathy form of Guillain-Barre Syndrome in the literature. We report a case of acute motor-sensory axonal neuropathy, which showed characteristic pattern of predominant finger extensor weakness, and provide a summary of all reported cases to date. While previous reports suggested that this is a sign that carries good prognosis, our case report suggested otherwise as the patient succumbed to respiratory and autonomic complications. Further studies are needed to evaluate the clinical significance of this peculiar sign. PMID- 29760924 TI - Extensive subcutaneous emphysema following lobectomy. AB - We present a case report of extensive subcutaneous emphysema secondary to an elective left upper lobectomy. A 65-year-old gentleman was brought into a London teaching hospital's Accident and Emergency department following report of severe swelling. He was mistakenly treated by the paramedics as an allergic reaction and given hydrocortisone and salbutamol nebulisers with no effect. Upon arrival, the patient had widespread crepitus extending from his peri-orbital muscles down to mid-torso. A computer tomography scan revealed a pleuro-cutaneous fistula at the site of a recently sited chest drain, with extensive emphysema and a pneumothorax. A Seldinger chest drain was successfully inserted under blind technique following two attempts. This case highlights the risk of subcutaneous emphysema following thoracic surgery, the importance of correct diagnosis and the difficulties of left-sided intercostal drains in patients with subcutaneous emphysema. PMID- 29760925 TI - Methimazole-induced ANCA-associated vasculitis with diffuse alveolar haemorrhage. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) caused by methimazole (MMI) is known to be relatively rare; therefore, the optimal therapeutic approach for these cases remains to be established. A 59-year-old man who was treated with MMI for a diagnosis of Graves' disease was referred to our hospital because of progressive haemoptysis. The patient was diagnosed with diffuse alveolar haemorrhage (DAH) secondary to AAV based on increased inflammatory reactions with positive myeloperoxidase-ANCA in the serum and the results of bronchoalveolar lavage fluid. MMI was suspected as the cause of the AAV; therefore, the administration of MMI was discontinued. Thereafter, the patient's symptoms as well as chest radiographic abnormalities completely resolved, in conjunction with normalization of the serum ANCA level. Our experience with this case suggests that DAH secondary to AAV caused by MMI may improve with discontinuation of the offending drug alone, with no other treatment. PMID- 29760926 TI - Diffuse endobronchial metastasis from sigmoid carcinoma presenting as wheezing and respiratory failure. AB - A 66-year-old Thai man with underlying asthma, history of traumatic right haemothorax, and sigmoid carcinoma with bladder invasion developed productive cough, whitish sputum, dyspnoea, and wheezing for 2 months. Physical examination showed generalized expiratory wheezing in both lungs. Computed tomography scan of the chest revealed diffuse thickening of bronchial wall, predominantly at lower lobes; several various sizes of pulmonary nodules; diffuse interlobular septal thickening; multiple enlarged mediastinal lymph nodes and hilar lymph nodes; and right pleural effusion. The patient was intubated for respiratory failure with persistent wheezing and, subsequently, with difficulty weaning from mechanical ventilation. Bronchoscopy was performed, which revealed diffuse multiple small mucosal nodules in both lungs. Pathology of the nodules showed foci of adenocarcinoma. Positive immunochemical staining with CDX2 confirmed the diagnosis of endobronchial metastasis of sigmoid carcinoma. This case highlighted a rare presentation of endobronchial metastasis from sigmoid carcinoma with persistent wheezing, respiratory failure, and difficulty in weaning from mechanical ventilation. PMID- 29760927 TI - Is sperm FISH analysis still useful for Robertsonian translocations? Meiotic analysis for 23 patients and review of the literature. AB - Background: Robertsonian translocations (RobT) are common structural chromosome rearrangements where carriers display a majority of chromosomally balanced spermatozoa from alternate segregation mode. According to some monotony observed in the rates of balanced segregation, is sperm FISH analysis obsolete for RobT carriers? Methods: Retrospective cohort research study on 23 patients analyzed in our center from 2003 to 2017 and compared to the data of 187 patients in literature from 1983 to 2017.Robertsonian translocation carriers were divided in six groups according to the chromosomes involved in the translocation: 9 patients from our center and 107 from literature carrying 45,XY,der(13;14) karyotype, 3 and 35 patients respectively with 45,XY,der(14;21), 5 and 11 patients respectively with 45,XY,der(13;15), 4 and 7 patients respectively with 45,XY,der(14;15), 1 and 4 patients respectively with 45,XY,der(13;22),and 1 and 10 patients respectively with 45,XY,der(14;22). Results: Alternate segregation mode is predominant in our group of Robertsonian translocation carriers with 73.45% +/-8.05 of balanced spermatozoa (min 50.92%; max 89.99%). These results are compliant with the data from literature for all translocations types (p > 0.05) and are consistent among the different types of Robertsonian translocations (p > 0.05) except for der(13;15) that exhibit lower balanced spermatozoa rates (p < 0.05 versus der(13;14), der(14;21), (13;21) and der(15;22)). Normozoospermic patients also display a significantly (p < 0.01) higher rate of balanced sperm cells than patients with abnormal seminograms whatever the defect implied. Conclusions: According to the discrepancies observed between der(13;15) and all the other Rob T carriers, the differences observed among patients presenting normal and abnormal sperm parameters and the input in genetical counselling, sperm FISH does not seem obsolete for these patients. Moreover, it seems important to collect more data for rare RobT. PMID- 29760929 TI - Statin-associated myopathy. Assessment of frequency based on data of all statutory health insurance funds in Germany. AB - : Aim of the study was to assess the incidence of statin-associated myopathy (SAM) under real-life conditions in Germany. DATABASE: Administrative data (master data, diagnoses, prescriptions) for all individuals in Germany insured with the Statutory Health Insurance. Basic population: individuals 18 years and older who have been insured continually from 2009 to 2011 (52.9 million; 29.9 million men, 23.9 million women). Data access is provided by the German Institute of Medical Documentation and Information, DIMDI) according to the Data Transparency Regulation of 2012. Statins: identification with the ATC-Codes: C10AA, C10BA and C10BX. STUDY POPULATION: incident statin users in 2010 with a diagnosis of lipid disorders (ICD-10-GM E78, excluding patients with: E78.1, E78.3, E78.6 in eight quarters before index prescription. Definition of SAM: documentation of myopathy (ICD-10-GM G72.0, G72.8; G72.9, M60.8, M60.9, M79.1) in the first statin prescription quarter or in one of the three following quarters. The first event is considered for the incidence estimate. The daily doses included in a package were classified as "days under therapy" (by assuming one DDD) and taken as exposition time. SAM was found in 1.9% of 531 672 incident statin users. The percentage differs according to the patterns of statin use: the lowest incidence is observed in those with only one prescription (1.3%), the highest incidence with 5.0% is observed in those who not only stopped the treatment within 365 days, but who also had their statin changed. Administrative data including diagnoses from ambulatory care provide a realistic estimate of SAM frequency in every day practice. PMID- 29760928 TI - Aneurysmal subarachnoid hemorrhage: intensive care for improving neurological outcome. AB - Background: Aneurysmal subarachnoid hemorrhage is a life-threatening disease requiring neurocritical care. Delayed cerebral ischemia is a well-known complication that contributes to unfavorable neurological outcomes. Cerebral vasospasm has been thought to be the main cause of delayed cerebral ischemia, and although several studies were able to decrease cerebral vasospasm, none showed improved neurological outcomes. Our target is not cerebral vasospasm but improving neurological outcomes. The purpose of this review is to discuss what intensivists should know and can do to improve clinical outcomes in subarachnoid hemorrhage patients. Main body of the abstract: Delayed cerebral ischemia is thought to be due to not only vasospasm but also multifactorial mechanisms. Additionally, the concept of early brain injury, which occurs within the first 72 h after the hemorrhage, has become an important concern. Increasing sympathetic activity after the hemorrhage is associated with cardiopulmonary complications and poor outcomes. Serum lactate measurement may be a valuable marker reflecting the severity of sympathetic activity. The transpulmonary thermodilution method will bring about an advanced understanding of hemodynamic management. Fever is a well-recognized symptom and targeted temperature management is an anticipated intervention. To avoid hyperglycemia and hypoglycemia, performing moderate glucose control and minimizing glucose variability are important concepts in glycemic management, but the optimal target range remains unknown. Dysnatremia seems to be associated with negative outcomes. It is not clear yet that maintaining normonatremia actively improves neurological outcomes. Optimal duration of intensive care management has not been determined. Short conclusion: Although we have an advanced understanding of the pathophysiology and clinical characteristics of subarachnoid hemorrhage, there are many controversies in the intensive care unit management of subarachnoid hemorrhage. With an awareness of not only delayed cerebral ischemia but also early brain injury, more attention should be given to various aspects to improve neurological outcomes. PMID- 29760930 TI - Prevalence of thrombocytopenia before and after initiation of HAART among HIV infected patients at black lion specialized hospital, Addis Ababa, Ethiopia: a cross sectional study. AB - Background: Hematological abnormalities are common in HIV positive patients. Of these, thrombocytopenia is a known complication which has been associated with a variety of bleeding disorders. However, its magnitude and related factors have not been well-characterized in the era of highly active antiretroviral therapy (HAART) in Ethiopia. Therefore, this study aimed to assess the prevalence of thrombocytopenia before and after initiation of HAART among HIV positive patients attending Black Lion Specialized Hospital, Addis Ababa, Ethiopia. Methods: A cross sectional study was conducted from February to April 2017 in Black Lion Specialized Hospital, Addis Ababa, Ethiopia. A total of 176 patients on HAART were selected using simple random sampling techniques. Socio-demographic and clinical characteristics of the study patients were collected using structured questionnaire. Measurements of platelet counts and CD4 + T cell counts were made using Sysmex XT 2000i hematology analyzer and BD FACS Count CD4 analyzer, respectively. Statistical analysis of the data (Paired T- test and binary logistic regression) was done using SPSS version 20. P-value < 0.05 was considered as statistically significant. Results: A total of 176 patients (Age > 18 years old) were enrolled in this study and had a mean age of 40.08 +/- 9.38 years. There was significant increase in the mean values of platelet counts (218.44 +/- 106.6 * 103/MUl vs 273.65 +/- 83.8 * 103/MUl, p < 0.001) after six months of HAART initiation compared to the baseline. Prevalence of thrombocytopenia before and after HAART initiation was 25 and 5.7% respectively. HIV patients whose CD4 counts < 200 Cells/MUl were more likely to have thrombocytopenia than HIV patients whose CD4 count >=350 Cells/MUl. However, it was not statistically associated with prevalence of thrombocytopenia. Conclusions: This study has shown that the prevalence of thrombocytopenia after HAART initiation was decreased significantly. Based on our results, a number of study participants still had thrombocytopenia after initiation of HAART. Therefore, continuous screening for thrombocytopenia among HIV infected patients should be performed to decrease the risk of morbidity and mortality. PMID- 29760931 TI - Blood factory: which stem cells? AB - Blood transfusions are often essential for treatment of severe anaemia and pregnancy complications. The unavailability of blood is a medical concern, especially in developing countries. New sources of red blood cells (RBC) are under investigation. Several studies have attempted to produce functional RBC from CD34+ haematopoietic stem cells (HSC) isolated from peripheral blood and umbilical cord blood, from embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC). A recent article published in Nature Communications describes a novel model for generating RBC from a stable erythroid cell line obtained from bone marrow CD34+ haematopoietic stem cells (HSC). The cells generated by this method are phenotypically and functionally adult RBC, that resemble very well the donor RBC. In vivo experiments confirmed no difference in the survival of these RBC and donor RBC. The study therefore highlights that this immortalized line is a promising new source of adult RBC. PMID- 29760932 TI - Cardiovascular disease risk differences between bus company employees and general workers according to the Korean National Health Insurance Data. AB - Background: Bus drivers are known to be highly at risk of cardiovascular diseases. In this study, we assessed the cardiovascular disease prevalence of bus company employees in Seoul, South Korea, and compared the results to those of general workers. Methods: We analyzed the 2014 Korean National Health Insurance (NHI) data and defined hypertension, diabetes, dyslipidemia, ischemic heart disease, and cerebrovascular disease based on the KCD-6 medical diagnoses. We used bus company employees as surrogate participants of bus drivers due to the characteristics of Korean NHI data. We identified bus company employees in Seoul based on one's workplace which the insurance is registered. The prevalence of five diseases was compared between the bus company employees and general workers. We also calculated the odds ratios (OR) of five diseases between the bus company employees and general workers. To compensate the vast demographical differences between the two groups, we performed propensity score matching. Results: Bus company employees have higher OR for having hypertension (OR 1.33, 95% CI: 1.28 1.39), diabetes mellitus (1.14, 95% CI: 1.08-1.22), and dyslipidemia (1.23, 95% CI: 1.17-1.29) than the general workers or propensity score matched controls. However, the OR of having ischemic heart disease were not significant. The OR of cerebrovascular disease were lower in bus company employees than in the general workers after adjusting the covariates, but similar in the propensity score matched model. Conclusion: This study showed that the ORs of cardiovascular disease risk factors are high in bus company employees when compared to the general working population. Further studies with the longitudinal design should be conducted to confirm the causal association. PMID- 29760933 TI - A brief review of relationship between occupational benzene exposure and hematopoietic cancer. AB - We reviewed articles to clarify the current evidence status for 1) types of cancer which related to benzene exposure, and 2) certain benzene exposure level which might cause the hematopoietic cancers. Hematopoietic function of the bone marrow is involved in the production of all blood cells types. The benzene metabolites including benzoquinone and mucoaldehyde affect hematopoietic stem cells as well as differentiation steps of progenitor cells for each blood cell. Hence, we concluded that benzene was associated with all lymphohematic carcinogenesis. First, it is supported by biological plausibility. Second, it is supported by meta-analysis although sing study did not show relationship due to lack of sample size or statistical power. More recent studies show lesser exposed level related to risk of cancer, compare to past studies did. Actually, early studies show the risk of malignancies in workers who exposed more than 200 ppm years. However, only 0.5 to 1 ppm-year benzene exposed show significant linking to risk of malignancies in recent study. As reviewed research articles, we concluded that the relatively lower exposure level, such as 0.5-1 ppm-year, will be considering at risk of hematopoietic cancer. However, more research needs to be done on dose-response analysis. PMID- 29760935 TI - Intestinal obstruction caused by desmoid tumours: a review of the literature. AB - Intraabdominal desmoid tumours are rare and can cause intestinal obstruction. Based on the review of the literature, surgical resection with negative margins and adjuvant chemotherapy is the optimal strategy for treatment of this pathology. PMID- 29760934 TI - The association between high-sensitivity C-reactive protein and metabolic risk factors in black and white South African women: a cross-sectional study. AB - Background: High-sensitivity C-reactive protein (hsCRP) is associated with metabolic risk, however it is unclear whether the relationship is confounded by racial/ethnic differences in socioeconomic status (SES), lifestyle factors or central adiposity. The aims of the study was, (1) to investigate whether hsCRP levels differ by race/ethnicity; (2) to examine the race/ethnic-specific associations between hsCRP, HOMA-IR and serum lipids [total cholesterol (TC), triglycerides (TG), high-density lipoproteins (HDL-C) and low-density lipoproteins (LDL-C)]; and (3) to determine whether race/ethnic-specific associations are explained by SES, lifestyle factors or waist circumference (WC). Methods: The convenience sample comprised 195 black and 153 white apparently health women, aged 18-45 years. SES (education, assets and housing density) and lifestyle factors (alcohol use, physical activity and contraceptive use) were collected by questionnaire. Weight, height and WC were measured, and fasting blood samples collected for hsCRP, glucose, insulin, and lipids. Results: Black women had higher age- and BMI-adjusted hsCRP levels than white women (p = 0.047). hsCRP was associated with HOMA-IR (p < 0.001), TG (p < 0.001), TC (p < 0.05), HDL C (p < 0.05), and LDL-C (p < 0.05), independent of age and race/ethnicity. The association between hsCRP and lipids differed by race/ethnicity, such that hsCRP was positively associated with TG and LDL-C in white women, and inversely associated with HDL-C in black women. Higher hsCRP was also associated with higher TC in white women and lower TC in black women. Furthermore, when adjusting for SES and lifestyle factors, the associations between hsCRP, and TC and TG, remained, however the associations between hsCRP, and HDL-C and LDL-C, were no longer significant. Conclusion: Although circulating hsCRP may identify individuals at increased metabolic risk, the heterogeneity in these associations between racial/ethnic groups highlights the need for prospective studies investigating the role of hsCRP for risk prediction in different populations. PMID- 29760936 TI - Preliminary molecular evidence associating a novel BRCA1 synonymous variant with hereditary ovarian cancer syndrome. AB - Extensive molecular screening of the BRCA1/2 (BRCA) genes by massively parallel sequencing (MPS) identified variants of uncertain (or unknown) significance (VUS) and novel variants. We performed a molecular characterization of a novel BRCA1 synonymous variant discovered in a family with hereditary ovarian cancer (HOC) syndrome. We showed that the BRCA1 c.5073 A > T variant might play a pathogenic role in HOC syndrome in this family. PMID- 29760937 TI - A novel MLH1 intronic variant in a young Japanese patient with Lynch syndrome. AB - Lynch syndrome, an autosomal dominantly inherited disease, is characterized by an increased risk of developing colorectal cancer. We found a novel germline variant of MLH1 (IVS6+2T>C) that caused Lynch syndrome in a young Japanese patient who had multiple colorectal cancers. Accurate diagnosis will be highly beneficial in clinical practice for surveillance and genetic counseling of patients and their relatives. PMID- 29760938 TI - Novel COL4A1 mutation in a fetus with early prenatal onset of schizencephaly. AB - Porencephaly and schizencephaly are congenital brain disorders that can be caused by COL4A1 mutations, though the underlying mechanism and developmental processes are poorly understood. Here, we report a patient with schizencephaly, detected by fetal ultrasonography and fetal magnetic resonance imaging, with a de novo novel mutation in COL4A1 (c.2645_2646delinsAA, p.Gly882Glu). Our results suggest that the onset of damage that potentially results in schizencephaly occurs mid pregnancy. PMID- 29760939 TI - Novel TFAP2A mutation in a Japanese family with Branchio-oculo-facial syndrome. AB - Branchio-oculo-facial syndrome (BOFS) is a rare autosomal dominant disorder characterized by craniofacial, ocular, and ectodermal anomalies. BOFS is caused by mutation of the transcription factor AP2-alpha gene (TFAP2A). We performed detailed genetic analysis of a Japanese family with clinically suspected BOFS and identified a novel missense mutation resulting in a predicted amino-acid substitution in the highly conserved basic DNA-binding domain of TFAP2A (NM_003220.2:c.699A>C). PMID- 29760940 TI - Analyses of non-benzodiazepine-induced adverse events and prognosis in elderly patients based on the Japanese adverse drug event report database. AB - Background: The contents of the guidelines for the use of non-benzodiazepines (Z drugs) differ slightly between THE JAPANESE SOCIETY OF SLEEP RESEARCH and THE JAPAN GERIATRIC SOCIETY, and the recommended directions are conflicting. Therefore, we analyzed the use of the Japanese Adverse Drug Event Report database (JADER) for identifying adverse events (AEs) caused by Z-drugs and clarifying their occurrence trend and prognosis. Methods: The signal value for comparison was calculated by using the proportional reporting ratio (PRR) and chi-squared test (chi2) results of data of elderly and non-elderly patients. Among AEs for which signals were detected in the elderly, we determined that those with lower signal values for non-elderly patients that were half the signal value of the elderly should be used with particular caution in the elderly. We also compared the prognoses. Results: The AEs with > 1 risk ratio (RR) in elderly and non elderly patients were regarded as those that should be noted in the prognosis of AEs in elderly patients. Furthermore, 28 AEs were detected in elderly patients' signals. In this study, in addition to movement disorders such as "falls" and "bone fractures," identified by two academic societies, signal characteristics of the elderly were obtained for psychiatric disorders and eye disorders. Conclusions: There was no difference in prognosis, but these disorders could reduce the quality of life of patients. Therefore, we consider that in prescribing appropriate drug therapy for insomnia, attention should be paid to the occurrence of the AEs caused by the Z-drugs revealed by this study and the guidelines. PMID- 29760941 TI - Hip fracture in the elderly multidisciplinary rehabilitation (FEMuR) feasibility study: testing the use of routinely collected data for future health economic evaluations. AB - Background: Health economic evaluations rely on the accurate measurement of health service resource use in order to calculate costs. These are usually measured with patient completed questionnaires using instruments such as the Client Service Receipt Inventory (CSRI). These rely on participants' recall and can be burdensome to complete. Health service activity data are routinely captured by electronic databases.The aim was to test methods for obtaining these data and compare with those data collected using the CSRI, within a feasibility study of an enhanced rehabilitation intervention following hip fracture (Fracture in the Elderly Multidisciplinary Rehabilitation: FEMuR). Methods: Primary care activity including prescribing data was obtained from the Secure Anonymised Information Linkage (SAIL) Databank and secondary care activity (Emergency Department attendances, out-patient visits and in-patient days) directly from Betsi Cadwaladr University Health Board (BCUHB), North Wales, UK. These data were compared with patient responses from the CSRI using descriptive statistics and the intraclass correlation coefficient (ICC). Results: It was possible to compare health service resource use data for 49 out of 61 participants in the FEMuR study. For emergency department (ED) attendances, records matched in 23 (47%) cases, 21 (43%) over-reported on electronic records compared with CSRI and five participants (10%) under-reported, with an overall ICC of 0.42. For out-patient episodes, records matched in only six cases, 28 participants over-reported on electronic records compared with CSRI and 15 (12%) under-reported, with an overall ICC of only 0.27. For in-patient days, records matched exactly in only five cases (10%), but if an error margin of 7 days was allowed, then agreement rose to 39 (66%) cases, and the overall ICC for all data was 0.88.It was only possible to compare prescribing data for 12 participants. For prescribing data, the SAIL data reported 117 out of 118 items (99%) and the CSRI only 89 (79%) items. Conclusions: The use of routinely collected data has the potential to improve the efficiency of trials and other studies. Although the methodology to make the data available has been demonstrated, the data obtained was incomplete and the validity of using this method remains to be demonstrated. Trial registration: Trial registration: ISRCTN22464643 Registered 21 July 2014. PMID- 29760942 TI - Induction of chondrogenesis of human placenta-derived mesenchymal stem cells via heparin-grafted human fibroblast derived matrix. AB - Background: Formation of mature and functional articular cartilage is still challenging in cartilage tissue engineering. This study investigates the potential of using heparin-grafted decellularized extracellular matrix (ECM) as a novel growth factor delivery platform towards human placenta-derived mesenchymal stem cells (hPMSCs) chondrogenic differentiation. Human fibroblast-derived extracellular matrix (hFDM) is naturally obtained from in vitro-cultured human lung fibroblasts via a mild decellularization process. hFDM was then conjugated with heparin via N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) chemistry and subject to transforming growth factor (TGF)-beta1 immobilization. Once heparin grafted-hFDM (hFDM-hep) and hPMSCs were co-embedded into collagen gel, they were examined for in vitro and in vivo chondrogenesis of hPMSCs for 4 weeks. Results: We identified heparin moieties on hFDM via toluidine blue O assay and Fourier transform infrared spectroscopy, respectively. We found out that collagen spheroids containing hFDM-hep and TGF-beta1 exhibited a sustained release of growth factor for 28 days in vitro. Chondrogenesis of hPMSCs in vitro was supported by accumulated glycosaminoglycan (GAG) content and upregulated chondrogenic specific markers (collagen II, aggrecan, Sox9). Meanwhile, PKH26 - labeled hPMSCs incorporated collagen with either hFDM or hFDM hep was pre-conditioned in a chondrogenic media for 3 days and subcutaneously implanted in the back of nude mice for 4 weeks. The implanted collagen spheroids containing both hPMSCs and hFDM-hep retained more viable hPMSCs and showed higher level of chondrogenic differentiation, based on immunostaining of collagen type II over collagen alone or Col/hFDM group. In addition, histological examination showed more positive signals of GAG via Safranin-O staining. Conclusion: TGF beta1-immobilized hFDM-hep can provide an appropriate microenvironment for chondrogenic differentiation of hPMSCs in 3D collagen spheroid. PMID- 29760943 TI - High parity predicts use of long-acting reversible contraceptives in the extended postpartum period among women in rural Uganda. AB - Background: The use of implants and Intra-uterine devices (IUD) during the post partum period is very low in Uganda especially in rural settings. Long-acting reversible contraceptives (LARC) are known to be the most cost-effective for prevention of unintended pregnancy and unsafe abortions. This study aimed at determining the factors associated with long-acting reversible contraceptive use among women in the extended postpartum period in rural Uganda. Methods: We conducted a household-based, cross-sectional study among 400 women in two rural communities in Mityana district, central Uganda. Eligible women were aged 15 to 45 years who had childbirth within 12 months of study enrollment in September 2014. The outcome variable was self-reported use of a LARC method, either IUD or implants in the extended postpartum period. The main independent variables were previous childbirths (parity), fertility desire, willingness to use modern contraception, duration of postpartum period and previous pregnancies (gravidity). A logistic regression model was run in STATA v12.0 to compute adjusted odds ratios (AOR) for factors that predicted LARC use statistically significant at p < 0.05. Results: Four hundred respondents had a mean age of 27 years (SD = 12) and only 8.5% reported using a LARC method. Use of IUD and implant was 1.8% and 10.4% respectively. Most women using LARC (44.1%) had five or more childbirths (p = 0.01), 70.8% of non-LARC users were willing to use modern contraceptives (p = 0.07) and 2.5% ever had an induced abortion. Having five or more childbirths was independently associated with LARC use in the extended postpartum period (AOR = 4.07, 95%CI 1.08-15.4). Willingness to use modern contraception, desire for more children and postpartum duration had no significant association with LARC use in the extended postpartum period. Conclusion: This study revealed low use of LARC within twelve months of child birth despite women's willingness to use them. High parity (>=5 childbirths) predicted LARC use. The next logical step is to identify barriers to using LARC in the extended postpartum period and design appropriate interventions to increase access and use especially in multi-parous women. PMID- 29760944 TI - Characteristics of insulin-Naive people with type 2 diabetes who successfully respond to insulin glargine U100 after 24 weeks of treatment: a meta-analysis of individual participant data from 3 randomized clinical trials. AB - Background: To identify baseline/clinical characteristics associated with clinically meaningful responses to insulin glargine 100 U/mL (IGlar) in insulin naive people with type 2 diabetes mellitus (T2DM). Methods: Individual participant data were pooled from 3 randomized trials to compare baseline characteristics and clinical outcomes associated with 24-week response to IGlar in combination with non-insulin antihyperglycemic agents in participants with T2DM. Responders were defined as achieving endpoint HbA1c target < 53 mmol/mol (< 7%) and/or >= 11 mmol/mol (>= 1%) HbA1c reduction from baseline. Results: Differences in baseline characteristics for responders versus nonresponders were higher HbA1c (99 vs 91 mmol/mol [9.1 vs 8.3%]; P < 0.001), higher fasting blood glucose (FBG; 10.4 vs 8.8 mmol/L [187 vs 159 mg/dL; P < 0.001), and fewer participants (94% vs 98%; P = 0.006) taking oral medications targeting postprandial blood glucose (BG). Most participants (80%) achieved one or both components of composite endpoint. 12-week response was a strong predictor of subsequent 24-week response (sensitivity, 85.9%; predictive positive value, 91.4%). At both 12 and 24 weeks, < 40% of responders and nonresponders reached target FBG <= 5.6 mmol/L (<= 100 mg/dL). Responders at 24 weeks had higher incidence of hypoglycemia (total, 82.5% vs 70.4%; P < 0.001; nocturnal, 60.3% vs 50.5%; P = 0.002; documented symptomatic, 65.8% vs 55.6%; P < 0.001) than nonresponders. Conclusions: Baseline characteristics associated with response were identified. The strong predictability of 12-week response suggests that the magnitude of early HbA1c reduction should be considered when assessing response to IGlar. More aggressive IGlar titration may be reasonable for nonresponders and responders who have not reached FBG and HbA1c targets, taking into account other BG timepoints. PMID- 29760945 TI - Liraglutide and Dulaglutide therapy in addition to SGLT-2 inhibitor and metformin treatment in Indian type 2 diabetics: a real world retrospective observational study. AB - Background: Therapy for Type 2 diabetes (T2D) has been transformed by the introduction of newer agents like Glucagon like Peptide Receptor Agonists (GLP 1RA) and Sodium-glucose linked transporter inhibitors (SGLT2i). However with co initiation of SGLT2i and GLP-1RA in the DURATION 8 trial an improvement in HbA1c was noted but the beneficial effect was not equal to the sum of its parts. In view of this we proceeded to test the hypothesis that sequential addition of GLP 1RA therapy to metformin and SGLT-2i may be more beneficial. Methods: A retrospective real world observational case note study conducted in two diabetes care centres in India analyzed the first 60 consecutive T2D patients who could afford this therapy and had not achieved their glycaemic target (HbA1c < 7%)on metformin and SGLT2i. All these patients were additionally treated with either Dulaglutide or Liraglutide and followed up for 13 weeks. Results: Across the entire 13-week study period, both liraglutide and dulaglutide proved to be an excellent add on to metformin and SGLT-2 inhibitor. There was significant reduction in HbA1c and body weight. Liraglutide had an additional significant impact on systolic blood pressure reduction in contrast to the dulaglutide arm. Comparatively, liraglutide and dulaglutide achieved similar metabolic control. However, a larger proportion of patients achieved HbA1c below 7.0% in the liraglutide arm (63.3%) compared to the dulaglutide arm (30%) and this difference was statistically significant. Conclusion: In this retrospective study in Indian type 2 diabetic patients poorly controlled with metformin and SGLT-2 inhibitor we found a meaningful impact of adding a GLP-1 RA on all metabolic parameters. There were additional advantages seen with liraglutide as far achieving target HbA1c of less than 7% and also on the quantum of weight loss and systolic blood pressure reduction. PMID- 29760946 TI - Sequence determinants of specific pattern-recognition of bacterial ligands by the NAIP-NLRC4 inflammasome. AB - The NLR apoptosis inhibitory proteins (NAIPs) function as specific cytosolic receptors for bacterial ligands to form the NAIP-NLRC4 inflammasome for anti bacterial defenses. In mice, NAIP5/6 and NAIP2 recognize bacteria flagellin and the rod protein of the type III secretion system (T3SS), respectively. However, molecular mechanism for specific ligand pattern-recognition by the NAIPs is largely unknown. Here, through extensive domain swapping and truncation analyses, three structural domains, the pre-BIR, BIR1, and HD1, in NAIP2 and NAIP5 are identified, that are important for specific recognition of their respective ligand(s). The three domains are sufficient to confer the ligand specificity for NAIP2. Asp-18, Arg-108, and Arg-667, respectively, in the pre-BIR, BIR1 and HD1 of NAIP2 are further identified, each of which is essential for efficient binding to the rod protein. To our surprise, we find that the C-terminal leucine-rich repeat domain is dispensable for NAIP2 recognition of the T3SS rod protein, but is required for NAIP5 binding to flagellin. At the ligand side, we discover that the C-terminal 35 residues in flagellin are crucial for binding to NAIP5. Among the 35 residues, three critical residues are identified, which determine flagellin recognition by NAIP5 and subsequent inflammasome activation. The differences in the three amino-acid residues among flagellins from various pathogenic and commensal bacterial species correlate well with whether they are susceptible to NAIP5-mediated immune detection. Taken together, our studies identify critical sequence and amino-acid determinants in both NAIP receptors and the bacterial ligand flagellin that are important for the specificity of the pattern-recognition. PMID- 29760947 TI - Incorporating epilepsy genetics into clinical practice: a 360 degrees evaluation. AB - We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team. We held an educational workshop for paediatricians and nurses. We sent questionnaires to referring paediatricians and families. We analysed investigation costs for 16 neonatal epilepsy patients. Of 96 patients, a genetic diagnosis was made in 34% of patients with seizure onset < 2 years, and 4% > 2 years, with turnaround time of 21 days. Pathogenic variants were seen in SCN8A, SCN2A, SCN1A, KCNQ2, HNRNPU, GRIN2A, SYNGAP1, STXBP1, STX1B, CDKL5, CHRNA4, PCDH19 and PIGT. Clinician prediction was poor. Clinicians and families rated the service highly. In neonates, the cost of investigations could be reduced from L9362 to L2838 by performing gene panel earlier and the median diagnostic delay of 3.43 years reduced to 21 days. Panel testing for epilepsy has a high yield among children with onset < 2 years, and an appreciable clinical and financial impact. Parallel gene testing supersedes single gene testing in most early onset cases that do not show a clear genotype-phenotype correlation. Clinical interpretation of laboratory results, and in-depth discussion of implications for patients and their families, necessitate multidisciplinary input and skilled genetic counseling. PMID- 29760949 TI - New patient-controlled abdominal compression method in radiography: radiation dose and image quality. AB - Background: The radiation dose for patients can be reduced with many methods and one way is to use abdominal compression. In this study, the radiation dose and image quality for a new patient-controlled compression device were compared with conventional compression and compression in the prone position. Purpose: To compare radiation dose and image quality of patient-controlled compression compared with conventional and prone compression in general radiography. Material and Methods: An experimental design with quantitative approach. After obtaining the approval of the ethics committee, a consecutive sample of 48 patients was examined with the standard clinical urography protocol. The radiation doses were measured as dose-area product and analyzed with a paired t-test. The image quality was evaluated by visual grading analysis. Four radiologists evaluated each image individually by scoring nine criteria modified from the European quality criteria for diagnostic radiographic images. Results: There was no significant difference in radiation dose or image quality between conventional and patient-controlled compression. Prone position resulted in both higher dose and inferior image quality. Conclusion: Patient-controlled compression gave similar dose levels as conventional compression and lower than prone compression. Image quality was similar with both patient-controlled and conventional compression and was judged to be better than in the prone position. PMID- 29760948 TI - The diagnosis and treatment of primary vitreoretinal lymphoma: a review. AB - Background: To describe the recent diagnostic and treatment options for the most predominant form of primary vitreoretinal lymphoma (PVRL), namely diffuse large B cell lymphoma. This is mainly based on the experience at the Mayo Clinic as well as a partial review of the literature. MYD88 L265P mutation is seen in about 80% of cases; therefore, a polymerase chain reaction for this mutation helps in making the diagnosis that has been notoriously difficult to make. Local therapy using intravitreal methotrexate and rituximab has been very helpful in the treatment of the local disease. Systemic high-dose intravenous methotrexate is helpful in treating bilateral disease in conjunction with intravitreal therapy. Whether it is helpful in preventing or delaying the development of central nervous system lymphoma (CNSL) is still in dispute. If there is development of CNSL or recurrent ocular disease, alternatives to high-dose methotrexate under investigation include pomalidomide, stem cell transplantation, or ibrutinib, with or without local therapy. Vitrectomy alone might be helpful as a debulking procedure. Because of the risks of redevelopment of disease, local radiation should be given if other options are not possible. Aqueous levels of IL10 are helpful in following the redevelopment of local disease. Conclusion: Although PVRL is still a difficult disease to diagnose and treat, new advances are helping to make these easier. Larger collaborative studies will be helpful in determining better treatments. PMID- 29760950 TI - Genipin alleviates vascular hyperpermeability following hemorrhagic shock by up regulation of SIRT3/autophagy. AB - Genipin (GP) is commonly used to treat cardiovascular diseases; however, the protective action of GP against vascular hyperpermeability (VH) has not been reported. We previously reported that intrinsic apoptotic signaling (IAS) is involved in VH following hemorrhagic shock (HS). GP inhibits apoptosis, but the specific mechanism remains unclear. In the present study, we observed that GP protects against HS-induced VH in vitro and in vivo. We report that this protective effect is related to the inhibition of IAS by up-regulation of autophagy via sirtuin 3 (SIRT3). The endothelial cell hyperpermeability induced by HS was enhanced by GP; this was attenuated by 3-methyladenine (3MA), a specific inhibitor of autophagy, indicating the involvement of autophagy. Consistent with these results, we found that 3MA reversed the effects of GP on up regulation of autophagy, and also diminished the protective effect of GP against IAS activation following HS. Furthermore, knockout of SIRT3 inhibited GP-induced autophagy, indicating the requirement of SIRT3 in the regulation of autophagy by GP. In rats, GP improved HS-induced VH, which was repressed by 3MA and 3-(1H 1,2,3-triazol-4-yl)pyridine (3-TYP), a SIRT3 inhibitor. In conclusion, these findings suggest that autophagy plays a protective effect in VH following HS; the protective effect of autophagy is reinforced by GP, which protects against IAS and VH by up-regulating SIRT3. PMID- 29760951 TI - Molecular functional analyses revealed essential roles of HSP90 and lamin A/C in growth, migration, and self-aggregation of dermal papilla cells. AB - Previous expression study using quantitative proteomics has shown that immune mediated pathway may not be the main mechanism inducing alopecia areata (AA). Nevertheless, functional impact of such expression data set remained unknown and unexplored. This study thus aimed to define potentially novel mechanisms of the AA pathogenesis by functional investigations of the differentially expressed proteins previously identified from lesional biopsies. From 122 altered proteins, protein-protein interactions network analysis revealed that downregulated heat shock protein 90 (HSP90) and lamin A/C served as the central nodes of protein protein interactions involving in several crucial biological functions, including cytoskeleton organization, extracellular matrix organization, and tissue development. Interaction between HSP90 and lamin A/C in dermal papilla cells (DPCs) was confirmed by reciprocal immunoprecipitation and immunofluorescence co staining. Small-interfering RNA (siRNA) targeting to HSP90 (siHSP90) and lamin A/C (siLamin A/C) effectively reduced levels of HSP90 and lamin A/C, respectively and vice versa, comparing to non-transfected and siControl-transfected cells, strengthening their interactive roles in DPCs. Functional investigations revealed that DPCs transfected with siHSP90 and siLamin A/C had defective cell proliferation and growth, prolonged doubling time, cell cycle arrest at G0/G1 phase, and defective self-aggregation formation. Moreover, siHSP90-transfected cells had less spindle index, reduced levels of vimentin (mesenchymal marker) and fibronectin (extracellular matrix), and defective migratory activity. Our data have demonstrated for the first time that HSP90 and lamin A/C physically interact with each other. Moreover, both of them are essential for growth, migration, and self-aggregation of DPCs and can be linked to the disease mechanisms of AA. PMID- 29760952 TI - Downregulation of the psychiatric susceptibility gene Cacna1c promotes mitochondrial resilience to oxidative stress in neuronal cells. AB - Affective disorders such as major depression and bipolar disorder are among the most prevalent forms of mental illness and their etiologies involve complex interactions between genetic and environmental risk factors. Over the past ten years, several genome wide association studies (GWAS) have identified CACNA1C as one of the strongest genetic risk factors for the development of affective disorders. However, its role in disease pathogenesis is still largely unknown. Vulnerability to affective disorders also involves diverse environmental risk factors such as perinatal insults, childhood maltreatment, and other adverse pathophysiological or psychosocial life events. At the cellular level, such environmental influences may activate oxidative stress pathways, thereby altering neuronal plasticity and function. Mitochondria are the key organelles of energy metabolism and, further, highly important for the adaptation to oxidative stress. Accordingly, multiple lines of evidence including post-mortem brain and neuro imaging studies suggest that psychiatric disorders are accompanied by mitochondrial dysfunction. In this study, we investigated the effects of Cacna1c downregulation in combination with glutamate-induced oxidative stress on mitochondrial function, Ca2+ homeostasis, and cell viability in mouse hippocampal HT22 cells. We found that the siRNA-mediated knockdown of Cacna1c preserved mitochondrial morphology, mitochondrial membrane potential, and ATP levels after glutamate treatment. Further, Cacna1c silencing inhibited excessive mitochondrial reactive oxygen species formation and calcium influx, and protected the HT22 cells from oxidative cell death. Overall, our findings suggest that the GWAS confirmed psychiatric risk gene CACNA1C plays a major role in oxidative stress pathways with particular impact on mitochondrial integrity and function. PMID- 29760953 TI - Hyperglycemia potentiates a shift from apoptosis to RIP1-dependent necroptosis. AB - Apoptosis and necroptosis are the primary modes of eukaryotic cell death, with apoptosis being non-inflammatory while necroptosis is highly inflammatory. We previously demonstrated that, once activated, necroptosis is enhanced by hyperglycemia in several cell types. Here, we determine if hyperglycemia affects apoptosis similarly. We show that hyperglycemia does not enhance extrinsic apoptosis but potentiates a shift to RIP1-dependent necroptosis. This is due to increased levels and activity of RIP1, RIP3, and MLKL, as well as decreased levels and activity of executioner caspases under hyperglycemic conditions following stimulation of apoptosis. Cell death under hyperglycemic conditions was classified as necroptosis via measurement of markers and involvement of RIP1, RIP3, and MLKL. The shift to necroptosis was driven by RIP1, as mutation of this gene using CRISPR-Cas9 caused cell death to revert to apoptosis under hyperglycemic conditions. The shift of apoptosis to necroptosis depended on glycolysis and production of mitochondrial ROS. Importantly, the shift in PCD was observed in primary human T cells. Levels of RIP1 and MLKL increased, while executioner caspases and PARP1 cleavage decreased, in cerebral tissue from hyperglycemic neonatal mice that underwent hypoxia-ischemia (HI) brain injury, suggesting that this cell death shift occurs in vivo. This is significant as it demonstrates a shift from non-inflammatory to inflammatory cell death which may explain the exacerbation of neonatal HI-brain injury during hyperglycemia. These results are distinct from our previous findings where hyperglycemia enhanced necroptosis under conditions where apoptosis was inhibited artificially. Here we demonstrate a shift from apoptosis to necroptosis under hyperglycemic conditions while both pathways are fully active. Therefore, while our previous work documented that intensity of necroptosis is responsive to glucose, this work sheds light on the molecular balance between apoptosis and necroptosis and identifies hyperglycemia as a condition that pushes cells to undergo necroptosis despite the initial activation of apoptosis. PMID- 29760954 TI - The p53 activator overcomes resistance to ALK inhibitors by regulating p53-target selectivity in ALK-driven neuroblastomas. AB - Anaplastic lymphoma kinase (ALK) is an oncogenic receptor tyrosine kinase that is activated by gene amplification and mutation in neuroblastomas. ALK inhibitors can delay the progression of ALK-driven cancers, but are of limited use owing to ALK inhibitor resistance. Here, we show that resistance to ALK inhibitor in ALK driven neuroblastomas can be attenuated by combination treatment with a p53 activator. Either ALK inhibition or p53 activator treatment induced cell cycle arrest, whereas combination treatment induced apoptosis, and prevented tumour relapse both in vitro and in vivo. This shift toward apoptosis, and away from cell-cycle arrest, in the presence of an ALK inhibitor and a p53 activator, is mediated by inhibition of the ALK-AKT-FOXO3a axis leading to a specific upregulation of SOX4. SOX4 cooperates with p53 to upregulate the pro-apoptotic protein PUMA. These data therefore suggest a novel combination therapy strategy for treating ALK-driven neuroblastomas. PMID- 29760955 TI - NVP-BEZ235, a dual PI3K-mTOR inhibitor, suppresses the growth of FaDu hypopharyngeal squamous cell carcinoma and has a synergistic effect with Cisplatin. AB - NVP-BEZ235 is a dual phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibitor. A dual approach targeting more than one downstream effector is a promising strategy for treating cancers. The aim of this study was to evaluate the effect of NVP-BEZ235 in treating FaDu hypopharyngeal squamous cell carcinoma (HSCC), either alone or in combination with cisplatin. We found mTOR expression was higher in patients with HSCC. In the in vitro study, treatment with NVP-BEZ235 alone attenuated cell proliferation and suppressed p p70S6K and p-4E-BP1 expression in FaDu cells. When NVP-BEZ235 was combined with Cisplatin, apoptosis was induced more effectively than with either drug alone. In mice with a FaDu xenograft, cotreatment with NVP-BEZ235 and Cisplatin engendered synergistic effects and produced a greater antitumor response than did treatment with either drug alone. Resected tumor samples also showed decreased p-p70S6K expression. Collectively, these data demonstrate that NVP-BEZ235 inhibits HSCC growth through phospho-p70S6K suppression and has a synergistic effect with Cisplatin in treating HSCC. The data also provide a strategy for more effective HSCC treatment. PMID- 29760957 TI - Simulated microgravity induces a cellular regression of the mature phenotype in human primary osteoblasts. AB - Decreased mechanical loading on bones, such as prolonged bed rest and microgravity during space flights, leads to the development of an osteoporotic like phenotype. Although osteoblast hypo-functionality is reported to be involved in the progression of bone pathological conditions, the cellular mechanisms of this process remain largely unknown. The combined application of mass spectrometry "-omics" and histochemical and ultrastructural approaches have been employed to investigate the effects of the gravitational unloading on human bone cell biology. Here we show, ex vivo, that simulated microgravity (SMUg) on human primary osteoblasts (hpOB) induces an alteration of pro-osteogenic determinants (i.e., cell morphology and deposit of hydroxyapatite crystals), accompanied by a downregulation of adhesive proteins and bone differentiation markers (e.g., integrin beta-1, protein folding Crystallin Alpha B (CRYalpha-B), runt-related transcription factor 2 (RUNX-2), bone morphogenic protein-2 (BMP-2), and receptor activator of nuclear factor kappa-B ligand (RANK-L)), indicating an impairment of osteogenesis. Further, we observed for the first time that SMUg can trigger a transition toward a mesenchymal-like phenotype, in which a mature osteoblast displays an hampered vitamin A metabolism, loses adhesive molecules, gains mesenchymal components (e.g., pre-osteoblast state marker CD44), morphological protrusions (filopodium-like), enhances GTPase activities, which in turn allows it to acquire migrating properties. Although this phenotypic conversion is not complete and can be reversible, SMUg environment proves a plasticity potential hidden on Earth. Overall, our results suggest that SMUg can be a powerful physical cue for triggering ex vivo a dedifferentiation impulse on hpOBs, opening a new scenario of possible innovative therapeutical biomechanical strategies for the treatment of osteo-degenerative diseases. PMID- 29760956 TI - BH4 domain peptides derived from Bcl-2/Bcl-XL as novel tools against acute pancreatitis. AB - Biliary acute pancreatitis (AP) is a serious condition, which currently has no specific treatment. Taurolithocholic acid 3-sulfate (TLC-S) is one of the most potent bile acids causing cytosolic Ca2+ overload in pancreatic acinar cells (PACs), which results in premature activation of digestive enzymes and necrosis, hallmarks of AP. The inositol 1,4,5-trisphosphate receptor (IP3R) and the ryanodine receptor (RyR) play major roles in intracellular Ca2+ signaling. Inhibition of these endoplasmic reticulum-located channels suppresses TLC-S induced Ca2+ release and necrosis, decreasing the severity of AP. Anti-apoptotic B-cell lymphoma (Bcl)-2-family members, such as Bcl-2 and Bcl-XL, have emerged as important modulators of IP3Rs and RyRs. These proteins contain four Bcl-2 homology (BH) domains of which the N-terminal BH4 domain exerts critical roles in regulating intracellular Ca2+ release channels. The BH4 domain of Bcl-2, but not of Bcl-XL, binds to and inhibits IP3Rs, whereas both BH4 domains inhibit RyRs. Although clear cytoprotective effects have been reported for these BH4 domains, it remains unclear whether they are capable of inhibiting pathological Ca2+ overload, associated with AP. Here we demonstrate in PACs that the BH4 domains of Bcl-2 and Bcl-XL inhibit RyR activity in response to the physiological agonist cholecystokinin. In addition, these BH4 domains inhibit pathophysiological TLC-S induced Ca2+ overload in PACs via RyR inhibition, which in turn protects these cells from TLC-S-induced necrosis. This study shows for the first time the therapeutic potential of BH4 domain function by inhibiting pathological RyR mediated Ca2+ release and necrosis, events that trigger AP. PMID- 29760958 TI - Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer. AB - B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-kappaB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1 C->NF-kappaB->BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1 C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti apoptotic members of the BCL-2 family. PMID- 29760960 TI - Biochemical and Molecular Screening of Varieties of Chili Plants that are Resistant against Fusarium Wilt Infection. AB - Pakistan holds the position of top chilies producers. So Capsicum annuum L. production in Pakistan should be promoted by combating against diseases. The only solution is to cultivate resistant varieties. Presently six chili varieties were treated with Fusarium oxysporum Schlecht. and screened for the most resistant and the most susceptible varieties. Representative varieties were evaluated for their biochemical and transcriptional profiles to discover the bases of antifungal resistance. Results concluded that the most resistant variety was "Dandicut" and the most susceptible was "Ghotki". Tannins, coumarins, flavonoids, phenolics, Riboflavins and saponins were observed in higher quantities in Dandicut as compared to Ghotki. Defense related enzymes i.e. polyphenol oxidase, phenyl ammonia lyase and peroxidase were found in elevated amounts in Dandicut than in Ghotki. Transcriptional results showed that defense related genes i.e. PR2a, acidic glucanase; Chitinase 3, acidic; Osmotin-like PR5 and Metallothionein 2b like had higher expressional rates in Dandicut. Pearson's correlation coefficient revealed stronger direct interaction in signal transduction and salicylic acid pathway. Resistance of chili varieties is salicylic acid based. Results obtained from this study not only help to improve chili production in Pakistan but also facilitate variety development operations. Moreover, it also constructed a scale to evaluate innate resistance among varieties. PMID- 29760959 TI - Molecular Epidemiology of Multidrug-Resistant Bacteria Isolated from Libyan and Syrian Patients with War Injuries in Two Bundeswehr Hospitals in Germany. AB - Introduction: We assessed the molecular epidemiology of multidrug-resistant bacteria colonizing or infecting war-injured patients from Libya and Syria who were treated at the Bundeswehr hospitals Hamburg and Westerstede, Germany. Methods: Enterobacteriaceae and Gram-negative rod-shaped nonfermentative bacteria with resistance against third-generation methoxyimino cephalosporins or carbapenems as well as methicillin-resistant Staphylococcus aureus (MRSA) from war-injured patients from Libya and Syria were assessed by molecular typing, i.e., spa typing for MRSA strains and rep-PCR and next-generation sequencing (NGS) for Gram-negative isolates. Results: A total of 66 isolates were assessed - comprising 44 Enterobacteriaceae, 16 nonfermentative rod-shaped bacteria, and 6 MRSA from 22 patients - and 8 strains from an assessment of the patient environment comprising 5 Enterobacteriaceae and 3 nonfermentative rod-shaped bacteria. Although 24 out of 66 patient strains were isolated more than 3 days after hospital admission, molecular typing suggested only 7 likely transmission events in the hospitals. Identified clonal clusters primarily suggested transmission events in the country of origin or during the medical evacuation flights. Conclusions: Nosocomial transmissions in hospital can be efficiently prevented by hygiene precautions in spite of heavy colonization. Transmission prior to hospital admission like on evacuation flights or in crises zones needs further assessment. PMID- 29760961 TI - CTX-M-15 is Established in Most Multidrug-Resistant Uropathogenic Enterobacteriaceae and Pseudomonaceae from Hospitals in Nigeria. AB - beta-Lactam antibiotics are widely used to treat urinary tract infections in Nigeria. This study aimed to determine the presence and characteristics of extended spectrum beta-lactamases in commonly isolated uropathogenic Gram negative bacteria (GNB) in Nigeria. Fifty non-duplicate GNB isolates consisting of Escherichia coli, 19; Klebsiella pneumoniae, 21; and Pseudomonas aeruginosa, 10 were obtained from three tertiary hospitals in Nigeria. The antibiotic susceptibility testing of all isolates to a panel of antibiotics including minimum inhibitory concentrations (MICs) and extended spectrum beta-lactamases was determined. Polymerase chain reactions and sequencing were used to detect beta-lactam genes. Polymerase chain reactions and sequencing identified varying extended spectrum beta-lactamases (ESBLs) encoding genes for 24 isolates (48.0%). Cefotaximase-Munich (CTX-M) 15 was the dominant gene with 20/24 of the isolates positive at 83.3%; multiple genes (2 to 6 ESBL genes) were found in 20 of the isolates. The isolates encoded other genes such as CTX-M-14, 33.3%; sulfhydryl variable (SHV) variants, 58.3%; oxacillinase (OXA) variants, 70.8%; OXA-10, 29.2%; and Vietnamese extended beta-lactamase (VEB) 1, 25.0%. There was no difference between the MIC50 and MIC90 of all the isolates. The high-level multidrug resistance of uropathogens to third generation cephalosporins including other antibiotics used in this study is strongly associated with carriage of ESBLs, predominantly CTX-M-15, as well as CTX-X-M-14, OXA-10, and VEB-1. PMID- 29760962 TI - Phenotypic and Molecular Identification of Vancomycin Resistance in Clinical Staphylococcus Aureus Isolates in Osogbo, Nigeria. AB - The use of vancomycin for treatment of serious infections caused by MRSA strains has resulted in emergence of vancomycin-resistant Staphylococcus aureus (VRSA) in clinical settings. Following our previous report of phenotypic VRSA in Nigeria, the current study attempts to determine the genetic basis underlying this resistance. Over a period of 6 months, non-duplicate clinical S. aureus isolates from 73 consecutive patients with infective conditions at Ladoke Akintola University of Technology Teaching Hospital, Osogbo were tested against a panel of eight selected antibiotics by disk diffusion test. The Epsilom test strip was used to determine vancomycin minimum inhibitory concentration (MIC) and polymerase chain reaction (PCR) assay to amplify nuc, mecA, vanA, and vanB genes. Of 73 isolates, 61 (83.6%) had MIC of <=2 MUg/ml, 11 (15.1%) had 4-8 MUg/ml and 1 (1.4%) had 16 MUg/ml. The mecA gene was detected in 5 (6.8%) isolates but none contained vanA or vanB genes. Both vancomycin-susceptible and intermediate isolates were resistant to multiple antibiotics, while the only vancomycin resistant isolate was resistant to all eight antibiotics. The result confirms the occurrence of phenotypic vancomycin intermediate-resistant S. aureus (VISA) and VRSA infections in Nigeria, but the molecular basis will require further investigation. PMID- 29760963 TI - Effectiveness of a Day Rehabilitation Program in Improving Functional Outcome and Reducing Mortality and Readmission of Elderly Patients With Fragility Hip Fractures. AB - Introduction: The incidence of hip fracture is projected to increase in the next 25 years as the world population ages. Hip fracture is often associated with subsequent readmission and mortality. Nevertheless, elderly patients often may not achieve the same level of functional ability as prior to their injury. Several studies have shown that close collaboration between orthopedic surgeons and geriatricians can improve such outcomes and Geriatric Day Hospital (GDH) is one of the examples of collaboration to improve such outcomes. The aim of this descriptive retrospective study is to review the effectiveness of the day rehabilitation program provided by a GDH on functional outcomes, mortality, and readmission rate, among a sample of elderly patients with hip fracture. Methods: The medical records of patients from January 1, 2009, to December 31, 2012, were collected and evaluated. Demographic data of the patients and Charlson Comorbidity Index were collected. The Barthel Index, Elderly Mobility Scale, and Mini-Mental State Examination were measured on admission and at discharge of the patients to evaluate both physical and cognitive functions. Results: The results showed that the majority of patients benefited from rehabilitation in the GDH. The 12-month mortality rate of patients taking full-course rehabilitation in the GDH was improved. The age of patient was the most important factor influencing the rehabilitation outcomes. Gender was the only risk factor for 12-month mortality and 6-month readmission. Discussion: Since patients were selected to attend GDH, there was a bias during the selection of patients. Furthermore, it was difficult to compare patients attended GDH with patients who did not because outcomes of the latter were difficult to be recorded. Conclusions: Our study shows that postoperative geriatric hip fracture patients definitely can benefit from rehabilitation service offered by GDH in terms of functional and cognitive outcomes. PMID- 29760964 TI - Demographic Study of Hip Fractures in the Maltese Islands. AB - Introduction: Despite hip fractures being a great public health burden, only few studies have analyzed the relationship between hip fracture incidence and socioeconomic status. Many studies found an association; however, results are in part conflicting. Objective: To analyze the impact of regional-level socioeconomic status on the incidence of hip fractures in the Maltese Islands. Method: All individuals older than 50 years who presented to the acute care hospitals in Malta and Gozo with low-energy hip fractures between December 1, 2015, and November 30, 2016, were selected. Data on individual demographics, hip fracture type, surgical intervention, and hospital stay were collected. The percentage of hip fracture and socioeconomic status of each region in the Maltese Islands were calculated. These were then analyzed for any statistical association. Results: A moderate negative correlation (r = -0.5987, N = 454, P < .05) was found between the socioeconomic status and the incidence of hip fracture in each region. There was 5.9% (n = 27) mortality rate posed by these hip fractures. The average duration of hospital stay was 14 days, with an average delay to surgical intervention of 2 days. Conclusion: Despite the Maltese Islands having a small population (429 344 people) and a free universal national health service, our results show that districts with low socioeconomic status had a higher incidence of hip fracture. Further studies using individual socioeconomic data and longer duration are required. PMID- 29760965 TI - Age and Other Risk Factors Influencing Long-Term Mortality in Patients With Traumatic Cervical Spine Fracture. AB - Objective: To identify clinical or demographic variables that influence long-term mortality, as well as in-hospital mortality, with a particular focus on the effects of age. Summary and Background Data: Cervical spine fractures with or without spinal cord injury (SCI) disproportionately impact the elderly who constitute an increasing percentage of the US population. Methods: We analyzed data collected for 10 years at a state-designated level I trauma center to identify variables that influenced in-hospital and long-term mortality among elderly patients with traumatic cervical spine fracture with or without SCI. Acute in-hospital mortality was determined from hospital records and long-term mortality within the study period (2003-2013) was determined from the National Death Index. Univariate and multivariate regression analyses were used to identify factors influencing survival. Results: Data from patients (N = 632) with cervical spine fractures were analyzed, the majority (66%) of whom were geriatric (older than age 64). Most patients (62%) had a mild/moderate injury severity score (ISS; median, interquartile range: 6, 5). Patients with SCI had significantly longer lengths of stay (14.1 days), days on a ventilator (3.5 days), and higher ISS (14.9) than patients without SCI (P < .0001 for all). Falls were the leading mechanism of injury for patients older than age 64. Univariate analysis identified that long-term survival decreased significantly for all patients older than age 65 (hazard ratio [HR]: 1.07; P < .0001). Multivariate analysis demonstrated age (HR: 1.08; P < .0001), gender (HR: 1.60; P < .0007), and SCI status (HR: 1.45, P < .02) significantly influenced survival during the study period. Conclusion: This study identified age, gender, and SCI status as significant variables for this study population influencing long-term survival among patients with cervical spine fractures. Our results support the growing notion that cervical spine injuries in geriatric patients with trauma may warrant additional research. PMID- 29760966 TI - Fast localization method of an anomaly in tissue based on differential optical density. AB - The position of the source-detector (S-D) relative to an anomaly has an important influence on the detection effect in non-invasive near-infrared spectroscopy based methods. In this study, a single-source multi-detector structure was designed in order to realize the rapid localization of anomalies within tissue. This method uses finite element analysis of the optical density distribution for different horizontal positions, depths and diameters of anomalies. The difference in optical density between the detectors was then calculated. The simulation results show that the horizontal position of the anomaly in the tissue can be quickly located according to the differential optical density difference curves formed by the multiple detectors. The Gaussian fitting feature of these curves shows strong correlation with the horizontal positions, depths and diameters of the anomaly. Through the differential optical density difference curves, rapid localization within the region of interest can be achieved. This method provides an important reference for sources and detectors location for tumor detection, brain function optical imaging and other fields using near infrared spectroscopy, and improves its detection accuracy. PMID- 29760967 TI - Blood vessel detection, localization and estimation using a smart laparoscopic grasper: a Monte Carlo study. AB - For centuries, surgeons have relied on their sense of touch to identify vital structures such as blood vessels in traditional open surgery. Over the past two decades, surgeons have shifted to minimally invasive surgical (MIS) approaches, including laparoscopic surgery, which include benefits such as less scarring, less risk for infection, and quicker recovery times. In fact, some surgeries such as cholecystectomies have seen more than an 80% adoption of this technique because of those benefits. However, due to the fundamental challenges associated with using laparoscopic surgery, there has been a lower adoption in more complex specialties, such as colorectal and thoracic surgery, where the field of surgery has bleeding, fat, scar tissue, and adhesions. These problems are exacerbated by complicating factors such as inflammation, cancer, chronic disease, obesity, and re-operations. Importantly, surgeons will often convert from laparoscopy to open surgery if they can no longer proceed using the minimally invasive approach because of issues described with these complicating factors, thereby negating the benefits that the patient would have seen. When the surgeon does attempt these procedures with those issues, the surgery takes on average 30 min - 1 hour longer. A new method by which surgeons can visualize structures like blood vessels could reduce the conversion rates and operating time, thereby driving a greater adoption of laparoscopic surgery in these complex procedures. Here, we show that by adding near infrared (NIR) LEDs and a linear image sensor onto the opposing jaws of the laparoscopic graspers, blood vessels that are embedded within tissues can be detected and localized efficiently, even those not visible using current imaging techniques. We show the results of Monte Carlo simulations to support our claim, including that blood vessels ranging from 2 to 6 mm and buried under up to 1 cm of tissue can be detected. We also report developing a smart grasper handheld prototype to run ex vivo experiments. The results of these experiments matched with those of the Monte Carlo simulations and the estimated blood vessel size showed a strong correlation with the actual size. This technology will be incorporated into already existing laparoscopic tools to assist surgeons during MIS procedures. PMID- 29760968 TI - Analysis of hepatitis C infection using Raman spectroscopy and proximity based classification in the transformed domain. AB - This work presents a diagnostic system for the hepatitis C infection using Raman spectroscopy and proximity based classification. The proposed method exploits transformed Raman spectra using the proximity based machine learning technique and is denoted as RS-PCA-Prox. First, Raman spectral data is baseline corrected by subtracting noise and low intensity background. After this, a feature transformation of Raman spectra is adopted, not only to reduce the feature's dimensionality but also to learn different deviations in Raman shifts. The proposed RS-PCA-Prox shows significant diagnostic power in terms of accuracy, sensitivity, and specificity as 95%, 0.97 and 0.94 in PCA based transformed domain. The comparison of the RS-PCA-Prox with linear and ensemble based classifiers shows that proximity based classification performs better for the discrimination of HCV infected individuals and is able to differentiate the infected individuals from normal ones on the basis of molecular spectral information. Furthermore, it is observed that characteristic spectral changes are due to variation in the intensity of lectin, chitin, lipids, ammonia and viral protein as a consequence of the HCV infection. PMID- 29760969 TI - Automated spectroscopic retinal oximetry with visible-light optical coherence tomography. AB - Accurate, quantitative assessment of retinal blood oxygen saturation (sO2 ) may provide a useful early indicator of pathophysiology in several ocular diseases. Here, with visible-light optical coherence tomography (OCT), we demonstrate an automated spectroscopic retinal oximetry algorithm to measure the sO2 within the retinal arteries (A-sO2 ) and veins (V-sO2 ) in rats by automatically detecting the vascular posterior boundary on cross-sectional structural OCT. The algorithm was validated in vitro with flow phantoms and in vivo in rats by comparing the sO2 results, respectively, to those obtained using a blood gas analyzer and pulse oximetry. We also investigated the response of oxygen extraction (A-V sO2 ), including inter-session reproducibility, at different inhaled oxygen concentrations. PMID- 29760970 TI - Liquid phantoms for near-infrared and diffuse correlation spectroscopies with tunable optical and dynamic properties. AB - We present the recipe and characterization for preparing liquid phantoms that are suitable for both near-infrared spectroscopy and diffuse correlation spectroscopy. The phantoms have well-defined and tunable optical and dynamic properties, and consist of a solution of water and glycerol with fat emulsion as the scattering element. The recipe takes into account the effect of bulk refractive index changes due to the addition of glycerol, which is commonly used to alter the sample viscosity. PMID- 29760971 TI - Quantitative characterization of turbidity by radiative transfer based reflectance imaging. AB - A new and noncontact approach of multispectral reflectance imaging has been developed to inversely determine the absorption coefficient of MU a , the scattering coefficient of MUs and the anisotropy factor g of a turbid target from one measured reflectance image. The incident beam was profiled with a diffuse reflectance standard for deriving both measured and calculated reflectance images. A GPU implemented Monte Carlo code was developed to determine the parameters with a conjugate gradient descent algorithm and the existence of unique solutions was shown. We noninvasively determined embedded region thickness in heterogeneous targets and estimated in vivo optical parameters of nevi from 4 patients between 500 and 950nm for melanoma diagnosis to demonstrate the potentials of quantitative reflectance imaging. PMID- 29760972 TI - Selective delivery of laser energy to ester bonds of triacylglycerol in lipid droplets of adipocyte using a quantum cascade laser. AB - The recent development of quantum cascade lasers (QCLs) has facilitated the irradiation of a mid-infrared laser beam that is specifically absorbed by a target molecular bond. Aiming for a selective delivery of laser energy to a specific absorption at 1,738 cm-1 by the ester bonds of triacylglycerol (TAG), a QCL beam with a wavenumber of 1,710 cm-1 was irradiated to 3T3-L1 adipocytes and preadipocytes. Neutral red staining, and FITC-labeled annexin V and ethidium homodimer-III assays revealed the occurrence of adipocyte-specific cell death 24 h after QCL irradiation. The selective delivery of laser energy to endogenous molecules can affect biological processes in a living organism. PMID- 29760973 TI - Circumferential-scanning endoscopic optical coherence tomography probe based on a circular array of six 2-axis MEMS mirrors. AB - We present a novel circumferential-scan endoscopic optical coherence tomography (OCT) probe by using a circular array of six electrothermal microelectromechanical (MEMS) mirrors and six C-lenses. The MEMS mirrors have a 0.5 mm * 0.5 mm mirror plate and a chip size of 1.5 mm * 1.3 mm. Each MEMS mirror can scan up to 45 degrees at a voltage of less than 12 V. Six of those mirrors have been successfully packaged to a probe head; full circumferential scans have been demonstrated. Furthermore, each scan unit is composed of a MEMS mirror and a C-lens and the six scan units can be designed with different focal lengths to adapt for lesions with uneven surfaces. Configured with a swept source OCT system, this MEMS array-based circumferential scanning probe has been applied to image a swine's small intestine wrapped on a 20 mm-diameter glass tube. The OCT imaging result shows that this new MEMS endoscopic OCT has promising applications in large tubular organs. PMID- 29760974 TI - White light polarization sensitive optical coherence tomography for sub-micron axial resolution and spectroscopic contrast in the murine retina. AB - A white light polarization sensitive optical coherence tomography system has been developed, using a supercontinuum laser as the light source. By detecting backscattered light from 400 - 700 nm, an axial resolution of 1.0 um in air was achieved. The system consists of a free-space interferometer and two homemade spectrometers that detect orthogonal polarization states. Following system specifications, images of a healthy murine retina as acquired by this non-contact system are presented, showing high resolution reflectivity images as well as spectroscopic and polarization sensitive contrast. Additional images of the very low-density-lipoprotein-receptor (VLDLR) knockout mouse model were acquired. The high resolution allows the detection of small lesions in the retina. PMID- 29760975 TI - High-throughput intensity diffraction tomography with a computational microscope. AB - We demonstrate a motion-free intensity diffraction tomography technique that enables the direct inversion of 3D phase and absorption from intensity-only measurements for weakly scattering samples. We derive a novel linear forward model featuring slice-wise phase and absorption transfer functions using angled illumination. This new framework facilitates flexible and efficient data acquisition, enabling arbitrary sampling of the illumination angles. The reconstruction algorithm performs 3D synthetic aperture using a robust computation and memory efficient slice-wise deconvolution to achieve resolution up to the incoherent limit. We demonstrate our technique with thick biological samples having both sparse 3D structures and dense cell clusters. We further investigate the limitation of our technique when imaging strongly scattering samples. Imaging performance and the influence of multiple scattering is evaluated using a 3D sample consisting of stacked phase and absorption resolution targets. This computational microscopy system is directly built on a standard commercial microscope with a simple LED array source add-on, and promises broad applications by leveraging the ubiquitous microscopy platforms with minimal hardware modifications. PMID- 29760976 TI - Glioblastoma cells labeled by robust Raman tags for enhancing imaging contrast. AB - Complete removal of a glioblastoma multiforme (GBM), a highly malignant brain tumor, is challenging due to its infiltrative characteristics. Therefore, utilizing imaging agents such as fluorophores to increase the contrast between GBM and normal cells can help neurosurgeons to locate residual cancer cells during image guided surgery. In this work, Raman tag based labeling and imaging for GBM cells in vitro is described and evaluated. The cell membrane of a GBM adsorbs a substantial amount of functionalized Raman tags through overexpression of the epidermal growth factor receptor (EGFR) and "broadcasts" stronger pre defined Raman signals than normal cells. The average ratio between Raman signals from a GBM cell and autofluorescence from a normal cell can be up to 15. In addition, the intensity of these images is stable under laser illuminations without suffering from the severe photo-bleaching that usually occurs in fluorescent imaging. Our results show that labeling and imaging GBM cells via robust Raman tags is a viable alternative method to distinguish them from normal cells. This Raman tag based method can be used solely or integrated into an existing fluorescence system to improve the identification of infiltrative glial tumor cells around the boundary, which will further reduce GBM recurrence. In addition, it can also be applied/extended to other types of cancer to improve the effectiveness of image guided surgery. PMID- 29760977 TI - Fast volume-scanning light sheet microscopy reveals transient neuronal events. AB - Light sheet fluorescence microscopy offers considerable potential to the cellular neuroscience community as it makes it possible to image extensive areas of neuronal structures, such as axons or dendrites, with a low light budget, thereby minimizing phototoxicity. However, the shallow depth of a light sheet, which is critical for achieving high contrast, well resolved images, adds a significant challenge if fast functional imaging is also required, as multiple images need to be collected across several image planes. Consequently, fast functional imaging of neurons is typically restricted to a small tissue volume where part of the neuronal structure lies within the plane of a single image. Here we describe a method by which fast functional imaging can be achieved across a much larger tissue volume; a custom-built light sheet microscope is presented that includes a synchronized galvo mirror and electrically tunable lens, enabling high speed acquisition of images across a configurable depth. We assess the utility of this technique by acquiring fast functional Ca2+ imaging data across a neuron's dendritic arbour in mammalian brain tissue. PMID- 29760978 TI - Dielectric barrier discharge plasma treatment of modified SU-8 for biosensing applications. AB - In this work we demonstrate the use of a dielectric barrier discharge plasma for the treatment of SU-8. The resulting hydrophilic surface displays a 5 degrees contact angle and (0.40 +/- 0.012) nm roughness. Using this technique we also present a proof of concept of IgG and prostate specific antigen biodetection on a thin layer of SU-8 over gold via surface plasmon resonance detection. PMID- 29760979 TI - Non-invasive in vivo quantification of the developing optical properties and graded index of the embryonic eye lens using SPIM. AB - Graded refractive index lenses are inherent to advanced visual systems in animals. By understanding their formation and local optical properties, significant potential for improved ocular healthcare may be realized. We report a novel technique measuring the developing optical power of the eye lens, in a living animal, by exploiting the orthogonal imaging modality of a selective plane illumination microscope (SPIM). We have quantified the maturation of the lenticular refractive index at three different visible wavelengths using a combined imaging and ray tracing approach. We demonstrate that the method can be used with transgenic and vital dye labeling as well as with both fixed and living animals. Using a key eye lens morphogen and its inhibitor, we have measured their effects both on lens size and on refractive index. Our technique provides insights into the mechanisms involved in the development of this natural graded index micro-lens and its associated optical properties. PMID- 29760980 TI - Optimization of wavelength selection for multispectral image acquisition: a case study of atrial ablation lesions. AB - In vivo autofluorescence hyperspectral imaging of moving objects can be challenging due to motion artifacts and to the limited amount of acquired photons. To address both limitations, we selectively reduced the number of spectral bands while maintaining accurate target identification. Several downsampling approaches were applied to data obtained from the atrial tissue of adult pigs with sites of radiofrequency ablation lesions. Standard image qualifiers such as the mean square error, the peak signal-to-noise ratio, the structural similarity index map, and an accuracy index of lesion component images were used to quantify the effects of spectral binning, an increased spectral distance between individual bands, as well as random combinations of spectral bands. Results point to several quantitative strategies for deriving combinations of a small number of spectral bands that can successfully detect target tissue. Insights from our studies can be applied to a wide range of applications. PMID- 29760981 TI - A handheld microscope integrating photoacoustic microscopy and optical coherence tomography. AB - The combination of optical resolution photoacoustic microscopy (ORPAM) and optical coherence tomography (OCT) is capable of providing complementary imaging contrasts. Unfortunately, the miniaturization of ORPAM remains a major challenge in the development of a handheld dual-modality imaging microscope with OCT. Here, we report the design and evaluation of an integrated ORPAM and OCT imaging probe using a two-dimensional MEMS (micro-electro-mechanical-system)-based optical scanner. This microscope, weighting 35.4 g, has an ultracompact size of 65*30*18 mm3, and an effective imaging area of 2*2 mm2. The experimental lateral resolutions are 3.7 MUm (ORPAM) and 5.6 MUm (OCT), and the axial resolutions are measured as 120 MUm (ORPAM) and 7.3 MUm (OCT). Besides phantom and animal experiments, we carried out oral imaging of a healthy volunteer to show the clinical feasibility of this technique. PMID- 29760983 TI - Performance of optoacoustic and fluorescence imaging in detecting deep-seated fluorescent agents. AB - Fluorescent contrast agents are widely employed in biomedical research. While many studies have reported deep tissue imaging of fluorescent moieties using either fluorescence-based or absorption-based (optoacoustic) imaging systems, no systematic comparison has been performed regarding the actual performance of these imaging modalities in detecting deep-seated fluorescent agents. Herein, an integrated imager combining epi-fluorescence and volumetric optoacoustic imaging capabilities has been employed in order to evaluate image degradation with depth for several commonly-used near-infrared dyes in both modes. We performed controlled experiments in tissue-mimicking phantoms containing deeply embedded targets filled with different concentrations of Alexa Fluor 700, Alexa Fluor 750, indocyanine green (ICG) and IRDye 800CW. The results are further corroborated by multi-modal imaging of ICG through mouse tissues in vivo. It is shown that optoacoustics consistently provides better sensitivity in differentiating fluorescent targets located at depths beyond 2 mm in turbid tissues, as quantified by evaluating image contrast, signal to noise ratio and spatial resolution performance. PMID- 29760982 TI - Biodynamic digital holography of chemoresistance in a pre-clinical trial of canine B-cell lymphoma. AB - Biodynamic digital holography was used to obtain phenotypic profiles of canine non-Hodgkin B-cell lymphoma biopsies treated with standard-of-care chemotherapy. Biodynamic signatures from the living 3D tissues were extracted using fluctuation spectroscopy from intracellular Doppler light scattering in response to the molecular mechanisms of action of therapeutic drugs that modify a range of internal cellular motions. The standard-of-care to treat B-cell lymphoma in both humans and dogs is a combination CHOP therapy that consists of doxorubicin, prednisolone, cyclophosphamide and vincristine. The proportion of dogs experiencing durable cancer remission following CHOP chemotherapy was 68%, with 13 out of 19 dogs responding favorably to therapy and 6 dogs failing to have progression-free survival times greater than 100 days. Biodynamic signatures were found that correlate with inferior survival times, and biomarker selection was optimized to identify specific Doppler signatures related to chemoresistance. A machine learning classifier was constructed based on feature vector correlations and linear separability in high-dimensional feature space. Hold-out validation predicted patient response to therapy with 84% accuracy. These results point to the potential for biodynamic profiling to contribute to personalized medicine by aiding the selection of chemotherapy for cancer patients. PMID- 29760984 TI - The value of ultrahigh resolution OCT in dermatology - delineating the dermo epidermal junction, capillaries in the dermal papillae and vellus hairs. AB - Optical coherence tomography (OCT) imaging of the skin is gaining recognition and is increasingly applied to dermatological research. A key dermatological parameter inferred from an OCT image is the epidermal (Ep) thickness as a thickened Ep can be an indicator of a skin disease. Agreement in the literature on the signal characters of Ep and the subjacent skin layer, the dermis (D), is evident. Ambiguities of the OCT signal interpretation in the literature is however seen for the transition region between the Ep and D, which from histology is known as the dermo-epidermal junction (DEJ); a distinct junction comprised of the lower surface of a single cell layer in epidermis (the stratum basale) connected to an even thinner membrane (the basement membrane). The basement membrane is attached to the underlying dermis. In this work we investigate the impact of an improved axial and lateral resolution on the applicability of OCT for imaging of the skin. To this goal, OCT images are compared produced by a commercial OCT system (Vivosight from Michaelson Diagnostics) and by an in-house built ultrahigh resolution (UHR-) OCT system for dermatology. In 11 healthy volunteers, we investigate the DEJ signal characteristics. We perform a detailed analysis of the dark (low) signal band clearly seen for UHR-OCT in the DEJ region where we, by using a transition function, find the signal transition of axial sub resolution character, which can be directly attributed to the exact location of DEJ, both in normal (thin/hairy) and glabrous (thick) skin. To our knowledge no detailed delineating of the DEJ in the UHR-OCT image has previously been reported, despite many publications within this field. For selected healthy volunteers, we investigate the dermal papillae and the vellus hairs and identify distinct features that only UHR-OCT can resolve. Differences are seen in tracing hairs of diameter below 20 MUm, and in imaging the dermal papillae where, when utilising the UHR-OCT, capillary structures are identified in the hand palm, not previously reported in OCT studies and specifically for glabrous skin not reported in any other in vivo optical imaging studies. PMID- 29760986 TI - Analysis of dermal composite conditions using collagen absorption characteristics in the THz range. AB - The absorption characteristics of the dermis were reviewed in the terahertz range from 0.2 to 2 THz. The absorption magnitude of the dermis was higher than that of the epidermis model owing to the inclusion of collagen fibers. The heat denaturation of the collagen and the decrease of water content in the dermis caused a decrease in the absorption magnitude of the dermis. We verified that the absorption magnitude of collagen sheets at 1 THz similarly decreased by nearly 43% upon the heat treatment at approximately 70 degrees C. When the heat-treated sheet was used as a scaffold for cell culture, the average growth rate of the fibroblast increased. These findings suggest that variation in the ability of cell growth in the dermis can be predicted using the absorption of the collagen or the difference between the absorptions of dermis and water. PMID- 29760985 TI - Terahertz time-domain spectroscopy for non-invasive assessment of water content in biological samples. AB - We apply terahertz time-domain spectroscopy for the quantitative non-invasive assessment of the water content in biological samples, such as Carpinus caroliniana tree leaves and pork muscles. The developed experimental terahertz time-domain spectroscopy system operates both in transmission and reflection modes. The Landau-Looyenga-Lifshitz-based model is used for the calculation of the water concentration within the samples. The results of the water concentration measurements are compared with the results of the gravimetric measurements. The obtained results show that the water content in biological samples can be measured non-invasively, with a high accuracy, utilizing terahertz waves in transmission and reflection modes. PMID- 29760988 TI - Intra-class variability in diffuse reflectance spectroscopy: application to porcine adipose tissue. AB - Optical diffuse reflectance spectroscopy (DRS) has great potential in the study, diagnosis, and discrimination of biological tissues. Discrimination is based on massive measurements that conform training sets. These sets are then used to classify tissues according to the biomedical application. Classification accuracy depends strongly on the training dataset, which typically comes from different samples of the same class, and from different points of the same sample. The variability of these measurements is not usually considered and is assumed to be purely random, although it could greatly influence the results. In this work, spectral variations within and between samples of different animals of ex-vivo porcine adipose tissue are evaluated. Algorithms for normalization, dimensionality reduction by principal component analysis, and variability control are applied. The PC analysis shows the dataset variability, even when a variability removal algorithm is applied. The projected data appear grouped by animal in the PC space. Mahalanobis distance is calculated for every group, and an ANOVA test is performed in order to estimate the variability. The results confirm that the variability is not random and is dependent at least on the anatomical location and the specific animal. The variability magnitude is significant, particularly if the classification accuracy is needed to be high. As a consequence, it should be taken generally into account in classification problems. PMID- 29760987 TI - 5-ALA fluorescence and laser Doppler flowmetry for guidance in a stereotactic brain tumor biopsy. AB - A fiber optic probe was developed for guidance during stereotactic brain biopsy procedures to target tumor tissue and reduce the risk of hemorrhage. The probe was connected to a setup for the measurement of 5-aminolevulinic acid (5-ALA) induced fluorescence and microvascular blood flow. Along three stereotactic trajectories, fluorescence (n = 109) and laser Doppler flowmetry (LDF) (n = 144) measurements were done in millimeter increments. The recorded signals were compared to histopathology and radiology images. The median ratio of protoporphyrin IX (PpIX) fluorescence and autofluorescence (AF) in the tumor was considerably higher than the marginal zone (17.3 vs 0.9). The blood flow showed two high spots (3%) in total. The proposed setup allows simultaneous and real time detection of tumor tissue and microvascular blood flow for tracking the vessels. PMID- 29760989 TI - Fiber-based tunable repetition rate source for deep tissue two-photon fluorescence microscopy. AB - Deep tissue multiphoton imaging requires high peak power to enhance signal and low average power to prevent thermal damage. Both goals can be advantageously achieved through laser repetition rate tuning instead of simply adjusting the average power. We show that the ideal repetition rate for deep two-photon imaging in the mouse brain is between 1 and 10 MHz, and we present a fiber-based source with an arbitrarily tunable repetition rate within this range. The performance of the new source is compared to a mode-locked Ti:Sapphire (Ti:S) laser for in vivo imaging of mouse brain vasculature. At 2.5 MHz, the fiber source requires 5.1 times less average power to obtain the same signal as a standard Ti:S laser operating at 80 MHz. PMID- 29760990 TI - Spatial and temporal identification of cerebral infarctions based on multiphoton microscopic imaging. AB - Ischemic stroke is a leading cause of death and permanent disability worldwide. Middle cerebral artery occlusion (MCAO) of variable duration times could be anticipated to result in varying degrees of injury that evolve spatially over time. Therefore, investigations following strokes require information concerning the spatiotemporal dimensions of the ischemic core as well as of perilesional areas. In the present study, multiphoton microscopy (MPM) based on two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) was applied to image such pathophysiological events. The ischemic time-points for evaluation were set at 6, 24, 48, and 72 hours after MCAO. Our results demonstrated that MPM has the ability to not only identify the normal and ischemic brain regions, but also reveal morphological changes of the cortex and striatum at various times following permanent MCAO. These findings corresponded well with the hematoxylin and eosin (H&E) stained tissue images. With the technologic progression of miniaturized imaging devices, MPM can be developed into an effective diagnostic and monitoring tool for ischemic stroke. PMID- 29760991 TI - Compact fiber-based multi-photon endoscope working at 1700 nm. AB - We present the design, implementation and performance analysis of a compact multi photon endoscope based on a piezo electric scanning tube. A miniature objective lens with a long working distance and a high numerical aperture (~ 0.5) is designed to provide a diffraction limited spot size. Furthermore, a 1700 nm wavelength femtosecond fiber laser is used as an excitation source to overcome the scattering of biological tissues and reduce water absorption. Therefore, the novel optical system along with the unique wavelength allows us to increase the imaging depth. We demonstrate that the endoscope is capable of performing third and second harmonic generation (THG/SHG) and three-photon excitation fluorescence (3PEF) imaging over a large field of view (> 400 MUm) with high lateral resolution (2.2 MUm). The compact and lightweight probe design makes it suitable for minimally-invasive in-vivo imaging as a potential alternative to surgical biopsies. PMID- 29760992 TI - Effective bidirectional scanning pattern for optical coherence tomography angiography. AB - We demonstrate the utility of a novel scanning method for optical coherence tomography angiography (OCTA). Although raster scanning is commonly used for OCTA imaging, a bidirectional approach would lessen the distortion caused by galvanometer-based scanners as sources continue to increase sweep rates. As shown, a unidirectional raster scan approach has a lower effective scanning time than bidirectional approaches; however, a strictly bidirectional approach causes contrast variation along the B-scan direction due to the non-uniform time interval between B-scans. Therefore, a stepped bidirectional approach is introduced and successfully applied to retinal imaging in normal controls and in a pathological subject with diabetic retinopathy. PMID- 29760993 TI - Assessing blood vessel perfusion and vital signs through retinal imaging photoplethysmography. AB - One solution to the global challenge of increasing ocular disease is a cost effective technique for rapid screening and assessment. Current ophthalmic imaging techniques, e.g. scanning and ocular blood flow systems, are expensive, complex to operate and utilize invasive contrast agents during assessment. The work presented here demonstrates a simple retinal imaging photoplethysmography (iPPG) system with the potential to provide screening, diagnosis, monitoring and assessment that is non-invasive, painless and radiationless. Time series of individual retinal blood vessel images, captured with an eye fundus camera, are processed using standard filtering, amplitude demodulation and principle component analysis (PCA) methods to determine the values of the heart rate (HR) and respiration rate (RR), which are in compliance with simultaneously obtained measurements using commercial pulse oximetry. It also seems possible that some information on the dynamic changes in oxygen saturation levels (SpO2) in a retinal blood vessel may also be obtained. As a consequence, the retinal iPPG modality system demonstrates a potential avenue for rapid ophthalmic screening, and even early diagnosis, against ocular disease without the need for fluorescent or contrast agents. PMID- 29760994 TI - Nth-order linear algorithm for diffuse correlation tomography. AB - The current approaches to imaging the tissue blood flow index (BFI) from diffuse correlation tomography (DCT) data are either an analytical solution or a finite element method, both of which are unable to simultaneously account for the tissue heterogeneity and fully utilize the DCT data. In this study, a new imaging concept for DCT, namely NL-DCT, was created by us in which the medical images are combined with light Monte Carlo simulation to provide geometrical and heterogeneous information in tissue. Moreover, the DCT data at multiple delay time are fully utilized via iterative linear regression. The unique merit of NL DCT in utilizing the medical images as prior information, when combined with a split Bregman algorithm for total variation minimization (Bregman-TV), was validated on a realistic human head model. Computer simulation outcomes demonstrate the accuracy and robustness of NL-DCT in localizing and separating the flow anomalies as well as the capability to preserve edges of anomalies. PMID- 29760995 TI - Intravital imaging of a pulmonary endothelial surface layer in a murine sepsis model. AB - Direct intravital imaging of an endothelial surface layer (ESL) in pulmonary microcirculation could be a valuable approach to investigate the role of a vascular endothelial barrier in various pathological conditions. Despite its importance as a marker of endothelial cell damage and impairment of the vascular system, in vivo visualization of ESL has remained a challenging technical issue. In this work, we implemented a pulmonary microcirculation imaging system integrated to a custom-design video-rate laser scanning confocal microscopy platform. Using the system, a real-time cellular-level microscopic imaging of the lung was successfully performed, which facilitated a clear identification of individual flowing erythrocytes in pulmonary capillaries. Subcellular level pulmonary ESL was identified in vivo by fluorescence angiography using a dextran conjugated fluorophore to label blood plasma and the red blood cell (RBC) exclusion imaging analysis. Degradation of ESL width was directly evaluated in a murine sepsis model in vivo, suggesting an impairment of pulmonary vascular endothelium and endothelial barrier dysfunction. PMID- 29760996 TI - Enhancement of morphological and vascular features in OCT images using a modified Bayesian residual transform. AB - A novel image processing algorithm based on a modified Bayesian residual transform (MBRT) was developed for the enhancement of morphological and vascular features in optical coherence tomography (OCT) and OCT angiography (OCTA) images. The MBRT algorithm decomposes the original OCT image into multiple residual images, where each image presents information at a unique scale. Scale selective residual adaptation is used subsequently to enhance morphological features of interest, such as blood vessels and tissue layers, and to suppress irrelevant image features such as noise and motion artefacts. The performance of the proposed MBRT algorithm was tested on a series of cross-sectional and enface OCT and OCTA images of retina and brain tissue that were acquired in-vivo. Results show that the MBRT reduces speckle noise and motion-related imaging artefacts locally, thus improving significantly the contrast and visibility of morphological features in the OCT and OCTA images. PMID- 29760997 TI - Six-wave mixing coherent anti-Stokes Raman scattering microscopy. AB - Acquiring images of biological tissues and cells without the assistance of exogenous labels with a fast repetition rate and chemical specificity is what coherent anti-Stokes Raman Scattering (CARS) imaging offers. Nonresonant background (NRB) is one of the main drawbacks of the CARS microscopy technique because it limits the detection of weak Raman lines and the detection of low concentration molecules. We show that a six-wave mixing process with two beams, which is a cascade effect of CARS, show better signal/NRB ratio and can be utilized for biological tissues imaging. The cascade CARS (CCARS) depends on chi 3 to the fourth power, instead of chi-3 squared as in the usual CARS signal; therefore, the contrast ratio with NRB is higher for CCARS than for CARS. We present analytic calculations showing that CCARS have better contrast over CARS in any situation. Comparison of the signals of both techniques generated on water ethanol solutions confirm these results. Finally, we acquired CCARS images of fresh biological tissues, attesting that it is a useful tool for biological studies. PMID- 29760998 TI - 3D + time blood flow mapping using SPIM-microPIV in the developing zebrafish heart. AB - We present SPIM-MUPIV as a flow imaging system, capable of measuring in vivo flow information with 3D micron-scale resolution. Our system was validated using a phantom experiment consisting of a flow of beads in a 50 MUm diameter FEP tube. Then, with the help of optical gating techniques, we obtained 3D + time flow fields throughout the full heartbeat in a ~3 day old zebrafish larva using fluorescent red blood cells as tracer particles. From this we were able to recover 3D flow fields at 31 separate phases in the heartbeat. From our measurements of this specimen, we found the net pumped blood volume through the atrium to be 0.239 nL per beat. SPIM-MUPIV enables high quality in vivo measurements of flow fields that will be valuable for studies of heart function and fluid-structure interaction in a range of small-animal models. PMID- 29760999 TI - Potential of short-wave infrared spectroscopy for quantitative depth profiling of stratum corneum lipids and water in dermatology. AB - We demonstrate the feasibility of short wave infrared (SWIR) spectroscopy combined with tape stripping for depth profiling of lipids and water in the stratum corneum of human skin. The proposed spectroscopic technique relies on differential detection at three wavelengths of 1720, 1750, and 1770 nm, with varying ratio of the lipid-to-water absorption coefficient and an 'isosbestic point'. Comparison of the data acquired using SWIR spectroscopy with that obtained by a gold standard for non-invasive quantitative molecular-specific skin measurements, namely confocal Raman spectroscopy (CRS), revealed specificity of the proposed modality for water and lipid quantification. At the same time, we provide evidence showing aberrant sensitivity of Corneometer hydration read-outs to the presence of skin surface lipids, and a lack of sensitivity of the Sebumeter when attempting to measure the lipids of the cornified lipid envelope and intracellular lipid layers. We conclude that a spectroscopic SWIR-based spectroscopic method combined with tape stripping has the potential for depth profiling of the stratum corneum water and lipids, due to superior measurement sensitivity and specificity compared to the Corneometer and Sebumeter. PMID- 29761000 TI - Quantitative multispectral ex vivo optical evaluation of human ovarian tissue using spatial frequency domain imaging. AB - About 85-90% of all ovarian cancers are carcinomas; these manifest clinically as mass-forming epithelial proliferations involving the ovary. In this study, a visible light spatial frequency domain imaging (SFDI) system was used for multispectral ex vivo imaging and quantitative evaluation of freshly excised benign and malignant human ovarian tissues. A total of 14 ovaries from 11 patients undergoing oophorectomy were investigated. Using a logistic regression model with seven significant spectral and spatial features extracted from SFDI images, a sensitivity of 94.06% and specificity of 93.53% were achieved for prediction of histologically confirmed invasive carcinoma. PMID- 29761001 TI - Multiscale nonlinear microscopy and widefield white light imaging enables rapid histological imaging of surgical specimen margins. AB - The ability to histologically assess surgical specimens in real-time is a long standing challenge in cancer surgery, including applications such as breast conserving therapy (BCT). Up to 40% of women treated with BCT for breast cancer require a repeat surgery due to postoperative histological findings of close or positive surgical margins using conventional formalin fixed paraffin embedded histology. Imaging technologies such as nonlinear microscopy (NLM), combined with exogenous fluorophores can rapidly provide virtual H&E imaging of surgical specimens without requiring microtome sectioning, facilitating intraoperative assessment of margin status. However, the large volume of typical surgical excisions combined with the need for rapid assessment, make comprehensive cellular resolution margin assessment during surgery challenging. To address this limitation, we developed a multiscale, real-time microscope with variable magnification NLM and real-time, co-registered position display using a widefield white light imaging system. Margin assessment can be performed rapidly under operator guidance to image specific regions of interest located using widefield imaging. Using simulated surgical margins dissected from human breast excisions, we demonstrate that multi-centimeter margins can be comprehensively imaged at cellular resolution, enabling intraoperative margin assessment. These methods are consistent with pathology assessment performed using frozen section analysis (FSA), however NLM enables faster and more comprehensive assessment of surgical specimens because imaging can be performed without freezing and cryo-sectioning. Therefore, NLM methods have the potential to be applied to a wide range of intra operative applications. PMID- 29761002 TI - Large retrospective study of artificial dura substitute in patients with traumatic brain injury undergo decompressive craniectomy. AB - Background: Decompressive craniectomy is widely used for treating patients with traumatic brain injury (TBI). Usually patients have dura mater defect due to surgery or injury itself. The defective area may left open or repaired by artificial dura substitutes. A variety of artificial dura substitutes have been used for this purpose. Objective: This study aimed to evaluate bovine-derived pericardium membrane as artificial dural material for patients with decompressive craniectomy. Methods: Totally 387 patients with severe TBI in our hospital were included in this study. Among them, 192 patients were treated with standard decompressive craniectomy without dura repair (control group). One hundred and ninety-five TBI patients were treated with dura repair by artificial dura materials (ADM). Nonlyophilized bovine pericardium membranes were used as artificial dura material. The postoperative complications were compared in both groups, including infection, seizure, and cerebrospinal fluid (CSF) leakage. Results: Patients in control group have higher complication rates than patients in ADM group, including subcutaneous hematoma (13.02% in control vs. 4.01% in ADM group, p = .004), infection (12.5% in control vs. 5.64% in ADM group, p = .021), CSF leakage (13.02% in control vs. 5.13% in ADM group, p = .012), and seizure (10.42% in control vs. 3.08% in ADM group, p = .007). Patients in ADM group are only associated with higher incidence of foreign body reaction (6 of 195 patients in ADM vs. none from control group). Conclusion: Bovine-derived pericardium membranes are successfully used as artificial dural substitutes for decompressive craniectomy. Patients with ADM have better clinical outcome than control group. PMID- 29761003 TI - The asymmetry of neural symptoms in Wilson's disease patients detecting by diffusion tensor imaging, resting-state functional MRI, and susceptibility weighted imaging. AB - Objective: To investigate the cause of the motor asymmetry in Wilson's disease (WD) patients using functional MRI. Methods: Fifty patients with WD and 20 age matched healthy controls were enrolled. Neurological symptoms were scored using the modified Young Scale. All study subjects underwent diffusion tensor imaging (DTI), susceptibility-weighted imaging (SWI), and resting-state functional MRI (rs-fMRI) of the brain. Six regions of interest (ROI) were chosen. Fiber volumes between ROIs on DTI, corrected phase (CP) values on SWI, amplitude of low frequency fluctuation (ALFF), and regional homogeneity (REHO) values on rs-fMRI were determined. Asymmetry index (right or left value/left or right value) was evaluated. Results: Asymmetry of rigidity, tremor, choreic movement, and gait abnormality (asymmetry index = 1.33, 1.39, 1.36, 1.40), fiber tracts between the GP and substantia nigra (SN), GP and PU, SN and thalamus (TH), SN and cerebellum, head of the caudate nucleus (CA) and SN, PU and CA, CA and TH, TH and cerebellum (asymmetry index = 1.233, 1.260, 1.269, 1.437, 1.503, 1.138, 1.145, 1.279), CP values in the TH, SN (asymmetry index = 1.327, 1.166), ALFF values, and REHO values of the TH (asymmetry index = 1.192, 1.233) were found. Positive correlation between asymmetry index of rigidity and fiber volumes between the GP and SN, SN and TH (r = .221, .133, p = .043, .036), and tremor and fiber volumes between the CA and TH (r = .045, p = .040) was found. Conclusions: The neurological symptoms of patients with WD were asymmetry. The asymmetry of fiber projections may be the main cause of motor asymmetry in patients with WD. PMID- 29761004 TI - Exploring the impact of chronic high-altitude exposure on visual spatial attention using the ERP approach. AB - Introduction: Previous studies have reported the slowing of reaction times to attentionally demanding tasks due to a reduction in cognitive resource as a result of chronic high-altitude exposure. However, it is still largely unknown whether this reaction slowness can be attributed to the attentional allocation change and/or response patterns. Methods: To clarify this issue, this study investigated attention-related (N2pc and N2 cc) and response-related (MP and RAP) event-related potentials (ERPs) to identify the performance of a visual search task by individuals who had lived in high-altitude areas for three years compared with those living at sea level. Results: This study showed that the reaction times in response to a visual search task were significantly longer in the high altitude subjects than in the sea level subjects. Corresponding to this behavioral observation, we found a significantly lower N2pc amplitude and a larger N2 cc amplitude in the high-altitude subjects, suggesting a reduction in spatial attention allocation to the target (N2pc) in these subjects, indicating they need to work harder to preclude cross-talk between response selection and attention direction (N2 cc). Moreover, we also discovered higher MP amplitudes and longer RAP latencies in the high-altitude subjects, which further indicated that these subjects were slower and required greater cortical activation while preparing and executing correctly selected responses (MP and RAP). Conclusion: Nevertheless, this study collectively provided new insights into the attention reaction slowness from high-altitude exposure. PMID- 29761005 TI - Beauty-related perceptual bias: Who captures the mind of the beholder? AB - Introduction: To explore the beauty-related perceptual bias and answers the question: Who can capture the mind of the beholder? Many studies have explored the specificity of human faces through ERP or other ways, and the materials they used are general human faces and other objects. Therefore, we want to further explore the difference between attractive faces and beautiful objects such as flowers. Methods: We recorded the eye movement of 22 male observers and 23 female observers using a standard two-alternative forced choice. Results: (1) The attractive faces were looked at longer and more often in comparison with the beautiful flowers; (2) fixation counts of female participants are more than male participants; and (3) the participants watched the beautiful flowers first, followed by the attractive faces, but there was no significant difference on the first fixation duration between the beautiful flowers and the attractive faces. Conclusions: The data in this study may suggest that people prefer attractive faces to beautiful flowers. PMID- 29761006 TI - Sodium valproate compared to phenytoin in treatment of status epilepticus. AB - Background: Status epilepticus (SE) is a neurological emergency which can be life threatening. Several medical regimens are used in order to control it. In this study, we intended to evaluate the clinical efficacy and tolerability of sodium valproate and intravenous phenytoin (IV PHT) in the control of SE. Methods: One hundred and ten consecutive patients suffering from benzodiazepine refractory SE who were referred to the emergency ward from March 2014 to March 2015 were randomly divided into two groups. The first group received intravenous sodium valproate, 30 mg/kg as loading dose and then 4-8 mg/kg every 8 hr as maintenance regimen. The second group received IV PHT 20 mg/kg as loading dose and then 1.5 mg/kg for 8 hr as maintenance therapy. All patients were monitored for vital signs every 2 hr up to 12 hr. The patients were also followed up for 7 days regarding drug response and adverse effects. Results: The administration of sodium valproate and phenytoin respectively resulted in seizure control in 43 (78.18%) and 39 (70.90%) of the patients within 7 days of drug administration (p = .428). Seven-day mortality rate was similar in both groups (12.73% vs. 12.73%; p = .612). There was no significant difference in adverse effects between two groups. Conclusion: Sodium valproate is preferred to IV PHT for treatment and control of SE due to its higher tolerability and lower hemodynamic instability. PMID- 29761007 TI - Behavioral changes induced through adenosine A2A receptor ligands in a rat depression model induced by olfactory bulbectomy. AB - Background: Major depressive disorders are characterized by their severity and long-lasting symptoms, which make such disorders highly disabling illnesses. Unfortunately, 50% of major depressive patients experience relapses, perhaps partly because drug research has been performed only in animal models that screen for antidepressant drugs that appear to only ameliorate acute depression symptoms. The bilateral olfactory bulbectomy (OBX) animal model presents the advantage of mimicking the symptoms of chronic depression by means of brain surgery. Adenosine purinergic receptors A2A (A2AR) have been the target of interest in the field of psychiatric diseases. This study aimed to show which A2A receptor ligands exert antidepressive-like effects in the OBX rat model. Methods: Forty Sprague-Dawley male rats were divided into four groups: control, OBX + vehicle, OBX + ZM 241385, and OBX + adenosine groups. Pharmacological treatment was administered for 14 days, and the rats were examined via the forced swim test (FST), open field test (OFT), and sucrose preference test (SPT). Results: The OBX + ZM 241385 group exhibited decreased immobility time in the FST, decreased isolation time in the OFT, and reversed anhedonia behavior in the SPT compared to the vehicle group. However, no significant differences for adenosine treatment were found. Conclusions: ZM 241385 administration (2 mg/kg i.p.) restored behavioral changes associated with OBX-induced depression. PMID- 29761008 TI - The importance of hippocampal dynamic connectivity in explaining memory function in multiple sclerosis. AB - Introduction: Brain dynamics (i.e., variable strength of communication between areas), even at the scale of seconds, are thought to underlie complex human behavior, such as learning and memory. In multiple sclerosis (MS), memory problems occur often and have so far only been related to "stationary" brain measures (e.g., atrophy, lesions, activation and stationary (s) functional connectivity (FC) over an entire functional scanning session). However, dynamics in FC (dFC) between the hippocampus and the (neo)cortex may be another important neurobiological substrate of memory impairment in MS that has not yet been explored. Therefore, we investigated hippocampal dFC during a functional (f) magnetic resonance imaging (MRI) episodic memory task and its relationship with verbal and visuospatial memory performance outside the MR scanner. Methods: Thirty-eight MS patients and 29 healthy controls underwent neuropsychological tests to assess memory function. Imaging (1.5T) was obtained during performance of a memory task. We assessed hippocampal volume, functional activation, and sFC (i.e., FC of the hippocampus with the rest of the brain averaged over the entire scan, using an atlas-based approach). Dynamic FC of the hippocampus was calculated using a sliding window approach. Results: No group differences were found in hippocampal activation, sFC, and dFC. However, stepwise forward regression analyses in patients revealed that lower dFC of the left hippocampus (standardized beta = -0.30; p = .021) could explain an additional 7% of variance (53% in total) in verbal memory, in addition to female sex and larger left hippocampal volume. For visuospatial memory, lower dFC of the right hippocampus (standardized beta = -0.38; p = .013) could explain an additional 13% of variance (24% in total) in addition to higher sFC of the right hippocampus. Conclusion: Low hippocampal dFC is an important indicator for maintained memory performance in MS, in addition to other hippocampal imaging measures. Hence, brain dynamics may offer new insights into the neurobiological mechanisms underlying memory (dys)function. PMID- 29761009 TI - Hippocampal gray matter increases following multimodal psychological treatment for combat-related post-traumatic stress disorder. AB - Introduction: Smaller hippocampal volumes are one of the most consistent findings in neuroimaging studies of post-traumatic stress disorder (PTSD). However, very few prospective studies have assessed changes in hippocampal gray matter prior to and following therapy for PTSD, and no neuroimaging studies to date have longitudinally assessed military populations. Methods: A pilot study was conducted, assessing patients with combat-related PTSD with structural MRI. Participants were then assigned either to a treatment group or waiting-list control group. After the treatment group received multimodal psychological therapy for approximately 6 weeks, both groups completed a second neuroimaging assessment. Results: Region-of-interest analysis was used to measure gray matter volume in the hippocampus and amygdala. There was a group by time interaction; the therapy group (n = 6) showed a significant increase in hippocampal volume and a nonsignificant trend toward an increase in amygdala volume following therapy, while no change was observed in the waiting-list group (n = 9). Conclusions: This study provides initial evidence for increases in gray matter volume in the hippocampus in response to therapy for combat-related PTSD. PMID- 29761011 TI - Associations between apparent diffusion coefficient and electromyography parameters in myositis-A preliminary study. AB - Objective: MRI is widely used in several muscle disorders. Diffusion-weighted imaging (DWI) is an emergent imaging modality sensitive to microstructural alterations in tissue. The apparent diffusion coefficient (ADC) is used to quantify the random motion of water molecules. Electromyography (EMG) is a clinically used diagnostic tool in myositis. The aim of this study was to elucidate possible associations between ADC values and EMG findings in myositis patients. Method: Seven patients (eight investigated muscles) with myositis (mean age 51.43 +/- 19 years) were included in this study. The diagnosis was confirmed by histopathology in every case. DWI was obtained with a 1.5-T scanner using two b-values 0 and 1000 s/mm2. In all patients, a needle electromyography (EMG) was performed within 3 days to the MRI. The following EMG parameters were studied: motor unit action potential (MUAP) amplitudes and durations, as well as pathological spontaneous activity. Spearman's correlation coefficient was used to analyze associations between investigated parameters. Results: The estimated mean ADC mean value was 1.51 +/- 0.29 * 10-3 mm2/s, mean ADC min was 1.28 +/- 0.27 * 10-3 mm2/s, and mean ADC max was 1.73 +/- 0.28 * 10-3 mm2/s. Correlation analysis identified significant associations between ADC mean and duration of the MUAP (p = .78 P = .0279) and between ADC min and duration of the MUAP (p = .85, P = .01). There were no significant differences according to pathological spontaneous activity. Conclusion: ADC mean and ADC min showed strong positive correlations with the duration of the MUAP in myositis patients. Both modalities might similarly reflect muscle fiber loss in myositis patients. PMID- 29761010 TI - Central cholinergic system mediates working memory deficit induced by anesthesia/surgery in adult mice. AB - Background: Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality, which has become a major concern of patients and caregivers. Although POCD occurs mainly in aged patients, it happens at any age. Previous studies demonstrated that anesthesia/surgery had no effects on reference memory of adult mice. However, whether it impairs working memory remains unclear. Working memory deficit would result in many deficits of executive function. We hypothesized that anesthesia/surgery impaired the working memory of adult mice and the central cholinergic system was involved. Method: Tibial fracture internal fixation under the anesthesia of isoflurane was performed in two-month-old C57BL/6 mice. Two days later, the spatial reference memory and working memory were measured by a Morris Water Maze (MWM). Donepezil, an inhibitor of acetylcholinesterase (AChE), was administered in another cohort mice for 4 weeks. Then, the working memory was measured by MWM 2 days after anesthesia/surgery. Western blot was used to detect the protein levels of acetylcholine transferase (ChAT), AChE, vesicular acetylcholine transporter (VAChT), and choline transporter (ChT) in the prefrontal cortex (PFC). Results: We found that anesthesia/surgery had no effects on the reference memory, but it impaired the working memory in adult mice. Meanwhile, we also found that the protein level of ChAT in PFC decreased significantly compared with that in control group. Donepezil pretreatment prevented working memory impairment and the decrease of the protein levels of ChAT induced by anesthesia/surgery. Conclusion: These results suggest that anesthesia/surgery leads to working memory deficits in adult mice and central cholinergic system impairment is involved. PMID- 29761013 TI - Guillain-Barre syndrome mimics. AB - The Brighton Collaboration criteria have standardized the clinical and laboratory supported diagnosis of Guillain-Barre syndrome (GBS) and Miller Fisher syndrome (MFS) in a way that is applicable in many parts of the world with variable resources. The caveat within the criteria, "absence of an identified alternative diagnosis for weakness" makes GBS a diagnosis of exclusion. Accurate diagnosis of GBS requires a good understanding of an updated, locally contextualised list of mimics, and features that distinguish them from GBS. PMID- 29761015 TI - The influence of THC:CBD oromucosal spray on driving ability in patients with multiple sclerosis-related spasticity. AB - Background: Driving ability is a key function for the majority of patients with multiple sclerosis (MS) to help maintain daily interactions. Both physical and cognitive disability, as well as treatments, may affect the ability to drive. Spasticity is a common symptom associated with MS, and it may affect driving performance either directly or via the medications used to treat it. In this article, we review the evidence relating the antispasticity medicine, Delta9 tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex(r)), and its potential impact on driving performance. Methods: Articles were identified by searching PubMed from 1/1/2000 to 30/6/2017 using a specified list of search terms. The articles identified using these search terms were augmented with relevant references from these papers and other articles known to the authors. Results: The results from THC:CBD oromucosal spray driving studies and real-world registries did not show any evidence of an increase in motor vehicle accidents associated with THC:CBD oromucosal spray. The majority of patients reported an improvement in driving ability after starting THC:CBD oromucosal spray, and it was speculated that this may be related to reduced spasticity and/or better cognitive function. It should be noted that THC blood levels are significantly lower than the levels associated with recreational use of herbal cannabis. Conclusions: THC:CBD oromucosal spray was shown not to impair driving performance. However, periodic assessment of patients with MS driving ability is recommended, especially after relapses and changes in treatment. Blood THC measurements might be above authorized thresholds for some countries following administration of THC:CBD oromucosal spray, thus specific knowledge of each country's driving regulations and a medical certificate are recommended. PMID- 29761014 TI - Strain-specific differential expression of astrocytes and microglia in the mouse hippocampus. AB - Introduction: Genetic background influences neurotransmitter expression and function of the hippocampus. Genetic background influences the phenotype of the hippocampus, but expression of neuroglia in hippocampus has not been well established dependent on various mouse strains. Objectives: In this study, we investigated the effects of genetic background on cell population of astrocytes and microglia in eight widely used inbred strains (C57BL/6J, A/J, BALB/c, C3H/HeJ, FVB, 129/SvJ, DBA/1, and DBA/2) and one outbred strain (ICR). Methods: In all mouse strains, glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes and ionized calcium-binding adaptor molecule 1 (Iba-1)-immunoreactive microglia were found in almost all layers of hippocampal CA1-4 regions and the dentate gyrus. Results: We observed significant differences in the number of astrocytes and microglia. In the CA1 and CA3 regions, the number of GFAP immunoreactive astrocytes was highest in the C3H/HeJ strain, and lowest in the 129/SvJ and FVB strains. In the polymorphic layer of the dentate gyrus, the number was highest in the DBA/1 strain and lowest in the 129/SvJ strain. Among the nine mouse strains, the number of Iba-1-immunoreactive microglia was highest in the CA1 and CA3 regions in the ICR and in the dentate gyrus of the C57BL/6 strain. The CA1 region of the FVB strain and the CA3 region and dentate gyrus of DBA/2 had the lowest number of Iba-1-immunoreactive microglia. Conclusion: These results suggest that the numbers of astrocytes and microglia differ depending on the mouse strain and these differences may be related to strain-dependent function of astrocytes. PMID- 29761016 TI - The effects of cognitive behavioral therapy on resting-state functional brain network in drug-naive patients with obsessive-compulsive disorder. AB - Objectives: Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD), the treatment mechanisms remain poorly understood. This study aimed to investigate the effects of CBT on changes in the intrinsic whole-brain functional network of OCD patients. Materials and Methods: Twenty drug-naive and noncomorbid OCD patients were recruited, and resting-state functional magnetic resonance imaging was performed before and after 12 weeks of CBT. Moreover, 20 healthy controls were scanned twice with a 12-week interval. A graph-theory degree centrality (DC) approach and functional connectivity method were used to analyze the whole-brain functional network hub and connectivity changes in OCD patients before and after CBT treatment. Results: A significant group * time interaction on DC was found in the left dorsolateral prefrontal cortex (DLPFC); the DC in the left DLPFC was significantly reduced after CBT treatment. Resting-state functional connectivity (RSFC) between the left DLPFC and right orbitofrontal cortex was increased in the OCD patients at baseline, and normalized after CBT treatment. RSFC changes between the left DLPFC and default mode network (DMN) positively correlated with changes in clinical symptoms in OCD patients. Conclusions: These findings suggest that CBT can modulate changes in intrinsic functional network hubs in the cortico-striato-thalamo-cortical circuit in OCD patients. Cognitive control network and DMN connectivity may be a potential imaging biomarker for evaluating CBT treatment for OCD. PMID- 29761017 TI - Eleven years' experience with Intrathecal Baclofen - Complications, risk factors. AB - Objective: Treatment with intrathecal baclofen (ITB) is commonly used in patients with severe spasticity. However, complications may occur after implantation of the ITB-device, albeit mainly procedure- and device-related problems. The aim of the study was to assess surgical- as well as catheter- and pump-related complications and define their risk factors. Methods: We retrospectively evaluated all patients with an implanted ITB-device who were treated at the Department of Neurology, Hochzirl Hospital, Zirl, Austria, between 2006 and 2016. Results: Twenty-nine of 116 (25%) patients experienced 32 complications: 5 procedure- and 27 device-related (4 pump- and 23 catheter-associated) problems occurred. Risk factors for sustaining any complication were a spinal localization of lesion (odds ratio [OR] OR 2.71, p = .021), other catheter types than an Ascenda(r) catheter (OR 3.87, p = .041), a lower modified Rankin Scale (median 4 vs. 5; OR 2.86, p = .015) and a higher Barthel Index (median 53 vs. 0; OR 2.84, p = .006). The median time from the last ITB-related surgery to the first complication was 18 (IQR 1-57) months. Overall, 47% complications occurred within the first year after any surgical procedure regarding the ITB-device, thereof 25% within the first month. Conclusions: Procedure- and device-related complications are frequent after implantation of an ITB-device with catheter-associated complications as the most frequently encountered problems. Patients with a spinal origin of spasticity, a lower modified Rankin Scale and a higher Barthel Index have a higher risk to sustain a complication. PMID- 29761018 TI - Behavioral and neurophysiological abnormalities during cued continuous performance tasks in patients with mild traumatic brain injury. AB - Objective: This study's aim was to investigate the features and neural mechanisms of sustained attention in patients with mild traumatic brain injury (mTBI) by comparing and analyzing neuropsychological, behavioral, event-related potentials, and event-related desynchronization and synchronization between mTBI patients and healthy controls. Methods: Twenty mTBI patients with mTBI and 20 healthy controls underwent the Mini-Mental State Examination (MMSE) and a cued continuous performance task (AX-CPT). Neuropsychological, behavioral, and electroencephalogram (EEG) data were collected and analyzed. Results: There were significant differences between the mTBI group and the control group in their MMSE total scores, attention, and calculation, but there were no significant differences in orientation, memory, recall, and verbal scores. There were significant differences between the mTBI group and the control group in hitting the number, reaction time, and the number of errors of omission, but there were no significant differences in the number of false errors. The amplitude of Go-N2 and Nogo-N2 was significantly smaller for the mTBI group than that for the control group. The amplitude of Go-P3 was significantly smaller for the mTBI group than that for the control group, but not for the amplitude of Nogo-P3. The Go-alphaERS were significantly less for the mTBI group than for the control group during the 0-200 ms after the stimulus onset. The Go-alphaERD and Nogo-alphaERD were significantly less for the mTBI group than for the control group during the 600-1,000 ms after the stimulus onset. The Go-betaERS were significantly less for the mTBI group than for the control group during the 200-400 ms after the stimulus onset. There were no significant differences in the Nogo-alphaERS and Nogo-betaERD/ERS between the mTBI group and the control group. Conclusion: Patients with mTBI exhibited impairments in sustained attention and conflict monitoring, while response inhibition may have been spared. PMID- 29761012 TI - An overview of protective strategies against ischemia/reperfusion injury: The role of hyperbaric oxygen preconditioning. AB - Introduction: Ischemia/reperfusion (I/R) injury, such as myocardial infarction, stroke, and peripheral vascular disease, has been recognized as the most frequent causes of devastating disorders and death currently. Protective effect of various preconditioning stimuli, including hyperbaric oxygen (HBO), has been proposed in the management of I/R. Methods: In this study, we searched and reviewed up-to date published papers to explore the pathophysiology of I/R injury and to understand the mechanisms underlying the protective effect of HBO as conditioning strategy. Results: Animal study and clinic observation support the notion that HBO therapy and conditioning provide beneficial effect against the deleterious effects of postischemic reperfusion. Several explanations have been proposed. The first likely mechanism may be that HBO counteracts hypoxia and reduces I/R injury by improving oxygen delivery to an area with diminished blood flow. Secondly, by reducing hypoxia-ischemia, HBO reduces all the pathological events as a consequence of hypoxia, including tissue edema, increased affective area permeability, postischemia derangement of tissue metabolism, and inflammation. Thirdly, HBO may directly affect cell apoptosis, signal transduction, and gene expression in those that are sensitive to oxygen or hypoxia. HBO provides a reservoir of oxygen at cellular level not only carried by blood, but also by diffusion from the interstitial tissue where it reaches high concentration that may last for several hours, improves endothelial function and rheology, and decreases local inflammation and edema. Conclusion: Evidence suggests the benefits of HBO when used as a preconditioning stimulus in the setting of I/R injury. Translating the beneficial effects of HBO into current practice requires, as for the "conditioning strategies", a thorough consideration of risk factors, comorbidities, and comedications that could interfere with HBO-related protection. PMID- 29761019 TI - Assessment of sleep quality using cardiopulmonary coupling analysis in patients with Parkinson's disease. AB - Objectives: To assess the sleep quality of patients with Parkinson's disease (PD) and evaluate the effect of cardiopulmonary coupling (CPC) analysis on sleep quality and its correlation with subjective complaints in patients with PD. Methods: Our study included 42 patients with PD and 30 healthy controls. CPC analysis and the Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the sleep quality of subjects. Results: High-frequency coupling (HFC) and sleep efficiency were significantly lower in the PD than in the control group, whereas very low-frequency coupling (VLFC) and sleep latency were significantly higher in the PD than in the control group. PSQI scores were significantly higher in the PD than in the control group (all p < .05). The PSQI score showed a negative correlation with the HFC ratio in the PD group (r = -.478, p = .001). Factors related to the occurrence of PD with poor sleep quality were the unified Parkinson's disease rating scale (UPDRS) score and nocturia. Conclusions: The sleep quality of patients with PD was generally decreased. CPC analysis can reflect the subjective sleep quality of patients with PD and serve as an effective sleep monitoring tool. PMID- 29761020 TI - Tested and reported executive problems in children and youth epilepsy. AB - Objectives: Executive problems in children and youth with epilepsy influence their ability to handle important aspects of daily life activities. The present study sought to explore factors associated with executive problems for patients with epilepsy in this age group. Methods: The cohort consisted of 97 consecutive patients at the National Centre for Epilepsy in Norway, aged 10-19 years, with focal or genetic generalized epilepsy. All underwent tests of executive functions (D-KEFS), the Behavior Rating Inventory for Executive Function (BRIEF), and screening for psychiatric symptoms, using the Strengths and Difficulties Questionnaire (SDQ). Results: Parent-reported cognitive executive dysfunction (BRIEF, Metacognitive Index) was the strongest independent predictor for tested executive dysfunction and vice versa. Furthermore, male gender correlated strongest with parent-reported behavioral regulation problems (BRIEF, Behavioral Regulation Index) along with borderline/pathological score on the SDQ and parent reported cognitive executive dysfunction. Conclusions: A strong association between parent-reported cognitive executive dysfunction and tested executive dysfunction was found. Male gender correlated strongest with parent-reported behavioral regulation problems. The latter was probably related to a higher frequency of symptoms associated with psychopathology among the boys than the girls. The frequency of executive deficits according to the different modes of measurement varied from 16% to 43%, suggesting that they capture different aspects of behavior under the executive umbrella. PMID- 29761022 TI - Ketogenic diet effects on 52 children with pharmacoresistant epileptic encephalopathy: A clinical prospective study. AB - Objective: To evaluate the clinical impact of ketogenic diet (KD) on children with pharmacoresistant epileptic encephalopathy. Methods: In all, 52 children with pharmacoresistant epileptic encephalopathy that diagnosed in our hospital from July 2012 to June 2015 were selected, including West syndrome 38 cases, Lennox-Gastaut Syndrome 7 cases, Doose Syndrome 1 case, and Dravet syndrome 6 cases, and the effect, compliance, adverse reactions, electroencephalogram (EEG), and cognitive function were analyzed. Modified Johns Hopkins protocol was used to initiate KD, and Engel scale was used to evaluate the effect, and evaluated the effect of KD on the cognition, language, and motor function. Results: At 12 weeks of KD treatment, the patients achieved I, II, III, and IV grade effect were accounted for 26.9% (14/52 cases), 17.3% (9/52 cases), 11.5% (6/52 cases), and 44.2% (23/52 cases), respectively, according to Engel scale. KD has different effect on different epileptic syndromes, best effect on Doose syndromes of 100%, and better effect on West syndrome with the effect rate of 57.9%, and the total effect number was 22 cases. The reduction of epileptiform discharges in the awake state before KD treatment was correlated with the seizure time after 3 months of KD treatment (r = .330, p = .017). The cognitive function of 23 patients was improved, 12 patients had language improvement, and the motor function was improved in 10 patients. In all, 23 patients had adverse reactions, and all patients were tolerated and improved. Conclusion: KD has certain effect on children with pharmacoresistant epileptic encephalopathy, and it can reduce interictal epileptic discharge frequency, and improve the background rhythm of EEG. The reduction of epileptiform discharges in awake state is in favor of the reduction of seizures frequency, thus increasing the efficacy, and improve the cognitive function, language, and motor function to varying degrees, combined with less adverse reaction, which is worthy of clinical application. PMID- 29761023 TI - Comparing outcome and recanalization results in patients with anterior circulation stroke following endovascular treatment with and without a treatment with rt-PA: A single-center study. AB - Objectives: Endovascular treatment (ET), in addition to a therapy with intravenous recombinant tissue plasminogen activator IV rt-PA in patients with acute ischemic stroke, has been found to improve outcome. However, data about ET in patients who have not received therapy with rt-PA due to contraindications for IV rt-PA are sparse. Comparison of ET with IV rt-PA versus ET alone in patients with stroke is done using a proximal intracranial arterial occlusion (internal carotid artery, middle cerebral artery (M1-Segment)). Methods: During a 5-year period (2011-2016), 236 patients (mean age, 69 +/- 14 years; 46% women; median NIHSS score 13 +/- 5) who were treated at the Department of Neurology and Neuroradiology at the University of Lubeck, undergoing ET with or without IV rt PA were included and analyzed. Results: A total of 144 patients (61%) underwent ET + IV rt-PA, and 92 patients (39%) underwent ET only. The ET with IV rt-PA is associated with a higher rate of favorable functional outcomes (mRS<=2) at discharge from hospital (51.4% vs. 23.1%, p < .001) and lower rate of in-hospital mortality (9% vs. 19.6%, p = .019) and symptomatic intracerebral hemorrhage [sICH] (2.1% vs. 8.7%; p = .019) compared to ET, whereas the modified treatment in cerebral infarction score (mTICI) did not differ between the groups.In the adjusted logistic regression analysis, the ET + IV rt-PA was associated with an increased probability of favorable functional outcome (OR, 4.3; 95% confidence interval [CI], 2.2-8.5; p < .001). For the in-hospital mortality (OR, 0.74; 95% CI, 0.29-1.9; p = .76) and sICH (OR, 0.3; 95% CI, 0.07-1.2; p = .09), no differences were found. Conclusion: Recanalization results after endovascular treatment are not relevantly improved in patients receiving rt-PA. However, an additional therapy with IV rt-PA has a positive impact on functional outcome. PMID- 29761021 TI - Human iNPC therapy leads to improvement in functional neurologic outcomes in a pig ischemic stroke model. AB - Introduction: Stroke is the leading cause of disability in the United States but current therapies are limited with no regenerative potential. Previous translational failures have highlighted the need for large animal models of ischemic stroke and for improved assessments of functional outcomes. The aims of this study were first, to create a post-stroke functional outcome assessment scale in a porcine model of middle cerebral artery occlusion (MCAO) and second, to use this scale to determine the effect of human-induced-pluripotent-cell derived neural progenitor cells (iNPCs) on functional outcome in this large animal stroke model. Materials and Methods: Eight 6-month-old Landrace mix pigs underwent permanent MCAO. Five days following MCAO, pigs received intraparenchymal injections of either iNPCs or PBS. A post-stroke assessment scale was developed to measure functional outcome. Evaluations were performed at least 1-3 days prior to MCAO and repeated 1 day, 3 days, and 5 days post-stroke as well as 1 day, 3 days, 1 week, 2 weeks, 4 weeks, 6 weeks, 9 weeks, and 12 weeks post-injection. Comparisons of scores between animals receiving iNPCs or PBS only were compared using a two-way ANOVA and a Tukey's post-hoc t test. Results: The developed scale was able to consistently determine differences between healthy and stroked pigs at all time points. iNPC-treated pigs showed a significantly faster recovery in their overall scores relative to PBS-only treated pigs with the parameters of appetite and body posture exhibiting the most improvement in the iNPC-treated group. Conclusions: We developed a robust and repeatable functional assessment tool that can reliably detect stroke and recovery, while also showing for the first time that iNPC therapy leads to functional recovery in a translational pig ischemic stroke model. These promising results suggest that iNPCs may 1 day serve as a first in class cell therapeutic for ischemic stroke. PMID- 29761024 TI - Relationships between activity and well-being in people with parkinson's disease. AB - Objectives: The complex symptomatology of Parkinson' disease (PD) usually goes along with reduced physical activity. Previous studies have indicated positive effects of activating therapies on patients' well-being. This study, therefore, examined how activity in daily life is related to patients' subjective condition. Materials and Methods: Twenty-one PD patients rated their condition every two hours during two routine days and documented the duration and type of their activities (based on the PRISCUS-Physical Activity Questionnaire) during the respective time intervals. They were furthermore assessed regarding motor and nonmotor symptoms, personality factors, and coping strategies. Results: Patients spent on average 8.59 +/- 2.93 hr per day at physical rest and 5.47 +/- 2.93 hr physically active. We found highly significant associations between positive condition ratings (such as happiness, motivation, and concentration) and the duration of subsequent physical activities (adj.r2 = .689) as well as between the duration of these activities and a subsequent improvement in the subjective condition (adj.r2 = .545). This was strongest in patients using active coping strategies and showing agreeable and conscientious personality traits (adj.r2 = .380). Nonmotor symptom severity was weakly inversely related to the daily amount of activities (adj.r2 = .273), whereas no significant association with motor symptom severity was found. Conclusions: The results suggest a feedback process between a positive subjective condition and physical activities in PD patients. This appears to depend on the use of active coping strategies and nonmotor symptoms rather than on motor symptom severity. The results should encourage physicians to address the importance of everyday physical activities and to provide patients with behavioral advice. PMID- 29761026 TI - Conservative management of nivolumab-induced pericardial effusion: a case report and review of literature. AB - Background: Nivolumab is an immune checkpoint inhibitor targeting programmed death-1 protein and has been approved for the treatment of multiple advanced malignancies. Adverse effects of immune checkpoint inhibitors are distinct from conventional cytotoxic chemotherapy and can be life-threatening if left unrecognized. Here, we present a case of nivolumab-induced pericardial effusion successfully managed with high-dose corticosteroids. Case presentation: A 70-year old Caucasian female with a history of 50-pack-year cigarette smoking was diagnosed of recurrent adenocarcinoma of lung after initial surgery. She progressed through multiple lines of chemotherapy and was eventually started on nivolumab. She developed a large pericardial effusion, grade 3 by Common Terminology Criteria for Adverse Events v4.0, about 4 days after receiving first nivolumab treatment. She was treated with oral prednisone at 1 mg/kg daily with gradual resolution of pericardial effusion over 5 weeks while she still received nivolumab every 2 weeks. Prednisone treatment was eventually tapered off about 10 weeks from initial nivolumab treatment. However 1 week after stopping prednisone, she again presented with shortness of breath and bilateral ankle edema, imaging confirmed recurrent pericardial effusion measuring 2.8 cm. Nivolumab was stopped and patient was again started back on prednisone 1 mg/kg daily which resulted in complete resolution of pericardial effusion in 3 weeks. Nivolumab was resumed 1 week afterwards while patient was on tapering dose of prednisone. There was no recurrent pericardial effusion when she continued low-dose prednisone during the remaining course of nivolumab treatment. Conclusions: With increasing use of immune checkpoint inhibitors, clinicians need to be aware of the unusual immune related adverse events in order to provide timely management and effective patient care. To our knowledge, this is the first reported case of immune-related pericardial effusion from nivolumab successfully managed with high-dose corticosteroids. Furthermore, recurrent pericardial effusion was prevented by using low-dose corticosteroids as maintenance in order for patient to continue nivolumab treatment. PMID- 29761025 TI - The dissociations of visual processing of "hole" and "no-hole" stimuli: An functional magnetic resonance imaging study. AB - Introduction: "Where to begin" is a fundamental question of vision. A "Global first" topological approach proposed that the first step in object representation was to extract topological properties, especially whether the object had a hole or not. Numerous psychophysical studies found that the hole (closure) could be rapidly recognized by visual system as a primitive property. However, neuroimaging studies showed that the temporal lobe (IT), which lied at a late stage of ventral pathway, was involved as a dedicated region. It appeared paradoxical that IT served as a key region for processing the early component of visual information. Did there exist a distinct fast route to transit hole information to IT? We hypothesized that a fast noncortical pathway might participate in processing holes. Methods: To address this issue, a backward masking paradigm combined with functional magnetic resonance imaging (fMRI) was applied to measure neural responses to hole and no-hole stimuli in anatomically defined cortical and subcortical regions of interest (ROIs) under different visual awareness levels by modulating masking delays. Results: For no-hole stimuli, the neural activation of cortical sites was greatly attenuated when the no-hole perception was impaired by strong masking, whereas an enhanced neural response to hole stimuli in non-cortical sites was obtained when the stimulus was rendered more invisible. Conclusions: The results suggested that whereas the cortical route was required to drive a perceptual response for no-hole stimuli, a subcortical route might be involved in coding the hole feature, resulting in a rapid hole perception in primitive vision. PMID- 29761027 TI - The Power of the Group: Integrative Medicine Group Visits. PMID- 29761030 TI - Medical School Hotline: Mala La'au Lapa'au - John A. Burn School of Medicine's Hawaiian Healing Garden. PMID- 29761028 TI - Racial/Ethnic and County-level Disparity in Inpatient Utilization among Hawai'i Medicaid Population. AB - We investigated racial/ethnic and county-level disparities in inpatient utilization for 15 clinical conditions among Hawaii's Medicaid population. The study was conducted using inpatient claims data from more than 200,000 Hawai'i Medicaid beneficiaries, reported in the year 2010. The analysis was performed by stratifying the Medicaid population into three age groups: children and adolescent group (1-20 years), adult group (21-64 years), and elderly group (65 years and above). Among the differences found, Asians had a low probability of inpatient admissions compared to Whites for many disease categories, while Native Hawaiian/Pacific Islanders had higher probabilities than Whites, across all age groups. Pediatric and adult groups from Hawai'i County (Big Island) had lower probabilities for inpatient admissions compared to Honolulu County (O'ahu) for most disease conditions, but higher probabilities were observed for several conditions in the elderly group. Notably, the elderly population residing on Kaua'i County (Kaua'i and Ni'ihau islands) had substantially increased odds of hospital admissions for several disease conditions, compared to Honolulu. PMID- 29761029 TI - Treatment of Prurigo Pigmentosa with Diet Modification: A Medical Case Study. AB - Prurigo pigmentosa is a rare inflammatory dermatitis first described in 1971. While the etiology of Prurigo pigmentosa is yet unknown, conditions associated with ketosis often accompany this rash. Prurigo pigmentosa is successfully treated with antibiotics and by resolution of ketosis. However, there is no dietary treatment option to successfully treat the rash without sacrificing ketosis. We report two cases successfully treated with increase of dietary carbohydrate intake. The second case suggests that cessation of ketosis may not be necessary to resolve Prurigo pigmentosa. PMID- 29761031 TI - Insights in Public Health: Hyperuricemia and Gout in Hawai'i. PMID- 29761033 TI - Diagnosis and Treatment of Congenital Sensorineural Hearing Loss. AB - Purpose of Review: The aim of this report is to review current literature regarding the work-up and management of congenital sensorineural hearing loss. Recent Findings: Diagnostic evaluation of a newborn with sensorineural hearing loss begins with a complete audiologic evaluation and comprehensive history and physical exam. This review presents a diagnostic algorithm for the work-up of congenital hearing loss, focusing on the three following modalities: cytomegalovirus testing, genetic evaluation, and imaging. Summary: Newborn hearing loss is a common problem and may be attributed to genetic and non-genetic factors. Complete diagnostic evaluation and treatment are essential for preventing delays in language development. Treatment consists of early intervention services and consideration of hearing aid amplification and cochlear implantation. PMID- 29761034 TI - The rice XA21 ectodomain fused to the Arabidopsis EFR cytoplasmic domain confers resistance to Xanthomonas oryzae pv. oryzae. AB - Rice (Oryza sativa) plants expressing the XA21 cell-surface receptor kinase are resistant to Xanthomonas oryzae pv. oryzae (Xoo) infection. We previously demonstrated that expressing a chimeric protein containing the ELONGATION FACTOR Tu RECEPTOR (EFR) ectodomain and the XA21 endodomain (EFR:XA21) in rice does not confer robust resistance to Xoo. To test if the XA21 ectodomain is required for Xoo resistance, we produced transgenic rice lines expressing a chimeric protein consisting of the XA21 ectodomain and EFR endodomain (XA21:EFR) and inoculated these lines with Xoo. We also tested if the XA21:EFR rice plants respond to a synthetic sulfated 21 amino acid derivative (RaxX21-sY) of the activator of XA21 mediated immunity, RaxX. We found that five independently transformed XA21:EFR rice lines displayed resistance to Xoo as measured by lesion length analysis, and showed that five lines share characteristic markers of the XA21 defense response (generation of reactive oxygen species and defense response gene expression) after treatment with RaxX21-sY. Our results indicate that expression of the XA21:EFR chimeric receptor in rice confers resistance to Xoo. These results suggest that the endodomain of the EFR and XA21 immune receptors are interchangeable and the XA21 ectodomain is the key determinant conferring robust resistance to Xoo. PMID- 29761035 TI - Small tropical islands with dense human population: differences in water quality of near-shore waters are associated with distinct bacterial communities. AB - Water quality deterioration caused by an enrichment in inorganic and organic matter due to anthropogenic inputs is one of the major local threats to coral reefs in Indonesia. However, even though bacteria are important mediators in coral reef ecosystems, little is known about the response of individual taxa and whole bacterial communities to these anthropogenic inputs. The present study is the first to investigate how bacterial community composition responds to small scale changes in water quality in several coral reef habitats of the Spermonde Archipelago including the water column, particles, and back-reef sediments, on a densely populated and an uninhabited island. The main aims were to elucidate if (a) water quality indicators and organic matter concentrations differ between the uninhabited and the densely populated island of the archipelago, and (b) if there are differences in bacterial community composition in back-reef sediments and in the water column, which are associated with differences in water quality. Several key water quality parameters, such as inorganic nitrate and phosphate, chlorophyll a, and transparent exopolymer particles (TEP) were significantly higher at the inhabited than at the uninhabited island. Bacterial communities in sediments and particle-attached communities were significantly different between the two islands with bacterial taxa commonly associated with nutrient and organic matter-rich conditions occurring in higher proportions at the inhabited island. Within the individual reef habitats, variations in bacterial community composition between the islands were associated with differences in water quality. We also observed that copiotrophic, opportunistic bacterial taxa were enriched at the inhabited island with its higher chlorophyll a, dissolved organic carbon and TEP concentrations. Given the increasing strain on tropical coastal ecosystems, this study suggests that effluents from densely populated islands lacking sewage treatment can alter bacterial communities that may be important for coral reef ecosystem function. PMID- 29761036 TI - Sponge community of the western Black Sea shallow water caves: diversity and spatial distribution. AB - Marine caves possess unique biocoenotic and ecological characteristics. Sessile benthic species such as sponges associated with cave habitats typically show a marked zonation from the cave entrance towards the end of the cave. We describe three semi-submerged karstic caves of 50 to 83 m length and 936 to 2,291 m3 volume from the poorly explored cavernicolous fauna of North-East Bulgaria. We surveyed sponge diversity and spatial variability. Eight demosponge species were identified based on morphological and molecular data, of which six are known from the adjacent open sea waters of the Black Sea. Two species, Protosuberites denhartogi van Soest & de Kluijver, 2003 and Halichondria bowerbanki Burton, 1930, are reported from the Black Sea for the first time. The spatial sponge distribution inside the caves is in general similar, but shows some differences in species composition and distribution depending on cave relief and hydrodynamics. The species composition of sponges of Bulgarian caves is found to be different from Crimean caves. An updated checklist of the Black Sea sponges is provided. PMID- 29761038 TI - A new large-bodied thalattosuchian crocodyliform from the Lower Jurassic (Toarcian) of Hungary, with further evidence of the mosaic acquisition of marine adaptations in Metriorhynchoidea. AB - Based on associated and three-dimensionally preserved cranial and postcranial remains, a new thalattosuchian crocodyliform, Magyarosuchus fitosi gen. et sp. nov. from the Lower Jurassic (Upper Toarcian) Kisgerecse Marl Formation, Gerecse Mountains, Hungary is described here. Phylogenetic analyses using three different datasets indicate that M. fitosi is the sister taxon of Pelagosaurus typus forming together the basal-most sub-clade of Metriorhynchoidea. With an estimated body length of 4.67-4.83 m M. fitosi is the largest known non-metriorhynchid metriorhynchoid. Besides expanding Early Jurassic thalattosuchian diversity, the new specimen is of great importance since, unlike most contemporaneous estuarine, lagoonal or coastal thalattosuchians, it comes from an 'ammonitico rosso' type pelagic deposit of the Mediterranean region of the Tethys. A distal caudal vertebra having an unusually elongate and dorsally projected neural spine implies the presence of at least a rudimentary hypocercal tail fin and a slight ventral displacement of the distal caudal vertebral column in this basal metriorhynchoid. The combination of retaining heavy dorsal and ventral armors and having a slight hypocercal tail is unique, further highlighting the mosaic manner of marine adaptations in Metriorhynchoidea. PMID- 29761039 TI - Fine grained compositional analysis of Port Everglades Inlet microbiome using high throughput DNA sequencing. AB - Background: Similar to natural rivers, manmade inlets connect inland runoff to the ocean. Port Everglades Inlet (PEI) is a busy cargo and cruise ship port in South Florida, which can act as a source of pollution to surrounding beaches and offshore coral reefs. Understanding the composition and fluctuations of bacterioplankton communities ("microbiomes") in major port inlets is important due to potential impacts on surrounding environments. We hypothesize seasonal microbial fluctuations, which were profiled by high throughput 16S rRNA amplicon sequencing and analysis. Methods & Results: Surface water samples were collected every week for one year. A total of four samples per month, two from each sampling location, were used for statistical analysis creating a high sampling frequency and finer sampling scale than previous inlet microbiome studies. We observed significant differences in community alpha diversity between months and seasons. Analysis of composition of microbiomes (ANCOM) tests were run in QIIME 2 at genus level taxonomic classification to determine which genera were differentially abundant between seasons and months. Beta diversity results yielded significant differences in PEI community composition in regard to month, season, water temperature, and salinity. Analysis of potentially pathogenic genera showed presence of Staphylococcus and Streptococcus. However, statistical analysis indicated that these organisms were not present in significantly high abundances throughout the year or between seasons. Discussion: Significant differences in alpha diversity were observed when comparing microbial communities with respect to time. This observation stems from the high community evenness and low community richness in August. This indicates that only a few organisms dominated the community during this month. August had lower than average rainfall levels for a wet season, which may have contributed to less runoff, and fewer bacterial groups introduced into the port surface waters. Bacterioplankton beta diversity differed significantly by month, season, water temperature, and salinity. The 2013-2014 dry season (October-April), was warmer and wetter than historical averages. This may have driven significant differences in beta diversity. Increased nitrogen and phosphorous concentrations were observed in these dry season months, possibly creating favorable bacterial growth conditions. Potentially pathogenic genera were present in the PEI. However their relatively low, non-significant abundance levels highlight their relatively low risk for public health concerns. This study represents the first to sample a large port at this sampling scale and sequencing depth. These data can help establish the inlet microbial community baseline and supplement the vital monitoring of local marine and recreational environments, all the more poignant in context of local reef disease outbreaks and worldwide coral reef collapse in wake of a harsh 2014-16 El Nino event. PMID- 29761040 TI - Viromes of one year old infants reveal the impact of birth mode on microbiome diversity. AB - Establishing a diverse gut microbiota after birth is being increasingly recognised as important for preventing illnesses later in life. It is well established that bacterial diversity rapidly increases post-partum; however, few studies have examined the infant gut virome/phageome during this developmental period. We performed a metagenomic analysis of 20 infant faecal viromes at one year of age to determine whether spontaneous vaginal delivery (SVD) or caesarean section (CS) influenced viral composition. We find that birth mode results in distinctly different viral communities, with SVD infants having greater viral and bacteriophage diversity. We demonstrate that CrAssphage is acquired early in life, both in this cohort and two others, although no difference in birth mode is detected. A previous study has shown that bacterial OTU's (operational taxonomic units) identified in the same infants could not discriminate between birth mode at 12 months of age. Therefore, our results indicate that vertical transmission of viral communities from mother to child may play a role in shaping the early life microbiome, and that birth mode should be considered when studying the early life gut virome. PMID- 29761041 TI - Seasonal migrations, body temperature fluctuations, and infection dynamics in adult amphibians. AB - Risks of parasitism vary over time, with infection prevalence often fluctuating with seasonal changes in the annual cycle. Identifying the biological mechanisms underlying seasonality in infection can enable better prediction and prevention of future infection peaks. Obtaining longitudinal data on individual infections and traits across seasons throughout the annual cycle is perhaps the most effective means of achieving this aim, yet few studies have obtained such information for wildlife. Here, we tracked spiny common toads (Bufo spinosus) within and across annual cycles to assess seasonal variation in movement, body temperatures and infection from the fungal parasite, Batrachochytrium dendrobatidis (Bd). Across annual cycles, toads did not consistently sustain infections but instead gained and lost infections from year to year. Radio tracking showed that infected toads lose infections during post-breeding migrations, and no toads contracted infection following migration, which may be one explanation for the inter-annual variability in Bd infections. We also found pronounced seasonal variation in toad body temperatures. Body temperatures approached 0 degrees C during winter hibernation but remained largely within the thermal tolerance range of Bd. These findings provide direct documentation of migratory recovery (i.e., loss of infection during migration) and escape in a wild population. The body temperature reductions that we observed during hibernation warrant further consideration into the role that this period plays in seasonal Bd dynamics. PMID- 29761042 TI - Ultrasound-promoted synthesis of 2-organoselanyl-naphthalenes using Oxone(r) in aqueous medium as an oxidizing agent. AB - A green methodology to synthesize 2-organoselanyl-naphthalenes based on the reaction of alkynols with diaryl diselenides is described. The electrophilic species of selenium were generated in situ, by the oxidative cleavage of the Se Se bond of diaryl diselenides by Oxone(r) using water as the solvent. The reactions proceeded efficiently under ultrasonic irradiation as an alternative energy source, using a range of alkynols and diorganyl diselenides as starting materials. Through this methodology, the corresponding 2-organoselanyl naphthalenes were obtained in moderate to good yields (56-94%) and in short reaction times (0.25-2.3 h). PMID- 29761037 TI - Uncovering the hidden players in Lepidoptera biology: the heritable microbial endosymbionts. AB - The Lepidoptera is one of the most widespread and recognisable insect orders. Due to their remarkable diversity, economic and ecological importance, moths and butterflies have been studied extensively over the last 200 years. More recently, the relationship between Lepidoptera and their heritable microbial endosymbionts has received increasing attention. Heritable endosymbionts reside within the host's body and are often, but not exclusively, inherited through the female line. Advancements in molecular genetics have revealed that host-associated microbes are both extremely prevalent among arthropods and highly diverse. Furthermore, heritable endosymbionts have been repeatedly demonstrated to play an integral role in many aspects of host biology, particularly host reproduction. Here, we review the major findings of research of heritable microbial endosymbionts of butterflies and moths. We promote the Lepidoptera as important models in the study of reproductive manipulations employed by heritable endosymbionts, with the mechanisms underlying male-killing and feminisation currently being elucidated in moths and butterflies. We also reveal that the vast majority of research undertaken of Lepidopteran endosymbionts concerns Wolbachia. While this highly prevalent bacterium is undoubtedly important, studies should move towards investigating the presence of other, and interacting endosymbionts, and we discuss the merits of examining the microbiome of Lepidoptera to this end. We finally consider the importance of understanding the influence of endosymbionts under global environmental change and when planning conservation management of endangered Lepidoptera species. PMID- 29761043 TI - Differential expression patterns of housekeeping genes increase diagnostic and prognostic value in lung cancer. AB - Background: Using DNA microarrays, we previously identified 451 genes expressed in 19 different human tissues. Although ubiquitously expressed, the variable expression patterns of these "housekeeping genes" (HKGs) could separate one normal human tissue type from another. Current focus on identifying "specific disease markers" is problematic as single gene expression in a given sample represents the specific cellular states of the sample at the time of collection. In this study, we examine the diagnostic and prognostic potential of the variable expressions of HKGs in lung cancers. Methods: Microarray and RNA-seq data for normal lungs, lung adenocarcinomas (AD), squamous cell carcinomas of the lung (SQCLC), and small cell carcinomas of the lung (SCLC) were collected from online databases. Using 374 of 451 HKGs, differentially expressed genes between pairs of sample types were determined via two-sided, homoscedastic t-test. Principal component analysis and hierarchical clustering classified normal lung and lung cancers subtypes according to relative gene expression variations. We used uni- and multi-variate cox-regressions to identify significant predictors of overall survival in AD patients. Classifying genes were selected using a set of training samples and then validated using an independent test set. Gene Ontology was examined by PANTHER. Results: This study showed that the differential expression patterns of 242, 245, and 99 HKGs were able to distinguish normal lung from AD, SCLC, and SQCLC, respectively. From these, 70 HKGs were common across the three lung cancer subtypes. These HKGs have low expression variation compared to current lung cancer markers (e.g., EGFR, KRAS) and were involved in the most common biological processes (e.g., metabolism, stress response). In addition, the expression pattern of 106 HKGs alone was a significant classifier of AD versus SQCLC. We further highlighted that a panel of 13 HKGs was an independent predictor of overall survival and cumulative risk in AD patients. Discussion: Here we report HKG expression patterns may be an effective tool for evaluation of lung cancer states. For example, the differential expression pattern of 70 HKGs alone can separate normal lung tissue from various lung cancers while a panel of 106 HKGs was a capable class predictor of subtypes of non-small cell carcinomas. We also reported that HKGs have significantly lower variance compared to traditional cancer markers across samples, highlighting the robustness of a panel of genes over any one specific biomarker. Using RNA-seq data, we showed that the expression pattern of 13 HKGs is a significant, independent predictor of overall survival for AD patients. This reinforces the predictive power of a HKG panel across different gene expression measurement platforms. Thus, we propose the expression patterns of HKGs alone may be sufficient for the diagnosis and prognosis of individuals with lung cancer. PMID- 29761044 TI - The brown anole dewlap revisited: do predation pressure, sexual selection, and species recognition shape among-population signal diversity? AB - Animal signalling structures are amongst the most variable characteristics, as they are subjected to a diversity of selection pressures. A well-known example of a diverse signalling system in the animal kingdom is the dewlap of Anolis lizards. Dewlap characteristics can vary remarkably among and within species, and also between sexes. Although a considerable amount of studies have attempted to disentangle the functional significance of the staggering dewlap diversity in Anolis, the underlying evolutionary processes remain elusive. In this study, we focus on the contribution of biotic selective pressures in shaping geographic variation in dewlap design (size, colour, and pattern) and dewlap display behaviour at the intraspecific level. Notably, we have tried to replicate and extend previously reported results hereof in both sexes of the brown anole lizard (Anolis sagrei). To do this, we assembled a dataset consisting of 17 A. sagrei heterogeneous island populations from the Caribbean and specifically tested whether predation pressure, sexual selection, or species recognition could explain interpopulational variation in an array of dewlap characteristics. Our findings show that in neither males nor females estimates of predation pressure (island size, tail break frequency, model attack rate, presence of predatory Leiocephalus lizards) or sexual selection (sexual size dimorphism) could explain variation in dewlap design. We did find that A. sagrei males from larger islands showed higher dewlap display intensities than males from smaller islands, but the direct connection with predation pressure remains ambiguous and demands further investigation. Last, we could show indirect support for species recognition only in males, as they are more likely to have a 'spotted' dewlap pattern when co occurring with a higher number of syntopic Anolis species. In conclusion, we found overall limited support for the idea that the extensive interpopulational variability in dewlap design and use in A. sagrei is mediated by variation in their biotic environment. We propose a variety of conceptual and methodological explanations for this unexpected finding. PMID- 29761045 TI - Porcine rotavirus C in pigs with gastroenteritis on Thai swine farms, 2011-2016. AB - Swine are economically important food animals, but highly contagious porcine epidemic diarrhea virus (PEDV) and rotavirus can afflict pig herds and contribute significantly to piglet morbidity and mortality. While there have been studies on rotavirus group A (RVA) in Thailand, reports of rotavirus group C (RVC) are limited. Here, we aimed to identify the prevalence of RVC circulating on Thai commercial swine farms. We analyzed 769 feces and intestine mucosal contents of pigs affected with diarrhea between 2011 and 2016 using RT-PCR specific for the PEDV spike (S), rotavirus glycoprotein (G) VP7, and protease-sensitive protein (P) VP4 genes. We found that 6.6% (51/769) of samples tested positive for RVC, of which 11 samples were co-infected with RVA and four samples were co-infected with PEDV. Three samples tested positive for all three viruses. Phylogenetic analysis of the VP7 gene showed that the most frequent RVC genotype was G1, which grouped with the prototypic RVC Cowden strain. While G6 and G9 were also common, G3 was relatively rare. Analysis of the VP4 gene revealed that the most common P type was P[5], followed by P[4], P[7], and P[1]. In all, there were six G/P combinations (G6P[5], G1P[1], G1P[4], G1P[5], G9P[4], and G9P[7]), of which G6P[5] was the most predominant. PMID- 29761048 TI - Crystallization and structure analysis of the core motif of the Pks13 acyltransferase domain from Mycobacterium tuberculosis. AB - Type I polyketide synthase 13 (Pks13) is involved in the final step of the biosynthesis of mycolic acid in Mycobacterium tuberculosis. Recent articles have reported that Pks13 is an essential enzyme in the mycolic acid biosynthesis pathway, and it has been deeply studied as a drug target in Tuberculosis. We report a high-resolution structure of the acyltransferase (AT) domain of Pks13 at 2.59 A resolution. Structural comparison with the full-length AT domain (PDB code, 3TZW, and 3TZZ) reveals a different orientation of the C-terminal helix and rearrangement of some conserved residues. PMID- 29761049 TI - Effects of nettle slurry (Urtica dioica L.) used as foliar fertilizer on potato (Solanum tuberosum L.) yield and plant growth. AB - Organic agriculture is becoming increasingly important, and many natural products are now available for organic farmers to manage and improve their crops. Several ethnobotanical studies have indicated that the use of nettle slurry as fertilizer in organic farming for horticultural crops is spreading. Sometimes, however, the consequences of using these natural products have been poorly evaluated, and there is very little scientific evidence for the effects of using these slurries. In this study, we aimed to analyze the possible effect of nettle slurry on potato yields produced by organic farming. To achieve this main objective, we assessed the effect of nettle slurry on potato yields, plant size and growth parameters, chlorophyll content, and the presence of pests and diseases. Different slurry doses were assessed in 36 plots and nine variables were measured during the crop cycle. Under these field experimental conditions, nettle slurry (including one treatment with Urtica in combination with Equisetum) had no significant effects on yield, chlorophyll content, or the presence of pests and diseases in organic potato crops. The highest chlorophyll content was found in the double dose treatment, but the difference was not significant. This result, together with a small improvement in plant height with the double dose treatment, might indicate very slight crop enhancement which, under our experimental conditions, was not enough to improve yield. The Urtica and Equisetum slurry chemical analyses showed very low levels of nitrogen, phosphorus, and potassium. PMID- 29761047 TI - A survey of the views and capabilities of community pharmacists in Western Australia regarding the rescheduling of selected oral antibiotics in a framework of pharmacist prescribing. AB - Background: Antibiotic misuse in the community contributes to antimicrobial resistance. One way to address this may be by better utilizing community pharmacists' skills in antibiotic prescribing. The aims of this study were to examine the level of support for "down-scheduling" selected antibiotics and to evaluate factors determining the appropriateness of community pharmacist prescribing for a limited range of infections, including their decision to refer to a doctor. Methods: Self-administered questionnaires, including graded case vignette scenarios simulating real practice, were sent to Western Australian community pharmacists. In addition to descriptive statistics and chi-square testing, a General Estimating Equation (GEE) was used to identify factors associated with appropriateness of therapy and the decision to refer, for each of the seven vignettes. Results: Of the 240 pharmacists surveyed, 90 (37.5%) responded, yielding 630 responses to seven different case vignettes. There was more than 60% respondent support for expanded prescribing (rescheduling) of commonly prescribed antibiotics. Overall 426/630 (67.6%) chose to treat the patient while the remaining 204/630 (32.4%) referred the patient to a doctor. Of those electing to treat, 380/426 (89.2%) opted to use oral antibiotics, with 293/380 (77.2%) treating with an appropriate selection and regimen. The GEE model indicated that pharmacists were more likely to prescribe inappropriately for conditions such as otitis media (p = 0.0060) and urinary tract infection in pregnancy (p < 0.0001) compared to more complex conditions. Over 80% of all pharmacists would refer the patient to a doctor following no improvement within 3 days, or within 24 h in the case of community acquired pneumonia. It was more common for younger pharmacists to refer the patient to a doctor (p = 0.0165). Discussion: This study adds further insight into community pharmacy/pharmacist characteristics associated with appropriateness of oral antibiotic selection and the decision to refer to doctors. These findings require consideration in designing pharmacist over-the-counter prescribing models for oral antibiotics. PMID- 29761046 TI - Low bacterial community diversity in two introduced aphid pests revealed with 16S rRNA amplicon sequencing. AB - Bacterial endosymbionts that produce important phenotypic effects on their hosts are common among plant sap-sucking insects. Aphids have become a model system of insect-symbiont interactions. However, endosymbiont research has focused on a few aphid species, making it necessary to make greater efforts to other aphid species through different regions, in order to have a better understanding of the role of endosymbionts in aphids as a group. Aphid endosymbionts have frequently been studied by PCR-based techniques, using species-specific primers, nevertheless this approach may omit other non-target bacteria cohabiting a particular host species. Advances in high-throughput sequencing technologies are complementing our knowledge of microbial communities by allowing us the study of whole microbiome of different organisms. We used a 16S rRNA amplicon sequencing approach to study the microbiome of aphids in order to describe the bacterial community diversity in introduced populations of the cereal aphids, Sitobion avenae and Rhopalosiphum padi in Chile (South America). An absence of secondary endosymbionts and two common secondary endosymbionts of aphids were found in the aphids R. padi and S. avenae, respectively. Of those endosymbionts, Regiella insecticola was the dominant secondary endosymbiont among the aphid samples. In addition, the presence of a previously unidentified bacterial species closely related to a phytopathogenic Pseudomonad species was detected. We discuss these results in relation to the bacterial endosymbiont diversity found in other regions of the native and introduced range of S. avenae and R. padi. A similar endosymbiont diversity has been reported for both aphid species in their native range. However, variation in the secondary endosymbiont infection could be observed among the introduced and native populations of the aphid S. avenae, indicating that aphid-endosymbiont associations can vary across the geographic range of an aphid species. In addition, we discuss the potential role of aphids as vectors and/or alternative hosts of phytopathogenic bacteria. PMID- 29761050 TI - Plasma proteomic analysis of systemic lupus erythematosus patients using liquid chromatography/tandem mass spectrometry with label-free quantification. AB - Context: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with unknown etiology. Objective: Human plasma is comprised of over 10 orders of magnitude concentration of proteins and tissue leakages. The changes in the abundance of these proteins have played an important role in various human diseases. Therefore, the research objective of this study is to identify the significantly altered expression levels of plasma proteins from SLE patients compared with healthy controls using proteomic analysis. The plasma proteome profiles of both SLE patients and controls were compared. Methods: A total of 19 active SLE patients and 12 healthy controls plasma samples were analyzed using high-resolution electrospray ionization liquid chromatography-tandem mass spectrometry (LC-ESI-MS/MS) followed by label-free quantification. Results: A total of 19 proteins showed a significant level of expression in the comparative LC-ESI-MS/MS triplicate analysis; among these, 14 proteins had >1.5- to three fold up-regulation and five had <0.2- to 0.6-fold down-regulation. Gene ontology and DAVID (Database Annotation Visualization, and Integrated Discovery) functional enrichment analysis revealed that these proteins are involved in several important biological processes including acute phase inflammatory responses, complement activation, hemostasis, and immune system regulation. Conclusion: Our study identified a group of differentially expressed proteins in the plasma of SLE patients that are involved in the imbalance of the immune system and inflammatory responses. Therefore, these findings may have the potential to be used as prognostic/diagnostic markers for SLE disease assessment or disease monitoring. PMID- 29761051 TI - Global opportunities for mariculture development to promote human nutrition. AB - An estimated two billion people worldwide currently suffer from micronutrient malnutrition, and almost one billion are calorie deficient. Providing adequate nutrition is a growing global challenge. Seafood is one of the most important sources of both protein and micronutrients for many, yet production from wild capture fisheries has stagnated. In contrast, aquaculture is the world's fastest growing food production sector and now supplies over half of all seafood consumed globally. Mariculture, or the farming of brackish and marine species, accounts for roughly one-third of all aquaculture production and has received increasing attention as a potential supplement for wild-caught marine fisheries. By analyzing global patterns in seafood reliance, malnutrition levels, and economic opportunity, this study identifies where mariculture has the greatest potential to improve human nutrition. We calculate a mariculture opportunity index for 117 coastal nations by drawing on a diverse set of seafood production, trade, consumption, and nutrition data. Seventeen primary variables are combined into country-level scores for reliance on seafood, opportunity for nutritional improvement, and opportunity for economic development of mariculture. The final mariculture opportunity score identifies countries with high seafood reliance combined with high nutritional and economic opportunity scores. We find that island nations in Southeast Asia and the Caribbean are consistently identified as countries with high mariculture opportunity. In other regions, nutritional and economic opportunity scores are not significantly correlated, and we discuss the implications of this finding for crafting appropriate development policy. Finally, we identify key challenges to ameliorating malnutrition through mariculture development, including insufficient policy infrastructure, government instability, and ensuring local consumption of farmed fish. Our analysis is an important step towards prioritizing nations where the economic and nutritional benefits of expanding mariculture may be jointly captured. PMID- 29761052 TI - Asymmetries in mother-infant behaviour in Barbary macaques (Macaca sylvanus). AB - Asymmetries in the maternal behaviour and anatomy might play an important role in the development of primate manual lateralization. In particular, early life asymmetries in mother's and infant's behaviour have been suggested to be associated with the development of the hand preference of the offspring. The aim of this study was to investigate the presence of behavioural asymmetries in different behavioural categories of mother-infant dyads of zoo-living Barbary macaques (Macaca sylvanus). The study subjects were 14 Barbary macaques involved in seven mother-infant dyads housed in Parco Natura Viva, Italy. For the mothers, bouts of hand preference for maternal cradling and infant retrieval were collected. For the infants, we focused on nipple preference and hand preference for clinging on mother ventrum. Moreover, we collected bouts of hand preference for food reaching in both groups. No significant group-level bias was found for any of the behavioural categories in either mothers or infants. However, at the individual level, six out of seven mothers showed a significant cradling bias, three toward the right hand and three toward the left hand. Moreover, all infants showed a significant nipple preference, six toward the mother's right nipple, one toward the left nipple. Furthermore, a significant correlation was found between the infant nipple preference and their hand preference for food reaching, suggesting that maternal environment rather than behaviour might affect the development of hand preference in Old World monkeys. Our findings seem partially to add to previous literature on perceptual lateralization in different species of non-primate mammals, reporting a lateral bias in mother-infant interactions. Given the incongruences between our study and previous research in great apes and humans, our results seem to suggest possible phylogenetic differences in the lateralization of mothers and infants within the Primates order. PMID- 29761054 TI - Is high-intensity interval cycling feasible and more beneficial than continuous cycling for knee osteoarthritic patients? Results of a randomised control feasibility trial. AB - Background: Knee osteoarthritis (OA) patients often suffer joint pain and stiffness, which contributes to negative changes in body composition, strength, physical performance (function), physical activity and health-related quality of life. To reduce these symptoms and side effects of knee OA, moderate-intensity continuous training (MICT) cycling is often recommended. While resistance training is considered the optimal form of training to improve sarcopenic outcomes, it imposes higher joint loads and requires supervision, either initially or continuously by trained exercise professionals. Therefore, this pilot study sought to gain some insight into the feasibility and potential benefits of high-intensity interval training (HIIT) cycling as an alternative exercise option to MICT cycling for individuals with knee OA. Methods: Twenty seven middle-aged and older adults with knee OA were randomly allocated to either MICT or HIIT, with both programs involving four unsupervised home-based cycling sessions (~25 min per session) each week for eight weeks. Feasibility was assessed by enrolment rate, withdrawal rate, exercise adherence and number of adverse effects. Efficacy was assessed by health-related quality of life (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne index), physical function (Timed Up and Go (TUG), Sit to Stand (STS) and preferred gait speed) and body composition (body mass, BMI, body fat percentage and muscle mass). Results: Twenty-seven of the interested 50 potential participants (54%) enrolled in the study, with 17 of the 27 participants completing the trial (withdrawal rate of 37%); with the primary withdrawal reasons being unrelated injuries or illness or family related issues. Of the 17 participants who completed the trial, exercise adherence was very high (HIIT 94%; MICT 88%). While only three individuals (one in the MICT and two in the HIIT group) reported adverse events, a total of 28 adverse events were reported, with 24 of these attributed to one HIIT participant. Pre-post-test analyses indicated both groups significantly improved their WOMAC scores, with the HIIT group also significantly improving in the TUG and STS. The only significant between-group difference was observed in the TUG, whereby the HIIT group improved significantly more than the MICT group. No significant changes were observed in the Lequesne index, gait speed or body composition for either group. Discussion: An unsupervised home-based HIIT cycle program appears somewhat feasible for middle aged and older adults with knee OA and may produce similar improvements in health related quality of life but greater improvements in physical function than MICT. These results need to be confirmed in larger randomised controlled trials to better elucidate the potential for HIIT to improve outcomes for those with knee OA. Additional research needs to identify and modify the potential barriers affecting the initiation and adherence to home-based HIIT cycling exercise programs by individuals with knee OA. PMID- 29761055 TI - Primary producers may ameliorate impacts of daytime CO2 addition in a coastal marine ecosystem. AB - Predicting the impacts of ocean acidification in coastal habitats is complicated by bio-physical feedbacks between organisms and carbonate chemistry. Daily changes in pH and other carbonate parameters in coastal ecosystems, associated with processes such as photosynthesis and respiration, often greatly exceed global mean predicted changes over the next century. We assessed the strength of these feedbacks under projected elevated CO2 levels by conducting a field experiment in 10 macrophyte-dominated tide pools on the coast of California, USA. We evaluated changes in carbonate parameters over time and found that under ambient conditions, daytime changes in pH, pCO2, net ecosystem calcification (NEC), and O2 concentrations were strongly related to rates of net community production (NCP). CO2 was added to pools during daytime low tides, which should have reduced pH and enhanced pCO2. However, photosynthesis rapidly reduced pCO2 and increased pH, so effects of CO2 addition were not apparent unless we accounted for seaweed and surfgrass abundances. In the absence of macrophytes, CO2 addition caused pH to decline by ~0.6 units and pCO2 to increase by ~487 uatm over 6 hr during the daytime low tide. As macrophyte abundances increased, the impacts of CO2 addition declined because more CO2 was absorbed due to photosynthesis. Effects of CO2addition were, therefore, modified by feedbacks between NCP, pH, pCO2, and NEC. Our results underscore the potential importance of coastal macrophytes in ameliorating impacts of ocean acidification. PMID- 29761056 TI - Pelagic larval duration, growth rate, and population genetic structure of the tidepool snake moray Uropterygius micropterus around the southern Ryukyu Islands, Taiwan, and the central Philippines. AB - The relationships between pelagic larval duration (PLD) and geographic distribution patterns or population genetic structures of fishes remain obscure and highly variable among species. To further understand the early life history of the tidepool snake moray Uropterygius micropterus and the potential relationship between PLD and population genetic structure of this species, otolith microstructure and population genetics based on concatenated mtDNA sequence (cytochrome b and cytochrome oxidase subunit I, 1,336 bp) were analyzed for 195 specimens collected from eight locations around the southern Ryukyu Islands, Taiwan, and the central Philippines. Eels with longer PLD and lower otolith growth rates were observed at relatively higher latitudes with lower water temperatures (54.6 +/- 7.7 days and 1.28 +/- 0.16 um day-1 on Ishigaki Island, Japan, vs. 43.9 +/- 4.9 days and 1.60 +/- 0.19 um day-1 on Badian, the Philippines), suggesting that leptocephali grew faster and had shortened pelagic periods in warmer waters. Meanwhile, the eels along the southwest coast of Taiwan had relatively longer PLD (57.9 +/- 10.5 days), which might be associated with the more complex ocean current systems compared to their counterparts collected along the east coast of Taiwan (52.6 +/- 8.0 days). However, the southwestern and eastern Taiwan groups had similar otolith growth rates (1.33 +/- 0.19 um day-1 vs. 1.36 +/- 0.16 um day-1). Despite the intergroup variation in PLD, genetic analysis revealed fluent gene flow among the tidepool snake morays in the study regions, implying that intraspecies PLD variation had a weak effect on genetic structure. The leptocephalus stage might have ensured the widespread gene flow among the study areas and leptocephalus growth was likely influenced by regional water temperature. PMID- 29761053 TI - Nature-derived lignan compound VB-1 exerts hair growth-promoting effects by augmenting Wnt/beta-catenin signaling in human dermal papilla cells. AB - Background: Vitexin is a kind of lignan compound which has been shown to possess a variety of pharmacological effects, such as anti-inflammatory, anti-oxidative and anti-cancer activities. However the effect of vitexin on hair regeneration has not been elaborated. Methods: The proliferation of human dermal papilla cells (hDPCs) was examined by cell counting and continuous cell culture after vitexin compound 1 (VB-1) was treated. The expression of lef1, wnt5a, bmp2, bmp4, alpl and vcan was examined by RT-PCR. The expression of dkk1, tgf-beta1, active-beta Catenin, and AXIN2 was examined by RT-PCR or immunoblotting. Hair shaft growth was measured in the absence or presence of VB-1. Results: We demonstrated that VB 1 significantly promotes the proliferation of hDPCs in a concentration-dependent manner within a certain concentration range. Among the hair growth-related genes investigated, dkk1 was clearly down-regulated in hDPCs treated with VB-1. The increased active beta-Catenin and decreased AXIN2 protein levels suggest that VB 1 facilitates Wnt/beta-catenin signaling in hDPCs in vitro. The expression of DP signature genes was also upregulated after VB-1 treatment. Our study further indicated that VB-1 promotes human hair follicle (HF) growth by HF organ culture assay. Discussion: VB-1 may exert hair growth-promoting effects via augmenting Wnt/beta-catenin signaling in hDPCs. PMID- 29761057 TI - The performance of cleaner wrasse, Labroides dimidiatus, in a reversal learning task varies across experimental paradigms. AB - Testing performance in controlled laboratory experiments is a powerful tool for understanding the extent and evolution of cognitive abilities in non-human animals. However, cognitive testing is prone to a number of potential biases, which, if unnoticed or unaccounted for, may affect the conclusions drawn. We examined whether slight modifications to the experimental procedure and apparatus used in a spatial task and reversal learning task affected performance outcomes in the bluestreak cleaner wrasse, Labroides dimidiatus (hereafter "cleaners"). Using two-alternative forced-choice tests, fish had to learn to associate a food reward with a side (left or right) in their holding aquarium. Individuals were tested in one of four experimental treatments that differed slightly in procedure and/or physical set-up. Cleaners from all four treatment groups were equally able to solve the initial spatial task. However, groups differed in their ability to solve the reversal learning task: no individuals solved the reversal task when tested in small tanks with a transparent partition separating the two options, whereas over 50% of individuals solved the task when performed in a larger tank, or with an opaque partition. These results clearly show that seemingly insignificant details to the experimental set-up matter when testing performance in a spatial task and might significantly influence the outcome of experiments. These results echo previous calls for researchers to exercise caution when designing methodologies for cognition tasks to avoid misinterpretations. PMID- 29761058 TI - Exotic lagomorph may influence eagle abundances and breeding spatial aggregations: a field study and meta-analysis on the nearest neighbor distance. AB - The introduction of alien species could be changing food source composition, ultimately restructuring demography and spatial distribution of native communities. In Argentine Patagonia, the exotic European hare has one of the highest numbers recorded worldwide and is now a widely consumed prey for many predators. We examine the potential relationship between abundance of this relatively new prey and the abundance and breeding spacing of one of its main consumers, the Black-chested Buzzard-Eagle (Geranoaetus melanoleucus). First we analyze the abundance of individuals of a raptor guild in relation to hare abundance through a correspondence analysis. We then estimated the Nearest Neighbor Distance (NND) of the Black-chested Buzzard-eagle abundances in the two areas with high hare abundances. Finally, we performed a meta-regression between the NND and the body masses of Accipitridae raptors, to evaluate if Black-chested Buzzard-eagle NND deviates from the expected according to their mass. We found that eagle abundance was highly associated with hare abundance, more than with any other raptor species in the study area. Their NND deviates from the value expected, which was significantly lower than expected for a raptor species of this size in two areas with high hare abundance. Our results support the hypothesis that high local abundance of prey leads to a reduction of the breeding spacing of its main predator, which could potentially alter other interspecific interactions, and thus the entire community. PMID- 29761059 TI - Biodiversity of the Great Barrier Reef-how adequately is it protected? AB - Background: The Great Barrier Reef (GBR) is the world's most iconic coral reef ecosystem, recognised internationally as a World Heritage Area of outstanding significance. Safeguarding the biodiversity of this universally important reef is a core legislative objective; however, ongoing cumulative impacts including widespread coral bleaching and other detrimental impacts have heightened conservation concerns for the future of the GBR. Methods: Here we review the literature to report on processes threatening species on the GBR, the status of marine biodiversity, and evaluate the extent of species-level monitoring and reporting. We assess how many species are listed as threatened at a global scale and explore whether these same species are protected under national threatened species legislation. We conclude this review by providing future directions for protecting potentially endangered elements of biodiversity within the GBR. Results: Most of the threats identified to be harming the diversity of marine life on the GBR over the last two-three decades remain to be effectively addressed and many are worsening. The inherent resilience of this globally significant coral reef ecosystem has been seriously compromised and various elements of the biological diversity for which it is renowned may be at risk of silent extinction. We show at least 136 of the 12,000+ animal species known to occur on the GBR (approximately 20% of the 700 species assessed by the IUCN) occur in elevated categories of threat (Critically Endangered, Endangered or Vulnerable) at a global scale. Despite the wider background level of threat for these 136 species, only 23 of them are listed as threatened under regional or national legislation. Discussion: To adequately protect the biodiversity values of the GBR, it may be necessary to conduct further targeted species-level monitoring and reporting to complement ecosystem management approaches. Conducting a vigorous value of information analysis would provide the opportunity to evaluate what new and targeted information is necessary to support dynamic management and to safeguard both species and the ecosystem as a whole. Such an analysis would help decision-makers determine if further comprehensive biodiversity surveys are needed, especially for those species recognised to be facing elevated background levels of threat. If further monitoring is undertaken, it will be important to ensure it aligns with and informs the GBRMPA Outlook five year reporting schedule. The potential also exists to incorporate new environmental DNA technologies into routine monitoring to deliver high-resolution species data and identify indicator species that are cursors of specific disturbances. Unless more targeted action is taken to safeguard biodiversity, we may fail to pass onto future generations many of the values that comprise what is universally regarded as the world's most iconic coral reef ecosystem. PMID- 29761060 TI - Loss anticipation and outcome during the Monetary Incentive Delay Task: a neuroimaging systematic review and meta-analysis. AB - Background: Reward seeking and avoidance of punishment are key motivational processes. Brain-imaging studies often use the Monetary Incentive Delay Task (MIDT) to evaluate motivational processes involved in maladaptive behavior. Although the bulk of research has been done on the MIDT reward events, little is known about the neural basis of avoidance of punishment. Therefore, we conducted a meta-analysis of brain activations during anticipation and receipt of monetary losses in healthy controls. Methods: All functional neuro-imaging studies using the MIDT in healthy controls were retrieved using PubMed, Google Scholar & EMBASE databases. Functional neuro-imaging data was analyzed using the Seed-based d Mapping Software. Results: Thirty-five studies met the inclusion criteria, comprising 699 healthy adults. In both anticipation and loss outcome phases, participants showed large and robust activations in the bilateral striatum, (anterior) insula, and anterior cingulate gyrus relatively to Loss > Neutral contrast. Although relatively similar activation patterns were observed during the two event types, they differed in the pattern of prefrontal activations: ventro-lateral prefrontal activations were observed during loss anticipation, while medial prefrontal activations were observed during loss receipt. Discussion: Considering that previous meta-analyses highlighted activations in the medial prefrontal cortex/anterior cingulate cortex, the anterior insula and the ventral striatum, the current meta-analysis highlighted the potential specificity of the ventro-lateral prefrontal regions, the median cingulate cortex and the amygdala in the loss events. Future studies can rely on these latter results to examine the neural correlates of loss processing in psychiatric populations characterized by harm avoidance or insensitivity to punishment. PMID- 29761062 TI - Glycosylceramide modifies the flavor and metabolic characteristics of sake yeast. AB - In the manufacture of sake, Japanese traditional rice wine, sake yeast is fermented with koji, which is steamed rice fermented with the non-pathogenic fungus Aspergillus oryzae. During fermentation, sake yeast requires lipids, such as unsaturated fatty acids and sterols, in addition to substances provided by koji enzymes for fermentation. However, the role of sphingolipids on the brewing characteristics of sake yeast has not been studied. In this study, we revealed that glycosylceramide, one of the sphingolipids abundant in koji, affects yeast fermentation. The addition of soy, A. oryzae, and Grifola frondosa glycosylceramide conferred a similar effect on the flavor profiles of sake yeast. In particular, the addition of A. oryzae and G. frondosa glycosylceramide were very similar in terms of the decreases in ethyl caprylate and ethyl 9-decenoate. The addition of soy glycosylceramide induced metabolic changes to sake yeast such as a decrease in glucose, increases in ethanol and glycerol and changes in several amino acids and organic acids concentrations. Tricarboxylic acid (TCA) cycle, pyruvate metabolism, starch and sucrose metabolism, and glycerolipid metabolism were overrepresented in the cultures incubated with sake yeast and soy glycosylceramide. This is the first study of the effect of glycosylceramide on the flavor and metabolic profile of sake yeast. PMID- 29761064 TI - Development of a site fidelity index based on population capture-recapture data. AB - Background: Site fidelity is considered as an animal's tendency to return to a previously occupied place; this is a component of animal behaviour that allows us to understand movement patterns and aspects related to the animal's life history. Although there are many site fidelity metrics, the lack of standardisation presents a considerable challenge in terms of comparability among studies. Methods: This investigation focused on the theoretical development of a standardised composite site fidelity index and its statistical distribution in order to obtain reliable population-level site fidelity comparisons. The arithmetic and harmonic means were used as mathematical structures in order to create different indexes by combining the most commonly used indicators for site fidelity such as Occurrence, Permanence and Periodicity. The index performance was then evaluated in simulated populations and one real population of Commerson's dolphins (Cephalorhynchus commersonii (Lacepede 1804)). In the first case, the indexes were evaluated based on how they were affected by different probability values such as the occurrence of the individual within the study area (phi) and capture probability (p). As a precision measure for the comparison of the indexes, the Wald confidence interval (CI) and the mean square error were applied. Given that there was no previous data concerning the distribution parameters of this population, bootstrap CIs were applied for the study case. Results: Eight alternative indexes were developed. The indexes with an arithmetic mean structure, in general, had a consistently inferior performance than those with a harmonic mean structure. The index IH4, in particular, achieved the best results in all of the scenarios and in the study case. Additionally, this index presented a normal distribution. As such, it was proposed as a standardised measure for site fidelity (Standardised Site Fidelity Index-SSFI). Discussion: The SSFI is the first standardised metric that quantifies site fidelity at a populational level. It is an estimator that varies between zero and one and works in situations where detection is not perfect and effort can be constant or not. Moreover, it has an associated CI that allows users to make comparisons. PMID- 29761063 TI - Screening of polyhydroxyalkanoate-producing bacteria and PhaC-encoding genes in two hypersaline microbial mats from Guerrero Negro, Baja California Sur, Mexico. AB - Hypersaline microbial mats develop through seasonal and diel fluctuations, as well as under several physicochemical variables. Hence, resident microorganisms commonly employ strategies such as the synthesis of polyhydroxyalkanoates (PHAs) in order to resist changing and stressful conditions. However, the knowledge of bacterial PHA production in hypersaline microbial mats has been limited to date, particularly in regard to medium-chain length PHAs (mcl-PHAs), which have biotechnological applications due to their plastic properties. The aim of this study was to obtain evidence for PHA production in two hypersaline microbial mats of Guerrero Negro, Mexico by searching for PHA granules and PHA synthase genes in isolated bacterial strains and environmental samples. Six PHA-producing strains were identified by 16S rRNA gene sequencing; three of them corresponded to a Halomonas sp. In addition, Paracoccus sp., Planomicrobium sp. and Staphylococcus sp. were also identified as PHA producers. Presumptive PHA granules and PHA synthases genes were detected in both sampling sites. Moreover, phylogenetic analysis showed that most of the phylotypes were distantly related to putative PhaC synthases class I sequences belonging to members of the classes Alphaproteobacteria and Gammaproteobacteria distributed within eight families, with higher abundances corresponding mainly to Rhodobacteraceae and Rhodospirillaceae. This analysis also showed that PhaC synthases class II sequences were closely related to those of Pseudomonas putida, suggesting the presence of this group, which is probably involved in the production of mcl-PHA in the mats. According to our state of knowledge, this study reports for the first time the occurrence of phaC and phaC1 sequences in hypersaline microbial mats, suggesting that these ecosystems may be a novel source for the isolation of short- and medium-chain length PHA producers. PMID- 29761061 TI - Transcriptomic studies reveal a key metabolic pathway contributing to a well maintained photosynthetic system under drought stress in foxtail millet (Setaria italica L.). AB - Drought stress is one of the most important abiotic factors limiting crop productivity. A better understanding of the effects of drought on millet (Setaria italica L.) production, a model crop for studying drought tolerance, and the underlying molecular mechanisms responsible for drought stress responses is vital to improvement of agricultural production. In this study, we exposed the drought resistant F1 hybrid, M79, and its parental lines E1 and H1 to drought stress. Subsequent physiological analysis demonstrated that M79 showed higher photosynthetic energy conversion efficiency and drought tolerance than its parents. A transcriptomic study using leaves collected six days after drought treatment, when the soil water content was about ~20%, identified 3066, 1895, and 2148 differentially expressed genes (DEGs) in M79, E1 and H1 compared to the respective untreated controls, respectively. Further analysis revealed 17 Gene Ontology (GO) enrichments and 14 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in M79, including photosystem II (PSII) oxygen-evolving complex, peroxidase (POD) activity, plant hormone signal transduction, and chlorophyll biosynthesis. Co-regulation analysis suggested that these DEGs in M79 contributed to the formation of a regulatory network involving multiple biological processes and pathways including photosynthesis, signal transduction, transcriptional regulation, redox regulation, hormonal signaling, and osmotic regulation. RNA-seq analysis also showed that some photosynthesis-related DEGs were highly expressed in M79 compared to its parental lines under drought stress. These results indicate that various molecular pathways, including photosynthesis, respond to drought stress in M79, and provide abundant molecular information for further analysis of the underlying mechanism responding to this stress. PMID- 29761065 TI - Pulsed Magnetic Resonance to Signal-Enhance Metabolites within Seconds by utilizing para-Hydrogen. AB - Diseases such as Alzheimer's and cancer have been linked to metabolic dysfunctions, and further understanding of metabolic pathways raises hope to develop cures for such diseases. To broaden the knowledge of metabolisms in vitro and in vivo, methods are desirable for direct probing of metabolic function. Here, we are introducing a pulsed nuclear magnetic resonance (NMR) approach to generate hyperpolarized metabolites within seconds, which act as metabolism probes. Hyperpolarization represents a magnetic resonance technique to enhance signals by over 10 000-fold. We accomplished an efficient metabolite hyperpolarization by developing an isotopic labeling strategy for generating precursors containing a favorable nuclear spin system to add para-hydrogen and convert its two-spin longitudinal order into enhanced metabolite signals. The transfer is performed by an invented NMR experiment and 20 000-fold signal enhancements are achieved. Our technique provides a fast way of generating hyperpolarized metabolites by using para-hydrogen directly in a high magnetic field without the need for field cycling. PMID- 29761066 TI - Anterior Skull Base Reconstruction: Does Fat Preparation Matter? AB - Objectives This article aims (1) to determine whether there is any difference in cerebrospinal fluid (CSF) leak rate after anterior skull base autologous fat reconstruction based on how the fat is prepared, and (2) to measure impact on surgical times by reconstruction type. Design Translational animal model surgical technique 3-arm trial, comparing two different methods of autologous fat skull base reconstruction versus a nonreconstructed control group. Setting Animal study. Subjects Adult Sprague-Dawley rats. Main Outcome Measures Resolution of CSF rhinorrhea after repair of a surgically created anterior skull base defect. Results Both wet (uncompressed) and dry (compressed) fat reconstruction of an anterior skull base defect demonstrated lower CSF leak rates than nonreconstructed defects. Dry fat reconstruction achieved significance in superiority of controlling CSF leak over no reconstruction (64% success vs. 31%); while wet fat reconstruction trended toward significance (50% vs. 31%). Reconstruction procedure time was longer than nonreconstructed controls, but there was no significant difference between type of fat preparation in surgical time. Conclusions This study demonstrates that drying and compressing the fat graft improves autologous fat reconstruction success for anterior skull base defects, and does not add significantly to surgical time over nonprepared fat. PMID- 29761069 TI - The History of the European Bone and Joint Infection Society (EBJIS). AB - The European Bone and Joint Infection Society (EBJIS) was founded by a French initiative as a Study Group in 1982. The group of 26 founding members increased to around 60 members in 1992, and membership was limited to surgeons from Europe, experienced in orthopedic infections. In 1993, a transformation to a Society was performed with a more open structure for all kind of doctors and scientists. Annual meetings, a Travelling Fellowship, research projects and instructional courses were organized. Professional support and improved publicity has resulted in an increase to more than 400 members, from worldwide. PMID- 29761068 TI - Antibiotic Containing Bone Substitute in Major Hip Surgery: A Long Term Gentamicin Elution Study. AB - Objectives: The objective is to present the antibiotic elution from a locally implanted gentamicin containing hydroxyapatite and calcium sulphate bone substitute with an extended follow up of 30 days. We also compare the pharmacokinetics of the ceramic bone substitute with a published study on gentamicin containing poly (methyl methacrylate) (PMMA) bone cement used in primary total hip arthroplasty. Methods: Gentamicin release was measured in the urine for a month and the serum for 4 days in 10 patients operated for trochanteric hip fractures and 10 patients in uncemented hip revisions. 17 patients were followed up at one year and 3 patients at 6 months. Results and Discussion: The gentamicin concentrations measured in serum were low and approximately 100 times less than in urine during the first days, indicating high local concentrations at the implant site. The elution from the biphasic bone substitute showed a stronger burst and higher gentamicin concentrations for the first week compared to that reported for PMMA used in hip arthroplasty. Also, for the bone substitute a complete gentamicin elution was obtained after 30 days, while for the PMMA cement sub-inhibitory MIC levels of gentamicin were still present in urine 60 days past surgery. No infections were detected. Conclusions: A new biphasic bone substitute containing antibiotics could potentially be used to prevent infection in patients treated for trochanteric hip fractures or uncemented hip revisions. The gentamicin elution from the bone substitute is efficient with high initial local gentamicin concentrations and complete release at 30 days. PMID- 29761070 TI - Postscript to The History of the European Bone and Joint Infection Society. PMID- 29761071 TI - Long-term Conventionally Dosed Vancomycin Therapy In Patients With Orthopaedic Implant-related Infections Seems As Effective And Safe As Long-term Penicillin Or Clindamycin Therapy. A Retrospective Cohort Study Of 103 Patients. AB - Objectives: Antimicrobial therapy is one of the cornerstones of orthopaedic implant-related infections (OIRI) treatment. Infections with Gram-positive bacteria are often treated with vancomycin, penicillin or clindamycin. A recent IDSA guideline suggests increasing the dose of vancomycin to increase the trough vancomycin target serum concentrations. This is deemed necessary because of an observed decrease in vancomycin susceptibility among Gram-positive bacteria. However, elevated vancomycin concentrations are correlated with the risk of nephrotoxicity, especially with prolonged therapy. Compared to most countries, rates of resistance against antibiotics among bacteria in the Netherlands are lower for currently available antibiotics, therefore lower target concentrations of vancomycin are probably efficacious for the treatment of infections. In this study we evaluated the efficacy and safety of long-term conventionally dosed vancomycin therapy, as an initial therapy for OIRI, and compared this with long term penicillin and clindamycin therapy, as initial therapy, in patients with Gram-positive orthopaedic implant-related infections. Methods: A retrospective, observational study was conducted in 103 adult patients treated for OIRI, with vancomycin, penicillin or clindamycin for at least 10 days. The target trough serum concentration of vancomycin was 10-15 mg/l. Results: 74% of our patients were treated successfully with vancomycin, as initial therapy, (no reinfection within 1 year) versus 55% of our patients treated with either an antibiotic of the penicillin class (mostly flucloxacillin) or clindamycin (p=0.08), as initial therapy. For patients treated with vancomycin we observed a serum creatinine increase of 6 MUmol/l, for patients treated with either an antibiotic of the penicillin class or clindamycin the serum creatinine increase was 4 MUmol/l (p=0.395). Conclusions: In our population of patients with OIRI long-term treatment with conventionally dosed vancomycin, as initial therapy, was not significantly less effective and safe as long-term treatment with an antibiotic of the penicillin class or clindamycin, as initial therapy. PMID- 29761072 TI - Sezary syndrome manifesting as posttransplant lymphoproliferative disorder. AB - Posttransplant lymphoproliferative disorders (PTLDs) of T-cell orgin are rare biologically heterogeneous diseases of mature lymphoid cells manifesting in immunosuppressed patients. Only a few cases of mycosis fungoides diagnosed post allogeneic hematopoietic cell transplant (alloHSCT) have been described so far. We present a patient with myelodysplastic syndrome (MDS) post matched unrelated donor alloHSCT who was on long-term immunosuppressive therapy due to graft versus host disease. Three years after an alloHSCT, she developed generalized erythroderma and peripheral blood lymphocytosis. Both skin biopsy and peripheral blood flow cytometry revealed atypical CD4+ T-cell population consistent with diagnosis of Sezary syndrome. Chimerism studies revealed 100% donor engraftment. Therapy with extracorporeal photopheresis resulted in complete response in blood and skin. PMID- 29761073 TI - Radiation Oncology in the 21st Century: Prospective Randomized Trials That Changed Practice... or Didn't! AB - In a two-part article published in 2009, we discussed the limitations of conventional radiation therapy, the challenges of studying new technologies in radiation oncology, and summarized the state-of-the science for various malignancies (1, 2). Here, we summarize some of the most important prospective, randomized trials that during the intervening years have attempted to improve the tumor control and/or decrease the adverse effects of radiation therapy. For consistency, we have focused here on the null and alternate hypotheses as articulated by the investigators at the onset of each trial, since the outcome of the investigational treatment should be considered clinically significant only if the null hypothesis was rejected. The readers (and patients) are of course free to make their own judgments about the clinical significance of the results when the null hypothesis was not rejected. PMID- 29761067 TI - Current therapies in treatment and prevention of fracture wound biofilms: why a multifaceted approach is essential for resolving persistent infections. AB - Traumatic orthopedic injuries, particularly extremity wounds, are a significant cause of morbidity. Despite prophylactic antibiotic treatment and surgical intervention, persistent infectious complications can and do occur. Persistent bacterial infections are often caused by biofilms, communities of antibiotic tolerant bacteria encased within a matrix. The structural and metabolic differences in this mode of growth make treatment difficult. Herein, we describe both established and novel, experimental treatments targeted at various stages of wound healing that are specifically aimed at reducing and eliminating biofilm bacteria. Importantly, the highly tolerant nature of these bacterial communities suggests that most singular approaches could be circumvented and a multifaceted, combinatorial approach will be the most effective strategy for treating these complicated infections. PMID- 29761074 TI - The Clinical Utility of Cell-Free DNA Measurement in Differentiated Thyroid Cancer: A Systematic Review. AB - Background: Cell-free DNA (cfDNA) can be detected in the circulation of healthy individuals, but is found in higher concentrations in cancer patients. Furthermore, mutations in tumor cells can be identified in circulating DNA fragments. This has been the subject of significant interest in the field of cancer research, but little has been published in thyroid cancer. Objectives: To assess all available evidence on the use of circulating cfDNA in the diagnosis, management and surveillance of patients with differentiated thyroid cancer, and collate it into a systematic review to guide future research. Methods: A comprehensive literature search on the measurement of cfDNA in thyroid cancer was undertaken, and results from relevant studies collated into a systematic review. Results: Nine studies were identified, with varying methodologies and findings. Key techniques and findings are summarized. Conclusion: There is limited but promising evidence that somatic mutations in thyroid cancer can be detected in circulating cfDNA and are associated with more advanced disease. Further research is required to develop a clinically useful tool based on cfDNA to improve the management of thyroid cancers. PMID- 29761076 TI - Synchronous Bone Metastasis From Multiple Myeloma and Prostate Adenocarcinoma as Initial Presentation of Coexistent Malignancies. AB - The radiographic appearance of bone metastases is usually determined by tumor histology and can be osteolytic, osteoblastic, or mixed. We present a patient with coexistent bone metastasis from multiple myeloma and prostate adenocarcinoma who exhibited synchronous bone involvement of both histologies within the same bone lesion, a rare phenomenon that has not been previously reported and led to atypical radiographic findings. The radiograph of a 71-year-old man with thigh swelling and pain demonstrated a lytic femoral lesion. Magnetic resonance imaging (MRI) confirmed a destructive process, but showed coexistent metaphyseal sclerosis. Multiple myeloma was suspected by demonstration of monoclonal gammopathy and confirmed by computed tomography (CT)-guided biopsy. Incidentally, CT demonstrated areas of sclerosis corresponding to T2 hypointensity on MRI. Further studies revealed osteoblastic spinal metastasis, prostate enhancement on CT and prostate-specific antigen (PSA) level of 90 ng/mL, concerning for concomitant prostate neoplasm. After endoprosthetic reconstruction, pathology of the femur identified both plasma cell neoplasm and metastatic prostate adenocarcinoma. An association between prostate cancer and multiple myeloma is hypothesized due to tumor microenvironment similarities and possible common genetic variations, however, coexisting bone metastases have never been reported. This unusual finding explains the discrepant imaging features in our patient and is evidenced that certain clinical situations merit contemplation of atypical presentations of common malignancies even if this leads to additional testing. PMID- 29761077 TI - Anatomical Cadaver Study of Endolaryngeal Vascularization: Focus on the Glottis, Supraglottis, and Subglottis From the Transoral Microsurgical Point of View. AB - Introduction: Carbon dioxide laser coagulation during transoral laser microsurgery (TLM) for laryngeal cancer allows control of bleeding from vessels smaller than 0.5 mm. Therefore, larger arteries and veins must be carefully managed by clipping and/or monopolar cautery. The aim of this paper is to detail endolaryngeal vascular anatomy and identify areas of possible bleeding during TLM. Methods: We performed an anatomical study on a series of 11 fresh-frozen human cadavers. After injection of a bicomponent red silicone into the innominate, left common carotid, and left subclavian arteries, 22 hemilarynges were dissected, the course of the supraglottic, glottic, and subglottic vessels were traced after microdissection of the intervening structures, and their size measured at specific landmark points where such vessels are more frequently encountered during TLM. Results: Three vessels arising from the superior laryngeal artery were identified after its entry point at the level of the thyro hyoid membrane: (1) the epiglottic artery (EA), documented in 100% of cases, a common trunk dividing into two main vessels (2) the postero-inferior artery (PIA), present in 100% of the specimens, running downward and dividing in a posterior (pPIA), and anterior (aPIA) branches (3) the antero-inferior artery (AIA), present in 95% of our specimens, running downward to the anterior commissure (AC). Two transverse anastomotic networks (TANs) connected the AIA and PIA, both parallel to the vocal muscle, one lateral (present in 100% of cases), and another medial (91% of specimens). Finally, a fourth vessel supplying the glottic plane was found to be the endolaryngeal paracommissural branch of the crico-thyroid artery (PCA), arising from the inferior laryngeal artery and emerging just below the AC, through the crico-thyroid membrane (reported in 100% of the specimens). This vessel anastomosed in 91% of cases with the AIA, through one or both of the TANs. Conclusion: The course of the endolaryngeal arteries, their relationships with adjacent structures, and size at specific landmark points have been herein described in order to provide surgeons with a map to guide them during the steep learning curve of transoral surgery of the larynx, with special emphasis given to TLM. PMID- 29761075 TI - Transforming Growth Factor-beta Signaling Plays a Pivotal Role in the Interplay Between Osteosarcoma Cells and Their Microenvironment. AB - Osteosarcomas are the most frequent form of primary bone tumors and mainly affect children, adolescents, and young adults. Despite encouraging progress in therapeutic management, including the advent of multidrug chemotherapy, the survival rates have remained unchanged for more than four decades: 75% at 5 years for localized disease, but two groups of patients are still at high risk: metastatic at diagnosis (overall survival around 40% at 5 years) and/or poor responders to chemotherapy (20% at 5 years). Because these tumors are classified as "complex genomic," it is extremely difficult to determine the signaling pathways that might be targeted by specific therapies. A hypothesis has thus emerged, stating that the particular microenvironment of these tumors may interfere with the tumor cells that promote chemoresistance and the dissemination of metastases. The stroma is composed of a large number of cell types (immune cells, endothelial cells, mesenchymal stromal cells, etc.) which secrete growth factors, such as transforming growth factor-beta (TGF-beta), which favors the development of primary tumors and dissemination of metastases by constituting a permissive niche at primary and distant sites. Rather than targeting the tumor cells themselves, which are very heterogeneous in osteosarcoma, the hypothesis is instead to target the key actors secreted in the microenvironment, such as TGF betas, which play a part in tumor progression. In the last decade, numerous studies have shown that overexpression of TGF-beta is a hallmark of many cancers, including primary bone tumors. In this context, TGF-beta signaling has emerged as a crucial factor in the cross talk between tumor cells and stroma cells in poor prognosis cancers. Secretion of TGF-beta by tumor cells or stroma cells can effectively act in a paracrine manner to regulate the phenotype and functions of the microenvironment to stimulate protumorigenic microenvironmental changes. TGF beta can thus exert its protumorigenic function in primary bone tumors by promoting angiogenesis, bone remodeling and cell migration, and by inhibiting immunosurveillance. This review focuses on the involvement of TGF-beta signaling in primary bone tumor development, and the related therapeutic options that may be possible for these tumors. PMID- 29761080 TI - Erratum. AB - [This corrects the article DOI: 10.1159/000448464.]. PMID- 29761078 TI - Novel Immunotherapy Options for Extranodal NK/T-Cell Lymphoma. AB - Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3epsilon and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein-Barr virus (EBV) and specific ethnic genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody-drug conjugates, such as daratumumab (naked anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E), have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1) and LMP2] with activation of the NF-kappaB/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed patients including five with a complete response (CR). Furthermore, cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 have shown encouraging results with durable CRs as either maintenance therapy after initial induction chemotherapy or in the relapsed/refractory setting. In this paper, we review this exciting field of novel immunotherapy options against ENKTCL that hopefully will change the treatment paradigm in this deadly disease. PMID- 29761079 TI - Various Indices of Arterial Stiffness: Are They Closely Related or Distinctly Different? AB - Arterial stiffness is an independent risk factor for cardiovascular disease. There are a number of techniques and devices that have been developed and utilized to capture the information pertaining to the elasticity of the blood vessel. Almost all the available indices of arterial stiffness are known to increase with advancing age and are elevated in the presence of hypertension and coronary heart disease. It is not known how closely these different measures of arterial stiffness are related to each other. Available evidence indicates that arterial stiffness indices that share a homogeneous methodology appear to demonstrate good correlations. However, there are no significant associations between some measures. These overall results may be surprising considering that all the indices are supposed to reflect the same property of the arterial wall (i.e., arterial elasticity). Interestingly, no or weak correlations between indices of vascular function are not confined only to arterial stiffness and can be extended to endothelial function and vascular reactivity measures. PMID- 29761081 TI - Enhanced Aortic Pressure Wave Reflection in Patients with Aortic Coarctation after Aortic Arch Repair. AB - Background: In patients with aortic coarctation after successful aortic arch repair, it is well known that early-onset cardiovascular diseases can develop. Summary: We studied the pressure waveform in patients after aortic arch repair focusing on a pressure wave reflection. In patients after aortic arch repair, the repaired portion generates a new reflected pressure wave. As a result, the newly generated pressure wave causes aortic pressure augmentation, loss of pressure amplification, and left ventricular hypertrophy with fibrosis. Balloon dilatation of the aortic arch may also generate a new pressure wave reflection. Key Messages: In patients with aortic coarctation after aortic arch repair, the reconstructed site generates a new pressure wave reflection. This could be one of the causes of their future cardiovascular diseases. PMID- 29761082 TI - Associations between Type 2 Diabetes Mellitus and Arterial Stiffness: A Prospective Analysis Based on the Maine-Syracuse Study. AB - Background: The aim of this study was to investigate prospective associations between type 2 diabetes mellitus status and the gold standard non-invasive method for ascertaining arterial stiffness, carotid femoral pulse wave velocity. Methods: The prospective analysis employed 508 community-dwelling participants (mean age 61 years, 60% women) from the Maine-Syracuse Longitudinal Study. Pulse wave velocity at wave 7 (2006-2010) was compared between those with type 2 diabetes mellitus at wave 6 (2001-2006) (n = 52) and non-diabetics at wave 6 (n = 456), with adjustment for demographic factors, cardiovascular risk factors and lifestyle- and pulse wave velocity-related factors. Results: Type 2 diabetes mellitus status was associated with a significantly higher pulse wave velocity (12.5 +/- 0.36 vs. 10.4 +/- 0.12 m/s). Multivariate adjustment for other cardiovascular risk factors and lifestyle- and pulse wave velocity-related variables did not attenuate the findings. The risk of an elevated pulse wave velocity (>=12 m/s) was over 9 times higher for those with uncontrolled type 2 diabetes mellitus than for those without diabetes (OR 9.14, 95% CI 3.23-25.9, p < 0.001). Conclusions: Type 2 diabetes mellitus, particularly if uncontrolled, is significantly associated with risk of arterial stiffness later in life. Effective management of diabetes mellitus is an important element of protection from arterial stiffness. PMID- 29761085 TI - Logical Management of Aortic Coarctation. PMID- 29761083 TI - Lower Heart Rate Variability Is Associated with Lower Pulse Pressure Amplification: Role of Obesity. AB - Background: Heart rate variability (HRV), pulse pressure amplification, and obesity represent risk factors for cardiovascular events. The aims of the present study are (1) to explore the impact of HRV on pulse pressure amplification and (2) to investigate whether the association between HRV and pulse pressure amplification differs in obese and lean subjects. Methods: A total of 342 patients (age 61 +/- 11 years) were enrolled. HRV was analyzed concerning both the frequency and time domain as well as concerning the HRV triangular index. Pulse pressure amplification was estimated as the ratio between brachial and carotid pulse pressure, the latter measured with SphygmoCor. Results: Time domain HRV indices were directly correlated with pulse pressure amplification (the lower the HRV indices, the lower the pulse pressure amplification). This association was stronger in obese than in lean subjects after controlling for age and sex. Conclusion: Larger controlled studies are needed to provide a more detailed insight into the relation between HRV and pulse pressure amplification and to determine which pathways are differentially activated in lean and obese subjects. PMID- 29761087 TI - Heart Rate Variability and Pulse Pressure Amplification: Lessons from Diabetic Patients. PMID- 29761084 TI - Options for Dealing with Pressure Dependence of Pulse Wave Velocity as a Measure of Arterial Stiffness: An Update of Cardio-Ankle Vascular Index (CAVI) and CAVI0. AB - Pulse wave velocity (PWV), a marker of arterial stiffness, is known to change instantaneously with changes in blood pressure. In this mini-review, we discuss two main approaches for handling the blood pressure dependence of PWV: (1) converting PWV into a pressure-independent index, and (2) correcting PWV per se for the pressure dependence. Under option 1, we focus on cardio-ankle vascular index (CAVI). CAVI is essentially a form of stiffness index beta - CAVI is estimated for a (heart-to-ankle) trajectory, whereas beta is estimated for a single artery from pressure and diameter measurements. Stiffness index beta, and therefore also CAVI, have been shown to theoretically exhibit a slight residual blood pressure dependence due to the use of diastolic blood pressure instead of a fixed reference blood pressure. Additionally, CAVI exhibits pressure dependence due to the use of an estimated derivative of the pressure-diameter relationship. In this mini-review, we will address CAVI's blood pressure dependence theoretically, but also statistically. Furthermore, we review corrected indices (CAVI0 and beta0) that theoretically do not show a residual blood pressure dependence. Under option 2, three ways of correcting PWV are reviewed: (1) using an exponential relationship between pressure and cross-sectional area, (2) by statistical model adjustment, and (3) through reference values or rule of thumb. Method 2 requires a population to be studied to characterise the statistical model, and method 3 requires a representative reference study. Given these limitations, method 1 seems preferable for correcting PWV per se for its blood pressure dependence. In summary, several options are available to handle the blood pressure dependence of PWV. If a blood pressure-independent index is sought, CAVI0 is theoretically preferable over CAVI. If correcting PWV per se is required, using an exponential pressure-area relationship provides the user with a method to correct PWV on an individual basis. PMID- 29761086 TI - Aortic-Brachial Pulse Wave Velocity Ratio: A Measure of Arterial Stiffness Gradient Not Affected by Mean Arterial Pressure. AB - Background: Aortic stiffness, measured by carotid-femoral pulse wave velocity (cf PWV), is used for the prediction of cardiovascular risk. This mini-review describes the nonlinear relationship between cf-PWV and operational blood pressure, presents the proposed methods to adjust for this relationship, and discusses a potential place for aortic-brachial PWV ratio (a measure of arterial stiffness gradient) as a blood pressure-independent measure of vascular aging. Summary: PWV is inherently dependent on the operational blood pressure. In cross sectional studies, PWV adjustment for mean arterial pressure (MAP) is preferred, but still remains a nonoptimal approach, as the relationship between PWV and blood pressure is nonlinear and varies considerably among individuals due to heterogeneity in genetic background, vascular tone, and vascular remodeling. Extrapolations from the blood pressure-independent stiffness parameter beta (beta0) have led to the creation of stiffness index beta, which can be used for local stiffness. A similar approach has been used for cardio-ankle PWV to generate a blood pressure-independent cardio-ankle vascular index (CAVI). It was recently demonstrated that stiffness index beta and CAVI remain slightly blood pressure-dependent, and a more appropriate formula has been proposed to make the proper adjustments. On the other hand, the negative impact of aortic stiffness on clinical outcomes is thought to be mediated through attenuation or reversal of the arterial stiffness gradient, which can also be influenced by a reduction in peripheral medium-sized muscular arteries in conditions that predispose to accelerate vascular aging. Arterial stiffness gradient, assessed by aortic brachial PWV ratio, is emerging to be at least as good as cf-PWV for risk prediction, but has the advantage of not being affected by operating MAP. Key Messages: The negative impacts of aortic stiffness on clinical outcomes are proposed to be mediated through attenuation or reversal of arterial stiffness gradient. Aortic-brachial PWV ratio, a measure of arterial stiffness gradient, is independent of MAP. PMID- 29761089 TI - Association of Haemodynamic Indices of Central and Peripheral Pressure with Subclinical Target Organ Damage. AB - Background: Central aortic pressure has often been shown to be more closely associated with markers of vascular function and incidence of cardiovascular events compared to peripheral pressure. However, the potential clinical use of central aortic or peripheral haemodynamic indices as markers of target organ damage (TOD) has not been fully established. Methods: We evaluated associations of TOD with central aortic and peripheral haemodynamic indices (central aortic [cPP] and peripheral pulse pressure [pPP], central aortic augmentation index, and central and peripheral waveform factor) in 770 hospital inpatients (age 60 +/- 10 years, 473 males) with primary hypertension. TOD was quantified in terms of arterial stiffness as measured by carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (IMT), and urine albumin-to-creatinine ratio (ACR). Subclinical TOD was defined as carotid IMT >0.9 mm, urine ACR >3.5 mg/mmol in females and >2.5 mg/mmol in males and/or cfPWV >12 m/s. Results: Both cPP and pPP showed significant correlation with cfPWV (r = 0.41 vs. 0.40; p < 0.01), ACR (r = 0.24 vs. 0.27; p < 0.01) and carotid IMT (r = 0.14 vs. 0.15; p < 0.01). Each SD increase in pPP and cPP was associated with increased risk of cfPWV >12 m/s (odds ratio [OR] = 2.7 and 2.9 for pPP and cPP, respectively), ACR >2.5 mg/mmol (OR = 1.2 and 1.4, respectively), and carotid IMT >0.9 mm (OR = 1.46 and 1.53, respectively). Compared to pPP, cPP had higher predictive power for TOD for age >=60 years (OR = 3.07, p < 0.001). Conclusions: Although both pPP and cPP show an association with TOD in a hypertensive population, cPP provides additional information beyond pPP associated with TOD in a hypertensive cohort. Central aortic haemodynamic indices as potential biomarkers of subclinical TOD need to be validated by further prospective studies. PMID- 29761091 TI - Increase in the Arterial Velocity Pulse Index of Patients with Peripheral Artery Disease. AB - Background: Recently, a simple parameter calculated from the brachial pressure waveform recorded using an oscillometric device (arterial velocity pulse index [AVI]: ratio of the forward/reflected pressure wave amplitudes) has become available to assess the pathophysiological abnormalities associated with vascular damage. Peripheral artery disease (PAD) represents one of the disease entities associated with the advanced stages of atherosclerotic vascular damage. The present study was conducted to examine whether an increase in the AVI might be influenced by the presence of PAD. Methods and Results: The AVI was measured from oscillometric recordings of the brachial pressure waveform, and the ankle brachial pressure index (ABPI) was determined by an oscillometric method. Study 1: In 341 consecutive patients admitted for the management of cardiovascular disease and/or cardiovascular risk factors, the ABPI and the AVI were measured simultaneously. An ABPI <=0.90 was observed in 19 subjects, and logistic regression analysis revealed a significant association between AVI and ABPI <=0.90 (odds ratio = 1.81; 95% confidence interval = 1.15-2.84; p = 0.01). Study 2: In another 19 patients with PAD, percutaneous transluminal angioplasty resulted in a decrease in the AVI from 31 +/- 8 to 27 +/- 8 (p < 0.01). Conclusion: Possible presence of PAD must be taken into account while applying the AVI for the assessment of vascular damage. PMID- 29761088 TI - Vascular Aging and Cognitive Dysfunction: Silent Midlife Crisis in the Brain. AB - Background: Vascular aging may cause cerebral microvascular damage and cognitive dysfunction. There is incremental evidence that consistently implicates arterial stiffness being involved in the manifestation of cognitive impairment in the elderly. However, few investigations have examined the relationship between arterial stiffness and cognitive impairment in midlife. Summary: Past studies inconsistently showed improved cognitive outcomes after antihypertensive therapy in elderly populations. Nevertheless, recent findings revealed that blood pressure-lowering treatment in young adults might eliminate or halt the progression of the detrimental effects related to arterial stiffness, indicating that younger adults may have more favorable outcomes in cognition than their older counterparts if early intervention is conducted at the subclinical stage. Stiffening of the aorta may lead to an excessive flow pulsatility in the brain that may cause microvascular structural brain damage and worse cognitive performance. Recent investigations have suggested that arterial stiffness is likely to trigger initial silent brain damage, possibly preceding midlife, while the manifestation of cognitive decline and deterioration can be foreseen in the subsequent life span. Key Message: Despite the recent novel findings, definite conclusions on causality between vascular aging and cognitive dysfunction cannot be drawn at present. Further well-powered longitudinal studies with superior neuroimaging indicator, vascular mechanical biomarkers, and sensitive cognitive assessment tools that examine a broad range of age populations may help extend our understanding of the association between vascular aging and cognitive dysfunction throughout the life span. PMID- 29761090 TI - The Role of Vascular Calcification in Heart Failure and Cognitive Decline. AB - Vascular calcification is heterogeneous and triggered by multiple mechanisms. It has been implicated in the development of heart failure with preserved ejection fraction (HFpEF) and cognitive function impairment. Understanding the pathophysiology of vascular calcification may help us improve the management of HFpEF, atherosclerosis, accelerated arterial stiffness, hypertension, and cognitive dysfunction. Currently, there are no effective strategies for treating accelerated arterial stiffness. This may indicate that once arterial stiffness or vascular calcification has developed, it may be less likely to stop the ongoing pathophysiology. Therefore, earlier intervention targeting the probable pathways of vascular calcification may benefit the patients with vascular calcification and related pathological conditions. In this review, we briefly discuss the proposed pathophysiological roles of vascular calcification in the development of heart failure and cognitive decline, the animal models used to study the link between vascular calcification and cardiovascular diseases, and the possible corresponding management strategies. PMID- 29761092 TI - Validation of a Piezoelectric Sensor Array-Based Device for Measurement of Carotid-Femoral Pulse Wave Velocity: The Philips Prototype. AB - Background: Multiple piezoelectric pressure mechanotransducers topologized into an array might improve efficiency and accuracy in collecting arterial pressure waveforms for measurement of pulse wave velocity (PWV). Objective: In the present study, we validated a piezoelectric sensor array-based prototype (Philips) against the validated and clinically widely used Complior device (Alam Medical). Methods: We recruited 33 subjects with a wide distribution of PWV. For the validation, PWV was measured sequentially with the Complior device (four times) and the Philips prototype (three times). With the 99 paired PWV values, we investigated the agreement between the Philips prototype and the Complior device using Pearson correlation analysis and Bland-Altman plot. We also performed analysis on the determinants and reproducibility of PWV measured with both devices. Results: The correlation coefficient for PWV measured with the two devices was 0.92 (p < 0.0001). Compared with the Complior device, the Philips prototype slightly overestimated PWV by 0.24 (+/- 2 standard deviations, +/- 1.91) m/s, especially when PWV was high. The correlation coefficient between the difference and the average of the Philips and Complior measurements was 0.21 (p = 0.035). Nonetheless, they had similar determinants. Age, mean arterial pressure, and sex altogether explained 81.6 and 83.9% of the variance of PWV values measured with the Philips prototype and Complior device, respectively. When the two extremes of the three PWV values measured with the Philips prototype and the Complior device were investigated, the coefficients of variation were 8.26 and 3.26%, respectively. Conclusions: Compared with the Complior device, the Philips prototype had similar accuracy, determinants, and reproducibility in measuring PWV. PMID- 29761094 TI - 2017 Dutch Report Card+: Results From the First Physical Activity Report Card Plus for Dutch Youth With a Chronic Disease or Disability. AB - Background: The Dutch Active Healthy Kids (AHK) Report Card+ (RC+) consolidates and translates research and assesses how the Netherlands is being responsible in providing physical activity (PA) opportunities for youth (< 18 years) with a chronic disease or disability. The aim of this article is to summarize the results of the Dutch RC+. Methods: Nine indicators were graded using the AHK Global Alliance RC development process, which includes a synthesis of best available research, surveillance, policy and practice findings, and expert consensus. Two additional indicators were included: weight status and sleep. Results: Grades assigned were: Overall Physical Activity, D; Organized Sports Participation, B-; Active Play, C-; Active Transportation, A-; Sedentary Behavior, C; Sleep C; For Weight Status, Family and Peers, School, Community and Built Environment, Government Strategies, and Investments all INC. Conclusions: The youth with disabilities spend a large part of the day sedentary, since only 26% of them met the PA norm for healthy physical activity. Potential avenues to improve overall physical activity are changing behaviors regarding sitting, screen time, and active play. The Netherlands is on track regarding PA opportunities for youth with disabilities, however they are currently not able to participate unlimited in sports and exercise. PMID- 29761093 TI - Functional Characterization of Novel ATP7B Variants for Diagnosis of Wilson Disease. AB - Background: Diagnosis of rare Wilson disease (WD) in pediatric patients is difficult, in particular when hepatic manifestation is absent. Genetic analysis of ATP7B represents the single major determinant of the diagnostic scoring system in WD children having mild symptoms. Objectives: To assess the impact of molecularly expressed ATP7B gene products in order to assist diagnosis of Wilson disease in pediatric patients having a novel mutation and subtle neuropsychiatric disease. Methods: The medical history, clinical presentation, biochemical parameters, and the genetic analysis of ATP7B were determined. Due to ambiguous clinical and biochemical findings and identification of a novel compound ATP7B mutation with unknown disease-causing status, a molecular analysis of the ATP7B gene products in a previously well characterized cell model was performed. Results: The ATP7B variants were transgenically expressed and the respective gene function molecularly characterized. Despite normal mRNA expression, low ATP7B protein expression of the mutants p.L168P and p.S1423N was observed (34.3 +/- 8% and 66.0 +/- 8%, respectively). Copper exposure did not result in decreased viability of transgenic cells as compared to wild type. Intracellular copper accumulation was reduced (<=47.9 +/- 8%) and intracellular protein trafficking was impaired. Conclusion: Our report suggests that functional characterization of novel ATP7B mutants can assist diagnosis; however mild functional impairments of ATP7B variants may hamper the value of such approaches. PMID- 29761096 TI - Editorial: Precision Public Health. PMID- 29761095 TI - An "All Teach, All Learn" Approach to Research Capacity Strengthening in Indigenous Primary Health Care Continuous Quality Improvement. AB - In Australia, Indigenous people experience poor access to health care and the highest rates of morbidity and mortality of any population group. Despite modest improvements in recent years, concerns remains that Indigenous people have been over-researched without corresponding health improvements. Embedding Indigenous leadership, participation, and priorities in health research is an essential strategy for meaningful change for Indigenous people. To centralize Indigenous perspectives in research processes, a transformative shift away from traditional approaches that have benefited researchers and non-Indigenous agendas is required. This shift must involve concomitant strengthening of the research capacity of Indigenous and non-Indigenous researchers and research translators all must teach and all must learn. However, there is limited evidence about how to strengthen systems and stakeholder capacity to participate in and lead continuous quality improvement (CQI) research in Indigenous primary health care, to the benefit of Indigenous people. This paper describes the collaborative development of, and principles underpinning, a research capacity strengthening (RCS) model in a national Indigenous primary health care CQI research network. The development process identified the need to address power imbalances, cultural contexts, relationships, systems requirements and existing knowledge, skills, and experience of all parties. Taking a strengths-based perspective, we harnessed existing knowledge, skills and experiences; hence our emphasis on capacity "strengthening". New insights are provided into the complex processes of RCS within the context of CQI in Indigenous primary health care. PMID- 29761097 TI - Commentary: Human Liver Flukes. PMID- 29761098 TI - Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening. AB - Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4,000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 and 1.79 MUM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 MUM), compounds 2a and 3a displayed 5- and 3 fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report. PMID- 29761099 TI - Mechanically Robust and Thermally Stable Colorful Superamphiphobic Coatings. AB - Colorful super anti-wetting coatings are receiving growing attention, but are challenging to invent. Here, we report a general method for preparing mechanically robust and thermally stable colorful superamphiphobic coatings. A composite of palygorskite (PAL) nanorods and iron oxide red (IOR) was prepared by solid-state grinding or hydrothermal reaction, which was then modified by hydrolytic condensation of silanes to form a suspension. Superamphiphobic coatings were prepared by spray-coating the suspension onto substrates. The superamphiphobicity depends upon the surface microstructure and chemical composition, which are controllable by the PAL/IOR concentration and the solid state grinding time. The colorful coatings show excellent superamphiphobicity with high contact angles and low sliding angles for water and various organic liquids of low surface tension, e.g., toluene and n-decane. The coatings also feature high mechanical, chemical and thermal stability, which is superior to all the reported colorful super anti-wetting coatings. Moreover, superamphiphobic coatings of different colors can be prepared via the same procedure using the other metal oxides instead of IOR. We believe the colorful superamphiphobic coatings may find applications in many fields like anti-climbing of oils and restoration of cultural relics, as the coatings are applicable onto various substrates. PMID- 29761103 TI - Considering Cell Therapy Product "Good Manufacturing Practice" Status. PMID- 29761102 TI - Reactivation of a Vaccine Escape Hepatitis B Virus Mutant in a Cambodian Patient During Anti-Hepatitis C Virus Therapy. AB - A 76-year-old Cambodian man co-infected with hepatitis B virus (HBV) and hepatitis C virus (HCV) 6c-1 presented for care. HBV DNA was intermittently detectable despite anti-HBs levels being above the protective threshold. During treatment for HCV, HBV DNA levels increased. Sequencing revealed multiple mutations including vaccine escape mutation and mutations predicted to enhance fitness. This case represents exacerbation of an HBV vaccine escape mutant during a direct-acting antiviral therapy. PMID- 29761101 TI - Fibromyalgia Syndrome: A Case Report on Controlled Remission of Symptoms by a Dietary Strategy. AB - A 34-year-old woman suffered from significant chronic pain, depression, non restorative sleep, chronic fatigue, severe morning stiffness, leg cramps, irritable bowel syndrome, hypersensitivity to cold, concentration difficulties, and forgetfulness. Blood tests were negative for rheumatic disorders. The patient was diagnosed with Fibromyalgia syndrome (FMS). Due to the lack of effectiveness of pharmacological therapies in FMS, she approached a novel metabolic proposal for the symptomatic remission. Its core idea is supporting serotonin synthesis by allowing a proper absorption of tryptophan assumed with food, while avoiding, or at least minimizing the presence of interfering non-absorbed molecules, such as fructose and sorbitol. Such a strategy resulted in a rapid improvement of symptoms after only few days on diet, up to the remission of most symptoms in 2 months. Depression, widespread chronic pain, chronic fatigue, non-restorative sleep, morning stiffness, and the majority of the comorbidities remitted. Energy and vitality were recovered by the patient as prior to the onset of the disease, reverting the occupational and social disabilities. The patient episodically challenged herself breaking the dietary protocol leading to its negative test and to the evaluation of its benefit. These breaks correlated with the recurrence of the symptoms, supporting the correctness of the biochemical hypothesis underlying the diet design toward remission of symptoms, but not as a final cure. We propose this as a low risk and accessible therapeutic protocol for the symptomatic remission in FMS with virtually no costs other than those related to vitamin and mineral salt supplements in case of deficiencies. A pilot study is required to further ground this metabolic approach, and to finally evaluate its inclusion in the guidelines for clinical management of FMS. PMID- 29761100 TI - Moving the Cellular Peptidome by Transporters. AB - Living matter is defined by metastability, implying a tightly balanced synthesis and turnover of cellular components. The first step of eukaryotic protein degradation via the ubiquitin-proteasome system (UPS) leads to peptides, which are subsequently degraded to single amino acids by an armada of proteases. A small fraction of peptides, however, escapes further cytosolic destruction and is transported by ATP-binding cassette (ABC) transporters into the endoplasmic reticulum (ER) and lysosomes. The ER-resident heterodimeric transporter associated with antigen processing (TAP) is a crucial component in adaptive immunity for the transport and loading of peptides onto major histocompatibility complex class I (MHC I) molecules. Although the function of the lysosomal resident homodimeric TAPL-like (TAPL) remains, until today, only loosely defined, an involvement in immune defense is anticipated since it is highly expressed in dendritic cells and macrophages. Here, we compare the gene organization and the function of single domains of both peptide transporters. We highlight the structural organization, the modes of substrate binding and translocation as well as physiological functions of both organellar transporters. PMID- 29761105 TI - Prevalence of Proteinuria and Albuminuria in an Obese Population and Associated Risk Factors. AB - Obesity has been increasingly recognized as a risk factor for kidney disease and both proteinuria and microalbuminuria have been associated with obesity. The actual prevalence of microalbuminuria and proteinuria in obese patients in the United States (US) has not been clearly described in the literature. Furthermore, obesity is associated with risk factors of kidney disease, such as diabetes and hypertension (HTN), and the prevalence of proteinuria and albuminuria excluding these risk factors is uncertain. In this study, we collected urine albumin/creatinine and urine protein/creatinine ratios on obese patients undergoing bariatric surgery to determine the prevalence of albuminuria and proteinuria in obese patients with and without associated diabetes and HTN. The study included 218 obese patients undergoing bariatric surgery at a New York City hospital. The mean age was 42.1 +/- 11.3 years. The mean body mass index (BMI) was 43.9 +/- 8.1. Diabetes (DM) was present in 25%. HTN was present in 47%. The prevalence of proteinuria and albuminuria was 21% (95% CI: 15.8-27.1%) and 19.7% (95% CI: 14.2-26.2%) respectively. Among those without DM but who had HTN, 22.6% (95% CI: 12.9-35) had proteinuria and 17% (95% CI 8.4-30.9) had albuminuria. Of patients with neither DM nor HTN, 13.3% (95% CI: 7.3-21.6) and 11% (95% CI: 5 17%) had proteinuria and albuminuria, respectively. Diabetics had a significantly higher prevalence of proteinuria and albuminuria than the non-diabetic groups. The non-diabetic groups did not differ significantly from each other in terms of prevalence of proteinuria and albuminuria. The BMI for diabetics did not differ from non-diabetics. On multivariate analysis, only the presence of diabetes was associated with proteinuria and albuminuria. BMI, age, and HTN were not predictive. In conclusion, we found a relatively high prevalence of microalbuminuria and proteinuria in an urban, US, obese population undergoing bariatric surgery. When diabetics were excluded, there was a lower prevalence. Even patients who had neither diabetes nor HTN, still, however, had much greater amounts than seen in the general US population, likely reflecting an adverse effect of obesity itself on renal physiology. PMID- 29761106 TI - Current Strategies and Future Directions to Optimize ACL Reconstruction in Adolescent Patients. AB - The incidence of anterior cruciate ligament (ACL) injuries in the pediatric population has risen in recent years. These injuries have historically presented a management dilemma in skeletally immature patients with open physes and significant growth remaining at time of injury. While those nearing skeletal maturity may be treated with traditional, transphyseal adult techniques, these same procedures risk iatrogenic damage to the growth plates and resultant growth disturbances in younger patients with open physes. Moreover, conservative management is non-optimal as significant instabilities of the knee remain. Despite the development of physeal-sparing reconstructive techniques for younger patients, there remains debate over which procedure may be most suitable on a patient to patient basis. Meanwhile, the drivers behind clinical and functional outcomes following ACL reconstruction remain poorly understood. Therefore, current strategies are not yet capable of optimizing surgical ACL reconstruction on an individualized basis with absolute confidence. Instead, aims to improve surgical treatment of ACL tears in skeletally immature patients will rely on additional approaches in the near future. Namely, finite element models have emerged as a tool to model complex knee joint biomechanics. The inclusion of several individualized variables such as bone age, three dimensional geometries around the knee joint, tunnel positioning, and graft tension collectively present a possible means of better understanding and even predicting how to enhance surgical decision-making. Such a tool would serve surgeons in optimizing ACL reconstruction in the skeletally immature individuals, in order to improve clinical outcomes as well as reduce the rate of post-operative complications. PMID- 29761107 TI - Intramolecular Fuzzy Interactions Involving Intrinsically Disordered Domains. AB - Structural disorder is an essential ingredient for function in many proteins and protein complexes. Fuzzy complexes describe the many instances where disorder is maintained as a critical element of protein interactions. In this minireview we discuss how intramolecular fuzzy interactions function in signaling complexes. Focussing on the Src family of kinases, we argue that the intrinsically disordered domains that are unique for each of the family members and display a clear fingerprint of long range interactions in Src, might have critical roles as functional sensor or effectors and mediate allosteric communication via fuzzy interactions. PMID- 29761108 TI - A trial like ALIC4E: why design a platform, response-adaptive, open, randomised controlled trial of antivirals for influenza-like illness? AB - ALIC4E is the first publicly funded, multicountry, pragmatic study determining whether antivirals should be routinely prescribed for influenza-like illness in primary care. The trial aims to go beyond determining the average treatment effect in a population to determining effects in patients with combinations of participant characteristics (age, symptom duration, illness severity, and comorbidities). It is one of the first platform, response-adaptive, open trial designs implemented in primary care, and this article aims to provide an accessible description of key aspects of the study design. 1) The platform design allows the study to remain relevant to evolving circumstances, with the ability to add treatment arms. 2) Response adaptation allows the proportion of participants with key characteristics allocated to study arms to be altered during the course of the trial according to emerging outcome data, so that participants' information will be most useful, and increasing their chances of receiving the trial intervention that will be most effective for them. 3) Because the possibility of taking placebos influences participant expectations about their treatment, and determining effects of the interventions on patient help seeking and adherence behaviour in real-world care is critical to estimates of cost-effectiveness, ALIC4E is an open-label trial. PMID- 29761104 TI - Platelets in Immune Response to Virus and Immunopathology of Viral Infections. AB - Platelets are essential effector cells in hemostasis. Aside from their role in coagulation, platelets are now recognized as major inflammatory cells with key roles in the innate and adaptive arms of the immune system. Activated platelets have key thromboinflammatory functions linking coagulation to immune responses in various infections, including in response to virus. Recent studies have revealed that platelets exhibit several pattern recognition receptors (PRR) including those from the toll-like receptor, NOD-like receptor, and C-type lectin receptor family and are first-line sentinels in detecting and responding to pathogens in the vasculature. Here, we review the main mechanisms of platelets interaction with viruses, including their ability to sustain viral infection and replication, their expression of specialized PRR, and activation of thromboinflammatory responses against viruses. Finally, we discuss the role of platelet-derived mediators and platelet interaction with vascular and immune cells in protective and pathophysiologic responses to dengue, influenza, and human immunodeficiency virus 1 infections. PMID- 29761109 TI - Mesenchymal Stem Cells Differentiate to Endothelial Cells Using Recombinant Vascular Endothelial Growth Factor -A. AB - Background: Vascular endothelial growth factor-A (VEGF-A), an endothelial cell specific mitogen produced by various cell types, plays important roles in cell differentiation and proliferation. In this study we investigated the effect of recombinant VEGF-A on differentiation of mesenchymal stem cells (MSCs) to endothelial cells (ECs). Methods: VEGF-A was expressed in E. coli BL21 (DE3) and BL21 pLysS competent cells with the pET32a expression vector. Recombinant VEGF-A protein expression was verified by SDS-PAGE and western blotting. Mesenchymal stem cell differentiation to ECs in the presence of VEGF-A was evaluated by flow cytometry and fluorescence microscopy. Results: Recombinant VEGF-A was produced in E. coli BL21 (DE3) cells at 0.8 mg/mL concentration. Expression of CD31 and CD 144 was significantly greater, while expression of CD90, CD73, and CD44 was significantly less, in MSCs treated with our recombinant VEGF-A than in those treated with the commercial protein (p < 0.05). Conclusion: Recombinant VEGF-A expressed in a prokaryotic system can induce MSCs differentiation to ECs and can be used in research and likely therapeutic applications. PMID- 29761111 TI - Myocardial Infarction as an Early Presentation in Thrombotic Thrombocytopenic Purpura: A Rare Case Series. AB - Renal and neurological involvements are frequently seen in thrombotic thrombocytopenic purpura (TTP). Cardiac involvement, however, has been rarely reported. In this article, we present 2 cases of myocardial infarction in patients with TTP. In the first case, a young man presented with non-ST-segment elevation myocardial infarction that resolved promptly with plasmapheresis. The second patient developed ST-segment elevation myocardial infarction early in the course of the disease and died before plasmapheresis could be initiated. Hence, a high degree of suspicion with prompt diagnosis and treatment is needed to prevent mortality associated with cardiac involvement in TTP. PMID- 29761110 TI - Granulomatous Invasive Aspergillus flavus Infection Involving the Nasal Sinuses and Brain. AB - Invasive fungal infections are commonly associated with some form of immunosuppression. On the nasal epithelial surface, Aspergillus flavus, under favorable conditions, can aggressively breach multiple cell lines invading the local tissues. We present the case of a 35-year-old woman with granulomatous invasive Aspergillus flavus infection involving the nasal sinuses and the brain. Antifungal agents administered in the previous episodes contained the infection; however, the infected site evolved over time surrounded with calcified tissues in the left maxillary sinus. The current infection involved the other side of the maxillary sinus and extended to the orbital cavity eroding the parts of the skull and retro-orbital structures and was treated with a long course of isavuconazole therapy. PMID- 29761112 TI - Takotsubo Cardiomyopathy Mimicking Stent Thrombosis After Percutaneous Coronary Intervention. AB - Takotsubo cardiomyopathy, also known as "broken heart syndrome," is a transient left ventricular dysfunction associated with stress (usually emotional) induced myocardial injury and stunning. It often presents as myocardial infarction on surface electrocardiogram (EKG). Diagnosis is made by coronary angiography, which rules out coronary artery disease and shows pathognomonic apical ballooning. In this article, we present a case of a 72-year-old woman who initially presented with an ST segment elevation myocardial infarction on EKG. Coronary angiography showed severe left anterior descending artery and diagonal lesions requiring percutaneous coronary intervention. Post-percutaneous coronary intervention, EKG changes resolved. The next day, the patient developed recurrent chest pain and her EKG showed diffuse T-wave inversion in precordial leads with reemerging ST segment elevations concerning for stent thrombosis. The patient underwent repeat emergent coronary angiography, which showed patent stents and findings consistent with takotsubo cardiomyopathy. PMID- 29761113 TI - Differences in Hip Joint Biomechanics and Muscle Activation in Individuals With Femoroacetabular Impingement Compared With Healthy, Asymptomatic Individuals: Is Level-Ground Gait Analysis Enough? AB - Background: Femoroacetabular impingement (FAI) is a recognized cause of hip and groin pain and a significant factor in hip joint function during sport. Objective tests for understanding hip function are lacking in this population. Purpose: To determine whether biomechanical and electromyographic features of hip function during level-ground walking differ between a group diagnosed with FAI and those with no symptoms of FAI. Study Design: Controlled laboratory study. Methods: A total of 20 asymptomatic individuals and 20 individuals with FAI walked on a dual belt instrumented treadmill at self-selected walking velocities. Sagittal and frontal plane joint motions, moments, and muscle activation for the gluteus medius, gluteus maximus, rectus femoris, and medial and lateral hamstrings were analyzed. Discrete measures were extracted from each biomechanical waveform, and principal component analysis was used to determine hip joint muscle activation and hip adduction moment patterns. Statistical significance was determined by use of Student t tests with Bonferroni adjustments for multiple comparisons (alpha = .05). Results: Individuals with FAI walked more slowly (P = .015) and had lower self-reported function (P < .001). No differences in muscle strength were found between the symptomatic and contralateral legs in the FAI group (P > .017), but those with FAI had lower strength in the knee extensors and flexors and the hip extensors, flexors, and adductors compared with the asymptomatic group (P < .017). Individuals with unilateral symptomatic FAI walked with similar biomechanical and hip muscle electromyographic results bilaterally. The only differences found were a greater amplitude of gluteus maximus activation in the FAI symptomatic leg compared with the asymptomatic group and greater medial hamstring activation than lateral hamstring activation in the FAI group in both limbs compared with the asymptomatic group. Conclusion: Individuals with FAI were generally deconditioned and reported significantly more functional limitations. No biomechanical differences existed between groups during level walking, yet hamstring and gluteus maximus activation differed when the symptomatic group was compared with the asymptomatic group. Clinical Relevance: The field lacks objective testing of hip joint function to understand implications of FAI for dynamic movements, particularly with applications to biomechanics and electromyography. Level walking was of limited value for understanding FAI hip function, and the development of a more challenging gait assessment is warranted. PMID- 29761114 TI - Preoperative PROMIS Scores Predict Postoperative Outcomes After Primary ACL Reconstruction. AB - Background: PROMIS (Patient-Reported Outcomes Measurement Information System) scores in patients undergoing anterior cruciate ligament (ACL) reconstruction have not been fully described in the literature to date. The ability of preoperative patient-reported outcome scores to directly predict postoperative outcomes in patients who undergo primary ACL reconstruction is unknown. Hypothesis: Postoperative PROMIS physical function (PF), pain interference (PI), and depression (D) scores in patients who undergo ACL reconstruction will show improvement when compared with preoperative scores. Additionally, preoperative PROMIS PF, PI, and D scores will predict which patients will not achieve a minimal clinically important difference (MCID) postoperatively. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 233 patients who underwent primary ACL reconstruction between 2015 and 2016 and had completed PROMIS measures both preoperatively (within 60 days of surgery) and postoperatively (100-240 days after surgery) were included in this study. PROMIS PF, PI, and D scores were compared. Accuracy analyses were performed to determine whether preoperative PROMIS scores from each domain could predict postoperative achievement of MCID in the same domain. Cutoff scores were then calculated. Results: PROMIS PF, PI, and D scores all showed a significant improvement after ACL reconstruction (all P < .001). Preoperative scores from all 3 PROMIS domains showed a strong ability to predict clinically meaningful improvement, as defined by MCID, with areas under the receiver operating characteristic curve from 0.72 to 0.84. Optimal cutoffs for preoperative PROMIS scores showed that patients with a PF score of <42.5, PI score of >56.2, or D score of >44.8 were more likely to achieve MCID. Conclusion: PROMIS PF, PI, and D scores improved significantly in patients who underwent primary ACL reconstruction. Preoperative PROMIS PF, PI, and D scores were highly predictive of outcome in the early postoperative period. The reported cutoff scores showed high probability in predicting which patients would and would not achieve a clinically meaningful improvement. PMID- 29761115 TI - Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. AB - Objective: DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Methods: Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression. Results: Here we report a zebrafish model of Depdc5 loss-of-function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy-associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein. Interpretation: This study demonstrates that Depdc5 knockdown leads to early-onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy-associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1 dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5-inherited forms of focal epilepsy. PMID- 29761116 TI - Estimation of intrathecal IgG synthesis: simulation of the risk of underestimation. AB - Objective: The low level of passively diffused IgG through the blood-brain barrier is sufficient to blur the estimation of intrathecal IgG synthesis (ITS). Therefore, this estimation requires a mathematical calculation derived from empirical laws, but the range of normal values in healthy controls is wide enough to prevent a precise calculation. This study investigated the precision of various methods of ITS estimations and their application to two clinical situations: plasma exchange and immune suppression targeting ITS. Methods: Based on a mathematical model of ITS, we constructed a population of healthy controls and applied a tunable ITS. Results: We demonstrate the following results: underestimation of ITS is common at individual level but true ITS is well fitted by cohorts; Q IgG increases after plasma exchange; IgG Loc calculation based on Qlim falsely increases when Q Alb decreases; the sample size required to demonstrate a decrease in ITS increases exponentially with larger Q Alb. Interpretation: Studies evaluating changes in ITS level should be adjusted to Q Alb. Low amounts of ITS could be largely underestimated. PMID- 29761118 TI - Susceptibility-weighted and diffusion kurtosis imaging to evaluate encephalomalacia with epilepsy after traumatic brain injury. AB - Objective: Encephalomalacia after traumatic brain injury (TBI) is one of the factors leading to epilepsy. In this study, magnetic resonance imaging (MRI) was used to explore the brain image features of epilepsy after traumatic encephalomalacia, and to provide objective evidence for predicting the possible occurrence of epilepsy after traumatic encephalomalacia. Methods: Two-hundred fifty-two patients with traumatic encephalomalacia were prospectively enrolled in the study. All patients underwent MRI after discharge from the hospital. At the 1 year follow-up, participants were divided into epilepsy and nonepilepsy groups. All participants underwent MRI including conventional imaging, susceptibility weighted imaging (SWI), and diffusion kurtosis imaging (DKI). The lesion volume, iron deposition, mean diffusion (MD), and mean kurtosis (MK) around the lesions were calculated for each group and compared using t-tests. P values < 0.05 were considered statistically significant. Results: Sixty patients with epilepsy and 91 without epilepsy were reported. There were no significant differences in Glasgow Coma Scale (GCS), lesion volume, encephalomalacia, or MD values between the two groups. Iron deposition was significantly higher in the epilepsy group (P < 0.05). The MK values were significantly different (P < 0.05). Interpretation: Advanced MRI is an important means of evaluating risk of developing epilepsy at 1 year due to encephalomalacia in patients with TBI. SWI and DKI could be used to assess the microstructural changes around the encephalomalacia, and therefore be used to evaluate risk of developing epilepsy at 1 year. PMID- 29761117 TI - Genomic analysis identifies masqueraders of full-term cerebral palsy. AB - Objective: Cerebral palsy is a common, heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent studies have suggested genetic diseases can be misdiagnosed as cerebral palsy. We hypothesized that two simple criteria, that is, full-term births and nonspecific brain MRI findings, are keys to extracting masqueraders among cerebral palsy cases due to the following: (1) preterm infants are susceptible to multiple environmental factors and therefore demonstrate an increased risk of cerebral palsy and (2) brain MRI assessment is essential for excluding environmental causes and other particular disorders. Methods: A total of 107 patients-all full-term births-without specific findings on brain MRI were identified among 897 patients diagnosed with cerebral palsy who were followed at our center. DNA samples were available for 17 of the 107 cases for trio whole-exome sequencing and array comparative genomic hybridization. We prioritized variants in genes known to be relevant in neurodevelopmental diseases and evaluated their pathogenicity according to the American College of Medical Genetics guidelines. Results: Pathogenic/likely pathogenic candidate variants were identified in 9 of 17 cases (52.9%) within eight genes: CTNNB1,CYP2U1,SPAST,GNAO1,CACNA1A,AMPD2,STXBP1, and SCN2A. Five identified variants had previously been reported. No pathogenic copy number variations were identified. The AMPD2 missense variant and the splice-site variants in CTNNB1 and AMPD2 were validated by in vitro functional experiments. Interpretation: The high rate of detecting causative genetic variants (52.9%) suggests that patients diagnosed with cerebral palsy in full-term births without specific MRI findings may include genetic diseases masquerading as cerebral palsy. PMID- 29761119 TI - Antibodies against cell adhesion molecules and neural structures in paraneoplastic neuropathies. AB - Objective: Paraneoplastic neurological syndromes (PNS) are rare neurological disorders in which ectopic expression of neural antigens by a tumor results in an autoimmune attack against the nervous system. Onconeural antibodies not only guide PNS diagnosis but may also help detecting underlying malignancies. Our project aims to uncover new potential antibodies in paraneoplastic neuropathies (PN). Methods: Thirty-four patients fulfilling diagnostic criteria of possible (n = 9; 26.5%) and definite (n = 25; 73.5%) PN without onconeural antibodies and 28 healthy controls were included in our study. Sera were tested for known antibodies against neural cell adhesion molecules and screened for novel IgG and IgM reactivities against nerve components: dorsal root ganglia (DRG) neurons, motor neurons, and Schwann cells. Patients showing autoantibodies against any of these cell types were used for immunoprecipitation (IP) studies. Results: Overall, 9 (26.5%) patients showed significant reactivity against DRG neurons, motor neurons, or Schwann cells, whereas 5 (17.9%) healthy controls only showed moderate reactivity. Compared with control sera, serum samples from patients with paraneoplastic sensory-motor neuropathies had a higher frequency of IgM antibodies against Schwann cells (0% vs. 40%; P = 0.0028). No novel antigens were identified from our IP experiments. Antibodies against the neural adhesion molecules CNTN1, NF155, NF140, NF186, NCAM1, L1CAM, and the CNTN1/CASPR1 complex were not detected in patients with PN. One (2.9%) patient with CIDP and thymoma had CASPR2 antibodies. Interpretation: Almost 30% of patients with PN harbor antibodies targeting neural structures, suggesting that novel neoplasm-associated antigens remain to be discovered. PMID- 29761120 TI - An image-based model of brain volume biomarker changes in Huntington's disease. AB - Objective: Determining the sequence in which Huntington's disease biomarkers become abnormal can provide important insights into the disease progression and a quantitative tool for patient stratification. Here, we construct and present a uniquely fine-grained model of temporal progression of Huntington's disease from premanifest through to manifest stages. Methods: We employ a probabilistic event based model to determine the sequence of appearance of atrophy in brain volumes, learned from structural MRI in the Track-HD study, as well as to estimate the uncertainty in the ordering. We use longitudinal and phenotypic data to demonstrate the utility of the patient staging system that the resulting model provides. Results: The model recovers the following order of detectable changes in brain region volumes: putamen, caudate, pallidum, insula white matter, nonventricular cerebrospinal fluid, amygdala, optic chiasm, third ventricle, posterior insula, and basal forebrain. This ordering is mostly preserved even under cross-validation of the uncertainty in the event sequence. Longitudinal analysis performed using 6 years of follow-up data from baseline confirms efficacy of the model, as subjects consistently move to later stages with time, and significant correlations are observed between the estimated stages and nonimaging phenotypic markers. Interpretation: We used a data-driven method to provide new insight into Huntington's disease progression as well as new power to stage and predict conversion. Our results highlight the potential of disease progression models, such as the event-based model, to provide new insight into Huntington's disease progression and to support fine-grained patient stratification for future precision medicine in Huntington's disease. PMID- 29761122 TI - Bortezomib treatment for severe refractory anti-NMDA receptor encephalitis. AB - Objective: To evaluate the therapeutic potential of bortezomib, a proteasome inhibitor that target plasma cells, in order to revive stalled recovery in patients with anti-N-methyl-d-aspartate (NMDA) receptor encephalitis who remain bedridden even after aggressive immunotherapy. Methods: We consecutively enrolled patients with anti-NMDA receptor encephalitis who remained bedridden after first line immunotherapy (steroids and intravenous immunoglobulin), second-line immunotherapy (rituximab), and tocilizumab treatment, and treated them with subcutaneous bortezomib. Clinical response, functional recovery, and changes in antibody titer in the serum and cerebrospinal fluid were measured. Results: Before the bortezomib treatment, the five patients with severe refractory anti NMDA receptor encephalitis were in a vegetative state. During the 8 months of follow-up period, three patients improved to minimally conscious states within 2 months of bortezomib treatment, one failed to improve from a vegetative state. However, no patient achieved functional recovery as measured by the modified Rankin Scale score (mRS). Three patients advanced to a cyclophosphamide with bortezomib and dexamethasone regimen, which only resulted in additional adverse events, without mRS improvement. Among the four patients whose antibody titer was followed, two demonstrated a twofold decrease in the antibody titer in serum and/or cerebrospinal fluid after 2 cycles of bortezomib. Interpretation: Although there were some improvements in severe refractory patients, clinical response to bortezomib was limited and not clearly distinguishable from the natural course of the disease. The clinical benefit of bortezomib in recent studies requires further validation in different clinical settings. PMID- 29761121 TI - Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers. AB - Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression. PMID- 29761123 TI - Zika virus and Guillain-Barre syndrome in Bangladesh. AB - Objective: Previous studies have associated Guillain-Barre syndrome (GBS) with Zika virus (ZIKV) outbreaks in South America and Oceania. In Asia, ZIKV is known to circulate widely, but the association with Guillain-Barre syndrome is unclear. We investigated whether endemic ZIKV infection is associated with the development of GBS. Methods: A prospective study was conducted from 2011 to 2015 in Bangladesh. A total of 418 patients and 418 healthy family controls were included in the study. Patients were diagnosed with GBS prior to inclusion according to established criteria. Detailed information on the epidemiology, clinical presentation, electrophysiology, diagnosis, disease severity, and clinical course were obtained during a follow-up of 1 year using a predefined protocol. Results: ZIKV-neutralizing antibodies were detected in our study from 2013 onwards. The prevalence of ZIKV-neutralizing antibodies was not significantly higher in patients with GBS compared to healthy controls (OR 2.23, P = 0.14, 95% CI 0.77 6.53). Serological evidence for prior ZIKV infection in patients with GBS was associated with more frequent cranial, sensory, and autonomic nerve involvement compared to GBS patients with Campylobacter jejuni, the predominant preceding infection in GBS worldwide. Nerve-conduction studies revealed that ZIKV antibodies were associated with a demyelinating subtype of GBS, while C. jejuni infections were related to an axonal subtype. Interpretation: No significant association was found between ZIKV infection and GBS in Bangladesh, but GBS following ZIKV infection was characterized by a distinct clinical and electrophysiological subtype compared to C. jejuni infection. These findings indicate that ZIKV may precede a specific GBS subtype but the risk is low. PMID- 29761124 TI - Progranulin levels in blood in Alzheimer's disease and mild cognitive impairment. AB - Objective: Changes in progranulin (GRN) expression have been hypothesized to alter risk for Alzheimer's disease (AD). We investigated the relationship between GRN expression in peripheral blood and clinical diagnosis of AD and mild cognitive impairment (MCI). Methods: Peripheral blood progranulin gene expression was measured, using microarrays from Alzheimer's (n = 186), MCI (n = 118), and control (n = 204) subjects from the University of California San Francisco Memory and Aging Center (UCSF-MAC) and two independent published series (AddNeuroMed and ADNI). GRN gene expression was correlated with clinical, demographic, and genetic data, including APOE haplotype and the GRN rs5848 single-nucleotide polymorphism. Finally, we assessed progranulin protein levels, using enzyme-linked immunosorbent assay, and methylation status using methylation microarrays. Results: We observed an increase in blood progranulin gene expression and a decrease in GRN promoter methylation in males (P = 0.007). Progranulin expression was 13% higher in AD and MCI patients compared with controls in the UCSF-MAC cohort (F2,505 = 10.41, P = 3.72*10-5). This finding was replicated in the AddNeuroMed (F2,271 = 17.9, P = 4.83*10-8) but not the ADNI series. The rs5848 SNP (T-allele) predicted decreased blood progranulin gene expression (P = 0.03). The APOE4 haplotype was positively associated with progranulin expression independent of diagnosis (P = 0.04). Finally, we did not identify differences in plasma progranulin protein levels or gene methylation between diagnostic categories. Interpretation: Progranulin mRNA is elevated in peripheral blood of patients with AD and MCI and its expression is associated with numerous genetic and demographic factors. These data suggest a role in the pathogenesis of neurodegenerative dementias besides frontotemporal dementia. PMID- 29761125 TI - Inflammation is a key risk factor for persistent seizures in neurocysticercosis. AB - Objective: We conducted a retrospective, case-control study of neurocysticercosis patients to ascertain early markers that identify subjects likely to develop treatment-resistant seizures. Methods: Clinical histories and imaging studies from 38 neurocysticercosis patients who had been followed for 18 months after treatment were evaluated. Both pairwise and multifactorial analyses were conducted to identify factors associated with continued seizures. Results: Eleven of 38 patients continued to have seizures during the follow-up period. On univariate analysis, the number of neurocysticercosis lesions, number of bands on the baseline neurocysticercosis western blot, edema volumes on follow-up MRI scans, edema volume changes between baseline and follow-up images, and proportion of calcified lesions with perilesional edema were all significantly increased in subjects who had persistent seizures during the 18-month follow-up period. On multivariate analyses using recursive partition and random forest algorithms, variables associated with persistent seizures included: the number of total and calcified lesions, presence of perilesional edema, the rate of change in the lesion and edema volumes from baseline to follow-up, and the number of bands on the neurocysticercosis western blot. Interpretation: Measures of both inflammation and disease burden are key risk factors for persistent seizures despite anticonvulsant treatments in patients with neurocysticercosis. Inflammation is therefore a potentially modifiable risk factor for the frequently seen severe seizure disorders in patients with neurocysticercosis. PMID- 29761126 TI - Seronegative antibody-mediated neurology after immune checkpoint inhibitors. AB - Checkpoint inhibitor medications have revolutionized oncology practice, but frequently induce immune-related adverse events. During autoimmune neurology practice over 20 months, we prospectively identified four patients with likely antibody-mediated neurological diseases after checkpoint inhibitors: longitudinally extensive transverse myelitis, Guillain-Barre syndrome, and myasthenia gravis. All patients shared three characteristics: symptoms commenced 4 weeks after drug administration, responses to conventional immunotherapies were excellent, and autoantibodies traditionally associated with their syndrome were absent. However, serum immunoglobulins from the myelitis and Guillain-Barre syndrome patients showed novel patterns of tissue reactivity. Vigilance is required for antibody-mediated neurology after checkpoint inhibitor administration. This phenomenon may inform the immunobiology of antibody-mediated diseases. PMID- 29761127 TI - Elevated LGI1-IgG CSF index predicts worse neurological outcome. AB - To determine whether CSF leucine-rich glioma-inactivated 1(LGI1)-IgG titer, index or IgG subclass has prognostic significance, we tested serum and CSF specimens collected concomitantly from 39 seropositive patients. LGI1-IgG index was elevated (>1) in 21 patients (54%), suggesting intrathecal synthesis. Patients with worse outcome at last follow-up (modified Rankin Scale >2) had significantly higher index (median 6.57 vs. 0.5, P = 0.048) compared to those with better outcome. Higher CSF LGI1-IgG4 subclass-specific titer and index correlated with worse outcome (P < 0.005 for both). These data suggest that evidence of intrathecal LGI1-IgG synthesis may correlate with neuronal injury and warrant consideration of aggressive immunotherapy. PMID- 29761129 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/acn3.255.]. PMID- 29761130 TI - Spinal Muscular Atrophy With Respiratory Distress Type 1-A Child With Atypical Presentation. AB - The authors report a child with spinal muscular atrophy with respiratory distress type 1 (SMARD1). She presented atypically with hypothyroidism and heart failure due to septal defects that required early heart surgery and microcephaly in association with cerebral atrophy and thin corpus collosum. The subsequent asymmetrical onset of diaphragmatic paralysis, persistent hypotonia, and generalized muscle weakness led to the suspicion of spinal muscular atrophy with respiratory distress type 1. Sanger sequencing confirmed a compound heterozygous mutation in the Immunoglobulin Mu Binding Protein 2 (IGHMBP2) gene, with a known mutation c.2362C > T (p.Arg788*) and a novel frameshift mutation c.2048delG (p.Gly683A1afs*50). Serial nerve conduction study and electromyography confirmed progressive sensorimotor polyneuropathy and neuronopathy. In summary, this case report describes a child with spinal muscular atrophy with respiratory distress type 1 also with congenital cardiac disease and endocrine dysfunction, expanding the phenotypic spectrum of this condition. A high index of suspicion is needed in diagnosing this rare condition to guide the management and genetic counseling. PMID- 29761128 TI - Brain-computer interfaces for post-stroke motor rehabilitation: a meta-analysis. AB - Brain-computer interfaces (BCIs) can provide sensory feedback of ongoing brain oscillations, enabling stroke survivors to modulate their sensorimotor rhythms purposefully. A number of recent clinical studies indicate that repeated use of such BCIs might trigger neurological recovery and hence improvement in motor function. Here, we provide a first meta-analysis evaluating the clinical effectiveness of BCI-based post-stroke motor rehabilitation. Trials were identified using MEDLINE, CENTRAL, PEDro and by inspection of references in several review articles. We selected randomized controlled trials that used BCIs for post-stroke motor rehabilitation and provided motor impairment scores before and after the intervention. A random-effects inverse variance method was used to calculate the summary effect size. We initially identified 524 articles and, after removing duplicates, we screened titles and abstracts of 473 articles. We found 26 articles corresponding to BCI clinical trials, of these, there were nine studies that involved a total of 235 post-stroke survivors that fulfilled the inclusion criterion (randomized controlled trials that examined motor performance as an outcome measure) for the meta-analysis. Motor improvements, mostly quantified by the upper limb Fugl-Meyer Assessment (FMA-UE), exceeded the minimal clinically important difference (MCID=5.25) in six BCI studies, while such improvement was reached only in three control groups. Overall, the BCI training was associated with a standardized mean difference of 0.79 (95% CI: 0.37 to 1.20) in FMA-UE compared to control conditions, which is in the range of medium to large summary effect size. In addition, several studies indicated BCI-induced functional and structural neuroplasticity at a subclinical level. This suggests that BCI technology could be an effective intervention for post-stroke upper limb rehabilitation. However, more studies with larger sample size are required to increase the reliability of these results. PMID- 29761131 TI - Depression and Anxiety Among Patients on Chronic Opioid Therapy. AB - Background: Chronic noncancer pain (CNCP) and chronic opioid therapy (COT) commonly coexist with comorbid depression and anxiety. We investigated the prevalence of depression and anxiety and their correlates at the time of controlled substance agreement (CSA) enrollment among patients with CNCP and a history of depression or anxiety on COT. Methods: Retrospective analysis of 1066 patients in a Midwest primary care practice enrolled in CSAs for COT between May 9, 2013, and August 15, 2016. Patients with self-reported symptoms or a clinical history of depression or anxiety were screened at CSA enrollment using the Patient Health Questionnaire-9 item scale and the Generalized Anxiety Disorder-7 item scale. Results: The percentage of patients screening positive for depression and anxiety at CSA enrollment was 15.4% and 14.4%, respectively. Patients screening positive for depression or anxiety were more likely to be younger, unmarried, unemployed, and live alone compared to patients not screening positive. Patients screening positive for depression or anxiety were more likely to smoke cigarettes and report concern from friends or relatives regarding alcohol consumption. Compared to patients screening negative, patients screening positive for depression had higher odds of receiving opioid doses of >=50 morphine milligram equivalents per day (adjusted odds ratio: 1.62; 95% confidence interval: 1.01-2.58). Conclusion: Anxiety and depression are prevalent at enrollment in CSAs among patients receiving COT. Future research is needed to determine whether recognition of anxiety and depression leads to improved management and outcomes for this population. PMID- 29761132 TI - The Risk Factors of Performance-Based Early Frailty in Midlife and Older Age. AB - Background: Identifying impairments prior to onset of physical frailty may inform targeted interventions. An objective, clinically feasible early frailty measure, termed performance-based early frailty (PBEF) was developed, and antecedent and current risk factors were examined. Method: Data were from N = 104 participants of the Fels Longitudinal Study. PBEF was derived from age-specific cut points for time to complete five chair stands and walk four meters. "Pre-PBEF" and "PBEF" were defined as impairment in one or both measures, respectively. Candidate PBEF risk factors included body composition, health and quality of life, grip strength, and biomarker measures. Results: Pre-PBEF was identified in 26% and 30% of midlife and older adults, and PBEF was identified in 11% and 14% of midlife and older adults, respectively. When predicting midlife PBEF, only current physical activity was significant (odds ratio [OR] = 0.18). In older adults, PBEF status was predicted by previous heavier drinking (OR = 3.09), previous better grip strength (OR = 0.92), current poorer sleep habits (OR = 1.19), and current higher C-reactive protein concentrations (OR = 1.20). Conclusion: Differing age group patterns of predictors emerged, suggesting that PBEF in midlife is likely a state influenced by current health status, whereas older age PBEF is influenced by both current and antecedent factors. PMID- 29761133 TI - The Impact of Blood Pressure Dipping Status on Cognition, Mobility, and Cardiovascular Health in Older Adults Following an Exercise Program. AB - Objectives: To determine whether a dual-task gait and aerobic exercise intervention differentially impacted older adults with normal blood pressure (BP) dipping status (dippers) compared to those with nondipping status (nondippers). Methods: This study was a secondary analysis involving participants (mean age = 70.3 years, 61% women) who attended a laboratory-based exercise intervention over a 6-month period (40 min/day and 3 days/week). Participants were assessed in measures of cognition, mobility, and cardiovascular health at baseline, 3, 6, and 12 months (after a 6-month no-contact follow-up). Results: We observed improvements in cognition in both groups at 6 and 12 months, although no between group differences were seen. Nondippers demonstrated superior improvements in usual gait velocity and step length after the exercise intervention compared to dippers. Dippers reduced daytime systolic BP at 6 and 12 months to a greater extent than nondippers. Discussion: BP dipping status at baseline did not influence exercise benefits to cognition but did mediate changes in mobility and cardiovascular health. PMID- 29761137 TI - A Variant of Herlyn-Werner-Wunderlich Syndrome Presenting With Acute Abdomen: A Case Report and Review of Literature. PMID- 29761136 TI - Yield of Echocardiogram and Predictors of Positive Yield in Pediatric Patients: A Study in an Urban, Community-Based Outpatient Pediatric Cardiology Clinic. AB - The yield of outpatient echocardiograms varies based on the indication for the echocardiogram and the age of the patient. The purpose of this study was to determine the cumulative yield of outpatient echocardiograms by age group and reason for the test. A secondary aim was to determine the predictors of a positive echocardiogram in an outpatient cardiology clinic at a large community teaching hospital. We retrospectively reviewed the charts of 891 patients who had a first-time echocardiogram between 2011 and 2015. Positive yield was defined as echocardiographic findings that explained the reason for the echocardiogram. The overall positive yield was 8.2%. Children between birth and 3 months of age had the highest yield (34.2%), and children between 12 and 18 years of age had the lowest yield (1%). Patients with murmurs (18.1%) had the highest yield compared with patients with other signs or symptoms. By age group and reason, the highest yields were as follows: 0 to 3 months of age, murmur (39.2%); 4 to 11 months of age, >1 symptom (50%); and 1 to 5 years of age, shortness of breath (66.7%). Based on our study, the overall yield of echocardiograms in the outpatient pediatric setting is low. Age and symptoms should be considered before ordering an echocardiogram. PMID- 29761138 TI - Integrating Parenting Support Within and Beyond the Pediatric Medical Home. AB - Positive parenting programs, developmental support services, and evidence-based home visiting programs can effectively provide parenting support and improve health and developmental outcomes for at-risk children. Few models, however, have integrated referrals for on-site support and home visiting programs into the provision of routine pediatric care within a medical home. This article describes an innovative approach, through partnership with a community-based organization, to deliver on-site and home visiting support services for children and families within and beyond the medical home. Our model offers a system of on-site services, including parenting, behavior, and/or development support, with optional intensive home visiting services. Assessment included description of the population served, delineation of services provided, and qualitative identification of key themes of the impact of services, illustrated by case examples. This replicable model describes untapped potential of the pediatric medical home as a springboard to mitigate risk and optimize children's health and development. PMID- 29761134 TI - Mild Cognitive Impairment in Republic of Georgia. AB - Objective: The goal of this study was to estimate the prevalence of mild cognitive impairment (MCI) in Georgia. Method: A population-based study was conducted using Georgian version of the Montreal Cognitive Assessment (MoCA) and its cognitive domain index score. Results: Of the initial cohort of 1,000 subjects, 851 met inclusion criteria. The prevalence of MCI was 13.3%, and it was associated with age >65 years (odds ratio [OR] = 4.51, 95% confidence interval [CI] = [3.00, 6.75]), urban residence (OR = 0.53, 95% CI = [0.33, 0.88]), lower education (OR = 3.99, 95% CI = [2.66, 5.93]), and hypertension (OR = 2.51, 95% CI = [1.68, 3.76]), while amnestic MCI was documented in 9.3%, with higher risk in older subjects (OR = 2.69, 95% CI = [1.66, 4.20]), and diabetics (OR = 2.69, 95% CI = [1.25, 5.98]). Conclusion: In this first population-based study of MCI in Georgia, prevalence was comparable with those reported from the United States and Europe. Observed association of MCI with cardiovascular risk factors has important clinical implication for dementia prevention in Georgia. PMID- 29761139 TI - Prophylactic Antibiotics After Stented, Distal Hypospadias Repair: Randomized Pilot Study. AB - The usage of prophylactic oral antibiotics following distal hypospadias repair with stenting has been recently challenged. This study evaluated the incidence of symptomatic urinary tract infections (UTIs) following stented, distal hypospadias repair and the impact of prophylactic antibiotic therapy. Subjects 0 to 5 years of age with distal hypospadias were randomized to either Group 1 (antibiotics) or Group 2 (no prophylactic therapy). Urinalysis/urine culture was obtained intraoperatively with no preoperative antibiotics given. Phone interviews at 1 month and 3 months after surgery were done. Forty-eight patients were successfully randomized to either Group 1 (24) or Group 2 (24). The incidence of symptomatic UTI in this pilot study is low, and prophylactic antibiotic therapy does not appear to lower the incidence of symptomatic UTI. A larger, randomized, multicenter trial is needed to determine whether antibiotic prophylaxis reduces the risk of symptomatic UTIs following stented, distal hypospadias repair. PMID- 29761141 TI - Unexpected Height Loss in an Adolescent With Cystic Fibrosis. AB - This case report describes an adolescent with pancreatic insufficient cystic fibrosis, malnutrition, and cystic fibrosis-related diabetes found to have a loss in height at a routine outpatient clinic visit. He was subsequently admitted to the hospital for treatment of a pulmonary exacerbation and was found to have multiple, nontraumatic vertebral compression fractures. This report emphasizes the importance of routine review of growth charts and aggressive treatment of vitamin deficiencies and malnutrition in people with cystic fibrosis. PMID- 29761140 TI - Hearing Impairment Among Children Referred to a Public Audiology Clinic in Gaborone, Botswana. AB - Objective. To describe and quantify hearing impairment among children referred to the audiology clinic in Princess Marina Hospital, a public referral hospital in Botswana. Methods. In a retrospective case series, we reviewed medical records of children aged 10 years and younger whose hearing was assessed between January 2006 and December 2015 at the audiology clinic of Princess Marina Hospital in Gaborone, Botswana. Results. Of 622 children, 50% were male, and median age was 6.7 years (interquartile range = 5.0-8.3). Hearing impairment was diagnosed in 32% of clinic attendees, comprising sensorineural (23%), conductive (25%), and mixed (11%) hearing loss, while 41% of children with diagnosed hearing impairment did not have a classification type. Hearing impairment was mild in 22.9%, moderate in 22.4%, severe in 19.4%, profound in 16.9%, and of undocumented severity in 18.4%. Children younger than 5 years were 2.7 times (95% confidence interval = 1.29-5.49; P = .008) more likely to be diagnosed with sensorineural hearing impairment compared with those older than 5 years. By contrast, children older than 5 years were 9.6 times (95% confidence interval = 2.22-41.0; P = .002) more likely to be diagnosed with conductive hearing loss compared with those under 5 years. Conclusion. Hearing impairment was common among children referred to this audiology clinic in Botswana. Of those with hearing impairment, more than a third had moderate or severe deficits, suggesting that referrals for hearing assessments are not occurring early enough. Hearing awareness programs individually tailored to parents, educators, and health care workers are needed. Neonatal and school hearing screening programs would also be beneficial. PMID- 29761143 TI - The New Road for GE - Portuguese Journal of Gastroenterology: Into the Highway! PMID- 29761144 TI - The Burden of Hepatobiliary Diseases in Portugal: What Can We Learn from Mortality Data. PMID- 29761142 TI - A Systematic Review of Longitudinal Cohort Studies Examining Unintentional Injury in Young Children. AB - Objective. Injury is the leading cause of death and long-term disability in children. Longitudinal cohorts are designed to follow subjects longitudinally in order to determine if early-life exposures are related to certain health outcomes. Methods. We conducted a systematic review to identify studies of children from birth through 5 years who were followed longitudinally with unintentional injury as an outcome of interest. Results. Of the 1892 unique references based on the search criteria, 12 (published between 2000 and 2013) were included. The studies varied on the population of focus, injury definition, and incidence rates. Existing studies that longitudinally follow children aged 0 to 5 years are limited in number, scope, and generalizability. Conclusions. Further study using population-based longitudinal cohorts is necessary to more comprehensively estimate incidence of injury in young children. PMID- 29761145 TI - Peroral Cholangiopancreatoscopy: New Advances Bring New Concerns. PMID- 29761146 TI - Early Buried Bumper Syndrome - To Leave or Not to Leave. PMID- 29761147 TI - Efficacy of Long-Term Oral Vitamin B12 Supplementation after Total Gastrectomy: Results from a Prospective Study. AB - Background/Objectives: Vitamin B12 (VB12) deficiency is a common complication after total gastrectomy which may be associated with megaloblastic anemia and potentially irreversible neurologic symptoms. Intramuscular supplementation of VB12 has been considered the standard treatment, although it is associated with high costs and patient discomfort. Patients/Methods: We performed a prospective uncontrolled study (ACTRN12614000107628) in order to evaluate the clinical and laboratory efficacy of long-term oral VB12 supplementation in patients submitted to total gastrectomy. All patients received daily oral VB12 (1 mg/day) and were evaluated every 3 months (clinical and laboratory evaluation: hemoglobin, VB12, total iron, ferritin, and folate). Results: A total of 26 patients were included with a mean age of 64 years (29-79). Patients were included with a mean period of 65 months (3-309) after total gastrectomy. At inclusion time, 17/26 patients were under intramuscular VB12, and 9 had not started supplementation yet. There were normal serum VB12 levels in 25/26 patients (mean VB12 serum levels: 657 pg/mL). The mean follow-up period was 20 (8.5-28) months. During follow-up, all patients had normal VB12 levels and there was no need for intramuscular supplementation. The patient with low VB12 levels had an increase to adequate levels, which remained stable. There were no differences with statistical significance among VB12 levels at 6 (867 pg/mL), 12 (1,008 pg/mL), 18 (1,018 pg/mL), and 24 (1,061 pg/mL) months. Iron and folate supplementation was necessary in 21 and 7 patients, respectively. Conclusions: Oral VB12 supplementation is effective and safe in patients who underwent total gastrectomy and should be considered the preferential form of supplementation. PMID- 29761148 TI - Mortality Associated with Hepatobiliary Disease in Portugal between 2006 and 2012. AB - Introduction: Hepatobiliary disease is becoming a major public health problem, and recent data suggest that the burden of liver disease is higher than previously thought. Our aim was to quantify the mortality from hepatobiliary disease in Portugal and to compare this with the mortality related o other causes over a 7-year period (2006-2012). Materials and Methods: A statistical analysis of mortality data according to cause, sex, age, and region from the National Statistics Institute in Portugal was carried out. The data related to 14 causes of death, the most frequent of which were alcoholic liver disease (ALD) (International Classification of Diseases code K70), unspecified cirrhosis of liver (UCL) (K74.6), hepatocellular carcinoma (HCC) (C22.0), unspecified malignant neoplasm of liver (C22.9), and cholangiocarcinoma (C22.1). Results: Between 2006 and 2012, 18,279 deaths (24.5/100,000) from hepatobiliary disease were registered in Portugal, constituting the 8th leading cause of death. The main causes of death from hepatobiliary disease were ALD (7.1/100,000), UCL (5.5/100,000), and HCC (4.3/100,000), with a male predominance (72%). ALD was the main aetiology in younger age groups (40-65 years), while primary neoplasms of the liver and the intrahepatic bile ducts were predominant in the elderly (>80 years). The mortality related to HCC increased by 66% between 2006 and 2012. Conclusion: These data outline the burden of hepatobiliary disease in Portugal (8th cause of death) and highlight a potential impact on economic productivity. PMID- 29761149 TI - How SpyGlassTM May Impact Endoscopic Retrograde Cholangiopancreatography Practice and Patient Management. AB - Introduction: Cholangiopancreatoscopy with SpyGlassTM Direct Visualization System (SGDVS) is being used in specialized centers for improving the sensitivity of endoscopic retrograde cholangiopancreatography (ERCP) in patients with indeterminate pancreatobiliary strictures (PBS). The aims of this study were to report our initial experience with SGDVS in the evaluation of indeterminate PBS, and discuss the improvements of ERCP brought by this technique in our center. Methods: The usefulness of SGDVS in patients with indeterminate PBS (defined after nondiagnostic previous ERCP with brush cytology) was evaluated in a prospective observational cohort study conducted at a single tertiary biliopancreatic unit. The accuracy of diagnosis by the SGDVS visual findings, SGDVS-guided biopsy, technical success, image quality, change in patient management after the procedure, and complication rate were assessed. Results: In our single-center cohort, there were 13 SGDVS procedures for evaluating indeterminate PBS. Technical success, defined by the ability to progress with the SpyScope to the target lesion, was achieved in all the cases. The diagnostic accuracy of visual findings (87.5%) was superior to SGDVS-guided biopsy (55%). In 11 (85%) procedures, the image quality was considered good. The procedure permitted exclusion of malignancy and avoiding surgery in 9 patients (69%). There were no complications during the procedures. However, in the post-procedure monitoring, 3 patients developed acute pancreatitis (19%) and 2 patients developed acute cholangitis (13%). Conclusion: The SGDVS can be considered useful in the context of indeterminate PBS. The intervention is associated with high procedural success and alters clinical outcome compared to conventional approaches. PMID- 29761150 TI - Endoscopic Retrograde Cholangiopancreatography and Endoscopic Ultrasound: To Be One Traveler in Converging Roads. AB - Background: Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) were initially introduced into the world of gastroenterology as purely diagnostic procedures. With progressive evolution of intervention, both these techniques conquered fields in the treatment of many conditions that had once been exclusively surgical domains. Nowadays, more and more clinical situations have an indication to perform both EUS and ERCP, and these two techniques are frequently required at the same time for the same patient. More than competitors, ERCP and EUS are truly complementary, with great ability for mutual aid. They share their main indications, equipment, accessories, and main technical gestures. Objectives and Methods: We review the major indications to perform both techniques, sequentially or complementarily, describe the common things that these two techniques essentially share, and discuss the ERCP-EUS single session. Also, the issues of learning curves and education of upcoming biliopancreatic endoscopists are highlighted. Conclusion: In recent years the complementation between ECRP and EUS has been growing both from a diagnostic and a therapeutic point of view, allowing optimization of the use of these techniques and the creation of a more systematized approach of patients with biliopancreatic pathology. Endoscopists with experience in both techniques will be increasingly important, suggesting a parallel formation in the training plans of future endoscopists with interest in the area. PMID- 29761151 TI - Endoscopic Ultrasound-Guided Choledochoduodenostomy as Palliative Treatment: A Challenging Case Report. AB - We report the case of an 88-year-old female with obstructive jaundice due to a periampullary tumor. The patient developed acute cholangitis and consequent clinical deterioration, so it was decided to perform palliative biliary drainage. Due to duodenal tumor invasion, it was not possible to perform endoscopic retrograde cholangiopancreatography. A different approach was attempted and it was decided to carry out an endoscopic ultrasound-guided choledochoduodenostomy. This procedure was performed with a linear echoendoscope, and using a duodenal bulbar approach, a fistula was created between the bulb and the common bile duct. A self-expandable fully covered metal biliary stent was placed in the common bile duct under endoscopic and fluoroscopic guidance, allowing biliary drainage. The patient presented clinical improvement. However, 3 weeks after being discharged, she was readmitted to our department with hematemesis associated with the migration of the biliary stent to the duodenal bulb. Endoscopic hemostasis was performed but the patient had multiple bleeding relapses that were controlled through arterial embolization. Despite the migration of the biliary stent, the fistula between the duodenum and the common bile duct remained patent, allowing a successful palliation of the obstructive jaundice. Therefore, despite the occurred complication, we admitted a technical and clinical success of the endoscopic ultrasound-guided choledochoduodenostomy. This is an emerging technique and a valuable alternative for palliative biliary drainage in cases of malignant distal obstruction. This clinical report supports this finding, reporting technical aspects of the procedure, associated complications and their management as well as the clinical outcomes. PMID- 29761152 TI - The Challenging Acute Buried Bumper Syndrome: A Case Report. AB - Percutaneous endoscopic gastrostomy (PEG) is the preferred route of feeding and nutritional support in patients requiring long-term enteral nutrition. Major complications related to the procedure are rare. Buried bumper syndrome is a late major complication, occurring in 0.3-2.4% of patients. Although considered a late complication, it can rarely occur in an acute setting early after the procedure. We present the case of an early buried bumper syndrome, presenting 1 week after PEG tube placement, with local stoma infection associated with an infected cavity within the abdominal wall with feeding content, successfully managed with antibiotic therapy and PEG tube repositioning through the original track. PMID- 29761153 TI - Early Presentation of Buried Bumper Syndrome. PMID- 29761154 TI - Rare Manifestations of Hydatid Disease. PMID- 29761155 TI - Stenosis of Hepaticojejunal Anastomosis with Intrahepatic Lithiasis: Treatment with Single-Balloon Enteroscopy-Assisted ERCP. PMID- 29761156 TI - Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson's disease. AB - Motor aspects of Parkinson's disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of "wearable" technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson's disease (PD) is defining cutoff values that separate "controlled" from "uncontrolled" symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base. PMID- 29761159 TI - Association between sporting event attendance and self-rated health: an analysis of multiyear cross-sectional national data in Japan. AB - Background: This study examined the extent to which sporting event attendance is associated with self-rated health. Drawing from an economic model of health production and psychological research on the health benefits of psychosocial resources, sporting event attendance was hypothesized to have a positive relationship with self-rated health. Methods: A two-level multilevel ordered logistic regression was used to analyze multiyear cross-sectional data collected from national surveys in Japan. Results: The results demonstrate that, controlling for the effects of personal and environmental characteristics, sporting event attendance positively correlates with self-rated health over a 12 year period. Specifically, when compared to individuals who did not attend any sporting event during the past year, those who attended a sporting event were 33% more likely to indicate a higher level of self-rated health. Conclusions: These findings provide evidence for a positive association between sport spectatorship and the perception of general health and contribute to the literature examining the relationship between sport spectatorship and health outcomes. PMID- 29761158 TI - Phase II study of ruxolitinib, a selective JAK1/2 inhibitor, in patients with metastatic triple-negative breast cancer. AB - Preclinical data support a role for the IL-6/JAK2/STAT3 signaling pathway in breast cancer. Ruxolitinib is an orally bioavailable receptor tyrosine inhibitor targeting JAK1 and JAK2. We evaluated the safety and efficacy of ruxolitinib in patients with metastatic breast cancer. This was a non-randomized phase II study enrolling patients with refractory, metastatic triple-negative breast cancer. The primary endpoint was objective response by RECIST 1.1. The study was designed to enroll patients whose archival tumor tissue was pSTAT3-positive (T-score >5) by central immunohistochemistry. pSTAT3 staining was available from 171 of 217 consented patients and pSTAT3 T-score was positive in 67/171 (39.2%) tumors, suggesting that JAK-STAT activation is frequent. Twenty-three patients including one patient with inflammatory breast cancer were enrolled. Ruxolitinib was well tolerated with infrequent grade 3 or higher toxicities with fatigue as the most common toxicity. Among 21 patients who received at least one dose of protocol therapy, no objective responses were observed and the study was closed to further accrual. Pharmacodynamic analyses of baseline vs. cycle 2 biopsies suggest on target activity, including a significant decrease in the proportion of pSTAT3+ cells in three patients with paired biopsies and downregulation of JAK-STAT target genes and signatures via transcriptional analyses of 11 total baseline and four metastatic biopsies. Immuno-FISH analyses demonstrate intratumoral heterogeneity of pSTAT3 and JAK2 amplification. Ruxolitinib, as a single agent, did not meet the primary efficacy endpoint in this refractory patient population despite evidence of on-target activity. PMID- 29761161 TI - Natural compound sanguinarine chloride targets the type III secretion system of Salmonella enterica Serovar Typhimurium. AB - The type III secretion system (T3SS) is a key virulence mechanism of many Gram negative bacterial pathogens. Upon contact between bacteria and host cells, T3SS transfers a series of effectors from the bacterial cytosol to host cells. It is widely known that a mutation in T3SS does not impair bacterial growth, thereby avoiding any subsequent development of resistance. Thus, T3SS is expected to be a candidate therapeutic target. While developing the T3SS screening method, we discovered that sanguinarine chloride, a natural compound, could decrease the production of the SPI-1 type III secretion system main virulence proteins SipA and SipB and prevent the invasion of HeLa cells by Salmonella enterica serovar Typhimurium without affecting the growth of Salmonella. Furthermore, sanguinarine chloride downregulated the transcription of HilA and consequently regulated the expression of the SPI-1 apparatus and effector genes. In summary, our study directly demonstrated that this putative SPI-1 inhibitor belongs to a novel class of anti-Salmonella compounds. PMID- 29761162 TI - Empirical comparison of item response theory models with rater's parameters. AB - In various assessment contexts including entrance examinations, educational assessments, and personnel appraisal, performance assessment by raters has attracted much attention to measure higher order abilities of examinees. However, a persistent difficulty is that the ability measurement accuracy depends strongly on rater and task characteristics. To resolve this shortcoming, various item response theory (IRT) models that incorporate rater and task characteristic parameters have been proposed. However, because various models with different rater and task parameters exist, it is difficult to understand each model's features. Therefore, this study presents empirical comparisons of IRT models. Specifically, after reviewing and summarizing features of existing models, we compare their performance through simulation and actual data experiments. PMID- 29761157 TI - A Next-Generation Sequencing Primer-How Does It Work and What Can It Do? AB - Next-generation sequencing refers to a high-throughput technology that determines the nucleic acid sequences and identifies variants in a sample. The technology has been introduced into clinical laboratory testing and produces test results for precision medicine. Since next-generation sequencing is relatively new, graduate students, medical students, pathology residents, and other physicians may benefit from a primer to provide a foundation about basic next-generation sequencing methods and applications, as well as specific examples where it has had diagnostic and prognostic utility. Next-generation sequencing technology grew out of advances in multiple fields to produce a sophisticated laboratory test with tremendous potential. Next-generation sequencing may be used in the clinical setting to look for specific genetic alterations in patients with cancer, diagnose inherited conditions such as cystic fibrosis, and detect and profile microbial organisms. This primer will review DNA sequencing technology, the commercialization of next-generation sequencing, and clinical uses of next generation sequencing. Specific applications where next-generation sequencing has demonstrated utility in oncology are provided. PMID- 29761160 TI - Measuring and preventing alcohol use and related harm among young people in Asian countries: a thematic review. AB - Background: The paper reviews alcohol consumption patterns and alcohol-related social and health issues among 15-29-year old young people in Asian countries, and discusses strategies for preventing and controlling alcohol use and related harms. Methods: We searched Google Scholar, PubMed, and Web of Science for reports, reviews and journal articles published in English between 1st Jan 1990 and 31st August 2016. Results: Forty-one reports, reviews and journal papers were identified and included in the final review. The current drinking levels and prevalence among young people are markedly different between eight included Asian countries, ranging from 4.2% in Malaysia to 49.3% in China. In a majority of the selected Asian countries, over 15% of total deaths among young men and 6% among young women aged 15-29 years are attributable to alcohol use. Alcohol use among young people is associated with a number of harms, including stress, family violence, injuries, suicide, and sexual and other risky behaviours. Alcohol policies, such as controlling sales, social supply and marketing, setting up/raising a legal drinking age, adding health warning labels on alcohol containers, and developing a surveillance system to monitor drinking pattern and risky drinking behaviour, could be potential means to reduce harmful use of alcohol and related harm among young people in Asia. Conclusions: The review reveals that drinking patterns and behaviours vary across eight selected Asian countries due to culture, policies and regional variations. The research evidence holds substantial policy implications for harm reduction on alcohol drinking among young people in Asian countries -- especially for China, which has almost no alcohol control policies at present. PMID- 29761164 TI - Periostin and mesothelin: Potential predictors of malignant progression in intrahepatic cholangiocarcinoma. PMID- 29761163 TI - Determination of Bilateral Symmetry of Carotid Artery Structure and Function in Children and Adolescents. AB - We compared the symmetry of carotid arteries in youth with high-resolution ultrasound. Participants (n=230 (121 females),13.8 +/- 2.9 years old) were assessed for: intima media thickness (cIMT), lumen diameter (cLD), incremental elastic modulus (cIEM), diameter compliance (cDC), cross-sectional compliance (cCSC), diameter distensibility (cDD), and cross-sectional distensibility (cCSD). No significant differences (P >0.05 all) were found for cIMT (0.49 +/- 0.09 mm vs. 0.49 +/- 0.08 mm), cIEM (1095 +/- 382 mmHg vs. 1116 +/- 346mmHg), cDC (0.01 +/- 0.0 mm/mmHg vs. 0.01 +/- 0.0 mm/mmHg), cCSC (0.01 +/- 0.001/mmHg vs. 0.01 +/- 0.001/mmHg), cDD (14.0 +/- 3.16% vs. 13.7 +/- 3.18%), and cCSD (30.1 +/- 7.37% vs. 29.4 +/- 7.36%). Significant differences were found for cLD (6.06 +/- 0.62 mm vs. 6.33 +/- 0.64 mm, P <0.001). These data suggest that these values may be used interchangeably if one side is inaccessible. PMID- 29761165 TI - A real-world observational cohort of patients with primary biliary cholangitis: TARGET-primary biliary cholangitis study design and rationale. AB - Primary biliary cholangitis (PBC) is a rare chronic cholestatic liver disease that may progress to biliary cirrhosis if left untreated. The first-line therapy for PBC is ursodeoxycholic acid (UDCA). Unfortunately, 1 of 3 patients does not respond to UDCA. These patients are at risk for developing clinical events, including cirrhosis, complications of portal hypertension, hepatocellular carcinoma, liver transplant, or death. Recently, the U.S. Food and Drug Administration approved obeticholic acid to be used in certain patients with PBC. Off-label therapies are also used, and several other therapies are currently under evaluation. Real-world effectiveness of newly approved and off-label therapies remains unknown. TARGET-PBC is a 5-year, longitudinal, observational study of patients with PBC that will evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. Enrollment will take place at both academic and community sites. In addition to consenting to medical records review, participants will be asked to provide an annual blood sample and complete patient reported outcome surveys at predetermined intervals. Any available liver biopsies will be digitally preserved. Conclusion: Key study outcomes will be the evaluation of the safety and effectiveness of PBC interventions and the assessment of disease progression under real-world conditions. (Hepatology Communications 2018;2:484 491). PMID- 29761166 TI - NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. AB - NI-0801 is a fully human monoclonal antibody against chemokine (C-X-C motif) ligand 10 (CXCL10), which is involved in the recruitment of inflammatory T cells into the liver. The safety and efficacy of NI-0801 was assessed in patients with primary biliary cholangitis. In this open-label phase 2a study, patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid received six consecutive intravenous administrations of NI-0801 (10 mg/kg) every 2 weeks. Patients were followed up for 3 months after the last infusion. Liver function tests, safety assessments, as well as pharmacokinetic and pharmacodynamic parameters were evaluated at different time points throughout the dosing period and the safety follow-up period. Twenty-nine patients were enrolled in the study and were treated with NI-0801. The most frequently reported adverse events included headaches (52%), pruritus (34%), fatigue (24%), and diarrhea (21%). No study drug-related serious adverse events were reported. NI-0801 administration did not lead to a significant reduction in any of the liver function tests assessed at the end of the treatment period (i.e., 2 weeks after final NI-0801 administration) compared to baseline. Conclusion: Despite clear pharmacologic responses in the blood, no therapeutic benefit of multiple administrations of NI-0801 could be demonstrated. The high production rate of CXCL10 makes it difficult to achieve drug levels that lead to sustained neutralization of the chemokine, thus limiting its targetability. (Hepatology Communications 2018;2:492-503). PMID- 29761167 TI - Phenotypic spectrum and diagnostic pitfalls of ABCB4 deficiency depending on age of onset. AB - Genetic variants in the adenosine triphosphate-binding cassette subfamily B member 4 (ABCB4) gene, which encodes hepatocanalicular phosphatidylcholine floppase, can lead to different phenotypes, such as progressive familial intrahepatic cholestasis (PFIC) type 3, low phospholipid-associated cholelithiasis, and intrahepatic cholestasis of pregnancy. The aim of this multicenter project was to collect information on onset and progression of this entity in different age groups and to assess the relevance of this disease for the differential diagnosis of chronic liver disease. Clinical and laboratory data of 38 patients (17 males, 21 females, from 29 families) with homozygous or (compound) heterozygous ABCB4 mutations were retrospectively collected. For further analysis, patients were grouped according to the age at clinical diagnosis of ABCB4-associated liver disease into younger age (<18 years) or adult age (>=18 years). All 26 patients diagnosed in childhood presented with pruritus (median age 1 year). Hepatomegaly and splenomegaly were present in 85% and 96% of these patients, respectively, followed by jaundice (62%) and portal hypertension (69%). Initial symptoms preceded diagnosis by 1 year, and 13 patients received a liver transplant (median age 6.9 years). Of note, 9 patients were misdiagnosed as biliary atresia, Alagille syndrome, or PFIC type 1. In the 12 patients with diagnosis in adulthood, the clinical phenotype was generally less severe, including intrahepatic cholestasis of pregnancy, low phospholipid-associated cholelithiasis, or (non)cirrhotic PFIC3. Conclusion: ABCB4 deficiency with onset in younger patients caused a more severe PFIC type 3 phenotype with the need for liver transplantation in half the children. Patients with milder phenotypes are often not diagnosed before adulthood. One third of the children with PFIC type 3 were initially misdiagnosed, indicating the need for better diagnostic tools and medical education. (Hepatology Communications 2018;2:504-514). PMID- 29761169 TI - Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. AB - Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. We assessed the efficacy and durability of short and prolonged CVC therapy in a diet-induced mouse model of NASH, the choline deficient, L-amino acid-defined, high-fat diet (CDAHFD) model. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. CVC (10 mg/kg/day and 30 mg/kg/day for 4 weeks and 20 mg/kg/day and 30 mg/kg/day for 14 weeks) was initiated simultaneously with the CDAHFD. At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. High-dose CVC (30 mg/kg/day) therapy in CDAHFD mice for 4 or 14 weeks inhibited intrahepatic accumulation of Ly6Chigh bone marrow-derived macrophages. Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti-inflammatory macrophages in the high-dose CVC group. Despite ongoing steatohepatitis, there was significantly less fibrosis in CDAHFD mice receiving high-dose CVC for 14 weeks based on histologic and molecular markers, mirroring observations in human NASH CVC trials. CVC also directly inhibited the profibrotic gene signature of transforming growth factor beta-stimulated primary mouse hepatic stellate cells in vitro. Conclusion: CVC is a novel therapeutic agent that is associated with reduced fibrosis despite ongoing steatohepatitis. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. (Hepatology Communications 2018;2:529-545). PMID- 29761168 TI - Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. AB - Progressive familial intrahepatic cholestasis (PFIC) with normal circulating gamma-glutamyl transpeptidase levels can result from mutations in the ATP8B1 gene (encoding familial intrahepatic cholestasis 1 [FIC1] deficiency) or the ABCB11 gene (bile salt export protein [BSEP] deficiency). We investigated the outcomes of partial external biliary diversion, ileal exclusion, and liver transplantation in these two conditions. We conducted a retrospective multicenter study of 42 patients with FIC1 deficiency (FIC1 patients) and 60 patients with BSEP deficiency (BSEP patients) who had undergone one or more surgical procedures (57 diversions, 6 exclusions, and 57 transplants). For surgeries performed prior to transplantation, BSEP patients were divided into two groups, BSEP-common (bearing common missense mutations D482G or E297G, with likely residual function) and BSEP other. We evaluated clinical and biochemical outcomes in these patients. Overall, diversion improved biochemical parameters, pruritus, and growth, with substantial variation in individual response. BSEP-common or FIC1 patients survived longer after diversion without developing cirrhosis, being listed for or undergoing liver transplantation, or dying, compared to BSEP-other patients. Transplantation resolved cholestasis in all groups. However, FIC1 patients commonly developed hepatic steatosis, diarrhea, and/or pancreatic disease after transplant accompanied by biochemical abnormalities and often had continued poor growth. In BSEP patients with impaired growth, this generally improved after transplantation. Conclusion: Diversion can improve clinical and biochemical status in FIC1 and BSEP deficiencies, but outcomes differ depending on genetic etiology. For many patients, particularly BSEP-other, diversion is not a permanent solution and transplantation is required. Although transplantation resolves cholestasis in patients with FIC1 and BSEP deficiencies, the overall outcome remains unsatisfactory in many FIC1 patients; this is mainly due to extrahepatic manifestations. (Hepatology Communications 2018;2:515-528). PMID- 29761171 TI - Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist. AB - LY2409021 is a glucagon receptor antagonist that was associated with hepatic steatosis and elevated aminotransferases in phase 2 diabetes studies. We investigated the relationship between selected genetic variants and hepatic steatosis and elevated alanine aminotransferases (ALTs) associated with LY2409021. Patients participated in a 6-week placebo-controlled trial (I1R-MC GLDI [GLDI], n = 246) and a 52-week placebo- and active comparator-controlled trial (I1R-MC-GLDJ [GLDJ], n = 158). GLDJ had endpoints at 6 months, including measures of hepatic fat fraction (HFF) by magnetic resonance imaging. The five genes tested were patatin-like phospholipase domain containing 3 (PNPLA3) (rs738409 and rs738491), transmembrane 6 superfamily member 2 (TM6SF2) (rs58542926), peroxisome proliferative activated receptor gamma coactivator 1 alpha (PPARGC1A) (rs4361373, rs3774921, rs2970849), adenylate cyclase 3 (ADCY3) (rs713586), and insulin-like growth factor 1 (IGF-1) (rs1520220). In GLDI, PNPLA3 I148M (P = 0.001) and TM6SF2 E167K (P = 0.001) were significantly associated with an increase in ALT at 6 weeks for LY2409021 but not for placebo. In GLDJ, PNPLA3 I148M showed the same effect (P = 0.007) on ALT at 6 months but the placebo or sitagliptin did not. In GLDJ, both PNPLA3 and TM6SF2 risk-allele carriers showed increases in HFF that were numerically greater but not statistically significant. The carriers of PNPLA3 and/or TM6SF2 risk alleles showed significantly increased ALT (GLDI, +13.28 U/L in carriers versus +4.84 U/L in noncarriers, P = 4 * 10-5; GLDJ, +14.6 U/L in carriers versus +1.7 in noncarriers, P = 0.0018) and HFF (GLDJ, +5.35% in carriers versus 2.38% in noncarriers, P = 0.048). Elevation of transaminase and HFF were also noted in the noncarriers but at a significantly lower degree. Conclusion: The carriers of PNPLA3 and/or TM6SF2 variant alleles are at risk for hepatic steatosis and elevated ALT levels caused by LY2409021, a glucagon receptor antagonist. More studies are needed to investigate if our observations are generalizable to hepatic steatosis caused by other medications. (Hepatology Communications 2018;2:561-570). PMID- 29761170 TI - Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 modulates inflammatory vigor during nonalcoholic fatty liver disease progression in mice. AB - Nonalcoholic fatty liver disease (NAFLD) represents a disease spectrum ranging from benign steatosis to life-threatening cirrhosis and hepatocellular carcinoma. Elevated levels of reactive oxygen species (ROS) and exacerbated inflammatory responses have been implicated in NAFLD progression. Nicotinamide adenine dinucleotide phosphate (reduced) oxidase 2 (NOX2; also known as gp91Phox), the main catalytic subunit of the nicotinamide adenine dinucleotide phosphate (reduced) oxidase complex, modulates ROS production, immune responsiveness, and pathogenesis of obesity-associated metabolic derangements. However, the role of NOX2 in the regulation of immune cell function and inflammatory vigor in NAFLD remains underdefined. Here, we demonstrate that obesogenic diet feeding promoted ROS production by bone marrow, white adipose tissue, and liver immune cells. Genetic ablation of NOX2 impeded immune cell ROS synthesis and was sufficient to uncouple obesity from glucose dysmetabolism and NAFLD pathogenesis. Protection from hepatocellular damage in NOX2-deficient mice correlated with reduced hepatic neutrophil, macrophage, and T-cell infiltration, diminished production of key NAFLD-driving proinflammatory cytokines, and an inherent reduction in T-cell polarization toward Th17 phenotype. Conclusion: Current findings demonstrate a crucial role of the NOX2-ROS axis in immune cell effector function and polarization and consequent NAFLD progression in obesity. Pharmacologic targeting of NOX2 function in immune cells may represent a viable approach for reducing morbidity of obesity-associated NAFLD pathogenesis. (Hepatology Communications 2018;2:546-560). PMID- 29761172 TI - Loss of hypoxia inducible factor-1alpha aggravates gammadelta T-cell-mediated inflammation during acetaminophen-induced liver injury. AB - Acetaminophen (APAP)-induced liver injury is closely associated with acute hepatic inflammation. Hypoxia-inducible factor-1 (HIF-1) is activated during immunological processes and regulates gene expressions in various types of immune cells. Although HIF-1 controls the differentiation and functions of conventional T cells in chronic inflammation, the pathological importance of HIF-1 in innate like T cells during acute inflammation remains unknown. Here, we investigated the role of HIF-1 in innate-like gammadelta T cells during APAP-induced acute liver injury. In response to APAP administration, T-cell-specific Hif-1alpha gene knockout mice sustained severe liver damage compared to wild-type control mice but without any impacts on the initial hepatic insult. This severe liver damage was accompanied by excessive neutrophil infiltration into the liver, increased serum interleukin (IL)-17A levels, and increased hepatic expressions of C-X-C chemokine ligand (Cxcl) 1 and Cxcl2. Neutrophil depletion and IL-17A neutralization completely abolished the aggravated phenotypes in T-cell-specific Hif-1alpha gene knockout mice. Loss of the Hif-1alpha gene enhanced the aberrant accumulation of IL-17A-producing innate-like gammadelta T cells in the affected liver with no apparent effects on their IL-17A-producing ability. Adoptive transfer of Hif-1alpha-deficient splenic gammadelta T cells into recombination activating gene 2 (Rag2)-deficient mice aggravated APAP-induced liver injury with increased neutrophil accumulation in the liver compared to that of wild-type gammadelta T cells. Furthermore, Hif-1alpha-deficient gammadelta T cells selectively showed aberrantly enhanced migratory ability. This ability was totally abolished by treatment with the mitochondrial adenosine triphosphate synthase inhibitor oligomycin. Conclusion: Deletion of Hif-1alpha gene in T cells aggravates APAP-induced acute inflammatory responses by enhancing aberrant innate like gammadelta T-cell recruitment, thereby increasing excessive neutrophil infiltration into the liver. (Hepatology Communications 2018;2:571-581). PMID- 29761173 TI - Liver-enriched transcription factor expression relates to chronic hepatic failure in humans. AB - The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4alpha, HNF1alpha, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)alpha, and CEBPbeta. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho-ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p-ERM], phospho-myosin light chain [p-MLC], low-density lipoprotein receptor related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child-Pugh classification, Model for End Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4alpha expression was down-regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4alpha expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho associated protein kinase pathways, which have been implicated in the regulation of HNF4alpha, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4alpha and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582 594). PMID- 29761174 TI - Elbasvir/grazoprevir in Asia-Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection. AB - The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia-Pacific countries and Russia. In this phase 3, randomized, placebo-controlled, double-blind study, treatment-naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate-treatment group [ITG]) or placebo (deferred-treatment group [DTG]) once daily for 12 weeks (Protocol PN-5172-067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty-seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow-up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, -0.3%; 95% confidence interval, -12.3, 11.9). Conclusion: EBR/GZR for 12 weeks provides an effective and well-tolerated regimen for chronic HCV GT1 infection in treatment-naive people from Asia-Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018;2:595-606). PMID- 29761177 TI - Enantioselective separation of RS-mandelic acid using beta-cyclodextrin modified Fe3O4@SiO2/Au microspheres. AB - Chiral magnetic microspheres show great potential in direct enantioseparation. Herein novel chiral magnetic microspheres were prepared by self-assembling beta cyclodextrin on magnetic Fe3O4@SiO2/Au composite microspheres. The prepared materials were characterized by transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), X-ray diffraction (XRD), vibrating sample magnetometry (VSM) and Fourier transform infrared spectroscopy (FTIR). The results showed that the functional microspheres have a three-ply structure and high saturation magnetization. beta-Cyclodextrin-immobilized magnetic Fe3O4@SiO2/Au microspheres (Fe3O4@SiO2/Au/beta-CD) were applied in the direct chiral separation of RS-mandelic acid. The analysis results of HPLC revealed that the Fe3O4@SiO2/Au/beta-CD magnetic microspheres exhibited stronger enantioselective adsorption for R-mandelic acid than S-mandelic acid. The chiral selector functionalized magnetic microspheres are therefore expected to be an efficient and economical chiral separation method for use in further research. PMID- 29761175 TI - Anti-tumoral effects of exercise on hepatocellular carcinoma growth. AB - Regular physical exercise has many beneficial effects, including antitumor properties, and is associated with a reduced risk of developing hepatocellular carcinoma (HCC). Less is known about the impact of exercise on HCC growth and progression. Here, we investigated the effects of exercise on HCC progression and assessed whether any beneficial effects would be evident under sorafenib treatment and could be mimicked by metformin. American Cancer Institute rats with orthotopic syngeneic HCC derived from Morris Hepatoma-3924A cells were randomly assigned to exercise (Exe) and sedentary groups, or sorafenib+/-Exe groups or sorafenib+/-metformin groups. The Exe groups ran on a motorized treadmill for 60 minutes/day, 5 days/week for 4 weeks. Tumor viable area was decreased by exercise, while cell proliferation and vascular density were reduced. Exercise increased the expression of phosphatase and tensin homolog deleted from chromosome 10 and increased the phosphorylation of adenosine monophosphate activated protein kinase, while the phosphorylation of protein kinase B, S6 ribosomal protein, and signal transducer and activator of transcription 3 were decreased. Transcriptomic analysis suggested major effects of exercise were on nontumoral liver rather than tumor tissue. Exercise demonstrated similar effects when combined with sorafenib. Moreover, similar effects were observed in the group treated with sorafenib+metformin, revealing an exercise-mimicking effect of metformin. Conclusion: Exercise attenuates HCC progression associated with alterations in key signaling pathways, cellular proliferation, tumor vascularization, and necrosis. These beneficial effects are maintained when combined with sorafenib and can be mimicked by metformin. (Hepatology Communications 2018;2:607-620). PMID- 29761178 TI - Dual functional PDMS sponge SERS substrate for the on-site detection of pesticides both on fruit surfaces and in juice. AB - In this study, a versatile dual-functional polydimethylsiloxane (PDMS) sponge Surface Enhanced Raman Scattering (SERS) substrate has been fabricated for the on site detection of pesticide residues both on the surface and in solution with minimum or no sample pretreatment. The PDMS sponge was fabricated using white granulated sugar and soft white sugar as pore-forming reagents. Later, multiple rounds of Ag NP deposition were performed by incubating the PDMS sponge in the Ag NP solution with the help of 3-mercaptopropyltrimethoxysilane (APTMS). The highest SERS enhancement was achieved through 2 rounds of Ag NP deposition. Under optimum conditions, with Rhodamine 6G (R6G) as the probe molecule, the limit of detection (LOD) reached 2 femtomoles (20 MUL at a concentration of 100 pM). The analytical performance for potential on-site applications of the substrate has been demonstrated with pesticide-spiked agricultural products taken as examples. Without sample pretreatment, the pesticide triazophos and methyl parathion were successfully detected by swabbing on the fruit surface with LODs of 0.79 ng and 1.58 ng, respectively. In addition, the lowest detected concentrations of triazophos and methyl parathion in fruit juice were found to be 100 ppb and 1 ppm. More importantly, the PDMS sponge SERS substrate can be safely stored for 36 days without affecting its SERS activity. PMID- 29761179 TI - Tuning the electronic properties of thiophene-annulated NDIs: the influence of the lateral fusion position. AB - A new asymmetric thiophene-annulated NDI (NTTI) has been designed and synthesized. NTTI exhibits an enhanced polarized electronic structure relative to the symmetric analogue (NDTI). The fusion position of thiophene affects the optical, electrochemical, and charge transport properties. The OFET device based on single crystalline microribbons of C8-NTTI shows an electron mobility up to 1.47 cm2 V-1 s-1. PMID- 29761176 TI - Androgen Deprivation Therapy Is Associated With Prolongation of QTc Interval in Men With Prostate Cancer. AB - Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with increased cardiovascular mortality and sudden cardiac death, with some events occurring early after initiation of ADT. Testosterone levels are inversely associated with corrected QT (QTc) interval duration; therefore, prolongation of QTc duration could be responsible for some of these events during ADT. Objective: To evaluate changes in QTc duration during ADT. Design and Interventions: A 6-month prospective cohort study that enrolled men with PCa about to undergo ADT (ADT group) and a control group of men who previously underwent prostatectomy for PCa and never received ADT (non-ADT group). Patients: At study entry, all participants were eugonadal and had no history of cardiac arrhythmias or complete bundle branch block. Outcomes: Difference in change in QTc duration from baseline on a 12-lead electrocardiogram at 6, 12, and 24 weeks after initiation of ADT compared with electrocardiograms performed at the same intervals in the non-ADT group. PR, QRS, and QT interval durations were also evaluated. Results: Seventy-one participants formed the analytical sample (33 ADT and 38 non-ADT). ADT was associated with prolongation of the QTc by 7.4 ms compared with the non-ADT group [95% confidence interval (CI) 0.08 to 14.7 ms; P = 0.048]. ADT was also associated with shortening of the QRS interval by 2.4 ms (95% CI -4.64 to -0.23; P = 0.031). Electrolytes did not change. Conclusions: Men undergoing ADT for PCa experienced prolongation of the QTc. These findings might explain the increased risk of sudden cardiac death seen in these patients. PMID- 29761180 TI - Covalent switching, involving divinylbenzene ligands within 3D coordination polymers, indicated by changes in fluorescence. AB - Reversible cycloaddition reactions between 1,4-bis[2-(3-pyridyl)ethenyl]benzene and its photodimers were performed within a pair of three-dimensional coordination polymers with retention of single crystal character. In each case, switching between two crystalline forms could be followed by monitoring the flourescence behaviour. PMID- 29761181 TI - Self-assembly and ring-opening metathesis polymerization of cyclic conjugated molecules on highly ordered pyrolytic graphite. AB - Cyclic conjugated monomers comprising cyclopentadithiophene-vinylene trimers and their polymers on HOPG are observed using STM and AFM. ROMP of the monomers is performed using a Grubbs catalyst. Their STM images exhibit single chains of planar polymers, whereas their AFM images show elongation of the polymer chains on HOPG. PMID- 29761182 TI - Effect of pi-bridge units on properties of A-pi-D-pi-A-type nonfullerene acceptors for organic solar cells. AB - Acceptor-pi-donor-pi-acceptor (A-pi-D-pi-A)-types of small molecules are very promising nonfullerene acceptors to overcome the drawbacks of fullerene derivatives such as the weak absorption ability and electronic adjustability. However, only few attempts have been made to develop pi-bridge units to construct highly efficient acceptors in OSCs. Herein, taking the reported acceptor P1 as a reference, five small-structured acceptors (P2, P3, P4, P5, and P6) have been designed via the replacement of the pi-bridge unit. A combination of quantum chemistry and Marcus theory approaches is employed to investigate the effect of different pi-bridge units on the optical, electronic, and charge transport properties of P1-P6. The calculation results show that the designed molecules P2 and P5 can become potential acceptor replacements of P1 due to their red-shifted absorption bands, appropriate energy levels, low exciton binding energy, and high electron affinity and electron mobility. Additionally, compared with P3HT/P1, P3HT/P2 and P3HT/P5 exhibit stronger and wider absorption peaks, larger electron transfer distances (DCT), greater transferred charge amounts (Deltaq), and smaller overlaps (Lambda), which shows that P2 and P5 have more significant electron transfer characteristics and favorable exciton dissociation capabilities for enhancing the short-circuit current density (JSC) and thus, they are potential acceptors in OSCs. PMID- 29761183 TI - Diagrams for comprehensive molecular orbital-based chemical reaction analyses: reactive orbital energy diagrams. AB - Reactive orbital energy diagrams are presented as a tool for comprehensively performing orbital-based reaction analyses. The diagrams rest on the reactive orbital energy theory, which is the expansion of conceptual density functional theory (DFT) to an orbital energy-based theory. The orbital energies on the intrinsic reaction coordinates of fundamental reactions are calculated by long range corrected DFT, which is confirmed to provide accurate orbital energies of small molecules, combining with a van der Waals (vdW) correlation functional, in order to examine the vdW effect on the orbital energies. By analysing the reactions based on the reactive orbital energy theory using these accurate orbital energies, it is found that vdW interactions significantly affect the orbital energies in the initial reaction processes and that more than 70% of reactions are determined to be initially driven by charge transfer, while the remaining structural deformation (dynamics)-driven reactions are classified into identity, cyclization and ring-opening, unimolecular dissociation, and H2 reactions. The reactive orbital energy diagrams, which are constructed using these results, reveal that reactions progress so as to delocalize the occupied reactive orbitals, which are determined as contributing orbitals and are usually not HOMOs, by hybridizing the unoccupied reactive orbitals, which are usually not LUMOs. These diagrams also raise questions about conventional orbital-based diagrams such as frontier molecular orbital diagrams, even for the well established interpretation of Diels-Alder reactions. PMID- 29761184 TI - Tuning thin-film bijels with applied external electric fields. AB - The tunability of thin-film bijels using applied external electric fields is explored using a Cahn-Hilliard Langevin dynamics computational model. Dielectric contrast between liquid domains governs liquid domain alignment and was varied in the simulations. Dielectric contrast between colloidal particles and liquid matrix induces dipolar particle interactions and was also varied in the simulations. The study reveals unique internal morphologies including those with through-thickness liquid domains. Significant results include identification of electric field effects on phase evolution and final morphology as well as relevant mechanisms. It was also found that particle chains act as nucleation sites for phase separation. The resultant morphologies were analyzed in terms of particle attachment to phase interface regions as well as the average channel diameter. Electric field effects and mechanisms on morphology are identified and compared with other morphology-tuning parameters such as particle loading and liquid-liquid composition. PMID- 29761185 TI - Cationic hydrophobicity promotes dissolution of cellulose in aqueous basic solution by freezing-thawing. AB - The physical dissolution of cellulose in aqueous solutions of tetramethyl ammonium hydroxide, triethylmethyl ammonium hydroxide, tetraethyl ammonium hydroxide, benzyltrimethyl ammonium hydroxide, benzyltriethyl ammonium hydroxide, NaOH and LiOH via freezing-thawing was investigated. Increasing the hydrophobicity of the cation greatly improved its dissolution capacity, leading to significant enhancement of cellulose solubility and stability against chain aggregation and gelation. The hydrophobic cations accumulated at the cellulose interface and decreased the surface tension, favouring dispersion of the disintegrated cellulose due to its amphiphilicity; this was consistent with molecular dynamics simulations. On the other hand, the solubility of cellulose followed the Hofmeister series, and cations with greater kosmotropicity originating from their greater hydrophobicity exhibited stronger dissolution power; this observed interaction pattern may be useful for further exploration and designation of novel solvents of cellulose. These aqueous quaternary ammonium hydroxides can be readily recycled and reused, which presents great potential in the green chemistry field. PMID- 29761186 TI - Regioselective C-H alkenylation of imidazoles and its application to the synthesis of unsymmetrically substituted benzimidazoles. AB - A palladium-catalyzed C-H alkenylation of imidazoles has been developed. High C5 selectivity was achieved for C2-unsubstituted and C2-substituted imidazoles using oxygen and copper(ii) acetate, respectively, as oxidants. The obtained products were applied to benzannulation through a sequence involving transposition of N alkyl groups to give C4-alkenyl imidazoles, alkenylation, thermal 6pi electrocyclization, and oxidation, affording unsymmetrically substituted benzimidazoles. PMID- 29761188 TI - Peptide and protein nanotechnology into the 2020s: beyond biology. PMID- 29761189 TI - Molecular dynamic simulation for thermal decomposition of RDX with nano-AlH3 particles. AB - Molecular dynamic simulation of a high explosive, RDX, mixed with AlH3 nanoparticles was performed by a newly parameterized ReaxFF force field. Testing of the ReaxFF shows that the mean absolute errors of the densities and bond lengths between calculated and experimental values are less than 7% and 3%, respectively. Using the ReaxFF, effects of AlH3 nanoparticles with different radii on the thermal decomposition of RDX were revealed. A new mechanism of the generation and the consumption of H2 was discovered in the explosion. The H2 is released by AlH3 firstly and then it reacts with NO2 and CO2 from the decomposition of RDX, leading to an increase of H2O, NO and CO. Meanwhile, the size effect of AlH3 upon the reaction was also revealed. As a result, the number of produced H2O and CO2 molecules increases by 10.38% and 56.85%, respectively, when the radius of AlH3 nanoparticles decreases from 1.10 to 0.68 nm. This showed that RDX decomposes more completely with smaller AlH3 nanoparticles, which was further demonstrated by the analysis of reaction residues and diffusion coefficients. PMID- 29761190 TI - Efficient, non-stochastic, Monte-Carlo-like-accurate method for the calculation of the temperature-dependent mobility in nanocrystal films. AB - We present a new non-stochastic framework for the calculation of the temperature dependence of the mobility in nanocrystal films, that enables speed-ups of several orders of magnitude compared to conventional Monte Carlo approaches, while maintaining a similar accuracy. Our model identifies a new contribution to the reduction of the mobility with increasing temperature in these systems (conventionally attributed to interactions with phonons), that alone is sufficient to explain the observed experimental trend up to room temperature. Comparison of our results with the theoretical predictions of the hopping model and the observed temperature dependence of recent field-effect mobility measurements in nanocrystal films, provides the means to discriminate between band-like and hopping transport and a definitive answer to whether the former has been achieved in quantum dot films. PMID- 29761191 TI - Highlights from the Faraday Discussion on Ionic Liquids: From Fundamental Properties to Practical Applications, Cambridge, UK, September 2017. AB - For the third time, a Faraday Discussion addressed ionic liquids. Encompassing the wealth of research in this field, the contributions ranged from fundamental insights to the diverse applications of ionic liquids. Lively discussions initiated in the lecture hall and during poster sessions then seamlessly continued during the social program. PMID- 29761192 TI - Structural and photodynamic properties of the anti-cancer drug irinotecan in aqueous solutions of different pHs. AB - This work reports on photophysical studies of the irinotecan (IRT) anti-cancer drug in water solutions of different acidities (pH = 1.11-9.46). We found that IRT co-exists as mono-cationic (C1), di-cationic (C2), or neutral (N) forms. The population of each prototropic species depends on the pH of the solution. At pH = 1.11-3.01, the C1 and C2 structures are stabilized. At pH = 7.00, the most populated species is C1, while at pH values larger than 9.46 the N form is the most stable species. In the 1.11-2.61 pH range, the C1* emission is efficiently quenched by protons to give rise to the emission from C2*. The dynamic quenching constant, KD, is ~32 M-1. While the diffusion governs the rate of excited-state proton-transfer (ESPT) under these conditions, the reaction rate increases with the proton concentration. A two-step diffusive Debye-Smoluchowski model was applied at pH = 1.11-2.61 to describe the protonation of C1*. The ESPT time constants derived for C1* are 382 and 1720 ps at pH = 1.11 and 1.95, respectively. We found that one proton species is involved in the protonation of C1* to give C2*, in the analyzed acidic pH range. Under alkaline conditions (pH = 9.46), the N form is the most stable structure of IRT. These results indicate the influence of the pH of the medium on the structural and dynamical properties of IRT in water solution. They may help to provide a better understanding on the relationship between the structure and biological activity of IRT. PMID- 29761193 TI - Hydrogen bond basicity of ionic liquids and molar entropy of hydration of salts as major descriptors in the formation of aqueous biphasic systems. AB - Aqueous biphasic systems (ABS) composed of ionic liquids (ILs) and conventional salts have been largely investigated and successfully used in separation processes, for which the determination of the corresponding ternary phase diagrams is a prerequisite. However, due the large number of ILs that can be prepared and their high structural versatility, it is impossible to experimentally cover and characterize all possible combinations of ILs and salts that may form ABS. The development of tools for the prediction and design of IL based ABS is thus a crucial requirement. Based on a large compilation of experimental data, a correlation describing the formation of IL-based ABS is shown here, based on the hydrogen-bonding interaction energies of ILs (EHB) obtained by the COnductor-like Screening MOdel for Real Solvents (COSMO-RS) and the molar entropy of hydration of the salt ions. The ability of the proposed model to predict the formation of novel IL-based ABS is further ascertained. PMID- 29761194 TI - Partial wetting of thin solid sheets under tension. AB - We consider the equilibrium of liquid droplets sitting on thin elastic sheets that are subject to a boundary tension and/or are clamped at their edge. We use scaling arguments, together with a detailed analysis based on the Foppl-von Karman equations, to show that the presence of the droplet may significantly alter the stress locally if the tension in the dry sheet is weak compared to an intrinsic elasto-capillary tension scale gamma2/3(Et)1/3 (with gamma the droplet surface tension, t the sheet thickness and E its Young modulus). Our detailed analysis suggests that some recent experiments may lie in just such a "non perturbative" regime. As a result, measurements of the tension in the sheet at the contact line (inferred from the contact angles of the sheet with the liquid vapour interface) do not necessarily reflect the true tension within the sheet prior to wetting. We discuss various characteristics of this non-perturbative regime. PMID- 29761195 TI - Convection inside condensing and evaporating droplets of aqueous solution. AB - We experimentally study the fluid convection inside a condensing droplet of aqueous NaCl solution and compare it with that of an evaporating droplet. The droplets are sandwiched between two horizontal hydrophobic surfaces and surrounded by a reservoir with solution of different concentration. Condensation and evaporation of the droplets occur due to the vapor pressure difference between the droplet and the reservoir solution. The micro-PIV technique has been used to study the velocity field inside the droplets. Buoyancy driven Rayleigh convection is observed inside both the condensing and evaporating droplets. In the condensing droplet, water condenses on the liquid-air interface creating a low density region near the interface. There is upward movement of fluid along the condensing interface towards the top region of the droplet which recirculates back from the center region of the droplet in the downward direction. In contrast, the fluid moves in the downward direction along the interface in the case of an evaporating droplet with an upward plume like flow at the center region of the droplet. Both evaporating and condensing droplets show a recirculating loop inside the droplets of opposite direction. PMID- 29761196 TI - Three primary color emissions from single multilayered nanocrystals. AB - The achievement of three-primary-color luminescence in a single material will lead to revolutionary developments of many advanced applications such as dynamic display with ultra-high resolution, and complex anti-counterfeiting. Here we report the realization of steady-state three-primary-color emission in single multilayered NaYF4 upconversion (UC) nanoparticles. In this core-shell structure, a novel design of a tri-sensitizer, i.e., Nd3+, Yb3+ and Er3+ ions, is utilized, which effectively absorbs the excitation photons of 808, 980 and 1550 nm, and then exhibits blue, red and green emissions, respectively. By simply combining the three primary color emissions, tunable full-color luminescence was achieved in this single material. These nanoparticles have demonstrated promising potential applications in dynamic display and multiple anti-counterfeiting. PMID- 29761197 TI - Facile fabrication of thermo/redox responsive hydrogels based on a dual crosslinked matrix for a smart on-off switch. AB - Stimuli-responsive or "smart" soft materials have raised considerable attention due to their ability to spontaneously respond to external environmental variations and have a great potential for wide applications. Herein, a thermo/redox responsive hydrogel is facilely constructed based on a dual crosslinked matrix: the primary chemical crosslinked copolymer is composed of thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) and poly(ionic liquid), and the secondary physical crosslinking component is generated by the ionic coordination between iron ions and carboxyl groups in the poly(ionic liquid). The non-covalent ion coordination crosslinking is introduced into a covalently crosslinked network, which further strengthens the soft PNIPAM matrix and enhances the mechanical performances of the hydrogels. The excellent thermosensitivity of PNIPAM and the good conductive property of poly(ionic liquid) provide the hydrogel with an attractive performance as a thermo responsive switch. Moreover, the trapped iron ions in the network endow the hydrogels with redox-responsiveness, which could be reversibly chemically oxidized and reduced. The mechanical strength of hydrogels could also be tuned by the crosslinked capacity of iron ions within the gel matrix between the strong binding of the oxidized state (Fe3+) and poor coordination of the reduced state (Fe2+). These stimuli-responsive hydrogels have the potential to be used as smart materials for stimuli-responsive devices. PMID- 29761198 TI - Kinetics of Cd(ii) adsorption and desorption on ferrihydrite: experiments and modeling. AB - The kinetics of Cd(ii) adsorption/desorption on ferrihydrite is an important process affecting the fate, transport, and bioavailability of Cd(ii) in the environment, which was rarely systematically studied and understood at quantitative levels. In this work, a combination of stirred-flow kinetic experiments, batch adsorption equilibrium experiments, high-resolution transmission electron microscopy (HR-TEM), and mechanistic kinetic modeling were used to study the kinetic behaviors of Cd(ii) adsorption/desorption on ferrihydrite. HR-TEM images showed the open, loose, and sponge-like structure of ferrihydrite. The batch adsorption equilibrium experiments revealed that higher pH and initial metal concentration increased Cd(ii) adsorption on ferrihydrite. The stirred-flow kinetic results demonstrated the increased adsorption rate and capacity as a result of the increased pH, influent concentration, and ferrihydrite concentration. The mechanistic kinetic model successfully described the kinetic behaviors of Cd(ii) during the adsorption and desorption stages under various chemistry conditions. The model calculations showed that the adsorption rate coefficients varied as a function of solution chemistry, and the relative contributions of the weak and strong ferrihydrite sites for Cd(ii) binding varied with time at different pH and initial metal concentrations. Our model is able to quantitatively assess the contributions of each individual ferrihydrite binding site to the overall Cd(ii) adsorption/desorption kinetics. This study provided insights into the dynamic behavior of Cd(ii) and a predictive modeling tool for Cd(ii) adsorption/desorption kinetics when ferrihydrite is present, which may be helpful for the risk assessment and management of Cd contaminated sites. PMID- 29761202 TI - Kinetic theory for the formation of diamond nanothreads with desired configurations: a strain-temperature controlled phase diagram. AB - Diamond nanothreads (DNTs) are a brand-new one-dimensional carbon nanomaterial that was synthesized recently by compressing benzene. Compared with sp2 carbon nanotubes, DNTs may possess a much higher interfacial load-transfer ability. However, previous studies have shown that the mechanical properties of DNTs are highly sensitive to the composition of Stone-Wales (SW) transformed sites. Up to now, it remained unclear what roles SWs play in the structure stability and how to engineer its molecular structure for novel mechanical properties. Using ab initio calculations, here we show that the most stable structure of a DNT is composed of alternative SW and hydrogenated carbon nanotube (3,0) units, suggesting that SW plays an essential role in stabilizing DNT. Interestingly, we found that the SW transition barrier is a nearly linear function of the applied strain, enabling strain engineering of its molecular structure. To do so, we propose a strain-temperature-stretching rate phase diagram to guide the construction of desired molecular structures to achieve superplastic behavior of DNTs. Our findings not only enrich our understanding of this novel carbon material, but also provide a strategy to control its structural and mechanical properties for novel applications, such as energy absorption, energy storage and materials reinforcement. PMID- 29761203 TI - The Weighing Chair of Sanctorius Sanctorius: A Replica. AB - In 1614, the physician Sanctorius Sanctorius (1561-1636) published his most famous work entitled Ars [...] de statica medicina (On static medicine). This is a work composed of aphorisms that present the practical results of a series of weighing procedures, rather than theoretical observations. De statica medicina is the result of a large number of test series that Sanctorius carried out over many years with the weighing chair he constructed himself in order to quantify the so called perspiratio insensibilis, an insensible perspiration of the human body. Through his weighing experiments, Sanctorius introduced the idea of quantitative research into physiology. Although historical accounts ascribe an important role to Sanctorius as the founder of a new medical science, up until now the design of his weighing chair and the method of measurement have not been closely analysed. The aim of this paper is to close this gap. Through a collaboration between the Max Planck Institute for the History of Science and the Technical University of Berlin (Institute of Vocational Education and Work Studies), Sanctorius's weighing chair was reconstructed and experiments carried out with it. This opened new perspectives on Sanctorius's work and led to a reconsideration of the function and purpose of his weighing chair. With his static medicine, Sanctorius repurposed an old instrument. The replication of the weighing chair and the repetition of the experiments demonstrate that this novel application of scales posed some challenges for the mechanical design of the instrument. We recognized that the instrument fulfilled different functions that might in turn have affected its design, precision, and the measuring method applied. Although in the end we could not clarify how Sanctorius actually conducted his measurements, we were nevertheless able to develop an understanding of Sanctorius's mechanical and practical knowledge that would not have been possible for us to develop solely on the basis of the written sources. PMID- 29761204 TI - [Recognition and prevention of problems in lacrimal duct surgery]. AB - Surgical management of lacrimal duct obstruction beyond the canaliculi proves to be a promising endeavor in most cases. To realize the full potential of endonasal dacryocystorhinostomy, some aspects of diagnosis and differential indication setting should be considered in order to avoid errors and problems during patient selection, execution of the technical procedure, and communication with ophthalmologists. These issues are described according to the clinical management of patients; current literature is cited. PMID- 29761205 TI - Cellular mechanisms responsible for cell-to-cell spreading of prions. AB - Prions are infectious agents that cause fatal neurodegenerative diseases. Current evidence indicates that they are essentially composed of an abnormally folded protein (PrPSc). These abnormal aggregated PrPSc species multiply in infected cells by recruiting and converting the host PrPC protein into new PrPSc. How prions move from cell to cell and progressively spread across the infected tissue is of crucial importance and may provide experimental opportunity to delay the progression of the disease. In infected cells, different mechanisms have been identified, including release of infectious extracellular vesicles and intercellular transfer of PrPSc-containing organelles through tunneling nanotubes. These findings should allow manipulation of the intracellular trafficking events targeting PrPSc in these particular subcellular compartments to experimentally address the relative contribution of these mechanisms to in vivo prion pathogenesis. In addition, such information may prompt further experimental strategies to decipher the causal roles of protein misfolding and aggregation in other human neurodegenerative diseases. PMID- 29761207 TI - Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. AB - Bosentan is well known to induce cholestatic liver toxicity in humans. The present study was set up to characterize the hepatotoxic effects of this drug at the transcriptomic, proteomic, and metabolomic levels. For this purpose, human hepatoma-derived HepaRG cells were exposed to a number of concentrations of bosentan during different periods of time. Bosentan was found to functionally and transcriptionally suppress the bile salt export pump as well as to alter bile acid levels. Pathway analysis of both transcriptomics and proteomics data identified cholestasis as a major toxicological event. Transcriptomics results further showed several gene changes related to the activation of the nuclear farnesoid X receptor. Induction of oxidative stress and inflammation were also observed. Metabolomics analysis indicated changes in the abundance of specific endogenous metabolites related to mitochondrial impairment. The outcome of this study may assist in the further optimization of adverse outcome pathway constructs that mechanistically describe the processes involved in cholestatic liver injury. PMID- 29761206 TI - Imaging of oxygen and hypoxia in cell and tissue samples. AB - Molecular oxygen (O2) is a key player in cell mitochondrial function, redox balance and oxidative stress, normal tissue function and many common disease states. Various chemical, physical and biological methods have been proposed for measurement, real-time monitoring and imaging of O2 concentration, state of decreased O2 (hypoxia) and related parameters in cells and tissue. Here, we review the established and emerging optical microscopy techniques allowing to visualize O2 levels in cells and tissue samples, mostly under in vitro and ex vivo, but also under in vivo settings. Particular examples include fluorescent hypoxia stains, fluorescent protein reporter systems, phosphorescent probes and nanosensors of different types. These techniques allow high-resolution mapping of O2 gradients in live or post-mortem tissue, in 2D or 3D, qualitatively or quantitatively. They enable control and monitoring of oxygenation conditions and their correlation with other biomarkers of cell and tissue function. Comparison of these techniques and corresponding imaging setups, their analytical capabilities and typical applications are given. PMID- 29761208 TI - Location of a grasped object's effector influences perception of the length of that object via dynamic touch. AB - Perception of properties of a grasped object via dynamic touch (wielding) contributes to dexterity in tool use (e.g., using a hammer, screwdriver) and sports (e.g., hockey, tennis). These activities differ from simple object manipulation in that they involve making contact with an intended target. In the present study, we examined whether and how making (percussive) contact with a target influences perception of the length of a grasped object via dynamic touch. Making contact with a target by the tip resulted in a more accurate perception of the length than simple wielding. However, making contact with the target at a point along the length did not influence the accuracy of perception. These findings suggest that the location of a grasped object's effector influences perception of properties of that object via dynamic touch. We discuss these findings in terms of time-varying properties of vibrations generated by the percussive contact of the grasped object and target. PMID- 29761210 TI - Biochemical properties of bacterial reverse transcriptase-related (rvt) gene products: multimerization, protein priming, and nucleotide preference. AB - Cellular reverse transcriptase-related (rvt) genes represent a novel class of reverse transcriptases (RTs), which are only distantly related to RTs of retrotransposons and retroviruses, but, similarly to telomerase RTs, are immobilized in the genome as single-copy genes. They have been preserved by natural selection throughout the evolutionary history of large taxonomic groups, including most fungi, a few plants and invertebrates, and even certain bacteria, being the only RTs present across different domains of life. Bacterial rvt genes are exceptionally rare but phylogenetically related, consistent with common origin of bacterial rvt genes rather than eukaryote-to-bacteria transfer. To investigate biochemical properties of bacterial RVTs, we conducted in vitro studies of recombinant HaRVT protein from the filamentous gliding bacterium Herpetosiphon aurantiacus (Chloroflexi). Although HaRVT does not utilize externally added standard primer-template combinations, in the presence of divalent manganese, it can polymerize very short products, using dNTPs rather than NTPs, with a strong preference for dCTP incorporation. Furthermore, we investigated the highly conserved N- and C-terminal domains, which distinguish RVT proteins from other RTs. We show that the N-terminal coiled-coil motif, which is present in nearly all RVTs, is responsible for the ability of HaRVT to multimerize in solution, forming up to octamers. The C-terminal domain may be capable of protein priming, which is abolished by site-directed mutagenesis of the catalytic aspartate and greatly reduced in the absence of the conserved tyrosine residues near the C-terminus. The unusual biochemical properties displayed by RVT in vitro will provide the basis for understanding its biological function in vivo. PMID- 29761211 TI - Comparative Study of UMA Jeunesse Classic(r) and UMA Jeunesse Ultra(r). AB - INTRODUCTION: The emergence of hyaluronic acid dermal fillers with lidocaine has transformed the minimally invasive treatment of wrinkles, lines and folds of the face. Patients can be treated quickly, painlessly and without the need for large doses of lidocaine. Therefore, it is important to scientifically evaluate the merits of lidocaine-containing products over those without. METHODS: The two products, with (UJU) and without lidocaine (UJ), were randomly injected into nasolabial folds of 75 healthy volunteers with varying skin types in a split face study, age ranging 26-60 years. Only 73 subjects completed the follow-up. There were 68 females and 5 males with medium-to-deep nasolabial folds. All subjects were randomly injected with the two products on one or the other side of the face. Patients were followed up for 9 months. RESULTS: Both products achieved significant improvement in the wrinkle severity score. Overall results were slightly better with UJU due to ease of injection, lack of pain and avoidance of topical or parenteral anaesthetic. In all other respects, differences in clinical data were not statistically significant. UJU(r) was preferred by patients and injectors due to less pain during and after injection as compared to UJ(r) (P < 0.0001). The overall rate of early and late complications with the two products was similar. Duration of maintenance of aesthetic effect between products also showed similarity. Optimum aesthetic effect was maintained in most cases for over 9 months with both products but patients in the 30-50-year age group did better. The patient acceptability rate was much higher with UJU. CONCLUSION: Clinical data from this study suggest that performance and outcomes of treatment of medium to-deep nasolabial folds with UJ and UJU are quite similar. However, treatment with UJU offers enhanced patient comfort and is preferred by patients and injectors. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29761212 TI - The elastic capacity of a tendon-repair construct influences the force necessary to induce gapping. AB - PURPOSE: Most biomechanical investigations of tendon repairs were based on output measures from hydraulic loading machines, therefore, accounting for construct failure rather than true gapping within the rupture zone. It was hypothesized that the elastic capacity of a tendon-repair construct influences the force necessary to induce gapping. METHODS: A tendon-repair model was created in 48 porcine lower hind limbs, which were allocated to three fixation techniques: (1) Krackow, (2) transosseous and (3) anchor fixation. Loading was performed based on a standardized phased load-to-failure protocol using a servohydraulic mechanical testing system MTS (Zwick Roell, Ulm, Germany). Rupture-zone dehiscence was measured with an external motion capture device. Factors influencing dehiscence formation was determined using a linear regression model and adjustment performed as necessary. A 3-mm gap was considered clinically relevant. Analysis of variance (ANOVA) was used for comparison between groups. RESULTS: The elastic capacity of a tendon-repair construct influences the force necessary to induce gapping of 3 mm (F3mm) [beta = 0.6, confidence interval (CI) 0.4-1.0, p < 0.001]. Furthermore, the three methods of fixation did not differ significantly in terms of maximum force to failure (n.s) or F3mm (n.s). CONCLUSION: The main finding of this study demonstrated that the higher the elastic capacity of a tendon-repair construct, the higher the force necessary to induce clinically relevant gapping. LEVEL OF EVIDENCE: Controlled biomechanical study. PMID- 29761213 TI - Can such an animal model truly represent Henoch-Schonlein purpura? PMID- 29761209 TI - Polymorphous adenocarcinoma of the salivary glands: reappraisal and update. AB - Although relatively rare, polymorphous adenocarcinoma (PAC) is likely the second most common malignancy of the minor salivary glands (MiSG). The diagnosis is mainly based on an incisional biopsy. The optimal treatment comprises wide surgical excision, often with adjuvant radiotherapy. In general, PAC has a good prognosis. Previously, PAC was referred to as polymorphous low-grade adenocarcinoma (PLGA), but the new WHO classification of salivary gland tumours has also included under the PAC subheading, the so-called cribriform adenocarcinoma of minor salivary glands (CAMSG). This approach raised controversy, predominantly because of possible differences in clinical behaviour. For example, PLGA (PAC, classical variant) only rarely metastasizes, whereas CAMSG often shows metastases to the neck lymph nodes. Given the controversy, this review reappraises the definition, epidemiology, clinical presentation, diagnostic work-up, genetics, treatment modalities, and prognosis of PAC of the salivary glands with a particular focus on contrasting differences with CAMSG. PMID- 29761214 TI - Analysis of resistance genes of clinical Pannonibacter phragmitetus strain 31801 by complete genome sequencing. AB - To clarify the resistance mechanisms of Pannonibacter phragmitetus 31801, isolated from the blood of a liver abscess patient, at the genomic level, we performed whole genomic sequencing using a PacBio RS II single-molecule real-time long-read sequencer. Bioinformatic analysis of the resulting sequence was then carried out to identify any possible resistance genes. Analyses included Basic Local Alignment Search Tool searches against the Antibiotic Resistance Genes Database, ResFinder analysis of the genome sequence, and Resistance Gene Identifier analysis within the Comprehensive Antibiotic Resistance Database. Prophages, clustered regularly interspaced short palindromic repeats (CRISPR), and other putative virulence factors were also identified using PHAST, CRISPRfinder, and the Virulence Factors Database, respectively. The circular chromosome and single plasmid of P. phragmitetus 31801 contained multiple antibiotic resistance genes, including those coding for three different types of beta-lactamase [NPS beta-lactamase (EC 3.5.2.6), beta-lactamase class C, and a metal-dependent hydrolase of beta-lactamase superfamily I]. In addition, genes coding for subunits of several multidrug-resistance efflux pumps were identified, including those targeting macrolides (adeJ, cmeB), tetracycline (acrB, adeAB), fluoroquinolones (acrF, ceoB), and aminoglycosides (acrD, amrB, ceoB, mexY, smeB). However, apart from the tripartite macrolide efflux pump macAB-tolC, the genome did not appear to contain the complete complement of subunit genes required for production of most of the major multidrug-resistance efflux pumps. PMID- 29761215 TI - Myocardial calcifications following sepsis. PMID- 29761217 TI - Dokdonia ponticola sp. nov., A Carrageenan-Degrading Bacterium of the Family Flavobacteriaceae Isolated from Seawater. AB - A Gram-stain-negative, aerobic, non-motile, and carrageenan-degrading bacterial strain, designated OISW-17T, was isolated from seawater around Oido, an island of South Korea, and its taxonomic position was determined using a polyphasic study. Optimal growth of the novel strain occurred at 20-25 degrees C and in the presence of 2.0% (w/v) NaCl. Phylogenetic trees using 16S rRNA gene sequences showed that strain OISW-17T forms a cluster with the type strains of Dokdonia species. The novel strain exhibited 16S rRNA gene sequence similarities of 95.7 96.3% to the type strains of Dokdonia species and of < 93.4% to the type strains of the other recognized species. Menaquinone-6 (MK-6) was found as the predominant menaquinone and iso-C15:0, iso-C15:1 G, and iso-C17:0 3-OH were the major fatty acids. Phosphatidylethanolamine, one unidentified lipid, and one unidentified aminolipid were major polar lipids detected in strain OISW-17T. Strain OISW-17T had DNA G+C content of 39.7 mol%. The differential phenotypic characteristics, along with the phylogenetic data, made strain OISW-17T to be distinct from recognized species of the genus Dokdonia. On the basis of the data given, strain OISW-17T represents a novel species of the genus Dokdonia, for which the name Dokdonia ponticola sp. nov. is proposed. The type strain of the novel species is OISW-17T (= KACC 19437T = KCTC 62187T = CGMCC 1.16527T). PMID- 29761218 TI - Bilateral Inferior Vestibular Nerve Lesion a Late Neurotoxic Effect of Liposoluble Myelographic Contrast Agent : Case Report with Imaging and Electrophysiological Confirmation. PMID- 29761216 TI - Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. AB - PURPOSE: To assess the effect of low dose corticosteroids on outcomes in adults with septic shock. METHODS: We systematically reviewed randomised clinical trials (RCTs) comparing low-dose corticosteroids to placebo in adults with septic shock. Trial selection, data abstraction and risk of bias assessment were performed in duplicate. The primary outcome was short-term mortality. Secondary and tertiary outcomes included longer-term mortality, adverse events, quality of life, and duration of shock, mechanical ventilation and ICU stay. RESULTS: There were 22 RCTs, including 7297 participants, providing data on short-term mortality. In two low risk of bias trials, the relative risk (RR) of short-term mortality with corticosteroid versus placebo was 0.98 [95% confidence interval (CI) 0.89-1.08, p = 0.71]. Sensitivity analysis including all trials was similar (RR 0.96; 95% CI 0.91-1.02, p = 0.21) as was analysis of longer-term mortality (RR 0.96; 95% CI 0.90-1.02, p = 0.18). In low risk of bias trials, the risk of experiencing any adverse event was higher with corticosteroids; however, there was substantial heterogeneity (RR 1.66; 95% CI 1.03-2.70, p = 0.04, I2 = 78%). No trials reported quality of life outcomes. Duration of shock [mean difference (MD) -1.52 days; 95% CI -1.71 to -1.32, p < 0.0001], duration of mechanical ventilation (MD -1.38 days; 95% CI -1.96 to -0.80, p < 0.0001), and ICU stay (MD -0.75 days; 95% CI 1.34 to -0.17, p = 0.01) were shorter with corticosteroids versus placebo. CONCLUSIONS: In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced. PROSPERO registration no. CRD42017084037. PMID- 29761219 TI - Intracranial Rescue Stent Angioplasty After Stent-Retriever Thrombectomy : Multicenter Experience. AB - PURPOSE: Stent-retriever thrombectomy (SRT) for acute intracranial large artery occlusion (LAO) may not result in permanent recanalization in rare cases, e.g. due to an underlying stenosis or dissection. In this specific patient group, rescue stent angioplasty (RSA) may be the only treatment option to achieve permanent vessel patency and potentially a good clinical outcome. To date, the experience with RSA is limited. METHODS: In this retrospective analysis, interventional and clinical data of patients with acute intracranial LAO of the anterior and posterior circulation who underwent RSA after SRT due to an underlying lesion between 2012-2017 in four neurovascular centers were studied. RESULTS: In this study 34 patients (mean age 67 years) were included whereby 18 patients had anterior circulation LAO and 16 patients posterior circulation LAO. The SRT maneuver count ranged between 1 and 15 (median 2). Indications for RSA were an immediate re-occlusion in 25 (74%), and a persistent high-grade stenosis in 9 patients (26%). The RSA was technically feasible in 33 patients (97%). A mTICI 2b/3 result was obtained in 26 patients (76%). Median onset-to recanalization time was 248 min (range 80-650 min). After 3 months 10/34 patients (29%) had a good clinical outcome (modified Rankin Scale, mRS 0-2). In detail, 4/18 patients (22%) with anterior circulation LAO and 6/16 patients (38%) with posterior circulation LAO were functionally independent. CONCLUSION: The use of RSA can be considered for acute intracranial LAO in cases with immediate re occlusion or high-grade stenosis after SRT alone. PMID- 29761221 TI - Interest of short implants in hip arthroplasty for osteonecrosis of the femoral head: comparative study "uncemented short" vs "cemented conventional" femoral stems. AB - PURPOSES: Osteonecrosis of the femoral head (ONFH) is a dramatic condition resulting in joint destruction in the late stages. Total hip arthroplasty allows function recovery with satisfactory implant survival. Recently, the use of uncemented short stems has been suggested to improve the conservation of bone stock. METHODS: We performed a retrospective study on 16 hip arthroplasties-11 patients-implanted for ONFH between 2008 and 2017. We aimed to compare the outcomes of the two types of arthroplasty-"uncemented short" vs "cemented conventional" femoral stem-in terms of pain (visual analogue scale), function (Harris Hip Score), and survival (radiography). RESULTS: We included six "uncemented short" and ten "cemented conventional" femoral stems. Mean pre operative EVA was 7.5 and the mean HHS was 40.3. At last follow-up of seven years, mean VAS was 1.2 (SD +/- 0.83) in the "uncemented short" group and 1.6 (SD +/- 0.97) in the "cemented conventional" group. Mean HHS was 94 (SD +/- 0.81) in the "uncemented short" group and 92.6 (SD +/- 2.69) in the "cemented conventional" group. However, radiographic analysis revealed a lower stress shielding in the "uncemented short" stem group. One complication occurred (hip dislocation in the "cemented conventional" stem group). CONCLUSION: Uncemented short stems total hip arthroplasties may be an interesting alternative to more conventional implants with similar functional results but less stress shielding and a bone stock economy in this young population of patients. PMID- 29761220 TI - Transcriptomic analysis of the harvested endothelial cells in a swine model of mechanical thrombectomy. AB - PURPOSE: In mechanical thrombectomy (MT) for ischemic stroke, endothelial cells (ECs) from intracranial blood vessels adhere to the stent retriever device and can be harvested. However, understanding the molecular biology and the role of the endothelium in different pathological conditions remains insufficient. The purpose of the study was to characterize and analyze the molecular aspect of harvested ECs using cell culture and transcriptomic techniques in an MT swine model relevant to clinical ischemic stroke. METHODS: In swine, preformed thrombi were injected into the external carotid and subclavian arteries to occlude their branches. MT was performed according to clinical routine. The stent retriever device and thrombus were treated with cell dissociation buffer. The resulting cell suspension was analyzed by immunohistochemistry and was cultured. Cultured cells were analyzed using single-cell RNA sequencing (scRNA-seq) after fluorescence-activated cell sorting (FACS). RESULTS: A total number of 37 samples were obtained containing CD31-positive cells. Cell culture was successful in 90% of samples, and the cells expressed multiple typical EC protein markers. Eighty nine percent of the sorted cells yielded high-quality transcriptomes, and single cell transcriptomes from cultured cells showed that they expressed typical endothelial gene patterns. Gene expression analysis of ECs from an occluded artery did not show distinctive clustering into subtypes. CONCLUSION: ECs harvested during MT can be cultured and analyzed using single-cell transcriptomic techniques. This analysis can be implemented in clinical practice to study the EC gene expression of comorbidities, such as hypertension, diabetes mellitus, and metabolic syndrome, in patients suffering from acute ischemic stroke. PMID- 29761222 TI - English-language videos on YouTube as a source of information on self-administer subcutaneous anti-tumour necrosis factor agent injections. AB - The aim of this study was to evaluate the reliability, content, and quality of videos for patients available on YouTube for learning how to self-administer subcutaneous anti-tumour necrosis factor (TNF) injections. We searched for the terms Humira injection, Enbrel injection, Simponi injection, and Cimzia injection. Videos were categorised as useful information, misleading information, useful patient opinion, and misleading patient opinion by two physicians. Videos were rated for quality on a 5-point global quality scale (GQS; 1 = poor quality, 5 = excellent quality) and reliability and content using the 5-point DISCERN scale (higher scores represent greater reliability and more comprehensive videos). Of the 142 English videos, 24 (16.9%) videos were classified as useful information, 6 (4.2%) as misleading information, 47 (33.1%) as useful patient opinion, and 65 (45.8%) as misleading patient opinion. Useful videos were the most comprehensive and had the highest reliability and quality scores. The useful information and useful patient opinion videos had the highest numbers of views per day (median 8.32, IQR: 3.40-14.28 and 5.46, IQR: 3.06-14.44), as compared with 2.32, IQR: 1.63-6.26 for misleading information videos and 2.15, IQR: 1.17 7.43 for misleading patient opinion videos (p = 0.001). Almost all (91.5%) misleading videos were uploaded by individual users. There are a substantial number of English-language YouTube videos, with high quality, and rich content and reliability that can be sources of information on proper technique of anti TNF self-injections. Physicians should direct patients to the reliable resources of information and educate them in online resource assessment, thereby improving treatment outcomes. PMID- 29761223 TI - Serum profile of transferrin isoforms in juvenile idiopathic arthritis: a preliminary study. AB - It is reported that alterations in protein glycosylation are present in adult rheumatic diseases; however, the data related to pediatric rheumatic conditions are very scarce. The aim of this study was to assess the effect of juvenile idiopathic arthritis (JIA) on the serum glycosylation profile of transferrin isoforms. Twenty-five patients with different clinical forms of an active JIA and 22 healthy controls were studied. Serum samples were analyzed by capillary electrophoresis on MINICAP electrophoretic system (Sebia, France) to determine the levels of transferrin isoforms. In patients with JIA, tetrasialotransferrin (median 82.6%; range 68.8-99.5) concentration was lower (P = 0.032), and pentasialotransferrin (median 14%; range 0.5-31.2) was higher (P = 0.020) in comparison to controls (median 84.45; range 79.8-87.4; median 11.55; range 9.7 16.1, respectively). No significant correlations between concentration of transferrin isoforms and disease activity score (JADAS 27) or the degree of disability (VAS and CHAQ) were found. Erythrocyte sedimentation rate and CRP levels correlated positively with disialotransferrin (R = 0.493, P = 0.017; R = 0.850, P < 0.001, respectively) and pentasialotransferrin (R = 0.533, P = 0.006; R = 0.491, P = 0.045, respectively), and negatively with trisialotransferrin (R = - 0.546, P = 0.007; R = - 0.515, P = 0.049, respectively) and tetrasialotransferrin (R = - 0.436, P = 0.029; R = - 0.504, P = 0.039, respectively). This preliminary study shows the shifts in transferrin isoforms profile among patients with JIA. Our data indicate a potential clinical utility of the transferrin isoforms measurement, especially tetrasialotransferrin and pentasialotransferrin. Further prospective studies on larger groups of patients should be conducted to validate the results. PMID- 29761224 TI - Cardiopulmonary factors affecting 6-min walk distance in patients with idiopathic inflammatory myopathies. AB - Idiopathic inflammatory myopathies involve skeletal muscles and can be associated with interstitial lung disease and/or heart dysfunction, which may reduce exercise capacity. We aimed to clarify cardiopulmonary factors affecting the 6 min walk distance in patients who were able to walk without leg pain or fatigue. Twenty-three patients with inactive adult idiopathic inflammatory myopathies, and 18 age- and gender-matched healthy controls were evaluated for hemodynamic responses using noninvasive impedance cardiography during the 6-min walk test. The patients were also examined by the pulmonary function test for forced vital capacity and diffusing capacity for carbon monoxide (DLCO), and by echocardiography for left ventricular ejection fraction and right ventricular systolic pressure. Interstitial lung disease was diagnosed in 19 patients using high-resolution computed tomography. There was no difference in 6-min walk distance or cardiac output after walking between the patients and healthy controls. However, stroke volume during the 6-min walk test was significantly lower in the patients than in healthy controls, suggesting malfunction in the heart. Moreover, the increased heart rate matched the cardiac output. Spearman's correlation analysis demonstrated a correlation between 6-min walk distance and stroke volume, cardiac output after walking and DLCO, but not left ventricular ejection fraction or right ventricular systolic pressure, as this study lacked the patients with pulmonary hypertension. In conclusion, impaired DLCO due to interstitial lung disease was suggested to be a fundamental parameter affecting exercise capacity, in addition to heart involvement, in patients with idiopathic inflammatory myopathies. PMID- 29761225 TI - Pathological characteristics and prognostic indicators of different histopathological types of urinary bladder cancer following radical cystectomy in a large single-center Egyptian cohort. AB - OBJECTIVE: To evaluate differences in pathological features and prognostics across four bladder cancer histopathological types: urothelial carcinoma (UC), urothelial carcinoma with variant histology (UCV), squamous cell carcinoma (SCC) and adenocarcinoma (ADC), utilizing a large cohort of radical cystectomy (RC) patients. METHODS: A retrospective analysis of patients who underwent RC at a single institution in Egypt between 1997 and 2004 was performed. Kaplan-Meier and multivariable analyses were performed to evaluate the prognostic significance of pathological features including tumor stage, grade, lymphovascular invasion (LVI), and lymph node (LN) involvement in the different subtypes on disease-free survival (DFS). RESULTS: 1238 patients (975 male, 263 female) were included, of whom 577 (47%) had UC, 174 (14%) UCV, 398 (32%) SCC, and 89 (7%) ADC. Median age was 54 (20-87) years and median follow-up was 40 months (0-110). There were significant differences in stage, grade, LVI, LN involvement, and presence of schistosomiasis across the subtypes (all p < 0.05). The prognostic significance of LVI was more evident in SCC (HR 2.14, p = 0.003) and ADC (HR 2.17, p = 0.044) than in UC (HR 1.66, p = 0.008). LN involvement was the strongest prognostic factor in UCV (HR 2.14, p = 0.012). CONCLUSIONS: There are significant differences in clinicopathological features and their prognostic impact across bladder cancer subtypes. The prognostic significance of LVI is more evident in SCC and ADC, while LN involvement is more prognostic in UCV. Determining independent predictors in individual subtypes can guide multimodal treatment selection and clinical trial design. PMID- 29761226 TI - Renal stone composition does not affect the outcome of percutaneous nephrolithotomy in children. AB - PURPOSE: We sought to investigate the association between renal stone composition and percutaneous nephrolithotomy outcomes in pediatric patients and define the characterization of the stone composition. METHODS: The data of 1157 children who underwent percutaneous nephrolithotomy between 1991 and 2012 were retrieved from the multicenter database of the Turkish Pediatric Urology Society. The study population comprised 359 children (160 girls, 199 boys) with stone analyses. Patients were divided into five groups according to the stone composition [group 1: calcium oxalate; group 2: calcium phosphate; group 3: infection stones (magnesium ammonium phosphate, ammonium urate); group 4: cystine; group 5: uric acid, xanthine stones]. RESULTS: Patient characteristics, perioperative, postoperative, and stone characteristics were compared considering the stone composition. There were no significant differences between the groups concerning age, sex, side involved, preoperative hematocrit levels, and solitary renal unit. Patients with cystine stones were more likely to have a history of stone treatment. Groups 2 and 5 had mostly solitary stones. However, group 3 had staghorn stone more often, and group 4 frequently had multiple stones. Overall stone-free rate (79.4%) was similar among the groups. Although stone composition was related to blood transfusion and prolonged operative and fluoroscopy screening times on univariate analysis, it was not a significant predictor of them on multivariate analysis. CONCLUSIONS: Stone composition was not a predictor of outcomes of pediatric percutaneous nephrolithotomy. However, cystine and infection stones, which are larger and filled multiple calyxes due to the nature of stone forming, were more challenging cases that need multiple tracts. PMID- 29761227 TI - Outcome of flexible ureteroscopy for renal stone with overnight ureteral catheterization: a propensity score-matching analysis. AB - PURPOSE: To evaluate the influence of overnight ureteral catheterization and determine if routine long-term post-stenting can be avoided in flexible ureterorenoscopy (fURS) procedure for kidney stone. METHODS: Three hundred ninety three patients who underwent single fURS for kidney stone between January 2013 and June 2016 at a single institute were retrospectively analyzed. The stone-free (SF) and perioperative complication rates in patients with routine long-term post stenting after fURS (long-term stent group) were compared with those of patients with overnight ureteral catheterization (short-term stent group). Propensity score-matching analysis was used to adjust the difference in baseline preoperative parameters between the two groups. All preoperative parameters were chosen to develop the propensity score, and 74 patients in the short-term stent group were retrospectively matched with the patients in the long-term stent group at a 1:1 ratio. RESULTS: Patient characteristics included age, sex, side of involvement, height, body weight, body mass index, number of stone(s), stone volume, Hounsfield units of stone, preoperative white blood cell count, preoperative C-reactive protein, preoperative creatinine, pretreatment, pre stenting, stenosis of the ureter, and procedure duration. The SF rates were 91.9 and 93.2% in the short-term and long-term stent groups, respectively. Perioperative complications were 14.9 and 12.2%. No difference was noted between the two groups in terms of SF and perioperative complication rates. CONCLUSIONS: Short-term post-stenting using overnight ureteral catheterization in uncomplicated cases after fURS for kidney stone was as effective as conventional long-term post-stenting in reducing postoperative complications. These preliminary data suggest the possibility that routine long-term post-stenting was unnecessary. PMID- 29761228 TI - Patterns of care analysis for head & neck cancer of unknown primary site: a survey inside the German society of radiation oncology (DEGRO). AB - BACKGROUND: Due to the absence of randomized trials, the optimal management for squamous cell cancer of unknown primary in the head and neck region (SCCHN CUP) remains controversial. Current strategies are based on retrospective studies, clinical experience, and institutional policies. METHODS: An anonymous questionnaire with a total of 24 questions was created and distributed by the use of an online version (Google Forms(r), Google, Mountain View, CA, USA) as well as a printout version as equivalent option. An email with a link to the survey and the questionnaire as attachment was sent to 361 DEGRO(German Society of Radiation Oncology)-associated departments. Frequency distributions of responses for each question were calculated. The data were also analyzed by type of practice. Representativity of the sample size for the DEGRO was also evaluated. RESULTS: 66 responses were received including answers from 20 (30%) university departments, 16 (24%) non-university institutions, and 30 (46%) radiation oncology practices. 95% of the participants routinely present these cases in an interdisciplinary tumor board and use intensity modulated radiotherapy (IMRT) techniques for SCCHN CUP treatment. Surgery includes neck dissection in 83% and tonsillectomy in 73% of the cases. Human papilloma virus (HPV) status is routinely determined in 82% of the departments. Statistically significant differences between universities and institutions and clinics and practices could be found with respect to positron emission tomography-computed tomography (PET-CT) utilization, indications for chemotherapy, radiotherapy volumes, and cumulative doses. CONCLUSION: Diagnostics and treatment for SCCHN CUP within the DEGRO remain heterogeneous. A prospective register trial with standard operation procedures is warranted to homogenize and possibly improve management. PMID- 29761230 TI - Ghrelin receptor signaling targets segregated clusters of neurons within the nucleus of the solitary tract. AB - Ghrelin is a stomach-derived hormone that regulates a variety of biological functions such as food intake, gastrointestinal function and blood glucose metabolism, among others. Ghrelin acts via the growth hormone secretagogue receptor (GHSR), a G-protein-coupled receptor located in key brain areas that mediate specific actions of the hormone. GHSR is highly expressed in the nucleus of the solitary tract (NTS), which is located in the medulla oblongata and controls essential functions, including orofacial, autonomic, neuroendocrine and behavioral responses. Here, we used a mouse model, in which the expression of enhanced green fluorescent protein (eGFP) is controlled by the promoter of GHSR (GHSR-eGFP mice), to gain neuroanatomical and functional insights of the GHSR expressing neurons of the NTS. We found that GHSR-expressing neurons of the NTS are segregated in clusters that were symmetrically distributed to the midline: (1) a pair of rostral clusters, and (2) a caudal and medially located cluster. We also identified that a subset of GHSR neurons of the caudal NTS are GABAergic. Finally, we found that rostral NTS GHSR neurons increase the levels of the marker of neuronal activation c-Fos in mice exposed to fasting/refeeding or high-fat diet bingeing protocols, while caudal NTS GHSR neurons increase the levels of c Fos in mice exposed to gastric distension or LiCl-induced malaise protocols. Thus, current data provide evidence that ghrelin receptor signaling seems to target segregated clusters of neurons within the NTS that, in turn, may be activated by different stimuli. PMID- 29761231 TI - New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition. AB - In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be useful for small molecule interactions with extravascularly located targets. Including target turnover, ligand-target complex kinetics and binding properties in expressions of potency and efficacy will improve our understanding of within and between individual (and across species) variability. The new expressions of potencies highlight the fact that the level of drug-induced target suppression is very much governed by target turnover properties rather than by the target expression level as such. PMID- 29761229 TI - Idiopathic Pulmonary Fibrosis Among Young Patients: Challenges in Diagnosis and Management. AB - INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is considered a disease of older patients, being rare in patients <= 50 years. Still, IPF can occur in younger patients, but this particular patient group is not well characterised so far. The aim of this study was to compare the diagnostic certainty, clinical features, comorbidities and survival in young versus older IPF patients. METHODS: We reviewed our medical records from February 2011 until February 2015, to identify IPF patients, who were then classified as young (<= 50 years) or older IPF (> 50 years). Radiographic and histological findings, lung function parameters, comorbidities, disease progression and survival were analysed and compared between the two groups. RESULTS: Of 440 patients with interstitial lung disease, 129 patients with IPF were identified, including 30 (23.3%) <=50 years and 99 (76.7%) > 50 years. There were no differences between age groups in baseline demographics; younger patients were less likely to have a confirmed diagnosis by high-resolution computed tomography (p = 0.014), more likely to require a biopsy (p = 0.08) and less likely to have received antifibrotic therapy (p = 0.006). Despite an overall limited prognosis, younger patients had a significantly better median survival after diagnosis (p = 0.0375), with a significantly higher proportion of older patients dying due to respiratory failure (p = 0.0383). CONCLUSION: IPF patients under the age of 50 years have similar features and clinical course compared to older IPF patients. These patients should be diagnosed by adopting a multidisciplinary team approach, potentially benefitting from earlier intervention with effective antifibrotic therapy. PMID- 29761233 TI - Liver transplantation: Japanese contributions. PMID- 29761232 TI - Succession of bacterial microbiota in tilapia fillets at 4 degrees C and in situ investigation of spoilers. AB - The succession of bacterial microbiota in tilapia fillets during cold storage at 4 degrees C was investigated employing PCR-DGGE method. Results showed that Pseudomonas was the most dominant genus during entire storage period. Shewanella and Psychrobacter were also always present, but became dominant only after 3 days of storage. Acinetobacter, Brevibacterium, Flavobacterium, Dietzia and Janthinobacterium were always the minor genera, among which Acinetobacter and Brevibacterium disappeared 6 days later, and Dietzia and Janthinobacterium only appeared at the end of storage. Further, the potential spoiler(s) of tilapia fillets at 4 degrees C were investigated in situ. The spoilage ability of a specific group of bacteria was evaluated as follows: Certain preservatives were selectively added to fillets to inhibit a specific group of bacteria, and then the changes in spoilage degree of fillets were determined. In this way the spoilage ability of the inhibited bacteria was evaluated. Our experiments showed that protamine strongly inhibited Pseudomonas but rarely inhibited Psychrobacter, Acinetobacter and Brevibacterium, but garlic juice, on the contrary, strongly inhibited the latter three but rarely inhibited the former. The mixed preservative, which consisted of protamine and garlic juice, didn't play better than protamine alone in preventing the spoilage of fillets. This indicated that Psychrobacter, Acinetobacter and Brevibacterium contribute little to the spoilage of tilapia fillets. PMID- 29761234 TI - Prevalence and predictors of small intestinal bacterial overgrowth in irritable bowel syndrome: a systematic review and meta-analysis. AB - BACKGROUND: The reported prevalence of small intestinal bacterial overgrowth (SIBO) among individuals with irritable bowel syndrome (IBS) is highly variable. The aim of the study is to estimate the prevalence and identify predictors of SIBO in IBS. METHODS: PubMed, Cochrane Library, and EMBASE through July 2017 were searched to identify studies evaluating the prevalence of SIBO in IBS. The pooled prevalence of SIBO among individuals with IBS and the pooled odds ratio (OR) of SIBO among those with IBS compared with healthy controls were calculated. Predictors of SIBO among IBS patients were also evaluated. RESULTS: Fifty studies (8398 IBS, 1432 controls) met the inclusion criteria. Overall pooled prevalence of SIBO in IBS was 38% (95% CI 32-44) and was higher among individuals with IBS (OR 4.7, 95% CI 3.1-7.2) compared with controls. The pooled prevalence of SIBO in IBS was higher in studies diagnosed by breath tests (40%, 95% CI 33-46) compared with cultures (19%, 95% CI 8-30). Among those with IBS, female gender (OR 1.5, 95% CI 1.0-2.1), older age (standard mean difference 3.1 years, 95% CI 0.9-5.4), and IBS-diarrhea (OR 1.7, 95% CI 1.3-2.3) compared with other IBS subtypes increased the odds of SIBO; proton pump inhibitor (PPI) use (OR 1.1, 95% CI 0.7 1.7) was not associated with SIBO. CONCLUSIONS: More than one-third of IBS patients tested positive for SIBO, and the odds of SIBO in IBS were increased by nearly fivefold. The prevalence of SIBO varied according to the diagnostic modality performed. Female gender, older age, and IBS-diarrhea, but not PPI use, were associated with SIBO among individuals with IBS. PMID- 29761235 TI - Characteristics of sports and recreation-related emergency department visits among school-age children and youth in North Carolina, 2010-2014. AB - BACKGROUND: Sports and recreational activities are an important cause of injury among children and youth, with sports-related traumatic brain injuries (TBIs) being of particular concern given the developing brain. This paper reports the characteristics of sport and recreation-related (SR) emergency department (ED) visits among school-age children and youth in a statewide population. METHODS: This study included all injury-related visits made to all North Carolina 24/7 acute-care civilian hospital-affiliated EDs by school-age youth, 5-18 years of age, during 2010-2014 (N = 918,662). Population estimates were based on US decennial census data. Poisson regression methods were used to estimate incidence rates and rate ratios. RESULTS: During the five-year period, there were 767,075 unintentional injury-related ED visits among school-age youth, of which 213,518 (27.8%) were identified as SR injuries. The average annual absolute number and incidence rate (IR) of SR ED visits among school-age youth was 42,704 and 2374.5 ED visits per 100,000 person-years (95% confidence interval [CI], 2364.4-2384.6), respectively. In comparison to other unintentional injuries among school-age youth, SR ED visits were more likely to be diagnosed with an injury to the upper extremity (Injury Proportion Ratio [IPR] = 1.28; 95% CI, 1.27-1.29), the lower extremity (IPR = 1.14; 95% CI, 1.13-1.15), and a TBI or other head/neck/facial injury (IPR = 1.12; 95% CI, 1.11-1.13). Among ED visits made by school-age youth, the leading cause of SR injury was sports/athletics played as a group or team. The leading cause of team sports/athletics injury was American tackle football among boys and soccer among girls. The proportion of ED visits diagnosed with a TBI varied by age and sex, with 15-18 year-olds and boys having the highest population-based rates. CONCLUSIONS: Sports and recreational activities are an important component of a healthy lifestyle, but they are also a major source of injury morbidity among school-age youth. Physical activity interventions should take into account sex and age differences in SR injury risk. PMID- 29761236 TI - Different pedicle osteosynthesis for thoracolumbar vertebral fractures in elderly patients. AB - INTRODUCTION: Pedicle screws' stability, especially in osteoporotic fractures, is a really problem for spinal surgeons. Nowadays, little is known about the influence of different screw types and amount of cement applied. This single center retrospective observational study has the aim of evaluating the middle- to long-term mechanical performances of different types of screws in elderly patients with thoracolumbar fractures. MATERIALS AND METHODS: A total of 91 patients (37 males and 54 females), treated between 2011 and 2016, affected by somatic osteoporotic fractures aged over 65 years were treated. We divided patients into three different populations: solid screws, cannulated screws and cannulated screws augmented with poly methyl methacrylate cement (PMMA). Patients were radiologically evaluated with X-rays in pre- and post-surgery and at the follow-up (FU). Clinical evaluations were made with VAS and Oswestry Disability Index. RESULTS: A total of 636 screws were implanted (222 pedicle screws, 190 cannulated and 224 cannulated screws with PMMA augmentation). At FU, we found significative differences between populations in terms of mechanical performances. We founded five cases of loosening; these were reported in solid screws group and in cannulated screws one. No mechanical failures were reported in cannulated screws with augmentation of PMMA. No rods breakage cases were reported. CONCLUSION: All stabilization methods showed good clinical results, but cannulated screws augmented with PMMA seem to provide better implant stability with the lowest rate of loosening. These slides can be retrieved under Electronic Supplementary Material. PMID- 29761238 TI - Cadmium sorption and extractability in tropical soils with variable charge. AB - The availability of cadmium (Cd) for plants and its impact in the environment depends on Cd sorption in soil colloids. The study of Cd sorption in soil and its fractionation is an interesting tool for the evaluation of Cd affinity with soil pools. The objective with this study was to evaluate Cd sorption and desorption in tropical soils with variable charge (three Oxisols), in a Mollisol and in two Entisols with diverse physical, chemical, and mineralogical attributes. We used a thermodynamic approach to evaluate Cd sorption and performed a chemical fractionation of Cd in the six soils. Data from Cd sorption fit the Langmuir model (r > 0.94), and the sorption capacity ranged from 0.33 to 11.5 mmol kg-1. The Gibbs standard free energy was positively correlated to Cd sorption capacity (r = 0.74, except for the Quartzipsamments), and it was more favorable in soils with great sorption capacity. Distribution of Cd among fractions was not affected (t test, alpha = 0.05) by initial concentration, and there was a predominance of Cd extractable in 0.1 mol L-1 CaCl2. PMID- 29761237 TI - Determining the Effect of pH on the Partitioning of Neutral, Cationic and Anionic Chemicals to Artificial Sebum: New Physicochemical Insight and QSPR Model. AB - PURPOSE: Sebum is an important shunt pathway for transdermal permeation and targeted delivery, but there have been limited studies on its permeation properties. Here we report a measurement and modelling study of solute partition to artificial sebum. METHODS: Equilibrium experiments were carried out for the sebum-water partition coefficients of 23 neutral, cationic and anionic compounds at different pH. RESULTS: Sebum-water partition coefficients not only depend on the hydrophobicity of the chemical but also on pH. As pH increases from 4.2 to 7.4, the partition of cationic chemicals to sebum increased rapidly. This appears to be due to increased electrostatic attraction between the cationic chemical and the fatty acids in sebum. Whereas for anionic chemicals, their sebum partition coefficients are negligibly small, which might result from their electrostatic repulsion to fatty acids. Increase in pH also resulted in a slight decrease of sebum partition of neutral chemicals. CONCLUSIONS: Based on the observed pH impact on the sebum-water partition of neutral, cationic and anionic compounds, a new quantitative structure-property relationship (QSPR) model has been proposed. This mathematical model considers the hydrophobic interaction and electrostatic interaction as the main mechanisms for the partition of neutral, cationic and anionic chemicals to sebum. PMID- 29761239 TI - Kinetics and Characterization of Non-enzymatic Fragmentation of Monoclonal Antibody Therapeutics. AB - PURPOSE: To understand non-enzymatic hydrolytic fragmentation of a monoclonal antibody therapeutic under temperature stressed conditions and investigating possible mechanism for the same. METHODS: The mAb therapeutic was incubated at 50 degrees C in phosphate buffer at pH 6.5 and fragmentation was monitored at different ionic strengths under stressed conditions. The incubated mAb was sampled at regular time intervals by analytical Size Exclusion Chromatography (SEC). RESULTS: It was observed that 57% of the mAb product fragmented over 4 days into two fragment species - Fc-Fab and Fab with molecular weights of 97 KDa and 47 KDa, respectively, as measured by mass spectrometry (MS) and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). The fragmentation rate was slow initially and then accelerated with time. No change in % aggregate level was observed in this duration, implying that degradation was primarily via fragmentation at high temperature. Kinetics of hydrolytic fragmentation was hypothesized and SEC data was fitted to estimate the kinetic rate constants. While degradation of the monomer into fragment species was non-Arrhenius with a negative activation energy, further degradation of Fab-Fc fragments into Fab or Fc fragments followed Arrhenius Law with an activation energy of 2.1 and 15.38 kcal/mol, respectively. CONCLUSION: High temperature (50 degrees C) causes mAb to cleave at the hinge region to form Fab-Fc and Fab/Fc, as confirmed by dynamic light scattering, SDS-PAGE, SEC, and MS. A kinetic model for hydrolytic fragmentation has been proposed. The results are expected to assist end users in formulation development as well as in monitoring stability of biotherapeutic products. PMID- 29761243 TI - Influence of chloride ions on the reduction of mercury species in the presence of dissolved organic matter. AB - Mercuric species, Hg(II), interacts strongly with dissolved organic matter (DOM) through the oxidation, reduction, and complexation that affect the fate, bioavailability, and cycling of mercury, Hg, in aquatic environments. Despite its importance, the reactions between Hg(II) and DOM have rarely been studied in the presence of different concentrations of chloride ions (Cl-) under anoxic conditions. Here, we report that the extent of Hg(II) reduction in the presence of the reduced DOM decreases with increasing Cl- concentrations. The rate constants of Hg(II) reduction ranged from 0.14 to 1.73 h-1 in the presence of Cl- and were lower than the rate constant (2.41 h-1) in the absence of Cl-. Using a thermodynamic model, we showed that stable Hg(II)-chloride complexes were formed in the presence of Cl-. We further examined that H(0) was oxidized to Hg(II) in the presence of the reduced DOM and Cl- under anoxic conditions, indicating that Hg(II) reduction is inhibited by the Hg(0) oxidation. Therefore, the Hg(II) reduction by the reduced DOM can be offset due to the Hg(II)-chloride complexation and Hg(0) oxidation in chloride-rich environments. These processes can significantly influence the speciation of Hg and have an important implication for the behavior of Hg under environmentally relevant concentrations. PMID- 29761242 TI - Safety and Efficacy of Benzbromarone and Febuxostat in Hyperuricemia Patients with Chronic Kidney Disease: A Prospective Pilot Study. AB - BACKGROUND: To compare the safety and efficacy of benzbromarone and febuxostat in hyperuricemia patients with estimated glomerular filtration rate (eGFR) 20-60 mL/min/1.73 m2. METHODS: This study was a single-centered, parallel-grouped, randomized clinical trial (RCT). We randomly assigned hyperuricemia participants with eGFR 20-60 mL/min/1.73 m2 into benzbromarone and febuxostat treatment group. Drugs were adjusted by titration from small doses. RESULTS: Seventy-three eligible participants enrolled, 66 subjects (33 in each group) were included finally for analysis. When compared to baseline, serum uric acid (SUA) decreased significantly after treatment in both groups, but no differences were detected among all the follow-up points. After 12-month treatment, eGFR did not have significant change in both groups. In the benzbromarone group, kidney stones in one case increased in quantity. In the febuxostat group, kidney stones in one case became smaller in size and in two cases vanished completely. Both drugs did not increase myocardial enzymes significantly after the treatment. In addition, hemoglobin increased significantly in the two groups (p < 0.05). CONCLUSIONS: Benzbromarone and febuxostat could reduce SUA and maintain renal function in chronic kidney disease (CKD) patients with eGFR 20-60 mL/min/1.73 m2. Urate lowering therapy with benzbromarone or febuxostat could increase serum hemoglobin level and potentially improve anemia. PMID- 29761241 TI - Glucocorticoids in the treatment of patients with primary focal segmental glomerulosclerosis and moderate proteinuria. AB - BACKGROUND: To compare the efficacy of glucocorticoids in primary focal segmental glomerulosclerosis (pFSGS) patients with moderate proteinuria. Registered at http://www.chictr.org.cn/ , study No. ChiCTR-OPN-17012789. METHODS: pFSGS patients with urine protein between 1.0 and 3.5 g/24 h were recruited from 2006 to 2016. No decline in urine protein > 50% was observed after 2 months of run-in angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB) treatment. Patients were assigned to study group (glucocorticoids with ACEI/ARB) or control group (ACEI/ARB without glucocorticoids). Variables including 24-h urinary protein, serum albumin and serum creatinine during the trial were recorded. Remission was defined as proteinuria < 0.3 g/24 h or declined > 50%, and our composite end point as > 30% decrease of eGFR or eGFR < 30 ml/min. RESULTS: A total of 102 patients were enrolled (study group N = 52, control group N = 50), and the median follow-up time was 36 (12-117) months without significant difference between groups. During the 12-month follow-up, the remission rate was significantly higher in study group [73.1 vs 50.0% (P = 0.01)], and the initial median response time was 3 months in the study group while 6 in the control group. The end point was reached by 22.2% cases in study group, and 42.0% in control. The medium survival times were study group 72 months and control 57 (P = 0.03). Minor adverse reactions were observed in 10 patients (study group N = 8, control group N = 2). CONCLUSIONS: Additional glucocorticoids therapy is more efficacious compared to ACEI/ARB alone in the treatment of patients with pFSGS and moderate proteinuria. PMID- 29761245 TI - Correction to: Measurement of the 15N/14N ratio of phenylalanine in fermentation matrix by isotope ratio mass spectrometry. AB - The publisher was alerted that the following important entry in the references of this article was missing. PMID- 29761244 TI - Copper-tolfenamic acid: evaluation of stability and anti-cancer activity. AB - The non-steroidal anti-inflammatory drug, Tolfenamic acid (TA) acts as an anti cancer agent in several adult and pediatric cancer models. Copper (Cu) is an important element with multiple biological functions and has gained interest in medical applications. Recently, [Cu(TA)2(bpy)] (Cu-TA) has been synthesized in order to enhance therapeutic activity. In this study, we synthesized Cu-TA using an established method, characterized it by UV visible spectroscopy and Fourier transform infrared spectroscopy (FTIR), and tested its anti-cancer activity using twelve cell lines representing various cancers, such as Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, pancreatic and prostate. The anti proliferative activity of Cu-TA was determined at 48 h post-treatment and compared with the parental compound, TA. The IC50 values were calculated using GraphPad Prism software. The biological stability of Cu-TA was evaluated using twelve-month-old powder and six-month-old stock solution. Cardiomyocytes (H9C2) were used to test the cytotoxicity in non-malignant cells. Cu-TA showed higher anti-proliferative activity, and the IC50 values were 30 to 80% lower when compared with TA. H9C2 cells were non-responsive to Cu-TA, suggesting that it is selective towards malignant cells. Comparison of the twelve-month-old powder and six-month-old stock solution using the Panc1 cell line showed similar IC50 values (<5% variation), confirming the stability of Cu-TA either in powder or solution form. These findings demonstrate the potential of Cu-TA as an effective anti cancer agent. Further studies to delineate the detailed mechanism of action of Cu TA for specific cancer model are underway. PMID- 29761246 TI - Larval antlions show a cognitive ability/hunting efficiency trade-off connected with the level of behavioural asymmetry. AB - Recently, antlion larvae with greater behavioural asymmetry were shown to have improved learning abilities. However, a major evolutionary question that remained unanswered was why this asymmetry does not increase in all individuals during development. Here, we show that a trade-off exists between learning ability of larvae and their hunting efficiency. Larvae with greater asymmetry learn better than those with less, but the latter are better able to sense vibrational signals used to detect prey and can capture prey more quickly. Both traits, learning ability and hunting efficiency, present obvious fitness advantages; the trade-off between them may explain why behavioural asymmetry, which presumably stems from brain lateralization, is relatively rare in natural antlion populations. PMID- 29761247 TI - Beneficial effects of fenofibrate in pulmonary hypertension in rats. AB - Pulmonary hypertension (PH) is a morbid complication of cardiopulmonary as well as several systemic diseases in humans. It is rapidly progressive and fatal if left untreated. In the present study, we investigated the effect of PPARalpha agonist fenofibrate (FF) on monocrotaline (MCT)-induced PH in rats. FF, because of its pleiotropic property, could be helpful in reducing inflammation, oxidative stress, and reactive oxygen species. On day 1, MCT (50 mg/kg, s.c.) was given to all the rats in MCT, sildenafil, and FF group except normal control rats. After 3 days of giving MCT, sildenafil (175 ug/kg, orally) and FF (120 mg/kg, orally) were given for 25 days. Echocardiography, hemodynamic parameters, fulton's index, histopathology, oxidative stress parameters, inflammatory markers, Bcl2/Bax gene expression ratio in the right ventricle, and protein expression for NOX-1 in lungs were studied in all the groups. FF has shown to prevent decrease in ratio of pulmonary artery acceleration time to ejection time, increase in ratio of right ventricular outflow tract dimension to aortic outflow dimension, rise in right ventricular systolic pressure, right ventricular hypertrophy, increase in the percentage medial wall thickness (%MWT), increase in oxidative stress and inflammation, increase in NADPH oxidase-1 (NOX-1) expression, and decrease in mRNA expression of Bcl2/Bax ratio caused by MCT. To conclude, FF prevented MCT induced PH in rats by various mechanisms. It might be helpful in preventing PH in patients who are likely to develop PH. PMID- 29761248 TI - Biglycan promotes the chemotherapy resistance of colon cancer by activating NF kappaB signal transduction. AB - Biglycan (BGN) is overexpressed in cancer stem cells of colon cancer and induces the activation of NF-kappaB pathway which contributes to the chemotherapy resistance of diverse cancer types. Therefore, we hypothesized that the overexpression of BGN also promoted the development of multiple drug resistance (MDR) in colon cancer via NF-kappaB pathway. The expression of BGN was bilaterally modulated in colon cancer cell lines HT-29 and SW-480 and the effect of treatments on the cell proliferation and resistance to 5-FU was assessed. Moreover, the role of NF-kappaB signaling in the BGN-mediated formation of MDR was further investigated by subjecting BGN-overexpressed SW-480 cells to the co treatment of chemo-agents and NF-kappaB inhibitor, PDTC. The inhibition of BGN expression decreased the proliferation potential of HT-29 cells while the induction of BGN expression increased the potential of SW-480 cells. BGN knockdown increased HT-29 cells' sensitivity to 5-FU, represented by the lower colony number and higher apoptotic rate. To the contrary, BGN overexpression promoted the resistance of SW-480 cells to 5-FU. The effect of BGN modulation on colon cancer cells was associated with the changes in apoptosis and NF-kappaB pathways: BGN inhibition increased the expressions of pro-apoptosis indicators and suppressed NF-kappaB pathway activity while BGN overexpression had the opposite effect. It was also found that the BGN-mediated formation of MDR was impaired when NF-kappaB pathway was blocked. Findings outlined in the current study showed that BGN contributed to the formation of chemotherapy resistance in colon cancer cells by activating NF-kappaB signaling. PMID- 29761250 TI - Sarcoma in neurofibromatosis 2: case report and review of the literature. AB - Neurofibromatosis type 2 (NF2) is associated with the development of several types of benign nervous system tumours, while malignancies are rare. We report a 22-year-old man who presented with retroperitoneal and spinal high-grade sarcomas with epithelial features. Samples showed a mixed epithelioid and spindled cell content with little associated matrix and inconclusive immunochemistry. Genetic analysis of a schwannoma and matched blood samples demonstrated a constitutional de novo substitution at the splice donor site of intron 8 of the NF2 gene and aa acquired large deletion of the entire NF2 gene as a second hit, with some loss of SMARCB1. The sarcoma also showed evidence of loss of SMARCB1 and NF2 with loss of INI1 staining. Unfortunately the mass was unresectable and the patient died 6 months after diagnosis. This malignancy was most consistent with SMARCB1 deficient epithelioid malignant peripheral nerve sheath tumour, although a significant differential was proximal-type epithelial sarcoma. Each differential has previously been reported only once with NF2. This demonstrates an extremely rare potential complication of the condition. PMID- 29761251 TI - Correlation of 99mTc sucralfate scan and endoscopic grading in caustic oesophageal injury. AB - PURPOSE: To determine a correlation between the 99mTc sucralfate scan and the endoscopy findings in children with caustic oesophageal injury. METHODS: This is an observational analytic study of children who had both 99mTc sucralfate scan and endoscopy after caustic substance ingestion at our institution in a period between January 2009 and September 2016. The oesophageal injury was classified into low grade and high grade according to the degree of adhesion on 99mTc sucralfate scan and modification of Zargar endoscopic grading. RESULTS: Out of a total of 197 children, 40 children were identified who had both investigations done on average 26 h post-injury. Low-grade adhesion on 99mTc sucralfate scan was found in 27 children (68%), and all had low-grade Zargar's oesophageal injuries. None of these subsequently developed residual pathology. Thirteen had high-grade adhesion and five of these had high-grade injury on endoscopy. Three (23%) developed oesophageal strictures. Correlation of 99mTc sucralfate and endoscopic findings reached statistical significance with a p value of 0.0014. No morbidity was associated with either the scan or endoscopy. CONCLUSIONS: We concluded that low-grade sucralfate scan finding has the potential to successfully eliminate the need for invasive endoscopy under general anaesthesia and thereby reducing procedure-related morbidity, hospitalization and associated costs. However, mandatory endoscopy is required in children with high-grade adhesion seen on 99mTc sucralfate scan. This requires confirmation using a larger prospective study. PMID- 29761249 TI - Targeting glioblastoma-derived pericytes improves chemotherapeutic outcome. AB - Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment. PMID- 29761252 TI - Testing and Treating Small Intestinal Bacterial Overgrowth Reduces Symptoms in Patients with Inflammatory Bowel Disease. AB - BACKGROUND: Common mechanisms against small intestinal bacterial overgrowth (SIBO), including an intact ileocecal valve, gastric acid secretion, intestinal motility, and an intact immune system, are compromised in inflammatory bowel disease (IBD), and therefore, a relatively high incidence of SIBO has been reported in this population. AIMS: We aimed to determine whether an improvement in IBD clinical activity scores is seen after testing and treating SIBO. METHODS: A retrospective cohort study of 147 patients with inflammatory bowel disease who were referred for SIBO breath testing from 1/2012 to 5/2016 was performed. Characteristics of SIBO positive and treated patients were compared to SIBO negative patients, including the changes in Partial Mayo Score or Harvey Bradshaw Index (HBI), using Student's t test for continuous variables and Chi-squared or Fisher's exact test for categorical variables. RESULTS: 61.9% were SIBO positive and treated, and 38.1% were SIBO negative. In Crohn's disease, the median HBI decreased from 5 to 3 and 5 to 4, in the SIBO positive and negative groups, respectively (p = 0.005). In ulcerative colitis, the Partial Mayo Score decreased from 2 to 1.5 and 2 to 1, respectively (p = 0.607). CONCLUSIONS: This study examines the clinical effect of testing and treating for SIBO in an IBD population. We see a significant reduction in HBI after testing for and treating SIBO. Future prospective studies are necessary to further investigate the role of SIBO in the evaluation and management of IBD. PMID- 29761254 TI - CatroxMP-II: a heme-modulated fibrinogenolytic metalloproteinase isolated from Crotalus atrox venom. AB - It has been recently demonstrated that the hemotoxic venom activity of several species of snakes can be inhibited by carbon monoxide (CO) or a metheme forming agent. These and other data suggest that the biometal, heme, may be attached to venom enzymes and may be modulated by CO. A novel fibrinogenolytic metalloproteinase, named CatroxMP-II, was isolated and purified from the venom of a Crotalus atrox viper, and subjected to proteolysis and mass spectroscopy. An ion similar to the predicted singly charged m/z of heme at 617.18 was identified. Lastly, CORM-2 (tricarbonyldichlororuthenium (II) dimer, a CO releasing molecule) inhibited the fibrinogenolytic effects of CatroxMP-II on coagulation kinetics in human plasma. In conclusion, we present the first example of a snake venom metalloproteinase that is heme-bound and CO-inhibited. PMID- 29761253 TI - Endoscopic Interventions in the Treatment of Obesity and Diabetes. AB - Obesity is a global health problem which is on the rise and is strongly associated with the development of type 2 diabetes and other comorbidities. Bariatric surgery is now an established treatment for both these conditions, leading to impressive results in weight loss and glycemic control. More recently, we have seen the development of various endoscopic devices as potential alternatives or adjuncts to bariatric surgery. In this state-of-the-art review, we outline the current landscape of endoscopic treatments available for the management of both obesity and diabetes, including the clinical evidence supporting their use, efficacy, safety, and potential mechanisms of action. PMID- 29761255 TI - Considering axiological integrity: a methodological analysis of qualitative evidence syntheses, and its implications for health professions education. AB - Qualitative evidence synthesis (QES) is a suite of methodologies that combine qualitative techniques with the synthesis of qualitative knowledge. They are particularly suited to medical education as these approaches pool findings from original qualitative studies, whilst paying attention to context and theoretical development. Although increasingly sophisticated use is being made of qualitative primary research methodologies in health professions education (HPE) the use of secondary qualitative reviews in HPE remains underdeveloped. This study examined QES methods applied to clinical humanism in healthcare as a way of advancing thinking around the use of QES in HPE in general. A systematic search strategy identified 49 reviews that fulfilled the inclusion criteria. Meta-study was used to develop an analytic summary of methodological characteristics, the role of theory, and the synthetic processes used in QES reviews. Fifteen reviews used a defined methodology, and 17 clearly explained the processes that led from data extraction to synthesis. Eight reviews adopted a specific theoretical perspective. Authors rarely described their reflexive relationship with their data. Epistemological positions tended to be implied rather than explicit. Twenty five reviews included some form of quality appraisal, although it was often unclear how authors acted on its results. Reviewers under-reported qualitative approaches in their review methodologies, and tended to focus on elements such as systematicity and checklist quality appraisal that were more germane to quantitative evidence synthesis. A core concern was that the axiological (value) dimensions of the source materials were rarely considered let alone accommodated in the synthesis techniques used. QES can be used in HPE research but only with careful attention to maintaining axiological integrity. PMID- 29761256 TI - Quantitative analysis of cranial-orbital changes in infants with anterior synostotic plagiocephaly. AB - PURPOSE: The effects of premature fusion of one coronal suture cause skull and orbital alterations in term of side-to-side asymmetry. This study aimed to quantify the cranio-orbital complex changes related to the severity of skull base dysmorphology in patients with unicoronal synostosis. METHODS: Twenty-four infants affected by unicoronal synostosis were subdivided in three subgroups according to the severity of skull base deformity and their high-resolution CT images were quantitatively analyzed (groups IIa, IIb, III). Dimensions of cranial fossae, intracranial volume (ICV), ICV synostotic and ICV non synostotic side, whole brain volume (WBV), orbital volumes (OV), ICV/WBV, ICVsynostotic/ICVnon synostotic, and OVsynostotic/OVnon-synostotic were evaluated. RESULTS: Asymmetry and reduction in the growth of the anterior and middle fossae were found in all groups while asymmetry of the posterior cranial fossa was found only in IIb and III groups. In all groups, ICV, WBV, and ICV/WBV were not significantly different while ICVsynostotic/ICVnon-synostotic and OVsynostotic/OVnon-synostotic resulted significant difference (p < 0.05). ICVsynostotic side resulted reduction only in group III. OV on the synostotic side was not significantly reduced although a trend in progressively reducing volumes was noted according to the severity of the group. CONCLUSION: Skull and orbital changes revealed a side-to-side asymmetry but the effects of the premature synostosis were more severe in group III suggesting an earlier timing of premature unicoronal synostosis in group III with respect to the other groups. The assessment of the skull base deformity might be an indirect parameter of severity of skull orbital changes and it might be useful for surgical planning. PMID- 29761258 TI - [Back to the roots of training and further training in anesthesiology]. PMID- 29761257 TI - Critical Places Beyond the Psychology of Well-Being and Competitiveness. AB - The purpose of the present contribution is to look beyond the limits evident in dualistic discourses in educational practices. Torn between the promises of well being or the hard facts of competitiveness, educational institutions at all levels of instruction might miss the point of a more holistic approach to learning and creativity. Looking beyond dichotomous discourses in educational practices is harder than ever, in a world where globalisation demands high standards of competitiveness and neoliberalism denies all but economic growth targets. Approaches that envision different solutions are necessarily imaginative, critical and alternative to rigid discourses. In order to find foundational evidence for alternative ways of thinking and talking about learning, I will look at how Dewian and Vygotskyan conceptualisations walk the same paths and go towards holistic suggestions. Concluding remarks will address the disruptive potential of critical thinking in schools for the future. PMID- 29761260 TI - Fetal Type Rhabdomyoma of the Soft Palate in an Adult Patient: Report of One Case and Review of the Literature. AB - Rhabdomyoma is a rare benign tumor with skeletal muscle differentiation. Rhabdomyoma is further classified into cardiac, adult, fetal, and genital subtypes. Out of these, fetal type rhabdomyoma (FTR) is the rarest. Only a small number of cases have been recorded in the literature. FTR typically affects male infants and young children and occurs predominantly in the head and neck region. FTR is exceedingly rare in the adult, with less than 30 cases reported. The classic FTR is composed of primitive undifferentiated spindle cells with scant eosinophilic cytoplasm embedded in a myxoid stroma. Immunohistochemically, the tumor cells are positive for desmin, muscle specific actin, and myogenin. Awareness and proper recognition of this rare entity is of considerable importance to avoid misdiagnosis of embryonal rhabdomyosarcoma. In this study, we report one case of FTR in an adult patient and reviewed the literature about the clinical and pathologic presentation of FTR in the adult. PMID- 29761259 TI - [Sense of Coherence Scale according to Antonovsky as a possible predictor for return to work for cardiac surgery intensive care patients]. AB - BACKGROUND: For cardiac surgery patients who were employed prior to surgery, the return to their professional life is of special importance. In addition to medical reasons, such as pre-existing conditions, the success of the operation or postoperative course and patient-intrinsic reasons, which can be assessed with the Sense of Coherence (SOC) scale by Antonovsky, may also play a role in the question of a possible return into working life. METHODS: In this study 278 patients (invasive coronary artery bypass graft surgery and/or surgery on heart valves, age < 60 years, employed) were questioned postoperatively via post with the SOC questionnaire. The SOC questionnaire was used in addition to questions about return to work. The cohort was stratified according to the time of return to work. Subsequently, the point of maximum sensitivity and specificity was determined for the total SOC score and the prediction power was considered. RESULTS: Of the 278 patients, 61 questionnaires (22%) were considered as eligible and included in the analysis. Of these, 47 participants had returned to work after undergoing cardiac surgery and 14 participants had not. We observed significant differences in SOC values between both groups (146.07 +/- 29.76 versus 124.29 +/- 28.8, p = 0.020). Patients that returned to work within the first 6 months after surgery showed even higher SOC scores (148.56 +/- 28.98, p = 0.034). CONCLUSION: Patients with an SOC score < 130 are at greater risk not to return to their professional life after cardiac surgery. The SOC is an easily obtainable score that reliably predicts the probability of return to work after cardiac surgery. PMID- 29761261 TI - Editorial: Single Anastomosis Procedures, IFSO Position Statement. PMID- 29761262 TI - Correction to: Comparison of Early Morbidity and Mortality Between Sleeve Gastrectomy and Gastric Bypass in High-Risk Patients for Liver Disease: Analysis of American College of Surgeons National Surgical Quality Improvement Program. AB - The authors regret that some of the article text, which was in the original manuscript and was intended for and addressed to the reviewers during the review process of this article, was mistakenly overlooked during the proofs stage and remains in the published article. PMID- 29761263 TI - Measuring the Health of an Invisible Population: Lessons from the Colorado Transgender Health Survey. AB - BACKGROUND: Transgender people, those whose gender identity does not match their sex assigned at birth, face barriers to receiving health care. These include discrimination, prohibitive cost, and difficulty finding transgender-inclusive providers. As transgender identities are not typically recognized in public health research, the ability to compare the health of the transgender population to the overall population is limited. OBJECTIVE: The Colorado Transgender Health Survey sought to explore current disparities and their effects on the health of transgender people in Colorado. DESIGN AND PARTICIPANTS: The Colorado Transgender Health Survey, based on the Behavioral Risk Factor Surveillance System (BRFSS), was developed by the Colorado Department of Public Health and Environment, transgender advocates, and transgender community members. Outreach was targeted to transgender-inclusive events and organizations. MAIN MEASURES: Responses to the 2014 Colorado Transgender Health Survey were compared side by side to Colorado 2014 BRFSS data. RESULTS: Results from 406 transgender or gender nonconforming adults who live in Colorado were included in the analysis. Forty percent of respondents report delaying medical care due to cost, inadequate insurance, and/or fear of discrimination. Respondents report significant mental health concerns, with 43% reporting depression, 36% reporting suicidal thoughts, and 10% attempting suicide in the past year. Respondents with a transgender inclusive provider were more likely to receive wellness exams (76 versus 48%), less likely to delay care due to discrimination (24 versus 42%), less depressed (38 versus 54%), and less likely to attempt suicide (7 versus 15%) than those without. CONCLUSIONS: The transgender community in Colorado faces significant disparities, especially around mental health. However, a transgender-inclusive provider is associated with improved mental and physical health and health behaviors. Further population-level research and provider education on transgender health should to be incorporated into national efforts to eliminate health disparities. PMID- 29761264 TI - Concise Research Report: The Future of Medicaid: State Legislator Views on Policy Waivers. PMID- 29761266 TI - Evaluation of thyroid gland as an organ at risk after breast cancer radiotherapy: a systematic review and meta-analysis. AB - BACKGROUND: Radiotherapy can often lead to thyroid dysfunction. Some studies demonstrated that treatment of breast cancer by RT can expose thyroid gland to high doses of radiation. The aim of this systematic review is to evaluate consideration of thyroid gland as an organ at risk. METHODS: In this systematic review and meta-analysis to select initial studies, a comprehensive search by two independent reviewers was performed. Electronical databases following: Web of Science, Google Scholar, Scopus, PubMed, Elsevier, Embase, ProQuest and Persian databases such as Iranmedex, Magiran, and SID were searched. All searches were restricted to English language between 1985 and 2017. A random effect meta analysis is applied to estimate pooled effect size across initial studies. Funnel plot with Egger's test is used to assess potential publication bias. RESULTS: Totally, five studies (478 samples) were included in meta-analysis. The meta analyses of result showed that thyroid gland is affected by radiotherapy significantly and the TSH increased after radiotherapy (z = 2.68, P = 0.007). The pooled estimate of difference mean for TSH was 0.90 (95% CI 0.24, 1.55). In studies among patients with breast cancer RT, hypothyroidism was reported more than other thyroid disorders. There was not showed possibility publication bias among studies (P > 0.05). CONCLUSION: This study demonstrated that thyroid gland is affected by radiotherapy significantly and the TSH increased after radiotherapy. Protecting thyroid gland during radiation and follow-up of patients with breast cancer RT are suggested for the assessment of thyroid gland dysfunction. PMID- 29761267 TI - Porcine FcepsilonRI Mediates Porcine Reproductive and Respiratory Syndrome Virus Multiplication and Regulates the Inflammatory Reaction. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) shows characteristic antibody-dependent enhancement (ADE) of infection and causes porcine systemic inflammation, which is similar to a type I allergic reaction; however, the role of porcine FcepsilonRI in ADE is still unclear. In this study, the expression of different Fc receptors (FcRs) on macrophages was investigated in a PRRSV 3D4/21 cell infection model in the presence or absence of PRRSV antibody. The transcription level of FcgammaII and FcepsilonRI was significantly up-regulated under PRRSV-antibody complex infection. Internalization and proliferation of PRRSV were promoted by the ADE mechanism when FcepsilonRI was expressed in permissive 3D4/21 cells and the non-permissive cell line HEK 293T. Transcriptome sequencing data showed that the expression levels of AKT, ERK and other signal molecules in the anti-inflammatory pathway were significantly increased, especially in the cells infected with the PRRSV-antibody immune complex. Inflammatory regulatory molecules such as PLA2G6, LOX, TRPM8 and TRPM4 were significantly up-regulated following PRRSV infection but significantly down regulated in the cells infected with the PRRSV-antibody immune complex. Our results demonstrated that FcepsilonRI could be involved in PRRSV ADE, the antigen presenting process and regulation of the inflammatory response during PRRSV infection, which provides new insights into PRRSV infection mediated by FcepsilonRI and the PRRSV-antibody immune complex. PMID- 29761269 TI - Effects of running a marathon on irisin concentration in men aged over 50. AB - Our aim was to verify whether running a marathon is associated with changes in irisin concentration in healthy, endurance-trained men. In an observational study, we assessed baseline biochemical and fitness parameters of 28 middle-aged runners (mean +/- SD age, BMI, VO2max: 58 +/- 8 years; 24.5 +/- 3 kg/m2; 51.1 +/- 1.7 ml/kg/min). We evaluated irisin before, immediately after, and 7 days after the marathon. Irisin concentration decreased from a baseline value of 639 +/- 427 to 461 +/- 255 ng/ml immediately after the marathon (p < 0.05). After 7 days, it was still significantly lower than before the race, at 432 +/- 146 ng/ml (p < 0.05). We found no correlations between irisin concentration and the training history of the studied subjects. We conclude that a long-distance run may have a negative impact on irisin release in men. This effect was not correlated with the training history of runners. PMID- 29761270 TI - Functional emergence of a column-like architecture in layer 5 of mouse somatosensory cortex in vivo. AB - To investigate how the functional architecture is organized in layer 5 (L5) of the somatosensory cortex of a mouse in vivo, the input-output relationship was investigated using an all-optical approach. The neural activity in L5 was optically recorded using a Ca2+ sensor, R-CaMP2, through a microprism inserted in the cortex under two-photon microscopy, while the L5 was regionally excited using optogenetics. The excitability was spread around the blue-light irradiated region, but the horizontal propagation was limited to within a certain distance (lambda < 130 MUm from the center of the illumination spot). When two regions were photostimulated with a short interval, the excitability of each cluster was reduced. Therefore, a column-like architecture had functionally emerged with reciprocal inhibition through a minimal number of synaptic relays. This could generate a synchronous output from a region of L5 with simultaneous enhancement of the signal-to-noise ratio by silencing of the neighboring regions. PMID- 29761268 TI - Towards a comprehensive picture of C-to-U RNA editing sites in angiosperm mitochondria. AB - KEY MESSAGE: Our understanding of the dynamic and evolution of RNA editing in angiosperms is in part limited by the few editing sites identified to date. This study identified 10,217 editing sites from 17 diverse angiosperms. Our analyses confirmed the universality of certain features of RNA editing, and offer new evidence behind the loss of editing sites in angiosperms. RNA editing is a post transcriptional process that substitutes cytidines (C) for uridines (U) in organellar transcripts of angiosperms. These substitutions mostly take place in mitochondrial messenger RNAs at specific positions called editing sites. By means of publicly available RNA-seq data, this study identified 10,217 editing sites in mitochondrial protein-coding genes of 17 diverse angiosperms. Even though other types of mismatches were also identified, we did not find evidence of non canonical editing processes. The results showed an uneven distribution of editing sites among species, genes, and codon positions. The analyses revealed that editing sites were conserved across angiosperms but there were some species specific sites. Non-synonymous editing sites were particularly highly conserved (~ 80%) across the plant species and were efficiently edited (80% editing extent). In contrast, editing sites at third codon positions were poorly conserved (~ 30%) and only partially edited (~ 40% editing extent). We found that the loss of editing sites along angiosperm evolution is mainly occurring by replacing editing sites with thymidines, instead of a degradation of the editing recognition motif around editing sites. Consecutive and highly conserved editing sites had been replaced by thymidines as result of retroprocessing, by which edited transcripts are reverse transcribed to cDNA and then integrated into the genome by homologous recombination. This phenomenon was more pronounced in eudicots, and in the gene cox1. These results suggest that retroprocessing is a widespread driving force underlying the loss of editing sites in angiosperm mitochondria. PMID- 29761271 TI - Multiple coronary stenting negatively affects myocardial recovery after coronary bypass grafting. AB - OBJECTIVES: We aimed to elucidate the relationship between the magnitude of myocardial recovery after coronary artery bypass grafting (CABG) and the prognosis and to explore the predictors of myocardial non-recovery. METHODS: Eighty-one patients with a preoperative left ventricular ejection fraction (LVEF) <= 40% who underwent isolated CABG between 2002 and 2015 and had undergone echocardiographic follow-up (median follow-up, 3.1 years; interquartile range 1.2 6.0 years) were analyzed. The Recovery group comprised patients with LVEF improvement >= 10%, whereas the Non-recovery group comprised those with an LVEF improvement < 10%. Group differences in overall survival, freedom from major adverse cardiac events (MACEs), and readmission due to heart failure were evaluated. In addition, the risk factors for LVEF non-recovery were evaluated in a multivariate analysis. RESULTS: A total of 39 patients (48%) were in the Recovery group, whereas 42 patients (52%) were in the Non-recovery group. Although the survival and freedom from MACE rates were comparable, the rate of freedom from heart failure requiring hospitalization at 1, 5, and 8 years of follow-up was significantly lower in the Non-recovery group than in the Recovery group (p = 0.012). A history of percutaneous coronary intervention (PCI) was an exclusive independent risk factor for post-CABG myocardial non-recovery (odds ratio, 16.0; 95% confidence interval, 3.44-125). Furthermore, the number of coronary stents was negatively correlated with LVEF recovery (r = - 0.460, p = 0.024). CONCLUSIONS: Great consideration should be taken when performing CABG in patients with left ventricular dysfunction and a history of PCI, particularly in those with multiple coronary stents. PMID- 29761272 TI - Primary paraesophageal hernia repair with Gore(r) Bio-A(r) tissue reinforcement: long-term outcomes and association of BMI and recurrence. AB - BACKGROUND: Laparoscopic repair remains the gold-standard treatment for paraesophageal hernia (PEH). We analyzed long-term symptomatic outcomes and surgical reintervention rates after primary PEH repair with onlay synthetic bioabsorbable mesh (W. L. Gore & Associates, Inc., Flagstaff, AZ) and examined body mass index (BMI) as a possible risk factor for poor outcomes and for recurrence. METHODS: We queried a prospectively maintained database to identify patients who underwent laparoscopic primary PEH repair with onlay patch of a bioprosthetic absorbable mesh (Bio-A(r) Gore(r)) between 05/28/2009 and 12/31/2013. Electronic health records were accessed to record demographic and operative data and were reviewed up to the present to identify any repeat procedures. Patients were grouped according to preoperative BMI (A: BMI < 25; B: BMI = 25-29.9; C: BMI = 30-34.9; D: BMI >= 35). Patients completed standardized satisfaction and symptom surveys. RESULTS: In total, 399 patients were included. Most patients (n = 261; 65.4%) were women. Mean age was 59.6 +/- 13.4 years; mean BMI was 29.9 +/- 5.0 kg/m2. The patients were grouped as follows: A, 53 patients (13.3%); B, 166 (41.6%); C, 115 (28.8%); D: 65 (16.3%). Four procedures (1.0%) were converted from laparoscopy to open procedures. All patients underwent an antireflux procedure (225 Nissen, 170 Toupet, 4 Dor). A mean follow-up of 44.7 +/ 22.8 months was available for 305 patients (76.4%). 24/305 patients (7.9%) underwent reoperation, and the number of reoperations did not differ among groups (P = 0.64). Long-term symptomatic outcomes were available for 217/305 patients (71.1%) at a mean follow-up of 54.0 +/- 13.1 months; no significant difference was observed among groups. 194/217 patients (89.4%) reported good to excellent satisfaction, with no significant differences among the groups. CONCLUSIONS: Laparoscopic primary PEH repair with onlay Bio-A(r) mesh is a safe and feasible procedure with excellent long-term patient-centered outcomes and acceptable symptomatic recurrence rate. BMI does not appear to be related to the need for surgical reintervention. PMID- 29761273 TI - A randomised trial of observational learning from 2D and 3D models in robotically assisted surgery. AB - BACKGROUND: Advances in 3D technology mean that both robotic surgical devices and surgical simulators can now incorporate stereoscopic viewing capabilities. While depth information may benefit robotic surgical performance, it is unclear whether 3D viewing also aids skill acquisition when learning from observing others. As observational learning plays a major role in surgical skills training, this study aimed to evaluate whether 3D viewing provides learning benefits in a robotically assisted surgical task. METHODS: 90 medical students were assigned to either (1) 2D or (2) 3D observation of a consultant surgeon performing a training task on the daVinci S robotic system, or (3) a no observation control, in a randomised parallel design. Subsequent performance and instrument movement metrics were assessed immediately following observation and at one-week retention. RESULTS: Both 2D and 3D groups outperformed no observation controls following the observation intervention (ps < 0.05), but there was no difference between 2D and 3D groups at any of the timepoints. There was also no difference in movement parameters between groups. CONCLUSIONS: While 3D viewing systems may have beneficial effects for surgical performance, these results suggest that depth information has limited utility during observational learning of surgical skills in novices. The task constraints and end goals may provide more important information for learning than the relative motion of surgical instruments in 3D space. PMID- 29761274 TI - Lower intra-abdominal pressure has no cardiopulmonary benefits during laparoscopic colorectal surgery: a double-blind, randomized controlled trial. AB - BACKGROUND: Higher intra-abdominal pressure may impair cardiopulmonary functions during laparoscopic surgery. While 12-15 mmHg is generally recommended as a standard pressure, the benefits of lower intra-abdominal pressure are unclear. We thus studied whether the low intra-abdominal pressure compared with the standard pressure improves cardiopulmonary dynamics during laparoscopic surgery. METHODS: Patients were randomized according to the intra-abdominal pressure and neuromuscular blocking levels during laparoscopic colorectal surgery: low pressure (8 mmHg) with deep-block (post-tetanic count 1-2), standard pressure (12 mmHg) with deep-block, and standard pressure with moderate-block (train-of-four count 1-2) groups. During the laparoscopic procedure, we recorded cardiopulmonary variables including cardiac index, pulmonary compliance, and surgical conditions. We also assessed postoperative pain intensity and recovery time of bowel movement. The primary outcome was the cardiac index 30 min after onset of laparoscopy. RESULTS: Patients were included in the low pressure with deep-block (n = 44), standard pressure with deep-block (n = 44), and standard pressure with moderate-block (n = 43) groups. The mean (SD) of cardiac index 30 min after laparoscopy was 2.7 (0.7), 2.7 (0.9), and 2.6 (1.0) L min-1 m-2 in each group (P = 0.715). The pulmonary compliance was higher but the surgical condition was poorer in the low intra-abdominal pressure than the standard pressure (both P < 0.001). Other variables were comparable between groups. CONCLUSION: We observed few cardiopulmonary benefits but poor surgical conditions in the low intra abdominal pressure during laparoscopy. Considering cardiopulmonary dynamics and surgical conditions, the standard intra-abdominal pressure may be preferable to the low pressure for laparoscopic surgery. PMID- 29761275 TI - Quantitative transrectal shear wave elastography undergoing salvage extraperitoneal laparoscopic radical prostatectomy following failed radiotherapy. AB - BACKGROUND: To evaluate pre-surgical quantitative transrectal shear wave elastography (SWE) in the detection and characterisation of radioresistant prostate cancer. METHODS: Twelve men with recurrent prostate cancer following external beam radiotherapy were included in a prospective protocol-driven study. All underwent MR imaging and quantitative shear wave elastographic assessment of recurrent disease prior to salvage laparoscopic radical prostatectomy procedures. Images were used to construct 3D mold printing and histopathological processing of surgical specimen. Statistical analyses including ROC were generated using software programmes. RESULTS: There were 48 cancer foci identified on final histopathology using patient-specific mold-based approach in 12 patients. Mean number of lesion was 3.4 (range 2-4). Quantitative transrectal SWE showed a sensitivity and specificity 0.77 (95% CI 0.627-0.880) and 0.82 (95% CI 0.642 0.942), respectively. The diagnostic accuracy increased with increasing size of the lesions with overall AUC of 0.89. CONCLUSIONS: In our series, quantitative transrectal SWE showed a good diagnostic accuracy in the detection and characterisation of recurrent prostate cancer following failed radiotherapy treatment. These findings may help in targeting biopsies or future focal treatment options. PMID- 29761277 TI - Treatment of differentiated thyroid cancer: can endoscopic thyroidectomy via a chest-breast approach achieve similar therapeutic effects as open surgery? AB - BACKGROUND: An analysis of some special factors was performed to further evaluate and discuss whether endoscopic surgery and traditional open surgery have similar therapeutic outcomes for differentiated thyroid cancer (DTC). METHODS: A retrospective study was performed on 76 patients undergoing surgery to treat DTC. Forty patients were treated by endoscopic thyroidectomy via the chest-breast approach (endoscopic group) and thirty-six patients were treated by open surgery (open group). Serum thyroglobulin (sTg), radioactive iodine uptake (RAIU), radioactive technetium uptake (RATU), radionuclide imaging of the thyroid residual area (RITRA), radionuclide imaging of suspicious lymph nodes metastasis (RISLNM), and other general indexes were analyzed and compared between the two groups. RESULTS: All surgeries were successfully completed in both groups. There were no significant differences between the two groups regarding gender (P = 0.120), postoperative hospital stay (P = 0.766), operation time (P = 0.065), intra-operative blood loss (P = 0.064), tumor diameter (P = 0.059), and overall complications (P = 0.828). Among these complications, there was no significant difference between the two approaches in transient hypoparathryoidism (P = 0.771), transient recurrent laryngeal injury (P = 0.474) and serious neck skin traction sensation (2.5 vs. 0%, P = 1.000). Age and body mass index were lower in the endoscopic group than the open group (P < 0.05). No significant difference was found in special factors between two groups concerning surgical range (P = 0.872), RAIU-2 h/24 h (P = 0.660/P = 0.955), RATU (P = 0.116), number of dissected lymph nodes (P = 0.157), sTg before radioiodine therapy (P = 0.188), sTg after radioiodine therapy (P = 0.159), RITRA at different time points (99mTc 15 min: P = 0.144; 131I 24 h: P = 0.243; 131I 72 h: P = 0.624) and RISLNM (none: P = 0.805; central: P = 0.744; lateral: P = 1.000; central + lateral: P = 0.958). CONCLUSION: Endoscopic total thyroidectomy and central lymph nodes dissection via a chest-breast approach are safe and effective. Through the detection of the postoperative special factors, a well-trained surgeon can achieve similar therapeutic results for selected patients with DTC, compared with open surgery. PMID- 29761278 TI - Laparoscopic totally extraperitoneal (TEP) inguinal hernia repair in patients with previous lower abdominal surgery. AB - BACKGROUND: We have performed laparoscopic totally extraperitoneal (TEP) repair for inguinal hernia repair for the last 20 years. We use two balloon dilators (sphere and kidney type) to dissect the preperitoneal space for the TEP repair. It may be difficult to obtain exposure in patients who previously underwent lower abdominal surgery, because of adhesions to the abdominal wall. We reviewed our experience with inguinal hernia repairs to retrospectively analyze factors that limit the laparoscopic TEP approach. METHODS: From 2006 to 2016, 313 patients (281 men and 32 women) underwent laparoscopic TEP inguinal hernia repair at Yuki Hospital. The medical records of these patients were reviewed, and data for patients who previously underwent lower abdominal surgery were analyzed. RESULTS: Eighty-four patients previously underwent lower abdominal surgery including appendectomy (N = 23), inguinal hernia repair [N = 45; including contralateral TEP repair (N = 26), ipsilateral anterior approach (N = 11)], and laparotomy with a lower abdominal midline incision (N = 22). TEP repair was successfully completed in 75 patients (75/84; 89%) and the procedure changed in nine patients to an anterior approach (N = 5), or transabdominal preperitoneal (TAPP) repair (N = 4). The reasons for changing the procedure included difficulty to develop the operative field (N = 5), violation of the integrity of the peritoneal envelope (N = 2), and intraoperative bleeding (N = 2). Seven patients had a contralateral inguinal hernia after TEP repair. CONCLUSION: The majority of patients with an inguinal hernia and previous lower abdominal surgery underwent successful laparoscopic TEP repair. There is no need to avoid the laparoscopic TEP approach, even in patients with a history of previous lower abdominal surgery. However, patients after TEP repair of a contralateral inguinal hernia may be at increased risk for peritoneal injury and the approach may need to be changed. PMID- 29761279 TI - Recurrence patterns after laparoscopic resection of colorectal liver metastases. AB - BACKGROUND: The major issue after liver resection for colorectal liver metastases (CRLM) is the high incidence of recurrence. Unlike open liver resection (OLR), recurrence following laparoscopic liver resection (LLR) is not well documented. The aim of this study was to analyze recurrence patterns and treatment following LLR for CRLM. STUDY DESIGN: All patients who underwent LLR for CRLM from 2000 to 2016 were reviewed. Patients who presented with recurrence were compared to those who did not. Recurrence-free survival (RFS), overall survival (OS), and risk of recurrence and survival prognostic factors were analyzed. RESULTS: Overall, 273 patients were included, of which 157 (57.5%) were treated for one liver metastasis (LM). Median follow-up was 41 (12-187) months and associated extrahepatic disease was present in 27% of patients (mainly pulmonary, 65%). After a median of 16 (3-151) months, 197 (72%) patients presented with recurrence. Recurrences were early (< 6 months) in 22.8% of cases, occured in a single site in 66% and were intrahepatic, extrahepatic, or both in 44, 30, and 26%, respectively. Recurrences were treated with surgery or chemotherapy only in 45 and 47%, respectively. 3-, 5-, and 10-year OS was 82, 71, and 43%, respectively. Independent risk factors for recurrence were node-positive primary tumor, extrahepatic disease before hepatectomy, and R1 resection. CONCLUSION: LLR for CRLM does not seem to be associated with distinctive recurrence patterns. LLR for CRLM yielded satisfying RFS and OS and should therefore be considered whenever possible. PMID- 29761276 TI - Does robotic rectal cancer surgery improve the results of experienced laparoscopic surgeons? An observational single institution study comparing 168 robotic assisted with 184 laparoscopic rectal resections. AB - BACKGROUND: The role of robotic assistance in colorectal cancer surgery has not been established yet. We compared the results of robotic assisted with those of laparoscopic rectal resections done by two surgeons experienced in laparoscopic as well as in robotic rectal cancer surgery. METHODS: Two surgeons who were already experienced laparoscopic colorectal surgeons in 2005 started robotic surgery with the daVinci SI system in 2012. All their rectal cancer resections between 2005 and 2015 were retrieved from a prospectively recorded colorectal database of routinely collected patient data. Multi-organ resections were excluded. Patient data, diagnostic data, data on preceding operations and neoadjuvant treatment, perioperative and operative data, logistic data, and short term outcomes were gathered. Multivariable analyses (multiple linear and logistic regression) were used to assess differences in several outcomes between the two resection methods while adjusting for all potential confounders we could identify. Results are presented as adjusted mean differences for continuous outcome variables or as adjusted odds ratios (OR) for dichotomous outcome variables. RESULTS: Three hundred and fifty-two patients with rectal cancers were identified: 168 robotic and 184 conventional laparoscopic cases, 178 operated by surgeon A and 174 operated by surgeon B. Adjusted mean operation time was 215 min in the robotic group which was 40 min (95% CI 24-56; p < 0.0005) longer than the 175 min in the laparoscopic group. Robotic treatment had significantly lesser numbers of conversions (OR 0.09 (0.03-0.32); p < 0.0005) and other complications (SSI and anastomic leakage excluded) (OR 0.32 (0.15-0.69); p = 0.004), adjusted for potential confounders. CONCLUSIONS: Our study suggests that robotic surgery in the hands of experienced laparoscopic rectal cancer surgeons improves the conversion rate and complication rate drastically compared to conventional laparoscopic surgery, but operation time is longer. PMID- 29761280 TI - Adverse effects of media reports on the treatment of osteoporosis. AB - PURPOSE: The review focused on the role that media reporting plays in the level of public awareness about osteoporosis and its influence on osteoporosis treatment decisions. METHODS: We reviewed the literature on the role of media on three main aspects influencing patient adherence to osteoporosis treatment: the awareness of osteoporosis as a major health problem, the perception of the effectiveness of osteoporosis medications, and the fear of adverse effects with osteoporosis medications. RESULTS: A review of the literature confirmed what is routinely observed in clinical practice-that media report can strongly influence the level of awareness of osteoporosis and fracture risk. Inadequate and/or incorrect information on osteoporosis in the media are associated with a low level of awareness of the disease. High-risk patients may have a poor understanding of the need for treatment. Alarming information in the media over the last 2 decades regarding effectiveness and safety of long-term osteoporosis treatment is associated with reduction in the use of osteoporosis medications. CONCLUSIONS: There is a gap between the application of clinical recommendations and patient perceptions of osteoporosis and its treatment. There is a need for better education of patients and practitioners aimed at recognizing the serious consequences of fractures and understanding the expected benefits and potential risks of treatment. Media reports that disseminate evidence-based information on the balance of benefits and risks could help to reduce the osteoporosis treatment gap and mitigate the crisis in osteoporosis care. PMID- 29761281 TI - Characteristics, Quality and Contribution to Signal Detection of Spontaneous Reports of Adverse Drug Reactions Via the WEB-RADR Mobile Application: A Descriptive Cross-Sectional Study. AB - INTRODUCTION: Spontaneous reporting of suspected adverse drug reactions is key for efficient post-marketing safety surveillance. To increase usability and accessibility of reporting tools, the Web-Recognising Adverse Drug Reactions (WEB RADR) consortium developed a smartphone application (app) based on a simplified reporting form. OBJECTIVE: The objective of this study was to evaluate the characteristics, quality and contribution to signals of reports submitted via the WEB-RADR app. METHODS: The app was launched in the UK, the Netherlands and Croatia between July 2015 and May 2016. Spontaneous reports submitted until September 2016 with a single reporter were included. For each country, app reports and reports received through conventional means in the same time period were compared to identify characteristic features. A random subset of reports was assessed for clinical quality and completeness. The contribution to signal detection was assessed by a descriptive analysis. RESULTS: Higher proportions of app reports were submitted by patients in the UK (28 vs. 18%) and Croatia (32 vs. 7%); both p < 0.01. In the Netherlands, the difference was small (60 vs. 57%; p = 0.5). The proportion of female patients and the median patient ages in app reports submitted by patients were similar to the reference. The proportion of reports of at least moderate quality was high in both samples (app: 78-85%, reference: 78-98%), for all countries. App reports contributed to detecting eight potential safety signals at the national level, four of which were eventually signalled. CONCLUSION: The WEB-RADR app offers a new route of spontaneous reporting that shows promise in attracting reports from patients and that could become an important tool in the future. Patient demographics are similar to conventional routes, report quality is sufficient despite a simplified reporting form, and app reports show potential in contributing to signal detection. PMID- 29761284 TI - Hurricane by Proxy. PMID- 29761283 TI - Cardiovascular Disease in the Nation's Capital: How Policy and the Built Environment Contribute to Disparities in CVD Risk Factors in Washington, D.C. AB - On average, Washington D.C. residents experience low levels of cardiovascular disease (CVD) behavioral risk factors compared to the rest of the country. Despite presenting as a city of low risk, CVD mortality is higher than the national average. Driving this inconsistency are vast racial disparities as Black D.C. residents die from CVD at a much higher rate than their White counterparts. A closer examination of the data also reveals significant disparities between White and Black populations with regard to behavioral risk factors. Segregation and the built environments of sections of the city with large Black populations may be contributing to risk factor disparities. We examine factors in those built environments that contribute to disparities and assess the intentionality and effectiveness of policies focused on food access, physical activity, and tobacco use implemented between 2003 and 2014. We found that D.C. enacted few policies intentionally designed to reduce barriers in the physical environment that contributed to disparate outcomes, and the few that were implemented showed mixed results in their levels of effectiveness. Our findings demonstrated that both racial and geographical disparities have persisted for more than a decade and half. It is possible that the formation of intentional policies may help reduce barriers in the physical environment and disparate CVD outcomes. PMID- 29761285 TI - Understanding Health Disparities Through the Eyes of Community Members: a Structural Competency Education Intervention. PMID- 29761286 TI - A Qualitative Analysis of Stress and Relaxation Themes Contributing to Burnout in First-Year Psychiatry and Medicine Residents. AB - OBJECTIVE: Qualitative research on trainee well-being can add nuance to the understanding of propagators of burnout, and the role for interventions aimed at supporting well-being. This qualitative study was conducted to identify (i) situations and environments that cause stress for trainees, (ii) stress-reducing activities that trainees utilize, and (iii) whether trainees who report distress (high burnout and depression scores) describe different stressors and relaxation factors than those who do not. METHODS: The study was conducted with a convenience sample of first-year medicine and psychiatry residents at a large urban teaching hospital. Participants were asked to complete electronic stress and relaxation diaries daily for 1 week. Diary entries were coded for recurrent themes. Participants were screened for burnout and depression. Codes were compared by subgroup based on baseline burnout and depression status to elucidate if specific themes emerged in these subgroups. RESULTS: Study sample included 51 interns. Sixteen (16/50, 32%) screened positive for burnout and three (3/50, 14%) had a positive depression screen. The most common stressors related to aspects of the learning environment, compounded by feeling under-equipped, overwhelmed, or out of time. The majority of relaxation activities involved social connection, food, other comforts, and occurred outside of the hospital environment. CONCLUSIONS: This study reveals that interns (regardless of burnout or depression screen) identify stressors that derive primarily from organizational, interpersonal, and cultural experiences of the learning environment; whereas relaxation themes are diversely represented across realms (home, leisure, social, health), though emphasize activities that occur outside of the work place. PMID- 29761288 TI - The Handmaid's Tale. Hulu. Season 1 (April-June 2017). Television. PMID- 29761287 TI - Activation of the mTORC1 pathway by inflammation contributes to vascular calcification in patients with end-stage renal disease. AB - BACKGROUND: Chronic inflammation plays an important role in the progression of vascular calcification (VC). This study was designed to explore the effects and underlying mechanisms of inflammation on VC in the radial arteries of patients with end-stage renal disease (ESRD) with arteriovenostomy. METHODS: Forty-eight ESRD patients were divided into control (n = 25) and inflammation groups (n = 23) according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in this study. Alizarin Red S staining was used to examine calcium deposition. The expression of inflammation markers, bone structure-associated proteins and mammalian target of rapamycin complex1 (mTORC1) pathway-related proteins was assessed by immunohistochemical staining. RESULTS: The expression of tumor necrosis factor-alpha (TNF-alpha) and monocyte chemotactic protein-1 (MCP-1) was increased in the radial arteries of the inflammation group. Additionally, Alizarin Red S staining revealed a marked increase in calcium deposition in the inflammation group compared to controls. Further analysis by immunohistochemical staining demonstrated that the deposition was correlated with the increased expression of bone-associated proteins such as bone morphogenetic proteins-2 (BMP 2) and osteocalcin and collagen I, which suggested that inflammation induces osteogenic differentiation in vascular tissues and that osteogenic cells are the main cellular components involved in VC. Interestingly, there was a parallel increase in the expression of phosphorylated mTOR (p-mTOR) and pribosomal protein S6 kinase 1 (p-S6K1) in the inflammation group. Furthermore, mTORC1 pathway related proteins were significantly associated with the enhanced expression of bone formation biomarkers. CONCLUSIONS: Inflammation contributed to VC in the radial arteries of ESRD patients via the induction of osteogenic differentiation in vessel walls, which could be regulated by the activation of the mTORC1 pathway. PMID- 29761290 TI - Isolation and functional characterization of a floral repressor, BcFLC2, from Pak choi (Brassica rapa ssp. chinensis). AB - MAIN CONCLUSION: BcFLC2 functioned as a repressor of flowering by directly regulating BcTEM1, BcMAF2, BcSOC1 and BcSPL15 in Pak-choi. FLOWERING LOCUS C (FLC) plays an important role in regulating flowering time. Here, we functionally described an FLC homologous gene, BcFLC2, that negatively regulated flowering in Pak-choi (Brassica rapa ssp. chinensis). The sequence comparison to Arabidopsis FLC showed that BcFLC2 also had a MADS-box domain at the N terminus. BcFLC2 was highly expressed in the leaves, roots, stems and stamens, and its expression was repressed by vernalization in Pak-choi. Interestingly, BcFLC2 expression exhibited a small peak at 2 weeks of vernalization treatment, suggesting that BcFLC2 may be involved in preventing premature flowering under short-term cold exposure in Pak-choi, which is different from the AtFLC expression pattern. Overexpression of BcFLC2 in Arabidopsis caused late flowering, while silencing of BcFLC2 in Pak-choi caused early flowering. BcFLC2 localized to the cell nucleus and functioned as a transcription factor. Yeast one-hybrid analysis revealed that BcFLC2 could bind to the promoters of Pak-choi Tempranillo 1 (BcTEM1), SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (BcSOC1), SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 15 (BcSPL15) and MADS AFFECTING FLOWERING 2 (BcMAF2). Taken together, the present results suggested that BcFLC2 played a key role in flowering regulation as a negative regulator by controlling BcTEM1, BcMAF2, BcSOC1 and BcSPL15 expression. PMID- 29761289 TI - Prevalence and Risk Factors for Diabetes Mellitus in Nigeria: A Systematic Review and Meta-Analysis. AB - INTRODUCTION: There has been no nationwide health (diabetes) survey in Nigeria since 1992, when a diabetes mellitus (DM) prevalence of 2.2% was reported. We aimed to determine the prevalence of and risk factors for DM in Nigeria by performing a systematic review and meta-analysis. METHODS: We searched Medline, EMBASE, PubMed, PapersFirst, the Cochrane Library, Scopus, Bioline, African Journals Online, Institute of Scientific Information, and Google Scholar from the year 1990 to 2017. Using MeSH headings, the terms "diabetes mellitus," "risk factors," "prevalence," and "Nigeria" as well as variations thereof were searched for. The last search was performed on 26 November 2017. We only included studies that utilized the random plasma glucose test, the fasting plasma glucose test, the oral glucose tolerance test (OGTT), or HbA1c to diagnose DM. A total of 23 studies (n = 14,650 persons) were evaluated. A random effects model was used to estimate the pooled prevalence of DM. We estimated the overall pooled prevalence of DM and subgroup-specific DM prevalences while accounting for inter-study and intra-study variability/heterogeneity. RESULTS: The overall pooled prevalence of DM was 5.77% (95% CI 4.3-7.1). The pooled prevalences of DM in the six geopolitical zones of Nigeria were 3.0% (95% CI 1.7-4.3) in the north-west, 5.9% (95% CI 2.4-9.4) in the north-east, 3.8% (95% CI 2.9-4.7) in the north-central zone, 5.5% (95% CI 4.0-7.1) in the south-west, 4.6% (95% CI 3.4-5.9) in the south east, and 9.8% (95% CI 7.2-12.4) in the south-south zone. Risk factors for the pooled prevalence of DM were a family history of DM (4.6%; 95% CI 3.5-5.6); urban dwelling (6.0%; 95% CI 4.3-7.8); unhealthy dietary habits (8.0%; 95% CI 5.4 10.5); cigarette smoking (4.4%; 95% CI 1.3-10.2); older age (6.6%; 95% CI 4.5 8.7); physical inactivity (4.8%; 95% CI 3.2-6.4); and obesity (5.3%; 95% CI 3.8 6.9). CONCLUSION: There has been an increase in the prevalence of DM in Nigeria. All regions of the country have been affected, with the highest prevalence seen in the south-south geopolitical zone. Urban dwelling, physical inactivity, advanced age, and unhealthy diet are important risk factors for DM among Nigerians. A national diabetes care and prevention policy is highly recommended. PMID- 29761292 TI - [Chronic hepatitis B and D (delta) : Current and future treatments]. AB - BACKGROUND: Worldwide, hepatitis B virus (HBV) infection is among the 30 leading causes of death, despite effective vaccination and therapeutic options. Chronic hepatitis delta (coinfection with hepatitis D virus) leads to a rapid disease progression. AIMS: Based on current international guidelines and studies, an overview about present and future therapeutic options for chronic hepatitis B and delta is provided. RESULTS: Therapy with nucleoside or nucleotide analogues leads to nearly complete HBV DNA suppression, which is associated with regression of liver fibrosis and a lower risk for the development of hepatocellular carcinoma. Therapy of chronic hepatitis delta with pegylated interferon alfa achieves only low response rates with high risk for virological relapse. Various therapeutic approaches are currently being investigated in preclinical and clinical studies and have led to a significant reduction of hepatitis B surface antigen (HBsAg) and HDV RNA. CONCLUSION: Current therapies of chronic HBV infection can effectively reduce subsequent complications. New therapeutic approaches promise functional cure (HBsAg loss) of HBV infection and effective treatment options for patients with chronic hepatitis delta. PMID- 29761291 TI - Adherence to Highly Active Antiretroviral Therapy Among Children in Ethiopia: A Systematic Review and Meta-analysis. AB - Adherence to highly active antiretroviral therapy (HAART) is the mainstay of the strategy in reducing morbidity and mortality of HIV-infected children. Different primary studies were conducted in Ethiopia. Thus, we aimed to conduct a meta analysis of the national prevalence of optimal adherence to HAART in children. In addition, associated factors of HAART adherence were reviewed. A weighted inverse variance random-effects model was applied. The 88.7 and 93.7% of children were adhering to HAART at 07 and 03 days prior to an interview respectively. The subgroup analysis showed that HAART adherence was 93.4% in Amhara, 90.1% in Addis Ababa and 87.3% in Tigray at 07 days prior to an interview. Our study suggests that, within short window reported time, adherence to HAART in Ethiopian children may be in a good progress. Emphasis on specific adherence interventions need further based on individual predictors to improve overall HAART adherence of children. PMID- 29761294 TI - Monoclonal antibodies for migraine: an update. PMID- 29761293 TI - Stable but Progressive Nature of Heart Failure: Considerations for Primary Care Physicians. AB - Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients' quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including beta-blockers and inhibitors of the renin angiotensin-aldosterone system. Recently, two new HF treatments have become available in clinical practice. Ivabradine was approved to reduce the risk of hospitalization for HF in patients with stable, symptomatic HF. Additionally, the angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, was found to be significantly superior to enalapril in reducing risks of cardiovascular death and HF-related hospitalization. The respective 2016 and 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America clinical practice guideline updates recommend that patients taking angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy be switched to ARNI therapy to further reduce morbidity and mortality. For HF management to be maximally effective, physicians must be knowledgeable about the risks and benefits of treatments and stay engaged with patients to identify signs of disease progression. This article provides an overview of the progressive nature of HF in apparently stable patients and describes areas for treatment improvement that may help to optimize patient care. PMID- 29761295 TI - A startling acoustic stimulus facilitates voluntary lower extremity movements and automatic postural responses in people with chronic stroke. AB - A startling acoustic stimulus (SAS) involuntary releases prepared movements at accelerated latencies, known as the StartReact effect. Previous work has demonstrated intact StartReact in paretic upper extremity movements in people after stroke, suggesting preserved motor preparation. The question remains whether motor preparation of lower extremity movements is also unaffected after stroke. Here, we investigated StartReact effects on ballistic lower extremity movements and on automatic postural responses (APRs) following perturbations to standing balance. These APRs are particularly interesting as they are critical to prevent a fall following balance perturbations, but show substantial delays and poor muscle coordination after stroke. Twelve chronic stroke patients and 12 healthy controls performed voluntary ankle dorsiflexion movements in response to a visual stimulus, and responded to backward balance perturbations evoking APRs. Twenty-five percent of all trials contained a SAS (120 dB) simultaneously with the visual stimulus or balance perturbation. As expected, in the absence of a SAS muscle and movement onset latencies at the paretic side were delayed compared to the non-paretic leg and to controls. The SAS accelerated ankle dorsiflexion onsets in both the legs of the stroke subjects and in controls. Following perturbations, the SAS accelerated bilateral APR onsets not only in controls, but for the first time, we also demonstrated this effect in people after stroke. Moreover, APR inter- and intra-limb muscle coordination was rather weak in our stroke subjects, but substantially improved when the SAS was applied. These findings show preserved movement preparation, suggesting that there is residual (subcortical) capacity for motor recovery. PMID- 29761296 TI - Neuroimaging in Lewy body dementia. AB - Lewy body dementia (DLB) is a common form of cognitive impairment, accounting for 30% of dementia cases in ages over 65 years. Early diagnosis of DLB has been challenging; particularly in the context of differentiation with Parkinson's disease dementia and other forms of dementias, such as Alzheimer's disease and rapidly progressive dementias. Current practice involves the use of [123I]FP-CIT SPECT, [18F]FDG PET and [123I]MIBG molecular imaging to support diagnostic procedures. Structural imaging techniques have an essential role for excluding structural causes, which could lead to a DLB-like phenotype, as well as aiding differential diagnosis through illustrating disease-specific patterns of atrophy. Novel PET molecular imaging modalities, such as amyloid and tau imaging, may provide further insights into DLB pathophysiology and may aid in early diagnosis. A multimodal approach, through combining various established techniques and possibly using novel radioligands, might further aid towards an in-depth understanding of this highly disabling disease. In this review, we will provide an overview of neuroimaging applications in patients with DLB. PMID- 29761297 TI - Severe neurologic complications of immune checkpoint inhibitors: a single-center review. AB - BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising class of anticancer drugs associated with immune-related adverse events (IRAEs). In registration studies of selected cancer populations, neurologic IRAEs were rare. Post-marketing experience describing their prevalence in clinical practice continues to be reported. METHODS: A retrospective cohort of patients treated at our institution with ICIs from 2005 to 2017 was identified. Patients with new neurologic ICD codes documented during or after ICI treatment were enrolled. Comprehensive medical record review identified patients with neurologic IRAEs causally linked to ICIs. This study focused on CTCAE grade 2-4 IRAEs. RESULTS: 526 patients were screened; 55 candidate patients were identified; 5 cases met criteria for neurologic IRAEs, an incidence of 0.95% (n = 5/526). IRAEs identified were transverse myelopathy, demyelinating sensorimotor polyneuropathy, oculomotor nerve palsy, sensory neuropathy, and posterior reversible encephalopathy syndrome. ICIs were held in three patients, rechallenged in one, and dose-reduced in one. Corticosteroids were given in three patients, and response varied from complete symptom resolution to minimal response and ultimately death. Other treatments were based on IRAE presentation, including gabapentin, antihypertensives, and IV immunoglobulin. Patients with combination therapy appeared to suffer more severe IRAEs producing more substantial long-term morbidity and mortality. CONCLUSION: In this clinical practice study, the incidence of neurologic IRAEs from ICIs was 0.95%. Although rare, neurologic IRAEs can be highly variable and severe, and patients with combination immunotherapy appeared to suffer more severe IRAEs. Neurologists play an important role in the early identification and management of IRAEs to reduce long term morbidity and mortality. PMID- 29761300 TI - Natural Selection and Drift as Individual-Level Causes of Evolution. AB - In this paper I critically evaluate Reisman and Forber's (Philos Sci 72(5):1113 1123, 2005) arguments that drift and natural selection are population-level causes of evolution based on what they call the manipulation condition. Although I agree that this condition is an important step for identifying causes for evolutionary change, it is insufficient. Following Woodward, I argue that the invariance of a relationship is another crucial parameter to take into consideration for causal explanations. Starting from Reisman and Forber's example on drift and after having briefly presented the criterion of invariance, I show that once both the manipulation condition and the criterion of invariance are taken into account, drift, in this example, should better be understood as an individual-level rather than a population-level cause. Later, I concede that it is legitimate to interpret natural selection and drift as population-level causes when they rely on genuinely indeterministic events and some cases of frequency dependent selection. PMID- 29761298 TI - Lumbar muscle atrophy caused by harness replacement in a chronic calf model of total artificial heart implantation. AB - The postoperative care of animals implanted with mechanical circulatory support devices is complex. The standard of care requires continuous monitoring of hemodynamic parameters post implant, wound care, and maintenance of the animal's well-being, but also includes controlling the animal's biomechanics under conditions of continuous restraint and harnessing. In such studies, a harness provides secure fixation of the exteriorized device driveline and pressure lines and aids animal handling (lifting, position adjustment, and assistance with standing up). Harnessing is a key element in large-animal surgery. It affects the animal's conditions, safety, and post-procedure troubleshooting and thus may drastically worsen postoperative outcomes if improperly handled. Here we report a case associated with an unplanned harness replacement in a chronic animal model implanted with the Cleveland Clinic continuous-flow total artificial heart. Inadvertent changes to the harness resulted in posture change caused by muscular atrophy of the calf's spine that had been under long-term harness support. PMID- 29761299 TI - VEGFA and VEGFR2 RNAscope determination in gastric cancer. AB - Gastric cancer is the fifth most common cancer and third leading cause of cancer related death worldwide. Several studies on angiogenic blocking agents in gastric cancer revealing promising results by the use of monoclonal antibodies against VEGFA or its receptor VEGFR2 or against VEGFA activating pathway. The validation of biomarkers useful to better organize the clinical trials involving anti angiogenic therapies is crucial. Molecular markers such as RNA are increasingly used for cancer diagnosis, prognosis, and therapy guidance as in the case of the targeted therapies concerning the inhibition of angiogenesis. The aim of this study is to set the conditions for evaluating the expression of VEGFA and VEGFR2 in gastric cancer specimens and in healthy gastric mucosa by the use of RNAscope, a novel RNA in situ hybridization (ISH) method that allows the visualization of a specific gene expression in individual cells. We found the increased expression of VEGFA in the tubular glands and VEGFR2 in the endothelium of gastric cancer samples mainly in the T2, T3 and T4 stages of tumor progression as compared to the healthy controls. These results obtained by the application of this highly sensitive method for oligonucleotide detection the role of angiogenesis in gastric cancer progression already highlighted by conventional immunohistochemical methods, and offer significant promise as a new platform for developing and implementing RNA-based molecular diagnostics also in the conditions in which immunohistochemistry is not applicable. PMID- 29761301 TI - Importance of Initial Concentration of Factor VIII in a Mechanistic Model of In Vitro Coagulation. AB - This computational study generates a hypothesis for the coagulation protein whose initial concentration greatly influences the course of coagulation. Many clinical malignancies of blood coagulation arise due to abnormal initial concentrations of coagulation factors. Sensitivity analysis of mechanistic models of blood coagulation is a convenient method to assess the effect of such abnormalities. Accordingly, the study presents sensitivity analysis, with respect to initial concentrations, of a recently developed mechanistic model of blood coagulation. Both the model and parameters to which model sensitivity is being analyzed provide newer insights into blood coagulation: the model incorporates distinct equations for plasma-phase and platelet membrane-bound species, and sensitivity to initial concentrations is a new dimension in sensitivity analysis. The results show that model predictions are most uncertain with respect to changes in initial concentration of factor VIII, and this hypothesis is supported by results from other models developed independently. PMID- 29761304 TI - Metal Accumulation Strategies of Emergent Plants in Natural Wetland Ecosystems Contaminated with Coke-Oven Effluent. AB - The release of industrial effluents into natural wetlands is a ubiquitous problem worldwide, and phytoremediation could be a viable option for treatment. The present study assessed metal accumulation strategies of three dominant emergent plants [Colocasia esculenta (L.) Schott, Scirpus grossus (L.) f., and Typha latifolia L.] growing in a wetland contaminated with coke-oven effluent. Metals concentration (mg kg-1) in wetland sediment followed the order Mn (408) > Cu (97) > Co (14.2) > Cr (14) > Cd (2.7). Plant tissues (root and shoot) showed metal specific accumulation at different extents due to plant response against metal utility or toxicity. Bioconcentration factor (BCF) and translocation factor (TF) of metals in plants revealed Cd and Mn pollution could be remediated through phytoextraction (BCF > 1 and TF > 1); however, Co, Cu, and Cr pollution could be remediated through phytostabilization (BCF > 1 and TF < 1). PMID- 29761303 TI - Racial differences in the relationship between tobacco, alcohol, and the risk of head and neck cancer: pooled analysis of US studies in the INHANCE Consortium. AB - There have been few published studies on differences between Blacks and Whites in the estimated effects of alcohol and tobacco use on the incidence of head and neck cancer (HNC) in the United States. Previous studies have been limited by small numbers of Blacks. Using pooled data from 13 US case-control studies of oral, pharyngeal, and laryngeal cancers in the International Head and Neck Cancer Epidemiology Consortium, this study comprised a large number of Black HNC cases (n = 975). Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for several tobacco and alcohol consumption characteristics. Blacks were found to have consistently stronger associations than Whites for the majority of tobacco consumption variables. For example, compared to never smokers, Blacks who smoked cigarettes for > 30 years had an OR 4.53 (95% CI 3.22-6.39), which was larger than that observed in Whites (OR 3.01, 95% CI 2.73-3.33; pinteraction < 0.0001). The ORs for alcohol use were also larger among Blacks compared to Whites. Exclusion of oropharyngeal cases attenuated the racial differences in tobacco use associations but not alcohol use associations. These findings suggest modest racial differences exist in the association of HNC risk with tobacco and alcohol consumption. PMID- 29761302 TI - CFTR prevents neuronal apoptosis following cerebral ischemia reperfusion via regulating mitochondrial oxidative stress. AB - : The cystic fibrosis transmembrane conductance regulator (CFTR) is linked to cell apoptosis and abundantly expressed in brain tissue. Mitochondrial oxidative stress plays a key role in activating apoptotic pathway following cerebral ischemia reperfusion (IR) injury. Reduced glutathione (GSH) is exclusively synthesized in cytosol but distributed in mitochondria. In the present study, we investigated whether CFTR affected mitochondrial oxidative stress via regulating GSH and thereby protected neurons against apoptosis following cerebral IR. Brains were subjected to global IR by four-vessel occlusion and CFTR activator forskolin (FSK) was used in vivo. CFTR silence was performed in vitro for neurons by RNA interference. We found that FSK suppressed neuronal apoptosis whereas CFTR silence enhanced neuronal apoptosis. FSK prevented the elevations in reactive oxygen species (ROS) and caspase activities while FSK inhibited the reductions in complex I activity and mitochondrial GSH level following IR. FSK decreased mitochondrial oxidative stress partially and preserved mitochondrial function. On the contrary, CFTR silence exaggerated mitochondrial dysfunction. CFTR loss increased hydrogen peroxide (H2O2) level and decreased GSH level in mitochondria. Importantly, we showed that CFTR was located on mitochondrial membrane. GSH transport assay suggested that GSH decrease may be a consequence not a reason for mitochondrial oxidative stress mediated by CFTR disruption. Our results highlight the central role of CFTR in the pathogenesis of cerebral IR injury. CFTR regulates neuronal apoptosis following cerebral IR via mitochondrial oxidative stress-dependent pathway. The mechanism of CFTR-mediated mitochondrial oxidative stress needs further studies. KEY MESSAGES: CFTR activation protects brain tissue against IR-induced apoptosis and oxidative stress. CFTR disruption enhances H2O2 induced neuronal apoptosis and CFTR loss leads to mitochondrial oxidative stress. CFTR regulates IR-induced neuronal apoptosis via mitochondrial oxidative stress. CFTR may be a potential therapeutic target to cerebral IR damage. PMID- 29761305 TI - UV-B susceptibility and photoreactivation in embryonic development of the two spotted spider mite, Tetranychus urticae. AB - Developmental errors are often induced in the embryos of many organisms by environmental stress. Ultraviolet-B radiation (UV-B) is one of the most serious environmental stressors in embryonic development. Here, we investigated susceptibility to UV-B (0.5 kJ m-2) in embryos of the two-spotted spider mite, Tetranychus urticae, to examine the potential use of UV-B in control of this important agricultural pest worldwide. Peak susceptibility to UV-B (0% hatchability) was found in T. urticae eggs 36-48 h after oviposition at 25 degrees C, which coincides with the stages of morphogenesis forming the germ band and initial limb primordia. However, hatchability recovered to ~ 80% when eggs irradiated with UV-B were subsequently exposed to visible radiation (VIS) at 10.2 kJ m-2, driving photoreactivation (the photoenzymatic repair of DNA damage). The recovery effect decreased to 40-70% hatchability, depending on the embryonic developmental stage, when VIS irradiation was delayed for 4 h after the end of exposure to UV-B. Thus UV-B damage to T. urticae embryos is critical, particularly in the early stages of morphogenesis, and photoreactivation functions to mitigate UV-B damage, even in the susceptible stages, but immediate VIS irradiation is needed after exposure to UV-B. These findings suggest that nighttime irradiation with UV-B can effectively kill T. urticae eggs without subsequent photoreactivation and may be useful in the physical control of this species. PMID- 29761308 TI - Can positron emission tomography help stratify the risk of sudden cardiac death in patients with hypertrophic cardiomyopathy? PMID- 29761306 TI - Low expression of CD40L in tumor-free lymph node of oral cavity cancer related with poor prognosis. AB - BACKGROUND: Recently, the genetic alterations associated with tumor progression and impaired host immunity against transformed cells draw increased attention. Here, we characterized the differential gene expression patterns and protein expression in tumor-free lymph node from recurrent and non-recurrent tumors to identify independent prognostic markers for oral squamous cell carcinoma (OSCC). METHODS: A cDNA microarray analysis was performed to identify the differentially expressed genes in regional tumor-free lymph nodes from OSCC patients with and without recurrence. Then, the protein expression of the selected genes was analyzed by immunohistochemistry in 60 OSCC patients to determine their association with survival. RESULTS: Widespread down-regulation of genes involved in antigen processing and recognition in lymph nodes was a distinctive feature. In univariate Kaplan-Meier analysis, lower expression of CD40L and CD80 in tumor free lymph nodes was significantly correlated with poorer survival. In multivariate Cox regression analysis, CD40L was identified as an independent prognostic marker of disease-free survival. CONCLUSION: Our data indicate that impaired host immunity (decreased CD40L expression) along with the TNM staging might be an important factor determining the prognosis of OSCC. PMID- 29761307 TI - Intravesical bacillus Calmette-Guerin therapy after second transurethral resection for primary T1 bladder cancer. AB - BACKGROUND: To evaluate the effect of intravesical bacillus Calmette-Guerin (BCG) instillation therapy after second transurethral resection (TUR) on primary T1 bladder cancer. METHODS: The subjects were 180 patients diagnosed with T1 bladder cancer at our university and at affiliated hospitals between January 1990 and December 2015. Tumor residual rate, intravesical recurrence rate, and risk factors for intravesical recurrence were investigated. RESULTS: The median follow up period was 26 (1-175) months. Of the 180 patients, 78 (43%) underwent a second TUR. Residual tumors were detected in 42 patients (53.8%), and no up-staging cases were observed. Within the whole group, 42 patients were treated with intravesical BCG therapy following a second TUR (group 1), 36 were treated with second TUR alone (group 2), 28 were treated with intravesical BCG therapy alone (group 3), and 74 were treated without second TUR or intravesical BCG therapy (group 4). The 1- and 5-year recurrence-free survival rates of the four groups were 80.7 and 59.7% (group 1), 69.0 and 26.3% (group 2), 76.3 and 56.6% (group 3), 64.6 and 48.6% (group 4), respectively. There was no significant difference between group 1 and group 3 (p = 0.401). Intravesical BCG therapy was the only factor preventing intravesical recurrence (p = 0.013). CONCLUSIONS: Intravesical BCG therapy alone showed a significant preventive effect with regard to intravesical recurrence. In our cohort, however, second TUR did not improve recurrence-free survival in those individuals who underwent BCG instillation. PMID- 29761309 TI - Is there a role for cardiac positron emission tomography in hypertrophic cardiomyopathy? AB - Coronary microvascular dysfunction and, its functional consequence, myocardial ischemia are common pathologic features in patients with hypertrophic cardiomyopathy (HCM). Both have been commonly invoked as potential triggers of and/or contributors to the underlying pathophysiological processes leading to heart failure, and malignant ventricular arrhythmias. Positron emission tomography (PET) with myocardial blood flow quantification provides a unique opportunity to evaluate the integrity and function of the coronary microcirculation in HCM. The purpose of the present review is to summarize all the pertinent literature and future perspectives of the role of PET in the evaluation and risk stratification of patients with HCM. PMID- 29761310 TI - Characteristics of patients with a relatively greater minimum VE/VCO2 against peak VO2% and impaired exercise tolerance. AB - PURPOSE: Cardiopulmonary exercise testing (CPX) is used to evaluate functional capacity and assess prognosis in cardiac patients. Ventilatory efficiency (VE/VCO2) reflects ventilation-perfusion mismatch; the minimum VE/VCO2 value (minVE/VCO2) is representative of pulmonary arterial blood flow in individuals without pulmonary disease. Usually, minVE/VCO2 has a strong relationship with the peak oxygen uptake (VO2), but dissociation can occur. Therefore, we investigated the relationship between minVE/VCO2 and predicted peak VO2 (peak VO2%) and evaluated the parameters associated with a discrepancy between these two parameters. METHODS: A total of 289 Japanese patients underwent CPX using a cycle ergometer with ramp protocols between 2013 and 2014. Among these, 174 patients with a peak VO2% lower than 70% were enrolled. Patients were divided into groups based on their minVE/VCO2 [Low group: minVE/VCO2 < mean - SD (38.8-5.6); High group: minVE/VCO2 > mean + SD (38.8 + 5.6)]. The characteristics and cardiac function at rest, evaluated using echocardiography, were compared between groups. RESULTS: The High group had a significantly lower ejection fraction, stroke volume, and cardiac output, and higher brain natriuretic peptide, tricuspid regurgitation pressure gradient, right ventricular systolic pressure, and peak early diastolic LV filling velocity/peak atrial filling velocity ratio compared with the Low group (p's < 0.01). In addition, the Low group had a significantly higher prevalence of pleural effusion than did the High group (26 vs 11%, p < 0.01). CONCLUSIONS: Patients with a relatively greater minVE/VCO2 in comparison with peak VO2 had impaired cardiac output as well as restricted pulmonary blood flow increase during exercise, partly due to accumulated pleural effusion. PMID- 29761311 TI - Comparison of fatigue responses and rapid force characteristics between explosive and traditional-resistance-trained males. AB - PURPOSE: To compare maximal and rapid force characteristics, as well as fatigability, between traditional (TRT) and explosive (ERT) resistance-trained men. METHODS: Fourteen TRT (mean age = 25 years) and twelve ERT (mean age = 22 years) men performed rapid maximal contractions followed by an isokinetic fatigue protocol consisting of 50 maximal knee extension (KE) and flexions (KF) at a moderate speed (180 degrees s-1). Baseline measures included: isokinetic peak torque (PT), isometric rate of torque development (RTD0-50), peak acceleration (ACCmax), and peak velocity (Vmax). Changes in torque with fatigue were used to calculate a fatigue index (FI%). RESULTS: The ERT group (M +/- SD; 1199.05 +/- 404.12) displayed a significantly higher isometric RTD0-50 (p = 0.049) during KE than the TRT group (931.73 +/- 244.75). No other significant differences in the dependent variables (PT, FI%, ACCmax, Vmax; all p >= 0.05) were observed between groups (TRT vs. ERT) for either of the muscle groups (KE and KF). CONCLUSIONS: The results of the present study indicated that only knee extension RTD was able to discriminate between the two groups. These findings suggest that rapid force production may be more sensitive at distinguishing training-specific muscular adaptations than peak acceleration or velocity. PMID- 29761313 TI - Genomewide DNA Methylation Responses in Patients with beta-Thalassemia Treated with Yisui Shengxue Granules (). AB - OBJECTIVE: To examine the clinical effects of Yisui Shengxue Granules () in the treatment of beta-thalassemia and explore its mechanism on DNA methylation levels. METHODS: A randomized placebo-controlled double-blinded trial was conducted. Forty patients with beta-thalassemia were recruited and distributed randomly by envelope method into an experimental group and a control group, 20 patients in each group. The patients were given Yisui Shengxue Granules in the experimental group and placebo in the control group (12 g/bag three times a day) during a 3-month intervention. Before and after 1, 2, and 3 months of treatment, peripheral intravenous blood was sampled, and blood parameters such as hemoglobin (Hb), red blood cells (RBCs), reticulocytes (Ret), and fetal hemoglobin (HbF) were analyzed. Mononuclear cells from 5 patients, who showed an obvious treatment effect, were isolated by density gradient centrifugation. DNA methylation was analyzed using an Affymetrix USA GeneChip Human Promoter 1.0 Array and Input promoter 1.0. RESULTS: Compared with pre-treatment, there was an obvious increase in Hb and RBCs counts after 1, 2, and 3 months in the experiment group (P<0.01 or P<0.05). Meanwhile, HbF increased from the 2nd to the 3rd month (P<0.05). In the control group, Hb and RBCs showed no obvioas change. After 3-month treatment, DNA methylation results from 5 patients revealed that there were 24 hypomethylated genes and 3,685 hypermethylated genes compared with pre-treatment. Genes of insulin-like growth factor 1 receptor (IGF1R) and Janus kinase 3 (JAK3) revealed the most relations with other genes (degree: 21) and genes of 1 phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma 2 (PLCG2) and mitogen-activated protein kinase 10 (MAPK10) showed a stronger intermediary role (betweenness centrality=0.04). CONCLUSIONS: JAK3 and MAPK10 are two key genes in bone marrow and the lymphatic system, and JAK3 is likely to be related to hematopoietic cytokines in the process of early hematopoiesis. (Registration No. NCT01549080). PMID- 29761314 TI - PCL-Based Composite Scaffold Matrices for Tissue Engineering Applications. AB - Biomaterial-based scaffolds are important cues in tissue engineering (TE) applications. Recent advances in TE have led to the development of suitable scaffold architecture for various tissue defects. In this narrative review on polycaprolactone (PCL), we have discussed in detail about the synthesis of PCL, various properties and most recent advances of using PCL and PCL blended with either natural or synthetic polymers and ceramic materials for TE applications. Further, various forms of PCL scaffolds such as porous, films and fibrous have been discussed along with the stem cells and their sources employed in various tissue repair strategies. Overall, the present review affords an insight into the properties and applications of PCL in various tissue engineering applications. PMID- 29761312 TI - Recovery of upper-body muscle power after short intensive exercise: comparing boys and men. AB - PURPOSE: Boys' lower-body muscle power generation (PO) recovers faster than men's following intensive exercise. The purpose of this study was to examine whether boys differ from adult men in recovering from upper-body muscle power generation following intensive exercise. METHODS: Fifteen prepubertal boys (M +/- SD age 10.6 +/- 1.0 years) and 13 men (31.1 +/- 5.0 years) performed two upper-body Wingate Anaerobic Tests (WAnT), separated by either 2-min or 10-min recovery intervals. WAnT parameters, pre-and post-WAnT heart rates (HR), and blood lactate ([La]) were measured during recovery from the WAnTs. RESULTS: Boys' mean power (MP) of the repeated WAnT (WAnT2) following 2- and 10-min recoveries was 97.3 +/- 7.2% and 99.4 +/- 3.9%, respectively, compared to MP of the first test (WAnT1) (p > 0.05 for both tests). In contrast, in men's MP of the WAnT2 following the 2-min recovery, was significantly lower than that of the WAnT1 (84.4 +/- 6.7%, p = 0.0001). While boys' and men's HR recovery after 2 min differed significantly (p = 0.046), no between-group differences were found following the 10-min recovery. Peak [La] in boys was 37-44% lower than that in men (p = 0.002). CONCLUSIONS: The faster recovery of PO in boys after supra-maximal upper-body exercise is partially explained by the lower power generated by boys, attributed in part to a lower anaerobic capacity and to the greater relative contribution of aerobic processes to performance and recovery from anaerobic-type tasks. Further research is needed to determine the physiologic, neurologic and biochemical basis of the rapid muscle power recovery in children. PMID- 29761315 TI - Hair detection and lesion segmentation in dermoscopic images using domain knowledge. AB - Automated segmentation and dermoscopic hair detection are one of the significant challenges in computer-aided diagnosis (CAD) of melanocytic lesions. Additionally, due to the presence of artifacts and variation in skin texture and smooth lesion boundaries, the accuracy of such methods gets hampered. The objective of this research is to develop an automated hair detection and lesion segmentation algorithm using lesion-specific properties to improve the accuracy. The aforementioned objective is achieved in two ways. Firstly, a novel hair detection algorithm is designed by considering the properties of dermoscopic hair. Second, a novel chroma-based geometric deformable model is used to effectively differentiate the lesion from the surrounding skin. The speed function incorporates the chrominance properties of the lesion to stop evolution at the lesion boundary. Automatic initialization of the initial contour and chrominance-based speed function aids in providing robust and flexible segmentation. The proposed approach is tested on 200 images from PH2 and 900 images from ISBI 2016 datasets. Average accuracy, sensitivity, specificity, and overlap scores of 93.4, 87.6, 95.3, and 11.52% respectively are obtained for the PH2 dataset. Similarly, the proposed method resulted in average accuracy, sensitivity, specificity, and overlap scores of 94.6, 82.4, 97.2, and 7.20% respectively for the ISBI 2016 dataset. Statistical and quantitative analyses prove the reliability of the algorithm for incorporation in CAD systems. Graphical Abstract Overview of proposed system. PMID- 29761316 TI - Impact of visual feedback on dose-volume histograms for organs at risk in postoperative radiotherapy with deep inspiration breath-holding for patients treated with breast-conserving therapy: a planning study. AB - BACKGROUND: We evaluated the effectiveness of visual feedback (VF) on radiotherapy with deep inspiration breath-holding (DIBH), and reviewed the dose for organs at risk (OARs). METHODS: Respiratory motions during DIBH for 15 s were monitored during planning computed tomography (CT)-scanning and simulation for 40 patients after breast-conserving surgery from June 2007 to February 2008. For 22 of 40 patients, a goggle-type liquid crystal display monitor was used for VF. The opposing tangential field was planned. The prescribed dose was 50.0 Gy in 25 fractions. RESULTS: The mean differences of the chest wall respiratory movement in DIBH between planning CT-scanning and simulation were 4.7 +/- 2.6 mm for the patients without VF and 1.0 +/- 0.9 mm for those with VF (p < 0.01). The mean chest wall excursion as a whole in DIBH using VF (2.0 +/- 1.0 mm) was smaller than in those without VF (4.1 +/- 2.4 mm) (p < 0.01). According to reproducibility and stability parameters, 4 mm was added as a posterior margin to the clinical target volume for RT with VF, and 10 mm for those without VF. The mean heart doses were 1.3 +/- 0.5 Gy with VF and 2.4 +/- 1.1 Gy without VF (p < 0.01). Mean dose and max dose of right breast were significantly reduced in procedures with VF use vs. in those without VF (p < 0.01 and < 0.01, respectively). CONCLUSIONS: VF increases the accuracy of postoperative radiotherapy with DIBH, and also helps reduce the dose for OARs. PMID- 29761317 TI - High sodium intake and sodium to potassium ratio may be linked to subsequent increase in vascular damage in adults aged 40 years and older: the Korean multi rural communities cohort (MRCohort). AB - PURPOSE: Subclinical vascular damage is a chronic intermediate process in cardiovascular disease (CVD) and high sodium (Na) has been regarded as an adverse factor in subclinical vascular health; however, the longitudinal relationship between Na intake and subclinical vascular damage has not been studied. We aimed to evaluate the longitudinal relationship of dietary Na intake and sodium to potassium ratio (Na:K) with brachial-ankle pulse wave velocity (baPWV) and carotid intima media thickness (cIMT) in healthy adults aged 40 years and older in Korea. METHODS: The present study was based on participants (n = 2145 for baPWV analysis and n = 2494 for cIMT analysis) who visited three times during 2005-2013 (median 5.3 years of follow-up). We used both dietary Na intake and Na:K at baseline and its average (baseline, 2nd, 3rd), which was obtained from food frequency questionnaire (FFQ) as exposure at every visit. baPWV and cIMT levels at the third visit and change from baseline to the third visit were used to represent the level of subclinical vascular damage. RESULTS: After adjustment for potential confounders, significant positive relationships between dietary Na intake and both baPWV3rd and cIMT3rd were observed (baPWV: p for trend <= 0.0001 for Naaverage; cIMT: p for trend = 0.013 for Naaverage). Compared with Na:Ks less than 1.0, the levels of both baPWV and cIMT were higher for participants with Na:Ks over 1.0 (baPWV: p for trend = 0.0002 for Na:Kaverage; cIMT: p for trend = 0.005 for Na:Kaverage). Similar significant trends were shown in relationships between dietary Na intake and Na:K and changes in baPWV and cIMT levels. CONCLUSIONS: In conclusion, dietary Na intake and Na:K may be positively linked to subsequent baPWV and cIMT levels in adults aged 40 years and older in Korea. Our findings may provide informative evidence on subclinical vascular damage, particularly for populations with relatively high dietary Na intake and low dietary K intake. PMID- 29761318 TI - Association of sugar sweetened beverages consumption with non-alcoholic fatty liver disease: a systematic review and meta-analysis. AB - PURPOSE: The relationship between consumption of sugar sweetened beverages (SSB) and NAFLD has been reported in several epidemiological studies, but the results are inconsistent. The present systematic review and meta-analysis of observational studies was carried out to assess the relationship between sugar sweetened beverages consumption and NAFLD. METHODS: Online databases were searched systematically through December, 2016 for studies investigating association between SSB consumption and NAFLD but limited to observational studies in human. Pooled odds ratio (OR) and 95% confidence intervals were calculated using Der-Simonian and Laird method while random effects meta-analysis was used, taking into account conceptual heterogeneity. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I2 statistic. RESULTS: Of the 1015 identified articles, 42 were reviewed in depth and six studies (four cross-sectional, one case-control, and one cohort) met the criteria for inclusion in our systematic review with 6326 participants and 1361 cases of NAFLD in both men and women. Finally, four cross-sectional studies were included in the meta-analysis. Higher intake of SSBs (highest compared to lowest categories) was significantly associated with NAFLD, with a 40% increased Odds of NAFLD after adjusting for important potential confounders (pooled odds ratio 1.40; 95% CI 1.07, 1.82). There was no evidence for significant heterogeneity across studies [P = 0.226 (Q statistics), I2 = 31.0%]. A significant positive association between SSB consumption and NAFLD was observed consistently in a sensitivity analysis [range of summary ORs 1.39-1.49]. There was no evidence of publication bias for the association between SSB and NAFLD. CONCLUSIONS: This meta-analysis supports a positive significant association between higher consumption of SSB and NAFLD in both men and women. These findings strengthen the evidence that intake of SSBs should be limited to reduce fatty liver disease. PMID- 29761319 TI - Gaussian graphical models identified food intake networks and risk of type 2 diabetes, CVD, and cancer in the EPIC-Potsdam study. AB - PURPOSE: The aim of the study was to investigate the association between the previously identified Gaussian graphical models' (GGM) food intake networks and risk of major chronic diseases as well as intermediate biomarkers in the European Prospective Investigation into Cancer and nutrition (EPIC)-Potsdam cohort. METHODS: In this cohort analysis of 10,880 men and 13,340 women, adherence to the previously identified sex-specific GGM networks as well as principal component analysis identified patterns was investigated in relation to risk of major chronic diseases, using Cox-proportional hazard models. Associations of the patterns with intermediate biomarkers were cross-sectionally analyzed using multiple linear regressions. RESULTS: Results showed that higher adherence to the GGM Western-type pattern was associated with increased risk (Hazard Ratio: 1.55; 95% CI 1.13-2.15; P trend = 0.004) of type 2 diabetes (T2D) in women, whereas adherence to a high-fat dairy (HFD) pattern was associated with lower risk of T2D both in men (0.69; 95% CI 0.54-0.89; P trend < 0.001) and women (0.71; 95% CI: 0.53, 0.96; P trend = 0.09). Among PCA patterns, HFD pattern was associated with lower risk of T2D (0.74; 95% CI 0.58-0.95; P trend < 0.001) in men and bread and sausage pattern was associated with higher risk of T2D (1.79; 95% CI 1.29-2.48; P trend < 0.001) in women. Moreover, The GGM-HFD pattern was positively associated with HDL-C in men and inversely associated with C-reactive protein in women. CONCLUSION: Overall, these results show that GGM-identified networks reflect dietary patterns, which could also be related to risk of chronic diseases. PMID- 29761321 TI - Correction to: Reduced interference in working memory following mindfulness training is associated with increases in hippocampal volume. AB - The article Reduced interference in working memory following mindfulness training is associated with increases in hippocampal volume, written by Jonathan Greenberg, Victoria L. Romero, Seth Elkin-Frankston, Matthew A. Bezdek, Eric H. Schumacher, and Sara W. Lazar. PMID- 29761322 TI - Concurrent risk-reduction surgery in patients with increased lifetime risk for breast and ovarian cancer: an analysis of the National Surgical Quality Improvement Program (NSQIP) database. AB - BACKGROUND: Patients with genetic susceptibility to breast and ovarian cancer are eligible for risk-reduction surgery. Surgical morbidity of risk-reduction mastectomy (RRM) with concurrent bilateral salpingo-oophorectomy (BSO) is unknown. Outcomes in these patients were compared to patients undergoing RRM without BSO using a large multi-institutional database. METHODS: A retrospective cohort analysis was conducted using the American College of Surgeon's National Surgical Quality Improvement Program (NSQIP) 2007-2016 datasets, comparing postoperative morbidity between patients undergoing RRM with patients undergoing RRM with concurrent BSO. Patients with genetic susceptibility to breast/ovarian cancer undergoing risk-reduction surgery were identified. The primary outcome was 30-day postoperative major morbidity. Secondary outcomes included surgical site infections, reoperations, readmissions, length of stay, and venous thromboembolic events. A multivariate analysis was performed to determine predictors of postoperative morbidity and the adjusted effect of concurrent BSO on morbidity. RESULTS: Of the 5470 patients undergoing RRM, 149 (2.7%) underwent concurrent BSO. The overall rate of major morbidity and postoperative infections was 4.5% and 4.6%, respectively. There was no significant difference in the rate of postoperative major morbidity (4.5% vs 4.7%, p = 0.91) or any of the secondary outcomes between patients undergoing RRM without BSO vs. those undergoing RRM with concurrent BSO. Multivariable analysis showed Body Mass Index (OR 1.05; p < 0.001) and smoking (OR 1.78; p = 0.003) to be the only predictors associated with major morbidity. Neither immediate breast reconstruction (OR 1.02; p = 0.93) nor concurrent BSO (OR 0.94; p = 0.89) were associated with increased postoperative major morbidity. CONCLUSION: This study demonstrated that RRM with concurrent BSO was not associated with significant additional morbidity when compared to RRM without BSO. Therefore, this joint approach may be considered for select patients at risk for both breast and ovarian cancer. PMID- 29761320 TI - Strong specificity and network modularity at a very fine phylogenetic scale in the lichen genus Peltigera. AB - Identifying the drivers and evolutionary consequences of species interactions is a major goal of community ecology. Network-based analyses can provide mathematical tools to detect non-random patterns of interactions, and potentially help predicting the consequences of such patterns on evolutionary dynamics of symbiotic systems. Here, we characterize the structure of a lichen network at a very fine phylogenetic scale, by identifying the photosynthetic partners (i.e., cyanobacteria of the genus Nostoc) of lichenized fungi belonging to a monophyletic section of a single genus (i.e., section Polydactylon of the genus Peltigera), worldwide. Even at such a fine phylogenetic scale, we found that interactions were highly modular and anti-nested, indicating strong preferences in interactions. When considering local Peltigera communities, i.e., datasets at small spatial scales with only a slightly broader phylogenetic range, interactions remained modular but were asymmetric, with generalist Nostoc partners interacting with specialized Peltigera species. This asymmetry was not detected with our global spatial scale dataset. We discuss these results in the light of lichen community assembly, and explore how such interaction patterns may influence coevolution in lichens and the evolutionary stability of the mutualism in general. PMID- 29761323 TI - Effect of glucocorticoid use on survival in patients with stage I-III breast cancer. AB - PURPOSE: Glucocorticoids (GCs) are commonly used in breast cancer patients to ameliorate emesis induced by chemotherapy. Some preclinical studies have suggested that systemic GCs might promote survival of estrogen receptor (ER) negative breast cancer cells. This study aims to clarify their clinical effect on patient survival. METHODS: A total of 18,596 women with newly diagnosed stage I III breast cancer in 2002-2006 were identified from the Taiwan Cancer Database and drug treatment was examined from the Taiwan National Health Insurance Claims Database. Of these, 3989 who did not receive adjuvant chemotherapy (non chemotherapy cohort) and 3237 patients who received six cycles of adjuvant anthracycline-based chemotherapy (anthracycline cohort) were included. The impact of GC use on survival was analyzed separately in these two cohorts using Cox proportional hazards models. RESULTS: In the non-chemotherapy cohort, GC use was associated with aggressive clinicopathological features of breast cancer. High dose GC was associated with shorter overall survival in univariate analysis but not in multivariate analysis. In the anthracycline cohort, multivariate analysis showed that GC use at each dose level was significantly associated with longer breast cancer-specific survival (HR 0.65, 0.70, and 0.70 for low-dose, median dose, and high-dose GC, respectively) and overall survival (HR 0.72, 0.76, and 0.73, respectively) when compared with those receiving no GC. The associations were significant in both ER-positive and ER-negative subgroups for breast cancer specific survival, and in ER-negative subgroup for overall survival. CONCLUSION: Concomitant use of GC improved survival in patients receiving adjuvant anthracycline-based chemotherapy for stage I-III breast cancer. PMID- 29761324 TI - Temporary self-expandable metallic stent placement in post-gastrectomy complications. AB - BACKGROUND: Self-expandable metallic stents in the upper gastrointestinal tract are used for treating malignant esophageal or gastroduodenal outlet obstructions and fistulas. Recently, self-expandable metallic stent use has been expanded to benign esophageal or gastroduodenal strictures and post-operative complications. However, there is scarce data available regarding efficacy, long-term complications, and outcomes with the use of self-expandable metallic stent in benign disease, especially post-gastrectomy complications. METHODS: Data of 57 patients who underwent upper gastrointestinal tract self-expandable metallic stent insertion for post-operative complications between March 2009 and June 2017 were analyzed. All patients underwent a curative gastrectomy for gastric cancer. Data collected included patient demographics, indication for procedure, type of stent used, complications, and patient outcomes. RESULTS: Self-expandable metallic stent placement was technically successful in all patients. Of the 57 patients, 33 had self-expandable metallic stent placement for anastomosis site leakage, 12 for anastomosis site refractory stricture, and 12 for obstruction due to angulation. After self-expandable metallic stent placement, symptomatic improvement was achieved in 56 patients (98.2%), among which, three patients (5.4%) had recurrent symptoms, two underwent repeated stent insertion, and one underwent balloon dilatation. After self-expandable metallic stent placement, median time to initiating dietary intake was 6 days (range 1-30 days), and median duration of hospitalization was 13 days (range 3-135 days). At the follow-up (mean 24.6 months), migration was the most commonly reported complication, which developed in 15 (26.3%) patients. CONCLUSIONS: Self-expandable metallic stent placement is an effective and safe treatment for post-gastrectomy anastomosis site leakage, stricture, and obstruction, which can decrease the risk of reoperation related mortality and modalities. PMID- 29761325 TI - Correction to: Rapid Identification of Seven Waterborne Exophiala Species by RCA DNA Padlock Probes. AB - The Editorial Office of Mycopathologia reports that several paragraphs of Najafzadeh et al. were transcribed with only minor edits from previously published material by Najafzadeh M.J. PMID- 29761326 TI - Fusariosis in a Captive South American Sea Lion (Otaria flavescens): A Case Report. AB - Superficial mycoses are commonly reported in captive pinnipeds, usually maintained in wet and warm environments, favorable to fungal growth. Most superficial mycoses in pinnipeds have been described as difficult to treat; however, the majority of the reports come from past decades. Cutaneous lesions associated with opportunistic Fusarium sp. infections have been previously recognized in this taxon. We described the clinical signs, associated lesions and diagnosis (thermography, imprint cytology, histopathology, culture, electron microscopy, PCR) of a fusariosis case by Fusarium sp. in the nails and skin of an adult male captive South American sea lion (Otaria flavescens) recently transferred from another zoological institution, and its successful long-term treatment with Ketoconazole PO (60 days) and Miconazole solution spray TO, followed by Itraconazole PO (30 days). Herein we provide a successful approach to the diagnosis and treatment of fusariosis. PMID- 29761327 TI - Effects of genetic manipulation of the activity of photorespiration on the redox state of photosystem I and its robustness against excess light stress under CO2 limited conditions in rice. AB - Under CO2-limited conditions such as during stomatal closure, photorespiration is suggested to act as a sink for excess light energy and protect photosystem I (PSI) by oxidizing its reaction center chlorophyll P700. In this study, this issue was directly examined with rice (Oryza sativa L.) plants via genetic manipulation of the amount of Rubisco, which can be a limiting factor for photorespiration. At low [CO2] of 5 Pa that mimicked stomatal closure condition, the activity of photorespiration in transgenic plants with decreased Rubisco content (RBCS-antisense plants) markedly decreased, whereas the activity in transgenic plants with overproduction of Rubisco (RBCS-sense plants) was similar to that in wild-type plants. Oxidation of P700 was enhanced at [CO2] of 5 Pa in wild-type and RBCS-sense plants. PSI was not damaged by excess light stress induced by repetitive saturated pulse-light (rSP) in the presence of strong steady-state light. On the other hand, P700 was strongly reduced in RBCS antisense plants at [CO2] of 5 Pa. PSI was also damaged by rSP illumination. These results indicate that oxidation of P700 and the robustness of PSI against excess light stress are hampered by the decreased activity of photorespiration as a result of genetic manipulation of Rubisco content. It is also suggested that overproduction of Rubisco does not enhance photorespiration as well as CO2 assimilation probably due to partial deactivation of Rubisco. PMID- 29761329 TI - Bactericidal and Virucidal Activity of Povidone-Iodine and Chlorhexidine Gluconate Cleansers in an In Vivo Hand Hygiene Clinical Simulation Study. AB - INTRODUCTION: Standard in vitro and in vivo tests help demonstrate efficacy of hand hygiene products; however, there is no standard in vivo test method for viruses. We investigated the bactericidal and virucidal efficacy of povidone iodine (PVP-I) 7.5% scalp and skin cleanser, chlorhexidine gluconate (CHG) 4% hand cleanser and the reference hand wash (soft soap) in 15 healthy volunteers following European Standard EN1499 (hygienic hand wash test method for bacteria), which was adapted for virucidal testing. METHODS: Separate test series were performed for bactericidal (Escherichia coli) and virucidal [murine norovirus (MNV)] testing. After pre-washing and artificial contamination of hands with test organisms, volunteers underwent testing with 3 and 5 mL of each product for contact times of 15, 30 and 60 s according to a Latin-square randomization. The number of test organisms released from fingertips into sampling fluids was assessed before and after hand washing and mean log10 reduction factor (RF) was calculated. RFs (test-reference) were compared using a Wilcoxon-Wilcox multiple comparisons test per EN1499; efficacy was concluded if p <= 0.01. RESULTS: PVP-I 7.5% and CHG 4% cleansers both passed EN1499 requirements against E. coli, with statistically significantly greater (p <= 0.01) mean log10 RFs compared with reference soft soap across all tests (PVP-I: 4.09-5.27; CHG: 4.12-5.22; soap: 2.75-3.11). The experimental design using EN1499 was applicable to testing with MNV as discriminatory and reproducible results were generated. Mean log10 RFs of MNV were statistically significantly greater for PVP-I (1.57-2.57) compared with soft soap (1.24-1.62), while mean log10 RFs with CHG (0.90-1.34) were lower than for soft soap across all tests. CONCLUSION: PVP-I 7.5% cleanser showed superior efficacy against MNV compared to soft soap and CHG 4% cleanser, while both PVP-I and CHG were superior to soft soap against E. coli. The experimental set-up may be applicable to future testing for antiviral hand washes. FUNDING: Mundipharma Manufacturing Pte Ltd. Plain language summary available for this article. PMID- 29761331 TI - FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Neoadjuvant Treatment of Resectable and Borderline Resectable Pancreatic Head Adenocarcinoma. AB - BACKGROUND: Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA. METHODS: A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT. RESULTS: In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012). CONCLUSIONS: Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9 month improvement in survival compared with G-nP after adjustment for covariates. PMID- 29761330 TI - A Review of Long-Term Toxicity of Antiretroviral Treatment Regimens and Implications for an Aging Population. AB - : Human immunodeficiency virus (HIV) is a chronic infectious disease currently requiring lifelong antiretroviral therapy (ART). People living with HIV (PLWH) face an increased risk of comorbidities associated with aging, chronic HIV, and the toxicity arising from long-term ART. A literature review was conducted to identify the most recent evidence documenting toxicities associated with long term ART, particularly among aging PLWH. In general, PLWH are at a greater risk of developing fractures, osteoporosis, renal and metabolic disorders, central nervous system disorders, cardiovascular disease, and liver disease. There remains limited evidence describing the economic burden of long-term ART. Overall, an aging HIV population treated with long-term ART presents a scenario in which the clinical, humanistic, and economic burden for healthcare systems will demand thoughtful policy solutions that preserve access to treatment. Newer treatment regimens with fewer drugs may mitigate some of the cumulative toxicity burden of long-term ART. FUNDING: ViiV Healthcare. PMID- 29761332 TI - Clinical Complete Response After Neoadjuvant Therapy for Esophageal Cancer: What's Lurking Under the Surface? PMID- 29761333 TI - Adrenal Incidentalomas During Diagnostic Work-up of Colorectal Cancer Patients: What is the Risk of Metastases? AB - BACKGROUND: Adrenal incidentalomas (AIs) are regularly discovered on staging computed tomography (CT) of patients with colorectal cancer (CRC). Although CRC is considered unlikely to metastasize to the adrenal gland, it is not known how often an AI appears to be a CRC metastasis. This causes a diagnostic dilemma for many patients with newly diagnosed CRC. This study aimed primarily to describe the incidence of AIs and adrenal metastases in CRC patients. METHODS: A single center cohort of 475 consecutive patients with newly diagnosed CRC was defined. Retrospectively, all radiology reports and multidisciplinary team meeting reports were assessed for the presence of adrenal abnormalities. All AIs shown on staging CT were reevaluated for the purpose of this study, and the sizes of these adrenal glands were determined. Based on the CT reevaluation, follow-up imaging, and clinical follow-up assessment, conclusions on the presence or absence of adrenal metastases were drawn. RESULTS: The incidence of AIs in this CRC patient cohort was 10.5% (50/475). In 96% (48/50) of the patients with AIs, adrenal metastases could be ruled out. No solitary adrenal metastases were encountered. In two patients who had widespread systemic disease without curative treatment options, the AIs were considered to be adrenal metastases (cohort incidence, 0.4%). CONCLUSION: This is the first study to report on adrenal incidentalomas in CRC patients. In newly diagnosed CRC patients without disseminated disease, AIs can be considered benign, and no additional imaging is indicated to rule out adrenal metastases in this group. PMID- 29761334 TI - [Do we need syncope units? : Experience from Bolzano, South Tyrol (Italy)]. AB - Syncope is a common cause for presentation to the emergency department. Because of the numerous differential diagnoses which can be life-threatening, it can be a challenging work-up for the physician. This often results in admission rates that are too high and hospital stays that are too long with consequent high costs. Several studies have shown the inferiority of best-clinical practice to an evidence-based approach in syncope work-up, which results in underdiagnosis and often incorrect diagnosis of syncope. The consequences are undirected therapies and subsequently high recurrence rates of syncope, which lead to limited quality of life and readmissions. For this reason, the European Society of Cardiology (ESC) Guidelines for the diagnosis and management of syncope recommend the organization of Syncope Units. Through a standardized and evidence-based approach, the diagnostic and therapeutic work-up can be done in a safe and effective manner, allowing an organized follow-up and further management of patients with syncope. This article summarizes the reasons for the need of syncope units and explains the practical implementation of the guidelines using the example of the Syncope Unit in Bolzano, South Tyrol (Italy). PMID- 29761335 TI - [Biomarkers and atrial fibrillation : Prediction of recurrences and thromboembolic events after rhythm control management]. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical praxis and is associated with an increased risk for cardio- and cerebrovascular complications leading to an increased mortality. Catheter ablation represents one of the most important and efficient therapy strategies in AF patients. Nevertheless, the high incidence of arrhythmia recurrences after catheter ablation leads to repeated procedures and higher treatment costs. Recently, several scores had been developed to predict rhythm outcomes after catheter ablation. Biomarker research is also of enormous interest. There are many clinical and blood biomarkers pathophysiologically associated with AF occurrence, progression and recurrences. These biomarkers-including different markers in blood (e. g. von Willebrand factor, D-dimer, natriuretic peptides) or urine (proteins, epidermal grown factor receptor) but also cardiac imaging (echocardiography, computed tomography, magnetic resonance imaging)-could help to improve clinical scores and be useful for individualized AF management and optimized patients' selection for different AF treatment strategies. In this review, the role of diverse biomarkers and their predictive value related to AF-associated complications are discussed. PMID- 29761336 TI - [Syncope in children and adolescents]. AB - Syncope is common in children and adolescents. Neurally mediated syncope including pallid and cyanotic breath holding spells, vagovasal syncope and neurocardiogenic syncope is based on a common pathomechanism and accounts for approximately 75% of cases. A potentially life-threatening cardiac cause of syncope may be present in up to 6%. Detailed history, physical examination and 12 lead electrocardiogram (ECG) allow discrimination between benign and serious syncope in the majority of pediatric patients. Tilt-testing can be useful when diagnosis is unclear. In neurally mediated syncope, education on awareness of prodromes, modification of life-style and reassurance of the family on benign character of the disease is sufficient for preventing further syncopal episodes in the majority of cases. In pediatric patients unresponsive to these measures midodrine is often effective. Fludrocortisone and cardiac pacing may be considered in selected patients. beta-Blockers are not beneficial in pediatric neurally mediated syncope. Cardiac causes need specific disease-targeted therapy. PMID- 29761337 TI - [Psychogenic non epileptic seizures : Differential diagnostic features]. AB - Psychogenic nonepileptic seizures (PNES) are to be considered in the differential diagnosis of a transient loss of consciousness. Their discrimination from syncope, epileptic seizures or vascular events can be difficult and requires profound knowledge about the semiology and clinical presentation of PNES and their differential diagnoses. Erroneous diagnoses and the resulting therapies lead to elevated morbidity, elevated costs and a poorer outcome. The aim of the present article is to provide an overview on PNES and their delineation from the clinical pictures of epilepsy and syncope. PMID- 29761339 TI - [Syncope in hypertrophic (obstructive) cardiomyopathy]. AB - Hypertrophic cardiomyopathy is the most common genetic cardiac disease. The most important pathophysiological finding is dynamic (outflow tract) obstruction of the left ventricle in about 70% of affected patients. Especially in younger patients, an increased risk of sudden cardiac death has been observed. Syncope and presyncope-in addition to extremely variable cardiac symptoms (dyspnea and angina)-are common. The etiology of syncope is complex. The most important aspect for diagnosis is a detailed history regarding the accompanying circumstances of the syncope. In principle, an attempt must be made to distinguish between rhythmogenic and hemodynamic causes. Diagnostic work-up should be performed under the criteria of a possible prognostic-with implantation of an implantable cardioverter-defibrillator (ICD) in patients at increased risk of sudden cardiac death-and symptomatic therapy. Depending on the underlying morphology and the experience of the surgeon, percutaneous septal ablation and operative myectomy are complementary options for symptomatic treatment if medical therapy with beta blockers and/or verapamil is inadequate. PMID- 29761338 TI - [Journey of the S-ICD to first-line therapy]. AB - The subcutaneous implantable cardioverter-defibrillator (S-ICD(r), Boston Scientific, Marlborough, MA, USA, previously Cameron Health, San Clemente, CA, USA) represents an important milestone in ICD therapy for prevention of sudden cardiac death (SCD). Since the introduction of the S-ICD in 2010, the device has undergone further development. Based on the unique feature of an entirely extracardiac implantation, the S-ICD is able to reduce the common perioperative and long-term complications of the usual endovascular implanted ICD systems. Especially for patients with a complex anatomy and no option of an endovascular lead implantation, the S-ICD offers a potential alternative. Regarding the initial uncertainty if this innovative ICD approach is actually reliable in detecting and terminating ventricular arrhythmias has been resolved by multiple clinical studies and trials providing evidence for an effective treatment. Based on the obvious advantages compared to conventional ICD systems, the question arises if the S-ICD should actually be the first choice in the majority of all primary prevention patients in the future. Furthermore, recent data from large registries show that S-ICD indications are also expanding in secondary prevention patients. As a consequence the S-ICD was listed in the 2015 ESC guidelines as an alternative therapeutic option with a class IIa recommendation in patients with an ICD indication not requiring pacing for bradycardia, cardiac resynchronization therapy or anti-tachycardia pacing (ATP). In addition, the American Heart Association guidelines refer to class I recommendation for patients with a complex anatomy and venous access problems or at a high risk for infections who need ICD therapy. Limitations with respect to the not available pacing option of S-ICD might be also overcome by a potential combination with a leadless pacemaker in the near future. This article provides an overview of recent developments of the S-ICD and reviews the most recent literature and ongoing studies. PMID- 29761340 TI - Reduction of Direct Health Costs Associated with Pertussis Vaccination with Acellular Vaccines in Children Aged 0-9 Years with Pertussis in Catalonia (Spain). AB - OBJECTIVES: The aim of this study was to assess direct health costs in children with pertussis aged 0-9 years who were vaccinated, partially vaccinated, and unvaccinated during childhood, and to assess the association between pertussis costs and pertussis vaccination in Catalonia (Spain) in 2012-2013. METHODS: Direct healthcare costs included pertussis treatment, pertussis detection, and preventive chemotherapy of contacts. Pertussis patients were considered vaccinated when they had received 4-5 doses, and unvaccinated or partially vaccinated when they had received 0-3 doses of vaccine. The Chi square test and the odds ratios were used to compare percentages and the t test was used to compare mean pertussis costs in different groups, considering a p < 0.05 as statistically significant. The correlation between pertussis costs and study variables was assessed using the Spearman's rho, with a p < 0.05 as statistically significant. Multiple linear regression analysis (IBM-SPSS program) was used to quantify the association of pertussis vaccination and other study variables with pertussis costs. RESULTS: Vaccinated children with pertussis aged 0-9 years had significantly lower odds ratios of hospitalizations (OR 0.02, p < 0.001), laboratory confirmation (OR 0.21, p < 0.001), and severe disease (OR 0.02, p < 0.001) than unvaccinated or partially vaccinated children with pertussis of the same age. Mean direct healthcare costs were significantly lower (p < 0.001) in vaccinated patients (?190.6) than in unvaccinated patients (?3550.8), partially vaccinated patients (?1116.9), and unvaccinated/partially vaccinated patients (?2330). Multivariable linear regression analysis showed that pertussis vaccination with 4-5 doses was associated with a non-significant reduction of pertussis costs of ?107.9 per case after taking into account the effect of other study variables, and ?200 per case after taking into account pertussis severity. CONCLUSIONS: Direct healthcare costs were lower in children with pertussis aged 0 9 years vaccinated with 4-5 doses of acellular vaccines than in unvaccinated or partially vaccinated children with pertussis of the same age. PMID- 29761341 TI - The prevalence of developmental defects of enamel, a prospective cohort study of adolescents in Western Sweden: a Barn I TAnadvarden (BITA, children in dental care) study. AB - AIM: To describe the prevalence of different types of developmental defects of the enamel (DDE) in varying age-cohorts and habitations, and to analyse if early trauma to the primary teeth and early subsequent serious health problems were related to DDE in the permanent dentition. Dental fear and anxiety, and aesthetic problems as a consequence of DDE were also investigated. METHODS: DDE was registered over 5 years annually in three age cohorts (796 children). The DDE index (FDI Commision on Oral Health, Research and Epidemiology, Int Dent J 42:411 426, 1992) was used. Information on diseases in early childhood, trauma to the primary teeth, and dental fear and anxiety were collected. RESULTS: The prevalence of DDE was 33.2% (boys 37.1%, girls 29.3%, p = 0.02). Demarcated opacities (DEO), solely, were the most frequent kind of defect, affecting 18%. Five percent (5%) had diffuse opacities (DIO) and 1% had hypoplasias, whereas 7% had teeth with both DEO and DIO. The most frequently affected teeth of DEO, as well as of DIO, were the first permanent molars and maxillary central incisors. Dental injuries to the primary anterior teeth raised the risk for DDE in the permanent teeth, but early serious health problems did not. Generalised DDE was common (8.4%). The paediatric dentists assessed the DDE in the maxillary anterior teeth as more serious than did the affected children and their parents. CONCLUSIONS: Generalised DDE was more frequent than expected, as well as the occurrence of both DEO and DIO in the same individual. The first permanent molars and the upper central incisors were the most affected teeth. PMID- 29761342 TI - Impact of oral hygiene and socio-demographic factors on dental caries in a suburban population in Nigeria. AB - AIM: This was to determine dental caries determinants in the study participants. METHODOLOGY: This was a secondary data study extracted from primary data through a school-based study that recruited students from primary and secondary schools in a suburban population in Nigeria. The variables included age, gender, socio economic status, oral hygiene status, type of parenting, birth rank, family size and presence of dental caries. The diagnosis of dental caries was based on the World Health Oral Health Survey recommendations while oral hygiene was determined using simplified-oral hygiene index (OHI-S). Data was analysed using STATA version 13, statistical significance was set at P < 0.05. RESULTS: The prevalence of dental caries for the study population was 12.2%, DMFT and dmft were 0.16 and 0.06 respectively. Children within age groups 11-13 and 14-16 years had reduced chances of having dental caries (P = 0.01; P = 0.01); children with fair oral hygiene and poor oral hygiene had increased odds of having dental caries (P <= 0.001; P <= 0.001), last child of the family also had increased odds of having dental caries while children from large family size had reduced odds of having dental caries. This study also showed that first permanent molars and second primary molars were mostly affected by dental caries but there was no significant difference between distribution of the maxillary or mandibular jaw or between right and left quadrants. CONCLUSION: Age, oral hygiene, birth rank and family size were the significant determinants of dental caries in the study population and the teeth mostly affected were first permanent molars and second primary molars. PMID- 29761345 TI - Mutational Analysis of the Cysteine-Rich Region of the Iron-Responsive GATA Factor Fep1. Role of Individual Cysteines as [2Fe-2S] Cluster Ligands. AB - Fep1, the iron-dependent GATA-type transcriptional repressor of the methylotrophic yeast Pichia pastoris, has a dimeric structure and binds an iron sulfur cluster of the [2Fe-2S] type. In this work, we extend the characterization of this protein by analysis of the optical and CD spectroscopic properties of a set of mutants where cysteines within the conserved Cys-X5-Cys-X8-Cys-X2-Cys motif have been targeted, in order to evaluate their role as [2Fe-2S] ligands. The results suggest that all four cysteine residues are essential because replacing them with serines in different combinations invariably produces a protein unable to correctly bind the [2Fe-2S] cluster. PMID- 29761346 TI - Ethical dilemmas in global anesthesia and surgery. PMID- 29761344 TI - Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis. AB - Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) characterized by neuroinflammation, neurodegeneration and impaired repair mechanisms that lead to neurological disability. The crux of MS is the patient's own immune cells attacking self-antigens in the CNS, namely the myelin sheath that protects nerve cells of the brain and spinal cord. Restoring antigen-specific tolerance via therapeutic vaccination is an innovative and exciting approach in MS therapy. Indeed, leveraging the body's attempt to prevent autoimmunity, i.e., tolerization, focuses on the underlying cause of the disease and could be the key to solving neuroinflammation. In this perspective, antigen specific vaccination targets only the detrimental and aberrant immune response against the specific disease-associated antigen(s) involved while retaining the capacity of the immune system to respond to unrelated antigens. We review the experimental approaches of tolerance-inducing vaccination in relapsing and progressive forms of MS that have reached the clinical development phase, including vaccination with autologous T cells, autologous tolerogenic dendritic cells, T cell receptor peptide vaccination, altered peptide ligand, ATX-MS-1467, cluster of differentiation (CD)-206-targeted liposomal myelin basic protein peptides and DNA vaccination. Failures, successes and future directions are discussed. PMID- 29761343 TI - Role of Exogenous Progesterone in the Treatment of Men and Women with Substance Use Disorders: A Narrative Review. AB - Substance use disorders (SUDs) remain problematic as many individuals are untreated or do not benefit from the currently available interventions. Thus, there is an urgent need to develop novel pharmacological interventions to treat SUDs. Evidence suggests that the female sex hormone, progesterone, attenuates the craving for and the euphoric effects of drugs of abuse. Research to date has demonstrated that progesterone may modulate responses to drugs of abuse and may have utility as a novel treatment for SUDs. A literature search was conducted to identify and examine studies that administered exogenous progesterone. Sixteen publications were identified, exploring the utility of exogenous progesterone or its metabolite, allopregnanolone, among a range of substances, including amphetamines (one study), benzodiazepines (one study), cocaine (nine studies), and tobacco/nicotine (five studies). Results indicated that exogenous progesterone and, its metabolite allopregnanolone, demonstrated preliminary efficacy as a treatment for substance use in both men and women. Notably, progesterone appears to target negative affect and augment cognitive functioning, especially among female substance users. Additional research is needed to explore the potential use of exogenous progesterone and allopregnanolone in the treatment of SUDs, including that associated with alcohol and opioids, but considering the current promising findings, exogenous progesterone and allopregnanolone may have utility as novel pharmacological treatments for SUDs. PMID- 29761347 TI - Negligible impact of differential item functioning between Black and White dialysis patients on the Kidney Disease Quality of Life 36-item short form survey (KDQOLTM-36). AB - PURPOSE: Black dialysis patients report better health-related quality of life (HRQOL) than White patients, which may be explained if Black and White patients respond systematically differently to HRQOL survey items. METHODS: We examined differential item functioning (DIF) of the Kidney Disease Quality of Life 36-item (KDQOLTM-36) Burden of Kidney Disease, Symptoms and Problems with Kidney Disease, and Effects of Kidney Disease scales between Black (n = 18,404) and White (n = 21,439) dialysis patients. We fit multiple group confirmatory factor analysis models with increasing invariance: a Configural model (invariant factor structure), a Metric model (invariant factor loadings), and a Scalar model (invariant intercepts). Criteria for invariance included non-significant chi2 tests, > 0.002 difference in the models' CFI, and > 0.015 difference in RMSEA and SRMR. Next, starting with a fully invariant model, we freed loadings and intercepts item-by-item to determine if DIF impacted estimated KDQOLTM-36 scale means. RESULTS: DeltaCFI was 0.006 between the metric and scalar models but was reduced to 0.001 when we freed intercepts for the burdens and symptoms and problems of kidney disease scales. In comparison to standardized means of 0 in the White group, those for the Black group on the Burdens, Symptoms and Problems, and Effects of Kidney Disease scales were 0.218, 0.061, and 0.161, respectively. When loadings and thresholds were released sequentially, differences in means between models ranged between 0.001 and 0.048. CONCLUSION: Despite some DIF, impacts on KDQOLTM-36 responses appear to be minimal. We conclude that the KDQOLTM-36 is appropriate to make substantive comparisons of HRQOL between Black and White dialysis patients. PMID- 29761348 TI - Deprivation is associated with worse physical and mental health beyond income poverty: a population-based household survey among Chinese adults. AB - PURPOSE: In studying health inequality, poverty as measured by income is frequently used; however, this omits the aspects of non-monetary resources and social barriers to achieving improved living standard. Therefore, our study aimed to examine the associations of individual-level deprivation of material and social necessities with general physical and mental health beyond that of income poverty. METHODS: A territory-wide two-stage stratified random sample of 2282 community-dwelling Hong Kong adults was surveyed between 2014 and 2015. Income poverty and a Deprivation Index were used as the main independent variables. General health was assessed using the validated 12-item Short-Form Health Survey version 2, from which physical component summary and mental component summary were derived. RESULTS: Our results in multivariable ordinal logistic regressions consistently showed that, after adjusting for income poverty, socio-demographic and lifestyle factors, being deprived was significantly associated with worse physical (OR 1.66; CI 1.25-2.20) and mental health (OR 1.83; CI 1.43-2.35). Being income poor was also significantly associated with worse mental health (OR 1.63; CI 1.28-2.09) but only marginally with physical health (OR 1.34; CI 1.00-1.80) after adjustments. CONCLUSIONS: Income does not capture all aspects of poverty that are associated with adverse health outcomes. Deprivation of non-monetary resources has an independent effect on general health above and beyond the effect of income poverty. Policies should move beyond endowment and take into account the multidimensionality of poverty, in order to address the problem of health inequality. PMID- 29761349 TI - Intracochlear administration of steroids with a catheter during human cochlear implantation: a safety and feasibility study. AB - Suppression of foreign body reaction, improvement of electrode-nerve interaction, and preservation of residual hearing are essential research topics in cochlear implantation. Intracochlear pharmaco- or cell-based therapies can open new horizons in this field. Local drug delivery strategies are desirable as higher local concentrations of agents can be realized and side effects can be minimized compared to systemic administrations. When administered locally at accessible, basal parts of the cochlea, drugs reach apical regions later and in much lower concentrations due to poor diffusion patterns in cochlear fluids. Therefore, new devices are needed to warrant rapid distribution of agents into all parts of the cochlea. Five patients received a deep intracochlear injection of triamcinolone with a specifically designed cochlear catheter during cochlear implantation right before inserting a cochlear implant electrode. As a measure for formation of fibrous tissue around the electrode, electrical impedances were measured in the operation room and over 4 months thereafter. No adverse events were observed peri and postoperatively. The handling of the device was easy. Severe damage to the microstructure of the cochlea was excluded as far as possible by cone beam computed tomography and vestibular testing. A delayed rise of the impedances was seen in the catheter group compared to controls over all regions of the cochlea. A statistical significance, however, was only obtained at the midregion of the cochlea. Consequently, the cochlear catheter is a safe and feasible device for local drug delivery of pharmaceutical agents into deeper regions of the cochlea. PMID- 29761351 TI - Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis. AB - BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration. PMID- 29761352 TI - Examining validity evidence for a simulation-based assessment tool for basic robotic surgical skills. AB - Increasing focus on patient safety makes it important to ensure surgical competency among surgeons before operating on patients. The objective was to gather validity evidence for a virtual-reality simulator test for robotic surgical skills and evaluate its potential as a training tool. Surgeons with varying experience in robotic surgery were recruited: novices (zero procedures), intermediates (1-50), experienced (> 50). Five experienced surgeons rated five exercises on the da Vinci Skills Simulator. Participants were tested using the five exercises. Participants were invited back 3 times and completed a total of 10 attempts per exercise. The outcome was the average simulator performance score for the 5 exercises. 32 participants from 5 surgical specialties were included. 38 participants completed all 4 sessions. A moderate correlation between the average total score and robotic experience was identified for the first attempt (Spearman r = 0.58; p = 0.0004). A difference in average total score was observed between novices and intermediates [median score 61% (IQR 52-66) vs. 83% (IQR 75 91), adjusted p < 0.0001], as well as novices and experienced [median score 61% (IQR 52-66) vs. 80 (IQR 69-85), adjusted p = 0.002]. All three groups improved their performance between the 1st and 10th attempts (p < 0.00). This study describes validity evidence for a virtual-reality simulator for basic robotic surgical skills, which can be used for assessment of basic competency and as a training tool. However, more validity evidence is needed before it can be used for certification or high-stakes assessment. PMID- 29761353 TI - Trends in Chronic Diseases Reported by Refugees Originating from Burma Resettling to the United States from Camps Versus Urban Areas During 2009-2016. AB - We examined changes in the prevalence of chronic health conditions among US-bound refugees originating from Burma resettling over 8 years by the type of living arrangement before resettlement, either in camps (Thailand) or in urban areas (Malaysia). Using data from the required overseas medical exam for 73,251 adult (>= 18 years) refugees originating from Burma resettling to the United States during 2009-2016, we assessed average annual percent change (AAPC) in proportion >= 45 years and age- and sex-standardized prevalence of obesity, diabetes, hypertension, chronic obstructive pulmonary disease (COPD), and musculoskeletal disease, by camps versus urban areas. Compared with refugees resettling from camps, those coming from urban settings had higher prevalence of obesity (mean 18.0 vs. 5.9%), diabetes (mean 6.5 vs. 0.8%), and hypertension (mean 12.7 vs. 8.1%). Compared with those resettling from camps, those from urban areas saw greater increases in the proportion with COPD (AAPC: 109.4 vs. 9.9) and musculoskeletal disease (AAPC: 34.6 vs. 1.6). Chronic conditions and their related risk factors increased among refugees originating from Burma resettling to the United States whether they had lived in camps or in urban areas, though the prevalence of such conditions was higher among refugees who had lived in urban settings. PMID- 29761350 TI - Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques. AB - This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP 0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5 ml; following wash out, 1 or 4 ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24 h. Vaginal and rectal tissue biopsies were collected at 4 and 24 h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 104-105 ng/g, 105-106 ng/ml, and 103-105 ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24 h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 103-105 ng/ml and ~ 102-103 ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 101-103 ng/g). For 1 ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive. PMID- 29761354 TI - Stress and Health of Internally Displaced Female Yezidis in Northern Iraq. AB - Burden and vulnerability factors after the genocide by ISIS accumulate to a high risk of health for displaced Yezidi women having survived or escaped the "ISIS" persecutions and massacres 2014. In May 2017, standardized interviews, including tests for the acquisition of healthrelated quality of life (SF12), stress (PSS10) and experienced trauma were performed with 29 and a medical anamnesis with 10 displaced female Yezidi in camps for internally displaced people (IDP) and unofficial settlements in Northern Iraq. 58, 62% stated their general health as "poor", 17.24% each as "fair" or "good" and 3.45% each as "very good" or "excellent". In the assessment of health-related quality of life, physical as well as mental health showed significantly reduced values, while simultaneously a high level of stress was recorded. 79.3% reported about having experienced at least one traumatic event. Chronic stress due to living conditions and traumatization is most likely responsible for the recorded poor health. PMID- 29761355 TI - Application of triolein-embedded cellulose acetate membrane (TECAM) passive sampler to study phase distribution of hexabromocyclododecanes (HBCDs) in sediment. AB - Hexabromocyclododecanes (HBCDs) are a class of widely used brominated flame retardants (BFRs) that exhibit strong hydrophobicity. The ubiquity and persistence of HBCDs in sediment have attracted significant attention because of public health concerns. The environmental fate and ecological risks of HBCDs closely depend on their phase distribution in sediments. However, little information is available regarding the freely dissolved concentrations (C free ) of HBCDs in sediment porewater. In this study, we developed a method to measure C free of HBCDs in sediment porewater using triolein-embedded cellulose acetate membranes (TECAM). The TECAM-to-water partitioning coefficient (log K TECAM ) was 4.69, 4.77, and 4.63 for alpha-HBCD, beta-HBCD, and gamma-HBCD, respectively. In sediments, HBCDs sorbed to the sediment solid phase accounted for more than 99% of the total chemical mass. The dissolved organic carbon (DOC)-water partition coefficient (K DOC ) values were derived from TECAM measurements, and the log K DOC values ranged from 5.77 to 6.23 for the three HBCD diastereomers, suggesting a strong tendency for HBCDs to sorb to DOC. The high sorption of HBDCs for DOC implies a potential for DOC-facilitated transport which may enhance the environmental mobility of HBCDs. PMID- 29761356 TI - Iron nanoparticles in situ encapsulated in lignin-derived hydrochar as an effective catalyst for phenol removal. AB - In this work, we have developed a low-cost and green strategy for nanoscale zero valent iron (ZVI) in situ encapsulated in lignin-derived hydrochar (Fe@HC) by a facile one-pot synthesis route. The as-synthesized Fe@HC was characterized for physicochemical properties by X-ray diffraction (XRD), X-ray photoelectron spectra (XPS), scanning electron microscopy (SEM), energy-dispersive spectroscopy (EDS), transmission electron microscope (TEM), thermal gravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FT-IR). Further catalytic experiment revealed that phenol could be completely degraded by Fe@HC-800 within 20 min with peroxymonosulfate (PMS) at mild temperatures. Fe@HC-800 catalyst also exhibited stable performance after three runs of regeneration. The XPS and XRD results proved the key role of Fe0 in the degradation of phenol. This approach is of great potential to the development of green materials biomass-derived carbon materials for wastewater treatment applications. PMID- 29761357 TI - Classifying brain metastases by their primary site of origin using a radiomics approach based on texture analysis: a feasibility study. AB - OBJECTIVE: To examine the capability of MRI texture analysis to differentiate the primary site of origin of brain metastases following a radiomics approach. METHODS: Sixty-seven untreated brain metastases (BM) were found in 3D T1-weighted MRI of 38 patients with cancer: 27 from lung cancer, 23 from melanoma and 17 from breast cancer. These lesions were segmented in 2D and 3D to compare the discriminative power of 2D and 3D texture features. The images were quantized using different number of gray-levels to test the influence of quantization. Forty-three rotation-invariant texture features were examined. Feature selection and random forest classification were implemented within a nested cross validation structure. Classification was evaluated with the area under receiver operating characteristic curve (AUC) considering two strategies: multiclass and one-versus-one. RESULTS: In the multiclass approach, 3D texture features were more discriminative than 2D features. The best results were achieved for images quantized with 32 gray-levels (AUC = 0.873 +/- 0.064) using the top four features provided by the feature selection method based on the p-value. In the one-versus one approach, high accuracy was obtained when differentiating lung cancer BM from breast cancer BM (four features, AUC = 0.963 +/- 0.054) and melanoma BM (eight features, AUC = 0.936 +/- 0.070) using the optimal dataset (3D features, 32 gray levels). Classification of breast cancer and melanoma BM was unsatisfactory (AUC = 0.607 +/- 0.180). CONCLUSION: Volumetric MRI texture features can be useful to differentiate brain metastases from different primary cancers after quantizing the images with the proper number of gray-levels. KEY POINTS: * Texture analysis is a promising source of biomarkers for classifying brain neoplasms. * MRI texture features of brain metastases could help identifying the primary cancer. * Volumetric texture features are more discriminative than traditional 2D texture features. PMID- 29761358 TI - Deep learning for staging liver fibrosis on CT: a pilot study. AB - OBJECTIVES: To investigate whether liver fibrosis can be staged by deep learning techniques based on CT images. METHODS: This clinical retrospective study, approved by our institutional review board, included 496 CT examinations of 286 patients who underwent dynamic contrast-enhanced CT for evaluations of the liver and for whom histopathological information regarding liver fibrosis stage was available. The 396 portal phase images with age and sex data of patients (F0/F1/F2/F3/F4 = 113/36/56/66/125) were used for training a deep convolutional neural network (DCNN); the data for the other 100 (F0/F1/F2/F3/F4 = 29/9/14/16/32) were utilised for testing the trained network, with the histopathological fibrosis stage used as reference. To improve robustness, additional images for training data were generated by rotating or parallel shifting the images, or adding Gaussian noise. Supervised training was used to minimise the difference between the liver fibrosis stage and the fibrosis score obtained from deep learning based on CT images (FDLCT score) output by the model. Testing data were input into the trained DCNNs to evaluate their performance. RESULTS: The FDLCT scores showed a significant correlation with liver fibrosis stage (Spearman's correlation coefficient = 0.48, p < 0.001). The areas under the receiver operating characteristic curves (with 95% confidence intervals) for diagnosing significant fibrosis (>= F2), advanced fibrosis (>= F3) and cirrhosis (F4) by using FDLCT scores were 0.74 (0.64-0.85), 0.76 (0.66-0.85) and 0.73 (0.62 0.84), respectively. CONCLUSIONS: Liver fibrosis can be staged by using a deep learning model based on CT images, with moderate performance. KEY POINTS: * Liver fibrosis can be staged by a deep learning model based on magnified CT images including the liver surface, with moderate performance. * Scores from a trained deep learning model showed moderate correlation with histopathological liver fibrosis staging. * Further improvement are necessary before utilisation in clinical settings. PMID- 29761359 TI - CT colonography: size reduction of submerged colorectal polyps due to electronic cleansing and CT-window settings. AB - OBJECTIVES: To assess whether electronic cleansing (EC) of tagged residue and different computed tomography (CT) windows influence the size of colorectal polyps in CT colonography (CTC). METHODS: A database of 894 colonoscopy-validated CTC datasets of a low-prevalence cohort was retrospectively reviewed to identify patients with polyps >=6 mm that were entirely submerged in tagged residue. Ten radiologists independently measured the largest diameter of each polyp, two dimensionally, before and after EC in colon, bone, and soft-tissue-windows, in randomised order. Differences in size and polyp count before and after EC were calculated for size categories >=6 mm and >=10 mm. Statistical testing involved 95% confidence interval, intraclass correlation and mixed-model ANOVA. RESULTS: Thirty-seven patients with 48 polyps were included. Mean polyp size before EC was 9.8 mm in colon, 9.9 mm in bone and 8.2 mm in soft-tissue windows. After EC, the mean polyp size decreased significantly to 9.4 mm in colon, 9.1 mm in bone and 7.1 mm in soft-tissue windows. Compared to unsubtracted colon windows, EC, performed in colon, bone and soft-tissue windows, led to a shift of 6 (12,5%), 10 (20.8%) and 25 (52.1%) polyps >=6 mm into the next smaller size category, thus affecting patient risk stratification. CONCLUSIONS: EC and narrow CT windows significantly reduce the size of polyps submerged in tagged residue. Polyp measurements should be performed in unsubtracted colon windows. KEY POINTS: * EC significantly reduces the size of polyps submerged in tagged residue. * Abdominal CT-window settings significantly underestimate 2D sizes of submerged polyps. * Size reduction in EC is significantly greater in narrow than wide windows. * Underestimation of polyp size due to EC may lead to inadequate treatment. * Polyp measurements should be performed in unsubtracted images using a colon window. PMID- 29761360 TI - Tumour volume of resectable oesophageal squamous cell carcinoma measured with MRI correlates well with T category and lymphatic metastasis. AB - OBJECTIVES: To determine association of gross tumour volume (GTV) of resectable oesophageal squamous cell carcinoma (SCC) measured on T2-weighted imaging (T2WI), contrast-enhanced T1-weighted imaging (CE-T1WI) and diffusion-weighted imaging (DWI) with T category and lymphatic metastasis (LM). METHODS: Sixty oesophageal SCC patients underwent fat-suppressed T2WI, CE-T1WI and DWI with b values of 0, 500 and 800 s/mm2. GTV was measured on three sequences. Statistical analyses were performed to determine association of GTV with T category and LM. RESULTS: Spearman's rank correlation analysis showed positive association of GTV with T category and LM (all p values < 0.01). Differences in GTV were found between T1 and T2 or T3 categories shown by Kruskal-Wallis H and one-way ANOVA tests, and between T1/T2 and T3 and between tumours with and without LM by Mann-Whitney U tests (all p values < 0.05). Receiver operating characteristic analyses showed cut-off GTVs of 5.795, 5.276 and 10.11 cm3 on CE-T1WI could better differentiate T1 from T2 categories, T1 from T3, and T1-2 from T3 than those of 7.066, 7.045 and 8.504 cm3 on T2WI, of 5.793, 6.609 and 6.989 cm3 on DWI with b value of 500 s/mm2, and of 4.156, 4.519 and 4.985 cm3 with b value of 800 s/mm2, respectively. Cut-off of 10.462 cm3 on DWI with b value of 500 s/mm2 could better identify LM than of 12.38, 8.793 and 9.600 cm3 on T2WI, CE-T1WI and DWI with b value of 800 s/mm2, respectively. CONCLUSIONS: GTVs on T2WI, CE-T1WI and DWI are associated with T category of and LM of oesophageal SCC. KEY POINTS: * GTV is associated with T category and lymphatic metastasis of oesophageal SCC * GTV measured on contrast-enhanced T 1 -weighted imaging better identifies T category * GTV measured on DWI with b value of 500 s/mm 2 better identifies lymphatic metastasis. PMID- 29761362 TI - Pulmonary hypertension due to left heart disease: diagnostic and prognostic value of CT in chronic systolic heart failure. AB - OBJECTIVES: To evaluate the ability of chest computed tomography (CT) to predict pulmonary hypertension (PH) and outcome in chronic heart failure with reduced ejection fraction (HFrEF). METHODS: We reviewed 119 consecutive patients with HFrEF by CT, transthoracic echocardiography (TTE) and right heart catheterization (RHC). CT-derived pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio), left atrial, right atrial, right ventricular (RV) and left ventricular volumes were correlated with RHC mean pulmonary arterial pressure (mPAP) . Diagnostic accuracy to predict PH and ability to predict primary composite endpoint of all-cause mortality and HF events were evaluated. RESULTS: RV volume was significantly higher in 81 patients with PH compared to 38 patients without PH (133 ml/m2 vs. 79 ml/m2, p < 0.001) and was moderately correlated with mPAP (r=0.55, p < 0.001). Also, RV volume had higher ability to predict PH (area under the curve: 0.88) than PA diameter (0.79), PA:A ratio (0.76) by CT and tricuspid regurgitation gradient (0.83) and RV basal diameter by TTE (0.84, all p < 0.001). During the follow-up period (median: 3.4 years), 51 patients (43%) had HF events or died. After correction for important clinical, TTE and RHC parameters, RV volume (adjusted hazard ratio [HR]: 1.71, 95% CI 1.31 2.23, p < 0.001) and PA diameter (HR: 1.61, 95% CI 1.18-2.22, p = 0.003) were independent predictors of the primary endpoint. CONCLUSION: In patients with HFrEF, measurement of RV volume and PA diameter on ungated CT are non-invasive markers of PH and may help to predict the patient outcome. KEY POINTS: * Right ventricular (RV) volume measured by chest CT has good ability to identify pulmonary hypertension (PH) in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF). * The accuracy of pulmonary artery (PA) diameter and PA to ascending aorta diameter ratio (PA:A ratio) to predict PH was similar to previous studies, however, with lower cut-offs (28.1 mm and 0.92, respectively). * Chest CT-derived PA diameter and RV volume independently predict all-cause mortality and HF events and improve outcome prediction in patients with advanced HFrEF. PMID- 29761363 TI - Scientific iconoclasm and active imagination: synthetic cells as techno scientific mandalas. AB - Metaphors allow us to come to terms with abstract and complex information, by comparing it to something which is structured, familiar and concrete. Although modern science is "iconoclastic", as Gaston Bachelard phrases it (i.e. bent on replacing living entities by symbolic data: e.g. biochemical and mathematical symbols and codes), scientists are at the same time prolific producers of metaphoric images themselves. Synthetic biology is an outstanding example of a technoscientific discourse replete with metaphors, including textual metaphors such as the "Morse code" of life, the "barcode" of life and the "book" of life. This paper focuses on a different type of metaphor, however, namely on the archetypal metaphor of the mandala as a symbol of restored unity and wholeness. Notably, mandala images emerge in textual materials (papers, posters, PowerPoints, etc.) related to one of the new "frontiers" of contemporary technoscience, namely the building of a synthetic cell: a laboratory artefact that functions like a cell and is even able to replicate itself. The mandala symbol suggests that, after living systems have been successfully reduced to the elementary building blocks and barcodes of life, the time has now come to put these fragments together again. We can only claim to understand life, synthetic cell experts argue, if we are able to technically reproduce a fully functioning cell. This holistic turn towards the cell as a meaningful whole (a total work of techno-art) also requires convergence at the "subject pole": the building of a synthetic cell as a practice of the self, representing a turn towards integration, of multiple perspectives and various forms of expertise. PMID- 29761364 TI - [Low emission zones in Germany : A reliable measure for keeping current air quality standards?] AB - Low Emission Zones (LEZs) were implemented as a measure for improving the quality of ambient air. As of February 2018, 58 LEZs were in operation in Germany; however they differ significantly, especially regarding their size.The effectiveness of LEZs has been investigated by dispersion modelling as well as by analysis of PM10 (particles which pass through a size-selective inlet with a 50 % efficiency cut-off at 10 MUm aerodynamic diameter) and nitrogen dioxide (NO2) measurement values. Recent studies show a clear trend. In sufficiently large and strictly regulated LEZs, a reduction of PM10 concentration between 5 and 10% can be shown, and at some traffic sites above 10%. The current (currently valid) limit values for PM10 were introduced in 2005, mainly due to the adverse health effects of fine particles on respiratory and cardiovascular morbidity and mortality. The most health-relevant PM10 particle fraction consists mainly of traffic-related particles and here especially of diesel soot particles. Therefore, the German regulations for LEZs promote using diesel particulate filters in diesel cars.Unfortunately, the evaluation of the LEZ effects is mostly restricted to PM10, a particle fraction containing only a comparatively small portion of highly toxic exhaust-related particles. The analysis of air pollutants that are more traffic specific (such as elemental carbon, ultrafine particles, PM2.5 [particles which pass through a size-selective inlet with a 50 % efficiency cut-off at 10 MUm aerodynamic diameter]) would be more adequate. For "powerful" LEZs, more pronounced reductions of such pollutants have clearly been shown. This also means that the benefit of LEZs on human health is by far greater than is presently visible from routine measurements of PM10.Since the stickers for LEZs are in fact meant to reduce particulate matter, it is not surprising that the introduction of LEZs has not resulted in a demonstrable reduction in NO2 concentrations. PMID- 29761361 TI - Ultrasonography in diagnosing clinically occult groin hernia: systematic review and meta-analysis. AB - OBJECTIVES: To provide an updated systematic review on the performance of ultrasonography (US) in diagnosing clinically occult groin hernia. METHODS: A systematic search was performed in MEDLINE and Embase. Methodological quality of included studies was assessed. Accuracy data of US in detecting clinically occult groin hernia were extracted. Positive predictive value (PPV) was pooled with a random effects model. For studies investigating the performance of US in hernia type classification (inguinal vs femoral), correctly classified proportion was assessed. RESULTS: Sixteen studies were included. In the two studies without verification bias, sensitivities were 29.4% [95% confidence interval (CI), 15.1 47.5%] and 90.9% (95% CI, 70.8-98.9%); specificities were 90.0% (95% CI, 80.5 95.9%) and 90.6% (95% CI, 83.0-95.6%). Verification bias or a variation of it (i.e. study limited to only subjects with definitive proof of disease status) was present in all other studies. Sensitivity, specificity, and negative predictive value (NPV) were not pooled. PPV ranged from 58.8 to 100%. Pooled PPV, based on data from ten studies with low risk of bias and no applicability concerns with respect to patient selection, was 85.6% (95% CI, 76.5-92.7%). Proportion of correctly classified hernias, based on data from four studies, ranged between 94.4% and 99.1%. CONCLUSIONS: Sensitivity, specificity and NPV of US in detecting clinically occult groin hernia cannot reliably be determined based on current evidence. Further studies are necessary. Accuracy may strongly depend on the examiner's skills. PPV is high. Inguinal and femoral hernias can reliably be differentiated by US. KEY POINTS: * Sensitivity, specificity and NPV of ultrasound in detecting clinically occult groin hernia cannot reliably be determined based on current evidence. * Accuracy may strongly depend on the examiner's skills. * PPV of US in detection of clinically occult groin hernia is high [pooled PPV of 85.6% (95% confidence interval, 76.5-92.7%)]. * US has very high performance in correctly differentiating between clinically occult inguinal and femoral hernia (correctness of 94.4- 99.1%). PMID- 29761366 TI - Correction to: An SIV macaque model of SIV and HAND: the need for adjunctive therapies in HIV that target activated monocytes and macrophages. AB - Due to an oversight, acknowledgement and source of funding was inadvertently omitted from the original article. PMID- 29761365 TI - Visual Rating and Computer-Assisted Analysis of FDG PET in the Prediction of Conversion to Alzheimer's Disease in Mild Cognitive Impairment. AB - BACKGROUND: Fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful to predict Alzheimer's disease (AD) conversion in patients with mild cognitive impairment (MCI). However, few studies have examined the extent to which FDG PET alone can predict AD conversion and compared the efficacy between visual and computer-assisted analysis directly. OBJECTIVE: The current study aimed to evaluate the value of FDG PET in predicting the conversion to AD in patients with MCI and to compare the predictive values of visual reading and computer-assisted analysis. METHODS AND MATERIALS: A total of 54 patients with MCI were evaluated with FDG PET and followed-up for 2 years with final diagnostic evaluation. FDG PET images were evaluated by (1) traditional visual rating, (2) composite score of visual rating of the brain cortices, and (3) composite score of computer assisted analysis. Receiver operating characteristics (ROC) curves were compared to analyze predictive values. RESULTS: Nineteen patients (35.2%) converted to AD from MCI. The area under the curve (AUC) of the ROC curve of the traditional visual rating, composite score of visual rating, and computer-assisted analysis were 0.67, 0.76, and 0.79, respectively. ROC curves of the composite scores of the visual rating and computer-assisted analysis were comparable (Z = 0.463, p = 0.643). CONCLUSIONS: Visual rating and computer-assisted analysis of FDG PET scans were analogously accurate in predicting AD conversion in patients with MCI. Therefore, FDG PET may be a useful tool for screening AD conversion in patients with MCI, when using composite score, regardless of the method of interpretation. PMID- 29761367 TI - In Vivo Pharmacokinetics of Bromfenac Ophthalmic Solution 0.075%, Bromfenac Ophthalmic Solution 0.07%, and Nepafenac/Amfenac Ophthalmic Suspension 0.3% in Rabbits. AB - INTRODUCTION: Little is known of the ocular distribution characteristics of currently branded non-steroidal anti-inflammatory drugs (NSAIDs) in the United States. This study was designed to predict the ocular bioavailability characteristics in humans using Dutch Belted rabbits as a surrogate. Commercially available, topically-applied NSAIDs containing bromfenac or nepafenac/amfenac were evaluated. METHODS: 126 healthy adult Dutch Belted rabbits were randomly assigned to three treatment cohorts (BromSite(r) twice daily [BID] in the right eye, BromSite(r) once daily [QD] in the right eye, Prolensa(r) QD in the right eye and IlevroTM QD in the left eye) and 7 post-dosing time points (0.5, 1, 2, 4, 8, 12, 24 h after final instillation). The study eyes received 40 uL of the assigned drug for a consecutive 9 days. Samples of aqueous humor, iris-ciliary body, choroid, sclera, and retina were harvested from the study eyes at the assigned time point after the last dose on the 9th day. NSAID content in ocular tissues was analyzed using high-performance liquid chromatography (HPLC), and area under the curve (AUC0.5-24h), maximum concentration (Cmax), and time to maximum concentration (Tmax) were determined. RESULTS: Peak NSAID concentrations were reached within 1-3 h in the anterior segment and within 1-3 h in the posterior segment after last dose. Throughout the ocular tissues, both AUC and Cmax for BromSite(r) (BID and QD) were consistently higher than respective NSAID concentrations of Prolensa(r) QD and Ilevro(r) QD. When comparing BromSite(r) BID to QD, the BID regimen produced generally higher but statistically similar bromfenac concentrations throughout the ocular tissues except in the aqueous humor and iris-ciliary body, where the AUC BID was statistically significantly higher with BromSite(r) BID. CONCLUSION: As a surrogate to human ocular bioavailability, BromSite(r) demonstrated significantly greater NSAID compared to Prolensa(r) QD and Ilevro(r) QD. The DuraSite(r) component of BromSite(r) appears to enhance ocular penetration throughout both anterior and posterior tissues. FUNDING: Sun Pharmaceutical Industries Ltd. PMID- 29761370 TI - Multispecies individuals. AB - We assess the arguments for recognising functionally integrated multispecies consortia as genuine biological individuals, including cases of so-called 'holobionts'. We provide two examples in which the same core biochemical processes that sustain life are distributed across a consortium of individuals of different species. Although the same chemistry features in both examples, proponents of the holobiont as unit of evolution would recognize one of the two cases as a multispecies individual whilst they would consider the other as a compelling case of ecological dependence between separate individuals. Some widely used arguments in support of the 'holobiont' concept apply equally to both cases, suggesting that those arguments have misidentified what is at stake when seeking to identify a new level of biological individuality. One important aspect of biological individuality is evolutionary individuality. In line with other work on the evolution of individuality, we show that our cases can be distinguished by focusing on the fitness alignment between the partners of the consortia. We conclude that much of the evidence currently presented for the ubiquity and importance of multi-species individuals is simply not to the point, at least unless the issue of biological individuality is firmly divorced from the question of evolutionary individuality. PMID- 29761368 TI - IDH1 mutation in human glioma induces chemical alterations that are amenable to optical Raman spectroscopy. AB - INTRODUCTION: Mutations in the isocytrate dehydrogenase 1 (IDH1) gene are early genetic events in glioma pathogenesis and cause profound metabolic changes. Because this genotype is found in virtually every tumor cell, therapies targeting mutant IDH1 protein are being developed. The intraoperative administration of those therapies would require fast technologies for the determination of IDH1 genotype. As of today, there is no such diagnostic test available. Recently, infrared spectroscopy was shown to bridge this gap. Here, we tested Raman spectroscopy for analysis of IDH1 genotype in glioma, which constitutes an alternative contact-free technique with the potential of being applicable in situ. METHODS: Human glioma samples (n = 36) were obtained during surgery and cryosections were prepared. IDH1 mutations were assessed using DNA sequencing and 100 Raman spectra were obtained for each sample. RESULTS: Analysis of Raman spectra revealed increased intensities in spectral bands related to DNA in IDH1 mutant glioma while bands assigned to molecular vibrations of lipids were significantly decreased. Moreover, intensities of Raman bands assigned to proteins differed in IDH1 mutant and IDH1 wild-type glioma, suggesting alterations in the protein profile. The selection of five bands (498, 826, 1003, 1174 and 1337 cm-1) allowed the classification of Raman spectra according to IDH1 genotype with a correct rate of 89%. CONCLUSION: Raman spectroscopy constitutes a simple, rapid and safe procedure for determination of the IDH1 mutation that shows great promise for clinically relevant in situ diagnostics. PMID- 29761369 TI - Oligodendrogliomas in pediatric and teenage patients only rarely exhibit molecular markers and patients have excellent survivals. AB - Although oligodendrogliomas appear histologically similar in adult and pediatric patients, the latter have only been rarely studied and most of those studies did not have long follow-up. We examined 55 oligodendroglial tumors from pediatric and teenage patients for their biomarkers with formalin-fixed paraffin-embedded tissues and studied their survival status. None of the tumors harbored 1p/19q codeletion or IDH mutation. Mutations in TERTp (4%), BRAF (11%), FGFR1 (3%) and H3F3A (5%), fusions of BRAF (8%) and FGFR1 (8%) were found sparingly and almost all in a mutually exclusive manner. Molecular events were exclusively found in tumors with classic oligodendroglial histology. Survival analysis showed remarkably excellent prognosis compared to the adult counterparts. 5-year overall survival was 95% in our cohort with median follow-up of 8.1 years and in nine patients with follow-up more than 10 years, the 10-year overall survival was 100%. The 5-year and 10-year progression-free survivals of our cohort were 89 and 77%, respectively. FGFR1 fusion seemed to confer a poor prognosis in pediatric oligodendrogliomas. Patients receiving adjuvant chemotherapy (p = 0.046) or harboring Grade II histology (p < 0.001) had longer interval to recurrence. Our study demonstrated the distinct indolent clinical course of pediatric and teenage oligodendrogliomas compared to the adult tumors. Molecular markers commonly seen in adult oligodendrogliomas and other pediatric low-grade gliomas were only rarely seen. Since there is no clinical or molecular evidence suggesting that pediatric "oligodendrogliomas" are the same as adult oligodendrogliomas albeit histologic similarity, a case can be made for their separation from adult oligodendrogliomas in the next WHO classification. PMID- 29761373 TI - Response to "Commentary on: Lung cancer screening with MRI: results of the first screening round": Ngam Pei Ing et al. PMID- 29761371 TI - Tolerability and efficacy of deferasirox in patients with transfusional iron overload: results from a German 2-year non-interventional study. AB - BACKGROUND: Iron overload (IOL) due to repetitive transfusions of packed red blood cells (pRBC) has a major impact on morbidity and mortality in patients with inherited bone marrow failure syndromes and hemoglobinopathies such as thalassemia and sickle cell disease. However, whether IOL influences the outcome of elderly patients with myeloid malignancies is not yet clear. Moreover, clinical trials have reported high drop-out rates during treatment with the oral iron chelator deferasirox (DFX). AIM: Here we report the results of a 2-year prospective observational study that aimed at describing the routine use of DFX in patients with hematological malignancies with regard to safety, efficacy and handling of the drug in a routine setting. RESULTS: A total of 406 patients were included. 58% of the patients were male. Most of the patients had myelodysplastic syndromes (MDS) (68%) and myeloproliferative neoplasms (MPN) (14%). Median time from first transfusion to study enrollment was 1.1 years (0-25.5 years) and most patients were chelation naive (91%) at enrollment. With regard to transfusion burden, most of the patients were moderately or mildly transfusion-dependent with 53% receiving 2-4 and 27% receiving less than 2 units of pRBC per month. Serum ferritin decreased from a mean of 2305 MUg/l (+/- 1449 MUg/l) to a mean of 1910 MUg/l (+/- 1529 MUg/l) at 24 months. There was no substantial change in transfusion-dependence during the observation period. Dose adjustments were reported in 48% of the patients with dose-escalation strategies being the most frequent reason for dosage increases (49%). The median observation time was 355 days (5-1080 days). Median duration of exposure to DFX was 322 days (2-1078 days). Two-hundred and ninety (72%) patients discontinued the trial prematurely after a median time of 235 days (1-808 days). Death (29%) and adverse events (23%) were the main reasons for discontinuation. Eleven percent of the patients discontinued treatment due to sufficient decrease in serum ferritin. Most frequent adverse events were decrease in creatinine clearance (22%), increase in serum creatinine (18%) and diarrhea (16%). CONCLUSION: This descriptive trial confirms the efficacy of DFX in decreasing the serum ferritin. Moreover, the high drop-out rates seen in prospective trials are recapitulated in this study, which can be attributed to adverse events in a substantial proportion of patients. PMID- 29761372 TI - Outcomes of Takotsubo cardiomyopathy in hospitalized cancer patients. AB - BACKGROUND: Chemotherapy-induced cardiomyopathy is a critical complication of treatment for cancer. The emotional stress of a cancer diagnosis, ongoing chemotherapy, abnormal cancer-related wasting syndrome may contribute to cardiac morbidity in these patients. The burden of Takotsubo Cardiomyopathy (TCM) in cancer patients is unknown. The incidence of TCM and related outcomes in cancer patients was investigated in this study. METHODS: The 2007-2013 National Inpatient Sample (NIS) was analyzed for patients with a prior and new diagnosis of TCM with and without malignancy. Risk factors for mortality were adjusted for associated conditions by multivariable logistic regression analysis. RESULTS: From 2007 to 2013, an estimated 122,855 adults were admitted with a diagnosis of TCM. In 2013, the incidence of admissions in US of patients with coexisting TCM and malignancy was 1.13%. Patients admitted for TCM with coexisting malignancy had a significantly higher mortality (13.8 vs. 2.9%, p < 0.0001), length of stay (7 vs. 4 days, p < 0.0001) and total charges ($29,291 vs. $36,231, p < 0.0001), compared to those with no malignancy. In patients with a primary diagnosis of TCM and without any underlying malignancy, males had a higher mortality (4.02 vs. 1.03%, p < 0.0001), whereas there was no gender difference in mortality in those with coexisting malignancy (6.25 vs. 6.45%, p = 0.965). On multivariable logistic regression analysis, risk factors associated with mortality were solid cancer (OR 3.43, p = 0.008), stroke (OR 18.33, p < 0.0001) and heart failure (OR 1.918, p = 0.004). CONCLUSIONS: Outcomes are significantly worse in patients with TCM and malignancy. Hence, this patient population must be regarded as high-risk and early diagnostic consideration for TCM is warranted. Early intervention may help lower mortality, decrease resource utilization and reduce the health care costs in these patients. PMID- 29761374 TI - The prognostic role of HBV infection in chronic lymphocytic leukemia. AB - PURPOSE: We attempt to assess the impact of hepatis-B virus (HBV) status on the prognosis of chronic lymphocytic leukemia (CLL) using a Chinese case cohort. METHODS: Five hundred and one consecutive newly diagnosed subjects with CLL were enrolled in this case cohort. HBV infection was defined as hepatitis B surface antigen (HBsAg) positive or hepatitis-B core antibody (HBcAb) positive. Univariate and stepwise multivariate Cox regression analyses were used to screen the prognostic risk factors associated with the end point of time-to-treatment (TTT) or overall survival (OS). Bootstrap re-sampling method was used to evaluate the model's internal validity. The discriminative ability of the models was evaluated using time-dependent receiver-operator characteristic (ROC) curves and corresponding areas under the curve (AUC). RESULTS: One hundred and twenty-one subjects (24%) among 501 patients were HBV positive. HBV infection was an independent predictor for the prognosis of TTT (HR = 1.37; 95% CI 1.04-1.80) or OS (HR =2.85; 95% CI 1.80-4.52). The AUCs for HBV infection were 0.62 (95% CI 0.58-0.66) for TTT and 0.69 (95% CI 0.66-0.72) for OS, respectively. When we combined HBV infection with the traditional clinical and biological factors, significant improvements for model's discrimination were observed for TTT [AUC: 0.81 (95% CI: 0.77-0.85) vs. 0.78 (95% CI: 0.74-0.82), P < 0.001] and OS [AUC: 0.81 (95% CI 0.76-0.86) vs. 0.76 (95% CI 0.71-0.82), P < 0.001). Further bootstrap re-sampling method revealed good internal consistence for the final optimal models (Average AUC: 0.78 for TTT and 0.79 for OS based on 1000 bootstraps). CONCLUSIONS: Our results indicated that HBV infection should be served as an important risk predictor for prognosis of CLL (TTT and OS). PMID- 29761376 TI - Measurement of urinary biomarkers in a case of tubulointerstitial nephritis and uveitis syndrome during glucocorticoid treatment. AB - Tubulointerstitial nephritis and uveitis (TINU) is a rare syndrome in which idiopathic interstitial nephritis coexists with chronic recurrent uveitis. This syndrome often represents systemic disorders such as arthralgia, rash, prolonged fever, anaemia and ocular symptoms that require medication including glucocorticoid administration. Recently, novel urinary biomarkers, such as kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and liver-type fatty acid-binding protein, were shown to be associated with tubulointerstitial damage and were elevated in interstitial nephritis. We evaluated these urinary biomarkers in a case of TINU syndrome before and during treatment and found that their levels were elevated at onset and decreased during treatment, especially NGAL. We conclude that these urinary biomarkers are useful to evaluate and predict prognosis in interstitial nephritis. PMID- 29761377 TI - How different direct association routes influence the indirect route in the same Simon-like task. AB - The location-, word-, and arrow-based Simon effects are usually attributed to the result of a direct route (the spatially corresponding stimulus-response association, activated automatically) that interferes with an indirect route (the association of task-relevant information and response, activated in accordance with the instructed stimulus-response mapping). We examined whether and how distinct direct routes (stimulus-location-response position and location word response position or arrow direction-response position associations) affect responding on the basis of the same indirect route (a stimulus color-response association) in a Simon-like task. For this task, left-right keypresses were made to indicate the ink colors of location words or left- or right-pointing arrows, presented eccentrically in left or right locations. The location-based Simon effect occurred at the levels of mean reaction time (RT) and RT distribution in the word Simon-like task, whereas the word-based Simon effect only occurred at the level of RT distribution. In the arrow Simon-like task, the location-based Simon effect did not occur at the level of mean RT, but did at the level of RT distribution, whereas the opposite pattern occurred for the arrow-based Simon effect. These results could imply that one direct route influences the effects of the other direct route on the responses, depending on the task context. PMID- 29761375 TI - Internal control beliefs and reference frame concurrently impact early performance monitoring ERPs. AB - This study investigated the impact of criterion-based vs. social reference frames on behavioural and neural correlates of performance monitoring while taking individual differences in control beliefs into account. We conducted two experiments administering a time estimation task in which feedback was either delivered pertaining to participants' own performance (nonsocial/criterion-based reference) or to the performance of a reference group of previous participants (social reference). In Experiment 1, 34 male volunteers participated. To test generalizability of the observed results to both sexes/genders, we recruited 36 female volunteers for Experiment 2. P2 and P300 amplitudes were generally larger in social than in nonsocial reference trials in the male participants of Experiment 1. DeltaFRN amplitudes were larger for social compared to non-social reference trials in Experiment 1. No effects of reference frame were found in the female sample of Experiment 2. Rather, P2 and DeltaFRN effects showed opposing patterns for nonsocial versus social reference frames. However, stronger internal control beliefs were accompanied by larger FRN amplitudes of negative social reference trials in both samples, suggesting generalizable effects independent of sex/gender. Enhanced P2 and DeltaFRN amplitudes for social versus nonsocial reference trials suggest enhanced attentional capture and higher saliency of socially framed feedback in male participants only. In both sexes/genders, however, the social reference frame possibly challenges internal control beliefs and by this enhances performance monitoring. Our results demonstrate the complex interplay of trait variables and reference frames during performance monitoring influencing our daily lives-reference frames are omnipresent in education and one's working environment. PMID- 29761378 TI - Inhibition and Substrate Specificity Properties of FKBP22 from a Psychrotrophic Bacterium, Shewanella sp. SIB1. AB - SIB1 FKBP22 is a peptidyl prolyl cis-trans isomerase (PPIase) member from a psychrotrophic bacterium, Shewanella sp. SIB1, consisting of N- and C-domains responsible for dimerization and catalytic PPIase activity, respectively. This protein was assumed to be involved in cold adaptation of SIB1 cells through its dual activity of PPIase activity and chaperone like-function. Nevertheless, the catalytic inhibition by FK506 and its substrate specificity remain unknown. Besides, ability of SIB1 FKBP22 to inhibit phosphatase activity of calcinuerin is also interesting to be studied since it may reflect wider cellular functions of SIB1 FKBP22. In this study, we found that wild type (WT) SIB1 FKBP22 bound to FK506 with IC50 of 77.55 nM. This value is comparable to that of monomeric mutants (NNC-FKBP22, C-domain+ and V37R/L41R mutants), yet significantly higher than that of active site mutant (R142A). In addition, WT SIB1 FKBP22 and monomeric variants were found to prefer hydrophobic residues preceding proline. Meanwhile, R142A mutant has wider preferences on bulkier hydrophobic residues due to increasing hydrophobicity and binding pocket space. Surprisingly, in the absence of FK506, SIB1 FKBP22 and its variants inhibited, with the exception of N domain, calcineurin phosphatase activity, albeit low. The inhibition of SIB1 FKBP22 by FK506 is dramatically increased in the presence of FK506. Altogether, we proposed that local structure at substrate binding pocket of C-domain plays crucial role for the binding of FK506 and peptide substrate preferences. In addition, C-domain is essential for inhibition, while dimerization state is important for optimum inhibition through efficient binding to calcineurin. PMID- 29761379 TI - A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model. AB - This study investigated the safety and efficacy of a sustained release of basic fibroblast growth factor (bFGF) with biodegradable gelatin hydrogel sheets as therapeutic angiogenesis in canine chronic myocardial infarction (MI) models. Canine chronic MI model was induced by ligating the left anterior descending coronary artery and its diagonal branches. At 4 week post-induction, we applied either saline (Control group, n = 5) or 200 MUg of bFGF (Treatment group, n = 6) soaked gelatin hydrogel sheets on the ischemic area of the left ventricular (LV) wall. At 6 weeks after the procedure, we evaluated the efficacy by echocardiography and immunohistochemical study. There were no procedure-related adverse events or deaths. The serum bFGF level was under detectable levels in all animals at any sampling points. In terms of efficacy, echocardiographic evaluation demonstrated that fractional shortening was significantly improved in the treatment group. In addition, immunohistochemical study showed that the capillary density in the border zone of the MI area, as well as the MI area, significantly increased in the treatment group. Therapeutic angiogenesis by bFGF using biodegradable gelatin hydrogel sheets was safe, increased the capillary density, and improved LV function in canine chronic MI models. PMID- 29761380 TI - Saliva Production and Enjoyment of Real-Food Flavors in People with and Without Dysphagia and/or Xerostomia. AB - Non-food gustatory stimulation has multiple potential therapeutic benefits for people with dysphagia and xerostomia. This study examined palatability and saliva flow associated with dissolvable flavored films. Taste strips with real-food flavors dissolved on the tongues of 21 persons with dysphagia and/or xerostomia and 21 healthy age- and sex-matched adults while sublingual gauze pads absorbed saliva over randomized 3-min trials. Participants rated taste enjoyment for each trial on a hedonic general labeled magnitude scale. Flavored strips elicited more saliva than baseline for both groups, and production was higher for controls than patients (M = 2.386 and 1.091 g, respectively; p = 0.036). Main effects of flavor were observed for saliva production (p = 0.002) and hedonics (p < 0.001). Hedonic ratings and saliva production were weakly correlated (r = 0.293, p < 0.001). Results support dissolvable taste strips as a tool for providing low-risk taste stimulation in dysphagia and for eliciting an increase in saliva flow that may provide temporary relief from dry mouth symptoms. The preferred flavors were, on average, also the ones that elicited greater saliva production. Taste strips have the potential to be beneficial for swallowing-related neural activity, timing, and safety in dysphagia. Further, they may ameliorate complications of xerostomia. PMID- 29761382 TI - Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension. AB - Latanoprostene bunod ophthalmic solution 0.024% (hereafter referred to as latanoprostene bunod 0.024%) [VyzultaTM] is a nitric oxide (NO)-donating prostaglandin F2alpha analogue approved in the USA for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension. It is thought to lower IOP by increasing aqueous humour outflow through the uveoscleral pathway (mediated by latanoprost acid) and increasing the facility of aqueous humour outflow through the trabecular meshwork pathway (mediated by NO). Results from two multinational, phase III studies (APOLLO and LUNAR) and a pooled analysis of these studies demonstrated the noninferiority of latanoprostene bunod 0.024% to timolol ophthalmic solution 0.5% (hereafter referred to as timolol 0.5%) in terms of IOP-lowering efficacy over 3 months in patients with OAG or ocular hypertension, with the superiority of latanoprostene bunod 0.024% over timolol 0.5% subsequently demonstrated in APOLLO and the pooled analysis. Moreover, there was no apparent loss of IOP-lowering effect in subsequent safety extension periods of up to 9 months. The IOP-lowering efficacy seen in APOLLO and LUNAR was confirmed in a phase III study (JUPITER) in Japanese patients, with IOP reductions observed early (week 4) and maintained over the longer-term (12 months). Latanoprostene bunod 0.024% was well tolerated over up to 12 months in these studies, with most ocular treatment-emergent adverse events (TEAEs) being mild to moderate in severity. Thus, current evidence indicates once daily latanoprostene bunod 0.024% is an effective and well tolerated treatment option for the reduction of IOP in adults with OAG or ocular hypertension. PMID- 29761383 TI - Culture of Human Monocyte-Derived Macrophages. AB - The study of human macrophages is often hampered by access to tissue and inability of this cell type to survive in vitro following isolation. The culture of human monocyte-derived macrophages (MDMs) represents a tool to study macrophages, with monocytes known to give rise to tissue macrophages influenced by certain environmental cues. Here we describe a method of culturing monocyte derived macrophages from CD14+ blood monocytes and polarization toward different macrophage phenotypes. PMID- 29761384 TI - A Simple Multistep Protocol for Differentiating Human Induced Pluripotent Stem Cells into Functional Macrophages. AB - Macrophages differentiated from human induced pluripotent stem cells (hiPSCs) provide an alternative new tool overcoming some of the limitations of existing models for human macrophages, such as human macrophage-like cell lines and primary monocyte-derived macrophages. A combination of different cytokines and growth factors can differentiate hiPSCs toward myeloid lineage. Here we describe a simple multistep protocol for differentiating hiPSCs into functional macrophages. This includes derivation of three germ-line containing embryoid bodies (EBs) from iPSCs, generation of myeloid precursors from EBs, and finally maturation of myeloid precursors into functional macrophages. Technical procedure and specific culture conditions associated with each of these steps are discussed in detail. PMID- 29761381 TI - Impaired Tongue Function as an Indicator of Laryngeal Aspiration in Adults with Acquired Oropharyngeal Dysphagia: A Systematic Review. AB - Tongue function assessment typically forms part of a clinical bedside swallowing evaluation (CBSE). The predictive value of lingual function for calculating aspiration risk in isolation is not known. The aim of this systematic review was to collate current evidence on the utility of assessing lingual deficits for predicting aspiration. Health databases Medline, CINAHL, Cochrane Library, SpeechBITE, AMED and Embase were searched from inception to November 2016. Studies were included if there was a comparison between a clinical lingual assessment (index test) and aspiration on instrumental assessments (reference test) in adults who had been diagnosed with oropharyngeal dysphagia. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess the quality of the studies. Sensitivity, specificity, predictive values, likelihood ratios and odds ratios were extracted or calculated where possible. A best evidence synthesis and receiver operator curve (ROC) analysis for sensitivity and specificity were conducted. Twelve studies were included, of which only one had a low risk of bias. The ROC curve, predictive values and likelihood ratios did not show a relationship between lingual function and aspiration. Best evidence synthesis showed moderate evidence that when motility and strength are jointly assessed, they are not associated with aspiration. Other lingual assessment variables indicated either limited or conflicting evidence of an association. There is currently no evidence to indicate that there is a predictive relationship between lingual deficits as part of a CBSE and aspiration in adults with acquired oropharyngeal dysphagia. Recommendations for clinical practice and future research are made. PMID- 29761385 TI - Growing Murine Bone Marrow-Derived Macrophages. AB - Bone marrow-derived macrophages (BMDM) are primary macrophages obtained by in vitro differentiation of bone marrow cells in the presence of macrophage colony stimulating factor (M-CSF or CSF1). They are easy to obtain in high yields, can be stored by freezing, and can be obtained from genetically modified mice strains. They are therefore widely used as prototypical macrophages for in vitro studies. In this chapter, we present the method for obtaining BMDMs and freezing them. PMID- 29761386 TI - Immortalization of Murine Bone Marrow-Derived Macrophages. AB - Macrophages are specialized phagocytes that display a variety of important functions for the host immune system. They are particularly important for the recognition of exogenous and endogenous danger signals, forming the defensive front line as part of innate immune response. As such, murine macrophages are commonly used for in vitro cell-based assays examining the mechanisms of innate immune activation, which can require the ongoing breeding and housing of a large number of genetically modified mouse strains. Here, we describe a robust protocol for the generation of immortalized bone marrow-derived macrophages (iBMDMs) from primary murine bone marrow cells. We further provide general protocols for harvesting, freezing, and thawing of bone marrow cells, maintaining iBMDMs in culture and generation of monoclonal iBMDM populations by single-cell cloning. PMID- 29761387 TI - Isolation and Identification of Murine Serous Cavity Macrophages. AB - Accessibility and ease of leukocyte extraction led to the peritoneal cavity becoming one of the most commonly used sites to obtain primary macrophages for in vitro analyses and to model inflammation. However, the advent of multiparameter flow cytometry has highlighted the complexity of the mononuclear phagocyte compartment of the serous cavities, which contains multiple populations of macrophages, dendritic cells, and monocytes that coexist with other leukocytes. Given that serous cavity macrophages are known to contribute to both the maintenance of tissue homeostasis and the generation and resolution of inflammation, a thorough understanding of the cells that comprise the peritoneal macrophage compartment, how to identify them from related mononuclear phagocytes, and the processes required to isolate them for ex vivo and in vitro analysis is important if we are to fully understand their function in different tissue contexts. Here, we detail commonly used methods to isolate leukocytes from the peritoneal and pleural cavities and describe reliable strategies to identify the discrete populations of mononuclear phagocytes in these sites. PMID- 29761388 TI - Isolation and Identification of Interstitial Macrophages from the Lungs Using Different Digestion Enzymes and Staining Strategies. AB - Interstitial macrophages (IMs) are present in multiple organs. Although there is limited knowledge of the unique functional role IM subtypes play, macrophages, in general, are known for their contribution in homeostatic tissue maintenance and inflammation such as clearing pathogens and debris and secreting inflammatory mediators and growth factors. IM subtypes have been identified in the heart, skin, and gut, and more recently we identified three distinct IMs in the lung. IMs express on their surface high levels of MerTK, CD64, and CD11b, with differences in CD11c, CD206, and MHC II expression, and referred to the three pulmonary IM subtypes as IM1 (CD11cloCD206+MHCIIlo), IM2 (CD11cloCD206+MHCIIhi), and IM3 (CD11chiCD206loMHCIIhi). In this chapter, we highlight how to extract IMs from the lung using three different digestion enzymes: elastase, collagenase D, and Liberase TM. Of these three commonly used enzymes, Liberase TM was the most effective at IM extraction, particularly IM3. Furthermore, alternative staining strategies to identify IMs were examined, which included CD64, MerTK, F4/80, and Tim4. Thus, future studies highlighting the functional role of IM subtypes will help further our understanding of how tissue homeostasis is maintained and inflammatory conditions are induced and resolved. PMID- 29761389 TI - Isolation and Phenotyping of Adult Mouse Microglial Cells. AB - Microglia are the resident macrophages of the central nervous system parenchyma and fulfill crucial roles in brain development, homeostasis, and inflammation. The isolation of a pure microglia population from brain tissue enables the examination of microglial phenotypes without the interference of other cell populations. Microglial extractions from the neonatal brain have been described in various protocols, yet the more established and complex adult mouse brain poses a greater challenge. Here we describe a refined protocol including enzymatic and mechanical dissociation of adult mouse brain tissue and removal of myelin by Percoll density gradient. Microglial cells were subsequently extracted by an immunomagnetic approach. This isolation procedure enables the use of functionally viable cells for various applications such as cell culture, flow cytometry, functional assays including bacteria- or bead-based phagocytosis, stimulation assays, and transcriptome profiling techniques such as qRT-PCR and microarray/RNA sequencing. PMID- 29761390 TI - Isolation and Phenotyping of Bone Marrow Macrophages. AB - Macrophages are present in most of the tissues in the organism. They are basically separated into two categories: the resident macrophages, specific of the tissue and capable of proliferation, and the macrophages deriving from the monocyte differentiation. In the bone marrow, the "resident" macrophages are part of the hematopoietic stem cell niche.Those macrophages are known to have a role in the support of erythropoiesis (Chow, Nat Med 19:429-436, 2013), the maintenance of stem cell in their niches (Chow, J Exp Med 208:261-271, 2011), and are an independent self-renewing population (Hashimoto, Immunity 38:792-804, 2013). PMID- 29761391 TI - Isolation and Phenotyping of Intestinal Macrophages. AB - Macrophages are one of the most abundant leucocytes in the intestinal mucosa where they are essential for maintaining homeostasis. However they are also implicated in the pathogenesis of disorders such as inflammatory bowel disease (IBD), offering potential targets for novel therapies.Tissue macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche specific functions. These unique phenotypes likely reflect the heterogeneity of tissue macrophage origins and influence the tissue environment in which they reside. Here we describe how we can characterize and isolate the colonic macrophages. PMID- 29761392 TI - Phenotyping Tumor-Associated Macrophages. AB - Multi-parametric flow cytometry of tumor-bearing murine nonlymphoid tissue allows for characterization, isolation, and examination of immune cell composition, phenotype, and function. Here we describe an approach to process nonlymphoid tissues and then utilize a base antibody panel to define all of the major immune cell types in a single staining condition. This panel can be used to phenotype tumor-associated macrophages. PMID- 29761393 TI - Activating Murine Macrophages In Vitro. AB - Macrophage activation is a process that is highly relevant in both infectious and chronic diseases and so the study of macrophage activation is of high interest to investigators in many fields of biomedical research. Bone marrow-derived macrophages are a popular choice for studying macrophage activation in vitro, as these cells are relatively hardy and many macrophages can be produced from just one mouse. Here we describe the activation of mouse macrophages in vitro, including special considerations for cell culture, detachment, kinetics, and activation states. PMID- 29761394 TI - Polarizing Macrophages In Vitro. AB - Macrophages are a heterogeneous population of innate myeloid cells involved in health and disease, which are the most functionally diverse cells of the hematopoietic system. The main functions of macrophages include responding to pathogens and modulating the adaptive immune response, induction and resolution of inflammation, tissue repair, and homeostasis. Macrophages exhibit remarkable plasticity, in which the different populations of macrophages with distinct physiological and pathological roles can be developed in response to different stimuli. Depending on the types of stimuli that macrophages are exposed to, these cells will be able to polarize to M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages. M1 macrophages are induced by stimulation with IFNgamma and LPS. Based on the stimuli and the achieved transcriptional changes, the M2 macrophages can be classified into four subdivisions: alternative activated macrophages (M2a, activated by IL-4 or IL-13), type 2 macrophages (M2b, activated by immune complexes and LPS), deactivated macrophages (M2c, activated by glucocorticoids or IL-10), and M2-like macrophages (M2d, activated by adenosines or IL-6). In this chapter, we describe the methods to generate different phenotypes of activated macrophages by adding certain stimuli and we also summarize the distinct markers and/or cytokines used for verification of each activated macrophage. PMID- 29761395 TI - Viral Replication Assay in Bone Marrow-Derived Macrophages. AB - The selection of macrophages as a cell type for investigating virus-host interactions is based on cellular tropism of the virus during infection as well as contribution of these cells to pathogenesis in the host. In response to mouse cytomegalovirus (MCMV) infection, bone marrow-resident monocytes that mobilize to infected tissues to differentiate into macrophages and dendritic cells are hijacked in order to facilitate viral persistence. These cells contribute significantly to MCMV biology and, thus, are actively recruited by the virus encoded chemokine. In this chapter, we provide detailed methodologies employed in our laboratory to assess MCMV replication in bone marrow-derived macrophages. PMID- 29761397 TI - Quantitative Phagocytosis Assays in Primary and Cultured Macrophages. AB - This chapter describes methods to induce and quantify phagocytosis in primary macrophages and in myeloid cell lines. To this end, we initially detail the isolation of primary human monocytes and their differentiation into macrophages. Because primary cells are comparatively refractory to molecular manipulation, we also describe the culture of RAW 264.7 cells-an immortalized monocyte/macrophage cell line, which is more tractable. The chapter also includes methods for preparation of phagocytic targets, specifically sheep erythrocytes opsonized with immunoglobulin G (IgG), as well as means of distinguishing bound from internalized targets, using fluorescently labeled secondary antibodies. PMID- 29761396 TI - Macrophage Bactericidal Assays. AB - The search for the bactericidal activity of macrophage (Mphi) is crucial not only during infection, but also to explore its functional activities in normal and pathological conditions, such as autoimmune and inflammatory disorders, allergic inflammation, and cancer. There are several methods exploring the phagocytic and bactericidal activities of Mphi. This chapter focuses specifically on the technique called antibiotic protection assay and on the methods for the determination of Mphi production of nitric oxide and hydrogen peroxide as antimicrobial agents and biomarkers of respiratory burst. The protocols presented herein are valid for both Mphi cell lines and monocyte-derived Mphis (MDMs). PMID- 29761398 TI - Observing Frustrated Phagocytosis and Phagosome Formation and Closure Using Total Internal Reflection Fluorescence Microscopy (TIRFM). AB - Complementary methods to observe frustrated phagocytosis and phagosome closure using total internal reflection fluorescence microscopy (TIRFM) are described here. Frustrated phagocytosis occurs when phagocytic cells are exposed to an opsonized surface and spread as if trying to engulf it, allowing for the observation of phagocytic spreading and the biochemical events that directly precede it. Phagosome formation and closure is an inherently three-dimensional process though, and cannot be studied in the "frustrated" situation. Here we describe a method to visualize with unprecedented high-resolution phagosome formation and closure in three dimensions. It allows for observation of the base of the phagocytic cup, the extending pseudopods, as well as the precise site of phagosome scission. PMID- 29761399 TI - Chromatin Immunoprecipitation in Macrophages. AB - Macrophages are highly polymorphic depending upon their cellular origin and their tissue environment. The different forms that a macrophage can adopt fundamentally reflect different transcription patterns. In addition, macrophages are exquisitely sensitive to a wide variety of signals coming from either infectious agents or damaged tissues. Most of the responses to these signals involve rapid and massive modifications of transcription. The control of transcription relies on the one hand on the posttranslational modification of histones, and on the other hand on the binding on the chromatin of multiple protein complexes. Immunoprecipitation of cross-linked chromatin with specific antibodies will allow to identify the DNA regions bound by the targeted protein, or carrying the targeted histone modification. By taking a snapshot of the macrophage chromatin composition, this technique will be useful to address specific macrophage biology questions at the DNA level, but also to tackle fundamental problems in transcriptional control in a highly suited model cellular system. In this chapter we describe a protocol of chromatin immunoprecipitation in murine bone marrow derived macrophages that can easily be adapted to other macrophage populations. PMID- 29761400 TI - Transfecting Macrophages. AB - Transfection is defined as the transfer of foreign nucleic acids into cells. In general, transfection may achieve either overexpression of a gene by the transfer of plasmid DNA or suppression of gene expression by RNA interference after transfer of small interfering RNA. Both approaches allow for the detailed investigation of the function of a particular gene product or mechanisms of gene regulation. Macrophages are considered as hard-to-transfect cells, as they have evolved to recognize foreign nucleic acids and to initiate an immune response to these molecules. The presented electroporation protocol provides an effective tool to efficiently transfect human THP-1 macrophages with siRNA or plasmid DNA while avoiding macrophage activation. PMID- 29761401 TI - In Vitro Migration Assays. AB - The timely recruitment of innate and adaptive immune cells to sites of inflammation and repair is essential for host defense against pathogens and repair of damaged tissues. The development of bioassays such as in vitro chemotaxis assays played an important role in the original purification of chemoattractant cytokines including interleukin-1 and the CC and CXC chemokines. The earliest chemotaxis methods were based on the principle of the Boyden chamber, first described in 1962. In this chapter we give detailed protocols for more recent techniques that allow determination of macrophage chemotaxis in real time. These techniques have given new insights into the regulation of macrophage responses to chemotaxis in vitro and in vivo. PMID- 29761402 TI - Cytokine-Induced Acute Inflammatory Monoarticular Arthritis. AB - Animal models of arthritis enable us to investigate the pathogenesis of the disease and also to evaluate new therapies. Here we describe two different acute inflammatory monoarticular arthritis models (mBSA/IL1beta and mBSA/GM-CSF) providing a more rapid and potentially simplified approach to investigate the pathogenesis. PMID- 29761403 TI - Characterizing Activation, Proliferation, and Ontogeny of Murine Macrophages in Parasitic Helminth Infections. AB - Helminth parasites infect approximately 1/3 of the human population. They induce a characteristic immune response whose main focus seems to be to contain the worm parasites and avoid excessive damage to the host. Macrophages are a central player in this response and research using helminth infection models has highlighted the heterogeneity of macrophage responses including distinct recruitment mechanisms, subset-specific activation profiles, and functional diversity. Thus, helminth infection models offer the excellent opportunity to analyze a unique part of the macrophage activation spectrum as well as dissect the functional contributions of macrophages to a wide variety of biologically relevant conditions like wound healing, fibrosis, and immunoregulation.As an example for the analysis of macrophages associated with helminth infection this chapter describes the isolation and magnetic enrichment of pleural macrophages from mice infected with the natural rodent parasite Litomosoides sigmodontis. In addition, it includes a detailed description of how to determine the ontogeny and proliferation status of macrophage populations in helminth infections. Although the focus of this chapter is on helminth infection-derived macrophages, the described methods can easily be adapted to other disease models. PMID- 29761404 TI - Genetic Models of Macrophage Depletion. AB - Macrophages are a heterogeneous population of innate immune cells and are distributed in most adult tissues. Certain tissue-resident macrophages with a prenatal origin, together with postnatal monocyte-derived macrophages, serve as the host scavenger system to eliminate invading pathogens, malignant cells, senescent cells, dead cells, cellular debris, and other foreign substances. As a key member of the mononuclear phagocyte system, macrophages play essential roles in regulation of prenatal development, tissue homeostasis, and disease progression. Over the past two decades, considerable efforts have been made to generate genetic models of macrophage ablation in mice. These models support investigations of the precise functions of tissue-specific macrophages under physiological and pathological conditions. Herein, we overview the currently available mouse strains for in vivo genetic ablation of macrophages and discuss their respective advantages and limitations. PMID- 29761405 TI - Depleting Macrophages In Vivo with Clodronate-Liposomes. AB - In order to decipher the role of macrophages in vivo, it could be necessary to establish a model of macrophage depletion in the whole animal. One method to obtain animal models efficiently depleted in macrophages in different tissues (bone marrow, spleen, liver, lungs, brain, gut, peritoneal cavity, lymph nodes/vessels) and blood is the use of a clodronate-liposome solution.Here, we describe the protocol used to deplete efficiently macrophages in mouse bone marrow. PMID- 29761406 TI - Cre Driver Mice Targeting Macrophages. AB - The Cre/loxP system is a widely applied technology for site-specific genetic manipulation in mice. This system allows for deletion of the genes of interest in specific cells, tissues, and whole organism to generate a diversity of conditional knockout mouse strains. Additionally, the Cre/loxP system is useful for development of cell- and tissue-specific reporter mice for lineage tracing, and cell-specific conditional depletion models in mice. Recently, the Cre/loxP technique was extensively adopted to characterize the monocyte/macrophage biology in mouse models. Compared to other relatively homogenous immune cell types such as neutrophils, mast cells, and basophils, monocytes/macrophages represent a highly heterogeneous population which lack specific markers or transcriptional factors. Though great efforts have been made toward establishing macrophage specific Cre driver mice in the past decade, all of the current available strains are not perfect with regard to their depletion efficiency and targeting specificity for endogenous macrophages. Here we overview the commonly used Cre driver mouse strains targeting macrophages and discuss their major applications and limitations. PMID- 29761407 TI - Editorial: Special Issue on Heart Valve Mechanobiology : New Insights into Mechanical Regulation of Valve Disease and Regeneration. PMID- 29761408 TI - Parametric Imaging for the Assessment of Cardiac Motion: A Review. AB - The assessment of wall motion abnormalities such as hypokinesia or dyskinesia and the identification of their extent as well as their degree of severity allow an accurate evaluation of several ischemic heart diseases and an early diagnosis of heart failure. These dysfunctions are usually revealed by a drop of contraction indicating a regional hypokinesia or a total absence of the wall motion in case of akinesia. The discrimination between these contraction abnormalities plays also a significant role in the therapeutic decision through the differentiation between the infarcted zones, which have lost their contractile function, and the stunned areas that still retain viable myocardial tissues. The lack of a reliable method for the evaluation of wall motion abnormalities in cardiac imaging presents a major limitation for a regional assessment of the left ventricular function. In the past years, several techniques were proposed as additional tools for the local detection of wall motion deformation. Among these approaches, the parametric imaging is likely to represent a promising technique for the analysis of a local contractile function. The aim of this paper is to review the most recent techniques of parametric imaging computation developed in cardiac imaging and their potential contributions in clinical practice. PMID- 29761409 TI - The Roles of Matrix Stiffness and beta-Catenin Signaling in Endothelial-to Mesenchymal Transition of Aortic Valve Endothelial Cells. AB - Valve stiffening is a hallmark of aortic valve stenosis caused by excess extracellular matrix accumulation by myofibroblasts. We aimed to elucidate whether matrix stiffness regulates endothelial-to-mesenchymal transition (EndMT) of adult valvular endothelial cells (VECs) to myofibroblasts as a mechanism to further promote valve fibrosis. In addition, we specifically examined the role of the Wnt/beta-catenin signaling pathway in the development of myofibroblasts during EndMT, as Wnt/beta-catenin signaling has been implicated in EndMT during heart development, is reactivated in valve disease, and is required for mechanically-regulated myofibrogenesis of valve interstitial cells. Clonally derived porcine VECs were cultured on soft (5 kPa) or stiff (50 kPa) silicone Sylgard 527 substrates and treated with transforming growth factor (TGF)-beta1 to induce EndMT. Immunofluorescent staining revealed that TGF-beta1 preferentially promoted EndMT in VECs on stiffer substrates, evidenced by a decrease in the endothelial marker VE-cadherin and an increase in the myofibroblast marker alpha smooth muscle actin (alpha-SMA). These changes were accompanied by beta-catenin nuclear localization both in vitro and in vivo, assessed by immunostaining. Degradation of beta-catenin with endostatin reduced VEC myofibroblast transition, as indicated by decreased alpha-SMA fiber expression. We conclude that TGF-beta1 induced EndMT in aortic VECs is dependent on matrix stiffness and Wnt/beta catenin signaling promotes myofibrogenesis during EndMT. PMID- 29761411 TI - Detection of Pathogenic Viruses in the Ambient Air in Seoul, Korea. AB - The possible transport of pathogenic microorganisms during Asian dust events could be an important concern for health workers; however, this is still uncertain owing to a lack of supporting evidence. The present study aimed to investigate the presence of pathogenic microorganisms in air samples collected during the Asian and non-Asian dust periods. Between March and September 2016, air samples were collected at three weather observation stations in Seoul using a high-volume air sampler. Multiplex PCR was performed using the AllplexTM respiratory and gastrointestinal panel assay kits to detect 46 microorganisms. RT PCR was performed for klassevirus, Aichivirus, and human parechovirus (HPeV) detection. In total, 71 air samples were collected during the Asian (8 samples) and non-Asian (63 samples) dust events. During an Asian dust event, only one human rhinovirus (HRV)-positive air sample was collected on April 23. During the non-Asian dust period, HRV, HPeV, norovirus (NoV), enteroaggregative Escherichia coli (EAEC), enterotoxigenic E. coli (ETEC), and Blastocystis hominis were detected in four, two, one, one, one, and one air samples, respectively. Pathogenic viruses were mostly detected in ambient air samples during the non Asian dust period, which suggests a possible air-borne transmission of viral pathogens; however, the role of Asian dust in epidemics caused by pathogenic viruses is unclear. PMID- 29761412 TI - Persistence of Hepatitis A Virus in Fresh Produce and Production Environments, and the Effect of Disinfection Procedures: A Review. AB - Although information is limited, it is evident that prolonged persistence of infectious Hepatitis A virus (HAV) is a factor in the transmission of the virus via fresh produce. Consequently, data on persistence of the virus on produce, and in environments relevant to production, such as soils, water and surfaces, are required to fully understand the dynamics of transmission of HAV via foods. Furthermore, information on effective disinfection procedures is necessary to implement effective post-harvest control measures. This review summarises current information on HAV persistence in fresh produce and on relevant disinfection procedures. On vegetables, HAV can remain infectious for several days; on frozen berries, it can persist for several months. HAV can remain infectious on surfaces for months, depending on temperature and relative humidity, and can survive desiccation. It can survive for several hours on hands. Washing hands can remove the virus, but further data are required on the appropriate procedure. Chlorination is effective in water, but not when HAV is associated with foodstuffs. Bleach and other sodium hypochlorite disinfectants at high concentrations can reduce HAV on surfaces, but are not suitable for use on fresh produce. There is only limited information on the effects of heating regimes used in the food industry on HAV. HAV is resistant to mild pasteurisation. Some food components, e.g. fats and sugars, can increase the virus' resistance to higher temperatures. HAV is completely eliminated by boiling. Quantitative prevalence data are needed to allow the setting of appropriate disinfection log reduction targets for fresh produce. PMID- 29761413 TI - Comparison of B0 versus B0 and B1 field inhomogeneity correction for glycosaminoglycan chemical exchange saturation transfer imaging. AB - PURPOSE: The study compares glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging of intervertebral discs corrected for solely B0 inhomogeneities or both B0 and B1 inhomogeneities. METHODS: Lumbar intervertebral discs of 20 volunteers were examined with T2-weighted and gagCEST imaging. Field inhomogeneity correction was performed with B0 correction only and with correction of both B0 and B1. GagCEST effects measured by the asymmetric magnetization transfer ratio (MTRasym) and signal-to-noise ratio (SNR) were compared between both methods. RESULTS: Significant higher MTRasym and SNR values were obtained in the nucleus pulposus using B0 and B1 correction compared with B0 corrected gagCEST. The GagCEST effect was significantly different in the nucleus pulposus compared with the annulus fibrosus for both methods. CONCLUSION: The B0 and B1 field inhomogeneity correction method leads to an improved quality of gagCEST imaging in IVDs compared with only B0 correction. PMID- 29761416 TI - Bioluminescence Imaging of Transplanted Mesenchymal Stem Cells by Overexpression of Hepatocyte Nuclear Factor4alpha: Tracking Biodistribution and Survival. AB - PURPOSE: The purposes of this study were to construct immortalized human bone marrow mesenchymal stem cells (UE7T-13) with overexpression of the hepatocyte nuclear factor4alpha (hHNF4alpha) and luciferase2-mKate2 dual-fusion reporter gene, further investigate their impact on treating acute liver injury (ALI) in rats, and track their biodistribution and survival by bioluminescence imaging (BLI). PROCEDURES: The hHNF4alpha and luciferase2-mKate2 genes were transduced by a lentiviral vector into UE7T-13 cells (named E7-hHNF4alpha-R cells), and expression was verified by immunofluorescence, RT-PCR, and flow cytometry. E7 hGFP-R cells expressing the luciferase2-mKate2/hGFP gene served as a negative group. A correlation between the bioluminescence signal and cell number was detected by BLI. The ALI rats were established and divided into three groups: PBS, E7-hGFP-R, and E7-hHNF4alpha-R. After transplantation of 2.0 * 106 cells, BLI was used to dynamically track their biodistribution and survival. The restoration of biological functions was assessed by serum biochemical and histological analyses. RESULTS: Stable high-level expression of hHNF4alpha and mKate2 protein was established in the E7-hHNF4alpha-R cells in vitro. The E7 hHNF4alpha-R cells strongly expressed hGFP, hHNF4alpha, and mKate2 proteins, and the hHNF4alpha gene. hGFP-mKate2 dual-positive cell expression reached approximately 93 %. BLI verified that a linear relationship existed between the cell number and bioluminescence signal (R2 = 0.9991). The cells improved liver function in vivo after transplantation into the ALI rat liver, as evidenced by the fact that AST and ALT temporarily returned to normal levels in the recipient ALI rats. The presence of the transplanted E7-hGFP-R and E7-hHNF4alpha-R cells in recipient rat livers was confirmed by BLI and immunohistochemistry. However, the cells were cleared by the immune system a short time after transplantation into ALI rats with a normal immune system. CONCLUSION: Our data revealed that the E7 hHNF4alpha-R cells can transiently improve damaged liver function and were rapidly cleared by the immune system. In addition, BLI is a useful tool to track transplanted cell biodistribution and survival. PMID- 29761415 TI - Effects of genetic distance on heterosis in a Drosophila melanogaster model system. AB - Habitat fragmentation and small population sizes can lead to inbreeding and loss of genetic variation, which can potentially cause inbreeding depression and decrease the ability of populations to adapt to altered environmental conditions. One solution to these genetic problems is the implementation of genetic rescue, which re-establishes gene flow between separated populations. Similar techniques are being used in animal and plant breeding to produce superior production animals and plants. To optimize fitness benefits in genetic rescue programs and to secure high yielding domestic varieties in animal and plant breeding, knowledge on the genetic relatedness of populations being crossed is imperative. In this study, we conducted replicated crosses between isogenic Drosophila melanogaster lines from the Drosophila Genetic Reference Panel. We grouped lines in two genetic distance groups to study the effect of genetic divergence between populations on the expression of heterosis in two fitness components; starvation resistance and reproductive output. We further investigated the transgenerational effects of outcrossing by investigating the fitness consequences in both the F1- and the F3-generations. High fitness enhancements were observed in hybrid offspring compared to parental lines, especially for reproductive output. However, the level of heterosis declined from the F1- to the F3-generation. Generally, genetic distance did not have strong impact on the level of heterosis detected, although there were exceptions to this pattern. The best predictor of heterosis was performance of parental lines with poorly performing parental lines showing higher hybrid vigour when crossed, i.e. the potential for heterosis was proportional to the level of inbreeding depression. Overall, our results show that outcrossing can have very strong positive fitness consequences for genetically depauperate populations. PMID- 29761414 TI - Spatially resolved kinetics of skeletal muscle exercise response and recovery with multiple echo diffusion tensor imaging (MEDITI): a feasibility study. AB - OBJECTIVES: We describe measurement of skeletal muscle kinetics with multiple echo diffusion tensor imaging (MEDITI). This approach allows characterization of the microstructural dynamics in healthy and pathologic muscle. MATERIALS AND METHODS: In a Siemens 3-T Skyra scanner, MEDITI was used to collect dynamic DTI with a combination of rapid diffusion encoding, radial imaging, and compressed sensing reconstruction in a multi-compartment agarose gel rotation phantom and within in vivo calf muscle. An MR-compatible ergometer (Ergospect Trispect) was employed to enable in-scanner plantar flexion exercise. In a HIPAA-compliant study with written informed consent, post-exercise recovery of DTI metrics was quantified in eight volunteers. Exercise response of DTI metrics was compared with that of T2-weighted imaging and characterized by a gamma variate model. RESULTS: Phantom results show quantification of diffusivities in each compartment over its full dynamic rotation. In vivo calf imaging results indicate larger radial than axial exercise response and recovery in the plantar flexion challenged gastrocnemius medialis (fractional response: nT2w = 0.385 +/- 0.244, nMD = 0.163 +/- 0.130, nlambda1 = 0.110 +/- 0.093, nlambdarad = 0.303 +/- 0.185). Diffusion and T2-weighted response magnitudes were correlated (e.g., r = 0.792, p = 0.019 for nMD vs. nT2w). CONCLUSION: We have demonstrated the feasibility of MEDITI for capturing spatially resolved diffusion tensor data in dynamic systems including post-exercise skeletal muscle recovery following in-scanner plantar flexion. PMID- 29761417 TI - Lack of Association Between DNMT3B Polymorphisms and Sporadic Parkinson's Disease in a Han Chinese Population. PMID- 29761419 TI - Measuring Geographic Migration Patterns Using Matriculas Consulares. AB - In this article, we show how to use administrative data from the Matricula Consular de Alta Seguridad (MCAS) identification card program to measure the joint distribution of sending and receiving locations for migrants from Mexico to the United States. Whereas other data sources cover only a small fraction of source or destination locations or include only very coarse geographic information, the MCAS data provide complete geographic coverage of both countries, detailed information on migrants' sources and destinations, and a very large sample size. We first confirm the quality and representativeness of the MCAS data by comparing them with well-known household surveys in Mexico and the United States, finding strong agreement on the migrant location distributions available across data sets. We then document substantial differences in the mix of destinations for migrants from different places within the same source state, demonstrating the importance of detailed substate geographical information. We conclude with an example of how these detailed data can be used to study the effects of destination-specific conditions on migration patterns. We find that an Arizona law reducing employment opportunities for unauthorized migrants decreased emigration from and increased return migration to Mexican source regions with strong initial ties to Arizona. PMID- 29761418 TI - Growing and Learning When Consumption Is Seasonal: Long-Term Evidence From Tanzania. AB - This article shows that the seasonality of food consumption during childhood, conditional on average consumption, affects long-run human capital development. We develop a model that distinguishes differences in average consumption levels, seasonal fluctuations, and idiosyncratic shocks, and estimate the model using panel data from early 1990s Tanzania. We then test whether the mean and seasonality of a child's consumption profile affect height and educational attainment in 2010. Results show that the negative effects of greater seasonality are 30 % to 60 % of the magnitudes of the positive effects of greater average consumption. Put differently, children expected to have identical human capital based on annualized consumption measures will have substantially different outcomes if one child's consumption is more seasonal. We discuss implications for measurement and policy. PMID- 29761420 TI - Long-Term Radiographic and Patient-Reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses. AB - INTRODUCTION: Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient reported physical function. METHODS: This was a post hoc analysis of two 24 month, phase III randomized controlled trials in methotrexate (MTX)-naive (ORAL Start [NCT01039688]) or MTX-inadequate responder (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). RESULTS: Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of < 1.9 most closely approximated CDAI remission (<= 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low disease activity (LDA) at month 6 reported normative HAQ-DI scores (< 0.5) at month 24 than did those with CDAI MDA/HDA. CONCLUSION: Regardless of treatment, in both MTX-naive and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of < 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation. FUNDING: Pfizer Inc. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT01039688 and NCT00847613. PMID- 29761421 TI - Correction to: Predictive Simulations of Neuromuscular Coordination and Joint Contact Loading in Human Gait. AB - In the "Materials and Methods" section, the link provided at the bottom of the second paragraph should be https://simtk.org/home/dcwithjtcontact/ . PMID- 29761422 TI - Computational Pre-surgical Planning of Arterial Patch Reconstruction: Parametric Limits and In Vitro Validation. AB - Surgical treatment of congenital heart disease (CHD) involves complex vascular reconstructions utilizing artificial and native surgical materials. A successful surgical reconstruction achieves an optimal hemodynamic profile through the graft in spite of the complex post-operative vessel growth pattern and the altered pressure loading. This paper proposes a new in silico patient-specific pre surgical planning framework for patch reconstruction and investigates its computational feasibility. The proposed protocol is applied to the patch repair of main pulmonary artery (MPA) stenosis in the Tetralogy of Fallot CHD template. The effects of stenosis grade, the three-dimensional (3D) shape of the surgical incision and material properties of the artificial patch are investigated. The release of residual stresses due to the surgical incision and the extra opening of the incision gap for patch implantation are simulated through a quasi-static finite-element vascular model with shell elements. Implantation of different unloaded patch shapes is simulated. The patched PA configuration is pressurized to the physiological post-operative blood pressure levels of 25 and 45 mmHg and the consequent post-operative stress distributions and patched artery shapes are computed. Stress-strain data obtained in-house, through the biaxial tensile tests for the mechanical properties of common surgical patch materials, Dacron, Polytetrafluoroethylene, human pericardium and porcine xenopericardium, are employed to represent the mechanical behavior of the patch material. Finite element model is experimentally validated through the actual patch surgery reconstructions performed on the 3D printed anatomical stenosis replicas. The post-operative recovery of the initially narrowed lumen area and post-op tortuosity are quantified for all modeled cases. A computational fluid dynamics solver is used to evaluate post-operative pressure drop through the patch reconstructed outflow tract. According to our findings, the shorter incisions made at the throat result in relatively low local peak stress values compared to other patch design alternatives. Longer cut and double patch cases are the most effective in repairing the initial stenosis level. After the patch insertion, the pressure drop in the artery due to blood flow decreases from 9.8 to 1.35 mmHg in the conventional surgical configuration. These results are in line with the clinical experience where a pressure gradient at or above 50 mmHg through the MPA can be an indication to intervene. The main strength of the proposed pre-surgical planning framework is its capability to predict the intra-operative and post operative 3D vascular shape changes due to intramural pressure, cut length and configuration, for both artificial and native patch materials. PMID- 29761423 TI - Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium. AB - Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case-control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case-control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968-2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (ORCC 1.05, 95% CI 1.00-1.11; ORNCC 1.04, 95% CI 1.01 1.07). A similar positive association with advanced maternal age was observed only in the NCC results (ORCC 0.99, 95% CI 0.91-1.07, heterogeneity I2 = 58%, p = 0.002; ORNCC 1.05, 95% CI 1.01-1.08). The positive association between parental age and risk of ALL was most marked among children aged 1-5 years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms. PMID- 29761427 TI - The Importance of Experimental Design, Quality Assurance, and Control in Plant Metabolomics Experiments. AB - The output of metabolomics relies to a great extent upon the methods and instrumentation to identify, quantify, and access spatial information on as many metabolites as possible. However, the most modern machines and sophisticated tools for data analysis cannot compensate for inappropriate harvesting and/or sample preparation procedures that modify metabolic composition and can lead to erroneous interpretation of results. In addition, plant metabolism has a remarkable degree of complexity, and the number of identified compounds easily surpasses the number of samples in metabolomics analyses, increasing false discovery risk. These aspects pose a large challenge when carrying out plant metabolomics experiments. In this chapter, we address the importance of a proper experimental design taking into consideration preventable complications and unavoidable factors to achieve success in metabolomics analysis. We also focus on quality control and standardized procedures during the metabolomics workflow. PMID- 29761426 TI - Predictors of self-reported adherence to direct oral anticoagulation in a population of elderly men and women with non-valvular atrial fibrillation. AB - There is a general lack of studies evaluating medication adherence with self report scales for elderly patients in treatment with direct oral anticoagulants (DOACs). The aim of the study was to assess the degree of adherence to DOAC therapy in a population of elderly outpatients aged 65 years or older affected by non-valvular atrial fibrillation (NVAF), using the 4-item Morisky Medication Adherence Scale, and to identify potential factors, including the geriatric multidimensional evaluation, which can affect adherence in the study population. A total of 103 subjects, anticoagulated with DOACs for NVAF in primary or secondary prevention, were eligible; 76 showed adequate adhesion to anticoagulant therapy, while 27 showed inadequate adherence. Participants underwent biochemical assessment and Morisky Scale, Instrumental Activities of Daily Living, CHA2DS2 VASc, HAS-BLED, mental status and nutritional evaluations were performed. 2% of subjects assumed Dabigatran at low dose, while 7.8% at standard dose, 9.7% assumed low-dose of Rivaroxaban and 30.1% at standard dose, 6.8% assumed Apixaban at low dose and 39.7% at standard dose, and finally 1% assumed Edoxaban at low dose and 2.9% at standard dose. Most subjects took the DOACs without help (80.6%), while 16 subjects were helped by a family member (15.5%) and 4 were assisted by a caregiver (3.9%). Binary logistic regression considered inappropriate adherence as a dependent variable, while age, male sex, polypharmacotherapy, cognitive decay, caregiver help for therapy assumption, duration of DOAC therapy and double daily administration were considered as independent variables. The double daily administration was an independent factor, determining inappropriate adherence with an OR of 2.88 (p = 0.048, CI 1.003 8.286). PMID- 29761428 TI - Standard Key Steps in Mass Spectrometry-Based Plant Metabolomics Experiments: Instrument Performance and Analytical Method Validation. AB - Studies of the plant metabolome include the analysis of a wide range of chemical species with very diverse physicochemical properties requiring powerful analytical tools for the separation, characterization, and quantification of this vast compound diversity present in plant matrices. In quantitative metabolomics studies, major efforts are put into optimizing sample extraction and separation as well as instrument conditions to measure specific plant metabolites. Here, challenges in the use of mass spectrometry (MS) as a quantitative tool in plant metabolomics experiments are discussed, and an overview of the most critical steps in the development and validation of MS-based analytical methods is presented. PMID- 29761425 TI - Genistein has the function of alleviating and treating disseminated intravascular coagulation caused by lipopolysaccharide. AB - Symptoms of disseminated intravascular coagulation (DIC) include thromboembolism, acute attrition bleeding and multiple organ failure. Genistein isolated from leguminous plants has been shown to be effective in oxidation resistance and tumor inhibition. The present study was designed to evaluate the therapeutic effects of genistein in DIC and preliminarily discuss the mechanisms regarding the anti-inflammatory and anticoagulant effect of genistein. Swiss mice were randomly divided into the following groups-(1) lipopolysaccharide (LPS), (2) genistein, (3) dimethyl sulfoxide (DMSO, the non-major solvent component of genistein), (4) DMSO + LPS, (5) saline control group, and (6) heparin control group. LPS was injected intraperitoneally in all the groups except the DMSO group and saline control group. Our results significantly showed that the morphological structure of the liver and kidneys was improved and the fiber protein deposition was decreased, with remarkable improvement of coagulation indicators, function indicators and inflammatory factors in the genistein treatment group compared with the LPS group. In vitro phosphorylated-nuclear factor kappa-light-chain enhancer of activated B cells and interleukin-6 were obviously reduced in the genistein treatment group compared with the LPS group in RAW 264.7 murine macrophage cells. All the results suggested that genistein has the function of alleviating and treating LPS-induced DIC by anti-inflammatory and anticoagulation effects. We tentatively propose that genistein is a potential drug for auxiliary treatment of DIC. PMID- 29761424 TI - Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. AB - Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2 = 1.06, 95% CI 0.99-1.14) or in men (HRlog2 = 0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2 = 0.91, 95% CI 0.85 0.97) and positively associated with rectal cancer in women (HRlog2 = 1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women. PMID- 29761429 TI - Guidelines for Sample Normalization to Minimize Batch Variation for Large-Scale Metabolic Profiling of Plant Natural Genetic Variance. AB - Recent methodological advances in both liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) have facilitated the profiling highly complex mixtures of primary and secondary metabolites in order to investigate a diverse range of biological questions. These techniques usually face a large number of potential sources of technical and biological variation. In this chapter we describe guidelines and normalization procedures to reduce the analytical variation, which are essential for the high-throughput evaluation of metabolic variance used in broad genetic populations which commonly entail the evaluation of hundreds or thousands of samples. This chapter specifically deals with handling of large-scale plant samples for metabolomics analysis of quantitative trait loci (mQTL) in order to reduce analytical error as well as batch-to-batch variation. PMID- 29761431 TI - Carbon Atomic Survey for Identification of Selected Metabolic Fluxes. AB - Stable-isotope-labeling experiments have become a frequently used tool to investigate different metabolic systems. They have been recently applied to several comprehensive studies in plant metabolomics providing interesting insights into metabolic dynamics and regulation. However, the complexity of mass spectrometry data originating from such experiments is rarely fully explored. Data analysis often considers metabolites in their entirety which obscures important information at the atomic level. Recently, the use of mass spectrometry fragmentation for obtaining positional-labeling information was described for a few specific metabolites. Here, we describe a general methodology that can be applied for extracting positional-labeling information based on the characterization of fragments that are inherent in gas chromatography electron impact mass spectrometry (GC-EI-MS) chromatograms. PMID- 29761430 TI - Gas Chromatography-Mass Spectrometry-Based 13C-Labeling Studies in Plant Metabolomics. AB - Stable-isotope labeling analysis has been used to discover new metabolic pathways and their key regulatory points in a wide range of organisms. Given the complexity of the plant metabolic network, this analysis provides information complementary to that obtained from metabolite profiling that can be used to understand how plants cope with adverse conditions, and how metabolism varies between different cells, tissues, and organs. Here we describe the experimental procedures from sample harvesting and extraction to mass spectral analysis and interpretation that allow the researcher to perform 13C-labeling experiments. A wide range of plant material, from single cells to whole plants, can be used to investigate the metabolic fate of the 13C from a predefined tracer. Thus, a key point of this analysis is to choose the correct biological system, the substrate and the condition to be investigated; all of which implicitly relies on the biological question to be investigated. Rapid sample quenching and a careful data analysis are also critical points in such studies. By contrast to other metabolomic approaches, stable-isotope labeling can provide information concerning the fluxes through metabolic networks, which is essential for understanding and manipulating metabolic phenotypes and therefore of pivotal importance for both systems biology and plant metabolic engineering. PMID- 29761432 TI - Quantification of Low-Abundant Phosphorylated Carbohydrates Using HILIC-QqQ MS/MS. AB - Phosphorylated carbohydrates are central metabolites involved in key plant metabolic pathways, such as glycolysis and central carbon metabolism. Such pathways influence plant growth, development, and stress responses to environmental changes, and ultimately, reflect the plant's energy status. The high polarity of these metabolites, the variety of isomeric structures (e.g., glucose-1-phosphate (G1P)/fructose-6-phosphate (F6P)/mannose-6-phosphate (M6P)/G6P, sucrose-6-phosphate (S6P)/T6P), and rapid metabolic turnover makes their analysis particularly challenging. In this chapter, we describe the use of a set of known phosphorylated carbohydrates to develop and validate a hydrophilic interaction chromatography (HILIC) triple quadrupole (QqQ) tandem mass spectrometry (MS/MS) method in the highly sensitive and selective multiple reaction monitoring (MRM) mode for the target analysis of G1P, F6P, M6P, G6P, S6P, T6P, and the sugar nucleotide uridine 5-diphospho-glucose (UDPG). We present detailed information regarding HILIC column chemistry and practical considerations when coupling it with a QqQ-MS system. PMID- 29761433 TI - Quantification of Soluble Sugars and Sugar Alcohols by LC-MS/MS. AB - Sugars are simple carbohydrates composed primarily of carbon, hydrogen, and oxygen. They play a central role in metabolism as sources of energy and as building blocks for synthesis of structural and nonstructural polymers. Many different techniques have been used to measure sugars, including refractometry, colorimetric and enzymatic assays, gas chromatography, high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy. In this chapter we describe a method that combines an initial separation of sugars by high performance anion-exchange chromatography (HPAEC) with detection and quantification by tandem mass spectrometry (MS/MS). This combination of techniques provides exquisite specificity, allowing measurement of a diverse range of high- and low-abundance sugars in biological samples. This method can also be used for isotopomer analysis in stable-isotope labeling experiments to measure metabolic fluxes. PMID- 29761434 TI - Untargeted Analysis of Semipolar Compounds by LC-MS and Targeted Analysis of Fatty Acids by GC-MS/GC-FID: From Plant Cultivation to Extract Preparation. AB - The way plants are grown and samples are harvested, prepared, and extracted has a profound impact on the output of a metabolomics experiment. In this chapter, we detail the experimental procedures from plant cultivation to extract preparation, in order to avoid difficulties that could result in contamination or undesired changes of the analytes. Two plant organs are mentioned as examples: tomato fruits (Solanum lycopersicum) and flax seeds (Linum usitatissimum). Extractions designed for the untargeted analysis of semipolar compounds by liquid chromatography-mass spectrometry (LC-MS) and targeted analysis of fatty acids by gas chromatography-mass spectrometry (GC-MS) or gas chromatography with flame ionization detector (GC-FID) are described. PMID- 29761435 TI - Extraction of Plant Lipids for LC-MS-Based Untargeted Plant Lipidomics. AB - Lipids are defined as hydrophobic or amphipathic small molecules which consist of a number of structurally and functionally distinct molecules that span from nonpolar to neutral to polar compounds. Lipidomics is the comprehensive analysis of all lipids in a biological system. Changes in lipid metabolism and composition, as well as of distinct lipid species have been linked with altered plant growth, development, and responses to environmental stresses including salinity. Recently, improved liquid chromatography mass spectrometry (LC-MS) based techniques have provided the rapid expansion of lipidomics research. Sample preparation and lipid extraction are important steps in lipidomics, and this chapter describes important considerations in lipid monophasic and biphasic extractions from plant tissues prior to untargeted plant lipidomics approaches with LC-MS. PMID- 29761436 TI - Semi-targeted Lipidomics of Plant Acyl Lipids Using UPLC-HR-MS in Combination with a Data-Independent Acquisition Mode. AB - In recent years, multiple mass-spectrometric methods have been developed to tackle fundamental analytical questions in the field of biology and biochemistry. One essential approach relies on the use of liquid chromatography (LC), for efficient compound separation, coupled to high-resolution mass spectrometry (HR MS). Even though these techniques are highly sensitive allowing for the reliable measurement of several thousand mass features, the major bottleneck is to convert the measured masses into annotated lipid species. To overcome this problem, we present a simple, example-based workflow, which provides an introduction to basic strategies for the manual validation of LC-MS-based lipidomic data. The whole strategy makes use of a data-independent acquisition (DIA) method, where alternating MS measurement cycles using high and low-energy scans are used. This measurement strategy allows to reliably annotate lipids, based on the exact mass measurements of intact, but also fragmented lipids from continuously recorded spectra. PMID- 29761437 TI - Plant Lipidomics Using UPLC-QTOF-MS. AB - Lipids are primary metabolites used for energy storage, signal transduction, and pigmentation, besides being common membrane components. Considering the importance of comprehensive lipid analysis (lipidomics) for a detailed understanding of cellular metabolic states, this chapter introduces liquid chromatography-quadrupole time-of-flight mass spectrometry as a powerful untargeted plant lipidomics technique. PMID- 29761438 TI - Targeted LC-MS Analysis for Plant Secondary Metabolites. AB - Recent technological developments and methodological advances of both liquid chromatography (LC) and mass spectrometry (MS) have allowed LC-MS-based plant metabolomics to become a common tool for investigating quantity, quality, and chemical diversity of plant metabolites. Targeted LC-MS metabolite analysis focuses on the detection and quantitation of the researcher's target metabolites. Whilst the word "target analysis" has been used for the analytical measurement to obtain the absolute concentrations evaluated by authentic and/or stable-isotope labeled standards, over time the phrase came to be also used in a broad sense for the measurement of annotatable metabolites by structural information obtained from the combination of different strategies such as MS/MS analysis, reference extracts, mutant analysis and database search. Here, we describe a general protocol for targeted LC-MS metabolite profiling of plant secondary metabolites. Additionally, we introduce some examples of peak annotation using the combination approach. PMID- 29761439 TI - An UHPLC-MS/MS Method for Target Profiling of Stress-Related Phytohormones. AB - The methodology described here represents an improved strategy for analysis of a broad range of stress-related plant hormones including jasmonates, salicylic acid, abscisic acid, and auxin metabolites. The method conditions are optimized in order to reduce the background effect of complicated plant matrix, allow effective preconcentration and thus perform highly sensitive profiling of multiple plant hormones by ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). PMID- 29761440 TI - A Complete Pipeline for Generating a High-Resolution LC-MS-Based Reference Mass Spectra Library. AB - Databases containing mass spectrometry (MS) spectral data (i.e., MS reference libraries) are currently the most reliable and widely accepted approach to annotate unknown features in MS-based metabolomics. While for gas chromatography (GC)-MS data, a strategy for collecting, storing, and comparing to raw data has been established, this is not the case for liquid chromatography (LC)-MS data. Here, we present our approach for high-throughput data collection and automated MS reference library generation, as applied recently in the WEIZMASS library of plant metabolites. Methodologies to experimentally generate pools of chemical standards and computationally convert them into a unique source of reference data are detailed. PMID- 29761441 TI - Quantification of Sugars and Organic Acids in Biological Matrices Using GC-QqQ MS. AB - Gas chromatography coupled with triple quadrupole mass spectrometry (GC-QqQ-MS) can be used to accurately quantify endogenous small molecules extracted from biological samples such as plants and human fluids including sera and urine. In order to quantify primary metabolites typically from central carbon metabolism such as sugars from glycolysis and the pentose phosphate pathway; and organic acids involved in the tricarboxylic acid (TCA) cycle; polar endogenous metabolites must be extracted from the samples of interest, chemically derivatized and quantified against a linear calibration curve to a corresponding authentic standard. This chapter describes how to quantify a combination of 48 primary metabolites belonging to classes of sugars, sugar alcohols, sugar acids, sugar phosphates, and organic acids using a robust, optimized, multiple reaction monitoring (MRM)-based GC-QqQ-MS method. PMID- 29761442 TI - Acquisition of Volatile Compounds by Gas Chromatography-Mass Spectrometry (GC MS). AB - Plants synthesize and emit a large range of volatile organic compounds (VOCs) that play important roles in their interactions with the environment, from attracting pollinators and seed dispersers to protectants such as repellants and pathogen inhibitors. As such, the development of techniques for headspace collection of volatiles in combination with gas chromatography-mass spectrometry (GC-MS) has an important impact on our understanding of the biosynthesis of plant VOCs. Furthermore, knowledge of the plant VOCs can be valuable in relation to plant breeding for improving fruit flavor or enhancing resistance to insects or pathogens. This chapter describes a reliable method for extracting volatile compounds by headspace solid-phase microextraction (HS-SPME), and separate and detect them by GC-MS. PMID- 29761443 TI - Mass Spectrometry Imaging (MSI) for Plant Metabolomics. AB - Mass spectrometry imaging (MSI) is a developing technique to measure the spatiotemporal distribution of many biomolecules in tissues. Over the preceding decade MSI has been adopted by plant biologists and applied in a broad range of areas including: primary metabolism, natural products, plant defense, plant responses to abiotic and biotic stress, plant lipids, and the developing field of spatial metabolomics. This methods chapter covers preparation of plant tissues for matrix-assisted laser desorption ionization (MALDI)-MSI, including sample embedding and freezing, sectioning, mounting, and matrix deposition using both sublimation and spray deposition prior to MSI analysis. PMID- 29761444 TI - Laser Ablation Electrospray Ionization-Mass Spectrometry Imaging (LAESI-MS) for Spatially Resolved Plant Metabolomics. AB - There is increasing demand to bring the level of metabolomics analyses down to the tissue or cell level. Significant progress has been made involving the use of in situ metabolomics imaging techniques where no tissue collection or extraction is needed prior to analysis. In this chapter we describe a relatively new method which is simple and easy to use. No ectopic matrix or vacuum is required, and analyses are performed with living plant materials directly from (or even still attached to) the plant. Although relatively straightforward, there are still a few caveats as regards this method which are described at the end of the chapter. PMID- 29761445 TI - Live Single-Cell Mass Spectrometry (LSC-MS) for Plant Metabolomics. AB - Live single-cell mass spectrometry (LSC-MS) allows for the detection of hundreds to thousands of metabolite peaks acquired from a single plant cell within a few minutes. Plant cells are first observed under a stereomicroscope, a cell of interest is chosen, and then sampled using a metal-coated glass microcapillary for subsequent analysis. A few microliters of ionization solvent is then added to the rear end of the capillary followed by the introduction of the capillary's content directly into the mass spectrometer. High voltage is applied between the capillary and the mass spectrometer inlet to induce nanospray ionization. Metabolite structural confirmation is performed using tandem mass spectrometry analysis (MS/MS) and fragments are matched with MS/MS databases to predict metabolic pathways. This method enables swift and direct molecular detection and identification of specific metabolites from a single plant cell along with their localization within the cell, which will allow for comprehensive understanding of plant metabolomics on a single cell level. PMID- 29761446 TI - Statistical and Multivariate Analysis of MS-Based Plant Metabolomics Data. AB - Raw data from metabolomics experiments are initially subjected to peak identification and signal deconvolution to generate raw data matrices m * n, where m are samples and n are metabolites. We describe here simple statistical procedures on such multivariate data matrices, all provided as functions in the programming environment R, useful to normalize data, detect biomarkers, and perform sample classification. PMID- 29761447 TI - Integration of Plant Metabolomics Data with Metabolic Networks: Progresses and Challenges. AB - In the last decade, plant genome-scale modeling has developed rapidly and modeling efforts have advanced from representing metabolic behavior of plant heterotrophic cell suspensions to studying the complex interplay of cell types, tissues, and organs. A crucial driving force for such developments is the availability and integration of "omics" data (e.g., transcriptomics, proteomics, and metabolomics) which enable the reconstruction, extraction, and application of context-specific metabolic networks. In this chapter, we demonstrate a workflow to integrate gas chromatography coupled to mass spectrometry (GC-MS)-based metabolomics data of tomato fruit pericarp (flesh) tissue, at five developmental stages, with a genome-scale reconstruction of tomato metabolism. This method allows for the extraction of context-specific networks reflecting changing activities of metabolic pathways throughout fruit development and maturation. PMID- 29761448 TI - Understanding the Functionality of a Biological System as a Whole: Comparative Data Analysis. AB - As part of a systems biology approach, metabolomics often aim at broadening our understanding of the functionality of biological systems as a whole. Observations from stand-alone experiments may reveal interesting changes in metabolites of a specific pathway or metabolite class. However, bringing these observations into context with more general biological processes requires the integration and comparison of different datasets. This chapter aims at introducing and explaining methods of comparative data analysis for plant metabolomics using the statistical software framework R. PMID- 29761449 TI - Regression-Based Modeling of Complex Plant Traits Based on Metabolomics Data. AB - Bridging metabolomics with plant phenotypic responses is challenging. Multivariate analyses account for the existing dependencies among metabolites, and regression models in particular capture such dependencies in search for association with a given trait. However, special care should be undertaken with metabolomics data. Here we propose a modeling workflow that considers all caveats imposed by such large data sets. PMID- 29761450 TI - Mathematical Modeling Approaches in Plant Metabolomics. AB - The experimental analysis of a plant metabolome typically results in a comprehensive and multidimensional data set. To interpret metabolomics data in the context of biochemical regulation and environmental fluctuation, various approaches of mathematical modeling have been developed and have proven useful. In this chapter, a general introduction to mathematical modeling is presented and discussed in context of plant metabolism. A particular focus is laid on the suitability of mathematical approaches to functionally integrate plant metabolomics data in a metabolic network and combine it with other biochemical or physiological parameters. PMID- 29761452 TI - Unrecognized failed back surgery syndrome: a paradigmatic case in a very young patient. PMID- 29761451 TI - Influence of arm position and respiration technique during liver examinations on the detectability of mammary lesions. AB - During liver computed tomography (CT), scanning is performed with the raised arm position and an inhalation technique. However, for liver magnetic resonance imaging (MRI), the arms are placed at the sides of the body and an exhalation technique is used. This study was aimed at evaluating the effect that the patient's arm position and respiration technique had on the ability to detect mammary glands in the scan range to discover unexpected mammary lesions during the liver MRI examination. Liver MRI and CT images were compared for 337 female patients. More than half of the mammary glands were included in 97.3% of MRI, but in 4.7% of CT. No mammary lesions were found during CT, whereas seven were found during MRI. The mammary lesions are more likely to be detected when the patient places her arms at the sides of the body and uses the exhalation technique during liver MRI. PMID- 29761453 TI - Identifying Sequenced Eukaryotic Genomes and Transcriptomes with diArk. AB - The diArk Eukaryotic Genome Database is a manually curated and updated repository of available eukaryotic genome and transcriptome assemblies. diArk is a key resource for researchers interested in comparative eukaryotic genomics, and the entry point to browsing sequenced eukaryotes in general and to find the most closely related species to the own organism of interest in particular. The exponentially increasing number of sequenced species demands sophisticated search and data presentation tools. In this chapter we describe how to navigate the diArk database keeping a first-time user in mind. PMID- 29761454 TI - An Introduction to the Saccharomyces Genome Database (SGD). AB - The Saccharomyces Genome Database (SGD) is a well-established, key resource for researchers studying Saccharomyces cerevisiae. In addition to updating and maintaining the official genomic sequence of this highly studied organism, SGD provides integrated data regarding gene functions and phenotypes, which are extracted from the published literature. The vast amount and variety of data housed in the database can prove challenging to navigate for the first-time user. Therefore, this chapter serves as an introduction describing how to search the database in order to discover new information. We introduce the different types of pages on the website, and describe how to manipulate the tables and diagrams therein to display, download, or analyze the data using various SGD tools. PMID- 29761455 TI - Using the Candida Genome Database. AB - Studying Candida biology requires access to genomic sequence data in conjunction with experimental information that together provide functional context to genes and proteins, and aid in interpreting newly generated experimental data. The Candida Genome Database (CGD) curates the Candida literature, and integrates functional information about Candida genes and their products with a set of analysis tools that facilitate searching for sets of genes and exploring their biological roles. This chapter describes how the various types of information available at CGD can be searched, retrieved, and analyzed. Starting with the guided tour of the CGD Home page and Locus Summary page, this unit shows how to navigate the various assemblies of the C. albicans genome, how to use Gene Ontology tools to make sense of large-scale data, and how to access the microarray data archived at CGD, as well as visualize high-throughput sequencing data through the use of JBrowse. PMID- 29761456 TI - PomBase: The Scientific Resource for Fission Yeast. AB - The fission yeast Schizosaccharomyces pombe has become well established as a model species for studying conserved cell-level biological processes, especially the mechanics and regulation of cell division. PomBase integrates the S. pombe genome sequence with traditional genetic, molecular, and cell biological experimental data as well as the growing body of large datasets generated by emerging high-throughput methods. This chapter provides insight into the curation philosophy and data organization at PomBase, and provides a guide to using PomBase for infrequent visitors and anyone considering exploring S. pombe in their research. PMID- 29761457 TI - EuPathDB: The Eukaryotic Pathogen Genomics Database Resource. AB - Fighting infections and developing novel drugs and vaccines requires advanced knowledge of pathogen's biology. Readily accessible genomic, functional genomic, and population data aids biological and translational discovery. The Eukaryotic Pathogen Database Resources ( http://eupathdb.org ) are data mining resources that support hypothesis driven research by facilitating the discovery of meaningful biological relationships from large volumes of data. The resource encompasses 13 sites that support over 170 species including pathogenic protists, oomycetes, and fungi as well as evolutionarily related nonpathogenic species. EuPathDB integrates preanalyzed data with advanced search capabilities, data visualization, analysis tools and a comprehensive record system in a graphical interface that does not require prior computational skills. This chapter describes guiding concepts common across EuPathDB sites and illustrates the powerful data mining capabilities of some of the available tools and features. PMID- 29761458 TI - The Ensembl Genome Browser: Strategies for Accessing Eukaryotic Genome Data. AB - The Ensembl Genome Browser provides a wealth of freely available genomic data that can be accessed for many purposes by genetics, genomics, and molecular biology researchers. Herein we present two protocols for exploring different aspects of these data: a phenotype and its associated variants and genes, and a promoter and the epigenetic marks and protein-binding activity associated with it. These workflows illustrate a subset of the data types available through the Ensembl Browser, and can be considered a springboard for further exploration. PMID- 29761459 TI - Mouse Genome Informatics (MGI) Is the International Resource for Information on the Laboratory Mouse. AB - Mouse Genome Informatics (MGI, http://www.informatics.jax.org/ ) web resources provide free access to meticulously curated information about the laboratory mouse. MGI's primary goal is to help researchers investigate the genetic foundations of human diseases by translating information from mouse phenotypes and disease models studies to human systems. MGI provides comprehensive phenotypes for over 50,000 mutant alleles in mice and provides experimental model descriptions for over 1500 human diseases. Curated data from scientific publications are integrated with those from high-throughput phenotyping and gene expression centers. Data are standardized using defined, hierarchical vocabularies such as the Mammalian Phenotype (MP) Ontology, Mouse Developmental Anatomy and the Gene Ontologies (GO). This chapter introduces you to Gene and Allele Detail pages and provides step-by-step instructions for simple searches and those that take advantage of the breadth of MGI data integration. PMID- 29761460 TI - A Primer for the Rat Genome Database (RGD). AB - The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have relevance to human physiology and disease. The Rat Genome Database (RGD, http://rgd.mcw.edu ) is a model organism database that provides access to a wide variety of curated rat data including disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components for genes, quantitative trait loci, and strains. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat. PMID- 29761461 TI - Bovine Genome Database: Tools for Mining the Bos taurus Genome. AB - The Bovine Genome Database (BGD; http://bovinegenome.org ) is a web-accessible resource that supports bovine genomics research by providing genome annotation and data mining tools. BovineMine is a tool within BGD that integrates BGD data, including the genome, genes, precomputed gene expression levels and variant consequences, with external data sources that include quantitative trait loci (QTL), orthologues, Gene Ontology, gene interactions, and pathways. BovineMine enables researchers without programming skills to create custom integrated datasets for use in downstream analyses. This chapter describes how to enhance a bovine genomics project using the Bovine Genome Database, with data mining examples demonstrating BovineMine. PMID- 29761462 TI - Navigating Xenbase: An Integrated Xenopus Genomics and Gene Expression Database. AB - Xenbase is the Xenopus model organism database ( www.xenbase.org ), a web accessible resource that integrates the diverse genomic and biological data for Xenopus research. It hosts a variety of content including current and archived genomes for both X. laevis and X. tropicalis, bioinformatic tools for comparative genetic analyses including BLAST and GBrowse, annotated Xenopus literature, and catalogs of reagents including antibodies, ORFeome clones, morpholinos, and transgenic lines. Xenbase compiles gene-specific pages which include manually curated gene expression images, functional information including gene ontology (GO), disease associations, and links to other major data sources such as NCBI:Entrez, UniProtKB, and Ensembl. We also maintain the Xenopus Anatomy Ontology (XAO) which describes anatomy throughout embryonic development. This chapter provides a full description of the many features of Xenbase, and offers a guide on how to use various tools to perform a variety of common tasks such as identifying nucleic acid or protein sequences, finding gene expression patterns for specific genes, stages or tissues, identifying literature on a specific gene or tissue, locating useful reagents and downloading our extensive content, including Xenopus gene-Human gene disease mapping files. PMID- 29761463 TI - Using ZFIN: Data Types, Organization, and Retrieval. AB - The Zebrafish Model Organism Database (ZFIN; zfin.org) was established in 1994 as the primary genetic and genomic resource for the zebrafish research community. Some of the earliest records in ZFIN were for people and laboratories. Since that time, services and data types provided by ZFIN have grown considerably. Today, ZFIN provides the official nomenclature for zebrafish genes, mutants, and transgenics and curates many data types including gene expression, phenotypes, Gene Ontology, models of human disease, orthology, knockdown reagents, transgenic constructs, and antibodies. Ontologies are used throughout ZFIN to structure these expertly curated data. An integrated genome browser provides genomic context for genes, transgenics, mutants, and knockdown reagents. ZFIN also supports a community wiki where the research community can post new antibody records and research protocols. Data in ZFIN are accessible via web pages, download files, and the ZebrafishMine (zebrafishmine.org), an installation of the InterMine data warehousing software. Searching for data at ZFIN utilizes both parameterized search forms and a single box search for searching or browsing data quickly. This chapter aims to describe the primary ZFIN data and services, and provide insight into how to use and interpret ZFIN searches, data, and web pages. PMID- 29761464 TI - EchinoBase: Tools for Echinoderm Genome Analyses. AB - The echinoderms are a phylum of invertebrate deuterostome animals that constitute important research models for a number of biological disciplines. EchinoBase ( www.echinobase.org ) is an echinoderm-specific genome database and web information system that provides a platform for the interrogation and exploration of echinoderm genomic data. This chapter outlines the datasets available on EchinoBase; from assembled genomes and genome annotations, to spatial and quantitative expression data, as well as functional genomics datasets. We also highlight the bioinformatic tools available on the website to facilitate rapid inquiries using these data (genome browsers, precompiled BLAST databases, etc.), and suggest optimized strategies for performing these inquiries. We conclude with a perspective on how one could integrate various genomic resources to predict putative noncoding regulatory regions. The available datasets and analyses they permit provide the basic components required for developing an understanding of how echinoderm genomes are regulated, especially during early development, and provides a platform for comparative genomic inquiries among species in this phylum. PMID- 29761465 TI - A Multi-Omics Database for Parasitic Nematodes and Trematodes. AB - Helminth.net ( www.helminth.net ) is a web-based resource that was launched in 2000 as simply " Nematode.net " to host and investigate gene sequences from nematode genomes. Over the years it has evolved to become the moniker for a collection of databases: Nematode.net and Trematode.net . These databases host information for 73 nematode (roundworms) and 17 trematode (flatworms) species and serve as backbone for a number of tools that allow users to query slices of the data for multifactorial combinations of species-omics properties. Recent focus has been on inclusion of gene and protein expression data, population genomics and cross-kingdom interactions (metagenomics datasets). This chapter describes the website, the available tools and some of the new features. PMID- 29761466 TI - Using WormBase: A Genome Biology Resource for Caenorhabditis elegans and Related Nematodes. AB - WormBase ( www.wormbase.org ) provides the nematode research community with a centralized database for information pertaining to nematode genes and genomes. As more nematode genome sequences are becoming available and as richer data sets are published, WormBase strives to maintain updated information, displays, and services to facilitate efficient access to and understanding of the knowledge generated by the published nematode genetics literature. This chapter aims to provide an explanation of how to use basic features of WormBase, new features, and some commonly used tools and data queries. Explanations of the curated data and step-by-step instructions of how to access the data via the WormBase website and available data mining tools are provided. PMID- 29761467 TI - Using WormBase ParaSite: An Integrated Platform for Exploring Helminth Genomic Data. AB - WormBase ParaSite ( parasite.wormbase.org ) is a comprehensive resource for the genomes of parasitic nematodes and flatworms (helminths). It currently includes genomic data for over 100 helminth species, adding value by way of consistent functional annotation, gene comparative analysis and gene expression analysis. We provide several ways of exploring the data including a choice of genome browsers, genome and gene summary pages, text and sequence searching, a query wizard, bulk downloads, and programmatic interfaces. WormBase ParaSite is released three to six times per year, and is developed in collaboration with WormBase ( www.wormbase.org ) and Ensembl Genomes ( www.ensemblgenomes.org ). PMID- 29761469 TI - Hymenoptera Genome Database: Using HymenopteraMine to Enhance Genomic Studies of Hymenopteran Insects. AB - The Hymenoptera Genome Database (HGD; http://hymenopteragenome.org ) is a genome informatics resource for insects of the order Hymenoptera, which includes bees, ants and wasps. HGD provides genome browsers with manual annotation tools (JBrowse/Apollo), BLAST, bulk data download, and a data mining warehouse (HymenopteraMine). This chapter focuses on the use of HymenopteraMine to create annotation data sets that can be exported for use in downstream analyses. HymenopteraMine leverages the InterMine platform to combine genome assemblies and official gene sets with data from OrthoDB, RefSeq, FlyBase, Gene Ontology, UniProt, InterPro, KEGG, Reactome, dbSNP, PubMed, and BioGrid, as well as precomputed gene expression information based on publicly available RNAseq. Built in template queries provide starting points for data exploration, while the QueryBuilder tool supports construction of complex custom queries. The List Analysis and Genomic Regions search tools execute queries based on uploaded lists of identifiers and genome coordinates, respectively. HymenopteraMine facilitates cross-species data mining based on orthology and supports meta-analyses by tracking identifiers across gene sets and genome assemblies. PMID- 29761468 TI - Using FlyBase to Find Functionally Related Drosophila Genes. AB - For more than 25 years, FlyBase ( flybase.org ) has served as an online database of biological information on the genus Drosophila, concentrating on the model organism D. melanogaster. Traditionally, FlyBase data have been organized and presented at a gene-by-gene level, which remains a useful perspective when the object of interest is a specific gene or gene product. However, in the modern era of a fully sequenced genome and an increasingly characterized proteome, it is often desirable to compile and analyze lists of genes related by a common function. This may be achieved in FlyBase by searching for genes annotated with relevant Gene Ontology (GO) terms and/or protein domain data. In addition, FlyBase provides preassembled lists of functionally related D. melanogaster genes within "Gene Group" reports. These are compiled manually from the published literature or expert databases and greatly facilitate access to, and analysis of, established gene sets. This chapter describes protocols to produce lists of functionally related genes in FlyBase using GO annotations, protein domain data and the Gene Groups resource, and provides guidance and advice for their further analysis and processing. PMID- 29761470 TI - Navigating the i5k Workspace@NAL: A Resource for Arthropod Genomes. AB - The i5k Workspace@NAL is a genome database tailored toward newly sequenced arthropod genomes and their research communities. With 56 arthropod genomes and counting, the i5k Workspace strives to facilitate public data access, visualization, and community curation across arthropod species. Any researcher with an arthropod genome project who would like to take advantage of the i5k Workspace facilities is encouraged to submit their data. In this chapter, we explain how to use the i5k Workspace@NAL to submit, find, and improve arthropod genomics data. PMID- 29761471 TI - The infrapatellar fat pad and the synovial membrane: an anatomo-functional unit. AB - The infrapatellar pad, a fibro-adipose tissue with peculiar microscopic and mechanical features, is gaining wide attention in the field of rheumatological research. The purpose of this descriptive review is to summarize the most recent published evidence on the anatomic, physiologic and biomechanical inter relationship between the infrapatellar fat pad and the knee synovial membrane. As an extrasynovial tissue, the infrapatellar fat pad does not directly interact with the articular cartilage; based on its location in close contact with the synovial membrane, and due to the metabolic properties of adipose tissue, it may influence the behavior of the synovial membrane. In fact, considering evidence of macroscopic and microscopic anatomy, the infrapatellar fat pad is the site of insertion of the infrapatellar and medial synovial plicae. Also biochemically, there is much evidence highlighting the interaction among these two structures; in the case of inflammation, the mutual interplay is ascribable to the release of pro-inflammatory mediators stimulating the proliferation of inflammatory cells and promoting tissue modifications in both. All these assumptions could support the emerging idea that the infrapatellar fat pad and the synovial membrane may be considered a morpho-functional unit. PMID- 29761472 TI - Cranial morphology in Mollisquama sp. (Squaliformes; Dalatiidae) and patterns of cranial evolution in dalatiid sharks. AB - Dalatiid sharks are members of a family of predominantly small, midwater meso- and bathypelagic chondrichthyans. The family is notable for both its number of monotypic genera and high morphological disparity. Three of the seven dalatiid genera are known only from holotype specimens (Mollisquama parini) or from only a handful of specimens (Euprotomicroides zantedeschia, Heteroscymnoides marleyi), with the only detailed anatomical work consistent across all taxa being studies of dentition. Here, we present detailed anatomical description of the second-ever specimen of Mollisquama (Mollisquama sp.) covering chondrocranial, jaw, dental, and muscular anatomy, derived from a phase-contrast synchrotron microtomographic scan. Mollisquama sp. is unique among dalatiids in possessing a deep carinal process, extending ventrally from the bar between the subethmoid region and basal angle in squaloid sharks, containing a large fenestra infiltrated by the suborbitalis muscle. Mollisquama sp. also exhibits additional possibly diagnostic features, including a planar configuration of the labial cartilages and the absence of labial folds; a pad-like orbital process on the palatoquadrate; and the origination of the suborbitalis muscle solely on the carina, rather than the intraorbital wall. Character optimization of anatomical data onto a phylogeny of dalatiid sharks suggests Mollisquama sp. to be among the most specialized in the family, expanding the existing dalatiid morphospace. However, the functional significance of such transformations remains unclear. Synchrotron-derived data, which do not require chemical pretreatment of specimens, may elucidate soft tissue functional correlates in future studies of undersampled taxa, such as dalatiids. PMID- 29761473 TI - Glucocorticosteroids for infants with biliary atresia following Kasai portoenterostomy. AB - BACKGROUND: Biliary atresia is a life-threatening disease characterised by progressive destruction of both intra- and extra-hepatic biliary ducts. The mainstay of treatment is Kasai portoenterostomy, as soon as the disease has been confirmed. Glucocorticosteroids are steroid hormones which act on the glucocorticoid receptor and have a range of metabolic and immunomodulatory effects. Glucocorticosteroids are used to improve the postoperative outcomes in infants who have undergone Kasai portoenterostomy. OBJECTIVES: To assess the beneficial and harmful effects of glucocorticosteroid administration versus placebo or no intervention following Kasai portoenterostomy in infants with biliary atresia. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, Science Citation Index Expanded (Web of Science), and online trial registries (last search: 20 December 2017) for randomised controlled trials. SELECTION CRITERIA: We included randomised clinical trials which assessed glucocorticosteroids for infants who have undergone Kasai portoenterostomy. For harm, we also considered quasi randomised studies, observational studies, and case-control studies that were identified amongst the search results. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed the risk of bias for each trial according to prespecified domains. We analysed data using both random-effects and fixed-effect models. We performed the analyses using Review Manager 5.3 and Trial Sequental Analysis software. We considered a P value of 0.025 or less, two-tailed, as statistically significant. We planned to calculate risk ratios (RRs) for dichotomous outcomes, and the mean difference (MD) for continuous outcomes. For all association measures, we planned to use 95% confidence intervals (CIs) as well as Trial Sequential Analysis-adjusted CIs. We used Trial Sequential Analyisis to control the risks of random errors; however, we were often unable to implement this beyond calculating the required information size as there were few trials and data. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We found two randomised controlled trials fulfilling the inclusion criteria of our review. The trials provided data for meta-analysis. We judged the two trials as trials at low risk of bias. The two trials randomised a total of 213 infants to glucocorticosteroids versus placebo. In our Trial Sequential Analysis, the required information size (that is, the meta-analytic sample size) was not reached for any outcome. Trials were funded by charities, public organisations, and received support from private sector companies, none of which seemed to have an interest in the outcome of the respective trials. The effect of glucocorticosteroids after Kasai portoenterostomy on all-cause mortality is uncertain; the confidence interval is consistent with appreciable benefit and harm (RR 1.00; 95% CI 0.14 to 6.90; low certainty evidence). The results showed little or no difference in adverse effects between the use of glucocorticosteroids or placebo after Kasai portoenterostomy, however this analysis was based on a single trial and we have low certainty in the result (RR 1.02; 95% CI 0.87 to 1.20;). Available data suggest that the proportions of infants who do not clear their jaundice at six months is similar between the two groups (RR 0.89; 95% CI 0.67 to 1.17; low certainty evidence). All-cause mortality or liver transplantation did not differ at two years between the two groups (RR 1.00; 95% CI 0.72 to 1.39; low-certainty evidence). There were no data regarding health-related quality of life.Our searches also yielded 19 observational studies, some of them containing limited information on harmful effects of glucocorticosteroid treatment. We presented the extracted information narratively. We identified one further ongoing trial with no currently available results. AUTHORS' CONCLUSIONS: The two meta-analysed randomised clinical trials present insufficient evidence to determine the effects of using glucocorticosteroids versus placebo after Kasai portoenterostomy in infants with biliary atresia on any of the primary or secondary review outcomes. There is insufficient evidence to support glucocorticosteroid use in the postoperative management of infants with biliary atresia for long-term outcomes of all-cause mortality or liver transplantation. It is also unclear if glucocorticosteroids are able to reduce the numbers of infants who did not clear their jaundice by six months. Further randomised, placebo-controlled trials are required to be able to determine if glucocorticosteroids may be of benefit in the postoperative management of infants with biliary atresia treated with Kasai portoenterostomy. Such trials need to be conducted as multicentre trials. PMID- 29761474 TI - Lipids, Apolipoproteins, and Inflammatory Biomarkers of Cardiovascular Risk: What Have We Learned? AB - Cardiovascular diseases (CVD) are the first cause of death in the world. CVD risk is influenced by multiple factors, some nonmodifiable such as age, sex, and genetic background, and others modifiable. Great progress has been made over the last decades in the identification of biomarkers of incident or recurrent CV risk and surrogate endpoints of CV outcomes. We present the current state of knowledge for CV biomarkers in plasma including lipids, apolipoproteins, inflammation related, and emerging omics-based biomarkers. Clinically validated surrogate endpoints for CV outcomes include plasma low-density lipoprotein-cholesterol reduction, and plasma triglyceride reduction is a likely relevant surrogate endpoint. High-density lipoprotein-cholesterol is not a validated surrogate endpoint, but is a useful biomarker of CV risk. CV risk biomarkers of interest include apolipoprotein B and non-HDL-cholesterol, lipoprotein (a), C-reactive protein, and recently, genetic and protein-based risk scores and gut microbiota derived trimethylamine oxide levels. PMID- 29761475 TI - Exhaled breath analysis in evaluation of psychological stress: A short literature review. AB - Physiological stress is pervasive in today's society. Its detection is normally performed through several unobtrusive methods, driving both caregivers and patients to take measures to reduce the burden of this condition on human health. Among the methods for assessing stress, exhaled breath analysis represents a non invasive, real-time alternative to classic laboratory tests. Therefore, a literature review was performed to assess the presence of altered parameters, related to psychological stress, in exhaled breath. Most studies in our review measured nitric oxide (NO), whose concentration was often correlated, either positively or negatively, with psychological stress, with reasonable scientific support. Other compounds (isoprene, terpene and so on) were rarely studied and with mixed evidence. Further investigations are needed to elucidate the involvement and the pathophysiological role of NO in stress, possibly including a greater number of individuals, as sample size actually represents the main limitation of the work published to date. PMID- 29761476 TI - Comparison of materno-fetal predictors and short-term outcomes between early and late onset pre-eclampsia in the low-income setting of Douala, Cameroon. AB - OBJECTIVE: To describe and compare materno-fetal predictors and short-term outcomes of early onset pre-eclampsia (EOPE) and late onset pre-eclampsia (LOPE) in Douala, Cameroon. METHODS: The present prospective hospital-based cross sectional study included women with pre-eclampsia attending obstetric units at four hospitals in Douala between December 1, 2016, and April 30, 2017. To determine maternal predictors, sociodemographic and medical data were recorded using a pretested questionnaire. Pregnancy outcomes, and maternal and fetal adverse events were recorded. Univariate and multivariate logistic regression analyses were used to examine associations. RESULTS: Of 170 participants, 58 (34.1%) had EOPE and 112 (65.9%) had LOPE. EOPE was associated with higher incidences of chronic hypertension (P=0.027) and history of pre-eclampsia (P=0.003) compared with LOPE. Higher incidences of nulliparity and a different partner from prior pregnancy (P=0.024) were associated with LOPE. Women with EOPE had higher odds of acute kidney injury (odds ratio [OR] 6.67, 95% confidence interval [CI] 1.73-25.73) and HELLP (hemolysis, elevated liver enzyme, low platelets) syndrome (OR 10.47, 95% CI 1.19-91.9), and lower odds of deliveries without perinatal adverse events (OR 0.19, 95% CI 0.09-0.38), compared with patients with LOPE. CONCLUSION: In the low-income setting of Douala, there was a higher rate of LOPE than EOPE. Factors associated with EOPE and LOPE varied, and outcomes were worse for women with EOPE. PMID- 29761477 TI - A comparison of prompts and feedback for promoting handwashing in university restrooms. AB - We compared the effects of prompts versus feedback on handwashing behavior across six restrooms at a large university. We evaluated the effects using two separate multiple baseline designs across three men's and three women's restrooms. Results indicate that feedback was more effective for increasing handwashing. PMID- 29761478 TI - Pain relief for women undergoing oocyte retrieval for assisted reproduction. AB - BACKGROUND: Various methods of conscious sedation and analgesia (CSA) have been used during oocyte retrieval for assisted reproduction. The choice of agent has been influenced by the quality of sedation and analgesia and by concerns about possible detrimental effects on reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of different methods of conscious sedation and analgesia for pain relief and pregnancy outcomes in women undergoing transvaginal oocyte retrieval. SEARCH METHODS: We searched; the Cochrane Gynaecology and Fertility specialised register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL, and trials registers in November 2017. We also checked references, and contacted study authors for additional studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different methods and administrative protocols for conscious sedation and analgesia during oocyte retrieval. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were intraoperative and postoperative pain. Secondary outcomes included clinical pregnancy, patient satisfaction, analgesic side effects, and postoperative complications. MAIN RESULTS: We included 24 RCTs (3160 women) in five comparisons. We report the main comparisons below. Evidence quality was generally low or very low, mainly owing to poor reporting and imprecision.1. CSA versus other active interventions.All evidence for this comparison was of very low quality.CSA versus CSA plus acupuncture or electroacupunctureData show more effective intraoperative pain relief on a 0 to 10 visual analogue scale (VAS) with CSA plus acupuncture (mean difference (MD) 1.00, 95% confidence interval (CI) 0.18 to 1.82, 62 women) or electroacupuncture (MD 3.00, 95% CI 2.23 to 3.77, 62 women).Data also show more effective postoperative pain relief (0 to 10 VAS) with CSA plus acupuncture (MD 0.60, 95% CI -0.10 to 1.30, 61 women) or electroacupuncture (MD 2.10, 95% CI 1.40 to 2.80, 61 women).Evidence was insufficient to show whether clinical pregnancy rates were different between CSA and CSA plus acupuncture (odds ratio (OR) 0.61, 95% CI 0.20 to 1.86, 61 women). CSA alone may be associated with fewer pregnancies than CSA plus electroacupuncture (OR 0.22, 95% CI 0.07 to 0.66, 61 women).Evidence was insufficient to show whether rates of vomiting were different between CSA and CSA plus acupuncture (OR 1.64, 95% CI 0.46 to 5.88, 62 women) or electroacupuncture (OR 1.09, 95% CI 0.33 to 3.58, 62 women).Trialists provided no usable data for other outcomes of interest.CSA versus general anaesthesia Postoperative pain relief was greater in the CSA group (0 to 3 Likert: mean difference (MD) 1.9, 95% CI 2.24 to 1.56, one RCT, 50 women).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 1.00, 95% CI 0.43 to 2.35, two RCTs, 108 women, I2 = 0%).Evidence was insufficient to show whether groups differed in rates of vomiting (OR 0.46, 95% CI 0.08 to 2.75, one RCT, 50 women) or airway obstruction (OR 0.14, 95% CI 0.02 to 1.22, one RCT, 58 women). Fewer women needed mask ventilation in the CSA group (OR 0.05, 95% CI 0.01 to 0.20, one RCT, 58 women).Evidence was also insufficient to show whether groups differed in satisfaction rates (OR 0.66, 95% CI 0.11 to 4.04, two RCTs, 108 women, I2 = 34%; very low-quality evidence).Trialists provided no usable data for outcomes of interest.2. CSA + paracervical block (PCB) versus other interventions.CSA + PCB versus electroacupuncture + PCB Intraoperative pain scores were lower in the CSA + PCB group (0 to 10 VAS: MD -0.66, 95% CI -0.93 to -0.39, 781 women, I2 = 76%; low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.96, 95% CI 0.72 to 1.29, 783 women, I2 = 9%; low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus general anaesthesiaEvidence was insufficient to show whether groups differed in postoperative pain scores (0 to 10 VAS: MD 0.49, 95% CI -0.13 to 1.11, 50 women; very low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.70, 95% CI 0.22 to 2.26, 51 women; very low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus spinal anaesthesiaPostoperative pain scores were higher in the CSA + PCB group (0 to 10 VAS: MD 1.02, 95% CI 0.48 to 1.56, 36 women; very low-quality evidence).Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.93, 95% CI 0.24 to 3.65, 38 women; very low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus PCBEvidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.93, 95% CI 0.44 to 1.96, 150 women; low-quality evidence) or satisfaction (OR 1.63, 95% CI 0.68 to 3.89, 150 women, low-quality evidence).Trialists provided no usable data for other outcomes of interest.CSA + PCB versus CSA only Evidence was insufficient to show whether groups differed in clinical pregnancy rates (OR 0.62, 95% CI 0.28 to 1.36, one RCT, 100 women; very low-quality evidence). Rates of postoperative nausea and vomiting were lower in the CS + PCB group (OR 0.42, 95% CI 0.18 to 0.97, two RCTs, 140 women, I2 = 40%; very low-quality evidence).Trialists provided no usable data for other outcomes of interest. AUTHORS' CONCLUSIONS: The evidence does not support one particular method or technique over another in providing effective conscious sedation and analgesia for pain relief during and after oocyte retrieval. Simultaneous use of sedation combined with analgesia such as the opiates, further enhanced by paracervical block or acupuncture techniques, resulted in better pain relief than occurred with one modality alone. Evidence was insufficient to show conclusively whether any of the interventions influenced pregnancy rates. All techniques reviewed were associated with a high degree of patient satisfaction. Women's preferences and resource availability for choice of pain relief merit consideration in practice. PMID- 29761479 TI - Antidepressants for insomnia in adults. AB - BACKGROUND: Insomnia disorder is a subjective condition of unsatisfactory sleep (e.g. sleep onset, maintenance, early waking, impairment of daytime functioning). Insomnia disorder impairs quality of life and is associated with an increased risk of physical and mental health problems including anxiety, depression, drug and alcohol abuse, and increased health service use. hypnotic medications (e.g. benzodiazepines and 'Z' drugs) are licensed for sleep promotion, but can induce tolerance and dependence, although many people remain on long-term treatment. Antidepressant use for insomnia is widespread, but none is licensed for insomnia and the evidence for their efficacy is unclear. This use of unlicensed medications may be driven by concern over longer-term use of hypnotics and the limited availability of psychological treatments. OBJECTIVES: To assess the effectiveness, safety and tolerability of antidepressants for insomnia in adults. SEARCH METHODS: This review incorporated the results of searches to July 2015 conducted on electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 6), MEDLINE (1950 to 2015), Embase (1980 to 2015) and PsycINFO (1806 to 2015). We updated the searches to December 2017, but these results have not yet been incorporated into the review. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults (aged 18 years or older) with a primary diagnosis of insomnia and all participant types including people with comorbidities. Any antidepressant as monotherapy at any dose whether compared with placebo, other medications for insomnia (e.g. benzodiazepines and 'Z' drugs), a different antidepressant, waiting list control or treatment as usual. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility and extracted data using a data extraction form. A third review author resolved disagreements on inclusion or data extraction. MAIN RESULTS: The search identified 23 RCTs (2806 participants).Selective serotonin reuptake inhibitors (SSRIs) compared with placebo: three studies (135 participants) compared SSRIs with placebo. Combining results was not possible. Two paroxetine studies showed significant improvements in subjective sleep measures at six (60 participants, P = 0.03) and 12 weeks (27 participants, P < 0.001). There was no difference in the fluoxetine study (low quality evidence).There were either no adverse events or they were not reported (very low quality evidence).Tricyclic antidepressants (TCA) compared with placebo: six studies (812 participants) compared TCA with placebo; five used doxepin and one used trimipramine. We found no studies of amitriptyline. Four studies (518 participants) could be pooled, showing a moderate improvement in subjective sleep quality over placebo (standardised mean difference (SMD) -0.39, 95% confidence interval (CI) -0.56 to -0.21) (moderate quality evidence). Moderate quality evidence suggested that TCAs possibly improved sleep efficiency (mean difference (MD) 6.29 percentage points, 95% CI 3.17 to 9.41; 4 studies; 510 participants) and increased sleep time (MD 22.88 minutes, 95% CI 13.17 to 32.59; 4 studies; 510 participants). There may have been little or no impact on sleep latency (MD -4.27 minutes, 95% CI -9.01 to 0.48; 4 studies; 510 participants).There may have been little or no difference in adverse events between TCAs and placebo (risk ratio (RR) 1.02, 95% CI 0.86 to 1.21; 6 studies; 812 participants) (low quality evidence).'Other' antidepressants with placebo: eight studies compared other antidepressants with placebo (one used mianserin and seven used trazodone). Three studies (370 participants) of trazodone could be pooled, indicating a moderate improvement in subjective sleep outcomes over placebo (SMD -0.34, 95% CI -0.66 to -0.02). Two studies of trazodone measured polysomnography and found little or no difference in sleep efficiency (MD 1.38 percentage points, 95% CI -2.87 to 5.63; 169 participants) (low quality evidence).There was low quality evidence from two studies of more adverse effects with trazodone than placebo (i.e. morning grogginess, increased dry mouth and thirst). AUTHORS' CONCLUSIONS: We identified relatively few, mostly small studies with short-term follow-up and design limitations. The effects of SSRIs compared with placebo are uncertain with too few studies to draw clear conclusions. There may be a small improvement in sleep quality with short-term use of low-dose doxepin and trazodone compared with placebo. The tolerability and safety of antidepressants for insomnia is uncertain due to limited reporting of adverse events. There was no evidence for amitriptyline (despite common use in clinical practice) or for long-term antidepressant use for insomnia. High-quality trials of antidepressants for insomnia are needed. PMID- 29761480 TI - Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer. AB - Testicular germ cell tumors (TGCTs) are a clinically and pathologically heterogeneous disease, and little is known of its genetic basis. Only low susceptibility risk loci have been identified for both sporadic and familial cases. Therefore, we tried to identify new susceptibility genes responsible for familial testicular cancer that may contribute to increasing our knowledge about the genetic basis of the disease. Nineteen Spanish families with at least two affected individuals with TGCT were selected. WES was performed on those individuals using an Illumina Hiseq2000 sequencing platform. Data were analyzed under a monogenic and polygenic model of inheritance, and candidate variants were evaluated in a case-control association study performed on 391 Spanish sporadic cases and 1,170 healthy Spanish controls. Results were replicated in a second series consisting of 101 TGCTs from the Cancer Genome Atlas (TGCA) and 27,000 controls from the Exome Aggregation Consortium (ExAC) database. Logistic regression was carried out to analyze the association strength (risk) of candidate variants obtained among cases and controls in different populations. Despite the sample size, we detected a significant earlier age of onset in familial TGCT (28y) than sporadic cases (33y), using a Mann-Whitney U test. We identified significant variants in the comparative study of TGCT cases (391) versus controls (almost 1,170), and three of them [PLEC (OR = 6.28, p = 6.42 * 10 23 ) (p.Arg2016Trp), EXO5 (OR = 3.37, p = 4.82 * 10-09 ) (p.Arg344AlafsTer10) and DNAH7 (OR = 1.64, p = 0.048)] were replicated as potential candidates that may contribute to explaining the genetic basis of TGCT. PMID- 29761483 TI - Epithelial barrier dysfunctions in atopic dermatitis: a skin-gut-lung model linking microbiome alteration and immune dysregulation. AB - BACKGROUND: Atopic dermatitis is a systemic disorder characterized by abnormal barrier function across multiple organ sites. Causes of epidermal barrier breakdown are complex and driven by a combination of structural, genetic, environmental and immunological factors. In addition, alteration in microflora diversity can influence disease severity, duration, and response to treatment. Clinically, atopic dermatitis can progress from skin disease to food allergy, allergic rhinitis, and later asthma, a phenomenon commonly known as the atopic march. The mechanism by which atopic dermatitis progresses towards gastrointestinal or airway disease remains to be elucidated. OBJECTIVES: This review addresses how epithelial dysfunction linking microbiome alteration and immune dysregulation can predispose to the development of the atopic march. METHODS: A literature search was conducted using the PubMed database for relevant articles with the keywords 'atopic dermatitis', 'epithelial barrier', 'skin', 'gut', 'lung', 'microbiome' and 'immune dysregulation'. RESULTS: Initial disruption in the skin epidermal barrier permits allergen sensitization and colonization by pathogens. This induces a T helper 2 inflammatory response and a thymic stromal lymphopoietin-mediated pathway that further promotes barrier breakdown at distant sites, including the intestinal and respiratory tract. CONCLUSIONS: As there are no immediate cures for food allergy or asthma, early intervention aimed at protecting the skin barrier and effective control of local and systemic inflammation may improve long-term outcomes and reduce allergen sensitization in the airway and gut. PMID- 29761481 TI - LncRNA NKILA suppresses TGF-beta-induced epithelial-mesenchymal transition by blocking NF-kappaB signaling in breast cancer. AB - TGF-beta plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-beta-induced EMT is NF-kappaB-dependent in various cancer types. However, it is largely unclear if NF-kappaB mediates TGF-beta-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-beta activates the NF-kappaB pathway. Inhibition of NF-kappaB signaling markedly abrogates TGF-beta-induced EMT. By studying the regulatory mechanism of TGF-beta-induced NF-kappaB signaling, we found that lncRNA NKILA was upregulated by TGF-beta and was essential for the negative feedback regulation of the NF-kappaB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-beta-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-beta-induced NF-kappaB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT. PMID- 29761482 TI - Timing of onset of gastrointestinal bleeding in the ICU: Protocol for a preplanned observational study. AB - BACKGROUND: Critically ill patients are at risk of gastrointestinal bleeding, but clinically important gastrointestinal bleeding is rare. The majority of intensive care unit (ICU) patients receive stress ulcer prophylaxis (SUP), despite uncertainty concerning the balance between benefit and harm. For approximately half of ICU patients with gastrointestinal bleeding, onset is early, ie within the first two days of the ICU stay. The aetiology of gastrointestinal bleeding and consequently the balance between benefit and harm of SUP may differ between patients with early vs late gastrointestinal bleeding. METHODS: This is a protocol and statistical analysis plan for a preplanned exploratory substudy of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) randomized clinical trial, comparing intravenous pantoprazole (40 mg once daily) with placebo in 3350 acutely ill adult ICU patients. We will describe baseline characteristics and assess the time to onset of the first clinically important episode of GI bleeding accounting for survival status and allocation to SUP or placebo. In addition, we will describe differences in therapeutic and diagnostic procedures used in patients with clinically important gastrointestinal bleeding according to early vs late bleeding and 90-day vital status. CONCLUSIONS: The study outlined in this protocol will provide detailed information on patient characteristics and the timing of onset of gastrointestinal bleeding in the patients enrolled in the SUP-ICU trial. This may provide additional knowledge and incentives for future studies on which patients benefit from SUP. PMID- 29761485 TI - Shaping complex functional communication responses. AB - Response efficiency plays an important role in the initial success of functional communication training (FCT). Although low-effort functional communication responses (FCRs) have been shown to be most effective in replacing problem behavior; more developmentally advanced FCRs are favored later in the treatment process. Attempts to teach these more complex FCRs, however, often lead to the resurgence of problem behavior. In this study, we provide a detailed description of an effective shaping process applied within a changing criterion design to develop complex FCRs from simple FCRs without resurgence of problem behavior. Four children with various language and intellectual abilities participated in this study. A practical shaping procedure, suitable for typical teaching contexts, is described for two participants in Experiment 1. The necessity and efficacy of the shaping process are demonstrated with the participants in Experiment 2. Implications for practice and research are discussed. PMID- 29761484 TI - Inbreeding, inbreeding depression, and infidelity in a cooperatively breeding bird. AB - Inbreeding depression plays a major role in shaping mating systems: in particular, inbreeding avoidance is often proposed as a mechanism explaining extra-pair reproduction in socially monogamous species. This suggestion relies on assumptions that are rarely comprehensively tested: that inbreeding depression is present, that higher kinship between social partners increases infidelity, and that infidelity reduces the frequency of inbreeding. Here, we test these assumptions using 26 years of data for a cooperatively breeding, socially monogamous bird with high female infidelity, the superb fairy-wren (Malurus cyaneus). Although inbred individuals were rare (~6% of offspring), we found evidence of inbreeding depression in nestling mass (but not in fledgling survival). Mother-son social pairings resulted in 100% infidelity, but kinship between a social pair did not otherwise predict female infidelity. Nevertheless, extra-pair offspring were less likely to be inbred than within-pair offspring. Finally, the social environment (the number of helpers in a group) did not affect offspring inbreeding coefficients or inbreeding depression levels. In conclusion, despite some agreement with the assumptions that are necessary for inbreeding avoidance to drive infidelity, the apparent scarcity of inbreeding events and the observed levels of inbreeding depression seem insufficient to explain the ubiquitous infidelity in this system, beyond the mother-son mating avoidance. PMID- 29761486 TI - TREatment of ATopic eczema (TREAT) Registry Taskforce: an international Delphi exercise to identify a core set of domains and domain items for national atopic eczema photo- and systemic therapy registries. AB - BACKGROUND: Evidence of immunomodulatory therapies to guide clinical management of atopic eczema (AE) is scarce, despite frequent and often off-label use. Patient registries provide valuable evidence for the effects of treatments under real-world conditions that can inform treatment guidelines, give the opportunity for health economic evaluation and the evaluation of quality of care, as well as pharmacogenetic and dynamic research, which cannot be adequately addressed in clinical trials. OBJECTIVES: The TREatment of ATopic eczema (TREAT) Registry Taskforce aims to seek international consensus on a core set of domains and items ('what to measure') for AE research registries, using a Delphi approach. METHODS: Participants from six stakeholder groups were included: doctors, nurses, nonclinical researchers, patients, industry and regulatory body representatives. The eDelphi comprised three sequential online rounds, requesting participants to rate the importance of each proposed domain item. Participants could add domain items to the proposed list in round 1. A final consensus meeting was held to ratify the core set. RESULTS: Participants (n = 479) from 36 countries accessed the eDelphi platform, of whom 86%, 79% and 74% completed rounds 1, 2 and 3, respectively. At the face-to-face consensus meeting attended by 42 participants the final core set was established containing 19 domains with 69 domain items (49 baseline and 20 follow-up items). CONCLUSIONS: This core set of domains and items to be captured by national AE systemic therapy registries will standardize data collection and thereby allow direct comparability across registries and facilitate data pooling between countries. Ultimately, it will provide greater insight into the effectiveness, safety and cost-effectiveness of photo- and systemic immunomodulatory therapies. PMID- 29761487 TI - The phytoestrogen genistein prevents trabecular bone loss and affects thyroid follicular cells in a male rat model of osteoporosis. AB - As a major phytoestrogen of soy, genistein effectively prevents bone loss in both humans and rat models of osteoporosis. However, although the bone-sparing effects of genistein are achieved directly through estrogen receptors, its mode of action on bone by modulation of other endocrine functions is not entirely clear. Thus, thyroid hormones and calcitonin (CT) have an essential influence on bone metabolism. Besides its action on bones, in this study we examined the effect of genistein on the activity of two different endocrine cell populations, thyroid follicular and C-cells. Fifteen-month-old Wistar rats were either bilaterally orchidectomized (Orx) or sham-operated (SO). Two weeks after surgery, half of the Orx rats were treated chronically with 30 mg kg-1 b.w. genistein (Orx + G) subcutaneously (s.c.) every day for 3 weeks, while the remaining Orx rats and the SO rats were given the same volume of sterile olive oil to serve as controls. For histomorphometrical analysis of the trabecular bone microarchitecture an ImageJ public domain image processing programme was used. Thyroid sections were analysed histologically and stereologically after visualization of follicular and C-cells by immunohistochemical staining for thyroglobulin and CT. Thyroid follicular epithelium, interstitium, colloid and CT-immunopositive C-cells were examined morphometrically. Serum concentrations of osteocalcin (OC), triiodothyronine (T3 ), thyroxine (T4 ) and CT were determined as well as urinary calcium (Ca2+ ) concentrations. Genistein treatment significantly increased cancellous bone area (B.Ar), trabecular thickness (TbTh) and trabecular number (TbN) (P < 0.05), but trabecular separation (Tb.Sp) was decreased (P < 0.05) compared with control Orx rats. In the thyroid, genistein treatment significantly elevated the relative volume density (Vv) of the follicular cells (P < 0.05) compared with Orx, whereas Vv of the colloid was lower (P < 0.05) than in the Orx. Evaluation of the biochemical parameters showed significant reductions in serum OC, T3 , T4 and urinary Ca2+ concentrations (P < 0.05), compared with Orx rats. These data indicate that genistein treatment improves the trabecular microarchitecture of proximal tibia, induces histomorphometrical changes in thyroid glands, and decreases circulating thyroid hormone levels in orchidectomized rat model of male osteoporosis. PMID- 29761488 TI - Psychological therapies for treatment-resistant depression in adults. AB - BACKGROUND: Antidepressants are a first-line treatment for adults with moderate to severe major depression. However, many people prescribed antidepressants for depression don't respond fully to such medication, and little evidence is available to inform the most appropriate 'next step' treatment for such patients, who may be referred to as having treatment-resistant depression (TRD). National Institute for Health and Care Excellence (NICE) guidance suggests that the 'next step' for those who do not respond to antidepressants may include a change in the dose or type of antidepressant medication, the addition of another medication, or the start of psychotherapy. Different types of psychotherapies may be used for TRD; evidence on these treatments is available but has not been collated to date.Along with the sister review of pharmacological therapies for TRD, this review summarises available evidence for the effectiveness of psychotherapies for adults (18 to 74 years) with TRD with the goal of establishing the best 'next step' for this group. OBJECTIVES: To assess the effectiveness of psychotherapies for adults with TRD. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (until May 2016), along with CENTRAL, MEDLINE, Embase, and PsycINFO via OVID (until 16 May 2017). We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov to identify unpublished and ongoing studies. There were no date or language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with participants aged 18 to 74 years diagnosed with unipolar depression that had not responded to minimum four weeks of antidepressant treatment at a recommended dose. We excluded studies of drug intolerance. Acceptable diagnoses of unipolar depression were based onthe Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) or earlier versions, International Classification of Diseases (ICD) 10, Feighner criteria, or Research Diagnostic Criteria. We included the following comparisons.1. Any psychological therapy versus antidepressant treatment alone, or another psychological therapy.2. Any psychological therapy given in addition to antidepressant medication versus antidepressant treatment alone, or a psychological therapy alone.Primary outcomes required were change in depressive symptoms and number of dropouts from study or treatment (as a measure of acceptability). DATA COLLECTION AND ANALYSIS: We extracted data, assessed risk of bias in duplicate, and resolved disagreements through discussion or consultation with a third person. We conducted random-effects meta-analyses when appropriate. We summarised continuous outcomes using mean differences (MDs) or standardised mean differences (SMDs), and dichotomous outcomes using risk ratios (RRs). MAIN RESULTS: We included six trials (n = 698; most participants were women approximately 40 years of age). All studies evaluated psychotherapy plus usual care (with antidepressants) versus usual care (with antidepressants). Three studies addressed the addition of cognitive-behavioural therapy (CBT) to usual care (n = 522), and one each evaluated intensive short-term dynamic psychotherapy (ISTDP) (n = 60), interpersonal therapy (IPT) (n = 34), or group dialectical behavioural therapy (DBT) (n = 19) as the intervention. Most studies were small (except one trial of CBT was large), and all studies were at high risk of detection bias for the main outcome of self-reported depressive symptoms.A random effects meta-analysis of five trials (n = 575) showed that psychotherapy given in addition to usual care (vs usual care alone) produced improvement in self reported depressive symptoms (MD -4.07 points, 95% confidence interval (CI) -7.07 to -1.07 on the Beck Depression Inventory (BDI) scale) over the short term (up to six months). Effects were similar when data from all six studies were combined for self-reported depressive symptoms (SMD -0.40, 95% CI -0.65 to -0.14; n = 635). The quality of this evidence was moderate. Similar moderate-quality evidence of benefit was seen on the Patient Health Questionnaire-9 Scale (PHQ-9) from two studies (MD -4.66, 95% CI 8.72 to -0.59; n = 482) and on the Hamilton Depression Rating Scale (HAMD) from four studies (MD -3.28, 95% CI -5.71 to 0.85; n = 193).High-quality evidence shows no differential dropout (a measure of acceptability) between intervention and comparator groups over the short term (RR 0.85, 95% CI 0.58 to 1.24; six studies; n = 698).Moderate-quality evidence for remission from six studies (RR 1.92, 95% CI 1.46 to 2.52; n = 635) and low quality evidence for response from four studies (RR 1.80, 95% CI 1.2 to 2.7; n = 556) indicate that psychotherapy was beneficial as an adjunct to usual care over the short term.With the addition of CBT, low-quality evidence suggests lower depression scores on the BDI scale over the medium term (12 months) (RR -3.40, 95% CI -7.21 to 0.40; two studies; n = 475) and over the long term (46 months) (RR -1.90, 95% CI -3.22 to -0.58; one study; n = 248). Moderate-quality evidence for adjunctive CBT suggests no difference in acceptability (dropout) over the medium term (RR 0.98, 95% CI 0.66 to 1.47; two studies; n = 549) and lower dropout over long term (RR 0.80, 95% CI 0.66 to 0.97; one study; n = 248).Two studies reported serious adverse events (one suicide, two hospitalisations, and two exacerbations of depression) in 4.2% of the total sample, which occurred only in the usual care group (no events in the intervention group).An economic analysis (conducted as part of an included study) from the UK healthcare perspective (National Health Service (NHS)) revealed that adjunctive CBT was cost effective over nearly four years. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that psychotherapy added to usual care (with antidepressants) is beneficial for depressive symptoms and for response and remission rates over the short term for patients with TRD. Medium- and long-term effects seem similarly beneficial, although most evidence was derived from a single large trial. Psychotherapy added to usual care seems as acceptable as usual care alone.Further evidence is needed on the effectiveness of different types of psychotherapies for patients with TRD. No evidence currently shows whether switching to a psychotherapy is more beneficial for this patient group than continuing an antidepressant medication regimen. Addressing this evidence gap is an important goal for researchers. PMID- 29761489 TI - Mortality in unipolar depression preceding and following chronic somatic diseases. AB - OBJECTIVE: It is largely unknown how depression prior to and following somatic diseases affects mortality. Thus, we examined how the temporal order of depression and somatic diseases affects mortality risk. METHOD: Data were from a Danish population-based cohort from 1995 to 2013, which included all residents in Denmark during the study period (N = 4 984 912). Nineteen severe chronic somatic disorders from the Charlson Comorbidity Index were assessed. The date of first diagnosis of depression and somatic diseases was identified. Multivariable Cox proportional Hazard models with time-varying covariates were constructed to assess the risk for all-cause and non-suicide deaths for individual somatic diseases. RESULTS: For all somatic diseases, prior and/or subsequent depression conferred a significantly higher mortality risk. Prior depression was significantly associated with a higher mortality risk when compared to subsequent depression for 13 of the 19 somatic diseases assessed, with the largest difference observed for moderate/severe liver disease (HR = 2.08; 95% CI = 1.79 2.44), followed by metastatic solid tumor (HR = 1.48; 95% CI = 1.39-1.58), and myocardial infarction (HR = 1.40; 95% CI = 1.34-1.49). CONCLUSION: A particularly high mortality risk was observed in the presence of prior depression for most somatic diseases. Future studies that assess the underlying mechanisms are necessary to adequately address the excessive mortality associated with comorbid depression. PMID- 29761491 TI - An evaluation of group activity schedules to promote social play in children with autism. AB - Children with autism spectrum disorder (ASD) often have deficits in social skills and may avoid engaging in play activities with typically developing peers. The purpose of this study was to identify the utility of activity schedules, with embedded scripts, to teach three children with ASD to play a complex social game. Specifically, children with ASD were taught to play hide-and-seek with typically developing peers. Once the activity schedules were introduced, participants began engaging in independent hide-and-seek behaviors. A secondary purpose of this study was to systematically fade the activity schedules to the least intrusive version. We faded all of the scripts and the majority of activity schedule components for the three participants. Participants continued to play hide-and seek with the faded versions of the schedules in a novel environment and 2 weeks after treatment concluded. PMID- 29761490 TI - Distinct timing of neurogenesis of ipsilateral and contralateral retinal ganglion cells. AB - In higher vertebrates, the circuit formed by retinal ganglion cells (RGCs) projecting ipsilaterally (iRGCs) or contralaterally (cRGCs) to the brain permits binocular vision and depth perception. iRGCs and cRGCs differ in their position within the retina and in expression of transcription, guidance and activity related factors. To parse whether these two populations also differ in the timing of their genesis, a feature of distinct neural subtypes and associated projections, we used newer birthdating methods and cell subtype specific markers to determine birthdate and cell cycle exit more precisely than previously. In the ventrotemporal (VT) retina, i- and cRGCs intermingle and neurogenesis in this zone lags behind RGC production in the rest of the retina where only cRGCs are positioned. In addition, within the VT retina, i- and cRGC populations are born at distinct times: neurogenesis of iRGCs surges at E13, and cRGCs arise as early as E14, not later in embryogenesis as reported. Moreover, in the ventral ciliary margin zone (CMZ), which contains progenitors that give rise to some iRGCs in ventral neural retina (Marcucci et al., 2016), cell cycle exit is slower than in other retinal regions in which progenitors give rise only to cRGCs. Further, when the cell cycle regulator Cyclin D2 is missing, cell cycle length in the CMZ is further reduced, mirroring the reduction of both i- and cRGCs in the Cyclin D2 mutant. These results strengthen the view that differential regulation of cell cycle dynamics at the progenitor level is associated with specific RGC fates and laterality of axonal projection. PMID- 29761492 TI - C7 vertebra homeotic transformation in domestic dogs - are Pug dogs breaking mammalian evolutionary constraints? AB - The number of cervical vertebrae in mammals is almost constant at seven, regardless of their neck length, implying that there is selection against variation in this number. Homebox (Hox) genes are involved in this evolutionary mammalian conservation, and homeotic transformation of cervical into thoracic vertebrae (cervical ribs) is a common phenotypic abnormality when Hox gene expression is altered. This relatively benign phenotypic change can be associated with fatal traits in humans. Mutations in genes upstream of Hox, inbreeding and stressors during organogenesis can also cause cervical ribs. The aim of this study was to describe the prevalence of cervical ribs in a large group of domestic dogs of different breeds, and explore a possible relation with other congenital vertebral malformations (CVMs) in the breed with the highest prevalence of cervical ribs. By phenotyping we hoped to give clues as to the underlying genetic causes. Twenty computed tomography studies from at least two breeds belonging to each of the nine groups recognized by the Federation Cynologique Internationale, including all the brachycephalic 'screw-tailed' breeds that are known to be overrepresented for CVMs, were reviewed. The Pug dog was more affected by cervical ribs than any other breed (46%; P < 0.001), and was selected for further analysis. No association was found between the presence of cervical ribs and vertebral body formation defect, bifid spinous process, caudal articular process hypoplasia/aplasia and an abnormal sacrum, which may infer they have a different aetiopathogenesis. However, Pug dogs with cervical ribs were more likely to have a transitional thoraco-lumbar vertebra (P = 0.041) and a pre sacral vertebral count of 26 (P < 0.001). Higher C7/T1 dorsal spinous processes ratios were associated with the presence of cervical ribs (P < 0.001), supporting this is a true homeotic transformation. Relaxation of the stabilizing selection has likely occurred, and the Pug dog appears to be a good naturally occurring model to further investigate the aetiology of cervical ribs, other congenital vertebral anomalies and numerical alterations. PMID- 29761493 TI - Experimental induction of mouthrot in Atlantic salmon smolts using Tenacibaculum maritimum from Western Canada. AB - Mouthrot, or bacterial stomatitis, is a disease which mainly affects farmed Atlantic salmon, (Salmo salar, L.), smolts recently transferred into salt water in both British Columbia (BC), Canada, and Washington State, USA. It is a significant fish welfare issue which results in economic losses due to mortality and antibiotic treatments. The associated pathogen is Tenacibaculum maritimum, a bacterium which causes significant losses in many species of farmed fish worldwide. This bacterium has not been proven to be the causative agent of mouthrot in BC despite being isolated from affected Atlantic salmon. In this study, challenge experiments were performed to determine whether mouthrot could be induced with T. maritimum isolates collected from outbreaks in Western Canada and to attempt to develop a bath challenge model. A secondary objective was to use this model to test inactivated whole-cell vaccines for T. maritimum in Atlantic salmon smolts. This study shows that T. maritimum is the causative agent of mouthrot and that the bacteria can readily transfer horizontally within the population. Although the whole-cell oil-adjuvanted vaccines produced an antibody response that was partially cross-reactive with several of the T. maritimum isolates, the vaccines did not protect the fish under the study's conditions. PMID- 29761494 TI - Control of xylem Na+ loading and transport to the shoot in rice and barley as a determinant of differential salinity stress tolerance. AB - Control of xylem Na+ loading has often been named as the essential component of salinity tolerance mechanism. However, it is less clear to what extent the difference in this trait may determine differential salinity tolerance between species. In this study, barley (Hordeum vulgare L. cv. CM72) and rice (Oryza sativa L. cv. Dongjin) plants were grown under two levels of salinity. Na+ and K+ concentrations in the xylem sap, and shoot and root tissues were measured at different time points after stress onset. Salt-exposed rice plants prevented xylem Na+ loading for several days, but failed to control this process in the longer term, ultimately resulting in a massive Na+ shoot loading. Barley plants quickly increased xylem Na+ concentration and its delivery to the shoot (most likely for the purpose of osmotic adjustment) but were able to reduce this process later on, keeping most of accumulated Na+ in the root, thus maintaining non-toxic shoot Na+ level. Rice plants increased shoot K+ concentration, while barley plants maintained higher root K+ concentration. Control of xylem Na+ loading is remarkably different between rice and barley; this difference may differentiate the extent of the salinity tolerance between species. This trait should be investigated in more detail to be used in the breeding programs aimed to improve salinity tolerance in crops. PMID- 29761495 TI - Changes in gene expression during germination reveal pea genotypes with either "quiescence" or "escape" mechanisms of waterlogging tolerance. AB - Waterlogging causes germination failure in pea (Pisum sativum L.). Three genotypes (BARI Motorshuti-3, Natore local-2 [NL-2], and Kaspa) contrasting in ability to germinate in waterlogged soil were exposed to different durations of waterlogging. Whole genome RNAseq was employed to capture differentially expressing genes. The ability to germinate in waterlogged soil was associated with testa colour and testa membrane integrity as confirmed by electrical conductivity measurements. Genotypes Kaspa and NL-2 displayed different mechanisms of tolerance. In Kaspa, an energy conserving strategy was indicated by a strong upregulation of tyrosine protein kinsase and down regulation of linoleate 9S-lipoxygenase 5, a fat metabolism gene. In contrast, a faster energy utilization strategy was suggested in NL-2 by the marked upregulation of a subtilase family protein and peroxisomal adenine nucleotide carrier 2, a fat metabolizing gene. Waterlogging susceptibility in germinating seeds of genotype BARI Motorshuti-3 was linked to upregulation of a kunitz-type trypsin/protease inhibitor that blocks protein metabolism and may lead to excessive lipid metabolism and the membrane leakage associated with waterlogging damage. Pathway analyses based on gene ontologies showed seed storage protein metabolism as upregulated in tolerant genotypes and downregulated in the sensitive genotype. Understanding the tolerance mechanism provides a platform to breed for adaptation to waterlogging stress at germination in pea. PMID- 29761496 TI - Contact dermatitis caused by dialkylcarbamoyl compounds in a medication used for chronic wounds. PMID- 29761497 TI - Vibration enhances PGE2 , IL-6, and IL-8 expression in compressed hPDL cells via cyclooxygenase pathway. AB - BACKGROUND: Although vibration combined with orthodontic force may accelerate orthodontic tooth movement, little is known about the mechanisms that regulate the associated cellular responses. The goal of this study was to investigate whether mechanical vibration combined with compressive force regulates cyclooxygenase (COX)-2/prostaglandin E2 (PGE2 ) and interleukin (IL)-6 and IL-8 messenger RNA (mRNA) and protein expression in human periodontal ligament (hPDL) cells via the COX pathway. METHODS: The primary cultured hPDL cells were exposed to mechanical vibration, compressive force or a combination of both mechanical vibration and compressive force at 24, 48, and 72 hours. The COX-2, IL-6, IL-8, receptor activator of nuclear factor kappa-Beta ligand (RANKL), and osteoprotegrin (OPG) mRNA expressions were determined using quantitative real time polymerase chain reaction (qPCR). The PGE2 , IL-6, and IL-8 protein expressions were quantified by enzyme-linked immunosorbent assay (ELISA). To demonstrate whether the expression of PGE2 , IL-6, and IL-8 was in the COX dependent pathway, the hPDL cells were treated with indomethacin. To determine whether PGE2 stimulated the hPDL cells to express IL-6 and IL-8, exogenous PGE2 was added to the culture media. RESULTS: The combination of mechanical vibration and compressive force synergistically upregulated RANKL/OPG, COX-2/PGE2 , IL-6 and IL-8 mRNA, and protein expression. The indomethacin significantly attenuated the increases of PGE2 , IL-6, and IL-8 expression in cells stimulated with compressive force or mechanical vibration combined with compressive force. In addition, exogenous PGE2 increased IL-6 and IL-8 mRNA and protein expressions in hPDL cells. CONCLUSION: Mechanical vibration may enhance alveolar bone resorption at the compression side during orthodontic tooth movement via a mechanism involving the cyclooxygenase pathway. PMID- 29761498 TI - Storage lipid accumulation is controlled by photoperiodic signal acting via regulators of growth cessation and dormancy in hybrid aspen. AB - The signalling pathways that control seasonal modulation of carbon metabolism in perennial plants are poorly understood. Using genetic, metabolic and natural variation approaches, we identify factors mediating photoperiodic control of storage lipid accumulation in the model tree hybrid aspen (Populus tremula * tremuloides). We characterized lipid accumulation in transgenic hybrid aspen with impaired photoperiodic and hormonal responses. Genome-wide association mapping was performed in Swedish aspen (P. tremula) genotypes to determine genetic loci associated with genotype variation in lipid content. Our data show that the storage lipid triacylglycerol (TAG) accumulates in cambial meristem and pith rays of aspen in response to photoperiodic signal controlling growth cessation and dormancy induction. We show that photoperiodic control of TAG accumulation is mediated by the FLOWERING LOCUS T/CONSTANS module, which also controls the induction of growth cessation. Hormonal and chromatin remodelling pathways also contribute to TAG accumulation by photoperiodic signal. Natural variation exists in lipid accumulation that is controlled by input from multiple loci. Our data shed light on how the control of storage metabolism is temporally coordinated with growth cessation and dormancy by photoperiodic signal, and reveals that storage lipid accumulation between seeds and perennating organs of trees may involve distinct regulatory circuits. PMID- 29761499 TI - Isobornyl acrylate contained in the insulin patch pump OmniPod as the cause of severe allergic contact dermatitis. PMID- 29761500 TI - Compositional and transcriptomic analysis associated with cuticle lipid production on rosette and inflorescence stem leaves in the extremophyte Thellungiella salsuginea. AB - The plant cuticle is a complex structure composed primarily of wax and cutin, but also contains cutan, glycerolipids, phenolics, polysaccharides and proteins. The cuticle plays an important protective role as barrier between plants and their environment. In this paper, 4-week-old leaves produced either on the rosette or on the inflorescence stem of the model extremophyte Thellungiella salsuginea were examined using scanning electron microscopy, cuticle permeability assays and chemical composition analysis. Results showed that stem leaves (SL) had more abundant cuticle lipids and lower cuticle permeability than rosette leaves (RL). SL were dominated by alkanes, especially the C29 and C31 homologs, whereas in RL the most abundant wax class was free very long-chain acids. The major cutin monomers for both leaf types were C18:2 dioic acids and 18-OH C18:2 acids. We performed Illumina high-throughput sequencing for SL and RL, and 3577 differentially expressed genes were identified. Sixty-five genes possibly involved in cuticular lipid biosynthesis, transport, or regulation was selected for further analysis. Many cuticle-associated genes exhibited differential expression levels that could be associated with compositional differences between these two leaf types. Furthermore, transcription factors and other regulatory proteins previously associated with cuticle production were expressed at higher levels in SL than in RL. The associations between gene expression and characteristics of this extremophile's leaf cuticles sheds new light on cuticle as an adaptive trait in extreme environments, and contributes new information that may guide efforts to modify crop cuticles for improved stress tolerance. PMID- 29761501 TI - Stem radial growth and water storage responses to heat and drought vary between conifers with differing hydraulic strategies. AB - We investigated stem radial growth and water storage dynamics of 2 conifer species differing in hydraulic carbon strategies, Juniperus monosperma and Pinus edulis, under conditions of ambient, drought (~45% reduction in precipitation), heat (~4.8 degrees C temperature increase), and the combination of drought + heat, in 2013 and 2014. Juniper maintained low growth across all treatments. Overall, the relatively isohydric pinon pine showed significantly greater growth and water storage recharge than the relatively anisohydric juniper across all treatments in the average climate year (2014) but no differences in the regionally dry year (2013). Pinon pine ceased growth at a constant predawn water potential across all treatments and at a less negative water potential threshold than juniper. Heat has a greater negative impact on pinon pines' growth and water storage than drought, whereas juniper was, in contrast, unaffected by heat but strongly impacted by drought. The whole-plant hydraulic carbon strategies, in this case captured using the isohydric/anisohydric concept, translate into alternative growth and water storage strategies under drought and heat conditions. PMID- 29761502 TI - Efficacy of tunnel technique in the treatment of localized and multiple gingival recessions: A systematic review and meta-analysis. AB - BACKGROUND: Tunnel technique (TUN) has recently gained popularity among clinicians for its promising clinical and esthetic results in treating gingival recession (GR) defects. However, evidence regarding the efficacy of the TUN is not yet conclusive. Therefore, the aim of the present systematic review and meta analysis was to investigate the predictability of TUN and its comparison to the coronally advanced flap (CAF) procedure. METHODS: A literature search on PubMed, Cochrane libraries, EMBASE, and hand-searched journals through November 2017 was conducted to identify clinical studies investigating TUN for root coverage procedures. Only randomized controlled trials (RCTs) were considered for the meta analysis comparing TUN to CAF. RESULTS: A total of 20 articles were included in the systematic review and six in the meta-analysis. The overall calculated mean root coverage (mRC) of TUN for localized and multiple GR defects was 82.75 +/- 19.7% and 87.87 +/- 16.45%, respectively. Superior results were found in maxillary and in Miller Class I and II GR defects. TUN outcomes may have been enhanced by split-thickness flap preparation and microsurgical approach. TUN and CAF had comparable mRC, complete root coverage (CRC), keratinized tissue gain, and root coverage esthetic score when varying combinations of graft material were evaluated. However, CAF demonstrated superior outcomes to TUN when the same graft (connective tissue or acellular dermal matrix) was used in both techniques. CONCLUSIONS: TUN is an effective procedure in treating localized and multiple GR defects. Limited evidence is available comparing TUN to CAF; however, CAF seemed to be associated with higher percentage of CRC than was TUN when the same grafts (connective tissue or acellular dermal matrix) were used in both techniques. PMID- 29761504 TI - The methylisothiazolinone contact allergy epidemic in Australia. PMID- 29761503 TI - Evaluation of the peritoneal surface disease severity score (PSDSS) in ovarian cancer patients undergoing cytoreductive surgery and HIPEC: Two pathogenetic types based study. AB - BACKGROUND AND OBJECTIVES: Clinical experience suggests that cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) play an important role in the management of ovarian cancer. In order to improve patient selection, the peritoneal surface disease severity score (PSDSS) was previously introduced for use in colorectal cancer patients. However, almost no data exist regarding the utility of the PSDSS index in ovarian cancer patients. METHODS: A retrospective study of the effectiveness of CRS and HIPEC was carried out in 59 patients with ovarian cancer. The PSDSS was based on three criteria: symptoms, extent of peritoneal dissemination, and primary tumor structure as assessed by histology and biomarker expression. RESULTS: The overall survival time for patients with ovarian cancer in PSDSS Stage I was 48 +/- 25.3 months. For PSDSS Stage II, the survival time was 26.5 +/- 4.7 months. For PSDSS Stage III, it was 15.5 +/- 4 months, and for PSDSS Stage IV, it was 6 +/- 4.3 months. A multivariate analysis showed that the PSDSS stage was the only independent survival predictor. CONCLUSIONS: These data demonstrate that a PSDSS based on two pathogenetic types may be useful for predicting survival outcomes in ovarian cancer patients treated with CRS/HIPEC. PMID- 29761505 TI - Clinical outcomes and cost effectiveness of computer-guided versus conventional implant-retained hybrid prostheses: A long-term retrospective analysis of treatment protocols. AB - BACKGROUND: Computer-guided systems were developed to facilitate implant placement at optimal positions in relation to the future prosthesis. However, the time, cost and, technique sensitivity involved with computer-guided surgery impedes its routine practice. The aim of this study is to evaluate survival rates and complications associated with computer-guided versus conventional implant placement in implant-retained hybrid prostheses. Furthermore, long-term economic efficiency of this approach was assessed. METHODS: Patients were stratified according to implant placement protocol into a test group, using computer-guided placement, and a control group, using traditional placement. Calibrated radiographs were used to measure bone loss around implants. Furthermore, the costs of the initial treatment and prosthetic complications, if any, were standardized and analyzed. RESULTS: Forty-five patients (149 implants in the test group and 111 implants in the control group) with a minimum follow-up of 5 years, and a mean follow-up of 9.6 years, were included in the study. While no significant difference was found between both groups in terms of biologic and technical complications, lower incidence of implant loss was observed in the test group (P < 0.001). A statistically significant difference in favor of the non guided implant placement group was found for the initial cost (P < 0.05) but not for the prosthetic complications and total cost (P > 0.05). CONCLUSIONS: Computer guided implant placement for an implant-supported hybrid prosthesis is a valid, reliable alternative to the traditional approach for implant placement and immediate loading. Computer-guided implant placement showed higher implant survival rates and comparable long-term cost to non-guided implant placement. PMID- 29761506 TI - Allergic contact dermatitis caused by plastic items containing the ultraviolet absorber drometrizole. PMID- 29761507 TI - Upregulation of the adipokine genes ADIPOR1 and SPP1 is related to poor survival outcomes in colorectal cancer. AB - BACKGROUND: Obesity is closely associated with colorectal cancer (CRC), but the underlying mechanism is unclear. We thus evaluated the expression of the adipokine gene family in CRC tissues and its clinicopathological implications. METHODS: Correlations between the mRNA expression levels of the adipokine gene family (ADIPOQ, ADIPOR1/2, LEP, LEPR, RETN, RETNLB, RBP4, SFRP5, NAMPT, and SPP1) in CRC tissue and clinicopathologic factors were analyzed using data from The Cancer Genome Atlas database. RESULTS: Tissue samples from 369 patients were analyzed, and 82 deaths occurred during follow-up (median, 670 days). Overall, mortality was associated with positive venous invasion, higher TNM stage, and increased ADIPOR1 (adiponectin receptor 1 gene) and SPP1 (secreted phosphoprotein gene 1) mRNA expression. Higher ADIPOR1 (odds ratio [OR]: 3.29, 95% confidence interval [CI]: 1.33-8.13) and SPP1 (OR: 2.31, 95%CI: 1.49-3.59) levels were independently associated with increased mortality. A Kaplan-Meier survival analysis showed shorter overall survival times in patients with higher ADIPOR1 (P = 0.006) and SPP1 (P < 0.001) expression. CONCLUSIONS: Upregulation of ADIPOR1 and SPP1, among the adipokine gene family, in cancer tissue is associated with poor survival in CRC, suggesting a potential mechanism linking obesity and CRC. ADIPOR1 and SPP1 expression could become useful prognostic indicators after further validation. PMID- 29761508 TI - The microscopic anatomy of the esophagus including the individual layers, specialized tissues, and unique components and their responses to injury. AB - The esophagus, a straight tube that connects the pharynx to the stomach, has the complex architecture common to the rest of the gastrointestinal tract with special differences that relate to its function as a conduit of ingested substances. For instance, it has submucosal glands that are unique and have a specific protective function. It has a squamous lining that exists nowhere else in the gut except the anus and it has a different submucosal nerve plexus when compared to the stomach and intestines. All of the layers of the esophageal wall and the specialized structures including blood and lymphatic vessels and nerves have specific responses to injury. The esophagus also has unique features such as patches of gastric mucosa called inlet patches at the very proximal part and it has a special sphincter mechanism at the most distal aspect. This review covers the normal microscopic anatomy of the esophagus and the patterns of reaction to stress and injury of each layer and each special structure. PMID- 29761509 TI - Similar geometric rules govern the distribution of veins and stomata in petals, sepals and leaves. AB - Investment in leaf veins (supplying xylem water) is balanced by stomatal abundance, such that sufficient water transport is provided for stomata to remain open when soil water is abundant. This coordination is mediated by a common dependence of vein and stomatal densities on cell size. Flowers may not conform to this same developmental pattern if they depend on water supplied by the phloem or have high rates of nonstomatal transpiration. We examined the relationships between veins, stomata and epidermal cells in leaves, sepals and petals of 27 angiosperms to determine whether common spacing rules applied to all tissues. Regression analysis found no evidence for different relationships within organ types. Both vein and stomatal densities were strongly associated with epidermal cell size within organs, but, for a given epidermal cell size, petals had fewer veins and stomata than sepals, which had fewer than leaves. Although our data support the concept of common scaling between veins and stomata in leaves and flowers, the large diversity in petal vein density suggests that, in some species, petal veins may be engaged in additional functions, such as the supply of water for high cuticular transpiration or for phloem delivery of water or carbohydrates. PMID- 29761511 TI - Overexpression of the TaSHN1 transcription factor in bread wheat leads to leaf surface modifications, improved drought tolerance, and no yield penalty under controlled growth conditions. AB - Transcription factors regulate multiple networks, mediating the responses of organisms to stresses, including drought. Here, we investigated the role of the wheat transcription factor TaSHN1 in crop growth and drought tolerance. TaSHN1, isolated from bread wheat, was characterized for molecular interactions and functionality. The overexpression of TaSHN1 in wheat was followed by the evaluation of T2 and T3 transgenic lines for drought tolerance, growth, and yield components. Leaf surface changes were analysed by light microscopy, SEM, TEM, and GC-MS/GC-FID. TaSHN1 behaves as a transcriptional activator in a yeast transactivation assay and binds stress-related DNA cis-elements, determinants of which were revealed using 3D molecular modelling. The overexpression of TaSHN1 in transgenic wheat did not result in a yield penalty under the controlled plant growth conditions of a glasshouse. Transgenic lines had significantly lower stomatal density and leaf water loss and exhibited improved recovery after severe drought, compared with control plants. The comparative analysis of cuticular waxes revealed an increased accumulation of alkanes in leaves of transgenic lines. Our data demonstrate that TaSHN1 may operate as a positive modulator of drought stress tolerance. Positive attributes could be mediated through an enhanced accumulation of alkanes and reduced stomatal density. PMID- 29761510 TI - Initiation of adjuvant therapy following surgical resection of pancreatic ductal adenocarcinoma (PDAC): Are patients from rural, remote areas disadvantaged? AB - BACKGROUND AND OBJECTIVES: Although race and socioeconomic status have been shown to affect outcomes in pancreatic ductal adenocarcinoma (PDAC), the impact of rural residence on the delivery of adjuvant therapy (AT) has not been studied. METHODS: Patients with resected PDAC were identified using the National Cancer Database (NCDB). Individuals were classified as living in a metro area, urban/rural adjacent to a metro area (URA), and urban/rural remote (URR) area. Multivariate logistic regression was used to assess geographic inhabitance as a predictor of receiving AT. RESULTS: A total of 32 521 individuals who underwent pancreatectomy for PDAC were identified. Univariate analysis demonstrated individuals in URR areas were less likely to receive adjuvant chemotherapy (ACT) than those living in URA or metro areas (55.3% vs 55.6% vs 58.8%, P = 0.011). However on multivariate analysis URR inhabitance was no longer a predictor of ACT (OR = 0.911 P = 0.125) or ART (OR = 0.953 P = 0.462). Cox proportional hazard modeling demonstrated URR inhabitance remained independently associated with poor OS (HR 1.076; 95% CI [1.008, 1.149], P < 0.029). CONCLUSIONS: URR inhabitance does not impact access to AT, however it is independently associated with a decreased OS. Attention must be focused on optimizing oncologic care to patients with disparate access to healthcare. PMID- 29761513 TI - Canine pancytopoenia and hemophagocytic lymphohistiocytosis. PMID- 29761512 TI - Oral anticoagulation and left atrial thrombi resolution in nonrheumatic atrial fibrillation or flutter: A systematic review and meta-analysis. AB - BACKGROUND: Oral anticoagulation (OAC) is prescribed for left atrial thrombi (LAT) in nonrheumatic atrial fibrillation (AF) and/or atrial flutter (AFL). The study objective was to review the existing evidence regarding LAT resolution in nonrheumatic AF and/or AFL with OAC agents. METHODS: Data sources included PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) between January 1, 1991 and February 10, 2017. English-language studies that assessed LAT resolution with OAC agents in subjects with nonrheumatic AF and/or AFL, by serial transesophageal echocardiography, and with follow-up times >= 3 weeks and < 1 year, were selected. Study quality was assessed using recommendations adapted from the Agency for Healthcare Research and Quality. Pooled LAT resolution rates were evaluated for vitamin K antagonist (VKA) studies and low risk of bias warfarin studies. RESULTS: The pooled LAT resolution rate of 619 subjects from 16 VKA studies was 63.7% (95% confidence interval [CI], 53.3% 72.9%). The pooled LAT resolution rate of 94 subjects from four studies that specified warfarin use, exclusion of prior long-term therapeutic OAC, and target international normalized ratio (INR) >= 2.0 and/or average achieved INR >= 2.0 was 79.3% (95% CI, 69.8%-86.4%). Two studies in direct-acting oral anticoagulants (DOACs) reported LAT resolution rates of 89.5% (17 of 19) for dabigatran and 41.5% (22 of 53) for rivaroxaban. CONCLUSIONS: Warfarin is the most studied initial OAC agent for treating LAT in nonrheumatic AF and/or AFL with a resolution rate of nearly 80%. Further studies in DOACs are warranted. PMID- 29761514 TI - Mandibular reconstruction in elderly patients. AB - BACKGROUND AND OBJECTIVES: The choice of reconstructive technique for a segmental mandibular defect in elderly patients is controversial. The aim of this study was to establish an algorithm for selecting a method of mandibular reconstruction in elderly patients. METHODS: We retrospectively evaluated 121 patients aged >=65 years who underwent immediate microvascular mandibular reconstruction after oncologic resection. Patients were divided into three groups based on method of reconstruction: vascularized bone graft (n = 49), mandibular reconstruction plate and soft tissue flap (n = 22), and soft-tissue flap (n = 50). We compared perioperative outcomes among groups and investigated factors affecting the choice of reconstructive technique. RESULTS: Rates of postoperative complications did not differ significantly among groups. Mandibular reconstruction plate was indicated only for anterior mandibular defects. Soft-tissue flap was indicated for posterior mandibular defects in patients aged >=75 years or with a poor postoperative Eichner index. CONCLUSIONS: Mandibular reconstruction plate and soft-tissue flap can be good alternatives to vascularized bone graft in the elderly. Our algorithm uses defect type, patient age, and postoperative Eichner index to determine reconstructive technique. PMID- 29761516 TI - Recurrence rate of atrial fibrillation after the first clinical episode: A prospective evaluation using continuous cardiac rhythm monitoring. AB - BACKGROUND: Decision making regarding a patient who has experienced a first clinical episode of atrial fibrillation (AF) is challenging, and the AF recurrences should be a significant consideration. Continuous long-term rhythm monitoring via implantable loop recorders (ILRs) has enabled us to evaluate the AF recurrence profile after the first clinical episode and to investigate clinical parameters associated with the course of the arrhythmia. HYPOTHESIS: Continuous rhythm monitoring via ILRs in AF patients after the first clinical episode is of clinical significance and precisely evaluate the AF recurrence profile. METHODS: Thirty consecutive patients with paroxysmal AF received an ILR after their first symptomatic episode. We evaluated the maximum duration of episodes and the recurrence rate of the arrhythmia during a follow-up period of 3 years. RESULTS: Three patients (10%) had no AF recurrence, whereas 4 patients (13.3%) presented only 1 episode. Almost half of the patients (46.7%) had a low recurrence rate (<5 episodes/year), whereas the majority of patients (19/30) suffered from episodes with maximum duration <=24 hours. Eleven patients (36.7%) presented either no episode or a low recurrence rate with episodes lasting <=24 hours. The use of statins was greater in patients with a low recurrence rate (P = 0.025). CONCLUSIONS: A significant percentage of patients either suffer no AF recurrence after their first symptomatic episode or show a low recurrence rate. Most patients present episodes of short duration. If these findings are confirmed in larger studies, they could have clinical implications ensuring individualized management of the arrhythmia in the future. PMID- 29761517 TI - Pharmacokinetics of intravenous gentamicin in healthy young-adult compared to aged alpacas. AB - The study objective was to evaluate the effects of age on aminoglycoside pharmacokinetics in eight young-adult (<4 years) and eight aged (>=14 years) healthy alpacas, receiving a single 6.6 mg/kg intravenous gentamicin injection. Heparinized plasma samples were obtained at designated time points following drug administration and frozen at -80 degrees C until assayed by a validated immunoassay (QMS(r) ). Compartmental and noncompartmental analyses of gentamicin plasma concentrations versus time were performed using WinNonlin (v6.4) software. Baseline physical and hematological parameters were not significantly different between young and old animals with the exception of sex. Data were best fitted to a two-compartment pharmacokinetic model. The peak drug concentration at 30 min after dosing (23.8 +/- 2.1 vs. 26.1 +/- 2 MUg/ml, p = .043) and area under the curve (70.4 +/- 10.5 vs. 90.4 +/- 17.6 MUg hr/ml, p = .015) were significantly lower in young-adult compared to aged alpacas. Accordingly, young alpacas had a significantly greater systemic clearance than older animals (95.5 +/- 14.4 and 75.6 +/- 16.1 ml hr-1 kg-1 ; p = .018), respectively). In conclusion, a single 6.6 mg/kg intravenous gentamicin injection achieves target blood concentrations of >10 times the MIC of gentamicin-susceptible pathogens with MIC levels <=2 MUg/ml, in both young-adult and geriatric alpacas. However, the observed reduction in gentamicin clearance in aged alpacas may increase their risk for gentamicin-related adverse drug reactions. PMID- 29761515 TI - Association of perioperative transfusion with survival and recurrence after resection of gallbladder cancer: A 10-institution study from the US Extrahepatic Biliary Malignancy Consortium. AB - BACKGROUND AND OBJECTIVES: Perioperative blood transfusion is associated with poor outcomes in several malignancies. Its effect in gallbladder cancer (GBC) is unknown. METHODS: All patients with GBC who underwent curative-intent resection at 10-institutions from 2000 to 2015 were included. The effect of blood transfusion on overall survival (OS) and recurrence-free (RFS) was evaluated. RESULTS: Of 262 patients with curative-intent resection for GBC, 61 patients (23%) received blood transfusions. Radical cholecystectomy was the most common procedure (80%), but major hepatectomy was more frequent in the transfusion versus no-transfusion group (13% vs 4%; P = 0.02). The transfusion group was less likely to have incidentally discovered disease (57% vs 74%) and receive adjuvant therapy (29% vs 48%), but more likely to have preoperative jaundice (23% vs 11%), T3/T4 tumors (60% vs 39%), LVI (71% vs 40%), PNI (71% vs 48%), and major complications (39% vs 12%) (all P < 0.05). Transfusion was associated with lower median OS compared to no-transfusion (20 vs 32 mos; P < 0.001), which persisted on multivariable (MV) analysis (HR:1.9; 95%CI 1.1-3.5; P = 0.035), controlling for comorbidities, serum albumin, INR, preoperative jaundice, major hepatectomy, incidental discovery, margin status, T-Stage, LN status, and major complications. Median RFS of transfused patients was 13mo compared to 49mo for non-transfused patients (P = 0.1). Transfusion, however, was an independent predictor of decreased RFS on MV analysis (HR:2.3; 95%CI 1.1-5.1; P = 0.035). CONCLUSIONS: Perioperative blood transfusion is associated with decreased OS and RFS after resection for GCC, accounting for other adverse factors. Transfusions should thus be administered with well-defined protocols. PMID- 29761518 TI - The value of inflammation based prognostic scores in patients undergoing surgical resection for oesophageal and gastric carcinoma. AB - BACKGROUND AND OBJECTIVES: Surgical interventions for oesophagogastric cancer carry a significant burden of morbidity and mortality. A range of inflammation based prognostic scores have been proposed in an attempt to predict outcome. This study evaluated five such prognostic scores in oesophageal and gastric carcinoma patients. METHODS: The modified Glasgow Prognostic Score (mGPS), Neutrophil Lymphocyte Ratio (NLR), Platelet Lymphocyte Ratio (PLR), Prognostic Index (PI), and Prognostic Nutrition Index (PNI) were calculated for 723 consecutive patients undergoing oesophagectomy or gastrectomy at a single center. The predictive accuracy of each score was assessed using ROC curves and survival analyses. RESULTS: Overall, only PLR and PNI were significantly predictive of patient survival (both P < 0.001), with no significant association detected for mGPS (P = 0.480), NLR (P = 0.210), or PI (P = 0.808). Subgroup analysis found the predictive accuracy of PNI to be significantly greater in oesophagectomy than gastrectomy patients (hazard ratio 2.75 vs 1.39, P = 0.016) and mGPS to be predictive of patient survival only in oesophagectomies (P < 0.001). CONCLUSIONS: Inflammation based prognostic scores may have a role in patients undergoing resection for oesophageal and gastric cancer. These scores are easily calculable from routinely collected data and could be used as an adjunct to existing staging modalities. PMID- 29761520 TI - Predicting lysine-malonylation sites of proteins using sequence and predicted structural features. AB - Malonylation is a recently discovered post-translational modification (PTM) in which a malonyl group attaches to a lysine (K) amino acid residue of a protein. In this work, a novel machine learning model, SPRINT-Mal, is developed to predict malonylation sites by employing sequence and predicted structural features. Evolutionary information and physicochemical properties are found to be the two most discriminative features whereas a structural feature called half-sphere exposure provides additional improvement to the prediction performance. SPRINT Mal trained on mouse data yields robust performance for 10-fold cross validation and independent test set with Area Under the Curve (AUC) values of 0.74 and 0.76 and Matthews' Correlation Coefficient (MCC) of 0.213 and 0.20, respectively. Moreover, SPRINT-Mal achieved comparable performance when testing on H. sapiens proteins without species-specific training but not in bacterium S. erythraea. This suggests similar underlying physicochemical mechanisms between mouse and human but not between mouse and bacterium. SPRINT-Mal is freely available as an online server at: http://sparks-lab.org/server/SPRINT-Mal/. (c) 2018 Wiley Periodicals, Inc. PMID- 29761519 TI - Evaluation of needle trap micro-extraction and solid-phase micro-extraction: Obtaining comprehensive information on volatile emissions from in vitro cultures. AB - Volatile organic compounds (VOCs) emitted from in vitro cultures may reveal information on species and metabolism. Owing to low nmol L-1 concentration ranges, pre-concentration techniques are required for gas chromatography-mass spectrometry (GC-MS) based analyses. This study was intended to compare the efficiency of established micro-extraction techniques - solid-phase micro extraction (SPME) and needle-trap micro-extraction (NTME) - for the analysis of complex VOC patterns. For SPME, a 75 MUm Carboxen(r)/polydimethylsiloxane fiber was used. The NTME needle was packed with divinylbenzene, Carbopack X and Carboxen 1000. The headspace was sampled bi-directionally. Seventy-two VOCs were calibrated by reference standard mixtures in the range of 0.041-62.24 nmol L-1 by means of GC-MS. Both pre-concentration methods were applied to profile VOCs from cultures of Mycobacterium avium ssp. paratuberculosis. Limits of detection ranged from 0.004 to 3.93 nmol L-1 (median = 0.030 nmol L-1 ) for NTME and from 0.001 to 5.684 nmol L-1 (median = 0.043 nmol L-1 ) for SPME. NTME showed advantages in assessing polar compounds such as alcohols. SPME showed advantages in reproducibility but disadvantages in sensitivity for N-containing compounds. Micro-extraction techniques such as SPME and NTME are well suited for trace VOC profiling over cultures if the limitations of each technique is taken into account. PMID- 29761521 TI - Negative Predictive Value of Contrast-Enhanced Ultrasound in Differentiating Avascular Solid-Appearing From Vascularized Masses: A Retrospective Consecutive Study. AB - OBJECTIVES: To determine the negative predictive value (NPV) of contrast-enhanced ultrasound (CEUS) to establish the lack of vascularity in a mass. METHODS: This work was an Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study. Acquisition of consent was waived. We included all CEUS examinations performed for tissue characterization between 2004 and 2014 that reported showing no vascularity in a mass. Contrast enhanced ultrasound findings were considered true-negative when there was stability on imaging for at least 1 year or no evidence of a solid mass, if biopsied, and false-negative if there was lesion growth on imaging within 12 months or an indication of a solid mass on the pathologic examination, if biopsied. One author reviewed all of the reports and follow-up examinations. We conducted a consensus review of all false-negative findings mixed with an equal number of true-negative findings by 2 reviewers, who were blinded to the final results. RESULTS: The study population consisted of 97 CEUS examinations in 97 patients, including 48 women and 49 men (mean age +/- SD, 65 +/- 14 years). Examinations were performed for lesion characterization in the liver (n = 23), pancreas (n = 17), kidney (n = 54), 1 gallbladder, 1 adnexa, and 1 peritoneal lesion. The overall false-negative rate on the official prospective review was 2% (2 of 97). Two false-negative findings were correctly identified on the consensus review. The NPV of CEUS was 97.9% (95 of 97; 95% confidence interval, 93%- 99%) on the official review. CONCLUSIONS: Contrast-enhanced ultrasound has a very high NPV to exclude the presence of flow in a mass, and it can be used to exclude the presence of a solid mass. PMID- 29761522 TI - Thrombotic characteristics of extracellular vesicles derived from prostate cancer cells. AB - BACKGROUND: Prostate cancer (PC) patients in advanced stages of the disease have high risk of blood coagulation complications. The procoagulant molecule Tissue factor (TF), and the fibrinolysis inhibitor plasminogen activator inhibitor-1 PAI 1 play important role in this complication. Extracellular vesicles (EV) shed from cancer cells may contribute to the regulation of TF and PAI-1. The procoagulant activity of EV can be associated with the oncogenic and metastatic characteristics of their cells. METHODS: We have expressed EGFRvIII in DU145 cells to assess the role of this oncogene in the procoagulant activity of EV. The intercellular exchange of TF via EV was assessed by downregulating its expression in DU145 cells using shRNA vector, and determining the transfer of TF via EV enriched with the protein. Two PC cell lines with different metastatic potential were used to assess the correlation between the procoagulant activity of EV and the metastatic potential of PC cells. Photometric assays were used to determine FXa-activity and thrombin generation as indicators for the procoagulant activity of EV. Double-tagged proteinase-activated receptor 1(PAR-1) expressed in CHO cells to assess its activation by EV. RESULTS: The expression of EGFRvIII in DU145 cells led to increased mRNA levels for TF and PAI-1, but the increase in these proteins expression was detected mostly in the EV. EV with enhanced levels of TF protein conferred higher TF procoagulant activity on the acceptor cells by intercellular exchange of this protein. Procoagulant activity of EV, assessed by FXa activity, and thrombin generation, was correlated with the oncogenic and metastatic potential of PC cells. The ability of EV to generate thrombin led to the activation of PAR-1, which was evident by the truncation of tagged-PAR-1. CONCLUSION: The active oncogene EGFRvIII increases the concentration of TF and PAI-1 in EV. The procoagulant activity of EV is associated with the oncogenic and metastatic characteristics of their PC cells. Also, EV may contribute to the high procoagulant activity in the tumour microenvironment by the intercellular exchange of TF. Finally, through the generation of thrombin, EV can activate PAR 1, which evidently contributes to cancer progression, linking the coagulation system to tumor progression. PMID- 29761523 TI - A novel cognitive disease progression model for clinical trials in autosomal dominant Alzheimer's disease. AB - Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM. PMID- 29761524 TI - The 24th Annual Prostate Cancer Foundation scientific retreat report. AB - INTRODUCTION: The 24th Annual Prostate Cancer Foundation (PCF) Scientific Retreat was held from October 5-7, 2017, at the Omni Shoreham Hotel in Washington, DC. METHODS: The PCF Scientific Retreat is a scientific conference that specifically focuses on cutting edge research deemed to have significant promise for accelerating advances in prostate cancer biology and treatment. RESULTS: Themes highlighted at this year's meeting included: (i) new understandings in prostate cancer biology and disease progression; (ii) new mechanisms and treatment targets in advanced prostate cancer; (iii) advances in precision medicine genomics, germline genetics, and selection of targeted therapies; (iv) PSMA-targeted agents for PET imaging and radionuclide therapy; (v) approaches for improving the efficacy of immunotherapy in prostate cancer; (vi) applications of 3D Genomics in prostate cancer research; and (vii) potential applications of artificial intelligence in prostate cancer. DISCUSSION: This article reviews the research presented at the PCF Scientific Retreat, in order to improve understanding of the current state of prostate cancer research, encourage discourse and exchange of novel ideas, and stimulate new basic, translational, and clinical research that will ultimately improve the lives of patients. PMID- 29761525 TI - ETS2 is a prostate basal cell marker and is highly expressed in prostate cancers aberrantly expressing p63. AB - BACKGROUND: Rare prostate carcinomas aberrantly express p63 and have an immunophenotype intermediate between basal and luminal cells. Here, we performed gene expression profiling on p63-expressing prostatic carcinomas and compared them to usual-type adenocarcinoma. We identify ETS2 as highly expressed in p63 expressing prostatic carcinomas and benign prostate basal cells, with lower expression in luminal cells and primary usual-type adenocarcinomas. METHODS: A total of 8 p63-expressing prostate carcinomas at radical prostatectomy were compared to 358 usual-type adenocarcinomas by gene expression profiling performed on formalin fixed paraffin embedded tumor tissue using Affymetrix 1.0 ST microarrays. Correlation between differentially expressed genes and TP63 expression was performed in 5239 prostate adenocarcinomas available in the Decipher GRID. For validation, ETS2 in situ hybridization was performed on 19 p63 expressing prostate carcinomas and 30 usual-type adenocarcinomas arrayed on tissue microarrays (TMA). RESULTS: By gene expression, p63-expressing prostate carcinomas showed low cell cycle activity and low Decipher prognostic scores, but were predicted to have high Gleason grade compared to usual-type adenocarcinomas by gene expression signatures and morphology. Among the genes over-expressed in p63-expressing carcinoma relative to usual-type adenocarcinoma were known p63 regulated genes, along with ETS2, an ETS family member previously implicated as a prostate cancer tumor suppressor gene. Across several cohorts of prostate samples, ETS2 gene expression was correlated with TP63 expression and was significantly higher in benign prostate compared to usual-type adenocarcinoma. By in situ hybridization, ETS2 gene expression was high in benign basal cells, and low to undetectable in benign luminal cells or usual-type adenocarcinoma. In contrast, ETS2 was highly expressed in 95% (18/19) of p63-expressing prostate carcinomas. CONCLUSIONS: ETS2 is a predominantly basally-expressed gene in the prostate, with low expression in usual-type adenocarcinoma and high expression in p63-expressing carcinomas. Given this pattern, the significance of ETS2 loss by deletion or mutation in usual-type adenocarcinomas is uncertain. PMID- 29761526 TI - A case of acrokeratoelastoidosis. PMID- 29761527 TI - A Quality Study to Explore Rationale for Pregnant Women to Decline Transvaginal Cervical Length Screening. AB - OBJECTIVES: To identify patient rationale for pregnant women to decline transvaginal cervical length screening. METHODS: Survey data from 511 women presenting for second-trimester anatomy and transvaginal cervical length sonography were collected during a 4-month period from September 2016 to January 2017. Each patient completed a medical questionnaire that includes demographic and obstetric history data and a survey to document their acceptance or declination of transvaginal cervical length screening. RESULTS: Of the 511 women included in the study, 5.9% (n = 30) declined transvaginal cervical length screening. Demographic characteristics and risk factors for prematurity were similar between those who accepted and declined. The sonographer performing the study was significantly associated with declination of transvaginal cervical length screening (P < .001), with 4 of 13 sonographers accounting for 83.3% of all declinations. The most frequently reported reasons for declining the transvaginal cervical length screening were feeling that it was not needed (47%; n = 14) and not feeling prepared for the transvaginal sonography (27%; n = 8). CONCLUSION: The findings of this study indicate that the sonographer performing transvaginal cervical length screening may be associated with declination. The most common reasons patients cited for declining included not feeling that the study was needed and not feeling prepared for the procedure. Increased sonographer education and sonographer use of a scripted approach when discussing the procedure with patients may improve patient acceptance. PMID- 29761528 TI - Nonerosive reflux disease: clinical concepts. AB - Esophageal symptoms can arise from gastroesophageal reflux disease (GERD) as well as other mucosal and motor processes, structural disease, and functional esophageal syndromes. GERD is the most common esophageal disorder, but diagnosis may not be straightforward when symptoms persist despite empiric acid suppressive therapy and when mucosal erosions are not seen on endoscopy (as for nonerosive reflux disease, NERD). Esophageal physiological tests (ambulatory pH or pH impedance monitoring and manometry) can be of value in defining abnormal reflux burden and reflux-symptom association. NERD diagnosed on the basis of abnormal reflux burden on ambulatory reflux monitoring is associated with similar symptom response from antireflux therapy for erosive esophagitis. Acid suppression is the mainstay of therapy, and antireflux surgery has a definitive role in the management of persisting symptoms attributed to NERD, especially when the esophagogastric junction is compromised. Adjunctive approaches and complementary therapy may be of additional value in management. In this review, we describe the evaluation, diagnosis, differential diagnosis, and management of NERD. PMID- 29761530 TI - An enlarging pedunculated nodule on the shoulder of a 21-year-old man. PMID- 29761532 TI - Dermatological aspects of tularaemia: a study of 168 cases. AB - BACKGROUND: Tularaemia is a zoonotic infectious disease caused by Francisella tularensis, an aerobic, uncapsulated, gram-negative coccobacillus. Several case reports have appeared on the dermatological manifestations of tularaemia, but relatively few longer-term studies are available. AIM: To identify skin features of tularaemia that aid in its diagnosis. METHODS: In total, 168 patients (68 male, 100 female) diagnosed with tularaemia were retrospectively examined. All dermatological data for these patients were evaluated. RESULTS: Of the 168 patients, 149 (88.69%) had tularaemia of the oropharyngeal type, 12 (7.73%) had the ulceroglandular type, 5 (2.9%) had the oculoglandular type and 2 (0.59%) had the pulmonary type. Secondary skin manifestations were found in 26 patients (15.47%). Sweet syndrome (SS) was found in 11 patients (6.54%), most of whom presented with the oropharyngeal form, while erythema nodosum (EN) was found in 7 patients (4.16%), dermatitis in 2 (1.19%), urticaria in 2 (1.19%), acneiform eruptions in 1 (0.59%), vasculitis-like eruptions in 1 (0.59%) and SS + EN in 1 (0.59%). Patients with the oropharyngeal form had a statistically significant (P < 0.001) higher number of skin findings than patients with the other forms. CONCLUSIONS: In clinical practice, tularaemia may present with various cutaneous manifestations, and dermatologists who work in endemic regions must be aware of the possibility of this disease. PMID- 29761529 TI - Pigmentation and vision: Is GPR143 in control? AB - Albinism, typically characterized by decreased melanin synthesis, is associated with significant visual deficits owing to developmental changes during neurosensory retina development. All albinism is caused by genetic mutations in a group of diverse genes including enzymes, transporters, G-protein coupled receptor. Interestingly, these genes are not expressed in the neurosensory retina. Further, regardless of cause of albinism, all forms of albinism have the same retinal pathology, the extent of which is variable. In this review, we explore the possibility that this similarity in retinal phenotype is because all forms of albinism funnel through the same final common pathway. There are currently seven known genes linked to the seven forms of ocular cutaneous albinism. These types of albinism are the most common, and result in changes to all pigmented tissues (hair, skin, eyes). We will discuss the incidence and mechanism, where known, to develop a picture as to how the mutations cause albinism. Next, we will examine the one form of albinism which causes tissue specific pathology, ocular albinism, where the eye exhibits the retinal albinism phenotype despite near normal melanin synthesis. We will discuss a potential way to treat the disease and restore normal retinal development. Finally, we will briefly discuss the possibility that this same pathway may intersect with the most common cause of permanent vision loss in the elderly. PMID- 29761531 TI - Fluctuations of the EEG-fMRI correlation reflect intrinsic strength of functional connectivity in default mode network. AB - Both functional magnetic resonance imaging (fMRI) and electrophysiological recordings have revealed that resting-state functional connectivity is temporally variable in human brain. Combined full-band electroencephalography-fMRI (fbEEG fMRI) studies have shown that infraslow (<.1 Hz) fluctuations in EEG scalp potential are correlated with the blood-oxygen-level-dependent (BOLD) fMRI signals and that also this correlation appears variable over time. Here, we used simultaneous fbEEG-fMRI to test the hypothesis that correlation dynamics between BOLD and fbEEG signals could be explained by fluctuations in the activation properties of resting-state networks (RSNs) such as the extent or strength of their activation. We used ultrafast magnetic resonance encephalography (MREG) fMRI to enable temporally accurate and statistically robust short-time-window comparisons of infra-slow fbEEG and BOLD signals. We found that the temporal fluctuations in the fbEEG-BOLD correlation were dependent on RSN connectivity strength, but not on the mean signal level or magnitude of RSN activation or motion during scanning. Moreover, the EEG-fMRI correlations were strongest when the intrinsic RSN connectivity was strong and close to the pial surface. Conversely, weak fbEEG-BOLD correlations were attributable to periods of less coherent or spatially more scattered intrinsic RSN connectivity, or RSN activation in deeper cerebral structures. The results thus show that the on average low correlations between infra-slow EEG and BOLD signals are, in fact, governed by the momentary coherence and depth of the underlying RSN activation, and may reach systematically high values with appropriate source activities. These findings further consolidate the notion of slow scalp potentials being directly coupled to hemodynamic fluctuations. PMID- 29761533 TI - Adaptation of the adult Functional Mobility Assessment (FMA) into a FMA-Family Centred (FMA-FC) paediatric version. AB - AIM: The aims of this study were to adapt an adult wheeled mobility outcome measure, the Functional Mobility Assessment, for use with children (FMA-Family Centred) and establish the new measure's content validity, test-retest reliability, and internal consistency. BACKGROUND: Although several tools exist to measure a child's ability to operate and move a wheeled mobility device, none focus on the ability of the wheeled mobility device to support children and their families as they perform daily activities. METHODS: After adapting the FMA items with examples relevant to children aged 3-21, parent/caregiver and therapist stakeholder groups recommended adaptations relevant for families with children who cannot respond for themselves. RESULTS: Six of the initial FMA items were retained with child-appropriate examples, and 4 new items were developed. CONCLUSION: The content validity of the FMA-Family Centred was strongly supported, and internal consistency and test-retest reliability met accepted psychometric standards. PMID- 29761534 TI - Co-contraction behaviour of masticatory and neck muscles during tooth grinding. AB - The objective of this study was to analyse the co-contraction behaviour of jaw and neck muscles during force-controlled experimental grinding in the supine position. Twelve symptom-free subjects were enrolled in the experimental study. Electromyographic (EMG) activity of semispinalis capitis, splenius capitis and levator scapulae muscles was recorded bilaterally with intramuscular fine-wire electrodes, whereas that of sternocleidomastoideus, infrahyoidal, suprahyoidal, masseter and anterior temporalis muscles were registered with surface electrodes. EMG and force measurements were performed during tasks simulating tooth grinding on custom-made intraoral metal splints. The mean EMG activity normalised by maximum voluntary contraction (% MVC) of each of the neck muscles studied during grinding was analysed and compared with previous data from jaw clenching at identical force (100 N) and (supine) position. The occurrence of low-level, long lasting tonic activation (LLTA) of motor units was also documented. The mean three-dimensional force vector of the grinding forces was 106 +/- 74 N. In the frontal plane, the incline to the midsagittal plane ranged between 10 degrees and 15 degrees . In the midsagittal plane, the incline to the frontal plane was negligibly small. Posterior neck muscle activity during grinding ranged between 4.5% and 12% MVC and during clenching with 100 N between 1.8% and 9.9% MVC. Masticatory muscle activity during grinding ranged between 17% and 21% MVC for contralateral masseter and ipsilateral temporalis and between 4% and 6.5% for ipsilateral masseter and contralateral temporalis. LLTA had an average duration of 195 +/- 10 seconds. The findings from this study do not support pathophysiological muscle chain theories postulating simple biomechanical coupling of neck and jaw muscles. Co-contractions of neck and masticatory muscles may instead occur as a result of complex neurophysiological interactions. PMID- 29761535 TI - Diagnostic Performance of Shear Wave Elastography in Patients With Autoimmune Liver Disease. AB - OBJECTIVES: To assess performance of shear wave elastography for evaluation of fibrosis and the histologic stage in patients with autoimmune liver disease (ALD) and to validate previously established advanced fibrosis cutoff values in this cohort. METHODS: Shear wave elastography was performed on patients with ALD with an Aixplorer ultrasound system (SuperSonic Imagine, Aix-en-Provence, France) using an SC6-1 transducer. The median estimated tissue Young modulus was calculated from sets of 8 to 10 elastograms. A blinded, subspecialty-trained pathologist reviewed biopsy specimens. The METAVIR classification was used to stage liver fibrosis and necroinflammation. Steatosis was graded from 0 to 4+. The Kendall tau-b correlation test was performed to identify the correlation between the estimated tissue Young modulus and fibrosis, steatosis, and the necroinflammatory score. The Spearman correlation test was performed to identify the correlation between the estimated tissue Young modulus and clinical data. The diagnostic performance of shear wave elastography for differentiating METAVIR stage F2 or higher from F0 and F1 fibrosis was evaluated by a receiver operating characteristic (ROC) curve analysis. RESULTS: Fifty-one patients with ALD were analyzed. The estimated tissue Young modulus was positively correlated with the fibrosis stage and necroinflammation score (r = 0.386; P < .001; r = 0.338; P = .002, respectively) but not steatosis (r = -0.091; P = .527). Serum aspartate aminotransferase, alanine aminotransferase, and total bilirubin values were positively correlated with the estimated tissue Young modulus (r = 0.501; P < .001; r = 0.44; P = .001; r = 0.291; P = .038). The serum albumin value was negatively correlated (r = -0.309; P = .033). The area under the ROC curve was 0.781 (95% confidence interval, 0.641-0.921) for distinguishing F2 or greater fibrosis from F0 and F1 fibrosis. Based on the ROC curve, an optimal cutoff value of 9.15 kPa was identified (sensitivity, 83.3%; specificity, 72.7%). CONCLUSIONS: Shear wave elastography is a novel noninvasive adjunct to liver biopsy in evaluation and staging of patients with ALD, showing the potential for serial evaluations of disease progression and treatment responses. PMID- 29761536 TI - Lichenoid paraneoplastic pemphigus associated with follicular lymphoma without detectable autoantibodies. PMID- 29761537 TI - Scapular Upward Rotator Morphologic Characteristics in Individuals With and Without Forward Head Posture: A Case-Control Study. AB - OBJECTIVES: There are several reports suggesting that forward head posture contributes to alterations in scapular kinematics and muscle activity, leading to the development of shoulder problems. Currently, it is unknown whether forward head posture alters the thickness of the scapular muscles. The aim of this study was to compare the thickness of the serratus anterior and upper and lower trapezius muscles at rest and during loaded isometric contractions in individuals with and without forward head posture. METHODS: Twenty individuals with forward head posture and 20 individuals with normal head posture participated in this case-control study. Three separate ultrasound images of the serratus anterior and upper and lower trapezius muscles were captured under 2 randomized conditions: at rest and during a loaded isometric contraction. RESULTS: The thickness of each muscle significantly increased from rest to the loaded isometric contraction (P < .001). The only difference between the groups was that the thickness of the serratus anterior muscle at rest in the normal-posture group was larger than that in the forward-posture group (P = .01). CONCLUSIONS: Forward head posture appears to be related to atrophy of the serratus anterior muscle, which may contribute to the development of shoulder problems. Further research is required to identify more about the association of forward head posture with the imbalance of shoulder girdle muscles and the impact of head posture on upper quadrant pain. PMID- 29761539 TI - "Fat is really a four-letter word": Exploring weight-related communication best practices in children with and without disabilities and their caregivers. AB - BACKGROUND: Health care professionals play a critical role in preventing and managing childhood obesity, but the American Academy of Pediatrics recently stressed the importance of using sensitive and nonstigmatizing language when discussing weight with children and families. Although barriers to weight-related discussions are well known, there are few evidence-based recommendations around communication best practices. Disability populations in particular have previously been excluded from work in this area. The objectives were to present the findings of a recent scoping review to children with and without disabilities and their caregivers for their reactions; and to explore the experiences and perceptions of the children and their caregivers regarding weight-related communication best practices. METHODS: Focus group and individual interviews were conducted with 7-18-year olds with and without disabilities and their caregivers. The interview guide was created using findings from a recent scoping review of weight-related communication best practices. Inductive thematic analysis was employed. RESULTS: Eighteen children (9 boys; 7 children with disabilities) and 21 caregivers (17 mothers, 1 step-father, 3 other caregivers) participated in 8 focus group and 7 individual interviews. Preferred communication strategies were similar across those with and without disabilities, although caregivers of children with autism spectrum disorder endorsed more concrete approaches. Discussions emphasizing growth and health were preferred over weight and size. Strengths-based, solution-focused approaches for weight conversations were endorsed, although had not been widely experienced. CONCLUSION: Perceptions of weight-related communication were similar across stakeholder groups, regardless of children's disability or weight status. Participants generally agreed with the scoping review recommendations, suggesting that they apply broadly across different settings and populations; however, tailoring them to specific circumstances is critical. Empirical evaluations are still required to examine the influence of weight-related communication on clinically important outcomes, including behaviour change and family engagement in care. PMID- 29761538 TI - Pharmacokinetics of cefuroxime in infants and neonates undergoing cardiac surgery. AB - AIMS: Very little data exist regarding the effect of cardiopulmonary bypass (CPB) on cefuroxime (CXM) pharmacokinetics in children less than one year of age. METHODS: 50 mg kg-1 CXM i.v. after induction were followed by 75 mg kg-1 into the CPB circuit. In 42 patients undergoing cardiac surgery, 15-20 samples were obtained between 5 and 360 min after the first dose. Total CXM concentrations were measured by high-performance liquid chromatography and a pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed. RESULTS: Using a fixed protein binding of 15.6% for CXM, peak plasma concentrations of unbound CXM were 229 +/- 52 MUg ml-1 after the first bolus and 341 +/- 86 MUg ml-1 on CPB. Nadir concentrations before CPB were 69 +/- 20 MUg ml-1 and six hours later decreased to 41 +/- 19 MUg ml-1 with and 24 +/- 14 MUg ml-1 without CPB. A two compartment model was fitted with the main covariates body weight, CPB and postmenstrual age (PMA). PK parameters were as follows: systemic clearance, 5.15 [95% CI 4.5-5.8] l h-1 ; central volume of distribution, 11.25 [9.41-13.09] l; intercompartmental clearance, 18.19 [14.79-21.58] l h-1 ; and peripheral volume, 17.07 [15.7-18.5] L. fT > MIC of 32 MUg ml-1 for an 8-h time period was between 70 and 100% (2.5-10 kg BW). According to our simulation, 25 mg ml-1 CXM as a primary bolus and into the prime plus a 5 mg kg-1 h-1 infusion maintain CXM concentrations continuously above 32 MUg ml-1 . CONCLUSIONS: The routine dosing regimen provided was sufficient for prophylaxis, but continuous dosing can provide a higher percentage of fT > MIC. PMID- 29761540 TI - Apixaban decreases brain thrombin activity in a male mouse model of acute ischemic stroke. AB - Factor Xa (FXa) plays a critical role in the coagulation cascade by generation of thrombin. During focal ischemia thrombin levels increase in the brain tissue and cause neural damage. This study examined the hypothesis that administration of the FXa inhibitor, apixaban, following focal ischemic stroke may have therapeutic potential by decreasing brain thrombin activity and infarct volume. Male mice were divided into a treated groups that received different doses of apixaban (2, 20, 100 mg/kg administered I.P.) or saline (controls) immediately after blocking the middle cerebral artery (MCA). Thrombin activity was measured by a fluorescence assay on fresh coronal slices taken from the mice brains 24 hr following the MCA occlusion. Infarct volume was assessed using triphenyltetrazolium chloride staining. A high dose of apixaban (100 mg/kg) significantly decreased thrombin activity levels in the ipsilateral hemisphere compared to the control group (Slice#5, p = .016; Slice#6, p = .016; Slice#7, p = .016; Slice#8, p = .036; by the nonparametric Mann-Whitney test). In addition, treatment with apixaban doses of both 100 mg/kg (32 +/- 8% vs. 76 +/- 7% in the treatment vs. control groups respectively; p = .005 by the nonparametric Mann Whitney test) and 20 mg/kg (43 +/- 7% vs. 76 +/- 7% in the treatment vs. control groups respectively; p = .019 by the nonparametric Mann-Whitney test) decreased infarct volumes in areas surrounding the ischemic core (Slices #3 and #8). No brain hemorrhages were observed either in the treated or control groups. In summary, I.P. administration of high dose of apixaban immediately after MCA occlusion decreases brain thrombin activity and reduces infarct size. PMID- 29761541 TI - Telfairia occidentalis-supplemented diet induces changes in sperm parameters and testosterone level in rats. AB - The growing patronage on herbal remedies and formulations from natural products in most developing countries has warranted research into certain health challenges including their antifertility effects. This study assessed the effects of boiled Telfairia occidentalis (TO) seed-supplemented diets on the level of testosterone and semen quality in Wistar rats. Boiled TO seed diets at 10%, 15% and 30% were given to rats for 60 days. Our study showed that sperm quality was impaired as evidenced by the decreased number of motile spermatozoa, epididymal sperm numbers, percentage live/dead ratio and increased numbers of abnormal spermatozoa comparable to control values (p < .05). Feeding of rats with 10% and 15% TO seed-supplemented diets increased testosterone levels nonsignificantly, while in the 30% TO seed diet animals, the level of serum testosterone was found to decrease significantly compared to control values. Furthermore, TO diet caused a nonsignificant increase in the activity of superoxide dismutase and the concentrations of reduced glutathione and malondialdehyde except for the significant increase in malondialdehyde level in the testes of the 10% TO diet group. A nonsignificant decrease in myeloperoxidase activity was also observed in the 10% and 15% but not 30% TO diet group. Histological damages characterised by severe loss of germ cells were more pronounced in the 10% TO diet group. Fourier transform infrared spectroscopy analysis of boiled TO seeds revealed the presence of esters, alkenes, hydroxyl and alcohol functional groups. Thus, boiled TO seed supplemented diet evoked antifertility effects in rats, and the effects on the toxicity end points investigated were not dose-dependent. PMID- 29761542 TI - Ameliorative effect of resveratrol on testicular oxidative stress, spermatological parameters and DNA damage in glyphosate-based herbicide-exposed rats. AB - In this study, the reproductive impacts of being exposed to glyphosate (GLF) and the protective impacts of resveratrol (RES) were assessed in 28 Wistar male rats, which were equally separated into four groups. Control group were fed normal diet without GLF or RES, group II received normal feed containing 20 mg kg-1 daily-1 RES, group III received normal feed containing 375 mg kg-1 daily-1 GLF, and group IV received normal feed containing 375 mg kg-1 daily-1 GLF+20 mg kg-1 daily-1 RES. GLF administration decreased sperm motility, sperm plasma membrane integrity, glutathione level and superoxide dismutase in the testicular tissue of rats. On the other hand, abnormal sperm rate, malondialdehyde level, and DNA damage were detected to be high in the group treated with GLF. The findings indicate that RES protects spermatological parameters and DNA damage, decreases GLF-induced lipid peroxidation, improves the antioxidant defence mechanism and regenerates tissue damage in the testis of rats. PMID- 29761544 TI - Effect of dietary counselling with prosthetic restoration on fruit and vegetable intake in partially dentate patients: A prospective study. AB - The aim of this study was to investigate the effects of a counselling-based dietary intervention on nutritional status in partially dentate patients receiving removable partial dentures (RPDs). Thirty-eight patients [mean age (standard deviation): 73.2 (7.7) years] who were scheduled to receive RPDs at a dental hospital and were currently eating <350 g of vegetables per day were included in the study. A dentist provided basic dietary counselling aimed at increasing dietary fruit and vegetable intake and improving dietary habits. Patients received dietary counselling directly after treatment with new RPDs and at 1 week after a 1-month follow-up evaluation (T1). Food intake was assessed via a validated brief-type self-administered diet history questionnaire, and carotenoids and vitamin C in 6-hour fasting blood samples were measured before RPD administration, and at 1 (T1) and 3 months (T3) thereafter. Vegetable but not the fruit intake increased significantly at T1 and T3 compared to before treatment. Alpha carotene significantly increased at T3 while beta significantly increased both at T1 and T3 compared to before treatment (P < .05). The number of occlusal units on natural teeth was significantly positively associated with increased vegetable and beta-carotene intake (P < .05). Serum carotenoids and vitamin C levels measured with 6-hour fasting blood samples remained constant. These results suggest that basic dietary counselling may improve vegetable intake in partially dentate patients receiving RPD treatment, but did not lead to haematological changes. The presence of occlusion of remaining posterior teeth may be critical for improving vegetable intake. PMID- 29761543 TI - Influence of backrest angle on swallowing musculature activity and physical strain during the head lift exercise in elderly women compared with young women. AB - The head lift exercise (HLE) is the most common exercise for strengthening the swallowing musculature in clinical situations. This study investigated whether a change in the backrest angle of a bed influences swallowing musculature activity and physical strain during the HLE and whether it can generate an appropriate exercise load for swallowing musculature activity for older women compared with younger women. Participants were 10 elderly women and 10 young women, each of whom performed the HLE with a backrest randomly angled at 0 degrees , 15 degrees , 30 degrees and 45 degrees . The activity of the suprahyoid, infrahyoid and sternocleidomastoid muscles was assessed with electromyography. The perception of fatigue was measured with the Borg Rating of Perceived Exertion Scale. The activity of the infrahyoid and sternocleidomastoid muscles in elderly women was significantly lower when the angle of the backrest was raised to 45 degrees vs 0 degrees . In both groups, the Borg rating decreased significantly at the 30 degrees and 45 degrees backrest positions vs the 0 degrees and 15 degrees positions. The activity required for the suprahyoid and infrahyoid muscles in elderly women at a 30 degrees backrest position was almost equal to the activity required by these muscles in young women at a 0 degrees backrest position. In elderly women, it is possible that the HLE with the backrest at a 30 degrees angle may be easier and provide a more appropriate exercise load for strengthening the swallowing muscles. PMID- 29761545 TI - Comparison of the large muscle group widths of the pelvic limb in seven breeds of dogs. AB - Orthopaedic diseases are common in the pelvic limbs of dogs, and reference values for large muscle groups of the pelvic limb may aid in diagnosis such diseases. As such, the objective of this study was to compare the large muscle groups of the pelvic limb in seven breeds of dogs. A total of 126 dogs from different breeds were included, and the widths of the quadriceps, hamstring and gastrocnemius muscles were measured from images of the lateral radiographies. The width of the quadriceps was not different between the breeds, but the widths of the hamstring and gastrocnemius muscles were significantly different between the breeds. The widest hamstring and gastrocnemius muscles were seen in the Rottweilers and the Boxers, respectively. The narrowest hamstring and gastrocnemius muscles were seen in the Belgian Malinois and the Golden retrievers, respectively. All ratios between the measured muscles differed significantly between the breeds. Doberman pinschers and Belgian Malinois had the highest ratio of gastrocnemius width:hamstring width. Doberman pinschers had also the highest ratio of quadriceps width:hamstring width. German shepherds had the highest ratio of gastrocnemius width:quadriceps width. The lowest ratios of quadriceps width:hamstring width were determined in the German shepherds. The ratios of the muscle widths may be used as reference values to assess muscular atrophy or hypertrophy in cases of bilateral or unilateral orthopaedic diseases of the pelvic limbs. Further studies are required to determine the widths and ratios of the large muscle groups of the pelvic limbs in other dog breeds. PMID- 29761546 TI - Caging Nb2 O5 Nanowires in PECVD-Derived Graphene Capsules toward Bendable Sodium Ion Hybrid Supercapacitors. AB - Sodium-ion hybrid supercapacitors (Na-HSCs) by virtue of synergizing the merits of batteries and supercapacitors have attracted considerable attention for high energy and high-power energy-storage applications. Orthorhombic Nb2 O5 (T-Nb2 O5 ) has recently been recognized as a promising anode material for Na-HSCs due to its typical pseudocapacitive feature, but it suffers from intrinsically low electrical conductivity. Reasonably high electrochemical performance of T-Nb2 O5 based electrodes could merely be gained to date when sufficient carbon content was introduced. In addition, flexible Na-HSC devices have scarcely been demonstrated by far. Herein, an in situ encapsulation strategy is devised to directly grow ultrathin graphene shells over T-Nb2 O5 nanowires (denoted as Gr Nb2 O5 composites) by plasma-enhanced chemical vapor deposition, targeting a highly conductive anode material for Na-HSCs. The few-layered graphene capsules with ample topological defects would enable facile electron and Na+ ion transport, guaranteeing rapid pseudocapacitive processes at the Nb2 O5 /electrolyte interface. The Na-HSC full-cell comprising a Gr-Nb2 O5 anode and an activated carbon cathode delivers high energy/power densities (112.9 Wh kg-1 /80.1 W kg-1 and 62.2 Wh kg-1 /5330 W kg-1 ), outperforming those of recently reported Na-HSC counterparts. Proof-of-concept Na-HSC devices with favorable mechanical robustness manifest stable electrochemical performances under different bending conditions and after various bending-release cycles. PMID- 29761547 TI - A novel combination of silane-coated silica colloid with hybrid RNA extraction protocol and RNA enrichment for downstream applications of spermatozoal RNA. AB - Spermatozoa are specialised cells with low RNA content as compared to somatic cells. The suitable sperm RNA extraction and enrichment protocols for downstream applications are available for human, cattle, stallion and mouse but not for buffalo spermatozoa. Therefore, the present work was conducted to find out suitable colloidal solution for sperm purification and appropriate protocol for sperm RNA extraction and enrichment/amplification of RNA. For purification, we used PVP-coated silica colloidal solution (PVP-Si), silane-coated silica colloidal solution (Silane-Si) and iodixanol. Sperm recovery rate, total sperm motility and progressive sperm motility were significantly improved after separation by Silane-Si and iodixanol compared to PVA-Si method. The combined guanidinium thiocyanate-phenol-chloroform (GTPC) with silica matrix (SM)-based RNA extraction yielded more quantity of RNA in compared to individual method. The hybrid of SM and GTPC into a single protocol yielded 360-450 ng RNA from 30 million buffalo spermatozoa. For the first time, we adopted new way to enrich sperm RNA that increased the RNA concentration 4-5 times that was sufficient for downstream applications. The linear amplification of sperm RNA increased RNA concentration around 27-45 times. In summary, Silane-Si colloid for sperm separation, hybrid SM and GTPC protocol for sperm RNA extraction followed by enrichment or amplification of RNA was found suitable for high-throughput analyses of buffalo sperm RNA. PMID- 29761548 TI - Variation of Carotid Intima Media Thickness With Body Mass Index in Healthy Adults of Black African Descent. AB - OBJECTIVES: Studies have shown that common carotid intima media thickness (CIMT) measured by B-mode sonography increases with body mass index (BMI) among subjects with cardiovascular diseases in different populations. However, association of body fat and subclinical atherosclerosis in the absence of these cardiovascular diseases is understudied. We aimed to evaluate the correlation between BMI and CIMT in a healthy adult population of black African ancestry. METHODS: This is a cross-sectional prospective study in 300 consecutive apparently healthy subjects aged 18 to 70 years without history of hypertension, dyslipidemia, diabetes mellitus, and renal disease. Subjects' common carotid artery intima media thickness was measured with a 7.5-MHz linear ultrasound transducer at a point 10 mm proximal to the carotid bulb. All subjects' biodata, medical history, anthropometric (weight and height from which BMI was calculated), laboratory (fasting lipid profile and blood glucose), and CIMT values were recorded on a pro forma. Data were analysed using SPSS version 21, and significant P was set at less than .05. RESULTS: The right, left, and average CIMT of both sides in our study subjects are 0.52 +/- 0.11 mm, 0.51 +/- 0.11 mm and 0.52 +/- 0.11 mm respectively, with no significant difference between the right and left sides (P > .05). The right, left, and average CIMT increased with increasing age and BMI category (all P < .01) but were not significantly different between men and women (all P > .05). Age (r = .824, .825, and .827; P < .01) and BMI (r = .503, .504, .507; P < .01) had strong positive correlations with right, left, and average CIMT. CONCLUSIONS: Increasing age and BMI category, but not sex, significantly influenced CIMT values in our apparently healthy black African population. PMID- 29761549 TI - Sprifermin treatment enhances cartilage integration in an in vitro repair model. AB - Cartilage integration remains a clinical challenge for treatment of focal articular defects. Cartilage exhibits limited healing capacity that declines with tissue maturation. Many approaches have been investigated for their ability to stimulate healing of mature cartilage or integration of repair tissue or tissue engineered constructs with native cartilage. Growth factors present in immature tissue may enhance chondrogenesis and promote integrative repair of cartilage defects. In this study, we assessed the role of one such factor, fibroblast growth factor 18 (FGF18). Studies using FGF18 have shown a variety of positive effects on cartilage, including stimulation of chondrocyte proliferation, matrix biosynthesis, and suppression of proteinase activity. To explore the role of FGF18 on cartilage defect repair, we hypothesized that treatment with recombinant human FGF18 (sprifermin) would increase matrix synthesis in a defect model, thus improving integration strength. To test this hypothesis, 6 mm cartilage cylinders were harvested from juvenile bovine knees. A central 3 mm defect was created in each explant, and this core was removed and replaced. Resulting constructs were cultured in control or sprifermin-containing medium (weekly 24-h exposure of 100 ng/ml sprifermin) for 4 weeks. Mechanical testing, biochemical analysis, micro CT, scanning electron microscopy, and histology were used to assess matrix production, adhesive strength, and structural properties of the cartilage cartilage interface. Results showed greater adhesive strength, increased collagen content, and larger contact areas between core and annular cartilage in the sprifermin-treated group. These findings present a novel treatment for cartilage injuries that have potential to enhance defect healing and lateral cartilage cartilage integration. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2648-2656, 2018. PMID- 29761550 TI - miR-26a suppresses autophagy in swine Sertoli cells by targeting ULK2. AB - A large number of microRNAs (miRNAs) have been detected from porcine testicular tissues thanks to the development of high-throughput sequencing technology. However, the regulatory roles of most identified miRNAs in swine testicular development or spermatogenesis are poorly understood. In our previous study, ULK2 (uncoordinated-51-like kinase 2) was predicted as a target gene of miR-26a. In this study, we aimed to investigate the role of miR-26a in swine Sertoli cell autophagy. The relative expression of miR-26a and ULK2 levels has a significant negative correlation (R2 = .5964, p <= .01) in nine developmental stages of swine testicular tissue. Dual-luciferase reporter assay results show that miR-26a directly targets the 3'UTR of the ULK2 gene (position 618-624). In addition, both the mRNA and protein expression of ULK2 were downregulated by miR-26a in swine Sertoli cells. These results indicate that miR-26a targets the ULK2 gene and downregulates its expression in swine Sertoli cells. Based on the expression of marker genes (LC3, p62 and Beclin-1), overexpression of miR-26a or knock-down of ULK2 inhibits swine Sertoli cell autophagy. Taken together, these findings demonstrate that miR-26a suppresses autophagy in swine Sertoli cells by targeting ULK2. PMID- 29761551 TI - Generalized Access to Mesoporous Inorganic Particles and Hollow Spheres from Multicomponent Polymer Blends. AB - Mesoporous inorganic particles and hollow spheres are of increasing interest for a broad range of applications, but synthesis approaches are typically material specific, complex, or lack control over desired structures. Here it is reported how combining mesoscale block copolymer (BCP) directed inorganic materials self assembly and macroscale spinodal decomposition can be employed in multicomponent BCP/hydrophilic inorganic precursor blends with homopolymers to prepare mesoporous inorganic particles with controlled meso- and macrostructures. The homogeneous multicomponent blend solution undergoes dual phase separation upon solvent evaporation. Microphase-separated (BCP/inorganic precursor)-domains are confined within the macrophase-separated majority homopolymer matrix, being self organized toward particle shapes that minimize the total interfacial area/energy. The pore orientation and particle shape (solid spheres, oblate ellipsoids, hollow spheres) are tailored by changing the kind of homopolymer matrix and associated enthalpic interactions. Furthermore, the sizes of particle and hollow inner cavity are tailored by changing the relative amount of homopolymer matrix and the rates of solvent evaporation. Pyrolysis yields discrete mesoporous inorganic particles and hollow spheres. The present approach enables a high degree of control over pore structure, orientation, and size (15-44 nm), particle shape, particle size (0.6-3 um), inner cavity size (120-700 nm), and chemical composition (e.g., aluminosilicates, carbon, and metal oxides). PMID- 29761552 TI - Analysis of the Bipolar Resistive Switching Behavior of a Biocompatible Glucose Film for Resistive Random Access Memory. AB - Resistive random access memory (RRAM) devices are fabricated through a simple solution process using glucose, which is a natural biomaterial for the switching layer of RRAM. The fabricated glucose-based RRAM device shows nonvolatile bipolar resistive switching behavior, with a switching window of 103 . In addition, the endurance and data retention capability of glucose-based RRAM exhibit stable characteristics up to 100 consecutive cycles and 104 s under constant voltage stress at 0.3 V. The interface between the top electrode and the glucose film is carefully investigated to demonstrate the bipolar switching mechanism of the glucose-based RRAM device. The glucose based-RRAM is also evaluated on a polyimide film to verify the possibility of a flexible platform. Additionally, a cross-bar array structure with a magnesium electrode is prepared on various substrates to assess the degradability and biocompatibility for the implantable bioelectronic devices, which are harmless and nontoxic to the human body. It is expected that this research can provide meaningful insights for developing the future bioelectronic devices. PMID- 29761553 TI - Method to estimate the approximate samples size that yield a certain number of significant GWAS signals in polygenic traits. AB - To argue for increased sample collection for disorders without significant findings, researchers resorted to plotting, for multiple traits, the number of significant findings as a function of the sample size. However, for polygenic traits, the prevalence of the disorder confounds the relationship between the number of significant findings and the sample size. To adjust the number of significant findings for prevalence, we develop a method that uses the expected noncentrality of the contrast between liabilities of cases and controls. We empirically find that, when compared to the sample size, this measure is a better predictor of number of significant findings. Even more, we show that the sample size effect on the number of signals is explained by the noncentrality measure. Finally, we provide an R script to estimate the required sample size (noncentrality) needed to yield a prespecified number of significant findings, along with the converse. PMID- 29761554 TI - Ultrastretchable Conductor Fabricated on Skin-Like Hydrogel-Elastomer Hybrid Substrates for Skin Electronics. AB - Printing technology can be used for manufacturing stretchable electrodes, which represent essential parts of wearable devices requiring relatively high degrees of stretchability and conductivity. In this work, a strategy for fabricating printable and highly stretchable conductors are proposed by transferring printed Ag ink onto stretchable substrates comprising Ecoflex elastomer and tough hydrogel layers using a water-soluble tape. The elastic modulus of the produced hybrid film is close to that of the hydrogel layer, since the thickness of Ecoflex elastomer film coated on hydrogel is very thin (30 um). Moreover, the fabricated conductor on hybrid film is stretched up to 1780% strain. The described transfer method is simpler than other techniques utilizing elastomer stamps or sacrificial layers and enables application of printable electronics to the substrates with low elastic moduli (such as hydrogels). The integration of printed electronics with skin-like low-modulus substrates can be applied to make wearable devices more comfortable for human skin. PMID- 29761555 TI - Computational optimization of graft tension in simulated superior capsule reconstructions. AB - Superior capsular reconstruction has received increased attention as a surgical technique to address massive "irreparable" rotator cuff tears; however, the functional limitations and surgical techniques associated with this repair have yet to be sufficiently explored. The goal of this study was to utilize a multidisciplinary approach to characterize the biomechanics of this repair by: (i) identifying activities of daily living that may overburden the graft; and (ii) optimizing surgical techniques used during implantation. This experiment was completed in three phases. First, graft failure mechanics were characterized by performing an in vitro experiment. Second, in vivo shoulder kinematics associated with various activities were recorded with 3-D motion capture techniques. Finally, an in silico model was used to assess graft strains. Results show that motions involving posterior shoulder rotation, such as back washing, lead to graft strains that may cause failure. Output from the optimization suggests that orienting the humerus in approximately 25 degrees abduction, and 20 degrees internal rotation during implantation will result in optimal graft performance. Clinical Significance: The novel paradigm used in this study demonstrates the utility of coupling in vitro, in vivo, and in silico modeling techniques in one cohesive experiment. This paradigm presents an additional tool, aside from clinical studies and cadaveric experimentation, to better predict and understand the strengths and limitations of superior capsular reconstruction. This approach has potential to be translated to other soft tissue repairs and may provide valuable information to clinicians and rehabilitative specialists to manage patient expectations and guide rehabilitation. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2789-2796, 2018. PMID- 29761556 TI - Effect of zoledronic acid dosing every 3 months in patients with prostate cancer with skeletal metastases: A multicenter prospective exploratory study with matched historical controls. PMID- 29761557 TI - Effects of dietary yeast cell wall on faecal bacteria and fermentation products in adult cats. AB - This study evaluated the effects of increasing concentrations of spray-dried yeast cell wall (YCW) in diets for healthy adult cats on apparent nutrient digestibility and on bacterial composition and fermentation products in the stool. Fourteen cats with an average weight of 4.40 +/- 1.05 kg and an average age of 6.2 +/- 0.54 years were used and assigned to treatments in an unbalanced randomized block design (by experimental period) with two blocks and three or four cats per diet in each block. Treatments included: control (0% YCW), 0.2% YCW, 0.4% YCW and 0.6% YCW, totalling seven animals per experimental diet. We found that YCW did not affect body weight, nutrient and food intake, faecal production, faecal score, faecal pH or urine output (p > .05). Regarding faecal bacteria, we observed a linear reduction in Clostridium perfringens, a quadratic reduction in Escherichia coli, and linear increases in Bifidobacterium spp. and Lactobacillus spp. (p < .05) with the inclusion of YCW. Regarding the faecal short-chain fatty acid profile, butyrate, valerate, total biogenic amines, putrescine, cadaverine and histamine increased linearly (p < .05) with the inclusion of YCW. It was concluded that in healthy adult cats, consumption of YCW modulates the faecal bacterial populations, with an increased presence of beneficial bacteria and a reduction in some potentially pathogenic bacteria. It was concluded that YCW modulated the levels of fermentation products. There was an increase in fermentation products coming from carbohydrate metabolism, an important effect that can potentially benefit the intestinal health of cats. The consumption of YCW also increased the fermentation of nitrogen compounds, which have not yet been defined as deleterious or beneficial. The fermentability of carbohydrates and nitrogen compounds may be associated. Therefore, YCW may cause rapid fermentation of both classes of compounds by enhancing the fermentability of one class. PMID- 29761558 TI - Synthesis and characterization of a deuterium labeled stercobilin: A potential biomarker for autism. AB - Stercobilin is an end-stage metabolite of hemoglobin, a component of red blood cells. It has been found that there is a significantly lower concentration of stercobilin in the urine of people diagnosed with autism spectrum disorders, suggesting potential use as a biomarker. In vitro, we have synthesized stercobilin from its precursor bilirubin through a reduction reaction proceeded by an oxidation reaction. In addition, we have isotopically labeled the stercobilin product with deuterium using this protocol. Nuclear magnetic resonance investigations show the products of the unlabeled stercobilin (Rxn 1) and the deuterated stercobilin (Rxn 2) both had a loss of signals in the 5.0- to 7.0-ppm range indicating proper conversion to stercobilin. Changes in the multiplicity of the sp3 region of the proton nuclear magnetic resonance suggest proper deuterium incorporation. Mass spectrometry studies of Rxn 1 show a difference in fragmentation patterns than that of Rxn 2 proposing potential locations for deuterium incorporation. This isotopologue of stercobilin is stable (>6 mo), and further analysis permits investigation for its use as a biomarker and potential quantitative diagnostic probe for autism spectrum disorders. PMID- 29761559 TI - Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model. AB - Apoptosis is recognized as the main mechanism of oligodendrocyte loss in Multiple Sclerosis caused either by immune mediated injury (Barnett & Prineas, ) or a direct degenerative process (oligodendrogliapathy; Lucchinetti et al., ). Cuprizone induced demyelination is the result of non-immune mediated apoptosis of oligodendrocytes (OL) and represents a model of oligodendrogliapathy (Simmons, Pierson, Lee, & Goverman, ). Glycogen Synthase Kinase (GSK) 3b has been shown to be pro-apoptotic for cells other than OL. Here, we sought to investigate whether GSK3b plays a role in cuprizone-induced apoptosis of OL by using a novel inducible conditional knockout (cKO) of GSK3b in mature OL. While depletion of GSK3b has no effect on survival of uninjured OL, it increases survival of mature OL exposed to cuprizone. We show that GSK3b-deficient OLs are protected against caspase-dependent, but not against caspase-independent apoptosis. Active GSK3b is present in the nuclei of OL at peak of caspase-dependent apoptosis. Significant preservation of myelinated axons is associated with GSK3b depletion and glial cell activation is markedly reduced. Collectively, the data show that GSK3b is pro-apoptotic for caspase-dependent cell death, likely through activation of nuclear GSK3b and its depletion promotes survival of oligodendrocytes and attenuates myelin loss. PMID- 29761560 TI - mTOR-mediated inactivation of 4E-BP1, an inhibitor of translation, precedes cartilage degeneration in rat osteoarthritic knees. AB - Proper control of protein synthesis is vital for tissue homeostasis and its deregulation is characteristic of many disorders including osteoarthritis (OA). The objectives of this work were to analyze and correlate changes in activity of the translation apparatus associated with cartilage degeneration in an animal model of OA. Osteoarthritis was induced surgically in rats by anterior cruciate ligament transection (ACLT). Using a modified Mankin scoring system and analysis of protein expression we demonstrated, that mechanistic target of rapamycin complex 1 (mTORC1)-mediated 4E-BP1 phosphorylation was detected significantly earlier than other mTORC1-mediated modifications, such as p70S6K and ULK1 phosphorylation. 4E-BP1 is an inhibitor of cap-dependent translation those functions are inhibited by mTORC1 mediated phosphorylation. This signaling event not only preceded prominent signs of cartilage degeneration but also the increase in global protein synthesis rate. These results suggest that abnormal mTORC1 activity is one of the primary dysregulations observed in OA cartilage. Importantly, it is distributed disproportionately between targets, with 4E-BP1 being phosphorylated earlier than other downstream targets. Thus, our work provides new insights into the sequence of molecular events leading to cartilage destruction in OA and identifies translational control as an important regulatory hub involved in initiating OA. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2728-2735, 2018. PMID- 29761561 TI - Ultrafast Zn2+ Intercalation and Deintercalation in Vanadium Dioxide. AB - Although rechargeable aqueous zinc-ion batteries have attracted extensive interest due to their environmental friendliness and low cost, they still lack suitable cathodes with high rate capabilities, which are hampered by the intense charge repulsion of bivalent Zn2+ . Here, a novel intercalation pseudocapacitance behavior and ultrafast kinetics of Zn2+ into the unique tunnels of VO2 (B) nanofibers in aqueous electrolyte are demonstrated via in situ X-ray diffraction and various electrochemical measurements. Because VO2 (B) nanofibers possess unique tunnel transport pathways with big sizes (0.82 and 0.5 nm2 along the b- and c-axes) and little structural change on Zn2+ intercalation, the limitation from solid-state diffusion in the vanadium dioxide electrode is eliminated. Thus, VO2 (B) nanofibers exhibit a high reversible capacity of 357 mAh g-1 , excellent rate capability (171 mAh g-1 at 300 C), and high energy and power densities as applied for zinc-ion storage. PMID- 29761562 TI - Comparison between capillary zone electrophoresis and capillary isoelectric focusing for thalassemia screening in southern China. AB - BACKGROUND: Capillary isoelectric focusing is a type of capillary electrophoresis method newly used for thalassemia screening in China. Although the good performance has been proved by several studies, whether it can best suit the special needs of Chinese patients still requires further investigations. METHODS: Comparisons were made between capillary zone electrophoresis method applied on Sebia Minicap and capillary isoelectric focusing method applied on Helena V8 platform E-class on identifying Hb E, Hb CS, Hb H, and Hb Barts for patients from southern China. And mixing studies were used to evaluate the lowest detection limits of these 2 kinds of capillary electrophoresis system. RESULTS: Helena V8 could not make a distinction between peaks of Hb E and peaks of Hb A2 as Sebia Minicap did. All chosen patients with Hb H and/or Hb Barts could be screened out by both 2 systems, but when analyzed by Helena V8, it was hard to distinguish Hb H from Hb Barts sometimes, while Sebia Minicap could make a clear distinction between peaks of Hb H and Hb Barts. Only a part of patients (3 of 8, 37.5%) with Hb CS could be screened out by Helena V8, while all patients could be identified by Sebia Minicap. Sebia Minicap had a lower detection limit for trace peaks than Helena V8 (near to 0.2% vs near to 0.6%). CONCLUSIONS: Compared with capillary zone electrophoresis, capillary isoelectric focusing applied on Helena V8 maybe is not the first choice for hemoglobinopathy testing in southern China. PMID- 29761563 TI - Editorial Comment to Recurrent stone-forming patients have high visceral fat ratio based on computed tomography images compared to first-time stone-forming patients. PMID- 29761564 TI - Laser-Induced Molybdenum Carbide-Graphene Composites for 3D Foldable Paper Electronics. AB - Versatile and low-cost manufacturing processes/materials are essential for the development of paper electronics. Here, a direct-write laser patterning process is developed to make conductive molybdenum carbide-graphene (MCG) composites directly on paper substrates. The hierarchically porous MCG structures are converted from fibrous paper soaked with the gelatin-mediated inks containing molybdenum ions. The resulting Mo3 C2 and graphene composites are mechanically stable and electrochemically active for various potential applications, such as electrochemical ion detectors and gas sensors, energy harvesters, and supercapacitors. Experimentally, the electrical conductivity of the composite is resilient to mechanical deformation with less than 5% degradation after 750 cycles of 180 degrees repeated folding tests. As such, the direct laser conversion of MCGs on papers can be applicable for paper-based electronics, including the 3D origami folding structures. PMID- 29761565 TI - Cooling-Triggered Shapeshifting Hydrogels with Multi-Shape Memory Performance. AB - Heating-triggered shape actuation is vital for biomedical applications. The likely overheating and subsequent damage of surrounding tissue, however, severely limit its utilization in vivo. Herein, cooling-triggered shapeshifting is achieved by designing dual-network hydrogels that integrate a permanent network for elastic energy storage and a reversible network of hydrophobic crosslinks for "freezing" temporary shapes when heated. Upon cooling to 10 degrees C, the hydrophobic interactions weaken and allow recovery of the original shape, and thus programmable shape alterations. Further, multiple temporary shapes can be encoded independently at either different temperatures or different times during the isothermal network formation. The ability of these hydrogels to shapeshift at benign conditions may revolutionize biomedical implants and soft robotics. PMID- 29761566 TI - Nanomaterial-Based Organelles Protect Normal Cells against Chemotherapy-Induced Cytotoxicity. AB - Chemotherapy-induced cytotoxicity in normal cells and organs triggers undesired lesions. Although targeted delivery is used extensively, more than half of the chemotherapy dose still concentrates in normal tissues, especially in the liver. Enabling normal cells or organs to defend against cytotoxicity represents an alternative method for improving chemotherapy. Herein, rationally designed nanomaterials are used as artificial organelles to remove unexpected cytotoxicity in normal cells. Nanocomposites of gold-oligonucleotides (Au-ODN) can capture intracytoplasmic doxorubicin (DOX), a standard chemotherapy drug, blocking the drug's access into the cell nucleus. Cells with implanted Au-ODN are more robust since their viability is maintained during DOX treatment. In vivo experiments confirm that the Au-ODN nanomaterials selectively concentrate in hepatocytes and eliminate DOX-induced hepatotoxicity, increasing the cell's capacity to resist the threatening chemotherapeutic milieu. The finding suggests that introducing functional materials as biological devices into living systems may be a new strategy for improving the regulation of cell fate in more complex conditions and for manufacturing super cells. PMID- 29761567 TI - The Use of Cyclometalated NHCs and Pyrazoles for the Development of Fully Efficient Blue PtII Emitters and Pt/Ag Clusters. AB - New bis-pyrazole complexes [Pt(C^C*)(RpzH)2 ]X, containing a cyclometalated N heterocyclic carbene ligand (HC^C*=1-(4-(ethoxycarbonyl)phenyl)-3-methyl-1H imidazol-2-ylidene) were prepared as chloride (X=Cl- , RpzH: 3,5-Me2 pzH 1 a, 4 MepzH 2 a, pzH 3 a), perchlorate (X=ClO4- , 1 b-3 b), or hexafluorophosphate (X=PF6- , RpzH: 3,5-Me2 pzH 1 c) salts. The X-ray structure of 1 a showed that the Cl- anion is trapped by the cation through two N-H???Cl bonds. In solution of methanol, acetone and THF at RT, 1 a-3 a coexist in equilibrium with the corresponding [PtCl(C^C*)(RpzH)] (B) and RpzH species. In CH2 Cl2 , this equilibrium takes place just for 2 a and 3 a, but it is completely shifted to the left at 243 and 223 K for 2 a and 3 a, respectively. The low-lying absorption and emission bands were assigned to intraligand (ILCT) charge transfer on the NHC group. Quantum yield measurements in PMMA films revealed that 1 b, 2 b and 1 c are amongst the most efficient blue-light emitters, with values up to 100 %. Proton abstraction from the coordinated 3,5-Me2 pzH in 1 b by NEt3 and replacement by Ag+ afforded a neutral [Pt2 Ag2 ] cluster containing Pt->Ag dative bonds. PMID- 29761568 TI - Electrospun N-Doped Hierarchical Porous Carbon Nanofiber with Improved Degree of Graphitization for High-Performance Lithium Ion Capacitor. AB - The lithium-ion capacitor (LIC) has been regarded as a promising device that combines the merits of lithium-ion batteries and supercapacitors, and that meets the requirements for both high energy and high power density. The development of advanced electrode materials is the key requirement. Herein, we report the bottom up synthesis of activated carbon nanofiber (a-PANF) with a hierarchical porous structure and a high degree of graphitization. Electrospinning has been employed to prepare an interconnected fiber network with macropores, and ferric acetylacetonate has been introduced as both a mesopore-creating agent and a graphitic catalyst to increase the degree of graphitization. Furthermore, chemical activation enlarges the specific surface area by producing abundant micropores. Half-cell evaluation of the as-prepared a-PANF gave a discharge capacity of 80 mA h g-1 at 0.1 A g-1 within 2-4.5 V and no capacity fading after 1000 cycles at 2 A g-1 , which represents a significant improvement compared to conventional activated carbon (AC). Furthermore, an as-assembled LIC with a-PANF cathode and Fe3 O4 anode showed a superior energy density of 124.6 W h kg-1 at a specific power of 93.8 W kg-1 , which remained at 103.7 W h kg-1 at 4687.5 W kg-1 . This indicates promising application potential of a-PANF as an electrode material for efficient energy storage systems. PMID- 29761569 TI - Cognitive and functional progression in Alzheimer disease: A prediction model of latent classes. AB - OBJECTIVE: We sought to replicate a previously published prediction model for progression, developed in the Cache County Dementia Progression Study, using a clinical cohort from the National Alzheimer's Coordinating Center. METHODS: We included 1120 incident Alzheimer disease (AD) cases with at least one assessment after diagnosis, originating from 31 AD centres from the United States. Trajectories of the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating sum of boxes (CDR-sb) were modelled jointly over time using parallel process growth mixture models in order to identify latent classes of trajectories. Bias-corrected multinomial logistic regression was used to identify baseline predictors of class membership and compare these with the predictors found in the Cache County Dementia Progression Study. RESULTS: The best-fitting model contained 3 classes: Class 1 was the largest (63%) and showed the slowest progression on both MMSE and CDR-sb; classes 2 (22%) and 3 (15%) showed moderate and rapid worsening, respectively. Significant predictors of membership in classes 2 and 3, relative to class 1, were worse baseline MMSE and CDR-sb, higher education, and lack of hypertension. Combining all previously mentioned predictors yielded areas under the receiver operating characteristic curve of 0.70 and 0.75 for classes 2 and 3, respectively, relative to class 1. CONCLUSIONS: Our replication study confirmed that it is possible to predict trajectories of progression in AD with relatively good accuracy. The class distribution was comparable with that of the original study, with most individuals being members of a class with stable or slow progression. This is important for informing newly diagnosed AD patients and their caregivers. PMID- 29761570 TI - Radical pericardiectomy for chronic constrictive pericarditis. AB - BACKGROUND: We studied the impact of radical pericardiectomy on early and long term patient survival, postoperative New York Heart Association (NYHA) functional class, and left ventricular ejection fraction in patients with chronic constrictive pericarditis compared to a sub-total pericardiectomy. METHODS: From 1991 to 2016, 41 patients underwent pericardiectomy for chronic constrictive pericarditis. Sub-total pericardiectomy was performed in 17 (41%) and radical pericardiectomy in 24 (59%) patients. Patients in the two study groups had statistically similar NYHA functional class, left ventricular ejection fraction, and cardiac catheterization data. Follow-up was 100% complete with a median time of 4 years. RESULTS: Radical pericardiectomy resulted in increased survival rates at 10 years (94%) compared to sub-total pericardiectomy (55%) (P = 0.014). In the idiopathic chronic constrictive pericarditis sub-group, long-term survival rates were also increased after a radical pericardiectomy (P = 0.001). Eighty-five percent of patients after a radical pericardiectomy were in NYHA functional class I or II after 5 years and 94% up to 25 years versus 53% and 63%, respectively, for the sub-total pericardiectomy group. CONCLUSIONS: Radical pericardiectomy provided superior 10-year survival and clinical functional improvement in patients with chronic constrictive pericarditis compared to sub-total pericaridectomy. PMID- 29761572 TI - 2D Binary Plasmonic Nanoassemblies with Semiconductor n/p-Doping-Like Properties. AB - The electronic, optical, thermal, and magnetic properties of an extrinsic bulk semiconductor can be finely tuned by adjusting its dopant concentration. Here, it is demonstrated that such a doping concept can be extended to plasmonic nanomaterials. Using two-dimensional (2D) assemblies of Au@Ag and Au nanocubes (NCs) as a model system, detailed experimental and theoretical studies are carried out, which reveal collective semiconductor n/p-doping-like plasmonic properties. A threshold doping concentration of Au@Ag NCs is observed, below which p-doping dominates and above which n-doping prevails. Furthermore, Au@Ag NC dopants can be converted into corresponding Au seed "voids" dopants by selectively removing Ag without changing the overall structural integrity. The results show that the plasmonic doping concept may serve as a general design principle guiding synthesis and assembly of plasmonic metamaterials for programmable optoelectronic devices. PMID- 29761571 TI - Frequency of shedding of respiratory pathogens in horses recently imported to the United States. AB - BACKGROUND: Imported horses that have undergone recent long distance transport might represent a serious risk for spreading infectious respiratory pathogens into populations of horses. OBJECTIVE: To investigate the frequency of shedding of respiratory pathogens in recently imported horses. ANIMALS: All imported horses with signed owner consent (n = 167) entering a USDA quarantine for contagious equine metritis from October 2014 to June 2016 were enrolled in the study. METHODS: Prospective observational study. Enrolled horses had a physical examination performed and nasal secretions collected at the time of entry and subsequently if any horse developed signs of respiratory disease during quarantine. Samples were assayed for equine influenza virus (EIV), equine herpesvirus type-1, -2, -4, and -5 (EHV-1, -2, -4, -5), equine rhinitis virus A (ERAV), and B (ERBV) and Streptococcus equi subspecies equi (S. equi) using quantitative PCR (qPCR). RESULTS: Equine herpesviruses were detected by qPCR in 52% of the study horses including EHV-2 (28.7%), EHV-5 (40.7%), EHV-1 (1.2%), and EHV-4 (3.0%). Clinical signs were not correlated with being qPCR-positive for EHV 4, EHV-2, or EHV-5. None of the samples were qPCR-positive for EIV, ERAV, ERBV, and S. equi. The qPCR assay failed quality control for RNA viruses in 25% (46/167) of samples. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical signs of respiratory disease were poorly correlated with qPCR positive status for EHV-2, 4, and -5. The importance of gamma-herpesviruses (EHV-2 and 5) in respiratory disease is poorly understood. Equine herpesvirus type-1 or 4 (EHV-1 or EHV-4) were detected in 4.2% of horses, which could have serious consequences if shedding animals entered a population of susceptible horses. Biosecurity measures are important when introducing recently imported horses into resident US populations of horses. PMID- 29761573 TI - Concise Review: Using Fat to Fight Disease: A Systematic Review of Nonhomologous Adipose-Derived Stromal/Stem Cell Therapies. AB - The objective of this Review is to describe the safety and efficacy of adipose stem/stromal cells (ASC) and stromal vascular fraction (SVF) in treating common diseases and the next steps in research that must occur prior to clinical use. Pubmed, Ovid Medline, Embase, Web of Science, and the Cochrane Library were searched for articles about use of SVF or ASC for disease therapy published between 2012 and 2017. One meta-analysis, 2 randomized controlled trials, and 16 case series were included, representing 844 human patients. Sixty-nine studies were performed in preclinical models of disease. ASCs improved symptoms, fistula healing, remission, and recurrence rates in severe cases of inflammatory bowel disease. In osteoarthritis, ASC and SVF improved symptom-related, functional, radiographic, and histological scores. ASC and SVF were also shown to improve clinical outcomes in ischemic stroke, multiple sclerosis, myocardial ischemia, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, chronic liver failure, glioblastoma, acute kidney injury, and chronic skin wounds. These effects were primarily paracrine in nature and mediated through reduction of inflammation and promotion of tissue repair. In the majority of human studies, autologous ASC and SVF from liposuction procedures were used, minimizing the risk to recipients. Very few serious, treatment-related adverse events were reported. The main adverse event was postprocedural pain. SVF and ASC are promising therapies for a variety of human diseases, particularly for patients with severe cases refractory to current medical treatments. Further randomized controlled trials must be performed to elaborate potential safety and efficacy prior to clinical use. Stem Cells 2018;36:1311-1328. PMID- 29761574 TI - Association between hyperinsulinaemia and laminitis severity at the time of pituitary pars intermedia dysfunction diagnosis. AB - BACKGROUND: Hyperinsulinaemia is the suspected component of insulin dysregulation having the strongest association with laminitis and occurs variably in equids with pituitary pars intermedia dysfunction (PPID). OBJECTIVES: We hypothesised that magnitude of hyperinsulinaemia correlates with laminitis severity in PPID affected equids. Furthermore, we hypothesised that owners can be unaware of chronic endocrinopathic laminitis. STUDY DESIGN: Cross-sectional study. METHODS: Serum insulin concentrations, owner-reported laminitis history and radiographic evidence of laminitis were determined in 38 client-owned horses and ponies with confirmed PPID. Laminitis severity was classified into four categories (normal [nonlaminitic], mild, moderate or severe laminitis) based on degree of distal phalangeal rotation. Animals were also categorised as normoinsulinaemic (<20 MUU/ml), mildly hyperinsulinaemic (20-50 MUU/ml) and severely hyperinsulinaemic (>50 MUU/ml). One-way ANOVA, t tests and Fisher's exact tests were performed. RESULTS: While owners reported laminitis in 37% of animals, 76% were laminitic based on study criteria (P = 0.01). Owners reported laminitis more frequently in hyperinsulinaemic vs. normoinsulinaemic animals; recognition increased with severity of hyperinsulinaemia (P = 0.03). Mean insulin concentrations were higher in equids with moderate to severe radiographic laminitis (geometric mean 74.1, 95% confidence interval (CI) 38.4-143.1 uU/ml) vs. those classified radiographically as normal to mild (31.9, 95% CI 21.1-48.1 uU/ml P = 0.03). MAIN LIMITATIONS: Dynamic insulin testing was not performed; some normoinsulinaemic animals might have had subtle insulin dysregulation. CONCLUSIONS: Although radiographic abnormalities were present in most animals at the time of PPID diagnosis, chronic laminitis remained unrecognised by many owners. Owner awareness of laminitis increased with severity of hyperinsulinaemia and higher insulin concentrations were detected in association with more severe radiographic changes. The Summary is available in Chinese - See Supporting Information. PMID- 29761575 TI - Different Selectivities in the Insertions into C(sp2 )-H Bonds: Benzofulvenes by Dual Gold Catalysis Competition Experiments. AB - An unprecedented, often almost quantitative access to tricyclic aromatic compounds by dual gold catalysis was developed. This synthetic route expands the scope of benzofulvene derivatives through a C(sp2 )-H bond insertion in easily available starting materials. The insertion takes place with an exclusive chemoselectivity with respect to the competing aromatic C-H positions. A bidirectional synthesis with two competing ortho-aryl C-H bonds in the selectivity-determining step also shows perfect selectivity; this result is explained by a computational investigation of the two conceivable intermediates. The intramolecular competition of two non-equivalent aryl C-H bonds with a benzylic methyl group also showed perfect selectivity. PMID- 29761576 TI - Nonuniform impacts of forward suppression on neural responses to preferred stimuli and nonpreferred stimuli in the rat auditory cortex. AB - In natural conditions, human and animals need to extract target sound information from noisy acoustic environments for communication and survival. However, how the contextual environmental sounds impact the tuning of central auditory neurons to target sound source azimuth over a wide range of sound levels is not fully understood. Here, we determined the azimuth-level response areas (ALRAs) of rat auditory cortex neurons by recording their responses to probe tones varying with levels and sound source azimuths under both quiet (probe alone) and forward masking conditions (preceding noise + probe). In quiet, cortical neurons responded stronger to their preferred stimuli than to their nonpreferred stimuli. In forward masking conditions, an effective preceding noise reduced the extents of the ALRAs and suppressed the neural responses across the ALRAs by decreasing the response strength and lengthening the first-spike latency. The forward suppressive effect on neural response strength was increased with increasing masker level and decreased with prolonging the time interval between masker and probe. For a portion of cortical neurons studied, the effects of forward suppression on the response strength to preferred stimuli was weaker than those to nonpreferred stimuli, and the recovery from forward suppression of the response strength to preferred stimuli was earlier than that to nonpreferred stimuli. We suggest that this nonuniform forward suppression of neural responses to preferred stimuli and to nonpreferred stimuli is important for cortical neurons to maintain their relative stable preferences for target sound source azimuth and level in noisy acoustic environments. PMID- 29761578 TI - Identification of the Coiled-Coil Domain as an Essential Methyl-CpG-Binding Domain Protein 3 Element for Preserving Lineage Commitment Potential of Embryonic Stem Cells. AB - Embryonic stem cells (ESCs) exhibit two salient features beneficial for regenerative medicine: unlimited self-renewal and pluripotency. Methyl-CpG binding domain protein 3 (Mbd3), a scaffolding component of the nucleosome remodeling deacetylase complex, is a specific regulator of pluripotency, as ESCs lacking Mbd3 are defective for lineage commitment potential but retain normal self-renewal properties. However, functional similarities and dissimilarities among the three Mbd3 isoforms (a, b, and c) have not been intensively explored. Herein, we demonstrated that Mbd3c, which lacks an entire portion of the MBD domain, exerted equivalent activity for counteracting the defective lineage commitment potential of Mbd3-knockout ESCs. Our analyses also revealed that the coiled-coil domain common to all three MBD3 isoforms, but not the MBD domain, plays a crucial role in this activity. Mechanistically, our data demonstrate that the activity of the coiled-coil domain is exerted, at least in part, through recruitment of polycomb repressive complex 2 to a subset of genes linked to development and organogenesis, thus establishing stable transcriptional repression. Stem Cells 2018;36:1355-1367. PMID- 29761577 TI - Polypharmacy and psychotropic drug loading in patients with schizophrenia in Asian countries: Fourth survey of Research on Asian Prescription Patterns on antipsychotics. AB - AIM: The aim of the present study was to survey the prevalence of antipsychotic polypharmacy and combined medication use across 15 Asian countries and areas in 2016. METHODS: By using the results from the fourth survey of Research on Asian Prescription Patterns on antipsychotics, the rates of polypharmacy and combined medication use in each country were analyzed. Daily medications prescribed for the treatment of inpatients or outpatients with schizophrenia, including antipsychotics, mood stabilizers, anxiolytics, hypnotics, and antiparkinson agents, were collected. Fifteen countries from Asia participated in this study. RESULTS: A total of 3744 patients' prescription forms were examined. The prescription patterns differed across these Asian countries, with the highest rate of polypharmacy noted in Vietnam (59.1%) and the lowest in Myanmar (22.0%). Furthermore, the combined use of other medications, expressed as highest and lowest rate, respectively, was as follows: mood stabilizers, China (35.0%) and Bangladesh (1.0%); antidepressants, South Korea (36.6%) and Bangladesh (0%); anxiolytics, Pakistan (55.7%) and Myanmar (8.5%); hypnotics, Japan (61.1%) and, equally, Myanmar (0%) and Sri Lanka (0%); and antiparkinson agents, Bangladesh (87.9%) and Vietnam (10.9%). The average psychotropic drug loading of all patients was 2.01 +/- 1.64, with the highest and lowest loadings noted in Japan (4.13 +/- 3.13) and Indonesia (1.16 +/- 0.68), respectively. CONCLUSION: Differences in psychiatrist training as well as the civil culture and health insurance system of each country may have contributed to the differences in these rates. The concept of drug loading can be applied to other medical fields. PMID- 29761579 TI - Latent class analysis differentiation of adjustment disorder and demoralization, more severe depressive and anxiety disorders, and somatic symptoms in patients with cancer. AB - OBJECTIVES: Demoralization as a form of existential distress involves poor coping, low morale, hopelessness, helplessness, and meaninglessness. In a secondary analysis of a cohort of German cancer patients, we aimed to explore latent class structure to assess the contribution that symptoms of demoralization make to anhedonic depression, anxiety, adjustment, and somatic disorders. METHODS: Measures of demoralization, depression, anxiety, physical symptoms, and functional impairment had been completed cross-sectionally by 1527 patients with early or advanced cancer. Latent class analysis used maximum likelihood techniques to define the unobserved latent constructs that can be predicted as symptom clusters. Individual patients were assigned to the most probable class. Classes were compared on demographics, and logistic regression assessed the odds of individual items predicting each class. RESULTS: A 4-class model provided the best fit. Class 1 (n = 829, 54.3%) was defined by the absence of distress; Classes 2 to 4 all carried functional impairment. Class 2 (n = 333, 21.8%) was differentiated by somatic symptoms (sleep, tiredness, and appetite); Class 3 (n = 163, 10.7%) by anhedonia, anxiety, and severe demoralization; and Class 4 (n = 202, 13.2%) by adjustment and moderate demoralization. Members of Class 3 were more likely to be younger, female, anhedonic, depressed, and anxious. In both Classes 3 and 4, functional impairment, physical symptom burden, and suicidal ideation were present. CONCLUSIONS: In contrast with the severe symptom cluster carrying anhedonia, anxiety, and demoralization, the moderate symptom cluster was formed by patients with demoralization and impaired functioning, a clinical picture consistent with a unidimensional model of adjustment disorder. PMID- 29761580 TI - Cross-modal restoration of ocular dominance plasticity in adult mice. AB - The temporal closure of one eye in juvenile and young adult mice induces a shift of the ocular dominance (OD) of neurons in the binocular visual cortex. However, OD plasticity typically declines with age and is completely absent in matured mice beyond postnatal day (PD) 110. As it has been shown that the deprivation of one sensory input can induce neuronal alterations in non-deprived sensory cortices, we here investigated whether cross-modal interactions have the potential to reinstall OD plasticity in matured mice. Strikingly, using intrinsic signal imaging we could demonstrate that both whisker deprivation and auditory deprivation for only one week reinstated OD plasticity in fully adult mice. These OD shifts were always mediated by an increase of V1 responsiveness to visual stimulation of the open eye, a characteristic feature of OD plasticity normally only found in young adult mice. Moreover, systemic administration of the competitive NMDA receptor antagonist CPP completely abolished cross-modally induced OD plasticity. Taken together, we demonstrate here for the first time that the deprivation of non-visual senses has the potential to rejuvenate the adult visual cortex. PMID- 29761582 TI - Blended diets for gastrostomy fed children and young people: a scoping review. AB - BACKGROUND: The present review aimed to identify what is known about the use of blended diets in gastrostomy fed children and young people (i.e. children and young people refers to those who are aged up to 25 years with special educational needs or a disability in accordance with Part 3 of the Children and Family Act 2014; within the review, the word children is used for simplicity but encompasses young people too) and to identify gaps in the literature on this topic to inform future research and policy. METHODS: A scoping review methodology was used searching the online databases PUBMED, PsychINFO, CINAHL, SCOPUS and AMED, EMBASE for articles that addressed issues pertaining to blended diets. The review identified a broad range of literature, regardless of study design, and described and evaluated the quality, range and nature of research activity related to the use of blenderised diets. RESULTS: Forty-three studies were included in the review. The studies focused on nutrition, equipment, the views of carers and patients, and the views of professionals. Several studies described the lack of evidence regarding pros and cons of blended diets and highlighted the need for further research into the field. CONCLUSIONS: There were gaps in the evidence base regarding the impact of blended diets on the health and well-being of the children who receive them and upon the carers who feed the children. The nutritional impact of blended diets is not fully understood and the knowledge and views of professionals involved in the care of those receiving blended diets varies. PMID- 29761581 TI - Congenital Zika syndrome: Pitfalls in the placental barrier. AB - Much progress with respect to congenital Zika virus (ZIKV) pathogenesis has been achieved after the 2015 outbreak in Brazil. It is now accepted that ZIKV is vertically transmitted, infects cells of the developing central nervous system and the placenta, yet it is unclear to what extent placental affection contributes to the development of congenital ZIKV. The association between fulminant villitis and severe fetal involvement emerges as a possibility. ZIKV is unique among the Flaviviruses in its ability to be sexually transmitted, possibly responsible for its teratogenicity. Furthermore, there is controversy over the participation of antibody dependent enhancement (ADE) in patients with non neutralizing anti-Flavivirus antibodies, a phenomenon previously recognized in serious DENV infections. Our aim was to analyze information regarding the contribution of the placental barrier as an actual player in neonatal ZIKV. Therefore, we underwent a systematic review with keywords "Zika virus" and "ZIKV". Articles were screened for relevance concerning the topics of microcephaly, transplacental transmission, sexual transmission, and ADE. We identified variables that affect the severity of congenital Zika syndrome: age of gestation at maternal infection, the extent of placental disruption (villitis), sexual transmission, initial viral replication at the uterine wall, anti-DENV antibodies, and the possibility of antibody-mediated transcytosis of ZIKV through the placenta. These questions may not seem relevant when Zika becomes endemic, and we are no longer witness to the extreme clinical sequelae seen when the virus moves through an immunologically naive population; however, characterizing the pathogenesis of congenital Zika syndrome will continue to further our understanding. PMID- 29761583 TI - Handwriting assessment to distinguish comorbid learning difficulties from attention deficit hyperactivity disorder in Chinese adolescents: A case-control study. AB - OBJECTIVES: Attention deficit hyperactivity disorder (ADHD) and learning difficulties (LDs) are proposed as 2 overlapping disorders. The objective of this study was to investigate the handwriting performance in ADHD and comorbid ADHD-LD adolescents. METHODS: The study examined the Chinese and English handwriting performance and sensorimotor skills of 32 ADHD, 12 ADHD-LD, and their matched controls. RESULTS: Participants with ADHD had comparable writing time and speed, but the readability was lower than their controls. Participants with ADHD-LD had lower writing speeds in both Chinese and English handwriting than their controls. The ADHD and ADHD-LD groups also showed larger variations in either speed or pen pressure than their controls. Chinese handwriting assessment effectively classified ADHD and ADHD-LD with good sensitivity and positive predictive value. CONCLUSIONS: Clinicians should be aware of the fundamental difference between the 2 disorders and make good use of handwriting assessment as a reference to deliver effective therapies and trainings. PMID- 29761584 TI - Reduction of Fibrosis and Scar Formation by Partial Reprogramming In Vivo. AB - Transient expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) to induce partial reprogramming while avoiding the pluripotent state and teratoma formation has recently been discussed as a strategy for regenerating damaged tissues in vivo, whereby the impact of partial reprogramming on tissue repair remains to be elucidated. Here, we activated OSKM transcription factors in cutaneous wounds of OSKM-inducible transgenic mice and found that induction of OSKM factors in excisional wounds caused a diminished fibroblast transdifferentiation to myofibroblasts and wound contraction. Gene expression analyses showed downregulation of the profibrotic marker genes transforming growth factor beta 1, Collagen I, and vascular endothelial growth factor. Consequently, histological analyses demonstrated that OSKM induction in incisional wounds resulted in reduced scar tissue formation. These data provide proof of concept that OSKM-mediated partial reprogramming in situ can diminish fibrosis and improve tissue healing with less scar formation without the risk of tumor formation. This new insight into the effects of partial reprogramming in vivo may be relevant for developing reprogramming-based regenerative therapies for tissue injury and fibrotic diseases. Stem Cells 2018;36:1216-1225. PMID- 29761586 TI - Preoperative predictors of occult nodal disease in cT1N0 oral cavity squamous cell carcinoma: Review of 2623 cases. AB - BACKGROUND: Nodal disease predicts survival in oral cavity squamous cell carcinoma (SCC). Currently, no large studies on predictors of occult nodal disease in cT1N0 oral cavity SCC exist. METHODS: The National Cancer Database (NCDB) review for cT1N0 oral cavity SCC with surgical resection and elective neck dissection (END). RESULTS: The number of patients found with occult nodal disease was 2623 (15.1%). In multivariable regression, female sex and tumor differentiation predict occult nodal disease. Occult nodal disease incidence was 5.9% in well-differentiated tumors, 17.4% in moderately differentiated tumors, and 28.5% in poorly differentiated tumor (P < .001). Women with oral tongue tumors had higher occult nodal disease (19.1%) than men (12%; P = .001). Adjusted odds ratios (aORs) for occult nodal disease in women were: aOR 1.26; 95% confidence interval (CI) 1.01-1.59; P = .045; moderately differentiated aOR 3.52; 95% CI 2.47-5.01; P < .001; and poorly differentiated aOR 6.25; 95% CI 4.17-9.38; P < .001. CONCLUSION: Sex and tumor differentiation significantly predict occult nodal disease. END is recommended for all moderately and poorly differentiated cT1N0 oral cavity SCC, regardless of the depth of invasion. One can consider not performing END in well-differentiated tumors. PMID- 29761587 TI - Neutrophil-to-lymphocyte ratio as a prognostic indicator in head and neck cancer: A systematic review and meta-analysis. AB - BACKGROUND: The purposes of this systematic review and meta-analysis were to investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and prognosis in head and neck cancer. METHODS: A systematic review and meta-analysis were done to investigate the role of NLR in overall survival (OS), disease specific survival (DSS), disease-free survival (DFS), and progression-free survival (PFS). RESULTS: For qualitative analysis, 33 cohorts with over 10 072 patients were included. For quantitative analysis, 15 studies were included with 5562 patients. The pooled data demonstrated that an elevated NLR significantly predicted poorer OS and DSS. CONCLUSION: An elevated pretreatment NLR is a prognostic marker for head and neck cancer. It represents a simple and easily obtained marker that could be used to stratify groups of high-risk patients who might benefit from adjuvant therapy. PMID- 29761588 TI - Infection is the chief cause of mortality and non death censored graft loss in the first year after renal transplantation in a resource limited population: a single center study. AB - BACKGROUND: Few studies have assessed the impact of infections after renal transplantation (RTX) in low and middle income countries. This single center study aimed to delineate the profile and impact of infections requiring hospitalisation (IRH) occurring in the first year after RTX in India. METHOD: Patients who underwent RTX between July 2012 and June 2015 were followed up for 12 months after transplantation. RESULTS: 60.2% of the 387 patients studied had atleast one IRH and total 492 infections were diagnosed. The most common were urinary tract (30.3%), gastrointestinal (17.1%) and pulmonary (11.2%) infections. Viral etiology (33.3%) was most frequent, followed by bacterial (23.6%), parasitic (5.1%), tuberculosis (4.5%), and fungal infections (3.9%). 86.4% deaths were due to infections. One year patient and graft survival were inferior among recipients with IRH compared to those with no IRH: 91.8% vs. 98.1 % (log rank= 0.010) and 90.1% vs. 97.4% (log rank= 0.006) respectively. Average monthly income/family member < 5000 Rupees (75 USD), NODAT, and acute rejection were independent risk factors for IRH. CONCLUSION: The profile of IRH is unique involving opportunistic, community acquired and endemic infections seen in this country. It is the predominant cause of mortality and graft loss in the first year after RTX. Poor economic status is an important determinant of IRH in our population. This article is protected by copyright. All rights reserved. PMID- 29761585 TI - Hepatitis B virus (HBV) reactivation-The potential role of direct-acting agents for hepatitis C virus (HCV). AB - Hepatitis C virus (HCV) is known to inhibit hepatitis B virus (HBV) replication in patients with HBV/HCV coinfection. Reactivation of HBV in patients treated for HCV with direct-acting agents (DAAs) has emerged recently as an important clinical consideration. A growing number of case reports and case series support the association between new HCV treatments and HBV reactivation. Yet, very little is known about the specific viral characteristics that facilitate reactivation as functional characterization of the reactivated HBV has been conducted only rarely. This review provides the most recent data on HBV reactivation in the context of DAA initiation and highlights the existing viral genomic data from reactivating viruses. Current functional studies of HBV reactivation are largely limited by the retrospective identification of cases, no standardization of genomic regions that are studied with respect to HBV reactivation, and the lack of inclusion of nonreactivating controls to establish specific viral mutations that are associated with HBV reactivation. Importantly, none of these sequencing studies included cases of HBV reactivation after initiation of DAAs. While new HCV treatments have revolutionized care for HCV infected patients, HBV reactivation will likely increase in frequency, as DAAs are more commonly prescribed. Pretreatment determination of HBV status and thoughtful management of HBV coinfections will be necessary and lead to improved patient safety and yield optimal treatment results. PMID- 29761589 TI - Prevalence and effect factors of dementia among the community elderly in Chongqing, China. AB - BACKGROUND: China is an ageing society, with around 150 million people aged 60 years or older. The prevalence of dementia will increase by more than 100% in the coming 20 years. This study aimed to investigate the prevalence and effects of dementia among the community elderly in Chongqing, China. METHODS: Cluster sampling was adopted. A sample of elderly individuals aged 60 years and older was extracted as research subjects from three counties within Chongqing, China. One on-one interviews were conducted through a general information questionnaire, and the Mini-Mental State Examination, Instrumental Activity of Daily Living Scale, and Geriatric Depression Scale were administered. The investigated data were tested by chi2 , and the effect factors of dementia were analyzed by multiple logistic regression analysis. Statistical significance was set at P < 0.05. RESULTS: We distributed 1850 questionnaire, and the response rate was 100%. However, only 1781 questionnaires were able to be used in the study. Of the 1781 elderly respondents, 186 (10.44%) presented with dementia. Our findings revealed that differences in regions, age, marital status, education level, occupation, tobacco consumption, alcohol consumption, freshwater fish consumption, exercise, intensive labour, mah-jong- and chess-playing habits, media consumption (i.e. watching TV, listening to the radio, or reading the newspaper), body mass index, hypertension, coronary heart disease, and depression were statistically significant in the prevalence of dementia (P < 0.05). CONCLUSIONS: According to multiple logistic regression analyses, living in a rural area, older age, being single, obesity, hypertension, coronary heart disease, and depression are risk factors for dementia. In contrast, cessation of smoking, freshwater fish consumption, moderate or frequent exercise, intensive labour, daily housework, outdoor activities, media consumption, and social activities are protective factors against dementia among community elderly in Chongqing, China. PMID- 29761590 TI - Interaction of antidiabetic alpha-glucosidase inhibitors and gut bacteria alpha glucosidase. AB - Carbohydrate hydrolyzing alpha-glucosidases are commonly found in microorganisms present in the human intestine microbiome. We have previously reported crystal structures of an alpha-glucosidase from the human gut bacterium Blaubia (Ruminococcus) obeum (Ro-alphaG1) and its substrate preference/specificity switch. This novel member of the GH31 family is a structural homolog of human intestinal maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) with a highly conserved active site that is predicted to be common in Ro-alphaG1 homologs among other species that colonize the human gut. In this report, we present structures of Ro-alphaG1 in complex with the antidiabetic alpha-glucosidase inhibitors voglibose, miglitol, and acarbose and supporting binding data. The in vitro binding of these antidiabetic drugs to Ro-alphaG1 suggests the potential for unintended in vivo crossreaction of the alpha-glucosidase inhibitors to bacterial alpha-glucosidases that are present in gut microorganism communities. Moreover, analysis of these drug-bound enzyme structures could benefit further antidiabetic drug development. PMID- 29761591 TI - Psychological distress in lung cancer survivors at least 1 year after diagnosis Results of a German multicenter cross-sectional study. PMID- 29761592 TI - The value of Bayes' theorem for pure likelihood clinical reasoning. PMID- 29761593 TI - Uncovering the drivers of host-associated microbiota with joint species distribution modelling. AB - In addition to the processes structuring free-living communities, host-associated microbiota are directly or indirectly shaped by the host. Therefore, microbiota data have a hierarchical structure where samples are nested under one or several variables representing host-specific factors, often spanning multiple levels of biological organization. Current statistical methods do not accommodate this hierarchical data structure and therefore cannot explicitly account for the effect of the host in structuring the microbiota. We introduce a novel extension of joint species distribution models (JSDMs) which can straightforwardly accommodate and discern between effects such as host phylogeny and traits, recorded covariates such as diet and collection site, among other ecological processes. Our proposed methodology includes powerful yet familiar outputs seen in community ecology overall, including (a) model-based ordination to visualize and quantify the main patterns in the data; (b) variance partitioning to assess how influential the included host-specific factors are in structuring the microbiota; and (c) co-occurrence networks to visualize microbe-to-microbe associations. PMID- 29761594 TI - Extracellular interleukin-17F has a protective effect in oral tongue squamous cell carcinoma. AB - BACKGROUND: Oral tongue squamous cell carcinoma (SCC) is characterized by early metastasis and poor prognosis. Interleukin-17F (IL-17F) plays a protective role in many tumors. However, IL-17F expression in oral tongue SCC tissue has not been investigated. METHODS: Immunostaining of 83 oral tongue SCC specimens and blinded scoring were used to map IL-17F expression, location, and distribution. Survival curves were constructed according to Kaplan-Meier method. The Cox proportional hazard model was applied for univariate and multivariate survival analyses. RESULTS: Mast cells are the major source of IL-17F in oral tongue SCC. In multivariate analysis, only the extracellular mast cell-derived IL-17F at the tumor invasion front was associated with better disease-specific survival in patients with all-stages and early-stages of oral tongue SCC. CONCLUSION: Extracellular mast cell-derived IL-17F is antitumorigenic in oral tongue SCC. It separates patients with early-stage disease who are at high risk from patients who are at low risk. Furthermore, when analyzing tentative prognostic molecules, we conclude that in addition to the staining intensity, attention must be paid to the cellular source, distribution, and location of the molecule. PMID- 29761595 TI - Radiomics analysis of apparent diffusion coefficient in cervical cancer: A preliminary study on histological grade evaluation. AB - BACKGROUND: The role of apparent diffusion coefficient (ADC)-based radiomics features in evaluating histopathological grade of cervical cancer is unresolved. PURPOSE: To determine if there is a difference between radiomics features derived from center-slice 2D versus whole-tumor volumetric 3D for ADC measurements in patients with cervical cancer regarding tumor histopathological grade, and systematically assess the impact of the b value on radiomics analysis in ADC quantifications. STUDY TYPE: Prospective. SUBJECTS: In all, 160 patients with histopathologically confirmed squamous cell carcinoma of uterine cervix. FIELD STRENGTH/SEQUENCE: Conventional and diffusion-weighted MR images (b values = 0, 800, 1000 s/mm2 ) were acquired on a 3.0T MR scanner. ASSESSMENT: Regions of interest (ROIs) were drawn manually along the margin of tumor on each slice, and then the center slice of the tumor was selected with naked eyes in the course of whole-tumor segmentation. A total of 624 radiomics features were derived from T2 weighted images and ADC maps. We randomly selected 50 cases and did the reproducibility analysis. STATISTICAL TESTS: Parameters were compared using Wilcoxon signed rank test, Bland-Altman analysis, t-test, and least absolute shrinkage and selection operator (LASSO) regression with crossvalidation. RESULTS: In all, 95 radiomics features were insensitive to ROI variation among T2 images, ADC map of b800, and ADC map of b1000 (P > 0.0002). There was a significant statistical difference between the performances of 2D center-slice and 3D whole-tumor radiomics models in both ADC feature sets of b800 and b1000 (P < 0.0001, P < 0.0001). Compared with ADC features of b800 (0.3758 +/- 0.0118), the model of b1000 ADC features appeared to be slightly lower in overall misclassification error (0.3642 +/- 0.0162) (P = 0.0076). DATA CONCLUSION: Several radiomics features extracted from T2 images and ADC maps were highly reproducible. Whole-tumor volumetric 3D radiomics analysis had a better performance than using the 2D center-slice of tumor in stratifying the histological grade of cervical cancer. A b value of 1000 s/mm2 is suggested as the optimal parameter in pelvic DWI scans. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 29761596 TI - The Electronic Pharmaceutical Record: A new method for medication reconciliation. AB - RATIONALE, AIM, AND OBJECTIVE: There are several ways to establish an accurate medication list in the hospital admission medication reconciliation (MedRec). The challenge for MedRec lies in the availability, reliability, and completeness of the data used. In France, the Electronic Pharmaceutical Record (ePR) was developed to register each medication taken by ambulatory patients, primarily to make dispensation in community pharmacies safe. We evaluated the suitability of this tool in the MedRec when patients were admitted to the hospital. METHOD: We conducted a 6-month pilot study of 249 MedRec files from a hospital diabetology department. The analysis was supplemented by the ePR for any patient for whom this information was recorded. The study evaluated the ePR as a new MedRec tool, as well as the clinical impact (CI) of the new data collected. RESULTS: The ePR was contributory for 28% of the patients. Discrepancies were associated with polypharmacy, most of which had a CI = 1. Medication omission was the most frequently found discrepancy (72%), but self-medication (8%) and lack of medication adherence (9%) were also observed. CONCLUSION: This tool provided added value for reconciliation, as it quickly identifies regular medications, adherence, and self-medication behaviour. The ePR is essential for conducting a thorough MedRec. PMID- 29761597 TI - The Mycobacterium tuberculosis complex has a pathway for the biosynthesis of 4 formamido-4,6-dideoxy-d-glucose. AB - Recent studies have demonstrated that the O-antigens of some pathogenic bacteria such as Brucella abortus, Francisella tularensis, and Campylobacter jejuni contain quite unusual N-formylated sugars (3-formamido-3,6-dideoxy-d-glucose or 4 formamido-4,6-dideoxy-d-glucose). Typically, four enzymes are required for the formation of such sugars: a thymidylyltransferase, a 4,6-dehydratase, a pyridoxal 5'-phosphate or PLP-dependent aminotransferase, and an N-formyltransferase. To date, there have been no published reports of N-formylated sugars associated with Mycobacterium tuberculosis. A recent investigation from our laboratories, however, has demonstrated that one gene product from M. tuberculosis, Rv3404c, functions as a sugar N-formyltransferase. Given that M. tuberculosis produces l rhamnose, both a thymidylyltransferase (Rv0334) and a 4,6-dehydratase (Rv3464) required for its formation have been identified. Thus, there is one remaining enzyme needed for the production of an N-formylated sugar in M. tuberculosis, namely a PLP-dependent aminotransferase. Here we demonstrate that the M. tuberculosis rv3402c gene encodes such an enzyme. Our data prove that M. tuberculosis contains all of the enzymatic activities required for the formation of dTDP-4-formamido-4,6-dideoxy-d-glucose. Indeed, the rv3402c gene product likely contributes to virulence or persistence during infection, though its temporal expression and location remain to be determined. PMID- 29761598 TI - The effects of enactment on communicative competence in aphasic casual conversation: a functional linguistic perspective. AB - BACKGROUND: Previous research has shown that speakers with aphasia rely on enactment more often than non-brain-damaged language users. Several studies have been conducted to explain this observed increase, demonstrating that spoken language containing enactment is easier to produce and is more engaging to the conversation partner. This paper describes the effects of the occurrence of enactment in casual conversation involving individuals with aphasia on its level of conversational assertiveness. AIMS: To evaluate whether and to what extent the occurrence of enactment in speech of individuals with aphasia contributes to its conversational assertiveness. METHODS & PROCEDURES: Conversations between a speaker with aphasia and his wife (drawn from AphasiaBank) were analysed in several steps. First, the transcripts were divided into moves, and all moves were coded according to the systemic functional linguistics (SFL) framework. Next, all moves were labelled in terms of their level of conversational assertiveness, as defined in the previous literature. Finally, all enactments were identified and their level of conversational assertiveness was compared with that of non enactments. OUTCOMES & RESULTS: Throughout their conversations, the non-brain damaged speaker was more assertive than the speaker with aphasia. However, the speaker with aphasia produced more enactments than the non-brain-damaged speaker. The moves of the speaker with aphasia containing enactment were more assertive than those without enactment. CONCLUSIONS & IMPLICATIONS: The use of enactment in the conversations under study positively affected the level of conversational assertiveness of the speaker with aphasia, a competence that is important for speakers with aphasia because it contributes to their floor time, chances to be heard seriously and degree of control over the conversation topic. PMID- 29761599 TI - Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients. AB - The BAP1-tumor predisposition syndrome (BAP1-TPDS) has been recently identified to predispose patients to a variety of cancers and preneoplastic lesions. About 130 unrelated probands have been identified worldwide; however, the impact of the syndrome is suspected to be much larger given the diversity of the cancer phenotype. To evaluate the frequency of germline BAP1 mutations in the general and cancer populations, we analyzed the Exome Aggregation Consortium (ExAC), a database that contains 53105 exomes of unrelated individuals unaffected by cancer (general population) and exomes of 7601 unrelated individuals affected by cancer provided by the Cancer Genome Atlas (TCGA, cancer subjects). BAP1 null variants were seen at much higher frequency in the cancer subjects (0.0526%) compared to the general population (0.00188%) with a relative risk of 27.93 and (P = 0.0011, [95% CI: 3.122-249.883], Fisher's exact test). We also studied a reported BAP1 null variant, c.1203T > G, p.T401* (rs200156887), observed commonly in the general population. Sequencing and restriction fragment polymorphism of the RT-4 cell line that contains this variant revealed that it is in fact a 3bp deletion/insertion, c.1201_1203delinsGAG, a likely benign missense alteration p.Y401E explaining the relative high frequency of this variant in the general population. In conclusion, germline null mutations in BAP1 have a significantly higher frequency in cancer patients than the general population. Given the low frequency of reported families with BAP1-TPDS, our results suggest that the syndrome is underreported especially in patients with cancer. PMID- 29761601 TI - Postnatal development of cholinergic input to the thalamic reticular nucleus of the mouse. AB - The thalamic reticular nucleus (TRN), a shell-like structure comprised of GABAergic neurons, gates signal transmission between thalamus and cortex. While TRN is innervated by axon collaterals of thalamocortical and corticothalamic neurons, other ascending projections modulate activity during different behavioral states such as attention, arousal, and sleep-wake cycles. One of the largest arise from cholinergic neurons of the basal forebrain and brainstem. Despite its integral role, little is known about how or when cholinergic innervation and synapse formation occurs. We utilized genetically modified mice, which selectively express fluorescent protein and/or channelrhodopsin-2 in cholinergic neurons, to visualize and stimulate cholinergic afferents in the developing TRN. Cholinergic innervation of TRN follows a ventral-to-dorsal progression, with nonvisual sensory sectors receiving input during week 1, and the visual sector during week 2. By week 3, the density of cholinergic fibers increases throughout TRN and forms a reticular profile. Functional patterns of connectivity between cholinergic fibers and TRN neurons progress in a similar manner, with weak excitatory nicotinic responses appearing in nonvisual sectors near the end of week 1. By week 2, excitatory responses become more prevalent and arise in the visual sector. Between weeks 3-4, inhibitory muscarinic responses emerge, and responses become biphasic, exhibiting a fast excitatory, and a long lasting inhibitory component. Overall, the development of cholinergic projections in TRN follows a similar plan as the rest of sensory thalamus, with innervation of nonvisual structures preceding visual ones, and well after the establishment of circuits conveying sensory information from the periphery to the cortex. PMID- 29761600 TI - Loss of Angiotensin-Converting Enzyme 2 Exacerbates Diabetic Retinopathy by Promoting Bone Marrow Dysfunction. AB - Angiotensin-converting enzyme 2 (ACE2) is the primary enzyme of the vasoprotective axis of the renin angiotensin system (RAS). We tested the hypothesis that loss of ACE2 would exacerbate diabetic retinopathy by promoting bone marrow dysfunction. ACE2-/y were crossed with Akita mice, a model of type 1 diabetes. When comparing the bone marrow of the ACE2-/y -Akita mice to that of Akita mice, we observed a reduction of both short-term and long-term repopulating hematopoietic stem cells, a shift of hematopoiesis toward myelopoiesis, and an impairment of lineage- c-kit+ hematopoietic stem/progenitor cell (HS/PC) migration and proliferation. Migratory and proliferative dysfunction of these cells was corrected by exposure to angiotensin-1-7 (Ang-1-7), the protective peptide generated by ACE2. Over the duration of diabetes examined, ACE2 deficiency led to progressive reduction in electrical responses assessed by electroretinography and to increases in neural infarcts observed by fundus photography. Compared with Akita mice, ACE2-/y -Akita at 9-months of diabetes showed an increased number of acellular capillaries indicative of more severe diabetic retinopathy. In diabetic and control human subjects, CD34+ cells, a key bone marrow HS/PC population, were assessed for changes in mRNA levels for MAS, the receptor for Ang-1-7. Levels were highest in CD34+ cells from diabetics without retinopathy. Higher serum Ang-1-7 levels predicted protection from development of retinopathy in diabetics. Treatment with Ang-1-7 or alamandine restored the impaired migration function of CD34+ cells from subjects with retinopathy. These data support that activation of the protective RAS within HS/PCs may represents a therapeutic strategy for prevention of diabetic retinopathy. Stem Cells 2018;36:1430-1440. PMID- 29761602 TI - Vacuole membrane protein 1 marks endoplasmic reticulum subdomains enriched in phospholipid synthesizing enzymes and is required for phosphoinositide distribution. AB - The multispanning membrane protein vacuole membrane protein 1 (VMP1) marks and regulates endoplasmic reticulum (ER)-domains associated with diverse ER-organelle membrane contact sites. A proportion of these domains associate with endosomes during their maturation and remodeling. We found that these VMP1 domains are enriched in choline/ethanolamine phosphotransferase and phosphatidylinositol synthase (PIS1), 2 ER enzymes required for the synthesis of various phospholipids. Interestingly, the lack of VMP1 impairs the formation of PIS1 enriched ER domains, suggesting a role in the distribution of phosphoinositides. In fact, depletion of VMP1 alters the distribution of PtdIns4P and proteins involved in the trafficking of PtdIns4P. Consistently, in these conditions, defects were observed in endosome trafficking and maturation as well as in Golgi morphology. We propose that VMP1 regulates the formation of ER domains enriched in lipid synthesizing enzymes. These domains might be necessary for efficient distribution of PtdIns4P and perhaps other lipid species. These findings, along with previous reports that involved VMP1 in regulating PtdIns3P during autophagy, expand the role of VMP1 in lipid trafficking and explain the pleiotropic effects observed in VMP1-deficient mammalian cells and other model systems. PMID- 29761603 TI - A "Sticky" Mucin-Inspired DNA-Polysaccharide Binder for Silicon and Silicon Graphite Blended Anodes in Lithium-Ion Batteries. AB - New binder concepts have lately demonstrated improvements in the cycle life of high-capacity silicon anodes. Those binder designs adopt adhesive functional groups to enhance affinity with silicon particles and 3D network conformation to secure electrode integrity. However, homogeneous distribution of silicon particles in the presence of a substantial volumetric content of carbonaceous components (i.e., conductive agent, graphite, etc.) is still difficult to achieve while the binder maintains its desired 3D network. Inspired by mucin, the amphiphilic macromolecular lubricant, secreted on the hydrophobic surface of gastrointestine to interface aqueous serous fluid, here, a renatured DNA-alginate amphiphilic binder for silicon and silicon-graphite blended electrodes is reported. Mimicking mucin's structure comprised of a hydrophobic protein backbone and hydrophilic oligosaccharide branches, the renatured DNA-alginate binder offers amphiphilicity from both components, along with a 3D fractal network structure. The DNA-alginate binder facilitates homogeneous distribution of electrode components in the electrode as well as its enhanced adhesion onto a current collector, leading to improved cyclability in both silicon and silicon graphite blended electrodes. PMID- 29761604 TI - Remaining hepatocellular carcinoma risk in chronic hepatitis B patients receiving entecavir/tenofovir in South Korea. AB - AIM: We aimed to identify the incidence rate of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with entecavir or tenofovir in South Korea, and to identify predictors of HCC development in these patients. METHODS: Between January 2007 and December 2015, 582 CHB patients initially received entecavir (n = 406, 69.8%) or tenofovir (n = 176, 30.2%) for CHB. RESULTS: During a median follow-up of 57.1 months, HCC developed in 38 (6.5%) of the 582 patients, regardless of antiviral agent type. Entecavir- and tenofovir-treated patients had similar HCC development rates (P = 0.471). For the 582 patients, 2-, 4-, and 6-year cumulative HCC development rates were 2.6%, 4.4%, and 8.3%, respectively, and the 2-, 4-, and 6-year cumulative HCC development rates of patients with liver cirrhosis were significantly greater than those of patients without liver cirrhosis (6.2%, 9.8%, and 18.4% vs. 0.3%, 1.1%, and 2.2%, respectively; P < 0.001). Older (>=60 years) patients, regardless of the presence of cirrhosis, and cirrhotic patients aged >=40 years showed significantly higher risk of HCC development compared to others (both P < 0.05). Multivariate analysis showed that an older age (>=50 years; hazard ratio [HR] 5.02, P = 0.009), and the presence of cirrhosis (HR 4.95, P = 0.002) independently predicted HCC development. CONCLUSIONS: The 6-year cumulative HCC development rate was 6.5% in CHB patients treated with entecavir or tenofovir. Age >=50 years and liver cirrhosis were found to predict HCC development in these patients. PMID- 29761605 TI - Solitary femoral metastasis in a locoregionally controlled laryngeal carcinoma. PMID- 29761606 TI - Euthanasia and surgeons: an overview of the Victorian Voluntary Assisted Dying Act 2017 and its relevance to surgical practice in Australia. AB - Surgeons play a significant role in the treatment of patients with many types of cancer, including the management of advanced and recurrent disease after long periods of apparent remission. The recently introduced Victorian Voluntary Assisted Dying (VAD) Act represents a shift in paradigm in Australian medical practice. To be eligible for VAD, the new legislation requires patient assessment by a physician with at least 5 years post-fellowship experience and relevant expertise in the patient's condition. Given many specialist surgeons' experience in managing advanced and often incurable malignancy, it is likely that many will receive referrals for assessment for VAD. It is foreseeable that other states and territories in Australia will follow suit with similar legislation. It is imperative that surgeons receiving referrals to assess patients seeking access to VAD are familiar with the legislation and assessment process. This article summarizes the current regulation of VAD in Australia, including the patient application and assessment process, briefly reviews world-wide assisted dying practices and discusses the relevance to surgeons practicing in Australia. PMID- 29761607 TI - Epidemiology and phylogenetic analysis of hepatitis D virus infection in Australia. AB - BACKGROUND: The incidence and trends of the hepatitis D virus (HDV) in Australia have not been recently assessed, and the circulating genotypes have never been determined. AIM: To characterise the current virology and epidemiology of HDV. METHODS: Notifiable disease surveillance and laboratory testing data were analysed to assess demographics, risk factors and trends. HDV serology and RNA testing were performed on requested samples from 2010 to 2016. Sequencing of a 500-nucleotide amplicon of the delta antigen and phylogenetic analysis of the strains from 2009 to 2016 were also conducted. RESULTS: Ninety HDV notifications were reported to the Victorian Department of Health and Human Services between 2010 and 2016. The majority (64.4%) of those diagnosed were born overseas, most commonly in Sudan, Pakistan and Vietnam. Over the same period, 190 patients tested positive for anti-HDV serology and 166 for HDV RNA. Sequencing of isolates from 169 individuals between 2009 and 2016 found that 80.5% strains were genotype 1, 16% genotype 5 and 3.5% genotype 2. Phylogenetic analysis confirmed the relatedness of strains from birth country, demonstrated the presence of the 'Pacific Island' genotype 1 strain in Queensland and supported possible transmission in correctional facilities and within families. CONCLUSIONS: This study demonstrates the ongoing need for routine HDV screening and engagement in clinical care for people living with HBV in Australia. Epidemiological findings highlight the diversity in those affected and provide insights into local and global geographic distribution and transmission patterns. PMID- 29761608 TI - Effect of renal denervation on coronary flow reserve in patients with resistant hypertension. AB - Renal denervation (RDN) is a potential modality in the treatment of patients with resistant hypertension (RH) and has shown beneficial effect on a variety of cardiovascular surrogate markers. Coronary flow reserve, as assessed by transthoracic Doppler echocardiography (TDE-CFR) is impaired in patients with hypertension and is an independent predictor of cardiac morbidity. However, data on the effect of RDN on TDE-CFR are scarce. The main objective of this study was to assess the effect of RDN on TDE-CFR. Twenty-six consecutive patients with RH (9 female and 17 male; mean age 62 +/- 8 years; mean number of antihypertensive drugs 4.2 +/- 1.6) underwent bilateral RDN. CFR was assessed at baseline and 6 months after intervention. Mean flow velocity was measured in the left anterior descending artery by transthoracic Doppler echocardiography at baseline and during adenosine infusion (TDE-CFR). Systolic office blood pressure was reduced at follow-up (174 +/- 24 versus 162 +/- 27 mmHG; P = 0.01). Mean systolic ambulatory blood pressure decreased from 151 +/- 21 to 147 +/- 18 (P = 0.17). TDE CFR remained unchanged 6 months after intervention (2.7 +/- 0.6 versus 2.7 +/- 0.7; P = 0.67). In conclusion, renal denervation was not associated with any changes in regard to coronary flow reserve at 6-month follow-up. PMID- 29761609 TI - Rb3 VO(O2 )2 CO3 : A Four-in-One Carbonatoperoxovanadate Exhibiting an Extremely Strong Second-Harmonic Generation Response. AB - A nonlinear optical (NLO) carbonatoperoxovanadate, Rb3 VO(O2 )2 CO3 , was synthesized through a simple solution-evaporation method in phase-pure form. Single-crystal X-ray diffraction revealed that the structure of Rb3 VO(O2 )2 CO3 consists of important noncentrosymmetric (NCS) chromophores, that is, pi delocalized (CO3 )2- groups, a second-order Jahn-Teller (SOJT) distortive V5+ cation, and pi-localized distorted O22- groups, as well as charge-balancing polarizable Rb+ ions. The powder second-harmonic generation (SHG) measurements indicated that Rb3 VO(O2 )2 CO3 is phase-matchable (Type I) and exhibits a remarkably strong SHG response circa 21.0 times that of potassium dihydrogen phosphate (KDP), which is the largest efficiency observed among carbonate NLO materials. First-principles calculation analysis suggests that the extremely large SHG response of Rb3 VO(O2 )2 CO3 is attributed to the synergistic effect of the cooperation of all the constituting NCS chromophores. PMID- 29761611 TI - Multidisciplinary team meetings appear to be effective in inflammatory bowel disease management: an audit of process and outcomes. AB - BACKGROUND: Multidisciplinary team meetings (MDTM) have proven efficacy in cancer management. Whilst widely implemented in inflammatory bowel disease (IBD) care, their value is yet to be investigated. We reviewed the performance of MDTM for IBD patients. METHODS: Retrospective review of MDTM from March 2013 to July 2016. Each patient's first MDTM was considered. Data collected included: report production and location, disease factors, recommendation(s), implementation and barriers to implementation. The MDTM process was considered successful when at least top-level recommendations were implemented within 6 months. RESULTS: MDTM attendance included an IBD gastroenterologist, surgeons, a radiologist, nurses, dieticians, psychologists and clinical trial staff. Initial MDTM encounters of 166 patients were reviewed: 86 females, mean age 40 years, 140 (84.3%) with Crohn disease and mean disease duration of 10.8 years (interquartile range 15 years). Electronic reports were filed for all patients, with hard copies in 84%. In 151 of 166 episodes, all (n = 127) or top-line (n = 24) recommendations were implemented, although there was a delay beyond 6 months in 5. Of 146 patients with a successful MDTM, 85 (58.2%) were in clinical remission at last review (median follow up: 27 months). Amongst patients with unsuccessful MDTM (n = 13), only two (15.4%) were in clinical remission at follow up. Barriers to implementation included patients declining recommendations and loss to follow up. CONCLUSION: The majority of MDTM encounters were successful from both a process and clinical outcome perspective. System opportunities to improve the process include ensuring that 100% of reports are available and addressing implementation delays. Patient factors that require addressing include improved engagement and understanding reasons for declining recommendations. PMID- 29761612 TI - Acute radiotherapy toxicity in 57 dogs with gross and microscopic mast cell tumours. AB - Mast cell tumours (MCTs) are commonly treated with radiation therapy, most often in a microscopic disease setting. Poorer outcomes are expected in patients with gross disease, and irradiation of gross disease may be associated with greater toxicity. The aim of this study was to compare acute radiation adverse events (AE) in dogs with gross and microscopic MCTs receiving radiotherapy. Fifty-seven dogs were included, 28 with gross disease and 29 with microscopic. In order to assess mucosal and skin toxicity, patients were assigned to 2 groups: head (29 patients, 14 patients with gross and 15 microscopic) and other sites (28 patients, 14 each). All were treated with external beam radiotherapy, and toxicity assessed at the end of treatment and 10 to 14 days later (first recheck). All patients developed some acute radiation toxicity by the end of the course. However, there was no difference in the severity of toxicity between gross and microscopic disease in either site group at either time point. The only variable associated with an increased frequency of grade 2 or 3 toxicity at the first recheck was the use of prednisolone prior to radiotherapy (P = .05). No other factors were identified which were associated with increased toxicity. For the head group, the site of highest grade toxicity was mucosa or, if included in the field, nasal planum, which was often more severely affected than the mucosa. No significant late toxicity was identified. Two dogs developed acute haematemesis during the radiotherapy course, but both completed the course without further events. PMID- 29761610 TI - Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories. AB - Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis. PMID- 29761613 TI - From Isolated Ions to Multilayer Functional Materials Using Ion Soft Landing. AB - The ability to deposit intact polyatomic ions with well-defined composition, charge state, and kinetic energy onto surfaces makes preparative mass spectrometry, also called ion soft landing, particularly attractive for preparing uniform molecular and ionic layers. Early studies characterized the structures, charge states, and reactivity of sparsely distributed soft-landed species. The recent development of high-flux ionization sources has opened up new opportunities for the precisely controlled preparation of both two-dimensional structures and three-dimensional multilayer architectures by ion soft landing. The deposition of large numbers of ions onto supports led to previously unknown phenomena being uncovered, thereby opening several exciting research directions. Furthermore, faster ion deposition has enabled fabrication of novel functional devices. This Review discusses important phenomena and highlights key developments pertaining to the preparation of well-defined interfaces for studies in energy storage, catalysis, soft materials, and biology. PMID- 29761614 TI - Diagnostic value of nailfold videocapillaroscopy in systemic sclerosis secondary pulmonary arterial hypertension: a meta-analysis. AB - BACKGROUND: Microvascular changes play a decisive role in systemic sclerosis (SSc) and occur early in the course of the disease. Pulmonary arterial hypertension (PAH) represents one of the main clinical expressions of the vascular changes in SSc, and the abnormal changes, especially capillary density and capillary width, are detectable at nailfold videocapillaroscopy (NVC). AIMS: To investigate the differences in capillary nailfold changes in SSc patients with and without PAH and to estimate the early diagnostic value of NVC in SSc secondary PAH (SSc-PAH). METHODS: A comprehensive literature search of MEDLINE and PUBMED was performed to identify published studies without language restrictions. The methodological quality of the included studies was evaluated. The pooled specificity, sensitivity, positive likelihood rate, negative likelihood rate, diagnostic odds ratio, area under the curve and Q value were found using Meta-Disc version 1.4 software packages. Finally, seven studies were included in this meta-analysis. RESULTS: The meta-analysis demonstrated that the diagnostic odds ratio, area under the curve and Q value were 5.84 (95% confidence interval: 1.95-17.54), 0.79 and 0.72 respectively. It indicated that the microvascular changes detected at NVC were significant in SSc-PAH and especially showed significantly lower capillary density and higher capillary width. CONCLUSION: The NVC may be a valuable tool for the early diagnosis of SSc-PAH. It can detect the early microvascular changes associated with the risk of PAH and has a significant role in the early prediction of SSc-PAH. PMID- 29761615 TI - Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 2 diabetes: A randomized, open-label clinical trial. AB - AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla) and Lantus (Sa-Gla) in people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This Phase 3, randomized, active-controlled, open-label, 24-week clinical trial (ClinicalTrials.gov number NCT02059187) enrolled 531 participants with T2DM (HbA1c <=11.0%) either eligible for or currently taking basal insulin (>=10 U/day). Participants were randomized 1:1 to once-daily Mk-Gla (n = 263) or Sa-Gla (n = 263). Titration of insulin was guided by a fasting plasma glucose (FPG)-based dosing algorithm. The primary efficacy objective was to demonstrate the non-inferiority of change from baseline in HbA1c (margin of 0.40% [4.4 mmol/mol]) with Mk-Gla versus Sa-Gla after 24 weeks. The primary safety objective was anti-insulin antibody development after 24 weeks. RESULTS: For Mk-Gla and Sa Gla, the least squares (LS) mean HbA1c change from baseline (95% CI) was -1.28 ( 1.41, -1.15)% (-14.0 [-15.4, -12.6] mmol/mol) and -1.30 (-1.43, -1.18)% (-14.2 [ 15.6, -12.8] mmol/mol). The LS mean HbA1c difference (Mk-Gla minus Sa-Gla) was 0.03 (-0.12, 0.18)% (0.3 [-1.4, 1.9] mmol/mol), meeting non-inferiority and equivalence (secondary objective) criteria. Insulin doses, FPG, and seven-point plasma glucose profiles were similar between groups. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins. The efficacy and safety of Mk-Gla and Sa Gla were similar both in participants who were insulin-treated or insulin-naive at baseline. CONCLUSIONS: Mk-Gla and Sa-Gla demonstrated similar efficacy and safety over 24 weeks of treatment in people with T2DM. PMID- 29761616 TI - Aerobic Oxidation of 5-(Hydroxymethyl)furfural Cyclic Acetal Enables Selective Furan-2,5-dicarboxylic Acid Formation with CeO2 -Supported Gold Catalyst. AB - The utilization of 5-(hydroxymethyl)furfural (HMF) for the large-scale production of essential chemicals has been largely limited by the formation of solid humin as a byproduct, which prevents the operation of stepwise batch-type and continuous flow-type processes. The reaction of HMF with 1,3-propanediol produces an HMF acetal derivative that exhibits excellent thermal stability. Aerobic oxidation of the HMF acetal with a CeO2 -supported Au catalyst and Na2 CO3 in water gives a 90-95 % yield of furan 2,5-dicarboxylic acid, an increasingly important commodity chemical for the biorenewables industry, from concentrated solutions (10-20 wt %) without humin formation. The six-membered acetal ring suppresses thermal decomposition and self-polymerization of HMF in concentrated solutions. Kinetic studies supported by DFT calculations identify two crucial steps in the reaction mechanism, that is, the partial hydrolysis of the acetal into 5-formyl-2-furan carboxylic acid involving OH- and Lewis acid sites on CeO2 , and subsequent oxidative dehydrogenation of the in situ generated hemiacetal involving Au nanoparticles. These results represent a significant advance over the current state of the art, overcoming an inherent limitation of the oxidation of HMF to an important monomer for biopolymer production. PMID- 29761617 TI - Efficient Visible-Light-Driven CO2 Reduction Mediated by Defect-Engineered BiOBr Atomic Layers. AB - Solar CO2 reduction efficiency is largely limited by poor photoabsorption, sluggish electron-hole separation, and a high CO2 activation barrier. Defect engineering was employed to optimize these crucial processes. As a prototype, BiOBr atomic layers were fabricated and abundant oxygen vacancies were deliberately created on their surfaces. X-ray absorption near-edge structure and electron paramagnetic resonance spectra confirm the formation of oxygen vacancies. Theoretical calculations reveal the creation of new defect levels resulting from the oxygen vacancies, which extends the photoresponse into the visible-light region. The charge delocalization around the oxygen vacancies contributes to CO2 conversion into COOH* intermediate, which was confirmed by in situ Fourier-transform infrared spectroscopy. Surface photovoltage spectra and time-resolved fluorescence emission decay spectra indicate that the introduced oxygen vacancies promote the separation of carriers. As a result, the oxygen deficient BiOBr atomic layers achieve visible-light-driven CO2 reduction with a CO formation rate of 87.4 MUmol g-1 h-1 , which was not only 20 and 24 times higher than that of BiOBr atomic layers and bulk BiOBr, respectively, but also outperformed most previously reported single photocatalysts under comparable conditions. PMID- 29761618 TI - Robot-assisted total hip arthroplasty: Clinical outcomes and complication rate. AB - BACKGROUND: The purpose of this study was to report minimum 2-year outcomes and complications for robotic-arm-assisted total hip arthroplasty (THA). METHODS: Data were prospectively collected and retrospectively reviewed between June 2011 and April 2014. Inclusion criteria were primary robotic-arm-assisted THAs treating idiopathic osteoarthritis with >= 2-year follow-up. Demographics, operating time, complications, 2-year outcome scores and satisfaction, and subsequent surgeries were recorded. RESULTS: There were 181 cases eligible for inclusion, of which 162 (89.5%) had minimum 2-year follow-up. At the latest follow-up, the mean visual analogue scale was 0.7, satisfaction was 9.3, Harris hip score was 91.1 and forgotten joint score was 83.1. Six (3.7%) intraoperative complications and six (3.7%) postoperative complications were reported. No leg length discrepancies (LLDs) or dislocations were reported. CONCLUSIONS: Robotic arm-assisted THA demonstrates favourable short-term outcomes and does not result in a higher complication rate compared to non-robotic THA as reported by the literature. PMID- 29761620 TI - Polyserositis: a diagnostic challenge. AB - BACKGROUND: Polyserositis (PS) is the inflammation, with effusion, of different serous membranes. It has been associated with different aetiologies, but the aetiology of PS remains unknown in a high percentage of patients. AIMS: The general objective of this retrospective study was to analyse the aetiology of PS cases seen at Son Llatzer Hospital in an 11-year period. Other objectives were to determine the epidemiological, clinical and analytical characteristics of these patients. METHODS: An observational, descriptive and retrospective study to analyse the aetiology of PS cases seen at Son Llatzer Hospital. The inflammation of two or more serous membranes confirmed by an imaging test was required and at least one of the serous fluid should be an exudate. RESULTS: A total of 92 patients was included in the study. The most common diagnosis was neoplasm (nearly one-third of cases) followed by infectious and autoimmune diseases. PS aetiology was unknown in more than one-third. Pleura and pericardium were the most common sites of serosal involvement (83%). Antinuclear antibodies' positivity in serum and increased levels of adenosine deaminase in pleural effusion were significantly associated with a final diagnosis of autoimmune disease. Increased pleural lactate dehydrogenase levels were significantly associated with a final diagnosis of neoplasm. In 9 of 14 patients with a previous cancer, PS represented a recurrence of their cancer. Cases of unknown aetiology presented most frequently as pleural and pericardial involvement, and the majority resolved. In very few patients, an infectious aetiology could be proven. CONCLUSION: PS is a frequent clinical entity that is associated with different diseases and its diagnosis could be challenging, with a high rate of unknown aetiologies. PMID- 29761619 TI - Changes in diabetes medication regimens and glycemic control in adolescents and young adults with youth-onset type 2 diabetes: The SEARCH for diabetes in youth study. AB - OBJECTIVE: The aim of this study was to describe recent medication patterns and changes in medication patterns and glycemic control in adolescents and young adults with incident type 2 diabetes (T2D). METHODS: Using data from the SEARCH for Diabetes in Youth Study, we conducted a cross-sectional analysis of treatments for adolescents and young adults with incident T2D in 2 periods (2002 2005 vs 2008/2012), and a longitudinal analysis of medications and glycemic control for a subset with baseline and follow-up visits. Comparisons were performed using chi2 , Fisher's exact, or ANOVA. RESULTS: Of 646 individuals in the cross-sectional analysis, a majority in each period received metformin (64.9% vs 70.4%) and/or insulin (38.1% vs 38.4%), while fewer used sulfonylureas (5.6% vs 3.6%) with non-significant changes over time. There was a significant reduction in thiazolidinedione use (5.0% vs 2.0%, P < .05). In the longitudinal analysis, 322 participants were followed for 7 years, on average. Baseline metformin users had a lower A1C (6.4% [46.7 mmol/mol]) compared to insulin (8.4% [68.2 mmol/mol], P < .001) or insulin plus any oral diabetes medication (ODM) users (7.7% [60.4 mmol/mol], P < .001). Among baseline metformin users (n = 138), 29.7% reported metformin at follow-up, with the remainder adding (19.6%) or switching to insulin (8.0%), ODM (15.9%), or lifestyle only (26.8%). Of those receiving insulin (+/-ODM) (n = 129), 76% reported insulin use at follow-up. Overall, 35% were at A1C goal (<7.0%, 53 mmol/mol) at follow-up. CONCLUSIONS: Youth-onset T2D is still largely being treated with metformin and/or insulin. The majority treated were not at American Diabetes Association (ADA)-recommended goal 7 years after diagnosis. PMID- 29761621 TI - Identification of driver and subclonal mutations in ASXL1 and IDH1/IDH2 genes in an Argentine series of patients with myelofibrosis. PMID- 29761622 TI - Host heme oxygenase-1: Friend or foe in tackling pathogens? AB - Infectious diseases are a major challenge in management of human health worldwide. Recent literature suggests that host immune system could be modulated to ameliorate the pathogenesis of infectious disease. Heme oxygenase (HMOX1) is a key regulator of cellular signaling and it could be modulated using pharmacological reagents. HMOX1 is a cytoprotective enzyme that degrades heme to generate carbon monoxide (CO), biliverdin, and molecular iron. CO and biliverdin (or bilirubin derived from it) can restrict the growth of a few pathogens. Both of these also induce antioxidant pathways and anti-inflammatory pathways. On the other hand, molecular iron can induce proinflammatory pathway besides making the cellular environment oxidative in nature. Since microbial infections often induce oxidative stress in host cells/tissues, role of HMOX1 has been analyzed in the pathogenesis of number of infections. In this review, we have described the role of HMOX1 in pathogenesis of bacterial infections caused by Mycobacterium species, Salmonella and in microbial sepsis. We have also provided a succinct overview of the role of HMOX1 in parasitic infections such as malaria and leishmaniasis. In the end, we have also elaborated the role of HMOX1 in viral infections such as AIDS, hepatitis, dengue, and influenza. (c) 2018 IUBMB Life, 70(9):869-880, 2018. PMID- 29761623 TI - Effects of biochar amendment on sorption, dissipation, and uptake of fenamiphos and cadusafos nematicides in sandy soil. AB - BACKGROUND: The application of biochar to soil is supposed to alter its adsorption/desorption potential toward pesticides, thereby affecting their bioavailability and efficacy. This is particularly relevant in the case of nematicides because these pesticides are directly applied to soil. RESULTS: Biochar was produced from date palm (PB) and eucalyptus (EB) waste at 450 degrees C and added at a rate of 1% to a sandy soil. The half-life (t1/2 ) of fenamiphos was increased from 2.7 to 18.3 and 18.6 days in PB- and EB-amended soils, respectively. By contrast, the half-life of cadusafos was unaffected. Freundlich Kf values increased from 1.22 and 0.39 (MUg1-Nf g-1 mLNf ) to 4.49 and 6.84 in 1% PB-amended soil, and to 3.49 and 4.62 in 1% EB-amended soil for cadusafos and fenamiphos, respectively. Plant uptake of both nematicides in tomato seedlings was reduced by approximately 97% (cadusafos) and 85% (fenamiphos). Although nematicide efficacy against Meloidogyne incognita was not altered at the recommended dosage, it was negatively affected at a half-dose rate. Under these conditions, it decreased from 43.1% in unamended sandy soil to only 18.3% in 1% PB-amended soil. CONCLUSIONS: Biochar addition increased the sorption capacity of soil. This resulted in a decrease of nematicide bioavailability, together with a reduction of both the dissipation rate and uptake by tomato plants. (c) 2018 Society of Chemical Industry. PMID- 29761624 TI - Quantification of 89 Zr-Iron oxide nanoparticle biodistribution using PET-MR and ultrashort TE sequences. PMID- 29761625 TI - Beam focal spot position determination for an Elekta linac with the Agility(r) head; practical guide with a ready-to-go procedure. AB - A novel phantomless, EPID-based method of measuring the beam focal spot offset of a linear accelerator was proposed and validated for Varian machines. In this method, one set of jaws and the MLC were utilized to form a symmetric field and then a 180o collimator rotation was utilized to determine the radiation isocenter defined by the jaws and the MLC, respectively. The difference between these two isocentres is directly correlated with the beam focal spot offset of the linear accelerator. In the current work, the method has been considered for Elekta linacs. An Elekta linac with the Agility(r) head does not have two set of jaws, therefore, a modified method is presented making use of one set of diaphragms, the MLC and a full 360o collimator rotation. The modified method has been tested on two Elekta Synergy(r) linacs with Agility(r) heads and independently validated. A practical guide with instructions and a MATLAB(r) code is attached for easy implementation. PMID- 29761626 TI - Photo-Induced Polymerization and Reconfigurable Assembly of Multifunctional Ferrocene-Tyrosine. AB - The photo-induced reconfigurable assembly of nanostructures via the simultaneous noncovalent and covalent polymerization of a functional ferrocene-tyrosine (Fc-Y) molecule is reported. The Fc-Y monomers can directly self-assemble into nanospheres with a smooth surface driven by noncovalent interactions. By covalent photo-crosslinking of the Fc-Y monomers, the nanospheres transform spontaneously into hollow vesicles composed of hierarchically ordered lamellar structures. It is worth noting that the formed nanostructures exhibit both reducing property for in situ mineralization of gold nanoparticles with tunable biocatalytic behavior, and the redox activity for superior energy storage capacity. The measured energy storage capacity is 31 mAh g-1 for the nanospheres, which is the highest value reported so far for peptide assemblages as supercapacitor. The results offer insights into the dynamic self-assembly of highly ordered multifunctional materials with promising applications in catalysis, sensing, energy and biomedical fields. PMID- 29761627 TI - Muscle fiber type diversity revealed by anti-myosin heavy chain antibodies. AB - Different forms of myosin heavy chains (MyHCs), coded by a large family of sarcomeric MYH genes, are expressed in striated muscles. The generation of specific anti-MyHC antibodies has provided a powerful tool to define the fiber types present in skeletal muscles, their functional properties, their response to conditions that affect muscle plasticity and their changes in muscle disorders. Cardiomyocyte heterogeneity has been revealed by the serendipitous observation that different MyHCs are present in atrial and ventricular myocardium and in heart conduction tissue. Developmental MyHCs present in embryonic and fetal/neonatal skeletal muscle are re-expressed during muscle regeneration and can be used to identify regenerating fibers in muscle diseases. MyHC isoforms provide cell type-specific markers to identify the signaling pathways that control muscle cell identity and are an essential reference to interpret the results of single-cell transcriptomics and proteomics. PMID- 29761628 TI - Recent advances for identification of new scaffolds and drug targets for Mycobacterium tuberculosis. AB - Tuberculosis (TB) is a leading cause of mortality and morbidity with an estimated 1.7 billion people latently infected with the pathogen worldwide. Clinically, TB infection presents itself as an asymptomatic infection, which gradually manifests to life threatening disease. The emergence of various drug resistant strains of Mycobacterium tuberculosis and lengthy duration of chemotherapy are major challenges in the field of TB drug development. Hence, there is an urgent need to develop scaffolds that possess a novel mechanism of action, can shorten the duration of therapy, and are active against both drug resistant and susceptible strains. In this review, we will discuss recent progress made in the field of TB drug development with emphasis on screening methods and drug targets from M. tuberculosis. The current review provides insights into mechanism of action of new scaffolds that are being evaluated in various stages of clinical trials. (c) 2018 IUBMB Life, 70(9):905-916, 2018. PMID- 29761629 TI - Simultaneous Local Heating/Thermometry Based on Plasmonic Magnetochromic Nanoheaters. AB - A crucial challenge in nanotherapies is achieving accurate and real-time control of the therapeutic action, which is particularly relevant in local thermal therapies to minimize healthy tissue damage and necrotic cell deaths. Here, a nanoheater/thermometry concept is presented based on magnetoplasmonic (Co/Au or Fe/Au) nanodomes that merge exceptionally efficient plasmonic heating and simultaneous highly sensitive detection of the temperature variations. The temperature detection is based on precise optical monitoring of the magnetic induced rotation of the nanodomes in solution. It is shown that the phase lag between the optical signal and the driving magnetic field can be used to detect viscosity variations around the nanodomes with unprecedented accuracy (detection limit 0.0016 mPa s, i.e., 60-fold smaller than state-of-the-art plasmonic nanorheometers). This feature is exploited to monitor the viscosity reduction induced by optical heating in real-time, even in highly inhomogeneous cell dispersions. The magnetochromic nanoheater/thermometers show higher optical stability, much higher heating efficiency and similar temperature detection limits (0.05 degrees C) compared to state-of-the art luminescent nanothermometers. The technological interest is also boosted by the simpler and lower cost temperature detection system, and the cost effectiveness and scalability of the nanofabrication process, thereby highlighting the biomedical potential of this nanotechnology. PMID- 29761630 TI - Specifying the Dimensions of Aquatic Life Benchmark Values in Clear, Complete, and Justified Problem Formulations. AB - Nations that develop water quality benchmark values have relied primarily on standard data and methods. However, experience with chemicals such as Se, ammonia, and tributyltin has shown that standard methods do not adequately address some taxa, modes of exposure, and effects. Development of benchmark values that are protective requires an explicit description of the issues, a problem formulation. In particular, the assessment endpoints and other dimensions should be specified for each chemical so that the necessary data will be obtained and appropriate analyses will be performed. Assessment endpoints specify the entity and attribute to be protected. In addition, the level of protection, including the magnitude of effect and the proportion effected, is specified. Magnitude and proportion are included because they are used to calculate the benchmark concentration. If uncertainty is considered in the benchmark, the proportion of the uncertainty distribution that is protected should be specified. Because effects are related to the duration of exposure and time for recovery, temporal dimensions should be specified. Clearly described exposure metrics are also needed because the relevant exposure parameter is not always total aqueous concentration. Finally, the benchmark may be applicable to particular geographic or climatological areas, water chemistries, taxa, or habitat types. Considering and justifying all the dimensions is likely to result in protective and more easily communicated benchmarks. Integr Environ Assess Manag 2018;14:631-638. Published 2018. This article is a US Government work and is in the public domain in the USA. PMID- 29761631 TI - Recent Progress in Some Amorphous Materials for Supercapacitors. AB - A breakthrough in technologies having "green" and sustainable energy storage conversion is urgent, and supercapacitors play a crucial role in this area of research. Owing to their unique porous structure, amorphous materials are considered one of the best active materials for high-performance supercapacitors due to their high specific capacity, excellent cycling stability, and fast charging rate. This Review summarizes the synthesis of amorphous materials (transition metal oxides, carbon-based materials, transition metal sulfides, phosphates, hydroxides, and their complexes) to highlight their electrochemical performance in supercapacitors. PMID- 29761632 TI - Coping strategies in individuals at ultra-high risk of psychosis: A systematic review. AB - AIM: The impact of dysfunctional coping strategies during the prodromal phase of psychosis has recently been explored by several studies. What has yet to be clarified is whether maladaptive coping is evident in the prodromal phase and the impact that this might have on symptomatic and functional outcomes. The aim of this study was to review the findings on coping in individuals at ultra-high risk of psychosis (UHR) in relation to symptoms and level of functioning. METHODS: Original articles were identified by searching 7 databases using the terms "prodrom*," "ultra high risk," "clinical high risk," "at-risk mental state," "coping style*," "coping strategies," "cope," "coping" and "psychosis". We included original articles that: (1) reported a measure of coping and (2) evaluated UHR individuals. RESULTS: A total of 9 original articles of 335 that examined coping in individuals at high risk of psychosis were included. UHR subjects were more likely to use maladaptive coping strategies than healthy controls and were more likely to use emotion-focussed than task-oriented coping. Maladaptive coping was associated with higher levels of negative symptoms, whereas positive coping was associated with fewer negative symptoms. The coping style employed by UHR individuals was found to negatively influence their psychosocial functioning. CONCLUSIONS: It is still unclear whether coping heightens or reduces the likelihood of transition to psychosis in relation to other factors, including environment. Longitudinal studies could clarify whether coping styles remain stable after the onset of psychosis or whether the emerging psychotic symptoms influence the coping strategies. PMID- 29761633 TI - Verification of the qLabs international normalized ratio point-of-care device for monitoring of patients attending an anticoagulation clinic. AB - INTRODUCTION: In the developing world, point-of-care (POC) testing for international normalized ratio (INR) plays an important role in the monitoring of patients on long-term warfarin therapy with limited access to healthcare ensuring safe and effective anticoagulation. A newly developed POC device for INR measurement by healthcare workers is the handheld qLabs POC device(r) (Micropoint Biotechnologies Incorporated, Guangdong, China). METHODS: The qLabs POC device(r) was evaluated in 262 patients attending an anticoagulation clinic with regards to accuracy and precision of the INR results. The results were compared to the results obtained on the Stago STA R Max(r) coagulation analyzer (Stago Diagnostica, Paris, France) on a wide range of normal and abnormal results of clinical relevance. RESULTS: The mean laboratory INR (2.50 +/- 1.08) was significantly higher than the qLabs POC device(r) INR (2.38 +/- 1.07) (P < .0001). The correlation coefficient (r) was .88, the slope coefficient was 1.0 (CI, 0.8-1.2), and the intercept was -0.10 (CI, -0.50 to 0.30). The mean of the differences was -0.13% (CI, -0.19 to -0.06). Dosage concordance was 85.46% and clinical agreement was 92.37%. However, clinical agreement was 42.42% in the subgroup above the target range (>3.5). The imprecision was within acceptable limits (<5%) and the error message rate was 4.38%. CONCLUSION: In conclusion, the qLabs POC device(r) is accurate and precise with high levels of dosage concordance and clinical agreement for INR values within and below the target range. PMID- 29761635 TI - Monitoring Based on Narrow-Band Resonance Raman for "Phase-Shifting" pi Conjugated Polydiacetylene Vesicles upon Host-Guest Interaction and Thermal Stimuli. AB - The present study reports a quantified monitoring by means of in situ resonance Raman scattering that analyzes phase-shifting characteristics of pi-systems upon interacting with target analytes. A chemo- and thermochromic polydiacetylene vesicular probe is evaluated with multiple-wavelength Raman scattering modes in resonance with its phases, respectively, and thus can trace the phase-shifts. This Raman scattering-based analytical quantification is also successful in monitoring host-guest recognition events by utilizing much narrower bands, compared to those in conventional absorption or photoluminescence (PL) methods. As one of the outcomes, the monitoring analysis overcomes the limitations based on widely used colorimetric response (%CR) or PL that failed in the case of interaction with a surfactant, CTAB. PMID- 29761636 TI - Physical activity and parents of very young children: The role of beliefs and social-cognitive factors. AB - OBJECTIVES: Despite the unequivocal benefits of regular physical activity, many parents engage in lower levels of physical activity (PA) following the birth of a child. Drawing on the theory of planned behaviour (TPB) and health action process approach (HAPA), an integrative model was developed to examine variables predicting PA in parents of very young children. In addition, key beliefs related to PA intentions and behaviour among parents of very young children were investigated. DESIGN: A prospective-correlational design with two waves of data collection, spaced one week apart, was adopted. METHODS: Parents (N = 297) completed an online- or paper-based questionnaire assessing TPB global constructs and belief-based items as well as family social support and planning from the HAPA. One week later, parents self-reported their PA behaviour. Data were analysed using latent variable structural equation modelling. RESULTS: Findings revealed the model was a good fit to the data, accounting for 62% and 27% of the variance in PA intentions and behaviour, respectively. Attitude, subjective norm, and perceived behavioural control predicted intentions. Family social support failed to predict both planning and intentions. Physical activity was predicted by planning only, with an indirect effect occurring from intentions to behaviour through planning. A number of key beliefs on intentions and behaviour were also identified. CONCLUSIONS: This formative research provides further understanding of the factors that influence the PA behaviour of parents of very young children. Results provide targets for future interventions to increase PA for parents in a transition phase where PA levels decline. Statement of Contribution What is already known on this subject? Despite physical activity benefits, many parents are inactive following the birth of a child Social-cognitive models have demonstrated efficacy in predicting physical activity Weaknesses are inherent in the use of single theories to explain behaviour What does this study add? Use of integrative models allows for meaningful prediction of parental physical activity A range of key beliefs were found to be related to parental physical activity Results can inform future physical activity interventions for parents of very young children. PMID- 29761634 TI - Extracephalic manifestations of nonchromosomal, nonsyndromic holoprosencephaly. AB - Nonchromosomal, nonsyndromic holoprosencephaly (NCNS-HPE) has traditionally been considered as a condition of brain and craniofacial maldevelopment. In this review, we present the results of a comprehensive literature search supporting a wide spectrum of extracephalic manifestations identified in patients with NCNS HPE. These manifestations have been described in case reports and in large cohorts of patients with "single-gene" mutations, suggesting that the NCNS-HPE phenotype can be more complex than traditionally thought. Likely, a complex network of interacting genetic variants and environmental factors is responsible for these systemic abnormalities that deviate from the usual brain and craniofacial findings in NCNS-HPE. In addition to the systemic consequences of pituitary dysfunction (as a direct result of brain midline defects), here we describe a number of extracephalic findings of NCNS-HPE affecting various organ systems. It is our goal to provide a guide of extracephalic features for clinicians given the important clinical implications of these manifestations for the management and care of patients with HPE and their mutation-positive relatives. The health risks associated with some manifestations (e.g., fatty liver disease) may have historically been neglected in affected families. PMID- 29761638 TI - Ultrasound-Guided Neurolysis of Six Genicular Nerves for Intractable Pain from Knee Osteoarthritis: A Case Series. AB - INTRODUCTION: Among the elderly population, chronic osteoarthritis of the knee joint is one of the leading causes of disability and causes considerable pain, joint stiffness, and functional limitations. Although knee replacement is a good option for advanced osteoarthritis, many patients could not undergo surgery due to comorbidities or other reasons. METHODS: Four patients with severe pain from grade 3 and 4 osteoarthritis of the knee had undergone ultrasound-guided alcohol neurolysis of the 6 genicular nerves after a positive genicular nerve block with local anesthetics. The demographics, pain intensity (NRS), Oxford Knee Score (OKS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and quality of life (SF-36) were analyzed. RESULTS: There was significant improvement in pain intensity at rest, on movement, and on weight bearing after the neurolysis and it has continued for 6 months (P < 0.05). The OKS and WOMAC score had improved from 7.75 +/- 1.25 and 77.75 +/- 4.34 at baseline, to 20.75 +/ 1.70 and 56.25 +/- 3.09 at 1 month, and to 18.25 +/- 0.95 and 52.00 +/- 2.16 at 6 months after the procedure, respectively (P < 0.05). There was also significant improvement in the quality of life after the procedure (P < 0.05). CONCLUSION: Ultrasound-guided alcohol neurolysis is a good alternative for patients having severe pain from knee osteoarthritis and provides significant pain relief for more than 6 months. PMID- 29761639 TI - Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature. AB - Holoprosencephaly (HPE) is a major structural birth defect of the brain that occurs in approximately 1 in 10,000 live births. Although some genetic causes of HPE are known, a substantial proportion of cases have an unknown etiology. Due to the low birth prevalence and rarity of exposure to many potential risk factors for HPE, few epidemiologic studies have had sufficient sample size to examine risk factors. A 2010 review of the literature identified several risk factors that had been consistently identified as occurring more frequently among cases of HPE, including maternal diabetes, twinning, and a predominance of females, while also identifying a number of potential risk factors that had been less widely studied. In this article, we summarize a systematic literature review conducted to update the evidence for nongenetic risk factors for HPE. PMID- 29761640 TI - Influence of collagen-based integrin alpha1 and alpha2 mediated signaling on human mesenchymal stem cell osteogenesis in three dimensional contexts. AB - Collagen I interactions with integrins alpha1 and alpha2 are known to support human mesenchymal stem cell (hMSC) osteogenesis. Nonetheless, elucidating the relative impact of specific integrin interactions has proven challenging, in part due to the complexity of native collagen. In the present work, we employed two collagen-mimetic proteins-Scl2-2 and Scl2-3- to compare the osteogenic effects of integrin alpha1 versus alpha2 signaling. Scl2-2 and Scl2-3 were both derived from Scl2-1, a triple helical protein lacking known cell adhesion, cytokine binding, and matrix metalloproteinase sites. However, Scl2-2 and Scl2-3 were each engineered to display distinct collagen-based cell adhesion motifs: GFPGER (binding integrins alpha1 and alpha2 ) or GFPGEN (binding only integrin alpha1 ), respectively. hMSCs were cultured within poly(ethylene glycol) (PEG) hydrogels containing either Scl2-2 or Scl2-3 for 2 weeks. PEG-Scl2-2 gels were associated with increased hMSC osterix expression, osteopontin production, and calcium deposition relative to PEG-Scl2-3 gels. These data indicate that integrin alpha2 signaling may have an increased osteogenic effect relative to integrin alpha1 . Since p38 is activated by integrin alpha2 but not by integrin alpha1 , hMSCs were further cultured in PEG-Scl2-2 hydrogels in the presence of a p38 inhibitor. Results suggest that p38 activity may play a key role in collagen-supported hMSC osteogenesis. This knowledge can be used toward the rational design of scaffolds which intrinsically promote hMSC osteogenesis. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2594-2604, 2018. PMID- 29761637 TI - Using gas mixtures of CO, CO2 and H2 as microbial substrates: the do's and don'ts of successful technology transfer from laboratory to production scale. AB - The reduction of CO2 emissions is a global effort which is not only supported by the society and politicians but also by the industry. Chemical producers worldwide follow the strategic goal to reduce CO2 emissions by replacing existing fossil-based production routes with sustainable alternatives. The smart use of CO and CO2 /H2 mixtures even allows to produce important chemical building blocks consuming the said gases as substrates in carboxydotrophic fermentations with acetogenic bacteria. However, existing industrial infrastructure and market demands impose constraints on microbes, bioprocesses and products that require careful consideration to ensure technical and economic success. The mini review provides scientific and industrial facets finally to enable the successful implementation of gas fermentation technologies in the industrial scale. PMID- 29761641 TI - Ultra high performance liquid chromatography with tandem mass spectrometry method for determining dinotefuran and its main metabolites in samples of plants, animal derived foods, soil, and water. AB - An ultra high-performance liquid chromatography with tandem triple quadrupole mass spectrometry residue method was developed and validated for the quantification and identification of dinotefuran and its main metabolites 1 methyl-3-(tetrahydro-3-furylmethyl) urea and 1-methyl-3-(tetrahydro-3 furylmethyl) guanidine in fruit (watermelon), vegetable (cucumber), cereal (rice), animal-derived foods (milk, egg, and pork), soil, and water. The samples were extracted with acetonitrile containing 15% v/v acetic acid and purified with dispersive solid-phase extraction with octadecylsilane, primary secondary amine, graphitized carbon black, or zirconia-coated silica prior to analysis. The method had an excellent linearity (R2 >= 0.9942, 1-500 MUg/L) and satisfactory recoveries (73-102%) at five spiked levels (0.001, 0.01, 0.05, 0.5, and 2 mg/kg) with intra- or interday precision in the range of 0.8-9.5% and 3.0-12.8% for the three compounds in the eight matrices. The limits of quantification were 10 MUg/kg for 1-methyl-3-(tetrahydro-3-furylmethyl) guanidine and 1 MUg/kg for 1 methyl-3-(tetrahydro-3-furylmethyl) urea and dinotefuran. The applicability of the developed method was demonstrated by determining the occurrence of dinotefuran, 1-methyl-3-(tetrahydro-3-furylmethyl) guanidine, and 1-methyl-3 (tetrahydro-3-furylmethyl) urea in various samples from plants, animal-derived foods, and the environment. From 80 samples, 70 contained dinotefuran (0.8-11.7 MUg/kg), among which six also contained 1-methyl-3-(tetrahydro-3-furylmethyl) urea (water and rice, 0.5-0.9 MUg/kg). PMID- 29761642 TI - Immunological blocking of spermidine-mediated host-pathogen communication provides effective control against Pseudomonas aeruginosa infection. AB - Pseudomonas aeruginosa is known to cause life-threatening infections. The previous studies showed that the type III secretion system (T3SS) of this pathogen is a key virulence determinant, which is activated by polyamines signals spermidine (Spd) and spermine (Spm) from mammalian host. To test the potential of blocking host-pathogen communication in disease control, in this study we developed a high potency mouse monoclonal antibody (Mab 4E4, IgG1 sub-isotype) by using Spm-protein conjugate as an immunogen. Antibody specificity analysis showed that the antibody specifically recognize Spd and Spm. In vitro study showed the antibody significantly protected A549 cells against P. aeruginosa infection, and this protection was achieved by blocking polyamine uptake and downregulating T3SS expression. In vivo single injection of mouse with Mab 4E4 drastically reduced the serum polyamine level, which was maintained for more than 1 week. In a murine model of P. aeruginosa acute infection, injection of Mab 4E4 protected mice from lung injury and significantly improved the survival rate of mice. PMID- 29761643 TI - Fluorescent 2D WS2 Nanosheets Bearing Chemical Affinity Elements for the Recognition of Glycated Hemoglobin. AB - It is required to exfoliate and functionalize 2D transition metal dichalcogenides (TMDs) in an aqueous solution for biological and medical applications. Herein, the approach for the simultaneous exfoliation and functionalization of 2D WS2 nanosheets using boronic acid-modified poly(vinyl alcohol) (B-PVA) in an aqueous solution is reported, and the B-PVA-functionalized WS2 nanosheets (B-PVA-WS2 ) are exploited as a fluorescent biosensor for the detection of glycated hemoglobin, HbA1c. The synthetic B-PVA polymer facilitates the exfoliation and functionalization of WS2 nanosheets from the bulk counterpart in the aqueous solution via a pulsed sonication process, resulting in fluorescent B-PVA-WS2 nanohybrids with a specific recognition of HbA1c. The fluorescence of the B-PVA WS2 is quenched in the presence of HbA1c, whereas PVA-functionalized WS2 (PVA-WS2 ), not bearing boronic acid as a recognition moiety, shows no fluorescence changes upon the addition of the target. The B-PVA-WS2 is able to selectively detect HbA1c at the concentration as low as 3.3 * 10-8 m based on its specific fluorescence quenching. PMID- 29761644 TI - Impact of Stoichiometry on the Structure of van der Waals Layered GeTe/Sb2 Te3 Superlattices Used in Interfacial Phase-Change Memory (iPCM) Devices. AB - Van der Waals layered GeTe/Sb2 Te3 superlattices (SLs) have demonstrated outstanding performances for use in resistive memories in so-called interfacial phase-change memory (iPCM) devices. GeTe/Sb2 Te3 SLs are made by periodically stacking ultrathin GeTe and Sb2 Te3 crystalline layers. The mechanism of the resistance change in iPCM devices is still highly debated. Recent experimental studies on SLs grown by molecular beam epitaxy or pulsed laser deposition indicate that the local structure does not correspond to any of the previously proposed structural models. Here, a new insight is given into the complex structure of prototypical GeTe/Sb2 Te3 SLs deposited by magnetron sputtering, which is the used industrial technique for SL growth in iPCM devices. X-ray diffraction analysis shows that the structural quality of the SL depends critically on its stoichiometry. Moreover, high-angle annular dark-field-scanning transmission electron microscopy analysis of the local atomic order in a perfectly stoichiometric SL reveals the absence of GeTe layers, and that Ge atoms intermix with Sb atoms in, for instance, Ge2 Sb2 Te5 blocks. This result shows that an alternative structural model is required to explain the origin of the electrical contrast and the nature of the resistive switching mechanism observed in iPCM devices. PMID- 29761645 TI - Redox-guided small molecule antimycobacterials. AB - The emergence of drug resistance has posed a major challenge to treatment of tuberculosis worldwide. The new drug candidates in the pipeline are few and therefore there is an urgent need to develop antimycobacterials with novel mechanisms of action. Maintenance of redox homeostasis is integral to mycobacterial survival and growth. Therefore, perturbation of this equilibrium can result in irreversible stress induction and inhibition of growth. Herein, we review a number of small molecules that have either been designed to induce redox stress or were found to do so after their discovery. A number of these small molecules are quite effective against drug-resistant mycobacterial strains and thus offer scope for exploration of potentially new mechanism of action. The progress in redox-guided antimycobacterial compounds and the challenges towards clinical applications are reviewed. (c) 2018 IUBMB Life, 70(9):826-835, 2018. PMID- 29761646 TI - Hydroxychloroquine fails to attenuate lesion development in a mouse model of neuromyelitis optica. PMID- 29761647 TI - Four polymorphisms in the IL-22 gene and the risk of cancer: A meta-analysis. AB - OBJECTIVE: IL-22 plays an important role in cancer carcinogenesis. However, the association between IL-22 polymorphisms and cancer risk was inconclusive. The objective of the current study was to assess these associations by meta-analysis. METHODS: PubMed, EMbase, CNKI, VIP, and Wanfang databases were searched up to 31 January 2018. The results were screened according to the inclusion and exclusion criteria. The associations between polymorphisms and cancer risk were estimated by meta-analysis. All analyses were performed using the Revman5.3 software. RESULTS: A total of four polymorphisms (rs2227485, rs1179251, rs1179246, and rs1182844) in seven studies were included. The results of meta-analysis indicated that the rs1179251 polymorphism [OR = 1.46, 95% CI (1.17, 1.82), P = 0.0008 for GG+GC vs. CC] was associated with increased risk of cancer, while the rs2227485, rs1179246, and rs1182844 polymorphisms were not associated with cancer risk. CONCLUSIONS: The current meta-analysis suggests that IL-22 gene rs1179251 polymorphism may be a risk factor for cancer. PMID- 29761648 TI - Poly(beta-amino ester)-co-poly(caprolactone) Terpolymers as Nonviral Vectors for mRNA Delivery In Vitro and In Vivo. AB - The production of new proteins with messenger RNA (mRNA) has gained a broad interest due to its potential for addressing a wide range of diseases. Here, the design and characterization of novel ionizable poly(beta-amino ester)-co poly(caprolactone) terpolymers, synthesized via the combination of the ring opening polymerization and the Michael step-growth polymerization, are reported. The versatility of this method is demonstrated by varying the number of caprolactone units attached to each poly(beta-amino ester) (PBAE) terpolymer. The ability of the novel poly-caprolactone (PCL)-based PBAE materials to deliver mRNA is shown to depend on the physiochemical characteristics of the material, such as lipophilicity, as well as the formulation method used to complex the polymer with the oligonucleotide. This latter variable represents a previously unstudied aspect of PBAE library screens that can play an important role in identifying true top candidates for nucleic acid delivery. The most stable terpolymer is injected intravenously (IV) in mice and shows a transfection efficacy several times higher than the polyethylenimine (PEI) which is focused in the spleen, opening the possibility to use these biodegradable carriers in the intravenous delivery of antigen-encoding mRNA for cancer immunotherapy and vaccination. PMID- 29761649 TI - Polyphenol-Poloxamer Self-Assembled Supramolecular Nanoparticles for Tumor NIRF/PET Imaging. AB - Self-assembled supramolecular nanoparticles have remarkable benefits in bioimaging and drug delivery. Here it is first reported that polyphenol and poloxamer self-assemble supramolecular nanoparticles (PPNPs). PPNPs are fabricated by multivalent hydrogen bonding between tannic acid and Pluronic F-127 together with hydrophobic interactions of poly(propylene oxide) chains, to be applied in tumor near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) imaging. With near-infrared fluorescent dyes such as IR780 encapsulated via hydrophobic interactions, PPNPs are used in NIRF imaging. PPNPs with excess phenolic hydroxyl groups chelating positron emitting radionuclide 89 Zr function as a PET contrast agent. The in vivo results show surprisingly higher fluorescence intensity in tumors than in other tissues. In addition, PPNPs exhibit good biocompatibility in various cell lines and do not induce hemolysis in vitro. In this study, it is demonstrated that biodegradable and biocompatible PPNPs are an excellent bimodal contrast agent for in vivo tumor imaging. PMID- 29761650 TI - In vitro and in vivo efficacy of a live attenuated Salmonella Typhimurium vaccine at preventing intestinal colonization in chicks. AB - Vaccination of chicks with Salmonella (S.) Typhimurium aroA deletion mutants has previously been shown to inhibit intestinal colonization of wild-type S. Typhimurium strains. In Australia, Bioproperties VaxSafeTM STM1 strain is the only licensed and commercially available S. Typhimurium vaccine. This vaccine is a live attenuated aroA deletion mutant. Currently, it is recommended that the first dose of the STM1 vaccine is administered through coarse spray. It is unclear whether this mode of administration effectively permits intestinal colonization. Furthermore, it is not known whether the STM1 strain prevents or inhibits Salmonella colonization of chicks following this first dose. This study investigated both in vitro and in vivo colonization parameters. Invasiveness was assessed using an in vitro invasion assay into sections of ileum and caecum collected from day-old chicks. The S. Typhimurium definitive types (DT) 9 and 44 exhibited the greatest invasion into both intestinal segments. STM1 was invasive but was significantly less so than both isolates of S. Typhimurium. In dual and triple infections, no competitive microbial interactions between STM1 and wild type Salmonella were observed. In vivo colonization inhibition was also tested. Vaccinated and nonvaccinated day-old chicks were challenged with S. Typhimurium DT9. Both STM1 and S. Typhimurium DT9 were found in spleen, liver, ileum, caecum and caecal contents from day 2 postinfection. No significant exclusion effect was observed in vaccinated and challenged chicks. PMID- 29761651 TI - MRpi: Inside the meat pie. AB - Meat pies have been adopted as one of Australia's favourite foods, and considered an icon by many. The hand-held convenience of the pie has made them a culinary necessity while watching sport, also beloved in Australia. An enduring question about the meat pie is what exactly is inside. This can be difficult to ascertain by digital, ocular or oral exploration. In this study we use MR imaging to study the contents of some of Australia's best loved pies. PMID- 29761652 TI - Vitamin D status and associated genetic polymorphisms in a cohort of UK children with non-alcoholic fatty liver disease. AB - BACKGROUND: Vitamin D deficiency has been associated with non-alcoholic fatty liver disease (NAFLD). However, the role of polymorphisms determining vitamin D status remains unknown. OBJECTIVES: The objectives of this study were to determine in UK children with biopsy-proven NAFLD (i) their vitamin D status throughout a 12-month period and (ii) interactions between key vitamin D-related genetic variants (nicotinamide adenine dinucleotide synthase-1/dehydrocholesterol reductase-7, vitamin D receptor, group-specific component, CYP2R1) and disease severity. METHODS: In 103 paediatric patients with NAFLD, serum 25-hydroxyvitamin D (25OHD) levels and genotypes were determined contemporaneously to liver biopsy and examined in relation to NAFLD activity score and fibrosis stage. RESULTS: Only 19.2% of children had adequate vitamin D status; most had mean 25OHD levels considered deficient (<25 nmol.L-1 , 25.5%) or insufficient (<50 nmol.L-1 , 55.3%). Patients had significantly lower 25OHD levels in winter months (95% CI: 22.7-31.2 nmol.L-1 ) when compared with spring (30.5-42.1 nmol.L-1 ; P = 0.0089), summer (36.3-47.2 nmol.L-1 ; P < 0.0001) and autumn (34.2-47.5 nmol.L-1 ; P = 0.0003). Polymorphisms in the nicotinamide adenine dinucleotide synthase 1/dehydrocholesterol reductase-7 (rs3829251, rs12785878) and vitamin D receptor (rs2228570) genes were independently associated with increased steatosis; while a group-specific component variant (rs4588) was associated with increased inflammation in liver biopsies. CONCLUSIONS: Children with NAFLD in the UK have particularly low winter vitamin D status, with vitamin D insufficiency prevalent throughout the year. Polymorphisms in the vitamin D metabolic pathway are associated with histological severity of paediatric NAFLD. PMID- 29761653 TI - Detection of porcine circovirus-like virus P1 in Hebei, China. AB - Porcine circovirus-like virus P1 is a novel unclassified circovirus that was first detected in China and may be associated with post-weaning multisystemic wasting syndrome (PMWS) and congenital tremor. In this study, we detected P1 infection in pigs in Hebei Province, China, in 2017. One hundred and forty of 500 (28.0%) serum samples from 25 pig farms with different PMWS status in seven cities were P1 positive on PCR. Twelve P1 strains were sequenced, and the complete genomes of 11 P1 strains were 648 nucleotides (nt) in length, whereas that of strain ZJK02 was 647 nt, with a G deletion at position of 183 in its genome. The complete genomic and capsid protein sequences of the 12 P1 strains analysed in this study shared 98.8%-100.0% and 86.5%-100.0% identity, respectively. A phylogenetic analysis based on the complete genomic and capsid sequences of 26 P1 strains showed that the 12 P1 sequences from Hebei Province clustered on two small branches. Further studies of the evolution and pathogenesis of P1 are required. PMID- 29761655 TI - Fennel induces cytotoxic effects against testicular germ cells in mice; evidences for suppressed pre-implantation embryo development. AB - Foeniculum vulgare (FVE; fennel) is an aromatic plant belonging to Umbelliferae family, which is widely used in traditional societies because of its different pharmaceutical properties. To uncover the fennel-derived essential oil (FVEO) induced effects on male reproductive potential, 24 mature male albino mice were divided into, control, 0.37, 0.75, and 1.5 mg kg-1 FVEO-received groups. Following 35 days, the animals were euthanized and the testicular tissue and sperm samples were collected. The histological alterations, tubular differentiation (TDI), spermiogenesis (SPI) indices, apoptosis ratio, and RNA damage of germinal cells were analyzed. Moreover, the sperm count, motility, viability, chromatin condensation, and DNA fragmentation were assessed. Finally, the pre-implantation embryo development including; the percentage of zygote, 2 cell embryos and blastocysts were assessed. Observations showed that the FVEO, dose dependently, increased histological damages, resulted in germ cells dissociation, depletion, nuclear shrinkage and significantly (P < .05) decreased tubular differentiation and spermiogenesis ratios. Moreover, the FVEO-received animals (more significantly in 1.5 mg kg-1 -received group) exhibited decreased sperm count, viability, and motility and represented enhanced percentage of sperms with decondensed chromatin and DNA fragmentation. Finally, the animals in FVEO-received group showed diminished zygote formation and represented decreased pre-implantation embryo development compared to control animals. In conclusion, our data showed that, FVEO albeit at higher doses, is able to adversely affect cellular DNA and RNA contents, which in turn is able to negatively affect the sperm count and morphology. All these impairments are able to negatively affect the fertilization potential as well as pre-implantation embryo development. PMID- 29761654 TI - Low-load resistance exercise during inactivity is associated with greater fibre area and satellite cell expression in older skeletal muscle. AB - BACKGROUND: Age-related sarcopenia is accelerated by physical inactivity. Low load resistance exercise (LLRE) counters inactivity-induced muscle atrophy in older adults, but changes in muscle fibre morphology are unstudied. We aimed to determine the impact of LLRE during short-term inactivity (step-reduction) on muscle fibre size and capillarity as well as satellite cell (SC) content in older skeletal muscle. METHODS: Fourteen older (~71 years) male adults underwent 14 days of step reduction (<1500 steps/day) while performing six sessions of LLRE (~30% maximal strength) with one leg (SR + EX) while the contralateral leg served as an untrained control (SR). Seven healthy ambulatory age-matched male adults (~69 years) served as a comparator group (COM). Muscle biopsies were taken from the vastus lateralis after 14 days, and immunohistochemical analysis was performed to determine muscle fibre cross-sectional area (CSA), myonuclear content, SC content (PAX7+ cells), and total (C:F) and fibre type-specific (C:Fi) capillary-to-fibre ratios. RESULTS: Type I and II fibre CSA was greater in SR + EX compared with SR. Whereas there were no differences across fibre types between SR + EX and CON, type II fibre CSA was significantly lower in SR compared with COM. Type II myonuclear domain was greater in SR + EX compared with COM and SR. Pax7+ cells associated with type I and II fibres were lower in SR compared with SR + EX. Type II PAX7+ cells were also lower in SR compared with COM with a similar trend for type I fibres. There were trends for a lower C:Fi in SR compared with SR + EX for both fibre types with no differences for each compared with COM. CONCLUSIONS: Minimal LLRE during a period of decreased physical activity is associated with greater muscle fibre CSA, SC content, and capillarization. These results support the use of LLRE as an effective countermeasure to inactivity-induced alterations in muscle morphology with age. PMID- 29761656 TI - A Two-Step Process for the Synthesis of Hydroxytyrosol. AB - A new process for the synthesis of hydroxytyrosol (3,4-dihydroxyphenylethanol), the most powerful natural antioxidant currently known, by means of a two-step approach is reported. Catechol is first reacted with 2,2-dimethoxyacetaldehyde in basic aqueous medium to produce the corresponding mandelic derivative with >90 % conversion of the limiting reactant and about 70 % selectivity to the desired para-hydroxyalkylated compound. Thereafter, the intermediate is hydrogenated to hydroxytyrosol by using a Pd/C catalyst, with total conversion of the mandelic derivative and 68 % selectivity. This two-step process is the first example of a synthetic pathway for hydroxytyrosol that does not involve the use of halogenated components or reduction methodologies that produce stoichiometric waste. It also avoids the complex procedure currently used for hydroxytyrosol purification when it is extracted from wastewater of olive oil production. PMID- 29761657 TI - Nesting environment may drive variation in eggshell structure and egg characteristics in the Testudinata. AB - Testudines exhibit considerable variation in the degree of eggshell calcification, which affects eggshell conductance, water physiology of the embryos, and calcium metabolism of embryos. However, the underlying reason for different shell types has not been explored. Phylogenetically controlled analyses examined relationships between egg size, shell mass, and clutch size in ~200 turtle species from a range of body sizes and assigned by family as laying either rigid- or pliable-shelled eggs. Shell type affected egg breadth relative to pelvic dimensions, egg mass, and relative shell mass but did not affect size, mass, or total shell mass of the clutch. These results suggest that calcium availability may be a function of body size and the type of shell may reflect in part the interplay between clutch size and egg size. It was further concluded that the eggshell probably evolved as a means of physical protection. Differences in shell calcification may not primarily reflect reproductive parameters but rather correlate with the acidity of a species' nesting environment. Low pH environments may have thicker calcareous layer to counteract the erosion caused by the soil and maintain the integrity of the physical barrier. Limited calcium availability may constrain clutch size. More neutral nesting substrates expose eggshells to less erosion so calcification per egg can be reduced and this allows larger clutch sizes. This pattern is also reflected in thick, calcified crocodilian eggs. Further research is needed to test whether eggshell calcification in the testudines correlates with nest pH in order to verify this relationship. PMID- 29761658 TI - Carbeniophosphines versus Phosphoniocarbenes: The Role of the Positive Charge. AB - The chemistry of carbeniophosphines and phosphoniocarbenes, which have general structures derived formally from the three-component "carbene/phosphine/positive charge" association, is presented. These two complementary classes of carbon phosphorus-based ligands, defined by the presence of an inverted cationic coordinating structure (C+ ~P: vs. P+ ~C:) have the common purpose of positioning a positive charge in the vicinity of the metal center. Through selected examples, the synthetic methods, coordination properties, and general reactivity of both cationic species is described. Particular emphasis is placed on the influence of the positive charge on the respective chemical behavior of the two classes of compound. PMID- 29761659 TI - Ruthenium Supported on High-Surface-Area Zirconia as an Efficient Catalyst for the Base-Free Oxidation of 5-Hydroxymethylfurfural to 2,5-Furandicarboxylic Acid. AB - Several ZrO2 -supported ruthenium catalysts were prepared and utilized in the oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) under base-free conditions. Full conversion of HMF and almost perfect selectivity towards FDCA (97 %) were achieved after 16 h by using pure O2 as an oxidant and water as a solvent. The catalytic tests show that the size of the Ru particles is crucial for the catalytic performance and that the utilization of high-surface area ZrO2 leads to formation of very small Ru particles. Superior activity was obtained for catalysts based on ZrO2 that had been synthesized by a surface casting method and has high surface areas up to 256 m2 g-1 . In addition to good activity and selectivity, these catalysts show also high stability and constant activity upon recycling, confirming the suitability of Ru/ZrO2 in the base-free oxidation of HMF. PMID- 29761661 TI - How Do We "Validate" a QSP Model? PMID- 29761660 TI - Feasibility of re-biopsy and EGFR mutation analysis in patients with non-small cell lung cancer. AB - BACKGROUND: In cases of EGFR-tyrosine kinase inhibitor (TKI) failure, re-biopsy may be useful to understand resistance mechanisms and guide further treatment decisions. However, performing re-biopsy is challenging because of several hurdles. We assessed the feasibility of re-biopsy in advanced non-small cell lung cancer (NSCLC) patients in real-world clinical practice. METHODS: We retrospectively reviewed the clinical and pathologic data of advanced NSCLC patients who experienced disease progression after previous treatment with EGFR TKIs at a single tertiary hospital in Korea between January 2014 and December 2016. Re-biopsy specimens included small biopsy, surgical tissue, or liquid-based cytology. EGFR mutation was tested using peptide nucleic acid-mediated clamping PCR. RESULTS: Of the 230 NSCLC patients that experienced progression after EGFR TKI therapy, 105 (45.7%) underwent re-biopsy. Re-biopsy was successfully performed in 94 (89.5%) patients, and 11 patients were diagnosed with no malignancy. The complication rate was 8.6%, including seven cases of pneumothorax. EGFR mutation testing was performed on 75 patients using re-biopsy specimens. Of the 57 patients who had sensitizing mutations at diagnosis, T790M mutations were found in 19 (33.3%), while 38 (66.7%) had no T790M mutation. Multivariate analysis showed that the re-biopsy group was younger (P = 0.002) and exhibited a previous response to EGFR-TKIs (P < 0.001). CONCLUSION: Re-biopsy in advanced NSCLC is feasible in real world clinical practice, particularly in younger patients and those who achieved a previous response to EGFR-TKIs. PMID- 29761662 TI - Identification of problems in search strategies in Cochrane Reviews. AB - OBJECTIVE: Search strategies are essential for the adequate retrieval of studies in a systematic review (SR). Our objective was to identify problems in the design and reporting of search strategies in a sample of new Cochrane SRs first published in The Cochrane Library in 2015. STUDY DESIGN AND SETTING: We took a random sample of 70 new Cochrane SRs of interventions published in 2015. We evaluated their design and reporting of search strategies using the recommendations from the Cochrane Handbook for Systematic Reviews of Interventions, the Methodological Expectations of Cochrane Intervention Reviews, and the Peer Review of Electronic Search Strategies evidence-based guideline. RESULTS: Most reviews complied with the reporting standards in the Cochrane Handbook and the Methodological Expectations of Cochrane Intervention Reviews; however, 8 SRs did not search trials registers, 3 SRs included language restrictions, and there was inconsistent reporting of contact with individuals and searches of the gray literature. We found problems in the design of the search strategies in 73% of reviews (95% CI, 60-84%) and 53% of these contained problems (95% CI, 38-69%) that could limit both the sensitivity and precision of the search strategies. CONCLUSION: We found limitations in the design and reporting of search strategies. We consider that a greater adherence to the guidelines could improve their quality. PMID- 29761663 TI - A prospective pilot study on early toxicity from a simultaneously integrated boost technique for canine sinonasal tumours using image-guided intensity modulated radiation therapy. AB - In order to overcome the common local treatment failure of canine sinonasal tumours, integrated boost techniques were tried in the cobalt/orthovoltage era, but dismissed because of unacceptable early (acute) toxicity. Intriguingly, a recent calculation study of a simultaneously integrated boost (SIB) technique for sinonasal irradiation using intensity-modulated radiation therapy (IMRT) predicted theoretical feasibility. In this prospective pilot study we applied a commonly used protocol of 10 * 4.2 Gy to the planning target volume (PTV) with a 20%-SIB dose to the gross tumour volume (GTV). Our hypothesis expected this dose escalation to be clinically tolerable if applied with image-guided IMRT. We included 9 dogs diagnosed with sinonasal tumours without local/distant metastases. For treatment planning, organs at risk were contoured according to strict anatomical guidelines. Planning volume extensions (GTV/CTV/PTV) were standardized to minimize interplanner variability. Treatments were applied with rigid patient positioning and verified daily with image guidance. After radiation therapy, we set focus on early ophthalmologic complications as well as mucosal and cutaneous toxicity. Early toxicity was evaluated at week 1, 2, 3, 8 and 12 after radiotherapy. Only mild ophthalmologic complications were found. Three patients (33%) had self-limiting moderate to severe early toxicity (grade 3 mucositis) which was managed medically. No patient developed ulcerations/haemorrhage/necrosis of skin/mucosa. The SIB protocol applied with image-guided IMRT to treat canine sinonasal tumours led to clinically acceptable side effects. The suspected increased tumour control probability and the risk of late toxicity with the used dose escalation of 20% has to be further investigated. PMID- 29761664 TI - Utilizing Waste Thermocol Sheets and Rusted Iron Wires to Fabricate Carbon-Fe3 O4 Nanocomposite-Based Supercapacitors: Turning Wastes into Value-Added Materials. AB - The synthesis of porous activated carbon (specific surface area=1883 m2 g-1 ), Fe3 O4 nanoparticles, and carbon-Fe3 O4 (C-Fe3 O4 ) nanocomposites from local waste thermocol sheets and rusted iron wires is demonstrated herein. The resulting carbon, Fe3 O4 nanoparticles, and C-Fe3 O4 composites are used as electrode materials for supercapacitor applications. In particular, C-Fe3 O4 composite electrodes exhibit a high specific capacitance of 1375 F g-1 at 1 A g-1 and longer cyclic stability with 98 % capacitance retention over 10 000 cycles. Subsequently, an asymmetric supercapacitor, namely, C-Fe3 O4 ?Ni(OH)2 /carbon nanotube device, exhibits a high energy density of 91.1 Wh kg-1 and a remarkable cyclic stability, with 98 % capacitance retention over 10 000 cycles. Thus, this work has important implications not only for the fabrication of low-cost electrodes for high-performance supercapacitors, but also for the recycling of waste thermocol sheets and rusted iron wires for value-added reuse. PMID- 29761665 TI - The effect of V-ATPase function defects in pathogenesis of Alzheimer's disease. PMID- 29761666 TI - Prevalence differentiations of periodontitis by diabetic status among US adults. PMID- 29761667 TI - Identification and ultra-high-performance liquid chromatography coupled with high resolution mass spectrometry characterization of biosurfactants, including a new surfactin, isolated from oil-contaminated environments. AB - Biosurfactant-producing bacteria were isolated from samples collected in areas contaminated with crude oil. The isolates were screened for biosurfactant production using qualitative drop-collapse test, oil-spreading and emulsification assays, and measurement of their tensoactive properties. Five isolates tested positive for in the screening experiments and displayed decrease in the surface tension below 30 mN m-1 . The biosurfactants produced by these isolates were further investigated and their molecular identification revealed that they are bacteria related to the Bacillus genus. Additionally, the biosurfactants produced were chemically characterized via UHPLC-HRMS experiments, indicating the production of surfactin homologues, including a new class of these molecules. PMID- 29761669 TI - Slugs (Arionidae) benefit from nocturnal artificial illumination. AB - Artificial illumination increases around the globe and this has been found to affect many groups of organisms and ecosystems. By manipulating nocturnal illumination using one large experimental field site with 24 streetlights and one dark control, we assessed the impact of artificial illumination on slugs over a period of 4 years. The number of slugs, primarily Arionidae, increased strongly in the illuminated site but not on the dark site. There are several nonexclusive explanations for this effect, including reduced predation and increased food quality in the form of carcasses of insects attracted by the light. As slugs play an important role in ecosystems and are also important pest species, the increase of slugs under artificial illumination cannot only affect ecosystem functioning but also have important economic consequences. PMID- 29761668 TI - Mechanism-Based Disease Progression Model Describing Host-Pathogen Interactions During the Pathogenesis of Acinetobacter baumannii Pneumonia. AB - The emergence of highly resistant bacteria is a serious threat to global public health. The host immune response is vital for clearing bacteria from the infected host; however, the current drug development paradigm does not take host-pathogen interactions into consideration. Here, we used a systems-based approach to develop a quantitative, mechanism-based disease progression model to describe bacterial dynamics, host immune response, and lung injury in an immunocompetent rat pneumonia model. Previously, Long-Evans rats were infected with Acinetobacter baumannii (A. baumannii) strain 307-0294 at five different inocula and total lung bacteria, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), cytokine-induced neutrophil chemoattractant 1 (CINC-1), neutrophil counts, and albumin were quantified. Model development was conducted in ADAPT5 version 5.0.54 using a pooled approach with maximum likelihood estimation; all data were co modeled. The final model characterized host-pathogen interactions during the natural time course of bacterial pneumonia. Parameters were estimated with good precision. Our expandable model will integrate drug effects to aid in the design of optimized antibiotic regimens. PMID- 29761671 TI - Risk Factors for Complications of Total/Subtotal Gastrectomy for Gastric Cancer: Prospectively Collected, Based on the Clavien-Dindo Classification System. AB - BACKGROUND: Recent studies have analyzed risk factors associated with complications after gastric cancer surgery using the Clavien-Dindo classification (CD). However, they have been based on Asian population cohorts (Chinese, Japanese, Korean). OBJECTIVES: To prospectively analyze all post-gastrectomy complications according to severity using CD classification and identify postoperative risk factors and complications. METHODS: We analyzed all gastrectomies for gastric cancer performed 2009-2014. Recorded parameters included demographic data, existing co-morbidities, neo-adjuvant treatment, intra operative findings, postoperative course, and histologic findings. Postoperative complications were graded using CD classification. RESULTS: The study comprised 112 patients who underwent gastrectomy. Mean age was 64.8 +/- 12.8 years; 53 patients (47%) underwent gastrectomy, 37 (34%) total gastrectomy, and 22 (19%) total extended gastrectomy. All patients had D2 lymphadenectomy. The average number of retrieved lymph nodes was 35 +/- 17. Severe complication rate (>= IIIa) was 14% and mortality rate was 1.8%. In a univariate analysis, age > 65 years; ASA 3 or higher; chronic renal failure; multi-organ resection; and tumor, node, and metastases (TNM) stage >= IIIc were found to be significantly associated with CD complication grade > III (P = 0.01, P = 0.05, P = 0.04, P = 0.04, and P = 0.01, respectively). Multivariate regression analysis revealed advanced stage (>= IIIc) and age > 65 years to be significant independent risk factors (P < 0.05). CONCLUSIONS: Age > 65 and advanced stage (>= IIIc) were the primary risk factors for complications of grade > III according to the CD classification following gastrectomy for gastric cancer. PMID- 29761670 TI - Arrhythmic Events in Brugada Syndrome: A Nationwide Israeli Survey of the Clinical Characteristics, Treatment; and Long-Term Follow-up (ISRABRU-VF). AB - BACKGROUND: Limited information exists about detailed clinical characteristics and management of the small subset of Brugada syndrome (BrS) patients who had an arrhythmic event (AE). OBJECTIVES: To conduct the first nationwide survey focused on BrS patients with documented AE. METHODS: Israeli electrophysiology units participated if they had treated BrS patients who had cardiac arrest (CA) (lethal/aborted; group 1) or experienced appropriate therapy for tachyarrhythmias after prophylactic implantable cardioverter defibrillator (ICD) implantation (group 2). RESULTS: The cohort comprised 31 patients: 25 in group 1, 6 in group 2. Group 1: 96% male, mean CA age 38 years (range 13-84). Nine patients (36%) presented with arrhythmic storm and three had a lethal outcome; 17 (68%) had spontaneous type 1 Brugada electrocardiography (ECG). An electrophysiology study (EPS) was performed on 11 patients with inducible ventricular fibrillation (VF) in 10, which was prevented by quinidine in 9/10 patients. During follow-up (143 +/- 119 months) eight patients experienced appropriate shocks, none while on quinidine. Group 2: all male, age 30-53 years; 4/6 patients had familial history of sudden death age < 50 years. Five patients had spontaneous type 1 Brugada ECG and four were asymptomatic at ICD implantation. EPS was performed in four patients with inducible VF in three. During long-term follow-up, five patients received >= 1 appropriate shocks, one had ATP for sustained VT (none taking quinidine). No AE recurred in patients subsequently treated with quinidine. CONCLUSIONS: CA from BrS is apparently a rare occurrence on a national scale and no AE occurred in any patient treated with quinidine. PMID- 29761672 TI - Emergency Department Administration of Oxycodone by Nurses Treating Musculoskeletal Pain: An Observational Prospective. AB - BACKGROUND: Acute musculoskeletal pain is one of the most commonly reported symptoms among patients visiting the emergency department (ED). Treatment with over-the-counter pain medications, given by nurses, results in improved pain management and reduces the waiting time to drug administration without significant side effects. Opioid analgesics are extensively used for acute pain in the ED. Compared to morphine, oxycodone has a much more specific pharmacological activity, higher analgesic potential, and more tolerable side effects. OBJECTIVES: To assess the degree of pain reduction using different protocols, including dypirone and oxycodone given by nurses, in treating acute musculoskeletal pain in the emergency department (primary outcome) and to evaluate the need for rescue medications (secondary outcome). METHODS: This observational prospective clinical trial compared two groups of 50 patients, each one visiting the ED due to musculoskeletal pain. One group was treated with dipyrone syrup and the other was treated with oxycodone syrup. The primary outcome was pain reduction measured by the Numeric Rating Scale (NRS). The secondary outcome was the difference in need for rescue medications. RESULTS: The reduction in the NRS was greater in the patients treated with oxycodone. This finding was statistically and clinically significant (P < 0.001). The need for rescue medications was also significantly reduced in this group of patients (P = 0.007). CONCLUSIONS: This study showed that the administration of over-the counter oxycodone syrup by nurses decreases the post-treatment pain reported by patients, reduces the need for rescue medications, and increases the satisfaction of the medical staff. PMID- 29761673 TI - Neonatal Risk Factors for Colonization with Extended-Spectrum Beta-Lactamase Producing Bacteria in the Neonatal Intensive Care Unit. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL) production is the most common antimicrobial resistance mechanism in the neonatal intensive care unit (NICU), with colonization and blood stream infections being a major threat to this population. Since 2013, all NICU admissions at our facility were screened twice weekly for ESBL colonization. OBJECTIVES: To determine independent risk factors for colonization of infants with ESBL-producing bacteria in the NICU. METHODS: A retrospective case study of ESBL-colonized infants vs. controls (matched by date of birth and gestational age) was conducted in the NICU of Soroka University Medical Center, Israel, between 2013 and 2014. Epidemiological, laboratory, and clinical data were extracted from medical files. Univariable and multivariable analyses were used to assess associations between ESBL colonization and possible clinical risk factors. RESULTS: Of 639 admissions during the study period, 87 were found to be ESBL-colonized (case infants) and were matched to 87 controls. Five case infants became infected (5.7%) with ESBL strains. Klebsiella pneumoniae was the most common isolated bacteria. The mean time from admission to colonization was 15 days. Univariable analysis showed an association of male gender and highest Apgar score at 1 and 5 minutes with ESBL colonization (P < 0.05). Multivariable analysis yielded only a possible association of higher Apgar score at 1 and 5 minutes (hazard ratio [HR] 1.515, 95% confidence interval [95%CI] 0.993-2.314; HR 1.603, 95%CI 0.958-2.682, respectively) with ESBL colonization. CONCLUSIONS: Future studies should focus on maternal colonization and possible strategies for preventing vertical transmission of ESBL strains to high-risk neonates. PMID- 29761674 TI - Screening Arab Israeli Pregnant Women for Group B Streptococcus by the AmpliVue GBS Assay: Are the Rates Higher than the National Average? AB - BACKGROUND: The recommendation of the U.S. Centers for Disease Control and Prevention regarding universal screening for Group B Streptococcus (GBS) at 35-37 weeks gestational age in pregnancy is not accepted in Israel. The National Council for Obstetrics, Neonatology and Genetics recommends intrapartum prophylaxis, mainly based on risk factors, to prevent early neonatal GBS infection. This policy is based on past studies demonstrating low colonization rates of the bacteria in Israeli pregnant women and very low neonatal sepsis rates. OBJECTIVES: To determine the applicability of the high-risk group prophylaxis policy for Arab Israeli pregnant women. METHODS: Vaginorectal swabs from Arab Israeli pregnant women who attended the labor ward between October 2015 and February 2016, were obtained before any pelvic examination for GBS identification using Quidel's AmpliVue(r) GBS assay. Women who tested positive received intrapartum antibiotic prophylaxis to prevent neonatal infection. Obstetric data were collected from each woman from a standardized questionnaire. Data regarding the delivery and neonates were collected as well. RESULTS: The study comprised 188 Arab pregnant women who met the inclusion criteria and signed a consent form to participate in the study. Of these, 59 had positive tests, and a carriage rate of 31%. No neonatal colonization of GBS was found. CONCLUSIONS: The carrier rate in Arab pregnant women in northern Israel is higher than the national average, at least partially due to the more sensitive method of GBS detection used in the present study. PMID- 29761675 TI - Telomere Length, Aggregates, and Capture in Cirrhosis. AB - BACKGROUND: Shortened telomeres were found in patients with cirrhosis, probably reflecting chronic liver injury, continuous regeneration, and destruction of hepatic nodules. OBJECTIVES: To test whether telomere shortening is a general marker of cirrhosis, independent of disease etiology. METHODS: We evaluated telomere length in patients with cryptogenic cirrhosis (largely a late sequela of steatohepatitis) compared to patients with cirrhosis caused by chronic hepatitis B and C (HBV/HCV). We also evaluated telomere aggregates, a sensitive parameter of telomere dysfunction and genetic instability. We analyzed peripheral lymphocytes from 25 patients with cryptogenic cirrhosis, 15 patients with cirrhosis due to chronic viral hepatitis, and 20 age-matched controls. Telomere length was analyzed using quantitative fluorescence in situ hybridization. Aggregate size was divided into three fusion groups of 2-5, 6-10, and 11-15 telomeres, relative to the size of a single telomere. RESULTS: Shorter telomere length was found in patients with cirrhosis from all three etiologies (mean 121.3 +/- 24.1) compared to controls (mean 63.5 +/- 23.5). In contrast, there was significantly more fusion of > 5 telomeres only in the HBV/HCV cirrhosis group compared to healthy controls (P = 0.023), but not in the cryptogenic cirrhosis group. CONCLUSIONS: While shortened telomeres in peripheral lymphocytes are a general marker of liver cirrhosis, telomere aggregates may signify a more sensitive genetic instability parameter for the diverse, etiology-based malignant potential of cirrhosis. This finding is in agreement with the well-known higher tendency toward developing hepatocellular carcinoma with cirrhosis caused by chronic hepatitis relative to steatohepatitis. PMID- 29761676 TI - Planned Re-Laparotomy in a Non-Trauma Setting: A Single Center Experience. AB - BACKGROUND: Damage control laparotomy (DCL) is the widely accepted procedure of choice in management of severely injured trauma patient. It has been implemented in non-trauma-related surgical pathology in the last decade. OBJECTIVES: To evaluate our experience with planned re-laparotomy (PRL) in non-trauma patients and compare it to other reports. METHODS: Charts of all patients admitted to Assaf Harofeh Medical Center who underwent PRL for non-trauma-related abdominal pathology during a 6 year period were reviewed. Data regarding demographics, vital signs, laboratory tests, indications for surgery, length of hospital stay, and mortality were obtained from medical charts. Indications for surgery, risk factors, and mortality were analyzed. RESULTS: The study was comprised of 181 patients. Primary abdominal sepsis (50), postoperative sepsis (49), mesenteric event (32), and intestinal obstruction (28) were the most common indications for PRL. Mortality rate was 48.6%. Factors correlating with increased mortality were advanced age, hypotension, hypothermia, metabolic acidosis, and renal failure. Bowel resection was performed on 122 patients (67%) and primary intestinal anastomosis constructed in 46.7%. Mortality rate was lower in patients who underwent PRL with primary anastomosis compared to patients with postponed bowel anastomosis (33.3% vs. 55.4%, P = 0.018). CONCLUSIONS: PRL in abdominal emergencies carries a high mortality rate. Primary anastomosis may be considered in non-trauma-related PRL. PMID- 29761677 TI - Pleural Fluid B-Type Natriuretic Peptide Level as an Additional Indicator for the Fluid's Etiology. AB - BACKGROUND: The identification of the etiology of a pleural effusion can be difficult. Measurement of serum B-type natriuretic peptide (BNP) levels is helpful in the diagnosis of congestive heart failure (CHF) as a cause of respiratory failure, but pleural fluid BNP measurement is still not part of the workup for pleural effusion. OBJECTIVES: To identify the correlation between pleural fluid BNP levels and clinical diagnosis. METHODS: In this cross-sectional study, data from 107 patients admitted to the department of internal medicine between November 2009 and January 2015 were obtained from medical records. Patients underwent a diagnostic thoracocentesis as part of their evaluation. They were grouped according to final diagnosis at discharge and clinical judgment of the attending physician. RESULTS: Serum BNP levels were significantly higher in the CHF patients compared to patients with non-cardiac causes of pleural effusion (1519.2 and 314.1 respectively, P < 0.0001). Mean pleural fluid BNP was also significantly higher in the CHF patients (1063.2 vs. 208.3, P < 0.0001). Optional cutoff points to distinguish between cardiac and non-cardiac etiology of pleural effusion were 273.4 pg/ml (sensitivity 83.3%, specificity 72.3%, accuracy 76.7%) or 400 pg/ml (sensitivity 78.6%, specificity 86.2%, accuracy 83.0%). A strong correlation was found between serum BNP and pleural fluid BNP levels. CONCLUSIONS: High levels of serum BNP in patients presenting with pleural effusion suggest CHF. In cases with doubt regarding the etiology of pleural effusion, high levels of pleural fluid BNP can support the diagnosis, but are not superior to serum BNP levels. PMID- 29761678 TI - Ultrasound of Jugular Veins for Assessment of Acute Dyspnea in Emergency Departments and for the Assessment of Acute Heart Failure. AB - BACKGROUND: When a patient arrives at the emergency department (ED) presenting with symptoms of acute decompensated heart failure (ADHF), it is possible to reach a definitive diagnosis through many different venues, including medical history, physical examination, echocardiography, chest X-ray, and B-type natriuretic peptide (BNP) levels. Point-of-care ultrasound (POCUS) has become a mainstream tool for diagnosis and treatment in the field of emergency medicine, as well as in various other departments in the hospital setting. Currently, the main methods of diagnosis of ADHF using POCUS are pleural B-lines and inferior vena cava (IVC) width and respiratory variation. OBJECTIVES: To examine the potential use and benefits of bedside ultrasound of the jugular veins in the evaluation of dyspneic patients for identification of ADHF. METHODS: A blood BNP level was drawn from each participant at time of recruitment. The area and size of the internal jugular vein (IJV) during inspiration and expiration were examined. RESULTS: Our results showed that the respiratory area change of the IJVs had a specificity and sensitivity of nearly 70% accuracy rate in indentifying ADHF in our ED. CONCLUSIONS: Ultrasound of the IJV may be a useful tool for the diagnosis of ADHF because it is easy to measure and requires little skill. It is also not affected by patient body habitus. PMID- 29761679 TI - Gender-Related Differences in Outcomes of Patients with Cardiac Resynchronization Therapy. AB - BACKGROUND: Gender-related differences (GRD) exist in the outcome of patients with cardiac resynchronization therapy (CRT). OBJECTIVES: To assess GRD in patients who underwent CRT. METHODS: A retrospective cohort of 178 patients who were implanted with a CRT in a tertiary center 2005-2009 was analyzed. Primary outcome was 1 year mortality. Secondary endpoints were readmission and complication rates. RESULTS: No statistically significant difference was found in 1 year mortality rates (14.6% males vs. 11.8% females, P = 0.7) or in readmission rate (50.7% vs. 41.2%, P = 0.3). The complication rate was only numerically higher in women (14.7% vs. 5.6%, P = 0.09). Men more often had CRT-defibrillator (CRT-D) implants (63.2% vs. 35.3%, P = 0.003) and had a higher rate of ischemic cardiomyopathy (79.2% vs. 38.2%, P < 0.001). There was a trend to higher incidence of ventricular fibrillation/ventricular tachycardia in men before CRT implantation (29.9% vs. 14.7%, P = 0.07%). A higher proportion of men upgraded from implantable cardioverter defibrillator (ICD) to CRT-D, 20.8% vs. 8.8%, P = 0.047. On multivariate model, chronic renal failure was an independent predictor of 1 year mortality (hazard ratio [HR] 3.6; 95% confidence interval [95%CI] 1.4 9.5), CRT-D had a protective effect compared to CRT-pacemaker (HR 0.3, 95%CI 0.12 0.81). CONCLUSIONS: No GRD was found in 1 year mortality or readmission rates in patients treated with CRT. There was a trend toward a higher complication rate in females. Men were implanted more often with CRT-D and more frequently underwent upgrading of ICD to CRT-D. PMID- 29761680 TI - The History of the Low Transverse Cesarean Section: The Pivotal Role of Munro Kerr. AB - BACKGROUND: Cesarean section has undergone a transformation that has radically changed the prognosis of both the pregnant woman and her unborn child. The attributed mortality rate of Cesarean section during the 19th century was over 50% worldwide. Today, mortality from Cesarean delivery is rare. However, the technique of transversely incising the uterus in its lower uterine segment, although less than a century old, is passed on from instructor to apprentice, often without either of them being aware of its noble history. In this brief review, we discuss the reported history regarding this incision and the significant role played by John Munro Kerr. PMID- 29761681 TI - Milestones in the Development of Fetal Cardiac Interventions. AB - BACKGROUND: Cardiac patients of all ages were managed in the past by internists who specialized in cardiology. During the past 50 years, the medical field has witnessed great strides in the management of congenital heart disease, and thus pediatric cardiology has become a subspecialty in many countries. This review article focuses on the advances in fetal cardiac interventions (FCI) since its inception by our group in 1975. Three major modes of FCI have evolved during the past 42 years: pharmacologic, closed FCI, and open FCI. All treatments require a careful approach by the heart team and are reserved for severe fetal cardiac conditions. They call for prenatal intervention in view of the severity and progressive nature of the diseases that are associated with high fetal morbidity and mortality if left untreated. The well-established pharmacologic FCI approach includes several new and effective agents with recommendations often varying between class I and class IIa and IIb. The advances in prenatal echocardiographic imaging and color flow Doppler has given an impetus to the development of the other FCI modes; however, the need for uterine incision and fetal cardiac bypass in the open technique have limited its advance. Long-term outcomes are still unknown and definite conclusions as to the efficacy and safety of FCI need further investigation, including multicenter trials with long-term data. PMID- 29761682 TI - Plasmapheresis in a Patient with Sarcoidosis Who Developed Multiple Myeloma and Massive Free Kappa Light Chains Nephropathy. PMID- 29761683 TI - Epipericardial Fat Necrosis. PMID- 29761684 TI - Single Coronary Artery Presenting as Acute Coronary Syndrome with Sudden Cardiac Death. PMID- 29761685 TI - Women with type 2 diabetes in pregnancy remain a high-risk group. PMID- 29761686 TI - Etiology and patterns of presentation of short stature in Eastern Cape of South Africa. PMID- 29761687 TI - Emergency extracorporeal shockwave lithotripsy as opposed to delayed shockwave lithotripsy for the treatment of acute renal colic due to obstructive ureteral stone: a prospective randomized trial. AB - BACKGROUND: The aim of this study was to assess the efficacy of emergency extracorporeal shockwave lithotripsy (eSWL) as first-line treatment in patients with acute colic due to obstructive ureteral stone. METHODS: Seventy-four patients were randomized to emergency SWL within 12 hours (eSWL group) and deferred SWL later than 3 days (dSWL group). Follow-up included ultrasound, KUB (kidney-ureter-bladder) radiography and CT (computed tomography) scan at 24 hours, 7 days, 1 and 3 months from the treatment. When necessary, repeated SWL (re-SWL) or ureteroscopy (auxiliary-URS) was performed. Preoperative and postoperative data were compared and stone free rates (SFR) and efficiency quotients (EQ) were evaluated. Analyses were performed using SAS software. RESULTS: Complete data of 70 patients were collected. 36 underwent eSWL and 34 dSWL. The mean patient age was 48.7. Mean stone size was 9.8 mm (CI 95%: 8.9 10.8). 25 (35.7%) were proximal and 45 (64.3%) distal. Mean SWL energy was 19.2 kV (CI 95%: 18.5-19.9) and mean number of shocks was 2657 (CI 95%: 2513-2802). eSWL patients needs less auxiliary-URS than dSWL patients (13.9% vs. 44.1%, P=0.039) and less re-SWL sessions (8.3% vs. 32.4%, P=0.093). SFR at 24 hours was 52.8% and 11.8% (P<0.001) and the EQ at 3 months was 79.1% and 57.5% in the eSWL and dSWL group respectively. Patients from the dSWL group spent more time in the hospital (2.21 vs. 1.36 days, P=0.046) and complication rates between the two groups were similar. CONCLUSIONS: eSWL is a safe procedure and delivers high SFR even within 24 hours especially for <10 mm stones. It is able to reduce the number of auxiliary procedures and hospitalization. PMID- 29761688 TI - Collagenase clostridium histolyticum: a novel medical treatment for Peyronie's disease. AB - INTRODUCTION: Peyronie's disease (PD) affects up to 9% of the male population. PD causes scarring of the tunica albuginea of the penis which leads to penile deformity making sexual intercourse difficult or impossible. PD also causes significant psychological, emotional and relationship difficulties for both patient and partner. Up until the licencing of Collagenase clostridium histolyticum (CCH) (Xiapex(r), Xiaflex(r)), surgical correction of the penile deformity was the mainstay of treatment. Many conservative treatment options had been previously tried, however, the safety and efficacy of these options has not been demonstrated in large well-designed clinical trials. Intra-lesional CCH is now the gold standard option for the non-surgical management of PD. It is the first and only treatment approved by the Food and Drug Administration and the European Medicines Agency for PD. In this review article, we will discuss the pharmacology, clinical efficacy, safety and future of CCH intralesional injection. EVIDENCE ACQUISITION: MEDLINE and PubMed search (from 1946). The search terms ("Collagenase Clostridium Histolyticum" OR "Xiapex" OR "Xiaflex") AND "Peyronie's disease" were used. EVIDENCE SYNTHESIS: The safety and efficacy of intra-lesional CCH in the management of PD has been demonstrated in 2 large scale multicenter, randomized, double-blind placebo-controlled clinical trials; the investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies I and II (IMPRESS I and IMPRESS II). A new study published by our group suggests a new modified shortened protocol that will reduce the cost and duration of treatment without compromising the safety or efficacy of treatment. CONCLUSIONS: CCH is the gold standard non-surgical option in the management of PD. The safety and efficacy of CCH has been demonstrated in large well-designed clinical trials. The new modified protocol, developed by our group, reduces the cost and inconvenience to patients whilst maintaining the efficacy. This will allow more men to benefit and will reduce the number of men undergoing surgical correction for their PD. PMID- 29761689 TI - Percutaneous nephrolithotomy in solitary kidneys: effective, safe and improves renal functions. AB - BACKGROUND: To evaluate success and complication rates of endourological stone treatments and to evaluate effects of percutaneous nephrolithotomy (PCNL) on renal functions, in patients with solitary kidneys. METHODS: In our center, 3150 patients underwent PCNL between 2003 and 2017 and 142 patients underwent retrograd intrarenal surgery (RIRS) between 2013 and 2017. We retrospectively analysed the data of 82 patients with solitary kidney who underwent PCNL and of 8 patients with solitary kidney who underwent RIRS. Complications were classified according to Clavien-Dindo Classification system. Serum creatinin was measured before the procedure, on the early postoperative period and at sixth month follow up in PCNL group. The estimated glomerular filtration rate (eGFR) was calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The 5 stage classification of chronic kidney disease (CKD) was used according to the National Kidney Foundation guideline. RESULTS: In the PCNL group, the initial stone-free and success rates were 82.9% and 95.1%, respectively. Complications occured in 18 (22%) patients. Transfusion was the most common complication (15.5%). One patient required JJ stenting. The stone-free rates of the patients who required multiple accesses were statistically lower than the patients who required single access (P=0.01). Transfusion rates were statistically higher in patients who required multiple accesses and who had complex stones (P=0.01 and P=0.02, respectively). GFRs calculated preoperatively, in the early and in the late period were 65.03, 62.85 (P=0.224) and 70.63 mL/min/1.73 m2 (P<0.001), respectively. At the postoperative 6th month, GFR was stable in CKD stage 1 patients and improved in CKD stage 2-4 patients (P<0.001, P<0.001 and P=0.012 respectively). In the RIRS group, 5 patients (62.5%) were stone free and the success rate was 75% (6 patients) after single procedure. Any complication did not occur in the RIRS group. CONCLUSIONS: PCNL in solitary kidney is a safe method with acceptable complication rates. Renal functions are preserved in patients with normal functioning kidney and improved in patients with renal insufficiency. RIRS may be an alternative method in selected patients with solitary kidney. PMID- 29761690 TI - Assessment of the relationship between renal volume and renal function after minimally-invasive partial nephrectomy: the role of computed tomography and nuclear renal scan. AB - BACKGROUND: To evaluate the correlation between the loss of renal function as assessed by Tc99MAG-3 renal scan and the loss of renal volume as calculated by volumetric assessment on CT-scan in patients who underwent minimally-invasive partial nephrectomy (PN). METHODS: PN prospectively-maintained database was retrospectively queried for patients who underwent minimally-invasive PN (2012 2017) for renal mass <=cT2 and had complete data on renal scan and contrast enhanced CT-scan (both performed in our Institution) both at preoperative assessment and at the third postoperative month follow-up. Tc99MAG-3 renal scan was performed to get renal functional data; renal volume was calculated by dedicated software from CT-scan with a semiautomated method. Statistical analysis aimed to identify relationships between loss of renal volume and loss of renal function and other patients' and surgical variables, particularly regarding lesion complexity (assessed by PADUA Score). RESULTS: Fifty-seven patients were analyzed. Both at univariate and multivariate analysis, the percentage of loss of renal function was significantly correlated to the loss of renal volume (P<0.001). Warm ischemia significantly correlated with the loss of renal volume (P=0.003). After stratification according to PADUA score categories, higher surgical complexity renal masses had stronger correlation between the loss of renal volume and the loss of renal function. CONCLUSIONS: The use of the semiautomated method for the 3D segmentation of the kidney to get the volumetric assessment could be a valid tool to support the future use of CT-scan as the tool to pair the oncological and the functional follow-up after PN. PMID- 29761691 TI - Extramammary Paget disease of the penis closely mimicking the penile analogue of stratified mucin-producing intraepithelial lesion (SMILE). PMID- 29761692 TI - Visualizing the Zero-Potential Line of Bipolar Electrodes with Arbitrary Geometry. AB - In a typical bipolar electrochemistry (BPE) configuration, voltage applied between the two driving electrodes induced a potential drop through solution filled in the microchannel, resulting in an interfacial potential difference between solution and BPE varied along the BPE. In the present work, we employed a recently developed plasmonic imaging technique to map the distribution of surface potential of bipolar electrodes with various geometries including round, triangle, hexagon, star, and rhombus shapes under the nonfaradaic charging process, from which the line of zero potential (LZP) was visualized and determined. We further investigated the dependence of LZP on electrode geometry and the distribution of external electric field and explained the experimental results with a charge balance mechanism. The triangular and star-shaped BPEs show quite different LZP features from the other ones with symmetrical geometry. These experimentally obtained potential distributions are all in good agreement with electromagnetic simulations. Finally, the line of zero overpotential (LZO) of the triangular-shaped BPE under faradaic reactions were investigated. The results confirm the shift of LZO when faradaic reactions occurred at the corresponding ends of BPE. The present work demonstrates the first experimental capability to map the potential distribution of BPE with arbitrary geometry under an arbitrary driving field. It is anticipated to help the design and optimization on the geometry of electrodes and microchannels with implications for boosting their applications in chemical sensing and materials synthesis. PMID- 29761693 TI - The Story of Ever Diminishing Vehicle Tailpipe Emissions as Observed in the Chicago, Illinois Area. AB - The University of Denver has collected on-road fuel specific vehicle emissions measurements in the Chicago area since 1989. This nearly 30 year record illustrates the large reductions in light-duty vehicle tailpipe emissions and the remarkable improvements in emissions control durability to maintain low emissions over increasing periods of time. Since 1989 fuel specific carbon monoxide (CO) emissions have been reduced by an order of magnitude and hydrocarbon (HC) emissions by more than a factor of 20. Nitric oxide (NO) emissions have only been collected since 1997 but have seen reductions of 79%. This has increased the skewness of the emissions distribution where the 2016 fleet's 99th percentile contributes ~3 times more of the 1990 total for CO and HC emissions. There are signs that these reductions may be leveling out as the emissions durability of Tier 2 vehicles in use today has almost eliminated the emissions reduction benefit of fleet turnover. Since 1997, the average age of the Chicago on-road fleet has increased 2 model years and the percentage of passenger vehicles has dropped from 71 to 52% of the fleet. Emissions are now so well controlled that the influence of driving mode has been completely eliminated as a factor for fuel specific CO and NO emissions. PMID- 29761694 TI - High-Performance Polymer Solar Cell with Single Active Material of Fully Conjugated Block Copolymer Composed of Wide-Band gap Donor and Narrow-Band gap Acceptor Blocks. AB - We synthesized a novel fully conjugated block copolymer, P3, in which a wide-band gap donor block (P1) was connected to a narrow-band gap acceptor block (P2). As P3 contains P1 block with a wide bandgap and P2 block with a narrow bandgap, it exhibits a very wide complementary absorption. Transient photoluminescence measurement using P3 dilute solution demonstrated intramolecular charge transfer between the P1 block and the P2 block, which was not observed in a P1/P2 blend solution. A P3 thin film showed complete PL quenching because the photoinduced inter-/intramolecular charge transfer states were effectively formed. This phenomenon can play an important role in the photovoltaic properties of P3-based polymer solar cells. A single active material polymer solar cell (SAMPSC) fabricated from P3 alone exhibited a high power conversion efficiency (PCE) of 3.87% with a high open-circuit voltage of 0.93 V and a short-circuit current of 8.26 mA/cm2, demonstrating a much better performance than a binary P1-/P2-based polymer solar cell (PCE = 1.14%). This result facilitates the possible improvement of the photovoltaic performance of SAMPSCs by inducing favorable nanophase segregation between p- and n blocks. In addition, owing to the high morphological stability of the block copolymer, excellent shelf-life was observed in a P3-based SAMPSC compared with a P1/P2-based PSC. PMID- 29761695 TI - Mercury Stable Isotopes Reveal Influence of Foraging Depth on Mercury Concentrations and Growth in Pacific Bluefin Tuna. AB - Pelagic ecosystems are changing due to environmental and anthropogenic forces, with uncertain consequences for the ocean's top predators. Epipelagic and mesopelagic prey resources differ in quality and quantity, but their relative contribution to predator diets has been difficult to track. We measured mercury (Hg) stable isotopes in young (<2 years old) Pacific bluefin tuna (PBFT) and their prey species to explore the influence of foraging depth on growth and methylmercury (MeHg) exposure. PBFT total Hg (THg) in muscle ranged from 0.61 to 1.93 MUg g-1 dw (1.31 MUg g-1 dw +/-0.37 SD; 99% +/- 6% MeHg) and prey ranged from 0.01 to 1.76 MUg g-1 dw (0.13 MUg g-1 dw +/-0.19 SD; 85% +/- 18% MeHg). A systematic decrease in prey delta202Hg and Delta199Hg with increasing depth of occurrence and discrete isotopic signatures of epipelagic prey (delta202Hg: 0.74 to 1.490/00; Delta199Hg: 1.76-2.960/00) and mesopelagic prey (delta202Hg: 0.09 to 0.900/00; Delta199Hg: 0.62-1.950/00) allowed the use of Hg isotopes to track PBFT foraging depth. An isotopic mixing model was used to estimate the dietary proportion of mesopelagic prey in PBFT, which ranged from 17% to 55%. Increased mesopelagic foraging was significantly correlated with slower growth and higher MeHg concentrations in PBFT. The slower observed growth rates suggest that prey availability and quality could reduce the production of PBFT biomass. PMID- 29761696 TI - Emergence of Kondo Resonance in Graphene Intercalated with Cerium. AB - The interaction between a magnetic impurity, such as cerium (Ce) atom, and surrounding electrons has been one of the core problems in understanding many body interaction in solid and its relation to magnetism. Kondo effect, the formation of a new resonant ground state with quenched magnetic moment, provides a general framework to describe many-body interaction in the presence of magnetic impurity. In this Letter, a combined study of angle-resolved photoemission (ARPES) and dynamic mean-field theory (DMFT) on Ce-intercalated graphene shows that Ce-induced localized states near Fermi energy, EF, hybridized with the graphene pi-band, exhibit gradual increase in spectral weight upon decreasing temperature. The observed temperature dependence follows the expectations from the Kondo picture in the weak coupling limit. Our results provide a novel insight how Kondo physics emerges in the sea of two-dimensional Dirac electrons. PMID- 29761697 TI - Identification of Proteins Using iTRAQ and Virus-Induced Gene Silencing Reveals Three Bread Wheat Proteins Involved in the Response to Combined Osmotic-Cold Stress. AB - Crops are often subjected to a combination of stresses in the field. To date, studies on the physiological and molecular responses of common wheat to a combination of osmotic and cold stresses, however, remain unknown. In this study, wheat seedlings exposed to osmotic-cold stress for 24 h showed inhibited growth, as well as increased lipid peroxidation, relative electrolyte leakage, and soluble sugar contents. iTRAQ-based quantitative proteome method was employed to determine the proteomic profiles of the roots and leaves of wheat seedlings exposed to osmotic-cold stress conditions. A total of 250 and 258 proteins with significantly altered abundance in the roots and leaves were identified, respectively, and the majority of these proteins displayed differential abundance, thereby revealing organ-specific differences in adaptation to osmotic cold stress. Yeast two hybrid assay examined five pairs of stress/defense-related protein-protein interactions in the predicted protein interaction network. Furthermore, quantitative real-time PCR analysis indicated that abiotic stresses increased the expression of three candidate protein genes, i.e., TaGRP2, CDCP, and Wcor410c in wheat leaves. Virus-induced gene silencing indicated that three genes TaGRP2, CDCP, and Wcor410c were involved in modulating osmotic-cold stress in common wheat. Our study provides useful information for the elucidation of molecular and genetics bases of osmotic-cold combined stress in bread wheat. PMID- 29761698 TI - Assessment of Compressive Raman versus Hyperspectral Raman for Microcalcification Chemical Imaging. AB - We experimentally implement a compressive Raman technology (CRT) that incorporates chemometric analysis directly into the spectrometer hardware by means of a digital micromirror device (DMD). The DMD is a programmable optical filter on which optimized binary filters are displayed. The latter are generated with an algorithm based on the Cramer-Rao lower bound. We compared the developed CRT microspectrometer with two conventional state-of-the-art Raman hyperspectral imaging systems on samples mimicking microcalcifications relevant for breast cancer diagnosis. The CRT limit of detection significantly improves, when compared to the CCD based system, and CRT ultimately allows 100* and 10* faster acquisition speeds than the CCD- and EMCCD-based systems, respectively. PMID- 29761699 TI - Synthesis of Highly Substituted 2-Arylindoles via Copper-Catalyzed Coupling of Isocyanides and Arylboronic Acids. AB - Highly functionalized 2-arylindoles were synthesized from 2 alkenylarylisocyanides and arylboronic acids using a simple, inexpensive copper catalyst. The reaction exhibits excellent functional group tolerance for both the arylisocyanide and boronic acid coupling partners. To avoid the direct handling of the pungent arylisocyanide starting materials, continuous flow chemistry is further demonstrated to provide safe and effective access to 2-arylindoles through in situ dehydration and cyclization of easy-to-handle 2-alkenyl- N formylanilines. PMID- 29761700 TI - Oil Droplet Size Distributions in Deep-Sea Blowouts: Influence of Pressure and Dissolved Gases. AB - To date, experimental investigations to determine the droplet size distribution (DSD) of subsea oil spills were mostly conducted at surface conditions, i.e. at atmospheric pressure, and with dead, i.e. purely liquid, oils. To investigate the influence of high hydrostatic pressure and of gases dissolved in the oil on the DSD, experiments with a downscaled blowout are conducted in a high-pressure autoclave at 150 bar hydrostatic pressure. Jets of "live", i.e. methane saturated, crude oil and n-decane are compared to jets of "dead" hydrocarbon liquids in artificial seawater. Experiments show that methane dissolved in the liquid oil increases the volume median droplet diameter significantly by up to 97%. These results are not in good accordance with state-of-the-art drop formation models, which are based on oil-only experiments at atmospheric pressure, and therefore show the need for a modification of such models which incorporates effects of hydrostatic pressure and dissolved gases for the modeling of deep-sea oil spills and blowouts. PMID- 29761701 TI - Semiquantitative Nucleic Acid Test with Simultaneous Isotachophoretic Extraction and Amplification. AB - Nucleic acid amplification tests (NAATs) provide high diagnostic accuracy for infectious diseases and quantitative results for monitoring viral infections. The majority of NAATs require complex equipment, cold chain dependent reagents, and skilled technicians to perform the tests. This largely confines NAATs to centralized laboratories and can significantly delay appropriate patient care. Low-cost, point-of-care (POC) NAATs are especially needed in low-resource settings to provide patients with diagnosis and treatment planning in a single visit to improve patient care. In this work, we present a rapid POC NAAT with integrated sample preparation and amplification using electrokinetics and paper substrates. We use simultaneous isotachophoresis (ITP) and recombinase polymerase amplification (RPA) to rapidly extract, amplify, and detect target nucleic acids from serum and whole blood in a paper-based format. We demonstrate simultaneous ITP and RPA can consistently detect 5 copies per reaction in buffer and 10 000 copies per milliliter of human serum with no intermediate user steps. We also show preliminary extraction and amplification of DNA from whole blood samples. Our test is rapid (results in less than 20 min) and made from low-cost materials, indicating its potential for detecting infectious diseases and monitoring viral infections at the POC in low resource settings. PMID- 29761702 TI - Ruthenium(II)-Catalyzed Positional Selective C-H Oxygenation of N-Aryl-2 pyrimidines. AB - Efficient Ru-catalyzed regioselective C-H oxygenation of N-aryl-2-pyrimidines is described with aryl carboxylic acids in the presence of AgSbF6 as an additive and Ag2CO3 as an oxidant. The reaction can be extended to alkyl, heteroaryl, and alpha,beta-unsaturated carboxylic acids. The regioselectivity, broad substrate scope, and functional group tolerance are the significant practical advantages. PMID- 29761703 TI - Nonfullerene Acceptor with "Donor-Acceptor Combined pi-Bridge" for Organic Photovoltaics with Large Open-Circuit Voltage. AB - In this work, a kind of "donor-acceptor (D-A) combined pi-bridge" based on the regioselective reactivity of monofluoro-substituted benzothiadiazole (FBT) to link a thiophene ring has been designed to construct a new A-pi-D-pi-A-type small molecular acceptor (IDT-FBTR) with indacenodithiophene (IDT) as a central core (D) and 3-octyl-2-(1,1-dicyanomethylene)rhodanine as an electron-withdrawing terminal group (A). Because of the strong intramolecular push-pull electron effect, the IDT-FBTR shows a strong and broad intramolecular charge-transfer absorption band in the range of 500-750 nm. Especially, as an electron-deficient FBT unit (A') and an electron-rich thiophene ring (D') in "D-A combined pi bridge" exert an "offset effect" to regulate the highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy levels of the molecule, a relatively high LUMO energy level can be maintained for IDT-FBTR that is helpful to enhance the open-circuit voltage ( Voc) for highly efficient organic solar cells (OSCs). Therefore, the optimized OSC device based on IDT-FBTR as the acceptor and PTB7-Th as the donor shows a much high Voc of 1.02 V with a relatively low Eloss of 0.56 eV and a best power conversion efficiency of 9.14%. PMID- 29761704 TI - Computation of the Hydrodynamic Radius of Charged Nanoparticles from Nonequilibrium Molecular Dynamics. AB - We have used nonequilibrium molecular dynamics to simulate the flow of water molecules around a charged nanoparticle described at the atomic scale. These nonequilibrium simulations allowed us to compute the friction coefficient of the nanoparticle and then to deduce its hydrodynamic radius. We have compared two different strategies to thermostat the simulation box, since the low symmetry of the flow field renders the control of temperature non trivial. We show that both lead to an adequate control of the temperature of the system. To deduce the hydrodynamic radius of the nanoparticle we have employed a partial thermostat, which exploits the cylindrical symmetry of the flow field. Thereby, only a part of the simulation box far from the nanoparticle is thermostated. We have taken into account the finite concentration of the nanoparticle when calculating the friction force acting on it. We have focused on the case of polyoxometalate ions, which are inorganic charged nanoparticles. It appears that, for a given structure of the nanoparticle at the atomic level, the hydrodynamic radius significantly increases with the nanoparticles charge, a phenomenon that had not been quantified so far using molecular dynamics. The presence of an added salt only slightly modifies the hydrodynamic radius. PMID- 29761705 TI - Dopamine and Caffeine Encapsulation within Boron Nitride (14,0) Nanotubes: Classical Molecular Dynamics and First Principles Calculations. AB - Classical molecular dynamics (MD) and density functional theory (DFT) calculations are developed to investigate the dopamine and caffeine encapsulation within boron nitride (BN) nanotubes (NT) with (14,0) chirality. Classical MD studies are done at canonical and isobaric-isothermal conditions at 298 K and 1 bar in explicit water. Results reveal that both molecules are attracted by the nanotube; however, only dopamine is able to enter the nanotube, whereas caffeine moves in its vicinity, suggesting that both species can be transported: the first by encapsulation and the second by drag. Findings are analyzed using the dielectric behavior, pair correlation functions, diffusion of the species, and energy contributions. The DFT calculations are performed according to the BLYP approach and applying the atomic base of the divided valence 6-31g(d) orbitals. The geometry optimization uses the minimum-energy criterion, accounting for the total charge neutrality and multiplicity of 1. Adsorption energies in the dopamine encapsulation indicate physisorption, which induces the highly occupied molecular orbital-lower unoccupied molecular orbital gap reduction yielding a semiconductor behavior. The charge redistribution polarizes the BNNT/dopamine and BNNT/caffeine structures. The work function decrease and the chemical potential values suggest the proper transport properties in these systems, which may allow their use in nanobiomedicine. PMID- 29761706 TI - Genotoxic and cytotoxic effects of Haas appliance in exfoliated buccal mucosa cells during orthodontic treatment. AB - OBJECTIVES: To evaluate the genotoxic and cytotoxic effects of Haas appliances through micronuclei test and cytogenetic damage analysis in buccal mucosa epithelial cells of patients undergoing orthodontic treatment. MATERIALS AND METHODS: Twenty-eight patients, 6-12 years of age and of both genders, who required a Haas appliance for the correction of a posterior crossbite were included. Epithelial cells from the mucosa were collected by gently scraping the inside of both the right and left cheeks. The cells were collected before the insertion of the appliance (T0), 1 month after the device was installed (T1), and again 3 months after the appliance was immobilized (T2). The cells were processed to obtain slides. Feulgen/Fast Green was used as the staining method, and the number of normal, karyolytic, pyknotic, nuclear buds, bi/trinucleated, and micronucleus cells were counted under light microscopy. Cellular abnormalities were evaluated with parametric and nonparametric tests for comparison of the means by analysis of variance testing, Tukey posttest, or the Kruskal-Wallis test and then by Dunn's posttest. The significance level was 5%. RESULTS: There were no statistically significant changes in the micronuclei in the evaluated periods ( P > .05). Nuclear buds increased at T1 ( P < .05), returning to baseline levels at T2. Other abnormalities (cariolytic, pyknotic, and bi/trinucleated cells) showed a significant increase at T1 and T2 ( P < .0001). CONCLUSIONS: The Haas appliance did not cause an increase in micronuclei in cells of the buccal mucosa. However, statistically significant increases in cariolytic, pyknotic, and bi/trinucleated cells were observed during treatment, suggesting possible DNA damage. PMID- 29761707 TI - Evaluation of the load system produced by a single intrusion bend in a maxillary lateral incisor bracket with different alloys. AB - OBJECTIVES: To evaluate if a 0.5-mm vertical bend applied on an incisor bracket produces movements in other planes and if different wires influence these effects. MATERIALS AND METHODS: An acrylic model of a treated patient with brackets passively bonded was attached to an Orthodontic Force Tester, and a load cell was attached to the left lateral incisor. Thirty 0.019 * 0.025-inch archwires were divided into three groups according to their alloy: SS (stainless steel), B-Ti (beta-titanium), and MF (beta-titanium wire coated with nickel titanium). Step-bends of 0.5 mm high were placed on the lateral incisor bracket using a universal plier, and the forces and moments in three dimensions were statistically analyzed by analysis of variance and Tukey post hoc test. RESULTS: SS produced a larger force (3.4 N) than the B-Ti (1.41 N) and the MF (0.53 N; P < .001). Lingual forces were produced by the SS (0.82 N) and B-Ti (0.31 N) groups, while in the MF group, the force was insignificant. SS produced a mesial force of 0.24 N, while the B-Ti force was insignificant and MF produced 0.09 N. Groups produced different crown-distal tipping moments (SS = 31.48 N-mm, B-Ti = 11.7 N mm, and MF = 4.55 N-mm) and different crown-buccal tipping moments. SS produced larger moments (3.63 N-mm) than B-Ti (1.02 N-mm) and MF (0.36 N-mm) wires. A mesial-out rotational moment was observed in all groups (SS = 7.17 N-mm, B-Ti = 3.46 N-mm, and MF = 0.86 N-mm). CONCLUSIONS: A 0.5-mm intrusion bend produced lingual and mesial side effects. In addition to the distal and buccal crown tipping moments, there was a mesial-out moment. Compared with SS, B-Ti and MF wires produced lower forces. These more flexible wires showed side effects with lesser intensity. PMID- 29761709 TI - Close, squeeze, open: introducing the cardiac cycle and pressure-volume loop. PMID- 29761708 TI - The potential of interprofessional education to translate physiology curricula effectively into future team-based healthcare. AB - Incorporating active interprofessional education (IPE) opportunities into the classroom setting is a potentially effective mechanism to enhance student learning both in the basic sciences and for future interprofessional collaboration. We integrated an IPE exercise into a graduate-level human physiology course at our health sciences center that enrolled physician assistant (PA), physical therapy (PT), and graduate studies students. Our activity adopted and targeted the four Interprofessional Education Collaborative (IPEC) competency domains of values/ethics (VE), roles/responsibilities, interprofessional communication, and teams and teamwork (TT). Effectiveness of the training exercise was determined via pre- and postsurveys, which assessed student self perceptions of IPEC competency domains, as well as student reflections and evaluations of the exercise itself. We noted a significant improvement in each of the targeted IPEC subcompetencies among all of the students, and within both PT and PA groups when analyzed separately. Moreover, a positive correlation was found between the number of previous IPE experiences and presurvey IPEC VE and TT subcompetency ratings. Our discoveries provide an example of broad acquisition of IPE learning within the context of a physiology curriculum. Perhaps more importantly, our findings indicate that a history of IPE training sets the stage for future IPE learning, reflecting a potential for IPE to transform basic physiological principles into team-based practice and improvement in patient outcomes. PMID- 29761710 TI - Who's the boss: determining the control pathways of cardiovascular and cellular immune responses to acute stress. AB - Acute stress responses are known to include increases in heart rate and blood pressure, as well as increases in the number of circulating immune cells, all of which are governed by the autonomic nervous system. This laboratory practical measures cardiovascular and circulating immune cell responses to a passive (cold pressor) and active (mental arithmetic) acute stress task in student participants. The results allow them to examine the different patterns of autonomic response they elicit (approximated by heart rate and blood pressure responses), and knowledge of these responses can then be used to infer the governing autonomic aspect of the increases in circulating immune cells from the results. This activity can be either adapted from teacher-led methods to inquiry, asking students to design the details of the acute stress tasks, or developed by asking students to design a follow-up experiment that could be used to provide direct evidence for their conclusions. Data collected provide a platform for teaching data analysis and interpretation, as well as critical thinking. PMID- 29761711 TI - A simple model for demonstrating the factors affecting glomerular filtration rate. PMID- 29761712 TI - An alternative introduction to reading and evaluating the primary literature for beginning graduate students. AB - Students are challenged in transitioning from acquiring knowledge and understanding through reading textbooks to their learning to select, read, evaluate, and synthesize the primary literature. A customary approach to teaching this transition to beginning graduate students is for a faculty member to assign "readings" from the recent literature that promise to become key publications; such assignments generally underscore recent, novel scientific content. We advocate here an alternative approach for coaching students very early in their training: first, to read, analyze, and discuss a paper that highlights critically important features of effective and valid experimental design; and, second, to study a paper that can be shown historically to have fundamentally changed the way in which physiological function is understood. We consider as an example of the first goal a study that purports to demonstrate a principle of thermoregulation, but that interaction between students and instructor reveals the study's lack of an essential control. The second goal requires sufficient time for the publication to concretely validate its contribution(s). The purpose is to identify those essential properties of the selected paper that contributed to its having become a truly exemplary study. We present a 1957 paper by Dr. A. C. Burton ( Am Heart J 54: 801-810, 1957) as an illustration and analyze the study with respect to those attributes that contributed to its lasting importance. These alternative approaches to introduce inexperienced students to the original literature can produce critical insight into the process and can help students inculcate essential practices, guiding them to more productive careers. PMID- 29761713 TI - Blockage of the tracheal bronchus: effects on blood oxygen content, partial pressure of oxygen, and intrapulmonary shunt. PMID- 29761714 TI - Design and implementation of a student-taught course on research in regenerative medicine. AB - In the Undergraduate School of Engineering and Applied Sciences (SEAS) at the University of Virginia (UVa), there are few opportunities for undergraduate students to teach, let alone develop, an introductory course for their major. As two undergraduate engineering students (D. N. Tavakol and C. J. Broshkevitch), we were among the first students to take advantage of a new initiative at UVa SEAS to offer student-led courses. As part of this new program, we designed a 1000 level, 1-credit, pass-fail course entitled Introduction to Research in Regenerative Medicine. During a student's first year at the University, opportunities to build research skills and gain exposure to topics within the field of the biomedical sciences are relatively rare, so, to fill this gap, we focused our course on teaching primarily freshman undergraduate students how to synthesize and contextualize scientific literature, covering both basic science and clinical applications. At the end of the course, students self-reported increased confidence in reading and discussing scientific papers and review articles. The critical impact of this course lies not only in an early introduction to the popularized field of regenerative medicine, but also encouragement for younger students to participate in research early on and to appreciate the value of interdisciplinary interactions. The teaching model can be extended for implementation of student-taught introductory courses across diverse undergraduate major tracks at an institution. PMID- 29761715 TI - A survey of student engagement with multiple resources in an undergraduate physiology course: retrieve or look it up. AB - Retrieval practice, a deep-learning technique in which the learner attempts to recall a concept of interest from memory, has been shown to be more effective than surface-learning techniques, such as rereading a textbook. Accordingly, textbook publishers are developing supplemental resources that are purported to improve student learning outcomes by encouraging deep learning and critical thinking. The purpose of this study is to 1) survey students in a physiology course about their use of multiple course resources; and 2) assess the effect of self-reported engagement in course resources on learning outcomes, as assessed by comparing course grades. Students who had completed an undergraduate physiology course were sent an online survey about their course experience; two reminders were e-mailed. Students were asked to report their physiology course grade, satisfaction with how much they had learned, which resources they had used, and how they had completed course assignments (critical thinking exercises and online quizzes), i.e., whether they had 1) looked up answers online, 2) looked up answers in the textbook, 3) tried to figure out the answers before using the textbook, or 4) only used their recall. Categories 1 and 2 were considered nonretrieval strategies, and categories 3 and 4 were considered retrieval strategies. There was no association with the type of resource students used and course grade or course satisfaction. Students who practiced retrieval strategies achieved significantly higher course grades than students who did not for both critical thinking exercises and online quizzes. PMID- 29761716 TI - From cheese curls to fatty acid structure: using "commonplace" analogies to teach science to nonmajors. PMID- 29761717 TI - 2017 Meeting of the National Directors of Graduate Studies in Pharmacology and Physiology. AB - The National Directors of Graduate Studies biennial meeting is a forum for directors from pharmacology and physiology graduate programs to discuss challenges and best practices for programs that are preparing trainees to be successful in the biomedical workforce. The 2017 meeting was held on the campus of Stony Brook University in Stony Brook, NY. Over the course of the 3-day event, several themes evolved, including graduate education training and curricula, diversity and career development, and scientific rigor and communication. Overall, presentations and discussions highlighted the challenges and opportunities for training PhD biomedical scientists and featured best practices from across the country. PMID- 29761718 TI - Explorations in statistics: the log transformation. AB - Learning about statistics is a lot like learning about science: the learning is more meaningful if you can actively explore. This thirteenth installment of Explorations in Statistics explores the log transformation, an established technique that rescales the actual observations from an experiment so that the assumptions of some statistical analysis are better met. A general assumption in statistics is that the variability of some response Y is homogeneous across groups or across some predictor variable X. If the variability-the standard deviation-varies in rough proportion to the mean value of Y, a log transformation can equalize the standard deviations. Moreover, if the actual observations from an experiment conform to a skewed distribution, then a log transformation can make the theoretical distribution of the sample mean more consistent with a normal distribution. This is important: the results of a one-sample t test are meaningful only if the theoretical distribution of the sample mean is roughly normal. If we log-transform our observations, then we want to confirm the transformation was useful. We can do this if we use the Box-Cox method, if we bootstrap the sample mean and the statistic t itself, and if we assess the residual plots from the statistical model of the actual and transformed sample observations. PMID- 29761719 TI - Chicken intestine: an alternative to the mammalian intestine for physiology experimentation. PMID- 29761720 TI - Ronald Malt or Chen Zhongwei: Who performed the first surgical replantation? AB - This article discusses the contributions of the two pioneers of the surgical procedure of replantation-Ronald Malt in the US and Chen Zhongwei in China. Ronald Malt performed the reattachment surgery on a boy who had an accident in 1962, but he published his case report two years later in 1964. Chen Zhongwei performed a similar surgery on a worker who cut off his forearm in 1963, but he published his case report the same year. There is some debate about which one of these reputed surgeons should be given credit for being the first one to perform this breakthrough surgery, because although Malt was the first to perform the procedure, Zhongwei was the first to report it. To shed light on this controversy, criteria for scientific priority suggested by Ronald Vale and Anthony Hyman were applied. Although the criteria mainly favored Zhongwei as the pioneer of this procedure, he did not entirely fulfill one of the criteria. Therefore, the article could not present a definitive answer to the question, and it concludes by pointing out the highly commendable achievements and contributions of both Ronald Malt and Chen Zhongwei. PMID- 29761721 TI - Association between serum S100A1 level and Global Registry of Acute Coronary Events score in patients with non-ST-segment elevation acute coronary syndrome. AB - Objective Acute coronary syndrome (ACS) is associated with several clinical syndromes, one of which is acute non-ST-segment ACS (NSTE-ACS). S100A1 is a calcium-dependent regulator of heart contraction and relaxation. We investigated the association between the serum S100A1 level and the Global Registry of Acute Coronary Events (GRACE) risk score in patients with NSTE-ACS and the potential of using the serum S100A1 level to predict the 30-day prognosis of NSTE-ACS. Methods The clinical characteristics of 162 patients with NSTE-ACS were analyzed to determine the GRACE score. The serum S100A1 concentration was determined using fasting antecubital venous blood. The patients were divided into different groups according to the serum S100A1 level, and the 30-day NSTE-ACS prognosis was evaluated using Kaplan-Meier analysis. Results The serum S100A1 levels differed significantly among the groups. Correlation analysis showed that the serum S100A1 level was positively correlated with the GRACE score. Kaplan-Meier analysis revealed that the number of 30-day cardiac events was significantly higher in patients with an S100A1 level of >3.41 ng/mL. Conclusions S100A1 is a potential biomarker that can predict the progression of NSTE-ACS and aid in its early risk stratification and prognosis. PMID- 29761722 TI - A multicenter randomized controlled trial of two group education programs for fatigue in multiple sclerosis: Long-term (12-month) follow-up at one site. AB - BACKGROUND: A four-site RCT of Fatigue: Take Control (FTC), a multicomponent group program, found no significant differences from a control program, MS: Take Control (MSTC), in fatigue on the Modified Fatigue Impact Scale (MFIS) through 6 months. OBJECTIVE: Assess FTC for a delayed effect on fatigue. METHODS: Of 78 subjects at one site, 74 randomized to FTC or MSTC completed the MFIS at 12 months. RESULTS: Compared to baseline, FTC produced greater improvements in MFIS scores than MSTC (FTC -8.9 (confidence interval (CI): 32.2, 45), MSTC -2.5 (CI 39.6, 47.7), p = 0.03) at 12 months. CONCLUSION: The delayed effect of FTC on fatigue suggests the need for longer follow-up when assessing interventions for fatigue. PMID- 29761724 TI - Characterization of the Microbiota in Air- or Vacuum-Packed Crisp Grass Carp ( Ctenopharyngodon idella C. et V.) Fillets by 16S rRNA PCR-Denaturing Gradient Gel Electrophoresis and High-Throughput Sequencing. AB - The microbial communities in air- and vacuum-packed crisp grass carp ( Ctenopharyngodon idella C. et V.) fillets have not been characterized during chilled storage. High-throughput sequencing of bacterial 16S rRNA has now revealed that the bacterial community in fresh fillets is diverse and distinct from that in spoiled samples. The predominant phylum was Proteobacteria, and 66 genera were identified. In fresh fillets, the most abundant genera were Acinetobacter (53.3%), Wautersiella (6.3%), unclassified Alcaligenaceae (4.4%), Stenotrophomonas (3.8%), unclassified Enterobacteriaceae (3.8%), and Enhydrobacter (3.6%). These genera diminished during chilled storage and sometimes disappeared. At the end of storage, Aeromonas and Pseudomonas were the most abundant. Similar results were obtained by PCR-denaturing gradient gel electrophoresis. These data provide detailed insight into the evolving bacterial communities in air- and vacuum-packed crisp grass carp fillets during storage, revealing Aeromonas and Pseudomonas as major spoilage organisms. These data may be useful for improvement of crisp grass carp quality and shelf life during chilled storage. PMID- 29761723 TI - Knowledge and Attitudes Regarding HPV and Vaccination Among Chinese Women Aged 20 to 35 Years in Fujian Province: A Cross-Sectional Study. AB - The use of the human papillomavirus (HPV) vaccine was recently approved in Mainland China. This study determined the knowledge and attitudes of young women aged 20 to 35 years in Fujian Province, China, with regard to HPV and vaccination and explored the potential factors influencing their attitudes toward HPV vaccination. This was a cross-sectional study that collected data regarding the knowledge on and attitudes toward HPV and vaccination using questionnaires. Furthermore, the prevalence of HPV was determined from the sampled participants. A total of 1001 young women were included in the survey. This study demonstrated that the HPV prevalence rate was 15.7% (157/1001). Among all patients, 44.9% (n = 449) had heard of HPV; however, detailed knowledge about HPV was lacking. The majority (83.7%) expressed a willingness to be vaccinated. Specifically, knowledge of the dangers of HPV infection was significantly associated with the willingness to be vaccinated. In this study, women cited some concerns and expressed high expectations for the HPV vaccine, but the costs of vaccination reduced their willingness to be vaccinated. This study found that most patients did not have a detailed knowledge of HPV. Thus, there is a need for continued HPV promotion and education efforts, especially on the dangers of HPV infection, among young women aged 20 to 35 years in Fujian Province, China. Furthermore, it is important to subsidize the costs of vaccination for promoting vaccination campaigns in China. PMID- 29761725 TI - Pental was not sodium thiopental. PMID- 29761726 TI - John Foster Dulles, his medical history and its impact on Cold War politics. AB - John Foster Dulles was the United States Secretary of State during the administration of President Dwight D Eisenhower. At the height of the Cold War, Dulles was Eisenhower's emissary, traveling over 450,000 international miles, leading United States foreign policy. In November of 1956, during an international crisis involving the Suez Canal, Dulles became ill and underwent an operation for a perforated colon cancer. During much of his impactful term as Secretary of State, Dulles was being treated for this cancer that ultimately resulted in his death in May of 1959. This paper highlights the medical care of John Foster Dulles and the global events during his illness. PMID- 29761727 TI - Tubular colonic duplication in an adult: case report and brief literature review. AB - Gastrointestinal tract duplication is a rare congenital anomaly that can occur anywhere along the alimentary tract. Most of the reported patients present with acute abdomen during childhood. We describe a case of tubular colonic duplication in an adult. The patient was a 25-year-old woman who presented with abdominal pain, bloating, nausea, and emesis for 3 days. The physical examination was remarkable for abdominal distension, tenderness, and rigidity. Abdominal computed tomography scan revealed abnormal intestinal dilatation. Exploratory laparotomy was performed, and tubular colonic duplication was identified intraoperatively. The diagnosis was verified by postoperative pathology results. The patient was discharged on postoperative day 14 and followed for 2 years without specific events or complications. Furthermore, we reviewed the published literature on colorectal duplication in adults for the past two decades. PMID- 29761728 TI - Safety Assessment of Hydrolyzed Wheat Protein and Hydrolyzed Wheat Gluten as Used in Cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the product use, formulation, and safety data on hydrolyzed wheat protein and hydrolyzed wheat gluten, which function as skin- and hair-conditioning agents. The Panel determined that data from clinical and laboratory studies were sufficient to demonstrate that these ingredients will not elicit type 1 immediate hypersensitivity reactions in sensitized individuals and will not induce sensitization when the polypeptide lengths of the hydrolysates do not exceed 30 amino acids. The Panel concluded that hydrolyzed wheat gluten and hydrolyzed wheat protein are safe for use in cosmetics when formulated to restrict peptides to an average molecular weight of 3,500 Da or less. PMID- 29761729 TI - Safety Assessment of Magnesium Sulfate as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of magnesium sulfate, which functions as a bulking agent in cosmetic products and is reportedly used at concentrations up to 11% and 25% in leave-on and rinse-off products, respectively. The Panel noted that the history of safe medical use of magnesium sulfate provides further confidence that there are no significant toxicity concerns relating to systemic exposure to this ingredient after cosmetic product application. Furthermore, the extensive clinical experience of the Panel, including the results of numerous patch tests, indicates that magnesium salts do not have the potential to induce sensitization. The Panel also noted that results were negative for 50% magnesium sulfate in a mouse skin irritation study and in an in vitro sensitization assay. The Panel concluded that magnesium sulfate is safe in cosmetics in the present practices of use and concentration described in the safety assessment. PMID- 29761730 TI - Safety Assessment of Tromethamine, Aminomethyl Propanediol, and Aminoethyl Propanediol as Used in Cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) reviewed the safety of tromethamine, aminomethyl propanediol, and aminoethyl propanediolas used in cosmetics. All 3 ingredients are reported to function in cosmetics as pH adjusters, and tromethamine and aminomethyl propanediol are also reported to function as fragrance ingredients. The Panel reviewed relevant animal and human data related to these ingredients, along with a previous safety assessment of aminomethyl propanediol. The Panel concluded that tromethamine, aminomethyl propanediol, and aminoethyl propanediol are safe in cosmetics in the practices of use and concentration as given in this safety assessment. PMID- 29761731 TI - Safety Assessment of Alkyl Betaines as Used in Cosmetics. AB - The Cosmetic Ingredient Review Expert Panel (Panel) reviewed the safety of 11 alkyl betaines as used in cosmetics. These ingredients are reported to function as hair and skin conditioning agents, antistatic agents, surfactants-cleansing agents, and viscosity-increasing agents in cosmetic products. Although there are data gaps, the shared chemical core structure, similar functions and concentrations of use in cosmetics, and the expected similarities in physicochemical properties enabled grouping these ingredients and reading across the available toxicological data to support the safety assessment of each individual compound in the entire group. The Panel concluded alkyl betaines were safe as cosmetic ingredients in the present practices of use and concentration, when formulated to be nonirritating. PMID- 29761732 TI - Safety Assessment of Polyether Lanolins as Used in Cosmetics. AB - The Cosmetic Ingredient Review (CIR) Expert Panel (Panel) assessed the safety of 39 polyether lanolin ingredients as used in cosmetics. These ingredients function mostly as hair conditioning agents, skin conditioning agent-emollients, and surfactant-emulsifying agents. The Panel reviewed available animal and clinical data, from previous CIR safety assessments of related ingredients and components. The similar structure, properties, functions, and uses of these ingredients enabled grouping them and using the available toxicological data to assess the safety of the entire group. The Panel concluded that these polyether lanolin ingredients are safe in the practices of use and concentration as given in this safety assessment. PMID- 29761733 TI - Letter regarding the article by Aatif et al. PMID- 29761736 TI - Treating neuromyelitis optica with azathioprine: 20-year clinical practice. AB - BACKGROUND: Neuromyelitis optica leads to severe disability. Preventive treatment includes steroids and immunosuppressants, and indications are based on retrospective and observational studies. METHODS: We analyzed 158 patients with neuromyelitis optica regarding disease course, prognostic factors, and treatment response to azathioprine, a widely available low-cost drug. Disability accumulation was used as an endpoint to treatment response. RESULTS: Eight patients with monophasic and 150 with relapsing disease with a median 7 years of disease duration and 4.6 years of follow-up were evaluated. All relapsing patients received preventive treatment, 100 with azathioprine. Only 30% reached Expanded Disability Status Scale (EDSS) 6, and 69% of patients presented no disability accumulation along follow-up. The time under azathioprine and prednisone use were inversely correlated to the hazard of disability accumulation (hazard ratio (HR) = 0.981 and 0.986, respectively; p < 0.01). Each month under azathioprine use reduced disability accumulation by 2.6% (HR = 0.974, p < 0.01), corresponding to an 80% decrease in EDSS progression over 5 years. INTERPRETATION: We report less disability accumulation than previous series on patients with neuromyelitis optica, two-thirds presenting no disability accumulation along follow-up. Continued azathioprine used from early disease onset was strongly associated to maintenance of neurological function and should be offered as a viable option for low-income scenarios. PMID- 29761735 TI - Spatial Release From Masking in 2-Year-Olds With Normal Hearing and With Bilateral Cochlear Implants. AB - This study evaluated spatial release from masking (SRM) in 2- to 3-year-old children who are deaf and were implanted with bilateral cochlear implants (BiCIs), and in age-matched normal-hearing (NH) toddlers. Here, we examined whether early activation of bilateral hearing has the potential to promote SRM that is similar to age-matched NH children. Listeners were 13 NH toddlers and 13 toddlers with BiCIs, ages 27 to 36 months. Speech reception thresholds (SRTs) were measured for target speech in front (0 degrees ) and for competitors that were either Colocated in front (0 degrees ) or Separated toward the right (+90 degrees ). SRM was computed as the difference between SRTs in the front versus in the asymmetrical condition. Results show that SRTs were higher in the BiCI than NH group in all conditions. Both groups had higher SRTs in the Colocated and Separated conditions compared with Quiet, indicating masking. SRM was significant only in the NH group. In the BiCI group, the group effect of SRM was not significant, likely limited by the small sample size; however, all but two children had SRM values within the NH range. This work shows that to some extent, the ability to use spatial cues for source segregation develops by age 2 to 3 in NH children and is attainable in most of the children in the BiCI group. There is potential for the paradigm used here to be used in clinical settings to evaluate outcomes of bilateral hearing in very young children. PMID- 29761737 TI - Predictive validity of NEDA in the 16- and 21-year follow-up from the pivotal trial of interferon beta-1b. AB - BACKGROUND: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS). OBJECTIVE: To examine the predictive validity of different NEDA definitions. METHODS: Predictive validity for negative disability outcomes (NDOs) at 16 years and survival at 21 years post-randomization were assessed. NEDA in the first 2 years was defined as follows: clinical NEDA: no relapses or Expanded Disability Status Scale (EDSS) progression from baseline to Year 2; NEDA-3a: no relapses, no confirmed ?1-point EDSS progression, and no new T2-active lesions; NEDA-3b: no relapses, no EDSS progression, and no increase in T2 burden of disease (T2-BOD); and NEDA-4: no relapses, no EDSS progression, and no increase in T2-BOD or atrophy. NDOs were defined as death, need for wheelchair, EDSS ?6, or progressive MS. RESULTS: A total of 245 and 371 patients were evaluated at 16 and 21 years, respectively. Clinical NEDA predicted NDOs ( p = 0.0029), as did baseline EDSS ( p < 0.0001), baseline T2-BOD ( p < 0.0001), and change in T2-BOD ( p = 0.0033). IFNB-1b treatment ( p = 0.0251), relapse rate in the 2 years before study start ( p = 0.0260), T2-BOD at baseline ( p = 0.0014), and change in T2-BOD ( p = 0.0129) predicted survival at 21 years. CONCLUSION: Clinical NEDA predicted long-term disability outcome. By contrast, definitions of NEDA that included on-therapy changes in magnetic resonance imaging variables did not increase the predictive validity. PMID- 29761734 TI - Functional effects of TrkA inhibition on system xC--mediated glutamate release and cancer-induced bone pain. AB - Breast cancer cells release the signalling molecule glutamate via the system xC- antiporter, which is upregulated to exchange extracellular cystine for intracellular glutamate to protect against oxidative stress. Here, we demonstrate that this antiporter is functionally influenced by the actions of the neurotrophin nerve growth factor on its cognate receptor tyrosine kinase, TrkA, and that inhibiting this complex may reduce cancer-induced bone pain via its downstream actions on xCT, the functional subunit of system xC-. We have characterized the effects of the selective TrkA inhibitor AG879 on system xC- activity in murine 4T1 and human MDA-MB-231 mammary carcinoma cells, as well as its effects on nociception in our validated immunocompetent mouse model of cancer induced bone pain, in which BALB/c mice are intrafemorally inoculated with 4T1 murine carcinoma cells. AG879 decreased functional system xC- activity, as measured by cystine uptake and glutamate release, and inhibited nociceptive and physiologically relevant responses in tumour-bearing animals. Cumulatively, these data suggest that the activation of TrkA by nerve growth factor may have functional implications on system xC--mediated cancer pain. System xC--mediated TrkA activation therefore presents a promising target for therapeutic intervention in cancer pain treatment. PMID- 29761738 TI - eMSQOL-29: Prospective validation of the abbreviated, electronic version of MSQOL 54. AB - BACKGROUND: We recently devised a shortened version of the 54-item Multiple Sclerosis Quality of Life (MSQOL-54) in paper (MSQOL-29, consisting of 25 items forming 7 subscales and 4 single items, and one filter question for 3 'sexual function' items) and electronic format (eMSQOL-29). OBJECTIVES: To prospectively assess eMSQOL-29 psychometric properties, acceptability/equivalence versus MSQOL 29. METHODS: Multiple sclerosis (MS) patients ( n = 623; Expanded Disability Status Scale (EDSS) range 0.0-9.0) completed eMSQOL-29, Hospital Anxiety and Depression Scale, Functional Assessment of MS (FAMS), European Quality of life Five Dimensions-3L, and received EDSS and Symbol Digit Modalities Test (SDMT). Equivalence versus MSQOL-29 was assessed in 242 patients (randomized cross-over design). RESULTS: 'Sexual function' items were filtered out by 273 patients (47%). No multi-item scale had floor effect, while five had ceiling effect. Cronbach's alpha range was 0.88-0.90. Confirmatory factor analysis showed good overall fit and the two-factor solution for composite scores was confirmed. Criterion validity was sub-optimal for 'cognitive function' (vs SDMT, r = 0.25) and 'social function' (vs FAMS social function, r = 0.38). eMSQOL-29 equivalence was confirmed and its acceptability was good. CONCLUSION: eMSQOL-29 showed good internal consistency, factor structure and no floor effect, while most subscales had some ceiling effect. Criterion validity was sub-optimal for two subscales. Equivalence and acceptability were good. PMID- 29761739 TI - Efficacy, safety and quality of life in patients receiving subcutaneous IgG treatment: experience in Bogota, Colombia. AB - AIM: Investigate efficacy, safety and quality of life of Gammanorm(r) 16.5% (subcutaneous immunoglobulin [SCIG]) in patients with primary immunodeficiencies (PIDs) and safety and to lesser extent efficacy in autoimmune diseases. PATIENTS & METHODS: Medical records were extracted from 31 pediatric and 12 adult patients who received SCIG as part of the Personalized Program at University Children's Hospital, Bogota, Colombia. RESULTS: Mean SCIG dose was 28.7 g/month. Serious bacterial infections were observed in 7/33 patients in the PID group, most often bacterial pneumonia (3/33). There were no serious adverse events related to SCIG treatment. Drug-related adverse reactions were reported in 2/43 patients. CONCLUSION: Self-administration of SCIG provided effective protection, favorable tolerability and improved quality of life in patients with PIDs and autoimmune diseases from Colombia. PMID- 29761740 TI - Treatment of Cutaneous Warts With Multiple Puncture Technique. AB - BACKGROUND: Despite a multitude of treatment options, cutaneous warts on the hands can be a recalcitrant clinical problem. METHODS: Based on Current Procedural Terminology ( CPT) billing codes, the office database was searched for a 10-year period of warts treated with a puncture technique after institutional review board approval. Office notes were examined, and patients were contacted to assess wart resolution or the need for further treatment as well as any complications. RESULTS: Of 16 patients who were identified with the treatment and diagnosis, 13 were able to be contacted. Median time to resolution was 22 days with a range of 10 to 30 days. Median size was 10 mm, range of 6 to 20 mm. Patients ages ranged from 7 to 88 years. Symptom duration prior to treatment was a median of 16 months, range of 5 to 48 months. Follow-up median was 6 years, range of 2 to 156 months. Three patients were less than 1 year from treatment, all others had follow-up more than 4 years. Complete resolution was seen in 11 patients (85%). Four patients had resolution of other warts in the local area who were not treated with puncture. Three patients had resolution of untreated warts at distant sites. Other than local tenderness, there were no complications. CONCLUSIONS: Barbotage, the multiple puncture of cutaneous warts, may be a reasonable treatment with minimal morbidity. PMID- 29761742 TI - ? PMID- 29761744 TI - ? PMID- 29761743 TI - ? PMID- 29761745 TI - ? PMID- 29761746 TI - ? PMID- 29761747 TI - Changes in Hindfoot Alignment After High or Low Tibial Osteotomy. AB - BACKGROUND: We aimed to determine the change in hindfoot alignment after high (HTO) or low tibial osteotomy (LTO), which is commonly performed to prevent the progression of arthritis of the knee or ankle. METHODS: We retrospectively reviewed the radiographic findings of patients who underwent HTO or LTO for arthritis with varus deformity of the knee or ankle joint. The hindfoot alignment view angle (HAVA), hindfoot alignment ratio (HAR), and hindfoot moment arm (HMA) were measured using the hindfoot alignment radiographs. All radiographic parameters were measured at 3, 6, and 12 months postoperatively to assess serial changes. RESULTS: In the HTO group, the HAVA and HMA were significantly increased at 12 months postoperatively compared to preoperatively ( P = .03 and .001, respectively). Similarly, the HAR increased from 0.23 preoperatively to 0.44 at 12 months postoperatively, which was a statistically significant change ( P = .001). In the LTO group, the 12-month postoperative HAVA, HAR, and HMA were significantly decreased ( P = .001 for each), which represented a hindfoot alignment change to the valgus position. CONCLUSIONS: After HTO, preoperative hindfoot valgus deviation was significantly decreased at 12 months and approached normal values, while the preoperative mild hindfoot varus alignment was changed to valgus deviation after LTO. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 29761748 TI - Transfemoral Amputation Adductor Myodesis Using FiberTape and Knotless Anchors. AB - : Transfemoral amputation is considered the last treatment option for severe infection, vascular disease, trauma, and malignant tumors of the lower extremity that have failed limb salvage. Unopposed pull of the hip abductors causes a flexion-abduction thigh deformity that results in abnormal biomechanics and increased oxygen consumption during ambulation. Myodesis of the adductor tendons is a critical component of transfemoral amputation that creates dynamic muscle balance, enhances prosthetic fitting and function, and improves clinical outcomes. Traditional adductor myodesis uses locking sutures passed through cortical drill holes along the anterolateral aspect of the distal femur that are tensioned and tied by hand. In this report we describe a novel technique for adductor myodesis using FiberTape suture and knotless anchors that we have found to be quick, easy, and reproducible with strong tendon-bone fixation. LEVEL OF EVIDENCE: Level V, expert opinion. PMID- 29761749 TI - Effects of Light and Temperature on Daily Activity and Clock Gene Expression in Two Mosquito Disease Vectors. AB - Most organisms feature an endogenous circadian clock capable of synchronization with their environment. The most well-known synchronizing agents are light and temperature. The circadian clock of mosquitoes, vectors of many pathogens, drives important behaviors related to vectoral capacity, including oviposition, host seeking, and hematophagy. Main clock gene expression, as well as locomotor activity patterns, has been identified in Aedes aegypti and Culex quinquefasciatus under artificial light-dark cycles. Given that these mosquito species thrive in tropical areas, it is reasonable to speculate that temperature plays an important role in the circadian clock. Here, we provide data supporting a different hierarchy of light and temperature as zeitgebers of two mosquito species. We recorded their locomotor activity and quantified mRNA expression of the main clock genes in several combinations of light and temperature cycles. We observed that A. aegypti is more sensitive to temperature, while C. quinquefasciatus is more responsive to light. These variations in clock gene expression and locomotor activity may have affected the mosquito species' metabolism, energy expenditure, fitness cost, and pathogen transmission efficiency. Our findings are relevant to chronobiology studies and also have epidemiological implications. PMID- 29761750 TI - Obesity Disrupts Rhythmic Clock Gene Expression in Maternal Adipose Tissue during Rat Pregnancy. AB - Obesity during pregnancy causes numerous maternal and fetal health complications, but the underlying mechanisms remain unclear. Adipose tissue dysfunction in obesity has previously been linked to disruption of the intrinsic adipose clock gene network that is crucial for normal metabolic function. This adipose clock also undergoes major change as part of the maternal metabolic adaptation to pregnancy, but whether this is affected by maternal obesity is unknown. Consequently, in this study we tested the hypothesis that obesity disturbs rhythmic gene expression in maternal adipose tissue across pregnancy. A rat model of maternal obesity was established by cafeteria (CAF) feeding, and adipose expression of clock genes and associated nuclear receptors ( Ppars and Pgc1alpha) was measured across days 15-16 and 21-22 of gestation (term = 23 days). CAF feeding suppressed the mesor and/or amplitude of adipose tissue clock genes (most notably Bmal1, Per2, and Rev-erbalpha) relative to chow-fed controls (CON) across both days of gestation. On day 15, the CAF diet also induced adipose Pparalpha, Ppardelta, and Pgc1alpha rhythmicity but repressed that of Ppargamma, while expression of Pparalpha, Ppardelta, and Pgc1alpha was reduced at select time points. CAF mothers were hyperleptinemic at both stages of gestation, and at day 21 this effect was time-of-day dependent. Fetal plasma leptin exhibited clear rhythmicity, albeit with low amplitude, but interestingly these levels were unaffected by CAF feeding. Our data show that maternal obesity disrupts rhythmic expression of clock and metabolic genes in maternal adipose tissue and leads to maternal but not fetal hyperleptinemia. PMID- 29761751 TI - Long-term clinical and cost-effectiveness of collaborative care (versus usual care) for people with mental-physical multimorbidity: cluster-randomised trial. AB - BACKGROUND: Collaborative care can support the treatment of depression in people with long-term conditions, but long-term benefits and costs are unknown.AimsTo explore the long-term (24-month) effectiveness and cost-effectiveness of collaborative care in people with mental-physical multimorbidity. METHOD: A cluster randomised trial compared collaborative care (integrated physical and mental healthcare) with usual care for depression alongside diabetes and/or coronary heart disease. Depression symptoms were measured by the symptom checklist-depression scale (SCL-D13). The economic evaluation was from the perspective of the English National Health Service. RESULTS: 191 participants were allocated to collaborative care and 196 to usual care. At 24 months, the mean SCL-D13 score was 0.27 (95% CI, -0.48 to -0.06) lower in the collaborative care group alongside a gain of 0.14 (95% CI, 0.06-0.21) quality-adjusted life years (QALYs). The cost per QALY gained was L13 069. CONCLUSIONS: In the long term, collaborative care reduces depression and is potentially cost-effective at internationally accepted willingness-to-pay thresholds.Declaration of interestNone. PMID- 29761752 TI - Addressing cancer patient and caregiver role transitions during home hospice nursing care. AB - OBJECTIVE: Many family caregivers and hospice patients experience role changes resulting from advancing illness and the need for increased caregiver responsibility. Successful navigation of conflicts that arise because of these role transitions has been linked to higher quality of patient care and improved caregiver bereavement adjustment. Nursing communication with patients and their caregivers plays an important role in facilitating these transitions. Our objective is to describe patient-caregiver-nurse communication during transitions at end of life. METHOD: A secondary, qualitative analysis was conducted on transcripts. Using an iterative process of constant comparison, coders inductively categorized nurse, caregiver, and patient communication behavior into overarching themes. Participants were home hospice nurses and cancer patient/spouse caregiver dyads; participants were >45 years of age, English speaking, and cognitively able to participate. Research took place in the home during nurse visits.ResultNineteen unique home hospice visits were analyzed. Patient-caregiver conflict occurred in two major content themes (1) negotiating transitions in patient independence and (2) navigating caregiver/patient emotions (e.g., frustration, sadness). Nurse responses to transition conflict included problem-solving, mediating, or facilitating discussions about conflicts. Nurse responses to emotional conflict included validation and reassurance.Significance of resultsOur findings provide insight into the topics and processes involved in patient and caregiver transitions in home hospice and the role hospice nursing communication plays in mediating potential conflict. Nurses are often asked to take on the role of mediator, often with little conflict resolution communication education; results can be used for nursing education. PMID- 29761753 TI - Against the Stream: religion and mental health - the case for the inclusion of religion and spirituality into psychiatric care. AB - This paper argues for the inclusion of religion and spirituality in psychiatric care. After discussing the antagonism of psychiatrists and psychologists to religion, I present a critical overview of studies examining the relationships between spirituality, religion and diverse aspects of mental health: depression, suicide, anxiety, delinquency, drug abuse and schizophrenia. The need to assesses the impact of religion in different faith groups is discussed. Measures of religious coping, both positive and negative, may provide a more accurate portrayal as to how individuals deploy religion in their lives than global measures such as belief and attendance. I highlight the fact that there is a dearth of research on ritual, prayer and other aspects of religious experience. While many studies demonstrate positive effects of religion on mental health, others find detrimental effects. Finally I examine the clinical implications of these findings.Declaration of interestNone. PMID- 29761754 TI - Pathways to Recovery: development and evaluation of a cognitive-behavioural therapy in-patient treatment programme for adults with anorexia nervosa. AB - : Aims and methodA cognitive-behavioural therapy in-patient treatment model for adults with severe anorexia nervosa was developed and evaluated, and outcomes were compared with the previous treatment model and other published outcomes from similar settings. RESULTS: This study showed the Pathways to Recovery outcomes were positive in terms of improvements in body mass index and psychopathology.Clinical implicationsAdults with anorexia nervosa can achieve good outcomes despite longer illness duration and comorbidities.Declaration of interestA.B., A.C. and L.H. work at The Retreat where the Pathways to Recovery were developed. PMID- 29761755 TI - A Deadly Wait for U.S. Health Insurance Coverage-Sitting on the Couch with Malaria. AB - Uninsured and unprepared travelers to countries with endemic tropical diseases pose great health-care burdens and financial risks on returning to the United States. We discuss the delayed presentation of an uninsured U.S. traveler returning from West Africa with severe malaria who required intensive care measures to save his life. Despite being critically ill on his return, he sat rigoring on his couch taking antipyretics for 3 days, while he applied for insurance on the Affordable Care Act website and waited for approval because he was fearful of the costs of seeking care. He also had limited access to affordable pretravel consultation and prophylactic medications and did not take them because he had no insurance. Average fees for a malaria hospitalization cost $25,789; however, this patient accumulated fees nearing $300,000-and his care was reimbursed by emergency Medicaid with $39,000, because his newly accepted insurance did not cover his hospitalization. This patients' experience in the U.S. health-care system with a deadly tropical disease exemplifies the need for affordable universal coverage of pretravel consultation and malaria prophylaxis. In this uncertain political time and the recent removal of the health insurance mandate, along with the White House and Congress wanting to reform health care, this case supports the American Society of Tropical Medicine and Hygiene (ASTMH) statements showing the need for funding of tropical medicine education, research, and public health services for travelers, not cuts to important agencies and insurances that keep our country safe from imported deadly tropical diseases. PMID- 29761756 TI - Evaluation of Standard and Mobile Health-Supported Clinical Diagnostic Tools for Assessing Dehydration in Patients with Diarrhea in Rural Bangladesh. AB - Diarrhea remains a leading cause of morbidity and mortality in patients worldwide. The objective of this study was to determine the relative inter-rater reliability and usability of standard and Mobile health (mHealth)-supported World Health Organization (WHO) algorithms for dehydration assessment in patients with acute diarrhea in a rural, low-income country hospital. Two nurses blinded to each other's examinations assessed dehydration status on patients soon after hospital arrival using either the standard WHO algorithm printed on a laminated card or an mHealth-supported WHO algorithm downloaded onto a smartphone. The assignment of assessment tool was based on odd or even enrollment date. The inter rater reliability for dehydration assessment between the two nurses was calculated using Cohen's K statistic for each study group. A total of 496 patients (< 5 years N = 349, > 5 years N = 147) were enrolled in the study; 132 (27%) had some or severe dehydration, and 364 (73%) had no dehydration on arrival. Cohen's K statistic demonstrated greater reliability for the mHealth supported dehydration assessment (0.59) compared with the standard assessment (0.50) in the overall population (P < 0.0001), as well as in the pediatric (0.43 versus 0.37, P < 0.0001) and adult (0.79 versus 0.57, P < 0.0001) populations individually. This is the first study to show that mHealth can improve the reliability of nursing dehydration assessment in patients with acute diarrhea and the first to report on the reliability of the WHO algorithm in adult patients specifically. Future studies should focus on the impact of mHealth-supported dehydration assessment on patient-centered outcomes and examine its reliability in different settings worldwide. PMID- 29761757 TI - Zika Virus: Knowledge Assessment of Residents and Health-Care Providers in Roatan, Honduras, following an Outbreak. AB - Few studies have evaluated the effectiveness of Zika virus (ZIKV) public health educational campaigns. Following a ZIKV educational campaign in Roatan, Honduras (October 2016), a survey was administered (March-May 2017) to residents (N = 348) and health-care professionals ([HCPs]; N = 44) to evaluate ZIKV knowledge, attitudes, and preventive practices, with attention to sexual health. Knowledge scores were calculated and mapped using participants' home locations. The knowledge scores between HCPs and residents were significantly different (mean 17 versus 11; P < 0.001). Only 6% of residents and 14% of HCPs knew that ZIKV was sexually transmissible. Few reported abstinence (2.6% residents; 9.4% HCPs) or condom use (1.6% residents; 12.5% HCPs) to prevent ZIKV infection. Of all subjects, 15.6% were pregnant or had a pregnant partner in the past year; 57.6% expressed concern over ZIKV. Mapping demonstrated spatial heterogeneity in knowledge. The findings suggest a need for improved public health messaging in ZIKV-affected areas. PMID- 29761758 TI - Genetic Variability of Plasmodium vivax in the North Coast of Peru and the Ecuadorian Amazon Basin. AB - In the Peruvian North Coast (PNC), the number of Plasmodium vivax malaria cases increased steadily from 2007 to 2010 despite a significant decline in the overall number of cases in Peru during the same period. To better understand the transmission dynamics of P. vivax populations in the PNC and the neighboring Ecuadorian Amazon Basin (EAB), we studied the genetic variability and population structure of P. vivax in these areas. One hundred and twenty P. vivax isolates (58 from Piura and 37 from Tumbes in the PNC collected from 2008 to 2010 and 25 from the EAB collected in Pastaza from 2001 to 2004) were assessed by five polymorphic microsatellite markers. Genetic variability was determined by expected heterozygosity (He) and population structure by Bayesian inference cluster analysis. We found very low genetic diversity in the PNC (He = 0-0.32) but high genetic diversity in the EAB (He = 0.43-0.70). Population structure analysis revealed three distinct populations in the three locations. Six of 37 (16%) isolates from Tumbes had an identical haplotype to that found in Piura, suggesting unidirectional flow from Piura to Tumbes. In addition, one haplotype from Tumbes showed similarity to a haplotype found in Pastaza, suggesting that this could be an imported case from EAB. These findings strongly suggest a minimal population flow and different levels of genetic variability between these two areas divided by the Andes Mountains. This work presents molecular markers that could be used to increase our understanding of regional malaria transmission dynamics, which has implications for the development of strategies for P. vivax control. PMID- 29761759 TI - Seasonal and Temporal Trends in Childhood Conjunctivitis in Burkina Faso. AB - Acute conjunctivitis follows a seasonal pattern. Although its clinical course is typically self-limited, conjunctivitis epidemics incur a substantial economic burden because of missed school and work days. This study investigated seasonal and temporal trends of childhood conjunctivitis in the entire country of Burkina Faso from 2013 to 2016, using routine monthly surveillance from 2,444 government health facilities. A total of 783,314 cases were reported over the 4-year period. Conjunctivitis followed a seasonal pattern throughout the country, with a peak in April. A nationwide conjunctivitis outbreak with a peak in September 2016 was noted (P < 0.001), with an excess number of cases first detected in June 2016. Nationwide passive surveillance was able to detect an epidemic 3 months before its peak, which may aide in allocation of resources for containment and mitigation of transmission in future outbreaks. PMID- 29761760 TI - Staphylococcus aureus Bacteremia Incidence and Methicillin Resistance in Rural Thailand, 2006-2014. AB - Staphylococcus aureus is a common cause of bloodstream infection and methicillin resistant S. aureus (MRSA) is a growing threat worldwide. We evaluated the incidence rate of S. aureus bacteremia (SAB) and MRSA from population-based surveillance in all hospitals from two Thai provinces. Infections were classified as community-onset (CO) when blood cultures were obtained <= 2 days after hospital admission and as hospital-onset (HO) thereafter. The incidence rate of HO-SAB could only be calculated for 2009-2014 when hospitalization denominator data were available. Among 147,524 blood cultures, 919 SAB cases were identified. Community-onset S. aureus bacteremia incidence rate doubled from 4.4 (95% confidence interval [CI]: 3.3-5.8) in 2006 to 9.3 per 100,000 persons per year (95% CI: 7.6-11.2) in 2014. The highest CO-SAB incidence rate was among adults aged 50 years and older. Children less than 5 years old had the next highest incidence rate, with most cases occurring among neonates. During 2009-2014, there were 89 HO-SAB cases at a rate of 0.13 per 1,000 hospitalizations per year (95% CI: 0.10-0.16). Overall, MRSA prevalence among SAB cases was 10% (90/911) and constituted 7% (55/736) of CO-SAB and 20% (22/111) of HO-SAB without a clear temporal trend in incidence rate. In conclusion, CO-SAB incidence rate has increased, whereas MRSA incidence rate remained stable. The increasing CO-SAB incidence rate, especially the burden on older adults and neonates, underscores the importance of strong SAB surveillance to identify and respond to changes in bacteremia trends and antimicrobial resistance. PMID- 29761761 TI - Leptospirosis among Returned Travelers: A GeoSentinel Site Survey and Multicenter Analysis-1997-2016. AB - Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand (N = 52), Costa Rica (N = 13), Indonesia, and Laos (N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases. PMID- 29761763 TI - In Southern Nigeria Loa loa Blood Microfilaria Density is Very Low Even in Areas with High Prevalence of Loiasis: Results of a Survey Using the New LoaScope Technology. AB - Ivermectin treatment can cause central nervous system adverse events (CNS-AEs) in persons with very high-density Loa loa microfilaremia (>= 30,000 mf/mL blood). Hypoendemic onchocerciasis areas where L. loa is endemic have been excluded from ivermectin mass drug administration programs (MDA) because of the concern for CNS AEs. The rapid assessment procedure for L. loa (RAPLOA) is a questionnaire survey to assess history of eye worm. If >= 40% of respondents report eye worm, this correlates with >= 2% prevalence of very high-density loiasis microfilaremia, posing an unacceptable risk of CNS-AEs after MDA. In 2016, we conducted a L. loa study in 110 ivermectin-naive, suspected onchocerciasis hypoendemic villages in southern Nigeria. In previous RAPLOA surveys these villages had prevalences between 10% and 67%. We examined 10,605 residents using the LoaScope, a cell phone-based imaging device for rapidly determining the microfilaria (mf) density of L. loa infections. The mean L. loa village mf prevalence was 6.3% (range 0 29%) and the mean individual mf count among positives was 326 mf/mL. The maximum individual mf count was only 11,429 mf/mL, and among 2,748 persons sampled from the 28 villages with >= 40% RAPLOA, the >= 2% threshold of very high Loa mf density could be excluded with high statistical confidence (P < 0.01). These findings indicate that ivermectin MDA can be delivered in this area with extremely low risk of L. loa-related CNS-AEs. We also concluded that in Nigeria the RAPLOA survey methodology is not predictive of >= 2% prevalence of very high density L. loa microfilaremia. PMID- 29761764 TI - Case Report: Filaria or Megasperm? A Cause of an Ultrasonographic "Filarial Dance Sign". AB - Bancroftian filariasis can cause genital abnormalities related to chronic inflammation and obstruction of the afferent lymphatic vessels, and may demonstrate a "filarial dance sign" on scrotal ultrasound with mobile echogenic particles observed. We present a patient with a positive "filarial dance sign," travel within Latin America, and negative filarial serology. PMID- 29761762 TI - Malaria Elimination: Time to Target All Species. AB - Important strides have been made within the past decade toward malaria elimination in many regions, and with this progress, the feasibility of eradication is once again under discussion. If the ambitious goal of eradication is to be achieved by 2040, all species of Plasmodium infecting humans will need to be targeted with evidence-based and concerted interventions. In this perspective, the potential barriers to achieving global malaria elimination are discussed with respect to the related diversities in host, parasite, and vector populations. We argue that control strategies need to be reorientated from a sequential attack on each species, dominated by Plasmodium falciparum to one that targets all species in parallel. A set of research themes is proposed to mitigate the potential setbacks on the pathway to a malaria-free world. PMID- 29761765 TI - Arbovirus Surveillance near the Mexico-U.S. Border: Isolation and Sequence Analysis of Chikungunya Virus from Patients with Dengue-like Symptoms in Reynosa, Tamaulipas. AB - A total of 1,090 residents of the city of Reynosa, Tamaulipas, on the Mexico-U.S. border presented at hospitals and clinics of the Secretariat of Health, Mexico, in 2015 with symptoms characteristic of dengue. Dengue virus (DENV) antigen was detected by enzyme-linked immunosorbent assay in acute sera from 134 (12.3%) patients. Sera from select patients (N = 34) were also tested for chikungunya virus (CHIKV) RNA by quantitative reverse transcription-polymerase chain reaction. Thirteen (38.2%) patients, including five DENV antigen-positive patients, were positive. Sera from three CHIKV RNA-positive patients were further assayed by virus isolation in cell culture and CHIKV was recovered on each occasion. The genome of one isolate and structural genes of the other two isolates were sequenced. In conclusion, we present evidence of CHIKV and DENV coinfections in patients who live near the Mexico-U.S. border and provide the first genome sequence of a CHIKV isolate from northern Mexico. PMID- 29761766 TI - Factors Associated with the Rapid and Durable Decline in Malaria Incidence in El Salvador, 1980-2017. AB - A decade after the Global Malaria Eradication Program, El Salvador had the highest burden of malaria in Mesoamerica, with approximately 20% due to Plasmodium falciparum. A resurgence of malaria in the 1970s led El Salvador to alter its national malaria control strategy. By 1995, El Salvador recorded its last autochthonous P. falciparum case with fewer than 20 Plasmodium vivax cases annually since 2011. By contrast, its immediate neighbors continue to have the highest incidences of malaria in the region. We reviewed and evaluated the policies and interventions implemented by the Salvadoran National Malaria Program that likely contributed to this progress toward malaria elimination. Decentralization of the malaria program, early regional stratification by risk, and data-driven stratum-specific actions resulted in the timely and targeted allocation of resources for vector control, surveillance, case detection, and treatment. Weekly reporting by health workers and volunteer collaborators distributed throughout the country by strata and informed via the national surveillance system-enabled local malaria teams to provide rapid, adaptive, and focalized program actions. Sustained investments in surveillance and response have led to a dramatic reduction in local transmission, with most current malaria cases in El Salvador due to importation from neighboring countries. Additional support for systematic elimination efforts in neighboring countries would benefit the region and may be needed for El Salvador to achieve and maintain malaria elimination. El Salvador's experience provides a relevant case study that can guide the application of similar strategies in other countries committed to malaria elimination. PMID- 29761767 TI - Evaluation of Argentinean Bird Species as Amplifying Hosts for St. Louis Encephalitis Virus (Flavivirus, Flaviviridae). AB - St.Louis encephalitis virus (SLEV) is an emerging human pathogen flavivirus in Argentina. Recently, it has reemerged in the United States. We evaluated the role as amplifying host of six resident bird species and analyzed their capacity as host during the 2005 encephalitis outbreak of SLEV in Cordoba. Eared Dove, Picui Ground Dove, and House Sparrow were the three species with highest host competence index. At a city level, Eared Dove and Picui Ground Dove were the most important amplifying hosts during the 2005 SLEV human outbreak in Cordoba city. This finding highlighted important differences in the SLEV ecology between Argentina and the United States. Characterizing and evaluating the SLEV hosts contribute to our knowledge about its ecology and could help us to understand the causes that promote its emergence as a human pathogen in South America. PMID- 29761769 TI - ? PMID- 29761768 TI - Treatment Delay among Pulmonary Tuberculosis Patients within the Pakistan National Tuberculosis Control Program. AB - Delay in diagnosis and treatment worsens the disease and clinical outcomes, which further enhances transmission of tuberculosis (TB) in the community. Therefore, this study aims to assess treatment delay and its associated factors among pulmonary TB patients in Pakistan. A cross-sectional study was conducted among 269 pulmonary TB patients in the district. Binary and multivariate logistic regressions were used to explore the factors associated with delay in TB treatment. Results reveal that most patients were from low socioeconomic backgrounds. For example, 74.7% were living in kacha houses, 54.7% were from lowest the income group (< 250 US$/month), 60.2% married, 54.3% illiterate, 62.5% rural, 56.1% had no house ownership, and 56.5% had insufficient income for daily family expenditures. Significant delays were revealed by this study: 160 patients had experienced a delay of more than 4 weeks, whereas the median delay was 5 weeks. Results show that the most important reason for patient delay was low income and poverty (42.0%) followed by unaware of TB center (41.6), stigma (felt ashamed = 38.7%), and treatment from local traditional healers. Old age (adjusted odds ratio [AOR] = 6.6; 95% confidence interval [CI] = 1.63-26.95); and rural areas patients (AOR = 2.1; 95% CI = 1.15-3.71) were more likely to have experienced delay. However, the higher income and sufficient income category (AOR = 0.5; 95% CI = 0.31-0.95) were associated factors and less likely to experience delay in patient treatment. Integrative prevention interventions, such as those involving community leaders, health extension workers such as lady health workers, and specialized TB centers, would help to reduce delay and expand access to TB-care facilities. PMID- 29761770 TI - [Combination therapy of thyroxine and triiodothyronine in hypothyroid patients]. AB - Decreased quality of life is described more often in hypothyroid patients, who are treated with a synthetic form of thyroxine (L-T4), than in euthyroid controls. A combination of L-T4 and a synthetic form of triiodothyronine (L-T3) has been suggested; however, previous meta-analyses on unselected patients did not find any effect. Recent studies demonstrate, that the overall hypothalamic pituitary-thyroid-tissue homeostasis could be more complex than previously suggested. Polymorphisms in deiodinase and thyroid hormone transporter genes could theoretically explain, why a minor subgroup of hypothyroid patients seem to have an effect of L-T4/L-T3 combination therapy. PMID- 29761771 TI - [Melatonin for children with insomnia]. AB - Treatment for insomnia with melatonin (MT) in children and adolescents aged 0-17 years has doubled since 2011. The efficacy and safety profile for MT in children has not been determined. Recent clinical trials indicate, that MT only has a clinical effect on sleep latency, not on total sleep time. Furthermore, it has emerged, that proper sleep hygiene can cure the sleep problem in 50% of the children. Typically, the safety evaluation only entails an unclassified report of adverse events. Two long-term studies investigate and dispel the potential influence of MT on puberty. PMID- 29761772 TI - [Track and trigger systems in Denmark - small country, great variations]. AB - A track and trigger (TAT) system and mobile emergency team (MET) can aid observation and care for admitted patients in the hospital ward. We have examined the literature and find evidence, though not strong, that the introduction of TAT and MET systems reduce hospital mortality. However, in Denmark, many different TAT systems are used, and several hospitals do not have MET. We believe, that a standardised national TAT system could encourage interregional research and the investigation of system compliance, cost-benefit and impact on intensive care unit admissions. PMID- 29761773 TI - [Dyskeratosis follicularis]. AB - Dyskeratosis follicularis (or Darier's disease) is a genetic skin disease with an autosomal dominant inheritance and a prevalence of 1:100,000-1:35,000. Mutations in the gene ATP2A2 encoding the Ca2+-ATPase SERCA2 in the endoplasmatic reticulum lead to acantholysis and dyskeratosis in the epidermis, nails and mucosal membranes with resultant brown-yellow coloured, often infested skin papules and nail changes. The newly established Danish database for genodermatoses is embarking on an extensive registration of all Danish patients with Darier's disease. Hopefully, the establishment of this database will lead to better research and the formation of a patient association. PMID- 29761774 TI - [Tuberculosis among asylum seekers]. AB - Global migration is increasing, including migration from tuberculosis (TB) high incidence countries to TB low-incidence countries as Denmark. Asylum seekers are at increased risk of having TB, and screening for TB is potentially highly relevant in Europe. However, there is a large variation in the ways screening is carried out and in the yield of the different screening programmes. There is a need of more quality data on how effectively to target the screening among asylum seekers, considering both the TB incidence in the country of origin and the risk factors along the migration route. PMID- 29761775 TI - [The role of the Food and Drug Administration as times change]. AB - The prestigious journal Biostatistics published in July 2017 six solicited commentaries on the role of the U.S. Food and Drug Administration (FDA), as times change, with ever developing technical tools for clinical trials and their evaluation, with increased focus on personalised medicine (possibly aided by genetic testing), and on patient self-determination. Two were written by American economists, four by leading biostatisticians, mostly from the USA. This paper summarises these texts for a Danish audience. PMID- 29761776 TI - ? PMID- 29761777 TI - [Clinical manifestations of Epstein-Barr virus infection in children and adolescents]. AB - The most commonly known clinical manifestation of primary Epstein-Barr virus infection is infectious mononucleosis. In this review we cover the diagnostics and basic patho-physiology of Epstein-Barr virus infection and present the many clinical manifestations of the virus, including less well-known diseases such as hepatitis, auto-immune haemolytic anaemia, and neurological and immunological diseases. Our aim is to strengthen the clinicians' awareness and understanding of these conditions in order to improve diagnostics and avoid delay of treatment. PMID- 29761778 TI - [The relation between depression and inflammation]. AB - Accumulating evidence suggests, that inflammatory processes contribute to the pathophysiology of major depressive disorder. Subgroups of patients have elevated plasma levels of pro-inflammatory cytokines, which seem to normalise in response to conventional antidepressive treatment. In this review of the current studies on the relation between depression and inflammation we discuss possible future directions for individualised treatment of major depressive disorder. PMID- 29761779 TI - [Diagnosing and treating of onychomycosis]. AB - Onychomycosis is a frequent disorder, which accounts for approximately 50% of nail changes. Many patients are treated for onychomycosis without a mycological verification being done. The patients may be in risk of being treated for a non existent fungal infection with lack of effect and potential adverse events. This review highlights the importance of choosing the correct sampling and diagnostic methods, as genus and/or species identification is essential when choosing the optimal treatment strategies. PMID- 29761780 TI - [Sweet syndrome manifestations]. AB - Sweet syndrome (SS) exists as classical, malignancy-associated, drug-induced and as the new variants: giant cellulitis-like SS and neutrophilic dermatosis of the hands. SS exhibits different morphologies. Skin manifestations are usually accompanied by fever and neutrocytosis. All variants respond to systemic corticosteroids, but SS can recur. SS may be the first sign of malignancy or recurrence of previous cancer. It is important to be aware of the disease, which may mimic other reactive and febrile diseases, to enable patients to obtain the correct diagnostic set-up and treatment. PMID- 29761781 TI - [Post-dural puncture headache]. AB - Post-dural puncture headache (PDPH) is a frequent complication to procedures involving dural puncture. The condition is caused by excessive leakage of cerebrospinal fluid through the puncture, and it is most often seen in young women. The risk can be significantly reduced by using smaller, atraumatic needles. PDPH is characterised by a dull headache, which worsens in postural position. Usually, PDPH is a self-limiting condition, which resolves within a week with conservative treatment, but it may become chronic. Treatment with epidural blood patch is effective both in acute and chronic stages of PDPH. PMID- 29761782 TI - [Vulvar intraepithelial neoplasia]. AB - Vulvar intraepithelial neoplasia (VIN) is a rare but premalig-nant condition. VIN has two aetiological pathways: a human papillomavirus (HPV)-dependent pathway, which is a vulvar high-grade squamous intraepithelial lesion (HSIL), and an HPV independent pathway, called differentiated VIN (d-VIN), associated with lichen sclerosus. d-VIN is more aggressive than vulvar HSIL. In case of symptoms, a biopsy should be performed. The recurrence risk is high: 25-50% regardless of treatment type. We recommend treatment with imiquimod as first choice to avoid mutilating surgery. Particular attention must be payed to immunosuppressed patients with VIN. HPV-vaccine can be discussed with patients with vulvar HSIL. PMID- 29761783 TI - Preoptic leptin signaling modulates energy balance independent of body temperature regulation. AB - The adipokine leptin acts on the brain to regulate energy balance but specific functions in many brain areas remain poorly understood. Among these, the preoptic area (POA) is well known to regulate core body temperature by controlling brown fat thermogenesis, and we have previously shown that glutamatergic, long-form leptin receptor (Lepr)-expressing neurons in the POA are stimulated by warm ambient temperature and suppress energy expenditure and food intake. Here we further investigate the role of POA leptin signaling in body weight regulation and its relationship to body temperature regulation in mice. We show that POA Lepr signaling modulates energy expenditure in response to internal energy state, and thus contributes to body weight homeostasis. However, POA leptin signaling is not involved in ambient temperature-dependent metabolic adaptations. Our study reveals a novel cell population through which leptin regulates body weight. PMID- 29761784 TI - Ripply2 recruits proteasome complex for Tbx6 degradation to define segment border during murine somitogenesis. AB - The metameric structure in vertebrates is based on the periodic formation of somites from the anterior end of the presomitic mesoderm (PSM). The segmentation boundary is defined by the Tbx6 expression domain, whose anterior limit is determined by Tbx6 protein destabilization via Ripply2. However, the molecular mechanism of this process is poorly understood. Here, we show that Ripply2 directly binds to Tbx6 in cultured cells without changing the stability of Tbx6, indicating an unknown mechanism for Tbx6 degradation in vivo. We succeeded in reproducing in vivo events using a mouse ES induction system, in which Tbx6 degradation occurred via Ripply2. Mass spectrometry analysis of the PSM-fated ES cells revealed that proteasomes are major components of the Ripply2-binding complex, suggesting that recruitment of a protein-degradation-complex is a pivotal function of Ripply2. Finally, we identified a motif in the T-box, which is required for Tbx6 degradation independent of binding with Ripply2 in vivo. PMID- 29761786 TI - Association of a four-locus gene model including IL13, IL4, FCER1B, and ADRB2 with the Asthma Predictive Index and atopy in Chinese Han children. AB - BACKGROUND AND OBJECTIVE: Asthma is a complex and heterogeneous disease. We found that gene-gene interactions among IL13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108 in asthmatic children of Chinese Han nationality. This four locus set constituted an optimal statistical interaction model. Objective: This study examined associations of the four-gene model consisting of IL13, IL4, FCER1B, and ADRB2 with the Asthma Predictive Index (API) and atopy in Chinese Han children. METHODS: Four single-nucleotide polymorphisms (SNPs) in the four genes were genotyped in 385 preschool children with wheezing symptoms using matrix assisted laser desorption ionization time-of-flight mass spectrometry. Student's t test and x2 tests were used for this analysis. RESULTS: : Significant correlations were found between the four-locus gene model and the stringent and loose API (both P<0.0001). Additionally, a high-risk asthma genotype was a risk factor for the positive API (stringent API: OR= 4.08, loose API: OR=2.36). We also found a statistically significant association of the four-locus gene model with atopy (P<0.01, OR= 2.09). CONCLUSIONS: Our results indicated that the four locus gene model consisting of L13 rs20541, IL4 rs2243250, ADRB2 rs1042713 and FCER1B rs569108 was associated with the API and atopy. These findings provide an evidence of the gene model for determining a high risk of developing asthma and atopy in Chinese Han children. PMID- 29761787 TI - Osteoinducing scaffolds with multi-layered biointerface. AB - This study was aimed to design and characterise hybrid tissue-engineered constructs composed of osteoinducing polylactide-based scaffolds with multi layered cellular biointerface for bone tissue reconstruction. Three-dimensional scaffolds with improved hydrophilic and osteoinducing properties were produced using the surface-selective laser sintering (SSLS) method. The designed scaffold pattern had dimensions of 8 * 8 * 2.5 mm and ladder-like pores (~700 MUm in width). Hyaluronic acid-coated polylactide microparticles (~100 MUm in diameter) were used as building blocks and water was used as the photosensitizer for SSLS followed by photocross-linking with Irgacure 2959 photoinitiator. Resulting scaffolds provided successful adhesion and expansion of human bone marrow mesenchymal stromal cells from a single-cell suspension. Induced calcium deposition by the cells associated with osteogenic differentiation was detected in 7-21 days of culturing in basal medium. The values were up to 60% higher on scaffolds produced at a higher prototyping speed under the experimental conditions. Innovative approach to graft the scaffolds with multi-layered cell sheets was proposed aiming to facilitate host tissue-implant integration. The sheets of murine MS-5 stromal cell line exhibited contiguous morphology and high viability in a modelled construct. Thus, the SSLS method proved to be effective in designing osteoinducing scaffolds suitable for the delivery of cell sheets. PMID- 29761788 TI - Block-based robust control of stepping using intraspinal microstimulation. AB - OBJECTIVE: The problem of motor control using intraspinal microstimulation (ISMS) can be approached at two levels of the motor system: individual muscles (motor pools) and motor primitives. The major challenges of direct ISMS at the level of individual muscle are the number of electrodes that are required to be implanted in order to recruit all muscles involving the motion and muscle selectivity. One solution to cope with these problems is the control of movement generated by appropriate combination of the movement primitives. In this paper, we proposed a robust control framework using primitives for fully automatic block-based control of the motion through ISMS. APPROACH: The control framework is based on an adaptive fuzzy terminal sliding mode control. The biggest advantage of the controller is the fast convergence compared to the conventional sliding mode control. MAIN RESULTS: The experiments were conducted on spinally-intact anesthetized cats. Based on electromyography activity of the hindlimbs muscles, different movement blocks were defined. The results of block-based air-stepping control show that the proposed control framework could generate the gait cycle with good tracking performance. The averages of tracking error, over five cats, were 9.3%, 11.2%, and 16.1%, for the ankle, knee, and hip joints, respectively. The results of walking control on the moving treadmill demonstrated that the gait cycle can be generated only with two movement blocks for each leg. SIGNIFICANCE: The results of the current study demonstrated that the normal gait pattern can be achieved by tracking control of the movement blocks using ISMS, while the controller requires no offline learning phase and no pre-adjustment of the stimulation level. The controller is able to automatically regulate the interactions between movement blocks without any preprogrammed block activities. PMID- 29761785 TI - Discovery and characterization of a prevalent human gut bacterial enzyme sufficient for the inactivation of a family of plant toxins. AB - Although the human gut microbiome plays a prominent role in xenobiotic transformation, most of the genes and enzymes responsible for this metabolism are unknown. Recently, we linked the two-gene 'cardiac glycoside reductase' (cgr) operon encoded by the gut Actinobacterium Eggerthella lenta to inactivation of the cardiac medication and plant natural product digoxin. Here, we compared the genomes of 25 E. lenta strains and close relatives, revealing an expanded 8-gene cgr-associated gene cluster present in all digoxin metabolizers and absent in non metabolizers. Using heterologous expression and in vitro biochemical characterization, we discovered that a single flavin- and [4Fe-4S] cluster dependent reductase, Cgr2, is sufficient for digoxin inactivation. Unexpectedly, Cgr2 displayed strict specificity for digoxin and other cardenolides. Quantification of cgr2 in gut microbiomes revealed that this gene is widespread and conserved in the human population. Together, these results demonstrate that human-associated gut bacteria maintain specialized enzymes that protect against ingested plant toxins. PMID- 29761789 TI - pH- and redox-responsive nanoparticles composed of charge-reversible pullulan based shells and disulfide-containing poly(beta-amino ester) cores for co delivery of a gene and chemotherapeutic agent. AB - A novel pH- and redox-responsive nanoparticle system was designed based on a charge-reversible pullulan derivative (CAPL) and disulfide-containing poly(beta amino ester) (ssPBAE) for the co-delivery of a gene and chemotherapeutic agent targeting hepatoma. The end-alkene groups of ssPBAE were reacted with diethylenetriamine to form amino-modified ssPBAE (NH-ssPBAE). Methotrexate (MTX), a chemotherapy agent, was then conjugated to NH-ssPBAE via an amide bond to obtain the polymeric prodrug ssPBAE-MTX. ssPBAE-MTX exhibited a good capability for condensing genes, including plasmid DNA (pDNA) and tetramethyl rhodamine labeled DNA (TAMRA-DNA), and almost completely condensed pDNA at the weight ratio of 5/1 to form spherical nanocomplexes with a uniform size. In a D,L dithiothreitol solution, the ssPBAE-MTX/pDNA nanocomplexes showed rapid release of pDNA and MTX, indicating their redox-responsive capability. CAPL, a pullulan derivative containing beta-carboxylic amide bond, was efficiently coated on the surfaces of ssPBAE-MTX/pDNA nanocomplexes to form polysaccharide shells, thus realizing co-loading of the gene and chemotherapeutic agent. CAPL/ssPBAE-MTX/pDNA nanoparticles displayed an obvious pH-responsive charge reversal ability due to the rupture of the beta-carboxylic amide bond under the weakly acidic condition. In human hepatoma HepG2 cells, CAPL/ssPBAE-MTX/TAMRA-DNA nanoparticles were efficiently internalized via endocytosis and successfully escaped from the endo/lysosomes into the cytoplasm, and CAPL/ssPBAE-MTX/pDNA nanoparticles remarkably inhibited the cell growth. In summary, this nanoparticle system based on CAPL and ssPBAE showed great potential for combined gene/chemotherapy on hepatomas. PMID- 29761790 TI - Contact resistance reduction of ZnO thin film transistors (TFTs) with saw-shaped electrode. AB - We report on a saw-shaped electrode architecture ZnO thin film transistor (TFT), which effectively increases the channel width. The contact line of the saw-shaped electrode is almost twice as long at the contact metal/ZnO channel junction. We experimentally observed an enhancement in the output drive current by 50% and a reduction in the contact resistance by over 50%, when compared to a typically shaped electrode ZnO TFT consuming the same chip area. This performance enhancement is attributed to the extension of the channel width. This technique can contribute to device performance enhancement, and in particular reduce the contact resistance, which is a serious challenge. PMID- 29761791 TI - Selective synthesis of turbostratic polyhedral carbon nano-onions by arc discharge in water. AB - Carbon nano-onions (CNOs), in their spherical or polyhedral forms, represent an important class of nanomaterials, due to their peculiar physical and electrochemical properties. Among the different methods of production, arc discharge between graphite electrodes sustained by deionized water is one of the most promising to obtain good quality CNOs in gram quantities. We applied the method with the aim to optimize the production of CNOs, using an innovative experimental arrangement. The discharges generate dispersed nanomaterials and a black hard cathodic deposit, which were studied by transmission electron microscopy-high-resolution TEM, scanning electron microscopy, Raman, thermogravimetric analysis and energy-dispersive x-ray spectroscopy. A simple mechanical grinding of the deposits permitted us to obtain turbostratic polyhedral CNOs that exhibited higher stability towards burning in air, compared to CNOs found in water. We propose a mechanism for the formation of the CNOs present in the deposit, in which the crystallization is driven by a strong temperature gradient existing close to the cathode surface at the beginning of the process, and subsequently close to the deposit surface whenever it is growing. PMID- 29761792 TI - Kommerell's diverticulum: a rare cause of esophageal subepithelial lesion. PMID- 29761793 TI - Albers-Schonberg disease. PMID- 29761794 TI - Successful treatment of tracheoesophageal fistula using a covered esophageal stent. PMID- 29761795 TI - Direct cholangioscopy with argon plasma coagulation of an intraductal papillary mucinous neoplasm of the bile duct. PMID- 29761798 TI - Controlled photorelease of alkynoic acids and their decarboxylative deprotection for copper-catalyzed azide/alkyne cycloaddition. AB - A controlled photorelease of alkynoic acids from the meso-methyl BODIPY photoremovable protecting group facilitates their subsequent efficient decarboxylation to give terminal alkynes for a CuI-catalyzed azide/alkyne cycloaddition. The quantum efficiencies of the photochemical step and the kinetics of the click reaction step are reported. PMID- 29761800 TI - Abnormal sergeants-and-soldiers effects of poly(quinoxaline-2,3-diyl)s enabling discrimination of one-carbon homologous n-alkanes through a highly sensitive solvent-dependent helix inversion. AB - Poly(quinoxaline-2,3-diyl)s bearing (S)-3-octyloxymethyl and n-propoxymethyl side chains show an abnormal sergeants-and-soldiers effect in n-alkane solvents, which allows the development of a series of PQXs that exhibit an extremely sensitive solvent-dependent helix inversion that permits the discrimination of n-alkane solvents that differ by a single methylene group (e.g. n-heptane and n-octane). PMID- 29761796 TI - Study on the Mechanism of Cell Cycle Checkpoint Kinase 2 (CHEK2) Gene Dysfunction in Chemotherapeutic Drug Resistance of Triple Negative Breast Cancer Cells. AB - BACKGROUND This study aimed to investigate the mechanism of CHEK2 gene dysfunction in drug resistance of triple negative breast cancer (TNBC) cells. MATERIAL AND METHODS To perform our study, a stable CHEK2 wild type (CHEK2 WT) or CHEK2 Y390C mutation (CHEK2 Y390C) expressed MDA-MB-231 cell line was established. MTT assay, cell apoptosis assay and cell cycle assay were carried out to analyze the cell viability, apoptosis, and cell cycle respectively. Western blotting and qRT-PCR were applied for related protein and gene expression detection. RESULTS We found that the IC50 value of DDP (Cisplatin) to CHEK2 Y390C expressed MDA-MB-231 cells was significantly higher than that of the CHEK2 WT expressed cells and the control cells. After treatment with DDP for 48 h, cells expressing CHEK2 WT showed lower cell viability than that of the CHEK2 Y390C expressed cells and the control cells; compared with the CHEK2 Y390C expressed cells and the control cells, cells expressing CHEK2 WT showed significant G1/S arrest. Meanwhile, we found that compared with the CHEK2 Y390C expressed cells and the control cells, cell apoptosis was significantly increased in CHEK2 WT expressed cells. Moreover, our results suggested that cells expressing CHEK2 WT showed higher level of p-CDC25A, p-p53, p21, Bax, PUMA, and Noxa than that of the CHEK2 Y390C expressed cells and the control cells. CONCLUSIONS Our findings indicated that CHEK2 Y390C mutation induced the drug resistance of TNBC cells to chemotherapeutic drugs through administrating cell apoptosis and cell cycle arrest via regulating p53 activation and CHEK2-p53 apoptosis pathway. PMID- 29761801 TI - Electrocatalytic and photocatalytic hydrogen evolution integrated with organic oxidation. AB - Renewable energy-driven hydrogen production from electrocatalytic and photocatalytic water splitting has been widely recognized as a promising approach to utilize green energy resources and hence reduces our dependence on legacy fossil fuels as well as alleviates net carbon dioxide emissions. The realization of large-scale water splitting, however, is mainly impeded by its slow kinetics, particularly because of its sluggish anodic half reaction, the oxygen evolution reaction (OER), whose product O2 is ironically not of high value. In fact, the co production of H2 and O2 in conventional water electrolysis may result in the formation of explosive H2/O2 gas mixtures due to gas crossover and reactive oxygen species (ROS); both pose safety concerns and shorten the lifetimes of water splitting cells. With these considerations in mind, replacing the OER with thermodynamically more favorable organic oxidation reactions is much more preferred, which will not only substantially reduce the voltage input for H2 evolution from water and avoid the generation of H2/O2 gas mixtures and ROS, but also possibly lead to the co-production of value-added organic products on the anode. Indeed, such an innovative strategy for H2 production integrated with valuable organic oxidation has attracted increasing attention in both electrocatalysis and photocatalysis. This feature article showcases the most recent examples along this endeavor. As exemplified in the main text, the oxidative transformation of a variety of organic substrates, including alcohols, ammonia, urea, hydrazine, and biomass-derived intermediate chemicals, can be integrated with energy-efficient H2 evolution. We specifically highlight the importance of oxidative biomass valorization coupled with H2 production, as biomass is the only green carbon source whose scale is comparable to fossil fuels. Finally, the remaining challenges and future opportunities are also discussed. PMID- 29761807 TI - Photochemical reductive homologation of hydrogen cyanide using sulfite and ferrocyanide. AB - Photoredox cycling during UV irradiation of ferrocyanide ([FeII(CN)6]4-) in the presence of stoichiometric sulfite (SO32-) is shown to be an extremely effective way to drive the reductive homologation of hydrogen cyanide (HCN) to simple sugars and precursors of hydroxy acids and amino acids. PMID- 29761808 TI - Diversion of a thioglycoligase for the synthesis of 1-O-acyl arabinofuranoses. AB - An arabinofuranosylhydrolase from the GH51 family was transformed into an acyl transferase by mutation of the catalytic acid/base amino acid. The resulting enzyme was able to transfer carboxylic acid onto the anomeric position of arabinose with complete chemo- and stereoselectivity. A wide range of acyl alpha l-arabinofuranoses was obtained with yields ranging from 25 to 83%. Using this method, ibuprofen and N-Boc phenylalanine were successfully transformed into their corresponding acyl conjugates, expanding the scope of the reaction to drugs and amino acids. PMID- 29761810 TI - Novel paramagnetic clays obtained through intercalation of Gd3+-complexes. AB - Novel paramagnetic lanthanide-exchanged saponite clays, bearing in the interlamellar region positively charged Gd3+-complexes, were synthesized using a hydrothermal approach followed by a classical ion exchange reaction. A detailed characterization was performed to assess the physico-chemical properties of the samples, which showed a hydrodynamic diameter between 50 and 90 nm and good thermal stability. 1H-NMR relaxometric studies in aqueous solution as a function of magnetic field and temperature were carried out to evaluate the local chemical environment of the intercalated paramagnetic centres and their interaction with water molecules. The data indicate a strong interaction of the confined complexes with the lamellae, resulting in a restriction of the local rotational dynamics and of the exchange process of water molecules between the inner coordination sphere of Gd3+ and the bulk. The stability over time in aqueous solutions of varying complexity was also studied by relaxometric techniques. PMID- 29761813 TI - On the origin of the photocurrent of electrochemically passivated p-InP(100) photoelectrodes. AB - III-V semiconductors such as InP are highly efficient light absorbers for photoelectrochemical (PEC) water splitting devices. Yet, their cathodic stability is limited due to photocorrosion and the measured photocurrents do not necessarily originate from H2 evolution only. We evaluated the PEC stability and activation of model p-InP(100) photocathodes upon photoelectrochemical passivation (i.e. repeated surface oxidation/reduction). The electrode was subjected to a sequence of linear potential scans with or without intermittent passivation steps (repeated passivation and continuous reduction, respectively). The evolution of H2 and PH3 gases was monitored by online electrochemical mass spectrometry (OLEMS) and the Faradaic efficiencies of these processes were determined. Repeated passivation led to an increase of the photocurrent in 0.5 M H2SO4, while continuous reduction did not affect the photocurrent of p-InP(100). Neither H2 nor PH3 formation increased to the same extent as the photocurrent during the repeated passivation treatment. Surface analysis of the spent electrodes revealed substantial roughening of the electrode surface by repeated passivation, while continuous reduction left the surface unaltered. On the other hand, photocathodic conditioning performed in 0.5 M HCl led to the expected correlation between photocurrent increase and H2 formation. Ultimately, the H2 evolution rates of the photoelectrodes in H2SO4 and HCl are comparable. The much higher photocurrent in H2SO4 is due to competing side-reactions. The results emphasize the need for a detailed evaluation of the Faradaic efficiencies of all the involved processes using a chemical-specific technique like OLEMS. Photo OLEMS can be beneficial in the study of photoelectrochemical reactions enabling the instantaneous detection of small amounts of reaction by-products. PMID- 29761815 TI - Probing the tricationic ionic liquid/vacuum interface: insights from molecular dynamics simulations. AB - The surface properties of three symmetric linear tricationic ionic liquids (LTILs) with the common anion, bis(trifluoromethylsulfonyl)imide ([NTf2]-), were studied using atomistic molecular dynamics simulation and identification of the truly interfacial molecules (ITIM) analysis. A refined version of the CL&P force field with the partial charges based on quantum calculations for isolated ion quartets was used to calculate the number densities, orientation of the cations, charge densities and surface tensions. The densities obtained from the simulation of the interface are on average 3% smaller than the densities of bulk NPT simulations, which is due to applying long-range corrections in the simulations of bulk liquids. New observations were reported for this new class of ILs through density profiles and orientational analysis. The ITIM analysis shows that the surface of the LTILs is more populated with anions rather than cations and it becomes smoother with a decrease in the alkyl chain length of the cations. The microscopic structural analysis of the orientational ordering at the interface shows that although for LTIL-1 and LTIL-2, the surface is more populated with anions and therefore has a negative charge, for LTIL-3 the surface is more populated with linkage alkyl chains and therefore has a small positive charge. This difference in the interfacial structures arises from the difference in the alkyl chain lengths. The results show that the LTILs with shorter alkyl chains (i.e. n = 3 and 6) form an inverse-arc shape structure while LTILs with longer alkyl chains (i.e. n = 10) form a sinuous like structure at the interface. The surface tension values of these ILs were calculated at 298 K using the mechanical definition. The simulations resulted in acceptable values for surface tension compared to the experimental trends. PMID- 29761816 TI - Mild and efficient synthesis of indoles and isoquinolones via a nickel-catalyzed Larock-type heteroannulation reaction. AB - A simple and efficient approach for the preparation of substituted indoles and isoquinolones via a nickel-catalyzed Larock-type heteroannulation reaction is reported. This transformation employed air-stable and inexpensive Ni(dppp)Cl2 as a precatalyst and Et3N as a mild base. Moreover, the reaction occurs efficiently under mild conditions, and a wide range of substituted indoles and isoquinolones bearing various functional groups are obtained in moderate to excellent yields. PMID- 29761817 TI - Fermi resonance in solvated H3O+: a counter-intuitive trend confirmed via a joint experimental and theoretical investigation. AB - The spectral features of H3O+ between 3000 and 3800 cm-1 are known to be dominated by coupling between the fundamentals of stretching modes and the overtones of bending modes. A strong Fermi resonance (FR) pattern has been observed in Ar-tagged H3O+, and the sensitive dependence of the FR pattern on the number of Ar tags has been analyzed by Li et al. [J. Phys. Chem. A, 2015, 119(44), 10887]. Based on ab initio anharmonic calculations with MP2/aug-cc-pvDZ, Tan et al. investigated the influence of different types of rare gas and found a counter-intuitive trend that the strength of the coupling between the overtones of bending modes and the fundamentals of stretching modes decreases as the strength of solvation increases [Phys. Chem. Chem. Phys., 2016, 18(44), 30721]. In the present work, we combine both experimental and theoretical tools to gain a better understanding of the FR in H3O+. Experimentally, spectra of H3O+ with light and much more weakly-bound Ne tags were measured for the first time and spectra of Ar-tagged H3O+ were re-measured for comparison. Theoretically, we have implemented several computational schemes to improve both the accuracy and efficiency of the anharmonic treatments with higher-level ab initio methods (up to CCSD/aug-cc-pVTZ). With the good agreement between the experimental and theoretical spectra, we are confident about the prediction of the modulation of coupling strength by the solvation environments. PMID- 29761819 TI - Strained azabora[2]ferrocenophanes. AB - Three [2]ferrocenophanes equipped with unsaturated BN moieties at bridging positions were synthesized and structurally characterized. As revealed by DFT calculations, these first examples of azabora[2]ferrocenophanes are similarly strained to the well-known Me2Si-bridged [1]ferrocenophane. PMID- 29761820 TI - Ultrasonic-assisted preparation of a pinhole-free BiVO4 photoanode for enhanced photoelectrochemical water oxidation. AB - A pinhole-free BiVO4 electrode was successfully synthesized using an ultrasonic assisted synthetic method on a conductive substrate. The pinhole-free BiVO4 electrode showed highly improved photoelectrochemical activity for both sulfite oxidation and water oxidation. The blocking recombination processes were examined to clarify the enhanced photoelectrochemical performances. PMID- 29761821 TI - Synthetic studies on daphniglaucins. AB - The synthetic approach to the core framework of daphniglaucin-type Daphniphyllum alkaloids is described herein. The B-C ring was constructed via a Rh-catalyzed [3+2] cycloaddition. Continuous quaternary centers were installed through [3+2] cycloaddition and alkylation. The attempt to build the A-D ring motif using dipolar cycloaddition of azomethine ylides was extensively investigated. PMID- 29761822 TI - Synthesis of fused tricyclic systems by thermal Cope rearrangement of furan substituted vinyl cyclopropanes. AB - A novel method for the stereoselective construction of hexahydroazuleno[4,5 b]furans from simple precursors has been developed. The route involves the use of our recently developed Bronsted acid catalysed cyclisation reaction of acyclic ynenones to prepare fused 1-furanyl-2-alkenylcyclopropanes that undergo highly stereoselective thermal Cope rearrangement to produce fused tricyclic products. Substrates possessing an E-alkene undergo smooth Cope rearrangement at 40 degrees C, whereas the corresponding Z-isomers do not react at this temperature. Computational studies have been performed to explain the difference in behaviour of the E- and Z-isomers in the Cope rearrangement reaction. The hexahydroazuleno[4,5-b]furans produced by Cope rearrangement have potential as advanced intermediates for the synthesis of members of the guaianolide family of natural products. PMID- 29761823 TI - Erythropoietin promotes network formation of transplanted adipose tissue-derived microvascular fragments. AB - The seeding of tissue constructs with adipose tissue-derived microvascular fragments (ad-MVF) is an emerging pre-vascularisation strategy. Ad-MVF rapidly reassemble into new microvascular networks after in vivo implantation. Herein it was analysed whether this process was improved by erythropoietin (EPO). Ad-MVF were isolated from green fluorescent protein (GFP)+ as well as wild-type C57BL/6 mice and cultivated for 24 h in medium supplemented with EPO (20 IU/mL) or vehicle. Freshly isolated, non-cultivated ad-MVF served as controls. Protein expression, cell viability and proliferation of ad-MVF were assessed by proteome profiler array and fluorescence microscopy. GFP+ ad-MVF were seeded on collagen glycosaminoglycan matrices, which were implanted into dorsal skinfold chambers of C57BL/6 mice, to analyse their vascularisation over 14 d by intravital fluorescence microscopy, histology and immunohistochemistry. Cultivation up regulated the expression of pro- and anti-angiogenic factors within both vehicle- and EPO-treated ad-MVF when compared with non-cultivated controls. Moreover, EPO treatment suppressed cultivation-associated apoptosis and significantly increased the number of proliferating endothelial cells in ad-MVF when compared with vehicle-treated and non-cultivated ad-MVF. Accordingly, implanted matrices seeded with EPO-treated ad-MVF exhibited an improved vascularisation, as indicated by a significantly higher functional microvessel density. The matrices of the three groups contained a comparably large fraction of GFP+ microvessels originating from the ad-MVF, whereas the tissue surrounding the matrices seeded with EPO treated ad-MVF exhibited a significantly increased microvessel density when compared with the other two groups. These findings indicated that EPO represents a promising cytokine to further boost the excellent vascularisation properties of ad-MVF in tissue-engineering applications. PMID- 29761824 TI - Impact of cardiosynchronous brain pulsations on Monte Carlo calculated doses for synchrotron micro- and minibeam radiation therapy. AB - PURPOSE: The purpose of this study was to assess the effects of brain movements induced by heartbeat on dose distributions in synchrotron micro- and minibeam radiation therapy and to develop a model to help guide decisions and planning for future clinical trials. METHODS: The Monte Carlo code PENELOPE was used to simulate the irradiation of a human head phantom with a variety of micro- and minibeam arrays, with beams narrower than 100 MUm and above 500 MUm, respectively, and with radiation fields of 1 * 2 cm and 2 * 2 cm. The dose in the phantom due to these beams was calculated by superposing the dose profiles obtained for a single beam of 1 MUm * 2 cm. A parameter delta, accounting for the total displacement of the brain during the irradiation and due to the cardiosynchronous pulsation, was used to quantify the impact on peak-to-valley dose ratios and the full width at half maximum. RESULTS: The difference between the maximum (at the phantom entrance) and the minimum (at the phantom exit) values of the peak-to-valley dose ratio reduces when the parameter delta increases. The full width at half maximum remains almost constant with depth for any delta value. Sudden changes in the two quantities are observed at the interfaces between the various tissues (brain, skull, and skin) present in the head phantom. The peak-to-valley dose ratio at the center of the head phantom reduces when delta increases, remaining above 70% of the static value only for minibeams and delta smaller than ~200 MUm. CONCLUSIONS: Optimal setups for brain treatments with synchrotron radiation micro- and minibeam combs depend on the brain displacement due to cardiosynchronous pulsation. Peak-to-valley dose ratios larger than 90% of the maximum values obtained in the static case occur only for minibeams and relatively large dose rates. PMID- 29761825 TI - Zinc mitigates renal ischemia-reperfusion injury in rats by modulating oxidative stress, endoplasmic reticulum stress, and autophagy. AB - Oxidative stress is a major factor involved in the pathogenesis of renal ischemia/reperfusion (I/R). Exogenous zinc (Zn) was suggested as a potent antioxidant; however, the mechanism by which it strengthens the organ resistance against the effects of reactive oxygen species (ROS) is not yet investigated. The present study aims to determine whether acute zinc chloride (ZnCl2 ) administration could attenuate endoplasmic reticulum (ER) stress, autophagy, and inflammation after renal I/R. Rats were subjected to either sham operation (Sham group, n = 6), or 1 hr of bilateral ischemia followed by 2 hr of reperfusion (I/R groups, n = 6), or they received ZnCl2 orally 24 hr and 30 min before ischemia (ZnCl2 group, n = 6). Rats were subjected to 1 hr of bilateral renal ischemia followed by 2 hr of reperfusion (I/R group, n = 6). Our results showed that ZnCl2 enhances renal function and reduces cytolysis (p < 0,05). In addition, it increased significantly the activities of antioxidant enzymes (SOD, CAT, and GPX) and the level of GSH in comparison to I/R (p < 0,05). Interestingly, ZnCl2 treatment resulted in significant decreased ER stress, as reflected by GRP78, ATF 6,p-eIF-2alpha, XPB-1, and CHOP downregulaion. Rats undergoing ZnCl2 treatment demonstrated a low expression of autophagy parameters (Beclin-1 and LAMP-2), which was correlated with low induction of apoptosis (caspase-9, caspase-3, and p JNK), and reduction of inflammation (IL-1beta, IL-6, and MCP-1) (p < 0,05). In conclusion, we demonstrated the potential effect of Zn supplementation to modulate ER pathway and autophagic process after I/R. PMID- 29761826 TI - Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants. AB - Emergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild-type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta-butyl(2S,4S)-4-amino-2-cyclopropyl-6 (trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate) to be more effective against PZA resistant Mtb strains in comparison to PZA. The lead molecule showed better drug-like properties such as high affinity and atomic interactions with wild-type and drug-resistant mutations in Mtb PncA proteins. Further, molecular dynamic simulation studies showed that this lead molecule has better conformational stability and compatibility with drug-resistant PncA proteins in comparison to PZA drug. We hypothesized that the predicted lead compound could be more effective, and thus may improve the treatment of PZA resistant tuberculosis. PMID- 29761827 TI - Factors related to dissociation between objective and subjective masticatory function in Japanese community-dwelling elderly adults. AB - Clinicians' evaluations of older adults sometimes reveal inconsistencies between objective and subjective dental status. This study investigated which factors contribute both to good objective masticatory function (OMF) and the poor subjective masticatory function (SMF) that often becomes a clinical issue. Study participants included 635 elderly community-dwelling Japanese adults who underwent a comprehensive geriatric health examination in 2012. SMF was assessed with a question from the Kihon Checklist on eating difficulties (poor or good). OMF was assessed by a colour-changing gum (poor or good). Also investigated were age, sex, depressive symptoms, instrumental activities of daily living (I-ADLs), number of people who joined the participant at dinner, grip strength, usual walking speed, number of remaining teeth, number of functional teeth and their occlusal force. The group with good OMF and good SMF, defined as group 1, and the group with good OMF but poor SMF, group 2, were compared. Logistic regression analyses confirmed that the number of remaining and functional teeth participants had was statistically unrelated to differences between OMF and SMF. Instead, differences were related to stronger depressive symptoms (OR = 1.67, CI = 1.14 2.44), less ability to conduct I-ADL activities (OR = 0.73, CI = 0.59-0.91), slower usual walking speeds (OR = 0.18, CI = 0.06-0.58) and less occlusal force (OR = 0.99, CI = 0.99-1.00). Depressive symptoms, I-ADLs, and physical function are shown to be significantly related to divergence between objective and subjective masticatory function in elderly Japanese. This suggests that dissociations between objective and subjective dental evaluations of elderly adults indicate need for assessment of their mental and physical function. PMID- 29761828 TI - Differential micronucleus frequency in isogenic human cells deficient in DNA repair pathways is a valuable indicator for evaluating genotoxic agents and their genotoxic mechanisms. AB - The micronucleus (MN) test has become an attractive tool both for evaluating the genotoxicity of test chemicals because of its ability to detect clastogenic and aneugenic events and for its convenience. As the MN assay has been mostly performed using only DNA repair-proficient mammalian cells, we believed that the comparison of the MN frequency between DNA repair-proficient and -deficient human cells may be an excellent indicator for detecting the genotoxic potential of test chemicals and for understanding their mode of action. To address this issue, the following five genes encoding DNA-damage-response (DDR) factors were disrupted in the TK6 B cell line, a human cell line widely used for the MN test: FANCD2, DNA polymerase zeta (REV3), XRCC1, RAD54, and/or LIG4. Using these isogenic TK6 cell lines, the MN test was conducted for four widely-used DNA-damaging agents: methyl methanesulfonate (MMS), hydrogen peroxide (H2 O2 ), gamma-rays, and mitomycin C (MMC). The frequency of micronuclei in the double strand break repair-deficient RAD54-/- /LIG4-/- cells after exposure to gamma-rays, H2 O2 , MMS and MMC was 6.2 7.5 times higher than that of parental wild-type TK6 cells. The percentages of cells exhibiting micronuclei in the base excision repair- and single strand break repair-deficient XRCC1-/- cells after exposure to H2 O2 , MMC and MMS were all ~5 times higher than those of wild-type cells. In summary, a supplementary MN assay using the combination of RAD54-/- /LIG4-/- , XRCC1-/- and wild-type TK6 cells is a promising method for detecting the genotoxic potential of test chemicals and their mode of action. Environ. Mol. Mutagen., 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29761829 TI - Pretransplant trends in alpha-fetoprotein levels as a predictor of recurrence after living donor liver transplantation for unresectable hepatoblastoma: A single-institution experience. AB - LT is a practical therapeutic alternative for unresectable hepatoblastoma; however, deciding when to perform LT is difficult. The aim of this study was to optimize the timing of LT for hepatoblastoma using pretransplant trends in AFP levels. Trends in pretransplant AFP levels and their influence on post-transplant outcomes were retrospectively evaluated. All patients who underwent living donor LT for hepatoblastoma in our institution since 2002 were included. Variables analyzed included history of prior tumor resection, pretransplant AFP responses to chemotherapy, metastatic disease at diagnosis, and post-transplant chemotherapy. Eight patients (seven boys and one girl; median age, 35 months; range, 15 months-12 years) were transplanted. The overall post-transplant recurrence-free survival rate was 62.5% (5/8) with a mean follow-up of 77 months. Patients with post-transplant recurrence showed a 0.573 log increase in AFP levels after the last chemotherapy session before LT. This was significantly higher than the 0.279 log decrease observed in patients without post-transplant recurrence (P = .024). Because the AFP response cannot be accurately predicted before each cycle of chemotherapy, it may be appropriate to perform LT when AFP levels do not decrease after the last cycle and before they are found to be elevated again. PMID- 29761830 TI - ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision. AB - Metformin drug-drug interaction (DDI) studies are conducted during development of drugs that inhibit organic cation transporters and/or multidrug and toxin extrusion proteins (OCTs/MATEs). Monitoring solely changes in systemic exposure, the typical DDI study endpoint appears inadequate for metformin, which is metabolically stable, has poor passive membrane permeability, and undergoes transporter-mediated tissue distribution and clearance. Evaluation of renal clearance, antihyperglycemic effects, and potentially lactate as an exploratory safety marker, can support rational metformin dose adjustment. The proposed DDI study design aims to adequately inform metformin dosing during comedication. PMID- 29761832 TI - Psychophysical Evaluation of a Tactile Display Based on Coin Motors. AB - Tactile vision substitution devices present visual images as tactile representations on the skin. In this study we have tested the performance of a prototype 96-tactor vibrotactile using a subset of 64 tactors. We have determined the tactile spatial acuity and intensity discrimination in 14 naive subjects. Spatial acuity was determined using a grating acuity task. Subjects could successfully identify the orientation of horizontal and vertical gratings with an average psychophysical threshold of 120 mm. When diagonal gratings were included in the analysis, the median performance dropped below psychophysical threshold, but was still significantly above chance at gratings of 142 mm wide. Intensity discrimination yielded an average Weber fraction of 0.44, corresponding to 13 discernable "gray levels" in the available dynamic range. Interleaved stimulation of the motors did not significantly affect spatial acuity or intensity discrimination. PMID- 29761831 TI - Evaluation of the ThroLy score for the prediction of venous thromboembolism in newly diagnosed patients treated for lymphoid malignancies in clinical practice. AB - The utility in clinical practice of a recently developed and validated predictive model for venous thromboembolism (VTE) events in lymphoma patients, known as the thrombosis lymphoma (ThroLy) score, is unknown. We evaluated the association of ThroLy with VTE in patients treated for diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL) undergoing ambulatory first-line chemotherapy. Retrospective analyses were performed on 428 patients (median age 50), 241 were newly diagnosed DLBCL, and 187 had HL. During initial chemotherapy, 64 (15%) patients developed VTE. According to the ThroLy, 322 (75.2%) patients were considered low risk, 88 (20.6%) patients had intermediate risk and 18 (4.2%) patients high risk for VTE development. Patients with DLBCL were more often in the high-risk ThroLy group and had more VTE events than HL. VTE occurred in; 38.9% (n = 7) high-risk patients, 29.5% (n = 26) intermediate risk, and 9.6% (n = 31) low risk according to the ThroLy score. However, in multivariate analysis, high ThroLy (OR 5.13; 95% CI: 1.83-14.36, P = .002), intermediate ThroLy (OR 3.96; 95% CI: 2.19-7.17, P < .001), and aggressive lymphoma-DLBCL (OR 1.91; 95% CI: 1.05-3.47, P = .034) were all significantly associated with development of VTE, 48% of the VTE events occurred in the low-risk ThroLy score group (the ROC AUC (95% CI) 0.40-0.70 and C statistic-0.55). In our study, the ThroLy score was not a suitably accurate model for predicting VTE events in patients at higher risk of VTE. Further research should be conducted to identify new biomarkers that will predict these events and to establish a new VTE risk assessment model. PMID- 29761833 TI - Hepatobiliary and Pancreatic: Pancreatic cancer with elevated serum IgG4 level due to multiple myeloma mimicking localized autoimmune pancreatitis. PMID- 29761834 TI - The protective scale of the Armidilo-S: The importance of forensic and clinical outcomes. AB - BACKGROUND: The Armidilo has two scales-the risk scale and the protective scale. Research has been confined to the risk scale which appears to predict future incidents with medium to large effect sizes. There have been no publications on the use of the protective scale. METHODS: The Armidilo was completed on four individuals with IDD who were either moving on from their placement or whose placement was in jeopardy because of new information or altered policies in the organization. The Armidilo was completed in the usual fashion. RESULTS: Risk and protective results show that for each individual, recommendations could be made that ensured the best outcome. For two participants, restrictive placements were avoided because of the data on protective factors. CONCLSIONS: The protective scale can be a powerful support for the clinician's case in offenders with IDD. The protective scale should be completed routinely for clinical evaluation. PMID- 29761836 TI - Acceptability and caregiver-reported outcomes for young children with autism spectrum disorder whose parents attended a preventative population-based intervention for anxiety: A pilot study. AB - This pilot study explored acceptability to parents and outcomes for children of a preventive intervention for anxiety problems in pre-schoolers with autism spectrum disorder (ASD) who were an identified sub-group within a population based randomised trial of the Cool Little Kids parenting group programme. The population trial included 545 temperamentally inhibited pre-schoolers recruited across eight economically diverse areas of Melbourne, Australia. Within this sample, 26 parents reported that their child had received an ASD diagnosis. Trial measures included baseline inhibited temperament and developmental problems, post intervention feedback on the programme, and caregiver-reported child mental health outcomes (anxiety diagnoses and internalising symptoms) at 1- and 2-year follow-up. Sample retention for the children with ASD over 2 years was strong (92%). At follow-up, fewer intervention than control children with ASD had anxiety disorders after 1 year (% (n): 25 (3) vs. 77 (10), P = .028) and separation anxiety symptoms after 2 years (M (SD): 4.22 (2.68) vs. 9.38 (5.91), P = .017). Similar effects favouring the intervention group were apparent across other child emotional outcome measures but without statistical significance in this small sample. Parents of the children with ASD reported that Cool Little Kids was "quite useful" in relation to their child's anxiety but also gave feedback that they would appreciate some tailoring of programme content to the context of ASD. These pilot findings suggest Cool Little Kids may be helpful for reducing comorbid anxiety in pre-schoolers with ASD. Further research is warranted to develop an ASD-specific adaptation which can be trialled with a larger sample of children with confirmed ASD diagnosis. Trial registration ISRCTN30996662 http://www.isrctn.com/ISRCTN30996662. Autism Res 2018, 11: 1166 1174. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Many children with autism spectrum disorder (ASD) also have anxiety. This pilot study explored acceptability to parents and outcomes for pre-schoolers with ASD of a parenting group programme to prevent anxiety problems. Among the sample of 26 pre-schoolers with ASD, we found reduced anxiety disorders and separation symptoms when their parents had received the intervention, as reported by caregivers in checklists and clinical interviews. Parents gave feedback that the programme was useful but suggested content be adapted to the context of ASD. PMID- 29761835 TI - Attention to speech and spoken language development in deaf children with cochlear implants: a 10-year longitudinal study. AB - Early auditory/language experience plays an important role in language development. In this study, we examined the effects of severe-to-profound hearing loss and subsequent cochlear implantation on the development of attention to speech in children with cochlear implants (CIs). In addition, we investigated the extent to which attention to speech may predict spoken language development in children with CIs. We tested children with CIs and compared them to chronologically age-matched peers with normal hearing (NH) on their attention to speech at four time points post implantation; specifically, less than 1 month, 3 to 6 months, 12 months, and 18 months post implantation. We also collected a variety of well-established speech perception and spoken language measures from the children with CIs in a 10-year longitudinal study. Children with CIs showed reduced attention to speech as compared to their peers with NH at less than 1 month post implantation, but a similar degree of attention to speech as their NH peers during later time points. In addition, attention to speech at 3 to 6 months post implantation predicts speech perception in children with CIs. These results inform language acquisition theories and bring insights into our understanding of early severe-to-profound hearing loss on infants' attention to speech skills. In addition, the findings have significant clinical implications for early intervention on hearing loss, which emphasizes the importance of developing strong listening skills. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=f7xiYo3Ua08&feature=youtu.be. PMID- 29761838 TI - Proliferation and invasion of colon cancer cells are suppressed by knockdown of TOP2A. AB - Recent research has shown that TOP2A plays an important role in the tumorigenesis of many malignancies, such as breast cancer, ovarian cancer, and prostate cancer. However, few studies have been conducted on TOP2A expression and functions in colon cancer. In the present study, we found that TOP2A expression was obviously elevated in colon cancer tissues compared to adjacent non-cancerous tissues. Depletion of TOP2A in HCT116 and SW480 colon cancer cells by transfection of specific small interfering RNA significantly suppressed proliferation and inhibited invasion of cells, even induced apoptosis as indicated by both MTT assay, Annexin V/propidium iodide staining, and Transwell assay. Furthermore, we explored the underlying mechanisms. Knockdown of TOP2A not only affects the expression of cell apoptosis-related (Bcl-2 and Bax) and invasion-related proteins (MMP-2 and MMP-9), but also reduced the phosphorylation levels of ERK and AKT. In conclusion, we showed that TOP2A was upregulated in colon cancer tissue samples and that TOP2A may serve as an oncogene in colon cancer. PMID- 29761837 TI - Augmentation of the cytotoxic effects of nitrogen-containing bisphosphonates in hypoxia. AB - OBJECTIVES: Tumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective in hypoxia is necessary. Nitrogen-containing bisphosphonates (N-BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia. Therefore, we investigated the cytotoxicity of N-BPs in cancer cells in hypoxia. METHODS: We studied the cytotoxicities of N-BPs, statins and anticancer drugs in human cancer cells under hypoxic conditions (1% O2 ). The expression levels of enzymes in the mevalonate pathway in hypoxia were measured by real-time reverse transcription polymerase chain reaction and Western blotting. KEY FINDINGS: In hypoxia, cell growth inhibition by 5-fluorouracil and cisplatin was not changed as compared to that in normoxia; however, cell growth inhibition by N BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate. CONCLUSIONS: The cytotoxicity of N-BPs, but not 5-fluorouracil and cisplatin, is potentiated in hypoxia, through the loss of HMG-CoA reductase function. N-BPs may be effective against cancer in normoxia and hypoxia. PMID- 29761839 TI - Effects of plasma transfusions on antithrombin levels after paediatric liver transplantation. AB - BACKGROUND AND OBJECTIVES: Thrombotic complications affect 3-10% of patients after liver transplantation (LT), leading to potentially life-threatening complications. In the days following LT, antithrombin (AT) is decreased longer than pro-coagulant factors, thus favouring a pro-thrombotic profile. Plasma transfusions are given empirically in some centres to correct AT levels following LT. We assessed the effect of plasma transfusion on AT levels after paediatric LT. MATERIALS AND METHODS: Prospective single-centre observational study in 20 consecutive paediatric LT recipients over a 24-month period. Plasma was administered twice daily (10 ml/kg/dose) according to an existing protocol. AT levels were measured once daily, immediately prior to and one hour after the morning plasma transfusion. Sample size was calculated based on a non-inferiority hypothesis. RESULTS: The median age and weight were 11.6 years (IQR 2.8; 14.7) and 40 kg (IQR 12.75; 44.8), respectively. We collected 85-paired blood samples. The median AT level prior to plasma transfusion was 58%. The median difference in AT levels before and after plasma transfusion was 4.2% (P = 0.001). Changes in AT levels after plasma transfusion were not correlated with baseline AT levels (R = 0.19) or patient weight (R = 0.18). CONCLUSION: Plasma transfusions only marginally increase AT levels in children after LT. Therefore, prophylactic plasma transfusions probably do not seem to confer an advantage in the routine management of paediatric LT patients. Randomized controlled trials are needed to identify the optimal anticoagulation strategy in this specific population. PMID- 29761840 TI - Ginsenoside Rg1 ameliorates liver fibrosis via suppressing epithelial to mesenchymal transition and reactive oxygen species production in vitro and in vivo. AB - Liver fibrosis remains a major cause of morbidity and mortality with a complicated etiology and notorious complications, but there is a lack of efficacious therapeutics. Epithelial to mesenchymal transition (EMT) has a central role in the course of liver fibrosis, and thus, prevention of the development of EMT may control and even reverse liver fibrosis. This study aimed to examine the beneficial effect of ginsenoside Rg1, a phrenological active component isolated from Ginseng, and interrogate the mechanism in vitro and in vivo, with a focus on transforming growth factor-beta (TGF-beta)/Smad and Nrf2 mediated signaling pathways. We employed a TGF-beta-induced EMT model in HSC-T6 cells and CCl4 -induced liver fibrosis in animal. We found that ginsenoside Rg1 significantly reduced cell proliferation and reversed transforming growth factor beta (TGF-beta)-induced EMT in HSC-T6 cells; and ginsenoside Rg1 induced cell apoptosis, Ginsenoside Rg1 decreased the cellular level of collagen I and III in HSC-T6 cells, indicating the amelioration of fibrosis. We showed that ginsenoside Rg1 reduced cellular reactive oxygen species (ROS). We also observed similar beneficial effects of ginsenoside Rg1 in vivo. The data showed that ginsenoside Rg1 decreased the level of alanine aminotransferase and aspartate aminotransferase, and collage type IV (IV-C), hyaluronic acid, and laminin in carbon tetrachloride (CCl4)-induced liver fibrotic model. Mechanistically, we showed that ginsenoside Rg1 tuned down the TGF-beta/Smad and stimulated Nrf-2 nuclear translocation, which could explain the beneficial effects. In aggregate, our results demonstrate that ginsenoside Rg1 exhibits a protective effect on liver fibrosis via suppressing EMT and cellular ROS level. (c) 2018 BioFactors, 2018. PMID- 29761841 TI - PRKAR2B promotes prostate cancer metastasis by activating Wnt/beta-catenin and inducing epithelial-mesenchymal transition. AB - Castration-resistant prostate cancers (CRPC) that occur after the failure of androgen-blocking therapies cause most of the deaths in prostate cancer (PCa) patients. In a previous study we identified that PRKAR2B expression is upregulated in CRPC and possesses potentials to develop CRPC. Here we further investigated the underlying mechanism of PRKAR2B in regulating prostate cancer metastasis. We established an androgen-independent LNCaPcell line (LNCaP-AI), and investigated the function of PRKAR2B on regulating cell invasion in vitro and in vivo. We found that PRKAR2B expression was markedly increased in LNCaP-AI cells and metastatic CRPC (mCRPC) tissues compared to LNCaP cells and primary PCa specimens, respectively. PRKAR2B level was significantly correlated with the Gleason score and lymph nodes metastasis in PCa. In vitro, PRKAR2B overexpression promoted cell invasion, whereas knockdown of PRKAR2B in CRPC cells inhibited cell invasion. PRKAR2B overexpression also promoted tumor metastasis in vivo. PRKAR2B resulted in a decreased expression of E-cadherin and an increased expression of Vimentin, N-cadherin, Fibronectin, indicating that PRKAR2B induced epithelial mesenchymal transition (EMT). PRKAR2B activated Wnt/beta-catenin signaling in CRPC cells. More important, inhibition of Wnt/beta-catenin attenuated PRKAR2B induced EMT and cancer cells invasion. Our results provided novel insights to PRKAR2B-driven CRPC cell invasion and indicated that PRKAR2B might be served as a potential target for CRPC therapy. PMID- 29761842 TI - Design and Performance Evaluation of Real-time Endovascular Interventional Surgical Robotic System with High Accuracy. AB - BACKGROUND: Endovascular interventional surgery (EIS) is performed under a high radiation environment at the sacrifice of surgeons' health. This paper introduces a novel endovascular interventional surgical robot that aims to reduce radiation to surgeons and physical stress imposed by lead aprons during fluoroscopic X-ray guided catheter intervention. METHODS: The unique mechanical structure allowed the surgeon to manipulate the axial and radial motion of the catheter and guide wire. Four catheter manipulators (to manipulate the catheter and guide wire), and a control console which consists of four joysticks, several buttons and two twist switches (to control the catheter manipulators) were presented. The entire robotic system was established on a master-slave control structure through CAN (Controller Area Network) bus communication, meanwhile, the slave side of this robotic system showed highly accurate control over velocity and displacement with PID controlling method. RESULTS: The robotic system was tested and passed in vitro and animal experiments. Through functionality evaluation, the manipulators were able to complete interventional surgical motion both independently and cooperatively. The robotic surgery was performed successfully in an adult female pig and demonstrated the feasibility of superior mesenteric and common iliac artery stent implantation. The entire robotic system met the clinical requirements of EIS. CONCLUSION: The results show that the system has the ability to imitate the movements of surgeons and to accomplish the axial and radial motions with consistency and high-accuracy. PMID- 29761843 TI - Calf Circumference: A Marker of Muscle Mass as a Predictor of Hospital Readmission. AB - Hospital readmissions (HRs) are common, potentially preventable, and a marker of poor quality in health services. This study aimed to identify risk factors for HR in clinical patients, with an emphasis on nutrition aspects, especially calf circumference (CC), as a marker of muscle mass. A prospective cohort study of patients admitted to the internal medicine ward was conducted. The short form of the Patient-Generated Subjective Global Assessment was performed in the first 24 hours of hospitalization. In addition, single-frequency bioelectrical impedance analysis was used to estimate the phase angle, CC as a surrogate of muscle mass, and handgrip strength as a marker of strength. The Charlson Comorbidity Index (CCI) was used to assess the severity of the comorbidities. Reassessments were performed every 7 days during hospitalization. HR was evaluated 30 days after discharge by phone contact. A sample of 161 patients was assessed; 54.6% were male, with a mean age of 59.2 +/- 17.8 years. The median CCI was 2.76 (interquartile range: 1-4), and nutrition risk and low CC were present in 77.6% and 46% of the patients, respectively. The readmission rate was 16.8% after 30 days. After controlling for sex and age, a CCI > 2 (odds ratio [OR]: 3.29; 95% confidence interval [CI]: 1.21-8.97), the presence of cancer (OR: 4.52; 95% CI: 1.11-18.42), nutrition risk (OR: 9.53; 95% CI: 1.16-77.9), and a low CC (OR: 3.89; 95% CI: 1.34-11.31) were significantly associated with 30 day HR. In conclusion, muscle mass loss, identified by CC, can be a good predictor of 30-day HR, even after controlling for other well-known risk factors. PMID- 29761844 TI - Editorial: Functional Connectivity: Dissecting the Relationship Between the Brain and "Pain Centralization" in Rheumatoid Arthritis. PMID- 29761845 TI - The O-methylated isoflavone, formononetin, inhibits human ovarian cancer cell proliferation by sub G0/G1 cell phase arrest through PI3K/AKT and ERK1/2 inactivation. AB - Formononetin is an isoflavone that is extracted from red clovers or soy. It has anti-oxidant, anti-proliferative, and anti-tumor effects against cells in various diseases. Several cohort studies have indicated that phytoestrogen intake, including formononetin, could reduce the risk of various carcinogenesis. In fact, many case-control studies have indicated the potential value of flavonoids as drug supplements in the treatment of many cancer patients. However, the toxic effects and the anti-cancer mechanism of formononetin in ovarian cancer are unknown. We investigated the toxicological mechanism of formononetin in ES2 and OV90 ovarian cancer cells. Formononetin suppressed cell proliferation through sub G0/G1 phase arrest and increased apoptosis in both cell lines. Furthermore, it induced loss of mitochondrial membrane potential and generation of reactive oxygen species in ES2 and OV90 cells. The formononetin-mediated regulation of cell proliferation and apoptosis involved decreased phosphorylation of ERK1/2, P90RSK, AKT, P70S6K, and S6 proteins, and increased phosphorylation of P38 protein in ES2 and OV90 cells. Co-treatment of formononetin with pharmacological inhibitors (LY294002 or U0126) revealed additional anti-proliferative effects on the two human ovarian cancer cell types. Conclusively, the results indicate the potential value of formononetin as an anti-cancer agent in human ovarian cancer. PMID- 29761846 TI - Stability of tapered and parallel-walled dental implants: A systematic review and meta-analysis. AB - BACKGROUND: Clinical trials have suggested that dental implants with a tapered configuration have improved stability at placement, allowing immediate placement and/or loading. The aim of this systematic review and meta-analysis was to evaluate the implant stability of tapered dental implants compared to standard parallel-walled dental implants. MATERIALS AND METHODS: Applying the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, randomized controlled trials (RCTs) were searched for in electronic databases and complemented by hand searching. The risk of bias was assessed using the Cochrane Collaboration's Risk of Bias tool and data were analyzed using statistical software. RESULTS: A total of 1199 studies were identified, of which, five trials were included with 336 dental implants in 303 participants. Overall meta-analysis showed that tapered dental implants had higher implant stability values than parallel-walled dental implants at insertion and 8 weeks but the difference was not statistically significant. Tapered dental implants had significantly less marginal bone loss compared to parallel-walled dental implants. No significant differences in implant failure rate were found between tapered and parallel-walled dental implants. CONCLUSIONS: There is limited evidence to demonstrate the effectiveness of tapered dental implants in achieving greater implant stability compared to parallel-walled dental implants. Superior short-term results in maintaining peri-implant marginal bone with tapered dental implants are possible. Further properly designed RCTs are required to endorse the supposed advantages of tapered dental implants in immediate loading protocol and other complex clinical scenarios. PMID- 29761847 TI - Letter from the Philippines. PMID- 29761848 TI - Preparative free-flow electrophoresis, a versatile technology complementing gradient centrifugation in the isolation of highly purified cell organelles. AB - Free-flow electrophoresis (FFE) exploits differences in the overall charge of bio particles separating cells, organelles, macromolecules, ions, etc. according to their distinct electrophoretic mobility and isoelectric point (pI) values. Indeed, around a neutral pH organelles usually exhibit a negative surface charge, migrating in an electric field from the cathode toward the anode. Since its introduction more than five decades ago by Barrollier et al., Z. Naturforsch. 1958, 13b, 745-755 and Hannig, Z. Anal. Chem. 1961, 181, 244-254, FFE has become an established analytical and preparative separation method for the isolation of a variety of organelles. Particularly, in sophisticated, multistep separating processes to separate subpopulations of organelles, it has gained, meanwhile, a position as a versatile technology and essential element. Relying on the distinct surface charges instead of buoyant densities of cell organelles, the FFE technology is best supporting a preceding centrifugation-based fractionation of subcellular compartments in the second dimension. In the following review, the two-step isolation and purification of subpopulations of classic animal and plant cell organelles will be mainly exemplified. PMID- 29761851 TI - Endocytosed factor V is trafficked to CD42b+ proplatelet extensions during differentiation of human umbilical cord blood-derived megakaryocytes. AB - Plasma- and platelet-derived factor Va are essential for thrombin generation catalyzed by the prothrombinase complex; however, several observations demonstrate that the platelet-derived cofactor, which is formed following megakaryocyte endocytosis and modification of the plasma procofactor, factor V, is more hemostatically relevant. Factor V endocytosis, as a function of megakaryocyte differentiation and proplatelet formation, was assessed by flow cytometry and microscopy in CD34+ hematopoietic progenitor cells isolated from human umbilical cord blood and cultured for 12 days in the presence of cytokines to induce ex vivo differentiation into megakaryocytes. Expression of an early marker of megakaryocyte differentiation, CD41, endocytosis of factor V, and the percentage of CD41+ cells that endocytosed factor V increased from days 6 to 12 of differentiation. In contrast, statistically significant decreases in expression of the stem cell marker, CD34, and in the percentage of CD34+ cells that endocytosed factor V were observed. A statistically significant increase in the expression of CD42b, a late marker of megakaryocyte differentiation, was also observed over time, such that by Day 12, all CD42b+ cells endocytosed factor V and expressed CD41. This endocytosed factor V was trafficked to proplatelet extensions and was localized in a punctate pattern in the cytoplasm consistent with its storage in alpha-granules. In conclusion, loss of CD34 and expression of CD42b define cells capable of factor V endocytosis and trafficking to proplatelet extensions during differentiation of megakaryocytes ex vivo from progenitor cells isolated from umbilical cord blood. PMID- 29761849 TI - MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin mediated mechanism. AB - Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active beta-catenin levels and, in-turn, down regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical outcomes in patients with AML. These findings emphasize the importance of MUC1-C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO-203 with Ara-C for the treatment of patients with AML. PMID- 29761850 TI - Unexpected regulation pattern of the IKKbeta/NF-kappaB/MuRF1 pathway with remarkable muscle plasticity in the Daurian ground squirrel (Spermophilus dauricus). AB - As a typical hibernator, the Daurian ground squirrel (Spermophilus dauricus) spends considerable time in a state of reduced activity with prolonged fasting. Despite this, they experience little muscle atrophy and have thus become an interesting anti-disuse muscle atrophy model. The IKKbeta/NF-kappaB signaling pathway is significant to muscle atrophy due to the protein degradation resulting from the upregulation of the E3 ubiquitin ligase MuRF1. The current study showed that the IKKbeta/NF-kappaB signaling pathway and MuRF1 maintained relatively steady mRNA and protein expression levels, with little muscle atrophy observed in the soleus (slow-twitch, SOL) or extensor digitorum longus (fast-twitch, EDL) during hibernation (HIB); however, mRNA expression significantly increased in the SOL and EDL muscle during interbout arousal (IBA), as did the MuRF1 mRNA level in the SOL and MuRF1 protein level in the EDL. Interestingly, the expressions of p50 and MuRF1 significantly increased during HIB in the gastrocnemius (mixed muscle, GAS) and showed moderate atrophy, but dramatically decreased during IBA. Elevated IKKbeta and p50 mRNA and protein expression in the cardiac muscle (CM) during HIB did not accompany increased MuRF1 expression or muscle wasting. Importantly, almost all increased or decreased indicators in the tested tissues recovered to pre-hibernation levels after HIB. This is the first study to report on the unexpected regulation of the IKKbeta/NF-kappaB/MuRF1 pathway with remarkable muscle plasticity in Daurian ground squirrels during hibernation. Furthermore, we found that different types of muscles exhibited different strategies to cope with prolonged hibernation-induced disuse muscle atrophy. PMID- 29761852 TI - The role of professionals in promoting independent living: Perspectives of self advocates and front-line managers. AB - BACKGROUND: Support from professionals plays an important role in helping people with intellectual disabilities to live an independent life. This research aims to analyse the role played by support professionals based on the perceptions of the professionals and self-advocates with intellectual disabilities. The research was conducted in Catalonia (Spain). METHOD: A total of 33 interviews were conducted with front-line managers and 10 focus groups with 72 self-advocates. These were recorded and transcribed, and then analysed using thematic content analysis. RESULTS: Self-advocates particularly value professionals' interpersonal skills and emotional support. Front-line managers and self-advocates highlight training actions aimed at enhancing autonomy in the home and propose fostering natural supports and increasing the involvement of people with disabilities. CONCLUSIONS: Making progress in the rights of people with intellectual disabilities to an independent life requires requires transforming the support model, promoting decision making among people with intellectual disabilities, and strengthening interpersonal skills linked to emotional support in the training of professionals. PMID- 29761853 TI - Splinted and unsplinted overdenture attachment systems: A systematic review and meta-analysis. AB - Splinted and unsplinted overdenture attachment systems have unique advantages and disadvantages. The aim of the present systematic review was to determine the influence of splinted and unsplinted overdenture attachment systems on the marginal bone loss, prosthetic complications and implant survival rate. PubMed/MEDLINE, Scopus and Cochrane databases were searched for articles published up to October 2017, using the following search terms: "overdenture AND attachment OR overdenture AND bar OR overdenture splinted." The PICO question "Do splinted overdenture attachment systems promote better clinical results in comparison to unsplinted systems?" was evaluated. Eligible studies included randomized controlled clinical trials, prospective studies with at least 10 participants and a minimum follow-up of 6 months, and studies published in English that compared splinted and unsplinted attachment systems within the same study. The 95% confidence interval (CI) was considered for all outcomes analysed. After completion of the different steps in the article selection process, nine articles were included in the qualitative and quantitative analyses. A total of 984 implants were placed in 380 patients (mean age: 62.8 years). The meta analysis demonstrated no statistically significant differences between splinted and unsplinted attachment systems with regard to marginal bone loss (P = .39; MD: -0.11; 95% CI: -0.37 to 0.14), complications (P = .31; RR: 1.26; CI: 0.80-1.99) and implant survival rate (P = .14; RR: 0.37% CI: 0.10-1.36). In addition, splinted and unsplinted overdenture attachment systems achieved similar results with regard to marginal bone loss, prosthetic complications and implant survival rate. PMID- 29761854 TI - Parenting adolescents with ASD: A multimethod study. AB - : A number of studies have concluded that parents of children with ASD experience high levels of parenting stress. However, little is known about their parenting behaviors. Especially few studies investigated parenting in adolescence, although this period is associated with additional challenges for both adolescents and their parents. In the present study, a multi-method approach was used, combining data from a self-report questionnaire and observation of mother-child interactions during different semi-structured (e.g., inventing and building a vehicle of the future with construction toys) and structured tasks (e.g., solving marble maze). Linear mixed models (LMM) were used to compare the means of parenting behaviors among mothers of adolescents with (n = 44) and without ASD (n = 38), aged 12 to 16 years old. During the observations, mothers of adolescents with ASD showed more sensitivity and creativity, compared to the general population control group. In addition, mothers in the ASD group reported on the self-report questionnaire to adapt the environment more, for example, by establishing routines. Furthermore, this study investigated the role of maternal characteristics, that is, ASD characteristics and parenting stress. Parenting stress was associated with less self-reported positive parenting. Higher levels of ASD characteristics of the mother were related to more negativity and less sensitivity during the observation, and more self-reported harsh punishment and adapting the environment. This study additionally examined whether the impact of these maternal characteristics was the same across the two groups. Whereas group by parenting stress interaction effects were not significant for any of the observed and self-reported parenting behaviors, significant group by ASD characteristics interaction effects were noticed for self-reported harsh punishment and adapting the environment. Autism Res 2018, 11: 1000-1010. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: A number of studies have concluded that parents of children with ASD experience high levels of parenting stress. However, little is known about their parenting behaviors. Especially parenting in adolescence remains under investigated, although this period is associated with additional challenges for both adolescents and their parents. In this study, 44 adolescents with ASD and a control group of 38 adolescents without ASD, aged 12-16 years old, participated together with their mother. We compared parenting behaviors between the two groups, based on observations of mother-child interactions and a questionnaire that was filled out by the mother. During the observation, mothers of adolescents with ASD showed more sensitivity and creativity, compared to the control group. In addition, the questionnaire responses indicated that mothers in the ASD group adapted the environment more by for example, establishing routines. Furthermore, this study investigated the role of parenting stress and ASD characteristics of the mother on parenting behavior. Parenting stress was associated with less self reported positive parenting. Higher levels of ASD characteristics of the mother were related to more negativity and less sensitivity during the observation in both groups, and more self-reported harsh punishment and adapting the environment in the control group only. PMID- 29761855 TI - Presence of SCF/CXCL12 double-positive large blast-like cells at the site of cutaneous extramedullary haematopoiesis. PMID- 29761856 TI - Autoimmune thyroiditis following HLA-matched sibling hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome. AB - WAS is a fatal X-linked combined immunodeficiency syndrome, the only cures for which are HSCT or gene therapy. AID occur in up to 72% of patients with WAS who do not receive HSCT, likely arising secondary to impaired multilineage immune autoregulatory function; AITD is not typically seen. In this article, we describe the case of a male patient who underwent HLA-matched HSCT for WAS at the age of 5 months, with his sister (a WAS carrier) acting as his donor and subsequently developed AITD 12 months post-transplant, with marked elevation of antithyroid peroxidase antibody titer. His donor sister was subsequently found to have elevated antithyroid peroxidase antibody titer with increasing trend and normal thyroid function. Although several mechanisms exist by which our patient may have developed AITD, we suggest the transfer of autoreactive donor immune cells as the most plausible explanation. PMID- 29761857 TI - Downregulated expression of microRNA-329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra. This study focuses on the effect of microRNA-329 (miR-329) on nigral dopaminergic neurons in a rat model of PD via the FoxO3a signaling pathway by binding to CDKN2D. Brain tissues from the substantia nigra were taken from the rats in two groups. TUNEL staining was used to observe tyrosine hydroxylase (TH)-positive neurons. Nigral dopaminergic neurons were randomized into the normal, blank, negative control (NC), miR-329 mimics, miR-329 inhibitors, small interfering (siRNA)-CDKN2D, and miR-329 inhibitors + siRNA-CDKN2D groups. Expressions of miR-329, CDKN2D, FoxO3a, AKT, caspase-3 and Bcl-2 were determined using RT-qPCR and western blotting. Apoptosis rate of nigral dopaminergic neurons in 7 groups was determined by flow cytometry. Compared with the blank and NC groups, the miR-329 mimics group showed increased miR-329 and caspase-3 expressions as well as decreased expressions of CDKN2D, FoxO3a, AKT, and Bcl-2, the siRNA-CDKN2D group indicated enhanced expressions of caspase-3 and declined expressions of CDKN2D, FoxO3a, AKT, and Bcl-2, and the miR 329 inhibitors group revealed decreased miR-329 and caspase-3 expressions and increased expressions of CDKN2D, FoxO3a, AKT, and Bcl-2. The apoptosis rate of nigral dopaminergic neurons was significantly increased in the miR-329 mimics and siRNA-CDKN2D groups, but was decreased in the miR-329 inhibitors group. Our data suggested that downregulated miR-329 could inhibit apoptosis of nigral dopaminergic neurons in a rat model of PD by upregulating the expression of CDKN2D via the activation of the FoxO3a signaling pathway. PMID- 29761858 TI - Predictive impact of the inflammation-based indices in colorectal cancer patients with adjuvant chemotherapy. AB - Increasing evidences reported that cancer-triggered inflammation was associated with survival prognosis from colorectal cancer (CRC). However, the comprehensive effects of inflammatory-based coNLR-PLR that combines neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) rarely remain to be determined during chemotherapy. We retrospectively analyzed clinical data and baseline laboratory parameters from 153 colorectal cancer patients who underwent palliative adjuvant chemotherapy between January 2009 to January 2012. Receiver operating characteristic (ROC) curves and linear regression analyzed the predictive ability of NLR, and PLR for calculating the score of coNLR-PLR. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated using the Kaplan-Meier method and analyzed by the Cox proportional hazards model in univariate and multivariate analysis. The optimal cut-off value of NLR and PLR was 2.24 and 186 by the ROC analysis. Kaplan-Meier method showed that patients with high coNLR-PLR score was associated with poorer OS and RFS (all P < .05). In univariate and multivariate analysis, it obtained that the coNLR-PLR severed as a strong independent prognostic factor for OS and RFS (all P < .05). These results highlight that coNLR-PLR index severed as a strong predictor of prognosis biomarker in CRC patients receiving adjuvant chemotherapy. Furthermore, its assessment could contribute to accurately predicting prognosis after chemotherapy in clinical practice. PMID- 29761860 TI - Hypermethylation of CpG islands is associated with increasing chromosomal damage in chinese lead-exposed workers. AB - Lead is a widely existing environmental pollutant with potential carcinogenicity. To investigate the association of blood lead level (B-Pb) with potential chromosomal damage and cancer, we analyzed micronucleus (MN) frequency of peripheral blood lymphocytes (PBLs) and the methylation status of six human tumor suppressor genes (TSGs) post lead exposure. In the study, 147 lead-exposed workers were divided into two groups according to their B-Pb P50 value, with other 50 lead-unexposed workers as a control group. The cytokinesis-blocked micronucleus (CBMN) assay was performed to detect chromosomal damage of PBLs of both lead-exposed and -unexposed workers. The methylation-specific polymerase chain reaction (MSP-PCR) was further used to examine the methylation status of six TSGs (GSTP1, hMLH1, MGMT, p14, p15, and p16). Results showed that MN frequencies of high B-Pb workers 8.1 +/- 3.10/00 and low B-Pb workers 5.7 +/- 2.30/00 were significantly higher than that of control group 2.8 +/- 1.90/00 (P < 0.01), while the MN frequency of high B-Pb workers was also higher than that of the low B-Pb workers (P < 0.01). The MN frequency in PBLs of lead-exposed group with the methylated TSGs was significantly higher than that in PBLs with the unmethylated TSGs (P < 0.05). Notably, the CpG island methylator phenotype (CIMP) correlated with chromosome damage (P < 0.05). Additionally, workers with high B Pb had higher chromosome damage than those with low B-Pb (P < 0.05). Taken altogether, the results suggest that lead-exposed workers with CIMP positive and high B-Pb have a higher risk of being vulnerable to tumorigenesis. Environ. Mol. Mutagen. 59:549-556, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29761859 TI - Systematic analyses of a novel lncRNA-associated signature as the prognostic biomarker for Hepatocellular Carcinoma. AB - Accumulating evidence implies that long noncoding RNAs (lncRNAs) play a crucial role in predicting survival for Hepatocellular carcinoma (HCC) patients. This study aims to capture the current research hotspots of HCC, based on the analysis of publications related to HCC research from 2013 to 2017, and to identify a novel lncRNA signature for HCC prognosis through the data mining in The Cancer Genome Atlas (TCGA). "Prognosis" and "biomarker" were located in the core of the HCC research hotspot. Moreover, long noncoding RNA was the top one research frontier in HCC research. The associations between survival outcome and the expression of lncRNAs were evaluated by the univariate and multivariate Cox proportional hazards regression analyses. Four lncRNAs (LINC00261, TRELM3P, GBP1P1, and CDKN2B-AS1) were identified as significantly correlated with overall survival (OS). These four lncRNAs were gathered as a single prognostic signature. There was a significant positive correlation between HCC patients with low-risk scores and overall survival (HR = 1.802, 95%CI [1.224-2.652], P = .003). Further analysis suggested that the prognostic value of this four-lncRNA signature was independent in clinical features. The enrichment analysis of prognostic lncRNA related gene was performed to find out the related pathways. Our study indicates that this novel lncRNA expression signature may be a useful biomarker of the prognosis for HCC patients, based on bioinformatics analysis. PMID- 29761861 TI - Implantable cardioverter-defibrillators in heart failure patients with reduced ejection fraction and diabetes. AB - AIM: There is limited information on the outcomes after primary prevention implantable cardioverter-defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes. METHODS AND RESULTS: A patient-level combined-analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all-cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow-up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all-cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46-0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7-1.12; interaction P = 0.015). CONCLUSION: Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all-cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes. PMID- 29761863 TI - Surgical treatment of esophageal cancer in the era of multimodality management. AB - Over the last decades, the treatment of resectable esophageal cancer has evolved into a multidisciplinary process in which all players are essential for treatment to be successful. Medical oncologists and radiation oncologists have been increasingly involved since the implementation of neoadjuvant therapy, which has been shown to improve survival. Although esophagectomy is still considered the cornerstone of curative treatment for locally advanced esophageal cancer, it remains associated with considerable postoperative morbidity, despite promising results of minimally invasive techniques. In this light, both physical status and response to neoadjuvant therapy may be important factors for selecting patients who will benefit from surgery. Furthermore, it is important to optimize the entire perioperative trajectory: from the initial outpatient clinic visit to postoperative discharge. Enhanced recovery after surgery is increasingly recognized for esophagectomy and emphasizes perioperative aspects, such as nutrition, physiotherapy, and pain management. To date, several facets of esophageal cancer treatment remain topics of debate, such as the preferred neoadjuvant treatment, anastomotic technique, extent of lymphadenectomy, organization of postoperative care, and the role of surgery beyond locally advanced disease. Here, we describe the current and future perspectives in the surgical treatment of patients with esophageal cancer in the context of the available literature. PMID- 29761862 TI - Cellular stress and apoptosis contribute to the pathogenesis of autism spectrum disorder. AB - : The molecular pathogenesis of autism spectrum disorder, a neurodevelopmental disorder, is still elusive. In this study, we investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. This study compared the activation of ER stress signals (protein kinase R-like endoplasmic reticulum kinase [PERK], activating transcription factor 6 [ATF6], inositol-requiring enzyme 1 alpha [IRE1alpha]) in different brain regions (prefrontal cortex, hippocampus, cerebellum) in subjects with autism and in age-matched controls. Our data showed that the activation of three signals of ER stress varies in different regions of the autistic brain. IRE1alpha was activated in cerebellum and prefrontal cortex but ATF6 was activated in hippocampus. PERK was not activated in the three regions. Furthermore, the activation of ER stress was confirmed because the expression of C/EBP-homologous protein (CHOP), which is the common downstream indicators of ER stress signals, and most of ER chaperones were upregulated in the three regions. Consistent with the induction of ER stress, apoptosis was found in the three regions by detecting the cleavage of caspase 8 and poly(ADP-ribose) polymerase as well as using the transferase dUTP nick end labeling assay. Moreover, our data showed that oxidative stress was responsible for ER stress and apoptosis because the levels of 4-Hydroxynonenal and nitrotyrosine-modified proteins were significantly increased in the three regions. In conclusion, these data indicate that cellular stress and apoptosis may play important roles in the pathogenesis of autism. Autism Res 2018, 11: 1076-1090. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism results in significant morbidity and mortality in children. The functional and molecular changes in the autistic brains are unclear. The present study utilized autistic brain tissues from the National Institute of Child Health and Human Development's Brain Tissue Bank for the analysis of cellular and molecular changes in autistic brains. Three key brain regions, the hippocampus, the cerebellum, and the frontal cortex, in six cases of autistic brains and six cases of non-autistic brains from 6 to 16 years old deceased children, were analyzed. The current study investigated the possible roles of endoplasmic reticulum (ER) stress, oxidative stress, and apoptosis as molecular mechanisms underlying autism. The activation of three signals of ER stress (protein kinase R-like endoplasmic reticulum kinase, activating transcription factor 6, inositol-requiring enzyme 1 alpha) varies in different regions. The occurrence of ER stress leads to apoptosis in autistic brains. ER stress may result from oxidative stress because of elevated levels of the oxidative stress markers: 4-Hydroxynonenal and nitrotyrosine modified proteins in autistic brains. These findings suggest that cellular stress and apoptosis may contribute to the autistic phenotype. Pharmaceuticals and/or dietary supplements, which can alleviate ER stress, oxidative stress and apoptosis, may be effective in ameliorating adverse phenotypes associated with autism. PMID- 29761865 TI - What the neighbor says. PMID- 29761864 TI - High-throughput detection and screening of plants modified by gene editing using quantitative real-time polymerase chain reaction. AB - Gene editing techniques are becoming powerful tools for modifying target genes in organisms. Although several methods have been developed to detect gene-edited organisms, these techniques are time and labour intensive. Meanwhile, few studies have investigated high-throughput detection and screening strategies for plants modified by gene editing. In this study, we developed a simple, sensitive and high-throughput quantitative real-time (qPCR)-based method. The qPCR-based method exploits two differently labelled probes that are placed within one amplicon at the gene editing target site to simultaneously detect the wild-type and a gene edited mutant. We showed that the qPCR-based method can accurately distinguish CRISPR/Cas9-induced mutants from the wild-type in several different plant species, such as Oryza sativa, Arabidopsis thaliana, Sorghum bicolor, and Zea mays. Moreover, the method can subsequently determine the mutation type by direct sequencing of the qPCR products of mutations due to gene editing. The qPCR-based method is also sufficiently sensitive to distinguish between heterozygous and homozygous mutations in T0 transgenic plants. In a 384-well plate format, the method enabled the simultaneous analysis of up to 128 samples in three replicates without handling the post-polymerase chain reaction (PCR) products. Thus, we propose that our method is an ideal choice for screening plants modified by gene editing from many candidates in T0 transgenic plants, which will be widely used in the area of plant gene editing. PMID- 29761866 TI - Occurrence of peri-implant diseases and risk indicators at the patient and implant levels: A multilevel cross-sectional study. AB - BACKGROUND: High prevalence rates of peri-implant diseases have been reported; however, the lack of standardization of definition criteria has lead to variations in the observed estimates. In addition, scarce data are available concerning patient and implant related factors associated to peri-implantitis. The aim of this study was to determine the prevalence of peri-implant diseases and their risk indicators at the patient and implant levels. METHODS: One hundred forty-seven patients with 490 dental implants were included. Dental implants were clinically and radiographically evaluated to determine their peri-implant conditions. Patient-related conditions and implant and prosthetic-related factors were recorded. Multivariable Poisson regression was fitted and prevalence ratios (PR) were reported. RESULTS: 85.3% of implants (95%CI 80.2 to 90.4) had mucositis and 9.2% (95%CI 4.7 to 13.7) had peri-implantitis. 80.9% (95%CI 73.8 to 86.8), and 19.1% (95%CI 12.6 to 25.5) of patients had mucositis and peri-implantitis. At the patient level, it was observed an increased probability of peri-implantitis in individuals with pocket depths >=6 mm (PR = 2.47) and with >=4 implants (PR = 1.96). Smoking increased the probability of peri-implantitis by three times (PR = 3.49). The final multilevel Poisson regression model at the implant level indicated that platform switching reduced the probability of peri-implantitis (PR = 0.18) and implants in function for >=5 years increased this probability (PR = 2.11). The final model including patient and implant level indicators demonstrated that higher time of function (PR = 2.76) and smoking (PR = 6.59) were associated with peri-implantitis. CONCLUSION: Peri-implant diseases are highly prevalent in the studied sample, and factors associated with the occurrence of peri-implantitis were presence of pockets >=6 mm, smoking, time of function, and type of platform. PMID- 29761867 TI - Airway physical examination tests for detection of difficult airway management in apparently normal adult patients. AB - BACKGROUND: The unanticipated difficult airway is a potentially life-threatening event during anaesthesia or acute conditions. An unsuccessfully managed upper airway is associated with serious morbidity and mortality. Several bedside screening tests are used in clinical practice to identify those at high risk of difficult airway. Their accuracy and benefit however, remains unclear. OBJECTIVES: The objective of this review was to characterize and compare the diagnostic accuracy of the Mallampati classification and other commonly used airway examination tests for assessing the physical status of the airway in adult patients with no apparent anatomical airway abnormalities. We performed this individually for each of the four descriptors of the difficult airway: difficult face mask ventilation, difficult laryngoscopy, difficult tracheal intubation, and failed intubation. SEARCH METHODS: We searched major electronic databases including CENTRAL, MEDLINE, Embase, ISI Web of Science, CINAHL, as well as regional, subject specific, and dissertation and theses databases from inception to 16 December 2016, without language restrictions. In addition, we searched the Science Citation Index and checked the references of all the relevant studies. We also handsearched selected journals, conference proceedings, and relevant guidelines. We updated this search in March 2018, but we have not yet incorporated these results. SELECTION CRITERIA: We considered full-text diagnostic test accuracy studies of any individual index test, or a combination of tests, against a reference standard. Participants were adults without obvious airway abnormalities, who were having laryngoscopy performed with a standard laryngoscope and the trachea intubated with a standard tracheal tube. Index tests included the Mallampati test, modified Mallampati test, Wilson risk score, thyromental distance, sternomental distance, mouth opening test, upper lip bite test, or any combination of these. The target condition was difficult airway, with one of the following reference standards: difficult face mask ventilation, difficult laryngoscopy, difficult tracheal intubation, and failed intubation. DATA COLLECTION AND ANALYSIS: We performed screening and selection of the studies, data extraction and assessment of methodological quality (using QUADAS 2) independently and in duplicate. We designed a Microsoft Access database for data collection and used Review Manager 5 and R for data analysis. For each index test and each reference standard, we assessed sensitivity and specificity. We produced forest plots and summary receiver operating characteristic (ROC) plots to summarize the data. Where possible, we performed meta-analyses to calculate pooled estimates and compare test accuracy indirectly using bivariate models. We investigated heterogeneity and performed sensitivity analyses. MAIN RESULTS: We included 133 (127 cohort type and 6 case-control) studies involving 844,206 participants. We evaluated a total of seven different prespecified index tests in the 133 studies, as well as 69 non-prespecified, and 32 combinations. For the prespecified index tests, we found six studies for the Mallampati test, 105 for the modified Mallampati test, six for the Wilson risk score, 52 for thyromental distance, 18 for sternomental distance, 34 for the mouth opening test, and 30 for the upper lip bite test. Difficult face mask ventilation was the reference standard in seven studies, difficult laryngoscopy in 92 studies, difficult tracheal intubation in 50 studies, and failed intubation in two studies. Across all studies, we judged the risk of bias to be variable for the different domains; we mostly observed low risk of bias for patient selection, flow and timing, and unclear risk of bias for reference standard and index test. Applicability concerns were generally low for all domains. For difficult laryngoscopy, the summary sensitivity ranged from 0.22 (95% confidence interval (CI) 0.13 to 0.33; mouth opening test) to 0.67 (95% CI 0.45 to 0.83; upper lip bite test) and the summary specificity ranged from 0.80 (95% CI 0.74 to 0.85; modified Mallampati test) to 0.95 (95% CI 0.88 to 0.98; Wilson risk score). The upper lip bite test for diagnosing difficult laryngoscopy provided the highest sensitivity compared to the other tests (P < 0.001). For difficult tracheal intubation, summary sensitivity ranged from 0.24 (95% CI 0.12 to 0.43; thyromental distance) to 0.51 (95% CI 0.40 to 0.61; modified Mallampati test) and the summary specificity ranged from 0.87 (95% CI 0.82 to 0.91; modified Mallampati test) to 0.93 (0.87 to 0.96; mouth opening test). The modified Mallampati test had the highest sensitivity for diagnosing difficult tracheal intubation compared to the other tests (P < 0.001). For difficult face mask ventilation, we could only estimate summary sensitivity (0.17, 95% CI 0.06 to 0.39) and specificity (0.90, 95% CI 0.81 to 0.95) for the modified Mallampati test. AUTHORS' CONCLUSIONS: Bedside airway examination tests, for assessing the physical status of the airway in adults with no apparent anatomical airway abnormalities, are designed as screening tests. Screening tests are expected to have high sensitivities. We found that all investigated index tests had relatively low sensitivities with high variability. In contrast, specificities were consistently and markedly higher than sensitivities across all tests. The standard bedside airway examination tests should be interpreted with caution, as they do not appear to be good screening tests. Among the tests we examined, the upper lip bite test showed the most favourable diagnostic test accuracy properties. Given the paucity of available data, future research is needed to develop tests with high sensitivities to make them useful, and to consider their use for screening difficult face mask ventilation and failed intubation. The 27 studies in 'Studies awaiting classification' may alter the conclusions of the review, once we have assessed them. PMID- 29761868 TI - Evaluating the Use of KIM-1 in Drug Development and Research Following FDA Qualification. AB - The Biomarker Qualification Program was established at the Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA) to expedite the integration of promising biomarkers across multiple drug development programs. The first set of biomarkers qualified in 2008 consisted of seven nonclinical safety biomarkers for the detection of acute drug-induced nephrotoxicity in rats, and included urinary kidney injury molecule-1 (KIM-1). This article discusses the use of KIM-1 in drug development and research before and after CDER's qualification of KIM-1. Use was determined by analyzing relevant documents identified by keyword searches using three databases: 1) an FDA internal database, Document Archiving, Reporting, and Regulatory Tracking System (DARRTS); 2) ClinicalTrials.gov; and 3) PubMed. The results indicate increased use of KIM-1 as a biomarker for detection of kidney injury in drug development programs reviewed by CDER, as well as in research following qualification. PMID- 29761869 TI - microRNA-665 promotes the proliferation and matrix degradation of nucleus pulposus through targeting GDF5 in intervertebral disc degeneration. AB - Growing evidences suggested that microRNAs (miRNAs) played important roles in the development of intervertebral disc degeneration (IDD). However, the expression level and function of miR-665 in IDD remain unknown. In this study, we showed that the expression level of miR-665 was upregulated in degenerative human NP samples. In addition, miR-665 expression level gradually increased with the exacerbation of disc degeneration grade. Moreover, miR-665 expression level was positively associated with the Pfirrmann grade. Ectopic expression of miR-665 promoted NP cell growth. Furthermore, miR-665 overexpression decreased aggrecan and Col II expression and ectopic expression of miR-665 increased MMP-3 and MMP 13 expression in NP cell. We identified growth differentiation factor 5 (GDF5) was a direct target gene of miR-665 in NP cell and enforced expression of miR-665 decreased GDF5 expression. Elevated expression of miR-665 enhanced NP cell proliferation and decreased aggrecan and Col II expression. In addition, ectopic expression of miR-665 increased MMP-3 and MMP-13 expression through inhibiting GDF5 expression in NP cells. These results suggested that dysregulated miR-665 expression might act an important role in the development of IDD. PMID- 29761870 TI - Intestinal disposition of quercetin and its phase-II metabolites after oral administration in healthy volunteers. AB - OBJECTIVES: Quercetin is one of the main dietary flavonoids and undergoes a substantial intestinal phase-II metabolism. Quercetin conjugates have been detected in plasma and in urine, but their presence in the small intestine has not been assessed. This study aimed to investigate the intestinal metabolism and metabolite excretion of quercetin by the human small intestinal wall after oral dosing. METHODS: Six healthy volunteers were given a capsule of 500 mg of quercetin with 240 ml of water. Duodenal fluids were collected using the intraluminal sampling technique for 4 h and analysed by LC-MS/MS. KEY FINDINGS: Phase-II metabolites of quercetin were detected and quantified in aspirated intestinal fluids. Metabolites appeared almost immediately after administration, indicating an intestinal metabolism and apical excretion into the lumen. Quercetin-3'-O-glucuronide was found to be the main intestinal metabolite. Our results could not conclude on the enterohepatic recycling of quercetin or its metabolites, although several individual profiles showed distinctive peaks. CONCLUSIONS: This study highlights the intestinal metabolism and excretion of quercetin and its conjugates in humans and gives insights into the relevant concentrations which should be used to investigate potential food-drug interactions in vitro. PMID- 29761871 TI - Autophagy May Protect Against Parenteral Nutrition-Associated Liver Disease by Suppressing Endoplasmic Reticulum Stress. AB - BACKGROUND: The objectives of this study were to address the role of autophagy in the pathogenesis of parenteral nutrition (PN)-associated liver disease (PNALD) and its possible mechanism in vivo. METHODS: Five-week-old male Sprague Dawley rats were fed Shoobree chow (Xietong Organism, Jiangsu, China) and administered intravenous 0.9% saline (sham group), PN (PN group), PN plus rapamycin (1 mg/kg; PN + Rapa group), or rapamycin (Rapa group) for 7 days. Before and after study, body weight, biochemical indicators, hepatic histology, level of autophagy, hepatocyte apoptosis, reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress indicators including binding immunoglobulin protein (BIP), spliced X box-binding protein-1 (sXBP1), and CCAAT-enhancer-binding protein homologous protein (CHOP) were measured. RESULTS: Autophagy was suppressed in the PNALD model, which was demonstrated by less light chain 3 fluorescence (LC3) puncta and lower LC3II expression. Rapamycin effectively induced hepatic autophagy in PN rats. The PN + Rapa group presented improved hepatic function, decreased pathology scores, and less steatosis than the PN group. In addition, rapamycin treatment decreased terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved-caspase 3 expression, indicating a lower level of hepatocyte apoptosis. Compared with the PN group, the PN + Rapa group had lower levels of ROS and reduced expression of ER stress-related protein markers, such as BIP, sXBP1 and CHOP. CONCLUSIONS: Autophagy was suppressed in the PNALD model. Rapamycin treatment induced autophagy and protected against PNALD, possibly by suppressing ROS-induced ER stress. PMID- 29761872 TI - Electronic Interactions in Illuminated Carbon Dot/MoS2 Ensembles and Electrocatalytic Activity towards Hydrogen Evolution. AB - The preparation, characterization, and photophysical and electrocatalytic properties of carbon dot (CD)/MoS2 ensembles is reported. Based on electrostatic interactions, ammonium-functionalized MoS2 , which was prepared upon reaction of 1,2-dithiolane tert-butyl carbamate with MoS2 followed by acidic deprotection, was coupled with CDs bearing multiple carboxylates on their periphery, as derived upon microwave-assisted polycondensation of citric acid and ethylenediamine followed by alkaline treatment. Insights into electronic interactions between the two species within CD/MoS2 ensembles emanated from absorption and photoluminescence titration assays. Efficient fluorescence quenching of CDs by MoS2 was observed and attributed to photoinduced electron/energy transfer as the decay mechanism for the transduction of the singlet excited state of CDs. Finally, the electrocatalytic performance of the CD/MoS2 ensemble was assessed towards the hydrogen evolution reaction and found to be superior to that of individual CDs species. PMID- 29761873 TI - Infection of Trichophyton verrucosum in cattle breeders, Poland: A 40-year retrospective study on the genomic variability of strains. AB - Trichophyton verrucosum is a zoophilic fungus that is the most frequent aetiological agent of dermatophytosis in cattle. During the last few years, the number of cases of T. verrucosum from humans has been increasing constantly, which is correlated with the presence of cattle-rearing farms. We identified and analysed T. verrucosum strains isolated from humans and cattle. Identification was carried out traditionally by correlating both the clinical manifestations with a micro- and macroscopic examination. To confirm the species affiliation fully, molecular differentiation methods were used. Direct analysis revealed the presence of arthrospores. The macro- and micromorphology of the isolates obtained from material sampled was homogeneous, and characterised for T. verrucosum. The phylogenetic analysis based on the ITS sequences demonstrated that the strains formed a monophyletic group with T. verrucosum ATCC10 695 with a support of 99%. The MP-PCR analysis indicates high invariability of genomes of strains from humans and animals. MSP-fingerprinting analysis gives the same results as the MP PCR analysis. To sum up, the rDNA ITS sequence analysis in combination with macro and micro-morphology only facilitated T. verrucosum species identification without the possibility of intraspecific differentiation. Finding and testing methods, especially molecular technique, with sufficient discriminatory power, is the present challenge for mycologists. PMID- 29761874 TI - Relapse rates in patients with unilesional primary cutaneous B-cell lymphoma treated with radiation therapy: a single-institution experience. PMID- 29761875 TI - miR-130 aggravates acute myocardial infarction-induced myocardial injury by targeting PPAR-gamma. AB - Cardiac remodeling is a common pathophysiological change associated with acute myocardial infarction (AMI). Recent evidence indicates that microRNAs are strong posttranscriptional regulators which play an important role in regulating the microenvironment of myocardial tissue after AMI. In this study, we sought to explore the potential role and underlying mechanism of miR-130 in AMI. H9c2 cells were cultured under hypoxic conditions to simulate myocardial infarction. The influence of aberrantly expressed miR-130 on H9c2 cells under hypoxia was also estimated with RT-PCR, western blot and enzyme-linked immunosorbent assay. Using bioinformatics methods, of miR-130 target genes were verified with luciferase reporter assay. Then, the effects of miR-130 on AMI were identified in an induced myocardial injury model in rats. The results show that miR-130 downregulation remarkably decreased hypoxia-induced inflammation and fibrosis related protein expression in H9c2 cells and reversed hypoxia-induced peroxisome proliferator activated receptor gamma (PPAR-gamma) inhibition. A bifluorescein reporter assay further confirmed that PPAR-gamma was a target gene of miR-130. This study verified that PPAR-gamma has a cardioprotective effect by inhibiting NFkappaB mediated inflammation and TGF-beta1-mediated fibrosis. In vivo experiments confirmed that downregulation of miR-130 expression promotes PPAR-gamma-mediated cardioprotective effects by suppressing inflammation and myocardial fibrosis. Taken together, these findings suggest that miR-130 knockdown alleviates infarction-induced myocardial injury by promoting PPAR-gamma expression. PMID- 29761876 TI - Differential GIP/GLP-1 intestinal cell distribution in diabetics' yields distinctive rearrangements depending on Roux-en-Y biliopancreatic limb length. AB - As incretins are known to play an important role in type 2 diabetics (T2D) improvement observed after Roux-en-Y gastric bypass (RYGB), our aim was to assess whether increasing the length of RYGB biliopancreatic limb in T2D would modify the incretin staining cell density found after the gastric outlet. Small intestine biopsies (n = 38) were harvested during RYGB at two different distances from the duodenal angle; either 60-90 cm (n = 28), from non-diabetic (n = 18) patients, and T2D (n = 10), or 200 cm (n = 10) from T2D. GIP and GLP-1 staining cells were identified by immunohistochemistry and GLP-1/GIP co-staining cells by immunofluorescence. Incretin staining cell density at the proximal small intestine of T2D and non-diabetic individuals was similar. At 200 cm, T2D patients depicted a significantly lower GIP staining cell density (0.181 +/- 0.016 vs 0.266 +/- 0.033, P = 0.038) with a similar GLP-1 staining cell density when compared to the proximal gut. GIP/GLP-1 co-staining cells was similar in all studied groups. In T2D patients, the incretin staining cells density in the distal intestine is significantly different from the proximal gut. Thus, a longer RYGB biliopancreatic limb produces a distinctive incretin cell pattern at the gastro-enteric anastomosis that can result in different endocrine profiles. PMID- 29761877 TI - Diagnostic accuracy of new and old cognitive screening tools for HIV-associated neurocognitive disorders. AB - OBJECTIVES: Considering the similarities between HIV-associated neurocognitive disorders (HAND) and neurodegenerative dementias and the frequency of executive dysfunctions among HIV-positive patients, we evaluated the accuracy of the Frontal Assessment Battery and Clock-Drawing Test together with the Three Questions Test and International HIV Dementia Scale to screen for HAND. METHODS: A cross-sectional monocentric study was conducted from 2010 to 2017. The index tests were represented by the four screening tools; the reference standard was represented by a comprehensive neurocognitive battery used to investigate 10 cognitive domains. Patients were screened by a trained infectious diseases physician and those showing International HIV Dementia Scale scores <= 10 and/or complaining of neurocognitive symptoms were then evaluated by a trained neuropsychologist. RESULTS: A total of 650 patients were screened and 281 received the full neurocognitive evaluation. HAND was diagnosed in 140 individuals. The sensitivity, specificity, correct classification rate and area under the receiver operating characteristic curve (AUROC) were, respectively, as follows: Frontal Assessment Battery, 40.7%, 95.1%, 68.3% and 0.81; International HIV Dementia Scale, 74.4%, 56.8%, 65.4% and 0.73; Clock-Drawing Test, 30.9%, 73.4%, 53.8% and 0.56; and Three Questions Test, 37.3%, 54.1% and 45.7%. Raising the Frontal Assessment Battery's cut-off to <= 16 improved its sensitivity, specificity and correct classification rate to 78.0%, 63.9% and 70.8%, respectively. CONCLUSIONS: We observed poor screening performances of the Three Questions and Clock-Drawing Tests. While the International HIV Dementia Scale showed a poor specificity, the Frontal Assessment Battery showed the highest correct classification rate and a promising performance at different exploratory cut-offs. PMID- 29761879 TI - High-Dose Human Milk Feedings Decrease Oxidative Stress in Premature Infant. AB - BACKGROUND: Premature infants are susceptible to oxidative stress, increasing the risk for serious morbidities. High-dose human milk (HM) feedings decrease morbidity risks and may reduce oxidative stress in this population. The purpose of this study was to compare oxidative stress using serial urinary F2 isoprostane concentrations in predominantly HM and preterm formula (PF)-fed premature infants over the first 21 days of life (DOL), while controlling for perinatal oxidative stress exposures including bovine-based human milk fortifier (HMF) or PF introduction to predominantly HM-fed infants. METHODS: This was a quasi-experimental design that categorized 22 premature infants into mutually exclusive comparison groups based on exposure to HM and PF. Serial urine samples (before and after first feeding, and DOL 7, 14, and 21) were used to determine urine F2 -isoprostane concentrations measured by enzyme-linked immunosorbent assays. We analyzed data using Mann-Whitney U test, Wilcoxon rank test, and multilevel models. RESULTS: Comparing the predominantly HM-fed and predominantly PF-fed groups over time, median F2 -isoprostane concentrations decreased significantly in the predominantly HM group (P = .003) and increased significantly in the predominantly PF group (P = .01). Perinatal oxidant exposures and the introduction of HMF did not affect results. CONCLUSIONS: Our results demonstrate that predominantly HM feedings were associated with decreased oxidative stress, whereas PF feedings increased oxidative stress in premature infants, even after controlling for perinatal oxidant exposures of HMF or PF introduction. PMID- 29761878 TI - C-H Activation Enables a Concise Total Synthesis of Quinine and Analogues with Enhanced Antimalarial Activity. AB - We report a novel approach to the classical natural product quinine that is based on two stereoselective key steps, namely a C-H activation and an aldol reaction, to unite the two heterocyclic moieties of the target molecule. This straightforward and flexible strategy enables a concise synthesis of natural (-) quinine, the first synthesis of unnatural (+)-quinine, and also provides access to unprecedented C3-aryl analogues, which were prepared in only six steps. We additionally demonstrate that these structural analogues exhibit improved antimalarial activity compared with (-)-quinine both in vitro and in mice infected with Plasmodium berghei. PMID- 29761880 TI - N-Arylamines Coupled with Aldehydes, Ketones, and Imines by Means of Photocatalytic Proton-Coupled Electron Transfer. AB - A photoredox-catalyzed umpolung strategy for coupling reactions between aldehydes, ketones, imines, and N-arylamines is reported. These reactions proceed by a Bronsted acid-activated proton-coupled electron transfer pathway, and the protocol was used to synthesize a broad scope of 1,2-amino alcohols and vicinal diamines, both of which are common motifs in biologically active natural products, pharmaceutically active molecules, and ligands. PMID- 29761881 TI - Expression of stem cell markers Nanog and Nestin in lip squamous cell carcinoma and actinic cheilitis. AB - : Cancer stem cell (CSC) proteins have been observed in several lesions and are associated with tumor beginning, evolution, and resistance to treatment. OBJECTIVES: To investigate the presence of NANOG, NESTIN, and beta-tubulin in lip squamous cell carcinoma (LSCC), actinic cheilitis (AC), and normal epithelium (NE). MATERIALS AND METHODS: Thirty cases of LSCC, thirty cases of AC (both analyzed according to the WHO classification and AC according to the binary classification), and twenty cases of NE were submitted to an immunohistochemical study. RESULTS: NANOG was more expressed in the nuclei of AC compared to NE (p = 0.007), as well as in high-risk AC cases (p = 0.017) and well-differentiated LSCCs (no significance). There was an accumulation of nuclear NANOG from mild to moderate and severe ACs. NESTIN was significantly less present in NE compared to AC (p = 0.001) and LSCC (p = 0.003). There was a higher expression in severe dysplasia or high-risk AC and well-differentiated LSCC. These results indicate an upregulation of NANOG and NESTIN in the early stages of carcinogenesis. beta tubulin was intensely present in all lesions. CONCLUSION: The results suggest an upregulation of NANOG and NESTIN in the biological behavior these diseases, mainly in the transformation from AC to LSCC. PMID- 29761882 TI - The prevalence of obesity in children and young people with Down syndrome. AB - BACKGROUND: Overweight and obesity is a growing concern among individuals with intellectual disabilities; however, little is known about the prevalence among children and youth with Down syndrome (CYDS). The purpose of this study was to determine the prevalence of overweight/obesity among CYDS in South West Ireland. METHODS: This cross-sectional study measured height and weight of 61 CYDS aged 4 16 years. Body mass index (BMI) was calculated and percentage body fat (PBF) was measured using bio-electrical impendence analysis (BIA). RESULTS: Using the International Obesity Task Force BMI cut-offs, 51.6% of males and 40% of females were overweight/obese compared to 32% and 14.8%, respectively, using PBF. The mean PBF for males was 18.76 versus females 22.38 (p < .05). There is a higher prevalence of overweight/obesity, particularly in males, compared to the general population of children. CONCLUSIONS: The difference in estimation of overweight/obesity between BMI and BIA has implications for research and clinical practice. PMID- 29761883 TI - Benchmarking QSP Models Against Simple Models: A Path to Improved Comprehension and Predictive Performance. AB - Quantitative Systems Pharmacology (QSP) models provide a means of integrating knowledge into a quantitative framework and, ideally, this integration leads to a better understanding of biology and better predictions of new experiments and clinical trials. In practice, these goals may be compromised by model complexity and uncertainty. To address these problems, we recommend that the predictive performance of QSP models be assessed through comparison with simpler models developed specifically for this purpose. PMID- 29761884 TI - Inhibitory effects of tubeimoside I on synoviocytes and collagen-induced arthritis in rats. AB - Advancements in rheumatoid arthritis (RA) therapies have shown considerable progresses in the comprehension of disease. However, the development of new potential medicines with relative safety and efficacy continues and natural compounds have been considered as alternatives or complementary agents to gain immense attractions. Tubeimoside I (TBMS I), a main triterpenoid saponin isolated from Bolbostemma paniculatum, has been reported to possess antiviral and anticancer effects. However, its effect on RA remains unknown. Here, we investigated the therapeutic effect of TBMS I in collagen-induced arthritis (CIA) rats and explored its underlying mechanism. Our results showed that TBMS I treatment efficaciously ameliorated inflammation and joint destruction of rats with CIA. In vitro studies revealed that TBMS I suppressed the production of pro inflammatory cytokines including IL-1beta, IL-6, IL-8 and TNFalpha, and downregulated the expression of MMP-9. In addition, TBMS I attenuated the destructive phenotypes of FLS of CIA rats including inhibiting proliferation and reducing migration rate. Further mechanistic analysis demonstrated that TBMS I suppressed TNFalpha-induced activations of NF-kappaB and MAPKs (p38 and JNK) leading to the downregulation of pro-inflammatory cytokines, which was beneficial to the anti-proliferative and anti-migratory activities of FLS cells. Taken together, TBMS I has a great potential to be developed into a novel therapeutic agent for the treatment of RA. PMID- 29761886 TI - Zinc toxicity to Daphnia magna in a two-species microcosm can be predicted from single-species test data: The effects of phosphorus supply and pH. AB - Ecological interactions and abiotic stress factors may significantly affect species sensitivities to toxicants, and these are not incorporated in standard single-species tests. The present study tests whether a model, calibrated solely on single-species data, can explain abiotic stress factors in a two-species microcosm, a test applied to the effects of nutritional stress (phosphorus [P] limitation) on zinc (Zn) toxicity to Daphnia magna. A population model was developed based on P- and Zn-dependent algal and daphnid growth. Two separate two species (phytoplankton Pseudokirchneriella subcapitata and consumer D. magna) microcosm experiments with P * Zn factorial combinations and a different pH (7.3 and 7.8) were set up to validate the model. The 21-d daphnid population size was considerably reduced by increased Zn and by decreased P supply, with a significant (p < 0.001) interaction between the 2 factors. The observed median effective concentration (EC50) of Zn on D. magna population size varied 12-fold (25 to 310 MUg Zn L-1 ), with the lowest EC50 values found at the highest pH and high P treatments. For both experiments, Zn toxicity to D. magna was correctly predicted within a factor of 2 for EC50 values, and this is explained by the model through 1) a higher phytoplankton Zn sensitivity at higher pH, affecting food supply to D. magna, and 2) an increased algal P content at higher Zn, offering a nutritional benefit to daphnids that counteracts direct Zn toxicity under P limitation. The present study illustrates that indirect effects of Zn via producer-consumer relationships can outweigh the direct toxic effects and that models calibrated solely on single-species test data can help with interpreting these results in two-species systems. Environ Toxicol Chem 2018;37:2153-2164. (c) 2018 SETAC. PMID- 29761885 TI - Immediate breast reconstruction for women having inflammatory breast cancer in the United States. AB - Inflammatory breast cancer (IBC) is an aggressive malignancy having a poor prognosis. Traditionally, reconstruction is not offered due to concerns about treatment delay, margin positivity, recurrence, and poor long-term survival. There is a paucity of literature, however, evaluating whether immediate breast reconstruction (IBR) is associated with greater mortality in patients with IBC. A population-based study was conducted via the SEER-Medicare-linked database (1991 2009). Female patients greater than 65 years were reviewed who had mastectomy and reconstruction claims for nonmetastatic IBC. Competing risk and Cox regression were used to assess whether IBR was associated with higher breast cancer-specific mortality (BCSM) or overall mortality (OM). Among 552 936 patients, 1472 (median age 74 years) were diagnosed with IBC and had a mastectomy. Forty-four patients (3%) underwent IBR. Younger age, a lower Charlson comorbidity score, and a greater median income were predictors of IBR use. Tumor grade, hormone receptor status, and lymph node status were independent predictors of adjusted OM and BCSM. There was no difference by IBR status in BCSM or covariate-adjusted BCSM (sHR 1.04; CI 0.71-1.54; P = .83 and sHR 1.13; CI 0.84-1.93; P = .58, respectively). Cumulative incidence of OM was lower among IR patients (P = .013), and IR did not influence the cumulative incidence of BCSM (P = .91). IBR was not associated with increased overall and BCSM mortality. Although further study of IBR in the IBC setting may be of value, these data suggest that IBC should not be considered an absolute contraindication to IBR. PMID- 29761887 TI - Telomere length and genetic variations affecting telomere length as biomarkers for facial regeneration with platelet-rich fibrin based on the low-speed centrifugation concept. AB - BACKGROUND: Platelet-Rich Fibrin (PRF), a fibrin matrix produced by single blood centrifugation that contains leukocytes, platelets, and growth factors, is increasingly being utilized for facial regeneration purposes. However, our understanding of the involved pathophysiological mechanisms affecting regeneration is limited and current protocols require better optimization. Biomarkers that are related to skin aging such as telomere length (TL) have been proposed as a mean to analyze patients' stratification. OBJECTIVE: Our aim is to study whether the outcomes of a facial regeneration protocol performed with PRF are related to TL and genetic variations affecting TL. This can aid in the standardization of a surgical aesthetic protocol. PATIENTS AND METHODS: In all, 41 patients treated with PRF produced with the low-speed centrifugation concept were included in this observational study. The correlation between TL and genetic variations were assessed versus treatment outcomes, namely the number of sessions and aesthetic results utilizing the FACE-Q skin satisfaction questionnaire. RESULTS: In all, 39 of the 41 patients completed the treatment. TL correlated with the initial responses to FACE-Q (rho = .33, P = .05). Genetic variations affecting TL was related to the change of FACE-Q (rho = .35, P = .034) as well as to the number of treatment sessions (rho = .38, P = .019). CONCLUSIONS: Telomere length (TL) was related to patient perceived facial skin appearance. In addition, genetic variations affecting TL were related to the final outcomes (number of sessions and improvements of FACE-Q results) and may be a useful biomarker for future regenerative procedures performed with PRF for facial regeneration. PMID- 29761888 TI - Idiopathic sterile pyogranuloma in three domestic cats. AB - Pyogranulomatous inflammation has been extensively described in cats, in particular in cases of feline infectious peritonitis and also associated with Mycobacteria, Actinomyces, Nocardia, Rhodococcus and fungal infections. Idiopathic sterile pyogranulomatous dermatitis has also been described. In this case series we describe the clinical presentation, histopathology and outcome of three cases of feline idiopathic sterile steroid-responsive pyogranuloma with different presentation and different locations of the lesion, but with the common feature of having a mass with no superficial skin involvement. PMID- 29761890 TI - Glucocorticoid receptor gene variants and lower expression of NR3C1 are associated with cocaine use. AB - Animal and cross-sectional human studies suggest that chronic cocaine use is associated with altered responsivity of the hypothalamic-pituitary-adrenal axis to stress. Moreover, increased susceptibility to stress has been proposed as an important factor for development, maintenance and relapse of cocaine addiction. As the glucocorticoid receptor gene (NR3C1) mediates genomic effects of the stress hormone cortisol, we investigated NR3C1 expression and the association of NR3C1 genotypes with cocaine use, addiction and comorbid psychiatric symptoms in 126 chronic cocaine users and 98 stimulant-naive healthy controls. A comprehensive psychiatric assessment was performed including severity of depressive symptoms and current psychological distress. Whole blood NR3C1 mRNA levels were determined and six NR3C1 polymorphisms (rs10482605, rs41423247, rs10052957, rs6189, rs56149945 and rs6198) were genotyped. Compared to controls, cocaine users showed significantly lower NR3C1 expression (P < 0.001), which was not affected by NR3C1 genotypes. In controls, rs41423247 [P < 0.01, false discovery rate (FDR)-corrected], haplotype 2 and haplotype 3 (both P < 0.05, FDR corrected) were associated with altered NR3C1 gene expression. Haplotype 3 (including minor alleles of rs10052957 and rs41423247) was associated with an increased risk for cocaine addiction (odds ratio = 2.74, P < 0.05, uncorrected). Moreover, addicted cocaine users carrying haplotype 3 showed higher depression scores (P < 0.01, FDR-corrected) than noncarriers. Considering possible confounding effects of alcohol and/or depression, we conclude that chronic cocaine use is associated with lower NR3C1 gene expression suggesting possible direct effects of the drug on the biological adaptation of stress-related genes. Finally, we postulate that haplotype 3 of NR3C1 might serve as a potential risk factor for stimulant addiction and associated psychiatric symptoms. PMID- 29761889 TI - A novel human S10F-Hsp20 mutation induces lethal peripartum cardiomyopathy. AB - Heat shock protein 20 (Hsp20) has been shown to be a critical regulator of cardiomyocyte survival upon cardiac stress. In this study, we investigated the functional significance of a novel human Hsp20 mutation (S10F) in peripartum cardiomyopathy. Previous findings showed that cardiac-specific overexpression of this mutant were associated with reduced autophagy, left ventricular dysfunction and early death in male mice. However, this study indicates that females have normal function with no alterations in autophagy but died within a week after 1-4 pregnancies. Further examination of mutant females revealed left ventricular chamber dilation and hypertrophic remodelling. Echocardiography demonstrated increases in left ventricular end-systolic volume and left ventricular end diastolic volume, while ejection fraction and fractional shortening were depressed following pregnancy. Subsequent studies revealed that cardiomyocyte apoptosis was elevated in mutant female hearts after the third delivery, associated with decreases in the levels of Bcl-2/Bax and Akt phosphorylation. These results indicate that the human S10F mutant is associated with dysregulation of cell survival signalling, accelerated heart failure and early death post-partum. PMID- 29761891 TI - Processed electroencephalogram and evoked potential techniques for amelioration of postoperative delirium and cognitive dysfunction following non-cardiac and non neurosurgical procedures in adults. AB - BACKGROUND: Postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) may complicate a patient's postoperative recovery in several ways. Monitoring of processed electroencephalogram (EEG) or evoked potential (EP) indices may prevent or minimize POD and POCD, probably through optimization of anaesthetic doses. OBJECTIVES: To assess whether the use of processed EEG or auditory evoked potential (AEP) indices (bispectral index (BIS), narcotrend index, cerebral state index, state entropy and response entropy, patient state index, index of consciousness, A-line autoregressive index, and auditory evoked potentials (AEP index)) as guides to anaesthetic delivery can reduce the risk of POD and POCD in non-cardiac surgical or non-neurosurgical adult patients undergoing general anaesthesia compared with standard practice where only clinical signs are used. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and clinical trial registry databases up to 28 March 2017. We updated this search in February 2018, but these results have not been incorporated in the review. SELECTION CRITERIA: We included randomized or quasi-randomized controlled trials comparing any method of processed EEG or evoked potential techniques (entropy, BIS, AEP etc.) against a control group where clinical signs were used to guide doses of anaesthetics in adults aged 18 years or over undergoing general anaesthesia for non-cardiac or non-neurosurgical elective operations. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were: occurrence of POD; and occurrence of POCD. Secondary outcomes included: all-cause mortality; any postoperative complications; and postoperative length of stay. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS: We included six randomized controlled trials (RCTs) with 2929 participants comparing processed EEG or EP indices-guided anaesthesia with clinical signs-guided anaesthesia. There are five ongoing studies and one study awaiting classification.Anaesthesia administration guided by the indices from a processed EEG (bispectral index) probably reduces the risk of POD within seven days after surgery with risk ratio (RR) of 0.71 (95% CI 0.59 to 0.85; number needed to treat for an additional beneficial outcome (NNTB) of 17, 95% CI 11 to 34; 2197 participants; 3 RCTs; moderate quality of evidence). Three trials also showed the lower rate of POCD at 12 weeks after surgery (RR 0.71, 95% CI 0.53 to 0.96; NNTB 38, 95% CI 21 to 289; 2051 participants; moderate-quality evidence), but it is uncertain whether processed EEG indices reduce POCD at one week (RR 0.84, 95% CI 0.69 to 1.02; 3 trials; 1989 participants; moderate-quality evidence), and at 52 weeks (RR 0.30, 95% CI 0.05 to 1.80; 1 trial; 59 participants; very low quality of evidence). There may be little or no effect on all-cause mortality (RR 1.01, 95% CI 0.62 to 1.64; 1 trial; 1155 participants; low-quality evidence). One trial suggested a lower risk of any postoperative complications with processed EEG (RR 0.51, 95% CI 0.37 to 0.71; 902 participants, moderate-quality evidence). There may be little or no effect on reduced postoperative length of stay (mean difference -0.2 days, 95% CI -2.02 to 1.62; 1155 participants; low-quality evidence). AUTHORS' CONCLUSIONS: There is moderate-quality evidence that optimized anaesthesia guided by processed EEG indices could reduce the risk of postoperative delirium in patients aged 60 years or over undergoing non-cardiac surgical and non-neurosurgical procedures. We found moderate-quality evidence that postoperative cognitive dysfunction at three months could be reduced in these patients. The effect on POCD at one week and over one year after surgery is uncertain. There are no data available for patients under 60 years. Further blinded randomized controlled trials are needed to elucidate strategies for the amelioration of postoperative delirium and postoperative cognitive dysfunction, and their consequences such as dementia (including Alzheimer's disease (AD)) in both non-elderly (below 60 years) and elderly (60 years or over) adult patients. The one study awaiting classification and five ongoing studies may alter the conclusions of the review once assessed. PMID- 29761892 TI - Perspective on the State of Pharmacometrics and Systems Pharmacology Integration. AB - Reliance on modeling and simulation in drug discovery and development has dramatically increased over the past decade. Two disciplines at the forefront of this activity, pharmacometrics and systems pharmacology (SP), emerged independently from different fields; consequently, a perception exists that only few examples integrate these approaches. Herein, we review the state of pharmacometrics and SP integration and describe benefits of combining these approaches in a model-informed drug discovery and development framework. PMID- 29761893 TI - Development of Safe and Flavor-Rich Doenjang (Korean Fermented Soybean Paste) Using Autochthonous Mixed Starters at the Pilot Plant Scale. AB - : Doenjang (Korean fermented soybean paste) with an improved flavor and safety was prepared by the simultaneous fermentation of autochthonous mixed starters at the pilot plan scale. First, whole soybean meju was fermented by coculturing safety-verified starters Aspergillus oryzae MJS14 and Bacillus amyloliquefaciens zip6 or Bacillus subtilis D119C. These fermented whole soybean meju were aged in a brine solution after the additional inoculation of Tetragenococcus halophilus 7BDE22 and Zygosaccharomyces rouxii SMY045 to yield doenjang. Four doenjang batches prepared using a combination of mold, bacilli, lactic acid bacteria, and yeast starters were free of safety issues and had the general properties of traditional doenjang, a rich flavor and taste. All doenjang batches received a high consumer acceptability score, especially the ABsT and ABsTZ batches. This study suggests that flavor-rich doenjang similar to traditional doenjang can be manufactured safely and reproducibly in industry by mimicking the simultaneous fermentation of autochthonous mixed starters as in traditional doenjang fermentation. PRACTICAL APPLICATION: The development of a pilot plant process for doenjang fermentation using safety-verified autochthonous mixed starter will facilitate the manufacture of flavor-rich doenjang similar to traditional doenjang safely and reproducibly in industry. PMID- 29761895 TI - Blurry halos after tattooing (tattoo blowouts): a review of 16 cases. PMID- 29761894 TI - Effects of fucoxanthin on autophagy and apoptosis in SGC-7901cells and the mechanism. AB - Autophagy and apoptosis are involved in the development of a variety of cancers. Fucoxanthin is a natural compound known to have antitumor effects, so we aimed to explore its effects on autophagy and apoptosis in gastric cancer SGC7901 cells. Specifically, we performed methyl thiazolyl tetrazolium assay, transmission electron microscopy, real-time polymerase chain reaction, Western blot analysis, immunofluorescence assay, and cell apoptosis analysis to clarify the role of fucoxanthin in SGC-7901 cells. Our results indicate that fucoxanthin significantly inhibits the viability of SGC-7901 cells, effectively inducing both autophagy and apoptosis by up-regulating the expressions of beclin-1, LC3, and cleaved caspase-3 (CC3), and by down regulating Bcl-2. Fucoxanthin-induced autophagy also seems to occur before, and may promote apoptosis. PMID- 29761897 TI - Chronic ethanol exposure of human pancreatic normal ductal epithelial cells induces cancer stem cell phenotype through SATB2. AB - The incidence of pancreatic cancer is on the rise. Risk factors for pancreatic cancer include alcohol toxicity and metabolic conditions such as obesity, hypertension, dyslipidaemia, insulin resistance and type 2 diabetes. However, the molecular mechanism by which chronic alcohol consumption contributes to pancreatic cancer is not well understood. The purpose of the study was to demonstrate the effects of long-term chronic ethanol exposure on the transformation of human pancreatic normal ductal epithelial (HPNE) cells. Our data showed that ethanol-transformed HPNE cells were more progressively transformed exhibiting spheroids and colonies, and anchorage-independent growth. These transformed cells contained high levels of reactive oxygen species and induced SATB2 expression. Furthermore, during ethanol-induced cellular transformation, cells gained the phenotypes of cancer stem cells (CSCs) by expressing pluripotency maintaining factors (Oct4, Sox2, cMyc and KLF4) and stem cell markers (CD24, CD44 and CD133). Ethanol-induced SATB2 can bind to the promoters of KLF4, Oct4, cMyc, Sox2, Bcl-2 and XIAP genes. Suppression of SATB2 expression in ethanol-transformed HPNE cells inhibited cell proliferation, colony formation and markers of CSCs and pluripotency. These data suggest that chronic alcohol consumption may contribute toward the development of pancreatic cancer by converting HPNE cells to cancer stem-like cells. PMID- 29761896 TI - Sphingolipids regulate neuromuscular synapse structure and function in Drosophila. AB - Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function, and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl-transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction (NMJ) revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although NMJ length is normal in lace mutants, the number of boutons per NMJ is reduced to ~50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig-domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine-tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg. PMID- 29761898 TI - Clinical Impact of Muscle Quantity and Quality in Colorectal Cancer Patients: A Propensity Score Matching Analysis. AB - BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass, accompanied by decreased muscle strength, and consists of myopenia and myosteatosis. Recent evidence has suggested the predictive value of sarcopenia for the risk of perioperative and oncological outcomes in various malignancies. The aim of this study was to clarify the clinical impact of myopenia and myosteatosis in colorectal cancer (CRC) patients. METHODS: We analyzed the preoperative psoas muscle mass index and intramuscular adipose tissue content using preoperative computed tomography images from 308 CRC patients using statistical methods. RESULTS: Despite no significant correlation between myosteatosis and prognosis, preoperative myopenia significantly correlated with clinicopathological factors for disease development, including advanced tumor depth (P = 0.009), presence of lymphatic vessel invasion (P = 0.006), distant metastasis (P = 0.0007), and advanced stage classification (P = 0.013). Presence of preoperative myopenia was an independent prognostic factor for both cancer specific survival (hazard ratio [HR]: 2.75, 95% confidence interval [CI]: 1.5 5.05, P = 0.001) and disease-free survival (HR: 3.15, 95% CI: 1.8-5.51, P = 0.0001), and was an independent risk factor for postoperative infectious complications in CRC patients (odds ratio: 2.03, 95% CI:1.17-3.55, P = 0.013). Furthermore, these findings were successfully validated using propensity score matching analysis. CONCLUSIONS: Preoperative myopenia could be useful for perioperative management, and quantification of preoperative skeletal muscle mass could identify patients as a high risk for perioperative and oncological outcomes in CRC patients. PMID- 29761901 TI - The fear for contrast-induced nephropathy in kidney transplant recipients: time for a paradigm shift? PMID- 29761899 TI - The use of hepatitis B immunoglobulin with or without hepatitis B vaccine to prevent de novo hepatitis B in pediatric recipients of anti-HBc-positive livers. AB - Prophylactic measures are used to reduce DNHB after HBsAg-negative patients receive anti-HBc-positive liver grafts. This study investigated the incidence of DNHB and clinical outcomes in pediatric LT recipients under HBIG prophylaxis, with or without hepatitis B vaccination. Between 1995 and 2013, 51 HBsAg-negative pediatric recipients underwent living-donor LT from anti-HBc-positive donors. The median (range) age was 4 (0.1-17) years, 23 (45%) were male, and 71% were negative for both anti-HBc and anti-HBc. During a median follow-up of 12.1 (0.06 19.9) years, 13 (25.4%) developed DNHB; 7 of the 13 achieved HBsAg seroconversion after administration of LAM or ETV. Among studied patients, 20 (39%) received hepatitis B vaccination, and 2 of them (10%) developed DNHB. At last follow-up, 41% (21/51) discontinued HBIG either after successful HBV vaccination (n = 17) or retransplantation with anti-HBc-negative grafts (n = 4). In conclusion, pediatric LT recipients of anti-HBc-positive grafts, most of them were naive to HBV infection, were at high risk of DNHB, and consistent monitoring for the early detection of DNHB was necessary. A combination use of post-LT vaccination is promising prophylactic strategy against DNHB. PMID- 29761900 TI - Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy. AB - Among several pathological mechanisms involved in diabetic nephropathy, oxidative stress, inflammation, and apoptosis play a prominent role. Fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, has markedly improved oxidative stress and inflammatory responses, but there is no evidence about its effects on interleukin-18 (IL-18), NADPH oxidase type 4 (NOX 4), and p53 expression in diabetic kidneys. The aim of this study was to evaluate possible effects of fenofibrate on improving the underlying mechanisms of diabetic nephropathy. Male Wistar rats were randomly divided into four groups namely, normal, normal treated, diabetic and diabetic treated (N = 6). Diabetes was induced by a single dose of streptozotocin (40 mg/kg; IV). Treated animals received fenofibrate for 8 weeks daily (80 mg/kg; po). All groups were sacrificed on day 56 and blood, urine, and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose were assessed. Then, serum levels of malondialdehyde (MDA), nitrate, and glutathione (GLT), as well as the activities of catalase (CAT) and superoxide dismutase (SOD) enzymes were measured. The expression level of NOX-4, IL-18, and p53 proteins at both mRNA and protein levels were evaluated. Diabetes significantly increased albuminuria, free radicals production, inflammation, and apoptosis in non-treated rats while lowered antioxidant capacity. Moreover, diabetes caused histological damages leading to renal failure. Treatment with fenofibrate improved renal function by improving creatinine clearance (P = 0.01) and protein excretion (P = 0.001) and lowering plasma levels of blood urea nitrogen (P = 0.001), creatinine (P = 0.001), and uric acid (P = 0.01). Fenofibrate potentiated antioxidant defense systems by enhancing CAT (P = 0.01) and SOD (P = 0.01) enzymes activities and GLT content (P = 0.01), and reduced oxidative damage by lowering MDA generation (P = 0.02). Fenofibrate also attenuated the expression of NOX-4 (P = 0.05), IL-18 (P = 0.05), and p53 (P = 0.05) at both mRNA and protein levels. In conclusion, treatment with fenofibrate improved renal function by suppression of oxidative stress, attenuation of inflammation, and inhibition of apoptosis. PMID- 29761902 TI - The influence of implant-abutment connection to peri-implant bone loss: A systematic review and meta-analysis. AB - PURPOSE: Different implant-abutment connections are available and it has been claimed they could have an effect on marginal bone loss. The aim of this review is to establish if implant connection configuration influences peri-implant bone loss (PBL) after functional loading. METHODS: A specific question was formulated according to the Population, Intervention, Control, and Outcome (PICO): Does the type of implant-abutment connection (external, internal, or conical) have an influence on peri-implant bone loss? A PubMed/MEDLINE electronic search was conducted to identify English language publications published in international journals during the last decade (from 2006 to 2016). The search was conducted by using the Medical Subject Headings (MeSH) keywords "dental implants OR dental abutment AND external connection OR internal connection OR conical connection OR Morse Taper." Selected studies were randomized clinical trials and prospective studies; in vitro studies, case reports and retrospective studies were excluded. Titles and abstracts and, in the second phase, full texts, were evaluated autonomously and in duplicate by two reviewers. RESULTS: A total of 1649 articles were found, but only 14 studies met the pre-established inclusion criteria and were considered suitable for meta-analytic analysis. The network meta-analysis (NMA) suggested a significant difference between the external and the conical connections; this was less evident for the internal and conical ones. Platform switching (PS) seemed to positively affect bone levels, non-regarding the implant connection it was applied to. CONCLUSIONS: Within the limitations of this systematic review, it can be concluded that crestal bone levels are better maintained in the short-medium term when internal kinds of interface are adopted. In particular, conical connections seem to be more advantageous, showing lower peri-implant bone loss, but further studies are necessary to investigate the efficacy of implant-abutment connection on stability of crestal bone levels. PMID- 29761904 TI - Prevalence and comorbidities associated with hidradenitis suppurativa in Korea: a nationwide population-based study. AB - BACKGROUND: The prevalence of hidradenitis suppurativa (HS) in Asia is unknown. The associations between HS and other autoimmune disorders have rarely been reported. OBJECTIVE: We sought to determine the prevalence of and diseases associated with HS using the National Health Insurance (NHI) database. METHODS: We examined Korean NHI claim database data from 2007 to 2016. We enrolled all patients with HS and age- and sex-matched control subjects without HS. We estimated the period prevalence of HS and associated comorbidities in Korea. RESULTS: We identified 28 516 patients with HS (61.3% males and 38.7% females). The period prevalence rate was 0.06%, 55.8 patients (95% confidence interval 55.1 56.4) per 100 000 persons, and the female-to-male ratio was 1 : 1.6. HS patients were at significantly increased risk of rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, ulcerative colitis, type 2 diabetes, hypertension, hyperlipidaemia, acne conglobata, pilonidal cysts, psoriasis, pyoderma gangrenosum, alopecia areata and vitiligo. CONCLUSION: The overall prevalence of HS in Korea was lower than that in Western populations, and male patients predominated. PMID- 29761905 TI - Stress-related salivary proteins affect the production of volatile sulfur compounds by oral bacteria. AB - OBJECTIVE: To determine whether stress-related substances and sex hormones influence the growth and in vitro production of volatile sulfur compounds (VSCs) by Solobacterium moorei and Fusobacterium nucleatum. MATERIALS AND METHODS: Bacteria growth and VSCs production were evaluated in the presence of alpha amylase, beta-defensin-2, mucin, estradiol, and progesterone. Growth was evaluated by colony counting, and the production of the VSCs hydrogen sulfide (H2 S) and methyl mercaptan (CH3 SH) was measured using the Oral ChromaTM instrument. RESULTS: Mucin induced the production of H2 S by both bacteria, but had a slight inhibitory effect on CH3 SH production by F. nucleatum. It also increased the viability of F. nucleatum. Alpha-amylase increased H2 S production by S. moorei and CH3 SH production by F. nucleatum, but had no effect on H2 S production by F. nucleatum. No substance altered the viability of S. moorei. No effects of beta defensin-2, estradiol, or progesterone were observed. CONCLUSION: The salivary stress-related proteins mucin and alpha-amylase altered VSCs production by F. nucleatum and S. moorei, favoring H2 S production. These findings are a step toward understanding the relation between stress and increased amounts of H2 S. PMID- 29761903 TI - The combination of a sphingosine kinase 2 inhibitor (ABC294640) and a Bcl-2 inhibitor (ABT-199) displays synergistic anti-myeloma effects in myeloma cells without a t(11;14) translocation. AB - Multiple myeloma (MM) remains an incurable disease in need of the development of novel therapeutic agents and drug combinations. ABT-199 is a specific Bcl-2 inhibitor in clinical trials for MM; however, its activity as a single agent was limited to myeloma patients with the t(11;14) translocation who acquire resistance due to co-expression of Mcl-1 and Bcl-xL. These limitations preclude its use in a broader patient population. We have recently found that a sphingosine kinase 2-specific inhibitor (ABC294640) induces apoptosis in primary human CD138+ cells and MM cell lines. ABC294640 is currently in phase I/II clinical trials for myeloma (clinicaltrials.gov: #NCT01410981). Interestingly, ABC294640 down-regulates c-Myc and Mcl-1, but does not have any effects on Bcl-2. We first evaluated the combinatorial anti-myeloma effect of ABC294640 and ABT-199 in vitro in 7 MM cell lines, all of which harbor no t(11;14) translocation. Combination index calculation demonstrated a synergistic anti-myeloma effect of the combination of ABC294640 and ABT-199. This synergistic anti-myeloma effect was maintained even in the presence of bone marrow (BM) stromal cells. The combination of ABC294640 and ABT-199 led to enhanced cleavage of PARP and caspase 3/9 and increased Annexin-V expression, consistent with the induction of apoptosis by the combination treatment. In addition, the combination of ABC294640 and ABT-199 resulted in the down-regulation of the anti-apoptotic proteins Mcl-1, Bcl-2, and Bcl-xL and the cleavage of Bax and Bid. The combination induced both the mitochondrial mediated- and caspase-mediated apoptosis pathways. Finally, the combination of ABC294640 and ABT-199 resulted in augmented anti-myeloma effect in vivo in a mouse xenograft model. These findings demonstrate that the co administration of ABC294640 and ABT-199 exhibits synergistic anti-myeloma activity in vitro and in vivo, providing justification for a clinical study of this novel combination in patients with relapsed/refractory multiple myeloma. PMID- 29761906 TI - The pharmacokinetics of cytarabine administered subcutaneously, combined with prednisone, in dogs with meningoencephalomyelitis of unknown etiology. AB - The objective of this study was to describe the pharmacokinetics (PK) of cytarabine (CA) after subcutaneous (SC) administration to dogs with meningoencephalomyelitis of unknown etiology (MUE). Twelve dogs received a single SC dose of CA at 50 mg/m2 as part of treatment of MUE. A sparse sampling technique was used to collect four blood samples from each dog from 0 to 360 min after administration. All dogs were concurrently receiving prednisone (0.5-2 mg kg-1 day-1 ). Plasma CA concentrations were measured by HPLC, and pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling (NLME). Plasma drug concentrations ranged from 0.05 to 2.8 MUg/ml. The population estimate (CV%) for elimination half-life and Tmax of cytarabine in dogs was 1.09 (21.93) hr and 0.55 (51.03) hr, respectively. The volume of distribution per fraction absorbed was 976.31 (10.85%) ml/kg. Mean plasma concentration of CA for all dogs was above 1.0 MUg/ml at the 30-, 60-, 90-, and 120-min time points. In this study, the pharmacokinetics of CA in dogs with MUE after a single 50 mg/m2 SC injection in dogs was similar to what has been previously reported in healthy beagles; there was moderate variability in the population estimates in this clinical population of dogs. PMID- 29761907 TI - Enantiomeric and Diastereomeric Self-Assembled Multivalent Nanostructures: Understanding the Effects of Chirality on Binding to Polyanionic Heparin and DNA. AB - A family of four self-assembling lipopeptides containing Ala-Lys peptides attached to a C16 aliphatic chain were synthesised. These compounds form two enantiomeric pairs that bear a diastereomeric relationship to one another (C16 -l Ala-l-Lys/C16 -d-Ala-d-Lys) and (C16 -d-Ala-l-Lys/C16 -l-Ala-d-Lys). These diastereomeric pairs have very different critical micelle concentrations (CMCs). The self-assembled multivalent (SAMul) systems bind biological polyanions as a result of the cationic lysine groups on their surfaces. For heparin binding, there was no significant enantioselectivity, but there was a binding preference for the diastereomeric assemblies with lower CMCs. Conversely, for DNA binding, there was significant enantioselectivity for systems displaying d-lysine ligands, with a further slight preference for attachment to l-alanine, with the CMC being irrelevant. PMID- 29761908 TI - Rituximab maintenance therapy of follicular lymphoma in clinical practice. AB - Standard of care for patients with symptomatic, advanced-stage follicular lymphoma (FL) is rituximab-containing chemoimmunotherapy followed by rituximab maintenance. This prospective, multicenter, noninterventional study analyzed how efficacy and safety data from randomized controlled trials translate into clinical practice in Germany. Both treatment-naive and relapsed/refractory patients with FL, who responded to rituximab-containing induction and were scheduled for rituximab maintenance, were observed for 24 months. Effectiveness was measured by response and Kaplan-Meier survival analysis. In addition, treatment patterns of induction and maintenance, as well as adverse events, were documented. The evaluable study population consisted of 310 first-line patients and 173 relapsed/refractory patients, including 116 patients with initial Ann Arbor stage I/II and 20 patients with FL grade 3B. Regarding first-line induction, a shift from R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) to R-bendamustine was observed over time, as well as a decline in radiotherapy. 2-year progression-free survival rates were 88.3% (95% confidence interval [CI] 84.0-92.6) for first-line patients and 76.0% (95% CI: 68.8-83.3) for relapsed/refractory patients. Conversion from partial to complete remission (PR, CR) occurred in 53.4% of analyzed first-line patients with PR, resulting in 69.4% CRs at study end (relapsed/refractory: conversion in 42.9%, final CRs 57.9%). Safety results were consistent with the known safety profile of rituximab in this setting. Both treatment-naive and relapsed/refractory patients with FL show favorable 2-year PFS rates and improvements in the remission status with postinduction rituximab monotherapy as maintenance and consolidation therapy. PMID- 29761909 TI - Perceptions of sex offenders with intellectual disability: A comparison of forensic staff and the general public. AB - BACKGROUND: Existing literature suggests that individuals with intellectual disability are not always held accountable for their actions and forensic staff are unlikely to report their sexually harmful behaviour. METHOD: This research explores how categorization of an offender as having intellectual disability and the framing of an offence as planned or opportunistic, impacts upon ratings of risk, blame and intent by forensic staff and the general public. The impact of pre-existing attitudes towards sex offenders upon these ratings was also considered. RESULTS: Differences are identified between participants' ratings when the offender is categorized as having an intellectual disability. More positive attitudes are associated with lower ratings of several factors. CONCLUSIONS: Individuals with overly positive attitudes towards sex offenders could underestimate the risk posed by sex offenders with intellectual disability. These results are important to consider alongside the NHS Transforming Care Agenda. PMID- 29761911 TI - The evaluation of salivary oxidative stress in patients with familial Mediterranean fever and chronic periodontitis. AB - BACKGROUND: Familial Mediterranean fever (FMF) is an inherent autoinflammatory disease and have a high prevalence in Mediterranean countries. The aim of this study was to evaluate salivary levels of oxidative stress parameters in patients with FMF and chronic periodontitis. METHODS: The study population consists of 81 patients with FMF and 85 systemically healthy controls. The test and control groups were classified as chronic periodontitis and periodontally healthy [FMF periodontitis (n = 37); FMF-periodontally healthy (n = 44); systemically healthy periodontitis (n = 37); systemically and periodontally healthy (n = 48]. Total salivary samples were collected. Clinical periodontal parameters including plaque index, gingival index (GI), probing depth (PD), the percentage of bleeding on probing (BOP%), and clinical attachment level (CAL), were measured. Salivary total antioxidant status (TAS), total oxidant status (TOS), 8 hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), and oxidative stress index (OSI) were evaluated. RESULTS: The FMF-periodontitis group had significantly higher levels of 8-OHdG, MDA, and OSI than that of the FMF-periodontally healthy group. In the FMF-periodontitis group, PD, 8-OHdG, MDA, and OSI levels were significantly higher than in the systemically healthy-periodontitis group (P = 0.035, P = 0.000, P = 0.000, and P = 0.000, respectively). 8-OHdG values were significantly correlated with BOP% and GI, and TOS values were significantly correlated with PD and CAL in the FMF-periodontitis group. CONCLUSIONS: In the presence of FMF and chronic periodontitis, there were increased salivary levels of oxidative stress. Thus, oxidative stress could be an important inflammatory mechanism in the FMF and chronic periodontitis. Further studies need to clarify the oxidative mechanisms of FMF and chronic periodontitis. PMID- 29761910 TI - IRX5 promotes NF-kappaB signalling to increase proliferation, migration and invasion via OPN in tongue squamous cell carcinoma. AB - Iroquois homeobox gene 5 (Irx5) is a highly conserved member of the Iroquois homeobox gene family. Members of this family play distinct and overlapping roles in normal embryonic cell patterning and development of malignancies. In this study, we observed that IRX5 was abnormally abundant in tongue squamous cell carcinoma (TSCC) tissues and cell lines. We used gain- and loss-of-function methods to overexpress and knockdown IRX5 expression in the TSCC cell line CAL27. Our results elucidated that elevated levels of IRX5 promoted proliferation, migration and invasion of TSCC cells, whereas stable or transient knockdown of IRX5 expression suppressed TSCC cell proliferation, migration and invasion. As a transcription factor, IRX5 performed this function by targeting osteopontin (OPN) promoter and activating the NF-kappaB pathway. Finally, studies in xenograft tumour model showed that IRX5 significantly enhanced OPN expression and promoted tumour growth. Taken together, our study elucidates a promotive effect of IRX5 in TSCC through the connection with OPN. These findings reveal the new molecular mechanism of TSCC, which may potentiate its use as a novel molecular therapy target for TSCC. PMID- 29761912 TI - Proteinase pattern of honeybee prepupae from healthy and American Foulbrood infected bees investigated by zymography. AB - American foulbrood disease (AFB) is the main devastating disease that affects honeybees' brood, caused by Paenibacillus larvae. The trend of the research on AFB has addressed the mechanisms by which P. larvae bacteria kill honeybee larvae. Since prepupae could react to the infection of AFB by increasing protease synthesis, the aim of this work was to compare protease activity in worker prepupae belonging to healthy colonies and to colonies affected by AFB. This investigation was performed by zymography. In gel, proteolytic activity was observed in prepupae extracts belonging only to the healthy colonies. In the prepupae extracts, 2D zimography followed by protein identification by MS allowed to detect Trypsin-1 and Chymotrypsin-1, which were not observed in diseased specimens. Further investigations are needed to clarify the involvement of these proteinases in the immune response of honeybee larvae and the mechanisms by which P. larvae inhibits protease production in its host. PMID- 29761913 TI - Functional variants in the LC3B gene promoter in acute myocardial infarction. AB - Acute myocardial infarction (AMI) is a common disease mainly caused by atherosclerosis, for which genetic causes remain largely unknown. Recently, low frequency and rare genetic variants have been proposed as risk factors. Autophagy has been involved in many cellular processes, such as lipid metabolism and inflammation, and implicated in human diseases, including cardiovascular diseases. In previous studies, we have reported reduced levels of LC3B, a core protein and a marker for autophagy, in AMI patients. In this study, the LC3B gene promoter was genetically and functionally analyzed in large cohorts of AMI patients (n = 383) and healthy controls (n = 390). A total of 25 DNA sequence variants (DSVs) including SNPs were found. Seven DSVs and three SNPs were only identified in AMI patients. All the DSVs and SNPs (except one) significantly decreased the transcriptional activity of the LC3B gene promoter in both HEK-293 and H9c2 cells (P < 0.05). Further electrophoretic mobility shift assay suggested that the DSVs affected the binding of transcription factors. In contrast, the DSVs and SNPs found only in controls or in both AMI patients and controls did not significantly affected LC3B gene promoter activity (P > 0.05). Therefore, our data suggested that the DSVs identified in AMI patients may change LC3B level by affecting the transcriptional activity of LC3B gene promoter, contributing to the AMI development. Upregulation of the LC3B gene expression may provide a novel and potential therapy for AMI patients. PMID- 29761914 TI - Molecular features in young vs elderly breast cancer patients and the impacts on survival disparities by age at diagnosis. AB - Young and elderly breast cancer patients are more likely to have a poorer outcome than middle-aged patients. The intrinsic molecular features for this disparity are unclear. We obtained data from the Cancer Genome Atlas (TCGA) on May 15, 2017 to test the potential mediation effects of the molecular features on the association between age and prognosis with a four-step approach. The relative contributions of the molecular features (PAM50 subtype, risk stratification, DNAm age, and mutations in TP53, PIK3CA, MLL3, CDH1, GATA3, and MAP3K1) to age disparities in survival were estimated by Cox proportional hazard models with or without the features. Young patients were significantly more likely to have basal like subtype, GATA3 mutations, and younger DNA methylation (DNAm) age than middle aged patients (P < .05). Both the young and elderly patients had a significantly increased risk of breast cancer recurrence after adjusted by race, tumor size, and node status (Hazard ratio [HR] (95% confidence interval [CI]): 2.81 [1.44, 5.45], 2.37 [1.45, 3.89], respectively). This increased risk was weakened in the young patients after further adjustments in the molecular features, particularly basal-like subtype, GATA3 mutations, and DNAm age (HR [95%CI]: 1.87 [0.81, 4.32]), resulting in 33.5% decreased risk of recurrence. Meanwhile, the adjustments of the molecular features did not alter the recurrence risk for the elderly patients. Compared with middle-aged patients of breast cancer, poorer prognosis of elderly patients may be caused by aging, while poorer prognosis of young patients was probably mediated through intrinsic characteristics, such as basal-like subtype, GATA3 mutations, and DNAm age of the cancerous tissues. PMID- 29761916 TI - "... but if you're afraid of things, how are you meant to belong?" What belonging means to people with intellectual disabilities? AB - BACKGROUND: A policy commitment to social inclusion has brought about some positive changes in the lives of people with intellectual disabilities; yet many also continue to experience social isolation, poverty and abuse. The authors introduce a framework for belonging from the literature and then present a study exploring the views of people with intellectual disabilities about belonging. These are discussed in relation to the framework identified from the literature. METHOD: Three focus groups with 24 participants with intellectual disabilities were conducted in New South Wales and Victoria (Australia). The authors used inductive content analysis to identify four meanings of belonging: (i) belonging in relation to place, (ii) as being part of a community, (iii) as having relationships and (iv) as identity. Also discussed are commonly experienced barriers to belonging identified by participants. CONCLUSIONS: Implications for policy, service provision and practice are discussed. PMID- 29761915 TI - Reduction of Parenteral Nutrition and Hydration Support and Safety With Long-Term Teduglutide Treatment in Patients With Short Bowel Syndrome-Associated Intestinal Failure: STEPS-3 Study. AB - BACKGROUND: Patients with intestinal failure associated with short bowel syndrome (SBS-IF) require parenteral support (PS) to maintain fluid balance or nutrition. Teduglutide (TED) reduced PS requirements in patients with SBS-IF in the randomized, placebo (PBO)-controlled STEPS study (NCT00798967) and its 2-year, open-label extension, STEPS-2 (NCT00930644). METHODS: STEPS-3 (NCT01560403), a 1 year, open-label extension study in patients with SBS-IF who completed STEPS-2, further monitored the safety and efficacy of TED (0.05 mg/kg/day). Baseline was the start of TED treatment, in either STEPS or STEPS-2. At the end of STEPS-3, patients treated with TED in both STEPS and STEPS-2 (TED-TED) received TED for <=42 months, and patients treated with TED only in STEPS-2 (no TED treatment [NT]/PBO-TED) received TED for <=36 months. RESULTS: Fourteen patients enrolled (TED-TED, n = 5; NT/PBO-TED, n = 9) and 13 completed STEPS-3. At the last dosing visit, mean (SD) PS was reduced from baseline by 9.8 (14.4 [50%]) and 3.9 (2.8 [48%]) L/week in TED-TED and NT/PBO-TED, respectively. Mean (SD) PS infusions decreased by 3.0 (4.6) and 2.1 (2.2) days per week from baseline in TED-TED and NT/PBO-TED, respectively. Two patients achieved PS independence; 2 additional patients who achieved independence in STEPS-2 maintained enteral autonomy throughout STEPS-3. All patients reported >=1 treatment-emergent adverse event (TEAE); 3 patients had TEAEs that were reported as treatment related. No patient had a treatment-related treatment-emergent serious AE. CONCLUSIONS: Long-term TED treatment yielded a safety profile consistent with previous studies, sustained efficacy, and a further decline in PS requirements. PMID- 29761919 TI - Serologic evidence for Schmallenberg virus circulation at high altitude, Central Portugal, 2015-2016. AB - A few years after the initial 2011 large scale Schmallenberg virus (SBV) epidemic that affected Europe, a subsequent decrease in new SBV infections was observed presumably associated with natural substitution of previously exposed animals. In the present work, a 2-year prospective serosurvey was performed to evaluate SBV circulation in a population of sheep living at high altitude in the central region of Portugal and with restricted movement. Blood from a representative sample of 168 autochthonous sheep was collected in 2015 and again in 2016, and tested for the presence of anti-SBV IgG by ELISA. Of the 2015 sample collection, seven animals tested positive for anti-SBV IgG, corresponding to a seroprevalence of 4.2% while of the 2016 sample collection, 10 presented SBV antibodies, showing a seroprevalence of 6.0% (p = 0.619). Results show that SBV is endemic in sheep of central Portugal, even in herds at high altitude locations. When comparing anti-SBV seroprevalences of 2015/2016 found in this study, to one detected in 2014 in the same region, a steep decrease could be observed (p < 0.001). This is in accordance with what has been documented in Western European countries, where a decrease in the number of SBV-infected sheep has been found, a fact which may pose a new threat for SBV re-emergence. PMID- 29761917 TI - Cationic Europium Complexes for Visualizing Fluctuations in Mitochondrial ATP Levels in Living Cells. AB - The ability to study cellular metabolism and enzymatic processes involving adenosine triphosphate (ATP) is impeded by the lack of imaging probes capable of signalling the concentration and distribution of intracellular ATP rapidly, with high sensitivity. We report here the first example of a luminescent lanthanide complex capable of visualizing changes in the concentration of ATP in the mitochondria of living cells. Four cationic europium(III) complexes [Eu.1-4]+ have been synthesized and their binding capabilities towards nucleoside polyphosphate anions examined in aqueous solution at physiological pH. Complexes [Eu.1]+ and [Eu.3]+ bearing hydrogen bond donor groups in the pendant arms showed excellent discrimination between ATP, ADP and monophosphate species. Complex [Eu.3]+ showed relatively strong binding to ATP (logKa =5.8), providing a rapid, long-lived luminescent signal that enabled its detection in a highly competitive aqueous medium containing biologically relevant concentrations of Mg2+ , ADP, GTP, UTP and human serum albumin. This EuIII complex responds linearly to ATP within the physiological concentration range (1-5 mm), and was used to continuously monitor the apyrase-catalyzed hydrolysis of ATP to ADP in vitro. We demonstrate that [Eu.3]+ can permeate mammalian (NIH-3T3) cells efficiently and localize to the mitochondria selectively, permitting real-time visualization of elevated mitochondrial ATP levels following treatment with a broad spectrum kinase inhibitor, staurosporine, as well as depleted ATP levels upon treatment with potassium cyanide under glucose starvation conditions. PMID- 29761918 TI - LncRNA HOXA11-AS promotes hepatocellular carcinoma progression by repressing miR 214-3p. AB - Accumulating studies supported that lncRNAs played important roles in tumorigenesis. LncRNA HOXA11-AS was a novel lncRNA that has been proved to involved in several tumours. However, the role of HOXA11-AS in the development of hepatocellular carcinoma (HCC) remains to be explained. In our study, we showed that HOXA11-AS expression was up-regulated in the HCC tissues, and the higher expression of HOXA11-AS was associated with the advanced stage in the HCC samples. In addition, we indicated that the expression of HOXA11-AS was up regulated in HCC cell lines (Hep3B, SMMC-7721, MHCC97-H and BEL-7402) compared with normal liver cell lines (HL-7702). Overexpression of HOXA11-AS promoted HCC proliferation and invasion and induced the epithelial-mesenchymal transition (EMT) and knockdown of HOXA11-AS suppressed the HCC cell proliferation and invasion. However, we showed that miR-214-3p expression was down-regulated in the HCC tissues and cell lines. Ectopic expression of miR-214-3p suppressed HCC cell proliferation and invasion. Furthermore, we indicated that overexpression of HOXA11-AS decreased the miR-214-3p expression and the expression of miR-214-3p was negatively related with the HOXA11-AS expression in HCC samples. Ectopic expression of HOXA11-AS increased HCC proliferation and invasion and induced EMT through inhibiting miR-214-3p expression. These data suggested that HOXA11-AS/miR 214-3p axis was responsible for development of HCC. PMID- 29761920 TI - Prospective plasma efavirenz concentration assessment in Chinese HIV-infected adults enrolled in a large multicentre study. AB - OBJECTIVES: Few studies have explored the optimal dosing for efavirenz in individuals from China. We investigated plasma efavirenz concentrations and their association with efficacy and tolerance of efavirenz 600 mg daily in Chinese HIV infected adults. METHODS: An analysis was performed using plasma samples from 455 patients enrolled in a prospective multicentre trial in China. A total of 1198 plasma samples collected at weeks 4, 24 and 48 following antiretroviral therapy initiation were analysed. The mid-dose interval efavirenz concentrations (C12 ) were determined using high-performance liquid chromatography. RESULTS: The median efavirenz concentration (interquartile range) steadily increased over time from 3.02 (2.28-4.23) to 3.71 (2.91-4.91) mg/L from week 4 to 48 (P < 0.001). The proportion of patients with C12 > 4.0 mg/L also rose from 28.0% to 34.2% and 43.8%, measured at 4, 24 and 48 weeks, respectively (P < 0.001). Five patients had efavirenz concentrations < 1.0 mg/L at week 4, 24 or 48. In the multivariable regression analysis, lower body weight and non-Han ethnicities were associated with higher efavirenz concentrations over time. At each time-point, patients with a body weight < 60 kg had significantly higher efavirenz C12 compared with those with body weight >= 60 kg (P < 0.05). CONCLUSIONS: Efavirenz concentrations increased steadily over 48 weeks, and a substantial proportion of participants had efavirenz C12 above the upper limit of the proposed therapeutic window, especially those with low body weight (< 60 kg). Based upon these findings, a dosage reduction of efavirenz to 400 mg daily may warrant consideration in this population, especially for those with lower body weight. PMID- 29761921 TI - Trans-cinnamic aldehyde inhibits Aggregatibacter actinomycetemcomitans-induced inflammation in THP-1-derived macrophages via autophagy activation. AB - BACKGROUND: Inflammation is an essential response against bacterial infection as a host defense mechanism, which can lead to tissue damage. Aggregatibacter actinomycetemcomitans (Aa) is major pathogen for aggressive periodontitis characterized by rapid destruction of periodontal tissue surrounding teeth. Trans cinnamic aldehyde is a key bioactive compound of the cinnamon extracts, which has anti-inflammatory, antioxidant, antipyretic, antimicrobial, and anti-cancer properties. The objective of the present study was to investigate the anti inflammatory effect of trans-cinnamic aldehyde against Aa infection in human THP 1 derived macrophages and on Aa-induced periodontitis in mice. METHODS: THP-1 cells were differentiated with phorbol 12-mystristate 13-acetate and were infected with live Aa. Trans-cinnamic aldehyde was pretreated 30 minutes before the bacterial infection. Cytokine production was determined by enzyme-linked immunosorbent assay (ELISA) and protein expressions were detected by Western blot analysis. Autophagosome formation was detected by Cyto-ID. Viable cell count was carried out to determine bacterial adhesion, internalization, and intracellular survival. Experimental periodontitis was induced by inoculating Aa orally to mice, and microcomputed tomography was used to evaluate bone loss. RESULTS: Pretreatment of trans-cinnamic aldehyde significantly inhibited Aa-stimulated release of tumor necrosis factor-alpha and interleukin (IL)-1beta. Pretreatment of trans-cinnamic aldehyde inhibited Aa-induced expression of TLR signaling pathway as well as the phosphorylation of JNK, p38, and nuclear factor (NF) kappaB. Also, trans-cinnamic aldehyde treatment downregulated the expression of pro-IL-1beta, caspase-1, and inflammasome components. Trans-cinnamic aldehyde treatment significantly decreased intracellular survival of Aa. Moreover, the autophagosome formation and the expressions of autophagy markers including Beclin 1, ATG5, and LC3 were increased. Finally, trans-cinnamic aldehyde significantly inhibited bone loss in Aa-induced mouse periodontitis. CONCLUSIONS: Trans cinnamic aldehyde inhibited Aa-stimulated expression of inflammatory responses and inhibited intracellular bacterial survival via autophagy activation. These results suggest that trans-cinnamic aldehyde may serve as an anti-inflammatory agent for aggressive periodontitis. PMID- 29761922 TI - FM19G11 inhibits O6 -methylguanine DNA-methyltransferase expression under both hypoxic and normoxic conditions. AB - FM19G11 is a small molecular agent that inhibits hypoxia-inducible factor-1-alpha (HIF-1alpha) and other signaling pathways. In this study, we characterized the modulating effects of FM19G11 on O6 -methylguanine DNA-methyltransferase (MGMT), the main regulator of temozolomide (TMZ) resistance in glioblastomas. This study included 2 MGMT-positive cell lines (GBM-XD and T98G). MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after FM19G11 treatment, and the roles of various signaling pathways were characterized. Under hypoxic conditions, MGMT mRNA and protein levels were significantly downregulated by FM19G11 via the HIF-1alpha pathway in both GBM-XD and T98G cells. In normoxic culture, T98G cells were strongly positive for MGMT, and MGMT expression was substantially downregulated by FM19G11 via the NF-kappaB pathway. In addition, TMZ resistance was reversed by treatment with FM19G11. Meanwhile, FM19G11 has no cytotoxicity at its effective dose. FM19G11 could potentially be used to counteract TMZ resistance in MGMT-positive glioblastomas. PMID- 29761923 TI - Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER study. AB - Look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses. Data from the UK Transfusion Medicine Epidemiology Review have been analysed to determine the accuracy of the blood donation history provided by the relatives of cases. Our results show that only a small percentage of cases were found to be registered as donors on UK Blood Service (UKBS) databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. PMID- 29761924 TI - Decreased hepatic response to glucagon, adrenergic agonists, and cAMP in glycogenolysis, gluconeogenesis, and glycolysis in tumor-bearing rats. AB - The response to glucagon and adrenaline in cancer cachexia is poorly known. The aim of this study was to investigate the response to glucagon, adrenergic agonists (alpha and beta) and cyclic adenosine monophosphate (cAMP) on glycogenolysis, gluconeogenesis, and glycolysis in liver perfusion of Walker-256 tumor-bearing rats with advanced cachexia. Liver ATP content was also investigated. Rats without tumor (healthy) were used as controls. Agonists alpha (phenylephrine) and beta (isoproterenol) adrenergic, instead of adrenaline, and cAMP, the second messenger of glucagon and isoproterenol, were used in an attempt to identify mechanisms involved in the responses. Glucagon (1 nM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in the liver of healthy and tumor-bearing rats, but their effects were lower in tumor-bearing rats. Isoproterenol (20 uM) stimulated glycogenolysis, gluconeogenesis, and glycolysis in healthy rats and had virtually no effect in tumor-bearing rats. cAMP (9 uM) also stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis in healthy rats but had practically no effect in tumor-bearing rats. Phenylephrine (2 uM) stimulated glycogenolysis and gluconeogenesis and inhibited glycolysis and these effects were also lower in tumor-bearing rats than in healthy. Liver ATP content was lower in tumor-bearing rats. In conclusion, tumor bearing rats with advanced cachexia showed a decreased hepatic response to glucagon, adrenergic agonists (alpha and beta), and cAMP in glycogenolysis, gluconeogenesis, and glycolysis, which may be due to a reduced rate of regulatory enzyme phosphorylation caused by the low ATP levels in the liver. PMID- 29761925 TI - Spectroscopic Studies on the Metal-Insulator Transition Mechanism in Correlated Materials. AB - The metal-insulator transition (MIT) in correlated materials is a novel phenomenon that accompanies a large change in resistivity, often many orders of magnitude. It is important in its own right but its switching behavior in resistivity can be useful for device applications. From the material physics point of view, the starting point of the research on the MIT should be to understand the microscopic mechanism. Here, an overview of recent efforts to unravel the microscopic mechanisms for various types of MITs in correlated materials is provided. Research has focused on transition metal oxides (TMOs), but transition metal chalcogenides have also been studied. Along the way, a new class of MIT materials is discovered, the so-called relativistic Mott insulators in 5d TMOs. Distortions in the MO6 (M = transition metal) octahedron are found to have a large and peculiar effect on the band structure in an orbital dependent way, possibly paving a way to the orbital selective Mott transition. In the final section, the character of the materials suitable for applications is summarized, followed by a brief discussion of some of the efforts to control MITs in correlated materials, including a dynamical approach using light. PMID- 29761926 TI - Incidence and pattern of implant fractures: A long-term follow-up multicenter study. AB - BACKGROUND: Currently, there is incomplete understanding of the fracture patterns in the implant and their association with clinical factors. PURPOSE: The aim of this study was to investigate the incidence and pattern of implant fracture (IF) by using 9-year, long-term multicenter follow-up data. MATERIALS AND METHODS: The association of the incidence and differences in fracture patterns with clinical factors (based on patient variables and implant variables) was assessed for statistical significance using the Chi-square and Fisher exact test, as appropriate. RESULTS: Among a total of 19 087 implants in 8501 patients (7838 male and 663 female) placed over 9 years, fractures were observed in 70 implants (0.4%) in 57 patients (50 male and 7 female). Cases with less than 50% bone loss had a higher incidence of horizontal and vertical IFs limited to the crest module, which are defined as Type I fractures (n = 13, 18.6%). In contrast, cases with >=50% severe bone loss exhibited a higher incidence of Type II vertical fractures (n = 22, 31.4%), extending beyond the crestal portion (P = .001). Type III fractures (n = 5, 7.1%), defined as a horizontal fracture beyond the crestal module, were also observed. CONCLUSION: Peri-implantitis-induced marginal and vertical bone loss and manufacturing-induced defects were considered to be major factors in IF. Therefore, using clinically verified implant systems and striving to minimize bone loss by preventing and actively treating peri-implantitis is essential to reduce IFs. PMID- 29761928 TI - Systematic Review of Hypersensitivity to Parenteral Nutrition. AB - Hypersensitivity to the components of parenteral nutrition (PN) is a rare but important complication of PN. We performed a systematic review of hypersensitivity to PN to enable us to build an approach to the individual patient who presents with PN hypersensitivity. A systematic literature search was performed in Ovid Medline, CINAHL, Scopus, and Web of Science using terms for "hypersensitivity" AND "parenteral nutrition" and relevant synonyms. A total of 28 articles were analyzed, and 33 hypersensitivities to PN or components of PN were reported in these 28 articles. Reports of hypersensitivity and subsequent conclusions were based on the clinical observations made by each reporting author. These reactions were evenly split between pediatric and adult patients. Hypersensitivity to PN occurred on day of starting PN in 60.6% patients and after that time in 36.3% patients (range: 1-21 days). Of the hypersensitivities that occurred on day 1 of PN, 70% occurred in the first 30 minutes of initiation of PN. Cutaneous manifestations were the most common, followed by anaphylaxis, respiratory symptoms, and hemodynamic instability. The components most frequently identified as allergens were intravenous fat emulsion (48.4%), multivitamin solution (33.3%), and amino acid solution (9%). Based on this review, an algorithm was created to guide the practitioner on management of PN after the occurrence of such a reaction. PMID- 29761927 TI - On the potential role of intestinal microbial community in hepatocarcinogenesis in chronic hepatitis B. AB - The chronic infection of hepatitis B virus (HBV) is the most potent risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The association of intestinal microbiota alteration with progressive liver disease has been investigated in recent studies. Overgrowth of potentially pathogenic bacteria of gram-negative species and, in particular, a significant increase in the fecal count of Escherichia coli (E. coli) are characterized in the presence of HCC. This study was conducted to describe the characteristics of the intestinal microbiota related to the presence of HCC in HBV-carrier patients. The available literature indicates the colonization of E. coli as principal source of portal vein lipopolysaccharide (LPS), in the gut may contribute to the carcinogenesis process by inducing chronic inflammation. This understanding could help to predict the clinical outcomes in HBV-carrier patients and innovative strategies to reduce the virulence of liver disease from intestinal dysbiosis. PMID- 29761929 TI - Assessment of polycyclic aromatic hydrocarbon exposure, lung function, systemic inflammation, and genotoxicity in peripheral blood mononuclear cells from firefighters before and after a work shift. AB - Firefighting is regarded as possibly carcinogenic, although there are few mechanistic studies on genotoxicity in humans. We investigated exposure to polycyclic aromatic hydrocarbons (PAH), lung function, systemic inflammation and genotoxicity in peripheral blood mononuclear cells (PBMC) of 22 professional firefighters before and after a 24-h work shift. Exposure was assessed by measurements of particulate matter (PM), PAH levels on skin, urinary 1 hydroxypyrene (1-OHP) and self-reported participation in fire extinguishing activities. PM measurements indicated that use of personal protective equipment (PPE) effectively prevented inhalation exposure, but exposure to PM occurred when the environment was perceived as safe and the self-contained breathing apparatuses were removed. The level of PAH on skin and urinary 1-OHP concentration were similar before and after the work shift, irrespective of self reported participation in fire extinction activities. Post-shift, the subjects had reduced levels of oxidatively damaged DNA in PBMC, and increased plasma concentration of vascular cell adhesion molecule 1 (VCAM-1). The subjects reporting participation in fire extinction activities during the work shift had a slightly decreased lung function, increased plasma concentration of VCAM-1, and reduced levels of oxidatively damaged DNA in PBMC. Our results suggest that the firefighters were not exposed to PM while using PPE, but exposure occurred when PPE was not used. The work shift was not associated with increased levels of genotoxicity. Increased levels of VCAM-1 in plasma were observed. Environ. Mol. Mutagen. 59:539-548, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29761930 TI - Multiple phosphorylation sites on gamma-tubulin are essential and contribute to the biogenesis of basal bodies in Tetrahymena. AB - The mechanisms that regulate gamma-tubulin, including its post-translational modifications, are poorly understood. gamma-Tubulin is important for the duplication of centrioles and structurally similar basal bodies (BBs), organelles which contain a ring of nine triplet microtubules. The ciliate Tetrahymena thermophila carries hundreds of cilia in a single cell and provides an excellent model to specifically address the role of gamma-tubulin in the BBs assembly and maintenance. The genome of Tetrahymena contains a single gamma-tubulin gene. We show here that there are multiple isoforms of gamma-tubulin that are likely generated by post-translational modifications. We identified evolutionarily conserved serine and threonine residues as potential phosphosites of gamma tubulin, including S80, S129, S131, T283, and S360. Several mutations that either prevent (S80A, S131A, T283A, S360A) or mimic (T283D) phosphorylation were conditionally lethal and at a higher temperature phenocopied a loss of gamma tubulin. Cells that overproduced S360D gamma-tubulin displayed phenotypes consistent with defects in the microtubule-dependent functions, including an asymmetric division of the macronucleus and abnormalities in the pattern of BB rows, including gaps, fragmentation, and misalignment. In contrast, overexpression of S129D gamma-tubulin affected the orientation, docking, and structure of the BBs, including a loss of either the B- or C-subfibers or the entire triplets. We conclude that conserved potentially phosphorylated amino acids of gamma-tubulin are important for either the assembly or stability of BBs. PMID- 29761931 TI - The intranuclear PEX domain of MMP involves proliferation, migration, and metastasis of aggressive adenocarcinoma cells. AB - Members of matrix metalloproteinase (MMP) family promote cancer cell migration, invasion, and metastasis through alteration of the tumor milieu, intracellular signaling pathways, and transcription. We examined gene expression signatures of colon adenocarcinoma cell lines with different metastatic potentials and found that rapidly metastatic cells powerfully expressed genes encoding MMP3 and MMP9. The non-proteolytic PEX isoform and proteolytic isoforms of MMPs were significantly expressed in the metastatic cells in vitro. Knockdown of MMP3 attenuated cancer cell migration and invasion in vitro and lung metastasis in vivo. Profound nuclear localization of MMP3/PEX was found in tumor-stroma marginal area. In contrast, MMP9 was localized in central area of subcutaneous tumors. Overexpression of the PEX isoform of MMP3 promoted proliferation and migration of the rapidly metastatic cells in vitro. Taken together, the non proteolytic PEX isoform of MMPs locating in cell nuclei involves proliferation, migration, and subsequent metastasis of aggressive adenocarcinoma cells. PMID- 29761932 TI - Attentional selection and suppression in children and adults. AB - The fundamental role of covert spatial attention is to enhance the processing of attended items while simultaneously ignoring irrelevant items. However, relatively little is known about how brain electrophysiological activities associated with target selection and distractor suppression are involved as they develop and become fully functional. The current study aimed to identify the neurophysiological bases of the development of covert spatial attention, focusing on electroencephalographic (EEG) markers of attentional selection (N2pc) and suppression (PD ). EEG data were collected from healthy young adults and typically developing children (9-15 years old) as they searched for a shape singleton target in either the absence or the presence of a salient-but irrelevant color singleton distractor. The ERP results showed that a lateral shape target elicited a smaller N2pc in children compared with adults regardless of whether a distractor was present or not. Moreover, the target-elicited N2pc was always followed by a similar positivity in both age groups. Counterintuitively, a lateral salient-but-irrelevant distractor elicited a large PD in children with low behavioral accuracy, whereas high-accuracy children exhibited a small and "adult-like" PD . More importantly, we found no evidence for a correlation between the target-elicited N2pc and the distractor-elicited PD in either age group. Our results provide neurophysiological evidence for the developmental differences between target selection and distractor suppression. Compared with adults, 9-15-year-old children deploy insufficient attentional selection resources to targets but use "adult-like" or even more attentional suppression resources to resist irrelevant distractors. A video abstract of this article can be viewed at: https://www.youtube.com/watch?v=NhWapx0d75I. PMID- 29761933 TI - Th1/Th17/Th22 immune response and their association with joint pain, imagenological bone loss, RANKL expression and osteoclast activity in temporomandibular joint osteoarthritis: A preliminary report. AB - It is well accepted that the presence of cytokines belonging to the Th1/Th17/Th22 axis of immuno-inflammatory response in the joint environment, such as IL-1beta, IL-17 and IL-22, respectively, are associated with pathogenesis of several synovial joint degenerative disorders. During temporomandibular joint osteoarthritis (TMJ-OA), IL-1beta and IL-17 have been implicated in the inflammation and resorption of sub-chondral bone; however, the role of Th22 response in the TMJ-OA pathophysiology has not been established. This study aimed to compare the expression of Th1/Th17/Th22-type cytokines, chemokines and chemokine receptors in synovial fluid samples obtained from TMJ-OA or disk displacement with reduction (DDWR) patients. In addition, it aimed to associate these levels with joint pain, imagenological signs of bone degeneration, RANKL production, osteoclastogenesis and osteoclast-induced bone resorption. Higher levels of IL-1beta, IL-17 and IL-22 were expressed in TMJ-OA compared with DDWR subjects, and these increased levels significantly correlated with RANKL expression, joint pain and articular bone degeneration. Higher levels of CCR5, CCR6 and CCR7, as well as their respective ligands CCL5 and CCL20, responsible for recruitment of IL-1beta, IL-17 and IL-22-producing cells, were over-expressed in TMJ-OA compared with DDWR subjects. Osteoclastogenesis and osteoclast-induced bone resorption were significantly greater in presence of synovial fluid from TMJ OA compared with DDWR subjects. These data demonstrate that cytokines, CCLs and CCRs associated with the Th1/Th17/Th22 axis of immuno-inflammatory response are involved in TMJ-OA pathogenesis. These findings suggest that IL-22 is involved in the RANKL expression in TMJ-OA, which in turn induces differentiation of osteoclasts and subsequent resorption of sub-chondral bone. PMID- 29761934 TI - Assessing the heterogeneity of autism spectrum symptoms in a school population. AB - : The aim of the present study was to assess whether the nature of the main autistic features (i.e., social communication problems and repetitive and restrictive patterns) are better conceptualized as dimensional or categorical in a school population. The study was based on the teacher ratings of two different age groups: 2,585 children between the ages of 10 and 12 (Primary Education; PE) and 2,502 children between the ages of 3 and 5 (Nursery Education; NE) from 60 mainstream schools. The analyses were based on Factor Mixture Analysis, a novel approach that combines dimensional and categorical features and prevents spurious latent classes from appearing. The results provided evidence of the dimensionality of autism spectrum symptoms in a school age population. The distribution of the symptoms was strongly and positively skewed but continuous; and the prevalence of high-risk symptoms for autism spectrum disorders (ASD) and social-pragmatic communication disorder (SCD) was 7.55% of NE children and 8.74% in PE. A categorical separation between SCD and ASD was not supported by our sample. In view of the results, it is necessary to establish clear cut points for detecting and diagnosing autism and to develop specific and reliable tools capable of assessing symptom severity and functional consequences in children with ASD. Autism Res 2018, 11: 979-988. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: The results of the present study suggest that the distribution of autism spectrum symptoms are continuous and dimensional among school-aged children and thus support the need to establish clear cut-off points for detecting and diagnosing autism. In our sample, the prevalence of high-risk symptoms for autism spectrum disorders and social pragmatic communication disorder was around 8%. PMID- 29761935 TI - The application of transcriptional benchmark dose modeling for deriving thresholds of effects associated with solar-simulated ultraviolet radiation exposure. AB - Considerable data has been generated to elucidate the transcriptional response of cells to ultraviolet radiation (UVR) exposure providing a mechanistic understanding of UVR-induced cellular responses. However, using these data to support standards development has been challenging. In this study, we apply benchmark dose (BMD) modeling of transcriptional data to derive thresholds of gene responsiveness following exposure to solar-simulated UVR. Human epidermal keratinocytes were exposed to three doses (10, 20, 150 kJ/m2 ) of solar simulated UVR and assessed for gene expression changes 6 and 24 hr postexposure. The dose response curves for genes with p-fit values (>= 0.1) were used to derive BMD values for genes and pathways. Gene BMDs were bi-modally distributed, with a peak at ~16 kJ/m2 and ~108 kJ/m2 UVR exposure. Genes/pathways within Mode 1 were involved in cell signaling and DNA damage response, while genes/pathways in the higher Mode 2 were associated with immune response and cancer development. The median value of each Mode coincides with the current human exposure limits for UVR and for the minimal erythemal dose, respectively. Such concordance implies that the use of transcriptional BMD data may represent a promising new approach for deriving thresholds of actinic effects. Environ. Mol. Mutagen. 59:502-515, 2018. (c) 2018 The Authors Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society. PMID- 29761936 TI - Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer. AB - Long non-coding RNAs (lncRNAs) are important regulators of many cellular processes, and their aberrant expression and/or function is associated with many different diseases, including cancer. However, the identification of functional lncRNAs in gastric cancer is still a challenge. In this study, we describe a novel functional lncRNA, linc00483, that is upregulated and associated with tumorigenesis, tumour size, metastasis and poor prognosis in gastric cancer. In our study, linc00483 promoted gastric cancer cell proliferation, invasiveness and metastasis in vitro and in vivo. Mechanistically, upregulated expression of linc00483 in gastric cancer acts as a sponge to absorb endogenous tumour suppressor miR-30a-3p. Furthermore, it restores SPAG9 expression, which is negatively regulated by miR-30a-3p, and actives MAPK signaling pathway in gastric cancer cells. Thus, linc00483 is an oncogenic lncRNA in gastric cancer and targeting linc00483 or its pathway can potentially be useful in development of targeted therapies for patients with gastric cancer. Our results show that linc00483 is an important regulator in carcinogenesis and may be a useful biomarker to predict prognosis of gastric cancer patients. We believe our findings are novel and will be of interest to scientists working in many areas related to biomarkers in cancer. PMID- 29761937 TI - "Mirror, Mirror on the Wall"... Pediatric liver transplantation in the case of situs inversus totalis with a disrupted inferior vena cava. AB - We present the unique case of a 15-month-old male born with biliary atresia and situs inversus totalis and disrupted inferior vena cava who underwent a successful liver transplantation. The patient had previously undergone a failed Kasai procedure and presented with persistent hyperbilirubinemia. The patient was transplanted with a left lateral segment donor having standard arterial anatomy. Technical considerations included identifying completely replaced arterial anatomy in the recipient from the superior mesenteric artery and creating a branch patch between the gastroduodenal artery and HA, anastomosing the donor left hepatic vein to confluences of the donor left, middle, and right hepatic veins, using a "lazy-S" configuration of portal vein anastomosis, and suspending the allograft to the abdominal wall. Post-operatively, his liver function tests and total bilirubin normalized and he progressed to tolerating an oral diet with tube-feed supplementation. PMID- 29761938 TI - Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD-L1. AB - Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death-ligand 1 (PD-L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD-L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD-L1 expression in the acquired cisplatin-resistant HNSCC cells was examined by PCR and WB in order to test PD-L1-induced chemoresistance. LfcinB inoculation in cisplatin-resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5-year survival rate, and a lower 5-year survival rate in the chemotherapy and radiotherapy-treated patients (P < .05). PD-L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD-L1 and IL-6 in the established cisplatin-resistant HNSCC cells were shown significantly higher (P < .05). IL-6 and PD-L1 expression were partially inhibited by the anti-IL-6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin-resistant HNSCC cells and HNSCC xenografts of cisplatin-resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL-6 and PD-L1 in cisplatin-resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD-L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL-6 and PD-L1. PMID- 29761940 TI - A Sign of the times? PMID- 29761939 TI - Keeping health in mind. PMID- 29761941 TI - Stamping out BULLYING. PMID- 29761942 TI - Making the case for prevention. PMID- 29761943 TI - HOT TO PROMOTE YOUR SERVICE. PMID- 29761944 TI - Please can we have some more? PMID- 29761945 TI - Kicking the habit. PMID- 29761946 TI - Out of the Shadows. PMID- 29761948 TI - Breaking down barriers. PMID- 29761947 TI - Beating bugs TOGETHER. PMID- 29761949 TI - [Research on coded excitation processing method for magneto-acoustic signal]. AB - Detecting and imaging method of biological electrical characteristics based on magneto-acoustic coupling effect gives valuable information of tissue in early tumor diagnosis and bioelectrical current monitoring. Normal exciting and receiving method is to use single pulse. In this method the signal to noise ratio (SNR) is limited, so the imaging quality and imaging speed are low. In this study, we propose a processing method based on coded excitation to improve SNR and shorten the processing time. The processing method using 13 bit Barker coded excitation and 16 bit Golay code excitation are studied by simulation and experiments. The results show that SNR of magneto-acoustic signal is improved by 20.96 dB and 20.62 dB by using 13 bit Barker coded and 16 bit Golay coded excitation, respectively. It also indicates the processing time is short compare to single pulse mode. In the case of the SNR increasing, the overall acquiring and processing time under 13 bit Barker coded excitation and the 16 bit Golay coded excitation is shortened to 3.62% and 4.73%, respectively, compared to the single pulse excitation with waveform averaging method. In conclusion, the coded excitation will be significant for the improvement of magneto-acoustic signal SNR and imaging quality. PMID- 29761950 TI - [Optimization of the pseudorandom input signals used for the forced oscillation technique]. AB - The forced oscillation technique (FOT) is an active pulmonary function measurement technique that was applied to identify the mechanical properties of the respiratory system using external excitation signals. FOT commonly includes single frequency sine, pseudorandom and periodic impulse excitation signals. Aiming at preventing the time-domain amplitude overshoot that might exist in the acquisition of combined multi sinusoidal pseudorandom signals, this paper studied the phase optimization of pseudorandom signals. We tried two methods including the random phase combination and time-frequency domain swapping algorithm to solve this problem, and used the crest factor to estimate the effect of optimization. Furthermore, in order to make the pseudorandom signals met the requirement of the respiratory system identification in 4-40 Hz, we compensated the input signals' amplitudes at the low frequency band (4-18 Hz) according to the frequency-response curve of the oscillation unit. Resuts showed that time frequency domain swapping algorithm could effectively optimize the phase combination of pseudorandom signals. Moreover, when the amplitudes at low frequencies were compensated, the expected stimulus signals which met the performance requirements were obtained eventually. PMID- 29761951 TI - [Research on cortical cross-modal reorganization of children with congenital severe deafness after cochlear implant]. AB - Cochlear implant (CI) is the only method for efficacious treatment of congenital severe deafness at present. However, for children with congenital severe deafness after CI, the mechanism of the structural and functional changes of their cerebral cortex is not clear. This study was based on the cross-modal reorganization of deaf patients. Event related potential (ERP) and source localization technique were used to visualize the change of cortical activity in children with congenital severe deafness during 1-year period (0, 1, 3, 6, 9 and 12 months after CI). We aimed to investigate the association between hearing restoration and cross-modal reorganization in children with congenital severe deafness after CI. The results showed that the cross-modal reorganization exists in children with congenital severe deafness. During hearing restoration, the function of the cross-modal reorganization reversed to the normal state. The method and conclusions of this study may be of significance in guiding the training and evaluation of hearing rehabilitation after CI in patients. PMID- 29761952 TI - [Automatic classification of first-episode, drug-naive schizophrenia with multi modal magnetic resonance imaging]. AB - A great number of studies have demonstrated the structural and functional abnormalities in chronic schizophrenia (SZ) patients. However, few studies analyzed the differences between first-episode, drug-naive SZ (FESZ) patients and normal controls (NCs). In this study, we recruited 44 FESZ patients and 56 NCs, and acquired their multi-modal magnetic resonance imaging (MRI) data, including structural and resting-state functional MRI data. We calculated gray matter volume (GMV), regional homogeneity (ReHo), amplitude of low frequency fluctuation (ALFF), and degree centrality (DC) of 90 brain regions, basing on an automated anatomical labeling (AAL) atlas. We then applied these features into support vector machine (SVM) combined with recursive feature elimination (RFE) to discriminate FESZ patients from NCs. Our results showed that the classifier using the combination of ReHo and ALFF as input features achieved the best performance (an accuracy of 96.97%). Moreover, the most discriminative features for classification were predominantly located in the frontal lobe. Our findings may provide potential information for understanding the neuropathological mechanism of SZ and facilitate the development of biomarkers for computer-aided diagnosis of SZ patients. PMID- 29761953 TI - [Epileptic electroencephalogram recognition based on discrete S transform and permutation entropy]. AB - Electroencephalogram(EEG) analysis has important reference value in the diagnosis of epilepsy. The automatic classification of epileptic EEG can be used to judge the patient's situation in time,which is of great significance in clinical application. In order to solve the problem that the recognition accuracy is not high by using the single feature of EEG signals and avoid the influence of wavelet basis function selection on recognition results,a method of automatic discrimination of epileptic EEG signals based on S transform and permutation entropy is proposed. Firstly, the original signals are decomposed by discrete S transform, and then we calculate the fluctuation index of coefficients of each rhythm and combine the permutation entropy of EEG signals into a feature vector and use Real AdaBoost classifier to discriminate the epileptic EEG signals in muti-period. In this study, we used the epilepsy database from University of Bonn. Three groups of EEG signals, including the data of normal people with their eyes open, the data collected inside of the epileptic foci from patients during their interictal period and the data during their ictal period, were used to test effectiveness. The results of this study showed that the fluctuation index of each rhythm could be used to characterize the normal, interictal and ictal epileptic EEG signals effectively, and the recognition accuracy of multiple features was much higher than that of single feature. The average recognition accuracy could reach 98.13%. Compared with time-frequency feature extraction method or nonlinear feature extraction method only,the recognition accuracy was increased by more than 1.2% and 8.1% respectively, which was superior to the methods recorded in many other literatures. Therefore, this method has a good application prospect in diagnosis of epilepsy. PMID- 29761954 TI - [Research on brain white matter network in cerebral palsy infant]. AB - Present study used diffusion tensor image and tractography to construct brain white matter networks of 15 cerebral palsy infants and 30 healthy infants that matched for age and gender. After white matter network analysis, we found that both cerebral palsy and healthy infants had a small-world topology in white matter network, but cerebral palsy infants exhibited abnormal topological organization: increased shortest path length but decreased normalize clustering coefficient, global efficiency and local efficiency. Furthermore, we also found that white matter network hub regions were located in the left cuneus, precuneus, and left posterior cingulate gyrus. However, some abnormal nodes existed in the frontal, temporal, occipital and parietal lobes of cerebral palsy infants. These results indicated that the white matter networks for cerebral palsy infants were disrupted, which was consistent with previous studies about the abnormal brain white matter areas. This work could help us further study the pathogenesis of cerebral palsy infants. PMID- 29761955 TI - [Effect of artery pulse on the osteonal interstitial fluid flow behavior]. AB - There are two main types of fluid in bone tissue: blood and interstitial fluid. The metabolism of cells mainly relies on the microenvironment of the interstitial fluid. Researches of osteonal fluid seepage behavior based on the microstructure of bone tissue have become a hot point. The aim of the present research work is to assess the effect of blood pressure oscillation on the osteonal interstitial fluid seepage behavior. We established finite element osteon models for a hollow and that considering blood pressure oscillation, respectively, with COMSOL Multiphysics software in order to compare their fluid flow behavior under the axial loading. The results predicted that the interstitial fluid pressure field was enlarged considering the blood pressure oscillation, while the velocity filed changed little. Specifically, the increase of blood pressure oscillatory amplitude could result in the increase of osteonal interstitial fluid pressure, while the blood pressure oscillatory frequency had limited effects on the osteonal pore fluid pressure. Moreover, the blood pressure oscillatory amplitude and frequency had no effect on the osteonal interstitial fluid velocity. The finite element model can be used for the study of the poroelastic behaviors of the osteon under non-axisymmetric loads and microcracks, and can also be a new way to study the mechanism of bone mechanotransduction and electromechanotransduction. PMID- 29761956 TI - [Research on adaptive quasi-linear viscoelastic model for nonlinear viscoelastic properties of in vivo soft tissues]. AB - The mechanical behavior modeling of human soft biological tissues is a key issue for a large number of medical applications, such as surgery simulation, surgery planning, diagnosis, etc. To develop a biomechanical model of human soft tissues under large deformation for surgery simulation, the adaptive quasi-linear viscoelastic (AQLV) model was proposed and applied in human forearm soft tissues by indentation tests. An incremental ramp-and-hold test was carried out to calibrate the model parameters. To verify the predictive ability of the AQLV model, the incremental ramp-and-hold test, a single large amplitude ramp-and-hold test and a sinusoidal cyclic test at large strain amplitude were adopted in this study. Results showed that the AQLV model could predict the test results under the three kinds of load conditions. It is concluded that the AQLV model is feasible to describe the nonlinear viscoelastic properties of in vivo soft tissues under large deformation. It is promising that this model can be selected as one of the soft tissues models in the software design for surgery simulation or diagnosis. PMID- 29761957 TI - [The research of near-infrared blood glucose measurement using particle swarm optimization and artificial neural network]. AB - Existing near-infrared non-invasive blood glucose detection modelings mostly detect multi-spectral signals with different wavelength, which is not conducive to the popularization of non-invasive glucose meter at home and does not consider the physiological glucose dynamics of individuals. In order to solve these problems, this study presented a non-invasive blood glucose detection model combining particle swarm optimization (PSO) and artificial neural network (ANN) by using the 1 550 nm near-infrared absorbance as the independent variable and the concentration of blood glucose as the dependent variable, named as PSO-2ANN. The PSO-2ANN model was based on two sub-modules of neural networks with certain structures and arguments, and was built up after optimizing the weight coefficients of the two networks by particle swarm optimization. The results of 10 volunteers were predicted by PSO-2ANN. It was indicated that the relative error of 9 volunteers was less than 20%; 98.28% of the predictions of blood glucose by PSO-2ANN were distributed in the regions A and B of Clarke error grid, which confirmed that PSO-2ANN could offer higher prediction accuracy and better robustness by comparison with ANN. Additionally, even the physiological glucose dynamics of individuals may be different due to the influence of environment, temper, mental state and so on, PSO-2ANN can correct this difference only by adjusting one argument. The PSO-2ANN model provided us a new prospect to overcome individual differences in blood glucose prediction. PMID- 29761958 TI - [Magnitude image-guided phase unwrapping algorithm of susceptibility weighted images]. AB - To better use the phase information to compensate the influence of blood flow, the phase unwrapping problem in susceptibility weighted imaging (SWI) is studied in this paper. In order to improve the accuracy of unwrapping, this paper proposes a magnitude image-guided phase unwrapping algorithm of SWI. The basic idea is as follows: (1) reduce the influence of noise by improving the rotational invariant non-local principal component analysis method (PRI-NL-PCA); (2) extract the corresponding solid region in the phase image to avoid the influence of the background noise on the phase unwrapping method; (3) use the phase compensation method to constrain the phase image reconstructed by the K-space. Finally, the reliability of the unwrapping method is evaluated by using four kinds of statistics as quantification index: the number, mean (M), variance (Var), and positive percentage (Pos) and negative percentage (Neg) of phasic error points. By comparing the simulated data with 226 sets of true head SWI data, the results show that the proposed algorithm has high accuracy compared with the classical branch cut method and the least squares method. PMID- 29761959 TI - [Metal artifact reduction for dental implants in kilovoltage computed tomography using megavoltage cone-beam computer tomography]. AB - This paper proposes a novel metal artifact reduction (MAR) algorithm for dental implants in kilovoltage computed tomography (kVCT) using megavoltage cone-beam computer tomography (MVCBCT). Firstly, two CT images were derived by scanning patient with dental implants using kVCT and MVCBCT. Metal image was derived by thresholding segmentation in kVCT. MVCBCT and kVCT images were fused to generate prior image which was forward projected to get surrogate sinogram of metal trace. The corrected image was generated by filtered backprojection (FBP) reconstruction in corrected sinogram. The results of proposed algorithm were compared with other frequently-used metal artifact reduction algorithm, such as normalized MAR (NMAR), normalized MAR using MVCBCT prior images (NMAR-MV), and linear interpolation MAR (LIMAR). The normalized root mean square deviation (NRMSD) and mean absolute deviation (MAD) were computed. The experiment showed that the proposed method removed serious metal artifacts without introducing new artifacts. The values of NRMSD and MAD for proposed method were the minimum in all methods. The values of NRMSD for NMAR, NMAR-MV, LIMAR and the proposed method were 21.0%, 22.1%, 41.9% and 17.0% respectively. And MAD values of them were 232, 235, 553, 205 HU, respectively. In conclusion, the proposed metal artifact reduction algorithm can successfully suppress metal artifacts for dental implants, and greatly improve the quality of CT image. PMID- 29761960 TI - [Research on algorithms of uterine contraction curve analysis and its real-time status identification]. AB - Identification of real-time uterine contraction status is very significant to labor analgesia, but the traditional uterine contraction analysis algorithms and systems cannot meet the requirement. According to the situations mentioned above, this paper designs a set of algorithms for the real-time analysis of uterine contraction status. The algorithms include uterine contraction signal preprocessing, uterine contraction baseline extraction based on histogram and linear iteration and an algorithm for the real-time analysis of uterine contraction status based on finite state machines theory. It uses the last uterine status and a series of state transfer conditions to identify the current uterine contraction status, as well as a buffer mechanism to avoid false status transitions. To evaluate the performance of the algorithm, we compare it with an existing uterine contraction analysis algorithm used in the electronic fetal monitor. The experiments show that our algorithm can analyze the uterine contraction status while monitoring the uterine contraction signal in a real time. Its sensitivity reaches 0.939 9 and its positive predictive value is 0.869 3, suggesting that the algorithm has high accuracy and meets the need of clinical monitoring. PMID- 29761961 TI - [Study on method of laparoscopic training based on eye gaze tracking techniques]. AB - In current domestic research on laparoscopic training, researchers usually consider instrument movement path in the hand-eye coordination relationship. However, they ignore the information contained in visual cues by which could guide and control instrument movements. Studies in other areas have shown that trainers can improve their perceptual-motor skills by gaze training. This paper was designed to examine the effectiveness of eye gaze tracking technology in laparoscopic training and to analyze gaze strategy of the subjects in different training methods. The Tobii X1 Light Eye Tracker was used to track the gaze position of subjects when they were performing the two-handed transferring task in box trainer, and to obtain parameters related to gaze strategy including the efficiency of task completion, as well as visual search, visual processing and observation transfer analysis based on Markov chain model. The results showed that the completion time during the last training in gaze training group was decreased by 101.5 s comparing to the first training. Compared with video training group, gaze strategy of gaze training group has a significant change, such as fixation and saccade duration rate was increased by 38%, fixation duration on target area was increased, and saccade amplitude increased by 0.58 degrees , and the probability of the fixation point transferring to equipment decreased by 15%. The results demonstrated that eye gaze tracking technology can be used in laparoscopic training, and can improve the subjects' skills and shorten the learning curve by learning gaze strategies of experts. PMID- 29761962 TI - [Study on regurgitation using the coupling model of left ventricular assist device and cardiovascular system]. AB - Regurgitation is an abnormal condition happens when left ventricular assist devices (LVADs) operated at a low speed, which causes LVAD to fail to assist natural blood-pumping by heart and thus affects patients' health. According to the degree of regurgitation, three LVAD's regurgitation states were identified in this paper: no regurgitation, slight regurgitation and severe regurgitation. Regurgitation index ( RI), which is presented based on the theory of dynamic closed cavity, is used to grade the regurgitation of LVAD. Numerical results showed that when patients are in exercising, resting and sleeping state, the critical speed between slight regurgitation and no regurgitation are 6 650 r/min, 7 000 r/min and 7 250 r/min, respectively, with corresponding RI of 0.401, 0.300 and 0.238, respectively. And the critical speed between slight regurgitation and severe regurgitation are 5 500 r/min, 6 000 r/min and 6 450 r/min, with corresponding RI of 0.488, 0.359 and 0.284 respectively. In addition, there is a negative relation correction between RI and rotational speed, so that grading the LVAD's regurgitation can be achieved by determining the corresponding critical speed. Therefore, the detective parameter RI based on the signal of flow is proved to be able to grade LVAD's regurgitation states effectively and contribute to the detection of LVAD's regurgitation, which provides theoretical basis and technology support for developing a LVADs controlling system with high reliability. PMID- 29761963 TI - [Research on spectrum feature of speech processing strategy for cochlear implant]. AB - Cochlear implant (CI) in present Chinese environment will lose pitch information and result in low speech recognition. In order to research Chinese feature-based speech processing strategy for cochlear implant contrapuntally and to improve the speech recognition for CI recipients, we improve the CI front-end signal acquisition platform and research the signal features. Our search includes the waveform, spectrogram, energy intensity, pitch and formant parameters for different speech processing strategies of cochlear implant. Features in two kinds of speech processing strategies are analyzed and extracted for the study of parameter characteristics. Therefore, the proposed aim of this paper is to extend the research on Chinese-based CI speech processing strategy. PMID- 29761964 TI - [Real-time investigation of dynamic morphology of live platelets and generation of platelet microparticles using hopping probe ion conductance microscopy]. AB - Platelets are rapidly activated by activators and produce a large number of platelet microparticles (PMPs) with high coagulation activity, resulting in coagulation dysfunction. However, the generation mechanism of PMPs is still not clear. Hopping probe ion conductance microscopy (HPICM) has special technical advantages in non-contact, real-time, high-resolution imaging of living cells under physiological conditions. Using HPICM, this study monitored the processes of platelet activation and generation of PMPs in real time in the presence of calcium ionophore A23187 and cytochalasin D (CD), respectively. The results proved that the intracellular calcium concentration and the cytoskeletal proteins played important roles in the platelet activation and the generation of PMPs. Compared with the low density spread shape platelets (LDSS), the high density bubble shape platelets (HDBS) were more sensitive to the calcium ionophore A23187 and cytochalasin D. This research has a guiding significance for the further study on the relationship between platelet activation and coagulation function using HPICM. PMID- 29761965 TI - [An optical coherent imaging system for measuring the strain of blood vessels]. AB - We aimed to establish an optical coherence tomography (OCT) system to measure the strain of blood vessels. A general OCT system was constructed firstly and its reliability was confirmed by comparing the OCT imaging of the porcine coronary and the corresponding histological slices. The strain of the porcine coronary was induced by static flow pressure and correlation algorithm was used to calculate the strain field of blood vessels within OCT images. The results suggest that bright-dark stratification of blood vessels displayed in OCT images is consistent with the intima and media layers of histological image. Furthermore, the strain of media layer is greater than that of the intima layer under the same static pressure. The optical coherence imaging system could not only measure the histological structure of the blood vessels, but also qualify the vessel strain under flow pressure. PMID- 29761966 TI - [Development of a microenvironment test chamber for airborne microbe research]. AB - One of the most important environmental cleanliness indicators is airborne microbe. However, the particularity of clean operating environment and controlled experimental environment often leads to the limitation of the airborne microbe research. This paper designed and implemented a microenvironment test chamber for airborne microbe research in normal test conditions. Numerical simulation by Fluent showed that airborne microbes were evenly dispersed in the upper part of test chamber, and had a bottom-up concentration growth distribution. According to the simulation results, the verification experiment was carried out by selecting 5 sampling points in different space positions in the test chamber. Experimental results showed that average particle concentrations of all sampling points reached 10 7 counts/m 3 after 5 minutes' distributing of Staphylococcus aureus, and all sampling points showed the accordant mapping of concentration distribution. The concentration of airborne microbe in the upper chamber was slightly higher than that in the middle chamber, and that was also slightly higher than that in the bottom chamber. It is consistent with the results of numerical simulation, and it proves that the system can be well used for airborne microbe research. PMID- 29761967 TI - [Optimization of the parameters of microcirculatory structural adaptation model based on improved quantum-behaved particle swarm optimization algorithm]. AB - The vessels in the microcirculation keep adjusting their structure to meet the functional requirements of the different tissues. A previously developed theoretical model can reproduce the process of vascular structural adaptation to help the study of the microcirculatory physiology. However, until now, such model lacks the appropriate methods for its parameter settings with subsequent limitation of further applications. This study proposed an improved quantum behaved particle swarm optimization (QPSO) algorithm for setting the parameter values in this model. The optimization was performed on a real mesenteric microvascular network of rat. The results showed that the improved QPSO was superior to the standard particle swarm optimization, the standard QPSO and the previously reported Downhill algorithm. We conclude that the improved QPSO leads to a better agreement between mathematical simulation and animal experiment, rendering the model more reliable in future physiological studies. PMID- 29761968 TI - [Computer-assisted quantitative analysis of contrast-enhanced ultrasonography in Takayasu arteritis carotid artery lesions]. AB - Takayasu arteritis (TA) is a chronic nonspecific inflammation that commonly occurs in the aorta and its main branches. Most patients with TA are lack of clinical manifestations, leading to misdiagnosis. When the TA is correctly diagnosed, the patients may already have stenosis or occlusion in the involved arteries, resulting in arterial ischemia and hypoxia symptoms, and in severe cases it will be life-threatening. Contrast-enhanced ultrasonography (CEUS) is an emerging method for assessing TA, but the assessment relies heavily on experiences of radiologists performing manual and qualitative analyses, so the diagnostic results are often not accurate. To overcome this limitation, this paper presents a computer-assisted quantitative analysis of TA carotid artery lesions based on CEUS. First, the TA lesion was outlined on the carotid wall, and one homogeneous rectangle and one polygon were selected as two reference regions in the carotid lumen. The temporal and spatial features of the lesion region and the reference regions were then calculated. Furthermore, the difference and ratio of the features between the lesion and the reference regions were computed as new features (to eliminate interference factors). Finally, the correlation was analyzed between the CEUS features and inflammation biomarkers consisting of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The data in this paper were collected from 34 TA patients in Zhongshan Hospital undergoing CEUS examination with a total of thirty-seven carotid lesions, where two patients were with two lesions before and after treatment and one patient was with left and right bilateral lesions. Among these patients, 13 were untreated primary patients with a total of 14 lesions, where one patient was with bilateral lesions. The results showed that for all patients, the neovascularization area ratio in the 1/3 inner region of a lesion (ARi 1/3) achieved a correlation coefficient ( r) of 0.56 ( P=0.001) with CRP, and for the primary patients, the neovascularization area ratio in the 1/2 inner region of a lesion (ARi 1/2) had an r-value of 0.76 ( P=0.001) with CRP. This study indicates that the proposed computer-assisted method can objectively and semi-automatically extract quantitative features from CEUS images, so as to reduce the effect on diagnosis due to subjective experiences of the radiologists, and thus it is expected to be used for clinical diagnosis and severity evaluation of TA carotid lesions. PMID- 29761969 TI - [A numerical simulation of dendritic cells migration and induction of T cell specific proliferation during the initiation of skin inflammatory]. AB - Dendritic cells (DCs) are the most potent and specialized antigen-presenting cells (APCs) currently known, which play a crucial role in initiating and amplifying both the innate and adaptive immune responses. During the process of immune function, migration ability of DCs and the number of effector T cells which activated by DCs are closely related to the efficiency of immune function. However, because of the complexity of immune system, in the immune response process caused by the skin chronic inflammatory, much is still unknown about the dynamic changes of cell count with time. Therefore, we created a differential equations model to reflect the initial stages of the immune response process caused by the skin chronic inflammatory via setting the function and initial conditions of parameters. The results showed that the model was able to simulate migration and proliferation of cells in vivo within realistic time scales in accordance with the proliferation and migration efficiency in real terms. In addition, the preliminary model can biologically predict the realistic dynamics of DCs and T cells at different time points. All these results may provide a theoretical reference for studying the immune function of DCs as well as guiding the clinical treatment for immune related diseases further. PMID- 29761970 TI - [Caveolin-1 in relation with mitochondria and cancer metabolism-a promising target for cancer therapy]. AB - To aggressively proliferate and metastasize, cancer cells are in extreme need of energy supply and nutrients. Therefore, a promising cancer therapy strategy is developed to target its hallmark feature of metabolism. Recent findings revealed the regulatory role of caveolin-1 (Cav-1), a structural protein of caveolae, in cancer metabolism. And low Cav-1 expression in tumor stroma was proved to be a central player of cancer malignant phenotype. Here, we summarized the progressions of studies on Cav-1, mitochondria and cancer metabolism to indicate that the altered metabolism induced by Cav-1 and mitochondria association is a major cause of cancer malignant phenotype. PMID- 29761971 TI - [The application of silicon nanowires field-effect transistor biosensor in medicine]. AB - Ultra-sensitive and quantitative analysis of proteins, nucleic acid, virus and other biochemical species are critical technologies for effective dianosis of disease, as well as medical studies. Silicon nanowires field-effect transistor (SiNWs-FET) biosensor is one of the most promising powerful platforms for label free, real-time, ultra-sensitive detection of analyte. Here, the working principle of SiNWs-FET biosensor and the applications of SiNWs-FET biosensors in medicine were introduced. Moreover, the methods for enhancing the sensitivity of SiNWs-FET biosensor were discussed. Lastly, the prospecting of SiNWs-FET biosensor was presented. PMID- 29761972 TI - [Progress of quantitative measurement of bone using 99mTc-methylene diphosphonate in osteoporosis]. AB - As the incidence of osteoporosis (OP) is increasing year by year, high morbidity and mortality caused by osteoporotic fractures have become major problems of health in China and over the world. Quantitative measurement of bone using 99mTc methylene diphosphonate ( 99mTc-MDP) provides global or local information of skeletal metabolism or transformation. In this paper, we make a brief review on the quantitative measurement of bone using 99mTc-MDP and expect to provide guidance for clinical diagnosis and treatment. PMID- 29761973 TI - [Research on vigilance detection based on pulse wave]. AB - This paper studied the rule for the change of vigilance based on pulse wave. 10 participants were recruited in a 95-minute Mackworth clock test (MCT) experiment. During the experiment, the vigilance of all participants were evaluated by Karolinska sleepiness scale (KSS) and Stanford sleepiness scale (SSS), and behavior data (the reaction time and the accuracy of target) and pulse wave signal of the participants were recorded simultaneously. The result indicated that vigilance of the participants can be divided into 3 classes: the first 30 minutes for high vigilance level, the middle 30 minutes for general vigilance level, and the last 30 minutes for low vigilance level. Besides, time domain features such as amplitude of secondary peak, amplitude of peak and the latency of secondary peak decreased with the decrease of vigilance, while the amplitude of troughs increased. In terms of frequency domain features, the energy of 4 frequency band including 8.600 ~ 9.375 Hz, 11.720 ~ 12.500 Hz, 38.280 ~ 39.060 Hz and 39.060 ~ 39.840 Hz decreased with the decrease of vigilance. Finally, under the recognition model established by the 8 characteristics mentioned above, the average accuracy of three-classification results over the 10 participants was as high as 88.7%. The results of this study confirmed the feasibility of pulse wave in the evaluation of vigilance, and provided a new way for the real-time monitoring of vigilance. PMID- 29761974 TI - [The analysis of event-related potentials in normal brain aging based on N-back cognitive tasks]. AB - The purpose of this study is to investigate the change of the whole brain event related potentials(P300) in normal brain aging based on N-back cognitive tasks. The P300 of 15 normal young people and 10 normal old people were evaluated based on N-back cognitive tasks and analyzed. The results showed that the P300 latency of old people was longer in whole brain than young people, and amplitude was increased in the frontal-central region, while significantly increased in the pre frontal region in the same load cognitive tasks. With the cognitive task load increasing, the amplitude of old people in high-load task was higher in the whole brain than that in low-load task, mainly in in the frontal region, but the difference was not statistically significant. The latency in the high-load task was shorter in the frontal-central region of right brain than the low-load task, and the difference was statistically significant. Thus, P300 showed that the normal brain aging process is mainly reflected in the pre-frontal region, and the high-load cognitive task could better reflect the change of brain function compared with the low-load cognitive task. The finding is of revelatory meaning for diagnosis of early dementia in patients. PMID- 29761975 TI - [Research on electroencephalogram emotion recognition based on the feature fusion algorithm of auto regressive model and wavelet packet entropy]. AB - Focused on the world-wide issue of improving the accuracy of emotion recognition, this paper proposes an electroencephalogram (EEG) signal feature extraction algorithm based on wavelet packet energy entropy and auto-regressive (AR) model. The auto-regressive process can be approached to EEG signal as much as possible, and provide a wealth of spectral information with few parameters. The wavelet packet entropy reflects the spectral energy distribution of the signal in each frequency band. Combination of them gives a better reflect of the energy characteristics of EEG signals. Feature extraction and fusion are implemented based on kernel principal component analysis. Six emotional states from a public multimodal database for emotion analysis using physiological signals (DEAP) are recognized. The results show that the recognition accuracy of the proposed algorithm is more than 90%, and the highest recognition accuracy is 99.33%. It indicates that this algorithm can extract the feature of EEG emotion well, and it is a kind of effective emotion feature extraction algorithm, providing support to emotion recognition. PMID- 29761976 TI - [Degree centrality of the functional network in schizophrenia patients]. AB - The aim of the present study was to investigate the alternations of brain functional networks at resting state in the schizophrenia (SCH) patients using voxel-wise degree centrality (DC) method. The resting-state functional magnetic resonance imaging (rfMRI) data were collected from 41 SCH patients and 41 matched healthy control subjects and then analyzed by voxel-wise DC method. The DC maps between the patient group and the control group were compared using by two sample t test. The correlation analysis was also performed between DC values and clinical symptom and illness duration in SCH group. Results showed that compared with the control group, SCH patients exhibited significantly decreased DC value in primary sensorimotor network, and increased DC value in executive control network. In addition, DC value of the regions with obvious differences between the two groups significantly correlated to Positive and Negative Syndrome Scale (PANSS) scores and illness duration of SCH patients. The study showed the abnormal functional integration in primary sensorimotor network and executive control network in SCH patients. PMID- 29761977 TI - [Severity classification of chronic obstructive pulmonary disease based on deep learning]. AB - In this paper, a deep learning method has been raised to build an automatic classification algorithm of severity of chronic obstructive pulmonary disease. Large sample clinical data as input feature were analyzed for their weights in classification. Through feature selection, model training, parameter optimization and model testing, a classification prediction model based on deep belief network was built to predict severity classification criteria raised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). We get accuracy over 90% in prediction for two different standardized versions of severity criteria raised in 2007 and 2011 respectively. Moreover, we also got the contribution ranking of different input features through analyzing the model coefficient matrix and confirmed that there was a certain degree of agreement between the more contributive input features and the clinical diagnostic knowledge. The validity of the deep belief network model was proved by this result. This study provides an effective solution for the application of deep learning method in automatic diagnostic decision making. PMID- 29761978 TI - [Synchronous analysis of corticomuscular coherence based on Gabor wavelet transfer entropy]. AB - Synchronization analysis of electroencephalogram (EEG) and electromyogram (EMG) could reveal the functional corticomuscular coupling (FCMC) during the motor task in human. A novel method combining Gabor wavelet and transfer entropy (Gabor-TE) is proposed to quantitatively analyze the nonlinearly synchronous corticomuscular function coupling and direction characteristics under different steady-state force. Firstly, the Gabor wavelet transform method was used to acquire the local frequency-band signals of the EEG and EMG signals recorded from nine healthy controls simultaneously during performing grip task with four different steady state forces. Secondly, the TE of local frequency-band was calculated and the unit area index of the transfer ( ATE) was defined to quantitatively analyze the synchronous corticomuscular function coupling and direction characteristics under steady-state force. Lastly, the effect of EEG and EMG signal power spectrum on Gabor-TE analysis was explored. The results showed that the coupling strength in the beta band was stronger in EEG->EMG direction than in EMG->EEG direction, and the ATE values in the beta band in EEG->EMG direction decreased with the force increasing. It is also shown that the difference in TE values of gamma band present a varying regularity as the increase of force in both directions. In addition, EMG power spectrum was significantly correlated with the result of Gabor-TE inspecific frequency band. The results of our study confirmed that Gabor TE can quantitatively describe the nonlinearly synchronous corticomuscular function coupling in both local frequency band and information transmission. The analysis of FCMC provides basic information for exploring the motor control and the evaluation of clinical rehabilitation. PMID- 29761979 TI - [Remodeling simulation of human femur under bed rest and spaceflight circumstances based on three dimensional finite element analysis]. AB - Astronauts who are exposed to weightless environment in long-term spaceflight might encounter bone density and mass loss for the mechanical stimulus is smaller than normal value. This study built a three dimensional model of human femur to simulate the remodeling process of human femur during bed rest experiment based on finite element analysis (FEA). The remodeling parameters of this finite element model was validated after comparing experimental and numerical results. Then, the remodeling process of human femur in weightless environment was simulated, and the remodeling function of time was derived. The loading magnitude and loading cycle on human femur during weightless environment were increased to simulate the exercise against bone loss. Simulation results showed that increasing loading magnitude is more effective in diminishing bone loss than increasing loading cycles, which demonstrated that exercise of certain intensity could help resist bone loss during long-term spaceflight. At the end, this study simulated the bone recovery process after spaceflight. It was found that the bone absorption rate is larger than bone formation rate. We advise that astronauts should take exercise during spaceflight to resist bone loss. PMID- 29761980 TI - [The biomechanical study to evaluate tightening condition for AO lag screw depending on pull-out strength and interfragmentary compressive force]. AB - The aim of this experimental study focused on the relationship between pull-out strength (POS) and interfragmentary compressive force (IFCF) of AO cancellous lag screw during tightening procedure. The 6.5 mm AO cancellous lag screw and synthetic cancellous bone were used for this research. The test contains rotation tests and the subsequent pull-out tests, to record the IFCF and POS under different tightening angle groups. The results of this study demonstrated the specific relationship between IFCF and POS and showed that they didn't reach the peak at the very same time. This study revealed the change of mechanical environment surrounding AO lag screw during tightening procedure and found the effective method to determine the optimum terminating time of AO lag screw inserting. PMID- 29761981 TI - [Plaque segmentation of intracoronary optical coherence tomography images based on K-means and improved random walk algorithm]. AB - In recent years, optical coherence tomography (OCT) has developed into a popular coronary imaging technology at home and abroad. The segmentation of plaque regions in coronary OCT images has great significance for vulnerable plaque recognition and research. In this paper, a new algorithm based on K-means clustering and improved random walk is proposed and Semi-automated segmentation of calcified plaque, fibrotic plaque and lipid pool was achieved. And the weight function of random walk is improved. The distance between the edges of pixels in the image and the seed points is added to the definition of the weight function. It increases the weak edge weights and prevent over-segmentation. Based on the above methods, the OCT images of 9 coronary atherosclerotic patients were selected for plaque segmentation. By contrasting the doctor's manual segmentation results with this method, it was proved that this method had good robustness and accuracy. It is hoped that this method can be helpful for the clinical diagnosis of coronary heart disease. PMID- 29761982 TI - [Study on the geometric characteristics and distribution of porosities in three dimensional printed Ti-6Al-4V titanium alloy]. AB - Three dimensional (3D) printing is considered as an advanced manufacturing technology because of its additive nature. Electron beam melting (EBM) is a widely used 3D printing processes for the manufacturing of metal components. However, the products printed via this process generally contain micro porosities which affect mechanical properties, especially the fatigue property. In this paper, two types of EBM printed samples of the Ti-6Al-4V alloy, one with a round cross section and the other with a triangle cross section, were employed to investigate the existence of porosities using computed tomography (CT). Statistical analyses were conducted on the number, volume, shape, and distribution of pores. The results show that small pores (less than 0.000 2 mm 3) account for 80% of all pores in each type of samples. Additionally, to some extent, the shape of sample has influence on the number of micro porosities in EBM made Ti-6Al-4V. The sphericity of the pores is relatively low and is inversely proportional to pore volume. It is found that re-melting on the free surface effectively reduce pore density near the surface. This study may help produce a medical implant with better fatigue resistance. PMID- 29761983 TI - [Imaging analysis of jaw defects reparation with antigen-extracted porcine cancellous bone]. AB - At present, most of the bone xenograft for clinical application comes from bovine. In recent years, many studies have been done on the clinical application of porcine xenograft bone. The goal of this study was to evaluate the effect of canine mandibular defects reparation with antigen-extracted porcine cancellous bone by imaging examination. Four dogs' bilateral mandibular defects were created, with one side repaired with autologous bone (set as control group) while the other side repaired with antigen-extracted porcine cancellous bone (set as experimental group). Titanium plates and titanium screws were used for fixation. Cone beam computed tomography (CBCT), computed tomography (CT), single-photon emission computed tomography (SPECT) were undertaken at week 12 and 24 postoperatively, and SPECT and CT images were fused. The results demonstrated that the remodeling of antigen-extracted porcine cancellous bone was slower than that of autologous bone, but it can still be used as scaffold for jaw defects. The results in this study provide a new choice for materials required for clinical reparation of jaw defects. PMID- 29761984 TI - [A study of magnetic shielding design for a magnetic resonance imaging linac system]. AB - One of the main technical challenges when integrating magnetic resonance imaging (MRI) systems with medical linear accelerator is the strong interference of fringe magnetic fields from the MRI system with the electron beams of linear accelerator, making the linear accelerator not to work properly. In order to minimize the interference of magnetic fields, a magnetic shielding cylinder with an open structure made of high permeability materials is designed. ANSYS Maxwell was used to simulate Helmholtz coil which generate uniform magnetic field instead of the fringe magnetic fields which affect accelerator gun. The parameters of shielding tube, such as permeability, radius, length, side thickness, bottom thickness and fringe magnetic fields strength are simulated, and the data is processed by MATLAB to compare the shielding performance. This article gives out a list of magnetic shielding effectiveness with different side thickness and bottom thickness under the optimal radius and length, which showes that this design can meet the shielding requirement for the MRI-linear accelerator system. PMID- 29761985 TI - [Design and implementation of hand-held electrocardiogram monitor]. AB - A hand-held electrocardiogram (ECG) monitor with capacitive coupling is designed in this study that can rapidly detect ECG signals through clothing. This new device improves many deficiencies of the traditional ECG monitor, such as infection due to direct skin contacting, inconvenience, and time-consuming. In specificity, the hand-held ECG monitor consists of two parts, a sensor and an embedded terminal. ECG signals are initially detected by a sensing electrode placed on the chest through clothing, then treated by single ended differential amplification, filtering and master amplification, and later processed through A/D conversion and ECG signal transmission by CC2540 module. The waveform and heart rate are finally displayed on the screen based on digital filtering and data processing for the received ECG signal on the embedded terminal. Results confirm that the newly developed hand-held ECG monitor is capable of detecting real-time ECG signals through clothing with advantages of simple operation, portability and rapid detection. PMID- 29761986 TI - [A capillary blood flow velocity detection system based on linear array charge coupled devices]. AB - In order to detect the flow characteristics of blood samples in the capillary, this paper introduces a blood flow velocity measurement system based on field programmable gate array (FPGA), linear charge-coupled devices (CCD) and personal computer (PC) software structure. Based on the analysis of the TCD1703C and AD9826 device data sheets, Verilog HDL hardware description language was used to design and simulate the driver. Image signal acquisition and the extraction of the real-time edge information of the blood sample were carried out synchronously in the FPGA. Then a series of discrete displacement were performed in a differential operation to scan each of the blood samples displacement, so that the sample flow rate could be obtained. Finally, the feasibility of the blood flow velocity detection system was verified by simulation and debugging. After drawing the flow velocity curve and analyzing the velocity characteristics, the significance of measuring blood flow velocity is analyzed. The results show that the measurement of the system is less time-consuming and less complex than other flow rate monitoring schemes. PMID- 29761987 TI - [Comparison of planning quality and delivery efficiency between volumetric modulated arc therapy and dynamic intensity modulated radiation therapy for nasopharyngeal carcinoma with more than 4 prescribed dose levels]. AB - The aim of this study is to compare the planning quality and delivery efficiency between dynamic intensity modulated radiation therapy (d-IMRT) and dual arc volumetric modulated arc therapy (VMAT) systematically for nasopharyngeal carcinoma (NPC) patients with multi-prescribed dose levels, and to analyze the correlations between target volumes and plan qualities. A total of 20 patients of NPC with 4-5 prescribed dose levels to achieve simultaneous integrated boost (SIB) treated by sliding window d-IMRT in our department from 2014 to 2015 were re-planned with dual arc VMAT. All optimization objectives for each VMAT plan were as the same as the corresponding d-IMRT plan. The dose parameters for targets and organ at risk (OAR), the delivery time and monitor units (MU) in two sets of plans were compared respectively. The treatment accuracy was tested by three dimensional dose validation system. Finally, the correlations between the difference of planning quality and the volume of targets were discussed. The conform indexes (CIs) of planning target volumes (PTVs) in VMAT plans were obviously high than those in d-IMRT plans ( P < 0.05), but no significant correlations between the difference of CIs and the volume of targets were discovered ( P > 0.05). The target coverage and heterogeneity indexes (HIs) of PTV 1 and PGTV nd and PTV 3 in two sets of plans were consistent. The doses of PTV 2 decreased and HIs were worse in VMAT plans. VMAT could provide better spinal cord and brainstem sparing, but increase mean dose of parotids. The average number of MUs and delivery time for d-IMRT were 3.32 and 2.19 times of that for VMAT. The gamma-index (3 mm, 3%) analysis for each plans was more than 97% in COMPASS (r) measurement for quality assurance (QA). The results show that target dose coverages in d-IMRT and VMAT plans are similar for NPC with multi prescribed dose levels. VMAT could improve the the CIs of targets, but reduce the dose to the target volume in neck except for PGTV nd. The biggest advantages of VMAT over d-IMRT are delivery efficiency and QA. PMID- 29761988 TI - [Research on preparation and performance of ceramic denture materials applied for three dimensional printing]. AB - The micro-flow extrusion forming of ceramic material has not been developed in three dimensional (3D) printing field. The shape forming of material is by bonding and stacking of filaments of ceramic slurry extruded through micro-sized pores with rather large gaps and porosities, which can affect material's density after sintering and its mechanical property thereafter. Aiming at such a deficiency of this process, the preparation method of ceramic denture printing paste applicable to the process is studied, and the properties of slurry and sintering performance are analyzed and tested. It is concluded that the rheological properties of the prepared ceramic slurry conforms the requirement of micro-flow extrusion process, and the green body after sintering can satisfy the mechanical property requirement of oral denture. This is a technologic breakthrough, laying a foundation for the application of micro-flow extrusion forming in 3D printing of ceramic material, and promoting its development and maturation. PMID- 29761989 TI - [Super-resolution reconstruction for lung four dimensional computed tomography images using multi-model Gaussian process regression]. AB - Lung four dimensional computed tomography (4D-CT) can lead to accurate radiotherapy. However, for the safety of patients, the scan spacing of 4D-CT cannot be too small so that the inter-slice resolution of lung 4D-CT is low, and thus the coronal and sagittal images need to be interpolated to obtain high resolution images. This paper presents a super-resolution reconstruction technique based on multi-model Gaussian process regression. We use the high resolution transversal images and the corresponding low-resolution images as the training sets. The high-resolution pixels of the coronal and sagittal images can be predicted by constructing multiple Gaussian process regression models. The experimental results show that our method is superior to bicubic algorithm, projections onto convex sets, sparse coding, multi-phase similarity based method and Gaussian process regression method based on self-learning block in terms of the edge and detail recovery. The results demonstrate that the proposed method can effectively improve the quality of lung 4D-CT images, and potentially be applied to better image-guided radiation therapy of lung cancer. PMID- 29761990 TI - [A computer tomography assisted method for the automatic detection of region of interest in dynamic kidney images]. AB - Glomerular filtration rate (GFR), which can be estimated by Gates method with dynamic kidney single photon emission computed tomography (SPECT) imaging, is a key indicator of renal function. In this paper, an automatic computer tomography (CT)-assisted detection method of kidney region of interest (ROI) is proposed to achieve the objective and accurate GFR calculation. In this method, the CT coronal projection image and the enhanced SPECT synthetic image are firstly generated and registered together. Then, the kidney ROIs are delineated using a modified level set algorithm. Meanwhile, the background ROIs are also obtained based on the kidney ROIs. Finally, the value of GFR is calculated via Gates method. Comparing with the clinical data, the GFR values estimated by the proposed method were consistent with the clinical reports. This automatic method can improve the accuracy and stability of kidney ROI detection for GFR calculation, especially when the kidney function has been severely damaged. PMID- 29761991 TI - [Study of neuronal spike-frequency adaptation with transcranial magneto acoustical stimulation]. AB - Transcranial magneto-acoustical stimulation (TMAS), utilizing focused ultrasound and a magnetostatic field to generate an electric current in tissue fluid to regulate the activities of neurons, has high spatial resolution and penetration depth. The neuronal spike-frequency adaptation plays an important role in the treatment of neural information. In this paper, we study the effects of ultrasonic intensity, magnetostatic field intensity and ultrasonic frequency on the neuronal spike-frequency adaptation based on the Ermentrout neuron model. The simulation results show that, the peak time interval becomes smaller, the interspike interval becomes shorter and the time of the firing of the neuron is shortened with the increasing of the magnetostatic field intensity. With the increase of the adaptive variables, the initial spike-frequency is shifted to the right with the magnetostatic field intensity, and the spike-frequency is linearly related to the increase of the magnetostatic field intensity in steady state. The simulation effect with change of the ultrasonic intensity is consistent with the change of magnetostatic field intensity. The change of the ultrasonic frequency has no effect on the neuronal spike-frequency adaptation. Under the different adaptive variables, with the increase of the adaptive variables, the initial spike-frequency amplitude decreased with the increasing of the ultrasonic frequency, and the spike-frequency is linearly related to the increase of the ultrasonic frequency in steady state. These results of the study can help us to reveal the mechanism of transcranial magneto-acoustical stimulation on the neuronal spike-frequency adaptation, and provide a theoretical basis for its application in the treatment of neurological disorders. PMID- 29761992 TI - [Combining speech sample and feature bilateral selection algorithm for classification of Parkinson's disease]. AB - Diagnosis of Parkinson's disease (PD) based on speech data has been proved to be an effective way in recent years. However, current researches just care about the feature extraction and classifier design, and do not consider the instance selection. Former research by authors showed that the instance selection can lead to improvement on classification accuracy. However, no attention is paid on the relationship between speech sample and feature until now. Therefore, a new diagnosis algorithm of PD is proposed in this paper by simultaneously selecting speech sample and feature based on relevant feature weighting algorithm and multiple kernel method, so as to find their synergy effects, thereby improving classification accuracy. Experimental results showed that this proposed algorithm obtained apparent improvement on classification accuracy. It can obtain mean classification accuracy of 82.5%, which was 30.5% higher than the relevant algorithm. Besides, the proposed algorithm detected the synergy effects of speech sample and feature, which is valuable for speech marker extraction. PMID- 29761993 TI - [Design and implementation of real-time continuous glucose monitoring instrument]. AB - Real-time continuous glucose monitoring can help diabetics to control blood sugar levels within the normal range. However, in the process of practical monitoring, the output of real-time continuous glucose monitoring system is susceptible to glucose sensor and environment noise, which will influence the measurement accuracy of the system. Aiming at this problem, a dual-calibration algorithm for the moving-window double-layer filtering algorithm combined with real-time self compensation calibration algorithm is proposed in this paper, which can realize the signal drift compensation for current data. And a real-time continuous glucose monitoring instrument based on this study was designed. This real-time continuous glucose monitoring instrument consisted of an adjustable excitation voltage module, a current-voltage converter module, a microprocessor and a wireless transceiver module. For portability, the size of the device was only 40 mm * 30 mm * 5 mm and its weight was only 30 g. In addition, a communication command code algorithm was designed to ensure the security and integrity of data transmission in this study. Results of experiments in vitro showed that current detection of the device worked effectively. A 5-hour monitoring of blood glucose level in vivo showed that the device could continuously monitor blood glucose in real time. The relative error of monitoring results of the designed device ranged from 2.22% to 7.17% when comparing to a portable blood meter. PMID- 29761994 TI - [Study on precise localization of intraoperative matrix electrode]. AB - In order to accurately localize the image coordinates and serial numbers of intraoperative subdural matrix electrodes, a matrix electrode localization algorithm for image processing is proposed in this paper. Firstly, by using point by-point extended electrode location algorithm, the electrode is expanded point by-point vertically and horizontally, and the initial coordinates and serial numbers of each electrode are determined. Secondly, the single electrode coordinate region extraction algorithm is used to determine the best coordinates of each electrode, so that the image coordinates and serial numbers of all electrodes are determined point-by-point. The results show that the positioning accuracy of electrode serial number is 100%, and the electrode coordinate positioning error is less than 2 mm. The algorithms in this paper can accurately localize the image coordinates and the serial numbers of a matrix electrode arranged in an arc, which could aid drawing of cortical function mapping, and achieve precise positioning of brain functional areas, so that it can be widely used in neuroscience research and clinical application based on electrocorticogram analysis. PMID- 29761995 TI - [The progress of research on three-dimensional printed jaw scaffolds]. AB - Large defects of jaw caused by tumor, trauma and so on in oral and maxillofacial region lead to facial deformity, language and chewing dysfunction, which severely damage the patient's life quality. Three-dimensional printing (3DP) is also named additive manufacturing (AM), which can print materials layer by layer to create three-dimensional objects. The complex shape of jaw defects can be accurately reconstructed using 3DP scaffold combined with image data, computer-aided-design and manufacture. It has specific advantages compared with traditional way of jaw reconstruction and has attracted much attention in the field of jaw tissue engineering recently. This article presented the progress of 3DP scaffold and its application in jaw reconstruction, providing a new idea for jaw reconstruction. PMID- 29761996 TI - [Research progress of competing endogenous RNA]. AB - The competing endogenous RNA (ceRNA) hypothesis is a new pattern of gene posttranscriptional regulation. Encoding mRNA, long noncoding RNA (lncRNA), pseudogene transcript, circular RNA (circRNA), etc. can regulate gene expression by binding microRNA (miRNA). According to the research, ceRNA regulatory network participates in the maintenance of normal physiological state, occurrence and development of diseases. This paper reviewed ceRNA with the following respects: the proposal of ceRNA hypothesis, members of ceRNA regulatory network, research status, limitations and future development directions of this hypothesis. It will contribute to clarify the pathogenesis of much diseases including tumor and provide a new strategy for the diagnosis and treatment of disease. PMID- 29761997 TI - [Research progress on characteristics and applications of melanin nanoparticles]. AB - Melanin nanoparticles (MNPs) not only retain the inherent characteristics of melanin (metal ion chelation, photothermal conversion property, etc.), but also can exhibit more excellent properties, such as high dispersion stability, good biocompatibility and biodegradability, etc. Furthermore, these performances can be enhanced to target the specific sites and treat diseases by the surface modification or combination with functional substance. In this paper, the characteristics, preparation methods and applications of MNPs were reviewed. It provides a reference for further development of application for MNPs, and theoretical basis for practice in biology, medicine and so on. PMID- 29761998 TI - Functional magnetic resonance imaging in glioma patients: from clinical applications to future perspectives. AB - Functional magnetic resonance imaging (fMRI) allows the non-invasive assessment of human brain activity in vivo. In glioma patients, fMRI is frequently used to determine the individual functional anatomy of the motor and language network in a presurgical setting to optimize surgical procedures and prevent extensive damage to functionally eloquent areas. Novel developments based on resting-state fMRI may help to improve presurgical planning for patients which are unable to perform structured tasks and might extend presurgical mapping to include additional functional networks. Recent advances indicate a promising potential for future applications of fMRI in glioma patients which might help to identify neoplastic tissue or predict the long-term functional outcome of individual patients. PMID- 29762000 TI - [Imiquimod combined with dendritic cell vaccine decreases Treg proportion and enhances anti-tumor responses in mice bearing melanoma]. AB - Objective: To investigate the therapeutic effect of Toll-like receptor 7( TLR7) agonist imiquimod combined with dendritic cell( DC)-based tumor vaccine on melanoma in mice and the potential mechanism. Methods: Melanoma-bearing mouse models were established by subcutanous injection of B16-OVA cells into C57 BL /6 mice. DCs were isolated from mouse bone marrow and propagated in culture medium with recombinant mouse granulocyte-macrophage colony-stimulating factor( rm GM CSF) and recombinant mouse interleukin-4( rm IL-4). DC vaccine( OVA-DC) was prepared by overnight incubation of DCs added with chicken ovalbumin. C57 BL /6 mice were separated into four groups which were treated with PBS,topical imiquimod application,OVA-DC intradermal injection and imiquimod plus OVA DC,respectively. The tumor size was calculated by digital vernier caliper. Peripheral blood CD4~+FOXP3~+Tregs of the tumor-bearing mice was detected by flow cytometry. The cytotoxicity of splenic lymphocyte against B16-OVA was assessed in vitro by CCK-8 assay. Results: Compared with the other three groups,B16-OVA bearing mice treated with imiquimod plus DC vaccine had the smallest tumor volume. The percentage of CD4~+FOXP3~+Tregs decreased significantly in the combined treated mice. The combined treatment enhanced significantly cytotoxicity of splenic lymphocytes against B16-OVA cells. Conclusion: Imiquimod combined with antigen-pulsed-DC vaccine could reduce CD4~+FOXP3~+Treg proportion and promote anti-tumor effect in mice with melanoma PMID- 29762001 TI - [Transplantation of bone marrow mesenchymal stem cell improves antioxidant capacity and immune activity of aging model rats ]. AB - Objective: To investigate the impact of bone marrow mesenchymal stem cell( BMSC) transplantation on the antioxidant capacity and immune activity of aging rats induced by D-galactose. Methods: Ten healthy male SD rats served as a control group( aged 2 months). To establish aging models,healthy SD rats were daily injected subcutaneously with D-galactose( 400 mg / kg). Then the aging model rats were randomized into aging model group and BMSC group( ten rats in each group). The BMSC group was injected with 3 * 106 BMSCs via tail vein. And rats in the control and model groups were injected with the same amount of normal saline. Blood samples were taken from the rats of the three groups to detect the content of malonaldehyde( MDA) and the activities of superoxide dismutase( SOD). The thymic mass was weighed and the indexes of thymus were calculated; thymus lymphocyte transforming index was measured with MTT assay; the levels of IL-2and IL-10 in the thymus were detected by ELISA; and the ultrastructural changes of the thymus in each group were observed under a transmission electron microscope. Results: BMSC transplantation can increase the activity of SOD,decrease the level of MDA. Compared with the model group,the indexes of thymus as well as thymus lymphocyte transforming index significantly increased in the BMSC group. And in the BMSC group,the level of IL-2 was higher,and the level of IL-10 was distinctly lower. The thymus cells were arranged loosely,some nuclei presented with characteristic changes of pyknosis or apoptosis,and adipose tissues increased in the aging model group. BMSC could protect the ultrastructures of thymus cells,reticulo-epithelial cells,and the cell organelles were abundant and complete. Conclusion: BMSC transplantation can improve antioxidant capacity and immune activity of aging rats,thus postponing immunosenescence. PMID- 29762002 TI - [Hydrogen-rich saline attenuates hyperalgesia and reduces cytokines in rats with post-herpetic neuralgia via activating autophagy]. AB - Objective: To investigate the role of autophagy in hydrogen-rich saline attenuating post-herpetic neuralgia( PHN) in rats. Methods: A total of 100 male SD rats were randomly divided into the five groups( n = 20) : control group,PHN group,PHN group treated with hydrogen-rich saline( PHN-H2group),PHN group treated with hydrogen-rich saline and3-MA( PHN-H2-3-MA group),PHN group treated with hydrogen-rich saline and rapamycin( PHN-H2-Rap group). PHN models were established by varicella-zoster virus( VZV) inoculation. After modeling,15 mg / kg 3-MA or 10 mg / kg rapamycin were intraperitoneally injected in corresponding rats with PHN once two days for 3 times. Hydrogen-rich saline( 10 m L / kg)was injected intraperitoneally twice a day for 7 consecutive days in PHN-H2 group,PHN H2-3-MA group and PHN-H2-Rap group after VZV injection. The paw withdrawal thresholds( PWT) of 50 rats were detected at 3,7,14 and 21 days after modeling. Spinal cord enlargements of the other 50 rats were collected to examine tumor necrosis factor alpha( TNF-alpha),interleukine 1beta( IL-1beta) and IL-6 by ELISA and autophagy protein microtubule-associated protein 1 light chain 3( LC3),beclin 1and P62 by Western blotting. Results: Compared with the control group,the rats in the PHN group presented with decreased PWT,increased levels of TNF-alpha,IL 1beta,IL-6,LC3II and beclin 1,and down-regulated P62 expression. Compared with PHN group,the rats in the PHN-H2 group and PHN-H2-Rap group showed increased PWT,decreased levels of TNF-alpha,IL-1beta and IL-6,further up-regulated expressions of LC3 and beclin 1 as wel as P62 expression. Compared with PHN-H2 group,the rats in the PHN-H2-3-MA group had reduced PWT,elevated expressions of TNF-alpha,IL-1beta and IL-6,suppressed expressions of LC3 and beclin 1,and enhanced p62 expression. Conclusion: Hydrogen-rich saline attenuated PWT and inhibited the release of cytokines TNF-alpha,IL-1beta,IL-6 in rats with PHN via activating autophagy. PMID- 29762004 TI - Sequence-Dependent Peptide Surface Functionalization of Metal-Organic Frameworks. AB - We report a noncovalent surface functionalization technique for water-stable metal-organic frameworks using short peptide sequences identified via phage display. Specific frameworks-binding peptides were identified for crystalline Zn(MeIM)2 (MeIM: 2-methylimidazole, ZIF-8), semiamorphous Fe-BTC (BTC: 1,3,5 benzene-tricarboxylate), and Al(OH)(C4H2O4) (MIL-53(Al)-FA, FA: fumaric acid), and their thermodynamic binding affinities and specificities were measured. Electron microscopy, powder X-ray diffraction, and gas adsorption analysis confirmed that the peptide-functionalized frameworks retained similar characteristics compared to their as-synthesized counterparts. Confocal laser scanning microscopy demonstrated that peptide was localized on the surface of the frameworks, whereas surface area measurements showed no evidence of pore blockage. Finally, we measured the pH-dependent release of fluorescein from peptide-functionalized frameworks and discovered that peptide binding can attenuate fluorescein release by improving framework stability under low pH conditions. Our results demonstrate that phage display can be used as a general method to identify specific peptide sequences with strong binding affinity to water-stable metal-organic frameworks and that these peptides can alter drug release kinetics by affecting framework stability in aqueous environments. PMID- 29762003 TI - [Decreased number and immune activity of splenic T lymphocytes in mice exposed to hypoxia at high altitude]. AB - Objective: To explore the changes of splenic T lymphocyte subsets and functions in mice under high-altitude hypoxic conditions. Methods: After mice were exposed to an altitude of 400 m,2200 m and 4200 m for 30 days,ELISA was used to detect the concentrations of interleukin-4( IL-4) and interferon-gamma( IFN-gamma) in the cultured splenocyte supernatant; MTT assay was used to analyze the proliferation of splenic T lymphocytes; flow cytometry was performed to examine the alterations of splenic T lymphocyte subsets. Results: After exposed to hypoxia for 30 days,in comparison with the control group( 400 m),the spleen index of the mice increased significantly in both the 2200 m and 4200 m groups,and the spleen index of the 4200 m group was apparently higher than that of the 2200 m group; the concentration of IFN-gamma in the splenocyte supernatant of the 4200 m and 2200 m groups significantly decreased,while the concentration of IL-4 had no obvious change. The proliferation of splenic T lymphocyte was reduced obviously in both the 2200 m and 4200 m groups,at the same time,the proliferation of T cells in the 4200 m group was markedly lower than that in the 2200 m group. The percentages of splenic CD3~+,CD4~+and CD8~+T lymphocytes decreased markedly in the 2200 m and 4200 m groups,among them,the number of CD4~+T cel s decreased significantly than CD8~+T cel s. In addition,CD3~+and CD4~+T lymphocyte percentages of the 4200 m group obviously decreased compared with the 2200 m group. Conclusion: In mice exposed to hypoxia at an altitude of 4200 m and 2200 m for 30 days,the number of T lymphocyte subsets and the proliferation ability of T cel s decrease,and the level of IFN-gamma is decreased as well. PMID- 29762006 TI - Beyond Fourier Transform Infrared Spectroscopy: External Cavity Quantum Cascade Laser-Based Mid-infrared Transmission Spectroscopy of Proteins in the Amide I and Amide II Region. AB - In this work, we present a setup for mid-IR measurements of the protein amide I and amide II bands in aqueous solution. Employing a latest generation external cavity-quantum cascade laser (EC-QCL) at room temperature in pulsed operation mode allowed implementing a high optical path length of 31 MUm that ensures robust sample handling. By application of a data processing routine, which removes occasionally deviating EC-QCL scans, the noise level could be lowered by a factor of 4. The thereby accomplished signal-to-noise ratio is better by a factor of approximately 2 compared to research-grade Fourier transform infrared (FT-IR) spectrometers at equal acquisition times. Employing this setup, characteristic spectral features of three representative proteins with different secondary structures could be measured at concentrations as low as 1 mg mL-1. Mathematical evaluation of the spectral overlap confirms excellent agreement of the quantum cascade laser infrared spectroscropy (QCL-IR) transmission measurements with protein spectra acquired by FT-IR spectroscopy. The presented setup combines performance surpassing FT-IR spectroscopy with large applicable optical paths and coverage of the relevant spectral range for protein analysis. This holds high potential for future EC-QCL-based protein studies, including the investigation of dynamic secondary structure changes and chemometrics-based protein quantification in complex matrices. PMID- 29762005 TI - Self-Assembling Hollow Carbon Nanobeads into Double-Shell Microspheres as a Hierarchical Sulfur Host for Sustainable Room-Temperature Sodium-Sulfur Batteries. AB - We report the use of passion fruit-like double-carbon-shell porous carbon microspheres (PCMs) as the sulfur substrate in room-temperature sodium-sulfur batteries. The PCMs are covered by microsized carbon shells on the outside and consisted of carbon nanobeads with hollow structure inside, leading to a unique multidimensional scaling double-carbon-shell structure with high electronic conductivity and strengthened mechanical properties. Sulfur is filled inside the PCMs (PCMs-S) and protected by the unique double-carbon-shell, which means the subsequently generated intermediate sodium polysulfide species cannot be exposed to the electrolyte directly and well protected inside. In addition, the inner interconnected porous structure provides room for the volume expansion of sulfur during discharge processes. It is found that the PCMs-S with a 63.6% initial Coulombic efficiency contributed to the 290 mA h g-1 at the current density of 100 mA g-1 after 350 cycles. More importantly, PCMs-S exhibited good rate performance with a capacity of 113 and 56 mA h g-1 at the current densities of 1000 and 2000 mA g-1, respectively. PMID- 29762007 TI - Improved Stability of Interfacial Energy-Level Alignment in Inverted Planar Perovskite Solar Cells. AB - Even though poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has been commonly used as a hole extraction layer (HEL) for p-i-n perovskite solar cells (PSCs), the cells' photovoltaic performance deteriorates because of the low and unstable work functions (WFs) of PEDOT:PSS versus those of a perovskite layer. To overcome this drawback, we synthesized a copolymer (P(SS- co TFPMA)) ionomer consisting of PSS and tetrafluoropropylmethacrylate (TFPMA) as an alternative to conventional PEDOT:PSS. The PEDOT:P(SS- co-TFPMA) copolymer solution and its film exhibited excellent homogeneity and high phase stability compared with a physical mixture of TFPMA with PEDOT:PSS solution. During spin coating, a self-organized conducting PEDOT:P(SS- co-TFPMA) HEL evolved and the topmost PEDOT:P(SS- co-TFPMA) film showed a hydrophobic surface with a higher WF compared to that of the pristine PEDOT:PSS film because of its chemically bonded electron-withdrawing fluorinated functional groups. Interestingly, the WF of the conventional PEDOT:PSS film dramatically deteriorated after being coated with a perovskite layer, whereas the PEDOT:P(SS- co-TFPMA) film represented a relatively small influence. Because of the superior energy-level alignment between the HEL and a perovskite layer even after the contact, the open-circuit voltage, short circuit current, and fill factor of the inverted planar p-i-n PSCs (IP-PSCs) with PEDOT:P(SS- co-TFPMA) were improved from 0.92 to 0.98 V, 18.96 to 19.66 mA/cm2, and 78.96 to 82.43%, respectively, resulting in a 15% improvement in the power conversion efficiency vs that of IP-PSCs with conventional PEDOT:PSS. Moreover, the IP-PSCs with PEDOT:P(SS- co-TFPMA) layer showed not only improved photovoltaic performance but also enhanced device stability due to hydrophobic surface of PEDOT:P(SS- co-TFPMA) film. PMID- 29762008 TI - Binary Hierarchical Porous Graphene/Pyrolytic Carbon Nanocomposite Matrix Loaded with Sulfur as a High-Performance Li-S Battery Cathode. AB - A N,O-codoped hierarchical porous nanocomposite consisting of binary reduced graphene oxide and pyrolytic carbon (rGO/PC) from chitosan is fabricated. The optimized rGO/PC possesses micropores with size distribution concentrated around 1.1 nm and plenty of meso/macropores. The Brunauer-Emmett-Teller specific surface area is 480.8 m2 g-1, and it possesses impressively large pore volume of 2.14 cm3 g-1. On the basis of the synergistic effects of the following main factors: (i) the confined space effect in the hierarchical porous binary carbonaceous matrix; (ii) the anchor effects by strong chemical bonds with codoped N and O atoms; and (iii) the good flexibility and conductivity of rGO, the rGO/PC/S holding 75 wt % S exhibits high performance as Li-S battery cathode. Specific capacity of 1625 mA h g-1 can be delivered at 0.1 C (1 C = 1675 mA g-1), whereas 848 mA h g-1 can be maintained after 300 cycles at 1 C. Even at high rate of 5 C, 412 mA h g-1 can be restrained after 1000 cycles. PMID- 29762009 TI - Wavelength Modulated Back-Scatter Interferometry for Universal, On-Column Refractive Index Detection in Picoliter Volumes. AB - Wavelength-modulated back scatter interferometry (M-BSI) is shown to improve the detection metrics for refractive index (RI) sensing in microseparations. In M BSI, the output of a tunable diode laser is focused into the detection zone of a separation channel as the excitation wavelength is rapidly modulated. This spatially modulates the observed interference pattern, which is measured in the backscattered direction. Phase-sensitive detection using a split photodiode detector aligned on one fringe of the interference pattern is used to monitor RI changes as analytes are separated. Using sucrose standards, we report a detection limit of 700 MUg/L in a 75 MUm i.d. capillary at the 3sigma level, corresponding to a detection volume of 90 pL. To validate the approach for electrophoretic separations, Na+ and Li+ were separated and detected with M-BSI and indirect-UV absorbance on the same capillary. A 4 mg/L NaCl and LiCl mixture leads to comparable separation efficiencies in the two detection schemes, with better signal-to-noise in the M-BSI detection, but less baseline stability. The latter arises in part from Joule heating, which influences RI measurements through the thermo-optic properties of the run buffer. To reduce this effect, a 25 MUm i.d. capillary combined with active temperature control was used to detect the separation of sucrose, glucose, and lactose with M-BSI. The lack of suitable UV chromophores makes these analytes challenging to detect directly in ultrasmall volumes. Using a 55 mM NaOH run buffer, M-BSI is shown to detect the separation of a mixture of 174 mg/L sucrose, 97 mg/L glucose, and 172 mg/L lactose in a 15 pL detection volume. The universal on-column detection in ultrasmall volumes adds new capabilities for microanalysis platforms, while potentially reducing the footprint and costs of these systems. PMID- 29762010 TI - Triple-Wavelength-Region Luminescence Sensing Based on a Color-Tunable Emitting Lanthanide Metal Organic Framework. AB - A series of isomorphic lanthanide metal-organic frameworks (Ln-MOFs), namely [Ln(dcbba)(DMF)2] n.H2O.0.5DMF [Ln = La (1), Eu (2) and Tb (3); H3dcbba = 4-(3, 5 dicarboxylatobenzyloxy)benzoic acid; DMF = N, N'-dimethylformamide] have been designed and synthesized by the solvothermal reactions of H3dcbba and La(NO3)3.6H2O. Single-crystal X-ray diffraction analysis reveals that the complexes 1-3 exhibit a (3,6)-connected open framework structure with binuclear [Ln2(COO)6] n secondary building units as 6-connected nodes and H3dcbba ligands as 3-connected nodes. The isostructural mixed La/Eu/Tb-dcbba (4) was obtained via the in-suit doping of different Ln3+ ions into the host framework, which is able to emit pure orange, white, and blue light when excited at 300, 305, and 350 nm, respectively. Subsequently, a novel and multifunctional sensing process was designed based on the excitation wavelength sensitive color tunable luminescent sample 4, which can detect HS- ions, THF (tetrahydrofuran), and Ag+ ions via different luminescence color change mechanisms. The remarkable color change, excellent selectivity, and high sensitivity further indicate the promise of this type of multifunctional luminescent materials for the sensing of anion, cation, and organic small molecule. PMID- 29762011 TI - Strategies toward Organic Carbon Monoxide Prodrugs. AB - Carbon monoxide is widely acknowledged as an important gasotransmitter in the mammalian system with importance on par with that of nitric oxide. It has also been firmly established as a potential therapeutic agent with a wide range of indications including organ transplantation, cancer, bacterial infection, and inflammation-related conditions such as colitis and sepsis. One major issue in developing CO based therapeutics is its delivery in a pharmaceutically acceptable form. Currently, there are generally five forms of deliveries: inhaled CO, photosensitive CO-releasing molecules, encapsulated CO, CO dissolved in drinks, and molecules that would release CO under physiological conditions without the need for light. For over a decade, the last category only included metal-based CO releasing molecules. What had been missing were organic CO prodrugs, which release CO under physiological conditions with tunable rates and in response to various exogenous and endogenous triggers such as water, chemical reagents, esterase, ROS, and changes in pH. This Account describes our work in this area as well as the demonstration for these organic prodrugs to recapitulate CO's pharmacological effects both in vitro and in vivo. Generally, two categories of CO prodrugs have been developed in our lab. Both can be considered as precursors of norbornadien-7-ones, which readily undergo cheletropic reaction under very mild conditions to extrude CO. The first category of CO prodrugs capitalizes on the inter- and intramolecular inverse electron demand Diels-Alder (DAinv) reaction to trigger CO release under physiological conditions. As for the bimolecular CO prodrugs, we proposed a new concept of "enrichment triggered CO release" by conjugating both components with a mitochondria-targeting moiety to achieve targeted CO delivery with improved biological outcomes in vitro and in vivo. As for the unimolecular CO prodrugs, the release half-lives can be readily tuned from minutes to days by varying the substituents on the dienone ring, the tethering linker, and the alkyne. Some significant structure-release rates relationships (SRRs) have been unveiled. An esterase-activated CO prodrug and a cascade prodrug system for co-delivery of CO and another payload have also been devised using such an intramolecular click and release strategy. The second category of CO prodrugs leverage on an elimination reaction to generate norbornadien-7-ones for CO release from norborn-2-en-7-ones. In the case of pH sensitive ones, the CO release is triggered by beta-elimination, and the release rate can be quantitatively predicted using the Hammett constant of the substituents on the leaving group. The ROS-activated ones take advantage of ROS induced selenoxide elimination to achieve targeted CO delivery to disease sites with elevated ROS level. We strongly believe that these CO prodrugs could serve as powerful tools for CO-associated biological studies and are promising candidates for ultimate clinical applications. PMID- 29762012 TI - Bioinspired Cocatalysts Decorated WO3 Nanotube Toward Unparalleled Hydrogen Sulfide Chemiresistor. AB - Herein, we incorporated dual biotemplates, i.e., cellulose nanocrystals (CNC) and apoferritin, into electrospinning solution to achieve three distinct benefits, i.e., (i) facile synthesis of a WO3 nanotube by utilizing the self-agglomerating nature of CNC in the core of as-spun nanofibers, (ii) effective sensitization by partial phase transition from WO3 to Na2W4O13 induced by interaction between sodium-doped CNC and WO3 during calcination, and (iii) uniform functionalization with monodispersive apoferritin-derived Pt catalytic nanoparticles (2.22 +/- 0.42 nm). Interestingly, the sensitization effect of Na2W4O13 on WO3 resulted in highly selective H2S sensing characteristics against seven different interfering molecules. Furthermore, synergistic effects with a bioinspired Pt catalyst induced a remarkably enhanced H2S response ( Rair/ Rgas = 203.5), unparalleled selectivity ( Rair/ Rgas < 1.3 for the interfering molecules), and rapid response (<10 s)/recovery (<30 s) time at 1 ppm of H2S under 95% relative humidity level. This work paves the way for a new class of cosensitization routes to overcome critical shortcomings of SMO-based chemical sensors, thus providing a potential platform for diagnosis of halitosis. PMID- 29762013 TI - Determination of Hexavalent Chromium Fractions in Plastics Using Laboratory Based, High-Resolution X-ray Emission Spectroscopy. AB - Cr(VI) is a well-known human carcinogen with many water-soluble moieties. Its presence in both natural and man-made substances poses a risk to public health, especially when contamination of groundwater is possible. This has led the European Union and other jurisdictions to include Cr(VI) in restriction of hazardous substances regulations. However, for several important industrial and commercial purposes, analytical capability to characterize Cr(VI) is known to be insufficient for regulatory purposes. For example, advanced X-ray spectroscopies, particularly synchrotron-based X-ray absorption fine structure (XAFS) studies, have shown that species interconversion and under-extraction can be difficult to prevent in many existing liquid extraction protocols when applied to plastics, mining ores and tailings, and paint sludges. Here, we report that wavelength dispersive X-ray fluorescence spectroscopy taken at energy resolutions close to the theoretical limit imposed by the core-hole lifetime, generally called X-ray emission spectroscopy (XES) in the synchrotron community, can be used in the laboratory setting for noninvasive, analytical characterization of the Cr(VI)/Cr ratio in plastics. The selected samples have been part of ongoing efforts by standards development organizations to create improved Cr(VI) testing protocols, and the present work provides a direct proof-of-principle for the use of such extremely high-resolution laboratory WDXRF as an alternative to liquid extraction methods for regulatory compliance testing of Cr(VI) content. As a practical application of this work, we report a value for the Cr(VI) mass fraction of the new NIST Standard Reference Material 2859 Restricted Elements in Polyvinyl Chloride. PMID- 29762014 TI - Selective and Sensitive Pull Down of Amyloid Fibrils Produced in Vitro and in Vivo by the Use of Pentameric-Thiophene-Coupled Resins. AB - Protein aggregation is a hallmark of several degenerative diseases, including Alzheimer's disease, Parkinson's disease and familial amyloidosis (Finnish type) (FAF). A method to isolate and detect amyloids is desired for the diagnosis of amyloid diseases. Here, we report the synthesis of pentameric thiophene amyloid ligand (p-FTAA) linked to agarose resin for selective purification of amyloid aggregates produced in vitro and in vivo. Using amyloid fibrils produced in vitro from alpha-synuclein, gelsolin, and Abeta1-40 and gelsolin amyloid aggregates extracted from tissue homogenates of a mouse model of FAF, we observed that p FTAA resin was able to pull down amyloid aggregates. The functionalized resin was also able to pull down oligomers produced in vitro from the A30P variant of alpha synuclein. The methodology described here can be useful for the diagnosis of amyloidogenic disease and also can be used to purify amyloid fibrils from biological samples, rendering the fibrils available for more accurate structural and biochemical characterization. PMID- 29762015 TI - Preferential Pt Nanocluster Seeding at Grain Boundary Dislocations in Polycrystalline Monolayer MoS2. AB - We show that Pt nanoclusters preferentially nucleate along the grain boundaries (GBs) in polycrystalline MoS2 monolayer films, with dislocations acting as the seed site. Atomic resolution studies by aberration-corrected annular dark-field scanning transmission electron microscopy reveal periodic spacing of Pt nanoclusters with dependence on GB tilt angles and random spacings for the antiphase boundaries ( i.e., 60 degrees ). Individual Pt atoms are imaged within the dislocation core sections of the GB region, with various positions observed, including both the substitutional sites of Mo and the hollow center of the octahedral ring. The evolution from single atoms or small few atom clusters to nanosized particles of Pt is examined at the atomic level to gain a deep understanding of the pathways of Pt seed nucleation and growth at the GB. Density functional theory calculations confirm the energetic advantage of trapping Pt at dislocations on both the antiphase boundary and the small-angle GB rather than on the pristine lattice. The selective decoration of GBs by Pt nanoparticles also has a beneficial use to easily identify GB areas during microscopic-scale observations and track long-range nanoscale variances of GBs with spatial detail not easy to achieve using other methods. We show that GBs have nanoscale meandering across micron-scale distances with no strong preference for specific lattice directions across macroscopic ranges. PMID- 29762016 TI - Rapid Two-Millisecond Interrogation of Electrochemical, Aptamer-Based Sensor Response Using Intermittent Pulse Amperometry. AB - In this manuscript, we employ the technique intermittent pulse amperometry (IPA) to interrogate equilibrium and kinetic target binding to the surface of electrochemical, aptamer-based (E-AB) sensors, achieving as fast as 2 ms time resolution. E-AB sensors comprise an electrode surface modified with a flexible nucleic acid aptamer tethered at the 3'-terminus with a redox-active molecule. The introduction of a target changes the conformation and flexibility of the nucleic acid, which alters the charge transfer rate of the appended redox molecule. Typically, changes in charge transfer rate within this class of sensor are monitored via voltammetric methods. Here, we demonstrate that the use of IPA enables the detection of changes in charge transfer rates (i.e., current) at times <100 MUs after the application of a potential pulse. Changes in sensor current are quantitatively related to target analyte concentration and can be used to create binding isotherms. Furthermore, the application of IPA enables rapid probing of the electrochemical surface with a time resolution equivalent to as low as twice the applied potential pulse width, not previously demonstrated with traditional voltammetric techniques employed with E-AB sensors (alternating current, square wave, cyclic). To visualize binding, we developed false-color plots analogous to those used in the field of fast-scan cyclic voltammetry. The use of IPA is universal, as demonstrated with two representative small molecule E AB sensors directed against the aminoglycoside antibiotic tobramycin and adenosine triphosphate (ATP). Intermittent pulse amperometry exhibits an unprecedented sub-microsecond temporal response and is a general method for measuring rapid sensor performance. PMID- 29762018 TI - Combining Measurements from Mobile Monitoring and a Reference Site To Develop Models of Ambient Ultrafine Particle Number Concentration at Residences. AB - Significant spatial and temporal variation in ultrafine particle (UFP; <100 nm in diameter) concentrations creates challenges in developing predictive models for epidemiological investigations. We compared the performance of land-use regression models built by combining mobile and stationary measurements (hybrid model) with a regression model built using mobile measurements only (mobile model) in Chelsea and Boston, MA (USA). In each study area, particle number concentration (PNC; a proxy for UFP) was measured at a stationary reference site and with a mobile laboratory driven along a fixed route during an ~1-year monitoring period. In comparing PNC measured at 20 residences and PNC estimates from hybrid and mobile models, the hybrid model showed higher Pearson correlations of natural log-transformed PNC ( r = 0.73 vs 0.51 in Chelsea; r = 0.74 vs 0.47 in Boston) and lower root-mean-square error in Chelsea (0.61 vs 0.72) but no benefit in Boston (0.72 vs 0.71). All models overpredicted log transformed PNC by 3-6% at residences, yet the hybrid model reduced the standard deviation of the residuals by 15% in Chelsea and 31% in Boston with better tracking of overnight decreases in PNC. Overall, the hybrid model considerably outperformed the mobile model and could offer reduced exposure error for UFP epidemiology. PMID- 29762017 TI - The Role of Structural Enthalpy in Spherical Nucleic Acid Hybridization. AB - DNA hybridization onto DNA-functionalized nanoparticle surfaces (e.g., in the form of a spherical nucleic acid (SNA)) is known to be enhanced relative to hybridization free in solution. Surprisingly, via isothermal titration calorimetry, we reveal that this enhancement is enthalpically, as opposed to entropically, dominated by ~20 kcal/mol. Coarse-grained molecular dynamics simulations suggest that the observed enthalpic enhancement results from structurally confining the DNA on the nanoparticle surface and preventing it from adopting enthalpically unfavorable conformations like those observed in the solution case. The idea that structural confinement leads to the formation of energetically more stable duplexes is evaluated by decreasing the degree of confinement a duplex experiences on the nanoparticle surface. Both experiment and simulation confirm that when the surface-bound duplex is less confined, i.e., at lower DNA surface density or at greater distance from the nanoparticle surface, its enthalpy of formation approaches the less favorable enthalpy of duplex formation for the linear strand in solution. This work provides insight into one of the most important and enabling properties of SNAs and will inform the design of materials that rely on the thermodynamics of hybridization onto DNA functionalized surfaces, including diagnostic probes and therapeutic agents. PMID- 29762020 TI - Can Electrochemical Measurements Be Used To Predict X-ray Photoelectron Spectroscopic Data? The Case of Ferrocenyl-beta-Diketonato Complexes of Manganese(III). AB - In order to better understand intramolecular communication between molecular fragments, a series of ferrocene-functionalized beta-diketonato manganese(III) complexes, [Mn(FcCOCHCOR)3] with R = CF3, 1, CH3, 2, Ph = C6H5, 3, and Fc = FeII(eta5-C5H4)(eta5-C5H5), 4, the mixed ligand beta-diketonato complex [Mn(FcCOCHCOFc)2(FcCOCHCOCH3)], 5, as well as the acac complex [Mn(CH3COCHCOCH3)3], 6, were subjected to an electrochemical and X-ray photoelectron spectroscopy (XPS) study. The ferrocenyl (FeII) and MnIII redox potentials, E degrees ', and photoelectron lines were sufficiently resolved in each complex to demonstrate a linear correlation between E degrees ' and group electronegativities of ligand R groups, chiR, or SigmachiR, as well as with binding energies of both the Fe 2p3/2 and Mn 2p3/2 photoelectron lines. These relationships are consistent with effective communication between molecular fragments of 1-5. From these relationships, prediction of Mn and Fe core electron binding energies in [Mn(R1COCHCOR2)3] complexes from known manganese and/or ferrocenyl redox potentials are, therefore, now possible. Ligand infrared carbonyl stretching frequencies were successfully related to binding energy as a measure of the energy required for inner-sphere reorganization. In particular it became possible to explain why, upon electrochemical oxidation or photoionization, the ferrocenyl FeII inner-shell of 1-5 needs more energy in complexes with ligands bearing electron-withdrawing (CF3) groups than in ligands bearing electron-donating groups such as ferrocenyl. The XPS determined entity Iratio (the ratio between the intensities of the satellite and main metal 2p3/2 photoelectron lines) is an indication not only of the amount of charge transferred, but also of the degree of inner-sphere reorganization. Just as for binding energy, the quantity Iratio was also found to be related to the energy requirements for the inner-sphere reorganization depicted by the vibrational frequency, vco. PMID- 29762019 TI - Insights into Magneto-Optics of Helical Conjugated Polymers. AB - Materials with magneto-optic (MO) properties have enabled critical fiber-optic applications and highly sensitive magnetic field sensors. While traditional MO materials are inorganic in nature, new generations of MO materials based on organic semiconducting polymers could allow increased versatility for device architectures, manufacturing options, and flexible mechanics. However, the origin of MO activity in semiconducting polymers is far from understood. In this paper, we report high MO activity observed in a chiral helical poly-3 (alkylsulfone)thiophene (P3AST), which confirms a new design for the creation of a giant Faraday effect with Verdet constants up to (7.63 +/- 0.78) * 104 deg T-1 m-1 at 532 nm. We have determined that the sign of the Verdet constant and its magnitude are related to the helicity of the polymer at the measured wavelength. The Faraday rotation and the helical conformation of P3AST are modulated by thermal annealing, which is further supported by DFT calculations and MD simulations. Our results demonstrate that helical polymers exhibit enhanced Verdet constants and expand the previous design space for polythiophene MO materials that was thought to be limited to highly regular lamellar structures. The structure-property studies herein provide insights for the design of next generation MO materials based upon semiconducting organic polymers. PMID- 29762021 TI - Spatial and Seasonal Distributions of Current Use Pesticides (CUPs) in the Atmospheric Particulate Phase in the Great Lakes Region. AB - The authors analyzed spatial and seasonal variations of current use pesticides (CUPs) levels in the atmospheric particulate phase in the Great Lakes basin. Twenty-four hour air samples were collected at six sites (two urban, two rural, and two remote) in 2015. The concentrations of 15 CUPs, including nine pyrethroid insecticides, four herbicides, one organophosphate insecticide, and one fungicide, were measured. The total CUPs concentrations were higher at the urban sites (0.38-1760 pg/m3) than at the rural and remote sites (0.07-530 pg/m3). The most abundant CUPs were pyrethroid insecticides at the urban sites. The levels of the other CUPs did not vary much among the six sites, except at the most remote site at Eagle Harbor, where the levels were significantly lower. Chlorothalonil was the most frequently detected CUP, which was detected in more than 76% of the samples. The atmospheric concentrations of total pyrethroid insecticides and total herbicides were correlated with local human population and developed land use. Significantly higher concentrations of most CUPs were observed in the warmer months than in the colder months at all sites. In addition to agricultural applications, which occur during the warmer months, the CUPs atmospheric concentrations may also be influenced by nonagricultural activities and the urban development. PMID- 29762022 TI - Counterion-Controlled Formation of an Octanuclear Uranyl Cage with cis-1,2 Cyclohexanedicarboxylate Ligands. AB - cis-1,2-Cyclohexanedicarboxylic acid ( c-chdcH2) was reacted with uranyl nitrate under (solvo-)hydrothermal conditions in the presence of different possible counterions. Two neutral complexes of 1:1 stoichiometry were obtained, [UO2( c chdc)(DMF)] (1) and [UO2( c-chdc)(H2O)] (2), which crystallize as two-dimensional coordination polymers and do not include the additional cations present in solution. In contrast, the complex [NH4][PPh4][(UO2)8( c-chdc)9(H2O)6].3H2O (3) crystallized in the presence of PPh4Br, ammonium cations being generated in situ from acetonitrile hydrolysis. This complex of 8:9 uranium:ligand stoichiometry contains an octanuclear anionic cage of D3 symmetry with a pseudo-cubic arrangement of uranium atoms. The ammonium cation is held within the cage through four hydrogen bonds with uranyl oxo groups directed inward. This cage complex is luminescent, although with a low quantum yield of 0.06, indicating limited potential as a photo-oxidant of included species. PMID- 29762023 TI - Reinforced Adversarial Neural Computer for de Novo Molecular Design. AB - In silico modeling is a crucial milestone in modern drug design and development. Although computer-aided approaches in this field are well-studied, the application of deep learning methods in this research area is at the beginning. In this work, we present an original deep neural network (DNN) architecture named RANC (Reinforced Adversarial Neural Computer) for the de novo design of novel small-molecule organic structures based on the generative adversarial network (GAN) paradigm and reinforcement learning (RL). As a generator RANC uses a differentiable neural computer (DNC), a category of neural networks, with increased generation capabilities due to the addition of an explicit memory bank, which can mitigate common problems found in adversarial settings. The comparative results have shown that RANC trained on the SMILES string representation of the molecules outperforms its first DNN-based counterpart ORGANIC by several metrics relevant to drug discovery: the number of unique structures, passing medicinal chemistry filters (MCFs), Muegge criteria, and high QED scores. RANC is able to generate structures that match the distributions of the key chemical features/descriptors (e.g., MW, logP, TPSA) and lengths of the SMILES strings in the training data set. Therefore, RANC can be reasonably regarded as a promising starting point to develop novel molecules with activity against different biological targets or pathways. In addition, this approach allows scientists to save time and covers a broad chemical space populated with novel and diverse compounds. PMID- 29762024 TI - Alkaline Hydrolysis of Methyl Decanoate in Surfactant-Based Systems. AB - Surfactant-modified reaction systems are one approach to perform organic reactions with water as the solvent involving hydrophobic reactants. Herein, the alkaline hydrolysis of the long-chain methyl decanoate in cationic and nonionic surfactant-modified systems is reported. The physicochemical behavior of the reaction mixture and the performance of the alkaline hydrolysis were systematically investigated. In water as the solvent, the reaction is slow, but at elevated temperatures, the alkaline hydrolysis of methyl decanoate is accelerated because the reaction product sodium decanoate acts as an ionic surfactant, leading to an increased solubility of methyl decanoate in the aqueous phase. The rate can be significantly increased by the addition of surfactants as solubilizers. In nonionic TX-100 solutions, the reaction rate can be increased by a factor of about 100 for a surfactant concentration of 5 wt %. If cationic surfactants are applied, the reaction rate can be further increased due to the electrostatic interaction between the hydroxide ions in solution and the charged head groups of the cationic micelles. PMID- 29762025 TI - A Spectroscopic and Computational Study of Cm3+ Incorporation in Lanthanide Phosphate Rhabdophane (LnPO4.0.67H2O) and Monazite (LnPO4). AB - This study investigates the incorporation of the minor actinide curium (Cm3+) in a series of synthetic La1- xGd xPO4 ( x = 0, 0.24, 0.54, 0.83, 1) monazite and rhabdophane solid-solutions. To obtain information on the incorporation process on the molecular scale and to understand the distribution of the dopant in the synthetic phosphate phases, combined time-resolved laser fluorescence spectroscopy and X-ray absorption fine structure spectroscopy investigations were conducted and complemented with ab initio atomistic simulations. We found that Cm3+ is incorporated in the monazite endmembers (LaPO4 and GdPO4) on one specific, highly ordered lattice site. The intermediate solid-solutions, however, display increasing disorder around the Cm3+ dopant as a result of random variations in nearest neighbor distances. In hydrated rhabdophane, and especially its La-rich solid-solutions, Cm3+ is preferentially incorporated on nonhydrated lattice sites. This site occupancy is not in agreement with the hydrated rhabdophane structure, where two-thirds of the lattice sites are associated with water of hydration (LnPO4.0.67H2O), implying that structural substitution reactions cannot be predicted based on the structure of the host matrix only. PMID- 29762026 TI - Polyoxometalate-Supported Bis(2,2'-bipyridine)mono(aqua)nickel(II) Coordination Complex: an Efficient Electrocatalyst for Water Oxidation. AB - A polyoxometalate (POM)-supported nickel(II) coordination complex, [NiII(2,2' bpy)3]3[{NiII(2,2'-bpy)2(H2O)}{HCoIIWVI12O40}]2.3H2O (1; 2,2'-bpy = 2,2' bipyridine), has been synthesized and structurally characterized. We could obtain a relatively better resolved structure from dried crystals of 1, NiII(2,2' bpy)3]3[{NiII(2,2'-bpy)2(H2O)}{HCoIIWVI12O40}]2.H2O (D1). Because the title compound has been characterized with a {NiII(2,2'-bpy)2(H2O)}2+ fragment coordinated to the surface of the Keggin anion ([H(CoIIW12O40]5-) via a terminal oxo group of tungsten and the [NiII(2,2'-bpy)3]2+ coordination complex cation sitting as the lattice component in the concerned crystals, the electronic spectroscopy of compound 1 has been described by comparing its electronic spectral features with those of [NiII(2,2'-bpy)2(H2O)Cl]Cl, [NiII(2,2'-bpy)3]Cl2, and K6[CoIIW12O40].6H2O. Most importantly, compound 1 can function as a heterogeneous and robust electrochemical water oxidation catalyst (WOC). To gain insights into the water oxidation (WO) protocol and to interpret the nature of the active catalyst, diverse electrochemical experiments have been conducted. The mode of action of the WOC during the electrochemical process is accounted for by confirmation that there was no formation/participation of metal oxide during various controlled experiments. It is found that the title compound acts as a true catalyst that has NiII (coordinated to POM surface) acting as the active catalytic center. It is also found to follow a proton-coupled electron-transfer pathway (two electrons and one proton) for WO catalysis with a high turnover frequency of 18.49 (mol of O2)(mol of NiII)-1 s-1. PMID- 29762027 TI - Chemoselective Peptide Modification via Photocatalytic Tryptophan beta-Position Conjugation. AB - Targeting tryptophan is a promising strategy to achieve high levels of selectivity for peptide or protein modification. A chemoselective peptide modification method via photocatalytic tryptophan beta-position conjugation has been discovered. This transformation has good substrate scope for both peptide and Michael acceptor, and has good chemoselectivity versus other amino acid residues. The endogenous peptides, glucagon and GLP-1 amide, were both successfully conjugated at the tryptophan beta-position. Insulin was studied as a nontryptophan control molecule, resulting in exclusive B-chain C-terminal selective decarboxylative conjugation. This transformation provides a novel approach toward peptide modification to support the discovery of new therapeutic peptides, protein labeling and bioconjugation. PMID- 29762028 TI - Selected-Nuclei Method for the Computation of Hyperfine Coupling Constants within Second-Order Moller-Plesset Perturbation Theory. AB - We introduce a new ansatz to compute hyperfine coupling constants of selected nuclei at the level of second-order Moller-Plesset perturbation (MP2) and double hybrid density functional theory with reduced computational effort, opening the route to the analyis of hyperfine coupling constants of large molecular structures. Our approach is based on a reformulation of the canonical MP2 term in atomic orbitals, thus exploiting the locality of electron correlation. We show that a perturbation-including integral screening reduces the scaling behavior of the number of significant two-electron integrals to sublinear. This selected nuclei approach allows for an efficient computation within scaled-opposite spin (SOS) RI-MP2 on massively parallelized architectures such as graphical processor units (GPUs), thus enabling studies on the influence of the environment on hyperfine coupling constants. PMID- 29762029 TI - Correction to "Chiral Organic Cages with a Triple-Stranded Helical Structure Derived from Helicene". PMID- 29762030 TI - Structure-Function Analysis of the Extended Conformation of a Polyketide Synthase Module. AB - Catalytic modules of assembly-line polyketide synthases (PKSs) have previously been observed in two very different conformations-an "extended" architecture and an "arch-shaped" architecture-although the catalytic relevance of neither has been directly established. By the use of a fully human naive antigen-binding fragment (Fab) library, a high-affinity antibody was identified that bound to the extended conformation of a PKS module, as verified by X-ray crystallography and tandem size-exclusion chromatography-small-angle X-ray scattering (SEC-SAXS). Kinetic analysis proved that this antibody-stabilized module conformation was fully competent for catalysis of intermodular polyketide chain translocation as well as intramodular polyketide chain elongation and functional group modification of a growing polyketide chain. Thus, the extended conformation of a PKS module is fully competent for all of its essential catalytic functions. PMID- 29762032 TI - ent-Kaurane Diterpenoids with Neuroprotective Properties from Corn Silk ( Zea mays). AB - Thirteen new ent-kaurane diterpenoids, stigmaydenes A-M (1-13), together with two known compounds (14, 15), were isolated from the crude extract of corn silk ( Zea mays). The structures of the compounds were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray diffraction. The absolute configurations of the compounds were also confirmed by comparison of experimental and calculated specific rotations. The compounds were evaluated for their neuroprotective effects against H2O2-induced SH-SY5Y cell injury, and compound 8 was active at 100 MUM, as determined by flow cytometry (annexin V-FITC/PI staining) and Hoechst 33258 staining. The results suggested that compound 8 could protect neuronal cells from H2O2-induced injury by inhibiting apoptosis in SH-SY5Y cells. PMID- 29762031 TI - Thermostability Improvement of the d-Allulose 3-Epimerase from Dorea sp. CAG317 by Site-Directed Mutagenesis at the Interface Regions. AB - d-Allulose is a low-calorie sweetener and has broad applications in the food, cosmetics, and pharmaceutical industries. Recently, most studies focus on d allulose production from d-fructose by d-allulose 3-epimerase (DAEase). However, the major blocker of industrial production of d-allulose is the poor thermostability. In this study, site-directed mutagenesis at the interface regions of Dorea sp. DAEase was carried out, and the F154Y/E191D/I193F mutation was obtained. The mutant protein displayed much higher thermostability, with a t1/2 value of 20.47 h (50 degrees C) and a Tm value of 74.18 degrees C. Compared with the wild-type DAEase, the t1/2 value at 50 degrees C increased by 5.4-fold, and the Tm value increased by 17.54 degrees C. In the d-allulose production from 500 g/L d-fructose, 148.2 g/L d-allulose could be obtained by F154Y/E191D/I193F mutant protein. The results suggest that site-directed mutagenesis at the interface regions is an efficient approach for improving the thermostability of DAEase. PMID- 29762033 TI - Isolation, Synthesis, and Antisepsis Effects of a C-Methylcoumarinochromone Isolated from Abronia nana Cell Culture. AB - Only a few isoflavones have been isolated from plants of the genus Abronia. The biological properties of compounds isolated from Abronia species have not been well established, and their antisepsis effects have not been reported yet. In the present study, a new C-methylcoumarinochromone, was isolated from Abronia nana suspension cultures. Its structure was deduced as 9,11-dihydroxy-10 methylcoumarinochromone (boeravinone Y, 1) by spectroscopic data analysis and verified by chemical synthesis. The potential inhibitory effects of 1 against high mobility group box 1 (HMGB1)-mediated septic responses were investigated. Results showed that 1 effectively inhibited lipopolysaccharide-induced release of HMGB1 and suppressed HMGB1-mediated septic responses, in terms of reduction of hyperpermeability, leukocyte adhesion and migration, and cell adhesion molecule expression. In addition, 1 increased the phagocytic activity of macrophages and exhibited bacterial clearance effects in the peritoneal fluid and blood of mice with cecal ligation and puncture-induced sepsis. Collectively, these results suggested that 1 might have potential therapeutic activity against various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 29762034 TI - Ionic-Liquid-Based Paclitaxel Preparation: A New Potential Formulation for Cancer Treatment. AB - Paclitaxel (PTX) injection (i.e., Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This communication reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/Tween-80/water. A significant enhancement in the solubility of PTX was observed with considerable correlation with the density and viscosity of the ILs, and with the side chain of the amino acids used as anions in the ILs. Moreover, the formulations were stable for up to 3 months. The driving force for the stability of the formulation was hypothesized to be the involvement of different types of interactions between the IL and PTX. In vitro cytotoxicity and antitumor activity of the IL-based formulations were evaluated on HeLa cells. The IL vehicles without PTX were found to be less cytotoxic than Taxol, while both the IL-based PTX formulation and Taxol exhibited similar antitumor activity. Finally, in vitro hypersensitivity reactions were evaluated on THP-1 cells and found to be significantly lower with the IL-based formulation than Taxol. This study demonstrated that specially designed ILs could provide a potentially safer alternative to Cremophor EL as an effective PTX formulation for cancer treatment giving fewer hypersensitivity reactions. PMID- 29762035 TI - Adsorption of Nitrogen Oxides on TiO2 Surface as a Function of NO2 and N2O5 Fraction in the Gas Phase. AB - The present study was devoted to the investigation of adsorption of nitrogen oxides on TiO2, with the focus on the effect of NO x concentration, composition, and flow rate. The inlet NO with a concentration of 200-800 ppm in pure N2 was mixed with ozone, produced from pure oxygen, and directed to a reactor with catalytic TiO2 powder. The oxidation of NO by ozone allowed to prepare mixtures with variable concentrations of NO and NO2 or NO2 and N2O5 which were adsorbed on the catalyst surface during the oxidation phase and were desorbed when only NO was flowing through the reactor. Diffuse reflectance infrared Fourier transform spectroscopy studies showed NO3- as the main adsorbed nitrogen oxide specimen on the surface. The amount of adsorbed nitrogen oxide species increased with the increasing fraction of NO2 in the gas phase and was inversely proportional with the gas-phase NO concentration. An important finding was the abrupt increase in the nitrogen oxide adsorption capacity of TiO2 when the inlet concentration of ozone became sufficiently large to oxidize NO x to N2O5. On the basis of the results, a model of the surface processes is proposed, involving the production of NO3 and N2O5 on the surface of TiO2. PMID- 29762036 TI - Biochemical Profiling of the Brain and Blood Metabolome in a Mouse Model of Prodromal Parkinson's Disease Reveals Distinct Metabolic Profiles. AB - Parkinson's disease is the second most common neurodegenerative disease. In the vast majority of cases the origin is not genetic and the cause is not well understood, although progressive accumulation of alpha-synuclein aggregates appears central to the pathogenesis. Currently, treatments that slow disease progression are lacking, and there are no robust biomarkers that can facilitate the development of such treatments or act as aids in early diagnosis. Therefore, we have defined metabolomic changes in the brain and serum in an animal model of prodromal Parkinson's disease. We biochemically profiled the brain tissue and serum in a mouse model with progressive synucleinopathy propagation in the brain triggered by unilateral injection of preformed alpha-synuclein fibrils in the olfactory bulb. In total, we accurately identified and quantified 71 metabolites in the brain and 182 in serum using 1H NMR and targeted mass spectrometry, respectively. Using multivariate analysis, we accurately identified which metabolites explain the most variation between cases and controls. Using pathway enrichment analysis, we highlight significantly perturbed biochemical pathways in the brain and correlate these with the progression of the disease. Furthermore, we identified the top six discriminatory metabolites and were able to develop a model capable of identifying animals with the pathology from healthy controls with high accuracy (AUC (95% CI) = 0.861 (0.755-0.968)). Our study highlights the utility of metabolomics in identifying elements of Parkinson's disease pathogenesis and for the development of early diagnostic biomarkers of the disease. PMID- 29762037 TI - Growth Rate and Cross-Linking Kinetics of Poly(divinyl benzene) Thin Films Formed via Initiated Chemical Vapor Deposition. AB - Initiated chemical vapor deposition (iCVD) allows for the formation of highly cross-linked, polymer thin films on a variety of substrates. Here, we study the impact of substrate stage temperature and filament temperature on the deposition and cross-linking characteristics of iCVD from divinyl benzene. Maintaining a constant monomer surface concentration reveals that deposition rates upward of 15 nm/min can be achieved at substrate stage temperatures of 50 degrees C. The degree of cross-linking is limited by the rate of initiation of the pendant vinyl bonds. At a filament temperature of 200 degrees C, the pendant vinyl bond conversion is highly sensitive to the surface concentration of initiator radicals. A significant decrease of the pendant vinyl bond conversion is observed with increasing stage temperatures. At higher filament temperatures, the pendant vinyl bond conversion appears to plateau at approximately 50%. However, faster deposition rates yield lower conversion. This trade-off is mitigated by increasing the filament temperature to increase initiator radical production. A higher flux of initiator radicals toward the surface at a constant deposition rate increases the rate of initiation of pendant vinyl bonds and therefore their overall conversion. At a deposition rate of ~7 nm/min, an increase in the filament temperature from 200 to 240 degrees C results in an 18% increase in the pendant vinyl bond conversion. PMID- 29762038 TI - Total Synthesis of the Marine Macrolide Amphidinolide F. AB - A new and efficient convergent approach toward the synthesis of amphidinolide F is described through the assembly of three fragments. The two trans tetrahydrofurans were built by a diastereoselective C-glycosylation with titanium enolate of bulky N-acetyloxazolidinethiones. The side chain was inserted by a Liebeskind-Srogl cross-coupling reaction. A sulfone condensation/desulfonylation sequence, a Stille cross-coupling, and a macrolactonization were applied to connect the fragments. PMID- 29762039 TI - Lewis Base/Bronsted Acid Dual-Catalytic C-H Sulfenylation of Aromatics. AB - A Lewis base/Bronsted acid catalyzed aromatic sulfenylation is reported. These studies demonstrated that the incorporation of electron-rich sulfenyl groups proceeded in the absence of a Lewis base, with kinetic studies indicating an autocatalytic mechanism. The incorporation of electron-poor sulfenyl groups demonstrated little autocatalysis necessitating the use of a Lewis base. This method proved amenable to diverse arenes and heterocycles and was effective in the context of the late-stage functionalization of biologically active small molecules. PMID- 29762040 TI - Orally Bioavailable and Effective Buparvaquone Lipid-Based Nanomedicines for Visceral Leishmaniasis. AB - Nanoenabled lipid-based drug delivery systems offer a platform to overcome challenges encountered with current failed leads in the treatment of parasitic and infectious diseases. When prepared with FDA or EMA approved excipients, they can be readily translated without the need for further toxicological studies, while they remain affordable and amenable to scale-up. Buparvaquone (BPQ), a hydroxynapthoquinone with in vitro activity in the nanomolar range, failed to clinically translate as a viable treatment for visceral leishmaniasis due to its poor oral bioavailability limited by its poor aqueous solubility (BCS Class II drug). Here we describe a self-nanoemulsifying system (SNEDDS) with high loading and thermal stability up to 6 months in tropical conditions and the ability to enhance the solubilization capacity of BPQ in gastrointestinal media as demonstrated by flow-through cell and dynamic in vitro lipolysis studies. BPQ SNEDDS demonstrated an enhanced oral bioavailability compared to aqueous BPQ dispersions (probe-sonicated), resulting in an increased plasma AUC0-24 by 55% that is 4-fold higher than any previous reported values for BPQ formulations. BPQ SNEDDS can be adsorbed on low molecular glycol chitosan polymers forming solid dispersions that when compressed into tablets allow the complete dissolution of BPQ in gastrointestinal media. BPQ SNEDDS and BPQ solid SNEDDS demonstrated potent in vitro efficacy in the nanomolar range (<37 nM) and were able to near completely inhibit parasite replication in the spleen while also demonstrating 48 +/- 48 and 56 +/- 23% inhibition of the parasite replication in the liver, respectively, compared to oral miltefosine after daily administration over 10 days. The proposed platform technology can be used to elicit a range of cost effective and orally bioavailable noninvasive formulations for a range of antiparasitic and infectious disease drugs that are needed for closing the global health innovation gap. PMID- 29762041 TI - Drainage from a Fluid-Handling Component Due to Centrifugal Acceleration. AB - The onset of drainage of liquids from plastic tubes was evaluated. One end of the tubes was plugged, filled with liquid, oriented horizontally, and attached to a rotor. With their open end facing outward, the filled tubes were spun at progressively higher speeds until they began to drain. Resistance to drainage was independent of the tube length, but depended on the surface tension and density of the liquids as well as the diameter and wettability of the tubing. We found that the onset of drainage could be explained in terms of a critical centrifugal acceleration. PMID- 29762042 TI - Interpreting the Ultraviolet Absorption in the Spectrum of 415 nm-Bandgap CdSe Magic-Size Clusters. AB - Colloidal semiconductor magic-size clusters (MSCs), a crucial link between molecular and bulk materials, have attracted attention in the past three decades. However, the identification of their nonbandgap electronic transitions via optical absorption has been challenging due to the possible presence of other bandgap ensembles in synthetic batches. For CdSe MSC-415, referred to as the optical absorption (1S(e)-1S3/2(h)) in nanometers of wavelength, we report our exploration on the origin of two commonly documented absorption peaks at 381 and 351 nm. We show that the evolution of the two peaks does not synchronize with that of the ~415 nm peak and seems to be respectively related to the disappearance of MSC-391 and MSC-361. Accordingly, these two peaks detected are probably not due to higher order electronic transitions in MSC-415. The present study shows the necessity of re-evaluating previous experimental results and of developing advanced theoretical models to better understand the quantized energy levels of MSCs. PMID- 29762044 TI - The International Society for Biological and Environmental Repositories Presents Abstracts from Its Annual Meeting Thinking BIG in TEXAS: Seizing BIG Opportunities in Biobanking Through Data, Collaboration, and Innovation May 20 24, 2018 Dallas, Texas. PMID- 29762046 TI - Effects of calcimimetics on long-term outcomes in dialysis patients: literature review and Bayesian meta-analysis. AB - AIM: Randomized controlled trials (RCTs) with clinical outcomes are considered the gold standard for regulatory approval. However, by design they are only able to answer a small number of clinical questions. Other high-quality studies are required for clinical decision-making. The EVOLVE was the largest RCT, evaluating the effects of cinacalcet on clinical outcomes among adult patients receiving maintenance dialysis suffering from secondary hyperparathyroidism. While the EVOLVE trial did not reach its primary end point, imbalance in subjects' age at randomization and discontinuation rates are two of the reasons that the lack of mortality benefit is in question. We undertook a systematic literature review and Bayesian meta-analysis combining randomized and observational studies on the estimated effects of the oral calcimimetic cinacalcet on clinical outcomes including all-cause mortality, cardiovascular-related mortality, hospitalization for cardiovascular events, fracture and parathyroidectomy among patients on maintenance dialysis. METHODS: Data sources included MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases. RCTs and observational studies were included. Data extraction was completed by two authors independently and in duplicate determined the methodological quality of the studies and extracted data. RESULTS: Of 564 unique citations identified, 16 studies were included: six observational studies and ten RCTs. Four high-quality studies (two observational and two RCTs) were deemed suitable for meta-analysis. Results indicated a statistically significant reduction in the risk of death associated with cinacalcet (hazard ratio: 0.83; 95% credible interval: 0.78-0.89). CONCLUSION: The results of this meta-analysis indicate that treatment of secondary hyperparathyroidism with calcimimetic therapy may in fact reduce mortality among patients receiving maintenance dialysis. This finding provides justification for a well-designed and adequately powered randomized trial to definitively address the question. PMID- 29762043 TI - Effects of Fish Oil on HIV-Related Inflammation and Markers of Immunosenescence: A Randomized Clinical Trial. AB - OBJECTIVE: To explore the safety and efficacy of fish oil to modulate parameters of inflammation and immunosenescence in HIV-infected older adults. DESIGN: This study uses a randomized, controlled, double-blind clinical trial. SETTING: The study was conducted in an outpatient HIV/AIDS clinic in a large urban Midwestern city in the United States. SUBJECTS: A total of 37 clinically stable HIV-infected adults between the ages of 40 and 70 years of age participated. INTERVENTIONS: Fish oil 1.6 g/day was administered for 12 weeks or placebo. OUTCOME MEASURES: Inflammatory cytokine production, surface markers of immunosenescence, and adverse events were measured. RESULTS: After 12 weeks of supplementation, there were no significant differences between the treatment and control groups on any measures of inflammation or immunosenescence in both CD4+ and CD8+ T lymphocytes. More participants in the treatment group reported adverse gastrointestinal events compared with the control group. CONCLUSIONS: A 12-week supplementation regimen of 1.6 g/day of fish oil did not favorably modulate parameters of inflammation or immune senescence in HIV-infected adults. Future studies should test agents that directly target mechanisms that underlie HIV-related inflammation to determine whether reducing inflammation can reverse immunosenescence. PMID- 29762049 TI - ISBER 2018 Abstract Category Index. PMID- 29762048 TI - Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen. AB - Alterations at the molecular level are a hallmark of cancer. Prostate cancer is associated with the overexpression of prostate-specific membrane antigen (PSMA) in a majority of cases, predominantly in advanced tumors, increasing with the grade or Gleason's score. PSMA can be selectively targeted using radiolabeled PSMA ligands. These small molecules binding the PSMA can be radiolabeled with gamma-emitters like 99mTc and 111In or positron emitters like 68Ga and 18F for diagnosis as well as with their theranostic pairs such as 177Lu (beta-emitter) or 225Ac (alpha-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology. PMID- 29762051 TI - Late Breaking Abstracts. PMID- 29762047 TI - Imaging of suspected pulmonary embolism and deep venous thrombosis in obese patients. AB - Obesity is a growing problem around the world, and radiology departments frequently encounter difficulties related to large patient size. Diagnosis and management of suspected venous thromboembolism, in particular deep venous thrombosis (DVT) and pulmonary embolism (PE), are challenging even in some lean patients, and can become even more complicated in the setting of obesity. Many obstacles must be overcome to obtain imaging examinations in obese patients with suspected PE and/or DVT, and to ensure that these examinations are of sufficient quality to diagnose or exclude thromboembolic disease, or to establish an alternative diagnosis. Equipment limitations and technical issues both need to be acknowledged and addressed. Table weight limits and scanner sizes that readily accommodate obese and even morbidly obese patients are not in place at many clinical sites. There are also issues with image quality, which can be substantially compromised. We discuss current understanding of the effects of patient size on imaging in general and, more specifically, on the imaging modalities used for the diagnosis and treatment of DVT and PE. Emphasis will be placed on the technical parameters and protocol nuances, including contrast dosing, which are necessary to refine and optimize images for the diagnosis of DVT and PE in obese patients, while remaining cognizant of radiation exposure. More research is necessary to develop consistent high-level evidence regarding protocols to guide radiologists, and to help them effectively utilize emerging technology. PMID- 29762050 TI - Dl-3-N-butylphthalide attenuates ischemic reperfusion injury by improving the function of cerebral artery and circulation. AB - Dl-3-N-butylphthalide (NBP) is approved in China for the treatment of ischemic stroke. Previous studies have shown that NBP promotes recovery after stroke via multiple mechanisms. However, the effect of NBP on vascular function and thrombosis remains unclear. Here, we aim to study the effect of NBP on vascular function using a rat model of transient middle cerebral artery occlusion (MCAO) and a state-of-the-art high-resolution synchrotron radiation angiography. Eighty SD rats underwent MCAO surgery. NBP (90 mg/kg) was administrated daily by gavage. Synchrotron radiation angiography was used to evaluate the cerebral vascular perfusion, vasoconstriction, and vasodilation in real-time. Neurological scores, brain infarction and atrophy were evaluated. Real-time PCR was used to assess the expression levels of thrombosis and vasoconstriction-related genes. Results revealed that NBP attenuated thrombosis after MCAO and reduced brain infarct and atrophy volume. NBP administrated at 1 and 4 h after MCAO prevented the vasoconstriction of the artery and maintained its diameter at normal level. Administrated at one week after surgery, NBP functioned as a vasodilator in rats after MCAO while displayed no vasodilating effect in sham group. Our results suggested that NBP attenuates brain injury via increasing the regional blood flow by reducing thrombosis and vasoconstriction. PMID- 29762053 TI - Factors Associated with Salmonella Prevalence in U.S. Swine Grower-Finisher Operations, 2012. AB - Nontyphoidal Salmonella is an important foodborne pathogen with diverse serotypes occurring in animal and human populations. The prevalence of the organism on swine farms has been associated with numerous risk factors, and although there are strong veterinary public health controls for preventing Salmonella from entering food, there remains interest in eradicating or controlling the organism in the preharvest environment. In this study, using data collected via the U.S. Department of Agriculture (USDA) National Animal Health Monitoring System Swine 2012 study, we describe nontyphoidal Salmonella and specific serotype prevalence on U.S. grower-finisher swine operations and investigate associations between Salmonella detection and numerous factors via multiple correspondence analysis (MCA) and regression analysis. MCA plots, complementary to univariate analyses, display relationships between covariates and Salmonella detection at the farm level. In the univariate analysis, Salmonella detection varied with feed characteristics and farm management practices, reports of diseases on farms and vaccinations administered, and administration of certain antimicrobials. Results from the univariate analysis reinforce the importance of biosecurity in managing diseases and pathogens such as Salmonella on farms. All multivariable regression models for the likelihood of Salmonella detection were strongly affected by multicollinearity among variables, and only one variable, pelleted feed preparation, remained in the final model. The study was limited by its cross sectional nature, timelines of data collection, and reliance on operator-reported data via a convenience sample. PMID- 29762052 TI - Effects of Physical Exercise on Adiponectin, Leptin, and Inflammatory Markers in Childhood Obesity: Systematic Review and Meta-Analysis. AB - BACKGROUND: New findings on adipose tissue physiology and obesity-associated inflammation status suggest that modification of the adipokine level can be relevant for the long-term prevention of obesity-associated chronic disease. OBJECTIVES: The scope of the present study was to investigate the effectiveness of physical exercise in reducing the systemic inflammation related to obesity in children. METHODS: We conducted a systematic review with meta-analysis of controlled randomized trials, identified through electronic database search, which investigated the effect of physical exercise, without concomitant dietary intervention, on adiponectin, leptin, and/or other inflammatory markers in children up to age 18 years with a body mass index greater than the 95th percentile for age and sex. RESULTS: Seven trials were included in the meta analysis, with a total of 250 participants. Compared with the control group without any lifestyle modification, the physical exercise resulted in a reduction in leptin [standardized mean difference (SMD) -1.13; 95% confidence interval (95%CI): -1.89 to -0.37; I2 = 79.9%] and interleukin-6 (SMD -0.84; 95%CI: -1.45 to -0.23, I2 = 0.9%) and an increase in adiponectin plasma concentration (SMD 0.69; 95%CI: 0.02-1.35; I2 = 74.3%). CONCLUSIONS: These results indicate that physical exercise improved the inflammatory state in children with obesity. It is unclear whether this effect can reduce the risk of cardiovascular and metabolic disease in adulthood. Clinical trials with a uniform intervention protocol and outcome measurements are required to put our knowledge on adipose tissue biology into a clinical perspective. PMID- 29762054 TI - Altered sarco(endo)plasmic reticulum calcium adenosine triphosphatase 2a content: Targets for heart failure therapy. AB - Sarco(endo)plasmic reticulum calcium adenosine triphosphatase is responsible for transporting cytosolic calcium into the sarcoplasmic reticulum and endoplasmic reticulum to maintain calcium homeostasis. Sarco(endo)plasmic reticulum calcium adenosine triphosphatase is the dominant isoform expressed in cardiac tissue, which is regulated by endogenous protein inhibitors, post-translational modifications, hormones as well as microRNAs. Dysfunction of sarco(endo)plasmic reticulum calcium adenosine triphosphatase is associated with heart failure, which makes sarco(endo)plasmic reticulum calcium adenosine triphosphatase a promising target for heart failure therapy. This review summarizes current approaches to ameliorate sarco(endo)plasmic reticulum calcium adenosine triphosphatase function and focuses on phospholamban, an endogenous inhibitor of sarco(endo)plasmic reticulum calcium adenosine triphosphatase, pharmacological tools and gene therapies. PMID- 29762055 TI - Evaluating the effect of increased pitch, iterative reconstruction and dual source CT on dose reduction and image quality. AB - OBJECTIVE: To compare radiation dose and image quality of thoracoabdominal scans obtained with a high-pitch protocol (pitch 3.2) and iterative reconstruction (Sinogram Affirmed Iterative Reconstruction) in comparison to standard pitch reconstructed with filtered back projection (FBP) using dual source CT. METHODS: 114 CT scans (Somatom Definition Flash, Siemens Healthineers, Erlangen, Germany), 39 thoracic scans, 54 thoracoabdominal scans and 21 abdominal scans were performed. Analysis of three protocols was undertaken; pitch of 1 reconstructed with FBP, pitch of 3.2 reconstructed with SAFIRE, pitch of 3.2 with stellar detectors reconstructed with SAFIRE. Objective and subjective image analysis were performed. Dose differences of the protocols used were compared. RESULTS: Dose was reduced when comparing scans with a pitch of 1 reconstructed with FBP to high pitch scans with a pitch of 3.2 reconstructed with SAFIRE with a reduction of volume CT dose index of 75% for thoracic scans, 64% for thoracoabdominal scans and 67% for abdominal scans. There was a further reduction after the implementation of stellar detectors reflected in a reduction of 36% of the dose length product for thoracic scans. This was not at the detriment of image quality, contrast-to-noise ratio, signal-to-noise ratio and the qualitative image analysis revealed a superior image quality in the high-pitch protocols. CONCLUSION: The combination of a high pitch protocol with iterative reconstruction allows significant dose reduction in routine chest and abdominal scans whilst maintaining or improving diagnostic image quality, with a further reduction in thoracic scans with stellar detectors. Advances in knowledge: High pitch imaging with iterative reconstruction is a tool that can be used to reduce dose without sacrificing image quality. PMID- 29762058 TI - Palliative Care for People with Respiratory Disease or Critical Illness. PMID- 29762056 TI - Fracture of ankle: MRI using opposed-phase imaging obtained from turbo spin echo modified Dixon image shows improved sensitivity. AB - OBJECTIVE: To evaluate if opposed-phase (OP) imaging obtained from the turbo spin echo (TSE) modified Dixon (mDixon) technique can increase the sensitivity of MRI for diagnosing ankle fractures. METHODS: This study included 95 CT-confirmed ankle fractures with additional MRI of the ankle using a TSE modified Dixon (mDixon) technique. Two groups of images were analyzed independently: Group 1 imaging group without OP imaging; Group 2-imaging group with OP imaging. Readers assessed the images using a 4-point confidence score to detect fractures. During the first review session, the fracture site was blinded. For the second review session, the fracture site was provided. Sensitivity and positive-predictive value were calculated. RESULTS: In both sessions, the sensitivity for Group 2 was significantly greater than that for Group 1 (Session 1: 76.3% vs 62.6%, p < 0.0001; Session 2: 80.5% vs 65.3%, p < 0.0001). The positive-predictive value of Group 2 was significantly lower in both sessions 1 and 2 (Session 1: 85.8% vs 97.5%, p < 0.0001; Session 2: 90.5% vs 96.9%, p = 0.0068). Among the 28 false negative fractures missed in Group 1 (Session 1), 12 (9 minimal displaced and 4 small diameter fractures) were identified in Group 2 (Session 1). While 8.9% showed lower movement, 33.6% showed upper movement in Group 2 compared with Group 1. Possible causes of false-positive lesions were subcutaneous fat, bone marrow edema, and intraosseous vessel mimic fractures. CONCLUSION: OP imaging obtained using the modified Dixon technique provided better sensitivity and improved descriptions of fractures, especially for minimal displaced fractures and small diameter fractures. However, caution is required when diagnosing fractures with OP imaging because pseudofractures can appear as a result of adjacent bone marrow edema, vascular structures, or subcutaneous fat lobules. Advances in knowledge: In MRI, minimal displaced or small chip bone fracture maybe missed, OP imaging obtained using the mDixon technique provided better sensitivity and improved descriptions of fractures using the black boundary artifact. PMID- 29762062 TI - Stop Scrolling, Start Living: The Growing Reality of Internet Addiction Disorder. PMID- 29762057 TI - Comparison of image quality and radiation exposure between conventional imaging and gemstone spectral imaging in abdominal CT examination. AB - OBJECTIVE: To compare patients' image quality and radiation exposure between gemstone spectral imaging (GSI) with rapid kV switching technique and conventional polychromatic imaging (CPI) performed in abdominal CT examinations. METHODS: Adult patients who were referred to abdominal CT from October 2015 to March 2016 were enrolled. Unenhanced CT with CPI mode and tri-phase (arterial/portal/delayed phase) contrast-enhanced scan with GSI mode were performed with different protocols respectively. Regions of interest (ROIs) were drawn on muscle and fat. Parametric results of the image noise, signal-to-noise ratio (SNR) and clinical image quality in these regions between the monochromatic images reconstructed at 65 keV and conventional polychromatic images were compared. Radiation dose was also compared between CPI and GSI. RESULTS: 43 patients were recruited. Compared to conventional imaging, the noise level was generally not significantly different between GSI images in arterial phase and portal phase, and significantly higher (around 10%) in delayed phase. The SNR of GSI in portal phase was significantly higher than that of conventional imaging, and was similar between arterial phase/delayed phase and conventional imaging. The clinical image quality between conventional imaging and GSI was generally not significantly different. The dose length product was reduced by 0.3-20.1% in GSI compared to conventional imaging. CONCLUSION: GSI reduces the radiation exposure slightly, however maintains or even improves image quality. These results may warrant the application of GSI in patients referred for abdominal CT. Advances in knowledge: Compared to CPI, GSI reduces the radiation exposure slightly, however maintains or even improves image quality in abdominal CT. These findings may warrant the application of GSI in patients referred for abdominal CT. PMID- 29762059 TI - Bullying and Suicidality in Urban Chinese Youth: The Role of Teacher-Student Relationships. AB - The aim of this study is to examine the link between bullying and the tendency toward suicide (suicidality). In particular, we tested the interaction effect of teacher-student relationships on the association between bullying and suicidality among urban youth in China. A total of 3,675 participants were recruited from 7 provinces in urban China. Three questions were used to capture suicidality related measures: suicide ideation, suicide planning, and attempting suicide. Traditional bullying and cyberbullying were used to measure the effect of being bullied. The results show that being bullied, traditionally or online, is significantly associated with suicidality. The interaction effect between traditional bullying and the teacher-student relationship for suicidal ideation is significant (odds ratio 1.34, 95% confidence interval 1.03-1.74). However, no significant interaction effects in teacher-student relationships have been found in the association between cyberbullying and suicidality. The results indicate that teacher-student relationships have a significant protective, but limited, effect on the relationship between bullying and suicidality. Future development of suicidality intervention strategies adapted to the development of society will be beneficial. PMID- 29762063 TI - Agency and Gender Influence Older Adults' Presence-Related Experiences in an Interactive Virtual Environment. AB - While virtual humans are increasingly used to benefit the elderly, considerably little is still known about older adults' virtual experiences. However, due to age-related changes, older adults' perceptions of virtual environments (VEs) may be unique. Hence, our objective was to examine possible gender differences in immersion, flow, and emotional states as well as physical and social presence in elderly males and females interacting either with a computer-controlled agent or a human-controlled avatar. Seventy-eight German-speaking older adults were randomly assigned to an avatar or an agent condition and were exposed to a brief social encounter in a virtual cafe. Results indicate no overall gender differences, but a significant effect of agency on social presence, physical presence, immersion, and flow. Participants in the avatar condition reported higher levels in all measures, except for involvement. Furthermore, significant gender * agency interactions were found, with females showing more social presence, spatial presence, and flow when interacting with a human-controlled avatar and more realism when conversing with an agent. Also, all participants showed significant changes in their affect post exposure. In sum, older adults' virtual experiences seem to follow unique patterns, yet, they do not preclude the elderly from successfully participating in VEs. PMID- 29762064 TI - Mobile Apps for Self-Injury: A Content Analysis. AB - A growing body of research points to the salience of the Internet and mobile material among individuals who self-injure. However, to date, no research has investigated the mobile apps related to nonsuicidal self-injury (NSSI). Such information would clarify which apps may be useful for those who self-injure while highlighting whether app-related content warrants improvement. The current study examined the content and usability of NSSI apps available on the two largest app-related platforms (Google Play and iTunes). Using content analysis, apps were examined regarding their content (e.g., presence of NSSI myths and types of coping strategies) as well as usability (e.g., app performance). Results indicate that NSSI apps have varied content, with few developed by, or affiliated with, a trusted source (e.g., university). NSSI apps tend to not propagate NSSI myths that vary with respect to the quality of coping strategies offered. They also tend to be rated favorably in terms of their usability. Overall, the present findings add to the NSSI literature and highlight several implications and avenues for future work, which are discussed. PMID- 29762065 TI - Reliability of the Arabic Smartphone Addiction Scale and Smartphone Addiction Scale-Short Version in Two Different Moroccan Samples. AB - The extensive accessibility to smartphones in the last decade raises the concerns of addictive behavior patterns toward these technologies worldwide and in developing countries, and Arabic ones in particular. In an area of stigmatized behavior such as Internet and smartphone addiction, the hypothesis extends to whether there is a reliable instrument that can assess smartphone addiction. To our knowledge, no scale in Arabic language is available to assess maladaptive behavior associated with smartphone use. This study aims to assess the factorial validity and internal reliability of the Arabic Smartphone Addiction Scale (SAS) and Smartphone Addiction Scale-Short Version (SAS-SV) in a Moroccan surveyed population. Participants (N = 440 and N = 310) completed an online survey, including SAS, SAS-SV, and questions about sociodemographic status. Factor analysis results showed six factors with factor loading ranging from 0.25 to 0.99 for SAS. Reliability, based on Cronbach's alpha, was excellent (alpha = 0.94) for this instrument. The SAS-SV showed one factor (unidimensional construct), and internal reliability was in the good range with an alpha coefficient of (alpha = 0.87). The prevalence of excessive users was 55.8 percent with highest symptom prevalence reported for tolerance and preoccupation. This study proved factor validity of the Arabic SAS and SAS-SV instruments and confirmed their internal reliability. PMID- 29762068 TI - Elevating Black Women in Contextually Relevant Ways: A Top Priority in Violence and HIV Prevention Work. PMID- 29762067 TI - Parenting and Cyberbullying Across Adolescence. AB - Cyberbullying perpetration continues to be a prevalent and harmful phenomenon. Despite the recent wealth of studies that examine cyberbullying frequency, further research is needed to investigate protective factors or variables that decrease the likelihood of engaging in cyberbullying perpetration. Past work has identified certain types of parenting as a potential protective factor against adolescent cyberbullying perpetration; however, there is a paucity of research testing these relations over time. This study explores parenting during early adolescence as predicting attitudes and behaviors associated with cyberbullying in late adolescence. Data were derived from the Flourishing Families Project (FFP) at Wave 2 (M age = 12) and Wave 9 (M age = 19). Results suggest that the authoritative parenting style-specifically the warmth and support dimension-was associated with less supportive attitudes toward cyberbullying and lower levels of cyberbullying in emerging adulthood. Moreover, particularly for boys, authoritarian parenting behaviors served as a risk factor for cyberbullying engagement. Suggestions are offered to advocate for greater positive parenting education during early adolescence as a potential protective factor against cyberbullying. PMID- 29762066 TI - The Role of Age on Multisensory Bodily Experience: An Experimental Study with a Virtual Reality Full-Body Illusion. AB - A growing body of evidence demonstrated that it is feasible to induce ownership over an artificial body to alter bodily experience. However, several uncharted aspects about full-body illusion applications need to be tackled before a complete exploitation of these methods in clinical practice. This work is devoted to explore possible individual age-related differences in shaping changes in body representations induced with a full-body illusion. A total of 40 women were divided into two different age groups according to the median of the variable age. Participants estimated the width of three different body parts (i.e., shoulders, abdomen, and hips) before the entire illusion was induced (baseline), and after the synchronous and the asynchronous conditions. Results revealed that 26-to-55-year-old participants were more resistant to changes induced by the bodily illusion, whereas 19-to-25-year-old participants underestimated their bodies after both conditions. The findings were discussed in terms of the literature exploring age differences in responses to bodily illusion, which could suggest a Bayesian mechanism underlying these individual differences. PMID- 29762070 TI - Developing a Palliative Care Competency Framework for Health Professionals and Volunteers: The Nova Scotian Experience. AB - BACKGROUND AND OBJECTIVES: In 2014, Nova Scotia released a provincial palliative care strategy and implementation working groups were established. The Capacity Building and Practice Change Working Group, comprised of health professionals, public advisors, academics, educators, and a volunteer supervisor, was asked to select palliative care education programs for health professionals and volunteers. The first step in achieving this mandate was to establish competencies for health professionals and volunteers caring for patients with life-limiting illness and their families and those specializing in palliative care. METHODS: In 2015, a literature search for palliative care competencies and an environmental scan of related education programs were conducted. The Irish Palliative Care Competence Framework serves as the foundation of the Nova Scotia Palliative Care Competency Framework. Additional disciplines and competencies were added and any competencies not specific to palliative care were removed. To highlight interprofessional practice, the framework illustrates shared and discipline-specific competencies. Stakeholders were asked to validate the framework and map the competencies to educational programs. Numerous rounds of review refined the framework. RESULTS: The framework includes competencies for 22 disciplines, 9 nursing specialties, and 4 physician specialties. CONCLUSIONS: The framework, released in 2017, and the selection and implementation of education programs were a significant undertaking. The framework will support the implementation of the Nova Scotia Integrated Palliative Care Strategy, enhance the interprofessional nature of palliative care, and guide the further implementation of education programs. Other jurisdictions have expressed considerable interest in the framework. PMID- 29762069 TI - A Common Variation in the Caveolin 1 Gene Is Associated with High Serum Triglycerides and Metabolic Syndrome in an Admixed Latin American Population. AB - BACKGROUND: The caveolin 1 (CAV1) gene has been associated with metabolic traits in animal models and human cohorts. Recently, a prevalent variant in CAV1 has been found to be related to metabolic syndrome in Hispanics living in North America. Since Hispanics represent an admixed population at high risk for cardiovascular diseases, in this study a Latin American population with a similar genetic background was assessed. OBJECTIVE: To analyze a genetic association between CAV1 and metabolic traits in an admixed Latin American population. METHODS: A cross-sectional study was carried out with adults from the Colombian Caribbean Coast, selected in urban clusters and work places through a stratified sampling to include diverse ages and socioeconomic groups. Blood pressure and waist circumference were registered. Serum concentrations of glucose, triglycerides, and high-density lipoprotein cholesterol were measured from an 8 hr fasting whole-blood sample. Two previously analyzed CAV1 single nucleotide polymorphisms were genotyped (rs926198 and rs11773845). A logistic regression model was applied to estimate the associations. An admixture adjustment was performed through a Bayesian model. RESULTS: A total of 605 subjects were included. rs11773845 was associated with hypertriglyceridemia [odds ratio (OR) = 1.33, p = 0.001] and the metabolic syndrome (OR = 1.53, p = 0.02). When admixture adjustment was performed these genetic associations preserved their statistical significance. There were no significant associations between rs926198 and metabolic traits. CONCLUSIONS: The CAV1 variation rs11773845 was found to be consistently associated with high serum triglycerides and the metabolic syndrome. This is the first report of a relationship between CAV1 variants and serum triglycerides in Latin America. PMID- 29762071 TI - VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption. AB - Melanoma is the most aggressive skin cancer in humans. One severe complication is the formation of brain metastasis, which requires extravasation of melanoma cells across the tight blood-brain barrier (BBB). Previously, VLA-4 has been assigned a role for the adhesive interaction of melanoma cells with non-BBB endothelial cells. However, the role of melanoma VLA-4 for breaching the BBB remained unknown. In this study, we used a mouse in vitro BBB model and imaged the shear resistant arrest of melanoma cells on the BBB. Similar to effector T cells, inflammatory conditions of the BBB increased the arrest of melanoma cells followed by a unique post-arrest behavior lacking immediate crawling. However, over time, melanoma cells intercalated into the BBB and compromised its barrier properties. Most importantly, antibody ablation of VLA-4 abrogated melanoma shear resistant arrest on and intercalation into the BBB and protected the BBB from barrier breakdown. A tissue microarray established from human brain metastasis revealed that indeed a majority of 92% of all human melanoma brain metastases stained VLA-4 positive. We propose VLA-4 as a target for the inhibition of brain metastasis formation in the context of personalized medicine identifying metastasizing VLA-4 positive melanoma. PMID- 29762072 TI - Healthcare Users' Experiences of Communicating with Healthcare Professionals About Children Who Have Life-Limiting Conditions: A Qualitative Systematic Review. AB - BACKGROUND: Globally, an estimated eight million children could benefit from palliative care each year. Effective communication about children with life limiting conditions is well recognized as a critical component of high-quality pediatric palliative care. OBJECTIVE: To synthesize existing qualitative research exploring healthcare users' experiences of communicating with healthcare professionals about children with life-limiting conditions. DESIGN: The results of a systematic literature search were screened independently by two reviewers. Raw data and analytic claims were extracted from included studies and were synthesized using thematic analysis methods for systematic reviews. DATA SOURCES: MEDLINE, PubMed, CINAHL, Embase, PsycINFO, Scopus, Web of Science, ProQuest, and ScienceDirect were searched for articles published in English between 1990 and May 2017. RESULTS: This review included 29 studies conducted across 11 countries and involving at least 979 healthcare users (adults [n = 914], patients [n = 25], and siblings [n = 40]). The four domains of communication experience identified through thematic synthesis are: Information, Emotion, Collaboration, and Relationship. Although included studies were from a range of settings and diverse populations, further research is needed to explore whether and how domains of communication experience differ across settings and populations. In particular, further research about children's palliative care experiences is needed. CONCLUSIONS: Healthcare users typically value communication with healthcare professionals: that (1) is open and honest, (2) acknowledges emotion, (3) actively involves healthcare users, and (4) occurs within established and trusting relationships. PMID- 29762073 TI - The Association of Socioeconomic Status with Severity of Glaucoma and the Impacts of Both Factors on the Costs of Glaucoma Medications: A Cross-Sectional Study in West Bengal, India. AB - PURPOSE: To evaluate the association of socioeconomic status (SES) with severity of glaucoma and assess the impacts of both SES and disease-severity factors on the costs of glaucoma medications among different glaucoma subtypes in West Bengal, India. METHODS: This cross-sectional study (2014-16) followed the treatment of 304 primary glaucoma patients for at least 18 months. The visual field based glaucoma staging was followed for stages 0-3; patients with field of vision <10 degrees were categorized as stage 4 (end stage). We checked only the mean cost of glaucoma medications per patient and not "direct costs." The individuals' monthly incomes were classified into: low, moderate, and higher SES. RESULTS: Urban residence (odds ratio [OR] 0.6, P < 0.009), higher SES (OR 0.3, P < 0.001), and higher awareness (nearly 50%, P < 0.007) significantly lowered the odds of having end-stage glaucoma. Sixty-nine percent primary angle-closure glaucoma (PACG) and 79% juvenile open-angle glaucoma (JOAG) belonged to low SES, forming the bulk of end-stage glaucoma. Overall medical cost from stage 0 to advanced stage in all subtypes rises except in primary open-angle glaucoma (POAG). Only 28% eyes from low SES were treated with branded drugs in early disease and that too declined to 16% in stage 4, while 57% higher SES used branded medications in early disease stage. Expenditure as a percent of income was the highest in JOAG (16%) followed by PACG (15%) and POAG (14%) among low SES. CONCLUSIONS: Results indicate SES influences on disease outcome, the clinical management, and the glaucoma medication expenses in West Bengal. Medical costs of glaucoma increase with worsening disease severity; greater use of generic drugs does not always ensure direct cost savings. PMID- 29762074 TI - Use of Artificial Hydration at the End of Life: A Survey of Australian and New Zealand Palliative Medicine Doctors. AB - BACKGROUND: Dying is ubiquitous, yet the optimal management of hydration in the terminal phase is undetermined. Palliative care (PC) doctors' practices may act as a de facto measure of the benefits and burdens of artificial hydration (AH) use. OBJECTIVE: To identify PC doctors' AH prescribing practices for imminently dying patients and possible influencing factors. METHODS: An online survey of doctors belonging to the Australian and New Zealand Society of Palliative Medicine. RESULTS: One hundred and thirty-six surveys were completed (30% response rate). AH use for patients in the prognosticated last week of life was low: 77% of respondents prescribed AH to 0-10% of patients and 3% of respondents prescribed to more than 20%. The most common reason for prescribing AH was palliation of family/patient concern rather than a physical symptom. The majority thought there was no effect of AH on survival, or on symptoms of fatigue (90%), reduced level of consciousness (88%), agitation (75%), nausea (69%), vomiting (68%), myoclonus (66%), thirst (65%), delirium (62%), cough (57%), or bowel obstruction (50%). AH was thought to worsen subcutaneous edema (94%), upper respiratory tract secretions (85%), ascites (73%), physical discomfort (72%), dyspnea (62%), and urinary symptoms (57%). CONCLUSION: PC doctors from Australia and New Zealand reported lower use of AH for dying patients compared to international counterparts. The study showed high concordance in respondents' opinions: most thought AH was unlikely to provide clinical benefit and might cause harm. Further studies are needed to determine best practice of AH use at the end of life. PMID- 29762075 TI - Predicting Length of Hospice Stay: An Application of Quantile Regression. AB - BACKGROUND: Use of the Medicare hospice benefit has been associated with high quality care at the end of life, and hospice length of use in particular has been used as a proxy for appropriate timing of hospice enrollment. Quantile regression has been underutilized as an alternative tool to model distributional changes in hospice length of use and hospice payments outside of the mean. OBJECTIVE: To test for heterogeneity in the relationship between patient characteristics and hospice outcomes across the distribution of hospice days. SETTING: Medicare Beneficiary Summary File and survey data (2014) for hospice beneficiaries in North and South Carolina with common terminal diagnoses. MEASUREMENTS: Distributional shifts associated with patient characteristics were evaluated at the 25th and 75th percentiles of hospice days and hospice payments using quantile regressions and compared to the mean shift estimated by ordinary least squares (OLS) regression. PRINCIPAL FINDINGS: Significant (p < 0.001) heterogeneity in the marginal effects on hospice days and costs was observed, with patient characteristics associated with generally larger shifts in the 75th percentile than the 25th percentile. Mean effects estimated by OLS regression overestimate the magnitude of the median marginal effects for all patient characteristics except for race. Results for hospice payments in 2014 were similar. CONCLUSIONS: Methodological decisions can have a meaningful impact in the evaluation of factors influencing hospice length of use or cost. PMID- 29762077 TI - Impact of the 2017 revisions to McDonald criteria on the diagnosis of multiple sclerosis. PMID- 29762076 TI - The Degeneration of the Vestibular Efferent Neurons After Intratympanic Gentamicin Administration. AB - Intratympanic gentamicin (ITG) has been used to treat refractory Meniere's disease. Disequilibrium after ITG was still a challenge for some patients, and the underlying mechanism is poorly understood. Our previous study demonstrated that gentamicin distributed in the bilateral vestibular efferent neurons (VEN) after ITG; however, does it lead to VEN damage and cause further disequilibrium in patients following ITG? In this study, we observed severe damaged gentamicin positive neurons of VEN and severe fractured myelin layer plates around neural fibers when viewed under transmission electron microscopy at day 3 after ITG. At day 30, neurons of VEN presented with relatively normal structures. Compared with the control group, the total number of choline acetyltransferase (CHAT) immunolabeling neurons in bilateral VEN showed a significant decrease both at day 3 and day 30. However, there was no significant difference in the total number of CHAT immunolabeling neurons between day 3 and day 30. It indicates that gentamicin is not only retrogradely transported into bilateral VEN, but also results in the degeneration of VEN after ITG. These findings may be related to patients' disequilibrium symptom after ITG. Furthermore, we speculate that VEN may play a role in vestibular compensation. PMID- 29762078 TI - Resveratrol Promoted Interferon-alpha-Induced Growth Inhibition and Apoptosis of SMMC7721 Cells by Activating the SIRT/STAT1. AB - Interferon-alpha (IFN-alpha) resistance is a major hurdle in the treatment of hepatocellular carcinoma (HCC). Signal transducers and activators of transcription 1 (STAT1) play a key role in exerting the antiproliferative and proapoptotic effects of IFN-alpha on tumors. In this study, we aimed to investigate whether resveratrol can promote IFN-alpha-induced growth inhibition and the apoptosis on HCC cells through the SIRT/STAT1 pathway. We found that IFN alpha induced growth inhibition and apoptosis of SMMC7721 cells, and the effects could be significantly enhanced and blocked by resveratrol and EX527, respectively. Resveratrol not only activated SIRT1 but also induced phosphorylation of STAT1. Further study revealed that ablation of STAT1 reduced the combined antitumor effects of IFN-alpha and resveratrol, lowered the rate of apoptosis, and improved the viability of SMMC7721 cells. Whereas STAT1 overexpression strengthened the combined antitumor effects of resveratrol and IFN alpha. Our findings suggest a novel strategy of using resveratrol to enhance the response of HCC to IFN-alpha treatment through the SIRT/STAT1 pathway. PMID- 29762079 TI - Does reducing food losses and wastes in sub-Saharan Africa make economic sense? AB - Reducing food losses and waste (FLW) is one of the sustainable ways of closing the food requirement gap in developing countries. However, there is not yet adequate knowledge on the extent of FLW by commodity type and stage of the food supply chain (FSC). Focusing on ten agrarian countries in Africa and building mainly on the Food and Agriculture Organization's Food Balance Sheets (FBSs), this study generates some new insights on the level of FLW by country, FSC and food type. Across the FSC, we find that these countries lose a cumulative amount equivalent to 28% (641 kilocalories per capita per day - kcal/cap/day) of the current calorie intake. Within the FSC, the production and post-harvest handling stages contribute the greater shares of the total losses with 38% or 244 kcal/cap/day and 34% or 218 kcal/cap/day, respectively. Our results also show that farm incomes would increase by 20% if the avoidable losses and waste were recovered. These results are troublesome given the level of poverty and food insecurity in these countries and suggest inefficient and unsustainable use of natural resources (water and cropland) associated with the FSC losses. PMID- 29762080 TI - Molecular Identification of Hysterothylacium spp. In Fishes From the Southern Mediterranean Sea (Southern Italy). AB - Samples obtained from 11 teleost fish species collected in waters off of the Mediterranean coasts of Sicily, Italy, were examined for the presence of Hysterothylacium spp. larvae. In total, 3,017 fish samples were examined, and the larvae recovered were used in subsequent phylogenetic studies. Fifty-eight raphidascaridid parasitic nematodes were found in the examined fish, with prevalence values ranging from 0.2% in anchovies to 60% in forkbeard samples. Twenty-seven parasites were identified as Hysterothylacium fabri and Hysterothylacium aduncum by sequencing the following regions: the nuclear ribosomal internal transcribed spacer ( ITS) and the mitochondrial cytochrome c oxidase subunit II ( COXII). Two other larvae collected from Lophius piscatorius had very low identity scores, with ITS and COXII sequences reported in GenBank and high genetic distances (AY603539). Pairwise comparisons between the ITS region of the H. fabri isolated from fishes from Sicilian coastal waters and those isolated from the Mediterranean Sea, Turkey (KC852206), revealed genetic differences ranging from 0.015 to 0.018. Our H. aduncum samples had very low genetic differences to H. aduncum from the Adriatic Sea (KP979763, 0.00-0.003). The concatenated phylogenetic examination of the ITS- COXII sequences by using maximum likelihood analyses indicated 3 distinct clades supported by high bootstrap values. Further molecular identification and detailed morphological analyses are needed to clarify these results and confirm the diversity and relationships within Hysterothylacium. PMID- 29762081 TI - Reliability and acceptability of the Multiple Sclerosis Quality of Life-29 questionnaire in an English-speaking cohort. AB - BACKGROUND: Multiple Sclerosis Quality-of-Life Questionnaire-54 (MSQoL-54) is a disease-specific instrument for assessing health-related quality of life (HRQoL). Due to the number of items, the time taken to complete it is long. A shorter 29 item version, Multiple Sclerosis Quality-of-Life Questionnaire-29 (MSQoL-29) is yet to be evaluated in English. OBJECTIVE: To assess reliability and acceptability of English version of MSQoL-29. METHODS: Among 100 participants with MS who first completed both MSQoL-54 and MSQoL-29, 91 completed MSQoL-29 after 4-8 weeks. We looked for internal consistency (Cronbach's alpha), acceptability, reliability (intraclass correlation coefficients (ICCs)) and agreement (Bland-Altman plots). RESULTS: ICCs were strongly positive between MSQoL-54 and MSQoL-29 (Physical Health Composite (PHC) -ICC = 0.914, confidence interval (CI) = 0.872-0.942; Mental Health Composite (MHC) - ICC = 0.875, CI = 0.814-0.916) and between the two MSQoL-29 (PHC - ICC = 0.970, CI = 0.955-0.980; MHC - ICC = 0.937, CI = 0.904-0.958). On Bland-Altman plots, the MSQoL-29 scores of 95% of participants during two visits were within the limits of agreement (LOAs). Time taken to complete MSQoL-29 was 7.2 +/- 2.9 minutes and MSQoL-54 was 19.79 +/- 5.4 minutes ( p = 0.0001). CONCLUSION: MSQoL-29 has good test-retest reliability in English-speaking population and was quicker to complete. PMID- 29762082 TI - Predicting and Optimizing Microswimmer Performance from the Hydrodynamics of Its Components: The Relevance of Interactions. AB - Interest in the design of bioinspired robotic microswimmers is growing rapidly, motivated by the spectacular capabilities of their unicellular biological templates. Predicting the swimming speed and efficiency of such devices in a reliable way is essential for their rational design, and to optimize their performance. The hydrodynamic simulations needed for this purpose are demanding and simplified models that neglect nonlocal hydrodynamic interactions (e.g., resistive force theory for slender, filament-like objects that are the typical propulsive apparatus for unicellular swimmers) are commonly used. We show through a detailed case study of a model robotic system consisting of a spherical head powered by a rotating helical flagellum that (a) the errors one makes in the prediction of swimming speed and efficiency by neglecting hydrodynamic interactions are never quite acceptable and (b) there are simple ways to correct the predictions of the simplified theories to make them more accurate. We also formulate optimal design problems for the length of the helical flagellum giving maximal energetic efficiency, maximal distance traveled per motor turn, or maximal distance traveled per unit of work expended, and exhibit optimal solutions. PMID- 29762083 TI - Independent Risk Factors for the Shivering Occurrence During Induction Period in Out-of-Hospital Cardiac Arrest Survivors Treated with Targeted Temperature Management. AB - The occurrence of shivering during the induction period of targeted temperature management (TTM) remains a therapeutic obstacle, which delays the achievement of target temperature. The aim of this study was to identify risk factors leading to shivering during the induction period. We analyzed a prospective cohort of adult out-of-hospital cardiac arrest (OHCA) survivors treated with TTM from January 2015 to June 2017. Patients who developed shivering during the induction period were compared to those who did not. Multivariable analysis was performed to determine risk factors of shivering. Among 80 patients treated with TTM, shivering occurred in 22 patients (27.5%). In the shivering group, the time to achieve target temperature was significantly delayed (245 minutes vs. 151 minutes, p = 0.005). Multivariable analysis showed that being underweight (OR, 18.40; 95% CI, 1.89-179.19) or overweight (OR, 8.65; 95% CI, 1.60-46.80), age <65 years (OR, 5.54; 95% CI, 1.25-16.12), and duration of cardiac arrest <20 minutes (OR, 4.50; 95% CI, 1.25-16.12) were predictors for the occurrence of shivering. OHCA patients with abnormal body weight, age <65 years, and duration of cardiac arrest <20 minutes should be monitored thoroughly for early recognition of shivering. PMID- 29762084 TI - Irritable bowel symptoms, use of healthcare, costs, sickness and disability pension benefits: A long-term population-based study. AB - OBJECTIVES: Irritable bowel syndrome (IBS) is associated with increased healthcare use and work absenteeism. We aimed to investigate long-term use of healthcare services and social benefits across IBS symptom groups. Additionally, we estimated excess healthcare costs. METHODS: A longitudinal population-based study comprising two 5-year follow-up studies: The Danish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (Dan-MONICA) 1 (1982-1987) and Inter99 (1999-2004) recruited from the western part of Copenhagen County. The total study population ( n = 7278) was divided into symptom groups according to degree of IBS definition fulfillment at baseline and/or 5-year follow-up and was followed until 31 December 2013 in Danish central registries. Poisson regression was used for the analyses adjusting for age, sex, length of education, comorbidity, cohort membership and mental vulnerability. RESULTS: IBS symptom groups compared to no IBS symptoms were associated with an increased number of contacts with primary and secondary healthcare, as well as weeks on sickness and disability benefits. Accounting for mental vulnerability decreased the estimates and all but two associations between IBS symptom groups and outcomes remained statistically significant. The two associations that became insignificant were contacts with psychiatric hospitals and weeks on disability pension. The excess unadjusted healthcare costs for IBS were 680 Euros per year and the overall association between symptom groups and total healthcare costs were statistically significant. CONCLUSIONS: IBS symptoms influence the long-term use and costs of healthcare, as well as the use of social benefits in the general population. Mental vulnerability explained some, but not all, of the use of healthcare and social benefits. PMID- 29762085 TI - Association between comorbid cancer and outcomes among admissions for acute ischemic stroke receiving systemic thrombolysis. AB - Background The impact of cancer on outcomes was not assessed in major trials of systemic thrombolysis in acute ischemic stroke. Aims To evaluate the association between comorbid cancer and hospital outcomes among patients receiving systemic thrombolysis for the treatment of acute ischemic stroke. Methods The 2013 and 2014 United States National Inpatient Sample was used to identify adult patients hospitalized for acute ischemic stroke who received systemic thrombolysis. Identified admissions were stratified into two cohorts based on the presence or absence of comorbid cancer. Multivariable logistic regression was performed to determine the association between comorbid cancer and the odds of in-hospital mortality and intracerebral hemorrhage after adjustment for age >=75 years and comorbid atrial fibrillation. Results A total of 13,993 acute ischemic stroke admissions were treated with systemic thrombolysis. Of these, 3.0% ( n = 416) had comorbid cancer. The overall incidence of in-hospital mortality was 7.0% and intracerebral hemorrhage occurred in 7.6% of patients. Upon multivariable adjustment, comorbid cancer was not associated with an increased odds of in hospital mortality (odds ratio = 1.24; 95% confidence interval = 0.88-1.76). However, the adjusted odds of intracerebral hemorrhage were higher among those with comorbid cancer (odds ratio = 1.60; 95% confidence interval = 1.17-2.17). Conclusions In this retrospective study of admissions for acute ischemic stroke receiving thrombolysis, comorbid cancer was not associated with a higher odds of in-hospital mortality but was associated with an increased odds of intracerebral hemorrhage. Factors driving this observed association should be explored in data sets containing clinical variables. PMID- 29762086 TI - Suggested modification of presentation of stroke trial results. AB - The modified Rankin Scale (mRS) at 90 days after stroke onset has become the preferred outcome measure in acute stroke trials, including recent trials of interventional therapies. Reporting the range of modified Rankin Scale scores as a paired horizontal stacked bar graph (colloquially known as "Grotta bars") has become the conventional method of visualizing modified Rankin Scale results. Grotta bars readily illustrate the levels of the ordinal modified Rankin Scale in which benefit may have occurred. However, complementing the available graphical information by including additional features to convey statistical significance may be advantageous. We propose a modification of the horizontal stacked bar graph with illustrative examples. In this suggested modification, the line joining the segments of the bar graph (e.g. modified Rankin Scale 1-2 in treatment arm to modified Rankin Scale 1-2 in control arm) is given a color and thickness based on the p-value of the result at that level (in this example, the p-value of modified Rankin Scale 0-1 vs. 2-6)-a thick green line for p-values <0.01, thin green for p-values of 0.01 to <0.05, gray for 0.05 to <0.10, thin red for 0.10 to <0.90, and thick red for p-values >=0.90 or outcome favoring the control group. Illustrative examples from four recent trials (ESCAPE, SWIFT PRIME, IST-3, ASTER) are shown to demonstrate the range of significant and non significant effects that can be captured using this proposed method. By formalizing a display of outcomes which includes statistical tests of all possible dichotomizations of the Rankin scale, this approach also encourages pre specification of such hypotheses. Prespecifying tests of all six dichotomizations of the Rankin scale provides all possible statistical information in an a priori fashion. Since the result of our proposed approach is six distinct dichotomized tests in addition to a primary test, e.g. of the ordinal Rankin shift, it may be prudent to account for multiplicity in testing by using dichotomized p-values only after adjustment, such as by the Bonferroni or Hochberg-Holm methods. Whether p-values are nominal or adjusted may be left to the discretion of the presenter as long as the presence or absence is clearly stated in the statistical methods. Our proposed modification results in a visually intuitive summary of both the size of the effect-represented by the matched bars and their connecting segments-as well as its statistical relevance. PMID- 29762088 TI - An Updated Taxonomy and a Graphical Summary Tool for Optimal Classification and Comprehension of Omics Research. AB - The volume of publications and the type of research approaches used in omics system sciences are vast and continue to expand rapidly. This increased complexity and heterogeneity of omics data are challenging data extraction, sensemaking, analyses, knowledge translation, and interpretation. An extended and dynamic taxonomy for the classification and summary of omics studies are essential. We present an updated taxonomy for classification of omics research studies based on four criteria: (1) type and number of genomic loci in a research study, (2) number of species and biological samples, (3) the type of omics technology (e.g., genomics, transcriptomics, and proteomics) and omics technology application type (e.g., pharmacogenomics and nutrigenomics), and (4) phenotypes. In addition, we present a graphical summary approach that enables the researchers to define the main characteristics of their study in a single figure, and offers the readers to rapidly grasp the published study and omics data. We searched the PubMed and the Web of Science from 09/2002 to 02/2018, including research and review articles, and identified 90 scientific publications. We propose a call toward omics studies' standardization for reporting in scientific literature. We anticipate the proposed classification scheme will usefully contribute to improved classification of published reports in genomics and other omics fields, and help data extraction from publications for future multiomics data integration. PMID- 29762089 TI - Juvenile Osteochondritis Dissecans: Cartilage T2 Mapping of Stable Medial Femoral Condyle Lesions. AB - Purpose To determine whether a T2 mapping sequence could depict early changes in the composition and microstructure of cartilage overlying stable lesions of the medial femoral condyle in patients with juvenile osteochondritis dissecans (JOCD). Materials and Methods This retrospective study analyzed a sagittal T2 mapping sequence performed between September 1, 2015, and March 31, 2017, on 16 patients (10 boys and six girls; median age, 11.5 years) with 18 stable medial femoral condyle JOCD lesions and 18 age-, sex-, and skeletal maturation-matched control participants (11 boys and seven girls; median age, 11.5 years). Cartilage T2 values were quantitatively measured within regions of interest placed around the cartilage within and overlying the JOCD lesion in patients with JOCD and around the cartilage on the weight-bearing medial femoral condyle in patients with JOCD and controls. Wilcoxon signed rank and Wilcoxon rank sum tests were used to compare T2 values. Results T2 values were significantly higher (P < .001) for cartilage within the JOCD lesion than for cartilage overlying the JOCD lesion in patients with JOCD. However, there were no significant differences in T2 values between cartilage overlying the JOCD lesion and cartilage on the weight bearing medial femoral condyle in patients with JOCD (P = .67) or in T2 values of the cartilage on the weight-bearing medial femoral condyle between patients with JOCD and controls (P = .30). Conclusion There were no significant quantifiable differences in T2 values of cartilage overlying stable JOCD lesions and normal cartilage on the medial femoral condyle, suggesting no substantial changes in cartilage composition and microstructure. PMID- 29762090 TI - Alzheimer Disease and Mild Cognitive Impairment: Integrated Pulsed Arterial Spin Labeling MRI and 18F-FDG PET. AB - Purpose To compare PET/MR hypoperfusion and hypometabolism in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) compared with healthy control (HC) participants. Materials and Methods Maps of cerebral blood flow (CBF; pulsed arterial spin-labeling [ASL] MRI), glucose metabolism (fluorine 18 [18F] fluorodeoxyglucose [FDG] PET), and gray matter (GM) volume (structural T1 weighted MRI) were calculated from integrated PET/MR data in 45 patients with AD (mean age, 69 years +/- 9 [standard deviation]; age range, 51-89 years), 20 patients with MCI (mean age, 64 years +/- 10; age range, 45-82 years), and 11 HC participants (mean age, 65 years +/- 8; age range, 54-80 years) between 2011 and 2014. After preprocessing, voxel-wise analyses of variance, volume of interest, and independent component analyses were performed for comparisons of CBF and glucose metabolism. Results Analyses revealed high overlap between components, regional and quantitative hypoperfusion, and hypometabolism in patients with AD compared with HC participants in precuneus, parietal, temporal, and occipital cortex. In patients with MCI compared with HC participants, FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus. Volume of-interest analysis in global GM in patients with AD compared with HC participants showed lower CBF (42 mL/100 g per minute +/- 8 vs 49 mL/100 g per minute +/- 7, respectively; P = .035) and lower FDG uptake (0.8 +/- 0.1 vs 1 +/- 0.1, respectively; P < .001). Conclusion In patients with AD, pulsed ASL MRI revealed regional and quantitative abnormalities and components similar to 18F FDG PET with a reduced extent. In patients with MCI, 18F-FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus, indicating higher sensitivity to detect preclinical AD compared with the currently used pulsed ASL MRI sequence. PMID- 29762087 TI - Genomics and Epigenomics of Congenital Heart Defects: Expert Review and Lessons Learned in Africa. AB - Congenital heart defects (CHD) are structural malformations found at birth with a prevalence of 1%. The clinical trajectory of CHD is highly variable and thus in need of robust diagnostics and therapeutics. Major surgical interventions are often required for most CHDs. In Africa, despite advances in life sciences infrastructure and improving education of medical scholars, the limited clinical data suggest that CHD detection and correction are still not at par with the rest of the world. But the toll and genetics of CHDs in Africa has seldom been systematically investigated. We present an expert review on CHD with lessons learned on Africa. We found variable CHD phenotype prevalence in Africa across countries and populations. There are important gaps and paucity in genomic studies of CHD in African populations. Among the available genomic studies, the key findings in Africa were variants in GATA4 (P193H), MTHFR 677TT, and MTHFR 1298CC that were associated with atrial septal defect, ventricular septal defect (VSD), Tetralogy of Fallot (TOF), and patent ductus arteriosus phenotypes and 22q.11 deletion, which is associated with TOF. There were no data on epigenomic association of CHD in Africa, however, other studies have shown an altered expression of miR-421 and miR-1233-3p to be associated with TOF and hypermethylation of CpG islands in the promoter of SCO2 gene also been associated with TOF and VSD in children with non-syndromic CHD. These findings signal the urgent need to develop and implement genetic and genomic research on CHD to identify the hereditary and genome-environment interactions contributing to CHD. These projected studies would also offer comparisons on CHD pathophysiology between African and other populations worldwide. Genomic research on CHD in Africa should be developed in parallel with next generation technology policy research and responsible innovation frameworks that examine the social and political factors that shape the emergence and societal embedding of new technologies. PMID- 29762092 TI - Barriers to Safety Event Reporting in an Academic Radiology Department: Authority Gradients and Other Human Factors. AB - Purpose To investigate barriers to reporting safety concerns in an academic radiology department and to evaluate the role of human factors, including authority gradients, as potential barriers to safety concern reporting. Materials and Methods In this institutional review board-approved, HIPAA-compliant retrospective study, an online questionnaire link was emailed four times to all radiology department staff members (n = 648) at a tertiary care institution. Survey questions included frequency of speaking up about safety concerns, perceived barriers to speaking up, and the annual number of safety concerns that respondents were unsuccessful in reporting. Respondents' sex, role in the department, and length of employment were recorded. Statistical analysis was performed with the Fisher exact test. Results The survey was completed by 363 of the 648 employees (56%). Of those 363 employees, 182 (50%) reported always speaking up about safety concerns, 134 (37%) reported speaking up most of the time, 36 (10%) reported speaking up sometimes, seven (2%) reported rarely speaking up, and four (1%) reported never speaking up. Thus, 50% of employees spoke up about safety concerns less than 100% of the time. The most frequently reported barriers to speaking up included high reporting threshold (69%), reluctance to challenge someone in authority (67%), fear of disrespect (53%), and lack of listening (52%). Conclusion Of employees in a large academic radiology department, 50% do not attain 100% reporting of safety events. The most common human barriers to speaking up are high reporting threshold, reluctance to challenge authority, fear of disrespect, and lack of listening, which suggests that existing authority gradients interfere with full reporting of safety concerns. PMID- 29762091 TI - Rapid Automated Quantification of Cerebral Leukoaraiosis on CT Images: A Multicenter Validation Study. AB - Purpose To validate a random forest method for segmenting cerebral white matter lesions (WMLs) on computed tomographic (CT) images in a multicenter cohort of patients with acute ischemic stroke, by comparison with fluid-attenuated recovery (FLAIR) magnetic resonance (MR) images and expert consensus. Materials and Methods A retrospective sample of 1082 acute ischemic stroke cases was obtained that was composed of unselected patients who were treated with thrombolysis or who were undergoing contemporaneous MR imaging and CT, and a subset of International Stroke Thrombolysis-3 trial participants. Automated delineations of WML on images were validated relative to experts' manual tracings on CT images, and co-registered FLAIR MR imaging, and ratings were performed by using two conventional ordinal scales. Analyses included correlations between CT and MR imaging volumes, and agreements between automated and expert ratings. Results Automated WML volumes correlated strongly with expert-delineated WML volumes at MR imaging and CT (r2 = 0.85 and 0.71 respectively; P < .001). Spatial-similarity of automated maps, relative to WML MR imaging, was not significantly different to that of expert WML tracings on CT images. Individual expert WML volumes at CT correlated well with each other (r2 = 0.85), but varied widely (range, 91% of mean estimate; median estimate, 11 mL; range of estimated ranges, 0.2-68 mL). Agreements (kappa) between automated ratings and consensus ratings were 0.60 (Wahlund system) and 0.64 (van Swieten system) compared with agreements between individual pairs of experts of 0.51 and 0.67, respectively, for the two rating systems (P < .01 for Wahlund system comparison of agreements). Accuracy was unaffected by established infarction, acute ischemic changes, or atrophy (P > .05). Automated preprocessing failure rate was 4%; rating errors occurred in a further 4%. Total automated processing time averaged 109 seconds (range, 79-140 seconds). Conclusion An automated method for quantifying CT cerebral white matter lesions achieves a similar accuracy to experts in unselected and multicenter cohorts. PMID- 29762094 TI - Ray A. Brinker, MD. PMID- 29762093 TI - Terrorist Attack in Nice, France, in July 2016: Massive Influx of Patients to a Radiology Department. PMID- 29762095 TI - CT-based Visual Classification of Emphysema: Association with Mortality in the COPDGene Study. AB - Purpose To determine whether visually assessed patterns of emphysema at CT might provide a simple assessment of mortality risk among cigarette smokers. Materials and Methods Of the first 4000 cigarette smokers consecutively enrolled between 2007 and 2011 in this COPDGene study, 3171 had data available for both visual emphysema CT scores and survival. Each CT scan was retrospectively visually scored by two analysts using the Fleischner Society classification system. Severity of emphysema was also evaluated quantitatively by using percentage lung volume occupied by low-attenuation areas (voxels with attenuation of -950 HU or less) (LAA-950). Median duration of follow-up was 7.4 years. Regression analysis for the relationship between imaging patterns and survival was based on the Cox proportional hazards model, with adjustment for age, race, sex, height, weight, pack-years of cigarette smoking, current smoking status, educational level, LAA 950, and (in a second model) forced expiratory volume in 1 second (FEV1). Results Observer agreement in visual scoring was good (weighted kappa values, 0.71-0.80). There were 519 deaths in the study cohort. Compared with subjects who did not have visible emphysema, mortality was greater in those with any grade of emphysema beyond trace (adjusted hazard ratios, 1.7, 2.5, 5.0, and 4.1, respectively, for mild centrilobular emphysema, moderate centrilobular emphysema, confluent emphysema, and advanced destructive emphysema, P < .001). This increased mortality generally persisted after adjusting for LAA-950. Conclusion The visual presence and severity of emphysema is associated with significantly increased mortality risk, independent of the quantitative severity of emphysema. Online supplemental material is available for this article. PMID- 29762096 TI - US Time-Harmonic Elastography: Detection of Liver Fibrosis in Adolescents with Extreme Obesity with Nonalcoholic Fatty Liver Disease. AB - Purpose To measure in vivo liver stiffness by using US time-harmonic elastography in a cohort of pediatric patients who were overweight to extremely obese with nonalcoholic fatty liver disease (NAFLD) and to evaluate the diagnostic value of time-harmonic elastography for differentiating stages of fibrosis associated with progressive disease. Materials and Methods In this prospective study, 67 consecutive adolescents (age range, 10-17 years; mean body mass index, 34.7 kg/m2; range, 21.4-50.4 kg/m2) with biopsy-proven NAFLD were enrolled. Liver stiffness was measured by using time-harmonic elastography based on externally induced continuous vibrations of 30 Hz to 60 Hz frequency and real-time B-mode guided wave profile analysis covering tissue depths of up to 14 cm. The diagnostic accuracy of time-harmonic elastography in staging liver fibrosis was assessed with area under the receiver operating characteristic curve (AUC) analysis. Liver stiffness cutoffs for the differentiation of fibrosis stages were identified based on the highest Youden index. Results Time-harmonic elastography was feasible in all patients (0% failure rate), including 70% (n = 47) of individuals with extreme obesity (body mass index above the 99.5th percentile). AUC analysis for the detection of any fibrosis (>= stage F1), moderate fibrosis (>= stage F2), and advanced fibrosis (>= stage F3) was 0.88 (95% confidence interval [CI]: 0.80, 0.96), 0.99 (95% CI: 0.98, 1.00), and 0.88 (95% CI: 0.80, 0.96), respectively. The best liver stiffness cutoffs were 1.52 m/sec for at least stage F1, 1.62 m/sec for at least stage F2, and 1.64 m/sec for at least stage F3. Conclusion US time-harmonic elastography allows accurate detection of moderate fibrosis even in pediatric patients with extreme obesity. Larger clinical trials are warranted to confirm the accuracy of US time-harmonic elastography. PMID- 29762097 TI - Does Integrated PET/MR Have a Role in the Management of Patients with Dementia? PMID- 29762098 TI - Liver Elastography Still in Its Infancy. PMID- 29762099 TI - Disaster Management. PMID- 29762100 TI - Top-Down Control of Alpha Phase Adjustment in Anticipation of Temporally Predictable Visual Stimuli. AB - Alpha oscillations (8-14 Hz) are proposed to represent an active mechanism of functional inhibition of neuronal processing. Specifically, alpha oscillations are associated with pulses of inhibition repeating every ~100 msec. Whether alpha phase, similar to alpha power, is under top-down control remains unclear. Moreover, the sources of such putative top-down phase control are unknown. We designed a cross-modal (visual/auditory) attention study in which we used magnetoencephalography to record the brain activity from 34 healthy participants. In each trial, a somatosensory cue indicated whether to attend to either the visual or auditory domain. The timing of the stimulus onset was predictable across trials. We found that, when visual information was attended, anticipatory alpha power was reduced in visual areas, whereas the phase adjusted just before the stimulus onset. Performance in each modality was predicted by the phase of the alpha oscillations previous to stimulus onset. Alpha oscillations in the left pFC appeared to lead the adjustment of alpha phase in visual areas. Finally, alpha phase modulated stimulus-induced gamma activity. Our results confirm that alpha phase can be top-down adjusted in anticipation of predictable stimuli and improve performance. Phase adjustment of the alpha rhythm might serve as a neurophysiological resource for optimizing visual processing when temporal predictions are possible and there is considerable competition between target and distracting stimuli. PMID- 29762101 TI - Stimulus Familiarity and Expectation Jointly Modulate Neural Activity in the Visual Ventral Stream. AB - Prior knowledge about the visual world can change how a visual stimulus is processed. Two forms of prior knowledge are often distinguished: stimulus familiarity (i.e., whether a stimulus has been seen before) and stimulus expectation (i.e., whether a stimulus is expected to occur, based on the context). Neurophysiological studies in monkeys have shown suppression of spiking activity both for expected and for familiar items in object-selective inferotemporal cortex. It is an open question, however, if and how these types of knowledge interact in their modulatory effects on the sensory response. To address this issue and to examine whether previous findings generalize to noninvasively measured neural activity in humans, we separately manipulated stimulus familiarity and expectation while noninvasively recording human brain activity using magnetoencephalography. We observed independent suppression of neural activity by familiarity and expectation, specifically in the lateral occipital complex, the putative human homologue of monkey inferotemporal cortex. Familiarity also led to sharpened response dynamics, which was predominantly observed in early visual cortex. Together, these results show that distinct types of sensory knowledge jointly determine the amount of neural resources dedicated to object processing in the visual ventral stream. PMID- 29762102 TI - Dynamic Encoding of Effort and Reward throughout the Execution of Action by External Globus Pallidus Neurons in Monkeys. AB - Humans and animals must evaluate the costs and expected benefits of their actions to make adaptive choices. Prior studies have demonstrated the involvement of the basal ganglia in this evaluation. However, little is known about the role of the external part of the globus pallidus (GPe), which is well positioned to integrate motor and reward-related information, in this process. To investigate this role, the activity of 126 neurons was recorded in the associative and limbic parts of the GPe of two monkeys performing a behavioral task in which different levels of force were required to obtain different amounts of liquid reward. The results first revealed that the activity of associative and limbic GPe neurons could be modulated not only by cognitive and limbic but also motor information at the same time, both during a single period or during different periods throughout the trial, mainly in an independent way. Moreover, as a population, GPe neurons encoded these types of information dynamically throughout the trial, when each piece of information was the most relevant for the achievement of the action. Taken together, these results suggest that GPe neurons could be dedicated to the parallel monitoring of task parameters essential to adjusting and maintaining goal-directed behavior. PMID- 29762103 TI - Differentiation Analysis of Continuous Electroencephalographic Activity Triggered by Video Clip Contents. AB - While viewing a video clip, we experience a wide variety of contents, from low level features of the images to high-level ideas such as the storyline. Each change in our experience must be supported by some corresponding change in neurophysiological activity. Differentiation analysis, which quantifies the differences in brain activity by measuring the distances between observed brain states, was applied here to continuous high-density electroencephalographic data recorded while participants watched short video clips. These clips were manipulated in various ways to change the degree of meaningfulness of their contents. We found that neurophysiological differentiation mirrored that of phenomenal differentiation, being higher for meaningful clips and lower for phase scrambled versions or random noise. The distinction between meaningful and meaningless clips was present even at the individual level, and moreover, differentiation values correlated with individual subjective reports of meaningfulness. Spatial and spectral breakdowns of the overall effect showed frontal and posterior ROIs and highlighted specific roles for different spectral bands. Comparing the results with a multivariate decoding approach reveals that the two methods are capturing different aspects of brain activity and highlights a crucial theoretical distinction between the level and pattern of activity. In future applications, differentiation analysis may be used to evaluate the subjective meaningfulness of stimuli when behavioral responses may be inadequate, as with disorders of consciousness. PMID- 29762104 TI - Combined Electrophysiological and Behavioral Evidence for the Suppression of Salient Distractors. AB - Researchers have long debated how salient-but-irrelevant features guide visual attention. Pure stimulus-driven theories claim that salient stimuli automatically capture attention irrespective of goals, whereas pure goal-driven theories propose that an individual's attentional control settings determine whether salient stimuli capture attention. However, recent studies have suggested a hybrid model in which salient stimuli attract visual attention but can be actively suppressed by top-down attentional mechanisms. Support for this hybrid model has primarily come from ERP studies demonstrating that salient stimuli, which fail to capture attention, also elicit a distractor positivity (PD) component, a putative neural index of suppression. Other support comes from a handful of behavioral studies showing that processing at the salient locations is inhibited compared with other locations. The current study was designed to link the behavioral and neural evidence by combining ERP recordings with an experimental paradigm that provides a behavioral measure of suppression. We found that, when a salient distractor item elicited the PD component, processing at the location of this distractor was suppressed below baseline levels. Furthermore, the magnitude of behavioral suppression and the magnitude of the PD component covaried across participants. These findings provide a crucial connection between the behavioral and neural measures of suppression, which opens the door to using the PD component to assess the timing and neural substrates of the behaviorally observed suppression. PMID- 29762106 TI - Metal induction of two metallothionein genes in the ectomycorrhizal fungus Suillus himalayensis and their role in metal tolerance. AB - Metallothioneins (MTs) are small proteins with highly conserved cysteine residues and are involved in metal homeostasis and metal detoxification. Two metallothionein genes ShMT1 and ShMT2 from the ectomycorrhizal fungus Suillus himalayensis were characterised for their potential role in heavy metal detoxification. The response of these MTs to the exogenous concentrations of copper and cadmium was studied by qPCR analysis. The exogenous copper but not the cadmium at the tested concentrations induced the expression of the MT genes. The functional role of ShMTs was validated by expressing the two genes through functional complementation in yeast mutant strain cup1Delta (copper-sensitive), ycf1Delta (cadmium- sensitive) and zrc1Delta (zinc-sensitive). The mutant strain successfully expressed the two genes resulting in wild-type phenotype restoration of copper, cadmium and zinc tolerance. The present study shows that the ectomycorrhizal fungus S. himalayensis encodes two metallothionein genes (ShMT1 and ShMT2) which are more inducible by copper than cadmium and could play an important role in their detoxification. PMID- 29762105 TI - Kandeliimicrobium roseum gen. nov., sp. nov., a new member of the family Rhodobacteraceae isolated from mangrove rhizosphere soil. AB - A Gram-stain-negative, non-flagellated, short rod-shaped bacterium, designated XY R6T, was isolated from the rhizosphere soil of a mangrove plant, Kandelia candel (L.) Druce, in Mai Po Nature Reserve, Hong Kong. Growth of strain XY-R6T was observed at pH 5.0-9.5 (optimum 6.5-8.0), between 8 and 42 degrees C (optimum 28 34 degrees C), and in the presence of 0-9.5 % (w/v) NaCl (optimum 1-4 %). The predominant isoprenoid quinone was ubiquinone-10. The major fatty acids were summed feature 8 (C18 : 1omega6c and/or C18 : 1omega7c) (55.61 %), C19 : 0cycloomega8c (21.59 %) and C16 : 0 (11.24 %). The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, aminolipid, phosphatidylcholine and diphosphatidylglycerol. The genomic DNA G+C content of strain XY-R6T was 69.3 mol%. Phylogenetic analyses, based on 16S rRNA gene sequences, revealed that strain XY-R6T belonged to the family Rhodobacteraceae of the class Alphaproteobacteria and formed a distinct lineage, showing the highest gene sequence similarities to the members of genus Wenxinia(94.5-94.3 %), followed by the genera Profundibacterium (94.3 %), Defluviimonas(93.8-92.5 %), Oceanicola (93.8 %) and Cereibacter (93.7 %). Similarities to other genera within the family Rhodobacteraceae were below 94.0 %. Based on comprehensive phenotypic, phylogenetic and chemotaxonomic characterization, it is indicated that strain XY R6T represents a novel species of a new genus in the family Rhodobacteraceae, for which the name Kandeliimicrobium roseum gen. nov., sp. nov. is proposed, with XY R6T (=MCCC 1K01498T=KCTC 52266T=DSM 104294T) as the type strain. PMID- 29762108 TI - Midterm Follow-up of Divergent Peg Glenoid Components in Total Shoulder Arthroplasty. AB - Glenoid component aseptic loosening is the most common source of total shoulder arthroplasty (TSA) revision. Divergent pegged glenoids may improve fixation. Thirty-four patients underwent divergent peg TSA. Data were reviewed for component loosening. Failure was defined as the need for revision after loosening. The last postoperative radiographs were graded on a Lazarus glenoid lucency scale. Mean follow-up was 5.6 years +/- 2.44 (range, 2-10 years). Radiolucency around one or fewer pegs was noted in 14/20 patients. Six glenoids had complete radiolucency around two pegs; one shoulder had gross loosening. No secondary surgery was performed. Improvements were seen in active elevation and internal rotation. The mean Shoulder Pain and Disability Index (SPADI) score decreased by 48.1 points (p = .039). Shoulder elevation, internal rotation, and SPADI scores significantly improved at final follow-up. No patients underwent revision for glenoid loosening. There were, however, a significant number of patients with radiolucency around two pegs. (Journal of Surgical Orthopaedic Advances 27(1):6-9, 2018). PMID- 29762107 TI - Musculoskeletal Manifestations of Amyloidosis: A Focused Review. AB - Amyloidosis is a poorly understood condition that can wreak havoc on numerous systems within the human body. In addition, this disease can present in multiple forms which each have their own unique physiology and subsequent effects. However, while the literature on the etiology and effect of amyloidosis on various organ systems is numerous, few have highlighted the musculoskeletal manifestations of this devastating disease. This review focuses on the recent research on amyloid deposition in the musculoskeletal system. Additionally, risk factors, classification, differential diagnoses, indications for biopsy, and manifestations of amyloidosis in the musculoskeletal system as well as in other tissues are discussed. Furthermore, the surgical and nonsurgical approaches to treatment are covered. (Journal of Surgical Orthopaedic Advances 27(1):1-5, 2018). PMID- 29762109 TI - Behavioral Economics and Physician Board Meetings: Opportunity Cost, Regret, and Their Mitigation in Orthopaedic Surgery. AB - Health care is a business. Health care providers must become familiar with terms such as opportunity costs, the potential loss or gain when one choice is made in lieu of another. The purpose of this study was to calculate the opportunity cost of two orthopaedic surgery society board meetings and discuss these in the context of behavioral economics and regret. A literature search was conducted to determine an orthopaedic surgeon's average yearly salary, hours worked per week, and weeks worked per year. The details of two orthopaedic surgery professional society meetings that one senior author (CSR) attended were used to calculate opportunity cost. Although the true benefits are multifactorial and difficult to objectively quantify, awareness of the cost-benefit ratio can help guide time and resource management to maximize the return on investment while minimizing buyer's remorse and perhaps influence the media by which medical meetings are held in the future. (Journal of Surgical Orthopaedic Advances 27(1):10-13, 2018). PMID- 29762110 TI - Surgical Complications Associated With Atypical Femur Fractures Attributed to Bisphosphonate Use. AB - Complications of atypical femur fractures (AFFs) are common. AFFs often receive the same treatment as other femoral fractures; however, there appears to be a higher rate of adverse outcomes. Nine patients sustained a total of 13 AFFs, had documented bisphosphonate use before fracture, and had surgery between 2006 and 2012. Complications included continued pain, surgical revision, nonunion, malunion, deformity, or heterotopic ossification. The overall complication rate was 33.3%, with four of the 12 surgeries performed at this institution resulting in one nonunion and three minor complications. None of the primary fixations required revision. There was a higher complication rate for AFFs when compared with non-bisphosphonate-related intramedullary nail femur fracture fixations. This cohort demonstrated a lower rate of major complications compared to the literature. Using a reamed, statically locked nail, halting bisphosphonate medication, and allowing early weight bearing is a safe and efficacious method to treat atypical femur fractures. (Journal of Surgical Orthopaedic Advances 27(1):14-20, 2018). PMID- 29762111 TI - Direct Anterior Approach Has Lower Deep Infection Frequency Than Less Invasive Direct Lateral Approach in Primary Total Hip Arthroplasty. AB - Debate continues over the direct anterior (DA) approach. The purpose of this study is to compare the frequency of deep infection between a DA approach and a less invasive direct lateral (LIDL) approach in a large consecutive series of primary total hip arthroplasty (THA). The authors identified 5702 primary THAs performed between 2007 and 2014. DA approach was used in 3540 hips and LIDL in 2162. Patient records were reviewed. Statistical analysis of reoperation, infection- or wound-related complication, and deep infection was performed. During the 8-year follow-up period, there were 98 reoperations in the DA group (2.8%) and 77 in the LIDL group (3.6%; p = .09 NS). Wound- or infection-related reoperation occurred in 32 DA THAs (0.9%) versus 36 LIDL THAs (1.7%; p = .01). Deep infection occurred in 7 DA THAs (0.2%) versus 21 LIDL THAs (0.97%; p > .0001). The risk of deep infection was statistically lower in the DA approach. (Journal of Surgical Orthopaedic Advances 27(1):21-24, 2018). PMID- 29762112 TI - Lumbar Discography Is Associated With Poor Return to Work Status Following Lumbar Fusion Surgery in a Workers' Compensation Setting. AB - Lumbar discography (LD) is used to guide surgical decision making in patients with degenerative disc disease (DDD). Its safety and diagnostic accuracy are under contention. This study evaluates LD's efficacy within the workers' compensation (WC) population. Multivariate logistic regression analysis was used to determine the impact that undergoing LD before lumbar fusion for DDD had on return to work (RTW) rates among 1407 WC subjects. Discography was negatively associated with RTW status (p = .042; OR 0.76); 22.2% (142/641) of LD subjects met the RTW criteria, compared with 29.6% (227/766) of controls. Additional preoperative risk factors included psychological comorbidity (p < .001; OR 0.34), age greater than 50 (p < .005; OR 0.64), male gender (p < .037; OR 0.75), chronic opioid use (p < .001; OR 0.53), legal representation (p < .034; OR 0.72), and fusion technique (p < .043). LD subjects used postoperative narcotics for an average of 123 additional days (p < .001). This raises concerns regarding the utility of discography in the WC population. (Journal of Surgical Orthopaedic Advances 27(1):25-32, 2018). PMID- 29762113 TI - Cervicothoracic Pedicle Morphometry: Using an Osteological Collection to Characterize Trends in Pedicle Size. AB - Pedicle screws are a common treatment option for spinal instability. Despite their popularity, pedicle screws carry the risk of transpedicular violation with subsequent neural and vascular damage. This study measured the pedicle dimensions of 500 dry specimens in an osteological collection. The data provide the orthopedic spine surgeon with an accurate measure of pedicle morphometry in light of previously limited and contradictory results. The study demonstrates that pedicle height at the cervicothoracic junction tends to increase with body height, particularly for females. Additionally, T1 pedicle width is smaller for females than males and, for males, tends to decrease with increasing body weight. These results are valuable to the spine surgeon because they suggest that taller patients may afford a larger margin for error in the vertical plane. However, they also demonstrate that heavier patients do not have wider pedicles and thus cannot be assumed to tolerate or require larger-diameter screws. (Journal of Surgical Orthopaedic Advances 27(1):33-38, 2018). PMID- 29762114 TI - Pectoralis Major Tendon Insertion Anatomy and Description of a Novel Anatomic Reference. AB - Pectoralis major rupture is an uncommon injury often treated surgically, requiring anatomic knowledge of the tendon insertion. This study defines the pectoralis major tendon insertion footprint and a novel anatomic relationship. Twelve cadaver shoulders were evaluated andmeasured using a standard surgical ruler to demonstrate the normal anatomic footprint. Measurements were taken from the anterior medial margin of the articular surface of the humeral head to the superior margin of the pectoralis major insertion and its relation to the latissimus dorsi tendon insertion. The average length and width of the pectoralis major insertion were 73.3 +/- 10.0 mm and 3.3 +/- 0.54 mm, respectively, consistent with previous publications. On average, the superior margin of the pectoralis tendon was within 1 mm of the latissimus dorsi insertion and 41.2 +/- 9.27 mm from the articular margin. These points form a new anatomic reference of the latissimus dorsi, providing an intraoperative reference point when performing pectoralis major muscle tendon repair. (Journal of Surgical Orthopaedic Advances 27(1):39-41, 2018). PMID- 29762115 TI - Effects of Accreditation Council for Graduate Medical Education Duty Hour Regulations on Clinical Preparedness of First-Year Orthopaedic Attendings: A Survey of Senior Orthopaedic Surgeons. AB - It is unclear how the Accreditation Council for Graduate Medical Education (ACGME) resident duty hour restriction has affected attending orthopaedic surgeons in their first year of practice. The purpose of this study was to compare the clinical preparedness of first-year orthopaedic attending surgeons who trained with ACGME duty hour regulations versus those trained without regulations. Senior orthopaedic surgeons with greater than 10 years of experience were surveyed and results indicate that first-year attendings who trained with ACGME duty hour regulations required more supervision reviewing cases preoperatively, required more assistance completing operative cases, had inferior technical skills, had more major operative complications, had poorer physical exam skills, and delivered an inferior quality of care. Private attendings were most critical. In the postregulatory era, residency programs must optimize the resident's time to ensure competency on graduation. Strategies include increasing midlevel staff, focusing on competencies outlined by ACGMEmilestones, and increasing the role of simulation. (Journal of Surgical Orthopaedic Advances 27(1):42-46, 2018). PMID- 29762117 TI - Smartphone Photography as a Tool to Measure Knee Range of Motion. AB - The objective of this study was to validate measuring knee range of motion (ROM) from smartphone photography. Thirty-two participants (64 knees) obtained smartphone photographs of knee flexion and extension. Surgeons obtained the same photographs and goniometric measurement of ROM. ROM was measured using Adobe Photoshop. Goniometer versus digital measurements, participant versus surgeon photographs, and interobserver measurements were analyzed. The average difference in goniometer and digital photograph measurements was 5 degrees . The interclass correlation was .642(L) and .656(R). The Bland-Altman plots demonstrated that 29/32 digital measurements were within the 95% confidence interval (CI). Participants' versus researchers' photographs averaged a 2 degrees difference. The interclass correlation was .924(L) and .91(R). Bland-Altman plots demonstrated that 31/32 measurements were within the 95% CI. Interobserver reliability averaged aROMdifference of 5 degrees . The concordance coefficients were .647(L) and .723(R). Bland-Altman plots demonstrated that 30 of 32 digital measurements were within the 95% CI. Measuring knee ROM using smartphone digital photography is valid and reliable. (Journal of Surgical Orthopaedic Advances 27(1):52-57, 2018). PMID- 29762116 TI - Incidence and Risk Factors for Reoperation Following Meniscal Repair in a Military Population. AB - The purpose of this study is to determine the reoperation rate following meniscal repair and the associated risk factors. The Military Health System Data Repository was queried for active duty patients between January 2009 and December 2012 undergoing meniscal repair by Current Procedural Terminology code (29882, 29883, and 27403). This cohort was then screened for subsequent procedures following the index procedure. Risk factors for reoperation were calculated using a Cox proportional hazard analysis. A total of 3259 primary meniscal repairs were identified over the study period, of which 1423 (43.7%) were performed in conjunction with anterior cruciate ligament (ACL) reconstruction. The reoperation rate was 13.6%, occurring at a median of 1.1 years following the index procedure. Marine Corps service, younger age (>35), enlisted or cadet rank, and junior rank status were identified as significant risk factors for requiring reoperation. Isolated repairs were significantly more likely to require a secondary procedure than those with concomitant ACL reconstruction. Meniscal repairs performed in the military demonstrate similar reoperation rates as published literature despite increased occupational demands. (Journal of Surgical Orthopaedic Advances 27(1):47-51, 2018). PMID- 29762118 TI - Pediatric Orthopaedic Consults From Chiropractic Care. AB - Alternative medicine in pediatrics is expanding, with chiropractic now a common choice for families seeking alternative medical care. Currently, there is sparse information in the literature exploring the role of chiropractic in orthopaedic pathology. The objective of this case series is to present pediatric patients who received treatment from chiropractors and orthopaedic physicians as well as to review the respective existing research. Data collected included chiropractic diagnosis, orthopaedic diagnosis, imaging studies, treatments, and complications. Twenty-three patients were studied. Scoliosis, Legg-Calve-Perthes disease, developmental dysplasia of the hip, cerebral palsy, skeletal dysplasia, and slipped capital femoral epiphysis were diagnoses included. Children had multiple sessions of chiropractic for management of these conditions. The parents' perception for chiropractic was positive in every case. Delayed referral, misdiagnosis, adverse events from manipulative therapy, and ineffective treatments were observed in the present study. More research is indicated to validate chiropractic in children with orthopaedic pathology. (Journal of Surgical Orthopaedic Advances 27(1):58-63, 2018). PMID- 29762119 TI - Hip Fracture Mortality: Differences Between Intertrochanteric and Femoral Neck Fractures. AB - The purpose of this study was to identify the specific risk factors that affect mortality in patients with hip fractures and differentiate mortality-associated factors between intertrochanteric (IT) and femoral neck (FN) fractures. A total of 1538 consecutive patients with hip fractures were treated at the authors' institution between January 2005 and October 2013. Ultimately 858 IT and 479 FN fracture patients were included on the basis of age >60 years with an isolated hip fracture. Mortality rate at 90 days was 12.1% for IT and 9.6% for FN fractures. In both IT and FN fractures, variables associated with mortality risk include increased age, greater days to surgery, male gender, decreased body mass index, and increased American Society of Anesthesiologists score. When evaluated independently, the presence of cardiac arrhythmia and chronic kidney disease was strongly associated with greater mortality risk in FN fracture patients. The presence of chronic kidney disease and hypertension correlated with decreased mortality risk among FN fracture patients. (Journal of Surgical Orthopaedic Advances 27(1):64-71, 2018). PMID- 29762120 TI - Readability of Patient Educational Materials for Total Hip and Knee Arthroplasty. AB - This study aimed to evaluate patient education materials that are focused on total hip arthroplasty (THA) and total knee arthroplasty (TKA) using health literacy best practices and plain language principles as frameworks. Readability assessments were conducted on a sample of nine patient education documents that are commonly given to THA and TKA surgery patients. Mean readability scores were compared across the sample. The mean readability grade level for the nine arthroplasty educational documents analyzed in this study was 11th grade (10.5). The mean readability ranged from 9th to 12th grade. The documents in this study were written at levels that exceed recommendations by health literacy experts. Health literacy best practices and plain language principles were suggested to reduce the demands on patients so that the documents are easier to understand. Incorporating health literacy best practices into patient education materials for THA and TKA can contribute to improved communication with patients that is necessary for patient understanding and satisfaction. (Journal of Surgical Orthopaedic Advances 27(1):72-76, 2018). PMID- 29762121 TI - Friction Syndromes of the Knee: The Iliotibial Band and Anterior Fat Pads. AB - As participation in sporting activities increases among the general population, the incidence of overuse injuries continues to rise. Friction syndromes of the knee are common and are often clinically diagnosed without the need for imaging. However, clinical symptoms may overlap with other joint abnormalities, and physical examination may be limited in individuals with excessive pain. Magnetic resonance imaging has remained the modality of choice for the evaluation of internal derangements of the joints and is a useful aid in the diagnosis of friction syndrome of the knee. This case report provides clinicians with an understanding of the most common friction syndromes of the knee joint as well as their imaging findings. (Journal of Surgical Orthopaedic Advances 27(1):77-80, 2018). PMID- 29762124 TI - Growth of two-dimensional decagonal colloidal quasicrystals. AB - The growth of quasicrystals, i.e. structures with long-range positional order but no periodic translational symmetry, is more complex than the growth of periodic crystals. By employing Brownian dynamics simulations in two dimensions for colloidal particles that interact according to an isotropic pair potential with two incommensurate lengths, we study the growth of quasicrystalline structures by sequentially depositing particles at their surface. We quantify the occurrence of quasicrystalline order as a function of the temperature and the rate of added particles. In addition, we explore defects like local triangular order or gaps within the quasicrystalline structure. Furthermore, we analyze the shapes of the surfaces in grown structures which tend to build straight lines along the symmetry axes of the quasicrystal. Finally, we identify phasonic flips which are rearrangements of the particles due to additional degrees of freedom. The number of phasonic flips decreases with the distance to the surface. PMID- 29762125 TI - Anomalous mobility of a driven active particle in a steady laminar flow. AB - We study, via extensive numerical simulations, the force-velocity curve of an active particle advected by a steady laminar flow, in the nonlinear response regime. Our model for an active particle relies on a colored noise term that mimics its persistent motion over a time scale [Formula: see text]. We find that the active particle dynamics shows non-trivial effects, such as negative differential and absolute mobility (NDM and ANM, respectively). We explore the space of the model parameters and compare the observed behaviors with those obtained for a passive particle ([Formula: see text]) advected by the same laminar flow. Our results show that the phenomena of NDM and ANM are quite robust with respect to the details of the considered noise: in particular for finite [Formula: see text] a more complex force-velocity relation can be observed. PMID- 29762123 TI - Identification of a critical sulfation in chondroitin that inhibits axonal regeneration. AB - The failure of mammalian CNS neurons to regenerate their axons derives from a combination of intrinsic deficits and extrinsic factors. Following injury, chondroitin sulfate proteoglycans (CSPGs) within the glial scar inhibit axonal regeneration, an action mediated by the sulfated glycosaminoglycan (GAG) chains of CSPGs, especially those with 4-sulfated (4S) sugars. Arylsulfatase B (ARSB) selectively cleaves 4S groups from the non-reducing ends of GAG chains without disrupting other, growth-permissive motifs. We demonstrate that ARSB is effective in reducing the inhibitory actions of CSPGs both in in vitro models of the glial scar and after optic nerve crush (ONC) in adult mice. ARSB is clinically approved for replacement therapy in patients with mucopolysaccharidosis VI and therefore represents an attractive candidate for translation to the human CNS. PMID- 29762122 TI - Distinct myocardial lineages break atrial symmetry during cardiogenesis in zebrafish. AB - The ultimate formation of a four-chambered heart allowing the separation of the pulmonary and systemic circuits was key for the evolutionary success of tetrapods. Complex processes of cell diversification and tissue morphogenesis allow the left and right cardiac compartments to become distinct but remain poorly understood. Here, we describe an unexpected laterality in the single zebrafish atrium analogous to that of the two atria in amniotes, including mammals. This laterality appears to derive from an embryonic antero-posterior asymmetry revealed by the expression of the transcription factor gene meis2b. In adult zebrafish hearts, meis2b expression is restricted to the left side of the atrium where it controls the expression of pitx2c, a regulator of left atrial identity in mammals. Altogether, our studies suggest that the multi-chambered atrium in amniotes arose from a molecular blueprint present before the evolutionary emergence of cardiac septation and provide insights into the establishment of atrial asymmetry. PMID- 29762126 TI - Simple and efficient LCAO basis sets for the diffuse states in carbon nanostructures. AB - We present a simple way to describe the lowest unoccupied diffuse states in carbon nanostructures in density functional theory calculations using a minimal LCAO (linear combination of atomic orbitals) basis set. By comparing plane wave basis calculations, we show how these states can be captured by adding long-range orbitals to the standard LCAO basis sets for the extreme cases of planar sp 2 (graphene) and curved carbon (C60). In particular, using Bessel functions with a long range as additional basis functions retain a minimal basis size. This provides a smaller and simpler atom-centered basis set compared to the standard pseudo-atomic orbitals (PAOs) with multiple polarization orbitals or by adding non-atom-centered states to the basis. PMID- 29762127 TI - Electrospun fiber surface nanotopography influences astrocyte-mediated neurite outgrowth. AB - Aligned, electrospun fiber scaffolds provide topographical guidance for regenerating neurons and glia after central nervous system injury. To date, no study has explored how fiber surface nanotopography affects astrocyte response to fibrous scaffolds. Astrocytes play important roles in the glial scar, the blood brain barrier, and in maintaining homeostasis in the central nervous system. In this study, electrospun poly L-lactic acid fibers were engineered with smooth, pitted, or divoted surface nanotopography. Cortical or spinal cord primary rat astrocytes were cultured on the surfaces for either 1 or 3 d to examine the astrocyte response over time. The results showed that cortical astrocytes were significantly shorter and broader on the pitted and divoted fibers compared to those on smooth fibers. However, spinal cord astrocyte morphology was not significantly altered by the surface features. These findings indicate that astrocytes from unique anatomical locations respond differently to the presence of nanotopography. Western blot results show that the differences in morphology were not associated with significant changes in glial fibrillary acidicprotein (GFAP) or vinculin in either astrocyte population, suggesting that surface pits and divots do not induce a reactive phenotype in either cortical or spinal cord astrocytes. Finally, astrocytes were co-cultured with dorsal root ganglia to determine how the surfaces affected astrocyte-mediated neurite outgrowth. Astrocytes cultured on the fibers for shorter periods of time (1 d) generally supported longer neurite outgrowth. Pitted and divoted fibers restricted spinal cord astrocyte-mediated neurite outgrowth, while smooth fibers increased 3 d spinal cord astrocyte-mediated neurite outgrowth. In total, fiber surface nanotopography can influence astrocyte elongation and influence the capability of astrocytes to direct neurites. Therefore, fiber surface characteristics should be carefully controlled to optimize astrocyte-mediated axonal regeneration. PMID- 29762128 TI - Collective excitations in Weyl semimetals in the hydrodynamic regime. AB - The spectrum of collective excitations in Weyl materials is studied by using consistent hydrodynamics. The corresponding framework includes the vortical and chiral anomaly effects, as well as the dependence on the separations between the Weyl nodes in energy b 0 and momentum [Formula: see text]. The latter are introduced via the Chern-Simons contributions to the electric current and charge densities in Maxwell's equations. It is found that, even in the absence of a background magnetic field, certain collective excitations (e.g. the helicon-like modes and the anomalous Hall waves) are strongly affected by the chiral shift [Formula: see text]. In a background magnetic field, the existence of the distinctive longitudinal and transverse anomalous Hall waves with a linear dispersion relation is predicted. They originate from the oscillations of the electric charge density and electromagnetic fields, in which different components of the fields are connected via the anomalous Hall effect in Weyl semimetals. PMID- 29762129 TI - Low-bias negative differential resistance in junction of a benzene between zigzag edged phosphorene nanoribbons. AB - We study the electron transport properties through the junction of a benzene molecule in conjunction with two monolayer zigzag-edged phosphorene nanoribbon (ZPNR) electrodes by applying the nonequilibrium Green's functions in combination with the density functional theory. We find that the molecular junction with two phosphorus-carbon bonds exhibits an interesting low-bias negative differential resistance effect with a peak-to-valley ratio of 29, which originates from the edge states in ZPNR due to the anisotropic band structure of phosphorene. Importantly, the performance of the junction can be tuned via the molecule-ZPNR interface bonding. The findings may be useful in sensitive-device applications. Furthermore, the physical mechanisms are revealed and discussed in terms of the electronic transmission spectrum, the evolution of the frontier molecular orbitals, the local device density of states around the Fermi level, and the projected density of states. PMID- 29762130 TI - Ionization chamber correction factors for MR-linacs. AB - Previously, readings of air-filled ionization chambers have been described as being influenced by magnetic fields. To use these chambers for dosimetry in magnetic resonance guided radiotherapy (MRgRT), this effect must be taken into account by introducing a correction factor k B. The purpose of this study is to systematically investigate k B for a typical reference setup for commercially available ionization chambers with different magnetic field strengths. The Monte Carlo simulation tool EGSnrc was used to simulate eight commercially available ionization chambers in magnetic fields whose magnetic flux density was in the range of 0-2.5 T. To validate the simulation, the influence of the magnetic field was experimentally determined for a PTW30013 Farmer-type chamber for magnetic flux densities between 0 and 1.425 T. Changes in the detector response of up to 8% depending on the magnetic flux density, on the chamber geometry and on the chamber orientation were obtained. In the experimental setup, a maximum deviation of less than 2% was observed when comparing measured values with simulated values. Dedicated values for two MR-linac systems (ViewRay MRIdian, ViewRay Inc, Cleveland, United States, 0.35 T/ 6 MV and Elekta Unity, Elekta AB, Stockholm, Sweden, 1.5 T/7 MV) were determined for future use in reference dosimetry. Simulated values for thimble-type chambers are in good agreement with experiments as well as with the results of previous publications. After further experimental validation, the results can be considered for definition of standard protocols for purposes of reference dosimetry in MRgRT. PMID- 29762131 TI - Two dimensional self-assembly zinc porphyrin and zinc phthalocyanine heterojunctions with record high power conversion efficiencies. AB - Compared to inorganic solar cells, the power conversion efficiencies (PCEs) of organic solar cells are much lower, but they are compensated by many merits such as lower cost, less weight, and tunable structures, making them prospective for further applications. Porphyrin and phthalocyanine are the two most significant materials for organic solar cells due to their strong light-absorbing properties and semiconductor characteristics. However, there is little research on the 2D heterojunction solar cells based on these two materials, meanwhile the PCEs of them are still low. Here we have self-assembled several 2D zinc porphyrins (ZnPors) and performed first-principles simulation to demonstrate their good stability, suitable light harvesting, and high charge carrier mobility. By perfectly matching lattice constants and molecular energy levels between those 2D ZnPors and our previous proposed zinc phthalocyanines (ZnPcs), 11 type-II organic heterojunctions are constructed to further improve their charge separation capability. Those advantages endow 2D ZnPors and ZnPcs appreciable PCEs for solar cells. Among them, the theoretical PCE of 2D ZnPors/ZnPcs heterojunctions achieves as high as 19.84%, which exceeds all reported organic solar cells, and even approaches the PCEs of inorganic solar cells. These results indicate that our 2D ZnPors and 2D ZnPcs are good candidate materials for future organic solar cells. PMID- 29762132 TI - Initial performance evaluation of a preclinical PET scanner available as a clip on assembly in a sequential PET/MRI system. AB - We evaluated the performance characteristics of a prototype preclinical PET scanner available as an easy clippable assembly that can dock to an MRI system. The single ring version of the PET system consists of eight detectors, each of which comprises a 12 * 12 silicon photomultipliers (SiPMs) array coupled with a dual layer of offset scintillation crystals to measure depth of interaction. The crystal arrays have 29 * 29 (30 * 30 for the outer layer) 4 mm long LYSO crystals (6 mm for the outer layer). The ring diameter is 119.2 mm and the axial field of view is 50.4 mm. The NEMA NU 4-2008 protocol was followed for studying the PET performance. Temperature stability of SiPMs was also investigated. The peak system absolute sensitivity was 4.70% with an energy window of 250-750 keV. The spatial resolution was 1.28/1.88/1.85 mm FWHM (radial/tangential/axial) at a distance of 5 mm from the center. Peak noise equivalent counting rate and scatter fraction for mouse phantom were 61.9 kcps at 14.9 MBq and 21.0%, respectively. The uniformity was 6.3% and the spill-over ratios in the images of the water-and air-filled chambers were 0.07 and 0.17, respectively. Recovery coefficients ranged from 0.13 to 0.96. Change in sensitivity as a function of ambient temperature was 0.3%/ degrees C. These first results indicate excellent spatial resolution performance for use with animal studies. Moreover, the clippable assembly can be upgraded to accept a second ring of SiPMs modules, leading to improved sensitivity and axial coverage. PMID- 29762133 TI - Evidence and evolution of magnetic polaron in HgCr2Se4 investigated by electron spin resonance. AB - The evidence and evolution of magnetic polarons (MPs) in HgCr2Se4 have been studied by electron spin resonance (ESR), magnetism and conductivity measurements in a temperature range of 5-300 K. A single paramagnetic resonance line is observed in the high-temperature range while multiple resonance lines appear in the low-temperature range. As temperature decreases, the peak-to-peak linewidth DeltaH pp shows a minimum at T min ~ 210 K, with the activation energy fitted by small polaron hopping model consistent with the bottleneck mechanism, providing an evidence for existence of small MPs above T min. The analysis of the temperature dependence of DeltaH pp, double integrated intensity I, and g factor of ESR signals, combined with the temperature dependence of magnetization and conductivity, reveals an evolution process from small MPs at zone I (T > T min) to correlated MPs at zone II (T c < T * ? T ? T min) in the paramagnetic regime. Three critical temperatures, T min (~210 K), T th (~175 K), and T * (~121 K), which determine the evolution characteristics of MPs, are distinguished. The magnetic correlation length xi of Cr3+-Se2--Cr3+ should account for the evolution of MPs. PMID- 29762134 TI - Scaling analysis of the non-Abelian quasiparticle tunneling in [Formula: see text] FQH states. AB - Quasiparticle tunneling between two counter propagating edges through point contacts could provide information on its statistics. Previous study of the short distance tunneling displays a scaling behavior, especially in the conformal limit with zero tunneling distance. The scaling exponents for the non-Abelian quasiparticle tunneling exhibit some non-trivial behaviors. In this work, we revisit the quasiparticle tunneling amplitudes and their scaling behavior in a full range of the tunneling distance by putting the electrons on the surface of a cylinder. The edge-edge distance can be smoothly tuned by varying the aspect ratio for a finite size cylinder. We analyze the scaling behavior of the quasiparticles for the Read-Rezayi [Formula: see text] states for [Formula: see text] and 4 both in the short and long tunneling distance region. The finite size scaling analysis automatically gives us a critical length scale where the anomalous correction appears. We demonstrate this length scale is related to the size of the quasiparticle at which the backscattering between two counter propagating edges starts to be significant. PMID- 29762135 TI - Surface morphology of molybdenum silicide films upon low-energy ion beam sputtering. AB - The surface morphology of molybdenum silicide (Mo x Si1-x ) films has been studied after low-energy Ar+ ion beam sputtering (IBS) to explore eventual pattern formation on compound targets and, simultaneously, gather information about the mechanisms behind silicide-assisted nanopatterning of silicon surfaces by IBS. For this purpose, Mo x Si1-x films with compositions below, equal and above the MoSi2 stoichiometry (x = 0.33) have been produced by magnetron sputtering, as assessed by Rutherford backscattering spectrometry (RBS). The surface morphology of silicon and silicide films before and after IBS has been imaged by atomic force microscopy (AFM), comprising conditions where typical nanodot or ripple patterns emerge on the former. In the case of irradiated Mo x Si1-x surfaces, AFM shows a marked surface smoothing at normal incidence with and without additional Mo incorporation (the former results in nanodot patterns on Si). The morphological analysis also provides no evidence of ion-induced phase separation in irradiated Mo x Si1-x . Contrary to silicon, Mo x Si1-x surfaces also do not display ripple formation for (impurity free) oblique irradiations, except at grazing incidence conditions where parallel ripples emerge in a more evident fashion than in the Si counterpart. By means of RBS, irradiated Mo x Si1 x films with 1 keV Ar+ at normal incidence have also been used to measure experimentally the (absolute) sputtering yield and rate of Si and Mo x Si1-x materials. The analysis reveals that, under the present working conditions, the erosion rate of silicides is larger than for silicon, supporting simulations from the TRIDYN code. This finding questions the shielding effect from silicide regions as roughening mechanism in metal-assisted nanopatterning of silicon. On the contrary, the results highlight the relevance of in situ silicide formation. Ripple formation on Mo x Si1-x under grazing incidence is also attributed to the dominance of sputtering effects under this geometry. In conclusion, our work provides some insights into the complex morphological evolution of compound surfaces and solid experimental evidences regarding the mechanisms behind silicide-assisted nanopatterning. PMID- 29762137 TI - Spatial frequency performance limitations of radiation dose optimization and beam positioning. AB - The flexibility and sophistication of modern radiotherapy treatment planning and delivery methods have advanced techniques to improve the therapeutic ratio. Contemporary dose optimization and calculation algorithms facilitate radiotherapy plans which closely conform the three-dimensional dose distribution to the target, with beam shaping devices and image guided field targeting ensuring the fidelity and accuracy of treatment delivery. Ultimately, dose distribution conformity is limited by the maximum deliverable dose gradient; shallow dose gradients challenge techniques to deliver a tumoricidal radiation dose while minimizing dose to surrounding tissue. In this work, this 'dose delivery resolution' observation is rigorously formalized for a general dose delivery model based on the superposition of dose kernel primitives. It is proven that the spatial resolution of a delivered dose is bounded by the spatial frequency content of the underlying dose kernel, which in turn defines a lower bound in the minimization of a dose optimization objective function. In addition, it is shown that this optimization is penalized by a dose deposition strategy which enforces a constant relative phase (or constant spacing) between individual radiation beams. These results are further refined to provide a direct, analytic method to estimate the dose distribution arising from the minimization of such an optimization function. The efficacy of the overall framework is demonstrated on an image guided small animal microirradiator for a set of two-dimensional hypoxia guided dose prescriptions. PMID- 29762136 TI - Evaluation of a clinical TOF-PET detector design that achieves ?100 ps coincidence time resolution. AB - Commercially available clinical positron emission tomography (PET) detectors employ scintillation crystals that are long ([Formula: see text]20 mm length) and narrow (4-5 mm width) optically coupled on their narrow end to a photosensor. The aspect ratio of this traditional crystal rod configuration and 511 keV photon attenuation properties yield significant variances in scintillation light collection efficiency and transit time to the photodetector, due to variations in the 511 keV photon interaction depth in the crystal. These variances contribute significant to coincidence time resolution degradation. If instead, crystals are coupled to a photosensor on their long side, near-complete light collection efficiency can be achieved, and scintillation photon transit time jitter is reduced. In this work, we compare the achievable coincidence time resolution (CTR) of LGSO:Ce(0.025 mol%) crystals 3-20 mm in length when optically coupled to silicon photomultipliers (SiPMs) on either their short end or long side face. In this 'side readout' configuration, a CTR of 102 +/- 2 ps FWHM was measured with [Formula: see text] mm3 crystals coupled to rows of [Formula: see text] mm2 SensL J SiPMs using leading edge time pickoff and a single timing channel. This is in contrast to a CTR of 137 +/- 3 ps FWHM when the same crystals were coupled to single [Formula: see text] mm2 SiPMs on their narrow ends. We further study the statistical limit on CTR using side readout via the Cramer-Rao lower bound (CRLB), with consideration given to ongoing work to further improve photosensor technologies and exploit fast phenomena to ultimately achieve 10 ps FWHM CTR. Potential design aspects of scalable front-end signal processing readout electronics using this side readout configuration are discussed. Altogether, we demonstrate that the side readout configuration offers an immediate solution for 100 ps CTR clinical PET detectors and mitigates factors prohibiting future efforts to achieve 10 ps FWHM CTR. PMID- 29762138 TI - Theranostic gold-magnetite hybrid nanoparticles for MRI-guided radiosensitization. AB - The main limitation of drug-enhanced radiotherapy concerns the difficulty to evaluate the effectiveness of cancer targeting after drug administration hindering the standardization of therapies based on current radiosensitizing compounds. The challenge regards the development of systems able to combine imaging and radiotherapy enhancement in order to perform highly reliable cancer theragnosis. For these reasons, gold-magnetite hybrid nanoparticles (H-NPs) are proposed as innovative theranostic nanotools for imaging-guided radiosensitization in cancer treatment. In this work we propose a novel method for the synthesis of hydrophilic and superparamagnetic Tween20-stabilized gold magnetite H-NPs. Morphology and chemical composition of nanoparticles were assessed by transmission electron microscopy, x-ray diffraction analysis and ion coupled plasma optical emission spectroscopy. Colloidal stability and magnetic properties of nanoparticles were determined by dynamic light scattering and magnetometry. The potentialities of H-NPs for magnetic resonance imaging were studied using a human 4T-MRI scanner. Nanoparticles were proven to induce concentration-dependent contrast enhancement in T2*-weighted MR-images. The cytotoxicity, the cellular uptake and the radiosensitization activity of H-NPs were investigated in human osteosarcoma MG63 cell cultures and murine 3T3 fibroblasts, using specific bioassays and laser scanning confocal microscopy. H NPs did not exhibit significant toxicity and were demonstrated to be internalized by cells. A significant x-ray enhancement at specific H-NPs exposure concentrations was evidenced on MG63 cell line. PMID- 29762139 TI - Biophysical constraints determine the selection of phenotypic fluctuations during directed evolution. AB - Phenotypes of individuals in a population of organisms are not fixed. Phenotypic fluctuations, which describe temporal variation of the phenotype of an individual or individual-to-individual variation across a population, are present in populations from microbes to higher animals. Phenotypic fluctuations can provide a basis for adaptation and be the target of selection. Here we present a theoretical and experimental investigation of the fate of phenotypic fluctuations in directed evolution experiments where phenotypes are subject to constraints. We show that selecting bacterial populations for fast migration through a porous environment drives a reduction in cell-to-cell variation across the population. Using sequencing and genetic engineering we study the genetic basis for this reduction in phenotypic fluctuations. We study the generality of this reduction by developing a simple, abstracted, numerical simulation model of the evolution of phenotypic fluctuations subject to constraints. Using this model we find that strong and weak selection generally lead respectively to increasing or decreasing cell-to-cell variation as a result of a bound on the selected phenotype under a wide range of parameters. However, other behaviors are also possible, and we describe the outcome of selection simulations for different model parameters and suggest future experiments. We analyze the mechanism of the observed reduction of phenotypic fluctuations in our experimental system, discuss the relevance of our abstract model to the experiment and explore its broader implications for evolution. PMID- 29762140 TI - Density anomaly of water at negative pressures from first principles. AB - Using molecular dynamics simulations based on ab initio trained high-dimensional neural network potentials, we study the equation of state of liquid water at negative pressures. From density isobars computed for various pressures down to p = -230 MPa we determine the line of density maxima for two potentials based on the BLYP and the RPBE functionals, respectively. In both cases, dispersion corrections are included to account for non-local long-range correlations that give rise to van der Waals forces. We have followed the density maximum down to negative pressures close to the spinodal instability. For both functionals, the temperature of maximum density increases with decreasing pressure under moderate stretching, but changes slope at [Formula: see text] MPa and [Formula: see text] MPa for BLYP and RPBE, respectively. Our calculations confirm qualitatively the retracing shape of the line of density maxima found for empirical water models, indicating that the spinodal line maintains a positive slope even at strongly negative pressures. PMID- 29762141 TI - PD-1 Expression in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and Large B-cell Richter Transformation (DLBCL-RT): A Characteristic Feature of DLBCL-RT and Potential Surrogate Marker for Clonal Relatedness. AB - Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a low-grade B-cell neoplasm and ~2% to 9% patients develop an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (Richter transformation, DLBCL-RT). Programmed death-1 (PD-1) pathway plays a crucial role in tumor host immunity evasion and its blockade has emerged as an effective anti-cancer immunotherapy. PD-L1 and PD-1 expression has shown predictive value in anti-PD cancer immunotherapy; however, it has not been well documented in CLL/SLL and DLBCL-RT. We evaluated PD-1 and PD-L1 expression by immunohistochemistry in 39 CLL/SLL, 15 DLBCL-RT, and 26 other DLBCL. In CLL/SLL, neoplastic B-cell PD-1 expression was weak and restricted to prolymphocytes/paraimmunoblasts within proliferation centers (PCs) and accentuated PCs of all sizes. Neoplastic B-cell PD-1 expression was highly prevalent and demonstrated increased intensity in DLBCL-RT, but in contrast was only rarely seen in other DLBCL (12/15 vs. 1/26; P<0.0001). An excellent correlation (90% concordance) was observed between neoplastic B-cell PD 1 immunohistochemistry positivity and molecularly defined CLL/SLL clonal relatedness in DLBCL-RT. PD-L1 expression was observed on the neoplastic B cells in rare DLBCL-RT and other DLBCL cases (1/15 vs. 1/26; P>0.05) as well as background histiocytes and dendritic cells. Overall survival of DLBCL-RT was significantly inferior to that of the other DLBCL (median, 16.9 vs. 106.1 mo; P=0.002). Our findings suggest a biological continuum from prolymphocytes/paraimmunoblasts in CLL/SLL PCs to the neoplastic B-cells in DLBCL RT. The characteristic PD-1 expression in DLBCL-RT makes it a potential surrogate marker for determining clonal relatedness to CLL/SLL, which may have important prognostic and therapeutic implications. PMID- 29762142 TI - Cytology Preparations of Formalin Fixative Aid Detection of Giardia in Duodenal Biopsy Samples: A Helpful Tool for Diagnosing Esophageal Candidiasis as Well? PMID- 29762143 TI - Mucositis and Cardiotoxicity Due to 5-Fluorouracil. PMID- 29762145 TI - A Succinct Critical Appraisal of Indications to Transanal Total Mesorectal Excision. PMID- 29762144 TI - Cardiovascular diseases in congenital prekallikrein deficiency: comparison with other chance-associated morbidities. AB - : To compare the prevalence of cardiovascular diseases with other chance associated morbidities in patients with congenital prekallikrein deficiency. Patients with prekallikrein deficiency were gathered from two time unlimited PubMed searches and from personal files. Inclusion criteria were prekallikrein level less than 15% of normal; correction of aPTT on long incubation times; prolonged aPTT corrected by normal plasma or serum; normal prothrombin time and normal FXII and FXI. Acquired forms were excluded. Out of 106 patients, we have found that 45 patients had at least one chance-associated defect or morbidity at the time of the diagnosis of the clotting defect. Twenty-nine of these 45 patients had cardiovascular disorders. Other comorbidities were found in a much smaller proportion. Congenital prekallikrein deficiency is frequently associated with cardiovascular conditions, namely hypertension, coronary disease, ischemic stroke, venous thrombosis. The significance of these findings is critically discussed as association between two diseases does not necessarily indicate the existence of a causative relation between the two. However, the findings presented here clearly indicate the possibility that such a relation might indeed exist. PMID- 29762146 TI - An augmented Pd/Pa response after contrast injection during intravenous adenosine induced hyperemia. PMID- 29762148 TI - Menopausal Hormone Therapy in Gynecologic Cancer Survivors: A Review of the Evidence and Practice Recommendations. AB - Gynecologic cancers are common in the United States and represent a significant health burden. Treatment of these cancers often causes premature cessation of ovarian function, with resultant symptoms that are often more severe than those associated with natural menopause. Hormone therapy is the most effective treatment for menopausal symptoms, but the decision-making process about its use can be complex for survivors of gynecologic cancer. In this review, we provide evidence-based recommendations about the use of hormone therapy after gynecologic cancer. PMID- 29762147 TI - Managing Menopause by Combining Evidence With Clinical Judgment. AB - In the United States, nearly 10 million women are currently in the menopause transition and 2.25 million women are 51 years of age, which is the average age of menopause. Approximately 75% of these women will experience vasomotor symptoms such as hot flashes and night sweats. Menopause hormone therapy (HT) remains the most effective treatment for menopausal symptoms, but the decision to use HT is complex and requires balancing the benefits and risks for the individual patient. The decision also requires clinical judgment and shared decision making with the patient. In this review, we discuss the current guidelines for HT use, the benefits and risks for the individual patient and a novel algorithm and clinical decision support tool for menopausal symptom management that facilitates shared decision making between clinician and patient. PMID- 29762149 TI - Pseudoadjuvant chemotherapy in resectable metastatic colorectal cancer. AB - PURPOSE OF REVIEW: In this article, we focus on the potential benefits and risks of chemotherapy administration before (perioperative) or after (pseudoadjuvant) a curative resection of colorectal cancer (CRC) metastases. RECENT FINDINGS: In the published evidence, there is a lack of survival benefit from peri or postoperative chemotherapy in the context of resectable metastatic CRC. However, high-risk patients may have a certain benefit when receiving a postoperative cytotoxic treatment. Apart from, according to the published data, the administration of a preoperative chemotherapy has been associated with serious parenchymal liver damage and an increase in the postoperative morbidity-mortality rate. SUMMARY: Surgery is the only potentially curative treatment for metastatic CRC, but the risk of recurrence remains high. The current guidelines recommend the administration of either a perioperative or a pseudoadjuvant chemotherapy in this setting despite the absence of survival benefit. A better selection of patients who may require and gain an advantage from chemotherapy in the setting of resectable metastasis is highly needed. In this view, a prospective trial enrolling patients at high risk of recurrence is ongoing. PMID- 29762150 TI - Physical activity and fitness for the prevention of hypertension. AB - PURPOSE OF REVIEW: The aim of this review is to evaluate the most recent literature about the role of physical activity, exercise, and fitness in hypertension prevention. RECENT FINDINGS: Strong evidence indicates that performing moderate-to-vigorous physical activity, particularly aerobic exercise, and improving cardiorespiratory fitness (CRF) reduce blood pressure (BP) levels and lower hypertension incidence. Although evidence is limited, performing resistance exercise or improving muscular strength appears to be associated with a lower incidence of hypertension. Furthermore, reducing sedentary time or replacing sedentary time with physical activity might lower BP. SUMMARY: To lower the risk of hypertension, promoting physical activity and improving fitness, especially CRF, should be encouraged. More research is needed to determine the effects of sedentary behavior, resistance exercise, and muscle strength on the development of hypertension across diverse populations and settings. Future studies should focus on dose-response relationships of exercise and physical activity with the development of hypertension to determine the minimal and optimal amount of exercise and physical activity for hypertension prevention. PMID- 29762151 TI - Comparison of the peripheral antinociceptive effect of somatostatin with bupivacaine and morphine in the rodent postoperative pain model. AB - BACKGROUND AND OBJECTIVES: Infiltration of surgical wound with local anaesthetics attenuate postoperative pain. However, side effects can also occur. Somatostatin (SST) and its analogues like octreotide reportedly reduce peripheral sensitisation. The current study evaluates peripherally mediated antinociceptive effect of SST in a rat model of postoperative pain. This was compared with bupivacaine and morphine under identical experimental conditions. DESIGN: Randomised vehicle-controlled blind study. SETTING: Pain research laboratory, All India Institute of Medical Sciences, New Delhi from February 2014 to July 2017. EXPERIMENTAL SUBJECT: Rodent hind paw incision model. INTERVENTIONS: Sprague Dawley rats were subjected to incision and one of the following drugs administered into the open wound once by a micropipette: SST (10, 30 or 100 MUg), bupivacaine (3, 10, 30, 50 or 100 MUg) or morphine (100 MUg). Antinociceptive effect of SST was further evaluated for its reversibility, site of action, effect on spinal c-fos expression and blood glucose level. The site of action of morphine was also investigated. MAIN OUTCOME MEASURE: Nociception was estimated by nonevoked (guarding behaviour) and evoked (mechanical allodynia and thermal hyperalgesia) pain behaviours between 2 h and days 4 to 7. RESULTS: Nociception was maximum 2 h after incision. SST (10 to 100 MUg) significantly attenuated guarding behaviour between 2 h and day 2. A delayed inhibitory effect was observed on allodynia. Bupivacaine (10 to 100 MUg doses) similarly decreased guarding score up to day 2 though evoked pain behaviours were relatively unaffected. In contrast, morphine produced a potent but transient inhibitory effect on guarding score at 2 h, which was mediated by both peripheral and central opioid receptors. The antinociceptive effect of SST was peripherally mediated by type 2 receptors and was associated with decreased c-fos staining. Blood glucose level was unaltered. CONCLUSION: Guarding behaviour, which likely represents pain-at-rest following surgery, was attenuated by both bupivacaine and SST to comparable extents. This novel peripherally mediated antinociceptive effect of SST needs further evaluation. PMID- 29762152 TI - Alzheimer's disease neuroimaging. AB - PURPOSE OF REVIEW: The aim of this study was to discuss the contribution of neuroimaging studies to our understanding of Alzheimer's disease. We now have the capability of measuring both tau and beta-amyloid (Abeta) proteins in the brain, which together with more traditional neuroimaging modalities, has led the field to focus on using neuroimaging to better characterize disease mechanisms underlying Alzheimer's disease. RECENT FINDINGS: Studies have utilized tau and Abeta PET, as well as [18F]fluorodeoxyglucose PET, and structural and functional MRI, to investigate the following topics: phenotypic variability in Alzheimer's disease , including how neuroimaging findings are related to clinical phenotype and age; multimodality analyses to investigate the relationships between different neuroimaging modalities and what that teaches us about disease mechanisms; disease staging by assessing neuroimaging changes in the very earliest phases of the disease in cognitively normal individuals and individuals carrying an autosomal dominant Alzheimer's disease mutation; and influence of other comorbidities and proteins to the disease process. SUMMARY: The findings shed light on the role of tau and Abeta, as well as age and other comorbidities, in the neurodegenerative process in Alzheimer's disease. This knowledge will be crucial in the development of better disease biomarkers and targeted therapeutic approaches. PMID- 29762153 TI - Increased Mortality and Reoperation Rates After Treatment for Septic Arthritis of the Knee in People Who Inject Drugs: Nationwide Inpatient Sample, 2000-2013. AB - BACKGROUND: The United States has a growing opioid epidemic impacting all aspects of health care including orthopaedic surgery. Septic arthritis of the knee is a condition commonly encountered by orthopaedic surgeons related to opioid and injection drug use (IDU). Changes in the frequency of hospitalizations for IDU related septic arthritis and differences in septic arthritis patient outcomes according to IDU status in the setting of the burgeoning opioid epidemic are unknown. QUESTIONS/PURPOSES: (1) What proportion of patients with septic arthritis of the knee use injection drugs? (2) Are there any differences in complications, reoperations, length of stay, and leaving against medical advice among patients with septic arthritis of the knee with and without IDU? (3) What are the age and racial trends in IDU-related septic arthritis of the knee from 2000 to 2013? METHODS: The Healthcare Cost and Utilization Project, Nationwide Inpatient Sample database of years 2000 to 2013 was utilized for patients between ages 15 and 64 years with a principal discharge diagnosis of native septic arthritis of the lower leg, the vast majority of which represents the knee. The Nationwide Inpatient Sample is the largest publicly available healthcare database in the United States that can show nationally representative clinical trends and outcomes. Septic arthritis was classified as related or unrelated to IDU based on previously published algorithms using billing codes. Patients with IDU-related septic arthritis were more likely to be black or Hispanic, younger, and use Medicare, Medicaid, or self-payment as their primary payment method. The yearly proportion of patients with septic arthritis who used injection drugs was determined. Hospitalization outcomes including length of stay, leaving against medical advice, number of procedures, and mortality rates were compared after adjusting for age, gender, and race in multivariable regression analyses. The yearly change in proportion of IDU-related septic arthritis in each age, race, and gender group was compared over the study period. RESULTS: The proportion of patients with IDU-related septic arthritis increased from 5% in 2000 to 11% in 2013. After adjusting for age, gender, and race, patients with IDU-related septic arthritis were more likely to die during hospitalization (adjusted odds ratio [AOR], 2.86; 95% confidence interval [CI], 1.51-5.39; p < 0.001) and undergo repeat arthroscopic (AOR, 1.24; 95% CI, 1.06-1.45; p = 0.007) or open irrigation and debridement (AOR, 1.68; 95% CI, 1.28-2.19; p < 0.001). Patients with IDU related septic arthritis were more likely to leave against medical advice (AOR, 7.13; 95% CI, 5.56-9.15; p < 0.001) and also had an additional 5 days in length of stay (95% CI, 4.1-5.5; p < 0.001) on average compared with patients with septic arthritis unrelated to IDU. There was an increasing proportion of patients with IDU-related septic arthritis who were aged 15 to 34 years and 55 to 64 years from 2000 to 2013. CONCLUSIONS: IDU is increasingly the cause of septic knee admissions and is associated with higher rates of mortality, reoperations, resource utilization, and leaving against medical advice. Orthopaedic surgeons must adequately screen for IDU among patients with septic arthritis and monitor them closely for reoperation with a low threshold to reaspirate a knee in the postoperative period. Future studies should determine the current use and potential benefits of a multidisciplinary approach, including addiction specialists, to aid in the management of the increasing number of these patients. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29762154 TI - Value-based Healthcare: Increasing Value by Reducing Implant-related Health Care Costs. PMID- 29762155 TI - CORR Insights(r): Can Augmented Reality Be Helpful in Pelvic Bone Cancer Surgery? An In Vitro Study. PMID- 29762156 TI - Preliminary Use of the Physical and Neurological Examination of Subtle Signs for Detecting Subtle Motor Signs in Adolescents With Sport-Related Concussion. AB - Sensitive examination tools are needed to optimize evaluation after sports related concussion. The Physical and Neurological Examination of Subtle Signs was preliminarily examined for sensitivity to motor changes in a pilot cohort of adolescents aged 13-17 yrs with sports-related concussion. A total of 15 adolescents (5 female adolescents) with sports-related concussion were evaluated up to three times: within 2 wks of injury, approximately 1 mo later (mean, 35 days between visits), and for those not recovered at the second visit, again after clinical recovery (mean, 70 days between the first and last visits for all participants). Comparison data were acquired from 20 age- and sex-matched healthy control athletes with no history of concussion who were evaluated twice (mean, 32 days apart). Main effects of group, time, and interaction effects were evaluated with an analysis of covariance, which controlled for socioeconomic status, times tested, and days between testing sessions. Adolescents with concussion had poorer Physical and Neurological Examination of Subtle Signs performance than controls did at all time points. Performance improved between visits within the concussion group, with no change within the control group. These findings suggest that the Physical and Neurological Examination of Subtle Signs merits additional study in larger cohorts and in combination with other markers of injury to facilitate an enhanced understanding of sports-related concussion and recovery. PMID- 29762157 TI - Recent Advances in the Classification of Low-grade Papillary-like Thyroid Neoplasms and Aggressive Papillary Thyroid Carcinomas: Evolution of Diagnostic Criteria. AB - Papillary thyroid carcinomas account for ~80% of well-differentiated thyroid tumors. During the past decade, several new variants of papillary-like thyroid neoplasms and papillary thyroid carcinomas have been recognized. Some of these neoplasms that were previously classified as malignant have been reclassified as low-grade neoplasms, as the diagnostic criteria have evolved. Similarly, some of the papillary thyroid carcinomas that were previously classified as conventional or classic papillary thyroid carcinomas have now been recognized as more aggressive variants of papillary thyroid carcinomas. Recognizing these differences becomes more important for the proper medical, surgical, and radiotherapeutic management of patients with these neoplasms. PMID- 29762159 TI - Vitamin D in inflammatory bowel disease: more than just a supplement. AB - PURPOSE OF REVIEW: The aim of this review is to explore the protective role of vitamin D on the gastrointestinal tract, summarize the epidemiology of vitamin D deficiency in inflammatory bowel disease (IBD), and highlight recent studies examining the impact of low vitamin D and vitamin D supplementation on IBD clinical outcomes. RECENT FINDINGS: Vitamin D protects the gut barrier by regulating tight junction proteins and inhibiting intestinal apoptosis. Vitamin D enhances innate immunity by inducing antimicrobial peptides and regulates adaptive immunity by promoting anti-inflammatory T cells and cytokines. Vitamin D may also alter the gut microbiota. The prevalence of vitamin D deficiency in IBD is 30-40%. Predictors of vitamin D deficiency in IBD include non-white ethnicity, IBD-related surgery, BMI more than 30, female sex, and pregnancy. Low vitamin D is associated with increased disease activity, inflammation, and clinical relapse. The effect of vitamin D supplementation on IBD clinical outcomes is inconclusive. SUMMARY: Vitamin D plays a protective role on gut health. Vitamin D deficiency in IBD is prevalent and associated with poor outcomes. The benefits of vitamin D supplementation in IBD is unclear. Measuring novel vitamin D metabolites and vitamin D absorption in IBD patients may help guide future studies. PMID- 29762158 TI - Recent Advances in the Diagnosis and Pathogenesis of Neurofibromatosis Type 1 (NF1)-associated Peripheral Nervous System Neoplasms. AB - The diagnosis of a neurofibroma or a malignant peripheral nerve sheath tumor (MPNST) often raises the question of whether the patient has the genetic disorder neurofibromatosis type 1 (NF1) as well as how this will impact the patient's outcome, what their risk is for developing additional neoplasms and whether treatment options differ for NF1-associated and sporadic peripheral nerve sheath tumors. Establishing a diagnosis of NF1 is challenging as this disorder has numerous neoplastic and non-neoplastic manifestations which are variably present in individual patients. Further, other genetic diseases affecting the Ras signaling cascade (RASopathies) mimic many of the clinical features of NF1. Here, we review the clinical manifestations of NF1 and compare and contrast them with those of the RASopathies. We also consider current approaches to genetic testing for germline NF1 mutations. We then focus on NF1-associated neurofibromas, considering first the complicated clinical behavior and pathology of these neoplasms and then discussing our current understanding of the genomic abnormalities that drive their pathogenesis, including the mutations encountered in atypical neurofibromas. As several neurofibroma subtypes are capable of undergoing malignant transformation to become MPNSTs, we compare and contrast patient outcomes in sporadic, NF1-associated and radiation-induced MPNSTs, and review the challenging pathology of these lesions. The mutations involved in neurofibroma-MPNST progression, including the recent identification of mutations affecting epigenetic regulators, are then considered. Finally, we explore how our current understanding of neurofibroma and MPNST pathogenesis is informing the design of new therapies for these neoplasms. PMID- 29762160 TI - Childbirth experiences of women living with HIV: a neglected event in the prevention of mother-to-child transmission care continuum. PMID- 29762161 TI - Anti-HIV IgM protects against mucosal SHIV transmission. AB - OBJECTIVE: Worldwide, most new HIV infections occur through mucosal exposure. Immunoglobulin M (IgM) is the first antibody class generated in response to infectious agents; IgM is present in the systemic circulation and in mucosal fluids as secretory IgM. We sought to investigate for the first time the role of IgM in preventing AIDS virus acquisition in vivo. DESIGN: Recombinant polymeric monoclonal IgM was generated from the neutralizing monoclonal IgG1 antibody 33C6 IgG1, tested in vitro, and given by passive intrarectal immunization to rhesus macaques 30 min before intrarectal challenge with simian-human immunodeficiency virus (SHIV) that carries an HIV-1 envelope gene. RESULTS: In vitro, 33C6-IgM captured virions more efficiently and neutralized the challenge SHIV with a 50% inhibitory molar concentration (IC50) that was 1 log lower than that for 33C6 IgG1. The IgM form also exhibited significantly higher affinity and avidity compared with 33C6-IgG1. After intrarectal administration, 33C6-IgM prevented viremia in four out of six rhesus macaques after high-dose intrarectal SHIV challenge. Five out of six rhesus macaques given 33C6-IgG1 were protected at a five times higher molar concentration compared with the IgM form; all untreated controls became highly viremic. Rhesus macaques passively immunized with 33C6-IgM with breakthrough infection had notably early development of autologous neutralizing antibody responses. CONCLUSION: Our primate model data provide the first proof-of-concept that mucosal IgM can prevent mucosal HIV transmission and have implications for HIV prevention and vaccine development. PMID- 29762163 TI - Transcriptional gene silencing limits CXCR4-associated depletion of bone marrow CD34+ cells in HIV-1 infection. AB - OBJECTIVES: Hematological abnormalities that include changes in bone marrow, such as in anemia and pancytopenia, are common among HIV-infected patients, particularly in the advanced stage of disease. Such abnormalities may be caused by a reduced bone marrow function for hematopoiesis. The aim of this study was to determine whether transcriptional gene silencing can help to preserve the hosts' hematopoietic potential in addition to peripheral CD4 T cells against CCR5-tropic HIV infection. DESIGN: NOD/SCID/JAK3 (NOJ) mice were transplanted with human cord derived CD34 cells with or without transduction with a lentiviral vector expressing a promoter-targeting shRNA called PromA. METHODS: At 16 weeks after transplantation, mice engrafted with CD34 cells were infected with CCR5-tropic HIV-1JRFL. RESULTS: At week 2 postinfection, HIV replication was observed in peripheral blood mononuclear cells and splenocytes. In mice transplanted with unmanipulated CD34 cells, viral replication was accompanied by a loss of peripheral/spleen CD4CCR5 T cells. Interestingly, bone marrow CD34 cells in HIV infected mice were also depleted, but in a CXCR4-associated manner. Conversely, the lentiviral transfer of PromA in CD34 cells prior to transplantation rendered the humanized NOJ mice resistant to HIV replication in CD4 T cells, resulting in better preservation of peripheral/spleen CD4CCR5 T cells and bone marrow CD34 cells at 2 weeks after infection. CONCLUSIONS: These results indicate that stable gene transfer of PromA to hematopoietic stem cells not only limited HIV replication but also led to preservation of different subsets of hematopoietic cells, including bone marrow stem/progenitor cells and CD4 T cells. PMID- 29762162 TI - Genetic characterization of the HIV-1 reservoir after Vacc-4x and romidepsin therapy in HIV-1-infected individuals. AB - OBJECTIVE: Therapeutic HIV-1 immunization followed by latency reversal has been suggested as a strategy to eradicate HIV-1. Here we investigate the phylogenetic composition of the HIV-1 regions targeted by the therapeutic HIV-1 peptide vaccine Vacc-4x in participants in a clinical trial. DESIGN: Seventeen participants on suppressive antiretroviral therapy were vaccinated with six doses of Vacc-4x followed by three doses of romidepsin. Seven study participants were selected for sequencing analysis. All participants underwent an analytical treatment interruption. METHODS: Single-genome/proviral sequencing of the p24-RT region was performed to genetically characterize proviral DNA, cell-associated RNA and outgrowth viruses during therapy as well as plasma HIV-1 RNA during an analytical treatment interruption. RESULTS: There were no changes in cell associated HIV-1 RNA (P = 0.83) and DNA (P = 0.09) diversity over the course of the study and no difference between cell-associated HIV-1 RNA and DNA diversity (P = 0.32). Only one participant showed signs of potential vaccine-related selection in the rebounding plasma virus. In five of seven participants, we identified human leukocyte antigen-specific cytotoxic T lymphocytes (CTL) epitopes containing nonsilent mutations in 100% of the sequences. CONCLUSION: We detected no evidence of selective immune pressure reflected in proviral diversity or by occurrence of specific mutation in the vaccine-targeted epitopes. Preexisting CTL epitope mutations may affect the potency of this therapeutic vaccine. This highlights the challenges of developing effective HIV-1 therapeutic vaccines. PMID- 29762164 TI - Cervical cancer screening among HIV-infected women in an urban, United States safety-net healthcare system. AB - OBJECTIVE: Little is known about cervical cancer screening and results patterns among HIV-infected (HIV+) women in real-world healthcare settings. We characterized two periods of screening opportunity. DESIGN: Retrospective cohort. SETTING: US safety-net healthcare system in Dallas County, Texas. PARTICIPANTS: We analyzed data from electronic medical records (EMR) of 1490 HIV+ women receiving care 2010-2014. MAIN OUTCOME MEASURES: At baseline, we categorized a woman's Pap status 15 months prior to index date as under-screened (vs. screened), and cytology result (normal vs. abnormal). Then, we examined screening completion and results, and colposcopy uptake and results after an abnormal screen, in the subsequent 15-month period. RESULTS: More than half of women (56%) had no evidence of a Pap test (i.e. under-screened) at baseline. Under-screened women were more likely to be older (50-64 years), have diabetes, and unknown viral load; they were less likely to be Black, Hispanic, have Medicaid, recently pregnant, have a HIV clinic visit, or a CD4 cell count at least 200 cells/MUl. Nearly half of under-screened women (46%, n = 383) remained under-screened in the subsequent 15 months. Among women under-screened at baseline who later completed screening and follow-up during the study period, 21 high-grade dysplasia and three cancers were diagnosed. Overall, 40% of women did not receive colposcopy when needed, with most failures to follow-up occurring in women who were under screened at baseline. CONCLUSION: Most HIV+ women receiving care in a safety-net system did not receive sufficient screening for cervical cancer and remained at exceptionally high risk of developing high-grade dysplasia. PMID- 29762167 TI - Integrated HIV-injury programming: an underutilized intersection to engage young adults in HIV care in low and middle-income countries. AB - : Adolescents/young adults, and especially men, are high-risk key populations that have been systematically missed by HIV services in low and middle-income countries (LMICs). Because these groups are also more likely to suffer injuries in LMICs, there are significant opportunities to engage these hard-to-reach persons via integrated HIV-injury programming provided during commonly sought acute/emergency care treatments of injuries. However, current facilities based HIV testing and treatment programs have failed to adequately capture these high risk individuals. As such, research to address the knowledge gaps in HIV care delivery among the injured is needed and has great potential to inform interventions that would identify and treat adolescents/young adults, many of whom have the greatest individual and societal margins for long-term benefits with HIV care globally. PMID- 29762165 TI - Improved fracture prediction using different fracture risk assessment tool adjustments in HIV-infected women. AB - OBJECTIVES: A fracture risk assessment tool (FRAX) using clinical risk factors (CRFs) alone underestimates fracture risk in HIV-infected men. Our objective was to determine whether accuracy of FRAX would be improved by considering HIV as a cause of secondary osteoporosis, and further improved with addition of dual energy X-ray absorptiometry parameters in HIV-infected women. DESIGN: Subgroup analysis of Women's Interagency HIV Study. METHODS: We included 1148 women (900 HIV-infected and 248 uninfected) over age 40 with data to approximate FRAX CRFs and 10-year observational data for incident fragility fractures; 181 (20%) HIV infected women had dual-energy X-ray absorptiometry data. Accuracy of FRAX was evaluated by the observed/estimated ratios of fracture in four models: CRFs alone; CRFs with HIV included as a cause of secondary osteoporosis; CRFs and femoral neck bone mineral density (FN BMD); and CRFs, FN BMD and trabecular bone score. RESULTS: FRAX using CRFs were less accurate in HIV-infected than uninfected women for major osteoporotic (observed/estimated ratio: 5.05 vs. 3.26, P < 0.001) and hip fractures (observed/estimated ratio: 19.78 vs. 7.94, P < 0.001), but improved when HIV was included as a cause of secondary osteoporosis. Among HIV-infected women, FRAX accuracy improved further with addition of FN BMD (observed/estimated ratio: 4.00) for hip fractures, but no further with trabecular bone score. CONCLUSION: FRAX using CRFs alone underestimated fracture risk more in older HIV-infected women than otherwise similar uninfected women. Accuracy is improved when including HIV as a cause of secondary osteoporosis for both major osteoporotic and hip fractures, whereas addition of FN BMD only improved accuracy for hip fracture. PMID- 29762166 TI - Undisclosed antiretroviral drug use in Botswana: implication for national estimates. AB - : Among 3596 HIV-positive participants enrolled in the Botswana Combination Prevention Project who self-reported no prior antiretroviral (ARV) therapy use and were tested for viral load (n = 951; 27% of all participants), 136 (14%) had HIV-1 RNA less than 400 copies/ml. ARV drugs were detected in 52 (39%) of 134 participants tested. Adjusting for undisclosed ARV use increased the overall estimate of virally suppressed individuals on ARV therapy by 1.4% from 70.2 to 71.6%. PMID- 29762168 TI - Multimorbidity, age-related comorbidities and mortality: association of activation, senescence and inflammation markers in HIV adults. AB - BACKGROUND: The widespread introduction of combination antiretroviral therapy (cART) has increased survival of HIV-infected patients. However, the prevalence of age-related comorbidities remains higher than that of the general population, suggesting that individuals with HIV suffer from accelerated aging. Immune activation, senescence and inflammation could play an important role in this process. METHODS: The CIADIS (Chronic Immune Activation anD Senescence) sub-study analyzed biomarkers of activation, differentiation and senescence of T cells in a cellular-CIADIS-weighted score, whereas biomarkers of inflammation were analyzed in a soluble CIADIS-weighted score using principal component analysis. Adjusted logistic regression and Cox proportional hazard models were used to determine the association between CIADIS-weighted scores and the presence of multimorbidity, time to occurrence of the first new age-related comorbidity and time to death, over a 3-year follow-up period. RESULTS: Of 828 patients with an undetectable viral load, a higher cellular-CIADIS-weighted score and higher TNFRI levels were independently associated with the presence of multimorbidity (OR 1.3; 95% CI 1.0 1.6; P = 0.02), but the soluble CIADIS-weighted score was not (OR = 1.1; 95% CI 0.9-1.3; P = 0.33). A higher cellular CIADIS-weighted score (hazard ratio 2.2; P < 0.01), higher levels of CD8 activation and a lower CD4/CD8 ratio were associated with a higher risk of age-related comorbidities. Only TNFRI was associated with mortality in a 3-year period. CONCLUSION: The cellular CIADIS weighted score was independently associated with both multimorbidity at inclusion and the risk of new age-related comorbidity during a 3- year follow-up. TNFRI was associated a higher risk for mortality. PMID- 29762169 TI - Change in sexual risk behaviour after 6 months of pre-exposure prophylaxis use: results from the Amsterdam pre-exposure prophylaxis demonstration project. AB - OBJECTIVE: HIV pre-exposure prophylaxis (PrEP) use may lead to higher STI incidence via behavioural risk compensation. We examined changes in sexual behaviour between baseline and 6 months after PrEP initiation among MSM and transgender women (TGW). DESIGN: Prospective, open-label demonstration study at a large sexually transmitted infection (STI) clinic in Amsterdam, the Netherlands. METHODS: Participants answered questions about sexual behaviour in the preceding 3 months, including number of anal sex partners and frequency of anal sex with and without condom by partner type and were tested for STI. Sexual behaviour at baseline was compared with 6 months after PrEP initiation using Wilcoxon signed rank tests. Logistic regression was used to identify factors associated with an increase in receptive condomless anal sex acts (rCASa) with casual partners. RESULTS: Data were available for 328 (99%) MSM and 2 (1%) TGW. The number of receptive and insertive condomless anal sex acts (CASa) increased (baseline: median 11, interquartile range 4-23; 6 months: median 14, interquartile range 6 26, P < 0.001), whereas the number of anal sex partners (P = 0.2) and anal sex acts (P = 0.8) remained unchanged. Prevalence of STI was stable. Older age, prior engagement in chemsex, recent use of postexposure prophylaxis and choosing a daily PrEP regimen at baseline were associated with an increase in rCASa with casual partners. CONCLUSION: Over the first 6 months after initiation of PrEP, an increase in insertive and receptive CASa with casual partners was observed. Long term follow-up data are needed and STI incidence needs to be closely monitored. PMID- 29762170 TI - A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis. AB - OBJECTIVE(S): Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear. DESIGN: Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection (n = 24) and age/sex-balanced uninfected controls (n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals (n = 15) and uninfected controls (n = 15). METHODS: The expression of 12 IFNalpha subtypes, IFNbeta and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined. RESULTS: IFNalpha1, IFNalpha2, IFNalpha4, IFNalpha5 and IFNalpha8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNbeta was undetectable. By contrast, IFNbeta was upregulated and all IFNalpha subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls. CONCLUSION: The IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNbeta being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response. PMID- 29762171 TI - HIV transmission in discordant couples in Africa in the context of antiretroviral therapy availability. AB - OBJECTIVE: The study aims to understand the basis of continued HIV-1 transmission in Zambian and Rwandan HIV-1-discordant couples in the context of antiretroviral therapy (ART). DESIGN: We identified nine Zambian and seven Rwandan acutely infected, epidemiologically-linked couples from government couples' voluntary counseling and testing (CVCT) clinics where transmitting partners reported being on ART near the time of transmission. METHODS: We quantified viral load and plasma antiretroviral drug concentrations near the time of transmission and used these as surrogate measures for adherence. We also sequenced the polymerase gene from both donor and recipient partners to determine the presence of drug resistance mutations (DRMs). RESULTS: In Zambia, all transmitting partners had detectable viral loads, and 8/9 were not on therapeutic antiretroviral regimens. In the remaining couple, despite being on a therapeutic regimen, DRMs were present and transmitted. In Rwanda, although six of seven transmitting partners had detectable viral loads, therapeutic levels of antiretroviral drugs were detected in four of seven, but were accompanied by DRMs. In the remaining three couples, either no antiretrovirals or subtherapeutic regimens were detected. CONCLUSIONS: A reduction of ART effectiveness in nontrial settings was associated with lack of antiretrovirals in plasma and detectable viral load, and also drug resistance. In Zambia, where CVCT is not widely implemented, inconsistent adherence was high in couples unaware of their HIV discordance. In Rwanda, where CVCT is deployed country-wide, virologic failure was associated with drug resistance and subsequent transmission. Together, these findings suggest that increasing ART availability in resource-limited settings without risk reduction strategies that promote adherence may not be sufficient to control the HIV epidemic in the post-ART era. PMID- 29762173 TI - A defucosylated bispecific multivalent molecule exhibits broad HIV-1-neutralizing activity and enhanced antibody-dependent cellular cytotoxicity against reactivated HIV-1 latently infected cells. AB - OBJECTIVE: Current treatments cannot completely eradicate HIV-1 owing to the presence of latently infected cells, which harbor transcriptionally silent HIV-1. However, defucosylated antibodies can readily kill latently infected cells after their activation to express envelope glycoprotein (Env) through antibody dependent cellular cytotoxicity (ADCC). We herein aimed to test a defucosylated bispecific multivalent molecule consisting of domain-antibody and single-domain CD4, LSEVh-LS-F, for its HIV-1 neutralizing activity and ADCC against the reactivated latently infected cells, compared with the nondefucosylated molecule LSEVh-LS. METHODS: LSEVh-LS-F's neutralizing activity against a panel of newly characterized Chinese HIV-1 clinical isolates was assessed by using TZM-bl-based and PBMC-based assays. LSEVh-LS-F-mediated ADCC in the presence of natural killer cells against cell lines that stably express Env proteins, HIV-1-infected cells and LRA-reactivated HIV-1 latent cells, was measured using a lactate dehydrogenase (LDH) cytotoxicity assay or flow cytometry. RESULTS: LSEVh-LS-F and LSEVh-LS were equally effective in neutralized infection of all HIV-1 isolates tested with IC50 and IC90 values 3~4-fold lower than those of VRC01. LSEVh-LS-F was more effective in natural killer-mediated killing of HIV-1 Env-expressing cell lines, HIV-1-infected cells, latency reactivation agents-reactivated ACH2 cells and reactivated latently infected resting CD4 T cell line as well as resting CD4 T lymphocytes isolated from patients receiving HAART. CONCLUSION: LSEVh-LS-F exhibits broad HIV-1 neutralizing activity and enhanced ADCC against HIV-1-infected cells, reactivated latently infected cell lines and primary CD4 T cells, thus being a promising candidate therapeutic for eradicating the HIV-1 reservoir. PMID- 29762172 TI - Achieving the fourth 90: healthy aging for people living with HIV. PMID- 29762174 TI - Reasons for non-adherence to the dapivirine vaginal ring: results of the MTN-032/ AHA study. AB - OBJECTIVE(S): METHODS:: Former ASPIRE participants were stratified by age group (18-21; 22-45) and randomly selected at seven sites in Malawi, South Africa, Uganda and Zimbabwe, 12-17 months after trial exit. Using in-depth interviews or focus group discussions, ring use barriers were explored using structured guides and visual tools including individual-level depictions of dapivirine levels detected in plasma and returned rings. RESULTS: 187 were enrolled; 37% were 18-21 when they began ASPIRE. Most (75%) had drug-level results suggesting inconsistent ring use throughout ASPIRE. Participants viewed themselves as adherent, while simultaneously describing regular instances and reasons for ring removal (e.g. for sex or menses). Less adherent women reported fears that partners would oppose the ring or feel it during sex. High adherers expressed altruistic motivations for ring use. Women of all ages attributed young women's non-adherence to their tendency to be less "serious" about the future, HIV prevention and the study; motivated predominantly by benefits; more fearful of fertility-related consequences; and to having less relationship control. CONCLUSIONS: When presented with objective adherence data, participants provided reasons for intermittent ring use, while simultaneously portraying themselves as consistent ring users. Further research is needed to understand how women could use the ring in a way that fits into the context of their relationships and their lives while still conferring adequate HIV prophylaxis. PMID- 29762175 TI - Pregnancy outcomes and infant growth among babies with in utero exposure to tenofovir-based pre-exposure prophylaxis for HIV prevention. AB - BACKGROUND: Global guidelines recommend pre-exposure prophylaxis (PrEP) use by women at risk for HIV, including during pregnancy, a period with heightened HIV risk. However, data to support safety of PrEP use during pregnancy are limited, particularly from women using PrEP throughout pregnancy. METHODS: In an open label delivery study of PrEP integrated with ART for high risk HIV serodiscordant couples in Kenya and Uganda (the Partners Demonstration Project), women who became pregnant while using PrEP were offered the option to continue PrEP throughout pregnancy. We compared pregnancy outcomes and one-year infant growth from pregnancies with exposure to PrEP throughout pregnancy to those without any exposure, with data from the placebo arm of a prior efficacy trial of PrEP conducted in the same setting. RESULTS: Outcomes from 30 women who elected to continue PrEP throughout pregnancy were compared to those from 96 pregnancies among PrEP-unexposed women. There were small non-significant decreases in the frequency of pregnancy loss (16.7% PrEP-exposed versus 23.5% PrEP-unexposed, adjusted odds ratio [aOR] = 0.59, p = 0.4) and preterm delivery (0 versus 7.7%, [aOR] = 0.54, exact p = 0.6). No congenital anomalies occurred among PrEP-exposed infants. PrEP-exposed infants had slightly lower adjusted mean z-scores for length (-1.73 versus -0.79, p = 0.05) and head circumference (0.24 versus 1.07, p = 0.04) one month after birth but were comparable to PrEP-unexposed infants in these measurements one year after birth. CONCLUSIONS: This first evaluation among women using PrEP throughout pregnancy indicates no greater frequency of adverse pregnancy outcomes or restricted infant growth; these findings support recommendations permitting PrEP use during pregnancy. PMID- 29762176 TI - Transactional sex and incident HIV infection in a cohort of young women from rural South Africa. AB - OBJECTIVE: In sub-Saharan Africa, young women who engage in transactional sex (the exchange of sex for money or gifts) with a male partner show an elevated risk of prevalent HIV infection. We analyse longitudinal data to estimate the association between transactional sex and HIV incidence. DESIGN: We used longitudinal data from a cohort of 2362 HIV-negative young women (aged 13-20 years) enrolled in a randomized controlled trial in rural, South Africa who were followed for up to four visits over 6 years. METHODS: The effect of transactional sex on incident HIV was analysed using stratified Cox proportional hazards models and cumulative incidence curves. Risk ratios were estimated using log-binomial models to compare the effects across visits. RESULTS: HIV incidence was higher for young women that reported transactional sex (hazard ratio 1.59, 95% confidence interval 1.02-2.19), particularly when money and/or gifts were received frequently (at least weekly) (hazard ratio 2.71, 95% confidence interval 1.44-5.12). We also find that effects were much stronger during the main trial and dissipate at the postintervention visit, despite an increase in both transactional sex and HIV. CONCLUSION: Transactional sex elevates the risk of HIV acquisition among young women, especially when it involves frequent exchanges of money and/or gifts. However, the effect was attenuated after the main trial, possibly due to the changing nature of transactional sex and sexual partners as women age. These findings suggest that reducing transactional sex among young women, especially during adolescence, is important for HIV prevention. PMID- 29762178 TI - Exercise Nonresponders: Genetic Curse, Poor Compliance, or Improper Prescription? PMID- 29762179 TI - Reinke's Edema: Implications for Airway Management. PMID- 29762177 TI - Neuropsychological phenotypes among men with and without HIV disease in the multicenter AIDS cohort study. AB - OBJECTIVE: Mild forms of HIV-associated neurocognitive disorder (HAND) remain prevalent in the combination antiretroviral therapy (cART) era. This study's objective was to identify neuropsychological subgroups within the Multicenter AIDS Cohort Study (MACS) based on the participant-based latent structure of cognitive function and to identify factors associated with subgroups. DESIGN: The MACS is a four-site longitudinal study of the natural and treated history of HIV disease among gay and bisexual men. METHODS: Using neuropsychological domain scores, we used a cluster variable selection algorithm to identify the optimal subset of domains with cluster information. Latent profile analysis was applied using scores from identified domains. Exploratory and posthoc analyses were conducted to identify factors associated with cluster membership and the drivers of the observed associations. RESULTS: Cluster variable selection identified all domains as containing cluster information except for Working Memory. A three profile solution produced the best fit for the data. Profile 1 performed below average on all domains, Profile 2 performed average on executive functioning, motor, and speed and below average on learning and memory, Profile 3 performed at or above average across all domains. Several demographic, cognitive, and social factors were associated with profile membership; these associations were driven by differences between Profile 1 and the other profiles. CONCLUSION: There is an identifiable pattern of neuropsychological performance among MACS members determined by all domains except Working Memory. Neither HIV nor HIV-related biomarkers were related with cluster membership, consistent with other findings that cognitive performance patterns do not map directly onto HIV serostatus. PMID- 29762180 TI - Presumed beta-Lactam Allergy and Cross-reactivity in the Operating Theater: A Practical Approach. PMID- 29762181 TI - Intraneural Ultrasound-guided Sciatic Nerve Block: Minimum Effective Volume and Electrophysiologic Effects. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Both extra- and intraneural sciatic injection resulted in significant axonal nerve damage. This study aimed to establish the minimum effective volume of intraneural ropivacaine 1% for complete sensory-motor sciatic nerve block in 90% of patients, and related electrophysiologic variations. METHODS: Forty-seven consecutive American Society of Anesthesiologists physical status I-II patients received an ultrasound-guided popliteal intraneural nerve block following the up-and-down biased coin design. The starting volume was 15 ml. Baseline, 5-week, and 6-month electrophysiologic tests were performed. Amplitude, latency, and velocity were evaluated. A follow-up telephone call at 6 months was also performed. RESULTS: The minimum effective volume of ropivacaine 1% in 90% of patients for complete sensory-motor sciatic nerve block resulted in 6.6 ml (95% CI, 6.4 to 6.7) with an onset time of 19 +/- 12 min. Success rate was 98%. Baseline amplitude of action potential (mV) at ankle, fibula, malleolus, and popliteus were 8.4 +/- 2.3, 7.1 +/- 2.0, 15.4 +/- 6.5, and 11.7 +/- 5.1 respectively. They were significantly reduced at the fifth week (4.3 +/- 2.1, 3.5 +/- 1.8, 6.9 +/- 3.7, and 5.2 +/- 3.0) and at the sixth month (5.9 +/- 2.3, 5.1 +/- 2.1, 10.3 +/- 4.0, and 7.5 +/- 2.7) (P < 0.001 in all cases). Latency and velocity did not change from the baseline. No patient reported neurologic symptoms at 6-month follow-up. CONCLUSIONS: The intraneural ultrasound-guided popliteal local anesthetic injection significantly reduces the local anesthetic dose to achieve an effective sensory-motor block, decreasing the risk of systemic toxicity. Persistent electrophysiologic changes suggest possible axonal damage that will require further investigation. PMID- 29762182 TI - Liquid Lightness. PMID- 29762183 TI - Butterfly Vertebrae. PMID- 29762184 TI - Histomorphometric Comparison of 3 Osteotomy Techniques. AB - PURPOSE: This pilot study compares the histomorphometric structure of osteotomy preparation through standard extraction drilling (SD), Summers osteotomes (SO), and a new method of nonextraction drilling called osseodensification (OD). METHOD AND MATERIALS: Fresh porcine tibia plateau was used as the surgical specimen. Three preparation methods (N = 6 for each) were used to prepare 18 osteotomies according to manufacturer protocols. Eighteen tapered screw-vent (4.7 * 13 mm) implants were placed. After osteotomy preparation and implant placement, all porcine tibias were placed in 10% formalin solution in preparation for histological staining and sectioning. Histomorphometric analysis of all samples was performed to compare immediate bone-to-implant contact (BIC) and the percentage of bone volume within a 2-mm zone surrounding the implant. RESULTS: OD achieved 60.3% BIC, SO 40.7% BIC, and standard extraction drilling (SD) 16.3% BIC. The percentage of bone volume in the surrounding 2-mm width from the implant body using the same area units per sample was found to be greatest for OD. CONCLUSION: This study demonstrated that osteotomy preparation can influence both BIC and percentage of bone volume around the implant. PMID- 29762185 TI - Intraosseous Heat Generation During Osteotomy Performed Freehand and Through Template With an Integrated Metal Guide Sleeve: An In Vitro Study. AB - OBJECTIVE: To investigate drill wear and consequent intraosseous temperature elevation during freehand and guided bone drilling, with attention to the effect of metal-on-metal contact during guided drilling. MATERIALS AND METHODS: Osteotomies were performed on bovine ribs, with 2.0 mm diameter stainless steel drill bits of the SMART Guide System, under 3 sterilization protocols, at 800, 1200, 1500, and 2000 rpm. Sterilization was performed after every 3 drilling. Temperature was measured after every 30 drilling. RESULTS: The studied contributing factors had a cumulative effect, and each contributed significantly to temperature elevation. Whether guide use led to a near-necrotic (47 degrees C) temperature increment depended largely on the applied sterilization protocol. CONCLUSION: The metal sleeve is a significant contributing factor to heat generation during guided osteotomy, but its effect can be offset by keeping the other studied factors under control. PMID- 29762186 TI - Decision Making for Management of Periimplant Diseases. AB - INTRODUCTION: Nonsurgical and surgical management of periimplant mucositis and periimplantitis have shown promising results in arresting periimplant marginal bone loss (MBL) and preventing implant loss. However, management of periimplant diseases still remains unpredictable for full reconstruction of lost tissues and completely arrests disease progression. The present study proposes a decision tree that compiles both clinical and radiographic presentation of failing implants to aid in the decision making for their management. MATERIALS AND METHODS: An extensive literature review was performed using 3 electronic databases (PubMed, Ovid MEDLINE, and Cochrane Central) on the most recent treatment modalities for the management of periimplant diseases. DISCUSSION: Evidence-based treatment suggestions were primarily derived from periimplant defect morphology, presence, and severity of periimplant MBL. More evidence is required supporting soft-tissue augmentation for the treatment of periimplant diseases. CONCLUSION: Management of periimplant diseases can include lasers, mechanical instrumentation, chemical detoxification, and antimicrobial agents for nonsurgical approaches. On the other hand, removal of failing implants, resective surgery, guided bone regeneration, and soft-tissue grafting are presented as valid options for the surgical treatment of periimplantitis. PMID- 29762187 TI - Reliability of the Osstell Implant Stability Quotient and Penguin Resonance Frequency Analysis to Evaluate Implant Stability. AB - PURPOSE: To evaluate the reliability of the Osstell implant stability quotient (ISQ) and Penguin resonance frequency analysis (RFA) devices in measuring implant stability. MATERIALS AND METHODS: Forty implants were embedded in self-curing acrylic resin, soft-lining material, polyvinyl siloxane impression material, and polycarboxylate cement (n = 10). After the initial setting times were completed, the stability of each implant was measured with Osstell ISQ and Penguin RFA with 3 repeated measurements. The "intraclass correlation coefficient" evaluated the correspondence between the measurements (P < 0.05). RESULTS: Polyvinyl siloxane impression material had lower ISQ values than soft-lining material, self-curing acrylic resin, and polycarboxylate cement in both devices (P < 0.05). The intraclass correlation was 1.00 in self-curing acrylic resin and 0.48 in polycarboxylate cement (P < 0.05) for Osstell. This value was 0.95 in self-curing acrylic resin and 0.38 in polycarboxylate cement (P < 0.05) for Penguin. There was no correlation between the repeated measurements in soft-lining material and polyvinyl siloxane impression material for both devices (P > 0.05). The repeatability was 0.90 for Osstell and 0.60 for Penguin (P < 0.05). CONCLUSIONS: Osstell ISQ and Penguin RFA are reliable only when the implants are embedded in stiff materials. Osstell ISQ is more reliable than Penguin RFA. PMID- 29762188 TI - The reliability of radiostereometric analysis in determining physeal motion in slipped capital femoral epiphysis in standard uniplanar and low-dose EOS biplanar radiography: a phantom model study. AB - Physeal closure after slipped capital femoral epiphysis fixation can be difficult to assess on two-dimensional conventional radiographs. Radiostereometric analysis offers improved motion detection over conventional radiography, whereas the EOS biplanar imager provides a means for low radiation weight-bearing images. This phantom study assessed the reliability of measuring motion using radiostereometric analysis in the EOS using a slipped capital femoral epiphysis model. The accuracy and precision were better than 0.09+/-0.05 mm and 0.20 degrees +/-0.36 degrees when centered in the imaging space, were within the limits of clinical significance, and were not different from a standard uniplanar radiostereometric system. PMID- 29762189 TI - Orthopaedic Resident Surgical Case Log Disparities Observed in the Next Accreditation System. AB - INTRODUCTION: With the institution of the Next Accreditation System (NAS), case log procedures fundamentally changed. Unless multiple entries are made, only one procedure per case is credited for procedure counts. We hypothesized that the NAS caused notable changes in national procedure data. METHODS: Accreditation Council for Graduate Medical Education Orthopaedic Surgery Case Logs National Data Reports from 2008 to 2016 were analyzed to calculate differences in case log data before and after NAS implementation. RESULTS: In the first academic year post NAS, the average total procedures decreased by 36%. Total procedures increased the following 2 years but still represent a decrease of >30% from pre-NAS data. An average of 580 fewer total procedures per resident were reported in the 3 years post-NAS (P = 0.001). Regression analysis showed notable decreases in credited procedures in all but two categories. CONCLUSIONS: The decrease in logged procedures with the NAS may be related to new guidance, resident logging habits, an actual decrease in surgical experience, or unknown causes, or combinations of these factors. A new baseline of case data may be emerging post NAS. To ensure the highest quality education, NAS case logs warrant continued study to determine how the data should be used in residency education and accreditation decisions. PMID- 29762190 TI - Epidemiological trends in the diagnosis of melanoma in a Southern European population: analysis of a large database from a tertiary referral center. AB - The aim of this study was to present the epidemiological, clinicopathological, and treatment characteristics of patients diagnosed and treated in a tertiary referral center and to analyze independent factors associated with these characteristics. In this cohort study, epidemiological, clinicopathological, and treatment characteristics of 1461 consecutive melanoma patients diagnosed and treated in a tertiary referral center in 1987-2015 were prospectively collected in a registry. All patients underwent resection of their melanoma lesion. Multiple logistic regression analysis was used to examine independent correlations between characteristics. Internal validation of these correlations was performed by the bootstrap method. The median age of the patients was 53 years. Female sex had a slight predominance, whereas the majority were of Southern European origin. Superficial spreading melanoma was associated with younger age (P<0.001), whereas the nodular melanoma histological subtype was associated independently with indoor occupation (P=0.021) and diagnosis in the years 2004-2015 (P=0.002). Melanomas with Breslow thickness above 1.0 mm were associated with skin type III-IV (P=0.021) and diagnosis in the years 1987-2003 (P=0.046). In addition, histological ulceration was associated with older age (P=0.004) and diagnosis in the years 1987-2003 (P<0.001), whereas histological regression was associated independently with older age (P=0.001). This study presented independent associations between epidemiological, histopathological, and treatment characteristics, which might help to better understand melanoma disease and treatment practices in Southern Europe. PMID- 29762191 TI - Endoscopic Findings in Lysosomal Acid Lipase Deficiency. PMID- 29762192 TI - Combination Antibiotics Improves Disease Activity and Alters Microbial Communities in Children With Ulcerative Colitis. PMID- 29762193 TI - STRONGkids: Predictive Validation in Brazilian Children. AB - OBJECTIVES: The aim of the study is to assess STRONGkids as a tool for predicting weight loss and length of hospital stay in children and to determine whether the anthropometric diagnosis of nutritional status at the time of admission was associated with weight loss and length of hospital stay. METHODS: A methodological study recruiting 245 children age between 1 and 10 years of age admitted to a tertiary hospital. The participants were weighed daily until discharge. Validation of the STRONGkids tool for the identification of patients sustaining weight loss at the end of hospitalization involved the calculation of sensitivity, specificity, and positive and negative predictive values, and anthropometric assessment. RESULTS: A total of 129 (52.7%) children lost weight at the end of hospitalization. Of these, 73 (56.6%) lost over 2% of their weight on admission. The tool had a sensitivity of 55.8%, a specificity of 38.8% and a positive predictive value of 50.3% in identifying children who lost weight. The anthropometric assessment had a sensitivity of 26.5%, a specificity of 75.9%, and a positive predictive value of 49.1%. CONCLUSIONS: The model used to develop the STRONGkids tool incorporated clinical evaluation to a greater extent than the assessment of nutritional status. The tool, however, had a low sensitivity and a high percentage of false positives. Therefore, it should be considered as a preliminary evaluation tool and its use should be complemented with clinical data. PMID- 29762194 TI - Revision Ulnar Collateral Ligament Reconstruction. AB - Ulnar collateral ligament injuries continue to occur despite efforts to educate pitchers, coaches, and families at the amateur and professional levels about pitch counts, mechanics, and injury prevention. Although the data on the incidence of ulnar collateral ligament reconstructions are inconclusive, an increase in these reconstructions may mean a corresponding increase in the number of reconstruction failures and revision reconstruction surgeries. Less is known about the outcomes of revision ulnar collateral ligament reconstruction; not unexpectedly, early results are not as promising as those observed with primary reconstruction. In response, interest in revision techniques, rehabilitation, and outcomes of revision ulnar collateral ligament reconstruction surgeries has grown. PMID- 29762195 TI - Functional Outcomes and Complications After Oncologic Reconstruction of the Proximal Humerus. AB - BACKGROUND: No consensus exists on the best method of articular reconstruction in patients who require proximal humerus resection for the management of primary bone sarcomas, soft-tissue sarcomas extending into the bone, benign and locally aggressive primary bone tumors, and metastatic disease. METHODS: We identified patients from two institutions who underwent wide resection of the proximal humerus along with oncologic reconstruction using osteoarticular allografts (OAs), endoprostheses, or allograft-prosthesis composites. We prospectively collected functional outcomes and retrospectively assessed complications and implant survival. RESULTS: A total of 150 patients were included in this study. The average Disabilities of the Arm, Shoulder and Hand questionnaire score was 26 for 25 patients, of which we gathered their functional data, with no differences in physical function among the three constructional methods according to the Disabilities of the Arm, Shoulder and Hand questionnaire, upper extremity Toronto Extremity Salvage Score, upper extremity Musculoskeletal Tumor Society, and Patient-Reported Outcomes Measurement Information System scores. Overall, the survival rate of the prosthesis was >50%. A trend was noted for a higher risk of failure in the OA group secondary to the allograft fracture. DISCUSSION: All three articular oncologic shoulder reconstructions were comparable in terms of function. This large series confirms a higher fracture rate in OAs, which explains the observed higher revision rate and apparent lower survival rate in this subgroup. PMID- 29762197 TI - High-Frequency Horizontal Semicircular Canal Function in Certain Meniere's Disease. AB - OBJECTIVES: To characterize video head impulse testing (vHIT) in definitive Meniere's disease and to investigate the relationship between vHIT results and other audiovestibular function tests. DESIGN: Fifty-four patients with certain Meniere's disease, that is, patients with clinically definite Meniere's disease and endolymphatic hydrops visualized by locally enhanced inner ear MR imaging, were recruited for this study. All patients underwent vHIT. The vestibular-ocular reflex gain at 60 ms and refixation saccades were the outcome parameters measured. Saccades were characterized by determining the saccade frequency, their mean latency, and their mean velocity. RESULTS: Seven of 54 patients had bilateral normal vHITs. Clearly pathologically vHITs with decreased gain and refixation saccades were observed in further seven patients. The majority of patients exhibited vHITs with refixation saccades but normal gain. Saccades mostly occurred bilaterally. There was no correlation between vHIT gain or saccades and caloric irrigation, cervical vestibular evoked myogenic potential or audiometry for Meniere's ears. Furthermore, vHIT gain or saccades correlated neither with age nor with the duration of the disease. CONCLUSIONS: Pathological low vHIT gain values are rarely observed in patients with certain Meniere's disease, while refixation saccades occur very frequently. In the majority of patients, saccades occur bilaterally. In Meniere's disease, in contrast to vestibular neuritis, there is no compensatory decrease of saccade latency over time. PMID- 29762196 TI - High-intensity Interval Training and Continuous Aerobic Exercise Interventions to Promote Self-initiated Quit Attempts in Young Adults Who Smoke: Feasibility, Acceptability, and Lessons Learned From a Randomized Pilot Trial. AB - OBJECTIVES: While exercise significantly reduces craving for cigarettes, the effect of exercise on self-initiation of quit attempts is less known. Therefore, this randomized pilot study explored the effect of starting an exercise program on self-initiated quit attempts, and also the feasibility and acceptability of a novel exercise intervention, high-intensity interval training (HIIT), as compared with a more traditional continuous aerobic (CA) exercise intervention. METHODS: Participants smoked (>=5 cigarettes/d), were aged 18 to 40 years, and wanted to increase their exercise. Participants were randomized into 1 of 3 groups: HIIT, CA, and delayed control. All participants attended follow-up visits at weeks 4, 8, and 12. Outcomes included measures of feasibility (eg, visit attendance) and acceptability (eg, satisfaction), and also changes in smoking behavior (eg, quit attempts during follow-up) and proxies to quit attempts (eg, positive affect). RESULTS: Overall, there were no differences in terms of feasibility and acceptability between the HITT (n = 12) and CA (n = 9) groups. Based on both self report and objective measurement, the exercise groups (HIIT and CA) increased their physical activity as compared with the delayed treatment group (n = 11). Compared with HIIT and delayed control, CA (n = 9) had significant favorable changes in positive affect (eg, at week 8, HIIT: +0.25 +/- 2.21, delayed control: -5.11 +/- 2.23, CA: +5.50 +/- 2.23; P = 0.0153). CONCLUSIONS: These observations suggest that HIIT is as feasible and acceptable as CA, though CA may have a more favorable effect on proxies to quit attempts (eg, positive affect). Fully powered studies are needed to examine the effect of HIIT versus CA on quit attempts. PMID- 29762198 TI - Endometrial cancer in the elderly: does age influence surgical treatments, outcomes, and prognosis? AB - OBJECTIVE: To compare clinicopathological characteristics, surgical outcomes, and survival rates for nonelderly (<75 years old) and elderly (>=75 years old) women with endometrial cancer (EC). METHODS: This retrospective study included consecutive patients who underwent surgery for EC at the gynecologic-oncologic surgery department of Hopital Europeen Georges-Pompidou (Paris, France) from January, 2002 to December, 2015. Independent-group t tests and chi-square tests were used to compare elderly and nonelderly women. Survival rates were compared using log-rank (Mantel-Cox) tests. RESULTS: In the nonelderly and elderly groups, the mean age at EC diagnosis was 63 (range 33-74) and 81 (range 75-95) years, respectively. Compared with nonelderly patients, elderly patients (n = 104) presented with more advanced disease and more aggressive histological findings. However, surgical approaches did not differ between the two groups, and 76% of all patients underwent minimally invasive surgery. Pelvic lymphadenectomy was performed in 65% and 44% of nonelderly and elderly patients, respectively (P = 0.01), whereas para-aortic lymphadenectomy was performed in 26% and 9% of nonelderly and elderly patients, respectively (P < 0.0001). The incidence of perioperative complications was almost the same in the elderly and nonelderly groups. The 5-year disease-free survival rate was higher in the nonelderly group (P = 0.023), and the 5-year cancer-specific mortality rate was higher in the elderly group (P = 0.042). CONCLUSIONS: Although elderly patients present with cancers that are more aggressive, the management of EC in this population is not optimal. Further clinical studies need to be conducted for elderly women with EC, and specific treatment guidelines should be developed to improve their prognosis. PMID- 29762200 TI - Management of genitourinary syndrome of menopause in women with or at high risk for breast cancer: consensus recommendations from The North American Menopause Society and The International Society for the Study of Women's Sexual Health. AB - The objective of The North American Menopause Society (NAMS) and The International Society for the Study of Women's Sexual Health (ISSWSH) Expert Consensus Panel was to create a point of care algorithm for treating genitourinary syndrome of menopause (GSM) in women with or at high risk for breast cancer. The consensus recommendations will assist healthcare providers in managing GSM with a goal of improving the care and quality of life for these women. The Expert Consensus Panel is comprised of a diverse group of 16 multidisciplinary experts well respected in their fields. The panelists individually conducted an evidence-based review of the literature in their respective areas of expertise. They then met to discuss the latest treatment options for genitourinary syndrome of menopause (GSM) in survivors of breast cancer and review management strategies for GSM in women with or at high risk for breast cancer, using a modified Delphi method. This iterative process involved presentations summarizing the current literature, debate, and discussion of divergent opinions concerning GSM assessment and management, leading to the development of consensus recommendations for the clinician.Genitourinary syndrome of menopause is more prevalent in survivors of breast cancer, is commonly undiagnosed and untreated, and may have early onset because of cancer treatments or risk-reducing strategies. The paucity of evidence regarding the safety of vaginal hormone therapies in women with or at high risk for breast cancer has resulted in avoidance of treatment, potentially adversely affecting quality of life and intimate relationships. Factors influencing decision-making regarding treatment for GSM include breast cancer recurrence risk, severity of symptoms, response to prior therapies, and personal preference.We review current evidence for various pharmacologic and nonpharmacologic therapeutic modalities in women with a history of or at high risk for breast cancer and highlight the substantial gaps in the evidence for safe and effective therapies and the need for future research. Treatment of GSM is individualized, with nonhormone treatments generally being first line in this population. The use of local hormone therapies may be an option for some women who fail nonpharmacologic and nonhormone treatments after a discussion of risks and benefits and review with a woman's oncologist. We provide consensus recommendations for an approach to the management of GSM in specific patient populations, including women at high risk for breast cancer, women with estrogen-receptor positive breast cancers, women with triple-negative breast cancers, and women with metastatic disease. PMID- 29762201 TI - To the Editor. PMID- 29762199 TI - Physical activity modifies genetic susceptibility to obesity in postmenopausal women. AB - OBJECTIVE: We conducted a gene-environment interaction study to evaluate whether the association of body mass index (BMI) associated meta genome-wide association study single-nucleotide polymorphisms (SNPs) (as a genetic risk score) and BMI is modified by physical activity and age. METHODS: In 8,206 women of European ancestry from the Women's Health Initiative (WHI), we used linear regression to examine main effects of the 95 SNP BMI genetic risk score (GRS) and physical activity on BMI, and evaluated whether genetic associations are modified by physical activity (two-way interaction) and age (three-way interaction). RESULTS: We found evidence for modification of the BMI GRS-BMI association according to both physical activity and age. We observed a significant two-way interaction of BMI GRS * physical activity in the crude model (P interaction = 0.05), where a smaller effect of the BMI GRS on BMI with increasing physical activity. The beta coefficient was 0.05 (standard error [SE] = 0.02, P = 0.01) for the high-activity group compared with beta = 0.13 (SE = 0.02, P = 4.8 * 10) for the sedentary group. The three-way interaction was statistically significant (adjusted P interaction = 0.01). Notably, in the 70+ age group, the BMI GRS-BMI association was attenuated and no longer significant in the high-activity group; the beta coefficient for the 70+ high-activity group was relatively small and nonsignificant (beta = 0.02, SE = 0.03, P = 0.58) compared with 70+ sedentary group (beta = 0.17, SE = 0.03, P = 2.5 * 10). CONCLUSION: Our study suggests that physical activity attenuates the influence of genetic predisposition to obesity, and this effect is more profound in the oldest age group. PMID- 29762202 TI - Hypertension guideline update: A new guideline for a new era. AB - In the United States, hypertension affects about one-third of adults and contributes to one out of every seven deaths. Evidence-based treatment is associated with reductions in incidence of stroke, myocardial infarction, and heart failure as well as associated disability and death. This article reviews the ACC/AHA Task Force on Clinical Practice Guidelines' 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. Key changes include reclassification of BP stages and lowering of hypertension treatment goals. PMID- 29762203 TI - Preparing patients for biologic medications for dermatologic and rheumatic diseases. AB - Psoriasis, psoriatic arthritis, and rheumatoid arthritis are prevalent conditions that often require a team of primary care and specialist healthcare professionals for the most optimum patient outcomes. Primary care providers can facilitate referrals to dermatology and rheumatology specialists by obtaining the needed screening workup for patients who need treatment with immunosuppressive therapies. This article reviews tuberculosis screening, hepatitis screening, and vaccinations to be administered before patients begin biologic medications. PMID- 29762205 TI - Bleach for Atopic Dermatitis. AB - Individuals with atopic dermatitis (AD) have used bleach baths to treat superinfections, although their mechanism of action is not well understood. The ClinicalTrials.gov, National Eczema Association, and PubMed databases were searched for studies that investigate the role bleach plays in modulating AD. Fifteen studies were included in this review. Bleach bath improves clinical symptoms of AD and restores surface microbiome by eradicating bacteria, most notably Staphylococcus aureus. Many studies have noted that this antimicrobial effect has reduced the need for topical corticosteroids or topical antibiotics. In addition, bleach seems to have strong anti-inflammatory and antipruritogenic effects. Lastly, bleach baths seem to be safe on human skin, without disrupting epidermal barrier function. Although the effects of bleach are promising, studies that investigate the long-term use of bleach alone, without concomitant AD treatment modalities, are needed. The emergence of new bleach-containing products warrants future investigations to examine their effects on cutaneous microbiome, epidermal barrier function, and immunity. PMID- 29762206 TI - Urushiol Patch Test Using the T.R.U.E. TEST System. AB - BACKGROUND: Poison ivy, poison oak, and poison sumac are the most common causes of allergic contact dermatitis in North America. Although extensive efforts have been made to develop therapies that prevent and treat allergic contact dermatitis to these plants, there lacks an entirely effective method, besides complete avoidance. Efforts to develop a more effective preventive therapy, such as a vaccine, are ongoing. To accurately evaluate the efficacy of these new therapies, an appropriate assessment tool is needed. OBJECTIVE: The aim of this study was to evaluate the safety and appropriate doses of urushiol required for a patch test based on the hydrogel delivery system of the Thin-Layer Rapid Use Epicutaneous Patch Test. METHODS: Nine subjects were patch tested with various doses of urushiol and a negative control on day 0. Patch test sites were inspected for any local reaction on days 2, 4, 7, 14, and 21 after the initial exposure and graded by standard morphology. CONCLUSIONS: All 9 subjects did not have any significant adverse effects. The urushiol patch test using the hydrogel delivery method demonstrated urushiol sensitivity. All doses of urushiol resulted in a local reaction, and severity of reactions was correlated with dosage of urushiol used in the patch test. PMID- 29762207 TI - Occupational Contact Dermatitis in the Canadian Aircraft Industry. AB - BACKGROUND: Aircraft building exposes workers to irritant and sensitizing products. OBJECTIVE: The aim of this article was to study occupational dermatoses among aircraft workers over 25 years. METHODS: The files of aerospace workers referred between 1990 and 2015 were extracted from the database of the McGill University Health Centre contact dermatitis clinic. These were subdivided according to demographics, type of work, patch testing results, and final diagnosis. RESULTS: Of 305 workers, 58% were 40 years or younger; one third were women. Onset of dermatitis varied from 2 months to 25 years, but 120 cases (39%) occurred during the first 3 years. Fifty-one percent of the cases involved assemblers, and 27% were composite material technicians, which were overrepresented as they constitute 10% of the workforce. Of the 305 workers, 152 suffered from allergic contact dermatitis, and 96 had irritant contact dermatitis. Of those with allergic contact dermatitis, 124 reacted to epoxy-based workplace products, but only 48 had positive patch tests to commercially available epoxy allergens. CONCLUSION: More than 60% of the cases of epoxy allergy would have been missed without testing with workplace products. PMID- 29762209 TI - Positive Occluded Patch Test in the Face of Negative Repeat Open Application Test. PMID- 29762208 TI - Prevalence of Atopic Dermatitis and Pattern of Drug Therapy in Malaysian Children. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing, noncontagious skin inflammation characterized by dry skin and itch. Mutation in filaggrin gene leads to defective skin barrier, allowing entry of allergen and eliciting immunological response. OBJECTIVES: The aims of this study were to investigate the prevalence of AD in Malaysian children and to understand the pattern of drug therapy. Such information could be useful to establish the relationship between ethnicity and family history of atopy and the development of associated signs and symptoms. METHODS: A cross-sectional survey was conducted among children attending kindergartens and nurseries. Standardized questionnaires were filled out by parents. RESULTS: Overall prevalence of AD was 13.4%. Of 384 participants recruited, the highest prevalence was observed in males, Malays, participants younger than 2 years, and those with atopic background such as asthma, hay fever, and family history of atopic diseases. Calamine and white soft paraffin were the preferred choice of nonprescription drugs, whereas topical hydrocortisone seemed to be the preferred choice of prescription drug in the management of AD. CONCLUSIONS: The overall prevalence is comparable to that reported in the International Study of Asthma and Allergies in Childhood Phase One. There is an association between ethnicity and AD prevalence. Topical corticosteroids and emollients are the mainstay of AD management among Malaysians. PMID- 29762211 TI - Trends in Eyelid Dermatitis: Erratum. PMID- 29762210 TI - Childhood Atopic Dermatitis and Risk of Problematic Substance Use. PMID- 29762212 TI - ALLERGY TO RUBBER GLOVES. PMID- 29762213 TI - Feasibility of a Cognitive-Behavioral and Environmental Intervention for Sleep Wake Difficulties in Community-Dwelling Cancer Patients Receiving Palliative Care. AB - BACKGROUND: High rates of sleep-wake difficulties have been found in patients with cancer receiving palliative care. Pharmacotherapy is the most frequently used treatment option to manage these difficulties despite numerous adverse effects and the absence of empirical evidence of its efficacy and innocuity in palliative care. OBJECTIVE: This pilot study aimed to assess the feasibility and acceptability of a cognitive-behavioral and environmental intervention (CBT-E) to improve insomnia and hypersomnolence in patients with a poor functioning level and to collect preliminary data on its effects. METHODS: Six patients with cancer receiving palliative care (Eastern Cooperative Oncology Group score 2-3), who had insomnia and/or hypersomnolence, received 1 CBT-E individual session at home. They applied the strategies for 3 weeks. Patients completed the Insomnia Severity Index, the Epworth Sleepiness Scale, a daily sleep diary, and a 24-hour actigraphic recording (7 days) at pretreatment and posttreatment, in addition to a semistructured interview (posttreatment). RESULTS: Participants found strategies easy to apply most of the time, and none was rated as impossible to use because of their health condition. However, their adherence and satisfaction toward CBT-E were highly variable. Results on the effects of CBT-E were heterogeneous, but improvements were observed in patients with a persistent insomnia disorder. CONCLUSIONS: The CBT-E protocol tested among this highly selected sample was fairly well received and suggested positive outcomes in some patients, particularly those with an insomnia complaint alone. IMPLICATIONS: Efforts should be pursued to adapt CBT-E and develop other nonpharmacological interventions, in order to provide an alternative to pharmacotherapy for sleep wake difficulties in this population. PMID- 29762214 TI - No Guts, No Recovery: A Rational Approach to Postoperative Gastrointestinal Dysfunction. PMID- 29762215 TI - Finding the Whey to Improve Surgical Outcomes: Perioperative Nutrition Screening and Intervention. PMID- 29762216 TI - Enhanced Recovery After Surgery: Is It Time to Drive Patient-Reported Outcomes Through Robust Measurement? PMID- 29762217 TI - Perioperative Nutrition: A High-Impact, Low-Risk, Low-Cost Intervention. PMID- 29762218 TI - Standardization of the Classification of Impaired Postoperative Gastric Function Within the Enhanced Recovery Pathways. PMID- 29762219 TI - Worldwide Standards of Practice for Anesthesia. PMID- 29762220 TI - Old Ways Do Not Open New Doors: Norepinephrine for First-Line Treatment of Spinal Hypotension. PMID- 29762221 TI - From Invention to Innovation: Bringing Perioperative Physiological Closed-Loop Systems to the Bedside. PMID- 29762222 TI - By FAER Means or Foul: The Road to Advancement for the Academic Anesthesiologist. PMID- 29762223 TI - Myocardial Postconditioning by the Melatonin Receptor Agonist Ramelteon: Putting Pieces to the Puzzle. PMID- 29762224 TI - Perioperative Betablockade: A Conundrum Still in Need of Study! PMID- 29762226 TI - Emergency General Surgery: Time for Anesthesiology and Surgery to Work Together to Drive Improvement in Outcomes: Erratum. PMID- 29762225 TI - Tsujikawa and Lipid Emulsion. PMID- 29762228 TI - Saline Flush After Rocuronium Bolus Reduces Onset Time and Prolongs Duration of Effect: A Randomized Clinical Trial: Erratum. PMID- 29762227 TI - "Mirror, Mirror on the Wall": Learning From Reflections on Quality: Erratum. PMID- 29762229 TI - What Is the Optimal Blood Pressure on Veno-Arterial Extracorporeal Membrane Oxygenation? Impact of Mean Arterial Pressure on Survival. AB - Blood pressure management is crucial for patients on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Lower pressure can lead to end-organ malperfusion, whereas higher pressure may compete with ECMO flow and cardiac output. The impact of mean arterial pressure (MAP) on outcomes of patients on VA ECMO was evaluated. Patients who were supported on VA ECMO from September 2010 to March 2016 were retrospectively analyzed for average MAP throughout their course on ECMO, excluding the first and last day. Survival and complications observed during ECMO were investigated by classifying patients into groups based on their average MAP. A total of 116 patients were identified. Average MAP was significantly higher in patients who survived to discharge (82 +/- 5.6 vs. 78 +/- 5.5 mm Hg, p = 0.0003). There was a positive association between MAP and survival. Survival was best with MAP higher than 90 mm Hg (71%) and worst with MAP less than 70 mm Hg, where no patient survived. MAP was an independent predictor of survival to discharge by multivariate analysis (odds ratio 1.17, p = 0.013). Vasopressors were used more frequently in patients with lower pressure (coefficient -3.14, p = 0.005) without affecting survival (odds ratio 0.95, p = 0.95). Although the MAP did not affect the probability of strokes or bleeding complications, patients with a higher MAP had a lower incidence of kidney injury (p = 0.007). In conclusion, survival of patients on VA ECMO was significantly greater with a higher MAP, without being affected by prolonged vasopressor use. PMID- 29762230 TI - Outcomes After Infections in Adolescents and Young Adults with Continuous-Flow Left Ventricular Assist Devices. AB - Infections in adult ventricular assist device patients increase subsequent mortality and stroke risk. Less is known about outcomes after infections in younger patients, where diabetes and obesity, risk factors associated with poor outcomes, are less prevalent. The purpose of this study was to examine outcomes after infections in adolescents and young adults with continuous-flow left ventricular assist devices (VAD) bridged to transplant. From Pediatric Interagency Registry for Mechanically Assisted Circulatory Support and Interagency Registry for Mechanical Circulatory Support registries, we identified patients aged 12-29 years with continuous-flow VADs implanted as bridged to transplant from September 2012 to March 2016. The primary predictor variable was first reported infection. The primary outcome was death on VAD support; secondary outcome was clinical stroke. Kaplan-Meier and Cox proportional hazard methods were used to compare outcomes between patients before or without infection and patients after infection. Ninety-two adolescents (12-18 years of age) and 224 young adults (19-29 years of age) with 3,748 patient-months of follow-up were included. Adolescents were smaller (body surface area 1.7 vs. 2.0 m, p < 0.01) and implanted at higher Interagency Registry for Mechanical Circulatory Support profiles (p = 0.005); there were no differences in diabetes and obesity, and survival on VAD was similar (p = 0.22). Among adolescents but not young adults, mortality increased after infection (hazard ratio 8.2, 95% confidence interval 1.6-42.6, p = 0.01). In contrast, stroke risk increased after infection in young adults (hazard ratio 3.1, 95% confidence interval 1.3-7.6, p = 0.01) but not in adolescents. Despite similar underlying risk factors, adolescents have increased mortality after infections, whereas young adults have increased strokes after infections. Both pre- and postimplant factors likely contribute to the discrepancy in outcomes between the two age cohorts. PMID- 29762231 TI - Surfactant Administration During Pediatric Cardiac Extracorporeal Membrane Oxygenation. AB - We investigated the safety and efficacy of surfactant during extracorporeal membrane oxygenation (ECMO) in children with cardiac disease. ECMO patients administered surfactant (surfactant group) were compared with patients who did not receive (control). Criteria to administer surfactant were based on a decreased lung compliance of <0.5 ml/kg/cm H2O. Efficacy was determined on pulmonary compliance change and the radiography-based respiratory distress severity (RDS) score. For the surfactant group, lung compliance measurements and RDS scores were obtained just before the first surfactant administration (T0), 24 hours after the last dose of surfactant (T1), and 24 hours after ECMO decannulation (T2). For the control group, measurements were obtained at baseline (T0), day of ECMO decannulation (T1), and 24 hours after ECMO decannulation (T2). Eighty were on ECMO, 29 in the surfactant, and 51 in the control group. Surfactant group was younger 20 (6-140) vs. 28 (8-928) days old (p = 0.03), had longer ECMO duration 110 (58-192) vs. 46 (29-84) hours (p = 0.001), and had longer mechanical ventilation 16 (11-26) vs. 7 (5-9) days (p = 0.003). The lung compliance and RDS scores in the surfactant group improved significantly between baseline and 24 hours after decannulation, 0.36 +/- 0.13 vs. 0.5 +/- 0.12 ml/kg/cm H2O (p = 0.002) and 13 +/- 3 vs. 12 +/- 2 (p = 0.04), respectively. None developed pneumothorax. Mild pulmonary hemorrhage occurred twice (one in each group). Hospital duration and survival were similar 36 (19-48) vs. 31 (18-48) days and 69% vs. 78% in surfactant and control groups, respectively. Although this is a relatively small study, surfactant appears to be safe in pediatric cardiac ECMO patients. PMID- 29762232 TI - Modified Exosomes Reduce Apoptosis and Ameliorate Neural Deficits Induced by Traumatic Brain Injury. AB - Apoptosis contributes to the pathogenesis of traumatic brain injury (TBI). Engineered exosomes incorporated with therapeutic nuclear acids have been explored for gene therapy for human diseases. The current study sought to investigate the effect of modified exosome-containing plasmids expressing B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X-protein (Bax) shRNA on apoptosis and neural functions after TBI. C57BL/6J mice were subjected to controlled cortical impact injury and were treated with the modified exosomes. The results showed that modified exosomes attenuated the decrease of Mcl-1, XIAP, and Survivin protein levels in the brain and reduced Cytochrome c release from mitochondria to cytosol after TBI. They also attenuated the impairments of miniature excitatory postsynaptic current (mEPSC) and LTP in the hippocampus of TBI mice and improved the motor and cognitive behaviors after TBI. These results suggested that the modified exosomes might reduce apoptosis and ameliorate neural and functional deficits in mouse models of TBI. PMID- 29762233 TI - Adrenal Histoplasmosis. AB - An 89-year-old woman presented with seizure and hyponatremia. CT and MRI demonstrated mass-like enlargement of the adrenal glands and multiple pulmonary nodules. PET/CT performed to evaluate for metastatic disease demonstrated intense F-FDG uptake within enlarged adrenal glands. Given mild uptake in the pulmonary nodules, the differential diagnosis for the adrenal uptake included lymphoma, granulomatous infection, and less likely, metastatic lung cancer. PMID- 29762234 TI - Quality and Safety in Health Care, Part XLI: The IMPACT Registry. AB - The IMPACT Registry is a repository of information for heart catheterizations for congenital heart disease regardless of age and also the catheterizations for acquired heart disease in children. The registry collects information on outcomes, provides quality improvement opportunities for participants, provides reports to participants comparing their results with national results, compares the volume of catheter work done at an institution with the frequency of adverse events, and provides information that may be helpful in evaluating the use of medical devices and treatment options. PMID- 29762235 TI - Quality and Safety in Health Care, Part XL: Stents and Unusual Indications for a PCI. AB - Percutaneous coronary interventions (PCI) are done for a variety of indications. Data from the CathPCI Registry is highly useful to evaluate the outcomes from performing a PCI procedure in unusual circumstances, such as in cases of chronic total coronary artery occlusion, cardiogenic shock after a myocardial infarction, syncopal patients, asymptomatic patients, and before surgery that is noncardiac. Registry information is also valuable in evaluating the efficacy of coronary stents. This article summarizes some of the information available on these subjects. PMID- 29762236 TI - Acute Pancreatitis Following Peptide Receptor Radionuclide Therapy: An Unusual Adverse Event. AB - A 54-year-old man with grade 2 rectal neuroendocrine tumor and hepatic, pancreatic, and bone metastases was treated with Lu-DOTATATE as second-line therapy, after failure of somatostatin analogues. Two weeks after the first injection, he presented at the emergency department with acute pancreatitis. We hypothesized that this unusual adverse event, never been reported so far, was the result of acute tumor irradiation after PRRT, leading to peritumoral inflammation and edema with obstruction of an accessory pancreatic duct. PMID- 29762237 TI - Growth Plate Suppression in an Adolescent Patient With Acute Lymphoblastic Leukemia After Treatment. AB - Osteotoxic effect is a common adverse effect of chemotherapy for childhood acute lymphoblastic leukemia. The pathophysiology of impaired bone growth is multifactorial and can affect both osteoblast and osteoclast function. Significant contribution in affecting skeletal metabolism belongs to high-dose corticosteroid treatment. We present the case of a 12-year-old adolescent girl who was treated for high-risk pro-B acute lymphoblastic leukemia. The Tc-MDP bone scan, as a sensitive indicator of osteoblastic activity, shows that growth plate inhibition after intensive treatment may be temporary and reversible. PMID- 29762239 TI - Quality and Safety in Health Care, Part XLIV: Cardiac Resynchronization Therapy and Subcutaneous Defibrillator Implantable Devices. AB - This article discusses 2 specialized implantable cardioverter defibrillator (ICD) devices. A special type of implantable device is available for cardiac resynchronization therapy, which can also have a defibrillator, in which case it is called a CRT-D device. In patients who meet guidelines for eligibility, a CRT D will diminish the number of significant cardiac events including death. A subcutaneous ICD device does not need any leads placed in the vascular system and therefore does not have some of the complications that may be seen with transvenous ICDs. Also, there are patients who are not candidates for a typical ICD implantation. On the other hand, there are important disadvantages to the subcutaneous ICD. PMID- 29762238 TI - Diagnostic Performance of 18F-Fluciclovine in Detection of Prostate Cancer Bone Metastases. AB - PURPOSE: F-fluciclovine is a synthetic amino acid radiotracer that has recently been approved in Europe and the United States for PET imaging in men with biochemical recurrence (BCR) of prostate cancer after prior definitive treatment. Accurate identification of the sites of disease in patients presenting with BCR of prostate cancer is important in determining the appropriate treatment. Bone is the most frequent site of metastatic disease in patients with prostate cancer. METHODS: We conducted a comprehensive review of the available preclinical and clinical data on the diagnostic performance of F-fluciclovine PET/CT in an attempt to draw practical and general conclusions on the utility and limitations of F-fluciclovine PET/CT in localization of osseous metastatic disease in prostate cancer. RESULTS: The cumulative preclinical data and results of some retrospective and 2 prospective clinical studies suggest that F-fluciclovine can detect early bone marrow involvement in patients with BCR of prostate cancer and negative prior bone-specific imaging findings. CONCLUSIONS: F-fluciclovine PET/CT seems to offer useful information for early detection of bone metastases in men with BCR of prostate cancer. Additional investigations will be needed to compare the diagnostic performance of F-fluciclovine PET/CT to other standard and novel imaging methods in initial staging, BCR, and castrate-resistant phases of disease. PMID- 29762241 TI - Quality and Safety in Health Care, Part XLIII: Selected Outcome Studies From the Implantable Cardioverter Defibrillator Registry. AB - To compare outcome results from different institutions in a registry, it is necessary to have a way to take into account differences in the risk characteristics of the patients. This model has been constructed for the Implantable Cardioverter Defibrillator (ICD) Registry, and the most important variables have been identified. In another study, it has also been found that many of these patients have comorbidities, and the mortality rate 60 months after a replacement ICD was 41.2%. In a third study, it was determined that for individuals at least 65 years of age, 60 months after ICD placement, 50.9% of the recipients used hospice services or were dead. PMID- 29762240 TI - Temporal Uptake Patterns of 18F-Fluorocholine Among Hyperfunctioning Parathyroid Glands. AB - Optimal scan time of F-fluorocholine (FCH) PET/CT for localization of hyperfunctioning parathyroid glands is poorly documented. We report a small series of 9 histologically proven hyperfunctioning parathyroid gland with heterogeneous temporal uptake profile. Thirty-minute dynamic acquisition starting just after F-fluorocholine administration and delayed acquisition were recorded. Three different uptake patterns are seen (early washout, stable uptake, late increase) indicating the importance of an early (5-10 minutes) acquisition. A late acquisition (60 minutes) could be useful when the early acquisition is negative. No correlations were noted between uptake profile and histological or genetic results. PMID- 29762242 TI - "Hepatic Superscan" in a Patient With Hepatosplenic Alphabeta T-cell Lymphoma: 18F-FDG PET/CT Findings. AB - A 36-year-old woman with a 2-week history of fever and markedly elevated lactate dehydrogenase levels. Nonenhanced CT and contrast-enhanced CT showed hepatosplenomegaly, diffusely decreased attenuation of the liver, and homogeneous enhancement in the hepatic and splenic parenchyma. F-FDG PET/CT revealed diffuse intense heterogeneous uptake by the liver (like superscan in bone scintigraphy). A liver needle biopsy confirmed the diagnosis of hepatosplenic alphabeta T-cell lymphoma. Subsequently, she received chemotherapy. The follow-up F-FDG PET/CT showed decreased F-FDG uptake in the liver and spleen. PMID- 29762243 TI - Primary Congenital Lymphedema. AB - We present the case of a 26-year-old man with congenital primary lymphedema. A lymphedema of the right upper limb appeared at the age of 2 years, followed by edemas of the right lower limb and of the right part of the head and neck. A lymphedema of the left lower limb began 5 years ago, and finally an edema of the external genitalia began 2 years ago. Lymphoscintigraphy of the lower limbs and pelvic/abdominal region (including SPECT/ldCT) revealed interesting abnormalities. PMID- 29762244 TI - BRCA2 Mutation as a Possible Cause of Poor Response to 177Lu-PSMA Therapy. AB - We present the case of a 66-year-old man with castration-resistant prostate cancer, with an increasing prostate-specific antigen level, and a progressive disease during Lu-PSMA radionuclide therapy. Because the patient had a BRCA2 mutation, poly-ADP ribose polymerase inhibitor therapy was started. The patient showed a dramatic subjective and biological response to this therapy with a progression-free survival of 5 months. PMID- 29762245 TI - IgG4-Related Disease Simulating Carcinoma Colon With Diffuse Peritoneal Carcinomatosis on 18F-FDG PET/CT. AB - IgG4-related disease (IgG4-RD) continues to be a diagnostic challenge and a great mimicker of malignancies. We report here a case of young man who presented with subacute intestinal obstruction with initial imaging and clinical features suggestive of carcinoma colon. F-FDG PET/CT showed diffuse peritoneal carcinomatosis pattern typically seen with abdominal malignancies. However, the histopathology and the raised IgG4 levels diagnosed it to be IgG4-RD. Although F FDG PET/CT has typical patterns corresponding to the multisystemic involvement of IgG4-RD, the index case did not show any such findings. PMID- 29762246 TI - BRAFV600E Mutation Does Not Significantly Affect the Efficacy of Radioiodine Therapy in Patients With Papillary Thyroid Carcinoma Without Known Distant Metastases. AB - PURPOSE: The BRAF mutation is the most common and specific oncogenic event in papillary thyroid carcinoma (PTC). However, its role in radioiodine therapy decision making has yet to be established. This study aimed to evaluate the impact of the BRAF mutation on the clinical response to radioiodine therapy. METHODS: This retrospective study included PTC patients who received total thyroidectomy with lymph node dissection, radioiodine therapy, and thyroid stimulating hormone suppression between January 2012 and March 2016. Included patients were divided into 2 groups based on the BRAF mutation status. The association between the clinicopathological characteristics and the BRAF mutation was evaluated. After a median follow-up of 37 months, the clinical outcome between these 2 groups was also compared based on the ongoing risk stratification. RESULTS: A total of 512 PTC patients without distant metastases were included, with a positive BRAF mutation in 338 patients. No significant association was observed between the BRAF mutation and clinicopathological characteristics, except for sex, tumor size, and extrathyroidal extension. The initial risk stratification between the positive and negative mutation groups revealed no significant difference (P = 0.845). At the end of follow-up, no significant difference regarding the clinical response to radioiodine therapy was demonstrated between these 2 groups for all patients or patients with high recurrence risk (P = 0.586 and P = 0.680, respectively). CONCLUSIONS: The BRAF mutation status may not impact the clinical response to radioiodine therapy for PTC patients without distant metastases. PMID- 29762248 TI - Vascular delivery of intraperitoneal Evans blue dye into the blood-brain barrier intact and disrupted rat brains. AB - Blood-brain barrier (BBB) integrity can be determined by tracer infusion into the circulation followed by measurements of its penetration into the brain parenchyma. Tracer injection through the intraperitoneal (i.p.) route (rather than intravascular injection) avoids confounding effects of animal anesthesia or immobilization/surgical stress. Evans blue dye (EBD) can be administered by i.p. injection, and once in circulation, it binds to plasma albumin to become an endogenous protein tracer. Here, we investigated whether a similar level of EBD is extravasated into the brain following i.p. versus intravenous (i.v.) injection in rats. In comparison with i.v. EBD injection, i.p. EBD injection resulted in much of the tracer residing in the peritoneal cavity. Accordingly, comparatively less EBD was found in the blood, liver, or brain of BBB-intact rat. In addition, following unilateral osmotic BBB disruption, i.v. but not i.p. EBD stained the ipsilateral hemisphere blue. Nevertheless, following either route of tracer administration in these rats, spectrophotometric quantification detected more EBD in the ipsilateral (BBB-disrupted) than in the contralateral hemisphere. Taken together, in contrast to a recent report, we found that i.p. EBD resulted in less tracer in circulation and in peripheral/central organs than EBD delivered i.v. We nevertheless conclude that i.p. EBD delivered sufficient tracer for the detection of regional BBB disruption. PMID- 29762247 TI - Lymph Node With the Highest FDG Uptake Predicts Distant Metastasis-Free Survival in Patients With Locally Advanced Nasopharyngeal Carcinoma. AB - PURPOSE: Distant failure is a major concern in patients with nasopharyngeal carcinoma. We evaluated whether the metabolic features on F-FDG PET/CT can predict distant metastasis-free survival (DMFS) in patients with locally advanced nasopharyngeal carcinoma. METHODS: We retrospectively reviewed 51 patients stage III, IVA, and IVB nasopharyngeal carcinoma who underwent F-FDG PET/CT at staging. The SUVmax for the primary site and the lymph nodes with the highest uptake as well as at the farthest station were divided by the SUVmean of the background liver (TLR, NLR-H, and NLR-F, respectively). The prognostic value of clinicopathologic factors and SUV parameters for predicting DMFS were assessed using a Cox proportional hazards model. Differences in DMFS were examined by the Kaplan-Meier method. RESULTS: In the median follow-up period of 50.4 +/- 39.3 months (median +/- interquartile range; range, 3.8-130.9), distant metastasis developed in 11 patients (21.6%). In univariate analyses, N stage (N3b) (P = 0.003) and NLR-H >5.70 (P = 0.02) were significant prognostic factors for DMFS, and remained significant in multivariate analysis, whereas TLR (P = 0.18) and NLR F (P = 0.76) did not. The Kaplan-Meier curves showed significantly poorer DMFS in patients with NLR-H >5.70 than in those with lower NLR-H (<=5.70) (1-year DMFS rate, 84.2% vs 93.5%; P = 0.01). CONCLUSIONS: In addition to anatomical N stage, higher NLR-H on pretreatment F-FDG PET/CT is an independent prognostic factor for worse DMFS in patients with locally advanced nasopharyngeal carcinoma. PMID- 29762249 TI - Numb-p72, but not Numb-p65, contributes to the trafficking of group I metabotropic glutamate receptors. AB - The protein Numb localizes to clathrin-coated vesicles and participates in the trafficking of transmembrane receptors. We previous reported that Numb promotes the presence of metabotropic glutamate receptor 1 (mGlu1) on neuronal membrane, and Numb deficiency impairs synaptic expression of mGlu1. However, the actions of different Numb isoforms on mGlu1 trafficking are unknown. Here, we found that Numb-p72 and Numb-p65 are distinctly expressed in HEK293T cells. Interestingly, Numb-p72, but not Numb-p65, binds to mGlu1alpha and promotes the membrane expression of mGlu1alpha by antagonizing its internalization. We hypothesize that the incomplete structure of Numb-p65 does not act in the same way as Numb-p72 on mGlu1 trafficking. PMID- 29762250 TI - Abnormal expression of ephrin-A5 affects brain development of congenital hypothyroidism rats. AB - EphA5 and its ligand ephrin-A5 interaction can trigger synaptogenesis during early hippocampus development. We have previously reported that abnormal EphA5 expression can result in synaptogenesis disorder in congenital hypothyroidism (CH) rats. To better understand its precise molecular mechanism, we further analyzed the characteristics of ephrin-A5 expression in the hippocampus of CH rats. Our study revealed that ephrin-A5 expression was downregulated by thyroid hormone deficiency in the developing hippocampus and hippocampal neurons in rats. Thyroxine treatment for hypothyroid hippocampus and triiodothyronine treatment for hypothyroid hippocampal neurons significantly improved ephrin-A5 expression but could not restore its expression to control levels. Hypothyroid hippocampal neurons in-vitro showed synaptogenesis disorder characterized by a reduction in the number and length of neurites. Furthermore, the synaptogenesis-associated molecular expressions of NMDAR-1 (NR1), PSD95 and CaMKII were all downregulated correspondingly. These results suggest that ephrin-A5 expression may be decreased in CH, and abnormal activation of ephrin-A5/EphA5 signaling affects synaptogenesis during brain development. Such findings provide an important basis for exploring the pathogenesis of CH genetically. PMID- 29762252 TI - High-Intensity Interval or Continuous Moderate Exercise: A 24-Week Pilot Trial. AB - PURPOSE: High-intensity interval training (HIIT) may lead to superior cardiometabolic improvements when compared with moderate-intensity continuous training (MICT). However, adherence to HIIT requires examination. The purpose of this pilot study was to examine moderate-to-vigorous physical activity (MVPA) adherence 24 wk after a brief counseling intervention combined with either HIIT or MICT. METHODS: Individuals at high risk of type 2 diabetes (T2D) were randomized to HIIT (n = 15) or MICT (n = 17) and completed 10 exercise sessions accompanied by a brief 10-min counseling intervention over a 2-wk period. Objectively measured purposeful MVPA (accelerometry) and cardiorespiratory fitness (VO2peak) were assessed at baseline and 24 wk postintervention. Self regulatory efficacy and task self-efficacy were examined at baseline, postintervention, and 24 wk postintervention. Using an intention-to-treat analysis, change scores were calculated for HIIT and MICT and compared between groups. RESULTS: Individuals assigned to HIIT increased their MVPA by 53 min (Cohen's d = 1.52) at 24 wk compared with 19 min in MICT. Both HIIT and MICT increased relative VO2peak by 2 and 1 mL.kg.min, respectively. Participants in both groups increased in their self-regulatory and task self-efficacy postintervention, but both groups demonstrated similar decline at 24 wk. CONCLUSION: This pilot intervention was successful in increasing, and maintaining, free-living MVPA over a 24-wk period in individuals at high risk of T2D. Speculation that HIIT is inappropriate or unattainable for overweight individuals at high risk of T2D may be unfounded. PMID- 29762251 TI - Prospective Assessment of Adenovirus Infection in Pediatric Kidney Transplant Recipients. AB - BACKGROUND: Adenovirus infection is associated with graft dysfunction and graft loss in pediatric cardiac, lung, and liver transplants in prior retrospective studies, but data in pediatric kidney transplant recipients is limited. METHODS: We conducted a prospective single-center cohort study of 75 consecutive pediatric kidney transplant recipients who underwent monthly screening for adenovirus viremia and symptom assessment for 2 years posttransplant. RESULTS: Adenovirus viremia was detected in 11 (14.7%) patients at a median onset of 173 days (interquartile range, 109-310 days) posttransplant, 6 (8%) had asymptomatic viremia, and 5 (6.7%) had symptomatic disease (2 with hematuria and 3 with an acute febrile respiratory illness). Viremic patients did not differ from nonviremic patients in age, immunosuppression management, or cytomegalovirus or Epstein-Barr virus serostatus, but were more likely to develop cytomegalovirus viremia during the first 2 years posttransplant. No patient had an increase in creatinine from baseline during the time of adenovirus viremia. In a Cox proportional hazards regression, subclinical adenovirus viremia was not associated with a faster time to a 30% decline in estimated glomerular filtration rate. CONCLUSIONS: Adenovirus infection is common among pediatric kidney transplant recipients and frequently causes symptomatic disease; however, symptoms are often mild and are not associated with a decline in graft function. Routine monitoring for adenovirus viremia in pediatric kidney transplant recipients may not be warranted. PMID- 29762253 TI - Glucose Tolerance is Linked to Postprandial Fuel Use Independent of Exercise Dose. AB - PURPOSE: The optimal short-term exercise dose to improve glucose tolerance in relation to metabolic flexibility and/or insulin resistance is unknown. Therefore, we tested if short-term, work-matched continuous (CONT) versus interval (INT) exercise training improves glucose tolerance in part by reducing insulin resistance and increasing metabolic flexibility independent of clinically meaningful fat loss in adults with prediabetes. METHODS: Subjects (age = 60.9 +/- 1.4 yr, body mass index = 33.5 +/- 1.1 kg.m) were screened for prediabetes using the American Diabetes Association criteria (75 g oral glucose tolerance test [OGTT] and/or HbA1c) and were randomized to 60 min.d of supervised CONT (n = 17, 70% HRpeak) or work-matched INT (n = 14; 90% HRpeak for 3 min and 50% HRpeak for 3 min) exercise for 12 bouts. Fitness (VO2peak) and body composition were assessed pre- and postintervention. A 180-min 75-g OGTT was performed, and glucose, insulin, and free fatty acids were collected to calculate glucose tolerance (tAUC180min) and whole-body as well as adipose tissue insulin resistance pre- and postintervention. RER (indirect calorimetry) was also measured at 0, 60, 120, and 180 min of the OGTT to assess fasting and postprandial metabolic flexibility. RESULTS: CONT and INT training improved VO2peak (L.min; P = 0.001) and glucose tolerance (P = 0.01) and reduced fasting RER (P = 0.006), as well as whole-body and adipose insulin resistance (both P = 0.02) with no effect on body fat (P = 0.18). Increased postprandial RER was correlated with reduced glucose tAUC180min (r = -0.38, P = 0.05) and increased 180-min RER related to decreased whole-body insulin resistance (r = -0.42, P = 0.03). CONCLUSION: Independent of exercise dose and fat loss, short-term training improves glucose tolerance in relation to enhanced postprandial fuel use. PMID- 29762254 TI - Short article: Influence of regulatory NLRC5 variants on colorectal cancer survival and 5-fluorouracil-based chemotherapy. AB - BACKGROUND: NLRC5 is an interferon gamma-inducible protein, which plays a role in immune surveillance with a potential influence on cancer survival. OBJECTIVE: We aimed to evaluate the effect of potential regulatory variants in NLRC5 on overall survival and survival after 5-fluorouracil (5-FU)-based therapy of colorectal cancer (CRC) patients. PATIENTS AND METHODS: We carried out a case-only study in a Czech population of 589 cases; 232 received 5-FU-based therapy. Eleven variants within NLRC5 were selected using in-silico tools. Associations between polymorphisms and survival were assessed by Cox regression analysis adjusting for age at diagnosis, sex, and TNM stage. Survival curves were derived using the Kaplan-Meier method. RESULTS: Two variants showed a significant association with survival. All patients and metastasis-free patients at the time of diagnosis (pM0) who were homozygous carriers of the minor allele of rs27194 had a decreased overall survival (OSall and OSpM0) and event-free survival (EFSpM0) under a recessive model (OSall P=0.003, OSpM0 P=0.005, EFSpM0 P=0.01, respectively). OS was also decreased for all patients and for pM0 patients who carried at least one minor allele of rs289747 (OSall P=0.03 and OSpM0 P=0.003, respectively). Among CRC patients, who underwent a 5-FU-based adjuvant regimen, rs12445252 was associated with OSall, OSpM0 and EFSpM0, according to the dosage of the minor allele T (OSall P=0.0004, OSpM0 P=0.0001, EFSpM0 P=0.008, respectively). CONCLUSION: Our results showed that polymorphisms in NLRC5 may be used as prognostic markers of survival of CRC patients, as well as for survival in response to 5-FU treatment. PMID- 29762256 TI - Computed Tomography Perfusion Measurements in Renal Lesions Obtained by Bayesian Estimation, Advanced Singular-Value Decomposition Deconvolution, Maximum Slope, and Patlak Models: Intermodel Agreement and Diagnostic Accuracy of Tumor Classification. AB - OBJECTIVES: The aims of this study were to evaluate the agreement of computed tomography (CT)-perfusion parameter values of the normal renal cortex and various renal tumors, which were obtained by different mathematical models, and to evaluate their diagnostic accuracy. MATERIALS AND METHODS: Perfusion imaging was performed prospectively in 35 patients to analyze 144 regions of interest of the normal renal cortex and 144 regions of interest of renal tumors, including 21 clear-cell renal cell carcinomas (RCC), 6 papillary RCCs, 5 oncocytomas, 1 chromophobe RCC, 1 angiomyolipoma with minimal fat, and 1 tubulocystic RCC. Identical source data were postprocessed and analyzed on 2 commercial software applications with the following implemented mathematical models: maximum slope, Patlak plot, standard singular-value decomposition (SVD), block-circulant SVD, oscillation-limited block-circulant SVD, and Bayesian estimation technique. Results for blood flow (BF), blood volume (BV), and mean transit time (MTT) were recorded. Agreement and correlation between pairs of models and perfusion parameters were assessed. Diagnostic accuracy was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: Significant differences and poor agreement of BF, BV, and MTT values were noted for most of model comparisons in both the normal renal cortex and different renal tumors. The correlations between most model pairs and perfusion parameters ranged between good and perfect (Spearman rho = 0.79-1.00), except for BV values obtained by Patlak method (rho = 0.61-0.72). All mathematical models computed BF and BV values, which differed significantly between clear cell RCCs, papillary RCCs, and oncocytomas, which introduces them as useful diagnostic tests to differentiate between different histologic subgroups (areas under ROC curve, 0.83-0.99). The diagnostic accuracy to discriminate between clear-cell RCCs and the renal cortex was the lowest based on the Patlak plot model (area under ROC curve, 0.76); BF and BV values obtained by other algorithms did not differ significantly in their diagnostic accuracy. CONCLUSIONS: Quantitative perfusion parameters obtained from different mathematical models cannot be used interchangeably. Based on BF and BV estimates, all models are a useful tool in the differential diagnosis of kidney tumors, with the Patlak plot model yielding a significantly lower diagnostic accuracy. PMID- 29762257 TI - Evaluation of Safety Guidelines on the Use of Iodinated Contrast Material: Conundrum Continued. AB - OBJECTIVES: Recently, safety guidelines for the use of intravascular iodinated contrast material have been updated, and the recommended threshold for giving prophylaxis to prevent contrast-induced nephropathy (CIN) has been reduced to estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 m. Data on this population in the context of CIN, especially evidence for efficacy of the recommendation of prophylactic intravenous hydration, are lacking. The aim of the current study was to test implicit assumptions underlying the guideline update: (1) patients with eGFR <30 mL/min/1.73 m, as opposed to former high-risk patients with eGFR >=30 mL/min/1.73 m, are at high risk of CIN and other unfavorable outcomes after intravascular iodinated contrast material administration; (2) prophylactic intravenous hydration mitigates this risk; and (3) the risk of administering prophylactic intravenous hydration does not outweigh the positive preventive effect. MATERIALS AND METHODS: Retrospectively, data were collected from all patients with eGFR <30 mL/min/1.73 m referred for an elective procedure with intravascular iodinated contrast material administration and excluded from the AMACING trial (A MAastricht Contrast-Induced Nephropathy Guideline trial). We compared these patients with those prospectively included in the AMACING trial (with eGFR 30-59 mL/min/1.73 m and risk factors). Main outcomes were CIN (defined as an increase in serum creatinine by more than 25% or 44 MUmol/L within 2-6 days postcontrast exposure), dialysis and mortality within 35 days postcontrast exposure, and complications of prophylactic intravenous hydration. RESULTS: A total of 28,803 patients referred for an elective procedure with intravascular iodinated contrast administration were prospectively screened for inclusion in the AMACING trial. One hundred fifty-seven (0.5%) patients had eGFR <30 mL/min/1.73 m, and 155 received intravascular iodinated contrast material. Standard prophylaxis was given to 119/155 of these patients. Data on 2- to 6-day serum creatinine, 35-day dialysis 35-day mortality, and complications of prophylactic intravenous hydration were available for 59/119 (50%), 118/119 (99%), 119/119 (100%), and 119/119 (100%) standard prophylaxis patients, respectively. Incidences in eGFR <30 mL/min/1.73 m versus AMACING patients are as follows: CIN 13.6% versus 2.7% (P = 0.0019); 35-day dialysis 0.9% versus 0.0% (P = 0.2646); 35-day mortality 9.2% versus 0.0% (P < 0.0001); complications of prophylactic intravenous hydration 5.9% versus 5.5% (P = 0.8529). CONCLUSIONS: Postcontrast incidences of CIN and mortality at 35 days are significantly higher in the population with eGFR <30 mL/min/1.73 m than in the former high-risk population with eGFR 30 to 59 mL/min/1.73 m, even after prophylactic intravenous hydration. The risk of complications of prophylactic intravenous hydration is similar and substantial in both populations. Obtaining evidence from a randomized trial that efficacy of prophylactic intravenous hydration outweighs the risk of complications is important but may not be feasible. PMID- 29762255 TI - Ombitasvir/paritaprevir/ritonavir+dasabuvir+ribavirin for chronic hepatitis C virus genotype 1b-infected cirrhotics (TURQUOISE-IV). AB - OBJECTIVE: An estimated 336 per 100 000 people in Russia are infected with hepatitis C virus, including up to 75% with genotype (GT) 1b. In the TURQUOISE II/-III trials, a 12-week regimen of the direct-acting antiviral agents ombitasvir (OBV), paritaprevir (PTV), ritonavir, and dasabuvir (DSV) in GT1b infected patients with compensated cirrhosis resulted in 12-week sustained virologic response (SVR) rates of 100%. PATIENTS AND METHODS: In TURQUOISE-IV, GT1b-infected patients (n=36) from Russia and Belarus with compensated cirrhosis, who were treatment naive or previously treated with pegylated interferon/ribavirin (RBV), received OBV/PTV/ritonavir+DSV+RBV for 12 weeks. The primary efficacy end point was SVR at 12 weeks. Safety assessments included adverse event (AE) monitoring and laboratory testing. RESULTS: At baseline, patients had Child-Pugh scores of 5 (92%) or 6 (8%). Overall, 69% were treatment experienced (44% prior null responders, 32% relapsers, and 16% partial responders). All patients achieved SVR at 12 weeks (36/36; 100%). No patient experienced a serious AE or discontinued treatment prematurely. Treatment emergent AEs possibly related to study drugs occurring in greater than or equal to 10% of patients were asthenia (19%), anemia (14%), cough (14%), and headache (11%); most events were mild in severity. Clinically significant laboratory abnormalities were infrequent. CONCLUSION: In Russian and Belarusian patients with hepatitis C GT1b infection and compensated cirrhosis, 100% achieved SVR at 12 weeks after 12 weeks' treatment with OBV/PTV/ritonavir+DSV+RBV. The treatment was well tolerated. PMID- 29762258 TI - Fast Abdominal Contrast-Enhanced Imaging With High Parallel-Imaging Factors Using a 60-Channel Receiver Coil Setup: Comparison With The Standard Coil Setup. AB - PURPOSE: The aim of this study was to assess a novel 60-channel receiver body coil (B60) setup for accelerated contrast-enhanced abdominal magnetic resonance imaging (MR) imaging with respect to signal-to-noise ratio (SNR) and image quality using high parallel-imaging technique (PAT) factors in comparison to a standard 30-channel coil setup. METHODS: All imaging data were acquired on a 3 T MR scanner using a novel B60 receiver coil setup in comparison to a standard 30 channel setup serving as reference standard. Phantom measurements were performed to systematically evaluate SNR and geometry factor performance in an ex vivo setting. To assess the in vivo application, additional measurements in 5 healthy volunteers and 17 patients were performed using a 3-dimensional T1w gradient-echo sequences with different acceleration factors. At first, the volunteers were examined. In a second step, standard contrast-enhanced abdominal images were acquired in the 17 patients, who were randomly assigned into 2 groups (group A: 60-channel, n = 8; group B: 30-channel, n = 9). Image quality, noise, lesion conspicuity, and artifacts were assessed by 2 radiologists independently on a 5 point Likert scale (5 = excellent). RESULTS: The phantom study revealed substantial advantages (SNR and geometry factor) of the B60 coil for measurements in the head-to-feet phase encoding direction, whereas only minor differences were found in other directions. Comparison of image quality in volunteers revealed significantly higher ratings of the B60 setup for all acquisitions (P <= 0.032), except for PAT = none. In patients, similar results were observed with comparable image quality at lower PAT factors and significantly superior image quality of the B60 setup for higher PAT factors (2 * 2 and 3 * 2; P = 0.008). CONCLUSIONS: The 60-channel coil setup facilitates improved SNR and image quality at high PAT factors with diagnostic image quality, which allows for accelerated contrast enhanced MR imaging of the abdomen. PMID- 29762259 TI - Precise and Automatic Patient Positioning in Computed Tomography: Avatar Modeling of the Patient Surface Using a 3-Dimensional Camera. AB - OBJECTIVES: The aim of this study was to evaluate the accuracy of a 3-dimensional (3D) camera algorithm for automatic and individualized patient positioning based on body surface detection and to compare the results of the 3D camera with manual positioning performed by technologists in routinely obtained chest and abdomen computed tomography (CT) examinations. MATERIALS AND METHODS: This study included data of 120 patients undergoing clinically indicated chest (n = 68) and abdomen (n = 52) CT. Fifty-two of the patients were scanned with CT using a table height manually selected by technologists; 68 patients were automatically positioned with the 3D camera, which is based on patient-specific body surface and contour detection. The ground truth table height (TGT) was defined as the table height that aligns the axial center of the patient's body region in the CT scanner isocenter. Off-centering was defined as the difference between the ground truth table height (TGT) and the actual table position used in all CT examinations. The t test was performed to determine significant differences in the vertical offset between automatic and manual positioning. The chi test was used to check whether there was a relationship between patient size and the magnitude of off-centering. RESULTS: We found a significant improvement in patient centering (offset 5 +/- 3 mm) when using the automatic positioning algorithm with the 3D camera compared with manual positioning (offset 19 +/- 10 mm) performed by technologists (P < 0.005). Automatic patient positioning based on the 3D camera reduced the average offset in vertical table position from 19 mm to 7 mm for chest and from 18 mm to 4 mm for abdomen CT. The absolute maximal offset was 39 mm and 43 mm for chest and abdomen CT, respectively, when patients were positioned manually, whereas with automatic positioning using the 3D camera the offset never exceeded 15 mm. In chest CT performed with manual patient positioning, we found a significant correlation between vertical offset greater than 20 mm and patient size (body mass index, >26 kg/m, P < 0.001). In contrast, no such relationship was found for abdomen CT (P = 0.38). CONCLUSIONS: Automatic individualized patient positioning using a 3D camera allows for accurate patient centering as compared with manual positioning, which improves radiation dose utilization. PMID- 29762260 TI - Clinical indications associated with opioid initiation for pain management in Ontario, Canada: a population-based cohort study. AB - Concerns over prescription opioids contributing to high levels of opioid use disorder and overdose have led policymakers and clinicians to seek means to reduce inappropriate and high-dose initial prescriptions. To inform such efforts, we sought to describe the clinical indications associated with opioid initiation and the characteristics of the initial prescriptions and patients through a retrospective population-based cohort study. Our cohort included Ontarians initiating prescription opioids for pain management between April 1, 2015, and March 31, 2016. We identified the apparent clinical indication for opioid initiation by linking prescription drug claims to procedural and diagnostic information on health service records on the day of, and 5 days preceding prescription. Outcomes included initial opioid type, prescription duration, and daily dose (in milligram morphine equivalents), stratified either by indication or indication cluster. Among 653,993 individuals, we successfully classified 575,512 (88.0%) people initiating opioids into 23 clinical indications in 6 clusters: dental (23.2%); postsurgical (17.4%); musculoskeletal (12.0%); trauma (11.2%); cancer/palliative care (6.5%); and other less frequent indications (17.7%). Individuals with postsurgical pain received the highest daily doses (40.5% with greater than 50 milligram morphine equivalent), and those with musculoskeletal pain received more initial prescriptions with a duration exceeding 7 days (34.2%). Opioids are initiated for a wide range of indications with varying doses and durations; yet, those who initiated opioids for postsurgical and musculoskeletal pain received the greatest doses and durations of therapy, respectively. These findings may help tailor and prioritize efforts to promote more appropriate opioid prescribing. PMID- 29762261 TI - A retrospective study of the clinical features in papillary thyroid microcarcinoma depending on age. AB - The aim of this study was to evaluate the clinical features and correlation of neck lymph node involvement of papillary thyroid microcarcinoma (PTMC) according to patients' age. We divided the patients into three groups according to age: young group (<45 years, n=83), middle group (45-54 years, n=80), and old group (>=55 years, n=53). The clinical features among the different groups were analyzed retrospectively. All of the 216 patients had received radioiodine ablation at least one time. Among these, 84 patients had central lymph node metastasis (CLNM), 11 patients had lateral lymph node metastasis (LLNM), and 26 patients had both CLNM and LLNM. We show that both lymph node metastasis (LNM) and the CLNM rate were significantly higher in young patients compared with old patients (P=0.000 and 0.000, separately). The radioactive iodine curative ratio in younger patients is also lower than that in the other two groups (37.35, 18.75, and 32.08%, separately, P=0.029). Further Bonferroni test among three groups identified that both LNM and the CLNM rate were significantly higher in the young group than in the old group (P=0.000 and 0.000, separately). Logistic regression analysis showed that young [odds ratio (OR): 2.087, 95% confidence interval (CI): 1.013-4.299, P=0.046] and middle age (OR: 4.049, 95% CI: 1.933 8.482, P=0.000), and extrathyroid extension (OR: 1.952, 95% CI: 1.027-3.711, P=0.041) are independent risk factors for neck LNM. Unlike LNM, young age (<45 years) (OR: 3.667, 95% CI: 1.732-7.761, P=0.001), extrathyroid extension (OR: 2.256, 95% CI: 1.189-4.282, P=0.013), and male sex (OR: 2.057, 95% CI: 1.042 4.061, P=0.038) were found to be independent risk factors for CLNM. However, no independent risk factors were found to be associated with LLNM. The patients with PTMCs had different clinical features according to age. PTMCs in young patients were more aggressive, especially in LNM. Hence, clinicians should consider an individualized treatment according to age in younger patients to achieve better therapeutic efficacy. PMID- 29762263 TI - AMSSM Position Statement on Cardiovascular Preparticipation Screening in Athletes: Current Evidence, Knowledge Gaps, Recommendations, and Future Directions: Erratum. PMID- 29762262 TI - 18F-fluorodeoxyglucose positron-emission tomography combined with computed tomography as a diagnostic tool in native valve endocarditis. AB - OBJECTIVE: The aim of the study was to investigate the value of F fluorodeoxyglucose positron-emission tomography combined with computed tomography (F-FDG-PET/CT) in diagnosing native valve endocarditis (NVE). PATIENTS AND METHODS: All patients with bacteremia and suspicion of NVE between January 2013 and June 2016 were identified from the hospitals' register and retrospectively included if echocardiography and F-FDG-PET/CT were performed within 14 days. F FDG-PET/CT scans were scored independently by two nuclear medicine physicians. F FDG-PET/CT was compared with the modified-Duke criteria and a multidisciplinary consensus. RESULTS: A total of 88 patients were included. In 10 patients with definite NVE according to the modified-Duke criteria, three (30.0%) patients had increased F-FDG uptake in or around the heart valves and seven (70.0%) patients had no increased F-FDG uptake. In patients without definite NVE according to the modified-Duke criteria, 89.7% (70/78) of the patients had no increased F-FDG uptake in or around the heart valves. Of all 20 patients with NVE according to multidisciplinary consensus, nine (45.0%) patients had increased F-FDG uptake in or around the heart valves and 11 (55.0%) patients had a normal F-FDG-PET/CT result. CONCLUSION: A negative F-FDG-PET/CT result should not be interpreted as an exclusion of NVE. In patients with possible or rejected NVE according to the modified-Duke criteria, F-FDG-PET/CT could be used in case of sustained suspicion of NVE owing to its high specificity in case of abnormal FDG uptake at the valve region. F-FDG-PET/CT is important for detecting metastatic infection which already warrants the need to perform F-FDG-PET/CT in all patients with suspected NVE. PMID- 29762264 TI - Achieving Guideline-Driven High-Intensity Statin Dose in Cardiac Rehabilitation Patients With Coronary Artery Disease. AB - PURPOSE: The 2013 American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends high-intensity statin therapy in patients aged <=75 y with clinical coronary artery disease (CAD). The effectiveness of cardiac rehabilitation (CR) in lipid management and guideline adherence is unknown. The purpose of this study is to determine whether CR participation affects guideline-driven achievement for statin use. METHODS: This multicenter retrospective study evaluated statin utilization in patients pre- and post-CR between January 1, 2014, and August 31, 2015. Records for patients with known CAD who completed 18 or more CR sessions were reviewed for statin-drug use and dose before and after CR and documented statin intolerance. RESULTS: Of the total 468 patients, 76% were male with mean age +/- SD = 66.0 +/- 10.8 y and range of 32 to 89 y. Patients aged <=75 y (n = 375) showed a modest but statistically significant increase (P = .0006) in high-intensity statin use post CR (56.3%-61.1%). Males demonstrated a significant increase in high-intensity statin use (P = .0005). Of the 146 patients aged <=75 y not on high-intensity statins post-CR, only 21 had history of statin intolerance. Of the subjects aged >75 y (n = 93), 91% were already on high- or moderate-intensity statins with no significant change during CR. CONCLUSIONS: Patients aged <=75 y following CR completion increased high-intensity statin use but only by 4.8% and 33% of subjects were inadequately treated. The updated 2013 treatment recommendations simplified statin use, yet substantial data continue to reveal that guideline achievement even post-CR remains limited. PMID- 29762265 TI - Link Between Celiac Disease and Inflammatory Bowel Disease. AB - GOAL: The aim of this analysis was to assess in patients with inflammatory bowel disease (IBD) the risk of celiac disease and in celiac disease patients the risk of IBD. BACKGROUND: Previous studies report a possible association between IBD and celiac disease; however, this link is controversial. STUDY: Using the search terms "inflammatory bowel disease" and "celiac disease," we identified initially 1525 publications. In total 27 studies met inclusion criteria. Proportions and 95% confidence intervals (CIs) for the prevalence of IBD in celiac disease and vice versa were compared with published prevalence rates for the respective geographic regions. RESULTS: We included 41,482 adult IBD patients (20,357 with Crohn's disease; 19,791 with ulcerative colitis; and 459 patients with celiac disease). Overall, in IBD patients the prevalence of celiac disease was 1110/100,000 (95% CI, 1010-1210/100,000) as compared with a prevalence of 620/100,000 (95% CI, 610-630/100,000) in the respective populations (odds ratio, 2.23; 95% CI, 1.99-2.50). In contrast, in patients with celiac disease, 2130/100,000 had IBD (95% CI, 1590-2670/100,000) as compared with 260/100,000 (95% CI, 250/100,000-270/100,000) in the respective populations (odds ratio, 11.10; 95% CI, 8.55-14.40). This effect was not different for ulcerative colitis and Crohn's disease. Although there was no evidence for publication bias for celiac disease in IBD, the funnel plot suggested that the association between IBD in celiac disease might be influenced by publication bias. CONCLUSIONS: The data are consistent with the notion that celiac disease is a risk factor for IBD and to lesser degree patients with IBD have an increased risk of celiac disease. PMID- 29762266 TI - Flow Cytometry: Evolution of Microbiological Methods for Probiotics Enumeration. AB - GOALS: The purpose of this trial was to verify that the analytical method ISO 19344:2015 (E)-IDF 232:2015 (E) is valid and reliable for quantifying the concentration of the probiotic Lactobacillus rhamnosus GG (ATCC 53103) in a finished product formulation. BACKGROUND: Flow cytometry assay is emerging as an alternative rapid method for microbial detection, enumeration, and population profiling. The use of flow cytometry not only permits the determination of viable cell counts but also allows for enumeration of damaged and dead cell subpopulations. Results are expressed as TFU (Total Fluorescent Units) and AFU (Active Fluorescent Units). In December 2015, the International Standard ISO 19344-IDF 232 "Milk and milk products-Starter cultures, probiotics and fermented products-Quantification of lactic acid bacteria by flow cytometry" was published. This particular ISO can be applied universally and regardless of the species of interest. STUDY: Analytical method validation was conducted on 3 different industrial batches of L. rhamnosus GG according to USP39<1225>/ICH Q2R1 in term of: accuracy, precision (repeatability), intermediate precision (ruggedness), specificity, limit of quantification, linearity, range, robustness. RESULTS: The data obtained on the 3 batches of finished product have significantly demonstrated the validity and robustness of the cytofluorimetric analysis. CONCLUSIONS: On the basis of the results obtained, the ISO 19344:2015 (E)-IDF 232:2015 (E) "Quantification of lactic acid bacteria by flow cytometry" can be used for the enumeration of L. rhamnosus GG in a finished product formulation. PMID- 29762267 TI - The More, the Better? The Usefulness of Brimonidine as the Fourth Antiglaucoma Eye Drop. AB - PURPOSE: The purpose of this article was to study the intraocular pressure (IOP) lowering effect of adding brimonidine as the fourth antiglaucoma medication to a preexisting therapy of 3 topical drugs. METHODS: This was a retrospective, register-based, cohort study of medical records and computerized medical information comprising 1 county in Sweden. The main outcome measure was change in IOP after brimonidine addition. Short-term and long-term effects were evaluated. RESULTS: Of 4910 patients on antiglaucoma medication, 69 (1.4%) initiated a treatment with brimonidine as the fourth drug during 2014. Fifty-three patients were eligible for analysis. Forty-six patients tolerated the treatment. Among them, short-term IOP decreased by 17% (confidence interval, 10%-25%; P<0.001) after a mean of 46 days (SD, 50 d). Twenty-eight patients, that is, 53% of the eligible, remained on unchanged therapy after a mean follow-up time of 368 days (SD, 61 d). The long-term mean IOP decrease in this group was 20% (confidence interval, 11%-29%; P<0.0001). An IOP reduction of at least 20% was reached by 28 and 14 patients, in the short-term and long-term follow-ups, respectively. CONCLUSIONS: Brimonidine has the potential to reduce the IOP significantly even when used as the fourth drug. In the short-term, half of the patients reached the target IOP reduction (>=20%). After 1 year, a quarter of the eligible patients had had a sustained, uneventful effect. Thus, brimonidine as the fourth adjunctive antiglaucoma drop seems a valuable option for a minority of patients. PMID- 29762268 TI - Influence of Removing the Large Retinal Vessels-related Effect on Peripapillary Vessel Density Progression Analysis in Glaucoma. AB - PURPOSE: To investigate the usefulness of removing the large vessel-related information from peripapillary optical coherence tomography angiography progression analysis. Peripapillary vessel density (VD) image series which had shown no progression with an earlier software version that did not separate capillary and large vessel-related effects were reevaluated for selective peripapillary capillary VD progression. MATERIALS AND METHODS: Prospective retinal nerve fiber layer thickness and peripapillary VD measurements were made using the Angiovue/RTvue-XR OCT on 1 eye of 9 normal, 20 under treatment ocular hypertensive, and 24 under treatment open-angle glaucoma patients at 6-month intervals for 2 years (5 visits). In the current investigation the previously analyzed images were reanalyzed. Linear regression analysis for capillary VD progression in the radial peripapillary capillaries layer of the superior and inferior peripapillary hemifields, respectively, was made using the instrument's new software (version 2017.1, Phase 7 update). RESULTS: A statistically significant negative capillary VD slope was found in 4 glaucoma eyes. Two eyes progressed in both hemifields, and 2 eyes in 1 hemifield. The rate of statistically significant progression ranged between -1.3% and-3.2% per year. In 2 eyes the spatially corresponding hemifield retinal nerve fiber layer thickness progression was also significant (-1.4 MUm/y and -1.8 MUm/y). No normal and ocular hypertensive eyes showed significant capillary VD progression. CONCLUSIONS: In this 2-year prospective study no eye showed progression for peripapillary VD when all vessel-related information was used. In contrast, software-provided removal of the large retinal vessels-related information resulted in detection of significant capillary VD progression in 17% of the glaucoma eyes. PMID- 29762269 TI - Clinical Observation About an Increase in Intraocular Pressure in the Fellow Eye After Surgery in 1 Eye. PMID- 29762270 TI - Preference-based Glaucoma-specific Health-related Quality of Life Instrument: Development of the Health Utility for Glaucoma. AB - PURPOSE: To develop a descriptive system for a glaucoma-specific preference-based health-related quality of life (HRQoL) instrument: the Health Utility for Glaucoma (HUG-5). METHODS: The descriptive system was developed in 2 stages: item identification and item selection. A systematic literature review of HRQoL assessment of glaucoma was conducted using a comprehensive search strategy. Purposeful sampling was used to recruit patients with different clinical characteristics. Relevant items were presented to glaucoma patients through face to-face, semistructured interviews. Framework methodology was applied to analyze interview content. The recurring themes identified through an iterative content analysis represented topics of most importance and relevance to patients. These themes formed the domains of the HUG-5 descriptive system. Three versions of the descriptive system, differing in explanatory detail, were pilot tested using a focus group. RESULTS: The literature review identified 19 articles which contained 266 items. These items were included for the full-text review and were used to develop an interview guide. From 12 patient interviews, 22 themes were identified and grouped into 5 domains that informed the 5 questions of the descriptive system. The HUG-5 measures visual discomfort, mobility, daily life activities, emotional well-being, and social activities. Each question has 5 response levels that range from "no problem" to "severe problem." The focus group comprised 7 additional patients unanimously preferred the version that contained detailed, specific examples to support each question. CONCLUSIONS: A 5-domain descriptive system of a glaucoma-specific preference-based instrument, the HUG-5, was developed and remains to be evaluated for validity and reliability in the glaucoma patient population. PMID- 29762271 TI - Economic Value of Greater Access to Bariatric Procedures for Patients With Severe Obesity and Diabetes. AB - OBJECTIVE: Designing optimal insurance is important to ensure access to care for individuals that are most likely to benefit. We examined the potential impact of lowering patient cost-sharing for bariatric procedures. METHODS: After defining 10 subgroups by body mass index (BMI) and type 2 diabetes mellitus (T2DM), we analyzed the National Health and Nutrition Examination Survey datasets to estimate the prevalence of each subgroup. The MarketScan claims database provided utilization rates and costs of bariatric procedures. Using an existing cost effectiveness model, we estimated the economic value of bariatric procedures under various cost-sharing levels (0%-25%) with 2 frameworks: (1) a traditional cost-effectiveness analysis and (2) a new approach that incorporates utilization effects across subgroups. RESULTS: The utilization rate was higher among individuals with T2DM than those without T2DM (90.4 vs. 59.1 cases per 100,000) for bariatric procedures, which were more cost-effective for those with T2DM and a higher BMI. After accounting for utilization effects, the economic value of bariatric surgery was $177 and $63 per individual from a lifetime and a 5-year time horizon, respectively. Under no patient cost-sharing for individuals with BMI>=40 and T2DM, utilization rates were expected to increase by 21 cases per 100,000, resulting in additional $2 realized value per patient and $7.07 million in returns at the US population level. CONCLUSIONS: Cost-sharing is a barrier to uptake of a clinical and cost-effective treatment for severe obesity. Reducing cost-sharing for patients with severe obesity and T2DM could potentially increase the utilization of bariatric procedures and result in greater economic value to payers. PMID- 29762272 TI - Differences in Experiences With Care Between Homeless and Nonhomeless Patients in Veterans Affairs Facilities With Tailored and Nontailored Primary Care Teams. AB - BACKGROUND: Homeless patients describe poor experiences with primary care. In 2012, the Veterans Health Administration (VHA) implemented homeless-tailored primary care teams (Homeless Patient Aligned Care Team, HPACTs) that could improve the primary care experience for homeless patients. OBJECTIVE: To assess differences in primary care experiences between homeless and nonhomeless Veterans receiving care in VHA facilities that had HPACTs available (HPACT facilities) and in VHA facilities lacking HPACTs (non-HPACT facilities). RESEARCH DESIGN: We used multivariable multinomial regressions to estimate homeless versus nonhomeless patient differences in primary care experiences (categorized as negative/moderate/positive) reported on a national VHA survey. We compared the homeless versus nonhomeless risk differences (RDs) in reporting negative or positive experiences in 25 HPACT facilities versus 485 non-HPACT facilities. SUBJECTS: Survey respondents from non-HPACT facilities (homeless: n=10,148; nonhomeless: n=309,779) and HPACT facilities (homeless: n=2022; nonhomeless: n=20,941). MEASURES: Negative and positive experiences with access, communication, office staff, provider rating, comprehensiveness, coordination, shared decision-making, and self-management support. RESULTS: In non-HPACT facilities, homeless patients reported more negative and fewer positive experiences than nonhomeless patients. However, these patterns of homeless versus nonhomeless differences were reversed in HPACT facilities for the domains of communication (positive experience RDs in non-HPACT versus HPACT facilities=-2.0 and 2.0, respectively); comprehensiveness (negative RDs=2.1 and -2.3), shared decision-making (negative RDs=1.2 and -1.8), and self-management support (negative RDs=0.1 and -4.5; positive RDs=0.5 and 8.0). CONCLUSIONS: VHA facilities with HPACT programs appear to offer a better primary care experience for homeless versus nonhomeless Veterans, reversing the pattern of relatively poor primary care experiences often associated with homelessness. PMID- 29762274 TI - Decomposing Medicaid Spending During Health System Reform and ACA Expansion: Evidence From Oregon. AB - BACKGROUND: Expansion of the Medicaid program is likely to create new budgetary pressures at the state and federal levels, creating a need for greater understanding of how program dollars are allocated and what drives spending growth. OBJECTIVE: To characterize Oregon Medicaid expenditures across diseases and medical conditions, during periods of payment reform and coverage expansion. RESEARCH DESIGN: Decomposition of changes in Medicaid expenditures using a person based allocation of spending across 50 diseases/medical conditions. Four indices describe changes in costs per enrolled member, demographic shifts, prevalence of treated disease/condition, and costs per treated member. SUBJECTS: Oregon Medicaid beneficiaries during 2011 (N=597,422), 2013 (N=614,858), and 2014 (N=978,237). RESULTS: Expenditures on pregnancy/birth and mental conditions accounted for 24% of 2011 spending. Oregon's 2012 payment reform was associated with reduced spending attributable primarily to decreased prevalence of treated conditions. The 2014 Medicaid expansion was marked by lower pregnancy and mental health expenditures and higher spending on treatment for substance use and heart disease. CONCLUSIONS: Medicaid spending is concentrated among a small group of medical conditions, not all of which are typically associated with the program. The relative expenditure burdens for some conditions are likely to change with health system reform and enrollment expansions. Decomposition into 4 indices and reporting by disease/condition elucidate variability in drivers of cost growth. PMID- 29762273 TI - Patient Engagement in ACO Practices and Patient-reported Outcomes Among Adults With Co-occurring Chronic Disease and Mental Health Conditions. AB - BACKGROUND: Accountable care organizations (ACOs) have increased their use of patient activation and engagement strategies, but it is unknown whether they achieve better outcomes for patients with comorbid chronic physical and mental health conditions. OBJECTIVES: To assess the extent to which practices with patient-centered cultures, greater shared decision-making strategies, and better coordination among team members have better patient-reported outcomes (PROs) for patients with diabetes and/or cardiovascular and comorbid mental health diagnoses. RESEARCH DESIGN: Sixteen practices randomly selected from top and bottom quartiles of a 39-item patient activation/engagement implementation survey of primary care team members (n=411) to assess patient-centered culture, shared decision-making, and relational coordination among team members. These data were linked to survey data on patient engagement and on emotional, physical, and social patient-reported health outcomes. SUBJECTS: Adult patients (n=606) with diabetes, cardiovascular, and comorbid mental health conditions who had at least 1 visit at participating primary care practices of 2 ACOs. MEASURES: Depression/anxiety, physical functioning, social functioning; patient-centered culture, patient activation/engagement implementation, relational coordination. RESULTS: Patients receiving care from practices with high patient-centered cultures reported better physical functioning (0.025) and borderline better emotional functioning (0.059) compared with less patient-centered practices. More activated patients reported better PROs, with higher activation levels partially mediating the relationship of patient-centered culture and better PROs. CONCLUSIONS: ACO patients with comorbid physical and mental health diagnoses report better physical functioning when practices have patient-centered cultures. More activated/engaged patients report better patient emotional, physical, and social health outcomes. PMID- 29762275 TI - Health-Related Quality of Life in Adulthood in Untreated and Treated Individuals with Adolescent or Juvenile Idiopathic Scoliosis. AB - BACKGROUND: Health-related quality of life in adults with idiopathic scoliosis diagnosed before maturity has been reported to be similar between brace-treated and surgically treated individuals. The aim of this study was to compare health related quality of life in untreated, brace-treated, and surgically treated adults with idiopathic scoliosis diagnosed before skeletal maturity. Subgroup analyses were performed on the basis of age at the time of the study, age of onset, surgical characteristics, and curve magnitude. METHODS: We included 1,187 adults with juvenile or adolescent idiopathic scoliosis with a mean age (and standard deviation) of 38.8 +/-12.7 years. Of these, 347 were untreated, 459 had been brace-treated, and 381 had been surgically treated. The Scoliosis Research Society-22r (SRS-22r) and EuroQol 5-Dimensions (EQ-5D) were used. Statistical analyses were performed using analysis of covariance. RESULTS: The mean SRS-22r subscore was 4.15 +/- 0.59 points for the untreated group, 4.10 +/- 0.57 points for the previously braced group, and 4.01 +/- 0.64 points for the surgically treated group (p = 0.007 adjusted for age and sex). The EQ-5D index was 0.82 +/- 0.20 for the untreated group, 0.82 +/- 0.20 for the previously brace-treated group, and 0.79 +/- 0.24 for the surgically treated group (p = 0.026, adjusted for age and sex). Brace cessation was at the mean age of 16.2 +/- 1.5 years, and the surgical procedure had been performed at the mean age of 15.3 +/- 2.1 years. A more caudal fusion was associated with a lower SRS-22r subscore and EQ-5D index. No differences were observed when comparing individuals with juvenile or adolescent onset scoliosis (all p > 0.05). CONCLUSIONS: Untreated adults with idiopathic scoliosis had similar health-related quality of life to previously brace-treated individuals, and they had marginally higher health-related quality of life compared with surgically treated individuals. Therefore, both surgical and brace treatments for idiopathic scoliosis could be considered successful from a health-related quality-of-life point of view in adulthood. The age of onset of idiopathic scoliosis does not seem to influence quality of life in adulthood. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762276 TI - Short-Term Effect of Low-Dose, Electromyography-Guided Botulinum Toxin A Injection in the Treatment of Chronic Lateral Epicondylar Tendinopathy: A Randomized, Double-Blinded Study. AB - BACKGROUND: Botulinum toxin A (BoNT-A) is a novel treatment for chronic lateral epicondylar tendinopathy. Preliminary studies have demonstrated promising results; however, confirmation of the effectiveness of BoNT-A treatment and further assessment of its side effects are required. This study investigated the analgesic effects of BoNT-A in the treatment of chronic lateral epicondylar tendinopathy. METHODS: This was a phase-III, single-center, randomized, double blinded, placebo-controlled study including 60 patients with chronic lateral epicondylar tendinopathy that had been resistant to treatment for >6 months. Patients received either a 40-IU injection of BoNT-A or saline solution placebo into the extensor carpi radialis brevis (ECRB) muscle, aided by electromyographic (EMG) stimulation. Follow-up was 3 months. The primary assessment criterion was the percentage of patients whose pain was reduced by >50% at 90 days after injection. Secondary outcomes, including pain intensity, pain frequency, interference with quality of life, sick leave taken, maximum grip strength, and side effects, were assessed at days 30 and 90, and the number of participants per group requesting additional therapies at day 90 was recorded. RESULTS: Twenty nine patients in the BoNT-A group and 28 patients in the placebo group were included in the day-90 analysis. Fifteen (51.7%) of the patients who were administered BoNT-A and 7 (25%) of the patients who received placebo reported a >50% reduction in initial pain intensity at day 90 (p = 0.005). Pain intensity and the effect on quality of life, measured using visual analog scales, were both significantly lower in the group treated with BoNT-A compared with placebo at day 90 (p < 0.05). The rate of clinically detected transitory paresis of the third finger on extension was 17.2% in the BoNT-A group, with no associated functional impairment. CONCLUSIONS: BoNT-A at 40 IU injected into the ECRB is an effective treatment for chronic lateral epicondylar tendinopathy that has been otherwise resistant to medical treatment. The rate of paresis of the third finger was low, with no associated functional impairment. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762277 TI - Impact of Clinical Practice Guidelines on Use of Intra-Articular Hyaluronic Acid and Corticosteroid Injections for Knee Osteoarthritis. AB - BACKGROUND: The efficacy of corticosteroid and hyaluronic acid injections for knee osteoarthritis has been questioned. The purpose of this study was to determine the impact of the American Academy of Orthopaedic Surgeons (AAOS) clinical practice guidelines on the use of these injections in the United States and determine if utilization differed by provider specialty. METHODS: Patients with knee osteoarthritis were identified within the Humana database from 2007 to 2015, and the percentage of patients receiving a knee injection relative to the number of patients having an encounter for knee osteoarthritis was calculated and was trended for the study period. The impact of each edition of the AAOS clinical practice guidelines on injection use was evaluated with segmented regression analysis. Injection trends were also analyzed relative to the specialty of the provider performing the injection. RESULTS: Of 1,065,175 patients with knee osteoarthritis, 405,101 (38.0%) received a corticosteroid injection and 137,005 (12.9%) received a hyaluronic acid injection. The rate of increase in hyaluronic acid use, per 100 patients with knee osteoarthritis, decreased from 0.15 to 0.07 injection per quarter year (p = 0.02) after the first clinical practice guideline, and the increase changed to a decrease at a rate of -0.12 injection per quarter (p < 0.001) after the second clinical practice guideline. After the first clinical practice guideline, the rate of increase in utilization of corticosteroids, per 100 patients with knee osteoarthritis, significantly lessened to 0.12 injection per quarter (p < 0.001), and after the second clinical practice guideline, corticosteroid injection use plateaued (p = 0.72). The trend in use of hyaluronic acid injections by orthopaedic surgeons and pain specialists decreased with time following the second-edition clinical practice guideline but did not change for primary care physicians or nonoperative musculoskeletal providers. CONCLUSIONS: Subtle but significant changes in hyaluronic acid and corticosteroid injections occurred following the publication of both clinical practice guidelines. Although the clinical practice guidelines did impact injection use, given the high costs of these injections and their questionable clinical efficacy, further interventions beyond publishing clinical practice guidelines are needed to encourage higher-value care for patients with knee osteoarthritis. PMID- 29762278 TI - Comparison of Intermediate to Long-Term Outcomes of Total Ankle Arthroplasty in Ankles with Preoperative Varus, Valgus, and Neutral Alignment. AB - BACKGROUND: Preoperative ankle coronal malalignment has been considered as a risk factor for poor outcomes and failure after total ankle arthroplasty. The present study evaluated whether intermediate to long-term outcomes of total ankle arthroplasty in ankles with preoperative varus and valgus malalignment (5 degrees to 20 degrees ) are comparable with those with neutral alignment (<5 degrees ). METHODS: We enrolled 144 consecutive ankles that underwent primary total ankle arthroplasty (140 patients) using a mobile-bearing HINTEGRA prosthesis with a minimum follow-up of 4 years; the mean overall follow-up duration was 89 months (51 to 145 months). We divided all patients into 3 groups according to the preoperative coronal plane tibiotalar angle: the varus group (59 ankles, 5 degrees to 20 degrees of varus), the valgus group (34 ankles, 5 degrees to 20 degrees of valgus), and the neutral group (51 ankles, <5 degrees ). Patients in each group showed similar characteristics in mean age, sex, body mass index, and follow-up period. RESULTS: The mean Ankle Osteoarthritis Scale pain and disability score, American Orthopaedic Foot & Ankle Society ankle-hindfoot score, Short Form-36 Physical Component Summary score, visual analog scale pain score, and ankle range of motion did not differ meaningfully among the 3 groups at the final follow-up. The final tibiotalar angle showed that the degree of coronal alignment of the varus group was significantly less corrected compared with the neutral group (p = 0.010). The varus group had significantly more concomitant procedures (42 procedures [71.2%]) compared with the neutral group (p = 0.003). The prevalence of major complications did not differ among the 3 groups (p = 0.124). The overall probability of implant survivorship was 91.1% (97.7% in the varus group, 81.1% in the valgus group, and 90.9% in the neutral group) at a mean follow-up of 7.3 years. CONCLUSIONS: In the intermediate to long-term follow-up, mobile-bearing total ankle arthroplasty showed similarly good outcomes in patients with varus and valgus malalignment up to 20 degrees compared with the neutral alignment group when neutrally aligned ankles were achieved postoperatively. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762279 TI - A 20-Year Prospective Longitudinal Study of Degeneration of the Cervical Spine in a Volunteer Cohort Assessed Using MRI: Follow-up of a Cross-Sectional Study. AB - BACKGROUND: Few studies have addressed in detail long-term degenerative changes in the cervical spine. In this study, we evaluated the progression of degenerative changes of the cervical spine that occurred over a 20-year period in an originally healthy cohort. We also sought to clarify the relationship between the progression of cervical degenerative changes and the development of clinical symptoms. METHODS: For this prospective follow-up investigation, we recruited 193 subjects from an original cohort of 497 participants who had undergone magnetic resonance imaging (MRI) of the cervical spine between 1993 and 1996. The subjects were asked about the presence or absence of cervical spine-related symptoms. Degenerative changes of the cervical spine were assessed on MRI using an original numerical grading system. The relationship between the progression of degenerative changes and the onset of clinical symptoms was evaluated by logistic regression analysis. RESULTS: Degeneration in the cervical spine was found to have progressed in 95% of the subjects during the 20-year period. The finding of a decrease in signal intensity of the intervertebral disc progressed in a relatively high proportion of the subjects in all age groups and occurred with similar frequency (around 60%) at all intervertebral disc levels. The rate of progression of other structural failures on MRI increased with age and was highest at C5-C6. The progression of foraminal stenosis was associated with the onset of upper-limb pain (odds ratio, 4.71 [95% confidence interval, 1.02 to 21.7]). CONCLUSIONS: A progression of degenerative changes in the cervical spine on MRI over the 20-year period was detected in nearly all subjects. There was no relationship between the progression of degeneration on MRI and the development of clinical symptoms, with the exception of an association found between foraminal stenosis and upper-limb pain. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762280 TI - Long-Term Outcomes of Pedicled Gastrocnemius Flaps in Total Knee Arthroplasty. AB - BACKGROUND: Deficient soft tissue following total knee arthroplasty (TKA) can jeopardize outcome. The gastrocnemius flap is an important means of providing coverage of a knee with deficient soft tissue. There is a paucity of long-term studies on the use of the gastrocnemius flap in the setting of TKA. The purpose of this study was to review the outcomes after the use of pedicled gastrocnemius flaps for coverage of a soft-tissue defect at the time of TKA. METHODS: Eighty three patients in whom a gastrocnemius flap had been used to cover the site of a primary (n = 18) or revision (n = 65) TKA over a 25-year period were identified. There were 48 women (58%) and 35 men (42%) with a mean age and body mass index (BMI) of 65 years and 32.6 kg/m. The mean wound size was 49 cm, and the wound was most commonly located over the anterior aspect of the knee/patellar tendon (n = 33). Patients were followed to the time of implant or flap revision, amputation, or death or for a minimum of 2 years (mean, 8 years). Clinical outcomes were assessed using the Knee Society Score (KSS) for pain and the KSS for function. The Kaplan-Meier method was used to assess revision and amputation-free survival. Risk factors for amputation and revision were identified with Cox regression. RESULTS: The 10-year revision and amputation-free survival rates following gastrocnemius flap coverage were 68% and 79%, respectively. The risk of implant failure was increased by morbid obesity (BMI of >=40 kg/m) (hazard ratio [HR] = 2.82, 95% confidence interval [CI] = 1.09 to 7.32, p = 0.03) and >=5 prior surgical procedures on the knee (HR = 2.68, 95% CI = 1.04 to 6.88, p = 0.04). The risk of amputation was increased in patients with >=5 prior surgical procedures (HR = 10.76, 95% CI = 2.38 to 48.58, p = 0.002), an age of >=65 years (HR = 4.94, 95% CI = 1.10 to 22.09, p = 0.03), and a wound size of >=50 cm (HR = 3.29, 95% CI = 1.14 to 9.53, p = 0.02). Preoperatively the mean KSSs for pain and function were 46 and 28, and these scores significantly (p < 0.05) improved to 78 and 43, respectively, at the time of follow-up. CONCLUSIONS: The gastrocnemius flap reliably provides coverage of components used in complex knee reconstruction. A history of multiple surgical procedures on the knee and larger soft-tissue defects increase the risk of revision TKA and of amputation. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762281 TI - An Increased Lateral Femoral Condyle Ratio Is a Risk Factor for Anterior Cruciate Ligament Injury. AB - BACKGROUND: The purpose of this study was to examine the relationship between distal femoral morphology and anterior cruciate ligament (ACL) injury, ACL reconstruction (ACLR) failure, and contralateral ACL injury. It was hypothesized that increased posterior femoral condylar depth, quantified as the lateral femoral condyle ratio, would correlate with increased risk of primary ACL injuries, ACLR failures, and contralateral ACL injuries. METHODS: The charts of consecutive patients who underwent arthroscopic knee surgery at an academic medical center from 2012 to 2016 with minimum follow-up of 24 months were retrospectively reviewed. Patients were stratified into 4 groups: (1) a control group of patients with no ACL injury, (2) patients with primary ACL injury, (3) patients with failed ACLR, and (4) patients with previous ACL injury and subsequent contralateral ACL injury. With use of lateral radiographs, the ratio of posterior femoral condylar depth to total condylar length was defined as the lateral femoral condyle ratio. Differences between study groups were identified with use of analysis-of-variance (ANOVA) and post-hoc testing with significance set at p < 0.05. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff for detecting increased risk of ACL injury. RESULTS: Two hundred patients met the inclusion criteria. The mean lateral femoral condyle ratios (and standard deviations) were 61.2% +/- 2.4% in the control group, 64.2% +/- 3.8% in the primary ACL injury group, 64.4% +/- 3.6% in the failed ACLR group, and 66.9% +/- 4.3% in the contralateral ACL injury group. Patients who had a primary ACL injury, failed ACLR, or contralateral ACL injury had significantly higher ratios compared with the control group (p < 0.008). ROC curve analysis demonstrated that a lateral femoral condyle ratio of >63% was associated with an increased risk for ACL injury, with a sensitivity of 77% and a specificity of 72%. CONCLUSIONS: The data from this study show that increased posterior femoral condylar depth, quantified as the lateral femoral condyle ratio, is associated with an increased risk of ACL injury, including primary and contralateral ACL injuries. The data from this study may help clinicians to identify patients at a greater risk of ACL injury. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762282 TI - Uncemented Tantalum Monoblock Tibial Fixation for Total Knee Arthroplasty in Patients Less Than 60 Years of Age: Mean 10-Year Follow-up. AB - BACKGROUND: Although tibial component loosening has been considered a concern after total knee arthroplasty without cement, such implants have been used in younger patients because of the potential for ingrowth and preservation of bone stock. However, mid-term and long-term studies of modern uncemented implants are lacking. We previously reported promising prospective 5-year outcomes after using an uncemented porous tantalum tibial component in patients who underwent surgery before the age of 60 years. The purpose of this study was to determine clinical and radiographic implant survivorship at 10 years in this large series of young patients. METHODS: The original cohort included 79 patients (96 knees) who were <60 years old at the time of surgery. All procedures were performed with an uncemented, posterior-stabilized femoral component and a porous tantalum monoblock tibial component by 1 high-volume arthroplasty surgeon at a single institution. Patients were followed prospectively. The Knee Society Score (KSS), radiographic findings, and any complications or revisions were recorded. RESULTS: At the latest follow-up, 76% (60) of the 79 patients (74% [71] of the 96 knees) were available for evaluation or had undergone revision (n = 6); 7 patients had died with the implants in place, and 12 patients were lost to follow-up. The average follow-up for the available implants was 10 years (range, 8 to 12 years). There were no progressive radiolucencies on radiographic review. The mean functional KSS was 68 points (range, 0 to 100 points). All revisions were for reasons unrelated to tibial fixation: femoral component loosening (1), stiffness (1), pain and swelling (2), and instability (2). The all-cause revision rate was 6% (6 of 96 knees). CONCLUSIONS: Uncemented porous tantalum monoblock tibial components provided reliable fixation, excellent radiographic findings, and satisfactory functional outcomes at a mean of 10 years postoperatively. We identified no cases of tibial component loosening. These promising clinical and radiographic results support the use of uncemented tibial components. Such implants may produce well-integrated, durable long-term constructs in young patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762283 TI - Five to Ten-Year Outcomes of Operatively Treated Scapular Fractures. AB - BACKGROUND: The purpose of this study was to assess the 5 to 10-year clinical and patient-reported functional outcomes after open reduction and internal fixation (ORIF) of intra-articular and extra-articular scapular fractures. METHODS: We conducted a retrospective review of prospectively collected data on 106 patients who underwent ORIF of a scapular fracture at a single level-I trauma center between January 2005 and December 2010. Eight patients were excluded from the study because they had either severe neurologic injury or an isolated process fracture, and 66 patients (37 with an isolated extra-articular fracture and 29 with an intra-articular fracture) participated in the 5 to 10-year follow-up, yielding a follow-up rate of 67%. A physical examination including a strength assessment and range-of-motion measurements was performed on 89% of the follow-up cohort. Disabilities of the Arm, Shoulder and Hand (DASH) and Short Form-12 version 2 (SF-12v2) or SF-36v2 questionnaires were completed by all participating patients. Intra-articular and extra-articular fractures were analyzed in separate groups. RESULTS: The mean follow-up was 7.8 years in the extra-articular group and 7.3 years in the intra-articular group, with a range of 4.7 to 10.3 years. The mean DASH score was 8.9 in the extra-articular group and 9.1 in the intra articular group (normal population = 10.1). Strength examination revealed no significant differences between the injured and uninjured shoulders for any movement (p > 0.05), while the range of external rotation was slightly decreased in both the extra-articular (p = 0.01) and the intra-articular (p = 0.01) group. The abduction range of motion was also slightly decreased in the intra-articular cohort (p = 0.03). Arthroplasty was indicated as a subsequent procedure for 2 patients in the intra-articular cohort. Sixty-one of the 66 patients returned to their original occupation or changed occupations for reasons unrelated to the shoulder injury. CONCLUSIONS: At 5 to 10 years after ORIF of a scapular fracture, patients have excellent functional outcomes albeit with a small decrease in external rotation motion relative to the contralateral, normal shoulder. Interestingly, we found the outcomes after intra-articular and extra-articular fractures to be comparable. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762284 TI - HSS Dysphagia and Dysphonia Inventory (HSS-DDI) Following Anterior Cervical Fusion: Patient-Derived, Validated, Condition-Specific Patient-Reported Outcome Measure Outperforms Existing Indices. AB - BACKGROUND: Dysphagia and dysphonia are common complications after anterior cervical spine surgery; however, reported prevalences vary greatly due to a lack of reliable clinical standards for measuring postoperative swallowing and speech dysfunction. The Hospital for Special Surgery Dysphagia and Dysphonia Inventory (HSS-DDI) was developed as a patient-derived, patient-reported instrument to measure dysphagia and dysphonia more accurately after anterior cervical spine surgery than existing indices. METHODS: This multiphase survey-development study implemented a mixed-methods approach. Phase 1 involved qualitative assessment of postoperative patient-reported swallowing or speaking deficiencies to assemble a draft survey. Phase 2 established test-retest reliability and finalized the 31 item HSS-DDI. Phase 3 compared the HSS-DDI with the Swallowing-Quality of Life (SWAL-QOL) questionnaire and the M.D. Anderson Dysphagia Inventory (MDADI) for validity and responsiveness. RESULTS: Phase 1, performed to formulate the draft survey, included 25 patients who were asked about speech and swallowing dysfunction after anterior cervical spine surgery involving at least 3 vertebral levels. Phase 2 included 49 patients who completed the draft survey twice. The mean scores (and standard deviation) for each administration of the HSS-DDI were 67 +/- 24 and 75 +/- 22, the Cronbach alpha coefficients were both 0.97, and the intraclass correlation coefficient was 0.80. The 31-item HSS-DDI was finalized with all but 2 items having weighted kappa values of >=0.40. Phase 3 included 127 patients and established external validity, with most correlation coefficients between the HSS-DDI and the SWAL-QOL and MDADI ranging from 0.5 to 0.7. Internal validity was established by identifying worsening HSS-DDI scores with increases in the number of vertebral levels involved (p = 0.02) and in the Surgical Invasiveness Index (p = 0.006). HSS-DDI responsiveness ascertained by effect size (0.73) was better than that of the SWAL-QOL and MDADI. The average administration time for the HSS-DDI was 2 minutes and 25 seconds. CONCLUSIONS: The HSS-DDI is efficient, valid, and more responsive to change after anterior cervical spine surgery than existing surveys. CLINICAL RELEVANCE: The HSS-DDI fills a gap in postoperative assessment by providing a reliable, more clinically sensitive, patient and condition-specific evaluation of dysphagia and dysphonia prospectively and longitudinally. PMID- 29762286 TI - In High Tibial Osteotomy, Closing and Opening Wedges Did Not Differ for Clinical Outcomes at Up to Two Years. PMID- 29762285 TI - Cone-Beam Computed Tomography-Guided Navigation in Complex Osteotomies Improves Accuracy at All Competence Levels: A Study Assessing Accuracy and Reproducibility of Joint-Sparing Bone Cuts. AB - BACKGROUND: The objective of this study was to assess the accuracy and reproducibility of a novel cone-beam computed tomography (CBCT)-guided navigation system designed for osteotomies with joint-sparing bone cuts. METHODS: Eighteen surgeons participated in this study. First, 3 expert tumor surgeons resected bone tumors in 3 Sawbones tumor models identical to actual patient scenarios. They first performed these osteotomies without navigation and then performed them using a navigation system and 3-dimensional (3D) planning tools based on CBCT imaging. The 2 sets of measurements were compared using image-based measurements from post-resection CBCT. Next, 15 residents, fellows, and orthopaedic staff surgeons were instructed on the use of the system, and their navigated resections were compared with navigated resections performed by the 3 expert tumor surgeons. RESULTS: One hundred and twenty-six navigated cuts done by the orthopaedic oncologists were compared with 126 non-navigated cuts by the same surgeons. The cuts violated the tumor in 22% (6) of the 27 non-navigated resections compared with none of the 27 navigated resections. The navigated cuts were significantly more accurate in terms of entry point, pitch, and roll (p < 0.001). The variation among the 3 surgeons when they used navigation was <0.6 mm for the entry cut and, on average, 1.5 degrees for pitch and roll. All 18 surgeons then completed a total of 144 navigated cuts. The level of experience did not result in a significant difference among groups with regard to cut accuracy. Two cuts went into the tumor. The mean distance from the planned bone cuts to the actual entry points into bone was 1.5 mm (standard deviation [SD] = 1.4 mm) for all users. The mean difference in pitch and roll between the planned and actual cuts was 3.5 degrees (SD = 2.8 degrees ) and 3.7 degrees (SD = 3.2 degrees ) for all users. CONCLUSIONS: Even in expert hands, navigated cuts were significantly more accurate than non-navigated cuts. When the osteotomies were aided by navigation, their accuracy did not differ according to the level of professional experience. CBCT-based metrics enable intraoperative assessments of cut accuracy and reconstruction planning. CLINICAL RELEVANCE: CBCT-guided navigated osteotomies can improve accuracy regardless of surgeon experience and decrease the variability among different surgeons. PMID- 29762287 TI - In Completely Displaced Midshaft Fractures of the Clavicle, Plate Fixation and Elastic Stable Intramedullary Nailing Did Not Differ in Function at One Year. PMID- 29762288 TI - In Lumbar Spinal Stenosis, Adding Corticosteroids to Lidocaine Epidural Injections Did Not Improve Pain or Function at 12 Months. PMID- 29762289 TI - Use of Intra-Articular Corticosteroids in Orthopaedics. PMID- 29762290 TI - What's New in Foot and Ankle Surgery. PMID- 29762291 TI - Profiles of Practicing Female Orthopaedists Caring for Medicare Patients in the United States. AB - BACKGROUND: The increase in the percentage of women in orthopaedics in the United States over the last half century has been substantially slower than in every other surgical specialty. While this percentage has improved recently, the current demographic and practice characteristics of female orthopaedic surgeons are not well known. This study defines the landscape of practicing female orthopaedic surgeons caring for Medicare patients. METHODS: Publicly available Medicare billing data sets from 2012 to 2014 were utilized to identify practicing orthopaedic surgeons. We analyzed demographics, medical training, practice characteristics, case volume, specialization, and procedure profiles of orthopaedic surgeons. Representative Current Procedural Terminology (CPT) codes were utilized for each subspecialty. Multivariate analysis was performed to confirm the independent characteristics that were associated with female orthopaedic surgeons after identification by univariate statistics. RESULTS: The percentage of practicing female orthopaedic surgeons caring for Medicare patients increased significantly from 4.7% (1,043 of 22,038) in 2012 to 5.2% (1,179 of 22,510) in 2014. Women had graduated from medical school in more recent years than men (mean, 14.9 versus 22.5 years, respectively; p < 0.001), and were more likely to have attended a top-25 medical school (27.5% versus 24.5%, respectively; p = 0.01). Women were more likely to be part of larger practices (median, 49.5 versus 24 partners, respectively; p < 0.001), and were more likely to leave practice (4.4% versus 3.1% in 2013, respectively; p = 0.02). Women submitted fewer claims for billing per year (median, 528 versus 1,193, respectively; p < 0.001), and performed 6.8% (9,852 of 144,492) of hand procedures compared with 1.5% (10,043 of 651,856) of all other common procedures (p < 0.001). Multivariate analysis demonstrated that despite confounders, gender was an independent predictor of number of claims, the likelihood of leaving clinical practice, and Medicare reimbursement. CONCLUSIONS: There are significant differences between female and male orthopaedic surgeons caring for Medicare patients in terms of subspecialty choices, education, billing practices, and attrition rates. Despite the recent increase in the number of female orthopaedic surgeons, there are significant gender differences within the specialty. PMID- 29762292 TI - A Dedicated Satellite Trauma Orthopaedic Program Operating Room Safely Increases Capacity. AB - BACKGROUND: Providing high-value care for urgent orthopaedic trauma patients requires effective and timely treatment. Herein, we describe the implementation of an innovative program utilizing the operating room (OR) capacity of a satellite campus to decrease stress on a pediatric tertiary care center without jeopardizing patient safety. METHODS: In addition to the daily emergency surgical room on the main campus, a dedicated orthopaedic trauma surgery OR was established in a satellite hospital location for 3 days per week in the summer and for 2 days per week for the rest of the year. Nonemergency, non-multitrauma operative fracture cases presenting to our tertiary care facility emergency department or orthopaedic clinic were considered for satellite referral. Eligible patients required clearance for transfer via orthopaedic, emergency department, and anesthesia checklists. An opt-out policy was established for provider judgment or patient family concern to overrule transfer decisions. Selected patients were discharged home with satellite OR scheduling or approved for same day satellite location admission. Short elective cases were performed when openings existed in the schedule. RESULTS: From June 1, 2016, through June 30, 2017, 480 cases (372 trauma, 108 elective) were completed in our satellite OR. The most common trauma cases that were treated in the satellite OR were type-II supracondylar humeral fractures (n = 76). Summer months averaged 41.75 trauma cases and 11.25 elective cases per month, with 3.15 trauma cases and 0.85 elective cases per day. Nonsummer months averaged 22.78 trauma cases and 7.00 elective cases per month, with 2.93 trauma and 0.90 elective cases per day. Of the 17 postoperative issues, the greatest number (n = 7 [41%]) involved symptomatic hardware. The remaining complications were not surgeon or geographic site-specific. There were no intraoperative complications, compartment syndrome episodes, or patients who required transfer back to our tertiary care facility for unexpected or serious medical issues. CONCLUSIONS: With the proper screening protocols in place for appropriate patient selection, the use of a dedicated satellite orthopaedic trauma OR can increase capacity without compromising patient safety. PMID- 29762294 TI - Are We Expanding the Limits of Preoperative Ankle Deformity in Patients Undergoing Total Ankle Arthroplasty?: Commentary on an article by Gun-Woo Lee, MD, et al.: "Comparison of Intermediate to Long-Term Outcomes of Total Ankle Arthroplasty in Ankles with Preoperative Varus, Valgus, and Neutral Alignment". PMID- 29762293 TI - Long-Term Outcome for Scoliosis Is Dependent on Several Factors: Commentary on an article by Elias Diarbakerli, PT, MSc, et al.: "Health-Related Quality of Life in Adulthood in Untreated and Treated Individuals with Adolescent or Juvenile Idiopathic Scoliosis". PMID- 29762295 TI - More Than a Snapshot of the Spine: Commentary on an article by Kenshi Daimon, MD, et al.: "A 20-Year Prospective Longitudinal Study of Degeneration of the Cervical Spine in a Volunteer Cohort Assessed Using MRI. Follow-up of a Cross-Sectional Study". PMID- 29762296 TI - A Novel Anatomic Risk Factor for Anterior Cruciate Ligament Injury?: Commentary on an article by Thomas R. Pfeiffer, MD, et al.: "An Increased Lateral Femoral Condyle Ratio Is a Risk Factor for Anterior Cruciate Ligament Injury". PMID- 29762297 TI - Raising Both the Ceiling and the Floor: Addressing Gender Diversity in Orthopaedic Surgery: Commentary on an article by Talia R. Chapman, MD, et al.: "Profiles of Practicing Female Orthopaedists Caring for Medicare Patients in the United States". PMID- 29762298 TI - Systematic review: the first step in developing a complex intervention. PMID- 29762299 TI - Effectiveness of mitigation interventions on occupational violence against emergency service workers: a mixed methods systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to develop an aggregated synthesis of qualitative and quantitative data on occupational violence (OV) mitigation interventions for Emergency Service Workers (ESW), to cultivate useful conclusions and recommendations for paramedic occupational safety and policy development. Emergency Service Worker is a broad term encompassing all elements of community-based emergency support and includes paramedics, firefighters, and police.The objective of the quantitative component of this review is to quantify the effectiveness of OV mitigation interventions for ESW.The objective of the qualitative component of this review is to explore the perceptions and experiences of ESW on the effectiveness of OV mitigation interventions.This review seeks to address the following questions. PMID- 29762300 TI - Health-related quality of life of young people and adults with primary or recurrent episodes of genital herpes: a mixed methods systematic review protocol. AB - REVIEW QUESTION: The review questions are:The specific objectives are:This mixed methods review seeks to develop an aggregated synthesis of quantitative and qualitative data on the HRQOL implications of genital herpes for the individual in order to derive conclusions and recommendations for clinical practice and policy decision making. PMID- 29762301 TI - Effectiveness of Nissen fundoplication versus anterior and posterior partial fundoplications for treatment of gastro-esophageal reflux disease: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to determine the relative effectiveness of Nissen fundoplication compared to anterior and posterior partial fundoplication in controlling the symptoms of gastro-esophageal reflux disease and reducing their side effect profile in adults.The specific questions posed by this review are: what is the effectiveness of Nissen fundoplication in comparison to anterior partial fundoplication (90 degree, 120 degree and 180 degree) and posterior 270 degree fundoplication in terms of symptom control of gastro-esophageal reflux disease, and what are the side effects of these surgical interventions? PMID- 29762302 TI - Experiences and perceptions of physical restraint policies and practices by health professionals in the acute care sector: a qualitative systematic review protocol. AB - REVIEW QUESTION: What are the experiences and perceptions of physical restraint policies and practices by health professionals, administrators and policy makers in the acute care sector? PMID- 29762303 TI - Nursing students' experiences with clinical placement in residential aged care facilities: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to analyze and synthesize the best available evidence on nursing students' experiences with clinical placement in residential aged care facilities.The specific review questions are. PMID- 29762304 TI - Effectiveness and harms of pharmacological interventions in the treatment of delirium in adults in intensive care units post cardiac surgery: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The review objective is to synthesize the best available evidence on the effectiveness and harms of pharmacological interventions in the treatment of delirium in adults in intensive care units (ICU) after cardiac surgery.The specific review question is: What is the effectiveness and what are the harms of pharmacological interventions in relation to the duration and severity of delirium episodes, length of stay in ICU, length of stay in hospital, functional capacity and quality of life and mortality for critically ill adult patients treated in intensive care after cardiac surgery? PMID- 29762305 TI - Components, skills and training for conducting initial telephone consultations in primary care: a scoping review protocol. AB - REVIEW OBJECTIVE/QUESTION: The objective of this scoping review is to examine the characteristics of initial telephone consultations conducted in primary care settings and to map the existing evidence on the components, skills and training recommended for initial telephone consultations in current primary care.This scoping review will be guided by the following questions. PMID- 29762306 TI - Prevalence and incidence of congenital anomalies amongst babies born to women with sickle cell disease and exposed to hydroxyurea during pregnancy: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: What is the prevalence and incidence of congenital anomalies among babies born to women with sickle cell disease (SCD) and who have been exposed to hydroxyurea (HU) therapy at any time in their pregnancy?The objective of this review is to identify the proportion of babies born with congenital anomalies among babies born to mothers with SCD who have been exposed to HU therapy at any point during pregnancy and to describe the specific types of congenital anomalies encountered. PMID- 29762307 TI - Parents' and guardians' experiences of barriers and facilitators in accessing autism spectrum disorder diagnostic services for their children: a systematic review protocol of qualitative evidence. AB - REVIEW QUESTION: What are parents' and guardians' experiences of barriers and facilitators in accessing autism spectrum disorder diagnostic services for their children? PMID- 29762308 TI - Effectiveness of behavioral and psychosocial interventions for continuous positive airway pressure adherence in obstructive sleep apnea patients: a quantitative systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to assess the effectiveness of behavioral and psychosocial interventions on adherence to continuous positive airway pressure among patients 18 years and over with obstructive sleep apnea. PMID- 29762309 TI - Effectiveness of extracellular matrix dressings and topical agents in the treatment of leg ulcers: a systematic review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the effectiveness of the application of extracellular matrix products as dressings or in topical form as treatment for venous, arterial and mixed leg ulcers, compared to compression therapy alone, any type of dressings and topical agents, or placebos in adults over 18 years in any care setting. PMID- 29762310 TI - Effectiveness of stellate ganglion blockade on refractory ventricular arrhythmias: a systematic review protocol. AB - REVIEW QUESTION: The question of this review is: what is the effectiveness of stellate ganglion blockade on refractory ventricular arrhythmias in patients 18 years or over? PMID- 29762311 TI - Mapping the implementation of evidence-based nutritional management in primary health care settings: a scoping review protocol. AB - REVIEW QUESTION/OBJECTIVE: The objective of this scoping review is to systematically map and categorize the wide variety of interventions and programs that might be classified under the umbrella term "evidence-based nutritional management in primary healthcare". The development of this scoping review will provide a better understanding of how evidence-based nutritional management has been implemented by healthcare professionals in primary health care settings, especially of barriers and facilitators to implementing evidence-based nutritional management. Therefore, three research questions were chosen to guide the scoping review. PMID- 29762312 TI - The influence of occupation on wellbeing, as experienced by the elderly: a systematic review. AB - OBJECTIVE: The objective of this review was to synthesize knowledge regarding which types of occupations the elderly perceive as important to and supporting their overall wellbeing. INTRODUCTION: Being active is an important part of managing the daily challenges of advanced old age. Occupational therapy and occupational science are based on the premise that a person's occupations are intertwined with their health and are thus needed for them to experience a meaningful life and improve their wellbeing. INCLUSION CRITERIA: This review, which included independently living elderly people aged 65 and over living in Europe, the USA, Canada and Australia, sought to uncover if the elderly see any specific types of occupations as enhancing their wellbeing. This review included qualitative studies with designs including, but not limited to, phenomenology, grounded theory, ethnography and action research. METHODS: A three-step search strategy using Joanna Briggs Institute methodology was utilized. Both published and unpublished studies were searched. The following databases were searched for studies up to 2017: CINAHL, Nursing and Allied Health Source, Web of Science, PubMed and OpenGrey. Using the JBI Critical Appraisal Checklist for Qualitative Research, two independent reviewers assessed whether each study had the methodological quality required to be included in the review. Any disagreements were resolved through discussion with a third reviewer. The standardized JBI data extraction tool for interpretive and critical research was used to extract data from the included studies. JBI tools were used to pool the qualitative research findings. The findings were then aggregated through a process of rating according to quality, and categorized according to similarity in meaning, which generated a set of statements for each category. These categories were then subjected to a meta-synthesis to produce a single comprehensive set of synthesized findings useful as a basis for evidence-based practice. RESULTS: All three of the included studies utilized qualitative interviews and followed a phenomenological approach. The studies included only participants aged 85 and over. Thirty-five findings were extracted and grouped into four categories, which were synthesized into two meta-syntheses: 1) The importance of "doing" alone - to feel good, I have to be the master of my own life; and 2) Old habits never die - a structured day is a good day. Based on the dependability and credibility of the three studies, the ranking was high (see Summary of Findings). CONCLUSIONS: The present review shows that two factors enhance elderly people's wellbeing: first, variation and independence in undertaking activities; second, having a choice between the occupations and a structure of activities that make up daily life. The two factors are influenced by a balance between having activities alone and with others. This review is not intended to identify specific occupations that enhance elderly people's wellbeing, but rather to indicate which types of occupations enhance the wellbeing of the elderly, and provide value and meaning to their daily lives.Both the dependability and the credibility of the studies have been rated as moderate. PMID- 29762313 TI - Experiences of undergraduate nursing students in peer assisted learning in clinical practice: a qualitative systematic review. AB - OBJECTIVES: The objective of this qualitative systematic review was to identify and synthesize the best available evidence on experiences of peer assisted learning (PAL) among student nurses in clinical practice so as to understand the value of PAL for this population. INTRODUCTION: Peer-assisted learning considers the benefits of peers working in collaboration and supporting each other in professional roles. This approach to facilitate learning is effective within universities, but there is limited exploration within the clinical practice environment. Within the UK, 50% of student nurses' learning is undertaken within clinical practice, providing a large portion of student allocation within these areas, but is unexplored in relation to PAL. Therefore, existing evidence examining PAL in clinical practice needs further exploration for a better understanding of its value to student nurses' learning. INCLUSION CRITERIA: The systematic review considered studies that included male and female nursing students aged 18-50 years that explored undergraduate nursing students' experiences of PAL within the clinical practice environment. Studies that utilized designs such as phenomenology, grounded theory, ethnography, action research and feminist research were considered. Other text such as opinion papers and reports were to be considered if no qualitative studies could be located. The review excluded quantitative studies, as well as those addressing PAL outside the nursing profession and students within the nursing profession but not including undergraduate student nurses. This review considered studies that included aspects related to experiences of PAL in the clinical practice setting, as seen by undergraduate nursing students and the researcher. METHODS: A three-step search strategy was undertaken to find both published and unpublished studies in English from 2003 to 2017 in various databases, and included searching of reference lists within articles selected for appraisal. Each of the included studies were assessed for methodological quality independently by two reviewers, using the Joanna Briggs Institute Critical Appraisal Form for Interpretive and Critical Research. Qualitative data was extracted using the standardized JBI qualitative data extraction tool. Qualitative research findings were synthesized using JBI methodology. RESULTS: From the eight included studies, 37 findings were extracted. These findings were further aggregated into seven categories, and then into three synthesized findings. These three synthesized findings are: 1) Challenges of clinical practice are mitigated by peer support; 2) Peers are role models for enhancing clinical knowledge; and 3) Support and feedback develop competence and confidence, and reduce stress and anxiety. CONCLUSIONS: Peer assisted learning exists in clinical practice in both formal and informal circumstances. Friendship and community are often expressed as occurring when peers work together. Support and feedback help students develop in their clinical role and enhance clinical knowledge. Outcomes include enhancing the competency and confidence of peers, and reducing stress and anxiety. Challenges of clinical practice are mitigated through PAL. PMID- 29762314 TI - Effectiveness of dexmedetomidine versus propofol on extubation times, length of stay and mortality rates in adult cardiac surgery patients: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the effects of dexmedetomidine versus propofol on extubation time, intensive care unit (ICU) length of stay, total hospital length of stay and in-hospital mortality rates in cardiac surgery patients. INTRODUCTION: Recovery from cardiovascular surgery involves weaning from mechanical ventilation. Mechanical ventilation decreases the work of breathing for patients by inhaling oxygen and exhaling carbon dioxide via a ventilator or breathing machine. Prolonged mechanical ventilation is associated with complications, such as pneumonia and lung injury, and increases the risk of morbidity and mortality. Major risk factors that contribute to lung injury are due to high tidal volumes and barotrauma. Cardiac surgery patients remain on the ventilator postoperatively due to the high dose opioid-based anesthesia and the initial vulnerable hemodynamic state. An important component of postoperative management following cardiac surgery is the use of sedation to reduce the stress response, facilitate assisted ventilation, and provide anxiolysis. Propofol and dexmedetomidine are two common sedative agents with differing pharmacological profiles used to provide comfort and minimize hemodynamic disturbances during this recovery phase. Choice of drug may have an impact on length of mechanical ventilation, length of stay and mortality. INCLUSION CRITERIA: Participants included were >=18 years, of any gender or ethnicity, undergoing valvular surgery, coronary artery bypass graft (CABG) surgery, or valvular surgery and CABG. Studies were excluded if participants received both dexmedetomidine and propofol concurrently as a primary sedative. Interventions were propofol compared to dexmedetomidine as continuous infusions for sedation after cardiac surgery. All variations of dosages and duration of both sedative agents were included. Outcomes of interest were: total time (hours) of mechanical ventilation after cardiac surgery, specifically from end of surgery to extubation; total length of stay (LOS) in the ICU (hours) following cardiac surgery, specifically from ICU admission to transfer to medical ward; total hospital LOS (hours) following cardiac surgery, from date of admission to date of discharge; and in-hospital mortality rates, from date of admission to date of discharge. Randomized controlled trials (RCTs), controlled trials, and prospective and retrospective cohort studies were considered for inclusion. METHODS: A search was conducted in MEDLINE via PubMed, Embase, Trip Database, ProQuest Nursing and Allied Health Source Database, Web of Science, ProQuest Dissertations and Theses Global, and MedNar to locate both published and unpublished studies between January 1, 1999 and November 23, 2017. Two reviewers assessed the methodological quality using standardized critical appraisal instruments from the Joanna Briggs Institute System for the Unified Management, Assessment and Review of Information (JBI SUMARI). Quantitative data were extracted using the standardized data extraction tool from JBI SUMARI. Data were pooled using Comprehensive Meta-Analysis Software Version 3 (Biostat, NJ, USA). Mean differences (95% confidence interval [CI]) and effect size estimates were calculated for continuous outcomes. Meta-analysis using a random-effects model was performed for length of mechanical ventilation, ICU LOS, and hospital LOS. Results have been presented in narrative form when findings could not be pooled using meta-analysis. Standard GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) evidence assessment of outcomes has been reported. RESULTS: A total of four studies were included in the review. Meta-analysis of three cohort studies revealed dexmedetomidine to be superior to propofol with an average reduction of 4.18 hours (95% CI -6.69 to 1.67, p = 0.001) on the extubation times, an average 9.89 hour (95% CI -18.6 to 1.19, p = 0.03) reduction in ICU LOS, and an average 37.9 hour (95% CI, -60.41 to -15.46, p = 0.00) reduction in overall hospital LOS. A RCT was excluded from pooling for meta-analysis, but its results were congruent with meta-analysis results. There was lack of sufficient data to perform meta-analysis on in hospital mortality rates. CONCLUSIONS: In postoperative cardiac surgery patients, dexmedetomidine is associated with a shorter time to extubation, shorter ICU LOS, and shorter hospital LOS in postoperative cardiac surgery patients compared to propofol. The quality of evidence for these findings however is low and no recommendations can be made to change current practice. There was insufficient evidence to determine significant differences in-hospital mortality rates. Sedation protocols still need to be formulated.There are significant gaps in the literature. Areas of further research include additional well-designed and appropriately powered RCTs with wide inclusion criteria to reflect this surgical population; quantitative, transparent, and standardized sedation, weaning, and extubation protocols; precise and standardized methods and measurements for interventions and outcomes, and short- and long-term morbidity and mortality follow-up. PMID- 29762315 TI - Effectiveness of psychosocial interventions on the psychological health and emotional well-being of family carers of people with dementia following residential care placement: a systematic review. AB - OBJECTIVE: To identify, appraise and synthesize existing evidence regarding the effectiveness of psychosocial interventions on the psychological health and emotional well-being of family carers of people with dementia who have moved into residential care. INTRODUCTION: Many carers experience stress, guilt, grief and depression following placement of a relative with dementia into residential care. Psychosocial interventions to support family carers may help to improve psychological health and emotional well-being; however, evidence for such interventions delivered to family carers following placement has yet to be appraised and synthesized. INCLUSION CRITERIA: Participant criteria included any family carers of people with dementia who have moved into residential or nursing or long term care. Interventions were included if they were designed to improve the psychological health and emotional well-being of family carers post placement. Comparators included no intervention, other non-pharmacological intervention or standard/usual care. Outcomes included carer burden, anxiety, stress, depression, guilt, grief and loss, quality of life, or satisfaction with care of the person with dementia. METHODS: Key databases (PubMed, CINAHL, PsycINFO) and trials registries (Cochrane, WHO Clinical Trials, UK Clinical Trials) were searched to identify both published and unpublished studies in English from 1990 to 2017. The recommended Joanna Briggs Institute approach to critical appraisal, study selection, data extraction and data synthesis was followed. Data from studies was pooled in statistical meta-analysis where possible, and presented in narrative and tabular form otherwise. RESULTS: Four studies were eligible for inclusion. Two studies were randomized controlled trials (RCTs) of individualized multicomponent interventions, and two were cluster RCTs of group multicomponent interventions. Interventions were mostly underpinned by stress appraisal and coping theories. Outcomes measured, measurement tools and length of follow-up varied between the studies. There was high risk of selection, attrition and detection bias.A total of 302 family carers were included. For the individualized interventions, significant improvements were reported for carer guilt (F = 5.00; p = 0.03), role overload (F = 5.00; p = 0.04) and distress (F = 6.13; p = 0.02), but no significant effect was found for satisfaction with the residential care facility. Meta-analyses indicated there was no overall effect at three to four months post-intervention on carer burden (weighted mean difference 2.38; 95% CI -7.72 to 12.48), and depression (weighted mean difference 2.17; 95% CI -5.07 to 9.40). For the group interventions, no significant effects on carer distress were found; however, significant improvements in carer "heartfelt sadness" at three months post-baseline (F = 5.04; p = 0.027) and guilt at six months (F = 4.93; p = 0.029) were reported in one study. CONCLUSIONS: Individualized multicomponent psychosocial interventions following residential care placement may be beneficial in improving family carers' role overload, psychological distress and guilt. Group interventions may also improve feelings of guilt and sadness. There is insufficient evidence that individualized or group interventions improve carer depression, burden or satisfaction. However, due to substantial heterogeneity between studies and methodological flaws, the grade of this evidence is very low.Further high quality RCTs that include different groups of carers are recommended. Comparative effects of individualized versus group interventions should be examined as these are likely to have cost implications. PMID- 29762316 TI - Nasoenteric feeding discharge planning for cancer patients in a Brazilian teaching hospital: a best practice implementation project. AB - OBJECTIVES: The objective of this project was to improve local practice in nasoenteric feeding discharge planning for cancer patients in a cancer teaching hospital in Sao Paulo, Brazil. INTRODUCTION: Nasoenteric tubes are commonly used for enteral nutrition in patients with cancer for over seven days during their recovery and this may be continued at home, with clear benefits. RESULTS: Baseline audit results indicated poor compliance (between 0% and 22%) with the current evidence, although good compliance (100%) was observed for three audit criteria. Implementation of the strategies, including changes to achieve higher participation of caregivers, resulted in an improvement of the audited criteria (100% compliance was maintained for three criteria, compliance increased from 22% to 67% for a further three criteria, with 0% compliance for one criterion). CONCLUSIONS: Despite the short time frame of this study, an increase in compliance with best practices proposed by the Joanna Briggs Institute was observed. Implementing a multidisciplinary meeting before patient discharge remains a challenge. PMID- 29762317 TI - Corrigendum: Effectiveness of interventions to prevent pre-frailty and frailty progression in older adults: a systematic review. PMID- 29762318 TI - Endoscopically Assisted Modified Caldwell-Luc Approach to Enucleation of Dentigerous Cyst With Ectopic Tooth From the Maxillary Sinus. AB - Dentigerous cysts in the craniomaxillofacial complex are a benign pathology commonly associated with ectopically placed teeth. Owing to slow and asymptomatic growth, they often attain considerable size before diagnosis that may compromise adjacent anatomical structures. Various techniques for removal of dentigerous cysts from the maxillary sinus have been described. This case report demonstrates a hybrid endoscopically assisted modification of the Caldwell-Luc approach to provide the technical advantages of both techniques. PMID- 29762319 TI - Comparison of Bone Grafts From Various Donor Sites in Human Bone Specimens. AB - The objective of the current study was to compare the three-dimensional (3D) morphometric microstructure in human cadaveric bone specimens taken from various commonly utilized donor sites for autogenous bone grafting. Autogenous bone grafts can be harvested from various anatomic sites and express heterogeneous bone quality with a specific 3D microstructure for each site. The long-term structural integrity and susceptibility to resorption of the graft depend on the selected donor bone. Micro-computed tomography generates high-resolution datasets of bone structures and calcifications making this modality versatile for microarchitecture analysis and quantification of the bone. Six bone specimens, 10 mm in length, where anatomically possible, were obtained from various anatomical sites from 10 human dentate cadavers (4 men, 6 women, mean age 69.5 years). Specimens were scanned using a micro-computed tomography device and volumetrically reconstructed. A virtual cylindrical inclusion was reconstructed to analyze the bone mineral density and structural morphometric analysis using bone indices: relative bone volume, surface density, trabecular thicknesses, and trabecular separation. Calvarial bone specimens showed the highest mineral density, followed by the chin, then mandibular ramus then the tibia, whereas iliac crest and maxillary tuberosity had lower bone mineral densities. The pairwise comparison revealed statistically significant differences in the bone mineral density and relative bone volume index in the calvaria, mandibular ramus, mandibular symphysis groups when compared with those in the iliac crest and maxillary tuberosity, suggesting higher bone quality in the former groups than in the latter; tibial specimens expressed variable results. PMID- 29762320 TI - Electromyographic Activity of the Masseter and Temporal Muscles in Patients With Nonsyndromic Complete Unilateral Cleft Lip and Palate: 2-Stage Versus 1-Stage Palate Repair. AB - OBJECTIVE: To assess the electromyographic activity of the masseter and temporal muscles in cleft patients who underwent 1-stage palate repair versus 2-stage palate repair. METHODS: Thirty-two patients with nonsyndromic complete unilateral cleft lip and palate operated by 2 different protocols for palate repair, 1-stage (group 1, n = 16) versus 2-stage with delayed hard palate closure (group 2, n = 16) were available in the retrospective longitudinal study. Standardized electromyographic records of the masseter and anterior portion of temporal muscles were obtained with 2 repetitions during mastication and rest. RESULTS: No statistically significant (all P > 0.05) differences were observed in the electromyographic data between the groups 1 and 2. CONCLUSION: There were similar electromyographic activity of masseter and temporal muscles during mastication and at rest after 1- and 2-stage palate closure. PMID- 29762321 TI - Greater Occipital Nerve Decompression for Occipital Neuralgia. AB - The aim of the study was to evaluate the effectiveness of greater occipital nerve decompression for the management of occipital neuralgia. Eleven patients of medical refractory occipital neuralgia were enrolled in the study. Local anaesthetic blocks were used for confirming diagnosis. All of them underwent surgical decompression of greater occipital nerve at the level of semispinalis capitis and trapezial tunnel. A pre and postoperative questionnaire was used to compare the severity of pain and number of pain episodes/month. Mean pain episodes reported by patients before surgery were 17.1 +/- 5.63 episodes per month. This reduced to 4.1 +/- 3.51 episodes per month (P < 0.0036) postsurgery. The mean intensity of pain also reduced from a preoperative 7.18 +/- 1.33 to a postoperative of 1.73 +/- 1.95 (P < 0.0033). Three patients reported complete elimination of pain after surgery while 6 patients reported significant relief of their symptoms. Only 2 patients failed to notice any significant improvement. The mean follow-up period was 12.45 +/- 1.29 months. Surgical decompression of greater occipital nerve is a simple and viable treatment modality for the management of occipital neuralgia. PMID- 29762322 TI - Maternal Folic Acid Supplementation and the Risk of Oral Clefts in Offspring. AB - INTRODUCTION: There is controversial evidence from the literature regarding the protective effect of folic acid supplementation during pregnancy against orofacial clefts. The authors undertook this meta-analysis to assess whether folate supplementation during pregnancy can reduce the risk of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) in infants. METHODS: Eligible articles were identified by searching databases, including PubMed, Medline, Scopus, ISI (Web of Knowledge) to September 2017. A meta analysis was performed to evaluate the effects of maternal supplementation on oral clefts. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using Stata software. Publication bias was assessed by the Begg and Egger test. (Registration ID: CRD42018083922) RESULTS:: Out of the 1630 articles found in the authors' initial literature searches, 6 cohort studies, and 31 case-control studies were included in the authors' final meta-analysis. The results of the main analysis revealed that maternal folate supplementation was associated with a modest but statically significant decreased risk of all cleft subtypes (OR = 0.69, 95% CI: 0.60, 0.78). Folic acid intake alone was inversely associated with CL/P (OR = 0.73, 95% CI: 0.62-0.85,) but to a lesser extent than CPO (OR = 0.75, 95% CI = 053-1.04). Multivitamin intake had a significant protective effect for CL/P (OR = 0.65 95% CI = 0.55-0.80) as well as CPO (OR = 0.69, 95% CI = 0.53 0.90). CONCLUSIONS: Our results indicate that maternal supplementation in early pregnancy reduces the risk of nonsyndromic CL/P and CPO in infants. These data can serve to reassure women planning a pregnancy to consume multivitamins during the periconception period to protect against oral clefts. PMID- 29762324 TI - A Giant Congenital Soft Tissue Sinonasal Fibromyxoma of the Nose in a Newborn Baby. AB - Myxomas of the nose are very rare benign neoplasms. They grow slowly, infiltrate the surrounding bone cortex, and develop multiple local recurrences with no distant metastasis. Almost, even knowing seen at any age, it is very rare in newborn. The authors present a patient with sinonasal soft tissue fibromyxoma in a newborn baby nose followed by the literature. PMID- 29762323 TI - Reinforcement of Lower Lateral Cartilage Using Sliced Costal Periphery to Reconfigure Nasal Tip in Asian Rhinoplasty. AB - BACKGROUND: Reinforcement of lower lateral crura (LLC) is an imperative prophylaxis against the secondary deformity of alar and nasal tip in Asian rhinoplasty. The common limitation of the existing techniques is loss of nasal tip's mobility to a large degree in exchange for structural stability. In search for a natural and animated postoperative nasal tip, the elasticity and rigidity of coastal periphery was taken into account. METHOD: Two pieces of sliced costal periphery (SCP) were used to reinforce the LLC. One hundred twenty patients who accepted this technique and completed 18-month follow-up were included in this study. They were all females in which 67 patients underwent the primary rhinoplasty, and the remaining 53 patients underwent the revision rhinoplasty. Two pieces of septal extension grafts and 2 strips of SCP were used in all patients. Videos and pictures were taken and analyzed preoperatively and at 18 months postoperatively. RESULT: The videos and pictures showed the pleasing contour and mobility of nasal tip. No complications associated with the LLC occurred. All patients who underwent primary rhinoplasty were pleased about the postoperative contour and mobility of nasal tip. In revision rhinoplasty group, 30 patients (56.6%) who had complained about the stiffness or mobility loss of the nasal tip before became satisfied with the soft and animated nasal tip after the surgery. CONCLUSION: Reinforcement of LLC by SCP is a promising technique to achieve natural and animated nasal tip. Moreover, this technique is helpful to prevent or restore the problems associated with the inherent weak or iatrogenic cripple of LLC in Asians rhinoplasty. Studies with longer follow-up and larger sample should be done to trace the reliability and practicability in the long run. PMID- 29762325 TI - Endoscopy-Assisted Frontal Sinus Obliteration. AB - Comminuted fractures of the anterior table of the frontal sinus involving frontonasal ducts are traditionally treated with sinus obliteration. This technique entails precise mucosa removal which requires unimpeded visualization of the bony recesses. To achieve adequate access to the mucosa, temporary removal of a large part of the frontal bone may often be necessary. This in turn increases fracture comminution requiring placement of additional hardware associated with the risk for bony malalignment, infection, plate palpability, and visibility, especially in thin-skin individuals. Endoscopy, offering magnified visualization and less invasive access, is reported to be beneficial in sinus injury management. Therefore, it may be also considered an adjunct in open approach management of severely comminuted fractures.The authors' patient suffered from comminuted fractures of the anterior and posterior tables of the frontal sinus and nasal bone fractures with involvement of the frontonasal ducts. Due to the extent of the injury he underwent frontal sinus obliteration procedure using the pericranial flap. To avoid additional osteotomy, endoscopic approach was undertaken to achieve the complete removal of the sinus mucosa. The fracture by itself offered an "access port" for the endoscope and electrical cautery. The patient's recovery was uneventful.Endoscopy employed in frontal sinus obliteration appears to be instrumental in obtaining meticulous mucosa removal, obviating the need for additional osteotomy of the frontal bone. PMID- 29762326 TI - Temporal Progression of Craniofacial Dysmorphology in Unilateral Coronal Synostosis: A Mechanistic Hypothesis. AB - AIM: This study chronicles skull base and face development in nonsyndromic unilateral coronal synostosis (UCS) during infancy, to characterize the mechanistic progression of facial dysmorphology. METHODS: Computed tomography scans from 51 subjects were reviewed (26 UCS, 25 controls) and data were reconstructed. Patients were stratified into 5 age groups. A series of measurements were taken from the reconstructions. RESULTS: All patients had a unilaterally fused coronal suture at the time of analysis. Asymmetry of the sphenoid wings was present across all age groups. The sphenoid wing ipsilateral to the fused suture consistently had a more acute angle from the midline. At 19 days of age, ipsilateral nasal root and cribriform plate deviation are noted, as well as increased contralateral zygoma antero-posterior length. Patients younger than 2 months also had elongated posterior cranial bases. At 2 to 3 months of age, the cranial base widens in the anterior portion of the middle cranial fossa with an increased ipsilateral pterion to sella distance. The most delayed change observed was the increase in contralateral orbital rim angle at 7 to 12 months of age compared to normal. CONCLUSION: After suture fusion, sphenoid wing changes are among the earliest restructural malformations to take place. This suggests that the cascade of dysmorphology in UCS originates in the cranial vault, then progresses to the skull base, and lastly to the facial structures. Ipsilateral orbital changes are early facial changes in UCS that begin before 2 months of age. This is then followed by changes in the contralateral face later in development. PMID- 29762327 TI - Nodular Tenosynovitis of the Temporomandibular Joint: An Entity Not Yet Described. AB - Nodular tenosynovitis usually affects the hands and it represents a benign pathology with locally aggressive behavior. Its etiology could be related to chronic inflammatory processes such as trauma, metabolic disturbance, and joint diseases. Histopathological analysis is required for a diagnosis of certainty and surgery represents the treatment of choice. There are no cases in the literature that describe a nodular tenosynovitis affecting the temporomandibular joint (TMJ) The main aim of the present report therefore, is to describe this unusual case and to show the utility of arthroscopic procedures in managing intra-articular tumors of the TMJ. PMID- 29762328 TI - Treatment of Craniosynostosis: The Impact of Hospital Surgical Volume on Cost, Resource Utilization, and Outcomes. AB - The authors aim to quantify the impact of hospital volume of craniosynostosis surgery on inpatient complications and resource utilization using national data. Children <12 months with nonsyndromic craniosynostosis who underwent surgery in 2012 at academic hospitals in the United States were identified from the Kids' Inpatient Database (KID) developed by the Healthcare Cost and Utilization Project (HCUP). Hospital craniosynostosis surgery volume was stratified into tertiles based on total annual hospital cases: low volume (LV, 1-13), intermediate volume (IV, 14-34), and high volume (HV, >=35). Outcomes of interest include major complications, blood transfusion, charges, and length of stay (LOS). In 2012, 154 hospitals performed 1617 total craniosynostosis surgeries. Of these 580 cases (35.8%) were LV, 549 cases (33.9%) were IV, and 488 cases (30.2%) were HV. There was no difference in major complications between hospital volume tertiles (4.3% LV; 3.8% IV; 3.1% HV; P = 0.487). The highest blood transfusion rates were seen at LV hospitals (47.8% LV; 33.9% IV; 26.2%; P < 0.001). Hospital charges were lowest at HV hospitals ($55,839) compared with IV hospitals ($65,624; P < 0.001) and LV hospitals ($62,325; P = 0.005). Mean LOS was shortest at HV hospitals (2.96 days) compared with LV hospitals (3.31 days; P = 0.001); however, there was no difference when compared with IV hospitals (3.07 days; P = 0.282). Hospital case volume may be an important associative factor of blood transfusion rates, LOS, and hospital charges; however, there is no difference in complication rates. These results may be used to guide quality improvement within the surgical management of craniosynostosis. PMID- 29762329 TI - A Case of Juvenile Psammomatoid Ossifying Fibroma on Skull Base. AB - Juvenile psammomatoid ossifying fibroma (JPOF) is a rare tumor that occurs in maxillary sinus or orbit. Complete removal is required due to the aggressive and locally destructive nature. It is hard to distinguish from psammomatoid meningioma in cranial lesion and to remove completely. The authors are presenting a case of 26-year-old male with JPOF on skull base and report this case with review of literature. PMID- 29762330 TI - Management of Severe Cicatricial Entropion With Labial Mucous Membrane Graft in Cicatricial Ocular Surface Disorders. AB - The management of cicatricial entropion represents a therapeutic challenge especially when the underlying causes are progressive cicatricial diseases that affect the ocular surface. The authors aimed to report long-term efficacy of labial mucous membrane graft to manage severe cicatricial entropion of the upper eyelid. This study is a retrospective chart review of patients who underwent tarsotomy associated with labial mucous membrane graft to treat severe cicatricial entropion of the upper eyelid. Surgeries were performed over a 16 year period. Clinical data (age, gender, etiology of the cicatricial entropion, improvement of symptoms, eyelid position, recurrence, complications, and follow up period) were extracted from these patients' charts. Etiology of the cicatricial entropion, improvement of symptoms, eyelid position, recurrence, complications, and follow-up period were evaluated. Sixty-three eyelids from 44 patients underwent surgery. Mean follow-up was 48.4 +/- 46.1 months (range 6 months to 15 years). Main underlying diagnoses were Stevens-Johnson syndrome (63%), trachoma (19%), chemical injury (8%), and trauma (5%). Forty-three patients (98%) reported improvement of ocular symptoms after the procedure. Complete resolution (restoration of the upper eyelid margin to normal anatomic position with good esthetic appearance) was achieved in 52 eyelids (83%). Recurrence occurred in 7 (11%) eyelids. No postoperative infection, failure of graft survival, or other complications were observed. The use of labial mucous membrane as a posterior lamella graft showed good functional and cosmetic outcomes, long-term stability and low recurrence rates in the treatment of severe cicatricial entropion of the upper eyelid. PMID- 29762331 TI - Rare Location for Pilonidal Sinus: the Nasal Dorsum. AB - Pilonidal sinuses are recurrent chronic inflammatory lesions which may occur due to penetration of hair particles into skin. Herein, the authors report a pilonidal sinus case that is unusually seen on nasal dorsum and totally excised with the open technique rhinoplasty method. A 20-year-old male patient was admitted to the authors' outpatient clinic with complaints of dysmorphism and discharge from nasal dorsum. Physical examination revealed a swelling in nasal dorsum and hair-containing fistula. Excision was performed with an open rhinoplasty approach. Histo-pathology examination revealed pilonidal sinus. While pilonidal sinus is usually located in sacro-coccygeal region, it may also be seen in atypical localizations like nasal dorsum. Although the prediagnosis of a hair containing lesion usually includes dermoid cyst, pilonidal sinus should also be considered and histo-pathological examination should certainly be performed. It is a problematic condition when it is symptomatic; however, management and treatment of the disease is easy when correct diagnosis is made. PMID- 29762334 TI - Toddler's Paralysis: An Acute Case of Leg Stiffening in a Previously Healthy 2 Year-Old. AB - Vegetarian and vegan diets are gaining popularity in the United States. Although appropriately planned vegetarian diets, including vegan diets, are healthful and nutritionally adequate and may provide health benefits in the prevention and treatment of certain diseases, not all families are aware of the nutritional supplements that may be required for their children. We describe a case of a 2 year-old previously healthy child consuming a vegan diet who presented to the pediatric emergency department with an acute inability to move her legs. Ionized calcium was found to be 0.89 mmol/L, and symptoms completely resolved within 2 hours of calcium gluconate infusion. PMID- 29762332 TI - Extended Release Liposomal Bupivacaine Injection (Exparel) for Early Postoperative Pain Control Following Palatoplasty. AB - INTRODUCTION: Liposomal bupivacaine (LB) is a long-acting local anesthetic reported to decrease postoperative pain in adults. The authors demonstrate the safe use of LB in pediatric patients with improved pain control following palatoplasty. MATERIALS AND METHODS: Retrospective patient series of all single surgeon palatoplasty patients treated at a tertiary craniofacial center from August 2014 to December 2015 were included. All patients received 1.3% LB intraoperatively as greater palatal nerve and surgical field blocks in 2-flap V-Y pushback palatoplasty. Postoperative oral intake, opioids administered, duration of hospitalization, and FLACC (face, legs, activity, cry, consolability) pain scores were measured. RESULTS: Twenty-seven patients (16 males and 11 females, average age of 10.8 months, weight 8.8 kg) received 2.9 +/- 0.9 mL (2.6 +/- 1.9 mg/kg) 1.3% LB. Average FLACC scores were 2.4 +/- 2.2/10 in the postanesthesia care unit and 3.8 +/- 1.8/10 while inpatients. Oral intake was first tolerated 10.3 +/- 11.5 hours postoperatively and tolerated 496.4 +/- 354.2 mL orally in the first 24 hours postoperatively. Patients received 8.5 +/- 8.4 mg hydrocodone equivalents (0.46 +/- 0.45 mg/kg per d hydrocodone equivalents) and were discharged 2.1 +/- 1.3 days postoperatively. Opioid-related adverse events included emesis in 7.4% and pruritis in 3.7% of patients. CONCLUSIONS: The LB may be used safely in pediatric patients. Intraoperative injection of LB during palatoplasty can yield low postoperative opioid use and an early and adequate volume of oral intake over an average hospital stay. Further cost-efficacy studies of LB are needed to assess its value in pediatric plastic surgery. PMID- 29762333 TI - Hemodynamic Shock Caused by Tension Pneumoperitoneum in a 5-Year-Old Girl. AB - Tension pneumoperitoneum is a relatively rare occurrence in the pediatric population. However, tension pneumoperitoneum is associated with significant morbidity and mortality if it is not promptly diagnosed and treated. A 5-year-old girl was admitted to emergency department with abdominal pain. She was in shock, and the radiograph film of the abdomen revealed a voluminous tension pneumoperitoneum. Aggressive fluid challenges were performed in intensive care followed by urgent laparotomy. Primary abdominal compartment due to trapped gas caused a decreased venous return and visceral perfusion. In the absence of hemodynamic improvement after vascular filling, needle decompression was performed before surgery. PMID- 29762335 TI - Correlation of Level of Trauma Activation With Emergency Department Intervention. AB - BACKGROUND: In-hospital trauma team activation criteria are formulated to identify severely injured patients requiring specialized multidisciplinary care. Efficacy of trauma activation (TA) criteria is commonly measured by emergency department (ED) disposition, injury severity score, and mortality. Necessity of critical ED interventions is another measure that has been proposed to evaluate the appropriateness of TA criteria. METHODS: Two-year retrospective cohort study of 1715 patients from our trauma registry at a Level 1 pediatric trauma center. We abstracted data on acute interventions, level and criterion of TA, ED disposition, and mortality. We report odds ratio (OR) with 95% confidence intervals (CIs), positive predictive value, and frequency of acute interventions. RESULTS: Trauma activation was initiated for 947 (55%) of the 1715 patients. There were 426 ED interventions performed on 235 patients (14%); 67.8% were in level 1 activations; 17.6% in level 2, and 14.6% in level 3. Highest-level activations were highly associated with need for ED interventions (OR, 16.1; 95% CI, 11.5-22.4). The ORs for requiring an ED intervention were low for lower level activations (OR, 0.4; 95% CI, 0.3-0.5), trauma service consults (OR, 0.3; 95% CI, 0.2-0.4), and certain mechanism-based criteria. The ORs for ED intervention for isolated motor vehicle collision (0.2; 95% CI, 0.1-0.7), isolated all-terrain vehicle rollover (0.4; 95% CI, 0.1-1.7), and suspected spinal cord injury (0.5; 95% CI, 0.1-3.7) were significantly lower than 1. CONCLUSIONS: Highest-level activation criteria correlate with high utilization of ED resources and interventions. Lower level activation criteria and trauma service consult criteria are not highly correlated with need for ED interventions. Downgrading isolated motor vehicle collision and all-terrain vehicle rollovers and suspected spinal cord injury to lower level activations could decrease the overtriage rate, and adding age-specific bradycardia as a physiologic criterion could improve our undertriage rate. PMID- 29762336 TI - Radiology Callbacks to a Pediatric Emergency Department and Their Clinical Impact. AB - BACKGROUND: Clinical impact of radiology callbacks (missed initial radiologic diagnosis) remains largely unknown in the pediatric emergency department (PED). OBJECTIVE: The aim of this study was to describe the incidence, nature of radiology callbacks, and the impact on clinical care during the return visit (RV). METHODS: We performed a retrospective chart review of quality assurance database of RVs for radiology callbacks to our PED over a 1-year period. RESULTS: Return visit rate to our PED was 3% (2765/92,000) of which 1.9% (55/2765) was for radiology callbacks. Radiology misses involved mostly x-ray interpretations (92.7%), occurred after-hours (83.6%), with fractures being the most common missed finding. Majority of patients (94.5%) required 1 or more interventions during the RV; 34.5% of radiology callbacks had a major impact on clinical management; 27.2% of radiology callbacks were false-positive. CONCLUSIONS: Although RVs secondary to radiology callback remain low, one third of them resulted in major changes in diagnosis, treatment, or disposition and impacted patient outcome. PMID- 29762337 TI - Real-life indications to ivabradine treatment for heart rate optimization in patients with chronic systolic heart failure. AB - : Ivabradine is a selective and specific inhibitor of If current. With its pure negative chronotropic action, it is recommended by European Society of Cardiology and American College of Cardiology/American Heart Association guidelines in symptomatic heart failure patients (NYHA >= 2) with ejection fraction 35% or less, sinus rhythm and heart rate (HR) at least 70 bpm, despite maximally titrated beta-blocker therapy. Data supporting this indication mainly derive from the SHIFT study, in which ivabradine reduced the combined endpoint of mortality and hospitalization, despite the fact that only 26% of patients enrolled were on optimal beta-blocker doses. The aim of the present analysis is to establish the real-life eligibility for ivabradine in a population of patients with systolic heart failure, regularly attending a single heart failure clinic and treated according to guideline-directed medical therapy (GDMT). The clinical cards of 308 patients with heart failure with reduced ejection fraction (HFrEF) through a 68 month period of observation were retrospectively analyzed. GDMT, including beta blocker up-titration to maximal tolerated dose, was implemented during consecutive visits at variable intervals. Demographic, clinical and echocardiographic data were collected at each visit, together with 12-leads ECG and N-terminal pro-B-type natriuretic peptide levels. Out of 308 analyzed HFrEF patients, 220 (71%) were on effective beta-blocker therapy, up-titrated to effective/maximal tolerated dose (55 +/- 28% of maximal dose) (HR 67 +/- 10 bpm). Among the remaining 88 patients, 10 (3.2%) were on maximally tolerated beta blocker and ivabradine; 21 patients (6.8%), despite being on maximal tolerated beta-blocker dose, had still HR >=70 bpm, ejection fraction 35% or less and were symptomatic NYHA >=2, being therefore eligible for ivabradine treatment. The remaining 57 (18%) patients were not on beta blocker due to either intolerance or major contraindications. Among them, 13 (4%) were taking ivabradine alone. Of the final 44 (14%) patients, 27 (9%) showed an inadequate HR control (74 +/- 6 bpm). Of these, only eight (3%) patients resulted to be eligible for ivabradine introduction according to HR and ejection fraction parameters. Overall ivabradine was indicated in 52 patients (16.8%) out of 308 enrolled.In conclusion, in a carefully managed population of patients with moderate and stable HFrEF, in which optimal GDMT is properly attained, indication to ivabradine treatment is around 17%. PMID- 29762338 TI - Incidence and Risk Factors for Instrumentation-related Complications After Scoliosis Surgery in Pediatric Patients With NF-1. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To assess the incidence and risk factors of instrumentation-related complication (IRC) in pediatric patients surgically treated for neurofibromatosis type 1 (NF-1) dystrophic scoliosis. SUMMARY OF BACKGROUND DATA: Surgical management including growing rods technique and early definitive fusion has been recommended to avoid progression of NF-1 scoliosis. However, no study has yet investigated the incidence and risk factors of IRC in these surgical interventions. METHODS: Data of 59 pediatric NF-1 patients who had been surgically treated for dystrophic scoliosis were retrospectively reviewed. All of their clinical and radiographic data were collected. We evaluated potential risk factors, including age, sex, curve type, preoperative Cobb angle, kyphosis angle and spinal length, and surgical procedure. The univariate analysis and multivariate logistic regression analysis were performed to identify the risk factors associated with IRC. RESULTS: Seventeen (28.8%) patients suffered 19 IRCs, including seven cases of curve progression, three cases of screw dislodgement, three cases of adding-on phenomenon, two cases of rod breakage, two cases of proximal junctional kyphosis, one case of cap loosing, and one case of pedicle cutting. The univariate logistic regression analysis revealed age<9, kyphosis>=50 degrees , and growing-rod techniques the significant risk factors (P < 0.05). Binomial logistic regression analysis demonstrated two independent risk factors of IRC, including kyphosis>=50 degrees (OR: 8.23; P = 0.025) and application of growing-rod technique (OR: 8.75; P = 0.032). CONCLUSION: 17/59 (28.8%) patients suffered IRCs and age less than 9 years, kyphosis more than 50 degrees and application of growing-rod are three risk factors for IRC after surgical treatment of NF-1 dystrophic scoliosis. Identification of these risk factors aids in stratifying preoperative risk to reduce IRC incidence. In addition, the results could be used in counseling patients and their families during the consent process. LEVEL OF EVIDENCE: 3. PMID- 29762339 TI - The Relationship Between Fear-Avoidance and Neuromuscular Measures of Function in Patients With Adult Degenerative Scoliosis. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: To examine the relationship of fear-avoidance beliefs and neuromuscular activity during gait in adult degenerative scoliosis (ADS) patients. SUMMARY OF BACKGROUND DATA: Among patients with chronic spine pain, fear-avoidance beliefs are predictive of poor surgical outcomes. Fear-avoi occurs when patients perceive that movement will worsen underlying physical problems. This process leads them to restrict activity, which further heightens emotional distress. Patients with ADS have previously been shown to have an altered gait pattern. Electromyography is evolving into a useful tool to further our understanding of the pathologic manifestations of ADS during gait. METHODS: Fifty ADS patients completed the Tampa Scale for Kinesiophobia (TSK) questionnaire and the Fear Avoidance Beliefs Questionnaire (FABQ). Surface electromyography electrodes were bilaterally placed on trunk and lower extremity muscles. Each patient performed a series of over-ground gait trials at a self selected comfortable speed. Pearson Product Correlation analysis was used to determine the relationship between the self-reported fear of movement measures and the neuromuscular gait analysis biomechanical data. RESULTS: The TSK total score and the FABQ physical were correlated with muscle onset of the External Oblique (P = 0.005), Gluteus Maximus (P = 0.018), Multifidi (P = 0.017), Erector Spinae (P = 0.014), Rectus Femoris (i = 0.008), Semitendinosus (P = 0.012), Tibilais Anterior (P = 0.012), and Medial Gastrocnemius (P = 0.010). Furthermore, the TSK total score, FABQ physical portion were correlated with muscle peak activity of Medial Gastrocnemius (P = 0.007), Multifidi (P = 0.014), and Tibilais Anterior (i = 0.050) and time to peak muscle activity of the Medial Gastrocnemius (P = 0.006) and Semitendinosus P = 0.038. CONCLUSION: This study demonstrates a strong correlation between neuromuscular gait parameters and fear-avoidance of movement which may reflect ADS patient experiences during ambulation. Further, it demonstrates that there are different aspects of fear-avoidance that may influence gait parameters. This study extends previous research on the role of fear-avoidance to include patients with spinal deformity. LEVEL OF EVIDENCE: 3. PMID- 29762341 TI - Radiation Exposure to the Surgeons and Patients in Fluoroscopic-Guided Segmental Pedicle Screw Placement for Pediatric Scoliosis. AB - STUDY DESIGN: Prospective case series. OBJECTIVE: To analyze the radiation exposure to the surgeons and patients in fluoroscopic-guided segmental pedicle screw placement for pediatric scoliosis. SUMMARY OF BACKGROUND DATA: Fluoroscopic guided pedicle screw placement is a safer technique for pedicle screw placement in spinal deformity. However, radiation exposure is a concern, particularly for spine surgeons due to the requirement of multiple pedicle screws in spinal deformity surgery. METHODS: We measured radiation dose to the surgeons and pediatric patients undergoing scoliosis surgery by a team of two surgeons (S1 and S2) from March 2016 to December 2017. Surgery was performed using fluoroscopic guided segmental pedicle screw placement. The dosimeters were placed at the forehead, inside and outside thyroid shield, both hands, back, and suprapubic under lead apron for each surgeon; and at the thyroid and gonads for patients. RESULTS: Thirty patients were included in the study. The mean numbers of pedicle screws per case were 23.2 +/- 3.4. The mean dose (mrem) per case for the two surgeons S1 and S2 was 0.07 and 0.47 at forehead, 0.07 and 0.37 at outside thyroid shield, 0.00 and 0.30 at inside thyroid shield, 16.87 and 13.73 at right hand, 6.07 and 11.37 at left hand, 0.50 and 0.00 at back, and 0.00 and 0.00 at suprapubic under lead apron, respectively. The mean dose (mrem) per case for the male and female patient was 3.67 and 14.71 for thyroid and 3.83 and 3.17 for gonads, respectively. CONCLUSION: The results of this study demonstrated that radiation exposure to the spine surgeons and patients is low using fluoroscopic guided segmental pedicle screw technique for pediatric scoliosis surgery. Both hands of the surgeons received much higher doses compared to other body areas and, and thus radiation-reducing gloves and careful attention to surgeon's hands need to be considered for this procedure. LEVEL OF EVIDENCE: 2. PMID- 29762340 TI - External Validation of the Adult Spinal Deformity (ASD) Frailty Index (ASD-FI) in the Scoli-RISK-1 Patient Database. AB - STUDY DESIGN: Analysis of a prospective multicenter database. OBJECTIVE: To assess the ability of the recently created Adult Spinal Deformity (ASD) Frailty Index (ASD-FI) to predict odds of major complications and length of hospital stay for patients who had more severe preoperative deformity and underwent more invasive ASD surgery compared with patients in the database used to create the index. SUMMARY OF BACKGROUND DATA: Accurate preoperative estimates of risk are necessary given the high complication rates currently associated with ASD surgery. METHODS: Patients were enrolled by participating institutions in Europe, Asia, and North America from 2009 to 2011. ASD-FI scores were used to classify 267 patients as not frail (NF) (<0.3), frail (0.3-0. 5), or severely frail (SF) (>0.5). Multivariable logistic regression, adjusted for preoperative and surgical covariates such as operative time and blood loss, was performed to determine the relationship between ASD-FI category and incidence of major complications, overall incidence of complications, and length of hospital stay. RESULTS: The mean ASD-FI score was 0.3 (range, 0-0.7). We categorized 105 patients as NF, 103 as frail, and 59 as SF. The adjusted odds of developing a major complication were higher for SF patients (odds ratio = 4.4; 95% CI 2.0, 9.9) compared with NF patients. After adjusting for covariates, length of hospital stay for SF patients increased by 19% (95% CI 1.4%, 39%) compared with NF patients. The odds of developing a major complication or having increased length of stay were similar between frail and NF patients. CONCLUSION: Greater patient frailty, as measured by the ASD-FI, is associated with a longer hospital stay and greater risk of major complications among patients who have severe preoperative deformity and undergo invasive surgical procedures. LEVEL OF EVIDENCE: 2. PMID- 29762342 TI - Humeral Stem Loosening Following Reverse Shoulder Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Aseptic stem loosening following reverse shoulder arthroplasty (RSA) is an uncommon complication. The timing and the factors contributing to aseptic stem loosening remain poorly understood. METHODS: We performed a systematic review that identified 75 articles; 65 of the included articles were case series (Level-IV evidence), 8 were cohort studies (7 Level III, 1 Level II), and 2 were prospective randomized controlled trials (Level I). A meta-analysis of 1,660 cemented and 805 uncemented RSA stems was performed. We compared the rates of aseptic stem loosening, humeral radiolucent lines, and revision for stem loosening (1) between cemented and uncemented stems in cohorts with short and long mean follow-up periods (<5 and >=5 years) as well as in all cohorts combined, and (2) among different etiological subgroups. RESULTS: Aseptic stem loosening occurred more commonly in the cohort with long compared with short follow-up time (2% versus 0.8%, p = 0.01). When comparing cemented with uncemented stems, there was no significant difference in the rates of aseptic stem loosening or revision for stem loosening in either the short or long-term follow-up groups. Humeral radiolucent lines were more common with cemented compared with uncemented stems (15.9% versus 9.5%, p = 0.002). Analyzed by etiology, the highest rate of aseptic stem loosening occurred in the tumor subgroup (10.8%), followed by RSA as a revision procedure after a failed arthroplasty (3.7%). No stems in the acute fracture or fracture sequelae subgroups developed aseptic stem loosening. CONCLUSIONS: Aseptic stem loosening occurred more commonly in cohorts with longer follow-up. There were no differences in the rates of aseptic stem loosening or revision for stem loosening between cemented and uncemented stems. Patients treated with RSA following excision of proximal humeral tumors and RSA as a revision procedure after a failed arthroplasty were at greater risk of aseptic stem loosening. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29762343 TI - Team Approach: Metastatic Disease of the Spine. PMID- 29762345 TI - Neutrophil Activation and Enhanced Release of Granule Products in HIV-TB Immune Reconstitution Inflammatory Syndrome: Erratum. PMID- 29762348 TI - This Month in Anesthesiology. PMID- 29762352 TI - Gas, Ether, and Jingles from Dr. C. A. Smith of Oneida. PMID- 29762350 TI - Big Decisions for Our Little Patients: Mask vs. IV Inductions. PMID- 29762353 TI - The French Connection of Somnoforme: Rolland and Rousseau of Bordeaux. PMID- 29762344 TI - Use of Nonantiretroviral Medications That May Impact Neurocognition: Patterns and Predictors in a Large, Long-Term HIV Cohort Study. AB - BACKGROUND: Neurocognitive impairment is a frequent and often disabling comorbidity of HIV infection. In addition to antiretroviral therapies, individuals with HIV infection may commonly use nonantiretroviral medications that are known to cause neurocognitive adverse effects (NC-AE). The contribution of NC-AE to neurocognitive impairment is rarely considered in the context of HIV and could explain part of the variability in neurocognitive performance among individuals with HIV. SETTING: Women's Interagency HIV Study, a prospective, multisite, observational study of US women with and without HIV. METHODS: After a literature review, 79 medications (excluding statins) with NC-AE were identified and reported by Women's Interagency HIV Study participants. We examined factors associated with self-reported use of these medications over a 10-year period. Generalized estimating equations for binary outcomes were used to assess sociodemographic, behavioral, and clinical characteristics associated with NC-AE medication use. RESULTS: Three thousand three hundred women (71% with HIV) and data from ~42,000 visits were studied. HIV infection was associated with NC-AE medication use (odds ratio = 1.52; 95% confidence interval: 1.35 to 1.71). After adjustment for HIV infection status, other predictors of NC-AE medication use included having health insurance, elevated depressive symptoms, prior clinical AIDS, noninjection recreational drug use, and an annual household income of <$12,000 (Ps < 0.004). NC-AE medication use was less likely among women who drank 1-7 or 8-12 alcoholic drinks/week (vs. abstaining) (P < 0.04). CONCLUSIONS: HIV infection was associated with NC-AE medication use, which may influence determinations of HIV-associated neurocognitive impairment. Providers should consider the impact of NC-AE medications when evaluating patients with HIV and concurrent neurocognitive symptoms. PMID- 29762354 TI - Troup to Waters: Save the Date, August of 1940...Better Make That 1948. PMID- 29762355 TI - The McKesson Oxygen Tent: The Role of the Rubber Sheet. PMID- 29762356 TI - Streams of Unconsciousness III: Analgesia Reflected in the Acheron...or by Charon? PMID- 29762357 TI - Costoclavicular Approach to the Supraclavicular Fossa: Journey behind the Dark Side of the Moon (Clavicle). PMID- 29762358 TI - In Reply. PMID- 29762359 TI - Nitrous Oxide and Decreased White Matter Integrity and Volume during Childhood. PMID- 29762360 TI - In Reply. PMID- 29762362 TI - On King Saul, Two Missing Mules, and Kingella kingae: The Serendipitous Discovery of a Pediatric Pathogen. AB - For the first 2 decades following Kingella kingae's initial characterization, this fastidious organism was considered an unusual cause of human infection until a study published in 1992 reported that inoculation of synovial fluid aspirates into blood culture vials improved the recovery of the bacterium. The authors of the original publication report herein the history of the discovery and review the progress made in the research of the organism. PMID- 29762361 TI - A Young Child with Recalcitrant Rhinorrhea. PMID- 29762363 TI - Immunogenicity and Safety of Primary and Booster Vaccinations of a Fully Liquid DTaP-IPV-HB-PRP-T Hexavalent Vaccine in Healthy Infants and Toddlers in Germany and the Czech Republic. AB - To support a fully liquid, diphtheria (D)-tetanus (T)-acellular pertussis (aP) inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b (PRP-T) vaccine in Europe using a 2, 3, 4 month primary series and a booster at 11-15 months of age. Phase III, randomized, observer-blind studies in Germany and the Czech Republic. Participants who had not received HB vaccine were randomized to a 2, 3, 4 month primary series of DTaP-IPV-HB-PRP-T (group 1; N = 266) or a reconstituted DTaP-HB-IPV//PRP-T comparator (group 2; N = 263) and a booster of the same vaccine. Pneumococcal vaccine (PCV13) and rotavirus vaccine were coadministered at 2, 3, 4 months, and the booster was coadministered with PCV13. Noninferiority (group 1 versus group 2) was tested postprimary series for seroprotection rates (anti-HB and anti-PRP) and vaccine response rates (anti pertussis toxin and anti-filamentous hemagglutinin). Safety was assessed by parental reports. Noninferiority was demonstrated with the lower bound of the 95% confidence interval for the difference (group 1 to group 2) being > -10% for each comparison. Primary series immune responses were high for all antigens and similar in each group. Prebooster antibody persistence was good, and there was a strong anamnestic response, both being similar for the investigational and control vaccines. Responses to PCV13 and rotavirus vaccine were similar in each group. There were no safety concerns. These data support the use of the DTaP-IPV HB-PRP-T vaccine in a 2, 3, 4 month schedule without a birth dose of HB vaccine, with a booster dose in the second year of life administered with routine childhood vaccines. PMID- 29762364 TI - Seroprevalence of Toxoplasma gondii infection Among Beta-Thalassemia Major Pediatric Population: Implications for Transfusion Transmissible Toxoplasmosis. AB - BACKGROUND: Children with beta-thalassemia major who regularly receive blood transfusion are at risk of developing transfusion-transmitted infection. Toxoplasmosis is a common and a serious parasitic disease with high prevalence and could be transmitted through blood transfusion from healthy asymptomatic donors. However, screening Toxoplasma gondii before blood donation has not been considered. OBJECTIVE: To determine the prevalence of T. gondii antibodies among thalassemia children undergoing blood transfusion. METHODS: In a case-control study, serum samples from 211 thalassemia children and 100 control children were investigated for Toxoplasma IgM and IgG using the enzyme-linked immunosorbent assay (ELISA). Positive serum samples for IgG antibodies to T. gondii were further subjected to IgG avidity ELISA. RESULTS: The seroprevalence of Toxoplasma infection among thalassemia children was 23.2% and 53.6% for IgM and IgG anti Toxoplasma antibodies, respectively. Whereas in the contro group, the prevalence was 5% and 18% for IgM and IgG anti-Toxoplasma antibodies, respectively. There is a significant statistical difference between thalassemia and control groups regarding the prevalence of toxoplasmosis. From these positive IgG samples, 65.5% have low avidity indicating recent infection while 38.73% have high avidity indicating past infection. CONCLUSION: Due to the high serologic infection rate of toxoplasmosis among thalassemia pediatric population in this study with no existing effective therapies and no available T. gondii vaccine, appropriate strategies are critical for reducing the risk of that infection. Screening of blood for T. gondii antibodies should be considered before transmission to those children especially in countries with a high prevalence of toxoplasmosis. PMID- 29762366 TI - Complementary Starch Feeding of the Young Child: Starch Digestion Consortium Workshop 18. PMID- 29762367 TI - The History of Maltose-active Disaccharidases. AB - The history of maltose-active disaccharidases is closely related to the history of the sugar and starch industry. It began in the 19th century, when a shortage of cane sugar occurred in continental Europe, because Napoleon Bonaparte decreed that no goods could be imported from England to the countries he occupied. Other sugar sources had to be found, and it led to the identification of sugar beets as alternative source of sugar by Marggraf in 1774, to the detection of starch hydrolysis by diluted sulfuric acid by Kirchhoff in 1812, and to the starch digestion enzyme, alpha-amylase, by Payen in 1833. In the 20th century, Borkstrom's group in Sweden investigated the absorption of nutrients in human adults by transintubation techniques and found that the luminal concentration of invertase was small compared to that of alpha-amylase. They speculated that the major locus of this enzyme activity must be in the intestinal cells. Borkstrom's coworker, Dahlqvist, investigated the maltose-active enzymes in pig intestine, and a second group around Semenza studied the maltase-active enzymes in rabbit intestine. After the first descriptions of congenital sucrase-isomaltase deficiency in 1960 and 1961, the research on disaccharidases increased. Dahlqvist published the first quantitative method to measure these enzymes. Consecutive research led to the discovery of 4 maltases, which were later identified as 2 complex enzymes: the sucrase-isomaltase complex and the maltase-glucoamylase complex. The homology of the 2 enzyme complexes was later determined when the cDNA sequences of the 2 complexes in human intestine were identified. PMID- 29762365 TI - Multiplex Real-time PCR Detection of Intestinal Protozoa in HIV-infected Children in Malawi: Enterocytozoon Bieneusi Is Common and Associated With Gastrointestinal Complaints and May Delay BMI (Nutritional Status) Recovery. AB - BACKGROUND: Intestinal protozoa are common opportunistic infections in HIV patients. Longitudinal studies on either the clinical relevance or the effect of immune reconstitution by antiretroviral therapy on intestinal protozoan infections in children are lacking however. This study investigates prevalence and clinical relevance of intestinal protozoa in HIV-infected Malawian children before and during their first year of antiretroviral treatment (ART). METHODS: Stool samples collected at enrolment and during follow-up were tested for nonopportunistic (Giardia lamblia, Dientamoeba fragilis, Entamoeba histolytica) and opportunistic protozoa (Enterocytozoon bieneusi, Encephalitozoon spp., Cryptosporidium spp. and Cystoisospora belli) using multiplex real-time polymerase chain reaction. Associations between infections and clinical symptoms were evaluated using univariate methods. RESULTS: Nonopportunistic and opportunistic protozoa were detected in 40% (14/35) and 46% (16/35) of children at baseline, respectively. E. bieneusi was the most prevalent protozoa (37%, 13/35) and associated with gastrointestinal complaints (43% in positive (10/13) versus 18% (4/22) in E. bieneusi-negative children, P = 0.001. Body mass index recovery during 12 months of ART was more commonly delayed in E. bieneusi positive children (+0.29 +standard deviation 0.83) than E. bieneusi-negative children (+1.03 +standard deviation 1.25; P = 0.05). E. bieneusi was not detected after 12 months of ART. CONCLUSIONS: E. bieneusi was the most prevalent opportunistic intestinal protozoa, present in over a third of study participants before initiation of ART. Although all children cleared E. bieneusi after 12 months of ART, E. bieneusi was associated with gastrointestinal complaints and may delay body mass index recovery. Trials to assess effect of treatment of E. bieneusi on nutritional status should be considered in HIV-infected African children. PMID- 29762368 TI - Maltase Has Most Versatile alpha-Hydrolytic Activity Among the Mucosal alpha Glucosidases of the Small Intestine. AB - Complete digestion of the glycemic carbohydrates to glucose takes place through the combined action of the 4 mucosal alpha-glucosidases (maltase-glucoamylase and sucrase-isomaltase) in the small intestine. Maltase digests alpha-1,2- and alpha 1,3-disaccharides better than the other alpha-glucosidases, and has, as well, the capability to effectively hydrolyze alpha-1,4 and alpha-1,6 linkages that form the major backbone of a starch molecule. This broad hydrolytic activity on alpha linkages makes it an enzyme that has the most versatile alpha-hydrolytic activity among the 4mucosal alpha-glucosidases. The slowly digestible properties of the unusual linkages from this research suggest the development of new glycemic oligosaccharides which will be hydrolyzed slowly, compared to alpha-1,4 linkages, for modulating the postprandial glycemic response. In addition, using mammalian mucosal alpha-glucosidases is a better fit to characterize carbohydrate digestion properties, compared to fungal amyloglucosidase which is currently applied in in vitro assays. PMID- 29762369 TI - Structural Studies of the Intestinal alpha-Glucosidases, Maltase-glucoamylase and Sucrase-isomaltase. AB - OBJECTIVES: Maltase-glucoamylase and sucrase-isomaltase are enzymes in the brush border membrane of the small intestinal lumen responsible for the breakdown of postamylase starch polysaccharides to release monomeric glucose. As such, they are critical players in healthy nutrition and their malfunction can lead to severe disorders. METHODS: This review covers investigations of the structures and functions of these enzymes. RESULTS: Each consists of 2 enzyme domains of the glycoside hydrolase family GH31 classification, yet with somewhat differing enzymatic properties. CONCLUSIONS: Crystallographic structures of 3 of the domains have been published. Insights into substrate binding and specificity will be discussed, along with future lines of inquiry related to the enzymes' roles in disease and potential avenues for therapeutics. PMID- 29762370 TI - Molecular Regulations of Mucosal Maltase Expressions. AB - Two major alpha-glucosidase (maltase) genes, sucrase-isomaltase (SI) and maltase glucoamylase (MGAM), respectively, are expressed in the small intestine. In this review, we have summarized whether jejunal expression of these maltase genes is regulated by dietary manipulations, which may affect carbohydrate availability from the luminal side, through changes in the binding of transcription factors and/or histone code on these genes. Studies using a model of mice fed either a low-starch or a high-starch diet for 7 days, found the mRNA levels of SI, MGAM, and Na-glucose cotransporter (SGLT1) genes in the jejunum to be increased in parallel by feeding a high-starch diet. Chromatin immunoprecipitation assays, using jejunal tissue of mice and rats fed a high-starch diet, revealed that the diet increased the acetylations of histones H3 and H4, bindings of coactivators, including general control of amino acid synthesis (GCN5) and the transcriptional factors, including caudal-related homeobox 2 (CDX2), and hepatocyte nuclear factor 1 (HNF1), not only in the promoter/enhancer regions, but also in the transcribed regions of SI and MGAM genes. Feeding rats a diet rich in resistant starch led to a concomitant reduction of mRNA levels of the MGAM gene and histone H3 modifications (acetylations and di-/tri-methylations) in the jejunum. These data suggest that a signal elicited by available glucose in the jejunal mucosa is associated with SI and MGAM gene expressions through a histone code, such as acetylation and di-/tri-methylations of histone H3 in the promoter/enhancer and transcribed regions of SI and MGAM genes. PMID- 29762371 TI - Posttranslational Processing and Function of Mucosal Maltases. AB - The final step of carbohydrate digestion in the intestine is performed by 2 major alpha-glucosidases of the intestinal mucosa, sucrase-isomaltase (SI) and maltase glucoamylase. Both of these enzymes are type II membrane glycoproteins, which share a significant level of homology in gene and protein structures and yet have differences in the posttranslational processing, substrate specificity and functional capacity. Insufficient activity of these disaccharidases particularly SI as a result of genetic mutations or secondary intestinal pathologies is associated with carbohydrate maldigestion and gastrointestinal intolerances. This review will discuss the maturation profiles of SI and maltase-glucoamylase relative to their functional capacities and deficiencies. PMID- 29762372 TI - Metabolic Impacts of Maltase Deficiencies. AB - The mucosal maltase enzymes are characterized by an activity that produces glucose from linear glucose polymers, assayed with the disaccharide maltose. The related enzyme isomaltase produces glucose from branched glucose polymers, assayed with palatinose. Maltase and isomaltase activities are part of the 4 disaccharidases assayed from clinical duodenal biopsy homogenates. The reported maltase activities are more difficult to interpret than lactase or sucrase activities because both the sucrase-isomaltase and maltase-glucoamylase proteins have overlapping maltase activities. The early work of Dahlqvist identified 4 maltase activities from human small intestinal mucosa. On one peptide, sucrase (maltase Ib) and isomaltase (maltase Ia) activities shared maltase activities but identified the enzymes as sucrase-isomaltase. On the other peptide, no distinguishing characteristics of the 2 maltase activities (maltases II and III) were detected and the activities identified as maltase-glucoamylase. The nutritional/clinical importance of small intestinal maltase and isomaltase activities are due to their crucial role in the digestion of food starches to absorbable free glucose. This review focuses on the interpretation of biopsy maltase activities in the context of reported lactase, sucrase, maltase, and palatinase biopsy assay activity patterns. We present a classification of mucosal maltase deficiencies and novel primary maltase deficiency (Ib, II, III) and provide a clarification of the role of maltase activity assayed from clinically obtained duodenal biopsies, as a path toward future clinical and molecular genomic investigations. PMID- 29762373 TI - Use of Starch and Modified Starches in Infant Feeding: A Historical Perspective. AB - There is a long history of the use of starch in infant feeding. Proprietary infant foods (1867-1920) contained added starch from either cereal grains or malted carbohydrates. When evaporated milk became available in the 1920s, the use of proprietary foods fell out of favor. Evaporated milk formulas were a mixture of milk, water, and modified starch or milk sugar (lactose). By the late 1920s, however, corn syrup became the most common modified starch added to evaporated milk formulas as it was widely available, inexpensive, and readily accepted. The ongoing development of the modern calorie-based infant formula, made from non-fat cow's milk, lactose, oleo and vegetable oils, largely replaced the evaporated milk formulas in the 1960s. On the other hand, after 1940, added starch and modified starch became increasingly important in the production of pureed fruits and vegetables. Not surprisingly, this included their use in the modern "industrialized" food for use in infants, including their use in a proliferation of grain based fortified infant cereals. This coincided with the increasing production largely due to the earlier introduction of complementary foods, commonly before 3 months of age by 1958. After 1969, the increasing public awareness and media scrutiny of infant foods lead to a growing criticism of the use of modified starches. Even though the National Research Council and the American Academy of Pediatrics concluded that modified starches were safe for use, continued public pressure led to their removal from most infant foods in the 1990s. This paralleled the natural food and organic food movements in the United States. Though modified starches are still used in infant dinners of mixed foods today, their use has been minimized and this issue is not currently of significant concern to the public. PMID- 29762374 TI - Structure and Digestion of Common Complementary Food Starches. AB - Starch is the major source of dietary glucose for rapid development of children. Starches from various crops naturally differ in molecular structures and properties. Cooking, processing, and storage may change their molecular properties and affect their digestibility and functionality. Starch digestion is affected by its susceptibility to alpha-amylase and alpha-glucosidase (maltase), and the susceptibility is determined by starch granule architecture and glucan structures, as well as the interaction between starch and other food components. Starch is given as a complementary feeding to young children in many cultures, and starch or modified starch, is used in special formulae of infant foods or supplements. Although indigestible starch does not provide much energy, it can benefit colonic health. PMID- 29762375 TI - Starch Consumption Patterns in Infants and Young Children. AB - BACKGROUND: The introduction of starch into an infant's diet is an important milestone in the feeding journey. Intestinal maturity and the presence of digestive enzymes are necessary for the physiologic breakdown of starch and other complementary foods. However, little is known about the consumption patterns of starch containing foods during complementary feeding. METHOD: The 2008 Feeding Infants and Toddlers Study (FITS) is a cross-sectional 24-hour dietary intake survey of a nationally representative sample of infants, toddlers, and preschoolers from birth to 48 months of age. We looked at the age-based prevalence of consumption of starch-containing foods during complementary feeding. RESULTS: We found that about 90% of infants were consuming starch by 6 and 8.9 months, with less than half of infants being exposed to complementary foods from multiple food groups under 6 months. The most common food source of starch was iron-fortified infant cereals, followed by vegetables and fruits. Rice and oats were the most prevalent cereal types, while sweet potatoes, peas and squash were the most commonly consumed starch-containing vegetables. Bananas were the leading starch-containing fruit that was consumed. Around 9 and 11 months, the prevalence of iron-fortified cereals declined and were replaced with lower iron-containing ready-to-eat cereals. There was also a drop in the prevalence of fruit and vegetable consumption once the infant became a toddler. Most bread products consumed by toddlers were not whole grain, but their cereal choices were often whole grain. Other sources of starch were mixed dishes, which contained grains like bread or pasta combined with other types of foods. CONCLUSIONS: Starch enters the infant's diet around the time of complementary feeding, though earlier exposure may occur from certain carbohydrate components of infant formula. Most infants are exposed to starch from grains, followed by vegetables and fruits. PMID- 29762376 TI - Microbial Fermentation of Starch: Its Impact on the Range of Acceptable Carbohydrate Intake. AB - Starch, a major source of carbohydrates in human nutrition, is extensively hydrolyzed in the gastrointestinal tract of children and adults. A small fraction of the ingested starch reaches the cecum and colon where it is fermented by the gut microbiome into short-chain fatty acids (SCFA) and other products. Recent data in humans and in animal models have demonstrated the extensive effects of short-chain fatty acids on whole body energy metabolism, appetite, insulin resistance, fatty acid oxidation, fat accretion, obesity, and diabetes. Clear discernible effects of SCFA on the rates of production of glucose, its oxidation and uptake in the fasting state were, however, not observed. In the fed state, the effects on glucose metabolism are related to the effects of SCFA on insulin sensitivity, possibly the consequence of their influence on lipid metabolism. The suggested limits of carbohydrate intake were based upon the kinetics and metabolism of glucose in the basal state and on the responses to glucose administration. It is postulated that in healthy subjects, the present data do not suggest any significant impact of microbial fermentation of starch on the range of acceptable intake of carbohydrates. PMID- 29762378 TI - History of Acquired Monosaccharide Intolerance in Houston, Texas. AB - It is appropriate that we begin the clinical part of this conference with a discussion of acquired monosaccharide intolerance. This disease is the most severe form of carbohydrate malabsorption and maldigestion that can afflict an infant. The following article describes the pathophysiology of the disease, as well as its treatment, much of which was based on studies done by the Section of Pediatric Gastroenterology and Nutrition at Baylor College of Medicine. Acquired monosaccharide intolerance has almost disappeared from the United States but remains a problem in the developing world where it is included as part of the diagnosis of environmental enteropathy. Present research on this disease seems to sometimes duplicate what is already known. PMID- 29762377 TI - Glucose Requirements of the Developing Human Brain. AB - Adequate nutrition is critical for human brain development, which depends particularly upon glucose. The adult human brain accounts for 20% to 25% of total body resting glucose consumption, and studies indicate that the developing brain requires an even greater percentage of glucose. Here we critically review the currently available data on glucose requirements for early childhood brain development. Implications of these findings are then discussed in the context of childhood malnutrition and future areas of investigation. PMID- 29762380 TI - Clinical Characteristics of Disaccharidase Deficiencies Among Children Undergoing Upper Endoscopy. AB - OBJECTIVES: The epidemiology and clinical significance of disaccharidase deficiencies have not been thoroughly characterized. Recent work suggests at least genetic sucrase-isomaltase deficiency is more prevalent than previously believed. Because lactase deficiency (LD) is well described, the present study focuses on the clinical characteristics of children with disaccharidase deficiencies determined by esophagogastroduodenoscopy. METHODS: Endoscopic records were reviewed from patients undergoing esophagogastroduodenoscopies with biopsies assayed for disaccharidase activity performed by 13 pediatric gastroenterologists during 5 years (2010-2014). Presenting symptoms, clinical and histological diagnosis, treatment, disaccharidase results, and demographic variables were obtained from medical and endoscopic records of those with maltase and sucrase deficiency (SD). RESULTS: Among 963 patients undergoing intestinal disaccharidase testing, 73 (7.6%) had SD on biopsy (enzyme activity <25 MUmol . min . g). Thirty-four (34/73; 47%) had normal duodenal histology and are the focus of this report. Four patients had SD without LD. Pan-disaccharidase deficiency was observed in 24 patients when maltase and palatinase assays were obtained (n = 646), and 11 had SD + LD when just those 2 enzymes were analyzed (n = 317). Those with SD without LD were younger 4.6 +/- 6.1 versus 14.1 +/- 3.6 years and uniformly presented with diarrhea. Patients with pan-disaccharidase deficiency or SD + LD primarily reported abdominal pain (33/35; 94%), diarrhea (16/35; 46%), nausea (14/35; 40%); and poor weight gain/weight loss (10/35; 29%); constipation, flatulence, and bloating were also noted. Maltase deficiency is less common (8/963; 0.8%), presenting with similar symptoms. CONCLUSIONS: Genetic sucrase-isomaltase deficiency often occurs together with lactase or pan disaccharide deficiency. Disaccharidase deficiency should be considered a potential cause of abdominal pain and/or diarrhea in children and adolescents. PMID- 29762379 TI - Demographic and Clinical Correlates of Mucosal Disaccharidase Deficiencies in Children With Functional Dyspepsia. AB - BACKGROUND: A subset of children with functional gastrointestinal disorders (FGIDs), which includes functional dyspepsia, may have duodenal disaccharidase deficiencies. OBJECTIVES: To determine the frequency, demographics, and clinical characteristics associated with duodenal disaccharidase deficiencies in children with functional dyspepsia. METHODS: Children ages 4 to 18 years undergoing esophagogastroduodenoscopy (EGD) evaluation for dyspepsia were enrolled in either a retrospective (study 1) or prospective (study 2) evaluation. Those with histologic abnormalities were excluded. Duodenal biopsies were obtained for disaccharidase enzyme analysis. In the retrospective study, both demographic and clinical characteristics were obtained via chart review. In the prospective study, parents completed the Rome II Questionnaire on Gastrointestinal Symptoms before the EGD. RESULTS: One hundred and twenty-nine children (n = 101, study 1; n = 28, study 2) were included. Mean age was 11.2 +/- 3.8 (SD) years in study 1 and 10.6 +/- 3.2 years in study 2. Forty-eight (47.5%) of subjects in study 1 and 13 (46.4%) of subjects in study 2 had at least 1 disaccharidase deficiency identified. All of those with a disaccharidase deficiency in both studies had lactase deficiency with 8 (7.9%) and 5 (17.9%) of those in studies 1 and 2, respectively, having an additional disaccharidase deficiency. The second most common disaccharidase deficiency pattern was that of pan-disaccharidase deficiency (PDD) in both studies. In study 1 (where both race and ethnicity were captured), self-identified Hispanic (vs non-Hispanic, P < 0.05) and non-white (vs white, P < 0.01) children were more likely to have lactase deficiency. Age, sex, and type of gastrointestinal symptom were not associated with presence or absence of a disaccharidase deficiency. CONCLUSIONS: Approximately half of children with functional dyspepsia undergoing EGD were identified as having a disaccharidase deficiency (predominantly lactase deficiency). Race/ethnicity may be associated with the likelihood of identifying a disaccharidase deficiency. Other clinical characteristics were not able to distinguish those with versus without a disaccharidase deficiency. PMID- 29762382 TI - Starch Malabsorption in Infants. AB - Based on the developmental physiology of pancreatic amylase production, starch digestion in young infants was anticipated to be compromised whenever compared with that in older infants and toddlers. This appears to be the case, but with great variability among infants to digest starch. Evidence points to the importance of maltase-glucoamylase in young infants and its effect on starch digestion. These observations have critical importance for recommendations regarding the feeding of starch-containing foods to young infants. PMID- 29762381 TI - 13C-Labeled-Starch Breath Test in Congenital Sucrase-isomaltase Deficiency. AB - BACKGROUND AND HYPOTHESES: Human starch digestion is a multienzyme process involving 6 different enzymes: salivary and pancreatic alpha-amylase; sucrase and isomaltase (from sucrose-isomaltase [SI]), and maltase and glucoamylase (from maltase-glucoamylase [MGAM]). Together these enzymes cleave starch to smaller molecules ultimately resulting in the absorbable monosaccharide glucose. Approximately 80% of all mucosal maltase activity is accounted for by SI and the reminder by MGAM. Clinical studies suggest that starch may be poorly digested in those with congenital sucrase-isomaltase deficiency (CSID). Poor starch digestion occurs in individuals with CSID and can be documented using a noninvasive C breath test (BT). METHODS: C-Labled starch was used as a test BT substrate in children with CSID. Sucrase deficiency was previously documented in study subjects by both duodenal biopsy enzyme assays and C-sucrose BT. Breath CO2 was quantitated at intervals before and after serial C-substrate loads (glucose followed 75 minutes later by starch). Variations in metabolism were normalized against C-glucose BT (coefficient of glucose absorption). Control subjects consisted of healthy family members and a group of children with functional abdominal pain with biopsy-proven sucrase sufficiency. RESULTS: Children with CSID had a significant reduction of C-starch digestion mirroring that of their duodenal sucrase and maltase activity and C-sucrase BT. CONCLUSIONS: In children with CSID, starch digestion may be impaired. In children with CSID, starch digestion correlates well with measures of sucrase activity. PMID- 29762383 TI - Starch Tolerance and the Short Bowel. AB - Short bowel syndrome with intestinal failure is a rare disease with a massive impairment in quality of life, requiring a multidisciplinary team approach to medical, surgical, and nutritional therapy. Current pharmacological and surgical therapeutic options are limited; an important cornerstone is enteral and parenteral nutrition. The changed physiology of carbohydrate digestion plays a major role in the adaptation process and can be a target for specific enteral nutrition interventions. An important prognostic factor is the preservation of at least portions of the colon in continuity with small bowel. This strategy has to include an evaluation of the anatomical situation and small bowel absorptive capacity, adaptation processes, and luminal microbiota including its fermentative properties. Starch is probably the most important complex carbohydrate in short bowel syndrome nutrition, because it is absorbed or fermented almost completely. Benefits of supplementation with complex carbohydrates include improved adaptive processes, positive trophic effects on the mucosa and its hormonal response, longer transit time, and possibly a faster time to wean from parenteral nutrition, but supplementation advice needs to weigh carefully the risks and benefits, especially considering bacterial overgrowth, osmotic load, and D lactate acidosis. PMID- 29762384 TI - Microbial Metabolism in the Mammalian Gut: Molecular Mechanisms and Clinical Implications. AB - Human intestinal microbes participate actively at the interface of diet, nutrition, and overall health status. These biodiverse communities of microorganisms have a broader metabolic repertoire compared with their host, and they are able to synthesize and degrade substrates that would be otherwise unavailable. In recent years, we have recognized that healthy microbial communities are important for energy harvest and the regulation of body systems outside the digestive tract. Microbial dysbiosis, however, has been implicated in a number of human disorders, including obesity and inflammation. This dichotomy highlights the need to understand the factors that determine the composition and metabolic output of our resident and transient microbes. Throughout the human lifespan, we know that diet plays a major role in shaping gut microbial communities, as well as directing the types and amounts of metabolites produced. Understanding the factors that affect microbial metabolic output within the host may help identify the roles of microbes in health, as well as new targets for treatment in disease. In this article, we review facets of the assembly and activities of the healthy human intestinal microbiome, as well as ways that the microbiota has been shown to influence the host via metabolism of two dietary macronutrients: carbohydrates and amino acids. PMID- 29762387 TI - Live Attenuated Influenza Vaccination Before 3 Years of Age and Subsequent Development of Asthma: ERRATUM. PMID- 29762388 TI - Methicillin-resistant Staphylococcus aureus Decolonization in Neonates and Children. PMID- 29762386 TI - Exposure-Response Analysis of Micafungin in Neonatal Candidiasis: Pooled Analysis of Two Clinical Trials. AB - BACKGROUND: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK) pharmacodynamic (PD) bridging studies. However, little is known about the how these PK-PD data translate clinically. METHODS: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software. Bayesian posterior estimates for infants with invasive candidiasis were used to evaluate the relationship between drug exposure and mycologic response using logistic regression. RESULTS: Sixty-four infants 3-119 days of age were included, of which 29 (45%) infants had invasive candidiasis. A 2-compartment PK model fits the data well. Allometric scaling was applied to clearance and volume normalized to the mean population weight (kg). The mean (standard deviation) estimates for clearance and volume in the central compartment were 0.07 (0.05) L/h/1.8 kg and 0.61 (0.53) L/1.8 kg, respectively. No relationship between average daily area under concentration-time curve or average daily area under concentration-time curve:minimum inhibitory concentration ratio and mycologic response was demonstrated (P > 0.05). Although not statistically significant, mycologic response was numerically higher when area under concentration-time curves were at or above the PD target. CONCLUSIONS: While a significant exposure response relationship was not found, PK-PD experiments support higher exposures of micafungin in infants with invasive candidiasis. More patients would clarify this relationship; however, low incidence deters the feasibility of these studies. PMID- 29762389 TI - Denouement. PMID- 29762391 TI - Role of the Father in Human Papillomavirus Transmission to Infants. PMID- 29762390 TI - Latent Tuberculosis Treatment Compliance in Children: A 10-Year Experience. PMID- 29762392 TI - Video-Recorded Direct Observation: A Step Forward for Physical Activity Measurement. PMID- 29762393 TI - Equity in Physical Activity is a Misguided Goal. PMID- 29762394 TI - Response. PMID- 29762395 TI - Society of Critical Care Medicine Presidential Address-47th Annual Congress, February 2018, San Antonio, Texas. PMID- 29762397 TI - Light Sedation Is the Goal: Making the Evidence Heavier. PMID- 29762396 TI - Bad Brains, Bad Outcomes: Acute Neurologic Dysfunction and Late Death After Sepsis. PMID- 29762398 TI - Critical Care Outcomes Among Opioid Users: Hidden Sequelae of a Growing Crisis? PMID- 29762400 TI - Race, Ethnicity, and Sepsis: Beyond Adjusted Odds Ratios. PMID- 29762401 TI - Steroids to Soften the Blow in Persistent Acute Respiratory Distress Syndrome. PMID- 29762399 TI - Ventilator-Associated Pneumonia-Quantum Uncertainty in the ICU? PMID- 29762402 TI - The Outcome of Patients With Acute Respiratory Distress Syndrome Admitted to an ICU. PMID- 29762403 TI - Look Homeward, Intensivist. PMID- 29762404 TI - Open Lung Biopsy in Nonresolving Acute Respiratory Distress Syndrome: Anything More Relevant? PMID- 29762405 TI - A Step Toward Personalized Glycemic Control. PMID- 29762406 TI - Conjecture and Fact: Prothrombin Complex Concentrates for Bleeding With Vitamin K Antagonists. PMID- 29762408 TI - Mortality Prediction Gets a "Boost". PMID- 29762407 TI - Brain Injured and Heart Strained. PMID- 29762409 TI - One (Not So Small) Step for Simulation-Based Competency Assessment in Critical Care. PMID- 29762410 TI - Renal Blood Flow Measurement in Early Clinical Sepsis-Can You Catch a Shadow? PMID- 29762411 TI - Hepcidin and the Anemia of Critical Illness. PMID- 29762412 TI - Interleukin-34: A New Player in the Sepsis Arena. PMID- 29762413 TI - Follow the Voxel-A New Method for the Analysis of Regional Strain in Lung Injury. PMID- 29762415 TI - Distinct Biological Effects of Time-Controlled Adaptive Ventilation in Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome: "One Small Step for Rats, One Giant Leap for Humans?" PMID- 29762414 TI - Losing Sleep Over Delirium. PMID- 29762416 TI - The Role of Platelets in Extracorporeal Circuit Thrombogenesis. PMID- 29762417 TI - The author replies. PMID- 29762418 TI - Emergency Intubation: Early Identification and Strategic Management (Can) Save Lives. PMID- 29762419 TI - The authors reply. PMID- 29762420 TI - Experience and Perception in Organ Donation: A Matter of Team Work. PMID- 29762421 TI - The authors reply. PMID- 29762422 TI - Timely Transthoracic Echocardiogram in Pulmonary Embolism-Is It Worth the Trouble? PMID- 29762423 TI - The authors reply. PMID- 29762424 TI - Concern About the Association Between Salivary Cortisol and Subsequent Anxiety Among Family Members of ICU Patients. PMID- 29762426 TI - Renal Replacement Therapy Modality and Renal Recovery From ICU Acute Kidney Injury. PMID- 29762425 TI - The authors reply. PMID- 29762427 TI - The authors reply. PMID- 29762429 TI - The Results of an Italian Quality Assurance Program Support the New American Society for Colposcopy and Cervical Pathology Recommendations for Colposcopy Practice. PMID- 29762428 TI - Outcomes of Conservative Management of High Grade Squamous Intraepithelial Lesions in Young Women. AB - OBJECTIVE: The aim of the study was to determine regression rates of cervical intraepithelial neoplasia (CIN) 2 and 3 in women younger than 24 years, followed conservatively for up to 24 months. MATERIALS AND METHODS: This is a retrospective chart review of colposcopy patients in clinic database based on the following: (1) younger than 24 years at first visit; (2) first visit January 1, 2010, to May 31, 2013, and at least 1 follow-up visit after diagnosis; (3) histologic diagnosis of CIN2+; and (4) optimal conservative management (observation for up to 24 months or to 24 years, whichever occurred first). Patient information and clinical/pathologic data were extracted from charts to examine patient characteristics and treatment outcomes, CIN2+ regression rates, median times to regression for CIN2 versus CIN3 (Kaplan-Meier survival analysis), and predictors of regression (multivariate logistic regression analysis). RESULTS: A total of 154 women met criteria. The most severe histological diagnoses were CIN2 in 99 (64.3%), CIN3 in 51 (33.1%), and adenocarcinoma in situ in 4 (2.6%). Adenocarcinoma in situ was immediately treated. In follow-up, CIN2 regressed to CIN1 or negative in 74 women (74.7%)-median time to regression, 10.8 months. Cervical intraepithelial neoplasia 3 regressed in 11 women (21.6%)-median time to regression not reached (last follow-up censored at 52.7 months). Cervical intraepithelial neoplasia 2 on biopsy, low grade referral Pap, and younger age predicted regression. Overall, 49 women (31.8%) were treated. CONCLUSIONS: Conservative management should continue to be recommended to young women with CIN2. Rigorous retention mechanisms are required to ensure that these women return for follow-up. PMID- 29762431 TI - To the Editor. PMID- 29762430 TI - The Impact of Varying Numbers of Quadrivalent Human Papillomavirus Vaccine Doses on Anogenital Warts in the United States: A Database Study. AB - OBJECTIVE: The aim of the study was to investigate the effects of 3 or less quadrivalent human papillomavirus (HPV) vaccine doses on anogenital warts in both males and females in the United States. MATERIALS AND METHODS: We conducted a retrospective database study that included males and females aged 9 to 26 years who received varying numbers of vaccine doses between 2006 and 2015. The primary outcome was the incidence of anogenital warts starting 3 months after the last dose of the HPV vaccine. Proportional hazard regression models were used to examine the association between the number of HPV vaccine doses and the incidence of anogenital warts. The Kaplan-Meier method was used to estimate the proportion of subjects. RESULTS: A total of 440,532 females and 133,394 males were included in the study. We found a significant 2-way interaction (p < .0001) between the number of doses and age. For the group between 15 and 19 years of age, the hazard ratio of anogenital warts for the 3-dose vaccine was 0.58 (95% CI = 0.49-0.70), whereas it was 0.65 (95% CI = 0.49-0.85) and 0.67 (95% CI = 0.51-0.89) for the 1- and 2-dose groups, respectively. CONCLUSIONS: Our findings showed that 1, 2, and 3 doses of the quadrivalent HPV vaccine were similarly effective against anogenital warts in 15- to 19-year-old adolescents, irrespective of sex. PMID- 29762432 TI - In response. PMID- 29762433 TI - To the Editor. PMID- 29762434 TI - In response. PMID- 29762435 TI - A Technique for Preoperative Estimation of Resection Weight in Vertical Reduction Mammoplasty Using 2 Breast-Specific Surface Measurements. AB - Insurance authorization of reduction mammoplasty can be a challenging process. Despite copious evidence of the benefits of this operation and evidence that specimen weight does not correlate with symptomatic relief, most insurance providers require estimated resection weights. Many formulas and techniques to predict resection weight are inconsistent or not specific to the vertical technique. This study describes a simple method for generating a surgeon-specific equation for accurately predicting vertical reduction mammoplasty resection weight using 2 breast surface measurements. PMID- 29762436 TI - Preoperative Analysis of Venous Anatomy Before Deep Inferior Epigastric Perforator Free-Flap Breast Reconstruction Using Ferumoxytol-enhanced Magnetic Resonance Angiography. AB - BACKGROUND: Venous congestion after deep inferior epigastric artery perforator (DIEP) flap breast reconstruction is a complication that may be partially attributable to variations in venous abdominal wall anatomy. In previous work, we have shown that ferumoxytol may be used as a bloodpool contrast agent to perform high-resolution venous imaging. Our current aim was to use this technology to perform a detailed analysis of the venous anatomy among patients undergoing DIEP flap breast reconstruction. METHODS: All patients undergoing DIEP flap reconstruction with preoperative ferumoxytol-enhanced magnetic resonance angiography (FE-MRA) were retrospectively reviewed. A detailed anatomic analysis of each abdominal wall on FE-MRA was performed before review of operative findings. Statistical analysis was used to determine venous characteristics associated with superficial inferior epigastric vein (SIEV) augmentation. RESULTS: From 2012 to 2016, 59 patients underwent preoperative FE-MRA. This resulted in imaging for 118 hemiabdomen and 99 flaps. Superficial-deep communication was identified in 117 of 118 hemiabdomen. Fifty (93%) of 59 patients had greater than 1-mm venous communication of the superficial system across midline. Reconstructed breasts were based on dominant medial row perforators in 82 (83%) of 99 flaps. The mean diameters of the SIEV and dominant venous perforator were 3.8 and 2.8 mm, respectively. Anatomic characteristics associated with SIEV augmentation included SIEV diameter (P = 0.01), dominant perforator diameter (P = 0.04), and the ratio between these 2 variables (P = 0.001). CONCLUSIONS: Ferumoxytol-enhanced magnetic resonance angiography provides excellent imaging of the venous system. Anatomic characteristics such as the diameter of the SIEV and the diameter of the dominant perforator may be useful in determining which flaps require venous augmentation using the SIEV. PMID- 29762437 TI - Primary Premaxillary Ostectomy and Setback: Dealing With the "Fly-away" Premaxilla. AB - OBJECTIVE: This study aimed to analyze our outcomes of primary premaxillary ostectomy and setback combined with lip adhesion as the first stage in repair of the bilateral cleft lip with fly-away premaxilla. METHODS: This retrospective study included all patients who required primary premaxillary setback by a single surgeon to achieve successful lip repair between 2011 and 2017 at a tertiary children's hospital. All patients had bilateral cleft lip and complete cleft palate with significant premaxillary protrusion. All patients either had failed presurgical orthodontic manipulation or were thought to be poor candidates because of the rigidity of the premaxilla on clinical examination. Patient data were obtained from review of medical records and photographs. Surgical technique is described. RESULTS: Eleven patients with bilateral cleft lip, all of whom also had complete cleft palate, underwent primary premaxillary setback and lip adhesion at an average age of 8.2 months. The mean follow-up was 1.9 years (range, 139 days to 4.5 years). All patients subsequently completed formal lip repair, of which 10 have undergone palatoplasty. Serial photography documented stable premaxillary position and successful lip repair within the follow-up time frame. No patient had postoperative premaxillary instability or vascular compromise. One patient had dehiscence of the lip adhesion requiring reoperation. CONCLUSIONS: Primary premaxillary ostectomy and setback allows for successful staged formal lip repair in patients with bilateral cleft lip and palate who have failed presurgical infant orthopedics. Further research is required regarding long-term follow-up with respect to midfacial growth. PMID- 29762438 TI - Venous Anastomoses in Anterolateral Thigh Flaps for the Lower Extremity: Vessel Selection In Lieu of Obligatory Number. AB - BACKGROUND: Dual venous drainage for anterolateral thigh flaps has been proposed to protect against flap-related complications in head and neck applications. Here we report our experience with single vs dual venous anastomosis during lower extremity free-tissue transfer. METHODS: All free anterolateral thigh flaps for lower extremity reconstruction from 2011 to 2017 were retrospectively reviewed. An algorithm was used to determine the type and number of venous anastomoses, emphasizing patient anatomy, venous quality, and size match. Patients were divided into single- and dual-venous-anastomosis groups. Univariate analysis determined differences between the groups. A multivariable analysis identified independent risk factors. RESULTS: Fifty patients met the inclusion criteria. Patient demographics, recipient sites, wound type, and flap characteristics were similar in 1 and 2 vein groups. Average follow-up was 9.6 months. Forty-two percent underwent single venous drainage anastomoses. Mean age was 52.7 years, 78.0% were male, and 60% had defects of the foot and ankle. Increased flap area and early dangling did not increase flap demise. Thirty-three percent of single drainage patients and 31.0% of dual-drainage patients had a complication. A body mass index of greater than 30 kg/m was a predictor for both flap complication (P = 0.025) and partial flap loss (P = 0.031) in univariate analysis. No independent predictors were found in multivariate analysis. CONCLUSIONS: The number of venous anastomoses, area, and dangling protocol did not influence outcomes while using our lower extremity vein method. Thoughtful evaluation of venous egress should outweigh the routine use of multiple veins in perforator flap reconstructions of the lower extremity. PMID- 29762439 TI - Clinical Outcomes of Explosion Injuries to the Hand. AB - PURPOSE: The purpose of this study is to report clinical outcomes in a cohort of 12 patients with explosion injuries to the hand. METHODS: Twelve male patients with a mean age of 42.4 years (SD, 7.2) were examined at a mean of 54 months after sustaining explosion injuries to the hand. All patients underwent primary reconstruction and early soft tissue coverage within 72 hours after their injuries. Total active range of motion and moving 2-point discrimination in each digit were recorded along with hand injury severity score (HISS), disability of the arm, shoulder, and hand (DASH) score, and American Medical Association (AMA) impairment ratings. RESULTS: For digits saved, the average total active motion at final follow-up was 215 degrees (SD, 66.5). Twenty-two digits had 6-mm 2-point discrimination, and 17 digits had 8- to 10-mm 2-point discrimination. Eight of the 12 patients had secondary procedures. We found a strong correlation between initial HISS and DASH scores at final follow-up. There was also a strong correlation between AMA impairment rating and DASH scores. CONCLUSIONS: Early reconstruction provides protective sensation and preserves some function after explosion injuries. Preoperative HISS correlates with the long-term functional outcome as measured by DASH scores. For this group of patients, postinjury AMA impairment ratings also correlate with functional outcomes for the upper extremity. PMID- 29762440 TI - Reconstruction of Extensive Post-Electric Burn Scalp Defects With Exposed Bones: A Study of 12 Cases. AB - The scalp is a unique part of the human body with respect to its shape and position. It is the part of the body that is usually exposed in its original form, with no covering by any means of clothing. In workplaces, especially in the electrical industry in the area of electrical substations and power transmission lines it is this part of the body that can easily come in contact with high tension electrical wires. Others who can be prone to suffer such injuries are pedestrians, people working on heights, ladies hanging clothes on terraces.This case series includes 12 patients who sustained high-voltage electric burn injury to the scalp. Of the reconstructive options used, 2 were free flaps, 1 was a distant flap, and 9 were local flaps. Of the 2 free flaps, there was loss of 1 free flap due to thrombosis, which was later reconstructed with extracorporeal radial forearm flap.Of the 9 local flaps, therewas partial flap necrosis in 2 cases, which required debridement and the wounrds healed secondarily. There was recurrent osteomyelitis in 1 patient who underwent sequestrectomy. In conclusion, the results obtained, in all the patients, were satisfactory without necessitating a bony reconstruction. PMID- 29762441 TI - A Risk-Stratified Comparison of High-Risk Findings in Reduction Mammoplasty. AB - BACKGROUND: Reduction mammoplasty is indicated for symptomatic macromastia or breast asymmetry after contralateral cancer surgery. Previous studies compared the incidence of high-risk lesions in resection specimens between these 2 groups. However, no studies have compared incidental findings in breast reduction specimens based on relative risk of cancer. Our study stratifies lesions by relative risk of malignant progression and compares the frequency of these findings in bilateral versus unilateral reduction mammoplasties. METHODS: Charts were reviewed from 422 patients undergoing breast reductions by a single surgeon over a 10-year period. Age, procedure, specimen weight, and histologic findings were recorded. Pathologic data were stratified by relative risk of malignant progression and compared between patients with and without cancer histories. RESULTS: Three hundred five patients underwent bilateral reduction mammoplasty and 117 patients underwent unilateral reduction mammoplasty over the 10-year period. Bilateral patients had a higher incidence of benign lesions (P = 0.02). Both groups had similar incidences of proliferative lesions (P = 0.48). Unilateral patients had a higher incidence of atypia (P = 0.05) and carcinoma in situ (P < 0.01). One unilateral patient had an incidentally found invasive carcinoma. CONCLUSIONS: Patients undergoing unilateral reduction after oncologic resection have a higher incidence of high-risk lesions compared with those undergoing bilateral reductions for macromastia. Although others have compared incidental findings between these cohorts, no group has compared these incidental findings stratified by risk. Our data underscore the importance of pathologic analysis of reduction specimens for early detection of high-risk lesions and will prove valuable for preoperative counseling before reduction mammoplasty for either of these indications. PMID- 29762442 TI - Postburn Neck Reconstruction With Preexpanded Upper Back Perforator Flaps: Free Style Design and An Update of Treatment Strategies. AB - BACKGROUND: For extensive postburn neck deformities, the preexpanded flaps in the upper back region were used and gained a uniform skin appearance and esthetic contours. Free-style perforator-based free-tissue transfer that represents the most recent advance in reconstructive surgery may provide more versatility of these flaps. METHODS: We retrospectively reviewed 31 patients treated at our institution for postburn neck contracture from March 2010 to May 2016. Various upper back flaps were designed according to the dominant perforators and the shape of the defect after fully releasing the neck contracture. RESULTS: Thirty one patients received neck reconstructions with the versatile applications of the preexpanded upper back perforator flaps. Tip necrosis was observed in one case, and the others survived completely. The donor sites were all primarily closed. No incision dehiscence was observed. CONCLUSION: The free-style design has significantly increased the potential and versatility of the upper back flaps in reconstruction of severe neck scar contracture. PMID- 29762443 TI - Abdominal Wall Reconstruction and Patient Comorbidities. PMID- 29762444 TI - Efficacy of Autologous Platelet Concentrates as Adjuvant Therapy to Surgical Excision in the Treatment of Keloid Scars Refractory to Conventional Treatments: A Pilot Prospective Study. AB - BACKGROUND: After conventional treatments, keloid scars show varying degrees of recurrence. The aim of this study was to assess the efficacy and safety of platelet-rich plasma in the treatment of postoperative keloid scars refractory to conventional treatments. METHODS: This pilot prospective study was conducted in 17 patients with keloid scars who did not respond to 4 injections of cortisone or radiotherapy after extralesional resection of keloid. Platelet-rich plasma was injected intraoperatively and then 3 times with a 1-month interval. The primary end point was the complete remission of keloid scars 2 years posttreatment. Scar pruritus severity was scored before and after treatment. The study protocol was approved by the ethics committee and authorized by the French National Agency. This trial was registered at ClinicalTrials.gov, identifier NCT02922972. RESULTS: Nine keloid scars (53%) were completely resolved at 2 years, and 5 (29%) completely relapsed after treatment. Pruritus severity score was significantly lower at 2 years compared with baseline (1.33 +/- 0.97 before treatment and 0.40 +/- 0.63 at 2 years, P < 0.003). The mean Vancouver Scar Scale score significantly improved (8.18 +/- 2.38 before treatment and 3.82 +/- 1.98 at 2 years, P < 0.001). CONCLUSIONS: Injecting platelet-rich plasma is an effective and safe method as adjunctive therapy to resection for treating keloid scars refractory to conventional therapy. PMID- 29762445 TI - Functional Results of a Modified Extracorporeal Septoplasty With Open Access. AB - BACKGROUND: Nasal septal deviation is one of the major causes of nasal respiratory flow disorders. During the rhinoseptoplasty, the septum can be treated through a closed traditional access or through an open access. To date, there are still no objective functional indications of the best access to use in rhinoseptoplasty. For this reason, we evaluated, objectively and subjectively, the functional efficiency of open access and compared it with that of closed access. The aim is to highlight any functional outcome differences between the 2 types of access. METHODS: The study involved up to 50 patients, from January 2006 to June 2017; 20 patients underwent modified extracorporeal rhinoseptoplasty with open access, and 30 patients underwent modified extracorporeal rhinoseptoplasty with closed access. We evaluated the nasal obstruction by using the validated questionnaire Nasal Obstruction Symptoms Evaluation (subjective method) and by performing the anterior active rhinomanometry (objective method). Both evaluations were performed in 3 different times: preoperative period, 3 months, and 6 months after surgery. RESULTS: In the open cohort, the rhinomanometric analysis showed a statistically significant increase between preoperative period and sixth month after surgery; however, the nose score had a statistically significant increase in both 3 and 6 months after surgery. At 3 months after surgery, the rhinomanometric score was higher in patients with closed access than patients with open access; this difference has disappeared at 6 months after surgery. At 3 and 6 months after surgery, the improvement in the Nasal Obstruction Symptoms Evaluation average score was greater in patients with open access compared with patients with closed access. No complications were observed. CONCLUSIONS: Based on the results obtained from our work, we can declare that open access is a functionally valid procedure. At 6 months after surgery, the 2 accesses have a comparable functional efficacy. PMID- 29762446 TI - Prospective Analysis of the Greater Occipital Nerve Location in Patients Undergoing Occipital Nerve Decompression. AB - BACKGROUND: Migraine surgery and onabotulinumtoxinA injections aim to deactivate neurovascular trigger points implicated in chronic headaches. The greater occipital nerve (GON) is a common trigger point. The depth of this nerve has not been previously described. The purpose of this study was to report the intraoperative location, including depth, of the GON in human subjects undergoing migraine surgery. METHODS: We reviewed records of patients who underwent GON decompression by a single surgeon. Intraoperative measurement of the GON location lateral to midline, inferior to the occipital protuberance, and deep to the skin was collected for 2 previously described positions: where GON (a) enters, "point #2," and (b) exits, "point #3," the semispinalis muscle as it travels from deep to superficial (Plast Reconstr Surg. 2010;126:1563-1572; Plast Reconstr Surg. 2004;113:693-697). RESULTS: Thirty-four subjects (60 nerves) were included. The mean depths of the GON were 20 mm (SD, 4) at point no. 3 and 30 mm (SD, 6) at point no. 2. In 26 subjects who underwent bilateral surgery, there was a difference between right and left nerve position lateral to midline at point no. 3 (P = 0.008). Female sex (P = 0.014) and body mass index of 29 kg/m or less (P < 0.001) were associated with a more superficial GON position. CONCLUSIONS: Knowledge of the GON depth (eg, mean of 20 mm where it emerges from the semispinalis muscle) may improve accuracy of procedural treatments for migraines. When performing bilateral interventions, nerve position may differ between sides, particularly with respect to lateral distance from midline. Differences in this study compared with previous anatomic studies may reflect the use of live subjects in a prone position compared with cadaver specimens. PMID- 29762447 TI - Gastrocnemius Myocutaneous Flaps for Knee Joint Coverage. AB - INTRODUCTION: The gastrocnemius muscular flap has already proven its efficiency for soft tissue coverage in cases of knee joint exposure. However, it may be too small to cover large defects and has not the same aesthetic and mechanical properties as normal skin. Perforator fasciocutaneous flaps have recently been described in knee joint coverage with good results as they replace skin by skin, but they can be hard to harvest. Gastrocnemius flaps can be easily harvested with a planned skin paddle designed over the chosen muscle. This simple technique combines the advantages of muscular and fasciocutaneous flaps for knee joint area coverage. Perforator fasciocutaneous flap take a growing place in coverage of this localization in recent literature, but very few articles report the results of gastrocnemius myocutaneous flaps (MCFs). METHODS: All patients who underwent knee joint coverage with the use of a lateral or medial gastrocnemius MCFs between January 2012 and February 2017 in our university institution were included in this retrospective study. RESULTS: Sixteen gastrocnemius MCFs (10 medial and 6 lateral) were performed. The indication was posttraumatic in 5 cases, posttumoral in 5 cases, and after total knee prosthesis exposure in 6 cases. Skin paddles up to 15 cm in width and 18 cm in length were harvested. Complete healing was achieved in 15 days in all cases without suffering or nonunion. Three flaps were secondarily raised to allow total knee prosthesis reimplantation or arthrodesis, and 4 patients were treated with postoperative radiotherapy without complication. CONCLUSIONS: In addition to its reliability and very easy harvesting, the gastrocnemius MCF allows a robust joint coverage and good skin resurfacing that makes eventual revision easier and allows early radiotherapy. Furthermore, skin paddle also increases the effective area of the flap. This technique should always be considered with the other classic alternatives. PMID- 29762448 TI - Pectoralis Major Musculocutaneous Flap With a Midline Sternal Skin Paddle for Head and Neck Reconstruction: A New Design. AB - PURPOSE: The pectoralis major musculocutaneous (PMMC) flap is a classic flap for head and neck reconstruction, relatively unpopular with the advancement of microsurgery and free flaps. The classic parasternal paddle design provided a thick flap with a small rotation arch leaving objectionable scarring. Our new symmetric midsternal design overcomes these problems. METHODS: Chart review was done from the years 2000 to 2017. Flap skin paddle was placed symmetrically on both sides of the midsternal line. The pectoralis major (PM) muscle and aponeurosis were attached in the lateral half of the skin paddle. Most of PM muscle was elevated with the thoracoacromial vessel and dissected to the main trunk, where the PM muscle was cut and used for bulk. The flap was transferred to the neck and lower mandibular area. The flap was inset either supraclavicularly, covering the anterior neck, or subclavicularly, for intraoral/maxillary defects. RESULTS: Eight patients underwent head and neck reconstruction using the new design of PMMC flap between the years 2000 and 2017. The etiologies of the defect were radiation necrosis in 3 patients, repair of cutaneous fistulas in 3, recurrent hypopharyngeal cancer in 1, and recurrent tongue cancer in 1 patient. There were no flap losses or major complications. CONCLUSIONS: With the advancement of free-flap techniques, the classic flaps have become less popular. Our new design supplements the PMMC flap by providing a thin pliable flap with a long pedicle and rotation arc, allowing a combination of different types of flaps to cover composite head and neck defects, especially in cases that lack a reliable recipient vessel due to radiation. PMID- 29762449 TI - Time to Procedure, Nuclear Imaging and Clinicopathological Characteristics as Predictive Factors for Sentinel Lymph Node Metastasis in Cutaneous Melanoma: A Single-Center Analysis. AB - OBJECTIVE: Sentinel lymph node (SLN) biopsy is a widely accepted staging procedure for cutaneous melanoma patients who are at risk of clinically occult nodal metastases. Numerous predictive factors for regional lymph node metastases have been identified; however, few have been found to be reproducibly significant. Also, the role of blue dye in identification was questioned in recent trials. Time to procedure was also found to be predictive of SLN positivity, but this was not confirmed in other studies. In our study, predictive factors for metastatic involvement of SLN were analyzed, together with the role of addition blue dye in imaging on detection rate and false-negative SLN rate. An impact of time interval to procedure on the rate of SLN positivity was also explored. METHODS: Data analysis was done in 362 cutaneous melanoma patients who underwent lymphoscintigraphy and SLN biopsy at our institution from 2010 to 2016, with a median follow-up of 29 months (1-98 months). To delineate the relation of each variable (demographical, time to procedure, and clinical and pathological variables, as well as the presence of in-transit nodes, the number of draining basins, and SLN localization on scintigraphy) with positive SLN status, we used univariate logistic regression with odds ratios representing effect size. RESULTS: Metastatic involvement SLN was found in 67 (18.8%) of 356 patients. Detection rate was similar with or without further intraoperative SLN identification with blue dye (98.8% vs 98.17%, P > 0.05). Time to procedure was not associated with higher SLN positivity rate (P > 0.05). In univariate analysis, Breslow thickness (P < 0.001), primary ulceration lesion (P = 0.001), and lymphovascular invasion (P = 0.006) were strongly correlated with SLN positivity, as well as the site of primary tumor (P = 0.024), tumor-infiltrating lymphocytes (TILs) (P = 0.021), and sex (P = 0.026). In multivariate analysis, Breslow thickness and TILs were found to be significant independent predictors of SLN status (P < 0.05). CONCLUSIONS: Addition of blue dye did not improve SLN detection rate; time to procedure was not found to be associated with higher SLN biopsy positivity rates. Breslow thickness and TILs, as a marker of immune response to tumor, were consistently found to be significant independent predictors of SLN status. PMID- 29762450 TI - Three-Dimensional Analysis of Mandibular Angle Classification and Aesthetic Evaluation of the Lower Face in Chinese Female Adults. AB - BACKGROUND: Reduction gonioplasty is very popular in East Asia. However, there has been little quantitative criteria for mandibular angle classification or aesthetics. The aim of this study was to investigate the quantitative differences of mandibular angle types and determine the morphologic features of mandibular angle in attractive women. METHODS: We created a database of skull computed tomography and standardized frontal and lateral photographs of 96 Chinese female adults. Mandibular angle was classified into 3 groups, namely, extraversion, introversion, and healthy group, based on the position of gonion. We used a 5 point Likert scale to quantify attractiveness based on photographs. Those who scored 4 or higher were defined as attractive women. Three types of computed tomography measurements of the mandible were taken, including 4 distances, 4 angles, and 3 proportions. Discriminant analysis was applied to establish a mathematic model for mandibular angle aesthetics evaluation. RESULTS: Significant differences were observed between the different types of mandibular angle in lower facial width (Gol-Gor), mandibular angle (Co-Go-Me), and gonion divergence angle (Gol-Me-Gor) (P < 0.01). Chinese attractive women had a mandibular angle of 123.913 +/- 2.989 degrees, a FH-MP of 27.033 +/- 2.695 degrees, and a Go-Me/Co-Go index of 2.0. The "healthy" women had a mandibular angle of 116.402 +/- 5.373 degrees, a FH-MP of 19.556 +/- 5.999 degrees, and a Go-Me/Co-Go index of 1.6. The estimated Fisher linear discriminant function for the identification of attractive women was as follows: Y = -0.1516X1(Co-Go) + 0.128X2(Go-Me) + 0.04936X3(Co-Go-Me) +0.0218X4(FH-MP). CONCLUSIONS: Our study quantified the differences of mandibular angle types and identified the morphological features of mandibular angle in attractive Chinese female adults. Our results could assist plastic surgeons in presurgical designing of new aesthetic gonion and help to evaluate lower face aesthetics. PMID- 29762451 TI - Modified Design of Anterolateral Thigh Flap for Total Pharyngolaryngectomy Reconstruction: A Single-Center Experience. AB - BACKGROUND: Defects after total pharyngolaryngectomy for hypopharyngeal cancer often require reconstruction via free tissue transfer. Recently, anterolateral thigh (ALT) flap has become the gold standard in many centers because of its advantages with respect to versatility, minimal donor-site morbidity, good speech quality, and relatively low fistula and anastomotic leakage rates. Moreover, ALT allows 2 surgical teams to work simultaneously. However, the height of the parallelogram in the ALT design for neoesophagus reconstruction is usually set at a minimum of 9.4 cm (circumference, 2pir) for smooth food passage. Because this height exceeds 8 cm, the donor site may not be closed primarily, which highly depends on the patient's body habitus and the skin tone or quality and requires other methods, such as local flap or skin graft for wound closure, which subsequently increase operating time and donor-site complication rate. OBJECTIVES: Thus, we aimed to construct a simple and modified ALT design that will not only include the advantages described earlier but also provide adequate donor-site primary closure without jeopardizing complication rates. METHODS: Ten patients with hypopharyngeal cancer underwent reconstructive surgery using our modified ALT design after total pharyngolaryngectomy between 2010 and 2017. Our modified ALT design converts this "classical" shape into a parallelogram so that the height of the modified design is always less than 8 cm, thus allowing for easy primary closure of the wound. RESULTS: The donor-site defects of all 10 patients were closed primarily. No donor-site complications and partial or total flap loss were observed. One patient experienced persistent wound infection with dehiscence, for which debridement was performed. The stricture and fistula rates were 10% (n = 1) and 20% (n = 2), respectively. The mean follow-up time is approximately 1 year. CONCLUSIONS: Minimizing donor-site morbidity is an important goal in reconstructive surgery. Our modified ALT flap design is simple, enabling easy primary closure of the donor-site defect, with improved results for the patient and operators. Furthermore, this design is also suitable for ALT flaps with widths larger than 8 cm. PMID- 29762452 TI - The Use of Expanded Polytetrafluoroethylene in Short Nose Elongation: Fourteen Years of Clinical Experience. AB - BACKGROUND: Short nose elongation is a relatively common rhinoplasty procedure, especially in Asia. The selection of the adequate graft material is challenging. Previous reports have described the application of expanded polytetrafluoroethylene (ePTFE) for dorsal augmentation rhinoplasty, but studies using ePTFE for nose elongation are lacking. We propose ePTFE as an alternative treatment for short noses, describe the technique, and discuss outcomes, patient selection, and complications based on our 14-year experience. METHODS: From February 2003 to December 2016, 206 patients with varying degrees of short noses were included in this retrospective study. All patients underwent nose elongation surgery using an ePTFE implant. Nasal lengths before and after surgery were measured using a 3-dimensional simulation technology. Outcomes and complications including possible underlying reasons were analyzed. Patient satisfaction was evaluated using a self-assessment survey. RESULTS: Nasal elongation was successfully achieved using ePTFE. Mean increase in nasal length was 4.36 +/- 0.85 mm. The mean follow-up period was 13.3 months, ranging from 6 months to 8 years. Follow-up examinations demonstrated stable results. The overall complication rate was 6.8%. Complications included infection, implant extrusion, migration, deviation, visibility, and/or prominence, tissue reaction, and reddening of the nasal skin. Most patients (93.6%) rated their outcome as improved and much improved. CONCLUSIONS: Nasal elongation using ePTFE implantation is a feasible therapeutic approach for patients with short noses. Reliable outcomes and the absence of donor site morbidity contribute to the high patient acceptance. Meticulous surgical technique and careful patient selection are prerequisites for successful results. PMID- 29762453 TI - Microvascular Replantation Following Facial Dog Bites in Children: Systematic Review and Management Algorithm. AB - BACKGROUND: Pediatric dog bite injuries account for 1% of emergency department visits per year and represent an underrecognized and underreported public health problem. Reconstructive surgery is frequently utilized, and in the most extreme injuries, microvascular replantation may be considered. We sought to systematically review the available literature on microvascular replantation after facial dog bite injuries in children, with particular attention to perioperative morbidity and long-term follow-up. METHODS: We reviewed a case of microvascular replantation after a facial dog bite injury in a child from our own institution and conducted a systematic literature search to identify other similar reports. Clinical variables were collected from the reported cases, and descriptive statistics were calculated. A management algorithm was developed from the reviewed published experience. RESULTS: We report the youngest child to date in the literature to undergo replantation after a facial dog bite injury. Nineteen other cases were found involving children aged 18 months to 17 years, with follow-up ranging from 2 weeks to 28 years. Anastomosis techniques varied considerably and included both an artery and vein in only 9 (47%) of 19 cases. Venous congestion was nearly universal, and multimodal techniques were used until native venous outflow was reestablished. Blood transfusion was common, but intensive care unit utilization was not frequently reported. Long-term outcomes were excellent, with growth of the replanted part and recovery of function; however, minor revision procedures were common. CONCLUSIONS: Microvascular replantation following facial dog bite amputation injuries in the pediatric population is the ultimate step in the reconstructive ladder. Strong consideration should be given to microvascular exploration with involvement of large or whole segments of the lip, nose, or ear; however, parents should be counseled extensively regarding the known morbidity of replantation surgery. With meticulous surgical technique and careful postoperative care, replantation after facial dog bite amputation injuries may successfully achieve dramatic and lasting results for pediatric patients. PMID- 29762454 TI - Correction of Tuberous Nipple Areolar Complex Deformity in Gynecomastia: The Deformity That Can Get Forgotten. AB - The desired end point of surgical reduction of gynecomastia is a masculine breast appearance and symmetry. This article concentrates on the tuberous deformity of the nipple areolar complex (NAC) that can present in gynecomastia and is sometimes overlooked at surgical correction.This deformity can be corrected at primary surgery if it is recognized preoperatively. If missed, or not adequately corrected, the postoperative result of primary reduction may be deemed incomplete by the patient and they will request revision.The deformity involves overprojection of the NAC in an anteroposterior direction, yet the base diameter may be close to normal. Correction involves reduction of the herniated breast bud, excision of excess areolar tissue, and careful radial scoring to flatten the NAC to a normal level of projection.For the NAC to have a masculine appearance, the areolae need to be symmetrical, of normal male size, and slightly oval in a transverse direction. The projection of both areola and nipple needs to be low, but present: not flattened. This article presents an operative technique to address primary or residual tuberous NAC deformity in the treatment of gynecomastia. PMID- 29762455 TI - The Anti-inflammatory Effect of Hydrogen on Lung Transplantation Model of Pulmonary Microvascular Endothelial Cells During Cold Storage Period. AB - BACKGROUND: Lung ischemia-reperfusion injury (LIRI) remains an important factor for the early mortality of lung transplantations. Hydrogen (H2) can attenuate lung injury and improve lung function in animal experiments. In previous studies, pulmonary microvascular endothelial cells (PMVECs) were used to simulate LIRI. We hypothesized that H2 can alleviate inflammatory injury in a PMVECs lung transplantation model in the cold ischemia phase. METHODS: Pulmonary microvascular endothelial cells were divided into 4 groups: blank, control, oxygen (O2), and H2. The blank group included PMVECs without treatment. During the cold storage period, the O2 group was aerated with 40% O2 and 60% N2, and the H2 group was aerated with 3% H2, 40% O2, and 57% N2. The control group was aerated without gases. The mixed gases were replaced every 20 minutes for 4 hours. During the transplantation period, the sealed containers were warmed for 1 hour at room temperature. In the reperfusion period, the containers were aerated with 50% O2, 5% CO2 and 45% N2 at 37 degrees C. RESULTS: The concentrations of interleukin-6 and tumor necrosis factor-alpha in the extracellular solutions were significantly decreased, and the concentration of interleukin-10 was increased in the H2 group. Intercellular adhesion molecule-1 expression was inhibited by H2. Furthermore, H2 decreased the activation of NF-kappaB and phosphorylation level of p38. Cell apoptosis was alleviated. The pathological changes in the cell and mitochondria were alleviated after H2 administration. CONCLUSIONS: Hydrogen attenuated inflammatory response in a PMVECs lung transplantation model during cold storage. The effect may be achieved by inhibition of p38 MAPK and NF-kappaB pathways. PMID- 29762456 TI - Parvovirus B19 Induced Red Cell Aplasia in a Heart Transplant Patient Diagnosed on Pleural Fluid. PMID- 29762457 TI - On Reporting of the Outcomes from Clinical Trials; a Call to Order. PMID- 29762458 TI - Association between duration of delayed graft function, acute rejection and allograft outcome after deceased donor kidney transplantation. AB - BACKGROUND: Prolonged duration of delayed graft function (DGF) may be associated with adverse allograft outcomes, but the association between threshold duration of DGF, acute rejection and long-term allograft loss remains undefined. We aimed to determine the impact of DGF duration on allograft outcomes and to assess whether this association was mediated by acute rejection. METHODS: Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, Cox proportional modelling was used to determine the association between quartiles of DGF duration, acute rejection at 6 months and death-censored graft loss (DCGL). Mediation analysis was conducted to determine whether acute rejection was a causal intermediate between DGF and DCGL. RESULTS: Of 7668 deceased donor kidney transplants between 1997-2014, 1497 (19.5%) recipients experienced DGF requiring dialysis. The median (interquartile range) duration of DGF was 7(9) days, with 25% requiring dialysis for >=14 days. Among recipients who had experienced DGF duration of 1-4 days, the adjusted HR for duration of 5 7, 8-13 and >=14 days were 1.13 (95%CI 0.83-1.55;p=0.43), 1.44 (1.08 1.91;p=0.013), and 1.99 (1.50-2.65;p<0.001), respectively for acute rejection; and were 1.10 (0.73-1.67;p=0.64), 1.45 (1.00-2.11;p=0.05) and 1.60 (1.10 2.31;p=0.01), respectively for DCGL. On average, 8% of the effects between DGF duration and DCGL were explained by acute rejection. CONCLUSIONS: There was a direct dose-dependent effect between DGF duration and DCGL, with acute rejection explaining <10% of the effects between DGF duration and DCGL. Future research identifying other potential modifiable mediators that lies in the causal pathway between DGF duration and allograft loss is essential. PMID- 29762459 TI - Pregnancy and Heart Transplantation: Giving Birth After a New Life. PMID- 29762460 TI - A New Life: Motherhood After Heart Transplantation. A Single-center Experience and Review of Literature. AB - BACKGROUND: Pregnancy after heart transplantation (HTx) may expose the recipient to hemodynamic and immunologic risks and the newborn to toxic effects of immunosuppressive therapy. Adequate preconception counseling is crucial to identify optimal timing and to modify immunosuppressive therapy to minimize risks for both the mother and the fetus. METHODS: We describe our experience with 12 pregnancies occurred in 11 women who had undergone HTx at our center. RESULTS: Pregnancies ran without severe complications or rejections, and none of the babies have shown major defects at birth. However, as reported in the literature, weight at birth rated in lower range in most of the newborns, probably due to in utero cyclosporine exposure. Up to now, none of the babies showed clinical signs of heart disease, although more than half of the mothers had an inherited or familial cardiomyopathy. CONCLUSIONS: Despite potential mother and fetal complications, successful pregnancy and delivery are possible after HTx, provided that optimum timing, close monitoring, and therapy adjustments are guaranteed. Becoming a mother appears to be an important achievement for young women after HTx, even when there is a risk to transmit an inheritable heart disease. PMID- 29762462 TI - The Safety and Utility of Fiberoptic Bronchoscopy in the Very Elderly. AB - BACKGROUND: Flexible bronchoscopy (FB) is a common modality for diagnostic sampling within the thorax. It is utilized often in the elderly population, but there is limited data on the safety and utility of the procedure in the very elderly. METHODS: FBs performed outside the intensive care unit in the San Antonio Military Health System on patients 85 years and older were reviewed. Outcomes including indications, complications, diagnostic yield, and final diagnosis were compared with a control group consisting of patients' ages of 65 to 79 years old. RESULTS: Seventy-three bronchoscopies were performed in each group. The mean age of the older group was 87.1+/-2.6 years, and had a higher American Society of Anesthesiology (ASA) class than the younger group (P=0.03). There were no significant differences in the indications for bronchoscopy (P>0.05), sampling performed (P>0.05), complication rates (P>0.05), diagnostic yield (P>0.05), or final diagnoses (P>0.05). Similar proportions of each group with a malignancy diagnosis received some form of therapy (P>0.05), although fewer of the older group underwent surgery (P=0.03). Analysis of the cohort demonstrated that ASA class 3 to 4 was associated with increased rate of complications and use of anesthesia compared with lower ASA class (P<0.02). CONCLUSION: FB in the elderly demonstrated no differences in procedural complications, diagnostic yield, and utility of the procedure for an underlying diagnosis. This study suggests bronchoscopy is as safe and useful in the very elderly as a population of the age of 65 to 79. PMID- 29762461 TI - Robotic Bronchoscopy for Diagnosis of Suspected Lung Cancer: A Feasibility Study. AB - BACKGROUND: Robotic bronchoscopy may offer alternative approaches to address limitations of current bronchoscopic techniques for biopsy of suspected peripheral lung lesions. This study sought to evaluate complications and feasibility of robotic bronchoscopy performed with the Robotic Endoscopy System (RES). METHODS: Adult patients from a single institution underwent bronchoscopy of suspected lesions with a bronchus sign with the RES. The primary outcome was complication rate, as assessed by the incidence of related serious adverse events (SAE). The secondary outcome was technical feasibility. Data are presented as median (range), counts, and percentage. P-value was calculated using the Mann Whitney U test. RESULTS: Of 17 screened patients, 15 were eligible. The median age was 67 (38 to 79) years. The lesions (12 peripheral and 3 central) were located in the right lower lobe (33%), right upper lobe (27%), left upper lobe (27%), and left lower lobe (13%). No SAE, including pneumothorax and significant bleeding, occurred. Biopsy samples were obtained from 93% of patients. One sampling (right upper lobe) required conventional bronchoscopy and another required surgery to confirm malignancy. Cancer was confirmed in 60% (9/15) of patients. Benign features were found in 5 of 6 patients. Time to biopsy location reduced from 45 (21 to 84) minutes (first 5 cases) to 20 (7 to 47) minutes (last 9 cases), P=0.039. CONCLUSIONS: The study results and absence of SAE support feasibility of the RES in accessing the periphery of the lung. The RES has potential to address challenges associated with biopsy of peripheral lung lesions. PMID- 29762463 TI - Hyperspectral Imaging and Spectrometry-Derived Spectral Features for Bitter Pit Detection in Storage Apples. AB - Bitter pit is one of the most important disorders in apples. Some of the fresh market apple varieties are susceptible to bitter pit disorder. In this study, visible-near-infrared spectrometry-based reflectance spectral data (350-2500 nm) were acquired from 2014, 2015 and 2016 harvest produce after 63 days of storage at 5 degrees C. Selected spectral features from 2014 season were used to classify the healthy and bitter pit samples from three years. In addition, these spectral features were also validated using hyperspectral imagery data collected on 2016 harvest produce after storage in a commercial storage facility for 5 months. The hyperspectral images were captured from either sides of apples in the range of 550-1700 nm. These images were analyzed to extract additional set of spectral features that were effective in bitter pit detection. Based on these features, an automated spatial data analysis algorithm was developed to detect bitter pit points. The pit area was extracted, and logistic regression was used to define the categorizing threshold. This method was able to classify the healthy and bitter pit apples with an accuracy of 85%. Finally, hyperspectral imagery derived spectral features were re-evaluated on the visible-near-infrared reflectance data acquired with spectrometer. The pertinent partial least square regression classification accuracies were in the range of 90-100%. Overall, the study identified salient spectral features based on both hyperspectral spectrometry and imaging techniques that can be used to develop a sensing solution to sort the fruit on the packaging lines. PMID- 29762464 TI - The Mediating Effect of Regulatory Emotional Self-Efficacy on the Association between Self-Esteem and School Bullying in Middle School Students: A Cross Sectional Study. AB - School bullying is negatively associated with self-esteem, but psychological mediators of bullying have yet to be clarified. We examined regulatory emotional self-efficacy (RESE) as a possible mediator in the association between self esteem and school bullying. A cross-sectional study of 995 adolescents was conducted in two middle schools of Xi'an. All of the participants completed the Chinese version of the School Bullying Experience Questionnaire (C-SBEQ), Self Esteem Scale (SES), and Regulatory Emotional Self-Efficacy Scale (RESE). Descriptive statistics analysis, the bias corrected percentile Bootstrap CI method, and structural equation modelling were used to analyze the data. The results showed that 418 students (42.0%) reported that they were involved in school bullying in the past year. Self-esteem was negatively associated with school bullying (total effect: beta = -0.275, 95% CI = -0.381--0.034), and RESE mediated the association between self-esteem and school bullying (indirect effect: beta = -0.136, 95% CI = -0.245--0.037). Furthermore, self-esteem had an indirect effect through perceived self-efficacy in managing negative affect, while self-esteem had no indirect effect through self-efficacy in the expression of positive affect. The present study suggests that school authorities and the related education departments should not only focus on improving students' self esteem, but should also pay more attention to students' RESE, in order to mitigate, and potentially reduce, the occurrence of bullying. PMID- 29762465 TI - External-Stimuli-Assisted Control over Assemblies of Plasmonic Metals. AB - Assembly of plasmonic nanoparticles (NPs) in suspensions is a promising approach for the control of optical and sensing properties that depend on the assembled states of plasmonic NPs. This review focuses on the controlling methods to assemble the NP via external stimuli such as pH, temperature, light, magnetic field, and electric field. External stimuli are introduced as powerful tools to assemble the NPs because of various operational factors, such as the intensity, application time, and frequency, which can be employed. In addition to a summary of recent studies on the controlling methods, a future study on the reversible control over assembled states of the plasmonic NPs via external stimuli is proposed. PMID- 29762466 TI - Validated 1H and 13C Nuclear Magnetic Resonance Methods for the Quantitative Determination of Glycerol in Drug Injections. AB - In the current study, we employed high-resolution proton and carbon nuclear magnetic resonance spectroscopy (1H and 13C NMR) for quantitative analysis of glycerol in drug injections without any complex pre-treatment or derivatization on samples. The established methods were validated with good specificity, linearity, accuracy, precision, stability, and repeatability. Our results revealed that the contents of glycerol were convenient to calculate directly via the integration ratios of peak areas with an internal standard in 1H NMR spectra, while the integration of peak heights were proper for 13C NMR in combination with an external calibration of glycerol. The developed methods were both successfully applied in drug injections. Quantitative NMR methods showed an extensive prospect for glycerol determination in various liquid samples. PMID- 29762468 TI - Multivariate Analysis as a Tool to Identify Concentrations from Strongly Overlapping Gas Spectra. AB - We applied a multivariate analysis (MVA) to spectroscopic data of gas mixtures in the mid-IR in order to calculate the concentrations of the single components which exhibit strongly overlapping absorption spectra. This is a common challenge in broadband spectroscopy. Photoacoustic (PA) measurements of different volatile organic compounds (VOCs) in the wavelength region of 3250 nm to 3550 nm served as the exemplary detection technique. Partial least squares regression (PLS) was used to calculate concentrations from the PA spectra. After calibration, the PLS model was able to determine concentrations of single VOCs with a relative accuracy of 2.60%. PMID- 29762467 TI - Inhibition of Proliferation in U937 Cells Treated by Blue Light Irradiation and Combined Blue Light Irradiation/Drug. AB - The cell viability and apoptosis of tumor U937 cells treated by blue light (BL) irradiation have been examined. BL irradiation can specially inhibit the proliferation and promote the apoptosis of U937 cells, relating to the production of reactive oxygen species (ROS) and the decline of mitochondrial membrane potential (DeltaPsim). The apoptosis is further associated with varying downregulated B-cell lymphoma-extra large (Bcl-XL) and B-cell lymphoma 2 (Bcl-2) genes, upregulated Bcl-2-associated X (Bax) gene, the activation of caspase-3 and caspase-9, and the cleavage of poly (ADP-ribose) polymerase (PARP) by the BL irradiation process. Moreover, BL irradiation induced proliferation inhibition is higher than that treated by a common chemotherapeutic drug of homoharringtonine (HHT). When we synergize BL irradiation with HHT (BL-HHT), a higher proliferation inhibition is obtained than that treated by BL irradiation or HHT alone. These results are helpful for establishing a low toxicity and high efficiency strategy of BL irradiation for clinical treatment of acute myeloid leukemia, not limited to U937 cells. PMID- 29762469 TI - Individualised Multimodal Treatment Strategies for Anaplastic and Poorly Differentiated Thyroid Cancer. AB - The prognosis of anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) is poor, due to their radioiodine refractoriness (RAI-R), high metastatic potential and current lack of effective treatment strategies. We aimed to examine the efficacy of the tyrosine kinase inhibitors (TKIs) sorafenib and selumetinib and the histone deacetylase inhibitor (HDACI) panobinostat in patient-derived tumor tissue (PDTT) of ATCs/PDTCs, the expression of sodium iodide symporter (NIS) and radioiodine up-take (RAI-U). High Mobility Group AT-Hook 2 (HMGA2) and associated miRNAs expression was correlated with the clinical course of the patients. Inhibitory effects of panobinostat, sorafenib and selumetinib were measured by real time cell analyser xCELLigence in five PDTTs and human foreskin fibroblasts (HF) used as control. Expression of NIS, HMGA2 and associated miRNAs hsa-let-7f-5p, hsa-let-7b-5p, hsa-miR-146b-5p and hsa-miR-146b-3p was performed by RT-qPCR and Western blot. RAI-U was performed by Gamma Counter with I-131. Panobinostat showed the strongest cytotoxic effect (10 nM) in all PDTTs and HF and caused a significant over-expression of NIS transcript. TKIs were able to up regulate NIS transcript in patient 5 and in HF. RAI-U was up-regulated after 24 h of treatment with TKIs and panobinostat in all PDTT and HF, except in patient 5. Selumetinib caused a significant suppression of HMGA2 in PDTT 1, 2, 4, 5 and HF; whereas sorafenib caused no change of HMGA2 expression. Panobinostat suppressed significantly HMGA2 in PDTT 2, 4 and HF. The expression of miRNAs hsa-let-7f-5p, has-let-7b-5p hsa-miR-146b-5p and hsa-miR-146b-3p was modulated heterogeneously. NIS protein level was over-expressed in three PDTTs (patients 1, 3 and 4) after 24 h of treatment with selumetinib, sorafenib and in particular with panobinostat. HF showed a stable NIS protein level after treatment. Panobinostat showed the strongest cytotoxicity in all treated PDTTs at the lowest dosage in comparison with TKI. All three compounds were able to modulate differently NIS, HMGA2 and related miRNAs. These factors represent valuable markers in PDTT for new treatment strategies for patients suffering from ATC/PDTC. Thus, the establishment of PDTT could be a useful tool to test the efficacy of compounds and to develop new and individualised multimodal treatment options for PDTCs and ATCs. PMID- 29762470 TI - Cast-In-Situ, Large-Sized Monolithic Silica Xerogel Prepared in Aqueous System. AB - This paper reports the preparation of cast-in-situ, large-sized monolithic silica xerogels by a two-step acid-base catalyzed approach under ambient pressure drying. Low-cost industrial silica sol and deionized water were used as the silicon source and the solvent, respectively. Hexadecetyltrimethylammonium bromide (CTAB) was used as a modification agent. Different amounts of polyethylene glycol 400 (PEG400) was added as a pore-forming agent. The prepared silica xerogels under ambient pressure drying have a mesoporous structure with a low density of 221 mg.cm-3 and a thermal conductivity of 0.0428 W.m-1.K-1. The low-cost and facile preparation process, as well as the superior performance of the monolithic silica xerogels make it a promising candidate for industrial thermal insulation materials. PMID- 29762473 TI - Zika Virus and the Risk for Renter Households. AB - Recent research on family income indicates that a lack of economic stability can affect healthy housing. Those with limited resources experience higher rates of inadequate and unstable housing many times forcing them to live in undesirable communities in which there can be several community-level health-related issues. One community-level health-related factor of concern has been the reemergence of Zika virus. Some research has indicated that a higher risk of catching Zika virus may exist in neighborhoods and areas with unhealthy housing. Therefore, this study sought to explore the existence of a relationship between rental housing and the Zika virus. Our findings indicated a significant correlation existed between renter occupied household units and the presence of Zika virus. This finding is notable as it indicates that renters have a higher chance of contracting Zika virus than non-renters. Future research should further examine the demographic and housing situation in other communities reporting cases of the Zika virus. PMID- 29762472 TI - Weaning Time in Preterm Infants: An Audit of Italian Primary Care Paediatricians. AB - INTRODUCTION: According to the 2016 Italian National Institute of Statistics (Istat) data in Italy, about 6.7% of all newborns are born prematurely. Due to the lack of data on current complementary feeding in preterm infants in Italy, the aim of the survey was to evaluate individual attitudes of primary care paediatricians, concerning the introduction of complementary foods in preterm infants. METHODS: An internet-based survey was conducted among primary care paediatricians, working in Italy, regarding (1) timing of the introduction of complementary foods to preterm newborns; (2) type of complementary foods introduced; (3) vitamin D and iron supplementations. RESULTS: A total of 347 primary care Italian paediatricians answered the questionnaire; 44% of responders based the timing of the introduction of solid food exclusively on an infant's age, 18% on an infant's neurodevelopmental status and 4% on the body weight; the remaining 34% based the timing on two or more of these aspects. The type of complementary foods did not comply with an evidence-based sequence; 98% of participants promoted vitamin D supplementation and 89% promoted iron supplementation with great diversity in timing and doses. CONCLUSIONS: Due to limited evidence, there is a great heterogeneity in the attitudes of primary care paediatricians concerning the introduction of complementary foods to preterm newborns. Further research is needed to provide evidence-based guidelines regarding weaning preterm newborns. PMID- 29762471 TI - The Impact of Caloric and Non-Caloric Sweeteners on Food Intake and Brain Responses to Food: A Randomized Crossover Controlled Trial in Healthy Humans. AB - Whether non-nutritive sweetener (NNS) consumption impacts food intake behavior in humans is still unclear. Discrepant sensory and metabolic signals are proposed to mislead brain regulatory centers, in turn promoting maladaptive food choices favoring weight gain. We aimed to assess whether ingestion of sucrose- and NNS sweetened drinks would differently alter brain responses to food viewing and food intake. Eighteen normal-weight men were studied in a fasted condition and after consumption of a standardized meal accompanied by either a NNS-sweetened (NNS), or a sucrose-sweetened (SUC) drink, or water (WAT). Their brain responses to visual food cues were assessed by means of electroencephalography (EEG) before and 45 min after meal ingestion. Four hours after meal ingestion, spontaneous food intake was monitored during an ad libitum buffet. With WAT, meal intake led to increased neural activity in the dorsal prefrontal cortex and the insula, areas linked to cognitive control and interoception. With SUC, neural activity in the insula increased as well, but decreased in temporal regions linked to food categorization, and remained unchanged in dorsal prefrontal areas. The latter modulations were associated with a significantly lower total energy intake at buffet (mean kcal +/- SEM; 791 +/- 62) as compared to WAT (942 +/- 71) and NNS (917 +/- 70). In contrast to WAT and SUC, NNS consumption did not impact activity in the insula, but led to increased neural activity in ventrolateral prefrontal regions linked to the inhibition of reward. Total energy intake at the buffet was not significantly different between WAT and NNS. Our findings highlight the differential impact of caloric and non-caloric sweeteners on subsequent brain responses to visual food cues and energy intake. These variations may reflect an initial stage of adaptation to taste-calorie uncoupling, and could be indicative of longer-term consequences of repeated NNS consumption on food intake behavior. PMID- 29762474 TI - Saccharomyces cerevisiae Boulardii Reduces the Deoxynivalenol-Induced Alteration of the Intestinal Transcriptome. AB - Type B trichothecene mycotoxin deoxynivalenol (DON) is one of the most frequently occurring food contaminants. By inducing trans-activation of a number of pro inflammatory cytokines and increasing the stability of their mRNA, trichothecene can impair intestinal health. Several yeast products, especially Saccharomyces cerevisiae, have the potential for improving the enteric health of piglets, but little is known about the mechanisms by which the administration of yeast counteracts the DON-induced intestinal alterations. Using a pig jejunum explant model, a whole-transcriptome analysis was performed to decipher the early response of the small intestine to the deleterious effects of DON after administration of S. cerevisiae boulardii strain CNCM I-1079. Compared to the control condition, no differentially expressed gene (DE) was observed after treatment by yeast only. By contrast, 3619 probes-corresponding to 2771 genes were differentially expressed following exposure to DON, and 32 signaling pathways were identified from the IPA software functional analysis of the set of DE genes. When the intestinal explants were treated with S. cerevisiae boulardii prior to DON exposure, the number of DE genes decreased by half (1718 probes corresponding to 1384 genes). Prototypical inflammation signaling pathways triggered by DON, including NF-kappaB and p38 MAPK, were reversed, although the yeast demonstrated limited efficacy toward some other pathways. S. cerevisiae boulardii also restored the lipid metabolism signaling pathway, and reversed the down-regulation of the antioxidant action of vitamin C signaling pathway. The latter effect could reduce the burden of DON-induced oxidative stress. Altogether, the results show that S. cerevisiae boulardii reduces the DON-induced alteration of intestinal transcriptome, and point to new mechanisms for the healing of tissue injury by yeast. PMID- 29762475 TI - Growth Hormone Secretion Patterns in German Landrace (DL) Fetuses and Piglets Compared to DL Piglets with Inherited 1,25-Dihydroxyvitamin D3 Deficiency. AB - The regulation of growth hormone (GH) release during prenatal development and during early postnatal life is not entirely clarified. In this study plasma GH concentrations in pigs with inherited pseudo vitamin D deficiency type I (PDDR I), which regularly show growth retardation, were compared during ontogeny with unaffected pigs of the same breed (German Landrace, DL) as control. Plasma GH concentrations were measured in plasma of chronically catheterized fetuses (beginning on day 101 after mating or after artificial insemination) and in piglets (day 37 postpartum (p.p.)-day 42 p.p.) of both lines. A growth curve beginning at day 7 p.p. was recorded for both lines. The relative amount of GH receptor (GHR) mRNA in liver was quantified by competitive reverse transcription polymerase chain reaction in piglets at day 42 p.p. A trend for higher GH concentrations was observed in PDDR-I fetuses (p < 0.1). In PDDR-I piglets compared to DL piglets higher plasma GH values (p < 0.01), were observed despite lower body weight. The relative quantity of GHR mRNA in liver was not significantly different between the two lines. Piglets with an inherited defect of vitamin D synthesis showed higher GH concentrations. A hormonal imprinting by low 1,25(OH)2D3 could be one reason for our observations and should be analysed in detail in future. PMID- 29762476 TI - Function of the ERFL1a Transcription Factor in Wheat Responses to Water Deficiency. AB - The APETALA2/ethylene response factor (AP2/ERF) superfamily is involved in the responses of plants to biotic and abiotic stresses; however, the functions and mechanisms of some members of this family in plants are unclear. In our previous study, expression of TaERFL1a, a member of the AP2/ERF family, was remarkably induced in wheat seedlings suffering freezing stress. In this study, we show that its expression was rapidly upregulated in response to salt, cold, and water deficiency, suggesting roles in the responses to abiotic stresses. Further, transient barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) resulted in significantly reduced tolerance to 20% PEG6000-stimulated water deficiency. Subcellular localization and transcriptional activation assays separately showed that TaERFL1a was targeted to the nucleus and possessed transcriptional activation activity. Yeast two-hybrid library screening identified six interacting proteins, and of these, the interactions between TaERFL1a and TaSGT1, and TaERFL1a and TaDAD2 proteins were further confirmed by yeast co transformation and bimolecular fluorescent complementation (BiFC). Collectively, our results suggest that TaERFL1a is a stress-responsive transcription factor, which could be functionally related to proteins involved in the abiotic stress responses of plants. PMID- 29762477 TI - Characterization of Curcumin/Cyclodextrin Polymer Inclusion Complex and Investigation on Its Antioxidant and Antiproliferative Activities. AB - The aims of this study were to characterize the curcumin/cyclodextrin polymer inclusion complex using X-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and UV-vis spectroscopy, and to determine the antioxidant activity of this complex by methods of scavenging 2,2-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals assays and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals assays. The inhibitory effect of inclusion complex on A375 cells was also investigated by CCK 8 assay, Annexin-V/PI staining assay, and caspase activity assay. The results showed that the complex exhibited different physicochemical characteristics from that of free curcumin. Moreover, the inclusion complex exhibited novel antioxidant activity by scavenging the ABTS and DPPH free radicals and displayed higher antiproliferative activity on A375 cells. Further investigation revealed that inclusion complex could induce A375 cell apoptosis. These findings suggest that inclusion complex could be developed as a novel natural antioxidant with potential applications in cancer chemoprevention. PMID- 29762479 TI - Development of a Polyphenol Oxidase Biosensor from Jenipapo Fruit Extract (Genipa americana L.) and Determination of Phenolic Compounds in Textile Industrial Effluents. AB - In this work, an innovative polyphenol oxidase biosensor was developed from Jenipapo (Genipa americana L.) fruit and used to assess phenolic compounds in industrial effluent samples obtained from a textile industry located in Jaragua GO, Brasil. The biosensor was prepared and optimized according to: the proportion of crude vegetal extract, pH and overall voltammetric parameters for differential pulse voltammetry. The calibration curve presented a linear interval from 10 to 310 uM (r2 = 0.9982) and a limit of detection of 7 uM. Biosensor stability was evaluated throughout 15 days, and it exhibited 88.22% of the initial response. The amount of catechol standard recovered post analysis varied between 87.50% and 96.00%. Moreover, the biosensor was able to detect phenolic compounds in a real sample, and the results were in accordance with standard spectrophotometric assays. Therefore, the innovatively-designed biosensor hereby proposed is a promising tool for phenolic compound detection and quantification when environmental contaminants are concerned. PMID- 29762478 TI - Insulin Sensitivity and Glucose Homeostasis Can Be Influenced by Metabolic Acid Load. AB - Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets results in the over-production of metabolic acids which has been associated with the development of chronic metabolic disturbances. Mild metabolic acidosis has been shown to impair peripheral insulin action and several epidemiological findings suggest that metabolic acid load markers are associated with insulin resistance and impaired glycemic control through an interference intracellular insulin signaling pathways and translocation. In addition, higher incidence of diabetes, insulin resistance, or impaired glucose control have been found in subjects with elevated metabolic acid load markers. Hence, lowering dietary acid load may be relevant for improving glucose homeostasis and prevention of type 2 diabetes development on a long-term basis. However, limitations related to patient acid load estimation, nutritional determinants, and metabolic status considerably flaws available findings, and the lack of solid data on the background physiopathology contributes to the questionability of results. Furthermore, evidence from interventional studies is very limited and the trials carried out report no beneficial results following alkali supplementation. Available literature suggests that poor acid load control may contribute to impaired insulin sensitivity and glucose homeostasis, but it is not sufficiently supportive to fully elucidate the issue and additional well-designed studies are clearly needed. PMID- 29762480 TI - Time-Course Microarray Analysis Reveals Differences between Transcriptional Changes in Tomato Leaves Triggered by Mild and Severe Variants of Potato Spindle Tuber Viroid. AB - Viroids are small non-capsidated non-coding RNA replicons that utilize host factors for efficient propagation and spread through the entire plant. They can incite specific disease symptoms in susceptible plants. To better understand viroid-plant interactions, we employed microarray analysis to observe the changes of gene expression in "Rutgers" tomato leaves in response to the mild (M) and severe (S23) variants of potato spindle tuber viroid (PSTVd). The changes were analyzed over a time course of viroid infection development: (i) the pre symptomatic stage; (ii) early symptoms; (iii) full spectrum of symptoms and (iv) the so-called 'recovery' stage, when stem regrowth was observed in severely affected plants. Gene expression profiles differed depending on stage of infection and variant. In S23-infected plants, the expression of over 3000 genes was affected, while M-infected plants showed 3-fold fewer differentially expressed genes, only 20% of which were specific to the M variant. The differentially expressed genes included many genes related to stress; defense; hormone metabolism and signaling; photosynthesis and chloroplasts; cell wall; RNA regulation, processing and binding; protein metabolism and modification and others. The expression levels of several genes were confirmed by nCounter analysis. PMID- 29762483 TI - A Feasibility Study on Timber Damage Detection Using Piezoceramic-Transducer Enabled Active Sensing. AB - In recent years, piezoelectric-based transducers and technologies have made significant progress towards structural health monitoring and damage evaluation for various metal and concrete structures. Timber is still commonly used as a construction material in practical engineering; however, there is a lack of research on the health monitoring of timber-based structures using piezoelectric based transducers and methods. This paper conducts a feasibility study on timber damage detection using surface-mounted piezoelectric patches, which enable the stress-wave-based active sensing approach. Typical damage modes in timber frame structures, such as surface cracks and holes, were investigated in this study. In the active sensing approach, one piezoceramic transducer is used as an actuator to generate stress waves, which propagate along the surface of the timber structure, and other piezoceramic transducers function as sensors to detect the propagating stress waves. Defects, such as a crack or a hole, induce additional attenuation to the propagating stress wave. Based on this attenuation, the proposed method can detect the defects using the wavelet-packet-based damage index, demonstrating its implementation potential for real-time timber damage detection. PMID- 29762481 TI - Buckwheat and CVD Risk Markers: A Systematic Review and Meta-Analysis. AB - The effects of buckwheat intake on cardiovascular diseases (CVDs) have not been systematically investigated. The aim of the present study was to comprehensively summarize studies in humans and animals, evaluating the impact of buckwheat consumption on CVD risk markers and to conduct a meta-analysis of relevant data. Thirteen randomized, controlled human studies, two cross-sectional human studies and twenty-one animal studies were identified. Using random-effects models, the weighted mean difference of post-intervention concentrations of blood glucose, total cholesterol and triglycerides were significantly decreased following buckwheat intervention compared with controls [differences in blood glucose: 0.85 mmol/L (95% CI: -1.31, -0.39), total cholesterol: 0.50 mmol/L (95% CI: 0.80, -0.20) and triglycerides: 0.25 mmol/L (95% CI: -0.49, -0.02)]. Responses of a similar magnitude were seen in two cross-sectional studies. For animal studies, nineteen of twenty-one studies showed a significant reduction in total cholesterol of between 12% and 54%, and fourteen of twenty studies showed a significant reduction in triglycerides of between 2% and 74%. All exhibited high unexplained heterogeneity. There was inconsistency in HDL cholesterol outcomes in both human and animal studies. It remains unclear whether increased buckwheat intake significantly benefits other markers of CVD risk, such as weight, blood pressure, insulin, and LDL-cholesterol, and underlying mechanisms responsible for any effects are unclear. PMID- 29762482 TI - Nanocomposites Based on Biodegradable Polymers. AB - In the present review paper, our main results on nanocomposites based on biodegradable polymers (on a time scale from 2010 to 2018) are reported. We mainly focused our attention on commercial biodegradable polymers, which we mixed with different nanofillers and/or additives with the final aim of developing new materials with tunable specific properties. A wide list of nanofillers have been considered according to their shape, properties, and functionalization routes, and the results have been discussed looking at their roles on the basis of different adopted processing routes (solvent-based or melt-mixing processes). Two main application fields of nanocomposite based on biodegradable polymers have been considered: the specific interaction with stem cells in the regenerative medicine applications or as antimicrobial materials and the active role of selected nanofillers in food packaging applications have been critically revised, with the main aim of providing an overview of the authors' contribution to the state of the art in the field of biodegradable polymeric nanocomposites. PMID- 29762484 TI - CRISPR/Cas9 Mutagenesis of UL21 in Multiple Strains of Herpes Simplex Virus Reveals Differential Requirements for pUL21 in Viral Replication. AB - Studies from multiple laboratories using different strains or species of herpes simplex virus (HSV) with deletions in UL21 have yielded conflicting results regarding the necessity of pUL21 in HSV infection. To resolve this discrepancy, we utilized CRISPR/Cas9 mutagenesis to isolate pUL21 deficient viruses in multiple HSV backgrounds, and performed a side-by-side comparison of the cell-to cell spread and replication phenotypes of these viruses. These analyses confirmed previous studies implicating the involvement of pUL21 in cell-to-cell spread of HSV. Cell-to-cell spread of HSV-2 was more greatly affected by the lack of pUL21 than HSV-1, and strain-specific differences in the requirement for pUL21 in cell to-cell spread were also noted. HSV-2 strain 186 lacking pUL21 was particularly crippled in both cell-to-cell spread and viral replication in non-complementing cells, in comparison to other HSV strains lacking pUL21, suggesting that the strict requirement for pUL21 by strain 186 may not be representative of the HSV-2 species as a whole. This work highlights CRISPR/Cas9 technology as a useful tool for rapidly constructing deletion mutants of alphaherpesviruses, regardless of background strain, and should find great utility whenever strain-specific differences need to be investigated. PMID- 29762485 TI - Stress-Induced and Diabetic Hyperglycemia Associated with Higher Mortality among Intensive Care Unit Trauma Patients: Cross-Sectional Analysis of the Propensity Score-Matched Population. AB - BACKGROUND: This study was designed to measure the effect of stress-induced hyperglycemia (SIH) and diabetic hyperglycemia (DH) versus non-diabetic normoglycemia (NDN) on the outcomes of trauma patients in the intensive care unit (ICU). METHODS: Diabetes mellitus (DM) was determined based on patient history and/or a hemoglobin A1c (HbA1c) level of ≥6.5% at admission. The patients who had serum glucose levels of ≥200 mg/dL in the absence or presence of DM were assigned into the groups SIH and DH, respectively. Diabetic normoglycemia (DN) and NDN were determined based on serum glucose levels of <200 mg/dL in patients with and without DM, respectively. Patients with burn injury or incomplete data were excluded. Detailed data of trauma patients in the ICU of a Level-I trauma center from 1 January 2009 to 31 December 2016 were retrieved from the database of the Trauma Registry System. These patients were classified into four exclusive groups, including NDN (n = 1745), DN (n = 306), SIH (n = 225) and DH (n = 206). The Pearson chi-square test was used to compare categorical data between groups. Continuous variables were compared using one-way analysis of variance along with the Games-Howell post hoc test. To decrease the confounding effect of the differences in sex and age, preexisting comorbidities and injury severity score (ISS) among different groups of patients, 1:1 ratio propensity score-matched cohorts were assigned using the NCSS software. The effect of hyperglycemia on the outcomes of patients with and without DM was assessed with a logistic regression analysis. RESULTS: Among those selected propensity score-matched patient cohorts, the patients with SIH and DH had a 3.88-fold (95% CI, 2.13-7.06; p < 0.001) and 1.83-fold (95% CI, 1.00-3.34; p = 0.048) higher mortality, respectively, than those with NDN. Moreover, the patients in the SIH group (10.0 vs. 7.4 days; p = 0.005) and those in the DH group (10.1 vs. 7.4 days; p = 0.006) who were admitted to the ICU had a significantly longer length of stay than those in the NDN group. In addition, the SIH group had a 2.13-fold (95% CI, 1.04-4.36; p = 0.038) higher adjusted odds ratio for mortality than the DH group. CONCLUSIONS: This study revealed significantly worse outcomes in terms of mortality among patients with SIH and DH who were admitted to the ICU after controlling for sex and age, preexisting comorbidities and ISS. In addition, patients who had SIH presented significantly higher adjusted odds for mortality than those DH patients. These results suggest that hyperglycemia is detrimental in patients with or without DM who were admitted to the ICU, and there is a different pathophysiological mechanisms behind the SIH and DH. PMID- 29762487 TI - Simple, Low-Cost Fabrication of Highly Uniform and Reproducible SERS Substrates Composed of Ag-Pt Nanoparticles. AB - Ag-Pt nanoparticles, grafted on Ge wafer, were synthesized by the galvanic replacement reaction based on their different potentials. Detailed characterization through scanning electron microscopy (SEM), energy-dispersive X ray spectrometry (EDS) and X-ray photo-elelctron spectroscopy (XPS) proved that Ag-Pt nanoparticles are composed of large Ag nanoparticles and many small Pt nanoparticles instead of an Ag-Pt alloy. When applied as surface-enhanced Raman scattering (SERS) substrates to detect Rhodamine 6G (1 * 10-8 M) or Crystal violet (1 * 10-7 M) aqueous solution in the line mapping mode, all of the obtained relative standard deviation (RSD) values of the major characteristic peak intensities, calculated from the SERS spectra of 100 serial spots, were less than 10%. The fabrication process of the SERS substrate has excellent uniformity and reproducibility and is simple, low-cost and time-saving, which will benefit studies on the platinum-catalyzed reaction mechanisms in situ and widen the practical application of SERS. PMID- 29762486 TI - Identification of Nutritional Components in Black Sesame Determined by Widely Targeted Metabolomics and Traditional Chinese Medicines. AB - Chemical composition of secondary metabolites is of great importance for quality control of agricultural products. Black sesame seeds are significantly more expensive than white sesame seeds, because it is thought that black sesame seeds are more beneficial to human health than white sesame seeds. However, the differences in nutrient composition between black sesame seeds and white sesame seeds are still unknown. The current study examined the levels of different metabolites in black and white sesame seeds via the use of a novel metabolomics strategy. Using widely targeted metabolomics data, we obtained the structure and content of 557 metabolites, out of which 217 metabolites were identified, and discovered 30 metabolic pathways activated by the secondary metabolites in both black and white sesame seeds. Our results demonstrated that the main pathways that were differentially activated included: phenylpropanoid biosynthesis, tyrosine metabolism, and riboflavin metabolism. More importantly, the biomarkers that were significantly different between black seeds and white sesame seeds are highly related to the functions recorded in traditional Chinese medicine. The results of this study may serve as a new theoretical reference for breeding experts to promote the genetic improvement of sesame seeds, and therefore the cultivation of higher quality sesame varieties. PMID- 29762488 TI - High Production of LukMF' in Staphylococcus aureus Field Strains Is Associated with Clinical Bovine Mastitis. AB - Staphylococcus aureus, a major cause of bovine mastitis, produces a wide range of immune-evasion molecules. The bi-component leukocidin LukMF' is a potent killer of bovine neutrophils in vitro. Since the role of LukMF' in development of bovine mastitis has not been studied in natural infections, we aimed to clarify whether presence of the lukM-lukF' genes and production levels of LukMF' are associated with clinical severity of the disease. Staphylococcus aureus was isolated from mastitis milk samples (38 clinical and 17 subclinical cases) from 33 different farms. The lukM-lukF' genes were present in 96% of the isolates. Remarkably, 22% of the lukM-lukF'-positive S. aureus isolates displayed a 10-fold higher in vitro LukMF' production than the average of the lower-producing ones. These high producing isolates were cultured significantly more frequently from clinical than subclinical mastitis cases. Also, the detection of LukM protein in milk samples was significantly associated with clinical mastitis and high production in vitro. The high producing LukMF' strains all belonged to the same genetic lineage, spa type t543. Analysis of their global toxin gene regulators revealed a point mutation in the Repressor of toxins (rot) gene which results in a non-functional start codon, preventing translation of rot. This mutation was only identified in high LukMF' producing isolates and not in low LukMF' producing isolates. Since rot suppresses the expression of various toxins including leukocidins, this mutation is a possible explanation for increased LukMF' production. Identification of high LukMF' producing strains is of clinical relevance and can potentially be used as a prognostic marker for severity of mastitis. PMID- 29762490 TI - Calibrating an Ionosonde for Ionospheric Attenuation Measurements. AB - Vertical ionospheric soundings have been performed at almost all ionospheric observatories with little attention to measuring the attenuation of the signal between transmission and reception. When the absorption has been determined, this has been achieved by comparing the received power after the first and second reflections, but this method has some limitations due to the unknown reflection coefficient of the ground and the non-continuous presence of the second reflection. This paper deals with a different method based on precise calibration of the sounding system, allowing determination of absolute signal attenuation after a single reflection. This approach is affected by a systematic error due to imperfect calibration of the antennas, but when the focus of interest is to measure a trend over a specified period, it is very accurate. The article describes how calibration was implemented, the measurement output formats, and finally it presents some results from a meaningful set of measurements in order to demonstrate what this method can accomplish. PMID- 29762489 TI - Comparison of Cell Arrays and Multi-Well Plates in Microscopy-Based Screening. AB - Multi-well plates and cell arrays enable microscopy-based screening assays in which many samples can be analysed in parallel. Each of the formats possesses its own strengths and weaknesses, but reference comparisons between these platforms and their application rationale is lacking. We aim to fill this gap by comparing two RNA interference (RNAi)-mediated fluorescence microscopy-based assays, namely epidermal growth factor (EGF) internalization and cell cycle progression, on both platforms. Quantitative analysis revealed that both platforms enabled the generation of data with the appearance of the expected phenotypes significantly distinct from the negative controls. The measurements of cell cycle progression were less variable in multi-well plates. The result can largely be attributed to higher cell numbers resulting in less data variability when dealing with the assay generating phenotypic cell subpopulations. The EGF internalization assay with a uniform phenotype over nearly the whole cell population performed better on cell arrays than in multi-well plates. The result was achieved by scoring five times less cells on cell arrays than in multi-well plates, indicating the efficiency of the cell array format. Our data indicate that the choice of the screening platform primarily depends on the type of the cellular assay to achieve a maximum data quality and screen efficiency. PMID- 29762491 TI - Study of Factors Influencing the Bioaccessibility of Triazolone in Cherry Tomatoes Using a Static SHIME Model. AB - Estimating the influence of bioaccessibility of pesticide residues in fruits and vegetables on dietary exposure is a challenge for human health risk assessment. This study investigated the bioaccessibility of pesticide residues in cherry tomatoes and contributing factors (digestion time, pH, solid/liquid ratio, and dietary nutrition) using an in vitro test simulating the human gastrointestinal tract. pH had the largest effect on triazolone precipitation in the simulated gastric intestinal juice, which had a significant impact on the bioaccessibility. The bioaccessibility of triazolone in the intestinal stage was slightly higher than that in the stomach stage, owing to bile salts and pancreatic enzymes present in the intestinal juice. The bioaccessibility of triazolone did not change significantly with digestion time. In the gastric stage, there was a logarithmic relationship between the bioaccessibility and solid/liquid ratio (R2 = 0.9941). The addition of oil significantly changed the bioaccessibility in the gastrointestinal stage. Protein and dietary fiber only affected bioaccessibility in the stomach stage. Dietary nutrition can reduce the release of pesticides from fruits and vegetables into the stomach, sharply reducing the bioaccessibility, and the dietary exposure of pesticide residues in fruits and vegetables can be properly evaluated. PMID- 29762493 TI - A Crowdsensing Based Analytical Framework for Perceptional Degradation of OTT Web Browsing. AB - Service perception analysis is crucial for understanding both user experiences and network quality as well as for maintaining and optimizing of mobile networks. Given the rapid development of mobile Internet and over-the-top (OTT) services, the conventional network-centric mode of network operation and maintenance is no longer effective. Therefore, developing an approach to evaluate and optimizing users' service perceptions has become increasingly important. Meanwhile, the development of a new sensing paradigm, mobile crowdsensing (MCS), makes it possible to evaluate and analyze the user's OTT service perception from end user's point of view other than from the network side. In this paper, the key factors that impact users' end-to-end OTT web browsing service perception are analyzed by monitoring crowdsourced user perceptions. The intrinsic relationships among the key factors and the interactions between key quality indicators (KQI) are evaluated from several perspectives. Moreover, an analytical framework of perceptional degradation and a detailed algorithm are proposed whose goal is to identify the major factors that impact the perceptional degradation of web browsing service as well as their significance of contribution. Finally, a case study is presented to show the effectiveness of the proposed method using a dataset crowdsensed from a large number of smartphone users in a real mobile network. The proposed analytical framework forms a valuable solution for mobile network maintenance and optimization and can help improve web browsing service perception and network quality. PMID- 29762494 TI - A Facile Electrochemical Sensor Based on PyTS-CNTs for Simultaneous Determination of Cadmium and Lead Ions. AB - A simple and easy method was implemented for the contemporary detection of cadmium (Cd2+) and lead (Pb2+) ions using 1,3,6,8-pyrenetetrasulfonic acid sodium salt-functionalized carbon nanotubes nanocomposites (PyTS-CNTs). The morphology and composition of the obtained PyTS-CNTs were characterized using scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), and X-ray photoelectron spectroscopy (XPS). The experimental results confirmed that the fabricated PyTS-CNTs exhibited good selectivity and sensitivity for metal ion sensing owing to the insertion of sulfonic acid groups. For Cd2+ and Pb2+, some of the electrochemical sensing parameters were evaluated by varying data such as the PyTS-CNT quantity loaded on the pyrolytic graphite electrode (PGE), pH of the acetate buffer, deposition time, and deposition potential. These parameters were optimized with differential pulse anodic sweeping voltammetry (DPASV). Under the optimal condition, the stripping peak current of the PyTS-CNTs/Nafion/PGE varies linearly with the heavy metal ion concentration, ranging from 1.0 MUg L-1 to 90 MUg L-1 for Cd2+ and from 1.0 MUg L-1 to 110 MUg L-1 for Pb2+. The limits of detection were estimated to be approximately 0.8 MUg L-1 for Cd2+ and 0.02 MUg L 1 for Pb2+. The proposed PyTS-CNTs/Nafion/PGE can be used as a rapid, simple, and controllable electrochemical sensor for the determination of toxic Cd2+ and Pb2+. PMID- 29762492 TI - Zika Virus Induces Autophagy in Human Umbilical Vein Endothelial Cells. AB - Autophagy is a common strategy for cell protection; however, some viruses can in turn adopt cellular autophagy to promote viral replication. Zika virus (ZIKV) is the pathogen that causes Zika viral disease, and it is a mosquito-borne virus. However, its pathogenesis, especially the interaction between ZIKV and target cells during the early stages of infection, is still unclear. In this study, we demonstrate that infecting human umbilical vein endothelial cells (HUVEC) with ZIKV triggers cellular autophagy. We observed both an increase in the conversion of LC3-I to LC3-II and increased accumulation of fluorescent cells with LC3 dots, which are considered to be the two key indicators of autophagy. The ratio of LC3 II/GAPDH in each group was significantly increased at different times after ZIKV infection at different MOIs, indicating that the production of lipidated LC3-II increased. Moreover, both the ratio of LC3-II/GAPDH and the expression of viral NS3 protein increased with increasing time of viral infection. The expression level of p62 decreased gradually from 12 h post-infection. Expression profile of double fluorescent protein labelling LC3 indicated that the autophagy induced by ZIKV infection was a complete process. We further investigated the role of autophagy in ZIKV replication. We demonstrated that either the treatment with inhibitors of autophagosomes formation or short hairpin RNA targeting the Beclin 1 gene, which is critical for the formation of autophagosomes, significantly reduced viral production. Taken together, our results indicate that ZIKV infection induces autophagy of HUVEC, and inhibition of ZIKV-induced autophagy restrains viral replication. PMID- 29762496 TI - Arc Discharges of a Pure Carbon Strip Affected by Dynamic Contact Force during Current-Carrying Sliding. AB - Arc discharges of a pure carbon strip induced by dynamic contact force were studied on a pin-on-disk tribometer. It was found that arc discharges were produced periodically in accordance with the period of the dynamic contact force. The arcing rate of the pure carbon strip increased with an increase of frequency f and amplitude B, which led to a decrease of current-carrying quality. These influences at high velocities became much more significant. A critical point of the arcing rate at around 2% was detected. Lower than 2%, the pure carbon strip was able to maintain its excellent current-carrying capability; higher than this point, the current-carrying quality deteriorated abruptly. SEM and XPS analysis show that the element Cu detected on the worn surface at lower arcing rates was metal Cu. CuO was found at higher arcing rates. This indicated that the wear mechanism transferred from mechanical wear to arc erosion with the increase of the arcing rate. PMID- 29762495 TI - Role of SdiA on Biofilm Formation by Atypical Enteropathogenic Escherichia coli. AB - Atypical enteropathogenic Escherichia coli are capable to form biofilm on biotic and abiotic surfaces, regardless of the adherence pattern displayed. Several E. coli mechanisms are regulated by Quorum sensing (QS), including virulence factors and biofilm formation. Quorum sensing is a signaling system that confers bacteria with the ability to respond to chemical molecules known as autoinducers. Suppressor of division inhibitor (SdiA) is a QS receptor present in atypical enteropathogenic E.coli (aEPEC) that detects acyl homoserine lactone (AHL) type autoinducers. However, these bacteria do not encode an AHL synthase, but they are capable of sensing AHL molecules produced by other species, establishing an inter species bacterial communication. In this study, we performed experiments to evaluate pellicle, ring-like structure and biofilm formation on wild type, sdiA mutants and complemented strains. We also evaluated the transcription of genes involved in different stages of biofilm formation, such as bcsA, csgA, csgD, fliC and fimA. The sdiA mutants were capable of forming thicker biofilm structures and showed increased motility when compared to wild type and complemented strains. Moreover, they also showed denser pellicles and ring-like structures. Quantitative real-time PCR (qRT-PCR) analysis demonstrated increased csgA, csgD and fliC transcription on mutant strains. Biofilm formation, as well as csgD, csgA and fimA transcription decreased on wild type strains by the addition of AHL. These results indicate that SdiA participates on the regulation of these phenotypes in aEPEC and that AHL addition enhances the repressor effect of this receptor on the transcription of biofilm and motility related genes. PMID- 29762497 TI - A Comparison of ACQ, AIE and AEE-Based Polymers Loaded on Polyurethane Foams as Sensors for Explosives Detection. AB - An aggregation-caused quenching (ACQ)-active polymer (PF), an aggregation-induced emission (AIE)-active polymer (PFTPE) and an aggregation-enhanced emission (AEE) active polymer (PTTPE) were synthesized by tetraphenylethane (TPE), fluorene and thiophene moieties. Polyurethane (PU) foams modified by PF, PFTPE and PTTPE, namely PU-PF, PU-PFTPE and PU-PTTPE, using ultrasonication-assisted method have been prepared. A comparative study of PU-PF, PU-PFTPE and PU-PTTPE for detection explosives had been performed, and significant fluorescence quenching was observed with the introduction of PA solutions. The as-prepared PU-PF, PU-PFTPE and PU-PTTPE sensors exhibited a superior sensitivity for PA solutions with different concentrations. Remarkably, PU-PF gave a quenching efficiency of 96.2%, higher than 93.5% for PU-PFTPE and 86.7% for PU-PTTPE at a PA concentration of 180 ug.mL-1 in methanol, which was attributed to the effective energy transfer from the fluorophore (PF) to the nitro explosive (PA). This suggested that some ACQ polymers, applied to detect explosives, could afford better performances than AIE or AEE polymers through modification of structures and selection of adequate carriers. At the same time, these chemical sensors can be recycled many times. PMID- 29762499 TI - A High Aspect Ratio Bifurcated 128-Microchannel Microfluidic Device for Environmental Monitoring of Explosives. AB - Design and evolution of explosives monitoring and detection platforms to address the challenges of trace level chemical identification have led investigations into the use of intricately designed microfluidic devices. Microfluidic devices are unique tools that possess distinct characteristics that, when designed properly and configured with optical and fluidic components, can produce detection platforms with unmatched performance levels. Herein, we report the design, fabrication and integration of a bifurcated high aspect ratio microfluidic device containing 128 microchannels (40 mm * 40 MUm * 250 MUm; L * W * H) for explosives detection at trace levels. Aspect ratios measuring >6:1 support improved receptor-target molecule interactions, higher throughput and extremely low limits of detection (LOD). In addition to superior assay sensitivity, the bifurcated microfluidic device provides greater durability and versatility for substrate modification. Using the explosive 2,4,6-trinitrotoluene (TNT) as the model compound in a fluorescence-based displacement immunoassay, we report LODs for TNT at 10 parts-per-trillion (pptr) using a neutravidin-coated biotinylated anti-TNT microfluidic device. Solution to wall interactions were also simulated in COMSOL Multiphysics to understand fluid flow characteristics. Reynolds numbers were calculated to be 0.27-2.45 with a maximum pressure of 1.2 * 10-2 psi. PMID- 29762498 TI - Cytoprotective Effect of Epigallocatechin Gallate (EGCG)-5'-O-alpha Glucopyranoside, a Novel EGCG Derivative. AB - Epigallocatechin gallate (EGCG) is a well-studied polyphenol with antioxidant effects. Since EGCG has low solubility and stability, many researchers have modified EGCG residues to ameliorate these problems. A novel EGCG derivative, EGCG-5'-O-alpha-glucopyranoside (EGCG-5'Glu), was synthesized, and its characteristics were investigated. EGCG-5'Glu showed antioxidant effects in cell and cell-free systems. Under SNP-derived radical exposure, EGCG-5'Glu decreased nitric oxide (NO) production, and recovered ROS-mediated cell viability. Moreover, EGCG-5'Glu regulated apoptotic pathways (caspases) and cell survival molecules (phosphoinositide 3-kinase (PI3K) and phosphoinositide-dependent kinase 1 (PDK1)). In another radical-induced condition, ultraviolet B (UVB) irradiation, EGCG-5'Glu protected cells from UVB and regulated the PI3K/PDK1/AKT pathway. Next, the proliferative effect of EGCG-5'Glu was examined. EGCG-5'Glu increased cell proliferation by modulating nuclear factor (NF)-kappaB activity. EGCG-5'Glu protects and repairs cells from external damage via its antioxidant effects. These results suggest that EGCG-5'Glu could be used as a cosmetics ingredient or dietary supplement. PMID- 29762500 TI - Circulating MicroRNAs in Young Patients with Acute Coronary Syndrome. AB - Circulating microRNAs (miRNAs) hold great potential as novel diagnostic markers for acute coronary syndrome (ACS). This study sought to identify plasma miRNAs that are differentially expressed in young ACS patients (mean age of 38.5 +/- 4.3 years) and evaluate their diagnostic potentials. Small RNA sequencing (sRNA-seq) was used to profile plasma miRNAs. Discriminatory power of the miRNAs was determined using receiver operating characteristic (ROC) analysis. Thirteen up regulated and 16 down-regulated miRNAs were identified in young ACS patients. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) validation showed miR-183-5p was significantly up-regulated (8-fold) in ACS patients with non-ST-segment elevated myocardial infarction (NSTEMI) whereas miR-134-5p, miR 15a-5p, and let-7i-5p were significantly down-regulated (5-fold, 7-fold and 3.5 fold, respectively) in patients with ST-segment elevated myocardial infarction (STEMI), compared to the healthy controls. MiR-183-5p had a high discriminatory power to differentiate NSTEMI patients from healthy controls (area under the curve (AUC) of ROC = 0.917). The discriminatory power for STEMI patients was highest with let-7i-5p (AUC = 0.833) followed by miR-134-5p and miR-15a-5p and this further improved (AUC = 0.935) with the three miRNAs combination. Plasma miR 183-5p, miR-134-5p, miR-15a-5p and let-7i-5p are deregulated in STEMI and NSTEMI and could be potentially used to discriminate the two ACS forms. PMID- 29762502 TI - Molecular Mechanisms of Apoptosis in HepaRG Cell Line Induced by Polyphyllin VI via the Fas Death Pathway and Mitochondrial-Dependent Pathway. AB - Polyphyllin VI, which is an active saponin, is mainly isolated from traditional medicinal plant Paris polyphylla, which causes liver damage in rats. In the present study, we aimed to explore the potential cytotoxicity of polyphyllin VI on the growth of HepaRG cells and to determine the molecular mechanism. The results revealed that polyphyllin VI changed cell morphology and induced apoptosis in HepaRG cells. Flow cytometric assay displayed that polyphyllin VI promoted the generation of reactive oxygen species (ROS), depolarized the mitochondrial membrane potential (MMP), and induced S phase cell cycle arrest by decreasing the expression of cyclin A2 and CDK2, while significantly increasing the expression of p21 protein. Polyphyllin VI induced the release of cytochrome c from the mitochondria to the cytosol and activated Fas, caspase-3, -8, -9, and PARP proteins. Pretreatment with NAC and Z-VAD-FMK (ROS scavenger and caspase inhibitor, respectively) on HepaRG cells increased the percentage of viable cells, which indicated that polyphyllin VI induced cell apoptosis through mitochondrial pathway by the generation of ROS and Fas death-dependent pathway. All of the effects are in dose- and time-dependent manners. Taken together, these findings emphasize the necessity of risk assessment to polyphyllin VI and offer an insight into polyphyllin VI-induced apoptosis of HepaRG cells. PMID- 29762501 TI - Immunomodulatory Function of Myeloid-Derived Suppressor Cells during B Cell Mediated Immune Responses. AB - Myeloid-derived suppressor cells (MDSCs) play roles in immune regulation during neoplastic and non-neoplastic inflammatory responses. This immune regulatory function is directed mainly toward T cells. However, MDSCs also regulate other cell populations, including B cells, during inflammatory responses. Indeed, B cells are essential for antibody-mediated immune responses. MDSCs regulate B cell immune responses directly via expression of effector molecules and indirectly by controlling other immune regulatory cells. B cell-mediated immune responses are a major component of the overall immune response; thus, MDSCs play a prominent role in their regulation. Here, we review the current knowledge about MDSC-mediated regulation of B cell responses. PMID- 29762504 TI - Remote Sensing of Wildland Fire-Induced Risk Assessment at the Community Level. AB - Wildland fires are some of the critical natural hazards that pose a significant threat to the communities located in the vicinity of forested/vegetated areas. In this paper, our overall objective was to study the structural damages due to the 2016 Horse River Fire (HRF) that happened in Fort McMurray (Alberta, Canada) by employing primarily very high spatial resolution optical satellite data, i.e., WorldView-2. Thus, our activities included the: (i) estimation of the structural damages; and (ii) delineation of the wildland-urban interface (WUI) and its associated buffers at certain intervals, and their utilization in assessing potential risks. Our proposed method of remote sensing-based estimates of the number of structural damages was compared with the ground-based information available from the Planning and Development Recovery Committee Task Force of Regional Municipality of Wood Buffalo (RMWB); and found a strong linear relationship (i.e., r2 value of 0.97 with a slope of 0.97). Upon delineating the WUI and its associated buffer zones at 10 m, 30 m, 50 m, 70 m and 100 m distances; we found existence of vegetation within the 30 m buffers from the WUI for all of the damaged structures. In addition, we noticed that the relevant authorities had removed vegetation in some areas between 30 m and 70 m buffers from the WUI, which was proven to be effective in order to protect the structures in the adjacent communities. Furthermore, we mapped the wildland fire-induced vulnerable areas upon considering the WUI and its associated buffers. Our analysis revealed that approximately 30% of the areas within the buffer zones of 10 m and 30 m were vulnerable due to the presence of vegetation; in which, approximately 7% were burned during the 2016 HRF event that led the structural damages. Consequently, we suggest to remove the existing vegetation within these critical zones and also monitor the region at a regular interval in order to reduce the wildland fire-induced risk. PMID- 29762505 TI - Features of Cross-Correlation Analysis in a Data-Driven Approach for Structural Damage Assessment. AB - This work discusses the advantage of using cross-correlation analysis in a data driven approach based on principal component analysis (PCA) and piezodiagnostics to obtain successful diagnosis of events in structural health monitoring (SHM). In this sense, the identification of noisy data and outliers, as well as the management of data cleansing stages can be facilitated through the implementation of a preprocessing stage based on cross-correlation functions. Additionally, this work evidences an improvement in damage detection when the cross-correlation is included as part of the whole damage assessment approach. The proposed methodology is validated by processing data measurements from piezoelectric devices (PZT), which are used in a piezodiagnostics approach based on PCA and baseline modeling. Thus, the influence of cross-correlation analysis used in the preprocessing stage is evaluated for damage detection by means of statistical plots and self-organizing maps. Three laboratory specimens were used as test structures in order to demonstrate the validity of the methodology: (i) a carbon steel pipe section with leak and mass damage types, (ii) an aircraft wing specimen, and (iii) a blade of a commercial aircraft turbine, where damages are specified as mass-added. As the main concluding remark, the suitability of cross correlation features combined with a PCA-based piezodiagnostic approach in order to achieve a more robust damage assessment algorithm is verified for SHM tasks. PMID- 29762503 TI - Comparison of the Incorporation of DHA in Circulatory and Neural Tissue When Provided as Triacylglycerol (TAG), Monoacylglycerol (MAG) or Phospholipids (PL) Provides New Insight into Fatty Acid Bioavailability. AB - Phospholipids (PL) or partial acylglycerols such as sn-1(3)-monoacylglycerol (MAG) are potent dietary carriers of long-chain polyunsaturated fatty acids (LC PUFA) and have been reported to provide superior bioavailability when compared to conventional triacylglycerol (TAG). The main objective of the present study was to compare the incorporation of docosahexaenoic acid (DHA) in plasma, erythrocytes, retina and brain tissues in adult rats when provided as PL (PL-DHA) and MAG (MAG-DHA). Conventional dietary DHA oil containing TAG (TAG-DHA) as well as control chow diet were used to evaluate the potency of the two alternative DHA carriers over a 60-day feeding period. Fatty acid profiles were determined in erythrocytes and plasma lipids at time 0, 7, 14, 28, 35 and 49 days of the experimental period and in retina, cortex, hypothalamus, and hippocampus at 60 days. The assessment of the longitudinal evolution of DHA in erythrocyte and plasma lipids suggest that PL-DHA and MAG-DHA are efficient carriers of dietary DHA when compared to conventional DHA oil (TAG-DHA). Under these experimental conditions, both PL-DHA and MAG-DHA led to higher incorporations of DHA erythrocytes lipids compared to TAG-DHA group. After 60 days of supplementation, statistically significant increase in DHA level incorporated in neural tissues analyzed were observed in the DHA groups compared with the control. The mechanism explaining hypothetically the difference observed in circulatory lipids is discussed. PMID- 29762506 TI - Optimal Resource Allocation for NOMA-TDMA Scheme with alpha-Fairness in Industrial Internet of Things. AB - In this paper, a joint non-orthogonal multiple access and time division multiple access (NOMA-TDMA) scheme is proposed in Industrial Internet of Things (IIoT), which allowed multiple sensors to transmit in the same time-frequency resource block using NOMA. The user scheduling, time slot allocation, and power control are jointly optimized in order to maximize the system alpha -fair utility under transmit power constraint and minimum rate constraint. The optimization problem is nonconvex because of the fractional objective function and the nonconvex constraints. To deal with the original problem, we firstly convert the objective function in the optimization problem into a difference of two convex functions (D.C.) form, and then propose a NOMA-TDMA-DC algorithm to exploit the global optimum. Numerical results show that the NOMA-TDMA scheme significantly outperforms the traditional orthogonal multiple access scheme in terms of both spectral efficiency and user fairness. PMID- 29762507 TI - m-Health: Lessons Learned by m-Experiences. AB - m-Health is an emerging area that is transforming how people take part in the control of their wellness condition. This vision is changing traditional health processes by discharging hospitals from the care of people. Important advantages of continuous monitoring can be reached but, in order to transform this vision into a reality, some factors need to be addressed. m-Health applications should be shared by patients and hospital staff to perform proper supervised health monitoring. Furthermore, the uses of smartphones for health purposes should be transformed to achieve the objectives of this vision. In this work, we analyze the m-Health features and lessons learned by the experiences of systems developed by MAmI Research Lab. We have focused on three main aspects: m-interaction, use of frameworks, and physical activity recognition. For the analysis of the previous aspects, we have developed some approaches to: (1) efficiently manage patient medical records for nursing and healthcare environments by introducing the NFC technology; (2) a framework to monitor vital signs, obesity and overweight levels, rehabilitation and frailty aspects by means of accelerometer enabled smartphones and, finally; (3) a solution to analyze daily gait activity in the elderly, carrying a single inertial wearable close to the first thoracic vertebra. PMID- 29762509 TI - Breathing Pattern Interpretation as an Alternative and Effective Voice Communication Solution. AB - Augmentative and alternative communication (AAC) systems tend to rely on the interpretation of purposeful gestures for interaction. Existing AAC methods could be cumbersome and limit the solutions in terms of versatility. The study aims to interpret breathing patterns (BPs) to converse with the outside world by means of a unidirectional microphone and researches breathing-pattern interpretation (BPI) to encode messages in an interactive manner with minimal training. We present BP processing work with (1) output synthesized machine-spoken words (SMSW) along with single-channel Weiner filtering (WF) for signal de-noising, and (2) k nearest neighbor (k-NN) classification of BPs associated with embedded dynamic time warping (DTW). An approved protocol to collect analogue modulated BP sets belonging to 4 distinct classes with 10 training BPs per class and 5 live BPs per class was implemented with 23 healthy subjects. An 86% accuracy of k-NN classification was obtained with decreasing error rates of 17%, 14%, and 11% for the live classifications of classes 2, 3, and 4, respectively. The results express a systematic reliability of 89% with increased familiarity. The outcomes from the current AAC setup recommend a durable engineering solution directly beneficial to the sufferers. PMID- 29762511 TI - PCPA: A Practical Certificateless Conditional Privacy Preserving Authentication Scheme for Vehicular Ad Hoc Networks. AB - Vehicle ad hoc networks (VANETs) is a promising network scenario for greatly improving traffic efficiency and safety, in which smart vehicles can communicate with other vehicles or roadside units. For the availability of VANETs, it is very important to deal with the security and privacy problems for VANETs. In this paper, based on certificateless cryptography and elliptic curve cryptography, we present a certificateless signature with message recovery (CLS-MR), which we believe are of independent interest. Then, a practical certificateless conditional privacy preserving authentication (PCPA) scheme is proposed by incorporating the proposed CLS-MR scheme. Furthermore, the security analysis shows that PCPA satisfies all security and privacy requirements. The evaluation results indicate that PCPA achieves low computation and communication costs because there is no need to use the bilinear pairing and map-to-point hash operations. Moreover, extensive simulations show that PCPA is feasible and achieves prominent performances in terms of message delay and message loss ratio, and thus is more suitable for the deployment and adoption of VANETs. PMID- 29762510 TI - Three New Cytotoxic Steroidal Alkaloids from Sarcococca hookeriana. AB - Three new steroidal alkaloids with an unusual 3alpha tigloylamide group, named sarchookloides A-C (1-3), were isolated along with four known compounds (4-7) from the roots of Sarcococca hookeriana. Their structures and relative configuration were elucidated on the basis of spectroscopic methods including MS, UV, IR, 1D, and 2D NMR data. The isolated compounds were evaluated for their cytotoxicity against five human cancer cell lines: Hela, A549, MCF-7, SW480, and CEM in vitro. All three amide substituted steroidal alkaloids exhibited significant cytotoxic activities with IC50 values of 1.05-31.83 MUM. PMID- 29762508 TI - DICER1 Syndrome: DICER1 Mutations in Rare Cancers. AB - DICER1 syndrome is a rare genetic disorder that predisposes individuals to multiple cancer types. Through mutations of the gene encoding the endoribonuclease, Dicer, DICER1 syndrome disrupts the biogenesis and processing of miRNAs with subsequent disruption in control of gene expression. Since the first description of DICER1 syndrome, case reports have documented novel germline mutations of the DICER1 gene in patients with cancers as well as second site mutations that alter the function of the Dicer protein expressed. Here, we present a review of mutations in the DICER1 gene, the respective protein sequence changes, and clinical manifestations of DICER1 syndrome. Directions for future research are discussed. PMID- 29762512 TI - Enhanced Photocatalytic Activity toward Organic Pollutants Degradation and Mechanism Insight of Novel CQDs/Bi2O2CO3 Composite. AB - Novel carbon quantum dots (CQDs) modified with Bi2O2CO3 (CQDs/Bi2O2CO3) were prepared using a simple dynamic-adsorption precipitation method. X-ray diffractometry (XRD), transmission electron microscopy (TEM), energy dispersive X ray spectroscopy (EDX), and scanning electron microscopy (SEM) were used to test the material composition, structure, and band structures of the as-prepared samples. Methylene blue (MB) and colorless phenol, as target organic pollutants, were used to evaluate the photocatalytic performance of the CQDs/Bi2O2CO3 hybrid materials under visible light irradiation. Experimental investigation shows that 2-5 nm CQDs were uniformly decorated on the surface of Bi2O2CO3; CQDs/Bi2O2CO3 possess an efficient photocatalytic performance, and the organic matter removal rate of methylene blue and phenol can reach up to 94.45% and 61.46% respectively, within 2 h. In addition, the degradation analysis of phenol by high performance liquid chromatography (HPLC) proved that there are no other impurities in the degradation process. Photoelectrochemical testing proved that the introduction of CQDs (electron acceptor) effectively suppresses the recombination of e--h+, and promotes charge transfer. Quenching experiments and electron spin resonance (ESR) suggested that .OH, h+, and .O2- were involved in the photocatalytic degradation process. These results suggested that the up-conversion function of CQDs could improve the electron transfer and light absorption ability of photocatalysts and .O2- formation. Furthermore, the up-conversion function of CQDs would help maintain photocatalytic stability. Finally, the photocatalytic degradation mechanism was proposed according to the above experimental result. PMID- 29762513 TI - Spatiotemporal Labeling of Melanocytes in Mice. AB - Melanocytes are pigment producing cells in the skin that give rise to cutaneous malignant melanoma, which is a highly aggressive and the deadliest form of skin cancer. Studying melanocytes in vivo is often difficult due to their small proportion in the skin and the lack of specific cell surface markers. Several genetically-engineered mouse models (GEMMs) have been created to specifically label the melanocyte compartment. These models give both spatial and temporal control over the expression of a cellular 'beacon' that has an added benefit of inducible expression that can be activated on demand. Two powerful models that are discussed in this review include the melanocyte-specific, tetracycline inducible green fluorescent protein expression system (iDct-GFP), and the fluorescent ubiquitination-based cell cycle indicator (FUCCI) model that allows for the monitoring of the cell-cycle. These two systems are powerful tools in studying melanocyte and melanoma biology. We discuss their current uses and how they could be employed to help answer unresolved questions in the fields of melanocyte and melanoma biology. PMID- 29762514 TI - Blackcurrant Leaf Chlorosis Associated Virus: Evidence of the Presence of Circular RNA during Infections. AB - Blackcurrant leaf chlorosis associated virus (BCLCaV) was detected recently by next-generation sequencing (NGS) and a new and distinct species in the genus Idaeovirus was proposed. Analysis of NGS-derived paired-end reads revealed the existence of bridge reads encompassing the 3'-terminus and 5'-terminus of RNA-2 or RNA-3 of BCLCaV. The full RNA-2 or RNA-3 could be amplified using outward facing or abutting primers; also, RNA-2/RNA-3 could be detected even after three consecutive RNase R enzyme treatments, with denaturation at 95 degrees C preceding each digestion. Evidence was obtained indicating that there are circular forms of BCLCaV RNA-2 and RNA-3. PMID- 29762515 TI - Iron Status and Gestational Diabetes-A Meta-Analysis. AB - A meta-analysis of the association of iron overload with gestational diabetes mellitus (GDM) may inform the health debate. We performed a meta-analysis investigating the association of iron biomarkers and dietary iron exposure with GDM. We identified 33 eligible studies (N = 44,110) published in 2001-2017. The standardized mean differences (SMD) in women who had GDM compared to pregnant women without were 0.25 ug/dL (95% CI: 0.001-0.50) for iron, 1.54 ng/mL (0.56 2.53) for ferritin, 1.05% (0.02 to 2.08) for transferrin saturation, and 0.81 g/dL (0.40-1.22) for hemoglobin. Adjusted odds ratio for GDM were 1.58 (95% CI: 1.20-2.08) for ferritin, 1.30 (1.01-1.67) for hemoglobin, and 1.48 (1.29-1.69) for dietary heme intake. We did not find any differences in TIBC or transferrin concentration in women with and without GDM. We also did not find any association of increased transferrin receptor or increased intake of total dietary iron, non heme iron or supplemental iron, with increased odds ratios for GDM. Considerable heterogeneity was present among the studies (0-99%), but no evidence of publication bias. Accumulating evidence suggests that circulating and dietary iron biomarkers among pregnant women are associated with GDM, but the results should be interpreted with caution due to the high heterogeneity of analyses. Randomized trials investigating the benefits of iron reduction in women at high risk for GDM are warranted. PMID- 29762518 TI - Performance Analysis of Two-Way Satellite Multi-Terrestrial Relay Networks with Hardware Impairments. AB - In this paper, we investigate the performance of a two-way hybrid satellite multi terrestrial cooperative network with hardware impairments (HIs). Particularly, opportunistic relay selection scheme is employed in the considered network, which can substantially enhance the spectral efficiency and spatial diversity gain. By considering both the amplify-and-forward (AF) and decode-and-forward (DF) relay protocols, the closed-form expressions of the outage probability (OP) and throughput for the system are derived. Furthermore, in order to observe the effects of HIs level and the number of terrestrial relays on the system performance at high signal-to-noise ratios (SNRs), the asymptotic expressions of the system performance are also derived. Finally, computer results are presented to reveal the correctness of the analytical results. PMID- 29762517 TI - The Potential Cost-Effectiveness and Equity Impacts of Restricting Television Advertising of Unhealthy Food and Beverages to Australian Children. AB - Television (TV) advertising of food and beverages high in fat, sugar and salt (HFSS) influences food preferences and consumption. Children from lower socioeconomic position (SEP) have higher exposure to TV advertising due to more time spent watching TV. This paper sought to estimate the cost-effectiveness of legislation to restrict HFSS TV advertising until 9:30 pm, and to examine how health benefits and healthcare cost-savings differ by SEP. Cost-effectiveness modelling was undertaken (i) at the population level, and (ii) by area-level SEP. A multi-state multiple-cohort lifetable model was used to estimate obesity related health outcomes and healthcare cost-savings over the lifetime of the 2010 Australian population. Incremental cost-effectiveness ratios (ICERs) were reported, with assumptions tested through sensitivity analyses. An intervention restricting HFSS TV advertising would cost AUD5.9M (95% UI AUD5.8M-AUD7M), resulting in modelled reductions in energy intake (mean 115 kJ/day) and body mass index (BMI) (mean 0.352 kg/m2). The intervention is likely to be cost-saving, with 1.4 times higher total cost-savings and 1.5 times higher health benefits in the most disadvantaged socioeconomic group (17,512 HALYs saved (95% UI 10,372 25,155); total cost-savings AUD126.3M (95% UI AUD58.7M-196.9M) over the lifetime) compared to the least disadvantaged socioeconomic group (11,321 HALYs saved (95% UI 6812-15,679); total cost-savings AUD90.9M (95% UI AUD44.3M-136.3M)). Legislation to restrict HFSS TV advertising is likely to be cost-effective, with greater health benefits and healthcare cost-savings for children with low SEP. PMID- 29762516 TI - Seasonal Patterns in the Prevalence and Diversity of Tick-Borne Borrelia burgdorferi Sensu Lato, Anaplasma phagocytophilum and Rickettsia spp. in an Urban Temperate Forest in South Western Slovakia. AB - In Europe, Ixodes ricinus is the most important vector of tick-borne zoonotic bacteria. It transmits spirochaetes from the Borrelia burgdorferi sensu lato complex, Anaplasma phagocytophilum and Rickettsia spp. Although spatial differences in the prevalence of tick-borne pathogens have been intensively studied, seasonal (within-year) fluctuations in the prevalence of these pathogens within sites are often overlooked. We analyzed the occurrence and seasonal dynamics of Ixodes ricinus in an urban forest in Bratislava, Slovakia. Furthemore, we examined temporal trends in the community structure of B. burgdorferi s.l., A. phagocytophilum and Rickettsia spp. in questing and bird feeding ticks. The total prevalence for B. burgdorferi s.l. in questing I. ricinus was 6.8%, involving six genospecies with the dominance of bird-associated B. garinii and B. valaisiana.A. phagocytophilum, R. helvetica and R. monacensis occurred in 5.9%, 5.0% and 0.2% of questing ticks, respectively. In total, 12.5% and 4.4% of bird-feeding I. ricinus ticks carried B. burgdorferi s.l. and R. helvetica. The total prevalence of B. burgdorferi s.l. in our study site was two times lower than the mean prevalence for Europe. In contrast, A. phagocytophilum prevalence was significantly higher compared to those in other habitats of Slovakia. Our results imply that tick propagation and the transmission, suppression and seasonal dynamics of tick-borne pathogens at the study site were primarily shaped by abundance and temporal population fluctuations in ruminant and bird hosts. PMID- 29762519 TI - An Effective Palmprint Recognition Approach for Visible and Multispectral Sensor Images. AB - Among several palmprint feature extraction methods the HOG-based method is attractive and performs well against changes in illumination and shadowing of palmprint images. However, it still lacks the robustness to extract the palmprint features at different rotation angles. To solve this problem, this paper presents a hybrid feature extraction method, named HOG-SGF that combines the histogram of oriented gradients (HOG) with a steerable Gaussian filter (SGF) to develop an effective palmprint recognition approach. The approach starts by processing all palmprint images by David Zhang's method to segment only the region of interests. Next, we extracted palmprint features based on the hybrid HOG-SGF feature extraction method. Then, an optimized auto-encoder (AE) was utilized to reduce the dimensionality of the extracted features. Finally, a fast and robust regularized extreme learning machine (RELM) was applied for the classification task. In the evaluation phase of the proposed approach, a number of experiments were conducted on three publicly available palmprint databases, namely MS-PolyU of multispectral palmprint images and CASIA and Tongji of contactless palmprint images. Experimentally, the results reveal that the proposed approach outperforms the existing state-of-the-art approaches even when a small number of training samples are used. PMID- 29762520 TI - Condom and Substance Use at Last Sex: Differences between MSMO and MSWO High School Youth. AB - HIV disproportionately impacts youth, particularly young men who have sex with men (YMSM), a population that includes subgroups of young men who have sex with men only (YMSMO) and young men who have sex with men and women (YMSMW). In 2015, among male youth, 92% of new HIV diagnoses were among YMSM. The reasons why YMSM are disproportionately at risk for HIV acquisition, however, remain incompletely explored. We performed event-level analyses to compare how the frequency of condom use, drug and/or alcohol use at last sex differed among YMSMO and YMSWO (young men who have sex with women only) over a ten-year period from 2005-2015 within the Youth Risk Behavior Survey (YRBS). YMSMO were less likely to use condoms at last sex compared to YMSWO. However, no substance use differences at last sexual encounter were detected. From 2005-2015, reported condom use at last sex significantly declined for both YMSMO and YMSWO, though the decline for YMSMO was more notable. While there were no significant differences in alcohol and substance use at last sex over the same ten-year period for YMSMO, YMSWO experienced a slight but significant decrease in reported alcohol and substance use. These event-level analyses provide evidence that YMSMO, similar to adult MSMO, may engage in riskier sexual behaviors compared to YMSWO, findings which may partially explain the increased burden of HIV in this population. Future work should investigate how different patterns of event-level HIV risk behaviors vary over time among YMSMO, YMSWO, and YMSMW, and are tied to HIV incidence among these groups. PMID- 29762521 TI - Structure of the Exopolysaccharide Secreted by a Marine Strain Vibrio alginolyticus. AB - Vibrio alginolyticus (CNCM I-4151) secretes an exopolysaccharide whose carbohydrate backbone is decorated with amino acids, likely conferring its properties that are appreciated in cosmetics. Here, the secreted polysaccharide of another strain of V. alginolyticus (CNCM I-5034) was characterized by chromatography and one- and two-dimensional NMR spectroscopy experiments. The structure was resolved and shows that the carbohydrate backbone is made of four residues: D-galactose (Gal), D-galacturonic acid (GalA) D-N-acetylglucosamine (GlcNAc) and D-glucuronic acid (GlcA), forming a tetrasaccharide repetition unit [->4)-beta-d-GlcA-(1->3)-alpha-d-Gal-(1->3)-alpha-d-GalA-(1->3)-beta-GlcNAc(1->]. GlcA is derivatized with a lactate group giving 'nosturonic acid', and GalA is decorated with the amino acid alanine. PMID- 29762524 TI - Comparative Physicochemical and Electrochemical Characterization of the Structure and Composition of Thin Pd Binary and Ternary Codeposits with Pt, Ru, and Rh. AB - Pd-Ru, Pd-Rh, Pd-Pt-Ru, and Pd-Rh-Ru electrodes were prepared as thin layers by potentiostatic codeposition or chemical co-precipitation of metals from baths containing mixtures of chloride salts. The formation of substitutional solid solutions, with lattice parameters smaller than that of pure Pd, was confirmed by X-ray diffraction (XRD). The compositions at various levels of sample volume and thickness were analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES), energy-dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), Auger electron spectroscopy (AES), and also electrochemically by cyclic voltammetry (CV) in 0.5 M H2SO4. The differences between surface, subsurface, and bulk compositions were compared for various systems in a wide composition spectrum. PMID- 29762525 TI - Electronic, Magnetic, Half-Metallic, and Mechanical Properties of a New Equiatomic Quaternary Heusler Compound YRhTiGe: A First-Principles Study. AB - We apply First-principles theory to study the electronic structure as well as the magnetic and mechanical characteristics of YRhTiGe, a newly-designed Y-based quaternary equiatomic Heusler compound. This compound is half-metallic in nature with a ferromagnetic ground state. The total magnetic moment of YRhTiGe is 2 MUB and it obeys the Slater-Pauling rule, Mt = Zt - 18, where Mt and Zt are the total magnetic moment and total number of valence electrons, respectively. The magnetic and half-metallic behaviors at its equilibrium and strained lattice constants have been discussed in detail. In addition, for FM-type YRhTiGe, its polycrystalline mechanical features such as Poisson's ratio, Lame constants, Kleinman parameter and hardness, are also computed according to the well-known Voigt-Reuss-Hill approximation. We investigate the mechanical anisotropy of YRhTiGe using the directional dependences of the Young's modulus and the shear modulus. Finally, we prove this compound is structurally and mechanically stable. This theoretical investigation provides further insight into the application of Y based compounds as spintronic materials. PMID- 29762522 TI - Dietary Pattern and Plasma BCAA-Variations in Healthy Men and Women-Results from the KarMeN Study. AB - Branched-chain amino acids (BCAA) in plasma are discussed as risk factors for the onset of several diseases. Information about the contribution of the overall diet to plasma BCAA concentrations is controversial. Our objective was to investigate which dietary pattern is associated with plasma BCAA concentrations and whether other additional nutrients besides BCAA further characterize this dietary pattern. Based on the cross-sectional KarMeN study, fasting plasma amino acid (AA) concentrations, as well as current and habitual dietary intake were assessed in 298 healthy individuals. Using reduced rank regression, we derived a habitual dietary pattern that explained 32.5% of plasma BCAA variation. This pattern was high in meat, sausages, sauces, eggs, and ice cream but low in nuts, cereals, mushrooms, and pulses. The age, sex, and energy intake adjusted dietary pattern score was associated with an increase in animal-based protein together with a decrease in plant-based protein, dietary fiber, and an unfavorable fatty acid composition. Besides BCAA, alanine, lysine and the aromatic AA were positively associated with the dietary pattern score as well. All of these factors were reported to be associated with risk of type 2 diabetes and cardiovascular diseases before. Our data suggest that rather than the dietary intake of BCAA, the overall dietary pattern that contributes to high BCAA plasma concentrations may modulate chronic diseases risk. PMID- 29762523 TI - Silver Nanoparticles: Two-Faced Neuronal Differentiation-Inducing Material in Neuroblastoma (SH-SY5Y) Cells. AB - We have previously demonstrated the potential of biologically synthesized silver nanoparticles (AgNP) in the induction of neuronal differentiation of human neuroblastoma, SH-SY5Y cells; we aimed herein to unveil its molecular mechanism in comparison to the well-known neuronal differentiation-inducing agent, all trans-retinoic acid (RA). AgNP-treated SH-SY5Y cells showed significantly higher reactive oxygen species (ROS) generation, stronger mitochondrial membrane depolarization, lower dual-specificity phosphatase expression, higher extracellular-signal-regulated kinase (ERK) phosphorylation, lower AKT phosphorylation, and lower expression of the genes encoding the antioxidant enzymes than RA-treated cells. Notably, pretreatment with N-acetyl-l-cysteine significantly abolished AgNP-induced neuronal differentiation, but not in that induced by RA. ERK inhibition, but not AKT inhibition, suppresses neurite growth that is induced by AgNP. Taken together, our results uncover the pivotal contribution of ROS in the AgNP-induced neuronal differentiation mechanism, which is different from that of RA. However, the negative consequence of AgNP-induced neurite growth may be high ROS generation and the downregulation of the expression of the genes encoding the antioxidant enzymes, which prompts the future consideration and an in-depth study of the application of AgNP differentiated cells in neurodegenerative disease therapy. PMID- 29762527 TI - Self-Assembled Ag-Cu2O Nanocomposite Films at Air-Liquid Interfaces for Surface Enhanced Raman Scattering and Electrochemical Detection of H2O2. AB - We employ a facile and novel route to synthesize multifunctional Ag-Cu2O nanocomposite films through the self-assembly of nanoparticles at an air-liquid interface. In the ethanol-water phase, AgNO3 and Cu(NO3)2 were reduced to Ag-Cu2O nanoparticles by NaBH4 in the presence of cinnamic acid. The Ag-Cu2O nanoparticles were immediately trapped at the air-liquid interface to form two dimensional nanocomposite films after the reduction reaction was finished. The morphology of the nanocomposite films could be controlled by the systematic regulation of experimental parameters. It was found that the prepared nanocomposite films serving as the substrates exhibited strong surface-enhanced Raman scattering (SERS) activity. 4-aminothiophenol (4-ATP) molecules were used as the test probes to examine the SERS sensitivity of the nanocomposite films. Moreover, the nanocomposite films synthesized by our method showed enhanced electrocatalytic activity towards hydrogen peroxide (H2O2) and therefore could be utilized to fabricate a non-enzymatic electrochemical H2O2 sensor. PMID- 29762528 TI - Performance-Enhanced Activated Carbon Electrodes for Supercapacitors Combining Both Graphene-Modified Current Collectors and Graphene Conductive Additive. AB - Graphene has been widely used in the active material, conductive agent, binder or current collector for supercapacitors, due to its large specific surface area, high conductivity, and electron mobility. However, works simultaneously employing graphene as conductive agent and current collector were rarely reported. Here, we report improved activated carbon (AC) electrodes (AC@G@NiF/G) simultaneously combining chemical vapor deposition (CVD) graphene-modified nickel foams (NiF/Gs) current collectors and high quality few-layer graphene conductive additive instead of carbon black (CB). The synergistic effect of NiF/Gs and graphene additive makes the performances of AC@G@NiF/G electrodes superior to those of electrodes with CB or with nickel foam current collectors. The performances of AC@G@NiF/G electrodes show that for the few-layer graphene addition exists an optimum value around 5 wt %, rather than a larger addition of graphene, works out better. A symmetric supercapacitor assembled by AC@G@NiF/G electrodes exhibits excellent cycling stability. We attribute improved performances to graphene enhanced conductivity of electrode materials and NiF/Gs with 3D graphene conductive network and lower oxidation, largely improving the electrical contact between active materials and current collectors. PMID- 29762529 TI - Combined Analysis of the Fruit Metabolome and Transcriptome Reveals Candidate Genes Involved in Flavonoid Biosynthesis in Actinidia arguta. AB - To assess the interrelation between the change of metabolites and the change of fruit color, we performed a combined metabolome and transcriptome analysis of the flesh in two different Actinidia arguta cultivars: "HB" ("Hongbaoshixing") and "YF" ("Yongfengyihao") at two different fruit developmental stages: 70d (days after full bloom) and 100d (days after full bloom). Metabolite and transcript profiling was obtained by ultra-performance liquid chromatography quadrupole time of-flight tandem mass spectrometer and high-throughput RNA sequencing, respectively. The identification and quantification results of metabolites showed that a total of 28,837 metabolites had been obtained, of which 13,715 were annotated. In comparison of HB100 vs. HB70, 41 metabolites were identified as being flavonoids, 7 of which, with significant difference, were identified as bracteatin, luteolin, dihydromyricetin, cyanidin, pelargonidin, delphinidin and ( )-epigallocatechin. Association analysis between metabolome and transcriptome revealed that there were two metabolic pathways presenting significant differences during fruit development, one of which was flavonoid biosynthesis, in which 14 structural genes were selected to conduct expression analysis, as well as 5 transcription factor genes obtained by transcriptome analysis. RT-qPCR results and cluster analysis revealed that AaF3H, AaLDOX, AaUFGT, AaMYB, AabHLH, and AaHB2 showed the best possibility of being candidate genes. A regulatory network of flavonoid biosynthesis was established to illustrate differentially expressed candidate genes involved in accumulation of metabolites with significant differences, inducing red coloring during fruit development. Such a regulatory network linking genes and flavonoids revealed a system involved in the pigmentation of all-red-fleshed and all-green-fleshed A. arguta, suggesting this conjunct analysis approach is not only useful in understanding the relationship between genotype and phenotype, but is also a powerful tool for providing more valuable information for breeding. PMID- 29762530 TI - Broadband Circularly Polarized Slot Antenna Loaded by a Multiple-Circular-Sector Patch. AB - In this paper, a microstrip-fed broadband circularly polarized (CP) slot antenna is presented. CP operation can be attained simply by embedding an S-shaped strip. By loading with a multiple-circular-sector patch, which consists of 12 circular sector patches with identical central angles of 30 degrees and different radii, the 3 dB axial ratio (AR) bandwidth is significantly broadened. To validate the performance of the proposed antenna, an antenna prototype is fabricated and tested. The fabricated antenna is 54 mm * 54 mm * 0.8 mm in size. The measured 10 dB reflection and 3 dB AR bandwidths are 81.06% (1.68-3.97 GHz) and 70.55% (1.89-3.95 GHz), respectively. Within the 3 dB AR bandwidth, the measured peak gain is 3.81 dBic. Reasonable agreement is also obtained between the measured and simulated results. PMID- 29762526 TI - Hypoxia, Metabolism and Immune Cell Function. AB - Hypoxia is a hallmark of inflamed, infected or damaged tissue, and the adaptation to inadequate tissue oxygenation is regulated by hypoxia-inducible factors (HIFs). HIFs are key mediators of the cellular response to hypoxia, but they are also associated with pathological stress such as inflammation, bacteriological infection or cancer. In addition, HIFs are central regulators of many innate and adaptive immunological functions, including migration, antigen presentation, production of cytokines and antimicrobial peptides, phagocytosis as well as cellular metabolic reprogramming. A characteristic feature of immune cells is their ability to infiltrate and operate in tissues with low level of nutrients and oxygen. The objective of this article is to discuss the role of HIFs in the function of innate and adaptive immune cells in hypoxia, with a focus on how hypoxia modulates immunometabolism. PMID- 29762531 TI - Synthesis, Spectroscopic, and Biological Studies of Mixed Ligand Complexes of Gemifloxacin and Glycine with Zn(II), Sn(II), and Ce(III). AB - Three novel mixed ligand metal complexes have been synthesized by the reaction of Zn(II), Sn(II), and Ce(III) with gemifloxacin (GMFX) in the presence of glycine (Gly) (1:1:1 molar ratio). The coordination possibility of the two ligands toward metal ions has been proposed in the light of elemental analysis, molar conductance, spectral infrared (IR), ultraviolet-visible (UV-Vis) and proton nuclear magnetic resonance (1H NMR), and magnetic studies. Results suggest that GMFX and Gly interact with the metal ions as bidentate ligands. Electronic and magnetic data proposed the octahedral structure for all complexes under investigation. Antibacterial screening of the compounds was carried out in vitro against two Gram-positive bacteria, Clavibacter michiganensis and Bacillus megaterium, and two Gram-negative bacteria, Escherichia coli and Xanthomonas campestris. Antifungal activity was performed in vitro against Rhizoctonia solani, Sclerotinia sclerotiorum, Aspergillus niger, Botrytis cinerea, and Penicillium digitatum. The ligands and their complexes were also screened for their antioxidant activity. Results showed that some metal complexes showed more biological efficiency than the parent GMFX drug. PMID- 29762533 TI - Self-Healing Capacity of Asphalt Mixtures Including By-Products Both as Aggregates and Heating Inductors. AB - Major advances have been achieved in the field of self-healing by magnetic induction in which the addition of metallic particles into asphalt mixtures enables repairing their own cracks. This technology has already been proven to increase the life expectancy of roads. Nevertheless, its higher costs in comparison with conventional maintenance caused by the price of virgin metallic particles still makes it unattractive for investment. This research aimed at making this process economically accessible as well as environmentally efficient. To this end, an intense search for suitable industrial by-products to substitute both the virgin metal particles and the natural aggregates forming asphalt mixtures was conducted. The set of by-products used included sand blasting wastes, stainless shot wastes, and polished wastes as metallic particles and other inert by-products as aggregates. The results demonstrated that the by products were adequately heated, which leads to satisfactory healing ratios in comparison with the reference mixture. PMID- 29762532 TI - Pregnancy Trimester-Specific Exposure to Ambient Air Pollution and Child Respiratory Health Outcomes in the First 2 Years of Life: Effect Modification by Maternal Pre-Pregnancy BMI. AB - Prenatal exposure to air pollution is associated with childhood respiratory health; however, no previous studies have examined maternal pre-pregnancy body mass index (BMI) as a potential effect modifier. We investigated whether maternal pre-pregnancy BMI modified the association of trimester-specific air pollution divided into quartiles of exposure (Q1-4) on respiratory health in the Growing Up in Singapore towards healthy Outcomes (GUSTO) study (n = 953) in 2-year-old children. For episodes of wheezing, children of overweight/obese mothers and who were exposed to particulate matter less than 2.5 MUm (PM2.5) in the first trimester had an adjusted incidence rate ratio (IRR) (95% confidence interval (CI)) of 1.85 (1.23-2.78), 1.76 (1.08-2.85) and 1.90 (1.10-3.27) in quartile (Q) 2-4, with reference to Q1. This association is seen in the second trimester for bronchiolitis/bronchitis. The risk of ear infection in the first year of life was associated with exposure to PM2.5 in the first trimester with adjusted Odds Ratio (adjOR) (95% CI) = 7.64 (1.18-49.37), 11.37 (1.47-87.97) and 8.26 (1.13-60.29) for Q2-4, and similarly in the second year with adjOR (95% CI) = 3.28 (1.00 10.73) and 4.15 (1.05-16.36) for Q2-3. Prenatal exposure to air pollution has an enhanced impact on childhood respiratory health, and differs according to maternal pre-pregnancy BMI. PMID- 29762534 TI - Tetrel Bonds with pi-Electrons Acting as Lewis Bases-Theoretical Results and Experimental Evidences. AB - MP2/aug-cc-pVTZ calculations were carried out for the ZFH3-B complexes (Z = C, Si, Ge, Sn and Pb; B = C2H2, C2H4, C6H6 and C5H5-; relativistic effects were taken into account for Ge, Sn and Pb elements). These calculations are supported by other approaches; the decomposition of the energy of interaction, Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbital (NBO) method. The results show that tetrel bonds with pi-electrons as Lewis bases are classified as Z...C links between single centers (C is an atom of the pi-electron system) or as Z...pi interactions where F-Z bond is directed to the mid-point (or nearly so) of the CC bond of the Lewis base. The analogous systems with Z...C/pi interactions were found in the Cambridge Structural Database (CSD). It was found that the strength of interaction increases with the increase of the atomic number of the tetrel element and that for heavier tetrel elements the ZFH3 tetrahedral structure is more deformed towards the structure with the planar ZH3 fragment. The results of calculations show that the tetrel bond is sometimes accompanied by the Z-H...C hydrogen bond or even sometimes the ZFH3-B complexes are linked only by the hydrogen bond interaction. PMID- 29762535 TI - Leveraging Energy Harvesting and Wake-Up Receivers for Long-Term Wireless Sensor Networks. AB - Wireless sensor nodes are traditionally powered by individual batteries, and a significant effort has been devoted to maximizing the lifetime of these devices. However, as the batteries can only store a finite amount of energy, the network is still doomed to die, and changing the batteries is not always possible. A promising solution is to enable each node to harvest energy directly in its environment, using individual energy harvesters. Moreover, novel ultra-low power wake-up receivers, which allow continuous listening of the channel with negligible power consumption, are emerging. These devices enable asynchronous communication, further reducing the power consumption related to communication, which is typically one the most energy-consuming tasks in wireless sensor networks. Energy harvesting and wake-up receivers can be combined to significantly increase the energy efficiency of sensor networks. In this paper, we propose an energy manager for energy harvesting wireless sensor nodes and an asynchronous medium access control protocol, which exploits ultra-low power wake up receivers. The two components are designed to work together and especially to fit the stringent constraints of wireless sensor nodes. The proposed approach has been implemented on a real hardware platform and tested in the field. Experimental results demonstrate the benefits of the proposed approach in terms of energy efficiency, power consumption and throughput, which can be up to more than two-times higher compared to traditional schemes. PMID- 29762537 TI - The Cardioprotective Effect of Metformin in Doxorubicin-Induced Cardiotoxicity: The Role of Autophagy. AB - The molecular mechanisms underlying doxorubicin-induced cardiotoxicity are still being investigated, but are known to involve oxidative stress, mitochondrial dysfunction, and the dysregulation of autophagy. The objective of the current study was to examine the protective role of metformin and its effect on autophagy in doxorubicin-induced cardiotoxicity. Sprague-Dawley rats were divided into four groups at random. The doxorubicin-treated group received doxorubicin (3 mg/kg every second day) intraperitoneally. The metformin-treated group received 250 mg/kg/day metformin via gavage. The doxorubicin + metformin-treated group received both at the above-mentioned doses. The control group received vehicle only. Following the two-week treatment, the hearts were isolated, and cardiac functions were registered. Serum levels of lactate dehydrogenase (LDH), creatine kinase iso-enzyme MB (CK-MB) enzyme, Troponin T, and cardiac malondialdehyde (MDA) were also measured. Heart tissue samples were histopathologically examined by using Masson's trichrome staining and Western blot analysis was conducted for evaluating the expression level of AMP-activated protein kinase (AMPK) and autophagy-associated proteins beclin-1, LC3B-II, and p62, respectively. The results revealed that treatment with metformin conferred increased cardiac protection against the development of cardiotoxicity manifested by a significant decrease in serum Troponin T and cardiac MDA levels, and remarkable improvement in heart function in connection with histopathological features. Furthermore, by focusing on the contribution of autophagic proteins, it was found that metformin normalised autophagy, which may help cardiomyocytes survive doxorubicin-induced toxicity. These results promote the use of metformin, which would be a preferable drug for patients receiving doxorubicin. PMID- 29762536 TI - Proteomics of Human Retinal Pigment Epithelium (RPE) Cells. AB - Retinal pigment epithelium (RPE) are specialized, multifunctional cells in the retina that form a monolayer of cuboidal, polarized cells adjoining the photoreceptor cells. The RPE are a critical component of the blood-retinal barrier, and they play essential functional roles for maintenance of retinal homeostasis and for support and health of photoreceptors. Age-dependent, progressive dysfunction and death of RPE cells and the resultant loss of photoreceptors contribute significantly to the development and progression of age related macular degeneration (AMD) and other retinal degenerative diseases. Several different RPE cell culture models have been developed and utilized extensively as surrogates for cellular and molecular examinations of the RPE, and a large body of knowledge on RPE function in normal and pathological scenarios has been amassed in studies with cultured RPE. Proteomics has been an integral part of research efforts aimed to advance our understanding of RPE cell biology in health and disease. This review focuses on applications of proteomics to in vitro qualitative and quantitative investigation of human RPE cell culture models. The disease context discussed focuses on AMD. PMID- 29762539 TI - Study on the Polar Extracts of Dendrobium nobile, D. officinale, D. loddigesii, and Flickingeria fimbriata: Metabolite Identification, Content Evaluation, and Bioactivity Assay. AB - The polar extract of the Dendrobium species or F. fimbriata (a substitute of Dendrobium), between the fat-soluble extract and polysaccharide has barely been researched. This report worked on the qualitative and quantitative studies of polar extracts from D. nobile, D. officinale, D. loddigesii, and F. fimbriata. Eight water-soluble metabolites containing a new diglucoside, flifimdioside A (1), and a rare imidazolium-type alkaloid, anosmine (4), were identified using chromatography as well as spectroscopic techniques. Their contents in the four herbs were high, approximately 0.9-3.7 mg/g based on the analysis of quantitative nuclear magnetic resonance (qNMR) spectroscopy. Biological activity evaluation showed that the polar extract of F. fimbriata or its pure component had good antioxidant and neuroprotective activity; compounds 1-4 and shihunine (8) showed weak alpha-glucosidase inhibitory activity; 4 and 8 had weak anti-inflammatory activity. Under trial conditions, all samples had no cytotoxic activity. PMID- 29762538 TI - Insufficient Sleep Duration and Overweight/Obesity among Adolescents in a Chinese Population. AB - OBJECTIVES: The objective of this study was to investigate the relationship between sleep duration and overweight/obesity among Chinese adolescents. METHODS: A school-based cross-sectional study was conducted among Chinese adolescents in 2016. In total, 2795 school-aged Chinese children aged 12 to 13 years participated in this study. Participants were asked to complete self-administered surveys during a 45-min class period in their classroom. Details of the questionnaire about health-related behaviors included sleep habits, physical activity, screen time, cigarette use, and alcohol use. Height, weight, waist circumference and hip circumference were directly measured. RESULTS: The mean sleep duration was 8.7 h/day. In total, 43.0% of the participants had a sleep duration of less than 9 h/day. Sleep duration was significantly inversely related to BMI, waist circumference, hip circumference and WHtR in multiple linear regression analyses in both genders. Logistic regression models showed that insufficient sleep (<9 h/day) was associated with high odds of overweight/obesity among both young boys and girls. CONCLUSIONS: Insufficient sleep duration was associated with overweight/obesity in Chinese adolescents, and short sleep duration was probably associated with central adiposity, especially among boys. PMID- 29762542 TI - Correction: Vitetta, L.; et al. Adjuvant Probiotics and the Intestinal Microbiome: Enhancing Vaccines and Immunotherapy Outcomes. Vaccines 2017, 5, 50. AB - The authors wish to make the following corrections to this paper due to a typesetting error in the conclusion of this article which was recently published in Vaccines. PMID- 29762541 TI - Biomechanical Gait Variable Estimation Using Wearable Sensors after Unilateral Total Knee Arthroplasty. AB - Total knee arthroplasty is a common surgical treatment for end-stage osteoarthritis of the knee. The majority of existing studies that have explored the relationship between recovery and gait biomechanics have been conducted in laboratory settings. However, seamless gait parameter monitoring in real-world conditions may provide a better understanding of recovery post-surgery. The purpose of this study was to estimate kinematic and kinetic gait variables using two ankle-worn wearable sensors in individuals after unilateral total knee arthroplasty. Eighteen subjects at least six months post-unilateral total knee arthroplasty participated in this study. Four biomechanical gait variables were measured using an instrumented split-belt treadmill and motion capture systems. Concurrently, eleven inertial gait variables were extracted from two ankle-worn accelerometers. Subsets of the inertial gait variables for each biomechanical gait variable estimation were statistically selected. Then, hierarchical regressions were created to determine the directional contributions of the inertial gait variables for biomechanical gait variable estimations. Selected inertial gait variables significantly predicted trial-averaged biomechanical gait variables. Moreover, strong directionally-aligned relationships were observed. Wearable-based gait monitoring of multiple and sequential kinetic gait variables in daily life could provide a more accurate understanding of the relationships between movement patterns and recovery from total knee arthroplasty. PMID- 29762540 TI - The Role of Peroxisome Proliferator-Activated Receptors and Their Transcriptional Coactivators Gene Variations in Human Trainability: A Systematic Review. AB - BACKGROUND: The peroxisome proliferator-activated receptors (PPARA, PPARG, PPARD) and their transcriptional coactivators' (PPARGC1A, PPARGC1B) gene polymorphisms have been associated with muscle morphology, oxygen uptake, power output and endurance performance. The purpose of this review is to determine whether the PPARs and/or their coactivators' polymorphisms can predict the training response to specific training stimuli. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses, a literature review has been run for a combination of PPARs and physical activity key words. RESULTS: All ten of the included studies were performed using aerobic training in general, sedentary or elderly populations from 21 to 75 years of age. The non-responders for aerobic training (VO2peak increase, slow muscle fiber increase and low-density lipoprotein decrease) are the carriers of PPARGC1A rs8192678 Ser/Ser. The negative responders for aerobic training (decrease in VO2peak) are carriers of the PPARD rs2267668 G allele. The negative responders for aerobic training (decreased glucose tolerance and insulin response) are subjects with the PPARG rs1801282 Pro/Pro genotype. The best responders to aerobic training are PPARGC1A rs8192678 Gly/Gly, PPARD rs1053049 TT, PPARD rs2267668 AA and PPARG rs1801282 Ala carriers. CONCLUSIONS: The human response for aerobic training is significantly influenced by PPARs' gene polymorphism and their coactivators, where aerobic training can negatively influence glucose metabolism and VO2peak in some genetically-predisposed individuals. PMID- 29762543 TI - High-Efficiency Visible Transmitting Polarizations Devices Based on the GaN Metasurface. AB - Metasurfaces are capable of tailoring the amplitude, phase, and polarization of incident light to design various polarization devices. Here, we propose a metasurface based on the novel dielectric material gallium nitride (GaN) to realize high-efficiency modulation for both of the orthogonal linear polarizations simultaneously in the visible range. Both modulated transmitted phases of the orthogonal linear polarizations can almost span the whole 2pi range by tailoring geometric sizes of the GaN nanobricks, while maintaining high values of transmission (almost all over 90%). At the wavelength of 530 nm, we designed and realized the beam splitter and the focusing lenses successfully. To further prove that our proposed method is suitable for arbitrary orthogonal linear polarization, we also designed a three-dimensional (3D) metalens that can simultaneously focus the X-, Y-, 45 degrees , and 135 degrees linear polarizations on spatially symmetric positions, which can be applied to the linear polarization measurement. Our work provides a possible method to achieve high-efficiency multifunctional optical devices in visible light by extending the modulating dimensions. PMID- 29762544 TI - Femtosecond Laser Texturing of Surfaces for Tribological Applications. AB - Laser texturing is an emerging technology for generating surface functionalities on basis of optical, mechanical, or chemical properties. Taking benefit of laser sources with ultrashort (fs) pulse durations features outstanding precision of machining and negligible rims or burrs surrounding the laser-irradiation zone. Consequently, additional mechanical or chemical post-processing steps are usually not required for fs-laser surface texturing (fs-LST). This work aimed to provide a bridge between research in the field of tribology and laser materials processing. The paper reviews the current state-of-the-art in fs-LST, with a focus on the tribological performance (friction and wear) of specific self organized surface structures (so-called ripples, grooves, and spikes) on steel and titanium alloys. On the titanium alloy, specific sickle-shaped hybrid micro nanostructures were also observed and tribologically tested. Care is taken to identify accompanying effects affecting the materials hardness, superficial oxidation, nano- and microscale topographies, and the role of additives contained in lubricants, such as commercial engine oil. PMID- 29762545 TI - Marine Microalgae with Anti-Cancer Properties. AB - Cancer is the leading cause of death globally and finding new therapeutic agents for cancer treatment remains a major challenge in the pursuit for a cure. This paper presents an overview on microalgae with anti-cancer activities. Microalgae are eukaryotic unicellular plants that contribute up to 40% of global primary productivity. They are excellent sources of pigments, lipids, carotenoids, omega 3 fatty acids, polysaccharides, vitamins and other fine chemicals, and there is an increasing demand for their use as nutraceuticals and food supplements. Some microalgae are also reported as having anti-cancer activity. In this review, we report the microalgal species that have shown anti-cancer properties, the cancer cell lines affected by algae and the concentrations of compounds/extracts tested to induce arrest of cell growth. We also report the mediums used for growing microalgae that showed anti-cancer activity and compare the bioactivity of these microalgae with marine anticancer drugs already on the market and in phase III clinical trials. Finally, we discuss why some microalgae can be promising sources of anti-cancer compounds for future development. PMID- 29762546 TI - Transcriptome Analysis in Chinese Cabbage (Brassica rapa ssp. pekinensis) Provides the Role of Glucosinolate Metabolism in Response to Drought Stress. AB - Although drought stress is one of the most limiting factors in growth and production of Chinese cabbage (Brassica rapa L. ssp. pekinensis), the underlying biochemical and molecular causes are poorly understood. In the present study, to address the mechanisms underlying the drought responses, we analyzed the transcriptome profile of Chinese cabbage grown under drought conditions. Drought stress transcriptionally activated several transcription factor genes, including AP2/ERFs, bHLHs, NACs and bZIPs, and was found to possibly result in transcriptional variation in genes involved in organic substance metabolic processes. In addition, comparative expression analysis of selected BrbZIPs under different stress conditions suggested that drought-induced BrbZIPs are important for improving drought tolerance. Further, drought stress in Chinese cabbage caused differential acclimation responses in glucosinolate metabolism in leaves and roots. Analysis of stomatal aperture indicated that drought-induced accumulation of glucosinolates in leaves directly or indirectly controlled stomatal closure to prevent water loss, suggesting that organ-specific responses are essential for plant survival under drought stress condition. Taken together, our results provide information important for further studies on molecular mechanisms of drought tolerance in Chinese cabbage. PMID- 29762548 TI - Host-Guest Interactions of Plumbagin with beta-Cyclodextrin, Dimethyl-beta Cyclodextrin and Hydroxypropyl-beta-Cyclodextrin: Semi-Empirical Quantum Mechanical PM6 and PM7 Methods. AB - Molecular interactions of plumbagin inclusion complexes with beta-cyclodextrin (BCD), dimethyl--cyclodextrin (MBCD), and hydroxypropyl-beta-cyclodextrin (HPBCD) were investigated by semi-empirical, Parameterization Method 6 and 7 (PM6, and PM7) in the aqueous phase using polarizable continuum calculations. The results revealed two different binding modes of the plumbagin molecule inside the BCD cavity with a negative value of the complexation energy. In conformation-I, the hydroxyl phenolic group of plumbagin was placed in the BCD cavity near the narrow side of the host molecule. In the other model, conformation-II, the methyl quinone group of plumbagin was placed in the cavity of BCD near the narrow-side of the host molecule. The higher the negative value of the complexation energy, the more favorable is the pathway of inclusion-complex formation. PMID- 29762549 TI - Frameless Stereotaxis for Subthalamic Nucleus Deep Brain Stimulation: An Innovative Method for the Direct Visualization of Electrode Implantation by Intraoperative X-ray Control. AB - The recent introduction of frameless devices has enabled stereotactic neurosurgery to reach a level of accuracy that is comparable to traditional frame based methodologies. Among frameless devices, the Nexframe appears to be very useful in implanting electrodes into the subthalamic nucleus or other structures for deep brain stimulation in Parkinson's disease. However, frameless devices, including the Nexframe, limit the possibility of intraoperative visual control of the placement of electrodes in the brain. Utilizing intraoperative O-arm Computed tomography (CT) scan or high-field Magnetic Resonance Imaging (MRI) could overcome this limitation, but their high cost restricts their use. Thus, in this paper we propose an innovation in Nexframe surgical planning that allows the intraoperative use of a C-arm X-ray apparatus to establish: (1) the progression of the electrode guide tube and the electrode in the brain; (2) the accuracy of the electrode trajectory; and (3) the correct attainment of the target. The proposed frameless technique using the Nexframe has been developed and successfully applied in our practice. It was shown to be helpful in overcoming the major issues that are usually encountered when electrodes are placed in the brain with frameless neurosurgery and reduced the risk of having to re-operate on patients to reposition the electrodes. PMID- 29762550 TI - HYSOGs250m, global gridded hydrologic soil groups for curve-number-based runoff modeling. AB - Hydrologic soil groups (HSGs) are a fundamental component of the USDA curve number (CN) method for estimation of rainfall runoff; yet these data are not readily available in a format or spatial-resolution suitable for regional- and global-scale modeling applications. We developed a globally consistent, gridded dataset defining HSGs from soil texture, bedrock depth, and groundwater. The resulting data product-HYSOGs250m-represents runoff potential at 250 m spatial resolution. Our analysis indicates that the global distribution of soil is dominated by moderately high runoff potential, followed by moderately low, high, and low runoff potential. Low runoff potential, sandy soils are found primarily in parts of the Sahara and Arabian Deserts. High runoff potential soils occur predominantly within tropical and sub-tropical regions. No clear pattern could be discerned for moderately low runoff potential soils, as they occur in arid and humid environments and at both high and low elevations. Potential applications of this data include CN-based runoff modeling, flood risk assessment, and as a covariate for biogeographical analysis of vegetation distributions. PMID- 29762551 TI - A pair of datasets for microRNA expression profiling to examine the use of careful study design for assigning arrays to samples. AB - We set out to demonstrate the logistic feasibility of careful experimental design for microarray studies and its level of scientific benefits for improving the accuracy and reproducibility of data inference. Towards this end, we conducted a study of microRNA expression using endometrioid endometrial tumours (n=96) and serous ovarian tumours (n=96) that were primary, untreated, and collected from 2000 to 2012 at Memorial Sloan Kettering Cancer Center. The same set of tumour tissue samples were profiled twice using the Agilent microRNA microarrays: once under an ideal experimental condition with balanced array-to-sample allocation and uniform handling; a second time by mimicking typical practice, with arrays assigned in the order of sample collection and processed by two technicians in multiple batches. This paper provides a detailed description of the generation and validation of this unique dataset pair so that the research community can re use it to investigate other statistical questions regarding microarray study design and data analysis, and to address biological questions on the relevance of microRNA expression in gynaecologic cancer. PMID- 29762552 TI - The electronic Rothamsted Archive (e-RA), an online resource for data from the Rothamsted long-term experiments. AB - The electronic Rothamsted Archive, e-RA (www.era.rothamsted.ac.uk) provides a permanent managed database to both securely store and disseminate data from Rothamsted Research's long-term field experiments (since 1843) and meteorological stations (since 1853). Both historical and contemporary data are made available via this online database which provides the scientific community with access to a unique continuous record of agricultural experiments and weather measured since the mid-19th century. Qualitative information, such as treatment and management practices, plans and soil information, accompanies the data and are made available on the e-RA website. e-RA was released externally to the wider scientific community in 2013 and this paper describes its development, content, curation and the access process for data users. Case studies illustrate the diverse applications of the data, including its original intended purposes and recent unforeseen applications. Usage monitoring demonstrates the data are of increasing interest. Future developments, including adopting FAIR data principles, are proposed as the resource is increasingly recognised as a unique archive of data relevant to sustainable agriculture, agroecology and the environment. PMID- 29762553 TI - A collection of public transport network data sets for 25 cities. AB - Various public transport (PT) agencies publish their route and timetable information with the General Transit Feed Specification (GTFS) as the standard open format. Timetable data are commonly used for PT passenger routing. They can also be used for studying the structure and organization of PT networks, as well as the accessibility and the level of service these networks provide. However, using raw GTFS data is challenging as researchers need to understand the details of the GTFS data format, make sure that the data contain all relevant modes of public transport, and have no errors. To lower the barrier for using GTFS data in research, we publish a curated collection of 25 cities' public transport networks in multiple easy-to-use formats including network edge lists, temporal network event lists, SQLite databases, GeoJSON files, and the GTFS data format. This collection promotes the study of how PT is organized across the globe, and also provides a testbed for developing tools for PT network analysis and PT routing algorithms. PMID- 29762554 TI - A multi-phenotypic imaging screen to identify bacterial effectors by exogenous expression in a HeLa cell line. AB - We present a high-content screen (HCS) for the simultaneous analysis of multiple phenotypes in HeLa cells expressing an autophagy reporter (mcherry-LC3) and one of 224 GFP-fused proteins from the Crohn's Disease (CD)-associated bacterium, Adherent Invasive E. coli (AIEC) strain LF82. Using automated confocal microscopy and image analysis (CellProfiler), we localised GFP fusions within cells, and monitored their effects upon autophagy (an important innate cellular defence mechanism), cellular and nuclear morphology, and the actin cytoskeleton. This data will provide an atlas for the localisation of 224 AIEC proteins within human cells, as well as a dataset to analyse their effects upon many aspects of host cell morphology. We also describe an open-source, automated, image-analysis workflow to identify bacterial effectors and their roles via the perturbations induced in reporter cell lines when candidate effectors are exogenously expressed. PMID- 29762555 TI - Global transcriptome analysis identifies weight regain-induced activation of adaptive immune responses in white adipose tissue of mice. AB - OBJECTIVE: Studies have indicated that weight regain following weight loss predisposes obese individuals to metabolic disorders; however, the molecular mechanism of this potential adverse effect of weight regain is not fully understood. Here we investigated global transcriptome changes and the immune response in mouse white adipose tissue caused by weight regain. DESIGN: We established a diet switch protocol to compare the effects of weight regain with those of weight gain without precedent weight loss, weight loss maintenance and chow diet. We conducted a time course analysis of global transcriptome changes in gonadal white adipose tissue (gWAT) during the weight fluctuation. Co-expression network analysis was used to identify functional modules associated with the weigh regain phenotype. Immune cell populations in gWAT were characterized by flow-cytometric immunophenotyping. Metabolic phenotypes were monitored by histological analysis of adipose tissue and liver, and blood-chemistry and body weight/composition analyses. RESULTS: In total, 952 genes were differentially expressed in the gWAT in the weight regain vs the weight gain group. Upregulated genes were associated with immune response and leukocyte activation. Co expression network analysis showed that genes involved in major histocompatibility complex I and II-mediated antigen presentation and T-cell activation function were upregulated. Consistent with the transcriptome analysis results, flow cytometry demonstrated significant increases in subsets of T cells and proinflammatory M1 macrophages in the gWAT in the weight regain as compared to the weight gain group. In addition, upregulation of adaptive immune responses was associated with high incidence of adipocyte death and upregulation of high mobility group box 1, a well-known component of damage-associated molecular patterns. CONCLUSIONS: Our global transcriptome analysis identified weight regain induced activation of adaptive immune responses in mouse white adipose tissue. Results suggest that activation of adipocyte death-associated adaptive immunity in adipose tissue may contribute to unfavorable metabolic effects of weight regain following weight loss. PMID- 29762557 TI - Sparsity-based reconstruction for super-resolved limited-view photoacoustic computed tomography deep in a scattering medium. AB - Delay-and-sum beamforming (DSB) of photoacoustic data does not incorporate a priori spatial sparsity of the imaging target. By incorporating this information into beamforming for limited-view photoacoustic computed tomography, we experimentally obtained enhanced resolution images of wires at a depth of 8.5 mm in a tissue mimicking scattering medium. Using a 21 MHz transducer, we improved the resolution from the 200 to 250 MUm achieved by DSB to 75 MUm. The sparsity based technique also generated a cleaner image with a background signal level of roughly -50 dB, much lower than the roughly -18 dB background signal level of DSB. PMID- 29762547 TI - The Role of Transposable Elements in Speciation. AB - Understanding the phenotypic and molecular mechanisms that contribute to genetic diversity between and within species is fundamental in studying the evolution of species. In particular, identifying the interspecific differences that lead to the reduction or even cessation of gene flow between nascent species is one of the main goals of speciation genetic research. Transposable elements (TEs) are DNA sequences with the ability to move within genomes. TEs are ubiquitous throughout eukaryotic genomes and have been shown to alter regulatory networks, gene expression, and to rearrange genomes as a result of their transposition. However, no systematic effort has evaluated the role of TEs in speciation. We compiled the evidence for TEs as potential causes of reproductive isolation across a diversity of taxa. We find that TEs are often associated with hybrid defects that might preclude the fusion between species, but that the involvement of TEs in other barriers to gene flow different from postzygotic isolation is still relatively unknown. Finally, we list a series of guides and research avenues to disentangle the effects of TEs on the origin of new species. PMID- 29762556 TI - Field-recorded data on the diet of six species of European Hydromantes cave salamanders. AB - The availability of data on the feeding habits of species of conservation value may be of great importance to develop analyses for both scientific and management purposes. Stomach flushing is a harmless technique that allowed us to collect extensive data on the feeding habits of six Hydromantes species. Here, we present two datasets originating from a three-year study performed in multiple seasons (spring and autumn) on 19 different populations of cave salamanders. The first dataset contains data of the stomach content of 1,250 salamanders, where 6,010 items were recognized; the second one reports the size of the intact prey items found in the stomachs. These datasets integrate considerably data already available on the diet of the European plethodontid salamanders, being also of potential use for large scale meta-analyses on amphibian diet. PMID- 29762558 TI - Single-beam spectrally encoded color imaging. AB - We have developed, to the best of our knowledge, a new method of conducting spectrally encoded color imaging using a single light beam. In our method, a single broadband light beam was incident on a diffraction grating, where the overlapped third order of the red, fourth order of the green, and fifth order of the blue spectral bands were focused on a line illuminating tissue. This configuration enabled each point on the line to be illuminated by three distinctive wavelengths, corresponding to red, green, and blue. A custom grating was designed and fabricated to achieve high diffraction efficiencies for the wavelengths and diffraction orders used for color spectrally encoded imaging. A bench system was built to test the new spectrally encoded color imaging method. For a beam diameter of 174 MUm, the bench system achieved 89,000 effective pixels over a 70 degrees circular field. Spectrally encoded color images of excised swine tissue revealed blood vessels with a similar color appearance to those obtained via a conventional color camera. The results suggest that this single beam spectrally encoded color method is feasible and can potentially simplify color spectrally encoded endoscopy probe designs. PMID- 29762559 TI - Gas spectroscopy with integrated frequency monitoring through self-mixing in a terahertz quantum-cascade laser. AB - We demonstrate a gas spectroscopy technique, using self-mixing in a 3.4 terahertz quantum-cascade laser (QCL). All previous QCL spectroscopy techniques have required additional terahertz instrumentation (detectors, mixers, or spectrometers) for system pre-calibration or spectral analysis. By contrast, our system self-calibrates the laser frequency (i.e., with no external instrumentation) to a precision of 630 MHz (0.02%) by analyzing QCL voltage perturbations in response to optical feedback within a 0-800 mm round-trip delay line. We demonstrate methanol spectroscopy by introducing a gas cell into the feedback path and show that a limiting absorption coefficient of ~1*10-4 cm-1 is resolvable. PMID- 29762560 TI - Microwave photonics instantaneous frequency measurement receiver based on a Sagnac loop. AB - A microwave photonics instantaneous frequency measurement receiver was conceived and practically demonstrated. The system is based on phase modulation inside a Sagnac loop and therefore needs no bias voltage, resulting in no DC bias drifts. The system provides a DC output whose amplitude is a function of input signal frequency, and thus no high-frequency photo-detector is required. Furthermore, the system exhibits a very good sensitivity without the aid of any sort of electrical noise cancellation techniques, such as lock-in amplification. This makes the system response faster, which would be another benefit for electronic warfare applications. Less than 6% measurement error was achieved over a 0.01-40 GHz frequency range for -30 dBm RF level. Also, a 10% error was achieved at -51 dBm RF power level. PMID- 29762561 TI - Wide dynamic range high-speed three-dimensional quantitative OCT angiography with a hybrid-beam scan. AB - We demonstrate a novel hybrid-beam scanning-based quantitative optical coherence tomography angiography (OCTA) that provides high-speed wide dynamic range blood flow speed imaging. The hybrid-beam scanning scheme enables multiple OCTA image acquisitions with a wide range of multiple time intervals simultaneously providing wide dynamic range blood flow speed imaging independent of the blood vessel orientation, which was quantified over a speed range of 0.6~104 mm/s through the blood flow phantom experiments. A fully automated high-speed hybrid beam scanning-based quantitative OCTA system demonstrates visualization of blood flow speeds in various vessels from the main arteries to capillaries in a 4 mm*4 mm area (1024 A-lines * 512 B-scans) in vivo in 20 s, showing its potential as a useful imaging tool for various biomedical applications. PMID- 29762562 TI - Lineshape-asymmetry elimination in weak atomic transitions driven by an intense standing wave field. AB - Owing to the ac-Stark effect, the lineshape of a weak optical transition in an atomic beam can become significantly distorted when driven by an intense standing wave field. We use an Yb atomic beam to study the lineshape of the 6s2S10 >5d6sD31 transition, which is excited with light circulating in a Fabry-Perot resonator. We demonstrate two methods to avoid the distortion of the transition profile. Of these, one relies on the operation of the resonator in multiple longitudinal modes, and the other in multiple transverse modes. PMID- 29762563 TI - Raman scattering enhancement of a single ZnO nanorod decorated with Ag nanoparticles: synergies of defects and plasmons. AB - Surface-enhanced Raman scattering (SERS) of a single ZnO nanorod (NR) is demonstrated by coating with Ag nanoparticles (NPs). An enhancement factor of 1.2*103 and 4.4*102 has been obtained for E2 (high) mode (437 cm-1) and A1 (TO) mode (378 cm-1), respectively. Electron paramagnetic resonance measurements reveal an unintentional donor state in ZnO NRs. The enhancement of deep-level emission and micro-absorption mapping of a single ZnO NR further confirms the presence of the donor state. The SERS is believed to result from the charge transfer between ZnO NRs and Ag NPs, which can be enhanced by the empty donor state in ZnO. Finally, single ZnO NRs coated with Ag can be used as good SERS substrates for small molecule detection. This Letter highlights the interaction between point defects and the SERS effect down to a single semiconductor NR. PMID- 29762564 TI - Coherence distance in indoor optical wireless communication channels. AB - The coherence distance (CD) is the spatial distance over which the channel does not change appreciably. It is a common and important wireless communication channel parameter. While adoption of this parameter in the realm of radio frequency is well established, it is a less familiar concept in the realm of optical wireless communication (OWC), where it can be beneficial as a measure for spatial optical channel changes. In this Letter, the average CD is proposed as a metric to characterize indoor OWC channels and a method for its evaluation is outlined. PMID- 29762565 TI - Nonlinear pulse compression based on a gas-filled multipass cell. AB - We demonstrate nonlinear temporal compression of a high-energy Yb-doped fiber laser source in a multipass cell filled with argon. The 160 MUJ 275 fs input pulses are compressed down to 135 MUJ 33 fs at the output, corresponding to an overall transmission of 85%. We also analyze the output beam, revealing essentially no space-time couplings. We believe this technique can be scalable to higher pulse energies and shorter pulse durations, enabling access to a wider parameter range for a large variety of ultrafast laser sources. PMID- 29762566 TI - Parallel sorting of orbital and spin angular momenta of light in a record large number of channels. AB - Parallel sorting of orbital and spin angular momentum components of structured optical beams is demonstrated. Both spin channels are multiplexed within the novel orbital angular momentum (OAM) sorter, reducing the size, weight, and number of elements. The sorted states are linearly spaced over 70 topological charge values. We experimentally and theoretically evaluate the operational range and crosstalk between neighboring channels and find that 30 orbital angular momentum states are available per spin channel for quantum communication or cryptography. This is achieved using an angular momentum sorter that we developed based on geometric phase optical elements. We present two devices consisting of liquid crystal polymer films photoaligned with complex two-dimensional patterns. PMID- 29762567 TI - Chemical elemental analysis of single acoustic-levitated water droplets by laser induced breakdown spectroscopy. AB - Laser-induced breakdown spectroscopy is presented for trace element detection of liquid samples by analyzing a single droplet levitated by ultrasonic waves. A single liquid droplet is placed in the node of a standing acoustic wave produced by a uniaxial levitator for further chemical analysis. The acoustic levitator consists of a commercial Langevin-type transducer, attached to a concave mechanical amplifier, and a concave reflector. A micro-syringe was used to manually place individual liquid droplet samples in the acoustic levitation system. For chemical analysis, a laser-induced plasma is produced by focusing a single laser pulse on the levitated water droplet after it partially dries. The performance of the acoustic levitator on micron-sized droplets is discussed, and the detection of Ba, Cd, Hg, and Pb at parts per million (milligrams/liter) and sub-parts per million levels is reported. The process, starting from placing the sample in the acoustic levitator and ending on the chemical identification of the traces, takes a few minutes. The approach is particularly interesting in applications demanding limited volumes of liquid samples and relative simple and inexpensive techniques. PMID- 29762568 TI - 1.8 mJ, 3.5 kW single-frequency optical pulses at 1572 nm generated from an all-fiber MOPA system. AB - High-energy single-frequency optical pulses at 1572 nm were generated from an all fiber MOPA system for atmospheric CO2 LIDAR system application. We report the experimental demonstration of 1.8 mJ, a peak power of 3.5 kW at the pulse repetition of 2.5 kHz, as well as 1.3 mJ, a peak power of 2.5 kW at the pulse repetition of 7.5 kHz single-frequency optical pulses at 1572 nm using single mode large-core polarization-maintaining Er-Yb co-doped silicate glass fiber amplifiers pumped at 976 nm. To the best of our knowledge, this is the highest pulse energy of single frequency at 1572 nm from an all-fiber amplifier system. PMID- 29762569 TI - Transition of Fabry-Perot and antiresonant mechanisms via a SMF-capillary-SMF structure. AB - In this Letter, we investigate the transition of the well-known Fabry-Perot (FP) and antiresonant (AR) mechanisms via a single-mode fiber (SMF)-capillary-SMF structure. The critical length for this transition is analytically found as a linear relation with the capillary inner diameter based on the ray optic method, which shows the agreement with both numerical simulations and experiments. Evolutions of the transmission and reflection spectra verify that FP and AR mechanisms are closely related to the critical length. An observed AR envelope modulated by the FP mechanism in the reflection strengthens gradually with the increase of the capillary length, which is expected to be a novel method for potential applications in multi-parameters sensing because of its combined mechanisms. The transition and critical lengths can be also found and explained using the same method in other types of AR fibers or waveguides with a hollow core. PMID- 29762570 TI - Photonic analog-to-digital conversion using a red frequency chirp in a semiconductor optical amplifier. AB - A photonic analog-to-digital conversion (PADC) based on intensity-to-frequency conversion using a frequency chirp in a semiconductor optical amplifier (SOA) is proposed. The presented PADC has a simple scheme whereby optical quantization is achieved using a single SOA with multiple rectangular bandpass filters placed in parallel. In this Letter, we successfully achieve 10 GSamples/s, eight-level optical quantization using a quantum-dot SOA. The PADC also has much lower input signal pulse power requirements for optical quantization, compared with conventional PADCs. PMID- 29762571 TI - Two-pole microring weight banks. AB - Weighted addition is an elemental multi-input to single-output operation that can be implemented with high-performance photonic devices. Microring (MRR) weight banks bring programmable weighted addition to silicon photonics. Prior work showed that their channel limits are affected by coherent inter-channel effects that occur uniquely in weight banks. We fabricate two-pole designs that exploit this inter-channel interference in a way that is robust to dynamic tuning and fabrication variation. Scaling analysis predicts a channel count improvement of 3.4-fold, which is substantially greater than predicted by incoherent analysis used in conventional MRR devices. Advances in weight bank design expand the potential of reconfigurable analog photonic networks and multivariate microwave photonics. PMID- 29762572 TI - Refractive index sensing by Brillouin scattering in side-polished optical fibers. AB - In this Letter, we demonstrate the possibility to measure the refractive index of a liquid, using the stimulating Brillouin scattering in a 3-cm-long side-polished optical fiber. In addition, we show that by depositing a high-refractive index layer on the polished surface the sensitivity of the Brillouin frequency shift (BFS) can be increased due to a higher penetration of the evanescent field in the outer medium. Experiments show a maximum BFS change of about 11 MHz when varying the refractive index of the external medium from 1 (air) to 1.402, and a BFS sensitivity to refractive index of about 293 MHz/RIU around 1.40. PMID- 29762573 TI - Multimilliwatt, tunable, continuous-wave, mid-infrared generation across 4.6-4.7 MUm based on orientation-patterned gallium phosphide. AB - We report the generation of tunable continuous-wave (cw) mid-infrared (mid-IR) radiation across 4608-4694 nm using the new nonlinear material, orientation patterned gallium phosphide (OP-GaP). By exploiting difference-frequency mixing between a cw Tm-fiber laser and a home-built cw optical parametric oscillator in a 40-mm-long crystal, we have generated up to 43 mW of cw output power, with >30 mW across >95% of the mid-IR tuning range. The output at 4608 nm exhibits high beam quality with a passive power stability of 2.5% rms over 1.5 min. The temperature acceptance bandwidth of the OP-GaP crystal has been measured and compared with theory. The performance of the mid-IR source at high pump powers and polarization-dependent transmission in OP-GaP has been investigated. PMID- 29762574 TI - Photoluminescence enhancement in non-polar ZnO films through metallodielectric mediated Al surface plasmons. AB - Non-polar ZnO thin films are grown on m-plane sapphire substrates by plasma assisted molecular beam epitaxy. Emission enhancement from non-polar ZnO thin films coated with Al/AlOx has been studied by photoluminescence spectroscopy. AlOx has been used to mediate the surface plasmon (SP) energy of Al nanoparticles. Taking advantage of the resonant coupling between the UV emission of non-polar ZnO film and Al nanoparticle SPs, an 84-fold enhancement of the UV emission and an 8.3-fold enhancement of internal quantum efficiency (etaint) have been achieved under the optimized sputtering time and energy of SPs. PMID- 29762575 TI - Intrinsic bias in Fisher information calculations for multi-mode image registration. AB - To address the need for the analysis of image processing and optical requirements in multi-mode imaging systems, such as multi-spectral and polarimetric imagers, I have developed a Fisher information matrix to quantify errors in estimating the shift between images with non-transformational feature differences. If images of the same field have differences not attributable to a geometric transformation, as is common for images acquired using different spectral or polarization filters, uncertainty in estimating the parameters of the transformation will be increased by intrinsic bias, or bias inherent in the data itself, as opposed to bias originating in the estimation algorithm. The approach to shift-estimation error analysis described in this Letter accounts for intrinsic bias, has intuitively expected properties and, given planned system sensitivity and operating conditions, can be used with simulated multi-mode imagery to estimate image registration error and develop realistic requirements. PMID- 29762576 TI - Thermo-optic soliton routing in nematic liquid crystals. AB - We demonstrate thermo-optic control on the propagation of optical spatial solitons in nematic liquid crystals. By varying the sample temperature, both linear and nonlinear optical properties of the reorientational material are modulated by acting on the refractive indices, the birefringence, and the elastic response. As a result, both the trajectory and transverse confinement of spatial solitons can be adjusted, demonstrating an effective means to tune and readdress self-induced optical waveguides. PMID- 29762577 TI - Controllable coherent backscattering of light in disordered media filled with liquid crystal. AB - We have investigated multiple scattering of light in a disordered system based on liquid crystals for a temperature-controllable random laser. Coherent backscattering measurements at several temperatures have been well fitted by the theoretical model deduced for a random collection of spherical point scatters based on a diffusion approximation. The transport mean free path exclusively depends on the diffusivity of the liquid crystalline phase of the hybrid scattering system. It is shown how the laser threshold excitation intensity is strongly correlated with the transport mean free path. PMID- 29762578 TI - Photon statistics as an interference phenomenon. AB - Interference of light fields, first postulated by Young, is one of the fundamental pillars of physics. Dirac extended this observation to the quantum world by stating that each photon interferes only with itself. A precondition for interference to occur is that no welcher-weg information labels the paths the photon takes; otherwise, the interference vanishes. This remains true, even if two-photon interference is considered, e.g., in the Hong-Ou-Mandel-experiment. Here, the two photons interfere only if they are indistinguishable, e.g., in frequency, momentum, polarization, and time. Less known is the fact that two photon interference and photon indistinguishability also determine the photon statistics in the overlapping light fields of two independent sources. As a consequence, measuring the photon statistics in the far field of two independent sources reveals the degree of indistinguishability of the emitted photons. In this Letter, we prove this statement in theory using a quantum mechanical treatment. We also demonstrate the outcome experimentally with a simple setup consisting of two statistically independent thermal light sources with adjustable polarizations. We find that the photon statistics vary indeed as a function of the polarization settings, the latter determining the degree of welcher-weg information of the photons emanating from the two sources. PMID- 29762579 TI - Surface plasmon resonance sensing in gaseous media with optical fiber gratings. AB - Surface plasmon resonance excitation with optical fiber gratings has been typically studied in aqueous solutions. This work describes the procedure to excite a plasmon wave in gaseous media and perform refractive index measurements in these environments. Grating photo-inscription with 193 nm excimer laser radiation allows us to obtain slightly tilted fiber Bragg gratings exhibiting a cladding mode resonance comb along several hundreds of nanometers. Their refractive index sensitive range extends from gases to liquids, so operation in both media is compared. We demonstrate that the thickness of the metal coating required for surface plasmon excitation in gases is roughly one third of the one usually used for liquids. The developed platforms exhibit a temperature insensitive response of 78 nm/RIU when tested with different gases. PMID- 29762580 TI - High-power, continuous-wave, tunable mid-IR, higher-order vortex beam optical parametric oscillator. AB - We report on a novel experimental scheme to generate continuous-wave (cw), high power, and higher-order optical vortices tunable across a mid-IR wavelength range. Using a cw, two-crystal, singly resonant optical parametric oscillator (T SRO) and pumping one of the crystals with a Gaussian beam and the other crystal with optical vortices of orders lp=1-6, we have directly transferred the vortices at near-IR to the mid-IR wavelength range. The idler vortices of orders li=1-6 are tunable across 2276-3576 nm with a maximum output power of 6.8 W at an order of li=1 for the pump power of 25 W, corresponding to a near-IR vortex to mid-IR vortex conversion efficiency as high as 27.2%. Unlike the SROs generating optical vortices restricted to lower orders (<=2) due to the elevated operation threshold of SROs with higher-order pump vortices, here the coherent energy coupling between the resonant signals of two crystals of T-SRO facilitates the transfer of pump vortex of any order to the idler wavelength without a stringent operation threshold condition. The generic experimental scheme can be used in any wavelength range across the electromagnetic spectrum and in all timescales, from cw to ultrafast regimes. PMID- 29762581 TI - Dielectric-mirror-less femtosecond optical parametric oscillator with ultrabroad band tunability. AB - We demonstrate a high average power, widely tunable, dielectric-mirror-less optical parametric oscillator (OPO) based on MgO:PPLN (MgO-doped periodically poled lithium niobate), which is synchronously pumped by a 1040 nm femtosecond fiber laser. The OPO does not require any dielectric coating mirrors. By exploiting the four-prism sequence system, combined with the gold mirrors, the oscillating laser pulses could span the spectral regions in both the signal and idler, and the output pulses of OPO can be tuned across 1367-1914 nm in the signal, and 2152-4480 nm in the idler as well. This device can deliver as much as 1.2 W of average power at 1482 nm in the signal and up to 411 mW at 3487 nm in the idler, respectively. The ultrabroad-band spectra tunability, along with the high average output property, makes the dielectric-mirror-less OPO an attractive alternative to conventional OPOs. PMID- 29762582 TI - Dispersion tuning in sub-micron tapers for third-harmonic and photon triplet generation. AB - Precise control of the dispersion landscape is of crucial importance if optical fibers are to be successfully used for the generation of three-photon states of light-the inverse of third-harmonic generation (THG). Here we report gas-tuning of intermodal phase-matched THG in sub-micron-diameter tapered optical fiber. By adjusting the pressure of the surrounding argon gas up to 50 bars, intermodally phase-matched third-harmonic light can be generated for pump wavelengths within a 15 nm range around 1.38 MUm. We also measure the infrared fluorescence generated in the fiber when pumped in the visible and estimate that the accidental coincidence rate in this signal is lower than the predicted detection rate of photon triplets. PMID- 29762583 TI - Diode-pumped 45 fs Yb:CALGO laser oscillator with 1.7 MW of peak power. AB - A high-power sub-50 fs diode-pumped Yb:CALGO laser oscillator is demonstrated. The peak power achieved for 45 fs pulses directly from the oscillator was 1.7 MW. To the best of our knowledge, this is the highest peak power in the sub-50 fs pulse regime that has ever been produced directly from any diode-pumped Yb-ion doped laser oscillator to date. The shortest generated pulses were 38 fs long with 187 kW of peak power. PMID- 29762584 TI - Wideband tunable optoelectronic oscillator based on a microwave photonic filter with an ultra-narrow passband. AB - A novel wideband tunable optoelectronic oscillator based on a microwave photonic filter (MPF) with an ultra-narrow passband is proposed and experimentally demonstrated. The single-passband MPF is realized by cascading an MPF based on stimulated Brillouin scattering and an infinite impulse response (IIR) MPF based on an active fiber recirculating delay loop. The measured full width at half maximum bandwidth of the cascaded MPFs is 150 kHz. To the best of my knowledge, this is the first time realizing such a narrow passband in single-passband MPF. The oscillation frequency of the OEO can be tuned from 0 to 40 GHz owing to the wideband tunability of the MPF. Thanks to the ultrahigh mode selectivity of the IIR filter, the mode hopping is successfully suppressed. A stable microwave signal at 8.18 GHz is obtained with a phase noise of -113 dBc/Hz at 10 kHz, and the side mode noise is below -95 dBc/Hz. The signal-to-noise ratio exceeds 50 dB during the tuning process. PMID- 29762585 TI - Unexpected large nanoparticle size of single dimer hotspot systems for broadband SERS enhancement. AB - We have numerically demonstrated the feasibility and possibility to achieve broadband surface-enhanced Raman scattering (SERS) enhancement in the visible and near-infrared wavelength range using single nanoparticle (NP) dimer hotspot systems. Instead of the conventionally reported sub-100 nm, we find that the optimal NP size is as large as 200 nm in diameter for both Ag and Au. The key lies in the continuous arising of the bonding dipole plasmon mode and higher order resonances at shorter wavelengths. Further, it is revealed that the near- and far-field optical responses of these hotspot systems correlate well with each other, despite the intrinsic enormous near- to far-field redshift for individual large NPs. The physical principles demonstrated here benefit significantly the fundamental understanding and engineering optimization of broadband SERS substrates. PMID- 29762586 TI - Subdiffraction-limited second harmonic photoacoustic microscopy based on nonlinear thermal diffusion. AB - We have developed a second harmonic photoacoustic microscopy (SH-PAM) for subdiffraction-limited imaging based on nonlinear thermal diffusion. When a sine modulated Gaussian temperature field is introduced by a laser beam, the temperature dependence of the thermal diffusivity induces a nonlinear photoacoustic (PA) effect and thus results in the production of second harmonic PA signals. We demonstrate through both simulation and experiment that the second harmonic PA images can be reconstructed with a lateral resolution exceeding that of conventional optical resolution PA microscopy. The feasibility of SH-PAM was verified on phantom samples. Amphioxus zygotes and germinated pollens have been studied by SH-PAM to demonstrate its biomedical imaging capability. This method expands the scope of conventional PA imaging and opens up new possibilities for super-resolution imaging, prefiguring great potential for biological imaging and material inspection. PMID- 29762587 TI - Fluoride-fiber-based side-pump coupler for high-power fiber lasers at 2.8 MUm. AB - A side-pump coupler made of fluoride fibers was fabricated and tested. The tested device had a coupling efficiency of 83% and was driven with an incident pump power of up to 83.5 W, demonstrating high-power operation. Stable laser output of 15 W at a wavelength of around 2.8 MUm was achieved over 1 h when using an erbium doped double-clad fiber as the active medium. To the best of our knowledge, this is the first time a fluoride-glass-fiber-based side-pump coupler has been developed. A test with two devices demonstrated further power scalability. PMID- 29762588 TI - Controlling the degree of polarization of partially coherent electromagnetic beams with lenses. AB - We show theoretically that the degree of polarization of a partially coherent electromagnetic beam changes dramatically as the beam is being focused. A low numerical aperture lens can considerably enhance the degree of polarization at its geometrical focus. When two identical lenses are employed in a 4f configuration, the degree of polarization of a beam can be tailored by using amplitude masks in the Fourier plane located in the middle of the two lenses. Our findings open up the possibility to control this fundamental property of random beams in a simple manner. PMID- 29762589 TI - Polymer/silica hybrid integration add-drop filter based on grating-assisted contradirectional coupler. AB - A polymer/silica hybrid integration add-drop filter based on a grating-assisted contradirectional coupler fabricated through simple and low-cost contact lithography is proposed. First, the structure pattern of the add-drop filter was formed in the lower silica cladding by contact lithography and inductively coupled plasma (ICP) etching. Then an SU-8 film was fabricated on top of it by a spin-coating method, and an inverted-rib waveguide structure was formed. Next, the slab layer of the inverted-rib waveguide was removed by ICP etching. We observe a rejection band with an extinction ratio of 13 dB and a 3 dB bandwidth of 0.6 nm at a wavelength of 1509.4 nm from the through port, and a passband with a side-mode suppression ratio of 12 dB and a 3 dB bandwidth of 0.5 nm at a wavelength of 1509.4 nm from the drop port. The shift of the passband with a temperature over the range of 25-55 degrees C is approximately 4.8 nm. This temperature dependence exhibits an average slope of -0.16 nm/ degrees C. PMID- 29762590 TI - Enhanced luminescence of CsPbBr3 perovskite nanocrystals on stretchable templates with Au/SiO2 plasmonic nanoparticles. AB - We propose stretchable plasmonic templates of Au and Au/SiO2 nanoparticles (NPs) to improve the luminescence of CsPbBr3 perovskite nanocrystals (PNCs). These templates are highly flexible and consist of polymer-metal NP composites that facilitate the luminescence enhancement by localized surface plasmons (LSPs) due to coupling with metal NP. This template also prevents the degradation of carrier transport properties for perovskite light-emitting diodes by embedding metal NPs in polymer. The luminescence of PNC film on the template with Au NPs decreases by 21% compared to PNC films on the reference (polymer film without metal NPs), while it increases by 54% for the templates with Au/SiO2 NPs. The observed effects are explained by the luminescence enhancement due to coupling to LSPs formed by the Au/SiO2 NPs and by the prevalence of electron tunneling and dumping for Au NPs. PMID- 29762591 TI - Centimeter-scale Yb-free heavily Er-doped silica fiber laser. AB - The laser behavior of a centimeter-scale Er3+/Al3+ codoped silica fiber with core numerical aperture and core diameter of 0.15 and 8 MUm, respectively, is reported. The core glass was prepared by the sol-gel method combined with high temperature sintering; it contained Er3+ ion concentration as high as 1.32*1020 ions/cm3 and an Al/Er mole ratio of 10. The high doping homogeneity of Er3+ ions in the fiber core was confirmed by an electron probe microanalyzer element scanning, long Er3+: I13/24 emission lifetime of 11.4 ms, and low refractive index fluctuation of fiber core (+/-1*10-4). The signal gain of fibers with 4.6 cm, 10 cm, and 16 cm lengths was tested in the 1500-1620 nm range. A gain of 7 dB is achieved at 1560 nm in a 16-cm-long EDF under 230 mW pump power. Aimed for CO2 sensor application, the laser behavior of Er/Al codoped fiber was tested at 1572 nm. A slope efficiency of 12% and an output power of 15 mW were achieved in a 10 cm-long fiber under 166 mW absorbed pump power. The newly developed silica fiber is promising for use in high-repetition-rate lasers. PMID- 29762592 TI - Out-of-plane band structure of a two-dimensional dispersive photonic crystal. AB - We calculated the out-of-plane band structure of a two-dimensional dispersive photonic crystal (PC). To achieve this goal, the plane wave expansion method was implemented in conjunction with a numerical algorithm, the dispersive photonic crystal iterative method. The PC is an array of circular cross-sectional dispersive MgO Lorentz single-pole rods in a square lattice. The frequency bands are calculated starting at Gamma as a function of the oblique component of the wave vector. For the lowest frequencies, it was found that the modes bend drastically to the horizon as the dielectric constant epsilon(omega) is increased to a very positive value. For frequencies above the longitudinal optical phonon circular frequency, where epsilon(omega) has very low positive values, the expected degeneration occurs in the transparency window, and a line of modes behaves close to the line of light. PMID- 29762593 TI - Spectroscopic properties and continuous-wave deep-red laser operation of Eu3+ doped LiYF4. AB - Eu3+-doped LiYF4 is reexamined as a laser material for the visible spectral region. Polarized absorption and emission cross sections as well as the fluorescence lifetime are determined. Branching ratios and radiative lifetime are calculated within the theory of 4f-4f transition intensities, which takes into account the influence of an excited configuration of the opposite parity 4fN-15d. Continuous-wave laser operation at 702 nm is demonstrated with a maximum output power of 15 mW and a slope efficiency of 4.6% under pumping with a frequency doubled Ti:sapphire laser at 393.5 nm. PMID- 29762594 TI - Flexible binary phase photon sieves on polyimide substrates by laser ablation. AB - A binary phase diffractive optical element photon sieve is fabricated by direct laser ablation of a thin, flexible polyimide substrate with a nanosecond-pulsed ultraviolet laser. The binary phase photon sieve operates at 633 nm and was designed with 19 rings and a focal length of 400 mm. The total time to fabricate the photon sieves was tens of seconds. The surface properties of the laser processed areas are examined, and the optical performance of the photon sieve is characterized and compared to FDTD simulations. By optimizing the laser fluence and travel distance between laser pulses, features with sub-wavelength surface roughness were achieved. The photon sieve showed good focusing ability with suppressed side-lobes. When the fractional area of photon sieve pinholes was made to approach 50%, the binary sieve diffraction efficiency approached 11%, matching the highest value reported in the literature for a photon sieve. Thus, this Letter demonstrates both high efficiency and lightweight diffractive optics suitable for space satellite and other applications, with capabilities for low cost and high throughput fabrication. PMID- 29762595 TI - Charge compensation effects of Yb3+ on the Bi+: near-infrared emission in PbF2 crystal. AB - The use of Yb3+ codoping for enhancing the near-infrared (NIR) emission in Bi, Yb codoped PbF2 crystal was investigated for the first time, to the best of our knowledge. The NIR and visible fluorescence emission properties of the as-grown crystals were investigated in detail. It was found that the Yb3+ ion can act as an effective charge compensated ion to bring about the conversion from Bi2+ to Bi+, enhancing the NIR fluorescence emission in Bi:PbF2 crystal. Moreover, the NIR fluorescence emission peaking at around 1090 and 1485 nm was demonstrated to be two different Bi+ related centers, Bi(I) and Bi(II), respectively. These results suggest that Bi, Yb codoped PbF2 crystal may become an attractive gain material for developing NIR broadband lasers under pumps of different wavelengths. PMID- 29762596 TI - Partially coherent sources with radial coherence. AB - Partially coherent sources with radial coherence are proposed. They present a circularly symmetric intensity profile and a degree of coherence whose absolute value only depends on the angular difference between the two considered points. In particular, the source is completely coherent at pairs of points belonging to the same radius. The modal structure of such sources is determined in the general case, and conditions are derived under which the field propagated in paraxial approximation remains radially coherent at any transverse plane. In such cases, the angular dependence of the correlation function is preserved upon propagation, although the intensity profile generally changes. An example of this kind of source has been experimentally synthesized by means of a simple setup, and its coherence characteristics have been tested by means of a Young interferometer. PMID- 29762597 TI - Universal holonomic single quantum gates over a geometric spin with phase modulated polarized light. AB - We demonstrate universal non-adiabatic non-abelian holonomic single quantum gates over a geometric electron spin with phase-modulated polarized light and 93% average fidelity. This allows purely geometric rotation around an arbitrary axis by any angle defined by light polarization and phase using a degenerate three level Lambda-type system in a negatively charged nitrogen-vacancy center in diamond. Since the control light is completely resonant to the ancillary excited state, the demonstrated holonomic gate not only is fast with low power, but also is precise without the dynamical phase being subject to control error and environmental noise. It thus allows pulse shaping for further fidelity. PMID- 29762598 TI - Resonance-domain diffractive lens for the terahertz region. AB - Diffractive optics has long served as the basis of spectroscopic measurements of materials. Operation in the resonance domain further allows these elements to achieve high efficiency and polarization control. An effective grating theory is a practical tool for modeling such optics, and here we extend use of this theory to the terahertz region, experimentally demonstrating an all-dielectric binary off-axis diffractive lens. We achieve a high-efficiency, polarization-independent optic that both focuses and disperses terahertz light, suggesting potential applications in pharmaceutical, security, and semiconductor imaging. PMID- 29762599 TI - Coaxial excitation longitudinal shear wave measurement for quantitative elasticity assessment using phase-resolved optical coherence elastography. AB - Optical coherence elastography (OCE) is an emerging imaging modality for the assessment of mechanical properties in soft tissues. Transverse shear wave measurements using OCE can quantify the elastic moduli perpendicular to the force direction, however, missing the elastic information along the force direction. In this study, we developed coaxial excitation longitudinal shear wave measurements for quantification of elastic moduli along the force direction using M-scans. Incorporating Rayleigh wave measurements using non-coaxial lateral scans into longitudinal shear wave measurements, directionally dependent elastic properties can be quantified along the force direction and perpendicular to the force direction. Therefore, the reported system has the capability to image elasticity of anisotropic biological tissues. PMID- 29762600 TI - Experimental demonstration of beaconless beam displacement tracking for an orbital angular momentum multiplexed free-space optical link. AB - In this Letter, we experimentally demonstrate beaconless beam displacement tracking for free-space optical communication link multiplexing multiple orbital angular momentum (OAM) beams, where the data-carrying OAM beams are used for position detection. 400 Gbit/s data transmission is demonstrated under emulated lateral displacement of up to +/-10 mm with power penalties of less than 3 dB for all channels. Channel crosstalk is reduced by the beam tracking system to below -18 dB. Moreover, we investigate using a Gaussian beacon for beam displacement tracking, and achieve similar channel crosstalk and power penalties, compared with using the beaconless beam tracking. PMID- 29762601 TI - Demonstration of a highly stable 10 GHz optical frequency comb with low timing jitter from a SCOWA-based harmonically mode-locked nested cavity laser. AB - An optical frequency comb with mode spacing of 10 GHz operating in the c-band is produced from a harmonically mode-locked laser using a slab-coupled optical waveguide amplifier device with a fiber-coupled external cavity. An intracavity Fabry-Perot etalon serves as a high finesse optical filter for supermode suppression and as the reference for cavity length stabilization using a multi combline Pound-Drever-Hall setup. The Allan deviation of a single optical combline near 193.4 THz is measured via a heterodyne beat with a cavity stabilized cw laser and reaches a minimum fractional frequency deviation of 3*10 13 at tau=30 ms. In addition, the phase noise of the photodetected pulsed output of the laser shows a timing jitter of <23 fs integrated from 1 Hz to the Nyquist frequency. PMID- 29762602 TI - Nonlinear optical susceptibility of two-dimensional WS2 measured by hyper Rayleigh scattering: erratum. AB - This erratum corrects errors in the expressions for ?betaTMD? and fitted form of IHRS and a consequent data point in Fig. 4 of a recent Letter [Opt. Lett.42, 5018 (2017)OPLEDP0146-959210.1364/OL.42.005018]. It also supplies data for the reference compound para-nitroaniline (pNA). The correction to ?betaTMD? improves experimental agreement from 46% to within 21% of independent scissors-corrected density functional theory (DFT) calculations. Central findings from the original Letter remain intact. PMID- 29762603 TI - Phase-shift-amplified interferometry. AB - We present a new technique for improving the sensitivity of an interferometer, phase-shift-amplified interferometry (PAI), which is based on two embedded interferometers. The internal interferometer, which is biased in anti-phase, amplifies the phase shift; the external interferometer converts this into an amplified intensity shift. PAI can improve the sensitivity of standard interferometers by an order of magnitude or more. The theory of PAI, including its enhanced immunity to relative intensity noise, phase noise, and other post detection noise and distortion components, is presented. We experimentally demonstrate a phase-shift amplification factor of 11. PMID- 29762604 TI - Terabit optical OFDM superchannel transmission via coherent carriers of a hybrid chip-scale soliton frequency comb. AB - We demonstrate seamless channel multiplexing and high bitrate superchannel transmission of coherent optical orthogonal frequency division multiplexing (CO OFDM) data signals utilizing a dissipative Kerr soliton (DKS) frequency comb generated in an on-chip microcavity. Aided by comb line multiplication through Nyquist pulse modulation, the high stability and mutual coherence among mode locked Kerr comb lines are exploited for the first time, to the best of our knowledge, to eliminate the guard intervals between communication channels and achieve full spectral density bandwidth utilization. Spectral efficiency as high as 2.625 bit/Hz/s is obtained for 180 CO-OFDM bands encoded with 12.75 Gbaud 8 QAM data, adding to the total bitrate of 6.885 Tb/s within a 2.295 THz frequency comb bandwidth. This Letter confirms that high coherence is the key superiority of Kerr soliton frequency combs over independent laser diodes, as a multi spectral coherent laser source for high-bandwidth high-spectral-density transmission networks. PMID- 29762605 TI - Quantum resonances of Landau damping in the electromagnetic response of metallic nanoslabs. AB - The resonant quantization of Landau damping in far-infrared absorption spectra of metal nano-thin films is predicted within the Kubo formalism. Specifically, it is found that the discretization of the electromagnetic and electron wave numbers inside a metal nanoslab produces quantum nonlocal resonances well-resolved at slab thicknesses smaller than the electromagnetic skin depth. Landau damping manifests itself precisely as such resonances, tracing the spectral curve obtained within the semiclassical Boltzmann approach. For slab thicknesses much greater than the skin depth, the classical regime emerges. Here the results of the quantum model and the Boltzmann approach coincide. Our analytical study is in perfect agreement with corresponding numerical simulations. PMID- 29762606 TI - Intensity-modulated directional torsion sensor based on in-line optical fiber Mach-Zehnder interferometer. AB - In this Letter, we demonstrated an intensity-modulated directional torsion sensor based on an in-line Mach-Zehnder interferometer in single-mode fiber. A non circular symmetric perturbation is created to excite non-circular symmetric cladding mode and then interference with the core mode at the second perturbation. An initial rotation angle is designed between two perturbations for the purpose of discriminating the torsion direction. Both experimental and theoretical results enforce that the spectral peak/dip turns to be the dip/peak when the fiber is twisted from the counter-clockwise to the clockwise direction. Benefiting from the reversal between peak and dip, an intensity-modulated directional torsion sensor is realized in the range from -50 rad/m to 50 rad/m with a sensitivity of 45.3%/(rad/cm). PMID- 29762607 TI - Efficient continuous-wave and passive Q-switched mode-locked Er3+ : CaF2-SrF2 lasers in the mid-infrared region. AB - An Er3+-doped CaF2-SrF2 mixed crystal was grown using the temperature gradient technique, and its laser characteristics were studied. In a compact linear cavity, a continuous-wave output power of 712 mW was obtained with the highest slope efficiency of 41.4%. Using a semiconductor saturable absorber mirror, a passive Q-switched mode-locked Er3+:CaF2-SrF2 laser emitting at 2729.5 nm was demonstrated for the first time, to the best of our knowledge. The maximum average output power of 125 mW was obtained at an absorbed pump power of 1.81 W, and the repetition rate of the Q-switched envelope was 4.17 kHz. The mode-locked pulses in the Q-switched pulse envelope had a repetition rate of 136.3 MHz, and its duration was estimated to be approximately 1.78 ns. These results indicate that the Er3+-doped CaF2-SrF2 mixed crystal is promising for the development of an ultrafast laser in the mid-infrared regime. PMID- 29762608 TI - Fabrication of controllably variable sub-100 nm gaps in silver nanowires by photothermal-induced stress. AB - A technique to fabricate nanogaps with controllably variable gap width in silver (Ag) nanowires (NWs) by photothermal-induced stress utilizing a focused continuous-wave laser (532 nm) is presented. For the case of an Ag NW on gold thin film, a gap width starting from ~20 nm is achieved with a critical minimum power (CMP) of about 160 mW, whereas in the case of an Ag NW placed on top of a zinc oxide NW, the attained gap width is as small as a few nm (<10 nm) with a CMP of only ~100 mW. In both cases, the CMP is much lower as compared to the required CMP (~280 mW) for an Ag NW placed on a bare silica substrate. The photothermal-induced stress combined with Rayleigh instability, melting, and sublimation of Ag aids in breaking the Ag NW. In particular, the former one plays a key role in attaining an extremely narrow gap. This technique to fabricate sub 100 nm nanogaps in metal NWs can be extensively implemented in fabrication and maintenance of nanomechanical, nanoplasmonic, and nanoelectronic devices. PMID- 29762609 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2050312118756663.]. PMID- 29762610 TI - Comments on "Knowledge Translation of the PERC Rule for Suspected Pulmonary Embolism: A Blueprint for Reducing the Number of CT Pulmonary Angiograms". PMID- 29762611 TI - Corrigendum. AB - [This corrects the article DOI: 10.1177/2050312118756804.]. PMID- 29762612 TI - Erratum: This Article Corrects: "Trends in Regionalization of Care for ST-Segment Elevation Myocardial Infarction". AB - [This corrects the article on p. 1010 in vol. 18, PMID: 29085531.]. PMID- 29762613 TI - Structural and catalytic properties of the Au25-xAgx(SCH3)18 (x = 6, 7, 8) nanocluster. AB - In this study, we explore the structural, electronic and catalytic properties of bimetallic nanoparticles of the form Au25-xAgx(SR)18 (for x = 6, 7, 8). Due to the combinatorial enormity of the number of different alloyed structures, we choose 500 random configurations corresponding to each alloying level and energetically optimize their structures. Here we report the properties of the lowest energy structures and determine the most favorable Ag alloying sites for these systems. We also show that nanoalloys with one Ag at the center and the rest in the outer shell of the Au13 kernel are less energetically favorable than the ones with all the Ag atoms occupying the surface of the Au13 kernel. We further present experimental results showing that catalytic oxidation of CO is adversely affected due to Ag alloying. We provide qualitative and quantitative evidence to explain this reduction of the catalytic activity using Fukui functions and average adsorption energies respectively. PMID- 29762614 TI - Ni(ii) complexes of the phosphine-oxime Ph2PC6H4-2-CH[double bond, length as m dash]NOH. AB - We report the solution and structural chemistry of nickel(ii) complexes of the phosphine-oxime Ph2PC6H4-2-CH[double bond, length as m-dash]NOH (PCH[double bond, length as m-dash]NOH). PCH[double bond, length as m-dash]NOH invariably binds in a bidentate manner as illustrated by cis-Ni(PCH[double bond, length as m dash]NOH)2Cl2 and cis-[Ni(PCH[double bond, length as m-dash]NOH)2]2+ (as its BF4- salt). Treatment of PCH[double bond, length as m-dash]NOH with Ni(OAc)2(H2O)4 gave charge-neutral trans-[Ni(PCH[double bond, length as m-dash]NO)2]0. Treatment of trans-[Ni(PCH[double bond, length as m-dash]NO)2]0 with BF3 gave [Ni(PCH[double bond, length as m-dash]NO)2BF2]BF4. The cation features a planar NiP2N2 center wherein the pair of oximate groups are linked by the difluoroboryl center. The 1 : 1 complexes of the oxime and the oximate are illustrated by [Ni(PCH[double bond, length as m-dash]NOH)Cl2]2 and [Ni(C6F5)(PCH[double bond, length as m-dash]NO)]2, which feature five- and four-coordinate Ni(ii) centers, respectively. All complexes in this series hydrolyze to give the trinickel oxo phosphine-oximate complex [Ni3(PCH[double bond, length as m-dash]NO)3O]+. One feature of the PCH[double bond, length as m-dash]NOH ligand is its wide bite angle combined with its protic OH center. These aspects are manifested in the structures of Ni(PCH[double bond, length as m-dash]NOH)2Cl2 and [Ni(PCH[double bond, length as m-dash]NOH)Cl2]2, which show intramolecular hydrogen bonding to terminal chloride ligands. PMID- 29762615 TI - Synthesis of hydrated KTaWO6 nanoparticles and Sn(ii) incorporation for visible light absorption. AB - The defect-pyrochlore stuctured semiconductor KTaWO6 has been prepared via hydrothermal synthesis, resulting in single-crystalline nanoparticles with adjustable crystallite size between 15 and 24 nm. With subsequent ion-exhange of K with Sn(ii) the band gap of this complex semiconductor can be reduced by 1.3 eV. We show that the ion-exchange is greatly facilitated by the incorporation of water into the crystal lattice. PMID- 29762616 TI - Synthesis, PtS-type structure, and anomalous mechanics of the Cd(CN)2 precursor Cd(NH3)2[Cd(CN)4]. AB - We report the nonaqueous synthesis of Cd(CN)2 by oxidation of cadmium metal with Hg(CN)2 in liquid ammonia. The reaction proceeds via an intermediate of composition Cd(NH3)2[Cd(CN)4], which converts to Cd(CN)2 on prolonged heating. Powder X-ray diffraction measurements allow us to determine the crystal structure of the previously-unreported Cd(NH3)2[Cd(CN)4], which we find to adopt a twofold interpenetrating PtS topology. We discuss the effect of partial oxidation on the Cd/Hg composition of this intermediate, as well as its implications for the reconstructive nature of the deammination process. Variable-temperature X-ray diffraction measurements allow us to characterise the anisotropic negative thermal expansion (NTE) behaviour of Cd(NH3)2[Cd(CN)4] together with the effect of Cd/Hg substitution; ab initio density functional theory (DFT) calculations reveal a similarly anomalous mechanical response in the form of both negative linear compressibility (NLC) and negative Poisson's ratios. PMID- 29762617 TI - Anticancer potential against cervix cancer (HeLa) cell line of probiotic Lactobacillus casei and Lactobacillus paracasei strains isolated from human breast milk. AB - Lactic acid bacteria have been categorized as probiotics and play a crucial role in human health by stimulating the supply of nutrients, shaping the immune system, and preventing the colonization of pathogenic microbes. This study investigated the mechanisms for the action of three potential probiotic Lactobacillus strains: Lactobacillus casei SR1, Lactobacillus casei SR2, and Lactobacillus paracasei SR4 isolated from human breast milk. These Lactobacillus strains were identified via 16S DNA sequencing and characterized via biochemical assays including acid resistance, bile resistance, antioxidant activity, and antibiotic susceptibility. The bioactivity of the cell-free culture supernatant (CFCS) secreted by these strains on the cervix cancer (HeLa) cell line was also evaluated via cytotoxicity assay and apoptosis analysis. The mechanism of anticancer activity was also investigated via RT-qPCR and western blotting. The results demonstrated that these newly isolated Lactobacillus strains from human milk displayed noticeable probiotic characteristics such as excellent antibiotic susceptibility, outstanding antioxidant activity, and promising resistance to low pH and high concentration of bile salts. The results of the conducted bioactivity assays verified that the CFCSs had acceptable anticancer effects on cervix cancer (HeLa) cells by upregulating the expression of apoptotic genes BAX, BAD, caspase3, caspase8, and caspase9 and by downregulating the expression of the BCl 2 gene. Overall, these results indicate that the Lactobacillus strains isolated from human breast milk could be considered as a topical medication with a potential therapeutic index due to their efficacy against cervix cancer cells. PMID- 29762618 TI - Theoretical investigation of the swelling of polysaccharide microgels in sugar solutions. AB - In this paper, we explain the increased swelling of crosslinked polysaccharide microgels by the increase of sugar concentration using a modified Flory-Rehner theory. This theory is validated via the investigation of the swelling of dextran microgels in sugar solutions, which can be viewed as a model system for crosslinked starch in sugar solution and custard. An essential part of our modified theory is that starch perceives the sugar solution as an effective solvent rendering a certain hydrogen bond density. Our simulations show that the often experimentally observed maximum in swelling of starch at 20% sugar concentration is probably due to the fact that equilibrium is not reached within practical time scales. Also, we discuss the use of our theory as a tool in sugar reformulation issues of custard. From simulation results one can produce a state diagram showing which formulations render a creamy, space-filling network. PMID- 29762619 TI - Isolation and genome sequencing of individual circulating tumor cells using hydrogel encapsulation and laser capture microdissection. AB - Circulating tumor cells (CTCs) are malignant cells released into the bloodstream with the potential to form metastases in secondary sites. These cells, acquired non-invasively, represent a sample of highly relevant tumor tissue that is an alternative to difficult and low-yield tumor biopsies. In recent years, there has been growing interest in genomic profiling of CTCs to enable longitudinal monitoring of the tumor's adaptive response to therapy. However, due to their extreme rarity, genotyping CTCs has proved challenging. Relevant mutations can be masked by leukocyte contamination in isolates. Heterogeneity between subpopulations of tumor cells poses an additional obstacle. Recent advances in single-cell sequencing can overcome these limitations but isolation of single CTCs is prone to cell loss and is prohibitively difficult and time consuming. To address these limitations, we developed a single cell sample preparation and genome sequencing pipeline that combines biophysical enrichment and single cell isolation using laser capture microdissection (LCM). A key component of this process is the encapsulation of enriched CTC sample in a hydrogel matrix, which enhances the efficiency of single-cell isolation by LCM, and is compatible with downstream sequencing. We validated this process by sequencing of single CTCs and cell free DNA (cfDNA) from a single patient with castration resistant prostate cancer. Identical mutations were observed in prostate cancer driver genes (TP53, PTEN, FOXA1) in both single CTCs and cfDNA. However, two independently isolated CTCs also had identical missense mutations in the genes for ATR serine/threonine kinase, KMT2C histone methyltransferase, and FANCC DNA damage repair gene. These mutations may be missed by bulk sequencing libraries, whereas single cell sequencing could potentially enable the characterization of key CTC subpopulations that arise during metastasis. PMID- 29762620 TI - MXP(M = Co/Ni)@carbon core-shell nanoparticles embedded in 3D cross-linked graphene aerogel derived from seaweed biomass for hydrogen evolution reaction. AB - Low-cost electrocatalysts play an important role in the hydrogen evolution reaction (HER). Particularly, transition metal phosphides (TMPs) are widely applied in the development of HER electrocatalysts. To improve the poor electrochemical reaction kinetics of HER, we introduce a facile way to synthesize carbon core-shell materials containing cobalt phosphide nanoparticles embedded in different graphene aerogels (GAs) (CoP@C-NPs/GA-x (x = 5, 10 and 20)) using seaweed biomass as precursors. The synthesized CoP@C-NPs/GA-5 exhibits efficient catalytic activity with small overpotentials of 120 and 225 mV at current densities of 10 mA cm-2, along with the low Tafel slopes of 57 and 66 mV dec-1, for HER in acidic and alkaline electrolytes, respectively. Compared with carbon aerogel (CA) containing cobalt phosphide nanoparticles (CoP-NPs@CA), the stability of CoP@C-NPs/GA-5 coated with carbon-shells (~0.8 nm) was significantly improved in acidic electrolytes. We also prepared carbon core-shell materials containing nickel phosphide nanoparticles embedded in GA (Ni2P@C-NPs/GA) to further expand this synthetic route. The graphene-Ni2P@C aerogel shows a similar morphology and better catalytic activity for HER in acidic and alkaline electrolytes. In this work, the robust three-dimensional (3D) GA matrix with abundant open pores and large surface area provides unblocked channels for electrolyte contact and electronic transfer and enables very close contact between the catalyst and electrolyte. The MxP@C core-shell structure prevents the inactivation of MxP NPs during HER processes, and the thin graphene oxide (GO) layers and 3D CA together build up a 3D conductive matrix, which not only adjusts the volume expansion of MxP NPs as well as preventing their aggregation, but also provides a 3D conductive pathway for rapid charge transfer processes. The present synthetic strategy for phosphides via in situ phosphorization with 3D GA can be extended to other novel high-performance catalysts. The simple synthesis and efficient catalytic activity of MXP@C-NPs/GA indicate good application prospects in HER. PMID- 29762621 TI - Ni-core CuO-shell fibers produced by electrospinning and electroplating as efficient photocathode materials for solar water splitting. AB - Charge recombination in CuO photocathodes inhibits efficient electron flow and limits the photo-electrochemical performance of these cathodes for solar water splitting. To circumvent this shortcoming, we introduce highly conductive Ni/CuO core-shell structured fibers. The photocurrent density (PCD) achieved with these core-shell fibers exceeded that of fibers without a Ni core by a factor of 2.6. The PCD enhancement arises from increased acceptor concentration and electron hole recombination time, as measured by electrochemical impedance spectroscopy. These core-shell nanofibers were fabricated via electrospinning and electroplating. First, a polyacrylonitrile fiber was electrospun and then seeded with metal via sputtering. Second, electroplating was used to encase and metalize the fiber with Ni and Cu. Finally, the outermost Cu shell was oxidized to CuO, which is an effective photocathode for solar water splitting. The Ni-CuO, core shell layers were characterized by scanning electron microscopy, elemental mapping, X-ray diffraction, and X-ray photoelectron spectroscopy. The core Ni content and number of core-shell fibers per area were optimized through parametric studies. PMID- 29762622 TI - Charge-switchable nanocapsules with multistage pH-responsive behaviours for enhanced tumour-targeted chemo/photodynamic therapy guided by NIR/MR imaging. AB - Multifunctional nanoplatforms have been developed into advanced drug delivery systems for cancer therapy. In this study, we report a charge-switchable nanocapsule with multistage pH-responsive behaviors. First, DOX-encapsulated and oleylamine-embedded hollow structures with a diameter of 132 +/- 21 nm are prepared via the double emulsion method. Subsequently, the hollow structures are encompassed by Gd-DTPA-, chlorin e6 (Ce6)-, and folate (FA)-modified BSA to form tumour-targeted, dual NIR/MR imaging-guided and chemo-photodynamic therapeutic nanoplatforms. Importantly, the nanocapsule can intelligently switch its surface charge to positive under mildly acidic conditions (pH 6.5) with no release of Ce6 and DOX, which is confirmed by xi-potential and cumulative release measurements. Moreover, confocal imaging pictures demonstrate that acid-sensitive DOX sealed in nanocapsules is progressively released into the nuclei of MGC-803 cells. These advantages as well as FA-targeting facilitate effective endocytosis and synergistic therapeutic efficacy. Selective tumour accumulation and long tumour retention time are further indicated by NIR/MR in vivo imaging. In addition, excellent therapeutic efficacy combined with chemotherapy (DOX) and photodynamic therapy (PDT) is observed with the tumour eventually ablating at the 15th day. All results demonstrate that the as-prepared nanocapsules hold great potential for clinical cancer theranostics. PMID- 29762623 TI - Nanowire lasers as intracellular probes. AB - We investigate a cadmium sulfide (CdS) nanowire (NW) laser that is spontaneously internalized into a single cell to serve as a stand-alone intracellular probe. By pumping with nano-joule light pulses, green laser emission (500-520 nm) can be observed inside cells with a peak linewidth as narrow as 0.5 nm. Due to the sub micron diameter (~200 nm), the NW has an appreciable fraction of the evanescent field outside, facilitating a sensitive detection of cellular environmental changes. By monitoring the lasing peak wavelength shift in response to the intracellular refractive index change, our NW laser probe shows a sensitivity of 55 nm per RIU (refractive index units) and a figure of merit of approximately 98. PMID- 29762624 TI - Recent progress of metal-graphene nanostructures in photocatalysis. AB - Metal-graphene nanostructures (NSs) as photocatalysts, prepared using simple and scalable synthesis methods, are gaining heightened attention as novel materials for water treatment and environmental remediation applications. Graphene, the unique few layers sheet-like arrangement of sp2 hybridized carbon atoms, has an inimitable two-dimensional (2D) structure. The material is highly conductive, has high electron mobility and an extremely high surface area, and can be produced on a large scale at low cost. Accordingly, it has been considered as an essential base component for producing various metal-based NSs. In particular, metal graphene NSs as photocatalysts have attracted considerable attention because of their special surface plasmon resonance (SPR) effect that can improve their performance for the removal of toxic dyes and other pollutants. This review summarizes the recent and advanced progress for the easy fabrication and design of graphene-based NSs as photocatalysts, as a novel tool, using a range of approaches, including green and biogenic approaches. PMID- 29762625 TI - An asymmetric fitting function for condensed-phase Raman spectroscopy. AB - Asymmetric lineshapes are experimentally observed in the Raman spectra of different classes of condensed matter. Determination of the peak parameters, typically done with symmetric pseudo-Voigt functions, in such situations yields unreliable results. While a wide choice of asymmetric fitting functions is possible, for the function to be practically useful, it should satisfy several criteria: simple analytic form, minimum parameters, description of the symmetric shape as "zero case", estimation of the desired peak parameters in a straightforward way and, above all, adequate description of the experimental data. In this work we formulate the asymmetric pseudo-Voigt function by damped perturbation of the original symmetric shapes with one asymmetry-related parameter. The damped character of the perturbation ensures by construction consistent behavior of the line tails. We test the asymmetric function by fitting the experimental Raman spectra. The results show that the function is able to describe a wide range of experimentally observed asymmetries for different natures of asymmetric broadening, including 3D and 2D crystals, nanoparticles, polymers, and molecular solids and liquids. PMID- 29762629 TI - Osseous Frame Index calculations of the early medieval South-West Germany. AB - ABSTRACT: The proper description of former populations is one of the most difficult tasks in anthropology. Archaeological material is often limited due to fragmented and sometimes poorly preserved bone material resulting in incomplete data. Published skeletal raw data are available from the past, but much of this data is either unavailable or not used for scientific studies. The authors seek to elicit more information about prehistoric times by using this dataset to introduce a new method. The purpose is to provide an approach to reconstruct a former population in respect to robusticity and health status. For this in the pilot study the Body Mass Index (BMI) and Frame Index (FI) of early medieval South-West Germany have been analysed. The FI, in contrast to the BMI, has not yet been used for robusticity analysis utilizing only skeletal remains. As far as we know, this is the first time that the FI has been calculated using archaeological material. Due to unknown soft-tissue thickness we introduce the Osseous Frame Index (OFI). The measured OFI reveals new insights in (pre )historic populations and allows comparisons with modern reference samples. Our OFI calculations are relatively similar to modern calculations. Males have a higher robusticity than females, slightly increasing during life-time compared to females. These calculations provide a better historical understanding of human body composition. PMID- 29762630 TI - Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics. AB - Definitions and descriptions of acute-on-chronic liver failure (ACLF) vary between Western and Eastern types, and alcoholism and hepatitis B virus (HBV) are, respectively, the main etiologies. To determine whether there are unified diagnostic criteria and common treatment programs for different etiologies of ACLF, a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European Consortium Acute-on-Chronic Liver Failure in Cirrhosis Study is urgently needed in Asia, where the prevalence of HBV is high. A multicenter prospective cohort of 2,600 patients was designed, drawing from 14 nationwide liver centers from tertiary university hospitals in China, and 2,600 hospitalized patients with chronic liver disease (both cirrhotic and noncirrhotic) of various etiologies with acute decompensation or acute hepatic injury were continuously recruited from January 2015 to December 2016. Data were collected during hospitalization, and follow-ups were performed once a month, with plans to follow all patients until 36 months after hospital discharge. Of these patients, 1,859 (71.5%) had HBV-related disease, 1,833 had cirrhotic disease, and 767 had noncirrhotic disease. The numbers and proportions of enrolled patients from each participating center and the baseline characteristics of the patients with or without cirrhosis are presented. PMID- 29762631 TI - Aqueous extracts of walnut (Juglans regia L.) leaves: quantitative analyses of hydroxycinnamic and chlorogenic acids. AB - Identification of both hydroxycinnamic and chlorogenic acids present in aqueous extracts of walnut leaves (Juglans regia L.) were carried out by using, for the first time, standard compounds not commercially available for qualitative identification. In particular, in addition to caffeic, ferulic, p-coumaric and sinapic acids, cis and trans mono-caffeoylquinic, dicaffeoylquinic, mono feruloylquinic and cis and trans mono-p-coumaroylquinic acid isomers were detected and quantified by Ultra High Pressure Liquid Chromatography and the seasonal variations of these secondary metabolites were investigated. PMID- 29762632 TI - Stratification of mouse vaginal epithelium 2. Identification of factors inducing stratification. AB - Stratification of the vaginal epithelium is regulated by stromal factors. To analyze the mechanisms of stratification in vitro, 3 dimensional (3D) co-culture models were established with clonal cell lines. In the models, stromal cells were embedded in collagen gel and epithelial cells were seeded on the gel. In the 3D co-culture, stromal SV-6c4a1b cells induced epithelial stratification but stromal MV-1e6g1a cells did not, suggesting that SV-6c4a1b cells secrete molecules to induce stratification. Microarray analyses of these stromal cell lines identified chordin-like 1 (Chrd1) and WNT1 inducible signaling pathway protein 2 (Wisp2) as candidate genes inducing stratification. Chrdl1 variant1 and variant2 mRNAs were expressed not only in stromal SV-6c4a1b and MV-1e6g1a cells but also in epithelial SV-4b6b cells. Wisp2-overexpressing MV-1e6g1a cells, secreting WISP2 as much as SV-6c4a1b cells, induced stratification of epithelial cells. In addition, Wisp2-knockdowned SV-6c4a1b cells were unable to induce epithelial stratification. These results suggest that WISP2 is one of the stromal factors inducing stratification of the mouse vaginal epithelium. PMID- 29762633 TI - Using a Mixture-of-Bivariate-Regressions Model to Explore Heterogeneity of Effects of the Use of Inhaled Corticosteroids on Gestational Age and Birth Weight Among Pregnant Women With Asthma. AB - Asthma is a heterogeneous disease, and responses to asthma medications vary noticeably among patients. A substantively oriented objective of this study was to explore the potentially heterogeneous effects of exposure to maternal inhaled corticosteroids (ICS) on gestational age (GA) at delivery and birth weight (BW) using a cohort of 6,197 pregnancies among women with asthma (Quebec, Canada, 1998 2008). A methodologically oriented objective was to comprehensively describe the application of a Bayesian 2-component mixture-of-bivariate-regressions model to address this issue and estimate the effects of ICS on GA and BW jointly. Based on the proposed model, no association between ICS and GA/BW was found for a large proportion of asthmatic pregnancies. However, a positive association between ICS exposure and GA/BW was revealed in a small subset of pregnancies comprising mainly preterm and low-birth-weight infants. A novel application of this model was also subsequently performed using BW z score instead of BW as the outcome variable. In conclusion, the studied mixture-of-bivariate-regressions model was useful for detecting heterogeneity in the effect of ICS on GA and BW in our population of women with asthma. These analyses pave the way for analogous uses of this model for general assessment of exposure effect heterogeneity for these perinatal outcomes. PMID- 29762634 TI - Lineage-associated underrepresented permutations (LAUPs) of mammalian genomic sequences based on a Jellyfish-based LAUPs analysis application (JBLA). AB - Motivation: This study addresses several important questions related to naturally underrepresented sequences: (i) are there permutations of real genomic DNA sequences in a defined length (k-mer) and a given lineage that do not actually exist or underrepresented? (ii) If there are such sequences, what are their characteristics in terms of k-mer length and base composition? (iii) Are they related to CpG or TpA underrepresentation known for human sequences? We propose that the answers to these questions are of great significance for the study of sequence-associated regulatory mechanisms, such cytosine methylation and chromosomal structures in physiological or pathological conditions such as cancer. Results: We empirically defined sequences that were not included in any well-known public databases as lineage-associated underrepresented permutations (LAUPs). Then, we developed a Jellyfish-based LAUPs analysis application (JBLA) to investigate LAUPs for 24 representative species. The present discoveries include: (i) lengths for the shortest LAUPs, ranging from 10 to 14, which collectively constitute a low proportion of the genome. (ii) Common LAUPs showing higher CG content over the analysed mammalian genome and possessing distinct CG*CG motifs. (iii) Neither CpG-containing LAUPs nor CpG island sequences are randomly structured and distributed over the genomes; some LAUPs and most CpG containing sequences exhibit an opposite trend within the same k and n variants. In addition, we demonstrate that the JBLA algorithm is more efficient than the original Jellyfish for computing LAUPs. Availability and implementation: We developed a Jellyfish-based LAUP analysis (JBLA) application by integrating Jellyfish (Marcais and Kingsford, 2011), MEME (Bailey, et al., 2009) and the NCBI genome database (Pruitt, et al., 2007) applications, which are listed as Supplementary Material. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762635 TI - An Epigenome-Wide Association Study (EWAS) of Obesity-Related Traits. AB - We conducted an epigenome-wide association study on obesity-related traits. We used data from two prospective, population-based cohort studies: the Rotterdam Study (RS) (2006-2013) and the Atherosclerosis Risk in Communities (ARIC) Study (1990-1992). We used RS (n = 1,454) as the discovery panel and ARIC (n = 2,097) as replication panel. Linear mixed-effect models were used to assess the cross sectional association between genome-wide DNA methylation in leukocytes with body mass index (BMI) and waist circumference (WC) adjusting for sex, age, smoking, leukocyte proportions, array number and position on array. The two latter were modelled as random effects. Fourteen CpGs were associated with BMI and 26 CpGs with WC in RS after Bonferroni-correction (P < 1.07 * 10-7), of which 12 and 13 CpGs replicated in ARIC Study, respectively. The most significant novel CpGs were located at MSI2 (cg21139312) and LARS2 (cg18030453) and were associated both with BMI and WC. CpGs at BRDT, PSMD1, IFI44L, MAP1A, and MAP3K5 were associated with BMI. CpGs at LGALS3BP, MAP2K3, DHCR24, CPSF4L, and TMEM49 were associated with WC. We report novel associations of methylation at MSI2 and LARS2 with obesity related traits. These results provide further insight in mechanisms underlying obesity-related traits, which can enable identification of new biomarkers in obesity-related chronic diseases. PMID- 29762638 TI - TimeXNet Web: identifying cellular response networks from diverse omics time course data. AB - Summary: Condition-specific time-course omics profiles are frequently used to study cellular response to stimuli and identify associated signaling pathways. However, few online tools allow users to analyze multiple types of high throughput time-course data. TimeXNet Web is a web server that extracts a time dependent gene/protein response network from time-course transcriptomic, proteomic or phospho-proteomic data, and an input interaction network. It classifies the given genes/proteins into time-dependent groups based on the time of their highest activity and identifies the most probable paths connecting genes/proteins in consecutive groups. The response sub-network is enriched in activated genes/proteins and contains novel regulators that do not show any observable change in the input data. Users can view the resultant response network and analyze it for functional enrichment. TimeXNet Web supports the analysis of high-throughput data from multiple species by providing high quality, weighted protein-protein interaction networks for 12 model organisms. Availability and implementation: http://txnet.hgc.jp/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762637 TI - SET8 is involved in the regulation of hyperglycemic memory in human umbilical endothelial cells. AB - Hyperglycemic memory occurs in diabetic cardiovascular complications, but the underlying mechanism remains to be elucidated. Although the depletion of SET8 leads to increased mitochondrial oxidative stress via increasing cellular reactive oxygen species (ROS) production, the role of SET8 in hyperglycemic memory-induced mitochondrial dysfunction is not well understood. Here, we investigated the role of SET8 in this setting. Our results showed that high glucose-induced vascular inflammation, ROS production and apoptosis remained at high levels even when glucose returned to normal level. Elevated glucose reduced SET8 expression, which also remained at low level after returning to normoglycemia. SET8 overexpression protected cells from elevated glucose and hyperglycemic memory-induced endothelial injury by blocking ROS accumulation, attenuating vascular inflammation, and restoring nitric oxide production. Thus, our results suggest that SET8 may be a key mediator in hyperglycemic memory. PMID- 29762641 TI - Functional genomics: paving the way for more successful cancer immunotherapy. AB - Immunotherapies have revolutionized cancer treatment. Immunotherapy is effective for the treatment of a wide range of cancer types and can mediate complete and durable tumor regression. Nonetheless, the field still faces many significant challenges, such as the need for personalized therapeutic strategies and better biomarkers, the difficulty of selecting the right combination therapy, and resistance to currently available immunotherapies. Both cancer and host immunity comprise significantly diverse and complex ecosystems, making immunogenomics an ideal field for functional genomics analysis. In this review, we describe the cancer-immunity cycle, how cancer cells manage to evade immune attack and the current hurdles in the path of cancer immunotherapy. Then, we discuss how functional genomics approaches can pave the way for more successful cancer immunotherapies. PMID- 29762640 TI - MRMAssayDB: an integrated resource for validated targeted proteomics assays. AB - Motivation: Multiple Reaction Monitoring (MRM)-based targeted proteomics is increasingly being used to study the molecular basis of disease. When combined with an internal standard, MRM allows absolute quantification of proteins in virtually any type of sample but the development and validation of an MRM assay for a specific protein is laborious. Therefore, several public repositories now host targeted proteomics MRM assays, including NCI's Clinical Proteomic Tumor Analysis Consortium assay portals, PeptideAtlas SRM Experiment Library, SRMAtlas, PanoramaWeb and PeptideTracker, with all of which contain different levels of information. Results: Here we present MRMAssayDB, a web-based application that integrates these repositories into a single resource. MRMAssayDB maps and links the targeted assays, annotates the proteins with information from UniProtKB, KEGG pathways and Gene Ontologies, and provides several visualization options on the peptide and protein level. Currently MRMAssayDB contains >168K assays covering more than 34K proteins from 63 organisms; >13.5K of these proteins are present in >2.3K KEGG biological pathways corresponding to >300 master pathways, and mapping to >13K GO biological processes. MRMAssayDB allows comprehensive searches for a targeted-proteomics assay depending on the user's interests, by using target protein name or accession number, or using annotations such as subcellular localization, biological pathway, or disease or drug associations. The user can see how many data repositories include a specific peptide assay, and the commonly used transitions for each peptide in all empirical data from the repositories. Availability and implementation: http://mrmassaydb.proteincentre.com. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762636 TI - Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Attention Deficit Hyperactivity Disorder in Offspring. AB - Children whose mothers experienced childhood abuse are more likely to suffer various neurodevelopmental deficits. Whether an association exists specifically for attention deficit hyperactivity disorder (ADHD) is unknown. We examined the association of maternal experience of childhood abuse with ADHD in offspring, assessed by maternal report of diagnosis and validated with the ADHD Rating Scale IV in a subsample, in the Nurses' Health Study II (n = 49,497 mothers; n = 7,607 case offspring; n = 102,151 control offspring). We examined whether 10 adverse perinatal circumstances (e.g., prematurity, smoking) or socioeconomic factors accounted for a possible association. Exposure to abuse was associated with greater prevalence of ADHD in offspring (8.7% of offspring of women exposed to severe abuse vs. 5.5% of offspring of women not abused, P = 0.0001) and with greater risk for ADHD when the model was adjusted for demographic factors (male offspring, risk ratio (RR) = 1.6, 95% confidence interval (CI): 1.3, 1.9; female offspring, RR = 2.3, 95% CI: 1.7, 3.0). After adjustment for perinatal factors, the association of maternal childhood abuse with ADHD in offspring was slightly attenuated (male offspring, RR = 1.5, 95% CI: 1.2, 1.8; female offspring, RR = 2.1, 95% CI: 1.6, 2.8). We identified an association between maternal experience of childhood abuse and risk for ADHD in offspring, which was not explained by several important perinatal risk factors or socioeconomic status. PMID- 29762642 TI - OnabotulinumtoxinA and Hyaluronic Acid in Facial Wrinkles and Folds: A Prospective, Open-Label Comparison. AB - Background: OnabotulinumtoxinA and hyaluronic acid are effective in improving moderate-to-severe facial wrinkles and folds, with treatment selection traditionally based upon facial area. Objective: This prospective, multicenter, open-label, crossover study evaluated physician-rated efficacy and patient-rated outcomes following moderate-to-severe facial wrinkles and folds treatment with onabotulinumtoxinA and hyaluronic acid. Methods: 152 subjects (25-65 years) were randomized (1:1) to a treatment-sequence of onabotulinumtoxinA/hyaluronic acid or hyaluronic acid/onabotulinumtoxinA, with initial treatment administered on Day 1 and 6 additional visits: Week 2 (touch-up); Week 4 (crossover); Week 6 (touch up); and Weeks 8, 12, and 24 (follow-up). Results: Between 92% and 100% of subjects in each treatment-sequence group exhibited at least some improvement from baseline at each study visit in the Physician Aesthetic Improvement Scale and the Objective Observer- and Patient-Global Assessments of Improvement, with no significant between-sequence differences. Subjects reported looking 3-6 years younger at each visit, with significant improvements in glabellar-, lateral canthal-, and horizontal forehead-lines, and nasolabial folds. Treatments were well-tolerated. Conclusion: OnabotulinumtoxinA and hyaluronic acid provide clinically meaningful improvements as rated by physicians, objective observers, and subjects, with clinical synergy in aesthetic effects and duration of response regardless of treatment administration order in subjects seeking improvement in moderate-to-severe facial wrinkles and folds. PMID- 29762645 TI - FlexiDot: highly customizable, ambiguity-aware dotplots for visual sequence analyses. AB - Summary: FlexiDot is a cross-platform dotplot suite generating high quality self, pairwise and all-against-all visualizations. To improve dotplot suitability for comparison of consensus and error-prone sequences, FlexiDot harbors routines for strict and relaxed handling of ambiguities and substitutions. Our shading modules facilitate dotplot interpretation and motif identification by adding information on sequence annotations and sequence similarities. Combined with collage-like outputs, FlexiDot supports simultaneous visual screening of large sequence sets, enabling dotplot use for routine analyses. Availability and implementation: FlexiDot is implemented in Python 2.7. Software and documentation are freely available at http://github.com/molbio-dresden/flexidot. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762644 TI - Indexed variation graphs for efficient and accurate resistome profiling. AB - Motivation: Antimicrobial resistance (AMR) remains a major threat to global health. Profiling the collective AMR genes within a metagenome (the 'resistome') facilitates greater understanding of AMR gene diversity and dynamics. In turn, this can allow for gene surveillance, individualized treatment of bacterial infections and more sustainable use of antimicrobials. However, resistome profiling can be complicated by high similarity between reference genes, as well as the sheer volume of sequencing data and the complexity of analysis workflows. We have developed an efficient and accurate method for resistome profiling that addresses these complications and improves upon currently available tools. Results: Our method combines a variation graph representation of gene sets with a locality-sensitive hashing Forest indexing scheme to allow for fast classification of metagenomic sequence reads using similarity-search queries. Subsequent hierarchical local alignment of classified reads against graph traversals enables accurate reconstruction of full-length gene sequences using a scoring scheme. We provide our implementation, graphing Resistance Out Of meTagenomes (GROOT), and show it to be both faster and more accurate than a current reference-dependent tool for resistome profiling. GROOT runs on a laptop and can process a typical 2 gigabyte metagenome in 2 min using a single CPU. Our method is not restricted to resistome profiling and has the potential to improve current metagenomic workflows. Availability and implementation: GROOT is written in Go and is available at https://github.com/will-rowe/groot (MIT license). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762643 TI - Educational Mobility Across Generations and Depressive Symptoms Over 10 Years Among US Latinos. AB - Few studies have collected intergenerational data to assess the association between educational mobility across multiple generations and offspring depression. Using data from the Sacramento Area Latino Study on Aging (1998 2008), we assessed the influence of intergenerational education on depressive symptoms over 10 years among 1,786 Latino individuals (mean age = 70.6 years). Educational mobility was classified: stable-low (low parent/low offspring education), upwardly mobile (low parent/high offspring education), stable-high (high parent/high offspring education), or downwardly mobile (high parent/low offspring education). Depressive symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D); higher scores indicated more depressive symptoms. To quantify the association between educational mobility and CES-D scores over follow-up, we used generalized estimating equations to account for repeated CES-D measurements and adjusted for identified confounders. Within individuals, depressive symptoms remained relatively stable over follow-up. Compared to stable-low education, stable-high education and upward mobility were associated with significantly lower CES-D scores (beta = -2.75 and -2.18, respectively). Downwardly mobile participants had slightly lower CES-D scores than stable-low participants (beta = -0.77). Our results suggest that sustained low educational attainment across generations may have adverse mental health consequences, and improved educational opportunities in under-resourced communities may counteract the adverse influence of low parental education on Latino depression. PMID- 29762646 TI - Correcting mistakes in predicting distributions. AB - Motivation: Many applications monitor predictions of a whole range of features for biological datasets, e.g. the fraction of secreted human proteins in the human proteome. Results and error estimates are typically derived from publications. Results: Here, we present a simple, alternative approximation that uses performance estimates of methods to error-correct the predicted distributions. This approximation uses the confusion matrix (TP true positives, TN true negatives, FP false positives and FN false negatives) describing the performance of the prediction tool for correction. As proof-of-principle, the correction was applied to a two-class (membrane/not) and to a seven-class (localization) prediction. Availability and implementation: Datasets and a simple JavaScript tool available freely for all users at http://www.rostlab.org/services/distributions. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762647 TI - Maternal Low Protein Diet Impairs Prostate Growth in Young Rat Offspring and Induces Prostate Carcinogenesis with Aging. AB - Carcinogenesis is frequently linked to genetic background, however, exposure to environmental risk factors has gained attention as the etiologic agent for several types of cancer, including prostate. The intrauterine microenvironment has been described as a preponderant factor for offspring health; and maternal exposure to insult has been linked to chronic disease in older offspring. Using a model of maternal exposure to low protein diet (LPD; 6% protein), we demonstrated that impairment of offspring rat prostatic growth on postnatal day (PND) 21 was associated with prostate carcinogenesis in older offspring (PND 540). One explanation is that maternal LPD consumption exposed offspring to an estrogenic intrauterine microenvironment, which potentially sensitized prostate cells early during glandular morphogenesis, increasing cellular response to estrogen in older rats. The onset of accelerated prostatic growth, observed on PND 21, associated with an unbalanced estrogen/testosterone ratio and increased circulating IGF-1 in older offspring appears to contribute to the development of prostate carcinoma in gestational groups on low protein (GLP) and gestational and lactational low protein (GLLP) diets (33% and 50%, respectively). Our study strongly indicated maternal exposure to LPD as a potential risk factor for induction of slow-growing prostate carcinogenesis in rat offspring later in life. PMID- 29762648 TI - A new framework for conceptualizing symptoms in frontotemporal dementia: from animal models to the clinic. AB - Behavioural-variant frontotemporal dementia is characterized by a number of ostensibly disparate clinical features, which have largely been considered independently. This Update proposes an integrated conceptual framework for these symptoms, by bringing together findings from animal studies, functional neuroimaging and behavioural neurology. The combined evidence indicates that many of the clinical symptoms--such as altered eating behaviour; overspending and susceptibility to scams; reduced empathy and socially inappropriate behaviour; apathy and stereotyped/ritualistic behaviour--can be conceptualized as a common underlying deficiency in goal-directed behaviour and the concomitant emergence of habits. This view is supported by similarities between the characteristic patterns of frontostriatal and insular atrophy in behavioural-variant frontotemporal dementia and the circuitry of homologous brain regions responsible for goal-directed and habitual behaviour in animals. Appreciating the impact of disturbance in goal-directed behaviour provides a new, integrated understanding of the common mechanisms underpinning prototypical clinical symptoms in behavioural-variant frontotemporal dementia. Furthermore, by drawing parallels between animal and clinical research, this translational approach has important implications for the development and evaluation of novel therapeutic treatments, from animal models through to behavioural interventions and clinical trials in humans. PMID- 29762649 TI - Residential Racial Isolation and Spatial Patterning of Type 2 Diabetes Mellitus in Durham, North Carolina. AB - Neighborhood characteristics such as racial segregation may be associated with type 2 diabetes mellitus, but studies have not examined these relationships using spatial models appropriate for geographically patterned health outcomes. We constructed a local, spatial index of racial isolation (RI) for black residents in a defined area, measuring the extent to which they are exposed only to one another, to estimate associations of diabetes with RI and examine how RI relates to spatial patterning in diabetes. We obtained electronic health records from 2007-2011 from the Duke Medicine Enterprise Data Warehouse. Patient data were linked to RI based on census block of residence. We used aspatial and spatial Bayesian models to assess spatial variation in diabetes and relationships with RI. Compared with spatial models with patient age and sex, residual geographic heterogeneity in diabetes in spatial models that also included RI was 29% and 24% lower for non-Hispanic white and black residents, respectively. A 0.20-unit increase in RI was associated with an increased risk of diabetes for white (risk ratio = 1.24, 95% credible interval: 1.17, 1.31) and black (risk ratio = 1.07, 95% credible interval: 1.05, 1.10) residents. Improved understanding of neighborhood characteristics associated with diabetes can inform development of policy interventions. PMID- 29762650 TI - Transform-MinER: transforming molecules in enzyme reactions. AB - Motivation: One goal of synthetic biology is to make new enzymes to generate new products, but identifying the starting enzymes for further investigation is often elusive and relies on expert knowledge, intensive literature searching and trial and error. Results: We present Transform Molecules in Enzyme Reactions, an online computational tool that transforms query substrate molecules into products using enzyme reactions. The most similar native enzyme reactions for each transformation are found, highlighting those that may be of most interest for enzyme design and directed evolution approaches. Availability and implementation: https://www.ebi.ac.uk/thornton-srv/transform-miner. PMID- 29762651 TI - Development of an LC-MS Method for 4-Fluoroaniline Determination in Ezetimibe. AB - A rapid and sensitive high-performance liquid chromatography-mass spectrometry method was developed and validated to determine 4-fluoroaniline concentration in ezetimibe. Chromatographic separation was achieved on a Phenomenex Gemini-NX C18 column (150 * 4.6 mm, 3 MUm) maintained at 30 degrees C. The liquid chromatography system was operated in gradient mode with an injection volume of 20 MUL at a flow rate of 1 mL/min. Mobile phase A was water and mobile phase B consisted of acetonitrile with 0.05% acetic acid. The detection was performed using a single quadrupole mass spectrometer in single ion monitoring mode by using positive ionization. An m/z value of 112 was selected for monitoring 4 fluoroaniline. The method showed good linearity over the concentration range of 0.94-30.26 ng/mL. The limit of quantification and limit of detection were 0.19 and 0.94 ng/mL, respectively. The precision relative standard deviations were less than 8.7% (n = 12), and the accuracy values were within 92-99%. A standard solution of 4-fluoroaniline was stable for at least 24 h at 25 degrees C. Small changes in the organic phase acidity of the mobile phase, flow rate, column temperature, and the instrument parameters had no significant effect on the results for 4-fluoroaniline. PMID- 29762654 TI - Testing of Disposable Protective Garments Against Isocyanate Permeation From Spray Polyurethane Foam Insulation. AB - Background: Diisocyanates (isocyanates), including methylene diphenyl diisocyanate (MDI), are the primary reactive components of spray polyurethane foam (SPF) insulation. They are potent immune sensitizers and a leading cause of occupational asthma. Skin exposure to isocyanates may lead to both irritant and allergic contact dermatitis and possibly contribute to systemic sensitization. More than sufficient evidence exists to justify the use of protective garments to minimize skin contact with aerosolized and raw isocyanate containing materials during SPF applications. Studies evaluating the permeation of protective garments following exposure to SPF insulation do not currently exist. Objectives: To conduct permeation testing under controlled conditions to assess the effectiveness of common protective gloves and coveralls during SPF applications using realistic SPF product formulations. Methods: Five common disposable garment materials [disposable latex gloves (0.07 mm thickness), nitrile gloves (0.07 mm), vinyl gloves (0.07 mm), polypropylene coveralls (0.13 mm) and Tyvek coveralls (0.13 mm)] were selected for testing. These materials were cut into small pieces and assembled into a permeation test cell system and coated with a two-part slow rise spray polyurethane foam insulation. Glass fiber filters (GFF) pretreated with 1-(9-anthracenylmethyl)piperazine) (MAP) were used underneath the garment to collect permeating isocyanates. GFF filters were collected at predetermined test intervals between 0.75 and 20.00 min and subsequently analyzed using liquid chromatography-tandem mass spectrometry. For each garment material, we assessed (i) the cumulative concentration of total isocyanate, including phenyl isocyanate and three MDI isomers, that effectively permeated the material over the test time; (ii) estimated breakthrough detection time, average permeation rate, and standardized breakthrough time; from which (iii) recommendations were developed for the use of similar protective garments following contamination by two component spray polyurethane foam systems and the limitations of such protective garments were identified. Results: Each type of protective garment material demonstrated an average permeation rate well below the ASTM method F-739 standardized breakthrough rate threshold of 100.0 ng/cm2 min-1. Disposable latex gloves displayed the greatest total isocyanate permeation rate (4.11 ng/cm2 min 1), followed by the vinyl and nitrile gloves, respectively. The Tyvek coverall demonstrated a greater average rate of isocyanate permeation than the polypropylene coveralls. Typical isocyanate loading was in the range of 900 to 15,000 ng MDI/cm2. Conclusion: Permeation test data collected during this study indicated that each type of protective garment evaluated, provided a considerable level of protection (i.e. 10-110-fold reduction from the level of direct exposure) against the isocyanate component of the SPF insulation mixture. Nitrile gloves and polypropylene coveralls demonstrated the lowest rate of permeation and the lowest cumulative permeation of total isocyanate for each garment type. PMID- 29762652 TI - SolCyc: a database hub at the Sol Genomics Network (SGN) for the manual curation of metabolic networks in Solanum and Nicotiana specific databases. AB - Database URL: https://solgenomics.net/tools/solcyc/. PMID- 29762653 TI - RecPhyloXML: a format for reconciled gene trees. AB - Motivation: A reconciliation is an annotation of the nodes of a gene tree with evolutionary events-for example, speciation, gene duplication, transfer, loss, etc.-along with a mapping onto a species tree. Many algorithms and software produce or use reconciliations but often using different reconciliation formats, regarding the type of events considered or whether the species tree is dated or not. This complicates the comparison and communication between different programs. Results: Here, we gather a consortium of software developers in gene tree species tree reconciliation to propose and endorse a format that aims to promote an integrative-albeit flexible-specification of phylogenetic reconciliations. This format, named recPhyloXML, is accompanied by several tools such as a reconciled tree visualizer and conversion utilities. Availability and implementation: http://phylariane.univ-lyon1.fr/recphyloxml/. PMID- 29762655 TI - Longitudinal Patterns of Physical Activity Among Older Adults: A Latent Transition Analysis. AB - Most epidemiologic studies of physical activity measure either total energy expenditure or engagement in a single type of activity, such as walking. These approaches may gloss over important nuances in activity patterns. We performed a latent transition analysis to identify patterns of activity, as well as neighborhood and individual determinants of changes in those activity patterns, over 2 years in a cohort of 2,023 older adult residents of New York, New York, surveyed between 2011 and 2013. We identified 7 latent classes: 1) mostly inactive, 2) walking, 3) exercise, 4) household activities and walking, 5) household activities and exercise, 6) gardening and household activities, and 7) gardening, household activities, and exercise. The majority of subjects retained the same activity patterns between waves (54% unchanged between waves 1 and 2, 66% unchanged between waves 2 and 3). Most latent class transitions were between classes distinguished only by 1 form of activity, and only neighborhood unemployment was consistently associated with changing between activity latent classes. Future latent transition analyses of physical activity would benefit from larger cohorts and longer follow-up periods to assess predictors of and long term impacts of changes in activity patterns. PMID- 29762656 TI - Prevention of prostate cancer by natural product MDM2 inhibitor GS25: In vitro and in vivo activities and molecular mechanisms. AB - Prostate cancer remains a major health problem in the US and worldwide. There is an urgent need to develop novel approaches to preventing primary and metastatic prostate cancer. We have identified 25-OCH3-protopanaxadiol (GS25), the most active ginsenoside that has been identified so far; it has potent activity against human cancers, including prostate cancer. However, it has not been proven if GS25 could be a safe and effective agent for cancer prevention. In the present study, we used the TRAMP model and clearly demonstrated that GS25 inhibited prostate tumorigenesis and metastasis with minimal host toxicity. Mechanistically, GS25 directly bound to the RING domain of MDM2, disrupted MDM2 MDMX binding, and induced MDM2 protein degradation, resulting in strong inhibition of prostate cancer cell growth and metastasis, independent of p53 and androgen receptor status. In conclusion, our in vitro and in vivo data support the potential use of GS25 in prevention of primary and metastatic prostate cancer. PMID- 29762658 TI - Science in Places of Grandeur: Communication and Engagement in National Parks. AB - The USA has set aside over 400 national parks and other protected areas to be managed by the National Park Service (NPS). Collectively, these sites attract over 300 million visits per year which makes the NPS one of the largest informal education institutions in the country. Because the NPS supports and facilitates scientific studies in parks, the national park system provides abundant opportunity for biologists and other scientists to engage global audiences in learning, exploring, and even conducting science. Those opportunities are best pursued through collaborations among scientists and the professional communication staff (interpreters, educators, media specialists, etc.) of parks and their partner organizations. This article describes unique opportunities and rationale for such collaborations, presents several examples that highlight the range of activities and lessons drawn from them, and invites scientists to conduct studies in parks and bring their science into the public eye. PMID- 29762657 TI - Prospects for Tuberculosis Elimination in the United States: Results of a Transmission Dynamic Model. AB - We estimated long-term tuberculosis (TB) trends in the US population and assessed prospects for TB elimination. We used a detailed simulation model allowing for changes in TB transmission, immigration, and other TB risk determinants. Five hypothetical scenarios were evaluated from 2017 to 2100: 1) maintain current TB prevention and treatment activities (base case); 2) provision of latent TB infection testing and treatment for new legal immigrants; 3) increased uptake of latent TB infection screening and treatment among high-risk populations, including a 3-month isoniazid-rifapentine regimen; 4) improved TB case detection; and 5) improved TB treatment quality. Under the base case, we estimate that by 2050, TB incidence will decline to 14 cases per million, a 52% (95% posterior interval (PI): 35, 67) reduction from 2016, and 82% (95% posterior interval: 78, 86) of incident TB will be among persons born outside of the United States. Intensified TB control could reduce incidence by 77% (95% posterior interval: 66, 85) by 2050. We predict TB may be eliminated in US-born but not non-US-born persons by 2100. Results were sensitive to numbers of people entering the United States with latent or active TB, and were robust to alternative interpretations of epidemiologic evidence. TB elimination in the United States remains a distant goal; however, strengthening TB prevention and treatment could produce important health benefits. PMID- 29762660 TI - Quality indicators and their regular use in clinical practice: results from a survey among users of two cardiovascular National Registries in Sweden. AB - Objective: To examine the regular use of quality indicators from Swedish cardiovascular National Quality Registries (NQRs) by clinical staff; particularly differences in use between the two NQRs and between nurses and physicians. Design: Cross-sectional online survey study. Setting: Two Swedish cardiovascular NQRs: (a) Swedish Heart Failure Registry and (b) Swedeheart. Participants: Clinicians (n =185; 70% nurses, 26% physicians) via the NQRs' email networks. Main Outcome Measures: Frequency of NQR use for (a) producing healthcare activity statistics; (b) comparing results between similar departments; (c) sharing results with colleagues; (d) identifying areas for quality improvement (QI); (e) surveilling the impact of QI efforts; (f) monitoring effects of implementation of new treatment methods; (g) doing research and (h) educating and informing healthcare professionals and patients. Results: Median use of NQRs was 10 times a year (25th and 75th percentiles range: 3-23 times/year). Quality indicators from the NQRs were used mainly for producing healthcare activity statistics. Median use of Swedeheart was six times greater than Swedish Heart Failure Registry (SwedeHF; P < 0.000). Physicians used the NQRs more than twice as often as nurses (18 vs. 7.5 times/year; P < 0.000) and perceived NQR work more often as meaningful. Around twice as many Swedeheart users had the role to participate in data analysis and in QI efforts compared to SwedeHF users. Conclusions: Most respondents used quality indicators from the two cardiovascular NQRs infrequently (<3 times/year). The results indicate that linking registration of quality indicators to using them for QI activities increases their routine use and makes them meaningful tools for professionals. PMID- 29762661 TI - Phototransduction Gene Expression and Evolution in Cave and Surface Crayfishes. AB - In the absence of light in caves, animals have repeatedly evolved reduced eyes and visual systems. Whether the underlying genetic components remain intact in blind species remains unanswered across taxa. The freshwater crayfish have evolved to live in caves multiple times throughout their history; therefore, this system provides an opportunity to probe the genetic patterns and processes underlying repeated vision loss. Using transcriptomic data from the eyes of 14 species of cave and surface crayfishes, we identify the expression of 17 genes putatively related to visual phototransduction. We find a similarly complete repertoire of phototransduction gene families expressed in cave and surface species, but that the expression levels of those transcripts are consistently lower in cave species. We find statistical support for episodic positive selection, increased and decreased selection strength in caves, depending on the gene family. Analyses of gene expression evolution suggest convergent and possibly adaptive downregulation of these genes across eye-reduction events. Our results reveal a combination of evolutionary processes acting on the sequences and gene expression levels of vision-related genes underlying the loss of vision in caves. PMID- 29762659 TI - Independent assessment and improvement of wheat genome sequence assemblies using Fosill jumping libraries. AB - Background: The accurate sequencing and assembly of very large, often polyploid, genomes remains a challenging task, limiting long-range sequence information and phased sequence variation for applications such as plant breeding. The 15-Gb hexaploid bread wheat (Triticum aestivum) genome has been particularly challenging to sequence, and several different approaches have recently generated long-range assemblies. Mapping and understanding the types of assembly errors are important for optimising future sequencing and assembly approaches and for comparative genomics. Results: Here we use a Fosill 38-kb jumping library to assess medium and longer-range order of different publicly available wheat genome assemblies. Modifications to the Fosill protocol generated longer Illumina sequences and enabled comprehensive genome coverage. Analyses of two independent Bacterial Artificial Chromosome (BAC)-based chromosome-scale assemblies, two independent Illumina whole genome shotgun assemblies, and a hybrid Single Molecule Real Time (SMRT-PacBio) and short read (Illumina) assembly were carried out. We revealed a surprising scale and variety of discrepancies using Fosill mate-pair mapping and validated several of each class. In addition, Fosill mate pairs were used to scaffold a whole genome Illumina assembly, leading to a 3-fold increase in N50 values. Conclusions: Our analyses, using an independent means to validate different wheat genome assemblies, show that whole genome shotgun assemblies based solely on Illumina sequences are significantly more accurate by all measures compared to BAC-based chromosome-scale assemblies and hybrid SMRT Illumina approaches. Although current whole genome assemblies are reasonably accurate and useful, additional improvements will be needed to generate complete assemblies of wheat genomes using open-source, computationally efficient, and cost-effective methods. PMID- 29762662 TI - National Costs Associated with Methicillin-susceptible and Methicillin-resistant S. aureus Hospitalizations in the United States, 2010-2014. AB - Background: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have been associated with worse patient outcomes and higher costs of care than susceptible (MSSA) infections. However, the healthcare landscape has changed since prior studies found these differences, including widespread dissemination of community-associated strains of MRSA. Our objective was to provide updated estimates of the excess costs of resistant S. aureus infections. Methods: We conducted a retrospective analysis using data from the National Inpatient Sample from the Agency for Healthcare Research and Quality for the years 2010 to 2014. We calculated costs for hospitalizations including MRSA- and MSSA-related septicemia and pneumonia infections, as well as MRSA- and MSSA-related infections from conditions classified elsewhere and of an unspecified site ("other infections"). Differences in the costs of hospitalization were estimated using propensity score adjusted mortality outcomes for 2010 through 2014. Results: In 2014, estimated costs were highest for pneumonia and sepsis-related hospitalizations. Propensity score-adjusted costs were significantly higher for MSSA-related pneumonia ($40,725 vs $38,561; p=0.045) and other hospitalizations ($15,578 vs $14,792; p<0.001) than for MRSA-related hospitalizations. Similar patterns were observed from 2010 to 2013, though crude cost differences between MSSA- and MRSA-related pneumonia hospitalizations rose from 25.8% in 2010 to 31.0% in 2014. MRSA-related hospitalizations had a higher adjusted mortality rate than MSSA-related hospitalizations. Conclusions: Though MRSA infections had been previously associated with higher hospitalization costs, our results suggest that in recent years, costs associated with MSSA-related infections have converged with and may surpass costs of similar MRSA-related hospitalizations. PMID- 29762664 TI - Behavioral and Serotonergic Changes in the Frontal Cortex Following Methamphetamine Self-Administration. AB - Background: Methamphetamine (METH) use is associated with a variety of negative health outcomes including psychosis. The frontal cortex serotonin (5-HT)-2 receptors are thought to contribute to psychosis-like behaviors. This study investigated changes in serotonergic markers in the frontal cortex following METH self-administration and hallucinogenic drug-induced behavior. Methods: Consistent with previously published studies, freely-cycling male and female rats were allowed to self-administer METH (Males: 0.12 mg/infusion; Females: 0.09 mg/infusion) or saline (10 uL) for 7 days. On the day following self administration or following 10 d of extinction training, animals were given the 5 HT2A/2C agonist, DOI (2 mg/kg, i.p.), and head-twitches were analyzed. Results: METH self-administration lead to an increase in DOI-induced head-twitch behavior compared to saline only on the day following self-administration. Increases in 5 HT2 receptors in the orbitofrontal cortex and decreases in 5-HT transporters in the orbitofrontal cortex and infralimbic cortex were observed following METH self administration as assessed by autoradiography. Conclusions: Methamphetamine self administration was associated with serotonergic alterations in the frontal cortex which may underlie behavioral changes related to METH-associated psychosis. PMID- 29762665 TI - miR-194-3p Represses the Progesterone Receptor and Decidualization in Eutopic Endometrium From Women With Endometriosis. AB - Progesterone resistance in the eutopic endometrium (EuE) is suggested to be a critical factor for decreased endometrial receptivity and implantation failure in reproductive-aged women with endometriosis. Altered expression of miRNAs has been reported to play an important role in the pathophysiology of endometriosis associated infertility. However, the underlying mechanisms of aberrant progesterone receptor (PR) and deficient decidualization regulated by miRNAs in endometriosis have not been thoroughly elucidated. The goal of this study was to explore the regulation and roles of miR-194-3p in aberrant PR expression and impaired decidualization in endometrial stromal cells (ESCs) from the EuE of women with mild or minimal endometriosis. Using a series of studies, we observed decreased PR mRNA expression and an increasing PR-A/PR-B mRNA ratio trend in the midsecretory phase of the EuE of women with minimal or mild endometriosis (n = 19) compared with controls (n = 14); the increased expression of miR-194-3p in the endometriosis group was consistent with previous microarray analysis. We also found that PR protein levels were inhibited by the transfection of ESCs with an miR-194-3p mimic and upregulated by miR-194-3p inhibition. As predicted by the bioinformatic analysis, the 3'-untranslated region luciferase assay indicated the direct regulation of PR expression by miR-194-3p. Furthermore, miR-194-3p overexpression inhibited the in vitro decidualization of ESCs via both cellular morphological changes and prolactin levels. Therefore, our study demonstrated that miR-194-3p contributes to progesterone resistance in endometriosis, which hinders fertility by repressing the levels of PR and decidualization in the EuE. Thus, miR-194-3p regulation is a future therapeutic strategy for endometriosis. PMID- 29762666 TI - Discovery and Validation of Methylation Biomarkers for Ulcerative Colitis Associated Neoplasia. AB - Background and aims: Ulcerative colitis (UC) is associated with a higher background risk of dysplasia and/or neoplasia due to chronic inflammation. There exist few biomarkers for identification of patients with dysplasia, and targeted biopsies in this group of patients are inaccurate in reliably identifying dysplasia. We aimed to examine the epigenome of UC dysplasia and to identify and validate potential biomarkers. Methods: Colonic samples from patients with UC associated dysplasia or neoplasia underwent epigenome-wide analysis on the Illumina 450K methylation array. Markers were validated by bisulphite pyrosequencing on a secondary validation cohort and accuracy calculated using logistic regression and receiver-operator curves. Results : Twelve samples from 4 patients underwent methylation array analysis and 6 markers (GNG7, VAV3, KIF5C, PIK3R5, TUBB6, and ZNF583) were taken forward for secondary validation on a cohort of 71 colonic biopsy samples consisting of normal uninflamed mucosa from control patients, acute and chronic colitis, "field" mucosa in patients with dysplasia/neoplasia, dysplasia, and neoplasia. Methylation in the beta-tubulin TUBB6 correlated with the presence of dysplasia (P < 0.0001) and accurately discriminated between dysplasia and nondysplastic tissue, even in the apparently normal field mucosa downstream from dysplastic lesions (AUC 0.84, 95% CI 0.81 0.87). Conclusions: Methylation in TUBB6 is a potential biomarker for UC- associated dysplasia. Further validation is needed and is ongoing as part of the ENDCAP-C study. PMID- 29762667 TI - Single Nucleotide Variations of the Human GR Gene Manifested as Pathologic Mutations or Polymorphisms. AB - The human genome contains numerous single nucleotide variations, and the human glucocorticoid receptor (GR) gene harbors ~450 of these genetic changes. Among them, extremely rare, nonsynonymous variants, known as pathologic GR gene mutations, develop a characteristic pathologic condition, familial/sporadic generalized glucocorticoid resistance syndrome, by replacing the amino acids critical for GR protein structure and functions, whereas others, known as pathologic polymorphisms, develop mild manifestations recognized mainly at population bases by changing the GR activities slightly. Recent progress on the structural analysis to the GR protein and subsequent computer-based structural simulation revealed details of the molecular defects caused by such pathologic GR gene mutations, including their impact on the receptor interaction to ligands, nuclear receptor coactivators (NCoAs) or DNA glucocorticoid response elements (GREs). Indeed, those found in the GR ligand-binding domain significantly damage protein structure of the ligand-binding pocket and/or the activation function-2 transactivation domain and change their molecular interaction to glucocorticoids or the LxxLL signature motif of NCoAs. Two mutations found in GR DNA-binding domain also affect interaction of the mutant receptors to GRE DNA by affecting the critical amino acid for the interaction or changing local hydrophobic circumstance. In this review, I discuss recent findings on the structural simulation of the pathologic GR mutants in connection to their functional and clinical impacts, along with a brief explanation to recent research achievement on the GR polymorphisms. PMID- 29762669 TI - Ethics of oocyte banking for third-party assisted reproduction: a systematic review. AB - BACKGROUND: The demand for donor oocytes has increased dramatically over the years. Today people in need of ART with the use of donor oocytes can appeal to commercial or public donor oocyte banks. The introduction of oocyte banks has shed a new light on the practice of ART using donor oocytes. The establishment and maintenance of oocyte banks should be sensitive to the ethical considerations. However, it is currently unclear which ethical aspects have to be taken into account. OBJECTIVE AND RATIONALE: The aim of this article is to identify the ethical aspects of establishing and maintaining oocyte banks for third-party ART. SEARCH METHODS: A systematic search was performed in July 2016 and February 2017 in both PubMed and Embase using a search string that combined synonyms for oocytes, donation or banking, reproductive care and ethics. We included a wide variety of English-language articles with a reasoned description of ethical aspects or moral considerations on oocyte donation or banking for third-party ART. OUTCOMES: The practice of oocyte banking consists of three components, namely, the intake, storage and distribution of donor oocytes, and each is associated with multiple ethical challenges. The majority of the literature discusses ethical aspects with regard to the intake of donor oocytes, taking into account both the interests of the donor and those of the potential child. Ethical aspects related to the donor are the risks and psychosocial impact of donation, motivations and compensation in donor recruitment, and requirements for informed consent. Ethical aspects related to the potential child are 2-fold: first, the welfare standard and the selection of donors, and second, anonymity and disclosure. Ethical aspects of storing donor oocytes for ART are quality standards, confidentiality, issues of ownership and control, and international transport of donor oocytes. Ethical aspects of the distribution of donor oocytes concern the selection of recipients and the acceptability of treatment of 'non traditional' families in particular, prioritization of recipients in case of scarcity, cross-border reproductive care, matching of recipients and donor oocytes, informed consent and counselling for recipients. WIDER IMPLICATIONS: Our review demonstrates that multiple ethical aspects have to be taken into account when establishing and maintaining an oocyte bank. Yet, for many of these aspects there is no consensus regarding what approach should be employed. Remarkably, the existing literature focuses mainly on ethical aspects related to the intake of donor oocytes, while aspects related to storage and distribution of donor oocytes are less often addressed. An important gap in the existing literature should therefore be acknowledged. To conclude, our findings can serve as a starting point for clinicians in the field of ART, to conceptualize what challenges arise when establishing and maintaining oocyte banks for third-party ART. The review may also stimulate policy makers to set up a trustworthy and adaptive governance structure for the intake, storage and distribution of donor oocytes. PMID- 29762663 TI - Population genomic data reveal genes related to important traits of quail. AB - Background: Japanese quail (Coturnix japonica), a recently domesticated poultry species, is important not only as an agricultural product, but also as a model bird species for genetic research. However, most of the biological questions concerning genomics, phylogenetics, and genetics of some important economic traits have not been answered. It is thus necessary to complete a high-quality genome sequence as well as a series of comparative genomics, evolution, and functional studies. Results: Here, we present a quail genome assembly spanning 1.04 Gb with 86.63% of sequences anchored to 30 chromosomes (28 autosomes and 2 sex chromosomes Z/W). Our genomic data have resolved the long-term debate of phylogeny among Perdicinae (Japanese quail), Meleagridinae (turkey), and Phasianinae (chicken). Comparative genomics and functional genomic data found that four candidate genes involved in early maturation had experienced positive selection, and one of them encodes follicle stimulating hormone beta (FSHbeta), which is correlated with different FSHbeta levels in quail and chicken. We re sequenced 31 quails (10 wild, 11 egg-type, and 10 meat-type) and identified 18 and 26 candidate selective sweep regions in the egg-type and meat-type lines, respectively. That only one of them is shared between egg-type and meat-type lines suggests that they were subject to an independent selection. We also detected a haplotype on chromosome Z, which was closely linked with maroon/yellow plumage in quail using population resequencing and a genome-wide association study. This haplotype block will be useful for quail breeding programs. Conclusions: This study provided a high-quality quail reference genome, identified quail-specific genes, and resolved quail phylogeny. We have identified genes related to quail early maturation and a marker for plumage color, which is significant for quail breeding. These results will facilitate biological discovery in quails and help us elucidate the evolutionary processes within the Phasianidae family. PMID- 29762668 TI - Benchmarking taxonomic assignments based on 16S rRNA gene profiling of the microbiota from commonly sampled environments. AB - Background: Taxonomic profiling of ribosomal RNA (rRNA) sequences has been the accepted norm for inferring the composition of complex microbial ecosystems. Quantitative Insights Into Microbial Ecology (QIIME) and mothur have been the most widely used taxonomic analysis tools for this purpose, with MAPseq and QIIME 2 being two recently released alternatives. However, no independent and direct comparison between these four main tools has been performed. Here, we compared the default classifiers of MAPseq, mothur, QIIME, and QIIME 2 using synthetic simulated datasets comprised of some of the most abundant genera found in the human gut, ocean, and soil environments. We evaluate their accuracy when paired with both different reference databases and variable sub-regions of the 16S rRNA gene. Findings: We show that QIIME 2 provided the best recall and F-scores at genus and family levels, together with the lowest distance estimates between the observed and simulated samples. However, MAPseq showed the highest precision, with miscall rates consistently <2%. Notably, QIIME 2 was the most computationally expensive tool, with CPU time and memory usage almost 2 and 30 times higher than MAPseq, respectively. Using the SILVA database generally yielded a higher recall than using Greengenes, while assignment results of different 16S rRNA variable sub-regions varied up to 40% between samples analysed with the same pipeline. Conclusions: Our results support the use of either QIIME 2 or MAPseq for optimal 16S rRNA gene profiling, and we suggest that the choice between the two should be based on the level of recall, precision, and/or computational performance required. PMID- 29762670 TI - Hens ranked as highly feed efficient have an improved albumen quality profile and increased polyunsaturated fatty acids in the yolk. AB - The shelf life of eggs that contain elevated levels of polyunsaturated fatty acids (PUFA) is compromised due to the relative instability and therefore greater potential for lipid peroxidation of unsaturated fatty acids (FA). Poultry that is highly feed efficiency (HFE) exhibits higher systemic levels of antioxidant enzymes and therefore may produce eggs with improved albumen quality and favorable FA profiles that are stable over time. We tested the hypothesis that HFE-laying hens produce eggs with improved internal egg quality and a favorable yolk FA profile prior to and following storage. Following an initial screening phase (7 wk) using 140 Isa Brown layers (28 wk old), the 10 most efficient (FCR < 1.99 +/- 0.05) and the 10 least efficient (FCR > 2.30 +/- 0.05) hens were identified and designated as HFE and low feed efficiency (LFE) groups, respectively. Internal quality and composition were determined on eggs (n = 10 per group) stored at 15 degrees C for 0, 14, and 28 d. At 0, 14, and 28 d, the albumen weight, albumen height, Haugh unit (HU), and albumen:yolk ratio of eggs from the HFE group were significantly higher (P < 0.01), whereas the eggs from the LFE group had heavier (P < 0.01) yolk than the HFE group. After 28-d storage, the yolk color score of the LFE group was lower (paler; P < 0.05) compared with that of the HFE group. The relative proportions of total PUFA and the ratio of total PUFA and total saturated fatty acids (SFA) were higher (P < 0.05) in HFE group of eggs. The LFE group of eggs contained higher (P < 0.05) levels of lipid peroxidation marker (thiobarbituric acid reactive substances; TBARS) values both in fresh and in stored eggs. The results suggest that HFE hens produce eggs with greater albumen quality and higher levels of yolk PUFA both at lay and after storage. PMID- 29762671 TI - Motor Impairments Correlate with Social Deficits and Restricted Neuronal Loss in an Environmental Model of Autism. AB - Background: Motor impairments are amongst the earliest and most consistent signs of autism spectrum disorders but are not used as diagnostic criteria. In addition, the relationship between motor and cognitive impairments and their respective neural substrates remain unknown. Methods: Here, we aimed at determining whether a well-acknowledged animal model of autism spectrum disorders, the valproic acid model, displays motor impairments and whether they may correlate with social deficits and neuronal loss within motor brain areas. For this, pregnant female mice (C57BL/6J) received valproic acid (450 mg/kg) at embryonic day 12.5 and offspring underwent a battery of behavioral analyses before being killed for histological correlates in motor cortex, nigrostriatal pathway, and cerebellum. Results: We show that while valproic acid male mice show both social and motor impairments, female mice only show motor impairments. Prenatal valproic acid exposure induces specific cell loss within the motor cortex and cerebellum and that is of higher magnitude in males than in females. Finally, we demonstrate that motor dysfunction correlates with reduced social behavior and that motor and social deficits both correlate with a loss of Purkinje cells within the Crus I cerebellar area. Conclusions: Our results suggest that motor dysfunction could contribute to social and communication deficits in autism spectrum disorders and that motor and social deficits may share common neuronal substrates in the cerebellum. A systematic assessment of motor function in autism spectrum disorders may potentially help the quantitative diagnosis of autism spectrum disorders and strategies aimed at improving motor behavior may provide a global therapeutic benefit. PMID- 29762672 TI - Population Serologic Immunity to Human and Avian H2N2 Viruses in the United States and Hong Kong for Pandemic Risk Assessment. AB - Background: Influenza A pandemics cause significant mortality and morbidity. H2N2 viruses have caused a prior pandemic, and are circulating in avian reservoirs. The age-related frequency of current population immunity to H2 viruses was evaluated. Methods: Hemagglutinin inhibition (HAI) assays against historical human and recent avian influenza A(H2N2) viruses were performed across age groups in Rochester, New York, and Hong Kong, China. The impact of existing cross reactive HAI immunity on the effective reproduction number was modeled. Results: One hundred fifty individual sera from Rochester and 295 from Hong Kong were included. Eighty-five percent of patients born in Rochester and Hong Kong before 1968 had HAI titers >=1:40 against A/Singapore/1/57, and >50% had titers >=1:40 against A/Berkeley/1/68. The frequency of titers >=1:40 to avian H2N2 A/mallard/England/727/06 and A/mallard/Netherlands/14/07 in subjects born before 1957 was 62% and 24%, respectively. There were no H2 HAI titers >1:40 in individuals born after 1968. These levels of seroprevalence reduce the initial reproduction number of A/Singapore/1/1957 or A/Berkeley/1/68 by 15%-20%. A basic reproduction number (R0) of the emerging transmissible virus <1.2 predicts a preventable pandemic. Conclusions: Population immunity to H2 viruses is insufficient to block epidemic spread of H2 virus. An H2N2 pandemic would have lower impact in those born before 1968. PMID- 29762675 TI - RXR Ligands Modulate Thyroid Hormone Signaling Competence in Young Xenopus laevis Tadpoles. AB - Appropriate thyroid hormone (TH) signaling through thyroid hormone receptors (TRs) is essential for vertebrate development. Amphibian metamorphosis is initiated and sustained through the action of TH on TRs, which are conserved across vertebrates. TRs heterodimerize with retinoid X receptors (RXRs) on thyroid hormone response elements (TREs) in the genome; however, in most cell line and adult animal studies, RXR ligands do not affect expression of TR target genes. We used a quantitative, precocious metamorphosis assay to interrogate the effects of the RXR agonist bexarotene (Bex) and the RXR antagonist UVI 3003 (UVI) on T3-induced resorption phenotypes in Xenopus laevis tadpoles 1 week postfertilization. Bex potentiated gill and tail resorption, and UVI abrogated T3 action. These results held in transgenic tadpoles bearing a TRE-driven luciferase reporter. Therefore, we used poly-A-primed RNA sequencing transcriptomic analysis to determine their effects on T3-induced gene expression. We also assayed the environmental pollutant tributyltin (TBT), which is an RXR agonist. We found that the proteases that carry out resorption were potentiated by Bex and TBT but were not significantly inhibited by UVI. However, several transcription factors from multiple families (sox4, fosl2, mxd1, mafb, nfib) were all inhibited by UVI and potentiated by Bex and TBT. All required T3 for induction. Time course analysis of gene expression showed that although the agonists could potentiate within 12 hours, the antagonist response lagged. These data indicate that the agonists and antagonist are not necessarily functioning through the same mechanism and suggest that RXR liganding may modulate TH competence in metamorphic signaling. PMID- 29762674 TI - Available energy and amino acid digestibility of defatted rice bran fed to growing pigs. AB - This study was conducted to determine and compare available energy and apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of CP and AA in 9 samples of defatted rice bran (DFRB) fed to growing pigs and to generate prediction equations for DE and ME based on chemical analysis. In Exp. 1, 60 crossbred growing pigs (Duroc * Landrace * Yorkshire; 40.7 +/- 3.5 kg BW) were fed 1 of 10 diets in a completely randomized design to determine the available energy of DFRB. The diets included a corn-soybean meal-basal diet and 9 experimental diets formulated by replacing the corn and soybean meal with 29.16% DFRB. In Exp. 2, 6 growing pigs (initial BW = 28.5 +/- 2.8 kg) were surgically equipped with a T-cannula in the distal ileum and arranged in a 6 * 6 Latin square design with 6 diets and 6 periods. The diets included an N-free diet based on cornstarch and sucrose and 5 experimental diets containing 60% DFRB as the sole source of AA. Chromic oxide (0.3%) was used as an indigestible marker. Among the 9 samples, the concentrations of ether extract (EE), crude fiber (CF), NDF, ADF, starch, Ca, and P averaged 1.33 (0.50% to 4.14%), 14.54 (9.78% to 23.85%), 28.62 (20.19% to 38.85%), 14.22 (9.32% to 23.99%), 38.80% (30.62% to 47.55%), 0.16% (0.09% to 0.24%), and 1.96% (1.11% to 2.28%), respectively. The average DE and ME were 2,643 and 2,476 kcal/kg DM, respectively, and ranged from 2,039 to 3,157 kcal/kg DM and 1,931 to 2,978 kcal/kg DM, respectively. In Exp. 2, there were significant differences in the AID and SID of CP and most AA except for His, Tyr, and Met (P < 0.05). The AID and SID of CP averaged 67.75% and 76.37%, respectively. The digestibility of Met was the greatest, averaging 86.15% and 90.08% for AID and SID, respectively. The AID and SID of Lys ranged from 51.88% to 71.43% (mean = 63.27%) and from 61.93% to 79.98% (mean = 72.97%), respectively. These results indicated that there is significant variability in chemical composition, energy content, and the SID and AID of CP and most AA among the selected DFRB. The DE and ME of DFRB are primarily related to their NDF and starch concentrations. PMID- 29762676 TI - Interleukin 38 Protects Against Lethal Sepsis. AB - Background: Interleukin 38 (IL-38) is the most recently characterized cytokine of the interleukin 1 family. However, its role in sepsis remains unknown. Methods: Circulating IL-38 levels were measured in 2 cohorts of adult and pediatric patients with sepsis. Using 2 murine models of lipopolysaccharide (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced sepsis, the effects of IL-38 on survival, inflammation, tissue injury, and bacterial clearance were assessed. Results: Serum IL-38 concentrations were significantly elevated in adult and pediatric patients with sepsis relative to corresponding healthy adult and pediatric controls, respectively. An increased IL-38 level negatively correlated with the number of blood leukocytes and with the level of inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in clinical sepsis. Anti-IL-38 antibody impaired survival and while recombinant IL-38 improved survival in the 2 murine models of LPS-induced endotoxemia and CLP-induced sepsis. IL-38 administration decreased the inflammatory response, as reflected by lower levels of cytokines and chemokines (including IL-6, TNF-alpha, interleukin 10, interleukin 17, interleukin 27, CXCL1, and CCL2), and less damage to tissues (including lung, liver, and kidney) in CLP-induced sepsis. Furthermore, IL-38 augmented bacterial clearance in CLP induced polymicrobial sepsis. Conclusions: These findings suggest that IL-38 attenuates sepsis by decreasing inflammation and increasing bacterial clearance, thus providing a novel tool for antisepsis therapy. PMID- 29762673 TI - A gene catalogue of the Sprague-Dawley rat gut metagenome. AB - Background: Laboratory rats such as the Sprague-Dawley (SD) rats are an important model for biomedical studies in relation to human physiological or pathogenic processes. Here we report the first catalog of microbial genes in fecal samples from Sprague-Dawley rats. Findings: The catalog was established using 98 fecal samples from 49 SD rats, divided in 7 experimental groups, and collected at different time points 30 days apart. The established gene catalog comprises 5,130,167 non-redundant genes with an average length of 750 bp, among which 64.6% and 26.7% were annotated to phylum and genus levels, respectively. Functionally, 53.1%, 21.8%,and 31% of the genes could be annotated to KEGG orthologous groups, modules, and pathways, respectively. Conclusions: A comparison of rat gut metagenome catalogue with human or mouse revealed a higher pairwise overlap between rats and humans (2.47%) than between mice and humans (1.19%) at the gene level. Ninety-seven percent of the functional pathways in the human catalog were present in the rat catalogue, underscoring the potential use of rats for biomedical research. PMID- 29762677 TI - Anti-dementia Drugs for Psychopathology and Cognitive Impairment in Schizophrenia: A Systematic Review and Meta-analysis. AB - Background: We conducted a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials of anti-dementia drugs plus antipsychotics (ADD+AP) for schizophrenia. Methods: Primary outcomes of efficacy and safety included improving overall symptoms (Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores) and all-cause discontinuation, respectively. Other outcomes included psychopathology subscales (positive, negative, general, and anxiety/depressive symptoms), cognitive function (attention/vigilance, reasoning/problem solving, social cognition, speed of processing, verbal learning, visual learning, working memory, and cognitive control/executive function), Mini-Mental State Examination (MMSE) scores, treatment discontinuation due to adverse events and inefficacy, and individual adverse events. We evaluated the effect size using a random effects model. Results: We identified 37 studies (n=1,574): 14 donepezil-based (n=568), 10 galantamine-based (n=371), 4 rivastigmine-based (n=146), and 9 memantine-based (n=489) studies. Pooled ADD+AP treatments were superior to placebo+AP in improving the overall symptoms (24 studies, 1,069 patients: standardized mean difference [SMD]=-0.34, 95% confidence interval [CI]=-0.61 to -0.08, P=0.01), negative symptoms (24 studies, 1,077 patients: SMD=-0.62, 95% CI=-0.92 to -0.32, Pcorrected=0.00018), and MMSE scores (7 studies, 225 patients: SMD=-0.79, 95% CI= 1.23 to -0.34, P=0.0006). No significant differences were found between ADD+AP and placebo+AP regarding other outcomes. Conclusions: Although the results suggest that ADD+AP treatment improves negative symptoms and MMSE scores in schizophrenia patients, they possibly were influenced by a small-study effect and some bias. However, it was not superior to placebo+AP in improving composite cognitive test score, which more systematically evaluates cognitive impairment than the MMSE score. Overall, ADD+AP treatment was well tolerated. PMID- 29762678 TI - Using statistical anomaly detection models to find clinical decision support malfunctions. AB - Objective: Malfunctions in Clinical Decision Support (CDS) systems occur due to a multitude of reasons, and often go unnoticed, leading to potentially poor outcomes. Our goal was to identify malfunctions within CDS systems. Methods: We evaluated 6 anomaly detection models: (1) Poisson Changepoint Model, (2) Autoregressive Integrated Moving Average (ARIMA) Model, (3) Hierarchical Divisive Changepoint (HDC) Model, (4) Bayesian Changepoint Model, (5) Seasonal Hybrid Extreme Studentized Deviate (SHESD) Model, and (6) E-Divisive with Median (EDM) Model and characterized their ability to find known anomalies. We analyzed 4 CDS alerts with known malfunctions from the Longitudinal Medical Record (LMR) and Epic(r) (Epic Systems Corporation, Madison, WI, USA) at Brigham and Women's Hospital, Boston, MA. The 4 rules recommend lead testing in children, aspirin therapy in patients with coronary artery disease, pneumococcal vaccination in immunocompromised adults and thyroid testing in patients taking amiodarone. Results: Poisson changepoint, ARIMA, HDC, Bayesian changepoint and the SHESD model were able to detect anomalies in an alert for lead screening in children and in an alert for pneumococcal conjugate vaccine in immunocompromised adults. EDM was able to detect anomalies in an alert for monitoring thyroid function in patients on amiodarone. Conclusions: Malfunctions/anomalies occur frequently in CDS alert systems. It is important to be able to detect such anomalies promptly. Anomaly detection models are useful tools to aid such detections. PMID- 29762679 TI - Spatial control of cell envelope biosynthesis in mycobacteria. AB - The mycobacterial cell envelope is a complex multilayered structure that provides the strength to the rod-shaped cell and creates the permeability barrier against antibiotics and host immune attack. In this review, we will discuss the spatial coordination of cell envelope biosynthesis and how plasma membrane compartmentalization plays a role in this process. The spatial organization of cell envelope biosynthetic enzymes as well as other membrane-associated proteins is crucial for cellular processes such as polar growth and midcell septum formation. We will highlight metabolic enzymes involved in the localized biosynthesis of envelope components such as peptidoglycan, arabinogalactan and outer/inner membrane lipids. The known and potential roles of cytoskeletal and coiled coil proteins in driving subcellular protein localization will also be summarized. Finally, we provide a comprehensive overview of known lateral heterogeneities in mycobacterial plasma membrane, with a particular focus on the intracellular membrane domain, recently revealed by biochemical fractionation and fluorescence microscopy. We consider how this dynamic and multifunctional membrane microdomain contributes to the subcellular localization of membrane proteins and spatially restricted cell envelope biosynthesis in mycobacteria. PMID- 29762681 TI - Risk of Lymphoma in Patients With Inflammatory Bowel Disease Treated With Anti Tumor Necrosis Factor Alpha Agents: A Systematic Review and Meta-analysis. AB - Background and Aims: The association between anti-tumor necrosis factor alpha agents and the risk of lymphoma in patients with inflammatory bowel disease has already been sufficiently reported. However, the results of these studies are inconsistent. Hence, this analysis was conducted to investigate whether anti tumor necrosis factor alpha agents can increase the risk of lymphoma in inflammatory bowel disease patients. Methods: MEDLINE, EMBASE and the Cochrane Library were searched to identify relevant studies which evaluated the risk of lymphoma in inflammatory bowel disease patients treated with anti-tumor necrosis factor alpha agents. A random-effects meta-analysis was performed to calculate the pooled incidence rate ratios as well as risk ratios. Results: Twelve studies comprising 285811 participants were included. The result showed that there was no significantly increased risk of lymphoma between anti-tumor necrosis factor alpha agents exposed and anti-tumor necrosis factor alpha agents unexposed groups (random effects: incidence rate ratio [IRR], 1.43 95%CI, 0.91-2.25, p= 0.116; random effects: risk ratio [RR], 0.83 95%CI, 0.47-1.48, p=0.534). However, monotherapy of anti-tumor necrosis factor alpha agents (random effects: IRR=1.65, 95%CI, 1.16-2.35; p=0.006; random effects: RR=1.00, 95%CI, 0.39-2.59; p=0.996) or combination therapy (random effects: IRR=3.36, 95%CI, 2.23-5.05; p< 0.001; random effects: RR=1.90, 95%CI, 0.66-5.44; p=0.233) can significantly increase the risk of lymphoma. Conclusions: Exposition of anti-tumor necrosis factor alpha agents in patients with inflammatory bowel disease is not associated with a higher risk of lymphoma. Combination therapy and anti-tumor necrosis factor alpha agents monotherapy can significantly increase the risk of lymphoma in patients with inflammatory bowel disease. PMID- 29762682 TI - Molecular detection of mutations involved in Helicobacter pylori antibiotic resistance in Algeria. AB - Objectives: In Algeria, there are limited data regarding the pattern of Helicobacter pylori primary antibiotic resistance. The aim of this study was to evaluate the primary resistance of H. pylori to clarithromycin, ciprofloxacin, tetracycline and rifampicin and to determine the molecular mechanisms involved in the resistance. Methods: Two hundred and seventy Algerian adults who had never received H. pylori treatment were enrolled in this study. Human biopsies were obtained for culture and antimicrobial susceptibility testing was performed by Etest for clarithromycin, ciprofloxacin, tetracycline and rifampicin. Real-time fluorescence resonance energy transfer (FRET)-PCR was also performed in all cases to assess primary clarithromycin resistance and point mutations involved, real time PCR was used to detect mutations involved in tetracycline primary resistance and sequencing of the QRDR of gyrA was performed to detect mutations involved in quinolone resistance. Results: No resistance to rifampicin was detected. Resistance to clarithromycin and ciprofloxacin was found in 29.7% and 17.9%, respectively. Results of real-time FRET-PCR showed that A2143G was the most frequent point mutation, A2142C was not found and 42 patients (15.5%) were infected by both resistant and susceptible genotypes. Only two isolates were resistant to tetracycline and exhibited an A926G mutation. Four mutations were found to be responsible for resistance to ciprofloxacin [N87K (44.73%), D91N (23.68%), N87I (18.42%) and D91G (7.89%)]. Conclusions: Local data regarding the primary resistance of H. pylori to clarithromycin, ciprofloxacin, tetracycline and rifampicin and the main genetic mutations involved in the resistance are necessary for a periodic evaluation of antibiotic consumption and new therapeutic strategies in Algeria. PMID- 29762683 TI - Peri-procedural routines, implantation techniques, and procedure-related complications in patients undergoing implantation of subcutaneous or transvenous automatic cardioverter-defibrillators: results of the European Snapshot Survey on S-ICD Implantation (ESSS-SICDI). AB - The aim of this European Heart Rhythm Association (EHRA) prospective snapshot survey is to assess peri-procedural practices, implantation techniques, and short term procedure-related complications associated with implantation of subcutaneous implantable cardioverter-defibrillator (S-ICD) or transvenous implantable cardioverter-defibrillator (TV-ICD), across tertiary European electrophysiology centres. An internet-based electronic questionnaire concerning implantation settings, peri-procedural routines, techniques, personnel, complications, and patient outcomes was sent to the centres routinely implanting both TV-ICDs and S ICDs. The centres were requested to prospectively include consecutive patients implanted with either TV-ICD or S-ICD during the 8-week enrolment period. Overall, 20 centres from 6 countries enrolled 429 consecutive patients. Subcutaneous implantable cardioverter-defibrillators (20%) compared with TV-ICD were implanted mainly under general anaesthesia (72% vs. 14%), in the surgical operation room settings (69% vs. 43%), with more frequent prophylactic antibiotic administration (82% vs. 91%), and post-implant defibrillation testing (85% vs. 7%, all P < 0.05). Feasibility (implantation duration of 45 min) and short-term complication rates (4%) were comparable for S-ICDs and TV-ICDs, but the spectrum of complications varied, despite different baseline characteristics of patients undergoing the S-ICD vs. TV-ICD implantation. This EHRA snapshot survey provides important insights into the implantable cardioverter-defibrillator implantation routines and patient outcomes. Our study showed differences between the S-ICD and TV-ICD implantation routines with respect to implantation settings, peri procedural management, and pre-defined procedural endpoints. However, the comparable duration of S-ICD or TV-ICD implantation and similar rates of peri procedural complications indicate that both devices can be routinely used in clinical practice. PMID- 29762684 TI - Effective Treatment of Experimental Lymphocytic Choriomeningitis Virus Infection: Consideration of Favipiravir for Use With Infected Organ Transplant Recipients. AB - Lymphocytic choriomeningitis virus (LCMV) poses a substantial risk to immunocompromised individuals. The case fatality rate in recent clusters of LCMV infection in immunosuppressed organ transplantation recipients has exceeded 70%. In the present study, we demonstrate potent antiviral activity of favipiravir against acute, disseminated LCMV infection in NZB mice. Treatment resulted in complete protection against mortality and dramatic reductions in viral loads. In contrast, ribavirin, the current antiviral of choice, was mostly ineffective. Our findings, and the high lethality associated with LCMV infection in transplant recipients, support the consideration of favipiravir as a first-line therapeutic option. PMID- 29762685 TI - Urine Multi-drug Screening with GC-MS or LC-MS-MS Using SALLE-hybrid PPT/SPE. AB - To intoxicated patients in the emergency room, toxicological analysis can be considerably helpful for identifying the involved toxicants. In order to develop a urine multi-drug screening (UmDS) method, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to determine targeted and unknown toxicants in urine. A GC-MS method in scan mode was validated for selectivity, limit of detection (LOD) and recovery. An LC-MS-MS multiple reaction monitoring (MRM) method was validated for lower LOD, recovery and matrix effect. The results of the screening analysis were compared with patient medical records to check the reliability of the screen. Urine samples collected from an emergency room were extracted through a combination of salting out assisted liquid-liquid extraction (SALLE) and hybrid protein precipitation/solid phase extraction (hybrid PPT/SPE) plates and examined by GC MS and LC-MS-MS. GC-MS analysis was performed as unknown drug screen and LC-MS-MS analysis was conducted as targeted drug screen. After analysis by GC-MS, a library search was conducted using an in-house library established with the automated mass spectral deconvolution and identification system (AMDISTM). LC-MS MS used Cliquid(r)2.0 software for data processing and acquisition in MRM mode. An UmDS method by GC-MS and LC-MS-MS was developed by using a SALLE-hybrid PPT/SPE and in-house library. The results of UmDS by GC-MS and LC-MS-MS showed that toxicants could be identified from 185 emergency room patient samples containing unknown toxicants. Zolpidem, acetaminophen and citalopram were the most frequently encountered drugs in emergency room patients. The UmDS analysis developed in this study can be used effectively to detect toxic substances in a short time. Hence, it could be utilized in clinical and forensic toxicology practices. PMID- 29762686 TI - Presenting self-monitoring test results for consumers: the effects of graphical formats and age. AB - Objective: To examine the effects of graphical formats and age on consumers' comprehension and perceptions of the use of self-monitoring test results. Methods: Participants (36 older and 36 young adults) were required to perform verbatim comprehension and value interpretation tasks with hypothetical self monitoring test results. The test results were randomly presented by four reference range number lines: basic, color enhanced, color/text enhanced, and personalized information enhanced formats. We measured participants' task performance and eye movement data during task completion, and their perceptions and preference of the graphical formats. Results: The 4 graphical formats yielded comparable task performance, while text/color and personalized information enhanced formats were believed to be easier and more useful in information comprehension, and led to increased confidence in correct comprehension of test results, compared with other formats (all p's < .05). Perceived health risk increased as the formats applied more information cues (p = .008). There were age differences in task performance and visual attention (all p's < .01), while young and older adults had similar perceptions for the 4 formats. Personalized information enhanced format was preferred by both groups. Conclusions: Text/color and personalized information cues appear to be useful for comprehending test results. Future work can be directed to improve the design of graphical formats especially for older adults, and to assess the formats in clinical settings. PMID- 29762680 TI - Tuberculosis and the art of macrophage manipulation. AB - Macrophages are first-line responders against microbes. The success of Mycobacterium tuberculosis (Mtb) rests upon its ability to convert these antimicrobial cells into a permissive cellular niche. This is a remarkable accomplishment, as the antimicrobial arsenal of macrophages is extensive. Normally bacteria are delivered to an acidic, degradative lysosome through one of several trafficking pathways, including LC3-associated phagocytosis (LAP) and autophagy. Once phagocytozed, the bacilli are subjected to reactive oxygen and nitrogen species, and they induce the expression of proinflammatory cytokines, which serve to augment host responses. However, Mtb hijacks these host defense mechanisms, manipulating host cellular trafficking, innate immune responses, and cell death pathways to its benefit. The complex series of measures and countermeasures between host and pathogen ultimately determines the outcome of infection. In this review, we focus on the diverse effectors that Mtb uses in its multipronged effort to subvert the innate immune responses of macrophages. We highlight recent advances in understanding the molecular interface of the Mtb macrophage interaction. PMID- 29762688 TI - A multivariate genetic analysis confirms rs5010528 in the human leucocyte antigen C locus as a significant contributor to Stevens-Johnson syndrome/toxic epidermal necrolysis susceptibility in a Mozambique HIV population treated with nevirapine. AB - Objectives: Nevirapine is used in developing countries for the treatment of HIV infection, but its use is associated with rare serious adverse reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Recently, an association between rs5010528 in the human leucocyte antigen (HLA)-C locus and SJS/TEN susceptibility has been described in sub-Saharan populations. Our aim was to verify this association in a population of nevirapine-treated patients from Mozambique. Methods: The rs5010528 SNP was analysed by direct sequencing in 27 patients who had developed SJS/TEN and 75 patients who did not develop adverse reactions after nevirapine treatment. A case-control association study was conducted. A multivariate analysis was performed in order to evaluate the role of HLA-C also in relation to other susceptibility genetic factors (CYP2B6, TRAF3IP2, HCP5, PSORS1C1 and GSTM1 genes). Results: rs5010528 was significantly associated with a higher risk of developing SJS/TEN; the variant allele was more frequent in cases than in controls, conferring a high risk of developing this adverse reaction in carriers (OR = 5.72 and P = 0.0002 at genotype level, OR = 3.51 and P = 0.0002 at allelic level). The multivariate analysis showed that the HLA-C SNP, CYP2B6 (rs28399499), TRAF3IP2 (rs76228616) and GSTM1 (null genotype) can explain 25% of the susceptibility to this reaction, with the HLA-C SNP as the most significant contributor (P = 0.02 and OR = 5.64). Conclusions: Our study confirmed the association of the rs5010528 SNP in the HLA-C region with susceptibility to developing SJS/TEN in a population from Mozambique, suggesting that it could be a good genomic biomarker for SJS/TEN susceptibility in different sub-Saharan populations. PMID- 29762687 TI - Glycine treatment enhances developmental potential of porcine oocytes and early embryos by inhibiting apoptosis. AB - Glycine, a component of glutathione (GSH), plays an important role in protection from reactive oxygen species (ROS) and inhibition of apoptosis. The aim of this study was to determine the effect of glycine on in vitro maturation (IVM) of porcine oocytes and their developmental competence after parthenogenetic activation (PA). We examined nuclear maturation, ROS levels, apoptosis, mitochondrial membrane potential (DeltaPsim), and ATP concentration, as well as the expression of several genes related to oocyte maturation and development. Our studies found that treatment with glycine in IVM culture medium increased nuclear maturation rate, but varying the concentrations of glycine (0.6, 6, or 12 mM) had no significant effect. Furthermore, 6 mM glycine supported greater blastocyst formation rates and lesser apoptosis after PA than the other concentrations (P < 0.05). All the glycine treatment groups had decreased levels of ROS in both matured oocytes and at the 2-cell stage (P < 0.05). At the 2-cell stage, the 6 mM glycine group had ROS levels that were lesser than the other 2 glycine treatment groups (0.6 and 12 mM). From this, we deemed 6 mM to be the optimal condition, and we then investigated the effects of 6 mM glycine on gene expression. The expression of both FGFR2 and Hsf1 were greater than the control group in mature oocytes. The glycine treatment group had greater levels of expression of an antiapoptotic gene (Bcl2) in mature oocytes and cumulus cells and lesser levels of expression of a proapoptotic gene (Bax) in PA blastocysts (P < 0.05). In addition, mitochondrial DeltaPsim and ATP concentration were increased in 6 mM glycine group compared with the control group. In conclusion, our results suggest that glycine plays an important role in oocyte maturation and later development by reducing ROS levels and increasing mitochondrial function to reduce apoptosis. PMID- 29762689 TI - Determining the relationship between early postmortem loin quality attributes and aged loin quality attributes using meta-analyses techniques. AB - Meta-analyses techniques using 11 independent datasets were used to determine correlations between pork loin quality evaluated at 1-d postmortem and quality evaluated at 12- to 28-d postmortem. Datasets encompassed approximately 3,957 loins. The effects of aging on ventral loin surface quality were determined using a paired-T test. Ventral loin surfaces become 8% lighter (P < 0.0001), 44.5% redder (P < 0.0001), and 46% more yellow (P < 0.0001) during the aging period. Therefore, it is apparent that loin quality changes during postmortem aging. Because of this, it becomes necessary to determine the correlation between early and aged pork quality parameters. Pearson correlation coefficients within original datasets were calculated, and then sample-weighted mean correlations r- and variances [Var(r)] were calculated across datasets. Early postmortem ventral instrumental lightness (L*) was moderately correlated with aged ventral L* r- = 0.50), aged ventral visual color r- = -0.38), aged chop face (freshly cut) L* r- = 0.44), and aged chop face visual color r- = -0.38). Early postmortem ventral instrumental redness (a*) was moderately correlated with aged ventral a* r- = 0.49) and aged chop face a* r- = 0.46). Early postmortem ventral visual color was moderately correlated with aged ventral L* r- = -0.51), aged ventral color (r- = 0.50), aged chop face L* r- = -0.43), and aged chop face visual color r- = 0.43). However, no instrumental or visual color parameters were moderately or strongly correlated with instrumental tenderness or sensory panel ratings of tenderness and juiciness (|r-| <= 0.36). Early postmortem ventral visual marbling was moderately correlated with aged ventral marbling r- = 0.63) and aged chop face visual marbling r- = 0.56). Visual marbling was not (|r-| <= 0.12) correlated with instrumental tenderness or sensory panel ratings of tenderness and juiciness. Stepwise regression, using a holo-analysis approach, was used to determine the predictive ability of early postmortem ventral color, marbling, firmness, and pH on sensory panels ratings of tenderness (R2 = 0.13), juiciness (R2 = 0.09), and flavor (R2 = 0.28). Early postmortem color and marbling are important pork quality traits in consumers purchasing decisions, but are poorly related to traits associated with eating experience. Still, they may be predicative of traits associated with purchasing intent. PMID- 29762690 TI - Intestinal Integrity Biomarkers in Early Antiretroviral-Treated Perinatally HIV-1 Infected Infants. AB - Intestinal fatty acid binding protein (iFABP) levels did not differ between human immunodeficiency virus type 1 (HIV-1)- infected infants and uninfected infants exposed to HIV-1, but those who breastfed had substantially lower levels. Zonulin levels increased from 3 to 5.3 months of age with perinatal acquisition of HIV-1 despite early antiretroviral treatment. Biomarkers of intestinal integrity (ie, iFABP and zonulin) were compared in 56 HIV-1-positive African infants who received early antiretroviral treatment and 53 HIV-1-exposed but uninfected (HEU) controls. Despite heightened inflammation and immune activation in HIV-positive infants, iFABP and zonulin levels at 3 months of age were not different from those in HEU infants and largely were not correlated with inflammatory and immune activation biomarkers. However, zonulin levels increased and became significantly higher in HIV-positive infants as compared to HEU infants by 5 months of age, despite viral suppression due to antiretroviral treatment. These findings have implications for intestinal integrity biomarker profiling in perinatal HIV-1 infection. PMID- 29762692 TI - Overarching Immunodominance Patterns and Substantial Diversity in Specificity and Functionality in the Circulating Human Influenza A and B Virus-Specific CD4+ T Cell Repertoire. AB - There is limited information on the antigen specificity and functional potential of the influenza virus-specific CD4+ T-cell repertoire in humans. Here, enzyme linked immunospot assays were used to examine circulating CD4+ T-cell specificities for influenza virus directly ex vivo in healthy adults. Our studies revealed CD4+ T-cell reactivity to multiple influenza virus proteins, including hemagglutinins, neuraminidases, M1 proteins, and nucleoproteins. Unexpectedly, the immunodominance hierarchies and functional potential of cells reactive toward influenza A virus were distinct from those toward influenza B virus. We also identified influenza virus-specific cells producing granzyme B. Our findings revealed individual and virus-specific patterns that may differentially poise humans to respond to infection or vaccination. PMID- 29762691 TI - Diagnostic accuracy of post-ACTH challenge salivary cortisol concentrations for identifying horses with equine glandular gastric disease. AB - The aims of this study were to better characterize the adrenal response to i.v. adrenocorticotropic hormone (ACTH) in horses with and without gastric disease and to validate and simplify the ACTH stimulation test by determining the diagnostic accuracy of six consecutive sampling time points after ACTH administration for equine glandular gastric disease (EGGD) and equine squamous gastric disease (ESGD). Twenty-six endurance and eventing horses without clinical disease [Sport Horse Population (SHP)] and an independent population of 62 horses [General Population (GP)] were grouped by gastroscopic findings (no/mild vs. moderate/severe EGGD, grade 0-1 vs. 2-4 ESGD, respectively) and underwent an ACTH stimulation test. Salivary cortisol (ng/mL) was analyzed before and 30, 60, 90, 120, and 150 min after i.v. injection of 1 ug/kg BW synthetic ACTH1-24. The association between having moderate or severe EGGD or ESGD and the amount of salivary cortisol was analyzed by means of receiver-operating characteristic (ROC) analysis. The following explanatory variables were considered: cortisol values for every time point, the area under the curve (AUC)-including all time points and corrected for the baseline-and the partial areas under the curve AUC0 90 and AUC90-150. Sampling after 60 min had highest association with moderate/severe EGGD. The diagnostic potential of the ACTH test was higher for the SHP [sensitivity 100% (95% CI 54% to 100%), specificity 75% (95% CI 51% to 91%), ROC-AUC 91% (95% CI 69% to 98%), 1-sided P-value < 0.001] than for the GP [sensitivity 75% (95% CI 48% to 93%), specificity 52% (95% CI 37% to 67%), ROC AUC 68% (95% CI 51% to 79%), 1-sided P-value = 0.0064]. There were, however, no significant associations with ESGD. The superiority of sampling after 60 min suggests that the initial release of cortisol rather than its peak or the AUC are relevant regarding EGGD. Even though the wide confidence intervals and thus the lack of diagnostic accuracy do not presently support clinical use, characterization of the adrenal response to an ACTH stimulus improves the understanding of EGGD pathophysiology and its relation to stress. PMID- 29762693 TI - Influence of feeding thermally peroxidized soybean oil to finishing barrows on processing characteristics and shelf life of commercially manufactured bacon. AB - Objectives were to evaluate effects of feeding soybean oil (SO) with varying levels of peroxidation on fresh belly characteristics, processing yields, and shelf life of commercially manufactured bacon stored under food-service-style conditions. Fifty-six barrows were randomly assigned to 1 of 4 diets containing 10% fresh SO (22.5 degrees C) or thermally processed SO (45 degrees C for 288 h, 90 degrees C for 72 h, or 180 degrees C for 6 h), each infused with air at a rate of 15 L/min. Individually housed pigs were provided ad libitum access to feed for 81 d. On day 82, pigs were slaughtered, and on day 83, carcasses were fabricated and bellies collected for recording of weight, dimensions, and flop distance. Belly adipose tissue cores were collected for the analysis of iodine value (IV) by near-infrared spectroscopy (NIR-IV). Bacon was manufactured at a commercial processing facility, and sliced bacon was subsequently transferred to food-service-style packaging and subjected to 0-, 30-, 60-, or 90-d storage at 20 degrees C. Stored bacon was evaluated for thiobarbituric acid reactive substances (TBARS) and trained sensory evaluation of oxidized odor and flavor. Fresh belly and bacon processing traits were analyzed as a 1-way ANOVA with the fixed effect of SO, whereas shelf life traits were analyzed as a 1-way ANOVA repeated in time. There was no effect (P >= 0.30) of SO on belly weight, length, width, or thickness, but bellies of pigs fed 90 degrees C SO had greater (P <= 0.04) flop distance (more firm) than all other SO treatments. Belly fat NIR-IV of pigs fed 90 degrees C SO were 10.22 units less (P < 0.0001) than pigs fed 180 degrees C SO, which were 2.99 and 3.29 units less than belly adipose tissue of pigs fed 22.5 and 45 degrees C SO, respectively. There was no effect of SO on brine uptake or cooking yield of commercially manufactured bacon. There was a trend (P = 0.09) for bacon manufactured from bellies of pigs fed 45 and 90 degrees C SO to have greater slicing yields than those from pigs fed 22.5 and 180 degrees C SO. There were no SO * storage time interactions (P >= 0.27) for any shelf life trait. There was no difference in TBARS, oxidized odor, or oxidized flavor among the 4 SO treatments, although all 3 shelf life metrics increased (P < 0.0001) with storage time. Overall, feeding SO thermally processed at 90 and 180 degrees C reduced belly adipose tissue IV, but feeding peroxidized SO did not affect processing yields or shelf life characteristics of commercially manufactured bacon. PMID- 29762694 TI - Comparative Study of Postmortem Concentrations of Antidepressants in Several Different Matrices. AB - Peripheral blood (PB) is considered to be the golden standard for measuring postmortem drug concentrations. In several cases, PB is however not available, but information regarding drug findings might still be crucial in order to determine the cause of death. Antidepressants are frequently detected in postmortem samples from forensic toxicology cases, but the literature investigating concentrations in other matrices than peripheral and heart blood is limited.We here describe a study for comparison of concentrations for a large number of different drugs in six different matrices. A total of 173 postmortem cases were included in the study material. The results from 44 cases with findings of antidepressants (amitriptyline/nortriptyline, citalopram, mianserin, mirtazapine, paroxetine, sertraline, trimipramine and venlafaxine) are presented in this article. Concentrations in peripheral and cardiac blood (CB), pericardial fluid (PF), two muscle samples and vitreous humour (VH) are compared. Ratios between concentrations in different matrices have also been compiled from available literature.All the investigated antidepressants were detected in all different matrices, and comparable concentration levels were found in the different matrices with a few exceptions. Concentrations in VH were generally lower than in the other matrices, and in a few cases with low concentrations in blood the antidepressants were not detected in VH. For most of the cases, ratios of 0.5-2 were found between concentration in PB and that in the other matrices. Some deviant concentrations where however found.This study shows that CB, PF, muscle and VH can provide important indications of the corresponding concentrations in PB when PB is not available. PMID- 29762695 TI - Development and validation of an extended database for yeast identification by MALDI-TOF MS in Argentina. AB - Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) has revolutionized the identification of microorganisms in clinical laboratories because it is rapid, relatively simple to use, accurate, and can be used for a wide number of microorganisms. Several studies have demonstrated the utility of this technique in the identification of yeasts; however, its performance is usually improved by the extension of the database. Here we developed an in-house database of 143 strains belonging to 42 yeast species in the MALDI Biotyper platform, and we validated the extended database with 388 regional strains and 15 reference strains belonging to 55 yeast species. We also performed an intra- and interlaboratory study to assess reproducibility and analyzed the use of the cutoff values of 1.700 and 2.000 to correctly identify at species level. The creation of an in-house database that extended the manufacturer's database was successful in view of no incorrect identification was introduced. The best performance was observed by using the extended database and a cutoff value of 1.700 with a sensitivity of .94 and specificity of .96. A reproducibility study showed utility to detect deviations and could be used for external quality control. The extended database was able to differentiate closely related species and it has potential in distinguishing the molecular genotypes of Cryptococcus neoformans and Cryptococcus gattii. PMID- 29762696 TI - Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells. AB - Familial dysautonomia (FD) is a severe genetic disorder causing sensory and autonomic dysfunction. It is predominantly caused by a c.2204+6T>C mutation in the IKBKAP gene. This mutation decreases the 5' splice site strength of IKBKAP exon 20 leading to exon 20 skipping and decreased amounts of full-length IKAP protein. We identified a binding site for the splicing regulatory protein hnRNP A1 downstream of the IKBKAP exon 20 5'-splice site. We show that hnRNP A1 binds to this splicing regulatory element (SRE) and that two previously described inhibitory SREs inside IKBKAP exon 20 are also bound by hnRNP A1. Knockdown of hnRNP A1 in FD patient fibroblasts increases IKBKAP exon 20 inclusion demonstrating that hnRNP A1 is a negative regulator of IKBKAP exon 20 splicing. Furthermore, by mutating the SREs in an IKBKAP minigene we show that all three SREs cause hnRNP A1-mediated exon repression. We designed splice switching oligonucleotides (SSO) that blocks the intronic hnRNP A1 binding site, and demonstrate that this completely rescues splicing of IKBKAP exon 20 in FD patient fibroblasts and increases the amounts of IKAP protein. We propose that this may be developed into a potential new specific treatment of FD. PMID- 29762697 TI - Sarcopenia is a Novel Predictor of the Need for Rescue Therapy in Hospitalized Ulcerative Colitis Patients. AB - Background: Acute severe ulcerative colitis (ASUC) affects one in four patients with UC. Clinical parameters perform modestly in predicting need for rescue therapy. Sarcopenia and visceral adiposity predict natural history in Crohn's disease, but the role of such metabolic factors on ASUC outcomes is unknown. Aim: To define the effect of sarcopenia and visceral adiposity on outcomes in ASUC. Methods: We studied patients hospitalized for ASUC who underwent an abdominal CT scan during the hospitalization. Quantification of skeletal muscle mass and visceral adiposity was performed by radiologists blinded to the outcome. Sarcopenia was defined as a skeletal muscle index < 55 cm2/m2 for men and < 39 cm2/m2 for women. The primary outcome of interest was need for medical or surgical rescue therapy. Results: Our study included 89 patients with ASUC among whom 39 (43.8%) patients required medical rescue therapy or surgery. Two-thirds of the cohort (70%) met the definition of sarcopenia (81% men, 48% women). Patients with sarcopenia had similar disease-characteristics and laboratory parameters as those with a normal muscle mass. However, a larger proportion of patients with sarcopenia required rescue therapy compared to those without (56% vs 28%, multivariable Odds ratio (OR) 3.98, 95% confidence interval (CI) 1.12 - 14.1). Visceral (p=0.23) or subcutaneous adiposity (p=0.53) did not predict need for rescue therapy. Conclusions: Sarcopenia as determined on abdominal CT was a novel predictor of need for rescue therapy in hospitalized UC. PMID- 29762698 TI - The Role of Plant Abiotic Factors on the Interactions Between Cnaphalocrocis medinalis (Lepidoptera: Crambidae) and its Host Plant. AB - Atmospheric temperature increases along with increasing atmospheric CO2 concentration. This is a major concern for agroecosystems. Although the impact of an elevated temperature or increased CO2 has been widely reported, there are few studies investigating the combined effect of these two environmental factors on plant-insect interactions. In this study, plant responses (phenological traits, defensive enzyme activity, secondary compounds, defense-related gene expression and phytohormone) of Cnaphalocrocis medinalis (Guenee) (Lepidoptera: Pyralidae) susceptible and resistant rice under various conditions (environment, soil type, variety, C. medinalis infestation) were used to examine the rice-C. medinalis interaction. The results showed that leaf chlorophyll content and trichome density in rice were variety-dependent. Plant defensive enzyme activities were affected environment, variety, or C. medinalis infestation. In addition, total phenolic content of rice leaves was decreased by elevated CO2 and temperature and C. medinalis infestation. Defense-related gene expression patterns were affected by environment, soil type, or C. medinalis infestation. Abscisic acid and salicylic acid content were decreased by C. medinalis infestation. However, jasmonic acid content was increased by C. medinalis infestation. Furthermore, under elevated CO2 and temperature, rice plants had higher abscisic acid content than plants under ambient conditions. The adult morphological traits of C. medinalis also were affected by environment. Under elevated CO2 and temperature, C. medinalis adults had greater body length in the second and third generations. Taken together these results indicated that elevated CO2 and temperature not only affects plants but also the specialized insects that feed on them. PMID- 29762699 TI - Cultivable bacteria from Pectinatella magnifica and the surrounding water in South Bohemia indicate potential new Gammaproteobacterial, Betaproteobacterial and Firmicutes taxa. AB - Pectinatella magnifica is a freshwater bryozoan, which has become a subject of scientific interest because of its invasive expansion worldwide. To obtain a comprehensive overview of its influence on environments, information on associated bacteria is needed. In this study, cultivable bacteria associated with P. magnifica were investigated. In total, 253 isolates were selected for preliminary identification by matrix-assisted laser desorption/ionisation time-of flight mass spectrometry and clustered based on repetitive extragenic palindromic PCR profiles. Among these, 169 strains were selected and identified using 16S rRNA gene comparative analyses. The sequences were grouped into 76 phylotypes and affiliated with 67 species. The majority of isolated bacteria belonged to Gammaproteobacteria, followed by Betaproteobacteria, Firmicutes, Bacteroidetes and Actinobacteria. Most strains within the Betaproteobacteria were isolated exclusively from bryozoan colonies. Aeromonas was the genus predominantly isolated from both P. magnifica and the water samples. Based on 16S rDNA similarity values, 15 putative new species belonging to the genera Aeromonas, Aquitalea, Clostridium, Herbaspirillum, Chromobacterium, Chryseobacterium, Morganella, Paludibacterium, Pectobacterium, Rahnella, Rhodoferax and Serratia, and putative new genera belonging to families Clostridiaceae and Sporomusaceae were revealed. The majority of the detected bacteria were species widely distributed in the environments; nevertheless, a possible symbiotic association of two new putative species with P. magnifica cannot be excluded. PMID- 29762701 TI - The times they are a changin'. PMID- 29762700 TI - CABS-flex 2.0: a web server for fast simulations of flexibility of protein structures. AB - Classical simulations of protein flexibility remain computationally expensive, especially for large proteins. A few years ago, we developed a fast method for predicting protein structure fluctuations that uses a single protein model as the input. The method has been made available as the CABS-flex web server and applied in numerous studies of protein structure-function relationships. Here, we present a major update of the CABS-flex web server to version 2.0. The new features include: extension of the method to significantly larger and multimeric proteins, customizable distance restraints and simulation parameters, contact maps and a new, enhanced web server interface. CABS-flex 2.0 is freely available at http://biocomp.chem.uw.edu.pl/CABSflex2. PMID- 29762702 TI - Christian Cabrol MD: A Tribute to pioneer cardiac surgeon Christian Cabrol 1 year after his death, on the 50th Anniversary of the First European Human Heart Transplantation that he performed in 1968. PMID- 29762703 TI - AED use before EMS arrival: When survival becomes a matter of law and system in Italy, which can be improved. PMID- 29762704 TI - New chief of cardiovascular medicine at Yale School of Medicine. PMID- 29762705 TI - Cardiology in Mekelle, Ethiopia: Setting up a modern heart cath lab in a University Hospital in Ethiopia was a 5-year endeavour for retired cardiology interventionist Christian Leuner MD. PMID- 29762706 TI - Rheumatic heart disease patient event: Cape Town hosts 4th Annual Listen to My Heart Rheumatic Heart Disease for patients at the South African Heart Association meeting in 2017. PMID- 29762707 TI - Extending the Antiviral Value of Favipiravir. PMID- 29762708 TI - The impact of cash transfers on social determinants of health and health inequalities in sub-Saharan Africa: a systematic review. AB - Cash transfers (CTs) are now high on the agenda of most governments in low- and middle-income countries. Within the field of health promotion, CTs constitute a healthy public policy initiative as they have the potential to address the social determinants of health (SDoH) and health inequalities. A systematic review was conducted to synthesise the evidence on CTs' impacts on SDoH and health inequalities in sub-Saharan Africa, and to identify the barriers and facilitators of effective CTs. Twenty-one electronic databases and the websites of 14 key organizations were searched in addition to grey literature and hand searching of selected journals for quantitative and qualitative studies on CTs' impacts on SDoH and health outcomes. Out of 182 full texts screened for eligibility, 79 reports that reported findings from 53 studies were included in the final review. The studies were undertaken within 24 CTs comprising 11 unconditional CTs (UCTs), 8 conditional CTs (CCTs) and 5 combined UCTs and CCTs. The review found that CTs can be effective in tackling structural determinants of health such as financial poverty, education, household resilience, child labour, social capital and social cohesion, civic participation, and birth registration. The review further found that CTs modify intermediate determinants such as nutrition, dietary diversity, child deprivation, sexual risk behaviours, teen pregnancy and early marriage. In conjunction with their influence on SDoH, there is moderate evidence from the review that CTs impact on health and quality of life outcomes. The review also found many factors relating to intervention design features, macro-economic stability, household dynamics and community acceptance of programs that could influence the effectiveness of CTs. The external validity of the review findings is strong as the findings are largely consistent with those from Latin America. The findings thus provide useful insights to policy makers and managers and can be used to optimise CTs to reduce health inequalities. PMID- 29762709 TI - Determinants of Gammaherpesvirus Shedding in Saliva Among Ugandan Children and Their Mothers. AB - Background: Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are transmitted via saliva, but factors associated with salivary shedding are unknown. Methods: We measured the DNA load of both viruses in saliva specimens collected from approximately 500 Ugandan mothers and their 6-year-old children, testing all participants for EBV and KSHV-seropositive individuals for KSHV. Results: EBV and KSHV were shed by 72% and 22% of mothers, respectively, and by 85% and 40% of children, respectively; boys were more likely than girls to shed KSHV (48% vs 30%) but were equally likely to shed EBV. Children shed more KSHV and EBV than mothers, but salivary loads of EBV and KSHV were similar. KSHV shedding increased with increasing anti-KSHV (K8.1) antibodies in mothers and with decreasing antimalarial antibodies both in mothers and children. Among mothers, 40% of KSHV shedders also shed EBV, compared with 75% of KSHV nonshedders; among children, EBV was shed by 65% and 83%, respectively. Conclusions: In summary, in this population, individuals were more likely to shed EBV than KSHV in saliva. We identified several factors, including child's sex, that influence KSHV shedding, and we detected an inverse relationship between EBV and KSHV shedding, suggesting a direct or indirect interaction between the two viruses. PMID- 29762711 TI - Use of random regression to estimate genetic parameters of temperament across an age continuum in a crossbred cattle population. AB - The objective was to estimate genetic parameters of temperament in beef cattle across an age continuum. The population consisted predominantly of Brahman British crossbred cattle. Temperament was quantified by 1) pen score (PS), the reaction of a calf to a single experienced evaluator on a scale of 1 to 5 (1 = calm, 5 = excitable); 2) exit velocity (EV), the rate (m/s) at which a calf traveled 1.83 m upon exiting a squeeze chute; and 3) temperament score (TS), the numerical average of PS and EV. Covariates included days of age and proportion of Bos indicus in the calf and dam. Random regression models included the fixed effects determined from the repeated measures models, except for calf age. Likelihood ratio tests were used to determine the most appropriate random structures. In repeated measures models, the proportion of B. indicus in the calf was positively related with each calf temperament trait (0.41 +/- 0.20, 0.85 +/- 0.21, and 0.57 +/- 0.18 for PS, EV, and TS, respectively; P < 0.01). There was an effect of contemporary group (combinations of season, year of birth, and management group) and dam age (P < 0.001) in all models. From repeated records analyses, estimates of heritability (h2) were 0.34 +/- 0.04, 0.31 +/- 0.04, and 0.39 +/- 0.04, while estimates of permanent environmental variance as a proportion of the phenotypic variance (c2) were 0.30 +/- 0.04, 0.31 +/- 0.03, and 0.34 +/- 0.04 for PS, EV, and TS, respectively. Quadratic additive genetic random regressions on Legendre polynomials of age were significant for all traits. Quadratic permanent environmental random regressions were significant for PS and TS, but linear permanent environmental random regressions were significant for EV. Random regression results suggested that these components change across the age dimension of these data. There appeared to be an increasing influence of permanent environmental effects and decreasing influence of additive genetic effects corresponding to increasing calf age for EV, and to a lesser extent for TS. Inherited temperament may be overcome by accumulating environmental stimuli with increases in age, especially after weaning. PMID- 29762710 TI - Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process. AB - Thymine DNA glycosylase (TDG) is a DNA repair enzyme that excises a variety of mismatched or damaged nucleotides (nts), e.g. dU, dT, 5fC and 5caC. TDG is shown to play essential roles in maintaining genome integrity and correctly programming epigenetic modifications through DNA demethylation. After locating the lesions, TDG employs a base-flipping strategy to recognize the damaged nucleobases, whereby the interrogated nt is extruded from the DNA helical stack and binds into the TDG active site. The dynamic mechanism of the base-flipping process at an atomistic resolution, however, remains elusive. Here, we employ the Markov State Model (MSM) constructed from extensive all-atom molecular dynamics (MD) simulations to reveal the complete base-flipping process for a G.T mispair at a tens of microsecond timescale. Our studies identify critical intermediates of the mispaired dT during its extrusion process and reveal the key TDG residues involved in the inter-state transitions. Notably, we find an active role of TDG in promoting the intrahelical nt eversion, sculpturing the DNA backbone, and penetrating into the DNA minor groove. Three additional TDG substrates, namely dU, 5fC, and 5caC, are further tested to evaluate the substituent effects of various chemical modifications of the pyrimidine ring on base-flipping dynamics. PMID- 29762713 TI - SNAP23-Kif5 complex controls mGlu1 receptor trafficking. AB - Metabotropic glutamate receptors are expressed at excitatory synapses and control synaptic transmission in mammalian brain. These receptors are involved in numerous patho-physiological functions. However, little is known about the molecular determinants responsible for their intracellular transport and membrane targeting. Here we investigated the nature of the molecular motor and adaptor protein responsible for trafficking and membrane localization of the group I metabotropic glutamate mGlu1 postsynaptic receptor in cultured hippocampal neurons. In proteomic studies, we identified the synaptosome-associated protein 23 (SNAP23) and the molecular motor Kif5 kinesin as proteins interacting with mGlu1 receptor. We showed that SNAP23, but not Kif5, directly interacts with mGlu1 receptor carboxyl terminus. Using a recombination approach to impair or enhance the interaction between SNAP23 and Kif5, we found that the SNAP23-Kif5 complex controls the trafficking of mGlu1 receptor along microtubules. Additional fluorescence recovery after cleavage experiments allowed us to identify a role of the complex in the receptor cell surface targeting. In conclusion, our study indicates that along dendritic processes Kif5-SNAP23 complex contributes to proper mGlu1 receptor trafficking and cell surface expression. PMID- 29762712 TI - Revealing the distinct folding phases of an RNA three-helix junction. AB - Remarkable new insight has emerged into the biological role of RNA in cells. RNA folding and dynamics enable many of these newly discovered functions, calling for an understanding of RNA self-assembly and conformational dynamics. Because RNAs pass through multiple structures as they fold, an ensemble perspective is required to visualize the flow through fleetingly populated sets of states. Here, we combine microfluidic mixing technology and small angle X-ray scattering (SAXS) to measure the Mg-induced folding of a small RNA domain, the tP5abc three helix junction. Our measurements are interpreted using ensemble optimization to select atomically detailed structures that recapitulate each experimental curve. Structural ensembles, derived at key stages in both time-resolved studies and equilibrium titrations, reproduce the features of known intermediates, and more importantly, offer a powerful new structural perspective on the time-progression of folding. Distinct collapse phases along the pathway appear to be orchestrated by specific interactions with Mg ions. These key interactions subsequently direct motions of the backbone that position the partners of tertiary contacts for later bonding, and demonstrate a remarkable synergy between Mg and RNA across numerous time-scales. PMID- 29762714 TI - Field Populations of Wild Apis cerana Honey Bees Exhibit Increased Genetic Diversity Under Pesticide Stress Along an Agricultural Intensification Gradient in Eastern India. AB - Pesticides have been reported to be one of the major drivers in the global pollinator losses. The large-scale decline in honey bees, an important pollinator group, has resulted in comprehensive studies on honey bee colonies. Lack of information on native wild pollinators has paved the way for this study, which highlights the underlying evolutionary changes occurring in the wild honey bee populations exposed to pesticides along an agricultural intensification landscape. The study reports an increased genetic diversity in native Apis cerana Fabricius (Hymenoptera: Apidae) populations continually exposed to pesticide stress. An increased heterozygosity, evidenced by a higher electrophoretic banding pattern, was observed in the pesticide-exposed populations for two isozymes involved with xenobiotic metabolism-esterase and glucose-6-phosphate dehydrogenase. Differential banding patterns also revealed a higher percentage of polymorphic loci, number of polymorphic bands, Nei's genetic distance, etc. observed in these populations in the Randomly Amplified Polymorphic DNA Polymerase Chain Reaction (RAPD-PCR) experiments using three random decamer primers. Higher heterozygosity, being indicative of a more resistant population, implies population survival within the threshold pesticide stress. This study reports such changes for the first time in native wild Indian honey bee populations exposed to pesticides and has far-reaching implications on the population adaptability under pesticide stress. PMID- 29762716 TI - CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. AB - CRISPOR.org is a web tool for genome editing experiments with the CRISPR-Cas9 system. It finds guide RNAs in an input sequence and ranks them according to different scores that evaluate potential off-targets in the genome of interest and predict on-target activity. The list of genomes is continuously expanded, with more 150 genomes added in the last two years. CRISPOR tries to provide a comprehensive solution from selection, cloning and expression of guide RNA as well as providing primers needed for testing guide activity and potential off targets. Recent developments include batch design for genome-wide CRISPR and saturation screens, creating custom oligonucleotides for guide cloning and the design of next generation sequencing primers to test for off-target mutations. CRISPOR is available from http://crispor.org, including the full source code of the website and a stand-alone, command-line version. PMID- 29762715 TI - Effect of diet type and added copper on growth performance, carcass characteristics, energy digestibility, gut morphology, and mucosal mRNA expression of finishing pigs. AB - A total of 757 pigs (PIC 337 * 1050; initially 27.6 kg BW) were used in a 117-d experiment to determine the effects of added Cu from tribasic copper chloride and diet type on growth performance, carcass characteristics, energy digestibility, gut morphology, and mucosal mRNA expression of finishing pigs. Pens of pigs were allotted to 1 of 4 dietary treatments, balanced on average pen weight in a randomized complete block design with 26 to 28 pigs per pen and 7 replications per treatment. Treatments were arranged in a 2 * 2 factorial with main effects of diet type, a corn-soybean meal-based diet (corn-soy) or a high by-product diet (by-product) with 30% distillers dried grains with solubles (DDGS) and 15% bakery meal, and added Cu (0 or 150 mg/kg added Cu). There were no Cu * diet type interactions for growth performance. Overall, neither added Cu nor diet type influenced growth performance. However, caloric efficiency was decreased (P = 0.001) for pigs fed the by-product diet compared to the corn-soy diet. Pigs fed the by-product diet had decreased (P < 0.05) carcass yield and carcass G:F) and marginally decreased (P < 0.07) HCW and carcass ADG compared to pigs fed the corn soy diet. A Cu * diet type interaction (P < 0.05) existed for DM and GE digestibility during the early finishing period as added Cu improved (P < 0.05) digestibility of DM and GE in the corn-soy diet, but not in the by-product diet. During the late finishing period, added Cu marginally increased (P = 0.060) DM and GE digestibility while pigs fed the by-product diet had decreased DM and GE digestibility (P = 0.001) compared to those fed the corn-soy diet. For gut morphology, pigs fed added Cu had decreased crypt depth (P = 0.017) in the distal small intestine compared to those fed no added Cu. Furthermore, relative mRNA expression of intestinal fatty acid binding protein (iFABP) was decreased (P = 0.032) in pigs fed added Cu compared to those fed no added Cu. In summary, adding 150 mg/kg added Cu or including 30% DDGS and 15% bakery meal into a corn-soy diet did not influence growth performance. However, HCW ADG and HCW G:F were reduced in pigs fed the by-product diet compared to the corn-soy diet. Only minor differences in gut morphology or mRNA expression were observed from feeding diets with high levels of Cu or by-products compared to a corn-soy diet. PMID- 29762719 TI - Repellence of Common Tobacco Flavorants on Lasioderma serricorne (Coleoptera: Anobiidae). AB - The cigarette beetle, Lasioderma serricorne (F.) (Coleoptera: Anobiidae) is a destructive pest species of tobacco. Olfactory repellents derived from permitted tobacco flavorants have the advantage of not adversely effecting tobacco flavor. Among 12 test compounds, neral exhibited the strongest repellent effect. Among six binary blends prepared, three blends (neral + ethyl cinnamate, neral + cinnamaldehyde, and neral + methyl cinnamate) evoked the strongest repellent response. The interactions between neral and any one of the cinnamic acid derivatives were additive, and the interactions between neral and the cinnamic acid derivatives were antagonistic. In a 32-d tobacco barn bioassay, neral + cinnamaldehyde (embedded in 0.5% agaropectin) showed the strongest repellent effect with a persistence of at least 30 d. The binary blend of two tobacco additives (neral and cinnamaldehyde) appears promising as a repellent for controlling cigarette beetles in tobacco barns. PMID- 29762717 TI - Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC. AB - Background: Vocimagene amiretrorepvec (Toca 511) is an investigational gamma retroviral replicating vector encoding cytosine deaminase that, when used in combination with extended-release 5-fluorocytosine (Toca FC), results preclinically in local production of 5-fluorouracil, depletion of immune suppressive myeloid cells, and subsequent induction of antitumor immunity. Recurrent high-grade glioma (rHGG) patients have a high unmet need for effective therapies that produce durable responses lasting more than 6 months. In this setting, relapse is nearly universal and most responses are transient. Methods: In this Toca 511 ascending-dose phase I trial (NCT01470794), HGG patients who recurred after standard of care underwent surgical resection and received Toca 511 injected into the resection cavity wall, followed by orally administered cycles of Toca FC. Results: Among 56 patients, durable complete responses were observed. A subgroup was identified based on Toca 511 dose and entry requirements for the follow-up phase III study. In this subgroup, which included both isocitrate dehydrogenase 1 (IDH1) mutant and wild-type tumors, the durable response rate is 21.7%. Median duration of follow-up for responders is 35.7+ months. As of August 25, 2017, all responders remain in response and are alive 33.9+ to 52.2+ months after Toca 511 administration, suggesting a positive association of durable response with overall survival. Conclusions: Multiyear durable responses have been observed in rHGG patients treated with Toca 511 + Toca FC in a phase I trial, and the treatment will be further evaluated in a randomized phase III trial. Among IDH1 mutant patients treated at first recurrence, there may be an enrichment of complete responders. PMID- 29762718 TI - Cell penetrating thiazole peptides inhibit c-MYC expression via site-specific targeting of c-MYC G-quadruplex. AB - The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of G-quadruplex ligands described thus far show little selectivity among different G-quadruplexes. In this work, we delineate the design and synthesis of a crescent-shaped thiazole peptide that preferentially stabilizes c-MYC quadruplex over other promoter G-quadruplexes and inhibits c-MYC oncogene expression. Biophysical analysis such as Forster resonance energy transfer (FRET) melting and fluorescence spectroscopy show that the thiazole peptide TH3 can selectively interact with the c-MYC G-quadruplex over other investigated G quadruplexes and duplex DNA. NMR spectroscopy reveals that peptide TH3 binds to the terminal G-quartets and capping regions present in the 5'- and 3'-ends of c MYC G-quadruplex with a 2:1 stoichiometry; whereas structurally related distamycin A is reported to interact with quadruplex structures via groove binding and end stacking modes with 4:1 stoichiometry. Importantly, qRT-PCR, western blot and dual luciferase reporter assay show that TH3 downregulates c-MYC expression by stabilizing the c-MYC G-quadruplex in cancer cells. Moreover, TH3 localizes within the nucleus of cancer cells and exhibits antiproliferative activities by inducing S phase cell cycle arrest and apoptosis. PMID- 29762721 TI - Clinical evaluation of the DermaGenius(r) Nail real-time PCR assay for the detection of dermatophytes and Candida albicans in nails. AB - Onychomycosis represents one of the most frequent mycoses in the world. Causative agents are mainly dermatophytes, but yeasts and nondermatophyte moulds can also be involved. Conventional diagnostic methods include direct microscopy (or histology) and culturing. However, molecular methods are becoming increasingly popular in this field. The DermaGenius(r) (DG) Nail multiplex assay (PathoNostics, The Netherlands) is a new commercial real-time polymerase chain reaction (PCR) kit, which can detect Trichophyton rubrum, Trichophyton interdigitale and Candida albicans directly in nails. The present study is a retrospective evaluation of the kit applied to 138 finger and toenail clippings in comparison to histology and culture methods. The sensitivity and specificity of the PCR assay are 80% (76/95) and 74.4% (32/43), respectively, when histology and culture are used as reference to define onychomycosis. DG performance is not different from histology combined with culture (P = .11) but the best diagnostic efficacy (88.4%, 122/138) is obtained by the combination of histology and DG. In conclusion, this study emphasizes the clinical usefulness of the DG in diagnostics. The high specificity of this test guarantees a better identification compared to culture that can lead to dermatophyte misidentifications. It is a reliable PCR assay that shortens the time to diagnosis and can unmask the presence of nongrowing fungal pathogens in nails. PMID- 29762720 TI - Evaluation of F1 cows sired by Brahman, Boran, and Tuli bulls for reproductive, maternal, and cow longevity traits. AB - This study evaluated reproductive, maternal performance, and longevity traits of 143 F1 cows sired by Brahman (Br), Boran (Bo), or Tuli (T) bulls from Angus or Hereford cows from 1994 to 2011. Cow traits were measured at 7 yr of age in 1999 and 2000 for 1992- and 1993-born cows, respectively. From 2004 to 2010, excluding 2008, incisor condition (solid, broken, smooth) scores were assigned to cows remaining in production; scores were evaluated with two models. Broken and solid mouths were each assigned a score of "1" and smooth assigned "0"; Br-sired (0.76) and Bo-sired cows (0.71) had higher scores (P < 0.05) than T-sired cows (0.54). When solid mouths were scored 1 and smooth and broken scored 0, Br-sired cows (0.34) were higher than T-sired (0.01) (P < 0.05), and Bo-sired (0.23) cows were not different from either (P > 0.05). Age level of the cow within birth year was important for all modeled calf traits (P < 0.05). Birth weights were not different among cow inheritance (P > 0.05). Cow type influenced (P < 0.05) 205-d adjusted weaning weight of calves; Br-sired dams (228.1 +/- 2.37 kg) produced the greatest weaning weight, followed by Bo-sired (213.7 +/- 3.10 kg), and T-sired (201.6 +/- 2.69 kg) dams (P < 0.05). Adjusted means for calving rate for Bo-sired (0.92 +/- 0.02) cows were higher (P < 0.05) than Br-sired (0.86 +/- 0.02) and T sired (0.86 +/- 0.02) cows. Adjusted mean weaning rate was greater (P < 0.05) for Bo-sired cows (0.86 +/- 0.02) than for cows sired by Br (0.77 +/- 0.02) bulls, but weaning rate for T-sired cows (0.80 +/- 0.02) were similar (P > 0.05). Cow weight was greater (P < 0.05) for Br-sired cows (590.5 +/- 8.35 kg) than for Bo sired (505.8 +/- 10.46 kg) or T-sired cows (508.5 +/- 9.37 kg). BCS at weaning for 7-yr-old cows was similar (P = 0.08) for Br-sired and Bo-sired cows and lower for T-sired cows (P = 0.0005, condition scores 6.0, 6.3, and 5.8, respectively). Boran-sired cows were older when they were removed from the herd, on average (12.7 +/- 0.74 y, P = 0.03) than T-sired (10.6 +/- 0.61 y); Br-sired cow persistence was intermediate and not different (11.05 +/- 0.60 y, P > 0.06) from the others. Boran-sired cows had higher calving and weaning rates and better mouth scores than the other groups; consequently, they had greater longevity as well. Boran-sired and T-sired cows were moderate in size and weighed less than Br sired cows throughout the study. Tuli-sired cows weaned the lightest calves and had the most tooth deterioration as they aged. PMID- 29762723 TI - pyABC: distributed, likelihood-free inference. AB - Summary: Likelihood-free methods are often required for inference in systems biology. While approximate Bayesian computation (ABC) provides a theoretical solution, its practical application has often been challenging due to its high computational demands. To scale likelihood-free inference to computationally demanding stochastic models, we developed pyABC: a distributed and scalable ABC Sequential Monte Carlo (ABC-SMC) framework. It implements a scalable, runtime minimizing parallelization strategy for multi-core and distributed environments scaling to thousands of cores. The framework is accessible to non-expert users and also enables advanced users to experiment with and to custom implement many options of ABC-SMC schemes, such as acceptance threshold schedules, transition kernels and distance functions without alteration of pyABC's source code. pyABC includes a web interface to visualize ongoing and finished ABC-SMC runs and exposes an API for data querying and post-processing. Availability and Implementation: pyABC is written in Python 3 and is released under a 3-clause BSD license. The source code is hosted on https://github.com/icb-dcm/pyabc and the documentation on http://pyabc.readthedocs.io. It can be installed from the Python Package Index (PyPI). Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29762722 TI - CalFitter: a web server for analysis of protein thermal denaturation data. AB - Despite significant advances in the understanding of protein structure-function relationships, revealing protein folding pathways still poses a challenge due to a limited number of relevant experimental tools. Widely-used experimental techniques, such as calorimetry or spectroscopy, critically depend on a proper data analysis. Currently, there are only separate data analysis tools available for each type of experiment with a limited model selection. To address this problem, we have developed the CalFitter web server to be a unified platform for comprehensive data fitting and analysis of protein thermal denaturation data. The server allows simultaneous global data fitting using any combination of input data types and offers 12 protein unfolding pathway models for selection, including irreversible transitions often missing from other tools. The data fitting produces optimal parameter values, their confidence intervals, and statistical information to define unfolding pathways. The server provides an interactive and easy-to-use interface that allows users to directly analyse input datasets and simulate modelled output based on the model parameters. CalFitter web server is available free at https://loschmidt.chemi.muni.cz/calfitter/. PMID- 29762724 TI - AAI-profiler: fast proteome-wide exploratory analysis reveals taxonomic identity, misclassification and contamination. AB - We present AAI-profiler, a web server for exploratory analysis and quality control in comparative genomics. AAI-profiler summarizes proteome-wide sequence search results to identify novel species, assess the need for taxonomic reclassification and detect multi-isolate and contaminated samples. AAI-profiler visualises results using a scatterplot that shows the Average Amino-acid Identity (AAI) from the query proteome to all similar species in the sequence database. Taxonomic groups are indicated by colour and marker styles, making outliers easy to spot. AAI-profiler uses SANSparallel to perform high-performance homology searches, making proteome-wide analysis possible. We demonstrate the efficacy of AAI-profiler in the discovery of a close relationship between two bacterial symbionts of an omnivorous pirate bug (Orius) and a thrip (Frankliniella occidentalis), an important pest in agriculture. The symbionts represent novel species within the genus Rosenbergiella so far described only in floral nectar. AAI-profiler is easy to use, the analysis presented only required two mouse clicks and was completed in a few minutes. AAI-profiler is available at http://ekhidna2.biocenter.helsinki.fi/AAI. PMID- 29762725 TI - Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. AB - Background: The aim of this meta-analysis was to assess the risks and incidence of nephrotoxicity and electrolyte abnormalities in patients receiving programmed cell death protein 1 (PD-1) inhibitors. Methods: We conducted a meta-analysis of clinical trials that monitored electrolyte levels and kidney functions during treatment with nivolumab or pembrolizumab by searching MEDLINE, EMBASE and the Cochrane Database from inception through April 2017. Our protocol is registered with International Prospective Register of Systematic Reviews; no.CRD42017060579. Results: A total of 48 clinical trials with a total of 11 482 patients were included. The overall pooled risk ratios (RR) of all acute kidney injury (AKI) and all electrolyte abnormalities in patients treated with PD-1 inhibitors were 1.86 [95% confidence interval (CI) 0.95-3.64] and 1.67 (95% CI 0.89-3.12), respectively. Compared with non-nephrotoxic controls, the pooled RR of AKI in patients treated with PD-1 inhibitors was 4.19 (95% CI 1.57-11.18). Prespecified subgroup analyses demonstrated a significant association between PD-1 inhibitors and hypocalcemia with a pooled RR of 10.87 (95% CI 1.40-84.16). The pooled estimated incidence rates of AKI and hypocalcemia in patients treated with PD-1 inhibitors were 2.2% (95% CI 1.5-3.0%) and 1.0% (95% CI 0.6-1.8%), respectively. Among patients who developed AKI with PD-1 inhibitors, the pooled estimated rate of interstitial nephritis was 16.6% (95% CI 10.2-26.0%). Conclusions: Treatment with PD-1 inhibitors is associated with a higher risk of AKI compared with non nephrotoxic agents. It will be important to characterize the AKI patients to better understand the etiology behind the event. In addition, treatment with PD-1 inhibitors is associated with an increased risk of hypocalcemia. This study highlights a rare but serious adverse event of anti-PD-1 antibodies and we recommend, in addition to electrolytes panel, routine calcium monitoring. PMID- 29762727 TI - Development of targeted therapy and immunotherapy for treatment of small cell lung cancer. AB - Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC. PMID- 29762726 TI - Supplementation with organic acids showing different effects on growth performance, gut morphology, and microbiota of weaned pigs fed with highly or less digestible diets. AB - Two studies were conducted to evaluate the effects of organic acid (OA) supplementation in a highly digestible (Exp. 1) or a less digestible diet (Exp. 2) on the growth performance and intestinal health of weaned pigs. In Exp. 1, a total of 240 pigs weaned at day 21 were assigned to one of five dietary treatments: negative control (NC) (basal diet, 3,000 ppm zinc oxide (ZnO) in the first 2 wk only); positive control (PC) (NC plus 10 mg/kg zinc bacitracin, 5 mg/kg colistin sulfate, and 5 mg/kg olaquindox); OA1 (NC plus a 0.2% blend of encapsulated butyrate, medium-chain fatty acids [MCFA], OA, and phenolics); OA2 (NC plus 0.3% blend of free and buffered short-chain fatty acids [SCFA] combined with MCFA); and OA1 plus OA2 (NC plus 0.2% OA1 plus 0.3% OA2) for 49 d. All treatments in Exp. 1 used the same highly digestible basal diet. At day 28, eight pigs from each group were sacrificed, to collect intestinal and digesta samples for biochemical analysis. Growth performance and intestinal morphology were not affected by the treatments. However, pigs subjected to the OA2 treatment had lower levels of Escherichia coli (P < 0.05) in the colon. In addition, the OA1 and OA2 treatments, and their combination resulted in higher concentrations of acetate and propionic acid in the cecum and colon (P < 0.01) in comparison to the NC. A less digestible diet without high levels of ZnO was used in Exp. 2. A similar design was used with the exception of the replacement of OA2 with another OA blend (OA3, a blend of free and buffered OA). In comparison to the NC, supplementation with OA1 and OA3 in a less digestible diet improved the ADG and the F:G ratio in the seventh week post-weaning (P < 0.01); reduced the diarrhea index of pigs during the first 3 wk post-weaning (P < 0.05); increased the ileal villus height (P < 0.05), and acetic and propionic acid concentrations in colon contents (P < 0.05). Moreover, the genus Prevotella was increased in the colon and the microbial community structure was significantly altered in the OA1 + OA3 treatment. The present research indicated that dietary supplementation with OA improved intestinal health. The OA blends showed a similar growth-promoting effect as antibiotics in the less digestible diet, to which high levels of ZnO had not been added. PMID- 29762729 TI - Corrigendum. PMID- 29762730 TI - The impact of free access to swimming pools on children's participation in swimming. A comparative regression discontinuity study. AB - Objective: Investigating the extent to which providing children with free swimming access during school holidays increased participation in swimming and whether this effect differed according to the socioeconomic deprivation of the neighbourhoods in which children lived. Setting: A highly disadvantaged local authority (LA) in North West England. Intervention: Provision of children with free swimming during the summer holidays. Outcome measures: Number of children swimming, and the number of swims, per 100 population in 2014. Design: Comparative regression discontinuity investigating the extent to which participation rates amongst children aged 5-15 were greater in the intervention LA compared to a similar control LA. We estimated the differential effect of the intervention across five groups, defined by quintiles of area deprivation. Results: Free swimming during the summer holidays was associated with an additional 6% of children swimming (95% CI: 4-9%) and an additional 33 swims per 100 children per year (95% CI: 21-44). The effects were greatest in areas with intermediate levels of deprivation (quintiles 3 and 4) within this deprived LA. Conclusion: Providing free facilities for children in disadvantaged areas is likely to increase swimming participation and may help reduce inequalities in physical activity. PMID- 29762728 TI - Atypical myopathy in Pere David's deer (Elaphurus davidianus) associated with ingestion of hypoglycin A. AB - From 2004 until 2016, 21 Pere David's deer (Elaphurus davidianus) have died for unknown reason at Zoo Duisburg. These deer, also known as milu, have succumbed from a myopathy that occurred seasonally in autumn and in spring. The clinical signs shown by the animals closely resembles those of a disease called equine atypical myopathy (EAM), which is formerly known in horses. The cause for EAM in Europe was found in the ingestion of hypoglycin A, contained in samaras and seedlings of the sycamore maple tree (Acer pseudoplatanus). To test the hypothesis that the mortality of milus was caused by ingestion of hypoglycin A, 79 sera from all zoos and wildlife parks that have kept milus in Germany and Austria, including 19 diseased and 60 healthy animals, were used. Selected biochemical values and additionally hypoglycin A, methylenecyclopropyl acetic acid-carnitine (MCPA-carnitine), and acylcarnitines, which have been found in horses suffering from EAM, were determined. The results showed greater values of serum activities of creatine kinase (P < 0.001) and aspartate aminotransferase (P < 0.001) in diseased milus comparing to healthy ones confirming a myopathy in affected animals. Moreover, hypoglycin A and MCPA-carnitine were found in the blood of Pere David's deer and thus, hypoglycin A intoxication was considered to be a potential cause for the myopathies by ingestion of sycamore maple samaras that were present in the enclosure of the affected animals. Hypoglycin A values were greater in diseased animals (P < 0.01) as well as MCPA-carnitine levels (P < 0.05). Additionally, affected milus showed greater C5-OH-carnitine (P < 0.01) and C6-carnitine (P < 0.001) values. Until now hypoglycin A intoxication was only known in the family of Equidae, in humans, and in laboratory rats, and it has not been previously described in other zoological families. Comparing to horses, ruminants do have a different digestive tract and it will need further investigation to find out if several factors are involved to trigger an outbreak in ruminants. PMID- 29762731 TI - Nutrient digestibility, rumen microbial protein synthesis, and growth performance in sheep consuming rations containing sea buckthorn pomace. AB - This experiment was conducted to investigate nutrient digestibility, rumen microbial protein synthesis, and growth performance when different proportions of sea buckthorn pomace (SBP) were included in the diet of sheep. A total of forty1/2 Dorper * 1/2 thin-tailed Han ram lambs (BW = 22.2 +/- 0.92 kg, age =120 +/- 11 d; mean +/- SD) were selected and divided into four groups in a randomized design and were randomly allocated to one of four treatment diets. Diets were formulated isonitrogenously and contained different levels of SBP: 1) 0% SBP (control), 2) 7.8% of DM SBP (8SBP), 3) 16.0% of DM SBP (16SBP), and 4) 23.5% of DM SBP (24SBP). A portion of corn and forages were replaced with SBP. DMI and ADG increased linearly (P = 0.001), but feed efficiency was not affected (P >= 0.460) by increasing SBP inclusion rate. As the SBP inclusion increased, OM, NDF, and ADF digestibility decreased linearly (P <= 0.005) and that CP increased linearly (P = 0.012). Response to inclusion level of SBP was quadratic (P = 0.003) for the estimated microbial CP yield with the greatest at intermediate SBP levels. For intestinally absorbable dietary protein, quadratic (P = 0.029) effects were observed among treatments. The metabolizable protein (MP) supplies were linearly (P < 0.0001) improved with increasing SBP inclusion rate. The results indicated that SBP can be incorporated in the ration of ram lambs and improve MP supply and ADG. However, high content of it in the diet was adverse for nutrient digestibility. The optimal proportion was 16.0% under the condition of this experiment. PMID- 29762732 TI - Calcium particle size effects on plasma, excreta, and urinary Ca and P changes in broiler breeder hens. AB - An experiment was conducted using non-colostomized and colostomized broiler breeder hens to determine the effects of feeding limestone of 2 different mean particle sizes (185 microns and 3490 microns) on P excretion, total P and Ca retention, and urinary P and Ca excretion during a 6-week feeding study. Additionally, changes in plasma inorganic P (iP) and ionic Ca (Ca++) and urinary excretion of P and Ca were determined in one egg laying cycle of 24 hours. One hundred-fifty non-colostomized and 6 colostomized broiler breeder hens, 30 wk of age, were divided into 2 groups and fed broiler breeder diets supplemented with either small particle or large particle limestone. Two % acid insoluble ash (Celite) was added to the feed as a marker. Diets, excreta, and urine samples were analyzed for total P and Ca by ionic coupling plasma (ICP) analysis. The non colostomized breeders fed large particle limestone compared to small limestone particles produced a significant increase in percent tibia ash (P < 0.0001) and egg specific gravity (P = 0.0382), but P excretion approached a tendency of being reduced (P = 0.1585). The urinary total P and Ca (~18 and 9%, respectively) of total P and Ca excretion for breeders fed both sizes of limestone was not significantly different in the colostomized breeders. In plasma, both iP and Ca++ reached a peak during 18 to 20 h and 20 to 24 h post oviposition for smaller and larger particle sized limestone fed groups, respectively. The maximal excretion of urinary P was found during 11 to 20 h post oviposition, whereas urinary Ca peaked during 0 to 11 h post oviposition for both smaller and larger particle sized limestone supplemented groups. In summary, the findings indicate that the particle size (smaller and larger) of calcium source did not significantly influence the quantitative total urinary excretion of Ca and P but did influence the timing of Ca and P excretion. PMID- 29762734 TI - Estimation of direct and maternal genetic parameters for individual birth weight, weaning weight, and probe weight in Yorkshire and Landrace pigs. AB - As a result of selecting for increased litter size, newborn piglets are being born lighter and have a lower chance of survival. Raising fewer pigs to market weight would have a negative impact on the industry and farmer profitability; thus, understanding the genetics of individual growth performance traits will determine whether these traits will play an important role in pig breeding schemes. This study aimed to estimate genetic parameters for individual birth weight (BW), weaning weight (WW), and probe weight (PW) in Canadian-purebred Yorkshire and Landrace pigs. PW is a live weight taken at the time of the ultrasound measurements, when pigs weigh about 100 kg. Data were collected from 2 large and related breeding herds from 2003 to 2015. Four linear animal models were used, which included the following: Model 1-direct additive genetic effect; Model 2-direct additive genetic and maternal genetic effect; Model 3-direct additive genetic and common litter effect; and Model 4-direct additive genetic, maternal genetic, and common litter effect. The model which included all 3 random effects (Model 4) was determined to be the best fit to the data. Low to moderate direct heritability estimates were observed as follows: 0.15 +/- 0.03 for BW, 0.04 +/- 0.01 for WW, and 0.33 +/- 0.03 for PW for the Yorkshire breed; and 0.05 +/- 0.01 for BW, 0.01 +/- 0.01 for WW, and 0.27 +/- 0.03 for PW in the Landrace breed. As expected, the direct heritability estimates increased with age as a result of decreased maternal influence on the trait. Bivariate animal models were also used to estimate genetic and environmental correlations between traits. Strong direct genetic correlations were observed between BW and WW in both breeds. Based on the estimates of genetic parameters, individual BW could be evaluated and considered in breeding programs aiming to increase BW and improve subsequent performance. Different selection emphasis could also be applied on direct and maternal additive genetic effects on BW to optimize the breeding programs and improve selection efficiency. PMID- 29762735 TI - Short periods of incubation, egg turning during storage and broiler breeder hens age for early development of embryos, hatching results, chicks quality and juvenile growth. AB - An effect of modification of storage conditions of the eggs of broiler breeder flocks at the age of 49-, 52- and 70-, 73-wks of life on an early embryonic development, hatching time and synchronization, hatchability rates, chicks quality and broiler growth was investigated. The eggs were divided into 4 experimental groups: COI = eggs storage 5 d, at turning every 12 h; NSP = eggs storage 12 d, at turning every 12 h; SPIDES = were treated with 4 h pre incubation at 30 degrees C and 50-55% air humidity, delivered at 5 and 10 d over of 12 d of storage, and turning every 12 h; NCOI = eggs storage 12 d, no turning and no pre-incubation. Eggs from older hens were characterized by poorer hatchability and poorer chicks quality. The use of 2 * 4 h pre-incubation in 12 d of eggs storage could have an effect on the initial acceleration of embryonic development in eggs of young hens, contributing to the alignment of embryos development in eggs from young and older hens to 72 h of incubation. Pre incubation had no effect on the length of incubation period, hatching window, but it increased the hatchability of the set and apparently fertilized eggs and decreased the number of eggs not hatched, and also improved chicks quality. Eggs turning by 90 degrees every 12 h during the storage positively affected the embryonic development, shortening the incubation time and the quality of chicks, but had no effect on hatchability rates and body weight in 42 d of life. Based on the obtained results, it can be concluded that the applied modifications can be effective in counteracting the negative effects of storage of hatching eggs from both young and older birds. PMID- 29762733 TI - The effect of vaginal microbial communities on colonization by Staphylococcus aureus with the gene for toxic shock syndrome toxin 1 (TSST-1): a case-control study. AB - Menstrual toxic shock syndrome is associated with vaginal colonization by Staphylococcus aureus strains that encode toxic shock syndrome toxin 1 (tst+). Interestingly, a small proportion of women are colonized by S. aureus tst+ but do not have symptoms of toxic shock syndrome. Here we sought to determine if differences in the species composition of vaginal bacterial communities reflect a differential risk of colonization by S. aureus capable of producing toxic shock syndrome toxin 1 (TSST-1). The composition of vaginal communities of women that were or were not colonized with S. aureus tst+ were compared based on terminal restriction fragment length polymorphism (T-RFLP) profiles and sequences of cloned 16S rRNA genes. There were no detectable differences in community composition or species rank abundance between communities of women vaginally colonized with S. aureus tst+ as compared to those that were not. Phylogenetic analysis of cloned 16S rRNA gene sequences showed that the predominant members of communities of women colonized with S. aureus tst+ were indistinguishable from those of other healthy women. The data suggest that the numerically dominant members of vaginal communities do not preclude colonization and proliferation of S. aureus tst+ within indigenous microbial communities of the vagina. PMID- 29762737 TI - Postnatal Lifestyle Intervention for Overweight Women With Previous Gestational Diabetes: A Randomized Controlled Trial. AB - Background: Gestational diabetes mellitus (GDM) is associated with a sevenfold increased lifetime risk of type 2 diabetes. Excessive gestational weight gain and postpartum weight retention are established predictors of long-term obesity. Objective: To determine the impact of a postnatal lifestyle intervention program for overweight women with previous gestational diabetes mellitus (PAIGE). Design: Postnatal overweight women with previous GDM participated in a multicenter randomized controlled trial between June 2013 and December 2014. The intervention comprised a 1-hour educational program, a free 3-month referral to a commercial weight management organization (Slimming World), a pedometer, and structured telephone and text support, in addition to usual care. The control group received usual care only. The primary outcome was weight loss at 6 months. Results: Sixty women were randomized (29 intervention; 31 control) in two centers based on their week of attendance. The intervention group demonstrated significant weight loss at 6 months after randomization compared with the control group: mean +/-SD, 3.9 +/- 7.0 kg vs 0.7 +/-3.8 kg (P = 0.02). Blood glucose levels did not significantly differ. With respect to well-being measures, a bodily pain was significantly reduced in the intervention group (P = 0.007). Conclusions: PAIGE resulted in significantly greater weight loss at 6 months compared with usual care. Such weight loss could prove beneficial in terms of better long-term health and subsequent prevention of type 2 diabetes in overweight women with previous GDM. Future interventions must consider recruitment strategies, timing of the intervention, and inclusion of partners and/or other family members. PMID- 29762738 TI - Successful treatment of suckling Red Angus calves for bovine respiratory disease is not associated with increased mean pulmonary arterial pressures at weaning. AB - The purposes of this study were to determine if the successful treatment of bovine respiratory disease (BRD) in suckling calves was associated with a long term increase in mean pulmonary arterial pressure (mPAP) and, to screen for associations between blood leukogram variables and mPAP. A cohort of Red Angus calves (n = 74) were followed from birth to weaning at an altitude of 975 m. Calves were weaned at 172 +/- 14 d when their mPAP was measured and whole blood collected. Thirty calves that had been treated for BRD (34 to 45 d prior) and 30 calves that had not required treatment for BRD were sampled. Treatment for BRD had no effect on mPAP (P = 0.37). Mean mPAP was 48 +/- 8 mm Hg (+/- SD) with a minimum of 34 mm Hg and a maximum at 69 mm Hg. Weaning weight and sex tended to be associated with mPAP, but they explained just 5% of the variation in mPAP (P = 0.08; Adj. r2 = 0.05). Fibrinogen (P = 0.008) and absolute lymphocyte count (P = 0.06) were negatively associated with mPAP, whereas absolute monocyte count was positively associated with mPAP (P = 0.01). The findings of this study suggest that pre-weaning treatment for BRD does not increase a calves' post-weaning risk of congestive right heart failure. Further, components of the immune and acute phase response system may play a role in the development and progression of pulmonary hypertension. PMID- 29762736 TI - Comparative transcriptome analysis of rumen papillae in suckling and weaned Japanese Black calves using RNA sequencing. AB - The length and density of rumen papillae starts to increase during weaning and growth of ruminants. This significant development increases the intraruminal surface area and the efficiency of VFA (acetate, propionate, butyrate, etc.) uptake. Thus, it is important to investigate the factors controlling the growth and development of rumen papillae during weaning. This study aimed to compare the transcriptomes of rumen papillae in suckling and weaned calves. Total RNA was extracted from the rumen papillae of 10 male Japanese Black calves (5 suckling calves, 5 wk old; 5 weaned calves, 15 wk old) and used in RNA-sequencing. Transcript abundance was estimated and differentially expressed genes were identified and these data were then used in Ingenuity Pathway Analysis (IPA) to predict the major canonical pathways and upstream regulators. Among the 871 differentially expressed genes screened by IPA, 466 genes were upregulated and 405 were downregulated in the weaned group. Canonical pathway analysis showed that "atherosclerosis" was the most significant pathway, and "tretinoin," a derivative of vitamin A, was predicted as the most active upstream regulator during weaning. Analyses also predicted IgG, lipopolysaccharides, and tumor necrosis factor-alpha as regulators of the microbe-epithelium interaction that activates rumen-related immune responses. The functional category and the up regulators found in this study provide a valuable resource for studying new candidate genes related to the proliferation and development of rumen papillae from suckling to weaning Japanese Black calves. PMID- 29762740 TI - Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease. PMID- 29762739 TI - CKD staging with cystatin C or creatinine-based formulas: flipping the coin. AB - Background: Chronic kidney disease (CKD) affects 10-13% of the population worldwide. CKD classification stratifies patients in five stages of risk for progressive renal disease based on estimated glomerular filtration rate (eGFR) by formulas and albuminuria. However, the reliability of formulas to reflect real renal function is a matter of debate. The effect of the error of formulas in the CKD classification is unclear, particularly for cystatin C-based equations. Methods: We evaluated the reliability of a large number of cystatin C and/or creatinine-based formulas in the definition of the stages of CKD in 882 subjects with different clinical situations over a wide range of glomerular filtration rates (GFRs) (4.2-173.7 mL/min). Results: Misclassification was a constant for all 61 formulas evaluated and averaged 50% for creatinine-based and 35% for cystatin C-based equations. Most of the cases were misclassified as one stage higher or lower. However, in 10% of the subjects, one stage was skipped and patients were classified two stages above or below their real stage. No clinically relevant improvement was observed with cystatin C-based formulas compared with those based on creatinine. Conclusions: The error in the classification of CKD stages by formulas was extremely common. Our study questions the reliability of both cystatin C and creatinine-based formulas to correctly classify CKD stages. Thus the correct classification of CKD stages based on estimated GFR is a matter of chance. This is a strong limitation in evaluating the severity of renal disease, the risk for progression and the evolution of renal dysfunction over time. PMID- 29762741 TI - A Longitudinal Analysis of the Intergenerational Transmission of Health Inequality. AB - Objectives: Empirical investigations of cumulative dis/advantage typically treat health inequality as an intra-individual process rooted in early-life conditions and operating within the span of the individual life course, while literature on processes of intergenerational transmission has historically focused on socioeconomic mobility, largely overlooking health. The current study examines the persistence of work disability across generations and multiple explanations for this relationship, including the role of early life disadvantage, childhood health, educational attainment, and social mobility. Methods: We model latent classes of midlife work disability characterized by timing and stability using longitudinal data from the intergenerational component of the U.S. Panel Study of Income Dynamics (N=3,328). Latent class analysis captures the initial risk of experiencing a work disability and how this risk changes across mid-life as a function of early life conditions, childhood health, educational attainment, mobility, and parent's work disability. Results: Early disadvantage, childhood health, and educational attainment were associated with patterns of midlife work disability, and although upward mobility provided some protection, intergenerational continuity in health remained net of all of these factors. Discussion: Findings support the importance of looking beyond the individual life course to the transmission of health inequality across generations within families. PMID- 29762742 TI - Effects of reduced digestible lysine density on myopathies of the Pectoralis major muscles in broiler chickens at 48 and 62 days of age. AB - Quantitative control of nutrient intake may decrease the incidence of wooden breast (WB) and white striping (WS) myopathies with some impairment of live performance. Two experiments (Exp) utilizing Yield Plus * Ross 708 male broilers were conducted to determine if a reduction in myopathies may be obtained through a qualitative approach by reducing digestible lysine (dLys) density. All birds received an identical starter diet until 11 d of age. In Exp 1 (63 pens; 22 birds/pen), each pen was then randomly assigned to 1 of the following 7 dietary treatments (TRT) for a 47 d production period. Seven dietary treatments were provided for the grower 1 (G1; 12 to 18 d of age) and grower 2 (G2; 19 to 26 d of age) phases: 1) 100% of primary breeder recommendations for dLys throughout Exp; 2) 85% of TRT 1 dLys for G1; 3) 85% of TRT 1 dLys for G2; 4) 85% of TRT 1 dLys for G1 and G2; 5) 75% of TRT 1 dLys for G1; 6) 75% of TRT 1 dLys for G2; 7) 75% of TRT 1 for G1 and G2. In Exp 2 (24 pens; 30 birds/pen), birds were randomly assigned to 1 of the following 4 dietary TRT (Table 2) during a 61 d production period. Four dietary treatments were provided for the grower (G; 12 to 28 d) and finisher 1 (F1; 29 to 40 d of age) phases: 1) 100% of primary breeder recommendations for dLys 2) 85% of TRT 1 dLys for G; 3) 85% of TRT 1 dLys for F1; 4) 85% of TRT 1 dLys for G and F1; thereafter, birds received common finisher 1 (Exp 1: 27 to 42 d of age), finisher 2 (Exp 2: 41 to 48 d of age) and withdrawal (Exp 1: 43 to 47 d of age; Exp 2: 49 to 61 d of age) diets. Ideal amino acid ratios were not maintained in reduced dLys diets in either Exp. At 48 (Exp 1; 18 birds/pen) and 62 (Exp 2; 30 birds/pen) d of age, selected birds were processed and fillets were visually scored for WB and WS. No differences (P > 0.05) in cumulative live performance responses between TRT 1 and the remaining TRT were observed in either Exp. In Exp 1, the incidence of severe WB (20.8%) and WS (42.3%) at 48 d of age among birds receiving TRT 7 was reduced (P < 0.01) compared with TRT 1 (WB: 36.6%; WS: 64.3%), at the expense of reduced (P = 0.003) breast weights and yield. In Exp 2, the incidence of severe WB (18.8%) and WS (17.8%) at 62 d of age for birds receiving TRT 4 was reduced (P < 0.05) compared with TRT 1 (WB: 39.3%; WS: 38.3%), without any detrimental effects on processing characteristics. These results indicate that altering dietary dLys during critical periods of the growth trajectory may be a viable strategy for reducing the incidence and severity of WB and WS. PMID- 29762744 TI - Forensically Relevant Blow Flies in Lebanon Survey and Identification Using Molecular Markers (Diptera: Calliphoridae). AB - Calliphoridae are among the first insects associated to decomposing animal remains. We have collected 1,841 specimens of three calliphorid genera: Calliphora, Lucilia, and Chrysomya, from different Lebanese localities as a first step in implementing a database of insects of forensic relevance for the country. Blow-flies are crucial for the estimation of the postmortem interval. DNA-based identification is a rapid and accurate method, often used for morphologically similar species, especially for immatures or incomplete specimens. In this study, we test the suitability of three genetic markers to identify adults and immature stages of calliphorids, viz., mitochondrial cytochrome c oxidase subunit I (COI) barcode, a region including partial sequences of mitochondrial Cyt-b-tRNAser-ND1, and second internal transcribed spacer (ITS2) region of nuclear ribosomal DNA. Forty Lebanese specimens of various developmental stages (egg, larva, wandering third instar, pupa, newly emerged adult, and mature adult) were identified among the three calliphorid genera: Calliphora, Lucilia, and Chrysomya, and compared with published sequences to confirm their specific assignation. Phylogenetic analyses showed the robustness of ITS2 and COI to identify calliphorids at species level. Nevertheless, ITS2 failed to discriminate Lucilia caesar (Linnaeus) (Diptera, Calliphoridae) from Lucilia illustris (Meigen) (Diptera, Calliphoridae), and COI had a similar issue with Lucilia sericata (Meigen) (Diptera, Calliphoridae) and Lucilia cuprina (Wiedemann) (Diptera, Calliphoridae). Thus, these two markers are complementary. This work contributes new nucleotide sequences for Lebanon. It is a first step in implementing a molecular database of forensic relevant insects for the country. PMID- 29762743 TI - Lipidome Evolution in Mammalian Tissues. AB - Lipids are essential structural and functional components of cells. Little is known, however, about the evolution of lipid composition in different tissues. Here, we report a large-scale analysis of the lipidome evolution in six tissues of 32 species representing primates, rodents, and bats. While changes in genes' sequence and expression accumulate proportionally to the phylogenetic distances, <2% of the lipidome evolves this way. Yet, lipids constituting this 2% cluster in specific functions shared among all tissues. Among species, human show the largest amount of species-specific lipidome differences. Many of the uniquely human lipidome features localize in the brain cortex and cluster in specific pathways implicated in cognitive disorders. PMID- 29762746 TI - Microsurgery Versus Stereotactic Radiosurgery for Brain Arteriovenous Malformations: A Matched Cohort Study. AB - BACKGROUND: Microsurgery (MS) and stereotactic radiosurgery (SRS) remain the preferred interventions for the curative treatment of brain arteriovenous malformations (AVM), but their relative efficacy remains incompletely defined. OBJECTIVE: To compare the outcomes of MS to SRS for AVMs through a retrospective, matched cohort study. METHODS: We evaluated institutional databases of AVM patients who underwent MS and SRS. MS-treated patients were matched, in a 1:1 ratio based on patient and AVM characteristics, to SRS-treated patients. Statistical analyses were performed to compare outcomes data between the 2 cohorts. The primary outcome was defined as AVM obliteration without a new permanent neurological deficit. RESULTS: The matched MS and SRS cohorts were each comprised of 59 patients. Both radiological (85 vs 11 mo; P < .001) and clinical (92 vs 12 mo; P < .001) follow-up were significantly longer for the SRS cohort. The primary outcome was achieved in 69% of each cohort. The MS cohort had a significantly higher obliteration rate (98% vs 72%; P = .001), but also had a significantly higher rate of new permanent deficit (31% vs 10%; P = .011). The posttreatment hemorrhage rate was significantly higher for the SRS cohort (10% for SRS vs 0% for MS; P = .027). In subgroup analyses of ruptured and unruptured AVMs, no significant differences between the primary outcomes were observed. CONCLUSION: For patients with comparable AVMs, MS and SRS afford similar rates of deficit-free obliteration. Nidal obliteration is more frequently achieved with MS, but this intervention also incurs a greater risk of new permanent neurological deficit. PMID- 29762747 TI - Detection of Babesia spp. in Dogs and Their Ticks From Peninsular Malaysia: Emphasis on Babesia gibsoni and Babesia vogeli Infections in Rhipicephalus sanguineus sensu lato (Acari: Ixodidae). AB - Canine babesiosis is an emerging tick-borne disease with a worldwide distribution, including Malaysia. While the prevalence of Babesia has been documented from dogs in Malaysia, occurrence of Babesia has been relatively little studied in their tick vectors. Accordingly, a total of 240 dogs and 140 Rhipicephalus sanguineus sensu lato (s.l.) (Acari: Ixodidae) ticks from Malaysia were molecularly screened for the presence of Babesia protozoa in the present study. Babesia gibsoni was only detected in ticks (1.4%), whereas Babesia vogeli was detected in both ticks (1.4%) and dogs (2.1%). This study highlights the detection of B. gibsoni and B. vogeli for the first time, in both adult and nymphal stages of R. sanguineus s.l. in Malaysia, suggesting the potential role of this tick species in transmitting canine babesiosis. PMID- 29762748 TI - Molecular-Type Specific Multiplex PCR produces a distinct VNII PCR pattern among Cryptococcus neoformans species complex. AB - Prevalence of molecular type VNII among Cryptococcus neoformans species complex is probably underestimated since it can be distinguished from VNI only using molecular typing methods such as URA5-RFLP, AFLP, MLST, or whole genome sequencing. Previously, we described a multiplex polymerase chain reaction (PCR) method able to identify VNI, VNIV, and VNIII hybrids, but, at that time, VNII molecular type was not described yet. In this study, 16 VNII global isolates were analyzed by our multiplex PCR method, and results showed that it was able to produce a specific pattern for all the studied VNII isolates, which was different from those of VNI, VNIV, and VNIII. PMID- 29762745 TI - Genome-wide association analysis identifies a meningioma risk locus at 11p15.5. AB - Background: Meningiomas are adult brain tumors originating in the meningeal coverings of the brain and spinal cord, with significant heritable basis. Genome wide association studies (GWAS) have previously identified only a single risk locus for meningioma, at 10p12.31. Methods: To identify a susceptibility locus for meningioma, we conducted a meta-analysis of 2 GWAS, imputed using a merged reference panel from the 1000 Genomes Project and UK10K data, with validation in 2 independent sample series totaling 2138 cases and 12081 controls. Results: We identified a new susceptibility locus for meningioma at 11p15.5 (rs2686876, odds ratio = 1.44, P = 9.86 * 10-9). A number of genes localize to the region of linkage disequilibrium encompassing rs2686876, including RIC8A, which plays a central role in the development of neural crest-derived structures, such as the meninges. Conclusions: This finding advances our understanding of the genetic basis of meningioma development and provides additional support for a polygenic model of meningioma. PMID- 29762749 TI - Siemens Immulite Aspergillus-specific IgG assay for chronic pulmonary aspergillosis diagnosis. AB - Chronic pulmonary aspergillosis (CPA) complicates underlying lung disease, including treated tuberculosis. Measurement of Aspergillus-specific immunoglobulin G (IgG) is a key diagnostic step. Cutoffs have been proposed based on receiver operating characteristic (ROC) curve analyses comparing CPA cases to healthy controls, but performance in at-risk populations with underlying lung disease is unclear. We evaluated optimal cutoffs for the Siemens Immulite Aspergillus-specific IgG assay for CPA diagnosis in relation to large groups of healthy and diseased controls with treated pulmonary tuberculosis. Sera from 241 patients with CPA attending the UK National Aspergillosis Centre, 299 Ugandan blood donors (healthy controls), and 398 Ugandans with treated pulmonary tuberculosis (diseased controls) were tested. Radiological screening removed potential CPA cases from diseased controls (234 screened diseased controls). ROC curve analyses were performed and optimal cutoffs identified by Youden J statistic. CPA versus control ROC area under curve (AUC) results were: healthy controls 0.984 (95% confidence interval 0.972-0.997), diseased controls 0.972 (0.959-0.985), screened diseased controls 0.979 (0.967-0.992). Optimal cutoffs were: healthy controls 15 mg/l (94.6% sensitivity, 98% specificity), unscreened diseased controls 15 mg/l (94.6% sensitivity, 94.5% specificity), screened diseased controls 25 mg/l (92.9% sensitivity, 98.7% specificity). Results were similar in healthy and diseased controls. We advocate a cutoff of 20 mg/l as this is the midpoint of the range of optimal cutoffs. Cutoffs calculated in relation to healthy controls for other assays are likely to remain valid for use in a treated tuberculosis population. PMID- 29762751 TI - Clinically Meaningful Gaps Between Clinical Trials and Patient Treatment. PMID- 29762750 TI - The apoptosis in arsenic-induced oxidative stress is associated with autophagy in the testis tissues of chicken. AB - The aim of this study is to investigate whether arsenic (As) could induce testicular poisoning and influence the oxidative stress, apoptosis and autophagy in chickens. Seventy-two 1-day-old male Hy-line chickens were divided into 4 groups which were exposed to 0, 0.625, 1.25, and 2.5 mg/kg body weight (BW) of arsenic trioxide (As2O3) for 30, 60 and 90 days, respectively. Histological and ultrastructural changes, antioxidant enzyme activity, mRNA and protein levels of apoptosis and autophagy-related genes were detected. Oxidative stress injuries were obvious in the testes exposure to As2O3, which resulted in the decreased activities of antioxidant enzymes, such as catalase (CAT) and superoxide dismutases (SOD). Meanwhile, the changes of mRNA and protein levels of apoptosis and autophagy-related genes showed that As2O3 exposure induced enhanced testicular apoptosis and increased the levels of autophagy markers such as Microtubule associated protein light chains 3-II (LC3-II), dynein, Beclin-1, Autophagy associated gene 5 (ATG5) and ATG4B but not LC3-I and mammalian target of rapamycin (mTOR), and demonstrated the cross-talk between apoptosis and autophagy. Histological and ultrastructural abnormalities confirm the changes of the above indicators. Taken together, our findings provide deeper insights into roles of excessive apoptosis and autophagy in the aggravation of testicular damage, which could contribute to a better understanding of As2O3-induced testicular poisoning in chickens. PMID- 29762752 TI - Variability and Coupling of Olfactory Identification and Episodic Memory in Older Adults. AB - Objectives: To determine whether assessment-to-assessment fluctuations in episodic memory (EM) reflect fluctuations in olfaction over time. Methods: Within person coupled variation in EM and the Brief Smell Identification Test (BSIT) was examined in 565 participants aged 58-106 with autopsy data from the Rush Memory and Aging Project. A growth model for up to 15 years of EM data, with BSIT as time-varying covariate, was estimated accounting for main effects of sex, education, epsilon4 allele, and Alzheimer's disease (AD) pathology, BSIT and time varying BSIT, as well as the interaction between AD pathology and time-varying BSIT. Results: Individuals with higher BSIT scores (b = 0.01, SE = 0.004, p = 0.009) had slower declines in EM. High AD pathology (b = -0.06, SE = 0.02, p = 0.001) was associated with more rapid declines in EM. The association between time-specific fluctuations in EM and BSIT differed by level of AD pathology (b = 0.08, SE = 0.034, p = 0.028), with a higher EM-BSIT association at higher levels of pathology. Discussion: BSIT and EM fluctuate together over measurement occasions, particularly for individuals with AD pathology. Repeated intra individual measurements provide information that could lead to early detection and inexpensive monitoring of accumulating AD pathology. PMID- 29762753 TI - Annular dark-field scanning confocal electron microscopy studied using multislice simulations. AB - Annular dark-field scanning confocal electron microscopy (ADF-SCEM) has been studied using multislice simulations. Thermal diffuse scattering was considered in the calculations. Geometric aberrations of the lenses were introduced. A finite-sized pinhole was taken into consideration, in addition to an ideal point pinhole. ADF-SCEM images of Al crystals aligned along a zone-axis exhibit elongated contrast along the optic axis. Results of simulations suggest that if geometric aberrations of an imaging lens are corrected, depth resolution in ADF SCEM can be improved by employing a large collection semi-angle of an annular aperture, even with a finite pinhole. PMID- 29762755 TI - Obstructive sleep apnea during rapid eye movement sleep is associated with early signs of atherosclerosis in women. AB - Study Objectives: Although obstructive sleep apnea (OSA) is associated with overall cardiovascular disease and mortality, the association with atherosclerotic cardiovascular disease is less clear, especially in women. Recently, it has been suggested that OSA during rapid eye movement (REM) sleep, associated with long apneas and deep desaturations, could have severe cardiometabolic consequences. The aim of this study was to investigate whether OSA during REM sleep is associated with early signs of atherosclerosis in a population-based sample of women. Methods: In the community-based "Sleep and Health in Women" (SHE) cohort study, 400 women underwent polysomnography, anthropometric measurements, blood sampling, blood pressure measurement, and answered questionnaires. Ten years later, 201 of the original participants, free of known atherosclerotic disease at baseline and without continuous positive airway pressure treatment for OSA, underwent a high-frequency ultrasound of the common carotid artery to assess the individual thickness of the layers of the artery wall. Results: Severe OSA during REM sleep (REM apnea-hypopnea index [AHI] >= 30) was associated with a thicker intima. This association was still significant after adjustment for age, body mass index, alcohol, and smoking, as well as for further adjustment for systolic blood pressure, low-density lipoprotein, C-reactive protein, and diabetes (beta-coefficient, 0.008; p-value, 0.022). The association between a REM AHI of >=30 and intima thickness was also seen in women with no or mild OSA and normal non-REM AHI. Conclusions: In this study of a community-based sample of women, severe OSA during REM sleep was independently associated with early signs of atherosclerosis. PMID- 29762754 TI - Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files. AB - Background: Sorted merging of genomic data is a common data operation necessary in many sequencing-based studies. It involves sorting and merging genomic data from different subjects by their genomic locations. In particular, merging a large number of variant call format (VCF) files is frequently required in large scale whole-genome sequencing or whole-exome sequencing projects. Traditional single-machine based methods become increasingly inefficient when processing large numbers of files due to the excessive computation time and Input/Output bottleneck. Distributed systems and more recent cloud-based systems offer an attractive solution. However, carefully designed and optimized workflow patterns and execution plans (schemas) are required to take full advantage of the increased computing power while overcoming bottlenecks to achieve high performance. Findings: In this study, we custom-design optimized schemas for three Apache big data platforms, Hadoop (MapReduce), HBase, and Spark, to perform sorted merging of a large number of VCF files. These schemas all adopt the divide and-conquer strategy to split the merging job into sequential phases/stages consisting of subtasks that are conquered in an ordered, parallel, and bottleneck free way. In two illustrating examples, we test the performance of our schemas on merging multiple VCF files into either a single TPED or a single VCF file, which are benchmarked with the traditional single/parallel multiway-merge methods, message passing interface (MPI)-based high-performance computing (HPC) implementation, and the popular VCFTools. Conclusions: Our experiments suggest all three schemas either deliver a significant improvement in efficiency or render much better strong and weak scalabilities over traditional methods. Our findings provide generalized scalable schemas for performing sorted merging on genetics and genomics data using these Apache distributed systems. PMID- 29762757 TI - How Are Real-time Opioid Prescribing Cognitions by Emergency Providers Influenced by Reviewing the State Prescription Drug Monitoring Program? AB - Objective: To understand how real-time opioid prescribing cognitions by emergency medicine (EM) providers are influenced by review of the state prescription drug monitoring program (PDMP). Methods: We collected prospective data from a convenience sample of 103 patient encounters for pain from 23 unique EM providers. After seeing the patient, before and immediately after reviewing the PDMP, EM providers answered how much they thought "the patient need[ed] an opioid to help manage their pain?", how concerned they were "about drug abuse and/or diversion?", and whether they planned to prescribe an opioid (yes/no). If they changed their decision to prescribe after querying the PDMP, they were asked to provide comments. We categorized encounters by opioid prescribing plan before/after PDMP review (e.g., O+/O- means plan changed from "yes" to "no") and examined changes in cognitions across categories. Results: Ninety-two of 103 (89.3%) encounters resulted in no change in opioid prescribing plan (61/92 [66.3%] O+/O+; 31/92 [33.7%] O-/O-). For the four O+/O- encounters, perceived patient opioid need decreased 75% of the time and concern for opioid abuse and/or diversion increased 75% of time. For the seven O-/O+ encounters, providers reported increased perceived patient opioid need 28.6% of the time and decreased concern for opioid abuse and/or diversion 14.3% of time. Conclusions: PDMP data rarely alter plans to prescribe an opioid among emergency providers. When changes in opioid prescribing plan were made, this was reflected by changes in cognitions. Findings support the need for a properly powered study to identify how specific PDMP findings alter prescribing cognitions. PMID- 29762756 TI - Prevalence, antimicrobial resistance profile and comparison of selective plating media for the isolation of Salmonella spp. in free-ranging waterfowl from Entre Rios, Argentina. AB - The present study was conducted to estimate the apparent prevalence of Salmonella spp. in free-ranging waterfowl that inhabitant Entre Rios, Argentina, determine the antimicrobial resistance of the isolated, and compare the performance of two selective plating media used for Salmonella isolation. Five hundred ninety nine free-living waterfowl were sampled one time by cloacal swab from April 2014 to July 2016. Only 6 samples from waterfowl belonged to all counties sampled were positive to Salmonella spp., so the apparent prevalence was 1%. Four serovars were isolated (Salmonella ser. Typhimurium, S. ser. Schwarzengrund, S. enterica subsp. I [4,12: i: -], S. enterica subsp. IIIb [60: r: e, n, x, z15]), which were susceptible to 15 antibiotics tested and resistant to erythromycin. Furthermore, some strains showed an intermediate resistant to neomycin, ciprofloxacin and/or streptomycin. The multiple antibiotic resistances index was 0.05. For Hektoen enteric agar and Salmonella Shigella agar, the relative accuracy, sensitivity, specificity, positive predictive value, and negative predictive value did not show any difference between them. The agreement was good between these two plating-media and the difference between these plating-media was not statistically significant. The low prevalence of Salmonella spp. in waterfowl in Entre Rios should not be discounted, since Salmonella ser. Typhimurium was the most prevalent serovar and some free-ranging waterfowl species studied can migrate from/to different countries, increasing the possibility to cross contaminated Salmonella to resident or other migrant birds. PMID- 29762758 TI - In Situ Left Azygous Anterior Cerebral Artery to Right Pericallosal Artery Bypass for Treatment of a Giant Right A1/2 Aneurysm: 2-Dimensional Operative Video. AB - Here we present a 46-yr-old man with recurrent syncopal episodes thought to be of cardiac origin. He was eventually found to harbor a giant, partially thrombosed, saccular aneurysm arising from the A1/A2 segment of the right anterior cerebral artery with foramen of Monro obstruction and a trapped left-sided ventricular system. An azygous left A2 artery segment supplied both callosomarginal arteries. We performed an in situ side-to-side anastomosis between the distal left azygous anterior cerebral artery and the right pericallosal artery, which was previously supplied by the right A1. The right A1 was clip ligated, and the aneurysm evacuated with an ultrasonic aspirator. Postoperatively, the patient did well with no recurrence of the aneurysm and resolution of his preoperative obstructive hydrocephalus. He continues to be independent >7 yr post surgery. His 6-mo follow up angiogram revealed a patent bypass. PMID- 29762760 TI - Evaluation of different dietary alterations in their ability to mitigate the incidence and severity of woody breast and white striping in commercial male broilers. AB - The following study was conducted to define how multiple nutritional strategies affect broiler performance, meat yield, and the presence and severity of white striping (WS) and woody breast (WB) in high-yielding broilers. Relative to a commercial set of reference broiler diets (Commercial reference diet; Trt 1) that were fed in a 4-phase program, the following nutritional strategies were investigated: increasing the ratio of digestible arginine: digestible lysine (dArg: dLys ranged from 113 to 126; Trt 2), supplementing Trt 1 with 94.4 mg vitamin C/kg feed (Trt 3), doubling the vitamin pack inclusion rate (Trt 4), reducing the digestible amino acid density (dAA) of only the grower phase by 15% and feeding the same Trt 1 starter, finisher, and withdraw diets (Trt 5), and combining the 4 strategies just mentioned (Trt 6). There was no difference in performance at the end of the starter phase (P = 0.066); however, at the end of the grower and finisher phases, feeding lower dAA grower diets suppressed BW (Trts 5 and 6; P < 0.001) and increased FCR. Differences in performance amongst all treatments disappeared at day 49 (P = 0.220). No differences were observed in average breast weight (P = 0.188); however, breast yield (as a % of live weight) was greatest for Trt 1 and least for Trt 6 (P = 0.041). The WB score dropped from 1.83 in Trt 1 to 1.49, 1.27, 1.74, 1.53, and 1.43 in treatments 2 to 6, respectively (P = 0.018). These changes were the result of a shift in WB score, where the WB class that contained scores of 2 and 3 shifted from 61.3% in Trt 1 to 49.3, 35.9, 60.0, 50.8, and 38.7 in treatments 2 to 6, respectively. Given the FCR, breast weight data and the fact that high WB scores result in a devaluation of breast meat, feeding a higher ratio of dArg: dLys, higher vitamin C, or lower dAA in the grower phase results in better breast meat quality and value. PMID- 29762761 TI - Burden of acute kidney injury in HIV patients under deoxycholate amphotericin B therapy for cryptococcal meningitis and cost-minimization analysis of amphotericin B lipid complex. AB - Deoxycholate amphotericin B (d-AMB) has a higher rate of acute kidney injury (AKI) in comparison of lipid formulations. However, lipid amphotericin B has high costs in developing countries. The aim of this study is to assemble a model of cost-minimization of amphotericin B lipid complex (ABLC) in patients with cryptococcal meningitis. This is a retrospective study done in a cohort of patients with cryptococcal meningitis to study the economic impact of its use in developing countries. Cost analysis were based on direct cost of different antifungal therapies, chronic dialysis after discharge, and survival of patients based on a retrospective cohort of 102 patients infected with human immunodeficiency virus with confirmed diagnosis of cryptococcal meningitis. From 102 patients treated with d-AMB, 60.78% developed any grade of AKI and 10.78% developed AKI demanding hemodialysis. The percentage of patients with meningeal cryptococcosis treated with d-AMB that requeired chronic HD was 2.39%. The same model was performed for patient that would be treated with ABLC, which resulted in 0.20% of patients demanding chronic HD due to its lower nephrotoxicity. When the model is applied in 100 patients, the total costs with d-AMB would be US$ 184,543 and with ABLC would be US$ 1,640,109 in 5 years. Treatment with ABLC would be cost saving in comparison to d-AMB treatment, if early switch of treatment occurred in patients presenting AKI. The change should be as soon as possible to avoid further complication, like dialysis, which is associated with a lower life expectancy. PMID- 29762763 TI - Yeasts isolated from cloacal swabs, feces, and eggs of laying hens. AB - Domestic and wild birds may act as carriers of human pathogenic fungi, although the role of laying hens in spreading yeasts has never been investigated. We evaluated the presence of yeasts in the cloaca (Group I, n = 364), feces (Group II, n = 96), and eggs (Group III, n = 270) of laying hens. The occurrence and the population size of yeasts on the eggshell, as well as in the yolks and albumens, were assessed at the oviposition time and during storage of eggs at 22 +/- 1 degrees C and 4 +/- 1 degrees C. A statistically higher prevalence and population size of yeasts were recorded in Group I (49.7% and 1.3 * 104 cfu/ml) and II (63.8% and 2.8 * 105 cfu/ml) than in Group III (20.7% and 19.9 cfu/ml). Candida catenulata and Candida albicans were the most frequent species isolated. Candida famata and Trichosporon asteroides were isolated only from the eggshells, whereas Candida catenulata was also isolated from yolks and albumens. During storage, the yeast population size on the shell decreased (from 37.5 to 8.5 cfu/ml) in eggs at 22 +/- 1 degrees C and increased (from 4.6 to 35.3 cfu/ml) at 4 +/- 1 degrees C. The laying hens harbor potentially pathogenic yeasts in their gastrointestinal tract and are prone to disseminating them in the environment through the feces and eggs. Eggshell contamination might occur during the passage through the cloaca or following deposition whereas yolk and albumen contamination might depend on yeast density on eggshell. PMID- 29762759 TI - Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage-Protocol of a Swiss Nationwide Observational Study (MoCA-DCI Study). AB - BACKGROUND: The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. OBJECTIVE: To evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2). METHODS: Prospective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited. EXPECTED OUTCOMES: Part 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA. DISCUSSION: The institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH. PMID- 29762762 TI - Coulomb and CH-pi interactions in (6-4) photolyase-DNA complex dominate DNA binding and repair abilities. AB - (6-4) Photolyases ((6-4)PLs) are flavoenzymes that repair the carcinogenic UV induced DNA damage, pyrimidine(6-4)pyrimidone photoproducts ((6-4)PPs), in a light-dependent manner. Although the reaction mechanism of DNA photorepair by (6 4)PLs has been intensively investigated, the molecular mechanism of the lesion recognition remains obscure. We show that a well-conserved arginine residue in Xenopus laevis (6-4)PL (Xl64) participates in DNA binding, through Coulomb and CH pi interactions. Fragment molecular orbital calculations estimated attractive interaction energies of -80-100 kcal mol-1 for the Coulomb interaction and -6 kcal mol-1 for the CH-pi interaction, and the loss of either of them significantly reduced the affinity for (6-4)PP-containing oligonucleotides, as well as the quantum yield of DNA photorepair. From experimental and theoretical observations, we formulated a DNA binding model of (6-4)PLs. Based on the binding model, we mutated this Arg in Xl64 to His, which is well conserved among the animal cryptochromes (CRYs), and found that the CRY-type mutant exhibited reduced affinity for the (6-4)PP-containing oligonucleotides, implying the possible molecular origin of the functional diversity of the photolyase/cryptochrome superfamily. PMID- 29762764 TI - Insomnia as a path to alcoholism: tolerance development and dose escalation. AB - Study Objectives: To assess the risks associated with the use of alcohol as a "sleep aid," we evaluated tolerance development to pre-sleep ethanol's sedative hypnotic effects, and subsequent ethanol dose escalation. Methods: Volunteers, 21 55 years old, with insomnia in otherwise good medical and psychiatric health and no history of alcoholism or drug abuse participated. In experiment 1 (n = 24) 0.0, 0.3, or 0.6 g/kg (n = 8 per dose) ethanol was administered before sleep and 8-hour nocturnal polysomnograms (NPSGs) were collected. In experiment 2, after six nights pretreatment with ethanol 0.45 g/kg (n = 6) versus placebo (n = 6), choice of pre-sleep ethanol or placebo was assessed over seven choice nights. Results: The 0.6 g/kg ethanol dose increased total sleep time and stage 3-4 sleep on night 2, but these effects were lost by night 6 (p < .05). Six nights of ethanol pretreatment produced on the choice nights more self-administered ethanol refills than the placebo pretreatment (p < .03). Conclusions: These are the first data to explicitly show the risks associated with the use of alcohol as a "sleep aid" among people with insomnia. Initially, a moderate dose of ethanol improved NPSG sleep, which was lost by night 6. Tolerance was associated with enhanced self-administration of pre-sleep ethanol. PMID- 29762766 TI - Diverse roles of regulatory non-coding RNAs. PMID- 29762765 TI - Global Epidemiology and Burden of Schizophrenia: Findings From the Global Burden of Disease Study 2016. AB - Introduction: The global burden of disease (GBD) studies have derived detailed and comparable epidemiological and burden of disease estimates for schizophrenia. We report GBD 2016 estimates of schizophrenia prevalence and burden of disease with disaggregation by age, sex, year, and for all countries. Method: We conducted a systematic review to identify studies reporting the prevalence, incidence, remission, and/or excess mortality associated with schizophrenia. Reported estimates which met our inclusion criteria were entered into a Bayesian meta-regression tool used in GBD 2016 to derive prevalence for 20 age groups, 7 super-regions, 21 regions, and 195 countries and territories. Burden of disease estimates were derived for acute and residual states of schizophrenia by multiplying the age-, sex-, year-, and location-specific prevalence by 2 disability weights representative of the disability experienced during these states. Findings: The systematic review found a total of 129 individual data sources. The global age-standardized point prevalence of schizophrenia in 2016 was estimated to be 0.28% (95% uncertainty interval [UI]: 0.24-0.31). No sex differences were observed in prevalence. Age-standardized point prevalence rates did not vary widely across countries or regions. Globally, prevalent cases rose from 13.1 (95% UI: 11.6-14.8) million in 1990 to 20.9 (95% UI: 18.5-23.4) million cases in 2016. Schizophrenia contributes 13.4 (95% UI: 9.9-16.7) million years of life lived with disability to burden of disease globally. Conclusion: Although schizophrenia is a low prevalence disorder, the burden of disease is substantial. Our modeling suggests that significant population growth and aging has led to a large and increasing disease burden attributable to schizophrenia, particularly for middle income countries. PMID- 29762767 TI - Concerns and Help-Seeking Among Patients Using Opioids for Management of Chronic Noncancer Pain. AB - Background: The safety and efficacy of long-term opioid treatment for chronic noncancer pain (CNCP) remains controversial. This study examined whether patients who report problematic opioid use sought help and/or perceived barriers to help seeking. Methods: Data were collected from 1,086 people prescribed opioids for CNCP via a large prospective cohort called the Pain and Opioids IN Treatment (POINT) study. Patients' characteristics and help-seeking were examined according to scores on the Prescribed Opioids Difficulties Scale (PODS). Results: Participants scoring "intermediate" (17%) or "high" (30%) on the PODS were younger and reported more complex pain presentations, higher opioid doses, poorer physical health, moderate to severe anxiety and depression, aberrant behavior, past month opioid use disorder and help-seeking (compared with the "low" PODS group, 53%). One-quarter (26%) had sought help, most commonly from a primary care physician, specialist pain clinic, family member/partner, counselor/psychologist, and the Internet. Participants in the "high" PODS group were more likely to have sought help from an alcohol or other drug service, addiction specialist, or drug information helpline. Common barriers to help-seeking were desire for self management and concern that their opioid treatment may be discontinued. Although 35% met criteria for likely opioid use disorder, only 4.8% reported lifetime treatment with methadone or buprenorphine; participants' ratings indicated significant perceived stigma associated with these medications. Conclusions: The PODS is effective in identifying patients who are concerned about their opioid use. Strategies to address stigma related to drug treatment, including better integration of primary health, specialist pain, and addiction services, are important in reducing opioid-related harm. PMID- 29762768 TI - Emergence of mature cortical activity in wakefulness and sleep in healthy preterm and full-term infants. AB - Study Objectives: Cortical activity patterns develop rapidly over the equivalent of the last trimester of gestation, in parallel with the establishment of sleep architecture. However, the emergence of mature cortical activity in wakefulness compared with sleep states in healthy preterm infants is poorly understood. Methods: To investigate whether the cortical activity has a different developmental profile in each sleep-wake state, we recorded 11-channels electroencephalography (EEG), electrooculography (EOG), and respiratory movement for 1 hr from 115 infants 34 to 43 weeks-corrected age, with 0.5-17 days of postnatal age. We characterized the trajectory of delta, theta, and alpha-beta oscillations in wakefulness, rapid eye movement (REM) sleep, and non-REM sleep by calculating the power spectrum of the EEG, averaged across artifact-free epochs. Results: delta-Oscillations in wakefulness and REM sleep decrease with corrected age, particularly in the temporal region, but not in non-REM sleep. theta Oscillations increase with corrected age in sleep, especially non-REM sleep, but not in wakefulness. On the other hand, alpha-beta oscillations decrease predominantly with postnatal age, independently of sleep-wake state, particularly in the occipital region. Conclusions: The developmental trajectory of delta and theta rhythms is state-dependent and results in changed cortical activity patterns between states with corrected age, which suggests that these frequency bands may have particular functional roles in each state. Interestingly, postnatal age is associated with a decrease in alpha-beta oscillations overlying primary visual cortex in every sleep-wake state, suggesting that postnatal experience (including the first visual input through open eyes during periods of wakefulness) is associated with resting-state visual cortical activity changes. PMID- 29762771 TI - Improving Early Neonatal Development in Conflict-affected Countries. PMID- 29762769 TI - Scandinavian Multicenter Acute Subdural Hematoma (SMASH) Study: Study Protocol for a Multinational Population-Based Consecutive Cohort. AB - BACKGROUND: Traumatic acute subdural hematomas (ASDHs) are associated with high rate of morbidity and mortality, especially in elderly individuals. However, recent reports indicate that the morbidity and mortality rates might have improved. OBJECTIVE: To evaluate postoperative (30-d) mortality in younger vs elderly (>=70 yr) patients with ASDH. Comparing younger and elderly patients, the secondary objectives are morbidity patterns of care and 6 mo outcome according to Glasgow outcome scale (GOS). Finally, in patients with traumatic ASDH, we aim to provide prognostic variables. METHODS: This is a large-scale population-based Scandinavian study including all neurosurgical departments in Denmark and Sweden. All adult (>=18 yr) patients surgically treated between 2010 and 2014 for a traumatic ASDH in Denmark and Sweden will be included. Identification at clinicaltrials.gov is NCT03284190. EXPECTED OUTCOMES: We expect to provide data on potential differences between younger vs elderly patients in terms of mortality and morbidity. We hypothesize that elderly patients selected for surgery have a similar pattern of care as compared with younger patients. We will provide functional outcome in terms of GOS at 6 mo in younger vs elderly patients undergoing ASDH evacuation. Finally, clinical useful prognostic factors for favorable (GOS 4-5) vs unfavorable (GOS 1-3) will be identified. DISCUSSION: An improved understanding of the clinical outcome, treatment and resource allocation, clinical course, and the prognostic factors of traumatic ASDH will allow neurosurgeons to make better treatment decisions. PMID- 29762770 TI - Carcass and meat quality characterization of indigenous and improved variety of chicken genotypes. AB - A study was conducted to examine four genotypes of chicken for their carcass and meat quality characteristics. From each genotype, 20 birds were slaughtered at their respective age of maturity. Breast and thigh muscles were evaluated for meat quality characteristics. Transport loss and carcass weight were highest in the white commercial broiler (WBR) and lowest in Aseel (ASL) and Indbro Aseel (ASR). Dressing percentage ranged between 66.41 and 72.56 and was not significantly different among genotypes. The yield of various cut-up parts for different genotypic birds was significantly different (P < 0.05). Highest percent yield for breast (29.15), thigh (15.57), drumstick (13.82) and wings (18.44) were observed in WBR, rainbow rooster (RR), ASR and rainbow rooster Plus (RRP), respectively. Giblet % was highest in RR and meat:bone ratio of thigh portion was highest in WBR. Higher ultimate pH was recorded for RR, RRP, and WBR, and higher water-holding capacity was detected in ASL and ASR. Further, bound water was higher in RR, RRP, and WBR, and free water was maximum in ASL and ASR. A significant (P < 0.05) higher shear force was observed in ASL and higher muscle fiber diameter in WBR. Cooking yield did not differ significantly among genotypes. The breast meat from ASL showed significantly (P < 0.05) higher redness value and WBR showed the lower redness. Further, ASL and ASR meats were darker and red in color than broiler meat. Meat from two indigenous birds (ASL and ASR) had significantly (P < 0.05) lower fat content compared to broilers and other crosses. ASL gave a slightly firmer meat as liked by consumers. The sensory evaluation showed breast meat from RR birds and ASL birds had better flavor scores than other birds. These results indicated that meat of indigenous chickens (ASL and ASR) has some unique features over commercial fast-growing birds that would increase their demand by consumers who prefer chewy, low-fat chicken meat. PMID- 29762772 TI - Executive Orders and the Trump Administration: A Guide for Social Workers. AB - With the election of Donald Trump, policies antithetical to our clients' well being, in areas as diverse as criminal justice, the environment, health care, and immigration, are being proposed at a rapid rate. Many of these policies are being transmitted through executive orders (EOs), a mechanism for exercising executive power less familiar to social workers. This article analyzes EOs issued by the Trump administration during its first five months, describing their purpose, content, and potential for policy change. Strategies for resistance and points of intervention for social workers and other advocates are also identified. PMID- 29762773 TI - Animal- and management-based welfare indicators for a conventional broiler strain in 2 barn types (Louisiana barn and closed barn). AB - The aim of this observational study was to describe health- and management related welfare indicators for a conventional broiler strain housed in 2 barn types (Louisiana barn and closed barn) on the same farm and to assess the impact of age and housing conditions on these indicators. Broilers were examined 4 times in each of 7 fattening periods. Their weight gain, gait score, and further animal based indicators did not differ between the barn types. On average 46% showed no sign, 51% a minor but visible, and 3% a profound lameness at the end of the fattening period (fattening day 39). Soiling of the plumage, skin scratches, foot pad dermatitis, and hock burns worsened with increasing age. Soiling of the plumage was correlated negatively with litter depth (Pearson, r = -0.549, P = 0.042) and positively with litter quality (Pearson, r = 0.641, P = 0.013). Skin scratches occurred in 89% of the broilers (32% deep with penetration of dermis) on fattening day 39 and were correlated positively with cumulative mortality (Pearson, r = 0.615, P = 0.019), indicating a severe animal welfare impact. Foot pad dermatitis did not correlate with health- or management-related indicators, whereas hock burn correlated positively with the broilers' weight (Pearson, r = 0.853, P < 0.001) and with ammonia concentrations (Pearson, r = 0.577, P = 0.031). Management-related indicators (antibiotic treatments, dead on arrival) and cumulative mortality did not differ between the barn types. At the end of the fattening period, the litter quality was worse and concentrations of ammonia and peaks of high carbon dioxide concentrations were higher in the Louisiana than in the closed barn. The light intensity was on average 20 times higher in the Louisiana than in the closed barn without any negative impact. Summarizing, the barn type did not seem to influence the investigated welfare indicators, but Louisiana barns might need a more precise management to maintain the required ranges of noxious gases and litter quality. PMID- 29762774 TI - Occurrence and antimicrobial susceptibility of Campylobacter spp. on fresh and refrigerated chicken meat products in Central Italy. AB - This study investigated the presence and the level of Campylobacter spp. contamination in 41 thigh samples (with skin) and 37 skinless breast samples collected at the end of slaughter (T1) and after 10 day period at refrigeration temperature (4 degrees C) (T2), corresponding to their commercial shelf life. The isolates were phenotypically classified as Campylobacter spp. and successively identified by conventional multiplex PCR. The antimicrobial susceptibility of the isolates from fresh thigh and breast samples was also determined via the microdilution method (MIC) in Eucamp microtitre plates with known scalar concentrations of: gentamicin (GEN), streptomycin (ST), ciprofloxacin (CIP), tetracycline (TET), erythromycin (ERY), and nalidixic acid (NA). A greater percentage of positivity for Campylobacter spp. (P < 0.001) was observed in thighs and C.jejuni appeared to be the most common species identified at this level (P < 0.001) followed from its association with C.coli. There was a global reduction of Campylobacter spp. in both thigh and breast samples at T2 (P < 0.001) showing that the refrigeration was able to reduce Campylobacter count. The prevalence of resistance to CIP, TET, NA, and ERY was evidenced for C.jejuni and C. coli. The co (TET-NA, CIP-NA) and multiple resistant (CIP-TET-NA, CIP-TET- NA ERY) isolates came from the thigh products. It should be highlighted the presence of Campylobacter spp. isolates resistant to ST occurred in breast samples, responsible for the ST-CIP co-resistance and ST-CIP-TE multi-resistance profiles, higher in breast than in thigh products (P > 0.001). The presence of Campylobacter isolates resistant to ST can be further investigated since it is used for therapeutic treatment of several bacterial diseases in humans. PMID- 29762775 TI - Combination Superficial Temporal Artery-Middle Cerebral Artery Bypass and M2-M2 Reanastomosis With Trapping of a Stented Distal Middle Cerebral Artery Aneurysm: 3-Dimensional Operative Video. AB - Distal middle cerebral artery (MCA) aneurysms often have non-saccular morphology and cannot be clipped, requiring revascularization and trapping instead. Combination bypasses are needed when 2 arteries exit the aneurysm, and extracranial-intracranial and intracranial-intracranial bypasses can be used. This video demonstrates a combination bypass used to treat a previously stented distal MCA aneurysm with both a superficial temporal artery (STA)-to-MCA bypass and an M2-to-M2 reanastomosis. This 56-yr-old man presented with distal left sided MCA aneurysm 2 years earlier and attempted stent-assisted coiling was aborted after the aneurysm was perforated with stenting alone. Follow-up angiography demonstrated progressive aneurysm enlargement, and he was referred for surgery. The patient consented for the procedure and a pterional craniotomy extended posteriorly exposed the distal Sylvian fissure and efferent M4-cortical arteries. After splitting the Sylvian fissure, the "flash fluorescence" technique with indocyanine green (ICG) videoangiography identified an M4 recipient artery from the deeper of 2 exiting branches for STA-MCA bypass.1 The aneurysm was then trapped, and inflow and the more superficial outflow arteries were anastomosed end to end (M2-M2 in-situ bypass). A platelet plug that developed at the reanastomosis site was broken apart with mechanical manipulation, and ICG videoangiography demonstrated patency of both bypasses. The patient recovered without any neurological deficits, and postoperative computed tomography angiography confirmed bypass patency. Combination bypasses are needed when unclippable bifurcation aneurysms require revascularization. Careful intraoperative evaluation of patency of the bypass is imperative and helps identifying and addressing any potential early bypass occlusion. PMID- 29762776 TI - Commentary: Neurological Surgery at Vanderbilt University: 1873 to Present. PMID- 29762777 TI - The Intracerebral Hemorrhage Score: A Self-Fulfilling Prophecy? AB - BACKGROUND: The ICH Score has become the standard for risk-stratification of 30-d mortality in patients with intracerebral hemorrhage (ICH), but treatment has evolved over the last 17 yr since its inception. We sought to determine if the ICH Score remains an accurate predictor of 30-d mortality in these high acuity patients. OBJECTIVE: To determine the role the ICH Score has on mortality in current treatment of patients. METHODS: A retrospective review of 554 patients treated for acute, spontaneous ICH at 2 large academic institutions between 2010 and 2014 was carried out. Surgical intervention in the form of external ventricular drain or craniotomy was performed when indicated. All patients were managed medically until discharge or death. RESULTS: Over half (53.6%) of the patients presented with ICH of the basal ganglia/thalamus and the majority (71%) presented with ICH Scores of 0 to 2. Overall mortality was 25.1%. Observed mortality in moderate grade ICH Score patients (3 and 4) was lower than expected (49% vs 72%, P < .001) and (71% vs 97%, P < .001) when compared to the original ICH Score results. Despite differences in ICH and intraventricular hemorrhage volume, and Glasgow Coma Scale there was no difference in surgical intervention (12.2% vs 11.8%, P = .94) between the two groups. Withdrawal of care was instituted in 56.6% of all patients who died and increased with ICH Score. CONCLUSION: In our cohort, the original ICH score did not accurately predict the mortality rate. Patient survival exceeded ICH Score-predicted mortality regardless of surgical intervention. Reevaluation of predictive scores could be useful to aid in more accurate prognoses. PMID- 29762778 TI - The effect of beta-mannanase on nutrient utilization and blood parameters in chicks fed diets containing soybean meal and guar gum. AB - The present study was conducted to determine whether the addition of beta mannanase in broiler feed changes hormonal profiles in the blood and broiler performance and nutrient availability. Five hundred and four Cobb male chickens were studied during d 7 to 21. Three corn-soybean meal (SBM) based diets 1) Low SBM (18% SBM); 2) High SBM (31% SBM); and 3) High SBM+GG (31% SBM + Guar Gum (GG) 0.5%) with 3 levels of beta-mannanase (0, 200, and 400 ppm) were mixed to produce 9 diets. A factorial design 3 * 3 was performed with JMP pro 13 (SAS, 2017). Analysis of variance and contrast analysis were used to test significance level at P < 0.05. Glucose (190 and 188 mg/dL) was increased with 200 and 400 ppm of beta-mannanase, respectively, compared to control (182 mg/dL) in the fasted state (P < 0.037). Glucose was higher in chicks fed with the High SBM and High SBM + GG diets but lower in the fasted re-fed state (P < 0.01). Insulin was higher with 200 and 400 ppm added beta-mannanase in the fed state (P < 0.021). Insulin-like growth factor-1 was higher with 400 ppm added to High SBM+GG. beta-mannanase improved feed conversion ratio (FCR) 9 points with 400 ppm in High SBM diet (P < 0.01) and 16 and 18 points with 200 and 400 ppm, respectively, added to the High SBM+GG diet (P < 0.01). Viscosity decreased from 19.2 to 7 cps with both enzyme doses in the High SBM + GG diet (P < 0.01). Digestible energy was +152 kcal/kg with 400 ppm beta-mannanase in the High SBM diet and +200 kcal/kg with both levels of enzyme in High SBM+GG diet. Digestibility of amino acids was improved from 0.8 to 3.6% with beta-mannanase in High SBM+GG diet (P < 0.05). In conclusion, chicks fed with High SBM and High SBM+GG diets with added beta mannanase significantly improved blood glucose and anabolic hormone homeostasis, FCR, digestible energy, and digestible amino acids compared to chicks fed with same diets without beta-mannanase. PMID- 29762781 TI - The TubR-centromere complex adopts a double-ring segrosome structure in Type III partition systems. AB - In prokaryotes, the centromere is a specialized segment of DNA that promotes the assembly of the segrosome upon binding of the Centromere Binding Protein (CBP). The segrosome structure exposes a specific surface for the interaction of the CBP with the motor protein that mediates DNA movement during cell division. Additionally, the CBP usually controls the transcriptional regulation of the segregation system as a cell cycle checkpoint. Correct segrosome functioning is therefore indispensable for accurate DNA segregation. Here, we combine biochemical reconstruction and structural and biophysical analysis to bring light to the architecture of the segrosome complex in Type III partition systems. We present the particular features of the centromere site, tubC, of the model system encoded in Clostridium botulinum prophage c-st. We find that the split centromere site contains two different iterons involved in the binding and spreading of the CBP, TubR. The resulting nucleoprotein complex consists of a novel double-ring structure that covers part of the predicted promoter. Single molecule data provides a mechanism for the formation of the segrosome structure based on DNA bending and unwinding upon TubR binding. PMID- 29762780 TI - An intersection network based on combining SNP coassociation and RNA coexpression networks for feed utilization traits in Japanese Black cattle. AB - Genome-wide association studies (GWAS) of quantitative traits have detected numerous genetic associations, but they encounter difficulties in pinpointing prominent candidate genes and inferring gene networks. The present study used a systems genetics approach integrating GWAS results with external RNA-expression data to detect candidate gene networks in feed utilization and growth traits of Japanese Black cattle, which are matters of concern. A SNP coassociation network was derived from significant correlations between SNPs with effects estimated by GWAS across 7 phenotypic traits. The resulting network genes contained significant numbers of annotations related to the traits. Using bovine transcriptome data from a public database, an RNA coexpression network was inferred based on the similarity of expression patterns across different tissues. An intersection network was then generated by superimposing the SNP and RNA networks and extracting shared interactions. This intersection network contained 4 tissue-specific modules: nervous system, reproductive system, muscular system, and glands. To characterize the structure (topographical properties) of the 3 networks, their scale-free properties were evaluated, which revealed that the intersection network was the most scale-free. In the subnetwork containing the most connected transcription factors (URI1, ROCK2, and ETV6), most genes were widely expressed across tissues, and genes previously shown to be involved in the traits were found. Results indicated that the current approach might be used to construct a gene network that better reflects biological information, providing encouragement for the genetic dissection of economically important quantitative traits. PMID- 29762783 TI - Repurposing the anthelminthic salicylanilide oxyclozanide against susceptible and clinical resistant Candida albicans strains. AB - Current antifungal drugs suffer from limitations including toxicity, adverse interactions with other commonly prescribed drugs, and the emergence of resistant strains. Here, we repurposed the anthelmintic oxyclozanide as a potent antifungal agent against both sensitive and resistant clinical isolates of Candida albicans, as well as other human opportunistic fungi. Antifungal activity of oxyclozanide was enhanced when C. albicans grew in nonfermentable carbon sources. Our data support a mechanism of action where oxyclozanide uncoupled the mitochondrial electron transport from oxidative phosphorylation and perturbed the mitochondrial membrane potential. PMID- 29762784 TI - Identification and characterization of probiotic yeast isolated from digestive tract of ducks. AB - The objective of this study was to isolate and identify yeast strains from the digestive tract of ducks, and evaluate in vitro their potential as probiotics in poultry. The yeast strains were isolated using malt extract agar medium, and identified through morphological, physiological, and biochemical tests as well as sequence homology analyses of 26S rDNA D1/D2 region. A total of 35 yeast strains were isolated from the guts of Cherry Valley meat ducks, including seven strains of Saccharomyces cerevisiae (S. cerevisiae). These seven strains of S. cerevisiae were further screened for their use as alternative yeast probiotics strains for poultry feed. The yeast strains were characterized for their cell surface hydrophobicity, autoaggregation ability, and resistance to high temperature (30 degrees C, 37 degrees C, and 42 degrees C), low pH (2.0, 3.0, and 4.0), bile salts (0.3% and 0.6%), and nutrition starvation (2, 4, 6, 8, 10, and 12 days). The isolates of WHY-2 and WHY-7 had a higher survival percentage at 37 degrees C, pH 2.0, 0.60% poultry bile salts, and 10 days of nutrition starvation, with higher cell surface hydrophobicity and autoaggregation, when compared with the other isolates, suggesting that the isolates WHY-2 and WHY-7, could be used as probiotic candidates. The data obtained in this study could help in selecting probiotic yeast candidates for use in poultry industry. PMID- 29762782 TI - MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. AB - We present a new update to MetaboAnalyst (version 4.0) for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since the last major update in 2015, MetaboAnalyst has continued to evolve based on user feedback and technological advancements in the field. For this year's update, four new key features have been added to MetaboAnalyst 4.0, including: (1) real-time R command tracking and display coupled with the release of a companion MetaboAnalystR package; (2) a MS Peaks to Pathways module for prediction of pathway activity from untargeted mass spectral data using the mummichog algorithm; (3) a Biomarker Meta-analysis module for robust biomarker identification through the combination of multiple metabolomic datasets and (4) a Network Explorer module for integrative analysis of metabolomics, metagenomics, and/or transcriptomics data. The user interface of MetaboAnalyst 4.0 has been reengineered to provide a more modern look and feel, as well as to give more space and flexibility to introduce new functions. The underlying knowledgebases (compound libraries, metabolite sets, and metabolic pathways) have also been updated based on the latest data from the Human Metabolome Database (HMDB). A Docker image of MetaboAnalyst is also available to facilitate download and local installation of MetaboAnalyst. MetaboAnalyst 4.0 is freely available at http://metaboanalyst.ca. PMID- 29762785 TI - Descriptive sensory analysis of marinated and non-marinated wooden breast fillet portions. AB - The wooden breast (WB) myopathy influences muscle composition and texture characteristics in broiler breast meat. It is unknown if marination reduces the negative influence of WB on meat sensory quality or if WB effects are uniform throughout the Pectoralis major. The objective of this study was to determine the effects of marination on the sensory attributes and instrumental shear force measurements of the ventral (skin-side) and dorsal (bone-side) portions of normal and severe WB meat. Sixty butterfly fillets (30 normal and 30 severe WB) were selected from the deboning line of a commercial processing plant. Individual fillets were portioned into ventral and dorsal halves. Portions from one side of each butterfly were used as non-marinated controls, and portions from the other side were vacuum-tumble marinated (16 rpm, -0.6 atm, 4 degrees C, 20 min) with 20% (wt/wt) marinade to meat ratio. Marinade was formulated to target a concentration of 0.75% (w/v) salt and 0.45% (w/v) sodium tripolyphosphate in the final product. Descriptive sensory analysis (9 trained panelists) was conducted to evaluate visual, texture, and flavor attributes (0-15 point scale) of breast portions along with Warner-Bratzler shear force. Significant interaction effects between WB and marination were not observed for the sensory attributes. Greater springiness, cohesiveness, hardness, fibrousness, and chewiness scores were observed in WB samples (P < 0.001). Marination decreased cohesiveness, hardness, and chewiness (P < 0.05) and increased juiciness (P = 0.002). The effects of WB on sensory texture attributes were more apparent in the ventral portions of the breast fillets. Flavor attributes (salty and brothy) increased (P < 0.001) with marination. In non-marinated samples, shear force was similar between normal and WB samples. In marinated samples, however, shear force was greater (P < 0.001) in WB samples. Data suggest that the WB effect on meat sensory quality is not uniform throughout the Pectoralis major and that WB-related differences in cooked meat sensory texture attributes are lessened but not eliminated by vacuum tumbling marination. PMID- 29762786 TI - Effect of standardized ileal digestible lysine and added copper on growth performance, carcass characteristics, and fat quality of finishing pigs. AB - Two, 120-d, experiments were conducted to determine the effects of standardized ileal digestible (SID) lysine (Lys), added Cu (tribasic copper chloride, Intellibond C; Micronutrients, Inc., Indianapolis, IN), and duration of Cu supplementation on growth performance, carcass characteristics, and fat quality in finishing pigs. In Exp. 1, 1,248 pigs (PIC 337 * 1050; initially 29.0 kg) were allotted to one of six dietary treatments, balanced on average pen weight in a randomized complete-block design with 26 pigs per pen and eight replications per treatment. Treatments were arranged in a 3 * 2 factorial with main effects of SID Lys (85, 92.5, and 100% of the estimated requirement) and added Cu (0 or 150 mg/kg). There were no Cu * SID Lys interactions observed for growth performance or liver Cu concentrations. Increasing SID Lys increased (linear, P < 0.05) ADG, feed efficiency (G:F), final weight, and HCW. Pigs fed 150 mg/kg added Cu had marginally increased (P < 0.10) ADG, G:F, and final weight. Liver Cu concentrations were greater (P = 0.001) in pigs fed added Cu. A marginal Cu * Lys interaction (P = 0.052) was observed for jowl fat iodine value (IV) as increasing SID Lys in pigs fed added Cu increased IV, but decreased IV in pigs not fed added Cu. For Exp. 2, 1,267 pigs (PIC 337 * 1,050; initially 26.4 kg) were allotted to one of eight dietary treatments arranged in a split-plot design. Whole-plot treatments included SID Lys (92.5 or 100% of the estimated requirement) and within each Lys level, there was a 2 * 2 factorial arrangement of treatments with either 0 or 150 mg/kg added Cu and two feeding durations (60 or 120 d). Added Cu did not affect growth performance. Pigs fed 100% of the SID Lys requirement had increased (P < 0.05) ADG, G:F, and final weight compared with those fed 92.5%. A Cu * SID Lys interaction (P < 0.05) was observed for carcass yield and backfat depth. Pigs fed 92.5% SID Lys had increased carcass yield and decreased backfat depth with added Cu; however, pigs fed 100% SID Lys had decreased carcass yield and increased backfat depth with added Cu. Hot carcass weight was increased (P < 0.05) by feeding 100% SID Lys and was marginally (P < 0.10) increased by adding Cu to the diets. In summary, the growth response to added Cu was inconsistent between experiments; however, increasing SID Lys improved growth performance and carcass characteristics. PMID- 29762787 TI - LitVar: a semantic search engine for linking genomic variant data in PubMed and PMC. AB - The identification and interpretation of genomic variants play a key role in the diagnosis of genetic diseases and related research. These tasks increasingly rely on accessing relevant manually curated information from domain databases (e.g. SwissProt or ClinVar). However, due to the sheer volume of medical literature and high cost of expert curation, curated variant information in existing databases are often incomplete and out-of-date. In addition, the same genetic variant can be mentioned in publications with various names (e.g. 'A146T' versus 'c.436G>A' versus 'rs121913527'). A search in PubMed using only one name usually cannot retrieve all relevant articles for the variant of interest. Hence, to help scientists, healthcare professionals, and database curators find the most up-to date published variant research, we have developed LitVar for the search and retrieval of standardized variant information. In addition, LitVar uses advanced text mining techniques to compute and extract relationships between variants and other associated entities such as diseases and chemicals/drugs. LitVar is publicly available at https://www.ncbi.nlm.nih.gov/CBBresearch/Lu/Demo/LitVar. PMID- 29762788 TI - Antilisterial effects of hop alpha and beta acids in turkey slurry at 7 and 37 degrees C. AB - Chemical components of hop resins effectively inhibit the growth of L. monocytogenes in microbiological culture media. This study was conducted to investigate antilisterial activities of hop alpha- and beta-acid in turkey slurry. Turkey slurries were inoculated with L. monocytogenes, formulated with hop alpha- or beta-acid from 0 to 1,000 ppm, and incubated at 37 degrees C for 24 h or at 7 degrees C for 12 days. During storage at 37 degrees C for 24 h, L. monocytogenes populations were reduced from 2.40 log CFU/g to non-detectable (<1 log CFU/g) in alpha-acid at >=750 ppm and beta-acid at 1,000 ppm, whereas the control (0 ppm) allowed the pathogen to grow to 8.0 log CFU/g. During storage at 7 degrees C for 12 d, the slurry treated with alpha-acid at >=100 ppm and beta acid at >=500 ppm showed listeristatic effects, while listericidal effects were observed in the slurries at 1,000 ppm, regardless of hop acid type. Hop alpha acid <= 50 ppm and beta-acid <= 100 ppm failed to inhibit L. monocytogenes, and the pattern of bacterial growth was similar to that of control with no significant difference (P > 0.05). Based on these results, the concentration of alpha-acid > 100 ppm or beta-acid > 500 ppm is minimally required to inhibit L. monocytogenes when turkey batters are formulated with hop acids as a single antilisterial agent prior to cooking and storage at 7 degrees C. PMID- 29762789 TI - An optimist's view on limiting necrotic enteritis and maintaining broiler gut health and performance in today's marketing, food safety, and regulatory climate. AB - The future poultry nutritionist, veterinarian, and husbandryman will have many new regulatory requirements and consumer preferences to navigate in addition to their normal responsibility of raising birds in a cost-efficient and wholesome manner. New challenges include changes to antibiotic use, increased food safety regulations, and more concern over how birds are raised and how to dispose of poultry house waste. All of these new programs and new regulations will alter how we have been raising birds for the last 60 years since the inception of the integrated poultry industry. The most significant change may be the voluntary or regulatory withdrawal of the use of antibiotics in poultry production. In North America, this withdrawal of antibiotic use includes removal of in-ovo antibiotics, performance-improving antibiotics or antibiotic growth promotors (AGP), and the polyether ionophore antibiotics (ionophore anticoccidials).The removal of antibiotics in poultry production may result in welfare concerns due to elevated mortality and less efficient feed conversion, resulting in greater environmental impacts from increased manure production and more use of grain per unit of meat produced. There also may be concerns with greater intestinal disease in the birds resulting in increased numbers of foodborne illness-causing bacteria such as Salmonella sp. or Campylobacter sp. on the carcass. A major impact will be the disease necrotic enteritis (NE). This review will focus on the pathophysiology of NE, the management of the disease, and the additional effects on growth rate, feed efficiency, and body weight that may be associated with NE. PMID- 29762791 TI - Confronting Assumptions. PMID- 29762790 TI - Dietary supplementation with Clostridium butyricum modulates serum lipid metabolism, meat quality, and the amino acid and fatty acid composition of Peking ducks. AB - The aim of this study was to investigate the effects of Clostridium butyricum (C. butyricum) on the performance, serum lipid metabolism, muscle morphology, meat quality, and fatty acid profiles of Peking ducks. A total of 1,500 Peking ducks were randomly divided into five groups with five replicates and were fed a non antibiotic basal diet (Control) or a basal diet supplemented with either 200, 400, or 600 mg/kg of C. butyricum (2.0 * 109 CFU/g) or 150 mg of aureomycin/kg for 42 d. Compared with the control group, supplementation with C. butyricum increased the average daily weight gain but reduced the feed/gain ratio from 1 to 42 d of age. Similarly, dietary C. butyricum increased the activities of antioxidant enzymes but decreased the malondialdehyde (MDA) and lipid metabolites concentration. C. butyricum supplementation increased the muscle pH value at 45 min postmortem, the redness of the meat, and the contents of inosine acid (IMP) and intramuscular fat (IMF) in Peking ducks. By contrast, C. butyricum supplementation lowered the lightness, drip loss, and the shear force of breast meat. Supplementation with C. butyricum increased the concentrations of essential amino acids and flavor amino acids, as well as arachidonic acid (AA), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and total polyunsaturated fatty acids (PUFA) in breast muscle. Dietary C. butyricum could positively improve performance, lipid metabolism, meat quality, and the amino acid and fatty acid composition in a dose-dependent manner. Therefore, C. butyricum is proposed as a feasible alternative feed additive for the production of healthier Peking duck meat with favorable properties. PMID- 29762792 TI - Medical Student Interest in Flexible Residency Training Options. AB - BACKGROUND AND OBJECTIVES: Medical residents continue to experience high rates of burnout during residency training even after implementation of the 2003 Accreditation Council for Graduate Medical Education duty-hour restrictions. The purpose of this study is to determine medical student interest in flexible residency training options. METHODS: Researchers developed an 11-question survey for second through fourth-year medical students. The populations surveyed included medical students who were: (1) attending the 2015 American Academy of Family Physicians National Conference, the 2015 Family Medicine Midwest Conference, and (2) enrolled at University of Chicago Pritzker School of Medicine, University of Illinois College of Medicine at Chicago, Drexel University College of Medicine, and Case Western Reserve University School of Medicine. RESULTS: The survey was completed by 789 medical students. Over half of medical students surveyed indicated that they would be interested in working part time during some portion of their residency training (51%), and that access to part-time training options would increase their likelihood of applying to a particular residency program (52%). When given the option of three residency training schedules of varying lengths, 41% of male students and 60% of female students chose a 60-hour workweek, even when that meant extending the residency length by 33% and reducing their yearly salary to $39,000. CONCLUSIONS: There is considerable interest among medical students in access to part-time residency training options and reduced-hour residency programs. This level of interest indicates that offering flexible training options could be an effective recruitment tool for residency programs and could improve students' perception of their work-life balance during residency. PMID- 29762793 TI - A Qualitative Study of the Communication Process for Medical Acupuncture in Family Medicine. AB - BACKGROUND AND OBJECTIVES: As evidence establishes the efficacy of medical acupuncture, more family physicians and family medicine residents may receive medical acupuncture training and need to know how to effectively communicate about the treatment option with patients. By identifying how physicians talk about acupuncture treatment with their patients, we aimed to develop a model for physician training that could enhance their ability to integrate and practice medical acupuncture in conventional clinical settings. METHODS: To capture the communication process that family physicians engage in when integrating acupuncture treatment into a clinical environment, we sought both physicians' and patients' perspectives. We conducted interviews with 17 family physicians and 15 patients in a US family medicine clinic that has integrated medical acupuncture into its practice. Audio recordings were transcribed and analyzed by two members of the study team in ATLAS.ti, using the constant comparative method. RESULTS: Integrating acupuncture into family medicine entailed a three-phase communication process: (1) introduce acupuncture, (2) explain the medical process, and (3) evaluate treatment outcomes. CONCLUSIONS: The emerging three-phase process of communicating acupuncture described here provides an initial model for teaching communication in the context of medical acupuncture. Given the exploratory nature of this initial study and the rarity of acupuncture treatment integrated into family medical settings, this is a first step in building knowledge in this realm of practice. Future research is needed to better understand the experience of patients who do not report notable results of acupuncture and to extend this study into other family medicine settings. PMID- 29762794 TI - Teaching Competencies for Community Preceptors. AB - BACKGROUND AND OBJECTIVES: Although community physicians provide one-fourth of the outpatient training received in medical school, usually there is no formal training of the preceptor. Currently there is no agreed-upon list of teaching competencies for community physician-preceptors. Using a modified Delphi process, the authors aimed to identify core teaching competencies for community preceptors for use in training and evaluation. METHODS: A medical educator and three faculty members with expertise in faculty development created a list of teaching competencies organized in five domains. These competencies were finalized through a multiround modified Delphi technique with key stakeholder groups including (1) nonphysician medical educators, (2) academic physicians involved in faculty development, (3) community physicians who regularly precept medical students, (4) family medicine residents, (5) third-year medical students in a 9-month-long longitudinal clerkship. Proposed competencies were retained if 70% of the participants ranked it as "very or extremely important." RESULTS: In the first round, 24 competencies were evaluated by 40 physician preceptors participating in a rural faculty development conference. These were refined, and four additional competencies were added by the cohort. Subsequent rounds utilized a survey approach with broader audiences resulting in a final list of 21 competencies in five domains. CONCLUSIONS: Five competency domains with 21 teaching competencies can now be used to guide community preceptors' training and evaluation. PMID- 29762795 TI - Addressing Racism in Medical Education An Interactive Training Module. AB - BACKGROUND AND OBJECTIVES: Education of health care clinicians on racial and ethnic disparities has primarily focused on emphasizing statistics and cultural competency, with minimal attention to racism. Learning about racism and unconscious processes provides skills that reduce bias when interacting with minority patients. This paper describes the responses to a relationship-based workshop and toolkit highlighting issues that medical educators should address when teaching about racism in the context of pernicious health disparities. METHODS: A multiracial, interdisciplinary team identified essential elements of teaching about racism. A 1.5-hour faculty development workshop consisted of a didactic presentation, a 3-minute video vignette depicting racial and gender microaggression within a hospital setting, small group discussion, large group debrief, and presentation of a toolkit. RESULTS: One hundred twenty diverse participants attended the workshop at the 2016 Society of Teachers of Family Medicine Annual Spring Conference. Qualitative information from small group facilitators and large group discussions identified some participants' emotional reactions to the video including dismay, anger, fear, and shame. A pre/postsurvey (N=72) revealed significant changes in attitude and knowledge regarding issues of racism and in participants' personal commitment to address them. DISCUSSION: Results suggest that this workshop changed knowledge and attitudes about racism and health inequities. Findings also suggest this workshop improved confidence in teaching learners to reduce racism in patient care. The authors recommend that curricula continue to be developed and disseminated nationally to equip faculty with the skills and teaching resources to effectively incorporate the discussion of racism into the education of health professionals. PMID- 29762796 TI - Institutional NIH Research Funding and a Culture of Support for Family Medicine Their Relationship to Family Medicine Specialty Choice. AB - BACKGROUND AND OBJECTIVES: The United States suffers from a low proportion of medical students pursuing family medicine (FM). Our objective was to examine institutional characteristics consistent with a focus on National Institutes of Health (NIH) research, institutional support for FM education, and the proportion of medical students choosing FM. METHODS: The 2015 CERA Survey of Family Medicine Clerkship Directors was merged with institutional NIH funding data from 2014 and medical student specialty choice in 2015. Institutional educational support was operationalized as (1) clerkship director's perception of medical school environment toward FM, and (2) amount of negative comments about FM made by faculty in other departments. The outcome was the percentage of students selecting FM. Bivariate statistics were computed. RESULTS: As NIH funding increases, the proportion of students entering FM decreases (r=-.22). Institutions with higher NIH funding had lower clerkship director perceptions of medical school support toward FM (r=-.38). Among private institutions, the negative correlation between NIH funding and the proportion of students entering FM strengthens to r=-.48, P=.001. As perceptions of support for FM increase, the proportion of students entering FM increase (r=.47). Among private schools, perceptions of support toward family medicine was strongly positively correlated with the proportion of students entering FM (r=.72, P=.001). CONCLUSIONS: Higher institutional NIH funding is associated with less support for FM and lower proportions of students choosing FM. These issues appear to be even more influential in private medical schools. Understanding how to integrate the goals of NIH-level research and increasing primary care workforce so that both can be achieved is the next challenge. PMID- 29762797 TI - Contrasting Incoming Medical Students' Attitudes Dual Degree vs Traditional Tracks. AB - BACKGROUND AND OBJECTIVES: The Warren Alpert Medical School of Brown University (AMS) recently implemented a novel dual degree MD-ScM program in primary care and population medicine (PC-PM) that enrolls up to 24 of its nearly 144 yearly matriculants. The overarching goal of this track is to train medical students to become physician leaders who focus on issues in population medicine within primary care. METHODS: We conducted a baseline assessment of the students enrolled in this parallel track in comparison to our traditional students to identify characteristics of and group differences between students in the PC-PM program and traditional students. Data was collected from first-year students matriculating in the 2015 and 2016 academic years (N=277) using portions of nine validated surveys with an emphasis on caring for the underserved and cultural competence, professionalism, working in interprofessional teams, tolerance of ambiguity, empathy, patient-provider interactions, and patient safety/quality improvement. RESULTS: We identified slightly higher significant baseline differences on three scales in which the PC-PM students (n=38) were higher than those in the traditional track students (n=239). These measured cultural competency (t[275]=-3.05, P=.003), professionalism (t[273]=-3.10, P=.002), and attitudes toward working with underserved populations (t[267]=2.31, P=.02). CONCLUSIONS: The higher differences for these three elements may be important to the success of the PC-PM program. We plan to track the growth of the PC-PM students as well as our traditional students through their 4 years of medical school to investigate growth and development throughout the academic career. PMID- 29762798 TI - A Prenatal Standardized Patient Experience for Medical Students on Their Family Medicine Clerkship. AB - BACKGROUND AND OBJECTIVES: Students on their family medicine clerkship at Herbert Wertheim College of Medicine get little clinical exposure to obstetric care, which is not commonly provided by family physicians in urban settings. To address this, we added to our clerkship didactic curriculum a 2-hour session involving a standardized patient (SP). The SP is collectively interviewed by the student group during four simulated prenatal visits, each of which present a different complication of pregnancy. The goal of this study was to evaluate the students' perception of this session's utility, the session's ability to increase student self-confidence regarding obstetric issues, and perceived relevance of obstetrics to family medicine. METHODS: During the 2016-2017 academic year, we evaluated this educational intervention using anonymous, immediate postsession surveys containing both Likert scale and open-ended questions. Qualitative answers were analyzed using a thematic analysis approach, with development of a codebook by consensus. RESULTS: Students overwhelmingly found this session to be pertinent to their learning needs and reported an increase in their self-confidence level regarding obstetrical care. Continuity of care, comprehensive care, and an emphasis on health prevention were identified themes relating how obstetrics embodies the principles of family medicine. CONCLUSIONS: We developed this prenatal standardized patient experience to expose our clerkship students to full spectrum family medicine, including primary care obstetrics. Our data suggests that this session increased students' self-confidence with obstetrics management, filled in gaps in their clinical exposure to full-spectrum family medicine, and addressed a perceived learning need. PMID- 29762799 TI - Integrated Behavioral Health Care in Family Medicine Residencies A CERA Survey. AB - BACKGROUND AND OBJECTIVES: Behavioral health integration (BHI) in primary care settings is critical to mental health care in the United States. Family medicine resident experience in BHI in family medicine residency (FMR) continuity clinics is essential preparation for practice. We surveyed FMR program directors to characterize the status of BHI in FMR training. METHODS: Using the Council of Academic Family Medicine Educational Research Alliance (CERA) 2017 survey, FMR program directors (n=478, 261 respondents, 54.6% response rate) were queried regarding the stage of BHI within the residency family medicine center (FMC), integration activities at the FMC, and the professions of the BH faculty. BHI was characterized by Substance Abuse and Mental Health Services Agency (SAMHSA) designations within FMRs, and chi-square or ANOVA with Tukey honest significant difference (HSD) post hoc testing was used to assess differences in reported BHI attributes. RESULTS: Program directors reported a high level of BHI in their FMCs (44.1% full integration, 33.7% colocated). Higher levels of BHI were associated with increased use of warm handoffs, same day consultation, shared health records, and the use of behavioral health (BH) professionals for both mental health and medical issues. Family physicians, psychiatrists, and psychologists were most likely to be training residents in BHI. CONCLUSIONS: Almost half of FMR programs have colocated BH care or fully integrated BH as defined by SAMHSA. Highly integrated FMRs use a diversity of behavioral professionals and activities. Residencies currently at the collaboration stage could increase BH provider types and BHI practices to better prepare residents for practice. Residencies with full BHI may consider focusing on supporting BHI-trained residents transitioning into practice, or disseminating the model in the general primary care community. PMID- 29762800 TI - Distance. PMID- 29762802 TI - Week One, Revisited. PMID- 29762803 TI - Body Shop. PMID- 29762804 TI - Red Velvet. PMID- 29762809 TI - Family Medicine for America's Health-4 Years Later, Heading Into the Future. PMID- 29762810 TI - ? PMID- 29762812 TI - ? PMID- 29762811 TI - ? PMID- 29762813 TI - ? PMID- 29762814 TI - ? PMID- 29762815 TI - ? PMID- 29762816 TI - Analysis of the correlation between non-alcoholic fatty liver disease and bone metabolism indicators in healthy middle-aged men. PMID- 29762817 TI - Cardiac magnetic resonance in systemic sclerosis patients with cardiac symptoms: do we really need it? PMID- 29762818 TI - Titanium alloy vs. stainless steel miniscrews: an in vivo split-mouth study. AB - OBJECTIVE: To compare in vivo Titanium Alloy (TiA) with Stainless Steel (SS) miniscrews Temporary Anchorage Devices (TADs) using removal torque and Scanning Electron Microscopic (SEM) analysis. PATIENTS AND METHODS: 15 subjects (6 males and 9 females) who required maximum anchorage were recruited. For each patient, a TiA TAD and a SS TAD with same length and width were implanted following a randomized split-mouth study design. Retraction was carried out with nickel titanium spring ligated directly from the anterior hooks of the archwire to the TADs to produce 90 to 100 g of force. When no further anchorage supplementation was needed, the TADs were removed. The removal torque values were registered with a digital screwdriver. After removal, the TADs were collected in a fixed solution and examined using SEM and X-ray microanalysis. RESULTS: All TADs remained intact, with a 100% success rate. There was no difference in removal torque between TiA and SS miniscrews (4.4 +/- 1.3 N-cm and 5.1 +/- 0.7 N-cm, respectively). All specimens' loss of gloss with signs of biological contaminations resulted in a dull implant surface. SEM photomicrographs of TiA miniscrews showed predominantly blood cells while SS miniscrews showed the precipitation of an amorphous layer with low cellular component. There was no difference in spectroscopic analysis between TiA and SS miniscrews. CONCLUSIONS: TiA and SS miniscrews had comparable removal torque values. SEM photomicrographs showed no evidence of osseointegration with both TADs having similar biological responses. PMID- 29762819 TI - MiR-134 inhibits infiltration of trophoblast cells in placenta of patients with preeclampsia by decreasing ITGB1 expression. AB - OBJECTIVE: Preeclampsia (PE) is an idiopathic disorder of pregnancy. The specific regulatory mechanisms of microRNAs (miRs) in the placenta of PE patients have not yet been completely revealed. This study mainly explored the mechanism of miR-134 in preeclampsia. PATIENTS AND METHODS: Real-time PCR and Western blot were used to detect the expression of miR-134 and ITGB1 in the placenta of patients with preeclampsia and normal pregnant women. Dual luciferase reporter assay was performed to detect luciferase activity in miR-134 and NC groups, respectively. Cell proliferation ability after transfection was evaluated by MTS colorimetric assay, and the effect of miR-134 on the infiltration of trophoblast cells was explored by cell invasion experiment. In addition, co-transfection of miR-134 and ITGB1 expression plasmids was carried out, and then changes in the cell invasiveness were also detected by cell invasion experiment. RESULTS: Compared with placenta of normal pregnant women, miR-134 was significantly up-regulated in the placenta of patients with preeclampsia and negatively correlated with the expression of ITGB1. MiR-134 suppressed the infiltration of trophoblast cells by targeting ITGB1. When ITGB1 was overexpressed, the suppression of invasiveness of trophoblast cells by miR-134 was almost abolished. Meanwhile, we found that miR 134 inhibitor could promote the invasiveness of trophoblast cells. In addition, tumor necrosis factor-alpha (TNF-alpha) was found to enhance miR-134 expression as well as inhibit ITGB1 expression. CONCLUSIONS: MiR-134 inhibited the infiltration of trophoblast cells in preeclampsia by down-regulating ITGB1 expression. PMID- 29762820 TI - Relation between mycoplasma infection and recurrent spontaneous abortion. AB - OBJECTIVE: This study explores the possible relation between cervical infections with Ureaplasma urealyticum (UU) and Mycoplasma hominis (MH) and the occurrence of recurrent spontaneous abortion (RSA). PATIENTS AND METHODS: 132 patients with RSA (observation group) and 96 normal pregnancy volunteers undergoing planned abortions (control group) were selected successively and enrolled in the investigation. Cervical secretion samples were obtained for each subject. Bacterial cultures were started to detect UU, MH and other bacterial infections, and fluorescence quantitative PCR was used to detect gene copy number in chorion and decidual tissues. Additionally, ELISA (enzyme-linked immunosorbent assay) was used to detect anticardiolipin antibody (ACA) to rate positivity of Immunoglobulin M (IgM) and IgG in secretions, and Western blot was applied to quantify the expression levels of Interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), prostacyclin (PGI2) and bax/bcl-2. RESULTS: Our results showed the UU, MH, and overall bacterial infection rate of chorionic and decidual tissues, and the gene copy number of UU, MH were higher in the observation group than those in the control group (p<0.05). Moreover, the ACA-IgM and IgG positive rates in secretions of the observation group were significantly higher than those in the control group (p<0.05). Finally, the expression levels of IL-6, TNF-alpha, PGI2, and bax/bcl-2 were higher than those in the control group as well (p<0.05). CONCLUSIONS: Our results support the notion that RSA might be associated with UU and MH infection, could influence the occurrence of other bacterial infections and could stimulate ACA expression, inflammatory response, thrombogenesis, and factors associated with cell apoptosis, increasing the risk for an abortion during pregnancy. PMID- 29762821 TI - The influencing mechanism of mTOR signal pathway mediated by mitofusin-2 in development of follicle. AB - OBJECTIVE: To investigate the influencing mechanism of mammalian target of rapamycin (mTOR) signal pathway mediated by mitofusin-2 (Mfn2) in the development of follicle. MATERIALS AND METHODS: We selected 20 healthy Sprague Dawley (SD) female rats aging between 6 and 8 weeks were divided into the control group and the polycystic ovarian syndrome (PCOS) model group. Rats in PCOS group received the lavage using 0.4 mL 1% carboxymethyl cellulose solution containing letrozole (1 mg/kg/d) consecutively for 20 to 25d. We compared the body weight and ovary weight of rats, and detected levels of sera E2, T, P, FSH and LH through RIA measurement. We also observed the histological morphology of ovary through hematoxylin eosin (HE) staining, as well as the positive expression and location of rMfn2 through immunohistochemistry staining. Finally, we detected the expressions of mTOR, p-Akt, beta-catenin, caspase-3, Bcl-2 and Bax in Mfn2 and mTOR signal pathways in the tissues through RT-PCR and Western blot assay. RESULTS: In the PCOS group, the body weight of rats was lower than that of the control group, but the ovary weight of rats was higher than that in the control group. The levels of T and LH in serum were elevated, the levels of E2, P and FSH were decreased (p < 0.05). In the model group, typical polycystic changes were observed in the rats under the microscope, but no corpus luteum was observed, and a significant decrease was identified in the layers of the granular cell of the follicle. Mfn2 was widely expressed in the granular cells of the ovary, follicular fluid, inner theca cells, corpus luteum, and ovarian stroma. However, the expression in the outer theca cells was relatively low. In the observation group, the positive expression rate of Mfn2 was significantly lower (p < 0.05) than that in the control group. In the PCOS group, the mRNA and protein relative expression levels of mTOR, p-Akt, beta-catenin, and Bcl-2 were significantly lower (p < 0.05) than those in the control group. Conversely, the levels of caspase-3 and Bax were significantly higher (p < 0.05) than those in the control group. CONCLUSIONS: Downregulated expression of Mfn2 may affect the regular development of follicle through the mediation of mTOR signal pathway. PMID- 29762822 TI - Linc-ROR promotes endometrial cell proliferation by activating the PI3K-Akt pathway. AB - OBJECTIVE: To observe the expressions of Linc-ROR and proteins in the PI3K-Akt pathway in an ectopic lesion of adenomyosis. PATIENTS AND METHODS: The expression of Linc-ROR in the ectopic endometrium, eutopic endometrium, and normal endometrium of adenomyosis was detected by qRT-PCR. Western blot was used to detect the protein expressions of PI3K-Akt in endometriosis and lesion endometriosis. Cell counting kit-8 (CCK-8) assay was utilized to detect cell proliferative activity. After interfering or overexpressing Linc-ROR, protein expressions of the PI3K-Akt pathway were detected by Western blot. RESULTS: Linc ROR expression in the ectopic endometrium of adenomyosis was higher than that in the eutopic endometrium and normal endometrium, and the expression level of PTEN in adenomyosis tissues was decreased, whilst expression levels of Akt, p-Akt, p PTEN were increased. Clinical data of enrolled patients indicated that there was a relationship between Linc-ROR expression and the type and severity of dysmenorrhea of adenomyosis. However, no relationship was observed between Linc ROR expression and age, cesarean section, uterine surgery, and menstrual cycle. Cell counting kit-8 (CCK-8) assay showed that the proliferative activity of cells was significantly decreased after knockdown of Linc-ROR in the adenomyosis cells. Western blot revealed that the expression level of PTEN increased but the expression levels of p-Akt, p-PTEN and p-PDK1 decreased. Overexpression of Linc ROR obtained the opposite results. CONCLUSIONS: Linc-ROR is highly expressed in the ectopic endometrium of adenomyosis, and it can promote the proliferative activity of endometrial cells by activating the PI3K-Akt pathway. PMID- 29762823 TI - H19 promotes the proliferation of osteocytes by inhibiting p53 during fracture healing. AB - OBJECTIVE: We explored the possible mechanism underlying the expression change of H19 during fracture healing. MATERIALS AND METHODS: A total of 18 male SD mice aged from 6-8 weeks old (18.5-24.6 g) were selected to establish tibial fracture models. The left tibia undergoing sham surgery was considered as the control group, and the right tibia undergoing sawing treatment was considered as the experimental group. The control tibia and fracture tibia from three mice were harvested at six time points after operation, respectively. QRT-PCR was utilized to detect the changes of H19 and p53 mRNA expression. RESULTS: Compared with the control group, the expression of H19 in the experimental group was significantly increased at 4, 8, and 12 d. However, there was no significant difference in the expression of H19 between the experimental group and the control group at 16, 20, and 24 d. The proliferation of chondrocytes and osteoblasts from mouse and human was significantly inhibited, and the apoptosis was significantly increased after interference of H19. As p19 plays important roles in diverse biological process, we detected the expression level of p19 after inference of H19. In addition, knockdown of H19 significantly up-regulated the expression of p53 in osteoblast cell lines, while the down-regulation of p53 expression reversed the proliferation of osteoblasts. CONCLUSIONS: H19, as a molecular marker for promoting fracture healing, promote the proliferation of osteocytes by inhibiting the expression of p53. PMID- 29762824 TI - Long noncoding RNA UCA1 promotes cell proliferation, migration and invasion of human leukemia cells via sponging miR-126. AB - OBJECTIVE: Acute myeloid leukemia (AML) is a bone marrow malignancy. Long non coding RNA (lncRNA) urothelial carcinoma-associated 1 (UCA1) plays an important role in several cancers. However, the role of lncRNA UCA1 in AML remained unclear. MATERIALS AND METHODS: LncRNA UCA1 expressions in different cell lines were determined by RT-PCR. In human myelogenous leukemia (ML) cell lines K562 and HL60, effects of lncRNA UCA1 knockdown on cell viability, migration, invasion, and apoptosis were assessed, respectively. Binding effects between lncRNA UCA1 and microRNA (miR)-126, and between miR-126 and RAC1 3'UTR were detected by RT PCR and luciferase activity assay. Involvements of miR-126 and RAC1 in lncRNA UCA1-mediated cell bioactivities were assessed. RESULTS: We found that lncRNA UCA1 was upregulated in ML cell lines. Knockdown of lncRNA UCA1 inhibited cell viability, migration, invasion, and prompted apoptosis of ML cells in vitro. LncRNA UCA1 could bind with miR-126 and downregulate miR-126 expression. Simultaneously, the anti-growth and anti-metastasis actions of lncRNA UCA1 knockdown on ML cells were reversed by miR-126 suppression. RAC1 was a target gene of miR-126, and the anti-ML actions of miR-126 were abolished by RAC1 overexpression. Moreover, PI3K/AKT and JAK/STAT signaling pathways were blocked by miR-126 overexpression while were activated by RAC1 overexpression. CONCLUSIONS: Taken together, this study elucidates a novel UCA1-miR-126-RAC1 regulatory network in ML cells, which may provide the feasibility for use lncRNA based therapy in AML treatment. PMID- 29762825 TI - The prognostic role of platelet to lymphocyte ratio and mean platelet volume in critically ill patients. AB - OBJECTIVE: The aim of this study was to identify the relationship between complete blood count parameters, mean platelet volume (MPV), and platelet to lymphocyte ratio (PLR) with mortality and hospitalization duration in critically ill patients. PATIENTS AND METHODS: A retrospective analysis was made of patients admitted to our tertiary adult intensive Care Unit (ICU) between January 2015 and January 2016. Hemoglobin (Hb), white blood cell (WBC), lymphocyte and platelet counts were obtained from the complete blood count performed at the time of admission. MPV and PLR levels were calculated from these data. Other data were retrieved from the patient follow-up records. RESULTS: The investigation included a total of 306 patients. The total mortality rate was 40.2%. The initial median PLR level was 206.7 (8.1-1675.0) for non-survivor patients and 194.5 (12.8 1236.6) for survivor patients. The PLR level was higher in the non-survivor group, but there was no statistically significant difference between the groups (p>0.05). The median MPV level was 7.66 (5.17-15.25) for the survivors and 8.09 (4.36-16.19) for the non-survivors, and there was no statistically significant difference between the groups (p=0.237). The median length of stay (LOS) of all patients was 7 (2-61) days. Only the Acute Physiology and Chronic Health Evaluation (APACHE) II score was found to have a positive correlation with LOS (p<0.05). CONCLUSIONS: PLR has no effect on mortality rates regardless of whether the patient has thrombocytopenia or not at the time of admission. MPV levels have no significant relationship with mortality. Neither MPV nor PLR have an effect on LOS. The use of these as a prognostic factor for mortality in critically ill patients is still unclear. PMID- 29762826 TI - MicroRNA-9 enhances invasion and migration of cervical carcinomas by directly targeting FOXO1. AB - OBJECTIVE: Cervical carcinoma is the third frequently diagnosed cancer among women worldwide. Increasing evidence suggests that dysfunctions of miRNAs are involved in human cancers and could act as either tumor suppressors or oncogenes. The purpose of this study is to elucidate pathobiological functions of miR-9 expression by targeting FOXO1 in cervical carcinoma. PATIENTS AND METHODS: Real time-PCR was utilized to detect miR-9 and FOXO1 level in cervical carcinoma tissues and cells. Transwell assays were employed to check out the roles of miR-9 on cells invasive and migratory potency. Luciferase reporter and Western blot were applied to verify FOXO1 as a target gene of miR-9. RESULTS: The results showed that miR-9 was significantly high expressed in cervical carcinoma cell lines and clinical tissues. miR-9 enhanced the ability of migration and invasion of C33A and HeLa cells. FOXO1 was confirmed as the direct target of miR-9, and miR-9 over-expression down-regulated the expression level of FOXO1. CONCLUSIONS: Our data demonstrate that miR-9 enhances invasion and migration of cervical carcinomas by directly targeting FOXO1. This may lead to a modern therapeutic strategy for the treatment of cervical carcinomas. PMID- 29762827 TI - Upregulation of long non-coding RNA HNF1A-AS1 is associated with poor prognosis in urothelial carcinoma of the bladder. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) play important roles in the pathogenesis of bladder cancer. A recent study reported that lncRNA HNF1A-AS1 (HNF1A-AS1) was upregulated in urothelial carcinoma of the bladder (UCB) and served as a tumor promoter. However, the clinical significance of HNF1A-AS1 in the prognosis of patients with UCB was poorly understood. This work was designed to investigate the relationship between HNF1A-AS1 expression level and the prognosis of UCB. PATIENTS AND METHODS: Relative expression levels of HNF1A-AS1 in UCB tissues were determined by qRT-PCR. Then, the associations between HNF1A-AS1 expression and clinical pathological parameters were further evaluated. Survival and Cox proportional-hazards regression analyses were performed to determine the correlation between HNF1A-AS1 expression levels and prognosis in the patients. RESULTS: Data showed that the majority of UCB tissues showed higher HNF1A-AS1 levels than the corresponding normal tissues controls (p < 0.01). Statistical assay revealed that high HNF1A-AS1 expression was significantly correlated with histological grade (p = 0.008), tumor stage T (p = 0.003) and lymph nodes metastasis (p = 0.007). In addition, the overall survival time of patients with high HNF1A-AS1 expression was significantly shorter compared to those with low HNF1A-AS1 expression. Furthermore, multivariate analysis confirmed that relative HNF1A-AS1 expression was an independent predictor of overall survival in patients with UCB. CONCLUSIONS: HNF1A-AS1 expression was upregulated in UCB, and it may be a useful prognostic biomarker for patients with UCB. PMID- 29762828 TI - Neoplasms and renal transplantation: impact of gender, comorbidity and age on in hospital mortality. A retrospective study in the region Emilia-Romagna of Italy. AB - OBJECTIVE: The aim of this retrospective study was to investigate the relationship between cancer, non-immunologic comorbidity, estimated by International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codification, gender and in-hospital mortality (IHM) in a large sample of renal transplant recipients (RTRs) living in the region Emilia-Romagna (RER) of Italy. PATIENTS AND METHODS: We evaluated IHM in RTRs admitted between 2000 and 2013 recorded in the RER database. By using ICD-9-CM codes, the Elixhauser index (EI) was calculated, and cancers were identified and classified as skin cancers (SC), solid organ cancers (SOC) and post-transplant lymphoproliferative disorders (PTLD). IHM was the dependent variable of the multivariate models, while age, gender, EI corrected removing the effect of malignancies (cEI), and different types of cancer were the independent ones. RESULTS: During the examined period, a total of 9,063 admissions in 3,648 RTRs were recorded, of whom 117 died (3.2%). The mean age was 52.9+/-13.1 years. Cancers were reported in 580 admissions (6.4%), and mean cEI was 3.5+/-3.4. Deceased RTRs were older, had a higher prevalence of PTLD and SOC, and had a higher cEI than survivors. IHM was independently associated with (in decreasing order) PTLD (OR 12.431, 95%CI 5.834 26.489, p<0.001), SOC (OR 6.804, 95%CI 4.323-10.707, p<0.001), female gender (OR 1.633, 95%CI 1.057-2.523, p=0.006), cEI (OR 1.106, 95%CI 1.068-1.145, p<0.001), and age (OR 1.049, 95%CI 1.031-1.068, p<0.001) CONCLUSIONS: Cancer, in particular SOC and PTLD, is strongly associated with IHM in RTRs. On the other hand, rather surprisingly, female gender exhibited a stronger association with IHM than other more expected factors, such as comorbidity and age. PMID- 29762829 TI - The role of miR-99b in mediating hepatocellular carcinoma invasion and migration. AB - OBJECTIVE: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults with a high rate of malignancy. The potent invasion and migration of HCC mainly impact the prognosis and recurrence of the disease. Our previous study found that miR-99b was highly expressed in HCC, and its expression was associated with vascular invasion. It was speculated that miR-99b may play a role in HCC invasion and migration, while the specific mechanism remains unclear. MATERIALS AND METHODS: qRT-PCR was applied to detect expressions of miR-99b and KAI1 genes in L02, HepG2, and MHCC97H cells. HepG2 cells were transfected with miR-99b inhibitor, miR-99b mimic, and NC. Flow cytometry was used to test cell cycle and apoptosis. Dual-luciferase reporter gene assay was adopted to validate the target gene of miR-99b. Wound healing assay was used to detect cell migration. Transwell assay was performed to detect cell invasion. Western blot was performed to detect KAI1, E-cadherin, and N-cadherin expressions. Immunofluorescence assay was adopted to test Vimentin expression. RESULTS: The level of miR-99b was reduced in L02 while up-regulated in MHCC97H. By contrast, the expression of KAI1 was increased in L02 but declined in MHCC97H. The transfection of miR-99b mimic inhibited HepG2 apoptosis and accelerated cell cycle. MiR-99b suppressed KAI gene expression through targeting its 3'-UTR. MiR 99b mimic or si-KAI1 transfection promoted cell invasion and migration, while their simultaneous action significantly enhanced cell invasion and migration. The overexpression of miR-99b or knockdown of KAI1 significantly weakened HepG2 cell adhesion, reduced E-cadherin expression, upregulated N-cadherin and Vimentin, and promoted cell epithelial-mesenchymal transition (EMT). CONCLUSIONS: MiR-99b contributes to promoting function in HCC migration and invasion through inhibiting KAI1 expression. PMID- 29762830 TI - LncRNALUADT1 is overexpressed in colorectal cancer and its expression level is related to clinicopathology. AB - OBJECTIVE: LncRNAs participate in the proliferation, apoptosis, and invasion of colorectal cancer. We aimed at investigating the uncovered effect of lncRNALUADT1 on colorectal cancer. PATIENTS AND METHODS: The relative expression level of lncRNALUADT1 in tumor specimen was tested by Real-time quantitative PCR. The association of lncRNALUADT1 with clinical pathological data was analyzed by univariate, multivariate Cox and Kaplan-Meier curve. RESULTS: LncRNALUADT1 expression was up-regulated in colorectal cancer, and correlated with tumor size, metastasis, and TNM staging. Both univariate analysis and multivariate test indicated that lncRNALUADT1 high expression, TNM staging, and lymph node metastasis were closely related. Moreover, high expression of lncRNALUADT1 suggested the poor overall survival of patients. CONCLUSIONS: LncRNA LUADT1 might contribute to the development of colorectal cancer. PMID- 29762831 TI - CircRNA_0023642 promotes migration and invasion of gastric cancer cells by regulating EMT. AB - OBJECTIVE: Non-coding circular RNAs (circRNAs) have displayed dysregulated expression in various tumor tissues. However, their role in the progression of cancers remains largely unknown. We aimed at examining the expression, functions, and molecular mechanisms of a new circRNA (circRNA_0023642) in gastric cancer (GC). PATIENTS AND METHODS: We evaluated the expression levels of circRNA_0023642 in GC tissues, adjacent normal tissues and cells lines using qRT-PCR. The functional roles of circRNA_0023642 in GC were determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assay, and flow cytometric analysis. Western blot was used to analyze the effect of circRNA_0023642 on the expression of EMT-related proteins. RESULTS: We found that circRNA_0023642 was upregulated in GC tissues and cell lines. Functionally, down-regulation of circRNA_0023642 displayed the tumor-inhibitory effects by suppressing cell proliferation, migration, and invasion as well as inducing apoptosis. Mechanically, our results revealed that the abnormal expression of circRNA_0023642 could influence the EMT signaling pathway, which was demonstrated by measuring the expression levels of N-cadherin, vimentin snail, and E-cadherin. CONCLUSIONS: Our findings suggest that circRNA_0023642 serves as a metastasis activator by promoting EMT and may represent a novel molecular therapeutic target for GC. PMID- 29762832 TI - LncRNA DQ786243 expression as a biomarker for assessing prognosis in patients with gastric cancer. AB - OBJECTIVE: Recent studies have revealed that long noncoding RNA DQ786243 (DQ786243) plays an important role in the development of gastric cancer (GC) and colorectal cancer. However, the expression and function of DQ786243 in GC patients remain largely unknown. The purpose of our study was to investigate the clinical significance of DQ786243 expression in GC. PATIENTS AND METHODS: qRT-PCR was used to examine DQ786243 expression in 172 paired GC samples and matched adjacent normal tissues. Besides, the relationship between DQ786243 expression and clinicopathologic characteristics was analyzed. Overall survival (OS) and progression-free survival (PFS) curves of patients in subgroups were constructed by the Kaplan-Meier method. Multivariate regression analyses were performed to analyze independent factors affecting prognosis. RESULTS: We found a significant up-regulation of DQ786243 in GC tissues compared to normal tissues (p < 0.01). High DQ786243 expression was closely associated with invasion depth (p = 0.006), TNM stage (p = 0.009) and lymphatic metastasis (p = 0.017). Moreover, Kaplan Meier analysis showed that patients with DQ786243 high expression tumors had worse OS (p = 0.0012) and PFS (p = 0.0002) compared to patients with DQ786243 low expression tumors. Finally, multivariate analysis showed that DQ786243 was a significant and independent prognostic predictor for both OS (p = 0.002) and PFS (p = 0.001) of GC patients. CONCLUSIONS: Our data suggest, for the first time, that the evaluation of the DQ786243 expression in GC tissues is a useful tool for predicting prognosis of GC. PMID- 29762833 TI - Low-expression of lncRNA FER1L4 might be a prognostic marker in osteosarcoma. AB - OBJECTIVE: To investigate the potential role of Long non-coding RNA (lncRNA) FER1L4 in the diagnosis and prognostic assessment of osteosarcoma. PATIENTS AND METHODS: LncRNA FER1L4 expression in osteosarcoma samples was detected by real time PCR. The Kaplan-Meier method was used to analyze the relationship between lncRNA FER1L4 expression and the survival time of patients. RESULTS: LncRNA FER1L4 expression was decreased in osteosarcoma samples. LncRNA FER1L4 was not related to the gender and age of patients, but was significantly associated with disease stage, metastasis, and tumor differentiation. CONCLUSIONS: Low-expression of lncRNA FER1L4 might be a prognostic marker in osteosarcoma. PMID- 29762834 TI - MicroRNA-520d-3p inhibits osteosarcoma progression by degradation of Akt1. AB - OBJECTIVE: To detect the expression of microRNA-520d-3p in osteosarcoma tissue and the function on the osteosarcoma cells proliferation. PATIENTS AND METHODS: We used qRT-PCR to access microRNA-520d-3p level from 10 cases of osteosarcoma and its adjacent tissues. The osteosarcoma cell lines were screened. The microRNA 520d-3p mimics or inhibitor was transfected into human osteosarcoma cells by liposome method, and the cell proliferation of each group was detected by the CCK8 assay. We used bioinformatics methods to detect and predict the target genes of microRNA-520d-3p. Luciferase reporter assay was utilized to detect the relative luciferase activity between microRNA-520d-3p and Akt1. Meanwhile, after cells were transfected with microRNA-520d-3p mimics, microRNA-520d-3p mimics + OE Akt1, microRNA-520d-3p inhibitor or microRNA-520d-3p inhibitor + si-Akt1, we detected cell viability using CCK-8 assay, respectively to access the interaction between Akt1 and microRNA-520d-3p. RESULTS: Lowly expressed microRNA-520d-3p in osteosarcoma tissues was observed in comparison with adjacent tissues. After transfecting with microRNA-520d-3p mimics, the viability of MG63 and U-20S cells decreased, which was higher in cells transfecting microRNA-520d-3p inhibitor. Bioinformatics prediction and dual luciferase reporter assay illustrated that microRNA-520d-3p targeted on Akt1. At the same time, Akt1 expression was higher in osteosarcoma tissues than in adjacent ones, cell proliferation was inhibited after blocking its expression. In addition, after transfected with microRNA-520d 3p mimic, viability of MG63 and U-20S cells decreased, which can be reversed by OE-Akt1. In contrast, the viability of MG63 and U-20S cells increased after transfection with microRNA-520d-3p inhibitor and which were reversed by si-Akt1. CONCLUSIONS: Lowly expressed microRNA-520d-3p was observed in osteosarcoma; overexpression of microRNA-520d-3p can target Akt1 thus inhibiting proliferation of osteosarcoma cells. PMID- 29762835 TI - MicroRNA-520a-3p inhibits cell growth and metastasis of non-small cell lung cancer through PI3K/AKT/mTOR signaling pathway. AB - OBJECTIVE: MicroRNAs are a class of small non-coding RNAs that be involved in the pathogenesis of non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the effects of miR-520a-3p in cell growth and metastasis. MATERIALS AND METHODS: The mimics and inhibitor of miR-520a-3p were used to identify the effects of miR-520a-3p on cell proliferation and apoptosis using methylthiazol tetrazolium (MTT) assay and flow-cytometric method, respectively. Transwell assay was used to evaluate the cell migration and invasion. The protein expression levels related PI3K/AKT/mTOR signaling pathways were measured by Western blot. RESULTS: The results showed that miR-520a-3p overexpression could significantly inhibit cell proliferation and induce apoptosis, suppress cell migration and invasion. MiR-520a-3p overexpression could markedly reduce the ratio of p AKT/AKT, p-PI3K/PI3K and Bcl-2/Bax, the levels of mTOR, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) compared with control. However, miR-520a-3p overexpression could increase caspase-3 expression compared with control group. After inhibited the expression of miR-520a-3p, the capacity of cell proliferation, migration and invasion were increased, cell apoptosis was inhibited compared with control group. The ratio of p-AKT/AKT, p-PI3K/PI3K and Bcl-2/Bax, the levels of mTOR, MMP-2 and MMP-9 were increased compared with control group. CONCLUSIONS: Our study suggested that miR-520a-3p could suppress the NSCLC proliferation, migration and invasion through PI3K/AKT/mTOR signaling pathway. PMID- 29762836 TI - LncRNA GHET1 predicts a poor prognosis of the patients with non-small cell lung cancer. AB - OBJECTIVE: Long non-coding RNAs (LcRNAs) is related to lung cancer progression. This study aimed at exploring lncRNA GHET1 in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: RT-PCR was used to detect lncRNA GHET1 expression in lung cancer specimen and cancer-adjacent areas. Kaplan-Meier assay was applied to investigate the prognosis of the patients with lung cancer. RESULTS: The expression of lncRNA GHET1 in lung cancer specimen was significantly higher than that in the cancer-adjacent tissues, which was related to the tumor size, differentiation degree of tumor cells, and lymph node metastasis of clinical specimens. Moreover, lncRNA GHET1 predicted a poor prognosis for the patients with lung cancer. CONCLUSIONS: LncRNA GHET1 might be a biomarker and molecular target of NSCLC, providing a potential therapeutic target of NSCLC. PMID- 29762837 TI - Stemness-related changes of CD133- cells in nasopharyngeal carcinoma after x-ray radiation at the median lethal dose. AB - OBJECTIVE: To investigate the effect of X-ray radiation at the median lethal dose (LD50) on the outcome of a cluster of differentiation 133 (CD133)- cells in nasopharyngeal carcinoma. MATERIALS AND METHODS: CD133- cells were obtained from human nasopharyngeal carcinoma cells (CNE-1 and CNE-2) based on CD133-labeled fluorescence-activated cell sorting (FACS) and magnetic-activated cell sorting (MACS), respectively. Changes in invasion ability and in-vivo tumorigenicity of CD133- cells before and after X-ray radiation at LD50 were observed. Moreover, CD133, SRY-related HMG-box 2 (SOX2), and organic carnitine transporter 4 (OCT4) expression changes were detected by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. RESULTS: The invasion ability and in-vivo tumorigenicity of CD133+ cell subsets were significantly stronger than those of CD133- cell subsets. After X-ray radiation at LD50, the invasion ability of CD133 cell subsets and in-vivo tumorigenicity were significantly increased. RT-PCR and Western blotting results manifested that the expression levels of CD133, SOX2, and OCT4 were remarkably up-regulated after radiation. CONCLUSIONS: X-ray radiation at LD50 can enhance the stemness potential by up-regulating the expression of stemness-related genes in nasopharyngeal carcinoma CD133- cells. PMID- 29762838 TI - MiRNA-93 functions as an oncogene in glioma by directly targeting RBL2. AB - OBJECTIVE: Glioma is a tumor of the brain. Although the clinical regimens and surgical techniques for glioma have improved, therapies of advanced glioma remain challenging, carrying dismal overall survival and therapeutic success rates. Evidence has shown that miRNAs played important roles in glioma development. The current study aimed at investigating the function of a novel cancerogenic miRNA, miR-93, in glioma progression by investigating the expression and mechanism of it. PATIENTS AND METHODS: qRT-PCR was conducted to assess the miR-93 expression and the mRNA expression of target gene in glioma tissues and cells. The invasion and migration abilities of the glioma cells were determined by transwell assays. Luciferase reporter assay was performed to confirm the target of miR-93. RESULTS: The results indicated that miR-93 expression in glioma tissues and cells was increased significantly than that in normal brain tissues and cells. Furthermore, miR-93 promoted glioma cell migration and invasion. RBL2 was recognized as a direct target of miR-93 in glioma cells, and overexpression of RBL2 could reverse the stimulative effect of miR-93 in glioma cell. CONCLUSIONS: The above findings suggested that miR-93 together with RBL2 could be diagnostic targets and novel prognostic markers for glioma. PMID- 29762839 TI - Circulating UCA1 is highly expressed in patients with systemic lupus erythematosus and promotes the progression through the AKT pathway. AB - OBJECTIVE: To investigate the role of Urothelial Carcinoma Associated 1 (UCA1) during the progression of systemic lupus erythematosus (SLE) and the underlying mechanism. PATIENTS AND METHODS: UCA1 expression in peripheral blood of SLE patients, as well as the expression of protein kinase B (AKT) in the peripheral blood mononuclear cell (PBMC), was detected by qRT-PCR. Expression differences in UCA1 and AKT between different groups were compared by t-test or univariate analysis. Through correlation analysis, the correlation between UCA1, AKT and clinical indicators of patients was analyzed. After overexpression and knockout of UCA1, the effect on phenotypes of BaF3 cell was examined. Finally, we analyzed the correlation between AKT and UCA1, and the effect on AKT pathway after overexpression and knockout of UCA1. RESULTS: We found that plasma level of UCA1 and AKT was significantly enhanced in SLE patients. By analyzing the clinical data, a higher UCA1 level was observed in female patients than in males. In addition, UCA1 level in SLE patients with active stage and pathological lesions was higher than those in a stable stage without organ involvement. Correlation analysis showed that there was a positive correlation between UCA1 and C3, anti ds-DNA, ESR and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Similarly, there was a positive correlation between AKT and C3, anti-ds-DNA, erythrocyte sedimentation rate (ESR) and SLEDAI, respectively. After overexpression and knockdown of UCA1, it was found that overexpression of UCA1 significantly enhanced cell proliferation, while the interference with UCA1 significantly inhibited cell proliferation. Western blot revealed increased expressions of PI3K and AKT after overexpressing UCA1, whereas knockdown of UCA1 led significantly decreased expressions of PI3K and AKT. CONCLUSIONS: UCA1 expression was significantly increased in SLE, which promoted the progression of SLE by activating AKT pathway. PMID- 29762840 TI - The effect of miR-146a gene silencing on drug-resistance and expression of protein of P-gp and MRP1 in epilepsy. AB - OBJECTIVE: To investigate the effect of miR-146a gene silencing on brain tissue and related drug-resistance proteins in rats and explore its resistance mechanism. MATERIALS AND METHODS: A rat model of chronic refractory epilepsy was established. The rats were divided into four groups: Normal group, Model group, Negative control group and AntagomiR-146a group. Hematoxylin and eosin (HE) stain was used to detect brain histopathological changes. We examined the expression of mRNA of miR-146a, multidrug resistance (MDR1) and multidrug-resistant associated protein (MRP1) by RT-PCR. The expressions of protein of High motility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4)/nuclear transcription factor-kappaB (NF kappaB) pathway and P-glycoprotein (P-gp), MRP1 were detected by Western blotting. RESULTS: We demonstrated that the pathological lesion was lighter in antagomiR-146a group compared with the model group. The mRNA expression of miR 146a in AntagomiR-146a group was significantly decreased compared to the model group. Furthermore, the mRNA expression of MDR1 and MRP1 in AntagomiR-146a group was lower than that in the model group. In addition, the protein expression of HMGB1, TLR4, NF-kappaB and P-gp, MRP1 in AntagomiR-146a group was lower than that in model group. CONCLUSIONS: These results demonstrated that miR-146a gene silencing can attenuate pathological changes and improve drug resistance in refractory epilepsy. Also, it is closely related to the HMGB1/TLR4/NF-kappaB signaling pathway regulation. PMID- 29762841 TI - Assessment of left ventricular systolic synchrony and cardiac function in patients with ischemic heart disease by echocardiography. AB - OBJECTIVE: To investigate the correlation between left ventricular systolic synchrony and cardiac function in patients with ischemic heart diseases of different degrees by echocardiography. PATIENTS AND METHODS: 84 cases of patients with ischemic heart diseases were consecutively selected including 28 cases of asymptomatic heart failure, 40 cases of mild to moderate heart failure, and 16 cases of severe and refractory heart failure. Interventricular synchrony was evaluated by echocardiography, and the result was expressed by interventricular mechanical delay (IVMD). The ventricular systolic synchrony was evaluated by the standard deviation of systole tmax (Ts-SD), cardiac function indexes included left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter (LVEDd), and BNP and QRS wave duration. RESULTS: IVMD, Ts-SD and QRS wave duration increased gradually following the exacerbation of heart failure; differences were statistically significant (p < 0.05). The ratio of the QRS wave duration that was equal to or greater than 120 ms among three groups showed no statistical difference (p = 0.593). In patients with QRS wave durations equal to or greater than 120 ms compared to patients with durations less than 120 ms, the levels of IVDM, Ts-SD, LVEDd, and serum BNP were increased (p < 0.05) while levels of LVEF were decreased (p < 0.05). There were no significant linear correlations among values of IVMD, Ts-SD with LVEF, LVEDd, BNP and QRS wave duration (p > 0.05). CONCLUSIONS: Left ventricular systole synchrony was different in patients with different degrees of ischemic heart diseases, and a comprehensive assessment of the combination of ventricular systole synchrony with cardiac function is needed. PMID- 29762842 TI - The role of commonly used clinical indicators in the diagnosis of acute heart failure. AB - OBJECTIVE: Acute heart failure (AHF) is one of the most commonly seen clinical cases, with a high rate of re-hospitalization and mortality. AHF can be divided into two categories based on the systolic function of the left ventricle, which are heart failure with reduced ejection fraction (HFREF) and heart failure with preserved ejection fraction (HFPEF). Pathogenesis and treatment of the two are quite different. In this article we attempted to explore the value of combined use of clinical and laboratory indicators in the differential diagnosis of AHFREF and AHFPEF. PATIENTS AND METHODS: AHF patients >=18 years old without valvular heart disease, acute myocardial infarction, renal dysfunction, ongoing hemodialysis or acute pulmonary embolism were chosen. Patients with left ventricular ejection fraction (LVEF) <0.5 fell into AHFREF group, and the remaining were placed in the AHFPEF group. Binary logistic regression analysis of age, gender, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), NT-proBNP, blood glucose, LVEF and cardiothoracic ratio (CTR) as covariates and AHF types as dependent variables. RESULTS: 166 patients were enrolled and, among them, 66 cases (39.8%) were in the AHFREF group and 100 cases (60.2%) in the AHFPEF group. We chose age, SBP, DBP, HR and NT-pro BNP as covariates in the binary logistic regression analysis, and obtained the regression equation and the results were statistically significant (chi2=32.177, p<0.001). Hosmer-Lemeshow model test was (chi2=8.654, p=0.372). Samples were tested with the remaining approximately 30% of the subjects. CONCLUSIONS: Combined application of clinical and laboratory indicators, such as age, blood pressure, HR and NT-proBNP play an important role in the differential diagnosis of AHFREF and AHFPEF. PMID- 29762843 TI - Diagnostic accuracy of natriuretic peptides for acute heart failure: a review. AB - The rising incidence of and the cost associated with heart failure have made it increasingly imperative to accurately diagnose heart failure upon presentation. Correctly identifying heart failure in an Emergency Department is extremely challenging, and according to estimates, is only confirmatory in approximately 40 50% of patients. For an accurate diagnosis of heart failure and the consequent treatment, there needs to be more accurate test relying on biochemical factors as opposed to general symptoms that patients are experiencing. Natriuretic peptides are now utilized in routine tests for heart disease diagnosis in emergency departments as it is relatively low cost, easy to use and is a quick way to exclude heart failure as a reason for dyspnea. In this review, we detail the role and value of individual natriuretic peptides, particularly BNP, NT-proBNP, and MR proANP, in diagnosing acute heart failure. PMID- 29762844 TI - Free fatty acids mediates human umbilical vein endothelial cells inflammation through toll-like receptor-4. AB - OBJECTIVE: To investigate the role of Toll-like receptor-4 (TLR4) in the free fatty acids (FFAs) induced human umbilical vein endothelial cells (HUVECs) inflammation and to explore the underlying mechanisms. MATERIALS AND METHODS: HUVECs and HEK293 cell lines were obtained from Shanghai Type Culture Collection. Cell counting kit-8 (CCK8) and flow cytometry (FCM) were performed to examine the cell viability and apoptosis rate of HUVECs induced by FFAs treatments with or without infection of toll-like receptor-4 interference (TLR4i) adenovirus. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammatory cytokines release. Quantitative polymerase chain reaction (qPCR) and Western Blot (WB) were used to test the molecular mechanisms of inflammation. RESULTS: FFAs induced inflammatory responses in HUVECs via modulating the TLR4 receptor complex. TLR4i adenovirus interference increased cell viability and decreased cell apoptosis rate. FFAs treatments significantly increased the expressions of inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), C-C motif chemokine ligand 5 (CCL5) and CXC chemokine ligand 10 (CXCL10), while TLR4i adenovirus interference significantly reduced these cytokines levels. TLR4 mediated myeloid differential protein-88 (MyD88) expression activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and inhabiting kappa B kinase-beta (IKK-beta). TLR4i adenovirus interference decreased the expressions of these genes at both mRNA level and protein level. CONCLUSIONS: TLR4 mediates FFAs induced inflammatory responses in HUVECs. TLR4 interference in HUVECs significantly reduces the inflammatory cytokines expression, decreases the cell apoptosis rate and increases cell viability. PMID- 29762845 TI - Peritoneal dialysis effectively removes toxic substances and improves liver functions of liver failure patients. AB - OBJECTIVE: Liver failure (LF) is a clinically complex disorder that characterizes with hepatic dysfunction. This study aimed at observing the therapeutic effects of peritoneal dialysis on liver function in LF patients. PATIENTS AND METHODS: This study involves 62 patients diagnosed as LF hospitalized from February 2005 to December 2016. The 62 LF patients were randomly divided into 3 groups, including artificial liver applying plasma exchange group (PE, n = 28), peritoneal dialysis group (PD, n = 22), and conservative treatment group (CT, n=12). Laboratory indexes, including serum total bilirubin (TBiL), alanine aminotransferase (ALT), albumin (ALB), blood ammonia (AMMO), international normalized ratio (INR), and creatinine (Cr) were evaluated. Inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL 6), and procalcitonin (PCT) were examined using enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Peritoneal dialysis significantly improves clinical outcomes, including decreased mortality, increased survival rate and total effective rate, compared to conservative treatment (p < 0.05). Peritoneal dialysis reduced hospitalization expenses compared to PE method and conservative treatment (p < 0.05). Peritoneal dialysis significantly removed toxic substances (including TBiL, AMMO, Cr) compared to conservative treatment (p < 0.05). The post-treatment level of Cr in peritoneal dialysis group was significantly lower compared to post-treatment level of Cr in PE group (p < 0.05). Peritoneal dialysis significantly improved liver function compared to conservative treatment (p < 0.05). Peritoneal dialysis prevented bleeding tendency compared to conservative treatment (p < 0.05). Peritoneal dialysis alleviated inflammatory response compared to conservative treatment (p < 0.05). CONCLUSIONS: Peritoneal dialysis effectively removed toxic substances and improved liver functions of liver failure patients and with a lower therapeutic cost. PMID- 29762846 TI - Neurotrophin-3 improves fracture healing in rats. AB - OBJECTIVE: This study aimed at investigating the role of Neurotrophin-3 (NT-3) in the bone fracture healing of rats and to provide a reference for clinical treatment. MATERIALS AND METHODS: 40 Sprague-Dawley (SD) rats were randomly divided into control group and NT-3 group. The tibia fracture model was made in NT-3 group, and the tibia bone mineral density (BMD) was measured before and after the surgery. The biomechanics indexes were inspected after the surgery, including elasticity modulus, max load, and bending rigidity. The levels of bone morphogenetic protein (BMP)-2 and transforming growth factor (TGF)-beta1 in serum were examined by enzyme-linked immunosorbent assay (ELISA). Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the levels of hypoxia inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) mRNA expression in callus tissue. The pathological profile of tibia fracture healing was characterized after the surgery. RESULTS: The levels of BMD in NT-3 group were significantly higher than that in control group after the surgery (p < 0.05). The levels of elasticity modulus, maximum load, stiffness of shinbone, BMP 2 and TGF-beta1 were significantly higher in NT-3 group than those in control group after the surgery (p < 0.05). Compared with the control group, the expression of HIF-1alpha mRNA was significantly lower and the expression of VEGF mRNA was significantly higher in NT-3 group after the surgery (p < 0.05). Histological study showed that the periosteal reaction, capillary proliferation, cartilage cells production and ossification were happened after treating NT-3 for tibia fracture model rats. CONCLUSIONS: NT-3 can significantly improve fracture healing in rats. PMID- 29762847 TI - Effects of fibroblast growth factors 2 and low intensity pulsed ultrasound on the repair of knee articular cartilage in rabbits. AB - OBJECTIVE: To investigate the effect of low intensity ultrasound irradiation combine with fibroblast growth factors (FGF2) on the repair of the knee articular cartilage and to explore its mechanism in rabbit. MATERIALS AND METHODS: The model of the rabbit knee joint injury was established. 40 rabbits were divided into four groups, including control group, model group, FGF2 group and FGF2 + low intensity pulsed ultrasound group (FGF2 + LIPU). The knee joints of rabbits were taken at 4 and 8 weeks, respectively. Histopathological changes were detected by Hematoxylin and Eosin stain (HE) and evaluated by Wakitani score. The expression of FGF2 mRNA was detected by Real-time polymerase chain reaction (RT-PCR) and the levels of Collagen I and Collagen II protein were analyzed by Western blotting. RESULTS: In FGF2 group and FGF2 + LIPU group, it was found that the tissues of knee joint were gradually repaired following the change of time. Further, the recovery was better in FGF2 + LIPU group. Cartilage defect areas were filled with cartilage-like cells and the repair surface was fused with surrounding cartilage in FGF2 and FGF2 + LIPU groups. Wakitani scores were consistent with HE results. The expressions of FGF2 mRNA were higher in FGF2 and FGF2 + LIPU group than the model group. Western blotting results showed that the levels of Collagen I and Collagen II protein in FGF2 and FGF2 + LIPU groups were significantly increased compared with that in model group. CONCLUSIONS: FGF2 and LIPU combined application on the rabbit knees joint repair is better than FGF2 alone. FGF2 and LIPU combination can promote the synthesis and secretion of collagen in chondrocytes, promote the differentiation and maturation of chondrocytes during the repair of cartilage defects. PMID- 29762848 TI - CXCR3 mediates chondrocyte injury through regulating nitric oxide. AB - OBJECTIVE: As a common joint disease, osteoarthritis exhibits increasing trend in recent years. C-X-C motif chemokine receptor 3 (CXCR3) is a kind of chemokine with the characteristic of recruiting inflammatory cells. Its function in osteoarthritis has not been clarified. This study aims to explore the role of CXCR3 in cartilage injury by affecting unfolded protein response (UPR) pathway. PATIENTS AND METHODS: The sample was obtained from osteoarthritis patients to test CXCR3 expression by Real-time polymerase chain reaction (PCR). Chondrocyte apoptosis model was established in vitro induced by interleukin 1beta (IL-1beta) and sodium nitroprusside (SNP). CXCR3 level was downregulated by using siRNA. Cell apoptosis was determined by using transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) assay. UPR pathway related factors C/EBP homology protein (CHOP) and glucose regulated protein 78 (GRP78) protein expressions were tested by using Western blot. RESULTS: CXCR3 protein level significantly increased in osteoarthritis patients (2.66 +/- 0.25 vs. 1.00 +/- 0.05, p<0.05). CXCR3 siRNA significantly reduced nitrate level in chondrocytes induced by IL-beta (35.22 +/- 1.76 vs. 17.82 +/- 0.89, p<0.05) without affecting cell apoptosis (1.13 +/- 0.05 vs. 0.859 +/- 0.04, p>0.05). CXCR3 siRNA markedly downregulated nitrate level in chondrocytes (50.63 +/- 2.53 vs. 30.63 +/- 1.63, p<0.05) and alleviated cell apoptosis induced by SNP (1.98 +/- 0.10 vs. 1.25 +/- 0.06, p<0.05). UPR pathway C/EBP homology protein (CHOP) and glucose regulated protein 78 (GRP78) participated in the process of chondrocyte apoptosis. CONCLUSIONS: Endoplasmic reticulum (ER) stress signaling pathway CHOP and GRP78 are involved in CXCR3 receptor attenuating chondrocyte apoptosis induced by SNP. PMID- 29762849 TI - Effects of smoking on thiol/disulfide homeostasis. AB - OBJECTIVE: Cigarette smoking is an important risk factor for many diseases. This study aimed to evaluate whether cigarette smoking is associated with changes in the thiol/disulfide homeostasis (TDH), a novel biomarker of systemic oxidative stress. PATIENTS AND METHODS: Eighty-four smokers and 86 non-smoking healthy volunteers were enrolled. Serum native thiol, disulfide and total thiol levels, disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios were analyzed using a new colorimetric method. Carbon monoxide (CO) levels were measured by a piCO smokerlyzer instrument. RESULTS: The native, total, and native/total thiol levels of smoking patients were significantly lower (p<0.001 for each), and disulfide, disulfide/native thiol, and disulfide/total thiol levels were significantly higher in smokers than the healthy controls (p<0.001 for each). The CO levels of all study participants were negatively correlated with native thiol (r= -0.627, p<0.001), total thiol (r= -0.569, p<0.001), native thiol/total thiol (r= -0.515, p<0.001), and positively correlated with disulfide (r=0.398, p<0.001), disulfide/native thiol (r=0.515, p<0.001) and disulfide/total thiol (r=0.515, p<0.001) levels. CONCLUSIONS: To our knowledge, this investigation is the first in the literature that investigated TDH in cigarette smokers. Our results show that cigarette smoking may lead to oxidative stress and TDH shifts through disulfide side compared to the healthy group. Further studies with larger sample size are needed to confirm our results for showing the changes in TDH to contribute to the clinical practice. PMID- 29762850 TI - Effect of treating renal failure with decorin gene therapy. AB - OBJECTIVE: To explore a new approach for treating renal insufficiency with gene therapy by implanting decorin (DCN)-expressing fibroblasts within the renal tissue of rats with renal failure to neutralize TGF-beta1 activity. MATERIALS AND METHODS: The 5/6 kidney of the selected male SD rats were removed under aseptic conditions. The rats were grouped randomly after the establishment of the model. There were 10 rats in the sham-operated group (Group A), 10 in the operation control group (without treatment, Group B), 10 in the blank control group [treated with empty vector-transfected fibroblasts (FB (LXSN) cells), Group C], and 10 in the treatment group [treated with FB (LDCNSN) cells, Group D]. The pathological changes of rats including body weight, blood lipids, renal function, and renal histology, were observed. The expression of TGF-beta1 and DCN in renal tissue was detected by immunohistochemistry. RESULTS: There were no significant differences in body weight and blood lipids between the groups at 4 weeks after treatment. The levels of blood urea nitrogen and serum creatinine in rats in Group D were significantly decreased compared with those in Group C (p < 0.05). Although the differences were not statistically significant, the levels of those pathological indicators are higher than baseline values. The expression of DCN in renal tissue increased significantly after 4 weeks in rats of Group D and the differences were significant compared with the other groups. There were no significant differences in TGF-beta1 expression between any two groups of Group D, B, and C. Furthermore, pathological damage to the renal interstitium of rats in Group D was significantly decreased compared with that of Group B and C. CONCLUSIONS: DCN can alleviate fibrosis and delay the progression of renal failure. PMID- 29762851 TI - miR-198 regulated the tumorigenesis of gastric cancer by targeting Toll-like receptor 4 (TLR4). AB - OBJECTIVE: To investigate the role of miR-198 and its target gene Toll-like receptor 4 (TLR4) of tumorigenesis of gastric cancer (GC). MATERIALS AND METHODS: The expression of miR-198 in GC cells was detected by quantitative polymerase chain reaction (qPCR). The proliferation, apoptosis, migration, and invasion of GC cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), flow cytometry, transwell chamber, and wound scratch assay. Bioinformatics analysis for the results of protein chip was performed to identify the target genes of miR-198. TLR4 was further confirmed to be the target gene of miR-198 by TLR4 luciferase reporter assay. RESULTS: miR-198 expression level in GC SGC-7901 cells significantly decreased compared with the normal cells. When the miR-198 was overexpressed, the proliferation, migration, and invasion of GC cells were significantly decreased, while the apoptosis was increased. The expression of TLR4 in SGC-7901 cells was significantly higher, while the expression of TLR4 in SGC-7901 cells transfected with miR-198 significantly lowered, which was consistent with the Western blot for TLR4. The luciferase reporter assay confirmed that TLR4 was the target genes of miR-198 in GC SGC7901 cells. CONCLUSIONS: miR-198 could induce apoptosis and inhibit the proliferation, migration, and invasion of GC cells through downregulating TLR4 expression. PMID- 29762852 TI - Inhibition of thyroid carcinoma cells with YAP1 protein interference and its mechanism. AB - OBJECTIVE: To investigate the effects and mechanism of yes-associated protein 1 (YAP1) on thyroid carcinoma cells. MATERIALS AND METHODS: Quantitative Real-time PCR (qRT-PCR) and Western blot assay were used to detect the expression of YAP1 in normal thyroid cells (HT-ori3) and four types of thyroid carcinoma cells: FTC 133, IHH-4, TPC-1 and NPA. The cell lines with the highest expression of YAP1 were selected as the experimental materials. qRT-PCR and Western blot assay were used to detect the interference effect of si-YAP1. The cell proliferation and the effect on the PI3K-Akt signal pathway were examined by MTT and Western blot. RESULTS: The expression of YAP1 significantly increased in the thyroid carcinoma cell line compared with normal thyroid cells, among which the expression of YAP1 in TPC-1 was the highest. Quantitative PCR and Western blot results showed significant interference effects. The MTT assay indicated that YAP1 interference suppressed the proliferation of cells and the expression of p-Akt. CONCLUSIONS: The interference of YAP1 can inhibit the growth of thyroid cancer cells, and its mechanism may be associated with the PI3K-Akt signaling pathway. PMID- 29762853 TI - Caffeine induces metformin anticancer effect on fibrosarcoma in hamsters. AB - OBJECTIVE: We investigated the effect of metformin and caffeine on fibrosarcoma in hamsters. MATERIALS AND METHODS: 32 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups, with a minimum of 6 animals per group. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group started peroral treatment with metformin 500 mg/kg daily, the second with caffeine 100 mg/kg daily and the third with a combination of metformin 500 mg/kg and caffeine 100 mg/kg daily, via a gastric probe 3 days before tumor inoculation. After 2 weeks, when the tumors were approximately 2 cm in the control group, all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were pathohistologically (HE) and immunohistochemically (Ki-67, CD 31, COX IV, GLUT-1, iNOS) assessed and the main organs toxicologically analyzed, including the control animals that had received metformin and caffeine. Tumor volume was determined using the formula LxS2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified. Images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances were determined by the Student's t-test. RESULTS: The combination of metformin and caffeine inhibited fibrosarcoma growth in hamsters without toxicity. CONCLUSIONS: Administration of metformin with caffeine might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment. PMID- 29762854 TI - The influence of palatable high-energy diet in diet-induced obesity pregnant rats on offspring oxidative stress in liver. AB - OBJECTIVE: We established an animal model of diet-induced obesity pregnant rats and their offsprings, and explored the effect of high-energy feeding on oxidative stress in filial rat liver, as well as the underlying mechanism. MATERIALS AND METHODS: Pregnant female Sprague-Dawley (SD) rats were randomly assigned into two groups: control group and palatable high-energy diet (PHED) group. Liver tissues were obtained 12 days after offspring rats were born for further study. The expressions of malondialdehyde (MDA), reduced glutathione (GSH) and antioxidative enzyme activities were measured, and pathological change of liver tissues was examined by HE staining. In addition, the expressions of inflammatory factors, tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and mRNA level of Heme oxygenase-1 (HO-1), were examined by ELISA and RT-PCR, respectively. Furthermore, COX-2 and nuclear factor kappa B (NF-kappaB) expressions were also examined by Western Blot. RESULTS: Offspring rats of PHED group displayed a significantly higher level of MDA than the control group, and significantly lower level of GSH. Significant reductions in the activities of a number of antioxidant enzymes, such as glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), were found in the PHED group offspring rats compared to the control group offspring rats. HE staining showed the liver cells in the control group offspring rats showed normal histopathological appearance, such as well-aligned cell patterning and unchanged cellular structure, but in the PHED group offspring rats showed slight structure deformation and misalignment. HO-1 mRNA in PHED group offspring rats is significantly higher than that in the control group offspring rats. Also, the expression of COX-2 and p-NF-kappaB-p65 in PHED group offspring rat liver is 72% and 38% higher than in the control group offspring rat liver, respectively. Expression of NF-kappaB-p65 in PHED group offspring rats is also significantly higher than that in the control group offspring rats. CONCLUSIONS: Palatable high-energy intake of obesity pregnant rats could lead to reduced antioxidant function in offspring rat liver, even increase the chance of chronical liver disease in the early ages of offsprings. The underlying mechanism is associated with the activity of NF-kappaB protein. PMID- 29762855 TI - Real world treatment practice in patients with advanced melanoma in the nivolumab era: five novel Italian case reports and a literature review. AB - OBJECTIVE: The approval of the anti-PD1 antibody nivolumab has provided a significant therapeutic opportunity in the landscape of metastatic melanoma. In pivotal clinical trials, nivolumab improved clinical outcomes with a great safety profile. However, in real-world practice, the majority of the population with metastatic melanoma does meet one or more eligibility criteria of pivotal trials, since they have an ECOG-PS >= 2 or active/untreated known brain metastases. Waiting for larger real-wold studies that are currently lacking, but would be crucial to confirm the efficacy of nivolumab in challenging patients and to detect rare adverse events that could not be noticed in pivotal trials, this review collects both literature and unpublished case reports on nivolumab treatment in metastatic melanoma. PATIENTS AND METHODS: Case reports, published from 2016 to February 2018, and five, unpublished case reports, representative of Italian clinical practice, were reported and potential issues that physicians could face with the use of nivolumab in the real world were discussed. RESULTS: Among Italian cases, one patient had a huge retro-nuchal mass, which significantly decreased with few cycles of nivolumab; two patients were affected by cardiovascular comorbidities and one had brain metastasis; the last had a long history of disease, firstly diagnosed in 1997. A literature review was mainly focused on the experience in the management of rare immune adverse events related to treatment. CONCLUSIONS: Nivolumab confirmed its efficacy and safety in real world; the decision-making process on starting and scheduling the treatment, even in the management of adverse events, should consider multiple factors related to both patient (i.e., BRAF status, ECOG PS, comorbidities) and disease (burden, metastasis). PMID- 29762856 TI - Vitamin D: a steroid hormone with progesterone-like activity. AB - OBJECTIVE: This review is aimed at demonstrating the progesterone-like activity exerted by the active form of vitamin D, or calcitriol (1,25(OH)2D). To achieve this outcome, we compared the effects in vivo and in vitro exerted by progesterone and vitamin D, with a special focus on the female reproductive system and pregnancy. MATERIALS AND METHODS: This is a literature review of the most important articles published in English on vitamin D as a hormone, mainly found by MEDLINE. Furthermore, a section of our review contains some unpublished data, concerning the analysis in silico of the similarities between the steric structure of progesterone and calcitriol, based on the availability of the experimental structures of progesterone and vitamin D3 receptors in complex with their physiological ligands in the RCSB Protein Data Bank. RESULTS: Vitamin D was shown to exert many physiological activities during the very early stages of gestation in perfect synchrony with progesterone. Both the molecules mutually help and reinforce the activity exerted by each one. A little bit later than progesterone is released, vitamin D secretion rises, but only if pregnancy occurs. Calcitriol contributes to prepare the endometrium to be receptive. Moreover, it supports the implantation process and the course of pregnancy through different but similar pathways to those used by progesterone, giving rise to a significant synergy of action. It is increasingly evident that vitamin D gives an essential support from the luteal phase onwards. CONCLUSIONS: Based on the evidence displayed in this review we may define appropriately vitamin D as a steroid hormone with progesterone-like activity. PMID- 29762857 TI - Inhibition effects of acridone on the growth of breast cancer cells in vivo. AB - OBJECTIVE: To investigate the anti-tumor effect of acridone against breast cancer in vivo and provide a therapeutic agent for treatment of breast cancer. MATERIALS AND METHODS: The nude mice xenografted tumor model was established by MCF-7 cells. The mice were randomly divided into four groups. The mice in each group (n=6) were intraperitoneally injected with 0.1 mg/kg saline (low-dose), 0.5 mg/kg (middle-dose) and 1.0 mg/kg (high-dose) of acridone for 21 days, respectively. At the end of the animal experiment, the weight of tumors was recorded to calculate the tumor inhibition rate. The serum hormone levels in peripheral blood were determined using ELISA. Hematoxylin and eosin (HE) staining was used to analyze the histopathological changes. The expression of ABCG2 protein and mRNA were determined by Western blot and RT-PCR, respectively. RESULTS: The inhibition rates of tumor growth in the high-dose, middle-dose, and low-dose groups were 29.18%, 17.21%, and 4.27%, respectively. Compared with control and low-dose group, the tumors growth rate in high-dose and middle-dose groups were decreased significantly. Histologically, the tumors were inhibited in the growth rate, the tissue structure was broken. Estrogen in all groups with acridone treatment decreased, the progesterone in high-dose and middle-dose groups increased remarkably. The expression of ABCG2 protein and ABCG2 mRNA decreased after treatment with acridone. CONCLUSIONS: We showed that acridone could induce cell apoptosis, inhibited ABCG2 (ATP-binding cassette sub-family G member 2) protein and adjusted hormone level. The results suggested that acridone could serve as a chemotherapeutic agent for treatment of breast cancer in vivo. PMID- 29762858 TI - Evaluation of cardiovascular risk profile: a comparative analysis between CUORE algorithm and the Framingham risk scores. AB - OBJECTIVE: Coronary heart diseases (CHD) are the leading cause of premature death and loss of disability adjusted life years in Europe. In order to implement appropriate health interventions as preventive tools, it is necessary to understand the epidemiological stratification of cardiovascular risk and the specific situation of each individual reality. This study investigates the reliability of two algorithms used to assess cardiovascular risk: the Framingham algorithm and the CUORE algorithm. PATIENTS AND METHODS: Data specific on patients of General Practitioners working in the Province of Rome were considered, and a total of 996 subjects of both genders were evaluated. The goodness of fit of the regression model was evaluated using the R2 value. RESULTS: The inferential analysis showed that the R2 value of the simple linear regression between CHD risk calculated according to the CUORE method (dependent variable) and CHD risk calculated according the Framingham method (independent variable), was initially equal to 0.350, and rose to 0.732 when the independent variables "Gender" and "Age" were added, thereby creating a multivariate regression. The R2 of the multivariate regression was 0.478 when using CHD Framingham as the dependent variable and CHD CUORE as the independent variable. CONCLUSIONS: It emerged that the CUORE score was less reliable than the Framingham risk score; in fact, in the multiple linear regression model, the coefficient of determination was greater when the independent variable was the Framingham scale for CHD risk. PMID- 29762859 TI - Meta-analyses on intra-aortic balloon pump in cardiogenic shock complicating acute myocardial infarction may provide biased results. AB - OBJECTIVE: Intra-aortic balloon pump (IABP) is the device most commonly investigated in patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI). Recently meta-analyses on this topic showed opposite results: some complied with the actual guideline recommendations, while others did not, due to the presence of bias. We investigated the reasons for the discrepancy among meta-analyses and strategies employed to avoid the potential source of bias. MATERIALS AND METHODS: Scientific databases were searched for meta-analyses of IABP support in AMI complicated by CS. The presence of clinical diversity, methodological diversity and statistical heterogeneity were analyzed. When we found clinical or methodological diversity, we reanalyzed the data by comparing the patients selected for homogeneous groups. When the fixed effect model was employed despite the presence of statistical heterogeneity, the meta analysis was repeated adopting the random effect model, with the same estimator used in the original meta-analysis. RESULTS: Twelve meta-analysis were selected. Six meta-analyses of randomized controlled trials (RCTs) were inconclusive because underpowered to detect the IABP effect. Five included RCTs and observational studies (Obs) and one only Obs. Some meta-analyses on RCTs and Obs had biased results due to presence of clinical and/or methodological diversity. The reanalysis of data reallocated for homogeneous groups was no more in contrast with guidelines recommendations. CONCLUSIONS: Meta-analyses performed without controlling for clinical and/or methodological diversity, represent a confounding message against a good clinical practice. The reanalysis of data demonstrates the validity of the current guidelines recommendations in addressing clinical decision making in providing IABP support in AMI complicated by CS. PMID- 29762860 TI - New pathogens, new tricks: emerging, drug-resistant fungal pathogens and future prospects for antifungal therapeutics. AB - Fungal pathogens are a growing threat to public health. As human immunodeficiency becomes increasingly common, fungal infections are becoming more prevalent. The use of antifungal agents for prophylaxis and treatment of fungal infections has favored the emergence of previously rare or unidentified species of drug resistant fungal pathogens, including several Candida and Cryptococcus species, as well as mold pathogens. As these new and increasingly drug-resistant fungal pathogens continue to emerge, novel strategies for rapid identification and treatment are necessary to combat these life-threatening infections. PMID- 29762861 TI - Pharmacokinetic/Pharmacodynamic Analysis of Isavuconazole Against Aspergillus spp. and Candida spp. in Healthy Subjects and Patients With Hepatic or Renal Impairment by Monte Carlo Simulation. AB - The aim of this pharmacokinetic/pharmacodynamic (PK/PD) study is to evaluate the efficacy of various isavuconazole dosing regimens for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamics (PD) data to determine the probabilities of target attainment and cumulative fractions of response in terms of area under the concentration curve/minimum inhibition concentration (AUC/MIC) targets of isavuconazole. A clinically recommended dosage regimen of isavuconazole (200 mg qd) obtained high cumulative fraction of response values of > 90% for all subjects against A. fumigatus, A. flavus, A. nidulans, A. terreus, A. versicolor, C. parapsilosis and C. tropicalis. For patients with mild or moderate hepatic impairment, the dosage should be halved only when treating invasive fungal infections caused by C. albicans, C. parapsilosis or C. tropicalis. However, dose adjustment is unlikely to be required in mild to severe renal impairment patients because all cumulative fraction of response values were similar to those of comparing with healthy subjects. Notably, all isavuconazole dosing regimens were not effective against C. glabrata and C. krusei in all subjects. These PK/PD based simulations rationalize and optimize the dosage regimens of isavuconazole for healthy individuals and patients with hepatic or renal impairment against Aspergillus spp. and Candida spp. PMID- 29762862 TI - Stress and the psyche-brain-immune network in psychiatric diseases based on psychoneuroendocrineimmunology: a concise review. AB - In the last decades, psychoneuroendocrineimmunology research has made relevant contributions to the fields of neuroscience, psychobiology, epigenetics, molecular biology, and clinical research by studying the effect of stress on human health and highlighting the close interrelations between psyche, brain, and bodily systems. It is now well recognized that chronic stress can alter the physiological cross-talk between brain and biological systems, leading to long lasting maladaptive effects (allostatic overload) on the nervous, immune, endocrine, and metabolic systems, which compromises stress resiliency and health. Stressful conditions in early life have been associated with profound alterations in cortical and subcortical brain regions involved in emotion regulation and the salience network, showing relevant overlap with different psychiatric conditions. This paper provides a summary of the available literature concerning the notable effects of stress on the brain and immune system. We highlight the role of epigenetics as a mechanistic pathway mediating the influences of the social and physical environment on brain structure and connectivity, the immune system, and psycho-physical health in psychiatric diseases. We also summarize the evidence regarding the effects of stress management techniques (mainly psychotherapy and meditation practice) on clinical outcomes, brain neurocircuitry, and immune inflammatory network in major psychiatric diseases. PMID- 29762863 TI - Objective physical activity levels in people with multiple sclerosis: Meta analysis. AB - To quantify physical activity (PA) levels in people with multiple sclerosis (pwMS) using objective measurement and to establish using a meta-analytical approach if pwMS are less active than the general population. A systematic search of eight databases was conducted. Cohort and intervention studies which included an objective measure of PA were included. Objective PA outputs of steps per day and minutes of moderate-vigorous activity (MVPA) per day were extracted from the MS studies and the published NHANES dataset. Meta-analysis was used to compare the differences between the groups for these parametric outcomes. A general population sample from the National Health and Nutritional Examination Survey (NHANES) in the United States of America was used as a comparative group. The systematic search resulted in 32 papers (n = 2 randomized control trials, n = 30 cohort studies). A total of 3 762 pwMS were included. The sample was largely female (n = 3 118, 82.8%) and ambulatory with/without use of an aid (n = 31 studies). There were significant differences between the MS and the published NHANES comparative group with respect to 1) steps per day [mean difference: -3845 (-4120.17, -3569.83), P < .0001, n = 10 studies] and 2) minutes of MVPA per day [mean difference: 9.00 (-12.5, -5.4), P < .0001, n = 3 studies], indicating pwMS are less physically active than the NHANES sample. Results suggest that pwMS are less physically active than a general population across PA outputs of steps per day and minutes of MVPA per day. There is a need to increase PA levels among pwMS. PMID- 29762864 TI - Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD. AB - A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 MUg/62.5 MUg/25 MUg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 MUg/12 MUg; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol). PMID- 29762865 TI - Population Pharmacokinetics of Vancomycin in Patients Undergoing Allogeneic Hematopoietic Stem-Cell Transplantation. AB - Vancomycin is a commonly used antimicrobial agent for patients undergoing allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Vancomycin has large inter- and intraindividual pharmacokinetic variability, which is mainly described by renal function; various studies have indicated that vancomycin pharmacokinetics are altered in special populations. However, little is known regarding vancomycin pharmacokinetics in patients undergoing allo-HSCT. Therefore, we aimed to develop a population pharmacokinetic (PopPK) model of vancomycin in patients undergoing allo-HSCT for effective and safe antimicrobial therapy and to develop a vancomycin dosing nomogram for a vancomycin optimal dosing strategy. In total, 285 observations from 95 patients undergoing allo-HSCT were available. The final PopPK parameter estimates were central volume of distribution (V1, L), 39.2; clearance (L/h), 4.25; peripheral volume of distribution (V2, L), 56.1; and intercompartmental clearance (L/h), 1.95. The developed vancomycin model revealed an increase in V1 and V2 compared with those in the general population that consisted of patients with methicillin-resistant Staphylococcus aureus. Moreover, serum creatinine was reduced because of an increase in the plasma fraction because of destruction of hematopoietic stem cells accompanying allo-HSCT pretreatment, suggesting that the Cockcroft-Gault equation-based creatinine clearance value was overestimated. To our knowledge, this is the first PopPK study to develop a dosing nomogram for vancomycin in patients undergoing allo-HSCT and was proven to be useful in optimizing the dosage and dosing interval of vancomycin in these patients. This strategy will provide more useful information for vancomycin therapy with an evidence-based dose adjustment. PMID- 29762867 TI - Shaping memory consolidation via targeted memory reactivation during sleep. AB - Recent studies have shown that the reactivation of specific memories during sleep can be modulated using external stimulation. Specifically, it has been reported that matching a sensory stimulus (e.g., odor or sound cue) with target information (e.g., pairs of words, pictures, and motor sequences) during wakefulness, and then presenting the cue alone during sleep, facilitates memory of the target information. Thus, presenting learned cues while asleep may reactivate related declarative, procedural, and emotional material, and facilitate the neurophysiological processes underpinning memory consolidation in humans. This paradigm, which has been named targeted memory reactivation, has been successfully used to improve visuospatial and verbal memories, strengthen motor skills, modify implicit social biases, and enhance fear extinction. However, these studies also show that results depend on the type of memory investigated, the task employed, the sensory cue used, and the specific sleep stage of stimulation. Here, we present a review of how memory consolidation may be shaped using noninvasive sensory stimulation during sleep. PMID- 29762868 TI - Candidemia in children: Epidemiology, prevention and management. AB - Candidemia is the leading cause of invasive fungal infections in hospitalised children. The highest rates of candidemia have been recorded in neonates and infants <1 year of age. Candidemia is more frequent in neonates and young infants than in adults, and is associated with better clinical outcomes, but higher inpatient costs. Over the last 10 years, a declining trend has been noted in the incidence of paediatric candidemia in the US and elsewhere due to the hospital wide implementation of central-line insertion and maintenance bundles that emphasise full sterile barrier precautions, chlorhexidine skin preparation during line insertion, meticulous site and tubing care, and daily discussion of catheter necessity. Additional interventions aiming at reducing gut-associated candidemia are required in immunocompromised and critically ill children. PMID- 29762869 TI - The organisation of critical care for burn patients in the UK: epidemiology and comparison of mortality prediction models. AB - In the UK, a network of specialist centres has been set up to provide critical care for burn patients. However, some burn patients are admitted to general intensive care units. Little is known about the casemix of these patients and how it compares with patients in specialist burn centres. It is not known whether burn-specific or generic risk prediction models perform better when applied to patients managed in intensive care units. We examined admissions for burns in the Case Mix Programme Database from April 2010 to March 2016. The casemix, activity and outcome in general and specialist burn intensive care units were compared and the fit of two burn-specific risk prediction models (revised Baux and Belgian Outcome in Burn Injury models) and one generic model (Intensive Care National Audit and Research Centre model) were compared. Patients in burn intensive care units had more extensive injuries compared with patients in general intensive care units (median (IQR [range]) burn surface area 16 (7-32 [0-98])% vs. 8 (1-18 [0-100])%, respectively) but in-hospital mortality was similar (22.8% vs. 19.0%, respectively). The discrimination and calibration of the generic Intensive Care National Audit and Research Centre model was superior to the revised Baux and Belgian Outcome in Burn Injury burn-specific models for patients managed on both specialist burn and general intensive care units. PMID- 29762870 TI - T cells and ILC2s are major effector cells in influenza-induced exacerbation of allergic airway inflammation in mice. AB - Influenza virus infection is an important cause of severe asthma exacerbations, but it remains unclear how a Th1-mediated antiviral response triggers a prototypical Th2 disease. We investigated CD4+ T cells and group 2 innate lymphoid cells (ILC2s) in influenza virus-infected mice. We found that ILC2s accumulated in the lung rapidly after influenza virus infection, but the induction of IL-5 and IL-13 secretion was delayed and concomitant with T cell activation. In an influenza-induced exacerbation of allergic airway inflammation model we noticed an initial reduction of ILC2 numbers and cytokine production in broncho-alveolar lavage compared to chronic house dust mite (HDM)-mediated airway inflammation alone. ILC2s phenotype was characterized by low T1/ST2, ICOS, KLRG1, and CD25 expression, resembling naive ILC2s. The contribution of ILC2s to type 2 cytokine production in the early stage of the influenza-induced exacerbation was limited. In contrast, T cells showed increased IL-4 and IL-5 production when exposed to both HDM and influenza virus. Upon virus clearance, ILC2s regained an activated T1/ST2high ICOShigh KLRG1high CD25high phenotype paired with cytokine production and were major contributors to the type 2 cytokine milieu. Collectively, our data indicate that both T cells and ILC2s contribute to influenza-induced exacerbation of allergic airway inflammation, but with different kinetics. PMID- 29762866 TI - Obesity as an immune-modifying factor in cancer immunotherapy. AB - Immunotherapy has achieved breakthrough status in many advanced stage malignancies and is rapidly becoming the fourth arm of cancer treatment. Although cancer immunotherapy has generated significant excitement because of the potential for complete and sometimes durable responses, there is also the potential for severe and occasionally life-threatening toxicities, including cytokine release syndrome and severe autoimmunity. A large body of work also points to a "metainflammatory" state in obesity associated with impairment of immune responses. Because immune checkpoint blockade (and other cancer immunotherapies) have altered the landscape of immunotherapy in cancer, it is important to understand how immune responses are shaped by obesity and how obesity may modify both immunotherapy responses and potential toxicities. PMID- 29762871 TI - Fast identification of dermatophytes by MALDI-TOF/MS using direct transfer of fungal cells on ground steel target plates. AB - Dermatophytes cause human infections limited to keratinised tissues. We showed that the direct transfer method allows reliable identification of non dermatophytes mould and yeast by MALDI-TOF/MS. We aimed at assessing whether the direct transfer method can be used for dermatophytes and whether an own mass spectra library would be superior to the Bruker library. We used the Bruker Biotyper to build a dermatophyte mass spectra library and assessed its performance by 1/testing a panel of mass spectrum produced with strains genotypically identified and, 2/comparing MALDI-TOF/MS identification to morphology-based methods. Identification of dermatophytes using the Bruker library is poor. Our library provided 97% concordance between ITS sequencing and MALDI-TOF/MS analysis with a panel of 1104 spectra corresponding to 276 strains. Direct transfer method using unpolished target plates allowed proper identification of 85% of dermatophytes clinical isolates most of which were common dermatophytes. A homemade dermatophyte MSP library is a prerequisite for accurate identification of species absent in the Bruker library but it also improves identification of species already listed in the database. The direct deposit method can be used to identify the most commonly found dermatophytes such as T. rubrum and T. interdigitale/mentagrophytes by MALDI-TOF/MS. PMID- 29762872 TI - The Effect of OnabotulinumtoxinA on Aura Frequency and Severity in Patients With Hemiplegic Migraine: Case Series of 11 Patients. AB - BACKGROUND: OnabotulinumtoxinA has been demonstrated to be effective for the preventive treatment of headache in individuals with chronic migraine and has been approved and recommended for this patient population. While the therapeutic effect of onabotulinumtoxinA on migraine headache is well documented, there is limited information on the effect of onabotulinumtoxinA on migraine aura. OBJECTIVE: Given the prolonged and often debilitating nature of aura in patients with hemiplegic migraine, our group sought to examine the effect of onabotulinumtoxinA on aura frequency and severity in this specific subset of migraine patients. METHODS: All clinical notes from July 1, 1994 to December 1, 2017 at our institution were retrospectively reviewed to identify patients diagnosed with hemiplegic migraine who received at least one set of onabotulinumtoxinA injections. Thirty-four patients were identified; and of those, 23 were excluded due to incomplete documentation regarding aura symptoms at follow-up visits. The clinical notes of the remaining 11 patients (4 with familial hemiplegic migraine [FHM] and 7 with sporadic hemiplegic migraine [SHM]) were reviewed, and the frequency and description of their headaches and aura before and after receiving onabotulinumtoxinA were recorded. RESULTS: Nine of the 11 patients in our series noted a decrease in the frequency, severity, and/or duration of their aura after receiving onabotulinumtoxinA. Of the 2 non responders, one was FHM and one was SHM. Of the 9 that noticed improved aura symptoms, 6 described a "wearing off" effect of onabotulinumtoxinA around week 9 or 10 of the 12-week cycle, with subsequent improvement after the next round. CONCLUSION: For 9 of 11 patients with hemiplegic migraine, onabotulinumtoxinA was helpful not only in reducing the frequency and severity of headaches but also in reducing the frequency and severity of the aura. In this manuscript, we speculate on potential pathophysiologic mechanisms that could have contributed to this effect. PMID- 29762874 TI - Direct manipulation of metallic nanosheets by shear force microscopy. AB - Micro/nanomanipulation is a rapidly growing technology and holds promising applications in various fields, including photonic/electronic devices, chemical/biosensors etc. In this work, we present that shear force microscopy (ShFM) can be exploited to manipulate metallic nanosheets besides imaging. The manipulation is realized via controlling the shear force sensor probe position and shear force magnitude based on our homemade ShFM system under an optical microscopy for in situ observation. The main feature of the ShFM system is usage of a piezoelectric bimorph sensor, which has the ability of self-excitation and detection. Moreover, the shear force magnitude as a function of the spring constant of the sensor and setpoint is obtained, which indicates that operation modes can be switched between imaging and manipulation through designing the spring constant before experiment and changing the setpoint during manipulation process, respectively. We believe that this alternative manipulation technique could be used to assemble other nanostructures with different shapes, sizes and compositions for new properties and wider applications. PMID- 29762873 TI - L-ornithine L-aspartate for prevention and treatment of hepatic encephalopathy in people with cirrhosis. AB - BACKGROUND: Hepatic encephalopathy is a common complication of cirrhosis and has high associated morbidity and mortality. The condition is classified as overt if it is clinically apparent or minimal if only evident though psychometric testing. The exact pathogenesis of this syndrome is unknown although ammonia is thought to play a key role. L-ornithine L-aspartate has ammonia-lowering properties and may, therefore, benefit people with cirrhosis and hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of L-ornithine L-aspartate versus placebo, no intervention, or other active interventions in people with cirrhosis and hepatic encephalopathy. SEARCH METHODS: We undertook electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS and Science Citation Index Expanded to December 2017 and manual searches of meetings and conference proceedings; checks of bibliographies; and corresponded with investigators and pharmaceutical companies. SELECTION CRITERIA: We included randomised clinical trials, irrespective of publication status, language, or blinding. We included participants with cirrhosis who had minimal or overt hepatic encephalopathy or who were at risk for developing hepatic encephalopathy. We compared: L-ornithine L-aspartate versus placebo or no intervention; and L-ornithine L-aspartate versus other active agents such as non absorbable disaccharides, antibiotics, probiotics, or branched-chain amino acids. DATA COLLECTION AND ANALYSIS: Two review authors, working independently, retrieved data from published reports and correspondence with investigators and pharmaceutical companies. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We undertook meta-analyses and presented the results as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed bias control using the Cochrane Hepato Biliary Group domains; we evaluated the risk of publication bias and other small trial effects in regression analyses; conducted subgroup and sensitivity analyses; and performed Trial Sequential Analyses. We determined the quality of the evidence using GRADE. MAIN RESULTS: We identified 36 randomised clinical trials, involving at least 2377 registered participants, which fulfilled our inclusion criteria including 10 unpublished randomised clinical trials. However, we were only able to access outcome data from 29 trials involving 1891 participants. Five of the included trials assessed prevention, while 31 trials assessed treatment. Five trials were at low risk of bias in the overall assessment of mortality; one trial was at low risk of bias in the assessment of the remaining outcomes.L-ornithine L-aspartate had a beneficial effect on mortality compared with placebo or no intervention when including all trials (RR 0.42, 95% CI 0.24 to 0.72; I2 = 0%; 19 trials; 1489 participants; very low quality evidence), but not when the analysis was restricted to the trials at low risk of bias (RR 0.47, 95% CI 0.06 to 3.58; 4 trials; 244 participants). It had a beneficial effect on hepatic encephalopathy compared with placebo or no intervention when including all trials (RR 0.70, 95% CI 0.59 to 0.83; 22 trials; 1375 participants; I2 = 62%; very low quality evidence), but not in the one trial at low risk of bias (RR 0.96, 95% CI 0.85 to 1.07; 63 participants). The analysis of serious adverse events showed a potential benefit of L-ornithine L-aspartate when including all randomised clinical trials (RR 0.63, 95% CI 0.45 to 0.90; 1 trial; 1489 participants; I2 = 0%; very low quality evidence), but not in the one trial at low risk of bias for this outcome (RR 0.83, 95% CI 0.15 to 4.65; 63 participants). The Trial Sequential Analyses of mortality, hepatic encephalopathy, and serious adverse events found insufficient evidence to support or refute beneficial effects. Subgroup analyses showed no difference in outcomes in the trials evaluating evaluating the prevention or treatment of either overt or minimal hepatic encephalopathy or trials evaluating oral versus intravenous administration We were unable to undertake a meta-analysis of the three trials involving 288 participants evaluating health-related quality of life. Overall, we found no difference between L-ornithine L-aspartate and placebo or no intervention in non-serious adverse events (RR 1.15, 95% CI 0.75 to 1.77; 14 trials; 1076 participants; I2 = 40%). In comparison with lactulose, L-ornithine L aspartate had no effect on mortality (RR 0.68, 95% CI 0.11 to 4.17; 4 trials; 175 participants; I2 = 0%); hepatic encephalopathy (RR 1.13, 95% CI 0.81 to 1.57); serious adverse events (RR 0.69, 95% CI 0.22 to 2.11); or non-serious adverse events (RR 0.05, 95% CI 0.01 to 0.18). In comparison with probiotics, L-ornithine L-aspartate had no effect on mortality (RR 1.01, 95% CI 0.11 to 9.51); serious adverse events (RR 1.07, 95% CI 0.23 to 4.88); or changes in blood ammonia concentrations from baseline (RR -2.30 95% CI -6.08 to 1.48), but it had a possible beneficial effect on hepatic encephalopathy (RR 0.71, 95% CI 0.56 to 0.90). Finally, in comparison with rifaximin, L-ornithine L-aspartate had no effect on mortality (RR 0.33, 95% CI 0.04 to 3.03; 2 trials; 105 participants); hepatic encephalopathy (RR 1.06, 95% CI 0.57 to 1.96); serious adverse events (RR 0.32, 95% CI 0.01 to 7.42), or non-serious adverse events (RR 0.32, 95% CI 0.01 to 7.42). AUTHORS' CONCLUSIONS: The results of this review suggest a possible beneficial effect of L-ornithine L-aspartate on mortality, hepatic encephalopathy, and serious adverse events in comparisons with placebo or no intervention, but, because the quality of the evidence is very low, we are very uncertain about these findings. There was very low quality evidence of a possible beneficial effect of L-ornithine L-aspartate on hepatic encephalopathy, when compared with probiotics, but no other benefits were demonstrated in comparison with other active agents. Additional access to data from completed, but unpublished trials, and new randomised placebo-controlled, double-blind clinical trials are needed. PMID- 29762876 TI - Constant conflict between Gypsy LTR retrotransposons and CHH methylation within a stress-adapted mangrove genome. AB - The evolutionary dynamics of the conflict between transposable elements (TEs) and their host genome remain elusive. This conflict will be intense in stress-adapted plants as stress can often reactivate TEs. Mangroves reduce TE load convergently in their adaptation to intertidal environments and thus provide a unique opportunity to address the host-TE conflict and its interaction with stress adaptation. Using the mangrove Rhizophora apiculata as a model, we investigated methylation and short interfering RNA (siRNA) targeting patterns in relation to the abundance and age of long terminal repeat (LTR) retrotransposons. We also examined the distance of LTR retrotransposons to genes, the impact on neighboring gene expression and population frequencies. We found differential accumulation amongst classes of LTR retrotransposons despite high overall methylation levels. This can be attributed to 24-nucleotide siRNA-mediated CHH methylation preferentially targeting Gypsy elements, particularly in their LTR regions. Old Gypsy elements possess unusually abundant siRNAs which show cross-mapping to young copies. Gypsy elements appear to be closer to genes and under stronger purifying selection than other classes. Our results suggest a continuous host-TE battle masked by the TE load reduction in R. apiculata. This conflict may enable mangroves, such as R. apiculata, to maintain genetic diversity and thus evolutionary potential during stress adaptation. PMID- 29762875 TI - In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects. AB - Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0 inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers >= 40 to <= 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects. PMID- 29762877 TI - Visualisation of insect tracheal systems by lactic acid immersion. AB - The endeavours to reveal the tracheal system of insects and some arachnids has a long history. The traditional way to observe a tracheal system in an insect body is by utilising the glycerin immersion method. In this study, we developed the lactic acid immersion method, which reveals a more complete tracheal system. By mounting various types of live specimens or body parts directly into lactic acid, multiple intact and complex tracheal systems were clearly visualised. The lactic acid immersion contributed to revealing tracheal systems by penetrating body tissue while reserving enough time for observation before the penetration of the tracheae. Preliminary comparisons were conducted between lactic acid and other mediae, including glycerin. It turned out that lactic acid immersion provides better details and more distinct structures. In our test, the optimal time for observing the tracheal system was 10-25 min after the organism was immersed in lactic acid. PMID- 29762878 TI - Risk of Hypoglycemia After Concomitant Use of Antidiabetic, Antihypertensive, and Antihyperlipidemic Medications: A Database Study. AB - Hypoglycemia is the most important complication of antidiabetic medications. Most patients with diabetes mellitus take multiple medications. In this study, we explored clinical drug-drug interactions that result in hypoglycemia by analyzing the Japanese Adverse Drug Event Report (JADER) database. The primary outcome was the report of hypoglycemia. The Noren and Gosho methods, which quantitatively measure the discrepancy between the observed and expected number of adverse events under the combination of 2 drugs, were used as the criteria for detecting drug-drug interactions. The JADER database contained patient characteristics with 468 292 records, drug information with 2 973 172 records, and adverse reactions with 741 016 records. We noted that hypoglycemia was reported in 6208 patients. Concomitant use of linagliptin/glibenclamide, sitagliptin/glibenclamide, sitagliptin/buformin, exenatide/voglibose, mitiglinide/perindopril, repaglinide/barnidipine, alogliptin/cilnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was noted using the 2 criteria for drug-drug interactions. Concomitant use of teneligliptin and barnidipine produced the highest values for the 2 criteria. The second-and third-highest values were observed for teneligliptin/urapidil and exenatide/candesartan combinations, respectively. The same analysis was performed using the US Food and Drug Administration Adverse Event Reporting System database to assess the validity of the result from the JADER database. The concomitant use of sitagliptin/buformin, exenatide/voglibose, repaglinide/barnidipine, teneligliptin/barnidipine, teneligliptin/urapidil, exenatide/candesartan, voglibose/barnidipine, voglibose/guanabenz, or exenatide/tocopherol was detected in both the JADER and Food and Drug Administration Adverse Event Reporting System databases. Combination therapy with the drugs listed above would show potential interactions that could result in hypoglycemia in patients with diabetes mellitus. PMID- 29762879 TI - Eosinophilic esophagitis: latest insights from diagnosis to therapy. AB - Eosinophilic esophagitis (EoE) represents a chronic, local immune-mediated esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Other systemic and local causes of esophageal eosinophilia should be excluded. Clinical manifestations or pathologic data should not be interpreted in isolation. EoE was first described as a distinct disease entity in 1993. Most patients are diagnosed with underlying food allergies. The first diagnostic and therapeutic guidelines were published in 2007 with a first update in 2011. In 2017, new international guidelines were published based on the GRADE methodology. These guidelines provide, among many other topics, insights on the role of proton pump inhibitor responsive esophageal eosinophilia. Over the last two decades, considerable progress was made by stakeholders regarding the understanding of EoE's pathogenesis, genetic background, natural history, allergy workup, standardization of assessment of disease activity, evaluation of minimally invasive diagnostic tools, and new therapeutic approaches. This brief review provides further insights into latest diagnostic and therapeutic advances. PMID- 29762880 TI - TRIM22 knockdown suppresses chronic myeloid leukemia via inhibiting PI3K/Akt/mTOR signaling pathway. AB - Tripartite motif-containing 22 (TRIM22) is reported to participate in numerous cellular activities. Recent studies confirm that TRIM22 is a target gene for P53, and inhibits clonogenic growth of leukemic U-937 cells. The current study aims to discover the effect of TRIM22 in progression of human chronic myeloid leukemia (CML) and explore the related mechanism. TRIM22 was knocked down by siRNA transfection in CML cell K562. We observed that TRIM22 knockdown decreased proliferation and invasion in K562 cells. TRIM22 knockdown significantly induced cell cycle arrest by regulating the level of CDK4, Cyclin D1, P70S6K, and P53 in K562 cell. Moreover, loss of TRIM22 also promoted apoptosis through modulation of Bcl-2, Bax and active Caspase 3 in K562 cell. Furthermore, we demonstrated that TRIM22 knockdown inhibited the activation of PI3K/Akt/mTOR pathway by decreasing the level of the phosphorylated form p-Akt and p-mTOR in K562 cell. In conclusion, loss of TRIM22 suppresses the progression and invasion of CML through regulation of PI3K/Akt/mTOR pathway, suggesting that TRIM22 might be as a potential target for the treatment strategy of CML. PMID- 29762881 TI - Colchicine, a microtubule-disassembling drug, in the therapy of cardiovascular diseases. AB - Colchicum autumnale, from which colchicine has been isolated more than 100 years ago, has been used as a treatment for pain and swelling for thousands of years. It is one of the few drugs known from that time period whose use has survived to modernity. Over the past decades, advances in the knowledge of (i) cytoskeletal microtubules (MT), and (ii) anti-inflammatory and anti-fibrotic effects of colchicine, a classical MT-disassembling (tubulin-targeting) agent, have led to potential new uses for this very old drug extended beyond acute gouty arthritis and familial Mediterranean fever. Here, in brief, I present the Bulgarian contribution to possible potential of colchicine in the therapy of cardiovascular diseases that has emerged in the early 1970s in the Laboratory of Electron Microscopy, Medical Institute, Varna, Bulgaria, studying the secretory function of vascular smooth muscle cells. From this time onward, low-dose colchicine (0.5 1.0 mg/daily) was increasingly administered orally for therapy of cardiovascular diseases such as acute coronary syndromes, postoperative atrial fibrillation (in cardiac surgery), pericarditis, cardiac hypertrophy-associated heart failure, restenosis after angioplasty, and systemic necrotizing vasculitis. Thus, colchicine might be a new tool in the present therapeutic armamentarium for cardiovascular diseases. It is simply an example of MT-disassembling drugs. Further studies will definitely be required before gaining real confidence in this kind of antitubulin pharmacology and therapy. This may lead to developing new and more specific antitubulins for cardiovascular diseases. PMID- 29762882 TI - The changes in dominant lactic acid bacteria and their metabolites during corn stover ensiling. AB - AIMS: Monitoring the succession of bacterial populations during corn stover ensiling is helpful for improving the silage quality. METHODS AND RESULTS: Fermentation characteristics were assessed and bacterial communities were described along with the ensiling process. The ensiled corn stover exhibited chemical traits, such as low pH value (3.92 +/- 0.02) and high levels of lactic acid (66.75 +/- 1.97 g kg-1 dry matter (DM)), which were associated with well ensiled forages, as well as moderate concentrations of acetic acid (19.69 +/- 1.51 g kg-1 DM) and small amounts of 1,2-propanediol (4.4 +/- 0.11 g kg-1 DM). In the early stages of the ensiling process, a significant increase and then reduction in the abundance of species, Lactococcus lactis, Leuconostoc pseudomesenteroides, Pediococcus pentosaceus and Weissella sp., were observed. The species Lactobacillus plantarum group and Lactobacillus brevis grew vigorously, and the species Lactobacillus farciminis and Lactobacillus parafarraginis gradually increased along with the course of ensiling. CONCLUSIONS: High-throughput sequencing was successfully used to describe bacterial communities throughout the process of corn stover ensiling. SIGNIFICANCE AND IMPACT OF THE STUDY: The knowledge about the ecological succession of the dominant lactic acid bacteria could lead to improved ensiling practices and the selection of corn stover silage inoculants. PMID- 29762884 TI - The use of overnight oximetry in neonates: A literature review. AB - There is much debate between neonatologists and paediatricians about appropriate oxygen saturation targets for babies with chronic neonatal lung disease (CNLD). Overnight oximetry is used to guide the fraction of inspired oxygen to use. We did this literature review to examine the current literature on the use of overnight oximetry in term infants, preterm infants and babies with CNLD (especially relevant to ex-preterm babies with CNLD going home on oxygen). We reviewed the literature from January 1990 to October 2017 by searching the following databases: Cochrane Central Register of Controlled Trials, The Joanna Briggs Institute, CINAHL, MEDLINE, Scopus, EMBASE, ProQuest and Science Direct. Sixteen articles were included in the review. The literature available on overnight oximetry in neonates is limited, it is not contemporary, and it reports studies that did not use oximeters with modern software for data collection and analysis. It is imperative that reference ranges be defined for overnight oximetry parameters so that babies are not inadvertently administered inappropriate amounts of oxygen. PMID- 29762883 TI - Associative bacteria influence maize (Zea mays L.) growth, physiology and root anatomy under different nitrogen levels. AB - Despite the great diversity of plant growth-promoting bacteria (PGPB) with potential to partially replace the use of N fertilisers in agriculture, few PGPB have been explored for the production of commercial inoculants, reinforcing the importance of identifying positive plant-bacteria interactions. Aiming to better understand the influence of PGPB inoculation in plant development, two PGPB species with distant phylogenetic relationship were inoculated in maize. Maize seeds were inoculated with Bacillus sp. or Azospirillum brasilense. After germination, the plants were subjected to two N treatments: full (N+) and limiting (N-) N supply. Then, anatomical, biometric and physiological analyses were performed. Both PGPB species modified the anatomical pattern of roots, as verified by the higher metaxylem vessel element (MVE) number. Bacillus sp. also increased the MVE area in maize roots. Under N+ conditions, both PGPB decreased leaf protein content and led to development of shorter roots; however, Bacillus sp. increased root and shoot dry weight, whereas A. brasilense increased photosynthesis rate and leaf nitrate content. In plants subjected to N limitation (N-), photosynthesis rate and photosystem II efficiency increased in maize inoculated with Bacillus sp., whilst A. brasilense contained higher ammonium, amino acids and total soluble sugars in leaves, compared to the control. Plant developmental and metabolical patterns were switched by the inoculation, regardless of the inoculant bacterium used, producing similar as well as distinct modifications to the parameters studied. These results indicate that even non diazotrophic inoculant strains can improve the plant N status as result of the morpho-anatomical and physiological modifications produced by the PGPB. PMID- 29762885 TI - Influence of chemical and physical conditions in selection of Gluconacetobacter hansenii ATCC 23769 strains with high capacity to produce bacterial cellulose for application as sustained antimicrobial drug-release supports. AB - AIMS: Obtain varieties of Gluconacetobacter hansenii from original strain ATCC 23729 with greater efficiency to produce bacterial cellulose (BC) membrane with better dry mass yield for application as support of sustained antimicrobials' drug release. METHODS AND RESULTS: Application of different chemical and physical conditions (pH, temperature and UV light exposure) to obtain different G. hansenii varieties with high capacity to produce BC membranes. Characterization of the G. hansenii variants was performed by scanning electron microscopy (SEM) and optical microscopy of the colony-forming units. BC membrane produced was characterized by SEM, infrared spectroscopy and X-ray diffraction. The BC produced by variants isolated after incubation at 35 degrees C showed elevated dry mass yield and high capacity of retention and sustained release of ceftriaxone antibiotic with the produced BC by original G. hansenii ATCC 23769 strain subjected to incubation at 28 degrees C and with commercial BC. CONCLUSION: The application of different chemical and physical conditions constitutes an important method to obtain varieties of micro-organisms with dissimilar metabolism advantageous in relation to the original strain in the BC production. SIGNIFICANCE AND IMPACT OF THE STUDY: These results demonstrate the importance of in vivo studies for the application, in medicine, of BC membranes as support for antimicrobial-sustained release for the skin wound treatment. PMID- 29762886 TI - Automatic M1-SO Montage Headgear for Transcranial Direct Current Stimulation (TDCS) Suitable for Home and High-Throughput In-Clinic Applications. AB - OBJECTIVES: Non-invasive transcranial direct current stimulation (tDCS) over the motor cortex is broadly investigated to modulate functional outcomes such as motor function, sleep characteristics, or pain. The most common montages that use two large electrodes (25-35 cm2 ) placed over the area of motor cortex and contralateral supraorbital region (M1-SO montages) require precise measurements, usually using the 10-20 EEG system, which is cumbersome in clinics and not suitable for applications by patients at home. The objective was to develop and test novel headgear allowing for reproduction of the M1-SO montage without the 10 20 EEG measurements, neuronavigation, or TMS. MATERIALS AND METHODS: Points C3/C4 of the 10-20 EEG system is the conventional reference for the M1 electrode. The headgear was designed using an orthogonal, fixed-angle approach for connection of frontal and coronal headgear components. The headgear prototype was evaluated for accuracy and replicability of the M1 electrode position in 600 repeated measurements compared to manually determined C3 in 30 volunteers. Computational modeling was used to estimate brain current flow at the mean and maximum recorded electrode placement deviations from C3. RESULTS: The headgear includes navigational points for accurate placement and assemblies to hold electrodes in the M1-SO position without measurement by the user. Repeated measurements indicated accuracy and replicability of the electrode position: the mean [SD] deviation of the M1 electrode (size 5 * 5 cm) from C3 was 1.57 [1.51] mm, median 1 mm. Computational modeling suggests that the potential deviation from C3 does not produce a significant change in brain current flow. CONCLUSIONS: The novel approach to M1-SO montage using a fixed-angle headgear not requiring measurements by patients or caregivers facilitates tDCS studies in home settings and can replace cumbersome C3 measurements for clinical tDCS applications. PMID- 29762887 TI - The underreporting of medication errors: A retrospective and comparative root cause analysis in an acute mental health unit over a 3-year period. AB - Medication errors remain a commonly reported clinical incident in health care as highlighted by the World Health Organization's focus to reduce medication-related harm. This retrospective quantitative analysis examined medication errors reported by staff using an electronic Clinical Incident Management System (CIMS) during a 3-year period from April 2014 to April 2017 at a metropolitan mental health ward in Western Australia. The aim of the project was to identify types of medication errors and the context in which they occur and to consider recourse so that medication errors can be reduced. Data were retrieved from the Clinical Incident Management System database and concerned medication incidents from categorized tiers within the system. Areas requiring improvement were identified, and the quality of the documented data captured in the database was reviewed for themes pertaining to medication errors. Content analysis provided insight into the following issues: (i) frequency of problem, (ii) when the problem was detected, and (iii) characteristics of the error (classification of drug/s, where the error occurred, what time the error occurred, what day of the week it occurred, and patient outcome). Data were compared to the state-wide results published in the Your Safety in Our Hands (2016) report. Results indicated several areas upon which quality improvement activities could be focused. These include the following: structural changes; changes to policy and practice; changes to individual responsibilities; improving workplace culture to counteract underreporting of medication errors; and improvement in safety and quality administration of medications within a mental health setting. PMID- 29762888 TI - Employing Theories Far beyond Their Limits - Linear Dichroism Theory. AB - Using linear polarized light, it is possible in case of ordered structures, such as stretched polymers or single crystals, to determine the orientation of the transition moments of electronic and vibrational transitions. This not only helps to resolve overlapping bands, but also assigning the symmetry species of the transitions and to elucidate the structure. To perform spectral evaluation quantitatively, a sometimes "Linear Dichroism Theory" called approach is very often used. This approach links the relative orientation of the transition moment and polarization direction to the quantity absorbance. This linkage is highly questionable for several reasons. First of all, absorbance is a quantity that is by its definition not compatible with Maxwell's equations. Furthermore, absorbance seems not to be the quantity which is generally compatible with linear dichroism theory. In addition, linear dichroism theory disregards that it is not only the angle between transition moment and polarization direction, but also the angle between sample surface and transition moment, that influences band shape and intensity. Accordingly, the often invoked "magic angle" has never existed and the orientation distribution influences spectra to a much higher degree than if linear dichroism theory would hold strictly. A last point that is completely ignored by linear dichroism theory is the fact that partially oriented or randomly-oriented samples usually consist of ordered domains. It is their size relative to the wavelength of light that can also greatly influence a spectrum. All these findings can help to elucidate orientation to a much higher degree by optical methods than currently thought possible by the users of linear dichroism theory. Hence, it is the goal of this contribution to point out these shortcomings of linear dichroism theory to its users to stimulate efforts to overcome the long-lasting stagnation of this important field. PMID- 29762889 TI - Endothelial cell density and characterization of corneal endothelial cells in the Tawny Owl (Strix aluco) using specular microscopy. AB - OBJECTIVE: To determine endothelial cell density (ECD) and morphology and morphometry of corneal endothelial cells in the tawny owl (Strix aluco), as well as to report the effects of aging on these parameters. ANIMAL STUDY AND PROCEDURES: Twenty tawny owls were included in the study and classified into 2 groups according to their age: fledglings (<1 year old) and adults (>1 year old). Central corneal endothelium was studied by means of noncontact specular microscopy (Specular Microscope SP-2000P; Topcon, Tokyo, Japan), and results for ECD (cells/mm2 ), mean cell area ((MCA (MUm2 )), polymegathism (CV), and pleomorphism (% hexagonal cells) were obtained. Results are described by median, interquartile range (25th, 75th percentiles), and absolute range for ECD, MCA, pleomorphism, and polymegathism. In addition, inferential analyses by Mann Whitney U test were also performed. A two-tailed Type I error of 5% was established. RESULTS: Results in fledglings were as follows: ECD = 2864 cells/mm2 , MCA = 348 MUm2 , % hexagonal cells = 72.75%, and CV = 21. Results in adults were as follows: ECD = 2602 cells/mm2 , MCA = 384 MUm2 , % hexagonal cells = 78.83%, and CV = 16. No significant differences in ECD and MCA were seen between the groups (P > .05), although there were significant differences in % hexagonal cells and CV (P < .05). CONCLUSIONS: Tawny owls present a uniform endothelium in cell size and shape, although ECD and MCA differ greatly from other bird species. Differences in ECD and MCA could not be found between fledglings and adults probably because of the youth of adult specimens, although there were differences in pleomorphism and polymegathism. PMID- 29762890 TI - Synthesis and Characterization of 4-(1,2,4-Triazole-5-yl)furazan Derivatives as High-Performance Insensitive Energetic Materials. AB - 3-Nitro-4-(5-nitro-1,2,4-triazol-3-yl)furazan (2), N,N'-bis(trinitroethyl)-3,5' diamino-4-(1,2,4-triazol-3-yl)furazan (3), N,N'-bis(trinitroethyl)-3,5' dinitramino-4-(1,2,4-triazol-3-yl)furazan (4) and eighteen nitrogen-rich salts (5 a, 5 b, 5 d-5 i, 5 g-1, 6 a-6 i) were designed and synthesized. These 4-(1,2,4 triazole-5-yl)furazan derivatives were fully characterized by IR and NMR spectra, elemental analysis, and differential scanning calorimetry (DSC). The solid-state structures of 2, 5 d, 5 e, 5 h, 5 g-1, 6 g, and 6 i were confirmed via single crystal X-ray analysis. Detonation performance (detonation velocities and pressures) of these energetic compounds was evaluated and the impact and friction sensitivities were measured using standard BAM technology. Some of the compounds, for example, 2 (D: 9152 m s-1 , P=37.1 GPa) and 4 (D: 9355 m s-1 , P=40.1 GPa) exhibit excellent detonation performance, which are comparable to the highly explosive benchmarks such as RDX (D: 8795 m s-1 , P=34.9 GPa) and HMX (D: 9144 m s-1 , P=39.2 GPa). PMID- 29762891 TI - Assistants in nursing working with mental health consumers in the emergency department. AB - Nursing students, regardless of setting, require skills in working with people with mental health issues. One way to provide students with learning opportunities within the context of limited undergraduate mental health content and lack of mental health placements is through employment as assistants in nursing (AIN). The purpose of the study was to investigate the use of AINs employed in an emergency department in South Australia to supervise (continuous observation) mental health consumers on inpatient treatment orders. Twenty-four participants took part in the study, with AINs (n = 8, all studying in an undergraduate nursing programme), nurse managers (n = 5), and nurses (n = 11) participating in semi-structured interviews. Data were analysed using thematic analysis. Themes focused on (i) the AIN role, their practice, boundaries or restrictions of their role, and the image consumers have of AINs; (ii) learning through experience, where the AIN role was a practical opportunity to learn and apply knowledge obtained through university studies; and (iii) support, which focused on how AINs worked with nursing staff as part of the healthcare team. Overall, participants believed that AINs played an important role in the ED in supervising consumers on involuntary mental health treatment orders, where their unique role was seen to facilitate more positive consumer experiences. The AIN role is one way for nursing students to develop skills in working with people with mental health issues. PMID- 29762892 TI - Understanding the Chemical Reactivity of Phosphonium-Based Ionic Liquids with Tellurium. AB - The chemical reactivity of phosphonium based ionic liquids (ILs) towards tellurium at temperatures above 220 degrees C was systematically investigated by a series of dissolution experiments, tracking the solute tellurium species by nuclear magnetic resonance, and characterizing the reaction products by X-ray diffraction and scanning electron microscopy. The initial step is the thermal elimination of an alkyl group of the phosphonium cation of the ILs, most probably via an SN 2 mechanism. The addition of tellurium follows to form trialkylphosphane tellurides as evidenced by 31 P and 125 Te NMR spectroscopic experiments. The trialkylphosphane tellurides can serve as a tellurium reservoir for the formation of metal tellurides, like Bi2 Te3 and Ag2 Te. It was observed that trihexyltetradecylphosphonium chloride ([P6 6 6 14 ]Cl) shows a very weak reactivity that is reflected by a low solubility of tellurium, while trihexyltetradecylphosphonium dicyanamide/decanoate ([P6 6 6 14 ][N(CN)2 ]/[P6 6 6 14 ][decanoate]) and tetrabutylphosphonium decanoate ([P4 4 4 4 ][decanoate]) dissolve tellurium to a much higher extent. We attribute these observations to the different Lewis basicity of the anions of the ILs as main influencing factor. PMID- 29762893 TI - Retrobulbar vs peribulbar regional anesthesia techniques using bupivacaine in dogs. AB - OBJECTIVE: To compare the effectiveness of retrobulbar anesthesia (RBA) and peribulbar anesthesia (PBA) in dogs. ANIMAL STUDIED: Six adult mixed-breed dogs (18-24 kg). PROCEDURES: In a randomized, masked, crossover trial with a 10-day washout period, each dog was sedated with intravenously administered dexmedetomidine and administered 0.5% bupivacaine:iopamidol (4:1) as RBA (2 mL via a ventrolateral site) or PBA (5 mL divided equally between ventrolateral and dorsomedial sites). The contralateral eye acted as control. Injectate distribution was evaluated by computed tomography. Following intramuscularly administered atipamezole, corneal and periocular skin sensation, intraocular pressure (IOP), and ocular reflexes, and appearance were evaluated for 24 hours. Comparisons were performed with mixed-effects linear regression (IOP) or the exact Wilcoxon signed rank test (scores). Significance was set at P <= .05. RESULTS: Injectate distribution was intraconal in 2/6 RBA- and 4/6 PBA-injected eyes. Eyes undergoing PBA had significantly reduced lateral, ventral, and dorsal periocular skin sensation for 2-3 hours, and significantly reduced corneal sensitivity for 4 hours, relative to control eyes. Chemosis and exophthalmos occurred in 33%-40% of eyes undergoing RBA and 83%-100% eyes undergoing PBA but resolved within 14 hours. Anterior uveitis developed in 2/6 and 1/6 eyes of RBA and PBA, respectively, of them corneal ulcer developed in one eye of each treatment. Both resolved 1-3 days following medical treatment. CONCLUSIONS: Peribulbar injection produced notable anesthesia more reliably than did retrobulbar injection. Both techniques may produce adverse effects, although the uveitis/ulcer could have resulted from the contrast agent used. PMID- 29762894 TI - What is a stem cell? AB - The historical roots of the stem cell concept are traced with respect to its usage in embryology and in hematology. The modern consensus definition of stem cells, comprising both pluripotent stem cells in culture and tissue-specific stem cells in vivo, is explained and explored. Methods for identifying stem cells are discussed with respect to cell surface markers, telomerase, label retention and transplantability, and properties of the stem cell niche are explored. The CreER method for identifying stem cells in vivo is explained, as is evidence in favor of a stochastic rather than an obligate asymmetric form of cell division. In conclusion, it is found that stem cells do not possess any unique and specific molecular markers; and stem cell behavior depends on the environment of the cell as well as the stem cell's intrinsic qualities. Furthermore, the stochastic mode of division implies that stem cell behavior is a property of a cell population not of an individual cell. In this sense, stem cells do not exist in isolation but only as a part of multicellular system. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Methods and Principles Adult Stem Cells, Tissue Renewal, and Regeneration > Environmental Control of Stem Cells. PMID- 29762895 TI - Cutaneous leishmaniasis: PCR of filter paper blots from an ulcer base is an alternative to biopsy. PMID- 29762896 TI - Vertical transmission of herpes simplex virus: an update. AB - Herpes simplex virus (HSV)-1 and -2 infections are highly prevalent worldwide. HSV infection during pregnancy can result in neonatal herpes infection, which is characterized by lifelong infection with periods of latency and reactivation. HSV can be acquired by an infant during one of three periods: in utero (5 %), peripartum (85 %), or postnatal (10 %). Neonatal HSV is a rare but significant infection that may be associated with severe morbidity and mortality, especially if there is dissemination or central nervous system involvement. Diagnostic and therapeutic advances have led to a reduction in mortality and, to a lesser extent, improvement of neurodevelopmental outcomes, but further developments are still needed. It is essential to improve the clinician's ability to identify infants who are at increased risk of HSV infection and to prevent mother-to-child transmission. The development of novel antiviral agents with higher efficacy is a worthwhile aim for the future. PMID- 29762897 TI - Integration of CO2 Reduction with Subsequent Carbonylation: Towards Extending Chemical Utilization of CO2. AB - Currently, it still remains a challenge to amplify the spectrum of chemical fixation of CO2 , although enormous progress has been achieved in this field. In view of the widespread applications of CO in a myriad of industrial carbonylation processes, an alternative strategy is proposed in which CO2 reduction to CO is combined with carbonylation with CO generated ex situ, which affords efficiently pharmaceutically and agrochemically attractive molecules. As such, CO2 in this study was efficiently reduced by triphenysilane using CsF to CO in a sealed two chamber reactor. Subsequently, palladium-catalyzed aminocarbonylation, carbonylative Sonogashira coupling of aryl iodides, and rhodium(I)-mediated Pauson-Khand-type reaction proceeded smoothly to yield amides, alkynones, and bicyclic cyclopentenones, respectively. Furthermore, the formed alkynones can further be successfully converted to a series of heterocycles, for example, pyrazoles, 3a-hydroxyisoxazolo[3,2-a]isoindol-8-(3aH)-one derivatives and pyrimidines in moderate yields. The striking features of this protocol include operational simplicity, high efficiency, and relatively broad application scope, which represents an alternative avenue for CO2 transformation. PMID- 29762899 TI - Metagenomics Analysis of Gut Microbiota in a High Fat Diet-Induced Obesity Mouse Model Fed with (-)-Epigallocatechin 3-O-(3-O-Methyl) Gallate (EGCG3"Me). AB - SCOPE: (-)-Epigallocatechin 3-O-(3-O-methyl) gallate (EGCG3"Me) has been shown to have a modulatory effect on human intestinal microbiota, and the relationship between intestinal flora and obesity has attracted more and more attention recently. Here, the potential link between EGCG3"Me and gut microbiota composition, as well as the underlying mechanisms of the anti-obesity activity of EGCG3"Me are investigated. METHODS AND RESULTS: EGCG3"Me was prepared from oolong tea by column chromatography, and the influence of EGCG3"Me on intestinal microbiota was analyzed using a human-flora-associated high fat diet (HFD) induced obesity mouse model by metagenomics. EGCG3"Me showed a weight reducing effect, ameliorated the HFD-induced gut dysbiosis, and significantly decreased the ratio of Firmicutes/Bacteroidetes. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) database provided significant differences in differentially expressed genes in response to EGCG3"Me treatment. The results showed enrichment of genes involved in the biosynthesis of amino acids, the two-component system, ATP-binding cassette (ABC) transporters, purine metabolism, and carbon metabolism. CONCLUSION: An EGCG3"Me supplemented diet produces promising effects on gut microecology by enhancing beneficial microbial populations and by affecting metabolic pathways including amino acids biosynthesis, the two component system, and ABC transporters, contributing to the improvement of host health. PMID- 29762898 TI - Predicting mammalian metabolism and toxicity of pesticides in silico. AB - Pesticides must be effective to be commercially viable but they must also be reasonably safe for those who manufacture them, apply them, or consume the food they are used to produce. Animal testing is key to ensuring safety, but it comes late in the agrochemical development process, is expensive, and requires relatively large amounts of material. Surrogate assays used as in vitro models require less material and shift identification of potential mammalian toxicity back to earlier stages in development. Modern in silico methods are cost effective complements to such in vitro models that make it possible to predict mammalian metabolism, toxicity and exposure for a pesticide, crop residue or other metabolite before it has been synthesized. Their broader use could substantially reduce the amount of time and effort wasted in pesticide development. This contribution reviews the kind of in silico models that are currently available for vetting ideas about what to synthesize and how to focus development efforts; the limitations of those models; and the practical considerations that have slowed development in the area. Detailed discussions are provided of how bacterial mutagenicity, human cytochrome P450 (CYP) metabolism, and bioavailability in humans and rats can be predicted. (c) 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29762900 TI - Multiplex gene editing in rice with simplified CRISPR-Cpf1 and CRISPR-Cas9 systems. AB - We developed simplified single transcriptional unit (SSTU) CRISPR systems for multiplex gene editing in rice using FnCpf1, LbCpf1 or Cas9, in which the nuclease and its crRNA array are co-expressed from a single Pol II promoter, without any additional processing machinery. Our SSTU systems are easy to construct and effective in mediating multiplex genome editing. PMID- 29762901 TI - Cell dynamic morphology classification using deep convolutional neural networks. AB - Cell morphology is often used as a proxy measurement of cell status to understand cell physiology. Hence, interpretation of cell dynamic morphology is a meaningful task in biomedical research. Inspired by the recent success of deep learning, we here explore the application of convolutional neural networks (CNNs) to cell dynamic morphology classification. An innovative strategy for the implementation of CNNs is introduced in this study. Mouse lymphocytes were collected to observe the dynamic morphology, and two datasets were thus set up to investigate the performances of CNNs. Considering the installation of deep learning, the classification problem was simplified from video data to image data, and was then solved by CNNs in a self-taught manner with the generated image data. CNNs were separately performed in three installation scenarios and compared with existing methods. Experimental results demonstrated the potential of CNNs in cell dynamic morphology classification, and validated the effectiveness of the proposed strategy. CNNs were successfully applied to the classification problem, and outperformed the existing methods in the classification accuracy. For the installation of CNNs, transfer learning was proved to be a promising scheme. (c) 2018 International Society for Advancement of Cytometry. PMID- 29762902 TI - Rational Design of Fe/N/S-Doped Nanoporous Carbon Catalysts from Covalent Triazine Frameworks for Efficient Oxygen Reduction. AB - Porous organic polymers (POPs) are promising precursors for developing high performance transition metal-nitrogen-carbon (M/N/C) catalysts for the oxygen reduction reaction (ORR). The rational design of POP precursors remain a great challenge, because of the elusive structural association between the sacrificial POPs and the final M/N/C catalysts. Based on covalent triazine frameworks (CTFs), we developed a series of S-doped Fe/N/C catalysts by selecting six different aromatic nitriles as building blocks. A new mixed solvent of molten FeCl3 and S was used for CTF polymerization, which benefited the formation of Fe-Nx sites and made the subsequent pyrolysis process more convenient. Comprehensive study of these CTF-derived catalysts showed that their ORR activities are not directly dependent on the theoretical N/C ratio of the building block, but closely correlated to the ratio of the nitrile group to benzene ring (Nnitrile /Nbenzene ) and geometries of the building blocks. The high ratios of Nnitrile /Nbenzene are crucial for ORR activity of the final catalysts owing to the formation of more N-doped micropores and Fe-Nx sites in pyrolysis possess. The optimized catalyst shows high ORR performances in acid and superior ORR activity to the Pt/C catalysts under alkaline conditions. PMID- 29762903 TI - The role of anatomy computer-assisted learning on spatial abilities of medical students. AB - Currently, medical education context poses different challenges to anatomy, contributing to the introduction of new pedagogical approaches, such as computer assisted learning (CAL). This approach provides insight into students' learning profiles and skills that enhance anatomy knowledge acquisition. To understand the influence of anatomy CAL on spatial abilities, a study was conducted. A total of 671 medical students attending Musculoskeletal (MA) and Cardiovascular Anatomy (CA) courses, were allocated to one of three groups (MA Group, CA Group, MA + CA Group). Students' pre-training and post-training spatial abilities were assessed through Mental Rotations Test (MRT), with scores ranging between 0-24. After CAL training sessions, students' spatial abilities performance improved (9.72 +/- 4.79 vs. 17.05 +/- 4.57, P < 0.001). Although male students in both MA Group and CA Group show better baseline spatial abilities, no sex differences were found after CAL training. The improvement in spatial abilities score between sessions (Delta MRT) was correlated with Musculoskeletal Anatomy training sessions in MA Group (r = 0.333, P < 0.001) and MA + CA Group (r = 0.342, P < 0.001), and with Cardiovascular Anatomy training sessions in CA Group (r = 0.461, P = 0.001) and MA + CA Group (r = 0.324, P = 0.001). Multiple linear regression models were used, considering the Delta MRT as dependent variable. An association of Delta MRT to the amount of CAL training and the baseline spatial abilities was observed. The results suggest that CAL training in anatomy has positive dose dependent effect on spatial abilities. Anat Sci Educ 00: 000-000. (c) 2018 American Association of Anatomists. PMID- 29762904 TI - The design and evaluation of a master of science program in anatomical sciences at Queen's University Canada. AB - The purpose of this study was to describe the design and evolution of a unique and successful Master of Science program in anatomical sciences at one Canadian post-secondary institution and to evaluate its long-term impact on student learning. This program prepares students to teach anatomy and design curricula in the anatomical sciences and is structured around three pillars of competency content (disciplinary knowledge and transferable skills), pedagogy, and inquiry. Graduates of the program from the last ten years were surveyed, to better understand the knowledge, skills, and habits of mind they have adopted and implemented since completion. Interest was taken in identifying aspects of the program that students found particularly beneficial and areas that needed to be further developed. Based on the findings, this program has been a highly valuable experience for the graduates especially in helping them develop transferable skills, and grow as individuals. The hope is that other institutions that have similar programs in place or are considering developing them would benefit from this description of the program design and the sharing of the lessons learned. PMID- 29762905 TI - Pharmacokinetics and the transition to extended half-life factor concentrates: communication from the SSC of the ISTH. AB - Extended half-life proteins (EHL) are increasingly used in clinical practice, but there is no standardized approach to sampling, interpretation and implementation of pharmacokinetics (PK) data to maximize treatment benefit. The goal of EHL treatment is to attain a trough level sufficient to protect against spontaneous bleeds and reduce infusion frequency and limitations on individual activity and lifestyle. Performing classical PK assessments requires multiple blood samples, which is burdensome for patients and providers. Herein we review a population pharmacokinetic (popPK) approach to estimate individual PK parameters to transition patients from standard half-life (SHL) to EHL concentrates. We propose that a minimum of two to four post-infusion samples is sufficient to estimate individual PK profiles, with sufficient certainty to maintain factor levels above 1% and achieve bleed-free lifestyles. We also survey current PK use in patients transitioning to EHL, review key PK parameters and popPK models, and recommend an approach to using PK in patients initiating or switching to EHL. PMID- 29762906 TI - Response to "It is time to revise the kidney allocation system to restore the pediatric advantage". PMID- 29762907 TI - Genetic differences between type 1 diabetes with and without other autoimmune diseases. AB - BACKGROUND: Clusters of autoimmune diseases (ADs) are present in some people with type 1 diabetes. This clustering suggests the existence of common genetic backgrounds for abnormal autoimmunity in these individuals. However, the genetic differences between type 1 diabetes patients with and without other ADs are not well known. METHODS: To investigate the clinical background and genetic differences between type 1 diabetes patients with and without other ADs, single nucleotide polymorphisms (SNPs) in the CTLA4, SUMO4, PTPN22, IRF5, STAT4, and BLK genes were analysed by using either a TaqMan assay or direct sequencing. The frequencies of alleles, genotypes of each gene, and the human leukocyte antigen (HLA) haplotype were analysed to investigate differences among 3 groups: type 1 diabetes with systemic ADs (group A), type 1 diabetes with other organ-specific ADs (group B), and type 1 diabetes without other ADs (group C). RESULTS: The frequency of the C allele in the -1123G > C SNP in the PTPN22 gene promoter was significantly higher in groups A and B than in group C (P = .0258 and .0207, respectively). The allele frequencies of the other SNPs were comparable. The frequency of HLA DRB1*0405-DQB1*0401 was significantly higher in groups A and B than in group C (P = .021 and .0395, respectively). CONCLUSIONS: The -1123G > C SNP in the PTPN22 gene promoter and HLA DRB1*0405-DQB1*0401 might influence the concurrence of systemic and organ-specific ADs in patients with type 1 diabetes. PMID- 29762909 TI - Open-Label, Dose-Escalation, Phase 1 Study of Safety and Single and Multiple-Dose Pharmacokinetics of Dichlorphenamide in Healthy Volunteers. AB - Single-and multiple-dose pharmacokinetics and safety were investigated in this phase 1 study of dichlorphenamide, a carbonic anhydrase inhibitor approved in the United States for treatment of primary periodic paralysis. Dichlorphenamide was administered to 6 cohorts (n = 6 each) of healthy adults. Cohorts A through E received single doses of 25-400 mg followed by 50-800 mg/day in divided doses for 10 total doses. Cohort F (safety analysis only) received up to 28 titrated doses from 100-800 mg/day. Plasma for pharmacokinetics sampling was obtained predose and up to 48 hours postdose. Twenty-five of 36 enrolled subjects completed. Median time to maximum plasma concentration ranged from 1.5-3 hours, and mean half-life from 32-68 hours. Mean area under the concentration-time curve from time 0 to tau (length of the dosing interval estimated using the trapezoidal method) and maximum observed plasma concentration increased dose-proportionally after multiple doses. The incidence and severity of adverse events (AEs) were dose-related, with at least one mild AE reported among 17%, 17%, and 67% of patients in cohorts A, B, and C, respectively; and at least one mild-to-moderate AE among 100% of subjects in cohorts D, E, and F. One serious AE of rash was reported in cohort F. Eleven subjects discontinued; 10 due to AEs at 400 or 800 mg/day (cohorts E and F), including 100% of cohort F. Hypokalemia contributed to 5 of 6 discontinuations in cohort F (all 800 mg/day). PMID- 29762910 TI - "Why did you really do it?" A mixed-method analysis of the factors underpinning motivations to register as a body donor. AB - Individuals who register as body donors do so for various reasons, with aiding medical science a common motivation. Despite awareness of several key reasons for donation, there are few in-depth explorations of these motivations to contextualize persons' reasons for donating. This study undertakes a mixed-method exploration of motivations for body donation to facilitate deeper understanding of the reasons underpinning donor registration. A survey of all newly registered body donors at a New Zealand university was performed over a single year. The survey included basic demographic information, a categorical question on reason for donation, a free-text question on donation motivation, and a free-text question allowing "other" comments on body donation. Basic statistical analysis was performed on demographic and categorical data, and thematic analysis used on free-text responses. From 169 registrants, 126 people (average age 70.5 years; 72 female) returned completed surveys (response rate 75%). Categorical data indicate a primary motivation of aiding medical science (86%). Fifty-one respondents (40%) provided free-text data on motivation, with other comments related to motivation provided by forty-one (33%). Common themes included reference to usefulness, uniqueness (pathophysiology and anatomy), gift-giving, kinship, and impermanence of the physical body. Consistent with previous studies, the primary reason for body donation was aiding medical science, however underpinning this was a complex layer of themes and sub-themes shaping motivations for choices. Findings provide important information that can guide development of robust informed consent processes, aid appropriate thanksgiving service delivery, and further contextualize the importance of medical professionals in body donation culture. PMID- 29762908 TI - The era of "Warm Organ Transplantation" is coming. PMID- 29762911 TI - Ultrastructural observation in a case of mucinous nevus. PMID- 29762912 TI - Professional and personal competency development in near-peer tutors of gross anatomy: A longitudinal mixed-methods study. AB - There are many benefits to peer and near-peer tutoring. The current literature suggests that near-peer teaching within the domain of gross anatomy may lead to the development of numerous competencies for burgeoning medical professionals. The aim of this study was a quantitative and qualitative approach to explore which professional and personal competencies anatomy tutors developed as a result of their teaching activities in a gross anatomy course at a medical school in Germany. For a period of 18 months, 24 peer tutors were followed and queried multiple times via questionnaire and semi-structured interviews. It was found that most of the skills tutors developed or strengthened over one semester matched most of the core competencies described in various official competency frameworks used for physician education. In particular, tutors thought that tutoring gross anatomy had improved their knowledge of professional behavior as well as their communication skills. They also felt that they had learned to take on more responsibility and to use available resources more effectively. Overall, tutoring gross anatomy was perceived as very challenging, but also very rewarding, mainly because it provided the opportunity to develop and strengthen important skills such as self-confidence, self-awareness, positive thinking, self insight, and stress management. Ultimately, these are all factors that contribute to resilience, an important attribute for physicians. Anat Sci Educ. (c) 2018 American Association of Anatomists. PMID- 29762913 TI - An Online Compendium of CHO RNA-Seq Data Allows Identification of CHO Cell Line Specific Transcriptomic Signatures. AB - Chinese hamster ovary (CHO) cell lines can fold, assemble, and modify proteins post-translationally to produce human-like proteins; as a consequence, it is the single most common expression systems for industrial production of recombinant therapeutic proteins. A thorough knowledge of cultivation conditions of different CHO cell lines has been developed over the last decade, but comprehending gene or pathway-specific distinctions between CHO cell lines at transcriptome level remains a challenge. To address these challenges, a compendium of 23 RNA-Seq studies from public and in-house data on CHO cell lines, i.e., CHO-S, CHO-K1, and DG44 is compiled. Significantly differentially expressed (DE) genes particularly related to subcellular structure and macromolecular categories are used to identify differences between the cell lines. A R-based web application is developed specifically for CHO cell lines to further visualize expression values across different cell lines, and make available the normalized full CHO data set graphically as a CHO research community resource. This study quantitatively categorizes CHO cell lines based on patterns at transcriptomic level and detects gene and pathway specific key distinctions among sibling cell lines. Studies such as this can be used to select desired characteristics across various CHO cell lines. Furthermore, the availability of the data as an internet-based application can be applied to broad range of CHO engineering applications. PMID- 29762914 TI - Cutaneous metastatic breast cancer simulating angiosarcoma on the face and neck of a woman. PMID- 29762916 TI - Painful circumscribed bullous dermatosis of the left hand after contact with African four-toed hedgehogs. PMID- 29762915 TI - Women's periconceptional diet and risk of biliary atresia in offspring. AB - INTRODUCTION: We examined the association of biliary atresia with maternal dietary intake, using National Birth Defects Prevention Study (NBDPS) data from 152 cases and 11,112 nonmalformed controls born 1997-2011. METHODS: NBDPS is a multisite, population-based case-control study. Exposure data were from maternal telephone interviews, which included a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were generated from logistic regression models that included nutritional factors as continuous variables and were adjusted for energy intake only or energy intake plus covariates (maternal race ethnicity, education, age, prepregnancy body mass index, vitamin/mineral supplement intake, conception during summer). Models included a quadratic term for the nutrient if p < 0.10. ORs reflect odds of having biliary atresia for nutrient values at the 75th compared to 25th percentile values of each nutrient, based on distributions among controls. RESULTS: ORs for which the 95% CI excluded 1.00 were energy-adjusted ORs for calcium (0.63), protein (0.65), riboflavin (0.71), and diet quality index (0.69), and fully adjusted ORs for calcium (0.68) and vitamin E (0.72). ORs that were fully adjusted for covariates tended to be closer to 1.0 than ORs adjusted only for energy intake. ORs for the other studied nutrients had 95% CIs that included 1.00. CONCLUSIONS: NBDPS is the first study to include detailed information on maternal dietary intake and risk of biliary atresia. Our results suggest reduced risks associated with some nutrients, which may provide etiologic clues but should be interpreted with caution given the small number of cases and novelty of the investigation. PMID- 29762917 TI - Association of Change in Patient-Reported Health Status after Transcatheter Aortic Valve Replacement, and Postoperative Outcomes. AB - BACKGROUND: The study aim was to investigate the relationship between postoperative morbidity after transcatheter aortic valve replacement (TAVR) and short-term patient-reported health status, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: The association between 30-day post-procedure changes in patient-reported heath status and post-TAVR outcomes was examined. Patients were stratified into three groups based on observed changes in KCCQ Overall scores (OS): Group A, increase in KCCQ-OS >=10 points; Group B, KCCQ-OS scores <10 points; and Group C, decline in KCCQ-OS >=10 points. Variation components of KCCQ scores were determined using paired t-tests. Postoperative morbidity was investigated. Multivariable logistic regression was used to identify pre-procedural factors associated with an increase or decline in KCCQ-OS at 30 days. RESULTS: A total of 223 patients with complete baseline and postoperative 30-day KCCQ responses was studied. At the 30-day follow up there was a significant change in baseline mean KCCQ-OS for all patients (mean difference 14.1; p <0.0001). Improvement in KCCQ-OS >=10 was observed in 130 patients (58%), 64 patients (29%) had no change, and 29 patients (13%) had a decline in KCCQ-OS >=10. The incidence of acute kidney injury (AKI), permanent pacemaker (PPM) placement and new-onset arrhythmia (NOA) was higher in group C than in groups A and B: AKI, 11%, 0%, 0%; p <0.001; PPM, 21%, 4%, 6%; p = 0.004; and NOA, 21%, 5%, 8%, p = 0.026. Independent predictors of decline in KCCQ scores after TAVR were PPM requirement (estimate: 0.76 CI 0.22, 1.29; p = 0.005) and NYHA functional class (III/IV) (estimate: -0.41 CI -0.71, 0.10; p = 0.009). CONCLUSIONS: TAVR patients experienced an improvement in health status after the procedure, but for a smaller proportion their health status worsened. Patients who experience perioperative complications may have a decline in their health status after the procedure in the short term. PMID- 29762918 TI - Impact of Heart Rate on Flow Measurements in Aortic Regurgitation. AB - BACKGROUND: Flow measurements using cardiac magnetic resonance imaging (CMRI) enable quantification of the stroke volume, regurgitant volume (RV) and regurgitant fraction (RF) in patients with aortic regurgitation (AR). These variables are used to assess the severity of the valve disease and for the timing of surgery. The aim of the study was to investigate the impact of an increased heart rate on measurement of the RV and RF in patients with AR. METHODS: Among 13 patients with known moderate or severe AR, regurgitant flow measurements, using phase-contrast cine magnetic resonance imaging, were obtained in the ascending aorta. Flow measurements were obtained at rest and at increased heart rates after intravenous administration of atropine. RESULTS: The mean heart rate was 61 beats per min at rest and 91 beats per min after atropine administration. The RV and RF were 52 ml and 35% at rest, respectively, and 34 ml (p <0.001) and 30% (p = 0.065) at increased heart rate, respectively. CONCLUSIONS: An increased heart rate leads to a decreased RV. The RF is more stable and may therefore be preferable for severity grading in AR. PMID- 29762919 TI - Incremental Value of Transesophageal Echocardiography Integrated with Transthoracic Echocardiography in the Assessment of Aortic Stenosis Severity. AB - BACKGROUND: Transthoracic echocardiography (TTE) is the standard method for evaluating the severity of aortic stenosis (AS), while transesophageal echocardiography (TEE) is useful for morphologic characterization. The study aim was to assess the impact of complementary TEE to TTE in refining hemodynamic assessment of AS severity. METHODS: A retrospective analysis was conducted of sequential TTE and TEE studies performed in 100 patients with moderate or severe AS confirmed on prior TTE. The left ventricular outflow tract (LVOT) velocity time-integral (VTI1) and the aortic valve velocity-time integral (VTI2) were measured for both modalities. The highest values of VTI1 and VTI2 and mean gradients and peak velocities were selected from the sequential TTE/TEE study for indexed aortic valve area (AVAi) calculation and AS severity determination through an integrated assessment. RESULTS: AVAi determined by TTE was not significantly different from that determined by TEE (mean difference -0.008 cm2; p = 0.38). The dimensionless velocity index (DVI) was higher when assessed by TTE than by TEE (mean difference 0.0126 +/- 0.04; p = 0.003). Using the integrated AS assessment, six of 13 patients with a TTE-based diagnosis of moderate AS were re classified as severe AS. A slight lowering of the recommended TTE-derived DVI threshold for severe AS, from 0.25 to 0.24, improved the ability to discriminate moderate versus severe AS, as determined by the integrated assessment. CONCLUSIONS: TEE integrated with TTE may improve the detection of severe AS, particularly in patients with moderate AS criteria assessed by TTE, but with a DVI ratio <=0.24. PMID- 29762920 TI - Outcomes of a New-Generation Stentless Aortic Valve: A Single-Center Experience with 251 Consecutive Implants. AB - BACKGROUND: The study aim was to investigate the hemodynamic behavior over time and ease of implant and durability of the Sorin Pericarbon Freedom (SPF)(r) stentless pericardial aortic xenograft. METHODS: Between March 2003 and April 2010, a total of 251 consecutive, non-selected patients (mean age 70.1 years; range: 17-89 years; 17.1% aged >80 years) received a SPF bioprosthesis as an aortic valve substitute at the authors' institution. All implantations were performed by a single surgeon using a classical, double-line, subcoronary implant technique. Of these patients. 108 (43%) underwent a concomitant procedure. The mean logistic EuroSCORE was 8.3. Patients were followed for complications and hemodynamic evaluation. Echocardiographic controls and clinical data were obtained at discharge, and at six months' and eight years' follow up. RESULTS: The in-hospital/30-day mortality was 1.2% for the entire group, but 0% for patients with isolated valve replacement. A total of 27 deaths had occurred at the time of the last follow up (22 were due to non-cardiac causes). At follow up (mean 3.7 years; range: 0-7.8 years), 91.1% of survivors were in NYHA classes I or II. Freedom from reoperation and from structural valve deterioration was 96.0% and 96.8%, respectively, at 7.8 years. The mean pressure gradient of the series (measured using echocardiography) was 10.3 +/- 4.5 mmHg at discharge, and 8.3 +/- 4.5mmHg at the time of the last follow up. The mean effective orifice area was 1.85 +/- 0.70 cm2 for the entire series, and there was an absence of prosthesis patient mismatch in 90% of patients. CONCLUSIONS: The study results confirmed the favourable hemodynamic behavior, low risk of implantation and acceptable durability of the pericardial stentless SPF aortic prosthesis. The data also endorsed use of the SPF as an aortic valve substitute, even in a young and active population, and particularly in the presence of a small aortic annulus. The accuracy of implantation remains a crucial factor for durability and subsequent satisfactory hemodynamic performance. A longer follow up would provide further information with regards to complications and durability of the SPF prosthesis. PMID- 29762921 TI - Long-Term (up to 21 Years) Follow Up after Biological and Mechanical Aortic Valve Replacement in Younger Patients. AB - BACKGROUND: Despite the limited durability of biological aortic valves, increasing numbers of younger patients are choosing to receive them, due mainly to the lack of a need for permanent anticoagulation. Few data exist, however, regarding the outcomes of valve replacement in patients aged <55 years, and additional data are required in this patient population. METHODS: Between 1993 and 2014, at the authors' institution, a total of 448 patients (237 males, 101 females; mean age 45.8 +/- 8.0 years) underwent aortic valve replacement (AVR) with either a mechanical prosthesis (M1 group, n = 318) or a biological prosthesis (B1 group, n = 130). The mean follow up was 8.5 +/- 5.8 years (range: 4 days to 20.8 years) in the M1 group, and 4.9 +/- 4.6 years (range: 2 days to 21 years) in the B1 group. The entire collective (EC) (n = 448 patients) was compared and analyzed with a selective collective (SC) (n = 109 patients) after exclusion of patients with concomitant procedures or comorbidities (M2 group, n = 74; B2 group, n = 35). RESULTS: Early mortality was greater after biological AVR in the EC (6.1% versus 1.9%), but in the SC no early deaths were observed after both primary and redo procedures. The reoperation rate was greater after biological AVR in both collectives. The late mortality, survival and endocarditis rates were comparable in both collectives. Bleeding occurred more often in the EC after mechanical AVR. CONCLUSIONS: Biological AVR in patients aged <55 years provides satisfactory outcomes, whereas reoperations were performed less commonly in patients with mechanical valve substitutes. In selective patients, AVR can be performed with zero mortality. PMID- 29762922 TI - Redo Scoring for Prediction of Success of Redo-Percutaneous Balloon Mitral Valvuloplasty in Patients with Mitral Restenosis. AB - BACKGROUND: Echocardiographic predictors of redo-percutaneous balloon mitral valvuloplasty (redo-PBMV) have not been well studied, and indications are based mainly on Wilkins score. The study aim was to evaluate the immediate results of redo-PMBV and to introduce a simplified redo-score to predict the success of redo PBMV. METHODS: Two cohorts of symptomatic patients (derivation group, n = 218; validation group, n = 100) who had undergone redo-PBMV at a mean of 8.1 +/- 2.9 years after a first successful PBMV were enrolled in the study. The mean Wilkins scores were 8.5 +/- 1.7 in the derivation group and 8.4 +/- 1.8 in the validation group. PBMV was performed using a multi-track technique. Independent echocardiographic predictors of outcome were assigned a points value: mitral valve area <=1.0 cm2 (2 points), posterior mitral valve leaflet length (PMVL)/anterior mitral valve leaflet length (AMVL) ratio <=1/2 (2 points), doming distance <=12 mm (3 points), mitral annular calcification (mild = 1 point; moderate = 2 points; severe = 3 points), commissural status (no fusion = 0 points; uni-fusion = 2 points; bi-fusion = 3 points) and chordal length <=10 mm (2 points). RESULTS: The minimum score was 5 and the maximum was 13. A receiver operating curve analysis showed the redo score to be highly significant in predicting redo-PBMV immediate results. The cut-off value of redo score to predict a favorable outcome was <=8, with a sensitivity of 96% and specificity of 85% in the derivation cohort, and a sensitivity of 95% and specificity of 83% in the validation cohort. A Wilkins score <=8 had a sensitivity of 71% and a specificity of 59% in the derivation cohort, while sensitivity was 70% and specificity 62% in the validation cohort. CONCLUSIONS: The described scoring system was significantly more predictive than the Wilkins score, and was particularly valuable in predicting outcome in patients with a prior PBMV. It may serve as a satisfactory scoring system for correctly selecting patients with mitral restenosis for PBMV. PMID- 29762923 TI - Intraoperative Transesophageal Echocardiography for Surgical Repair of Degenerative Mitral Regurgitation. AB - BACKGROUND: Segmental analysis of diseased mitral valves is important to predict a successful surgical valve repair. An assessment was made of the comparative accuracy of intraoperative three-dimensional (3D) and two-dimensional (2D) transesophageal echocardiography (TEE) in the evaluation of mitral valve lesions when compared with intraoperative surgical segmental analysis. METHODS: A total of 42 consecutive patients (12 females, 30 males; mean age 70.5 +/- 14 years) with severe mitral valve regurgitation due to degenerative disease and who underwent mitral valve repair was enrolled in the study. Complete 2D- and 3D-TEE were performed before surgery. The findings obtained using the different echocardiographic techniques were compared with intraoperative segmental analysis performed by a single operator who was blinded to the 2D- and 3D-TEE findings until the end of the inspection. The sensitivity and specificity of echocardiographic evaluations of involved scallops were compared with surgical inspection. RESULTS: 3D-TEE allowed an accurate identification of all mitral lesions. Thirty-three patients had simple lesions at 3D-TEE and underwent a simple surgical procedure, while nine patients had complex lesions; in these latter cases complex surgical procedures were performed. 3D-TEE showed more sensitivity than 2D-TEE in the analysis of the anterior leaflet (A), in particular for A3 lesion (100% versus 25%, p <0.001) and for complex lesion (100% versus 33.3%, p <0.009). CONCLUSIONS: 3D-TEE allowed a more accurate identification of mitral valve lesions compared with 2D-TEE. The greatest accuracy was achieved for analysis of the anterior leaflet. 3D-TEE should be regarded as an important adjunct to standard 2D-TEE in decisions regarding mitral valve repair. PMID- 29762924 TI - Early Improvement in Mitral Regurgitation after Cardiac Resynchronization Therapy in Cardiomyopathy Patients. AB - BACKGROUND: The study aim was to investigate factors affecting the improvement of mitral regurgitation (MR) severity within 48 hours after cardiac resynchronization therapy (CRT) in patients with cardiomyopathy. METHODS: Sixty nine cardiomyopathy patients (48 males, 21 females; mean age 59.12 +/- 9.66 years) in NYHA functional class >=III, with left ventricular ejection fraction (LVEF) <=35%, and QRS duration >120 ms, with MR >=moderate, were included in the study. Conventional echocardiography was performed before and within 48 h after CRT, and all patients underwent tissue Doppler imaging prior to CRT. Improved MR was defined as a reduction of at least one grade in MR severity. RESULTS: After CRT, 49 patients (71%) showed MR improvement but 20 (29%) had no MR improvement. The mean MR severity grade was reduced significantly, from 2.70 +/- 0.77 before CRT to 1.90 +/- 0.94 after CRT (p<0.001). The group with improved MR had a significantly higher rate of left bundle branch block (75.5% versus 45%; p = 0.015), a higher QRS duration (172.00 +/- 31.98 versus 147.25 +/- 28.75 ms; p = 0.001), a higher median septal lateral delay (70 versus 35 ms, p = 0.035), and a higher median anteroseptal to posterior-wall delay by M mode (200 versus 130 ms, p = 0.041). Older age, longer QRS duration, and septallateral delay remained significant independent predictors of MR improvement. A greater proportion of patients with improved MR showed >=5% increase in LVEF (55.1% versus 30.0%, p = 0.058). CONCLUSIONS: CRT acutely reduced the severity of functional MR in the majority of cardiomyopathy patients. Those patients with improved MR showed a higher frequency of >=5% increase in LVEF after CRT. Older age, longer QRS duration, and septallateral delay were independent predictors of MR improvement after CRT. PMID- 29762925 TI - Association Between Myxomatous Mitral Valve Disease and Skeletal Back Abnormalities. AB - BACKGROUND: Myxomatous mitral valve disease (MMVD) is one of the most prevalent valvular heart diseases, while back pain, neck pain and upper-extremity numbness are some of the most common complaints in outpatient settings. Decreased thoracic kyphosis (straight back) is a known cause of hastening back or neck problems, radiculopathy, or even myelopathy. The study aim was to examine the relationship between MMVD, straight back, and the need for cervical fusion. METHODS: In this single-center retrospective study, patients who underwent mitral valve repair or replacement due to MMVD (cases) based on age, gender and body mass index (BMI), were matched with patients who underwent coronary artery bypass grafting (CABG) surgery and had no history of mitral valve disease (controls). The number of patients in each group who required cervical fusion was also noted. Patients included were aged <65 years at the time of surgery, which was performed between January 2014 and December 2015. Thoracic kyphosis curvature was measured from the length of a perpendicular line drawn from the middle of the anterior border of T8 vertebral body to a vertical line connecting anterior superior T4 and anterior inferior T12 on a lateral chest radiograph (AP distance). An AP distance <12 mm was defined as straight back. A Wilcoxon rank-sum test was used to compare the AP distance between cases and controls, and a chi-square test was used to compare the prevalence of straight back in the two groups. RESULTS: The study cohort included 75 patients in the MMVD group and 225 patients in the CABG group. Straight back was present in 27% of the MMVD group versus only 6.7% of the CABG group (p <0.0001) (Odds ratio 5.1; 95% CI 2.4-10.6). The mean AP distance in the MMVD group was 19.8 +/- 8 mm, compared to 22.4 +/- 6 mm for CABG cohort (p = 0.017). Of those patients with MMVD who had straight back, 10% required cervical fusion, compared to none in the CABG group. CONCLUSIONS: MMVD is associated with straight back and a relatively high requirement for cervical fusion. Patients with MMVD should be screened for straight back and, if the condition is identified, should consider preventive measures to obviate the need for cervical fusion. PMID- 29762926 TI - Genetic Complexity of Mitral Valve Prolapse Revealed by Clinical and Genetic Evaluation of a Large Family. AB - BACKGROUND: A genetic component to familial mitral valve prolapse (MVP) has been proposed for decades. Despite this, very few genes have been linked to MVP. Herein is described a four-generation pedigree with numerous individuals affected with severe MVP, some at strikingly young ages. METHODS: A detailed clinical evaluation performed on all affected family members demonstrated a spectrum of MVP morphologies and associated phenotypes. RESULTS: Linkage analysis failed to identify strong candidate loci, but revealed significant regions, which were investigated further using whole-exome sequencing of one of the severely affected family members. Whole-exome sequencing identified variants in this individual that fell within linkage analysis peak regions, but none was an obvious pathogenic candidate. Follow up segregation analysis of all exome-identified variants was performed to genotype other affected and unaffected individuals in the family, but no variants emerged as clear pathogenic candidates. Two notable variants of uncertain significance in candidate genes were identified: p.I1013S in PTPRJ at 11p11.2 and FLYWCH1 p.R540Q at 16p13.3. Neither gene has been previously linked to MVP in humans, although PTPRJ mutant mice display defects in endocardial cushions, which give rise to the cardiac valves. PTPRJ and FLYWCH1 expression was detected in adult human mitral valve cells, and in-silico analysis of these variants suggests they may be deleterious. However, neither variant segregated completely with all of the affected individuals in the family, particularly when 'affected' was broadly defined. CONCLUSIONS: While a contributory role for PTPRJ and FLYWCH1 in this family cannot be excluded, the study results underscored the difficulties involved in uncovering the genomic contribution to MVP, even in apparently Mendelian families. PMID- 29762927 TI - Isolated Pulmonary Valve Fungal Endocarditis with Candida parapsilosis: Management Considerations of a Rare Case. AB - Pulmonary valve infections without the involvement of other valves account for only 1.5- 2% of all infective endocarditis cases. Isolated pulmonary valve endocarditis due to fungus is extremely rare. The case is presented of a 36-year old male who was found to have isolated pulmonary valve endocarditis caused by a very rare organism, Candida parapsilosis, and that was solely managed with medical therapy. The patient was evaluated for three weeks of lowgrade fever, generalized rash and fatigue, and found to have C. parapsilosis in the blood. Transesophageal echocardiography (TEE) demonstrated a 4.5 cm vegetation on the pulmonary valve, without involvement of other valves. The patient was deemed not to be a surgical candidate and was subsequently started on intravenous liposomal amphotericin B and 5-flucytosine, with excellent clinical outcome. Based on these case details, it must be emphasized that in selective cases and if there are no known complications, fungal endocarditis can be managed successfully using anti fungal agents. PMID- 29762928 TI - Early Thrombosis of a Mitral Annuloplasty Ring in a Patient with MTHFR and Factor V Leiden Mutations. AB - Mitral annuloplasty ring thrombosis is an extremely infrequent pathology, for which no evidence-based antithrombotic management has yet been described. Herein is presented a case of heterozygous Factor V Leiden (FVL) and hyperhomocysteinemia with homozygous methylenetetrahydrofolate reductase (MTHFR) mutations that caused early thrombosis of the mitral annuloplasty ring. The clinical management and antithrombotic treatment of the patient, and the implications of hyperhomocysteinemia, are discussed. Video 1: Mobile 9-mm thrombus of mitral annuloplasty ring on two-dimensional (2D) transesophageal echocardiography. Video 2: Mitral annuloplasty ring thrombus on real time three dimensional (RT-3D) transesophageal echocardiography. Video 3: 2D video showing the morphologic change of mitral annuloplasty ring thrombus after prolonged UFH infusion. PMID- 29762929 TI - Trileaflet Mitral Valve Treated with the MitraClip(r) System. AB - A 79-year-old woman with a history of ischemic dilated cardiomyopathy, severely depressed left ventricular ejection fraction and significant mitral regurgitation (MR) was admitted to the authors' institution for percutaneous mitral valve repair. Transesophageal echocardiography (TEE) revealed the presence of a posterior mitral cleft at the P2 level, causing a trileaflet mitral valve that contributed significantly to the regurgitant jet. The procedure was performed under general anesthesia and guided by real-time three-dimensional TEE. Three MitraClip(r) devices (Abbott Vascular, Santa Clara, CA, USA) were implanted, which reduced the MR to grade 1+. PMID- 29762930 TI - Cusp Tear of Trifecta? Aortic Bioprosthesis Resulting in Acute Heart Failure. AB - Herein is presented the case of an 83-year-old male patient in cardiogenic shock with acute aortic regurgitation that occurred six years after aortic valve replacement (AVR) with a 23 mm TrifectaTM valve. Prosthesis endocarditis was initially suspected because of a floating structure attached to the aortic valve that was visible on echocardiography. Emergency redo-AVR surgery was performed, but no signs of endocarditis were found intraoperatively. Hence, cusp tearing of the implanted bioprosthesis was considered to be the reason for the severe aortic regurgitation. PMID- 29762931 TI - MitraClip Technique Five Years after Alfieri Stitch Mitral Valve Repair. AB - The case is described of a successful MitraClip procedure performed on an 88-year old patient with severe mitral regurgitation (MR), five years after she had undergone mitral valve repair using the Alfieri surgical procedure. It is suggested that the MitraClip procedure is an option in patients with severe MR persisting after the Alfieri procedure. Video 1: Transesophageal echocardiography before the MitraClip procedure. Severe mitral regurgitation with preserved left ventricular systolic function. The main regurgitant jet originates from the medial commissure. Video 2: Transesophageal echocardiography: clip placement and jet reduction. A single clip placement on the medial portion of the mitral valve, resulting in elimination of the medial jet and reduction of the overall mitral regurgitant jet from grade 4+ to grade 2+. PMID- 29762932 TI - Pulmonary Hypertension as a Possible Cause of Paradoxical Low-Flow, Low-Gradient Aortic Stenosis. AB - Paradoxical low-flow, low-gradient aortic stenosis (LFLG AS) is recognized as a subtype of aortic stenosis. A small left ventricular (LV) cavity with marked LV concentric remodeling leads to a reduced stroke volume in this condition. The case is reported of a paradoxical LFLG AS patient who was undergoing treatment for pulmonary hypertension (PH) and interstitial pneumonia associated with scleroderma. Echocardiography demonstrated enlargement of the right ventricle and a diminished LV cavity. Moreover, the aortic valve opening was restricted despite a preserved LV ejection fraction (61%). The patient's aortic valve area (obtained with the continuity equation) was 0.57 cm2 (indexed AVA was 0.39 cm2/m2), and the mean gradient was 16 mmHg. Multi-detector computed tomography findings confirmed that the aortic valve calcification was not severe. The main mechanism responsible for LFLG AS was considered to be a reduced LV cavity secondary to PH, rather than a sclerotic aortic valve. Thus, a decision was taken to treat the patient with additional medical management prior to performing any invasive procedures. It should be borne in mind that PH can lead to paradoxical LFLG AS, and that appropriate treatment should be contemplated depending on the underlying mechanisms. Video 1: Transthoracic echocardiography in the parasternal long-axis view showing right ventricular dilatation and a diminished left ventricular cavity. Video 2: Transthoracic echocardiography in the shortaxis view showing enlargement of the right ventricle and septal flattening due to pulmonary hypertension. Video 3: Transesophageal echocardiography clearly demonstrates an insufficient valve opening. PMID- 29762933 TI - Ross Procedure Following a Dislodged Transcatheter Aortic Valve Replacement. AB - A 36-year-old pregnant woman with a history of rheumatic heart disease and prior aortic valve replacement and mitral valve repair presented to an outside hospital with severe aortic stenosis. The patient had a cardiac arrest upon labor induction and underwent a transcatheter aortic valve replacement (TAVR), which dislodged two days later. Five months later, the patient underwent removal of the dislodged TAVR and a Ross procedure at the authors' institution. The patient was stable upon discharge, with minimal aortic and pulmonary regurgitation. To the authors' knowledge, the present report is the first of the Ross procedure being used under such circumstances. It is suggested that caution be taken when using bioprosthetic and transcatheter aortic valves in young patients, and primary use of the Ross procedure is encouraged at experienced centers. PMID- 29762934 TI - Rescue TAVI for Aortic Regurgitation after Left Ventricular Assist Device Implantation Following Preoperative Impella(r) Support. AB - A patient presented with a decompensated cardiomyopathy requiring invasive hemodynamic support with an Impella(r) heart pump. Extracorporeal life support (ECLS) became necessary during the further course and the patient was bridged to left ventricular assist device (LVAD) implantation. Postoperatively, the patient did not improve as expected due to new aortic regurgitation (AR) that was most likely caused by the previously placed Impella. A SAPIEN 3 transcatheter aortic valve was implanted as a bail-out strategy; an additional valve-in-valve rescue was required due to paravalvular regurgitation. This resulted in a restitution of valvular function and hemodynamic improvement. TAVI appears to be a valuable bail out option for postoperative AR following LVAD implantation. PMID- 29762935 TI - Septic Shock, Meningoencephalitis and Multiple Pulmonary Emboli: Case Report of an Uncommon Clinical Presentation of Ventricular Septal Defect Acute Infective Endocarditis. AB - The case is reported of a 55 year-old woman, with a previously known congenital septal defect, who was admitted to the emergency department with a diagnosis of meningoencephalitis, septic shock, and rapid clinical deterioration. Echocardiography revealed a vegetation occupying the right-side heart. Endocarditis affectation of the septal defect, aortic and tricuspid valves was noted and blood cultures were positive for Staphylococcus aureus. Urgent surgical treatment was performed whereby the ventricular septal defect was closed, a meticulous debridement of the affected area was conducted, and the aortic and tricuspid valves were replaced. PMID- 29762936 TI - Bentall?s Procedure in Pediatric Mixed Connective Tissue Disease Syndrome: Management of Pediatric Aortic Aneurysm - A Brief Review. AB - Mixed connective tissue disease (MCTD) syndrome in children may lead to large aortic aneurysms, which in turn pose a difficult surgical problem. Valve-sparing root replacement is not always a viable option as the disease process invariably affects the aortic valve leaflets. Among pediatric patients, the Ross procedure is contraindicated on account of weakness of the pulmonary root, while Bentall surgery is the 'gold standard' treatment of aortic aneurysm, with reproducible and excellent long-term results. The case is presented of a three-year-old girl with a large thoracic aortic aneurysm in whom Bentall's surgery was performed, with a good result. The present patient, with MCTD syndrome, was too young to have undergone aortic root replacement with a composite mechanical valved graft. PMID- 29762937 TI - Endoaneurysmorrhaphy for a Giant Inferobasal Left Ventricular Aneurysm Restoring Mitral Function. AB - Over the years, the surgery of ventricular postinfarction aneurysm has evolved from linear resection to endoaneurysmorrhaphy using a patch. Technically, several aims that include the restoration of ventricular shape and function, exclusion of dead space, minimization of the risk of thrombus formation and restoration of valve function are pursued. Herein is reported the case of a 58-year-old male with a giant inferobasal aneurysm involving the mitral valve apparatus who underwent successful endoaneurysmorrhaphy. Correct sizing of the patch proved to be the 'road to success' in this patient. The present case is the second reported instance of a giant ventricular aneurysm involving the mitral valve, with favorable outcome. PMID- 29762938 TI - My daughter's death shows why toxic air is a public health issue. PMID- 29762939 TI - Abuse of trust How to support victims of child sexual abuse. PMID- 29762940 TI - Safeguarding the children of offenders. PMID- 29762941 TI - 'Let's support parents to have a joyful family l'fe'. PMID- 29762942 TI - Can fathers'groups help to improve the family dynamic? PMID- 29762943 TI - Smoothing the transition process Caitlin's legacy. PMID- 29762944 TI - Brush strokes Teenagers and oral health. PMID- 29762945 TI - STRIAING FOR MUDERNILED BALINESE MEITICS (GEGULAA). AB - Balinese have built amazing residences and temples by using many tools. The tools are not only effective in a physical sense, also in the value of ethics. One of the tools is gegulak. The nearest same tool in ergonomics is anthropometrics. The gegulak and anthropometrics are used to humans to be humane. Besides gegulak, there is another tool named sikut natar. LontarAsta Kosali is a kind of Balinese traditional book about material measurement to build a house, and Asta Kosala to build a temple. Even if studied further, this book does not merely determine measuring materials of the housing, but inherent in the spiritual aspects of measurement. Balinese understand that the three main standards are: nista, madya, and utama. They contain the physical and spiritual values. Balinese ancestors have been aware if the land they are living in is a small island, and lacks energy sources. As reflected in the ways of their life, these standards have been persevered on lontar, tools, buildings, arts genealogically and performing ceremonials. Since modernization influences to Balinese life, it has been decreasing many aspects of traditional values. Therefore, the kindness and power from ancient values should be integrated through mind over body. Balinese could be working side by side wisely for the sake of the quality of life. PMID- 29762946 TI - COMFORT FROM HEARING PROTECTORS. PMID- 29762947 TI - DETERMINATION OF THE OPTIMAL DURATION OF WORK EXPOSURE WHILE SITTING IN A SQUATTING POSITION TO AVOID LOW BACK PAIN: A SIMULATION STUDY. AB - The objective of this stuay was to determine the optimal duration of work exposure while sitting in a squatting posture. A simulation study was formulated on work similar to the traditional jewellery manufacturing activity. The task of metal setting was simulated in a controlled environment. Fifteen young adult males participated in this study. The results of 12 participants were included as others discontinued the study for their personal reasons. The study continued for 2 hours. Trunk muscle strength and body part discomfort (BPD) were measured before and after completion of the task. BPD ratings in CR 10 scale were also collected after each 15 minutes of work. The mean age (year), height (cm), weight (kg) and BMI (kg/n2) of the subject were 24.25 +/- 2.14, 172.47 +/- 3.88, 65.08 +/- 4.52 and 21.88 +/- 1.33, respectively. Using inferential statistics, a predictive equation was developed to determine the optimal duration of exposure in a squatting position similar to traditional jewellery manufacturing activity. An hour of work with a small break was suggested after considering the study result for the workers who worked in a squatting posture like traditional jewellery manufacturing. PMID- 29762949 TI - ODA MEMBER SPOTLIGHT. Raj Patel, DDS Tulsa, OK. PMID- 29762948 TI - How to Cultivate Loyal Dental Patients. PMID- 29762950 TI - Tips for the New Dental School Grads. PMID- 29762951 TI - Efficacy of Steroid and Physiotherapy in Early Reported Lagophthalmos of Patient Affected with Leprosy. A Report from Trbal Dominated Leprosy Endemic State of India. AB - Lagophthalmos is one of the well-known complications of leprosy due to involvement of the facial nerve. In the present study an attempt has been made to elucidate the role of early intervention with steroids and adjunct physiotherapy in early reported lagophthalmos in patients affected with leprosy at a tertiary referral institute under the Disability Prevention and Medical rehabilitation (DPMR) programme. During April 2008 to March 2014, 62 patients affected with leprosy reported to Regional leprosy Training and Research Institute with lagophthalmos. Cases reporting within six months of difficulty in closure were categorized as early reporting group. These were either referred from a peripheral health centre (63%) or self-reported (37%). These patients were examined clinically and details were noted in a pretested Performa. The standard dosages of the steroids were given to patients as per NLEP guidelines. Lid gaps on direct gaze and with both gentle and forced closure were assessed using standard measuring technique by a physiotherapist. During the follow-up period the patients were imparted active and passive physiotherapy and any change in the lid gap was recorded. The data was analysed and appropriate test of significance was applied. Out of 62 lagophthalmos patients, 49(79.1%) were males and 13 (20.9%) were females. 56 (90.3%) cases were from MB category and 6 (9.7%) cases were from PB category. 53(85.4%) patients presented with unilateral eye involvement, while 9 (14.6%) had bilateral lagophthalmos. 53 (74.6%) of the eyes achieved complete lid closure, while the remaining 18 (25.4%) eyes had gap on gentle closure. During six month follow-up the amount of recession of lid gap among the early reported lagophthalmos was 4.15 mm with standard steroid regimen and physiotherapy. With the use of the steroid and regular physiotherapy lagophthalmos diagnosed and treated in initial stages shows significant improvement in the lid gap reduction. PMID- 29762952 TI - Dapsone: An Update. AB - Dapsone is an extensively Used drug for the treatment of leprosy as well as'some other clinical problems worldwide: Its use has been predicted to increase further, especially in non leprosy conditions. Treatment with Dapsone is sometimes known'to be associated with side-effects, which include gastrointestinal intolerance, haemolysis, methaemoglobinaemia, agranulocytosis, psychosis, peripheral neuritis and varied dermatological conditions, varying from simple rash to severe life threatening epidermolytic reactions and Dapsone hypersensitivity syndrome (DHS). DHS is a rare delayed hypersensitivity reaction involving multiple organs. the condition is associated with high morbidity and is potentially fatal. In this article, the focus is on etiopathogenesis, diagnosis and management of DHS. Awareness of the varied presentation/s of the condition, early recognition, withdrawal of the drug and proper management helps in rapid reduction in morbidity and preventing fatalities associated with it. PMID- 29762953 TI - Correlates of Defaulting from MDT among Leprosy Patients. AB - In order to analyse the factors of demographic as well as disease related variables and their correlation with Rate of Defaulting (ROD) from Multi Drug Therapy (MDT) among leprosy patients, secondary data have been collected from 3,579 new cases registered for MDT, during a period of 4 years from 2007 to 2010 in four leprosy hospitals/ treatment centers across the four high endemic states viz. Uttar Pradesh, Chhattisgarh; Maharashtra and Andhra Pradesh. Year wise percentage of patients defaulted was calculated on aggregate as well as with reference to each centre and cross tabulated with demographic and disease related factors. Findings show that out of the total 3,579 new cases, 1944,(54.3%) defaulted with variation across centers ranged from 44 to 66 percent. Comparison of ROD against type of leprosy indicated that MB types defaulted (55.7%) more than PB (50.6%) types, (statistically significant difference, (p=0,04). ROD of male patients across the centers ranged from 45% to 67.7% in comparison with 42.4% to 61.5% of female patients. A-statistically significant difference (p=6.04) was found between the overall ROD of males (56.35%) and females (51.47%). The ROD among those with more severe disabilities (WHO Gr-2) ranged between 44% to 67.5% across the centers, while the same among those'with less severe disabilities (Gr-0&1) ranged from 42.6 to 72.7 percent. Comparison of ROD against severity of disability was found statistically significant only across 2 centers. No statistically significant variation was found when ROD of adult patients with refeince to each centr ranged between (43.6% to 65.4%) was compared with the same of children ranged beeIen (36.2% to 69.3%). Across each of these categories and centers,'the ROD remained consistent over the ,4 years. Based on the above findings'this may be concluded that male sex and MB types are significant correlates of default from treatment. Severity of disabilities plays significant role only in certain areas, probably due to other interfering factors, which needs to be further investiged. PMID- 29762954 TI - A Traditional NSAID Aspirin along with Clofazimine in Erythema Nodosum Leprosum Reaction: Study of Six Cases. AB - Six male patients of lepromatous leprosy with erythema nodosum leprosum reaction (ENL) reactions diagnosed clinically and by slit skin smear were treated with aspirin and clofazimine. Aspirin was given in the daily dosage of 75mg/kg body weight up to a maximum of 2.8 grams in four divided doses, along with daily 300mg clofazimine in three divided doses and dapsone 100mg daily with rifampicin 600mg once a month. Aspirin was continued in the same dosage for a month before being tapered and stopped at the end of third month when clofazimine was also reduced to 50 mg daily. All the six cases had an excellent response in 15 days. PMID- 29762955 TI - Erythema Necroticans - A Case Report. AB - Erythema Nodosum Leprosum (ENL) is characterized by evanescent, erythematous, painful raised nodules which fade within 48-72 hours. Necrotic and ulcerative forms are rare presentations of severe ENL. A 27 year old male patient presented with multiple erythematous nodules on trunk and extremities associated with high grade fever, joint pain and pedal edema. Patient developed ulceration of nodules associated with pain and burning sensation over another 3 days. Slit smear showed clumps of granular bacilli. Biopsy showed superficial dermis showing edema with dense focal perivascular infiltrate of lymphocytes, macrophages and few scattered neutrophils. Fite-Faraco stain was negative. Patient was diagnosed as a case of erythema necroticans and started on oral steroids and thalidomide. The histological findings illustrate the need to consider leprosy diagnosis in necrotizing vasculitis even when Virchow's cells are not found in the infiltrate. Thalidomide is the drug of choice in such cases. This patient showed a marked response to the drug with healing of all ulcers within 2 weeks of starting thalidomide. PMID- 29762957 TI - Tropical Diseases Bulletin Vol 112 Nos June-Dec 2015. PMID- 29762956 TI - A Breast Lump in an Elderly Lady - Carcinoma or else ?. AB - Breast tuberculosis (TB) is rare form of extra-pulmonary TB. It is most commonly seen in women of reproductive age group, especially in young, multiparous women who are breast feeding. In geriatric women, breast TB in some cases simulates with breast carcinoma due to common signs which include hard breast lump with nodular surface, ulceration, fixity to skin, discharging sinus, retraction of nipple, axillary lymphadenopathy etc. Hence, it is very difficult to differentiate breast TB from breast cancer, especially in elderly women on clinical ground only, and therefore, histopathological diagnosis is mandatory. Fine needle aspiration cytology is frequently inconclusive due to very small amount of tissue material, and open biopsy or lumpectomy followed by histopathological examination is necessary to confirm the diagnosis of breast TB. Six-month course of anti-tuberculous therapy - ATT (rifampicin, isoniazid, pyrazinamide and ethambutol) is adequate for complete resolution. Here, we report a case of breast TB in an elderly women presenting with left sided breast lump with ulceration of overlying skin and ipsilateral axillary lymphadenopathy. This case of tuberculous mastitis was suspected to be carcinoma due to presence of hard, tender, breast lump with irregular margin, nodular surface, ulceration, purulent discharge and ipsilateral axillary lymphadenopathy in absence of any constitutional symptoms of TB, and heterogenous, hypoechoic mass on USG, which was confirmed by histopathological examination of resected breast lump and responded fully to ATT. PMID- 29762958 TI - Poor Beginnings one year on: The path to better outcomes? PMID- 29762959 TI - Bucking the trend. PMID- 29762960 TI - Maternal mental health: why it's everyone's business. PMID- 29762961 TI - A helping hand: Supporting parents of premature babies. PMID- 29762962 TI - Clinical update: Childhood enuresis. PMID- 29762963 TI - Women's experiences of telephone-based peer support during the transition to parenthood. AB - This paper presents findings of a qualitative evaluation exploring how telephone peer support was experienced by a sample of pregnant women and parents of young children who contacted a national helpline. Peer support can be beneficial for parents experiencing difficulties related to childbirth or early parenthood by alleviating distress and contributing to maternal and infant wellbeing. In 2010 the National Childbirth Trust launched a free, confidential telephone peer support service enabling expectant parents and parents with a young child to share concerns or worries with other carefully selected parents who had previously experienced similar concerns. Telephone interviews with 12 women revealed that they contacted the helpline with postnatal worries, traumatic birth experiences and baby feeding issues. Prior experiences of disconnected encounters and absence of affirmation from health professionals prompted women to call. Talking to a peer supporter helped women to feel connected and gave them hope to move forward with a sense of belief and self-confidence. Telephone peer support can contribute to the wellbeing of women who experience difficulties related to childbirth or early parenting. There is potential to extend peer support services alongside health services and health visitors can play a role in signposting parents to accessible support. PMID- 29762964 TI - Behavioural interviewing as part of values-based recruitment for postgraduate community nursing programmes. AB - The widespread implementation of values-based recruitment [VBR1 has been indicated as a priority in both health settings and the recruitment of students within higher education institutes (HEls]. This opportunity prompts organisations to evaluate recruitment processes, and essentially the values, behaviours and attitudes of applicants. VBR begins at the point of advertisement, but for the purpose of this paper the selection process will be the focus. There is an expectation that organisations will move away from 'conventional' interview panel questions that explore hypothesised responses to a scenario (situational interviewing) in favour of behavioural interviewing. This paper explores the process of behavioural interviewing as part of VBR for postgraduate community nurse programmes at Oxford Brookes University. The university has implemented a three- stage approach to selection, including an unseen presentation, a group work exercise and an interview panel (behavioural interview techniques) for each candidate successfully shortlisted. This paper explores the selection process of candidates in a bid to understand the outcomes of VBR, particularly exploring the element of behavioural interviewing as an interview technique. PMID- 29762965 TI - SINGLE-CHANNEL ION CURRENTS IN THE NUCLEAR ENVELOPE OF RAT CARDIOMYOCYTES. AB - Using the patch clamp technique in nucleus attached configuration we have found that the nuclear membrane of rat cardiomyocytes contains different types of ion channels with conductances in the range from 10 to 400 pS. In particular, we recorded inositol 1,4,5-trisphosphate receptors with conductance of 384 +/- 5 pS and 209 +/- 13 pS cation channels similar to LCC-channels, previously reported in neurons. In addition, we found at least two types of ion channels with significantly higher conductance than that of LCC-channels and several types of ion channels with lower conductance (10-90 pS). PMID- 29762966 TI - The role of hydrogen sulfide in diastolic function restoration during aging. AB - The objective of the study was to examine the effect of exogenous hydrogen sulde donor; sodium hydrosulfide (NaHS), on thefree radical generation, cNOS uncoupling in the myocardium, and diastolicfunction in old rats. To evaluate diastolic function of the heart, we used pressure-volume (PV) conductance catheter system (Millar Instruments, USA). It was shown that H2S levels in. the isolated mitochondria and whole heart homogenates obtained from old age rats were significantly lower comparing with adult animals. The markers of combined oxidative and nitrosative stress (the rate of 0 20 H generation, pools of H202, diene conjugates, malondialdehyde, uric acid, the activity of iNOS, nitrate reductase, and NO pools) were increased in the old hearts in line with cNOS uncoupling. Such changes in NOS coupling resulted in the loss of diastolic relaxation (decrease of the rate of relaxation of the left ventricle (dp/dtmin) by 33%, 3-times increase of the end-diastolic pressure, 1.5-time increase of the time constant of left ventricular relaxation (Tau g) and 2-time increase of the end-diastolic stiffness). It has been found that NaHS inhibits oxidative and nitrosative stress, restores cNOS coupling and constitutive de novo synthesis of nitric oxide (NO), which promotes an improvement of the diastolic function (increase of the dp/dtmin by 20% and decrease of Tau g by 13%) . Key words: aging; cNOS uncoupling; heart; hydrogen sulfide; nitrosative stress; oxidative stress. PMID- 29762967 TI - Modulation of the hippocampal propensity to non- synaptic epileptiform synchronization in low-calcium model of epilepsy. AB - The CA3 and CAI regions are the main stages of the "three-synaptic pathway", which plays a role in the generation of hyper-synchronous events in the hippocampus. Under certain experimental conditions, this brain structure might support pathological epileptiform synchronization that is independent of active chemical synaptic transmission. In present work, we estimated the conditions that would facilitate non- synaptic synchronization of the hippocampus. Non-synaptic epileptiform activity was induced in hippocampal slices by the omission calcium ions from the extracellular milieu. The propensity of hippocampal regions to nonsynaptic interactions was estimated by measuring the delay time neededfor the development of low-Ca2+ discharges in the CA3 and CAI. Next, an increase of neuronal excitability was induced by the pre- incubation ofhippocampal slices in 4-aminopyridine (4-AP) and by the reduction ofextracellular osmolarity. Pre incubation of hippbcampal slices with 4-AP under normal osmotic conditions resulted in decreased latency for non-synaptic discharges in the CA3, but not in the CAl. However hypo-osmotic conditions caused increased excitability of the CA3 region, which resulted in decreased delay time for nonsynaptic discharges and this level of cellular excitability was not further enhanced by the pre incubation with 4-AR. PMID- 29762968 TI - THE RATIO OF P53-PROAPOPTOTIC AND BCL-2 ANTIAPOPTOTIC ACTIVITY IN THE HIPPOCAMPUS OF RATS WITH BRAIN ISCHEMIA-REPERFUSION AND EXPERIMENTAL DIABETES. AB - The dynamics of the balance of indices of pro- and p53- Bcl-2 anti-apoptotic processes in the hippocampus of rats with experimental diabetes mellitus (DM) complicated by incomplete global cerebral ischemia-reperfusion was investigated. It is shown that p53 proapoptotic processes in animals without diabetes after 20 minutes of ischemia/l hour reperfusion in all fields of the hippocampus are activated in the background of increasing Bcl-2 antiapoptotic processes in the fields CAl, CA2, CA4 and depression of it - in the CA3 field. In the early postischemic period in rats with DM activity of the p53-proapoptotic processes in fields CAl, CA3, CA4 significantly exceeds that in non-diabetic rats (area of p53 IRM increases on 110, 60 and 27 %), and was significantly lower than that detected in CA2 field. On the 12th day of post-ischemic period, activation of apoptosis in field CAl occurs in the background of inert antiapoptotic processes, in animals without diabetes, as well as in diabetic rats, but the indicators characterizing of apoptotic activity in rats with diabetes were higher (specific contents of p53 protein and area ofp53 -IRM increases on 38 and 43 %). During this period, in the CA2 region of the non-diabetic animals, some depression of the antiapoptotic processes with a slight predominance of proapoptotic processes was detected. In the field of CA3 region of rats without diabetes, the retention of activity of proapoptotic processes and the deepening in the dynamics of depression of antiapoptotic processes were showed. In rats with DM, the oppression of both mechanisms with a significant depression of antiapoptotic processes was observed. On the 12th day of experiment in the field CA4, the most balanced relationship were detected between the studied of the processes due to their parallel and unidirectional changes both in the rats without diabetes as well as with DM. The results point on the modifying effect ofDM on susceptibility ofhippocampal fields to ischemic-reperfusion injury. PMID- 29762969 TI - ROLE OF NITRIC OXIDE METABOLITES WITHIN THE IMPACT OF THE SUB-TOXIC SUCCINAMIDES DOSES ON STATE OF HEMOSTASIS. AB - We investigated the role of changes in the endogenous nitric oxide (NO) metabolism during the influence of succinic acid amides as biotransformation products of an anti-diabetic drug on the state of hemostasis. In experiment with rats, synthetic succinamides were applied in quanti- ties equimolar to the sub toxic dose of the pharmaceutical substance. We investigated the indicators characterizing the state of platelet and coagulation hemostasis in the blood plasma, the content of the stable NO metabolites and the activity of nitrogen oxide synthase (NOS) in the liver homogenate, blood plasma and urine of rats. We found that sub-chronic succinamides introduction reduced the nitrite and nitrate anions concentration in the blood plasma (by 30-50 and 20-35% resp.), liver (by 16-19 and 14-18%) and urine (by 50-70 and 38-55%). These changes were essentially dependent on the reduction in the NOS activity (by 33%). The studied compounds showed a 1.5 fold increase in the coagulation potential of the blood plasma and cause a 20% boost in the aggregation of thrombocytes. Analysis of the pair correlation coefficients showed positive association of the changes in indicators of the NO metabolism and hemostasis. The obtained results suggest that the registered manifestation of the pro-coagulation and thrombogenic action of succinamides applied in the sub-toxic doses is partially determined by a drop of the vasoactive NO pool that in turn, occurs due to a decline of the NOS activity. PMID- 29762970 TI - Polymorphism Pro12 --Ala of the peroxisome proliferator-activated receptors gamma gene effect on lipid peroxidation and antioxidant defense in patients with type 2 diabetes. AB - In this research, we discover effect ofpolymorphism rs1801282 of the PPARG gene on the formation oxidative stress in patients with type 2 diabetes, depending on the duration of the disease: till 5 years, 5-10 years and more than 10 years. Activity of lipidperoxidation was assess in terms of diene conjugates (DC) and malonic dealdehid (MDA) and antioxidant system status - the activity of superoxide dismutase (SOD), catalase and the level of a-tocopherol (a-TF). Molecular genetic studies conducted by the method ofpolymerase chain reaction (PCR) in real time. During disease 5-10 years, found increase levels of DC and MDA in patients with polymorphism Pro12--Ala for 34.9 and 34.7%, in compared with ProPro12 --Pro (P=O. 01). Availability ProPro12 --Pro stipulated reduction of catalase activity during disease 5-10 years at 75% (P=O. 001), andfor those, who are illfor more than 10 years at 2,04 times (P=O.01), which is not different from the reference level (F=1. 19; P=O. 600), but in the case ProPro12 --Ala, this figure was in 2 times higher The main conclu- sion is that the type ProPro12 - +Ala ofpolymorphism rs1801282 of the PPARG gene causes the development of oxidative stress in patients with type 2 diabetes with 5-10 years durations, and Pro Pro12 --Pro - deficiency the enzyme catalase level of antioxidant system in patients with durations of disease more than 5 years. PMID- 29762971 TI - NO-ERGIC CONTROL OF BLOOD CIRCULATION IN THE MEDULLA OBLONGATA OF RATS WITH EXPERIMENTAL HEMIPARKINSONIZM UNDER EXPOSURE TO CONTINUOUS LIGHT. AB - The study was conducted on rats with unilateral damage to dopaminergic (DA) neurons in substantia nigra of the midbrain (experimental hemiparkinsonism). Degeneration of dopaminergic (DA) neurons was accompanied by hyperactivity of those neurons that remained intact and responded to apomorphine (Apo) test by rotational movements. Depending on the number of rotations, three groups of animals were defined. In the medulla oblongata of rats with unilateral damage to dopaminergic (DA) neurons, a significant increase in the activity of inducible NO synthase (iNOS) was observed, while the activity of constitutive NO-synthase (cNOS) tended to decrease compared with that in control rats. An activation of neuronal NO-synthase (nNOS) in those rats by injections of L-arginine in the medullary nuclei was accompanied by weakening of the hemodynamic effects compared to those in control rats. An exposure of animals to continuous light for three weeks was accompanied by increasing the number of damaged DA-ergic neurons in substantia nigra. At that, a significant decrease in cNOS activity in the medulla oblongata was observed, leading to the inhibition of de novo synthesis of nitric oxide (NO). The reduction of NO synthesis in the medulla oblongata neurons of rats with experimental hemiparkinsonism following their exposure to continuous light was also evidenced by the reduction. PMID- 29762972 TI - PROGESTERONE RECEPTOR GENE POLYMORPHISMS AS GENETIC RISK FACTOR OF THREATENED ABORTION. AB - Determination of the progesterone receptor gene polymor- phisms rs590688 C/G and rs500760 A/G was provided using PCR method. To investigate the genetical precursors of threatened abortion the next groups were included: 67 patients with threatened abortion and 93 healthy persons. These allelic variants have the significantly different at rs590688 study: C/C - 23,9%, C/G - 44,8%, GIG - 31,3%, and C/C - 27,2%, C/G - 58,7%, GIG - 14,1% in the control group (P<0,05 by x2 test). The allelic variants of the rs500760 polymorphism did not differ statistically in the study group A/A 53,7%, A/G - 40,3%, GIG - 6% in the control group A/A- 52,2%, A/G - 44,6%, GIG - 3,3% (P>0,05 by x2-test). Distribution of minor homozygote GIG polymorphism rs590688 progesterone receptor gene in patients with threatened abortion in our study almost in 10 times higher in comparing with women of Taiwanese Han population, who had idiopathic recurrent pregnancy loss. The obtained data indicate significant ethnic differences in PGR and show polymorphism rs590688 clinical significance. PMID- 29762973 TI - DOXORUBICIN-INDUSED DISTURBANCES OF CARDIOMYOCYTE CONTRACTILE ACTIVITY. AB - The aim of our study was to find out the mechanisms of cardiomyocyte contractile activity disturbances under the influence of anthracycline antibiotics and curcumin correction capabilities, to clarify the role of the mitochondrial membrane potential changes in cardiomyocyte contractile activity. It was investigated disturbances of contractile activity of the rat neonatal cardiomyocytes under the influence of anthracycline antibiotics (doxorubicin), and the possibility of correcting these violations using antioxidant curcumin. In addition, there was researched the role of mitochondrial membrane potential changes in reducing contractile activity of the cardiomyocytes. We established that doxorubicin causes significant changes in all reduction parameters compared to control: increased frequency of spontaneous contractions, violation of rhythm, lower amplitude and the shortening %, increase in the maximum speed of contraction and relaxation without changes in duration of these processes. Compatible incubation with doxorubicin and curcumin caused a consid- erable decrease of the incidence of spontaneous emission (3 times), restored their rhythm, increasing the amplitude of 2 times and the shortening % (8,15 +/- 0,37), rising the maximum speed reduction to 1,8 times and the relaxation speed of 16 %, with no significant change in duration of these processes compared to monoincubation with doxorubicin. In the fluorescence study of neonatal cardiomyocytes mitochondrial potential was detected a significant reduction in mitochondria color brightness under the influence of doxorubicin - in 1,7 times compared to control. A compatible incubation of cells with curcumin and doxorubicin resulted in an elevation of mitochondria fluorescence (2,2 times compared to using of doxorubicin only). PMID- 29762974 TI - RESTRUCTURING OF SKELETAL MUSCLE, LUNG AND HEART TISSUES OF RATS UNDER HYPOXIA TRAINING. AB - We studied some specific features of the changes in mor- pho- and stereometric characteristics of the ultrastructure of tissues of lungs, heart, and muscles, their capillarization, and the mitochondrial apparatus of cells in adult male Wistar rats under long-term physical loads. It is shown that the influence of a sustained training accompanied by the development of exercise-induced hypoxia on the structural readjustments of tissues of muscles, lungs, and myocardium can be conditionally divided into 2 groups: with destructive and compensatoryadaptive features. The changes with destructive character include, firstly, those of the ultrastructure of biological bar- riers such as, in particular, hyperhydration of barriers on the whole and their separate layers, which deteriorates the conditions of oxygen diffusion; second, the destructive changes in mitochondria (it increased the number of damaged lung organelles by 4.1 times, in the heart - at 4.5-5.5 times depending on subpopulations and in muscle - by 3.5-12.2 times also depending on the subpopulation of mitochondria), which are accompanied by a decrease in the energy potential of the mitochondrial apparatus, are observed. To the changes with compensatory-adaptive character, we refer an increase in the number of functioning capillaries (by 80% in the gastrocnemius muscle and by 60% in the myocardium), which prevents the development of secondary tissue hypoxia; intensification of pinocytosis in endotheliocytes; activation of mitochondrial morphogenesis, which was accompanied by an increase of the number of organelles at gastrocnemius muscle by 65%, in the lungs - in 4 times and in heart by 60-80% depending on the mitochondrial subpopulations; and appearance of young mitochondria and mitochondria with moderate degree of swelling, which favors the growth of the energy power of the mitochondrial apparatus of cells. PMID- 29762975 TI - STATES OF PSYCHOPHYSIOLOGICAL FUNCTIONS OF ELITE ATHLETES IN DIFFERENT AGING GROUPS. AB - The influences of aging peculiarities in elite athletes on the psychophysiological states on the stage of the maximum capacity were studied. Three groups of athletes with different age were studied. The first group was composed of the athletes aged 18-20, the second one included athletes aged 21-25, the third group included athletes aged 26-34, and were the members of the team of Ukraine in Greco-Roman wrestling. We revealed that elite athletes of older age group were significantly different from the younger by the presence of a large fatigue with the decline of autonomy when forming strategies of sports activities and more perfect the mechanism of autonomic reactions. The aging deterioration of perception of visual information in elite athletes of older age group manifested in a significant decrease of productivity, efficiency and speed for comparison with the groups of younger athletes. Also, in elite athletes older age group there is a significantly higher level of tension of autonomic regulation of heart rhythm compared with young athletes and the presence of more optimal activation of the sympathetic division of the autonomic nervous system. PMID- 29762976 TI - MORPHOLOGICAL CHANGES PANCREAS AFTER OF MELATONIN'S EFFECT IN DIFFERENT SEASONS. AB - Morphological changes of the pancreas of young rats after exposure of exogenous melatonin in the spring and autumn periods was investigated. Exogenous melatonin (Unipharm Inc., USA) was administered to experimental group of animals daily'at a dose 5 mg/kg. The duration of the experiment was 28 days. It was revealed that the exocrine part of the.pancreas responds differently to the effects of melatonin at different times of the year. Thus, after administration of melatonin in the spring increase of the size of acinus, the height of the epithelium (by 7 %), area exocrinocytes (by 58 %), of their nucleus (by 20 %) and cytoplasm (69 %), the amount of nucleoli in cells (18 %), reduction the amount of connective tissue elements. Melatonin introduction in the autumn decrease in the size of acinus, height and area of exocrinocytes, growth the number of exocrinocytes in the acinus, nucleoli and width layers interlobular connective tissue in the gland. This may indicate that melatonin increases in the spring of the synthetic activity of the exocrine pancreas, whereas in the autumn (for the majority of the morphometric parameters) - somewhat reduces its functional state. The administration of melatonin in the spring (mostly) and in the autumn periods increased the functional activity of the endocrine pancreas. This is indicated by growth in the size of Langerhans islets, increasing the number and density of the (autumn) endocrinocytes. PMID- 29762977 TI - THE STUDY OF THE RELATIONSHIP BETWEEN THE ACTIVITY OF EPIPHYSIS AND GONADS IN MALE RATS IN DIFFERENT SEASONS. AB - In male rats of different ages, we studied the functional activity of the pineal gland and the gonads during different seasons by determining the levels of melatonin and testosterone in the blood serum. It was found that the highest levels of melatonin observed in male rats in summer and winter, and the lowest - in autumn. The lowest level of melatonin has been established in the group of rats aged 9 months - 127.28+5.11 pmol/l that was 22% lower than the level of melatonin in 3 months old rats (P!0,05), and 20% below the level of melatonin in rats of 15 months old (Ps0,05). The highest level determined in rats aged 3 months (corresponds to the age of man -14 years old), the lowest - in rats 20 months-(corresponds to the age 55-56 years old). At the same time, the low level of melatonin was defined in rats aged 9 months in the autumn (corresponds to the age of man 29-30 years). In the study of testosterone levels in different seasons it was found that the highest level in all age groups presents in autumn, the lowest - in winter. When comparing the levels of testosterone in different age groups, it was determined that the fall of the highest level of testosterone present in the blood of males age 9 months and 15 months, which corresponds to the age of 29-30 and 43-44 of human years. Significant difference between the levels of testosterone in the groups that correspond to the reproductive age - rats of age 3, 9 and 15 months, are present only in the autumn; spring and summer - significant differences between the levels of testosterone absent. The degree of correlation differed in rats of different ages in different seasons: the highest correlation between the levels of melatonin and testosterone was determined in rats aged 9 months in autumn. The correlation coefficients in rats aged 20 months old have been weak - from 0.05 in the spring to 0.17 in autumn that shows the changes in neurohormonal regulation which occur with age. PMID- 29762978 TI - EVALUATION OF THE FUNCTIONAL STATE OF LIVER AND THE EFFICIENCY OF THERAPY FOR ENTEROPATHY OF CALVES. AB - Comprehensive study of hepatospecific biochemical blood markers and haemostatic system in calves which recovered from gastrointestinal pathology at age 2-7 days, was con- ducted. Implementation of a complex of tests for evaluation of the liver's functional state and the efficiency of therapeutic regimens shown that the experimental animals compared to control at the 30th day of life demonstrated significantly increased conjugated bilirubin concentration (1.6 times), aspartate and alanin aminotransferase activity (1.2 times), gamma-glutamyl transpeptidase (1.5 times) and alkaline phosphatase (1.4 times), and content of soluble fibrin monomer complexes (4 times). Such deviation from the norm of the mentioned parameters of liver's functional state suggests the need to monitor the liver state even 3 weeks after their clinical health is confirmed. To prevent the development of secondary hepatopathology it is recommended to conduct further medical correction of the functional state of the liver. It is found that to stimulate recovery of liver function in case of toxic dyspepsia in newborn calves, it is advisable to implement a phospholipid containing supplement =5 lp/cm) of half-fan scanning conditions were inferior to those (>=7 lp/cm) of ful-fan mode. The accuracies of spatial linear distance and angle were within+/-1%. HUs in air density plug were constant, but HUs of other plugs with different conditions had the signifi cant difference (F=660.84,P=0). Under different conditions in a year, the mean HUs showed a good agreement. Conclusions: HUs of CBCT image under different scanning conditions exist a little difference, but there is a good consistency for the long term stability analysis. It is helpful for CBCT images directly used for dose re-calculation in adaptive radiation therapy (ART). PMID- 29763219 TI - [Study of Motion Artifacts Correction Algorithm in Optical Coherence Tomography Images Based on C-Scan of Optic Disc]. AB - Optical Coherence Tomography(OCT) system may cause dislocations and distortions of the collected image volumetric?data when proceeding dynamic 3D imaging because of the involuntary movements of eyebal, which wil result in misdiagnoses during clinical diagnosis. The optic disk region of human eye has much more complex structure and further more blood vessels compared with macular region, which means the conventional image correction method aiming at macular region can not apply to optic disk region. In this paper, we propose a X direction artifact correcting method based on pixel row correlation matching algorithm of C-Scan, specifi c to the structural features of human eye optic disk region OCT images. Moreover, using this method, we can estimate whether the image sequences with motion artifacts have part image repetition or missing or not, and we can further confi rm the positions and numbers of repetition and missing with the help of Y direction 2D scan images. Model verifi cation indicates that this method can effectively rebuild the real image sequences and truly refl ect the physiology structure of retina. PMID- 29763220 TI - [A Method of Ultrasonic Probe Calibration Based on Optical Positioning System]. AB - Inorder to track the ultrasonic imaging plane using a 3D spatial tracking device in application such as ultrasound guided interventional operation, a transform between ultrasound probe and the ultrasound image has to be determined by calibration. Based on the N-phantom, we use a phantom that 8 points is known and NDI optical positioning system for calibration to do this. The calibration process divides into three steps:fi rstly getting 8 bright spots orderly in the ultrasound image when the phantom is scanned by the ultrasound probe with a receiver sensor; secondly using the NDI optical positioning system get the transform between receiver and transmitter coordinate, the transmitter and phantom coordinate; lastly realizing the calibration by extracting feature points of the image bright spots and deciding the position relation matrix according to least square method. It is proved that the calibration method is convenient to use, and the calibration precision is not only meet the demand of ultrasound guide and exceed to conventional approach and reach to 2.72 mm,laying a good foundation for further 3D reconstruction. PMID- 29763221 TI - [Analysis and Control of Endoscopic Security Risk in Digital Integrated Environment]. AB - Taking Endoscopy in hospitals as the research object, study on the safety risk characteristics in digital integration environment. On the basis of risk analysis, risk prevention and control measures are proposed from personnel, equipment, water and electricity, disinfection and the surrounding environment. Establish the endoscope safety risk management safeguard system to improve the safety risk management level of endoscopy. PMID- 29763222 TI - [The Intelligent Beds Monitoring System Based on Sensor Technology]. AB - An inteligent beds monitoring system based on sensor technology is developed. Through the instalation of sensors in the bed, the patient's vital signs like heart rate, breathing rate can be acquired, other information such as rol over, in/out of bed can be real-time monitored. Also, the system can automaticaly analysis data and remind the nurse if abnormal events happened. After one year's clinical application, the system received the affi rmation from patients and medical staff. PMID- 29763223 TI - [Development of an Alarm Device for Non-contact Detection of Sleep Apnea]. AB - To non-contact alarm the sleep apnea under low physical and mental load condition a device was designed including the modules of minimized bio-radar, signal conditioning, control, alarm and power supply, which can realize the function of non-contat detection of the breathing signal, sleep apnea detection and alarm. Experimental results showed that the device can not only non-contact detection the breathing signal without any sensors or electrodes touching the human body, but also has the advantages of smal volume, low power consumption and low price, which may be widely used in monitor the patients with sleep apnea at home or in the hospital. PMID- 29763224 TI - [An Emerging Simulation Method Used in System Simulation of Flow Chamber of Hematology Analyzer]. AB - In fluid flow field analysis, the common simulation method is 1-D simulation or 3 D simulation, In order to analyze blood fluid system more quickly and accurately and choose the appropriate sample tube at the beginning of design for the system, this paper adopts a recently emerging 1D-3D simulation method to make simulations of flow chamber subsystem. Respectively using Flow master and ANSYS system modeling, use MpCCI connects the two parameter coupling, realize the sheath fluid velocity of research. The software can meet the needs of design and analysis of the Hematology Analyzer fluid system. In this paper, the method of co-simulation for medical apparatus and instruments of Hematology Analyzer fluid system development provides a new method, has important significance on the subsequent simulation. PMID- 29763225 TI - [Second Design and Development of SC-600 Type Double Pressure Breathing Machine]. AB - In view of the large noise and high failure rate of the valve of the SC-600 type double pressure breathing machine during clinical using, the paper describes the main improvement methods of the second design and development of this type of machine. PMID- 29763226 TI - [A Multifunctional Portable Universal Safety Type Bone Hole Probe Pen]. AB - Objective: In order to overcome the problems that the ordinary sounder's volume is bulky, has less function, is inconvenient to carry, its adaptation is weak, easy faling damage or occurrence of sharp instrument injury and other defects, the multifunctional portable universal safety type bone hole probe pen is developed. Methods: This pen set detection, loading and unloading, twisting and winding, straight, guide and maintenance functions in one. Take reference to contrast with ordinary sounder after surgery, experiment and teaching application. Results: This pen is a multipurpose, safe and universal, damage resistant and portable, high cost-effective. Conclusions: This pen is easy to carry and store, the apparatus preparation is simple and quick, it can free instrument box, prevent of sharp injuries, improve the operating efficiency. Its adaptation is high, it is suitable both in peacetime and in wartime. PMID- 29763227 TI - [Applications of Instant Biochemical Detector in Pediatrics Based on POCT Mode]. AB - Based on the analysis of many problems in the process of pediatric biochemical testing, this paper summarizes the technical basis and advantages of POCT (point of-care testing) mode, and introduces several applications of instant biochemical detector in pediatrics on POCT mode. The prospects of the POCT mode are discussed at the end. PMID- 29763228 TI - [Current Situation and Prospects of Emergency Medical Equipment in Our Country]. AB - This article analyzes the new demand of emergency medical equipment in the current development trend based on the analysis of the development and current situation of emergency medicine in our country. At the same time it introduces the current industrial characteristics of our country. Finally it analyzes the development trend of this kind of equipment in the new emergency medicine field. PMID- 29763229 TI - [Study of the Determination Method of Protein Content in Chitosan]. AB - Objective: Using the Coomassie briliant blue method to solve the problem of the precipitation when detecting the protein content in chitosan. Methods: Improving the Coomassie briliant blue method. Results: Use the Coomassie briliant blue solution with hydrochloric acid concentration of 5% as stain, stain 15 min , the maximum absorption wavelength is 598 nm. the standard curve of absorbance-protein concentration isy=0.003x+0.017 9.r2=0.991, the linear correlation is good within the protein concentration scope of 5MUg/mL~40MUg/mL, the lowest detection limit is 1MUg/mL, and its recovery is 97.8%~103.7%. Conclusions: In this paper, the method of determining the content of protein in chitosan is high accurate, stable, reliable and reproducible, and can be widely used in product testing. PMID- 29763230 TI - [Research of Determining Complete Degradation Time in Vitro Based on Cellulose Absorbable Hemostatic Products]. AB - To develop a method for determining complete degradation time of solublehemostatic products in vitro with accuracy, high speed and effectiveness, the current weight loss method originated from GB/T 16886 serial standards was optimized by using dialysis bag combined with assay of reducing sugar. The degradation was carried out with 3% hydrogen peroxide solution, at 37C, 150 rpm. The dialysis bags were taken out in the 3rd, 6th, 8th, 10th and 14th day, vacuum drying folowed by percentage of weight loss testing. Cumulative content of reducing sugar in degradation solution out of dialysis bag was determined simultaneously. The correlation analysis was performed by SPSS 22.0 equipped with Pearson Correlation Coeffi cient. The correlation coeffi cient between percentage of weight loss and cumulative content of reducing sugar was 0.957, which ilustrated high correlation with each other. Hence dialysis bag combined with assay of reducing sugar is capable of evaluating the degradation endpoint of soluble hemostatic products in vitro. The method also provides a way for the evaluation of degradation of other degradable biomaterials in vitro. PMID- 29763231 TI - [Infant Incubator Temperature Monitoring Difference Analysis and Research]. AB - Objective: To discuss the temperature difference of infant incubator treatment for the baby to provide important guarantee, to ensure its safe operation. Methods: Using a completely independent of the infant incubator's temperature monitoring and alarm system of infant incubator temperature and monitoring and alarm system, 20 sets of real-time monitoring and automatic logging data, different brand infant incubator temperature changes compared with infant incubator's own body temperature, and analysis. Results: 20 sets of different brand infant incubator, 10(50%) in the devices panel display data with a monitoring device differences in measured data, clinical pose a safety hazard. Conclusions: For clinical use of infant incubator temperature real-time monitor, by the monitoring system for additional auxiliary monitoring and alarm, thereby improve infant incubator clinical application security, reduce the incidence of related medical accidents, improve the quality of medical treatment. PMID- 29763232 TI - [Investigation of the Problems and Solutions for CO2 Laser Treatment Apparatus in Hospital]. AB - The current situation of the CO2 laser treatment apparatus in hospital was evaluated through actual investigation and testing data in this paper. The existing problems have been analyzed and the solutions are proposed, which wil play a role in maintenance, testing and drafting standards for this kind of medical devices being used in hospital. PMID- 29763233 TI - [Analysis and Study of Adverse Event about Ophthalmic Sodium Hyaluronate Gel]. AB - Objective: To investigate and analysis the multiple medical adverse events about Ophthalmic Sodium Hyaluronate Gel during clinical using in Zhejiang Province. Methods: Analysis, evaluation of the related adverse events about the Ophthalmic Sodium Hyaluronate Gel according to adverse events andevent primary reason statement which happened in the period from January 1, 2009 to June 30, 2014 in Zhejiang province. Results: Reports mainly lelates to four aspects. Conclusions: On the premise of the quality of the products wil be continuously upgraded, and measures of products logistics wil be effectively controled, professional qualities and skils of department of ophthalmology wil be constantly improved, prevent recurrence and spread of the serious adverse events during the using of process. PMID- 29763249 TI - [Development of a Compared Software for Automatically Generated DVH in Eclipse TPS]. AB - Objective: This study is to automatically calculate the dose volume histogram(DVH) for the treatment plan, then to compare it with requirements of doctor's prescriptions. Methods: The scripting language Autohotkey and programming language C# were used to develop a compared software for automatically generated DVH in Eclipse TPS. This software is named Show Dose Volume Histogram (ShowDVH), which is composed of prescription documents generation, operation functions of DVH, software visualization and DVH compared report generation. Results: Ten cases in different cancers have been separately selected, in Eclipse TPS 11.0 ShowDVH could not only automatically generate DVH reports but also accurately determine whether treatment plans meet the requirements of doctor's prescriptions, then reports gave direction for setting optimization parameters of intensity modulated radiated therapy. Conclusions: The ShowDVH is an user-friendly and powerful software, and can automatically generated compared DVH reports fast in Eclipse TPS 11.0. With the help of ShowDVH, it greatly saves plan designing time and improves working efficiency of radiation therapy physicists. PMID- 29763234 TI - [The Determination of Tungsten Extracted from Prefi llable Syringes by ICP-MS]. AB - First, simply expounded the purpose and meaning of detecting tungsten extracted from prefi lable syringes: And then, designed simulation experiment for extracting tungsten from prefi lable glass syringes. and established determination methods of tungsten content by ICP-MSL Finaly, evaluated the limit of content of tungsten ?extracting from simulation experiment. PMID- 29763251 TI - One-Third of Patients with Anxiety Disorder Will Relapse When Antidepressant Treatment Stops. PMID- 29763250 TI - Primary Closure of Animal Bites. PMID- 29763252 TI - Charcot Foot: Clinical Clues, Diagnostic Strategies, and Treatment Principles. AB - Acute Charcot neuroarthropathy of the foot and ankle is often difficult to diagnose because of limited findings in the patient history, physical examination, imaging, and laboratory studies. Delay in treatment results in the development of rigid foot and ankle deformities, increasing the risk of ulceration, infection, and major lower extremity amputation. Acute Charcot neuroarthropathy should be suspected in any patient 40 years or older with obesity and peripheral neuropathy who presents with an acutely swollen foot following minimal or no recalled trauma and who reports minimal to no pain, particularly if radiography and laboratory markers of infection are normal. Magnetic resonance imaging or computed tomography should be performed in these cases. If changes consistent with acute Charcot neuroarthropathy are observed, prompt immobilization and/or referral to a foot and ankle subspecialist is needed to minimize sequelae. Immobilization should continue until lower extremity edema and warmth resolve, and serial radiography shows evidence of osseous consolidation. Intranasal calcitonin salmon may have a role as adjunctive therapy. Although controversial, surgery may be indicated if there is severe dislocation or instability, concern for skin breakdown, or failure of conservative treatment to obtain a stable, plantigrade foot. PMID- 29763254 TI - Gender-Dysphoric/Gender-Incongruent Persons: Treatment Recommendations from the Endocrine Society. PMID- 29763253 TI - Croup: Diagnosis and Management. AB - Croup is a common respiratory illness affecting 3% of children six months to three years of age. It accounts for 7% of hospitalizations annually for fever and/or acute respiratory illness in children younger than five years. Croup is a manifestation of upper airway obstruction resulting from swelling of the larynx, trachea, and bronchi, leading to inspiratory stridor and a barking cough. Many patients experience low-grade fevers, but fever is not necessary for diagnosis. Less commonly, stridor can be associated with acute epiglottitis, bacterial tracheitis, and foreign body airway obstruction. Laboratory studies are seldom needed for diagnosis of croup. Viral cultures and rapid antigen testing have minimal impact on management and are not routinely recommended. Radiography and laryngoscopy should be reserved for patients in whom alternative diagnoses are suspected. Randomized controlled trials have demonstrated that a single dose of oral, intramuscular, or intravenous dexamethasone improves symptoms and reduces return visits and length of hospitalization in children with croup of any severity. In patients with moderate to severe croup, the addition of nebulized epinephrine improves symptoms and reduces length of hospitalization. PMID- 29763255 TI - Antiepileptic Drug Monotherapy for Epilepsy. PMID- 29763256 TI - Exercise Alone and Various Combinations of Interventions Reduce the Risk of Injurious Falls in Older Adults. PMID- 29763257 TI - Clinical and Personal Utility of Genetic Risk Testing. PMID- 29763258 TI - Lumbar Fusion of Variable Value Based on Treating Diagnosis, with Significant Complication Rates. PMID- 29763260 TI - AAPF News: AFP Edition. PMID- 29763259 TI - Single Question Is Useful for Identifying Acute Mountain Sickness in Travelers at High Altitude. PMID- 29763261 TI - Obesity in Pregnancy: Risks and Management. PMID- 29763262 TI - Omega-3 Fatty Acids and Cardiovascular Disease. PMID- 29763263 TI - Effectiveness of Pneumococcal Vaccines. PMID- 29763265 TI - Pregabalin (Lyrica) for Acute Fibromyalgia Pain. PMID- 29763264 TI - Hyperpigmented Patches on the Dorsal Hands. PMID- 29763266 TI - Effectiveness and Safety of Celecoxib for the Treatment of Rheumatoid Arthritis. PMID- 29763268 TI - Croup: What You Should Know. PMID- 29763267 TI - Top 20 Research Studies of 2017 for Primary Care Physicians. AB - Based on systematic surveillance of more than 110 medical journals, 247 studies met criteria as POEMs (patient-oriented evidence that matters) in 2017. Members of the Canadian Medical Association identified 20 of these POEMs as most relevant to practice. This article reviews the clinical questions and bottom-line answers from these studies. Blood pressure should be measured after a period of rest, using a bare arm, and orthostatic blood pressure is more predictive when measured after one minute of standing rather than three minutes. Intensive blood pressure lowering results in cardiovascular benefits but also renal harms in high-risk patients with an average age of 68 years. The initiation of a statin for primary prevention does not reduce cardiovascular events in adults 65 years or older. Sterile gloves do not reduce the risk of infection for common outpatient skin procedures, and the preferred approach to managing onychomycosis is empiric oral terbinafine. Routine home glucose monitoring is not needed in patients with type 2 diabetes mellitus, and trying to achieve an A1C target level of 6.0% rather than 7.0% to 7.9% does not improve outcomes and may be harmful. Fasting blood glucose and A1C levels have limited accuracy for identifying glucose intolerance, and patients 65 years and older with thyroid-stimulating hormone levels between 4.6 and 10.0 mIU per mL should be rechecked before considering treatment. Gabapentin and pregabalin are not effective for acute or chronic low back pain, even in patients with sciatica. Physical therapy does not provide any additional benefit over usual care in patients with acute ankle sprain, and corticosteroid injections for knee osteoarthritis are ineffective and may damage cartilage. A two-question screening test can rule out depression in older adults; a large U.S. trial continued to find no benefit to prostate cancer screening; and clinicians need to be thoughtful about how they discuss recommendations to stop screening for cancer in older patients. Finally, ibuprofen, naproxen, and celecoxib have similar risks of adverse events, and continuous positive airway pressure in patients with obstructive sleep apnea does not reduce the risk of cardiovascular events. PMID- 29763269 TI - Screening for Adolescent Idiopathic Scoliosis: Recommendation Statement. PMID- 29763270 TI - Screening for Adolescent Idiopathic Scoliosis. PMID- 29763271 TI - Adults with Developmental Disabilities: A Comprehensive Approach to Medical Care. AB - Developmental disabilities are attributable to a cognitive impairment, physical impairment, or both. They manifest during the developmental period from birth to early adulthood, and are likely to continue indefinitely. The life expectancy of most persons with developmental disabilities now approaches that of the general population. According to the neurodiversity model of care, developmental disability is accepted as a valued part of human neurologic diversity. The social model focuses on improving participation in society with accommodations such as adaptive equipment or improvements to the social and physical environment. The goal of health care for patients with developmental disabilities is to improve their well-being, function, and participation in family and community. Physicians should communicate directly with their patients, even those who have communication or cognitive differences. Communication may include speech, sign language, writing, letter boards, voice output devices, pictures, facial expressions, gestures, vocalizations, and behavior. Supported decision making is a paradigm, support practice, and emerging legal structure that focuses on assisting patients with communicating their wants and needs as an alternative to guardianship or power of attorney. When establishing care, it is critical to get a detailed history of baseline traits and characteristics in the areas of cognition and communication; neuromuscular function; sensory function such as vision, hearing, and sensory processing; seizure threshold; mental health; and behavior. In general, guidelines for age-appropriate health maintenance in the general population should be followed unless the risk outweighs the benefit for an individual patient. With accurate diagnosis, psychiatric conditions can be treated effectively with the same medical, behavioral, and therapeutic modalities used in the general population. Just like any patient, those with developmental disabilities should have access to a full range of life-sustaining, curative, and end-of-life services. PMID- 29763272 TI - Colorectal Cancer Screening and Prevention. AB - Colorectal cancer is a common cause of morbidity and mortality in the United States. Most colorectal cancers arise from preexisting adenomatous or serrated polyps. The incidence and mortality of colorectal cancer can be reduced with screening of average-risk adults 50 to 75 years of age. Randomized controlled trials show evidence of reduced colorectal cancer-specific mortality with guaiac based fecal occult blood tests and flexible sigmoidoscopy. There are no randomized controlled trials on the effectiveness of colonoscopy to reduce colorectal cancer-specific mortality; however, several randomized controlled trials comparing colonoscopy with other strategies are in progress. The best available evidence supporting colonoscopy is from prospective cohort studies that demonstrate decreased incidence of colorectal cancer and colorectal cancer related mortality in individuals undergoing colonoscopy. Other screening options include fecal immunochemical testing, computed tomographic colonography, and multitargeted stool DNA testing combined with fecal immunochemical testing. There is good evidence that aspirin, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, and hormone therapy decrease the risk of colorectal cancer and adenomatous polyps, but potential harms limit their usefulness. There is good evidence that calcium supplementation, moderate dairy consumption, reduced red meat consumption, increased physical activity, decreased body mass index, and statin use decrease the risk of colorectal cancer and adenomatous polyps. Although increased alcohol intake and tobacco use are associated with an increased risk of colorectal cancer, there is no direct evidence that reducing alcohol consumption or smoking cessation decreases the risk. PMID- 29763273 TI - A Woman with Multiple Joint Dislocations. PMID- 29763274 TI - Eosinophilic Esophagitis: A Mimic of Gastroesophageal Reflux Disease. PMID- 29763275 TI - General Parenting Strategies: Practical Suggestions for Common Child Behavior Issues. AB - Parents often seek guidance from physicians on child behavior problems. Questions may range from general parenting strategies to managing specific child behaviors. Physicians and their staff can identify problematic parent-child interactions or behaviors within the office setting and assist parents by providing effective monitoring tools for behavior problems. Effective strategies for influencing a child's behavior include positive reinforcement to increase appropriate behavior, extinction (planned ignoring) for most low-level problematic behaviors, and time out from reinforcement for more problematic behaviors. Written contracting provides parents the opportunity to communicate with their children about important behaviors and strengthens the commitment of each party to improve behavior. Parents should be cautioned about the use of punishment (e.g., scolding, taking away privileges or possessions) because it suppresses behavior only temporarily. Physicians should discourage physical or corporal punishment because it is related to negative parent-child relationships, increased aggressiveness, antisocial behavior, lower cognitive ability, lower self-esteem, mental health problems, and increased risk of physical abuse. PMID- 29763276 TI - Hyperpronation Method for Reduction of Nursemaid's Elbow. PMID- 29763277 TI - Infectious Diarrhea: IDSA Updates Guidelines for Diagnosis and Management. PMID- 29763278 TI - Implantable Buprenorphine (Probuphine) for Maintenance Treatment of Opioid Use Disorder. PMID- 29763280 TI - Maternal Obesity and Labor Induction. PMID- 29763281 TI - Persons with Disabilities: I'm the Expert About My Body. PMID- 29763282 TI - Colon Cancer. PMID- 29763283 TI - A Parent's Guide to Using Time Out. PMID- 29763284 TI - General Parenting Tips. PMID- 29763285 TI - Inverse Opal Photonic Crystals as an Optofluidic Platform for Fast Analysis of Hydrocarbon Mixtures. AB - Most of the reported optofluidic devices analyze liquid by measuring its refractive index. Recently, the wettability of liquid on various substrates has also been used as a key sensing parameter in optofluidic sensors. However, the above-mentioned techniques face challenges in the analysis of the relative concentration of components in an alkane hydrocarbon mixture, as both refractive indices and wettabilities of alkane hydrocarbons are very close. Here, we propose to apply volatility of liquid as the key sensing parameter, correlate it to the optical property of liquid inside inverse opal photonic crystals, and construct powerful optofluidic sensors for alkane hydrocarbon identification and analysis. We have demonstrated that via evaporation of hydrocarbons inside the periodic structure of inverse opal photonic crystals and observation of their reflection spectra, an inverse opal film could be used as a fast-response optofluidic sensor to accurately differentiate pure hydrocarbon liquids and relative concentrations of their binary and ternary mixtures in tens of seconds. In these 3D photonic crystals, pure chemicals with different volatilities would have different evaporation rates and can be easily identified via the total drying time. For multicomponent mixtures, the same strategy is applied to determine the relative concentration of each component simply by measuring drying time under different temperatures. Using this optofluidic sensing platform, we have determined the relative concentrations of ternary hydrocarbon mixtures with the difference of only one carbon between alkane hydrocarbons, which is a big step toward detailed hydrocarbon analysis for practical use. PMID- 29763286 TI - Engineering of Neuron Growth and Enhancing Cell-Chip Communication via Mixed SAMs. AB - The interface between cells and inorganic surfaces represents one of the key elements for bioelectronics experiments and applications ranging from cell cultures and bioelectronics devices to medical implants. In the present paper, we describe a way to tailor the biocompatibility of substrates in terms of cell growth and to significantly improve cell-chip communication, and we also demonstrate the reusability of the substrates for cell experiments. All these improvements are achieved by coating the substrates or chips with a self assembled monolayer (SAM) consisting of a mixture of organic molecules, (3 aminopropyl)-triethoxysilane and (3-glycidyloxypropyl)-trimethoxysilane. By varying the ratio of these molecules, we are able to tune the cell density and live/dead ratios of rat cortical neurons cultured directly on the mixed SAM as well as neurons cultured on protein-coated SAMs. Furthermore, the use of the SAM leads to a significant improvement in cell-chip communications. Action potential signals of up to 9.4 +/- 0.6 mV (signal-to-noise ratio up to 47) are obtained for HL-1 cells on microelectrode arrays. Finally, we demonstrate that the SAMs facilitate a reusability of the samples for all cell experiments with little re processing. PMID- 29763287 TI - Insight Studies on Metal-Organic Framework Nanofibrous Membrane Adsorption and Activation for Heavy Metal Ions Removal from Aqueous Solution. AB - Electrospun nanofiber composite membranes containing water-stable metal-organic frameworks (MOFs) particles (Zr-based MOF-808) supported on polyacrylonitrile (PAN) nanofiber synthesized via co-electrospinning have been prepared. MOF particles were dispersed in the organic polymer, and their subsequent presence was inferred by scanning electron microscopy. Membrane performance in heavy metal ion adsorption in batch filtration was evaluated on the basis of Cd2+ and Zn2+ ions sequestration. The adsorption capacities of the pristine MOF and the MOF composite membrane revealed that MOF particles in the membrane could be accessed for adsorption in the hydrophilic PAN membranes. The maximum adsorption capacities were 225.05 and 287.06 mg g-1 for Cd2+ and Zn2+, respectively. Conventional thermal activation of pristine MOF and composite membrane revealed a crystal downsizing, while "hydractivation" produced an expanded MOF with enhanced adsorption potentials. The PAN/MOF-808 "hydractivated" composite membrane could treat 580 mL of Cd, whereas the conventional vacuum-activated composite treated 464 mL. The high separation performance and reusability of the membranes and the outstanding water stability of the MOFs suggested the developed membrane as a potential candidate for water treatment. PMID- 29763288 TI - Quantum Dot Fullerene-Based Molecular Beacon Nanosensors for Rapid, Highly Sensitive Nucleic Acid Detection. AB - Spherical fullerene (C60) can quench the fluorescence of a quantum dot (QD) through energy-transfer and charge-transfer processes, with the quenching efficiency regulated by the number of proximate C60 on each QD. With the quenching property and its small size compared with other nanoparticle-based quenchers, it is advantageous to group a QD reporter and multiple C60-labeled oligonucleotide probes to construct a molecular beacon (MB) probe for sensitive, robust nucleic acid detection. We demonstrated a rapid, high-sensitivity DNA detection method using the nanosensors composed of QD-C60-based MBs carried by magnetic nanoparticles. The assay was accelerated by first dispersing the nanosensors in analytes for highly efficient DNA capture resulting from short distance three-dimensional diffusion of targets to the sensor surface and then concentrating the nanosensors to a substrate by magnetic force to amplify the fluorescence signal for target quantification. The enhanced mass transport enabled a rapid detection (<10 min) with a small sample volume (1-10 MUL). The high signal-to-noise ratio produced by the QD-C60 pairs and magnetic concentration yielded a detection limit of 100 fM (~106 target DNA copies for a 10 MUL analyte). The rapid, sensitive, label-free detection method will benefit the applications in point-of-care molecular diagnostic technologies. PMID- 29763289 TI - Interfacial Constructing Flexible V2O5@Polypyrrole Core-Shell Nanowire Membrane with Superior Supercapacitive Performance. AB - Flexible membrane consisting of ultralong V2O5@conducting polypyrrole (V2O5@PPy) core-shell nanowires is prepared by a facile in situ interfacial synthesis approach. The V2O5 is for the first time demonstrated to show versatile function of reactive template to initiate the uniform and conformal polymerization of PPy nanocoating without the need for extra oxidants. The freestanding PPy encapsulated V2O5 nanowire membrane is of great benefit in achieving strong electrochemical harvest by increasing electrical conductivity, shortening ion/electron transport distance, and enlarging electrode/electrolyte contact area. When evaluated as binder- and additive-free supercapacitor electrodes, the V2O5@PPy core-shell hybrid delivers a significantly enhanced specific capacitance of 334 F g-1 along with superior rate capability and improved cycling stability. The present work would provide a simple yet powerful interfacial strategy for elaborate constructing V2O5/conducting polymers toward various energy-storage technologies. PMID- 29763290 TI - Protons as Versatile Reporters in Solid-State NMR Spectroscopy. AB - Solid-state nuclear magnetic resonance (ssNMR) is a spectroscopic technique that is used for characterization of molecular properties in the solid phase at atomic resolution. In particular, using the approach of magic-angle spinning (MAS), ssNMR has seen widespread applications for topics ranging from material sciences to catalysis, metabolomics, and structural biology, where both isotropic and anisotropic parameters can be exploited for a detailed assessment of molecular properties. High-resolution detection of protons long represented the holy grail of the field. With its high natural abundance and high gyromagnetic ratio, 1H has naturally been the most important nucleus type for the solution counterpart of NMR spectroscopy. In the solid state, similar benefits are obtained over detection of heteronuclei, however, a rocky road led to its success as their high gyromagnetic ratio has also been associated with various detrimental effects. Two exciting approaches have been developed in recent years that enable proton detection: After partial deuteration of the sample to reduce the proton spin density, the exploitation of protons could begin. Also, faster MAS, nowadays using tiny rotors with frequencies up to 130 kHz, has relieved the need for expensive deuteration. Apart from the sheer gain in sensitivity from choosing protons as the detection nucleus, the proton chemical shift and several other useful aspects of protons have revolutionized the field. In this Account, we are describing the fundamentals of proton detection as well as the arising possibilities for characterization of biomolecules as associated with the developments in our own lab. In particular, we focus on facilitated chemical shift assignment, structure calculation based on protons, and on assessment of dynamics in solid proteins. For example, the proton chemical-shift dimension adds additional information for resonance assignments in the protein backbone and side chains. Chemical shifts and high gyromagnetic ratio of protons enable direct readout of spatial information over large distances. Dynamics in the protein backbone or side chains can be characterized efficiently using protons as reporters. For all of this, the sample amounts necessary for a given signal-to noise have drastically shrunk, and new methodology enables assessment of molecules with increasing monomer molecular weight and complexity. Taken together, protons are able to overcome previous limitations, by speeding up processes, enhancing accuracies, and increasing the accessible ranges of ssNMR spectroscopy, as we shall discuss in detail in the following. In particular, these methodological developments have been pushing solid-state NMR into a new regime of biological topics as they realistically allow access to complex cellular molecules, elucidating their functions and interactions in a multitude of ways. PMID- 29763291 TI - Classics in Neuroimaging: The Serotonergic 2A Receptor System-from Discovery to Modern Molecular Imaging. AB - Already in 1953, Woolley and Shaw speculated that serotonin could be involved in a range of central nervous system (CNS) disorders. Lysergic acid diethylamide (LSD) displayed an important role in this respect. It was used not only to antagonize biological effects of serotonin and to study the system itself, but also to identify serotonergic subtype receptors. The 5-HT2A receptor was discovered in the 1970s and identified as the responsible receptor mediating psychedelic effects of LSD. The development of positron emission tomography (PET) allowed to study this receptor system in vivo. Parameters such as abundance of 5 HT2A neuroreceptors or receptor occupancy can be determined using PET. As such, the development of 5-HT2A receptor tracers started immediately after the introduction of PET in the mid-1970s. In this Viewpoint, we provide a historical overview from the discovery of serotonin to the identification of the 5-HT2A receptor subtype and the subsequent development of 5-HT2A receptor subtype specific PET tracers over the last four decades. We emphasize the interplay between pharmacology, medicinal chemistry, radiochemistry, and nuclear medicine that is important while developing a PET tracer. Moreover, we highlight selected examples applying 5-HT2A receptor PET tracers within neurological diseases and drug occupancy studies. PMID- 29763292 TI - Self-Resistance of Natural Product Producers: Past, Present, and Future Focusing on Self-Resistant Protein Variants. AB - Nature is a prolific producers of bioactive natural products with an array of biological activities and impact on human and animal health. But with great power comes great responsibility, and the organisms that produce a bioactive compound must be resistant to its biological effects to survive during production/accumulation. Microorganisms, particularly bacteria, have developed different strategies to prevent self-toxicity. Here, we review a few of the major mechanisms including the mechanism of resistance with a focus on self-resistant protein variants, target proteins that contain amino acid substitutions to reduce the binding of the bioactive natural product, and therefore its inhibitory effects are highlighted in depth. We also try to identify some future avenues of research and challenges that need to be addressed. PMID- 29763293 TI - Enhancing Oxygen Evolution Electrocatalysis via the Intimate Hydroxide-Oxide Interface. AB - The development of electrocatalysts with high activity and stability for oxygen evolution reaction (OER) is critically important, the one being regarded as the bottleneck process of overall water splitting. Herein, we fulfill significant OER improvement in both activity and stability by constructing a class of Ni(OH)2 CeO2 supported on carbon paper (Ni xCe y@CP) with an intimate hydroxide (Ni(OH)2) oxide (CeO2) interface. Such interface largely promotes the OER activity with a low overpotential of 220 mV at 10 mA cm-2 and a small Tafel slope of 81.9 mV dec 1 in 1 M KOH. X-ray photoelectron spectroscopy analysis shows that the intimate interface induced by the strong electronic interactions between Ni(OH)2 and CeO2 involves the modulation of binding strength between intermediates and catalysts, making a great contribution to the OER enhancement. Importantly, such intimate interface structures can be largely maintained even after a long-time stability test. We have further demonstrated that, when pairing the Ni4Ce1@CP after phosphorization (P-Ni4Ce1@CP), the Ni4Ce1@CP and P-Ni4Ce1@CP assembly is highly active and stable for overall water splitting with a low voltage of 1.68 V at 25 mA cm-2 and negligible stability delay over 30 h of continuous operation, which are much better than the commercial Ir/C and Pt/C. PMID- 29763294 TI - Hierarchical Pore-Patterned Carbon Electrodes for High-Volumetric Energy Density Micro-Supercapacitors. AB - Micro-supercapacitors (MSCs) are attractive for applications in next-generation mobile and wearable devices and have the potential to complement or even replace lithium batteries. However, many previous MSCs have often exhibited a low volumetric energy density with high-loading electrodes because of the nonuniform pore structure of the electrodes. To address this issue, we introduced a uniform pore carbon electrode fabricated by 3D interference lithography. Furthermore, a hierarchical pore-patterned carbon (hPC) electrode was formed by introducing a micropore by chemical etching into the macropore carbon skeleton. The hPC electrodes were applied to solid-state MSCs. We achieved a constant volumetric capacitance and a corresponding volumetric energy density for electrodes of various thicknesses. The hPC MSC reached a volumetric energy density of approximately 1.43 mW h/cm3. The power density of the hPC MSC was 1.69 W/cm3. We could control the capacitance and voltage additionally by connecting the unit MSC cells in series or parallel, and we confirmed the operation of a light-emitting diode. We believe that our pore-patterned electrodes will provide a new platform for compact but high-performance energy storage devices. PMID- 29763295 TI - Supraparticles: Functionality from Uniform Structural Motifs. AB - Under the right process conditions, nanoparticles can cluster together to form defined, dispersed structures, which can be termed supraparticles. Controlling the size, shape, and morphology of such entities is a central step in various fields of science and technology, ranging from colloid chemistry and soft matter physics to powder technology and pharmaceutical and food sciences. These diverse scientific communities have been investigating formation processes and structure/property relations of such supraparticles under completely different boundary conditions. On the fundamental side, the field is driven by the desire to gain maximum control of the assembly structures using very defined and tailored colloidal building blocks, whereas more applied disciplines focus on optimizing the functional properties from rather ill-defined starting materials. With this review article, we aim to provide a connecting perspective by outlining fundamental principles that govern the formation and functionality of supraparticles. We discuss the formation of supraparticles as a result of colloidal properties interplaying with external process parameters. We then outline how the structure of the supraparticles gives rise to diverse functional properties. They can be a result of the structure itself (emergent properties), of the colocalization of different, functional building blocks, or of coupling between individual particles in close proximity. Taken together, we aim to establish structure-property and process-structure relationships that provide unifying guidelines for the rational design of functional supraparticles with optimized properties. Finally, we aspire to connect the different disciplines by providing a categorized overview of the existing, diverging nomenclature of seemingly similar supraparticle structures. PMID- 29763296 TI - Delivery of a Proapoptotic Peptide to EGFR-Positive Cancer Cells by a Cyclic Peptide Mimicking the Dimerization Arm Structure of EGFR. AB - A cyclic decapeptide, CQTPYYMNTC (1), which mimics the dimerization arm of the EGF receptor (EGFR), was previously found to be captured into cells. We have sought to investigate the promising potential of this peptide as an intracellular delivery vehicle directed to EGFR-positive cells. The selectivity of peptide 1 to the EGFR was confirmed by a positive correlation between the expression level of the receptor and the cellular uptake of peptide 1 as shown by siRNA knockdown of the EGFR. The proapoptotic domain (PAD) peptide ([KLAKLAK]2) has limited use due to a deficiency of cell membrane permeability resulting from cationic sequences and lack of specificity for cancer cells. As a proof-of-concept study, the cellular delivery of the PAD peptide was challenged by conjugation with peptide 1. The cellular uptake of a conjugated peptide 2, which was composed of peptide 1, the PAD peptide, and a linker cleavable with a protease, was evaluated by treatment of an EGFR-positive lung carcinoma cell line, A549. Significant suppression of proliferation by peptide 2 was shown in the results of a cell viability assay. The PAD peptide alone had no effect on the cells. The results suggest that peptide 1 is a promising lead compound as a new intracellular delivery vehicle for therapeutically effective peptides. PMID- 29763297 TI - Nitrobenzoxadiazole-Appended Cell Membrane Modifiers for Efficient Optoporation with Noncoherent Light. AB - FLNBD-BAMPEG2k, bearing a nitrobenzoxadiazole (NBD) unit and an oleyl terminus conjugated via a poly(ethylene glycol) (PEG) spacer ( Mn = 2,000), was designed to fluorescently label cell membranes by docking its hydrophobic oleyl terminus. During laser scanning microscopy in a minimal essential medium (MEM), human hepatocellular carcinoma Hep3B cells labeled with FLNBD-BAMPEG2k appeared to undergo optoporation at their plasma membrane. We confirmed this unprecedented possibility by a series of cellular uptake experiments using negatively charged and therefore membrane-impermeable quantum dots (QDs; Dh = 4.7 nm). Detailed studies indicated that the photoexcited NBD unit can generate singlet oxygen (1O2), which oxidizes the constituent phospholipids to transiently deteriorate the cell membrane. Reference membrane modifiers FLNBD-Oleyl and FLNBD-BAMPEG8k having shorter or longer hydrophilic spacers between the NBD and oleyl units showed a little or substantially no optoporation. For understanding these results, one must consider the following contradictory factors: (1) The photosensitized 1O2 generation efficiently occurs only when the NBD unit is in aqueous media, and (2) the lifetime of 1O2 in aqueous media is very short (3.0 3.5 MUs). As supported experimentally and computationally, the hydrophilic spacer length of FLNBD-BAMPEG2k is optimal for compromising these factors. Further to note, the optoporation using FLNBD-BAMPEG2k is not accompanied by cytotoxicity. PMID- 29763299 TI - In Vivo Assimilation of One-Carbon via a Synthetic Reductive Glycine Pathway in Escherichia coli. AB - Assimilation of one-carbon compounds presents a key biochemical challenge that limits their use as sustainable feedstocks for microbial growth and production. The reductive glycine pathway is a synthetic metabolic route that could provide an optimal way for the aerobic assimilation of reduced C1 compounds. Here, we show that a rational integration of native and foreign enzymes enables the tetrahydrofolate and glycine cleavage/synthase systems to operate in the reductive direction, such that Escherichia coli satisfies all of its glycine and serine requirements from the assimilation of formate and CO2. Importantly, the biosynthesis of serine from formate and CO2 does not lower the growth rate, indicating high flux that is able to provide 10% of cellular carbon. Our findings assert that the reductive glycine pathway could support highly efficient aerobic assimilation of C1-feedstocks. PMID- 29763300 TI - Fish Stocking as an Overlooked Driver of Methylmercury Cycling and Exposure in Aquatic Ecosystems. PMID- 29763298 TI - Cooperative Assembly of Hsp70 Subdomain Clusters. AB - Many molecular chaperones exist as oligomeric complexes in their functional states, yet the physical determinants underlying such self-assembly behavior, as well as the role of oligomerization in the activity of molecular chaperones in inhibiting protein aggregation, have proven to be difficult to define. Here, we demonstrate direct measurements under native conditions of the changes in the average oligomer populations of a chaperone system as a function of concentration and time and thus determine the thermodynamic and kinetic parameters governing the self-assembly process. We access this self-assembly behavior in real time under native-like conditions by monitoring the changes in the micrometer-scale diffusion of the different complexes in time and space using a microfluidic platform. Using this approach, we find that the oligomerization mechanism of the Hsp70 subdomain occurs in a cooperative manner and involves structural constraints that limit the size of the species formed beyond the limits imposed by mass balance. These results illustrate the ability of microfluidic methods to probe polydisperse protein self-assembly in real time in solution and to shed light on the nature and dynamics of oligomerization processes. PMID- 29763301 TI - Effects of Short-Term Biosolarization Using Mature Compost and Industrial Tomato Waste Amendments on the Generation and Persistence of Biocidal Soil Conditions and Subsequent Tomato Growth. AB - Conventional solarization and biosolarization with mature compost and tomato processing residue amendments were compared with respect to generation of pesticidal conditions and tomato ( Solanum lycopersicum L.) plant growth in treated soils. Soil oxygen depletion was examined as a response that has previously not been measured across multiple depths during biosolarization. For biosolarized soil, volatile fatty acids were found to accumulate concurrent with oxygen depletion, and the magnitude of these changes varied by soil depth. Two consecutive years of experimentation showed varying dissipation of volatile fatty acids from biosolarized soils post-treatment. When residual volatile fatty acids were detected in the biosolarized soil, fruit yield did not significantly differ from plants grown in solarized soil. However, when there was no residual volatile fatty acids in the soil at the time of planting, plants grown in biosolarized soil showed a significantly greater vegetation amount, fruit quantity, and fruit ripening than those of plants grown in solarized soil. PMID- 29763302 TI - Assessment of Density Functional Methods for Geometry Optimization of Bimolecular van der Waals Complexes. AB - We explore the suitability of three popular density functionals (B97-D3, B3LYP D3, M05-2X) for producing accurate equilibrium geometries of van der Waals (vdW) complexes with diverse binding motifs. For these functionals, optimizations using Dunning's aug-cc-pVDZ basis set best combine accuracy and a reasonable computational expense. Each DFT/aug-cc-pVDZ combination produces optimized equilibrium geometries for 21 small vdW complexes of organic molecules (up to four non-hydrogen atoms total) that agree with high-level CCSD(T)/CBS reference geometries to within +/-0.1 A for the averages of the center-of-mass displacement and the mean least root-mean-squared displacement. The DFT/aug-cc-pVDZ combinations are also able to reproduce the optimal center-of-mass displacements interpolated from CCSD(T)/CBS radial potential energy surfaces in both NBC7x and HBC6 test sets to within +/-0.1 A. We therefore conclude that each of these denisty functional methods, together with the aug-cc-pVDZ basis set, is suitable for producing equilibrium geometries of generic nonbonded complexes. PMID- 29763304 TI - Synthesis, Structure-Activity Relationships, and Preclinical Evaluation of Heteroaromatic Amides and 1,3,4-Oxadiazole Derivatives as 5-HT4 Receptor Partial Agonists. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the alpha-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model. PMID- 29763305 TI - Alkynylplatinum(II) Terpyridine System Coupled with Rhodamine Derivative: Interplay of Aggregation, Deaggregation, and Ring-Opening Processes for Ratiometric Luminescence Sensing. AB - The synthesis and characterization of a platinum(II) terpyridine system tethered with a latent organic dye of rhodamine derivative as colorimetric and luminescent sensory moiety is reported to show selective Hg2+ ion sensing behavior. The interplay of aggregation/deaggregation behavior of the alkynylplatinum(II) terpyridine complex and the ring-opening process of rhodamine derivative was investigated. The spectral change of aggregation near-infrared emission at 800 nm and rhodamine fluorescence at 585 nm provides a possible ratiometric luminescence measurement. Morphological studies from transmission electron microscopy and scanning electron microscopy images showing nanospherical structures confirmed the aggregation in the absence of Hg2+ ion. PMID- 29763303 TI - Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis. AB - The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors. PMID- 29763306 TI - One-Pot Synthesis of Indole-3-acetic Acid Derivatives through the Cascade Tsuji Trost Reaction and Heck Coupling. AB - A practical palladium-mediated cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives using a Pd(OAc)2/P( o tol)3/DIPEA system is described for a straightforward synthesis of indole-3 acetic acid derivatives. This methodology was successfully applied to synthesize various substituted indole/azaindole-3-acetic acid derivatives and Almotriptan, which is a drug for the acute treatment of migraines. Moreover, a plausible cyclization mechanism has been proposed. PMID- 29763307 TI - Genetic Code Expansion in Rhodobacter sphaeroides to Incorporate Noncanonical Amino Acids into Photosynthetic Reaction Centers. AB - Photosynthetic reaction centers (RCs) are the membrane proteins responsible for the initial charge separation steps central to photosynthesis. As a complex and spectroscopically complicated membrane protein, the RC (and other associated photosynthetic proteins) would benefit greatly from the insight offered by site specifically encoded noncanonical amino acids in the form of probes and an increased chemical range in key amino acid analogues. Toward that goal, we developed a method to transfer amber codon suppression machinery developed for E. coli into the model bacterium needed to produce RCs, Rhodobacter sphaeroides. Plasmids were developed and optimized to incorporate 3-chlorotyrosine, 3 bromotyrosine, and 3-iodotyrosine into RCs. Multiple challenges involving yield and orthogonality were overcome to implement amber suppression in R. sphaeroides, providing insights into the hurdles that can be involved in host transfer of amber suppression systems from E. coli. In the process of verifying noncanonical amino acid incorporation, characterization of this membrane protein via mass spectrometry (which has been difficult previously) was substantially improved. Importantly, the ability to incorporate noncanonical amino acids in R. sphaeroides expands research capabilities in the photosynthetic field. PMID- 29763308 TI - Variable Asymmetric Chains in Transition Metal Oxyfluorides: Structure-Second Harmonic-Generation Property Relationships. AB - Four novel transition metal oxyfluorides, [Zn(pz)3][MoO2F4].0.1H2O (1), [Zn(pz)2F2][Zn(pz)3]2[WO2F4]2 (2), [Cd(pz)4][Cd(pz)4(H2O)][MoO2F4]2.0.625H2O (3), and [Zn(mpz)3]2[MoO2F4]2 (4) (pz = pyrazole; mpz = 3-methyl pyrazole) have been synthesized. Compounds 1 and 4 contain helical chains. Compound 2 accommodates zigzag chains, and compound 3 has quasi-one-dimensional linear chains. The variable chain structures are found to be attributable to the different structure directing anionic groups and hydrogen bonding interactions. Compound 4 crystallized in the noncentrosymmetric (NCS) polar space group, Pna21, is nonphase-matchable (Type I), and reveals a moderate second-harmonic-generation (SHG) efficiency (10 * alpha-SiO2). The observed SHG efficiency of compound 4 is due to the small net polarization occurring from the arrangement of ZnN3F2 trigonal bipyramids. Spectroscopic and thermal characterizations along with calculations for the title materials are reported. PMID- 29763309 TI - Characterization and Structural Analysis of a Novel exo-Type Enzyme Acting on beta-1,2-Glucooligosaccharides from Parabacteroides distasonis. AB - beta-1,2-Glucan is a polysaccharide produced mainly by some Gram-negative bacteria as a symbiosis and infectious factor. We recently identified endo-beta 1,2-glucanase from Chitinophaga pinensis ( CpSGL) as an enzyme comprising a new family. Here, we report the characteristics and crystal structure of a CpSGL homologue from Parabacteroides distasonis, an intestinal bacterium (BDI_3064 protein), which exhibits distinctive properties of known beta-1,2-glucan degrading enzymes. BDI_3064 hydrolyzed linear beta-1,2-glucan and beta-1,2 glucooligosaccharides with degrees of polymerization (DPs) of >=4 to produce sophorose specifically but did not hydrolyze cyclic beta-1,2-glucan. This result indicates that BDI_3064 is a new exo-type enzyme. BDI_3064 also produced sophorose from beta-1,2-glucooligosaccharide analogues that have a modified reducing end, indicating that BDI_3064 acts on its substrates from the nonreducing end. The crystal structure showed that BDI_3064 possesses additional N-terminal domains 1 and 2, unlike CpSGL. Superimposition of BDI_3064 and CpSGL complexed with ligands showed that R93 in domain 1 overlapped subsite -3 in CpSGL. Docking analysis involving a beta-1,2-glucooligosaccharide with DP4 showed that R93 completely blocks the nonreducing end of the docked beta-1,2 glucooligosaccharide. This indicates that BDI_3064 employs a distinct mechanism of recognition at the nonreducing end of substrates to act as an exo-type enzyme. Thus, we propose 2-beta-d-glucooligosaccharide sophorohydrolase (nonreducing end) as a systematic name for BDI_3064. PMID- 29763310 TI - Stability, Elastic Properties, and Deformation of LiBN2: A Potential High-Energy Material. AB - Searching for high-energy-density materials is of great interest in scientific research and for industrial applications. Using an unbiased structure prediction method and first-principles calculations, we investigated the phase stability of LiBN2 from 0 to100 GPa. Two new structures with space groups P421 m and Pnma were discovered. The theoretical calculations revealed that Pnma LiBN2 is stable with respect to a mixture of 1/3Li3N, BN, and 1/3N2 above 22 GPa. The electronic band structure revealed that Pnma LiBN2 has an indirect band gap of 2.3 eV, which shows a nonmetallic feature. The Pnma phase has a high calculated bulk modulus and shear modulus, indicating its incompressible nature. The microscopic mechanism of the structural deformation was demonstrated by ideal tensile shear strength calculations. It is worth mentioning that Pnma LiBN2 is dynamically stable under ambient conditions. The decomposition of this phase is exothermic, releasing an energy of approximately 1.23 kJ/g at the PBE level. The results provide new thoughts for designing and synthesizing novel high-energy compounds in ternary systems. PMID- 29763311 TI - Thyroid Disruption by Bisphenol S Analogues via Thyroid Hormone Receptor beta: in Vitro, in Vivo, and Molecular Dynamics Simulation Study. AB - Bisphenol S (4-hydroxyphenyl sulfone, BPS) is increasingly used as a bisphenol A (BPA) alternative. The global usage of BPS and its analogues (BPSs) resulted in the frequent detection of their residues in multiple environmental media. We investigated their potential endocrine-disrupting effects toward thyroid hormone receptor (TR) beta. The molecular interaction of BPSs toward TRbeta ligand binding domain (LBD) was probed by fluorescence spectroscopy and molecular dynamics (MD) simulations. BPSs caused the static fluorescence quenching of TRbeta LBD. The 100 ns MD simulations revealed that the binding of BPSs caused significant changes in the distance between residue His435 at helix 11(H11) and residue Phe459 at H12 in comparison to no ligand-bound TRbeta LBD, indicating relative repositioning of H12. The recombinant two-hybrid yeast assay showed that tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A (TBBPA) have potent antagonistic activity toward TRbeta, with an IC10 of 10.1 and 21.1 nM, respectively. BPS and BPA have the antagonistic activity with IC10 of 312 and 884 nM, respectively. BPSs significantly altered the expression level of mRNA of TRbeta gene in zebrafish embryos. BPS and TBBPS at environmentally relevant concentrations have antagonistic activity toward TRbeta, implying that BPSs are not safe BPA alternatives in many BPA-free products. Future health risk assessments for TR disruption and other adverse effects should focus more on the structure-activity relationship in the design of environmentally benign BPA alternatives. PMID- 29763313 TI - Phase Equilibrium Investigation on 2-Phenylethanol in Binary and Ternary Systems: Influence of High Pressure on Density and Solid-Liquid Phase Equilibrium. AB - Ionic liquids (ILs) are important new solvents proposed for applications in different separation processes. Herein, an idea of possible use of high pressure in a general strategy of production of 2-phenylethanol (PEA) is discussed. In this work, we present the influence of pressure on the density in binary systems of {1-hexyl-1-methylpyrrolidynium bis{(trifluoromethyl)sulfonyl}imide, [HMPYR][NTf2], or 1-dodecyl-3-methylimidazolium bis{(trifluoromethyl)sulfonyl}imide, [DoMIM][NTf2] + PEA} in a wide range of temperatures (298.15-348.15 K) and pressures (0.1-40 MPa). The densities at ambient and high pressures are measured to present the physicochemical properties of the ILs used in the process of separation of PEA from aqueous phase. The Tait equation was used for the correlation of density of one-component and two component systems as a function of mole fraction, temperature, and pressure. The influence of pressure is not significant. These systems exhibit mainly negative molar excess volumes, VE. The solid-liquid phase equilibrium (SLE) of [DoMIM][NTf2] in PEA at atmospheric pressure was measured and compared to the SLE high-pressure results. Additionally, the ternary liquid-liquid phase equilibrium (LLE) at ambient pressure in the {[DoMIM][NTf2] (1) + PEA (2) + water (3)} at temperature T = 308.15 K was investigated. The solubility of water in the [DoMIM][NTf2] is quite high in comparison with that measured by us earlier for ILs ( x3 = 0.403) at T = 308.15 K, which results in not very successful average selectivity of extraction of PEA from the aqueous phase. The [DoMIM][NTf2] has shown strong interaction with PEA without the immiscibility region. The ternary system revealed Treybal's type phase equilibrium in which two partially miscible binaries ([DoMIM][NTf2] + water) and (PEA + water) exist. From the results of LLE in the ternary system, the selectivity and the solute distribution ratio of separation of water/PEA were calculated and compared to the results obtained for the ILs measured earlier by us. The popular NRTL model was used to correlate the experimental tie-lines in ternary LLE. These results may help in a new technological project of "in situ" extraction of PEA from aqueous phase during the biosynthesis. PMID- 29763312 TI - Deep-Sea-Derived Butyrolactone I Suppresses Ovalbumin-Induced Anaphylaxis by Regulating Mast Cell Function in a Murine Model. AB - Deep-sea-derived butyrolactone I (BTL-I), which was identified as a type of butanolide, was isolated from Aspergillus sp. Ovalbumin (OVA)-induced BALB/c anaphylaxis was established to explore the antifood allergic activity of BTL-I. As a result, BTL-I was able to alleviate OVA-induced allergy symptoms, reduce the levels of histamine and mouse mast cell proteinases, inhibit OVA-specific IgE, and decrease the population of mast cells in the spleen and mesenteric lymph nodes. BTL-I also significantly suppressed mast-dependent passive cutaneous anaphylaxis. Additionally, the maturation of bone marrow-derived mast cells (BMMCs) declined as BTL-I caused down-regulation of c-KIT receptors. Furthermore, molecular docking analyses revealed that BTL-I interacted with the inhibitory receptor, FcgammaRIIB. In conclusion, the reduction of mast cell function by deep sea-derived BTL-I as well as its interactions with the inhibitory receptor, FcgammaRIIB, may contribute to BTL-I-related protection against food anaphylaxis. PMID- 29763314 TI - Shedding (Incoherent) Light on Quantum Effects in Light-Induced Biological Processes. AB - Light-induced processes that occur in nature, such as photosynthesis and photoisomerization in the first steps in vision, are often studied in the laboratory using coherent pulsed laser sources, which induce time-dependent coherent wavepacket molecule dynamics. Nature, however, uses stationary incoherent thermal radiation, such as sunlight, leading to a totally different molecular response, the time-independent steady state. It is vital to appreciate this difference in order to assess the role of quantum coherence effects in biological systems. Developments in this area are discussed in detail. PMID- 29763315 TI - Similarity Between Amorphous and Crystalline Phases: The Case of TiO2. AB - Amorphous and crystalline materials differ in their long-range structural order. On the other hand, short-range order in amorphous and crystalline materials often appears similar. Here, we use a recently introduced method for obtaining quantitative measures for structural similarity to compare crystalline and amorphous materials. We compare seven common crystalline polymorphs of TiO2, all assembled out of TiO6 or TiO7 polyhedral building blocks, to liquid and amorphous TiO2 in a quantitative two-dimensional similarity plot. We find high structural similarity between a model of amorphous TiO2, obtained by ab initio molecular dynamics, and the B-TiO2 crystalline polymorph. The general approach presented here sheds new light on a long-standing controversy in the structural theory of amorphous solids. PMID- 29763316 TI - Solvation-Mediated Tuning of the Range-Separated Hybrid Functional: Self Sufficiency through Screened Exchange. AB - We propose a simple procedure that restores the ionization potential theorem as the sole tuning criterion for both the long- and short-range Fock exchange of the range-separated hybrid functional. The procedure works by screening out an opposing effect of the short-range Fock fraction at long range, through the 1/ epsilonr dielectric correction in combination with a popular continuum solvation model. Our method proves to be a consistent and accurate way of tuning for both the isolated and solvated molecules. PMID- 29763317 TI - Chemoproteomic Profiling Reveals Ethacrynic Acid Targets Adenine Nucleotide Translocases to Impair Mitochondrial Function. AB - Ethacrynic acid (EA) is a diuretic drug that is widely used to treat high-blood pressure and swelling caused by congestive heart failure or kidney failure. It acts through noncovalent inhibition of the Na+-K+-2Cl- cotransporter in the thick ascending limb of Henle's loop. Chemically, EA contains a Michael acceptor group that can react covalently with nucleophilic residues in proteins; however, the proteome reactivity of EA remains unexplored. Herein, we took a quantitative chemoproteomic approach to globally profile EA's targets in cancer cells. We discovered that EA induces impaired mitochondrial function accompanied by increased ROS production. Our profiling revealed that EA targets functional proteins on mitochondrial membranes, including adenine nucleotide translocases (ANTs). Site-specific mapping identified that EA covalently modifies a functional cysteine in ANTs, a mutation of which resulted in the rescuing effect on EA induced mitochondrial dysfunction. The newly discovered modes of action offer valuable information to repurpose EA for cancer treatment. PMID- 29763318 TI - Peculiar Molecular Shape and Size Dependence of the Dynamics of Fluids Confined in a Small-Pore Metal-Organic Framework. AB - Force-field-based molecular dynamics simulations were deployed to systematically explore the dynamics of confined molecules of different shapes and sizes, that is, linear (CO2 and N2) and spherical (CH4) fluids, in a model small pore system, that is, the metal-organic framework SIFSIX-2-Cu-i. These computations unveil an unprecedented molecular symmetry dependence of the translational and rotational dynamics of fluids confined in channel-like nanoporous materials. In particular, this peculiar behavior is reflected by the extremely slow decay of the Legendre reorientational correlation functions of even-parity order for the linear fluids, which is associated with jump-like orientation flips, while the spherical fluid shows a very fast decay taking place on a subpicosecond time scale. Such a fundamental understanding is relevant to diverse disciplines such as in chemistry, physics, biology, and materials science, where diatomic or polyatomic molecules of different shapes/sizes diffuse through nanopores. PMID- 29763319 TI - Degenerately n-Doped Colloidal PbSe Quantum Dots: Band Assignments and Electrostatic Effects. AB - We present a spectroscopic study of colloidal PbSe quantum dots (QDs) that have been photodoped to introduce excess delocalized conduction-band (CB) electrons. High-quality absorption spectra are obtained for these degenerately doped QDs with excess electron concentrations up to ~1020 cm-3. At the highest doping levels, electrons have completely filled the 1Se orbitals of the CB and partially populated the higher-energy 1Pe orbitals. Spectroscopic changes observed as a function of carrier concentration permit an unambiguous assignment of the second excitonic absorption maximum to 1Ph-1Pe transitions. At intermediate doping levels, a clear absorption feature appears between the first two excitonic maxima that is attributable to parity-forbidden 1Sh,e-1Pe,h excitations, which become observable because of electrostatic symmetry breaking. Redshifts of the main excitonic absorption features with increased carrier concentration are also analyzed. The Coulomb stabilization energies of both the 1Sh-1Se and 1Ph-1Pe excitons in n-doped PbSe QDs are remarkably similar to those observed for multiexcitons with the same electron count. The origins of these redshifts are discussed. PMID- 29763320 TI - Physicochemical Phenomena and Application in Solar Cells of Perovskite:Fullerene Films. AB - Beyond the use of fullerenes as electron-transporting layers in perovskite solar cells, their introduction into a perovskite active layer has been ascertained as a very promising strategy for device improvement. In this sense, this Perspective summarizes the studies in which perovskite:fullerene systems were employed, covering the different methodologies for introducing fullerenes inside the perovskite layer. In particular, fill factor was the most benefited parameter, which was ascribed to minimized pinhole density and fullerene passivating role. We discussed the importance of their ability to passivate trap states and, in this regard, focused on the affinity of fullerenes toward these sites. Additionally, the different nature of the fullerene and its environment in the active layer were found to determine the proper distribution of fullerene so that they could passivate the defects along grain boundaries. Understanding this mechanism would provide further insights for new methodologies and fullerene derivatives with enhanced trap-passivating ability. PMID- 29763321 TI - Antiaromaticity of Planar Bisdehydro[12]- and Tetrakisdehydro[16]annulenes Fused with Dithieno[3,4- b:3',4'- d]thiophenes. AB - Thermally stable bisdehydro[12]- and tetrakisdehydro[16]annulenes with planar structures were successfully synthesized by fusion with two dithieno[3,4- b:3',4' d]thiophene units. The planarized [4n]annulene cores induced substantial antiaromaticity. However, the HOMO-LUMO gap slightly increased as the pi-core expanded from the planar cyclooctatetraene. This phenomenon, in contrast to that of typical pi-conjugated systems, was attributed to the decrease in antiaromaticity of the [4n]annulene cores. Both TD-HF and GIAO-HF calculations supported this conclusion. PMID- 29763322 TI - Radical Hydrosilylation of Alkynes Catalyzed by Eosin Y and Thiol under Visible Light Irradiation. AB - A visible light-promoted hydrosilylation of alkynes has been explored and achieved using 1 mol % organic dye Eosin Y as the photocatalyst and a catalytic amount of thiol as the radical quencher. The corresponding alkenylsilanes were provided with high regio- and stereoselectivites in the reactions of various terminal and internal alkynes. The experimental evidence shows that the reaction is preferentially initiated by a single electron transfer process, and a photoredox pathway is suggested. PMID- 29763324 TI - The Fate of Atomic Spin in Atomic Scattering off Surfaces. AB - We explore model electron dynamics of an atom scattering off a surface within the time-dependent complete active space self-consistent field (TD-CASSCF) approximation. We focus especially on the scattering of a hydrogen atom and its resulting spin dynamics starting from an initially spin-polarized state. Our results reveal competing electronic time scales that are governed by the electronic structure of the surface as well as the character of the atom. The time scales and nonadiabaticity of the dynamics are reported on by the final spin polarization of the scattered atom, which may be probed in future experiments. PMID- 29763323 TI - Synthesis, Reactivity, Functionalization, and ADMET Properties of Silicon Containing Nitrogen Heterocycles. AB - Silicon-containing compounds have been largely ignored in drug design and development, despite their potential to improve not only the potency but also the physicochemical and ADMET ( absorption, distribution, metabolism, excretion, toxicity) properties of drug-like candidates because of the unique characteristics of silicon. This deficiency is in large part attributable to a lack of general methods for synthesizing diverse organosilicon structures. Accordingly, a new building block strategy has been developed that diverges from traditional approaches to incorporation of silicon into drug candidates. Flexible, multi-gram-scale syntheses of silicon-containing tetrahydroquinoline and tetrahydroisoquinoline building blocks are described, along with methods by which diversely functionalized silicon-containing nitrogen heterocycles can be rapidly built using common reactions optimized to accommodate the properties of silicon. Furthermore, to better clarify the liabilities and advantages of silicon incorporation, select compounds and their carbon analogues were challenged in ADMET-focused biological studies. PMID- 29763325 TI - Identifying (BN)2-pyrenes as a New Class of Singlet Fission Chromophores: Significance of Azaborine Substitution. AB - Singlet fission converts one photoexcited singlet state to two triplet excited states and raises photoelectric conversion efficiency in photovoltaic devices. However, only a handful of chromophores have been known to undergo this process, which greatly limits the application of singlet fission in photovoltaics. We hereby identify a recently synthesized diazadiborine-pyrene ((BN)2-pyrene) as a singlet fission chromophore. Theoretical calculations indicate that it satisfies the thermodynamics criteria for singlet fission. More importantly, the calculations provide a physical chemistry insight into how the BN substitution makes this happen. Both calculation and transient absorption spectroscopy experiments indicate that the chromophore has a better absorption than pentacene. The convenient synthesis pathway of the (BN)2-pyrene suggests an in situ chromophore generation in photovoltaic devices. Two more (BN)2-pyrene isomers are proposed as singlet fission chromophores. This study sets a step forward in the cross-link of singlet fission and azaborine chemistry. PMID- 29763326 TI - Three-Dimensional Spin Texture in Hybrid Perovskites and Its Impact on Optical Transitions. AB - Hybrid perovskites such as MAPbI3 (MA = CH3NH3) exhibit a unique spin texture. The spin texture (as calculated within the Rashba model) has been suggested to be responsible for a suppression of radiative recombination due to a mismatch of spins at the band edges. Here we compute the spin texture from first principles and demonstrate that it does not suppress recombination. The exact spin texture is dominated by the inversion asymmetry of the local electrostatic potential, which is determined by the structural distortion induced by the MA molecule. In addition, the rotation of the MA molecule at room temperature leads to a dynamic spin texture in MAPbI3. These insights call for a reconsideration of the scenario that radiative recombination is suppressed and provide an in-depth understanding of the origin of the spin texture in hybrid perovskites, which is crucial for designing spintronic devices. PMID- 29763327 TI - Stability and Degradation in Hybrid Perovskites: Is the Glass Half-Empty or Half Full? AB - Methylammonium lead iodide (CH3NH3PbI3) is an extensively used perovskite material with a remarkable potential for solar energy conversion. Despite its high photovoltaic efficiency, the material suffers from fast degradation when aging in atmospheric conditions and/or under sunlight. Here we review the principal degradation mechanisms of CH3NH3PbI3, focusing on the thermodynamic, environmental and polymorphic parameters that impact the stability of the material. A critical analysis of the available data indicates that degradation under ambient conditions is a defect-generation process that is highly localized on surfaces and interfaces, while it is further enhanced above the tetragonal cubic transition at ~54 degrees C. Within this context, we discuss the conservative role of N2 and propose strategies for the emergence of industrially viable hybrid photovoltaics. PMID- 29763328 TI - Synthesis of alpha-(4-Oxazolyl)amino Esters via Bronsted Acid Catalyzed Tandem Reaction. AB - A one-step, Bronsted acid catalyzed tandem reaction for the synthesis of alpha-(4 oxazolyl)amino esters was developed. 4-Nitrobenzenesulfonic acid was found to be an efficient catalyst for the coupling of ethyl 2-oxobut-3-ynoates with amides to provide various alpha-(4-oxazolyl)amino esters. The experimental and X-ray crystallographic data suggest that a series of bond-forming reactions including imine formation, intermolecular Michael addition, and intramolecular Michael addition are involved to generate both the oxazole and amino acid functionalities. PMID- 29763329 TI - Fullerene-Cation-Mediated Noble-Metal-Free Direct Introduction of Functionalized Aryl Groups onto [60]Fullerene. AB - Aryl[60]fullerenyl cations (ArC60+), which were generated by heating aryl[60]fullerenyl dimers (ArC60-C60Ar) to generate aryl[60]fullerenyl radicals (ArC60*) followed by oxidation using Cu(II) salts (Cu(BF4)2(aq)), were reacted with various functionalized aryl boronic acids to produce functionalized 1,4 diaryl[60]fullerenes. This protocol tolerated various functional groups, such as OH, NH2, COCH3, and Cl substituents, with yields reaching 93%. C60Ar1Ar2 (Ar2 = p NH2C6H4) was used as a dopant in a photoactive CH3NH3PbI3 layer of a perovskite solar cell. PMID- 29763330 TI - Synthesis of [1,2,4]Triazolo[4,3- a]piperazin-6-ones: An Approach to the Triazole Fused Ketopiperazine Scaffold. AB - A stereoconservative synthesis to access the triazole-fused ketopiperazine (TKP) scaffold is presented. This underexplored platform offers a wide range of structural modulations with several points of diversity and chiral centers. A series of [1,2,4]triazolo[4,3- a]piperazin-6-ones was synthesized from optically pure dipeptides. The methodology was then successfully applied to access the pyrrolo[1,2- a]triazolo[3,4- c]piperazin-6-one tricycle. Importantly, the crystal structures of representative TKPs confirmed that the configuration of the chiral centers was controlled during the synthetic route and facilitated description of the orientation of the substituents depending on their nature and position on the TKP scaffold. PMID- 29763331 TI - Transition-Metal-Free Reductive Deoxygenative Olefination with CO2. AB - A new transition-metal-free reductive deoxygenative olefination of phosphorus ylides with CO2, an abundant and sustainable C1 chemical feedstock, is described. This catalytic CO2 fixation afforded beta-unsubstituted acrylates and vinyl ketones in good yields with broad scope and good functional group tolerance under mild reaction conditions. Cost-effective and easily handled polymethylhydrosiloxane was used as a reductant. Bis(silyl)acetal was proved to be the key intermediate in this reductive functionalization of CO2. PMID- 29763332 TI - Asymmetric [3 + 2] Cycloaddition Employing N, N'-Cyclic Azomethine Imines Catalyzed by Chiral-at-Metal Rhodium Complex. AB - An efficient asymmetric 1,3-dipolar cycloaddition of alpha,beta-unsaturated 2 acyl imidazoles with N, N'-cyclic azomethine imines catalyzed by a chiral-at metal rhodium complex is reported. The corresponding N, N'-bicyclic pyrazolidine derivatives with three contiguous tertiary stereocenters were obtained in good yields (up to 99%) with excellent stereoselectivities (>20:1 dr and >99% ee). Remarkably, as little as 0.5 mol % of a chiral Rh(III) complex can promote a gram scale reaction with excellent yield and enantioselectivity. PMID- 29763333 TI - Linker-Directed Assembly of Twisted ortho-Phenylene-Based Macrocycles. AB - o-Phenylene tetramers have been coassembled with linkers into macrocycles through imine condensation. Variation of linker connectivity and length allows both [1 + 1] and [2 + 2] macrocycles to be obtained, complementing (previously reported) [3 + 3] macrocycles. For the [1 + 1] macrocycles, linker length has a clear effect on o-phenylene geometry and macrocycle stability. For the [2 + 2] macrocycles, both homo- and heterochiral configurations are observed, suggesting limited communication of helix handedness in these systems. PMID- 29763334 TI - Corrigendum. AB - Chang CWD. Match 2017: blindsided or fumbled? Otolaryngol Head Neck Surg. 2018;158:594-597. (Original DOI: 10.1177/0194599817751890) On page 594 of this article from the April 2018 issue, the match rate nadir for ranked US seniors in 2013 should have been listed as 71% rather than 81%. The corrected sentence is as follows: "Traditionally, the specialty has enjoyed an era of desirability and competitiveness, with match rate nadir for ranked US seniors at 71% in 2013." PMID- 29763335 TI - Nintedanib in Severe Pulmonary Arterial Hypertension. PMID- 29763336 TI - Adjustable-Loop Femoral Cortical Suspensory Fixation for Patellar Tendon Anterior Cruciate Ligament Reconstruction: A Time Zero Biomechanical Comparison With Interference Screw Fixation. AB - BACKGROUND: Adjustable-loop cortical buttons for femoral fixation of bone-tendon bone grafts have potential advantages over interference screw fixation; however, these devices have not been benchmarked biomechanically against interference screws. Purpose/Hypothesis: The purpose was to compare the time zero biomechanical properties of commercially available, adjustable-loop cortical button and metallic interference screws for femoral fixation of bone-tendon-bone grafts. It was hypothesized that no significant differences would be found in biomechanical properties between fixation techniques. STUDY DESIGN: Controlled laboratory study. METHODS: Adjustable-loop cortical buttons (n = 8) and metallic interference screws (n = 8) were used to fix matched pairs of human bone-tendon bone allografts in porcine distal femurs. These constructs were preconditioned (10 N to 50 N at 1 Hz, 10 cycles), subjected to cyclic loading (50 N to 250 N at 1 Hz, 500 cycles), and then pulled to failure at 20 mm/min. RESULTS: The loads to failure (mean +/- SD, 700 +/- 256 N vs 688 +/- 215 N, P = .92) and linear stiffnesses (219 +/- 48 N/mm vs 218 +/- 49 N/mm, P = .97) for the adjustable-loop cortical button and metallic interference screws, respectively, were not significantly different. Cyclic displacement was higher in the adjustable-loop cortical button group (2.1 +/- 0.6 mm vs 1.3 +/- 0.4 mm, P = .01). The mechanism of failure was different between groups, with bone block slippage occurring most commonly in the interference screw group (n = 5) and fracture of the bone block through the suture hole occurring most commonly in the adjustable-loop cortical button group (n = 6). CONCLUSION: Adjustable-loop cortical buttons and interference screws have similar time zero failure loads, although cyclic displacement was higher with the adjustable-loop cortical buttons. The mean difference in displacement was less than 1 mm compared with the interference screw. CLINICAL RELEVANCE: Adjustable-loop cortical buttons may be an acceptable alternative to an interference screw for femoral fixation of bone-tendon-bone grafts in anterior cruciate ligament reconstruction. The clinical relevance of the observed differences in cyclic displacement is unknown and should be evaluated in future studies. PMID- 29763337 TI - Raman Spectroscopy for Inverted Papilloma: A Proof-of-Concept Study. AB - Inverted papillomas are tumors of the sinonasal tract with a propensity to recur. Raman spectroscopy can potentially identify inverted papillomas from other tissue based on biochemical signatures. A pilot study comparing Raman spectroscopy to histopathology for 3 types of sinonasal tissue was performed. Spectral data of biopsies from patients with normal sinonasal mucosa, chronic rhinosinusitis, and inverted papillomas are compared to histopathology using principal component analysis and linear discriminant analysis after data preprocessing. A total of 18 normal, 15 chronic rhinosinusitis, and 18 inverted papilloma specimens were evaluated. The model distinguished normal sinonasal mucosa, chronic rhinosinusitis, and inverted papilloma tissue with an overall accuracy of 90.2% (95% confidence interval, 0.86-0.94). In conclusion, Raman spectroscopy can distinguish inverted papilloma, normal sinonasal mucosa, and chronically rhinosinusitis tissue with acceptable accuracy. PMID- 29763338 TI - Retrieval of an Unusually Displaced Implant With Healing Cap Into the Mandibular Canal. AB - Accidental displacement of dental implants into the anatomical spaces is a rare complication that may be accompanied by tissue damage, functional disturbance, psychological distress, and medicolegal conditions. The aim of this report is to present an unusual case of a dental implant that displaced into the mandibular canal and to highlight the importance of adequate preoperative planning and surgical knowledge. PMID- 29763340 TI - Reply to Thille et al.: Are Sleep Alterations the Cause of ICU Delirium? PMID- 29763339 TI - The V-Shaped Distal Triceps Tendon Repair: A Comparative Biomechanical Analysis. AB - BACKGROUND: Restoring footprint anatomy, minimizing gap formation, and maximizing the strength of distal triceps tendon repairs are essential factors for a successful healing process and return to sport. HYPOTHESIS: The novel V-shaped distal triceps tendon repair technique with unicortical button fixation closely restores footprint anatomy, provides minimal gap formation and high ultimate failure load, and minimizes iatrogenic fracture risk in acute/subacute distal triceps tendon tears. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty four cadaveric elbows (mean +/- SD age, 66 +/- 5 years) were randomly assigned to 1 of 3 repair groups: the transosseous cruciate repair technique (gold standard), the knotless suture-bridge repair technique, and the V-shaped distal triceps tendon repair technique. Anatomic measurements of the central triceps tendon footprint were obtained in all specimens with a 3-dimensional digitizer before and after the repair. Cyclic loading was performed for a total of 1500 cycles at a rate of 0.25 Hz, pulling in the direction of the triceps. Displacements were measured on the medial and lateral tendon sites with 2 differential variable reluctance transducers. Load to failure and construct failure mode were recorded. RESULTS: The mean triceps bony insertion area was 399.05 +/- 81.23 mm2. The transosseous cruciate repair technique restored 36.6% +/- 16.8% of the native tendon insertion area, which was significantly different when compared with the knotless suture-bridge repair technique (85.2% +/- 14.8%, P = .001) and the V shaped distal triceps tendon repair technique (88.9% +/- 14.8%, P = .002). Mean displacement showed no significant difference between the V-shaped distal triceps tendon repair technique (medial side, 0.75 +/- 0.56 mm; lateral side, 0.99 +/- 0.59 mm) and the knotless suture-bridge repair technique (1.61 +/- 0.97 mm and 1.29 +/- 0.8 mm) but significance between the V-shaped distal triceps tendon repair technique and the transosseous cruciate repair technique (4.91 +/- 1.12 mm and 5.78 +/- 0.9 mm, P < .001). Mean peak failure load of the V-shaped distal triceps tendon repair technique (732.1 +/- 156.0 N) was significantly higher than that of the knotless suture-bridge repair technique (505.4 +/- 173.9 N, P = .011) and the transosseous cruciate repair technique (281.1 +/- 74.8 N, P < .001). Mechanism of failure differed among the 3 repairs, with the only olecranon fracture occurring in the knotless suture-bridge repair technique at the level of the lateral row suture anchors. CONCLUSION: At time zero, the V-shaped distal triceps tendon repair technique and the knotless suture-bridge repair technique both provided anatomic footprint coverage. Ultimate load to failure was highest for the V-shaped distal triceps tendon repair technique, while gap formation was different only in comparison with the transosseous cruciate repair technique. CLINICAL RELEVANCE: The V-shaped distal triceps tendon repair technique provides an alternative procedure to other established repairs for acute/subacute distal triceps tendon ruptures. The reduced repair site motion of the V-shaped distal triceps tendon repair technique and the knotless suture-bridge repair technique at the time of surgery may allow a more aggressive rehabilitation program in the early postoperative period. PMID- 29763341 TI - Reply to M.S. Copur et al. PMID- 29763342 TI - Molecular Testing Guideline for the Selection of Patients With Lung Cancer for Targeted Therapy. PMID- 29763343 TI - Clinical and Patient-Related Outcomes of a Tapered Implant System With Switched Platform Conical Abutments: A Private Practice Field Trial. AB - The aim of this prospective cohort observational field trial was to examine 1 year survival and success rates of a recently introduced tapered implant system with switched platform conical abutments and to evaluate patient related outcomes of therapy. Partially edentulous patients aged between 18 and 75 years, with available bone height for dental implants >=10 mm desiring to restore the missing tooth/teeth with implant supported restoration, were recruited by 7 periodontists in their respective private practices. Dental implants were installed according to standard implant therapy protocol. Three to 6 months postoperatively, after evaluating interim implant success, implants were restored by the referring dentists. Patient, Ramfjord teeth, and implant data, including baseline and 1 year postoperative, were collected. A total of 60 patients were recruited and received 117 implants. Complete 1-year clinical and radiographic data were available for 83 and 65 implants, respectively. Two implants failed during the first year, resulting in a 1-year survival rate of 98.3%. Mean implant probing pocket depth was 2.29 +/- 0.84 mm. Mean radiographic bone distance from implant's shoulder at the mesial and distal sites at 1 year was 0.66 +/- 0.5 and 0.79 +/- 0.64mm, respectively, resulting in a success rate of 95.4%. Patient subjective evaluation of therapy exhibited a median pain experience of 1 and median esthetics, function, and general satisfaction evaluation of 10 on a scale of 1 to 10. The tapered conical connection dental implant system, used in private dental practices, shows good 1-year survival and success rates that are similar to other implant systems on the market. PMID- 29763344 TI - From the Valley of Death to the Crossroads of Opportunity: A Discussion of Evolving Benefit/Risk Evaluation Standards. AB - A series of recent US Food and Drug Administration (FDA) approvals (such as Sarepta's Exondys 51, Merck's Keytruda, and Portola's Bevyxxa) has generated significant interest within the drug development ecosystem. Facilitated regulatory pathways aimed toward expediting medicines to patients suffering from serious and life-threatening conditions are a good thing, even if it raises curiosity and introduces some degree of uncertainty. Over the last 20 years, two key words in drug development have been speed and innovation. Going forward, the patient voice, data quality, and evidence generation must be added to that list. There is a raging debate over the level of evidence expected to first introduce a treatment to patients. Some argue for less data followed by postapproval follow up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in the regulatory framework is happening in front of our eyes. How are these shifts in regulatory science interpreted within the context of 21st-century drug development-and how can these learnings help advance patient care while placing into context the expected uncertainty we find in benefit-risk data? PMID- 29763345 TI - Tissue Engineering of Necrotic Dental Pulp of Immature Teeth with Apical Periodontitis in Dogs: Radiographic and Histological Evaluation. AB - AIM: To evaluate tissue engineering technology to regenerate pulp-dentin like tissues in pulp canals of immature necrotic permanent teeth with apical periodontitis in dogs. STUDY DESIGN: The study was performed on 36 teeth in 12 dogs. The experiment was carried out using split mouth design. In each dog 3 teeth were selected for implementing the study procedure. Apical periodontitis was induced in Group A and B teeth. Group (A): immature upper left 2nd permanent incisors that were transplanted with a construct of autologous dental pulp stem cells with growth factors seeded in a chitosn hydrogel scaffold. Group (B): immature upper right 2nd permanent incisor that received only growth factors with scaffold. A third tooth in each dog was selected randomly for isolation of dental pulp stem cells (DPSCs). Both groups were closed with a double coronal seal of white MTA (Mineral trioxide aggregate) and glass ionomer cement. Both groups were monitored radiographically for 4 months and histologically after sacrificing the animals. RESULTS: There was no statistically significant difference in radiographic findings between group (A) and group (B) for healing of radiolucencies, while there was statistically significant difference between group (A) and group (B) regarding radicular thickening, root lengthening and apical closure. Histologically, group (A) teeth showed regeneration of pulp- dentin like tissue while group (B) teeth did not show any tissue regeneration. CONCLUSION: Dental pulp stem cells and growth factors incorporated in chitosan hydrogel are able to regenerate pulp- dentine like tissue and help in complete root maturation of non-vital immature permanent teeth with apical periodontitis in dogs. PMID- 29763346 TI - Mandibular Condylar Aplasia Treated with a Functional Appliance: A Five years Follow Up. AB - This report presents a follow up of a clinical case published five years ago by the same authors. In the previous report, the authors showed a young girl treated with a myofunctional appliance due to a mandibular condylar agenesia. After a traditional graft had failed, the patient successfully responded to the functional treatment by forming a mandibular condyle. In this new report, the authors are showing how the mandibular condyle has continued developing within normal limits and, the mandibular ramus has continued positively remodeling. The bone biology embedded in the biological process reported here is discussed by the authors. PMID- 29763347 TI - Passive Observer Instruction on Parental Satisfaction in a Dental Setting. AB - PURPOSE: To assess the effect of a single pre-operative instruction given to parents to be a passive observer on satisfaction with their child's dental visit. STUDY DESIGN: Parents of 105 healthy three to nine year-old patients presenting for their first restorative appointment were randomly assigned to the test or control group. The former received an oral instruction at the beginning of the appointment from the treating dentist to be a passive observer while the latter received a mock instruction. The dentist assessed whether the parent remained a passive observer during the visit. Parents completed a survey assessing satisfaction with their child's dental visit. RESULTS: More parents were rated as passive in the test group than in the control group, 67.3% vs. 32.1%, (P<0.01). However, no statistically significant difference was found in parental satisfaction between the test and the control group. CONCLUSION: Asking parents to act as passive observers may help preserve the advantages of parental presence in the operatory while eliminating many of the disadvantages. A single preoperative instruction given orally by the treating dentist to be a passive observer was effective and did not lead to a reduction in parental satisfaction. PMID- 29763348 TI - Histological Alterations from Condyle Repositioning with Functional Appliances in Rats. AB - OBJECTIVE: This study was designed to assess the morphological and histological alterations of the condyle of rats undergoing forward mandibular repositioning via functional appliance. MATERIALS AND METHODS: Functional appliances were mounted onto the upper jaws of rats. Morphological analysis was conducted on micro-CT images of sacrificed animals. Histological changes in condyle were examined by immunohistochemistry using proliferating cell nuclear antigen (PCNA), matrix metalloproteases (MMPs), vascular endothelial growth factor (VEGF), tissue inhibitors of matrix metalloproteinases (TIMP-1), interleukin 1b (IL-1beta), Aggrecan and Type II collagen. Osteoclast activity was identified by tartrate resistant acid phosphatase (TRAP) staining. RESULTS: Morphological analysis confirmed the forward positioning of the condyles of rats by the appliance, but the position gradually returned to normal on days 14 after treatment. An increase in PCNA positive cells was observed in the posterior region of the condyles on days 7, whereas PCNA positive cells decreased in the anterior region. Aggrecan and Type II collagen localization increased in the posterior region throughout the entire period, but decreased in the anterior region on days 14. In both regions, IL-1beta and VEGF localization was significantly increased for 14 days while MMPs localization was evident throughout the entire period. The TRAP positive cells were significantly elevated on days 3 and 7. CONCLUSIONS: These results suggest that the functional appliance therapy induces significant morphological and histological changes in the anterior and posterior regions of the condyle and subsequently causes adaptive cellular functions such as chondrocyte differentiation and cartilage matrix formation. PMID- 29763349 TI - Molar-Incisor Hypomineralization: Positive Correlation with Atopic Dermatitis and Food Allergies. AB - AIM: Molar-incisor hypomineralization is a disturbance in dental development that involves first permanent molars as well as permanent incisors with a prevalence that ranges from 2.5% to 40%. The objective of this study was to investigate the etiology of molar-incisor hypomineralization among school children from two randomly selected towns in the province of Barcelona, Spain. STUDY DESIGN: A cross-sectional study was conducted with 705 children ranging in age from six years-old to 14 years and 11 months-old. Full mouth examinations were carried out in accordance with the European Academy of Paediatric Dentistry criteria for the diagnosis of molar-incisor hypomineralization, from April to July 2016. RESULTS: A total of 56 cases of molar-incisor hypomineralization were found in 22 (39.3%) boys and 34 (60.7%) girls. MIH was significantly more prevalent among those who had atopic dermatitis (OR=90.9; 33.4-247.1 CI 95%), food allergies (OR=104.2; 12.2-887.5 CI 95%), bronchitis/asthma (OR=5.3; 2.7-10.1 CI 95%), varicella (OR=96.3; 41.9-221.1 CI 95%), otitis media (OR=12.2; 6.3-23.5 CI 95%), pneumonia (OR=276.7; 35.1-2183.7 CI 95%), and febrile syndrome (OR=7.8; 4.1-14.8 CI 95%). CONCLUSIONS: The present research reveals for the first time a statistically significant relationship between atopic dermatitis and food allergies with the presence of molar-incisor hypomineralization. PMID- 29763350 TI - Fluoride Exposure in Early Life as the Possible Root Cause of Disease In Later Life. AB - Fluoride, one of the most celebrated ingredients for the prevention of dental caries in the 20th century, has also been controversial for its use in dentifrices and other applications. In the current review, we have concentrated primarily on early-life exposure to fluoride and how it may affect the various organs. The most recent controversial aspects of fluoride are related to toxicity of the developing brain and how it may possibly result in the decrease of intelligence quotient (IQ), autism, and calcification of the pineal gland. In addition, it has been reported to have possible effects on bone and thyroid glands. If nutritional stress is applied during a critical period of growth and development, the organ(s) and/or body will never recover once they pass through the critical period. For example, if animals are force-fed during experiments, they will simply get fat but never reach the normal size. Although early-life fluoride exposure causing fluorosis is well reported in the literature, the dental profession considers it primarily as an esthetic rather than a serious systemic problem. In the current review, we wanted to raise the possibility of future disease as a result of early-life exposure to fluoride. It is not currently known how fluoride will become a cause of future disease. Studies of other nutritional factors have shown that the effects of early nutritional stress are a cause of disease in later life. PMID- 29763351 TI - Concomitant Temporomandibular Joint Ankylosis and Maxillomandibular Fusion in a Child with Klippel- Feil Syndrome: A Case Report. AB - Klippel-Feil syndrome (KFS) is classically characterized by fusion of any of the two of seven cervical vertebrae. It is identified by the presence of a triad of clinical signs including short neck, limitation of head and neck movements and low posterior hairline. Unusual bony malformations leading to facial asymmetry is the most common oral manifestation associated with KFS. Such maxillomandibular fusion can also result in restricted mouth opening in children. It's a challenge to provide complete rehabilitation in such children. This paper presents a report of a type II KFS with both maxillomandibular fusion and temporomandibular joint ankylosis which led to the limited mouth opening in a six-year-old child. Also, the child showed an inadequate development of speech, facial asymmetry and compromised oral health owing to the restricted mouth opening. After thorough investigations, surgery was done which restored limited mouth opening which led to normalizing of speech and oral health. PMID- 29763352 TI - Pyogenic Granuloma in the Tongue in a Five Year Old: A Case Report. AB - Pyogenic granuloma, also called lobular capillary hemangioma, is a benign vascular lesion of the skin and mucous membranes. While the majority of pyogenic granulomas in the oral cavity involve the gingiva, they also infrequently present at other sites including lips, oral mucosa, palate, and tongue. We report a case of a pyogenic granuloma of the tongue in a five-year old female patient. PMID- 29763353 TI - Effect of Probiotic Lactobacillus reuteri on Salivary Cariogenic Bacterial Counts among Groups of Preschool Children in Jeddah, Saudi Arabia: A Randomized Clinical Trial. AB - OBJECTIVES: To evaluate the effect of probiotic Lactobacilli reuteri lozenges on caries-associated salivary bacterial counts (Mutans streptococci and Lactobacillus), dental plaque accumulation, and salivary buffer capacity in a group of preschool children. STUDY DESIGN: The study group consisted of 178 healthy children (aged 3-6 years). Children were randomly grouped: the experimental group (n = 90) received L. reuteri probiotic lozenges and the control group (n = 88) received placebo lozenges, twice daily, for 28 days. Salivary Mutans streptococci and Lactobacillus counts, and buffer capacity were assessed using chair-side caries-risk test (CRT(r)) kits. The Simplified Oral Hygiene index (OHI-S) was used to assess dental plaque accumulation at baseline and after 28 days. RESULTS: After 28 days, the experimental group had a statistically significant reduction in Mutans streptococci and lactobacilli (p = 0.000 and p = 0.020, respectively) and both groups had less plaque accumulation than at baseline. While the buffer capacity in the experimental group increased more than in the control group, it was not statistically significant (p = 0.577). Compliance was 90%, with no adverse events. CONCLUSIONS: Consumption of probiotic lozenges containing L. reuteri reduces caries-associated bacterial counts significantly. Probiotics consumption may have a beneficial caries-preventive effect. PMID- 29763354 TI - Randomized Controlled Trial of Pulpotomy in Primary Molars using MTA and Formocresol Compared to 3Mixtatin: A Novel Biomaterial. AB - OBJECTIVE: This study was conducted to compare the efficacy of 3Mixtatin (a combination of simvastatin and 3Mix antibiotic) with MTA and Formocresol for the pulpotomy of primary molars. STUDY DESIGN: 114 children aged 3-6 years old with 150 primary molars were randomly allocated to three groups. MTA, Formocresol or 3Mixtatin were used for Pulpotomies. Hard setting zinc oxide eugenol was used to cover these materials. The teeth were restored with amalgam. Blinded radiographic and clinical examinations were conducted at 6, 12 and 24 months after treatment for the presence of pain, tenderness to palpation and percussion, sinus tract, swelling, presence of internal or external root resorption, inter-radicular radiolucency, and periapical lesion. RESULTS: 122 teeth were available for 24 month follow-up study. The overall success rate was 78.9% for FC, 90.5% for 3Mixtatin and 88.1% for MTA group. There was no significant difference in overall success rate among the groups after 24-month follow-up (X2=2.43, df = 2, P =0.27). CONCLUSION: Our findings demonstrated remarkable results of 3Mixtatin in pulpotomy of primary teeth at the 24-month follow-up. Therefore, 3Mixtatin may be considered as an effective material in pulpotomy of primary teeth because of its successful results. PMID- 29763355 TI - Risk Factors of Early Childhood Caries among Young Children in Hong Kong: A Cross Sectional Study. AB - OBJECTIVE: Early childhood caries (ECC) was prevalent in Hong Kong. Children with ECC risk should be identified early for prevention. This study aimed to identify common risk factors of ECC in Hong Kong 3-year-old children. STUDY DESIGN: Sample size calculation showed at least 6,321 of 3-year-old children should be invited in this study. A consent form and a questionnaire enquiring the children's oral health behaviours and social-economic background were distributed to their parents. Children with parental consent were examined by a trained dentist. Caries status was recorded in dmft index. Chi-square test and logistic regression analysis were performed to identify the risk factors of ECC. RESULTS: A total of 5,167 children from the 6,331 children invited were examined. Among them, 1,130 children (22%) had ECC (dmft>0). Logistic regression analysis found age of starting tooth brushing, snack-intake frequency, dental visit experience, birthplace, family monthly income, primary caretaker, and mother's education level were factors associated with ECC of the children. CONCLUSIONS: Children who started tooth brushing later, had higher snack-intake frequency, were not born in Hong Kong, and whose family monthly income was lower, mother's education level was lower, primary caretaker was not domestic helper, had a statistically significant higher chance of having ECC. PMID- 29763356 TI - Chairside CAD/CAM Composite Onlays for the Restoration Of Primary Molars. AB - After pulp therapy or with multi-surface caries in primary molars, pre-formed stainless steel crowns are usually placed to ensure tooth longevity. Esthetic alternatives, such as zirconia crowns, have been proposed, but they are invasive. Here we describe two cases of chairside computer-aided design and computer-aided manufacturing (CAD/CAM) technology used to treat extended and/or deep caries on primary molars. A powder-free chairside CAD/CAM system, a milling unit and machinable high-performance composite blocks were used. The tooth preparation consisted of preparing the cavity without undercut, to have supra-gingival margins whenever possible, occlusal reduction of thin walls, and proximal box finishing by ultrasonic tips. After the optical impression, the virtual onlay was designed and adapted (from the morphology of a first permanent molar), then chairside-manufactured out of a composite block and bonded by using a self adhesive resin cement. This technique combines minimally invasive treatment; high strength, biocompatible and aesthetic material; no gingival trauma; easy execution; and patient and parent satisfaction. However, the equipment is quite expensive and the software still does not include the morphology of primary teeth. PMID- 29763357 TI - Comparative Evaluation of Endovac and Conventional Irrigating Syringe on Apical Extrusion in Primary Molars. An in vitro Study. AB - OBJECTIVES: The present study was undertaken to evaluate and compare the apical extrusion of irrigant and depth of irrigant penetration into dentine using the EndoVac irrigating system and manual irrigation system in primary molar teeth. STUDY DESIGN: Twenty five extracted primary molars satisfying the inclusion and exclusion criteria were divided into two groups with 29 roots in each group with an equal distribution of apical foramen area. The teeth were mounted in pre weighed glass bottles and the canals were irrigated with 5.25% sodium hypochlorite solution mixed with acid fuchsin using either of irrigating systems according to the group ascertained. The amount of irrigant extruded was recorded. The roots were sectioned at two mm, four mm and six mm from the apex and examined under a stereomicroscope for depth of irrigant penetration. RESULTS: Apical extrusion of the irrigant solution was significantly less with the EndoVac system (1.18+/-1.04) when compared with the manual irrigation system (2.3+/-1.55) (P=0.002)*. Results showed that greater irrigant penetration was achieved using the EndoVac irrigation system compared to the manual irrigation system (P= 0.000)*. With both the irrigation systems, the depth of irrigant penetration was better in the six mm sections followed by the four mm sections and two mm sections (P=0.000)*. CONCLUSION: The EndoVac irrigation system demonstrated better efficacy compared to manual irrigation system with less apical extrusion and better depth of irrigant penetration into dentine. PMID- 29763358 TI - Bone Marrow Stimulation Technique Augmented by an Ultrapurified Alginate Gel Enhances Cartilage Repair in a Canine Model. AB - BACKGROUND: The optimal treatment for a medium- or large-sized cartilage lesion is still controversial. Since an ultrapurified alginate (UPAL) gel enhances cartilage repair in animal models, this material is expected to improve the efficacy of the current treatment strategies for cartilage lesions. HYPOTHESIS: The bone marrow stimulation technique (BMST) augmented by UPAL gel can induce hyaline-like cartilage repair. STUDY DESIGN: Controlled laboratory study. METHODS: Two cylindrical osteochondral defects were created in the patellar groove of 27 beagle dogs. A total of 108 defects were divided into 3 groups: defects without intervention (control group), defects with the BMST (microfracture group), and defects with the BMST augmented by implantation of UPAL gel (combined group). At 27 weeks postoperatively, macroscopic and histological evaluations, micro-computed tomography assessment, and mechanical testing were performed for each reparative tissue. RESULTS: The defects in the combined group were almost fully covered with translucent reparative tissues, which consisted of hyaline-like cartilage with well-organized collagen structures. The macroscopic score was significantly better in the combined group than in the control group ( P < .05). The histological scores in the combined group were significantly better than those in the control group ( P < .01) and microfracture group ( P < .05). Although the repaired subchondral bone volumes were not influenced by UPAL gel augmentation, the mechanical properties of the combined group were significantly better than those of the microfracture group ( P < .05). CONCLUSION: The BMST augmented by UPAL gel elicited hyaline-like cartilage repair that had characteristics of rich glycosaminoglycan and matrix immunostained by type II collagen antibody in a canine osteochondral defect model. The present results suggest that the current technique has the potential to be one of the autologous matrix-induced chondrogenesis techniques of the future and to expand the operative indications for the BMST without loss of its technical simplicity. CLINICAL RELEVANCE: The data support the clinical reality of 1-step minimally invasive cartilage-reparative medicine with UPAL gel without harvesting donor cells. PMID- 29763359 TI - Are Sleep Alterations the Cause of ICU Delirium? PMID- 29763360 TI - THREE-DIMENSIONAL FINITE ELEMENT ANALISYS OF STRESS DISTRIBUTION IN ZIRCONIA AND TITANIUM DENTAL IMPLANTS. AB - Zirconia has been presented as an alternative biomaterial to titanium, commercially presented as a single body implant and / or as an abutment, demonstrating clinically biocompatible favorable results in white and rose aesthetics, However, the amount of long-term in-vivo studies and mechanical tests evaluating the response of stress distribution compared with titanium implants are still limited. The aim of the study was to compare by the finite element method, the principal stresses peaks in the peri implantar bone around titanium and zirconia implants. Four groups of three-dimensional models were constructed for the tests: G1) external hexagon titanium implant with a zirconia abutment G2) zirconia implant with a zirconia abutment G3) single body titanium implant and G4) single body zirconia implant. Axial and oblique loads 100 N with 45 degrees were simulated in the prosthetic crown. The bone results showed that the peak stresses decreased by 12% in zirconia implants with two parts for axial load and 30% for the oblique load. In single body implants, the peak stresses decreased 12% in the axial load and 34% in the oblique load when a zirconia implant was used compared with a titanium implant. Although the stress values in megapascal (MPa) are similar, it can be concluded that the zirconia implants decrease the stress peaks at the peri implant bone area around the implant platform when compared to titanium implants. PMID- 29763361 TI - Corrigendum. PMID- 29763362 TI - Fracture Strength and Precision of Fit of Implant-Retained Monolithic Zirconia Crowns. AB - New monolithic zirconia materials can be used to fabricate full-contour fixed dental prostheses with the computer-aided design/computer-aided manufacturing (CAD/CAM) method. The aim of this study was to examine the fracture strength and precision of fit of screw-retained monolithic zirconia crowns made directly on implants or by cementing on prefabricated titanium (Ti) bases. Monolithic screw retained implant crowns (n = 6) were produced by CAD/CAM method using partially (PSZ) and fully stabilized (FSZ) zirconia. Industrially produced zirconia crowns were used as a reference. A lateral incisor study model was made onto an implant replica. Crowns were produced either directly on the implant or through cementing on a prefabricated titanium base (PSZ+Ti, FSZ+Ti). The crowns were tightened to implant replicas with a torque of 35 Ncm. The gap between the replica and the abutment or crown was measured from *400 scanning electron microscope images for precision of fit. Mechanical testing until failure was completed with a universal testing machine with loading angle of 45 degrees . Statistical analysis was performed (analysis of variance). Mean (+/-SD) failure loads were 259 +/- 23 (PSZ), 140 +/- 13 (FSZ), 453 +/- 25 (PSZ+Ti), 439 +/- 41 (FSZ+Ti), and 290 +/- 39 (Procera). Mean (+/-SD) gap values were 2.2 +/- 0.2 (PSZ), 2.5 +/- 1.0 (FSZ), 7.0 +/- 1.0 (PSZ+Ti), 7.7 +/- 1.6 (FSZ+Ti), and 6.7 +/- 1.7 (Procera). Monolithic zirconia crowns with a Ti base clearly show higher fracture strengths than the crowns fixed directly on the implant surface. Better marginal fit can be achieved with direct zirconia crowns than with crowns on a titanium base or industrially produced zirconia crowns. PMID- 29763363 TI - A Pilot Study of a Culturally Grounded Breastfeeding Intervention for Pregnant, Low-Income African American Women. AB - BACKGROUND: Increasing breastfeeding rates among low-income African American women may work toward the achievement of health equity. The dynamic breastfeeding assessment process (D-BAP) is a community-grounded, equity-focused intervention designed to increase prenatal breastfeeding self-efficacy. Research aim: The aims of the pilot study were (a) to determine the effect of the D-BAP on breastfeeding self-efficacy among pregnant, low-income African American women, (b) to examine the findings among women with no previous breastfeeding experience, and (c) to compare the findings between women with prior breastfeeding experience and those without it. METHODS: A pre/post, paired-samples design was utilized. Convenience sampling was used to recruit pregnant, low-income African American women ( N = 25). Participants completed the Breastfeeding Self-Efficacy Scale-Short Form prior to and following the D-BAP. RESULTS: The Wilcoxon signed rank test indicated that participation in the D-BAP had a statistically significant influence on breastfeeding self-efficacy ( z = -2.01, p = .04). Among a subsample of participants with no previous breastfeeding experience ( n = 12), completion of the D-BAP resulted in a statistically significant increase in breastfeeding self-efficacy ( z = -2.36, p = .02). There was no statistically significant difference between those with prior breastfeeding experience and those without it. CONCLUSION: Breastfeeding among low-income African American women is a health equity issue for which culturally responsive, effective breastfeeding interventions are needed. This research demonstrates an association between completion of the D-BAP and an increase in prenatal breastfeeding self-efficacy. PMID- 29763364 TI - The loss of copper is associated with the increase in copper metabolism MURR domain 1 in ischemic hearts of mice. AB - The distribution of copper (Cu) in the biological system is regulated by Cu transporters and chaperones. It has been known for a long time that myocardial ischemia is accompanied by the loss of Cu from the heart, but the mechanism by which this occurs remains unknown. The present study was undertaken to understand the relationship between Cu loss and alterations in Cu transporters during the pathogenesis of myocardial ischemia. Male mice (C57 BL/6J) were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial ischemia. Changes in Cu concentrations in serum and hearts were determined from blood and tissue samples harvested at different time points for a total of 28 days after the operation. Cu concentrations in the ischemic myocardium were continuously decreased starting at the fourth day after LAD artery ligation, gradually depleted by more than 80% of the normal level at the 10th day, and remained at the lowest level (about 20% of normal levels) thereafter. Serum Cu concentrations were correspondingly increased starting at the fourth day, reached to the highest level between day 7 and 10, and gradually recovered to the normal level until 21st day after the operation. Along with the same time course, the intracellular Cu exporter copper metabolism MURR domain 1 (COMMD1) was significantly and sustainably increased, but ATP7A and ATP7B were not significantly changed in the ischemic myocardium. These results suggest that during the pathogenesis of myocardial ischemia, COMMD1 would play a critical role in exporting Cu from the ischemic myocardium to the blood. Impact statement In this work, we found that copper efflux from the ischemic heart leads to the elevation of serum copper concentrations, addressing a long-term question related to serum copper elevation in myocardial ischemia patients. The efflux of copper from the ischemic heart results at least in part from the upregulation of copper metabolism MURR domain 1 (COMMD1) in the heart upon ischemic insult. This work provides a novel insight into copper homeostasis and alteration in cardiovascular system. PMID- 29763365 TI - Effect of cross-linked chitosan iron (III) on vascular calcification in uremic rats. AB - Cross-linked chitosan iron (III) is a chitin-derived polymer with a chelating effect on phosphorus, but it is untested in vascular calcification. We evaluated this compound's ability to reduce hyperphosphatemia and its effect on vascular calcification in uremic rats using an adenine-based, phosphorus-rich diet for seven weeks. We used a control group to characterize the uremia. Uremic rats were divided according the treatment into chronic kidney disease, CKD-Ch-Fe(III)CL (CKD-Ch), CKD-calcium carbonate, or CKD-sevelamer groups. We measured creatinine, phosphorus, calcium, alkaline phosphatase, phosphorus excretion fraction, parathyroid hormone, and fibroblast growth factor 23. Vascular calcification was assessed using the aortic calcium content, and a semi-quantitative analysis was performed using Von Kossa and hematoxylin-eosin staining. At week seven, rats in the chronic kidney disease group had higher creatinine, phosphorus, phosphorus excretion fraction, calcium, alkaline phosphatase, fibroblast growth factor 23, and aortic calcium content than those in the Control group. Treatments with cross linked chitosan iron (III) and calcium carbonate prevented phosphorus increase (20%-30% reduction). The aortic calcium content was lowered by 88% and 85% in the CKD-Ch and CKD-sevelamer groups, respectively. The prevalence of vascular changes was higher in the chronic kidney disease and CKD-calcium carbonate (62.5%) groups than in the CKD-Ch group (37.5%). In conclusion, cross-linked chitosan iron (III) had a phosphorus chelating effect similar to calcium carbonate already available for clinical use, and prevented calcium accumulation in the aorta. Impact statement Vascular calcification (VC) is a common complication due to CKD-related bone and mineral disorder (BMD) and is characterized by deposition of calcium in vessels. Effective therapies are not yet available but new phosphorus chelators can prevent complications from CV. We tested the effect of chitosan, a new phosphorus chelator, on the VC of uremic animals. It has recently been proposed that chitosan treatment may be effective in the treatment of hyperphosphataemia. However, its action on vascular calcification has not been investigated yet. In this study, we demonstrated that chitosan reduced the calcium content in the aorta, suggesting that this may be a therapeutic approach in the treatment of hyperphosphatemia by preventing CV. PMID- 29763366 TI - Right ventricle performances with echocardiography and 99mTc myocardial perfusion imaging in pulmonary arterial hypertension patients. AB - Right heart catheterization is commonly used to measure right ventricle hemodynamic parameters and is the gold standard for pulmonary arterial hypertension diagnosis; however, it is not suitable for patients' long-term follow-up. Non-invasive echocardiography and nuclear medicine have been applied to measure right ventricle anatomy and function, but the guidelines for the usefulness of clinical parameters remain to be established. The goal of this study is to identify reliable clinical parameters of right ventricle function in pulmonary arterial hypertension patients and analyze the relationship of these clinical parameters with the disease severity of pulmonary arterial hypertension. In this study, 23 normal subjects and 23 pulmonary arterial hypertension patients were recruited from January 2015 to March 2016. Pulmonary arterial hypertension patients were classified into moderate and severe pulmonary arterial hypertension groups according to their mean pulmonary arterial pressure levels. All the subjects were subjected to physical examination, chest X-ray, 12-lead electrocardiogram, right heart catheterization, two-dimensional echocardiography, and technetium 99m (99mTc) myocardial perfusion imaging. Compared to normal subjects, the right heart catheterization indexes including right ventricle systolic pressure, right ventricle end diastolic pressure, pulmonary artery systolic pressure, pulmonary artery diastolic pressure, pulmonary vascular resistance, and right ventricle end systolic pressure increased in pulmonary arterial hypertension patients and were correlated with mean pulmonary arterial pressure levels. Echocardiography parameters, including tricuspid regurgitation peak velocity, tricuspid regurgitation pressure gradient, tricuspid annular plane systolic excursion and fractional area, right ventricle-myocardial performance index, were significantly associated with the mean pulmonary arterial pressure levels in pulmonary arterial hypertension patients. Furthermore, myocardial perfusion imaging was not observed in the normal subjects but in pulmonary arterial hypertension patients, especially severe pulmonary arterial hypertension subgroup, and showed potential diagnostic properties for pulmonary arterial hypertension. In conclusion, mean pulmonary arterial pressure levels are correlated with several right heart catheterization and echocardiography markers in pulmonary arterial hypertension patients; echocardiography and 99mTc myocardial perfusion can be used to evaluate right ventricle performance in pulmonary arterial hypertension patients. Impact statement In this study, we analyzed the clinical parameters for evaluating RV function, including right ventricle catheterization (RHC), echocardiography, and technetium 99m (99mTc) myocardial perfusion imaging (MPI) in normal Asian subjects and PAH patients ( n = 23 for each group). Our results demonstrated that six RHC indexes, four echocardiography indexes and MPI index were significantly altered in PAH patients and correlated with the levels of mean pulmonary arterial pressure. Importantly, we evaluated the diagnostic performance of MPI and found that MPI has a strong diagnostic accuracy in PAH patients. The findings from this study will be of interest to clinical investigators who make diagnosis and therapeutic strategies for PAH patients. PMID- 29763367 TI - HSP70 protects rats and hippocampal neurons from central nervous system oxygen toxicity by suppression of NO production and NF-kappaB activation. AB - During diving, central nervous system oxygen toxicity may cause drowning or barotrauma, which has dramatically limited the working benefits of hyperbaric oxygen in underwater operations and clinical applications. The aim of this study is to understand the effects and the underlying mechanism of heat shock protein 70 on central nervous system oxygen toxicity and its mechanisms in vivo and in vitro. Rats were given geranylgeranylacetone (800 mg/kg) orally to induce hippocampal expression of heat shock protein 70 and then treated with hyperbaric oxygen. The time course of hippocampal heat shock protein 70 expression after geranylgeranylacetone administration was measured. Seizure latency and first electrical discharge were recorded to evaluate the effects of HSP70 on central nervous system oxygen toxicity. Effects of inhibitors of nitric oxide synthase and nuclear factor-kappaB on the seizure latencies and changes in nitric oxide, nitric oxide synthase, and nuclear factor-kappaB levels in the hippocampus tissues were examined. In cell experiments, hippocampal neurons were transfected with a virus vector carrying the heat shock protein 70 gene (H3445) before hyperbaric oxygen treatment. Cell viability, heat shock protein 70 expression, nitric oxide, nitric oxide synthase, and NF-kappaB levels in neurons were measured. The results showed that heat shock protein 70 expression significantly increased and peaked at 48 h after geranylgeranylacetone was given. Geranylgeranylacetone prolonged the first electrical discharge and seizure latencies, which was reversed by neuronal nitric oxide synthase, inducible nitric oxide synthase and NF-kappaB inhibitors. Nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels in the hippocampus were significantly increased after hyperbaric oxygen exposure, but reversed by geranylgeranylacetone, while heat shock protein 70 inhibitor quercetin could inhibit this effect of geranylgeranylacetone. In the in vitro study, heat shock protein 70-overexpression decreased the nitric oxide, nitric oxide synthase, and inducible nitric oxide synthase levels as well as the cytoplasm/nucleus ratio of nuclear factor-kappaB and protected neurons from hyperbaric oxygen-induced cell injury. In conclusion, overexpression of heat shock protein 70 in hippocampal neurons may protect rats from central nervous system oxygen toxicity by suppression of neuronal nitric oxide synthase and inducible nitric oxide synthase mediated nitric oxide production and translocation of nuclear factor-kappaB to nucleus. Impact statement Because the pathogenesis of central nervous system oxygen toxicity (CNS-OT) remains unclear, there are few interventions available. To develop an efficient strategy against CNS-OT, it is necessary to understand its pathogenesis and in particular, the relevant key factors involved. This study examined the protective effects of heat shock protein 70 (HSP70) on CNS-OT via in vivo and in vitro experiments. Our results indicated that overexpression of HSP70 in hippocampal neurons may protect rats from CNS-OT by suppression of nNOS and iNOS-mediated NO production and the activation of NF-kappaB. These findings contribute to clarification of the role of HSP70 in CNS-OT and provide us a potential novel target to prevent CNS-OT. Clarification of the involvement of NO, NOS and NF-kappaB provides new insights into the mechanism of CNS-OT and may help us to develop new approach against it by interfering these molecules. PMID- 29763368 TI - Matrix metalloproteinase-9 gene polymorphisms and their interaction with environment on subarachnoid hemorrhage risk. AB - The current study aimed to investigate the relations of three single nucleotide polymorphisms of matrix metalloproteinase-9 gene, and single nucleotide polymorphisms-smoking interaction to subarachnoid hemorrhage risk. The optimal pattern of the interaction among single nucleotide polymorphisms and smoking was selected by generalized multifactor dimensionality reduction. The association between the three single nucleotide polymorphisms within the matrix metalloproteinase-9 gene was analyzed by logistic regression test. As well as genetic risk of subarachnoid hemorrhage interactions with smoking, the risk of subarachnoid hemorrhage in carriers with the rs3918242 (T) was significantly higher than in carriers carrying CC (genotype: CT + TT vs. CC), adjusted OR (95% CI) = 1.58 (1.25-2.03), and in carriers carrying rs17576- (genotype: AG + GG vs. AA), adjust OR (95% CI) = 1.62 (1.19-2.13). However, after adjusting for covariates, we did not find any direct association between rs17577 and subarachnoid hemorrhage risk. The generalized multifactor dimensionality reduction model shows a potential relation between rs3918242 and smoking risk for subarachnoid hemorrhage ( P = 0.0010). After covariates adjustment, current smokers with rs3918242-CT or TT genotype, compared to never-smokers with rs3918242-CC genotype, OR (95% CI) = 2.57 (1.74-3.46), have a higher subarachnoid hemorrhage risk. Our study showed that the rs3918242 (T) and rs17576 (G), the cross reaction between rs3918242 and smoking increased the risk of subarachnoid hemorrhage. Impact statement Matrix metalloproteinase-9 ( MMP-9) is a possible candidate gene for some diseases, including metabolic syndrome, stroke, coronary artery disease (CAD). But to date, limited data focused on the relationship between MMP-9 gene SNPs and SAH susceptibility. The purpose of this study was to evaluate SNPs of MMP-9 gene and their interaction with environmental factors with SAH risk based on a Chinese population. PMID- 29763369 TI - Adipose Y5R mRNA is higher in obese than non-obese humans and is correlated with obesity parameters. AB - Neuropeptide Y is mainly expressed in the central nervous system to regulate food intake via its receptors, Y receptors, and in various peripheral tissues including adipose tissue. The objectives of this study were to compare Y5R mRNA and adipocyte parameters consisting of area, width, height, and perimeter either between obese and non-obese subjects or between subcutaneous and visceral fat as well as to compare between NPY, Y1R, Y2R, and Y5R mRNA expressions in subcutaneous and visceral adipose tissues. In subcutaneous and visceral adipose tissues, Y5R was greater in obese than in non-obese humans (both P < 0.05). Y1R mRNA expression was highest followed by Y5R, Y2R, and NPY mRNA expressions, respectively, in subcutaneous and visceral adipose tissues. Visceral Y5R mRNA had positive correlations with body weight, body mass index, waist circumference, hip circumference (R ? 0.4), and visceral Y1R mRNA (R = 0.773), but had a negative correlation with the quantitative insulin sensitivity check index (R=-0.421) (all P < 0.05). Subcutaneous and visceral adipocyte parameters were positively correlated with body weight, waist circumference, hip circumference, and waist-to hip ratio, with greater values of correlation coefficient shown in visceral (R ? 0.5-0.8) than in subcutaneous adipocytes (R ? 0.4-0.6, all P < 0.05). The parameters of visceral adipocytes had positive correlations with serum NPY levels (R ? 0.4, all P < 0.05). Y5R mRNA in visceral adipose tissue is related to increased obesity and reduced insulin sensitivity. The dominant Y receptors in subcutaneous and visceral adipose tissue might be the Y1R and Y5R. Visceral adipocytes show higher correlations with obesity parameters than subcutaneous adipocytes, suggestive of an increased risk of metabolic syndrome in visceral obesity. Y1R and Y5R in visceral adipose tissue might be targets of drug development in prevention or treatment of adiposity. Impact statement Obesity, defined as excess fat accumulation, has been increasingly diagnosed worldwide causing adverse health consequences. The novel findings of this study were that Y5R mRNA expression in both subcutaneous and visceral fat was higher in obese than non-obese subjects. Furthermore, Y5R only in visceral fat, not subcutaneous fat, was positively correlated with visceral Y1R and obesity parameters but it was negatively correlated with the QUICKI. Moreover, we found that Y1R expression was highest followed by Y5R and Y2R, respectively, in both subcutaneous and visceral fat. Our results suggested that Y5R in visceral fat was associated with increased obesity and decreased insulin sensitivity. Y1R and Y5R might be the dominant receptors that mediate the effect of NPY-induced fat accumulation in both subcutaneous and visceral adipose tissues. Y1R and Y5R in visceral adipose tissue might be targets of drug development in prevention or treatment of obesity. PMID- 29763370 TI - Novel interleukin-33 and its soluble ST2 receptor as potential serum biomarkers in parotid gland tumors. AB - An increasing number of patients with parotid gland tumors have been observed in recent years. The relationship between the immune system and tumor formation is thoroughly investigated. However, newly discovered molecules offer a new insight into the pathophysiology of malignancies. It would be ideal to find an easily determinable biomarker of tumor existence, its malignant potential or a biomarker suggesting the probability of disease recurrence. Our study is the first to examine serum concentrations of IL-33 and its sST2 receptor in patients with various types of parotid gland tumors. Serum IL33, sST2, IL-4 and IL-10 concentrations were determined in patients with benign and malignant parotid gland tumors (pleomorphic adenoma, Warthin's tumor, myoepithelioma and acinic cell carcinoma). We observed for the first time that serum IL-33 level was significantly elevated in patients with various types of parotid gland tumors and sST2 levels were significantly higher in pleomorphic adenoma and acinic cell carcinoma patients compared to the controls. Our results demonstrate for the first time that serum IL-33 and its sST2 receptor may be important factors in the pathology of parotid gland tumors. Although our results are promising, further investigations are required to detect if serum concentrations of those molecules may be a biomarker in parotid gland tumors. Impact statement Parotid gland tumors seem to be an increasingly important medical challenge, mostly due to a noticeable increase in the incidence. It would be crucial to find an easily determinable biomarker of tumor existence, its recurrence or malignant potential. We observed for the first time that serum IL-33 level was significantly elevated in patients with various types of parotid gland tumors and its sST2 receptor levels were significantly higher in pleomorphic adenoma and acinic cell carcinoma patients compared to the controls. We believe that our study helps to understand the biology of the tumors and a potential role of a relatively newly identified cytokine IL-33 in the pathophysiology of the parotid gland tumors. PMID- 29763372 TI - Acetyl-CoA from inflammation-induced fatty acids oxidation promotes hepatic malate-aspartate shuttle activity and glycolysis. AB - Hepatic metabolic syndrome is associated with inflammation, as inflammation stimulates the reprogramming of nutrient metabolism and hepatic mitochondria generated acetyl-CoA, but how acetyl-CoA affects the reprogramming of nutrient metabolism, especially glucose and fatty acids, in the condition of inflammation is still unclear. Here, we used an acute inflammation model in which pigs were injected with lipopolysaccharide (LPS) and found that hepatic glycolysis and fatty acid oxidation are both promoted. Acetyl-proteome profiling of LPS-infected pigs liver showed that inflammatory stress exacerbates the acetylation of mitochondrial proteins. Both mitochondrial glutamate oxaloacetate transaminase 2 (GOT2) and malate dehydrogenase 2 (MDH2) were acetylated, and the malate aspartate shuttle (MAS) activity was stimulated to maintain glycolysis. With the use of 13C-carbon tracing in vitro, acetyl-CoA was found to be mainly supplied by lipid-derived fatty acid oxidation rather than glucose-derived pyruvate oxidative decarboxylation, while glucose was mainly used for lactate production in response to inflammatory stress. The results of the mitochondrial experiment showed that acetyl-CoA directly increases MDH2 and, in turn, the GOT2 acetylation level affects MAS activity. Treatment with palmitate in primary hepatocytes from LPS injected pigs increased the hepatic production of acetyl-CoA, pyruvate, and lactate; MAS activity; and hepatic MDH2 and GOT2 hyperacetylation, while the deficiency of long-chain acetyl-CoA dehydrogenase resulted in the stabilization of these parameters. These observations suggest that acetyl-CoA produced by fatty acid oxidation promotes MAS activity and glycolysis via nonenzymatic acetylation during the inflammatory stress response. PMID- 29763371 TI - Normobaric hyperoxia inhibits the progression of lung cancer by inducing apoptosis. AB - Hypoxia is a critical characteristic of solid tumors with respect to cancer cell survival, angiogenesis, and metastasis. Hyperoxic treatment has been attempted to reverse hypoxia by enhancing the amount of dissolved oxygen in the plasma. In this study, we evaluated the effects of normobaric hyperoxia on the progression of lung cancer to determine whether oxygen toxicity can be used in cancer therapy. Following a tail vein injection of the Lewis lung carcinoma cells, C57BL/6J mice were exposed to a 24-h normobaric hyperoxia/normoxia cycle for two weeks. In addition, A549 lung cancer cells were incubated in a normobaric hyperoxia chamber for a 24-h period. As a result, the size and number of tumors in the lung decreased significantly with exposure to normobaric hyperoxia in the mouse model. Cell viability, colony-forming ability, migration, and invasion all decreased significantly in A549 cells exposed to normobaric hyperoxia and the normal control group exposed to normobaric hyperoxia showed no significant damage. Oxidative stress was more prominent with exposure to normobaric hyperoxia in cancer cells. A549 cells exposed to normobaric hyperoxia showed a significantly higher cell apoptosis ratio compared with A549 cells without normobaric hyperoxia exposure and normal human lung cells (BEAS-2B cells). The Bax/Bcl-2 mRNA expression ratio also increased significantly. Changes in the key regulators of apoptosis were similar between in vivo and in vitro conditions. The p-ERK level decreased, while the p-JNK level increased, after normobaric hyperoxia exposure in A549 cells. This study demonstrated the role of normobaric hyperoxia in inhibiting lung cancer. Normal tissue and cells showed no significant hyperoxic damage in our experimental setting. The anti-tumor effect of normobaric hyperoxia may due to the increased reactive oxygen species activity and apoptosis, which is related to the mitogen-activated protein kinase pathway. Impact statement Normobaric hyperoxia (NBO) is a feasible therapy for cancer with a low complication rate. Although NBO may be beneficial in cancer treatment, very few studies have been conducted; thus, the evidence is thin. This is the first study to clearly demonstrate morphological changes in lung cancer with NBO exposure and to investigate the underlying mechanisms both in vivo and in vitro. This study will arouse interest in NBO treatment and promote further research. PMID- 29763373 TI - Oral glucose challenge impairs skeletal muscle microvascular blood flow in healthy people. AB - Skeletal muscle microvascular (capillary) blood flow increases in the postprandial state or during insulin infusion due to dilation of precapillary arterioles to augment glucose disposal. This effect occurs independently of changes in large artery function. However, acute hyperglycemia impairs vascular function, causes insulin to vasoconstrict precapillary arterioles, and causes muscle insulin resistance in vivo. We hypothesized that acute hyperglycemia impairs postprandial muscle microvascular perfusion, without disrupting normal large artery hemodynamics, in healthy humans. Fifteen healthy people (5 F/10 M) underwent an oral glucose challenge (OGC, 50 g glucose) and a mixed-meal challenge (MMC) on two separate occasions (randomized, crossover design). At 1 h, both challenges produced a comparable increase (6-fold) in plasma insulin levels. However, the OGC produced a 1.5-fold higher increase in blood glucose compared with the MMC 1 h postingestion. Forearm muscle microvascular blood volume and flow (contrast-enhanced ultrasound) were increased during the MMC (1.3- and 1.9 fold from baseline, respectively, P < 0.05 for both) but decreased during the OGC (0.7- and 0.6-fold from baseline, respectively, P < 0.05 for both) despite a similar hyperinsulinemia. Both challenges stimulated brachial artery flow (ultrasound) and heart rate to a similar extent, as well as yielding comparable decreases in diastolic blood pressure and total vascular resistance. Systolic blood pressure and aortic stiffness remained unaltered by either challenge. Independently of large artery hemodynamics, hyperglycemia impairs muscle microvascular blood flow, potentially limiting glucose disposal into skeletal muscle. The OGC reduced microvascular blood flow in muscle peripherally and therefore may underestimate the importance of skeletal muscle in postprandial glucose disposal. PMID- 29763375 TI - Chromosomal architecture and placental expression of the human growth hormone gene family are targeted by pre-pregnancy maternal obesity. AB - The human (h) placental lactogenic hormone chorionic somatomammotropin (CS) is highly produced during pregnancy and acts as a metabolic adaptor in response to maternal insulin resistance. Maternal obesity can exacerbate this "resistance", and a >75% decrease in CS RNA levels was observed in term placentas from obese vs. lean women. The genes coding for hCS ( hCS-A and hCS-B) and placental growth hormone ( hGH-V) as well as the hCS-L pseudogene and pituitary growth hormone (GH) gene ( hGH-N) are located at a single locus on chromosome 17. Three remote hypersensitive sites (HS III-V) located >28 kb upstream of hGH-N as well as local hCS gene promoter and enhancer regions are implicated in hCS gene expression. A placenta-specific chromosomal architecture, including interaction between HS III V and hCS but not hGH gene promoters, was detected in placentas from lean women (BMI <25 kg/m2) by using the chromosome conformation capture assay. This architecture was disrupted by pre-pregnancy maternal obesity (BMI >35 kg/m2), resulting in a predominant interaction between HS III and the hGH-N promoter, which was also observed in nonplacental tissues. This was accompanied by a decrease in hCS levels, which was consistent with reduced RNA polymerase II and CCAAT/enhancer-binding protein-beta association with individual hCS promoter and enhancer sequences, respectively. Thus, pre-pregnancy maternal obesity disrupts the placental hGH/CS gene locus chromosomal architecture. However, based on data from obese women who develop GDM, insulin treatment partially recapitulates the chromosomal architecture seen in lean women and positively affects hCS production, presumably facilitating prolactin receptor-related signaling by hCS. PMID- 29763374 TI - Transgenic overexpression of CTRP3 prevents alcohol-induced hepatic triglyceride accumulation. AB - This study tested the ability of a novel adipose tissue derived cytokine, C1q TNF Related Protein 3 (CTRP3), to prevent alcohol-induced hepatic lipid accumulation, or alcoholic fatty liver disease (ALD). Previous work has demonstrated that CTRP3 is effective at preventing high fat diet-induced fatty liver, however, the potential of CTRP3 to inhibit ALD has not been explored. To test the potential protective effects of CTRP3, transgenic mice overexpressing CTRP3 (Tg) or wildtype littermates (WT) were subjected to one of two different models of ALD. In the first model, known as the NIAAA model, mice were fed control or alcohol containing liquid diets (5% v/v) for 10 days followed by a single gavage of ethanol (5 g/kg). In the second model, the chronic model, mice were fed control or alcohol-containing diets for 6 weeks with no gavage. This study found that CTRP3 reduced triglyceride accumulation in the chronic model of alcohol consumption by ~50%, whereas no reduction was observed in the NIAAA model. Further analysis of isolated primary hepatocytes from WT and Tg mice demonstrated that CTRP3 increased oxygen consumption in the presence of fatty acids, indicating that CTRP3 increases hepatic fatty acid utilization. In conclusion, this study indicates that CTRP3 attenuates hepatic triglyceride accumulation in response to long-term chronic but not short-term alcohol consumption. PMID- 29763376 TI - Antitumor Effect of GO-PEG-DOX Complex on EMT-6 Mouse Breast Cancer Cells. AB - OBJECTIVE: Doxorubicin (DOX) can be used to treat malignant tumors, but with multiple adverse effects. Graphene oxide-polyethylene glycol (GO-PEG) is a novel nanoscale carrier material and can elevate solubility and biocompatibility of drugs. This study prepared a GO-PEG-DOX complex, whose toxicity and antitumor effects were evaluated on mouse EMT-6 breast cancer cells. MATERIALS AND METHODS: GO-PEG-DOX complex was prepared for calculating the drug carrier rate of DOX on GO-PEG by MV approach. EMT-6 cells were treated with 40 MUg/mL GO-PEG, 1 MUg/mL DOX, or 40 MUg/mL +1 MUg/mL GO-PEG-DOX for 72 h of incubation. Cells without treatment were considered the control group. Cell survival rate and apoptotic rate were tested at different time points. RESULTS: GO-PEG and GO-PEG-DOX complex were successfully prepared with satisfactory solubility. After 72 h of incubation, EMT-6 cells after GO-PEG-DOX treatment had significantly higher survival rate than GO-PEG group (p < 0.05). All three treatment groups had significantly elevated apoptotic rates than control group (p < 0.05). GO-PEG-DOX group had much more apoptosis (p < 0.05 compared with DOX group). Moreover, with elongated treatment time, all groups showed decreased survival rate (p < 0.05). CONCLUSION: GO-PEG did not reduce the cytotoxicity of DOX on EMT-6 cells. GO-PEG DOX complex can increase the water solubility and targeting sensitivity of DOX, with facilitating effects on DOX-induced tumor cell apoptosis. PMID- 29763377 TI - Influence of POLG on Radiosensitivity of Nasopharyngeal Carcinoma Cells. AB - BACKGROUND AND OBJECTIVE: There is a high incidence of nasopharyngeal carcinoma (NPC), malignant head and neck tumors, in southern China. Radioresistance is the main cause affecting the efficacy of NPC treatments. The POLG gene particularly plays an important role in radiation-induced damage repair. In this study, the authors established RNAi CNE-1 and CNE-2 knockdown in two NPC cell lines to observe whether this gene affects the radiosensitivity of NPC cells. MATERIALS AND METHODS: Four short hairpin RNA (shRNA) expression plasmids targeting POLG gene were constructed and transfected into the NPC cell lines CNE-1 and CNE-2. Screening was performed to evaluate the stable expression of cloned cells, which were named CNE-1/POLG-shRNA1, CNE-1/POLG-shRNA2, CNE-2/POLG-shRNA1, and CNE 2/POLG-shRNA2. The negative controls CNE-1/Neg-shRNA and CNE-2/Neg-shRNA were additionally used. The MTT method, flow cytometry, clone formation analysis, cell migration, and other experimental methods were employed to verify changes in the radiosensitivity of the NPC cells. RESULTS: Fluorescent quantitative PCR and Western blot confirmed the downregulation of the PLOG gene through diminished PLOG messenger RNA and protein levels. Consequently, the authors report the stable knockdown of the POLG gene in an NPC model. Dose-dependent radiation exposure of POLG inhibited NPC cell growth and increased apoptosis compared with control cells (p < 0.01), as demonstrated through colony formation assay and flow cytometry. Functional assays indicated that knockdown of the POLG in CNE-1 and CNE-2 cells remarkably reduced cell viability and proliferation. Specifically, POLG knockdown led to G1 phase arrest and apoptosis. CONCLUSIONS: Overall, the authors conclude that POLG downregulation alters the radiosensitivity of NPC cells, indicating that the gene is likely involved in conferring the radiation response of the cells. In addition, findings in this study suggest a novel role for POLG as a potential predictive marker for NPC radiotherapy efficiency. POLG gene can be used as a potential clinical target to effectively improve the radiosensitivity of NPC. PMID- 29763378 TI - Characterization of Thermally Activated Metalloenediyne Cytotoxicity in Human Melanoma Cells. AB - Enediynes are a highly cytotoxic class of compounds. However, metallation of these compounds may modulate their activation, and thus their cytotoxicity. We previously demonstrated that cytotoxicity of two different metalloenediynes, including (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8 diamine] (PyED), is potentiated when the compounds are administered to HeLa cells during hyperthermia treatment at concentrations that are minimally or not cytotoxic at 37 degrees C. In this study, we further characterized the concentration, time and temperature dependence of cytotoxicity of PyED on human U 1 melanoma cells. We also investigated the potential mechanisms by which PyED cytotoxicity is enhanced during hyperthermia treatment. Cell killing with PyED was dependent on concentration, temperature during treatment and time of exposure. Potentiation of cytotoxicity was observed when cells were treated with PyED at temperatures >=39.5 degrees C, and enhancement of cell killing increased with temperature and with increasing time at a given temperature. All cells treated with PyED were shown to have DNA damage, but substantially more damage was observed in cells treated with PyED during heating. DNA repair was also inhibited in cells treated with the drug during hyperthermia. Thus, potentiation of PyED cytotoxicity by hyperthermia may be due to enhancement of drug-induced DNA lesions, and/or the inhibition of repair of sublethal DNA damage. While the selective thermal activation of PyED supports the potential clinical utility of metalloenediynes as cancer thermochemotherapeutic agents, therapeutic gain could be optimized by identifying compounds that produce minimal toxicity at 37 degrees C but which become activated and show enhancement of cytotoxicity within a tumor subjected to localized hyperthermic or thermal ablative treatment, or which might act as bifunctional agents. We thus also describe the development and initial characterization of a novel cofactor complex of PyED, platinated PyED (Pt-PyED). Pt-PyED binds to DNA-like cisplatin, and much like PyED, cytotoxicity is greatly enhanced after treatment with the drug at elevated temperatures. However, in contrast to PyED, Pt-PyED is only minimally cytotoxic at 37 degrees C, at concentrations at which cytotoxicity is enhanced by hyperthermia. Further development of cisplatin-based enediynes may result in compounds which, when activated, will possess multiple DNA binding modalities similar to cisplatin, but produce less side effects in tissues at normothermic temperatures. PMID- 29763380 TI - Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK like cells from patients with colorectal cancer. AB - NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56brightCD16dim/-CD9+CD49+ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9 TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer. PMID- 29763381 TI - The Mfge8-alpha8beta1-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation. AB - Asthma affects ~300 million people worldwide. Despite multiple treatment options, asthma treatment remains unsatisfactory in a subset of patients. Airway obstruction is a hallmark of allergic asthma and is largely due to airway smooth muscle hypercontractility induced by airway inflammation. Identification of molecular pathways that regulate airway smooth muscle hypercontractility is of considerable therapeutic interest. We previously identified roles for milk fat globule epidermal growth factor-like 8 (Mfge8) in opposing the effects of allergic inflammation on increasing airway smooth muscle contractile force. In this study, we delineate the signaling pathway by which Mfge8 mediates these effects. By using genetic and pharmacologic approaches, we show that the alpha8beta1 integrin and the phosphatase and tensin homolog (PTEN) mediate the effects of Mfge8 on preventing IL-13-induced increases in airway contractility. Tracheal rings from mice with smooth muscle-specific deletion of alpha8beta1 or PTEN have enhanced contraction in response to treatment with IL-13. Enhanced IL 13-induced tracheal ring contraction in Mfge8-/- mice was abolished by treatment with the PI3K inhibitor. Mechanistically, IL-13 induces ubiquitination and degradation of PTEN protein. Our findings identify a role for the Mfge8 alpha8beta1-PTEN pathway in regulating the force of airway smooth muscle contraction in the setting of allergic inflammation.-Khalifeh-Soltani, A., Gupta, D., Ha, A., Podolsky, M. J., Datta, R., Atabai, K. The Mfge8-alpha8beta1-PTEN pathway regulates airway smooth muscle contraction in allergic inflammation. PMID- 29763379 TI - Hypothyroidism after Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study. AB - While thyroid cancer risks from exposure to ionizing radiation early in life are well characterized quantitatively, the association of radiation with nonmalignant, functional thyroid disorders has been less studied. Here, we report on a risk analysis study of hypothyroidism with radiation dose to the thyroid gland and the hypothalamic-pituitary axis among survivors of childhood cancer. Utilizing data from the Childhood Cancer Survivor Study, a cohort of 14,364 five year survivors of childhood cancer diagnosed at 26 hospitals in the U.S. and Canada between 1970 and 1986 and followed through 2009, the occurrence of hypothyroidism was ascertained among 12,015 survivors through serial questionnaires. Radiation doses to the thyroid gland and pituitary gland were estimated from radiotherapy records. Binary outcome regression was used to estimate prevalence odds ratios for hypothyroidism at five years from diagnosis of childhood cancer and Poisson regression to model incidence rate ratios (RR) after the first five years. A total of 1,193 cases of hypothyroidism were observed, 777 (65%) of which occurred five or more years after cancer diagnosis. The cumulative proportion affected with hypothyroidism (prevalence at five years after cancer diagnosis plus incidence through 30 years after cancer diagnosis) was highest among five-year survivors of Hodgkin lymphoma (32.3%; 95% CI: 29.5 34.9) and cancers of the central nervous system (17.7%; 95% CI: 15.2-20.4). The incidence rate was significantly associated with radiation dose to the thyroid and pituitary. The joint association of hypothyroidism with thyroid and pituitary dose was sub-additive for pituitary doses greater than 16 Gy. In particular, a very strong thyroid radiation dose dependence at low-to-moderate pituitary/hypothalamic doses was diminished at high pituitary doses. Radiation related risks were higher in males than females and inversely associated with age at exposure and time since exposure but remained elevated more than 25 years after exposure. Our findings indicated that hypothyroidism was significantly associated with treatment with bleomycin (RR = 3.4; 95% CI: 1.6-7.3) and the alkylating agents cyclohexyl-chloroethyl-nitrosourea (CCNU) (RR = 3.0; 95% CI: 1.5-5.3) and cyclophosphamide (RR = 1.3; 95% CI: 1.0-1.8), with a significant dose response for CCNU ( P < 0.01). The risk of hypothyroidism among childhood cancer survivors treated with radiation depends both on direct, dose-dependent radiation-induced damage to the thyroid gland and on dose-dependent indirect effects secondary to irradiation of the hypothalamic-pituitary axis. The dose response relationship for each site depends on dose to the other. Radiation related risk persists for more than 25 years after treatment. Treatment with certain chemotherapy agents may increase the risk of hypothyroidism. PMID- 29763382 TI - KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing. AB - The methylation of histone H3 lysine 79 (H3K79) is an active chromatin marker and is prominent in actively transcribed regions of the genome; however, demethylase of H3K79 remains unknown despite intensive research. Here, we show that KDM2B, also known as FBXL10 and a member of the Jumonji C family of proteins known for its histone H3K36 demethylase activity, is a di- and trimethyl H3K79 demethylase. We demonstrate that KDM2B induces transcriptional repression of HOXA7 and MEIS1 via occupancy of promoters and demethylation of H3K79. Furthermore, genome-wide analysis suggests that H3K79 methylation levels increase when KDM2B is depleted, which indicates that KDM2B functions as an H3K79 demethylase in vivo. Finally, stable KDM2B-knockdown cell lines exhibit displacement of NAD+-dependent deacetylase sirtuin-1 (SIRT1) from chromatin, with concomitant increases in H3K79 methylation and H4K16 acetylation. Our findings identify KDM2B as an H3K79 demethylase and link its function to transcriptional repression via SIRT1 mediated chromatin silencing.-Kang, J.-Y., Kim, J.-Y., Kim, K.-B., Park, J. W., Cho, H., Hahm, J. Y., Chae, Y.-C., Kim, D., Kook, H., Rhee, S., Ha, N.-C., Seo, S.-B. KDM2B is a histone H3K79 demethylase and induces transcriptional repression via sirtuin-1-mediated chromatin silencing. PMID- 29763383 TI - EB 2017 Article: Soy protein isolate feeding does not result in reproductive toxicity in the pre-pubertal rat testis. AB - The isoflavone phytoestrogens found in the soy protein isolate used in soy infant formulas have been shown to have estrogenic actions in the developing male reproductive tract resulting in reproductive toxicity. However, few studies have examined potential estrogenicity of soy protein isolate as opposed to that of pure isoflavones. In this study, we fed weanling male Sprague-Dawley rats a semi purified diet with casein or soy protein isolate as the sole protein source from postnatal day 21 to 33. Additional groups were fed casein or soy protein isolate and treated s.c. with 10 ug/kg/d estradiol via osmotic minipump. Estradiol treatment reduced testis, prostate weights, and serum androgen concentrations ( P < 0.05). Soy protein isolate had no effect. Estradiol up-regulated 489 and down regulated 1237 testicular genes >1.5-fold ( P < 0.05). In contrast, soy protein isolate only significantly up-regulated expression of 162 genes and down regulated 16 genes. The top 30 soy protein isolate-up-regulated genes shared 93% concordance with estradiol up-regulated genes. There was little overlap between soy protein isolate down-regulated genes and those down-regulated by estradiol treatment. Functional annotation analysis revealed significant differences in testicular biological processes affected by estradiol or soy protein isolate. Estradiol had major actions on genes involved in reproductive processes including down-regulation of testicular steroid synthesis and expression of steroid receptor activated receptor (Star) and cytochrome P450 17alpha hydroxylase/(Cyp17a1). In contrast, soy protein isolate primarily affected pathways associated with macromolecule modifications including ubiquitination and histone methylation. Our results indicate that rather than acting as a weak estrogen in the developing testis, soy protein isolate appears to act as a selective estrogen receptor modulator with little effect on reproductive processes. Impact statement Soy protein isolate (SPI) is the sole protein used to make soy-based infant formulas. SPI contains phytoestrogens, which are structurally similar to estradiol. These phytoestrogens, daidzein, genistein, and equol, fit the definition of endocrine-disrupting compounds, and at high concentrations, have estrogenic actions resulting in reproductive toxicity in the developing male, when provided as isolated chemicals. However, few animal studies have examined the potential estrogenicity of SPI as opposed to pure isoflavones. In this study, SPI feeding did not elicit an estrogenic response in the testis nor any adverse outcomes including reduced testicular growth, or androgen production during early development in rats when compared to those receiving estradiol. These findings are consistent with emerging data showing no differences in reproductive development in males and female children that received breast milk, cow's milk formula, or soy infant formula during the postnatal feeding period. PMID- 29763384 TI - The effects of dihydroartemisinin on inflammatory bowel disease-related bone loss in a rat model. AB - Bone loss is one of the important extra-intestinal manifestations in patients with inflammatory bowel diseases (IBDs). Compounds derived from natural products have been used to treat IBDs. However, the role of natural products on IBD induced bone loss is not completely clarified. In the present study, we observed the effects of dihydroartemisinin (DHA), an antimalaria drug, on IBD and IBD induced bone loss in a rat model. Chronic IBD model was established in Sprague Dawley rats by giving them 2.5% dextran sodium sulfate in drinking water. DHA was given by intraperitoneal injection. Blood, colon, and bone samples were collected for biomarker assay and histological analysis. There was an obvious increase in tumor necrotic factor (TNF) alpha and receptor activator of nuclear factor (NF) kB ligand (RANKL), and decrease in procollagen type 1 N-terminal propeptide (P1NP) level in IBD groups compared with the normal control (p < 0.05). The disease activity score of IBD rats was significantly higher than the control (p < 0.01). Obvious decrease in disease activity score, TNFalpha, and RANKL level and increase in P1NP were observed in DHA-treated IBD rats. Bone loss, shown as the decrease in bone mineral density, bone volume fraction, and trabecular number and increase in trabecular separation were observed in IBD rats compared with control (p < 0.01). DHA treatment obviously abolished the bone loss, in particular in the high-dose group (p < 0.05). DHA treatment also inhibited the excessive osteoclast formation; RANKL protein expression; and RANK, TRAF6, Fra-1, NFATc1 mRNA expression induced by IBD. Our data indicated that DHA may be a potential therapeutic agent for IBD and IBD-induced bone loss. Impact statement Bone loss is one of the important extra-intestinal manifestations in patients with inflammatory bowel diseases (IBDs). Studies have shown that compounds derived from natural products are useful in the treatment of IBDs. However, few studies have investigated the role of compounds derived from natural products in treatment of osteoporosis in IBDs. The current study aimed to show the effects of dihydroartemisinin (DHA), antimalaria drug, on bone loss in a rat model of IBD. The findings showed that DHA intervention dose dependently protected against bone loss in IBD rats by inhibiting tumor necrotic factor alpha production and osteoclast formation. These findings highlights that DHA may be beneficial for bone health in those patients with IBD. PMID- 29763385 TI - Pyruvate-enriched resuscitation for shock. AB - This commentary addresses the recent retraction of an article which reported favorable outcomes in septic patients treated with intravenous pyruvate. The retracted report was cited in the authors' recent minireview on the cellular mechanisms and clinical application of pyruvate to improve cardiac performance. Because the retracted article reports pyruvate-enhanced resuscitation of critically ill patients, the authors wish to inform the readership, especially critical care providers, that this particular clinical application of pyruvate is not now supported by robust evidence. After discussing the retraction's implications for the clinical application of pyruvate-enriched resuscitation for sepsis, this commentary summarizes the extensive preclinical evidence of the efficacy and mechanisms of pyruvate resuscitation in animal models of hemorrhagic and septic shock, which argues for renewed clinical investigation of pyruvate enriched resuscitation. Impact statement This commentary addresses the recent retraction of a clinical report of significant benefits of intravenous pyruvate resuscitation in septic patients, including sharply lowered mortality and decreased circulating pro-inflammatory cytokines, which was cited in the authors' minireview in Experimental Biology and Medicine. The potential implications of the retraction, and the extensive preclinical evidence supporting the use of pyruvate-enriched resuscitation for shock states, are summarized and discussed. PMID- 29763386 TI - Trends in polymeric electrospun fibers and their use as oral biomaterials. AB - Electrospinning is one of the techniques to produce structured polymeric fibers in the micro or nano scale and to generate novel materials for biomedical proposes. Electrospinning versatility provides fibers that could support different surgical and rehabilitation treatments. However, its diversity in equipment assembly, polymeric materials, and functional molecules to be incorporated in fibers result in profusion of recent biomaterials that are not fully explored, even though the recognized relevance of the technique. The present article describes the main electrospun polymeric materials used in oral applications, and the main aspects and parameters of the technique. Natural and synthetic polymers, blends, and composites were identified from the available literature and recent developments. Main applications of electrospun fibers were focused on drug delivery systems, tissue regeneration, and material reinforcement or modification, although studies require further investigation in order to enable direct use in human. Current and potential usages as biomaterials for oral applications must motivate the development in the use of electrospinning as an efficient method to produce highly innovative biomaterials, over the next few years. Impact statement Nanotechnology is a challenge for many researchers that look for obtaining different materials behaviors by modifying characteristics at a very low scale. Thus, the production of nanostructured materials represents a very important field in bioengineering, in which the electrospinning technique appears as a suitable alternative. This review discusses and provides further explanation on this versatile technique to produce novel polymeric biomaterials for oral applications. The use of electrospun fibers is incipient in oral areas, mainly because of the unfamiliarity with the technique. Provided disclosure, possibilities and state of the art are aimed at supporting interested researchers to better choose proper materials, understand, and design new experiments. This work seeks to encourage many other researchers-Dentists, Biologists, Engineers, Pharmacists-to develop innovative materials from different polymers. We highlight synthetic and natural polymers as trends in treatments to motivate an advance in the worldwide discussion and exploration of this interdisciplinary field. PMID- 29763387 TI - Spider peptide toxin lycosin-I induces apoptosis and inhibits migration of prostate cancer cells. AB - Spider toxins are molecularly diverse and some display not only a strong antibacterial effect but also exhibit significant inhibition of tumor growth and promote tumor cell apoptosis. The aim of the present investigation was to explore different antitumor effects of the spider peptide toxin lycosin-I through different pathways at different concentrations. It was found that by inactivating STAT3 pathway, high concentrations of lycosin-I induce apoptosis in prostate cancer cells and low concentrations of lycosin-I inhibit the migration of prostate cancer cells. This finding provides favorable evidence for further study of the molecular diversity of spider toxins. Impact statement The spider peptide toxin has become an important research topic. These toxins are molecularly diverse and some display not only a strong antibacterial effect but also exhibit significant inhibition of tumor growth and promote tumor cell apoptosis. Inspired by previous studies, the present study aims to investigate the effects of different concentrations of lycosin-I on the invasiveness and apoptosis of human prostate cancer cells. The findings provide favorable evidence for further study of the molecular diversity of spider toxins. PMID- 29763388 TI - How Should Trauma Patients' Informed Consent or Refusal Be Regarded in a Trauma Bay or Other Emergency Settings? AB - The precipitous and unexpected nature of trauma requires training health care practitioners to think and act quickly, according to the best medical interest of the patient. The urgency of treatment for trauma patients, who frequently have temporary alterations in their abilities to make autonomous and competent decisions, often results in presumed consent for medically necessary treatment. Academic trauma centers use protocol-based management of injuries to facilitate their simultaneous evaluation by multiple clinicians and to avoid delays in treatment, ensuring that trauma patients receive the best possible care. In this article, we will discuss the issues of deferred informed consent and surgical education as they relate to trainees' graduated responsibility in the trauma bay. PMID- 29763389 TI - How Should Complex Communication Responsibilities Be Distributed in Surgical Education Settings? AB - Part of any trauma surgeon's job is communicating effectively in difficult, often time-limited, situations. The ability to effectively discuss topics like goals of care in these settings has a direct effect on patient care. Many factors contribute to the complexity of these conversations, including patient, physician, surrogate, and system-specific factors. In responding to the case of Mr. D and Dr. J, we attempt to outline and analyze some of the moral challenges and ethical questions that this professional responsibility poses to trauma surgeons and trainees. PMID- 29763390 TI - What Are Ethical Implications of Regionalization of Trauma Care? AB - Outcomes for severely injured patients are improved when they are treated at trauma centers. However, interfacility transfers can delay time-sensitive treatments not requiring the resources of tertiary institutions. Regionalized trauma systems allow physicians to decrease delays in care, prevent inadequate treatment, and ultimately reduce preventable deaths. Although precise risks and benefits of triage choices are unknowable, estimating them is a process well known to surgeons. Recognizing patient transfers as integral to optimal care delivery systems, rather than as detracting from them, is essential. PMID- 29763391 TI - Should Trauma Physicians Treat a Severely Injured Patient for the Sake of Elucidating Preferences about Organ Donation? AB - Organ donation potential is not a motivator of care in the trauma bay, and it is ethically problematic to consider organ donor potential during the active resuscitation of a trauma patient. Despite organ donation being a public good, the role of the trauma physician is to maintain focus on the patient as an individual and to respect a patient's right to life and autonomy. This tenet of medicine is the foundation of the trust that a community and individuals must have in order for the health care system to function. Fortunately, there are guidelines and systems in place to allow physicians to care for the patient in front of them while simultaneously making morally sound decisions regarding donation in the setting of the current organ shortage. PMID- 29763392 TI - Should Family Be Permitted in a Trauma Bay? AB - This essay explores how some of the arguments advanced for and against family presence during cardiopulmonary resuscitation might apply to the question of whether family should be permitted in the trauma bay. While the first section suggests that many of the proposed benefits might apply to family presence during trauma resuscitations, the second section contends that family presence in the trauma bay could detract from the quality of patient care, violate patient privacy, and be psychologically damaging for the witnessing family. The essay concludes by proposing a chaperoning system that could mitigate some of the proposed concerns with a family presence policy and by analyzing some of the ethical commitments that underlie the discussion of family in the trauma bay. PMID- 29763393 TI - Defining "Community" and "Consultation" for Emergency Research that Requires an Exception from Informed Consent. AB - Trauma care requires rapid interventions to optimize the chances for survival. Many patients are either in shock or unconscious and are, therefore, unable to provide informed consent even for standard procedures. Research-related interventions must similarly be initiated rapidly with no opportunity to obtain consent from the patient or the patient's legally authorized representative. Federal regulations allow for an exception from informed consent in these circumstances once the investigators complete a process of community consultation and public disclosure. The challenges for investigators include how to define the at-risk community for enrollment in the trial and then how to adequately reach out to that community. Many approaches have been used, with varying success. What constitutes true engagement with the community needs to be further explored. PMID- 29763394 TI - Gun Violence Research and the Profession of Trauma Surgery. AB - The effects of violence are clearly a central component of any trauma surgeon's job. The role trauma surgeons should play in its prevention and advocacy, however, is not clearly defined. In this article, we discuss the statistics and lack of research on gun violence and survey some of the moral frameworks that define a trauma surgeon's professional responsibilities in violence prevention at a practice and a policy level. PMID- 29763395 TI - What Is the Institutional Duty of Trauma Systems to Respond to Gun Violence? AB - In the past, trauma centers have almost exclusively focused on caring for patients who suffer from physical trauma resulting from violence. However, as clinicians' perspectives on violence shift, violence prevention and intervention have been increasingly recognized as integral aspects of trauma care. Hospital based violence intervention programs are an emerging strategy for ending the cycle of violence by focusing efforts in the trauma center context. These programs, with their multipronged, community-based approach, have shown great potential in reducing trauma recidivism by leveraging the acute experience of violence as an opportunity to introduce services and assess risk of re-injury. In this article, we explore the evolving role of trauma centers and consider their institutional duty to address violence broadly, including prevention. PMID- 29763396 TI - The Evolving Surgeon Image. AB - The stereotype of the abrasive, technically gifted white male surgeon is ubiquitous among members of the public and the medical profession. Yet modern surgeons are far more diverse and socially adept than the stereotype suggests. While the stereotype is largely a relic of days gone by, it continues to influence patients' expectations and surgeons' interactions with their clinical colleagues. The #ILookLikeASurgeon movement and subsequent #NYerORCoverChallenge demonstrate the changing face of surgery and the roles of social media in resisting the social and cultural force of long-standing stereotypes. PMID- 29763397 TI - Memento Mori and Photographic Perspective of Roadside Trauma. AB - David Nance's photographs invite us to cross the liminal space between road and roadside and to consider the experience that trauma surgeons share with injured patients and the families of the injured and the dead. Just as trauma surgeons use the tools of science and surgery to make order out of the chaos of "the scene," so patients' families use art, found objects, and grief to transform anonymous roadsides into specific, personal remembrances. Bound together by the uncertainties of trauma, we can all stand at the side of the road bearing witness to both the inevitability and unpredictability of death. PMID- 29763398 TI - Does Family Presence in the Trauma Bay Help or Hinder Care? AB - Family presence during a pediatric resuscitation remains somewhat controversial. Opponents express concern that family presence would be detrimental to team performance and that exposure to such a traumatic event could put family members at risk of posttraumatic stress. Proponents argue that family presence affords families a sense of closure by easing their anxieties and assuring them that everything was done for their loved ones in addition to improving clinicians' professional behavior by humanizing the patient. This article will review the literature on the potential benefits and pitfalls of family presence during a pediatric resuscitation. PMID- 29763399 TI - Can Congress Get 'Right to Try' Right? AB - A federal bill would expand access to experimental treatments to seriously ill patients, but critics say the right to try would take away FDA oversight and create a "Wild West." Proponents counter that the FDA's current process can be onerous for people with just a few months to live. Meanwhile, most states' right to-try laws have gone unused. PMID- 29763400 TI - A Reality Check for Checkpoint Inhibitors. AB - They take the brakes off the immune system so it attacks cancer cells. But many people don't respond to checkpoint inhibitors, so researchers are looking for ways to defeat the resistance. PMID- 29763401 TI - Altarum's MESA Turns High-Deductible Coverage on its Head. AB - The architects of Medical Episode Spending Allowance (MESA) benefits are radically reframing coverage as allowances for episodes of care and have a plan for engaging members in making better choices. MESA could catch on quickly, particularly with plan sponsors who have seen consumer-directed plan designs work against them. PMID- 29763402 TI - Kymriah: A Sign of More Difficult Decisions To Come. AB - The CAR-T therapy may pass ICER cost-effectiveness muster, but can the health care system afford more drugs like it? PMID- 29763403 TI - Cost of Cancer Drugs: Something Has To Give. AB - The drugs often are more effective and have fewer side effects. The science-often just amazing. Medically, cancer treatment has never been in a better place. But are high prices making it unaffordable? Payers, providers, policymakers, and drugmakers themselves are wrestling with the issue. Meanwhile, many patients are being priced out of treatments that could save their lives. PMID- 29763404 TI - Indication-specific Drug Pricing - Simple in Theory, Complex in Reality. AB - Varying drug prices by indication could be an important value-based strategy in oncology, where multiple indications are becoming the rule. But will administrative costs offset any benefit? And legal and regulatory obstacles could get in the way. PMID- 29763405 TI - A Neglected and Deadly Cancer. AB - The deadliness of liver cancer is undisputed, but a growing body of data shows that too often, patients, and particularly those who are uninsured or nonwhite, miss out on earlier diagnosis and potentially life-saving surgery. PMID- 29763406 TI - In Cancer Care, Can We Afford To Hope? AB - At last count, the pharmaceutical industry's new product pipeline included more than 7,000 products in late-stage development, roughly half of which are deemed "specialty." The reality is, our health care system is poorly equipped to address this issue head-on. PMID- 29763407 TI - Violence Against Nurses: Casualties of Caring. AB - Sometimes patients are angry. Sometimes it is a symptom of their illness. Either way, nurses are on the front lines of health care and bear the brunt of the physical and verbal abuse from patients; gender may be a factor. In California, hospitals and other health care providers are now required to keep a log of violent incidents and develop violence prevention plans. Federal legislation has been introduced. PMID- 29763408 TI - Occam's Razor, Health Care Costs, And Insurance Coverage. AB - It's no mystery why this country has both the highest per capita health care costs and the lowest overall percentage of people with coverage. The two are connected, but as if on a teeter-tooter: As one goes up, the other goes down. PMID- 29763409 TI - The Patient-centered Medical Home: Expensive and in Need of Repair. AB - On the one hand, the PCMH is an admirable effort to gather in one place all the disparate and disorganized clinical and social supports the patient needs. At the same time, though, medical homes employ provider-defined business models and conventional performance measures, belying the patient-centered in the name. PMID- 29763410 TI - Health Care's Forth and Back: While Medical Progress Marches Forward Prescriptions Get Abandoned. AB - The breast cancer mortality rate in 2012 declined 49% compared with the expected baseline, and 63% of that reduction was from treatment drugs. You'd think that patients would take their cancer medicines no matter what. But when cost sharing reached between $100 and $500, the abandonment rate soared to 32%. PMID- 29763411 TI - Characteristics and health care resource use of subjects with COPD in the year before initiating LAMA monotherapy or LAMA+LABA combination therapy: A U.S. database study. AB - PURPOSE: To characterize subjects with chronic obstructive pulmonary disease (COPD) newly initiated on long-acting muscarinic antagonists (LAMA) or dual LAMA/long-acting beta2-adrenergic agonist (LABA) therapy. DESIGN: This pilot/preliminary analysis was a retrospective crosssectional study of subjects with COPD from the Optum Impact National Managed Care Benchmark Database. METHODOLOGY: Subjects with at least one LAMA prescription in the index period (July 2008-June 2009) were included and stratified by treatment. Data were collected in the year before the index date and included comorbidities, medication use, COPD-related costs, health care resource use, and exacerbations. RESULTS: Of 5,311 eligible subjects, 2,057 initiated LAMA therapy (LAMA cohort) and 191 initiated LAMA+LABA therapy (LAMA+LABA cohort). The Charlson comorbidity index was slightly lower in the LAMA+LABA cohort than the LAMA cohort (mean+/-SD: 0.63+/-1.13 vs. 0.66+/-1.28), but the number of prescriptions was higher (mean+/ SD: 42.9+/-23.2 vs. 30.5+/-27.2). The LAMA+LABA cohort had higher short-acting inhaled beta2 agonist (56.0% vs. 35.7%), oral corticosteroid (37.7% vs. 32.6%), and home oxygen therapy use (14.1% vs. 3.2%) than the LAMA cohort. Total medical costs were greater in the LAMA+LABA cohort than the LAMA cohort (mean+/-SD: $3,320.40+/-4085.9 vs. $1,226.20+/-3602.9), although emergency department ($11.00+/-66.8 vs. $30.70+/-259.2) and outpatient visit ($39.60+/-163.1 vs. $41.70+/-424.3) costs were lower. Resource use and exacerbation incidence were similar between cohorts. CONCLUSION: In this first look, subjects with COPD initiating LAMA or LAMA+LABA therapy exhibited different clinical and resource use characteristics in the year before treatment. Subjects receiving LAMA+LABA were older, with higher COPD co-medication use, more prescriptions, and associated higher pharmacy costs compared with subjects initiating LAMA. These differences may reflect a higher severity of COPD in those starting LABA+LAMA treatment. PMID- 29763412 TI - Thermoacoustic sound projector: exceeding the fundamental efficiency of carbon nanotubes. AB - The combination of smooth, continuous sound spectra produced by a sound source having no vibrating parts, a nanoscale thickness of a flexible active layer and the feasibility of creating large, conformal projectors provoke interest in thermoacoustic phenomena. However, at low frequencies, the sound pressure level (SPL) and the sound generation efficiency of an open carbon nanotube sheet (CNTS) is low. In addition, the nanoscale thickness of fragile heating elements, their high sensitivity to the environment and the high surface temperatures practical for thermoacoustic sound generation necessitate protective encapsulation of a freestanding CNTS in inert gases. Encapsulation provides the desired increase of sound pressure towards low frequencies. However, the protective enclosure restricts heat dissipation from the resistively heated CNTS and the interior of the encapsulated device. Here, the heat dissipation issue is addressed by short pulse excitations of the CNTS. An overall increase of energy conversion efficiency by more than four orders (from 10-5 to 0.1) and the SPL of 120 dB re 20 MUPa @ 1 m in air and 170 dB re 1 MUPa @ 1 m in water were demonstrated. The short pulse excitation provides a stable linear increase of output sound pressure with substantially increased input power density (>2.5 W cm-2). We provide an extensive experimental study of pulse excitations in different thermodynamic regimes for freestanding CNTSs with varying thermal inertias (single-walled and multiwalled with varying diameters and numbers of superimposed sheet layers) in vacuum and in air. The acoustical and geometrical parameters providing further enhancement of energy conversion efficiency are discussed. PMID- 29763413 TI - Bioinspired magnetoreception and navigation using magnetic signatures as waypoints. AB - Diverse taxa use Earth's magnetic field in conjunction with other sensory modalities to accomplish navigation tasks ranging from local homing to long distance migration across continents and ocean basins. However, despite extensive research, the mechanisms that underlie animal magnetoreception are not clearly understood, and how animals use Earth's magnetic field to navigate is an active area of investigation. Concurrently, Earth's magnetic field offers a signal that engineered systems can leverage for navigation in environments where man-made systems such as GPS are unavailable or unreliable. Using a proxy for Earth's magnetic field, and inspired by migratory animal behavior, this work implements a behavioral strategy that uses combinations of magnetic field properties as rare or unique signatures that mark specific locations. Using a discrete number of these signatures as goal waypoints, the strategy navigates through a closed set of points several times in a variety of environmental conditions, and with various levels of sensor noise. The results from this engineering/quantitative biology approach support existing notions that some animals may use combinations of magnetic properties as navigational markers, and provides insights into features and constraints that would enable navigational success or failure. The findings also offer insights into how autonomous engineered platforms might be designed to leverage the magnetic field as a navigational resource. PMID- 29763414 TI - CD93 promotes beta1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis. AB - Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel associated extracellular matrix. CD93 is a transmembrane receptor that is upregulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates beta1 integrin signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytic cleavage. The CD93-MMRN2 complex was required for activation of beta1 integrin, phosphorylation of focal adhesion kinase (FAK), and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of beta1 integrin and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy. PMID- 29763415 TI - Efficacy, Safety, and Cost of Therapy of the Traditional Chinese Medicine, Catalpol, in Patients Following Surgical Resection for Locally Advanced Colon Cancer. AB - BACKGROUND The aim of this study was to evaluate the efficacy, safety, and cost of treatment of the traditional Chinese herbal medicine, catalpol, in patients following surgical resection for locally advanced colon cancer. MATERIAL AND METHODS The 345 patients who had undergone surgical resection for locally advanced colon adenocarcinoma, were divided into three groups: a placebo-treated group (n=115); patients treated with an intraperitoneal injection of 10 mg/kg catalpol twice a day for 12 weeks (treatment group) (n=115); patients treated with 5 mg/kg intravenous bevacizumab twice a week for 12 weeks (control group) (n=115). Serum levels of carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), matrix metalloproteinases-2 (MMP-2), and matrix metalloproteinases 9 (MMP-9) were measured. Patient overall survival (OS), cancer-free survival (CFS), adverse effects, and cost of therapy were evaluated. Statistical analysis included the Wilcoxon rank sum test and Tukey's test for clinicopathological response at 95% confidence interval (CI). RESULTS Patients in the catalpol treated group had significantly reduced serum levels of CA 19-9 (p=0.0002, q=3.202), CEA (p=0.0002, q=3.007), MMP-2 (pL0.0001, q=6.883), and MMP-9 (p<0.0001, q=3.347). Only non-fatal adverse effects occurred in the catalpol treatment group (p<0.0001, q=5.375). OS and CFS were significantly increased in the catalpol treatment group compared with the placebo group (p<0.0001 q=7.586). The cost of catalpol treatment compared favorably with other treatments (p<0.0001, q=207.17). CONCLUSIONS In this preliminary study, treatment with the Chinese herbal medicine, catalpol, showed benefits in clinical outcome, at low cost, and with no serious complications. PMID- 29763416 TI - Mitigating circumstances: A model-based analysis of associations between risk environment and infrequent condom use among Chinese street-based sex workers. AB - BACKGROUND: Little is known about how freelance street-based sex workers navigate condom use while soliciting. Traditional behavioural model may fail to account for the complex risk environment that most street-based sex workers work within. We examine first the association of self-efficacy and the infrequent condom use, then we investigated the roles of clients and venues frequented on this association. METHOD: Using a purposive chain-referral sampling method, we surveyed 248 street-based sex workers in Shanghai. The survey focused on sex workers HIV risk factors, sex work patterns, HIV knowledge, and related HIV self efficacy. Clients types and behaviours, and characteristics of the venues frequented by these commercial sex workers were also collected. We conducted a series of multiple logistic regression models to explore how the association between a sex worker's self-efficacy with infrequent condom use change as client and venue characteristics were added to the models. RESULTS: We find that within the basic model, low self-efficacy was marginally associated with infrequent condom use (54.9% vs. 45.1%, AOR = 1.70, 95% CI = 0.95-3.03). As client- and venue- characteristics were added, the associations between self-efficacy and condom use were strengthened (AOR = 2.10 95% CI = 1.12-3.91 and 2.54 95% CI = 1.24-5.19 respectively). Those who reported middle-tiered income were more likely to report infrequent condom use compared to their peers of high income (AOR = 3.92 95% CI = 1.32-11.70) whereas such difference was not found between low income and high income sex workers. Visiting multiple venues and having migrant workers as clients were also associated with infrequent condom use. CONCLUSION: Our findings suggest sex worker's self-efficacy matters in their HIV risk behaviours only when environment characteristics were adjusted. Risk environment for street-based sex workers are complex. Programming addressing behavioural changes among female sex workers should adopt holistic, multilevel models with the consideration of risk environments. PMID- 29763417 TI - Meta-analyses of individual versus group interventions for pre-school children with autism spectrum disorder (ASD). AB - : There is little evidence regarding the effects of individual and group intervention for children with autism spectrum disorder (ASD) on important outcomes. We performed meta-analyses using a random effects model to investigate the effectiveness of the individual and group intervention studies and to compare the effectiveness of these two types if possible. The main analysis which excluded studies at a high risk of bias (Analysis I) included 14 randomised controlled trials targeting children with ASD<=6 years of age (594 children). The results suggested that both individual and group interventions showed significant effects compared to the control condition on "reciprocity of social interaction towards others" (standard mean difference[SMD] [95%confidence interval{CI}] = 0.59[0.25, 0.93], p = 0.16; 0.45[0.02, 0.88], p = 0.39, respectively). Only individual interventions showed significant effects compared to the control condition on "parental synchrony" (SMD [95%CI] = 0.99 [0.70, 1.29], p<0.01). Our results showed no significant differences between individual and group interventions in effects on "autism general symptoms" (no study available for group intervention), "developmental quotient" (no study available for group intervention), "expressive language" (p = 0.56), "receptive language" (p = 0.29), "reciprocity of social interaction towards others" (p = 0.62), or "adaptive behaviour" (p = 0.43). We also performed sensitivity analyses including studies that had been excluded due to being at a high risk of potential bias (Analysis II). The results suggested that "reciprocity of social interactions towards others" showed significant effects for individual intervention compared to the control condition (0.50[0.31,0.69], p<0.001) but not for group intervention (0.23[-0.33, 0.78], p = 0.42). Individual intervention also showed significant effects on "parental synchrony" (0.98[0.30,1.66], p = 0.005) in the sensitivity analysis. The results also suggested no significant difference on all the outcomes between the individual and group interventions. We also reanalysed the data using cluster-robust standard errors as sensitivity analyses (Analysis III). Analysis III showed no significant effects in the intervention condition compared to the control condition on all the outcomes for both individual and group interventions. When Analysis II was reanalysed using cluster-robust standard errors (Analysis IV), individual interventions showed significant effects compared to the control condition on "reciprocity of social interaction towards others" and "parental synchrony" (mean estimate[95%CI], robust standard error, p = 0.50[0.20, 0.81], 0.13, 0.006; and 1.06[0.08, 2.05], 0.42, 0.04, respectively), and none of the outcomes showed significant effects under the intervention condition compared to the control condition for group interventions. The discrepancies in the results between the main analysis (Analysis I) and the sensitivity analyses (Analyses II, III, and IV) may be due to the small number of included studies. Since the outcome of "reciprocity of social interaction towards others" can be a dependent variable that is usually measured in a context-bound setting with the child's parent, we cannot conclude that individual interventions for pre-school children with ASD have significant effects on generalised skills for engaging in reciprocal interactions with others, even if the interventions have significant effects on the outcome. However, the outcomes of "reciprocity of social interaction towards others" may be promising targets for both individual and group interventions involving pre-school children with ASD. "Parental synchrony" may also be a promising target for individual interventions. TRIAL REGISTRATION: (CRD42011001349). PMID- 29763418 TI - Dietary patterns and nutritional status of HIV-infected children and adolescents in El Salvador: A cross-sectional study. AB - INTRODUCTION: The present study aimed to assess the nutritional status, the dietary patterns and its associated factors in the HIV-infected population of children and adolescents on antiretroviral treatment at the El Salvador reference center for pediatric HIV care (CENID). METHODS: A cross-sectional survey was carried out between December 2010 and December 2011. Socio-demographic and clinical characteristics were collected from 307 children and adolescents aged 2 18 years and receiving antiretroviral therapy. Nutritional status was assessed by height-for-age, weight-for-height and body mass index-for-age. Dietary data was collected through a 24 hour recall, and through a weekly food frequency questionnaire. Dietary patterns were identified by principal component analysis. Bivariate and multivariable statistical methods were used to assess the factors associated with "high adherence" to the "healthy diet" pattern. RESULTS: More than a third of the study group (33.2%) were stunted, 3.3% were identified as being wasted, and 10% were overweight or obese. Their diets were predominantly based on a high consumption of cereals, beans, eggs and processed foods and a low consumption of fruits, vegetables and dairy products. Three dietary patterns were identified: "healthy diet", "high fat/sugar diet" and "low diversity diet". Being female (OR: 1.63; 95%CI: 0.97-2.75), younger (OR: 2.37; 95%CI: 1.28-4.36) and institutionalized (OR: 14.5; 95%CI: 5.35-39.50) increased the odds to adhere to the "healthy diet" pattern. CONCLUSION: Our findings reveal a high prevalence of stunting and overweight in HIV-infected children in El Salvador. Institutionalized children were more likely to adhere to a healthy dietary pattern whereas children in poverty were more likely to have less varied and healthy diets. These results highlight the need to assess the dietary patterns of HIV-infected children and adolescents in order to guide public policies to design healthy life style interventions for this population at risk. PMID- 29763419 TI - Tabu search algorithm for the distance-constrained vehicle routing problem with split deliveries by order. AB - The vehicle routing problem (VRP) has a wide range of applications in the field of logistics distribution. In order to reduce the cost of logistics distribution, the distance-constrained and capacitated VRP with split deliveries by order (DCVRPSDO) was studied. We show that the customer demand, which can't be split in the classical VRP model, can only be discrete split deliveries by order. A model of double objective programming is constructed by taking the minimum number of vehicles used and minimum vehicle traveling cost as the first and the second objective, respectively. This approach contains a series of constraints, such as single depot, single vehicle type, distance-constrained and load capacity limit, split delivery by order, etc. DCVRPSDO is a new type of VRP. A new tabu search algorithm is designed to solve the problem and the examples testing show the efficiency of the proposed algorithm. This paper focuses on constructing a double objective mathematical programming model for DCVRPSDO and designing an adaptive tabu search algorithm (ATSA) with good performance to solving the problem. The performance of the ATSA is improved by adding some strategies into the search process, including: (a) a strategy of discrete split deliveries by order is used to split the customer demand; (b) a multi-neighborhood structure is designed to enhance the ability of global optimization; PMID- 29763420 TI - Knee pain and health-related quality of life among older patients with different knee osteoarthritis severity in Saudi Arabia. AB - OBJECTIVE: There is a lack of knowledge about health-related quality of life (HRQoL) in Saudi patients with musculoskeletal impairment, particularly among older adult populations. Thus, the current research aimed to determine the association of knee osteoarthritis (OA) severity with knee pain (KP) and HRQoL among older patients in Riyadh, Saudi Arabia. METHODS: In a multicenter cross sectional study, we recruited 209 consecutive males and females aged >=55 years with radiographically diagnosed knee OA from five hospitals across Riyadh, Saudi Arabia. According to the Kellgren & Lawrence classification, patients were classified into two groups: mild/moderate knee OA (n = 126) and severe knee OA (n = 83). KP and HRQoL were assessed using the pain visual analogue scale (VAS) and the 36-Item Short Form Health Survey (SF-36), respectively. A higher score on the pain VAS and the SF-36 represented worse KP and better HRQoL, respectively. RESULTS: Severe knee OA was significantly associated with an increased score of 3.47 (p <.0001) points on the pain VAS compared with the score reported by patients with mild/moderate knee OA. Additionally, it was significantly associated with reduced scores of 6.83 and 5.82 (both: p <.0001) points on the physical and mental composite summary subscales of the SF-36, respectively, compared with the scores of patients with mild/moderate knee OA, even after adjusting for all covariates. CONCLUSION: Older patients with severe knee OA had significantly worse KP and reduced HRQoL compared to patients with mild/moderate knee conditions, even after controlling for confounders. PMID- 29763422 TI - Capturing farm diversity with hypothesis-based typologies: An innovative methodological framework for farming system typology development. AB - Creating typologies is a way to summarize the large heterogeneity of smallholder farming systems into a few farm types. Various methods exist, commonly using statistical analysis, to create these typologies. We demonstrate that the methodological decisions on data collection, variable selection, data-reduction and clustering techniques can bear a large impact on the typology results. We illustrate the effects of analysing the diversity from different angles, using different typology objectives and different hypotheses, on typology creation by using an example from Zambia's Eastern Province. Five separate typologies were created with principal component analysis (PCA) and hierarchical clustering analysis (HCA), based on three different expert-informed hypotheses. The greatest overlap between typologies was observed for the larger, wealthier farm types but for the remainder of the farms there were no clear overlaps between typologies. Based on these results, we argue that the typology development should be guided by a hypothesis on the local agriculture features and the drivers and mechanisms of differentiation among farming systems, such as biophysical and socio-economic conditions. That hypothesis is based both on the typology objective and on prior expert knowledge and theories of the farm diversity in the study area. We present a methodological framework that aims to integrate participatory and statistical methods for hypothesis-based typology construction. This is an iterative process whereby the results of the statistical analysis are compared with the reality of the target population as hypothesized by the local experts. Using a well-defined hypothesis and the presented methodological framework, which consolidates the hypothesis through local expert knowledge for the creation of typologies, warrants development of less subjective and more contextualized quantitative farm typologies. PMID- 29763421 TI - Discovery of chitin in skeletons of non-verongiid Red Sea demosponges. AB - Marine demosponges (Porifera: Demospongiae) are recognized as first metazoans which have developed over millions of years of evolution effective survival strategies based on unique metabolic pathways to produce both biologically active secondary metabolites and biopolymer-based stiff skeletons with 3D architecture. Up to date, among marine demosponges, only representatives of the Verongiida order have been known to synthetize biologically active substances as well as skeletons made of structural polysaccharide chitin. This work, to our knowledge, demonstrates for the first time that chitin is an important structural component within skeletons of non-verongiid demosponges Acarnus wolffgangi and Echinoclathria gibbosa collected in the Red Sea. Calcofluor white staining, FTIR and Raman analysis, ESI-MS, SEM, and fluorescence microscopy as well as a chitinase digestion assay were applied in order to confirm, with strong evidence, the finding of alpha-chitin in the skeleton of both species. We suggest that, the finding of chitin within these representatives of Poecilosclerida order is a promising step in the evaluation of these sponges as novel renewable sources for both biologically active metabolites and chitin, which are of prospective application for pharmacology and biomedicine. PMID- 29763423 TI - From one incision to one port: The surgical technique and the evolution of segmentectomy in patients with pulmonary tuberculosis. AB - OBJECTIVES: We retrospectively reviewed the evolution of segmentectomy for pulmonary tuberculosis (TB) and the feasibility of multi- and single-incision video-assisted thoracoscopic segmentectomy. METHODS: Of 348 patients undergoing surgery for TB, the medical records of 121 patients undergoing segmentectomy between January 1996 and November 2015 were reviewed. Clinical information and computed tomography (CT) image characteristics were investigated and analyzed. RESULTS: Eighteen patients underwent direct or intended thoracotomy. Sixty-four underwent video-assisted thoracoscopic segmentectomy (VATS), including 53 multi incision thoracoscopic segmentectomy (MITS), and 11 single-incision thoracoscopic segmentectomy (SITS). Thirty-nine were converted to thoracotomy. The intended thoracotomy group had more operative blood loss (p = 0.005) and hospital stay (p = 0.001) than the VATS group although the VATS group had higher grade of cavity (p = 0.007). The intended thoracotomy group did not differ from converted thoracotomy in operative time, blood loss, or hospital stay, and the grade of pleural thickening was higher in the converted thoracotomy group (p = 0.001). The converted thoracotomy group had more operative blood loss, hospital stay, and complication rate than the MITS group (p = 0.001, p<0.001, and p = 0.009, respectively). The MITS group had lower pleural thickening, peribronchial lymph node calcification, cavity, and tuberculoma grading than the converted thoracotomy group (p<0.001, p = 0.001, 0.001, and 0.017, respectively). The SITS group had lower grading in pleural thickening, peribronchial lymph node calcification, and aspergilloma grading than the converted thoracotomy group (p = 0.002, 0.010, and 0.031, respectively). Four patients in the intended thoracotomy group and seven in the converted thoracotomy group had complications compared with three patients in the MITS and two in the SITS group. Risk factors of conversion were pleural thickening and peribronchial lymph node calcification. CONCLUSION: Although segmentectomy is technically challenging in patients with pulmonary TB, it could be safely performed using MITS or SITS and should be attempted in selected patients. Its efficacy for medical treatment failure needs investigation. PMID- 29763424 TI - Prevalence of primary Sjogren's syndrome in patients undergoing evaluation for pulmonary arterial hypertension. AB - BACKGROUND: The prevalence of pulmonary arterial hypertension (PAH) in primary Sjogren's syndrome (SS) had been reported to be rare. However, recent studies using echocardiography as a screening method showed conflicting results, and the true prevalence is still unclear. Since diagnosing primary SS is difficult because of its heterogeneous nature, a number of patients with primary-SS associated PAH may be misdiagnosed with idiopathic PAH, losing their chance to undergo immunosuppressive therapy. Therefore, we sought to elucidate the prevalence of primary SS among patients who initially present with PAH. METHODS: From our prospective institutional PAH database, 40 consecutive patients without any obvious cause of PAH at the time of PAH diagnosis were identified. We retrospectively evaluated the prevalence of primary SS diagnosed during or after the initial assessment of PAH. RESULTS: During the initial assessment, one patient was diagnosed with primary-SS-associated PAH. Among the 25 patients who were initially diagnosed with idiopathic PAH, five were diagnosed with primary SS during their course of the disease. Of the five patients, three had key signs suggesting primary SS and were probably underdiagnosed at the time of initial evaluation. The remaining two patients, who were finally diagnosed with primary SS, did not have any specific signs suggesting primary SS at the time of initial evaluation but showed positive conversion of their autoantibodies during the course of PAH. CONCLUSION: The prevalence of primary-SS-associated PAH may be relatively high among patients who undergo initial evaluation for PAH. Furthermore, primary-SS-associated PAH may be underdiagnosed with routine evaluation for the primary cause of PAH. Clinicians should pay specific attention and carefully evaluate the possibility of primary SS in patients with PAH. PMID- 29763425 TI - A positive association between nutritional risk and the incidence of surgical site infections: A hospital-based register study. AB - Surgical site infections (SSI) are amongst the most common health care-associated infections and have adverse effects for patient health and for hospital resources. Although surgery guidelines recognize poor nutritional status to be a risk factor for SSI, they do not tell how to identify this condition. The screening tool Nutritional Risk Screening 2002 is commonly used at hospitals to identify patients at nutritional risk. We investigated the association between nutritional risk and the incidence of SSI among 1194 surgical patients at Haukeland University Hospital (Bergen, Norway). This current study combines data from two mandatory hospital-based registers: a) the incidence of SSI within 30 days after surgery, and b) the point-prevalence of patients at nutritional risk. Patients with more than 30 days between surgery and nutritional risk screening were excluded. Associations were assessed using logistic regression, and the adjusted odds ratio included age (continuous), gender (male/female), type of surgery (acute/elective) and score from The American Society of Anesthesiologists Physical Status Classification System. There was a significant higher incidence of SSI among patients at nutritional risk (11.8%), as compared to those who were not (7.0%) (p = 0.047). Moreover, the incidence of SSI was positively associated with the prevalence of nutritional risk in both simple (OR 1.76 (95% CI: 1.04, 2.98)) and adjusted (OR 1.81 (95% CI: 1.04, 3.16)) models. Answering "yes" to the screening questions regarding reduced dietary intake and weight loss was significantly associated with the incidence of SSI (respectively OR 2.66 (95% CI: 1.59, 4.45) and OR 2.15 (95% CI: 1.23, 3.76)). In conclusion, we demonstrate SSI to occur more often among patients at nutritional risk as compared to those who are not at nutritional risk. Future studies should investigate interventions to prevent both SSI and nutritional risk among surgical patients. PMID- 29763426 TI - Environmental concentrations of metformin exposure affect aggressive behavior in the Siamese fighting fish, Betta splendens. AB - Metformin, the medicine most commonly prescribed for treatment of Type II diabetes, is among the most abundant pharmaceuticals being introduced into the environment. Pharmaceuticals are increasingly found in wastewater and surface waters around the world, often due to incomplete metabolism in humans and subsequent excretion in human waste. Risk analyses and exposure studies have raised concerns about potential negative impacts of pharmaceuticals at current environmental levels. Results of the present study indicate that metformin at concentrations in the range of what has been documented in freshwater systems and waste-water effluent (40 MUg/L) affects aggressive behavior in adult male Betta splendens. Subjects exhibited less aggression toward a male dummy stimulus after four weeks exposure to metformin-treated water when compared to behavior measured immediately prior to their exposure, and in comparison to a separate cohort of un exposed control fish. This effect persisted after 20 weeks exposure as well. Subjects exposed to metformin at a concentration twice that currently observed in nature (80 MUg/L) exhibited an even more substantial reduction in aggressive behaviors compared to controls and pre-exposure measurements than those observed in the low-dose treatment group. Such changes in behavior have the potential to affect male fitness and possibly impact the health of natural populations of aquatic organisms exposed to the drug. PMID- 29763427 TI - Correction: A High-Content Assay Enables the Automated Screening and Identification of Small Molecules with Specific ALDH1A1-Inhibitory Activity. AB - [This corrects the article DOI: 10.1371/journal.pone.0170937.]. PMID- 29763428 TI - Physical and cognitive doping in university students using the unrelated question model (UQM): Assessing the influence of the probability of receiving the sensitive question on prevalence estimation. AB - STUDY OBJECTIVES: In order to increase the value of randomized response techniques (RRTs) as tools for studying sensitive issues, the present study investigated whether the prevalence estimate for a sensitive item [Formula: see text] assessed with the unrelated questionnaire method (UQM) is influenced by changing the probability of receiving the sensitive question p. MATERIAL AND METHODS: A short paper-and-pencil questionnaire was distributed to 1.243 university students assessing the 12-month prevalence of physical and cognitive doping using two versions of the UQM with different probabilities for receiving the sensitive question (p ~ 1/3 and p ~ 2/3). Likelihood ratio tests were used to assess whether the prevalence estimates for physical and cognitive doping differed significantly between p ~ 1/3 and p ~ 2/3. The order of questions (physical doping and cognitive doping) as well as the probability of receiving the sensitive question (p ~ 1/3 or p ~ 2/3) were counterbalanced across participants. Statistical power analyses were performed to determine sample size. RESULTS: The prevalence estimate for physical doping with p ~ 1/3 was 22.5% (95% CI: 10.8-34.1), and 12.8% (95% CI: 7.6-18.0) with p ~ 2/3. For cognitive doping with p ~ 1/3, the estimated prevalence was 22.5% (95% CI: 11.0-34.1), whereas it was 18.0% (95% CI: 12.5-23.5) with p ~ 2/3. Likelihood-ratio tests revealed that prevalence estimates for both physical and cognitive doping, respectively, did not differ significantly under p ~ 1/3 and p ~ 2/3 (physical doping: chi2 = 2.25, df = 1, p = 0.13; cognitive doping: chi2 = 0.49, df = 1, p = 0.48). Bayes factors computed with the Savage-Dickey method favored the null ("the prevalence estimates are identical under p ~ 1/3 and p ~ 2/3") over the alternative ("the prevalence estimates differ under p ~ 1/3 and p ~ 2/3") hypothesis for both physical doping (BF = 2.3) and cognitive doping (BF = 5.3). CONCLUSION: The present results suggest that prevalence estimates for physical and cognitive doping assessed by the UQM are largely unaffected by the probability for receiving the sensitive question p. PMID- 29763429 TI - Factors affecting femoral rotational angle based on the posterior condylar axis in gap-based navigation-assisted total knee arthroplasty for valgus knee. AB - BACKGROUND: Achieving proper rotational alignment of the femoral component in total knee arthroplasty (TKA) for valgus knee is challenging because of lateral condylar hypoplasia and lateral cartilage erosion. Gap-based navigation-assisted TKA enables surgeons to determine the angle of femoral component rotation (FCR) based on the posterior condylar axis. This study evaluated the possible factors that affect the rotational alignment of the femoral component based on the posterior condylar axis. MATERIALS AND METHODS: Between 2008 and 2016, 28 knees were enrolled. The dependent variable for this study was FCR based on the posterior condylar axis, which was obtained from the navigation system archives. Multiple regression analysis was conducted to identify factors that might predict FCR, including body mass index (BMI), Kellgren-Lawrence grade (K-L grade), lateral distal femoral angles obtained from the navigation system and radiographs (NaviLDFA, XrayLDFA), hip-knee-ankle (HKA) axis, lateral gap under varus stress (LGVS), medial gap under valgus stress (MGVS), and side-to-side difference (STSD, MGVS - LGVS). RESULTS: The mean FCR was 6.1 degrees +/- 2.0 degrees . Of all the potentially predictive factors evaluated in this study, only NaviLDFA (beta = 0.668) and XrayLDFA (beta = -0.714) predicted significantly FCR. CONCLUSIONS: The LDFAs, as determined using radiographs and the navigation system, were both predictive of the rotational alignment of the femoral component based on the posterior condylar axis in gap-based TKA for valgus knee. A 1 degrees increment with NaviLDFA led to a 0.668 degrees decrement in FCR, and a 1 degrees increment with XrayLDFA led to a 0.714 degrees decrement. This suggests that symmetrical lateral condylar hypoplasia of the posterior and distal side occurs in lateral compartment end-stage osteoarthritis with valgus deformity. PMID- 29763430 TI - Policosanol fabrication from insect wax and optimization by response surface methodology. AB - BACKGROUND: Insect wax is a famous biological resource for the role in economic production in China. Insect wax is a good source of policosanol, which may is a candidate supplement in foodstuff and pharmaceuticals that has important physiological activities. Therefore, this work aims to investigate a high-yield and rapid method for policosanol fabrication from insect wax. RESULTS: The conditions for policosanol fabrication were optimized as follows: an oil bath temperature of 112.7 degrees C and reductant dosage of 0.97 g (used for the reduction of 10.00 g of insect wax). The yield of policosanol reached 83.20%, which was 4 times greater than that of existing methods, such as saponification. The total content of policosanol obtained under the optimal conditions reached 87%. In other words, a high yield of policosanol was obtained from insect wax (723.84 mg/g), that was 55 times higher than that generated from beeswax-brown via saponification. The concentrations of metal residues in policosanol were within the limits of the European Union regulations and EFSA stipulation. The LD50 values for oral doses of insect wax and policosanol were both > 5 g/kg. CONCLUSION: Policosanol was fabricated via solvent-free reduction from insect wax using LiAlH4 at a high yield. The fabrication conditions were optimized. Policosanol and insect wax showed high security, which made them potential candidates as supplements in foods, pharmaceuticals and cosmetics. The rapid and high-yield method has great potential for commercial manufacturing of policosanol. PMID- 29763431 TI - The efficacy of Life Review Therapy combined with Memory Specificity Training (LRT-MST) targeting cancer patients in palliative care: A randomized controlled trial. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of an intervention combining Life Review Therapy (LRT) and Memory Specificity Training (MST) (LRT MST) to improve ego-integrity and despair among cancer patients in palliative care. METHODS: In this multicentre randomized controlled trial, cancer patients in palliative care were randomized to the intervention group (LRT-MST; n = 55) or waiting-list control group (n = 52). LRT-MST is a 4-session home-based psychological intervention that aims to retrieve specific positive memories, to re-evaluate life events and to reconstruct the story of a patient's life, including the diagnosis of incurable cancer. Outcome measures were ego-integrity and despair (NEIS), psychological distress, anxiety and depression (HADS), quality of life (EORTC QLQ-C15-PAL), and specificity of the autobiographical memory (AMT). NEIS, HADS and EORTC QLQ-C15-PAL were assessed at baseline (T0), 1 month later (post-treatment; T1), and at 1 month follow-up (T2). AMT was assessed at T0 and T1. Linear mixed models (intention to treat) were used to assess group differences in changes over time. Independent samples t-tests were used to assess group differences at T0, T1, and T2, and effect sizes (ES) were calculated at T1 and T2. RESULTS: The course of ego-integrity (not despair) improved significantly over time (p = .007) in the intervention group compared to the waiting-list control group, with moderate, but insignificant, effect sizes at T1 (ES = .42) and T2 (ES = .48). Compliance rate was 69% and total dropout rate was 28%, both primarily related to disease progression and death. CONCLUSIONS: LRT-MST seems effective among cancer patients in palliative care to improve the course of ego integrity. PMID- 29763433 TI - Injury and death during the ISIS occupation of Mosul and its liberation: Results from a 40-cluster household survey. AB - BACKGROUND: Measurement of mortality and injury in conflict situations presents many challenges compared with stable situations. However, providing information is important to assess the impact of conflict on populations and to estimate humanitarian needs, both in the immediate and longer term. Mosul, Iraq's second largest city, was overrun by fighters of the Islamic State of Iraq and Syria (ISIS) on June 4, 2014. In this study, we conducted household surveys to measure reported deaths, injuries, and kidnappings in Mosul, Iraq, both during the occupation of the city by fighters of ISIS and the months of Iraqi military action known as the liberation. METHODS AND FINDINGS: Mosul was overrun by ISIS forces on June 4, 2014, and was under exclusive ISIS control for 29 months. The military offensive by Iraqi forces, supported by coalition artillery and airstrikes, began on October 17, 2016, in east Mosul and concluded in west Mosul with the defeat of ISIS on June 29, 2017. We conducted a 40-cluster population based survey as soon as the security forces permitted access for the survey team. The objective of the survey was to measure reported deaths, injuries, and kidnappings in Mosul households during 29 months of ISIS-exclusive control (June 2014-October 2016) and the nine months of Iraqi military action known as the liberation (October 2016-June 2017). In east Mosul, the survey was conducted from March 23 to March 31, 2017, and in west Mosul from July 18 to July 31, 2017. Sampling was based on pre-ISIS population distribution, with revisions made following the extensive destruction in west Mosul. The 1,202 sampled households included 7,559 persons: 4,867 in east Mosul and 2,692 in west Mosul. No households declined to participate. During the time from June 4, 2014, to the time of the survey, there were 628 deaths reported from the sampled households, of which 505 were due to intentional violence, a mortality rate of 2.09 deaths per 1,000 person-months. Over the entire time period, the group with the highest mortality rates from intentional violence was adults aged 20 to 39: 1.69 deaths per 1,000 person-months among women and 3.55 among men. In the 29 months of ISIS exclusive control, mortality rates among all males were 0.71 reported deaths per 1,000 person-months and for all females were 0.50 deaths per 1,000 person-months. During the nine months of the military liberation, the mortality rates jumped to 13.36 deaths per 1,000 person-months for males and 8.33 for females. The increase was particularly dramatic in west Mosul. The leading cause of reported deaths from intentional violence was airstrikes-accounting for 201 civilian deaths followed by 172 deaths from explosions. Reported deaths from airstrikes were most common in west Mosul, while reported deaths from explosions were similar on both sides of Mosul. Gunshots accounted for 86 cases, predominantly in west Mosul where ISIS snipers were particularly active. There were 35 persons who were reported to have been kidnapped, almost entirely prior to the military offensive. By the time of the survey, 20 had been released, 8 were dead, and 7 still missing, according to household reports. Almost all of the 223 injuries reported were due to intentional violence. Limitations to population-based surveys include a probable large survivor bias, the reliance on preconflict population distribution figures for sampling, and potential recall bias among respondents. CONCLUSIONS: Death and injuries during the military offensive to liberate Mosul considerably exceeded those during ISIS occupation. Airstrikes were the major reported cause of deaths, with the majority occurring in west Mosul. The extensive use of airstrikes and heavy artillery risks an extensive loss of life in densely populated urban areas. The high probability of survivor bias in this survey suggests that the actual number of injuries, kidnappings, and deaths in the neighborhoods sampled is likely to be higher than we report here. PMID- 29763432 TI - Distinctive types of postzygotic single-nucleotide mosaicisms in healthy individuals revealed by genome-wide profiling of multiple organs. AB - Postzygotic single-nucleotide mosaicisms (pSNMs) have been extensively studied in tumors and are known to play critical roles in tumorigenesis. However, the patterns and origin of pSNMs in normal organs of healthy humans remain largely unknown. Using whole-genome sequencing and ultra-deep amplicon re-sequencing, we identified and validated 164 pSNMs from 27 postmortem organ samples obtained from five healthy donors. The mutant allele fractions ranged from 1.0% to 29.7%. Inter and intra-organ comparison revealed two distinctive types of pSNMs, with about half originating during early embryogenesis (embryonic pSNMs) and the remaining more likely to result from clonal expansion events that had occurred more recently (clonal expansion pSNMs). Compared to clonal expansion pSNMs, embryonic pSNMs had higher proportion of C>T mutations with elevated mutation rate at CpG sites. We observed differences in replication timing between these two types of pSNMs, with embryonic and clonal expansion pSNMs enriched in early- and late replicating regions, respectively. An increased number of embryonic pSNMs were located in open chromatin states and topologically associating domains that transcribed embryonically. Our findings provide new insights into the origin and spatial distribution of postzygotic mosaicism during normal human development. PMID- 29763434 TI - Ibuprofen versus pivmecillinam for uncomplicated urinary tract infection in women A double-blind, randomized non-inferiority trial. AB - BACKGROUND: Although uncomplicated urinary tract infections (UTIs) are often self limiting, most patients will be prescribed antibiotic treatment. We assessed whether treatment with ibuprofen was non-inferior to pivmecillinam in achieving symptomatic resolution by day 4, with a non-inferiority margin of 10%. METHODS AND FINDINGS: This was a randomized, controlled, double-blind non-inferiority trial. We recruited patients from 16 sites in a general practice setting in Norway, Sweden, and Denmark. Non-pregnant women aged 18-60 years presenting with symptoms of uncomplicated UTI were screened for eligibility from 11 April 2013 to 22 April 2016. Patients with informed consent were randomized (1:1 ratio) to treatment with either 600 mg ibuprofen or 200 mg pivmecillinam 3 times a day for 3 days. The patient, treating physician, and study personnel were blinded to treatment allocation. The primary outcome was the proportion of patients who felt cured by day 4, as assessed from a patient diary. Secondary outcomes included the proportion of patients in need of secondary treatment with antibiotics and cases of pyelonephritis. A total of 383 women were randomly assigned to treatment with either ibuprofen (n = 194, 181 analyzed) or pivmecillinam (n = 189, 178 analyzed). By day 4, 38.7% of the patients in the ibuprofen group felt cured versus 73.6% in the pivmecillinam group. The adjusted risk difference with 90% confidence interval was 35% (27% to 43%) in favor of pivmecillinam, which crossed the prespecified non-inferiority margin. Secondary endpoints were generally in favor of pivmecillinam. After 4 weeks' follow-up, 53% of patients in the ibuprofen group recovered without antibiotic treatment. Seven cases of pyelonephritis occurred, all in the ibuprofen group, giving a number needed to harm of 26 (95% CI 13 to 103). Five of these patients were hospitalized and classified as having serious adverse events; 2 recovered as outpatients. A limitation of the study was the extensive list of exclusion criteria, eliminating almost half of the patients screened. We did not register symptoms in the screening process; hence, we do not know the symptom burden for those who declined to participate. This might make our results less generalizable. CONCLUSIONS: Ibuprofen was inferior to pivmecillinam for treating uncomplicated UTIs. More than half of the women in the ibuprofen group recovered without antibiotics. However, pyelonephritis occurred in 7 out of 181 women using ibuprofen. Until we can identify those women who will develop complications, we cannot recommend ibuprofen alone as initial treatment to women with uncomplicated UTIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01849926 EU Clinical Trials Register (EU-CTR), EudraCT Number 2012-002776-14. PMID- 29763435 TI - Personality differentially affects individual mate choice decisions in female and male Western mosquitofish (Gambusia affinis). AB - Consistent individual differences in behavioral tendencies (animal personality) can affect individual mate choice decisions. We asked whether personality traits affect male and female mate choice decisions similarly and whether potential personality effects are consistent across different mate choice situations. Using western mosquitofish (Gambusia affinis) as our study organism, we characterized focal individuals (males and females) twice for boldness, activity, and sociability/shoaling and found high and significant behavioral repeatability. Additionally, each focal individual was tested in two different dichotomous mate choice tests in which it could choose between computer-animated stimulus fish of the opposite sex that differed in body size and activity levels, respectively. Personality had different effects on female and male mate choice: females that were larger than average showed stronger preferences for large-bodied males with increasing levels of boldness/activity (i.e., towards more proactive personality types). Males that were larger than average and had higher shoaling tendencies showed stronger preferences for actively swimming females. Size-dependent effects of personality on the strength of preferences for distinct phenotypes of potential mating partners may reflect effects of age/experience (especially in females) and social dominance (especially in males). Previous studies found evidence for assortative mate choice based on personality types or hypothesized the existence of behavioral syndromes of individuals' choosiness across mate choice criteria, possibly including other personality traits. Our present study exemplifies that far more complex patterns of personality-dependent mate choice can emerge in natural systems. PMID- 29763436 TI - Treatment of limb wounds of horses with orf virus IL-10 and VEGF-E accelerates resolution of exuberant granulation tissue, but does not prevent its development. AB - Bandaging of limb wounds in horses leads to formation of exuberant granulation tissue (EGT) that retards healing due to protracted inflammation, aberrant vascularisation and delayed epithelialisation. EGT is not observed if wounds are left undressed or when wounds are on the body. A previous study showed that short term administration of proteins derived from orf virus dampened inflammation and promoted epithelialisation of open wounds in horses. Here, we investigated the impact of orf virus interleukin-10 and vascular endothelial growth factor-E on the development and resolution of EGT. Excisional wounds were created on the forelimb of four horses, and bandages were maintained until full healing to induce EGT formation. Matching body wounds were created to ensure EGT was limited to the limb, and to differentiate the effects of the viral proteins on normal healing and on EGT formation. Viral proteins or the hydrogel vehicle control were administered topically to site-matched wounds at day 1, with repeat administration at day 8. Wound healing and EGT formation were monitored macroscopically. Wound margin samples were harvested at 2, 7 and 14 days, and at full healing, with histology used to observe epithelialisation, immunofluorescence used to detect inflammatory cells, angiogenesis and cell death, and qPCR to measure expression of genes regulating inflammation and angiogenesis. Limb wounds developed EGT, and exhibited slower healing than body wounds. Viral protein treatment did not accelerate healing at either location nor limit EGT formation in limb wounds. Treatment of limb wounds did however increase epithelialisation and angiogenesis, without dampening inflammatory cell infiltration or gene expression. The healed wounds also had less occlusion and death of blood vessels and fewer epidermal rete ridges following viral protein treatment. These findings indicate that the viral protein treatment does not suppress wound inflammation or EGT formation, but does promote vascular and epidermal repair and EGT resolution. PMID- 29763437 TI - Postnatal colonization with human "infant-type" Bifidobacterium species alters behavior of adult gnotobiotic mice. AB - Accumulating studies have defined a role for the intestinal microbiota in modulation of host behavior. Research using gnotobiotic mice emphasizes that early microbial colonization with a complex microbiota (conventionalization) can rescue some of the behavioral abnormalities observed in mice that grow to adulthood completely devoid of bacteria (germ-free mice). However, the human infant and adult microbiomes vary greatly, and effects of the neonatal microbiome on neurodevelopment are currently not well understood. Microbe-mediated modulation of neural circuit patterning in the brain during neurodevelopment may have significant long-term implications that we are only beginning to appreciate. Modulation of the host central nervous system by the early-life microbiota is predicted to have pervasive and lasting effects on brain function and behavior. We sought to replicate this early microbe-host interaction by colonizing gnotobiotic mice at the neonatal stage with a simplified model of the human infant gut microbiota. This model consortium consisted of four "infant-type" Bifidobacterium species known to be commensal members of the human infant microbiota present in high abundance during postnatal development. Germ-free mice and mice neonatally-colonized with a complex, conventional murine microbiota were used for comparison. Motor and non-motor behaviors of the mice were tested at 6-7 weeks of age, and colonization patterns were characterized by 16S ribosomal RNA gene sequencing. Adult germ-free mice were observed to have abnormal memory, sociability, anxiety-like behaviors, and motor performance. Conventionalization at the neonatal stage rescued these behavioral abnormalities, and mice colonized with Bifidobacterium spp. also exhibited important behavioral differences relative to the germ-free controls. The ability of Bifidobacterium spp. to improve the recognition memory of both male and female germ-free mice was a prominent finding. Together, these data demonstrate that the early-life gut microbiome, and human "infant-type" Bifidobacterium species, affect adult behavior in a strongly sex-dependent manner, and can selectively recapitulate the results observed when mice are colonized with a complex microbiota. PMID- 29763438 TI - Phasome analysis of pathogenic and commensal Neisseria species expands the known repertoire of phase variable genes, and highlights common adaptive strategies. AB - Pathogenic Neisseria are responsible for significantly higher levels of morbidity and mortality than their commensal relatives despite having similar genetic contents. Neisseria possess a disparate arsenal of surface determinants that facilitate host colonisation and evasion of the immune response during persistent carriage. Adaptation to rapid changes in these hostile host environments is enabled by phase variation (PV) involving high frequency, stochastic switches in expression of surface determinants. In this study, we analysed 89 complete and 79 partial genomes, from the NCBI and Neisseria PubMLST databases, representative of multiple pathogenic and commensal species of Neisseria using PhasomeIt, a new program that identifies putatively phase-variable genes and homology groups by the presence of simple sequence repeats (SSR). We detected a repertoire of 884 putative PV loci with maxima of 54 and 47 per genome in gonococcal and meningococcal isolates, respectively. Most commensal species encoded a lower number of PV genes (between 5 and 30) except N. lactamica wherein the potential for PV (36-82 loci) was higher, implying that PV is an adaptive mechanism for persistence in this species. We also characterised the repeat types and numbers in both pathogenic and commensal species. Conservation of SSR-mediated PV was frequently observed in outer membrane proteins or modifiers of outer membrane determinants. Intermittent and weak selection for evolution of SSR-mediated PV was suggested by poor conservation of tracts with novel PV genes often occurring in only one isolate. Finally, we describe core phasomes-the conserved repertoires of phase-variable genes-for each species that identify overlapping but distinctive adaptive strategies for the pathogenic and commensal members of the Neisseria genus. PMID- 29763439 TI - Marginal ancestral contributions to atrial fibrillation in the Standardbred racehorse: Comparison of cases and controls. AB - Admissions of Standardbred racehorses (Std) to the Ontario Veterinary College Teaching Hospital (OVCTH) for treatment of atrial fibrillation (AF) began to increase in the early 1990s. The arrhythmia has been shown to have a modest heritability (h2 ? 0.15), with some stallions appearing as sires or sires of mares used in breeding (broodmares) of affected horses more frequently than others. The objective of this study was to determine the marginal genetic contributions of ancestors to cohorts of Std affected with AF and their contemporary control groups, and whether these ancestors contribute significantly more to the affected cohorts than to controls. All Std admitted to OVCTH for treatment of AF that were born between 1993 and 2007 comprised the affected case group (n = 168). Five randomly selected racing contemporaries for each Std admitted, assumed to not suffer from the arrhythmia, comprised the control group (n = 840). Three-year overlapping cohorts were created for case and control horses, determined according to year of birth, for a total of 26 cohorts. Marginal genetic contributions of ancestors to each cohort were determined and differences analyzed for statistical significance using a two-tailed paired t test, with P <= 0.05 considered significant. The marginal contributions of 26 ancestors were significant, with 11 contributing significantly more to affected cohorts than the corresponding controls, and 15 contributing significantly more to controls than the corresponding affected cohorts. One stallion and one broodmare were very highly significant to affected cohorts at P <= 0.001, and nine stallions and three broodmares were very highly significant to control cohorts at P <= 0.001. Therefore, a number of stallions have statistically significant contributions to the genetics of Std affected with AF, while many others have statistically significant contributions to healthy Std. The arrhythmia appears to be particularly prevalent in the descendants of one sire family. PMID- 29763440 TI - Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia. AB - Microvascular endothelial cells play a pivotal role in the pathogenesis of sepsis induced inflammatory responses and multiple organ failure. Therefore, they represent an important target for pharmacological intervention in the treatment of sepsis. Glucocorticosteroids were widely used in the treatment of sepsis but vast evidence to support their systemic use is lacking. The limited effects of glucocorticoids in the treatment of sepsis may be explained by differential effects of drug initiated NF-kappaB inhibition in different cell types and insufficient drug delivery in target cells. The current study aimed therefore to investigate the effects of an endothelial targeted delivery of dexamethasone in a mouse model of endotoxemia induced by two consecutive i.p. injections of lipopolysaccharide (LPS). To achieve endothelial cell specific delivery of dexamethasone, we modified SAINT-O-Somes, a new generation of liposomes that contain the cationic amphiphile SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl pyridinium chloride, with antibodies against vascular cell adhesion molecule-1 (VCAM-1). In LPS challenged mice, the systemic administration of free dexamethasone had negligible effects on the microvascular inflammatory endothelial responses. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically localized at VCAM-1 expressing endothelial cells in the microvasculature of inflamed organs. This was associated with a marginal attenuation of the expression of a few pro-inflammatory genes in kidney and liver, while no effects in the lung were observed. This study reveals that, although local accumulation of the targeted drug was achieved, endothelial targeted dexamethasone containing anti-VCAM-1 SAINT-O-Somes exhibited marginal effects on inflammatory endothelial cell activation in a model of endotoxemia. Studies with more potent drugs encapsulated into anti-VCAM-1 SAINT-O-Somes will in the future reveal whether this delivery system can be further developed for efficacious endothelial directed delivery of drugs in the treatment of sepsis. PMID- 29763441 TI - Chemical composition of barks from Quercus faginea trees and characterization of their lipophilic and polar extracts. AB - The bark from Quercus faginea mature trees from two sites was chemically characterized for the first time. The barks showed the following composition: ash 14.6%, total extractives 13.2%, suberin 2.9% and lignin 28.2%. The polysaccharides were composed mainly of glucose and xylose (50.3% and 35.1% of all monosaccharides respectively) with 4.8% of uronic acids. The suberin composition was: omega-hydroxyacids 46.3% of total compounds, alpha,omega alkanoic diacids 22.3%, alkanoic acids 5.9%, alkanols 6.7% and aromatics 6.9% (ferulic acid 4.0%). Polar extracts (ethanol-water) had a high phenolic content of 630.3 mg of gallic acid equivalents (GAE)/g of extract, condensed tannins 220.7 mg of catechin equivalents (CE)/g extract, and flavonoids 207.7 mg CE/g of extract. The antioxidant activity was very high corresponding to 1567 mg Trolox equivalents/g of extract, and an IC50 of 2.63 MUg extract/ml. The lipophilic extracts were constituted mainly by glycerol and its derivatives (12.3% of all compounds), alkanoic acids (27.8%), sterols (11.5%) and triterpenes (17.8%). In view of an integrated valorization, Quercus faginea barks are interesting sources of polar compounds including phenols and polyphenols with possible interesting bioactivities, while the sterols and triterpenes contained in the lipophilic extracts are also valuable bioactive compounds or chemical intermediates for specific high-value market niches, such as cosmetics, pharmaceuticals and biomedicine. PMID- 29763443 TI - Understanding how patients perceive physician wellness and its links to patient care: A qualitative study. AB - Despite increased interest in physician wellness, little is known about patients' views on the topic. We explore patients' perceptions of physician wellness and how it links to patient care. This exploratory, qualitative study employed semi structured interviews with a convenience sample of 20 patients from outpatient care settings in a western Canadian city. Using inductive thematic analysis, interview transcripts were independently coded by two authors and then discussed to ensure consensus and to abstract into higher-level themes. Three overarching premises were identified. First, patients notice cues that they interpret as signs of physician wellness. These include overt indicators, such as a physician's demeanor or physical appearance, along with a general impression about a physician's wellness. Second, patients form judgments based on what they notice, and these judgments affect patients' views about their care; feelings, such as trust, in their interactions with physicians; and actions, such as following care plans. Third, participants perceive a bi-directional link between physician wellness and patient care. Physician wellness impacts patient care, but physician wellness is also impacted by the care they provide and the challenges they face within the healthcare system. Patients' judgments regarding physician wellness may have important impacts on the doctor-patient relationship. Furthermore, patients appear to have a nuanced understanding about how physicians' work may put physicians at risk for being unwell. Patients may be powerful allies in supporting physician wellness initiatives focused on the shared responsibility of individual physicians, the medical profession, and healthcare organizations. PMID- 29763442 TI - Platinum corrosion products from electrode contacts of human cochlear implants induce cell death in cell culture models. AB - Despite the technological progress made with cochlear implants (CI), impedances and their diagnosis remain a focus of interest. Increases in impedance have been related to technical defects of the electrode as well as inflammatory and/or fibrosis along the electrode. Recent studies have demonstrated highly increased impedances as the result of corroded platinum (Pt) electrode contacts. This in vitro study examined the effects of Pt ions and compounds generated by corrosion of the electrode contacts of a human CI on cell metabolism. Since traces of solid Pt in surrounding cochlear tissues have been reported, the impact of commercially available Pt nanoparticles (Pt-NP, size 3 nm) on the cell culture model was also determined. For this purpose, the electrode contacts were electrically stimulated in a 0.5% aqueous NaCl solution for four weeks and the mass fraction of the platinum dissolute (Pt-Diss) was determined by mass spectrometry (ICP-MS). Metabolic activity of the murine fibroblasts (NIH 3T3) and the human neuroblastoma (SH-SY5Y) cells was determined using the WST-1 assay following exposure to Pt-Diss and Pt-NP. It was found that 5-50 MUg/ml of the Pt-NP did not affect the viability of both cell types. In contrast, 100 MUg/ml of the nanoparticles caused significant loss in metabolic activity. Furthermore, transmission electron microscopy (TEM) revealed mitochondrial swelling in both cell types indicating cytotoxicity. Additionally, TEM demonstrated internalized Pt-NP in NIH 3T3 cells in a concentration dependent manner, whereas endocytosis in SH-SY5Y cells was virtually absent. In comparison with the Pt-NP, the corrosion products (Pt-Diss) with concentrations between 1.64 MUg/ml and 8.2 MUg/ml induced cell death in both cell lines in a concentration dependent manner. TEM imaging revealed both mitochondrial disintegration and swelling of the endoplasmic reticulum, suggesting that Pt ions trigger cytotoxicity in both NIH 3T3 and SH-SY5Y cell lines by interacting with the respiratory chain. PMID- 29763444 TI - Cholelithiasis and choledocholithiasis in children; risk factors for development. AB - PURPOSE: To compare anthropometric data (body mass index [BMI]) in patients without lithiasis to patients with symptomatic simple cholelithiasis or choledocholithiasis. METHODS: We retrospectively reviewed data from 147 patients undergoing laparoscopic cholecystectomy between 2001-2015. Complete growth data from 98 patients was compared with anthropometric data from the population of the Czech Republic and a control group (BMI of 100 consecutive patients without biliary stones in abdominal ultrasound who were admitted to a surgical department for suspected appendicitis). RESULTS: The BMI of 75 children with simple cholelithiasis and 23 with choledocholithiasis was compared to the standard Czech pediatric population and to the control group. The median age (simple cholelithiasis and choledocholithiasis) was 16 years, and 35 patients (24%) had a family history of gallstones. Types of lithiasis included multiple (n = 120), solitary (n = 11), and sludge (n = 10). Five cases had polyps and one had gallbladder dysplasia. Patients with simple cholelithiasis had significantly higher BMI compared to the control group without cholelithiasis (p<0.0001) and the standard Czech population (p = 0.03). Patients with choledocholithiasis had a mean BMI significantly higher than that of the general population (p = 0.001) and the control group (p = 0.0001). Patients with choledocholithiasis had significantly higher BMI than those with simple cholelithiasis (p = 0.03). CONCLUSION: Patients with cholelithiasis had significantly higher BMI than the general population, and patients with choledocholithiasis had significantly higher BMI than patients with simple lithiasis. Elevated BMI is a risk factor for developing choledocholithiasis. ERCP and early laparoscopic cholecystectomy in patients with choledocholithiasis offer equivalent outcomes in patients with simple cholelithiasis. PMID- 29763445 TI - Pyrethroid insecticides maintain repellent effect on knock-down resistant populations of Aedes aegypti mosquitoes. AB - Pyrethroid-treated clothing is commonly worn for protection against mosquitoes; pyrethroids are both insecticides and repellents. Pyrethroid resistance has become increasingly common in Aedes aegypti, the vector of dengue, Zika, and other arboviruses, but it is not clear whether resistance is associated with reductions in repellency. In order to determine whether long-lasting permethrin impregnated (LLPI) clothing is protective, we used Aedes aegypti from New Orleans, LA (pyrethroid-sensitive) and San Juan, PR (resistant) to measure both lethality and repellency. PCR and Sanger sequencing were used to confirm resistance status by detecting mutations in the kdr gene at positions 1016 and 1534. Arm-in-cage trials of 100 Aedes aegypti females from both populations were performed for 10 minutes to bare arm or an arm clothed in untreated military camouflage or military camouflage impregnated with deltamethrin, permethrin, or etofenprox. Trials were repeated 4-5 times on different days. Number of landings, number of blood meals, and immediate and 24-hour mortality were recorded. Mortality was extremely low in all trials. Compared to untreated cloth, mosquitoes demonstrated a trend towards a 2%-63% reduction in landings and a statistically significant 78-100% reduction in blood feeding on pyrethroid treated cloth for most insecticides. Effects were observed in both pyrethroid sensitive and pyrethroid-resistant mosquito populations. Our data show that kdr mutations are associated with pyrethroid resistance but are likely not the only contributors. Pyrethroids appear to maintain repellent effect against resistant mosquitoes. This finding suggests that even in places where pyrethroid resistance is widespread, permethrin still has a role for use as a repellent on clothing to protect against mosquito bites. PMID- 29763446 TI - Detector-specific correction factors in radiosurgery beams and their impact on dose distribution calculations. AB - Silicon-diode-based detectors are commonly used for the dosimetry of small radiotherapy beams due to their relatively small volumes and high sensitivity to ionizing radiation. Nevertheless, silicon-diode-based detectors tend to over respond in small fields because of their high density relative to water. For that reason, detector-specific beam correction factors ([Formula: see text]) have been recommended not only to correct the total scatter factors but also to correct the tissue maximum and off-axis ratios. However, the application of [Formula: see text] to in-depth and off-axis locations has not been studied. The goal of this work is to address the impact of the correction factors on the calculated dose distribution in static non-conventional photon beams (specifically, in stereotactic radiosurgery with circular collimators). To achieve this goal, the total scatter factors, tissue maximum, and off-axis ratios were measured with a stereotactic field diode for 4.0-, 10.0-, and 20.0-mm circular collimators. The irradiation was performed with a Novalis(r) linear accelerator using a 6-MV photon beam. The detector-specific correction factors were calculated and applied to the experimental dosimetry data for in-depth and off-axis locations. The corrected and uncorrected dosimetry data were used to commission a treatment planning system for radiosurgery planning. Various plans were calculated with simulated lesions using the uncorrected and corrected dosimetry. The resulting dose calculations were compared using the gamma index test with several criteria. The results of this work presented important conclusions for the use of detector specific beam correction factors ([Formula: see text] in a treatment planning system. The use of [Formula: see text] for total scatter factors has an important impact on monitor unit calculation. On the contrary, the use of [Formula: see text] for tissue-maximum and off-axis ratios has not an important impact on the dose distribution calculation by the treatment planning system. This conclusion is only valid for the combination of treatment planning system, detector, and correction factors used in this work; however, this technique can be applied to other treatment planning systems, detectors, and correction factors. PMID- 29763447 TI - Hepatitis B and C: Seroprevalence, knowledge, practice and associated factors among medicine and health science students in Northeast Ethiopia. AB - BACKGROUND: Health care professionals, especially medical students, are at greater risk of contracting hepatitis B and C virus infections due to their occupational exposure to percutaneous injuries and other body fluids. The aim of this study was to determine the seroprevalence of hepatitis B and C virus infections among medicine and health science students in Northeast Ethiopia and to assess their knowledge and practice towards the occupational risk of viral hepatitis. METHODS: A cross-sectional study was conducted among a total of 408 medicine and health science students during the period from March to September 2017. A pre-coded self-administered questionnaire was used to collect data on students' socio- demographic characteristics, knowledge and practice of hepatitis B and C infections. Blood samples were collected and screened for hepatitis B surface antigen (HBsAg) and anti-HCV antibodies. SPSS version 20 statistical software was used for data analysis. RESULTS: The seroprevalence of HBV infection was 4.2% (95% CI 2.5 to 6.1%) and 0.7% (95% CI 0.0 to 1.7%) for HCV. Older age (AOR = 15.72, 95% CI 1.57-157.3) and exposure to needlestick injury (AOR = 3.43, 95% CI 1.10-10.73) were associated with a higher risk of HBV infection. Majority of the students (80.1%) had an adequate knowledge about hepatitis B and C infection, mode of transmission and preventive measures. Only 50.0% of students had safe practice towards occupational risk of viral hepatitis infection. Almost half (49.8%) of students experienced a needlestick injury; of which, 53.2% reported the incidence, and only 39.4% had screening test result for viral hepatitis. CONCLUSION: A high seroprevalence but poor practice of hepatitis B and C virus infection was found in the study area despite their good knowledge towards occupational risk of viral hepatitis infection. PMID- 29763448 TI - Modulation of functional activity and connectivity by acupuncture in patients with Alzheimer disease as measured by resting-state fMRI. AB - Acupuncture has been used in the therapy of Alzheimer disease (AD); however, its neural mechanisms are still unclear. The aim of this study is to examine the effect of acupuncture on the functional connectivity in AD by using resting-state functional magnetic resonance imaging (rs-fMRI). Twenty-eight subjects (14 AD and 14 normal controls) participated in this study. The rs-fMRI data were acquired before and after acupuncture stimulation at the acupoints of Tai chong (Liv3) and Hegu (LI4). During the baseline resting state, by using the amplitude of low frequency fluctuations (ALFF), we found a significantly decreased or increased ALFF in the AD patients relative to the controls. These regions were located in the right superior frontal gyrus (SFG), left postcentral gyrus, subgenual cingulate cortex (SCC), right middle cingulate cortex (MCC), right inferior frontal gyrus (IFG), right hippocampus and the right inferior temporal gyrus (ITG). Then, we selected these brain regions as seeds to investigate whether regional activity and functional connectivity could be modulated by acupuncture in the AD patients. When compared to the pre-acupuncture stage, several of the above regions showed an increased or decreased ALFF after acupuncture in the AD patients. In addition, the functional connectivity between the hippocampus and the precentral gyrus showed enhancement after acupuncture in the AD patients. Finally, there were close correlations between the functional activity, connectivity and clinical performance in the AD patients. The current study confirmed that acupuncture at Tai chong (Liv3) and He gu (LI4) can modulate functional activity and connectivity of specific cognition-related regions in AD patients. PMID- 29763449 TI - A novel specific duplex real-time RT-PCR method for absolute quantitation of Grapevine Pinot gris virus in plant material and single mites. AB - Grapevine Pinot gris virus (GPGV) is a widely distributed grapevine pathogen that has been associated to the grapevine leaf mottling and deformation disease. With the aim of better understanding the disease epidemiology and providing efficient control strategies a specific and quantitative duplex TaqMan real-time RT-PCR assay has been developed. This method has allowed reliable quantitation of the GPGV titer ranging from 30 up to 3 x 108 transcript copies, with a detection limit of 70 viral copies in plant material. The assay targets a grapevine internal control that reduces the occurrence of false negative results, thus increasing the diagnostic sensitivity of the technique. Viral isolates both associated and non-associated to symptoms from Greece, Slovakia and Spain have been successfully detected. The method has also been applied to the absolute quantitation of GPGV in its putative transmission vector Colomerus vitis. Moreover, the viral titer present in single mites has been determined. In addition, in the current study a new polymorphism in the GPGV genome responsible for a shorter movement protein has been found. A phylogenetic study based on this genomic region has shown a high variability among Spanish isolates and points to a different evolutionary origin of this new polymorphism. The methodology here developed opens new possibilities for basic and epidemiological studies as well as for the establishment of efficient control strategies. PMID- 29763450 TI - Pre-processing by data augmentation for improved ellipse fitting. AB - Ellipse fitting is a highly researched and mature topic. Surprisingly, however, no existing method has thus far considered the data point eccentricity in its ellipse fitting procedure. Here, we introduce the concept of eccentricity of a data point, in analogy with the idea of ellipse eccentricity. We then show empirically that, irrespective of ellipse fitting method used, the root mean square error (RMSE) of a fit increases with the eccentricity of the data point set. The main contribution of the paper is based on the hypothesis that if the data point set were pre-processed to strategically add additional data points in regions of high eccentricity, then the quality of a fit could be improved. Conditional validity of this hypothesis is demonstrated mathematically using a model scenario. Based on this confirmation we propose an algorithm that pre processes the data so that data points with high eccentricity are replicated. The improvement of ellipse fitting is then demonstrated empirically in real-world application of 3D reconstruction of a plant root system for phenotypic analysis. The degree of improvement for different underlying ellipse fitting methods as a function of data noise level is also analysed. We show that almost every method tested, irrespective of whether it minimizes algebraic error or geometric error, shows improvement in the fit following data augmentation using the proposed pre processing algorithm. PMID- 29763451 TI - Episodic memory and delayed recall are significantly more impaired in younger patients with deficit schizophrenia than in elderly patients with amnestic mild cognitive impairment. AB - BACKGROUND: Both amnestic mild cognitive impairment (aMCI) and schizophrenia, in particular deficit schizophrenia, are accompanied by cognitive impairments. The aim of the present study was to examine the cognitive differences between aMCI and (non)deficit schizophrenia. METHODS: Towards this end we recruited 60 participants with aMCI, 40 with deficit and 40 with nondeficit schizophrenia and 103 normal volunteers. Cognitive measures were assessed with the Consortium to Establish a Registry for Alzheimer's disease (CERAD) using the Verbal Fluency Test (VFT), Boston Naming Test (BNT), Mini-Mental State Examination (MMSE), Word list memory (WLM), Word list recall (WLRecall) and Word list recognition (WLRecognition). Data were analyzed using multivariate analyses and machine learning techniques. RESULTS: BNT scores were significantly lower in aMCI as compared with nondeficit schizophrenia. Patients with deficit schizophrenia had significantly lower MMSE, WLM, WL True Recall and WL Recognition than aMCI patients, while WL False Recall was significantly higher in deficit schizophrenia than in aMCI. Neural network importance charts show that deficit and nondeficit schizophrenia are best separated from aMCI using total BNT score, while WLM and WL false Recall follow at a distance. CONCLUSIONS: Patients with schizophrenia and aMCI have a significantly different neurocognitive profile. Memory impairments, especially in episodic memory, are significantly worse in younger patients with deficit schizophrenia as compared with elderly patients with aMCI, while the latter show more dysnomia than patients with schizophrenia. PMID- 29763452 TI - Factors affecting forest area change in Southeast Asia during 1980-2010. AB - While many tropical countries are experiencing rapid deforestation, some have experienced forest transition (FT) from net deforestation to net reforestation. Numerous studies have identified causative factors of FT, among which forest scarcity has been considered as a prerequisite for FT. In fact, in SE Asia, the Philippines, Thailand and Viet Nam, which experienced FT since 1990, exhibited a lower remaining forest area (30+/-8%) than the other five countries (68+/-6%, Cambodia, Indonesia, Laos, Malaysia, and Myanmar) where forest loss continues. In this study, we examined 1) the factors associated with forest scarcity, 2) the proximate and/or underlying factors that have driven forest area change, and 3) whether causative factors changed across FT phases (from deforestation to net forest gain) during 1980-2010 in the eight SE Asian countries. We used production of wood, food, and export-oriented food commodities as proximate causes and demographic, social, economic and environmental factors, as well as land-use efficiency, and wood and food trade as underlying causes that affect forest area change. Remaining forest area in 1990 was negatively correlated with population density and potential land area of lowland forests, while positively correlated with per capita wood production. This implies that countries rich in accessible and productive forests, and higher population pressures are the ones that have experienced forest scarcity, and eventually FT. Food production and agricultural input were negatively and positively correlated, respectively, with forest area change during 1980-2009. This indicates that more food production drives deforestation, but higher efficiency of agriculture is correlated with forest gain. We also found a U-shaped response of forest area change to social openness, suggesting that forest gain can be achieved in both open and closed countries, but deforestation might be accelerated in countries undergoing societal transition. These results indicate the importance of environmental, agricultural and social variables on forest area dynamics, and have important implications for predicting future tropical forest change. PMID- 29763453 TI - Anisotropic conductivity tensor imaging for transcranial direct current stimulation (tDCS) using magnetic resonance diffusion tensor imaging (MR-DTI). AB - Transcranial direct current stimulation (tDCS) is a widely used non-invasive brain stimulation technique by applying low-frequency weak direct current via electrodes attached on the head. The tDCS using a fixed current between 1 and 2 mA has relied on computational modelings to achieve optimal stimulation effects. Recently, by measuring the tDCS current induced magnetic field using an MRI scanner, the internal current pathway has been successfully recovered. However, up to now, there is no technique to visualize electrical properties including the electrical anisotropic conductivity, effective extracellular ion-concentration, and electric field using only the tDCS current in-vivo. By measuring the apparent diffusion coefficient (ADC) and the magnetic flux density induced by the tDCS, we propose a method to visualize the electrical properties. We reconstruct the scale parameter, which connects the anisotropic conductivity tensor to the diffusion tensor of water molecules, by introducing a repetitive scheme called the diffusion tensor J-substitution algorithm using the recovered current density and the measured ADCs. We investigate the proposed method to explain why the iterative scheme converges to the internal conductivity. We verified the proposed method with an anesthetized canine brain to visualize electrical properties including the electrical properties by tDCS current. PMID- 29763454 TI - Multivariate classification of Brugada syndrome patients based on autonomic response to exercise testing. AB - Ventricular arrhythmias in Brugada syndrome (BS) typically occur at rest and especially during sleep, suggesting that changes in the autonomic modulation may play an important role in arrhythmogenesis. The autonomic response to exercise and subsequent recovery was evaluated on 105 patients diagnosed with BS (twenty four were symptomatic), by means of a time-frequency heart rate variability (HRV) analysis, so as to propose a novel predictive model capable of distinguishing symptomatic and asymptomatic BS populations. During incremental exercise, symptomatic patients showed higher HFnu values, probably related to an increased parasympathetic modulation, with respect to asymptomatic subjects. In addition, those extracted HRV features best distinguishing between populations were selected using a two-step feature selection approach, so as to build a linear discriminant analysis (LDA) classifier. The final features subset included one third of the total amount of extracted autonomic markers, mostly acquired during incremental exercise and active recovery, thus evidencing the relevance of these test segments in BS patients classification. The derived predictive model showed an improved performance with respect to previous works in the field (AUC = 0.92 +/- 0.01; Se = 0.91 +/- 0.06; Sp = 0.90 +/- 0.05). Therefore, based on these findings, some of the analyzed HRV markers and the proposed model could be useful for risk stratification in Brugada syndrome. PMID- 29763455 TI - Correction: mRNA-Mediated Gene Supplementation of Toll-Like Receptors as Treatment Strategy for Asthma In Vivo. AB - [This corrects the article DOI: 10.1371/journal.pone.0154001.]. PMID- 29763456 TI - Comprehensive evaluation of blood-brain barrier-forming micro-vasculatures: Reference and marker genes with cellular composition. AB - Primary brain microvessels (BrMV) maintain the cellular characters and molecular signatures as displayed in vivo, and serve as a vital tool for biomedical research of the blood-brain barrier (BBB) and the development/optimization of brain drug delivery. The variations of relative purities or cellular composition among different BrMV samples may have significant consequences in data interpretation and research outcome, especially for experiments with high throughput genomics and proteomics technologies. In this study, we aimed to identify suitable reference gene (RG) for accurate normalization of real-time RT qPCR analysis, and determine the proper marker genes (MG) for relative purity assessment in BrMV samples. Out of five housekeeping genes, beta-actin was selected as the most suitable RG that was validated by quantifying mRNA levels of alpha-L-iduronidase in BrMV isolated from mice with one or two expressing alleles. Four marker genes highly/selectively expressed in BBB-forming capillary endothelial cells were evaluated by RT-qPCR for purity assessment, resulting in Cldn5 and Pecam1 as most suitable MGs that were further confirmed by immunofluorescent analysis of cellular components. Plvap proved to be an indicator gene for the presence of fenestrated vessels in BrMV samples. This study may contribute to the building blocks toward overarching research needs on the blood-brain barrier. PMID- 29763457 TI - Overlap in signaling between Smoothened and the alpha subunit of the heterotrimeric G protein G13. AB - The Hedgehog family of morphogens has long been known to utilize, through the 7 transmembrane protein Smoothened (Smo), the heterotrimeric G protein Gi in both canonical and noncanonical forms of signaling. Other G proteins, while not specifically utilized by Smo, may nonetheless provide access to some of the events controlled by it. We reported several years ago that the G protein G13 activates one or more forms of the Gli family of transcription factors. While the Gli transcription factors are well known targets for Smo, the uncertain mechanism of activation by G13 and the identity of the targeted Gli(s) limited predictions as to the extent to which G13 might mimic Smo's actions. We evaluate here the potential for overlap in G13 and Smo signaling using C3H10T1/2 and 3T3-L1 cells as models of osteogenesis and adipogenesis, respectively. We find in C3H10T1/2 cells that a constitutively active form of Galpha13 (Galpha13QL) increases Gli1 mRNA, as does a constitutively active form of Smo (SmoA1). We find as well that Galpha13QL induces alkaline phosphatase activity, a marker of osteogenesis, albeit the induction is far less substantial than that achieved by SmoA1. In 3T3 L1 cells both Galpha13QL and SmoA1 markedly suppress adipogenic differentiation as determined by triglyceride accumulation. RNA sequencing reveals that Galpha13QL and SmoA1 regulate many of the same genes but that quantitative and qualitative differences exist. Differences also exist, we find, between SmoA1 and purmorphamine, an agonist for Smo. Therefore, while comparisons of constitutively active proteins are informative, extrapolations to the setting of agonists require care. PMID- 29763458 TI - Immunity levels to poliovirus in Lao children and adults before the vaccine derived poliovirus outbreak: A retrospective study. AB - In 2015, several provinces in Lao People's Democratic Republic (Lao PDR) experienced a vaccine-derived poliovirus outbreak. This survey was conducted (i) to evaluate the vaccination coverage in different settings and cohorts using the seroprevalence of anti-poliovirus (PV) antibodies as a surrogate measure, and (ii) to explore the usefulness of an ELISA in a country with limited resources and a specific epidemiological setting. IgG antibodies were assessed by ELISA in Lao children (n = 1216) and adults (n = 1228), including blood donors and health care workers. Protective antibody titers against the 3 vaccine serotypes were determined by microneutralization (VNT) in a subset of participants. More than 92% of the children had anti-poliovirus antibodies, regardless of nutritional status or access to health care, highlighting the success of the vaccination outreach activities in the country. In contrast, anti-poliovirus seroprevalence reached only 81.7% in blood donors and 71.9% in health care workers. Participants born before the introduction of poliovirus vaccination in Lao PDR were considerably less likely to be seropositive. These findings align with the epidemiology of the outbreak. Neutralizing antibodies against at least one of the 3 poliovirus serotypes were detected in all children (99/99) and 93/99 had antibodies against all serotypes. Similarly, all health care workers had neutralizing antibodies against at least one and 92/99 against all serotypes. The comparison of both assays shows an acceptable underestimation of vaccine coverage in children by ELISA, but a low sensitivity of the ELISA in the adults. We show that the ELISA is a reasonable alternative to the VNT in particular in vaccinated children, that an improved version should be serotype specific, and that negativity thresholds should be revisited for optimal sensitivity and specificity. Thus, polio-free countries with an uncertain vaccination coverage and limited laboratory capacity, that are at risk of vaccine-derived poliovirus outbreaks or of re-importation of wild poliovirus may benefit from an improved ELISA for cohort studies to evaluate their immunization program in children. PMID- 29763459 TI - The benefit of combining a deep neural network architecture with ideal ratio mask estimation in computational speech segregation to improve speech intelligibility. AB - Computational speech segregation attempts to automatically separate speech from noise. This is challenging in conditions with interfering talkers and low signal to-noise ratios. Recent approaches have adopted deep neural networks and successfully demonstrated speech intelligibility improvements. A selection of components may be responsible for the success with these state-of-the-art approaches: the system architecture, a time frame concatenation technique and the learning objective. The aim of this study was to explore the roles and the relative contributions of these components by measuring speech intelligibility in normal-hearing listeners. A substantial improvement of 25.4 percentage points in speech intelligibility scores was found going from a subband-based architecture, in which a Gaussian Mixture Model-based classifier predicts the distributions of speech and noise for each frequency channel, to a state-of-the-art deep neural network-based architecture. Another improvement of 13.9 percentage points was obtained by changing the learning objective from the ideal binary mask, in which individual time-frequency units are labeled as either speech- or noise-dominated, to the ideal ratio mask, where the units are assigned a continuous value between zero and one. Therefore, both components play significant roles and by combining them, speech intelligibility improvements were obtained in a six-talker condition at a low signal-to-noise ratio. PMID- 29763460 TI - Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling. AB - The HMG-CoA reductase inhibitors, statins, have been used as lipid lowering drugs for decades and several epidemiological studies suggest statin usage correlates with a decreased incidence of cancer specific mortality in patients. However, the mechanism of this mortality benefit remains unclear. Here, we demonstrate that statin drug lipophilicity and affinity for its target enzyme, HMGCR, determine their growth suppressive potency against various tumor cell lines. The lipophilic atorvastatin decreases cancer cell proliferation and survival in vitro. Statin sensitivity coincided with Ras localization to the cytosol instead of the membrane, consistent with a decrement in prenylation. To investigate signaling pathways that may be involved with sensitivity to statin therapy, we employed inhibitors of the PI3K-Akt and Mek-Erk signaling cascades. We found that inhibition of PI3K signaling through Akt potentiated statin sensitivity of breast cancer cells in vitro and in co-culture with primary human hepatocytes. The same effect was not observed with inhibition of Mek signaling through Erk. Moreover, the sensitivity of breast cancer cells to atorvastatin-mediated growth suppression correlated with a decrease in EGF-mediated phosphorylation of Akt. As an increase in Akt activity has been shown to be involved in the metastasis and metastatic outgrowth of many cancer types (including breast), these data suggest a mechanism by which statins may reduce cancer specific mortality in patients. PMID- 29763461 TI - Night shift work exposure profile and obesity: Baseline results from a Chinese night shift worker cohort. AB - AIMS: This study aimed to evaluate the associations between types of night shift work and different indices of obesity using the baseline information from a prospective cohort study of night shift workers in China. METHODS: A total of 3,871 workers from five companies were recruited from the baseline survey. A structured self-administered questionnaire was employed to collect the participants' demographic information, lifetime working history, and lifestyle habits. Participants were grouped into rotating, permanent and irregular night shift work groups. Anthropometric parameters were assessed by healthcare professionals. Multiple logistic regression models were used to evaluate the associations between night shift work and different indices of obesity. RESULTS: Night shift workers had increased risk of overweight and obesity, and odds ratios (ORs) were 1.17 (95% CI, 0.97-1.41) and 1.27 (95% CI, 0.74-2.18), respectively. Abdominal obesity had a significant but marginal association with night shift work (OR = 1.20, 95% CI, 1.01-1.43). A positive gradient between the number of years of night shift work and overweight or abdominal obesity was observed. Permanent night shift work showed the highest odds of being overweight (OR = 3.94, 95% CI, 1.40-11.03) and having increased abdominal obesity (OR = 3.34, 95% CI, 1.19-9.37). Irregular night shift work was also significantly associated with overweight (OR = 1.56, 95% CI, 1.13-2.14), but its association with abdominal obesity was borderline (OR = 1.26, 95% CI, 0.94-1.69). By contrast, the association between rotating night shift work and these parameters was not significant. CONCLUSION: Permanent and irregular night shift work were more likely to be associated with overweight or abdominal obesity than rotating night shift work. These associations need to be verified in prospective cohort studies. PMID- 29763463 TI - Effects of lanthanum and acid rain stress on the bio-sequestration of lanthanum in phytoliths in germinated rice seeds. AB - REEs in the environment can be absorbed by plants and sequestered by plant phytoliths. Acid rain can directly or indirectly affect plant physiological functions. Currently, the effects of REEs and acid rain on phytolith-REEs complex in plants are not yet fully understood. In this study, a high-silicon accumulation crop, rice (Oryza sativa L.), was selected as a representative of plants, and orthogonal experiments were conducted under various levels of lanthanum [La(III)] and pH. The results showed that various La(III) concentrations could significantly improve the efficiency and sequestration of phytolith La(III) in germinated rice seeds. A pH of 4.5 promoted phytolith La(III) sequestration, while a pH of 3.5 inhibited sequestration. Compared with the single treatment with La(III), the combination of La(III) and acid rain inhibited the efficiency and sequestration of phytolith La(III). Correlation analysis showed that the efficiency of phytolith La(III) sequestration had no correlation with the production of phytolith but was closely correlated with the sequestration of phytolith La(III) and the physiological changes of germinated rice seeds. Phytolith morphology was an important factor affecting phytolith La(III) sequestration in germinated rice seeds, and the effect of tubes on sequestration was more significant than that of dumbbells. This study demonstrated that the formation of the phytolith and La(III) complex could be affected by exogenous La(III) and acid rain in germinated rice seeds. PMID- 29763464 TI - Directional virtual backbone based data aggregation scheme for Wireless Visual Sensor Networks. AB - Data gathering is a fundamental task in Wireless Visual Sensor Networks (WVSNs). Features of directional antennas and the visual data make WVSNs more complex than the conventional Wireless Sensor Network (WSN). The virtual backbone is a technique, which is capable of constructing clusters. The version associating with the aggregation operation is also referred to as the virtual backbone tree. In most of the existing literature, the main focus is on the efficiency brought by the construction of clusters that the existing methods neglect local-balance problems in general. To fill up this gap, Directional Virtual Backbone based Data Aggregation Scheme (DVBDAS) for the WVSNs is proposed in this paper. In addition, a measurement called the energy consumption density is proposed for evaluating the adequacy of results in the cluster-based construction problems. Moreover, the directional virtual backbone construction scheme is proposed by considering the local-balanced factor. Furthermore, the associated network coding mechanism is utilized to construct DVBDAS. Finally, both the theoretical analysis of the proposed DVBDAS and the simulations are given for evaluating the performance. The experimental results prove that the proposed DVBDAS achieves higher performance in terms of both the energy preservation and the network lifetime extension than the existing methods. PMID- 29763462 TI - The annotation of repetitive elements in the genome of channel catfish (Ictalurus punctatus). AB - Channel catfish (Ictalurus punctatus) is a highly adaptive species and has been used as a research model for comparative immunology, physiology, and toxicology among ectothermic vertebrates. It is also economically important for aquaculture. As such, its reference genome was generated and annotated with protein coding genes. However, the repetitive elements in the catfish genome are less well understood. In this study, over 417.8 Megabase (MB) of repetitive elements were identified and characterized in the channel catfish genome. Among them, the DNA/TcMar-Tc1 transposons are the most abundant type, making up ~20% of the total repetitive elements, followed by the microsatellites (14%). The prevalence of repetitive elements, especially the mobile elements, may have provided a driving force for the evolution of the catfish genome. A number of catfish-specific repetitive elements were identified including the previously reported Xba elements whose divergence rate was relatively low, slower than that in untranslated regions of genes but faster than the protein coding sequences, suggesting its evolutionary restrictions. PMID- 29763465 TI - Expression of the three components of linear ubiquitin assembly complex in breast cancer. AB - Proteins belonging to the linear ubiquitin assembly complex (LUBAC) are believed to be important in tumorigenesis. LUBAC has been demonstrated to be composed of RBCK1, RNF31 and SHARPIN. The aim of this study was to explore all members of the LUBAC complex as novel biomarkers in breast cancer. We have already reported that RNF31 mRNA levels are higher in breast cancer samples compared to adjacent non tumor tissue. In this study we extend these findings by demonstrating that the mRNA levels of RBCK1 and SHARPIN are also higher in tumors compared to adjacent non-tumor tissue in the same cross sectional study of samples (p < 0.001). In addition, up-regulated mRNA expression of all three members of the LUBAC complex displayed high predictive value in distinguishing tumor tissues from adjacent non tumor tissue as determined by ROC curve analysis. Furthermore, we investigated whether there is an association between the mRNA and protein expression levels of RBCK1, RNF31 and SHARPIN and clinicopathological parameters including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) status and found that RNF31 protein is significantly higher in ERalpha-negative tumors than ERalpha-positive tumors (p = 0.034). Collectively, our findings indicate that up-regulated mRNA expression of RNF31, RBCK1 and SHARPIN could potentially be diagnostic biomarkers of breast cancer and RNF31 might be a drug target for ERalpha-negative breast cancers. PMID- 29763466 TI - The enhancement effect of estradiol on contextual fear conditioning in female mice. AB - Several studies have reported regulatory effects of estrogens on fear conditioning in female rodents. However, these studies used different doses, durations, and/or administration methods, and reported inconsistent results. To clarify the effect of estrogen on fear conditioning, we investigated the effects of different doses and durations of estradiol administration on freezing behavior during contextual fear conditioning in ovariectomized (OVX) mice. In Experiment 1, OVX ICR mice received a single subcutaneous (s.c.) injection of either oil vehicle (control, 0.1 ml sesame oil) or varied doses (0.5 MUg/0.1 ml, 5 MUg/0.1 ml, or 50 MUg/0.1 ml) of 17beta-estradiol-3-benzoate (EB). Fear conditioning was conducted two days post-EB treatment, and the mice were tested for the learned fear response the following day. In Experiment 2, OVX female mice received an s.c. implantation of a Silastic capsule (I.D. 1.98 * 20.0 mm) containing either vehicle or varied doses (0.05 MUg/0.1 ml, 0.5 MUg/0.1 ml, 5 MUg/0.1 ml, 50 MUg/0.1 ml) of EB. Two weeks after implantation, fear conditioning was conducted. During the tests conducted 24 h after conditioning, the high dose EB group showed longer freezing times in both experiments, and lower locomotor activity compared to the control or lower dose groups. In Experiment 3, serum estradiol concentrations of the mice that were treated like those in Experiment 2, were measured; the serum levels of estradiol increased linearly according to the dose of EB administered. The results suggest that mice treated with a high dose of EB exhibit enhanced fear learning, regardless of treatment duration. As a woman's vulnerability to emotional disorders increases in the peripregnancy period, during which estrogen levels are high, the results from the high-dose EB groups may be important for understanding the hormonal mechanisms involved in these disorders. PMID- 29763467 TI - Natural disease history of the dy2J mouse model of laminin alpha2 (merosin) deficient congenital muscular dystrophy. AB - Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice. PMID- 29763468 TI - Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis. AB - Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4-88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66-5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99-6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19-2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis. PMID- 29763469 TI - Rapid diagnosis of bloodstream infections in the critically ill: Evaluation of the broad-range PCR/ESI-MS technology. AB - Bloodstream infection (BSI) and associated sepsis represent a major source of mortality in industrialized countries. Prompt treatment with targeted antibiotics affects both the financial impact and the clinical outcome of BSI: every hour gained in initiating the correct antimicrobial therapy significantly increases the probability of patient survival. However, the current standard-of-care, which depends on blood culture-based diagnosis, are often unable to provide such a fast response. Fast and sensitive molecular techniques for the detection of sepsis related pathogens from primary blood samples are strongly needed. The aim of this study was to assess the usefulness of the IRIDICA BAC BSI Assay, a PCR/ESI-MS based technology for the early diagnosis of bloodstream infections from primary blood samples in critical patients. This evaluation has been performed by comparison with the traditional culture-based methods. The study was performed on a total of 300 prospective whole blood specimens obtained from patients suspected of sepsis, admitted to enrolling ER units from The Greater Romagna Area. The overall concordance between the two techniques was of 86%, with a calculated sensitivity of 76% and an assay specificity of 90%. The clinical significance of discrepant results was evaluated reviewing the patients' clinical records and the results of additional relevant microbiological tests. The data here obtained support the ability of the IRIDICA BAC BSI Assay to identify a broad range of bacteria directly from primary whole blood samples, within eight hours. This might allow a timely administration of a suitable treatment. PMID- 29763470 TI - The influence of spinal-pelvic parameters on the prevalence of endplate Modic changes in degenerative thoracolumbar/lumbar kyphosis patients. AB - BACKGROUND: The typical degeneration of the vertebral endplate shown in MRI imaging is Modic change. The aim of this study was to observe the distribution of the Modic changes of vertebral endplate in degenerative thoracolumbar/lumbar kyphosis (DTK/LK) patients and analyse the correlation between spinal-pelvic parameters and Modic changes. METHODS: The imaging data of 58 patients diagnosed with DTK/LK (coronal Cobb angle<10 degrees with sagittal imbalance) in our hospital from March 2016 to May 2017 were reviewed retrospectively. Observe the prevalence, type and distribution characteristics of Modic changes occurred at the vertebral endplate from T10 to S1;analyse the correlation between Modic changes and disc degeneration, the sagittal vertical axis (SVA), thoracic kyphosis (TK), thoracolumbar kyphosis (TLK), lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT) and pelvic incidence (PI). RESULTS: Of the 928 intervertebral endplates from 58 patients, Modic changes occurred at 90 endplates (9.7%) of 30 patients (51.7%). 5 endplates (0.5%) of 3 patients (5.2%) were classified as type I, 68 endplates (7.3%) of 25 patients (43.1%) as type II, 17 endplates (1.8%) of 9 patients (15.5%) as type III. The location of the degenerative endplates: 2 (2.2%) superior and inferior endplates of L1, 3 (3.3%) inferior endplates of T11and T12, 4 (4.4%) superior endplates of L2, 6 (6.7%) inferior endplates of L2 and L4, 8 (8.9%) superior endplates of S1, 9 (10%) superior endplates of L3, 11 (12.2%) inferior endplates of L3 and L5 and superior endplates of L4, 12 (13.3%) superior endplates of L5. Modic changes were significantly correlated with intervertebral disc degeneration (r = 0.414, p<0.01); the amount of Modic changes were significantly correlated with LL (r = 0.562, p = 0.012), SS (r = -0.46, p = 0.048), PT (r = 0.516, p = 0.024). CONCLUSIONS: Most of the Modic changes of vertebral endplates in DTK/LK patients are type II which are prevalently located at L3/4, L4/5 and L5/S1. The Modic changes of vertebral endplates were found to be significantly correlated with disc degeneration, LL, SS, and PT. PMID- 29763472 TI - P values in display items are ubiquitous and almost invariably significant: A survey of top science journals. AB - P values represent a widely used, but pervasively misunderstood and fiercely contested method of scientific inference. Display items, such as figures and tables, often containing the main results, are an important source of P values. We conducted a survey comparing the overall use of P values and the occurrence of significant P values in display items of a sample of articles in the three top multidisciplinary journals (Nature, Science, PNAS) in 2017 and, respectively, in 1997. We also examined the reporting of multiplicity corrections and its potential influence on the proportion of statistically significant P values. Our findings demonstrated substantial and growing reliance on P values in display items, with increases of 2.5 to 14.5 times in 2017 compared to 1997. The overwhelming majority of P values (94%, 95% confidence interval [CI] 92% to 96%) were statistically significant. Methods to adjust for multiplicity were almost non-existent in 1997, but reported in many articles relying on P values in 2017 (Nature 68%, Science 48%, PNAS 38%). In their absence, almost all reported P values were statistically significant (98%, 95% CI 96% to 99%). Conversely, when any multiplicity corrections were described, 88% (95% CI 82% to 93%) of reported P values were statistically significant. Use of Bayesian methods was scant (2.5%) and rarely (0.7%) articles relied exclusively on Bayesian statistics. Overall, wider appreciation of the need for multiplicity corrections is a welcome evolution, but the rapid growth of reliance on P values and implausibly high rates of reported statistical significance are worrisome. PMID- 29763471 TI - Importance of extracellular matrix and growth state for the EA.hy926 endothelial cell response to polyunsaturated fatty acids. AB - Consumption of different PUFAs (polyunsaturated fatty acids) can induce functional changes in blood vessels via endothelial cells, which interact with dietary factors in the circulation. The basement membrane that separates the endothelium from the smooth muscle cells of the medial layer can also influence the functional state of endothelial cells. However, the effect of basement membrane on the endothelial response to dietary PUFAs in relation to growth state (e.g. proliferation versus quiescence) has never been investigated. We therefore compared the viability (CCK kit) and proliferation (bromodeoxyuridine incorporation) of EA.hy926 endothelial cells grown on Matrigel or collagen versus non-coated plates. EA.hy926 viability and proliferation were also assessed after treatment with 0-150 MUM of PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. Our study showed that only cells grown on Matrigel-coated plates reached quiescence after becoming confluent with a decreased level of MCM2 and p-cyclin D1 (T286), increased levels of p27kip1 and a low level of apoptosis and senescence. AA, EPA and DHA decreased the viability and proliferation of subconfluent cells grown on plastic dishes in a dose-dependent manner, while the presence of Matrigel made the cells resistant to these adverse effects. Confluent cell viability was less sensitive to higher concentrations of AA, EPA and DHA than subconfluent cells, and a significant increase in caspase-3 cleavage was only observed in confluent cells treated with DHA. Higher concentrations of AA, EPA and DHA suppressed DNA synthesis by both subconfluent and confluent cells, while precursor C18 PUFAs (LA and ALA) had no negative effects on viability and proliferation. Our study is the first to show that extracellular matrix and growth state are important factors in the EA.hy926 cell response to PUFAs, and that the mechanisms by which individual PUFAs operate may be growth state dependent. PMID- 29763473 TI - Maternal folate genes and aberrant DNA hypermethylation in pediatric acute lymphoblastic leukemia. AB - BACKGROUND: There is evidence that maternal genotypes in folate-related genes are associated with pediatric acute lymphoblastic leukemia (ALL) independent of offspring genotype. We evaluated the relationship between maternal genotypes in methionine synthase (MTR) and DNA methylation status in ALL to better characterize the molecular mechanism underlying this association. PROCEDURE: We obtained bone marrow samples from 51 patients with ALL at diagnosis and from 6 healthy donors. Mothers of patients provided a saliva sample and were genotyped at 11 tagSNPs in MTR. DNA methylation was measured in bone marrow mononuclear cells of patients and six healthy marrow donors. We used hierarchical clustering to identify patients with a hypermethylator phenotype based on 281 differentially methylated promoter CpGs. We used logistic regression to estimate the effects of maternal genotype on the likelihood of DNA hypermethylation in ALL and Ingenuity Pathway Analysis to identify networks enriched for differentially methylated genes. RESULTS: Twenty-two cases (43%) demonstrated promoter hypermethylation, which was more frequent among those with ETV6-RUNX1 fusion and initial white blood cell count < 50 x 109/L. Maternal rs12759827 was associated with aberrant DNA methylation (odds ratio [OR] 4.67, 95% confidence interval 1.46-16.31); non significantly elevated ORs were observed for all other SNPs. Aberrantly methylated promoter CpGs aligned to genes with known cancer-related functions. DISCUSSION: Maternal folate metabolic genotype may be associated with DNA methylation patterns in ALL in their offspring. Therefore, the effect of maternal genotypes on ALL susceptibility may act through aberrant promoter methylation, which may contribute to the in utero origins of ALL. PMID- 29763474 TI - Early prenatal alcohol exposure alters imprinted gene expression in placenta and embryo in a mouse model. AB - Prenatal alcohol exposure (PAE) can harm the embryonic development and cause life long consequences in offspring's health. To clarify the molecular mechanisms of PAE we have used a mouse model of early alcohol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first eight days of gestation (GD 0.5-8.5). Owing to the detected postnatal growth-restricted phenotype in the offspring of this mouse model and both prenatal and postnatal growth restriction in alcohol-exposed humans, we focused on imprinted genes Insulin-like growth factor 2 (Igf2), H19, Small Nuclear Ribonucleoprotein Polypeptide N (Snrpn) and Paternally expressed gene 3 (Peg3), which all are known to be involved in embryonic and placental growth and development. We studied the effects of alcohol on DNA methylation level at the Igf2/H19 imprinting control region (ICR), Igf2 differentially methylated region 1, Snrpn ICR and Peg3 ICR in 9.5 embryonic days old (E9.5) embryos and placentas by using MassARRAY EpiTYPER. To determine alcohol-induced alterations globally, we also examined methylation in long interspersed nuclear elements (Line-1) in E9.5 placentas. We did not observe any significant alcohol-induced changes in DNA methylation levels. We explored effects of PAE on gene expression of E9.5 embryos as well as E9.5 and E16.5 placentas by using quantitative PCR. The expression of growth promoter gene Igf2 was decreased in the alcohol-exposed E9.5 and E16.5 placentas. The expression of negative growth controller H19 was significantly increased in the alcohol-exposed E9.5 embryos compared to controls, and conversely, a trend of decreased expression in alcohol-exposed E9.5 and E16.5 placentas were observed. Furthermore, increased Snrpn expression in alcohol-exposed E9.5 embryos was also detected. Our study indicates that albeit no alterations in the DNA methylation levels of studied sequences were detected by EpiTYPER, early PAE can affect the expression of imprinted genes in both developing embryo and placenta. PMID- 29763477 TI - Gone fishing: a unique histologic pattern in cutaneous angiosarcoma. AB - Cutaneous angiosarcoma is a rare but aggressive vascular malignancy that can present a diagnostic challenge due to a wide variety of clinical appearances and histologic features. Final diagnosis traditionally is yielded by corroborating the histologic and immunohistochemical findings with the clinical presentation; however, a histologic feature known as "fish in the creek," which consists of free-floating or tufted pleomorphic spindle cells within the vascular lumen, may be an additional diagnostic clue. In this study, we aimed to determine the diagnostic utility of this finding in cutaneous angiosarcoma. Our results suggest that "fish in the creek" has the potential to be an additional useful diagnostic tool for an otherwise challenging and deceptive malignancy. PMID- 29763475 TI - TRESK background potassium channel is not gated at the helix bundle crossing near the cytoplasmic end of the pore. AB - Two-pore domain K+ channels (K2P) are responsible for background K+ currents and regulate the resting membrane potential and cellular excitability. Their activity is controlled by a large variety of physicochemical factors and intracellular signaling pathways. The majority of these effects converge on the intracellular C terminus of the channels, resulting in the modification of the gating at the selectivity filter. Another gating mechanism, the activation gate at the helix bundle crossing is also well documented in other K+ channel families, however, it remains uncertain whether this type of gating is functional in K2P channels. The regulation of TWIK-related spinal cord K+ channel (TRESK) is different from the other K2P channels. Regulatory factors acting via the C-terminus are not known, instead channel activity is modified by the phosphorylation/dephosphorylation of the unusually long intracellular loop between the 2nd and 3rd transmembrane segments. These unique structural elements of the regulation lead us to examine channel gating at the bundle crossing region. Ba2+ was applied to the intracellular side of excised membrane patches and the characteristics of the channel block were determined. We compared the kinetics of the development of Ba2+ block when the channels were phosphorylated (inhibited) or dephosphorylated (activated) and also in different mutants mimicking the two functional states. Neither the phosphorylation/dephosphorylation nor the point mutations influenced the development of Ba2+ block, suggesting that the conformational changes of the bundle crossing region do not contribute to the phosphorylation-dependent gating of TRESK. PMID- 29763476 TI - Drug-induced linear IgA bullous dermatosis in a patient with a vancomycin impregnated cement spacer. AB - Linear IgA bullous dermatosis (LABD) is an autoimmune blistering rash caused by IgA autoantibodies against the epidermal basement membrane zone. It commonly is drug induced, often in association with systemic vancomycin. We report a case of a previously healthy 77-year-old man who developed a diffuse macular rash and hemorrhagic bullae on the left leg 10 days after placement of a vancomycin impregnated cement spacer (VICS) during a revision knee arthroplasty and initiation of postoperative treatment with intravenous (IV) vancomycin. The lesions initially were limited to the leg in which the hardware was placed, but the patient later developed painful palmoplantar and oropharyngeal blisters as well as edematous, erythematous plaques on the back and buttocks. A punch biopsy from a lesion on the left thigh revealed neutrophil-rich subepidermal bullae, and immunofluorescence revealed linear IgA and C3 deposition along the dermoepidermal junction, confirming a diagnosis of LABD. This report illustrates the importance of considering antibiotic-impregnated cement spacers, which frequently are used to manage prosthetic joint infections, as potential culprits in patients with cutaneous eruptions. PMID- 29763478 TI - A case of pustular psoriasis of pregnancy with positive maternal-fetal outcomes. AB - Pustular psoriasis of pregnancy (PPP), also known as impetigo herpetiformis, is a rare condition that affects women in the third trimester of pregnancy through the postpartum period. The relative infrequency of PPP presents both clinical and pathologic challenges in the diagnosis and management of this condition. We report a case of a woman who presented at 32 weeks' gestation with a generalized rash demonstrating clinicopathologic features consistent with PPP. Based on prior reports of adverse maternal-fetal outcomes in PPP, coordinated efforts from our patient's dermatologic and obstetric teams ensured positive outcomes for the patient and the neonate. PMID- 29763479 TI - Facial involvement in progressive macular hypomelanosis. AB - Progressive macular hypomelanosis (PMH) is a skin disorder that historically has been described as having a predominantly truncal distribution. We report 4 adult cases of PMH with facial involvement. The diagnosis was made for all 4 patients after excluding other hypopigmented diseases. This report underscores the importance of considering PMH as part of the differential for hypopigmented lesions on the face. PMID- 29763480 TI - Spontaneous regression of Merkel cell carcinoma. AB - A 96-year-old woman presented with a rapidly enlarging lesion overlying the suprasternal notch. The lesion originated as a small, erythematous, scaly macule that rapidly increased in size over 8 weeks and became an ulcerated nodule measuring 5 cm in diameter and 4.5 cm in thickness. A 4-mm punch biopsy showed a poorly differentiated tumor with cells that were positive for CAM 5.2 and cytokeratin 20 in a dotlike paranuclear pattern and negative for cytokeratin 5/6, human melanoma black 45, and leukocyte common antigen. Two weeks after the punch biopsy, the lesion noticeably decreased in size, and within 8 weeks of the biopsy the tumor had completely resolved with no further intervention. Regression of Merkel cell carcinoma (MCC) is a very rare event, with as few as 30 cases reported. The mechanism of this phenomenon remains unclear; however, T-cell mediated immunity and apoptosis appear to play a major role. PMID- 29763481 TI - Cutting edge technology in dermatology: virtual reality and artificial intelligence. PMID- 29763482 TI - Disseminated vesicles and necrotic papules. PMID- 29763483 TI - Melanoma in US Hispanics: recommended strategies to reduce disparities in outcomes. AB - Cutaneous melanoma is the most fatal form of skin cancer and presents a considerable public health concern in the United States. Although the age adjusted incidence of melanoma among US Hispanics is lower than that of non Hispanic whites (NHWs), Hispanics who are diagnosed with melanoma are more likely to present with thicker primary tumors, metastatic disease, and lower 5-year melanoma-specific survival rates than NHWs. Melanoma risk factors and reasons for late presentation among Hispanics are not completely understood. In this review, the epidemiology and clinical presentation of melanoma in Hispanics is summarized, and recommendations for a research agenda to advance understanding of this disease in the most rapidly growing segment of the US population is provided. PMID- 29763484 TI - Perianal condyloma acuminatum-like plaque. PMID- 29763485 TI - What's eating you? Ixodes tick and related diseases, part 2: diagnosis and treatment of regional tick-borne diseases. AB - The Ixodes tick is an important arthropod vector in the transmission of human disease. Although Lyme disease is the most prevalent zoonosis transmitted by Ixodes ticks, other less common diseases may be encountered, including human granulocytic anaplasmosis, babesiosis, Powassan virus infection, tick-borne encephalitis, Borrelia miyamotoi disease, and tick paralysis. In part 2 of this review, disease presentation, diagnosis, and treatment of these less commonly encountered tick-borne diseases are discussed. PMID- 29763486 TI - Update on noninvasive body contouring techniques. AB - Noninvasive body contouring is the fastest growing area of cosmetic dermatology. It entails the use of specific technology to optimize the definition, smoothness, and shape of the human body in a safe and effective manner. There are currently 4 leading modalities used for noninvasive body contouring: cryolipolysis, radiofrequency, high-intensity focused ultrasound, and laser therapy. This article provides an overview of each modality. PMID- 29763487 TI - Painful violaceous nodule with peripheral hyperpigmentation. PMID- 29763488 TI - Pigmented peduncule on the leg. PMID- 29763489 TI - Intralymphatic histiocytosis treated with intralesional triamcinolone acetonide and pressure bandage. AB - Intralymphatic histiocytosis is a rare disorder associated with a variety of inflammatory conditions. We report the case of an 89-year-old woman with a history of a right knee replacement and a ruptured popliteal cyst who developed an erythematous indurated plaque over the surgical scar. Histopathology revealed fibrosis, chronic inflammation, and histiocytes within the lymphatics consistent with intralymphatic histiocytosis. The plaque flattened following intralesional injection of triamcinolone acetonide 10 mg/cc*1.6 cc once monthly for 2 consecutive months and application of a pressure bandage, with no recurrence after 4 months. This treatment may be useful for recalcitrant disease. PMID- 29763490 TI - Climate change and skin disease. AB - Despite commanding essentially universal scientific consensus, climate change remains a divisive and poorly understood topic in the United States. Familiarity with this subject is not just for climate scientists. The impact of climate change on human morbidity and mortality may be considerable; thus, physicians also should be knowledgeable in this realm. Climate change science can seem opaque and inferential, creating fertile ground for political polemics and undoubtedly contributing to confusion among the general public. This puts physicians in a pivotal position to facilitate a practical understanding of climate change in the public sphere by discussing changes in disease patterns and their possible relationship to a changing climate. This article provides a background on climate change for dermatologists and highlights how climate change may impact the management of skin disease across the United States. PMID- 29763491 TI - Penile squamous cell carcinoma with urethral extension treated with Mohs micrographic surgery. AB - Penile squamous cell carcinoma (SCC) with considerable urethral extension is uncommon and difficult to manage. It often is resistant to less invasive and nonsurgical treatments and frequently results in partial or total penectomy, which can lead to cosmetic disfigurement, functional issues, and psychological distress. We report a case of penile SCC in situ with considerable urethral extension with a focus of cells suspicious for moderately well-differentiated and invasive SCC that was treated with Mohs micrographic surgery (MMS). A review of the literature on penile tumors treated with MMS also is provided. PMID- 29763492 TI - Perianal extramammary Paget disease treated with topical imiquimod and oral cimetidine. AB - Extramammary Paget disease (EMPD) is a rare intraepithelial adenocarcinoma. The current mainstay of treatment is wide local excision. We present the case of a 56 year-old woman with perianal EMPD that recurred 4 years after initial treatment with wide local excision with Mohs micrographic surgery tissue processing of marginal tissue. Upon recurrence with anal canal involvement, the patient was treated with a 16-week combination course of topical imiquimod and oral cimetidine. There is growing evidence to support both the use of topical imiquimod for the treatment of EMPD as well as the antioncogenic effects of oral cimetidine. We present this case of primary perianal EMPD to highlight an alternative treatment regimen for poor surgical candidates. PMID- 29763493 TI - Clinical Outcomes of Vertical Distraction Osteogenesis for Dental Implantation: A Systematic Review and Meta-Analysis. AB - PURPOSE: The aim of this study was to evaluate the clinical outcomes of vertical distraction osteogenesis (VDO) for patients with vertically deficient alveolar ridges in terms of (1) the cumulative implant survival rate, (2) bone gain, (3) bone resorption before and after implant insertion, and (4) complications. MATERIALS AND METHODS: An electronic search was conducted via MEDLINE (PubMed), EMBASE, and the Cochrane Library, complemented by manual searches, to identify eligible clinical studies of VDO before dental implantation. Two reviewers independently performed the study selection and data extraction. The implant survival rate, mean bone gain, and bone resorption amount, with 95% confidence intervals (CIs), were pooled separately. A random-effects model or fixed-effects model was chosen based on the heterogeneity. A funnel plot and Egger's test were performed to identify publication bias. RESULTS: Of the 4,391 records after removal of duplicates, 113 full-text articles were obtained for further analysis, and 12 articles were ultimately included in the analysis. Two studies were defined as low quality. The estimated cumulative implant survival rate was 98.00% (95% CI: 96.02% to 99.40%), with a mean follow-up of 3.52 years. The bone gain was 7.92 mm (95% CI: 6.27 to 9.57 mm), with a range from 4 to 20 mm, and the level of bone relapse between the end of the distraction and the implant insertion was 0.97 mm (95% CI: 0.68 to 1.26 mm). The complication rate was high, with rates of 0.728 per site and 0.821 per patient. The most common major complication was basal bone fracture, with a rate of 2.27%, and the most common minor complication was displacement of the transport segments, with a rate of 16.71%. CONCLUSION: Vertical alveolar defects could be rehabilitated successfully with distraction osteogenesis, and the implant placed in the distraction sites showed a high cumulative survival rate. However, the high complication rate necessitates caution. Due to the observed heterogeneity, the results of this meta analysis should be interpreted with caution. PMID- 29763494 TI - Expression Levels of Semaphorins 3A, 3B, 4A, and 4D on Human Peri-implantitis. AB - PURPOSE: To evaluate the gene expression levels of semaphorins 3A, 3B, 4A, and 4D in both healthy and diseased implants. MATERIALS AND METHODS: Subjects with peri implantitis presented clinical attachment loss, probing depth >= 5 mm, bleeding on probing and/or suppuration, and radiographic bone loss > 4 mm. Peri-implant tissue biopsy specimens were sampled for analysis of the mRNA expression levels for semaphorins 3A, 3B, 4A, and 4D. A real-time polymerase chain reaction was performed, and the gene expression levels of semaphorins in relation to the housekeeping gene were analyzed by using the nonparametric Mann-Whitney test (P < .05). RESULTS: Thirty-five subjects (16 men, 19 women; mean age: 54.12 +/- 2.34 years) with implant-supported restorations, using screw-shaped dental implants with internal or external hexagon were enrolled in this study. Higher levels of semaphorins 3A and 4D were detected in the peri-implantitis compared with the healthy tissues (P = .0011 and P = .0404, respectively), whereas Sem4A levels were significantly higher in the control group (P < .0001). Differences between groups in the expression levels of Sem3B were not significant. CONCLUSION: Advanced peri-implantitis lesions showed higher levels of gene expression for Sem3A and Sem4D and lower levels of Sem4A in comparison to tissues obtained from a healthy dental implant. PMID- 29763495 TI - Early Response of Fibroblasts and Epithelial Cells to Pink-Shaded Anodized Dental Implant Abutments: An In Vitro Study. AB - PURPOSE: This research aimed to assess whether pink-shaded anodized surfaces could enhance the adhesion of soft tissue cells compared with untreated machined titanium surfaces. MATERIALS AND METHODS: Two types of Ti-Al-V titanium samples were prepared: machined titanium (Ti) and anodized titanium (AnoTi). The microstructure was studied by means of a scanning electron microscope. X-ray photoelectron spectroscopy (XPS) was carried out as well. The wetting properties were investigated by the sessile drop technique with water and diiodomethane. To investigate the biologic response in vitro, the epithelial cell line HaCaT and the fibroblastic cell line NHDF were used. Cell adhesion, morphology, and proliferation were evaluated. RESULTS: The microstructure of the tested surfaces was irregularly smooth for both types of samples with no relevant morphologic differences. The XPS and HR-XPS performed on the AnoTi samples confirmed the presence of Ti, O, and C, along with Ti oxides. Following the optical contact angle measurements, the anodization process induced a slight transition toward the hydrophobic regime. Consequently, the surface free energy values differed significantly between the anodized and the machined samples. Anodized Ti significantly increased the adhesion and proliferation of both epithelial cells and fibroblasts when compared with the pristine Ti controls. CONCLUSION: Compared with the clinical standard, anodized surfaces could enhance the adhesion of the two major cell types within the peri-implant soft tissues, which makes pink anodization a promising option for implant dentistry. PMID- 29763496 TI - Comparison of Marginal Bone Loss Between Implants with Internal and External Connections: A Systematic Review. AB - PURPOSE: The objective of this systematic review was to compare the loss of marginal bone between implants with internal and external connections by analyzing results reported in studies published after 2010. MATERIALS AND METHODS: A literature search in MEDLINE with the keywords "dental implant connections, external internal implant connection, bone loss implant designs, internal and external connection implant studies in humans" was conducted. Clinical trials on human beings, comparing both connections and published in English, from 2010 to 2016 were selected. Their methodologic quality was assessed using the Jadad scale. RESULTS: From the initial search, 415 articles were obtained; 32 were chosen as potentially relevant based on their titles and abstracts. Among them, only 10 finally met the inclusion criteria. A total of 1,523 patients with 3,965 implants were analyzed. Six out of 10 studies observed that internal connections showed significantly less bone loss compared with external connections. The remaining four articles did not find statistically significant differences between the two connections. CONCLUSION: According to this systematic review and considering its limitation due to the degree of heterogeneity between the included studies, both internal and external connections present high survival rates. To assess whether marginal bone loss differs significantly between the two connections, more homogenous clinical studies are needed with identical implant characteristics, larger samples, and longer follow-up periods. Studies included in this review and characterized by long-term follow-ups showed that the external connection is a reliable connection on a long-term basis. PMID- 29763497 TI - Additively Manufactured Titanium and Cobalt-Chromium Implant Frameworks: Fit and Effect of Ceramic Veneering. AB - PURPOSE: The purpose of this study was to evaluate the fit of additively manufactured cobalt-chromium and titanium and CNC-milled titanium frameworks before and after ceramic veneering. MATERIALS AND METHODS: Ten stone casts simulating an edentulous maxilla provided with six abutment analogs were produced. For each stone cast, one additively manufactured cobalt-chromium framework (AM CoCr) and one titanium framework (AM Ti) were fabricated. The fit was analyzed with a coordinate measuring machine in three dimensions (x, y, and z axes) using best-fit virtual matching of center point coordinates, before and after ceramic veneering. CNC-milled titanium frameworks (CNC Ti) and earlier results from CNC-milled cobalt-chromium frameworks (CNC CoCr) were used for comparison. RESULTS: All frameworks presented minor misfit before and after veneering in the horizontal plane (x- and y-axes) between 2.9 and 13.5 MUm and in the vertical plane (z-axis) between 1.6 and 5.4 MUm. Ceramic veneering affected the fit of all groups of frameworks. Both AM Ti and AM CoCr presented significantly smaller distortion in the vertical plane compared with the CNC milled frameworks. CONCLUSION: Implant-supported frameworks can be produced in either Ti or CoCr using either CNC milling or additive manufacturing with a fit well within the range of 20 MUm in the horizontal plane and 10 MUm in the vertical plane. The fit of frameworks of both materials and production techniques are affected by the ceramic veneering procedure to a small extent. PMID- 29763498 TI - Effect of Avocado/Soybean Unsaponifiables (ASU) on Osseointegration in Rats with Experimental Arthritis. AB - PURPOSE: To evaluate the influence of the use of avocado/soybean unsaponifiables (ASU) on osseointegration of implants in animals with experimental arthritis. MATERIALS AND METHODS: One hundred twenty rats were randomly divided into four groups: CTR, healthy animals and saline solution administration; ASU, healthy animals and ASU administration; ART, arthritic animals and saline solution administration; and ART/ASU, arthritic animals and ASU administration. The solutions were administered daily by gavage, beginning 7 days before the surgical procedures until the completion of the experimental period (15, 30, and 60 days after the placement of the implants in the tibia). The osseointegration of the implants was evaluated by histometric analysis (bone-to-implant contact [% BIC], bone area between the threads [% BBT]) and biomechanical analysis. Microcomputed tomography (micro-CT) analysis was used to assess bone volume in the vicinity of the implant. Immunohistochemistry analysis was performed to assess the expression of osteocalcin and transforming growth factor beta 1 (TGF-beta1). RESULTS: The ART/ASU group showed a decreased percentage of bone in the area around the implant compared with the ASU and ART groups (15 and 30 days). The ART/ASU group showed increased removal torque values (30 days) and % BIC and % BBT (30 to 60 days) compared with the ART group. The ASU group had increased % BIC values compared with the ART and CTR groups (60 days). The CTR group had the highest expression of osteocalcin, while the ASU group presented the highest expression of TGF-beta1 at 60 days. CONCLUSION: The ASU administration improved the osseointegration, particularly in animals with induced arthritis. PMID- 29763499 TI - Flap Management in Alveolar Ridge Preservation: A Systematic Review and Meta Analysis. AB - PURPOSE: This systematic review aimed to identify the effects of certain flap management procedures on ridge preservation on the basis of existing literature. MATERIALS AND METHODS: Electronic (MEDLINE, EMBASE, and Cochrane Central Register of controlled trials) and manual searches of the literature were conducted until February 2017. Randomized controlled trials (RCTs), controlled clinical trials (CCTs), and prospective cohort studies that involved at least 10 subjects were eligible for this systematic review. To evaluate the beneficial effects of flap management on ridge preservation, changes in the bone width, bone height, and keratinized gingiva width were calculated using a random effects model. RESULTS: Eleven studies (nine RCTs and two CCTs) were included in this review. No statistically significant differences in bone width and height changes were identified between the flapped and flapless ridge preservation techniques and between the free gingival graft and flapless ridge preservation techniques. A statistically significant shrinkage in keratinized gingiva width was noted with flapped ridge preservation compared with flapless ridge preservation (weighted mean differences, -3.21 mm; 95% confidence interval, -4.10 to -2.33; P < .00001; heterogeneity, 51%; chi2, 0.15). CONCLUSION: Within the limitations, this review reveals that flapless ridge preservation was more effective in preserving bone width, bone height, and keratinized gingiva width. To present pertinent evidence regarding which flap management should be recommended for ridge preservation, more controlled and high-quality studies are warranted. PMID- 29763500 TI - The Fate of Lateral Ridge Augmentation: A Systematic Review and Meta-Analysis. AB - PURPOSE: Owing to volumetric changes after tooth extraction, lateral ridge augmentation has become a common procedure prior or simultaneous to implant placement. Nonetheless, little is known with regard to the dimensional remodeling after healing of these lateral ridge augmentation procedures. Hence, the purpose of this systematic review was to assess the stability of bone grafting material between augmentation procedures and final healing, in terms of resorption rate. MATERIALS AND METHODS: An electronic and hand literature search was conducted in several databases, such as the Cochrane Oral Health Group Trials Register, Embase, and Cochrane Central Register of Controlled Trials, up until February 2017. Only randomized controlled trials (RCTs) with a mean follow-up of at least 6 months after implant placement aiming to evaluate the stability of grafting material for lateral ridge augmentation were included and quantitatively analyzed. RESULTS: A total of 35 articles were evaluated; however, only 17 RCTs met the inclusion criteria. A total of 15 studies reported information on bone resorption, leading to a total sample of 304 implants. The estimated overall mean horizontal bone gain at the time of regeneration was 3.71 +/- 0.24 mm, with 4.18 +/- 0.56 mm for the block graft technique and 3.61 +/- 0.27 mm for guided bone regeneration (GBR). The estimated overall net bone gain at final re-evaluation (11.9 +/- 7.8) was 2.86 +/- 0.23 mm. The estimated mean (+/- SD) resorption after 6 months was 1.13 +/- 0.25 mm, with 0.75 +/- 0.59 mm for the block graft technique and 1.22 +/- 0.28 mm for GBR. The implant survival rate was 97% to 100%. CONCLUSION: Regardless of the material used for regeneration, different degrees of graft resorption should be expected. Given the sample of investigations analyzed in this review, block grafts seemed to maintain the volume of the initial augmentation site more than GBR techniques. During the initial stages of healing, the GBR technique experienced more changes compared with block grafts. The resorption of the xenograft group was inferior compared with the combination of xenograft and autologous bone groups. Consequently, overcorrection of the horizontal defects should be performed to compensate for the resorption of the grafting materials. PMID- 29763501 TI - Influence of Lateral Windows with Decreased Vertical Height Following Maxillary Sinus Floor Augmentation: A 1-year Clinical and Radiographic Study. AB - PURPOSE: To verify whether lateral sinus floor elevation (LSFE) with the vertical height of the osteotomy decreased to 3 to 5 mm can achieve improvement compared with a conventional lateral window in terms of implant survival, graft stability, and related complications. MATERIALS AND METHODS: Of the 49 patients who were selected for inclusion in this retrospective study, 25 patients were in the test group and 24 were in the control group based on the vertical height of the lateral window. Each patient received the LSFE treatment using deproteinized bovine bone mineral (DBBM) based on the two different vertical heights of the lateral window (test group: 3 to 5 mm; control group: 6 to 8 mm in vertical height). Residual bone dimensions were measured preoperatively, and graft dimensions were measured immediately after the procedure (baseline), 6 months (T1), and 1 year (T2) postoperatively on the basis of cone beam computed tomography (CBCT) scans. CBCT scan data at the baseline were analyzed with image processing software to evaluate the volume of augmented material, and they were transformed into three-dimensional reconstruction images to calibrate the window dimension. Implant failure and recorded intraoperative and postoperative complications were counted. RESULTS: A prominent augmented graft height was obtained in both groups (test group: 9.48 +/- 3.27 mm; control group: 10.44 +/- 3.01 mm) with no significant difference; likewise, no difference was observed concerning augmented graft volume. Neither cumulative survival rate (CSR) nor augmented graft height decrement had any statistical intergroup difference during each follow-up interval. CSRs were detected as 100% for the test group and 94.28% and 91.67% for the control group based on implants and patients, respectively. Intraoperative membrane perforation was reported in two cases with a few nosebleeds the first night in the test group, while one case occurred in the control group. All the perforations were successfully sealed intraoperatively by a collagen membrane. CONCLUSION: Osteotomy of LSFE with decreased vertical height yielded similar results to the control group with conventional dimensions in terms of implant survival, graft stability, and related complications with 1 year of follow-up. Notwithstanding, a prospective split-mouth randomized controlled trial with long-term observation is imperative to further investigate the influence of decreased vertical height of the lateral window on maturation and consolidation of DBBM. PMID- 29763502 TI - Thermal Changes During Guided Flapless Implant Site Preparation: A Comparative Study. AB - PURPOSE: To compare intrabony thermal changes induced by two different protocols for guided implant surgery during the whole drilling procedure. MATERIALS AND METHODS: Two protocols for guided implant placement were evaluated in vitro using artificial bone cylinders. The control protocol provided traditional metal sleeves and a standard drilling sequence composed of four cylindrical triflute drills (cutting surface length = 16 mm). The test protocol provided a three-slot polyurethane sleeve and two cylindrical drills (second drill cutting surface length = 4 mm). Forty automated intermittent and graduated osteotomies (depth = 14 mm) were performed under external irrigation. Temperatures were measured in real time by three sensors at different depths (2, 8, and 13 mm). The temperature changes generated by the final drill of each protocol during the shearing and withdrawing processes were recorded as experimental results and subjected to the Student t test. RESULTS: Maximum temperature increases were recorded during the process of withdrawing in both protocols. In the control group, the mean thermal changes were 10.18 degrees C, 8.61 degrees C, and 5.78 degrees C at depths of 2, 8, and 13 mm, respectively. In the test group, the mean thermal changes were 1.44 degrees C, 4.46 degrees C, and 3.58 degrees C at depths of 2, 8, and 13 mm, respectively. The control group revealed statistically significantly (P < .0001) higher thermal changes than the test group, both in the superficial and deeper bone areas. CONCLUSION: An appropriate irrigation system could be crucial for thermal lowering during a guided implant osteotomy mainly in the coronal and middle third of the implant site. Copious irrigation should be provided during the withdrawing process since greater thermal increases could be expected. Lower temperature increases could be achieved, reducing drill-to-bone contact, ie, cutting surface length, due to short frictional force exposure. PMID- 29763503 TI - Clinical Performance of Dental Implants Following Sinus Floor Augmentation: A Systematic Review and Meta-Analysis of Clinical Trials with at Least 3 Years of Follow-up. AB - PURPOSE: The purpose of this systematic review was to assess the survival of implants placed in augmented sinuses on a medium- to long-term basis, and identify factors affecting implant survival such as surgical technique, bone grafts, and timing of implant placement. MATERIALS AND METHODS: A literature search up to July 2016 was performed to identify prospective clinical studies on sinus floor augmentation in conjunction with implant placement with a minimum follow-up of 3 years. Meta-analytic methods were implemented to calculate implant survival rates and relative risks (RR) for failure and the effect of surgical technique, use of bone graft, graft type, use of membrane, mean residual bone height, and timing of implant insertion. RESULTS: A total of 17 clinical trials (1 randomized and 16 prospective nonrandomized) were included, which pertained to 637 patients (at least 48% male) and 1,610 implants placed after sinus floor augmentation with the osteotome (transalveolar) or lateral window approach. The pooled implant survival rate at 3 to 6 years of follow-up was 97.7% (17 studies; 95% CI = 94.4% to 99.7%) with high heterogeneity. Smoking was associated with significantly worse implant survival (2 studies; RR = 4.8; 95% CI = 1.2 to 19.4; P < .05). However, evidence of influencing factors varied from very low to moderate after adopting the GRADE approach, due to risk of bias, imprecision, inconsistency, and small-study effects. CONCLUSION: Current evidence suggests that implants in augmented sinuses have high survival rates, with smoking playing a potentially important negative role in their prognosis. Both indirect and direct maxillary sinus floor augmentation seem to have a low frequency of manageable complications. PMID- 29763504 TI - Investigational Clinical Trial of a Prototype Optoelectronic Computer-Aided Navigation Device for Dental Implant Surgery. AB - PURPOSE: New digital technologies enable real-time computer-aided (CA) three dimensional (3D) guidance during dental implant surgery. The aim of this investigational clinical trial was to demonstrate the safety and effectiveness of a prototype optoelectronic CA-navigation device in comparison with the conventional approach for planning and effecting dental implant surgery. MATERIALS AND METHODS: Study participants with up to four missing teeth were recruited from the pool of patients referred to the University of Toronto Graduate Prosthodontics clinic. The first 10 participants were allocated to either a conventional or a prototype device study arm in a randomized trial. The next 10 participants received implants using the prototype device. All study participants were restored with fixed dental prostheses after 3 (mandible) or 6 (maxilla) months healing, and monitored over 12 months. The primary outcome was the incidence of any surgical, biologic, or prosthetic adverse events or device related complications. Secondary outcomes were the incidence of positioning of implants not considered suitable for straightforward prosthetic restoration (yes/no); the perception of the ease of use of the prototype device by the two oral surgeons, recorded by use of a Likert-type questionnaire; and the clinical performance of the implant and superstructure after 1 year in function. Positioning of the implants was appraised on periapical radiographs and clinical photographs by four independent blinded examiners. Peri-implant bone loss was measured on periapical radiographs by a blinded examiner. RESULTS: No adverse events occurred related to placing any implants. Four device-related complications led to a switch from using the prototype device to the conventional method. All implants placed by use of the prototype device were in a position considered suitable for straightforward prosthetic restoration (n = 21). The qualitative evaluation by the surgeons was generally positive, although ergonomic challenges were identified. All study participants were present for the 1-year examination (n = 20 patients, 41 implants, 32 superstructures), and no complications or failures with any implants or superstructures were revealed. The peri-implant bone loss was less than 1 mm for all implants. CONCLUSION: Within the limitations of this trial, the prototype device provided placement of dental implants without adverse events. PMID- 29763505 TI - Influence of Alveolar Bone Defects on the Stress Distribution in Quad Zygomatic Implant-Supported Maxillary Prosthesis. AB - PURPOSE: The purpose of this study was to create three-dimensional composite models of quad zygomatic implant-supported maxillary prostheses with a variety of alveolar bone defects around implant sites, and to investigate the stress distribution in the surrounding bone using the finite element analysis (FEA) method. MATERIALS AND METHODS: Three-dimensional models of titanium zygomatic implants, maxillary prostheses, and human skulls were created and assembled using Mimics based on microcomputed tomography and cone beam computed tomography images. A variety of additional bone defects were created at the locations of four zygomatic implants to simulate multiple clinical scenarios. The volume meshes were created and exported into FEA software. Material properties were assigned respectively for all the structures, and von Mises stress data were collected and plotted in the postprocessing module. RESULTS: The maximum stress in the surrounding bone was located in the crestal bone around zygomatic implants. The maximum stress in the prostheses was located at the angled area of the implant-abutment connection. The model with anterior defects had a higher peak stress value than the model with posterior defects. All the models with additional bone defects had higher maximum stress values than the control model without additional bone loss. CONCLUSION: Additional alveolar bone loss has a negative influence on the stress concentration in the surrounding bone of quad zygomatic implant-supported prostheses. More care should be taken if these additional bone defects are at the sites of anterior zygomatic implants. PMID- 29763506 TI - Simplifying Zygomatic Implant Site Preparation Using Ultrasonic Navigation: A Technical Note. AB - Zygomatic implant site preparation could be considered a challenging procedure because of the use of a very long twist drill that could sometimes be difficult to control due to the need for drilling the malar bone on an oblique surface. Ultrasound was recently suggested to achieve better control, but the specific long tips required are not readily available, and the elongated tip also tends to reduce the efficacy. This technical note describes a proposal of a novel computer aided technique to simplify the procedure of zygomatic implant site preparation. This method uses a standard-length ultrasonic tip to prepare the crestal bone and the zygomatic bone in two individual steps. The desired implant trajectory can be achieved during preparation using a real-time tracking navigation system. The combined use of the navigation system and the ultrasonic tips could aid the surgeon, during the first steps, in achieving optimal control of the instruments employed for the implant site preparation and keeping the planned zygomatic implant position. If the efficacy of the procedure is confirmed through clinical trials, this technique could also contribute to reducing the invasiveness of the procedure, promoting a smaller flap, and reducing the soft tissue damage. PMID- 29763507 TI - Effect of Titanium Surfaces on the Osteogenic Differentiation of Human Adipose Derived Stem Cells. AB - PURPOSE: To investigate whether human adipose-derived stem cells will form a functional bone-like matrix on titanium substrates. The behavior of human adipose derived stem cells was examined when grown in either serum-free, xeno-free stem cell growth medium or osteogenic differentiation medium and cultured on either machined titanium (MTi) or on roughened alumina-blasted titanium (ABTi) discs. MATERIALS AND METHODS: Cellular proliferation, extracellular mineralized matrix production, osteogenic-related protein production (RUNX2 and osteocalcin), and gene expression for pluripotency and self-renewal (TERT and OCT4) and osteogenic related (MSX2, RUNX2, and BGLAP) genes were performed. RESULTS: Human adipose derived stem cells in serum-free medium (hADSC) proliferated at a higher rate compared with osteogenically differentiated cells (hOS-ADSC); however, the osteogenically committed cells produced more mineralized matrix on the titanium surfaces compared with either tissue culture plastic or the undifferentiated cells. The immunofluorescence analysis showed that human adipose-derived stem cells cultured in serum-free medium and osteogenic differentiation medium produced RUNX2 on both the machined titanium surface and on the alumina-blasted titanium surface after 7 days in culture. Only osteogenically differentiated cells produced osteocalcin after 21 days. Relative gene expression showed stable expression of MSX2, RUNX2, and BGLAP over time on all surfaces. Only osteogenically differentiated cells displayed osteogenic characteristics over time. CONCLUSION: This study confirmed that human adipose-derived stem cells could be successfully grown in serum-free, xeno-free culture medium suitable for clinical use. Adipose-derived stem cells thus show potential utility for bone regeneration in association with titanium surfaces. PMID- 29763508 TI - WITHDRAWN: Nursing record systems: effects on nursing practice and healthcare outcomes. AB - BACKGROUND: A nursing record system is the record of care that was planned or given to individual patients and clients by qualified nurses or other caregivers under the direction of a qualified nurse. Nursing record systems may be an effective way of influencing nurse practice. OBJECTIVES: To assess the effects of nursing record systems on nursing practice and patient outcomes. SEARCH METHODS: For the original version of this review in 2000, and updates in 2003 and 2008, we searched: the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register; MEDLINE, EMBASE, CINAHL, BNI, ISI Web of Knowledge, and ASLIB Index of Theses. We also handsearched: Computers, Informatics, Nursing (Computers in Nursing); Information Technology in Nursing; and the Journal of Nursing Administration. For this update, searches can be considered complete until the end of 2007. We checked reference lists of retrieved articles and other related reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs), controlled before and after studies, and interrupted time series comparing one kind of nursing record system with another in hospital, community or primary care settings. The participants were qualified nurses, students or healthcare assistants working under the direction of a qualified nurse, and patients receiving care recorded or planned using nursing record systems. DATA COLLECTION AND ANALYSIS: Two review authors (in two pairs) independently assessed trial quality and extracted data. MAIN RESULTS: We included nine trials (eight RCTs, one controlled before and after study) involving 1846 people. The studies that evaluated nursing record systems focusing on relatively discrete and focused problems, for example effective pain management in children, empowering pregnant women and parents, reducing loss of notes, reducing time spent on data entry of test results, reducing transcription errors, and reducing the number of pieces of paper in a record, all demonstrated some degree of success in achieving the desired results. Studies of nursing care planning systems and total nurse records demonstrated uncertain or equivocal results. AUTHORS' CONCLUSIONS: We found some limited evidence of effects on practice attributable to changes in record systems. It is clear from the literature that it is possible to set up the randomised trials or other quasi-experimental designs needed to produce evidence for practice. Qualitative nursing research to explore the relationship between practice and information use could be used as a precursor to the design and testing of nursing information systems. PMID- 29763509 TI - Surgical approach to hysterectomy and barriers to using minimally invasive methods. AB - Minimally invasive approaches to hysterectomy have been shown to be safe, effective and have recovery advantages over open hysterectomy, yet in Australia 36% of hysterectomies are still conducted by open surgery. In 2006, a survey of Australian gynaecological specialists found the main impediment to increasing laparoscopic hysterectomy to be a lack of surgical skills training opportunities. We resurveyed specialists to explore contemporary factors influencing surgeons' approaches to hysterectomy; 258 (estimated ~19%) provided analysable responses. Despite >50% of surveyed specialists wishing to practise laparoscopic hysterectomy in the future, lack of surgical skills, arising from the lack of training opportunities, remains the main impediment. PMID- 29763510 TI - Trihexyphenidyl for dystonia in cerebral palsy. AB - BACKGROUND: Cerebral palsy occurs in up to 2.1 of every 1000 live births and encompasses a range of motor problems and movement disorders. One commonly occurring movement disorder amongst those with cerebral palsy is dystonia: sustained or intermittent involuntary muscle spasms and contractions that cause twisting, repetitive movements and abnormal postures. The involuntary contractions are often very painful and distressing and cause significant limitations to activity and participation.Oral medications are often the first line of medical treatment for dystonia. Trihexyphenidyl is one such medication that clinicians often use to treat dystonia in people with cerebral palsy. OBJECTIVES: To assess the effects of trihexyphenidyl in people with dystonic cerebral palsy, according to the World Health Organization's (WHO) International Classification of Functioning, Disability and Health (ICF) domains of impairment, activity and participation. We also assessed the type and incidence of adverse effects in people taking the drug. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, eight other databases and two trials registers in May 2017, and we checked reference lists and citations to identify additional studies. SELECTION CRITERIA: We included randomised controlled trials comparing oral trihexyphenidyl versus placebo for dystonia in cerebral palsy. We included studies in children and adults of any age with dystonic cerebral palsy, either in isolation or with the associated movement disorders of spasticity, ataxia, chorea, athetosis and/or hypotonia. We included studies regardless of whether or not the study authors specified the method used to diagnose dystonia in their study population. Primary outcomes were change in dystonia and adverse effects. Secondary outcomes were: activity, including mobility and upper limb function; participation in activities of daily living; pain; and quality of life. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified one study, which was set in Australia, that met the inclusion criteria. This was a randomised, double-blind, placebo-controlled, cross-over trial in 16 children (10 boys and 6 girls) with predominant dystonic cerebral palsy and a mean age of 9 years (standard deviation 4.3 years, range 2 to 17 years). We considered the trial to be at low risk of selection, performance, detection, attrition, reporting and other sources of bias. We rated the GRADE quality of the evidence as low.We found no difference in mean follow-up scores for change in dystonia as measured by the Barry Albright Dystonia Scale (BADS), which assesses eight body regions for dystonia on a 5-point scale (0 = none to 4 = severe), resulting in a total score of 0 to 32. The BADS score was 2.67 points higher (95% confidence interval (CI) -2.55 to 7.90; low-quality evidence), that is, worse dystonia, in the treated group. Trihexyphenidyl may be associated with an increased risk of adverse effects (risk ratio 2.54, 95% CI 1.38 to 4.67; low quality evidence).There was no difference in mean follow-up scores for upper limb function as measured by the Quality of Upper Extremity Skills Test, which has four domains that collectively assess 36 items (each scored 1 or 2) and produces a total score of 0 to 100. The score in the treated group was 4.62 points lower (95% CI -10.98 to 20.22; low-quality evidence), corresponding to worse function, than in the control group. We found low-quality evidence for improved participation (as represented by higher scores) in the treated group in activities of daily living, as measured by three tools: 18.86 points higher (95% CI 5.68 to 32.03) for the Goal Attainment Scale (up to five functional goals scored on 5-point scale (-2 = much less than expected to +2 = much more than expected)), 2.91 points higher (95% CI 1.01 to 4.82) for the satisfaction subscale of the Canadian Occupational Performance Measure (COPM; satisfaction with performance in up to five problem areas scored on a 10-point scale (1 = not satisfied at all to 10 = extremely satisfied)), and 2.24 points higher (95% CI 0.64 to 3.84) for performance subscale of the COPM (performance in up to five problem areas scored on a 10-point scale (1 = not able to do to; 10 = able to do extremely well)).The study did not report on pain or quality of life. AUTHORS' CONCLUSIONS: At present, there is insufficient evidence regarding the effectiveness of trihexyphenidyl for people with cerebral palsy for the outcomes of: change in dystonia, adverse effects, increased upper limb function and improved participation in activities of daily living. The study did not measure pain or quality of life. There is a need for larger randomised, controlled, multicentre trials that also examine the effect on pain and quality of life in order to determine the effectiveness of trihexyphenidyl for people with cerebral palsy. PMID- 29763511 TI - A review of non-invasive imaging in extramammary Paget's disease. AB - Extramammary Paget's Disease (EMPD) is a rare intraepithelial adenocarcinoma that classically manifests with pruritic, erythematous and scaling plaques. The clinical picture frequently mimics inflammatory or infectious conditions and is thus commonly misdiagnosed. The assessment of tumour margins is equally challenging as tumours have a propensity to spread beyond clinically visible boundaries. Appropriate non-invasive diagnostic tools can assist in the early detection, diagnosis and management of EMPD. This paper will review the literature on non-invasive imaging modalities used in EMPD. Articles from the PubMed database were selected based on relevance to the topic of this review. Articles that were not specific to EMPD and non-invasive imaging were excluded. Search strategy is further described in the methods section below. Eighteen articles were selected for this review: six PET/CT, five reflectance confocal microscopy (RCM), two photodynamic diagnosis (PDD), two dermoscopy, two MRI and one optical coherence tomography (OCT) paper(s). Dermoscopy, PDD, RCM and OCT can help to distinguish malignant conditions, including EMPD, from benign conditions. RCM and OCT can identify atypical cells in real-time, and have the potential to improve the accuracy of surgical margins intraoperatively and overall management. Distinctive confocal characteristics of EMPD have been described using RCM. The sensitivity and specificity of these findings require additional validation. Radiographic techniques also play a central role in the diagnosis of EMPD and assessment of disease spread. PET/CT and MRI can detect primary disease, nodal and distant metastases, with superior delineation of disease spread on MRI. Limitations of PET/CT are mainly related to primary tumour thickness, and size and FDG-avidity of nodal and distant metastases. Limitations of MRI include the fact that few studies have examined its use in EMPD; additional research is warranted. Randomized controlled trials and large prospective studies evaluating the use of non-invasive imaging in EMPD are needed. PMID- 29763512 TI - Protonation of polyaniline-coated silica stationary phase affects the retention behavior of neutral hydrophobic solutes in reversed-phase capillary liquid chromatography. AB - Because of its high conductivity when acid doped, polyaniline is known as a synthetic metal and is used in a wide range of applications, such as supercapacitors, biosensors, electrochromic devices, or solar and fuel cells. Emeraldine is the partly oxidized, stable form of polyaniline, consisting of alternating diaminobenzenoid and iminoquinoid segments. When acidified, the nitrogen atoms of emeraldine become protonated. Due to electrostatic repulsion between positive charges, the polarity and morphology of emeraldine chains presumably change; however, the protonation effects on emeraldine have not yet been clarified. Thus, we investigated these changes by reversed-phase capillary liquid chromatography using a linear solvation energy relationship approach to assess differences in dominant retention interactions under a significantly varied mobile phase pH. We observed that hydrophobicity dominates the intermolecular interactions under both acidic and alkaline eluent conditions, albeit to different extents. Therefore, by tuning the mobile phase pH, we can even modulate the retention of neutral hydrophobic solutes, such as aromatic hydrocarbons, because the pH-dependent charge and structure of polymer chains of the emeraldine-coated silica stationary phase show a mixed-mode separation mechanism. PMID- 29763513 TI - Child-onset thrombotic thrombocytopenic purpura caused by p.R498C and p.G259PfsX133 mutations in ADAMTS13. AB - INTRODUCTION: Patients suffering from congenital thrombotic thrombocytopenic purpura (cTTP) have a deficiency in ADAMTS13 due to mutations in their ADAMTS13 gene. OBJECTIVE: The aim of this study was to determine ADAMTS13 parameters (activity, antigen, and mutations), to investigate if the propositus suffered from child-onset cTTP, and to study the in vitro effect of the ADAMTS13 mutations. METHODS: ADAMTS13 activity and antigen were determined using the FRETS VWF73 assay and ELISA and ADAMTS13 mutations via sequencing of the exons. Mutant proteins were expressed in Chinese hamster ovary cells, and their expression was studied using fluorescence microscopy and ELISA. Molecular modeling was used to evaluate the effect of the mutations on ADAMTS13 structure and stability. RESULTS: The propositus was diagnosed with cTTP at the age of 20. ADAMTS13 activity was below 10%, and 2 compound heterozygous mutations, the p.R498C point and the p.G259PfsX133 frameshift mutation, were identified. Expression of ADAMTS13 mutants revealed that the p.R498C and the p.G259PfsX133 mutation cause secretion and translation defects in vitro, respectively. Molecular modeling showed that the R498 intra-domain interactions are lacking in the p.R498C mutant, resulting in protein instability. CONCLUSION: The ADAMTS13 mutations result in a severe ADAMTS13 deficiency explaining the patient's phenotype. PMID- 29763514 TI - Measurement of healthcare quality in atopic dermatitis - development and application of a set of quality indicators. AB - BACKGROUND: Quality indicators are essential tools for the assessment of health care, in particular for guideline-based procedures. OBJECTIVE: Development of a set of indicators for the evaluation of process and outcomes quality in atopic dermatitis (AD) care. Application of the indicators to a cross-sectional study and creation of a global process quality index. METHODS: An expert committee consisting of 10 members of the German guideline group on AD condensed potential quality indicators to a final set of 5 outcomes quality and 12 process quality indicators using a Delphi panel. The outcomes quality and 7 resp. 8 process quality indicators were retrospectively applied to a nationwide study on 1678 patients with atopic dermatitis (AtopicHealth). Each individual process quality indicator score was then summed up to a global index (ranges from 0 [no quality achieved] to 100 [full quality achieved]) displaying the quality of health care. RESULTS: In total, the global process quality index revealed a median value of 62.5 and did not or only slightly correlate to outcomes quality indicators like the median SCORing Atopic Dermatitis (SCORAD; rp = 0.08), Dermatology Life Quality Index (DLQI; rp = 0.256) and Patient Benefit Index (PBI; rp = -0.151). CONCLUSION: Process quality of AD care is moderate to good. The healthcare process quality index does not substantially correlate to the health status of AD patients measured by 5 different outcomes quality indicators. Further research should include the investigation of reliability, responsiveness and feasibility of the proposed quality indicators for AD. PMID- 29763515 TI - Individualized breathlessness interventions may improve outcomes in patients with advanced COPD. AB - BACKGROUND AND OBJECTIVE: Many patients with advanced COPD experience refractory breathlessness and individualized breathlessness interventions may improve management of this complex symptom. The aims of this study were to develop, implement and assess the efficacy of a breathlessness intervention for patients with COPD and refractory breathlessness and to evaluate patient acceptability. METHODS: An individualized breathlessness plan, information leaflets, breathlessness education and a hand-held fan were offered to consecutive patients with severe COPD and refractory breathlessness attending a tertiary integrated respiratory and palliative care service. Validated dyspnoea, quality of life and anxiety/depression questionnaires were administered at baseline and after 6 weeks, with change in dyspnoea scores being the primary outcome measure. A subset of patients participated in a structured telephone interview to qualitatively assess the intervention. RESULTS: Twenty-six patients with severe COPD (mean forced expiratory volume in 1 s (FEV1 ) 38%) were included, with a mean age of 74 years. Mean modified Medical Research Council Breathlessness Scale score was 3.5. Anxiety and depression were common, being present in 38% and 35% of participants. At 6 weeks, there was a clinically significant improvement in breathlessness severity as measured by the Numerical Rating Scale. The subset of patients with anxiety/depression also saw significant improvement in all domains of the Self Administered Standardized Chronic Respiratory Questionnaire (CRQ-SAS). Patients reported that the intervention was highly useful and acceptable. CONCLUSION: This feasibility study of individualized breathlessness interventions in patients with severe COPD and refractory breathlessness is the first to demonstrate a clinically significant reduction in dyspnoea scores, with high levels of patient acceptability. PMID- 29763516 TI - Influence of plaque control on the relationship between rheumatoid arthritis and periodontal health status among Japanese rheumatoid arthritis patients. AB - BACKGROUND: Functional disability of the finger joints in rheumatoid arthritis (RA) patients could affect their oral hygiene and periodontal status because of poor plaque control. We examined the influence of plaque control on the relationship between the severity of RA and periodontal status in RA patients. METHODS: This study recruited 89 Japanese RA patients who reported no difficulty in performing oral hygiene. We assessed RA severity using four indices: the Steinbrocker stage and class, the Health Assessment Questionnaire (HAQ) and the Disease Activity Score (DAS). Probing depth (PD), clinical attachment level (CAL), and bleeding on probing (BOP) were taken as parameters of periodontal status. Oral hygiene status was assessed using the plaque index (PlI). We examined the association between the severity of RA and periodontal parameters using multivariable linear regression analyses. RESULTS: In multivariable linear regression analyses not including PlI, Steinbrocker stage III-IV patients had significantly higher PlI scores and greater PD compared with those of stage I. The class III-IV patients had significantly higher PlI scores and greater PD. Patients with an HAQ score >=0.5 had a significantly higher PlI score than those with an HAQ score of 0. However, when PlI was added to each multivariable model as an independent variable, no significant relationship between RA severity and periodontal status was observed. CONCLUSIONS: This study suggests that it is important to consider the influence of plaque control when assessing the relationship between RA severity and periodontal health status in RA patients. PMID- 29763517 TI - Novel engineered tendon-fibrocartilage-bone composite with cyclic tension for rotator cuff repair. AB - Surgical repair of rotator cuff tears presents a significant clinical challenge with high failure rates and inferior functional outcomes. Graft augmentation improves repair outcomes; however, currently available grafting materials have limitations. Although cell-seeded decellularized tendon slices may facilitate cell infiltration, promote tendon incorporation, and preserve original mechanical strength, the unique fibrocartilage zone is yet to be successfully reestablished. In this study, we investigated the biological and mechanical properties of an engineered tendon-fibrocartilage-bone composite (TFBC) with cyclic tension (3% strain; 0.2 Hz). Decellularized TFBCs seeded with bone marrow-derived mesenchymal stem cell (BMSCs) sheets and subjected to mechanical stimulation for up to 7 days were characterised by histology, immunohistochemistry, scanning electron microscopy, mechanical testing, and transcriptional regulation. The decellularized TFBC maintained native enthesis structure and properties. Mechanically stimulated TFBC-BMSC constructs displayed increased cell migration after 7 days of culture compared with static groups. The seeded cell sheet not only integrated well with tendon scaffold but also distributed homogeneously and aligned to the direction of stretch under dynamic culture. Developmental genes were regulated including scleraxis, which was significantly upregulated with mechanical stimulation. The Young's modulus of the cell-seeded constructs was significantly higher compared with the noncell-seeded controls. In conclusion, the results of this study reveal that the TFBC-BMSC composite provides an ideal multilayer construct for cell seeding and growth, with mechanical preconditioning further enhances cell penetration and differentiation. The BMSC cell sheet revitalised TFBC in conjunction with mechanical stimulation could serve as a novel and primed biological patch to improve rotator cuff repair. PMID- 29763518 TI - Tattoo-associated uveitis with or without systemic sarcoidosis: a comparative review of the literature. AB - Sarcoidosis is a systemic disease of unknown aetiology characterized by the presence of non-caseating epithelioid cell granulomas in multiple organs, mainly the lungs and the lymphatic system. It is also one of the leading cause of inflammatory eye diseases. For the past 70 years, sarcoidal granulomas on tattoos and permanent make-up have been documented. They can be the first and sometimes unique cutaneous manifestation of systemic sarcoidosis. A few cases of sarcoidosis with uveitis and granulomatous reactions within tattoos have been described. However, since the end 60s, a singular entity has been reported associating isolated uveitis with granulomatous cutaneous reaction restricted to tattoos in the notable absence of systemic sarcoidosis. It remains unclear whether this entity must be distinguished from sarcoidosis. This review summarizes the currently available data on this topic and compares cases of sarcoidosis with granulomatous tattoo reaction and uveitis to the cases without notable sarcoidosis. We propose the acronym TAGU (TAttoo Granulomas with Uveitis) as an exclusion diagnosis that emcompasses the patients for whom we fail to find any sarcoidosis or other causes after extensive investigation. PMID- 29763519 TI - Generation and Characterization of the First Persistent Platinum(I)-Centered Radical. AB - The first persistent platinum(I)-centered radical was generated by homolytic cleavage of a Pt-HgSiR3 bond of a mercury-substituted platinum(II) complex. The PtI radical was characterized by EPR spectroscopy, chemical trapping experiments, and density functional theory (DFT) calculations. PMID- 29763520 TI - The Arabidopsis CrRLK1L protein kinases BUPS1 and BUPS2 are required for normal growth of pollen tubes in the pistil. AB - In flowering plants, the interaction of pollen tubes with female tissues is important for the accomplishment of double fertilization. Little information is known about the mechanisms that underlie signalling between pollen tubes and female tissues. In this study, two Arabidopsis pollen tube-expressed CrRLK1L protein kinases, Buddha's Paper Seal 1 (BUPS1) and BUPS2, were identified as being required for normal tip growth of pollen tubes in the pistil. They are expressed prolifically in pollen and pollen tubes and are localized on the plasma membrane of the pollen tube tip region. Mutations in BUPS1 drastically reduced seed set. Most of the bups1 mutant pollen tubes growing in the pistil exhibited a swollen pollen tube tip, leading to failure of fertilization. The bups2 pollen tubes had a slightly abnormal morphology but could still accomplish double fertilization. The bups1 bups2 double mutant exhibited a slightly enhanced phenotype compared to the single bups1 mutants. The BUPS1 proteins could form homomers and heteromers with BUPS2, whereas BUPS2 could only form heteromers with BUPS1. The BUPS proteins could interact with the Arabidopsis pollen-expressed RopGEFs in the yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays. The results indicated that the BUPSs may mediate normal polar growth of pollen tubes in the pistil. PMID- 29763521 TI - Screening and investigation of triplex DNA binders from Stephania tetrandra S. Moore by a combination of peak area-fading ultra high-performance liquid chromatography with orbitrap mass spectrometry and optical spectroscopies. AB - The identification and screening of triplex DNA binders are important because these compounds, in many cases, are potential anticancer agents as well as promising drug candidates. Therefore, the ability to screen for these compounds in a high-throughput mode could dramatically improve the drug screening process. A method involving a combination of 96-well plate format and peak area-fading ultra high-performance liquid chromatography coupled with Orbitrap mass spectrometry was employed for screening bioactive compounds binding to the triplex DNA from the extracts of Stephania tetrandra S. Moore. Two compounds were screened out and identified as fangchinoline and tetrandrine based on the comparison of retention time and tandem mass spectrometry data with those of standards. The binding mechanisms of fangchinoline and tetrandrine at the molecular level were explored using tandem mass spectrometry, fluorescence spectroscopy, ultraviolet-visible spectroscopy, and circular dichroism. Collision induced dissociation experiments showed that the complexes with fangchinoline and tetrandrine were dissociated by ligand elimination. According to these measurements, an intercalating binding is the most appropriate binding mode of these two alkaloids to the triplex DNA. The current work provides not only deep insight into alkaloid-triplex DNA complexes but also useful guidelines for the design of efficient anticancer agents. PMID- 29763522 TI - Genetic polymorphism of thymic stromal lymphopoietin in Korean patients with atopic dermatitis and allergic march. PMID- 29763523 TI - Role of BASIC PENTACYSTEINE transcription factors in a subset of cytokinin signaling responses. AB - Cytokinin plays diverse roles in plant growth and development, generally acting by modulating gene transcription in target tissues. The type-B Arabidopsis response regulators (ARR) transcription factors have emerged as primary targets of cytokinin signaling and are required for essentially all cytokinin-mediated changes in gene expression. The diversity of cytokinin function is likely imparted by the activity of various transcription factors working with the type-B ARRs to alter specific sets of target genes. One potential set of co-regulators modulating the cytokinin response are the BARLEY B-RECOMBINANT/BASIC PENTACYSTEINE (BBR/BPC) family of plant-specific transcription factors. Here, we show that disruption of multiple BPCs results in reduced sensitivity to cytokinin. Further, the BPCs are necessary for the induction of a subset of genes in response to cytokinin. We identified direct in vivo targets of BPC6 using ChIP Seq and found an enrichment of promoters of genes differentially expressed in response to cytokinin. Further, a significant number of BPC6 regulated genes are also direct targets of the type-B ARRs. Potential cis-binding elements for a number of other transcription factors linked to cytokinin action are enriched in the BPC binding fragments, including those for the cytokinin response factors (CRFs). In addition, several BPCs interact with a subset of type-A ARRs. Consistent with these results, a significant number of genes whose expression is altered in bpc mutant roots are also mis-expressed in crf1,3,5,6 and type-A arr3,4,5,6,7,8,9,15 mutant roots. These results suggest that the BPCs are part of a complex network of transcription factors that are involved in the response to cytokinin. PMID- 29763524 TI - Separating Extreme pH Gradients Using Amphiphilic Copolymer Membranes. AB - Polymeric vesicles, also called polymersomes, are highly efficient biomimetic systems. They can generate compartmentalized volumes at the nanoscale supported by synthetic amphiphilic membranes that closely mimic their biological counterparts. Membrane permeability and the ability to separate extreme pH gradients is a crucial condition a successful biomimetic system must meet. We show that polymersomes formed by non-ionic polybutadiene-b-polyethylene oxide (PBd-b-PEO) amphiphilic block copolymers engineer robust and stable membranes that are able to sustain pH gradients of 10 for a minimum of eight days. The cells' endo-lysomal compartments separate gradients between three and one, while we generated a pH gradient of threefold as great. This feature clearly is of great importance for applications as nanoreactors and drug-delivery systems where separating different aqueous volumes at the nanoscale level is an essential requirement. PMID- 29763525 TI - [Bis(imidazolyl)-BH2 ]+ [Bis(triazolyl)-BH2 ]- Ionic Liquids with High Density and Energy Capacity. AB - [Bis(imidazolyl)-BH2 ]+ [bis(triazolyl)-BH2 ]- and [bis(imidazolyl)-BH2 ]+ [tris(triazolyl)-BH]- were synthesized, the cations and anions of which were functionalized with B-H groups and azoles. As B-H groups contribute to the hypergolic activity and azole groups improve the energy output, the resulting ionic liquids exhibited ignition delay times as low as 20 ms and energy outputs as high as 461.1 kJ mol-1 . In addition, densities (1.07-1.22 g cm-3 ) and density-specific impulse (~360 s g cm-3 ) values reached a relatively high level. These ionic liquids show great promise as sustainable rocket fuels. PMID- 29763526 TI - Extra-Virgin Olive Oil with Natural Phenolic Content Exerts an Anti-Inflammatory Effect in Adipose Tissue and Attenuates the Severity of Atherosclerotic Lesions in Ldlr-/-.Leiden Mice. AB - SCOPE: The present study investigates the effect of olive oils with different phenolic content in high-fat diets (HFDs) on hypertrophy and inflammation in adipose tissue and associated atherosclerosis, in the context of obesity. METHODS AND RESULTS: Ldlr-/-.Leiden mice were fed three different HFDs for 32 weeks and were compared with mice fed the standard low-fat diet (LFD). The different fats provided in the HFDs were lard (HFD-L), extra-virgin olive oil (EVOO; 79 mg kg-1 of phenolic compounds, HFD-EVOO), or EVOO rich in phenolic compounds (OL, 444 mg kg-1 of phenolic compounds, HFD-OL). All HFD-fed mice became obese, but only HFD L-induced adipocyte hypertrophy. HFD-EVOO mice exhibited the greatest levels of Adiponectin in adipose tissue and presented atherosclerotic lesions similar to the LFD group, with a very low count of monocyte/macrophage compared with HFD-L and HFD-OL mice. Enrichment of the phenolic content of olive oil reduced the secretion of nitrites/nitrates in the aorta, but atherosclerosis was not attenuated in HFD-OL mice compared to other HFD mice. CONCLUSION: Consumption of olive oil with a natural content of phenolic compounds attenuates adipose tissue hypertrophy and inflammation and exerts antiatherosclerotic effects in mice. A higher phenolic content of olive oil did not provide further benefits in the prevention of atherosclerosis. PMID- 29763527 TI - Caregiver to all RNs share stories, offer strategies for staying healthy when stretched too thin. PMID- 29763528 TI - Nurses bring their expertise to Cancer Moonshot Initiative. PMID- 29763529 TI - [Not Available]. PMID- 29763530 TI - Why we still need to look out for electronic cigarettes. PMID- 29763531 TI - Pool of potential family caregivers shrinking. PMID- 29763532 TI - Palliative Care Occupies Growing Presence in ED. AB - As the benefits of palliative care become more evident in clinical trials, there is growing interest in making such resources available to patients at an earlier stage, such as the ED. However, experts note that emergency staff first must identify available resources and make sure that providers have the primary palliative care skills needed to effectively introduce the topic to appropriate patients and families. Research shows that initiating the call for a palliative care consult while the patient is in the ED can deliver quality-of-life benefits even three months later. For EDs that lack resources in house, experts advise staff to form partnerships with hospices in the community; some offer sophisticated services and will come to the ED to evaluate patients. Emergency staff should establish flexible criteria to identify when palliative care is an appropriate option to introduce to patients and families. PMID- 29763533 TI - Assessing Risk for Future Firearms Violence in Young People Who Present to ED. AB - A new clinical index tool designed specifically for the emergency environment predicts the risk for future firearms violence in young people 14-24 years of age. The approach employs a brief, 10-point instrument that can be administered in one to two minutes, according to investigators. They also note that while the tool is based on data from a single ED in Flint, Ml, the tool should be applicable to urban EDs in regions that have similar characteristics. To create the tool, investigators used data from the Flint Youth Injury Study, an investigation of a group of patients 14-24 years of age who reported using drugs in the previous six months and accessed care at a Level I trauma center. Using a machine learning classification approach, investigators combed through the data, finding that the most predictive factors for firearm violence could be categorized into four domains: peer and partner violence victimization, community violence exposure, peer/family influences, and fighting. Ideally, investigators note the tool will be employed along with interventions targeted toward patients at high risk for future firearms violence. PMID- 29763534 TI - Health Systems Turn to Communication and Resolution Programs to Identify Errors. PMID- 29763535 TI - Team-based Pod System Reduces Lengths of Stay for Treat-and-Release Patients. AB - To boost performance on a range of metrics, the 55-bed ED at NYU Lutheran Medical Center in Brooklyn, NY, transitioned to a pod system in August 2016. The approach, which is designed to foster team-based care, involves assigning physicians and nurses to designated geographic areas throughout the day, minimizing the movement of physicians as well as the need for phone communication. When coupled with other changes, including the introduction of point-of- care testing, the pod initiative has enabled the ED to reduce lengths of stay for all treat-and-release patients to less than three hours for the first time in the history of the department, according to administrators. There were multiple challenges involved with the transition to a pod system, including the need to match physician schedules with patient volume, but clinicians note the approach has produced improved physician-nurse communications. Administrators credit the creation of a process improvement team with giving frontline staff a voice in planned improvements while also facilitating the change process. PMID- 29763536 TI - Institute a Thorough Process to Manage Payer Audits. PMID- 29763537 TI - [The Simulation Experiment of Control System for Left Ventricular Assist Device]. AB - Objective: To test the accuracy, the reliability and the stability of flow controlling method of a new percutaneous left ventricular assist device. Methods: With the AMEsim to set up a simulation model, analysis the variations of motor speed, flow and pressure by adjusting the size of valve. and we test the improved theoretical model with outside experiment. Results: In the simulation experiment, with the variations of pressure from A, the system can regulate the motor speed to maintain the pump outlet pressure 1.1*105 Pa~1.2*105 Pa and control the flow. With the B valve size changes, the flow-controlling by the system identify and change the motor speed, to maintain the pump inlet pressure from-0.25*105 Pa to 0.10*105 Pa. In outside experiment, with the variations of the size of valve A and valve B, the pump can change the voltage by self-regulation, maintain the entrance and exit of pressure is relatively stable and control the flow. Conclusions: It is a fast-responding and better robust way, by adding the pressure sensor to adjust the speed of motor, to control the flow accurately. PMID- 29763538 TI - [Evaluation of the EDOSE for IMRT Delivery Quality Assurance]. AB - Objective: Evaluation of intensity-modulated radiation therapy(IMRT) delivery quality assurance(DQA) using EDOSE software based on accelerator electronic portal imaging device (EPID). Methods: Analysed the dose response uniformity correction of EPID imaging plate in different fields and the gamma pass rates about the fields; And compared the calculated parameters of the EDOSE and the Pinnacle planning station. Results: The uniformities on the homogeneous region of thefi elds are good after who corrected by EDOSE. The gamma(gamma, 3mm/3%) pass rates are in the ideal range. The volume of the organs at risk(OAR) have no statistical signifi cance except the right lung; A part of the parameters have statistical signifi cance. Conclusions: The results of the calculation and analysis of EDOSE has a high agreement with the planning system. PMID- 29763539 TI - [The Explore of the Security Strategy Model in Hospital Mobile Clinic New Mode]. AB - The paper elaborates and analyzes the current status of mobile hospital information security, then puts forward a security new model of the mobile treatment, then its architecture and solutions is elaborated. The use of this model makes the overall security level of hospital information to be further improved and enhanced, it has a positive signifi cance to promote the overal hospital management level. PMID- 29763540 TI - [A Comparative Study on the Damage Rate of Flow Rate Trigger and Pressure Trigger During the Process of Mechanical Ventilation and Spray]. AB - Objective: To investigate the damage rate of the air flow sensor caused by the flow velocity and pressure in the process of mechanical ventilation and spray. Methods: 12 wire type flow sensor were randomly divided into flow rate trigger group and pressure trigger group. Every time sprayed 15 minutes, then removed flow sensor, a total number of times gathered statistics when flow sensor failed, statistical analysis was performed using SPSS software. Results: The flow rate trigger group was 410.83+/-29.8 times and was significantly less than that of the pressure trigger group of 955.67+/-84.54 times, the difference was statistically significant (P<0.05). Conclusions: The flow rate trigger during the process of mechanical ventilation and spray was significantly increased the damage rate of output flow sensor comparing with pressure trigger. PMID- 29763541 TI - [A Comparative Study on the Damage Rate of Flow Rate Trigger and Pressure Trigger During the Process of Mechanical Ventilation and Spray] PMID- 29763542 TI - Insight into the Role of Facultative Bacteria Stimulated by Microaeration in Continuous Bioreactors Converting LCFA to Methane. AB - Conversion of unsaturated long chain fatty acids (LCFA) to methane in continuous bioreactors is not fully understood. Palmitate (C16:0) often accumulates during oleate (C18:1) biodegradation in methanogenic bioreactors, and the reason why this happens and which microorganisms catalyze this reaction remains unknown. Facultative anaerobic bacteria are frequently found in continuous reactors operated at high LCFA loads, but their function is unclear. To get more insight on the role of these bacteria, LCFA conversion was studied under microaerophilic conditions. For that, we compared bioreactors treating oleate-based wastewater (organic loading rates of 1 and 3 kg COD m-3 d-1), operated under different redox conditions (strictly anaerobic-AnR, -350 mV; microaerophilic-MaR, -250 mV). At the higher load, palmitate accumulated 7 times more in the MaR, where facultative anaerobes were more abundant, and only the biomass from this reactor could recover the methanogenic activity after a transient inhibition. In a second experiment, the abundance of facultative anaerobic bacteria, particularly Pseudomonas spp. (from which two strains were isolated), was strongly correlated ( p < 0.05) with palmitate-to-total LCFA percentage in the biofilm formed in a continuous plug flow reactor fed with very high loads of oleate. This work strongly suggests that microaeration stimulates the development of facultative bacteria that are critical for achieving LCFA conversion to methane in continuous bioreactors. Microbial networks and interactions of facultative and strict anaerobes in microbial communities should be considered in future studies. PMID- 29763543 TI - Reactions of Laser-Ablated Aluminum Atoms with Cyanogen: Matrix Infrared Spectra and Electronic Structure Calculations for Aluminum Isocyanides Al(NC)1,2,3 and Their Novel Dimers. AB - Laser-ablated Al atoms react with (CN)2 in excess argon during condensation at 4 K to produce AlNC, Al(NC)2, and Al(NC)3, which were computed (B3LYP) to be 27, 16, and 28 kJ/mol lower in energy, respectively, than their cyanide counterparts. Irradiation at 220-580 nm increased absorptions for the above molecules and the very stable Al(NC)4- anion. Annealing to 30, 35, and 40 K allowed for diffusion and reaction of trapped species and produced new bands for the Al(NC)1,2,3 dimers including a rhombic ring core (C)(AlN)2(C) with C's attached to the N's, a (NC)2Al(II)-Al(II)(NC)2 dimer with a computed Al-Al length of 2.557 A, and the dibridged Al2(NC)6 molecule with a calculated D2 h structure and rhombic ring core like Al2H6. In contrast, the Al(NC)4- anion was destroyed on annealing presumably due to neutralization by Al+. B3LYP calculations also show that aluminum chlorides form the analogous molecules and dimers. In our search for possible new products, we calculated Al(NC)4 and found it to be a stable molecule, but it was not detected here. PMID- 29763544 TI - Multifluorophore DNA Origami Beacon as a Biosensing Platform. AB - Biosensors play increasingly important roles in many fields, from clinical diagnosis to environmental monitoring, and there is a growing need for cheap and simple analytical devices. DNA nanotechnology provides methods for the creation of sophisticated biosensors, however many of the developed DNA-based sensors are limited by cumbersome and time-consuming readouts involving advanced experimental techniques. Here we describe design, construction, and characterization of an optical DNA origami nanobiosensor device exploiting arrays of precisely positioned organic fluorophores. Two arrays of donor and acceptor fluorophores make up a multifluorophore Forster resonance energy-transfer pair that results in a high-output signal for microscopic detection of single devices. Arrangement of fluorophores into arrays increases the signal-to-noise ratio, allowing detection of signal output from singular biosensors using a conventional fluorescence microscopy setup. Single device analysis enables detection of target DNA sequences in concentrations down to 100 pM in <45 min. We expect that the presented nanobiosensor can function as a general platform for incorporating sensor modules for a variety of targets and that the strong signal amplification properties may allow detection in portable microscope systems to be used for biosensor applications in the field. PMID- 29763545 TI - Structural Stability of Peptidic His-Containing Proton Wire in Solution and in the Adsorbed State. AB - Molecular wires are functional molecules applicable in the field of transfer processes in technological and biochemical applications. Besides molecular wires with the ability to transfer electrons, research is currently focused on molecular wires with high proton affinity and proton transfer ability. Recently, proposed peptidic proton wires (H wires) are one example. Their ability to mediate the transport of protons from aqueous solutions onto the surface of a Hg electrode in a catalytic hydrogen evolution reaction was investigated by constant current chronopotentiometric stripping. However, elucidating the structure of H wires and rationalizing their stability are key requirements for their further research and application. In this article, we focus on the His (H) and Ala (A) containing peptidic H wire A3-(H-A2)6 in solution and after its immobilization onto the electrode surface in the presence of the secondary structure stabilizer 2,2,2-trifluoroethanol (TFE). We found that the solvent containing more than 25% of TFE stabilizes the helical structure of A3-(H-A2)6 not only in solution but also in the adsorbed state. The TFE efficacy to stabilize alpha-helical structure was confirmed using high-resolution nuclear magnetic resonance, circular dichroism, and molecular dynamics simulation. Experimental and theoretical results indicated A3-(H-A2)6 to be a high proton-affinity peptidic H wire with an alpha-helical structure stabilized by TFE, which was confirmed in a comparative study with hexahistidine as an example of a peptide with a definitely disordered and random coil structure. The results presented here could be used for further investigation of the peptidic H wires and for the application of electrochemical methods in the research of proton transfer phenomena in general. PMID- 29763547 TI - Tracer Transport Probes Relaxation and Structure of Attractive and Repulsive Glassy Liquids. AB - Dynamic coupling of small penetrants to slow, cooperative relaxations within crowded cells, supercooled liquids, and polymer matrices has broad consequences for applications ranging from drug delivery to nanocomposite processing. Interactions between the constituents of these and other disordered media alter the cooperative relaxations, but their effect on penetrant dynamics remains incompletely understood. We use molecular dynamics simulations to show that the motions of hard-sphere tracer particles probe differences in local structure and cooperative relaxation processes in attractive and repulsive glassy liquid matrices with equal bulk packing fractions and long-time diffusivities. Coupling of the tracer dynamics to collective relaxations in each matrix affects the shape of tracer trajectories, which are fractal within the repulsive matrix and more compact in the attractive. These results reveal that the structure of relaxations controls penetrant transport and dispersion in cooperatively relaxing systems and provide insight into dynamical heterogeneity within glassy liquids. PMID- 29763546 TI - Direct Structural Annotation of Membrane Protein Aggregation Loci using Peptide Based Reverse Mapping. AB - Membrane protein aggregation is associated with neurodegenerative diseases. Despite remarkable advances to map protein aggregation, molecular elements that drive the structural transition from functional to amyloidogenic beta-sheet polymers remain elusive. Here, we report a simple and reliable reverse-mapping method to identify the molecular elements. We validate our approach by obtaining molecular details of aggregation loci of human beta-barrel nanopore ion channels that are vital for cell survival. By coupling bottom-up synthesis with time resolved aggregation kinetics and high-resolution imaging, we identify molecular elements that switch folded channels to polymeric beta-rich aggregates. We prove that intrinsic protein aggregation and amyloidogenicity does not depend on total hydrophobicity but on single residue differences in the primary sequence. Our method offers effective strategies for sequence-based design of aggregation inhibitors in biomedicine for neurodegenerative diseases. PMID- 29763548 TI - Zein Increases the Cytoaffinity and Biodegradability of Scaffolds 3D-Printed with Zein and Poly(epsilon-caprolactone) Composite Ink. AB - Electrohydrodynamic printing (EHDP) has attracted extensive interests as a powerful technology to fabricate micro- to nano-scale fibrous scaffolds in a custom-tailored manner for biomedical applications. A few synthetic biopolymer inks are applicable to this EHDP technology, but the fabricated scaffolds suffered from low mechanical strength, biocompatibility, and biodegradability. In this study, a series of poly(epsilon-caprolactone) (PCL)/zein composite inks were developed and their printability was examined on a solution-based EHDP system for scaffold fabrication. Multilayer grid scaffolds were manufactured by PCL, PCL/zein-10, and PCL/zein-20 inks, respectively and characterized. The mechanical strength of scaffolds printed by PCL/zein composite inks was remarkably enhanced in terms of Young's modulus and yield stress. The enzyme-accelerated in vitro degradation study demonstrated that zein-containing scaffolds exhibited dose responsive improvement on the degradation rate as evidenced by surface morphological change of fibers. Moreover, the biocompatibility of PCL/zein scaffolds, tested on mice embryonic fibroblast (NIH/3T3) and human nonsmall lung cancer cell (H1299), manifested better cell affinity. Our findings suggest that scaffolds fabricated by the solution-based EHDP with PCL/zein composite inks can significantly improve Young's modulus, yield stress, biocompatibility, and biodegradability and have potential applications in drug delivery systems, 3D cell culture modeling, or tissue engineering. PMID- 29763551 TI - Fluorescence Polarization Anisotropy in Microdroplets. AB - Chemical reactions can be greatly accelerated in microdroplets, but the factors that lead to acceleration are still being elucidated. Using rhodamine 6G (R6G) as a model compound, we studied the density distribution and fluorescence polarization anisotropy of this dye in water-in-oil microdroplets. We found the density of R6G is higher on the surface of the microdroplets, and the ratio of the surface density to that of the center grows with increasing microdroplet radius or with decreasing R6G concentration. The measured fluorescence polarization anisotropy at the surface is almost the same for droplets of different sizes but becomes larger when the concentration is lowered. We also performed three-dimensional simulations by treating R6G+ and its associated anion as a dipole of fixed length and magnitude. The simulation results match quite well the experimental measurements, showing that the density distribution and fluorescence polarization anisotropy can be largely explained by a simple electrostatic model. PMID- 29763549 TI - Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1. AB - In vivo positron emission tomography (PET) imaging of the gamma-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[11C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [18F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4 [18F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z) [18F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[18F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[18F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres. PMID- 29763550 TI - Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo. AB - Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults and is often associated with constitutive tyrosine kinase signaling. These pathways involve the nonreceptor tyrosine kinases Fes, Syk, and the three Src family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from 20 of 26 AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn. No correlation was observed with Flt3 expression or mutational status, with the four most sensitive patient samples being wild-type for Flt3. Kinome-wide target specificity profiling coupled with in vitro kinase assays demonstrated a narrow overall target specificity profile for TL02-59, with picomolar potency against the myeloid Src-family member Fgr. In a mouse xenograft model of AML, oral administration of TL02-59 for 3 weeks at 10 mg/kg completely eliminated leukemic cells from the spleen and peripheral blood while significantly reducing bone marrow engraftment. These results identify Fgr as a previously unrecognized kinase inhibitor target in AML and TL02-59 as a possible lead compound for clinical development in AML cases that overexpress this kinase independent of Flt3 mutations. PMID- 29763552 TI - Simple-to-Complex Transformation in Liquid Rubidium. AB - We investigated the atomic structure of liquid Rb along an isothermal path at 573 K, up to 23 GPa, by X-ray diffraction measurements. By raising the pressure, we observed a liquid-liquid transformation from a simple metallic liquid to a complex one. The transition occurs at 7.5 +/- 1 GPa which is slightly above the first maximum of the T-P melting line. This transformation is traced back to the density-induced hybridization of highest electronic orbitals leading to the accumulation of valence electrons between Rb atoms and to the formation of interstitial atomic shells, a behavior that Rb shares with Cs and is likely to be common to all alkali metals. PMID- 29763553 TI - Effective Remodelling of Human Osteoarthritic Cartilage by sox9 Gene Transfer and Overexpression upon Delivery of rAAV Vectors in Polymeric Micelles. AB - Recombinant adeno-associated virus (rAAV) vectors are well suited carriers to provide durable treatments for human osteoarthritis (OA). Controlled release of rAAV from polymeric micelles was already shown to increase both the stability and bioactivity of the vectors while overcoming barriers, precluding effective gene transfer. In the present study, we examined the convenience of delivering rAAV vectors via poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) polymeric (PEO-PPO-PEO) micelles to transfer and overexpress the transcription factor SOX9 in monolayers of human OA chondrocytes and in experimentally created human osteochondral defects. Human osteoarthritic (OA) chondrocytes and human osteochondral defect models were produced using human OA cartilage obtained from patients subjected to total knee arthroplasty. Samples were genetically modified by adding a rAAV-FLAG-h sox9 vector in its free form or via polymeric micelles for 10 days relative to control conditions (unmodified cells). The effects of sox9 overexpression in human OA cartilage samples were monitored by biochemical, histological, and immunohistochemical analyses. Delivery of rAAV-FLAG-h sox9 via polymeric micelles enhanced the levels of sox9 expression compared with free vector administration, resulting in increased proteoglycan deposition and in a stimulated cell proliferation index in OA chondrocytes. Moreover, higher production of type II collagen and decreased hypertrophic events were noted in osteochondral defect cultures when compared with control conditions. Controlled therapeutic rAAV sox9 gene delivery using PEO-PPO-PEO micelles is a promising, efficient tool to promote the remodelling of human OA cartilage. PMID- 29763554 TI - Template-Catalyzed, Disulfide Conjugation of Monoclonal Antibodies Using a Natural Amino Acid Tag. AB - The high specificity and favorable pharmacological properties of monoclonal antibodies (mAbs) have prompted significant interest in re-engineering this class of molecules to add novel functionalities for enhanced therapeutic and diagnostic potential. Here, we used the high affinity, meditope-Fab interaction to template and drive the rapid, efficient, and stable site-specific formation of a disulfide bond. We demonstrate that this template-catalyzed strategy provides a consistent and reproducible means to conjugate fluorescent dyes, cytotoxins, or "click" chemistry handles to meditope-enabled mAbs (memAbs) and memFabs. More importantly, we demonstrate this covalent functionalization is achievable using natural amino acids only, opening up the opportunity to genetically encode cysteine meditope "tags" to biologics. As proof of principle, genetically encoded, cysteine meditope tags were added to the N- and/or C-termini of fluorescent proteins, nanobodies, and affibodies, each expressed in bacteria, purified to homogeneity, and efficiently conjugated to different memAbs and meFabs. We further show that multiple T-cell and Her2-targeting bispecific molecules using this strategy potently activate T-cell signaling pathways in vitro. Finally, the resulting products are highly stable as evidenced by serum stability assays (>14 d at 37 degrees C) and in vivo imaging of tumor xenographs. Collectively, the platform offers the opportunity to build and exchange an array of functional moieties, including protein biologics, among any cysteine memAb or Fab to rapidly create, test, and optimize stable, multifunctional biologics. PMID- 29763555 TI - Biodegradation of Polyethylene and Plastic Mixtures in Mealworms (Larvae of Tenebrio molitor) and Effects on the Gut Microbiome. AB - Recent studies have demonstrated the ability for polystyrene (PS) degradation within the gut of mealworms ( Tenebrio molitor). To determine whether plastics may be broadly susceptible to biodegradation within mealworms, we evaluated the fate of polyethylene (PE) and mixtures (PE + PS). We find that PE biodegrades at comparable rates to PS. Mass balances indicate conversion of up 49.0 +/- 1.4% of the ingested PE into a putative gas fraction (CO2). The molecular weights ( Mn) of egested polymer residues decreased by 40.1 +/- 8.5% in PE-fed mealworms and by 12.8 +/- 3.1% in PS-fed mealworms. NMR and FTIR analyses revealed chemical modifications consistent with degradation and partial oxidation of the polymer. Mixtures likewise degraded. Our results are consistent with a nonspecific degradation mechanism. Analysis of the gut microbiome by next-generation sequencing revealed two OTUs ( Citrobacter sp. and Kosakonia sp.) strongly associated with both PE and PS as well as OTUs unique to each plastic. Our results suggest that adaptability of the mealworm gut microbiome enables degradation of chemically dissimilar plastics. PMID- 29763557 TI - Calculation of the Saturation Properties of a Model Octane-Water System Using Monte Carlo Simulation. AB - We use Monte Carlo simulation to compute the saturation properties of a model octane-water system. The system phase separates into water-rich liquid and vapor phases, octane-rich liquid and vapor phases, and water-rich liquid and octane rich liquid phases at various conditions. We outline a strategy for determining the saturation properties of the mixture over a wide range of temperatures, pressures, and compositions. The approach begins with direct calculations that enable one to locate a single saturation point. A variety of expanded ensemble schemes are then used to trace saturation curves along paths of interest. We show how the overall strategy provides a means to construct pressure-composition diagrams at a fixed temperature and temperature-composition diagrams at a fixed pressure. In addition, we demonstrate how the approach is used to trace the liquid-liquid-vapor triple line over a wide range of temperatures. Simulation data are compared with experimental data, when available. Overall, our results show that the approach provides an efficient means to calculate the saturation properties of a binary system. PMID- 29763556 TI - Gate-Defined Quantum Confinement in InSe-Based van der Waals Heterostructures. AB - Indium selenide, a post-transition metal chalcogenide, is a novel two-dimensional (2D) semiconductor with interesting electronic properties. Its tunable band gap and high electron mobility have already attracted considerable research interest. Here we demonstrate strong quantum confinement and manipulation of single electrons in devices made from few-layer crystals of InSe using electrostatic gating. We report on gate-controlled quantum dots in the Coulomb blockade regime as well as one-dimensional quantization in point contacts, revealing multiple plateaus. The work represents an important milestone in the development of quality devices based on 2D materials and makes InSe a prime candidate for relevant electronic and optoelectronic applications. PMID- 29763558 TI - Atmospheric Oxidation Mechanism and Kinetics of Hydrofluoroethers, CH3OCF3, CH3OCHF2, and CHF2OCH2CF3, by OH Radical: A Theoretical Study. AB - In the present work, the reaction mechanism of two segregated hydrofluoroethers (HFEs), CH3OCF3 (HFE-143a) and CH3OCHF2 (HFE-152a), and a nonsegregated HFE, CHF2OCH2CF3 (HFE-245fa2), with OH radical is studied using electronic structure calculations. The initial reaction between HFE and OH radical is studied by considering two (three for CHF2OCH2CF3) pathways, H-atom abstraction and C-O bond breaking, OH addition reaction and C-C bond breaking, and OH addition reaction, which leads to the formation of alkyl radical intermediate. The dominant atmospheric fate of initially formed alkyl radical intermediate is its reaction with O2. The peroxy radicals thus formed exit through the reaction with HO2 radical and NO radical resulting in the formation of products, carbonyl fluoride (COF2), trifluoromethylformate, trifluoro(hydroperoxymethoxy)methane, difluoro(hydroperoxy methoxy)methane, difluoromethylformate, 2-(difluoromethoxy) 1,1,1-trifluoro-2-hydroperoxyethane, and difluoromethyl ester. The rate constant is calculated for the initial H-atom abstraction reaction using canonical variational transition state theory with small curvature tunnelling corrections over the temperature range 272-350 K. The atmospheric lifetime and global warming potential of HFEs are obtained from the calculated reaction potential energy surface and rate constant. The results are discussed with respect to the atmospheric implications of CH3OCF3 (HFE-143a), CH3OCHF2 (HFE-152a), and CHF2OCH2CF3 (HFE-245fa2). PMID- 29763559 TI - Long-Acting Release Microspheres Containing Novel GLP-1 Analog as an Antidiabetic System. AB - Glucagon-like peptide 1 (GLP-1) has recently received significant attention as an efficacious way to treat diabetes mellitus. However, the short half-life of the peptide limits its clinical application in diabetes. In our previous study, a novel GLP-1 analog (PGLP-1) with a longer half-life was synthesized and evaluated. Herein, we prepared the PGLP-1-loaded poly(d,l-lactide- co-glycolide) microspheres to achieve long-term effects on blood glucose control. The incorporation of zinc ion into the formulation can effectively decrease the initial burst release, and a uniform drug distribution was obtained, in contrast to native PGLP-1 encapsulated microspheres. We demonstrated that the solubility of the drug encapsulated in microspheres played an important role in in vitro release behavior and drug distribution inside the microspheres. The Zn-PGLP-1 microspheres had a prominent acute glucose reduction effect in the healthy mice. A hypoglycemic effect was observed in the streptozotocin (STZ) induced diabetic mice through a 6-week treatment of Zn-PGLP-1-loaded microspheres. Meanwhile, the administration of Zn-PGLP-1 microspheres led to the beta-cell protection and stimulation of insulin secretion. The novel GLP-1 analog-loaded sustained microspheres may greatly improve patient compliance along with a desirable safety feature. PMID- 29763560 TI - Mechanism of Ti-Catalyzed Oxidative Nitrene Transfer in [2 + 2 + 1] Pyrrole Synthesis from Alkynes and Azobenzene. AB - A combined computational and experimental study on the mechanism of Ti-catalyzed formal [2 + 2 + 1] pyrrole synthesis from alkynes and aryl diazenes is reported. This reaction proceeds through a formally TiII/TiIV redox catalytic cycle as determined by natural bond orbital (NBO) and intrinsic bond orbital (IBO) analysis. Kinetic analysis of the reaction of internal alkynes with azobenzene reveals a complex equilibrium involving Ti?NPh monomer/dimer equilibrium and Ti?NPh + alkyne [2 + 2] cycloaddition equilibrium along with azobenzene and pyridine inhibition equilibria prior to rate-determining second alkyne insertion. Computations support this kinetic analysis, provide insights into the structure of the active species in catalysis and the roles of solvent, and provide a new mechanism for regeneration of the Ti imido catalyst via disproportionation. Reductive elimination from a 6-membered azatitanacyclohexadiene species to generate pyrrole-bound TiII is surprisingly facile and occurs through a unique electrocyclic reductive elimination pathway similar to a Nazarov cyclization. The resulting TiII species are stabilized through backbonding into the pi* of the pyrrole framework, although solvent effects also significantly stabilize free TiII species that are required for pyrrole loss and catalytic turnover. Further computational and kinetic analysis reveals that in complex reactions with unysmmetric alkynes the resulting pyrrole regioselectivity is driven primarily by steric effects for terminal alkynes and inductive effects for internal alkynes. PMID- 29763561 TI - Evaluation of Feruloylated and p-Coumaroylated Arabinosyl Units in Grass Arabinoxylans by Acidolysis in Dioxane/Methanol. AB - The arabinosyl side chains of grass arabinoxylans are partially acylated by p coumarate ( pCA) and ferulate (FA). These aromatic side chains can cross-couple wall polymers resulting in modulation of cell wall physical properties. The determination of p-coumaroylated and feruloylated arabinose units has been the target of analytical efforts with trifluoroacetic acid hydrolysis the standard method to release feruloylated and p-coumaroylated arabinose units from arabinoxylans. Herein, we report on a more robust method to measure these acylated units. Acidolysis of extractive-free grass samples in a dioxane/methanol/aqueous 2 M HCl mixture provided the methyl 5- O- p-coumaroyl- and 5- O-feruloyl-l-arabinofuranoside anomers ( pCA-MeAra and FA-MeAra). These conjugates were readily analyzed by liquid chromatography combined with both UV and MS detection. The method revealed the variability of the relative acylation of arabinose units by pCA or FA in grass cell walls. This methodology will permit delineation of hydroxycinnamate acylation patterns in arabinoxylans. PMID- 29763562 TI - Unraveling the Enzymatic Activity of Oxygenated Carbon Nanotubes and Their Application in the Treatment of Bacterial Infections. AB - Carbon nanotubes (CNTs) and their derivatives have emerged as a series of efficient biocatalysts to mimic the function of natural enzymes in recent years. However, the unsatisfiable enzymatic efficiency usually limits their practical usage ranging from materials science to biotechnology. Here, for the first time, we present the synthesis of several oxygenated-group-enriched carbon nanotubes (o CNTs) via a facile but green approach, as well as their usage as high-performance peroxidase mimics for biocatalytic reaction. Exhaustive characterizations of the enzymatic activity of o-CNTs have been provided by exploring the accurate effect of various oxygenated groups on their surface including carbonyl, carboxyl, and hydroxyl groups. Because of the "competitive inhibition" effect among all of these oxygenated groups, the catalytic efficiency of o-CNTs is significantly enhanced by weakening the presence of noncatalytic sites. Furthermore, the admirable enzymatic activity of these o-CNTs has been successfully applied in the treatment of bacterial infections, and the results of both in vitro and in vivo nanozyme-mediated bacterial clearance clearly demonstrate the feasibility of o CNTs as robust peroxidase mimics to effectively decrease the bacterial viability under physiological conditions. We believe that the present study will not only facilitate the construction of novel efficient nanozymes by rationally adjusting the degree of the "competitive inhibition" effect, but also broaden the biological usage of o-CNT-based nanomaterials via their satisfactory enzymatic activity. PMID- 29763564 TI - Inhibitors of Melanogenesis: An Updated Review. AB - Melanins are pigment molecules that determine the skin, eye, and hair color of the human subject to its amount, quality, and distribution. Melanocytes synthesize melanin and provide epidermal protection from various stimuli, such as harmful ultraviolet radiation, through the complex process called melanogenesis. However, serious dermatological problems occur when there is excessive production of melanin in different parts of the human body. These include freckles, melasma, senile lentigo, pigmented acne scars, and cancer. Therefore, controlling the production of melanin is an important approach for the treatment of pigmentation related disorderes. In this Perspective, we focus on the inhibitors of melanogenesis that directly/indirectly target a key enzyme tyrosinase as well as its associated signaling pathways. PMID- 29763563 TI - Rh(DPEPhos)-Catalyzed Alkyne Hydroacylation Using beta-Carbonyl-Substituted Aldehydes: Mechanistic Insight Leads to Low Catalyst Loadings that Enables Selective Catalysis on Gram-Scale. AB - The detailed mechanism of the hydroacylation of beta-amido-aldehyde, 2,2-dimethyl 3-morpholino-3-oxopropanal, with 1-octyne using [Rh( cis-kappa2-P,P DPEPhos)(acetone)2][BArF4]-based catalysts, is described [ArF = (CF3)2C6H3]. A rich mechanistic landscape of competing and interconnected hydroacylation and cyclotrimerization processes is revealed. An acyl-hydride complex, arising from oxidative addition of aldehyde, is the persistent resting state during hydroacylation, and quaternary substitution at the beta-amido-aldehyde strongly disfavors decarbonylation. Initial rate, KIE, and labeling studies suggest that the migratory insertion is turnover-limiting as well as selectivity determining for linear/branched products. When the concentration of free aldehyde approaches zero at the later stages of catalysis alkyne cyclotrimerization becomes competitive, to form trisubstituted hexylarenes. At this point, the remaining acyl-hydride turns over in hydroacylation and the free alkyne is now effectively in excess, and the resting state moves to a metallacyclopentadiene and eventually to a dormant alpha-pyran-bound catalyst complex. Cyclotrimerization thus only becomes competitive when there is no aldehyde present in solution, and as aldehyde binds so strongly to form acyl-hydride when this happens will directly correlate to catalyst loading: with low loadings allowing for free aldehyde to be present for longer, and thus higher selectivites to be obtained. Reducing the catalyst loading from 20 mol % to 0.5 mol % thus leads to a selectivity increase from 96% to ~100%. An optimized hydroacylation reaction is described that delivers gram scale of product, at essentially quantitative levels, using no excess of either reagent, at very low catalyst loadings, using minimal solvent, with virtually no workup. PMID- 29763566 TI - Low-Power Optical Trapping of Nanoparticles and Proteins with Resonant Coaxial Nanoaperture Using 10 nm Gap. AB - We present optical trapping with a 10 nm gap resonant coaxial nanoaperture in a gold film. Large arrays of 600 resonant plasmonic coaxial nanoaperture traps are produced on a single chip via atomic layer lithography with each aperture tuned to match a 785 nm laser source. We show that these single coaxial apertures can act as efficient nanotweezers with a sharp potential well, capable of trapping 30 nm polystyrene nanoparticles and streptavidin molecules with a laser power as low as 4.7 mW. Furthermore, the resonant coaxial nanoaperture enables real-time label free detection of the trapping events via simple transmission measurements. Our fabrication technique is scalable and reproducible, since the critical nanogap dimension is defined by atomic layer deposition. Thus our platform shows significant potential to push the limit of optical trapping technologies. PMID- 29763565 TI - Controllable Growth and Formation Mechanisms of Dislocated WS2 Spirals. AB - Two-dimensional (2D) layered metal dichalcogenides can form spiral nanostructures by a screw-dislocation-driven mechanism, which leads to changes in crystal symmetry and layer stackings that introduce attractive physical properties different from their bulk and few-layer nanostructures. However, controllable growth of spirals is challenging and their growth mechanisms are poorly understood. Here, we report the controllable growth of WS2 spiral nanoplates with different stackings by a vapor phase deposition route and investigate their formation mechanisms by combining atomic force microscopy with second harmonic generation imaging. Previously not observed "spiral arm" features could be explained as covered dislocation spiral steps, and the number of spiral arms correlates with the number of screw dislocations initiated at the bottom plane. The supersaturation-dependent growth can generate new screw dislocations from the existing layers, or even new layers templated by existing screw dislocations. Different number of dislocations and orientation of new layers result in distinct morphologies, different layer stackings, and more complex nanostructures, such as triangular spiral nanoplates with hexagonal spiral pattern on top. This work provides the understanding and control of dislocation-driven growth of 2D nanostructures. These spiral nanostructures offer diverse candidates for probing the physical properties of layered materials and exploring new applications in functional nanoelectronic and optoelectronic devices. PMID- 29763567 TI - Super-Temporal-Resolved Microscopy Reveals Multistep Desorption Kinetics of alpha Lactalbumin from Nylon. AB - Insight into the mechanisms driving protein-polymer interactions is constantly improving due to advances in experimental and computational methods. In this study, we used super-temporal-resolved microscopy (STReM) to study the interfacial kinetics of a globular protein, alpha-lactalbumin (alpha-LA), adsorbing at the water-nylon 6,6 interface. The improved temporal resolution of STReM revealed that residence time distributions involve an additional step in the desorption process. Increasing the ionic strength in the bulk solution accelerated the desorption rate of alpha-LA, attributed to adsorption-induced conformational changes. Ensemble circular dichroism measurements were used to support a consecutive reaction mechanism. Without the improved temporal resolution of STReM, the desorption intermediate was not resolvable, highlighting both STReM's potential to uncover new kinetic mechanisms and the continuing need to push for better time and space resolution. PMID- 29763568 TI - Near-Infrared Activatable Phthalocyanine-Poly-L-Glutamic Acid Conjugate: Enhanced in Vivo Safety and Antitumor Efficacy toward an Effective Photodynamic Cancer Therapy. AB - We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near infrared (NIR) light absorptivity (lambdamax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 +/- 5%) when compared to high dose ZnPc (8 mg/kg, -50 +/- 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 +/- 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT. PMID- 29763569 TI - Direct Observation of the Dipole-Induced Energetic Disorder in Rubrene Single Crystal Transistors by Scanning Kelvin Probe Microscopy. AB - It is commonly accepted that gate dielectric dipoles can induce energetic disorder in organic field-effect transistors. However, convincing experimental evidence that directly demonstrate this effect are still in lack. In this work, we present a combined experimental and theoretical study to reveal this effect. We have investigated the temperature-dependent mobility of two rubrene single crystal transistors with different polymer dielectrics. Model fittings of the data indicate there is higher energetic disorder in the device on dielectric with larger permittivity. Scanning Kelvin probe microscopy was then employed to directly characterize the density of tail states, which is correlated with energetic disorder, in the devices. The results further confirm that dielectric dipoles can increase energetic disorder in organic semiconductors. PMID- 29763570 TI - Influence of Multiple Conformations and Paths on Rate Constants and Product Branching Ratios. Thermal Decomposition of 1-Propanol Radicals. AB - The potential energy surface involved in the thermal decomposition of 1-propanol radicals was investigated in detail using automated codes (tsscds2018 and Q2DTor). From the predicted elementary reactions, a relevant reaction network was constructed to study the decomposition at temperatures in the range 1000-2000 K. Specifically, this relevant network comprises 18 conformational reaction channels (CRCs), which in general exhibit a large wealth of conformers of reactants and transition states. Rate constants for all the CRCs were calculated using two approaches within the formulation of variational transition-state theory (VTST), as incorporated in the TheRa program. The simplest, one-well (1W) approach considers only the most stable conformer of the reactant and that of the transition state. In the second, more accurate approach, contributions from all the reactant and transition-state conformers are taken into account using the multipath (MP) formulation of VTST. In addition, kinetic Monte Carlo (KMC) simulations were performed to compute product branching ratios. The results show significant differences between the values of the rate constants calculated with the two VTST approaches. In addition, the KMC simulations carried out with the two sets of rate constants indicate that, depending on the radical considered as reactant, the 1W and the MP approaches may display different qualitative pictures of the whole decomposition process. PMID- 29763571 TI - Attentional bias toward emotional stimuli in accidentally injured Chinese patients with different posttraumatic growth levels. AB - Extensive evidence has been obtained that supports an association between an attentional bias (AB) toward negative stimuli and vulnerability to stress-related psychopathology, little is known regarding the characteristics of individual AB in different posttraumatic growth (PTG) levels. The current study used a modified dot-probe task to investigate if individual differences in AB towards either positive or negative emotional stimuli, are related to self-reported PTG. A sample of 202 patients completed the experiment. Patients with low levels of PTG did not exhibit AB toward negative or positive stimuli, patients with medium levels of PTG had difficulty disengaging attention from negative stimuli, patients with high levels of PTG had difficulty disengaging attention from positive stimuli. And the AB towards positive stimuli was only predictive for PTG. An implication of this finding is that there are different characteristics of implicit cognitive processing in patients with different levels of PTG, suggesting the necessity of psychological intervention on the accidentally injured patients. PMID- 29763572 TI - Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials. AB - RATIONALE: Roflumilast reduces exacerbations in patients with severe chronic obstructive pulmonary disease associated with chronic bronchitis and a history of exacerbations. Further characterization of patients most likely to benefit is warranted. OBJECTIVES: Define characteristics that most robustly identify patients who derive greatest exacerbation risk reduction with roflumilast. METHODS: Predefined, pooled analyses of REACT (Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment; NCT01329029) and RE2SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy; NCT01443845) multicenter, randomized, double-blind, placebo-controlled studies. The primary endpoint was rate of moderate or severe exacerbations per patient per year. MEASUREMENTS AND MAIN RESULTS: In the overall intention-to treat population (n = 4,287), roflumilast reduced moderate or severe exacerbations by 12.3% (rate ratio, 0.88, 95% confidence interval, 0.80-0.97; P = 0.0086) and severe exacerbations by 16.1% (0.84; 0.71-0.99; P = 0.0409) versus placebo. The reduction in moderate or severe exacerbations with roflumilast was most pronounced in patients who had been hospitalized for an exacerbation in the prior year (0.74; 0.63-0.88; P = 0.0005); had more than two exacerbations in the prior year (0.79; 0.65-0.96; P = 0.0160); or had baseline eosinophils >=150 cells/MUl (0.81; 0.71-0.93; P = 0.0020), >=150 to <300 cells/MUl (0.84; 0.71 0.98; P = 0.0282), or >=300 cells/MUl (0.77; 0.61-0.97; P = 0.0264). Similar subgroup results were noted for severe exacerbations. In patients with prior hospitalization and higher baseline blood eosinophil concentrations, roflumilast reduced moderate or severe exacerbations by 34.5% at >=150 cells/MUl (0.65; 0.52 0.82; P = 0.0003) and 42.7% at >=300 cells/MUl (0.57; 0.37-0.88; P = 0.0111) versus placebo. CONCLUSIONS: This prespecified, pooled analysis confirms the benefit of roflumilast in decreasing exacerbations in patients with prior hospitalization for exacerbation, greater exacerbation frequency, and higher (>=150 cells/MUl, >=150 to <300 cells/MUl, or >=300 cells/MUl) baseline blood eosinophil count. PMID- 29763573 TI - A Cross-Sectional Assessment of Rhinitis Symptoms and Nasal Patency in Relation to Welding Exposure. PMID- 29763574 TI - How low can you go? Analytical performance of five automated testosterone immunoassays. AB - BACKGROUND: Testosterone is commonly measured using immunoassays, yet concerns with the accuracy and quality of testing by these methods exist, particularly for low testosterone concentrations. Study objectives were to evaluate selective performance characteristics, including functional sensitivity (FS), of 5 automated immunoassays for total testosterone. METHODS: FS, imprecision, assay interference, limit of blank, linearity, and accuracy were assessed using the Abbott ARCHITECT i2000SR, SIEMENS ADVIA Centaur and IMMULITE 2000, Beckman Coulter DxI 800, and Roche MODULAR E170. Comparisons to an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method were performed using patient samples from men, women, boys, and girls. RESULTS: FS at 20% coefficient of variation (CV) for the ARCHITECT, Centaur, DxI, E170 and IMMULITE assays were 0.14, 1.23, 0.36, 0.77, 3.49 nmol/L, respectively. Total CVs for the 5-day imprecision study were <= 9.0% for all methods. All assays met manufacturer's claims for hemolysis, icterus, and lipemia interference and limit of blank. Dilution linearity studies had deviations from the target recoveries ranging from 3.4% (ARCHITECT) to 14.3% (DxI). Using National Institute of Standards and Technology Standard Reference Material 971, recoveries ranged from 79.2-149.2% (DxI, male and female, respectively). When compared to LC-MS/MS, more immunoassays under-recovered in men and women and over-recovered in boys and girls. Slopes ranged from 0.71 (IMMULITE, women) to 1.35 (DxI, boys). The combined average for percent bias was higher in boys (28.0%) than men (11.6%), women (22.8%), and girls (25.7%). CONCLUSIONS: Challenges with accurately measuring testosterone appear to remain for some immunoassays, but not all. While most immunoassays remain optimized for concentrations observed in healthy men, some showed acceptable performance when challenged at lower concentrations. PMID- 29763575 TI - Social isolation reduces serotonergic fiber density in the inferior colliculus of female, but not male, mice. AB - Early-life experiences, including maternal deprivation and social isolation during adolescence, have a profound influence on a range of adult social behaviors. Post-weaning social isolation in rodents influences behavior in part through the alteration of neuromodulatory systems, including the serotonergic system. Of significance to social behavior, the serotonergic system richly innervates brain areas involved in vocal communication, including the auditory system. However, the influence of isolation on serotonergic input to the auditory system remains underexplored. Here, we assess whether 4 weeks of post-weaning individual housing alters serotonergic fiber density in the inferior colliculus (IC), an auditory midbrain nucleus in which serotonin alters auditory-evoked activity. Individually housed male and female mice were compared to conspecifics housed socially in groups of three. Serotonergic projections were subsequently visualized with an antibody to the serotonin transporter, which labels serotonergic fibers with relatively high selectivity. Fiber densities were estimated in the three major subregions of the IC using line-scan intensity analysis. Individually housed female mice showed a significantly reduced fiber density relative to socially housed females, which was accompanied by a lower body weight in individually housed females. In contrast, social isolation did not affect serotonergic fiber density in the IC of males. This finding suggests that sensitivity of the serotonergic system to social isolation is sex-dependent, which could be due to a sex difference in the effect of isolation on psychosocial stress. Since serotonin availability depends on social context, this finding further suggests that social isolation can alter the acute social regulation of auditory processing. PMID- 29763577 TI - Comparison of the Regenerative Effects of Platelet-Rich Fibrin and Plasma Rich in Growth Factors on Injured Peripheral Nerve: An Experimental Study. AB - PURPOSE: The aim of this study was to investigate the effects of platelet-rich fibrin (PRF) and plasma rich in growth factors (PRGF) on peripheral nerve injury in the early period of healing. MATERIAL AND METHODS: Thirty Wistar albino rats were used in this study. Rats were divided into control (C), damaged (D), PRF, and PRGF groups. The left sciatic nerves of each group were identified as group C. Crush-type injury was performed on the right sciatic nerves of the D, PRF, and PRGF groups. In the PRF and PRGF groups, blood 2 mL was obtained to prepare the PRF and PRGF and the biomaterials were applied to the injured nerve area. After 8 weeks, functional, electrophysiologic, and stereological evaluations were performed. RESULTS: For the electrophysiologic evaluation, the latency and amplitude values in the D, PRF, and PRGF groups were significantly lower than those in the C group (P > .05). According to the sciatic functional index result, there were significant differences between groups D and PRF and between groups D and PRGF (P = .000). For the stereological evaluations, although no significant difference was observed between the PRGF and C groups (P > .05), a significant difference was observed among the D, PRF, and PRGF groups for myelinated axon number. There were significant differences between groups D and PRF and between groups D and PRGF for axon area (P = .021 and .001, respectively). No significant difference was observed among the D, PRF, and PRGF groups for myelin sheath thickness and ratio of axon area to myelin sheath thickness (P > .05). CONCLUSIONS: The results of this study suggest that PRGF increases nerve regeneration in the early period of healing and that the limited early action of PRF should be re-evaluated in the late period. PMID- 29763578 TI - An Homage to the In Focus Section of JOGNN. PMID- 29763579 TI - Social Ecological Examination of Factors That Influence the Treatment of Newborns With Neonatal Abstinence Syndrome. AB - Health care systems are challenged with issues of overdiagnosis and overtreatment. Neonatal abstinence syndrome (NAS) may be overdiagnosed with standardized assessment protocols and may be overtreated with current NICU-based models of care. Clinical approaches to caring for neonates with NAS and their families have not significantly changed for 40 years, and there is growing interest in revisiting long-standing routine practices. I used Bronfenbrenner's social ecological systems framework to organize an exploration of factors that contribute to overdiagnosis and overtreatment in the care of neonates with NAS. PMID- 29763576 TI - Gi protein functions in thalamic neurons to decrease orofacial nociceptive response. AB - Orofacial pain includes neuronal pathways that project from the trigeminal nucleus to and through the thalamus. What role the ventroposterior thalamic complex (VP) has on orofacial pain transmission is not understood. To begin to address this question an inhibitory G protein (Gi) designer receptor exclusively activated by a designer drug (DREADD) was transfected in cells of the VP using adeno-associated virus isotype 8. Virus infected cells were identified by a fluorescent tag and immunostaining. Cells were silenced after injecting the designer drug clozapine-n-oxide, which binds the designer receptor activating Gi. Facial rubbing and local field potentials (LFP) in the VP were then recorded in awake, free moving Sprague Dawley rats after formalin injection of the masseter muscle to induce nociception. Formalin injection significantly increased LFP and the nociceptive behavioral response. Activation of DREADD Gi with clozapine-n oxide significantly reduced LFP in the VP and reduced the orofacial nociceptive response. Because DREADD silencing can result from Gi-coupled inwardly-rectifying potassium channels (GIRK), the GIRK channel blocker tertiapin-Q was injected. Injection of GIRK blocker resulted in an increase in the nociceptive response and increased LFP activity. Immunostaining of the VP for glutamate vesicular transporter (VGLUT2) and gamma-aminobutyric acid vesicular transporter (VGAT) indicated a majority of the virally transfected cells were excitatory (VGLUT2 positive) and a minority were inhibitory (VGAT positive). We conclude first, that inhibition of the excitatory neurons within the VP reduced electrical activity and the orofacial nociceptive response and that the effect on excitatory neurons overwhelmed any change resulting from inhibitor neurons. Second, inhibition of LFP and nociception was due, in part, to GIRK activation. PMID- 29763580 TI - Detailed investigation of anticancer activity of sulfamoyl benz(sulfon)amides and 1H-pyrazol-4-yl benzamides: An experimental and computational study. AB - Cancer is the second leading cause of mortality worldwide. Therapeutic approach to cancer is a multi-faceted one, whereby many cellular/enzymatic pathways have been discovered as important drug targets for the treatment of cancer. A major disadvantage of most of the currently available anticancer drugs is their non selective cytotoxicity towards cancerous as well as healthy cells. Another major hurdle in cancer therapy is the development of resistance to anticancer drugs. This necessitates the discovery of new molecules with potent and selective cytotoxic activity towards only cancerous cells, with minimum or no damage to the normal/healthy cells. Herein we report detailed investigation into the anticancer activity of sulfamoyl benz(sulfon)amides (1a-1g, 2a-2k) and 1H-pyrazol-4-yl benzamides (3a-3j) against three cancer cell lines, breast cancer cells (MCF-7), bone-marrow cancer cells (K-562) and cervical cancer cells (HeLa). For comparison, screening against healthy baby hamster kidney cells (BHK-21) was carried out. All compounds exhibited selective cytotoxicity towards cancerous cells. Cell cycle analysis was carried out using flow cytometry, followed by fluorescence microscopic analysis. DNA interaction and docking studies were also carried out. PMID- 29763581 TI - Intraoperative ultrasound-assisted enucleation of residual fibroids following laparoscopic myomectomy. AB - AIM: To investigate if intraoperative ultrasounds by laparoscopic and transvaginal ultrasonography (LUS and TVS) could improve enucleating the residual fibroids following laparoscopic myomectomy (LM). METHODS: From March to December 2016, 78 women with uterine fibroids underwent LM, LUS and TVS were applied to detect residual fibroids and to guide surgeons to enucleate them after the visible fibroids were removed during LM operation. RESULTS: The total number of residual fibroids found by LUS was 140, and the total number found by TVS was 127 following LM (P = 0.03). LUS is statistically superior to TVS in the detection of residual fibroids in the anterior wall (P = 0.004), in the detection of intramural fibroids (P = 0.002), and in the detection of fibroids with a diameter ranging from 0.5 to 1 cm (P = 0.002). According to the total number of enucleated fibroids by LM, patients were divided into three groups (Group 1: 2 to 4, Group 2: 5 to 7 and Group 3: >=8 fibroid counts). The percentages of patients in each group with residual fibroids at the end of surgery were 22.2%, 51.9% and 66.7% respectively. CONCLUSIONS: Both LUS and TVS are beneficial to surgical treatment of fibroids by assisting enucleation of residual fibroids following LM, while LUS is more effective in localizing residual fibroids than TVS. PMID- 29763582 TI - The pathogenic role of dendritic cells in non-infectious anterior uveitis. AB - BACKGROUND: Anterior uveitis (AU) is characterised by infiltration of immune cells into the anterior chamber of the eye. Dendritic cells (DC) are professional antigen presenting cells that initiate and promote inflammation. This study aims to characterise DC in AU and to examine the effects of aqueous humor (AqH) on DC maturation and function. METHODS: The frequency and phenotype of AU and healthy control (HC) circulating DC was examined. AU and HC AqH was immunostained and assessed by flow cytometry. The effect of AU and HC AqH on DC activation and maturation was examined and subsequent effects on CD4+ T cell proliferation assessed. RESULTS: AU peripheral blood demonstrated decreased circulating myeloid and plasmacytoid DC. Within AU AqH, three populations of CD45+ cells were significantly enriched compared to HC; DCs (CD11c+ HLA-DR+), neutrophils (CD15+ CD11c+) and T cells (CD4+ and CD8+). A significant increase in IFNgamma, IL8 and IL6 was observed in the AU AqH, which was also significantly higher than that of paired serum. AU AqH induced expression of CD40 and CD80 on DC, which resulted in increased T cell proliferation and the production of GM-CSF, IFNgamma and TNFalpha. CONCLUSION: DC are enriched at the site of inflammation in AU. Our data demonstrate an increase in inflammatory mediators in the AU inflamed microenvironment. AU AqH can activate DC, leading to subsequent proliferation and activation of effector T cells. Thus, the AU microenvironment contributes to immune cell responses and intraocular inflammation. PMID- 29763583 TI - Muller glial cells contribute to dim light vision in the spectacled caiman (Caiman crocodilus fuscus): Analysis of retinal light transmission. AB - In this study, we show the capability of Muller glial cells to transport light through the inverted retina of reptiles, specifically the retina of the spectacled caimans. Thus, confirming that Muller cells of lower vertebrates also improve retinal light transmission. Confocal imaging of freshly isolated retinal wholemounts, that preserved the refractive index landscape of the tissue, indicated that the retina of the spectacled caiman is adapted for vision under dim light conditions. For light transmission experiments, we used a setup with two axially aligned objectives imaging the retina from both sides to project the light onto the inner (vitreal) surface and to detect the transmitted light behind the retina at the receptor layer. Simultaneously, a confocal microscope obtained images of the Muller cells embedded within the vital tissue. Projections of light onto several representative Muller cell trunks within the inner plexiform layer, i.e. (i) trunks with a straight orientation, (ii) trunks which are formed by the inner processes and (iii) trunks which get split into inner processes, were associated with increases in the intensity of the transmitted light. Projections of light onto the periphery of the Muller cell endfeet resulted in a lower intensity of transmitted light. In this way, retinal glial (Muller) cells support dim light vision by improving the signal-to-noise ratio which increases the sensitivity to light. The field of illuminated photoreceptors mainly include rods reflecting the rod dominance of the of tissue. A subpopulation of Muller cells with downstreaming cone cells led to a high-intensity illumination of the cones, while the surrounding rods were illuminated by light of lower intensity. Therefore, Muller cells that lie in front of cones may adapt the intensity of the transmitted light to the different sensitivities of cones and rods, presumably allowing a simultaneous vision with both receptor types under dim light conditions. PMID- 29763584 TI - Sequence-to-Conformation Relationships of Disordered Regions Tethered to Folded Domains of Proteins. AB - Intrinsically disordered proteins and regions (IDPs/IDRs) are characterized by well-defined sequence-to-conformation relationships (SCRs). These relationships refer to the sequence-specific preferences for average sizes, shapes, residue specific secondary structure propensities, and amplitudes of multiscale conformational fluctuations. SCRs are discerned from the sequence-specific conformational ensembles of IDPs. A vast majority of IDPs are actually tethered to folded domains (FDs). This raises the question of whether or not SCRs inferred for IDPs are applicable to IDRs tethered to FDs. Here, we use atomistic simulations based on a well-established forcefield paradigm and an enhanced sampling method to obtain comparative assessments of SCRs for 13 archetypal IDRs modeled as autonomous units, as C-terminal tails connected to FDs, and as linkers between pairs of FDs. Our studies uncover a set of general observations regarding context-independent versus context-dependent SCRs of IDRs. SCRs are minimally perturbed upon tethering to FDs if the IDRs are deficient in charged residues and for polyampholytic IDRs where the oppositely charged residues within the sequence of the IDR are separated into distinct blocks. In contrast, the interplay between IDRs and tethered FDs has a significant modulatory effect on SCRs if the IDRs have intermediate fractions of charged residues or if they have sequence intrinsic conformational preferences for canonical random coils. Our findings suggest that IDRs with context-independent SCRs might be independent evolutionary modules, whereas IDRs with context-dependent SCRs might co-evolve with the FDs to which they are tethered. PMID- 29763585 TI - Seasonal changes in acute stressor-mediated plasma glucocorticoid regulation in New World flying squirrels. AB - Southern flying squirrels have higher circulating cortisol levels than most vertebrates. However, regulation of tissue exposure to cortisol by the hormone's carrier protein, corticosteroid-binding globulin (CBG), appears to be altered due to lower-than-expected CBG expression levels, and a reduced affinity for cortisol. To assess the capacity of flying squirrels to regulate acute stress mediated cortisol levels, we used the dexamethasone (DEX) suppression test followed by the adrenocorticotropic hormone (ACTH) stimulation test in both the breeding and non-breeding seasons, and quantified resultant changes in plasma cortisol and relative CBG levels. Regulation of cortisol via negative feedback, and the acute stress response appeared to function as they do in other vertebrates during the breeding season, but response to DEX in the non-breeding season showed that the sensitivity of the negative feedback mechanism changed across seasons. The relatively high concentrations of DEX required to induce negative feedback suggests that southern flying squirrels have a reduced sensitivity to cortisol compared with other vertebrates, and that high circulating cortisol levels may be required to compensate for low target tissue responsiveness in this species. Cortisol, but not CBG levels, were higher during the non-breeding than breeding season, and females had higher cortisol and CBG levels than males. Our data suggest that flying squirrel cortisol levels are regulated by negative feedback at a higher set point than in related species. Seasonal changes in cortisol levels, target tissue sensitivity to DEX, and in the capacity to respond to stressors appear to be part of the underlying physiology of southern flying squirrels, and may be required to maximize fitness in the face of tradeoffs between survival and reproduction. PMID- 29763586 TI - Postnatal testis development in the collared peccary (Tayassu tajacu), with emphasis on spermatogonial stem cells markers and niche. AB - Collared peccaries (Tayassu tajacu) present a unique testis cytoarchitecture, where Leydig cells (LC) are mainly located in cords around the seminiferous tubules (ST) lobes. This peculiar arrangement is very useful to better investigate and understand the role of LC in spermatogonial stem cells (SSCs) biology and niche. Recent studies from our laboratory using adult peccaries have shown that the undifferentiated type A spermatogonia (Aund or SSCs) are preferentially located in ST regions adjacent to the intertubular compartment without LC. Following these studies, our aims were to investigate the collared peccary postnatal testis development, from birth to adulthood, with emphasis on the establishment of LC cytoarchitecture and the SSCs niche. Our findings demonstrated that the unique LC cytoarchitecture is already present in the neonate peccary's testis, indicating that this arrangement is established during fetal development. Based on the most advanced germ cell type present at each time period evaluated, puberty (the first sperm release in the ST lumen) in this species was reached at around one year of age, being preceded by high levels of estradiol and testosterone and the end of Sertoli cell proliferation. Almost all gonocytes and SSCs expressed Nanos1, Nanos2 and GFRA1. The analysis of SSCs preferential location indicated that the establishment of SSCs niche is coincident with the occurrence of puberty. Taken together, our findings reinforced and extended the importance of the collared peccary as an animal model to investigate testis function in mammals, particularly the aspects related to testis organogenesis and the SSCs biology and niche. PMID- 29763588 TI - Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway. AB - Chronic inflammatory pain is a severe clinical problem that greatly affects patients' quality of life and causes huge economic burden. Microglia-mediated neuroinflammation exerts critical roles in the pathogenic progression of inflammatory pain. Recent evidence corroborates the anti-inflammatory and neuroprotective efficacy of glycyrrhizin; however, its function in inflammatory pain remains poorly elucidated. In the present study, glycyrrhizin suppressed LPS induced activation of microglial cell BV2 by inhibiting NO production and expression of microglial marker IBA-1. Intriguingly, LPS-induced high expression and generation of inflammatory cytokines (i.e., IL-6, TNF-alpha and IL-1beta) was notably reversed by glycyrrhizin pre-treatment. Mechanistic analysis confirmed that high expression of high-mobility group box 1 (HMGB1) in LPS-activated microglia was inhibited following glycyrrhizin. More importantly, restoring HMGB1 expression by recombinant adenovirus vector of Ad-HMGB1 counteracted glycyrrhizin restrained inflammatory response in microglia upon LPS stimulation. Furthermore, glycyrrhizin dampened the activation of subsequent TLR4-NF-kappaB pathway in LPS stimulated microglia, which was abrogated by HMGB1 elevation. Furthermore, blocking this pathway by si-TLR4 transfection reversed the effects of HMGB1 overexpression on the inhibitor roles of glycyrrhizin in microglia-triggered inflammation. Additionally, glycyrrhizin administration also alleviated CFA evoked mechanical allodynia and thermal hyperalgesia in inflammatory pain model of mice, concomitant with suppression in inflammatory response and microglial activation. Simultaneously, elevation of HMGB1, TLR4 and p65-NF-kappaB protein expression induced by CFA injection was also abrogated after glycyrrhizin. Accordingly, this study reveal that glycyrrhizin may act as a promising therapeutic avenue for the treatment of inflammatory pain. PMID- 29763587 TI - Mice exposed to bisphenol A exhibit depressive-like behavior with neurotransmitter and neuroactive steroid dysfunction. AB - Fetal exposure to endocrine disrupting chemicals (EDCs) has been associated with adverse neurobehavioral outcomes across the lifespan and can persist across multiple generations of offspring. However, the underlying mechanisms driving these changes are not well understood. We investigated the molecular perturbations associated with EDC-induced behavioral changes in first (F1) and second (F2) filial generations, using the model EDC bisphenol A (BPA). C57BL/6J dams were exposed to BPA from preconception until lactation through the diet at doses (10 MUg/kg bw/d-lower dose or 10 mg/kg bw/d-upper dose) representative of human exposure levels. As adults, F1 male offspring exhibited increased depressive-like behavior, measured by the forced swim test, while females were unaffected. These behavioral changes were limited to the F1 generation and were not associated with altered maternal care. Transcriptome analysis by RNA sequencing in F1 control and upper dose BPA-exposed adult male hippocampus revealed neurotransmitter systems as major pathways disrupted by developmental BPA exposure. High performance liquid chromatography demonstrated a male-specific reduction in hippocampal serotonin. Administration of the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg bw) rescued the depressive-like phenotype in males exposed to lower, but not upper, dose BPA, suggesting distinct mechanisms of action for each exposure dose. Finally, high resolution mass spectrometry revealed reduced circulating levels of the neuroactive steroid dehydroepiandrosterone in BPA-exposed males, suggesting another potential mechanism underlying the depressive-like phenotype. Thus, behavioral changes associated with early life BPA exposure may be mediated by sex-specific disruptions in the serotonergic system and/or sex steroid biogenesis in male offspring. PMID- 29763589 TI - alpha1-Antitrypsin Polymerizes in Alveolar Macrophages of Smokers With and Without alpha1-Antitrypsin Deficiency. AB - BACKGROUND: The deficiency of alpha1-antitrypsin (AAT) is secondary to misfolding and polymerization of the abnormal Z-AAT in liver cells and is associated with lung emphysema. Alveolar macrophages (AMs) produce AAT; however, it is not known whether Z-AAT can polymerize in AMs, further decreasing lung AAT and promoting lung inflammation. Our intention was to investigate whether AAT polymerizes in human AMs and to study the possible relation between polymerization and degree of lung inflammation. METHODS: Immunohistochemical analysis with 2C1 monoclonal antibody specific for polymerized AAT was performed in sections of the following: nine lungs from individuals with AAT deficiency (AATD) and severe COPD; 35 smokers with normal AAT levels, of whom 24 had severe COPD and 11 did not have COPD; and 13 nonsmokers. AMs positive for AAT polymers were counted and expressed as the percentage of total AMs in the lungs. RESULTS: AAT polymerization was detected in 27% (4%-67%) of AMs from individuals with AATD but also in AMs from smokers with normal AAT with (24% [0%-70%]) and without (24% [0%-60%]) COPD, but not in AMs from nonsmokers (0% [0%-1.5%]) (P < .0001). The percentage of AMs with polymerized AAT correlated with pack-years smoked (r = 0.53, P = .0001), FEV1/FVC (r = -0.41, P = .005), small airways disease (r = 0.44, P = .004), and number of CD8+ T cells and neutrophils in alveolar walls (r = 0.51, P = .002; r = 0.31, P = .05, respectively). CONCLUSIONS: Polymerization of AAT in alveolar macrophages occurs in the lungs of individuals with AATD but also in smokers with normal AAT levels with or without COPD. Our findings highlight the similarities in the pathophysiology of COPD in individuals with and without AATD, adding a potentially important step to the mechanism of COPD. PMID- 29763592 TI - Coomassie does it (better): A Robin Hood approach to total protein quantification. AB - Quantitative comparative proteomics require accurate and reproducible assessments of total protein concentration. We report a straightforward, cost-effective adaptation of an established commercial method for total protein quantification (EZQTM), utilising non-proprietary materials and colloidal Coomassie Brilliant Blue (cCBB) staining to achieve greater reproducibility, equal sensitivity, and optimal linearity of signal within a practical concentration range for proteins in common solubilisation buffers (i.e. for isoelectric focussing and/or SDS PAGE). This method provided more accurate and precise determinations of total protein concentration in human serum prepared for two-dimensional gel electrophoresis, indicating it may be better suited as the lead-in to most quantitative proteomic analyses. PMID- 29763590 TI - A novel miR17/protein tyrosine phosphatase-oc/EphA4 regulatory axis of osteoclast activity. AB - Information about the molecular mechanisms leading to the activation of the osteoclast is relatively limited. While there is compelling evidence that the signaling mechanisms of Src and integrin beta3 are essential for osteoclast activation, the regulation of these two signaling mechanisms is not fully understood. In this review, evidence supporting a novel regulatory axis of osteoclast activation that plays an upstream regulatory role in both the Src and integrin beta3 signaling during osteoclast activation is discussed. This regulatory axis contains three unique components: a structurally unique transmembrane protein-tyrosine phosphatase, PTP-oc, EphA4, and miR17. In the first component, PTP-oc activates the Src signaling through dephosphorylation of the inhibitory tyr-527 of Src. This in turn activates the integrin beta3 signaling, enhances the JNK2/NFkappaB signaling, promotes the ITAM/Syk signaling, and suppresses the ITIM/Shp1 signaling; the consequence of which is activation of the osteoclast. In the second component, EphA4 inhibits osteoclast activity by suppressing the integrin beta3 signaling. PTP-oc relieves the suppressive actions of EphA4 by directly dephosphorylating EphA4. In the third component, PTP-oc expression is negatively regulated by miR17. Accordingly, suppression of miR17 during osteoclast activation upregulates the PTP-oc signaling and suppresses the EphA4 signaling, resulting in the activation of the osteoclast. This regulatory axis is unique, in that each of the three components acts to exert suppressive action on their respective immediate downstream inhibitory step. Because the final downstream event is the EphA4-mediated inhibition of osteoclast activation, the overall effect of this mechanism is the stimulation of osteoclast activity. PMID- 29763591 TI - Scp-2/Scp-x ablation in Fabp1 null mice differentially impacts hepatic endocannabinoid level depending on dietary fat. AB - Dysregulation of the hepatic endocannabinoid (EC) system and high fat diet (HFD) are associated with non-alcoholic fatty liver disease. Liver cytosol contains high levels of two novel endocannabinoid binding proteins-liver fatty acid binding protein (FABP1) and sterol carrier protein-2 (SCP-2). While Fabp1 gene ablation significantly increases hepatic levels of arachidonic acid (ARA) containing EC and sex-dependent response to pair-fed high fat diet (HFD), the presence of SCP-2 complicates interpretation. These issues were addressed by ablating Scp-2/Scp-x in Fabp1 null mice (TKO). In control-fed mice, TKO increased hepatic levels of arachidonoylethanolamide (AEA) in both sexes. HFD impacted hepatic EC levels by decreasing AEA in TKO females and decreasing 2-arachidonoyl glycerol (2-AG) in WT of both sexes. Only TKO males on HFD had increased hepatic 2-AG levels. Hepatic ARA levels were decreased in control-fed TKO of both sexes. Changes in hepatic AEA/2-AG levels were not associated with altered amounts of hepatic proteins involved in AEA/2-AG synthesis or degradation. These findings suggested that ablation of the Scp-2/Scp-x gene in Fabp1 null mice exacerbated hepatic EC accumulation and antagonized the impact of HFD on hepatic EC levels suggesting both proteins play important roles in regulating the hepatic EC system. PMID- 29763594 TI - Patient-Controlled Paravertebral Block for Video-Assisted Thoracic Surgery: A Randomized Trial. AB - BACKGROUND: Paravertebral block (PVB) has been proven to be an efficient way to control postoperative pain in patients who have undergone a thoracotomy. This study explored whether the use of a patient-controlled PVB can provide benefits over intravenous patient-controlled analgesia (PCA) for 3-port single-intercostal video-assisted thoracic surgery. METHODS: From May 2015 to December 2016, patients who had solitary pulmonary nodules or spontaneous pneumothorax and underwent single-intercostal video-assisted thoracic surgery were randomly allocated to receive patient-controlled PVB or intravenous PCA. Intramuscular dezocine (10 mg) was used as a rescue medication. None of the surgeons, patients, or investigators assessing outcomes or analyzing the data were blinded to the group assignments. Pain level was measured by the visual analog score. RESULTS: There were 86 patients assigned to the PVB group and 85 patients assigned to the PCA group. The difference in the mean visual analog score between these two groups was not significant (p = 0.115). For patients who needed rescue medication, the cumulative dezocine dose in the PVB group was significantly lower than that in the PCA group (21.7 mg vs 30.9 mg, p = 0.001) throughout the 4 postoperative days. The frequencies of severe vomiting (p = 0.003) and hypotension (p = 0.005) were significantly lower in the PVB group. CONCLUSIONS: PVB, which resulted in lower cumulative dezocine doses and produced fewer side effects than PCA, can provide effective pain relief for patients undergoing video assisted thoracic surgery. PMID- 29763595 TI - Comparison of Wedge Versus Lobar Resection for Stage 1 Non-Small Cell Lung Cancer: A SEER-Medicare Analysis. PMID- 29763596 TI - Combined Rehabilitation and Nutritional Coaching After Cardiac Surgery: Sex Differences. PMID- 29763593 TI - Midlife vascular risk factors and midlife cognitive status in relation to prevalence of mild cognitive impairment and dementia in later life: The Atherosclerosis Risk in Communities Study. AB - INTRODUCTION: The interplay between midlife vascular risk factors and midlife cognitive function with later life mild cognitive impairment (MCI) and dementia (DEM) is not well understood. METHODS: In the Atherosclerosis Risk in Communities Study, cardiovascular risk factors and cognition were assessed in midlife, ages 45-64 years. In 2011-2013, 20-25 years later, all consenting Atherosclerosis Risk in Communities participants underwent a cognitive and neurological evaluation and were given adjudicated diagnoses of cognitively normal, MCI, or DEM. RESULTS: In 5995 participants with complete covariate data, midlife diabetes, hypertension, obesity, and hypercholesterolemia were associated with late-life MCI and DEM. Low midlife cognition function was also associated with greater likelihood of late life MCI or DEM. Both midlife vascular risk factors and midlife cognitive function remained associated with later life MCI or DEM when both were in the model. DISCUSSION: Later life MCI and DEM were independently associated with midlife vascular risk factors and midlife cognition. PMID- 29763597 TI - A Hem-o-Lok-Induced Tracheoesophageal Fistula Cured by Temporary Airway Stenting Modified With Three-Dimensional Printing. AB - We present the case of a fistula between the trachea and the esophagogastric anastomosis in a 58-year-old man after esophagectomy. A Hem-o-Lok clip (Teleflex, Morrisville, NC) used at the time to ligate the azygos vein was discovered by esophagoscopy and bronchoscopy to be eroding into both structures. A covered self expandable Y-shaped metallic tracheobronchial stent was customized with a three dimensional printed airway model and inserted in place with endoscopic injection of fibrin glue to the anastomotic site. The stent was withdrawn 64 days after implantation, with complete healing of the fistula. PMID- 29763598 TI - Minimally Invasive Repair of Pectus Carinatum: Bar Number and Technique. PMID- 29763599 TI - Giant Circumflex Artery Aneurysm With a Coronary Sinus Fistula. AB - Giant coronary artery aneurysms are extremely rare entities, and the authors are aware of only 13 case reports of such aneurysms of the circumflex artery. This case report is provided to add evidence of the natural history and pathophysiology and describe the successful surgical treatment of this condition. PMID- 29763600 TI - Reply. PMID- 29763601 TI - The p.S85C-mutation in MATR3 impairs stress granule formation in Matrin-3 myopathy. PMID- 29763603 TI - PIM1-catalyzed CBX8 phosphorylation promotes the oncogene-induced senescence of human diploid fibroblast. AB - The proto-oncogene PIM1 encodes Ser/Thr kinase and regulates cell growth, differentiation and apoptosis. However, more and more studies including ours have found that PIM1 can induce senescence in normal human diploid fibroblasts and behave as a tumor suppressor. But the relevant molecular mechanism of this process is not yet clear. It has been reported that Chromobox homolog 8 (CBX8) binds directly to INK4A as a transcriptional repressor, thereby suppressing stress-induced senescence. Here we report that PIM1 can phosphorylate CBX8 to promote its degradation, thereby up-regulating p16, during PIM1-induced cell senescence. Overexpression of CBX8 can inhibit PIM1-induced cell senescence. These data suggest that to promote CBX8 degradation may be an important molecular mechanism of PIM1-induced cell senescence. PMID- 29763602 TI - A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice. AB - Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high-fat diet or a high-fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8 weeks of high-fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome-induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high-fat-fed mice, and were similar to exercised, high-fat-fed mice. High-fat-fed, exercised and ketogenic-fed mice had mildly elevated blood glucose; conversely, ketogenic diet-fed mice were unique in having reduced serum insulin levels. Ketogenic diet-fed mice never developed mechanical allodynia contrary to mice fed a high-fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high-fat fed-induced metabolic changes but was able to significantly reverse a high-fat diet-induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction. PMID- 29763604 TI - Attenuation of macrophage accumulation and polarisation in obese diabetic mice by a small molecule significantly improved insulin sensitivity. AB - Accumulation and polarization of anti-inflammatory M2 to proinflammatory M1 macrophage in the adipose tissue of obese diabetic mice is an important pathogenic signature. It worsens lipid induced inflammation and insulin resistance. Here we demonstrate that a small molecule, a peroxyvanadate compound i.e. DmpzH [VO(O2)2 (dmpz)] or dmp, could robustly decrease macrophage infiltration, accumulation and their polarization in high fat diet (HFD) induced obese diabetic mice. In searching the underlying mechanism it was revealed that SIRT1 level was strikingly low in the inflamed adipose tissue of HFD mice as compared to mice fed with standard diet (SD). Administration of dmp markedly increased SIRT1 level by inducing its gene expression with a consequent decrease in macrophage population. Elevation of SIRT1 coincided with the decrease of MCP1, Fetuin-A (FetA) and IFNgamma. Since MCP1 and FetA drive macrophage to inflamed adipose tissue and IFNgamma promotes M2 to M1 transformation, both recruitment and M1 induced inflammation were found to be significantly repressed by dmp. In addressing the question about how dmp induced excess SIRT1 could reduce MCP1, FetA and IFNgamma levels, we found that it was due to the inactivation of NFkappaB because of its deacetylation by SIRT1. Since NFkappaB is the transcriptional regulator of these molecules, their expressions were significantly suppressed and that caused sharp decline in macrophage recruitment and their polarity to M1. This effected a marked fall in proinflammatory cytokine level which significantly improved insulin sensitivity. dmp is likely to be the first molecule that rescues inflammatory burden contributed by macrophage in obese diabetic mice adipose tissue which causes significant increase in insulin sensitivity therefore it may be a meaningful choice to treat type 2 diabetes. PMID- 29763605 TI - iNOS inhibits hair regeneration in obese diabetic (ob/ob) mice. AB - Previous studies have shown that androgenic alopecia is associated with metabolic syndrome and diabetes. However, the detailed mechanism whereby diabetes causes alopecia still remains unclear. We focused on the inflammatory response that is caused by diabetes or obesity, given that inflammation is a risk factor for hair loss. Inducible nitric oxide synthase (iNOS) is known to be upregulated under conditions of acute or chronic inflammation. To clarify the potential role of iNOS in diabetes-related alopecia, we generated obese diabetic iNOS-deficient (ob/ob; iNOS-KO mice). We observed that ob/ob; iNOS-KO mice were potentiated for the transition from telogen (rest phase) to anagen (growth phase) in the hair cycle compared with iNOS-proficient ob/ob mice. To determine the effect of nitric oxide (NO) on the hair cycle, we administered an iNOS inhibitor intraperitoneally (compound 1400 W, 10 mg/kg) or topically (10% aminoguanidine) in ob/ob mice. We observed that iNOS inhibitors promoted anagen transition in ob/ob mice. Next, we administered an NO donor (S-nitrosoglutathione, GSNO), to test whether NO has the telogen elongation effects. The NO donor was sufficient to induce telogen elongation in wild-type mice. Together, our data indicate that iNOS-derived NO plays a role in telogen elongation under the inflammatory conditions associated with diabetes in mice. PMID- 29763607 TI - Biomedical Applications of Lumazine Synthase. AB - Lumazine synthase (LS) is a family of enzyme involved in the penultimate step in the biosynthesis of riboflavin. Its enzymatic mechanism has been well defined, and many LS structures have been solved using X-ray crystallography or cryoelectron microscopy. LS is composed of homooligomers, which vary in size and subunit number, including pentamers, decamers, and icosahedral sixty-mers, depending on its species of origin. Research on LS has expanded beyond the initial focus on its enzymatic function to properties related to its oligomeric structure and exceptional conformational stability. These attributes of LS systems have now been repurposed for use in various biomedical fields. This review primarily focuses on the applications of LS as a flexible vaccine presentation system. Presentation of antigens on the surface of LS results in a high local concentration of antigens displayed in an ordered array. Such repetitive structures enable the cross-linking of B-cell receptors and result in strong immune responses through an avidity effect. Potential issues with the use of this system and corresponding solutions are also discussed with the objective of improved utilization of the LS system in vaccine development. PMID- 29763606 TI - MiR-216a-5p/Hexokinase 2 axis regulates uveal melanoma growth through modulation of Warburg effect. AB - Hexokinase-2 (HK2), the initial as well as the rate-limiting step in glycolysis, is overexpressed in many human cancers, and correlates with poor clinical outcomes. Aerobic glycolysis is a hallmark of cancer, and drugs targeting its enzymes, including HK2, are being developed. However, the mechanisms of HK2 inhibition and the physiological significance of the HK2 inhibitors in cancer cells are rarely reported. Here, we show that microRNA-216a-5p (miR-216a-5p) inhibits HK2 expression by directly targeting its 3'-UTR in uveal melanoma cells. Through inhibition of HK2, miR-216a-5p dampens glycolysis by reducing HK activity, glucose uptake, lactate production, ATP generation, extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in uveal melanoma cells. Importantly, glycolysis regulated by miR-216a-5p is critical for its regulating uveal melanoma tumor growth both in vitro and in vivo. miR-216a-5p expression is negatively correlated with HK2 expression and predicts better outcome in uveal melanoma patients. Our findings provide clues regarding the role of miR-216a-5p as a tumor suppressor in uveal melanoma through the inhibition of HK2. Targeting HK2 through miR-216a-5p could be a promising therapeutic strategy in uveal melanoma. PMID- 29763608 TI - Early prognostic factors of outcomes in monochorionic twin pregnancy: systematic review and meta-analysis. AB - BACKGROUND: Monochorionic twin pregnancies are high-risk, however at present, no screening test is available to predict which monochorionic twin pregnancy will develop complications. OBJECTIVE: We sought to assess ability of first-trimester pregnancy-related factors (ultrasound measurements, maternal characteristics, biomarkers) to predict complications in monochorionic twin pregnancies. DATA SOURCES: Data sources were MEDLINE, Embase, ISI Web of Science, CINAHL, the Cochrane Central Registration of Controlled Trials and Research Registers, and Google Scholar, from inception to May 12, 2017. Gray literature and bibliographies of articles were checked. STUDY ELIGIBILITY CRITERIA: Studies that reported ultrasound measurements, maternal characteristics, or potential biomarkers, measured in the first trimester in monochorionic-diamniotic twin pregnancies, where the potential prognostic ability between the variable and twin twin transfusion syndrome, growth restriction, or intrauterine fetal death could be assessed, were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Quality assessment was evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology checklist by 2 reviewers independently. For meta analysis, odds ratios using a random effects model, or standardized mean difference were calculated. If a moderate association was found, the prognostic ability was evaluated by calculating the sensitivity and specificity. Risk of heterogeneity was reported as I2 and publication bias was visually assessed by funnel plots and quantitatively by Egger test. RESULTS: In all, 48 studies were eligible for inclusion. Twenty meta-analyses could be performed. A moderate association was demonstrated in 3 meta-analyses, between: nuchal translucency >95th centile in one/both fetuses and twin-twin transfusion syndrome (odds ratio, 2.29 [95% confidence interval, 1.05-4.96], I2 = 6.6%, 4 studies, 615 pregnancies); crown-rump length discordance >=10% and twin-twin transfusion syndrome (odds ratio, 2.43 [95% confidence interval, 1.13-5.21], I2 = 14.1%, 3 studies, 708 pregnancies); and maternal ethnicity and twin-twin transfusion syndrome (odds ratio, 2.12 [95% confidence interval, 1.17-3.83], I2 = 0.0%, 5 studies, 467 pregnancies), but none demonstrated a prognostic ability for any outcome under investigation. CONCLUSION: It is not currently possible to predict adverse outcomes in monochorionic twin pregnancies. We have revealed a lack of research investigating first-trimester biomarkers in monochorionic twin pregnancies. Different assessment methods and definitions of each variable and outcome were an issue and this highlights the need for a large cohort study to evaluate these factors. PMID- 29763609 TI - Cervical ripening balloon with and without oxytocin in multiparas: a randomized controlled trial. AB - BACKGROUND: The optimal method for induction of labor for multiparous women with an unfavorable cervix is unknown. OBJECTIVE: We sought to determine if induction of labor with simultaneous use of oxytocin and a cervical ripening balloon, compared with sequential use, increases the likelihood of delivery within 24 hours in multiparous women. STUDY DESIGN: We performed a randomized controlled trial from November 2014 through June 2017. Eligible participants were multiparous women with a vertex presenting, nonanomalous singleton gestation >=34 weeks undergoing induction of labor. Women were excluded for admission cervical examination >2 cm, ruptured membranes, chorioamnionitis or evidence of systemic infection, placental abruption, low-lying placenta, >1 prior cesarean delivery, or contraindication to vaginal delivery. Patients were randomly allocated to the following cervical ripening groups: simultaneous (oxytocin with cervical ripening balloon) or sequential (oxytocin following cervical ripening balloon expulsion). The primary outcome was delivery within 24 hours of cervical ripening balloon placement. Secondary outcomes included induction-to-delivery interval, time to cervical ripening balloon expulsion, mode of delivery, and adverse maternal or neonatal outcomes. RESULTS: In all, 180 patients were randomized (90 simultaneous, 90 sequential). Baseline demographic and obstetric characteristics were similar between study groups. Women in the simultaneous group were significantly more likely to deliver within 24 hours of cervical ripening balloon placement compared to the sequential group (87.8% vs 73.3%, P = .02). The simultaneous group also had a significantly shorter induction-to-delivery interval and greater cervical dilation at cervical ripening balloon expulsion. There were no differences in mode of delivery, chorioamnionitis, or adverse maternal or neonatal outcomes. CONCLUSION: In multiparous women with an unfavorable cervix, the simultaneous use of cervical ripening balloon and oxytocin results in an increased frequency of delivery within 24 hours and a shorter induction-to-delivery interval. PMID- 29763610 TI - Sequential interactions-in which one player plays first and another responds promote cooperation in evolutionary-dynamical simulations of single-shot Prisoner's Dilemma and Snowdrift games. AB - Cooperation is a central topic in evolutionary biology because (a) it is difficult to reconcile why individuals would act in a way that benefits others if such action is costly to themselves, and (b) it underpins many of the 'major transitions of evolution', making it essential for explaining the origins of successively higher levels of biological organization. Within evolutionary game theory, the Prisoner's Dilemma and Snowdrift games are the main theoretical constructs used to study the evolution of cooperation in dyadic interactions. In single-shot versions of these games, wherein individuals play each other only once, players typically act simultaneously rather than sequentially. Allowing one player to respond to the actions of its co-player-in the absence of any possibility of the responder being rewarded for cooperation or punished for defection, as in simultaneous or sequential iterated games-may seem to invite more incentive for exploitation and retaliation in single-shot games, compared to when interactions occur simultaneously, thereby reducing the likelihood that cooperative strategies can thrive. To the contrary, I use lattice-based, evolutionary-dynamical simulation models of single-shot games to demonstrate that under many conditions, sequential interactions have the potential to enhance unilaterally or mutually cooperative outcomes and increase the average payoff of populations, relative to simultaneous interactions-benefits that are especially prevalent in a spatially explicit context. This surprising result is attributable to the presence of conditional strategies that emerge in sequential games that can't occur in the corresponding simultaneous versions. PMID- 29763611 TI - Risk of Glaucoma Surgery After Corneal Transplant Surgery in Medicare Patients. AB - PURPOSE: Glaucoma is a well-documented complication of corneal transplants, contributing significantly to ultimate visual loss. Reported incidence of glaucoma following corneal transplants is highly variable, and definitions of posttransplant glaucoma are inconsistent. Here we use glaucoma surgery as a more rigid and specific endpoint to compare rates following different corneal transplant surgeries. DESIGN: Retrospective cohort study. METHODS: A 5% random sample of Medicare beneficiaries from 2010-2013 was obtained and patients were identified with Current Procedural Terminology (CPT) codes for penetrating keratoplasty (PK), endothelial keratoplasty (EK), anterior lamellar keratoplasty (ALK), and keratoprosthesis (KPro). Rates of glaucoma surgery within the same year following the abovementioned corneal transplants were analyzed. Subgroup analyses included patients who carried preexisting glaucoma diagnoses prior to corneal transplant surgery. RESULTS: There were 3098 patients who underwent corneal transplants during the study period, including 1919 EK, 1012 PK, 46 ALK, 32 KPro, and 89 both PK and EK. Rates of glaucoma surgery ranged from 6.1% to 9.4% in the corneal transplant groups, without statistically significant differences among groups. However, 10.0% of patients with preexisting glaucoma required glaucoma surgery following any transplant surgery, compared with 5.3% of patients without preexisting glaucoma. This included 12.4% of PK patients with preexisting glaucoma compared with 2.8% of PK patients without preexisting glaucoma (P < .01). CONCLUSIONS: Despite literature suggesting that more angle altering cornea surgeries confer higher risk, we found no statistically significant differences among various transplant groups. Patients with preexisting glaucoma, however, had higher risk of glaucoma surgery within the same year following corneal transplant surgery, which was especially pronounced in the PK group. These patients require special care when considering long-term effects of corneal transplants. PMID- 29763612 TI - Topographic Correspondence of Macular Atrophy With Choroidal Neovascularization in Ranibizumab-treated Eyes of the TREX-AMD Trial. AB - PURPOSE: To quantify the extent of topographic correspondence between baseline (BSL) choroidal neovascularization (CNV) and macular atrophy (MA) at follow-up in eyes with neovascular age-related macular degeneration (NVAMD). DESIGN: Post hoc analysis of randomized controlled clinical trial data. METHODS: Sixty treatment naive NVAMD patients from the TREX-AMD trial were followed for 18 months. Regions of month 18 macular atrophy (MA) were graded on fundus autofluorescence (FAF) with guidance of spectral-domain optical coherence tomography (SDOCT). CNV lesions were graded manually on fluorescein angiography (FA) with lesion components including classic and occult CNV delineated. FAF and FA images were registered to quantitate area and location of overlap between CNV and MA. Outcome measures included overlap of month 18 MA to BSL CNV subtype and progression of MA from BSL to month 18. RESULTS: Twenty-six eyes had both MA at month 18 and CNV at BSL. A total of 84.6% of eyes showed evidence of MA and CNV overlap. MA appeared by month 18 in regions corresponding to BSL classic CNV in 36.4% of eyes and occult CNV in 40.9%, and in both regions in 22.7%, with more area of MA (AMA) in regions of occult than classic CNV. MA position at BSL corresponded to BSL classic CNV in 76.9% of eyes and occult CNV in 61.5%, and to both regions in 15.4%, with more AMA in regions of occult than classic CNV. Among eyes with MA and CNV at BSL but with no overlap, 50% progressed to involve regions with BS CNV. Six eyes had no BSL MA but developed MA at month 18 within regions of BSL CNV. CONCLUSIONS: In ranibizumab-treated eyes with NVAMD, more MA lesions develop within the region of baseline CNV (type 1, CNV-based MA) than outside (type 2, CNV-independent MA). Baseline-MA also tends to be located within regions of CNV in the pretreatment phase. PMID- 29763613 TI - Neuroprotective effect of duloxetine in a mouse model of diabetic neuropathy: Role of glia suppressing mechanisms. AB - AIMS: Painful diabetic neuropathy (PDN) is one of the most frequent complications of diabetes and the current therapies have limited efficacy. This study aimed to study the neuroprotective effect of duloxetine, a serotonin noradrenaline reuptake inhibitor (SNRI), in a mouse model of diabetic neuropathy. MAIN METHODS: Nine weeks after developing of PDN, mice were treated with either saline or duloxetine (15 or 30 mg/kg) for four weeks. The effect of duloxetine was assessed in terms of pain responses, histopathology of sciatic nerve and spinal cord, sciatic nerve growth factor (NGF) gene expression and on the spinal expression of astrocytes (glial fibrillary acidic protein, GFAP) and microglia (CD11b). KEY FINDINGS: The present results highlighted that duloxetine (30 mg/kg) increased the withdrawal threshold in von-Frey test. In addition, both doses of duloxetine prolonged the licking time and latency to jump in the hot-plate test. Moreover, duloxetine administration downregulated the spinal expression of both CD11b and GFAP associated with enhancement in sciatic mRNA expression of NGF. SIGNIFICANCE: The current results highlighted that duloxetine provided peripheral and central neuroprotective effects in neuropathic pain is, at least in part, related to its downregulation in spinal astrocytes and microglia. Further, this neuroprotective effect was accompanied by upregulation of sciatic expression of NGF. PMID- 29763614 TI - Association of oral Helicobacter pylori with gastric complications. AB - AIM: This study was aimed to identify the presence of Helicobacter pylori (H. pylori) genes in oral mucosa and find out their relationship between oral H. pylori infection and gastric complications. METHODS: This study is a case control study consists of 567 subjects with periodontal infection (278 gastric complication cases and 289 controls normal gastric intestinal mucosa) with age range of 20-80 years. Oral health status was recorded by calculating oral hygiene index (OHI), probing depths (PD) and clinical attachment loss (CAL). Each participant provided gastric biopsy and plaque samples which were subjected to H. pylori detection. Polymerase chain reaction (PCR) with different primers specifically beta globulin, 16SrRNA, babA, cagA, ureA, ureC and vacA gene was performed which were then analyzed using gel electrophoresis. RESULTS: No significant differences (chi2 = 11.873, p value > 0.05) were observed between oral H. pylori and gastric infections/complications. However, H. pylori increase the risk of developing gastro-esophageal reflux grade II (OR = 1.458, 95%CI = 0.659-3.226), normal upper GIT mucosa with lax esophageal sphincters (OR = 1.215, 95%CI = 0.285-5.181) and duodenal ulcer/duodenitis (OR = 2.187, 95%CI = 0.225 21.278). This study also showed a significant increased risk of gastritis with babA gene. CONCLUSION: Oral pathogenic H. pylori genes may enhance the severity of the gastric infection. PMID- 29763616 TI - Influence of continuous flash suppression mask frequency on stimulus visibility. AB - The continuous flash suppression (CFS) paradigm is increasingly used in consciousness research, but its mechanisms are still not fully understood. To better understand its temporal properties, we presented the CFS masks at 9 frequencies, and examined their influence on stimuli visibility, while taking into account the inter-individual variability and the change of CFS suppression as the experiment progressed. The frequencies consisted of fundamental frequencies of 3, 4 and 5 Hz, and their 2nd and 3rd harmonics, which included the 10 Hz frequency typically used in most of the CFS studies. We found that the suppression of stimulus awareness was stronger under 4, 6 and 8 Hz than 10 Hz. After controlling for inter-individual variability with mixed-effects analysis, we found that the number of seen trials was lower for the 4 Hz-basis frequencies than the 5 Hz ones, and was lower for the 2nd than 3rd harmonic. We propose that this may be caused by an interaction between the CFS masks and the ongoing sampling of the attentional mechanism. Examining individual data, we also found a habituation effect that the participants saw significantly more stimuli as the experiment progressed. Our results suggest that these factors need to be taken care of in future CFS studies in order to achieve optimal visual awareness suppression and ensure the generalizability of results. PMID- 29763615 TI - Anticancer activity study of A3 adenosine receptor agonists. AB - AIMS: A3 adenosine receptor (A3AR) signalling activation seems to mediate anticancer effect, and it has been targeted for drug development. The identification of potent and selective A3AR agonists could be crucial for cancer drug development. MATERIALS AND METHODS: In the present study was determined the in vitro activity of known 1-3 and newly 4-6 synthesized compounds with high A3AR affinity and selectivity (Ki in the low nanomolar range) in binding studies. Effect of known and novel A3AR agonists on human prostate cancer (PC3), hepatocellular carcinoma (Hep G2), and epithelial colorectal carcinoma (Caco-2) cells were analysed by cytotoxicity assay, dose and time dependent inhibitor assay, migration, apoptosis, autophagy and reactive oxygen species (ROS) assays. KEY FINDINGS: Results show that the anticancer effect is not due to A3AR activation alone. In fact, the more active and selective agonist versus A3AR, compound 1, results inactive on cancer cells such as compounds 2-4. Moreover, results show that the novel compound 5, at micromolar concentration range (IC50 = 28.0 MUM), inhibits the growth of PC3, Hep G2, and Caco-2 cells and their migration in time- and dose- dependent manner. The mechanism involved in cell death is attributable to apoptosis. At the same time compound 5 promotes autophagy, which induce apoptosis producing autophagic cell death. Further investigation revealed that compound 5 elevates the level of ROS in all cancer cells tested, suggesting the involvement of ROS in cell death. SIGNIFICANCE: These results show that the new compound 5 exerts inhibitory effect on cancer cells through differential effect and may serve as a potential anticancer agent. PMID- 29763617 TI - A-to-I RNA Editing: An Overlooked Source of Cancer Mutations. AB - RNA editing is a source of transcriptomic diversity, mainly in non-coding regions, and is found to be altered in cancer. In this issue of Cancer Cell, Peng et al. show that RNA editing events are manifested at the proteomic levels and are a source of cancer protein heterogeneity. PMID- 29763618 TI - Genomic Features of Response to Combination Immunotherapy in Lung Cancer. AB - In this issue of Cancer Cell, Hellmann et al. describe in two clinical trials the importance of tumor mutational burden as an independent predictive marker for outcomes with combination nivolumab plus ipilimumab as first-line therapy in metastatic non-small-cell lung cancer and in relapsed small-cell lung cancer. PMID- 29763619 TI - Targeting the (Un)differentiated State of Cancer. AB - Dedifferentation in cancer is associated with intrinsic and acquired resistance to therapies. In this issue of Cancer Cell, Tsoi et al. identify four differentiation states in melanoma and provide evidence that melanoma cells develop drug resistance through a stepwise dedifferentiation process, making them vulnerable to ferroptotic cell death-inducing compounds. PMID- 29763620 TI - Targeting Therapy Resistance: When Glutamine Catabolism Becomes Essential. AB - Identifying contexts in which cancer cells become addicted to specific nutrients is critical for developing targeted metabolic therapies. In this issue of Cancer Cell, Momcilovic et al. report that suppressed glycolysis following mTOR inhibition is countered by adaptive glutamine catabolism in lung squamous cell carcinoma, sensitizing tumors to glutaminase inhibition. PMID- 29763621 TI - It's ALL in the Family: IKZF1 and Hereditary Leukemia. AB - IKZF1 plays an essential role in lymphopoiesis, and somatic IKZF1 variants in acute lymphoblastic leukemia (ALL) are associated with poor prognosis. In this issue of Cancer Cell, Churchman et al. add to the list of leukemia predisposition genes with the identification and characterization of germline IKZF1 variants in childhood ALL. PMID- 29763624 TI - The GSK3 Signaling Axis Regulates Adaptive Glutamine Metabolism in Lung Squamous Cell Carcinoma. AB - Altered metabolism is a hallmark of cancer growth, forming the conceptual basis for development of metabolic therapies as cancer treatments. We performed in vivo metabolic profiling and molecular analysis of lung squamous cell carcinoma (SCC) to identify metabolic nodes for therapeutic targeting. Lung SCCs adapt to chronic mTOR inhibition and suppression of glycolysis through the GSK3alpha/beta signaling pathway, which upregulates glutaminolysis. Phospho-GSK3alpha/beta protein levels are predictive of response to single-therapy mTOR inhibition while combinatorial treatment with the glutaminase inhibitor CB-839 effectively overcomes therapy resistance. In addition, we identified a conserved metabolic signature in a broad spectrum of hypermetabolic human tumors that may be predictive of patient outcome and response to combined metabolic therapies targeting mTOR and glutaminase. PMID- 29763626 TI - Profiling of small RNAs derived from cucumber mosaic virus in infected Nicotiana benthamiana plants by deep sequencing. AB - In plants, RNA silencing is a conserved mechanism underlying antiviral immunity. To investigate antiviral responses in Nicotiana benthamiana, we analyzed the profiles of the virus-derived small RNAs (vsRNAs) in wild-type N. benthamiana and NbRDR6 mutant plants infected with the cucumber mosaic virus (CMV) 2b-deficient mutant. We observed that NbRDR6 regulates RNA silencing by producing vsRNAs that trigger an effective antiviral response, while NbRDR1 may nonredundantly and synergistically function with NbRDR6 to mediate immune responses. The vsRNAs in N. benthamiana and NbRDR6 mutant plants mainly comprised 21 or 22 nucleotides, and mostly consisted of a 5'-terminal adenine. Additionally, NbAGO2 expression was significantly up-regulated in N. benthamiana and NbRDR6 mutant plants, suggesting that NbAGO2 is closely associated with the antiviral activities of vsRNAs. The distribution of vsRNAs in the CMV genome was biased toward RNA sense strands in both N. benthamiana and NbRDR6 mutant plants. These findings indicate the specific and conserved antiviral immunity in Nicotiana benthamiana. PMID- 29763625 TI - Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade. AB - HER2-driven cancers require phosphatidylinositide-3 kinase (PI3K)/Akt signaling through HER3 to promote tumor growth and survival. The therapeutic benefit of HER2-targeting agents, which depend on PI3K/Akt inhibition, can be overcome by hyperactivation of the heregulin (HRG)/HER3 pathway. Here we describe an unbiased phenotypic combinatorial screening approach to identify a bispecific immunoglobulin G1 (IgG1) antibody against HER2 and HER3. In tumor models resistant to HER2-targeting agents, the bispecific IgG1 potently inhibits the HRG/HER3 pathway and downstream PI3K/Akt signaling via a "dock & block" mechanism. This bispecific IgG1 is a potentially effective therapy for breast cancer and other tumors with hyperactivated HRG/HER3 signaling. PMID- 29763622 TI - A Convergence-Based Framework for Cancer Drug Resistance. AB - Despite advances in cancer biology and therapeutics, drug resistance remains problematic. Resistance is often multifactorial, heterogeneous, and prone to undersampling. Nonetheless, many individual mechanisms of targeted therapy resistance may coalesce into a smaller number of convergences, including pathway reactivation (downstream re-engagement of original effectors), pathway bypass (recruitment of a parallel pathway converging on the same downstream output), and pathway indifference (development of a cellular state independent of the initial therapeutic target). Similar convergences may also underpin immunotherapy resistance. Such parsimonious, convergence-based frameworks may help explain resistance across tumor types and therapeutic categories and may also suggest strategies to overcome it. PMID- 29763623 TI - Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. AB - The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population. PMID- 29763627 TI - Evaluation of MinION nanopore sequencing for rapid enterovirus genotyping. AB - Enteroviruses (EV) are associated with a range of serious infections, including aseptic meningitis, hand foot and mouth disease, myocarditis, acute flaccid paralysis and encephalitis. Improved methods for assessing EV genotypic diversity could assist molecular epidemiology studies, clinical diagnosis and environmental surveillance. We report new methods for EV genome amplification, and subsequent genotyping using the miniaturised MinION sequencing device. Importantly, this next-generation sequencer enabled correct strain-level assignment of identity for the EV-A71 isolate assessed, where strains with up to 99.7% similarity were discriminated. In addition, an accurate consensus sequence was produced for EV A71 isolate RNA, with 99.3-99.6% similarity to the reference sequence. Thus, the long nanopore reads enabled rapid whole genome sequencing and strain level identification of EV- A71 isolate RNA. We also demonstrated potential for using MinION sequencing for direct detection of EV in water samples, which may have application for diversity analysis, water quality monitoring, and environmental surveillance. PMID- 29763628 TI - Whole snake venoms: Cytotoxic, anti-metastatic and antiangiogenic properties. AB - Currently, biological and organic substances are screened in order to find a new generation of therapeutics active against cancer. Previous research has identified promising candidate peptides in snake venom. In this study, venoms from different snake species (Naja annulifera, Naja kaouthia, Ophiophagus hannah and Echis carinatus) were screened for potential anti-cancer properties using pancreatic tumour cells as the assay system. The cells were incubated with venom and then subjected to the following analyses: (i) in vitro cell death (ii) in vitro migration (iii) in vivo dissemination and (iv) in vivo angiogenesis. For the in vivo assays, the cells, after incubation and labelling, were transplanted into the yolk sac of zebrafish embryos for motility and angiogenesis. The results showed strong effects in cells treated with venoms from Ophiophagus hannah and Echis carinatus in the in vitro assays. In the in vivo assays, venom derived from Ophiophagus hannah had the most potent effects with respect to angiogenesis. These venoms might therefore be considered as candidates for further studies. PMID- 29763631 TI - Safety evaluation of genetically modified DAS-40278-9 maize in a subchronic rodent feeding study. AB - Genetically modified (GM) maize, DAS-40278-9, expresses the aryloxyalkanoate dioxygenase-1 (AAD-1) protein, which confers tolerance to 2,4 dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) herbicides. The aad-1 gene, which expresses the AAD-1 protein, was derived from Gram-negative soil bacterium, Sphingobium herbicidovorans. A 90-day sub-chronic toxicity study was conducted on rats as a component of the safety evaluation of DAS-40278-9 maize. Rats were given formulated diets containing maize grain from DAS-40278-9 or a non-GM near isogenic control comparator at an incorporation rate of 12.5%, 25%, or 50% (w/w), respectively for 90 days. In addition, another group of rats was fed a basic rodent diet. Animals were evaluated by cage-side and hand held detailed clinical observations, ophthalmic examinations, body weights/body weight gains, feed consumption, hematology, serum chemistry, selected organ weights, and gross and histopathological examinations. Under the condition of this study, DAS-40278-9 maize did not cause any treatment-related effects in rats compared with rats fed diets containing non-GM maize. PMID- 29763630 TI - Clinical and molecular epidemiologic characteristics of carbapenem-resistant Klebsiella pneumoniae infection/colonization among neonates in China. AB - BACKGROUND: The spread of carbapenem-resistant Klebsiella pneumoniae (CR-KPN) is a major concern, but data on CR-KPN infection/colonization in paediatric populations are limited. AIM: To analyse epidemiologic and clinical characteristics, and therapeutic options for CR-KPN infections in neonates in China. METHODS: A retrospective study was performed at the Children's Hospital of Fudan University, including 88 neonates with CR-KPN admitted between November 2015 and October 2016. Forty-seven CR-KPN isolates were chosen at random for further study, including antimicrobial susceptibility testing, potential beta lactamase screening and homology analysis. FINDINGS: In total, 44.3% (39/88) of the neonates with CR-KPN were infected, and 71.8% (28/39) were nosocomial infections. Of these, pneumonia and urinary tract infection accounted for 50.0% (14/28) and 42.9% (12/28), respectively. All infected patients were cured or improved with fosfomycin and/or carbapenem-containing combination therapy, except one case in whom treatment was withdrawn. All 47 cases of CR-KPN were resistant to ertapenem and 95.7% were resistant to imipenem/meropenem. Overall, 87.2% (41/47) were positive for blaNDM-1, and belonged to 11 pulsed-field gel electrophoresis types; 53.7% (22/41) were designated as ST278 and 17.1% (7/41) were designated as ST2735 by multi-locus sequence typing. CONCLUSIONS: Most of the CR-KPN isolated from neonates produced New Delhi metallo-beta-lactamase-1 and were highly homologous. Fosfomycin-containing regimens and meropenem-/panipenem containing combination therapy were efficient for CR-KPN infection in neonates. PMID- 29763633 TI - Estradiol-induced enhancement of fear extinction in female rats: The role of NMDA receptor activation. AB - Converging cross-species evidence indicates that fear extinction (the laboratory basis of exposure therapy for anxiety disorders) in females is modulated by endogenous and exogenous estradiol. The mechanisms underlying estradiol's influences on fear extinction are largely undefined. However, one likely candidate is the NMDA-receptor (NMDAr), activation of which is necessary for estradiol-mediated enhancements in structural and functional neural plasticity, as well as extinction consolidation in males. Here, we demonstrate that systemic co-administration of the non-competitive NMDAr antagonist, MK801, blocked the enhancement of fear extinction by systemic estradiol in ovariectomized rats. In intact rats, MK801 during diestrus (rising estradiol) prevented the enhancement in extinction recall in rats that received extinction training during proestrus (peak estradiol). Systemic administration of the partial NMDAr agonist D cycloserine (DCS) prior to extinction training facilitated extinction in ovariectomized rats, mimicking the effects of estradiol. In intact rats, DCS administered on the afternoon of proestrus and the morning of estrus (declining estradiol) facilitated extinction in rats that received extinction training during metestrus (low estradiol). Finally, DCS also facilitated extinction in ovariectomized rats when administered immediately after extinction training. Combined, these findings suggest that endogenous and exogenous estradiol enhance fear extinction via NMDAr-dependent mechanisms. Moreover, these findings raise the possibility that fear extinction deficits during periods of low endogenous estradiol levels can be reversed by increasing NMDAr activation via DCS administration, either well prior to, or immediately after, extinction training. PMID- 29763632 TI - Lack of value of juvenile animal toxicity studies for supporting the safety of pediatric oncology phase I trials. AB - Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals. The present paper examines pediatric-specific clinical findings to focus on dose setting in pediatric oncology patients and safety monitoring in terms of the potential value of JAS. Our assessment demonstrates that pediatric starting doses were safe for all 29 therapeutics examined in that no life-threatening toxicities occurred in the first cohort, and overall the ratio of the pediatric maximum tolerated dose (MTD) to the recommended adult dose was close to 1. In addition, the 4 serious adverse events (SAEs) that weren't detectable with standard monitoring plans for pediatric oncology trials would not have been detectable in a standard JAS. This review demonstrates that safe starting doses in pediatric oncology patients for these therapeutics could have been solely based on adult doses without any knowledge of findings in JAS. PMID- 29763629 TI - Ventricular pro-arrhythmic phenotype, arrhythmic substrate, ageing and mitochondrial dysfunction in peroxisome proliferator activated receptor-gamma coactivator-1beta deficient (Pgc-1beta-/-) murine hearts. AB - INTRODUCTION: Ageing and age-related bioenergetic conditions including obesity, diabetes mellitus and heart failure constitute clinical ventricular arrhythmic risk factors. MATERIALS AND METHODS: Pro-arrhythmic properties in electrocardiographic and intracellular recordings were compared in young and aged, peroxisome proliferator-activated receptor-gamma coactivator-1beta knockout (Pgc-1beta-/-) and wild type (WT), Langendorff-perfused murine hearts, during regular and programmed stimulation (PES), comparing results by two-way ANOVA. RESULTS AND DISCUSSION: Young and aged Pgc-1beta-/- showed higher frequencies and durations of arrhythmic episodes through wider PES coupling-interval ranges than WT. Both young and old, regularly-paced, Pgc-1beta-/- hearts showed slowed maximum action potential (AP) upstrokes, (dV/dt)max (~157 vs. 120-130 V s-1), prolonged AP latencies (by ~20%) and shortened refractory periods (~58 vs. 51 ms) but similar AP durations (~50 ms at 90% recovery) compared to WT. However, Pgc 1beta-/- genotype and age each influenced extrasystolic AP latencies during PES. Young and aged WT ventricles displayed distinct, but Pgc-1beta-/- ventricles displayed similar dependences of AP latency upon (dV/dt)max resembling aged WT. They also independently increased myocardial fibrosis. AP wavelengths combining activation and recovery terms paralleled contrasting arrhythmic incidences in Pgc 1beta-/- and WT hearts. Mitochondrial dysfunction thus causes pro-arrhythmic Pgc 1beta-/- phenotypes by altering AP conduction through reducing (dV/dt)max and causing age-dependent fibrotic change. PMID- 29763634 TI - Novel long noncoding RNA NMR promotes tumor progression via NSUN2 and BPTF in esophageal squamous cell carcinoma. AB - Long noncoding RNAs (lncRNA) have been implicated in cancer but most of them remain largely unstudied. Here, we identified a novel NSUN2 methylated lncRNA (NMR), which was significantly upregulated in esophageal squamous cell carcinoma (ESCC), functioned as a key regulator of ESCC tumor metastasis and drug resistance. Upregulation of NMR correlated with tumor metastasis and indicated poor overall survival in ESCC patients. Functionally, NMR could promote tumor cell migration and invasion, inhibit cisplatin-induced apoptosis and increase drug resistance in ESCC cells. Mechanistically, transcription of NMR could be upregulated by NF-kappaB activation after IL-1beta and TNF-alpha treatment. NMR was methylated by NSUN2 and might competitively inhibit methylation of potential mRNAs. NMR could directly bind to chromatin regulator BPTF, and potentially promote MMP3 and MMP10 expression by ERK1/2 pathway through recruiting BPTF to chromatin. Taken together, NMR functions as an oncogenic gene and may serve as new biomarker and therapeutic target in ESCC. PMID- 29763635 TI - Cortical thickness and gyrification patterns in patients with psychogenic non epileptic seizures. AB - Psychogenic non-epileptic seizures (PNES) are often viewed as manifestations of altered motor and sensory function resulting from psychological responses to adverse experiences. Yet many patients and non-expert healthcare professionals find it difficult to understand how severe disturbances in normal neurological functioning can solely result from underlying psychological mechanisms to the exclusion of other physical causes. Perhaps importantly, recent advances using neuroimaging techniques point to possible structural and functional correlates in PNES. In an attempt to further our understanding of the neurobiological correlates of this condition, we compared the brain scans of 20 patients with PNES (14 females, mean age 41.05, range 19-62) and 20 age- and gender-matched healthy controls (14 females, mean age 40.65, range 21-61) to investigate group differences for cortical thickness and gyrification patterns using FreeSurfer. Compared to controls, patients with PNES showed cortical thickness increases in motor, sensory and occipital areas as well as cortical thickness decreases in temporal and frontal brain regions. In addition, we observed age-related changes in cortical thickness in the right lateral occipital area in PNES. However, contrary to our prediction that atypical gyrification may be present, we did not find any evidence of abnormalities on a measure thought to reflect prenatal and early childhood cortical development and organization. Nor did we find significant correlations between cortical thickness results and clinical features. These findings partly corroborate, but also differ from previous morphometric studies in PNES. These inconsistencies likely reflect the aetiology and phenomenological heterogeneity of PNES. PMID- 29763636 TI - Inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate crystal-induced inflammation. AB - Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E synthase-1 (mPGES-1)-derived eicosanoids play an essential role in human inflammatory disorders. Here, we investigated whether inhibition of COX-2/mPGES-1 and 5-LOX in macrophages by leonurine ameliorates monosodium urate (MSU) crystal induced inflammation. Virtual screening assay and in vitro enzyme inhibition assay showed that leonurine was a potential inhibitor of COX-2, mPGES-1 and 5 LOX. Compared with COX-2 inhibitor celecoxib, leonurine (30 mg/kg) significantly decreased ankle perimeter, gait score and neutrophil number in synovial fluid in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, mPGES-1 and 5-LOX and production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in the synovial fluid macrophages. In addition, leonurine decreased representative M1 marker (iNOS and CD86) expression, NLRP3 inflammasome activation and M1 cytokine (TNF-alpha and IL-1beta) production. In the in vitro cultured RAW264.7 and human monocyte-derived macrophages (MDMs), blockade of COX 2/mPGES-1 and 5-LOX by leonurine inhibited macrophage M1 polarization and NLRP3 inflammasome activation in response to MSU crystals, and thus down-regulated IL 1beta and TNF-alpha with STAT1 and NF-kappaB inactivation. Conversely, these effects were partially abolished by overexpression of COX-2, mPGES-1, 5-LOX or STAT1. Furthermore, leonurine prevented a positive feedback loop between COX 2/mPGES-1/5-LOX and IL-1beta/TNF-alpha in MSU crystal-induced inflammation. Together, simultaneous down-regulation of COX-2/mPGES-1 and 5-LOX by leonurine ameliorates MSU crystal-induced inflammation through decreasing IL-1beta and TNF alpha production. Our study may provide novel multi-target agents toward the arachidonic acid (AA) network for gouty arthritis therapy. PMID- 29763638 TI - Effects of SC99 on cerebral ischemia-perfusion injury in rats: Selective modulation of microglia polarization to M2 phenotype via inhibiting JAK2-STAT3 pathway. AB - Inhibition of Janus kinases 2-Signal transducers and activators of transcription3 (JAK2-STAT3) pathway has been shown to exert anti-inflammatory actions. SC99, a novel specific inhibitor targeting JAK2-STAT3 pathway, has been verified to negatively modulate platelet activation and aggregation in vitro. In current study, a middle cerebral artery occlusion and reperfusion (MCAO/R) model was established in Sprague Dawley rats and primary cultured microglia was exposed to oxygen and glucose deprivation (OGD/R) in vitro. Different dosages were employed to detect the effects of SC99 on cerebral ischemia-perfusion (I/R) injury and evaluate the underlying mechanisms. Our results showed that intracerebroventricular injection of SC99 (10 mmol/L, 15 MUL) produced an effective inhibitory effect on the phosphorylation of JAK2 and STAT3. Correspondingly, SC99 ameliorated neuronal apoptosis and degeneration, neurobehavioral deficits, inflammatory response and brain edema. And SC99 promoted microglia polarization to an anti-inflammatory M2 phenotype. We concluded that SC99 could alleviate brain damage and play an anti-inflammatory action by promoting microglia polarization to an anti-inflammatory phenotype after I/R injury, which provides an emerging and promising alternative to protect the brain against MCAO/R injury in the future investigations. PMID- 29763637 TI - Neurosteroid pregnenolone sulfate, alone, and as augmentation of lurasidone or tandospirone, rescues phencyclidine-induced deficits in cognitive function and social interaction. AB - BACKGROUND: Pregnenolone sulfate (PregS), an endogenous neurosteroid, which negatively and positively modulates gamma amino butyric acid subunit A (GABAA) and N-methyl D-aspartate (NMDA) receptors (R) respectively, among other potential neuroplastic changes on synaptic processes, has shown some beneficial effects on treating cognitive impairment associated with schizophrenia (CIAS) and negative symptoms. Lurasidone (Lur), an atypical antipsychotic drug (AAPD), and tandospirone (Tan), a 5-HT1A R partial agonist, have also been reported to improve cognitive or negative symptoms, or both, in some schizophrenia patients. METHODS: We tested whether PregS, by itself, and in combination with Lur or Tan could rescue persistent deficits produced by subchronic treatment with the NMDAR antagonist, phencyclidine (PCP)-in episodic memory, executive functioning, and social behavior, using novel object recognition (NOR), operant reversal learning (ORL), and social interaction (SI) tasks, in male C57BL/6 J mice. RESULTS: PregS (10, but not 3 mg/kg) significantly rescued subchronic PCP-induced NOR and SI deficits. Co-administration of sub-effective doses (SEDs) of PregS (3 mg/kg) + Lur (0.1 mg/kg) or Tan (0.03 mg/kg) rescued scPCP-induced NOR and SI deficits. Further, PregS (30, but not 10 mg/kg) rescued PCP-induced ORL deficit, as did the combination of SED PregS (10 mg/kg) +SED Lur (1 mg/kg) or Tan (1 mg/kg). CONCLUSION: PregS was effective alone and as adjunctive treatment for treating two types of cognitive impairments and negative symptoms in this schizophrenia model. Further study of the mechanisms by which PregS alone and in combination with AAPDs and 5-HT1A R partial agonists, rescues the deficits in cognition and SI in this preclinical model is indicated. PMID- 29763639 TI - Complete genome sequence of Gordonia sp. YC-JH1, a bacterium efficiently degrading a wide range of phthalic acid esters. AB - Phthalic acid esters (PAEs) are a family of recalcitrant pollutants mainly used as plasticizer. The strain Gordonia sp.YC-JH1, isolated from petroleum contaminated soil, is capable of efficiently degrading a wide range of PAEs. In order to pertinently investigate the genetic mechanism of PAEs catabolism by strain YC-JH1, its complete genome sequencing has been performed by SMRT sequencing technology. The genome comprises a circular chromosome and a plasmid with a size of 4,101,557 bp and 91,767 bp respectively. Based on the genome sequence, 3563 protein-coding genes are predicted, of which the genes responsible for PAEs degradation are identified, including the two genes of PAEs hydrolase and the gene clusters for phthalic acid and protocatechuic acid degradation. The genome information provides genomic basis of PAEs degradation to allow the complete metabolism of PAEs. The wide substrate spectrum and its genetic basis of this strain should expand its application potential for environments bioremediation, provide novel gene resources involved in PAEs degradation for biotechnology and gene engineering, and contribute to shed light on the mechanism of PAEs metabolism. PMID- 29763640 TI - Development of fluorescent reverse transcription loop-mediated isothermal amplification (RT-LAMP) using quenching probes for the detection of the Middle East respiratory syndrome coronavirus. AB - Clinical detection of Middle East respiratory syndrome (MERS) coronavirus (MERS CoV) in patients is achieved using genetic diagnostic methods, such as real-time RT-PCR assay. Previously, we developed a reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay for the detection of MERS-CoV [Virol J. 2014. 11:139]. Generally, amplification of RT-LAMP is monitored by the turbidity induced by precipitation of magnesium pyrophosphate with newly synthesized DNA. However, this mechanism cannot completely exclude the possibility of unexpected reactions. Therefore, in this study, fluorescent RT-LAMP assays using quenching probes (QProbes) were developed specifically to monitor only primer-derived signals. Two primer sets (targeting nucleocapsid and ORF1a sequences) were constructed to confirm MERS cases by RT-LAMP assay only. Our data indicate that both primer sets were capable of detecting MERS-CoV RNA to the same level as existing genetic diagnostic methods, and that both were highly specific with no cross-reactivity observed with other respiratory viruses. These primer sets were highly efficient in amplifying target sequences derived from different MERS-CoV strains, including camel MERS-CoV. In addition, the detection efficacy of QProbe RT-LAMP was comparable to that of real-time RT-PCR assay using clinical specimens from patients in Saudi Arabia. Altogether, these results indicate that QProbe RT LAMP assays described here can be used as powerful diagnostic tools for rapid detection and surveillance of MERS-CoV infections. PMID- 29763641 TI - Ischemic stroke across sexes: what is the status quo? AB - Stroke prevalence is expected to increase in the next decades due to the aging of the Western population. Ischemic stroke (IS) shows an age- and sex-dependent distribution in which men represent the most affected population within 65 years of age, being passed by post-menopausal women in older age groups. Furthermore, a sexual dimorphism concerning risk factors, presentation and treatment of IS has been widely recognized. In order to address these phenomena, a number of issue have been raised involving both socio-economical and biological factors. The latter can be either dependent on sex hormones or due to intrinsic factors. Although women have poorer outcomes and are more likely to die after a cerebrovascular event, they are still underrepresented in clinical trials and this is mirrored by the lack of sex-tailored therapies. A greater effort is needed in the future to ensure improved treatment and quality of life to both sexes. PMID- 29763642 TI - A new insight into the oxidative mechanism of caffeine and related methylxanthines in aprotic medium: May caffeine be really considered as an antioxidant? AB - BACKGROUND: Antioxidant properties have been recently suggested for caffeine that seems showing protective effects against damages caused by oxidative stress. In particular, a HO scavenging activity has been ascribed to caffeine. Even if the oxidation of caffeine has been widely studied, the antioxidant mechanism is still far to be understood. METHODS: The electrochemical behavior of caffeine, theobromine and theophylline was studied in aprotic medium by cyclic voltammetry and electrolysis in UV-vis cell; a computational analysis of the molecular structures based on the Density Functional Theory was performed; the reactivity of all substrates towards lead dioxide, superoxide and galvinoxyl radical was followed by UV-vis spectrophotometry. RESULTS: Results supported the mono electronic oxidation of the C4C5 bond for all substrates at high oxidation potentials, the electron-transfer process leading to a radical cation or a neutral radical according to the starting methylxanthine N7-substituted (caffeine and theobromine) or N7-unsubstituted (theophylline), respectively. A different following chemical fate might be predicted for the radical cation or the neutral radical. No interaction was evidenced towards the tested reactive oxygen species. CONCLUSIONS: No reactivity via H-atom transfer was evidenced for all studied compounds, suggesting that an antiradical activity should be excluded. Some reactivity only with strong oxidants could be predicted via electron-transfer. The acclaimed HO scavenging activity should be interpreted in these terms. The study suggested that CAF might be hardly considered an antioxidant. GENERAL SIGNIFICANCE: Beyond the experimental methods used, the discussion of the present results might provide food for thought to the wide audience working on antioxidants. PMID- 29763644 TI - Immunomodulatory effect of Celecoxib on HMGB1/TLR4 pathway in a recurrent seizures model in immature rats. AB - Epileptic seizures constitute an important problem in pediatric neurology during the developmental period. The frequency and nosological significance of seizures, as well as their association with epileptogenesis, may be related to underlying mechanisms such as neuroinflammation. Those mechanisms of response activate inflammatory molecules induced in the neurons, activated glial cells and endothelial cells via the key HMGB1/TLR4 pathway. In this study, the drug celecoxib (CCX) was used as a blocker of the cyclooxygenase 2 (COX-2) and HMGB1/TLR-4 pathways. The experimental model was implemented in 10-day-old neonatal Sprague Dawley rats to induce recurrent seizures with kainic acid (KA, 1.4 mg/kg). Data were evaluated at early (14 PND) and late (30 PND) time points. The results showed that the CCX and CCX + pentobarbital (PB) groups exhibited a protective effect by significantly increasing the time latency of seizures compared to the KA group at both early (p < 0.01) and late (p < 0.001) times. When the CCX group was compared to the KA group, there was also a significant decrease in the number of HMGB1 and TLR-4 transcripts (p < 0.05) and in COX-2 protein expression (p < 0.05) in the most important areas for seizure generation (the hippocampus and cortex) at both the early and late time points. These results demonstrated that CCX treatment after epileptic seizures has a neuroprotective effect due to the inhibition of proinflammatory proteins and associated signaling pathways and reduces seizure susceptibility. Additionally, the timely intervention of inflammatory pathways will reduce the risk of developing epilepsy in adulthood. PMID- 29763643 TI - Polysaccharide PRM3 from Rhynchosia minima root enhances immune function through TLR4-NF-kappaB pathway. AB - BACKGROUND: Polysaccharides, one of the active ingredients in herbal medicine, are proved to enhance innate immunity against infections. The aim of this study is to explore the immunoregulatory ability of polysaccharides from Rhynchosia minima root in vitro and in vivo. METHODS: Polysaccharide fractions of R. minima root were obtained by chromatographic column. The content of NO was measured by spectrophotometry. The levels of cytokines (tumor necrosis factor-alpha, TNF alpha; interleukin-6, IL-6; and monocyte chemoattractant protein-1, MCP-1) were determined by enzyme-linked immuno-sorbent assay (ELISA) kits. The translocation of p65 into the nucleus was imaged by confocal microscopy. The mRNA expression of TNF-alpha, IL-6, and MCP-1 was determined by quantitative real-time PCR. T lymphocyte subgroups of spleen from immunosuppressive mouse were evaluated by flow cytometry. RESULTS: PRM3 remarkably enhanced the phagocytic ability of macrophages and promoted the release of NO and the secretion of cytokines (TNF alpha, IL-6, and MCP-1) from macrophages. Simultaneously, PRM3 potently activated NF-kappaB signaling pathway via Toll-like receptor 4 (TLR4). In addition, PRM3 obviously increased the levels of serum cytokines, markedly up-regulated the percentages of CD3+ and CD4+ T lymphocytes and the CD4+/CD8+ ratio of splenocytes, and effectively attenuated cyclophosphamide induced immunosuppression in mice. CONCLUSIONS: PRM3 profoundly enhanced the immune function in vitro and in vivo through TLR4-NF-kappaB pathway and is a promising candidate of immunopotentiator which could be applied in functional foods or drugs. GENERAL SIGNIFICANCE: This study reported a polysaccharide PRM3 from R. minima root exhibited potent immunoenhancing activity and significantly alleviated cyclophosphamide-induced immunosuppression through TLR4-NF-kappaB pathway. PMID- 29763645 TI - Agmatine potentiates neuroprotective effects of subthreshold concentrations of ketamine via mTOR/S6 kinase signaling pathway. AB - Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well tolerated antidepressant/augmenter drug. In this study, the exposure of HT22 hippocampal neuronal cell line to corticosterone (50 MUM) induced a significant neuronal cell death. Interestingly, the incubation of HT22 cells with the fast acting antidepressant drug ketamine (1 MUM) prevented the corticosterone-induced toxicity. Similarly, agmatine caused a significant cytoprotection at the concentration of 0.1 MUM against corticosterone (50 MUM) cell damage. Notably, the incubation with a subthreshold concentration of ketamine (0.01 MUM) in combination with a subthreshold concentration of agmatine (0.001 MUM) prevented the neuronal damage elicited by corticosterone (50 MUM). A 24 h co-incubation with subthreshold concentrations of ketamine (0.01 MUM) and agmatine (0.001 MUM) was able to cause a significant increase in the phosphorylation levels of Akt (Ser473) and p70S6 kinase (Thr389) as well as PSD95 immunocontent. Neither glycogen synthase kinase-3beta (Ser9) phosphorylation nor beta catenin immunocontent were altered by a 24 h co-incubation period. Finally, the co incubation of cells for 30 min did not produce any effect in the phosphorylation or immunocontent of any protein investigated. Taken together, our results support the notion that the combination of subthreshold concentrations of ketamine and agmatine has cytoprotective effects against corticosterone-induced cell death. This effect is accompanied by its ability to activate Akt and mTOR/S6 kinase signaling pathway, and increase the expression of synaptic proteins. PMID- 29763647 TI - A simple cell-based high throughput screening (HTS) assay for inhibitors of Salmonella enterica RNA polymerase containing the general stress response regulator RpoS (sigmaS). AB - RNA polymerase containing the stress response regulator sigmaS subunit (RpoS) plays a key role in bacterial survival in hostile environments in nature and during infection. Here we devise and validate a simple cell-based high throughput luminescence assay for this holoenzyme suitable for screening large chemical libraries in a robotic platform. PMID- 29763646 TI - Genetic parameter and breeding value estimation of donkeys' problem-focused coping styles. AB - Donkeys are recognized therapy or leisure-riding animals. Anecdotal evidence has suggested that more reactive donkeys or those more easily engaging flight mechanisms tend to be easier to train compared to those displaying the natural donkey behaviour of fight. This context brings together the need to quantify such traits and to genetically select donkeys displaying a neutral reaction during training, because of its implication with handler/rider safety and trainability. We analysed the scores for coping style traits from 300 Andalusian donkeys from 2013 to 2015. Three scales were applied to describe donkeys' response to 12 stimuli. Genetic parameters were estimated using multivariate models with year, sex, husbandry system and stimulus as fixed effects and age as a linear and quadratic covariable. Heritabilities were moderate, 0.18 +/- 0.020 to 0.21 +/- 0.021. Phenotypic correlations between intensity and mood/emotion or response type were negative and moderate (-0.21 and -0.25, respectively). Genetic correlations between the same variables were negative and moderately high (-0.46 and -0.53, respectively). Phenotypic and genetic correlations between mood/emotion and response type were positive and high (0.92 and 0.95, respectively). Breeding values enable selection methods that could lead to endangered breed preservation and genetically selecting donkeys for the uses that they may be most suitable. PMID- 29763648 TI - Autism Spectrum Disorder: Classification, diagnosis and therapy. AB - Autism Spectrum Disorder (ASD) refers to a group of neurodevelopmental disorders including autism, Asperger's syndrome (AS) and pervasive developmental disorder not otherwise specified (PDD-NOS). The new diagnostic criteria of ASD focuses on two core domains: social communication impairment and restricted interests/repetitive behaviors. The prevalence of ASD has been steadily increasing over the past two decades, with current estimates reaching up to 1 in 36 children. Hereditary factors, parental history of psychiatric disorders, pre term births, and fetal exposure to psychotropic drugs or insecticides have all been linked to higher risk of ASD. Several scales such as the Childhood Autism Rating Scale (CARS), The Autism Spectrum Disorder-Observation for Children (ASD OC), The Developmental, Dimensional, and Diagnostic Interview (3di), are available to aid in better assessing the behaviors and symptoms associated with ASD. Nearly 75% of ASD patients suffer from comorbid psychiatric illnesses or conditions, which may include attention-deficit hyperactivity disorder (ADHD), anxiety, bipolar disorder, depression, Tourette syndrome, and others. Both pharmacological and non-pharmacological interventions are available for ASD. Pharmacological treatments include psychostimulants, atypical antipsychotics, antidepressants, and alpha-2 adrenergic receptor agonists. These medications provide partial symptomatic relief of core symptoms of ASD or manage the symptoms of comorbid conditions. Non-pharmacological interventions, which show promising evidence in improving social interaction and verbal communication of ASD patients, include music therapy, cognitive behavioral therapy and social behavioral therapy. Hormonal therapies with oxytocyin or vasopressin receptor antagonists have also shown some promise in improving core ASD symptoms. The use of vitamins, herbal remedies and nutritional supplements in conjunction with pharmacological and behavioral treatment appear to have some effect in symptomatic improvement in ASD, though additional studies are needed to confirm these benefits. Developing novel disease-modifying therapies may prove to be the ultimate intervention for sustained improvement of symptoms in ASD. PMID- 29763649 TI - Differentiation of umbilical cord derived mesenchymal stem cells to hepatocyte cells by transfection of miR-106a, miR-574-3p, and miR-451. AB - Studying the profile of micro RNAs (miRs) elucidated the highest expressed miRs in hepatic differentiation. In this study, we investigated to clarify the role of three embryonic overexpressed miRs (miR-106a, miR-574-3p and miR-451) during hepatic differentiation of human umbilical cord derived mesenchymal stem cells (UC-MSCs). We furthermore, aimed to explore whether overexpression of any of these miRs alone is sufficient to induce the differentiation of the UC-MSCs into hepatocyte-like cells. UC-MSCs were transfected either alone or together with miR 106a, miR-574-3p and miR-451 and their potential hepatic differentiation and alteration in gene expression profile, morphological changes and albumin secretion ability were investigated. We found that up-regulation of any of these three miRs alone cannot induce expression of all hepatic specific genes. Transfection of each miR alone, led to Sox17, FoxA2 expression that are related to initiation step of hepatic differentiation. However, concurrent ectopic overexpression of three miRs together can induce UC-MSCs differentiation into functionally mature hepatocytes. These results show that miRs have the capability to directly convert UC-MSCs to a hepatocyte phenotype in vitro. PMID- 29763650 TI - Reanalyzing the Palaeoptera problem - The origin of insect flight remains obscure. AB - The phylogenetic relationships of the winged insect lineages - mayflies (Ephemeroptera), damselflies and dragonflies (Odonata), and all other winged insects (Neoptera) - are still controversial with three hypotheses supported by different datasets: Palaeoptera, Metapterygota and Chiastomyaria. Here, we reanalyze available phylogenomic data with a focus on detecting confounding and alternative signal. In this context, we provide a framework to quantitatively evaluate and assess incongruent molecular phylogenetic signal inherent in phylogenomic datasets. Despite overall support for the Palaeoptera hypothesis, we also found considerable signal for Chiastomyaria, which is not easily detectable by standardized tree inference approaches. Analyses of the accumulation of signal across gene partitions showed that signal accumulates gradually. However, even in case signal only slightly supported one over the other hypothesis, topologies inferred from large datasets switch from statistically strongly supported Palaeoptera to strongly supported Chiastomyaria. From a morphological point of view, Palaeoptera currently appears to be the best-supported hypothesis; however, recent analyses were restricted to head characters. Phylogenetic approaches covering all organ systems including analyses of potential functional or developmental convergence are still pending so that the Palaeoptera problem has to be considered an open question in insect systematics. PMID- 29763651 TI - Ejection fraction: the swan song of a timeless index or the battle against strain will still go on? PMID- 29763652 TI - Ultrasound-Guided Laparoscopic-Assisted Abdominal Cerclage in Pregnancy. PMID- 29763653 TI - Author's Reply. PMID- 29763654 TI - Obturator Neuromodulation with Laparoscopic Placement of an Obturator Lead for the Treatment of Intractable Opioid-Dependent Chronic Pelvic Pain due to Obturator Neuralgia. AB - Chronic pelvic pain (CPP) is a common condition in women that can have a devastating effect on quality of life. Some of the most severe forms of CPP are related to peripheral nerve injuries, causing persistent neuropathic pain. We present a case of a young woman with severe opioid-dependent chronic pelvic and right groin pain due to obturator neuralgia. She had failed amultitude of treatments, including multiple medications, manual physical therapy, nerve blocks, surgical neurolysis, and spinal cord stimulation, without significant benefit. She underwent a trial of peripheral neuromodulation of the obturator nerve with laparoscopic placement of a quadripolar lead. During the 6-day trial, she experienced almost complete relief of her pain; therefore, she underwent permanent implantation of an intermittent pulse generator. Over the next 6 months, she was completely weaned off chronic opioids. At 23 months postimplantation, she had essentially no pain and was no longer receiving any analgesic, antidepressant, or membrane-stabilizing medications. PMID- 29763656 TI - Canalization and genetic assimilation: Reassessing the radicality of the Waddingtonian concept of inheritance of acquired characters. AB - Genetic assimilation is often mixed up with the Baldwin effect. For Waddington, genetic assimilation was both a phenomenon and a specific mechanism of adaptive evolution which was grounded in the concept of canalization. This theoretical link between canalization and genetic assimilation, which was pivotal in Waddington's view, has been weakened since the early 1960s. The aim of the present article is to emphasize the specificity and to reassess the possible radicality of Waddington's proposal. What he claimed to have elaborated was an actual and genuine mechanism of inheritance of acquired characters that did not rely on soft Lamarckian inheritance. Consequently his "theory" of genetic assimilation, unlike the Baldwin effect, might not be as easily integrated in the framework of the Modern Synthesis. PMID- 29763655 TI - No evidence of adverse pregnancy outcome after exposure to ibuprofen in the first trimester - Evaluation of the national Embryotox cohort. AB - Ibuprofen is an analgesic frequently used in the 1st and 2nd trimester of pregnancy. Most relevant studies deal with NSAID as a group and do not specifically focus on ibuprofen. In this study, 1117 women exposed to ibuprofen in the 1st trimester were compared to 2229 non-exposed women. Data were retrieved from the German Embryotox database. No significantly increased risk of major birth defects (4.8% vs. 4.1%; OR adjusted 1.11, 95% CI 0.75-1.64) or a distinct pattern of birth defects were found. The cumulative incidences of spontaneous abortions were similar across cohorts (15.5% vs. 16.6%; HR adjusted 0.85; 95% CI, 0.65-1.11). Subgroup analyses of pregnancies exposed for >=7 (n = 223) and >=30 days (n = 72) did not reveal a higher risk with increasing treatment duration. Ibuprofen does not seem to carry a substantial embryotoxic risk regarding the investigated endpoints. PMID- 29763657 TI - A mHealth-based care model for improving hypertension control in stroke survivors: Pilot RCT. AB - PURPOSE: Hypertension (HTN) is significantly under-treated in stroke survivors. We examined usability and efficacy of a mHealth -based care model for improving post-stroke HTN control (Funding: AHRQ R21HS021794). METHODS: We used a RCT design. Planned study duration was 90 days. Intervention arm (IA) participants measured their BP daily using a smart phone and wireless BP monitor. This was transmitted automatically to the study database. Investigators (Physician + PharmD) made bi-weekly medication adjustments to achieve the BP goal. Control arm (CA) participants received a digital BP monitor and usual care. We examined Usability (measured with Marshfield System Usability Survey) and HTN control efficacy using an ITT (intent-to-treat) and as-treated (AT) analyses. RESULTS: Fifty participants (IA = 28; CA = 22) completed the study. The Marshfield survey question, "I thought the system was easy to use" mean score was 4.6, (5 = strongly agree). Mean SBP declined significantly between enrollment and study completion in the IA. In ITT, IA SBP declined 9.88 mm, p = 0.005. In AT, IA SBP declined 10.81 mm, p = 0.0036. CA SBP decline was 5-6 mm Hg (not significant). In the ITT, baseline HTN control (SBP < 140 mm Hg) was 50% in IA and CA. At study completion, HTN was controlled in 82% (23/28) of IA and 64% (14/22) of CA (p = 0.14). In the AT, HTN was controlled in 89% (23/26) of IA and 58% (14/24) of CA, (p = 0.015). CONCLUSION: A mHealth-based HTN care model had excellent usability and provided better HTN control than usual care in stroke survivors. CLINICAL TRIAL: gov: NCT01875094. PMID- 29763658 TI - Event related potential analysis techniques for autism spectrum disorders: A review. AB - Autism Spectrum Disorders (ASD) comprise all pervasive neurodevelopmental diseases marked by deficits in social and communication skills, delayed cognitive development, restricted and repetitive behaviors. The core symptoms begin in early childhood, may continue life-long resulting in poor performance in adult stage. Event-related potential (ERP) is basically a time-locked electroencephalogram signal elicited by various stimuli, related to sensory and cognitive processes. The various ERP based techniques used for the study of ASD are considered in this review. ERP based study offers the advantage of being a non-invasive technique to measure the brain activity precisely. The techniques are categorized into three based on the processing domain: time, frequency and time-frequency. Power spectral density, coherence, phase synchrony, multiscale entropy, modified multiscale entropy, sum of signed differences, synchrostates and variance are some of the measures that have been widely used to study the abnormalities in frequency bands and brain connectivity. Various signal processing techniques such as Fast Fourier Transform, Discrete Fourier Transform, Short-Time Fourier Transform, Principal Component Analysis, Wavelet Transform, Directed Transfer Function etc. have been used to analyze the recorded signals so as to unravel the distinctive event-related potential patterns in individuals with ASD. The review concludes that ERP proves to be an efficient tool in detecting the brain abnormalities and connectivity issues, indicating the heterogeneity of ASD. Many advanced techniques are utilized to decipher the underlying neural circuitry so as to aid in therapeutic interventions for improving the core areas of deficits. PMID- 29763659 TI - Safety and pharmacokinetics of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) in healthy adult subjects of Japanese descent. AB - INTRODUCTION: BGF MDI, a budesonide, glycopyrronium, and formoterol fumarate dihydrate triple fixed-dose combination metered dose inhaler formulated using co suspension delivery technology, is currently in Phase III global development for chronic obstructive pulmonary disease. METHODS: This was a Phase I, randomized, double-blind, placebo-controlled, ascending-dose, crossover study to assess the safety and pharmacokinetic profiles of two doses of BGF MDI in healthy adult subjects of Japanese descent (NCT02197975). Safety assessments included monitoring for adverse events (AEs). Pharmacokinetic parameters were assessed following a single dose and 7-days chronic dosing with BGF MDI 160/14.4/10 MUg and BGF MDI 320/14.4/10 MUg. RESULTS: Twenty subjects were randomized and included in the safety and pharmacokinetic populations; mean age 29.7 years; 65% male; and mean body mass index of 21.9 kg/m2. The incidences of treatment emergent AEs (TEAEs) were similar between treatments. All the TEAEs were mild to moderate in severity. Budesonide area under the plasma concentration-time curve from 0 to 12 h (AUC0-12) and maximum observed plasma concentration (Cmax) values were approximately double for the higher dose of BGF MDI compared with the lower dose on Day 1 and also following chronic dosing on Day 8. Glycopyrronium and formoterol AUC0-12 and Cmax values on Day 8 were comparable between the two doses of BGF MDI. DISCUSSION: Both doses of BGF MDI were well tolerated in healthy subjects of Japanese descent and the systemic exposure to budesonide was dose proportional for BGF MDI 160/14.4/10 MUg and BGF MDI 320/14.4/10 MUg. The safety and pharmacokinetics for BGF MDI 160/14.4/10 MUg and BGF MDI 320/14.4/10 MUg in Japanese subjects were comparable to data from previous studies in Western populations, which suggests that the safety and efficacy profile of BGF MDI should be similar in Western and Japanese subjects. PMID- 29763660 TI - Docosahexaenoic acid-derived oxidized lipid metabolites modulate the inflammatory response of lipolysaccharide-stimulated macrophages. AB - Docosahexaenoic acid (DHA) supplementation has demonstrated beneficial effects in a number of inflammatory diseases. Increasingly, important contributions to its favorable effects are attributed downstream metabolites called docosanoids. Herein, we investigated the role of DHA-derived oxidized lipid metabolites on inflammatory mediator expression by RAW 264.7 murine macrophages. Specifically, macrophage incorporation of DHA, and the resultant biosynthesis of selected pro resolving docosanoids was quantified. Docosanoid effects on the expression of selected pro-inflammatory cytokines in LPS-stimulated cultures was determined. Macrophages incorporated DHA in significant amounts. In the presence of DHA macrophages produced statistically significant amounts of several putative pro resolving docosanoids compared to untreated controls. Among them, resolvins D1 and D2 and maresin 1 abrogated COX-2 and IL-1beta gene expression in LPS stimulated macrophages. In addition to these mediators, protectin DX inhibited LPS-stimulated macrophage expression of IL-6. Our results demonstrate that macrophages incorporate DHA in quantities sufficient for the biosynthesis of biologically-relevant concentrations of a number of pro-resolving docosanoids, certain of which modulate the inflammatory response of macrophages under conditions mimicking acute inflammation. These data provide further information on the mechanism(s) by which DHA exerts salutary effects on the inflammatory response of macrophages. PMID- 29763661 TI - Prominent release of lipoxygenase generated mediators in a murine house dust mite induced asthma model. AB - The profile of activation of lipid mediator (LM) pathways in asthmatic airway inflammation remains unclear. This experimental study quantified metabolite levels of omega3-, omega6- and omega9-derived polyunsaturated fatty acids in bronchoalveolar lavage fluid (BALF) after 4-weeks of repeated house dust mite (HDM) exposure in a murine (C57BL/6) asthma model. The challenge induced airway hyperresponsiveness, pulmonary eosinophil infiltration, but with low and unchanged mast cell numbers. Of the 112 screened LMs, 26 were increased between 2 to >25-fold in BALF with HDM treatment (p < 0.05, false discovery rate = 5%). While cysteinyl-leukotrienes were the most abundant metabolites at baseline, their levels did not increase after HDM treatment, whereas elevation of PGD2, LTB4 and multiple 12/15-lipoxygenase products, such as 5,15-DiHETE, 15-HEDE and 15-HEPE were observed. We conclude that this model has identified a global lipoxygenase activation signature, not linked to mast cells, but with aspects that mimic chronic allergic airway inflammation in asthma. PMID- 29763662 TI - Mt-rps3 is an ancient gene which provides insight into the evolution of fungal mitochondrial genomes. AB - The nuclear ribosomal protein S3 (Rps3) is implicated in the assembly of the ribosomal small subunit. Fungi and plants present a gene copy in their mitochondrial (mt) genomes. An analysis of 303 complete fungal mt genomes showed that, when rps3 is found, it is either a free-standing gene or an anchored gene within the omega intron of the rnl gene. Early divergent fungi, Basidiomycota and all yeasts but the CTG group belong to the first case, and Pezizomycotina to the second. Its position, size and genetic code employed are conserved within species of the same Order. Size variability is attributed to different number of repeats. These repeats consist of AT-rich sequences. MtRps3 proteins lack the KH domain, necessary for binding to rRNA, in their N-terminal region. Their C-terminal region is conserved in all Domains of life. Phylogenetic analysis showed that nuclear and mtRps3 proteins are descendants of archaeal and a-proteobacterial homologues, respectively. Thus, fungal mt-rps3 gene is an ancient gene which evolved within the endosymbiotic model and presents different evolutionary routes: (a) coming from a-proteobacteria, it was relocated to another region of the mt genome, (b) via its insertion to the omega intron, it was transferred to the nucleus and/or got lost, and (c) it was re-routed to the mt genome again. Today, Basidiomycota and Saccharomycetales seem to follow the first evolutionary route and almost all Pezizomycotina support the second scenario with their exceptions being the result of the third scenario, i.e., the gene's re-entry to the mt genome. PMID- 29763663 TI - Biodiversity and apomixis: Insights from the East-Asian holly ferns in Polystichum section Xiphopolystichum. PMID- 29763664 TI - DNA profiling reveals Neobenedenia girellae as the primary parasitic monogenean in global fisheries and aquaculture. AB - Accurate identification of parasite species and strains is crucial to mitigate the risk of epidemics and emerging disease. Species of Neobenedenia are harmful monogenean ectoparasites that infect economically important bony fishes in aquaculture worldwide, however, the species boundaries between two of the most notorious taxa, N. melleni and N. girellae, has been a topic of contention for decades. Historically, identifications of Neobenedenia isolates have overwhelmingly been attributed to N. melleni, and it has been proposed that N. girellae is synonymous with N. melleni. We collected 33 Neobenedenia isolates from 22 host species spanning nine countries and amplified three genes including two nuclear (Histone 3 and 28S rDNA) and one mitochondrial (cytochrome b). Four major clades were identified using Maximum Likelihood and Bayesian inference analyses; clades A-D corresponding to N. girellae, N. melleni, N. longiprostata and N. pacifica, respectively. All unidentified isolates and the majority of Neobenedenia sequences from GenBank fell into clade A. The results of this study indicate that N. girellae is a separate species to N. melleni, and that a large proportion of previous samples identified as N. melleni may be erroneous and a revision of identifications is needed. The large diversity of host species that N. girellae is able to infect as determined in this study and the geographic range in which it is present (23.8426 degrees S and 24.1426 degrees N) makes it a globally cosmopolitan species and a threat to aquaculture industries around the world. PMID- 29763665 TI - Selection and paucity of phylogenetic signal challenge the utility of alpha tubulin in reconstruction of evolutionary history of free-living litostomateans (Protista, Ciliophora). AB - The class Litostomatea represents a highly diverse but monophyletic group, uniting both free-living and endosymbiotic ciliates. Ribosomal RNA genes and ITS region sequences helped to recognize and define the main litostomatean lineages, but did not provide enough phylogenetic signal to unambiguously resolve their interrelationships. In this study, we attempted to improve the resolution among main free-living predatory lineages by adding the gene coding for alpha-tubulin. However, our phylogenetic analyses challenged the performance of alpha-tubulin in reconstruction of evolutionary history of free-living litostomateans. We identified several mutually interconnected problems associated with the ciliate alpha-tubulin gene: the paucity of phylogenetic signal, molecular homoplasies and non-neutral evolution. Positive selection may generate molecular homoplasies (parallel evolution), while negative selection may cause a small number of changes and hence little phylogenetic informativness. Both problems were encountered in nucleotide and amino acid alpha-tubulin alignments, indicating an action of various selective pressures. Taking into account the involvement of alpha-tubulin in many essential biological processes, this protein could be so strongly affected by purifying selection that it even might have become an inappropriate molecular marker for reconstruction of phylogenetic relationships. Therefore, a great caution should be paid when tubulin genes are included in phylogenetic and/or phylogenomic analyses. PMID- 29763666 TI - Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors. AB - Immune checkpoint inhibitors (ICIs) are a newly developed component of cancer care that expands the treatment possibilities for patients. Their use has been associated with several immune-related adverse events, including ICI-induced sarcoidosis-like reactions. This article reviews the data concerning ICI-induced sarcoidosis-like reactions currently available in the medical literature. These reactions have been reported in three classes of ICIs: anti-cytotoxic T lymphocyte associated protein 4 antibodies, programmed death 1 inhibitors and programmed death ligand 1 inhibitors. These reactions are indistinguishable from sarcoidosis with a similar histology, pattern of organ involvement, and pattern of clinical manifestations. The most common locations to observe granulomatous inflammation from these reactions is in intrathoracic locations (the lung and/or mediastinal lymph nodes) and the skin. The median time between initiation of an ICI and the development of a sarcoidosis-like reaction averaged 14 weeks. Clinicians have opted to use corticosteroids and/or discontinue the ICI, or take no action when these reactions have developed. Regardless of whether the clinician performed an intervention or not, these reactions have uniformly improved or resolved after ICI-treatment, which provides additional temporal evidence supporting the presence of a sarcoidosis-like reaction as opposed to sarcoidosis. There is even evidence that the development of an ICI-induced sarcoidosis-like reaction suggests that the ICI is effective as an anti-tumor agent and should be continued. As is the case for sarcoidosis, sarcoidosis-like reactions do not mandate antisarcoidosis therapy, especially if the condition is asymptomatic. When treatment of sarcoidosis-like reaction is required, it may be prudent to continue ICI therapy and add antisarcoidosis therapy because standard antisarcoidosis regimens seem to be effective. Further research into the mechanisms involved in the development of ICI-induced sarcoidosis-like reactions may give insights into the immunopathogenesis of sarcoidosis. PMID- 29763667 TI - Selection of a round convex tablet shape that mitigates the risk of chipping and capping based on systematic evaluation by utilizing multivariate analysis. AB - Selecting a tablet shape that minimizes the risk of chipping and capping during manufacture is important in pharmaceutical industry. Here, the selection was performed based on systematic evaluation for the first time. Abrasion and stress relaxation time were utilized as indices of the occurrences of chipping and capping, respectively. Partial least square regression models that used tablet shape parameters to estimate the tablet's abrasion and stress relaxation time were utilized to develop response surface plots of the effect of the tablet shapes on the occurrence of chipping and capping systematically, and to identify an optimum tablet shape that is expected to have a low occurrence of chipping and capping. A verification study using commercial scale facilities proved that the optimum tablet shape had a lower occurrence of chipping and capping compared to suboptimum examples as speculated by their abrasion and stress relaxation time. The observed mathematical relationship between the tablet shapes and the occurrence of chipping and capping were consistent with the previous studies based on the comparison of limited number of tablet shapes using different formulations. Consequently, it is expected to be applicable to other formulations beyond the evaluated formulation in the present study. PMID- 29763670 TI - Goodpasture's autoimmune disease - A collagen IV disorder. AB - Goodpasture's (GP) disease is an autoimmune disorder characterized by the deposition of pathogenic autoantibodies in basement membranes of kidney and lung eliciting rapidly progressive glomerulonephritis and pulmonary hemorrhage. The principal autoantigen is the alpha345 network of collagen IV, which expression is restricted to target tissues. Recent discoveries include a key role of chloride and bromide for network assembly, a novel posttranslational modification of the antigen, a sulfilimine bond that crosslinks the antigen, and the mechanistic role of HLA in genetic susceptibility and resistance to GP disease. These advances provide further insights into molecular mechanisms of initiation and progression of GP disease and serve as a basis for developing of novel diagnostic tools and therapies for treatment of Goodpasture's disease. PMID- 29763671 TI - Searching for signals of recent natural selection in genes of the innate immune response - ancient DNA study. AB - The last decade has seen sharp progress in the field of human evolutionary genetics and a great amount of genetic evidence of natural selection has been provided so far. Since host-pathogen co-evolution is difficult to trace due to the polygenic nature of human susceptibility to microbial diseases, of particular interest is any signal of natural selection in response to the strong selective pressure exerted by pathogens. Analysis of ancient DNA allows for the direct insight into changes of a gene pool content over time and enables monitoring allele frequency fluctuations. Among pathogenic agents, mycobacteria are proved to have remained in an intimate, long-lasting relation with humans, reflected by the current high level of host resistance. Therefore, we aimed to investigate the prevalence of several polymorphisms within innate immune response genes related to susceptibility to mycobacterial diseases (in SLC11A1, MBL2, TLR2, P2RX7, IL10, TNFA) in time series data from North and East Poland (1st-18th century AD, n = 207). The comparison of allele frequencies over time revealed a predominant role of genetic drift in shaping past gene pool of small, probably isolated groups, which was explained by the high level of population differentiation and limited gene flow. However, the trajectory of frequency fluctuations of two SNPs suggested the possibility of their non-neutral evolution and the results of applied forward simulations further strengthened the hypothesis of natural selection acting on those loci. However, we observed an unusual excess of homozygosity in the profile of several SNPs, which pinpoints to the necessity of further research on temporally and spatially diverse samples to support our inference on non-stochastic evolution, ideally employing pathway-based approaches. Nevertheless, our study confirms that time series data could help to decipher very recent human adaptation to life-threatening pathogens and assisting demographic events. PMID- 29763668 TI - Evaluation of automated loop-mediated amplification (LAMP) for routine malaria detection in blood samples of German travelers - A cross-sectional study. AB - BACKGROUND: We assessed a commercial loop-mediated amplification (LAMP) platform for its reliability as a screening tool for malaria parasite detection. METHODS: A total of 1000 blood samples from patients with suspected or confirmed malaria submitted to the German National Reference Center for Tropical Pathogens were subjected to LAMP using the Meridian illumigene Malaria platform. Results were compared with microscopy from thick and thin blood films in all cases. In case of discordant results between LAMP and microscopy (n = 60), confirmation testing was performed with real-time PCR. Persistence of circulating parasite DNA was analyzed by serial assessments of blood samples following malaria treatment. RESULTS: Out of 1000 blood samples analyzed, 238 were positive for malaria parasites according to microscopy (n = 181/1000) or PCR (additional n = 57/60). LAMP demonstrated sensitivity of 98.7% (235/238), specificity of 99.6% (759/762), positive predictive value (PPV) of 98.7% (235/238) and negative predictive value (NPV) of 99.6% (759/762), respectively. For first slides of patients with malaria and for follow-up slides, sensitivity values were 99.1% (106/107) and 98.5% (129/131), respectively. CONCLUSIONS: The performance of the Meridian illumigene Malaria platform is suitable for initial screening of patients suspected of clinical malaria. PMID- 29763669 TI - Travel-related health problems in the immunocompromised traveller: An exploratory study. AB - BACKGROUND: Immunocompromised travellers (ICTs) are at increased risk of travel related health problems. Therefore, they are advised to attend specialised pre travel clinics for advice on vaccination, malaria chemoprophylaxis and on-demand antibiotics. However, studies yield conflicting data regarding travel-related health problems encountered by ICTs; questioning the rationale for certain advices, and particularly the advice of on-demand antibiotics. OBJECTIVE: To evaluate self-reported travel-related health problems, antibiotic use, medical visits and risk behaviours in ICTs and controls. METHODS: We conducted a questionnaire-based observational study with pilot character. We recruited participants from a (medical) pre-travel clinic. Telephone interviews were conducted 2-4 weeks post-travelling, applying a structured questionnaire. RESULTS: We included 30 ICTs and 30 controls. More ICTs than controls reported travel-related health problems, antibiotic use and medical visits, although not statistically significant. Travellers' diarrhoea appeared to be more severe in ICTs. Furthermore one ICT was hospitalized post-travel due to pneumonia. Of ICTs, 2/30 (7%) used on demand antibiotics while not indicated (according to the protocol of the Dutch national coordinating centre for travel advice or prescribed by a physician). Reversely, 6/30 (20%) did not use on demand antibiotics while actually indicated according to this protocol. DISCUSSION: Our findings substantiate the recommendation of on demand antibiotics. However, ICTs did often not use on demand antibiotics correctly; they therefore need very careful instructions. PMID- 29763672 TI - Using 3D spatial correlations to improve the noise robustness of multi component analysis of 3D multi echo quantitative T2 relaxometry data. AB - PURPOSE: We present a computationally feasible and iterative multi-voxel spatially regularized algorithm for myelin water fraction (MWF) reconstruction. This method utilizes 3D spatial correlations present in anatomical/pathological tissues and underlying B1+-inhomogeneity or flip angle inhomogeneity to enhance the noise robustness of the reconstruction while intrinsically accounting for stimulated echo contributions using T2-distribution data alone. METHODS: Simulated data and in vivo data acquired using 3D non-selective multi-echo spin echo (3DNS-MESE) were used to compare the reconstruction quality of the proposed approach against those of the popular algorithm (the method by Prasloski et al.) and our previously proposed 2D multi-slice spatial regularization spatial regularization approach. We also investigated whether the inter-sequence correlations and agreements improved as a result of the proposed approach. MWF quantifications from two sequences, 3DNS-MESE vs 3DNS-gradient and spin echo (3DNS-GRASE), were compared for both reconstruction approaches to assess correlations and agreements between inter-sequence MWF-value pairs. MWF values from whole-brain data of six volunteers and two multiple sclerosis patients are being reported as well. RESULTS: In comparison with competing approaches such as Prasloski's method or our previously proposed 2D multi-slice spatial regularization method, the proposed method showed better agreements with simulated truths using regression analyses and Bland-Altman analyses. For 3DNS MESE data, MWF-maps reconstructed using the proposed algorithm provided better depictions of white matter structures in subcortical areas adjoining gray matter which agreed more closely with corresponding contrasts on T2-weighted images than MWF-maps reconstructed with the method by Prasloski et al. We also achieved a higher level of correlations and agreements between inter-sequence (3DNS-MESE vs 3DNS-GRASE) MWF-value pairs. CONCLUSION: The proposed algorithm provides more noise-robust fits to T2-decay data and improves MWF-quantifications in white matter structures especially in the sub-cortical white matter and major white matter tract regions. PMID- 29763674 TI - Septin-associated protein kinase Gin4 affects localization and phosphorylation of Chs4, the regulatory subunit of the Baker's yeast chitin synthase III complex. AB - Chitin is mainly formed by the chitin synthase III complex (CSIII) in yeast cells. This complex is considered to be composed of the catalytic subunit Chs3 and the regulatory subunit Chs4, both of which are phosphoproteins and transported to the plasma membrane by different trafficking routes. During cytokinesis, Chs3 associates with Chs4 and other proteins at the septin ring, which results in an active CSIII complex. In this study, we focused on the role of Chs4 as a regulatory subunit of the CSIII complex. We analyzed the dynamic localization and interaction of Chs3 and Chs4 during cell division, and found that both proteins transiently co-localize and physically interact only during bud formation and later in a period during septum formation and cytokinesis. To identify unknown binding partners of Chs4, we conducted different screening approaches, which yielded several novel candidates of Chs4-binding proteins including the septin-associated kinase Gin4. Our further studies confirmed this interaction and provided first evidence that Chs4 phosphorylation is partially dependent on Gin4, which is required for proper localization of Chs4 at the bud neck. PMID- 29763675 TI - Efficient genome editing in Fusarium oxysporum based on CRISPR/Cas9 ribonucleoprotein complexes. AB - The Fusarium oxysporum species complex (FOSC) is an economically important group of pathogenic filamentous fungi that are able to infect both animals and plants. Reverse genetic techniques, including gene disruption/deletion methods, to study these fungi are available although limitations exist resulting in decreased efficiency. Herein we describe a gene editing system developed using a F. oxysporum-optimized Cas9 ribonucleoprotein (RNP) and protoplast transformation method. The Cas9 protein and sgRNA were assembled to form a stable RNP in vitro and this complex was transferred into fungal protoplasts for gene editing with PEG-mediated transformation. In order to determine if the Cas9 RNP system is functional in the FOSC protoplasts and assess the efficacy of the system, two genes, URA5 and URA3, were selected for targeted disruption generating uracil auxotroph mutants that are resistant to 5-fluoroorotic acid, 5-FOA. In addition, a gene in a secondary metabolite biosynthetic cluster, the ortholog of BIK1, was mutated using this system and the maximum efficiency of this gene disruption was about 50%. Further analysis of the bik1 mutant confirmed that this polyketide synthase was involved in the synthesis of the red pigment, bikaverin. The mutants generated in this study displayed the strong expected phenotypes, demonstrating this F. oxysporum-optimized CRISPR/Cas9 system is stable and can efficiently disrupt the genes of interest. PMID- 29763673 TI - The distribution of pain activity across the human neonatal brain is sex dependent. AB - In adults, there are differences between male and female structural and functional brain connectivity, specifically for those regions involved in pain processing. This may partly explain the observed sex differences in pain sensitivity, tolerance, and inhibitory control, and in the development of chronic pain. However, it is not known if these differences exist from birth. Cortical activity in response to a painful stimulus can be observed in the human neonatal brain, but this nociceptive activity continues to develop in the postnatal period and is qualitatively different from that of adults, partly due to the considerable cortical maturation during this time. This research aimed to investigate the effects of sex and prematurity on the magnitude and spatial distribution pattern of the long-latency nociceptive event-related potential (nERP) using electroencephalography (EEG). We measured the cortical response time locked to a clinically required heel lance in 81 neonates born between 29 and 42 weeks gestational age (median postnatal age 4 days). The results show that heel lance results in a spatially widespread nERP response in the majority of newborns. Importantly, a widespread pattern is significantly more likely to occur in females, irrespective of gestational age at birth. This effect is not observed for the short latency somatosensory waveform in the same infants, indicating that it is selective for the nociceptive component of the response. These results suggest the early onset of a greater anatomical and functional connectivity reported in the adult female brain, and indicate the presence of pain-related sex differences from birth. PMID- 29763676 TI - Effect of single-session dual-tDCS before physical therapy on lower-limb performance in sub-acute stroke patients: A randomized sham-controlled crossover study. AB - Anodal stimulation increases cortical excitably, whereas cathodal stimulation decreases cortical excitability. Dual transcranial direct current stimulation (tDCS; anodal over the lesioned hemisphere, cathodal over the non-lesioned hemisphere) was found to enhance motor learning. The corresponding tDCS-induced changes were reported to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and restore the normal balance of the interhemispheric inhibition. Most studies were devoted to the possible modification of upper-limb motor function after tDCS; however, almost no study has demonstrated its effects on lower-limb function and gait, which are also commonly disordered in stroke patients with motor deficits. In this randomized sham-controlled crossover study, we included 19 patients with sub-acute stroke. Participants were randomly allocated to receive real or sham dual-tDCS followed by conventional physical therapy with an intervention interval of at least 1 week. Dual-tDCS was applied over the lower-limb M1 at 2-mA intensity for 20min. Lower-limb performance was assessed by the Timed Up and Go (TUG) and Five-Times Sit-To-Stand (FTSTS) tests and muscle strength was assessed by peak knee torque of extension. We found a significant increase in time to perform the FTSST for the real group, with improvements significantly greater than for the sham group; the TUG score was significantly increased but not higher than for the sham group. An after-effect on FTSTS was found at approximately 1 week after the real intervention. Muscle strength was unchanged in both limbs for both real and sham groups. Our results suggest that a single session of dual-tDCS before conventional physical therapy could improve sit-to-stand performance, which appeared to be improved over conventional physical therapy alone. However, strength performance was not increased after the combination treatment. PMID- 29763677 TI - Neurotoxic lesions of the pedunculopontine tegmental nucleus impair the elaboration of postictal antinociception. AB - Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0 MUg/0.2 MUL) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64 mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0 min) and subsequently at 10-min intervals until 130 min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130 min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity. PMID- 29763678 TI - Acute aerobic exercise induces a preferential mobilisation of plasmacytoid dendritic cells into the peripheral blood in man. AB - Dendritic cells (DCs) are important sentinel cells of the immune system responsible for presenting antigen to T cells. Exercise is known to cause an acute and transient increase in the frequency of DCs in the bloodstream in humans, yet there are contradictory findings in the literature regarding the phenotypic composition of DCs mobilised during exercise, which may have implications for immune regulation and health. Accordingly, we sought to investigate the composition of DC sub-populations mobilised in response to acute aerobic exercise. Nine healthy males (age, 21.9 +/- 3.6 years; height, 177.8 +/- 5.4 cm; body mass, 78.9 +/- 10.8 kg; body mass index, 24.9 +/- 3.3 kg.m2; VO2 MAX, 41.5 +/- 5.1 mL.kg.min-1) cycled for 20 min at 80% VO2 MAX. Blood was sampled at baseline, during the final minute of exercise and 30 min later. Using flow cytometry, total DCs were defined as Lineage- (CD3, CD19, CD20, CD14, CD56) HLA-DR+ and subsequently identified as plasmacytoid DCs (CD303+) and myeloid DCs (CD303-). Myeloid DCs were analysed for expression of CD1c and CD141 to yield four sub-populations; CD1c-CD141+; CD1c+CD141+; CD1c+CD141- and CD1c-CD141-. Expression of CD205 was also analysed on all DC sub-populations to identify DCs capable of recognising apoptotic and necrotic cells. Total DCs increased by 150% during exercise (F(1,10) = 60; p < 0.05, eta2 = 0.9). Plasmacytoid DCs mobilised to a greater magnitude than myeloid DCs (195 +/- 131% vs. 131 +/- 100%; p < 0.05). Among myeloid DCs, CD1c-CD141- cells showed the largest exercise-induced mobilisation (167 +/- 122%), with a stepwise pattern observed among the remaining sub-populations: CD1c+CD141- (79 +/- 50%), followed by CD1c+CD141+ (44 +/- 41%), with the smallest response shown by CD1c-CD141+ cells (23 +/- 54%) (p < 0.05). Among myeloid DCs, CD205- cells were the most exercise responsive. All DC subsets returned to resting levels within 30 min of exercise cessation. These results show that there is a preferential mobilisation of plasmacytoid DCs during exercise. Given the functional repertoire of plasmacytoid DCs, which includes the production of interferons against viral and bacterial pathogens, these findings indicate that exercise may augment immune-surveillance by preferentially mobilising effector cells; these findings have general implications for the promotion of exercise for health, and specifically for the optimisation of DC harvest for cancer immunotherapy. PMID- 29763679 TI - Maternal dietary nitrate intake and risk of neural tube defects: A systematic review and dose-response meta-analysis. AB - Despite growing evidence for the potential teratogenicity of nitrate, knowledge about the dose-response relationship of dietary nitrate intake and risk of specific birth defects such as neural tube defects (NTDs) is limited. Therefore, the aim of this meta-analysis was to synthesize the knowledge about the dose response relation between maternal dietary nitrate intake and the risk of NTDs. We conducted a systematic search in PubMed, ISI Web of Science and Scopus up to February 2018 for observational studies. Risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated using a random-effects model for highest versus lowest intake categories. The linear and non-linear relationships between nitrate intake and risk of NTDs were also investigated. Overall, 5 studies were included in the meta-analyses. No association was observed between nitrate intake and NTDs risk in high versus low intake (RR: 1.33; 95% CI: 0.89-1.99, p = 0.158) and linear dose-response (RR: 1.03; 95% CI: 0.99-1.07, p = 0.141) meta-analysis. However, there were positive relationships between nitrate intake and risk of NTDs in non-linear (pnon-linearity<0.05) model. Findings from this dose-response meta-analysis indicate that maternal nitrate intake higher than ~3 mg/day is positively associated with NTDs risk. PMID- 29763680 TI - Risk assessment of fluoroquinolones from poultry muscle consumption: Comparing healthy adult and pre-school populations. AB - Antibiotics, especially fluoroquinolones (FQs), have been largely used in animal husbandry namely poultry production. Therefore, this study aimed to identify, quantify and estimate the daily intake for adult and 3-year-old populations of the FQs norfloxacin (NOR), ciprofloxacin (CIP) and enrofloxacin (ENR) through poultry muscle consumption. The results showed detection frequencies of 78% and 62% in supermarket and school canteen samples, respectively. Of the 182 analysed samples, 4 did not comply with ENR maximum residue level (MRL), and 9 were contaminated with NOR, not allowed as a veterinary medicine of food-producing animals. The highest estimated daily intake value was obtained for the 3-year-old population regarding the sum of ENR and CIP (0.46 MUg kg-1 day-1); value substantially lower than the established acceptable daily intake (2.0 MUg kg-1 day-1). Although the low risk found, the high detection frequencies support the apprehension of the different international organizations, towards the emergence of human bacterial resistances to FQs originated from poultry production. PMID- 29763681 TI - Manuka honey attenuates oxidative damage induced by H2O2 in human whole blood in vitro. AB - Manuka honey has been widely researched regarding its biological properties, in particular its antimicrobial and antioxidant capacities. We tested the genotoxic and genoprotective properties of Manuka honey, ranging from 25-1000 MUg/mL, by performing an in vitro comet assay after exposure to human whole blood. No genotoxic effect on whole blood cells was observed within the tested concentration range (p = 0.154). Then, the antigenotoxic potency of Manuka honey against oxidative DNA damage to whole blood cells was assessed. Prior to Manuka honey treatment a modest decrease of H2O2-induced DNA damage was detected in cells, with no statistical significance (p = 0.087). Post-treatment, Manuka honey displayed a stronger potential to attenuate damaged cells at all tested concentrations, with a statistical significant difference (p < 0.001), where concentrations of 25 and 100 MUg/mL were most efficient. Manuka honey exhibited a marked potential to protect DNA of whole blood cells from oxidative damage induced by hydrogen peroxide in vitro. PMID- 29763682 TI - Melatonin attenuates arsenic induced nephropathy via the regulation of oxidative stress and inflammatory signaling cascades in mice. AB - Arsenic is a potent inducer of several acute and chronic nephrotoxic disorders. It promotes deleterious phenomenon like oxidative stress, inflammation, cell death and altered glucose uptake leading to distorted kidney homeostasis that end up in chronic kidney disease. This study investigated the possible protective role of melatonin; a natural antioxidant produced by the pineal gland, against arsenic induced nephrotoxicity. Melatonin successfully ameliorated arsenic induced renal toxicity both in in vitro and in vivo models. Elevated BUN, creatinine, urine glucose and protein levels and altered renal histopathological conditions were observed in arsenic intoxicated mice. Significant oxidative stress induced damage of biomolecules along with downregulation in antioxidant enzymes and thiols were also detected in the kidney tissues of arsenic intoxicated mice. These alterations along with mitochondrial dysfunction ultimately triggered TNFalpha mediated inflammatory and cell death cascades. Interestingly arsenic also led to disruption of glucose uptake in the kidney. These findings suggest that melatonin protects the kidney against toxic effect of arsenic, presumably through its antioxidant, anti-inflammatory and antidiabetic properties by inhibiting inflammatory outburst, apoptosis, necroptosis and stimulating glucose uptake. As melatonin is a natural antioxidant molecule, detailed pharmacokinetic and pharmacodynamic studies are expected to establish it as an effective nephro-protective agent in future. PMID- 29763683 TI - Sexual and gender minority cigarette smoking disparities: An analysis of 2016 Behavioral Risk Factor Surveillance System data. AB - We examined the association between lesbian, gay, bisexual, and transgender (LGBT) identity, cigarette and e-cigarette use, and potential risk factors in the United States. Using data from 198,057 adults in 26 states in the 2016 Behavioral Risk Factor Surveillance System (BRFSS), we estimated the prevalence of cigarette use, e-cigarette use, and potential risk factors by gender identity and sexual identity. Overall and sex-stratified bivariate and multivariate logistic regressions examined whether the relationship between sexual and gender identity and cigarette and e-cigarette use persisted after adjusting for demographics, socio-economic status, and other unhealthy behaviors. After adjusting for covariates, gender minority identity was no longer associated with increased likelihood of currently smoking cigarettes and ever use of e-cigarettes. Sexual minority identity continued to be significant after adjusting for covariates, indicating that sexual identity disparities in cigarette and e-cigarette use are not fully explained by these factors. Findings varied by identity. Compared to their straight peers, likelihood of tobacco product use among LGB individuals varied between sexes, by product, and by sexual identity (gay/lesbian versus bisexual). More research is needed to understand the mechanisms that influence diverse patterns of cigarette and e-cigarette use among sexual and gender minority adults. PMID- 29763684 TI - Promoting health equity to prevent crime. AB - Traditionally, research activities aimed at diminishing health inequalities and preventing crime have been conducted in isolation, with relatively little cross fertilization. We argue that moving forward, transdisciplinary collaborations that employ a life-course perspective constitute a productive approach to minimizing both health disparities and early delinquent involvement. Specifically, we propose a multidimensional framework that integrates findings on health disparities and crime across the early life-course and emphasizes the role of racial and socioeconomic disparities in health. Developing the empirical nexus between health disparities research and criminological research through this multidimensional framework could fruitfully direct and organize research that contributes to reductions in health inequalities and the prevention of crime during the early life course. We also propose that this unified approach can ultimately enhance public safety policies and attenuate the collateral consequences of incarceration. PMID- 29763685 TI - Autophagy plays a pro-survival role against methamphetamine-induced apoptosis in H9C2 cells. AB - Methamphetamine (METH) is a commonly abused psychostimulant that can induce severe neurotoxicity. Cardiovascular injury caused by METH has recently gained increasing attention; however, the underlying mechanisms remain unclear. As autophagy has been shown to be associated with cell injury, the association between autophagy and METH-mediated cell apoptosis was investigated in the present study. METH treatment significantly increased the expression of two key autophagy proteins, i.e., Beclin-1 and LC3-II, in the cardiomyocyte cell line H9C2. Furthermore, according to western blot and flow cytometry analyses, METH contributed to cell injury and markedly enhanced cleaved-caspase 3 and PARP expression. In addition, the corresponding AKT-mTOR survival pathway axis was appeared deactivated. The autophagic activity was closely associated with METH mediated cell injury because rapamycin, which is an autophagy inducer, markedly attenuated METH-induced cell injury, while 3-Methyladenine (3-MA), which is an autophagy inhibitor, and bafilomycinA1 (Baf-A1), which is a blocker of autophagosome-lysosome fusion, markedly exacerbated METH-induced cell injury. Notably, defective autophagosome-lysosome fusion might be partially involved in the METH-induced enhancement of LC3-II expression and cell injury. However, the underlying mechanisms require further investigation. PMID- 29763686 TI - Mice deficient in aldo-keto reductase 1a (Akr1a) are resistant to thioacetamide induced liver injury. AB - Aldehyde reductase (Akr1a) has been reported to be involved in detoxification of reactive aldehydes as well as in the synthesis of bioactive compounds such as ascorbic acid (AsA). Because Akr1a is expressed at high levels in the liver and is involved in xenobiotic metabolism, our objective was to investigate the hepato protective role of Akr1a in a thioacetamide (TAA)-induced hepatotoxicity model using Akr1a-deficient (Akr1a-/-) mice. Wild-type (WT) and Akr1a-/- mice were injected intraperitoneally with TAA and the extent of liver injury in the acute phase was assessed. Intriguingly, the extent of TAA-induced liver damage was less in the Akr1a-/- mice than in the WT mice. Biomarkers for the ER stress-induced apoptosis pathway were markedly decreased in the livers of Akr1a-/- mice, whereas AsA levels in plasma did not change significantly in any of the mice. In the liver, TAA is converted to reactive metabolites such as TAA S-oxide and then to TAA S, S-dioxide via the action of CYP2E1. In Akr1a-/- mice, CYP2E1 activity was relatively lower than WT mice at the basal level, leading to reactive TAA metabolites being produced at lower levels after the TAA treatment. The levels of liver proteins that were modified with these metabolites were also lower in the Akr1a-/- mice than the WT mice after the TAA treatment. Furthermore, after a lethal dose of a TAA challenge, the WT mice all died within 36 h, whereas almost all of the Akr1a-/- mice survived. These collective results suggest that Akr1a-/- mice are resistant to TAA-induced liver injury, and it follows that the absence of Akr1a might modulate TAA bioactivation. PMID- 29763687 TI - Therapeutic efficacy of lipid emulsions of docetaxel-linoleic acid conjugate in breast cancer. AB - Docetaxel (DTX) solution is among the most widely-used parenteral formulations used in advanced breast cancer therapy. However, severe side effects have been observed due to the use of ethanol and polysorbate 80. Herein, a novel DTX-based prodrug, docetaxel-linoleic acid conjugate (DTX-LA) was successfully synthesized. The high lipid solubility of DTX and DTX-LA resulted in a tendency for them to become entrapped in the oil core of the emulsions. As anticipated, nano-sized, sterically stabilized oil-in-water lipid emulsions (LMs) of DTX-LA LMs and DTX LMs were successfully constructed. Unlike DTX solution, LMs exhibited high colloidal stability and sustained-release behavior, having a narrow size distribution that was ~220 nm in diameter. Compared with DTX LMs, DTX-LA LMs had a greater drug-loading capacity. Although the cytotoxicity of DTX-LA LMs was reduced in comparison with DTX solution, the pharmacokinetic study demonstrated increased bioavailability (p < 0.001) and half-life (p < 0.01). Finally, DTX-LA LMs displayed significant antitumor efficacy with reduced side effects in a 4T1 breast cancer xenograft model. Thus, the novel lipid emulsion-based docetaxel prodrug delivery system may be a promising strategy for improving intravenous administration for breast cancer treatment. PMID- 29763688 TI - Combined effects of the drug distribution and mucus diffusion properties of self microemulsifying drug delivery systems on the oral absorption of fenofibrate. AB - We present the absorption improvement mechanism of fenofibrate (FFB), a Biopharmaceutics Classification System (BCS) class II drug, from self microemulsifying drug delivery systems (SMEDDS), centered on improving the diffusion of FFB through the unstirred water layer (UWL). Four SMEDDS formulations containing LabrafacTM lipophile WL 1349 (WL1349) or Labrafil(r) M 1944CS (M1944) oils and NIKKOL HCO-40 (HCO40) or NIKKOL HCO-60 (HCO60) surfactants were prepared. Every SMEDDS formulation formed microemulsion droplets of approximately 30 nm. In vitro tests showed that the microemulsion droplets containing M1944 had relatively small FFB solubilization capacities, causing larger amounts of FFB to be dissolved in the bulk water phase, compared to the droplets containing WL1349. The diffusivity of the microemulsion droplets through the mucin solution layer was enhanced when using HCO40 compared to HCO60. The oral absorption in rats was the highest when using the SMEDDS formulation containing M1944 and HCO40. High FFB distribution in the bulk water phase and fast diffusion of microemulsion droplets through the mucus layer contributed to the efficient delivery of FFB molecules through the UWL to the epithelial cells, leading to enhanced FFB absorption. PMID- 29763689 TI - Surface engineered excipients: II. Simultaneous milling and dry coating for preparation of fine-grade microcrystalline cellulose with enhanced properties. AB - A solventless process for simultaneously milling and dry coating microcrystalline cellulose (MCC) was investigated for producing fine excipients in five different sizes (~20, 25, 30, 35, 40 um) having high bulk density (BD), good flow function coefficient (FFC), and excellent compaction. Avicel PH-102, used as the starting material, was milled and coated with two grades of silicas, hydrophobic and hydrophilic (R972P and A200), using a fluid energy mill (FEM). Through judicious selection of the FEM feed rate, feeding pressure, and grinding pressure, five desired milled sizes were produced. The bulk density of all the milled-coated (1 wt% A200) excipients was significantly better than uncoated-milled MCC, Avicel PH 102, and Prosolv 50 and 90. Whereas the FFC values were greater than uncoated milled MCC, Avicel PH-102, and Prosolv 50 (latter for ~30, 35, and 40 um sizes). The tablet compaction testing was used to evaluate compactibility (tensile strength vs tablet porosity), compressibility (tablet porosity vs compaction pressure), and tabletibility (tensile strength vs compaction pressure). The results indicate that all finer grade milled and A200 coated MCC had lower porosity and higher tablet strengths than Prosolv 50 and 90 at all compaction pressures. Surprisingly, the BD and FFC were better for A200 than for R972P coated-milled MCCs; explained through analyzing inter-particle contact models. Finally, milling did not increase the moisture content but coating with silica led to a slight increase; A200 higher than R972P. It is hoped that these engineered excipients would help formulators with a multitude of options for finer excipients without loss of flow and bulk density. PMID- 29763691 TI - Insights on the age dependent neurodegeneration induced by Monocrotophos, (an organophosphorous insecticide) in Caenorhabditis elegans fed high glucose: Evidence in wild and transgenic strains. AB - The higher susceptibility of high glucose fed C. elegans to Monocrotophos (MCP, an organophosphorus insecticide) - induced dopaminergic (DA) neuronal degeneration was recently demonstrated. Employing this acute exposure model, the impact of MCP on DA degeneration among worms of two age groups (8 and 13 d old) fed control (CO) and high glucose (GF) diet with specific focus on phenotypic alterations, oxidative impairments and associated molecular perturbations employing both wild (N2) and transgenic strains(BZ555 and NL5901) was investigated. In general, 13 d worms exhibited higher susceptibility to MCP intoxication compared to 8 d old worms. Further, MCP-exposure caused an enhanced degree of DA degeneration among glucose fed (GF) worms as evidenced by lower chemotaxis index, reduced long-term memory and increased nonanone repulsion. Biochemical analysis of 13 d GF worms also revealed a significant increase in ROS, protein carbonyls and reduced ADP/ATP ratio. Interestingly, marked increase in degeneration of dopaminergic neurons and increased in alpha-synuclein content was evident among 13 d GF worms exposed to MCP. Significant alterations in the mRNA expression levels of daf-2, age-1, sir 2.1 and aak-2 among 13 d GF worms was evident. Collectively these findings suggest that high intake of glucose diet aggravates MCP associated dopaminergic neuronal degeneration and the impact of increasing age under such a condition. Moreover it provides an experimental paradigm to explore the molecular targets and mechanism/s underlying the possible relationship between insecticide exposure-associated dopaminergic degeneration in humans under hyperglycemic conditions. PMID- 29763690 TI - The citrus flavonone hesperetin attenuates the nuclear translocation of aryl hydrocarbon receptor. AB - The environmental polycyclic aromatic hydrocarbons (PAH) and dioxins are carcinogens and their adverse effects have been largely attributed to the activation of AhR. Hesperetin is a flavonone found abundantly in citrus fruits and has been shown to be a biologically active agent. In the present study, the effect of hesperetin on the nuclear translocation of AhR and the downstream gene expression was investigated in MCF-7 cells. Confocal microscopy indicated that 7, 12-dimethylbenz[alpha]anthracene (DMBA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) -induced nuclear translocation of AhR was deterred by hesperetin treatment. The reduced nuclear translocation could also be observed in Western analysis. Reporter-gene assay further illustrated that the induced XRE transactivation was weakened by the treatment of hesperetin. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay demonstrated that the gene expressions of CYP1A1, 1A2, and 1B1 followed the same pattern of AhR translocation. These results suggested that hesperetin counteracted AhR transactivation and suppressed the downstream gene expression. PMID- 29763692 TI - Pharmacological evidence that DAPI inhibits NHE2 in Fundulus heteroclitus acclimated to freshwater. AB - Ionoregulation in the euryhaline killifish Fundulus heteroclitus has been intensively studied over the last two decades using a variety of techniques. However, there has been limited use of pharmacological inhibitors to identify proteins involved in ion transport for this species. In this study, we used a range of pharmacological inhibitors (EIPA, DAPI, ethoxzolamide, bumetanide, bafilomycin, phenamil, hydrochlorothiazide) to investigate the proteins involved in Na+ transport in freshwater (1 mM Na+) acclimated F. heteroclitus. Our results indicate that Na+ uptake under these conditions is sensitive to both EIPA (NHE specific inhibitor) and DAPI (putative ASIC-specific inhibitor), but not to any of the other inhibitors. Results for EIPA are consistent with previous studies indicating F. heteroclitus relies solely on NHE2 for Na+ transport across the apical membrane of ionocytes. In contrast, results for DAPI are surprising given previous studies that have indicated the H+-ATPase is basolaterally located in F. heteroclitus and so cannot contribute to Na+ uptake via ASIC. The lack of bafilomycin sensitivity in the current study is consistent with a basolaterally located H+-ATPase. This suggests that DAPI is not an ASIC-specific inhibitor as has been previously assumed, and that it may also inhibit NHE2. Finally, we did not observe Na+ uptake to be sensitive to ethoxzolamide, suggesting that carbonic anhydrase may not be involved in generating the H+ needed to maintain NHE activity in freshwater as has been previously proposed. PMID- 29763695 TI - Representation of facial identity includes expression variability. AB - In this study, we investigate the contribution of expression variability in the formation of face representations. We trained participants to learn new identities from face images either low or high in expressiveness, and compared their performance in a recognition test. After low expressiveness training, recognition of novel test images was modulated by image expressiveness: the more expressive the image, the slower the response. This differed from recognition after high expressiveness training, which showed little evidence of expression dependence. These findings are not readily explained by exemplar and prototype theories of face representation. However, we propose that our results can be explained by a combination of these theories, according to which average and exemplar representations co-exist - the latter of which preserve expressions and other within-person variability. We conclude that this study provides evidence that variability of expressions is, therefore, incorporated in the representation of an individual's face. Moreover, our results demonstrate that learning to recognise someone from their face entails learning how their face is changed by expressions. PMID- 29763693 TI - Influence of lipopolysaccharide on proinflammatory gene expression in human corneal, conjunctival and meibomian gland epithelial cells. AB - PURPOSE: Lipopolysaccharide (LPS), a bacterial endotoxin, is known to stimulate leuokotriene B4 (LTB4) secretion by human corneal (HCECs), conjunctival (HConjECs) and meibomian gland (HMGECs) epithelial cells. We hypothesize that this LTB4 effect represents an overall induction of proinflammatory gene expression in these cells. Our objective was to test this hypothesis. METHODS: Immortalized HCECs, HConjECs and HMGECs were cultured in the presence or absence of LPS (15 MUg/ml) and ligand binding protein (LBP; 150 ng/ml). Cells were then processed for RNA isolation and the analysis of gene expression by using Illumina BeadChips, background subtraction, cubic spline normalization and GeneSifter software. RESULTS: Our findings show that LPS induces a striking increase in proinflammatory gene expression in HCECs and HConjECs. These cellular reactions are associated with a significant up-regulation of genes associated with inflammatory and immune responses (e.g. IL-1beta, IL-8, and tumor necrosis factor), including those related to chemokine and Toll-like receptor signaling pathways, cytokine-cytokine receptor interactions, and chemotaxis. In contrast, with the exception of Toll-like signaling and associated innate immunity pathways, almost no proinflammatory ontologies were upregulated by LPS in HMGECs. CONCLUSIONS: Our results support our hypothesis that LPS stimulates proinflammatory gene expression in HCECs and HConjECs. However, our findings also show that LPS does not elicit such proinflammatory responses in HMGECs. PMID- 29763694 TI - Corneal fluorescein staining and ocular symptoms but not Schirmer test are useful as indicators of response to treatment in chronic ocular GVHD. AB - PURPOSE: To evaluate long-term ocular surface clinical signs and symptoms response to therapy in patients with chronic ocular GVHD. METHODS: Retrospective review and data modeling. We reviewed the records of post-bone marrow transplantation patients who were newly diagnosed with ocular GVHD and initiated therapy, and analyzed changes in symptoms (Ocular Surface Disease Index [OSDI]; Symptom Assessment in Dry Eye [SANDE]) and signs (corneal fluorescein staining [CFS]; Schirmer test). We used a LOESS technique to fit a model in function of data variations and obtain a predictive value of the scores progression over time. RESULTS: The records of 123 patients who were followed-up for over 2 years (up to 62 months) were reviewed. The median baseline scores recorded were: OSDI 52 units, SANDE 62.2 units, CFS 2.0 Oxford units, and Schirmer 4 mm. After six months of follow up, scores improved for OSDI (-18.6 units, p = 0.007), SANDE (23.7 units, p = 0.01), and CFS (-0.7 Oxford units, p < 0.001). Data analysis showed that after a 2-year follow up the three parameters continued to improve: OSDI -13.67 units (27% reduction), SANDE -17.55 units (28%), CFS -1.1 units (54%), but Schirmer test scores progressively worsened -1.2 mm (22%). CONCLUSION: In patients with ocular GVHD symptoms and corneal fluorescein staining improved after initiation of treatment, meanwhile Schirmer scores declined progressively. This indicates that appropriate treatment in chronic ocular GVHD can lead to mid- and long-term improvements in symptoms and corneal epitheliopathy; however, sustained reduction in Schirmer test scores suggests chronic tear production impairment. PMID- 29763696 TI - Feature-based attention elicited by precueing in an orientation discrimination task. AB - Specific visual features can be attended to and processed with a higher priority by our brain, termed feature-based attention (FBA). Two potential mechanisms for FBA have been suggested: goal-driven attentional mediating and stimulus-driven feature priming. Some researchers argued that several reported top-down FBA effects might also involve the influence of feature priming. To clarify this confusion, we used an orientation discrimination task in which the target was tilted randomly from the horizontal or vertical axis and presented at one of four iso-eccentric positions. The target's orientation was precued from trial to trial by an oriented line (Experiment 1) or by a symbolic arrow presented peripherally (Experiment 2) or centrally (Experiments 3/4). The cue could be either valid or invalid according to the congruency of its indicating orientation with the target's nearest cardinal axis. Our results demonstrate that the discrimination speed was significantly faster following a valid than an invalid cue (validity effect) in the session with 80% cue validity when both response accuracy and speed were emphasized. Moreover, this validity effect could also be observed in the session with 50% cue validity using the line cue (Experiment 1), even though its magnitude was significantly reduced, which illustrates the impact of feature priming. However, we did not find the validity effect in the session with 50% cue validity using the symbolic cue (Experiments 2/3). These modulations on the magnitude of the validity effect should be ascribed to top-down attentional mediating that is independent of spatial attention (illustrated by Experiment 3). Importantly, when response accuracy was stressed over speed in Experiment 4, the accuracy was significantly higher following a valid than an invalid cue in the session with 80% cue validity but not in the session with 50% cue validity. Our findings indicate that both top-down attentional mediating and feature priming are important mechanisms for FBA. PMID- 29763697 TI - The effect of load on spatial attention depends on preview: Evidence from a reading study. AB - The spatio-temporal distribution of covert attention has usually been studied under unfamiliar tasks with static viewing. It is important to extend this work to familiar tasks such as reading where sequential eye movements are made. Our previous work with reading showed that covert spatial attention around the gaze location is affected by the fixated word frequency, or the processing load exerted by the word, as early as 40 ms into the fixation. Here, we hypothesised that this early effect of frequency is only possible when the word is previewed and thus pre-processed before being fixated. We tested this hypothesis by preventing preview. We investigated the dynamics of spatial attention around the gaze location while the observer read strings of random words. The words were either always exposed (normal preview) or only exposed while being fixated (masked preview). We probed spatial attention when a target word with either high or low printed frequency - or low or high load, respectively - was fixated. The results confirmed that, early in a fixation, allocation of spatial attention 6 characters from the gaze was affected by the word's frequency but only when the word was exposed before being fixated, so that processing of the word could start before it was fixated. Our results indicate that the ongoing processing load of a word is modulated by its pre-processing and affects the dynamics of covert spatial attention around the word once it is fixated. PMID- 29763698 TI - Engineered mixed oxide-based polymeric composites for enhanced antimicrobial activity and sustained release of antiretroviral drug. AB - Here, pH-responsive engineered polymeric composites were fabricated from sodium alginate and mixed Cu/Zn oxides. The resulting alginate-CuxZn1-xO composites were characterized by FTIR, SEM and XRD, then used as an efficient carrier for the antiretroviral drug (zidovudine, AZT) and exhibited remarkable antibacterial properties. The resulting polymeric composites had specific surface areas of 185.2-198.6 m2/g as confirmed by the Brunauer-Emmett-Teller analysis. The metal oxide distribution within the alginate matrix was confirmed from the X-ray diffraction and scanning electron microscopy analyses. The zidovudine, an antiretroviral drug was encapsulated in 30 mg of alginate-Cu0.7Zn0.3O with 68% encapsulation efficiency. The release of AZT in simulated intestinal fluid (pH 7.4) was studied, a slow and sustained release of AZT (~96.2%) was observed. The AZT release kinetics is sufficiently described by the Korsmeyer-Peppas model and follows the Fickian transport profile. Results herein demonstrated that A Cu0.7Zn0.3O, A-Cu0.3Zn0.7O and Cu0.5Zn0.5O exhibited excellent bacterial devastation property. A dose of 8 MUg/mL A-Cu0.7Zn0.3O and 13 MUg/mL A Cu0.3Zn0.7O are sufficient to completely killed E. coli DH5a and S. aureus NSUHS 151 within 24 h. PMID- 29763699 TI - Structural elucidation and antioxidant activity of lignin isolated from rice straw and alkali-oxygen black liquor. AB - Alkali-oxygen cooking of lignocellulose offers lignin many structural properties and bioactivities for biorefinery. In this work, milled wood lignin (MWL) and alkali-oxygen lignin (AOL) were isolated from rice straw and alkali-oxygen black liquor, respectively. The lignin structure was characterized by spectroscopy and wet chemistry. Antioxidant activity of lignins was assessed by DPPH.and ABTS scavenging ability assay. Results showed the oxidization and condensation of lignin occurred during alkali-oxygen cooking. The p-hydroxyphenyl was more easily removed from rice straw than guaiacyl and syringyl units. The ester or ether linkages derived from hydroxycynnamic acids, and the main interunit linkages, i.e. beta-O-4' bonds, were mostly cleaved. Lignin-xylan complex had high reactivity under alkali-oxygen condition. Tricin, incorporated into lignin, was detected in MWL but was absent in AOL. Nitrobenzene oxidation showed MWL can well represent the protolignin of rice straw, and the products yield decreased dramatically after alkali-oxygen cooking. AOL had higher radical scavenging ability than MWL indicating alkali-oxygen cooking was an effective pathway for the enhancement of antioxidant activity of lignin. PMID- 29763700 TI - Grafting polymerization of acrylic acid onto chitosan-cellulose hybrid and application of the graft as highly efficient ligand for elimination of water hardness: Validation of high selectivity in presence of interfering ions. AB - Graft Copolymer resulting from polymerization of acrylic acid from chitosan is non-coherent, brittle and exhibit modest swelling in water, which limits its application. Chitosan-cellulose hybrid was initially prepared and novel polymeric ligand ((CTS/Cell)-g-PAA) derived from grafting polymerization of acrylic acid from this hybrid was fabricated and investigated using fourier transform infrared (FTIR) and Scanning electron microscopy (SEM). Also, the graft copolymer exhibited high mass transfer under a wide range of pH values due to its elevated hydrophilicity in addition to a good mechanical strength with respect to the comparable graft derived from chitosan as sole backbone for the grafting. The high content of different oxygen and nitrogen-containing groups in a crowded chemical atmosphere along with the high swelling qualified the graft to act as very efficient polymeric ligand with high capacity of removal of metal ions from water under broad conditions. The polymeric ligand performed outstandingly and competitively in the removal of water hardness even in presence of other interfering ions. PMID- 29763701 TI - Differences in water soluble non-digestible polysaccharides and anti-inflammatory activities of fruiting bodies from two cultivated Xylaria nigripes strains. AB - Polysaccharides including beta-glucans are important bioactive components of mushroom. Xylaria nigripes is a popular medicinal fungus that has been used for treating trauma, insomnia and mental illness. This study examined the physicochemical characteristics and anti-inflammatory activities of water soluble non-digestible polysaccharides (TXNP and CXNP) from fruiting bodies of two cultivated X. nigripes strains (TXN and CXN). Results showed that both TXNP and CXNP possessed relatively similar FT-IR spectra. TXNP had a triple helix conformation and molecular weight of 853.8 kDa, whereas the molecular weight of CXNP was 14.7 kDa. The monosaccharide composition of TXNP was predominantly glucose, whereas CXNP contained xylose, mannose and glucose. Although both TXNP and CXNP dose-dependently suppressed the production of NO, IL-1beta, TNF-alpha and PGE2, as well as the expression of iNOS, COX-2 and NF-kappaB in the lipopolysaccharide-induced RAW264.7 macrophages, the potency of TXNP was stronger. This study reveals that under similar conditions of cultivation and extraction procedures, the different physicochemical characteristics of polysaccharides from TXN and CXN may have contributed to the differences in their anti-inflammatory potency. PMID- 29763702 TI - Immunostimulant effects and potential application of beta-glucans derived from marine yeast Debaryomyces hansenii in goat peripheral blood leucocytes. AB - Debaryomyces hansenii has been described to be effective probiotic and immunostimulatory marine yeast in fish. Nonetheless, to the best of our knowledge, it has been not assayed in ruminants. This study attempts to describe the immunostimulatory effects of its beta-glucan content through in vitro assays using goat peripheral blood leukocytes at 24 h of stimulation. The structural characterization of yeast glucans by proton nuclear magnetic resonance indicated structures containing (1-6)-branched (1-3)-beta-D-glucan. In vitro assays using peripheral blood leukocytes stimulated with beta-glucans derived from three D. hansenii strains and zymosan revealed that beta-glucans significantly increased cell immune parameters, such as phagocytic ability, reactive oxygen species production (respiratory burst), peroxidase activity and nitric oxide production. Antioxidant enzymes revealed an increase in superoxide dismutase and catalase activities in leukocytes stimulated with yeast beta-glucans. This study revealed that yeast beta-glucans were able to activate dectin-1 mRNA gene expression in leukocytes. The TLR4 gene expression was up-regulated in leukocytes after stimulation with yeast beta-glucans. In conclusion, beta-glucans were able to modulate the immune system by promoting cell viability, phagocytic activity, antioxidant immune response and immune-related gene expression in leukocytes. Therefore, beta-glucans derived from Debaryomyces hansenii should be considered a potential immunostimulant for goat production systems. PMID- 29763704 TI - Preparation and characterization of a new type of porous starch microspheres (PSM) and effect of physicochemical properties on water uptake rate. AB - Porous starch (PS) is a multifunctional biomaterial and has been widely applied in both pharmaceutical and food industry. This study was carried out to develop a new type of porous starch microspheres (PSM) through the dual-modification of the alcohol-alkaline treatment and inverse crosslinking-emulsion method, which could rapidly uptake water. The chemical and physical characteristics of the PSMs were determined by FTIR, SEM, XRD, DSC, ESD (equilibrium swelling ratio) and WS (water solubility). The results showed that PSMs could reach its saturated water uptake volume (about 1 mL/100 mg) in 60 s. The PSMs also revealed rough surface with observable pores and lower crystallinity degree after the dual-modification according to SEM and XRD. The use of epichlorohydrin (ECH) as a crosslinking agent could introduce crosslinks between starch molecular chains, which was determined by ESD, WS and the thermal properties. These results indicated that the dual-modification could be successfully used for preparation of rapid water uptake PSMs with enhanced structure stability. PMID- 29763703 TI - Influence of nitrogen on growth, biomass composition, production, and properties of polyhydroxyalkanoates (PHAs) by microalgae. AB - This study sought to evaluate influence of nitrogen availability on cell growth, biomass composition, production, and the properties of polyhydroxyalkanoates during cultivation of microalgae Chlorella minutissima, Synechococcus subsalsus, and Spirulina sp. LEB-18. The cellular growth of microalgae reduced with the use of limited nitrogen medium, demonstrating that nitrogen deficiency interferes with the metabolism of microorganisms and the production of biomass. The biochemical composition of microalgae was also altered, which was most notable in the degradation of proteins and chlorophylls and the accumulation of carbonaceous storage molecules such as lipids and polyhydroxyalkanoates. Chlorella minutissima did not produce these polymers even in a nitrogen deficient environment. The largest accumulations of the polyhydroxyalkanoates occurred after a 15 days culture, with a concentration of 16% (dry cell weight) produced by the Synechococcus subsalsus strain and 12% by Spirulina sp. LEB-18. Polyhydroxyalkanoates produced by Synechococcus subsalsus and Spirulina sp. LEB 18 presented different thermal and physical properties, indicating the influence of producing strain on polyhydroxyalkanoates properties. The polymers obtained consisted of long chain monomers with 14 to 18 carbon atoms. This composition is novel, as it has not previously been found in PHAs obtained from Synechococcus subsalsus and Spirulina sp. LEB-18. PMID- 29763705 TI - Detecting pathway biomarkers of diabetic progression with differential entropy. AB - Gene expression profiling techniques measure the transcriptional dynamics of thousands of genes in parallel manners. The available high-throughput transcriptomic datasets provide unprecedented opportunities of detecting biomarkers or signatures of complex diseases such as diabetes. In this work, we propose a computational method based on differential entropy to identify diabetic pathway biomarkers in rats from gene expression profiling data. We first collect the knowledgebase-documented pathways and map them with the corresponding gene expressions in control and disease samples, respectively. The pathway entropies are defined to evaluate their dysfunction-related activities and implications during the development and progression of type 2 diabetes. We rank these pathways via their differential status of entropy dynamics in the time series. The pathway biomarkers are then screened out by their classification ability of distinguishing diabetes from controls. The comparative studies with the other alternative methods demonstrate the effectiveness and advantage of our proposed strategy of biomarker identification. The classification performances on independent datasets further validate the diagnosis applicability of these identified pathway biomarkers. The functional enrichment analyses of these pathway biomarkers also indicate the pathogenesis of diabetes. PMID- 29763706 TI - Exploiting semantic patterns over biomedical knowledge graphs for predicting treatment and causative relations. AB - BACKGROUND: Identifying new potential treatment options for medical conditions that cause human disease burden is a central task of biomedical research. Since all candidate drugs cannot be tested with animal and clinical trials, in vitro approaches are first attempted to identify promising candidates. Likewise, identifying different causal relations between biomedical entities is also critical to understand biomedical processes. Generally, natural language processing (NLP) and machine learning are used to predict specific relations between any given pair of entities using the distant supervision approach. OBJECTIVE: To build high accuracy supervised predictive models to predict previously unknown treatment and causative relations between biomedical entities based only on semantic graph pattern features extracted from biomedical knowledge graphs. METHODS: We used 7000 treats and 2918 causes hand-curated relations from the UMLS Metathesaurus to train and test our models. Our graph pattern features are extracted from simple paths connecting biomedical entities in the SemMedDB graph (based on the well-known SemMedDB database made available by the U.S. National Library of Medicine). Using these graph patterns connecting biomedical entities as features of logistic regression and decision tree models, we computed mean performance measures (precision, recall, F-score) over 100 distinct 80-20% train-test splits of the datasets. For all experiments, we used a positive:negative class imbalance of 1:10 in the test set to model relatively more realistic scenarios. RESULTS: Our models predict treats and causes relations with high F-scores of 99% and 90% respectively. Logistic regression model coefficients also help us identify highly discriminative patterns that have an intuitive interpretation. We are also able to predict some new plausible relations based on false positives that our models scored highly based on our collaborations with two physician co-authors. Finally, our decision tree models are able to retrieve over 50% of treatment relations from a recently created external dataset. CONCLUSIONS: We employed semantic graph patterns connecting pairs of candidate biomedical entities in a knowledge graph as features to predict treatment/causative relations between them. We provide what we believe is the first evidence in direct prediction of biomedical relations based on graph features. Our work complements lexical pattern based approaches in that the graph patterns can be used as additional features for weakly supervised relation prediction. PMID- 29763707 TI - Predicting microRNA-disease associations using label propagation based on linear neighborhood similarity. AB - Interactions between microRNAs (miRNAs) and diseases can yield important information for uncovering novel prognostic markers. Since experimental determination of disease-miRNA associations is time-consuming and costly, attention has been given to designing efficient and robust computational techniques for identifying undiscovered interactions. In this study, we present a label propagation model with linear neighborhood similarity, called LPLNS, to predict unobserved miRNA-disease associations. Additionally, a preprocessing step is performed to derive new interaction likelihood profiles that will contribute to the prediction since new miRNAs and diseases lack known associations. Our results demonstrate that the LPLNS model based on the known disease-miRNA associations could achieve impressive performance with an AUC of 0.9034. Furthermore, we observed that the LPLNS model based on new interaction likelihood profiles could improve the performance to an AUC of 0.9127. This was better than other comparable methods. In addition, case studies also demonstrated our method's outstanding performance for inferring undiscovered interactions between miRNAs and diseases, especially for novel diseases. PMID- 29763708 TI - PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Clustering Epilepsy. AB - PCDH19-Girls Clustering Epilepsy (PCDH19-GCE) is a childhood epileptic encephalopathy characterised by a spectrum of neurodevelopmental problems. PCDH19 GCE is caused by heterozygous loss-of-function mutations in the X-chromosome gene, Protocadherin 19 (PCDH19) encoding a cell-cell adhesion molecule. Intriguingly, hemizygous males are generally unaffected. As PCDH19 is subjected to random X-inactivation, heterozygous females are comprised of a mosaic of cells expressing either the normal or mutant allele, which is thought to drive pathology. Despite being the second most prevalent monogeneic cause of epilepsy, little is known about the role of PCDH19 in brain development. In this study we show that PCDH19 is highly expressed in human neural stem and progenitor cells (NSPCs) and investigate its function in vitro in these cells of both mouse and human origin. Transcriptomic analysis of mouse NSPCs lacking Pcdh19 revealed changes to genes involved in regulation of neuronal differentiation, and we subsequently show that loss of Pcdh19 causes increased NSPC neurogenesis. We reprogramed human fibroblast cells harbouring a pathogenic PCDH19 mutation into human induced pluripotent stem cells (hiPSC) and employed neural differentiation of these to extend our studies into human NSPCs. As in mouse, loss of PCDH19 function caused increased neurogenesis, and furthermore, we show this is associated with a loss of human NSPC polarity. Overall our data suggests a conserved role for PCDH19 in regulating mammalian cortical neurogenesis and has implications for the pathogenesis of PCDH19-GCE. We propose that the difference in timing or "heterochrony" of neuronal cell production originating from PCDH19 wildtype and mutant NSPCs within the same individual may lead to downstream asynchronies and abnormalities in neuronal network formation, which in-part predispose the individual to network dysfunction and epileptic activity. PMID- 29763709 TI - Fenofibrate effects on carotid artery intima-media thickness in adults with type 2 diabetes mellitus: A FIELD substudy. AB - AIM: Dyslipidemia in type 2 diabetes contributes to an increased risk of cardiovascular disease. Fenofibrate, a lipid-regulating peroxisome proliferator activated receptor-alpha (PPARalpha) agonist, has been shown to reduce vascular complications in adults with type 2 diabetes. The mechanisms for such benefit, however, are not yet well understood. We examined the effects of fenofibrate on carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis, in adults with type 2 diabetes. METHODS: In a prospectively designed substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, we assessed carotid IMT in a subset of 422 representative adults. Traditional risk factors and IMT were assessed at 2 and 4 years after randomisation to fenofibrate (200 mg daily) or placebo. The prespecified primary study endpoint was the difference in IMT between treatment groups at 4 years. Post-hoc analyses were performed according to dyslipidemia and metabolic syndrome status. RESULTS: There was no difference in carotid IMT comparing those assigned to fenofibrate or placebo at 2 or 4 years, despite statistically significant improvement in lipid and lipoprotein parameters at 2 and 4 years, including TC, LDL-C and TG, and HDL C at 4 months and 2 years. Similarly, there was no difference in carotid IMT on fenofibrate compared with placebo in those with dyslipidemia or metabolic syndrome. CONCLUSIONS: Fenofibrate was not associated with improved carotid IMT in adults with type 2 diabetes when compared with placebo, despite a statistically significant improvement in TC, LDL-C and TG at 2 and 4 years, and HDL-C at 4 months and 2 years. PMID- 29763710 TI - Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry. AB - Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200,301 patients with DM of the German Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes. Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 +/- 165 and 384 +/- 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups. FRDA patients did not show overweight and HbA1c levels were even lower than in T1Dm or T2Dm patients, respectively, indicating good overall diabetes control. FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided. PMID- 29763711 TI - Efficacy and acceptability of non-invasive brain stimulation for the treatment of adult unipolar and bipolar depression: A systematic review and meta-analysis of randomised sham-controlled trials. AB - We examined the efficacy and acceptability of non-invasive brain stimulation in adult unipolar and bipolar depression. Randomised sham-controlled trials of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS) and theta-burst stimulation (TBS), without co-initiation of another treatment, were included. We analysed effects on response, remission, all-cause discontinuation rates and continuous depression severity measures. Fifty-six studies met our criteria for inclusion (N = 3058, mean age = 44.96 years, 61.73% female). Response rates demonstrated efficacy of high-frequency rTMS over the left DLPFC (OR = 3.75, 95% CI [2.44; 5.75]), right-sided low-frequency rTMS (OR = 7.44, 95%CI [2.06; 26.83]) bilateral rTMS (OR = 3.68,95%CI [1.66; 8.13]), deep TMS (OR = 1.69, 95%CI [1.003; 2.85]), intermittent TBS (OR = 4.70, 95%CI [1.14; 19.38]) and tDCS (OR = 4.17, 95% CI [2.25; 7.74]); but not for continuous TBS, bilateral TBS or synchronised TMS. There were no differences in all-cause discontinuation rates. The strongest evidence was for high-frequency rTMS over the left DLPFC. Intermittent TBS provides an advance in terms of reduced treatment duration. tDCS is a potential treatment for non-treatment resistant depression. To date, there is not sufficient published data available to draw firm conclusions about the efficacy and acceptability of TBS and sTMS. PMID- 29763712 TI - Cerebral tissue oximetry levels during prehospital management of cardiac arrest - A prospective observational study. AB - INTRODUCTION: Near-infrared spectroscopy (NIRS) enables continuous monitoring of regional oximetry (rSO2). The aim of this study was to describe dynamics of regional cerebral oximetry levels during out of hospital cardiac arrest (OHCA) resuscitation, specifically around the time of restoration of spontaneous circulation (ROSC). METHODS: This prospective observational study was performed in the prehospital setting during cardio-pulmonary resuscitation (CPR) of OHCA patients. In the three-year study period, two-hundred eighty OHCA's were responded to; rSO2 was continuously measured throughout CPR and after attaining ROSC. RESULTS: Final data analysis included 53 patients. Continuous rSO2dynamics were described and data was compared amongst ROSC (22 cases) and no-ROSC (31 cases) groups. Initial rSO2levels were below 15% (not detectable) in both groups. With ongoing CPR, rSO2levels were higher in the ROSC group (median 22% vs. 14% in no-ROSC group, p = 0.030). Until ROSC, rSO2levels were higher throughout CPR before ROSC (mean maximal value 47% at ROSC vs. 31% no-ROSC, p < 0.01). Furthermore, we found a pattern of significant, rapid and sustained rise in rSO2levels minutes prior to ROSC and normalization thereafter. CONCLUSIONS: Initial rSO2levels during OHCA are generally undetectable by the time EMS teams initiate CPR. With CPR, rSO2levels rise and are higher during CPR in patients who later achieve ROSC. Patients who achieve ROSC exhibit significant, rapid, and sustained rise in rSO2minutes prior to attaining ROSC, and normalization of rSO2 levels thereafter. Persistently low levels of rSO2 during CPR likely portend poor neurologic outcomes. PMID- 29763713 TI - Practice of mechanical ventilation in cardiac arrest patients and effects of targeted temperature management: A substudy of the targeted temperature management trial. AB - AIMS: Mechanical ventilation practices in patients with cardiac arrest are not well described. Also, the effect of temperature on mechanical ventilation settings is not known. The aims of this study were 1) to describe practice of mechanical ventilation and its relation with outcome 2) to determine effects of different target temperatures strategies (33 degrees C versus 36 degrees C) on mechanical ventilation settings. METHODS: This is a substudy of the TTM-trial in which unconscious survivors of a cardiac arrest due to a cardiac cause were randomized to two TTM strategies, 33 degrees C (TTM33) and 36 degrees C (TTM36). Mechanical ventilation data were obtained at three time points: 1) before TTM; 2) at the end of TTM (before rewarming) and 3) after rewarming. Logistic regression was used to determine an association between mechanical ventilation variables and outcome. Repeated-measures mixed modelling was performed to determine the effect of TTM on ventilation settings. RESULTS: Mechanical ventilation data was available for 567 of the 950 TTM patients. Of these, 81% was male with a mean (SD) age of 64 (12) years. At the end of TTM median tidal volume was 7.7 ml/kg predicted body weight (PBW)(6.4-8.7) and 60% of patients were ventilated with a tidal volume <= 8 ml/kg PBW. Median PEEP was 7.7cmH2O (6.4-8.7) and mean driving pressure was 14.6 cmH2O (+/-4.3). The median FiO2 fraction was 0.35 (0.30-0.45). Multivariate analysis showed an independent relationship between increased respiratory rate and 28-day mortality. TTM33 resulted in lower end-tidal CO2 (Pgroup = 0.0003) and higher alveolar dead space fraction (Pgroup = 0.003) compared to TTM36, while PCO2 levels and respiratory minute volume were similar between groups. CONCLUSIONS: In the majority of the cardiac arrest patients, protective ventilation settings are applied, including low tidal volumes and driving pressures. High respiratory rate was associated with mortality. TTM33 results in lower end-tidal CO2 levels and a higher alveolar dead space fraction compared to TTTM36. PMID- 29763714 TI - Optic nerve sheath diameter measured using early unenhanced brain computed tomography shows no correlation with neurological outcomes in patients undergoing targeted temperature management after cardiac arrest. AB - AIM: Previous studies indicated that the optic nerve sheath diameter (ONSD) measured using brain computed tomography (CT) is a prognostic factor for poor neurological outcome after cardiac arrest. However, these studies were retrospective or included a small sample size. We performed a prospective multi centre observational study to investigate the correlation between the ONSD on early brain CT and neurological outcomes in patients undergoing targeted temperature management (TTM). METHODS: This study used data from the Korean Hypothermia Network prospective registry between November 2015 and October 2016. Out-of-cardiac arrest patients who underwent brain CT within 2 h after return of spontaneous circulation (ROSC) were included. The primary endpoint was neurological outcomes at 6 months (cerebral performance category; CPC); the secondary outcome was hospital mortality. The ONSD was measured using unenhanced brain CT images. RESULTS: In total, 374 patients were included from 18 hospitals, and 329 underwent CT within 2 h after ROSC. Six months after cardiac arrest, good (CPC 1-2) and poor (CPC 3-5) neurological outcomes were observed in 99 (30.09%) and 230 (69.91%) patients, respectively. There was no significant difference in the ONSD between groups (good outcome group: 5.61 +/- 0.59 mm, poor outcome group: 5.69 +/- 0.79 mm; p = 0.275), nor between discharged patients who survived and those with hospital mortality (5.63 +/- 0.64 mm and 5.70 +/- 0.67 mm, respectively, p = 0.399). CONCLUSION: The ONSD on initial brain CT after ROSC was not correlated with neurological outcome at 6 months in patients who underwent TTM. PMID- 29763715 TI - Near-infrared light-activated red-emitting upconverting nanoplatform for T1 weighted magnetic resonance imaging and photodynamic therapy. AB - : Photodynamic therapy (PDT) has increasingly become an efficient and attractive cancer treatment modality based on reactive oxygen species (ROS) that can induce tumor death after irradiation with ultraviolet or visible light. Herein, to overcome the limited tissue penetration in traditional PDT, a novel near-infrared (NIR) light-activated NaScF4: 40% Yb, 2% Er@CaF2 upconversion nanoparticle (rUCNP) is successfully designed and synthesized. Chlorin e6, a photosensitizer and a chelating agent for Mn2+, is loaded into human serum albumin (HSA) that further conjugates onto rUCNPs. To increase the ability to target glioma tumor, an acyclic Arg-Gly-Asp peptide (cRGDyK) is linked to rUCNPs@HSA(Ce6-Mn). This nanoplatform enables efficient adsorption and conversion of NIR light (980 nm) into bright red emission (660 nm), which can trigger the photosensitizer Ce6-Mn complex for PDT and T1-weighted magnetic resonance imaging (T1-weighted MRI) for glioma diagnosis. Our in vitro and in vivo experiments demonstrate that NIR light activated and glioma tumor-targeted PDT can generate large amounts of intracellular ROS that induce U87 cell apoptosis and suppress glioma tumor growth owing to the deep tissue penetration of irradiated light and excellent tumor targeting ability. Thus, this nanoplatform holds potential for applications in T1 weighted MRI diagnosis and PDT of glioma for antitumor therapy. STATEMENT OF SIGNIFICANCE: A near-infrared (NIR) light-activated nanoplatform for photodynamic therapy (PDT) was designed and synthesized. The Red-to-Green (R/G) ratio of NaScF4: 40% Yb, 2% Er almost reached 9, a value that was much higher than that of a traditional Yb/Er-codoped upconversion nanoparticle (rUCNP). By depositing a CaF2 shell, the red-emission intensities of the rUCNPs were seven times strong as that of NaScF4: 40% Yb, 2% Er. The enhanced red-emitting rUCNPs could be applied in many fields such as bioimaging, controlled release, and real-time diagnosis. The nanoplatform had a strong active glioma-targeting ability, and all results achieved on subcutaneous glioma demonstrated that our NIR light-activated red emitting upconverting nanoplatform was efficient for PDT. By loading Ce6-Mn complex into rUCNPs@HSA-RGD, the nanoplatform could be used as a T1-weighted magnetic resonance imaging agent for tumor diagnosis. PMID- 29763716 TI - Prognostic factors in primary anorectal melanoma: a clinicopathological study of 60 cases in China. AB - To investigate the clinicopathological features and prognostic factors of primary anorectal melanoma, we described the clinical presentations, histopathology, and prognosis of 60 cases in China. Patients' age ranged from 17 to 86 years, with a female-to-male ratio of 2.33:1. The prevalent anatomic site of tumor was the anorectum. The mean tumor thickness was 11.5 mm, and mean tumor size was 2.9 cm. Abdominoperineal resection was performed on 38 (63.3%) patients, whereas wide local excision was performed on 22 (36.7%) patients. Thirty-three (55.0%) patients were pathologically confirmed to have lymph node metastasis, and 9 (15%) patients had clinically distant metastasis at diagnosis. Histologically, epithelioid cell (91.7%) was the predominant cell type, followed by spindle (31.7%), pleomorphic (25.0%), and small round cell (5.0%). Solid sheet, nest, pseudopapillary, and pseudoalveolar growth patterns were noted in 45 (75.0%), 22 (36.7%), 13 (21.7%), and 6 (10.0%) cases, respectively. After a median follow-up of 44 months, the 5-year disease-specific survival rate was 33.3%. Age, tumor size, depth of invasion, tumor thickness, lymphatic metastasis, and lymphovascular and perineural invasion were significantly correlated with survival in univariate analysis. Multivariate analysis revealed that age greater than 70 years and tumor invasion beyond deep muscular layer/sphincter ani externus were independent poor prognostic factors. As the largest single institution study of anorectal melanoma in an Asian population, we concluded that anorectal melanoma is a rare and lethal malignant neoplasm with morphologic diversity. Large population-based studies are still needed to establish an efficient staging system in evaluation of prognosis and facilitation of treatment for anorectal melanoma patients. PMID- 29763718 TI - TPL2 expression is correlated with distant metastasis and poor prognosis in colorectal cancer. AB - Tumor progression locus 2 (TPL2) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K). The present study aimed to elucidate the clinicopathological significance and prognostic role of TPL2 expression in colorectal cancer (CRC) through immunohistochemistry. In the present study, the correlations between TPL2 expression and clinicopathological parameters, including survival rate, were investigated using 262 archival paraffin-embedded CRC tissue samples. In addition, the correlation between TPL2 expression and tumor-infiltrating lymphocytes was evaluated using immunoscore. High TPL2 expression was found in 40.1% of the 262 CRCs analyzed. Patients with high TPL2 expression had frequent distant metastasis compared to patients with low TPL2 expression. However, there was no significant correlation between high TPL2 expression and other clinicopathological parameters. High TPL2 expression was significantly correlated with low immunoscore. In subgroup analysis based on distant metastasis, there was a significant correlation between high TPL2 expression and low immunoscore in only CRCs without distant metastasis. High TPL2 expression significantly correlated with poor overall survival. In both CRCs with and without distant metastasis, CRCs with high TPL2 expression showed worse prognosis compared to CRCs with low TPL2 expression (P = .034 and P = .010, respectively). Taken together, our results showed that high TPL2 expression was significantly correlated with distant metastasis and low immunoscore. In addition, TPL2 expression can be useful for predicting the prognosis of patients with CRC. PMID- 29763717 TI - Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract. AB - Pathologic examination of hepatic metastasectomies from patients with metastatic small intestinal or pancreatic neuroendocrine tumor frequently reveals micrometastases undetectable by radiologic or macroscopic gross examination. This finding raises the possibility that undetectable micrometastases remain in these patients after metastasectomy. Here we examined liver resections for micrometastases and assessed their impact on prognosis. Hepatic metastasectomies from 65 patients with neuroendocrine tumor of the small intestine (N = 43) or pancreas (N = 22) were reviewed for the presence of micrometastases, which were defined as microscopic tumor foci <=1 mm in greatest dimension. Medical records were also reviewed for patient demographics, clinical history, and follow-up data. Micrometastasis was identified in 36 (55%) of 65 hepatic resection specimens. More hepatic micrometastases were seen in small intestinal cases than in pancreatic cases (29/43, 67%, versus 7/22, 32%; P < .01). They were typically present within portal tracts, sometimes with extension into the periportal region or sinusoidal spaces away from the portal tracts. Patients without hepatic micrometastases had fewer macrometastases or more R0 hepatic resections than those with micrometastases. The presence of hepatic micrometastases was associated with poor overall survival both before (hazard ratio [HR] 3.43; 95% CI 1.14-10.30; P = .03) and after accounting for confounding variables in stratified Cox regression (HR 4.82; 95% CI 1.0621.79; P = .04). In conclusion, hepatic micrometastases are common in patients with metastatic small intestinal or pancreatic neuroendocrine tumor and are independently associated with poor prognosis. These data suggest that surgical resection of hepatic metastases is likely not curative in these patients. PMID- 29763720 TI - BAP1 loss is unusual in well-differentiated papillary mesothelioma and may predict development of malignant mesothelioma. AB - Literature on BRCA1-associated protein 1 (BAP1) expression status in well differentiated papillary mesothelioma (WDPM) is limited. In the present study, we examined the prevalence of BAP1 loss in WDPM by immunohistochemistry with clinical correlation, along with CDKN2A deletion status by fluorescence in situ hybridization (FISH). Eight patients diagnosed as having WDPM were identified from the surgical pathology file. Adenomatoid tumors (n = 8) and malignant mesothelioma (MM) (n = 39) were included for comparison. BAP1 immunohistochemistry was performed on representative block(s) from each case. CDKN2A FISH was also performed in the WDPMs and adenomatoid tumors. Clinical information was obtained from the medical records. Three of 8 WDPM patients showed synchronous or metachronous MM. All 3 cases showed BAP1 loss in both WDPM and the matched MM. Single-nucleotide polymorphism genomic microarray (n = 3) demonstrated a similar genetic profile in the WDPM and MM components, which supports their clonal relationship. The remaining 5 WDPM cases had intact BAP1 expression and had no evidence of disease on follow-up imaging studies at 1 to 71 months (median, 35 months). All 8 adenomatoid tumors had intact BAP1 expression, whereas 17 of 39 MM had BAP1 loss. CDKN2A FISH was negative for deletion in 4 WDPMs tested (including the case that developed MM) and all 8 adenomatoid tumors. In our study, WDPM did not show CDKN2A deletion in any case. BAP1 loss was also absent in all pure WDPM cases but was identified in all WDPM with synchronous or metachronous MM. Similar genetic landscape in WDPM and MM components suggested their clonal relationship. PMID- 29763719 TI - Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases. AB - Small cell carcinoma (SmCC) of the bladder is a rare disease. We retrospectively studied a large series of bladder SmCC from a single institution. The patients included 69 men and 12 women with a mean age of 68 years. Most bladder SmCCs were presented at advanced stage, with tumors invading the muscularis propria and beyond (n = 77). SmCC was pure in 27 cases and mixed with other histologic types in 54 cases, including urothelial carcinoma (UC) (n = 32), UC in situ (n = 26), glandular (n = 14), micropapillary (n = 4), sarcomatoid (n = 4), squamous (n = 3), and plasmacytoid (n = 1) features. Most SmCCs expressed neuroendocrine markers synaptophysin (41/56), chromogranin (26/55), and CD56 (39/41); however, they did not express UC luminal markers CK20 (0/17), GATA3 (1/30), and uroplakin II (1/22). Some SmCCs showed focal expression of CK5/6 (9/25), a marker for the basal molecular subtype. Furthermore, expression of the retinoblastoma 1 (RB1) gene protein was lost in most of the bladder SmCCs (2/23). The patients' survival was significantly associated with cancer stage but did not show a significant difference between mixed and pure SmCCs. Compared with conventional UC at similar stages, SmCC had a worse prognosis only when patients developed metastatic diseases. In conclusion, bladder SmCC is an aggressive disease that is frequently present at an advanced stage. A fraction of SmCCs show a basal molecular subtype, which may underlie its good response to chemotherapy. Inactivation of the RB1 gene may be implicated in the oncogenesis of bladder SmCC. PMID- 29763721 TI - New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1alpha. AB - Ribonuclease T2 (RNASET2) is a pleiotropic and polyfunctional protein, which exerts several different activities in neoplastic cells since the early steps of tumor development. Besides having an antitumorigenic activity, RNASET2 inhibits both bFGF-induced and VEGF-induced angiogenesis and has a role as a stress response, alarmin-like, protein. In this study, we investigated RNASET2 expression in well-differentiated and poorly differentiated neuroendocrine neoplasms of the lung (Lu-NENs), which are known to show clear-cut differences in morphology, biology and clinical behavior. In addition, we explored possible relationships between RNASET2 expression and a series of immunohistochemical markers related to hypoxic stress, apoptosis, proliferation and angiogenesis. Our results showed a significantly higher expression of RNASET2, HIF-1alpha, and its target CA IX in poorly differentiated than in well-differentiated Lu-NENs, the former also showing higher proliferation and apoptotic rates, as well as a lower microvessel density (MVD) than the latter. Moreover, we were able to demonstrate in vitro an overexpression of RNASET2 in consequence of the activation of HIF 1alpha. In conclusion, we suggest that in poorly differentiated Lu-NENs, RNASET2 expression may be induced by HIF-1alpha, behaving as an alarmin-like molecule. In this aggressive group of cancers, which have highly deregulated proliferation pathways, RNASET2 fails to exert the growth-inhibiting effects described in other types of neoplasms. Its increased expression, however, may contribute to the typical phenotypic alterations seen in poorly differentiated Lu-NENs, such as the high apoptotic rate and the extensive necrosis, and may also enhance the low MVD observed in these neoplasms. PMID- 29763723 TI - Anther Endothecium-Derived Very-Long-Chain Fatty Acids Facilitate Pollen Hydration in Arabidopsis. PMID- 29763722 TI - Lifestyle determinants of healthy ageing in a Mediterranean population: The multinational MEDIS study. AB - BACKGROUND: To evaluate modifiable, lifestyle risk factors of cardiovascular disease (CVD) among older adults, across ageing, in the Mediterranean area. METHODS: During 2005-2017, 3131 individuals from 26 Mediterranean islands of 5 countries, >=65 years of age, were voluntarily enrolled. Anthropometrical, clinical and socio-demographic characteristics, dietary habits, lifestyle parameters were measured through standard procedures. Analyses were performed by year and across consecutive age groups of the participants. RESULTS: A decrease in the prevalence of current smoking (p < 0.001), engagement in physical activities (p = 0.001) and participation in social events (p = 0.001) for every year increase in age was found. Moderate alcohol drinking increased through ageing (p = 0.008), whereas adherence to Mediterranean diet remained stable, but adequate (p = 0.90). Trend analysis also revealed that a quadratic (U-shape) function better characterized the association between ageing and total cardiometabolic risk factors burden (p for trend <0.001). CONCLUSIONS: The gaps in the understanding of factors affecting longevity and healthy ageing remain; public health authorities and stakeholders should focus on the lifestyle determinants of healthy ageing, that seems to be an effective mean for improving older peoples' health. PMID- 29763724 TI - Influence of environmental and genotypic factors on biofilm formation by clinical isolates of group B streptococci. AB - Group B Streptococcus (GBS) colonizes the gastrointestinal and urogenital tracts of approximately 30% of women, and it can cause sepsis and meningitis in neonates. GBS has been shown to form biofilms in vitro, but the effects of environmental and genotypic factors upon GBS biofilm formation are unclear. The aim of the present study was to optimize culture conditions for enhanced GBS biofilm production. Furthermore, this study also investigated the influences of strain lineage, pilus profile, and isolation source on GBS biofilm formation. The results demonstrate that the fed-batch mode and acidic pH strongly enhanced GBS biofilm formation in vitro. These findings suggest that the fed-batch mode may be suitable for both screening and fundamental studies of GBS biofilm formation. Moreover, this study demonstrated a correlation between the hyper virulent clonal complex 17 and a strong biofilm phenotype. PMID- 29763725 TI - Salmonella infection may alter the expression of toll like receptor 4 and immune related cells in chicken bursa of Fabricius. AB - Toll like receptor 4 (TLR4), eosinophils and mast cells play significant role in host immunity during several pathogenic infections. However in vivo tissue expression of TLR4 and distribution pattern of eosinophils and mast cells in chicken bursa of Fabricius (BF) during Salmonella enterica serovar Typhimurium (STm) infection is poorly studied. Therefore, herein, following immunostaining, we found localization of TLR4 in follicular cortex and medulla and its expression was statistical increased after 36 h and 72 h of STm stimulation. Chromotrope 2R staining revealed that eosinophils were mostly distributed in follicular cortex, inter-follicular spaces and in or around blood vessels and their number in BF were statistical increased after 72 h of STm stimulation. The presence of eosinophils was confirmed using immunostaining with anti-rabbit eosinophil cationic protein antibody. Toluidine blue stained mast cells were mostly distributed in connective tissues between inter-follicular spaces while some were also present in follicular cortex of BF. However, STm stimulation illustrated non significant effect on the number of mast cells or their de-granulation, instead their number were gradually decreased in BF with advancement in age of chickens. Hence, this study provided novel information about in vivo tissue distribution of TLR4, eosinophils and mast cells in BF during STm infection. PMID- 29763726 TI - Susceptibility of ruminal bacteria isolated from large and small ruminant to multiple conventional antibiotics. AB - The pivotal aim of the present context was to isolate diversified group of bacteria from the ruminants and to evaluate their antibiogram pattern against 22 antibiotics of 14 different classes. The bacterial isolates from small and large ruminant (sheep, cattle and calves) were isolated from the rumen based on various colonies morphology, and subjected for preliminary antibiotics susceptibility assay using disc diffusion method. The most sensitive isolates (based on zone of inhibition) were selected for determining the minimum inhibitory concentration (MIC) of each antibiotic ranging from 1 to 256 MUg/mL. Results revealed the concentration dependent growth inhibitory property of antibiotics a species specific process. The maximum tolerable concentration (MTC) of each antibiotic was further determined using disc diffusion method, and results exhibited that the tolerance nature of ruminal isolates to antibiotics is a species-specific mechanism. Based on the MIC and MTC values of antibiotics, amikacin, ciprofloxacin, and amoxicilline were observed to be the most potent antibiotics in terms of inhibiting the growth of ruminal isolates. In brief, the findings of the current study showed that despite the overexploitation of antibiotics as additives in the animal's feed, most of the ruminal isolates are sensitive to multiple conventional antibiotics tested. The growth inhibitory trait of antibiotics proves these antimicrobials a propitious agent against the pathogenesis of ruminal isolates in livestock. PMID- 29763727 TI - Antibacterial activity of flavonoid isolated from Trianthema decandra against Pseudomonas aeruginosa and molecular docking study of FabZ. AB - The natural product flavonoid demonstrates an extensive sort of pharmacological properties including antimicrobial activity. Although its Pseudomonas aeruginosa inhibition has been discovered, no target for action against flavonoid has been revealed to date. The anti - P. aeruginosa activity of the 2 - (3', 4' dihydroxy phenyl) - 3, 5, 7-trihydroxy-chromen-4-one isolated from T. decandra was evaluated by disc diffusion and minimum inhibitory concentration methods. The molecular docking of the flavonoid isolated from T. decandra was carried out using CDOCKER (Discovery Studio 2.0). The flavonoid isolated from T. decandra was found to inhibit the growth of P. aeruginosa and the zone of inhibition was found to be 22 +/- 0.04 mm at 20 MUg/ml while chloramphenicol showed 23 +/- 0.05 mm at 30 MUg/ml. P. aeruginosa was found to be the most sensitive to both isolated flavonoid and standard control chloramphenicol with MIC values 39.05 MUg/ml and 25 MUg/ml respectively. Further, the FAS II beta-hydroxyacyl-ACP (FabZ) of P. aeruginosa was found to be a potential target of the flavonoid as it docked in silico effectively. Our work has demonstrated the anti - P. aeruginosa activity of flavonoid isolated from T. decandra and also resulted in the elucidation of a plausible mechanism of action of the isolated flavonoid by inhibiting the FabZ using in silico analysis. PMID- 29763728 TI - In vitro and in silico antimicrobial activity of sterol and flavonoid isolated from Trianthema decandra L. AB - Phytochemical study on the leaves of Trianthema decandra leads to the isolation and characterization of two compounds from chloroform extract. The compounds were characterized using HPLC, UV, FT-IR, NMR, LCMS and CHNS. The structure of compounds were elucidated from spectral data and named according to rules laid down in IUPAC nomenclature. A novel sterol was named as 17-(5-ethyl-6 methylheptan-2-yl) -4, 4, 10, 13-tetramethyl-hexadecahydro-1H-cyclopenta (alpha) phenanthren-3-ol and the flavonoid was named as 2-(3, 4 dihydroxy - phenyl)-3, 5, 7 - trihydroxy-chromen-4 one. The antimicrobial activity of sterol and flavonoid isolated from T. decandra were examined by disc diffusion and broth dilution assays. The isolated compounds showed excellent activity against all the tested microorganisms. Sterol exhibits MIC value of 39.05 MUg/ml against S. typhi whereas flavonoid shows 78.10 MUg/ml against V. cholerae. The plausible mode of action of these compounds was studied using in silico molecular docking with Penicillin Binding Protein (PBP) as target. PMID- 29763730 TI - Virtual screening of plant compounds and nonsteroidal anti-inflammatory drugs for inhibition of quorum sensing and biofilm formation in Salmonella. AB - Salmonella belongs to the Enterobacteriaceae family which is widely distributed in the environment due to its adaptive capacity to stress conditions. In addition, Salmonella is able to perform a type of cell-to-cell communication called quorum sensing, which leads to differential gene expression. The quorum sensing system mediated by AI-1, acyl homoserine lactones (AHLs), is incomplete in Salmonella because the luxI homolog gene, which encodes for AI-1 synthase, is missing in the genome. However, a homologue of LuxR, known as SdiA, is present and allows the detection of signaling molecules produced by other species of bacteria, leading to regulation of gene expression, mainly related to virulence and biofilm formation. Thus, in view of the importance of quorum sensing on the physiology regulation of microorganisms, the aim of the present study was to perform a virtual screening of plant compounds and nonsteroidal anti-inflammatory drugs (NASIDs) for inhibition of quorum sensing by molecular docking and biofilm formation in Salmonella. In general, most plant compounds and all NSAIDs bound in, at least, one of the three modeled structures of SdiA proteins of Salmonella Enteritidis PT4 578. In addition, many tested compounds had higher binding affinities than the AHLs and the furanones which are inducers and inhibitors of quorum sensing, respectively. The Z-phytol and lonazolac molecules were good candidates for the in vitro inhibition tests of quorum sensing mediated by AI-1 and biofilm formation in Salmonella. Thus, this study directs future prospecting of plant extracts for inhibition of quorum sensing mechanism depending on AHL and biofilm formation. In addition, the use of inhibitors of quorum sensing and biofilm formation can be combined with antibiotics for better treatment efficacy, as well as the use of these compounds to design new drugs. PMID- 29763729 TI - In silico identification of molecular mimics involved in the pathogenesis of Clostridium botulinum ATCC 3502 strain. AB - Bacterial pathogens invade and disrupt the host defense system by means of protein sequences structurally similar at global and local level both. The sharing of homologous sequences between the host and the pathogenic bacteria mediates the infection and defines the concept of molecular mimicry. In this study, various computational approaches were employed to elucidate the pathogenicity of Clostridium botulinum ATCC 3502 at genome-wide level. Genome wide study revealed that the pathogen mimics the host (Homo sapiens) and unraveled the complex pathogenic pathway of causing infection. The comparative 'omics' approaches helped in selective screening of 'molecular mimicry' candidates followed by the qualitative assessment of the virulence potential and functional enrichment. Overall, this study provides a deep insight into the emergence and surveillance of multidrug resistant C. botulinum ATCC 3502 caused infections. This is the very first report identifying C. botulinum ATCC 3502 proteome enriched similarities to the human host proteins and resulted in the identification of 20 potential mimicry candidates, which were further characterized qualitatively by sub-cellular organization prediction and functional annotation. This study will provide a variety of avenues for future studies related to infectious agents, host-pathogen interactions and the evolution of pathogenesis process. PMID- 29763731 TI - Interactive web-based identification and visualization of transcript shared sequences. AB - We have developed TraC (Transcript Consensus), a web-based tool for detecting and visualizing shared sequences among two or more mRNA transcripts such as splice variants. Results including exon-exon boundaries are returned in a highly intuitive, data-rich, interactive plot that permits users to explore the similarities and differences of multiple transcript sequences. The online tool (http://labs.pathology.jhu.edu/nauen/trac/) is free to use. The source code is freely available for download (https://github.com/nauenlab/TraC). PMID- 29763733 TI - In-depth profiling of miRNA regulation in the body wall of sea cucumber Apostichopus japonicus during skin ulceration syndrome progression. AB - MicroRNAs (miRNAs) are small non-coding RNAs that mediate mRNA degradation or translation repression. Previous study showed that the expression of miRNAs was significantly changed in the body wall of sea cucumber Apostichopus japonicus after skin ulceration syndrome (SUS) infection, which is a dynamic process. However, the critical miRNAs from body wall that involved in different infection stages of SUS remain unknown. In this study, four cDNA libraries were constructed with the body wall from healthy and three SUS-infected stages of A. japonicus. A total of 248 conserved miRNAs and five novel miRNAs were identified through Illumina HiSeq 2000 platform. Compared to the control, 238 miRNAs showed significant differential expression at three stages of SUS progression. Totally, 3149 miRNA-mRNA pairs were identified by target prediction and 314 miRNA-mRNA pairs showed negative correlation. It is noteworthy that 15 miRNAs and four mRNAs were located at the crucial positions of the network built with the anti correlated miRNA-mRNA pairs. GO and KEGG enrichment analysis indicated that the predicted targets were involved in many immune-related processes. Deep analysis of miR-31c-5p, miR-29b-3p, NF-kB, mucin 2 and titin showed that they may play important roles in the pathogens attachment and recognition, signaling transduction and lesions repair of A. japonicus after SUS infection. These results would be useful for further investigating the potential roles of critical miRNAs and mRNAs in A. japonicus immune regulation. PMID- 29763734 TI - Antioxidant enzymes, hematology and histology of spleen in Nile tilapia fed supplemented diet with natural extracts challenged with Aeromonas hydrophila. AB - This study investigated the effects of dietary supplementation with the extrats of propolis and Aloe barbadensis (aloe) on the antioxydant enzime activity, hematology and histology of the spleen of Nile tilapia challenged with Aeromonas hydrophila. Seventy two juvenile Nile tilapia were divided in four treatments and three replicates and fed extract mixture for 15 days: fish fed supplemented diet with 1% of the mixture of extracts of propolis and aloe (1:1) injected with phosphate-buffered saline (PBS); fish fed suplemented diet with 1% of the mixture of extracts of propolis and aloe (1:1) injected with the A. hydrophila, fish fed supplemented diet with the mixture of propolis extracts and aloe, injected with PBS and injected with A. hydrophila. The influence of the supplementation of propolis and Aloe extracts on the immunomodulation in tilapias was observed by the evaluation of the survival of the animals after challenge with A. hydrophila. Non-supplemented fish had a 44.5% survival rate and those supplemented with 1% of the mixture of extracts showed 55.6% survival 7 days after challenge. The supplemented animals also showed a significant increase in the number of lymphocytes in the evaluation of the blood parameters and, consequently, in the histopathological evaluation, presented greater presence of centers of melanomacrophages. In addition, the activity of the antioxidant enzymes glutathione reductase (GR) in the spleen presented a significant difference in fish supplemented with 1% of the extracts mixture, being superior in the animals injected with PBS when compared to those challenged with A. hydrophila. PMID- 29763732 TI - Development, activation, and therapeutic potential of thermogenic adipocytes. AB - During the last decade, significant progress has been made in understanding adipocytes with a particular focus on thermogenic fat cells, which effectively convert chemical energy into heat in addition to their other metabolic functions. It has been increasingly recognized that different types and subtypes of adipocytes exist and the developmental origins of various types of fat cells are being intensively investigated. Previous work using immortalized fat cell lines has established an intricate transcriptional network that regulates adipocyte function. Recent work has illustrated how these key transcriptional components mediate thermogenic activation in fat cells. Last but not least, cumulative evidence supports an incontestable role of thermogenic fat in influencing systemic metabolism in humans. Here we summarize the exciting advancements in our understanding of thermogenic fat, discuss the advantages and limitations of the experimental tools currently available, and explore the future directions of this fast-evolving field. PMID- 29763736 TI - Generating a recombinant phosphothreonine-binding domain for a phosphopeptide of the human transcription factor, c-Myc. AB - Transcription factor c-Myc is an oncoprotein that is regulated at the post translational level through phosphorylation of two conserved residues, Serine 62 (Ser62) and Threonine 58 (Thr58). A highly specific tool capable of recognizing Myc via pThr58 is needed to monitor activation and localization. Through phage display, we have isolated 10 engineered Forkhead-associated (FHA) domains that selectively bind to a phosphothreonine (pThr)-containing peptide (53 FELLPpTPPLSPS-64) segment of human c-Myc. One domain variant was observed to bind to the Myc-pThr58 peptide with a KD value of 800 nM and had >1000-fold discrimination between the phosphorylated and non-phosphorylated peptide. The crystal structure of the engineered FHA Myc-pThr-binding domain (Myc-pTBD) was solved in complex with its cognate ligand. The Myc-pTBD was observed to be structurally similar to the yeast Rad9 FHA1 domain, except that its beta4-beta5 and beta10-beta11 loops form a hydrophobic pocket to facilitate the interaction between the domain and the peptide ligand. The Myc-pTBD's specificity for its cognate ligand was demonstrated to be on a par with 3 commercial polyclonal antibodies, suggesting that this recombinant reagent is a viable alternative to antibodies for monitoring Myc regulation. PMID- 29763735 TI - Effects of flexibility of the alpha2 chain of type I collagen on collagenase cleavage. AB - Cleavage of collagen by collagenases such as matrix metalloproteinase 1 (MMP-1) is a key step in development, tissue remodeling, and tumor proliferation. The abundant heterotrimeric type I collagen composed of two alpha1(I) chains and one alpha2(I) chain is efficiently cleaved by MMP-1 at a unique site in the triple helix, a process which may be initiated by local unfolding within the peptide chains. Atypical homotrimers of the alpha1(I) chain, found in embryonic and cancer tissues, are very resistant to MMP cleavage. To investigate MMP-1 cleavage, recombinant homotrimers were constructed with sequences from the MMP cleavage regions of human collagen chains inserted into a host bacterial collagen protein system. All triple-helical constructs were cleaved by MMP-1, with alpha2(I) homotrimers cleaved efficiently at a rate similar to that seen for alpha1(II) and alpha1(III) homotrimers, while alpha1(I) homotrimers were cleaved at a much slower rate. The introduction of destabilizing Gly to Ser mutations within the human collagenase susceptible region of the alpha2(I) chain did not interfere with MMP-1 cleavage. Molecular dynamics simulations indicated a greater degree of transient hydrogen bond breaking in alpha2(I) homotrimers compared with alpha1(I) homotrimers at the MMP-1 cleavage site, and showed an extensive disruption of hydrogen bonding in the presence of a Gly to Ser mutation, consistent with chymotrypsin digestion results. This study indicates that alpha2(I) homotrimers are susceptible to MMP-1, proves that the presence of an alpha1(I) chain is not a requirement for alpha2(I) cleavage, and supports the importance of local unfolding of alpha2(I) in collagenase cleavage. PMID- 29763737 TI - Validation of inflammatory genetic variants associated with long-term cancer related fatigue in a large breast cancer cohort. AB - BACKGROUND: Studies to date have reported several associations between single nucleotide polymorphisms (SNPs) and cancer related fatigue (CRF), but have been limited by small sample sizes, missing adjustment for relevant covariates or multiple testing, as well as varying CRF definitions, i.e. time and method of assessment. This study aimed to validate previously reported associations using the largest independent breast cancer sample to date and to evaluate further functional cytokine variants in relation to total CRF and all relevant CRF subdomains (physical, cognitive, and affective CRF). METHOD: 45 candidate SNPs in inflammatory pathway genes were selected based on previous reports (16 SNPs) or regulatory function (29 SNPs). Breast cancer patients recruited between 2002 and 2005 provided information on CRF at first follow-up (FU1) (N = 1389) and second follow-up (FU2) (N = 950), a median of 6.2 years and 11.7 years respectively after diagnosis. SNP associations were assessed using linear regression models on CRF scores separately for FU1 and FU2. Additionally, patients with persistent fatigue (fatigued at both time-points) were compared to those never fatigued using logistic regression models (N = 684). All analyses were adjusted for relevant covariates. Secondary analyses were conducted for CRF subdomains. RESULTS: For total CRF none of the previously reported associations were confirmed after correction for multiple testing. The p-value distribution of all SNPs was not different than the one expected by chance. Analyses of CRF subdomains yielded a significant association between TNF-alpha rs3093662 and persistent physical CRF (Odds Ratio (OR) = 3.23, 95% Confidence Interval (CI) = 1.71-6.10, p = 0.0003). CONCLUSION: We were unable to confirm previously reported findings, suggesting that individual SNPs are unlikely to be of clinical utility. Further investigations in well powered studies are warranted, which consider genetic heterogeneity according to subdomains of CRF. PMID- 29763738 TI - Prediction of early caries prognosis after fluoride application based on the severity of lesions: An in situ study. AB - PURPOSE: The aim of this in situ study was to measure baseline fluorescence loss values (DeltaF(0)) using the quantitative light-induced fluorescence (QLF) technology to screen enamel lesions for effective remineralization following fluoride application. METHODS: In this single-blinded in situ study, 20 adult volunteers wore intraoral appliances containing 4 specimens of human enamel. The surfaces of the specimens were divided into 3 regions: sound, demineralized, and treated regions. After generating 80 artificial enamel lesions with varying DeltaF values, all specimens were covered with 1.23% acidulated phosphate fluoride gel for 1 min. Three repeated QLF-digital measures of DeltaF values were then obtained for the lesions, immediately after demineralization and at 1 and 4 weeks after fluoride application. RESULTS AND CONCLUSION: Fluoride application was found to increase the DeltaF values of lesions significantly over time (p < 0.001). The groups with lower DeltaF(0) values showed significantly larger changes in DeltaF values over time (p < 0.001). Receiver operating characteristics analysis showed that baseline lesion values of DeltaF(0) = -17.50 and -25.50 would allow for lesion DeltaF to recover to -10 at 1 and 4 weeks after fluoride application, respectively (p < 0.001). The findings of this study indicate that clinicians can establish prognostic criteria for early carious lesions using the QLF technology, and hence predict the efficacy of fluoride treatment and devise effective lesion-specific treatment plans. PMID- 29763739 TI - Antimicrobial effect of photodynamic therapy using erythrosine/methylene blue combination on Streptococcus mutans biofilm. AB - BACKGROUND: Photodynamic therapy (PDT) has demonstrated promising results in the treatment of several clinical pathologies through the photochemical reaction caused by the combination of a photosensitizer and a light source. The objective of this study was to evaluate the antimicrobial effect of the combination of the photosensitizers (PSs) erythrosine/methylene blue activated by a white halogen light device on Streptococcus mutans biofilm. METHODS: Two separate experiments were conducted, the first using the PSs at the concentration of 100 MUM, and the second 250 MUM. The PSs were tested on S. mutans biofilms cultured for 24 h in isolation, in combination, with and without light activation for 2 min fractionated in 4 periods of 30 s. After treatment, biofilms were diluted and plated on BHI medium and incubated for 24 h for colony forming units (CFU) counting. The results (log10) were analyzed with ANOVA followed by Tukey test (p < 0.05). RESULTS: The erythrosine/methylene blue combination activated by white halogen light at 100 and 250 MUM, and erythrosine at 250 MUM, methylene blue at 250 MUM presented significantly reduced cell counts (3.2 log10, 5.3 log10, 4.5 log10, 4.3 log10, respectively) when compared to controls (p < 0.05). CONCLUSION: PDT with the combination of erythrosine/methylene blue demonstrated better results that the PSs in isolation regardless of the concentration. The use of this combination at the concentration of 250 MUM shows promise as an antibacterial treatment for carious lesions and should be further assessed. PMID- 29763740 TI - Combining Magnetic Resonance Imaging (MRI) and Medical Infrared Thermography (MIT) in the pre- and peri-operating management of severe Hidradenitis Suppurativa (HS). AB - Hidradenitis suppurativa (HS) is a chronic, inflammatory, and recurrent skin disease. Surgical excision of wounds appears to be the only curative treatment for the prevention of recurrence of moderate to severe stages. Magnetic resonance imaging (MRI) is a standard reference examination for the detection of HS peri anal inflammatory fistula. In this case study, the use of real-time medical infrared thermography, in combination with MRI as appropriate imaging, is proposed. The aim is to assist surgeons in the pre- and peri-surgical management of severe perianal hidradenitis suppurativa with the intent to ensure that all diseased lesions were removed during surgery and therefore to limit recurrence. The results show that medical infrared thermography (MIT), coupled with MRI, could be highly effective strategy to address thermally distinguished health tissues and inflammatory sites during excision, as characterised by differential increases in temperature. Medical infrared thermography could be used to check the total excision of inflammatory lesions as a noninvasive method that is not painful, not radiant, and is easily transportable during surgery. Ultimately, this method could be complementary with MRI in providing clinicians with objective data on the status of tissues below the perianal skin surface in the pre- and per-operating management of severe hidradenitis suppurativa. PMID- 29763741 TI - Bayesian estimation of multidimensional latent variables and its asymptotic accuracy. AB - Hierarchical learning models, such as mixture models and Bayesian networks, are widely employed for unsupervised learning tasks, such as clustering analysis. They consist of observable and latent variables, which represent the given data and their underlying generation process, respectively. It has been pointed out that conventional statistical analysis is not applicable to these models, because redundancy of the latent variable produces singularities in the parameter space. In recent years, a method based on algebraic geometry has allowed us to analyze the accuracy of predicting observable variables when using Bayesian estimation. However, how to analyze latent variables has not been sufficiently studied, even though one of the main issues in unsupervised learning is to determine how accurately the latent variable is estimated. A previous study proposed a method that can be used when the range of the latent variable is redundant compared with the model generating data. The present paper extends that method to the situation in which the latent variables have redundant dimensions. We formulate new error functions and derive their asymptotic forms. Calculation of the error functions is demonstrated in two-layered Bayesian networks. PMID- 29763742 TI - Period-adding bifurcation and chaos in a hybrid Hindmarsh-Rose model. AB - Recently, the hybrid neuron models which combine the basic neuron models with impulsive effect(the state reset process) had been proposed, however, the preset value and the reset value of membrane potential were both fixed constants in the known models. In this paper, the Hindmarsh-Rose neuron model with nonlinear reset process is presented where the preset value and the reset value of membrane potential are variable constants. We conduct a qualitative analysis in the vicinity of the equilibrium point or the limit cycle of the proposed system by using the theories of impulsive semi-dynamical systems. Firstly, the more detailed impulsive set and phase set are given, then using the fixed point of Poincare map, the existences of order-1and order-k(k>=2) period solutions are investigated subsequently. Furthermore, numerical investigations including period adding bifurcation, multiple attractors coexistence, switch-like behavior are presented to further describe the bifurcation and chaos phenomena. Finally, the obtained results and possible applications of the proposed model are elaborated. PMID- 29763743 TI - Affect recognition from facial movements and body gestures by hierarchical deep spatio-temporal features and fusion strategy. AB - Affect presentation is periodic and multi-modal, such as through facial movements, body gestures, and so on. Studies have shown that temporal selection and multi-modal combinations may benefit affect recognition. In this article, we therefore propose a spatio-temporal fusion model that extracts spatio-temporal hierarchical features based on select expressive components. In addition, a multi modal hierarchical fusion strategy is presented. Our model learns the spatio temporal hierarchical features from videos by a proposed deep network, which combines a convolutional neural networks (CNN), bilateral long short-term memory recurrent neural networks (BLSTM-RNN) with principal component analysis (PCA). Our approach handles each video as a "video sentence." It first obtains a skeleton with the temporal selection process and then segments key words with a certain sliding window. Finally, it obtains the features with a deep network comprised of a video-skeleton and video-words. Our model combines the feature level and decision level fusion for fusing the multi-modal information. Experimental results showed that our model improved the multi-modal affect recognition accuracy rate from 95.13% in existing literature to 99.57% on a face and body (FABO) database, our results have been increased by 4.44%, and it obtained a macro average accuracy (MAA) up to 99.71%. PMID- 29763744 TI - Characterization of electroencephalography signals for estimating saliency features in videos. AB - Understanding the functions of the visual system has been one of the major targets in neuroscience for many years. However, the relation between spontaneous brain activities and visual saliency in natural stimuli has yet to be elucidated. In this study, we developed an optimized machine learning-based decoding model to explore the possible relationships between the electroencephalography (EEG) characteristics and visual saliency. The optimal features were extracted from the EEG signals and saliency map which was computed according to an unsupervised saliency model (Tavakoli and Laaksonen, 2017). Subsequently, various unsupervised feature selection/extraction techniques were examined using different supervised regression models. The robustness of the presented model was fully verified by means of ten-fold or nested cross validation procedure, and promising results were achieved in the reconstruction of saliency features based on the selected EEG characteristics. Through the successful demonstration of using EEG characteristics to predict the real-time saliency distribution in natural videos, we suggest the feasibility of quantifying visual content through measuring brain activities (EEG signals) in real environments, which would facilitate the understanding of cortical involvement in the processing of natural visual stimuli and application developments motivated by human visual processing. PMID- 29763745 TI - Analysis of malondialdehyde in human plasma samples through derivatization with 2,4-dinitrophenylhydrazine by ultrasound-assisted dispersive liquid-liquid microextraction-GC-FID approach. AB - A sensitive and reliable ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) procedure was developed and validated for extraction and analysis of malondialdehyde (MDA) as an important lipids-peroxidation biomarker in human plasma. In this methodology, to achieve an applicable extraction procedure, the whole optimization processes were performed in human plasma. To convert MDA into readily extractable species, it was derivatized to hydrazone structure-base by 2,4-dinitrophenylhydrazine (DNPH) at 40 degrees C within 60 min. Influences of experimental variables on the extraction process including type and volume of extraction and disperser solvents, amount of derivatization agent, temperature, pH, ionic strength, sonication and centrifugation times were evaluated. Under the optimal experimental conditions, the enhancement factor and extraction recovery were 79.8 and 95.8%, respectively. The analytical signal linearly (R2 = 0.9988) responded over a concentration range of 5.00-4000 ng mL-1 with a limit of detection of 0.75 ng mL-1 (S/N = 3) in the plasma sample. To validate the developed procedure, the recommend guidelines of Food and Drug Administration for bioanalytical analysis have been employed. PMID- 29763747 TI - Roads less traveled: My journey through electrophysiology and beyond. PMID- 29763746 TI - Ionic liquid-type surfactant modified attapulgite as a novel and efficient dispersive solid phase material for fast determination of pyrethroids in tea drinks. AB - In this study, a novel ionic liquid-type surfactant modified attapulgite named as 1-dodecyl-3-methylimidazolium bromide-attapulgite (C12MIM-ATP) is successfully prepared and applied in dispersive solid phase extraction (dSPE) for the fast determination of pyrethroid residues in tea drinks. The primary factors that influenced the extraction efficiency, including sorbent type, amount of sorbent, extraction time, desorption conditions, pH and ionic strength, are investigated. The optimized results reveal that the extraction and desorption equilibria are rapidly obtained within 1 min. Under the optimized conditions, good linearity (2 500 MUg/L) is observed for four pyrethroids in tea drinks with determination coefficients (r2) ranged from 0.9992 to 1.0000. The limits of detection (LODs) are 0.6 MUg/L for all pesticides. Acceptable extraction recoveries of target analytes are found from 90.28 to 107.56% with relative standard deviations (RSDs) less than 8.30% in real tea drink samples. The batch-to-bath repeatability is evaluated by recovery test on five independent synthesized C12MIM-ATP sorbents. Satisfactory batch-to-batch repeatability is obtained with the recovery factors varied in 15%. A small matrix effect is observed using C12MIM-ATP as the sorbent for detection pyrethroids in tea drinks. PMID- 29763748 TI - Right Hemisphere Cognitive Functions: From Clinical and Anatomic Bases to Brain Mapping During Awake Craniotomy Part I: Clinical and Functional Anatomy. AB - The nondominant hemisphere (usually the right) is responsible for primary cognitive functions such as visuospatial and social cognition. Awake surgery using direct electric stimulation for right cerebral tumor removal remains challenging because of the complexity of the functional anatomy and difficulties in adapting standard bedside tasks to awake surgery conditions. An understanding of semiology and anatomic bases, along with an analysis of the available cognitive tasks for visuospatial and social cognition per operative mapping allow neurosurgeons to better appreciate the functional anatomy of the right hemisphere and its relevance to tumor surgery. In this article, the first of a 2-part review, we discuss the anatomic and functional basis of right hemisphere function. Whereas part II of the review focuses primarily on semiology and surgical management of right-sided tumors under awake conditions, this article provides a comprehensive review of knowledge underpinning awake surgery on the right hemisphere. PMID- 29763750 TI - Genome sequence and analysis of Mycobacterium tuberculosis strain SWLPK. AB - OBJECTIVES: Multidrug-resistant Mycobacterium tuberculosis poses a global threat, particularly in developing countries such as Pakistan. Genome sequencing, comparative genomic analysis and drug resistance gene analysis could be beneficial for understanding and monitoring M. tuberculosis disease severity in Pakistan by elucidating the biology of M. tuberculosis. METHODS: Here the draft genome of M. tuberculosis strain SWLPK was sequenced, assembled and annotated using an Illumina MiSeq system. De novo genomic assembly was conducted using Geneious ProTM v.10. The assembled genome of strain SWLPK was annotated using the Rapid Annotation using Subsystem Technology (RAST) server, tRNAscan-SE 1.21 and RNAmmer v.1.2, which provide high-quality functional annotation. RESULTS: Mycobacterium tuberculosis strain SWLPK yielded an average read depth of 68.5 fold, which covered 97% of the genome of reference strain H37Rv. The genome contains 4305 protein-coding genes, including key drug resistance and virulence associated genes such as type seven secretion systems. Additionally, it has a 65.6% GC content and contains 48 RNAs and 12 contigs. We determined that all proteins encoded by this strain contain conserved domains, except OxyR, which is associated with first-line antituberculosis drugs such as ethambutol, rifampicin, streptomycin, pyrazinamide and isoniazid. CONCLUSIONS: This genome sequence provides information regarding the drug resistance genes and virulence propensity of M. tuberculosis strain SWLPK. Strain SWLPK appears to be multidrug-resistant, similar to the Beijing genotype, as it clusters in the same group. These findings will pave the way for genomic characterisation, which will provide further insights into adaptation and evolution in human hosts by transcriptome studies and gene manipulation. PMID- 29763749 TI - Combined Surgical and Endovascular Treatment of a Complex Posterior Communicating Artery Aneurysm at One-Stage in a Hybrid Operating Room. AB - BACKGROUND: Although clipping and coiling of intracranial aneurysms are effective treatment options, they each have limitations. With the advent of the hybrid operating room, combined clipping and coiling for complex aneurysms in one stage becomes feasible. We report a successful case of a left posterior communicating artery aneurysm where combined clipping and endovascular treatment were applied. CASE DESCRIPTION: A 57-year-old man had been complaining of severe headache for 10 days. The computed tomography scan from a previous hospital revealed a parasellar lesion, and the computed tomography angiography in our hospital showed a 16-mm posterior communicating artery aneurysm. Clipping of the aneurysm was scheduled in our hybrid operating room, which enabled intervention of intraoperative digital subtraction angiography (DSA). However, once the aneurysm was clipped, intraoperative DSA revealed that the aneurysm was remnant. We readjusted the clip and reran DSA, but the residual neck was still present. In an effort to preserve the parent artery and perforators, we decided to perform endovascular treatment. Coiling was achieved, followed by angiography, indicating that the aneurysm was almost eliminated. Overall, the patient underwent 4 angiographic explorations during surgery. CONCLUSIONS: Combined open surgical and endovascular approaches to treat complex cerebral aneurysms in an hybrid operating room could offer an alternative when the aneurysms appear unclipped or remnant intraoperatively. In our experience, simultaneous clipping and coiling is a safe and effective procedure for efficient treatment of aneurysms. PMID- 29763751 TI - Integration of summary data from GWAS and eQTL studies identified novel causal BMD genes with functional predictions. AB - PURPOSE: Osteoporosis is a common global health problem characterized by low bone mineral density (BMD) and increased risk of fracture. Genome-wide association studies (GWAS) have identified >100 genetic loci associated with BMD. However, the functional genes responsible for most associations remain largely unknown. We conducted an innovative summary statistic data-based Mendelian randomization (SMR) analysis to identify novel causal genes associated with BMD and explored their potential functional significance. METHODS: After quality control of the largest GWAS meta-analysis data of BMD and the largest expression quantitative trait loci (eQTL) meta-analysis data from peripheral blood samples, 5967 genes were tested using the SMR method. Another eQTL data was used to verify the results. Next we performed a fine-mapping association analysis to investigate the functional SNP in the identified loci. Weighted gene co-expression network analysis (WGCNA) was used to explore functional relationships for the identified novel genes with known putative osteoporosis genes. Further, we assessed functions of the identified genes through in vitro cellular study or previous functional studies. RESULTS: We identified two potentially causal genes (ASB16 AS1 and SYN2) associated with BMD. SYN2 was a novel osteoporosis candidate gene and ASB16-AS1 locus was known to be associated with BMD but was not the nearest gene to the top GWAS SNP. Fine-mapping association analysis showed that rs184478 and rs795000 was predicted to be possible causal SNPs in ASB16-AS1 and SYN2, respectively. ASB16-AS1 co-expressed with several known putative osteoporosis risk genes. In vitro cellular study showed that over-expressed ASB16-AS1 increased the expression of osteoblastogenesis related genes (BMP2 and ALPL), indicating its functional significance. CONCLUSION: Our findings support that ASB16-AS1 and SYN2 may represent two novel functional genes underlying BMD variation. The findings provide a basis for further functional mechanistic studies. PMID- 29763752 TI - Commentary: Disclosure in the criminal justice system. PMID- 29763754 TI - Determinants of cancer treatment and mortality in older cancer patients using a multi-state model: Results from a population-based study (the INCAPAC study). AB - INTRODUCTION: Several studies have reported disparities in the care management and survival of older cancer patients. The aim of our study was to identify determinants of treatment administration in this population of cancer patients aged over 65 years taking into account competing risks of death. METHODS: The INCAPAC study is a population-based study. Four cancer registries and three prospective cohort studies on older subjects (age >=65 years) from Gironde, a French department, were merged to identify older cancer patients. We used a non parametric multi-state model including three states (cancer, treatment and all cause death). This model allowed studying determinants of treatment administration (all treatments including curative, symptomatic and palliative treatments) and mortality considering that patients can move from cancer state to death state, either directly or through the treatment phase. Studied variables were demographic and socioeconomic-, cancer-, health-, and geriatric-related. RESULTS: A total of 450 patients were included in the analyses. They were mainly aged 85 and over, men and educated. Among included patients, 372 (83%) received cancer treatment. In the final multivariate model, dementia was associated with a lower likelihood of receiving cancer treatment (HR = 0.68, 95% CI = 0.47-0.99). In treated patients, age, sex, comorbidities, dependency and stage at diagnosis were associated to all-cause mortality, and in untreated patients, diagnosis of dementia and stage at diagnosis were associated to mortality. CONCLUSION: Further studies are necessary to understand the impact of geriatric impairments on treatment administration and to develop clinical practice guidelines. PMID- 29763753 TI - A prospective study of cancer survivors and risk of sepsis within the REGARDS cohort. AB - BACKGROUND: Hospitalized cancer patients are nearly 10 times more likely to develop sepsis when compared to patients with no cancer history. We compared the risk of sepsis between cancer survivors and no cancer history participants, and examined whether race was an effect modifier. METHODS: We performed a prospective analysis of data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We categorized participants as "cancer survivors" or "no cancer history" derived from self-reported responses of being diagnosed with any cancer, excluding non-melanoma skin cancer. We defined sepsis as hospitalization for a serious infection with >=2 systemic inflammatory response syndrome criteria. We performed Cox proportional hazard models to examine the risk of sepsis after cancer (adjusted for sociodemographics, health behaviors, and comorbidities), and stratified by race. RESULTS: Among 29,693 eligible participants, 2959 (9.97%) were cancer survivors, and 26,734 (90.03%) were no cancer history participants. Among 1393 sepsis events, the risk of sepsis was higher for cancer survivors (adjusted HR: 2.61, 95% CI: 2.29-2.98) when compared to no cancer history participants. Risk of sepsis after cancer survivorship was similar for Black and White participants (p value for race and cancer interaction = 0.63). CONCLUSION: In this prospective cohort of community-dwelling adults we observed that cancer survivors had more than a 2.5-fold increased risk of sepsis. Public health efforts should attempt to mitigate sepsis risk by awareness and appropriate treatment (e.g., antibiotic administration) to cancer survivors with suspected infection regardless of the number of years since cancer remission. PMID- 29763755 TI - Salmonella enterica growth and biofilm formation in flesh and peel cantaloupe extracts on four food-contact surfaces. AB - Salmonella enterica is responsible for the highest number of foodborne disease outbreaks pertaining to cantaloupe industry. The objective of this study was to examine the growth and biofilm formation by outbreak strains of S. enterica ser. Poona (S. Poona), S. enterica ser. Stanley (S. Stanley) and S. enterica ser. Montevideo (S. Montevideo) on different food-contact processing surfaces in cantaloupe flesh and peel extracts at 22 degrees C and 10 degrees C. The generation time of all S. enterica strains tested was shorter in the high concentration (50 mg/ml) of cantaloupe extract and high temperature. In 50 mg/ml of cantaloupe flesh or peel extract, the populations of S. enterica were increased by 5 log CFU/ml in 24 h at 22 degrees C and 1 log CFU/ml in 72 h at 10 degrees C. In 2 mg/ml of cantaloupe flesh or peel extracts, the populations of S. enterica were increased by 3.5 log CFU/ml in 56 h at 22 degrees C, but there were no changes in 72 h at 10 degrees C. The biofilm production of S. enterica was greater at 50 mg/ml of cantaloupe extract and 22 degrees C, but no major differences (P >= 0.05) were found among the strains tested. In 50 mg/ml cantaloupe extract, S. enterica produced 5-6 log CFU/cm2 biofilm in 4-7 d at 22 degrees C and approximately 3.5-4 log CFU/cm2 in 7 d at 10 degrees C. In 2 mg/ml of cantaloupe extract, S. enterica produced 4-4.5 log CFU/cm2 biofilms in 4-7 d at 22 degrees C and 3 log CFU/cm2 in 7 d at 10 degrees C. Biofilm formation by S. Poona (01A4754) was lowest on buna-n rubber compared to stainless steel, polyethylene and polyurethane surfaces under the majority of conditions tested. Overall, these findings show that S. enterica strains can grow rapidly and form biofilms on different cantaloupe processing surfaces in the presence of low concentrations of cantaloupe flesh or peel extracts. PMID- 29763756 TI - Tobramycin mediated silver nanospheres/graphene oxide composite for synergistic therapy of bacterial infection. AB - Graphene-based materials have attracted a significant attention in constructing hybrid systems for drug delivery with enhanced antimicrobial activities. In our work, we demonstrated the formation of silver nanoparticles (AgNPs) on graphene oxide (GO) using tobramycin (TOB), an aminoglycoside antibiotic, as reducing and decorating agent. The TOB decorated GO AgNPs (TOB-GO-Ag) composite was used as an antibacterial agent against multi-drug resistant Gram-negative E-coli (BL21 DE3). The reversal of surface potential from -30 mV (GO) to +20 mV confirms the successful reduction of GO by TOB. Atomic force microscopy (AFM) and high resolution transmission electron microscopic (HRTEM) analyses confirmed the formation of uniformly distributed AgNPs on the reduced GO with an approximate particle size of 5 nm. The as-synthesized nanocomposite displayed significant antibacterial activity as compared to pure AgNPs and TOB. The positively charged TOB-GO-Ag interacts with the negatively charged E. coli membrane and inhibit bacterial growth by the antibacterial actions of the released silver, GO and tobramycin from the TOB-GO-Ag composite. The significant loss of bacterial membrane potential from -52 +/- 2 mV (control) to -2 +/- 1 mV (treated) indicates a severe cell wall damage caused by TOB-GO-Ag composite. Furthermore, fluorescence study also demonstrated a severe membrane disruption in bacterial cells treated with TOB-GO-Ag composite as compared to pure AgNPs and GO. In conclusion, the development of such hybrid systems would help in enhancing the efficacy of available drugs and eradicating the emerging bacterial resistance. PMID- 29763757 TI - Synthesis and characterization of phytochemical fabricated zinc oxide nanoparticles with enhanced antibacterial and catalytic applications. AB - A "green route" to fabricate nanoparticles has emerged as a revolutionary approach. The reported work presents a green approach to synthesize ZnO nanoparticles using Conyza canadensis plant leaves extract. The synthesis of ZnO was conducted at two different temperatures i.e. 30 degrees C and 80 degrees C. ZnO nanoparticles prepared at 80 degrees C were smaller in size and exhibited spherical morphology. The prepared nanomaterials were examined for the reduction of organic dyes i.e. methylene blue and methyl orange. The fabricated ZnO nanoparticles synthesized at 80 degrees C were found to be highly active for the reduction of aforementioned dyes with 94.5% reduction of MO and 85.3% reduction of MB in 45 min and 20 min respectively. The rate constant (k) for this reduction of MO was found to be 5.781 * 10-3 s-1 in the absence of a catalyst and 5.843 * 10-2 s-1 in the presence of ZnO NPs catalyst. The rate constant (k) for the reduction of MB was found to be 4.7 * 10-3 s-1 in the absence of a catalyst and 9.936 * 10-3 s-1 in the presence of ZnO NPs catalyst. ZnO nanoparticles synthesized at 80 degrees C were examined for their antibacterial activity. The biogenic ZnO nanoparticles exhibited strong antibacterial activity against E. coli and S. aureus with a zone of inhibition (16 mm) and (14 mm) respectively. This high antibacterial and catalytic activity of biogenic ZnO nanoparticles can be attributed to its small size, good dispersion, and well-defined morphology. PMID- 29763758 TI - Probe of ZrTiO2 thin films with TiO2-ZrO2 binary oxides deposited by dip coating technique. AB - Zirconium Titanium dioxide (TiO2: Zr) thin films were synthesized on glass substrates by the dip coating technique. The structural, optical, magnetic, photo catalytic and antibacterial properties were explored for the films synthesized with zirconium concentration 10, 15, 20, 25 and 30 at.%. X-ray diffraction (XRD) revealed that the thin films contain anatase-rutile-brookite TiO2 and cubic-ZrO2 phases. Moreover, it was noticed that ZrO2 retarded the anatase-to-rutile transformation at high Zr doping percentage.The crystallite size of ZrO2 phase was in the range of 10.93-18.22 nm, whereas it was in the range of 13.5-21.59 nm for TiO2 phase for same Zr doping percentage. The band gap of films was in the range of 2.99-3.17 eV. The band gap value decreased with increase in Zr-doping percentage due to the creation localized levels near the conduction band providing a large number of electrons to reach the conduction band. Films showed room temperature ferro-magnetism due to the defects produced by Zr in TiO2 lattice. The antibacterial efficiency of ZrTiO2 thin films was investigated by utilizing disc diffusion method. Band gap was quite low, then pure TiO2 in the range 2.99-3.14 eV with Zr percentage 10-30% atom. The ZrTiO2 thin films with 20 and 25% Zr showed better antibacterial activity against Escherichia coli than 10, 15 and 30% Zr. It was found that ZrTiO2 thin films were effective solar light photo-catalyst. PMID- 29763760 TI - Multispectroscopic and bioimaging approach for the interaction of rhodamine 6G capped gold nanoparticles with bovine serum albumin. AB - Binding interaction of Bovine Serum Albumin (BSA) with newly prepared rhodamine 6G-capped gold nanoparticles (Rh6G-Au NPs) under physiological conditions (pH 7.2) was investigated by a wide range of photophysical techniques. Rh6G-Au NPs caused the static quenching of the intrinsic fluorescence of BSA that resulted from the formation of ground-state complex between BSA and Rh6G-Au NPs. The binding constant from fluorescence quenching method (Ka = 1.04 * 104 L mol-1; LoD = 14.0 MUM) is in accordance with apparent association constant (Kapp = 1.14 * 101 M-1), which is obtained from absorption spectral studies. Forster resonance energy transfer (FRET) efficiency between the tryptophan (Trp) residue of BSA and fluorophore of Rh6G-Au NPs during the interaction was calculated to be 90%. The free energy change (DeltaG = -23.07 kJ/mol) of BSA-Rh6G-Au NPs complex was calculated based on modified Stern-Volmer Plot. The time-resolved fluorescence analysis confirmed that quenching of BSA follows static mechanism through the formation of ground state complex. Furthermore, synchronous and three-dimensional fluorescence measurement, Raman spectral analysis and Circular Dichroism spectrum results corroborate the strong binding between Rh6G-Au NPs and BSA, which causes the conformational changes on BSA molecule. In addition, fluorescence imaging experiments of BSA in living human breast cancer (HeLa) cells was successfully demonstrated, which articulated the value of Rh6G-Au NPs practical applications in biological systems. PMID- 29763759 TI - An eco-benign synthesis of AgNPs using aqueous extract of Longan fruit peel: Antiproliferative response against human breast cancer cell line MCF-7, antioxidant and photocatalytic deprivation of methylene blue. AB - Plants mediated synthesis of noble metal nanoparticles is encountered as a clean, environment friendly, lucrative and benign loom. The current study consists of clean and green synthesis of Silver nanoparticles (AgNPs). Phytoconstituents from Longan (Euphorbia longana Lam.) fruit peel were used to reduce Ag+ into AgNPs. Different analytical techniques i.e. UV-vis Spectroscopy, X-ray diffraction spectroscopy (XRD), electron dispersive X-ray (EDX), High-resolution transmission electron microscopy (HRTEM) and Fourier transform infrared spectroscopy (FTIR) were used to analyze the synthesized AgNPs. AgNPs have localized surface plasmon resonance (LSPR) peak at 445 nm which is confirmed by UV-vis spectroscopy. HRTEM showed that the prepared AgNPs are spheroid in shape and well dispersed while XRD results showed that the AgNPs are face centered cubic crystalline. EDX confirmed the elemental composition of AgNPs. The antiproliferative response of AgNPs was assayed by an exhaustive MTT assay. AgNPs showed potent anticancer activity (88%) against breast cancer cells MCF-7. Moreover, the green produced AgNPs effectively scavenged 91% of the stable and harmful 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical which confirms its' efficient antioxidant nature. AgNPs have profound photocatalytic degradation (99%) of methylene blue in a short period of time (7 min). The noteworthy biological and photocatalytic responses of the green and cleanly produced AgNPs are encountered to their well dispersion, petite volume and round shaped structure. PMID- 29763761 TI - Toxicity of functionalized fullerene and fullerene synthesis chemicals. AB - Fullerene is one of the most studied carbon-based nanoparticles due to its unique structure and potential for diverse applications. This study focuses on toxicological effects of two fullerene nanomaterials, contributing to ecological as well as human risk assessment strategies. The biological responses from two basic fullerene materials, aqueous-nanoC60 and alkaline-synthesized fullerenol, were examined using four model organisms. Bioassays were conducted on bacteria (Pseudomonas aeruginosa and Staphylococcus aureus) to determine population impacts and to assess mechanisms of cellular effects for both Gram-negative and Gram-positive species. LC50 of aqu-nC60 stirred for 28 days for P. aeruginosa was estimated to be 1336 mg/L; however, toxicity of the same aqu-nC60 preparation for S. aureus was insignificant. Freshwater green algae Raphidocelus subcapitata and invertebrate Ceriodaphnia dubia were exposed to 28-day stirred aqu-nC60 with no significant toxicological impact. Aqu-nC60 stirred for 14 days bore no toxicity within two orders of magnitude greater than the highest concentration administered. LC50 for organisms exposed to alkaline-synthesized fullerenol prepared in the laboratory was 2409 mg/L for P. aeruginosa with no determinable toxicity to S. aureus, and 1462 mg/L and 45.2 mg/L for R. subcapitata and C. dubia, respectively. Toxicity thresholds for commercially-prepared fullerenol were lower for all species, an impact attributed to the presence of impurities. Mechanistic analysis of membrane damage on bacteria by laboratory-prepared fullerenol indicated necrotic and apoptotic responses with and without photoactivation. Toxicological responses from fullerenol synthesis by-products were only determinable for C. dubia with effects attributable to impurities. PMID- 29763763 TI - Key parameters in testing biodegradation of bio-based materials in soil. AB - Biodegradation of plastics in soil is currently tested by international standard testing methods (e.g. ISO 17556-12 or ASTM D5988-12). Although these testing methods have been developed for plastics, it has been shown in project KBBPPS that they can be extended also to lubricants with small modifications. Reproducibility is a critical issue regarding biodegradation tests in the laboratory. Among the main testing variables are the soil types and nutrients available (mainly nitrogen). For this reason, the effect of the soil type on the biodegradation rates of various bio-based materials (cellulose and lubricants) was tested for five different natural soil types (loam, loamy sand, clay, clay loam, and silt-loam organic). It was shown that use of samples containing 1 g of C in a substrate of 300 g of soil with the addition of 0.1 g of N as nutrient strongly improves the reproducibility of the test making the results practically independent of the soil type with the exception of the organic soil. The sandy soil was found to need addition of higher amount of nutrients to exhibit similar biodegradation rates as those achieved with the other soil types. Therefore, natural soils can be used for Standard biodegradation tests of bio-based materials yielding reproducible results with the addition of appropriate nutrients. PMID- 29763764 TI - Machine learning based brain tumour segmentation on limited data using local texture and abnormality. AB - Brain tumour segmentation in medical images is a very challenging task due to the large variety in tumour shape, position, appearance, scanning modalities and scanning parameters. Most existing segmentation algorithms use information from four different MRI-sequences, but since this is often not available, there is need for a method able to delineate the different tumour tissues based on a minimal amount of data. We present a novel approach using a Random Forests model combining voxelwise texture and abnormality features on a contrast-enhanced T1 and FLAIR MRI. We transform the two scans into 275 feature maps. A random forest model next calculates the probability to belong to 4 tumour classes or 5 normal classes. Afterwards, a dedicated voxel clustering algorithm provides the final tumour segmentation. We trained our method on the BraTS 2013 database and validated it on the larger BraTS 2017 dataset. We achieve median Dice scores of 40.9% (low-grade glioma) and 75.0% (high-grade glioma) to delineate the active tumour, and 68.4%/80.1% for the total abnormal region including edema. Our fully automated brain tumour segmentation algorithm is able to delineate contrast enhancing tissue and oedema with high accuracy based only on post-contrast T1 weighted and FLAIR MRI, whereas for non-enhancing tumour tissue and necrosis only moderate results are obtained. This makes the method especially suitable for high grade glioma. PMID- 29763762 TI - Removal of PCDD/Fs, PCP and mercury from sediments: Thermal oxidation versus pyrolysis. AB - A continuous pilot-scale system (CPS) equipped with effective air pollution control devices (APCDs) is used for remediating the sediments contaminated with PCDD/Fs, PCP and Hg simultaneously. The removal efficiencies of these three pollutants in sediments collected from seawater pond and river, respectively, are evaluated via thermal treatment processes. PAHs and CBz formed during thermal oxidation and pyrolysis are also analyzed for better understanding the behaviors of chlorinated organic compounds. Experimental results indicate that low molecular-weight PAHs are closely related to the formation of CBz, PCDD/Fs, and CPs, while low chlorinated PCDD/Fs and CBz are predominant in flue gas with thermal oxidation. However, the PM concentration is higher in thermal oxidation than pyrolysis due to the higher air flow rate of thermal oxidation. It may bring more particles out of the furnace and have a greater potential to form PCDD/Fs within APCDs. Besides, the high air flow also dilutes the Hg vapor in flue gas and would require more energy to condense and collect Hg with the quench tower. Furthermore, for removal of total amount of PCDD/Fs, pyrolysis is better than thermal oxidation. Thus, pyrolysis is more suitable for remediating the contaminated sediment. The removal efficiencies of PCDD/Fs, PCP and Hg in sediments achieved with pyrolysis increase with increasing operating temperature and retention time in CPS. Overall, the residual concentrations of PCDD/Fs and PCP in river sediment are higher than that in seawater-pond sediment since significant formation of tar is observed due to higher organic matter content in river sediment. PMID- 29763765 TI - Towards understanding the complexity of cardiovascular oscillations: Insights from information theory. AB - Cardiovascular complexity is a feature of healthy physiological regulation, which stems from the simultaneous activity of several cardiovascular reflexes and other non-reflex physiological mechanisms. It is manifested in the rich dynamics characterizing the spontaneous heart rate and blood pressure variability (HRV and BPV). The present study faces the challenge of disclosing the origin of short term HRV and BPV from the statistical perspective offered by information theory. To dissect the physiological mechanisms giving rise to cardiovascular complexity in different conditions, measures of predictive information, information storage, information transfer and information modification were applied to the beat-to beat variability of heart period (HP), systolic arterial pressure (SAP) and respiratory volume signal recorded non-invasively in 61 healthy young subjects at supine rest and during head-up tilt (HUT) and mental arithmetics (MA). Information decomposition enabled to assess simultaneously several expected and newly inferred physiological phenomena, including: (i) the decreased complexity of HP during HUT and the increased complexity of SAP during MA; (ii) the suppressed cardiorespiratory information transfer, related to weakened respiratory sinus arrhythmia, under both challenges; (iii) the altered balance of the information transferred along the two arms of the cardiovascular loop during HUT, with larger baroreflex involvement and smaller feedforward mechanical effects; and (iv) an increased importance of direct respiratory effects on SAP during HUT, and on both HP and SAP during MA. We demonstrate that a decomposition of the information contained in cardiovascular oscillations can reveal subtle changes in system dynamics and improve our understanding of the complexity changes during physiological challenges. PMID- 29763766 TI - Breakfast food health and acute exercise: Effects on state body image. AB - Food intake and exercise have been shown to alter body satisfaction in a state dependent manner. One-time consumption of food perceived as unhealthy can be detrimental to body satisfaction, whereas an acute bout of moderate-intensity aerobic exercise can be beneficial. The current study examined the effect of exercise on state body image and appearance-related self-esteem following consumption of isocaloric foods perceived as healthy or unhealthy in 36 female college students (18-30 years old) in the Northeastern United States. Using a randomized-controlled design, participants attended six study sessions with breakfast conditions (healthy, unhealthy, no food) and activity (exercise, quiet rest) as within-participants factors. Body image questionnaires were completed prior to breakfast condition, between breakfast and activity conditions, and following activity condition. Results showed that consumption of an unhealthy breakfast decreased appearance self-esteem and increased body size perception, whereas consumption of a healthy breakfast did not influence appearance self esteem but increased body size perception. Exercise did not influence state body image attitudes or perceptions following meal consumption. Study findings suggest that morning meal type, but not aerobic exercise, influence body satisfaction in college-aged females. PMID- 29763767 TI - To deliver or not to deliver cognitive behavioral therapy for eating disorders: Replication and extension of our understanding of why therapists fail to do what they should do. AB - OBJECTIVE: This study investigated the extent to which therapists fail to apply empirically supported treatments in a sample of clinicians in The Netherlands, delivering cognitive behavioral therapy for eating disorders (CBT-ED). It aimed to replicate previous findings, and to extend them by examining other potential intra-individual factors associated with the level of (non-)use of core CBT-ED techniques. METHOD: Participants were 139 clinicians (127 women; mean age 41.4 years, range = 24-64) who completed an online survey about the level of use of specific techniques, their beliefs (e.g., about the importance of the alliance and use of pretreatment motivational techniques), anxiety (Intolerance of Uncertainty Scale), and personality (Ten Item Personality Inventory). RESULTS: Despite some differences with Waller's (2012) findings, the present results continue to indicate that therapists are not reliably delivering the CBT-ED techniques that would be expected to provide the best treatment to their patients. This 'non-delivery' appears to be related to clinician anxiety, temporal factors, and clinicians' beliefs about the power of the therapeutic alliance in driving therapy outcomes. DISCUSSION: Improving treatment delivery will involve working with clinicians' levels of anxiety, clarifying the lack of benefit of pre-therapy motivational enhancement work, and reminding clinicians that the therapeutic alliance is enhanced by behavioral change in CBT-ED, rather than the other way around. PMID- 29763768 TI - Effects on estrogen-dependent and triple negative breast cancer cells growth of Ni(II), Zn(II) and Cd(II) complexes with the Schiff base derived from pyridine-2 carboxaldehyde and 5,6-diamino-1,3-dimethyluracil explored through the renin angiotensin system (RAS)-regulating aminopeptidases. AB - A series of Ni(II), Zn(II) and Cd(II) complexes with the Schiff base derived from the condensation 1:1 from pyridine-2-carboxaldehyde and 5,6-diamino-1,3 dimethyluracil (6-amino-1,3-dimethyl-5-[(pyridin-2-ylmethylidene) amino]pyrimidine-2,4(1H,3H)-dione, DAAUPic) were synthesized and subsequently characterized by means of elemental analysis, FT-IR, NMR and nine of them by X ray diffraction. Except the [Zn(MU-O,O'-AcO)(N5,N6,N1F-DAAUPicH-1)]2 and [Cd(O,O' NO3)(MU-O4,(N5,N6,N1F)-DAAUPicH-1)(H2O)]2.2H2O dimers and the [Cd(MU-S,N SCN)(N5,N6,N1F-DAAUPicH-1)]n chain-like polymer, all of them display monomeric molecular structures. The anticancer activity of compounds was also explored studying their effects on renin-angiotensin system (RAS)-regulating aminopeptidases on estrogen-dependent and triple negative breast cancer cell lines. At the concentrations used, some of the complexes showed different effects on (RAS) peptidases, which support the idea that their effects on cell growth/proliferation could be related to autocrine/paracrine regulatory functions of their corresponding peptide substrates. PMID- 29763769 TI - Associations of body weight and weight change with cardiovascular events and mortality in patients with coronary heart disease. AB - BACKGROUND AND AIMS: It is recommended that patients with coronary heart disease (CHD) pursue a normal body weight, while the effects of body weight and weight change on prognosis are still controversial. The present study was to assess these effects using a large-scale population with CHD in China. METHODS: A total of 5276 patients with CHD were included from Jan 2000 to Dec 2014. Baseline and endpoint weights were measured. Outcomes including mortality and cardiovascular events were obtained. RESULTS: Relative to patients with normal weight, risks for adverse outcomes were lowest in overweight patients and similar in obese patients. Hazard ratios (HRs) and 95% confidence interval (95% CI) for all-cause death were 1.42 (1.06, 1.91) if overweight turned into normal weight and were 2.01 (1.28, 3.16) or 5.33 (2.81, 10.1) if obese turned into overweight or normal weight. Death risk increased with the extent of weight loss and moderate or large weight gain (p<0.05 for all). Similar results were found when risks for cardiovascular mortality and events were considered. Furthermore, these results remained significant when the patients were stratified by several covariates and even when several definitions of weight change were considered. CONCLUSIONS: Obesity did not increase adverse outcome risks in patients with CHD. Both weight loss and weight gain increased adverse outcome risks regardless of baseline body weight. The findings suggest that maintaining a stable weight may be a better strategy for the reduction of risks for cardiovascular outcomes and all-cause death in patients with CHD. PMID- 29763770 TI - The development of object-based attention in infants. AB - We examined whether infants aged 6-8 months show object-based attention using the preferential looking method. In object-based attention, which is a prerequisite function for efficient real-world processing of various stimuli, a target that appears at a cued object is detected and processed faster than a target appearing at an uncued object. We presented 6- to 8-month-old infants with the visual stimuli consisting of two white vertical rectangles side by side, in which a target appearing at 1) the cued location, 2) the end opposite to the cued location, and 3) another rectangle's end following the cue, using an established paradigm, and measured each infant's first saccade to the target. We found that (1) infants of all ages could make the first saccade to the target appearing at the cued location, (2) only 8-month-old infants made the first saccade to the target appearing at the opposite end to the cued location more accurately than to the target appearing at the other rectangle's end. These results indicate that object-based attention might be acquired around 8 months compared with the spatial cueing effect that appears at around 6 months. Our findings suggest that the objects play a role in visual attention in 8-month-old infants. PMID- 29763771 TI - Influence of pH on wet-synthesis of silver decorated hydroxyapatite nanopowder. AB - Here, effect of solution pH on precipitation of silver decorated hydroxyapatite (Ag-HAp) nano powder during its wet-synthesis was systematically studied. XRD pattern of Ag-HAp nano powder synthesised at pH ranging from 5 to 10 shows that calcium hydrogen phosphate was formed as dominating phase when the solution pH was between 5 and 9 and this phase was gradually transformed into a stable HAp above pH 9. A quantitative analysis of silver amount in Ag-HAp nano powder synthesised at different pH showed that silver can be precipitated to its maximum amount at pH 8 and the further addition of ammonia leads to the formation of a silver-ammonium complex, thereby remaining in the solution. HR-TEM and XPS analysis further confirmed the presence of silver in HAp nanocrystals, synthesised at an optimum pH 9. This trace amount of silver in HAp nano powder showed effective antibacterial activity against Staphylococcus aureus and Escherichia coli. In addition, the cytocompatibility studies carried out on MG63 cells further confirmed the present optimised silver concentration of the Ag-HAp nano powder is well within the toxic limit to be useful in various biomedical applications. PMID- 29763772 TI - Graphene-kaolin composite sponge for rapid and riskless hemostasis. AB - Kaolin is an effective and safe hemostatic agent for hemostasis. However, its ontic powder is difficult to use in actual practice. To develop a wieldy and powerful hemostat, composite strategy is usually a good choice. Herein, we developed a graphene-kaolin composite sponge (GKCS), synthesized with graphene oxide sheets, linker molecules and kaolin powders through a facile hydrothermal reaction. SEM observations support that GKCS has a porous structure, and EDS mapping further confirms that kaolin powders are embedded in graphene sheets. Once GKCS is exposed to bleeding, plasma is quickly absorbed inside the sponge, meanwhile blood cells are gathered at the interface. The gathered blood cells are in favor of accelerating clotting due to multi stimulations, including concentration, surface charge and activation of hemostatic factors, originating from both kaolin powders and graphene sponge. As a result, GKCS could stop bleeding in approximately 73 s in rabbit artery injury test. Besides, cytotoxicity and hemolysis assessments highlight that GKCS has a good biocompatibility. These remarkable properties suggest that GKCS is a potential riskless hemostatic agent for trauma treatment. PMID- 29763773 TI - Ultrasound Doppler as an Imaging Modality for Selection of Murine 4T1 Breast Tumors for Combination Radiofrequency Hyperthermia and Chemotherapy. AB - Noninvasive radiofrequency-induced (RF) hyperthermia has been shown to increase the perfusion of chemotherapeutics and nanomaterials through cancer tissue in ectopic and orthotopic murine tumor models. Additionally, mild hyperthermia (37 degrees C-45 degrees C) has previously shown a synergistic anticancer effect when used with standard-of-care chemotherapeutics such as gemcitabine and Abraxane. However, RF hyperthermia treatment schedules remain unoptimized, and the mechanisms of action of hyperthermia and how they change when treating various tumor phenotypes are poorly understood. Therefore, pretreatment screening of tumor phenotypes to identify key tumors that are predicted to respond more favorably to hyperthermia will provide useful mechanistic data and may improve therapeutic outcomes. Herein, we identify key biophysical tumor characteristics in order to predict the outcome of combinational RF and chemotherapy treatment. We demonstrate that ultrasound imaging using Doppler mode can be utilized to predict the response of combinational RF and chemotherapeutic therapy in a murine 4T1 breast cancer model. PMID- 29763774 TI - Precisely controlled delivery of magnesium ions thru sponge-like monodisperse PLGA/nano-MgO-alginate core-shell microsphere device to enable in-situ bone regeneration. AB - A range of magnesium ions (Mg2+) used has demonstrated osteogenic tendency in vitro. Hence, we propose to actualize this concept by designing a new system to precisely control the Mg2+ delivery at a particular concentration in vivo in order to effectively stimulate in-situ bone regeneration. To achieve this objective, a monodisperse core-shell microsphere delivery system comprising of poly (lactic-co-glycolic acid) (PLGA) biopolymer, alginate hydrogel, and magnesium oxide nano-particles has been designed by using customized microfluidic capillary device. The PLGA-MgO sponge-like spherical core works as a reservoir of Mg2+ while the alginate shell serves as physical barrier to control the outflow of Mg2+ at ~50 ppm accurately for 2 weeks via its adjustable surface micro-porous network. With the aid of controlled release of Mg2+, the new core-shell microsphere system can effectively enhance osteoblastic activity in vitro and stimulate in-situ bone regeneration in vivo in terms of total bone volume, bone mineral density (BMD), and trabecular thickness after operation. Interestingly, the Young's moduli of formed bone on the core-shell microsphere group have been restored to ~96% of that of the surrounding matured bone. These findings indicate that the concept of precisely controlled release of Mg2+ may potentially apply for in-situ bone regeneration clinically. PMID- 29763775 TI - Glycosaminoglycan-based hybrid hydrogel encapsulated with polyelectrolyte complex nanoparticles for endogenous stem cell regulation in central nervous system regeneration. AB - The poor regenerative capability of stem cell transplantation in the central nervous system limits their therapeutic efficacy in brain injuries. The sustained inflammatory response, lack of structural support, and trophic factors deficiency restrain the integration and long-term survival of stem cells. Instead of exogenous stem cell therapy, here we described the synthesis of nanohybrid hydrogel containing sulfated glycosaminoglycan-based polyelectrolyte complex nanoparticles (PCN) to mimic the brain extracellular matrix and control the delivery of stromal-derived factor-1alpha (SDF-1alpha) and basic fibroblast factor (bFGF) in response to matrix metalloproteinase (MMP) for recruiting endogenous neural stem cells (NSC) and regulating their cellular fate. Bioactive factors are delivered by electrostatic sequestration on PCN to amplify the signaling of SDF-1alpha and bFGF to regulate NSC in vitro. In in vivo ischemic stroke model, the factors promoted neurological behavior recovery by enhancing neurogenesis and angiogenesis. These combined strategies may be applied for other tissue regenerations by regulating endogenous progenitors through the delivery of different kinds of glycosaminoglycan-binding molecules. PMID- 29763776 TI - Dimethyl fumarate downregulates the immune response through the HCA2/GPR109A pathway: Implications for the treatment of multiple sclerosis. AB - BACKGROUND: The mechanisms of action of dimethyl fumarate (DMF), and its metabolite, monomethyl fumarate (MMF), for the treatment of multiple sclerosis are not completely elucidated. OBJECTIVES: To discuss the role of DMF/MMF-induced hydroxycarboxylic acid receptor 2 (HCA2/GPR109A) pathway activation in the immune response and treatment of MS. METHODS: A narrative (traditional) review of the current literature. RESULTS: Studies have shown that binding of DMF/MMF to HCA2 on dendritic cells inhibits the production of pro-inflammatory cytokines in vitro and in MS murine models. Evidence suggests that activation of HCA2 expressed in immune cells and gut epithelial cells by DMF/MMF, may induce anti-inflammatory responses in the intestinal mucosa. CONCLUSION: Although the DMF/MMF mechanism of action remains unclear, evidence suggests that the activation of HCA2/GPR109A pathway downregulates the immune response and may activate anti-inflammatory response in the intestinal mucosa, possibly leading to reduction in CNS tissue damage in MS patients. PMID- 29763777 TI - Incorporation of point-of-care ultrasound into morning round is associated with improvement in clinical outcomes in critically ill patients with sepsis. AB - OBJECTIVES: Point-of-care ultrasound (POCUS) has been widely used in the intensive care unit (ICU). However, it is largely unknown whether the use of POCUS is associated with improved patient-important outcomes. The study aimed to investigate whether incorporation of POCUS during morning round on a routine basis was able to improve clinical outcomes in critically ill patients with sepsis. DESIGN: It was a prospective observational study. SETTING: A tertiary care emergency intensive care unit. PATIENTS: All patients admitted to the emergency ICU from January 2016 to December 2017 were screened for potential eligibility. Sepsis was defined as infection plus signs of organ dysfunction. INTERVENTION: The intervention group incorporated POCUS during morning round on a routine basis, and a checklist was developed to improve the compliance. The control group did not have the mandates to perform POCUS during morning round, but could use POCUS when necessary. MEASUREMENTS: Clinical outcomes of mortality, length of stay in ICU, durations of vasopressors and mechanical ventilation were compared between the intervention and control groups. Multivariable regression model was employed to adjust for confounding factors. MAIN RESULTS: A total of 129 subjects, including 88 in the control group and 41 in the intervention group, were included for analysis. Univariate analysis showed that the intervention group had shorter durations of mechanical ventilation (MV) (4.5 +/- 1.2 vs. 5.7 +/- 1.0 days; p = 0.034) and more negative fluid balance (-143 vs. 48 ml/24 h; p = 0.003) on day 3. In multivariable model, routine incorporation of POCUS was associated with lower risk of prolonged (>7 days) ICU stay (OR: 0.39, 95% CI: 0.29-0.88; p = 0.029). CONCLUSIONS: The study showed that incorporation of POCUS during morning round on a routine basis was associated with shortened duration of MV and length of stay in ICU. The possible mechanism underlying the relationship may be via reduced fluid administration. Future randomized controlled trials are needed to validate current findings. PMID- 29763778 TI - MAGE-A antigens as targets for cancer immunotherapy. AB - Targeted anti-cancer therapies aim at reducing side effects while retaining their anti-cancer efficacy. Immunotherapies e.g. monoclonal antibodies, adoptive T cell therapy and cancer vaccines are used to combat cancer, but the number of available cancer specific targets is limited and new approaches are needed to generate more effective and patient tailored treatments. Unique cancer intracellular epitopes can be presented on the cell surface by MHC class I molecules, which can function as epitopes for targeted therapies. The intracellular MAGE proteins belong to a sub-class of Cancer Testis (CT) antigens which are expressed in germline cells and a wide variety of tumors of different histological origin. Evidence has emerged that their expression is linked to pro tumorigenic activities like increased cell motility, resisting cell death, and tumor promoting inflammation. Intracellular MAGE proteins are processed by the proteasome and their peptides are presented by MHC class I molecules on the cell surface of cancer cells thereby making them ideal cancer specific antigens. Here we review the previous and ongoing (pre-) clinical studies on the use of surface expressed MAGE antigens for their employment in targeted anti-cancer therapies. We present and analyze study outcomes and discuss possible future directions and improvements for MAGE directed anti-cancer immunotherapies. PMID- 29763779 TI - Clinical implications of the non-luminal intrinsic subtypes in hormone receptor positive breast cancer. AB - Gene expression profiling has had a considerable impact on our understanding ofbreastcancer biology. Duringthelast decade, 4 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like) have been identified and intensively studied. In this article, we review and discuss the clinical implications of the 2 non-luminal subtypes (i.e. HER2-E and Basal like) identified within hormone receptor (HR)-positive disease. After reviewing 32 studies for a total of 13,091 samples, ~8% and ~ 15% of early and metastatic HR+/HER2-negative breast cancer, respectively, were found to be non-luminal. Clinically, HR+/HER2-negative/non-luminal subtypes have been associated with estrogen independence, chemo-sensitivity, resistance to CDK4/6 inhibition and poor outcome. Interestingly, EGFR/HER2 tyrosine kinase inhibition might be of value in the HR+/HER2-negative/HER2-E subtype. Finally, the HER2-E subtype within HR+/HER2 + disease represents ~ 30% and has been associated with anti-HER2 sensitivity, chemo-sensitivity and resistance to CDK4/6 inhibition. In the upcoming years, retrospective and prospective clinical trials evaluating both biomarkers should lead to improvements in patient outcomes. PMID- 29763780 TI - Polymorphonuclear neutrophil integrity and functionality are preserved when exposed to saliva. AB - OBJECTIVE: Polymorphonuclear neutrophils (PMNs) are the most abundant innate immune cells and are also important effectors in the maintenance of oral health. However, little is known about the effects of saliva on the PMN. We therefore aimed to investigate the effect of saliva on the PMNs' morphology and functioning. DESIGN: Effect of saliva on the membrane integrity of PMNs isolated from blood was evaluated with FACS using Annexin V (apoptosis marker) and propidum iodide (membrane integrity marker). The effect on cell morphology was examined using transmission electron imaging. Binding and phagocytosis of the oral bacterium Fusobacterium nucleatum by PMNs was analysed by FACS. Reactive oxygen species (ROS) production was measured with chemiluminescence. RESULTS: Incubation with saliva for 60 min had no detectable effects on the membrane integrity or the morphology of PMNs. In contrast, preincubation of F. nucleatum with saliva inhibited its subsequent interaction with PMNs, resulting in a diminished production of ROS. CONCLUSIONS: Saliva does not impair the function of PMNs. However, interaction of salivary components with F. nucleatum may affect their recognition by PMNs resulting in a diminished functional response. PMID- 29763781 TI - Inhibition of VEGF gene expression in osteoblast cells by different NSAIDs. AB - OBJECTIVE: To determine the effect of different nonsteroidal anti-inflammatory drugs (NSAIDs) on vascular endothelial growth factor (VEGF) gene expression in two osteoblast cell populations. DESIGN: Osteoblasts obtained by primary culture (HOp) and human osteosarcoma cell line MG63 (MG-63), which were treated with 10 MUM doses of acetaminophen, indomethacin, ketoprofen, diclofenac, ibuprofen, ketorolac, naproxen or piroxicam. At 24 h of treatment, their gene expression of VEGF was evaluated by real-time polymerase chain reaction (RT-PCR) and compared with the expression in untreated cells (control group). RESULTS: The treatment with the different NSAIDs significantly reduced VEGF expression regardless of the cell line and NSAID studied. CONCLUSION: The results of this study suggest that these drugs may have undesirable effects on the osteoblast and its bone-forming capacity, given the effect of this growth factor on these cells. Further studies are warranted to determine their repercussions on bone tissue and to elucidate the cell signaling mechanism/s involved. PMID- 29763782 TI - High correlation of chemical composition with genotype in cryptic species of the liverwort Aneura pinguis. AB - Chemical constituents of cryptic species detected within the liverwort Aneura pinguis were identified using headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Fibre coating with divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) was used. A total of 48 samples of A. pinguis were analysed. The studied plants were identified genetically based on barcode DNA sequences and represented three cryptic species (A, B and F) of A. pinguis. Cryptic species A and B are genetically diverse; both represent three evolutionary lineages: A1, A2, A3 and B1, B2, B3, respectively. The cryptic species F that was recently detected is not diverse. The most characteristic compounds in analysed samples were sesquiterpene hydrocarbons (up to 17.7% for A1; 15.7% for A2; 20.6% for A3; 7.7% for B1; 2.0% for B2; 3.7% for B3; 10.2% for F), oxygenated sesquiterpenoids (up to 68.0% for A1; 54.7% for A2; 52.6% for A3; 63.5% for B1; 88.7% for B2; 82.7% for B3; 78.8% for F), and linear aliphatic hydrocarbons (up to 14.8% for A1; 1.1% for A2; 12.1% for A3; 6.9 for B1; 5.2% for B2; 1.1% for B3; 7.0% for F). The dominant compound in the studied samples was pinguisone. The second dominant compound present in the tested plant material was deoxopinguisone, except for lineage B2, where only a small relative concentration of this compound was found. A high content of deoxopinguisone in cryptic species A (lineages A1, A2 and A3) was accompanied by the presence of isopinguisone and methyl norpinguisonate, whereas these two compounds were not detected in cryptic species B (lineages B1 and B3) and F. The chemical compounds detected in the studied samples of A. pinguis were subjected to multivariate statistical analysis. The results showed that the chemical composition depends mainly on the genotype of the plant and slightly on the habitat. However, there was no clear correlation between the volatile compounds and the date of collection of the studied plants. PMID- 29763783 TI - Sex differences in the ACTH and cortisol response to pharmacological probes are stressor-specific and occur regardless of alcohol dependence history. AB - Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 MUg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor specific endocrine responses in humans regardless of alcohol dependence history. PMID- 29763784 TI - Alterations in the distribution of actin and its binding proteins in the porcine endometrium during early pregnancy: Possible role in epithelial remodeling and embryo adhesion. AB - During early pregnancy, uterine epithelial cells undergo major transformations in their cytoskeleton that make the endometrium receptive for conceptus attachment. Actin binding proteins (ABPs) such as cofilin, gelsolin, and vinculin are involved in regulating actin polymerization, severing or crosslinking actin to integrins. However, whether ABPs are involved in epithelial remodeling or embryo adhesion in pigs is unknown. Therefore, the expression and distribution of these proteins were investigated in porcine endometrium on Days 10 and 13 (pre implantation period), and 16 (attachment phase) of the estrous cycle or pregnancy. While day and pregnancy status had no effect on ABP gene expression, the protein abundance of vinculin was significantly higher on Day 13 than on Day 10 (p < 0.05) of the estrous cycle, and its abundance was highest on Day 16 in the pregnant endometrium. Immunofluorescent staining showed alterations in the distribution of these proteins depending on the day of the estrous cycle or early pregnancy examined. Double immunofluorescent staining for the ABPs and actin revealed that while cofilin co-localized with actin in the apical epithelium on Days 13 and 16 of the estrous cycle, in pregnant animals, it was strongly associated with actin in the sub-epithelial stroma of the endometrium. Gelsolin was also co-localized with actin in the apical epithelium on Days 13 and 16 of the estrous cycle, but this association was absent in the pregnant endometrium. Vinculin co-localized with actin in the sub-epithelial stroma on Days 13 and 16 irrespective of the reproductive status, but was additionally associated with actin in the apical epithelium on Day 16 of pregnancy. Vinculin interacted with phosphorylated focal adhesion kinase in the endometrial epithelium, and the interaction was dependent on estradiol-17beta, a conceptus-secreted pregnancy recognition factor in pigs. Furthermore, silencing vinculin in the endometrial epithelial cells negatively affected trophoblast adhesion to them. In conclusion, the influence of stage and reproductive status on the specific localization of actin and its binding proteins in the porcine endometrium suggests that they play a role in regulating the endometrial cytoskeleton. Moreover, vinculin may facilitate conceptus attachment to the epithelium by interacting with focal adhesion kinase. PMID- 29763786 TI - Born equal? The distribution of government Medicare spending for children. AB - Providing equitable care is an objective of many national healthcare systems. Using the birth cohort of the nationally representative Longitudinal Study of Australian Children linked with the Medicare Benefits Scheme billing data who were recruited in 2004 at ages 0-1 years and assessed biennially for six waves, we assessed the distribution of out-of-hospital government Medicare spending by household income. 4853 children followed over 11 years were included in the study. Distributions of major spending components including general practitioner and specialist care were assessed using concentration indices. Trends in the inequalities as children grow were investigated. The results showed that after controlling for health care needs, total government Medicare spending over 0-11 years of age favoured the rich (concentration index 0.041). The Medicare spending for general practitioner care was equal (concentration index 0.005) while for specialist care and diagnostics and imaging were 'pro-rich' (concentration index 0.108 and 0.088 respectively). Children from poorer families were most disadvantaged when aged 0-1 years in specialist spending, and the disparity lessened as children approached adolescence. Our findings suggest that income related inequalities exist in government Medicare spending particularly in the first few years of life. As early years of life are a critical window in childhood development and building block for future health, the results warrant further investigation and attention from policy makers. PMID- 29763785 TI - Exposure to progesterone previous to the protocol of ovulation synchronization increases the follicular diameter and the fertility of suckled Bos indicus cows. AB - The objective was to evaluate the effect of injectable progesterone previous to the timed artificial insemination (TAI) protocol on follicular growth, ovulation and pregnancy rate of suckled Bos indicus cows. In experiment 1, 10 days before the beginning to TAI protocol (D-10), 431 suckled-anestrus Nelore cows (249 multiparous and 182 primiparous), were allocated to one of three treatments groups (control, P4i and P4iGnRH). At this moment, cows in the P4i and P4iGnRH group received 150 mg of injectable progesterone intramuscularly (Sincrogest injetavel(r), Ouro Fino, Brazil). On Day 0 (D0), all cows were synchronized using an estradiol/progesterone-based TAI protocol. Simultaneously, in the P4iGnRH group, cows received 10 MUg of Busereline intramuscularly (Sincroforte(r), Ouro Fino, Brazil). Ultrasound exams were performed to evaluate the diameter of the largest follicle (D0, D8 and D10), ovulation rate and diameter of the corpus luteum (D24). In experiment 2, 681 suckled Nelore cows (356 multiparous and 325 primiparous) were synchronized using an estradiol/progesterone-based TAI protocol and received treatments similar to experiment 1. TAI was performed 48 h after removal of the progesterone (P4) device. Pregnancy diagnosis was 30 d after TAI. In experiment 3, blood samples were collected to evaluated the progesterone concentration for 168 h after administration of injectable progesterone intramuscularly. Statistical analyses were performed by GLIMMIX procedure of SAS. In experiment 1, the diameter of the largest follicle (LF) on D10 (P = 0.21), follicular growth rate (P = 0.34) and ovulation rate (P = 0.62) were similar among experimental groups. However, there was difference among groups for the LF on D0 [Control (10.9 +/- 0.2 mm)b, P4i (12.7 +/- 0.3 mm)a and P4iGnRH (12.6 +/- 0.3 mm)a; P = 0.001], LF on D8 [Control (9.7 +/- 0.2 mm)b, P4i (10.4 +/- 0.2 mm)a and P4iGnRH (9.9 +/- 0.2 mm)ab; P = 0.05], presence of the CL on D8 [Control 0% (0/136)b, P4i 0% (0/140)band P4iGnRH 26.4% (38/144)a; P = 0.001], diameter of the CL on D24 [Control (19.7 +/- 0.4 mm)ab, P4i (20.1 +/- 0.4 mm)a and P4iGnRH (18.5 +/- 0.4 mm)b; P = 0.001] and pregnancy rate [Control 35.0% (78/223)b, P4i 45.9% (105/229)a and P4iGnRH 40.6% (93/229)ab; P = 0.01]. The circulating concentration of P4 remained above 1.5 ng/mL until 168 h after the P4i treatment. In conclusion, the injectable progesterone previous to the TAI protocol increased diameter of the LF on D0 and D8 without interfering on the ovulation rate. Furthermore, such exposure increases the pregnancy rate in suckled Nelore cows. PMID- 29763787 TI - Laugh and grow fat: Happiness affects body mass index among Urban Chinese adults. AB - Previous studies have extensively examined the relationship between body mass index (BMI) and subjective well-being (SWB) but have mainly focused on the effects of BMI on SWB, leaving the question of whether BMI can be influenced by SWB largely neglected. In this study, we present the first empirical evidence on the effects of SWB on BMI among adults, using data combined from four waves of the Chinese General Social Survey (CGSS) (2010-2013). We find that, among urban Chinese adults, those who have a higher level of happiness tend to have higher BMI, after extensively controlling for a constellation of individual sociodemographic and health attributes. Further analyses using the instrumental variable method and propensity score matching provided similar results. PMID- 29763788 TI - HIV as social and ecological experience. AB - The spread and varied impacts of the HIV/AIDS epidemic demonstrate the complex and reciprocal relationships between the socio-political and biophysical dimensions of human health. Yet even with increasing research and policy attention there remain critical gaps in the literature on how HIV-positive households manage health through their engagement with social and ecological systems. This is particularly urgent given improvements in the global response to the epidemic, whereby expanded access to antiretroviral therapy has extended the possibility for survival for years or decades. Because many HIV-positive families and communities in the Global South remain dependent upon a diverse set of resources to generate income and meet subsistence needs, the impacts of disease must be understood within a mix of social processes, including the maintenance of land and collection of natural resources. Similarly, biophysical systems disrupted by HIV/AIDS vary depending upon resource use and locally-specific dynamics that influence opportunities for agrarian production. This paper reports on the findings from a structured survey completed in three communities in northeast South Africa in 2013 that is integrated with focus group discussions and qualitative interviews conducted from 2012-2016. We concentrate upon the diverse ways that individuals and families experience HIV through livelihood systems that are reliant on economic and natural resources. Because the access and use of these resources are mediated by existing social, cultural, and institutional systems, as well as historical spatial economies, we analyze how this produces differential lived experiences for HIV-positive individuals and households in the age of expanded access to antiretroviral therapy. PMID- 29763790 TI - The language of smell: Connecting linguistic and psychophysical properties of odor descriptors. AB - The olfactory sense is a particularly challenging domain for cognitive science investigations of perception, memory, and language. Although many studies show that odors often are difficult to describe verbally, little is known about the associations between olfactory percepts and the words that describe them. Quantitative models of how odor experiences are described in natural language are therefore needed to understand how odors are perceived and communicated. In this study, we develop a computational method to characterize the olfaction-related semantic content of words in a large text corpus of internet sites in English. We introduce two new metrics: olfactory association index (OAI, how strongly a word is associated with olfaction) and olfactory specificity index (OSI, how specific a word is in its description of odors). We validate the OAI and OSI metrics using psychophysical datasets by showing that terms with high OAI have high ratings of perceived olfactory association and are used to describe highly familiar odors. In contrast, terms with high OSI have high inter-individual consistency in how they are applied to odors. Finally, we analyze Dravnieks's (1985) dataset of odor ratings in terms of OAI and OSI. This analysis reveals that terms that are used broadly (applied often but with moderate ratings) tend to be olfaction-unrelated and abstract (e.g., "heavy" or "light"; low OAI and low OSI) while descriptors that are used selectively (applied seldom but with high ratings) tend to be olfaction-related (e.g., "vanilla" or "licorice"; high OAI). Thus, OAI and OSI provide behaviorally meaningful information about olfactory language. These statistical tools are useful for future studies of olfactory perception and cognition, and might help integrate research on odor perception, neuroimaging, and corpus-based linguistic models of semantic organization. PMID- 29763789 TI - Quantification of anomeric structural changes of glucose solutions using near infrared spectra. AB - Glucose is the most abundant carbohydrate found in living organisms. It exists as two anomers: alpha-D-glucose and beta-D-glucose, which differ in how the hydroxyl group on the C1 carbon is directed. In solutions, the ratio between alpha- and beta-D-glucose is typically 4:6 but can vary depending on the surrounding ions or temperature. In this study, we obtained near-infrared (NIR) spectra of the glucose anomers based on concentration, and analyzed the spectral difference between each anomer by spectra subtraction and principal component analysis, respectively. Moreover, by simultaneously measuring the optical rotation and NIR spectra from dissolution to equilibration, we showed that NIR spectra quantitatively estimated the specific rotations of glucose solutions using partial least-squares regression in the 1100-1800 nm wavelength range. All the analytical results indicated that the absorption at 1742 nm possess the potential to distinguish each glucose anomer quantitatively. Therefore, we addressed the prediction of the specific rotation by the absorption at 1742 nm, and demonstrated that the absorption normalized by line subtraction showed the high correlation with measured specific rotation. The absorption at 1742 nm reflects structural changes of the glucose anomers in solution. Our spectroscopy study not only provides spectral information about glucose anomers, which are the most fundamental chemical compounds in organisms, but also shows the possibility to detect the anomer ratio in vivo for the fields of agriculture and medicine by taking advantage of NIR. PMID- 29763791 TI - The global precedence effect in English and Korean native speakers with Roman, Korean Hangul and Thai compound letters. AB - The aim was to investigate whether native English speakers (Experiment 1) and native Korean speakers (Experiment 2) processed familiar letters in an analytic manner in comparison to unfamiliar letters or symbols. Participants performed a two-alternative-forced-choice identification task with Roman, Korean Hangul and Thai Navon compound letters (large letters made up of small letters). The English speakers were familiar with Roman script but not Korean or Thai, whereas the Korean speakers were familiar with Korean and Roman script but not Thai. The global precedence effect (GPE), an indication of holistic processing, is characterised by a global advantage (global processing is faster than local processing) and asymmetric congruence (global processing interferes with the processing of local features). Based on previous research, it was predicted that there would be a global precedence effect for unfamiliar but not familiar letters. Results from the English speakers did not support this prediction as we found a GPE for familiar Roman as well as unfamiliar Thai letters but not for unfamiliar Korean letters. In contrast, for the Korean speakers, we found support for the prediction as we found a GPE for Thai letters but not for familiar Korean and Roman letters. Based on this evidence, we propose that the Koreans are processing Korean and Roman letters in a more analytic manner than the English native speakers for Roman script. Due to the characteristics of Korean Hangul, Korean readers may be processing letters in a more analytic manner than the English readers. PMID- 29763792 TI - Impact assessment of pollutants from waste-related operations as a feature of holistic logistic tool. AB - Waste management has still been a developing and progressing field, which demands continual improvements in waste transportation as well as proper selection of locations and technical operation of new treatment facilities. Most of research papers on waste management planning have been dealing with optimisation of network flows, thus minimising the cost and improving economic criteria. The shortest paths to treatment facilities are considered together with detailed analysis of their operation including heat and electricity demands in their vicinity. The tasks sometimes include social and global environmental criterions, however, the direct local consequences also play an important role and should be examined. A decision-making strategy in waste management updated with the local emission impact on the population is proposed in this paper. The paper focuses on the first move in analysing the production, dispersion, and impact of pollutants, originating in transport, with regards to the population living close to routes. The calculation of emission produced during the transport of waste takes into consideration the altitude profiles of routes, container loads, and specific types of vehicles. The consecutive estimated impact on the population reckons with the distances between routes and municipalities as well as their sizes in terms of the numbers of inhabitants, where the transportation routes are divided into smaller segments and dispersion is limited with threshold value. The proposed approach describing the emission effect has been tested using real-life operating data corresponding to the specific, 81 km long route along which approximately 25 t of waste is transported 800 times a year. The impact of pollutants on the population was evaluated and discussed. Results of the analysis were quantified for this route to create an edge characterisation needed for further calculations. This approach applied to the whole network then yields input data needed for future research of novel strategies in facility location problems. Other possible extensions of the presented approach include more accurate dispersion function or detailed calculation of the impact of pollutants with respect to specific locations of residential houses. PMID- 29763794 TI - Design and experimental validation of Unilateral Linear Halbach magnet arrays for single-sided magnetic resonance. AB - Single-sided NMR has the potential for broad utility and has found applications in healthcare, materials analysis, food quality assurance, and the oil and gas industry. These sensors require a remote, strong, uniform magnetic field to perform high sensitivity measurements. We demonstrate a new permanent magnet geometry, the Unilateral Linear Halbach, that combines design principles from "sweet-spot" and linear Halbach magnets to achieve this goal through more efficient use of magnetic flux. We perform sensitivity analysis using numerical simulations to produce a framework for Unilateral Linear Halbach design and assess tradeoffs between design parameters. Additionally, the use of hundreds of small, discrete magnets within the assembly allows for a tunable design, improved robustness to variability in magnetization strength, and increased safety during construction. Experimental validation using a prototype magnet shows close agreement with the simulated magnetic field. The Unilateral Linear Halbach magnet increases the sensitivity, portability, and versatility of single-sided NMR. PMID- 29763793 TI - A measurement system of high-temperature oxidation environment with ultrasonic Ir0.6Rth0.4 alloy thermometry. AB - Iridium-rhodium is generally applied as a thermocouple material, with max operating temperature about 2150 degrees C. In this study, a ultrasonic temperature measurement system was designed by using Iridium-rhodium (60%Ir 40%Rh) alloy as an acoustic waveguide sensor material, and the system was preliminarily tested in a high-temperature oxidation environment. The result of ultrasonic temperature measurement shows that this system can indeed work stably in high-temperature oxidation environments. The relationship between temperature and delay time of ultrasonic thermometry up to 2200 degrees C was illustrated. Iridium-rhodium materials were also investigated in order to fully elucidate the proposed waveguide sensor's performance in a high-temperature oxidation environment. This system lays a foundation for further application of high temperature measurement. PMID- 29763795 TI - Protective effects of echinacoside against anoxia/reperfusion injury in H9c2 cells via up-regulating p-AKT and SLC8A3. AB - Echinacoside is a natural ingredient with various pharmacological activities. In this study, we investigated the protective effects of echinacoside on cardiomyocytes (rat H9c2 cells) in an anoxia/reperfusion (A/R) model. Further, the regulatory function of sodium-calcium exchanger protein 3 (SLC8A3/NCX3) as well as the protein kinase B (AKT) signaling were studied. The present results indicated that echinacoside protected against A/R-induced apoptosis in a dose manner, which was characterized by a decrease in the apoptosis and caspase 3 protein levels in H9c2 cells. Further, Ca2+ uptake were dose-dependently reduced in H9c2 cells by echinacoside under A/R conditions. Whereas, relative mRNA expression of SLC8A3 and protein levels of SLC8A3 and p-AKT showed opposite tendency. On the one hand, the A/R-induced abnormalities in H9c2 cells were remarkably ameliorated by activated p-AKT and over-expression of SLC8A3 but aggravated by inhibited p-AKT, and the aggravated effection were ameliorated by echinacoside. Moreover, protein levels of SLC8A3 were positively regulated by p AKT signaling. On the other hand, apoptosis and Ca2+ uptake as well as protein levels of caspase 3 were significantly increased by SLC8A3 silencing in H9c2 cells under normoxic conditions, and this symptom was remarkably reversed by echinacoside or Nimodipine (an antagonis of Ca2+) treatment. Collectively, echinacoside has showed a cardioprotective effect against A/R treatment in a dose dependent manner in vitro, and this cardioprotective effect was potentially achieved via up-regulating p-AKT and SLC8A3. PMID- 29763797 TI - Ultrasensitive detection of hazardous reactive oxygen species using flexible organic transistors with polyphenol-embedded conjugated polymer sensing layers. AB - Here we report that superoxide, one of the hazardous reactive oxygen species (ROS), can be quickly detected by flexible organic field-effect transistors (OFETs) with the polyphenol-embedded conjugated polymer micro-channels. Rutin, one of the abundant polyphenols found in a variety of plants, was employed as a sensing molecule and embedded in the poly(3-hexylthiophene) (P3HT) matrix. The rutin-embedded P3HT layers showed randomly distributed micro-domains, which became bigger as the rutin content increased. The best transistor performance was achieved at the rutin content of 10 wt%, while the OFETs exhibited proper and controllable transistor performances even in the phosphate buffer solutions. The sensing test revealed that the present OFET sensors could stably detect superoxide using very small amount (<10 MUl) of samples at extremely low concentrations (500 pM), while they exhibited outstanding stability and durability upon repeated detection and storage-reuse tests. Finally, the present flexible OFET sensors could deliver confident sensing results for the detection of superoxide generated from the mouse RAW264.7 macrophages. PMID- 29763796 TI - Raw hematite based Fe(III) bio-reduction process for humified landfill leachate treatment. AB - Microorganisms from paddy soils and raw hematite are used for enhancing natural Fe(III) bio-reduction, in order to remove macromolecular organic pollutants from humified landfill leachate. Based on batch experiments, 60% of refractory organics can be adsorbed by hematite in 12 days. In the presence of Fe(III) reducing bacteria, 489.60 +/- 0.14 mg L-1 of dissolved organic matters can be degraded to 51.90 +/- 3.96 mg L-1 within 50 days; twelve types of semi volatile organic compounds can be degraded; hereby, the reaction follows a first-order kinetics. Crystalline Fe(III) is transformed into the amorphous form and reduced to Fe(II), hydroquinone functional groups in the humic acid (HA) are transformed to quinone ones, and the formation of HA-hematite ligands is promoted. Comparing with most of the studies about electron shuttling of HA, the transformation of quinone in the HA to hydroquinone could not be observed in the present bio system. Based on column evaluations, more than 93% of chemical oxygen demand (influent concentration of 658 +/- 19 mg L-1) could be removed microbially under flow conditions, when the hydraulic retention time was 45 h. Raw hematite-based Fe(III) bio-reduction has a promising potential for the removal of humic and benzene series in humified landfill leachate. PMID- 29763798 TI - Effect of blockage ratios on the characteristics of methane/air explosion suppressed by BC powder. AB - To investigate the effect of blockage ratios on the explosion suppression by powder suppressant, an experimental study was performed to suppress the methane air explosion in a 5L duct with different blockage ratios and various concentrations of BC dry powder. The results indicate that flames experienced both the spherical and finger-shaped stages. Furthermore, the smoothness of flame front initially decreased and then increased. Flame propagation velocities were higher with larger blockage ratios except for phi = 1. The maximum peak overpressure (MPP) with the blockage ratio was slightly increased till phi reached 0.7 then surged sharply. The MPP decreased as the powder concentration increased. The maximum drop rate in the MPP being 34.8%-59.9%, depending on powder concentrations, occurred at the blockage ratio between 0.4 and 0.6. The result is ascribed to the competition between the suppression augmentation by the higher venting-generated turbulence and the suppression attenuation by the shorter residence time of the particle. However, the drop rate was relatively less promoted by increasing the concentration from 80 g/m3 to 240 g/m3. The inhibitor at higher concentration was less effective. An inhibition mechanism is explained by analogy to droplet group combustion, in which the decomposition regime of NaHCO3 differs at different concentrations. PMID- 29763799 TI - The electrochemical regeneration of granular activated carbons: A review. AB - The electrochemical treatment of exhausted granular activated carbon (GAC) has been identified as an effective alternative to traditional adsorbent regeneration methods (e.g. thermal, chemical, and microbial). However, despite its proven potential and initial investigation over two decades ago, the development of this technology has been progressing slowly, hindering its deployment in industrial applications. Thus, a review has been conducted that aims to present the fundamentals of GAC electrochemical regenerative methods, what research has been conducted to develop the technology to the present day, and lastly, identify limitations and future prospects associated with electrochemical methods. The regenerative mechanism is firstly discussed, followed by a presentation of the varying reactor configurations and operating parameters utilized during the electrochemical treatment of GAC materials exhausted with a broad range of wastewater contaminants. Finally, emerging electrochemical technologies used for the commercial treatment of exhausted adsorbent materials and contaminated soils are discussed. PMID- 29763800 TI - Potentials of using mixed culture bacteria incorporated with sodium bicarbonate for hydrogen production from water hyacinth. AB - The aim of this study is to assess the potentials of using mixed culture bacteria incorporated with different concentrations of NaHCO3 for hydrogen production from water hyacinth (WH). The lowest hydrogen yield (HY) of 30.4 +/- 1.9 mL/gTVS, H2 content (HC) of 19.5 +/- 1.5% and hydrogenase enzyme (HE) activity of 0.06 +/- 0.01 mgM.Breduced/min were registered for the cultures without supplementation of NaHCO3. The HY, HC, and HE activity were maximized at levels of 69.2 +/- 4.3 mL/gTVS, 58.4 +/- 3.6% and 0.18 +/- 0.01 mgM.Breduced/min. respectively for the anaerobes supplied with 3.0 g NaHCO3/L. Furthermore, cellulose, hemicellulose, and lignin destruction efficiencies were 37.2 +/- 2.3, 30.0 +/- 1.9 and 20.9 +/- 1.3% respectively due to the increase of cellulase and xylanase activities up to 2.73 +/- 0.17 and 1.87 +/- 0.12 U/mL, respectively. Moreover, the abundance of Firmicutes was substantially increased and accounted for 71% of the total OTU's. Microbes belonging to the order Clostridiales and OPB54 were particularly enriched in the medium supplemented with NaHCO3. PMID- 29763801 TI - Bubble coalescence suppression driven carbon monoxide (CO)-water mass transfer increase by electrolyte addition in a hollow fiber membrane bioreactor (HFMBR) for microbial CO conversion to ethanol. AB - This study investigated the effects of electrolytes (CaCl2, K2HPO4, MgSO4, NaCl, and NH4Cl) on CO mass transfer and ethanol production in a HFMBR. The hollow fiber membranes (HFM) were found to generate tiny gas bubbles; the bubble coalescence was significantly suppressed in electrolyte solution. The volumetric gas-liquid mass transfer coefficients (kLa) increased up to 414% compared to the control. Saturated CO (C*) decreased as electrolyte concentrations increased. Overall, the maximum mass transfer rate (Rmax) in electrolyte solution ranged from 106% to 339% of the value obtained in water. The electrolyte toxicity on cell growth was tested using Clostridium autoethanogenum. Most electrolytes, except for MgSO4, inhibited cell growth. The HFMBR operation using a medium containing 1% MgSO4 achieved 119% ethanol production compared to that without electrolytes. Finally, a kinetic simulation using the parameters got from the 1% MgSO4 medium predicted a higher ethanol production compared to the control. PMID- 29763802 TI - Sorption of norfloxacin, sulfamerazine and oxytetracycline by KOH-modified biochar under single and ternary systems. AB - Pollution of water by single antibiotics has been investigated in depth. However, in reality, a wide range of different contaminants is often mixed in the aquatic environment (contaminant cocktail). Here, single and competitive sorption dynamics of ionizable norfloxacin (NOR), sulfamerazine (SMR) and oxytetracycline (OTC) by both pristine and modified biochars were investigated. Sorption kinetics of the three antibiotics was faster in ternary-solute than single-solute system. Sorption efficiency was enhanced in the competitive system for NOR by the pristine biochar, and for OTC by both the pristine biochar and the modified biochar, while SMR sorption by the pristine biochar and the KOH-modified biochar was inhibited. Sorption was governed by electrostatic interactions, pi-pi EDA and H-bonds for antibiotics sorption by biochar. SMR and OTC sorption by biochar was influenced by cation bridging and surface complexation, respectively. This research finding will guide the development of treatment procedures for water polluted by multiple antibiotics. PMID- 29763803 TI - Study of the Mozart effect in children with epileptic electroencephalograms. AB - PURPOSE: To establish if listening to Mozart's Sonata for two pianos in D major (K448) has an anti-epileptic effect on the EEGs (electroencephalograms) of children. METHODS: Forty five children (2-18 years; mean 7 years 10 months) who had epileptiform activity on EEG were recruited from those attending for scheduled EEG investigations. Mozart's Sonata for two pianos in D major (K448) and an age-appropriate control music were played during the EEG. There were five consecutive states during the record, each lasting 5 min; before Mozart music (baseline), during Mozart music, after Mozart music/before control music, during control music and after control music. Epileptic discharges were counted manually and the mean frequency of epileptic discharges calculated in each state. RESULTS: A significant reduction (p < 0.0005) in the frequency of epileptic discharges was found during listening to the Mozart music compared to the baseline. No evidence of a difference in mean epileptic discharges was found between the baseline and the other three states or between listening to the Mozart music and control music. CONCLUSION: This study confirms an anti-epileptic effect of Mozart music on the EEG in children, which is not present with control music. The role of 'Mozart therapy' as a treatment for drug-resistant epilepsy warrants further investigation. PMID- 29763804 TI - Chalcones and bis-chalcones: As potential alpha-amylase inhibitors; synthesis, in vitro screening, and molecular modelling studies. AB - Despite of a diverse range of biological activities associated with chalcones and bis-chalcones, they are still neglected by the medicinal chemist for their possible alpha-amylase inhibitory activity. So, the current study is based on the evaluation of this class for the identification of new leads as alpha-amylase inhibitors. For that purpose, a library of substituted chalcones 1-13 and bis chalcones 14-18 were synthesized and characterized by spectroscopic techniques EI MS and 1H NMR. CHN analysis was carried out and found in agreement with the calculated values. All compounds were evaluated for in vitro alpha-amylase inhibitory activity and demonstrated good activities in the range of IC50 = 1.25 +/- 1.05-2.40 +/- 0.09 uM as compared to the standard acarbose (IC50 = 1.04 +/- 0.3 uM). Limited structure-activity relationship (SAR) was established by considering the effect of different groups attached to aryl rings on varying inhibitory activity. SMe group in chalcones and OMe group in bis-chalcones were found more influential on the activity than other groups. However, in order to predict the involvement of different groups in the binding interactions with the active site of alpha-amylase enzyme, in silico studies were also conducted. PMID- 29763805 TI - Design, synthesis and biological evaluation of novel quinazoline-2,4-diones conjugated with different amino acids as potential chitin synthase inhibitors. AB - A series of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) has been designed to inhibit the action of fungus chitin synthase enzyme (CHS). The synthesis of the designed compounds was carried out in four steps starting from the reaction between 1-methylquinazoline-2,4(1H,3H) dione and ethyl chloroacetate to yield the ethyl acetate derivative. This ester was hydrolyzed to the corresponding carboxylic acid derivative that was then utilized to couple several amino acids getting the final designed compounds. The synthesized compounds were tested for their inhibition against CHS. Compound 7 showed the highest potency among others with minimum inhibitory concentration (IC50) of 0.166 mmol/L, while polyoxin B (the positive control) had IC50 of 0.17 mmol/L. The synthesized compounds were also evaluated for their in vitro antifungal activity using Aspergillus fumigates, Aspergillus flavus, Crytococcus neoformans and Candida albicans. Unfortunately, the 14 synthesized compounds showed lower in vitro activity compared to the used active controls. However, compound 6m and fluconazole have synergistic effect on Aspergillus flavus; Compounds 7 and fluconazole have synergistic effects on Aspergillus fumigates. PMID- 29763806 TI - A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer's disease. AB - Alzheimer's disease (AD), the most common form of dementia, is a multifactorial neurodegenerative disease. The target enzymes inhibition including cholinesterase, beta-secretase, monoamine oxidase and inhibition of amyloid-beta aggregation as well as oxidative stress and metal chelation play an important role in the pathogenesis of AD. Chroman-4-one scaffold with benzo-gamma-pyrone network is a privileged structure in organic synthesis and drug design. A large number of research has been carried out on modified naturally occurring chromanone scaffolds and/or synthesized new analogues, to obtain effective drugs for AD management. The present review summarizes aspects related to the multi target-directed ligands (MTDLs) strategy in enzyme targets modulation performed with natural and synthesized chroman-4-one-based structures to look at their potential in the management of multifactorial Alzheimer's disease. PMID- 29763807 TI - Positional scanning library applied to the human eosinophil cationic protein/RNase3 N-terminus reveals novel and potent anti-biofilm peptides. AB - Eradication of established biofilm communities of pathogenic bacteria is one of the pending challenges in the development of new antimicrobial agents. In particular, the dreaded nosocomial Pseudomonas aeruginosa forms microbial communities that offer an enhanced resistance to conventional antibiotics. Recently, we have described an engineered antimicrobial peptide derived from the human RNase3, also named the eosinophil cationic protein (ECP), RN3 (5-36), which combines bactericidal activity with high cell agglutination and lipopolysaccharide (LPS) affinity. Through a single replacement scan library using the SPOT methodology we have evaluated both the contribution of sequence positioning and amino acid singularity towards the peptide biological and physicochemical properties. Results indicate that the ECP N-terminus has already been extensively improved through evolution to provide high antimicrobial activity; hence most substitutions improving its antimicrobial performance are in detriment of safety towards host tissues. Only three positions were identified, occupied by polar residues on the first alpha-helix of the protein and replaceable by a hydrophobic residue, allowing an extended N-terminal patch that mediates bacterial agglutination. Among the best candidates, an Ile replacement proved best in improving the peptide therapeutic window. The novel engineered peptides encompass both the LPS-binding and aggregation-prone regions of parental ECP, providing the appropriate structural features for peptide attachment to the bacterial exopolysaccharide layer and bacterial cell membrane destabilization, thereby promoting biofilm removal at micro molar concentrations. We conclude that the novel engineered peptides are promising lead candidates against Gram-negative biofilms. PMID- 29763809 TI - The impact of methamphetamines in patients with traumatic brain injury, a retrospective review. AB - OBJECTIVE: Both neurotoxic and neuroprotective effects of methamphetamines (METH) are being studied. There are few studies evaluating the effects of METH on patients with traumatic brain injury (TBI). The objective of this study is to compare clinical outcomes after TBI in METH users versus non-METH users. PATIENT AND METHODS: A retrospective review of 304 patients with severe traumatic head injury were performed. Patients were evaluated and stratified based on toxicology screening for methamphetamines (METH) or none. Of the patients reviewed with a full toxicology, 24 of those patients were positive for METH, and 60 patients were negative. Patients were evaluated based on demographics, type of injury, Glasgow Coma Scale (GCS), and Glasgow Outcome Scale (GOS). RESULTS: METH patients were younger upon presentation (43.5 versus 55.8, p = 0.003), with a larger improvement in GCS and GOS upon discharge (P = 0.012, 0.0001 respectively). There was no significant difference in length of hospital stay, initial presenting GCS and GOS, or discharge GCS and GOS. CONCLUSIONS: Our findings demonstrate an improved change in GCS and GOS for those positive with METH than those without. Surprisingly, substance positive patients did not have a worse outcome score. Further investigation is necessary to evaluate the potential neuro-protective effects of METH in TBI. PMID- 29763808 TI - Design, synthesis and evaluation of novel multi-target-directed ligands for treatment of Alzheimer's disease based on coumarin and lipoic acid scaffolds. AB - A novel series of coumarin-lipoic acid conjugates were synthesized via cycloaddition click reaction to find out new multi-target-directed ligands (MTDLs) for treatment of Alzheimer's disease (AD). All of synthesized compounds were screened for neuroprotective and anti-cholinesterase activities. Based on primary screening, two compounds (5 and 11) were subjected to further biological evaluations. In particular, compound 11 which was the most potent AChE inhibitor showed good inhibitory effect on Abeta-aggregation and intracellular ROS (reactive oxygen species) formation, as well as the ability of selective bio metal chelation and neuroprotection against H2O2- and Abeta1-42-induced cytotoxicity. In the light of these results, the applied hybridization approach introduced new promising lead compound with desired multifunctional properties, being useful in the treatment of Alzheimer's disease. PMID- 29763810 TI - Forensic drug intelligence and the rise of cryptomarkets. Part II: Combination of data from the physical and virtual markets. AB - Technology provides new ways to access customers and suppliers while enhancing the security of off-line criminal activity. Since the first cryptomarket, Silk Road, in 2011, cryptomarkets have transformed the traditional drug sale by facilitating the creation of a global network of vendors and buyers. Due to the fragmented nature of traces that result from illegal activities, combining the results of concurrent processes based on traces of different nature should provide supplementary benefit to understand the drug market. This article compares the data of the Australian virtual market (in particular data extracted from cryptomarkets) to the data related to traditional market descriptors, namely national seizures and arrests, prevalence data, shipping countries of seized post shipments as well as outcomes of specific surveys targeting users' behaviour online. Results revealed the domestic nature of the online illicit drug trade in Australia which is dominated by amphetamine-type substances (ATS), in particular methylamphetamine and cannabis. These illicit drugs were also the most seized drugs on the physical market. This article shows that the combination of different information offers a broader perspective of the illicit drug market in Australia and thus provides stronger arguments for policy makers. It also highlights the links between the virtual and physical markets. PMID- 29763811 TI - Current status and environment impact of direct straw return in China's cropland A review. AB - With the development of grain production technologies and improvement of rural living standard, the production and utilization of straw have significantly been changed in China. More than 1 billion tones of straw are produced per year, and vast amount of them are discarded without effective utilization, leading various environmental and social impacts. Straw return is an effective approach of the straw utilization that has been greatly recommended by government and scientists in China. This paper discussed the current status of the straw return in China. Specifically, the production and models of straw return were explored and their environmental impacts were extensively evaluated. It was concluded that straw could be positively effective on the improvement of the soil quality and the grain production. However, it appeared that the straw return also had several neglect negative effects, implying that further research and assessment on the returned straw are required before its large-scale promotion in China. PMID- 29763812 TI - Computation of hip rotation kinematics retrospectively using functional knee calibration during gait. AB - BACKGROUND: Hip rotation kinematics during gait is a key parameter to support clinical decision making, for example in children with lower limb torsional deformities. However, hip rotation kinematics is also one of the least repeatable parameter because it is difficult to locate the position of the medio-lateral axis of the femur. Functional knee calibration provides an alternative to locate the medio-lateral axis of the femur and may be performed retrospectively, using the movement of the knee joint during gait. Although not necessarily more anatomically accurate, functional calibration may lead to increased repeatability between sessions, which would be useful to compare gait analysis data from sessions pre- and post-treatment, or to reprocess data in large gait databases. METHODS: This study presents a workflow to perform knee functional calibration using knee kinematics during gait and update hip rotation kinematics accordingly. The workflow was applied to investigate the inter-subject, inter-session and inter-trial variance components of multiple calibration methods in a group a 10 typically developing children. RESULTS: Results indicated that one or two degrees of freedom functional calibration methods were more repeatable inter-session (SD: 1.8 degrees ) than conventional calibration using the knee alignment device (SD: 4.7 degrees ). However, simulated reduced range of movement at the knee during gait increased inter-session variance for the functional calibration algorithms. Functional calibration did not provide any improvement over the conventional calibration when knee range of movement was reduced and flexion greater than 20 degrees during gait, i.e. 'crouch gait'. SIGNIFICANCE: The workflow presented allows the re-processing of gait analysis data using knee kinematics during gait only. The workflow may also be used to investigate functional axes of other joints, for example the ankle. PMID- 29763813 TI - Age and gymnastic experience effects on sensory reweighting processes during quiet stand. AB - BACKGROUND: The relative contribution of sensory inputs to control balance while standing is dynamically adjusted. These sensory reweighting processes could be impacted by age and sport expertise capabilities, especially when the sport emphasizes equilibrium like artistic gymnastics. RESEARCH QUESTION: The aim of this study was to explore the sensory reweighting processes to adjust standing posture in children and adults with different gymnastic expertise (gymnasts, G, and non-gymnast, NG). METHODS: All participants were asked to stand quietly on a force plate in two visual conditions (eyes open, EO, and eyes closed, EC). Within a trial, proprioception was altered with two vibrators strapped at the Achilles tendon level. The center of pressure (COP) displacements in the anterior posterior and medio-lateral directions were calculated and normalized by the base of support. The effect of vibration application was characterized by the COP speed, maximal posterior displacement and the time when it occurred. The effect of vibration removal was depicted by the time between the motor switched off and the achievement of balance values similar to baseline and the COP speed and movement units performed during this time. RESULTS: G children presented shorter posterior displacement during vibrations, needed less time to recover initial balance, and produced less movements units than NG children. In general, adults and EO showed better reweighting responses than children and EC, respectively. SIGNIFICANCE: These results suggest that age could have a positive effect on reweighting processes and that gymnastic experience may benefit the development of proprioceptive reweighting processes in children but not in adults. PMID- 29763814 TI - Inter-segment foot motion in girls using a three-dimensional multi-segment foot model. AB - BACKGROUND: Several multi-segment foot models (MFMs) have been introduced for in vivo analyses of dynamic foot kinematics. However, the normal gait patterns of healthy children and adolescents remain uncharacterized. We sought to determine normal foot kinematics according to age in clinically normal female children and adolescents using a Foot 3D model. METHODS: Fifty-eight girls (age 7-17 years) with normal function and without radiographic abnormalities were tested. Three representative strides from five separate trials were analyzed. Kinematic data of foot segment motion were tracked and evaluated using an MFM with a 15-marker set (Foot 3D model). As controls, 50 symptom-free female adults (20-35 years old) were analyzed. RESULTS: In the hindfoot kinematic analysis, plantar flexion motion in the pre-swing phase was significantly greater in girls aged 11 years or older than in girls aged <11 years, thereby resulting in a larger sagittal range of motion. Coronal plane hindfoot motion exhibited pronation, whereas transverse plane hindfoot motion exhibited increased internal rotation in girls aged <11 years. Hallux valgus angles increased significantly in girls aged 11 years or older. The foot progression angle showed mildly increased internal rotation in the loading response phase and the swing phase in girls aged <11 years old. CONCLUSION: The patterns of inter-segment foot motion in girls aged 11 years or older showed low-arch kinematic characteristics, whereas those in girls aged 11 years or older were more similar to the patterns in young adult women. PMID- 29763815 TI - Gait pathology subtypes are not associated with self-reported fall frequency in children with cerebral palsy. AB - BACKGROUND: Trips and falls are common concerns reported by parents of children with cerebral palsy. Specific gait pathologies (excessive internal hip rotation, intoeing, and stiff knee gait) are anecdotally associated with higher rates of falls. RESEARCH QUESTION: Is fall frequency higher for the aforementioned gait pathologies? METHODS: Parent-reported fall frequency from 1063 children with cerebral palsy who also had a three-dimensional gait analysis was retrospectively reviewed. Frequency of 10 common gait pathologies was determined and fall frequency for the gait pathologies of interest were compared to matched control groups. Possible effects of Gross Motor Functional Classification System (GMFCS) level and age on fall frequency were also assessed and matched in the control group, as appropriate. RESULTS: In general, parent-reported fall frequency increased from GMFCS level I to II and then decreased until level IV. Moreover, younger children tended to report greater fall frequency, though children who reported never falling were of similar age as those who reported weekly falls, resulting in an inverted-U shaped relationship. Children with cerebral palsy who walked with excessive internal hip rotation, excessive intoeing, or stiff knee gait did not report increased fall frequencies compared to other children with cerebral palsy matched on GMFCS level and age that did not walk with those gait patterns. Approximately 35% of children reported never falling, 35% reported falling daily, and 30% reported falling monthly or weekly for each gait pattern. Therefore, elevated fall frequency appears to be a generic problem for most children with CP rather than a function of a specific gait pattern. SIGNIFICANCE: Clinicians should be aware of these relationships, or lack thereof, when trying to decipher the cause of a child's falling and when determining appropriate interventions. Future studies may seek to more objectively quantify fall frequency, as self-report is the main limitation of this study. PMID- 29763816 TI - Design of a Phase 3 trial of intracoronary administration of human adenovirus 5 encoding human adenylyl cyclase type 6 (RT-100) gene transfer in patients with heart failure with reduced left ventricular ejection fraction: The FLOURISH Clinical Trial. AB - The prognosis of patients with HFrEF remains poor despite the use of current medical and device therapies. Preclinical studies of HFrEF using IC delivery of RT-100, a replication deficient, E1/E3-deleted human adenovirus 5 encoding human AC6 was associated with favorable effects on LV function and remodeling. A recent multicenter, double-blind, placebo-controlled, phase 2 study demonstrated the safety of IC delivery of RT-100 in HFrEF patients and potential efficacy at the higher doses. This phase 2 dose finding study, which included doses not expected to be effective, identified a potential reduction in congestive heart failure admissions in the AC6-treated group one year after randomization. The FLOURISH study is designed to investigate the prospect of reduction of heart failure hospitalization and other clinical adverse events and improvement in EF. The FLOURISH study is a double-blind, placebo-controlled, multicenter Phase 3 clinical trial that will randomize 536 patients to a one-time IC administration of RT-100 (1012 vp) or placebo in a 1:1 ratio. Subjects will be 18-80 years of age, on optimal standard of care HF therapy with LVEF >=10% and <=35% by echocardiogram, and will undergo IC administration of RT-100 vs. placebo on Day 1. Follow-up study visits will be performed at Weeks 1 and 4, and Months 3, 6, and 12. Patients will be followed for an additional 36 months for safety assessments with telephone contact at Months 24, 36, and 48. The primary objective is to determine the efficacy of IC RT-100 vs. placebo in reducing the event rate of all (first and repeat) HF hospitalizations occurring from baseline to 12 months. The secondary objectives are to determine the efficacy of IC RT-100 on CV death, all cause death, and all HF events and in improving NYHA functional classification. Exploratory endpoints will include echocardiographic parameters of left ventricular systolic and diastolic function, HF symptoms and physical limitations, 6-minute walking distance, Borg dyspnea score, and NT-proBNP levels. The FLOURISH study, which received fast track designation from the Food and Drug Administration in December 2017, will further investigate the role of a one-time intracoronary injection of RT-100 in reducing HF hospitalizations and will serve as a registration trial (potentially pivotal investigation) for RT-100 as a treatment for HFrEF. PMID- 29763817 TI - Escalating heat-stress mortality risk due to global warming in the Middle East and North Africa (MENA). AB - Climate change will substantially exacerbate extreme temperature and heatwaves. The impacts will be more intense across the Middle East and North Africa (MENA), a region mostly characterized by hot and arid climate, already intolerable for human beings in many parts. In this study, daily climate data from 17 fine resolution Regional Climate Models (RCMs) are acquired to calculate wet-bulb temperature and investigate the mortality risk for people aged over 65 years caused by excessive heat stress across the MENA region. Spatially adaptive temperature thresholds are implemented for quantifying the mortality risk, and the analysis is conducted for the historical period of 1951-2005 and two future scenarios of RCP4.5 and RCP8.5 during the 2006-2100 period. Results show that the mortality risk will increase in distant future to 8-20 times higher than that of the historical period if no climate change mitigation is implemented. The coastal regions of the Red sea, Persian Gulf, and Mediterranean Sea indicate substantial increase in mortality risk. Nonetheless, the risk ratio will be limited to 3-7 times if global warming is limited to 2 degrees C. Climate change planning and adaptation is imperative for mitigating heat-related mortality risk across the region. PMID- 29763819 TI - Estimation of personal ozone exposure using ambient concentrations and influencing factors. AB - Evidence is limited regarding whether ambient monitoring can properly represent personal ozone exposure. We conducted a longitudinal panel study to measure personal exposure to ozone using real-time personal ozone monitors. Corresponding ambient ozone concentrations and possible influencing factors (meteorological conditions and activity patterns) were also collected. We used linear mixed effect models to analyze personal-ambient ozone concentration associations and possible influencing factors. Ambient ozone concentrations were around two to three times higher than personal ozone (43.1 MUg/m3 on average) and their correlations were weak with small slopes (0.35) and marginal R square (RM2) values (0.24). Larger RM2 values were found under high temperature (>29.5 degrees C), low humidity (<62.1%), good ventilation conditions (>4 h) and for individuals spent longer time outdoors (>0.6 h). In final model, personal ozone exposure was positively associated with ambient concentrations and ventilation conditions, but inversely correlated with ambient temperature and humidity. The models explained >50% of personal ozone concentration variabilities. Our results highlight that ambient ozone concentration alone is not a suitable surrogate for individual exposure assessment. Meteorological conditions (temperature and humidity) and activity patterns (windows opening and outdoor activities) that affecting personal ozone exposure should be taken into account. PMID- 29763818 TI - Associations between birth outcomes and maternal PM2.5 exposure in Shanghai: A comparison of three exposure assessment approaches. AB - BACKGROUND: Few studies have estimated effects of maternal PM2.5 exposure on birth outcomes in China due to the lack of historical air pollution data. OBJECTIVES: We estimated the associations between maternal PM2.5 exposure and birth outcomes using gap-filled satellite estimates in Shanghai, China. METHODS: We obtained birth registration records of 132,783 singleton live births during 2011-2014 in Shanghai. PM2.5 exposures were assessed from satellite-derived estimates or central-site measurements. Linear and logistic regressions were used to estimate associations with term birth weight and term low birth weight (LBW), respectively. Logistic and discrete-time survival models were used to estimate associations with preterm birth. Effect modification by maternal age and parental education levels was investigated. RESULTS: A 10 MUg/m3 increase in gap-filled satellite-based whole-pregnancy PM2.5 exposure was associated with a -12.85 g (95% CI: -18.44, -7.27) change in term birth weight, increased risk of preterm birth (OR 1.27, 95% CI: 1.20, 1.36), and increased risk of term LBW (OR 1.22, 95% CI: 1.06, 1.41). Sensitivity analyses during 2013-2014, when ground PM2.5 measurements were available, showed that the health associations using gap-filled satellite PM2.5 concentrations were higher than those obtained using satellite PM2.5 concentrations without accounting for missingness. The health associations using gap-filled satellite PM2.5 had similar magnitudes to those using central site measurements, but with narrower confidence intervals. CONCLUSIONS: The magnitude of associations between maternal PM2.5 exposure and adverse birth outcomes in Shanghai was higher than previous findings. One reason could be reduced exposure error of the gap-filled high-resolution satellite PM2.5 estimates. PMID- 29763820 TI - One particle, two targets: A combined action of functionalised gold nanoparticles, against Pseudomonas fluorescens biofilms. AB - Attempts to deal with the problem of detrimental biofilms using nanoparticle technologies have generally focussed on exploiting biocidal approaches. However, it is now recognised that biofilm matrix-components may be targets for the disruption or dispersion of biofilms. Here, we show that the functionalization of gold nanoparticles with the enzyme, proteinase-K (PK) led to both biocidal and matrix disruption effects within Pseudomonas fluorescens biofilms and released cells. This study highlights the potential mechanisms underpinning the properties of Proteinase-K functionalized gold nanoparticles. With the emergence of biocide resistant biofilm-forming organisms, novel nanoparticle strategies may provide the ideal solution for disrupting and inactivating biofilm cells, thereby minimising the use of biocides or antibiotics. PMID- 29763821 TI - Specific ion effects on thermoresponsive polymer brushes: Comparison to other architectures. AB - Thermoresponsive polymers have received significant research attention as smart materials with particular interest in biomedical applications. The composition and architecture are known to strongly influence the thermoresponsive properties of the materials. For example, the strong overlap of end-grafted polymer chains in polymer brushes leads to a broader collapse transition relative to linear ungrafted chains as well as temperature dependent adhesion. The temperature response of free polymer has been widely reported to depend on the concentration and identity of ions in solution and is further modified by the composition of the solvent and presence of cosolutes. However, the influence of polymer architecture on these specific ion effects is relatively unknown. Herein, we compare the current understanding of specific ion effects on free polymer chains and gels with recent studies of polymer brushes. Further studies on mixed salt systems are found to be the next step to predicting the behaviour of these materials in biological systems. PMID- 29763822 TI - Construction of novel Sr0.4H1.2Nb2O6.H2O/g-C3N4 heterojunction with enhanced visible light photocatalytic activity for hydrogen evolution. AB - Construction of heterojunction is an effective strategy to conquer the severe charge carrier recombination limitation of single component g-C3N4 photocatalyst. In the present work, novel heterojunctions composed of g-C3N4 nanosheets and Sr0.4H1.2Nb2O6.H2O nanooctahedrons were constructed via a simple hydrothermal method. The as-prepared Sr0.4H1.2Nb2O6.H2O/g-C3N4 (HSN/CN) heterojunction showed high photocatalytic activity in the water splitting reactions. Specially, it is found that the developed 20 wt%-HSN/CN heterojunction shows high water splitting activity with H2 evolution rate up to 469.4 MUmol g-1, which was much higher than that of bare CN. This enhanced photocatalytic activity for H2 evolution can be mainly attributed to the matched energy level and heterojunction structure which could improve the photo-generated charge carriers separation and transfer. This work implies that construction of heterojunctions with a wide band gap semiconductor is a feasible strategy for enhancement of photocatalytic activity of CN materials. PMID- 29763824 TI - Use of continuous wavelet transform approach for simultaneous quantitative determination of multicomponent mixture by UV-Vis spectrophotometry. AB - In the present paper, a multicomponent analysis approach based on spectrophotometry method was developed for simultaneous determination of Guaifenesin (GU), Chlorpheniramine (CHL) and Pseudoephedrine (PSE) without any separation steps. The method under study is signal processing method based on Continuous Wavelet Transform (CWT) coupled with zero cross point technique. In this paper, CWT method was tested by synthetic ternary mixtures and was applied to the commercial cough syrup as a real sample and assessed by applying the standard addition technique. For demonstrate the accuracy of the results, other applications of signal processing, such as Derivative Transform (DT), Partial Least Squares (PLS) regression and Principal Components Regression (PCR) were used as comparative methods. Afterwards, the obtained results from analyzing the cough syrup by all methods were compared to the High-Performance Liquid Chromatography (HPLC) as a reference method. One-way analysis of variance test at 95% confidence level showed no significant differences between CWT and other applications. PMID- 29763823 TI - Synthesis of uniform Ag nanosponges and its SERS application. AB - With the aid of amino acid, various Ag nanostructures were successfully synthesized via the reaction between silver nitrate and hydrazine hydrate at room temperature. The as-prepared products were characterized by X-ray diffraction and scanning electron microscopy. It was found that the morphology of the as-prepared Ag products depended on the sorts of amino acid and solvents. The uniform Ag nanosponges could be obtained in glycol with aid of glycine. Using rhodamine 6G (R6G) as probe, the surface-enhanced Raman scattering (SERS) performance was also investigated, which showed that the uniform Ag nanosponges exhibited an intensive and enhanced Raman scattering. Pazufloxacin mesilate (PM) were detected conveniently using these uniform nanosponges as SERS substrates. The present work might afford some guidance for the rationally controllable synthesis of other metal nanomaterials. PMID- 29763825 TI - Reconstructing the colour palette of the Konstantinos Parthenis' burnt paintings. AB - This case study focuses on the reconstruction of the colour palette and the possibility of laser cleaning of burnt paintings. The paintings ORPHEUS IN THE UNDERWORLD and CONCORDIA, composed by the Greek artist Konstantinos Parthenis (1878-1967), have been severely damaged by fire. The colour palette of Parthenis is thoroughly investigated for the first time, and to perform this, a multi analytical spectroscopic approach was employed. Non-destructive in situ analysis was performed on multiple areas of the paintings by portable XRF. SEM-EDS and Raman, supported by reflected visible light optical microscopy, and ultraviolet light microscopy, as well as structural XRD and molecular FTIR were performed for identifying the pigments, the binder and the substrate of the paintings. This work also unveiled new aspects of the painting technique used by the artist, such as the uncommon use of multiple pigments of red hue in the upper paint layers, comparatively with the rest of Parthenis' paintings. Molecular spectroscopic techniques (i.e., Raman and FTIR) were effective in identifying pigments like chrome yellow (crocoite mineral), chrome orange (phoenicochroite mineral) and viridian green (hydrated chromium oxide). The spectroscopic analyses were also essential in the laser cleaning restoration because of the detection of pigments (i.e., lead white, vermilion etc.) prone to phase transformations due to photothermal and/or photochemical effects. Our investigation establishes the basis on the application of non-conventional cleaning methods on damaged paintings, such as laser irradiation, in order to remove the damaged layer and/or the superficial accretions, while preserving the hues of the original painting. PMID- 29763826 TI - Towards a better comprehension of interactions in the crystalline N acetylbenzylamine and its sulphur analogue N-benzyl-ethanethioamide. IR, Raman, DFT studies and Hirshfeld surfaces analysis. AB - This paper presents the investigation results of the polarized IR spectra of the hydrogen bond in crystals of N-acetylbenzylamine and its sulphur analogue N benzyl-ethanethioamide. The spectra were measured at 298 and 77 K by a transmission method, with the use of polarized light. The Raman spectroscopy, Hirshfeld surfaces analysis and DFT studies have been also reported. Theoretical calculations of the isolated molecule were performed by using density functional theory (DFT) method at B3LYP/6-311(d,p), B3LYP/6-311++G(d,p) and B3LYP/6 311++G(3df,2pd) basis set levels. The geometrical parameters of analyzed compounds are in good agreement with the XRD experiment. The vibrational frequencies were calculated and subsequently values have been compared with the experimental Infrared and Raman spectra. It has been shown that the observed and calculated frequencies are found to be in good agreement, as well as the analysis of the Hirshfeld surface has been well correlated to the spectroscopic studies. Additionally, the highest occupied molecular orbital energy (EHOMO), lowest unoccupied molecular orbital energy (ELUMO), the energy gap between EHOMO and ELUMO (DeltaEHOMO-LUMO), molecular electrostatic potential and global reactivity descriptors viz. chemical potential, global hardness and electrophilicity have been calculated. In N-acetylbenzylamine the presence of the N-benzylamide fragment is essential for activity. PMID- 29763827 TI - Site preference for luminescent activator ions in doped fluoroperovskite RbZnF3. AB - With the dual objective of investigating the site preferences of larger sized activator ions and to append luminescence property to the perovskite structured RbZnF3, doping of manganese(II), cerium(III), europium(III) and terbium(III) ions (5 mol%) was carried out. Although cubic symmetry of RbZnF3 was preserved for all the doped samples, site preference of rare-earth ions for the A-site Rb+ leading to an inverse perovskite arrangement has been noticed from careful analysis of lattice parameters from refinement of powder X-ray diffraction data. Undoped RbZnF3 exhibited rod-like morphology in the transmission electron microscopic image. In addition to an intense band around 230 nm assignable to the charge transfer from ZnF3- to Rb+, typical transitions of respective dopant ions were observed in their UV-visible spectra. The doped samples showed luminescence in blue, green and red regions and time decay experiments suggested uniform dispersion of them without any clustering effect. The lower phonon energy of RbZnF3 matrix by virtue of the presence of heavier rubidium at the A-site together with its doping with rare-earth ions resulting in an inverse perovskite like arrangement could favour their utility in various practical applications. PMID- 29763828 TI - Combinatorial multispectral, thermodynamics, docking and site-directed mutagenesis reveal the cognitive characteristics of honey bee chemosensory protein to plant semiochemical. AB - In the chemoreceptive system of insects, there are always some soluble binding proteins, such as some antennal-specific chemosensory proteins (CSPs), which are abundantly distributed in the chemosensory sensillar lymph. The antennal-specific CSPs usually have strong capability to bind diverse semiochemicals, while the detailed interaction between CSPs and the semiochemicals remain unclear. Here, by means of the combinatorial multispectral, thermodynamics, docking and site directed mutagenesis, we detailedly interpreted a binding interaction between a plant semiochemical beta-ionone and antennal-specific CSP1 from the worker honey bee. Thermodynamic parameters (DeltaH < 0, DeltaS > 0) indicate that the interaction is mainly driven by hydrophobic forces and electrostatic interactions. Docking prediction results showed that there are two key amino acids, Phe44 and Gln63, may be involved in the interacting process of CSP1 to beta-ionone. In order to confirm the two key amino acids, site-directed mutagenesis were performed and the binding constant (KA) for two CSP1 mutant proteins was reduced by 60.82% and 46.80% compared to wild-type CSP1. The thermodynamic analysis of mutant proteins furtherly verified that Phe44 maintained an electrostatic interaction and Gln63 contributes hydrophobic and electrostatic forces. Our investigation initially elucidates the physicochemical mechanism of the interaction between antennal-special CSPs in insects including bees to plant semiochemicals, as well as the development of twice thermodynamic analysis (wild type and mutant proteins) combined with multispectral and site directed mutagenesis methods. PMID- 29763830 TI - Rare earth-doped barium gallo-germanate glasses and their near-infrared luminescence properties. AB - Near-infrared luminescence properties of Nd3+ and Ho3+ ions in barium gallo germanate glasses have been reported. Several spectroscopic parameters for Nd3+ and Ho3+ ions have been determined from the Judd-Ofelt analysis and absorption/luminescence measurements. Quite large luminescence lifetime, quantum efficiency and stimulated emission cross-section have been obtained for the main 4F3/2 -> 4I11/2 (Nd3+) and 5I7 -> 5I8 (Ho3+) laser transitions of rare earths in barium gallo-germanate glasses. It suggests that barium gallo-germanate glass is promising for near-infrared laser application at emission wavelengths 1064 nm (Nd3+) and 2020 nm (Ho3+). PMID- 29763831 TI - Patients' involvement in nursing students' clinical education: A scoping review. AB - BACKGROUND: Actual contacts with patients are crucial in developing the skills that students need when working with patients. Patients are accustomed to the presence of students. The concept of learning from patients has emerged recently, shifting the focus from learning from professionals as role models to the relationship between the student and patient. AIM: With focus on patients' perspective in clinical practice placements, this scoping review aims to review and summarize the existing empirical literature regarding patients' involvement in nursing students' clinical education. DESIGN AND METHOD: A broad search without time limitations was performed in the databases CINAHL, Medline, PsycINFO and ERIC. A manual search was also performed. Only empirical studies describing aspects of patient involvement in nursing education from the patient's perspective were taken into account. Thirty-two studies published from 1985 to June 2016 met the selection criteria and were analysed using inductive content analysis. RESULTS: The perspective of real patients focused on their role in students' learning and assessment processes. In general, patients appreciated the opportunity to contribute to a student's learning process and thus enhance the quality of patient care. However, the patients' approaches varied from active to passive participants, comprising active participants contributing to students' learning, followers of care and advice, and learning platforms with whom students practiced their skills. Some patients perceived themselves as active participants who facilitated students' learning by sharing knowledge and experience about their own care and wellbeing as well as assessed students' performance by providing encouraging feedback. CONCLUSION: The state and degrees of patient involvement in nursing students' clinical education were made explicit by the literature reviewed. However, the number of studies examining the involvement of real patients in students' education in clinical settings is very limited. To understand this untapped resource better and to promote its full realization, recommendations for nursing education and future research are made. PMID- 29763829 TI - Silver-loaded graphene as an effective SERS substrate for clotrimazole detection: DFT and spectroscopic studies. AB - Vibrational infrared, Raman and surface-enhanced Raman scattering (SERS) spectra of clotrimazole (CTZ) were documented and evaluated. Density-functional theory, B3LYP/6-311++G(d,p), approach was implemented to identify the possible conformations, develop the electrostatic potential map, evaluate frontier molecular orbitals and calculate the vibrational spectra of the target compound. The silver-loaded graphene was shown to be an effective SERS substrate for CTZ trace detection. The SERS spectrum showed two enhanced bands at 670 cm-1 and 700 cm-1 which confirmed the absorption of the silver substrate through chlorine and nitrogen atoms. A detection limit as low as 5 nM could be reached with a determination coefficient of 0.9988 using the band at 670 cm-1. The protein ligand interaction with Secreted Aspartic Proteinase 2 (SAP2) of C. albicans showed that the four stable forms of CTZ maintain a free energy of binding of 6-7 kcal/mol, which could give insights into the mode of action in treating Candidiasis. PMID- 29763833 TI - beta2-Adrenoceptor signalling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases. AB - Inhaled selective beta2-agonists are the most widely used treatment for obstructive airway diseases. The classical mechanism of action of these drugs is considered as their ability to activate beta2-adrenergic receptors (beta2-AR) on airway smooth muscle leading to G-protein activation and subsequent generation of c-AMP causing bronchodilation. However, there is now growing evidence to suggest that binding of beta2-agonists to beta2-AR is pleotropically coupled to many intracellular pathways whereby depending on the state of the beta2-AR when activated, a subset of different intracellular responses can be triggered. This is called biased agonism (or functional selectivity) and this type of activity has now been observed with different types of G protein-coupled receptor (GPCR), not just beta2-AR. Accordingly, drug efficacy for many agonists binding to GPCRs can no longer be solely described in terms of a single relationship between binding of a ligand to a receptor and the subsequent magnitude of the cellular response, but is often far more complex reflecting a specific complement of signals following binding of a ligand to its receptor. These differences in responses depending on what state the receptor is in when the ligand binds to it can subsequently influence the intracellular signalling that in turn can influence the efficacy of beta2-AR ligands. Such findings suggest that in the future it may be possible to develop new synthetic beta2-agonists that could preferentially confine their activity in stabilizing/activating the receptor to a certain conformation which could lead to improved drugs either to reduce adverse responses or to avoid drugs that activate certain conformations of the receptors that may lead to tolerance or desensitization following repeated activation. PMID- 29763832 TI - The impact of a pain assessment intervention on pain score and analgesic use in older nursing home residents with severe dementia: A cluster randomised controlled trial. AB - BACKGROUND: Pain is highly prevalent in older adults, especially those in institutional settings such as nursing homes. The presence of dementia may increase the risk of underdiagnosed and undertreated pain. Pain assessment tools are not regularly used in clinical practice, however, there are indications that the regular use of pain assessments tools may influence the recognition of pain by nursing staff and thereby affect pain management. OBJECTIVES: To assess whether regular pain assessment using a pain assessment tool is associated with changes in i) pain scores and ii) analgesic use in nursing home residents with severe dementia. DESIGN: Cluster-randomised controlled trial. SETTING: The study was conducted in 16 nursing homes in four counties in Norway. PARTICIPANTS: A total of 112 nursing home residents aged 65 years and older with dementia who lacked the capacity for self-reporting pain or were non-verbal. METHODS: The experimental group were regularly assessed pain with a standardised pain scale (the Doloplus-2) twice a week for a 12-week intervention period. The control group received usual care. The primary outcome was pain score measured with the Doloplus-2, and the secondary outcome was analgesic use (oral morphine equivalents and milligram/day paracetamol). Data on the outcomes were collected at baseline and at the end of week 12. The nursing staff in both the experimental and the control groups received training to collect the data. Linear mixed models were used to assess possible between-group difference over time. RESULTS: No overall effect of regular pain assessment was found on pain score or analgesic use. The mean score of Doloplus-2 and analgesic use remained unchanged and above the established cut-off in both groups. CONCLUSION: The current intervention did not change analgesic use or pain score compared with the control condition. However, there is not sufficient evidence to conclude that regular pain assessment using a pain assessment tool is not clinically relevant. Furthermore, our results indicated that pain continued to be inadequately treated in nursing home residents with severe dementia. Therefore, further research on how standardised pain assessment can be used to support effective pain management in this population is needed. PMID- 29763834 TI - Parkinsonism is associated to fronto-caudate disconnectivity and cognition in schizophrenia. AB - The present work studies the possible relation of parkinsonism and fronto-caudate dysconnectivity, as well as its relation to cognition in schizophrenia patients. We assessed parkinsonism using Simpson-Angus scale and prefronto-caudate connectivity using diffusion magnetic resonance in 22 schizophrenia patients (11 first-episodes) and 14 healthy controls. Fractional anisotropy was calculated for the white matter tracts directly linking rostral middle prefrontal (RMPF) and superior medial prefrontal (SMPF) regions with caudate nucleus. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia Scale (BACS). Total parkinsonism scores were negatively related to fractional anisotropy in the right SMPF-caudate tract in patients, which was also found in the first-episode patients alone, but not in controls. Parkinsonism was also inversely associated in patients to performance in social cognition, verbal memory, working memory and performance speed tests. In conclusion, our data support the involvement of fronto-striatal dysconnectivity in parkinsonism in schizophrenia. PMID- 29763835 TI - Predictors of reduced smoking quantity among recovering alcohol dependent men in a smoking cessation trial. AB - INTRODUCTION: Adults with alcohol dependence (AD) have exceptionally high smoking rates and poor smoking cessation outcomes. Discovery of factors that predict reduced smoking among AD smokers may help improve treatment. This study examined baseline predictors of smoking quantity among AD smokers in a pharmacotherapy trial for smoking cessation. METHODS: The sample includes male, AD smokers (N = 129) with 1-32 months of alcohol abstinence who participated in a 12-week trial of medication (topiramate vs. placebo) and adjunct counseling with 6 months of follow-up. Baseline measures of nicotine dependence, AD severity, psychopathology, motivation to quit smoking, and smoking-related cognitions were used to predict smoking quantity (cigarettes per day) at post-treatment and follow-up. RESULTS: Overall, the sample had statistically significant reductions in smoking quantity. Greater nicotine dependence (Incidence rate ratios (IRRs) = 0.82-0.90), motivation to quit (IRRs = 0.65-0.85), and intrinsic reasons for quitting (IRRs = 0.96-0.98) predicted fewer cigarettes/day. Conversely, greater lifetime AD severity (IRR = 1.02), depression severity (IRRs = 1.05-1.07), impulsivity (IRRs = 1.01-1.03), weight-control expectancies (IRRs = 1.10-1.15), and childhood sexual abuse (IRRs = 1.03-1.07) predicted more cigarettes/day. CONCLUSIONS: Smokers with AD can achieve large reductions in smoking quantity during treatment, and factors that predict smoking outcomes in the general population also predict greater smoking reductions in AD smokers. Treatment providers can use severity of nicotine dependence and AD, motivation to quit, smoking-related cognitions, and severity of depression to guide treatment and improve outcomes among AD smokers. PMID- 29763836 TI - Salicylic acid and nitric oxide alleviate high temperature induced oxidative damage in Lablab purpureus L plants by regulating bio-physical processes and DNA methylation. AB - Salicylic acid (SA) and sodium nitroprusside (SNP, NO donor) modulates plant growth and development processes and recent findings have also revealed their involvement in the regulation of epigenetic factors under stress condition. In the present study, some of these factors were comparatively studied in hyacinth bean plants subjected to high temperature (HT) environment (40-42 degrees C) with and without exogenous application of SA and SNP under field condition. Exogenous application of SA and SNP substantially modulated the growth and biophysical process of hyacinth bean plants under HT environment. Exogenous application of SA and SNP also remarkably regulated the activities of antioxidant enzymes, modulated mRNA level of certain enzymes, improves plant water relation, enhance photosynthesis and thereby increasing plant defence under HT. Coupled restriction enzyme digestion-random amplification (CRED-RA) technique revealed that many methylation changes were "dose dependent" and HT significantly increased DNA damages as evidenced by both increase and decrease in bands profiles, methylation and de-methylation pattern. Thus, the result of the present study clearly shows that exogenous SA and SNP regulates DNA methylation pattern, modulates stress-responsive genes and can impart transient HT tolerance by synchronizing growth and physiological acclimatization of plants, thus narrowing the gaps between physio-biochemical and molecular events in addressing HT tolerance. PMID- 29763837 TI - Different meteorological parameters influence metapneumovirus and respiratory syncytial virus activity. AB - BACKGROUND: Both human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) cause epidemics during the cold season in temperate climates. OBJECTIVES: The purpose of this study was to find out whether climatic factors are associated with RSV and hMPV epidemics. STUDY DESIGN: Our study was based on data from 4300 patients admitted to the Dijon University Hospital for acute respiratory infection (ARI) over three winter seasons chosen for their dissimilar meteorological and virological patterns. Cases of hMPV and RSV were correlated with meteorological parameters recorded in the Dijon area. The relationship between virus data and local meteorological conditions was analyzed by univariate and multivariate negative binomial regression analysis. RESULTS: RSV detection was inversely associated with temperature and positively with relative humidity and air pressure, whereas hMPV was inversely associated with temperature and positively with wind speed. CONCLUSIONS: The association among meteorological variables and weekly ARIs cases due to RSV and hMPV demonstrated the relevance of climate factors as contributors to both hMPV and RSV activities. Meteorological drivers of RSV and hMPV epidemics are different. Low temperatures influence both hMPV and RSV activity. Relative humidity is an important predictor of RSV activity, but it does not influence hMPV activity. PMID- 29763838 TI - The overweight increases circulating inflammatory mediators commonly associated with obesity in young individuals. AB - Obesity is a serious and growing world healthy problem affecting developed and developing countries. The new conception of obesity as a basal inflammatory condition has opened a new window of possibilities to identify inflammatory biomarkers to be used in the diagnosis or prognosis of obesity-associated comorbidities. This present work aims the identification of the adipokines (leptin and resistin), chemokines (CCL2, CCL5, CXCL16) and the BMP-2 and their association with the clinical, biochemical (fasting glucose, hemogram, cholesterol, T3, T4 and TSH) and anthropometric (weight, height, body circumferences, skinfold thickness and percentage of body fat) parameters in young adults (18-30 years old) presenting obesity and overweight. Our data showed increasing in anthropometric parameters and in the plasma inflammatory levels in those individuals presenting overweight and obesity. We observed a higher plasma levels of CCL2, CCL5, CXCL16, leptin and resistin in those overweigh and obese individuals. In addition, the CCL2, CCL5 presented a positive correlation with the body mass index and the body fat percentage. Assuming the obesity as a systemic inflammatory process, in this current study, the overweight individuals possess a close similar pattern of circulating inflammatory mediators which might be a potential risk of the development of obesity comorbidities. Further studies are still needed to precise the role of the biomarkers CCL2, CCL5, CXCL16 and BMP 2 in the clinical prognosis related to the overweight or obese individuals. PMID- 29763839 TI - Salivary fingerprint of simple obesity. AB - BACKGROUND: The nature of a link between poor oral health and obesity is not fully understood. It is also unclear if saliva contributes to it and whether the properties of saliva change as a result of an increase in body mass or rather as a consequence of obesity-associated comorbidities. This pilot study was undertaken in an attempt to determine if salivary biomarkers can identify obesity per se. METHODS: Whole mixed saliva was analysed for 16 soluble parameters covering 4 categories (inflammation, oxidative stress, endothelial dysfunction, adipokines). In the discovery group, 19 obese and 25 non-obese women matched for age, with similar hygiene habits, with no comorbidities and not taking any medication known to affect saliva secretion were analysed. In the validation group, a cohort of no-preselected 81 individuals (34 obese) were analysed. RESULTS: Individuals with obesity had significantly higher salivary concentrations of several cytokines and adipokines, of which TNF-R1, serpin A12 and PAI-1 were identified as parameters discriminating between obese and non obese subjects with the highest sensitivity and specificity. CONCLUSIONS: Obesity per se leads to distinct changes in the concentration of several parameters in saliva. These findings may have diagnostic implications for distinguishing the effects of obesity and obesity-linked comorbidities on oral health. PMID- 29763840 TI - The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm. AB - BACKGROUND: Interleukin (IL)-4 and IL-10 are viewed mainly as anti-inflammatory cytokines. Yet, high concentrations have also been associated with inflammation related diseases in newborns. METHODS: We measured the concentrations of IL-4 and IL-10, as well as IL-8 and ICAM-1 in blood specimens collected on postnatal day 21 (N = 555), day 28 (N = 521), and both days 21 and 28 (N = 449) from children born extremely preterm (EP) (<28 weeks gestation) who at age 10 years had a DAS II IQ Z-score > -2 (which approximates a score of >70) and the following assessments, CCC-2, and CSI-4, DAS-II, NEPSY-II, OWLS-II, SCQ, and WIAT-III. Selected children also were assessed with the ADI-R and the ADOS-2. We modeled the risk of low scores or dysfunctions associated with top quartile concentrations of IL-4 and IL-10 on each day and on both days. RESULTS: The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions. CONCLUSION: Among children born EP, those who had top quartile concentrations of IL-4 and/or IL-10 on postnatal days 21 and/or 28 were more likely than their peers to have low scores on components of the NEPSY-II, OWLS II, and WIAT-III assessments, as well as identification as having an ASD. What is known: What is not known: What this study adds. PMID- 29763841 TI - Nursing and midwifery students' perceptions of spirituality, spiritual care, and spiritual care competency: A prospective, longitudinal, correlational European study. AB - BACKGROUND: Nurses and midwives care for people at some of the most vulnerable moments of their lives, so it is essential that they have the skills to give care which is compassionate, dignified, holistic and person-centred. Holistic care includes spiritual care which is concerned with helping people whose beliefs, values and sense of meaning, purpose and connection is challenged by birth, illness or death. Spiritual care is expected of nurses/midwives but they feel least prepared for this part of their role. How nursing and midwifery students can be prepared for spiritual care is the focus of this study. OBJECTIVES: 1. To describe undergraduate nursing and midwifery student's perceptions of spirituality/spiritual care, their perceived competence in giving spiritual care and how these perceptions change over time. 2. To explore factors contributing to development of spiritual care competency. METHODS: Prospective, longitudinal, multinational, correlational survey design. A convenience sample of 2193 undergraduate nursing and midwifery students (69% response rate, dropping to 33%) enrolled at 21 universities in eight countries completed questionnaires capturing demographic data (purpose designed questionnaire) and measuring perception of spirituality/spiritual care (SSCRS), spiritual care competency (SCCS), spiritual wellbeing (JAREL) and spiritual attitude and involvement (SAIL) on 4 occasions (start of course n = 2193, year 2 n = 1182, year 3 n = 736, end of course n = 595) between 2011 and 2015. Data were analysed using descriptive, bivariate and multivariate analyses as appropriate. RESULTS: Perceived competency increased significantly over the course of students' study which they attributed to caring for patients, events in their own lives and teaching/discussion in university. Two factors were significantly correlated with perceived spiritual care competency: perception of spirituality/spiritual care, where a broad view was preferable, and personal spirituality, where high spiritual wellbeing (JAREL) and spiritual attitude and involvement (SAIL) scores were preferable. CONCLUSIONS: We have provided the first international evidence that perceived spiritual care competence is developed in undergraduate nursing and midwifery students and that students' perceptions of spirituality and personal spirituality contribute to that development. Implications for teaching and learning and student selection are discussed. The study is limited by attrition which is common in longitudinal research. PMID- 29763842 TI - Influences of the T102C polymorphism in the 5-HT2A receptor gene on the five factor model of Positive and Negative Syndrome Scale and treatment response to aripiprazole in patients with acute schizophrenia. PMID- 29763843 TI - Mutation analysis of the WNT7A gene in patients with schizophrenia. AB - Aberrant WNT signaling has been implicated in the pathophysiology of schizophrenia. WNT7A, a member of the WNT gene family, is considered a potential candidate of schizophrenia. All exons of WNT7A in 570 schizophrenic patients and 563 controls were sequenced, and protein functional analysis was conducted. Five common variants were identified, but none were noted to be associated with schizophrenia. Nevertheless, nine rare mutations, including one schizophrenia specific missense mutation (c.305G > A), were discovered. However, immunoblot analysis findings revealed that the c.305G > A mutation did not affect protein expression. These results suggest that WNT7A is unlikely to be associated with susceptibility to schizophrenia. PMID- 29763845 TI - Intellectual factors in false memories of patients with schizophrenia. AB - The current study explored the intellectual factors in false memories of 139 patients with schizophrenia, using a recognition task and an IQ test. The full scale IQ score of the participants ranged from 57 to 144 (M = 100, SD = 14). The full IQ score had a negative correlation with false recognition in patients with schizophrenia, and positive correlations with high-confidence true recognition and discrimination rates. Further analyses with the subtests' scores revealed that false recognition was negatively correlated with scores of performance IQ (and one of its subtests: picture arrangement), whereas true recognition was positively correlated with scores of verbal IQ (and two of its subtests: information and digit span). High-IQ patients had less false recognition (overall or high-confidence false recognition), more high-confidence true recognition, and higher discrimination abilities than those with low IQ. These findings contribute to a better understanding of the cognitive mechanism in false memory of patients with schizophrenia, and are of practical relevance to the evaluation of memory reliability in patients with different intellectual levels. PMID- 29763846 TI - NPAS3 exonic SNP genotype is linked to working memory performance in healthy young adults. PMID- 29763844 TI - Developing image sets for inducing obsessive-compulsive checking symptoms. AB - Visual stimuli are often used for obsessive-compulsive (OC) symptom provocation in research studies. We tested the induction of anxiety and OC checking symptoms across different types of checking provocation stimuli in three populations: individuals with obsessive compulsive disorder (OCD), individuals with checking symptoms but without a diagnosis of OCD, and control individuals with neither checking symptoms nor a clinical diagnosis. One set of provocative images depicted objects that are commonly associated with checking anxiety. Another set ('enhanced provocative images') depicted similar objects but also included contextual cues suggesting a specific harmful scenario that could occur. As expected, the enhanced provocative images were more effective at inducing anxiety and OC symptoms than the standard provocative images. Future studies requiring checking symptom provocation should therefore consider incorporating similarly suggestive images. Individuals with clinical OCD reported the greatest provocation in response to these images, followed by those with nonclinical checking, followed by control individuals. Thus, these stimuli are able to provoke OC checking symptoms and anxiety differentially across groups, with the intensity of provocation reflecting diagnostic status. All groups demonstrated a similar qualitative pattern of provocation across images. Finally, in all groups, reported anxiety closely tracked intrusive thoughts and checking urges. PMID- 29763847 TI - Race/ethnicity, psychological resilience, and social support among OEF/OIF combat veterans. AB - This study examined the relationship between race/ethnicity and psychological resilience, and the moderating role of social support in this relationship among non-Hispanic White (n = 605), Hispanic (n = 107), African American (n = 141), and Asian American (n = 97) Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) combat veterans. Veterans were primarily male (88%) with a mean age of 31.4 years (SD = 8.35). An analysis of covariance showed that Asian American veterans reported significantly lower psychological resilience than non-Hispanic White veterans. The interaction of race/ethnicity and social support with psychological resilience was examined via linear regression. We found that the relationship between psychological resilience and social support significantly differed by race/ethnicity such that social support was positively associated with psychological resilience among non-Hispanic White veterans, but not among other racial/ethnic groups. Our findings are consistent with previous studies that show Asian American veterans report lower psychological resilience than non Hispanic White veterans. Cultural differences in how and why individuals use social support may underlie racial/ethnic differences in the relationship between social support and psychological resilience. Future qualitative and quantitative research is encouraged to better understand how social support relates to psychological resilience among minority OEF/OIF combat veterans. PMID- 29763849 TI - Heart rate variability as candidate endophenotype of social anxiety: A two generation family study. AB - BACKGROUND: Social anxiety disorder (SAD) is the extreme fear and avoidance of one or more social situations. The goal of the current study was to investigate whether heart rate variability (HRV) during resting state and a social performance task (SPT) is a candidate endophenotype of SAD. METHODS: In this two generation family study, patients with SAD with their partner and children, and their siblings with partner and children took part in a SPT (total n = 121, 9 families, 3-30 persons per family, age range: 8-61 years, 17 patients with SAD). In this task, participants had to watch and evaluate the speech of a female peer, and had to give a similar speech. HRV was measured during two resting state phases, and during anticipation, speech and recovery phases of the SPT. We tested two criteria for endophenotypes: co-segregation with SAD within families and heritability. RESULTS: HRV did not co-segregate with SAD within families. Root mean square of successive differences during the first resting phase and recovery, and high frequency power during all phases of the task were heritable. LIMITATIONS: It should be noted that few participants were diagnosed with SAD. Results during the speech should be interpreted with caution, because the duration was short and there was a lot of movement. CONCLUSIONS: HRV during resting state and the SPT is a possible endophenotype, but not of SAD. As other studies have shown that HRV is related to different internalizing disorders, HRV might reflect a transdiagnostic genetic vulnerability for internalizing disorders. Future research should investigate which factors influence the development of psychopathology in persons with decreased HRV. PMID- 29763848 TI - Prevalence and correlates of adolescents' e-cigarette use frequency and dependence. AB - BACKGROUND: Understanding predictors of e-cigarette use among adolescents in the context of wide availability and extreme popularity of these products is important for prevention and treatment. This study identifies correlates of e cigarette use frequency and dependence among adolescent users. METHODS: Adolescent e-cigarette users (N = 173) were recruited from the San Francisco Bay Area. Participants reported demographic and psychosocial characteristics, e cigarette use behaviors, and cigarette use. Bivariate relationships between potential correlates were examined, and correlates significant at p < .10 were included in full models predicting frequency and dependence. RESULTS: In the full models, frequent use was associated with receiving one's first e-cigarette from a family member rather than a friend (r = -0.23, p < .001) or a store ( = -0.13, p = .037), using nicotine in all e-cigarettes versus some e-cigarettes (r = -0.17, p = .007) or unknown nicotine use (r = -0.15, p = .014), using a customizable device versus a Juul (r = -0.22, p < .001), vape pen (r = -0.20, p = .002), or other/unknown device (r = -0.16, p = .009), and friends' e-cigarette use (r = 0.20, p = .002). Dependence was associated with younger age of first use (r = 0.18, p = .012), friends' use (r = 0.18, p = .01), and recent cigarette use (r = 0.17, p = .019). CONCLUSIONS: When assessing problematic e-cigarette use among adolescents, it is important to consider social factors (e.g., friends' and family members' e-cigarette use), device type, and dual use with cigarettes. PMID- 29763850 TI - Laparoscopic surgery for a Bochdalek hernia triggered by pregnancy in an adult woman: A case report. AB - INTRODUCTION: A Bochdalek hernia (BH) is a type of congenital diaphragmatic hernia. We herein describe an adult woman with a BH triggered by pregnancy and treated by laparoscopic surgery. PRESENTATION OF CASE: A 26-year-old woman was referred to our hospital because of abdominal pain and dyspnea resulting from a left diaphragmatic hernia. She was diagnosed with a BH and underwent laparoscopic surgery. Her postoperative progress was satisfactory, and no recurrence was found at follow-up approximately 1 year later. DISCUSSION: A recently published study reviewing detailed cases of laparoscopic and/or thoracoscopic repair of adult BH from 1999 to 2016 identified 30 cases. A laparoscopic approach for treatment of BH has recently attracted increasing interest. CONCLUSION: Laparoscopic surgery can be safely performed on adults with BH without complications. PMID- 29763852 TI - Addiction in Pakistan -Time to be taken seriously? PMID- 29763851 TI - Pancreaticoduodenal arcades as salvage route for transarterial embolization of life-threatening hepatic hemorrhage in patients with severe celiac axis stenosis: Case series. AB - INTRODUCTION: Various transarterial embolotherapies for different hepatic etiologies are performed through the celiac axis (CA). However, this pathway is not always patent due to the extensive stenosis or occlusion of the origin of CA. In such situations, the pancreaticoduodenal arcades (PDAs) catheterization is the main alternative to gain access to the hepatic arteries as demonstrated in clinical studies. PRESENTATION OF CASE: We report two cases of life-threating hepatic hemorrhage indicated for emergency transarterial embolization (TAE). DISCUSSION: The massive hemorrhage was due to spontaneous rupture of hepatocellular carcinoma (HCC) in the first case and due to post liver blunt trauma in the second case. Owing to severe stenosis of the origin of CA, PDAs were used as a salvage alternative route for emergency TAE of hepatic arteries. CONCLUSION: Endovascular management of massive hepatic hemorrhage in cases of inaccessibility to hepatic arteries through CA is a highly challenging situation in which the technical success depends on the operator experience, choice of the material and anatomical knowledge of hepatic arterial collateral supply. PMID- 29763853 TI - Text mining and network analysis to find functional associations of genes in high altitude diseases. AB - BACKGROUND AND OBJECTIVES: Travel to elevations above 2500 m is associated with the risk of developing one or more forms of acute altitude illness such as acute mountain sickness (AMS), high altitude cerebral edema (HACE) or high altitude pulmonary edema (HAPE). Our work aims to identify the functional association of genes involved in high altitude diseases. METHOD: In this work we identified the gene networks responsible for high altitude diseases by using the principle of gene co-occurrence statistics from literature and network analysis. First, we mined the literature data from PubMed on high-altitude diseases, and extracted the co-occurring gene pairs. Next, based on their co-occurrence frequency, gene pairs were ranked. Finally, a gene association network was created using statistical measures to explore potential relationships. RESULTS: Network analysis results revealed that EPO, ACE, IL6 and TNF are the top five genes that were found to co-occur with 20 or more genes, while the association between EPAS1 and EGLN1 genes is strongly substantiated. CONCLUSION: The network constructed from this study proposes a large number of genes that work in-toto in high altitude conditions. Overall, the result provides a good reference for further study of the genetic relationships in high altitude diseases. PMID- 29763854 TI - Inhibition of pregnancy-associated granulocytic myeloid-derived suppressor cell expansion and arginase-1 production in preeclampsia. AB - Myeloid-derived suppressor cells (MDSCs) expand in maternal peripheral blood and cord blood during normal pregnancy to maintain maternal-fetal tolerance. Here we investigated the expansion and function of MDSCs in preeclampsia (PE) patients. Maternal peripheral blood mononuclear cells (PBMCs) and cord blood mononuclear cells (CBMCs) were sampled from healthy pregnant women and PE patients, and analyzed for the frequencies and phenotypes of MDSCs and T cells. Serum levels of key human MDSC effector enzymes were measured using appropriate detection kits. Peripheral blood samples of healthy non-pregnant women were used as controls. We found that normal pregnancy is associated with a significant increase of immunosuppressive MDSCs and regulatory T (Treg) cells. There was no significant difference in the frequency of Treg cells between normal pregnancies and PE patients, but the pregnancy-associated increase of granulocytic MDSCs (G-MDSCs), but not monocytic MDSCs (M-MDSCs), in both PBMCs and CBMCs was markedly inhibited in PE patients. Furthermore, serum levels of Arg-1, an important effector molecule for G-MDSC were significantly reduced in PE patients compared to healthy pregnant women. In conclusion, the lack of G-MDSC expansion is a most notable feature of PE-associated immune-cell alterations, suggesting that restoring G MDSCs may have the potential to treat PE. PMID- 29763855 TI - Identification of new phosphorylation sites of CD23 in B-cells of patients with chronic lymphocytic leukemia. AB - B-cell chronic lymphocytic leukemia (B-CLL) is the most common lymphoproliferative disorder in adults. Patients with B-CLL strongly express the CD23 - C type of lectin (low affinity IgE receptor, Fc epsilon RII), which is linked to B cell activation and proliferation. Phosphorylation in lymphocytes is tightly associated with regulation of protein activities, functional regulation and cell signaling, and may thus affect initiation and/or progression of the disease. Here we report changes in the phosphorylation of CD23 on threonine (pThr314) and two serine residues (pSer254, pSer265) in B lymphocytes of B-CLL patients, using a flow cytometry approach. The majority of tested patients with active forms of B-CLL presented a notable overexpression of CD23 along with pThr314, pSer254, and pSer265 CD23 phosphorylation positivity. Moreover, we have experimentally stimulated the CD23 phosphorylations in a subset of peripheral blood lymphocytes of healthy controls by phorbol-12-myristate-13-acetate treatment. This affects the activation of competent phosphorylation mediating kinases, resulting in the enhanced phosphorylation pattern. Together, these data confirm that CD23 protein is phosphorylated in B cells of B-CLL patients, report the identification of new CD23 phosphorylation sites, and suggest a possible role(s) of such phosphorylations in the activation of CD23 during the process of lymphocytic activation in B-CLL. PMID- 29763856 TI - Hospital readmission risks in older adults following inpatient subacute care: A six-month follow-up study. AB - BACKGROUND: High rates of unplanned hospital readmissions are a burden on healthcare systems and individuals. This study examined factors at, and after initial hospital discharge and their associations with unplanned hospital readmission for older adults up to six months post-discharge from subacute care. METHODS: Older subacute care patients were surveyed prior to discharge, and assessed monthly post-discharge for six months. Data included the Geriatric Depression Scale, Phone-Fitt sub-scales, Friendship Scale, modified Lubben Social Network Scale, unplanned hospital readmission, self-reported physical capacity and falls in the last month were collected. Regression analyses were used to examine relationships between unplanned hospital readmission and variables that may predispose this outcome. RESULTS: Participants (n = 311) completed the baseline assessment. N = 218 (70%) completed all at six-month post-discharge. Eighty-nine (29%) participants shared 143 readmissions. Those with cancer history (adjusted OR [95% CI]) (1.97 [1.15, 3.39]), neurological disease other than stroke (2.95 [1.32, 6.57]) and dependence on others to assist in bending tasks (1.94 [1.14, 3.29]) at initial discharge were associated with readmission within six months post-discharge. Those who fell in the last month (adjusted OR [robust 95% CI]) (2.28 [1.43, 3.64]), being less physical active (0.98 [0.96, 0.99]), and dependence on others in moving around residence (2.63 [1.37, 5.06]) after initial discharge were associated with a readmission in the next month within six months post-discharge. CONCLUSION: Trials investigating the effectiveness of strategies to reduce falls, build physical capacity, increase physical activity level, and connection with health care services after discharge to prevent readmission are warranted. PMID- 29763857 TI - The pillars of land plants: new insights into stem development. AB - In spite of its central importance in evolution, plant architecture and crop improvement, stem development remains poorly understood relative to other plant organs. Here, we summarise current knowledge of stem ontogenesis and its regulation, including insights from new image analysis and biophysical approaches. The stem initiates in the rib zone (RZ) of the shoot apical meristem, under transcriptional control by DELLA and BLH proteins. Links have emerged between these regulators and cell proliferation, patterning and oriented growth in the RZ. During subsequent internode elongation, cell wall properties and mechanics have been analysed in detail, revealing pectin modification as a prominent control point. Recent work has also highlighted signalling to coordinate growth of stem tissues with different mechanical properties. PMID- 29763859 TI - Negative parental attributions mediate associations between risk factors and dysfunctional parenting: A replication and extension. AB - The primary goal of the current study was to replicate our previous study in which was found that negative maternal attributions mediate the association between parenting stress and harsh and abusive discipline. In addition, we investigated this association in fathers, and added observational parenting data. During two home visits mothers and fathers were observed with their children (age 1.5-6.0 years), filled in questionnaires, and completed the Parental Attributions of Child behavior Task (PACT; a computerized attribution task). Similar to our previous study, negative parental attributions mediated the relation between parenting stress and self-reported harsh and abusive parenting for both mothers and fathers. For mothers, this mediation effect was also found in the relation between parenting stress and lower levels of observed supportive parenting in a challenging disciplinary task. In addition, the relation of partner-related stress and abuse risk with harsh, abusive, and (low) supportive parenting were also mediated by maternal negative attributions. When parenting stress, partner related stress, and abuse risk were studied in one model, only parenting stress remained significant. Results are discussed in terms of the importance of targeting parental attributions for prevention and intervention purposes in families experiencing stress. PMID- 29763858 TI - The oncologic impact of hormone replacement therapy in premenopausal breast cancer survivors: A systematic review. AB - SYNOPSIS: This is the first systematic review to investigate the risk of recurrence in breast cancer survivors <50 years old who have used hormone replacement therapy (HRT). BACKGROUND: The risk of HRT in premenopausal breast cancer survivors is unclear. Due to the higher incidence of estrogen receptor negative tumours in women <50, the potential for HRT to promote breast cancer recurrence may differ from older age groups. METHODS: We performed a search of Medline, EMBASE and CINAHL through June 2016. For the observational studies relative risk (RR) and 95% confidence interval (CI) were calculated for the recurrence rate among HRT users and nonusers. A random effects model was used to estimate the combined RR using the Mantel-Haenszel method. RESULTS: Four papers satisfied our inclusion criteria. 3477 subjects were analyzed. On pooled meta analysis of breast cancer recurrence in the observational studies, no significant association was found between HRT and risk of recurrence (RR 1.04 [95% CI 0.45, 2.41]). The randomized controlled trial (RCT) included found an increased risk of recurrence with HRT among women <50 (HR 1.56 [95% CI 1.1-2.2]). However, among women of all ages with an estrogen receptor negative tumour there was no significant difference in recurrence when compared to hormone receptor positive tumours (HR 1.15 [95% CI 0.7-1.8, p = 0.55]). DISCUSSION: This review on HRT in breast cancer survivors <50 revealed conflicting results between randomized and observational study data. Further studies are warranted to investigate the association between HRT and recurrence rates in younger breast cancer survivors. PMID- 29763860 TI - Ants and their nests as indicators for industrial heavy metal contamination. AB - Ants accumulate heavy metals and respond to pollution with modification in species composition, community structure, altered behaviour and immunity. However, the levels of heavy metals in ants' nests and explicit individual-level responses towards heavy metals have not been revealed. We found that red wood ants Formica lugubris accumulate high and correlated values of such heavy metals as Al, Cd, Co, Cu, Fe, Ni, Pb and Zn both in ants and nest material near cobalt smelter in Finland. Relative differences in metal concentrations were higher in nests than in ants. The highest values were obtained for elements such as Co (36.6), Zn (14.9), Cd (9.7), Pb (8.5), Cu (7.4), Ni (6.4), As (4.7), Cr (2.9) and Fe (2.4) in nest material, and Co (32.7), Cd (6.3), Pb (6), Fe (2.8), Ni (2.9) and Zn (2.1) in ants. In industrial and reference areas, ants have no differences in size, but differed in dry and residual body mass. In polluted areas, F. lugubris had less melanised heads, but not thoraxes. The sensitivity of cuticular colouration in red wood ants subjected to heavy metal pollution might be related to metal-binding properties of melanins. The overall results are useful for the improvement of biomonitoring techniques using ants as indicators of industrial contamination and for further discovery of novel ecotoxicological biomarkers. PMID- 29763861 TI - Source discrimination of atmospheric metal deposition by multi-metal isotopes in the Three Gorges Reservoir region, China. AB - Concentrations of heavy metals, as well as isotopic compositions of mercury (Hg) and lead (Pb), in mosses (Bryum argenteum) from the Three Gorges Reservoir (TGR) region were investigated to decipher the sources of atmospheric metals in this region. Higher contents of metals (0.90 +/- 0.65 mg/kg of Cd, 24.6 +/- 27.4 mg/kg of Cu, and 36.1 +/- 51.1 mg/kg of Pb) in the mosses from TGR were found compared with those from pollution-free regions. Principal component analysis (PCA) grouped the moss metals into four main components which were associated with both anthropogenic and natural sources. The ratios of Pb isotopes of the mosses (1.153 1.173 for 206Pb/207Pb and 2.094-2.129 for 208Pb/206Pb) fell between those of the traffic emissions and coals. Similarly, the compositions of delta202Hg (-4.29~ 2.330/00) and Delta199Hg (within +/-0.20/00) were comparable to those of the coals and coal combustion emissions from China and India. These joined results of Pb and Hg isotope data give solid evidences that the coal combustion and traffic emissions are the main causes of metal accumulation in the TGR region. PMID- 29763862 TI - Hydrogen peroxide treatment promotes chlorophytes over toxic cyanobacteria in a hyper-eutrophic aquaculture pond. AB - Controlling blooms of toxigenic phytoplankton, including cyanobacteria, is a high priority for managers of aquatic systems that are used for drinking water, recreation, and aquaculture production. Although a variety of treatment approaches exist, hydrogen peroxide (H2O2) has the potential to be an effective and ecofriendly algaecide given that this compound may select against cyanobacteria while not producing harmful residues. To broadly evaluate the effectiveness of H2O2 on toxigenic phytoplankton, we tested multiple concentrations of H2O2 on (1) four cyanobacterial cultures, including filamentous Anabaena, Cylindrospermopsis, and Planktothrix, and unicellular Microcystis, in a 5-day laboratory experiment and (2) a dense cyanobacterial bloom in a 7-day field experiment conducted in a nutrient-rich aquaculture pond. In the laboratory experiment, half-maximal effective concentrations (EC50) were similar for Anabaena, Cylindrospermopsis, and Planktothrix (average EC50 = 0.41 mg L-1) but were ~10x lower than observed for Microcystis (EC50 = 5.06 mg L-1). Results from a field experiment in an aquaculture pond showed that >=1.3 and >= 6.7 mg L-1 of H2O2 effectively eliminated Planktothrix and Microcystis, respectively. Moreover, 6.7 mg L-1 of H2O2 reduced microcystin and enhanced phytoplankton diversity, while causing relatively small negative effects on zooplankton abundance. In contrast, 20 mg L-1 of H2O2 showed the greatest negative effect on zooplankton. Our results demonstrate that H2O2 can be an effective, rapid algaecide for controlling toxigenic cyanobacteria when properly dosed. PMID- 29763864 TI - Residues, bioaccumulations and biomagnification of perfluoroalkyl acids (PFAAs) in aquatic animals from Lake Chaohu, China. AB - Residual levels of perfluoroalkyl acids (PFAAs) in seven species of aquatic animals were analyzed by liquid chromatography-mass spectrometry. The distribution, composition, bioaccumulation, and biomagnification of PFAAs and their effect factors were studied. The results showed that: 1) Wet weight concentrations of 17 PFAAs in the aquatic animals ranged from 1.77 to 38.65 ng/g, with a mean value of 12.71 +/- 9.21 ng/g. PFOS was the predominant contaminant (4.57 +/- 4.57 ng/g, 6.76%-46.25%), followed by PFDA (1.95 +/- 1.37 ng/g, 11.68% 21.25%) and PFUdA (1.84 +/- 1.21 ng/g, 9.73%-35.34%. 2) PFAA residual levels in Culter erythropterus (30.98 +/- 6.65 ng/g) were the highest, followed by Hemibarbus maculatus (16.79 +/- 1.88 ng/g), while the PFAA levels in Carassius auratus were the lowest (2.22 +/- 0.60 ng/g). 3) Biota-water bioaccumulation factors (BAFs), biota-suspended solid accumulation factors (BSSAFs) and biota sediment accumulation factors (BSAFs) ranged from 0.35 to 12,370.51, 7.77 to 8452.92 and 9.10 to 6984.61, respectively. Bioaccumulation by shrimp and snails was significantly affected by Kow. 4) Food web magnification factors were greater than 1, indicating that biomagnification of PFAAs occurs across trophic levels. The bioaccumulation and biomagnification of PFAAs were significantly correlated with carbon chain length. PMID- 29763865 TI - The impact of seasonal varied human activity on characteristics and sources of heavy metals in metropolitan road dusts. AB - Due to significant human activity, road dust is becoming contaminated by heavy metals in many cities. To comprehensively investigate the variation of contamination level and sources of heavy metals in road dust, 10 heavy metals in road dust samples from Beijing, China, in both summer and winter, were evaluated by spatial analysis using geographic information system (GIS) mapping technology and the positive matrix factorization (PMF) Model. Although the concentrations of some heavy metals between summer and winter had similarities, the differences of others and spatial distributions of heavy metals between summer and winter were considerable. The mean concentrations of As, Cd, Cr, Cu, and Fe were lower in winter, while those of Hg, Mn, Ni, Pb, and Zn were higher. According to the values of the Pollution Index (PI) and Nemerow Integrated Pollution Index (NIPI), there were no obvious differences between summer and winter, but the range between different sites in winter was nearly twice that of summer. Based on the PMF model, four sources of heavy metals in the dust samples were identified. Although the types of sources were consistent, the relative contributions of each source differed between summer and winter. Non-exhaust vehicle emissions was the most important source in summer (34.47 wt%), while fuel combustion contributed the largest proportion to the total heavy metals in winter (32.40 wt%). The impact of each source also showed spatial variation different trends in summer and winter. With the alteration of seasons, intensity of human activities also changed, such as the number of tourists, energy needs for building temperature regulation, construction, and the amount of pesticides and fertilizer. That might be the reason for the variation of heavy metal concentrations and relative contribution of their sources between summer and winter. PMID- 29763866 TI - Dynamics of vegetation autumn phenology and its response to multiple environmental factors from 1982 to 2012 on Qinghai-Tibetan Plateau in China. AB - Autumn phenological shifts induced by environmental change have resulted in substantial impacts on ecosystem processes. However, autumn phenology and its multiple related controlling factors have not been well studied. In this study, the spatiotemporal patterns of the end date of the vegetation growing season (EGS) and their multiple controls (climate change, summer vegetation growth and human activities) over the Qinghai-Tibetan Plateau (QTP) were investigated using the satellite-derived normalized difference vegetation index (NDVI) based on GIMMS3g datasets during 1982-2012. The results showed that there was no significant temporal trend in the EGS during the period of 1982-2012. Spatially, there was a notable advancing trend in the southwest region and a delayed trend in the other regions of the QTP during 1982-2000, and this spatial trend was reversed during 2001-2012. We found average temperature, precipitation and sunshine duration of autumn exerted positive effects on EGS on the QTP, while average temperature and sunshine duration of summer exerted negative effects. Our results indicated that vegetation growth in summer tends to induce an earlier EGS in alpine vegetation, whereas summer vegetation degradation could delay the EGS on the QTP. In contrast, moderate grazing delays vegetation browning in autumn, while overgrazing leads to advancement of grass senescence. This study improves our understanding of how multiple environmental variables jointly affect autumn phenology and highlights the importance of biotic controls for autumn phenology on the QTP. PMID- 29763867 TI - Shiga toxigenic Escherichia coli incidence is related to small area variation in cattle density in a region in Ireland. AB - Shiga toxigenic Escherichia coli (STEC) are pathogenic E. coli that cause infectious diarrhoea. In some cases infection may be complicated by renal failure and death. The incidence of human infection with STEC in Ireland is the highest in Europe. The objective of the study was to examine the spatial incidence of human STEC infection in a region of Ireland with significantly higher rates of STEC incidence than the national average and to identify possible risk factors of STEC incidence at area level. Anonymised laboratory records (n = 379) from 2009 to 2015 were obtained from laboratories serving three counties in the West of Ireland. Data included location and sample date. Population and electoral division (ED) data were obtained from the Irish 2011 Census of Population. STEC incidence was calculated for each ED (n = 498) and used to map hotspots/coldspots using the Getis-Ord Gi* spatial statistic and significant spatial clustering using the Anselin's Local Moran's I statistic. Multivariable regression analysis was used to consider the importance of a number of potential predictors of STEC incidence. Incidence rates for the seven-year period ranged from 0 to 10.9 cases per 1000. A number of areas with significant local clustering of STEC incidence as well as variation in the spatial distribution of the two main serogroups associated with disease in the region i.e. O26 and O157 were identified. Cattle density was found to be a statistically significant predictor of STEC in the region. GIS analysis of routine data indicates that cattle density is associated STEC infection in this high incidence region. This finding points to the importance of agricultural practices for human health and the importance of a "one-health" approach to public policy in relation to agriculture, health and environment. PMID- 29763863 TI - Environmental tin exposure in a nationally representative sample of U.S. adults and children: The National Health and Nutrition Examination Survey 2011-2014. AB - : Tin is a naturally occurring heavy metal that occurs in the environment in both inorganic and organic forms. Human exposure to tin is almost ubiquitous; however, surprisingly little is known about factors affecting environmental tin exposure in humans. This study analyzed demographic, socioeconomic and lifestyle factors associated with total urinary tin levels in adults (N = 3522) and children (N = 1641) participating in the National Health and Nutrition Examination Survey (NHANES) 2011-2014, a nationally representative health survey in the United States. Urinary tin levels, a commonly used biomarker of environmental tin exposure, were determined by inductively coupled plasma mass spectrometry (ICP MS). Detection frequencies of tin were 87.05% in adults and 91.29% in children. Median and geometric mean levels of urinary tin in the adult population were 0.42 MUg/L and 0.49 MUg/L, respectively. For children, median and geometric mean levels of urinary tin were 0.60 MUg/L and 0.66 MUg/L, respectively. Age was identified as an important factor associated with urinary tin levels. Median tin levels in the >=60 year age group were almost 2-fold higher than the 20-39 year age group. Tin levels in children were 2-fold higher than in adolescents. Race/ethnicity and household income were associated with tin levels in both adults and children. In addition, physical activity was inversely associated with urinary tin levels in adults. These results demonstrate that total tin exposures vary across different segments of the general U.S. POPULATION: Because the present study does not distinguish between organic and inorganic forms of tin, further studies are needed to better characterize modifiable factors associated with exposures to specific tin compounds, with the goal of reducing the overall exposure of the U.S. POPULATION: PMID- 29763868 TI - The concentrations and cumulative risk assessment of phthalates in general population from Shanghai: The comparison between groups with different ages. AB - Phthalates are predominantly used as plasticizers in daily consumer products. People are regularly exposed to phthalates through contact with these products. Phthalates are suspected to cause adverse effects in general population. We detected 10 metabolites of 6 phthalates in 3348 urine samples of general population (infants (0-1 yr), children and adolescents (2-19 yr), adults (>=20 yr), and pregnant women) from Shanghai. The Daily intake for phthalates was estimated based on the levels of urinary metabolites. Hazard quotient (HQ) was used to evaluate the risk from the exposure to a single chemical. For the cumulative risk calculation, HQs of different phthalates were added to produce the Hazard index (HI). Overall, exposure was low in adults but presented at a relatively high level throughout childhood. The exposure to some specific phthalates was high in infants and pregnant women. The cumulative risk assessment showed cause for concern mainly for infants and children subgroups. The results indicated that general population from Shanghai was widely exposed to phthalates and the infants were possibly at a high risk of cumulative exposure to phthalates. PMID- 29763869 TI - Exposure of dioxin-like chemicals in participants of the Anniston community health survey follow-up. AB - : The 2014 follow-up of the Anniston Community Health Survey (ACHS II) consisted of 338 surviving participants from the 2005-2007 baseline study (ACHS) who had previous polychlorinated biphenyl (PCB) measurements, were not pregnant, and were not institutionalized. Questionnaires and blood samples provided the demographic, personal history, and chemical concentration data of the Anniston residents. Approximately 51% of participants were African American, 72% were female, and the mean age was 63 years old. The objectives of this study were to provide an exposure assessment of dioxin-like chemicals in the ACHS II participants and compare the measurements with the general United States (U.S.) population via the National Health and Nutrition Examination Survey (NHANES). Stratified analyses revealed significantly higher average total dioxin toxic equivalencies (TEQs) among African Americans compared to Whites (33.1 vs. 19.2 pg/g lipid), and in females compared to males (29.8 vs. 17.0 pg/g lipid). When adjusting for age, sex, and race in linear regression, we found ACHS II participants to have significantly higher total dioxin TEQ than the general 2014 U.S. population that we estimated for using half-life and NHANES 2003/04 data (most recent NHANES individual samples data), by 16.7 pg/g lipid. Principal component analyses showed that non-ortho and mono-ortho PCBs were separated from the other dioxin-like chemicals among the Anniston residents, whereas the chemicals were all clustered together for estimated NHANES 2014. The concentrations of dioxin-like chemicals, especially non-ortho and mono-ortho PCBs, in Anniston residents who resided near the former PCB production plant were higher than those in the general U.S. POPULATION: Although data strongly supported this difference, these inferences are limited because NHANES 2013/14 data were unavailable and we used estimated NHANES 2014 levels that we imputed from NHANES 2003/04 data in conjunction with half-life values estimated from Milbrath et al., 2009. PMID- 29763870 TI - The dissipation and microbial ecotoxicity of tebuconazole and its transformation products in soil under standard laboratory and simulated winter conditions. AB - Tebuconazole (TBZ) is a widely used triazole fungicide at EU level on cereals and vines. It is relatively persistent in soil where it is transformed to various transformation products (TPs) which might be environmentally relevant. We assessed the dissipation of TBZ in soil under contrasting incubation conditions (standard vs winter simulated) that are relevant to its application scheme, determined its transformation pathway using advanced analytical tools and 14C labeled TBZ and assessed its soil microbial toxicity. Mineralization of 14C triazole-ring-labeled TBZ was negligible but up to 11% of 14C-penyl-ring-labeled TBZ evolved as 14CO2 within 150 days of incubation. TBZ persistence increased at higher dose rates (*10 compared to the recommended agronomical dose *1) and under winter simulated conditions compared to standard incubation conditions (at *1 dose rate DT50 of 202 and 88 days, respectively). Non-target suspect screening enabled the detection of 22 TPs of TBZ, among which 17 were unknown. Mass spectrometry analysis led to the identification of 1-(4-chlorophenyl) ethanone, a novel TP of TBZ, the formation of which and decay in soil was determined by gas chromatography mass spectrometry. Three hypothetical transformation pathways of TBZ, all converging to 1H-1,2,4-triazole are proposed based on suspect screening. The ecotoxicological effect of TBZ and of its TPs was assessed by measuring by qPCR the abundance of the total bacteria and the relative abundance of 11 prokaryotic taxa and 4 functional groups. A transient impact of TBZ on the relative abundance of all prokaryotic taxa (except alpha-proteobacteria and Bacteroidetes) and one functional microbial group (pcaH-carrying microorganisms) was observed. However the direction of the effect (positive or negative) varied, and in certain cases, depended on the incubation conditions. Proteobacteria was the most responsive phylum to TBZ with recovery observed 20 days after treatment. The ecotoxicological effects on the soil microorganisms were not correlated with 1-(4-chlorophenyl) ethanone. PMID- 29763871 TI - Simulating climate change and socio-economic change impacts on flows and water quality in the Mahanadi River system, India. AB - Delta systems formed by the deposition of sediments at the mouths of large catchments are vulnerable to sea level rise and other climate change impacts. Deltas often have some of the highest population densities in the world and the Mahanadi Delta in India is one of these, with a population of 39 million. The Mahanadi River is a major river in East Central India and flows through Chattisgarh and Orissa states before discharging into the Bay of Bengal. This study uses an Integrated Catchment Model (INCA) to simulate flow dynamics and water quality (nitrogen and phosphorus) and to analyze the impacts of climate change and socio-economic drivers in the Mahanadi River system. Future flows affected by large population growth, effluent discharge increases and changes in irrigation water demand from changing land uses are assessed under shared socio economic pathways (SSPs). Model results indicate a significant increase in monsoon flows under the future climates at 2050s (2041-2060) and 2090s (2079 2098) which greatly enhances flood potential. The water availability under low flow conditions will be worsened because of increased water demand from population growth and increased irrigation in the future. Decreased concentrations of nitrogen and phosphorus are expected due to increased flow hence dilution. Socio-economic scenarios have a significant impact on water quality but less impact on the river flow. For example, higher population growth, increased sewage treatment discharges, land use change and enhanced atmospheric deposition would result in the deterioration of water quality, while the upgrade of the sewage treatment works lead to improved water quality. In summary, socio economic scenarios would change future water quality of the Mahanadi River and alter nutrient fluxes transported into the delta region. This study has serious implications for people's livelihoods in the deltaic area and could impact coastal and Bay of Bengal water ecology. PMID- 29763872 TI - Effect of compost application on the dynamics of carbon in a nectarine orchard ecosystem. AB - The aim of the present study was to compare the quantity and the type of carbon (C) stored during the 14-year lifetime of a commercial nectarine orchard ecosystem fertilized with mineral or organic fertilizers. The study was carried out in the Po valley, Italy, in a nectarine orchard of the variety Stark RedGold, grafted on GF677 hybrid peach * almond. Since orchard planting in August 2001, the following treatments were applied in a randomized complete block design with four replicates per block and compared: 1. unfertilized control; 2. mineral fertilization (including P and K at planting and N applied as NO3NH4 yearly at the rate of 70-130 kg ha-1); 3. compost application at a rate of 5 Mg DW ha-1 yr 1; 4. compost application at a rate of 10 Mg DW ha-1 yr-1. Compost was obtained from domestic organic wastes mixed with pruning material from urban ornamental trees and garden management after a 3-month stabilization period. Application of compost at the highest rate increased C in the soil; the amount of C sequestered was approximately 60% from amendment source and 40% from the net primary production of trees and grasses with a net increase of C compared to mineral fertilization. Compost application was found to be a win-win strategy to increase C storage in soil and, at the same time, to promote plant growth and yield to levels similar to those obtained with mineral fertilization. The rate of C application is crucial, indicated by the fact that compost supply at the rate of 10 Mg ha-1 yr-1 was the only fertilization strategy of the ones tested that resulted in higher C sequestration. This shows that compost amendment may stimulate an increase in the net primary production of plants. PMID- 29763873 TI - Estimates of abundance and diversity of Shewanella genus in natural and engineered aqueous environments with newly designed primers. AB - Shewanella species have a diverse respiratory ability and wide distribution in environments and play an important role in bioremediation and the biogeochemical cycles of elements. Primers with more accuracy and broader coverage are required with consideration of the increasing number of Shewanella species and evaluation of their roles in various environments. In this work, a new primer set of 640F/815R was developed to quantify the abundance of Shewanella species in natural and engineered environments. In silico tools for primer evaluation, quantitative polymerase chain reaction (qPCR) and clone library results showed that 640F/815R had a higher specificity and coverage than the previous primers in quantitative analysis of Shewanella. Another newly developed primer pair of 211F/815cR was also adopted to analyze the Shewanella diversity and demonstrated to be the best candidate in terms of specificity and coverage. We detected more Shewanella-related species in freshwater environments and found them to be substantially different from those in marine environments. Abundance and diversity of Shewanella species in wastewater treatment plants were largely affected by the process and operating conditions. Overall, this study suggests that investigations of abundance and diversity of Shewanella in various environments are of great importance to evaluate their ecophysiology and potential ecological roles. PMID- 29763874 TI - Corrigendum to "Assessing drivers of benthic macroinvertebrate community structure in African highlands: an exploration using multivariate analysis" [Sci. Total Environ. 601-602 (2017) 1340-1348]. PMID- 29763875 TI - Green zero valent iron nanoparticles dispersion through a sandy column using different injection sequences. AB - The contamination of soils is a global environmental problem that urges an increased effort to recover polluted sites. In Europe, there are an estimated 20,000 polluted sites that need to be remediated and around 350,000 sites that are classified as potentially contaminated by the European Environment Agency (EEA). Remediation is a part of the solution to this problem, requiring the most innovative and sustainable technologies. In this context, the use of zero valent iron nanoparticles (nZVI) is a promising, low cost and efficient technology for the remediation of soil and groundwater contaminated with a wide range of organic and inorganic pollutants. Among the nZVIs, the ones produced using Green synthesis methods (green nZVIs (gnZVI)) using natural extracts, such as green tea, are increasingly considered an alternative technology for the future. However, there are issues related to the application of gnZVI in soil that are still not fully understood, requiring further research, among these is the study of their transport in soils. Therefore, this work aims to study the transport of gnZVIs in sandy soils under diverse conditions such as soil particle size, soil saturation level and injection sequence. Several experiments were performed in an acrylic column with two sandy soils with different particle sizes (between 0.5 and 1.0 mm and higher than 1.0 mm), using two distinct water saturation conditions (saturated and dry) and four injection sequences. After these tests the distribution of the gnZVI along the soil column was determined by atomic absorption spectroscopy. This work allowed concluding that the injection sequence might be one of the most important factors influencing the rate of nZVI dispersion through a sandy column. According to the results it was possible to propose, for distinct types of contamination (deep, superficial, hot spot or dispersed), the most appropriate injection sequence. PMID- 29763876 TI - Mercury wet deposition and speciated mercury air concentrations at rural and urban sites across New York state: Temporal patterns, sources and scavenging coefficients. AB - Measurements of ambient speciated mercury (Hg) concentrations and Hg wet deposition were made at two urban sites (Bronx, NY and Rochester, NY) and one rural site (Potsdam, NY) in New York State in 2013 and 2014 to: 1) determine the factors influencing Hg wet deposition concentrations, 2) identify the contribution of gaseous oxidized Hg (GOM) and particulate bound Hg (PBM) scavenging to Hg wet deposition concentrations, and 3) identify potential source areas associated with high concentration events. The Bronx had the highest mean gaseous elemental Hg (GEM) and GOM concentrations, Rochester had the highest mean PBM and the lowest GOM concentrations, and Potsdam had the lowest mean GEM and PBM concentrations. The annual volume weighted mean (VWM) Hg concentrations and Hg wet deposition fluxes in the Bronx, Rochester, and Potsdam were significantly different with mean values of 10.3 +/- 8.16, 10.2 +/- 9.06, and 5.07 +/- 1.79 ngL 1 and 8.45 +/- 0.64, 6.65 +/- 0.21, and 5.25 +/- 0.49 MUg/m2 year-1, respectively. Hg wet deposition flux and precipitation depth were positively correlated at all three sites as were Hg concentration in precipitation and weekly GOM concentrations at the Bronx and Potsdam sites. Scavenging coefficients (SC) of 680, 630, 850 for GOM and 410, 320, and 410 for PBM at Bronx, Rochester, and Potsdam, respectively, suggest GOM is responsible for most of the scavenged Hg. Measured GOM and PBM concentrations were relatively constant before precipitation events and Hg concentrations in precipitation did not vary significantly during precipitation events implying the scavenging process mainly occurred in clouds. VWM Hg concentrations, monthly accumulated Hg flux, and SCs for GOM and PBM were higher at the urban sites and significantly different for non-snow and snow events. Local sources appeared more important at the rural site while regional sources affected high urban concentrations. PMID- 29763877 TI - Impacts and responses to environmental change in coastal livelihoods of south west Bangladesh. AB - Aquatic ecosystems are of global importance for maintaining high levels of biodiversity and ecosystem services, and for the number of livelihoods dependent on them. In Bangladesh, coastal and delta communities rely on these systems for a livelihood, and the sustainability of the productivity is seriously threatened by both climate change and unsustainable management. These multiple drivers of change shape the livelihood dependence and adaptation responses, where a better understanding is needed to achieve sustainable management in these systems, while maintaining and improving dependent livelihoods. This need has been addressed in this study in the region of Satkhira, in the southwest coast of Bangladesh, where livelihoods are highly dependent on aquatic systems for food supply and income. Traditional wild fish harvest in the rivers and aquaculture systems, including ghers, ponds, and crab points have been changing in terms of the uses and intensity of management, and suffering from climate change impacts as well. By means of six focus groups with 50 participants total, and validated by expert consultations, we conduct an analysis to understand the main perceived impacts from climate and human activities; and the adaptation responses from the aquatic system livelihoods. We find that biodiversity has decreased drastically, while farmed species have increased and shrimp gher farming turned more intensive becoming the main source of income. All these changes have important implications for food supply in the region and environmental sustainability. Dramatic responses taken in the communities include exit the fisheries and migration, and more adaptive responses include species diversification, crab fattening and working more on the pond and gher infrastructure. This study evidences the results of the combination of multiple stressors in productive systems and the barriers to adaptation in aquatic ecosystem dependent communities. PMID- 29763878 TI - Ca-containing amendments to reduce the absorption and translocation of Pb in rice plants. AB - The influence of three Ca-containing amendments (dolomite, slaked lime, and limestone) on soil water soluble Pb (Pb-w) levels, Pb accumulation by two rice plants (TJ-8, japonica and II-3301, indica), and the factors affecting Pb-w were investigated. Pot experiment was performed under waterlogged conditions using Pb contaminated soil collected from an agricultural field near a mine. It was found that the soil amendments significantly reduced Pb content in the rice plants in the order dolomite > slaked lime > limestone, irrespective of rice cultivar. The Pb content of brown rice with the added soil amendments was lower than that of the recommended limit (0.2 mg kg-1, GB2762-2017) except for cultivar II-3301 with slaked lime. There was a significant positive correlation between the Pb content of the roots, stems, leaves, and grains and the soil Pb-w levels. The amendments reduced soil Eh, Fe, and Mn concentrations in the pore water and increased soil pH. The total organic carbon (TOC) in the pore water significantly decreased for II-3301 but not for TJ-8 at the ripening stage after addition of the amendments. Among soil Eh, pH, TOC, Fe, and Mn in the pore water, Fe and Mn were the most influential in lowering soil Pb-w levels. The amendments inhibited the formation of iron plaques on the root surface and reduced Pb adsorption. The Pb content of the roots was positively correlated with that in iron plaque. These findings are significant as they imply that the application of Ca-containing amendments in Pb contaminated paddy soils near mines is an effective approach for in situ immobilization of Pb and reduction in Pb levels in the edible parts of crops. PMID- 29763879 TI - Plant and vegetation functional responses to cumulative high nitrogen deposition in rear-edge heathlands. AB - Elevated atmospheric nitrogen (N) deposition is a major driver of change, altering the structure/functioning of nutrient-poor Calluna vulgaris-heathlands over Europe. These effects amply proven for north-western/central heathlands may, however, vary across the ecosystem's distribution, especially at the range limits, as heathlands are highly vulnerable to land-use changes combined with present climate change. This is an often overlooked and greatly understudied aspect of the ecology of heathlands facing global change. We investigated the effects of five N-fertilisation treatments simulating a range of N deposition rates (0, 10, 20, and 50 kg N ha-1 yr-1 for 1 year; and 56 kg N ha-1 yr-1 for 9 years) on the Calluna-plants, the plant functional groups, species composition and richness of two life-cycle stages (building/young- and mature-phase) of Calluna-heathlands at their rear-edge limit. Our findings revealed a dose-related response of the shoot length and number of flowers of young and mature Calluna plants to the addition of N, adhering to the findings from other heathland locations. However, cumulative high-N loading reduced the annual growth and flowering of young plants, showing early signs of N saturation. The different plant functional groups showed contrasting responses to the cumulative addition of N: annual/perennial forbs and annual graminoids increased with quite low values; perennial graminoids were rather abundant in young heathlands but only slightly augmented in mature ones; while bryophytes and lichens strongly declined at the two heathland life-cycle stages. Meanwhile there were no significant N driven changes in plant species composition and richness. Our results demonstrated that Calluna-heathlands at their low-latitude distribution limit are moderately resistant to cumulative high-N loading. As north-western/central European heathlands under high-N inputs broadly experienced the loss of plant diversity and pronounced changes in plant species dominance, rear-edge locations may be of critical importance to unravel the mechanisms of heathland resilience to future global change. PMID- 29763880 TI - Anti-neuroinflammatory effects of 20C from Gastrodia elata via regulating autophagy in LPS-activated BV-2 cells through MAPKs and TLR4/Akt/mTOR signaling pathways. AB - 20C, a novel bibenzyl compound, is isolated from Gastrodia elata. In our previous study, 20C showed protective effects on tunicamycin-induced endoplasmic reticulum stress, rotenone-induced apoptosis and rotenone-induced oxidative damage. However, the anti-neuroinflammatory effect of 20C is still with limited acquaintance. The objective of this study was to confirm the anti neuroinflammatory effect of 20C on Lipopolysaccharide (LPS)-activated BV-2 cells and further elucidated the underlying molecular mechanisms. In this study, 20C significantly attenuated the protein levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin (IL)-1beta, and secretion of nitric oxide (NO) and tumor necrosis factor (TNF)-alpha induced by Lipopolysaccharide (LPS) in BV-2 cells. Moreover, 20C up-regulated the levels of autophagy-related proteins in LPS-activated BV-2 cells. The requirement of mitogen-activated protein kinases (MAPKs) has been well documented for regulating the process of autophagy. Both 20C and rapamycin enhanced autophagy by suppressing the phosphorylation of MAPKs signaling pathway. Furthermore, 20C treatment significantly inhibited the levels of toll like receptor 4 (TLR4), phosphorylated protein kinase B (Akt) and phosphorylated-mechanistic target of rapamycin (mTOR), indicating blocking TLR4/Akt/mTOR might be an underlying basis for the anti inflammatory effect of 20C. These findings suggest that 20C has therapeutic potential for treating neurodegenerative diseases in the future. PMID- 29763881 TI - Orally administered brown seaweed-derived beta-glucan effectively restrained development of gastric dysplasia in A4gnt KO mice that spontaneously develop gastric adenocarcinoma. AB - beta-Glucan refers to a heterogeneous group of chemically defined storage polysaccharides containing beta-(1,3)-d-linked glucose polymers with branches connected by either beta-(1,4) or beta-(1,6) glycosidic linkage. To date, an extensive amount of scientific evidence supports their multifunctional biological activities, but their potential involvement in the progression of premalignant lesions remains to be clarified. A4gnt KO mice that lack alpha1,4-N acetylglucosamine-capped O-glycans in gastric gland mucin are a unique animal model for gastric cancer because the mutant mice spontaneously develop gastric cancer through hyperplasia-dysplasia-adenocarcinoma sequence. In particular, A4gnt KO mice show gastric dysplasia during 10-20 weeks of age. Here we investigated the putative gastro-protective activity of brown seaweed-derived beta-glucan (Laminaran) against development of gastric dysplasia, precancerous lesion for gastric cancer in A4gnt KO mice. The mutant mice at 12 weeks of age were randomly assigned into three treatment groups namely, wildtype control + distilled water (normal control), A4gnt KO mice + distilled water (untreated control), and A4gnt KO mice + 100 mg/kg Laminaran. After 3 weeks, the stomach was removed and examined for morphology and gene expression patterns. In contrast to the untreated control group, administration of Laminaran substantially attenuated gastric dysplasia development and counterbalanced the increased induction in cell proliferation and angiogenesis. Furthermore, Laminaran treatment effectively overcame the A4gnt KO-induced alteration in the gene expression profile of selected cytokines as revealed by real-time PCR analysis. Collectively, our present findings indicate that beta-glucan can potentially restrain the development of gastric dysplasia to mediate their tissue-preserving activity. PMID- 29763882 TI - Thymoquinone influences the expression of genes involved in self-renewal and immunomodulatory potential of mouse bone marrow-derived mesenchymal stem cells in vitro. AB - Thymoquinone (TQ) is an active ingredient of some medicinal herbs. Despite extensive studies on the biological and pharmacological properties of TQ, its effect on the characteristics of stem cells remains to be clarified. Therefore, this study was aimed to investigate the effect of TQ on viability, proliferation and immunomodulatory potential of mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) in vitro. The BM-MSCs were isolated from young NMRI mice. The cytotoxic effect of TQ on the BM-MSCs was evaluated using MTT assay. Then, the effect of TQ on the proliferation of BM-MSCs and the mRNA expression of genes involved in self-renewal and immunomodulatory potential of MSCs was assessed by the cell counting and real-time PCR assays. Results showed that TQ reduces the number of BM-MSCs in a dose- and time-dependent manner. In addition, the half maximal inhibitory concentration values of TQ on the BM-MSCs were 8 MUg/ml at 24h and 4 MUg/ml at 48 and 72h after treatment. Furthermore, about 90% of the BM-MSCs were alive after treatment with concentrations <=2 MUg/ml of TQ for 24h. The results of cell counting assay indicated that TQ at concentrations of 1-2 MUg/ml significantly enhanced the proliferation of BM-MSCs (P < 0.05). The gene expression analysis also showed that Tlr3, Tlr4, Ccl2, Ccl3, Sox2, and Rex1 are overexpressed (Fold change >=1.5) in the TQ-treated BM-MSCs compared with the untreated samples. In conclusion, these findings propose that TQ may regulate self-renewal and immunomodulatory potential of MSCs. However, the exact mechanisms and the roles of this regulation are required to be elucidated in further study. PMID- 29763883 TI - Impact of common environmental chemicals bisphenol A and bisphenol S on the physiology of Lumbriculus variegatus. AB - Bisphenol A (BPA) is a component of polycarbonate plastics and a near ubiquitous environmental endocrine disrupting chemical. Bisphenol S (BPS), a substitute of BPA, is also hormonally active. This study examines the effects of aqueous exposure to BPA and BPS on the freshwater annelids Lumbriculus variegatus, a keystone species in shallow water ecosystems. Both BPA and BPS, at both low dose (10-9 M) and high dose (10-6 M), retarded the initial phase of body regrowth after cutting/fragmentation, which is the main mode of reproduction of L. variegatus. Both acute and five day exposure to BPA and BPS increased pulse rate of the dorsal blood vessel. For all the measured endpoints, the effects of BPA and BPS were nearly indistinguishable. These results indicate that BPA and BPS have similar and significant effects on the physiology of L. variegatus. These findings have implication for the potential impact of these bisphenols on invertebrates in the ecosystem. PMID- 29763885 TI - Intrauterine Growth Restriction Affects Cerebellar Granule Cells in the Developing Guinea Pig Brain. AB - Intrauterine growth restriction (IUGR) can lead to adverse neurodevelopmental sequelae in postnatal life. However, the effects of IUGR on the cerebellum are still to be fully elucidated. A major determinant of growth and development of the cerebellum is proliferation and subsequent migration of cerebellar granule cells. Our objective was to determine whether IUGR, induced by chronic placental insufficiency (CPI) in guinea pigs, results in abnormal cerebellar development due to deficits suggestive of impaired granule cell proliferation and/or migration. CPI was induced by unilateral ligation of the uterine artery at mid gestation, producing growth-restricted (GR) foetuses at 52 and 60 days of gestation (dg), and neonates at 1 week postnatal age (term approx. 67 dg). Controls were from sham-operated animals. In GR foetuses compared with controls at 52 dg, the external granular layer (EGL) width and internal granular layer (IGL) area were similar. In GR foetuses compared with controls at 60 dg: (a) the EGL width was greater (p < 0.005); (b) the IGL area was smaller (p < 0.005); (c) the density of Ki67-negative (postmitotic) granule cells in the EGL was greater (p < 0.01); (d) the somal area of Purkinje cells was reduced (p < 0.005), and (e) the linear density of Bergmann glia was similar. The EGL width in GR foetuses at 60 dg was comparable to that of 52 dg control and GR foetuses. The pattern of p27 immunoreactivity in the EGL was the inverse of Ki67-immunoreactivity at both foetal ages; there was no difference between control and GR foetuses at either age in the width of p27-immunoreactivity, or in the percentage of the EGL width that it occupied. In the molecular layer of GR neonates compared with controls there was an increase in the areal density of granule cells (p < 0.05) and in the percentage of migrating to total number of granule cells (p < 0.01) at 1 week but not at 60 dg (p > 0.05). Thus, we found no specific evidence that IUGR affects granule cell proliferation, but it alters the normal program of migration to the IGL and, in addition, the development of Purkinje cells. Such alterations will likely affect the development of appropriate circuitry and have implications for cerebellar function. PMID- 29763884 TI - Joint angle and movement velocity effects on muscle activity of elderly with knee osteoarthritis - Categorized and probabilistic analysis. AB - The aim of the study was to determine the effects of joint angle position and angular velocity on concentric and eccentric knee muscles activity of elderly with osteoarthritis (OA) in a deterministic and probabilistic approach compared to matched controls. Concentric and eccentric muscle activation of vastus medialis (VM) and semitendinous (ST) muscles were recorded of eleven elderly women with knee OA (median (Md (25-75%)) age of 62 years (60-72) and Md of body mass index (BMI) of 26 kg/m2 (24.5-27.2)) and ten controls (Md 65 years (62-69) and Md of BMI 24.5 kg/m2 (23.6-28.9), during twenty-five knee extension-flexion movements. Activation type, angular velocities (90 degrees s-1 and 240 degrees s-1) and joint angle intervals were categorized into groups. The cumulative frequency distributions of the normalized sEMG envelope were computed and the probability to be out of specific norm-reference limits (controls) was calculated. No statistical differences between groups were found. Higher probabilities were found for VM and ST (concentric) and ST (eccentric) activation to be out of norm (55%, 53% and 84%, respectively) at 240 s-1 in different joint angles. During dynamic contractions, concentric and eccentric activity of medial knee muscles of elderly with OA were affected in a different way by joint angles and angular velocity compared to matched controls. The probabilistic analysis provided an additional understanding of the muscle activation between elderly with knee OA and healthy older people. PMID- 29763887 TI - Comparison between Nonmydriatic Spectral Domain Optical Coherence Tomography and Conventional Ophthalmologic Examination in Detecting Adult Macular Pathology. AB - OBJECTIVE: To compare nonmydriatic spectral domain optical coherence tomography (NMOCT) to comprehensive ophthalmologic evaluation (COE) in detecting adult macular abnormalities. METHODS: This is a single-reader observational pilot study of adults older than 50 years with no known ophthalmologic problems to assess the correlation between NMOCT and COE in detecting macular abnormalities classified as epiretinal, intraretinal, subretinal, or a combination thereof. Subjects underwent NMOCT of the macula followed by COE which included a dilated fundus examination and ancillary tests as needed. RESULTS: A total of 771 eyes of 406 patients were included. Cohen's kappa coefficient of agreement between NMOCT and COE for detecting any abnormality was high (0.90, p < 0.0001), with NMOCT having an overall sensitivity of 82.65% and specificity of 98.97%. Sensitivities and specificities of NMOCT in detecting each category of macular abnormalities were as follows: epiretinal (86.36%, 99.73%), intraretinal (80.00%, 99.58%), and subretinal (88.89%, 99.73%), respectively. CONCLUSION: NMOCT is a promising tool for detecting adult macular abnormalities. PMID- 29763886 TI - Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors. AB - BACKGROUND/AIMS: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). METHODS: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. RESULTS: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 +/- 29.17% to 120.94 +/- 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). CONCLUSIONS: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics. PMID- 29763888 TI - Hydrogen Therapy in Cardiovascular and Metabolic Diseases: from Bench to Bedside. AB - Hydrogen (H2) is colorless, odorless, and the lightest of gas molecules. Studies in the past ten years have indicated that H2 is extremely important in regulating the homeostasis of the cardiovascular system and metabolic activity. Delivery of H2 by various strategies improves cardiometabolic diseases, including atherosclerosis, vascular injury, ischemic or hypertrophic ventricular remodeling, intermittent hypoxia- or heart transplantation-induced heart injury, obesity and diabetes in animal models or in clinical trials. The purpose of this review is to summarize the physical and chemical properties of H2, and then, the functions of H2 with an emphasis on the therapeutic potential and molecular mechanisms involved in the diseases above. We hope this review will provide the future outlook of H2-based therapies for cardiometabolic disease. PMID- 29763889 TI - Neutrophil-Lymphocyte Ratio Predicts Functional and Safety Outcomes after Endovascular Treatment for Acute Ischemic Stroke. AB - BACKGROUND AND OBJECTIVE: Endovascular treatment (EVT) is proven to be safe and effective for treating acute large vessel occlusion stroke (LVOS). The neutrophil lymphocyte ratio (NLR) reflects systemic inflammation, which plays an important role in the process of treating ischemic stroke. This study aims to explore the relationship between NLR and the clinical outcomes of LVOS patients undergoing EVT. METHODS: Patients were selected from the EVT for acUte Anterior circuLation (ACTUAL) ischemic stroke registry. The laboratory data (neutrophil count, lymphocyte count) before EVT were collected. Poor functional outcome was defined as modified Rankin Scale (mRS) of 3-6 at 3 months. Multivariable logistic regression analyses were performed to explore the relationship of NLR with functional outcome, symptomatic intracranial hemorrhage (sICH), and mortality. RESULTS: We eventually included 616 patients (median of age, 66 years; 40.3% female). There were 350 (56.7%) patients achieving mRS of 3-6 at 3 months, 98 (15.9%) patients with sICH, and the mortality at 3 months was 24.8% (153/616). Baseline NLR was independently associated with poor functional outcome (OR 1.58; 95% CI 1.02-2.45; p = 0.039) and sICH (OR 1.84; 95% CI 1.09-3.11; p = 0.023) but showed a trend for predicting 3-month mortality (OR 1.57; 95% CI 0.94-2.65; p = 0.088). CONCLUSIONS: NLR independently predicts 3-month functional outcome and sICH but the existence of a trend association with mortality after EVT for acute anterior circulation LVOS patients. PMID- 29763890 TI - MiR-301a-3p Suppresses Estrogen Signaling by Directly Inhibiting ESR1 in ERalpha Positive Breast Cancer. AB - BACKGROUND/AIMS: MiRNA-301a-3p is an oncogenic miRNA whose expression is associated with tumor development, metastases and overall poor prognosis. Estrogen receptor alpha (ERalpha) is one of the estrogen hormone-activated transcription factors, which regulates a large number of genes and is involved in the mammary gland development. Expression of ERalpha is considered to be a good indicator for endocrine therapy and breast cancer survival. Loss of ERalpha in breast cancer patients indicates invasiveness and poor prognosis. In this study, we focus on the regulation of ERalpha by miR-301a and its role in transition from estrogen-dependent to estrogen-independent breast cancer. METHODS: Expression of miR-301a-3p was measured by qRT-PCR in tumor tissue samples from 111 patients with primary breast carcinoma and in mammospheres representing in vitro model of cancer stem-like cells. Dual reporter luciferase assay and complementary experiments were performed to validate ESR1 as a direct target of miR-301a-3p. The effect of miR-301a-3p on estrogen signaling was evaluated on the level of gene and protein expression and growth response to estrogens. Finally, the effect of miR-301a-3p expression on tumor growth was studied in nude mice. RESULTS: We identified ESR1 as a direct target of miR-301a-3p. Ectopic miR-301a-3p causes a decrease in ESR1 mRNA and protein level and modulates the expression of ERalpha target genes in ERalpha positive breast cancer cells. Consistently, miR-301a-3p causes a decrease in sensitivity of MCF7 cells to 17beta-estradiol and inhibits the growth of estrogen dependent tumor in nude mice. Yet, the mice tumors have significantly increased expression of genes related to cancer stem-like cells and epithelial to mesenchymal transition suggesting enrichment of the population of cells with more invasive properties, in line with our observation that miR-301a 3p expression is highly increased in mammospheres which show a decrease in estrogenic signaling. Importantly, miR-301a-3P level is also increased in primary breast cancer samples exhibiting an ER/PR negative phenotype. CONCLUSION: Our results confirm ESR1 as a direct target of miR-301a-3p and suggest that miR-301a 3p likely contributes to development of estrogen independence, which leads to a more invasive phenotype of breast cancer. PMID- 29763891 TI - Endothelial Progenitor Cells and Kidney Diseases. AB - Endothelial progenitor cells (EPC) are bone marrow derived or tissue-resident cells that play major roles in the maintenance of vascular integrity and repair of endothelial damage. Although EPCs may be capable of directly engrafting and regenerating the endothelium, the most important effects of EPCs seem to be depended on paracrine effects. In recent studies, specific microvesicles and mRNAs have been found to mediate the pro-angiogenic and regenerative effects of EPCs on endothelium. EPC counts have important prognostic implications in cardiovascular diseases (CVD). Uremia and inflammation are associated with lower EPC counts which probably contribute to increased CVD risks in patients with chronic kidney disease. Beneficial effects of the EPC therapies have been shown in studies performed on different models of CVD and kidney diseases such as acute and chronic kidney diseases and glomerulonephritis. However, lack of a clear definition and specific marker of EPCs is the most important problem causing difficulties in interpretation of the results of the studies investigating EPCs. PMID- 29763893 TI - Patterns of Infancy Growth and Metabolic Hormonal Profile Are Different in Very Low-Birth-Weight Preterm Infants Born Small for Gestational Age Compared to Those Born Appropriate for Gestational Age. AB - BACKGROUND/AIMS: An increased preterm birth survival rate is associated with long term neurological and metabolic risks; thus, our aim was to evaluate whether early patterns of infancy anthropometry and metabolic hormonal profile differ in preterm infants born small for gestational age (SGA) or appropriate for gestational age (AGA) from birth to 36 months of corrected age (CA). METHODS: We recruited 110 very-low-birth-weight (VLBW) preterm infants (AGA = 60 and SGA = 50) with a mean birth weight of -2.39 +/- 0.77 versus 0.57 +/- 0.54 standard deviation scores (SDS) (p < 0.01) and birth length of -2.1 +/- 1.05 versus -0.44 +/- 0.82 SDS (p < 0.01), respectively. Anthropometry and blood sampling for insulin, insulin-like growth factor (IGF)-II, IGF-I, and leptin were performed for up to 3 years. RESULTS: All neonates increased their weight, length, and head circumference SDS during the early inpatient period. Up to 90% reached a normal length within this period. The IGF-II, insulin, and glycemia concentrations changed in parallel with weight. In the first year of CA, only SGA infants gained weight and height SDS. The homoeostatic model assessment had a trend toward higher values in SGA infants at 24 and 36 months (p = 0.06 and p = 0.07). CONCLUSION: Being SGA is the strongest predictor of early recovery of height in VLBW preterm infants. Follow-up will allow us to determine whether the differences in the growth patterns of VLBW preterm infants by birth weight SDS persist. PMID- 29763892 TI - Interleukin-33 Predicts Poor Prognosis and Promotes Renal Cell Carcinoma Cell Growth Through its Receptor ST2 and the JNK Signaling Pathway. AB - BACKGROUND/AIMS: Renal cell carcinoma (RCC) is currently the ninth most common cancer in men. Interleukin (IL)-33 expression has previously been associated with a number of cancers; however, its biological role in RCC is poorly understood. In this study, we sought to elucidate the role of IL-33 in RCC. METHODS: Serum IL-33 levels were measured by ELISA. IL-33 expression in clinical RCC samples was examined by immunocytochemistry. The proliferation and apoptosis rate of RCC were determined by CCK8 and flow cytometry. Mcl1 and Bcl-2 expression were measured by quantitative real-time PCR and western blotting. JNK expression were measured by western blotting and flow cytometry. The in vivo role of IL-33 in RCC tumorigenesis was examined by animal models. RESULTS: We found that increased expression of IL-33 in RCC was associated with tumor-lymph node-metastasis (TNM) stage and inversely correlated with prognosis. IL-33 enhances RCC cell growth in vivo and stimulates RCC cell proliferation and prevents chemotherapy-induced tumor apoptosis in vitro. Furthermore, we demonstrated that IL-33 promotes RCC cell proliferation and chemotherapy resistance via its receptor ST2 and the JNK signaling activation in tumor cells. CONCLUSION: Our findings suggest that targeting IL-33/ST2 and JNK signaling may have potential value in the treatment of RCC. PMID- 29763894 TI - The Understanding and Management of Organism Toxicity in Septic Shock. AB - The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells' pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored. PMID- 29763895 TI - Voice and Swallowing Outcomes after Hyoid Suspension Surgery in Patients with Obstructive Sleep Apnea. AB - OBJECTIVE: The role of hyoidthyroidpexia (HTP) surgery in the management of patients with obstructive sleep apnea (OSA) is well described with good reported outcomes. The effect of HTP on other laryngeal functions is not well discussed. This study was designed to evaluate voice and swallowing outcomes after HTP. PATIENTS AND METHODS: This study was applied on a selected group of OSA patients. HTP (as a sole procedure) was performed in 17 patients and 14 patients had simultaneous palatal procedures (e.g., anterior palatoplasty). Pre- and postoperative assessment of voice and swallowing were done. RESULTS: Comparison between pre- and postoperative results of voice and swallowing measures revealed a nonsignificant difference. CONCLUSION: HTP (as a sole technique or as part of a multilevel intervention) could help with airway collapse and might be considered a safe, simple, and effective technique in the management of selected patients experiencing OSA. In addition, it seems to have no hazardous effect on either the voice or swallowing function of patients. PMID- 29763897 TI - Does the Pituitary Gland Volume Change in Polycystic Ovary Syndrome? AB - AIMS: Polycystic ovary syndrome (PCOS) is the commonest cause of menstrual irregularity and hirsutism during reproductive age. We hypothesized in the alterations in the pituitary gland in PCOS. METHODS: We measured the volume of the pituitary gland in 39 PCOS patients and 42 age-matched healthy controls using 0.35 mm thick T1-weighted sagittal cranial images. Serum levels of estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were measured on days 3-5 of the menstrual cycle of the participants. RESULTS: There was a significant difference in terms of LH, FSH, and LH/FSH ratio (p < 0.05) between groups. Mean pituitary gland volume (PGV) was 4.1 +/- 1.36 mm3 for the study group and 3.4 +/- 0.77 mm3 for the control group. PGV was statistically significantly higher in PCOS group than the control group (p < 0.05). There was no correlation between hormone levels and PGVs in groups. CONCLUSION: Enlarged pituitary volume in PCOS may be due to excessive LH release. PMID- 29763896 TI - Evaluation of the HER2 and Hormone Receptor Status in Metastatic Breast Cancer Using Cell Blocks: A Multi-Institutional Study. AB - OBJECTIVE: We explore the problems associated with the cell block (CB) method for receptor analysis in breast cancer metastases and propose a method for reporting the results. STUDY DESIGN: Nine institutions used the CB method for the analysis of hormone receptors (HRs) and HER2 (human epidermal growth factor receptor 2) protein in cytological specimens of breast cancer metastases in routine practice. The stained slides were independently evaluated by 8 pathologists. Dual in situ hybridization assay was performed in cases of discordant results for HER2 protein. Based on the results, we propose a method for receptor scoring in the CB method. RESULTS: Of 61 specimens, 57 contained tumor cells. Two or more pathologists disagreed on the results for the estrogen receptor, progesterone receptor, and HER2 protein in 3 (5.3%), 13 (22.8%), and 19 (33.3%) cases, respectively. The discrepant results for the HRs were attributed to the presence of a few positive cells or faintly stained cells. The high interobserver discordance rate for HER2 protein was explained by interobserver differences in the scoring criteria. CONCLUSION: The use of categorical scoring into positive and negative is recommended for evaluating the HR expressions. Use of strict criteria for HER2 protein 2+ and 3+ cases is recommended, as HER2-positive cases should not be missed. PMID- 29763898 TI - FGFR4 Links Glucose Metabolism and Chemotherapy Resistance in Breast Cancer. AB - BACKGROUND/AIMS: Poor response to chemotherapy leads to the relapse and metastatic progression of tumors. Reprogrammed glucose metabolism is one of the important hallmarks of cancer that facilitates cancer cell survival, proliferation and chemoresistance. However, the precise fate of glucose metabolism and its role in therapy responsiveness in cancers remains largely unexplored. METHODS: The glycolytic phenotype of doxorubicin (ADR)-resistant breast cancer cells and their parental cells was assessed by measuring glucose uptake, lactate release, and extracellular acidification rate (ECAR). Protein expression was detected by Western blotting analysis and mRNA expression was detected using q-PCR. Cell survival ratio was determined by the cell counting kit 8 assay. The role of fibroblast growth factor receptor 4 (FGFR4) in glycolysis, chemoresistance, and the underlying mechanisms were studied by using gene expression microarray and short hairpin RNA-mediated gene knockdown. RESULTS: We found that glycolytic flux are increased in two doxorubicin (ADR)-resistant breast cancer cell lines compared with their parental wild type cells, as demonstrated by increased glucose uptake, lactate release, and extracellular acidification rate (ECAR). By gene expression microarray, we identified FGFR4 as a critical modulator of ADR resistance and enhanced glucose metabolism. Genetic silencing of FGFR4 increased the chemosensitivity and suppressed the enhanced glycolytic flux in ADR-resistant cells. Mechanistically, activation of FGFR4 signaling in ADR-resistant cells led to the phosphorylation of FGF receptor substrate 2 (FRS2) and further activated the downstream MAPK/ERK signaling. Pharmacological inhibition of FGFR4-FRS2-ERK signaling pathway significantly blocked the chemoresistant and glycolytic phenotypes of ADR-resistant cells. CONCLUSION: Our findings suggest that high levels of FGFR4 can increase glucose metabolism and lead to chemoresistance in breast cancer and reveal the mechanistic basis for targeting FGFR4 as a therapeutic opportunity for chemoresistant tumors. PMID- 29763900 TI - C-proSP-B: A Possible Biomarker for Pulmonary Diseases? AB - BACKGROUND: Detection of surfactant proteins A and D (SP-A and SP-D) in the serum of patients with pulmonary diseases is thought to reflect an injury of the alveolar epithelial barrier and as such serve as a biomarker for these diseases. However, the data for SP-B are limited. OBJECTIVES: The aim of this feasibility study was to assess whether immature SP-B pre-proteins might have value as a possible biomarker for pulmonary diseases. METHODS: In serum samples from patients with different chronic lung diseases (interstitial lung diseases [ILDs], chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary hypertension, inflammation, patients on ventilator support; total n = 283), C proSP-B was measured using an electrochemiluminescence immunoassay based on mouse monoclonal anti-C-proSP-B antibodies. Levels were correlated to lung functional and clinical parameters. RESULTS: The highest C-proSP-B levels were detected in the serum of idiopathic pulmonary fibrosis (IPF) patients. In a multivariate analysis, C-proSP-B levels were able to discriminate IPF patients from patients with all other pulmonary diseases (p < 0.0001). No significant correlations were found between C-proSP-B levels and lung function, smoking history, or disease extent. CONCLUSIONS: SP-B pre-proteins might serve as a biomarker in pulmonary diseases with alveolar or interstitial damage such as ILDs, especially in IPF. Their role in the long-term monitoring of such diseases has to be clarified further. PMID- 29763899 TI - Tanshinone IIA Attenuates Contrast-Induced Nephropathy via Nrf2 Activation in Rats. AB - BACKGROUND/AIMS: Tanshinone IIA is a chemical compound extracted from Salvia miltiorrhiza Bunge, a perennial plant also known as red sage used in traditional Chinese medicine. Tanshinone IIA has been shown to protect against various organ injuries. In this study, we hypothesized that Tanshinone IIA could play an anti oxidative role in contrast-induced nephropathy (CIN) through enhancing Nrf2/ARE activation. METHODS: To test whether Tanshinone IIA can attenuate CIN, oxidative stress, and apoptosis, we utilized two models: an in vivo Sprague-Dawley rat model of ioversol-induced CIN and an in vitro cell model of oxidative stress in which HK2 cells, a human renal tubular cell line, are treated with hydrogen peroxide (H2O2). Rats were randomly assigned to 4 groups (n = 6 per group): control group, ioversol group (ioversol-induced CIN), vehicle group (ioversol induced CIN rats pretreated with vehicle), and Tanshinone IIA group (ioversol induced CIN rats pretreated with 25mg/kg Tanshinone IIA). Renal functions, renal injuries and apoptosis were evaluated by using serum creatinine, histological scoring, and TUNEL staning respectively. Malondialdehyde, 8-hydroxy-2' deoxyguanosine, and intracellular reactive oxygen species were used for oxidative stress assessment. Levels of Nrf2 and heme oxygenase-1 (HO-1) were measured in vivo and in vitro. RESULTS: Tanshinone IIA attenuated renal tubular necrosis, apoptosis and oxidative stress in rats and oxidative stress in HK2 cells. Furthermore, Tanshinone IIA activated Nrf2, and up-regulated HO-1 expression in vivo and in vitro, resulting in a reduction in oxidative stress. CONCLUSION: Tanshinone IIA may protect against CIN through enhancing Nrf2/ARE activation. PMID- 29763901 TI - 5-Aminolevulinic Acid-Mediated Sonodynamic Therapy Alleviates Atherosclerosis via Enhancing Efferocytosis and Facilitating a Shift in the Th1/Th2 Balance Toward Th2 Polarization. AB - BACKGROUND/AIMS: We and other groups have demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (ALA-SDT) induces macrophage and foam cell apoptosis and stabilizes atherosclerosis (AS) plaques in animal models. Lymphocytes also play vital roles in the development of AS. The primary purpose of the present study was to investigate the effects of ALA-SDT on T helper (Th) cell fate and function, Th subset differentiation, and atherosclerotic lesion stability. METHODS: We utilized ALA-SDT on Western diet-fed apoE-/-mice in vivo and human Jurkat cells in vitro. Hematoxylin and eosin staining and TUNEL assays were used to evaluate the atherosclerotic plaque size and apoptosis within the atheroma. ALA induced cytotoxicity on cultured Jurkat cells was determined with CCK-8 assay. To address the mechanisms, levels of intracellular reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and mitochondrial permeability transition pore (MPTP) opening were evaluated by staining with fluorescent probes. Western blot analysis and confocal microscopy were used to analyze the protein levels of caspases, Bax and cytochrome c and the release of cytochrome c. Cell apoptosis and necrosis and phagocytosis were examined by flow cytometry. ELISAs and immunofluorescent staining were used to assess the corresponding cytokine levels and Th subset cell numbers within the atheroma. RESULTS: Our studies revealed that ALA-SDT significantly enhanced CD4+ cell apoptosis and macrophage-mediated phagocytosis and hence reduced the necrotic core size. ALA-SDT activated the mitochondrial apoptotic signaling pathway with minimal necrosis in Jurkat cells. ALA-SDT inhibited the Th1 response and enhanced the Th2 response. These effects of ALA-SDT were mediated primarily through the generation of ROS. CONCLUSION: ALA-SDT alleviates AS by enhancing cytotoxic effects on Th cells, subsequently stimulating efferocytosis and facilitating a shift in the Th1/Th2 balance toward Th2 cells, a discovery that might help elucidate the mechanism underlying SDT as a potential treatment to prevent atherothrombotic events. PMID- 29763902 TI - Prognostic Factors of Renal Involvement in Systemic Sclerosis. AB - BACKGROUND/AIMS: Renal involvement is common in systemic sclerosis (SSc), including asymptomatic reduction of glomerular filtration rate (GFR), increased renal resistance indices, scleroderma renal crisis (SRC) and ANCA-associated vasculitis. The aim was to evaluate type and evolution of renal involvement for a period of five years. METHODS: 121 SSc patients (100 F, 21 M) with mean age of 54.9 +/- 13.8, disease duration of 9 +/- 6 years, of which 62 had a diffused form and 59 limited form were enrolled. All patients were screened annually for renal function by laboratory examination, ultrasound and color Doppler ultrasound of renal arteries. RESULTS: Over the five-year observation period, 6 SRC (3 M, 3 F) occurred, four of which required dialysis. One patient developed ANCA-related proliferative glomerulonephritis and the other one acute tubular necrosis. The remaining 113 patients had a preserved renal function (serum creatinine 0.75 +/- 0.24 mg/dl, GFR 93.8 +/- 20 ml/min, 24h proteinuria 0.20 +/- 0.15 g). Doppler indices of intrarenal arterial stiffness increased with progression of capillaroscopic damage and with presence of digital ulcers. A negative correlation was observed between estimated GFR and pulsatile index (p< 0,05, r= 0.198), resistive index(p< 0,01, r=0.267), S/D ratio (p< 0,01, r=-0.237). CONCLUSION: In SSc patients, renal function was normal for 4.1 years despite the presence of increased intrarenal arterial stiffness. SRC was observed in 4.9% of SSc patients. In SSc patients, a periodic follow-up based on clinical and laboratory evaluation, colorDoppler ultrasound and, in some cases, renal biopsy is required to evaluate renal involvement. PMID- 29763903 TI - Central Precocious Puberty Caused by a Heterozygous Deletion in the MKRN3 Promoter Region. AB - CONTEXT: Loss-of-function mutations in the coding region of MKRN3, a maternally imprinted gene at chromosome 15q11.2, are a common cause of familial central precocious puberty (CPP). Whether MKRN3 alterations in regulatory regions can cause CPP has not been explored to date. We aimed to investigate potential pathogenic variants in the promoter region of MKRN3 in patients with idiopathic CPP. PATIENTS/METHODS: A cohort of 110 patients with idiopathic CPP was studied. Family history of precocious sexual development was present in 25%. Mutations in the coding region of MKRN3 were excluded in all patients. Genomic DNA was extracted from peripheral blood leukocytes, and 1,100 nucleotides (nt) of the 5' regulatory region of MKRN3 were amplified and sequenced. Luciferase assays were performed in GT1-7 cells transiently transfected with plasmids containing mutated and wild-type MKRN3 promoter. RESULTS: We identified a rare heterozygous 4-nt deletion (c.-150_-147delTCAG; -38 to -41 nt upstream to the transcription start site) in the proximal promoter region of MKRN3 in a girl with CPP. In silico analysis predicted that this deletion would lead to the loss of a binding site for a downstream res-ponsive element antagonist modulator (DREAM), a potential transcription factor for MKRN3 and GNRH1 expression. Luciferase assays demonstrated a significant reduction of MKRN3 promoter activity in transfected cells with a c.-150_- 147delTCAG construct plasmid in both homozygous and heterozygous states when compared with cells transfected with the corresponding wild-type MKRN3 promoter region. CONCLUSION: A rare genetic alteration in the regulatory region of MKRN3 causes CPP. PMID- 29763904 TI - Treatment of Cutaneous Ulcers with Multilayered Mixed Sheets of Autologous Fibroblasts and Peripheral Blood Mononuclear Cells. AB - BACKGROUND/AIMS: We have developed a mixed-cell sheet consisting of autologous fibroblasts and peripheral blood mononuclear cells with a high potency for angiogenesis and wound healing against refractory cutaneous ulcers in mouse and rabbit models. To increase the effectiveness of the mixed sheet, we developed a multilayered mixed sheet. METHODS: We assessed the therapeutic effects of multilayered sheets on cutaneous ulcers in mice. Growth factors and chemokines were assessed by enzyme-linked immunosorbent assay. Angiogenesis and fibroblast migration were measured by using tube formation and migration assays. Wound healing rate of cutaneous ulcers was evaluated in mice with diabetes mellitus. RESULTS: The concentration of secreted vascular endothelial growth factor, hepatocyte growth factor, transforming growth factor, C-X-C motif chemokine ligand (CXCL)-1, and CXCL-2 in multilayered sheets was much higher than that in single-layered mixed-cell sheets (single-layered sheets) and multilayered sheets of fibroblasts alone (fibroblast sheets). The supernatant in multilayered sheets enhanced angiogenic potency and fibroblast migration compared with single-layered and fibroblast sheets in an in vitro experiment. The wound healing rate in the multilayered sheet-treated group was higher compared with the no-treatment group (control) at the early stage of healing. Moreover, both vessel lumen area and microvessel density in tissues treated with multilayered sheets were significantly increased compared with tissues in the control group. CONCLUSION: Multilayered sheets promoted wound healing and microvascular angiogenesis in the skin by supplying growth factors and cytokines. Accordingly, our data suggest that multilayered sheets may be a promising therapeutic material for refractory cutaneous ulcers. PMID- 29763905 TI - SCCA, TSGF, and the Long Non-Coding RNA AC007271.3 are Effective Biomarkers for Diagnosing Oral Squamous Cell Carcinoma. AB - BACKGROUND/AIMS: Oral squamous cell carcinoma (OSCC) is one of the most lethal malignancies worldwide and the most common type of oral cancer, characterized by invasive growth, frequent regional metastases, high recurrence, and poor prognosis. In the current study, we investigated the use of long non-coding RNAs (lncRNAs), tumor-specific growth factor (TSGF), and squamous cell carcinoma antigen (SCCA) as potential biomarkers for OSCC screening. METHODS: LncRNA expression was measured by microarray analysis in three sets of OSCC and paired normal mucosal tissues. The potential lncRNAs involved in OSCC development were investigated by bioinformatics and verification experiments. We also determined the expression of these potential biomarkers in tissue and serum samples in a case-control study of 80 OSCC cases and 70 controls. Receiver operating characteristics, decision curve analysis, and the combined detection of lncRNA AC007271.3, TSGF, and SCCA were carried out to screen for OSCC biomarkers. RESULTS: A total of 691 lncRNAs (433 upregulated and 258 downregulated) were differentially expressed in OSCC tissues compared with normal controls (p< 0.05). Based on Gene Ontology and pathway analysis, we selected four differentially expressed lncRNAs (AC007271.3, AC007182.6, LOC283481, and RP11-893F2.9), and showed that aberrant AC007271.3 levels in OSCC patients were significantly associated with clinical stage, especially in early-stage disease, in an expanded case-control study. The combination of AC007271.3 and SCCA (AUC=0.902, p< 0.001) showed significantly better ability to discriminate between OSCC and controls compared with SCCA or AC007271.3 alone. Serum AC007271.3, SCCA, and TSGF levels could also discriminate between OSCC and normal controls with sensitivities of 77.6%, 55.0%, and 63.3%, and specificities of 84.5%, 93.3%, and 66.7%, respectively. CONCLUSIONS: These results suggest that AC007271.3, SCCA, and TSGF could be novel circulating biomarkers for the determination of OSCC. However, further validation in large-scale prospective studies is necessary. PMID- 29763906 TI - The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease. AB - BACKGROUND/AIMS: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM 1highMSCs may significantly improve their immunomodulatory effect. METHODS: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. RESULTS: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. CONCLUSIONS: Taken together, these data demonstrate that ICAM-1highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD. PMID- 29763907 TI - Beyond Irritable Bowel Syndrome: The Efficacy of the Low Fodmap Diet for Improving Symptoms in Inflammatory Bowel Diseases and Celiac Disease. AB - BACKGROUND AND AIM: To evaluate the usefulness of a low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) diet on patients with irritable bowel syndrome (IBS), non-active inflammatory bowel diseases (IBD), and celiac disease (CD) on a gluten-free diet (GFD). METHODS: Dietetic interventional prospective study. IBS, IBD, and CD subjects were evaluated to check if they fulfilled the Rome III criteria. Each subject was educated to follow a low FODMAP diet after being evaluated by filling out questionnaires that assessed the quality of life (QoL) and symptoms experienced (IBS-SSS and SF-36), and was reevaluated after 1 and 3 months. RESULTS: One hundred twenty-seven subjects were enrolled: 56 with IBS, 30 with IBD, and 41 with CD. IBS-SSS showed that abdominal symptoms improved after 1 and 3 months of diet in all subjects, with significant difference among the 3 groups at T0 (average scores IBS: 293 +/- 137, IBD: 206 +/- 86, CD: 222 +/- 65, p < 0.001), but no difference at T3 (IBS: 88 +/- 54, IBD: 73 +/- 45, CD: 77 +/- 49, p = ns). By analyzing the SF-36 questionnaire, we did not observe any difference between the 3 groups, in terms of response to diet (p = ns), we observed a clinical improvement from T0 to T3 for most of the questionnaire's domains. CONCLUSIONS: A low FODMAP diet could be a valid option to counter -abdominal symptoms in patients with IBS, non-active IBD, or CD on a GFD, and thus, improve their QoL and social -relations. PMID- 29763908 TI - Connexin 43 Modulates Osteogenic Differentiation of Bone Marrow Stromal Cells Through GSK-3beta/Beta-Catenin Signaling Pathways. AB - BACKGROUND/AIMS: Bone marrow stromal cells (BMSCs) are multipotent precursors that give rise to osteoblasts, and contribute directly to bone formation. Connexin 43 (Cx43) is the most ubiquitous gap junction protein expressed in bone cell types, and plays crucial roles in regulating intercellular signal transmission for bone development, differentiation and pathology. However, the precise role and mechanism of Cx43 in BMSCs are less known. Here, we investigate the function of Cx43 in osteogenic differentiation of BMSCs in vitro. METHODS: BMSCs were isolated by whole bone marrow adherent culture. Knock down of Cx43 was performed by using lentiviral transduction of Cx43 shRNA. BMSCs were induced to differentiate by culturing in a-MEM, 10% FBS, 50 uM ascorbic acid, 10 mM beta glycerophosphate, and 100 nM dexamethasone. Alkaline phosphatase (ALP) activity and alizarin red S staining were used to evaluate osteogenic differentiation in calcium nodules. Target mRNAs and proteins were analyzed by using real-time quantitative PCR (qPCR) and western blotting. RESULTS: Cx43 expression markedly increased during osteogenic differentiation. Osteogenic differentiation was suppressed following lentiviral-mediated knockdown of Cx43 expression, as judged by decreased levels of Runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP), osteocalcin (Bglap), Osterix (Osx), alkaline phosphatase (ALP) activity and the number of calcium nodules in response to osteogenic differentiation stimuli. Knock down of Cx43 reduced the level of phosphorylation of GSK-3beta at Ser9 (p-GSK-3beta), resulting in decreased beta-catenin expression and activation. Furthermore, treatment of Cx43-knockdown cells with lithium chloride (LiCl), a GSK-3beta inhibitor, reduced osteogenic differentiation and decreased GSK-3beta levels, as well as partially rescued levels of both total and activated beta-catenin. CONCLUSION: These findings indicate that Cx43 positively modulates osteogenic differentiation of BMSCs by up regulating GSK-3beta/beta-catenin signaling pathways, suggesting a potential role for Cx43 in determining bone mass and bone mineral density by modulating osteogenesis. PMID- 29763909 TI - Cardiac Ablation of SOCS3 Aggravates DOCA-Salt-Induced Hypertrophic Remodeling by Activation of Gp130-Dependent Signaling in Mice. AB - BACKGROUND/AIMS: Cardiac remodeling is a critical pathogenetic process leading to heart failure. Suppressor of cytokine signaling-3 (SOCS3) is demonstrated as a key negative regulator of the gp130 receptor to inhibit cardiac hypertrophy. However, the role of SOCS3 in deoxycorticosterone-acetate (DOCA)-salt-induced cardiac remodeling remains unclear. METHODS: Cardiac-specific SOCS3 knockout (SOCS3cKO) and wild-type (WT) C57BL/6J mice were subjected to uninephrectomy and DOCA-salt for 3 weeks. The effect of SOCS3 on cardiac remodeling and inflammation was evaluated by histological analysis. Gene and protein levels were measured by real-time PCR and immunoblotting analysis. RESULTS: After DOCA-salt treatment, the expression of SOCS3, activation of gp130/JAK/STAT3, cardiac dysfunction and fibrosis in DOCA-salt mice were significantly elevated, which were markedly attenuated by eplerenone, a specific mineralocorticoid receptor (MR) blocker. Moreover, DOCA-salt-induced cardiac dysfunction, hypertrophy, fibrosis and inflammation were aggravated in SOCS3cKO mice, but were significantly reduced in AAV9-SOCS3-injected mice. These effects were mostly associated with activation of gp130/STAT3/AKT/ERK1/2, TGF-beta/Smad2/3 and NF-kappaB signaling pathways. CONCLUSIONS: Our data demonstrate that loss of SOCS3 in cardiomyocytes promotes DOCA-salt-induced cardiac remodeling and inflammation, and it may be a novel potential therapeutic target for hypertensive heart disease. PMID- 29763910 TI - Different Relevance of Peripheral, Central or Nighttime Blood Pressure Measurements in the Prediction of Chronic Kidney Disease Progression in Patients with Mild or No-Proteinuria. AB - BACKGROUND/AIMS: Arterial hypertension is one of the leading factors aggravating the course of chronic kidney disease (CKD). It seems that the novel parameters used in the assessment of the blood pressure (BP) load (i.e. central blood pressure, nighttime blood pressure) may be more precise in predicting the cardiovascular risk and the progression of CKD in comparison with the traditional peripheral blood pressure measurements in the office conditions. The aim of the study was to assess the impact of the central, or nighttime blood pressure on the progression of CKD in patients with mild or no-proteinuria (autosomal, dominant polycystic kidney disease or IgA nephropathy). METHODS: In each of the enrolled 46 patients with CKD stage 3 or 4, serum creatinine concentration was assessed, eGFR (MDRD) was calculated, also central blood pressure and pulse wave velocity (PWV) was assessed and the 24-hour ambulatory blood pressure monitoring (ABPM) was conducted at the beginning of the study and then repeated after one-year observation period. RESULTS: During the observation period mean eGFR decreased from 44.1 (33.2-50.6) mL/min to 36.7 (29.7-46.3) mL/min. No significant differences were observed in the peripheral blood pressure or central blood pressure parameters. After one-year observation period the values of diastolic blood pressure dipping during the night significantly decreased from 16 (13-19) mmHg to 12 (10-15) mmHg; p< 0.05. The values of systolic dipping during the night or the mean BP values recorded in ABPM did not change significantly. Additionally, no significant differences in the PWV values were found. In the multivariate regression model the change of serum creatinine concentration was explained by the initial diastolic dipping values. CONCLUSION: 1. In patients with CKD stages 3 or 4 and mild or no- proteinuria, peripheral and central blood pressure did not change significantly during a one-year observation period despite the significant decline of eGFR and seems not to participate in the CKD progression. 2. Reduced magnitude of the diastolic dipping, which reflects the increase of diastolic blood pressure load during the nighttime, may play an important role in the pathogenesis of deterioration of kidney function in these patients. PMID- 29763911 TI - Clinical Correlates of Ambulatory Blood Pressure Phenotypes at a Tertiary Care Hospital in Turkey. AB - BACKGROUND/AIMS: Hypertension and its complications are major public health issues worldwide due to their association with high cardiovascular morbidity and mortality. Despite significant progress in health, the prevalence of hypertension is increasing. Ambulatory blood pressure monitoring (ABPM) is becoming increasingly important for the management of hypertension. In this study, we aimed to investigate the clinical and laboratory correlates of ambulatory blood pressure (ABP) phenotypes at a tertiary care hospital in Turkey. METHODS: The characteristics of 1053 patients were retrospectively obtained from the hospital database. Hypertension was defined as patients with office blood pressure (BP) >=140/90 mmHg and/or previously diagnosed hypertension and/or the use of antihypertensive medication. According to the office BP and ABPM results patients were identified namely: (1) sustained normotensive (SNT) patients (both office BP and ABPM were normal), (2) sustained hypertensive (SHT) patients (both office BP and ABPM were high), (3) masked hypertensive (MHT) patients (office BP were normal, but ABPM were high), (4) white coat hypertensive (WCHT) patients (office BP were above limits, but ABPM were normal). RESULTS: A total of 1053 patients were included to the study (female/male: 608/445 and mean age 55 +/- 15 years). The mean age of patients with hypertension was significantly higher than without hypertension (p< 0.0001). Hypertension was more frequent in females (p=0.009). The rates of history of diabetes mellitus (DM), hyperlipidemia (HL), and chronic kidney disease (CKD) were higher in patients with hypertension (p< 0.0001). Among patients with hypertension (n=853, 81%), ABPM results showed that 388 (45%) of patients had SHT, 92 (11%) had MHT, and 144 (17%) had WCHT, whereas 229 (27%) had SNT. Patients with MHT were significantly older than patients with SNT (p=0.025). The prevalence of SHT was higher in men than in women, whereas the prevalence of WCHT was higher in women than in men (p< 0.0001). There was no significant difference between 4 groups with regard to body mass index (p=0.142), a history of DM (p=0.189) and smoking status (self-reported) (p=0.306). Patients with SHT had the highest prevalence of history of hypertension, HL and CKD (p< 0.0001). Among patients without hypertension, 26 (13%) of patients had MHT and none of those patients was on antihypertensive treatment. CONCLUSION: Potential usages of ABPM in Turkey may include screening of high risk individuals who have traditional cardiovascular risk factors. It also provides clinicians valuable information on abnormal ABP phenotypes. Future studies are needed to clarify the risk factors of different ABP phenotypes and to evaluate the role of ABPM on detection and control of hypertension. PMID- 29763912 TI - A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells. AB - BACKGROUND: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of alpha-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1). METHODS: WST-1 and cell analyzers were employed to analyze the effects of T3E on cell viability and apoptosis of human MM cell lines (H2452, H28). Real time PCR and Western blot were performed to evaluate the expression at mRNA and protein levels. Methylation status and epigenetic modifications of DKK1's promoter regions after T3E treatment in MM cells were studied using methylation specific PCR and Chromatin immunoprecipitation. Small interfering RNA-mediated knockdown -(siRNA), and specific inhibitors, were used to validate DKK1 as a target of T3E. RESULTS: T3E markedly impaired MM cell viability, increased the expression of phosphorylated-JNK and DKK1 and suppressed cyclin D, a downstream target gene of Wnt signaling. Knockdown of DKK1 expression by siRNA or a specific JNK inhibitor confirmed the contribution of DKK1 and JNK to T3E-induced cytotoxicity in MM cells. On the other hand, cytoskeleton-associated protein 4 (CKAP4) expression, which promotes cell proliferation as a Wnt-independent DKK1 receptor was inhibited by T3E. Silencing CKAP4 by -siRNA did not appear to directly affect MM cell viability, thereby indicating that expression of both DKK1 and CKAP4 is required. Furthermore, T3E-mediated inhibition of both DNA methyltransferases (DNMT1, 3A, and 3B) and histone deacetylases (HDAC1, 2, 3, and 8) in MM cells leads to increased DKK1 expression, thereby promoting tumor growth inhibition. MM cells treated with Zebularine (a DNMT inhibitor) and sodium butyrate (an HDAC inhibitor) exhibited cytotoxic effects, which may explain the inhibitory action of T3E on MM cells. In addition, an enhanced expression of DKK1 in MM cells following T3E treatment is positively correlated with the methylation status of its promoter; T3E decreased DNA methylation and increased histone acetylation. Moreover, T3E specifically increased histone H3 lysine 4 (H3K4) methylation activity, whereas no effects were observed on histone H3K9 and H3K27. CONCLUSIONS: Targeting the epigenetic induction of DKK1 may lead to effective treatment of MM, and T3E has great potential to induce anti-MM activity. PMID- 29763914 TI - Epidemiology of Traumatic Spinal Cord Injury in Ireland, 2010-2015. AB - BACKGROUND: The International Spinal Cord Society and World Health Organisation recommend the collection of epidemiological data on traumatic spinal cord injury (TSCI). A 1-year prospective study is ongoing in Ireland. While the results of this study are awaited, it was concluded from a feasibility exercise that a complete retrospective dataset, 2010-2015, could be obtained and would be useful for service planning. METHODS: All patients with TSCI discharged from the national SCI acute and rehabilitation centres were included. Data was collected on gender, age, aetiology, level of injury, American Spinal Injuries Association impairment scale, length of rehabilitation admission and discharge destination. Population denominators were national census figures 2006 and 2011, rolled forward. RESULTS: The incidence of TSCI remained constant throughout the study period, 11.5-13.3 per million per year. The mean age of injury onset was 48.9 (SD 19.8) years. Males accounted for 71.5%. The most common injury level/AIS was incomplete tetraplegia, accounting for 43.2% of all TSCI. Leading aetiology was falls, accounting for 53.3% of injuries. Patients with incomplete tetraplegia were older than those with all other injuries (p < 0.001). CONCLUSIONS: The epidemiological trends identified are similar to those prevalent elsewhere in the developed world. More incomplete tetraplegia among an older patient population necessitates a review of how acute care and rehabilitation services are delivered. PMID- 29763913 TI - Intraventricular Injection of LKB1 Inhibits the Formation of Diet-Induced Obesity in Rats by Activating the AMPK-POMC Neurons-Sympathetic Nervous System Axis. AB - BACKGROUND/AIMS: Obesity is increasingly becoming a major public health problem worldwide. Peripheral LKB1 inhibits white fat generation, but the effect of central LKB1 on diet-induced obesity (DIO) is unknown. Therefore, we examined whether LKB1 over-expression in the hypothalamus can inhibit the development of obesity. METHODS: Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus. LKB1-AAV-EGFP (2.0 * 108 or 2.0 * 1010 vector genomes) or Control-AAV-EGFP (2.0 * 108 vector genomes) was injected into the third ventricle. After administration, the rats were fed a high-fat diet (HFD) for 9 weeks to induce obesity. Rats fed a chow fat diet were used as normal controls. RESULTS: LKB1 delivery decreased body weight, energy intake, fat mass, and serum lipid levels. LKB1 also improved HFD-induced hepatic fatty degeneration. Interestingly, LKB1 over-expression in the hypothalamus activated the AMPK-POMC neurons-sympathetic nervous system (SNS) axis, which can release epinephrine to promote white fat browning. Conversely, the elevated expression of MC3R/MC4R inhibited food intake. These two factors worked together to inhibit the development of obesity. CONCLUSIONS: LKB1 in the hypothalamus may have therapeutic potential for DIO through the activation of the AMPK-POMC neurons-SNS axis. PMID- 29763916 TI - Perineal Wound Closure Using Biological Mesh Following Extralevator Abdominoperineal Excision. AB - AIMS: This study aimed to describe the short-term perineal healing rates in patients with perineal reconstruction using a biological mesh following extralevator abdominoperineal excision (elAPE). METHODS: In a retrospective, descriptive single-centre cohort study, 88 consecutive patients treated with elAPE and perineal closure using a biological mesh between January 2011 and December 2015 were reviewed. All available data from electronic hospital records was collected. Patients were followed for 1 year following surgery and perineal wound status assessed at 3 months and at 1 year. RESULTS: In total, 63 patients were male and all but 8 patients were treated for primary rectal cancer. All patients but 3 had received radiotherapy prior to surgery. Multivisceral excisions were performed in 19 patients. Omentoplasty was performed in 55 patients and 3 different types of meshes were used during the study period. At 3 months, 58 patients (66%) had a healed perineum. No association was detected between patient, tumour or perioperative characteristics and perineal wound status at 3 months. At 1 year, 4 patients were deceased and among the remaining 84, the perineal wound was healed in 77 patients (92%). CONCLUSION: The use of biological meshes in perineal reconstruction following elAPE is feasible and safe, and the perineal wound is healed in the majority of the patients within 3 months. PMID- 29763915 TI - Serum from Chronic Hepatitis B Patients Promotes Growth and Proliferation via the IGF-II/IGF-IR/MEK/ERK Signaling Pathway in Hepatocellular Carcinoma Cells. AB - BACKGROUND/AIMS: Chronic hepatitis B virus (HBV) infection (CHB) plays a central role in the etiology of hepatocellular carcinoma (HCC). Emerging evidence implicates insulin-like growth factor (IGF)-II as a major risk factor for the growth and development of HCC. However, the relationship between HBV infection and IGF-II functions remains to be elucidated. METHODS: Levels of circulating IGF II and IGF-I receptor (IGF-IR) in healthy donors (HDs) and CHB patients were tested by ELISA. Human HCC cell lines (HepG-2, SMMC-7721, MHCC97-H) were incubated with serum from HDs and CHB patients at various concentrations for 24, 48, and 72 h. MTT and plate colony formation assays, BrdU ELISA, ELISA, small interfering RNA (siRNA) transfection, quantitative real-time PCR, and western blot were applied to assess the functional and molecular mechanisms in HCC cell lines. RESULTS: Serum levels of IGF-II and IGF-IR were significantly higher in CHB patients than in HDs. Additionally, serum from CHB patients directly induced cell growth, proliferation, IGF-II secretion, and HDGF-related protein-2 (HRP-2) and nuclear protein 1 (NUPR1) mRNA and protein expression in HCC cells. Moreover, serum from CHB patients increased IGF-II-induced cell growth, proliferation, and HRP-2 and NUPR1 mRNA and protein expression in HCC cells. Blockade of IGF-IR clearly inhibited the above effects. Most importantly, interference with IGF-II function markedly repressed the cell proliferation and HRP-2 and NUPR1 mRNA and protein expression induced by serum from CHB patients. Furthermore, serum from CHB patients induced ERK phosphorylation via IGF-IR, with the MEK inhibitor PD98059 significantly decreasing CHB patient serum-induced IGF-II secretion, cell proliferation, and HRP-2 and NUPR1 mRNA and protein expression. CONCLUSION: Serum from CHB patients increases cell growth and proliferation and enhances HRP-2 and NUPR1 expression in HCC cells via the IGF-II/IGF-IR/MEK/ERK signaling pathway. These findings help to explain the molecular mechanisms underlying HBV-related HCC and may lead to the development of effective therapies. PMID- 29763917 TI - Relevance of Dementia in Atrial Fibrillation Patients within a Specific European Health Care Area. AB - INTRODUCTION: Atrial fibrillation might increase the risk of dementia. We aim to test the hypothesis that dementia could reclassify the actual risk of stroke and death predicted by the CHA2DS2-VASc in patients with atrial fibrillation (AF). METHODS: A prospective study performed in a specific health care area. RESULTS: From our health care area (n = 348,985), throughout 2013, AF was codified in 7,990 (2.08%). Mean age was 76.83 +/- 10.5, mean CHA2DS2-VASc = 3.5, 4,056 (50.8%) were females and 287 (3.6%) were diagnosed to have dementia. Patients with dementia were older and presented a higher rate of all the components of the CHA2DS2-VASc-expect vasculopathy. Differences in overall mortality were observed but not in stroke and haemorrhagic events. After propensity score matched analysis, dementia was independently associated with all-cause mortality. Addition of dementia to CHA2DS2-VASc reclassified 7.7 and 16.6% of the cohort with regard to thromboembolic events and death risk respectively. CONCLUSIONS: Patients with dementia presented a more adverse risk profile, with significant differences in all-cause mortality. PMID- 29763918 TI - Comprehensive Effects of Suppression of MicroRNA-383 in Human Bone-Marrow-Derived Mesenchymal Stem Cells on Treating Spinal Cord Injury. AB - BACKGROUND/AIMS: Transplantation of bone-marrow-derived mesenchymal stem cells (MSCs) promotes neural cell regeneration after spinal cord injury (SCI). Recently, we showed that suppression of microRNA-383 (miR-383) in MSCs increased the protein levels of glial cell line derived neurotrophic factor (GDNF), resulting in improved therapeutic effects on SCI. However, the overall effects of miR-383 suppression in MSCs on SCI therapy were not determined yet. Here, we addressed this question. METHODS: We used bioinformatics tools to predict all miR 383-targeting genes, confirmed the functional bindings in a dual luciferase reporter assay. The effects of alteration of candidate genes in MSCs on cell proliferation were analyzed by MTT assay and by Western blotting for PCNA. The effects on angiogenesis were assessed by HUVEC assay. The effects on SCI in vivo were analyzed by transplantation of the modified MSCs into nude rats that underwent SCI. RESULTS: Suppression of miR-383 in MSCs not only upregulated GDNF protein, but also increased vascular endothelial growth factor A (VEGF-A) and cyclin-dependent kinase 19 (CDK19), two other miR-383 targets. MiR-383 suppression-induced increases in CDK19 resulted in a slight but significant increase in MSC proliferation, while miR-383-suppression-induced increases in VEGF-A resulted in a slight but significant increase in MSC-mediated angiogenesis. CONCLUSIONS: Upregulation of CDK19 and VEGF-A by miR-383 suppression in MSCs further improve the therapeutic potential of MSCs in treating SCI in rats. PMID- 29763920 TI - Interdisciplinary Management of Testicular Germ Cell Tumors - More Needed than Ever! PMID- 29763919 TI - Inhalation of Hydrogen of Different Concentrations Ameliorates Spinal Cord Injury in Mice by Protecting Spinal Cord Neurons from Apoptosis, Oxidative Injury and Mitochondrial Structure Damages. AB - BACKGROUND/AIMS: Hydrogen selectively neutralizes reactive oxygen species (ROS) and ameliorates various ROS-induced injuries. Spinal cord injury (SCI) is a serious injury to the central nervous system, and secondary SCI is closely related to excessive ROS generation. We hypothesized that hydrogen inhalation ameliorates SCI, and the mechanism of action may be related to the protective effects of hydrogen against oxidative stress, apoptosis, and mitochondrial damage. METHODS: Mechanically injured spinal cord neurons were incubated with different concentrations of hydrogen in vitro. Immunofluorescence staining and transmission electron microscopy were used to confirm the protective effects of hydrogen. ROS and related proteins were detected with dihydroethidium fluorescence staining, enzyme-linked immunosorbent assays, and western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays, flow cytometry, and western blotting were used to detect neuronal apoptosis. ATP concentrations, Janus Green B staining, and mitochondrial permeability transition pore (mPTP) status were assessed to investigate mitochondrial damage. RNA sequencing was performed to screen potential target genes of hydrogen application. Hydrogen was administered to mice after spinal cord contusion injury was established for 42 days. The Basso Mouse Scale (BMS) and footprint analyses were used to assess locomotor functions, and immunofluorescence staining of the injured spinal cord segments was performed to detect oxidative stress status. RESULTS: Spinal cord neurons were preserved by hydrogen administration after mechanical injury in a dose-dependent manner. ROS generation, oxidative stress injury-related markers, and the number of apoptotic neurons were significantly reduced after hydrogen treatment. The ATP production and mPTP function in injured neurons were preserved by hydrogen incubation. The expression levels of Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were inhibited by hydrogen treatment. BMS scores and the footprint assessment of mice with SCI were improved by hydrogen inhalation. CONCLUSIONS: Hydrogen inhalation (75%) ameliorated SCI in vivo and attenuated neuronal mechanical injuries in vitro, and its protective effect on spinal cord neurons was exerted in a dose-dependent manner. The underlying mechanisms included reducing ROS generation and oxidative stress, inhibiting neuronal apoptosis, and restoring mitochondrial construction and function. Cox8b, Cox6a2, Cox7a1, Hspb7, and Atp2a1 were identified as potential target genes of hydrogen treatment. PMID- 29763922 TI - Testis-Sparing Surgery in Patients with Germ Cell Cancer: Indications and Clinical Outcome. AB - Testicular cancer affects mainly young men between 20 and 30 years of age. Due to the availability of effective chemotherapy, the majority of patients are cured. Despite an increased risk of metachronous testicular cancer, it should be carefully considered whether immediate orchiectomy is indicated. This mini review gives an account of the available literature on testis-sparing surgery in patients with unilateral or bilateral synchronous or metachronous testicular cancer. PMID- 29763921 TI - Peptidomic Analysis of Endometrial Tissue from Patients with Ovarian Endometriosis. AB - BACKGROUND/AIMS: Ovarian endometriosis (OvE) is ovarian cyst that is lined with endometrial tissue. They are found in 17-44% of women with endometriosis. Their clinical manifestations include pelvic pain, dysmenorrhea, dyspareunia, and infertility. Although the incidence of OvE has increased yearly, the exact pathogenesis of OvE is still unclear. We used peptidomics, an emerging branch of proteomics, to identify differentially expressed peptides in order to determine the possible roles of these peptides in the pathogenesis of OvE. METHODS: The ectopic and eutopic endometria of OvE were used to extract peptides with 10-kDa molecular weight cutoff filters, and the peptide precursor proteins were then identified with PEAKS software, followed by quantification with the TMT labeling method and subsequent analysis by liquid chromatography-tandem mass spectrometry. Gene ontology (GO) analysis, pathway analysis, SMART, and SABLE were used to study the possible functions of these peptide according to their precursor proteins' function. The effects of peptides derived from VCAM-1 (PDFV) on endometrial stromal cell (ESC) migration and invasion were examined with wound healing assays and Transwell assays and the expression of E-cadherin was detected by western blotting. RESULTS: A total of 491 peptides were identified with abundant differences between the two groups of samples (p < 0.05, and absolute fold change >= 2). SMART and SABLE database showed that 42 of the 491 peptides were located in the conserved structural domains of their protein precursors and contained secondary structure and, among them, 2 peptides' precursor proteins were associated with the cell proliferation. Additionally, 5 peptides' precursor proteins were associated with endometriosis. Our study confirmed that PDFV promoted ESC migration and invasion and reduced E-cadherin expression (p < 0.05). CONCLUSION: PDFV and its precursor protein VCAM-1 may be involved in the process of OvE formation by reducing the expression of E-cadherin. The peptidomics analysis provides new insight for future studies of the mechanisms of OvE development. PMID- 29763923 TI - Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients. AB - BACKGROUND: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. METHODS: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. RESULTS: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. CONCLUSIONS: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients. PMID- 29763924 TI - Absence of Complications after Endoscopic Mucosal Biopsy. AB - BACKGROUND: There is no clarity with regard to the occurrence of serious complications from EGD-driven mucosal biopsy. This is important for considering both clinically indicated procedures and mucosal sampling for research. METHODS: We sought to quantify rates of serious complications from esophagogastroduodenoscopy (EGD) with biopsy. We studied 13,233 patients undergoing outpatient EGD with biopsy over 5 years in 2 North Dakota community hospitals, based on the reasoning that serious complications would cause hospitalization within 30 days. We reviewed the records of all patients with a diagnostic or procedure code or admission within 30 days after the outpatient EGD with biopsy. RESULTS: Of the 13,233 patients who underwent outpatient EGD with biopsy, 411 were admitted within 30 days, most of them because of their underlying diagnosis. Two patients were admitted due to complications that resulted because of additional simultaneous procedures. No patient was admitted because of complications that could be ascribed to conscious sedation, upper GI endoscopic access, or mucosal biopsy. CONCLUSIONS: These data confirm that EGD biopsy is safe within community settings and suggest that the risk/benefit ratio for performing EGD biopsy for research is likely to be favorable if the research has scientific merit. Serious complications or perforation following EGD biopsy did not occur in 13,233 patients in community hospitals in North Dakota. PMID- 29763926 TI - Clinical Stage IIA-IIC Seminoma: Radiation Therapy versus Systemic Chemotherapy versus Retroperitoneal Lymph Node Dissection. AB - BACKGROUND: Clinical stage II (CSII) seminoma is defined by the presence of pure seminoma accompanied by retroperitoneal lymph node metastases. In patients with bulky disease (lymph nodes > 5 cm in diameter), platinum-based chemotherapy is the widely accepted standard of care. However, the optimal choice of treatment for CSIIA and IIB is more controversial. METHODS: We performed a PubMed search using the key words stage II seminoma, BEP (cisplatin, etoposide, and bleomycin), hockey-stick radiotherapy, dog-leg radiotherapy and retroperitoneal lymph node dissection. Most relevant publications were summarized for this review. RESULTS: To date, no randomized trials have prospectively compared radiotherapy (RT), chemotherapy (CT) and retroperitoneal lymph node dissection (RLND) for CSII seminoma. Because of the predominantly retrospective analyses and only few prospective trials data interpretation is complex. In CSIIA with lymph nodes of < 2 cm, RT and CT seem to be equally effective, while in CSIIB, a decreased number of relapses were observed in CT-treated patients. In addition, RT seems to be associated with a higher incidence of long-term sequelae when compared with CT. CONCLUSION: Prospective clinical trials are needed to systematically compare the different treatment modalities. De-escalation of treatment intensity without loss of efficacy is required to improve long-term outcome for this young patient population. PMID- 29763927 TI - Reactive Lymphoid Hyperplasia or Tubercular Lymphadenitis: Can Real-Time PCR on Fine-Needle Aspirates Help Physicians in Concluding the Diagnosis? AB - BACKGROUND: Enlarged lymph nodes in adult patients often present a diagnostic challenge. In the absence of granuloma or necrosis, the cytology/tissue findings are misleading and relate the enlarged lymph nodes to reactive lymphoid hyperplasia (RLH), because granuloma formation is an immunological response that usually takes 14-100 days to develop. This study assesses the role of real-time (RT)-PCR in the diagnosis of the Mycobacterium complex (MTBC) in lymph node aspirates compared with culture in cases of RLH. METHODS: A cross-sectional study was conducted on 112 patients, aged 15-74 years, with a diagnosis of RLH on cytology. RT-PCR for MTBC detection and culture on Lowenstein-Jensen medium for tubercular bacilli was done on lymph node aspirates. Comparative values with reference to culture were calculated. The chi2 value, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios (LR) were calculated. RESULTS: Out of 112 RLH cases, 35 (31%) were positive on both RT-PCR and culture. RT-PCR was positive in 43 cases and culture was positive in 44 cases. The chi2 test was found to be highly significant. PPV, NPV, positive LR, and negative LR were 81.4%, 87%, 6.76, and 0.23, respectively. CONCLUSION: RT-PCR for MTBC proves to be useful in arriving at a conclusive diagnosis in patients with a cytological diagnosis of RLH. PMID- 29763925 TI - The Influence of Hyperlipidemia on Endothelial Function of FPN1 Tek-Cre Mice and the Intervention Effect of Tetramethylpyrazine. AB - BACKGROUND/AIMS: Systemic iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including AS (Atherosclerosis). The hepcidin-ferroportin axis plays the key role in regulation of iron homeostasis and modulation of this signaling could be a potential therapeutic strategy in the treatment of these diseases. TMP (Tetramethylpyrazine) has been reported to have therapeutical effect on AS. Here, we aimed to investigate the effect of iron overload under hyperlipidemia condition on the endothelial injury, inflammation and oxidative stress by employing FPN1 Tek-cre mouse model with or without TMP intervention. METHODS: Subjects for this study were 80 FPN1 Tek-cre mice and 40 C57BL/6 mice and we randomly divided them into six groups: Group N: C57BL/6 mice with normal diet, Group M: C57BL/6 mice with high-fat diet, Group FN: FPN1 Tek cre mice with normal diet, Group FNT: FPN1 Tek-cre mice with normal diet and TMP injection, Group FM: FPN1 Tek-cre mice with high-fat diet, Group FMT: FPN1 Tek cre mice with high-fat diet and TMP injection. After seven days of treatment, blood samples were obtained to detect the levels of blood lipids, Hepcidin, NO, ET-1, ROS, MDA, SOD, IL-1, IL-6 and TNF-alpha respectively. The liver and aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE). RESULTS: Hyperlipidemia could cause iron overload in the aorta and increased serum hepcidin level, particularly in FPN1 Tek-cre mice, and can be reversed by TMP intervention. Knockout of Fpn1 induced increase of serum hepcidin, exacerbated endothelial dysfunction, oxidative stress and inflammatory response, particularly under hyperlipidemia condition. TMP intervention attenuated these processes. CONCLUSIONS: Our study signifies the potential application of certain natural compounds to ameliorating iron disorders induced by hyperlipidemia and protecting on endothelial function through modulation of hepcidin-ferroportin signaling. PMID- 29763929 TI - Using Gene Genealogies to Localize Rare Variants Associated with Complex Traits in Diploid Populations. AB - BACKGROUND AND AIMS: Many methods can detect trait association with causal variants in candidate genomic regions; however, a comparison of their ability to localize causal variants is lacking. We extend a previous study of the detection abilities of these methods to a comparison of their localization abilities. METHODS: Through coalescent simulation, we compare several popular association methods. Cases and controls are sampled from a diploid population to mimic human studies. As benchmarks for comparison, we include two methods that cluster phenotypes on the true genealogical trees: a naive Mantel test considered previously in haploid populations and an extension that takes into account whether case haplotypes carry a causal variant. We first work through a simulated dataset to illustrate the methods. We then perform a simulation study to score the localization and detection properties. RESULTS: In our simulations, the association signal was localized least precisely by the naive Mantel test and most precisely by its extension. Most other approaches had intermediate performance similar to the single-variant Fisher exact test. CONCLUSIONS: Our results confirm earlier findings in haploid populations about potential gains in performance from genealogy-based approaches. They also highlight differences between haploid and diploid populations when localizing and detecting causal variants. PMID- 29763928 TI - Identification and Verification of Candidate Genes Regulating Neural Stem Cells Behavior Under Hypoxia. AB - BACKGROUND/AIMS: Neural stem cells (NSCs) reside in a hypoxic environment, and hypoxia plays an important role in their development and differentiation. This study aimed to explore the underlying mechanisms by which hypoxia affects NSC behavior. METHODS: In the current study, we downloaded the gene expression dataset GSE68572 and identified the differentially expressed genes (DEGs) by analyzing high-throughput gene expression in hypoxic and normoxic NSCs. Subsequently, we analyzed these data using a combined bioinformatics approach and predicted the microRNAs (miRNAs) targeting the key gene using miRNA databases. Quantitative real-time PCR (qRT-PCR) was used to validate the expression of the top five DEGs. RESULTS: In total, 1347 genes were identified as DEGs. We identified the predominant gene ontology categories and Kyoto Encyclopedia of Genes and Genomes pathways that were significantly over-represented in the hypoxic NSCs. A protein-protein interaction network he identification of miRNAs and their putative targets may offer new diagnostic and therapeutic strategies for liver cancer the top 10 core genes. Vascular endothelial growth factor A (VEGFA) had the highest degree and may be the key gene concerning NSC behavior under hypoxia. Further validation of the top five DEGs by qRT-PCR demonstrated that four DEGs were significantly higher and one DEG was significantly lower in the hypoxic group than in the control group. Seven miRNAs were predicted and proved to target VEGFA. CONCLUSION: This preliminary study can prompt the understanding of the molecular mechanisms by which hypoxia has an impact on NSC behavior and can help to optimize stem cell therapies for central nervous system injuries and diseases. PMID- 29763930 TI - Rotigotine Improves Abnormal Circadian Rhythm of Blood Pressure in Parkinson's Disease. AB - INTRODUCTION: Cardiovascular autonomic failure is commonly associated with Parkinson's disease (PD), affecting the daily lives of patients. Rotigotine was recently reported not to influence cardiovascular autonomic responses in contrast to other dopaminergic drugs. The effect of rotigotine on daily blood pressure (BP) fluctuations might reflect autonomic failure in patients with PD. METHODS: Twenty-five PD patients who were receiving rotigotine and 12 patients not receiving rotigotine were recruited. Systolic BP during the daytime and nighttime was measured by 24-h BP monitoring at an interval of 2 years. The patients were divided into 3 groups according to the BP fluctuation type: dippers (nocturnal fall in BP >=10%), non-dippers (0-10%), and risers (< 0%). The time course of BP was compared between the patients given rotigotine and those not given rotigotine. RESULTS: Among the 25 patients who received rotigotine, the BP type worsened in 2 patients, was unchanged in 16 patients, and improved in 7 patients. Among the 12 patients who were not receiving rotigotine, the BP type worsened in 5 patients, was unchanged in 4 patients, and improved only in 3 patients (p = 0.042). CONCLUSION: Rotigotine improves the abnormal circadian rhythm of BP in patients with PD. Rotigotine was suggested to have favorable effects on cardiovascular autonomic responses and circadian rhythm in patients with PD. PMID- 29763931 TI - A functional Variant (Rs35592567) in TP63 at 3q28 is Associated with Gastric Cancer Risk via Modifying its Regulation by MicroRNA-140. AB - BACKGROUND/AIMS: TP63 was believed to play an important role in the development of many malignancies, while the polymorphisms located at the miRNA binding sites within the 3'UTR of TP63 mRNA may interfere with its expression. In this study, we aimed to study the role of TP63 regulation in the tumorigenesis of gastric cancer (GC). METHODS: Computational and luciferase analysis were used to search and confirm the target of miR-140. Real-time PCR, western-blot, MTT assay, and flow cytometry cell cycle analysis were utilized to explore the molecular pathway of miR-140 involved in the progression of GC. RESULTS: TP63 was identified as a direct target gene of miR-140. In HT-29 cells over-expressing miR-140, the luciferase activity was decreased when the cells were transfected with wild-type TP63 3'UTR, but remained unchanged when the cells were transfected with mutant 1 and mutant 2 TP63 3'UTR. In addition, the level of TP63 in HT-29 cells transfected with miR-140 mimic was evidently down-regulated, whereas the level of TP63 in HT-29 cells transfected with miR-140 inhibitor was significantly up regulated. Furthermore, based on the results from MTT assay and flow cytometry cell cycle analysis, HT-29 cells transfected with miR-140 mimics were associated with significantly higher viability compared to the cells transfected with the control plasmid, suggesting that an increased expression of miR-140 protected HT 29 cells against apoptosis. Finally, when miR-140 expression was high, the number of cells at the G1 phase was notably increased, accompanied by a remarkably diminished number of cells at the S phase. CONCLUSIONS: The rs35592567 polymorphism in TP63 affected the expression of TP63 by interfering with its interaction with miR-140, and could serve as an explanation for the increased risk of GC. PMID- 29763933 TI - The Calcium-Sensing Receptor Gene Polymorphism rs1801725 and Calcium-Related Phenotypes in Hemodialysis Patients. AB - BACKGROUND/AIMS: The calcium-sensing receptor gene (CASR) rs1801725 variant is responsible for a non-conservative amino-acid change (A986S) in the calcium sensing receptor cytoplasmic tail. We hypothesized that rs1801725 polymorphism might be helpful in understanding Ca-related abnormalities in HD patients. METHODS: In 1215 subjects (245 on cinacalcet), we determined the associations of rs1801725 with secondary hyperparathyroidism (sHPT)-related laboratory parameters, PTH-decreasing effect of cinacalcet hydrochloride, coronary artery disease (CAD), myocardial infarction (MI), nephrolithiasis-related ESRD, and mortality. CASR rs7652589(AT) haplotypes and rs1801725 epistatic interactions with vitamin D signaling pathway genes were examined for associations with selected phenotypes. RESULTS: The rs1801725 variant allele showed an increasing independent effect on plasma PTH (Pcorrected = 0.009). CASR rs7652589_rs1801725 AT haplotype was associated with 1.7-fold higher frequency of PTH levels over 437 pg/mL than the reference haplotype GG (P = 0.001). CASR rs7652589_rs1801725 AG haplotype was 1.5-fold more frequent in nephrolithiasis related ESRD than the GG haplotype (P = 0.004). There were no significant associations between rs1801725, CAD, MI, and response to cinacalcet. Variant homozygosity of rs1801725 correlated independently with higher infection-related mortality compared with heterozygosity (HR 7.95, 95%CI 2.15 - 29.37, P = 0.003) and major homozygosity (HR 5.89, 95%CI 1.69 - 20.55, P = 0.040). CASR rs1801725 did not show epistatic interactions with vitamin D signaling pathway genes concerning tested associations. CONCLUSION: The variant allele of CASR rs1801725 solely and together with the variant allele of rs7652589 increases risk of more advanced sHPT. Homozygosity of the rs1801725 variant allele contributes to infection-related mortality in HD patients. PMID- 29763934 TI - Inactivation of USP14 Perturbs Ubiquitin Homeostasis and Delays the Cell Cycle in Mouse Embryonic Fibroblasts and in Fruit Fly Drosophila. AB - BACKGROUND/AIMS: The 26S proteasome is the key proteolytic complex for recognition and degradation of polyubiquitinated target substrates in eukaryotes. Among numerous proteasome-associated proteins, a deubiquitinating enzyme (DUB) USP14 has been identified as an endogenous inhibitor of the proteasome. Here, we explored the complex regulatory functions of USP14 that involve ubiquitin (Ub) homeostasis and substrate degradation in flies and mammals. METHODS: USP14-null primary and immortalized mouse embryonic fibroblasts (MEFs) and USP14 knocked down Drosophila were analyzed in this study. We measured proteasome and DUB activities using fluorogenic reporter substrates and adduct-forming probes. To examine the levels of ubiquitin, we performed immunoblotting and immunohistochemistry. Mass spectrometry (MS) was used to examine polyUb chain linkages and USP14-interacing proteins. Cell cycle was analyzed by flow cytometry, BrdU labeling, and phospho-histone H3 staining. RESULTS: The homeostasis of Ub in USP14-/-MEFs was markedly perturbed because of facilitated clearance of Ub. This phenomenon was recapitulated in muscles of USP14-deficient Drosophila with old ages. Absolute quantitation using MS also revealed that USP14 /- MEFs contained significantly increased amounts of Ub, compared with wild-type. The key phenotype of USP14-/- MEFs was their delayed proliferation originated from prolonged interphase possibly through aberrant degradation of cyclins A and B1. We found that knocking down USP14 in Drosophila resulted in delayed eye development associated with reduced mitotic activity. CONCLUSION: Our study identifies novel cellular functions of USP14 not only in cellular Ub hometostasis but also in cell cycle progression. USP14 was also essential for proper Drosophila eye development. These results strongly suggest that the USP14 mediated proteasome activity regulation may be directly related to various human diseases including cancer. PMID- 29763935 TI - Comorbidities Are Associated with Altered Health Services Use in Multiple Sclerosis: A Prospective Cohort Study. AB - BACKGROUND: Persons with multiple sclerosis (MS) use health resources with greater frequency than the general population. However, little is known regarding which patient characteristics might contribute. OBJECTIVE: The study aimed to evaluate characteristics associated with healthcare use in MS patients. METHODS: Consecutive MS clinic attendees were recruited (September-November 2010), with clinical, demographic, and patient-completed questionnaires collected at 3 visits over 2 years. Linkage with administrative data (hospital, physician, and pharmacy records) provided healthcare use outcomes until December 31, 2013. Findings were reported as adjusted rate ratios (adjRRs) using negative binomial regression. RESULTS: A total of 340 MS patients with a mean (SD) age of 48.4 (12.0) years and subsequent follow-up of 3.1 (0.34) years were included. Fatigue and high physical comorbidity count (>=3 vs. none) were significantly associated with higher rates of physician encounters (adjRRs: 1.37 and 1.52, respectively), prescriptions filled (adjRRs: 1.25 and 1.40), and hospitalizations (adjRRs: 4.02 and 3.45). In addition, anxiety, disruptive pain, and perceived functional cognitive difficulties were associated with higher rates of physician encounters and prescriptions dispensed (adjRR ranged from 1.28 to 1.48). DISCUSSION: The presence of fatigue and higher physical comorbidity burden were associated with higher rates of health services use. Findings have implications for those examining healthcare burden or organizing health services for persons with MS. PMID- 29763932 TI - Microvesicles from Human Adipose Tissue-Derived Mesenchymal Stem Cells as a New Protective Strategy in Osteoarthritic Chondrocytes. AB - BACKGROUND/AIMS: Chronic inflammation contributes to cartilage degeneration during the progression of osteoarthritis (OA). Adipose tissue-derived mesenchymal stem cells (AD-MSC) show great potential to treat inflammatory and degradative processes in OA and have demonstrated paracrine effects in chondrocytes. In the present work, we have isolated and characterized the extracellular vesicles from human AD-MSC to investigate their role in the chondroprotective actions of these cells. METHODS: AD-MSC were isolated by collagenase treatment from adipose tissue from healthy individuals subjected to abdominal lipectomy surgery. Microvesicles and exosomes were obtained from conditioned medium by filtration and differential centrifugation. Chondrocytes from OA patients were used in primary culture and stimulated with 10 ng/ml interleukin(IL)-1beta in the presence or absence of AD MSC microvesicles, exosomes or conditioned medium. Protein expression was investigated by ELISA and immunofluorescence, transcription factor-DNA binding by ELISA, gene expression by real-time PCR, prostaglandin E2 (PGE2) by radioimmunoassay, and matrix metalloproteinase (MMP) activity and nitric oxide (NO) production by fluorometry. RESULTS: In OA chondrocytes stimulated with IL 1beta, microvesicles and exosomes reduced the production of inflammatory mediators tumor necrosis factor-alpha, IL-6, PGE2 and NO. The downregulation of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 would lead to the decreased PGE2 production while the effect on NO could depend on the reduction of inducible nitric oxide synthase expression. Treatment of OA chondrocytes with extracellular vesicles also decreased the release of MMP activity and MMP-13 expression whereas the production of the anti-inflammatory cytokine IL-10 and the expression of collagen II were significantly enhanced. The reduction of inflammatory and catabolic mediators could be the consequence of a lower activation of nuclear factor-kappaB and activator protein-1. The upregulation of annexin A1 specially in MV may contribute to the anti-inflammatory and chondroprotective effects of AD-MSC. CONCLUSIONS: Our data support the interest of AD-MSC extracellular vesicles to develop new therapeutic approaches in joint conditions. PMID- 29763938 TI - ? PMID- 29763936 TI - Synergistic Inhibition of Thalidomide and Icotinib on Human Non-Small Cell Lung Carcinomas Through ERK and AKT Signaling. AB - BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been widely used in the treatment of non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. However, the survival of patients with EGFR-TKI administration is limited by the inevitable development of acquired drug resistance. Recently, multi-targeted drugs combination has been shown to be a promising strategy to improve the efficacy of EGFR-TKI treatment and enable the reduction of drug resistance in NSCLC. MATERIAL AND METHODS Humanized NSCLC cell lines PC9 and A549 were co-cultured with thalidomide and/or icotinib to test for anti-tumor efficiency. Cell proliferation was measured by MTT assay, cell apoptosis by flow cytometry and cell migration by wound healing assay. Western blot was performed to determine the expression of caspase-3, -8, -9, Bax, EGFR, VEGF-R, AKT, ERK, MMP2, MMP9, and NF-kappaB. The xenograft mouse model was used to explore the effects of thalidomide and icotinib in vivo. Immunohistochemical testing was used to determine the expression of Ki-67 and TUNEL staining in tumor tissues. RESULTS Treatments of thalidomide and/or icotinib reduced cell viability, induced apoptosis, and suppressed migration. Attenuation of pEGFR and pVEGF-R resulted in deactivation of ERK and AKT pathways, which eventually increased the anti-proliferative response. In PC9 xenograft model, combined administration of thalidomide and icotinib restrained tumor growth with remarkable reduced Ki-67 index and increased TUNEL positive cells. CONCLUSIONS Thalidomide sensitizes icotinib to increase apoptosis and prevent migration, and it may be a potentially promising anti-tumor drug in lung cancer multi-modality therapy. PMID- 29763937 TI - Bacteriophage cocktail for biocontrol of Escherichia coli O157:H7: Stability and potential allergenicity study. AB - Escherichia coli O157:H7 has become a global public health and a food safety problem. Despite the implementation of control strategies that guarantee the safety in various products, outbreaks persist and new alternatives are necessary to reduce this pathogen along the food chain. Recently, our group isolated and characterised lytic bacteriophages against E. coli O157:H7 with potential to be used as biocontrol agents in food. To this end, phages need certain requirements to allow their manufacture and application. The aim of this study was to determine the physical stability and allergenic potential of free and microencapsulated (ME) bacteriophage cocktails against E. coli O157:H7. In vitro and in vivo studies were performed to determine phage survival under different pH, gastrointestinal conditions, temperature and UV light intensities. Results showed that the stability of ME phages was significantly (P<0.05) higher than free phages after ultraviolet irradiation, pH conditions between 3 to 7, and exposure to temperatures between at -80 degrees C and 70 degrees C. Both formulations were highly sensitive to very low pH in simulated gastric fluid, but stable in bile salts. In vivo studies in mice confirmed these phages passed through the gastrointestinal tract and were excreted in faeces. In silico, full length alignment analysis showed that all phage proteins were negative for allergenic potential, but different predicting criteria classified seven phage proteins with a very low probability to be an allergen. In conclusion, these data demonstrated that microencapsulation provided a greater stability to phage formulation under stress conditions and assure a more suitable commercial formulation for the biological control of E. coli O157:H7. PMID- 29763939 TI - Erratum: Intra-Arterial Thrombolytic Therapy Is Not a Therapeutic Option for Filler-Related Central Retinal Artery Occlusion. PMID- 29763940 TI - Simultaneous Septal Perforation Repair with Septorhinoplasty: A 31-Year Experience. AB - Septal perforation repair and septorhinoplasty (SRP) each present unique surgical challenges. However, in many instances, these procedures may be performed together successfully. In this study, the authors aim to determine the safety and effectiveness of combining primary or revision SRP and septal perforation repair via an open approach. A retrospective review was carried out of all consecutive patients who had SRP and septal perforation repair via an open approach between 1986 and 2017 in the senior author's practice. Perforation closure in surgery and at the patient's last follow-up, resolution of presenting symptoms, cosmetic results, and complications were analyzed. Records for 141 patients who had simultaneous septal perforation repair and SRP via an open approach, with a mean follow-up of 3.24 years, were reviewed. The mean anterior-posterior perforation dimension was 1.41 +/- 0.89 cm, and the mean vertical perforation dimension was 1.16 +/- 0.59 cm. The most common etiologies for septal perforation were previous SRP (35.4%) and septoplasty (24.1%). An overall 93.6%, perforation closure, 91.1% symptom relief, and 91.2% patient satisfaction with cosmetic results were achieved. Septal perforations under 1.5 cm in height were closed in 96.7% of patients as opposed to 71.4% of patients with perforations 1.5 cm or taller. Minor revision rhinoplasties were performed in 7.0% of patients. Postoperative infections were rare and noted in only two (1.4%) patients. In the largest study of its kind to date, the authors have shown that in experienced hands septal perforation repair may be performed simultaneously with primary or revision SRP via an open approach without compromising the perforation repair outcome. The vertical dimension of a septal perforation and presence of mucosa above and below a perforation are important considerations for the difficulty of a perforation closure, as septal mucosa is recruited from these locations in our technique of four-quadrant intranasal bipedicled mucosal advancement flap closure. PMID- 29763942 TI - ? PMID- 29763941 TI - Comprehensive Surgical Strategies for the Management of Pachydermoperiostosis. AB - The cosmetic and functional deformities induced by thickened folds and furrows are the main complaints of patients in pachydermoperiostosis (PDP). However, traditional drug therapy only has a limited effect for its unclear genetic pathogenesis. Surgical treatment has now become one of the optimal strategies mainly aiming for its cosmetic improvement. Here we describe a comprehensive management of PDP approached with surgical procedure thereby showing markedly improved cosmetic outcome. Experientially, the surgical treatment of PDP is effective and may be preferentially recommended for PDP patients especially of severe degree. PMID- 29763943 TI - Limonoids from Aphanamixis polystachya Leaves and Their Interaction with Hsp90. AB - A phytochemical study of n-hexane, CHCl3, and CHCl3-MeOH extracts of Aphanamixis polystachya leaves led to the isolation of 10 compounds. Five of them turned out to be new natural compounds, including two mexicanolide-type (1, 2: ) and three polyoxyphragmalin-type (3: -5: ) limonoids, together with two known andirobin type limonoids (6, 7: ) and three phenolic derivatives. The structures of the new compounds were established on the basis of spectroscopic methods to be 8-hydro 14,15-en-cabralin (1: ), 3-deacetyl-8-hydro-cabralin-14,15-en-3-one (2: ), 20,22 dihydroxy-21,23-dimethoxytetrahydrofuran khayanolide A (3: ), 1-deacetyl-3 dehydroxy-3-oxokhaysenelide E (4: ), and meliaphanamixin A (5: ). All compounds were isolated for the first time from this species. The ability of the isolated limonoids to interact with the molecular chaperone Hsp90 was tested. Compounds 6: and 7: were the most active. PMID- 29763946 TI - ? PMID- 29763944 TI - Baicalin Ameliorates Imiquimod-Induced Psoriasis-Like Inflammation in Mice. AB - Baicalin is the main flavonoid from the roots of an important medicinal plant, Scutellaria baicalensis, which shows a variety biological activities. Psoriasis is a chronic immune-mediated inflammatory disease that affects the skin. The unmet need of psoriasis is that many patients do not respond adequately to available clinical treatment. In this study, we found that baicalin showed inhibited dermal inflammation in a murine model of psoriasis via topical application of imiquimod. After a 5-day topical imiquimod application, baicalin or the control vehicle cream was to applied to the lesions of BALB/c mice for a further 4 days. The erythema, scaling, and thickness of the epidermal layer significantly improved in the baicalin-treated mice. The levels of interleukin 17A, interleukin-22, interleukin-23, and tumor necrosis factor in the skin significantly decreased after baicalin treatment. Baicalin also inhibited imiquimod-induced interleukin-17A production in skin draining lymph node cells. The infiltration of gammadelta T cells into the skin lesions induced by imiquimod was also suppressed after baicalin treatment. These results suggest that baicalin inhibited skin inflammation through the inhibition of the interleukin 17/interleukin-23 axis in a murine model of psoriasis. PMID- 29763945 TI - Leishmanicidal Effects of Piperlongumine (Piplartine) and Its Putative Metabolites. AB - Piperlongumine is an amide alkaloid found in Piperaceae species that shows a broad spectrum of biological properties, including antitumor and antiparasitic activities. Herein, the leishmanicidal effect of piperlongumine and its derivatives produced by a biomimetic model using metalloporphyrins was investigated. The results showed that IC50 values of piperlongumine in promastigote forms of Leishmania infantum and Leishmania amazonensis were 7.9 and 3.3 uM, respectively. The IC50 value of piperlongumine in the intracellular amastigote form of L. amazonensis was 0.4 uM, with a selectivity index of 25. The piperlongumine biomimetic derivatives, Ma and Mb, also showed leishmanicidal effects. We also carried out an in vitro metabolic degradation study showing that Ma is the most stable piperlongumine derivative in rat liver microsome incubations. The results presented here indicate that piperlongumine is a potential leishmanicidal candidate and support the biomimetic approach for development of new antileishmanial derivatives. PMID- 29763947 TI - ? PMID- 29763948 TI - ? PMID- 29763950 TI - ? PMID- 29763949 TI - [Radiological Findings in Osteopoikilosis]. PMID- 29763954 TI - ? PMID- 29763953 TI - In reply. PMID- 29763952 TI - Appropriate Normal Range of Lumbar Disc T1rho of Men and Women with Respect to Physiological Aging. PMID- 29763955 TI - ? PMID- 29763951 TI - Dynamic 4D-CT Angiography for Guiding Transarterial Chemoembolization: Impact on the Reduction of Contrast Material, Operator Radiation Exposure, Catheter Consumption, and Diagnostic Confidence. AB - PURPOSE: This study was carried out to investigate the impact of abdominal dynamic four-dimensional CT angiography (4D-CTA) for guiding transarterial chemoembolization (TACE) on the amount of contrast material used, operator radiation exposure, catheter consumption, and diagnostic confidence. MATERIALS AND METHODS: Written consent was waived for this IRB-approved retrospective study. 29 patients (20 men; mean age: 65.7 +/- 11.5 years) with malignant liver lesions underwent 4D-CTA, prior to initial TACE. Time-resolved volume-rendering technique (VRT), maximum-intensity projection (MIP), and multiplanar reconstruction (MPR) series were reconstructed, enabling a direct selective catheterization of the tumor-supplying artery without prior conventional digital subtraction angiography (DSA). 29 patients (16 men; mean age: 69.4 +/- 13.9) who underwent traditional TACE served as the control group. The amount of administered contrast media, operator radiation exposure, and catheter consumption during TACE were compared. Two radiologists assessed diagnostic confidence in the exclusion of portal vein thrombosis. RESULTS: 4D-CTA TACE resulted in a significant reduction in the amount of contrast media used, compared to traditional TACE (-61.0 ml/ -66.3 % intra-arterial, -12.8 ml/ -13.8 % overall; P < 0.001). The dose-area product indicating operator radiation exposure during intervention was reduced by 50.5 % (P < 0.001), and 0.7 fewer catheters on average were used (P = 0.063), while 4D-CTA data was available to guide TACE. Diagnostic confidence in the exclusion of portal vein thrombosis was significantly enhanced by 4D-CTA, compared to traditional DSA images (scores, 3.9 and 2.4, respectively; P < 0.001). CONCLUSION: Dynamic 4D-CTA enables TACE with a substantially reduced amount of contrast material, decreases operator radiation exposure, and increases diagnostic confidence in the exclusion of portal vein thrombosis. KEY POINTS: . 4D-CTA prior to TACE decreases the amount of utilized contrast material.. . The intra-arterial fraction of contrast media can be reduced by two-thirds.. . The risk of CIN may be decreased by means of 4D-CTA TACE.. . Operator radiation exposure is lower using 4D-CTA for guiding TACE.. . 4D-CTA portography allows for a higher diagnostic confidence than conventional DSA images.. CITATION FORMAT: . Albrecht MH, Vogl TJ, Wichmann JL et al. Dynamic 4D-CT Angiography for Guiding Transarterial Chemoembolization: Impact on the Reduction of Contrast Material, Operator Radiation Exposure, Catheter Consumption, and Diagnostic Confidence. Fortschr Rontgenstr 2018; 190: 513 - 520. PMID- 29763956 TI - ? PMID- 29763957 TI - ? PMID- 29763958 TI - ? PMID- 29763960 TI - ? PMID- 29763961 TI - The Novel Protease-Activated Receptor 1 Antagonist Vorapaxar as a Treatment for Thrombosis in Afibrinogenemia. PMID- 29763959 TI - ? PMID- 29763962 TI - Car Travel-Related Thrombosis: Fact or Fiction? AB - The condition sometimes referred to as "economy class syndrome," and also known as "traveler's thrombosis," is a distinctive pathological condition characterized by occurrence of venous thromboembolism (VTE) in a patient who has recently experienced a long journey (i.e., >= 4 h). Typically, the identified travel is by airplane, but travel with other vehicles, such as trains, trucks, buses, or cars, could potentially qualify as contributing to VTE events. Although the enhanced risk of VTE after long haul flights is now widely acknowledged, albeit potentially overhyped, the risk of venous thrombosis after prolonged travel by other modes of transport, in particular, by cars, is less well appreciated. Current evidence, collected from some epidemiological studies, suggests that if any risk of VTE can be attributed to prolonged and uninterrupted car travels, and we give moderate credibility to such an association, the risk may be similar to that already proven for long haul flights. The risk is especially high in individuals undergoing uninterrupted car journeys lasting 4 hours or longer, in vehicles with a narrow seat-pitch, and in particularly would affect those with pre-existing acquired or inherited prothrombotic conditions. The putative biological mechanisms basically entail venous stasis and edema, which are often compounded by a certain degree of hypercoagulability. When these factors are combined with preexistent prothrombotic conditions, the risk may be substantially magnified. In this perspective, then, 'car thrombosis' may be regarded as a trigger rather than a risk factor for venous thrombosis. Although the current evidence is certainly not solid enough to endorse the use of general chemical prophylaxis for lowering the risk of car-related VTE, a set of possible precautionary measures, with no or very little side effects, may be suggested before planning prolonged car travels, especially for at risk individuals. PMID- 29763963 TI - Medication trade-offs-Not all noncompliance is what it seems. PMID- 29763964 TI - Incidental Fetal Ultrasound Findings: Interpretation and Management. AB - Ultrasonography is a common component of prenatal care worldwide and is often used in early pregnancy to determine gestational age, number of fetuses, fetal cardiac activity, and placental location. Patients and their families may also consider ultrasonography a social event, as it provides confirmation and reassurance of a normal pregnancy. Ultrasound screening is typically scheduled in the second trimester to visualize fetal anatomy and confirm gestational age. Most ultrasound examinations are reassuring, but some incidentally identify structural anomalies and soft markers for aneuploidy, making it necessary for health care providers to correctly interpret these findings. The health care provider's ability to prepare patients prior to the ultrasound and deliver the necessary information needed to make informed decisions regarding any follow-up screening or diagnostic testing is critical to reducing parental anxiety. Preparation for the anatomic survey should include counseling for normal and abnormal findings. The ethical concepts of patient autonomy and shared decision making are used as a guide in providing this critical information and enabling informed choices during follow-up for incidental ultrasound findings. PMID- 29763965 TI - Proximal restoration increases the risk of clinical attachment loss. AB - AIM: To estimate the effect of proximal direct restorations in the adjacent periodontal tissues in adults from a birth cohort. MATERIALS AND METHODS: A representative sample (n = 539) of all 5,914 births occurring in Pelotas, Brazil in 1982 was prospectively investigated, being clinical attachment loss (CAL), probing depth (PD), and bleeding on probing (BOP) assessed at 31-year old. For each site, tooth surface was evaluated as sound or restored, being the restoration extension (subgingival or supragingival) and restoration material (composite and amalgam) considered. Covariables included family income, untreated caries, and service utilization patterns during life course. Multilevel Poisson regression models were used, considering three levels of variables organization: periodontal site, dental, and individual level. RESULTS: Among the 28,796 periodontal sites evaluated, CAL and PD >= 4 mm was observed in 1.5% and 4.8%, respectively. Multilevel models showed that proximal restorations had a significant effect on CAL and PD. Subgingival and amalgam restorations showed greater effect when compared to supragingival and composite restorations, respectively. CONCLUSIONS: The present study partially supports the hypothesis that proximal restorations are associated with the presence of periodontal damage. Although not indicative of disease, a significant increase was observed in CAL and PD at restored sites. PMID- 29763966 TI - Quantitative analysis of thyroid tumors vascularity: A comparison between 3-D contrast-enhanced ultrasound and 3-D Power Doppler on benign and malignant thyroid nodules. AB - PURPOSE: To perform a comparative quantitative analysis of Power Doppler ultrasound (PDUS) and Contrast-Enhancement ultrasound (CEUS) for the quantification of thyroid nodules vascularity patterns, with the goal of identifying biomarkers correlated with the malignancy of the nodule with both imaging techniques. METHODS: We propose a novel method to reconstruct the vascular architecture from 3-D PDUS and CEUS images of thyroid nodules, and to automatically extract seven quantitative features related to the morphology and distribution of vascular network. Features include three tortuosity metrics, the number of vascular trees and branches, the vascular volume density, and the main spatial vascularity pattern. Feature extraction was performed on 20 thyroid lesions (ten benign and ten malignant), of which we acquired both PDUS and CEUS. MANOVA (multivariate analysis of variance) was used to differentiate benign and malignant lesions based on the most significant features. RESULTS: The analysis of the extracted features showed a significant difference between the benign and malignant nodules for both PDUS and CEUS techniques for all the features. Furthermore, by using a linear classifier on the significant features identified by the MANOVA, benign nodules could be entirely separated from the malignant ones. CONCLUSIONS: Our early results confirm the correlation between the morphology and distribution of blood vessels and the malignancy of the lesion, and also show (at least for the dataset used in this study) a considerable similarity in terms of findings of PDUS and CEUS imaging for thyroid nodules diagnosis and classification. PMID- 29763968 TI - Binding to type I collagen is essential for the infectivity of Vibrio parahaemolyticus to host cells. AB - Vibrio parahaemolyticus is a globally present marine bacterium that often leads to acute gastroenteritis. Two type III secretion systems (T3SSs), T3SS1 and T3SS2, are important for host infection. Type I collagen is a component of the extracellular matrix and is abundant in the small intestine. However, whether type I collagen serves as the cellular receptor for V. parahaemolyticus infection of host cells remains enigmatic. In this study, we discovered that type I collagen is not only important for the attachment of V. parahaemolyticus to host cells but is also involved in T3SS1-dependent cytotoxicity. In addition, 2 virulence factors, MAM7 and VpadF enable V. parahaemolyticus to interact with type I collagen and mediate T3SS2-dependent host cell invasion. Type I collagen, the collagen receptor alpha1 integrin, and its downstream factor phosphatidylinositol 3-kinase (PI3K) are responsible for V. parahaemolyticus invasion of host cells. Further biochemical studies revealed that VpadF mainly relies on the C-terminal region for type I collagen binding and MAM7 relies on mce domains to bind to type I collagen. As MAM7 and/or VpadF homologues are widely distributed in the genus Vibrio, we propose that Vibrios have evolved a unique strategy to infect host cells by binding to type I collagen. PMID- 29763969 TI - Hormone replacement therapy for women previously treated for endometrial cancer. AB - BACKGROUND: Endometrial cancer is the sixth most common cancer in women worldwide and most commonly occurs after the menopause (75%) (globocan.iarc.fr). About 319,000 new cases were diagnosed worldwide in 2012. Endometrial cancer is commonly considered as a potentially 'curable cancer,' as approximately 75% of cases are diagnosed before disease has spread outside the uterus (FIGO (International Federation of Gynecology and Obstetrics) stage I). The overall five-year survival for all stages is about 86%, and, if the cancer is confined to the uterus, the five-year survival rate may increase to 97%. The majority of women diagnosed with endometrial cancer have early-stage disease, leading to a good prognosis after hysterectomy and removal of the ovaries (oophorectomy), with or without radiotherapy. However, women may have early physiological and psychological postmenopausal changes, either pre-existing or as a result of oophorectomy, depending on age and menopausal status at the time of diagnosis. Lack of oestrogen can cause hot flushes, night sweats, genital tract atrophy and longer-term adverse effects, such as osteoporosis and cardiovascular disease. These changes may be temporarily managed by using oestrogens, in the form of hormone replacement therapy (HRT). However, there is a theoretical risk of promoting residual tumour cell growth and increasing cancer recurrence. Therefore, this is a potential survival disadvantage in a woman who has a potentially curable cancer. In premenopausal women with endometrial cancer, treatment induces early menopause and this may adversely affect overall survival. Additionally, most women with early-stage disease will be cured of their cancer, making longer-term quality of life (QoL) issues more pertinent. Following bilateral oophorectomy, premenopausal women may develop significant and debilitating menopausal symptoms, so there is a need for information about the risk and benefits of taking HRT, enabling women to make an informed decision, weighing the advantages and disadvantages of using HRT for their individual circumstances. OBJECTIVES: To assess the risks and benefits of HRT (oestrogen alone or oestrogen with progestogen) for women previously treated for endometrial cancer. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to April, week 4, 2017) and Embase (1980 to 2017, week 18). We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs), in all languages, that examined the efficacy of symptom relief and the safety of using HRT in women treated for endometrial cancer, where safety in this situation was considered as not increasing the risk of recurrence of endometrial cancer above that of women not taking HRT. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We identified 2190 unique records, evaluated the full text of seven studies and included one study with 1236 participants. This study reported tumour recurrence in 2.3% of women in the oestrogen arm versus 1.9% of women receiving placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.54 to 2.50; very low certainty evidence). The study reported one woman in the HRT arm (0.16%) and three women in the placebo arm (0.49%) who developed breast cancer (new malignancy) during follow-up (RR 0.80, 95% CI 0.32 to 2.01; 1236 participants, 1 study; very low-certainty evidence). The study did not report on symptom relief, overall survival or progression-free survival for HRT versus placebo. However, they did report the percentage of women alive with no evidence of disease (94.3% in the HRT group and 95.6% in the placebo group) and the percentage of women alive irrespective of disease progression (95.8% in the HRT group and 96.9% in the placebo group) at the end of the 36 months' follow-up. The study did not report time to recurrence and it was underpowered due to closing early. The authors closed it as a result of the publication of the Women's Health Initiative (WHI) study, which, at that time, suggested that risks of exogenous hormone therapy outweighed benefits and had an impact on study recruitment. No assessment of efficacy was reported. AUTHORS' CONCLUSIONS: Currently, there is insufficient high-quality evidence to inform women considering HRT after treatment for endometrial cancer. The available evidence (both the single RCT and non randomised evidence) does not suggest significant harm, if HRT is used after surgical treatment for early-stage endometrial cancer. There is no information available regarding use of HRT in higher-stage endometrial cancer (FIGO stage II and above). The use of HRT after endometrial cancer treatment should be individualised, taking account of the woman's symptoms and preferences, and the uncertainty of evidence for and against HRT use. PMID- 29763970 TI - Technical Note: Experimental verification of magnetic field-induced beam deflection and Bragg peak displacement for MR-integrated proton therapy. AB - PURPOSE: Given its sensitivity to anatomical variations, proton therapy is expected to benefit greatly from integration with magnetic resonance imaging for online anatomy monitoring during irradiation. Such an integration raises several challenges, as both systems mutually interact. The proton beam will experience quasi-continuous energy loss and energy-dependent electromagnetic deflection at the same time, giving rise to a deflected beam trajectory and an altered dose distribution with a displaced Bragg peak. So far, these effects have only been predicted using Monte Carlo and analytical models, but no clear consensus has been reached and experimental benchmark data are lacking. We measured proton beam trajectories and Bragg peak displacement in a homogeneous phantom placed inside a magnetic field and compared them to simulations. METHODS: Planar dose distributions of proton pencil beams (80-180 MeV) traversing the field of a 0.95 T NdFeB permanent magnet while depositing energy in a PMMA slab phantom were measured using EBT3 radiochromic films and simulated using the Geant4 toolkit. Deflected beam trajectories and the Bragg peak displacement were extracted from the measured planar dose distributions and compared against the simulations. RESULTS: The lateral beam deflection was clearly visible on the EBT3 films and ranged from 1 to 10 mm for 80 to 180 MeV, respectively. Simulated and measured beam trajectories and Bragg peak displacement agreed within 0.8 mm for all studied proton energies. CONCLUSIONS: These results prove that the magnetic field induced Bragg peak displacement is both measurable and accurately predictable in a homogeneous phantom at 0.95 T, and allows Monte Carlo simulations to be used as gold standard for proton beam trajectory prediction in similar frameworks for MR integrated proton therapy. PMID- 29763972 TI - Rare cases of hidradenitis suppurativa (Verneuil's disease) of perineum and perianal region. PMID- 29763971 TI - Evaluation of the effects of the solution used for electrochemical dissolution of nickel-titanium endodontic files on dentine structure, microhardness and cell viability. AB - AIM: To evaluate the effects of the [NaF 12 g L-1 + NaCl 1 g L-1 ] solution used in the electrochemical dissolution process of fractured endodontic files, as well as its NiTi-containing product, on dentine hardness, topography and human fibroblast viability. METHODOLOGY: Sixty single-rooted human teeth were evaluated for dentine microhardness using the Vickers hardness test and the area and number of dentinal tubules by scanning electron microscopy. The samples were divided according to the dentine surface treatment: distilled water; 17% EDTA; [NaF 12 g L-1 + NaCl 1 g L-1 ]; and 17% EDTA + [NaF 12 g L-1 + NaCl 1 g L-1 ]. Thirty-six single-rooted human teeth were divided according to the irrigation protocol: Dulbecco's Modified Eagle's Medium + 10% foetal bovine serum; 5.25% NaOCl; [NaF 12 g L-1 + NaCl 1 g L-1 ]; and [NaF 12 g L-1 + NaCl 1 g L-1 + NiTi]. The extracts in contact with the apical foramen were used in the MTT assay to evaluate human fibroblast viability, with dilutions of 100%, 50%, 25% and 12.5%. Statistical tests used were paired t-tests, one-way anova, Tukey's test, Kruskal Wallis test and Dunn's post-test. RESULTS: The [NaF 12 g L-1 + NaCl 1 g L-1 ] solution did not modify dentine microhardness or the average dentinal tubule area. However, EDTA induced changes in dentine structure and microhardness (P < 0.05). The [NaF 12 g L-1 + NaCl 1 g L-1 ] solution, and its NiTi-containing product had lower cytotoxicity than NaOCl at dilutions of 25% and 50% (P < 0.01). CONCLUSIONS: The [NaF 12 g L-1 + NaCl 1 g L-1 ] solution did not alter dentine microhardness or damage the dentine structure. It also demonstrated lower cytotoxicity than NaOCl. PMID- 29763973 TI - Impact of changing the recruitment and interview procedures for cornea donation on the consent rate at a University hospital in Switzerland. PMID- 29763967 TI - Machine learning algorithms for outcome prediction in (chemo)radiotherapy: An empirical comparison of classifiers. AB - PURPOSE: Machine learning classification algorithms (classifiers) for prediction of treatment response are becoming more popular in radiotherapy literature. General Machine learning literature provides evidence in favor of some classifier families (random forest, support vector machine, gradient boosting) in terms of classification performance. The purpose of this study is to compare such classifiers specifically for (chemo)radiotherapy datasets and to estimate their average discriminative performance for radiation treatment outcome prediction. METHODS: We collected 12 datasets (3496 patients) from prior studies on post (chemo)radiotherapy toxicity, survival, or tumor control with clinical, dosimetric, or blood biomarker features from multiple institutions and for different tumor sites, that is, (non-)small-cell lung cancer, head and neck cancer, and meningioma. Six common classification algorithms with built-in feature selection (decision tree, random forest, neural network, support vector machine, elastic net logistic regression, LogitBoost) were applied on each dataset using the popular open-source R package caret. The R code and documentation for the analysis are available online (https://github.com/timodeist/classifier_selection_code). All classifiers were run on each dataset in a 100-repeated nested fivefold cross-validation with hyperparameter tuning. Performance metrics (AUC, calibration slope and intercept, accuracy, Cohen's kappa, and Brier score) were computed. We ranked classifiers by AUC to determine which classifier is likely to also perform well in future studies. We simulated the benefit for potential investigators to select a certain classifier for a new dataset based on our study (pre-selection based on other datasets) or estimating the best classifier for a dataset (set-specific selection based on information from the new dataset) compared with uninformed classifier selection (random selection). RESULTS: Random forest (best in 6/12 datasets) and elastic net logistic regression (best in 4/12 datasets) showed the overall best discrimination, but there was no single best classifier across datasets. Both classifiers had a median AUC rank of 2. Preselection and set-specific selection yielded a significant average AUC improvement of 0.02 and 0.02 over random selection with an average AUC rank improvement of 0.42 and 0.66, respectively. CONCLUSION: Random forest and elastic net logistic regression yield higher discriminative performance in (chemo)radiotherapy outcome and toxicity prediction than other studied classifiers. Thus, one of these two classifiers should be the first choice for investigators when building classification models or to benchmark one's own modeling results against. Our results also show that an informed preselection of classifiers based on existing datasets can improve discrimination over random selection. PMID- 29763974 TI - Engineering a human skin equivalent to study dermis remodelling and epidermis senescence in vitro after UVA exposure. AB - Utra Violet type A (UVA) exposure strongly affects the ageing of human skin by modifying both epidermis and dermis and their cross talk as well. The possibility to get a deep understanding in vitro of such crucial mechanism would have a huge impact in the development of antiageing compounds. Here, we present a full thickness model of human skin equivalent formed by a millimeter-sized dermis completely composed of fibroblasts embedded in their own extracellular matrix. We show that such endogenous nature of the dermis compartment allows the replication of the complexity of the mutual interactions occurring between cellular and extracellular components of the skin under UVA exposure: (a) oxidative stress formation in the whole tissue (dermis and epidermis); (b) senescence of germinative layer of epidermal tissue in terms of p63, ki67, and activated caspase-3 regulation; (c) modification of the collagenous network architecture in the dermis compartment. By using this human skin model, it is possible to study a widely shared assumptions not yet proved in vitro such the effect of UVA on the self-renewal capability of skin stem cells. PMID- 29763976 TI - Effects of Swaddled and Sponge Bathing Methods on Signs of Stress and Pain in Premature Newborns: Implications for Evidence-Based Practice. AB - AIMS: To determine the effects of sponge baths and swaddled bathing on premature infants' vital signs, oxygen saturation levels, crying times, pain, and stress levels. METHODS: This study was a clinical trial with a crossover design. Data were conducted in the neonatal intensive care unit of a public hospital in Denizli, Turkey. A total of 35 premature infants, who were born at 33-37 weeks gestation with a birth weight <1,500 g, were enrolled in the study. Two bathing methods were applied at 3-day intervals. Vital signs and oxygen saturation levels were measured before and at minutes 1, 5, 15, 30 after bathing. Infants' bathing was video recorded to assess pain and stress behaviors. The pain and stress behaviors of infants were evaluated by independent observers. A significance level of .05 was used for all statistical analyses. RESULTS: There were statistically significant differences between bathing methods on vital signs, oxygen saturation levels, and crying times. Levels of stress and pain according to bathing type were significantly higher in the sponge bath condition (p < .05). LINKING EVIDENCE TO ACTION: Swaddled bathing has a positive effect on the infant's vital signs, oxygen saturation levels, crying time, and level of stress and pain compared to the sponge bath condition. Swaddled bathing is a harmless and safe nursing practice. PMID- 29763975 TI - Chemical Constituents of the Seed Cake of Camellia oleifera and Their Antioxidant and Antimelanogenic Activities. AB - There is a growing interest in the exploitation of agricultural byproducts. This study explored the potential beneficial health effects from the main biowaste, tea seed pomace of Camellia oleifera Abel (Theaceae), produced when tea seed is processed. Eighteen compounds were isolated from the 70% EtOH extract of the seed cake of C. oleifera. Their structures were determined by ESI-MS, 1 H- and 13 C NMR together with literature data. All fractions and compounds were evaluated for the antioxidant and melanogenesis inhibitory activities. As the result, AcOEt fraction has the best in vitro antioxidant and antimelanogenesis activities, compounds 7 - 12 and 15 showed remarkable antioxidant activity, compounds 4, 6, 8, and 15 - 17 exhibited superior inhibitory activities against melanogenesis. Furthermore, tyrosinase inhibitory activity assay suggested that compound 8 could suppress melanogenesis by inhibiting the expression of tyrosinase. PMID- 29763977 TI - Transforming Care to Evidence-Based Practice With Scripted Messages: An Improvement Project for Pain Management in Outpatient Surgical Patients. AB - BACKGROUND: Outpatient surgeries are common and most patients experience pain postoperatively requiring nursing attention to pain management. Scripting, recommended for consistent, targeted communication to improve patient satisfaction, has limited evidence to support its use. AIMS: To explore the effect of scripted messages on self-reported pain control and patient satisfaction with care in outpatient surgical patients. METHODS: A retrospective medical record review pre- and postintervention evaluated a pain management scripted message delivered at two time points (preoperatively and postoperatively). Intention to treat analysis compared patient reports of pain control and patient satisfaction with care 48 hours postdischarge from outpatient surgical procedures. RESULTS: A total of 231 records (98 preintervention; 133 postintervention) were analyzed. The sample included 144 (62%) male, 156 (68%) married with mean age of 57.6 (SD = 16.1) years. The majority (90%) received general anesthesia, and the most common surgical procedures were urologic (24%), colorectal (17%), and laparoscopy (13%). A Mann-Whitney U test indicated patient reported pain control was statistically significantly greater for the postintervention group (mean rank = 62.66) compared to the preintervention group (mean rank = 51.95), U = 1,258, p = .01 with an effect size phi = .223. LINKING EVIDENCE TO ACTION: A scripted message showed statistical significance and a small clinical effect in pain control that adds to the body of knowledge around the effectiveness of scripting delivered by nurses. Although it is encouraging that even the small dose of scripting had a significant effect on postoperative pain control, the feasibility issues around similar study designs will require considerable resources to surmount. Practice change is a complex process requiring sensitivity to work and patient flow especially in specialty care units. Resistance to change when evidence is not robust may be especially difficult related to scripting, often perceived as a mandated intrusion into the nurse-patient relationship. PMID- 29763978 TI - Circulating human papillomavirus DNA as a surveillance tool in head and neck squamous cell carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: The incidence of human papillomavirus-induced (HPV+) head and neck squamous cell carcinoma (HNSCC), that is, especially oropharyngeal cancers (OPSCC), is increasing, and a significant proportion of patients encounter disease progression. A simple and sensitive test to identify patients with progression is an unmet need. OBJECTIVE OF REVIEW: To systematically review the literature and carry out a meta-analysis of studies, investigating circulating HPV-DNA as a biomarker for disease progression in patients with HNSCC. TYPE OF REVIEW: A systematic review and meta-analysis. SEARCH STRATEGY: PubMed, EMBASE and the Cochrane Library were systematically searched for articles published in English from January 1980 to November 2017. Search terms used were related to HPV, cancer sites, blood-based biomarkers and terms for specific use settings. EVALUATION METHOD: Articles reviewed and selected by authors and data on study design, demographic variables, location, HPV status, number of pre-treatment blood tests, number of post-treatment blood tests, blood HPV status and number of recurrences and length of follow-up were extracted. A meta-analysis of HPV-DNA as a diagnostic test for recurrence by means of a hierarchical summary receiver operating curve (HSROC) model was performed. RESULTS: We identified 5 studies (n = 600 subjects) examining circulating HPV-DNA in patients with HNSCC. In these 5 studies (n = 411), patients had both pre- and post-treatment blood samples. The pooled sensitivity, in detecting a recurrence, was estimated to be 54% (95% CI: 32%-74%), while the pooled specificity was 98% (95% CI: 93%-99.4%). The pooled false-positive rate is 2% (95% CI: 0.6%-7%). The area under the curve (AUC) of the summary HSROC was 0.93. Positive predictive value was estimated to 93% and the negative predictive value to 94%. CONCLUSIONS: Plasma HPV-DNA is a promising tool for surveillance in patients with HPV-related HNSCC, that is, OPSCC, and has a high specificity. By recent technical advances and by increasing follow-up blood samples, the sensitivity could likely be improved. PMID- 29763979 TI - Extended International Normalized Ratio testing intervals for warfarin-treated patients. AB - : Essentials Warfarin typically requires International Normalized Ratio (INR) testing at least every 4 weeks. We implemented extended INR testing for stable warfarin patients in six anticoagulation clinics. Use of extended INR testing increased from 41.8% to 69.3% over the 3 year study. Use of extended INR testing appeared safe and effective. SUMMARY: Background A previous single-center randomized trial suggested that patients with stable International Normalized Ratio (INR) values could safely receive INR testing as infrequently as every 12 weeks. Objective To test the success of implementation of an extended INR testing interval for stable warfarin patients in a practice-based, multicenter collaborative of anticoagulation clinics. Methods At six anticoagulation clinics, patients were identified as being eligible for extended INR testing on the basis of prior INR value stability and minimal warfarin dose changes between 2014 and 2016. We assessed the frequency with which anticoagulation clinic providers recommended an extended INR testing interval (> 5 weeks) to eligible patients. We also explored safety outcomes for eligible patients, including next INR values, bleeding events, and emergency department visits. Results At least one eligible period for extended INR testing was identified in 890 of 3362 (26.5%) warfarin treated patients. Overall, the use of extended INR testing in eligible patients increased from 41.8% in the first quarter of 2014 to 69.3% in the fourth quarter of 2016. The number of subsequent out-of-range next INR values were similar between eligible patients who did and did not have an extended INR testing interval (27.3% versus 28.4%, respectively). The numbers of major bleeding events were not different between the two groups, but rates of clinically relevant non major bleeding (0.02 per 100 patient-years versus 0.09 per 100 patient-years) and emergency department visits (0.07 per 100 patient-years versus 0.19 per 100 patient-years) were lower for eligible patients with extended INR testing intervals than for those with non-extended INR testing intervals. Conclusions Extended INR testing for stable warfarin patients can be successfully and safely implemented in diverse, practice-based anticoagulation clinic settings. PMID- 29763980 TI - Arterial stiffness in people with Type 2 diabetes and obstructive sleep apnoea. AB - AIMS: To examine whether people with Type 2 diabetes with concurrent obstructive sleep apnoea have increased arterial stiffness as compared with people with Type 2 diabetes without obstructive sleep apnoea. METHODS: In a study with a case control design, 40 people with Type 2 diabetes and treatment-naive moderate to severe obstructive sleep apnoea (Apnoea-Hypopnoea Index >=15) and a control group of 31 people with Type 2 diabetes without obstructive sleep apnoea (Apnoea Hypopnoea Index <5) were examined. Obstructive sleep apnoea status was evaluated using the ApneaLink(r) + home-monitoring device (Resmed Inc., San Diego, CA, USA), providing the Apnoea-Hypopnoea Index scores. Arterial stiffness was assessed according to carotid-femoral pulse wave velocity using the Sphygmocor device and the oscillometric Mobil-O-Graph(r) (I.E.M. GmbH, Stolberg, Germany). RESULTS: Carotid-femoral pulse wave velocity was not significantly different between participants with Type 2 diabetes with obstructive sleep apnoea and those without obstructive sleep apnoea (10.7+/-2.2 m/s vs 10.3+/-2.1 m/s; P=0.513), whereas oscillometric pulse wave velocity was significantly higher in participants with Type 2 diabetes with obstructive sleep apnoea than in those without obstructive sleep apnoea (9.5+/-1.0 m/s vs 8.6+/-1.4 m/s; P=0.002). In multiple regression analysis, age (P=0.002), gender (men; P=0.018) and HbA1c (P=0.027) were associated with carotid-femoral pulse wave velocity, and systolic blood pressure (P=0.004) and age (P<0.001) were associated with oscillometric pulse wave velocity. After adjustment, presence of obstructive sleep apnoea was not independently associated with pulse wave velocity whether assessed by tonometry or oscillometry. CONCLUSION: In conclusion, the present study did not find an age- and blood pressure-independent association between moderate to severe obstructive sleep apnoea and arterial stiffness in non-sleepy people with Type 2 diabetes. (Clinical trial registration number: NCT02482584). PMID- 29763981 TI - Antibacterial activity of Cladanthus arabicus and Bubonium imbricatum essential oils alone and in combination with conventional antibiotics against Enterobacteriaceae isolates. AB - : Multidrug-resistant bacteria have become common all over the world, necessitating the development of new therapeutic strategies. Synergistic interactions between conventional antibiotics and natural bioactive may have therapeutic benefits in a clinical setting. There are plenty of medicinal plants that have proven efficacy against broad spectrum of micro-organisms. The aim of the work was to assess the antibacterial activity of Cladanthus arabicus, a Moroccan medicinal plant, and Bubonium imbricatum, a Moroccan endemic plant. The evaluation of the synergistic effect of extracted essential oils (EOs) together with some conventional antibiotics was also investigated. Checkerboard test was used to evaluate the interaction of EOs in combination with amoxicillin and neomycin. The results showed that EOs contain a potent activity against the tested Enterobacteriaceae isolates, with inhibition zones values in the range of 8.05 +/- 0.1 and 13.1 +/- 0.11 mm and MIC values between 200 MUg ml-1 to 800 MUg ml-1 for C. arabicus and from 400 MUg ml-1 to 1600 MUg ml-1 for B. imbricatum, respectively. Moreover, the current study allowed concluding that both EOs showed not only satisfactory antibacterial properties but also active effects combined with conventional antibiotics demonstrated by the Fractional Inhibitory Concentration Index (FICI). These findings are very interesting since there are no previous studies on synergistic interactions of these two plants with antibiotics. SIGNIFICANCE AND IMPACT OF THE STUDY: The development of antibiotic resistance is multifactorial, including the specific nature of the relationship of bacteria to antibiotics. This situation has forced scientists to search for new antimicrobial substances from various sources as novel antimicrobial chemotherapeutic agents. Recently, medicinal plants and their derivatives (essential oils, extracts) have become very important in therapeutics because they encounter minimal challenges of the emergence of resistance. In this direction, the antimicrobial activity of the endemic Bubonium imbricatum plant and medicinal Cladanthus arabicus plant essential oils against multidrug resistant Enterobacteriaceae strains was demonstrated. PMID- 29763982 TI - Bone graft in posterior spine fusion for adolescent idiopathic scoliosis: a meta analysis. AB - BACKGROUNDS: The aim of this study was to systematically analyse and perform a meta-analysis on the current available literature comparing the fusion rates and complications associated with use of autograft, allograft and bone substitutes to supplement posterior spinal fusion for adolescent idiopathic scoliosis (AIS). METHODS: The electronic databases including Embase, PubMed, Medline, Cinahl and Cochrane Library were searched to identify relevant studies. A total of 12 studies with 2389 patients were included for meta-analysis. The primary outcome was fusion rate, while the secondary outcomes included blood loss, operation time, infection rates and post-operative pain. RESULTS: The current meta-analysis found no difference in fusion rates between groups with an overall fusion rate of 100% (95% confidence interval (CI) 0.99-1.00; P < 0.05). Total estimated blood loss was significantly higher in the iliac crest bone graft (ICBG) group compared with control group (1018 versus 861 mL; P < 0.01). In addition, the mean operative time was significantly higher in the ICBG group (259 versus 237 min; P < 0.001). The ICBG group also had increased post-operative pain issues compared with the control group (26 versus 9%; P < 0.001). There was no significant difference in terms of post-operative wound infection between groups with an overall infection rate of 1% (95% CI 0.0-0.02; P = 0.06). CONCLUSION: ICBG confers no advantage over the other graft options in achieving fusion in AIS surgery. Furthermore, crest harvesting was associated with significant increases in blood loss, operative time and post-operative pain issues. Therefore, allograft and bone substitutes are attractive alternatives to autogenous grafting during posterior fusion in AIS. PMID- 29763983 TI - Malpractice Verdicts and Changing Birthing Practices. PMID- 29763984 TI - Laparoscopic versus open approach to neurolytic celiac plexus block in inoperable pancreatic cancer. AB - BACKGROUND: Neurolytic celiac plexus block (NCPB) is an effective method of palliative pain control. The purpose of this study was to evaluate the feasibility and effectiveness of the laparoscopic NCPB versus open approach. METHODS: Eight patients (Group A) underwent diagnostic laparoscopy which revealed an inoperable pancreatic cancer. Forty millilitres of solution (20 mL of 95% ethanol mixed with 20 mL of xylocaine) was injected into either side of para aortic soft tissue. The same solution was injected in 10 patients (Group B), with inoperable pancreatic body cancer diagnosed during laparotomy. RESULTS: There were no intraoperative or post-operative, NCPB related, complications. Patients in both groups, reported significant pain relief in the early post-operative period. Using the visual analogue scale preoperatively, in second post-operative day, first and third post-operative month, no significant different was observed between the two groups. The mean hospital stay in both groups was 2.1 versus 5.2 (P = 0.0005) and the mean survival 8.1 versus 7.9 months (ns). CONCLUSIONS: The NCPB is feasible method for palliation in inoperable pancreatic cancer. Laparoscopic NCPB gives excellent results and could still be considered in selected cases, as an effective alternative during staging laparoscopy. PMID- 29763985 TI - Induced pluripotent stem cells (iPSCs) as a new source of bone in reconstructive surgery: A systematic review and meta-analysis of preclinical studies. AB - It is now well established that regenerative medicine and stem cell therapy are the most promising approach to obtain full tissue regeneration by using various cell types including stem cells isolated from adult tissues, embryonic stem cells, and induced pluripotent stem cells (iPSCs). Recently, iPSCs have been successfully differentiated into osteoprogenitors to facilitate repair and regeneration of bone defects. Thus, the purpose of this systematic review and meta-analysis is to summarize the articles published that assess the osteogenic potential of iPSCs in vitro and their ability to heal bone defects in reconstructive surgery. PICO questions were subjected to literature search in four different databases. Methodological and risk of bias assessment of the included in vitro and in vivo articles were performed. Grading of Recommendations Assessment, Development, and Evaluation approach was used to assess the quality of evidence for each outcome variable included in the systematic review. In vivo bone formation was selected as the primary outcome for meta-analysis, and publication bias was explored using funnel plots. Initial literature search retrieved 4,772 studies, whereas only 70 articles included in the review. Yamanaka set was the commonly used reprogramming factor introduced with different vectors into the somatic cells. Several somatic cell sources have been used to successfully produce the iPSCs. iPSCs have osteogenic differentiation capacities and would be considered as a new source of stem cells that can be used in reconstructive surgery for bone regeneration. PMID- 29763986 TI - Early IV-injected human dermis-derived mesenchymal stem cells after transient global cerebral ischemia do not pass through damaged blood-brain barrier. AB - There is lack of researches on effects of intravenously injected mesenchymal stem cells (MSCs) against transient cerebral ischemia (TCI). We investigated the disruption of the neurovascular unit (NVU), which comprises the blood-brain barrier and examined entry of human dermis-derived MSCs (hDMSCs) into the damaged hippocampal CA1 area in a gerbil model of TCI and their subsequent effects on neuroprotection and cognitive function. Impairments of neurons and blood-brain barrier were examined by immunohistochemistry, electron microscopy, and Evans blue and immunoglobulin G leakage. Neuronal death was observed in pyramidal neurons 5-day postischemia. NVU were structurally damaged; in particular, astrocyte end-feet were severely damaged from 2-day post-TCI and immunoglobulin G leaked out of the CA1 area 2 days after 5 min of TCI; however, Evans blue extravasation was not observed. On the basis of the results of NVU damages, ischemic gerbils received PKH2-transfected hDMSCs 3 times at early times (3 hr, 2, and 5 days) after TCI, and fluorescence imaging was used to detect hDMSCs in the tissue. PKH2-transfected hDMSCs were not found in the CA1 from immediate time to 8 days after injection, although they were detected in the liver. Furthermore, hDMSCs transplantation did not protect CA1 pyramidal neurons and did not improve cognitive impairment. Intravenously transplanted hDMSCs did not migrate to the damaged CA1 area induced by TCI. These findings suggest no neuroprotection and cognitive improvement by intravenous hDMSCs transplantation after 5 min of TCI. PMID- 29763988 TI - Adjusting the length and direction of the redundant duodenal stent using a detachable snare and endoclips. PMID- 29763987 TI - Hemodialysis catheter-associated fibrin sheath in a dog. AB - OBJECTIVE: To describe an intravascular fibrin sheath associated with a hemodialysis catheter in a dog. CASE SUMMARY: A 4-year-old dog presented for hemodialysis to treat acute kidney injury. Hemodialysis catheter dysfunction during the course of treatment was temporarily alleviated using a tissue plasminogen activator. A thrombus composed of fibrin and granulation tissue creating a sheath around the catheter and focally adherent to the vessel wall was identified on postmortem evaluation. NEW OR UNIQUE INFORMATION PROVIDED: Fibrin sheath formation is a commonly recognized problem of central venous catheters used for hemodialysis in people and is likely a common problem in veterinary patients undergoing dialysis as well. This report provides a description of the clinical features of the catheter dysfunction, response to treatment, postmortem radiographic and direct imaging, and histology of the fibrin sheath, and also provides a brief review of potential management techniques that have been described in people. PMID- 29763989 TI - Effect of polymorphisms in IL-12B p40, IL-17A and IL-23 A/G genes on the response of psoriatic patients to narrowband UVB. PMID- 29763990 TI - Mobile Applications for Women's Health and Midwifery Care: A Pocket Reference for the 21st Century. AB - Midwives and other women's health care providers are charged with providing high quality care to women based on the most current available evidence. Quick, reliable, and accurate access to evidence-based information is essential. Numerous smartphone and mobile device applications (apps) are available to assist clinicians in providing care for women. This article discusses clinical reference apps, including those for evidence-based care guidelines, women's health care, pharmacologic reference, laboratory and diagnostic guides, as well as apps for information storage and management, electronic health records, and client education. Midwives and other clinicians are encouraged to thoughtfully integrate mobile apps into their clinical practices to improve client outcomes and clinician and client satisfaction. Although the thousands of health care apps that are available may seem daunting, this article highlights key apps that may help clinicians improve their care of women. By adding one app at a time, midwives and other women's health care providers can successfully integrate mobile apps into clinical practice. PMID- 29763991 TI - Factors influencing reoperation following breast-conserving surgery. AB - BACKGROUND: Reoperation rates after breast-conserving surgery are highly variable and the best techniques for optimizing margin clearance are being evaluated. The aim was to identify the reoperation rate at our centre and identify influential factors, including a change in guidelines on margin recommendations and the introduction of in-theatre specimen X-ray. METHODS: A retrospective review of medical records was undertaken to identify 562 patients who underwent breast conservation at The Royal Melbourne Hospital and Royal Women's Hospital between 2013 and 2015. All cases that underwent subsequent re-excision or total mastectomy were captured and factors influencing margin excision recorded. RESULTS: Reoperation was undertaken in 19.5% of patients (110; 86 re-excisions and 24 total mastectomies). There was a reduction in reoperation rate from 25% to 17% (P = 0.01) with adoption of the margin guidelines in 2014, but no significant reduction with the introduction of in-theatre specimen X-ray in 2015 (21% versus 16%, P = 0.14). On multivariate analysis, factors that significantly influenced reoperation rates were the presence of multifocality on mammogram (odds ratio (OR): 5.3, 95% confidence interval (CI): 1.6-16.7, P < 0.01); lesion size on mammogram (OR: 2.2 per 10 mm, 95% CI: 1.4-3.6, P < 0.01); smaller excision specimen weight (OR: 0.5 per 25 g of resection, 95% CI: 0.3-0.8, P < 0.01); and pure ductal carcinoma in situ on final pathology (OR: 5.9, 95% CI: 1.9-16.7, P < 0.01). CONCLUSION: Optimizing reoperation rates following breast-conserving surgery remains a surgical challenge, particularly in patients with in situ or multifocal disease. Adoption of international margin guidelines reduced reoperation rates at our centre; however, introduction of intraoperative specimen X-ray had no influence. PMID- 29763993 TI - Weight Gain During Pregnancy. PMID- 29763992 TI - Development of an algorithm to identify pregnancy episodes and related outcomes in health care claims databases: An application to antiepileptic drug use in 4.9 million pregnant women in France. AB - PURPOSE: Access to claims databases provides an opportunity to study medication use and safety during pregnancy. We developed an algorithm to identify pregnancy episodes in the French health care databases and applied it to study antiepileptic drug (AED) use during pregnancy between 2007 and 2014. METHODS: The algorithm searched the French health care databases for discharge diagnoses and medical procedures indicative of completion of a pregnancy. To differentiate claims associated with separate pregnancies, an interval of at least 28 weeks was required between 2 consecutive pregnancies resulting in a birth and 6 weeks for terminations of pregnancy. Pregnancy outcomes were categorized into live births, stillbirths, elective abortions, therapeutic abortions, spontaneous abortions, and ectopic pregnancies. Outcome dates and gestational ages were used to calculate pregnancy start dates. RESULTS: According to our algorithm, live birth was the most common pregnancy outcome (73.9%), followed by elective abortion (17.2%), spontaneous abortion (4.2%), ectopic pregnancy (1.1%), therapeutic abortion (1.0%), and stillbirth (0.4%). These results were globally consistent with French official data. Among 7 559 701 pregnancies starting between 2007 and 2014, corresponding to 4 900 139 women, 6.7 per 1000 pregnancies were exposed to an AED. The number of pregnancies exposed to older AEDs, comprising the most teratogenic AEDs, decreased throughout the study period (-69.4%), while the use of newer AEDs increased (+73.4%). CONCLUSIONS: We have developed an algorithm that allows identification of a large number of pregnancies and all types of pregnancy outcomes. Pregnancy outcome and start dates were accurately identified, and maternal data could be linked to neonatal data. PMID- 29763994 TI - Decision Making about Hospital Arrival among Low-Risk Nulliparous Women after Spontaneous Labor Onset at Home. AB - INTRODUCTION: Postponing hospital admission until the active phase of labor is a recommended strategy to safely reduce the incidence of primary cesarean births. Success of this strategy depends on women's decisions about when to transfer from home to the hospital, a process that is largely absent from research about childbirth. This study aimed to determine the decision-making criteria used by women about when to go to the hospital after the self-identification of labor onset at home. METHODS: A qualitative study was conducted at an academic medical center with a sample of 21 nulliparous women who went into spontaneous labor at home and had term, singleton, and vertex-presentation births. The purposive sample consisted of women who decided to stay at home or go to the hospital in early labor. Birth narratives from in-depth interviews conducted in the postpartum period using a semistructured interview guide were subjected to content analysis. The verbatim transcriptions of the interviews were coded and categorized into a set of decision criteria. RESULTS: Criteria used by women in deciding to go to the hospital or stay at home in early labor included the degree of certainty with the self-identification of labor onset, ability to cope with labor pain, influence of social network members, health care provider advice, and concerns about travel to the hospital. Perception of childbirth risk and the need for reassurance about the normalcy of symptoms and fetal well-being also influenced women's decisions. DISCUSSION: Women use a common set of criteria in deciding when to arrive at the hospital during labor. Antenatal education and telephone triage interventions that incorporate the considerations of women deciding to seek or delay hospital admission in childbirth may facilitate health seeking in more advanced labor. Symptom recognition education about early labor onset and progression could reduce decisional uncertainty. PMID- 29763995 TI - The meaning of co-production for clinicians: An exploratory case study of Practitioner Trainers in one Recovery College. AB - WHAT IS KNOWN ON THE SUBJECT: Analysis of co-production in mental health and specifically Recovery Colleges has not previously considered the impact on clinicians and their clinical practice. Co-production as a concept is open to multiple interpretations. Core components of co-produced work are as follows: a focus on assets, mutuality, peer support and the use of a facilitative approach. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: Senior clinicians who have chosen to become Practitioner Trainers describe the experience of collaboration with service users in an educational rather than clinical context. Working together in this educational environment led to some shifts in their perceptions of professional power and authority, in some cases leading to personal disclosures about their mental health. This study suggests the mechanisms by which co production may transform professional practice: being in an educational rather than clinical context, the experience of being supported, the challenge of negotiating multiple roles (including that of being a colleague to someone with mental health needs) and experiencing a gradual shift of role emphasis as co trainer relationships develop. The practical challenge of holding a simultaneous role as clinician for and co-trainer with Peer Trainers has been articulated, with the caveat that mental health support may be a feature of collegiate as well as clinical roles. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Being a Practitioner Trainer could be a professionally transformative experience. Ground rules for how to support colleagues' mental health needs should be established and refined during co-produced working. Negotiating personal disclosure and professional role identity must be explored further in both co-production research and practice. ABSTRACT: Introduction Co-production between service users and clinicians is a desirable element of recovery-oriented practice in mental health, but the effect of co-production on clinicians has not been explored thoroughly. Aim To explore the meaning of co-production for clinicians based on their experience of co production in a Recovery College. Method Thematic analysis of eight semi structured interviews with clinicians who have co-produced and co-delivered workshops with a Recovery College Peer Trainer. Results The "meaning of co production" had four themes: definitions, power dynamics, negotiating roles and influence on practice. Clinicians' experience of co-production meant a reassessment of their expert role and power. They said that this altered their clinical practice, particularly the language they used and the personal information they shared. Discussion Role negotiation between Practitioner and Peer Trainers is an iterative process, whereby clinicians may revise their perspectives on personal disclosure, professional identity and collegiate support. The Peer and Practitioner Trainer relationship is characterized by reciprocity and mutuality, and there is some evidence that Practitioner involvement in a co-produced activity has the potential to transform service user and provider relationships beyond the Recovery College setting. Implications for practice Engaging in co-produced educational workshops can alter clinicians' perspectives on roles, power and clinical expertise. Findings from this case study must be tested against research on other Recovery Colleges. PMID- 29763996 TI - Rare case of pilomatrixoma of the lower eyelid following blunt trauma. PMID- 29763997 TI - Technical Note: Deep learning based MRAC using rapid ultrashort echo time imaging. AB - PURPOSE: In this study, we explore the feasibility of a novel framework for MR based attenuation correction for PET/MR imaging based on deep learning via convolutional neural networks, which enables fully automated and robust estimation of a pseudo CT image based on ultrashort echo time (UTE), fat, and water images obtained by a rapid MR acquisition. METHODS: MR images for MRAC are acquired using dual echo ramped hybrid encoding (dRHE), where both UTE and out-of phase echo images are obtained within a short single acquisition (35 s). Tissue labeling of air, soft tissue, and bone in the UTE image is accomplished via a deep learning network that was pre-trained with T1-weighted MR images. UTE images are used as input to the network, which was trained using labels derived from co registered CT images. The tissue labels estimated by deep learning are refined by a conditional random field based correction. The soft tissue labels are further separated into fat and water components using the two-point Dixon method. The estimated bone, air, fat, and water images are then assigned appropriate Hounsfield units, resulting in a pseudo CT image for PET attenuation correction. To evaluate the proposed MRAC method, PET/MR imaging of the head was performed on eight human subjects, where Dice similarity coefficients of the estimated tissue labels and relative PET errors were evaluated through comparison to a registered CT image. RESULT: Dice coefficients for air (within the head), soft tissue, and bone labels were 0.76 +/- 0.03, 0.96 +/- 0.006, and 0.88 +/- 0.01. In PET quantitation, the proposed MRAC method produced relative PET errors less than 1% within most brain regions. CONCLUSION: The proposed MRAC method utilizing deep learning with transfer learning and an efficient dRHE acquisition enables reliable PET quantitation with accurate and rapid pseudo CT generation. PMID- 29763998 TI - Media, Technology Use, and Attitudes: Associations With Physical and Mental Well Being in Youth With Implications for Evidence-Based Practice. AB - BACKGROUND: Previous research has shown that the use of technology and media, in their different available forms, may have detrimental effects on the physical and mental well-being of adolescents and young adults. AIMS: The present study aimed to investigate the use of different types of technology and media, attitudes toward them, and how they relate to physical and mental well-being in Lebanese university students. METHODS: A descriptive, correlational, cross-sectional design was used. A sample of 244 undergraduates completed a self-report measuring media and technology use and attitudes, eating-related variables (e.g., healthy eating, body image dissatisfaction [BID], and eating disorders [EDs] risk), trait emotional intelligence (TEI), and psychopathology indicators (stress, anxiety, and depression). RESULTS: The use of mobile phone multimedia (music, pictures, and videos) correlated with unhealthy eating and stress. Social media use was associated with BID, EDs risk, and the self-control construct of TEI. Anxiety of separation from technological devices and dependence on them was associated with increased BID, EDs risk, depression, and anxiety. LINKING EVIDENCE TO ACTION: Practical implications are discussed in terms of setting limits and boundaries on technology use during childhood and adolescence, and encouraging healthy eating and physical activity at home and on college campuses. Moreover, social media could be used as a platform for intervention and prevention programs to decrease BID, EDs, depression, and anxiety. PMID- 29763999 TI - Clinical markers associated with glycaemic response to dipeptidyl peptidase-4 inhibitor therapy. PMID- 29764000 TI - The Effect of Therapeutic Clowning on Handwashing Technique and Microbial Colonization in Preschool Children. AB - PURPOSE: This study aimed to determine the effect of therapeutic clowning on handwashing technique and microbial colonization in preschool children. DESIGN: This randomized controlled trial was conducted using pre-test and post-test experimental and control groups. METHODS: The study was conducted between March and June 2016 in two kindergartens in eastern Turkey. The study was completed with a total of 195 students, including 90 students in the experimental group and 105 students in the control group. A questionnaire was used for data collection. This questionnaire included sections about the subjects' descriptive characteristics and the results of the bacterial cultures of their hand swabs. For the collection of these swabs, the subjects were informed in advance, and samples were collected at predetermined times. The swabs were analyzed to determine the bacterial colonization of the subjects' hands. Clowns and video activities were used as intervention tools in the study. FINDINGS: In the post test, the microbial growth was <=103 in 68.9% and >103 in 31.1% of the subjects in the experimental group. In contrast, the growth was <=103 in 34.3% and >103 in 65.7% of the control group subjects. The difference in the post-test microbial growths of the two groups was statistically significant (p < .000). CONCLUSIONS: The hygienic handwashing technique taught in the therapeutic clowning and videos reduced the bacterial colonization on the preschool children's hands by 50%. Moreover, this method was effective in reducing the growth rate of coliform bacteria that indicate undesirable, poor hygiene of the hands. CLINICAL RELEVANCE: Considering these results, we recommend that pediatric healthcare professionals use entertaining methods such as those involving clowns to teach and guide children regarding hygienic handwashing techniques. PMID- 29764001 TI - Hypertensive Disorders of Pregnancy: Overview and Current Recommendations. AB - Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, preeclampsia-eclampsia, and chronic hypertension with superimposed preeclampsia. These disorders are an important cause of maternal and fetal morbidity and mortality. Although advances in effective treatments have been made, current research has yet to identify a biochemical or diagnostic imaging marker to reliably predict preeclampsia. Despite current guidelines that address diagnosis and management of hypertensive disorders in pregnancy, health care providers may overlook or be unaware of signs that require immediate evaluation and treatment. This article reviews the definitions of hypertensive disorders of pregnancy, diagnosis, pathophysiology of preeclampsia, indications for treatment, neurologic sequelae, and counseling about the implications of hypertension in pregnancy for subsequent health. PMID- 29764002 TI - Effect of lifestyle on 6-year periodontitis incidence or progression and tooth loss in older adults. AB - AIM: To evaluate the longitudinal association of combined healthy lifestyle factors with incidence or progression of periodontitis and tooth loss in older adults. MATERIALS AND METHODS: This 6-year study included 374 Japanese 70-year olds with 7,157 teeth, from a source eligible baseline population of 554 individuals. Four lifestyle factors-cigarette smoking, physical activity, relative weight, and dietary quality-were scored as healthy (1 point) or unhealthy (0 point). Adding the individual scores generated the "healthy lifestyle score" (0-4 points). Multilevel mixed-effects logistic regression models were applied to evaluate tooth-specific associations between the baseline healthy lifestyle score and the incidence or progression of periodontitis (increase in clinical attachment loss >=3 mm) and tooth loss. RESULTS: After 6 years, 19.0% of the teeth exhibited periodontitis incidence or progression and 8.2% were lost. Compared with a healthy lifestyle score of 0-1 (least healthy), the highest score (4 points) was associated with a significantly lower tooth specific risk of periodontitis (adjusted odds ratio = 0.32; 95% confidence interval: 0.16-0.62) and tooth loss (adjusted odds ratio = 0.42; 95% confidence interval: 0.23-0.77). CONCLUSIONS: Simultaneous adherence to multiple healthy lifestyle factors significantly lowers the risk of incidence or progression of periodontitis and tooth loss in older adults. PMID- 29764004 TI - Editorial Comment from Dr Yuasa to Prognostic impact of the pretreatment aspartate transaminase/alanine transaminase ratio in patients treated with first line systemic tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. PMID- 29764003 TI - A bioartificial kidney device with polarized secretion of immune modulators. AB - The accumulation of protein-bound toxins in dialyzed patients is strongly associated with their high morbidity and mortality. The bioartificial kidney device (BAK), containing proximal tubule epithelial cells (PTECs) seeded on functionalized synthetic hollow fibre membranes, may be a powerful solution for the active removal of those metabolites. In an earlier study, we developed an upscaled BAK containing conditionally immortalized human PTEC with functional organic cationic transporter 2. Here, we first extended this development to a BAK device having cells with the organic anionic transporter 1, capable of removing anionic uraemic wastes. We confirmed the quality of the conditionally immortalized human PTEC monolayer by confocal microscopy and paracellular inulin fluorescein isothiocyanate leakage, as well as by the active transport of anionic toxin, indoxyl sulphate. Furthermore, we assessed the immune safety of our system by measuring the production of relevant cytokines by the cells after lipopolysaccharide stimulation. Upon lipopolysaccharide treatment, we observed a polarized secretion of proinflammatory cytokines by the cells: 10-fold higher in the extraluminal space, corresponding to the urine compartment, as compared with the intraluminal space, corresponding to the blood compartment. To the best of our knowledge, our work is the first to show this favourable cell polarization in a BAK upscaled device. PMID- 29764007 TI - Anesthetic considerations during surgical intervention in Woake's syndrome: A case report. AB - Woake's syndrome (WS) is a recurrent nasal polyposis, accompanied by broadening of the nose, frontal sinus aplasia, dyscrinia, and bronchiectasis. There has been no previous report on anesthetic management in patients with WS. We describe a case involving a 13-year-old male patient with WS who was scheduled for septorhinoplasty for necrotic ethmoiditis. Anesthesia was induced and maintained with propofol and remifentanil using a target-controlled infusion device. The anesthetic considerations of this rare syndrome and the advantages of an intravenous infusion method over local and volatile anesthesia for these patients are discussed. We report on caveats, such as pulmonary dysfunction during the anesthetic management, and nasal structural problems encountered in WS patients. Given that conventional inhaled anesthesia reduces ciliary movement and that local anesthesia with sedative has several disadvantages, perioperative control and precautions against respiratory infections by using antibiotics, and preventing cilio-depressant actions, are important for anesthetic management. PMID- 29764008 TI - Unusual false passage formation during nasogastric tube insertion in an anesthetized patient. PMID- 29764006 TI - Tectorigenin Promotes Osteoblast Differentiation and in vivo Bone Healing, but Suppresses Osteoclast Differentiation and in vivo Bone Resorption. AB - Although tectorigenin (TG), a major compound in the rhizome of Belamcanda chinensis, is conventionally used for the treatment of inflammatory diseases, its effects on osteogenesis and osteoclastogenesis have not been reported. The objective of this study was to investigate the effects and possible underlying mechanism of TG on in vitro osteoblastic differentiation and in vivo bone formation, as well as in vitro osteoclast differentiation and in vivo bone resorption. TG promoted the osteogenic differentiation of primary osteoblasts and periodontal ligament cells. Moreover, TG upregulated the expression of the BMP2, BMP4, and Smad-4 genes, and enhanced the expression of Runx2 and Osterix. In vivo studies involving mouse calvarial bone defects with MUCT and histologic analysis revealed that TG significantly increased new bone formation. Furthermore, TG treatment inhibited osteoclast differentiation and the mRNA levels of osteoclast markers. In vivo studies of mice demonstrated that TG caused the marked attenuation of bone resorption. These results collectively demonstrated that TG stimulated osteogenic differentiation in vitro, increased in vivo bone regeneration, inhibited osteoclast differentiation in vitro, and suppressed inflammatory bone loss in vivo. These novel findings suggest that TG may be useful for bone regeneration and treatment of bone diseases. PMID- 29764009 TI - A Rare Duodenal Subepithelial Tumor: Duodenal Schwannoma. AB - Schwannomas are uncommon neoplasms that arise from Schwann cells of the neural sheath. Gastrointestinal schwannomas are rare among mesenchymal tumors of the gastrointestinal tract, and only a few cases have been reported to date. Duodenal schwannomas are usually discovered incidentally and achieving a preoperative diagnosis is difficult. Schwannomas can be distinguished from other subepithelial tumors on endoscopic ultrasonography; however, any typical endosonographic features of duodenal schwannomas have not been reported due to the rarity of these tumors. Immunohistochemistry is essential to distinguish schwannomas from gastrointestinal stromal tumors and leiomyomas. We report a case of duodenal schwannoma found incidentally during a health check-up endoscopy. On endoscopic ultrasonography, this tumor was suspected as a gastrointestinal stromal tumor; therefore, the patient underwent laparoscopic wedge resection of the tumor. Histopathology and immunohistochemistry confirmed that the duodenal lesion was a benign schwannoma. PMID- 29764010 TI - The "Tenting-into-an-External-Snare Technique": A Novel Single Channel Traction Approach for Endoscopic Resection of Difficult-to-Access Lesions Using a Wide Necked Cap. PMID- 29764005 TI - Identification of Novel Functional Variants of SIN3A and SRSF1 among Somatic Variants in Acute Myeloid Leukemia Patients. AB - The advent of massively parallel sequencing, also called next-generation sequencing (NGS), has dramatically influenced cancer genomics by accelerating the identification of novel molecular alterations. Using a whole genome sequencing (WGS) approach, we identified somatic coding and noncoding variants that may contribute to leukemogenesis in 11 adult Korean acute myeloid leukemia (AML) patients, with serial tumor samples (primary and relapse) available for 5 of them; somatic variants were identified in 187 AML-related genes, including both novel (SIN3A, C10orf53, PTPRR, and RERGL) and well-known (NPM1, RUNX1, and CEPBA) AML-related genes. Notably, SIN3A expression shows prognostic value in AML. A newly designed method, referred to as "hot-zone" analysis, detected two putative functional noncoding variants that can alter transcription factor binding affinity near PPP1R10 and SRSF1. Moreover, the functional importance of the SRSF1 noncoding variant was further investigated by luciferase assays, which showed that the variant is critical for the regulation of gene expression leading to leukemogenesis. We expect that further functional investigation of these coding and noncoding variants will contribute to a more in-depth understanding of the underlying molecular mechanisms of AML and the development of targeted anti cancer drugs. PMID- 29764012 TI - [Emphasis on expert consensus guidance for constantly promoting the levels of diagnosis and treatment of hypopharyngeal cancer in China]. PMID- 29764011 TI - Efficacy and Safety of Autologous Stromal Vascular Fraction in the Treatment of Empty Nose Syndrome. AB - OBJECTIVES: Regenerative treatment using stem cells may serve as treatment option for empty nose syndrome (ENS), which is caused by the lack of turbinate tissue and deranged nervous system in the nasal cavity. We aimed to assess the efficacy and safety of the autologous stromal vascular fraction (SVF) in the treatment of ENS. METHODS: In this prospective observational clinical study, we enrolled 10 ENS patients who volunteered to undergo treatment of ENS through the injection of autologous SVF. Data, including demographic data, pre- and postoperative Sino Nasal Outcome Test-25 (SNOT-25) scores, overall patient satisfaction, and postoperative complications, were prospectively collected. Nasal secretion was assessed using the polyurethane foam absorption method, and the levels of biological markers were analyzed in both ENS group and control group using enzyme linked immunosorbent assay. The SVF extracted from abdominal fat was diluted and injected into both inferior turbinates. RESULTS: Among the 10 initial patients, one was excluded from the study. Subjective satisfaction was rated as "much improved" in two and "no change" in seven. Among the improved patients, the mean preinjection SNOT-25 score was 55.0 and the score at 6 months after injection was 19.5. However, the average SNOT-25 score of nine participants at 6 months after injection (mean+/-standard deviation, 62.4+/-35.8) did not differ significantly from the baseline SNOT25 score (70.1+/-24.7, P>0.05, respectively). Among the various inflammatory markers assessed, the levels of interleukin (IL)-1beta, IL 8, and calcitonin gene-related peptide were significantly higher in ENS patients. Compared with preinjection secretion level, the nasal secretions from SVF-treated patients showed decreased expressions of IL-1beta and IL-8 after injection. CONCLUSION: Although SVF treatment appears to decrease the inflammatory cytokine levels in the nasal mucosa, a single SVF injection was not effective in terms of symptom improvement and patient satisfaction. Further trials are needed to identify a more practical and useful regenerative treatment modality for patients with ENS. PMID- 29764013 TI - [Experts consensus on diagnosis and treatment of tracheobronchial foreign bodies in children]. PMID- 29764014 TI - [Comprehensive treatment of 335 patients with pyriform sinus carcinoma by surgery via the paraglottic space approach]. AB - Objective: To report the experience in comprehensive surgical treatment of pyriform sinus carcinoma via the paraglottic space approach. Methods: Three hundred and thirty-five cases with pyriform sinus carcinoma (according to UICC 2012 criteria, stage I, 12 cases; II, 36; III, 79; IV, 208; T1, 26; T2, 139; T3, 121; T4, 49; cN0, 83; cN1, 61; cN2a-b, 118; cN2c, 71; cN3, 2) treated between 2006 and 2013 were retrospectively reviewed. There were 323 males and 12 females. Age aged from 36 to 80 years old with a median of 60 years old. There was no case with distant metastasis. All patients received modified neck dissection, including unilateral in 240 patients and bilateral in 95 patients. Pharyngoesophageal defects were reconstructed with directly suture in 246 cases, pectoralis major musculocutaneous flaps in 74 cases, and laryngotracheal flaps in 15 cases. Three hundred and nineteen patients received postoperative radiotherapy (55-65 Gy). Results: The overall 3 and 5 year survival rates were 68.6% (230/335) and 52.1%(139/267), respectively. The cervical lymph node metastases were found in 265 (79.1%) patients. Pathologic findings showed that all patients had squamous cell carcinoma. Laryngeal functions (voice, respiration and deglutition) were completely restored in 277 (82.7%) patients. Conclusions: The oncological efficacy of surgery via the paraglottic space approach is sure for pyriform sinus carcinoma, especially suitable for the early and medium-term lesions. The function of the larynx can retain after surgery, with the decreased incidences of cough and pharynx fistula. PMID- 29764015 TI - [Treatment and prognosis of 264 patients with hypopharyngeal carcinoma]. AB - Objective: To investigate the key factors influencing the prognosis of hypopharyngeal carcinoma and the therapeutic methods improving the efficacy of treatments for hypopharyngeal carcinoma. Methods: Two hundred and sixty-four cases of hypopharyngeal squamous cell carcinoma treated from May 2010 to May 2015 were analyzed retrospectively. There were 211 cases of pyriform sinus carcinoma, 37 cases of posterior pharyngeal wall carcinoma, and 16 cases of postcricoid carcinoma. According to UICC 2002 criteria, 2 cases were for stage I, 14 for stage II, 32 for stage III and 216 for stage IV. Postoperative circumferential defects existed in 112 (42.4%) cases, and 86 of them were reconstructed with free jejunum transplantation. Among all cases, 54 patients (20.5%) had the preservation of laryngeal functions after surgery and 210 patients (79.5%) with total laryngectomy; 238 cases (90.2%) underwent bilateral cervical lymph node dissection and 203 patients received posterior pharyngeal lymph node exploration and dissection, with positive metastases for posterior pharyngeal lymph nodes in 36 cases (17.7%). Eight cases with cervical lymph node metastasis extensively involving the soft tissue, prevertebral fascia or encases carotid artery received preoperative radiotherapy of 50 Gy. After surgery 13 patients received concurrent radiotherapy and chemotherapy, 337 underwent adjuvant radiotherapy with a dose of 50-60 Gy each, and 14 patients did not receive radiotherapy or did not completed their radiotherapy programs. SPSS 13.0 saftware was used to analyze the data. Results: All patients were followed up for more than 2 years. With Kaplan-Meier method, the 2-, 3- and 5-years survival rates were 69.6%, 62.8% and 51.3%, respectively. There were significant differences in 3-year survival rates between T1-2 group (75.5%) and T3-4 group (59.2%) (chi(2)=4.282 P=0.039), N0 group (81.6%) and N+ group (58.2%) (chi(2)=6.802 P=0.009), laryngeal functions preserved (81.8%) and unpreserved group (58.9%) (chi(2)=5.314 P=0.021). Multivariate Logistic regression analysis showed that cervical lymph node metastasis was an independent prognostic factor (P=0.027). The success rate of free jejunum transplantation was 98.8%. Local recurrence, cervical lymph node recurrence, second primary cancer, and distant metastasis accounted respectively for 11.2%, 18.8%, 12.5% and 45.0% of death cases. Conclusions: The prognosis associated factors for hypopharyngeal carcinoma should be taken into account, including the evaluation of the carcinogenesis of the mucosal area, early screening of premalignant lesion or second primary cancer in the esophagus and dissection of the posterior pharyngeal lymph nodes, which will help to improve the local control rate and recent survival rate in patients with hypopharyngeal cancer. PMID- 29764016 TI - [A retrospective study on combined modality therapy with or without surgery for advanced hypopharyngeal squamous cell carcinoma: an analysis of 119 cases]. AB - Objective: To compare the treatment outcomes for locally advanced hypopharyngeal carcinoma between surgery plus radio(chemo) therapy(SRT) and non-surgery chemoradiotherapy(CRT). Methods: A total of 119 patients diagnosed with advanced hypopharyngeal carcinoma without distant metastases between 2010 and 2014 were identified in the Chinese People's Liberation Army General Hospital, and they were divided into 2 groups: 42 cases in SRT group and 77 cases in CRT group. Patients' clinical information was collected. Survival rates and prognostic factors were analyzed by the Kaplan-Meier method with SPSS 23.0 software. The survival rates, laryngeal preservation rates and complication rates were compared between the two groups using the chi-square test.Among the 119 patients, 112 were males and 7 were females. Age ranged from 27 to 78 years, with an average age of 57 years. Results: There were no significant difference between the SRT and CRT group for five-year disease-free survival (DFS, 53.9% vs. 45.1%, chi(2)=1.251, P=0.263) and overall survival (OS, 54.9% vs. 45.6%, chi(2)=1.749, P=0.186). Compared to SRT group, CRT group did not showed the significant increase of treatment complications (chi(2)=0.858, P=0.354), with a higher laryngeal preservation rate (50.0% vs. 71.4%, chi(2)=6.493, P=0.011). Conclusions: Advanced hypopharyngeal carcinoma is of high malignancy and poor prognosis. Combined modality treatment is a main approach for advanced hypopharyngeal cancer. SRT offers disease-free survival and overall survival rates equivalent to CRT, but with a higher laryngeal preservation rate. PMID- 29764017 TI - [Significance of retropharyngeal node dissection in treatment of hypopharyngeal carcinoma]. AB - Objective: investigate the incidence of retropharyngeal lymph node (RPLN) metastasis and the risk factors for RPLN metastasis in hypopharyngeal cancer, and the relationship of planned dissection of the RPLN with the survival and tumor control rates in patients with hypopharyngeal cancer. Methods: A total of 203 patients with hypopharyngeal squamous cell carcinoma who underwent radical surgery as initial treatment from February 2011 to July 2015 were analyzed retrospectively. There were 167 cases of pyriform sinus carcinoma, 23 cases of posterior pharyngeal wall carcinoma, and 13 cases of postcricoid carcinoma. Results: The incidence of RPLN metastasis in HPC was 17.7%, with a highest rate of 43.5% in pharyngeal wall carcinoma. The incidence of RPLN metastasis in T3-4 pyriform sinus carcinoma was 18.3%, which significantly higher than 2.8% in T1-2 cases(chi(2)=5.360, P=0.020). The rate of RPLN metastasis was 23.8% in N2b-3 and 8.6% in N0-2a, with a statistically significant difference(chi(2)=7.637, P=0.006). There was no statistically significant difference in overall survival rates between patients with and without RPLN metastasis(P>0.05). Data were analyzed by SPSS 13.0 software. Conclusions: RPLN metastasis is not rare in hypopharyngeal carcinoma. Planned dissection of the RPLN should be performed with the initial surgery in patients with advanced hypopharyngeal cancer, especially posterior pharyngeal wall carcinoma, T3-4 pyriform sinus carcinoma and staged N2b 3 disease, which can reduce the regional recurrence rate and provided with a better prognosis. PMID- 29764018 TI - [Clinical application of modified bilobed chimeric thoracoacromial artery perforator flap for reconstruction of hypopharyngeal defect with anterior neck skin loss]. AB - Objective: To evaluate the efficacy of modified bilobed chimeric thoracoacromial artery perforator (TAAP) flap for the reconstruction of hypopharyngeal defect with anterior neck skin loss. Methods: Between May 2013 and September 2015, modified bilobed chimeric TAAP flap was used to reconstruct complex oncologic hypopharyngeal defects in 7 patients, including 6 males and 1 female. Patients' age ranged from 28 to 65 years old (mean age 50+/-3.4 years old). The size of hypopharyngeal defect ranged from 5.5 cm*3.5 cm to 12.0 cm*4.5 cm, and the size of anterior neck defect ranged from 8.0 cm*4.0 cm to 10.0 cm*4.0 cm. Results: The size of TAAP flap was from 6.5 cm*4.0 cm to 13.0 cm*5.0 cm.The size of pectoralis major flap was from 8.0 cm*4.5 cm to 11.0 cm*5.0 cm. The length of pedicle was 6.5-8.5 cm.The distance from pivot point of flap to central point of recipient site was 7.0-9.5 cm.All flaps survived thoroughly, the donor site was closed directly in all cases.The mean hospital stay ranged from 14 to 19 days (mean 15.5 days). The follow-up was 14, 15, 20, 18, 30, 25 and 38 months respectively.Patient possessed good appearance of neck surgical sites, and oral diet was restored in all patients.No recurrence, fistula, stenosis/stricture, dehiscence, or swelling occurred, only with scars left on the donor sites, and pectoralis major muscle function was completely preserved in all patients. Conclusions: Modified bilobed chimeric TAAP flap is a good choice for the reconstruction of hypopharyngeal defect with anterior neck skin loss. PMID- 29764019 TI - [The role of type 2 innate lymphoid cells in the pathogenesis of eosinophilic chronic rhinosinusitis with nasal polyps]. AB - Objective: To investigate the type 2 innate lymphoid cells (ILC2s) in eosinophilic nasal polyps, non-eosinophilic nasal polyps and controls, and to compare the characteristics of ILC2s indifferent types of nasal polyp. Methods: Flow cytometric analysis was used to quantify the ILC2s and Th2 cells in tissues from 19 patients with chronic rhinosinusitis with nasal polyp (CRSwNP) and 6 controls. The patients were classified into two groups as eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) and non-eosinophilic chronic rhinosinusitis with nasal polyps (non-ECRSwNP) based on eosinophil counts under hematoxylin-eosin staining. ILC2 and Th2 cell frenquencies, measured as a percentage of CD45(+) cells, were compared among ECRSwNP group (n=9), non-ECRSwNP group (n=10) and control group (n=6) using Mann-Whitney U test .The correlation between ILC2, Th2 cell frequencies and eosinophil count in tissues was analyzed using Pearson correlation coefficient. Results: ILC2 frequencies in ECRSwNP group were significantly higher than non-ECRSwNP group and controls ((0.051+/-0.025) vs (0.011+/-0.017), (0.051+/-0.025) vs (0.004+/-0.004), Z value was -3.185, -3.186, respectively, both P<0.05). There was no significant difference between ILC2 frequencies in non-ECRSwNP and controls ((0.011+/-0.017) vs (0.004+/-0.004), Z= 0.712, P=0.492). Th2 cell frequencies in ECRSwNP and non-ECRSwNP group were significantly higher than controls ((0.500+/-0.437) vs (0.106+/-0.102), (0.275+/ 0.170) vs (0.106+/-0.102), Z value was -2.946, -2.278, respectively, both P<0.05). There was no significant difference between Th2 frequencies in non ECRSwNP group and ECRSwNP group ((0.275+/-0.170) vs (0.500+/-0.437), Z=-1.306, P=0.211). ILC2 frequencies significantly correlated with Th2 cell frequencies (r=0.571, P=0.011) and tissue eosinophilia (r=0.579, P=0.009). Th2 cell frequencies significantly correlated with tissue eosinophilia (r=0.844, P=0.001). There was no significant association between ILC2 and allergic status. Conclusion: ILC2s are elevated in ECRSwNP, and not influenced by allergic status, suggesting that ILC2s play an important role in ECRSwNP without allergic diseases. PMID- 29764020 TI - [Effect of cricothyroid and thyroarytenoid muscle botulinum toxin injection on patients with dyspnea caused by bilateral recurrent laryngeal nerve paresis]. AB - Objective: To discuss the clinical effect of small dose of botulinum toxin injection in cricothyroid muscle and thyroarytenoid muscle on patients with incomplete bilateral recurrent laryngeal nerve paresis. Methods: Six patients were selected with Ior II or III degree of dyspnea diagnosed as bilateral recurrent laryngeal nerve injury by laryngeal electromyography, and small dose of botulinum toxin injection was performed in cricothyroid muscle and thyroarytenoid muscle as a treatment. Degree of dyspnea was assessed one month before and after the treatment, and the stroboscopic laryngoscope results, acoustic parameters and CT image of the patients were collected in the 6 patients. The relevant parameters were also collected one month before and after treatment, including the degree of dyspnea, stroboscopic laryngoscope results, acoustic parameters and CT image of the patients. The angle between bilateral vocal cords in stroboscopy at full inspiratory was calculated, acoustic parameters (F0, jitter, shimmer) were analysed, and vocal length, width and the vocal region were measured. Then, the paired t test was performed for statistical analysis between before and after one month injection, the one way analysis of variance was performed among vocal parameters in CT image. Result: Botulinum toxin injection was successfully completed in the 6 patients, followed without any serious complications. The degree of dyspnea was alleviated to some extent after treatment in all 6 patients; the angle between bilateral vocal cords at the end of a deep inspiration was significantly increased (t=2.44, P<0.05) after the treatment. The changes of F0 and jitter between before and after treatment were not statistically significant (t=0.72, t=1.42, P>0.05). Shimmer was significantly decreased after treatment (t=2.61, P<0.05). Vocal fold length, width and vocal region increased with F0, there was a statistically significant difference between different F0 before injection, and there was no statistically significant difference between different F0 after injection. The follow-up time was respectively seven months, 1 year, 1 year, 18 months, 22 months and 2 years respectively. Conclusion: Small dose of botulinum toxin injection in bilateral cricothyroid muscles and thyroarytenoid muscles can relieve the dyspnea caused by bilateral vocal cords paresis to some extent, accompanied without serious complications, despite the sound quality was slightly worse. PMID- 29764022 TI - [Diagnosis and treatment of plasma cell granuloma in nasal cavity and sinus]. PMID- 29764021 TI - [Misdiagnosic analysis and treatment of pyriform sinus fistula in children]. AB - Objective: To discuss the misdiagnosis of pyriform sinus fistula and to better understand this kind of illness. Methods: The analysis was based on twenty-eight patients with congenital pyriform sinus fistula aged from 11 months to 14 years, with the median age of 5 years, and who were surgically treated from January 2013 to January 2017 in Kunming Children's Hospital.Twenty patients were misdiagnosed in other hospital.After the routine examination of neck ultrasound and enhanced CT, internal fistula was found by self-retaining laryngoscope, traced by methylene blue, and excised by high ligation. Results: Twenty patients were misdiagnosed.The misdiagnosis time ranged from 6 months to 3 years.Under self retaining laryngoscope, piriform fossa fistula were found in all patients.Nineteen fistula were found in the left and 1 in the right.The fistula in patients was unilateral.Seven cases were misdiagnosed as suppurative lymphadensitis, undergone abscess incisional drainage many times.Three cases were misdiagnosed as thyroglossal duct cyst and performed excision of thyroglossal duct cyst.One case was treated by extended Sistruck operation again because the doctor considered that excision of middle segment of hyoid bone was not enough and the fistula was not ligated completely.One case was misdiagnosed as second branchial cleft fistula on the right side of the neck.Nine cases were misdiagnosed as hyroid-associated diseases including 2 cases suppurative thyroiditis, 2 cases subacute thyroiditis and 5 cases thyroid neoplasms.Among them, 2 cases underwent partial thyroidectomy.All the patients were treated with high ligation of fistula under general anesthesia.The operation was smooth, and no hoarseness, bucking and pharyngeal fistula occurred after the operation.Postoperative follow-up time ranged from 12 months to 4 years and the median follow-up was 18 months without recurrence.The diagnosis was confirmed pathologically. Conclusions: Pyriform sinus fistula in children was uncommon and easily misdiagnosed in clinic.The majority of physician including some otolaryngologists were lack of understanding of the disease.It should be regarded as one of the important differential diagnosis of neck mass in children.Children with recurrent left neck infection and/or abscess should be highly suspected.Self retaining laryngoscopic examination can make a definite diagnosis and high ligation of the fistula through the external neck approach can achieve good therapeutic effect. PMID- 29764023 TI - [Extraluminal foreign body originated from pharynx and esophagus: a series of 10 patients]. PMID- 29764024 TI - [Percutaneous dilational tracheostomy with preservation of the anesthesia cannula]. PMID- 29764025 TI - [Research progress in pathogenesis, treatment and prognosis of HPV positive head and neck squamous cell carcinoma]. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth common malignant tumors of whole body with a high incidence, which accounts for 90% of the head and neck malignant tumors. Previous studies have shown the risk factors, such as tobacco and alcohol, are related to the occurrence and development of HNSCC. However, recent studies have shown that the non-tobacco and non-alcohol related HNSCC increased year by year. At the same time, more and more studies have shown that HNSCC is related to the infection with human papilloma virus (HPV), and the occurrence and development of HPV-positive HNSCC has own characteristics in epidemiology, pathogenesis, treatment and prognosis. In this paper the research progress for HPV-positive HNSCC is reviewed. PMID- 29764027 TI - [Improvement and standardization of microsurgical techniques for brain tumors]. PMID- 29764026 TI - [Advances in postoperative thyroid-stimulating hormone suppression therapy in females with thyroid cancer]. AB - Differentiated thyroid cancer is the most common malignant carcinoma in female population.Postoperative long-term thyroid-stimulating hormone(TSH) suppression therapy can reduce the risk of recurrence for differentiated thyroid cancer and control the progress of the disease, but it also induces simultaneously subclinical hypothyroidism and imposes negative effect on female. In addition to cardiovascular disease, TSH suppression therapy can lead to the alteration of sex hormone metabolism, menstrual disorder, poor influence on pregnancy and osteoporosis. This article reviews the recent studies on postoperative TSH suppression therapy in women with thyroid cancer. PMID- 29764028 TI - [Application of 3D virtual reality technology with multi-modality fusion in resection of glioma located in central sulcus region]. AB - Objective: To explore the clinical and teaching application value of virtual reality technology in preoperative planning and intraoperative guide of glioma located in central sulcus region. Method: Ten patients with glioma in the central sulcus region were proposed to surgical treatment. The neuro-imaging data, including CT, CTA, DSA, MRI, fMRI were input to 3dgo sczhry workstation for image fusion and 3D reconstruction. Spatial relationships between the lesions and the surrounding structures on the virtual reality image were obtained. These images were applied to the operative approach design, operation process simulation, intraoperative auxiliary decision and the training of specialist physician. Results: Intraoperative founding of 10 patients were highly consistent with preoperative simulation with virtual reality technology. Preoperative 3D reconstruction virtual reality images improved the feasibility of operation planning and operation accuracy. This technology had not only shown the advantages for neurological function protection and lesion resection during surgery, but also improved the training efficiency and effectiveness of dedicated physician by turning the abstract comprehension to virtual reality. Conclusion: Image fusion and 3D reconstruction based virtual reality technology in glioma resection is helpful for formulating the operation plan, improving the operation safety, increasing the total resection rate, and facilitating the teaching and training of the specialist physician. PMID- 29764029 TI - [Staged transcranial and transsphenoidal surgery for giant pituitary adenomas: a retrospective study of 21 cases]. AB - Objective: To investigate the effect of the second-stage transcranial and transsphenoidal approach for giant pituitary tumors. Methods: A retrospective review of 21 patients, who had undergone the transcranial surgery and then transsphenoidal surgery for giant pituitary adenomas from 2012 to 2015 in the neurosurgery department of West China Hospital, was performed. Visual findings, endocrine presentation, complications, and tumor types were collected. All data were based on clinical feature, MRI, and follow-up. Results: Among the 21 cases, gross total resection of tumor was achieved in 7 of all patients, subtotal in 11, and partial in 3. No intracranial hemorrhage or death occurred postoperatively. Postoperative infectionoccurred in one patient and cerebrospinal fluid leakage occurred in 3 patients. Four patients recovered after treatment. Conclusion: According to the clinical feature and MRI, it is safe and effective to choose the transcranial surgery and then transsphenoidal surgery for specific giant pituitary adenomas, which can improve treatment effects and reduce postoperative complications. PMID- 29764030 TI - [Neuroendoscopy assisted microneurosurgery for posterior cranial fossa lesion]. AB - Objective: To study the value of neuroendoscopy assisted microneurosurgery technique in the treatment of posterior cranial fossa lesion. Methods: Clinical data of 36 patients with posterior fossa lesions who accepted neuroendoscopy assisted microneurosurgery (NEAM group) in the department of neurosurgery of the First Affiliated Hospital of Chongqing Medical University, from January 2014 to December 2016, were retrospectively enrolled. A total of 113 cases diagnosed with the same lesions and accepted conventional microneurosurgery (non-NEAM group) in the same period were analyzed as control group. The total tumor resection rate, postoperative leakage of cerebrospinal fluid, intracranial infection, operating time and the recovery of facial nerve function were compared between the two groups. Results: Ninety-three patients with acoustic neuroma were analyzed, which were divided into non-NEAM group 78 cases (removed posterior lip of internal auditory canal in different degrees) and NEAM group 15 cases (not removed posterior lip of internal auditory canal). The total tumor resection rate and postoperative facial nerve function had no significant statistical differences between two groups. The operating time of NEAM group was longer than that of non NEAM group (P=0.048, P<0.05), but the rate of leakage of cerebrospinal fluid and intracranial infection did not increase. Twenty-seven cases were diagnosed with cerebellopontine angle cholesteatoma. These cases were divided into two groups, 17 cases in non-NEAM group and 10 cases in NEAM group. NEAM group have higher total tumor resection rate (P=0.014, P<0.05), better short-term postoperative facial nerve function (P=0.039, P<0.05), and longer operating time (P=0.015, P<0.05), compared with non-NEAM group. No significant statistical differences were observed on long-term postoperative facial nerve function and postoperative complications. Of the 16 cases diagnosed tentorial meningioma, 10 cases were in non-NEAM group and 6 cases in NEAM group. Six cases in non-NEAM group and 4 cases in NEAM group were total removal. For the mean operating time, non-NEAM group was (6.6+/-1.0) hours and NEAM group was (7.1+/-0.7) hours. Thirteen cases were with fourth ventricular cholesteatoma, which all were totally resected, and 8 cases were in non-NEAM group and 5 cases in NEAM group. For non-NEAM group, 5 cases dissected cerebellar vermis and the mean operating time is (6.0+/-0.7) hours. However, NEAM group all did not dissect cerebellar vermis and the mean operating time is (6.4+/-0.4) hours. Conclusions: Neuroendoscopy assisted microneurosurgery for cranial fossa lesions was benefit to totally resect tumor and reduce unnecessary injury. It needed longer operating time, but not increase postoperative intracranial infection. PMID- 29764031 TI - [Dynamic retraction microneurosurgery for the treatment of medial tentorial meningiomas]. AB - Objective: To investigate the effectiveness and clinical significance of dynamic retraction microneurosurgery for the treatment of medial tentorial meningiomas. Methods: From January 2011 to December 2016, a cohort of 28 patients with medial tentorial meningiomas were treated by microneurosurgery at the First Affiliated Hospital of Chongqing Medical University. Patients who treated intraoperatively with dynamic retraction surgery from January 2014 to December 2016 were assigned into dynamic retraction group, and those with fixed retractors intraoperatively from January 2011 to December 2013 were assigned into retractor group. The surgical approaches tailored in our patients were based on predominant direction of tumor extension. The extent of tumor resection was scored according to the Simpson's classification scale. Comparisons of tumor size, operation time, hospitalization time, retraction-related injury, tumor Simpson resection grade and Karnofsky Performance Scale(KPS) score six months after surgery were also made between two groups. Results: A total of 12 patients(retractor group) were treated with the use of self-retaining brain retractors intraoperatively and dynamic retraction surgical procedure was performed intraoperatively in 16 patients(dynamic retraction group). The difference between two groups with regard to sex, age, tumor size, operation time and tumor Simpson resection grade was not statistically significant(all P>0.05). The mean duration of hospital time was shorter in the dynamic retraction group than that in the retractor group(18.3 d+/ 1.8 d vs 20.2 d+/-1.3 d, P=0.004). The dynamic retraction group had lower incidence of retraction-related injury compared with the retractor group(1/16 vs 6/12), P=0.022]. The dynamic retraction group had better neurological recovery rate with KPS >80 evaluated six months after surgery compared with the retractor group(14/16 vs 5/12, P=0.017). Conclusions: Dynamic retraction microneurosurgery for the treatment of medial tentorial meningiomas is feasible, which can obviate or reduce the amount of brain retraction needed, and may be of help in lowering the risk of postoperative neurological deficits and complications and leading to reduced hospitalization cost and improved surgical outcomes. PMID- 29764032 TI - [Genes polymorphism of BIN1 and ApoE in patients with amnestic mild cognitive impairment from Enshi Tujia area]. AB - Objective: To investigate the polymorphism of BIN1 and ApoE genes in amnestic mild cognitive impairment (aMCI) patients in Tujia minority area of Enshi, Hubei. Methods: A total of 107 patients with aMCI (aMCI group) and 150 healthy people (healthy control group) during the same period were included between December 2016 and October 2017 in Affiliated Minda Hospital of Hubei University for Nationalities, who were all the Tujia nationality. Three single nucleotide polymorphic site of BIN1 gene rs744373, rs7561528, rs6733839, and two single nucleotide polymorphic site of ApoE gene rs429358, rs7412, and Genotyping and sub genotyping of ApoE genes were tested using ligase detection reaction technique(LDR), and gene polymorphisms of BIN1 and ApoE were analyzed with Logistic regression analysis. Results: The basic information was not statistically significan different between healthy control group and aMCI group (P>0.05); there were no statistically significant in genotype distribution among the 3 SNPs of BIN1 gene(rs744373, rs7561528, rs6733839) and between the 2 SNPs of ApoE gene(rs429358, rs7412) and its allelic profile (P>0.05), which conformed to Hardy-Weinberg balance; BIN1 gene rs744373 polymorphic site allele C was the risk factor of aMCI (OR 2.33, 95% CI 1.09-4.98, P=0.029), especially BIN1 gene rs744373 polymorphic site recessive model CC/CT+ TT increased the risk of aMCI disease (OR 2.29, 95% CI 1.15-4.59, P=0.019). The difference in genotype distribution of ApoE sub-genotype epsilon2/2, epsilon2/3, epsilon2/4, epsilon3/3, epsilon3/4, epsilon4/4 and allele epsilon2, epsilon3, epsilon4 genes between two groups were significantly different (P<0.05), Carrying ApoEepsilon2 may be a protective factor for aMCI (OR 0.46, 95% CI 0.22-0.96, P=0.039) and carrying ApoE epsilon4 may be a risk factor for aMCI (OR 2.13, 95% CI 1.18-3.83, P=0.012). Conclusions: The incidence of aMCI in Tujia region of Enshi may be related to the rs744373 polymorphic site of BIN1 gene, ApoEepsilon2 is the protective factor and ApoEepsilon4 is the risk factor for aMCI in Tujia region of Enshi, but it still needs to be further verified by a large sample population. PMID- 29764033 TI - [The combined application of magnetic resonance DTI and 3D-pcASL in differential diagnosis of hyper-acute and acute ischemic cerebral infarction]. AB - Objective: To explore the clinical value of magnetic resonance diffusion tensor imaging (DTI) combined with 3D pseudo continuous arterial spin labeling (3D pcASL) perfusion imaging in differential diagnosis of hyper-acute and acute ischemic cerebral infarction. Methods: A total of 42 patients with confirmed unilateral ischemic cerebral infarction from February 2015 to October 2017 of Affiliated Yancheng Hospital of Southeast University Medical College were collected. DTI and 3D-pcASL images of hyper-acute (14 patients, group A) and acute (28 patients, group B) ischemic cerebral infarction were retrospectively analyzed. The slice with the biggest lesion on diffusion weighted imaging (DWI) was selected to measure the infarction area (S(DWI)) and abnormal cerebral blood flow (CBF) perfusion area (S(CBF)). Regions of interest (ROIs) were set on the infarction core (IC) area, mismatch area of S(CBF) and S(DWI) (MACD), and their corresponding contralateral regions. The values of CBF, average diffusion coefficient (DC(avg)), and fractional anisotropy (FA) parameter images in these ROIs in patients with both S(CBF)>S(DWI) and lower perfusion in the IC were recorded. The relative values of each infarction lesion to its corresponding contralateral region (rCBF, rFA, and rDC(avg)) were calculated. Differences of each parameter value between the IC, MACD and their corresponding contralateral regions and of the relative values between group A and group B were investigated. Results: The CBF and DC(avg) values in the IC and the CBF value in the MACD were lower than that of their corresponding contralateral regions in both groups (P<0.05). The DC(avg) in the MACD in group A patients and the FA in the IC in group B patients were lower than that in their corresponding contralateral regions (P<0.05). Compared to group A patients, group B patients showed decreased rFA, rDC(avg) in the IC and rFA in the MACD, and increased rDC(avg) and rCBF in the MACD (P<0.05). Receiver operating characteristics (ROC) curve analysis indicated that the best diagnosis cut off values of the rFA and rDC(avg) values in the IC and the rCBF, rFA, and rDC(avg) values in the MACD were 0.890 and 0.541 and 1.139, 0.902 and 0.455, respectively, for identifying two groups. Conclusion: The changes of the CBF, FA, and DC(avg) values and their relative values can be applied to differentially diagnose patients with hyper-acute and acute cerebral infarction, which could provide the basis for selecting more reasonable treatment protocols. PMID- 29764034 TI - [Application of low profile visualized intraluminal support (LVIS)stents in assisting coil embolization of intracranial aneurysms]. AB - Objective: To evaluate the safety and effectiveness of application of LVIS stent assisted coiling endovascular procedures in cerebral aneurysms . Methods: The clinical data of 41 patients with intracranial aneurysms , which were performed in LVIS stent-assisted coiling endovascular therapies from June 2015 to October 2017 in The First Affiliated Hospital of Bengbu Medical College were analyzed retrospectively. 13 patients were unruptured and 28 patients were ruptured. Immediate angiography outcomes and follow-up angiography outcomes were assessed by DSA. Clinical outcomes were evaluated by modified Rankin Scale (mRS). Results: The LVIS stents were successfully delivered in 39 cases, however there were 2 cases in which the LVIS stents did not fully open.The technical success rate was 95.1%(39/41). There were 2 cases had complications during perioperation, the rate of complications was 4.9%(2/41). One was thrombus formation in operation, there was no nerve function defect.The other was infarction three days after operation and which had mild function defect(mRS grade 2). Raymond grade 1 was 31 cases, Grade 2 was 2 cases , grade 3 was 8 cases, the effective embolism rate was 80.5%(33/41). Mean follow up time was 14.4 months, 32 cases were cured, the cure rate was 78.0%(32/41), 2 cases were reappeared, the recurrence rate was 4.9%(2/41). mRS grade 0 was 16 cases, grade 2 was 24 cases , grade 2 was 1 case , the cure rate of clinical symptom is 100%. Conclusion: LVIS stent-assisted coiling is safe and effective in the treatment of cerebral aneurysms. PMID- 29764035 TI - [Relationship between hyperuricemia and prognosis in patients with heart failure of coronary heart disease after revascularization]. AB - Objective: To explore the effect of hyperuricemia on prognosis in patients with heart failure of coronary heart disease (CHD) after revascularization. Methods: A single-center retrospective study of all subjects who underwent percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) as revascularization for CHD at Beijing Anzhen Hospital, Capital Medical University, between January 2005 and December 2014 was performed.Patients were divided into two groups by with or without hyperuricemia.The average follow-up was 1 818 d. Results: The Logistic regression analysis revealed that hyperuricemia was independent risk factors of readmission of heart failure(P=0.018, OR=1.499, 95%CI 1.071-2.098). The Cox regression analysis revealed that hyperuricemia was independent risk factor of all-cause mortality(P=0.002, RR=1.520, 95%CI 1.166 1.982), cardiovascular (CV) mortality(P=0.001, RR=1.811, 95%CI 1.279-2.566), heart failure mortality(P=0.006, RR=2.151, 95%CI 1.247-3.711). Conclusions: There is negative correlation between level of uric acid and left ventricular ejection fraction (LVEF). The patients with heart failure of coronary heart disease complicated with hyperuricemia have high risk of readmission of heart failure, all-cause mortality, CV mortality andheart failure mortality than patients with normal uric acid level. Hyperuricemia is an independent risk factor for patients with heart failure of coronary heart disease after revascularization. PMID- 29764036 TI - [Comparison of prognostic value of (18)F-FDG PET/CT myocardial metabolism imaging and coronary collateral circulation in patients with CTO lesions]. AB - Objective: To evaluate the location, extent of viable myocardial of chronic total coronary occlusions(CTO)lesions by (18)F-FDG PET myocardial metabolism imaging and then compare with coronary collateral circulation(CCC) to evaluate the prognostic evaluation in patients with CTO lesions. Methods: A total of Sixty consecutive patients with CTO lesions referred for viability assessment from April 2016 to April 2017 in Department of Cardiology, Beijing Anzhen Hospital were included in the study. These patients underwent (99m)Tc-sestamibi ECG-gated SPECT rest myocardial perfusion imaging and ECG-gated (18)F-FDG PET/CT myocardial metabolic imaging, as well as coronary arteriography were recruited in this study. LV functional parameters(EDV, ESV, and LVEF) were analyzed by QGS software. The extent of CCC to the area of CTO related artery was graded as poorly, or well developed collaterals, assessed by Rentrop classification. All patients were followed up for a median of 17 months(range 12-20 months) and evaluated the changes of NYHA. Then the prognostic value of (18)F-FDG PET myocardial metabolism imaging and CCC in patients with CTO lesions were analyzed and evaluated. Results: As the standard evaluation of NYHA in patients with CTO lesions after 12-20 months, fifty-three patients were assigned in this study. According to the changes of NYHA, the patients were divided into no progress group and progress group. There were no statistically difference in age, gender, high risk of CTO lesion and drugs in two groups, but there were significant statistical differences in myocardial parameters. LVEF was significantly increased in patients with CTO lesion in no progress group(42.3%+/-17.2% vs 22.2%+/-10.4%, P<0.01). The EDV and ESV in no progress group were significantly smaller than patients in progress group.The sensitivity(95.2% vs 75.7%) and specificity(62.8% vs 38.1%) of (18)F-FDG PET myocardial metabolism imaging was much better than CCC in the evaluation of prognosis in patients with CTO lesion. Conclusion: (18)F-FDG PET myocardial metabolism imaging has important role in the prognosis of patient with CTO lesions when compared with CCC. PMID- 29764037 TI - [The value of high resolution diffusion weighted imaging in differentiating benign and malignant epithelial tumors of parotid gland]. AB - Objective: To investigate the diagnostic value of RESOLVE DWI in the evaluation of benign and malignant epithelial tumors of parotid gland. Methods: A total of 106 patients in the First Affiliated Hospital of Zhengzhou University with epithelial tumors of parotid gland confirmed by pathology from July 2015 to October 2017 were retrospectively analyzed. All patients underwent preoperative routine MRI and RESOLVE DWI, the ADC average values were calculated, t test were used to compare the ADC values of benign and malignant epithelial tumors of parotid gland. Diagnostic performance of ADC value was compared using receiver operating characteristic (ROC)curves. Results: All lesions were solitary, including 69 benign epithelial tumors and 37 malignant epithelial tumors. The mean ADC values of pleomorphic adenoma and basal cell adenoma, adenolymphoma and malignant epithelial tumors were (1.47+/-0.16)*10(-3) mm(2)/s, (0.83+/-0.19)*10( 3) mm(2)/s and(1.14+/-0.14)*10(-3) mm(2)/s, the mean ADC value of adenolymphoma lower than the rest of the two groups, there were statistically significant differences among them (P<0.05). Using 0.94*10(-3) mm(2)/s<=ADC value<=1.28*10( 3)mm(2)/s as the critical value for diagnosing malignant epithelial tumors of parotid gland and comparing with pathological results, the result obtained had a sensitivity of 81.1%, specificity of 88.9%. ADC value had high correlations compared with pathological results, kappa value was 0.600. Conclusion: RESOLVE DWI can be applied in differential diagnosis between benign and malignant epithelial tumors of parotid gland. PMID- 29764038 TI - [Expression and distribution of programmed death receptor 1 and T cell immunoglobulin mucin 3 in breast cancer microenvironment and its relationship with clinicopathological features]. AB - Objective: To explore the expression and distribution of programmed death receptor 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3) in breast cancer microenvironment and analyze the their correlation with the clinicopathological features. Methods: The specimens of tumor tissue and adjacent tissues from 30 patients with infiltrative breast cancer who were diagnosed as breast cancer from June 2016 to May 2017 in The First Hospital of Jiaxing were collected, and the specimen were divided into two parts along the center. After embedding and cryosectioning, the expression and distribution of PD-1 and TIM-3 protein in tumor tissues were observed by immunofluorescence staining. Another part of the specimen was cut and digested, and non-continuous density gradient centrifugation was used to extract tumor-infiltrating lymphocytes (TILs), real-time quantitative PCR (qRT-PCR) was used to detect the mRNA expression of PD-1 and TIM-3 in TILs. Meanwhile, the protein expression was determined by Western blotting. The relationship between the expression of PD-1 and TIM-3 and pathological parameters of breast cancer was analyzed with correlation analysis. Results: Immunofluorescence results showed that more PD-1 and TIM-3 positive cells were observed in the tumor tissues compared with the tumor-adjacent tissues. The qRT PCR showed that the expression of PD-1 and TIM-3 mRNA in TILs were both significantly higher than those in paracancerous tissues (3.09+/-0.38 vs 1.26+/ 0.23, 3.42+/-0.31 vs 1.57+/-0.29, t=4.16, 4.37, both P<0.05). At the protein level, the expression of PD-1 and TIM-3 in tumor tissue lymphocytes(0.66+/-0.08, 0.80+/-0.11) was significantly higher than those in cancerous tissues(0.10+/ 0.01, 0.26+/-0.02) (t=6.79, 4.57, both P<0.05). There were significant differences in the expression of PD-1, TIM-3 mRNA in the TILs between the different tumor histological grades, tumor sizes, lymph node metastasis (t=2.22 2.99, all P<0.05). Correlation analysis showed that there was a significant positive correlation between the expression of PD-1 and TIM-3 in tumor tissues (r=0.616, P<0.01). Conclusions: In the breast cancer microenvironment, PD-1, TIM 3-mediated signaling pathway plays an important role in the occurrence and development of breast cancer, it provides a new basis for the combination therapy of breast cancer. PMID- 29764039 TI - [Long-term efficacy of cervical artificial disc replacement for cervical degenerative diseases]. AB - Objective: To evaluate the long-term efficacy of cervical artificial disc replacement for patients with cervical disc herniation and degenerative cervical canal stenosis. Methods: Total of sixty-eight patients underwent single-level Bryan artificial disc replacement in Beijing Jishuitan Hospital from December 2003 to December 2007 with a minimum 10-year follow-up were retrospectively analyzed. There were 43 males and 25 females with a mean age of (46+/-8) years. According to preoperative CT and MRI, the patients were divided into two groups: 27 patients in cervical disc herniation group and 41 patients in degenerative cervical canal stenosis group. The evaluation indexes before surgery and at last follow-up were compared between two groups. The clinical indexes included Japanese Orthopaedic Association (JOA) score, neck disability index (NDI) and Odom's grade; and the radiological indexes included the global and segmental range of motion (ROM), Cobb's angle at operated level. The continuous variable data were analyzed by independent sample t test. Results: In cervical disc herniation group, the improvement rate of JOA score was 83%+/-22%, NDI% decreased by 14%+/-9%, and Odom's grade was excellent in 17 patients, good in 10 patients. In degenerative cervical canal stenosis group, the improvement rate of JOA was 68%+/-34%, NDI% decreased by 11%+/-7%, and Odom's grade was excellent in 19 patients, good in 18 patients, fair in 4 patients. The segmental ROM was 10 degrees +/-4 degrees and 7 degrees +/-6 degrees in cervical disc herniation and degenerative cervical canal stenosis group at last follow-up (t=2.284, P=0.026). The global ROM was 50 degrees +/-9 degrees and 44 degrees +/-14 degrees in cervical disc herniation and degenerative cervical canal stenosis group at last follow-up (t=2.112, P=0.038). Conclusions: Cervical artificial disc replacement has a favorable long-term efficacy in treating cervical degenerative diseases. The postoperative global and segmental ROM in patients with cervical disc herniation are better than those in patients with degenerative cervical canal stenosis. PMID- 29764040 TI - Editor's Note. PMID- 29764041 TI - Corrigendum. PMID- 29764042 TI - Erratum. PMID- 29764043 TI - Association of matrix metalloproteinase-7A-181G variants with the risk of multiple sclerosis. AB - AIM: To investigate the influence of matrix metalloproteinase-7 (MMP-7) A-181G on the risk of multiple sclerosis (MS) and neurological disability. PATIENTS & METHODS: The variants of MMP-7 were studied in 126 MS patients and 190 healthy controls. RESULTS: The MMP-7 G allele and AG+GG genotype significantly increased the risk of MS in females (odds ratio: 1.59; p = 0.011) and patients with the age at disease onset of <=19 years (odds ratio: 8.77; p = 0.038), respectively. Patients with clinical course of secondary progressive MS carriers of AG genotype had higher mean Expanded Disability Status Scale (4.9 +/- 0.85; p = 0.01) compared with carriers of AA genotype (3.75 +/- 0.41). CONCLUSION: The MMP-7 A 181G polymorphism might be associated with susceptibility to MS in females and individuals with the age at disease onset of <=19 years and with neurological disability in secondary progressive MS. PMID- 29764044 TI - A possible future for the pharmaceutical industry. PMID- 29764045 TI - Molecular profiling and companion diagnostics: where is personalized medicine in cancer heading? AB - The goal of personalized medicine is to use the right drug at the right dose - with minimal or no toxicity - for the right patient at the right time. Recent advances in understanding cell biology and pathways, and in using molecular 'omics' technologies to diagnose cancer, offer a strategic bridge to personalized medicine in cancer. Modern personalized medicine takes into account an individual's genetic makeup and disease history before developing a treatment regimen. The future of clinical oncology will be based on the use of predictive and prognostic biomarkers in patient management. Once implemented widely, personalized medicine will benefit patients and the healthcare system greatly. PMID- 29764046 TI - Personalizing care for nonalcoholic fatty liver disease patients: what are the research priorities? AB - Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease whose prevalence has reached global epidemic proportions, not only in adults but also in children. From a clinical point of view, NAFLD stems a myriad of challenges to physicians, researchers and patients. In this study, we revise the current knowledge and recent insights on NAFLD pathogenesis and diagnosis in the context of a personalized perspective with special focus on the following issues: noninvasive biomarkers for the evaluation of disease severity and progression, lifestyle-related patients' recommendations, risk prediction of disease by genetic testing, management of NAFLD-associated comorbidities and patient oriented therapeutic intervention strategies. PMID- 29764047 TI - Past, current and future approaches to querying MAPK pathway activation: status and clinical implications. AB - MAPK pathway activation related to cancer development has drawn a great deal of attention in the field of personalized medicine in recent years. Many different approaches and assays have been developed to query the activation of this pathway and to develop life-saving treatments. The goal of this review article is threefold. First, to provide a brief overview of the many mutation assays that have been used to detect MAPK pathway activation, and to compare pros and cons of these assay platforms. Second, to focus on one custom-designed multiplexing mutation assay that is currently used to support an ongoing clinical trial and to show the novel features of this assay and its relevance in addressing unmet clinical needs. Third, to provide future perspectives of these MAPK pathway gene mutation detection efforts and to suggest how what we have learned from past and current approaches should guide future developments. PMID- 29764048 TI - Personhood and solidarity: what kind of personalized medicine do we want? AB - The concept of personalized medicine has attracted considerable criticism over recent years. Only a few studies, however, have questioned the meaning of the notion of the 'person' in this context. By leaving the meaning of this word unexplored, we risk taking on board two assumptions that are inherent in contemporary western thinking: first, that social practice can be reduced to decisions of individuals; and second, that people's actions are normally motivated by self-interest. Both assumptions are problematic in the context of medicine. One of the keys to realizing a form of personalization in medicine that fosters solidarity and is sensitive to people's needs lies in being cautious about what idea of personhood we use and promote. PMID- 29764049 TI - Toxgnostics: predicting and preventing chemotherapy-induced side effects. PMID- 29764050 TI - Working towards personalization of Medicine: Genomics in 2014. PMID- 29764051 TI - From pharmacogenomics to integrated personal omics profiling: a gap in implementation into healthcare. PMID- 29764052 TI - Personalized medicine in oncology: ethical implications for the delivery of healthcare. AB - While personalized medicine brings benefits for the treatment of cancer, there are still key ethical issues at stake in developing personalized medicine in oncology. We propose an ethical analysis of personalized medicine in oncology that highlights the particularities of cancer care, critically assesses the scientific advances behind personalized medicine in oncology and emphasizes fairness in resource allocation in the delivery of personalized healthcare. This allows for a broader understanding of the real impacts on both recipients and the healthcare system. PMID- 29764053 TI - Bridging genomics research between developed and developing countries: the Genomic Medicine Alliance. AB - The Genomic Medicine Alliance is a global academic research network that aims to establish and strengthen collaborative ties between the various genomic medicine stakeholders. Its focus lies on the translation of scientific research findings into clinical practice. It brings together experts from disciplines including genome informatics, pharmacogenomics, public health genomics, ethics in genomics and health economics, and it is supervised by a 14-member International Scientific Advisory Committee comprising internationally renowned scientists. The Alliance's official journal, Public Health Genomics, offers members a highly respected publication forum for their original research findings. In the short-to medium term, the Genomic Medicine Alliance hopes to harmonize research activities between developed and developing countries and to organize educational activities in the field of genomic medicine. PMID- 29764054 TI - Population pharmacokinetic/pharmacogenetic model of lopinavir/ritonavir in HIV infected patients. AB - AIM: This study aims to develop a population pharmacokinetic/pharmacogenetic model for lopinavir/ritonavir (LPV/r) in European HIV-infected patients. MATERIALS & METHODS: A total of 693 LPV/r plasma concentrations were assessed and 15 single-nucleotide polymorphisms were genotyped. The population pharmacokinetic/pharmacogenetic model was created using a nonlinear mixed-effect approach (NONMEM(r) v.7.2.0., ICON Development Solutions, Dublin, Ireland). RESULTS: Covariates significantly related to LPV/r apparent clearance (CL/F) were ritonavir trough concentration (RTC), BMI, high-density lipoprotein cholesterol (HDL-C) and certain single-nucleotide polymorphisms in genes encoding for metabolizing enzymes, which are representable as follows: CL/F = (0.216BMI + 0.0125HDL-C) * 0.713RTC * 1.26rs28371764[C/T] * 0.528rs6945984[C/C] * 0.302 CYP3A4[1461insA/del] Conclusion: The LPV/r standard dose appears to be appropriate for the rs28371764[C/T] genotype. However, lower doses should be recommended for the rs6945984[C/C] and CYP3A4[1461insA/del] genotypes and even for those patients without any of these variants, as the standard dose seems to be higher than that which is required in order to achieve therapeutic levels. PMID- 29764055 TI - Working towards personalization in medicine: main obstacles to reaching this vision from today's perspective. AB - Rapid advances in 'omics' sciences and technologies have elevated the relevance of personalized medicine. This article reviews the current advances in the application of personalized medicine, outlines and summarizes the key areas that still need to be addressed and gives recommendations in this direction. Eighteen relevant high-level reports on personalized medicine were reviewed in order to identify the gaps and needs that are present for the implementation of personalized medicine. We identify 12 key areas that represent the main obstacles on the road towards the personalization of medicine and divide these 12 key areas into four domains, namely: scientific research and stakeholder collaboration; translational tools; regulations and systematic early dialog with regulators; and uptake into healthcare systems. All of the evaluated reports agree on the imperative need for intensive collaboration among all stakeholders with early active participation and changes in the current healthcare infrastructure. PMID- 29764056 TI - Nonstandard personalized medicine strategies for cancer may lead to improved patient outcomes. AB - Cancer is an evolutionary process that is driven by mutation and selection. Tumors are genetically unstable, and research has shown that this is the most efficient way for cancers to evolve. Genetic instability leads to genetic heterogeneity and dynamic change within a single individual's tumor, in turn leading to therapeutic resistance. Cancer treatment has also evolved from an empirical science of killing dividing cells to the current era of 'personalized medicine', exquisitely targeting the molecular features of individual cancers. However, current personalized medicine regards a single individual's cancer as largely uniform and static. Moreover, from a strategic perspective, current personalized medicine thinks primarily of the immediate therapy selection. Ongoing research suggests that new, nonstandard personalized treatment strategies that plan further ahead and consider intratumoral heterogeneity and the evolving nature of cancer (due to genetic instability) may lead to the next level of therapeutic benefit beyond current personalized medicine. PMID- 29764057 TI - Personalized medicine for chronic, complex diseases: chronic obstructive pulmonary disease as an example. AB - Chronic, complex diseases represent the majority of healthcare utilization and spending in the USA today. Despite this, therapeutics that account for the heterogeneity of these diseases are lacking, begging for more personalized approaches. Improving our understanding of disease phenotypes through retrospective trials of electronic health record data will enable us to better categorize patients. Increased usage of next-generation sequencing will further our understanding of the genetic variants involved in chronic disease. Utilization of data warehousing will be necessary in order to securely handle, integrate and analyze the large sets of data produced with these methods. Finally, increased use of clinical decision support will enable the return of clinically actionable results that physicians can use to apply these personalized approaches. PMID- 29764058 TI - Avatars of personalized cancer therapy can lead to a reduction in head and neck cancer survival disparities. PMID- 29764059 TI - Leveraging next-generation phenotyping and pan-omics to identify novel biomarkers and pharmaceutical targets for cardiovascular disease. PMID- 29764060 TI - The pharmacogenomics of warfarin from the COAG and EU-PACT: where do we go from here? PMID- 29764061 TI - Highlights from the latest articles in suicide research. PMID- 29764063 TI - Translational Research 2.0: a framework for accelerating collaborative discovery. AB - The world wide web has revolutionized the conduct of global, cross-disciplinary research. In the life sciences, interdisciplinary approaches to problem solving and collaboration are becoming increasingly important in facilitating knowledge discovery and integration. Web 2.0 technologies promise to have a profound impact - enabling reproducibility, aiding in discovery, and accelerating and transforming medical and healthcare research across the healthcare ecosystem. However, knowledge integration and discovery require a consistent foundation upon which to operate. A foundation should be capable of addressing some of the critical issues associated with how research is conducted within the ecosystem today and how it should be conducted for the future. This article will discuss a framework for enhancing collaborative knowledge discovery across the medical and healthcare research ecosystem. A framework that could serve as a foundation upon which ecosystem stakeholders can enhance the way data, information and knowledge is created, shared and used to accelerate the translation of knowledge from one area of the ecosystem to another. PMID- 29764062 TI - Nutrigenetics and personalized nutrition: are we ready for DNA-based dietary advice? AB - Common genetic variation affects individual nutrient requirements and the use of DNA-based dietary advice, derived from nutrigenetics, has been growing. The growth is about to accelerate as the cost of genotyping continues to fall and research results from major nutrigenetics projects are published. There is still some skepticism; some barriers remain including some commercial tests, which make exaggerated, incorrect claims. There is a need for more public resources dedicated to unbiased, objective review and dissemination of nutrigenetics information; however, nutrigenetics evidence should be assessed in the context of standard nutritional evidence and should not require higher standards. This article argues that we are ready for some DNA-based dietary advice in general nutrition and it can be beneficial. Examples of the scientific validity and health utility of gene-diet interactions will be given and the development of guidelines for assessment and validation of benefits will be discussed. PMID- 29764065 TI - Toxicogenetics of lopinavir/ritonavir in HIV-infected European patients. AB - AIMS: We present a genetic association study in 106 European HIV-infected individuals aimed at identifying and confirming polymorphisms that have a significant influence on toxicity derived from treatment with lopinavir/ritonavir (LPV/r). PATIENTS & METHODS: Genotyping was performed by matrix-assisted laser desorption/ionization-time of flight and KASPar(r) (KBiosciences, Hoddesdon, UK); LPV/r plasma concentrations were quantified using HPLC with an UV detection system and the pharmacokinetic parameters were estimated using Bayesian algorithms. Genetic association analysis was performed with PASW Statistics 18 (SPSS Inc., IL, USA) and R for Windows (Microsoft, WA, USA). RESULTS: Suggestive relationships have been established between lipid plasma levels and total bilirubin and SNPs in CETP, MCP1, ABCC2, LEP and SLCO1B3 genes and between diarrhea and SNPs in IL6 gene. CONCLUSION: Replication analysis should confirm the novel results obtained in this study prior to its application in the clinical practice to achieve a safer LPV/r-based combined antiretroviral therapy. PMID- 29764066 TI - Translational informatics in personalized medicine: an update for 2014. AB - Many things have changed but much has remained the same as we have seen a dramatic increase in the generation of genetics, genomics and a variety of clinical data leading to increased data density and continued challenges in organizing and managing that data in pursuit of personalized medicine. Simultaneously, we have seen an increase in commercial and open-source solutions, and marked movement toward open sharing of tools and data in public-private partnerships, yet still few examples of traditional companion diagnostics for personalized medicine products. Most encouraging are examples of focused public and private efforts that have resulted in knowledge leading to critical assessment of existing therapies and the development of new therapies. These examples lay highly emulatable informatics foundations for rapid advances in personalized medicine. PMID- 29764067 TI - Opportunities and risks of diagnostic lab-on-a-chip systems in healthcare from a health system stakeholder's perspective. AB - AIM: The aim of personalized medicine is to respond to the needs of individuals with appropriate treatment. Lab-on-a-chip systems (LOCs) can help to individualize therapeutic algorithms at the point of care. Herein, we discuss the perspectives, demands and concerns associated with LOCs. METHODS: Interviews with 30 experts in the field of personalized medicine were conducted, addressing the requirements, potentials and risks of LOCs. The interviews were transcribed and evaluated by means of qualitative content analysis. RESULTS: The majority of experts emphasize a considerable potential for the lab-on-a-chip industry with the largest potential in the context of point-of-care diagnostics. The direct-to costumer use is regarded as risky, in particular with respect to the reliability of the results. CONCLUSION: In addition to a major potential of the implementation of LOCs, their impact on delivery of healthcare have to be considered, and early communication between physicians and LOC developers and manufacturers have to be ensured. PMID- 29764068 TI - Epigenetic primer for diagnostic applications: a window into personalized medicine. AB - Epigenetic testing, primarily in the form of DNA methylation analysis, is currently being used in healthcare settings to help identify and manage disease conditions and to develop and select drugs that specifically target epigenetic machinery. Yet, the clinical application of epigenetic analysis is still in its infancy. With a number of large-scale national and international epigenomic consortia projects in progress to identify tissue-specific epigenomes in normal and disease conditions, we are now poised for a new era of understanding disease processes based upon genetic changes that do not involve alterations to the DNA sequence. The developing epigenetic knowledge base will significantly advance the practice of personalized medicine and precision therapeutics. In this article, we provide a primer on the fundamentals of epigenetics with an emphasis on DNA methylation and review the prospective uses of epigenetic testing in advancing healthcare. PMID- 29764070 TI - Hepatitis B vaccination and India. PMID- 29764069 TI - Predictive testing for DPD deficiency in a patient with familial history of fluoropyrimidine-associated toxicity. AB - Reduced activity of DPD leads to severe toxicity in cancer patients receiving standard doses of fluoropyrimidines, particularly in the case of combination regimens. We describe a 38-year-old man with a resectable metastasis from hereditary nonpolyposis colorectal cancer, with indication of neoadjuvant chemotherapy and a family history of fluoropyrimidine-associated toxicity. We tested our patient for functional DPYD variants, before any choice of the neoadjuvant regimen, including for the c.496A>G, already described in his mother, and a deep intronic variant c.1129-5923C>G recently reported associated to severe toxicity. Our patient was found to be heterozygous for both c.469A>G and c.1129 5923C>G DPYD variants. We thus offered the most active perioperative regimen, capecitabine, oxaliplatin, irinotecan plus bevacizumab by which we reduced the dosing of capecitabine to 50%. Treatment was well tolerated, with grade 2 diarrhea as the most significant adverse event, and led to a complete pathological response after liver resection. We provide a rationale approach to improve the safety of fluoropirimidine-based therapy in a patient with family history of fluoropyrimidine-associated toxicity. PMID- 29764071 TI - Has the Medical Journal a future? PMID- 29764072 TI - Signed editorials. PMID- 29764073 TI - Plasma fibronectin levels in patients with idiopathic ulcerative colitis. AB - BACKGROUND: Deficiency of fibronectin-a naturally occurring glycoprotein-has been demonstrated in patients with Crohn's disease. We studied plasma fibronectin levels in idiopathic ulcerative colitis to see whether there was any correlation with disease activity. METHODS: Fifty patients and an equal number of age and sex matched healthy controls were studied by ELISA for plasma fibronectin. RESULTS: The mean plasma fibronectin levels were significantly lower (p<0.001) in patients with idiopathic ulcerative colitis (171+/-93 MUg/ml) as compared to those in controls (347+/-59 MUg/ml). There was, however, no significant difference (p>0.05) in fibronectin levels between those who had active colitis (176+/-103 MUg/ml) and those with quiescent colitis (163+/-73 MUg/ml). Plasma fibronectin levels did not show any correlation with the extent and duration of colitis or with steroid administration. CONCLUSION: Decreased fibronectin levels may be important in the pathophysiology of ulcerative colitis. PMID- 29764074 TI - Serological surveillance for HIV-l infection in Bombay. AB - BACKGROUND: Screening of populations for the antibody to the human immunodeficiency virus has been recommended to be a practical method for assessing the prevalence of the infection and its potential for spread. METHODS: Between 1987 and 1989 we carried out a serological survey for the detection of antibody to the human immunodeficiency virus type 1, using the enzyme linked immunosorbent assay, to screen 2123 persons belonging to different high-risk groups from various parts of Bombay. RESULTS: Eighty-four repeatedly positive samples were subjected to the Western blot test for confirmation and 58 were found to be positive-4 (0.6%) out of 670 in 1987, 9(1.2%) out of 740 in 1988 and 45 (6.3%) out of 713 in 1989. CONCLUSION: These data indicate that the human immunodeficiency virus type 1 infection has already spread in the cityof Bombay among the various high-risk groups and that its prevalence rose between 1987 and 1989. PMID- 29764076 TI - Steroids and growth. PMID- 29764075 TI - Identification of a contact depigmenting agent in Indian bindi. AB - INTRODUCTION: Bindis, which Indian women apply on their foreheads, occasionally depigment the skin. METHODS: We analysed the adhesive on bindi samples using thin layer chromatography, infrared spectrophotometry, high performance liquid chromatography and patch tested 15 patients with bindi depigmentation, 10 normal individuals and 14 patients with vitiligo. RESULTS: The bindi adhesive contained about 80% paratertiary butyl phenol-a depigmenting agent with a marked irritant action. Hypersensitivity to the agent did not occur. CONCLUSIONS: Para-tertiary butyl phenol causes depigmentation after bindi application on the forehead and we suggest that the use of this agent as an adhesive be banned. PMID- 29764077 TI - Reye's Syndrome. PMID- 29764078 TI - Dyspepsia: Should all patients undergo endoscopy? AB - BACKGROUND: The role of endoscopy in the diagnosis of dyspepsia is not clear and there are conflicting reports mainly from western countries. METHODS: All patients presenting with dyspepsia to the gastroenterology department of the M.L.N. Medical College, Allahabad, between January 1989 and April 1990, were subjected to endoscopy. Patients were divided into two age groups: younger (<=45 years) and older (>45 years). RESULTS: Ninety-two (16%) of 567 patients in the younger age group had endoscopic abnormalities and the majority had minor diseases such as peptic ulcer whereas 69 (42%) of 165 patients in the older age group had abnormalities (p<0.001)and 15(9%) had gastric carcinomas. CONCLUSION: We suggest that in cases of dyspepsia, only patients above the age of 45 years should be subjected to routine endoscopy. This will considerably reduce the load on endoscopy units and make the procedure more costeffective. PMID- 29764081 TI - Steroids and myasthenia gravis. PMID- 29764080 TI - Screening for prostatic cancer. PMID- 29764079 TI - "Do not resuscitate" orders in Delhi. AB - BACKGROUND: 'Do not resuscitate' orders are now well accepted in western countries. METHOD: In order to gauge opinion in Delhi, we interviewed 102 doctors who were working or had worked in intensive care units and hence had experience of treating patients 'beyond salvage'. RESULTS AND CONCLUSIONS: Nearly three fourths of the doctors were already practising 'do not resuscitate' orders and 80% were willing to practise such orders if it were made a state policy. All of them felt the need to legally revise the definition of death in order to recognize brain death. PMID- 29764082 TI - Follicular adenoma and carcinoma of thyroid: Evidence for uniform management. PMID- 29764083 TI - The orbitalis muscle identified. PMID- 29764084 TI - Will omeprazole succeed in refractory duodenal ulcer when the histamine receptor antagonists fail? PMID- 29764085 TI - Norfloxacin and spontaneous bacterial peritonitis. PMID- 29764086 TI - Supportive therapy in cancer. PMID- 29764087 TI - Nutritional support in adults. PMID- 29764088 TI - Paediatric surgery in India. PMID- 29764090 TI - Letter from London. PMID- 29764089 TI - Institute of medical sciences, Banaras Hindu University, Varanasi. PMID- 29764091 TI - Letter from Moscow. PMID- 29764093 TI - Erratum. PMID- 29764092 TI - Correspondence. PMID- 29764094 TI - Assessing functional recovery in the first 6 months after acute ischaemic stroke: a prospective, observational study. AB - BACKGROUND: Stroke is a major cause of short-term functional impairment, but the recovery timeframes are not well-established. AIM: This study aims to evaluate the progression of functional recovery during the first 24 weeks after acute ischaemic stroke, to determine the timeframes for (a) motor, (b) cognitive, and (c) overall recovery. DESIGN: Prospective observational study. SETTING: Tertiary care centre; 12-week inpatient period, followed by 12-week outpatient period. POPULATION: A group of 131 patients with acute stroke in the territory of the middle cerebral artery with age 18-85 years-old. METHODS: Patients received treatment according to routine clinical practice and underwent a closely controlled rehabilitation program for 24 weeks. Functionality assessments were conducted at 48 hours, 3 weeks, 12 weeks, and 24 weeks after acute stroke and included the modified Rankin Scale (mRS), the Functional Independence Measure (FIM), and the Stroke Upper Limb Capacity Scale (SULCS). RESULTS: Over the study period, patient functionality improved significantly (P<0.001) as measured by all scales. Assessment scores improved significantly from 48 hours to 3 weeks for all scales; the same occurred from 3 weeks to 12 weeks, except for C-FIM. From 12 weeks to 24 weeks, there were no statistically significant functional improvements for any scale. In comparative terms, cognitive impairment was less severe than motor disability in the acute phase. C-FIM scores at 48 hours were significant higher than M-FIM and mRS scores. Upper limb functioning measured by SULCS, showed a intermediate degree of disability compared to the C-FIM, M-FIM, and mRS. CONCLUSIONS: Functional recovery occurs at least until 24 weeks after acute stroke, but most the of the functional gains tend to be achieved during the first 12 weeks. Cognitive function tends to improve earlier than motor function, with the most substantial gains occurring within the first 3 weeks. From 12 to 24 weeks there are observable numerical gains in patient functionality, highlighting the need to maintain an adequate rehabilitation program. CLINICAL REHABILITATION IMPACT: This study provides insight into the recovery timeframe for stroke patients, which can support the development of more effective rehabilitation programs. PMID- 29764095 TI - Clinical outcomes in a cohort of patients with T1 high grade urothelial bladder cancer not receiving intravesical bacillus Calmette-Guerin: a 15 year experience PMID- 29764096 TI - Validating the Loop Mediated Isothermal Amplification (LAMP) technique to detect tuberculosis in a Sri Lankan laboratory setting PMID- 29764097 TI - Outcome of hepatic resection: First five-year experience in elderly and younger patients. PMID- 29764099 TI - Assessment of treatment field isolation during scaling, root planing and rinsing AB - Aim: Intensive application of highly concentrated antimicrobials during scaling and root planing may be hazardous if swallowed in quantity. This study evaluates two dental isolation systems for fluid leakage in conjunction with a sham treatment of scaling and root planing.Materials and methods: Eight volunteers were randomly assigned to wear a conventional rubber dam (RD) and a combined suction and isolation device (IsoLite(r) system [IL]) alternatively on contralateral maxillary and mandibular quadrants. RD was cut between the canine and the first molar and was fixed on the first molar with a rubber dam clamp and with a tissue adhesive (Histoacryl) on the gingiva. IL was applied as recommended by the manufacturer. Ultrasonic instrumentation with corresponding irrigation water was used for 5 min as sham treatment, i.e. no actual therapy. The irrigation liquid was collected and the difference between the amount of liquid applied and that collected during treatment was determined. The volunteers then reported on their comfort during treatment.Results: Neither of the devices offered complete isolation. Mean leakage with both systems was generally low, i.e. approximately 10% (of the applied irrigant). More leakage was recorded in the maxilla than in the mandible, for both systems. Both devices were deemed moderately comfortable to wear.Conclusion: RD and IL isolated the working field to a similar degree. Since RD represents the highest isolation standard currently available, the use of IL must also be considered sufficient to prevent noxious amounts of antiseptic rinses from leaking into the mouth. PMID- 29764100 TI - Convex versus Radial Echoendoscopes - Comparison of Capability for Evaluating the Pancreatobiliary Junction. PMID- 29764101 TI - Shaping Policy Change in Population Health: Policy Entrepreneurs, Ideas, and Institutions. AB - Political realities and institutional structures are often ignored when gathering evidence to influence population health policies. If these policies are to be successful, social science literature on policy change should be integrated into the population health approach. In this contribution, drawing on the work of John W. Kingdon and related scholarship, we set out to examine how key components of the policy change literature could contribute towards the effective development of population health policies. Shaping policy change would require a realignment of the existing school of thought, where the contribution of population health seems to end at knowledge translation. Through our critical analysis of selected literature, we extend recommendations to advance a burgeoning discussion in adopting new approaches to successfully implement evidence-informed population health policies. PMID- 29764102 TI - Assessment of the Effects of Economic Sanctions on Iranians' Right to Health by Using Human Rights Impact Assessment Tool: A Systematic Review. AB - BACKGROUND: Over the years, economic sanctions have contributed to violation of right to health in target countries. Iran has been under comprehensive unilateral economic sanctions by groups of countries (not United Nations [UN]) in recent years. They have been intensified from 2012 because of international community's uncertainty about peaceful purpose of Iran's nuclear program and inadequacy of trust-building actions of this country. This review aimed to identify the humanitarian effects of the sanctions on the right of Iranians to health and the obligations of Iran and international community about it. METHODS: To assess economic sanction policies and identify violated rights and the obligations of states according to international human rights laws, in this study, Human Rights Impact Assessments (HRIA) tool is used. Applying this tool requires collection of evidences regarding the situation of rights. To provide such evidence, a systematic review of literature which involved 55 papers retrieved from the web based databases and official webpages of Iran's government and UN' health and human rights committees and organizations was done. All articles about the consequences of economic sanctions related to nuclear activities of Iran on welfare and health of Iranians published from January 2012 till February 2017 in English and Persian languages were included. Search terms were economic sanctions, embargoes, Iran, welfare, health and medicine. Additional studies were identified by cross checking the reference lists of accessed articles. All selected papers were abstracted and entered into a matrix describing study design and findings, and categorized into a framework of themes reflecting the areas covered (health and its determinants). According to HRIA framework, related obligations of Iran and other states about adverse effects of the sanctions on Iranians' right to health were extracted. RESULTS: The sanctions on Iran caused a fall of country's revenues, devaluation of national currency, and increase of inflation and unemployment. These all resulted in deterioration of people's overall welfare and lowering their ability to access the necessities of a standard life such as nutritious food, healthcare and medicine. Also, the sanctions on banking, financial system and shipment led to scarcity of quality lifesaving medicines. The impacts of sanctions were more immense on the lives of the poor, patients, women and children. Humanitarian exemptions did not protect Iranians from the adverse effects of sanctions. CONCLUSION: Countries which imposed economic sanctions against Iran have violated Iranians' right to health. International community should have predicted any probable humanitarian effects of sanctions and used any necessary means to prevent it. Furthermore, Iran should have used any essential means to protect people from the adverse effects of sanctions. Now, they should work on alleviation of the negative effects of sanctions. Even though, some of the effects such as disability and death cannot be compensated. In future, before imposition of sanctions, decisions makers should advice an international order to prevent such impacts on targeted countries' populations. PMID- 29764103 TI - Unit Costing of Health Extension Worker Activities in Ethiopia: A Model for Managers at the District and Health Facility Level. AB - BACKGROUND: Over the last decade, Ethiopia has made impressive national improvements in health outcomes, including reductions in maternal, neonatal, infant, and child mortality attributed in large part to their Health Extension Program (HEP). As this program continues to evolve and improve, understanding the unit cost of health extension worker (HEW) services is fundamental to planning for future growth and ensuring adequate financial support to deliver effective primary care throughout the country. METHODS: We sought to examine and report the data needed to generate a HEW fee schedule that would allow for full cost recovery for HEW services. Using HEW activity data and estimates from national studies and local systems we were able to estimate salary costs and the average time spent by an HEW per patient/community encounter for each type of services associated with specific users. Using this information, we created separate fee schedules for activities in urban and rural settings with two estimates of non salary multipliers to calculate the total cost for HEW services. RESULTS: In the urban areas, the HEW fees for full cost recovery of the provision of services (including salary, supplies, and overhead costs) ranged from 55.1 birr to 209.1 birr per encounter. The rural HEW fees ranged from 19.6 birr to 219.4 birr. CONCLUSION: Efforts to support health system strengthening in low-income settings have often neglected to generate adequate, actionable data on the costs of primary care services. In this study, we have combined time-motion and available financial data to generate a fee schedule that allows for full cost recovery of the provision of services through billable health education and service encounters provided by Ethiopian HEWs. This may be useful in other country settings where managers seek to make evidence-informed planning and resource allocation decisions to address high burden of disease within the context of weak administrative data systems and severe financial constraints. PMID- 29764104 TI - The Response to and Impact of the Ebola Epidemic: Towards an Agenda for Interdisciplinary Research. AB - BACKGROUND: The 2013-2016 Ebola virus disease (EVD) epidemic in West Africa was the largest in history and resulted in a huge public health burden and significant social and economic impact in those countries most affected. Its size, duration and geographical spread presents important opportunities for research than might help national and global health and social care systems to better prepare for and respond to future outbreaks. This paper examines research needs and research priorities from the perspective of those who directly experienced the EVD epidemic in Guinea. METHODS: The paper reports the findings from a research scoping exercise conducted in Guinea in 2017. This exercise explored the need for health and social care research, and identified research gaps, from the perspectives of different groups. Interviews were carried out with key stakeholders such as representatives of the Ministry of Health, non governmental organizations (NGOs), academic and health service researchers and members of research ethics committees (N=15); health practitioners (N=12) and community representatives (N=11). Discussion groups were conducted with male and female EVD survivors (N=24) from two distinct communities. RESULTS: This research scoping exercise identified seven key questions for further research. An important research priority that emerged during this study was the need to carry out a comprehensive analysis of the wider social, economic and political impact of the epidemic on the country, communities and survivors. The social and cultural dynamics of the epidemic and the local, national and international response to it need to be better understood. Many survivors and their relatives continue to experience stigma and social isolation and have a number of complex unmet needs. It is important to understand what sort of support they need, and how that might best be provided. A better understanding of the virus and the long term health and social implications for survivors and non-infected survivors is also needed. CONCLUSION: This study identified a need and priority for interdisciplinary research focusing on the long-term sociocultural, economic and health impact of the EVD epidemic. Experiences of survivors and other non infected members of the community still need to be explored but in this broader context. PMID- 29764105 TI - What Factors Do Allied Health Take Into Account When Making Resource Allocation Decisions? AB - BACKGROUND: Allied health comprises multiple professional groups including dietetics, medical radiation practitioners, occupational therapists, optometrists and psychologists. Different to medical and nursing, Allied health are often organized in discipline specific departments and allocate budgets within these to provide services to a range of clinical areas. Little is known of how managers of allied health go about allocating these resources, the factors they consider when making these decisions, and the sources of information they rely upon. The purpose of this study was to identify the key factors that allied health consider when making resource allocation decisions and the sources of information they are based upon. METHODS: Four forums were conducted each consisting of case studies, a large group discussion and two hypothetical scenarios to elicit data. A thematic content analysis commenced during post-forum discussions of key factors by forum facilitators. These factors were then presented to an expert working party for further discussion and refinement. Transcripts were generated of all data recordings and a detailed thematic analysis was undertaken by one author to ensure coded data matched the initial thematic analysis. RESULTS: Twelve factors affecting the decision-making of allied health managers and clinicians were identified. One of these factors was disendorsed by the expert working party. The 11 remaining factors can be considered to be key decision-making principles that should be consistently applied to resource allocation. These principles were clustered into three overarching themes of readiness, impact and appropriateness. CONCLUSION: Understanding these principles now means further research can be completed to more effectively integrate research evidence into health policy and service delivery, create partnerships among policy-makers, managers, service providers and researchers, and to provide support to answer difficult questions that policy-makers, managers and service providers face. PMID- 29764106 TI - The Challenges of a Complex and Innovative Telehealth Project: A Qualitative Evaluation of the Eastern Quebec Telepathology Network. AB - BACKGROUND: The Eastern Quebec Telepathology Network (EQTN) has been implemented in the province of Quebec (Canada) to support pathology and surgery practices in hospitals that are lack of pathologists, especially in rural and remote areas. This network includes 22 hospitals and serves a population of 1.7 million inhabitants spread over a vast territory. An evaluation of this network was conducted in order to identify and analyze the factors and issues associated with its implementation and deployment, as well as those related to its sustainability and expansion. METHODS: Qualitative evaluative research based on a case study using: (1) historical analysis of the project documentation (newsletters, minutes of meetings, articles, ministerial documents, etc); (2) participation in meetings of the committee in charge of telehealth programs and the project; and (3) interviews, focus groups, and discussions with different stakeholders, including decision-makers, clinical and administrative project managers, clinicians (pathologists and surgeons), and technologists. Data from all these sources were cross-checked and synthesized through an integrative and interpretative process. RESULTS: The evaluation revealed numerous socio-political, regulatory, organizational, governance, clinical, professional, economic, legal and technological challenges related to the emergence and implementation of the project. In addition to technical considerations, the development of this network was associated with major changes and transformations of production procedures, delivery and organization of services, clinical practices, working methods, and clinicaladministrative processes and cultures (professional/organizational). CONCLUSION: The EQTN reflects the complex, structuring, and innovative projects that organizations and health systems are required to implement today. Future works should be more sensitive to the complexity associated with the emergence of telehealth networks and no longer reduce them to technological considerations. PMID- 29764107 TI - The Global Health Policies of the EU and its Member States: A Common Vision? AB - BACKGROUND: This article assesses the global health policies of the European Union (EU) and those of its individual member states. So far EU and public health scholars have paid little heed to this, despite the large budgets involved in this area. While the European Commission has attempted to define the 'EU role in Global Health' in 2010, member states are active in the domain of global health as well. Therefore, this article raises the question to what extent a common 'EU' vision on global health exists. METHODS: This is examined through a comparative framing analysis of the global health policy documents of the European Commission and five EU member states (France, Germany, the United Kingdom, Belgium, and Denmark). The analysis is informed by a two-layered typology, distinguishing global health from international health and four 'global health frames,' namely social justice, security, investment and charity. RESULTS: The findings show that the concept of 'global health' has not gained ground the same way within European policy documents. Consequently, there are also differences in how health is being framed. While the European Commission, Belgium, and Denmark clearly support a social justice frame, the global health strategies of the United Kingdom, Germany, and France put an additional focus on the security and investment frames. CONCLUSION: There are different understandings of global/international health as well as different framings within relevant documents of the EU and its member states. Therefore, the existence of an 'EU' vision on global health is questionable. Further research is needed on how this impacts on policy implementation. PMID- 29764108 TI - Factors That Influence Enrolment and Retention in Ghana' National Health Insurance Scheme. AB - BACKGROUND: The government of Ghana introduced the National Health Insurance Scheme (NHIS) in 2004 with the goal of achieving universal coverage within 5 years. Evidence, however, shows that expanding NHIS coverage and especially retaining members have remained a challenge. A multilevel perspective was employed as a conceptual framework and methodological tool to examine why enrolment and retention in the NHIS remains low. METHODS: A household survey was conducted after 20 months educational and promotional activities aimed at improving enrolment and retention rates in 15 communities in the Central and Eastern Regions (ERs) of Ghana. Observation, indepth interviews and informal conversations were used to collect qualitative data. Forty key informants (community members, health providers and district health insurance schemes' [DHISs] staff) purposely selected from two casestudy communities in the Central Region (CR) were interviewed. Several community members, health providers and DHISs' staff were also engaged in informal conversations in the other five communities in the region. Also, four staff of the Ministry of Health (MoH), Ghana Health Service (GHS) and National Health Insurance Authority (NHIA) were engaged in in-depth interviews. Descriptive statistics was used to analyse quantitative data. Qualitative data was analysed using thematic content analysis. RESULTS: The results show that factors that influence enrolment and retention in the NHIS are multi-dimensional and cut across all stakeholders. People enrolled and renewed their membership because of NHIS' benefits and health providers' positive behaviour. Barriers to enrolment and retention included: poverty, traditional risk-sharing arrangements influence people to enrol or renew their membership only when they need healthcare, dissatisfaction about health providers' behaviour and service delivery challenges. CONCLUSION: Given the multi dimensional nature of barriers to enrolment and retention, we suggest that the NHIA should engage DHISs, health providers and other stakeholders to develop and implement intervention activities to eliminate corruption, shortage of drugs in health facilities and enforce the compulsory enrolment stated in the NHIS policy to move the scheme towards universal coverage. PMID- 29764109 TI - Knowledge Translation in Healthcare - Towards Understanding its True Complexities Comment on "Using Complexity and Network Concepts to Inform Healthcare Knowledge Translation". AB - This commentary argues that to fully appreciate the complexities of knowledge transfer one firstly has to distinguish between the notions of "data, information, knowledge and wisdom," and that the latter two are highly context sensitive. In particular one has to understand knowledge as being personal rather than objective, and hence there is no form of knowledge that a-priori is more authoritative than another. Secondly, knowledge transfer in organisations can only be successful if the organisation is organised and managed as a "complex adaptive organisation" - its key characteristics arising from it's a-priori defined common "purpose, goals and values." Knowledge transfer, seen as "whole of system/organisation learning," is highly context sensitive; while the principles may apply to many organisations, knowledge as such is not transferable from one context to another, it always will be a unique learning exercise at this particular point in time in this particular organisation. PMID- 29764110 TI - Reaching Outside the Comfort Zone: Realising the FCTC's Potential for Public Health Governance and Regulation in the European Union Comment on "The Legal Strength of International Health Instruments - What It Brings to Global Health Governance?" AB - In their paper, Nikogosian and Kickbusch show how the effects of the adoption by the World Health Organization (WHO) of the Framework Convention on Tobacco Control (WHO FCTC) and its first Protocol extend beyond tobacco control and contribute to public health governance more broadly, by revealing new processes, institutions and instruments. While there are certainly good reasons to be optimistic about the impact of these instruments in the public health sphere, the experience of the FCTC's implementation in the context of the European Union (EU) shows that further efforts are still necessary for its full potential to be realised. Indeed, one of the main hurdles to the FCTC's success so far has been the difficulty in developing and maintaining comprehensive multisectoral measures and involving sectors beyond the sphere of public health. PMID- 29764111 TI - Public Spending on Health Services and Policy Research in Canada: A Reflection on Thakkar and Sullivan Comment on "Public Spending on Health Service and Policy Research in Canada, the United Kingdom, and the United States: A Modest Proposal". AB - Vidhi Thakkar and Terrence Sullivan have done a careful and thought-provoking job in trying to establish comparable estimates of public spending on health services and policy research (HSPR) in Canada, the United Kingdom and the United States. Their main recommendation is a call for an international collaboration to develop common terms and categories of HSPR. This paper raises two additional questions that have an international comparative dimension: There is little doubt that public spending on HSPR represents more than the "tip of the iceberg," but how much more? And how do the countries fare on the uptake of HSPR by decision makers? I have long speculated that probably as much or more is spent by provincial/territorial governments, regional health authorities, hospitals and other agencies on HSPR activities carried out by consultants in Canada than by the federal, provincial/territorial granting agencies. Support for this contention is provided in a paper by Penno and Gauld on spending on external consultancies by New Zealand's District Health Boards (DHBs). Their estimate of the amount spent on consultancies in 2014/15 represents 80% of the amount spent on research by the Health Research Council of New Zealand in 2015. In terms of the uptake of research Jonathan Lomas pioneered the concept of linking researchers with decisionmakers when he became the founding Chief Executive Officer (CEO) of the Canadian Health Services Research Foundation (CHSRF) in 1997. An early assessment was promising, and it would be interesting to know if other countries have tried this. Most assessments of research uptake and impact are short-term in nature. It might be insightful to assess HSPR developments over the long term, such as prospective reimbursement through diagnosis related groups (DRGs) that has been evolving internationally for more 40+ years. In the short term the prospects for a major infusion of funding in HSPR in Canada are not promising, although there have been welcome investments in the Canadian Foundation for Healthcare Improvement (formerly CHSRF). PMID- 29764112 TI - Human Rights Treaties Are an Important Part of the "International Health Instrumentariam" Comment on "The Legal Strength of International Health Instruments - What It Brings to Global Health Governance?" AB - In their commentary, Haik Nikogosian and Ilona Kickbusch argue for the necessity of new binding international legal instruments for health to address complex health determinants and offer a cogent analysis of the implications of such treaties for future global health governance. Yet in doing so they pay no attention to the existing instrumentarium of international legally binding treaties relevant to health, in the form of human rights treaties. International human rights law has entrenched individual entitlements and state obligations in relation to individual and public health through iterative human rights treaties since 1946. These treaties offer normative specificity, institutional monitoring and the possibility of enforcement and accountability. If we are to build a new 'international health instrumentariam' we should not ignore existing and important tools that can assist in this endeavor. PMID- 29764113 TI - Soda Taxes: The Importance of Analysing Policy Processes Comment on "The Untapped Power of Soda Taxes: Incentivising Consumers, Generating Revenue, and Altering Corporate Behaviours". AB - Sarah A. Roache and Lawrence O. Gostin's recent editorial comprehensively presents soda taxation rationales from a public health perspective. While we essentially agree that soda taxes are gaining momentum, this commentary expands upon the need for a better understanding of the policy processes underlying their development and implementation. Indeed, the umbrella concept of soda taxation actually covers a diversity of objectives and mechanisms, which may not only condition the feasibility and acceptability of a proposal, but also alter its impact. We briefly highlight some conditions that may have influenced soda tax policy processes and why further theory-driven case studies may be instructive. PMID- 29764114 TI - Accelerating the Worldwide Adoption of Sugar-Sweetened Beverage Taxes: Strengthening Commitment and Capacity Comment on "The Untapped Power of Soda Taxes: Incentivizing Consumers, Generating Revenue, and Altering Corporate Behavior". AB - In their recent article Roache and Gostin outline why governments and public health advocates should embrace soda taxes. The evidence is strong and continues to grow: such taxes can change consumer behavior, generate significant revenue and incentivize product reformulation. In essence, such taxes are an important and now well-established instrument of fiscal and public health policy. In this commentary we expand on their arguments by considering how the worldwide adoption of such taxes might be further accelerated. First, we identify where in the world taxes have been implemented to date and where the untapped potential remains greatest. Second, drawing upon recent case study research on country experiences we describe several conditions under which governments may be more likely to make taxation a political priority in the future. Third, we consider how to help strengthen the technical and legal capacities of governments to design and effectively administer taxes, with emphasis on low- and middle-income countries. We expect the findings to be most useful to public health advocates and policy makers seeking to promote healthier diets and good nutrition. PMID- 29764115 TI - Eating or Feeding Our Young: A Response to Recent Commentaries. PMID- 29764116 TI - Circulating Low Absolute CD4+ T Cell Counts May Predict Poor Prognosis in Extranodal NK/T-Cell Lymphoma Patients Treating with Pegaspargase-Based Chemotherapy. AB - Purpose: Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is a rare subtype of non-Hodgkin lymphoma, and asparaginase-based regimens are the best first-line treatments. Data on the role of specific circulating lymphocyte subsets in the progression of ENKTL are limited. The aim of this study was to investigate the clinical correlation and distribution of circulating absolute CD4+ T-cell counts (ACD4Cs) in ENKTL. Materials and Methods: We retrospectively searched medical records for 70 newly diagnosed ENKTL patients treated with pegaspargase-based regimens. Comparison of ACD4Cs as a continuous parameter in different groups was calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Results: Stage III/IV, B symptoms, elevated lactate dehydrogenase, monocytopenia, high-intermediate and high risk International Prognostic Index (IPI) and Korean Prognostic Index (KPI), high risk Prognostic Index of Natural Killer Lymphoma (PINK), and lower lymphocytes were significantly associated with low ACD4C at diagnosis. With a median follow-up time of 32 months, patients who had an ACD4C <0.30*109/L had a worse OS. Median OS was 11 months and median PFS was 5 months in the low ACD4C cohort. There were significant differences in both OS and PFS between the two cohorts. Moreover, multivariate Cox analysis identified ACD4Cs as an independent predictor for OS and PFS. Conclusion: Low ACD4Cs were associated with poorer survival and could act as a negative predictor for ENKTL patients treated with asparaginase-based regimens. PMID- 29764117 TI - Risk Factor Analysis for Secondary Malignancy in Dexrazoxane-Treated Pediatric Cancer Patients. AB - Purpose: Dexrazoxane has been used as an effective cardioprotector against anthracycline cardiotoxicity. This study intended to analyze cardioprotective efficacy and secondary malignancy development, and elucidate risk factors for secondary malignancies in dexrazoxane-treated pediatric patients. Materials and Methods: Data was collected from 15 hospitals in Korea. Patients who received any anthracyclines, and completed treatment without stem cell transplantation were included. For efficacy evaluation, the incidence of cardiac events and cardiac event free survival rates were compared. Data about risk factors of secondary malignancies were collected. Results: Data of total 1,453 cases were analyzed; dexrazoxane with every anthracyclines group (D group, 1,035 patients) and no dexrazoxane group (non-D group, 418 patients). Incidence of the reported cardiac events was not statistically different between two groups; however, the cardiac event-free survival rate of patients with more than 400 mg/m2 of anthracyclines was significantly higher in D group (91.2% vs. 80.1%, p=0.04). The 6-year cumulative incidence of secondary malignancy was not different between both groups after considering follow up duration difference (non-D, 0.52+/-0.37%; D, 0.60+/-0.28%; p=0.55). The most influential risk factor for secondary malignancy was the duration of anthracycline administration according to multivariate analysis. Conclusion: Dexrazoxane had an efficacy in lowering cardiac event-free survival rates in patients with higher cumulative anthracyclines. As a result of multivariate analysis for assessing risk factors of secondary malignancy, the occurrence of secondary malignancy was not related to dexrazoxane administration. PMID- 29764118 TI - Longitudinal Assessment of Intravoxel Incoherent Motion Diffusion Weighted Imaging in Evaluating the Radio-sensitivity of Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiation Therapy. AB - Purpose: Intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) was evaluated regarding its ability to preliminarily predict the short-term treatment response of nasopharyngeal carcinoma (NPC) following intensity-modulated radiation therapy. Methods: IVIM-DWI with 14 b-factors (0-1,000 s/mm2) was performed with a 3T MR system on 47 consecutive NPCs before, during (end of the 5th, 10th, 15th, 20th, and 25th fractions), and after fractional radiotherapy. IVIM parametrics (D, f, and D*) were calculated and compared to the baseline and Xth fraction. Patients were categorized into responders and non-responders after radiotherapy. IVIM parametrics were also compared between subgroups. Results: After fractional radiations, the D (except D5 and D at the end of the 5th fraction) after radiations were larger than the baseline D0 (p<0.05), and the post-radiation D* (except D*5 and D*10) were smaller than D*0 (p<0.05). f0 was smaller than f5 and f10 (p<0.001) but larger than fend (p<0.05). Furthermore, greater D5, D10, D15, and f10 coupled with smaller f0, D*20, and D*25 were observed in responders than non-responders (all p<0.01). Responders also presented larger DeltaD10, Deltaf10, DeltaD*20, and deltaD*20 than non-responders (p<0.05). Receiver operating characteristic curve analysis indicated that the D5, D*20, and f10 could better differentiate responders from non-responders. Conclusion: IVIM-DWI could efficiently assess tumor treatment response to fractional radiotherapy and predict the radio-sensitivity for NPCs. PMID- 29764119 TI - Founder Mutations for Early Onset Melanoma as Revealed by Whole Exome Sequencing Suggests That This is Not Associated with the Increasing Incidence of Melanoma in Poland. AB - Purpose: Germline mutations within melanoma susceptibility genes are present only in minority of melanoma patients and it is expected that additional genes will be discovered with next generation sequence technology and whole-exome sequencing. Material and Methods: Herein we performed whole-exome sequencing (WES) on a cohort of 96 unrelated Polish patients with melanoma diagnosed under the age of 40 years who all screened negative for the presence of CDKN2A-variants. A replication study using a set of 1200 melanoma patient DNA samples and similarly large series of healthy controls was undertaken. Results: We selected 21 potentially deleterious variants in 20 genes (VRK1, MYCT1, DNAH14, CASC3, MS4A12, PRC1, WWOX, CARD6, EXO5, CASC3, CASP8AP2, STK33, SAMD11, CNDP2, CPNE1, EFCAB6, CABLES1, LEKR, 1 NUDT17, RRP15), which were identified by WES and confirmed by Sanger sequencing for an association study. Evaluation of the allele distribution among carriers and their relatives in available family trios revealed that these variants were unlikely to account for many familial cases of melanoma. Replication study revealed no statistically significant differences between cases and controls. Conclusion: Although most of the changes seemed to be neutral we could not exclude an association between variants in VRK1, CREB3L3, EXO5 and STK33 with melanoma risk. PMID- 29764121 TI - In This Issue, Volume 9, Issue 5. PMID- 29764120 TI - Multiarm Nanoconjugates for Cancer Cell-Targeted Delivery of Photosensitizers. AB - Photodynamic therapy, a procedure that uses a photosensitizer to enable light therapy selectively at diseased sites, remains underutilized in oncological clinic. To further improve its cancer selectivity, we developed a polymeric nanosystem by conjugating a photosensitizer IRDye 700DX (IR700) and cancer targeting RGD peptide to 8-arm polyethylene glycol (PEG). The resulting nanoconjugates (RGD-8PEG-IR700) exhibited a hydrodynamic size of 6.6 nm with narrow distribution of size. The targeted nanoconjugates showed significantly higher intracellular uptake of IR700 in integrin alphavbeta3-expressing A375 and SKOV3 cells when compared with nontargeted control 8PEG-IR700, and an excess amount of RGD peptides could abolish this enhancement, indicating a receptor mediated uptake mechanism for the targeted polymer conjugates. Phototoxicity studies indicated that RGD-8PEG-IR700 produced massive cell killing in A375 cells after photoirradiation with an IC50 value of 57.8 nM for IR700. In contrast, free IR700 and the control 8PEG-IR700 conjugates did not produce any phototoxicity at the concentrations up to 1 MUM IR700. Upon photoirradiation, the RGD-8PEG-IR700 could produce sufficient singlet oxygen in the cells and induced cell apoptosis. The studies with three-dimensional tumor spheroids showed that they penetrated tumor spheroids deeply and produced strong phototoxicity. Thus, we conclude that the polymer nanoconjugates may provide a promising delivery system for targeted photodynamic therapy of cancers due to their small size, cancer cell specificity, and minimal side effects. PMID- 29764123 TI - The folding pathways and thermodynamics of semiflexible polymers. AB - Inspired by the protein folding and DNA packing, we have systematically studied the thermodynamic and kinetic behaviors of single semiflexible homopolymers by Langevin dynamics simulations. In line with experiments, a rich variety of folding products, such as rod-like bundles, hairpins, toroids, and a mixture of them, are observed in the complete diagram of states. Moreover, knotted structures with a significant population are found in a certain range of bending stiffness in thermal equilibrium. As the solvent quality becomes poorer, the population of the intermediate occurring in the folding process increases, which leads to a severe chevron rollover for the folding arm. However, the population of the intermediates in the unfolding process is very low, insufficient to induce unfolding arm rollover. The total types of folding pathways from the coil state to the toroidal state for a semiflexible polymer chain remain unchanged by varying the solvent quality or temperature, whereas the kinetic partitioning into different folding events can be tuned significantly. In the process of knotting, three types of mechanisms, namely, plugging, slipknotting, and sliding, are discovered. Along the folding evolution, a semiflexible homopolymer chain can knot at any stage of folding upon leaving the extended coil state, and the probability to find a knot increases with chain compactness. In addition, we find rich types of knotted topologies during the folding of a semiflexible homopolymer chain. This study should be helpful in gaining insight into the general principles of biopolymer folding. PMID- 29764124 TI - An implementation of the maximum-caliber principle by replica-averaged time resolved restrained simulations. AB - Inferential methods can be used to integrate experimental informations and molecular simulations. The maximum entropy principle provides a framework for using equilibrium experimental data, and it has been shown that replica-averaged simulations, restrained using a static potential, are a practical and powerful implementation of such a principle. Here we show that replica-averaged simulations restrained using a time-dependent potential are equivalent to the principle of maximum caliber, the dynamic version of the principle of maximum entropy, and thus may allow us to integrate time-resolved data in molecular dynamics simulations. We provide an analytical proof of the equivalence as well as a computational validation making use of simple models and synthetic data. Some limitations and possible solutions are also discussed. PMID- 29764125 TI - Analysis of three-phase equilibrium conditions for methane hydrate by isometric isothermal molecular dynamics simulations. AB - To develop prediction methods of three-phase equilibrium (coexistence) conditions of methane hydrate by molecular simulations, we examined the use of NVT (isometric-isothermal) molecular dynamics (MD) simulations. NVT MD simulations of coexisting solid hydrate, liquid water, and vapor methane phases were performed at four different temperatures, namely, 285, 290, 295, and 300 K. NVT simulations do not require complex pressure control schemes in multi-phase systems, and the growth or dissociation of the hydrate phase can lead to significant pressure changes in the approach toward equilibrium conditions. We found that the calculated equilibrium pressures tended to be higher than those reported by previous NPT (isobaric-isothermal) simulation studies using the same water model. The deviations of equilibrium conditions from previous simulation studies are mainly attributable to the employed calculation methods of pressure and Lennard Jones interactions. We monitored the pressure in the methane phase, far from the interfaces with other phases, and confirmed that it was higher than the total pressure of the system calculated by previous studies. This fact clearly highlights the difficulties associated with the pressure calculation and control for multi-phase systems. The treatment of Lennard-Jones interactions without tail corrections in MD simulations also contributes to the overestimation of equilibrium pressure. Although improvements are still required to obtain accurate equilibrium conditions, NVT MD simulations exhibit potential for the prediction of equilibrium conditions of multi-phase systems. PMID- 29764126 TI - Molecular simulation of the water-triolein-oleic acid mixture: Local structure and thermodynamic properties. AB - An artificial oil-in-water emulsion analogous to those found in bioresources or food matrices is simulated and studied experimentally. It is composed of one of the major natural free fatty acids (the oleic acid, OA) and the corresponding triacylglyceride (trioleic glyceride, or triolein, GTO). Because of the large time and length scales involved, the molecular simulations are done with the Martini force field, a coarse-grained model. This allowed us to study the water OA-GTO system at different compositions with more than 20 000 molecules and up to 2 MUs. Interfacial tension was measured using the pendant drop method and compared with molecular simulation results. We observe very good agreement at high OA concentrations and deviations up to 15% at low OA concentrations. The water solubility in the lipid phase is in fair agreement with experiments, between 0.03 and 0.32 mol/l, rising with the OA content. The area occupied by OA and GTO at the interface between water and the pure product fitted with experimental data (AOA = 36.6 A2 and AGTO = 152.1 A2). The consistency between simulation and experimental results allowed a structural analysis of the interface. A bilayer structure of the lipids at the water/oil interface is proposed, containing preferentially oleic acid but also triolein. Through all these results, the usefulness of coarse-grained simulation for the description of water-oil interfacial organization is demonstrated. This method will be used later to bring local information on the organization of target compounds, necessary in biomass fractionation processes or food additive formulations, for example. PMID- 29764127 TI - Non-perturbative calculation of orbital and spin effects in molecules subject to non-uniform magnetic fields. AB - External non-uniform magnetic fields acting on molecules induce non-collinear spin densities and spin-symmetry breaking. This necessitates a general two component Pauli spinor representation. In this paper, we report the implementation of a general Hartree-Fock method, without any spin constraints, for non-perturbative calculations with finite non-uniform fields. London atomic orbitals are used to ensure faster basis convergence as well as invariance under constant gauge shifts of the magnetic vector potential. The implementation has been applied to investigate the joint orbital and spin response to a field gradient-quantified through the anapole moments-of a set of small molecules. The relative contributions of orbital and spin-Zeeman interaction terms have been studied both theoretically and computationally. Spin effects are stronger and show a general paramagnetic behavior for closed shell molecules while orbital effects can have either direction. Basis set convergence and size effects of anapole susceptibility tensors have been reported. The relation of the mixed anapole susceptibility tensor to chirality is also demonstrated. PMID- 29764128 TI - The effect of sampling techniques used in the multiconfigurational Ehrenfest method. AB - In this paper, we compare and contrast basis set sampling techniques recently developed for use in the ab initio multiple cloning method, a direct dynamics extension to the multiconfigurational Ehrenfest approach, used recently for the quantum simulation of ultrafast photochemistry. We demonstrate that simultaneous use of basis set cloning and basis function trains can produce results which are converged to the exact quantum result. To demonstrate this, we employ these sampling methods in simulations of quantum dynamics in the spin boson model with a broad range of parameters and compare the results to accurate benchmarks. PMID- 29764129 TI - Electron paramagnetic resonance g-tensors from state interaction spin-orbit coupling density matrix renormalization group. AB - We present a state interaction spin-orbit coupling method to calculate electron paramagnetic resonance g-tensors from density matrix renormalization group wavefunctions. We apply the technique to compute g-tensors for the TiF3 and CuCl42- complexes, a [2Fe-2S] model of the active center of ferredoxins, and a Mn4CaO5 model of the S2 state of the oxygen evolving complex. These calculations raise the prospects of determining g-tensors in multireference calculations with a large number of open shells. PMID- 29764131 TI - NH2- in a cold ion trap with He buffer gas: Ab initio quantum modeling of the interaction potential and of state-changing multichannel dynamics. AB - We present an extensive range of accurate ab initio calculations, which map in detail the spatial electronic potential energy surface that describes the interaction between the molecular anion NH2- (1A1) in its ground electronic state and the He atom. The time-independent close-coupling method is employed to generate the corresponding rotationally inelastic cross sections, and then the state-changing rates over a range of temperatures from 10 to 30 K, which is expected to realistically represent the experimental trapping conditions for this ion in a radio frequency ion trap filled with helium buffer gas. The overall evolutionary kinetics of the rotational level population involving the molecular anion in the cold trap is also modelled during a photodetachment experiment and analyzed using the computed rates. The present results clearly indicate the possibility of selectively detecting differences in behavior between the ortho- and para-anions undergoing photodetachment in the trap. PMID- 29764130 TI - Conformational explosion: Understanding the complexity of short chain para dialkylbenzene potential energy surfaces. AB - The single-conformation ultraviolet and infrared spectroscopy of three short chain para-dialkylbenzenes (para-diethylbenzene, para-dipropylbenzene, and para dibutylbenzene) is reported for the jet-cooled, isolated molecules. The present study builds off previous work on single-chain n-alkylbenzenes, where an anharmonic local mode Hamiltonian method was developed to account for stretch bend Fermi resonance in the alkyl CH stretch region [D. P. Tabor et al., J. Chem. Phys. 144, 224310 (2016)]. The jet-cooled molecules are interrogated using laser induced fluorescence (LIF) excitation, fluorescence dip infrared spectroscopy, and dispersed fluorescence. The LIF spectra in the S1 <- S0 origin region show a dramatic increase in the number of resolved transitions with increasing length of the alkyl chains, reflecting an explosion in the number of unique low-energy conformations formed when two independent alkyl chains are present. Since the barriers to isomerization of the alkyl chain are similar in size, this results in an "egg carton" shaped potential energy surface. A combination of electronic frequency shift and alkyl CH stretch infrared spectra is used to generate a consistent set of conformational assignments. Using these experimental techniques in conjunction with computational methods, subsets of origin transitions in the LIF excitation spectrum can be classified into different conformational families. Two conformations are resolved in para-diethylbenzene, seven in para dipropylbenzene, and about nineteen in para-dibutylbenzene. These chains are largely independent of each other as there are no new single-chain conformations induced by the presence of a second chain. A cursory LIF excitation scan of para dioctylbenzene shows a broad congested spectrum at frequencies consistent with interactions of alkyl chains with the phenyl pi cloud. PMID- 29764132 TI - High-level theoretical characterization of the vinoxy radical (*CH2CHO) + O2 reaction. AB - Numerous processes in atmospheric and combustion chemistry produce the vinoxy radical (*CH2CHO). To understand the fate of this radical and to provide reliable energies needed for kinetic modeling of such processes, we have examined its reaction with O2 using highly reliable theoretical methods. Utilizing the focal point approach, the energetics of this reaction and subsequent reactions were obtained using coupled-cluster theory with single, double, and perturbative triple excitations [CCSD(T)] extrapolated to the complete basis set limit. These extrapolated energies were appended with several corrections including a treatment of full triples and connected quadruple excitations, i.e., CCSDT(Q). In addition, this study models the initial vinoxy radical + O2 reaction for the first time with multireference methods. We predict a barrier for this reaction of approximately 0.4 kcal mol-1. This result agrees with experimental findings but is in disagreement with previous theoretical studies. The vinoxy radical + O2 reaction produces a 2-oxoethylperoxy radical which can undergo a number of unimolecular reactions. Abstraction of a beta-hydrogen (a 1,4-hydrogen shift) and dissociation back to reactants are predicted to be competitive to each other due to their similar barriers of 21.2 and 22.3 kcal mol-1, respectively. The minimum energy beta-hydrogen abstraction pathway produces a hydroperoxy radical (QOOH) that eventually decomposes to formaldehyde, CO, and *OH. Two other unimolecular reactions of the peroxy radical are alpha-hydrogen abstraction (38.7 kcal mol-1 barrier) and HO2* elimination (43.5 kcal mol-1 barrier). These pathways lead to glyoxal + *OH and ketene + HO2* formation, respectively, but they are expected to be uncompetitive due to their high barriers. PMID- 29764133 TI - Quantum chemical approach for positron annihilation spectra of atoms and molecules beyond plane-wave approximation. AB - We report theoretical calculations of positron-electron annihilation spectra of noble gas atoms and small molecules using the nuclear orbital plus molecular orbital method. Instead of a nuclear wavefunction, the positronic wavefunction is obtained as the solution of the coupled Hartree-Fock or Kohn-Sham equation for a positron and the electrons. The molecular field is included in the positronic Fock operator, which allows an appropriate treatment of the positron-molecule repulsion. The present treatment succeeds in reproducing the Doppler shift, i.e., full width at half maximum (FWHM) of experimentally measured annihilation (gamma ray) spectra for molecules with a mean absolute error less than 10%. The numerical results indicate that the interpretation of the FWHM in terms of a specific molecular orbital is not appropriate. PMID- 29764134 TI - On the possibility of singlet fission in crystalline quaterrylene. AB - Singlet fission (SF), the spontaneous down-conversion of a singlet exciton into two triplet excitons residing on neighboring molecules, is a promising route to improve organic photovoltaic (OPV) device efficiencies by harvesting two charge carriers from one photon. However, only a few materials have been discovered that exhibit intermolecular SF in the solid state, most of which are acene derivatives. Recently, there has been a growing interest in rylenes as potential SF materials. We use many-body perturbation theory in the GW approximation and the Bethe-Salpeter equation to investigate the possibility of intermolecular SF in crystalline perylene and quaterrylene. A new method is presented for determining the percent charge transfer (%CT) character of an exciton wave function from double-Bader analysis. This enables relating exciton probability distributions to crystal packing. Based on comparison to known and predicted SF materials with respect to the energy conservation criterion (ES-2ET) and %CT, crystalline quaterrylene is a promising candidate for intermolecular SF. Furthermore, quaterrylene is attractive for OPV applications, thanks to its high stability and narrow optical gap. Perylene is not expected to exhibit SF; however, it is a promising candidate for harvesting sub-gap photons by triplet triplet annihilation. PMID- 29764135 TI - Fast-forward Langevin dynamics with momentum flips. AB - Stochastic thermostats based on the Langevin equation, in which a system is coupled to an external heat bath, are popular methods for temperature control in molecular dynamics simulations due to their ergodicity and their ease of implementation. Traditionally, these thermostats suffer from sluggish behavior in the limit of high friction, unlike thermostats of the Nose-Hoover family whose performance degrades more gently in the strong coupling regime. We propose a simple and easy-to-implement modification to the integration scheme of the Langevin algorithm that addresses the fundamental source of the overdamped behavior of high-friction Langevin dynamics: if the action of the thermostat causes the momentum of a particle to change direction, it is flipped back. This fast-forward Langevin equation preserves the momentum distribution and so guarantees the correct equilibrium sampling. It mimics the quadratic behavior of Nose-Hoover thermostats and displays similarly good performance in the strong coupling limit. We test the efficiency of this scheme by applying it to a 1 dimensional harmonic oscillator, as well as to water and Lennard-Jones polymers. The sampling efficiency of the fast-forward Langevin equation thermostat, measured by the correlation time of relevant system variables, is at least as good as the traditional Langevin thermostat, and in the overdamped regime, the fast-forward thermostat performs much better, improving the efficiency by an order of magnitude at the highest frictions we considered. PMID- 29764136 TI - Composition inversion in mixtures of binary colloids and polymer. AB - Understanding the phase behaviour of mixtures continues to pose challenges, even for systems that might be considered "simple." Here, we consider a very simple mixture of two colloidal and one non-adsorbing polymer species, which can be simplified even further to a size-asymmetrical binary mixture, in which the effective colloid-colloid interactions depend on the polymer concentration. We show that this basic system exhibits surprisingly rich phase behaviour. In particular, we enquire whether such a system features only a liquid-vapor phase separation (as in one-component colloid-polymer mixtures) or whether, additionally, liquid-liquid demixing of two colloidal phases can occur. Particle resolved experiments show demixing-like behaviour, but when combined with bespoke Monte Carlo simulations, this proves illusory, and we reveal that only a single liquid-vapor transition occurs. Progressive migration of the small particles to the liquid phase as the polymer concentration increases gives rise to composition inversion-a maximum in the large particle concentration in the liquid phase. Close to criticality, the density fluctuations are found to be dominated by the larger colloids. PMID- 29764137 TI - Stabilities of protonated water-ammonia clusters. AB - Branching ratios of water and ammonia evaporation have been measured for spontaneous evaporation from protonated mixed clusters H+(H2O)n(NH3)m in the size range 0 <= n <= 11 and 0 <= m <= 7. Mixed clusters evaporate water except for clusters containing six or more ammonia molecules, indicating the formation of a stable core of one ammonium ion surrounded by four ammonia molecules and a second shell consisting predominantly of water. We relate evaporative branching ratios to free energy differences between the products of competing channels and determine the free energy differences for clusters with up to seven ammonia molecules. Clusters containing up to five ammonia molecules show a very strong scaling of these free energy differences. PMID- 29764138 TI - Quantum optical measurement with tripartite entangled photons generated by triple parametric down-conversion. AB - Parametric down-conversion is a second-order nonlinear optical process annihilating a pump photon and creating a pair of photons in the signal and idler modes. Then, by using two parametric down-converters and introducing a path indistinguishability for the two generated idler modes, a quantum coherence between two conjugate signal beams can be induced. Such a double spontaneous or stimulated parametric down-conversion scheme has been used to demonstrate quantum spectroscopy and imaging with undetected idler photons via measuring one-photon interference between their correlated signal beams. Recently, we considered another quantum optical measurement scheme utilizing W-type tripartite entangled signal photons that can be generated by employing three spontaneous parametric down-conversion crystals and by inducing coherences or path indistinguishabilities between their correlated idler beams and between quantum vacuum fields. Here, we consider an extended triple stimulated parametric down conversion scheme for quantum optical measurement of sample properties with undetected idler and photons. Noting the real effect of vacuum field indistinguishability on the fringe visibility as well as the role of zero-point field energy in the interferometry, we show that this scheme is an ideal and efficient way to create a coherent state of W-type entangled signal photons. We anticipate that this scheme would be of critical use in further developing quantum optical measurements in spectroscopy and microscopy with undetected photons. PMID- 29764139 TI - Low-lying excited states of model proteins: Performances of the CC2 method versus multireference methods. AB - A benchmark set of relevant geometries of a model protein, the N acetylphenylalanylamide, is presented to assess the validity of the approximate second-order coupled cluster (CC2) method in studying low-lying excited states of such bio-relevant systems. The studies comprise investigations of basis-set dependence as well as comparison with two multireference methods, the multistate complete active space 2nd order perturbation theory (MS-CASPT2) and the multireference difference dedicated configuration interaction (DDCI) methods. First of all, the applicability and the accuracy of the quasi-linear multireference difference dedicated configuration interaction method have been demonstrated on bio-relevant systems by comparison with the results obtained by the standard MS-CASPT2. Second, both the nature and excitation energy of the first low-lying excited state obtained at the CC2 level are very close to the Davidson corrected CAS+DDCI ones, the mean absolute deviation on the excitation energy being equal to 0.1 eV with a maximum of less than 0.2 eV. Finally, for the following low-lying excited states, if the nature is always well reproduced at the CC2 level, the differences on excitation energies become more important and can depend on the geometry. PMID- 29764140 TI - Interplay between translational diffusion and large-amplitude angular jumps of water molecules. AB - Understanding the microscopic mechanism of water molecular translational diffusion is a challenging topic in both physics and chemistry. Here, we report an investigation on the interplay between the translational diffusion and the large-amplitude angular jumps of water molecules in bulk water using molecular dynamics simulations. We found that large-amplitude angular jumps are tightly coupled to the translational diffusions. Particularly, we revealed that concurrent rotational jumps of spatially neighboring water molecules induce inter basin translational jumps, which contributes to the fast component of the water translational diffusion. Consequently, the translational diffusion shows positional heterogeneity; i.e., the neighbors of the water molecules with inter basin translational jumps have larger probability to diffuse by inter-basin translational jumps. Our control simulations showed that a model water molecule with moderate hydrogen bond strength can diffuse much faster than a simple Lennard-Jones particle in bulk water due to the capability of disturbing the hydrogen bond network of the surrounding water molecules. Our results added to the understanding of the microscopic picture of the water translational diffusion and demonstrated the unique features of water diffusion arising from their hydrogen bond network structure compared with those of the simple liquids. PMID- 29764141 TI - Communication: Calculation of interatomic forces and optimization of molecular geometry with auxiliary-field quantum Monte Carlo. AB - We propose an algorithm for accurate, systematic, and scalable computation of interatomic forces within the auxiliary-field quantum Monte Carlo (AFQMC) method. The algorithm relies on the Hellmann-Feynman theorem and incorporates Pulay corrections in the presence of atomic orbital basis sets. We benchmark the method for small molecules by comparing the computed forces with the derivatives of the AFQMC potential energy surface and by direct comparison with other quantum chemistry methods. We then perform geometry optimizations using the steepest descent algorithm in larger molecules. With realistic basis sets, we obtain equilibrium geometries in agreement, within statistical error bars, with experimental values. The increase in computational cost for computing forces in this approach is only a small prefactor over that of calculating the total energy. This paves the way for a general and efficient approach for geometry optimization and molecular dynamics within AFQMC. PMID- 29764142 TI - Peristalticity-driven banded chemical garden. AB - Complex structures in nature are often formed by self-assembly. In order to mimic the formation, to enhance the production, or to modify the structures, easy-to use methods are sought to couple engineering and self-assembly. Chemical-garden like precipitation reactions are frequently used to study such couplings because of the intrinsic chemical and hydrodynamic interplays. In this work, we present a simple method of applying periodic pressure fluctuations given by a peristaltic pump which can be used to achieve regularly banded precipitate membranes in the copper-phosphate system. PMID- 29764143 TI - Stark effect of Kramers-Henneberger atoms. AB - The Electric Stark effect of a Kramers-Henneberger (KH) state of hydrogen atoms in both linearly and circularly polarized laser fields is studied. For the ground KH state of H atoms with a small quiver amplitude, the quadratic Stark effect is observed. For a large quiver amplitude, the Stark effect is quadratic only in a weak electric field and quickly changes to linear as the electric field increases. The atomic structure of the KH state is very sensitive to the electric field and can be easily polarized. The huge polarizability and induced dipole moment are comparable to those of Rydberg atoms. PMID- 29764144 TI - From intermediate anisotropic to isotropic friction at large strain rates to account for viscosity thickening in polymer solutions. AB - The steady-state extensional viscosity of dense polymeric liquids in elongational flows is known to be peculiar in the sense that for entangled polymer melts it monotonically decreases-whereas for concentrated polymer solutions it increases with increasing strain rate beyond the inverse Rouse time. To shed light on this issue, we solve the kinetic theory model for concentrated polymer solutions and entangled melts proposed by Curtiss and Bird, also known as the tumbling-snake model, supplemented by a variable link tension coefficient that we relate to the uniaxial nematic order parameter of the polymer. As a result, the friction tensor is increasingly becoming isotropic at large strain rates as the polymer concentration decreases, and the model is seen to capture the experimentally observed behavior. Additional refinements may supplement the present model to capture very strong flows. We furthermore derive analytic expressions for small rates and the linear viscoelastic behavior. This work builds upon our earlier work on the use of the tumbling-snake model under shear and demonstrates its capacity to improve our microscopic understanding of the rheology of entangled polymer melts and concentrated polymer solutions. PMID- 29764145 TI - Nucleus-size pinning for determination of nucleation free-energy barriers and nucleus geometry. AB - Classical Nucleation Theory (CNT) has recently been used in conjunction with a seeding approach to simulate nucleation phenomena at small-to-moderate supersaturation conditions when large free-energy barriers ensue. In this study, the conventional seeding approach [J. R. Espinosa et al., J. Chem. Phys. 144, 034501 (2016)] is improved by a novel, more robust method to estimate nucleation barriers. Inspired by the interfacial pinning approach [U. R. Pedersen, J. Chem. Phys. 139, 104102 (2013)] used before to determine conditions where two phases coexist, the seed of the incipient phase is pinned to a preselected size to iteratively drive the system toward the conditions where the seed becomes a critical nucleus. The proposed technique is first validated by estimating the critical nucleation conditions for the disorder-to-order transition in hard spheres and then applied to simulate and characterize the highly non-trivial (prolate) morphology of the critical crystal nucleus in hard gyrobifastigia. A generalization of CNT is used to account for nucleus asphericity and predict nucleation free-energy barriers for gyrobifastigia. These predictions of nuclei shape and barriers are validated by independent umbrella sampling calculations. PMID- 29764146 TI - Contrast between the mechanisms for dissociative electron attachment to CH3SCN and CH3NCS. AB - The kinetics of thermal electron attachment to methyl thiocyanate (CH3SCN), methyl isothiocyanate (CH3NCS), and ethyl thiocyanate (C2H5SCN) were measured using flowing afterglow-Langmuir probe apparatuses at temperatures between 300 and 1000 K. CH3SCN and C2H5SCN undergo inefficient dissociative attachment to yield primarily SCN- at 300 K (k = 2 * 10-10 cm3 s-1), with increasing efficiency as temperature increases. The increase is well described by activation energies of 0.17 eV (CH3SCN) and 0.14 eV (C2H5SCN). CN- product is formed at <1% branching at 300 K, increasing to ~30% branching at 1000 K. Attachment to CH3NCS yields exclusively SCN- ionic product but at a rate at 300 K that is below our detection threshold (k < 10-12 cm3 s-1). The rate coefficient increases rapidly with increasing temperature (k = 6 * 10-11 cm3 s-1 at 600 K), in a manner well described by an activation energy of 0.51 eV. Calculations at the B3LYP/def2 TZVPPD level suggest that attachment to CH3SCN proceeds through a dissociative state of CH3SCN-, while attachment to CH3NCS initially forms a weakly bound transient anion CH3NCS-* that isomerizes over an energetic barrier to yield SCN-. Kinetic modeling of the two systems is performed in an attempt to identify a kinetic signature differentiating the two mechanisms. The kinetic modeling reproduces the CH3NCS data only if dissociation through the transient anion is considered. PMID- 29764148 TI - Two-dimensional Fano lineshapes: Excited-state absorption contributions. AB - Fano interferences in nanostructures are influenced by dissipation effects as well as many-body interactions. Two-dimensional coherent spectroscopies have just begun to be applied to these systems where the spectroscopic signatures of a discrete-continuum structure are not known. In this article, we calculate the excited-state absorption contribution for different models of higher lying excited states. We find that the characteristic asymmetry of one-dimensional spectroscopies is recovered from the many-body contributions and that the higher lying excited manifolds have distorted lineshapes that are not anticipated from discrete-level Hamiltonians. We show that the Stimulated Emission cannot have contributions from a flat continuum of states. This work completes the Ground State Bleach and Stimulated Emission signals that were calculated previously [D. Finkelstein-Shapiro et al., Phys. Rev. B 94, 205137 (2016)]. The model reproduces the observations reported for molecules on surfaces probed by 2DIR. PMID- 29764147 TI - The strengths and limitations of effective centroid force models explored by studying isotopic effects in liquid water. AB - The development of effective centroid potentials (ECPs) is explored with both the constrained-centroid and quasi-adiabatic force matching using liquid water as a test system. A trajectory integrated with the ECP is free of statistical noises that would be introduced when the centroid potential is approximated on the fly with a finite number of beads. With the reduced cost of ECP, challenging experimental properties can be studied in the spirit of centroid molecular dynamics. The experimental number density of H2O is 0.38% higher than that of D2O. With the ECP, the H2O number density is predicted to be 0.42% higher, when the dispersion term is not refit. After correction of finite size effects, the diffusion constant of H2O is found to be 21% higher than that of D2O, which is in good agreement with the 29.9% higher diffusivity for H2O observed experimentally. Although the ECP is also able to capture the redshifts of both the OH and OD stretching modes in liquid water, there are a number of properties that a classical simulation with the ECP will not be able to recover. For example, the heat capacities of H2O and D2O are predicted to be almost identical and higher than the experimental values. Such a failure is simply a result of not properly treating quantized vibrational energy levels when the trajectory is propagated with classical mechanics. Several limitations of the ECP based approach without bead population reconstruction are discussed. PMID- 29764149 TI - Vacuum ultraviolet photoionization cross section of the hydroxyl radical. AB - The absolute photoionization spectrum of the hydroxyl (OH) radical from 12.513 to 14.213 eV was measured by multiplexed photoionization mass spectrometry with time resolved radical kinetics. Tunable vacuum ultraviolet (VUV) synchrotron radiation was generated at the Advanced Light Source. OH radicals were generated from the reaction of O(1D) + H2O in a flow reactor in He at 8 Torr. The initial O(1D) concentration, where the atom was formed by pulsed laser photolysis of ozone, was determined from the measured depletion of a known concentration of ozone. Concentrations of OH and O(3P) were obtained by fitting observed time traces with a kinetics model constructed with literature rate coefficients. The absolute cross section of OH was determined to be sigma(13.436 eV) = 3.2 +/- 1.0 Mb and sigma(14.193 eV) = 4.7 +/- 1.6 Mb relative to the known cross section for O(3P) at 14.193 eV. The absolute photoionization spectrum was obtained by recording a spectrum at a resolution of 8 meV (50 meV steps) and scaling to the single-energy cross sections. We computed the absolute VUV photoionization spectrum of OH and O(3P) using equation-of-motion coupled-cluster Dyson orbitals and a Coulomb photoelectron wave function and found good agreement with the observed absolute photoionization spectra. PMID- 29764150 TI - Effect of molecular conformations on the electronic transport in oxygen substituted alkanethiol molecular junctions. AB - The relationship between the molecular structure and the electronic transport properties of molecular junctions based on thiol-terminated oligoethers, which are obtained by replacing every third methylene unit in the corresponding alkanethiols with an oxygen atom, is investigated by employing the non equilibrium Green's function formalism combined with density functional theory. Our calculations show that the low-bias conductance depends strongly on the conformation of the oligoethers in the junction. Specifically, in the cases of trans-extended conformation, the oxygen-dominated transmission peaks are very sharp and well below the Fermi energy, EF, thus hardly affect the transmission around EF; the Au-S interface hybrid states couple with sigma-bonds in the molecular backbone forming the conduction channel at EF, resulting in a conductance decay against the molecular length close to that for alkanethiols. By contrast, for junctions with oligoethers in helical conformations, some pi-type oxygen orbitals coupling with the Au-S interface hybrid states contribute to the transmission around EF. The molecule-electrode electronic coupling is also enhanced at the non-thiol side due to the specific spatial orientation introduced by the twist of the molecular backbone. This leads to a much smaller conductance decay constant. Our findings highlight the important role of the molecular conformation of oligoethers in their electronic transport properties and are also helpful for the design of molecular wires with heteroatom-substituted alkanethiols. PMID- 29764151 TI - A full-dimensional potential energy surface and quantum dynamics of inelastic collision process for H2-HF. AB - A full-dimensional ab initio potential energy surface for the H2-HF van der Waals complex was constructed by employing the coupled-cluster singles and doubles with noniterative inclusion of connected triples with augmented correlation-consistent polarised valence quadruple-zeta basis set plus bond functions. Using the improved coupled-states approximation including the nearest neighbor Coriolis couplings, we calculated the state-to-state scattering dynamics for pure rotational and ro-vibrational energy transfer processes. For pure rotational energy transfer, our results showed a different dynamical behavior for para-H2 and ortho-H2 in collision with hydrogen fluoride (HF), which is consistent with the previous study. Interestingly, some strong resonant peaks were presented in the cross sections for ro-vibrational energy transfer. In addition, the calculated vibrational-resolved rate constant is in agreement with the experimental results reported by Bott et al. These dynamics data can be further applied to the numerical simulation of HF chemical lasers. PMID- 29764152 TI - Telegraph noise in Markovian master equation for electron transport through molecular junctions. AB - We present a theoretical approach to solve the Markovian master equation for quantum transport with stochastic telegraph noise. Considering probabilities as functionals of a random telegraph process, we use Novikov's functional method to convert the stochastic master equation to a set of deterministic differential equations. The equations are then solved in the Laplace space, and the expression for the probability vector averaged over the ensemble of realisations of the stochastic process is obtained. We apply the theory to study the manifestations of telegraph noise in the transport properties of molecular junctions. We consider the quantum electron transport in a resonant-level molecule as well as polaronic regime transport in a molecular junction with electron-vibration interaction. PMID- 29764153 TI - Communication: Symmetrical quasi-classical analysis of linear optical spectroscopy. AB - The symmetrical quasi-classical approach for propagation of a many degree of freedom density matrix is explored in the context of computing linear spectra. Calculations on a simple two state model for which exact results are available suggest that the approach gives a qualitative description of peak positions, relative amplitudes, and line broadening. Short time details in the computed dipole autocorrelation function result in exaggerated tails in the spectrum. PMID- 29764154 TI - Non-empirical exchange-correlation parameterizations based on exact conditions from correlated orbital theory. AB - Some of the exact conditions provided by the correlated orbital theory are employed to propose new non-empirical parameterizations for exchange-correlation functionals from Density Functional Theory (DFT). This reparameterization process is based on range-separated functionals with 100% exact exchange for long-range interelectronic interactions. The functionals developed here, CAM-QTP-02 and LC QTP, show mitigated self-interaction error, correctly predict vertical ionization potentials as the negative of eigenvalues for occupied orbitals, and provide nice excitation energies, even for challenging charge-transfer excited states. Moreover, some improvements are observed for reaction barrier heights with respect to the other functionals belonging to the quantum theory project (QTP) family. Finally, the most important achievement of these new functionals is an excellent description of vertical electron affinities (EAs) of atoms and molecules as the negative of appropriate virtual orbital eigenvalues. In this case, the mean absolute deviations for EAs in molecules are smaller than 0.10 eV, showing that physical interpretation can indeed be ascribed to some unoccupied orbitals from DFT. PMID- 29764155 TI - Fluctuation-dissipation relation and stationary distribution of an exactly solvable many-particle model for active biomatter far from equilibrium. AB - An exactly solvable, Hamiltonian-based model of many massive particles that are coupled by harmonic potentials and driven by stochastic non-equilibrium forces is introduced. The stationary distribution and the fluctuation-dissipation relation are derived in closed form for the general non-equilibrium case. Deviations from equilibrium are on one hand characterized by the difference of the obtained stationary distribution from the Boltzmann distribution; this is possible because the model derives from a particle Hamiltonian. On the other hand, the difference between the obtained non-equilibrium fluctuation-dissipation relation and the standard equilibrium fluctuation-dissipation theorem allows us to quantify non equilibrium in an alternative fashion. Both indicators of non-equilibrium behavior, i.e., deviations from the Boltzmann distribution and deviations from the equilibrium fluctuation-dissipation theorem, can be expressed in terms of a single non-equilibrium parameter alpha that involves the ratio of friction coefficients and random force strengths. The concept of a non-equilibrium effective temperature, which can be defined by the relation between fluctuations and the dissipation, is by comparison with the exactly derived stationary distribution shown not to hold, even if the effective temperature is made frequency dependent. The analysis is not confined to close-to-equilibrium situations but rather is exact and thus holds for arbitrarily large deviations from equilibrium. Also, the suggested harmonic model can be obtained from non linear mechanical network systems by an expansion in terms of suitably chosen deviatory coordinates; the obtained results should thus be quite general. This is demonstrated by comparison of the derived non-equilibrium fluctuation dissipation relation with experimental data on actin networks that are driven out of equilibrium by energy-consuming protein motors. The comparison is excellent and allows us to extract the non-equilibrium parameter alpha from experimental spectral response and fluctuation data. PMID- 29764156 TI - Nonlocal kinetic energy functionals by functional integration. AB - Since the seminal studies of Thomas and Fermi, researchers in the Density Functional Theory (DFT) community are searching for accurate electron density functionals. Arguably, the toughest functional to approximate is the noninteracting kinetic energy, Ts[rho], the subject of this work. The typical paradigm is to first approximate the energy functional and then take its functional derivative, deltaTs[rho]deltarho(r), yielding a potential that can be used in orbital-free DFT or subsystem DFT simulations. Here, this paradigm is challenged by constructing the potential from the second-functional derivative via functional integration. A new nonlocal functional for Ts[rho] is prescribed [which we dub Mi-Genova-Pavanello (MGP)] having a density independent kernel. MGP is constructed to satisfy three exact conditions: (1) a nonzero "Kinetic electron" arising from a nonzero exchange hole; (2) the second functional derivative must reduce to the inverse Lindhard function in the limit of homogenous densities; (3) the potential is derived from functional integration of the second functional derivative. Pilot calculations show that MGP is capable of reproducing accurate equilibrium volumes, bulk moduli, total energy, and electron densities for metallic (body-centered cubic, face-centered cubic) and semiconducting (crystal diamond) phases of silicon as well as of III-V semiconductors. The MGP functional is found to be numerically stable typically reaching self-consistency within 12 iterations of a truncated Newton minimization algorithm. MGP's computational cost and memory requirements are low and comparable to the Wang-Teter nonlocal functional or any generalized gradient approximation functional. PMID- 29764157 TI - Cancer immunotherapy-the end of the beginning. PMID- 29764158 TI - What is the role of immunotherapy in breast cancer? AB - The immune system plays a complex role in the recognition/prevention, early eradication as well as progression of cancer. Recently, we have witnessed great momentum in the field of immuno-oncology. Checkpoint inhibitors and chimeric antigen receptor T cell therapy have now entered the clinic, with impressive and durable clinical responses seen across a broad array of tumor types. There are several lines of evidence supporting the development of an immune targeted approach in breast cancer. Emerging data of early clinical trials evaluating monotherapy checkpoint inhibition have shown modest activity in breast cancer, in particular high grade and aggressive subtypes such as triple negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal B breast cancers. A considerable amount of effort is currently underway in exploring the use of combinatory strategies where therapies with distinct and potentially complementary mechanisms of actions may further enhance the immune response broadening out the group of breast cancer patients who would benefit from this strategy of cancer treatment. In this review, we discuss approaches to targeting the immune system in breast cancer adopted through understanding why the host immune system has failed in natural tumor suppression as well as the processes evolved by the tumor to circumvent an active immune system. PMID- 29764159 TI - Emerging role of immunotherapy for childhood cancers. AB - Recent developments in cell and gene therapy have a great impact on the new therapeutic approaches in pediatric cancers. Monoclonal antibodies for neuroblastoma and bispecific antibodies for leukemia have induced significant clinical responses for otherwise chemorefractory patients. Moreover, cellular therapeutic approaches including chimeric antigen receptor (CAR) T-cells as well as natural killer (NK) cells have the potential to cure patients with so far incurable malignancies and are the basis for future new therapies for pediatric cancer. Newer generations of cellular therapies, further development and improvement of such new strategies and their earlier use in therapeutic strategies will hopefully allow to significantly reduce the chemotherapeutic burden for children with cancer while increasing the cure rate. PMID- 29764160 TI - Combinatorial strategies of radiotherapy and immunotherapy in nasopharyngeal carcinoma. AB - Immunotherapy and radiation therapy (RT) have each demonstrated clinical success in the treatment of nasopharyngeal carcinoma (NPC) when utilized independently. Several characteristics of NPC make it particularly well suited for immunotherapeutic strategies, such as the association with viral infections like EBV and human papilloma virus (HPV), upregulation of PD-L1 expression, and the high number of tumor infiltrating lymphocytes. Immune checkpoint blockade is one such immunotherapeutic strategy that is gaining popularity rapidly. However, clinical benefit of immunotherapy using immune checkpoint inhibitors has been limited to only a small subset of patients with existing T cell responses. Additionally, they are frequently associated with dose-limiting immune-related toxicities. On the other hand, RT is a conventional strategy for NPC treatment, which has demonstrated high efficacy in local tumor control and has also been reported to exhibit immune modulatory effects. However, the abscopal effect of RT alone, i.e., the regression of distant metastases outside of the irradiation field, remains a rare phenomenon. Furthermore, RT treatment efficacy is also limited by radioresistance and radiation-related toxicities. Hence, the combination of RT and immunotherapy has the potential to improve treatment efficacy over either individual therapies alone. Here, we reviewed the clinical problem in locally advanced and recurrent/metastatic NPC, and discussed how combinatorial RT and immunotherapeutic strategies can be relevant to NPC treatment in each clinical scenario by examining the underlying mechanisms involved in the different strategies. PMID- 29764161 TI - The emerging role of oncolytic virus therapy against cancer. AB - This review discusses current clinical advancements in oncolytic viral therapy, with a focus on the viral platforms approved for clinical use and highlights the benefits each platform provides. Three oncolytic viruses (OVs), an echovirus, an adenovirus, and a herpes simplex-1 virus, have passed governmental regulatory approval in Latvia, China, and the USA and EU. Numerous other recombinant viruses from diverse families are in clinical testing in cancer patients and we highlight the design features of selected examples, including adenovirus, herpes simplex virus, measles virus, retrovirus, reovirus, vaccinia virus, vesicular stomatitis virus. Lastly, we provide thoughts on the path forward for this rapidly expanding field especially in combination with immune modulating drugs. PMID- 29764162 TI - The evolving role of immune oncology in colorectal cancer. AB - Metastatic colorectal cancer still remains an essentially non curable disease. However, with advances in chemotherapeutic and personalizing therapeutic approaches with the incorporation of targeted therapy such as anti-EGFR and anti VEGF agents survival associated with metastatic colorectal cancer has certainly improved over the last two decades. Patients who are not amenable to surgery median survival remain approximately 2 to 3 years. In an attempt to improve prognostic outcome over the last decade research has focused on therapeutic options geared towards harnessing the immune system with success observed with the use of immune checkpoint inhibitors in the realm of a number of solid tumors including lung and renal cancer. The use of immunomodulatory therapeutic approaches for the management of unselected advanced colorectal cancer has not seen the same success with low response rates reported. The turning point was our recent understanding that efficacy of immunotherapy was limited to a subset of patients with hyper mutated microsatellite instability-high (MSI-H) tumors. This review will focus on summarizing available knowledge on the immunological and molecular landscape of colorectal cancer that can help determine subsets of immunogenic CRC, determine potential predictive markers to help select patients for immunotherapeutic approaches as well looking at the existing evidence of incorporating immune checkpoint inhibitors to the therapeutic management of patients with mCRC. PMID- 29764163 TI - Onward and upward for immuno-oncology. PMID- 29764164 TI - Immunoregulatory antigens-novel targets for cancer immunotherapy. AB - Historically, the development of cancer vaccines has focused on the central role of tumor antigens in eliciting tumor-specific immune responses, with limited success. Recent advances with checkpoint blockade approaches have brought about a renewed appreciation of the importance of targeting immune suppression in cancer patients. Here we discuss a novel approach to cancer immunotherapy, namely to target recently described T cells that uniquely control cells with immune suppressive functions. Accumulating evidence support the existence of self reactive T cells that are specific to antigens derived from immunoregulatory proteins ("immunoregulatory antigens"), such as indoleamine 2,3-dioxygenase (IDO) and PD-L1. Vaccination approaches to potentiate these T cells have proven safe with minimal toxicity in the clinical phase I trials conducted thus far. Given that immunoregulatory antigens can be new targets for cancer immunotherapy, we propose here that they could be considered as a new class of tumor antigens. Targeting such antigens has advantages over targeting classical tumor antigens, as there is no requirement for identification of relevant antigens that are specific for the cancer type, and the targets are genetically stable. Furthermore, targeting immunoregulatory antigen-specific T cells potentially has dual mode of actions (I) targeting immune suppression and thereby potentiating anti-tumor effector T cell responses and (II) direct killing of immunoregulatory antigen-expressing tumor cells. PMID- 29764165 TI - Developing academic cancer immunotherapy in Asia-lessons, challenges, and a vision for Thailand. PMID- 29764166 TI - Chimeric antigen receptor T cells, a savior with a high price. AB - Chimeric antigen receptor (CAR) T cells represent a medical and scientific breakthrough that may represent a paradigm for the future of personalized medicine in the age of cancer immunotherapy. As with many new cancer agents, such novel and incredible results come with a high price. At the time of the writing of this article, there are two CAR T cells available, Kymriah, produced by Novrtis with a price tag of US$475,000 and Yescarta produced by Gilead Pharmaceuticals with a price tag of US$373,000, neither price including the required hospital admission in order to administer the agent in addition to potential treatment of side effects. There are several issues that are imperative to recognize when understanding the high cost, however the two more pertinent issues are low availability of the agent and no billing code. While only approved for less than a year, there are thoughts about how to bring the price down with more approved CAR T cells and more center with the ability to administer this therapy, however results may be years away before they are realized. In the short term, insurance companies are grappling over how to pay for CAR T therapy, with one of the biggest voids concerning the absence of a billing code for CAR T cells. Regardless, its high price tag highlights moral issues underlying value based payments and whether the treatment is worth the cost while evaluating the juxtaposition of life years and monetary values. As CAR T cells expand the boundaries of immunotherapy with extraordinary results, the need for a lower price in combination for more availability of CAR T cells will grow until some of these fundamental issues are addressed. PMID- 29764167 TI - Public health approaches to palliative care. PMID- 29764168 TI - New challenges for a newly emerging field. PMID- 29764169 TI - Palliative care-the new essentials. AB - BACKGROUND: If global palliative care is to successfully address challenges of unequal access, continuity of care, and health services reductionism, new practice models to address these issues need to be identified, debated and tested. This paper offers one such practice model based on a public health approach to palliative care that has so far shown promising evidence of effectiveness. METHODS: We describe how four essential elements within a public health model can work together to address quality and continuity of care as well as addressing the numerous barriers of access. These elements are: (I) specialist, and (II) generalist palliative care services working with (III) communities and neighbourhoods, working in their turn with their (IV) key civic institutions. RESULTS: The positive and negative impact and advantages of each of these elements is described and discussed. CONCLUSIONS: A solely clinical model of palliative care is inadequate to addressing the multiple co-morbidities and access issues characteristic of modern palliative care. A public health approach based on a close partnership between clinical services and communities/civic institutions is the optimal practice model. PMID- 29764170 TI - All with You: a new method for developing compassionate communities-experiences in Spain and Latin-America. AB - BACKGROUND: In recent years, compassion has motivated the development of programs oriented to create communities and societies involved in the relief of suffering. The development of compassionate communities and cities begins in each one of us, though it relies on organizations, providers and societies as a whole who need tools and methodologies as a part of a set of actions to help compassionate communities and cities to become a reality rooted widely in social values. In order to describe the "All with You(r)" methodology and its components: a method designed to develop compassionate communities and cities at the end of life that can be extended to organizations, communities, municipalities, cities or countries. In addition, this article tries to describe several experiences from applying the method in different cities and contexts. METHODS: A search of models for the development of compassionate communities was carried out initially to guide the elements and phases that could help to create a systematized method that will help organizations to create compassionate communities. After analysing the results, alliances were established with some of the main promoters at the time in the development of compassionate communities to validate the designed method. The city of Seville (Spain) was selected to validate the phases of the method and analyse the results based on a series of indicators. Finally, the methodology is being spread throughout cities in various countries, and the experiences are being evaluated with common indicators. RESULTS: The "All with You(r)" method (Todos Contigo(r) in Spanish) has been developed as a systematic approach that enables anyone interested in building compassionate communities or cities to include all of the elements outlined in the Compassionate City Charter. All with You(r) is a method that includes eight phases that allows organizations to be guided in the development of compassionate communities and cities towards a certification process that is evaluated through a series of structures, process and results indicators. The main actions of this method are based on social awareness, training, and the implementation of networks of care using innovative elements like Community Promoters and the RedCuida protocol to provide support, backing and care for those who face advanced chronic disease and end of life situations. Several cities in Spain and Latin America have already joined the movement of compassionate cities using this method, including four in Spain (Seville, Badajoz, Getxo and Pamplona), four in Colombia (Cali, Medellin, Fusagasuga and Bogota) and one in Argentina (Buenos Aires). CONCLUSIONS: The All with You(r) method has made the development of compassionate communities and cities possible, aligning organizations and cities to promote compassionate acts, and to start creating networks involved in a global community united by a vocation for caring. PMID- 29764171 TI - Compassionate communities: design and preliminary results of the experience of Vic (Barcelona, Spain) caring city. AB - BACKGROUND: A program of Compassionate City or Community (CC) has been designed and developed in the City of Vic (43,964 habitants, Barcelona, Spain), based on The Compassionate City Charter and other public health literature and experiments, with the joint leadership of the City Council and the Chair of Palliative Care at the University of Vic, and as an expansion of a comprehensive and integrated system of palliative care. METHODS: The program started with an assessment of needs of the city as identified by 48 social organizations with a foundational workshop and a semi-structured survey. After this assessment, the mission, vision, values and aims were agreed. The main aims consisted in promoting changes in social and cultural attitudes toward the end of life (EoL) and providing integrated care for people with advanced chronic conditions and social needs such as loneliness, poverty, low access to services at home, or conflict. The selected slogan was "Living with meaning, dignity, and support the end of life". RESULTS: The program for the first year has included 19 activities (cultural, training, informative, and mixed) and followed by 1,260 attendants, and the training activities were followed by 147 people. Local and regional sponsors are funding the initiative. After a year, a quantitative and qualitative evaluation was performed, showing high participation and satisfaction of the attendants and organizations. In the second year, the care for particular vulnerable people defined as targets (EoL and social factors described before) will start with volunteers with more organizations to join the project. CONCLUSIONS: The key identified factors for the initial success are: the strong joint leadership between social department of the Council and the University; clear aims and targets; high participation rates; the limited size of the geographical context; which allowed high participation and recognition; and the commitment to evaluate results. PMID- 29764172 TI - Developing compassionate communities in Australia through collective caregiving: a qualitative study exploring network-centred care and the role of the end of life sector. AB - BACKGROUND: The new public health palliative care movement calls for a move away from an individualised model of caregiving to a whole of community approach which will increase expectations on community carers. In order to avoid carer isolation, exploitation and potential burnout there is then a very real need to understand environments and relationships which support collective community caregiving. In this research we explored in-home caring networks to understand if and how network centred care supports carers of the dying while developing a whole of community approach. METHODS: Over a 6-year period the research team spoke to 301 caregivers, service providers and community members via interviews and focus groups in regional, rural and urban Australia. RESULTS: People are already caring for their dying at home and doing it well provided they are comprehensively supported by networks of care. Being part of a caring network provided people with a sense of achievement and developed their death literacy which flowed into a myriad of other community activities. While caring networks are essential they are not widely supported by service providers. At worst, services are obstructive of peoples stated preferences for place of death and caring and often adopt a paternalistic approach. Place of care, in this case the home, was supportive of maintaining networks and peoples' wellbeing. CONCLUSIONS: Operationalising public health approaches to palliative care requires moving to a place-based network centred model of care comprising formal and informal carers. Service systems need re-orienting to place caring networks as central to the caregiving process. This can be achieved by putting systems in place which initiate and maintain such networks and enable service providers to work with informal networks as equal and respectful partners. PMID- 29764173 TI - Developing palliative care programs in Indigenous communities using participatory action research: a Canadian application of the public health approach to palliative care. AB - BACKGROUND: The Indigenous people of Canada include First Nations, Inuit and Metis. This research focused on four diverse First Nations communities located in Ontario and Manitoba. First Nations communities have well-established culturally based social processes for supporting their community members experiencing dying, loss, grief and bereavement. However, communities do not have formalized local palliative care (PC) programs and have limited access to medical services, especially pain and symptom management. METHODS: Researchers conducted participatory action research (PAR) in partnership with four First Nations communities to create local PC programs. A conceptual framework for community capacity development (Kelley model) and an integrative framework for PC research with First Nations communities guided the research over 6 years. Based on a community assessment, Elders and Knowledge Carriers, community leaders and First Nations health care providers created PC programs grounded in the unique social, spiritual and cultural practices of each community, and integrated them into local health services. Maintaining local control, community members engaged external health care organizations to address gaps in health services. Strategies such as journey mapping clarified roles and strengthened partnerships between community and external health care providers. Finally, community members advocated for needed funding, medication and equipment to provide palliative home care. The research team provided mentorship, facilitation, support, education and resources to the community leaders and documented and evaluated their capacity development process. RESULTS: Our findings contribute to PC practice, policy and research. Four unique PC programs were created that offered First Nations people the choice to receive PC at home, supported by family, community and culture. A workbook of culturally relevant resources was developed for use by interested First Nations communities across Canada, including resources for program development, direct care, education, and engaging external partners. Policy recommendations and a policy framework to guide PC program development in First Nations communities were created. All research outcomes were published on a website and disseminated nationally and internationally. Our work also contributes to furthering discussions of research methods that can advance public health and PC initiatives. We demonstrated the achievements of PAR methods in strengthening community action, developing the personal skills of community health care providers and creating more supportive environments for First Nations people who wish to die at home. The Kelley model was adapted for use by First Nations communities. We also identified keys to success for capacity development. CONCLUSIONS: This research provides a Canadian example of implementing a public health approach to PC in an Indigenous context using PAR. It provides evidence of the effectiveness of a community capacity development as a strategy and illustrates how to implement it. This approach, fully grounded in local culture and context, has potential to be adapted to Indigenous communities elsewhere in Canada and internationally. PMID- 29764175 TI - Caring communities as collective learning process: findings and lessons learned from a participatory research project in Austria. AB - BACKGROUND: By now, the public health end-of-life care approach is well established and has induced diverse initiatives-subsumed under the concept of compassionate or caring communities-to engage the community in supporting vulnerable, dying people and their beloved ones. In the light of a participatory research project our paper examines the question: what are the deeper ideas behind caring communities and what constitutes a caring community? METHODS: A multi-level analysis based on (I) qualitative research with focus groups and interviews with community members within the project; (II) the reflection of the role of participatory research in caring community initiatives, and (III) the meta-analysis of an international expert workshop, which allowed to discuss our experiences and insights in the light of international caring community models and expertise. RESULTS: Our analysis of qualities ("ingredients") of a caring community, from the perspective of community members, highlighted the importance of the co-creation of supportive care relationships in the local care web, through everyday life solidarity in the neighbourhood, appreciating and exchanging the wisdom of care, and also marked the role of professionals as enablers. Participatory research in caring community developments has the potential to engage and empower citizens, and to interlink existential care stories with questions about the structural and political environments of appropriate end-of-life care. CONCLUSIONS: The caring community movement and public health end-of-life care has to maintain their critical potential against the commercialization and fragmentation of care (services), but also without "romanticizing" communities. Prospective caring community progresses need (I) an ecological health-promotion framework for action and (II) social learning processes along the existential experiences and the wisdom of community members, complementing each other. Organizing existential-political care dialogues can contribute to an ethic of caring in practice on a community level. PMID- 29764174 TI - Healthy End of Life Project (HELP): a progress report on implementing community guidance on public health palliative care initiatives in Australia. AB - BACKGROUND: Contemporary end of life care policies propose increasing community capacity by developing sustainable skills, policies, structures, and resources to support members of a community in caring for each other at the end of life. Public health approaches to palliative care provide strategies to bring this about. Practical implementation can however be ineffective, principally due to failures to grasp the systemic nature of public health interventions, or to ensure that programs are managed and owned by community members, not the professionals who may have introduced them. This article outlines a comprehensive community development project that identifies local end of life needs and meets them through the efficient use of community resources. METHODS: The project is the product of a three-phase enquiry. The first phase, carried out in a local community, examined carers' experiences of home-based dying, the networks that supported them during care, and broader community networks with the potential to extend care. Data were collected through in-depth research interviews, focus groups and consultation with a community research reference group. Findings were key issues to be targeted by a local community development strategy. In the second phase, these local findings were compared with other practice accounts to identify themes common to many contexts. A public health palliative care framework was then used to produce an evidence-informed community development model for end of life care. The third phase involves implementing and evaluating this model in different Australian contexts. RESULTS: A major theme emerging in phase one of the enquiry was the reluctance of carers to ask for, or even accept, offers of help from family, friends and community networks despite their evident need for support while providing end of life care at home. Others' willingness to provide support was thus hindered by uncertainty about what to offer, and concern about infringing on people's privacy. To develop community capacity for providing end of life care, these social norms need to change. Phase two brought public health strategies to bear on the themes identified in phase one to develop the Healthy End of Life Project (HELP), a strengths-based sustainable community development project. This provides evidence-based and research-informed resources that equip communities to work cooperatively with carers, family, friends and neighbors in support of residents wishing to receive end-of-life care in their home or a community setting. Services may initiate use of the framework, and will share their expertise on health and death matters, but communities are the experts to lead implementation in their local area. The third part of the article outlines current initiatives to implement and evaluate HELP in several Australian contexts. CONCLUSIONS: The substantive outcome of this enquiry is the 'Healthy End of Life Project (HELP); offering and providing, asking and accepting help'. PMID- 29764176 TI - Scotland's public health palliative care alliance. AB - People's experiences of death, dying and bereavement are only partially determined by formal health and social care services. A broad-based alliance of organisations and individuals was established in Scotland in 2011 with the aim of influencing a wider range of social, cultural and other environmental factors which impact on people's experiences towards the end of life. Called Good Life, Good Death, Good Grief (GLGDGG) this alliance has grown and developed over the past 6 years, with a current diverse membership of over 1,100. A small central resource hosted by the Scottish Partnership for Palliative Care (SPPC) provides infrastructure, resources, promotion, events and advocacy for the alliance. GLGDGG's approach is primarily to engage, support and enhance the assets of communities, organisations and individuals who have the potential to improve the experience of death, dying and bereavement in Scotland. In addition to having very limited financial and staff resources the alliance has faced and responded to some other major challenges; the breadth and diversity of areas needing action; a lack of evidence to inform prioritisation and advocacy; how to operationalise theory in specific contexts; risk aversion on the part of some institutions in relation to death, dying and bereavement; how to measure change and demonstrate impact. The alliance has developed or used different frameworks for conceptualising and organising its work, but always with an emphasis on practical and adaptable approaches to action. Key successes of GLGDGG include growth in the size and diversity of the membership and the development of a portfolio of resources, activities and events. Amongst events developed is To Absent Friends, a people' festival of storytelling and remembrance which gives people across Scotland an excuse to remember, to tell stories, to celebrate and to reminisce about people who have died but who remain important to them. GLGDGG promotes the festival, encourages involvement, provides ideas and support, and organises a small number of events. However, the vast majority of the activity which takes place during the festival is conceptualised and carried out by individuals and organisations on their own initiative. GLGDGG has been successful in influencing public policies relating to death, dying and bereavement. The experience of GLGDGG suggests that: enthusiasm for action exists widely in Scottish society; local ownership is the key for local action; national infrastructure and off-the-shelf resources are valued by local actors; small resource can make a big difference to local work; national events can act as a catalyst for local action. The next phase of work is to scale up existing activities and initiatives and to base future plans on scoping work currently being undertaken. PMID- 29764177 TI - Solidarity and compassion-prisoners as hospice volunteers in Poland. AB - Democracy in Eastern Europe arrived after a long fight with a communist regime, and the activities of medical volunteers have been developing in opposition to the existing then in Poland mentality called Homo Sovieticus. From 1981 onwards the Polish Hospice Movement there was inspired by practitioners and international experiences brought by visits of Dr. Cicely Saunders. The history of modern end of-life care in Poland was connected to caring communities, which could be called compassionate, because of the volunteering of all hospice team members. When palliative medicine started to become a part of the national healthcare programme, the hospice movement was slowly losing its exceptional character of professionals working together with volunteers, accompanied by considerable involvement of church communities. The new way of talking about end-of-life care was proposed in XXI century, and promotion of volunteering was part of it. In Gdansk an innovative program to reintegrate prisoners into society through voluntary work with hospice patients began. Since 2008 the WHAT project was aimed at social reintegration of prisoners through voluntary activities in hospices and correctional institutions from around Poland. In June 2009 Poland was awarded a prestigious prize 'The Crystal Scales of Justice' by The Council of Europe for a project called Voluntary Service of the Convicted in Poland implementing an innovative form of cooperation among prisons, hospices and social welfare homes. The research involving prisoners performing hospice-palliative care volunteering indicates a diverse range of life goals from the inmates not involved in hospices. These innovative correctional programs truly help local communities and prisoners who are currently working in 40 hospices and 70 nursing homes, helping those in need. Adequately prepared inmates who proved to be effective volunteers could be an inspiration to all who want to make end-of-life care more social, more humane and a more universal duty of compassionate communities. PMID- 29764178 TI - Compassionate Communities in Canada: it is everyone's responsibility. AB - Prof. Allan Kellehear first developed a contemporary public health approach to palliative and end-of-life care. Countries around the world have since adopted the theory of practice that mobilizes palliative care as a public health issue particularly the Compassionate Communities (CC) model. In the wake of Canada's Medical Assistance in Dying (MAiD) legislation and its growing senior population, quality palliative care has enjoyed a renewed focus. Pallium Canada is helping communities across the country understand and adopt the CC model, through education, knowledge mobilization, project facilitation, and leadership. Although it has made significant strides in the last few years, there is still progress to be made. The aim of this paper is to present the historical development of the public health approach to end-of-life care in Canada, including its successes and hardships thus far. Drawing from examples of regional, provincial, and national initiatives, future directions for community engagement as a public health approach to palliative care are discussed. PMID- 29764179 TI - Was the 5th International Public Health Palliative Care Conference 2017 Canada's tipping point? -a meeting report. PMID- 29764180 TI - Symptom control, treatment-induced nausea prophylaxis, and palliative radiation therapy. PMID- 29764181 TI - Symptom clusters using the EORTC QLQ-C15-PAL in palliative radiotherapy. AB - BACKGROUND: Patients with advanced cancer often experience a multitude of symptoms. Due to the potential interrelation of symptoms, symptom clusters of 2 or more concurrent symptoms have been advocated for use in the palliative setting to provide better management of symptoms. METHODS: The principal component analysis (PCA), exploratory factor analysis (EFA) and hierarchal cluster analysis (HCA) were conducted on responses to items 1-14 in the European Organisation for Research and Treatment of Cancer Quality of Life-C15-Palliative (EORTC QLQ-C15 PAL) at baseline and days 5 and 10 following RT. RESULTS: There was complete data for 109, 90 and 87 patients at baseline, day 5 and day 10 respectively. The average age was 72 years. The most common site of primary was the prostate (36.7%), and almost all patients presented with bone metastases (95.4%). Analyses identified 2-4 clusters at each interval. From baseline to day 10 follow-up, across all analyses, items associated with physical functioning clustered consistently with shortness of breath. Pain and pain interference clustered with nausea at baseline; and with sleep at both follow-up intervals. Cronbach's alpha values for the clusters ranged from 0.53 to 0.90. CONCLUSIONS: Fluctuation of symptom clusters was observed in a short time frame following palliative RT. Although clusters were dynamic, several items tended to cluster together. Further research is required to validate these clusters. PMID- 29764182 TI - The use of ketamine in a palliative-supportive care unit: a retrospective analysis. AB - BACKGROUND: To assess the response to ketamine in patients with difficult pain syndromes. METHODS: The charts of patients with uncontrolled pain despite opioid dose escalation of at least two opioids or a combination of them, selected for a burst of ketamine and midazolam were reviewed. One hundred mg/day of ketamine and midazolam 15 mg/day by a continuous intravenous infusion for about 48 hours was offered to patients. RESULTS: Forty-four patients received a burst of ketamine. Ten patients did not achieve any improvement. Pain intensity decreased from a mean of 7.8 (SD, 1.6) to 2.8 (SD, 1.3) (P<0.0005). The outcome was considered optimal, good, and mild in 24, 9, and 1 patients, respectively. Adverse effects attributable to ketamine did not have relevant intensity and no patient discontinued the treatment due to psychomimetic adverse effects. CONCLUSIONS: This data suggests that a burst of ketamine and midazolam at low doses, may reverse an unfavourable opioid response, assisting the opioid switching. Although the role of ketamine remains controversial, it should not deter physicians to do not use that in specific conditions. PMID- 29764183 TI - A pilot study with palonosetron in the prophylaxis of radiation-induced nausea and vomiting. AB - BACKGROUND: Palonosetron is an effective antiemetic in chemotherapy-induced nausea and vomiting (CINV), but has yet to be studied in the radiation setting. The purpose of the present study was to investigate the efficacy and safety of palonosetron in the prophylaxis of radiation-induced nausea and vomiting (RINV). METHODS: Patients without existing nausea and vomiting undergoing palliative radiotherapy to sites with emetic risk were prescribed palonosetron 0.5 mg orally before the start of radiation treatment, and every other day until completion of treatment. Patients were followed up in acute (day 1 of treatment to day 1 after treatment) and delayed phases (days 2-10 after treatment). The primary endpoint was control of vomiting. Complete control was defined as no use of rescue medication and no episodes of nausea or vomiting. Secondary endpoints included control of nausea and quality of life (QOL). QOL was assessed with the Functional Living Index-Emesis and the European Organisation for Research and Treatment of Cancer QOL Questionnaire-Core 15 Palliative (C15-PAL). RESULTS: In all evaluable patients (n=75), complete control of vomiting was 93.3% in the acute phase and 93.2% in the delayed phase. Complete control of nausea was 74.7% in the acute phase and 74.0% in the delayed phase. CONCLUSIONS: Results suggest improved control in RINV compared to historical reports with first generation serotonin receptor antagonists (RA). A randomized study will be needed to confirm this finding. PMID- 29764184 TI - Efficacy of the combination neurokinin-1 receptor antagonist, palonosetron, and dexamethasone compared to others for the prophylaxis of chemotherapy-induced nausea and vomiting: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV), a common side effect of chemotherapy, can substantially impair a patient's quality of life, interfere with a patient's compliance with anticancer therapy, and result in the manifestation of adverse events such as electrolyte imbalance, dehydration and malnutrition. The most recent guidelines published by the Multinational Association of Supportive Care in Cancer (MASCC) and European Society of Medical Oncology (ESMO) recommend the combination of dexamethasone (DEX), a 5 hydroxytrypatmine-3 receptor antagonist (5-HT3RA), preferably palonosetron (PALO), and a neurokinin-1 receptor antagonist (NK1RA) for prophylactic treatment of CINV in patients receiving highly emetogenic chemotherapy (HEC). The aim of this review was to examine the efficacy of triple agent, as reported in randomized controlled trials (RCTs), compared to any other prophylactic treatments. METHODS: A literature search was conducted in Ovid MEDLINE(R), Embase Classic & Embase, and the Cochrane Central Register of Controlled Trials. The primary endpoint was the proportion of patients achieving complete response (CR) in the acute, delayed and overall phase. Secondary endpoints included the percentage of patients who achieved complete control (CC), no nausea and no vomiting in the acute, delayed and overall phases. RESULTS: A total of 17 RCTs were included in this review, of which 3,146 patients were randomized to receive NK1RA, PALO and DEX, and 2,987 patients to receive other antiemetic treatments. The combination was not superior to other treatments in five endpoints-CC and CR in the acute phase, nausea and emesis control in the delayed phase, and nausea in the overall phase-but was superior in the other 11 endpoints. When looking only at HEC and moderately emetogenic chemotherapy (MEC) studies, the combination was only superior to others in three endpoints (delayed and overall CC, and overall emesis control) in HEC setting, which is less than the nine identified endpoints (delayed and overall CR, delayed and overall CC, acute and overall nausea control, and acute, delayed and overall phases for emesis control) in the MEC setting. CONCLUSIONS: The combination of NK1RA, PALO and DEX is superior in the majority of assessed endpoints of this meta-analysis. Further studies should investigate the efficacy and safety of the triple regimen compared to regimens lacking NK1RA, to add to the discussions about whether future CINV prophylaxis guidelines should include NK1RA as a first-line treatment in the MEC setting. PMID- 29764185 TI - Management of metastatic spinal cord compression among Veterans Health Administration radiation oncologists. AB - BACKGROUND: Optimal management of metastatic spinal cord compression (MSCC) improves functional outcomes in patients with metastatic disease. This survey study evaluated management of MSCC by Veterans Health Administration (VHA) radiation oncologists (ROs), to determine whether management of MSCC correlates with American College of Radiology (ACR) guidelines, and to compare times to initiation of treatment between surgery and radiotherapy (RT). METHODS: Surveys emailed to 79 VHA ROs included questions on steroid use, surgical care, palliative care, fractionation of irradiation, re-irradiation, and management of common MSCC case scenarios. Follow-up phone calls were made to encourage survey participation. Descriptive statistics and chi-square testing were done to show significant associations. RESULTS: The survey yielded an 81.0% response rate; 79.4% of ROs had read the ACR Appropriateness Criteria(r) Spinal Bone Metastases. The majority (87.3%) prefer 30 Gy/10 fractions for MSCC, and all respondents recommend steroid therapy in conjunction with RT. When used, RT was more often initiated within 24 hours than was neurosurgery (83.9% vs. 34.5%, P<0.001). All ROs report use of palliative care services. Re-irradiation is given by 66.1%: 30.7% with stereotactic body radiation therapy (SBRT), 17.7% using intensity modulated radiation therapy (IMRT), and 17.7% using conventional RT. For the case scenarios, most respondents' (>75%) management concurred with ACR guidelines. CONCLUSIONS: The majority of VHA ROs are familiar with the ACR Appropriateness Criteria(r) Spinal Bone Metastases and practice accordingly. Treatment within 24 hours is more likely when RT is the primary modality compared to when surgical decompression precedes RT. PMID- 29764186 TI - Patterns of symptom control and palliative care-focused original research articles in the International Journal of Radiation Oncology *Biology* Physics and the Radiotherapy and Oncology Journal, 2005-2014. AB - BACKGROUND: A significant portion of radiation treatment (30-40%) is delivered with palliative intent. Given the frequency of palliative care (PC) in radiation oncology, we determined the patterns of research focusing on symptom control and palliative care (SCPC) in two prominent radiation oncology journals from 2005 2014. METHODS: Original research manuscripts published from 2005-2014 in the International Journal of Radiation Oncology *Biology* Physics (Red Journal) and the Radiotherapy and Oncology Journal (Green Journal) were reviewed to categorize articles as PC and/or SCPC. Articles were categorized as PC if it pertained to any aspect of treatment of metastatic cancer, and as SCPC if symptom control in the metastatic cancer setting was the goal of the research inquiry and/or any domain of palliative clinical practice guidelines was the goal of research inquiry. RESULTS: From 2005-2014, 4.9% (312/6,386) of original research articles published in the Red Journal and 3.5% (84/2,406) published in the Green Journal pertained to metastatic cancer, and were categorized as PC. In the Red Journal, 1.3% (84/6,386) of original research articles were categorized as SCPC; 1.3% (32/2,406) of articles in the Green Journal were categorized as SCPC. There was no trend observed in the proportion of SCPC articles published over time in the Red Journal (P=0.76), the Green Journal (P=0.48), or both journals in aggregate (P=0.38). CONCLUSIONS: Despite the fact that palliative radiotherapy is a critical part of radiation oncology practice, PC and SCPC-focused original research is poorly represented in the Red Journal and the Green Journal. PMID- 29764187 TI - It's not about you-it's about me. PMID- 29764189 TI - Plagues & wars: the 'Spanish Flu' pandemic as a lesson from history. PMID- 29764188 TI - Effects of extruded flaxseed on layer performance, nutrient retention and yolk fatty acid composition. AB - 1. This study was conducted to determine the effects of feeding an extruded flaxseed (EF) on layer performance, apparent total tract nutrient retention (ATTR) and egg yolk fatty acid concentrations. 2. Seventy-two White Leghorn laying hens (58-week-old; three per cage) were randomly allotted to one of four dietary treatments: 0%, 7.5%, 15.0% and 22.5% of EF-supplemented diets for 8 weeks. 3. Supplementation with EF had no effect on feed intake, egg production, feed conversion ratio and egg weight. Egg components (yolk, albumen and shell percentages) were similar among treatments, except that shell percentage was greater for layers fed 22.5% EF than those fed 7.5% and 15% EF. The ATTR of dry matter and organic matter were highest for 0% and 7.5% EF, intermediate for 15% EF and lowest for 22.5% EF. Similar reductions on ATTR of crude protein and nitrogen-corrected apparent metabolisable energy were observed for layers fed 22.5% EF relative to those fed 0% or 7.5% EF. 4. Feeding EF at 7.5%, 15.0% and 22.5% of the diet markedly increased (by 92%, 198% and 271%, respectively) egg yolk concentrations of n-3 polyunsaturated fatty acid (PUFA) and reduced saturated fatty acid and n-6 PUFA concentrations. 5. It was concluded that omega 3 labelled eggs (300 mg/60 g of egg) may be produced with low (7.5% of diet) levels of dietary EF without compromising egg production parameters. However, feeding moderate to high levels of EF (i.e. 15% and 22.5% EF) may reduce total tract nutrient and energy utilisation. PMID- 29764191 TI - Implementing the Integrated Strategy for the Cultural Adaptation of Evidence Based Interventions: An Illustration. AB - Background Persons' cultural beliefs about a health problem can affect their perceived acceptability of evidence-based interventions, undermining evidence based interventions' adherence, and uptake to manage the problem. Cultural adaptation has the potential to enhance the acceptability, uptake, and adherence to evidence-based interventions. Purpose To illustrate the implementation of the first two phases of the integrated strategy for cultural adaptation by examining Chinese Canadians' perceptions of chronic insomnia and evidence-based behavioral therapies for insomnia. Methods Chinese Canadians ( n = 14) with chronic insomnia attended a group session during which they completed established instruments measuring beliefs about sleep and insomnia, and their perceptions of factors that contribute to chronic insomnia. Participants rated the acceptability of evidence based behavioral therapies and discussed their cultural perspectives regarding chronic insomnia and its treatment. Results Participants actively engaged in the activities planned for the first two phases of the integrated strategy and identified the most significant factor contributing to chronic insomnia and the evidence-based intervention most acceptable for their cultural group. Conclusions The protocol for implementing the two phases of the integrated strategy for cultural adaptation of evidence-based interventions was feasible, acceptable, and useful in identifying culturally relevant evidence-based interventions. PMID- 29764190 TI - Delafloxacin: an improved fluoroquinolone developed through advanced molecular engineering. AB - The emergence of antimicrobial resistance threatens current clinical practice across a range of infection types. Delafloxacin, a non-zwitterionic fluoroquinolone recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections, has been developed to address some of these challenges. Uniquely delafloxacin has increased intracellular penetration and enhanced antibacterial activity under acidic conditions, an environment seen in many infection sites including abscesses. Delafloxacin is active against a wide range of Gram-positive and -negative species including methicillin-resistant Staphylococcus aureus and many fluoroquinolone-resistant strains. Additionally, according to preclinical and clinical trial data, well known adverse events related to fluoroquinolone class do not appear to occur with this new molecule. Delafloxacin has been studied in acute bacterial skin and skin structure infections with >1400 patients exposed to both intravenous and oral formulation for up to 14 days and has shown noninteriority to vancomycin with or without aztreonam. For its interesting microbiological and pharmacokinetic/pharmacodynamics characteristics and for its safety profile, delafloxacin represents a very promising option for the treatment of infections caused by multidrug-resistant pathogens. PMID- 29764192 TI - Simvastatin Suppresses Interleukin Ibeta Release in Human Peripheral Blood Mononuclear Cells Stimulated With Cholesterol Crystals. AB - Statins are mainstream therapy in the treatment and prevention of cardiovascular disease through inhibitory effects on cholesterol synthesis. However, statins' beneficial effects in cardiovascular disease may also be attributable to their role as anti-inflammatory mediators. Here, we investigated the effects of simvastatin treatment on expression levels of interleukin (IL) 1beta in both patient with hyperlipidemia and healthy human peripheral blood mononuclear cells (PBMCs) using cholesterol crystals (CC), a cardiovascular pathogenic stimulus for activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome. Cholesterol crystal-induced NLRP3 inflammasome activation was used to trigger maturation and release of IL-1beta in PBMCs. Specifically, isolated PBMCs from patients with hyperlipidemia at baseline and following 8 weeks of in vivo treatment with simvastatin (10-20 mg) daily were stimulated with lipopolysaccharide (LPS; 100 ng/mL) for 3 hours to induce proIL-Ibeta expression followed by CC (2 mg/mL) stimulation for further 18 hours to activate the NLRP3 inflammasome complex to induce maturation/activation of IL-1beta. Peripheral blood mononuclear cells were also isolated from healthy donors and stimulated in vitro with simvastatin (50, 25, 5, and 2 umol/L) prior to stimulation with LPS and CC as described above. The effects of simvastatin treatment on levels of IL 1beta expression were determined by enzyme-linked immunosorbent assay and western blot. Both in vitro and in vivo treatments with simvastatin led to a significant reduction in the levels of expression of IL-1beta in response to stimulation with CC. Simvastatin inhibits the expression and activation of IL-1beta induced by CC in PBMCs, which may contribute to its protective role in patients with cardiovascular disease. PMID- 29764193 TI - Time and Personhood across Early and Late-stage Dementia. AB - How do time and personhood become related when dementia sets in? This article brings together ethnographies from a memory clinic and a dementia nursing home in Copenhagen, Denmark, pursuing how personhood and time become intertwined across early and late-stage dementia. In the memory clinic, the dementia diagnosis is enacted and experienced simultaneously as an indispensable prophecy of discontinuity of personhood and life for the patients, and as a prognosis that renders the future indeterminate and open to intervention. In the nursing home, institutionalized care marks the fulfillment of the prophecy of decline, yet nursing home staff insist on practicing prognoses for the residents. Across our empirical sites, we enquire what the tension between prophecy and prognosis mean for personhood and the possibilities of the present, arguing that people with dementia are made and unmade through different understandings and enactments of future-oriented temporalities. PMID- 29764194 TI - Division of parental leave and perceived parenting stress among mothers and fathers. AB - OBJECTIVE: To explore associations between division of parental leave and perceived parenting stress in mothers and fathers of infants. BACKGROUND: In Sweden, both parents have the same right to parental leave, and fathers use about a quarter of the total 480 benefit days. Little is known about the parents' psychological well-being in terms of stress arising from the parenting role and its association with equal or unequal division of parental leave. METHODS: 280 parents completed the Swedish Parenthood Stress Questionnaire (SPSQ) at 6 months and 18 months after childbirth. RESULTS: Fathers who shared parental leave equally were less affected by perceived parenting stress than those who shared unequally (adjusted B -0.20; 95% CI -0.33 to -0.06). No such association was found among mothers. CONCLUSION: Parents' choices regarding parental leave division were associated with perceived parenting stress among fathers, but not among mothers. Unequal division of leave contributed to parenting stress in fathers. PMID- 29764196 TI - A Dialectical and Dialogical Approach to Health Policies and Programs: The Case of Open Defecation in India. AB - A multi-pronged approach to health policy and programs related to open defecation (OD) is proposed via a qualitative study conducted in rural India. A dialogic and dialectic perspective is employed to interpret the key findings from nine focus groups, highlighting the dialectical views toward OD and latrines. Findings indicate that current policy may be too narrow as it does not fully deal with the multiple reasons, including social communication as well as gender, cultural, health and work identity issues, for OD. The results suggest that OD is more complicated than it appears and a multi-pronged, poly-vocal approach to health communication campaigns and policy should be considered. PMID- 29764195 TI - Eremophilane sesquiterpenes from the endophytic fungus Xylaria sp. GDG-102. AB - A new eremophilane sesquiterpene, xylareremophil (1), together with five known eremophilanes, 1alpha,10alpha-epoxy-3alpha-hydroxyeremophil-7(11)-en-12,8beta olide (2), 1,10alpha,13-trihydroxyeremophil-7(11)-en-12,8-olide (3), 1alpha,10alpha-epoxy-13-hydroxyeremophil-7(11)-en-12,8beta-olide (4), mairetolides B (5) and G (6) were isolated from the endophytic fungus Xylaria sp. GDG-102 cultured from Sophora tonkinensis. Their structures were elucidated on the basis of spectroscopic data analysis. The absolute configurations of 1 was determined by comparing computed electronic circular dichroism (ECD) and optical rotation (OR) with experimental results. Compounds 1, 5 and 6 showed antibacterial activities against Proteus vulgaris, Micrococcus luteus, Micrococcus lysodeikticus and Bacillus subtilis with MIC values of 25-100 MUg/mL. PMID- 29764197 TI - Re-thinking the chicken-Campylobacter jejuni interaction: a review. AB - Chickens are recognized as an imperative source of thermophilic Campylobacter spp., carrying this microorganism in high numbers in their intestinal tract. For a long time, Campylobacter jejuni has been considered as a commensal microorganism which colonizes its primary host rather than infecting it, in the absence of any obvious clinical signs. However, recent studies question this and argue for a deeper understanding of the host-bacteria interaction. Following oral uptake, it was demonstrated that C. jejuni interacts intimately with the gut epithelium and influences cellular functions of the host, with consequences on nutrient absorption. The immune reaction of the host which was revealed in some studies confirmed the infectious nature of C. jejuni. In agreement with this, an increased expression of pro-inflammatory cytokine genes was noticed. The ability to induce intestinal damage and to modulate the barrier function of the intestinal epithelia has further consequences on gut integrity, as it facilitates the paracellular passage of C. jejuni into the underlying tissues and it supports the translocation of luminal bacteria such as Escherichia coli to internal organs. This is associated with an alteration of the gut microbiota as infected birds have a significantly lower abundance of E. coli in different parts of the intestine. Some studies found that the gut microbiota influences the infection and translocation of C. jejuni in chickens in various ways. The effects of C. jejuni on the intestinal function of chickens already indicate a possible interference with bird performance and welfare, which was confirmed in some experimental studies. Furthermore, it could be demonstrated that a Campylobacter infection has an influence on the movement pattern of broiler flocks, supporting experimental studies. The intense interaction of C. jejuni with the chicken supports its role as an infectious agent instead of simply colonizing the gut. Most of the findings about the impact of Campylobacter on chickens are derived from studies using different Campylobacter isolates, a specific type of bird and varying experimental design. However, experimental studies demonstrate an influence of the aforementioned parameters on the outcome of a certain trial, arguing for improved standardization. This review summarizes the actual knowledge of the host-pathogen interaction of C. jejuni in chickens, emphasizing that there are still major gaps despite recently gained knowledge. Resolving the cascade from oral uptake to dissemination in the organism is crucial to fully elucidating the interaction of C. jejuni with the chicken host and to assess the clinical and economic implications with possible consequences on preventive interventions. PMID- 29764198 TI - Temporal bone contrast-enhanced high-resolution CT evaluation of pulsatile tinnitus after sigmoid sinus wall reconstruction. AB - BACKGROUND: Sigmoid sinus wall reconstruction (SSWR) is a proven effective treatment for pulsatile tinnitus (PT) caused by sigmoid sinus wall dehiscence (SSWD) with or without sigmoid sinus diverticulum (SSD); however, comprehensive analysis of the postoperative imaging manifestations has not yet been reported. PURPOSE: To analyze temporal bone computed tomography (CT) imaging features following SSWR in patients with PT. MATERIAL AND METHODS: Following SSWR, temporal bone contrast-enhanced high-resolution CT (HRCT) images from 33 PT cases were retrospectively analyzed. Patients were divided into two groups based on follow-up interval: a short-interval group (<=18 months, 12 cases) and a long interval group (>18 months, 21 cases). The mending material density and morphology was analyzed. Postoperative changes of the venous sinus were evaluated. Imaging manifestations of the normal temporal bone and mastoid air cells adjacent to the operative field were observed. RESULTS: The order of CT values of mending materials was significantly lower in the short-interval group than in the long-interval group (Z = -4.716, P < 0.001); the incidence of complete newly remodeled cortical bone on the rim of the mending materials was significantly higher in the long-interval group than in the short-interval group ( P < 0.001). Eleven patients (33.3%) showed varying degrees of remnant SSWD. The mending materials and normal mastoid bone structure showed complete fusion (n = 12, 36.4%), partial fusion (n = 16, 48.5%), or complete separation (n = 5, 15.2%). CONCLUSION: Temporal bone contrast-enhanced HRCT can be used to observe imaging features of the mending materials, venous sinus, adjacent normal temporal bone and mastoid air cells following SSWR. PMID- 29764199 TI - Change in microcalcifications on mammography after neoadjuvant chemotherapy in breast cancer patients: correlation with tumor response grade and comparison with lesion extent. AB - Background After neoadjuvant chemotherapy (NAC), persistent microcalcifications are often observed in spite of a decrease in the primary tumor size. Purpose To analyze the changes in microcalcifications after NAC and to evaluate the accuracy of residual microcalcifications in predicting the extent of residual cancer. Material and Methods Eighty patients who received NAC and underwent both mammography and magnetic resonance imaging (MRI) before and after the completion of NAC were included. The location of microcalcifications was classified into two types: inside the mass and outside the mass. Results The extent of the residual calcifications was larger than the pathologic residual lesion in 14 (74%) of 19 patients with complete response (CR) on MRI, but the discrepancy was <1 cm in eight (42%) patients. The median value of the discrepancy was significantly higher in patients showing CR with outside calcifications compared to CR with inside calcifications (2.0 cm vs. 0.7 cm, P = 0.008). After NAC, the decrease of calcifications was more frequently observed in cancers showing CR on MRI or Miller-Payne grade 5 and the increase of calcifications more frequently occurred in cancers showing progress disease on MRI or Miller-Payne grade 1 ( P < 0.001 and P = 0.044). Conclusion The change in microcalcifications after NAC was correlated with the tumor response to NAC. The discrepancy was highest in the group showing CR on MRI with outside calcifications. In tumors with inside calcifications, the discrepancy was relatively low within an acceptable range. PMID- 29764200 TI - Copper release rate needed to inhibit fouling on the west coast of Sweden and control of copper release using zinc oxide. AB - How zinc oxide influences copper release has been tested and the lowest release rate of copper from various combinations of copper and zinc in a paint matrix evaluated, whilst still deterring macrofouling, including barnacles and bryozoans. Copper (I) oxide was added to a generic AF paint in 0, 8.5, 11.7 or 16.3 wt% copper oxide in combination with 0, 10 or 20 wt% zinc oxide and applied on PMMA panels. The results show that zinc influences the release rate of copper. When 10 and 20 wt% zinc was added, the total amount of copper released significantly increased by on average 32 and 47% respectively. All treatments that included copper were successful in deterring macrofouling, including the treatment with the lowest average Cu release rate, ie 4.68 MUg cm-2 day-1. PMID- 29764201 TI - Cognitive predictors of sequential motor impairments in children with dyslexia and/or attention deficit/hyperactivity disorder. AB - This study examined cognitive predictors of sequential motor skills in 215 children with dyslexia and/or attention deficit/hyperactivity disorder (ADHD). Visual working memory and math fluency abilities contributed significantly to performance of sequential motor abilities in children with dyslexia (N = 67), ADHD (N = 66) and those with a comorbid diagnosis (N = 82), generally without differentiation between groups. In addition, primary diagnostic features of each disorder, such as reading and inattention, did not contribute to the variance in motor skill performance of these children. The results support a unifying framework of motor impairment in children with neurodevelopmental disorders such as dyslexia and ADHD. PMID- 29764202 TI - Comparative study of the synbiotic effect of inulin and fructooligosaccharide with probiotics with regard to the various properties of fermented soy milk. AB - Numerous combinations of probiotics were explored to find the suitable starter culture for the development of synbiotic soy yoghurt which can give good product characteristics and may be acceptable among consumers. Prebiotics (fructooligosaccharide (FOS) and inulin) were supplemented in an attempt to reduce the after-taste of soymilk, improve acidification profile and growth of probiotics. The addition of prebiotics in soy milk significantly enhanced the acidification rate (10.82 to 23.00 * 10-3 pH units/min) and condensed the fermentation completion time. FOS-supplemented fermented soy milk showed better acidification and post-acidification profile as compared to inulin supplemented samples. The Streptococcus salivarius subsp. thermophilus (ST) - Lactobacillus acidophilus (LA) with FOS gave the better textural properties with firmer gel (350.10), lower adhesiveness (-93.10) and springiness (0.92), higher gumminess (164.50) and average cohesiveness (0.47). FOS-supplemented ST-LA-fermented samples showed good gel characteristics with higher elastic modulus (1672.39 Pa), viscous modulus (416.41 Pa), complex modulus (1723.53 Pa), lower tan delta (14) and higher overall acceptability scores (7.40) on a 9-point hedonic scale. Developed synbiotic soy fermented milk showed more than the 9 log cfu/ml count throughout storage which is required for probiotic functional food. PMID- 29764203 TI - Pinellia ternata (Thunb.) Makino Preparation promotes sleep by increasing REM sleep. AB - Pinellia ternata (Thunb.) Makino Preparation (PTP) is widely used to treat insomnia in traditional Chinese medicine; however, its specific role is not clear. In this study, PTP was prepared at three concentrations. For locomotor activity tests, mice were treated with PTP and evaluated for 14 days. For polygraph recordings, mice were treated for 14 days and recorded after treatment. The main chemical constituents in PTP were identified by Ultra performance liquid chromatography/quadrupole time spectrometry (UPLC/Q-TOF-MS). The results showed that 0.9 g/mL PTP significantly reduced locomotor activity. The effect was related to the time of treatment. PTP reduced wakefulness and increased sleep in mice. Furthermore, PTP promoted sleep by increasing the number of REM sleep episodes with a duration of 64-128s and increasing the number of transitions from NREM sleep to REM sleep and from REM sleep to wakefulness. A total of 17 compounds were identified. PMID- 29764204 TI - Biotechnological potential of microbial consortia and future perspectives. AB - Design of a microbial consortium is a newly emerging field that enables researchers to extend the frontiers of biotechnology from a pure culture to mixed cultures. A microbial consortium enables microbes to use a broad range of carbon sources. It provides microbes with robustness in response to environmental stress factors. Microbes in a consortium can perform complex functions that are impossible for a single organism. With advancement of technology, it is now possible to understand microbial interaction mechanism and construct consortia. Microbial consortia can be classified in terms of their construction, modes of interaction, and functions. Here we discuss different trends in the study of microbial functions and interactions, including single-cell genomics (SCG), microfluidics, fluorescent imaging, and membrane separation. Community profile studies using polymerase chain-reaction denaturing gradient gel electrophoresis (PCR-DGGE), amplified ribosomal DNA restriction analysis (ARDRA), and terminal restriction fragment-length polymorphism (T-RFLP) are also reviewed. We also provide a few examples of their possible applications in areas of biopolymers, bioenergy, biochemicals, and bioremediation. PMID- 29764205 TI - Production of oils and fats by oleaginous microorganisms with an emphasis given to the potential of the nonconventional yeast Yarrowia lipolytica. AB - Recently, there has been a great upsurge of interest in studies related to several aspects of microbial lipid production, which is one of the top topics in relevant research fields due to the high demand of these fatty materials in food, medical, oleochemical and biofuel industries. Lipid accumulation by the so-called "oleaginous microorganisms" can generate more than 20% w/w of oil in dry biomass and is governed by a plethora of parameters, such as medium pH, incubation temperature, nutrient limitation and C/N (carbon/nitrogen) ratio, which drastically affect the lipid production bioprocess. Until now, considerable work has been undertaken to find the cheapest substrate to enable lipid fermentation by oleaginous microorganisms. This review principally details information regarding microbial lipids, suitable production conditions and focuses attention on using the yeast Yarrowia lipolytica to achieve these objectives. Lipid production by this yeast is discussed and the necessary conditions and suitable substrates are reviewed. PMID- 29764206 TI - Management of incidental aneurysms: comparison of single Centre multi disciplinary team decision making with the unruptured incidental aneurysm treatment score. AB - OBJECTIVE: To compare multidisciplinary team (MDT) decision making at our centre with the suggested management from the recently published Unruptured Intracranial Aneurysm Treatment Score (UIATS), with particular focus on disagreements between the two bodies of expert opinion. DESIGN: A retrospective audit of local practice. SUBJECTS: Adult patients with incidental cerebral saccular aneurysms referred to The National Hospital for Neurology and Neurosurgery Neurovascular MDT. METHODS: Review of MDT records from 2010-2015 and collection of UIATS criteria. MDT decisions for each aneurysm were designated as conservative or treatment group, then assessed for correlation with the UIATS. RESULTS: Data was collected on 398 aneurysms from 296 patients. 57% of aneurysms were managed conservatively and 43% were treated with endovascular or open repair. Total follow up was 8409 aneurysm months (mean: 21 months per aneurysm). The overall proportion of agreement (p0) was 66.6% (95% CI: 61.9-71.2). Cohen's Kappa (k) was 0.325 suggesting only a "fair" level of agreement between the two raters. Absolute agreement rates increased from 60% in 2010 to 74% in 2015. Aneurysm size was an important factor for disagreement, 77% of aneurysms treated following MDT, but not in agreement with the UIATS, were >7 mm, compared with only 70.5% in those treated following MDT and in agreement with UIATS. CONCLUSION: There was disagreement between the two expert opinions analysed in this study. A key factor was aneurysm size, with decision making at our centre seemingly more guided by older landmark papers such as work by the International Study of Unruptured Intracranial Aneurysms (ISUIA) group. However, agreement was at its highest at the end of the study period, suggesting increasing convergence between the two bodies of expert opinion. The reasons for disagreement and particularly clinicians' reliance on aneurysm size in decision making is something that needs consideration when planning and auditing aneurysm services. PMID- 29764207 TI - Practical Psychology in Medical Rehabilitation. PMID- 29764208 TI - De-esterified tragacanth-chitosan nano-hydrogel for methotrexate delivery; optimization of the formulation by Taguchi design. AB - The objective of the present study was to prepare and characterized de-esterified tragacanth-chitosan nanoparticles (DET-CS NPs) as a novel carrier for methotrexate, with a view to improve drug efficacy and target ability. The preparation process was optimized using Taguchi design. NPs were characterized for size, zeta potential, morphology, thermal stability, loading efficiency, cytotoxicity and cellular uptake. Taguchi design indicated that the molecular weight of chitosan possessed the most effect on the zeta potential, PDI, and zeta deviation, and the size of nanoparticles was significantly affected by the DET concentration. The size and zeta potential of drug loaded nanoparticles at optimum condition were 322.9 +/- 26 nm and 17.3 +/- 5.73 mV, and thermal analysis indicated ionic bond between DET and CS in NPs. The loading efficiency was 20.32% +/- 2.01, and the sustained release was observed within nine days. The IC50 was 280 ug/mL in HT-29, and the mitochondrial membrane potential in HT-29 was reduced more than that in MCF-7. The uptake of NPs in HT-29 was higher than that in MCF 7, and active endocytosis was the key mechanism of uptake. These phenomena altogether make DET-CS NPs a proper choice for targeted drug delivery to cells containing asialoglycoprotein receptors. PMID- 29764211 TI - Assessing Emotional Reactivity: Psychometric Properties of the Perth Emotional Reactivity Scale and the Development of a Short Form. AB - The Perth Emotional Reactivity Scale (PERS) is a 30-item self-report measure of trait levels of emotional reactivity. In this article, we examine the psychometric properties of the PERS subscale and composite scores in an adult community sample (N = 428), and develop an 18-item short form of the measure (PERS-S). The PERS and PERS-S are designed to assess the typical ease of activation, intensity, and duration of one's emotional responses, and do so for positive and negative emotions separately. Our confirmatory factor analyses supported that the PERS and PERS-S both had the same theoretically congruent factor structure, and that all subscale and composite scores displayed high internal consistency reliability. Correlations with scores from established measures of psychopathology and emotion regulation also supported the validity of PERS and PERS-S scores. Our data therefore suggest that the PERS-S subscale and composite scores retain the psychometric strengths of their longer PERS counterparts. We conclude that both forms of the measure have good utility. Clinical and research applications are discussed. PMID- 29764210 TI - Curative Ex Vivo Hepatocyte-Directed Gene Editing in a Mouse Model of Hereditary Tyrosinemia Type 1. AB - Hereditary tyrosinemia type 1 (HT1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetate hydrolase (FAH). It has been previously shown that ex vivo hepatocyte-directed gene therapy using an integrating lentiviral vector to replace the defective Fah gene can cure liver disease in small- and large-animal models of HT1. This study hypothesized that ex vivo hepatocyte directed gene editing using CRISPR/Cas9 could be used to correct a mouse model of HT1, in which a single point mutation results in loss of FAH function. To achieve high transduction efficiencies of primary hepatocytes, this study utilized a lentiviral vector (LV) to deliver both the Streptococcus pyogenes Cas9 nuclease and target guide RNA (LV-Cas9) and an adeno-associated virus (AAV) vector to deliver a 1.2 kb homology template (AAV-HT). Cells were isolated from Fah-/- mice and cultured in the presence of LV and AAV vectors. Transduction of cells with LV Cas9 induced significant indels at the target locus, and correction of the point mutation in Fah-/- cells ex vivo using AAV-HT was completely dependent on LV Cas9. Next, hepatocytes transduced ex vivo by LV-Cas9 and AAV-HT were transplanted into syngeneic Fah-/- mice that had undergone a two-thirds partial hepatectomy or sham hepatectomy. Mice were cycled on/off the protective drug 2-(2 nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) to stimulate expansion of corrected cells. All transplanted mice became weight stable off NTBC. However, a significant improvement was observed in weight stability off NTBC in animals that received partial hepatectomy. After 6 months, mice were euthanized, and thorough biochemical and histological examinations were performed. Biochemical markers of liver injury were significantly improved over non-transplanted controls. Histological examination of mice revealed normal tissue architecture, while immunohistochemistry showed robust repopulation of recipient animals with FAH+ cells. In summary, this is the first report of ex vivo hepatocyte-directed gene repair using CRISPR/Cas9 to demonstrate curative therapy in an animal model of liver disease. PMID- 29764212 TI - The clinical application of single-sperm-based SNP haplotyping for PGD of osteogenesis imperfecta. AB - : Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder, presenting either autosomal dominant, autosomal recessive or X-linked inheritance patterns. The majority of OI cases are autosomal dominant and are caused by heterozygous mutations in either the COL1A1 or COL1A2 gene. In these dominant disorders, allele dropout (ADO) can lead to misdiagnosis in preimplantation genetic diagnosis (PGD). Polymorphic markers linked to the mutated genes have been used to establish haplotypes for identifying ADO and ensuring the accuracy of PGD. However, the haplotype of male patients cannot be determined without data from affected relatives. Here, we developed a method for single-sperm-based single-nucleotide polymorphism (SNP) haplotyping via next-generation sequencing (NGS) for the PGD of OI. After NGS, 10 informative polymorphic SNP markers located upstream and downstream of the COL1A1 gene and its pathogenic mutation site were linked to individual alleles in a single sperm from an affected male. After haplotyping, a normal blastocyst was transferred to the uterus for a subsequent frozen embryo transfer cycle. The accuracy of PGD was confirmed by amniocentesis at 19 weeks of gestation. A healthy infant weighing 4,250 g was born via vaginal delivery at the 40th week of gestation. Single-sperm-based SNP haplotyping can be applied for PGD of any monogenic disorders or de novo mutations in males in whom the haplotype of paternal mutations cannot be determined due to a lack of affected relatives. ABBREVIATIONS: ADO: allele dropout; DI: dentinogenesis imperfect; ESHRE: European Society of Human Reproduction and Embryology; FET: frozen embryo transfer; gDNA: genomic DNA; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MDA: multiple displacement amplification; NGS: next-generation sequencing; OI: osteogenesis imperfect; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PGD: preimplantation genetic diagnosis; SNP: single-nucleotide polymorphism; STR: short tandem repeat; TE: trophectoderm; WGA: whole-genome amplification. PMID- 29764209 TI - Next-Gen Therapeutics for Skin Cancer: Nutraceuticals. AB - Growing modernization and lifestyle changes with limited physical activity have impacted diet and health, leading to an increased cancer mortality rate worldwide. As a result, there is a greater need than before to develop safe and novel anticancer drugs. Current treatment options such as chemotherapy, radiotherapy and surgery, induce unintended side effects, compromising patient's quality of life, and physical well-being. Therefore, there has been an increased global interest in the use of dietary supplements and traditional herbal medicines for treatment of cancer. Recently, nutraceuticals or "natural" substances isolated from food have attracted considerable attention in the cancer field. Emerging research suggests that nutraceuticals may indeed prevent and protect against cancer. The intent of this article is to review some of the current spice-derived nutraceuticals in the treatment of melanoma and skin cancer. PMID- 29764213 TI - A novel non-invasive strategy for low-level laser-induced cancer therapy by using new Ag/ZnO and Nd/ZnO functionalized reduced graphene oxide nanocomposites. AB - In the present research, an effective drug-free approach was developed to kill MCF7 breast cancer cells using low-level laser therapy (LLLT) combined with reduced graphene oxide (rGO)-based hybrid nanocomposites (NCs). Here, fruit extract of Rosa canina was used for the first time to obtain the rGO/ZnO, Ag ZnO/rGO and Nd-ZnO/rGO NCs by green synthesis. Physico/photochemical properties of these NCs were evaluated using FTIR, XRD, Raman, XPS, SEM/EDX, UV-Vis, DLS and AFM. The potential of the as-synthesized NCs on ROS generating and antioxidant activity were assessed by DPPH. After optimizing the proper concentration of the NCs their anti-tumoral efficacy were evaluated by DAPI staining and MTT assay tests for laser therapy on MCF7 breast cancer cells. Interestingly, cell death was increased dramatically by increasing irradiation dose from 8-32 J/cm2 and then decreased by enhancing laser dose. The maximum amount of cell death is 50% which was observed in the presence of ZnO/rGO 20% by irradiation dose of 32 J/cm2. Furthermore, in comparison with 810 nm, 630 nm lasers were more effective in LLLT of MCF7 cells. The results show the potential of using rGO-based NCs in LLLT, which may be combined with other therapeutic approaches to assist our fight against cancer. PMID- 29764214 TI - Chronotype influences response to antidepressant chronotherapeutics in bipolar patients. AB - Patient diurnal mood fluctuation, sleep characteristics and factors affecting sleep homeostasis predict antidepressant response to the combination of total sleep deprivation and light therapy (TSD + LT). In order to study if chronotype could influence response to TSD+LT, we considered 194 bipolar depressed patients. Severity of depression was rated with Hamilton Depression Rating Scale; perceived mood levels were assessed by a self-administered 10-cm visual analogue scale and chronotype was assessed using the Mornigness-Eveningness Questionnaire. More than 60% of patients resulted responders to treatment with chronotype influencing the antidepressant response with evening type subjects showing higher response rates. PMID- 29764215 TI - Myotonic dystrophytype 1 - report of non-24-h sleep-wake disorder with excessive daytime sleepiness. AB - Myotonic dystrophy (MD) is a neuromuscular disease with myotonia, progressive weakness, and involvement of CNS, heart, and gastrointestinal system. Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 (MD1) is related to sleep breathing diseases, restless leg syndrome, periodic limb movements during sleep and narcoleptic-like phenotype. However, authors highlight a central dysfunction of sleep regulation. We describe a 26-year-old, female, MD1 patient with EDS. Sleep diary/actigraphy evidenced two different circadian periods with values of 1442 and 1522 min. Agomelatine, 50 mg at night, was prescribed with improvement of the circadian rhythm and complaints of sleepiness. The identification of unanticipated causes of EDS, such as circadian rhythm disorders permits an appropriated treatment. As we know, it is the first relate of non-24-h sleep-wake disorder in patient with MD1. Sleep diary and actigraphy could be good options to investigate sleep-wake cycle disorder in patients with MD and EDS. PMID- 29764216 TI - Payroll data based description of working hours in the Danish regions. AB - The aim was to describe the organization of working hours in the Danish regions according to sex, age and calendar year. Based on the Danish Working Hour Database (DWHD), individuals were classified according to schedules: Permanent day (57.8%), evening (1.7%), or night (1.2%); day/evening (22.0%); day/night (6.6%); evening/night (0.6%); and day/evening/night (10.2%). More men (9.1%) than women (5.9%) worked day/night, whereas more women (10.9%) than men (7.4%) worked day/evening/night. More young than older employees worked day/evening/night, and fewer worked permanent day or night. From 2008 to 2015 we observed a trend towards more employees working permanent day and fewer employees working other schedules. Altogether DWHD provides a strong tool in research on working hours. PMID- 29764217 TI - Chronotype and depressive symptoms in students: An investigation of possible mechanisms. AB - Individuals with an evening chronotype are at increased risk of experiencing emotional problems, including depressive symptoms. However, the mechanisms underlying these associations remain unclear. The present study aimed to determine whether poor sleep quality, substance use and cognitive emotion regulation difficulties - which have been implicated in the etiology of depression - mediate the relationship between chronotype and depressive symptoms in a student sample, which was assessed cross-sectionally and after 1 year. A total of 742 Dutch students (75% women, mean age 21.4 +/- 2.9 years) completed the Quick Inventory of Depressive Symptomatology, the Morningness-Eveningness Questionnaire, the Pittsburgh Sleep Quality Index, a questionnaire assessing alcohol, caffeine, tobacco and cannabis use, the Cognitive Emotion Regulation Questionnaire and the Behavioral Inhibition/Activation Scale. A subsample (n = 115) was assessed 1 year later with the same questionnaires. Cross-sectional analyses showed that evening chronotype was associated with more depressive symptoms, adjusted for age and gender (beta = -0.082, p = 0.028). The relationship between eveningness and depressive symptoms was mediated by sleep quality, alcohol consumption and the cognitive emotion regulation strategies of self-blame and positive reappraisal. In longitudinal analyses, eveningness at baseline predicted more depressive symptoms at follow-up, adjusted for age and gender (beta = -0.29, p = 0.002); after additional adjustment for baseline depressive symptoms, chronotype remained a significant predictor of depressive symptoms at T2 (beta = -0.16, t = -2.01, p = 0.047). Only poor sleep quality at follow-up was a significant mediator of this relationship. Even though the effect is small in terms of explained variance, eveningness is related to depressive symptoms and this relationship is mediated by poor sleep quality, also in a prospective design. Self-blame and reduced positive reappraisal are correlated with eveningness. Further research is needed to assess the efficacy of chronotherapeutic interventions for the prevention of depression, in addition to sleep education and cognitive approaches. PMID- 29764218 TI - Coping with shift work-related circadian disruption: A mixed-methods case study on napping and caffeine use in Australian nurses and midwives. AB - INTRODUCTION: Two of the most ubiquitous fatigue countermeasures used by shift working nurses are napping and caffeine. This mixed-methods case study investigated the ways nurses and midwives utilised napping and caffeine countermeasures to cope with shift work, and associated sleep, physical health and psychological health outcomes. MATERIALS AND METHODS: N = 130 Australian shift-working nurses and midwives (mean age = 44 years, range = 21-67, 115F, 15M) completed the Standard Shiftwork Index. A sub-set of 22 nurses and midwives completed an in-depth interview. RESULTS: Nearly 70% of participants reported napping. Those who napped during night shifts had significantly less total sleep time before (F2,75 = 5.5, p < 0.01) and between days off (F2,82 = 3.9, p < 0.05). By the end of the night shift, average hours of time awake were significantly less for prophylactic and on-shift nappers compared to non-nappers (F2,85 = 97.2, p < 0.001). Since starting shift work, the percentage of high caffeine consumers (>400 mg/day) increased from 15% to 33% of the sample and an average of 4 (SD = 2) caffeinated beverages per day was reported. Increased caffeine consumption was associated with greater sleep disturbance (r = 0.26, p < 0.05), psychological distress (r = 0.37, p < 0.001), abdomen pain (r = 0.27, p < 0.05) and weight gain since starting shift work (r = 0.25, p < 0.05). Interviews confirmed these relationships and revealed that caffeine consumption on night shift was common, whereas napping on night shift was dependent on a number of factors including ability to sleep during the day. CONCLUSION: This study identified reasons shift workers chose to engage in or abstain from napping and consuming caffeine, and how these strategies related to poor sleep and health outcomes. Further research is required to help develop recommendations for shift workers regarding napping and caffeine consumption as fatigue countermeasures, whilst taking into account the associated hazards of each strategy. PMID- 29764219 TI - Morningness-eveningness preferences, learning approach and academic achievement of undergraduate medical students. AB - Several studies have focused on determining the effect of chronotype and learning approach on academic achievement separately indicating that morning types have an academic advantage over the evening types and so have the deep learners over the surface learners. But, surprisingly none have assessed the possible relationship between chronotype and learning approach. So, the current study aimed to evaluate this association and their individual influence on academic performance as indicated by the Cumulative Grade Point Average (CGPA) as well as the effect of their interaction on academic performance. The study included 345 undergraduate medical students who responded to reduced Morningness-Eveningness Questionnaire and Biggs Revised Two-Factor Study Process Questionnaire. Morning types indulged in deep learning while evening types in surface learning. Morning and evening types did not differ on academic performance but deep learners had better academic outcomes than their counterparts. The interaction between chronotype and learning approach was significant on determining academic achievement. Our findings gave the impression that chronotype could have an impact on academic performance not directly but indirectly through learning approaches. PMID- 29764220 TI - Wide-range CRP versus high-sensitivity CRP on Roche analyzers: focus on low-grade inflammation ranges and high-sensitivity cardiac troponin T levels. AB - Wide-range C-reactive protein (wr-CRP) has been proposed as an economical alternative to high-sensitivity C-reactive protein (hs-CRP) for the evaluation of low-grade inflammation-associated cardiovascular risk (LGI-CVR). Concomitant values of serum hs-CRP and plasma wr-CRP <=5 mg/L, and high-sensitivity cardiac troponin T (hs-cTnT), all assayed on Roche Diagnostics analyzers over a 1.8-year period, were extracted from a hospital laboratory database. Hs-CRP and wr-CRP values were compared (Bland-Altman method; Deming's correlation), then separately classified into low (<1 mg/L), moderate (1-3 mg/L) and high (>3 mg/L) LGI-CVR ranges for agreement test (kappa), assessed before and after Deming's regression based adjustment of wr-CRP (Adj-wr-CRP). Wr-CRP and hs-CRP values were strongly correlated, with linearity, whether below 5 mg/L (n = 744; tau = 0.933; p < .001) or below 1 mg/L (n = 283; tau = 0.823; p < .001). Overall, wr-CRP values were lower than hs-CRP (mean bias: -0.11 +/- 0.17 mg/L). Agreement was good, with 8.1% of wr-CRP values misclassified compared to hs-CRP (kappa: 0.874), and weakly improved after regression-based adjustment (7.7% reclassified values; kappa: 0.881). Lowering the Adj-wr-CRP cutoff of the moderate LGI-CVR subrange from 1.0 to 0.9 mg/L resulted in an almost perfect agreement (3.2% reclassified data; kappa: 0.950). Hs-cTnT concentration was positively associated with hs-CRP, wr CRP, and Adj-wr-CRP (p < .001). Within each LGI-CVR subrange, hs-cTnT medians were similar regardless of the hs-CRP, wr-CRP or Adj-wr-CRP used for risk classification. Based on hs-cTnT, this study supports the use of wr-CRP as a low cost alternative to hs-CRP for cardiovascular risk evaluation. PMID- 29764221 TI - Permanent night workers' sleep and psychosocial factors in hospital work. A comparison to day and shift work. AB - We aimed to study whether permanent night workers sleep and psychosocial factors differ from day workers and shift workers. The participants (n = 9 312, 92% females, average age 45 years, most commonly nurses and departmental secretaries) were day workers (DW, n = 2 672), shift workers (SW, n = 6 486) and permanent night workers (PNW, n = 154). The Finnish Public Sector survey responses from six hospital districts from 2012 were combined to payroll data from 91 days preceding the survey. The data were analyzed using Pearson chi2-test, one-way ANOVA and multinomial logistic regression analysis. The PNWs reported slightly longer average sleep length than the SWs or the DWs (7:27 vs. 7:13 and 7:10 h, p < 0.001). The PNWs reported least often difficulties in maintaining sleep (p < 0.001) compared to the SWs and the DWs. The PNWs reported most often difficulties to fall asleep and fatigue during free-time (p-values <0.001). The DWs and PNWs experienced less often work-life conflict than the SWs (25 and 26 vs. 38%, p < 0.001). The PNWs were more often satisfied with autonomy at work and appreciation and fair treatment by colleagues than the DWs or the SWs (p < 0.001). The SWs and PNWs reported remarkably higher occurrence of verbal (p < 0.001, OR 3.71, 95% CI 3.23-4.27 and OR 7.67, 95% CI 5.35-10.99, respectively) and physical workplace violence (p < 0.001, OR 9.24, 95% CI 7.17-11.90 and OR 28.34, 95% CI 16.64-43.06, respectively) compared to DWs. Conclusively, PNWs reported contradictory differences in sleep quality compared to DWs and SWs. PNWs are more often satisfied with their colleagues and autonomy at work than DWs or SWs but face workplace violence remarkably more often. PMID- 29764222 TI - Comparative efficacy of once-weekly semaglutide and SGLT-2 inhibitors in type 2 diabetic patients inadequately controlled with metformin monotherapy: a systematic literature review and network meta-analysis. AB - OBJECTIVE: Treatment intensification with additional anti-diabetic agents is recommended in type 2 diabetes (T2D) for patients inadequately controlled on metformin monotherapy. The present network meta-analysis (NMA) evaluated comparative efficacy and safety of once-weekly semaglutide and sodium-glucose co transporter 2 inhibitors (SGLT-2is) in T2D patients inadequately controlled with metformin. METHODS: Randomized controlled trials with >=20 weeks duration were searched in EMBASE, MEDLINE, and CENTRAL. Primary efficacy outcomes were: change from baseline in HbA1c, weight, systolic blood pressure (SBP), post-prandial blood glucose (PPG), and fasting blood glucose (FPG). Treatment effects at 26 (+/ 4) weeks were compared using Bayesian NMAs. Meta-regression and sensitivity analysis were used to address the trial heterogeneity. RESULTS: Eight trials were found eligible for this NMA. Statistically significant reductions in HbA1c were observed with both 1.0 mg and 0.5 mg doses of once-weekly semaglutide when compared to SGLT-2is. The mean differences in change from baseline in HbA1c for once-weekly semaglutide 1.0 mg vs SGLT-2is ranged from -0.66% for canagliflozin 300 mg (95% Credible Intervals [CrI]: -0.82, -0.50%) to -1.11% for dapagliflozin 5 mg (95% CrI: -1.37, -0.85%). Once-weekly semaglutide 1.0 mg performed significantly better than all SGLT-2is of interest in reducing weight and improving FPG levels: however, SBP reduction was not statistically differentiable. Results of sensitivity analysis and meta-regressions aligned with base-case results. NMAs were not possible for PPG and safety outcomes, due to lack of data. CONCLUSION: Once-weekly semaglutide treatment is significantly better compared to SGLT-2is in achieving adequate glycemic control in T2D patients inadequately controlled with metformin monotherapy. PMID- 29764223 TI - Insight into carrageenases: major review of sources, category, property, purification method, structure, and applications. AB - Carrageenan, a kind of linear sulfated polysaccharides consisting of D-galactose with alternating alpha-1,3 and beta-1,4 linkages, has been widely applied in the food and cosmetic industries as thickening and gelling agents due to excellent properties, such as gel-forming ability and chemical stability. It can be degraded by carrageenases to produce a series of even-numbered carrageenan oligosaccharides, which exhibit various fascinating functions, such as anti inflammation, anti-coagulation, anti-tumor, and anti-thrombosis effects. Numerous carrageenases have been isolated and identified from various sources. The enzymes are grouped into three categories, namely kappa-carrageenase, iota-carrageenase, and lambda-carrageenase based on their substrate specificities and primary sequences, respectively. Elucidating the paradigm of the enzyme at every aspect would definitely enhance our understanding of the marine carbon cycling and natural evolution of glycoside hydrolases (GHs). The structural features of these enzymes have been fully illustrated, which will improve our knowledge of its catalytic mechanisms. In this review, we have summarized the recent progresses of major sources, category, and the enzyme's biochemical characteristics. Additionally, structural characteristics and catalytic mechanisms have been introduced in detail. We conclude with a brief discussion of the potential of the carrageenases in possible future applications in preparing functional oligosaccharides with versatile activities. This comprehensive information should be helpful regarding the application of carrageenases. PMID- 29764224 TI - Hemolysis may cause false negative results and underdiagnosis of celiac disease when measuring anti-tissue transglutaminase antibodies in serum by immunoassays. PMID- 29764225 TI - Initial combination therapy with vildagliptin plus metformin in drug-naive patients with T2DM: a 24-week real-life study from Asia. AB - AIMS: To assess the effectiveness and safety of vildagliptin/metformin initial combination therapy in drug-naive patients with type 2 diabetes mellitus (T2DM). METHODS: INITIAL was a 24-week prospective, observational study in T2DM patients with glycated hemoglobin (HbA1c) >= 7.5%, and prescribed vildagliptin/metformin as initial combination therapy. The primary endpoint was change in HbA1c from baseline to week 24. Key secondary endpoints were HbA1c change from baseline to week 12, proportion of patients achieving HbA1c <=7.0%, change in body weight at 12 and 24 weeks, change in HbA1c by sub-groups (baseline HbA1c, age, body mass index [BMI], dosage strength, co-morbidities) from baseline to week 24, and safety. RESULTS: A total of 532 patients were enrolled. The mean age, HbA1c, and BMI were 49.6 +/- 11.27 years, 9.3 +/- 1.57%, and 26.7 +/- 4.50 kg/m2, respectively. Cardiovascular risk factors present at baseline were dyslipidemia (30.1%), hypertension (29.7%), and obesity (20.9%). The mean reductions in HbA1c from baseline to week 12 (-1.6 +/- 1.59%) and 24 (-1.9 +/- 1.70%) were statistically significant (p < .001). At 24 weeks, 39.6% of patients achieved HbA1c <= 7.0%, and the mean body weight reduction was -1.1 +/- 2.62 kg. HbA1c reductions were consistently seen from baseline to weeks 12 and 24 in the various sub-groups. Overall, 48 (9.0%) patients reported adverse events, including one hypoglycemic episode. There were no serious adverse events or deaths. CONCLUSIONS: Overall, in a relatively young drug-naive T2DM Asian study population with high baseline HbA1c and often associated with cardiovascular risk factors, vildagliptin/metformin combination therapy was associated with significant and clinically relevant HbA1c reduction from baseline. This effect was seen at week 12, was maintained over 24 weeks, and was accompanied by good tolerability. PMID- 29764226 TI - Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview. AB - BACKGROUND: The introduction of new disease-modifying therapies (DMTs) for remitting-relapsing multiple sclerosis (RRMS) has considerably transformed the landscape of therapeutic opportunities for this chronic disabling disease. Unlike injectable drugs, oral DMTs promote patient satisfaction and increase therapeutic adherence. REVIEW: This article reviews the salient features about the mode of action, efficacy, safety, and tolerability profile of approved oral DMTs in RRMS, and reviews their place in clinical algorithms in the Middle East and North Africa (MENA) region. A systematic review was conducted using a comprehensive search of MEDLINE, PubMed, Cochrane Database of Systematic Reviews (period January 1, 1995-January 31, 2018). Additional searches of the American Academy of Neurology and European Committee for Treatment and Research in Multiple Sclerosis abstracts from 2012-2017 were performed, in addition to searches of the Food and Drug Administration and European Medicines Agency websites, to obtain relevant safety information on these DMTs. CONCLUSIONS: Four oral DMTs: fingolimod, teriflunomide, dimethyl fumarate, and cladribine have been approved by the regulatory agencies. Based on the number needed to treat (NNT), the potential role of these DMTs in the management of active and highly active or rapidly evolving RRMS is assessed. Finally, the place of the oral DMTs in clinical algorithms in the MENA region is reviewed. PMID- 29764227 TI - Responsiveness of alpha2-adrenoceptor/I1-imidazoline receptor in the rostral ventrolateral medulla to cardiovascular regulation is enhanced in conscious spontaneously hypertensive rat. AB - Stimulation of alpha2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of alpha2-adrenoceptor/I1 imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an alpha2 adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective alpha2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2 methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of alpha2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats. PMID- 29764228 TI - Anti-infective chemoprophylaxis after solid-organ transplantation. AB - INTRODUCTION: Solid organ transplant (SOT) recipients are at high risk of opportunistic infections due to bacterial, viral, fungal, and parasitic pathogens. Anti-infective prophylaxis is a time-tested proven strategy for the prevention of these infections after SOT. Areas covered: The current recommendations for the prevention of surgical site infections, herpes simplex, cytomegalovirus, invasive fungal infections, and selected parasitic diseases are highlighted. Recent peer-reviewed publications on the prevention of infection after SOT were reviewed and their significance was discussed in the context of the current recommendations for preventing infectious complications. Expert commentary: The authors comment on the current approaches to infection prevention in transplant recipients, and discuss how these recommendations are implemented in their clinical practice. Notable findings published during the past year were highlighted, and their clinical significance was interpreted in the context of current recommendations. The evolution of diagnostic and immunologic assays was emphasized, with focus on their potential role in optimizing the current antimicrobial approaches to infection prevention after SOT. PMID- 29764229 TI - Use of MPH hemostatic powder for electrophysiology device implantation reduces postoperative rates of pocket hematoma and infection. AB - BACKGROUND: Surgical site bleeding and infection are potential complications after electrophysiology (EP) device implantation procedures. To date, there is a wide variety of tools for management of intraoperative bleeding but it still remains unclear what methods are preferred. OBJECTIVE: The aim of our study is to compare the rate of complications in patients who underwent cardiac implantable electronic device (CIED) implantation utilizing MPH hemostatic powder to the rate of complications in those patients who underwent standard procedure protocol without MPH hemostatic powder. METHODS: In our study, a new plant-derived microporous polysaccharide hemostatic powder (Arista) was used. A total of 283 consecutive patients were retrospectively studied to assess the rate of complications in patients who underwent CIED implantation with MPH hemostatic powder (n = 77, MPH hemostatic powder) and without (n = 206, no MPH hemostatic powder). Patients were followed for 12 months. RESULTS: The MPH hemostatic powder group of patients had a lower complication rate when compared to no MPH hemostatic powder, 0.3% vs. 1.7% (p < .05), respectively. The rate of device implantation site MPH hematoma in the MPH hemostatic powder group was 0.4%, versus 0.9% in the other group. There were no postoperative infections in the MPH hemostatic powder group versus 3.2% infections in the other group. The main predictor of increased risk of post-procedural complication was the usage of anticoagulation with a hazard ration of 2.7. CONCLUSION: Using MPH hemostatic powder for post-procedural hemostasis was shown to result in a significant reduction in the rate of overall post-procedural complications (a composite endpoint of hematoma and infections), and a trend in reduction of the infections rates and device implantation site hematoma rates. PMID- 29764230 TI - The modern role of antipsychotics for the treatment of agitation and psychosis in Alzheimer's disease. AB - INTRODUCTION: Antipsychotics have long been the mainstay of treatment for agitation and psychosis in Alzheimer's disease. Despite their current use successive studies have shown that they only confer a modest benefit which must be balanced against their well-established serious side effects (extrapyramidal symptoms, stroke, accelerated cognitive decline and mortality). Areas covered: This review outlines the current guidance on antipsychotic usage and the evidence of their continued usage against a backdrop of emerging pharmacological treatments and an increasing emphasis on the importance of non-pharmacological interventions. Expert commentary: The current justification for antipsychotic use in the context of the changing landscape of prescribing and provide a view on the most promising alternative candidates to this class of drug are appraised. PMID- 29764231 TI - Important considerations in pregnant patients with lupus nephritis. AB - INTRODUCTION: In the last few decades, identification of predictors of pregnancy outcome and appropriate pregnancy planning have significantly reduced the maternal and fetal risks in pregnant women with lupus nephritis. Areas covered: Successful pregnancies have been reported even in women with chronic renal disease and renal insufficiency. However, refractory hypertension and severe renal or cardiac chronic dysfunction are still considered contraindications to pregnancy. Pre-term delivery and fetal growth restriction may still occur in SLE patients more frequently than in healthy women, even in pregnancies regularly planned and monitored by a team of nephrologists and gynaecologists. Expert commentary: Stable disease remission is the most important factor for a successful pregnancy. In case of flare-ups of lupus, timely diagnosis and appropriate management may ensure a successful outcome in the majority of pregnant women. The negative role of anti-phospholipid antibodies and of chronic arterial hypertension may be countered with appropriate anticoagulation and anti hypertensive therapy. Further studies are needed to better assess the possible impact of pregnancy on the long-term outcome of lupus nephritis. PMID- 29764232 TI - Biological variables influencing the estimation of reference limits. AB - Reference limits (RLs) are required to evaluate laboratory results for medical decisions. The establishment of RL depends on the pre-analytical and the analytical conditions. Furthermore, biological characteristics of the sub population chosen to provide the reference samples may influence the RL. The most important biological preconditions are gender, age, chronobiological influences, posture, regional and ethnic effects. The influence of these components varies and is often neglected. Therefore, a list of biological variables is collected from the literature and their influence on the estimation of RL is discussed. Biological preconditions must be specified if RL are reported as well for directly as for indirectly estimated RL. The influence of biological variables is especially important if RL established by direct methods are compared with those derived from indirect techniques. Even if these factors are not incorporated into the estimation of RL, their understanding can assist the interpretation of laboratory results of an individual. PMID- 29764233 TI - The value of a registry negative urine pregnancy test for the prediction of a future unintended pregnancy among young women. AB - BACKGROUND: Performance of urine pregnancy test in general adolescents' clinic reflects caregiver or woman's concern that there might be a pregnancy. We aimed to assess whether young-unmarried women in whom a negative urine pregnancy test was registered would be at increased risk of a future unintended pregnancy. METHODS: The study cohort included consecutive women drafted by the Israeli military between 2013 and 2015. The risk of unintended pregnancy was compared between women with a negative urine pregnancy test (n = 2774), the study group, and those in whom urine pregnancy test was not carried out (n = 126,659), the control group. RESULTS: During the study period, 2147 (1.7%) women experienced an unintended pregnancy. The risk of unintended pregnancy was significantly higher in patients in whom a past pregnancy test was negative 4.3% (n = 118), as compared with the control group 1.6% (n = 2028) (odds ratio [OR], 2.7; 95% confidence interval [CI], 2.23-3.26). In multivariate analysis history of a negative pregnancy test results was an independent predictor for a future unintended pregnancy (adjusted OR, 2.0; 95% CI, 1.63-2.52). CONCLUSIONS: A history of a negative pregnancy test among young conscripted women is a significant risk indicator for a future unintended pregnancy. Directed efforts should be made in this particular vulnerable group of patients. PMID- 29764235 TI - Corrigendum. PMID- 29764234 TI - The role of diet in the management of irritable bowel syndrome: a focus on FODMAPs. AB - INTRODUCTION: Irritable bowel syndrome is a common condition that negatively impacts quality of life and results in significant health care expenditures. The vast majority of IBS patients associate their symptoms with eating. Numerous randomized, controlled trials suggest that restriction of dietary FODMAPs improves overall symptoms, abdominal pain, bloating and quality of life in more than half of IBS sufferers. There is emerging data which suggests that other diets (gluten free, guided elimination diets) might also be of benefit to IBS patients. Areas covered: Comprehensive literature review on dietary therapies available for IBS to date and exploration into individualized dietary therapy development based on diagnostic testing. Expert commentary: FODMAP elimination identifies IBS patients who are sensitive to FODMAPs. Responders should undergo a structured reintroduction of foods containing FODMAPs to determine a patient's sensitivities. This information can then be used to create a personalized, less restrictive low FODMAP diet. Future research should focus on the identification of other effective diet therapies focusing on supplementation of functional foods in addition to elimination and the development of biomarker-based diet treatment plans which identify the right treatment for the right patient. PMID- 29764236 TI - Toxic thrombocytopenia during Nerium oleander poisoning. PMID- 29764237 TI - Neuroprotective effect of clavulanic acid on trimethyltin (TMT)-induced cytotoxicity in PC12 cells. AB - Trimethyltin (TMT) is a short-chain trialkyltin with various applications in industry. In addition, it is a known neurotoxin, producing significant and selective neurodegeneration in the limbic system of both human and animals. Recently, effect of clavulanic acid (CA) in nervous system has been mentioned. Therefore, in this study, the role of CA in TMT-induced toxicity in PC12 cells was evaluated. For this study, PC12 cells were cultured and exposed to different concentrations of CA for 24 h. Then, TMT (20 uM) was added to cells. After that, MTT test was performed to assay cytotoxicity. Reactive oxygen species production (ROS) was determined using 2,7-dichlorofluorescein diacetate (DCFH-DA) method. Additionally, the levels of Bax, Bcl-2, caspase-3, CERB and p-CREB proteins were evaluated using Western blot analysis. The exposure of PC12 cells to TMT reduced cell viability, increased intracellular ROS production, elevated Bax/Bcl-2 ratio and enhanced the expression of caspase-3 (Pro and cleaved forms) protein. Pretreatment of cells with CA before TMT, significantly reduced ROS generation, diminished upregulation of proapoptotic Bax protein and attenuated caspase-3 protein expression. In conclusion, CA exhibited significant neuroprotective effects against neurotoxicity of TMT mainly throughout reduction of ROS production and regulation of proteins, which are involved in apoptosis pathway. PMID- 29764238 TI - Successful administration of BI 695501, an adalimumab biosimilar, using an autoinjector (AI): results from a Phase II open-label clinical study (VOLTAIRE(r) RL). AB - BACKGROUND: This study examined the patient handling experience and self injection success of patients with rheumatoid arthritis (RA) administering BI 695501 using an AI. METHODS: This Phase II, 7-week, open-label, interventional study (NCT02636907) included adult patients with moderately to severely active RA not adequately controlled by DMARDs, with no experience of self-injecting with AI/pen. Patients self-injected BI 695501 via AI every 2 weeks in the AI Assessment Period (AAP). Training was given on first injection; AI handling events were recorded. Percentage of self-injection success was the primary end point. Patients could enter a 42-week pre-filled syringe (PFS) safety extension. RESULTS: The AAP was completed by 73/77 patients. In total, 216/218 (99.1%) self injections on Days 15, 29, and 43, were successful. Nine (11.7%) patients had drug-related adverse events (AEs). Two patients reported four serious AEs (SAEs), none drug-related. Overall (in the AAP and PFS extension), 28 (36.4%) patients had drug-related AEs; nine patients had SAEs, one was considered drug-related. Five (6.5%) patients reported injection-site reactions in the AAP; 13 (18.1%) in the PFS extension. CONCLUSIONS: After training, almost all patients were successfully able to self-administer BI 695501 using an AI. BI 695501 via AI (and via PFS in the extension) was well tolerated. CLINICAL TRIAL REGISTRATION: NCT02636907. PMID- 29764239 TI - Horizontal sound localisation accuracy in individuals with conductive hearing loss: effect of the bone conduction implant. AB - OBJECTIVE: The objective of this study is to quantify the effect of the Bone Conduction Implant (BCI) on sound localisation accuracy in subjects with conductive hearing loss (CHL). DESIGN: The subjects were tested in a horizontal sound localisation task in which localisation responses were objectively obtained by eye-tracking, in a prospective, cross-sectional design. The tests were performed unaided and unilaterally aided. The stimulus used had a spectrum similar to female speech and was presented at 63 and 73 dB SPL. The main outcome measure was the error index (EI), ranging from 0 to 1 (perfect to random performance). STUDY SAMPLE: Eleven subjects (aged 21-75 years, five females) with BCI participated in the study. Their mixed/conductive hearing loss was either unilateral (n = 5) or bilateral (n = 6). RESULTS: Three of five subjects (60%) with unilateral CHL, and four of six subjects (67%) with bilateral CHL showed significantly improved sound localisation when using a unilateral BCI (p < .05). For the subjects with bilateral CHL, a distinct linear relation between aided sound localisation and hearing thresholds in the non-implant ear existed at 73 dB SPL (18% decrease in the EI per 10 dB decrease in pure-tone average, r = 0.98, p < .001). CONCLUSIONS: Individuals with mixed/conductive hearing loss may benefit from a unilateral BCI in sound localisation. PMID- 29764240 TI - Ferrous glycinate regulates cell energy metabolism by restrictinghypoxia-induced factor-1alpha expression in human A549 cells. AB - Iron or oxygen regulates the stability of hypoxia inducible factor-1alpha (HIF 1alpha). We investigated whether ferrous glycinate would affect HIF-1alpha accumulation, aerobic glycolysis and mitochondrial energy metabolism in human A549 lung cancer cells. Incubation of A549 cells with ferrous glycinate decreased the protein levels of HIF-1alpha, which was abrogated by proteosome inhibitor, or prolyl hydroxylase inhibitor. The addition of ferrous glycinate decreased protein levels of glucose transporter-1, hexokinase-2, and lactate dehydrogenase A, and decreased pyruvate dehydrogenase kinase-1 (PDK-1) and pyruvate dehydrogenase (PDH) phosphorylation in A549 cells. Ferrous glycinate also increased the expression of the mitochondrial transcription factor A (TFAM), and the mitochondrial protein, cytochrome c oxidase (COX-IV). Silencing of HIF-1alpha expression mimicked the effects of ferrous glycinate on PDK-1, PDH, TFAM and COX IV in A549 cells. Ferrous glycinate increased mitochondrial membrane potential and ATP production in A549 cells. These results suggest that ferrous glycinate may reverse Warburg effect through down regulating HIF-1alpha in A549 cells. PMID- 29764241 TI - Lack of respiratory and ocular effects following acute propylene glycol exposure in healthy humans. AB - OBJECTIVE: Propylene glycol (PG) is a widely used solvent, chemical intermediate and carrier substance for foods, pharmaceutical and cosmetic products. Professional and occupational exposure to PG aerosol and vapor may occur from theatrical smoke generators and during application of deicing products to airplanes. While PG is considered to have low toxicity, the results of one study suggested that brief (1-min) exposure to PG mist elicited ocular and respiratory effects in humans. Because the high concentrations and brief exposure duration in that study were not representative of most occupational exposures, a controlled experimental exposure study was conducted to clarify or confirm the earlier findings. MATERIALS AND METHODS: Ten males and 10 females were exposed to PG aerosol for 4 hrs at 20 and 100 mg/m3 and 30 min at 200 mg/m3. Total PG exposure concentrations (droplets plus gas phase) were 95.6, 442.4 and 871 mg/m3 for the three conditions, respectively. Participants rode a stationary bicycle to simulate physical effort at regular intervals during exposure. Objective measures evaluated in this study included ocular irritation via eye blink task and eye photography and pulmonary function via spirometry, while subjective measures included health symptoms ratings, irritation and dryness ratings of eyes, nose, throat and mouth. RESULTS: Objective measures of pulmonary function and ocular irritation did not reveal any exposure-related changes. Exposure-related changes in symptom reporting were observed; however, the highest symptom ratings did not exceed "slight" on the scale. CONCLUSIONS: The results indicate at the concentrations and acute durations tested, PG does not affect human respiratory function or produce ocular irritation. PMID- 29764242 TI - Morbidity and mortality resulting from acute inhalation exposures to hydrogen fluoride and carbonyl fluoride in rats. AB - OBJECTIVE: Experiments were undertaken to compare morbidity and mortality from brief inhalation exposures to high levels of hydrogen fluoride (HF) and carbonyl fluoride (COF2). METHODS: Rats from both sexes were exposed for durations of 5 and 10 min to nominal concentrations of 10,000 to 57,000 ppm HF or 500 to 10,000 ppm COF2. Respiration was monitored before, during, and after exposure. Animals were observed up to 6 days post-exposure. Terminal blood samples were collected for routine clinical chemistry and hematology. Post-mortem lung fluoride concentrations and lung weights were measured, and gross pathology noted. RESULTS: Both gases produced respiratory depression independent of concentration or exposure duration with minute ventilation decreasing to approximately 50% of baseline. Estimated mixed-gender HF and COF2 10-min LC50's were 48,661 ppm and 1083 ppm, respectively. HF mortalities were generally delayed 3 to 4 days post exposure, while COF2 mortalities occurred during or briefly after exposure. Lung fluoride levels increased with COF2 dose, though elevated lung weights occurred only at the mid-level exposures. Lung weights were unaffected in the HF-exposed animals, and their lung fluoride concentrations were variable. Clinical chemistry and hematology had few consistent trends with the exception of hemoconcentration primarily in HF-exposed males. These short-term exposure experiments conclude that COF2 is nearly 45 times more lethal than HF in rats. CONCLUSIONS: These experiments suggest that hydrolysis to HF cannot solely explain COF2 toxicity. Although HF and COF2 may have common injury mechanisms, they are expressed to markedly different degrees and temporal occurrence. PMID- 29764243 TI - The cost of preterm labor and preterm birth for mothers with uncomplicated pregnancies and their infants in Italy: a retrospective cohort study. AB - BACKGROUND: Preterm labor (PTL)/preterm birth (PTB) impose significant burden on health-care systems. Women with uncomplicated pregnancies at risk of PTL/PTB have not been widely investigated, and published evidence on the costs of these women and their infants in Italy is absent. We aimed to describe women with uncomplicated pregnancies and associated costs for these women and their infants. METHODS: Data on women aged 12-44 years with uncomplicated pregnancies who delivered between 1 September 2009 and 31 December 2014 with PTL diagnosis alone or PTL and PTB were included from four Italian databases. Costs were examined during pregnancy, delivery, and 3 years after delivery for mothers and infants, overall and by gestational age (GA). RESULTS: A total of 3058 mothers linked to 3333 infants were included. Costs during pregnancy were ?1777. Costs during delivery for PTL/PTB mothers and their infants ranged from ?3174 (GA >=37) to ?21007 (GA <28). Combined maternal and infant costs appeared higher for births with lower GAs (<37) in the three-year follow-up. CONCLUSIONS: In Italy, PTL/PTB mothers with uncomplicated pregnancies with infants at lower GAs appeared to incur higher medical costs compared to mothers with infants at higher GAs in all three time periods, with particularly marked differences found when considering mother and infant combined costs. PMID- 29764244 TI - Kinetics and tissue repair process following fractional bipolar radiofrequency treatment. AB - INTRODUCTION: Fractionated radiofrequency (RF) tissue tightening is an alternative method to fractionated laser treatment of skin wrinkling, laxity and acne scars, with reduced risk of scarring or persistent pigmentation. The aim of this study was to evaluate and quantify the wound healing process after RF treatment. MATERIALS AND METHODS: 12 patients were treated with a 64-pin fractional bipolar RF device with 60 mJ/pin applied energy. Confocal laser scanning microscopy (CLSM) examination was performed on day 1, day 2, day 7 and day 14 after treatment. Clinical wound healing process was measured and expressed as a percentage. RESULTS: All patients developed erythema, mild edema and crusts at the treated areas. Two weeks after treatment clinical symptoms resolved. During ablation patients reported moderate pain. Directly after ablation microscopic ablation zones could be detected in CLSM. Measurement of MAZ at epidermis, dermo-epidermal junction and papilary dermis showed a constant diameter until two weeks after treatment. Re-epithelization of the MAZ could be detected already 1 week after treatment. However, 2 weeks after ablation the honeycomb pattern of the epidermis was not yet completely restored. DISCUSSION: Bipolar fractionated RF treatment demonstrates clinically a rapid wound healing response. The subepidermal remodelling process still ongoing after 14 days, showing new granulation tissue. Therefore, treatment intervals of at least 14 days should be recommended to allow completion of the remodelling process. PMID- 29764245 TI - Pembrolizumab versus the standard of care for relapsed and refractory classical Hodgkin's lymphoma progressing after brentuximab vedotin: an indirect treatment comparison. AB - BACKGROUND: There is significant unmet need among patients with relapsed and refractory classical Hodgkin's lymphoma (RRcHL) who have failed multiple lines of therapy, including brentuximab vedotin (BV). Pembrolizumab, an immune checkpoint inhibitor, is one possible treatment solution for this population. RESEARCH METHODS: The objective of this study was to compare progression-free survival (PFS) with standard of care (SOC) versus pembrolizumab in previously BV treated RRcHL patients. A systematic literature review identified one observational study of SOC that was suitable for comparison with KEYNOTE-087, the principal trial of pembrolizumab in this population. Both naive and population-adjusted (using outcomes regression) pairwise indirect comparisons were conducted. The primary analysis included all patients who had failed BV, with a secondary analysis conducted including only those known to have failed BV that was part of definitive treatment. RESULTS: In the primary analysis, SOC was inferior to pembrolizumab in both the unadjusted comparison (HR 5.00 [95% confidence interval (CI) 3.56-7.01]) and the adjusted comparison (HR 6.35 [95% CI 4.04-9.98]). These HRs increased to 5.16 (95% CI 3.61-7.38) and 6.56 (95% CI 4.01-10.72), respectively, in the secondary analysis. CONCLUSION: Pembrolizumab offers a significant improvement in PFS compared to SOC in this population. PMID- 29764246 TI - Randomized, double-blind study on intralesional metronidazole versus intralesional sodium stibogluconate in Leishmania donovani cutaneous leishmaniasis. AB - OBJECTIVES: The aim of our study was to assess the efficacy of intralesional metronidazole on Leishmania donovani cutaneous leishmaniasis (CL). MATERIAL AND METHODS: A total of 188 patients with CL were randomly allocated to intralesional sodium stibogluconate (SSG) and intralesional metronidazole. Cure was assessed after 1-10 injections. Cure rates were assessed for statistical significance using chi-square test at p = .05 level (SLCTR/2014/028). RESULTS: When the treatment cutoff was taken at 100%, the rate of cure for SSG (n = 64, 65.6%) was higher than that of metronidazole (n = 45, 48.9%): statistically significant at p < .05 level (Yates corrected chi-square 5.37, df = 1, p < .5). When the treatment cutoff was taken at >80%, the rate of cure for SSG (n = 75, 77.1%) was also higher than that of metronidazole (n = 58, 63.0%): statistically significant at p < .05 level (Yates corrected chi-square 4.46, df = 1, p < .5). Since it is based on a smaller sample, we estimated the statistical power of the test at a cutoff of 100% [above 80%] results identified a risk ratio of 1.4 [1.3], and a statistical power based on normal approximation at 74.8% [70.0%], respectively. CONCLUSION: This study showed that intralesional SSG has the best response against CL, while intralesional metronidazole was an effective alternative treatment. PMID- 29764247 TI - Survey and analysis for impact factors of psychological distress in HIV-infected pregnant women who continue pregnancy. AB - OBJECTIVE: The objective of this study is to explore the psychological distress of HIV-infected pregnant women who continue pregnancy, and analyze the possible influencing factors. METHODS: A total of 194 HIV-infected pregnant women who continue pregnancy were enrolled for this study by a convenient sampling method during June 2012-August 2016. Participants completed questionnaires including Hospital Anxiety and Depression Scale (HADS), Berger HIV Stigma Scale (BHSS), Distress Thermometer (DT) and Problem List (PL), and to determine the cut-off value of DT in the group. RESULTS: The positive detection rate of psychological distress in the HIV-infected pregnant women who continue pregnancy was 69.1%, and the highest frequency of PL was the emotional problems. The positive detection rate of anxiety was 60.8%, the positive detection rate of depression was 54.1%, and the discrimination score was 113.16 +/- 19.21. Spearman relevant analysis showed that psychological distress score was positively correlated with anxiety, depression and discrimination score (p < .001). Multiple linear regression analysis showed that relationship between husband and wife, family misfortune, Medicaid, chronic disease or high-risk pregnancy, viral load, CD4+T cell count, infection and confidentiality could affect the psychological distress (p < .05). The ideal cut-off value of DT in the group was 5. CONCLUSION: HIV-infected pregnant women who continue pregnancy have higher incidence of psychological distress, and the psychological distress is not inferior to cancer patients. The influencing factors are mainly related to the infection and pregnancy characteristics, and have nothing to do with the general social demographic characteristics. The DT can be used as a screening tool to quickly identify psychological distress of the group. PMID- 29764248 TI - Interprofessional collaboration and the care and management of type 2 diabetic patients in the Middle East: A systematic review. AB - The World Health Organization has ranked the Middle East (ME) as the second most prevalent region globally for type 2 diabetes. Currently, treatment options initiated by physicians focus mainly on pharmaceuticals; however, lifestyle factors also have a tremendous impact on a patient's wellness or illness. A potential solution to this issue is to use an interprofessional team approach when caring for this patient population. The purpose of this systematic review is to look at the present literature involving the use of an interprofessional team approach to the care and maintenance of people with type 2 diabetes in the ME. A PRISMA flow diagram demonstrates the authors' literature search and screening process. The systematic review includes nine studies with mixed-methodologies performed in the Middle Eastern region in an outpatient or primary care setting, and demonstrates the use of interprofessional collaboration when providing care for type 2 diabetic patients. A meta-analysis was not included due to the heterogeneity of the studies; however, data analysis is discussed and results are demonstrated through an extraction tool developed by the authors based on The Cochrane Collaboration's data collection form. The aim of this review is to construct meaning surrounding the use and effectiveness of this collaborative approach with the adult and geriatric Middle Eastern diabetic patient population. Recommendations include continued support from multiple healthcare professions, involving nurses, pharmacists, dietitians, and physicians to promote holistic and patient-centred-care leading to fewer type 2 diabetes complications and hospital admissions. PMID- 29764249 TI - The effects of acrylamide and vitamin E on kidneys in pregnancy: an experimental study. AB - OBJECTIVES: The objective of this study is to investigate possible damages to kidney tissues of pregnant rats and their fetuses exposed to acrylamide during pregnancy and possible protective effects of vitamin E against these damages. MATERIAL AND METHODS: Rats were randomly assigned to five groups of control, corn oil, vitamin E, acrylamide, vitamin E + acrylamide, six pregnant rats in each. Mother and fetal kidney tissues were examined for malondialdehyde (MDA), reductase glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), total antioxidant status (TAS), total oxidant status (TOS), urea, creatine, trace elements such as Zn and Cu in the serum and histopathological analyses were conducted. RESULTS: It was determined that acrylamide, administered during pregnancy, statistically significantly increased MDA and TOS levels, maternal serum urea, creatinine, and Zn levels, while it decreased GSH, TAS, SOD, and CAT levels (p <= .05) when compared with all other groups in the kidney tissues of pregnant rats and their fetuses and caused tubular degeneration, hemorrhage, narrowing, and closure in Bowman's space, and, in the E vitamin group, it statistically significantly increased GSH, TAS, SOD, CAT, urea, creatinine, and Zn levels when compared with other groups and lowered TOS and MDA levels to those of the control group (p < .05) and there were no differences between the groups histologically. CONCLUSION: It was observed that acrylamide administered during pregnancy caused oxidative stress in kidney tissues of mother rats and their fetuses, resulting in tissue damage, and vitamin E application, which is considered to be a powerful antioxidant, inhibited oxidative stress. PMID- 29764251 TI - Future of human mitochondrial DNA editing technologies. AB - ATP and other metabolites, which are necessary for the development, maintenance, and functioning of bodily cells are all synthesized in the mitochondria. Multiple copies of the genome, present within the mitochondria, together with its maternal inheritance, determine the clinical manifestation and spreading of mutations in mitochondrial DNA (mtDNA). The main obstacle in the way of thorough understanding of mitochondrial biology and the development of gene therapy methods for mitochondrial diseases is the absence of systems that allow to directly change mtDNA sequence. Here, we discuss existing methods of manipulating the level of mtDNA heteroplasmy, as well as the latest systems, that could be used in the future as tools for human mitochondrial genome editing. PMID- 29764252 TI - Response properties of the human frequency-following response (FFR) to speech and non-speech sounds: level dependence, adaptation and phase-locking limits. AB - OBJECTIVE: The frequency-following response (FFR) is a neurophonic potential used to assess auditory neural encoding at subcortical stages. Despite the FFR's empirical and clinical utility, basic response properties of this evoked potential remain undefined. DESIGN: We measured FFRs to speech and nonspeech (pure tone, chirp sweeps) stimuli to quantify three key properties of this potential: level-dependence (I/O functions), adaptation and the upper limit of neural phase-locking. STUDY SAMPLE: n = 13 normal-hearing listeners. RESULTS: I/O functions showed FFR amplitude increased with increasing stimulus presentation level between 25 and 80 dB SPL; FFR growth was steeper for tones than speech when measured at the same frequency. FFR latency decreased 4-5 ms with decreasing presentation level from 25 and 80 dB SPL but responses were ~2 ms earlier for speech than tones. FFR amplitudes showed a 50% reduction over 6 min of recording with the strongest adaptation in the first 60 s (250 trials). Estimates of neural synchronisation revealed FFRs contained measurable phase-locking up to ~1200-1300 Hz, slightly higher than the single neuron limit reported in animal models. CONCLUSIONS: Findings detail fundamental response properties that will be important for using FFRs in clinical and empirical applications. PMID- 29764250 TI - Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia. AB - Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment. PMID- 29764253 TI - Anti-Inflammatory Local Effect of Hydroxytyrosol Combined with Pectin-Alginate and Olive Oil on Trinitrobenzene Sulfonic Acid-Induced Colitis in Wistar Rats. AB - PURPOSE: Evaluate the efficacy of hydroxytyrosol in the local treatment of inflammatory colitis. Currently, the existing treatments for inflammatory bowel diseases does not cure the disease and it is associated with high rates of side effects and complications. Hydroxytyrosol is a phenyl-ethyl-alcohol derived from the hydrolysis of oleuropein and present in olive oil, previous studies have demonstrated the anti-inflammatory effect of dietary hydroxytyrosol supplement, with no toxicity. MATERIALS & METHODS: Colitis has been induced by using Trinitrobenzene Sulfonic Acid at 40 rats. They were divided into four groups randomly: 10 rats without treatment; 10 rats with pectin/alginate mixture; 10 rats treated with pectin/alginate + olive oil; 10 rats treated with pectin/alginate + olive oil + hydroxytyrosol. Animals were sacrificed 10 days after induction of trinitrobenzene sulfonic acid, receiving 5 days of continuous treatment. Samples of the rectal area were studied and observed under a microscope to determine the damage by Hunter scoring modified, assessing inflammatory infiltration, number of intestinal walls involved, damage to the mucosal architecture, and edema. RESULTS: When the rectum was analyzed in a global way, nonsignificant differences were observed; however, when performing an individualized analysis, statistically significant differences in the inflammatory infiltrate are present in the samples, which were evaluated using the ANOVA and Student-T statistics. CONCLUSIONS: Local treatment with the natural antioxidant hydroxytyrosol combined with pectin/alginate and olive oil of inflammatory bowel disease has been shown to be effective against inflammatory infiltration of TNBS-induced colitis. PMID- 29764254 TI - Evaluation of a multi-channel algorithm for reducing transient sounds. AB - OBJECTIVE: The objective was to evaluate and select appropriate parameters for a multi-channel transient reduction (MCTR) algorithm for detecting and attenuating transient sounds in speech. DESIGN: In each trial, the same sentence was played twice. A transient sound was presented in both sentences, but its level varied across the two depending on whether or not it had been processed by the MCTR and on the "strength" of the processing. The participant indicated their preference for which one was better and by how much in terms of the balance between the annoyance produced by the transient and the audibility of the transient (they were told that the transient should still be audible). STUDY SAMPLE: Twenty English-speaking participants were tested, 10 with normal hearing and 10 with mild-to-moderate hearing-impairment. Frequency-dependent linear amplification was provided for the latter. RESULTS: The results for both participant groups indicated that sounds processed using the MCTR were preferred over the unprocessed sounds. For the hearing-impaired participants, the medium and strong settings of the MCTR were preferred over the weak setting. CONCLUSIONS: The medium and strong settings of the MCTR reduced the annoyance produced by the transients while maintaining their audibility. PMID- 29764255 TI - Knot positioning during McDonald cervical cerclage, does it make a difference? A cohort study. AB - OBJECTIVE: To study the effect of McDonald cerclage knot position on the different maternal and neonatal outcomes. METHODS: This historical cohort study included women with singleton pregnancy who had a prophylactic McDonald cervical cerclage between 1 May 2010 and 31 September 2017. Maternal and neonatal outcome parameters were compared between the anterior and posterior knot cerclage procedures. The primary outcome measure was the rate of term birth. RESULTS: 550 Women had a prophylactic McDonald cervical cerclage, 306 with anterior knot (Group A) and 244 with posterior knot (Group B). There were no statistically significant differences regarding gestational age (GA) at delivery (36.3 +/- 4.2 versus 35.8 +/- 5.3 for groups A and B respectively), term birth rate, post cerclage cervical length, symptomatic vaginitis, urinary tract infection, difficult cerclage removal and cervical lacerations. Similarly, there were no statistically significant differences as regards the studied neonatal outcomes including take home babies, neonatal intensive care admission, respiratory distress syndrome and neonatal sepsis. Survival analysis on GA at delivery demonstrated no statistically significant difference as regards the proportion of term deliveries in the anterior and posterior knot cerclage groups (log-rank test p-value = .478). CONCLUSIONS: Knot positioning during McDonald cervical cerclage, anteriorly or posteriorly, didn't significantly impact the studied maternal and neonatal outcomes. PMID- 29764256 TI - Strategies for the prediction of late preeclampsia. AB - OBJECTIVES: To evaluate different strategies for the prediction of late preeclampsia. METHODS: A retrospective study was undertaken. A predictive model including maternal parameters (maternal age, maternal BMI, maternal history of preeclampsia or intrauterine growth restriction (PE/IUGR) or maternal chronic disease, and maternal arterial pressure) and mean pulsatility index (PI) of uterine Doppler was created. It was evaluated as an independent model in each trimester, considering 11-13.6 weeks, 20-22.6 weeks and 32-33.6 weeks consequently, and as an integrated model. RESULTS: In the group of late preeclampsia, patients were more obese and had higher incidence of chronic hypertension. Uterine artery pulsatility index (UtA PI) and mean blood pressure were increased in all three trimesters. When evaluating all three models independently, third trimester model performed better than the other two with a sensitivity of 79% and specificity of 82%. The area under the receiver-operating characteristic (ROC) curve (AUC) was 0.86. The integration of all three determinations did not improve third trimester's model. CONCLUSION: Prediction of late preeclampsia at third trimester seems to be possible if maternal characteristics, blood pressure and UtA Doppler are included. PMID- 29764257 TI - Collaboration in the design and delivery of a mental health Recovery College course: experiences of students and tutors. AB - BACKGROUND: Recovery Colleges address mental health challenges using an educative approach underpinned by a collaborative recovery orientated philosophy. Research has been limited with no studies identified reporting research on the design and delivery of a specific course. AIMS: To understand how Recovery College students and tutors experience the design and delivery of a mental health Recovery College course, specifically the "'Building Resilience" course. METHOD: Thematic analysis of qualitative data related to the experience and process of collaboration in recovery college course design and delivery. Data included 13 qualitative individual interviews with course students and tutors and "naturally occurring" data generated through course preparation and delivery. RESULTS: Findings drew attention to the centrality of: prior experience and design related to students, tutors and the course structure; co-delivery related to tutors and co-learner impacts; and to the course methods and environment. CONCLUSIONS: Commitment to collaboration in design and delivery of Recovery College courses can mobilise the diverse experiences and expertise of tutors and students. The environment and methods of learning have a significant impact and should be considered alongside content. Boundaries between people and areas of knowledge and experience that arise can be viewed as sources of creativity that can enrich courses. PMID- 29764258 TI - Reference-less MR thermometry on pre-clinical thiel human cadaver for liver surgery with MRgFUS. AB - PURPOSE: Reference-less MR thermometry can be a promising technique for temperature mapping during liver treatment with Magnetic Resonance-guided Focused Ultrasound (MRgFUS), as it is more robust to breathing motion than Proton Resonance Frequency MR thermometry. However, there is a lack of a pre-clinical model for repeatable testing of reference-less thermometry. The purpose of this work was to verify the explanted Thiel embalmed human liver and whole Thiel embalmed human cadaver for application of a custom made reference-less thermometry algorithm during MRgFUS sonication. MATERIAL AND METHODS: Phase maps were generated during sonication as an input to the algorithm. A square Region-of Interest (ROI) was designed around the heated area. The ROI was interpolated using a two-dimensional polynomial to the surrounding phase map to calculate the background phase. RESULTS: Using the phase information from the images, the temperature rise was measured. Validation of the methodology showed accordance of temperatures with actual temperatures. CONCLUSIONS: The explanted liver and the whole cadaver constitute a promising and feasible model to study reference-less techniques for thermometry during MRgFUS, before clinical trials. PMID- 29764259 TI - Personalised and precision psychiatry: what do the CINP bipolar guidelines suggest? PMID- 29764261 TI - Ragweed sublingual tablet immunotherapy: part II - practical considerations and pertinent issues. AB - Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both efficacious and safe for the treatment of respiratory allergies such as allergic rhinoconjunctivitis or allergic asthma. Based on the clinical documentation of SLIT ragweed tablets, they have gained marketing authorization in the USA by the US FDA in 2014 for adult patients. Following clinical data from (pivotal) multicenter Phase II and III trials as performed in the USA and Canada and real life experience after registration in 2014, SLIT ragweed tablets can be recommended as efficacious and safe treatment option with disease modifying potential when adequately indicated and performed. Therefore, several practical issues should be considered for treating ragweed allergic patients with these tablets. This second part of a thorough review on ragweed SLIT tablets addresses important clinical questions which should be taken into account by the subscribing practitioner before initiation and during the treatment. PMID- 29764260 TI - Measuring fatigue and stress in laparoscopic surgery: validity and reliability of the star-track test. AB - BACKGROUND: The star-track test has been assessed as valid and reliable to measure manual dexterity in the context of open surgery. We aimed to determine the construct validity and test-retest reliability of the star-track test for manual dexterity in a laparoscopic setting. MATERIAL AND METHODS: The star-track test was performed in a laparoscopic box trainer. To determine construct validity an open-label, randomized four-period crossover trial was conducted. Alongside a baseline (non-interventional) measurement, interventions involved: physical fatigue, mental stress and a combination of these. The test-retest trial involved two separate (non-interventional) measurements. The primary outcome measures were accuracy, speed and manual dexterity (the integrated measure of accuracy and speed). RESULTS: Participants made significantly more errors when physically fatigued, whereas participants performed the test significantly slower when mentally stressed. Manual dexterity was significantly affected in the case of combined intervention. High test-retest reliability was found for errors (ICC = 0.90) and completion time (ICC = 0.64). Fair test-retest reliability for the integrated measure was found (ICC = 0.37). CONCLUSION: The star-track test is a valid and reliable tool to evaluate the effect of physical fatigue and/or mental stress on the characteristics of manual dexterity in a laparoscopic setting. PMID- 29764262 TI - IgPro20, the Polyneuropathy and Treatment with Hizentra(r) study (PATH), and the treatment of chronic inflammatory demyelinating polyradiculoneuropathy with subcutaneous IgG. AB - Subcutaneous IgG (SCIG) administration may be preferred over the intravenous route (IVIG) in chronic inflammatory demyelinating polyneuropathy (CIDP) because it minimizes 'end of cycle' treatment-related fluctuations, reduces systemic adverse effects, improves convenience/quality of life and potentially lowers overall costs. Early reports of the use of highly concentrated SCIG preparations suggested they were effective and well-tolerated in chronic inflammatory demyelinating polyneuropathy. This was confirmed in the Polyneuropathy and Treatment with Hizentra(r) study of 172 subjects randomized to receive maintenance therapy with placebo or one of two doses of IgPro20 (20% IgG stabilized with L-Proline) for 6 months. Risk of relapse was reduced by SCIG in a dose-related manner as compared with placebo. A total of 88% of polyneuropathy and treatment with hizentra subjects felt the subcutaneous method was 'easy to learn'. Local adverse events were mostly mild or moderate, and systemic adverse events were infrequent. Some patients may prefer maintenance therapy with SCIG over IVIG. PMID- 29764263 TI - Categorical perception of lexical tones in native Mandarin-speaking listeners with sensorineural hearing loss. AB - BACKGROUND: Categorical perception (CP) of lexical tones was examined in normal hearing (NH) people, but it was unclear whether lexical tones can be perceived categorically in sensorineural hearing loss (SNHL) people. OBJECTIVES: To explore the characteristic of lexical tone perception in native Mandarin speakers with SNHL. MATERIALS AND METHODS: Three types of continuum (Tone1/Tone2, Tone1/Tone4 and Tone2/Tone3) were constructed and each of them includes 15 stimuli which were resynthesized by applying the pitch-synchronous overlap and add (PSOLA) method implemented in Praat to the same Mandarin syllable, /a/, with a high-level tone produced by a female speaker. Forty native Mandarin NH speakers and 23 native Mandarin speakers with mild to moderate SNHL were recruited. A two alternative forced-choice identification task was used to acquire the tonal perceptual data. RESULTS: All tone perception curves owns the characteristic of CP in SNHL subjects. All tone perception curves were S-shape in SNHL subjects same as those in NH subjects. No significant difference of each continuum was observed between SNHL and NH. CONCLUSIONS: CP of lexical tone perception could be observed in native Mandarin speakers with mild to moderate SNHL. The slight damage in the peripheral auditory system did not change characteristic of lexical tone perception. PMID- 29764264 TI - Clermont-Ferrand versus Vectec uterine manipulator for total laparoscopic hysterectomy. AB - OBJECTIVE: To compare the operation time and performance of two uterine manipulators used for total laparoscopic hysterectomy (TLH). MATERIAL AND METHODS: Design: Retrospective cohort analysis. Design classification: Canadian Task Force Classification II-2. SETTING: Tertiary-care university-based teaching hospital and academic affiliated private hospital. PATIENTS: All consecutive patients who underwent for TLH between January 2014 and June 2017. All operations were performed by two expert endoscopic surgeons using one of the following uterine manipulators depending on surgeon preferences: Clermont-Ferrand (CF) or Vectec (VT) MAUT60. Patients were excluded if additional surgeries such as urogynecological procedures were performed, TLH was converted to laparotomy prior to colpotomy, and when their operation records could not be obtained. A total of 169 patients were added to final analysis. Operation time, colpotomy time and the subjective performance of manipulators such as movement of the uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were evaluated by watching un-edited operation videos. RESULTS: A total of 169 patients (83 patients in CF group; 86 patients in VT group) were included in the final analysis. Patients' baseline characteristics were comparable between groups. Operation time and time required for colpotomy were significantly shorter in the VT group. Lateral movements of the manipulators and elevation of the uterus were better with VT compared to CF (p = .001 for both). Compared to the CF, VT was superior for visualization of the vaginal fornices (p = .004) and maintenance of pneumoperitoneum (p < .001). Both surgeons had perfect agreement on the performance grading of manipulators (p < .001, Kappa values were between 0.86-0.92). There was no difference between groups in estimated blood loss and duration of hospital stay. Reinsertion or the need to change the manipulator was not required in either group. No pelvic or vaginal abscess, cuff cellulitis, dehiscence, or hematoma formations were noted. CONCLUSION: Laparoscopic hysterectomy assisted with the VT uterine manipulator is associated with shorter operation and colpotomy time. Furthermore, the movements of uterus, visualization of the vaginal fornices, and maintenance of pneumoperitoneum were significantly better with VT compared to the CF manipulator. PMID- 29764265 TI - Use of Methadone to Reverse Opioid Escalation in a Patient With Surgical Pain. AB - Acute pain is a prevalent issue for patients recovering from surgical procedures. Methadone has been recognized as a unique option for treatment of surgical pain due to its multiple mechanisms of analgesia and its potential to decrease tolerance to other opioids. Studies of methadone use in postoperative settings are sparse in part due to safety concerns, such as complex pharmacokinetics, risk of respiratory depression, and association with arrhythmias. In this case study of a 70-year-old male with postsurgical abdominal pain, methadone utilization over a period of 9 days resulted in patient-reported analgesia and aided in de escalating overall opioid use. More studies are needed to develop guidance on how methadone can be used to relieve pain following surgical procedures. PMID- 29764267 TI - Clinical narratives in residency education: Exploration of the learning process. AB - BACKGROUND: Post-professional residency educational programs aim to advance the knowledge and skills of therapists in a clinical specialty area, however, little is known about the process, outcomes, or effectiveness of residency education. PURPOSE: The purpose of this study was to use narrative as a teaching and learning tool to gain insight into the progressive development of the residents' learning process. DESIGN: Qualitative methods including a retrospective analysis of residents' narratives were used to explore the professional development and thought process of residents. METHODS: Six physical therapy residents wrote reflective narratives across 4 time placements during their one-year residency. Qualitative content analysis was used to analyze the data for types of reflection across time frames and to construct themes based on meaning statements. RESULTS: Four main themes evolved from the residents' clinical narratives: 1) developing clinical reasoning skills; 2) developing professional formation and identity; 3) moral agency; and 4) emerging characteristics of expertise Conclusions: In this study, clinical narratives served as a pedagogical tool to enhance aspects of clinical expertise. The utilization of clinical narrative may be used as one tool to help to create reflective practitioners with improved skills foundational to clinical practice. PMID- 29764266 TI - Impact of paliperidone palmitate one-month formulation on relapse prevention in patients with schizophrenia: A post-hoc analysis of a one-year, open-label study stratified by medication adherence. AB - BACKGROUND: Limited data are available to help identify patients with schizophrenia who are most likely to benefit from long-acting injectable antipsychotics. AIM: To investigate the efficacy of long-acting injectable antipsychotic paliperidone palmitate one-month formulation for preventing relapses, factors influencing time to first relapse, and the effect of different antipsychotic adherence levels on time to first relapse in Chinese patients with schizophrenia. METHODS: This was a post-hoc analysis from an open-label, single arm study of stable patients (Positive and Negative Syndrome Scale total score <70; n=367) receiving paliperidone palmitate one-month formulation at the end of an acute 13-week treatment phase, who entered a naturalistic one-year follow-up period, either continuing with flexibly dosed paliperidone palmitate one-month formulation (75-150 mg eq.) or switching to another antipsychotic(s). RESULTS: There were 362/367 patients (age=31.4+/-10.75 years) included in the analysis of time to first relapse (primary outcome) and 327/362 patients (39/327, poor antipsychotic adherence (<80%)) willing to receive antipsychotics were included in the exposure/adherence analysis. Overall, 84.6% (95% confidence interval=79.2 88.7) patients remained relapse-free. Poor adherence during follow-up (hazard ratio=2.97, 95% confidence interval=1.48-5.98, p=0.002) and frequent hospitalizations in the previous year (hazard ratio=1.29, 95% confidence interval=1.02-1.62, p=0.03) were associated with a significant risk of shorter time to first relapse in the univariate analysis. In patients with poor adherence, 'no use' (hazard ratio=13.13, 95% confidence interval=1.33-129.96, p=0.03) and 'interrupted use' (hazard ratio=11.04, 95% confidence interval=1.03 118.60, p=0.047) of paliperidone palmitate one-month formulation (vs continued use) showed a significantly higher risk of relapse; this was not observed in patients with good (>=80%) antipsychotic adherence. No new safety concerns were identified. CONCLUSION: Continued use of paliperidone palmitate one-month formulation/long-acting injectable antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence. PMID- 29764268 TI - Magnesium as an intrinsic component of human otoconia. AB - OBJECTIVES: To investigate morphology changes of artificial otoconia (CGC) in the presence of magnesium during growth under in vitro conditions. METHODS: Investigating human otoconia by environmental scanning electron microscope and determining their magnesium content by energy-dispersive X-ray microanalysis (EDX). Comparing structural and morphological data of human and artificial otoconia (CGC, Ca1Mg0) without and with magnesium substitution (Ca1-xMgx). RESULTS: EDX- and X-ray data reveals that the inorganic component in human otoconia consists of calcite containing a minor amount of magnesium substitution (Ca1-xMgx). CGC containing magnesium (length 397.0 +/- 146.4 um, diameter 325.6 +/- 100.1 um) are slimmer and significantly smaller (p < .01) than pure CGC (length 548.6 +/- 160 um, diameter 373.0 +/- 110.4 um) and reveal a significant influence on the final morphology. The length/diameter ratio is significantly higher by incorporation of magnesium into CGC (1.84 +/- 0.25 um versus 1.48 +/- 0.11 um in pure CGC, p < .01), which brings the overall shape to a close relationship with human otoconia (1.98 +/- 0.08 um). CONCLUSIONS: Magnesium is an intrinsic component of human otoconia by partial substitution of calcium in the calcite crystal structure (Ca1-xMgx) and affects the development of the shape of artificial otoconia (calcite gelatin composites, CGC). PMID- 29764269 TI - Factors influencing the use of outcome measures in knee osteoarthritis: A mixed method study of physiotherapists in Nigeria. AB - BACKGROUND: Osteoarthritis (OA) of the knee constitutes a significant proportion of musculoskeletal disorders managed in physiotherapy clinics worldwide. Best practice guidelines in the management of OA ensure the use of outcome measures. AIM: This study explored the factors influencing the use of outcome measures in management of patients with knee OA among physiotherapists in southwestern Nigeria. METHODS: Mixed method design was used that involved a cross-sectional survey of 77 purposively selected physiotherapists and a focus group discussion with another 6 physiotherapists. RESULTS: Participants (48 males, 29 females) were aged 35.3 +/- 7.3 years. Fifty-two (67.5%) participants reported the use of outcome measures in the treatment of the patients with knee OA. The perceived barriers reported were lack of time/heavy workload (55.9%); lack of standardization of outcome measures (45%); lack of motivation (36.4%); and nonavailability of outcome measures in the clinic (36.4%). Reported perceived facilitators include interest/need to track patient's progress and ethical practice (87.1%); familiarity with outcome measures (87.0%); and understanding of the benefits of using outcome measures (87.0%). CONCLUSION: There is a need to establish good organizational structure focusing on the use of outcome measures in practice and development of a concessional toolkit of short and easily applicable instruments with user description. PMID- 29764270 TI - Drunk decisions: Alcohol shifts choice from habitual towards goal-directed control in adolescent intermediate-risk drinkers. AB - BACKGROUND: Studies in humans and animals suggest a shift from goal-directed to habitual decision-making in addiction. We therefore tested whether acute alcohol administration reduces goal-directed and promotes habitual decision-making, and whether these effects are moderated by self-reported drinking problems. METHODS: Fifty-three socially drinking males completed the two-step task in a randomised crossover design while receiving an intravenous infusion of ethanol (blood alcohol level=80 mg%), or placebo. To minimise potential bias by long-standing heavy drinking and subsequent neuropsychological impairment, we tested 18- to 19 year-old adolescents. RESULTS: Alcohol administration consistently reduced habitual, model-free decisions, while its effects on goal-directed, model-based behaviour varied as a function of drinking problems measured with the Alcohol Use Disorders Identification Test. While adolescents with low risk for drinking problems (scoring <8) exhibited an alcohol-induced numerical reduction in goal directed choices, intermediate-risk drinkers showed a shift away from habitual towards goal-directed decision-making, such that alcohol possibly even improved their performance. CONCLUSIONS: We assume that alcohol disrupted basic cognitive functions underlying habitual and goal-directed decisions in low-risk drinkers, thereby enhancing hasty choices. Further, we speculate that intermediate-risk drinkers benefited from alcohol as a negative reinforcer that reduced unpleasant emotional states, possibly displaying a novel risk factor for drinking in adolescence. PMID- 29764271 TI - Effect of intratympanic steroid injection in light cupula. AB - OBJECTIVE: To evaluate the effects of intratympanic steroid injection (ITS) in light cupula. METHODS: A total of 47 patients showing persistent geotropic direction-changing positional nystagmus with null point (light cupula) were randomly classified into three groups: ITS (n = 15), vestibular suppressant (VS, n = 16) and canalith repositioning procedure (CRP, n = 16). Positional nystagmus and dizziness severity by dizziness handicap inventory (DHI) and visual analogue scale (VAS) were conducted before and 3 d and 1 week after first treatment to compare the effect of each treatment. RESULTS: DHI and VAS scores had decreased after each treatment; however, there were no differences among the three groups. A week after the first treatment, 7, 6 and 7 patients showed resolution of direction-changing positional nystagmus (DCPN) in the ITS, CRP and VS groups, respectively. There were no significant differences between the three groups. In the ITS group only, however, reversal of the stronger side on head roll test was observed in 6 patients, and 2 of them showed resolution of DCPN at the third day. CONCLUSIONS: ITS was not effective for patients with light cupula at 1-week follow-up. However, some patients in the ITS group showed resolution of DCPN at earlier follow-up. PMID- 29764272 TI - Does S100B have a potential role in affective disorders? A literature review. AB - BACKGROUND: S100B is a calcium-binding protein located in glial cells; it is regarded as a potential biomarker in affective disorders. AIM: To review the literature investigating the role of S100B in patients with affective disorders. METHOD: A systematic review of original English language studies investigating S100B in serum, cerebrospinal fluid, plasma and lymphocytes, in patients with affective disorders, was conducted. The literature search was conducted within the PubMed database. Effect sizes were calculated to adjust for systematic measurement effects. RESULTS: Twenty studies were included, with a total of 1292 participants. Of these, 398 patients had or have had depressive disorder, 301 patients had bipolar disorder and 593 were healthy controls. S100B levels in serum were consistently elevated in studies with statistically significant results which investigated acute affective episodes (comprising major depressive episode in major depressive disorder, and both manic and depressive episodes in patients with bipolar disorder), in comparison to healthy controls. There were few studies assessing S100B levels in cerebrospinal fluid, plasma or lymphocytes, and these had inconsistent results. CONCLUSION: The results indicated that elevated S100B levels might be associated with mood episodes in affective disorders. However, the role of S100B, and its possible impact in affective disorders, requires further investigation and at the present S100B does not have a role as clinically biomarker in affective disorder. Future longitudinal multicentre studies with larger transdiagnostic real life patient cohorts are warranted. PMID- 29764273 TI - The Association Between Sequential Organ Failure Assessment Scores and Mortality in Patients With Sepsis During the First Week: The JSEPTIC DIC Study. AB - OBJECTIVE: Predicting prognosis is a complex process, particularly in patients with severe sepsis or septic shock. This study aimed to determine the relationship between the Sequential Organ Failure Assessment (SOFA) scores for individual organs during the first week of admission and the in-hospital mortality in patients with sepsis. METHODS: This study was a post hoc evaluation of the Japan Septic Disseminated Intravascular Coagulation study and included patients admitted to 42 intensive care units in Japan for severe sepsis or septic shock, between January 2011 and December 2013. We assessed the relationship between the organ and total SOFA scores on days 1, 3, and 7 following admission and the in-hospital mortality using logistic regression analysis. RESULTS: We evaluated 2732 patients and found the in-hospital mortality rate was 29.1%. The mean age of the patients (standard deviation) was 70.5 (14.1) years, and the major primary site of infection was the abdomen (33.6%). The central nervous system (CNS) SOFA score exhibited the strongest relationship with mortality on days 1 (adjusted odds ratio [aOR]: 1.49, 95% confidence interval [CI]: 1.40 1.59), 3 (aOR: 1.75, 95% CI: 1.62-1.89), and 7 (aOR: 1.93, 95% CI: 1.77-2.10). The coagulation SOFA scores showed a weak correlation with mortality on day 1, but a strong correlation with mortality on day 7 (aOR: 2.04, 95% CI: 1.87-2.24). CONCLUSIONS: The CNS SOFA scores were associated with mortality in patients with severe sepsis on days 1, 3, and 7 following hospitalization. The coagulation SOFA score was associated with mortality on day 7. In clinical situations, the CNS SOFA scores during the acute phase and the CNS SOFA and coagulation SOFA scores during the subsequent phases should be evaluated in order to determine patient prognosis. PMID- 29764274 TI - Delayed transmastoid facial nerve decompression surgery in patients with Ramsay Hunt syndrome presenting with neurophysiologically complete paralysis. AB - OBJECTIVES: To determine the efficacy of delayed transmastoid facial nerve decompression in patients with Ramsay Hunt Syndrome (RHS) presenting with complete facial paralysis. METHODS: Twenty-five RHS patients with complete facial nerve paralysis presenting electroneuronographic (ENoG) degeneration >=90% underwent transmastoid facial nerve decompression more than 3 weeks after the onset of paralysis. The principal features measured were 12 months pre- and post operative House-Brackmann (HB) grades and the presence of a direct intraoperative neural response (INR) prior to decompression procedure. Correlations between these parameters, and the time between symptom onset and surgery (within or later than 30 and 50 d) were statistically analyzed. RESULTS: Of the 25 patients 13 (52%) exhibited good recovery (HB grade I or II) at 12 months-post-operatively. The timing of decompression generally did not significantly influence outcome but patients treated within 50 d of symptom onset enjoyed better outcomes than those treated later (p = .047). The presence of an INR significantly influenced outcomes (p = .0003). CONCLUSIONS: The success of delayed transmastoid facial nerve decompression in RHS patients was not affected between 25-30 and 30-40 d from symptom onset but was compromised when the delay was >50 d. The presence or absence of an INR was a good predictor of post-operative prognosis. PMID- 29764275 TI - The experience of type 2 diabetes self-management in adults with intellectual disabilities and their caregivers: A review of the literature using meta aggregative synthesis and an appraisal of rigor. AB - People with intellectual disabilities (ID) experience significant barriers to diabetes self-management (DSM), yet there remains a paucity of research within this population. An overview of the literature on people with ID and their caregivers' experiences of living with and self-managing type 2 diabetes is provided. Meta-aggregative methods were adopted to synthesize results, and an appraisal was reported of rigor. A total of eight studies met the inclusion criteria and four themes were extracted: (i) "Frustration over lifestyle adjustments," (ii) "Limited understanding and inadequate educational resources," (iii) "Limited training and knowledge in staff," and (iv) "Potential for effective DSM with appropriate support." Current support is inadequate to meet the needs of people with ID and their caregivers self-managing diabetes. Structured education to improve health literacy and diabetes knowledge in people with ID is required, together with training for caregivers which leads to a culture of nurturing autonomy. PMID- 29764276 TI - 'It's our everyday life' - The perspectives of persons with intellectual disabilities in Norway. AB - This study illuminates how adults with intellectual disabilities understand and describe their everyday life and its shortcomings when it comes to equal rights in the context of Norwegian community living. An inclusive research design, including nine persons with mild intellectual disability, two university researchers and two intellectual disability nurses from the municipality, was undertaken. An inductive thematic analysis of data identified three key themes: everyday life - context, rhythm and structure, social participation and staff - an ambiguous part of everyday life. Results show that service provision had institutional qualities; participants experienced lack of information and reduced possibilities for social inclusion and community participation like everyone else. More attention on the role of policy development, support staff and leadership, in relation to facilitating an everyday life with more user involvement, social inclusion and community participation of people needing support, is essential. Participatory, appreciative, action and reflection in workshops for persons with intellectual disabilities and support staff represent a promising approach to promote the voices and interests of persons with intellectual disabilities. Accessible abstract This article tells you about the everyday life of people with intellectual disabilities living in Norway. Nine people with intellectual disabilities worked together with two university researchers and two intellectual disability nurses in the community, in workshops. The people with intellectual disabilities liked to have their own apartment and going to work every day. They said that they wanted more social participation with friends and more participation in activities in the community, just like everyone else. They wanted to be treated with more respect by their staff. All participants in the project saw great value in working together and some of them are working together in a new project about involvement in the improvement of support services for people with intellectual disabilities. PMID- 29764277 TI - Human papillomavirus (HPV) is absent in branchial cleft cysts of the neck distinguishing them from HPV positive cystic metastasis. AB - BACKGROUND: Distinguishing branchial cleft cysts (BCCs) from cystic metastases of a human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) is challenging. Fine needle aspirates (FNAs) from cystic metastasis may be non-representative, while reactive squamous cells from BCC can be atypic. Based on cytology and with the support of HPV DNA positivity many centers treat cystic metastasis oncological and thus patients are spared neck dissection. To do so safely, one must investigate whether HPV DNA and p16INK4a overexpression is found exclusively in cystic metastases and not in BCC. PATIENTS AND METHODS: DNA was extracted from formalin fixed paraffin embedded (FFPE) surgically resected BCCs from 112 patients diagnosed 2007-2015 at Karolinska University Hospital and amplified by PCR. A multiplex bead-based assay used to detect 27 HPV-types and p16INK4a expression was analyzed by immunohistochemistry (IHC). RESULTS: All 112 BCCs were HPV DNA negative, and of 105 BCCs possible to evaluate for p16INK4a, none overexpressed p16INK4a. CONCLUSIONS: HPV DNA and p16INK4a overexpression were absent in BCCs. Lack of HPV DNA and p16 protein overexpression in BCCs is helpful to discriminate benign BCCs from HPV+ OPSCC metastasis. HPV testing definitely has a role in the diagnostics of cystic masses of the neck. PMID- 29764278 TI - Eating well, living well and weight management: A co-produced semi-qualitative study of barriers and facilitators experienced by adults with intellectual disabilities. AB - Adults with intellectual disabilities in England experience health inequalities. They are more likely than their non-disabled peers to be obese and at risk of serious medical conditions such as heart disease, stroke and type 2 diabetes. This semi-qualitative study engaged adults with intellectual disabilities in a co production process to explore their perceived barriers and facilitators to eating well, living well and weight management. Nineteen participants with intellectual disabilities took part in four focus groups and one wider group discussion. They were supported by eight of their carers or support workers. Several barriers were identified including personal income restrictions, carers' and support workers' unmet training needs, a lack of accessible information, inaccessible services and societal barriers such as the widespread advertising of less healthy foodstuffs. A key theme of frustration with barriers emerged from analysis of participants' responses. Practical solutions suggested by participants included provision of clear and accessible healthy lifestyle information, reasonable adjustments to services, training, 'buddying' support systems or schemes and collaborative working to improve policy and practice. PMID- 29764279 TI - The Modified Telephone-Administered Minnesota Cognitive Acuity Screen for Mild Cognitive Impairment. AB - OBJECTIVE: This study aimed to compare the sensitivity and specificity of a modified version of the Minnesota Cognitive Acuity Screen (MCAS-m), by adding learning and recognition memory components, to the original version MCAS to distinguish amnestic mild cognitive impairment (aMCI) from healthy controls (HCs). METHODS/DESIGN: A total of 30 individuals with aMCI and 30 HCs underwent neuropsychological testing, neurologic examination, laboratory, and brain imaging tests. Once diagnosis was confirmed, participants completed the MCAS and MCAS-m in counterbalanced order. RESULTS: The average administration time was 12.6 minutes for the MCAS and 13.5 minutes for the MCAS-m. Receiver operating characteristic curve analyses showed that the MCAS-m demonstrated 97% sensitivity and 97% specificity for distinguishing between aMCI and HC versus 97% and 87%, respectively, for the original MCAS in this sample. CONCLUSIONS: Both the MCAS and the MCAS-m were highly sensitive when distinguishing between normal cognition and aMCI; however, the MCAS-m demonstrated a 10% increase in specificity compared to the original version. Improved specificity is particularly relevant to screening in larger community samples with lower base rates of MCI than clinic populations. This modified screening measure presents a brief and cost-effective tool for identifying MCI. Given the risk of progression from aMCI to Alzheimer disease dementia (AD), the MCAS-m represents a modest improvement in telephone administered methods for the early detection of AD. PMID- 29764280 TI - Association between psychological factors, socio-demographic conditions, oral habits and anterior open bite in five-year-old children. AB - OBJECTIVE: The aim of the present study was to evaluate association between psychological factors, socio-demographic conditions, oral habits and anterior open bite in five-year-old preschool children. MATERIALS AND METHODS: A cross sectional study was conducted with 764 pairs of children and parents/caregivers in preschools. The parents/caregivers answered questionnaires addressing oral health-related quality of life (OHRQoL), sense of coherence, locus of control, oral habits and socio-demographic characteristics. The children answered a self report questionnaire addressing OHRQoL and were submitted to a clinical examination for the anterior open bite by examiners. Descriptive analysis was conducted, followed by Poisson's regression analysis. RESULTS: The prevalence of anterior open bite was 15.2%. The following variables remained significantly associated with anterior open bite: pacifier use (PR = 7.09; 95% CI: 4.06-12.39), attending a public preschool (PR = 2.40; 95% CI: 1.68-3.43), digit sucking (PR = 2.15; 95% CI: 1.27-3.62), greater number of residents in the home (PR = 1.67; 95% CI: 1.18-2.36) and impact on OHRQoL according to child's report (PR = 1.56; 95% CI: 1.11-2.20). CONCLUSIONS: Anterior open bite was associated with OHRQoL according to the children's reports. Moreover, attending a public preschool, a greater number of residents in the home, digit sucking and pacifier sucking were associated with this type of malocclusion. PMID- 29764281 TI - Parent Experiences and Preferences When Dysmelia Is Identified During the Prenatal and Perinatal Periods: A Qualitative Study Into Family Nursing Care for Rare Diseases. AB - Several rare diseases are regularly identified during the prenatal and perinatal periods, including dysmelia. How these are communicated to parents has a marked emotional impact, but minimal research has investigated this. The purpose of this study was to explore parent experiences and preferences when their baby was diagnosed with dysmelia. Mothers and fathers were interviewed. Data were analyzed using thematic analysis. The overriding emotion parents experienced was shock, but the extent of this was influenced by several factors including their previous experience of disability. Four key needs of parents were identified, including the need for signposting to peer support organizations, for information, for sensitive communication, and for a plan regarding their child's care. Parents wanted immediate information provision and signposting to peer support, and for discussions regarding possible causes of the dysmelia or termination (in the case of prenatal identification) to be delayed until they had processed the news. PMID- 29764282 TI - Animal-Assisted Therapy in Elderly Patients: Evidence and Controversies in Dementia and Psychiatric Disorders and Future Perspectives in Other Neurological Diseases. AB - Animal-assisted therapy (AAT) includes a set of nonpharmacological interventions aimed at improving human health through the use of trained or untrained animals. In recent decades, AAT has been trialed for different neurological and psychiatric disorders. In patients with dementia, interaction with animals seems to have a positive influence on aggressiveness and anxiety and to ameliorate quality of life and relationship skills. In psychiatric patients, AAT seems to increase motivation and self-esteem, improve prosocial conduct, and decrease behavioral problems. The aim of this study is to review the literature on AAT for elderly people with dementia and psychiatric disorders. Other fields of possible application for AAT are suggested. PMID- 29764283 TI - Minimally invasive thread trigger digit release: a preliminary report on 34 digits of the adult hands. AB - The trigger finger release was performed in 34 digits (11 thumbs and 23 fingers) of 24 patients through the thread transecting technique with the tip-to-tip approach, in which a 22-gauge needle inserts into a 18-gauge needle when both needles are inside the hand, guiding the 22-gauge needle to exit the hand at the same access point of 18-gauge needle. We prospectively evaluated the effectiveness and functional recovery of these patients. In all 34 digits, triggering and locking were resolved, and complete extension and flexion occurred immediately following the release. There were no complications, such as incomplete release, neurovascular or flexor tendon or A2 pulley injury, infection, or tendon bow-stringing. Patients did not require prescription pain medications. Most patients used their hands to meet their basic living needs the same day of the procedure. The hand function evaluated with the Quick Disabilities of the Arm, Shoulder and Hand questionnaire, and scored 4 within 3 months. Level of evidence: II. PMID- 29764285 TI - Expressions of Eotaxin-3, Interleukin-5, and Eosinophil-Derived Neurotoxin in Chronic Subdural Hematoma Fluids. AB - Eosinophils induce inflammation by releasing cytokines and cytotoxic granule proteins. Infiltration of eosinophilic granulocytes occurs in the outer membrane of chronic subdural hematomas (CSDHs). Eosinophils play an important role in the growth of CSDHs. However, the manner in which eosinophils accumulate within CSDH fluid remains undetermined. In the current study, we assessed the expression of eosinophil chemoattractants in CSDH fluids according to growth stage of CSDHs and examined the correlation between the two. CSDH fluids were obtained from 38 patients during trepanation surgery. Ecalectin, eotaxin-3, interleukin-5 (IL-5), and eosinophil-derived neurotoxin (EDN) concentrations were measured using enzyme linked immunosorbent assay kits. For use as controls, serum samples were collected from 5 healthy adults, and cerebrospinal fluid (CSF) samples were collected from 5 adults with unruptured aneurysms. The percentage of eosinophils (%eosinophil) in CSDH fluids was calculated using Giemsa staining. Concentrations of ecalectin, eotaxin-3, IL-5, and EDN were nearly equivalent in serum and CSF samples; however, their concentrations were high in CSDH fluids. In particular, ecalectin and EDN levels in CSDH fluids were significantly higher than those in serum and CSF. Levels of eotaxin-3, IL-5, EDN, and %eosinophil were significantly higher in laminar type of CSDH, whereas that of ecalectin was not. The correlations between eotaxin-3 and IL-5, IL-5 and EDN, and EDN and %eosinophil were statistically significant (p < 0.01). Our data suggest that eotaxin-3 is a chemoattractant of eosinophils. IL-5 induces the activation of eosinophils subsequent to degranulation of EDN into CSDH fluids. These factors may serve as novel therapeutic targets for managing CSDH. PMID- 29764286 TI - Environmental evaluation of flocculation efficiency in the separation of the microalgal biomass of Scenedesmus sp. cultivated in full-scale photobioreactors. AB - In this paper the environmental evaluation of the separation process of the microalgal biomass Scenedesmus sp. from full-scale photobioreactors was carried out at the Research and Development Nucleus for Sustainable Energy (NPDEAS), with different flocculants (iron sulfate - FeCl3, sodium hydroxide - NaOH, calcium hydroxide - Ca(OH)2 and aluminum sulphate Al2(SO4)3, by means of the life cycle assessment (LCA) methodology, using the SimaPro 7.3 software. Furthermore, the flocculation efficiency by means of optical density (OD) was also evaluated. The results indicated that FeCl3 and Al2(SO4)3 were highly effective for the recovery of microalgal biomass, greater than 95%. Though, when FeCl3 was used, there was an immediate change in color to the biomass after the orange colored salt was added, typical with the presence of iron, which may compromise the biomass use according to its purpose and Al2(SO4)3 is associated with the occurrence of Alzheimer's disease, restricting the application of biomass recovered through this process for nutritional purposes, for example. Therefore, it was observed that sodium hydroxide is an efficient flocculant, promoting recovery around 93.5% for the ideal concentration of 144 mg per liter. It had the best environmental profile among the compared flocculant agents, since it did not cause visible changes in the biomass or compromise its use and had less impact in relation to acidification, eutrophication, global warming and human toxicity, among others. Thus, the results indicate that it is important to consider both flocculation efficiency aspects and environmental impacts to identify the best flocculants on an industrial scale, to optimize the process, with lower amount of flocculant and obtain the maximum biomass recovery and decrease the impact on the extraction, production, treatment and reuse of these chemical compounds to the environment. However, more studies are needed in order to evaluate energy efficiency of the process coupled with other microalgal biomass recovery technologies. In addition, studies with natural flocculants, other polymers and changes in pH are also needed, as these are produced in a more sustainable way than synthetic organic polymers and have the potential to generate a biomass free of undesirable contaminants. PMID- 29764287 TI - Function of a membrane-embedded domain evolutionarily multiplied in the GPI lipid anchor pathway proteins PIG-B, PIG-M, PIG-U, PIG-W, PIG-V, and PIG-Z. AB - Distant homology relationships among proteins with many transmembrane regions (TMs) are difficult to detect as they are clouded by the TMs' hydrophobic compositional bias and mutational divergence in connecting loops. In the case of several GPI lipid anchor biosynthesis pathway components, the hidden evolutionary signal can be revealed with dissectHMMER, a sequence similarity search tool focusing on fold-critical, high complexity sequence segments. We find that a sequence module with 10 TMs in PIG-W, described as acyl transferase, is homologous to PIG-U, a transamidase subunit without characterized molecular function, and to mannosyltransferases PIG-B, PIG-M, PIG-V and PIG-Z. We conclude that this new, membrane-embedded domain named BindGPILA functions as the unit for recognizing, binding and stabilizing the GPI lipid anchor in a modification competent form as this appears the only functional aspect shared among all proteins. Thus, PIG-U's likely molecular function is shuttling/presenting the anchor in a productive conformation to the transamidase complex. PMID- 29764288 TI - Occurrence of parent and substituted polycyclic aromatic hydrocarbons in typical wastewater treatment plants and effluent receiving rivers of Beijing, and risk assessment. AB - Sixteen polycyclic aromatic hydrocarbons (PAHs) and some typical substituted polycyclic aromatic hydrocarbons (SPAHs) were investigated in wastewater treatment plants (WWTPs) and effluent effluent-receiving rivers in order to indentify the elimination of these compounds in WWTPs, as well as the potantial potential risk in the effluent-receiving rivers. The concentrations of SigmaPAHs in the total phase (combined dissolved and adsorbed phases) in influent were between 944.1 and 1246.5 ng.L-1, and SigmaSPAHs, including methyl PAHs (MPAHs) and oxygenated PAHs (OPAHs), between 684.9 and 844.9 ng.L-1. Regarding the SPAHs, the concentrations of SigmaOPAHs (312.3 ng.L-1) were higher than those of SigmaMPAHs (271.8 ng.L-1). The total removal efficiencies of PAHs in the biological treatment processes were between 59% and 68%, and those of SPAHs were a little lower (58-65%). The removal efficiency in the adsorbed phase was higher than in the dissolved phase. The concentrations of PAHs and SPAHs in the effluent were a little higher than in the receiving river. According to a PAH risk assessment of the effluent, 7 carcinogenic PAHs accounted for a relatively high proportion. Benzo[a]pyrene (BaP) and Dibenz[a,h]anthracene (DBA) were major contributors to the TEQs in the effluent of WWTPs, which should be taken into consideration. PMID- 29764284 TI - Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility. AB - The hypothalamic-pituitary-adrenal (HPA) axis is the major neuroendocrine axis regulating homeostasis in mammals. Glucocorticoid hormones are rapidly synthesized and secreted from the adrenal gland in response to stress. In addition, under basal conditions glucocorticoids are released rhythmically with both a circadian and an ultradian (pulsatile) pattern. These rhythms are important not only for normal function of glucocorticoid target organs, but also for the HPA axis responses to stress. Several studies have shown that disruption of glucocorticoid rhythms is associated with disease both in humans and in rodents. In this review, we will discuss our knowledge of the negative feedback mechanisms that regulate basal ultradian synthesis and secretion of glucocorticoids, including the role of glucocorticoid and mineralocorticoid receptors and their chaperone protein FKBP51. Moreover, in light of recent findings, we will also discuss the importance of intra-adrenal glucocorticoid receptor signaling in regulating glucocorticoid synthesis. PMID- 29764289 TI - Divergent Induction of Branched-Chain Aminotransferases and Phosphorylation of Branched Chain Keto-Acid Dehydrogenase Is a Potential Mechanism Coupling Branched Chain Keto-Acid-Mediated-Astrocyte Activation to Branched-Chain Amino Acid Depletion-Mediated Cognitive Deficit after Traumatic Brain Injury. AB - Deficient branched-chain amino acids (BCAAs) are implicated in cognitive dysfunction after traumatic brain injury (TBI). The mechanism remains unknown. BCAAs are catabolized by neuron-specific cytosolic and astrocyte-specific mitochondrial branched-chain aminotransferases (BCATc, BCATm) to generate glutamate and branched-chain keto-acids (BCKAs) that are metabolized by the mitochondrial branched-chain keto-acid dehydrogenase (BCKD) whose activity is regulated by its phosphorylation state. BCKD phosphorylation by BCKD kinase (BCKDK) inactivates BCKD and cause neurocognitive dysfunction, whereas dephosphorylation by specific phosphatase restores BCKD activity. Real-time polymerase chain reaction showed rapidly and significantly decreased BCATc messenger RNA (mRNA) levels, but significantly increased BCATm mRNA level post CCI (controlled cortical impact). BCKD and BCKDK mRNA decreased significantly immediately after CCI-induced TBI (CCI) in the rat. Phosphorylated BCKD proteins (pBCKD) increased significantly in the ipsilateral-CCI hemisphere. Immunohistochemistry revealed significantly increased pBCKD proteins in ipsilateral astrocytes post-CCI. BCKD protein expression is higher in primarily cultured cortical neurons than in astrocytes, whereas pBCKD protein level is higher in astrocytes than in cortical neurons. Transforming growth factor beta treatment (10 MUg/mL for 48 h) significantly increased pBCKD protein expression in astrocytes, whereas glutamate treatment (25 MUM for 24 h) significantly decreased pBCKD protein in neurons. Because increased pBCKD would lead to increased BCKA accumulation, BCKA-mediated astrocyte activation, cell death, and cognitive dysfunction as found in maple syrup urine disease; thus, TBI may potentially induce cognitive deficit through diverting BCAA from glutamate production in neurons to BCKA production in astrocytes through the pBCKD dependent mechanism. PMID- 29764290 TI - Unstable footwear as a speed-dependent noise-based training gear to exercise inverted pendulum motion during walking. AB - Previous research on unstable footwear has suggested that it may induce mechanical noise during walking. The purpose of this study was to explore whether unstable footwear could be considered as a noise-based training gear to exercise body center of mass (CoM) motion during walking. Ground reaction forces were collected among 24 healthy young women walking at speeds between 3 and 6 km h-1 with control running shoes and unstable rocker-bottom shoes. The external mechanical work, the recovery of mechanical energy of the CoM during and within the step cycles, and the phase shift between potential and kinetic energy curves of the CoM were computed. Our findings support the idea that unstable rocker bottom footwear could serve as a speed-dependent noise-based training gear to exercise CoM motion during walking. At slow speed, it acts as a stochastic resonance or facilitator that reduces external mechanical work; whereas at brisk speed it acts as a constraint that increases external mechanical work and could mimic a downhill slope. PMID- 29764291 TI - A 12-year retrospective review of bullous systemic lupus erythematosus in cutaneous and systemic lupus erythematosus patients. PMID- 29764292 TI - Evaluation of performance testing of different rapid diagnostic kits in comparison with EIAs to validate detection of hepatitis B virus among high risk group in Nigeria. AB - BACKGROUND: Hepatitis B virus (HBV) causes chronic liver-associated diseases and its early detection is of high public health importance. Its diagnosis is mainly based on immunological assays among which Enzyme-Linked Immunosorbent Assay (ELISA) and rapid tests are the most common and widespread methods. However, a major challenge is the discordance of results of any two laboratory assays which cannot be easily resolved. Therefore, this study was designed to evaluate the validity and reliability of commercially available five rapid test kits in comparison with two Enzyme Immunoassays (EIAs) in Nigeria using hepatitis B surface antigen as a reference marker. METHODS: A total of 100 sera of previously diagnosed consenting HBV-positive patients from private diagnostic laboratories in Ibadan between March and August, 2011 were tested using two EIA and five rapid commercially available HBV test kits in Nigeria. Data were analyzed by SPSS version 15, while bivariate and multivariate analyses were carried out to identify associations at P < 0.05 considered significant. RESULTS: Overall, the sensitivity rates of the two EIA kits were 100% and 99.9% (95% confidence interval [CI] = 98.9-99.7) with specificity of 100% and 99.9% (95% CI = 98.9 99.7), respectively. The sensitivity of the five rapid test kits ranged from 97.5% (95% CI = 96.4-97.6) to 98.9% (95% CI = 97.9-99.9) with specificity of 80% (95% CI = 79.3-80.9) to 90% (95% CI = 89.2-91.0). Also, the positive predictive value ranged from 88% (95% CI = 88.2-89.9) to 89% (95% CI = 88.2-89.9), while the negative predictive value ranged from 80% (95% CI = 79.3-80.9) to 90% (95% CI = 89.2-91.0) for the five rapid kits. However, that of the two EIAs ranged from 99.9% (98.9-99.7) to 100%. Further analysis showed significant (P = 0.033) variations in the sensitivity and specificity of the EIAs and rapid test kits. CONCLUSIONS: The results from this study have clearly revealed the challenges of diagnosis of HBV infections in Nigeria. This study has also demonstrated that the sensitivity of most of the rapid test kits may not be adequate when compared with EIA for early detection of HBV infections. The implications of possible misdiagnosis on the various intervention strategies that rely predominantly on correct HBV status of an individual are enormous. Therefore, there is the need to further compliment the use of rapid test kits with EIAs for HBV control in Nigeria. PMID- 29764294 TI - Impact of Muslim opinion leaders' training of healthcare providers on the uptake of MNCH services in Northern Nigeria. AB - Expanding access to maternal, newborn and child health (MNCH) services in traditional societies is a public health challenge, often complicated by cultural and religious beliefs about what is permitted or not permitted within a faith group. This is particularly true in the Muslim majority North of Nigeria, where deep suspicions of Western public health programmes, coupled with failing and underfunded health system, have led to the emergence of a new generation of Muslim Opinion Leaders (MOLs) with counter-narratives against family planning, immunisation and nutrition programmes. This paper reports on an innovative project implemented under the Saving Lives at Birth global partnership programme, where conservative MOLs transformed as champions were engaged as health communicators to train health providers on correct religious precepts related to MNCH. A matched subject type of study design was used to compare healthcare providers' performance in control and intervention health facilities. The result indicates a significant difference both in perception and in practices between healthcare providers in intervention and control facilities, with respect to MNCH uptake. This paper highlights the need for renewed focus on engaging faith leaders and organisations in health communication and service delivery and presents a model of sustainable engagement of champions in MNCH. PMID- 29764295 TI - Acoustic Sources of Accent in Second Language Japanese Speech. AB - This study reports an exploratory analysis of the acoustic characteristics of second language (L2) speech which give rise to the perception of a foreign accent. Japanese speech samples were collected from American English and Mandarin Chinese speakers ( n = 16 in each group) studying Japanese. The L2 participants and native speakers ( n = 10) provided speech samples modeling after six short sentences. Segmental (vowels and stops) and prosodic features (rhythm, tone, and fluency) were examined. Native Japanese listeners ( n = 10) rated the samples with regard to degrees of foreign accent. The analyses predicting accent ratings based on the acoustic measurements indicated that one of the prosodic features in particular, tone (defined as high and low patterns of pitch accent and intonation in this study), plays an important role in robustly predicting accent rating in L2 Japanese across the two first language (L1) backgrounds. These results were consistent with the prediction based on phonological and phonetic comparisons between Japanese and English, as well as Japanese and Mandarin Chinese. The results also revealed L1-specific predictors of perceived accent in Japanese. The findings of this study contribute to the growing literature that examines sources of perceived foreign accent. PMID- 29764293 TI - Can a brief biologically-based psychoeducational intervention reduce stigma and increase help-seeking intentions for depression in young people? A randomised controlled trial. AB - There is disagreement in the literature as to whether biological attribution increases or decreases stigma. This study investigated the effect of an online biological intervention on stigma and help-seeking intentions for depression among adolescents. A three-arm, pre-post test, double-blind randomised controlled trial (RCT) was used to compare the effects of a biological and a psychosocial intervention delivered online. Participants comprised secondary school students (N = 327) aged 16-19 years. Outcome measures included anticipated self-stigma for depression (primary), personal stigma, help-seeking intention for depression, and biological and psychosocial attribution. Neither the biological nor the psychosocial educational intervention significantly reduced anticipated self stigma or personal stigma for depression relative to the control. However, a small increase in help-seeking intention for depression relative to the control was found for the biological educational condition. The study was undertaken over a single session and it is unknown whether the intervention effect on help seeking intentions was sustained or would translate into help-seeking behaviour. A brief online biological education intervention did not alter stigma, but did promote a small increase in help-seeking intentions for depression among adolescents. This type of intervention may be a practical means for facilitating help-seeking among adolescents with current or future depression treatment needs. PMID- 29764296 TI - 'Medicine doesn't cure my worries': Understanding the drivers of mental distress in older Nepalese women living in the UK. AB - The mental health of migrant communities is an important public health concern. A growing body of literature suggests that social and cultural determinants of health significantly contribute to the mental health and wellbeing of older migrants in their host countries. Despite the increasing population of older Nepalese migrants in the UK, there is little research exploring the mental health needs of this community. This article explores older Nepalese women's experiences of drivers of mental distress in London. Data was collected using in-depth interviews with 20 older Nepalese women living in the London Borough of Greenwich. Grounded thematic analysis of women's narratives identified six overarching factors contributing to their emotional distress that pose potential risks to their mental health: absence of family, language barriers, housing problems, physical illness, lack of appropriate support, fears of death, and inadequate financial resources. In many cases, the impact of these factors was experienced in combination rather than isolation, often influenced by cultural dynamics. Findings highlight that re-settlement in the absence of family is at the heart of emotional challenges for older Nepalese women. The paper concludes with a series of recommendations for supporting processes of settlement to mitigate this risk among older Nepalese women in the UK. PMID- 29764297 TI - Identifying dyslexia risk for sport-related concussion management: Sensitivity and specificity of self-report and rapid naming. AB - BACKGROUND: Dyslexia is the most common type of learning disability and studies have shown that student-athletes with learning disabilities sustain more concussions than their non-affected peers. However, current methods of dyslexia identification in college students are potentially invalid because they rely on students to self-report formal dyslexia diagnoses. METHODS: To test the accuracy of self-report against two alternative methods of dyslexia screening, 94 college students completed three dyslexia symptom inventories, two rapid naming (RAN) tasks, and a standard word reading measure. RESULTS: Reliability was acceptable for screening purposes on the inventories (alpha =.70, -.72), and excellent for RAN (alpha = .91, -.94). Specificity was acceptable (82.5%), but sensitivity was low (14.3%) when students self-reported suspected diagnoses of reading impairment. Sensitivity and specificity were higher for the digit RAN task (71 and 98%, respectively) compared to the letter RAN task (57 and 90%). Sensitivity (92.7%) and specificity (92.5%) were optimal when a cut-score of >=27 seconds was used. A binary logistic regression showed digit RAN alone significantly predicted whether students were classified as typical or inefficient readers, p< .001, whereas the most reliable dyslexia inventory alone did not, p=.284. Including inventories along with RAN provided no additional predictive value. CONCLUSION: Self-report inventories missed many cases of inefficient word reading. The digit RAN task classified 93.6% of the cases correctly compared to 72.3% for self report inventory. Thus, we recommend that neuropsychologists working with college concussion management programs add to their baseline screening protocols the digit RAN task, which can be completed in less than one minute. PMID- 29764298 TI - The distal radius palmar cortical angle in adolescent versus adult populations. AB - PURPOSE: Volar distal radius plates are pre-contoured to aid restoration of anatomy during open reduction internal fixation of distal radius fractures. Incorrectly contoured plates can result in malreduction, leading to malunion, pain, and loss of function. The purpose of this study was to investigate whether adolescent distal radius anatomy on the palmar cortical surface differs from that in adults, in order to determine whether adult plates are suitable for use in adolescents. METHODS: Lateral wrist radiographs were used to measure the distal radius palmar cortical angle (PCA) in adolescent age groups (12-13, 14-15, and 16 17 years old) and compared to a skeletally mature control group (30-50 years old). Two assessors measured 423 PCAs twice. RESULTS: There was a statistically significant ( p = <0.05) difference in the PCA of the control group compared to each adolescent group. The mean PCA for both males and females decreased as age increased (increasing curvature of the volar distal radius with age). The mean PCA (male/female) was 164.38 degrees /163.00 degrees in ages 12-13, 162.14 degrees /160.92 degrees in ages 14-15, 157.52 degrees /158.18 degrees in ages 16-17, and 149.65 degrees /154.03 degrees in the control group aged 30-50 years. Agreement between assessors was high with an Interclass correlation coefficient (ICC) of 0.97. CONCLUSION: There is a statistically significant and potentially clinically important difference in the curvature of the distal radius volar cortex between adolescents and adults. This difference persists even in the 16-17 age group. As the PCA curvature is significantly greater in adults compared to adolescents, plates pre-contoured for adults may lead to malreduction of distal radius fractures into flexion in adolescent patients. PMID- 29764299 TI - Efficacy of sufficient operation view by ring-shaped thread counter traction for safer duodenal ESD. AB - BACKGROUND: Duodenal ESD is considered especially difficult with perforation and bleeding. This study assessed safer duodenal ESD procedures, especially with regard to obtaining a good operation view using a ring-thread method and closure of a post-ESD artificial ulcer. METHODS: From 2013 to 2015, 17 patients who were diagnosed with duodenal adenoma or early duodenal cancer >20 mm in diameter underwent conventional ESD (C group). From 2016 to 2017, 12 patients underwent ring-shaped thread counter traction ESD with hemoclips and/or Over-The-Scope Clip (OTSC) (Ovesco Endoscopy GmbH, Tuebingen, Germany) closure of post ESD artificial ulcer (ring group). An observational study between the C group and Ring group was conducted. The primary outcome was perforation events during ESD (UMIN000026184). RESULTS: There was a significant difference in perforation during ESD with five cases vs. 0 case in C and ring groups (p = .038). For bleeding that needed to be coagulated by forceps during ESD, there was a significant difference with four cases in the C group (p = .07). The total procedure time was 96.6 +/- 28.2 and 72.8 +/- 24.2 (min) with a significant difference (p = .027). CONCLUSIONS: Ring shaped thread counter traction makes the most difficult duodenal ESD safer and easier without complications. PMID- 29764300 TI - Integrating Implicit Leadership Theories, Leader-Member Exchange, Self-Efficacy, and Attachment Theory to Predict Job Performance. AB - The impact of implicit leadership theories on performance and the mechanism linking them have received insufficient theoretical and research attention. Drawing on Bandura's social cognitive theory, the present study contributes theory through examining the assertion that higher congruence between followers' implicit leadership theory and the characteristics of supervisors enhance job performance through higher quality of leader-member exchange and self-efficacy. Moreover, in the proposed model, attachment insecurity was considered as the antecedent of the congruence and leader-member exchange in addition to the moderator of the relationship between them. Capitalizing upon Structural Equation Modeling (SEM), this study tested the model in a field study using a sample of employees in knowledge-oriented firms in Iran. The results suggest that the congruence between followers' implicit leadership theory and the characteristics of supervisors does not directly impact performance and leader-member exchange and self-efficacy are the full mediators. The results also showed that attachment insecurity is the predictor of neither the congruence nor the leader-member exchange. Additionally, attachment insecurity moderates the relationship between these two variables in a way that when attachment insecurity is high, the congruence has more positive impact on leader-member exchange. PMID- 29764301 TI - Bioinspired, biocompatible and peptide-decorated silk fibroin coatings for enhanced osteogenesis of bioinert implant. AB - In this study, we develop an osteopromotive polyetheretherketone (PEEK) implant decorated with silk fibroin and bone forming peptide, in which the surface of bioinert PEEK implant is firstly sulfonated to form a three-dimensional, porous topography and then is functionalized with silk fibroin via spin-coating process and peptide decoration. The bio-test results show that cells on the functional bioinert implants exhibit better cell adhesion, proliferation and spreading, when compared with the uncoated ones. Moreover, the peptide-decorated silk fibroin coatings have ability to hasten the osteogenic differentiation and maturation of osteoblast-like cells. Our findings show the potential of the functional PEEK implants with superior bioactivity and osteoinductive property in orthopedics and dentistry. Besides, the facile, bioinspired, osteopromotive modification strategy can be used in other orthopedic and dental implants, such as titanium, zirconium dioxide. PMID- 29764303 TI - Relief from intractable phantom pain by combining psilocybin and mirror visual feedback (MVF). AB - AL's leg was amputated resulting in phantom-limb pain (PLP). (1) When a volunteer placed her foot on or near the phantom - touching it evoked organized sensations in corresponding locations on AL's phantom. (2) Mirror-visual-feedback (MVF) relieved PLP, as did, "phantom massage". (3) Psilocybin-MVF pairing produced synergistic effects, complete elimination of PLP, and reduction in paroxysmal episodes. (4) Touching the volunteer's leg where AL previously had external fixators, evoked sensation of nails boring through the leg. Using a "telescoping" nail, we created the illusion of a nail being removed with corresponding pain relief. (5) Artificial flames produced warmth in the phantom. PMID- 29764304 TI - Prednisolone-loaded coatable polyvinyl alcohol/alginate hydrogel for the treatment of atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting pruritic, erythema, edema, excoriation, and thickening of the skin, and thus leads to significant impairment in the patient's life. The objective of this study is to develop a steroid drug [prednisolone (PS)]-loaded coatable hydrogel for the treatment of AD. PS-loaded hydrogel was composed of PVA entrapped in mildly crosslinked alginate (PS-loaded PVA/ALG hydrogel). The PS concentration to be loaded in the hydrogel that takes AD efficacy without cell necrosis was determined from the cytotoxicity test using human dermal fibroblasts. The in vivo therapeutic effects for AD of the PS-loaded PVA/ALG hydrogel were evaluated using 2, 4-dinitrochlorobenzene (DNCB)-induced AD Balb/c mouse model. The PS-loaded hydrogel has an appropriate viscosity for easy application and provides moisturizing effect on the skin, as well as anti-inflammatory effect by the sustained drug release for effective AD treatment. From the animal study, the PS loaded PVA/ALG hydrogel showed effective suppressions of various AD symptoms such as ear edema, pruritus, high IgE levels, epidermal swelling, and mast cell infiltration. Our findings suggest that the PS-loaded coatable PVA/ALG hydrogel may be a promising therapeutic system for the treatment of AD. PMID- 29764302 TI - Anandamide and endocannabinoid system: an attractive therapeutic approach for cardiovascular disease. AB - Cardiovascular disease is currently not adequately managed and has become one of the main causes of morbidity and mortality worldwide. Current therapies are inadequate in terms of preventing its progression. There are several limitations, such as poor oral bioavailability, side effects, low adherence to treatment, and high dosage frequency of formulations due to the short half-life of the active ingredients used, among others. This review aims to highlight the most relevant aspects of the relationship between the cardiovascular system and the endocannabinoid system, with special attention to the possible translational effect of the use of anandamide in cardiovascular health. The deep and detailed knowledge of this interaction, not always beneficial, and that for years has gone unnoticed, is essential for the development of new therapies. We discuss the most recent and representative results obtained in the field of basic research, referring to the aforementioned subject, emphasizing fundamentally the main role of nitric oxide, renal physiology and its deregulation in pathological processes. PMID- 29764305 TI - Pregnancy experiences of women in rural Romania: understanding ethnic and socioeconomic disparities. AB - Women in rural Romania face significant health disadvantages. This qualitative pilot study describes the structural disadvantage experienced during pregnancy by women in rural Romania, focusing on the lived experiences of Roma women. We explore how women in rural communities experience pregnancy, their interactions with the healthcare system, and the role that ethnic and social factors play in pregnancy and childbearing. We conducted 42 semi-structured interviews with health and other professionals, seven narrative interviews with Roma and non-Roma women and a focus group with Roma women. Data were analysed using thematic analysis. We identified intersectional factors associated with women's pregnancy experiences: women perceiving pregnancy as both unplanned and wanted, joyful, and normal; women's and professionals' differing prenatal care perceptions; transport and cost related barriers to care; socioeconomic and ethnic discrimination; and facilitators to care such as social support, having a health mediator and having a doctor. Talking directly with professionals and Roma and non-Roma women helped us understand these many factors, how they are interconnected, and how we can work towards improving the pregnancy experiences of Roma women in rural Romania. PMID- 29764306 TI - Long-Term Complications of Appendectomy: A Systematic Review. AB - BACKGROUND AND AIMS: Appendectomy is a common surgical procedure, but no overview of the long-term consequences exists. Our aim was to systematically review the long-term complications of appendectomy for acute appendicitis. MATERIALS AND METHODS: This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A protocol was registered on PROSPERO (CRD42017064662). The databases PubMed and EMBASE were searched for original reports on appendectomy with n >= 500 and follow-up >30 days. The surgical outcomes were ileus and incisional hernia; other outcomes were inflammatory bowel disease, cancer, fertility, and mortality. RESULTS: We included 37 studies. The pooled estimate of the ileus prevalence was 1.0% over a follow-up period of 4.6 (range, 0.5-15) years. Regarding incisional hernia, we found a pooled estimate of 0.7% prevalence within a follow-up period of 6.5 (range, 1.9-10) years. Ulcerative colitis had a pooled estimate of 0.15% prevalence in the appendectomy group and 0.19% in controls. The opposite pattern was found regarding Crohn's disease with a pooled estimate of 0.20% prevalence in the appendectomy group and 0.12% in controls. No clear pattern was found regarding most of the examined cancers in appendectomy groups compared with background populations. Pregnancy rates increased after appendicitis compared with controls in most studies. Mortality was low after appendectomy. CONCLUSION: Appendectomy had a low prevalence of long-term surgical complications. We did not find any significant other long-term complications, though the prevalence of Crohn's disease was higher and the prevalence of ulcerative colitis was lower after appendectomy than in controls. Appendectomy did not impair fertility. PMID- 29764307 TI - Effectiveness of Hydrodilatation in Adhesive Capsulitis of Shoulder: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND AIMS:: Even though hydrodilatation has been used for 50 years, the evidence on its effectiveness is not clear. Only one earlier review has strictly focused on this treatment method. The aims of this study are to evaluate the evidence on the effectiveness of hydrodilatation in treatment of adhesive capsulitis and, if appropriate, to assess the correlation between the effects of this procedure and the amount of fluid injected. MATERIALS AND METHODS:: A literature search on MEDLINE, Embase, Scopus, Cochrane Central, Web of Science, and CINAHL databases was done; random-effects meta-analysis and meta-regression were employed; and cost-effectiveness and safeness analyses were left outside the scope of the review. RESULTS:: Of the 270 records identified through search, 12 studies were included in qualitative and quantitative analysis and seven were included in a meta-analysis. The lower 95% confidence interval for the effect of hydrodilatation on pain severity was 0.12 indicating small effect size and mean number needed to treat 12. The pooled effect of hydrodilatation on disability level was insignificant 0.2 (95% confidence interval: -0.04 to 0.44). The lower 95% confidence interval for the effect of hydrodilatation on the range of shoulder motion was close to zero (0.07) indicating small effect size with mean number needed to treat 12. The amount of injected solution did not have a substantial effect on pain severity or range of shoulder motion. The heterogeneity level I2 was acceptable from 0% to 60%. CONCLUSION:: According to current evidence, hydrodilatation has only a small, clinically insignificant effect when treating adhesive capsulitis. PMID- 29764308 TI - Balancing risk, interpersonal intimacy and agency: perspectives from marginalised women in Zambia. AB - Women are most exposed to sexual health risks within their marital relationships, primarily due to the sexually risky behaviours of their spouses. Studies show that expanding agency is critical for women to mitigate both physical and sexual health risks and is linked to increased psycho-social well-being and economic independence. Drawing on qualitative and quantitative primary data collected from a peri-urban community in Zambia, this paper explores how women exert agency in a community where few educational and economic opportunities and substantial food insecurity exacerbate women's risk for HIV within their marital relationships. It also examines how expressions of agency within marital unions can reduce HIV risk exposure and lead to socio-economic benefits. However, expressions of agency can also create physical, psycho-social and sexual health risks, particularly when spouses do not support independent decision-making and actions that women consider necessary to support the household and maintain intimacy. Findings highlight the importance of community involvement and addressing harmful socio cultural norms to foster the realisation of women's agency. PMID- 29764309 TI - Erratum. PMID- 29764310 TI - Conflicting contraceptive norms for men: equal responsibility versus women's bodily autonomy. AB - Most research investigating how men and women in heterosexual relationships negotiate contraceptive use focuses on the women's point of view. Using a sample of 44 interviews with men attending a western US university, this study examines norms governing men's participation in contraceptive use and pregnancy prevention and their responses to those norms. The paper demonstrates how competing norms around sexual health decision-making and women's bodily autonomy contribute to unintended outcomes that undermine young people's quest for egalitarian sexual relationships. While men largely agree that responsibility for sexual health decision-making should be shared with women, they also believe that women should have power over their own bodies and sexual health. However, the coexistence of these two competing norms - which call for both equal responsibility in decision making and women's bodily autonomy - results in a disconnect between men saying that sexual health decision-making should be equal, but not always participating equally. Thus, men largely give contraceptive decision-making power over to women, putting the burden of pregnancy prevention onto women and letting men off the hook. It is concluded that men's negotiation of these competing norms reinforces unequal power and inequality in sexual relationships. PMID- 29764311 TI - Changes in the swinging lifestyle: a US national and historical comparison. AB - Although engaging in extramarital relationships with permission from spouses has been practised for generations, relatively little is known about those who participate and how they have changed over the years. This study expands on existing research by comparing the demographics and sexual practices of those in swinging and non-swinging communities from the 1980s to those in 2016. Data from the 1980s were collected through membership forms submitted to a swinger organisation and a national dataset conducted in the USA (i.e. The General Social Survey), while the recent dataset was collected through an online survey. Compared to the non-swinging population, swingers were more likely to be Caucasian, younger, educated, wealthy and more satisfied with their marriage and sex life. Demographic comparisons of swingers from 1982 to 2016 showed an increase in diversity, growing connection to the US Democratic Party and increased use of protection to avoid sexually transmitted diseases. Marital satisfaction remained the same regardless of year measured, but the amount of sex engaged in over a year decreased over time. PMID- 29764312 TI - Angle-Dependent Distortions in the Perceptual Topology of Acoustic Space. AB - By moving sounds around the head and asking listeners to report which ones moved more, it was found that sound sources at the side of a listener must move at least twice as much as ones in front to be judged as moving the same amount. A relative expansion of space in the front and compression at the side has consequences for spatial perception of moving sounds by both static and moving listeners. An accompanying prediction that the apparent location of static sound sources ought to also be distorted agrees with previous work and suggests that this is a general perceptual phenomenon that is not limited to moving signals. A mathematical model that mimics the measured expansion of space can be used to successfully capture several previous findings in spatial auditory perception. The inverse of this function could be used alongside individualized head-related transfer functions and motion tracking to produce hyperstable virtual acoustic environments. PMID- 29764313 TI - 2,5-Hexanedione increases the percentage of proliferative Sox2+ cells in rat hippocampus. AB - n-Hexane is an organic solvent widely used in industry. 2,5-Hexanedione (2,5-HD), the major neurotoxic metabolite of n-hexane, decreases the levels of neurofilaments (NFs) in neurons. Neurogenesis occurs throughout life, and the hippocampal dentate gyrus is one of two major brain areas showing neurogenesis in adulthood. In the current study, rats were intraperitoneally injected with normal saline solution or 2,5-HD five times per week for five continuous weeks. 2,5-HD was administered to the low-dose and high-dose groups at 200 and 400 mg/kg/day, respectively. Then, immunoreactive cells were counted in the hippocampal granule cell layer (GCL) and subgranular zone (SGZ). Ki67+ cells significantly decreased in the high-dose group, while the percentage of proliferative Sox2+ cells significantly increased, consistent with high hippocampal Sox2 expression. Additionally, western blotting showed that exposure to high doses of 2,5-HD led to decreased NF-L in both the cortex and hippocampus, whereas low doses led to a significant reduction in the cortex only. In conclusion, 2,5-HD increases the percentage of proliferating neural stem and progenitor (Sox2+) cells in the SGZ/GCL. PMID- 29764314 TI - Implementation and Evaluation of a Life Narrative Interview Program for Medical Inpatients. AB - OBJECTIVES: Two studies in the early 1990s demonstrated that life narrative interviews conducted by age-peer volunteers strengthened the coping of older patients undergoing invasive medical procedures. The present article reports on the implementation of a similar life narrative interview program for medical inpatients and subsequent evaluation of the mood and coping effects of the intervention. METHODS: Three volunteers (mean age = 69 years) were trained to administer 45- to 60-minute life narrative interviews. Fifty-three inpatients (mean age = 70 years) on various units of a Mid-Atlantic non-profit hospital agreed to participate. The Positive and Negative Affect Schedule and Coping Self Efficacy Inventory (CSEI) were administered before and after the interviews. RESULTS: T-tests indicated a significant increase in positive affect and decrease in negative affect following the interview but no changes in the CSEI. Patient satisfaction questions administered after the interview indicated that patients had a high level of satisfaction with the interview experience. CONCLUSIONS: The life narrative interview program appeared to improve the overall mood of participants while providing a satisfying activity to engage in while in the hospital. CLINICAL IMPLICATIONS: The project demonstrated a cost-effective method for employing volunteers to enhance the experience of patients at healthcare facilities. PMID- 29764315 TI - Effects of Egg Consumption and Choline Supplementation on Plasma Choline and Trimethylamine-N-Oxide in a Young Population. AB - BACKGROUND: Plasma trimethylamine-N-oxide (TMAO) concentrations have been associated with cardiovascular disease risk. Eggs are a rich source of choline, which is a precursor of TMAO. OBJECTIVE: The effects of egg intake versus daily choline supplementation were evaluated on plasma choline and TMAO in a young, healthy population. METHODS: Thirty participants (14 males, 16 females; 25.6 +/- 2.3 years; body mass index = 24.3 +/- 2.9 kg/m2) were enrolled in this 13-week crossover intervention. After a 2-week washout, participants were randomized to consume either 3 eggs/d or a choline bitartrate supplement (~ 400 mg choline total in eggs or supplement) for 4 weeks. Following a 3-week washout, participants were switched to the alternate treatment. Dietary records were measured at the end of each period. Plasma TMAO and choline were measured at baseline and at the end of each dietary intervention. Gene expression of scavenger receptors associated with plasma TMAO were quantified at the end of each intervention. RESULTS: Compared to the choline supplement, intake of total fat, cholesterol, selenium, and vitamin E were higher (p < 0.05), whereas carbohydrate intake was lower (p < 0.001) with consumption of 3 eggs/d. Fasting plasma choline increased 20% (p = 0.023) with egg intake, while no changes were observed with choline supplementation. Plasma TMAO levels were not different between dietary treatments or compared to baseline. CONCLUSIONS: Dietary choline appears to be more bioavailable via egg consumption when compared to a choline supplement. Plasma TMAO concentrations were not affected in healthy participants after 4 weeks of taking ~400 mg/d choline either via eggs or choline supplementation. PMID- 29764316 TI - Systematic review of empiricism and theory in domestic minor sex trafficking research. AB - Empiricism and the application of human behavior theory to inquiry are regarded as markers of high-quality research. Unfortunately, scholars have noted that there are many gaps in theory and empiricism within the human trafficking literature, calling into question the legitimacy of policies and practices that are derived from the available data. To date, there has not been an analysis of the extent to which empirical methods and human behavior theory have been applied to domestic minor sex trafficking (DMST) research as a subcategory of human trafficking inquiry. To fill this gap in the literature, this systematic review was designed to assess the degree to which DMST publications are a) empirical, and b) apply human behavior theory to inquiry. This analysis also focuses on answering research questions related to patterns within DMST study data sources, and patterns of human behavior theory application. The results of this review indicate that a minority of sampled DMST publications are empirical, a minority of those articles that were empirical apply a specific human behavior theory within the research design and reporting of results, a minority of articles utilize data collected directly from DMST victims, and that there are no discernible patterns in the application of human behavior theory to DMST research. This research note suggests that DMST research is limited by the same challenges as the larger body of human trafficking scholarship. Based upon these overarching findings, specific recommendations are offered to DMST researchers who are committed to enhancing the quality of DMST scholarship. PMID- 29764317 TI - GenerateHope: a comprehensive treatment model for sex-trafficked women. AB - GenerateHope (GH) is a San Diego-based 501c3 nonprofit organization providing fully integrated, comprehensive rehabilitation services to adult female survivors of sex trafficking. While best practices for working with survivors of sex trafficking are slowly emerging, to date, there have been few publications on this subject and little data on either short- or long-term outcomes from the many and varied programs nationwide. This paper examines the GH residential program and provides early outcome results for residents living at the GH program between six and 12 months. GH has integrated the types of assistance requested by sex trafficking victims with clinical insights into trauma therapy, in turn establishing a live-in residence with a 30-hour per week schedule that includes academics, psychotherapy, and adjunct therapies. In this study, GH used three assessments to measure improvements in residents' overall well-being: Hamilton Depression Rating Scale (HAM-D), Post-Traumatic Stress Disorder (PTSD) Checklist Civilian Version (PCL-C), and Rosenberg Self-Esteem Scale (RSES). Analysis of the three assessments showed dramatic improvements in the overall participant well-being: Symptoms of depression and post-traumatic stress disorder (PTSD) decreased significantly, and self-esteem improved significantly. Findings suggest a program that is replicable, scalable, and transferable to other settings and geographies. This paper also describes ongoing challenges in program implementation and highlights areas where further research is needed. PMID- 29764318 TI - Destructive Thyroiditis Caused by Accidental Ingestion of a Press-Through Package. PMID- 29764319 TI - Rabies in Alaska, from the past to an uncertain future. AB - Rabies is a serious zoonotic disease with significant public health consequences in the circumpolar North. Recent studies have advanced our understanding of the disease ecology in Alaska. In this paper, we review historical records of rabies in Alaska ranging from the late nineteenth century to the present, analyse the public health impact in the state and review studies on disease ecology before assessing challenges and anticipated altered disease dynamics in the face of a rapidly changing North. Rabies is a disease that has been present in Alaska continuously for over 100 years. It is maintained in bats and foxes with the arctic fox likely playing a bigger role in maintaining the virus, although a multi-host system with both red and arctic foxes cannot be excluded. Some modelling evidence suggest a possible decrease in rabies due to a changing climate, although uncertainty is high around these predictions for rabies distribution in Alaska into the future. PMID- 29764320 TI - In Key Victory for Death Penalty Opponents, Supreme Court Sides With Death Row Inmate - McWilliams v. Dunn 1. PMID- 29764321 TI - The Patient-to-Prisoner Pipeline: The IMD Exclusion's Adverse Impact on Mass Incarceration in United States. AB - A component of the 1965 Medicaid Act, the Institutions for Mental Diseases ("IMD") Exclusion was supposed to be a remedy for the brutal, dysfunctional mental healthcare system run through state hospitals. In the years since Medicaid was created, the IMD Exclusion has instead barred thousands of those in need of intensive, inpatient treatment from receiving it. As a result, many severely mentally ill individuals are left without adequate care and without a home. They struggle in the street where they are otherized by those in their community and are susceptible to confrontational episodes with law enforcement. Many are ultimately incarcerated, where they are thrust into an abusive environment known to exacerbate mental health issues. This Note's central contention is that the IMD Exclusion creates an access gap for the poorest Americans who suffer from mental illness. Subsequently, prisons and jails fill that gap to the detriment of those individuals. The Note will proceed first by explaining the IMD Exclusion and how it applies to state-run medical care services and facilities. This Note will discuss the nationwide movement, in the 1950s through the 1960s and '70s, to deinstitutionalize notoriously abusive state psychiatric hospitals, a movement that culminated in the passage of the Medicaid Act in 1965, along with the IMD Exclusion. This Note will then shift focus to criticize the practical effects of the IMD Exclusion and its extensive role in the mass incarceration issue today. In doing so, this Note will identify the major weaknesses of the IMD Exclusion and explain how these weaknesses create an access gap for mentally ill persons, while simultaneously making them more vulnerable to contact with the police and the criminal justice system. PMID- 29764322 TI - Biting the Hands that Feed "the Alligators": A Case Study in Morbid Obesity Extremes, End-of-Life Care, and Prohibitions on Harming and Accelerating the End of Life. AB - Obesity, recognized as a disease in the U.S. and at times as a terminal illness due to associated medical complications, is an American epidemic according to the Centers for Disease Control and Prevention ("CDC"), American Heart Association ("AHA"), and other authorities. More than one third of Americans (39.8% of adults and 18.5% of children) are medically obese. This article focuses on cases of "extreme morbid obesity" ("EMO")-situations in which death is imminent without aggressive medical interventions, and bariatric surgery is the only treatment option with a realistic possibility of success. Bariatric surgeries themselves are very high risk for EMO patients. Individuals in this state have impeded mobility and are partially, if not entirely, bedridden, highly vulnerable, and dependent upon caregivers who often are enablers feeding their food addictions. The article draws from existing Centers for Medicare and Medicaid Services ("CMS") and Social Security Administration ("SSA") policies and procedures for severe obesity treatment and disability benefits. The discussion also encompasses myriad areas in which the law imposes a duty to report on professionals to protect vulnerable individuals from harm from others, and constraints and prohibitions on accelerating the end of life. The article proposes, among other law and policy measures, to introduce an obligation on medical professionals to investigate and report instances of enablement when food addiction has put the lives of individuals at risk of imminent death. The objectives of the proposals are to give providers more leverage to prevent food addiction enablers from impeding treatment and to enable EMO patients to comply with treatment protocols, to save lives and, ironically, to empower enablers to stand firm against the demands of individuals whose lives have been consumed by their food addictions. PMID- 29764323 TI - Swaps and Chains and Vouchers, Oh My!: Evaluating How Saving More Lives Impacts the Equitable Allocation of Live Donor Kidneys. AB - Live kidney donation involves a delicate balance between saving the most lives possible and maintaining a transplant system that is fair to the many thousands of patients on the transplant waiting list. Federal law and regulations require that kidney allocation be equitable, but the pressure to save patients subject to ever-lengthening waiting times for a transplant has been swinging the balance toward optimizing utility at the expense of justice. This article traces the progression of innovations created to make optimum use of a patient's own live donors. It starts with the simplest - direct donation by family members - and ends with voucher donations, a very recent and unique innovation because the donor can donate 20 or more years before the intended recipient is expected to need a kidney. In return for the donation, the intended recipient receives a voucher that can be redeemed for a live kidney when it is needed. Other innovations that are discussed include kidney exchanges and list paired donation, which are used to facilitate donor swaps when donor/recipient pairs have incompatible blood types. The discussion of each new innovation shows how the equity issues build on each other and how, with each new innovation, it becomes progressively harder to find an acceptable balance between utility and justice. The article culminates with an analysis of two recent allocation methods that have the potential to save many additional lives, but also affirmatively harm some patients on the deceased donor waiting list by increasing their waiting time for a life-saving kidney. The article concludes that saving additional lives does not justify harming patients on the waiting list unless that harm can be minimized. It also proposes solutions to minimize the harm so these new innovations can equitably perform their intended function of stimulating additional transplants and extending the lives of many transplant patients. PMID- 29764324 TI - Baby M Turns 30: The Law and Policy of Surrogate Motherhood. AB - This article marks the 30th anniversary of the Supreme Court of New Jersey's Baby M decision by offering a critical analysis of surrogacy policy in the United States. Despite fundamental changes in both science and society since the case was decided, state courts and legislatures remain bitterly divided on the legality of surrogacy. In arguing for a more uniform, permissive legal posture toward surrogacy, the article addresses five central debates in the surrogacy literature. First, should the legal system accommodate those seeking conception through surrogacy, or should it prohibit such arrangements? Second, if surrogacy is permitted, what steps can be taken to minimize the potential exploitation of women who are willing to rent their wombs for income? Third, what criteria should govern the eligibility to serve as a surrogate mother and an intended parent? Fourth, what principle(s) should serve as the basis for determining the parentage of children born through surrogacy? Fifth, is regulatory uniformity in the surrogacy realm desirable? Is it achievable? The article concludes that courts and legislatures should accept the validity of surrogacy contracts, determine parentage according to intent, and identify transparent criteria for the eligibility of both surrogates and intended parents. PMID- 29764325 TI - Responsiveness of the EQ-5D-3L in elective shoulder surgery: Does it adequately represent patient experience? AB - AIM: Generic patient-reported outcome measures (PROMs) allow comparison of health related quality of life across populations and pathologies. For these comparisons to be valid, the PROM must be responsive; the score must change when the patient's quality of life changes. This study aims to assess the responsiveness of the EQ-5D-three level (3L) in elective shoulder surgery. METHODS: Pre- and post-operative EQ-5D-3L and Oxford Shoulder Scores (OSS) were prospectively collected across a range of 204 elective shoulder surgeries. Internal responsiveness was assessed through significance testing of mean change scores and standardized response means (SRMs). External responsiveness of the EQ-5D-3L was assessed against the minimal clinically important difference in OSS, using receiver operating characteristic curve and change score correlation. RESULTS: Both EQ-5D-3L and OSS scores improved significantly over time ( p < 0.05). The SRM for the EQ-5D was 1.27 (95% CI 1.14-1.41) and for OSS 2.36 (2.22-2.52). Area under the curve for EQ-5D was 0.49. Only a weak correlation was found between EQ 5D and OSS change scores ( r = 0.21). DISCUSSION: The EQ-5D-3L is adequately internally responsive to change following elective shoulder surgery but is unable to differentiate patients demonstrating minimal clinically important change. The EQ-5D therefore only partially reflects patient experience. PMID- 29764326 TI - Why gerontology and geriatrics can teach us a lot about mentoring. AB - Gerontology, geriatrics, and mentoring have a lot in common. The prototype of this role was Mentor, an older adult in Homer's The Odyssey, who was enlisted to look after Odysseus' son, Telemachus, while his father was away fighting the Trojan War. Portrayed as an older man, the name "mentor" literally means "a man who thinks," which is not a bad characterization generally for faculty members in gerontology! In particular, gerontological and geriatrics education can teach us a lot about the importance of mentoring and provide some critical insights into this role: (1) the importance of interprofessional leadership and modeling, (2) the application of the concept of "grand-generativity" to mentoring, (3) "it takes a community" to be effective in mentoring others, and (4) the need to tailor mentorship styles to the person and the situation. This discussion explores these topics and argues that gerontological and geriatrics educators have a particularly important role and responsibility in mentoring students, colleagues, and administrators related to the very future of our field. PMID- 29764327 TI - To boldly go where no relationship has gone before: Commentary on interpersonal relationships in the digital age. AB - Individuals have a need to maintain positive social interactions, and with the advent of new-media technologies, there are a myriad ways individuals can satisfy this need by engaging socially in mediated (non-face-to-face) communication, hence the need for a special issue on "Relationships in the Digital Age." The articles in this special issue reflect the need to answer theoretical questions brought forth by the increased tendency for individuals to create and maintain interpersonal relationships through mediated forms of communication. The commentary highlights the need for increased research on mediated interpersonal relationships by psychologists and discusses how the articles in the issue can be used to answer theoretical questions about mediated interpersonal communication. The article ends with speculation on how media may create social spaces that may be advantageous for some individuals. PMID- 29764329 TI - Preliminary results of the first cervical cancer screening programme in the North Eastern region of Romania. AB - OBJECTIVE: Cervical cancer represents a major health problem in Romania. A national population-based cervical cancer screening programme was launched in 2012. The aims of the study were to assess the participation rate and to estimate the prevalence of epithelial cell abnormalities in the first four years of the programme in North Eastern Romania. METHODS: The participation rate, representing the proportion of eligible women screened in the programme, was evaluated for 2012-2016. The prevalence of cytological abnormalities was estimated by age group and calendar year. RESULTS: Of 107,968 Pap smears taken, 312 were unsatisfactory (0.3%). The number of smears decreased by year. The participation rate over the four years was 16.9%. Of the 107,656 satisfactory smears, 6.5% were positive for squamous and/or glandular lesion, among which 0.5% contained high-grade squamous intraepithelial or worse lesions. CONCLUSION: The participation rate in the first four years of the programme was low. The effectiveness of the screening programme should be improved by attendance monitoring of the target population, and follow up of screen-positive women. Measures should be taken to raise coverage and assure quality at all steps of the screening chain. The data collected should include all screening tests from both opportunistic and organized settings. PMID- 29764328 TI - Community-based hearing screening for young children using an mHealth service delivery model. AB - BACKGROUND: Hearing loss is one of the most common developmental disorders identifiable at birth with its prevalence increasing throughout school years. However, early detection programs are mostly unavailable in low- and middle income countries (LMICs) where more than 80% of children with hearing loss reside. OBJECTIVE: This study investigated the feasibility of a smartphone-based hearing screening program for preschool children operated by community healthcare workers (CHWs) in community-based early childhood development (ECD) centers. METHOD: Five CHWs were trained to map ECD centers and conduct smartphone-based hearing screenings within a poor community in South Africa over a 12-month period. The hearScreenTM smartphone application employed automated test protocols operating on low-cost smartphones. A cloud-based data management and referral function allowed for remote monitoring for surveillance and follow up. RESULTS: 6424 children (3-6 years) were screened for hearing loss with an overall referral rate of 24.9%. Only 39.4% of these children attended their follow-up appointment at a local clinic, of whom 40.5% referred on their second screening. Logistic regression analysis indicated that age, gender and environmental noise levels (1 kHz) had a significant effect on referral rates (p < 0.05). The quality index reflecting test operator test quality increased during the first few months of testing. CONCLUSION: Smartphone-based hearing screening can be used by CHWs to detect unidentified children affected by hearing loss within ECD centers. Active noise monitoring, quality indices of test operators and cloud-based data management and referral features of the hearScreenTM application allows for the asynchronous management of hearing screenings and follow-ups. PMID- 29764330 TI - Factors influencing the provision of fertility counseling and impact on quality of life in adolescents and young adults with cancer. AB - PURPOSE: This study investigated the impact of fertility-related discussions on Adolescent and Young Adult (AYA) cancer patients' quality of life (QoL) and the factors influencing provision of these discussions. METHODS: Recruitment was conducted through population-based state cancer registries. Eligible AYAs were 15 24 years at diagnosis, 3-24 months postdiagnosis, with any cancer (except early stage melanoma). As part of a larger survey, AYAs were asked about their experiences of fertility-related discussions and QoL (FACT-G). RESULTS: Of the 207 AYAs returning surveys (29% response rate) 88% reported a discussion about infertility risks, 75% reported a discussion about preservation options and 59% were offered a referral to a fertility specialist. Patients attending health services with an AYA focus were more likely than those attending other types of centers to report discussions of fertility preservation (FP) options (85% versus 67%) and referrals (75% versus 49%). Social well-being was positively related to discussions about preservation options and being provided fertility risk information in a sensitive, supportive manner. CONCLUSIONS: Providing a sensitive and proactive discussion about fertility-related risks may benefit AYAs' well being. Services with an AYA focus are fulfilling their mandate of ensuring optimal fertility-related care for AYA cancer patients. PMID- 29764331 TI - Psychological impact of von Hippel-Lindau genetic screening in patients with a previous history of hemangioblastoma of the central nervous system. AB - Von Hippel-Lindau (VHL) syndrome is a hereditary cancer syndrome characterized by a high risk of developing benign and malignant tumors, including central nervous system hemangioblastomas (CNS HBs). For an early diagnosis of VHL, before the occurrence of cancers (especially renal cell carcinoma), it is of huge importance to initiate VHL genetic testing in at-risk patients. The aim of the study was to assess the psychological impact of VHL genetic testing in patients previously diagnosed with a CNS HB. From 1999 until 2015, 55 patients underwent surgery for CNS HBs. Eleven patients were already screened for VHL mutations and 3 patients deceased before the start of the study. From the remaining 42 patients, 24 were accepted to be enrolled in the study. Assessment of psychological impact of VHL genetic testing was performed by measuring anxiety levels, mood disorders, quality of life, and psychological consequences of genetic screening. Twenty-one of the enrolled 24 patients underwent VHL genetic testing and 12 patients came back for the communication of positive genetic results. The baseline psychological status did not differ between these 2 groups. Patients who attended the visit of communication of genetic results had similar anxiety levels compared to those who had not. Furthermore, they also experienced an improvement in the level of anxiety and two QoL dimension scores compared to their baseline status. In summary, there is no evidence of a negative psychosocial impact of VHL genetic testing in patients with a previous history of CNS HB. We, therefore, recommend the recall of patients who have not been previously screened. PMID- 29764332 TI - Visual Perception Strategies of Foil Fencers Facing Right- Versus Left-Handed Opponents. AB - This study sought to determine differences in fencers' visual perceptions during duels (preparatory actions) with right- versus left-handed opponents. Participants were 12 top-ranking right-handed female foil fencers (aged 16-30 years, M = 20.86, SD = 4.76) taking part in a training camp. Testing employed SensoMotoric Instruments Eye Tracking Glasses (SMI ETG 2.0) with eye-tracking analyses covering the visual attention time devoted to various areas of the opposing fencer's body (areas of interest), average fixation, number of glances, and number of fixations during preparatory actions in duels. Each test was conducted during preparatory actions in 20-second staged duels, first against a right-handed, and then against a left-handed opponent. Against left-handed (vs. right-handed) opponents, fencers spent significantly more time looking at and significantly more often fixated on the armed hand. When fighting against right handed (vs. left-handed) opponents, fencers devoted more time and fixated more often on the opponent's upper torso. These results may point to an interesting phenomenon in which left-handed fencers benefit from weaker strategies adopted by their right-handed opponents who may fixate on the forearm and arm of the weapon hand. PMID- 29764333 TI - Is Fear of Falling the Missing Link to Explain Racial Disparities in Fall Risk? Data from the National Health and Aging Trends Study. AB - OBJECTIVES: Emerging research suggests Black older adults experience a 30% decreased risk for falls compared with their White U.S. counterparts, and this is mediated neither by physical performance nor activity. Fear of falling (FOF) is a significant risk factor for falls, yet we know little about how FOF varies by race/ethnicity. The purpose of this original research brief was to investigate the relationship between race/ethnicity and FOF among older adults. METHODS: 4,981 community-dwelling Medicare beneficiaries from the National Health and Aging Trends Study (NHATS) who had not self-reported a fall in the past 12 months were analyzed. Logistic regression analyses were conducted to examine the association between race/ethnicity and fear of falling, controlling for sex, age, total annual income, and mobility assistance. RESULTS: FOF differed significantly across racial groups. Black, non-Hispanic older adults were less likely to have FOF (OR = .87, 95% CI = .71,1.07) compared with their White, non-Hispanic counterparts. In the fully adjusted model, this difference persisted and became stronger (adjusted OR = .75, 95%CI = .61, .93). CONCLUSION: The decreased risk for falls in Black older adults could be explained by lower FOF in this group. CLINICAL IMPLICATIONS: These findings should inform public health fall prevention initiatives among community-dwelling older adults. PMID- 29764335 TI - Comparative bioaccumulation and effects of purified and cellular extract of cylindrospermopsin to freshwater fish Hoplias malabaricus. AB - Many tropical freshwater ecosystems are impacted by cyanobacteria blooms increasing the risk of cyanotoxins exposure to aquatic organisms while human populations may be exposed by eating fish, drinking water, or dermal swimming. However, few toxicological data are available on the influence of cyanobacteria blooms in particular, cylindrospermopsin (CYN) on Brazilian neotropical fish. A number of studies demonstrated the ability of CYN to bioaccumulate in freshwater organisms and consequently enter the human food chain. The aim of the current study was to examine the effects of CYN following single intraperitoneal injection (50 ug/kg) of purified CYN (CYNp) or aqueous extract of CYN-producing cyanobacteria extract (CYNex) after 7 or 14 days. Biomarkers such as histopathology (liver), oxidative stress (liver and brain), and acetylcholinesterase (AChE) activity (muscle and brain) were utilized in order to assess the influence of CYN on Hoplias malabaricus. In terms of AChE activity, administration of CYNex and CYNp both muscle and brains were used as target tissues. In brain an increase of glutathione S-transferase (GST) activity and lipid peroxidation (LPO) levels was noted suggesting an imbalance in redox cycling. The majority of biomarkers did not present significant alterations in liver, but an elevation in superoxide dismutase (SOD) and glucose 6 phosphate dehydrogenase (G6PDH) activities was found. Different profiles of GST activity were observed in both studied groups (CYNex and CYNp) while LPO (CYNex and CYNp) and protein carbonylation (PCO) (CYNp) levels increased after exposure to CYN. The incidence of necrosis, melanomacrophages centers, and free melanomacrophages were detected as evidence of cell death and immune responses. Nonprotein thiols (NPT) levels were not markedly affected in both exposed groups. Data demonstrated that in vivo exposure to CYN produced biochemical and morphological disturbances in liver and brain of H. malabaricus. PMID- 29764336 TI - Special section on loneliness and isolation among older adults. PMID- 29764334 TI - Obesity, physical activity, and dietary behaviors in an ethnically-diverse sample of cancer survivors with early onset disease. AB - PURPOSE: To assess weight status, physical activity, and dietary behaviors in an ethnically-diverse sample of breast and colorectal cancer survivors with early onset disease (<= 50 years). METHODS: Breast and colorectal cancer survivors, diagnosed between 1999 and 2009 with early-stage cancer diagnosed by 50 years of age, were identified through a population-based cancer registry and surveyed. Descriptive and regression analyses were conducted to characterize the sample and identify correlates of lifestyle behaviors. FINDINGS: The majority of participants (n = 156) were female (83%), insured (84%), and racial/ethnic minorities (29% Asian, 24% Latino, 15% African American). Participants' mean age at response was 50 years and mean time since diagnosis was 9 years. Over half of survivors were overweight or obese. Few participants reported engaging in regular physical activity (31%) and adhering to minimum guidelines for fruit and vegetable consumption (32%). A substantial proportion of survivors consumed fast food in the past week (75%) and nearly half (48%) reported daily consumption of sugar-sweetened beverages. Lower income was associated with inadequate fruit and vegetable intake. Fast food and sugar-sweetened beverage consumption was significantly higher among racial/ethnic minority survivors compared to non Latino whites. CONCLUSIONS: High prevalence of overweight and suboptimal adherence to recommended nutrition and physical activity behaviors were observed among cancer survivors with early onset disease. Cancer survivors diagnosed at a young age may benefit from targeted interventions to address overweight and suboptimal nutrition and physical activity. PMID- 29764337 TI - Response to Letter to the Editor: Implementation of a Cardiac Transitions of Care Pilot Program: A Prospective Study of Inpatient and Outpatient Clinical Pharmacy Services for Patients With Heart Failure Exacerbation or Acute Myocardial Infarction. PMID- 29764338 TI - The prognostic relevance of psychological factors with regard to participation and success in table-tennis. AB - This study examined the prognostic relevance of self-determined motivation, coping, burnout, perceived stress and recovery experienced by 159 youth table tennis players involved in intensive training centers with regard to their participation and success six years later. Results of ANCOVAs showed that players who still practiced at time 2 (T2; six years later; n = 130) reported lower time 1 (T1; while they were involved in intensive training centers) amotivation (large effect), disengagement-oriented coping, sport devaluation and reduced accomplishment (moderate effects) than their counterparts who dropped out at T2 (n = 29). Results of ANCOVAs also showed that international (n = 18) and/or national players (n = 86) at T2 reported significantly lower T1 amotivation (large effect), disengagement-oriented coping and sport devaluation (moderate effects) in comparison to regional (n = 26) players at T2. Finally results of correlational analyses showed that T2 performance and/or six-year performance progress were significantly and weakly correlated with introjected and external regulations, perceived stress and perceived recovery, and significantly and moderately correlated with amotivation, disengagement-oriented coping, sport devaluation, and reduced accomplishment. Overall, this study provided insights into the role played by self-determined motivation, coping, burnout, perceived stress and recovery in the table-tennis players' dropout and performance level six years later. PMID- 29764339 TI - Determination of plasma concentrations of organochlorine pesticides and polychlorinated biphenyls in pet cats and dogs. AB - The aim of this study was the determination of plasma concentrations of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in cats and dogs and evaluation of their prevalence and possible effects. The concentrations of nine OCPs, such as alpha-hexachlorocyclohexane (HCH), beta-HCH, gamma-HCH, hexachlorobenzene (HCB), aldrin, 2,4'-dichlorodiphenyltrichloroethane (2,4'-DDT), 4,4'-DDT, 2,4'-dichlorodiphenyldichloroethylene (2,4'-DDE) and 4,4'-DDE and 16 PCBs (PCB-28, -52, -70, -74, -81, -99, -101, -118, -138, -153, -156, -170, -180, 183, -187 and -208) were evaluated in the plasma samples of pet cats ( n = 15) and dogs ( n = 21). The concentrations of OCPs ranged from 1.12 ng g-1 lipid weight (lw) to 7.65 ng g-1 lw in cats and from 1.25 ng g-1 lw to 6.79 ng g-1 lw in dogs. In addition, mean PCB levels were 0.58-5.66 and 0.52-6.62 ng g-1 lw in cats and dogs, respectively. beta-HCH, gamma-HCH and PCB-138 levels were significantly higher in dogs ( p < 0.05). As far as could be determined, OCPs and PCBs were detected in the plasma samples of domestic cats and dogs in Turkey for the first time. Their concentrations were similar to those reported in earlier studies abroad. However, in contrast to other research, the levels of some OCPs were higher in dogs than in cats. It is concluded that, because of their high prevalence and potential health effects in animals and humans, OCP and PCB levels should be monitored systematically in domestic cats and dogs. PMID- 29764340 TI - In vitro and in vivo anti-cancer activity of silymarin on oral cancer. AB - Silymarin, a standardized extract from milk thistle fruits has been found to exhibit anti-cancer effects against various cancers. Here, we explored the anti cancer activity of silymarin and its molecular target in human oral cancer in vitro and in vivo. Silymarin dose-dependently inhibited the proliferation of HSC 4 oral cancer cells and promoted caspase-dependent apoptosis. A human apoptosis protein array kit showed that death receptor 5 may be involved in silymarin induced apoptosis, which was also shown through western blotting, immunocytochemistry, and reverse transcription-polymerase chain reaction. Silymarin increased cleaved caspase-8 and truncated Bid, leading to accumulation of cytochrome c. In addition, silymarin activated death receptor 5/caspase-8 to induce apoptotic cell death in two other oral cancer cell lines (YD15 and Ca9.22). Silymarin also suppressed tumor growth and volume without any hepatic or renal toxicity in vivo. Taken together, these results provide in vitro and in vivo evidence supporting the anti-cancer effect of silymarin and death receptor 5, and caspase-8 may be essential players in silymarin-mediated apoptosis in oral cancer. PMID- 29764341 TI - Brief report: sudden gains in cognitive-behavioral group therapy and group psychotherapy for social anxiety disorder among college students. AB - The present study examined sudden gains (SGs; large symptom improvements between adjacent treatment sessions) and its association with treatment outcome in a randomized-controlled trial comparing cognitive-behavioral group therapy (CBGT) versus group psychotherapy (GPT; designed to incorporate only non-specific factors) for social anxiety disorder (SAD). SAD symptoms were assessed after each treatment session in a sample of 45 college students. Independent assessors evaluated symptom severity at baseline, post-treatment and follow-up. A total of 10 (22.2%) participants experienced SGs during treatment. No differences were found in symptom improvement at post-treatment or follow-up between individuals with and without SGs. SGs appeared at similar rates across both treatments but were associated with greater improvements at post-treatment and follow-up in GPT compared to CBGT. Majority of SGs in CBGT occurred early in treatment before the provision of specific treatment techniques. These results suggest that non specific treatment factors may be important in promoting SGs. PMID- 29764343 TI - Virtual medicine: how virtual reality is easing pain, calming nerves and improving health. PMID- 29764344 TI - Botulinum toxin for spasticity: a case for change to the Pharmaceutical Benefits Scheme. PMID- 29764342 TI - Barriers to and facilitators of employment for people with psychiatric disabilities in Africa: a scoping review. AB - BACKGROUND: Despite the importance of inclusive employment, described in Goal 8 of the Sustainable Development Goals (SDGs), employment of persons with psychiatric disabilities in Africa is lower than among the general population. OBJECTIVE: The aim of this scoping review is to explore evidence related to the barriers to and facilitators of employment of persons with psychiatric disabilities in Africa. METHODS: A literature search was conducted using six relevant electronic databases of articles published between 1990 and 2017. RESULTS: Eight studies were identified and analysed regarding barriers and facilitators of employment of persons with psychiatric disabilities. The dynamic adaptation of the bio-psycho-social model was used as an analytical framework. Identified barriers include ill health, (anticipated) psychiatric illness, social stigma and discrimination, negative attitudes among employers and the lack of social support and government welfare. Facilitators of employment include stability of mental illness, heightened self-esteem, a personal decision to work despite stigma, competitive and supported employment, reduction in social barriers/stigma and workplace accommodations. CONCLUSION: Employment of persons with psychiatric disabilities is essential, yet there is dearth of scientific evidence to identify contextual models that might be useful in African countries and other low-and middle countries (LMICs). This gap in information would benefit from further research to improve the employment rates of persons with psychiatric disabilities in Africa. PMID- 29764346 TI - Identifying genes in Parkinson disease: state of the art. PMID- 29764347 TI - Tremor: a simple four-step approach to clinical assessment. PMID- 29764348 TI - James Parkinson's Essay on the shaking palsy, 1817-2017. PMID- 29764349 TI - The up-to-date version of an acclaimed book in the field of dementia. PMID- 29764350 TI - Neuroscience from a functional perspective. PMID- 29764351 TI - FIFO, FIFO, and off to work we woe. PMID- 29764352 TI - Psychotropic drug prescribing in residential aged care homes. PMID- 29764353 TI - Non-motor Parkinson disease: new concepts and personalised management. AB - Most patients with Parkinson disease (PD) have non-motor symptoms (NMS), and on average these can range from four to 19 different symptoms. NMS dominate the prodromal phase of PD and some may serve as clinical biomarkers of PD. NMS can be dopaminergic, non-dopaminergic, of genetic origin or drug induced. Clinical assessment of NMS should include the NMS Questionnaire (completed by patients) for screening, as recommended by the International Parkinson and Movement Disorders Society and other international societies. The total number of NMS in a patient with PD constitutes the NMS burden, which can be graded using validated cut-off scores on the NMS Questionnaire and Scale and can be used as an outcome measure in clinical trials. Despite NMS burden having a major effect on the quality of life of patients and carers, a large European study showed that NMS are often ignored in the clinic. The syndromic nature of PD is underpinned by non motor subtypes which are likely to be related to specific dysfunction of cholinergic, noradrenergic, serotonergic pathways in the brain, not just the dopaminergic pathways. NMS can be treated by dopaminergic and non-dopaminergic strategies, but further robust studies supported by evidence from animal models are required. The future of modern treatment of PD needs to be supported by the delivery of personalised medicine. PMID- 29764354 TI - Impact of ethnicity on the natural history of Parkinson disease. AB - Parkinson disease (PD) affects people of all races and ethnicity worldwide. PD is a multineurotransmitter and multisystem disorder and our current concept of the natural history of PD has changed considerably over the past decades. Many aspects of this heterogeneous condition still remain unexplained; one aspect that is poorly studied is the role of ethnicity and manifest motor and non-motor PD. Some preliminary data suggest that the prodromal risk of developing PD, clinical symptom expression and the experience of living with the condition may vary between different ethnic groups. Several factors might play a role in the influence of ethnicity on PD, such as pharmacogenetics, sociocultural aspects and environmental exposures. Increased knowledge on the role of ethnicity in PD may help shed light on the symptom expression and treatment response of PD, address inequalities in health care delivery worldwide and improve the delivery of personalised medicine. PMID- 29764356 TI - The case for uncertainty. PMID- 29764355 TI - Regulating e-cigarettes in Australia: implications for tobacco use by young people. PMID- 29764358 TI - Editorial: Glia-Neuron Crosstalk and its Therapeutic Implication in Neuropsychiatric Disorders. PMID- 29764359 TI - Editorial: The Role of Ca2+-activated K+ Channels of Intermediate Conductance in Glioblastoma Malignancy. PMID- 29764360 TI - Prediction of enhancer-promoter interactions via natural language processing. AB - BACKGROUND: Precise identification of three-dimensional genome organization, especially enhancer-promoter interactions (EPIs), is important to deciphering gene regulation, cell differentiation and disease mechanisms. Currently, it is a challenging task to distinguish true interactions from other nearby non interacting ones since the power of traditional experimental methods is limited due to low resolution or low throughput. RESULTS: We propose a novel computational framework EP2vec to assay three-dimensional genomic interactions. We first extract sequence embedding features, defined as fixed-length vector representations learned from variable-length sequences using an unsupervised deep learning method in natural language processing. Then, we train a classifier to predict EPIs using the learned representations in supervised way. Experimental results demonstrate that EP2vec obtains F1 scores ranging from 0.841~ 0.933 on different datasets, which outperforms existing methods. We prove the robustness of sequence embedding features by carrying out sensitivity analysis. Besides, we identify motifs that represent cell line-specific information through analysis of the learned sequence embedding features by adopting attention mechanism. Last, we show that even superior performance with F1 scores 0.889~ 0.940 can be achieved by combining sequence embedding features and experimental features. CONCLUSIONS: EP2vec sheds light on feature extraction for DNA sequences of arbitrary lengths and provides a powerful approach for EPIs identification. PMID- 29764362 TI - GPU-accelerated iterative reconstruction for limited-data tomography in CBCT systems. AB - BACKGROUND: Standard cone-beam computed tomography (CBCT) involves the acquisition of at least 360 projections rotating through 360 degrees. Nevertheless, there are cases in which only a few projections can be taken in a limited angular span, such as during surgery, where rotation of the source detector pair is limited to less than 180 degrees. Reconstruction of limited data with the conventional method proposed by Feldkamp, Davis and Kress (FDK) results in severe artifacts. Iterative methods may compensate for the lack of data by including additional prior information, although they imply a high computational burden and memory consumption. RESULTS: We present an accelerated implementation of an iterative method for CBCT following the Split Bregman formulation, which reduces computational time through GPU-accelerated kernels. The implementation enables the reconstruction of large volumes (>10243 pixels) using partitioning strategies in forward- and back-projection operations. We evaluated the algorithm on small-animal data for different scenarios with different numbers of projections, angular span, and projection size. Reconstruction time varied linearly with the number of projections and quadratically with projection size but remained almost unchanged with angular span. Forward- and back-projection operations represent 60% of the total computational burden. CONCLUSION: Efficient implementation using parallel processing and large-memory management strategies together with GPU kernels enables the use of advanced reconstruction approaches which are needed in limited-data scenarios. Our GPU implementation showed a significant time reduction (up to 48 *) compared to a CPU-only implementation, resulting in a total reconstruction time from several hours to few minutes. PMID- 29764363 TI - GATC: a genetic algorithm for gene tree construction under the Duplication Transfer-Loss model of evolution. AB - BACKGROUND: Several methods have been developed for the accurate reconstruction of gene trees. Some of them use reconciliation with a species tree to correct, a posteriori, errors in gene trees inferred from multiple sequence alignments. Unfortunately the best fit to sequence information can be lost during this process. RESULTS: We describe GATC, a new algorithm for reconstructing a binary gene tree with branch length. GATC returns optimal solutions according to a measure combining both tree likelihood (according to sequence evolution) and a reconciliation score under the Duplication-Transfer-Loss (DTL) model. It can either be used to construct a gene tree from scratch or to correct trees infered by existing reconstruction method, making it highly flexible to various input data types. The method is based on a genetic algorithm acting on a population of trees at each step. It substantially increases the efficiency of the phylogeny space exploration, reducing the risk of falling into local minima, at a reasonable computational time. We have applied GATC to a dataset of simulated cyanobacterial phylogenies, as well as to an empirical dataset of three reference gene families, and showed that it is able to improve gene tree reconstructions compared with current state-of-the-art algorithms. CONCLUSION: The proposed algorithm is able to accurately reconstruct gene trees and is highly suitable for the construction of reference trees. Our results also highlight the efficiency of multi-objective optimization algorithms for the gene tree reconstruction problem. GATC is available on Github at: https://github.com/UdeM-LBIT/GATC . PMID- 29764364 TI - Efficient algorithms for polyploid haplotype phasing. AB - BACKGROUND: Inference of haplotypes, or the sequence of alleles along the same chromosomes, is a fundamental problem in genetics and is a key component for many analyses including admixture mapping, identifying regions of identity by descent and imputation. Haplotype phasing based on sequencing reads has attracted lots of attentions. Diploid haplotype phasing where the two haplotypes are complimentary have been studied extensively. In this work, we focused on Polyploid haplotype phasing where we aim to phase more than two haplotypes at the same time from sequencing data. The problem is much more complicated as the search space becomes much larger and the haplotypes do not need to be complimentary any more. RESULTS: We proposed two algorithms, (1) Poly-Harsh, a Gibbs Sampling based algorithm which alternatively samples haplotypes and the read assignments to minimize the mismatches between the reads and the phased haplotypes, (2) An efficient algorithm to concatenate haplotype blocks into contiguous haplotypes. CONCLUSIONS: Our experiments showed that our method is able to improve the quality of the phased haplotypes over the state-of-the-art methods. To our knowledge, our algorithm for haplotype blocks concatenation is the first algorithm that leverages the shared information across multiple individuals to construct contiguous haplotypes. Our experiments showed that it is both efficient and effective. PMID- 29764361 TI - Ouroboros resembling competitive endogenous loop (ORCEL) in circular RNAs revealed through transcriptome sequencing dataset analysis. AB - BACKGROUND: Emerging evidence indicates that Circular RNAs (circRNAs) exert post transcriptional regulation of gene expression. A subclass of circRNA was found enriched with miRNA target sites. This evidence suggests that this kind of circRNA functions as natural miRNA sponge. Noticing the potential impacts of circular RNA research, we were motivated to identify novel circRNAs as well as putative circRNA-miRNA interactions through retroactive sourced transcriptome sequencing samples. RESULTS: Through the analysis in 465 RNA-seq runs and 22 reports published in recent years, putatively circRNA sponged miRNA that had been experimentally verified targeting circRNA host gene were found. From this observation, supporting evidence of the competitive endogenous relationship of circRNAs and miRNAs targeting circRNA host genes can be observed. Given the self regulation and self-induction nature of these circRNAs, this kind of hypothetical phenomenon was hereby called Ouroboros Resembling Competitive Endogenous Loop (ORCEL) in circular RNAs. CONCLUSIONS: The fact that miRNA sponge circRNA originated from region miRNA target sites enriched regions, while genes encoded from these regions are conserved to be miRNA targets rationalize the existence of ORCEL. PMID- 29764365 TI - Towards pan-genome read alignment to improve variation calling. AB - BACKGROUND: Typical human genome differs from the reference genome at 4-5 million sites. This diversity is increasingly catalogued in repositories such as ExAC/gnomAD, consisting of >15,000 whole-genomes and >126,000 exome sequences from different individuals. Despite this enormous diversity, resequencing data workflows are still based on a single human reference genome. Identification and genotyping of genetic variants is typically carried out on short-read data aligned to a single reference, disregarding the underlying variation. RESULTS: We propose a new unified framework for variant calling with short-read data utilizing a representation of human genetic variation - a pan-genomic reference. We provide a modular pipeline that can be seamlessly incorporated into existing sequencing data analysis workflows. Our tool is open source and available online: https://gitlab.com/dvalenzu/PanVC . CONCLUSIONS: Our experiments show that by replacing a standard human reference with a pan-genomic one we achieve an improvement in single-nucleotide variant calling accuracy and in short indel calling accuracy over the widely adopted Genome Analysis Toolkit (GATK) in difficult genomic regions. PMID- 29764366 TI - Phylogenetic signal from rearrangements in 18 Anopheles species by joint scaffolding extant and ancestral genomes. AB - BACKGROUND: Genomes rearrangements carry valuable information for phylogenetic inference or the elucidation of molecular mechanisms of adaptation. However, the detection of genome rearrangements is often hampered by current deficiencies in data and methods: Genomes obtained from short sequence reads have generally very fragmented assemblies, and comparing multiple gene orders generally leads to computationally intractable algorithmic questions. RESULTS: We present a computational method, ADSEQ, which, by combining ancestral gene order reconstruction, comparative scaffolding and de novo scaffolding methods, overcomes these two caveats. ADSEQ provides simultaneously improved assemblies and ancestral genomes, with statistical supports on all local features. Compared to previous comparative methods, it runs in polynomial time, it samples solutions in a probabilistic space, and it can handle a significantly larger gene complement from the considered extant genomes, with complex histories including gene duplications and losses. We use ADSEQ to provide improved assemblies and a genome history made of duplications, losses, gene translocations, rearrangements, of 18 complete Anopheles genomes, including several important malaria vectors. We also provide additional support for a differentiated mode of evolution of the sex chromosome and of the autosomes in these mosquito genomes. CONCLUSIONS: We demonstrate the method's ability to improve extant assemblies accurately through a procedure simulating realistic assembly fragmentation. We study a debated issue regarding the phylogeny of the Gambiae complex group of Anopheles genomes in the light of the evolution of chromosomal rearrangements, suggesting that the phylogenetic signal they carry can differ from the phylogenetic signal carried by gene sequences, more prone to introgression. PMID- 29764367 TI - Papain-like and legumain-like proteases in rice: genome-wide identification, comprehensive gene feature characterization and expression analysis. AB - BACKGROUND: Papain-like and legumain-like proteases are proteolytic enzymes which play key roles in plant development, senescence and defense. The activities of proteases in both families could be inhibited by a group of small proteins called cystatin. Cystatin family genes have been well characterized both in tobacco and rice, suggesting their potential roles in seed development. However, their potential targets, papain-like and legumain-like proteases, have not been well characterized in plants, especially in rice, a model plant for cereal biology. RESULTS: Here, 33 papain-like and 5 legumain-like proteases have been identified in rice genome, respectively. Gene structure, distribution in rice chromosome, and evolutionary relationship to their counterparts in other plants have been well characterized. Comprehensive expression profile analysis revealed that two family genes display divergent expression pattern, which are regulated temporally and spatially during the process of seed development and germination. Our experiments also revealed that the expression of most genes in these two families is sensitively responsive to plant hormones and different abiotic stresses. CONCLUSIONS: Genome-wide identification and comprehensive gene expression pattern analysis of papain-like and legumain-like proteases in rice suggests their multiple and cooperative roles in seed development and response to environmental variations, which provides several useful cues for further in-depth study. PMID- 29764368 TI - Airborne geographical dispersal of Q fever from livestock holdings to human communities: a systematic review and critical appraisal of evidence. AB - BACKGROUND: Q fever is a zoonotic disease caused by Coxiella burnetii. This bacterium survives harsh conditions and attaches to dust, suggesting environmental dispersal is a risk factor for outbreaks. Spatial epidemiology studies collating evidence on Q fever geographical contamination gradients are needed, as human cases without occupational exposure are increasing worldwide. METHODS: We used a systematic literature search to assess the role of distance from ruminant holdings as a risk factor for human Q fever outbreaks. We also collated evidence for other putative drivers of C. burnetii geographical dispersal. RESULTS: In all documented outbreaks, infective sheep or goats, not cattle, was the likely source. Evidence suggests a prominent role of airborne dispersal; Coxiella burnetii travels up to 18 km on gale force winds. In rural areas, highest infection risk occurs within 5 km of sources. Urban outbreaks generally occur over smaller distances, though evidence on attack rate gradients is limited. Wind speed / direction, spreading of animal products, and stocking density may all contribute to C. burnetii environmental gradients. CONCLUSIONS: Q fever environmental gradients depend on urbanization level, ruminant species, stocking density and wind speed. While more research is needed, evidence suggests that residential exclusion zones around holdings may be inadequate to contain this zoonotic disease, and should be species-specific. PMID- 29764369 TI - VAReporter: variant reporter for cancer research of massive parallel sequencing. AB - BACKGROUND: High throughput sequencing technologies have been an increasingly critical aspect of precision medicine owing to a better identification of disease targets, which contributes to improved health care cost and clinical outcomes. In particular, disease-oriented targeted enrichment sequencing is becoming a widely accepted application for diagnostic purposes, which can interrogate known diagnostic variants as well as identify novel biomarkers from panels of entire human coding exome or disease-associated genes. RESULTS: We introduce a workflow named VAReporter to facilitate the management of variant assessment in disease targeted sequencing, the identification of pathogenic variants, the interpretation of biological effects and the prioritization of clinically actionable targets. State-of-art algorithms that account for mutation phenotypes are used to rank the importance of mutated genes through visual analytic strategies. We established an extensive annotation source by integrating a wide variety of biomedical databases and followed the American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation and reporting of sequence variations. CONCLUSIONS: In summary, VAReporter is the first web server designed to provide a "one-stop" resource for individual's diagnosis and large scale cohort studies, and is freely available at http://rnd.cgu.edu.tw/vareporter . PMID- 29764370 TI - "Tuberculosis in advanced HIV infection is associated with increased expression of IFNgamma and its downstream targets". AB - BACKGROUND: Tuberculosis (TB) is the major cause of death in Human Immunodeficiency Virus (HIV)-infected individuals. However, diagnosis of TB in HIV remains challenging particularly when HIV infection is advanced. Several gene signatures and serum protein biomarkers have been identified that distinguish active TB from latent infection. Our study was designed to assess if gene expression signatures and cytokine levels would distinguish active TB in advanced HIV. METHODS: We conducted a case-control study of whole blood RNA-Seq and plasma cytokine/chemokine analysis in HIV-infected with CD4+ T cell count of <= 100 cells/MUl, with and without active TB. Next, the overlap of the differentially expressed genes (DEG) with the published signatures was performed and then receiver operator characteristic (ROC) analysis was done on small gene discriminators to determine their performance in distinguishing TB in advanced HIV. ELISA was performed on plasma to evaluate cytokine and chemokine levels. RESULTS: Hierarchical clustering of the transcriptional profiles showed that, in general, HIV-infected individuals with TB (TB-HIV) clustered separately from those without TB. IPA indicated that the TB-HIV signature was characterized by an increase in inflammatory signaling pathways. Analysis of overlaps between DEG in our data set with published TB signatures revealed that significant overlap was seen with one TB signature and one TB-IRIS signature. ROC analysis revealed that transcript levels of FcGR1A (AUC = 0.85) and BATF2 (AUC = 0.82), previously reported as consistent single gene classifiers of active TB irrespective of HIV status, performed successfully even in advanced HIV. Plasma protein levels of IFNgamma, a stimulator of FcGR1A and BATF2, and CXCL10, also up-regulated by IFNgamma, accurately classified active TB (AUC = 0.98 and 0.91, respectively) in advanced HIV. Neither of these genes nor proteins distinguished between TB and TB IRIS. CONCLUSIONS: Gene expression of FcGR1A and BATF2, and plasma protein levels of IFNgamma and CXCL10 have the potential to independently detect TB in advanced HIV. However, since other lung diseases were not included in this study, these final candidates need to be validated as specific to TB in the advanced HIV population with TB. PMID- 29764371 TI - Resolution effects in reconstructing ancestral genomes. AB - BACKGROUND: The reconstruction of ancestral genomes must deal with the problem of resolution, necessarily involving a trade-off between trying to identify genomic details and being overwhelmed by noise at higher resolutions. RESULTS: We use the median reconstruction at the synteny block level, of the ancestral genome of the order Gentianales, based on coffee, Rhazya stricta and grape, to exemplify the effects of resolution (granularity) on comparative genomic analyses. CONCLUSIONS: We show how decreased resolution blurs the differences between evolving genomes, with respect to rate, mutational process and other characteristics. PMID- 29764372 TI - Genomic evidence for intraspecific hybridization in a clonal and extremely halotolerant yeast. AB - BACKGROUND: The black yeast Hortaea werneckii (Dothideomycetes, Ascomycota) is one of the most extremely halotolerant fungi, capable of growth at NaCl concentrations close to saturation. Although dothideomycetous fungi are typically haploid, the reference H. werneckii strain has a diploid genome consisting of two subgenomes with a high level of heterozygosity. RESULTS: In order to explain the origin of the H. werneckii diploid genome we here report the genome sequencing of eleven strains isolated from different habitats and geographic locations. Comparison of nine diploid and two haploid strains showed that the reference genome was likely formed by hybridization between two haploids and not by endoreduplication as suggested previously. Results also support additional hybridization events in the evolutionary history of investigated strains, however exchange of genetic material in the species otherwise appears to be rare. Possible links between such unusual reproduction and the extremotolerance of H. werneckii remain to be investigated. CONCLUSIONS: H. werneckii appears to be able to form persistent haploid as well as diploid strains, is capable of occasional hybridization between relatively heterozygous haploids, but is otherwise limited to clonal reproduction. The reported data and the first identification of haploid H. werneckii strains establish this species as a good model for studying the effects of ploidy and hybridization in an extremotolerant system unperturbed by frequent genetic recombination. PMID- 29764373 TI - A subclinical high tricuspid regurgitation pressure gradient independent of the mean pulmonary artery pressure is a risk factor for the survival after living donor liver transplantation. AB - BACKGROUND: Portopulmonary hypertension (POPH) is characterized by pulmonary vasoconstriction, while hepatopulmonary syndrome (HPS) is characterized by vasodilation. Definite POPH is a risk factor for the survival after orthotopic liver transplantation (OLT), as the congestive pressure affects the grafted liver, while subclinical pulmonary hypertension (PH) has been acknowledged as a non-risk factor for deceased donor OLT. Given that PH measurement requires cardiac catheterization, the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography is used to screen for PH and congestive pressure to the liver. We investigated the impact of a subclinical high TRPG on the survival of small grafted living donor liver transplantation (LDLT). METHODS: We retrospectively analyzed 84 LDLT candidates. Patients exhibiting a TRPG >=25 mmHg on echocardiography were categorized as potentially having liver congestion (subclinical high TRPG; n = 34). The mean pulmonary artery pressure (mPAP) measured after general anesthesia with FIO20.6 (mPAP-FIO20.6) was also assessed. Patients exhibiting pO2 < 80 mmHg and an alveolar-arterial oxygen gradient (AaDO2) >= 15 mmHg were categorized as potentially having HPS (subclinical HPS; n = 29). The clinical course after LDLT was investigated according to subclinical high TRPG. RESULTS: A subclinical high TRPG (p = 0.012) and older donor age (p = 0.008) were correlated with a poor 40-month survival. Although a higher mPAP FIO20.6 was expected to correlate with a worse survival, a high mPAP-FIO20.6 with a low TRPG was associated with high frequency complicating subclinical HPS and a good survival, suggesting a reduction in the PH pressure via pulmonary shunt. CONCLUSION: In cirrhosis patients, mPAP-FIO20.6 may not accurately reflect the congestive pressure to the liver, as the pressure might escape via pulmonary shunt. A subclinical high TRPG is an important marker for predicting a worse survival after LDLT, possibly reflecting congestive pressure to the grafted small liver. PMID- 29764374 TI - Direct measurement of pervasive weak repression by microRNAs and their role at the network level. AB - BACKGROUND: A gene regulatory network (GRN) comprises many weak links that are often regulated by microRNAs. Since miRNAs rarely repress their target genes by more than 30%, doubts have been expressed about the biological relevance of such weak effects. These doubts raise the possibility of under-estimation as miRNA repression is usually estimated indirectly from equilibrium expression levels. RESULTS: To measure miRNA repression directly, we inhibited transcript synthesis in Drosophila larvae and collected time-course data on mRNA abundance, the decline of which reflects transcript degradation. The rate of target degradation in the absence of miR310s, a moderately expressed miRNA family, was found to decrease by 5 to 15%. A conventional analysis that does not remove transcript synthesis yields an estimate of 6.5%, within the range of the new estimates. These data permit further examinations of the repression mechanisms by miRNAs including seed matching types, APA (alternative polyadenylation) sites, effects of other highly-expressed miRNAs and the length of 3'UTR. Our direct measurements suggest the latter two factors have a measurable effect on decay rate. CONCLUSION: The direct measurement confirms pervasive weak repression by miRNAs, supporting the conclusions based on indirect assays. The confirmation suggests that this weak repression may indeed be miRNAs' main function. In this context, we discuss the recent proposal that weak repression is "cumulatively powerful" in stabilizing GRNs. PMID- 29764375 TI - The aquatic animals' transcriptome resource for comparative functional analysis. AB - BACKGROUND: Aquatic animals have great economic and ecological importance. Among them, non-model organisms have been studied regarding eco-toxicity, stress biology, and environmental adaptation. Due to recent advances in next-generation sequencing techniques, large amounts of RNA-seq data for aquatic animals are publicly available. However, currently there is no comprehensive resource exist for the analysis, unification, and integration of these datasets. This study utilizes computational approaches to build a new resource of transcriptomic maps for aquatic animals. This aquatic animal transcriptome map database dbATM provides de novo assembly of transcriptome, gene annotation and comparative analysis of more than twenty aquatic organisms without draft genome. RESULTS: To improve the assembly quality, three computational tools (Trinity, Oases and SOAPdenovo-Trans) were employed to enhance individual transcriptome assembly, and CAP3 and CD-HIT-EST software were then used to merge these three assembled transcriptomes. In addition, functional annotation analysis provides valuable clues to gene characteristics, including full-length transcript coding regions, conserved domains, gene ontology and KEGG pathways. Furthermore, all aquatic animal genes are essential for comparative genomics tasks such as constructing homologous gene groups and blast databases and phylogenetic analysis. CONCLUSION: In conclusion, we establish a resource for non model organism aquatic animals, which is great economic and ecological importance and provide transcriptomic information including functional annotation and comparative transcriptome analysis. The database is now publically accessible through the URL http://dbATM.mbc.nctu.edu.tw/ . PMID- 29764376 TI - Methicillin resistant Staphylococcus Aureus in emergency department patients in the United Arab Emirates. AB - BACKGROUND: Since the 1990s, community-associated methicillin resistant staphylococcus aureus (CA-MRSA) has emerged as an important global cause of skin and soft tissue infections. Little is known about the epidemiology of this pathogen in the Middle East. METHODS: We conducted a prospective observational study in a single large teaching hospital in Dubai to identify the incidence of community-acquired methicillin resistant staphylococcus aureus (MRSA) among ambulatory patients presenting with purulent skin and soft tissue infections. We performed wound cultures and administered standard questionnaires to 100 cases presenting to the emergency department. Bivariate and multivariate analyses were performed to identify risk factors for MSRA versus other pathogens. RESULTS: The prevalence of MRSA was 23% (18/78) among 78 culture-positive isolates and 29% (18/62) among Staphylococcus-positive isolates. 74% received antibiotics of which 4/74 (5%) received antibiotics appropriate for CA-MRSA infections. Multivariate adjusted analysis identified playing contact sports (OR 5.9 [95% CI 1.3-27.1]) and female sex (OR 6.3 [95% CI 1.6-24.8]) as independent risks for MRSA infection. CONCLUSIONS: This is the first study to describe the epidemiology of CA-MRSA in the ambulatory setting in the Middle East and demonstrates a substantial proportion of cases presenting with skin and soft tissue infections were CA-MRSA. Although most skin and soft tissue infections are abscesses for which the cornerstone of treatment is high quality incision and drainage, if adjunct antibiotics are prescribed in this setting, CA-MRSA-active antibiotics should be considered. PMID- 29764378 TI - GRIM-Filter: Fast seed location filtering in DNA read mapping using processing-in memory technologies. AB - BACKGROUND: Seed location filtering is critical in DNA read mapping, a process where billions of DNA fragments (reads) sampled from a donor are mapped onto a reference genome to identify genomic variants of the donor. State-of-the-art read mappers 1) quickly generate possible mapping locations for seeds (i.e., smaller segments) within each read, 2) extract reference sequences at each of the mapping locations, and 3) check similarity between each read and its associated reference sequences with a computationally-expensive algorithm (i.e., sequence alignment) to determine the origin of the read. A seed location filter comes into play before alignment, discarding seed locations that alignment would deem a poor match. The ideal seed location filter would discard all poor match locations prior to alignment such that there is no wasted computation on unnecessary alignments. RESULTS: We propose a novel seed location filtering algorithm, GRIM Filter, optimized to exploit 3D-stacked memory systems that integrate computation within a logic layer stacked under memory layers, to perform processing-in-memory (PIM). GRIM-Filter quickly filters seed locations by 1) introducing a new representation of coarse-grained segments of the reference genome, and 2) using massively-parallel in-memory operations to identify read presence within each coarse-grained segment. Our evaluations show that for a sequence alignment error tolerance of 0.05, GRIM-Filter 1) reduces the false negative rate of filtering by 5.59x-6.41x, and 2) provides an end-to-end read mapper speedup of 1.81x-3.65x, compared to a state-of-the-art read mapper employing the best previous seed location filtering algorithm. CONCLUSION: GRIM-Filter exploits 3D-stacked memory, which enables the efficient use of processing-in-memory, to overcome the memory bandwidth bottleneck in seed location filtering. We show that GRIM-Filter significantly improves the performance of a state-of-the-art read mapper. GRIM Filter is a universal seed location filter that can be applied to any read mapper. We hope that our results provide inspiration for new works to design other bioinformatics algorithms that take advantage of emerging technologies and new processing paradigms, such as processing-in-memory using 3D-stacked memory devices. PMID- 29764377 TI - Transcriptome display during tilapia sex determination and differentiation as revealed by RNA-Seq analysis. AB - BACKGROUND: The factors determining sex in teleosts are diverse. Great efforts have been made to characterize the underlying genetic network in various species. However, only seven master sex-determining genes have been identified in teleosts. While the function of a few genes involved in sex determination and differentiation has been studied, we are far from fully understanding how genes interact to coordinate in this process. RESULTS: To enable systematic insights into fish sexual differentiation, we generated a dynamic co-expression network from tilapia gonadal transcriptomes at 5, 20, 30, 40, 90, and 180 dah (days after hatching), plus 45 and 90 dat (days after treatment) and linked gene expression profiles to both development and sexual differentiation. Transcriptomic profiles of female and male gonads at 5 and 20 dah exhibited high similarities except for a small number of genes that were involved in sex determination, while drastic changes were observed from 90 to 180 dah, with a group of differently expressed genes which were involved in gonadal differentiation and gametogenesis. Weighted gene correlation network analysis identified changes in the expression of Borealin, Gtsf1, tesk1, Zar1, Cdn15, and Rpl that were correlated with the expression of genes previously known to be involved in sex differentiation, such as Foxl2, Cyp19a1a, Gsdf, Dmrt1, and Amh. CONCLUSIONS: Global gonadal gene expression kinetics during sex determination and differentiation have been extensively profiled in tilapia. These findings provide insights into the genetic framework underlying sex determination and sexual differentiation, and expand our current understanding of developmental pathways during teleost sex determination. PMID- 29764379 TI - Identification of usual interstitial pneumonia pattern using RNA-Seq and machine learning: challenges and solutions. AB - BACKGROUND: We developed a classifier using RNA sequencing data that identifies the usual interstitial pneumonia (UIP) pattern for the diagnosis of idiopathic pulmonary fibrosis. We addressed significant challenges, including limited sample size, biological and technical sample heterogeneity, and reagent and assay batch effects. RESULTS: We identified inter- and intra-patient heterogeneity, particularly within the non-UIP group. The models classified UIP on transbronchial biopsy samples with a receiver-operating characteristic area under the curve of ~ 0.9 in cross-validation. Using in silico mixed samples in training, we prospectively defined a decision boundary to optimize specificity at >=85%. The penalized logistic regression model showed greater reproducibility across technical replicates and was chosen as the final model. The final model showed sensitivity of 70% and specificity of 88% in the test set. CONCLUSIONS: We demonstrated that the suggested methodologies appropriately addressed challenges of the sample size, disease heterogeneity and technical batch effects and developed a highly accurate and robust classifier leveraging RNA sequencing for the classification of UIP. PMID- 29764380 TI - Osteoporosis, diabetes, and hypertension are major risk factors for mortality in older adults: an intermediate report on a prospective survey of 1467 community dwelling elderly healthy pensioners in Switzerland. AB - BACKGROUND: Osteoporosis is an important morbidity factor for ageing populations in developed countries. However, compared to the amount of information available on diabetes and cardiovascular disease, little is known about the direct impact of osteoporosis on general mortality in older age. METHODS: We obtained data from a prospective population-based cohort of pensioners from the SENIORLAB study who were subjectively healthy. The inclusion criteria were an age of at least 60 years and Swiss residence. We assessed and analysed clinical measures, voluntary reports, and laboratory values. RESULTS: In total, 1467 subjects were included in the cohort. The mean follow-up time was 3.68 years (95% confidence interval, 3.64 3.71). The ages of the included participants ranged from 60 to 99 years. At follow-up, there were 1401 survivors, and 66 participants had died. According to the multivariate analysis (Cox regression), osteoporosis was the most important risk factor for all-cause mortality (hazard ratio, 4.46; 95% confidence interval, 1.82-10.91), followed by diabetes (hazard ratio, 2.17; 95% confidence interval, 1.04-4.52) and hypertension (hazard ratio, 1.81; 95% confidence interval, 1.09 3.03). CONCLUSIONS: Osteoporosis is a major risk factor for all-cause mortality in a subjectively healthy senior population, followed by type 2 diabetes mellitus and hypertension. Osteoporosis should be more actively diagnosed in healthy pensioners before they develop osteoporosis-associated health incidents. TRIAL REGISTRATION: The present study was registered in the International Standard Randomized Controlled Trial Number registry: ISRCTN53778569 . PMID- 29764381 TI - Isolation of Mycobacterium arupense from pleural effusion: culprit or not? AB - BACKGROUND: Mycobacterium arupense, first identified in 2006, is a slow-growing nontuberculous mycobacterium (NTM) and an emerging cause of tenosynovitis, potentially associated with immunosuppression. However, unlike the diagnostic value of its isolation from osteoarticular specimens, the significance of detecting M. arupense in respiratory specimens is not yet clear. CASE PRESENTATION: To our knowledge, we, for the first time, described the identification of M. arupense from the pleural effusion of an immunocompetent patient, who presented with fever and chylothorax. The symptoms resolved with doxycycline treatment for 45 days and a low-fat, high-protein diet. Follow-up at 14 months showed no relapse. CONCLUSIONS: Because the patient fully recovered without combined anti-NTM treatment, we did not consider M. arupense the etiological cause in this case. This indicates that M. arupense detected in pleural effusion is not necessarily a causative agent and careful interpretation is needed in terms of its clinical relevance. PMID- 29764382 TI - Utility of routine ultrasonography follow-up after total thyroidectomy in patients with papillary thyroid carcinoma: a single-center study. AB - BACKGROUND: This study aimed to assess the appropriate number of sessions and interval of routine follow-up ultrasonography (US) in patients who underwent total thyroidectomy for papillary thyroid carcinoma (PTC). METHODS: Between January 2008 and December 2009, 569 patients underwent total thyroidectomy for PTC. Of the 569 patients, 44 were excluded from the study because of no US follow up data for the neck (n = 43) or owing to indeterminate tumor recurrence/persistence (n = 1). The follow-up US for all the patients was performed by a single radiologist. Based on the cytohistopathological results, tumor recurrence/persistence was determined. RESULTS: In the 525 patients, the mean interval to the last follow-up US was 54.7 months, and the mean number of follow-up US sessions was 4.4. Of the 525 patients, 31 (5.9%) showed nodal (n = 30) and non-nodal (n = 1) tumor recurrence/persistence. Patient age and N stage were independently associated with tumor recurrence/persistence. Among patients showing tumor recurrence/persistence after total thyroidectomy, the time at first detection of suspicious US findings on follow-up US was <=8 months in 2 patients, between 10 and 23 months in 21, and >= 25 months in 8. In a receiver operating characteristic curve analysis, the number of sessions and interval of the provided follow-up US were inappropriate for the detection of tumor recurrence/persistence. CONCLUSIONS: For the detection of tumor recurrence/persistence after total thyroidectomy in PTC patients, routine US follow-up with a 1- or 2-year interval may be excessive. PMID- 29764384 TI - Caesarean section audit to improve quality of care in a rural referral hospital in Tanzania. AB - BACKGROUND: Caesarean section (CS) is often a life-saving procedure, but can also lead to serious complications, even more so in low-resource settings. Therefore unnecessary CS should be avoided and optimal circumstances for vaginal delivery should be created. In this study, we aim to audit indications for Caesarean sections and improve decision-making and obstetric management. METHODS: Audit of all cases of CS performed from January to August 2013 was performed in a rural referral hospital in Tanzania. The study period was divided in three audit blocks; retrospective (before auditing), prospective 1 and prospective 2. A local audit panel (LP) and an external auditor (EA) judged if obstetric management was adequate and indications were appropriate or if CS could have been prevented and yet retain good pregnancy outcome. Furthermore, changes in modes of deliveries, overall pregnancy outcome and decision-to-delivery interval were monitored. RESULTS: During the study period there were 1868 deliveries. Of these, 403 (21.6%) were Caesarean sections. The proportions of unjustified CS prior to introduction of audit were as high as 34 and 75%, according to the respective judgments of LP and EA. Following introduction of audit, the proportions of unjustified CS decreased to 23% (p = 0.29) and 52% (p = 0.01) according to LP and EA respectively. However, CS rate did not change (20.2 to 21.7%), assisted vacuum delivery rate did not increase (3.9 to 1.8%) and median decision-to-delivery interval was 83 min (range 10 - 390 min). CONCLUSIONS: Although this is a single center study, these findings suggest that unnecessary Caesarean sections exist at an alarming rate even in referral hospitals and suggest that a vast number can be averted by introducing a focused CS audit system. Our findings indicate that CS audit is a useful tool and, if well implemented, can enhance rational use of resources, improve decision-making and harmonise practice among care providers. PMID- 29764383 TI - An automated algorithm for the detection of cortical interruptions and its underlying loss of trabecular bone; a reproducibility study. AB - BACKGROUND: We developed a semi-automated algorithm that detects cortical interruptions in finger joints using high-resolution peripheral quantitative computed tomography (HR-pQCT), and extended it with trabecular void volume measurement. In this study we tested the reproducibility of the algorithm using scan/re-scan data. METHODS: Second and third metacarpophalangeal joints of 21 subjects (mean age 49 (SD 11) years, 17 early rheumatoid arthritis and 4 undifferentiated arthritis, all diagnosed < 1 year ago) were imaged twice by HR pQCT on the same day with repositioning between scans. The images were analyzed twice by one operator (OP1) and once by an additional operator (OP2), who independently corrected the bone contours when necessary. The number, surface and volume of interruptions per joint were obtained. Intra- and inter-operator reliability and intra-operator reproducibility were determined by intra-class correlation coefficients (ICC). Intra-operator reproducibility errors were determined as the least significant change (LSCSD). RESULTS: Per joint, the mean number of interruptions was 3.1 (SD 3.6), mean interruption surface 4.2 (SD 7.2) mm2, and mean interruption volume 3.5 (SD 10.6) mm3 for OP1. Intra- and inter operator reliability was excellent for the cortical interruption parameters (ICC >=0.91), except good for the inter-operator reliability of the interruption surface (ICC = 0.70). The LSCSD per joint was 4.2 for the number of interruptions, 5.8 mm2 for interruption surface, and 3.2 mm3 for interruption volume. CONCLUSIONS: The algorithm was highly reproducible in the detection of cortical interruptions and their volume. Based on the LSC findings, the potential value of this algorithm for monitoring structural damage in the joints in early arthritis patients needs to be tested in clinical studies. PMID- 29764385 TI - A qualitative study about the gendered experiences of motherhood and perinatal mortality in mountain villages of Nepal: implications for improving perinatal survival. AB - BACKGROUND: We aim to examine the gendered contexts of poor perinatal survival in the remote mountain villages of Nepal. The study setting comprised two remote mountain villages from a mid-western mountain district of Nepal that ranks lowest on the Human Development Index (0.304), and is reported as having the lowest child survival rates in the country. METHODS: The findings are taken from a larger study of perinatal survival in remote mountain villages of Nepal, conducted through a qualitative methodological approach within a framework of social constructionist and critical theoretical perspectives. Data were collected through in-depth interviews with 42 women and their families, plus a range of healthcare providers (nurses/auxiliary nurses, female health volunteers, support staff, Auxiliary Health Worker and a traditional healer) and other stakeholders from February to June, 2015. Data were analysed with a comprehensive coding process utilising the thematic analysis technique. RESULTS: The social construction of gender is one of the key factors influencing poor perinatal survival in the villages in this study. The key emerging themes from the qualitative data are: (1) Gendered social construct and vulnerability for poor perinatal survival: child marriages, son preference and repeated child bearing; (2) Pregnancy and childbirth in intra-familial dynamics of relationships and power; and (3) Perception of birth as a polluted event: birth in Gotha (cowshed) and giving birth alone. CONCLUSIONS: Motherhood among women of a low social position is central to women and their babies experiencing vulnerabilities related to perinatal survival in the mountain villages. Gendered constructions along the continuum from pre-pregnancy to postnatal (girl settlement, a daughter in-law, ritual pollution about mother and child) create challenges to ensuring perinatal survival in these villages. It is imperative that policies and programmes consider such a context to develop effective working strategies for sustained reduction of future perinatal deaths. PMID- 29764386 TI - Parkinson's Disease Diagnostic Observations (PADDO): study rationale and design of a prospective cohort study for early differentiation of parkinsonism. AB - BACKGROUND: Differentiation of Parkinson's disease (PD) from the various types of atypical parkinsonism (AP) such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS) and vascular parkinsonism (VP), can be challenging, especially early in the disease course when symptoms overlap. A major unmet need in the diagnostic workup of these disorders is a diagnostic tool that differentiates the various disorders, preferably in the earliest disease stages when the clinical presentation is similar. Many diagnostic tests have been evaluated, but their added value was studied mostly in retrospective case-control studies that included patients with a straightforward clinical diagnosis. Here, we describe the design of a prospective cohort study in patients with parkinsonism in an early disease stage who have an uncertain clinical diagnosis. Our aim is to evaluate the diagnostic accuracy of (1) detailed clinical examination by a movement disorder specialist, (2) magnetic resonance imaging (MRI) techniques and (3) cerebrospinal fluid (CSF) biomarkers. METHODS/DESIGN: Patients with parkinsonism with an uncertain clinical diagnosis and a disease course less than three years will be recruited. Patients will undergo extensive neurological examination, brain MRI including conventional and advanced sequences, and a lumbar puncture. The diagnosis (including level of certainty) will be defined by a movement disorders expert, neuroradiologist and neurochemist based on clinical data, MRI results and CSF results, respectively. The clinical diagnosis after three years' follow-up will serve as the "gold standard" reference diagnosis, based on consensus criteria and as established by two movement disorder specialists (blinded to the test results). Diagnostic accuracy of individual instruments and added value of brain MRI and CSF analysis after evaluation by a movement disorder expert will be calculated, expressed as the change in percentage of individuals that are correctly diagnosed with PD or AP. DISCUSSION: This study will yield new insights into the diagnostic value of clinical evaluation by a movement disorder specialist, brain MRI and CSF analysis in discriminating PD from AP in early disease stages. The outcome has the potential to help clinicians in choosing the optimal diagnostic strategy for patients with an uncertain clinical diagnosis. TRIAL REGISTRATION: NCT01249768, registered November 26 2010. PMID- 29764387 TI - Genome-wide identification and comprehensive analysis of microRNAs and phased small interfering RNAs in watermelon. AB - BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs involved in the post-transcriptional gene regulation and play a critical role in plant growth, development and stress responses. Watermelon (Citrullus lanatus L.) is one of the important agricultural crops worldwide. However, the watermelon miRNAs and phasiRNAs and their functions are not well explored. RESULTS: Here we carried out computational and experimental analysis of miRNAs and phased small interfering RNAs (phasiRNAs) in watermelon by analyzing 14 small RNA profiles from roots, leaves, androecium, petals, and fruits, and one published small RNA profile of mixed tissues. To identify the targets of miRNAs and phasiRNAs, we generated a degradome profile for watermelon leaf which is analyzed using the SeqTar algorithm. We identified 97 conserved pre-miRNAs, of which 58 have not been reported previously and 348 conserved mature miRNAs without precursors. We also found 9 novel pre-miRNAs encoding 18 mature miRNAs. One hundred and one 21 nucleotide (nt) PHAS loci, and two hundred and forty one 24 nt PHAS loci were also identified. We identified 127 conserved targets of the conserved miRNAs and TAS3-derived tasiRNAs by analyzing a degradome profile of watermelon leaf. CONCLUSIONS: The presented results provide a comprehensive view of small regulatory RNAs and their targets in watermelon. PMID- 29764389 TI - Comparison of hyperdry amniotic membrane transplantation and conjunctival autografting for primary pterygium. AB - BACKGROUND: The purpose of this study was to evaluate the safety and effectiveness of the hyperdry amniotic membrane transplantation compared with conjunctival autografting for the treatment of primary pterygium. METHODS: One hundred and forty-one eyes from 130 patients with primary pterygium were treated with excision followed by hyperdry amniotic membrane or conjunctival autografting after random selection. Seventy-nine eyes from 71 patients received hyperdry amniotic membrane transplantation (HD-AM group), and 62 eyes from 59 patients received conjunctival autografting (CG group). Patients were followed up at one week and one, three, six, and 12 months post-surgery. Recurrence rate, postoperative complications, and final follow-up patient visits were prospectively evaluated. RESULTS: The mean follow-up duration was 12.56 +/- 4.35 months in the HD-AM group and 12.85 +/- 3.90 months in the CG group. Recurrences were detected in four eyes (5.06%) in the HD-AM group and 13 eyes (20.97%) in the CG group. A statistically significant difference in frequency of recurrence between the two groups (P = 0.003) was observed. The cumulative non-recurrence rates at six and 12 months in all patients stratified by age and sex were not significantly different (P = 0.642 and P = 0.451, respectively, by log-rank test). Graft retraction and necrosis were not detected in the two groups during the follow-up period. CONCLUSION: Hyperdry amniotic membrane transplantation was effective in preventing pterygium recurrence when compared with conjunctival autografting and can be considered a preferable and safe grafting procedure for primary pterygium. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16900270 , Retrospectively registered (Date of registration: 3 May 2018). PMID- 29764391 TI - Practice and outcomes of neonatal resuscitation for newborns with birth asphyxia at Kakamega County General Hospital, Kenya: a direct observation study. AB - BACKGROUND: About three - quarters of all neonatal deaths occur during the first week of life, with over half of these occurring within the first 24 h after birth. The first minutes after birth are critical to reducing neonatal mortality. Successful neonatal resuscitation (NR) has the potential to prevent these perinatal mortalities related to birth asphyxia. This study described the practice of NR and outcomes of newborns with birth asphyxia in a busy referral hospital. METHODS: Direct observations of 138 NRs by 28 healthcare providers (HCPs) were conducted using a predetermined checklist adapted from the national pediatric resuscitation protocol. Descriptive statistics were computed and chi - square tests were used to test associations between the newborn outcome at 1 h and the NR processes for the observed newborns. Logistic regression models assessed the relationship between the survival status at 1 h versus the NR processes and newborn characteristics. RESULTS: Nurses performed 72.5% of the NRs. A warm environment was maintained in 71% of the resuscitations. Airway was checked for almost all newborns (98%) who did not initiate spontaneous breathing after stimulation. However, only 40% of newborns were correctly cared for in case of meconium presence in airway. Bag and mask ventilation (BMV) was initiated in 100% of newborns who did not respond to stimulation and airway maintenance. About 86.2% of resuscitated newborns survived after 1 h. Removing wet cloth (P = 0.035, OR = 2.90, CI = 1.08-7.76), keeping baby warm (P = 0.018, OR = 3.30, CI = 1.22 8.88), meconium in airway (P = 0.042, OR = 0.34, CI = 0.12-0.96) and gestation age (P = 0.007, OR = 1.38, CI = 1.10-1.75) were associated with newborn outcome at 1 h. CONCLUSIONS: Mentorship and regular cost - effective NR trainings with focus on maintaining the warm chain during NR, airway maintenance in meconium presence, BMV and care for premature babies are needed for HCPs providing NR. PMID- 29764390 TI - Delineation of condition specific Cis- and Trans-acting elements in plant promoters under various Endo- and exogenous stimuli. AB - BACKGROUND: Transcription factors (TFs) play essential roles during plant development and response to environmental stresses. However, the relationships among transcription factors, cis-acting elements and target gene expression under endo- and exogenous stimuli have not been systematically characterized. RESULTS: Here, we developed a series of bioinformatics analysis methods to infer transcriptional regulation by using numerous gene expression data from abiotic stresses and hormones treatments. After filtering the expression profiles of TF encoding genes, 291 condition specific transcription factors (CsTFs) were obtained. Differentially expressed genes were then classified into various co expressed gene groups based on each CsTFs. In the case studies of heat stress and ABA treatment, several known and novel cis-acting elements were identified following our bioinformatics approach. Significantly, a palindromic sequence of heat-responsive elements is recognized, and also obtained from a 3D protein structure of heat-shock protein-DNA complex. Notably, overrepresented 3- and 4 mer motifs in an enriched 8-mer motif could be a core cis-element for a CsTF. In addition, the results suggest DNA binding preferences of the same CsTFs are different according to various conditions. CONCLUSIONS: The overall results illustrate this study may be useful in identifying condition specific cis- and trans- regulatory elements and facilitate our understanding of the relationships among TFs, cis-acting elements and target gene expression. PMID- 29764388 TI - Clinicopathological features, surgical strategy and prognosis of duodenal gastrointestinal stromal tumors: a series of 300 patients. AB - BACKGROUND: The relatively low incidence of duodenal gastrointestinal stromal tumors (GISTs) and the unique anatomy make the surgical management and outcomes of this kind of tumor still under debate. Thus, this study aimed to explore the optimal surgical strategy and prognosis of duodenal GISTs. METHODS: A total of 300 cases of duodenal GISTs were obtained from our center (37 cases) and from case reports or series (263 cases) extracted from MEDLINE. Clinicopathological features, type of resections and survivals of duodenal GISTs were analyzed. RESULTS: The most common location of duodenal GISTs was descending portion (137/266, 51.5%). The median tumor size was 4 cm (0.1-28). Most patients (66.3%) received limited resection (LR). Pancreaticoduodenectomy (PD) was mainly performed for GISTs with larger tumor size or arose from descending portion (both P < 0.05). For both the entire cohort and tumors located in the descending portion, PD was not an independent risk factor for disease-free survival (DFS) and disease-specific survival (DSS) (both P > 0.05). Duodenal GISTs were significantly different from gastric GISTs with respect to tumor size, mitotic index and NIH risk category (all P < 0.05). The DFS and DSS of duodenal GISTs was significantly worse than that of gastric GISTs (both P < 0.05). CONCLUSIONS: LR was a more prevalent surgical procedure and PD was mainly performed for tumors with larger diameter or located in descending portion. Type of resection was not an independent risk factor for the prognosis of duodenal GISTs. Prognosis of duodenal GISTs was significantly worse than that of gastric GISTs. PMID- 29764392 TI - 5-a-day fruit and vegetable food product labels: reduced fruit and vegetable consumption following an exaggerated compared to a modest label. AB - BACKGROUND: Food product labels based on the WHO 5-a-day fruit and vegetable (FV) message are becoming increasingly common, but these labels may impact negatively on complementary or subsequent FV consumption. This study aimed to investigate the impact of a '3 of your 5-a-day' versus a '1 of your 5-a-day' smoothie product label on subsequent FV consumption. METHODS: Using an acute experimental design, 194 participants (90 males, 104 females) were randomised to consume a smoothie labelled as either '3 of your 5-a-day' (N = 97) or '1 of your 5-a-day' (N = 97) in full, following a usual breakfast. Subsequent FV consumption was measured for the rest of the day using 24-h recall. Usual FV consumption was also assessed via 24-h recall for the day before the study. RESULTS: Regression analyses revealed a significantly lower subsequent FV consumption following smoothies displaying the '3 of your 5-a-day' label compared to the '1 of your 5-a-day' label (Beta = - 0.15, p = 0.04). Secondary analyses revealed these effects to be driven mainly by changes to consumption in usual high FV consumers, in females and in vegetable as opposed to fruit consumption. CONCLUSIONS: These findings demonstrate a role for label information in food intake, and the potential negative impacts of an exaggerated food product label on healthy food consumption and healthy dietary profiles. PMID- 29764393 TI - Telerehabilitation versus traditional centre-based pulmonary rehabilitation for people with chronic respiratory disease: protocol for a randomised controlled trial. AB - BACKGROUND: Pulmonary rehabilitation is an effective therapeutic intervention for people with chronic respiratory disease. However, fewer than 5% of eligible individuals receive pulmonary rehabilitation on an annual basis, largely due to limited availability of services and difficulties associated with travel and transport. The Rehabilitation Exercise At Home (REAcH) study is an assessor blinded, multi-centre, randomised controlled equivalence trial designed to compare the efficacy of home-based telerehabilitation and traditional centre based pulmonary rehabilitation in people with chronic respiratory disease. METHODS: Participants will undertake an 8-week group-based pulmonary rehabilitation program of twice-weekly supervised exercise training, either in person at a centre-based pulmonary rehabilitation program or remotely from their home via the Internet. Supervised exercise training sessions will include 30 min of aerobic exercise (cycle and/or walking training). Individualised education and self-management training will be delivered. All participants will be prescribed a home exercise program of walking and strengthening activities. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and 12-months post intervention. The primary outcome is change in dyspnea score as measured by the Chronic Respiratory Questionnaire - dyspnea domain (CRQ-D). Secondary outcomes will evaluate the efficacy of telerehabilitation on 6-min walk distance, endurance cycle time during a constant work rate test, physical activity and quality of life. Adherence to pulmonary rehabilitation between the two models will be compared. A full economic analysis from a societal perspective will be undertaken to determine the cost-effectiveness of telerehabilitation compared to centre-based pulmonary rehabilitation. DISCUSSION: Alternative models of pulmonary rehabilitation are required to improve both equity of access and patient-related outcomes. This trial will establish whether telerehabilitation can achieve equivalent improvement in outcomes compared to traditional centre based pulmonary rehabilitation. If efficacious and cost-effective, the proposed telerehabilitation model is designed to be rapidly deployed into clinical practice. TRIAL REGISTRATION: Clinical trial registered with the Australian and New Zealand Clinical Trials Register at ( ACTRN12616000360415 ). Registered 21 March 2016. PMID- 29764394 TI - Comprehensive analysis of coding-lncRNA gene co-expression network uncovers conserved functional lncRNAs in zebrafish. AB - BACKGROUND: Zebrafish is a full-developed model system for studying development processes and human disease. Recent studies of deep sequencing had discovered a large number of long non-coding RNAs (lncRNAs) in zebrafish. However, only few of them had been functionally characterized. Therefore, how to take advantage of the mature zebrafish system to deeply investigate the lncRNAs' function and conservation is really intriguing. RESULTS: We systematically collected and analyzed a series of zebrafish RNA-seq data, then combined them with resources from known database and literatures. As a result, we obtained by far the most complete dataset of zebrafish lncRNAs, containing 13,604 lncRNA genes (21,128 transcripts) in total. Based on that, a co-expression network upon zebrafish coding and lncRNA genes was constructed and analyzed, and used to predict the Gene Ontology (GO) and the KEGG annotation of lncRNA. Meanwhile, we made a conservation analysis on zebrafish lncRNA, identifying 1828 conserved zebrafish lncRNA genes (1890 transcripts) that have their putative mammalian orthologs. We also found that zebrafish lncRNAs play important roles in regulation of the development and function of nervous system; these conserved lncRNAs present a significant sequential and functional conservation, with their mammalian counterparts. CONCLUSIONS: By integrative data analysis and construction of coding-lncRNA gene co-expression network, we gained the most comprehensive dataset of zebrafish lncRNAs up to present, as well as their systematic annotations and comprehensive analyses on function and conservation. Our study provides a reliable zebrafish-based platform to deeply explore lncRNA function and mechanism, as well as the lncRNA commonality between zebrafish and human. PMID- 29764395 TI - Longitudinal changes in bone and mineral metabolism after cessation of cinacalcet in dialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: The calcimimetic agent cinacalcet is effective for the management of secondary hyperparathyroidism (SHPT) in dialysis patients. Changes to reimbursement of cinacalcet in Australia provided an opportunity to assess effects of medication cessation on biochemical and clinical outcomes in dialysis patients, including changes to novel biomarkers such as calciprotein particles (CPP). CPP are nanoparticles of mineral and protein in the circulation associated with increased vascular calcification in patients with chronic kidney disease. METHODS: Dialysis patients from a single center who ceased cinacalcet between August 2015 and March 2016 were included in a prospective observational study. Bloods were taken at the time of cessation of cinacalcet and at 1, 6 and 12 months. Clinical and biochemical outcomes were compared with an age- and gender matched cohort of cinacalcet-naive dialysis patients. RESULTS: Sixty-two patients participated in the study. Mean age was 69.6 +/- 13.2 years. Biochemical changes over 12 months following cessation of cinacalcet included an increase in serum parathyroid hormone (PTH) (42.2 [IQR 27.8-94.6] pmol/L to 114.8 [83.9-159.1] pmol/L [p < 0.001]), serum calcium (2.31 +/- 0.21 mmol/L to 2.46 +/- 0.14 mmol/L [p < 0.001]) and primary CPP (CPP-I) (p = 0.002). Changes in CPP were associated with an increase in PTH (p = 0.007), calcium (p = 0.002) and ferritin (p = 0.02) but a reduction in serum albumin (p = 0.001). Over the 12-month period, there were two fractures, five cardiovascular events, one episode of calciphylaxis, and one parathyroidectomy, with a mortality rate of 19% (n = 13). CONCLUSION: Uniquely we report the effects of cinacalcet withdrawal in a real world setting with demonstrated increases in PTH, serum calcium and CPP subsets, novel CKD-MBD related factors, over a 12-month period. PMID- 29764397 TI - Determinants of child anthropometric indicators in Ethiopia. AB - BACKGROUND: Malnutrition is one of the major contributors to child mortality in Ethiopia. Currently established, child nutrition status is assessed by four anthropometric indicators. However, there are other factors affecting children's anthropometric statuses. Thus, the main objective of this paper is to explore some of the determinants of child anthropometric indicators in Ethiopia. METHODS: Data from GROW (the Growing Nutrition for Mothers and Children), a survey including 1261 mothers and 1261 children was carried out in Ethiopia in 2016. Based on the data gathered, the goal of GROW is to improve the nutritional status of women of reproductive age (15-49), as well as boys and girls under 5 years of age in Ethiopia. In order to investigate the association between different factors and child anthropometric indicators, this study employs various statistical methods, such as ANOVA, T-test, and linear regressions. RESULTS: Child's sex (confidence intervals for (wasting = - 0.782, - 0.151; stunting = - 0.936,-0.243) (underweight = - 0.530, - 0.008), child's age (confidence intervals for (wasting = - 0.020, 0.007; stunting = - 0.042,-0.011) (underweight = - 0.025, - 0.002), maternal MUAC (confidence intervals for (wasting = 0.189, 0.985; BMI for-age = 0.077, 0.895), maternal education (stunting = 0.095, 0.897; underweight = 0.120, 0.729), and open defecation (stunting = 0.055, 0.332; underweight = 0.042, 0.257) were found to be significantly associated with anthropometric indicators. Contrary to some findings, maternal dietary diversity does not present significance in aforementioned child anthropometric indicators. CONCLUSION: Depending on the choice of children anthropometric indicator, different conclusions were drawn demonstrating the association between each factor to child nutritional status. Results showed child's sex, age, region, open defecation, and maternal MUAC significantly increases the risk of child anthropometric indicators. Highlighting the factors influencing child undernutrition will help inform future policies and programs designed to approach this major problem in Ethiopia. PMID- 29764398 TI - Challenges and motivators to physical activity faced by retired men when ageing: a qualitative study. AB - BACKGROUND: Active ageing reflects the message from World Health Organisation about addressing the challenge faced by the rapidly ageing population. Knowledge about barriers and facilitators to an active lifestyle must be given more attention. In addition, men seem to participate less in cultural activities and less in fall-prevention groups than women do. When mostly women work with the elderly in primary care, one might question whether the activities offered to older men meet their activity preferences. The aim of this study is to provide new knowledge about challenges and motivators encountered by retired men in maintaining physical activity when ageing. METHODS: Nine retired men, aged between 66 and 83, wrote a Time Geographic Diary for 7 days each. Two focus group discussions with the men were held. A Systemic Text Condensation was used to analyse the data. RESULTS: The analyses identified three categories to describe challenges in being physical active: differences between men and women; meaningful physical activity; and environmental - especially socio-cultural - constraints. Motivating conditions were seen as: new activities to get younger friends, and more information about how to cope. CONCLUSIONS: To achieve the aim of active ageing, service providers as well as local authorities need to have a better understanding of the challenges retired men encounter when ageing. This study highlights vital aspects of the challenges faced by retired men in maintaining their physical activity level. PMID- 29764396 TI - Functional connectivity of hippocampal subregions in PTSD: relations with symptoms. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with abnormal hippocampal activity; however, the functional connectivity (FC) of the hippocampus with other brain regions in PTSD and its relations with symptoms warrants further attention. We investigated subregional hippocampal FC in PTSD during a resting state compared with a trauma-exposed control (TEC) group. Based on extant research, we targeted the FCs of the anterior and posterior hippocampal subregions with the amygdala, medial prefrontal cortex (mPFC), and the posterior cingulate (PCC). METHODS: Resting-state functional magnetic resonance images were acquired from 11 individuals with PTSD and 13 trauma-exposed controls. Anterior and posterior hippocampal FC was compared between groups. Within the PTSD and TEC groups, subregional hippocampal FC was correlated with scores on the Clinician Administered PTSD Scale (CAPS) at time of scan and 4 months post-scan. RESULTS: Those with PTSD had significantly greater FC compared with the TEC group between the left posterior hippocampus and the bilateral PCC (g's > .96). Direct contrasts of the Fisher z-transformed coefficients indicated that the correlations between CAPS scores 4 months post scan and the FC between the left hippocampal head and the right PCC (z = - 2.07, p = .039) as well as the FC between the right hippocampal tail and the right mPFC (z = - 2.19, p = .029) were significantly greater in the PTSD group compared to the TEC group. CONCLUSIONS: These results support between-group differences in posterior hippocampal FC and different relations with PTSD future symptoms, underscoring associations with the anterior and posterior hippocampus. These findings enrich our understanding of PTSD pathophysiology and provide support for future investigations of imaging biomarkers predictive of disease progression. PMID- 29764399 TI - The reachability of contagion in temporal contact networks: how disease latency can exploit the rhythm of human behavior. AB - BACKGROUND: The symptoms of many infectious diseases influence their host to withdraw from social activity limiting their potential to spread. Successful transmission therefore requires the onset of infectiousness to coincide with a time when the host is socially active. Since social activity and infectiousness are both temporal phenomena, we hypothesize that diseases are most pervasive when these two processes are synchronized. METHODS: We consider disease dynamics that incorporate behavioral responses that effectively shorten the infectious period of the pathogen. Using data collected from face-to-face social interactions and synthetic contact networks constructed from empirical demographic data, we measure the reachability of this disease model and perform disease simulations over a range of latent period durations. RESULTS: We find that maximum transmission risk results when the disease latent period (and thus the generation time) are synchronized with human circadian rhythms of 24 h, and minimum transmission risk when latent periods are out of phase with circadian rhythms by 12 h. The effect of this synchronization is present for a range of disease models with realistic disease parameters and host behavioral responses. CONCLUSIONS: The reproductive potential of pathogens is linked inextricably to the host social behavior required for transmission. We propose that future work should consider contact periodicity in models of disease dynamics, and suggest the possibility that disease control strategies may be designed to optimize against the effects of synchronization. PMID- 29764400 TI - Low-cost HPV testing and the prevalence of cervical infection in asymptomatic populations in Guatemala. AB - BACKGROUND: A low cost and accurate method for detecting high-risk (HR) human papillomavirus (HPV) is important to permit HPV testing for cervical cancer prevention. We used a commercially available HPV method (H13, Hybribio) which was documented to function accurately in a reduced volume of cervical specimen to determine the most prevalent HPV types and the distribution of HPV infections in over 1795 cancer-free women in Guatemala undergoing primary screening for cervical cancer by cytology. METHODS: HR-HPV detection was attempted in cervical samples from 1795 cancer-free women receiving Pap smears using the HybribioTM real-time PCR assay of 13 HR types. The test includes a globin gene internal control. HPV positive samples were sequenced to determine viral type. Age specific prevalence of HPV was also assessed in the study population. RESULTS: A total of 13% (226/1717) of women tested HPV+, with 78 samples (4.3%) failing to amplify the internal control. The highest prevalence was found in younger women (< 30 years, 22%) and older ones (>=60 years, 15%). The six most common HR-HPV types among the 148 HPV+ typed were HPV16 (22%), HPV18 (11%), HPV39 (11%), HPV58 (10%), HPV52 (8%), and HPV45 (8%). CONCLUSIONS: In this sample of cancer free women in Guatemala, HPV16 was the most prevalent HR type in Guatemala and the age specific prevalence curve peaked in younger ages. Women in the 30-59-year age groups had a prevalence of HR-HPV of 8%, however, larger studies to better describe the epidemiology of HPV in Guatemala are needed. PMID- 29764402 TI - Association between induced abortion and suicidal ideation among unmarried female migrant workers in three metropolitan cities in China: a cross-sectional study. AB - BACKGROUND: Despite reports of mental health issues, suicidality has not been closely examined among the migrant population. The association between induced abortion and suicidal ideation is unknown among unmarried female migrant workers of reproductive age in China. This study aims to examine induced abortion and suicidality among the Chinese migrant population. METHODS: We recruited 5115 unmarried female migrant workers during 2015 to 2016 from Shanghai, Beijing and Guangzhou, and collected demographic, psychosocial, reproductive and mental health information using structured questionnaires. We used logistic regression models to examine the association between lifetime induced abortion and suicidal ideation during the past year among the subjects. RESULTS: Overall, 8.2% of the subjects had suicidal ideation during the past year, and 15.5% of the subjects experienced induced abortion. Induced abortion was associated with nearly twice the odds of having past-year suicidal ideation (Odds ratio, OR = 1.89; 95% confidence interval, CI: 1.46, 2.44) after adjusting for age, education, years in the working place, tobacco use, alcohol consumption, daily internet use, attitude towards premarital pregnancy, multiple induced abortion, self-esteem, loneliness, depression, and anxiety disorders. The association was stronger in those aged > 25 (OR = 3.37, 95% CI = 2.16, 5.28), with > 5 years of stay in the working place (OR = 2.98, 95% CI = 2.02, 4.39), the non-anxiety group (OR = 2.28, 95% CI = 1.74, 3.00), and the non-depression group (OR = 2.94, 95% CI = 2.08, 4.15). CONCLUSIONS: Induced abortion was associated with increased odds for suicidal ideation among the unmarried female migrant workers in urban cities in China. More attention should be paid to the mental health of the population. PMID- 29764403 TI - Meteorological factors affecting dengue incidence in Davao, Philippines. AB - BACKGROUND: Dengue fever is a major public health concern in the Philippines, and has been a significant cause of hospitalizations and deaths among young children. Previous literature links climate change to dengue, and with increasingly unpredictable changing climate patterns, there is a need to understand how these meteorological variables affect dengue incidence in a highly endemic area. METHODS: Weekly dengue incidences (2011-2015) in Davao Region, Philippines were obtained from the Department of Health. Same period of weekly local meteorological variables were obtained from the National Climatic Data Center (NCDC) and the National Oceanic and Atmospheric Administration (NOAA). Wavelet coherence analysis was used to determine the presence of non-stationary relationships, while a quasi-Poisson regression combined with distributed lag nonlinear model (DLNM) was used to analyze the association between meteorological variables and dengue incidences. RESULTS: Significant periodicity was detected in the 7 to 14-week band between the year 2011-2012 and a 26-week periodicity from the year 2013-2014. Overall cumulative risks were particularly high for rainfall at 32 mm (RR: 1.67, 95% CI: 1.07-2.62), while risks were observed to increase with increasing dew point. On the other hand, lower average temperature of 26 degrees C has resulted to an increased RR of dengue (RR: 1.96, 95% CI: 0.47-8.15) while higher temperature from 27 degrees C to 31 degrees C has lower RR. CONCLUSIONS: The observed possible threshold levels of these meteorological variables can be integrated into an early warning system to enhance dengue prediction for better vector control and management in the future. PMID- 29764401 TI - Management of acute respiratory failure in interstitial lung diseases: overview and clinical insights. AB - BACKGROUND: Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by widespread fibrotic and inflammatory abnormalities of the lung. Respiratory failure is a common complication in advanced stages or following acute worsening of the underlying disease. Aim of this review is to evaluate the current evidence in determining the best management of acute respiratory failure (ARF) in ILDs. METHODS: A literature search was performed in the Medline/PubMed and EMBASE databases to identify studies that investigated the management of ARF in ILDs (the last search was conducted on November 2017). RESULTS: In managing ARF, it is important to establish an adequate diagnostic and therapeutic management depending on whether the patient has an underlying known chronic ILD or ARF is presenting in an unknown or de novo ILD. In the first case both primary causes, such as acute exacerbations of the disease, and secondary causes, including concomitant pulmonary infections, fluid overload and pulmonary embolism need to be investigated. In the second case, a diagnostic work-up that includes investigations in regards to ILD etiology, such as autoimmune screening and bronchoalveolar lavage, should be performed, and possible concomitant causes of ARF have to be ruled out. Oxygen supplementation and ventilatory support need to be titrated according to the severity of ARF and patients' therapeutic options. High-Flow Nasal oxygen might potentially be an alternative to conventional oxygen therapy in patients requiring both high flows and high oxygen concentrations to correct hypoxemia and control dyspnea, however the evidence is still scarce. Neither Non-Invasive Ventilation (NIV) nor Invasive Mechanical Ventilation (IMV) seem to change the poor outcomes associated to advanced stages of ILDs. However, in selected patients, such as those with less severe ARF, a NIV trial might help in the early recognition of NIV-responder patients, who may present a better short-term prognosis. More invasive techniques, including IMV and Extracorporeal Membrane Oxygenation, should be limited to patients listed for lung transplant or with reversible causes of ARF. CONCLUSIONS: Despite the overall poor prognosis of ARF in ILDs, a personalized approach may positively influence patients' management, possibly leading to improved outcomes. However, further studies are warranted. PMID- 29764405 TI - Urinary iodine concentration and thyroid volume of pregnant women attending antenatal care in two selected hospitals in Ashanti Region, Ghana: a comparative cross-sectional study. AB - BACKGROUND: Iodine deficiency is a major public health problem affecting people worldwide, particularly pregnant women. Iodine requirements increase substantially during pregnancy making pregnant women vulnerable to iodine deficiency and its disorders such as abortions, stillbirths and pregnancy goitre as well as congenital abnormalities, cretinism and mental retardation in their children. The primary aim of this study was to evaluate the prevalence of iodine deficiency and goitre among pregnant women attending antenatal sessions at two selected hospitals in Ashanti region, Ghana. METHODS: A cross-sectional study was carried out in 239 pregnant women who attended the antenatal clinic at Kwame Nkrumah University of Science and Technology (KNUST) Hospital or Ejura District Hospital, both in Ashanti Region, Ghana. Socio-demographic data and information related to iodine were captured using a questionnaire. Urinary iodine concentration (UIC) was determined on spot urine samples using the Sandell Kolthoff reaction with ammonium persulfate as digesting agent. Each woman's thyroid volume was also measured by ultrasonography. RESULTS: The overall median UIC was 155.9 MUg/L, indicating adequate iodine intake in the study population. However, goitre prevalence in the pregnant women was 11.3%, denoting mild iodine deficiency. The median UIC for pregnant women who attended KNUST Hospital was higher (163.8 MUg/L) than that of Ejura District Hospital (149.0 MUg/L). The proportion of women who did not consume iodised salt was significantly higher (p < 0.001) in Ejura District Hospital (71.2%) than KNUST Hospital (28.0%). In total, 47.3% of the pregnant women studied had a UIC < 150 MUg/L. Only 16.3% knew about the increase in iodine requirement during pregnancy and 21.3% of them had knowledge of the effects of iodine deficiency during pregnancy with most (81.8%) knowing of pregnancy goitre. CONCLUSION: There is generally adequate iodine intake among the pregnant women, however, iodine deficiency and goitre still exist among some pregnant women. Thus, assessment and continuous monitoring of iodine nutritional status in pregnant women in the country are warranted. Also, intensification of effective public health campaigns (through radio and television) with regard to iodine utilization and its benefits in pregnancy are still recommended among Ghanaian pregnant women. PMID- 29764404 TI - Advanced sporadic renal epithelioid angiomyolipoma: case report of an extraordinary response to sirolimus linked to TSC2 mutation. AB - BACKGROUND: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. CASE PRESENTATION: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. CONCLUSION: NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs. PMID- 29764406 TI - Women's experiences of continuous support during childbirth: a meta-synthesis. AB - BACKGROUND: Despite the known benefits of continuous support during childbirth, the practice is still not routinely implemented in all maternity settings and women's views and experiences might not be considered. The purpose of the study was to integrate individual studies' findings related to women's experiences of continuous support during childbirth in order to expand the understanding of the phenomenon. The review question was: What were the views and experiences of women regarding continuous support during childbirth as reported in studies that adopted qualitative or mixed research methods (with a qualitative component) using semi-structured, in-depth or focus group interviews or case studies? METHODS: A detailed search was executed on electronic data bases: EBSCOhost: Medline, CINAHL, PsychINFO, SocINDEX, OAlster, Scopus, SciELO, Science Direct, PubMED and Google Scholar, using a predetermined search strategy. Reference lists of included studies were analysed to identify possible studies that were missing from electronic data bases. Pre-determined inclusion and exclusion criteria were applied during the selection of eligible sources. After critical appraisal, a total of 12 studies were included for data-extraction and meta-synthesis. RESULTS: Two themes were identified, namely the roles and attributes of the support persons and the type of support provided. Women's perceptions about continuous support during childbirth were influenced by the characteristics and attributes of the support person as well as the types of supportive care rendered. Women preferred someone with whom they were familiar and comfortable. CONCLUSION: Continuous support during childbirth was valued by most women. Their perceptions were influenced by the type of support person: a health professional or a lay support person. Health care institutions should include continuous support during childbirth in their policies and guidelines. PMID- 29764408 TI - Congenital Rhabdomyosarcoma: a different clinical presentation in two cases. AB - BACKGROUND: Rhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4-2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported. CASE PRESENTATION: We describe two cases with congenital RMS treated at Bambino Gesu Children's Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up. CONCLUSIONS: RMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613-20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets. PMID- 29764407 TI - Are we doing enough to prevent poor-quality antimalarial medicines in the developing world? AB - BACKGROUND: Malaria is a deadly parasitic disease that affects more than 3 billion people worldwide, in predominantly resource-poor countries. Despite malaria being preventable and treatable, a large number of adults and children, mostly in Africa, die from this disease each year. One contributor to needless morbidity and mortality is the production and distribution of poor-quality antimalarial medicines; indeed, it is estimated that over 122,000 deaths of children under 5 years of age in sub-Saharan countries were caused by poor quality antimalarial medicines, in 2013 alone. DISCUSSION: Poor-quality medicines include those that are deliberately falsified for monetary gain and may contain incorrect amounts or even no active ingredients at all, as well as products that are inadequate due to poor compliance to conventional quality standards and medicines that have degraded over time. Across a number of studies it has been reported that 4-92% of antimalarials tested are poor quality. This represents a massive risk to the population subjected to the use of these medicines, in the form of more severe and prolonged illness, additional costs to individuals who already have very little money, and lack of confidence in treatments. The continuing circulation of poor-quality medicines results from a number of factors, including insufficient regulatory capacity in susceptible countries, inadequate funding to perform regulatory functions, poor coordination between regulatory authorities, and inefficient import/export control systems. To combat the distribution of poor-quality medicines a number of organisations have developed guidelines for the procurement of antimalarials, and programs to educate consumers about the risks of poor-quality medicines and incentivise retailers to identify and report falsified medicines. The development of new technologies to quickly identify poor-quality medicines in the field is also essential, and some significant advances have been made. CONCLUSION: There has been considerable improvement in the delivery of high-quality antimalarials to those who need them; however, there is still an urgent need for a collective response by the international community, political leaders, regulatory bodies, and pharmaceutical companies. This should include political commitment for enhanced research and development funding, such as for new innovative track-and trace field devices, and international efforts to strengthen and harmonise drug regulation practices. PMID- 29764409 TI - Quadriceps combined with hip abductor strengthening versus quadriceps strengthening in treating knee osteoarthritis: a study protocol for a randomized controlled trial. AB - BACKGROUND: Lower limb strengthening, especially the quadriceps training, is of much necessity for patients with knee osteoarthritis (KOA). Previous studies suggest that strengthening of the hip muscles, especially the hip abductor, can potentially relieve the KOA-associated symptoms. Nevertheless, the effects of quadriceps combined with hip abductor strengthening remain unclear. Therefore, the current randomized controlled trial is designed aiming to observe whether quadriceps in combination with hip abductor strengthening can better improve the function and reduce pain in KOA patients than quadriceps training alone. METHODS: A total of 80 subjects with symptomatic KOA will be recruited from the communities and hospital outpatient, and will be randomly assigned to the experiment group (Quadriceps-plus-hip-abductor-strengthening) or the control group (Quadriceps-strengthening). Specifically, participants in the experiment group will complete 4 exercises to train the quadriceps and hip abductor twice a day for 6 weeks at home, while those in the control group will only perform 2 exercises to strengthen the quadriceps. Besides, all patients will also receive usual care management, including health education and physical agent therapy when necessary. Knee pain will be measured using the Visual Analogue Scale (VAS) at baseline, in every week during the course of treatment, as well as 8 and 12 weeks after randomization. Furthermore, knee function will be measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale, and the quality of life will be measured using the MOS Item Short-form Health Survey (SF-36). In this study, several simple tests will be applied to assess the objective function. All the assessments except for VAS will be carried out at baseline, and in the 6th, 8th and 12th weeks respectively. DISCUSSION: Our findings will provide more evidence for the effects of hip abductor strengthening on relieving pain and improving function in KOA patients. Hip abductor strengthening can be added into the muscle training program for KOA patients as a supplementary content if it is proved to be effective. TRIAL REGISTRATION: The current study has been registered with the Chinese Clinical Trials Registry (the registration number is ChiCTR-IOC-15007590 , 3rd December, 2015). PMID- 29764410 TI - Changes in risk perceptions during the 2014 Ebola virus disease epidemic: results of two consecutive surveys among the general population in Lower Saxony, Germany. AB - BACKGROUND: The Ebola virus disease (EVD) outbreak 2014 received extensive news media coverage, which faded out before the outbreak ended. News media coverage impacts risk perception; it is, however, unclear if the components of risk perception (affective and cognitive responses) change differently over time. METHODS: In an online panel, we asked participants (n = 1376) about EVD risk perceptions at the epidemic's peak (November 2014) and after news media coverage faded out (August 2015). We investigated worry (affective response), perceived likelihood of infection, perceived personal impact, and coping efficacy (dimensions of cognitive response), and knowledge about transmission. Differences between the surveys with respect to manifestations of affective and cognitive dimensions were tested using the Wilcoxon signed-rank test. The association between individual change in knowledge and worries about EVD in the first survey was investigated using linear regression. RESULTS: In November 2014, the survey was filled in by 974 participants. Ten months later, 662 of them were still members of the online panel and were invited to the follow-up survey. Among the 620 respondents, affective response decreased between the surveys. Knowledge about EVD also decreased; however, participants worried about EVD in 2014 had increased knowledge in 2015. Perceived likelihood of infection decreased over time, while perceived personal impact and coping efficacy did not. CONCLUSIONS: Risk communication appealing to cognitive reactions by informing clearly on the risk of infection in unaffected countries may decrease inappropriate behaviors. PMID- 29764411 TI - Contrast-enhanced ultrasonography of the pancreas shows impaired perfusion in pancreas insufficient cystic fibrosis patients. AB - BACKGROUND: Perfusion assessment of the pancreas is challenging and poorly evaluated. Pancreatic affection is a prevalent feature of cystic fibrosis (CF). Little is known about pancreatic perfusion in CF. We aimed to assess pancreatic perfusion by contrast-enhanced ultrasound (CEUS) analysed in the bolus-and-burst model and software. METHODS: We performed contrast enhanced ultrasound of the pancreas in 25 CF patients and 20 healthy controls. Perfusion data was analysed using a dedicated perfusion model providing the mean capillary transit-time (MTT), blood flow (BF) and blood-volume (BV). CF patients were divided according to exocrine function. RESULTS: The pancreas insufficient CF patients had longer MTT (p <= 0.002), lower BF (p < 0.001) and lower BV (p < 0.05) compared to the healthy controls and sufficient CF patients. Interrater analysis showed substantial agreement for the analysis of mean transit time. CONCLUSION: The bolus-and-burst method used on pancreatic CEUS-examinations demonstrates reduced perfusion in CF patients with pancreas affection. The perfusion model and software requires further optimization and standardization to be clinical applicable for the assessment of pancreatic perfusion. PMID- 29764412 TI - Causes of death among street-connected children and youth in Eldoret, Kenya. AB - BACKGROUND: Street-connected young people carry a disproportionate burden of morbidities, and engage in a variety of practices that may heighten their risk of premature mortality, yet there are currently no reports in the literature on the rates or risk factors for mortality among them, nor on their causes of death. In low- and middle-income countries they are frequently in situations that violate their human rights, likely contributing to their increased burden of morbidities and vulnerability to mortality. We thus sought to describe the number of deaths annually, causes of death, and determine the number of deaths attributable to HIV among street-connected young people aged 0 to 30 years in Eldoret, Kenya. METHODS: Eldoret, Kenya has approximately 1900 street-connected young people. We collected data on deaths occurring from October 2009 to December 2016 from Moi Teaching and Referral Hospital records, Academic Model Providing Access to Healthcare HIV program records, and utilized verbal autopsies when no records were available. Descriptive analyses were conducted stratified by sex and age category, and frequencies and proportions were calculated to provide an overview of the decedents. We used logistic regression to assess the association between underlying cause of death and sex, while controlling for age and location of death. RESULTS: In total there were 100-recorded deaths, 66 among males and 34 among females; 37% of were among those aged <=18 years. HIV/AIDS (37%) was the most common underlying cause of death, followed by assault (36%) and accidents (10%) for all decedents. Among males, the majority of deaths were attributable to assault (49%) and HIV/AIDS (26%), while females primarily died due to HIV/AIDS (59%). CONCLUSION: Our results demonstrate a high number of deaths due to assault among males and HIV/AIDS among males and females. Our findings demonstrate the need for studies of HIV prevalence and incidence among this population to characterize the burden of HIV, particularly among young women given the higher number of deaths attributed to HIV/AIDS among them. Most deaths were preventable and require the urgent attention of service providers and policymakers to implement programs and services to prevent premature mortality and uphold children's rights. PMID- 29764413 TI - Evidence for the use of complementary and alternative medicines during fertility treatment: a scoping review. AB - BACKGROUND: Complementary and alternative medicines (CAM) are sometimes used by individuals who desire to improve the outcomes of their fertility treatment and/or mental health during fertility treatment. However, there is little comprehensive information available that analyzes various CAM methods across treatment outcomes and includes information that is published in languages other than English. METHOD: This scoping review examines the evidence for 12 different CAM methods used to improve female and male fertility outcomes as well as their association with improving mental health outcomes during fertility treatment. Using predefined key words, online medical databases were searched for articles (n = 270). After exclusion criteria were applied, 148 articles were analyzed in terms of their level of evidence and the potential for methodological and author bias. RESULTS: Surveying the literature on a range of techniques, this scoping review finds a lack of high quality evidence that complementary and alternative medicine (CAM) improves fertility or mental health outcomes for men or women. Acupuncture has the highest level of evidence for its use in improving male and female fertility outcomes although this evidence is inconclusive. CONCLUSION: Overall, the quality of the evidence across CAM methods was poor not only because of the use of research designs that do not yield conclusive results, but also because results were contradictory. There is a need for more research using strong methods such as randomized controlled trials to determine the effectiveness of CAM in relation to fertility treatment, and to help physicians and patients make evidence-based decisions about CAM use during fertility treatment. PMID- 29764414 TI - Patient awareness/knowledge towards oral cancer: a cross-sectional survey. AB - BACKGROUND: Oral cancer (OC) is associated with multiple risk factors and high mortality rates and substantially contributes to the global cancer burden despite being highly preventable. This cross-sectional study sought to assess current knowledge, awareness, and behaviors of patients in rural communities surrounding OC risk. METHODS: An anonymous 21-question survey was distributed to patients in waiting rooms of a large integrated medical-dental health system serving north central Wisconsin. Survey results were summarized via descriptive statistics. Odds ratios surrounding health literacy on OC risk factors were obtained using unconditional univariate logistic regression analysis. RESULTS: Of 504 dental and 306 medical patients completing the survey, 62.2% were female, Caucasian/White (92%) with 41% having a <= high school diploma/equivalent. Current smoker/smokeless tobacco use was reported by 34%, while 39% reported former tobacco exposure. Alcohol use was reported by 54% of respondents at the following frequencies: < once/week, (35%); 1-2 times/week, (16%); 3-4 times/week, (6%); 5-6 times/week, (2%); and daily, (23%). Knowledge about tobacco and alcohol use and increased OC risk was reported by 94 and 40%, respectively. About 50% reported knowledgeability regarding cancer-associated symptomology. Tobacco cessation was reported by 20% of responders. Receipt of education on OC from healthcare providers and human papilloma virus links to OC causation was reported by 38 and 21%, respectively. CONCLUSION: Patients who smoked > 20+ cigarettes per day were more knowledgeable about tobacco and OC risk compared to non-smokers and those who smoked <= 19 cigarettes/day (p = 0.0647). Patients who were alcohol consumers exhibited higher knowledgeability surrounding increased OC risk with alcohol and tobacco exposures compared to alcohol abstainers (p = 0.06). We concluded that patients recognized links between tobacco and OC risk but demonstrated lower knowledge of other causal factors. Strategic patient education by providers could increase awareness of OC risk. PMID- 29764415 TI - Perioperative outcomes of zero ischemia radiofrequency ablation-assisted tumor enucleation for renal cell carcinoma: results of 182 patients. AB - BACKGROUND: To evaluate the perioperative outcomes of zero ischemia radiofrequency ablation-assisted tumor enucleation. METHODS: Patients undergoing zero ischemia radiofrequency ablation-assisted tumor enucleation were retrospectively identified from July 2008 to March 2013. The tumor was enucleated after RFA treatment. R.E.N.A.L., PADUA and centrality index (C-index) score systems were used to assess each tumor case. We analyzed the correlation of perioperative outcomes with these scores. Postoperative complications were graded with Clavien-Dindo system. Multivariate logistic regression analyses were used to assess risk of complications. RESULTS: Among 182 patients assessed, median tumor size, estimated blood loss, hospital stay and operative time were 3.2 cm (IQR 2.8 3.4), 80 ml (IQR 50-120), 7 days (IQR 6-8) and 100 min (IQR 90-120), respectively. All three scoring systems were strongly correlated with estimated blood loss, hospital stay and operative time. We found 3 (1.6%) intraoperative and 23 (12.6%, 13 [7.1%] Grade 1 and 10 [5.5%] Grade 2 & 3a) postoperative complications. The median follow-up was 55.5 months (IQR 45-70). Additionally, the complexities of R.E.N.A.L., PADUA and C-index scores were significantly correlated with complication grades (P < 0.001; P < 0.001; P < 0.001; respectively). As the representative, R.E.N.A.L. score was an independent predictive factor for postoperative complications and patients with a high complexity had an over 24-fold higher risk compared to those with a low complexity (OR 24.360, 95% CI 4.412-134.493, P < 0.001). CONCLUSIONS: Zero ischemia radiofrequency ablation-assisted tumor enucleation is considered an effective nephron-sparing treatment. Scoring systems could be useful for predicting perioperative outcomes of radiofrequency ablation-assisted tumor enucleation. PMID- 29764416 TI - Safety of a condom uterine balloon tamponade (ESM-UBT) device for uncontrolled primary postpartum hemorrhage among facilities in Kenya and Sierra Leone. AB - BACKGROUND: Postpartum hemorrhage is the leading cause of maternal mortality in low- and middle-income countries. While evidence on uterine balloon tamponade efficacy for severe hemorrhage is encouraging, little is known about safety of this intervention. The objective of this study was to evaluate the safety of an ultra-low-cost uterine balloon tamponade package (named ESM-UBT) for facility based management of uncontrolled postpartum hemorrhage (PPH) in Kenya and Sierra Leone. METHODS: Data were collected on complications/adverse events in all women who had an ESM-UBT device placed among 92 facilities in Sierra Leone and Kenya, between September 2012 and December 2015, as part of a multi-country study. Three expert maternal health investigator physicians analyzed each complication/adverse event and developed consensus on whether there was a potential causal relationship associated with use of the ESM-UBT device. Adverse events/complications specifically investigated included death, hysterectomy, uterine rupture, perineal or cervical injury, serious or minor infection, and latex allergy/anaphylaxis. RESULTS: Of the 201 women treated with an ESM-UBT device in Kenya and Sierra Leone, 189 (94.0%) survived. Six-week or longer follow up was recorded in 156 of the 189 (82.5%). A causal relationship between use of an ESM-UBT device and one death, three perineal injuries and one case of mild endometritis could not be completely excluded. Three experts found a potential association between these injuries and an ESM-UBT device highly unlikely. CONCLUSION: The ESM-UBT device appears safe for use in women with uncontrolled PPH. TRIAL REGISTRATION: Trial registration was not completed as data was collected as a quality assurance measure for the ESM-UBT kit. PMID- 29764417 TI - UPF1 silenced cellular model systems for screening of read-through agents active on beta039 thalassemia point mutation. AB - BACKGROUND: Nonsense mutations promote premature translational termination, introducing stop codons within the coding region of mRNAs and causing inherited diseases, including thalassemia. For instance, in beta039 thalassemia the CAG (glutamine) codon is mutated to the UAG stop codon, leading to premature translation termination and to mRNA destabilization through the well described NMD (nonsense-mediated mRNA decay). In order to develop an approach facilitating translation and, therefore, protection from NMD, ribosomal read-through molecules, such as aminoglycoside antibiotics, have been tested on mRNAs carrying premature stop codons. These findings have introduced new hopes for the development of a pharmacological approach to the beta039 thalassemia therapy. While several strategies, designed to enhance translational read-through, have been reported to inhibit NMD efficiency concomitantly, experimental tools for systematic analysis of mammalian NMD inhibition by translational read-through are lacking. RESULTS: We developed a human cellular model of the beta039 thalassemia mutation with UPF-1 suppressed and showing a partial NMD suppression. CONCLUSIONS: This novel cellular model could be used for the screening of molecules exhibiting preferential read-through activity allowing a great rescue of the mutated transcripts. PMID- 29764418 TI - Engineering xylose metabolism for production of polyhydroxybutyrate in the non model bacterium Burkholderia sacchari. AB - BACKGROUND: Despite its ability to grow and produce high-value molecules using renewable carbon sources, two main factors must be improved to use Burkholderia sacchari as a chassis for bioproduction at an industrial scale: first, the lack of molecular tools to engineer this organism and second, the inherently slow growth rate and poly-3-hydroxybutyrate [P(3HB)] production using xylose. In this work, we have addressed both factors. RESULTS: First, we adapted a set of BglBrick plasmids and showed tunable expression in B. sacchari. Finally, we assessed growth rate and P(3HB) production through overexpression of xylose transporters, catabolic or regulatory genes. Overexpression of xylR significantly improved growth rate (55.5% improvement), polymer yield (77.27% improvement), and resulted in 71% of cell dry weight as P(3HB). CONCLUSIONS: These values are unprecedented for P(3HB) accumulation using xylose as a sole carbon source and highlight the importance of precise expression control for improving utilization of hemicellulosic sugars in B. sacchari. PMID- 29764419 TI - Pyronaridine-artesunate and artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a randomized controlled non-inferiority trial. AB - BACKGROUND: Pyronaridine-artesunate is a novel artemisinin-based combination therapy. The efficacy and safety of pyronaridine-artesunate were compared with artemether-lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria in children. METHODS: This phase III open-label randomized controlled non inferiority trial was conducted in Western Kenya. Children aged 6 months to <= 12 years with a bodyweight > 5 kg and microscopically confirmed P. falciparum malaria were randomly assigned in a 1:1 ratio to orally receive pyronaridine artesunate or artemether-lumefantrine, dosed according to bodyweight, for 3 days. RESULTS: Of 197 participants, 101 received pyronaridine-artesunate and 96 received artemether-lumefantrine. The day-28 adequate clinical and parasitological response in the per-protocol population, PCR-corrected for reinfections, was 98.9% (93/94, 95% CI 94.2-99.8) for pyronaridine-artesunate and 96.4% (81/84, 95% CI 90.0-98.8) for artemether-lumefantrine. Pyronaridine artesunate was found to be non-inferior to artemether-lumefantrine: the treatment difference was 2.5% (95% CI - 2.8 to 9.0). Adverse events occurred in 41.6% (42/101) and 34.4% (33/96) of patients in the pyronaridine-artesunate group and the artemether-lumefantrine group, respectively. No participants were found to have alanine or aspartate aminotransferase levels > 3 times the upper limit of normal. CONCLUSIONS: Pyronaridine-artesunate was well tolerated, efficacious and non-inferior to artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria in Kenyan children. Results are in line with previous reports and inclusion of pyronaridine-artesunate in paediatric malaria treatment programmes should be considered. This study is registered at clinicaltrials.gov under NCT02411994. Registration date: 8 April 2015. https://clinicaltrials.gov/ct2/show/NCT02411994?term=pyronaridine artesunate&cond=Malaria&cntry=KE&rank=1. PMID- 29764421 TI - Computational analysis of the receptor binding specificity of novel influenza A/H7N9 viruses. AB - BACKGROUND: Influenza viruses are undergoing continuous and rapid evolution. The fatal influenza A/H7N9 has drawn attention since the first wave of infections in March 2013, and raised more grave concerns with its increased potential to spread among humans. Experimental studies have revealed several host and virulence markers, indicating differential host binding preferences which can help estimate the potential of causing a pandemic. Here we systematically investigate the sequence pattern and structural characteristics of novel influenza A/H7N9 using computational approaches. RESULTS: The sequence analysis highlighted mutations in protein functional domains of influenza viruses. Molecular docking and molecular dynamics simulation revealed that the hemagglutinin (HA) of A/Taiwan/1/2017(H7N9) strain enhanced the binding with both avian and human receptor analogs, compared with the previous A/Shanghai/02/2013(H7N9) strain. The Molecular Mechanics - Poisson Boltzmann Surface Area (MM-PBSA) calculation revealed the change of residue-ligand interaction energy and detected the residues with conspicuous binding preference. CONCLUSION: The results are novel and specific to the emerging influenza A/Taiwan/1/2017(H7N9) strain compared with A/Shanghai/02/2013(H7N9). Its enhanced ability to bind human receptor analogs, which are abundant in the human upper respiratory tract, may be responsible for the recent outbreak. Residues showing binding preference were detected, which could facilitate monitoring the circulating influenza viruses. PMID- 29764420 TI - Mental health supported accommodation services: a systematic review of mental health and psychosocial outcomes. AB - BACKGROUND: Post-deinstitutionalisation, mental health supported accommodation services have been implemented widely. The available research evidence is heterogeneous in nature and resistant to synthesis attempts, leaving researchers and policy makers with no clear summary what works and for whom. In this context, we undertook a comprehensive systematic review of quantitative studies in order to synthesise the current evidence on mental health and psychosocial outcomes for individuals residing in mental health supported accommodation services. METHODS: Using a combination of electronic database searches, hand searches, forward backward snowballing and article recommendations from an expert panel, 115 papers were identified for review. Data extraction and quality assessments were conducted, and 33 articles were excluded due to low quality, leaving 82 papers in the final review. Variation in terminology and service characteristics made the comparison of service models unfeasible. As such, findings were presented according to the following sub-groups: 'Homeless', 'Deinstitutionalisation' and 'General Severe Mental Illness (SMI)'. RESULTS: Results were mixed, reflecting the heterogeneity of the supported accommodation literature, in terms of research quality, experimental design, population, service types and outcomes assessed. There is some evidence that supported accommodation is effective across a range of psychosocial outcomes. The most robust evidence supports the effectiveness of the permanent supported accommodation model for homeless SMI in generating improvements in housing retention and stability, and appropriate use of clinical services over time, and for other forms of supported accommodation for deinstitutionalised populations in reducing hospitalisation rates and improving appropriate service use. The evidence base for general SMI populations is less developed, and requires further research. CONCLUSIONS: A lack of high-quality experimental studies, definitional inconsistency and poor reporting continue to stymie our ability to identify effective supported accommodation models and practices. The authors recommend improved reporting standards and the prioritisation of experimental studies that compare outcomes across different service models. PMID- 29764422 TI - hmmIBD: software to infer pairwise identity by descent between haploid genotypes. AB - BACKGROUND: A number of recent malaria studies have used identity by descent (IBD) to study epidemiological processes relevant to malaria control. In this paper, a software package, hmmIBD, is introduced for estimating pairwise IBD between haploid genomes, such as those of the malaria parasite, sampled from one or two populations. Source code is freely available. METHODS: The performance of hmmIBD was verified using simulated data and benchmarked against an existing method for detecting IBD within populations. Code for all tests is freely available. The utility of hmmIBD for detecting IBD across populations was demonstrated using Plasmodium falciparum data from Cambodia and Ghana. RESULTS: Alongside an existing method, hmmIBD was highly accurate, sensitive and specific. It is fast, requiring only 70 s on average to analyse 50 whole genome sequences on a laptop computer, and scales linearly in the number of pairwise comparisons. Treatment of different populations under hmmIBD improves detection of IBD across populations. CONCLUSION: Fast and accurate software for detecting IBD in malaria parasite genetic data sampled from one or two populations is presented. The latter will likely be a useful feature for malaria elimination efforts, since it could facilitate identification of imported malaria cases. Software is robust to possible misspecification of the genotyping error and the recombination rate. However, exclusion of data in regions whose rates vary greatly from their genome wide average is recommended. PMID- 29764423 TI - Multidisciplinary biopsychosocial rehabilitation for chronic low back pain: the need to present minimal important differences units in meta-analyses. AB - BACKGROUND: The results of meta-analyses are all too often elusive, making it difficult to interpret their relevance for clinical practice. Reporting them in minimal important difference (MID) units could improve the interpretation of evidence in meta-analyses. The aim of this study was to compare, via calculation of MID units, outcomes after multidisciplinary biopsychosocial rehabilitation (MBR) versus usual care for pain relief in chronic low back pain (LBP). METHODS: We re-analyzed the data of a published Cochrane review on MBR. To attribute a MID to each pain instrument, we first searched the literature for MIDs. The MID was imputed for instruments without an established MID. We compared outcomes after MBR versus usual care for chronic LBP in the short (< 3 months), mid (> 3 and < 12 months), and long (>=12 months) term. The results of the meta-analyses are reported in MID units and interpreted as follows: if the overall effect size was greater than 1, many patients gained clinically important benefits, if it lay between 0.5 and 1.0, an appreciable number benefited, and if it fell below 0.5 few did. RESULTS: Improvement in back pain was observed in an appreciable number of patients in the short- and medium-term after MBR: the MID was lower but still close to 1 (0.75 and 0.86 MID units, respectively). MBR probably had little or no benefit for the majority of patients in the long-term, where the MID approached 0 (0.27 MID units, confidence interval 0.07-0.48). CONCLUSIONS: Meta-analyses expressed in MID units may offer better insight into the clinical relevance of MBR: the intervention is highly recommended for reducing pain in the short- and medium-term but cannot be recommended for long-term pain reduction since the benefit decays rapidly. PMID- 29764426 TI - Outcome of capacity building intervention for malaria vector surveillance, control and research in Nigerian higher institutions. AB - BACKGROUND: Despite the availability of effective malaria vector control intervention tools, implementation of control programmes in Nigeria is challenged by inadequate entomological surveillance data. This study was designed to assess and build the existing capacity for malaria vector surveillance, control and research (MVSC&R) in Nigerian institutions. METHODS: Application call to select qualified candidates for the capacity building (CB) intervention training programme was advertised in a widely read newspaper and online platforms of national and international professional bodies. Two trainings were organized to train selected applicants on field activities, laboratory tools and techniques relevant to malaria vector surveillance and control research. A semi-structured questionnaire was administered to collect data on socio-demographic characteristics of participants, knowledge and access of participants to field and laboratory techniques in MVSC&R. Similarly, pre and post-intervention tests were conducted to assess the performance and improvement in knowledge of the participants. Mentoring activities to sustain CB activities after the training were also carried out. RESULTS: A total of 23 suitable applicants were shortlisted out of the 89 applications received. The South West, South East and North Central geopolitical zones of the country had the highest applications and the highest selected number of qualified applicants compared to the South South and North East geopolitical zones. The distribution with respect to gender indicated that males (72.7%) were more than females (27.3%). Mean score of participants' knowledge of field techniques was 27.8 (+/- 10.8) before training and 67.7 (+/- 9.8) after the training. Similarly, participants' knowledge on laboratory techniques also improved from 37.4 (+/- 5.6) to 77.2 (+/- 10.8). The difference in the mean scores at pre and post-test was statistically significant (p < 0.05). Access of participants to laboratory and field tools used in MVSC&R was generally low with insecticide susceptibility bioassays and pyrethrum spray collection methods being the most significant (p < 0.05). CONCLUSIONS: The capacity available for vector control research and surveillance at institutional level in Nigeria is weak and require further strengthening. Increased training and access of personnel to relevant tools for MVSC&R is required in higher institutions in the six geopolitical zones of the country. PMID- 29764425 TI - Mobility patterns and associated factors among pregnant internal migrant women in China: a cross-sectional study from a National Monitoring Survey. AB - BACKGROUND: Residential instability during pregnancy has been linked to poor health outcomes. As a first step toward providing better health care to pregnant migrant women, the size and characteristics of this population and factors associated with mobility during pregnancy should be studied. METHODS: Using the "Monitoring Data of Chinese Migrants" for 2012, from the Chinese National Population and Family Planning Commission, this study explored mobility patterns during pregnancy and associated factors among migrants within China. From a library of 158,556 participants, two subsamples were selected. Percentages, with chi-squared tests, and means and standard deviations, with ANOVAs, were adopted to describe mobility patterns during pregnancy (always staying in sending area, mainly staying in sending area, mainly staying in receiving area, and always staying in receiving area) and delivery location choice. Logistic regression analysis was used to explore the associated factors. RESULTS: We found that the percentage of migrants always or mainly staying in receiving areas during pregnancy rose from nearly 40% in 1985 to more than 80% in 2012, while the percentage of migrants who were mobile between receiving and sending areas during pregnancy fluctuated between 30 and 40% before 1995, and between 40 and 45% after 1995, decreasing to around 40% after 2008. The percentage of respondents who chose to deliver in receiving areas fluctuated but increased from 10% in 1985 to more than 50% in 2011. Among respondents who had delivered during the last year of the survey period, families with older pregnant women (OR = 1.09, 95% CI 1.05 1.13), their own housing (OR = 5.66, 95% CI 2.45-13.05), longer time in the receiving area (OR = 1.14, 95% CI 1.09-1.20), and strong will to integrate (OR = 1.32, 95% CI 1.15-1.51) always stayed in the receiving area during pregnancy, rather than the sending area, and families with broadly similar characteristics were inclined to choose the receiving area for their delivery. CONCLUSIONS: The mobility patterns of pregnant migrant women in China have been changing in recent years, with the percentage of them staying in receiving areas during pregnancy and delivering there increasing. Individual and family characteristics were also associated with mobility patterns and delivery location choice. PMID- 29764424 TI - Long non-coding RNA NEAT1-modulated abnormal lipolysis via ATGL drives hepatocellular carcinoma proliferation. AB - BACKGROUND: Abnormal metabolism, including abnormal lipid metabolism, is a hallmark of cancer cells. Some studies have demonstrated that the lipogenic pathway might promote the development of hepatocellular carcinoma (HCC). However, the role of the lipolytic pathway in HCC has not been elucidated. METHODS: We compared levels of adipose triglyceride lipase (ATGL) in human HCC and healthy liver tissues by real time PCR, western blot and immunohistochemistry. We measured diacylglycerol(DAG) and free fatty acid (FFA) levels in HCC cells driven by the NEAT1-ATGL axis and in HCC tissues. We also assessed the effects of ATGL, DAG, FFA, and NEAT1 on HCC cells proliferation in vitro and in an orthotopic xenograft HCC mouse model. We also performed a luciferase reporter assay to investigate the interaction between NEAT1/ATGL and miR-124-3p. RESULTS: We found that the lipolytic enzyme, ATGL is highly expressed in human HCC tissues and predicts poor prognosis. We also found that high levels of DAG and FFA are present in HCC tissues. Furthermore, the lncRNA-NEAT1 was found to modulate ATGL expression and disrupt lipolysis in HCC cells via ATGL. Notably, ATGL and its products, DAG and FFA, were shown to be responsible for NEAT1-mediated HCC cell growth. NEAT1 regulated ATGL expression by binding miR-124-3p. Additionally, NEAT1 knockdown attenuated HCC cell growth through miR-124 3p/ATGL/DAG+FFA/PPARalpha signaling. CONCLUSION: Our results reveal that NEAT1 modulates abnormal lipolysis via ATGL to drive HCC proliferation. PMID- 29764427 TI - COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect? AB - BACKGROUND: About 40-50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). METHODS: Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. RESULTS: In one family with four patients, we found evidence for the contribution of two co inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. CONCLUSIONS: A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts. PMID- 29764428 TI - Palatal dimensions at different stages of dentition in 5 to 18-year-old Iranian children and adolescent with normal occlusion. AB - BACKGROUND: This study was purposed to evaluate palatal width, height, and height index at various stages of dentition in Iranian children and adolescent with normal occlusion. METHODS: This cross-sectional study was conducted on a random sample of 237 children (45% male and 55% female, aged 5-18 years) with normal occlusion selected from kindergartens and elementary and high schools in Hamadan, Iran. The subjects were clinically examined and classified based on dentition to primary (21.5%), mixed (21.9%), and permanent (56.5%) stages. Dental casts were obtained from all subjects. Palatal width (inter-molar and -canine distances), and height (at molar and canine areas) were measured on the casts by Korkhaus' compass and digital caliper. Palatal height index was calculated for each dentition stage. Data were analyzed by SPSS 15 using one-way ANOVA followed by Tukey's post hoc test and t- test (p < 0.05). RESULTS: Palatal inter-molar and canine width values were increased from primary to permanent dentition. Palatal height and palatal height index in mixed dentition were significantly lower than those in primary and permanent dentition. Palatal width at inter-molar and canine distances was significantly higher in males than females. There was no significant difference in palatal height and palatal height index at molar area between males and females. However, palatal height and palatal height index at canine area were significantly higher in males compared to females. CONCLUSION: These findings showed that palatal width increased from primary to permanent stage. Palatal height and palatal height index decrease from primary to mixed dentation, then increase from mixed to permanent dentition. PMID- 29764429 TI - Health and quality of life outcomes impairment of quality of life in type 2 diabetes mellitus: a cross-sectional study. AB - BACKGROUND: Type 2 diabetes mellitus (DM2) is a chronic disease, and for treatment to succeed, it is necessary to harmonize the mental health of the patient with the environment, which impacts quality of life and adherence to medical regimens. The objetive of this study is describe the quality of life of patients with DM2 and the factors relates to its modification. METHODS: This investigation was a cross-sectional study. Patients over 18 years of age with DM2 were selected. The following variables related to quality of life were studied: age, sex, occupation, marital status, years of DM2 evolution, comorbidities and presence of depression (Beck Depression Inventory). Perceived quality of life was measured with a health-related quality of life (HRQoL) scale, the 36-Item Short Form Survey (SF-36). Patients were classified according to SF-36 HRQoL score (< 50, 51-75 and > 76 points). RESULTS: Among the 1394 patients included, the median age was 62 years. Global HRQoL had a median of 50.1 points. Bivariate analysis showed that age, marital status, sex, occupation, comorbidities, duration of DM2 and comorbidities had impacts on HRQoL. The logistic regression model identified age (odds ratio [OR] 1.04) and depression (OR 4.4) as independent factors that influenced overall quality of life. CONCLUSIONS: Patients with DM2 have poor HRQoL, which is associated with a high frequency of depression. Older age and the presence of depression impair patient HRQoL. TRIAL REGISTRATION: R-2013-781-052. Registered 20 December 2014. PMID- 29764430 TI - Drug prescribing during pregnancy in a central region of Italy, 2008-2012. AB - BACKGROUND: Drug consumption during pregnancy is a matter of concern, especially regarding drugs known or suspected to be teratogens. Little is known about drug use in pregnant women in Italy. The present study is aimed at examining the prevalence, and to detect potential inappropriateness of drug prescribing among pregnant women in Latium, a region of central Italy. METHODS: This retrospective study was conducted on a cohort of women aged 18-45 years who delivered between 2008 and 2012 in public hospitals. Women were enrolled through the Regional Birth Register. After linking the regional Health Information Systems and the Regional Drug Claims Register, women's clinical data and prescribed medications were analyzed. Italian Medicine Agency (AIFA) and US Food and Drug Administration (FDA) evidence were used to investigate inappropriate prescribing and teratogenic risk. RESULTS: Excluding vitamins and minerals, 80.6% (n = 153,079) of the women were prescribed at least one drug during pregnancy, with an average of 4.6 medications per pregnancy. Drugs for blood and hematopoietic organs were the most commonly prescribed (53.0%,), followed by anti-infectives for systemic use (50.7%). Among the inappropriate prescriptions, progestogen supplementation was given in 20.1% of pregnancies; teratogen drugs were prescribed in 0.8%, mostly angiotensin co-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) (0.3%). CONCLUSIONS: In Latium, drugs are widely used in pregnancy. Prescriptions of inappropriate drugs are observed in more than a fifth of pregnancies, and teratogens are still used, despite their known risk. Continuous updates of information provided to practitioners and an increased availability of information to women might reduce inappropriate prescribing. PMID- 29764431 TI - Cyclooxygenase-2 immunoexpression in intestinal epithelium and lamina propria of cats with inflammatory bowel disease and low grade alimentary lymphoma. AB - BACKGROUND: Cyclooxygenase 2 (COX-2) is an inducible isoform by cellular activation, proinflammatory cytokines and growth factors. The aims of the current study were to evaluate COX-2 immunoexpression in epithelial and lamina propria (LP) of cats with inflammatory bowel disease (IBD) and low grade alimentary lymphoma (LGAL), as well as to correlate them with clinical signs and histopathological scoring. Cats diagnosed with IBD and LGAL (2007-2013) were included in the current study. Feline chronic enteropathy activity index (FCEAI) was calculated for all cases. Control group was composed by 3 healthy indoor cats and 5 sick cats died or were euthanized (non-gastrointestinal illness). Diagnosis and classification of IBD and LGAL was established according to the WSAVA gastrointestinal standardization group template and the National Cancer Institute formulation, respectively. Furthermore, a modified WSAVA template was applied for LGAL evaluation. Immunolabelling for COX-2 (polyclonal rabbit anti-murine antibody) was performed on biopsy samples. Epithelial and LP (inflammatory or neoplastic cells) COX-2 immunolabelling was calculated according to the grade and intensity. The most representative segment scored by the WSAVA and the modified WSAVA were used for statistical analysis. RESULTS: Significant difference was found regarding COX-2 intensity overexpression in the epithelial cells of IBD and LGAL groups when compared to control cats, but not between the groups of sick cats, whereas no differences were found regarding the grade of immunoreactivity between groups. No difference was found for COX-2 immunoexpression at the LP between all groups. However, 3 cats from LGAL group showed COX-2 expression in neoplastic cells at the LP. There were no correlations between epithelial or LP COX-2 expression and FCEAI and histological alterations. CONCLUSIONS: Increased COX-2 intensity at the epithelial cells observed in cats with IBD and LGAL may be secondary to the inflammatory response or a protective function in the intestinal reparation. COX-2 expression at the LP was presented in 33% of LGAL. This result provides a reason for further investigation concerning the role of COX-2 expression in feline alimentary lymphoma. PMID- 29764432 TI - Post-traumatic cognitions and quality of life in terrorism victims: the role of well-being in indirect versus direct exposure. AB - BACKGROUND: The effect of indirect (versus direct) exposure to a traumatic event on the quality of life of terrorist attack victims has received considerable attention in the literature. However, more research is required to examine whether the symptoms and underlying processes caused by both types of exposure are equivalent. Our main hypothesis is that well-being plays a different role depending on indirect vs. direct trauma exposure. METHODS: In this cross sectional study, eighty direct victims of 11-M terrorist attacks (people who were traveling in trains where bombs were placed) and two-hundred indirect victims (individuals highly exposed to the 11-M terrorist attacks through communications media) voluntarily participated without compensation. To test our hypothesis regarding the mediating role of indirect exposure, we conducted a biased corrected bootstrapping procedure. To test our hypothesis regarding the moderating role of direct exposure, data were subjected to a hierarchical regression analysis. RESULTS: As predicted, for indirect trauma exposure, well being mediated the relationship between post-traumatic dysfunctional cognitions and trauma symptoms. However, for direct trauma exposure, well-being moderated the relationship between post-traumatic dysfunctional cognitions and trauma symptoms. CONCLUSIONS: The results of our study indicate that the different role of well-being found between indirect (causal factor) and direct exposure (protective factor) should be taken into consideration in interventions designed to improve victims' health. PMID- 29764433 TI - Detection of Anopheles rivulorum-like, a member of the Anopheles funestus group, in South Africa. AB - BACKGROUND: The Anopheles gambiae sensu lato (s.l.) and Anopheles funestus s.l. species complexes contain the most important malaria vectors in Africa. Within the An. funestus group of at least 11 African species, the vector status of all but the nominal species An. funestus appears poorly investigated, although evidence exists that Anopheles rivulorum and Anopheles vaneedeni may play minor roles. A new species, An. rivulorum-like, was described from Burkina Faso in 2000 and subsequently also found in Cameroon and Zambia. This is the first paper reporting the presence of this species in South Africa, thereby significantly extending its known range. METHODS: Mosquitoes were collected using dry-ice baited net traps and CDC light traps in the Kruger National Park, South Africa. Sixty-four An. funestus s.l. among an overall 844 mosquitoes were captured and identified to species level using the polymerase chain reaction assay. All samples were also analysed for the presence of Plasmodium falciparum circumsporozoite protein using the enzyme-linked-immunosorbent assay. RESULTS: Four members of the An. funestus group were identified: An. rivulorum-like (n = 49), An. rivulorum (n = 11), Anopheles parensis (n = 2) and Anopheles leesoni (n = 1). One mosquito could not be identified. No evidence of P. falciparum was detected in any of the specimens. CONCLUSION: This is the first report of An. rivulorum-like south of Zambia, and essentially extends the range of this species from West Africa down to South Africa. Given the continental-scale drive towards malaria elimination and the challenges faced by countries in the elimination phase to understand and resolve residual transmission, efforts should be directed towards determining the largely unknown malaria vector potential of members of the An. funestus group and other potential secondary vectors. PMID- 29764434 TI - Real-time monitoring of the budding index in Saccharomyces cerevisiae batch cultivations with in situ microscopy. AB - BACKGROUND: The morphology of yeast cells changes during budding, depending on the growth rate and cultivation conditions. A photo-optical microscope was adapted and used to observe such morphological changes of individual cells directly in the cell suspension. In order to obtain statistically representative samples of the population without the influence of sampling, in situ microscopy (ISM) was applied in the different phases of a Saccharomyces cerevisiae batch cultivation. The real-time measurement was performed by coupling a photo-optical probe to an automated image analysis based on a neural network approach. RESULTS: Automatic cell recognition and classification of budding and non-budding cells was conducted successfully. Deviations between automated and manual counting were considerably low. A differentiation of growth activity across all process stages of a batch cultivation in complex media became feasible. An increased homogeneity among the population during the growth phase was well observable. At growth retardation, the portion of smaller cells increased due to a reduced bud formation. The maturation state of the cells was monitored by determining the budding index as a ratio between the number of cells, which were detected with buds and the total number of cells. A linear correlation between the budding index as monitored with ISM and the growth rate was found. CONCLUSION: It is shown that ISM is a meaningful analytical tool, as the budding index can provide valuable information about the growth activity of a yeast cell, e.g. in seed breeding or during any other cultivation process. The determination of the single cell size and shape distributions provided information on the morphological heterogeneity among the populations. The ability to track changes in cell morphology directly on line enables new perspectives for monitoring and control, both in process development and on a production scale. PMID- 29764435 TI - Use of hospital palliative care according to the place of death and disease one year before death in 2013: a French national observational study. AB - BACKGROUND: Only limited data are available concerning the diseases managed before death and hospital palliative care (HPC) use according to place of death in France. We therefore conducted an observational study based on administrative health data in a large population to identify the diseases treated one year before death in 2013, the place of stay with or without hospital palliative care, and the place of death. METHODS: French health insurance general scheme beneficiaries were identified in the National Health data Information System (Snds) with a selection of information. Diseases were identified by algorithms from reimbursement data recorded in the Snds database. RESULTS: 347,253 people were included in this study (61% of all people who died in France). Place of death was short stay hospital for 51%, Rehab (7%), hospital at home (3%), skilled nursing home (13%) and other (26%). Chronic diseases managed in 2013 before death were cardiovascular/neurovascular diseases (56%), cancers (42%), and neurological and degenerative diseases (25%). During the year before death, 84% of people were hospitalized at least once, and 29% had received HPC. HPC was used by 52% of cancer patients (lung cancer: 62%; prostate cancer: 41%). In the absence of cancer, the use of HPC varied according to the disease: acute stroke: 24%, heart failure: 17%, dementia: 17%, multiple sclerosis: 23%. CONCLUSIONS: Health administrative data can refine the knowledge of the care pathway prior to death and the HPC utilisation and can be useful to evaluate heath policies and improve monitoring and assessment of HPC use. PMID- 29764436 TI - Prevalence and incidence of complications at diagnosis of T2DM and during follow up by BMI and ethnicity: a matched case-control analysis. AB - AIMS: To estimate the risk of developing long-term major cardiovascular and renal complications in relation to levels of body mass index (BMI) in a population of White European (WE), African-Caribbean (AC), and South Asian (SA) patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Patients with new diagnosis of T2DM, aged >= 18 years from January 2000 (n = 69,436) and their age sex-ethnicity matched non-diabetic controls (n = 272,190) were identified from UK primary care database. Incidence rates ratios (IRRs) for non-fatal major cardiovascular events (MACE) and chronic kidney disease (CKD) in patients with T2DM compared to controls were estimated using multivariate Mantel-Cox model. RESULTS: Among normal weight patients with T2DM, WEs had significantly higher prevalence of cardiovascular multi-morbidity (95% CI 9.5, 11.3), compared to SAs (95% CI 4.8, 9.5). AC and SA overweight and obese patients had similar prevalence, while obese WEs had significantly higher prevalence. During a median 7 years of follow-up, risk of MACE was significantly higher for overweight (95% CI of IRR 1.50, 2.46) and obese (95% CI of IRR 1.49, 2.43) SAs compared to their WE counterparts. However, similar risk levels were observed for normal weight WEs and SAs, respectively. Risk of CKD was higher and uniform for BMI >= 25 kg/m2 amongst WEs and ACs, whereas only overweight patients had significantly higher risk of CKD amongst SA [IRR 2.08 (95% CI 1.49, 2.93)]. CONCLUSION: Risk of MACE/CKD varies over levels of BMI within each ethnic group, with overweight SAs having a disproportionate risk of CKD. PMID- 29764437 TI - Caring for parents: an evolutionary rationale. AB - BACKGROUND: The evolutionary roots of human moral behavior are a key precondition to understanding human nature. Investigations usually start with a social dilemma and end up with a norm that can provide some insight into the origin of morality. We take the opposite direction by investigating whether the cultural norm that promotes helping parents and which is respected in different variants across cultures and is codified in several religions can spread through Darwinian competition. RESULTS: We show with a novel demographic model that the biological rule "During your reproductive period, give some of your resources to your post fertile parents" will spread even if the cost of support given to post-fertile grandmothers considerably decreases the demographic parameters of fertile parents but radically increases the survival rate of grandchildren. The teaching of vital cultural content is likely to have been critical in making grandparental service valuable. We name this the Fifth Rule, after the Fifth Commandment that codifies such behaviors in Christianity. CONCLUSIONS: Selection for such behavior may have produced an innate moral tendency to honor parents even in situations, such as those experienced today, when the quantitative conditions would not necessarily favor the maintenance of this trait. PMID- 29764438 TI - Larvicidal activity of Zanthoxylum acanthopodium essential oil against the malaria mosquitoes, Anopheles anthropophagus and Anopheles sinensis. AB - BACKGROUND: Zanthoxylum acanthopodium has insecticidal effect in Chinese traditional medicine. In this study, the essential oil from the dried Zanthoxylum plant was used as a larvicidal compound against the malaria mosquitoes, Anopheles anthropophagus and Anopheles sinensis. METHODS: Compounds in the Zanthoxylum essential oil were investigated by gas chromatography and mass spectroscopy (GC MS). The larvicidal bioassays of the whole oil, as well as the main compounds in the oil (estragole and eucalyptol) were performed using WHO method. RESULTS: In total, 63 main compounds (99.32%) were found in the oils, including estragole (15.46%), eucalyptol (10.94%), beta-caryophyllene (5.52%), cis-linalool oxide (3.76%), cis-limonene oxide (3.06%). A dose-dependent effect on mortality was recorded with increasing concentrations of essential oil and compounds increasing mortality of the larvae. Larvicidal bioassays revealed that 24 h LC50 of the whole essential oil was 36.00 mg/L and LC90 was 101.49 mg/L against An. anthropophagus, while LC50 was 49.02 mg/L and LC90 was 125.18 mg/L against An. sinensis. Additionally, 24 h LC50 of estragole were 38.56 and 41.67 mg/L against An. anthropophagus and An. sinensis, respectively, while the related LC90 were 95.90 and 107.89 mg/L. LC50 of eucalyptol were 42.41 and 45.49 mg/L against An. anthropophagus and An. sinensis, while the related LC90 were 114.45 and 124.95 mg/L. CONCLUSION: The essential oil of Z. acanthopodium and its several major compounds may have potential for use in the control of malaria mosquitoes. PMID- 29764439 TI - A survey on outcomes of accidental atovaquone-proguanil exposure in pregnancy. AB - BACKGROUND: Malaria chemoprophylaxis options in pregnancy are limited, and atovaquone-proguanil (AP) is not recommended because of insufficient safety evidence. An anonymous, internet-based survey was disseminated to describe outcomes of pregnancies accidentally exposed to AP. Outcomes of interest included miscarriage (defined as pregnancy loss before 20 weeks), stillbirth (defined as pregnancy loss at or after 20 weeks), preterm birth or live birth prior to 37 weeks, and the presence of congenital anomalies. RESULTS: A total of 487 women responded and reported on 822 pregnancies. Of the 807 pregnancies with information available on exposure and outcomes, 10 (1.2%) had atovaquone proguanil exposure, all in the first trimester, and all resulted in term births with no birth defects. CONCLUSIONS: Use of an anti-malarial not recommended in pregnancy is likely to occur before the woman knows of her pregnancy. This study adds to the limited evidence of the safety of AP in pregnancy. Further study on use of AP in pregnancy should be a high priority, as an alternative option for the prevention of malaria in pregnancy in non-immune travellers is urgently needed. PMID- 29764441 TI - Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy. AB - BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1beta mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1beta-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1beta mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported. CASE PRESENTATION: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband's phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1beta was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course. CONCLUSION: This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1beta missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes. PMID- 29764443 TI - Adrian Grant's pioneering use of evidence synthesis in perinatal medicine, 1980 1992. AB - Systematic reviews of existing research are needed to help reduce the enormous amount of wasted resources in biomedical research. Whether already available or needed but unavailable, systematic reviews are a key element in prioritising questions for new research, and for informing the design of additional studies. One of the most important of Adrian Grant's many contributions was to recognise this a decade before it began to become more widely accepted. In this sphere, as well as in many others, he was a real pioneer. PMID- 29764442 TI - Cross-cultural adaptation, validity, and reliability of the Persian version of the spine functional index. AB - BACKGROUND: There are various instruments and methods to evaluate spinal health and functional status. Whole-spine patient reported outcome (PRO) measures, such as the Spine Functional Index (SFI), assess the spine from the cervical to lumbo sacral sections as a single kinetic chain. The aim of this study was to cross culturally adapt the SFI for Persian speaking patients (SFI-Pr) and determine the psychometric properties of reliability and validity (convergent and construct) in a Persian patient population. METHODS: The SFI (English) PRO was translated into Persian according to published guidelines. Consecutive symptomatic spine patients (104 female and 120 male aged between 18 and 60) were recruited from three Iranian physiotherapy centers. Test-retest reliability was performed in a sub sample (n = 31) at baseline and repeated between days 3-7. Convergent validity was determined by calculating the Pearson's r correlation coefficient between the SFI-Pr and the Persian Roland Morris Questionnaire (RMQ) for back pain patients and the Neck Disability Index (NDI) for neck patients. Internal consistency was assessed using Cronbach's alpha. Exploratory Factor Analysis (EFA) used Maximum Likelihood Extraction followed by Confirmatory Factor Analysis (CFA). RESULTS: High levels of internal consistency (alpha = 0.81, item range = 0.78-0.82) and test-retest reliability (r = 0.96, item range = 0.83-0.98) were obtained. Convergent validity was very good between the SFI and RMQ (r = 0.69) and good between the SFI and NDI (r = 0.57). The EFA from the perspective of parsimony suggests a one-factor solution that explained 26.5% of total variance. The CFA was inconclusive of the one factor structure as the sample size was inadequate. There were no floor or ceiling effects. CONCLUSIONS: The SFI-Pr PRO can be applied as a specific whole-spine status assessment instrument for clinical and research studies in Persian language populations. PMID- 29764444 TI - Molecular and clinical characterization of PTPN2 expression from RNA-seq data of 996 brain gliomas. AB - BACKGROUND: Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNgamma signaling. METHODS: Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures. RESULTS: PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas. CONCLUSION: PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies. PMID- 29764440 TI - Psychometric properties of the Korean version of the medical outcomes study HIV health survey: results from a multicenter survey in Korea. AB - BACKGROUND: Precise assessment of health-related quality of life (HRQOL) with a reliable and valid measure is a prerequisite to the enhancement of HRQOL. This study examined the psychometric properties of the Korean version of the Medical Outcomes Study HIV Health Survey (K-MOS-HIV). METHODS: The reliability and validity of the K-MOS-HIV were examined in a multicenter survey involving 201 outpatients with human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS) from four teaching hospitals throughout Korea. RESULTS: Ceiling effects were observed in six subscales scores, particularly, for the role functioning (71.1%), social functioning (63.2%), and pain (48.8%) scores. The Cronbach's alpha for the physical health summary and mental health summary were 0.90 and 0.94, respectively, and it ranged from 0.78 to 0.95 for the subscales. The results of the exploratory structural equation modeling supported the two factor structure of the K-MOS-HIV (physical health summary and mental health summary). An examination of the mean square statistics values from the Rasch analysis showed that the information-weighted fit and outlier-sensitive fit statistics were within the acceptable ranges of 0.6-1.4 except for two items in the mental health summary. The convergent validity of the K-MOS-HIV was supported by its significant positive correlations with the World Health Organization Quality of Life-HIV-BREF subscale scores. Its known-group validity was proven with its ability to detect significant differences in several K-MOS-HIV subscale scores among participants with different sociodemographic and clinical characteristics. CONCLUSIONS: The K-MOS-HIV health survey appears to be a reliable and valid measure of HRQOL. PMID- 29764445 TI - Current practices of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal surface malignancies: an international survey of oncologic surgeons. AB - BACKGROUND: The goal of the study was to investigate the current clinical practices among oncologic surgeons regarding cytoreductive surgery (CRS) with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: From September to October 2016, an online questionnaire surveyed the oncologic surgeons by email. The questionnaire included 20 multiple-choice questions of the following: eligibility for the CRS with HIPEC procedure, perioperative staging and surgery skill, assessment of residual tumors, and method used for intraperitoneal HIPEC. RESULTS: The response rate was 16% (34/217). The majority of respondents (68%) worked at a university hospital. All respondents indicated that mesenteric invasion is the most crucial factor affecting treatment decision. Most surgeons (79%) used the Sugarbaker's staging system to intraoperatively measure the extent of peritoneal invasion. The methods used to measure the extent of miliary pattern of residual tumor spread, and the amount of residual tumor after electrocauterization varied among the surgeons. Most responders (65%) used the closed system of HIPEC. CONCLUSIONS: Despite the fact that CRS HIPEC is the standard treatment for PSM, the clinical practices are very different according to each clinical situation. Nevertheless, mesenteric invasion was found to be the most important factor impacting the treatment decision-making by the majority of responders. PMID- 29764446 TI - Comprehensive and integrative analysis identifies microRNA-106 as a novel non invasive biomarker for detection of gastric cancer. AB - BACKGROUND: Recently, accumulating evidences have revealed that microRNA-106 (miR 106) may serve as a non-invasive and cost-effective biomarker in gastric cancer (GC) detection. However, inconsistent results have prevented its application to clinical practice. METHODS: As a result of this, a comprehensive meta-analysis was conducted to evaluate the diagnostic performance of miR-106 alone and miR-106 related combination markers for GC detection. Meanwhile, an integrative bioinformatics analysis was performed to explore the function of miR-106 at the systems biology level. RESULTS: The results in our work showed that sensitivity of 0.71 (95% CI 0.65-0.76) and specificity of 0.82 (0.72-0.88), with the under area AUC (area under the curve) value of 0.80 (0.76-0.83) for miR-106 alone. Prospectively, miR-106-related combination markers improved the combined sensitivity, specificity and AUC, describing the discriminatory ability of 0.78 (0.65-0.87), 0.83 (0.77-0.89) and 0.88 (0.85-0.90) in the present analysis. Furthermore, targets of miR-106 were obtained and enriched by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis, revealing their associations with the occurrence and development of GC. Hub genes and significant modules were identified from the protein-protein interaction networks constructed by miR-106 targets and found closely associated with the initiation and progression of GC again. CONCLUSIONS: Our comprehensive and integrative analysis revealed that miR-106 may be suitable as a diagnostic biomarker for GC while microRNA combination biomarkers may provide a new alternative for clinical application. However, it is necessary to conduct large-scale population-based studies and biological experiments to further investigate the diagnostic value of miR-106. PMID- 29764447 TI - Efficacy of intra-articular hypertonic dextrose prolotherapy versus normal saline for knee osteoarthritis: a protocol for a triple-blinded randomized controlled trial. AB - BACKGROUND: Knee Osteoarthritis (KOA) is a very common condition with prevalence rising with age. It is a major contributor to global disability and has a large socioeconomic burden worldwide. Conservative therapies have marginal effectiveness, and surgery is reserved for severe symptomatic KOA. Dextrose Prolotherapy (DPT) is an evidence-based injection-based therapy for chronic musculoskeletal conditions including KOA. The standard "whole joint" injection method includes intra-articular injection and multiple extra-articular injections at soft tissue bony attachments. The procedure is painful and requires intensive procedural training often unavailable in conventional medical education, which potentially limits access. Intra-articular injection offers the possibility of a less painful, more accessible treatment. The aim of this project is to assess the clinical efficacy of intra-articular injection of DPT versus normal saline (NS) for KOA. METHOD: Seventy-six participants with KOA will be recruited from the community. We will conduct a single center, parallel group, superiority randomized controlled trial comparing DPT and NS injections, with blinding of physician, participants, outcome assessors and statisticians. Each group will receive injections at week 0, 4, 8 and 16. The primary outcome will be the Western Ontario McMaster University Osteoarthritis Index pain scale (WOMAC), and secondary outcomes include WOMAC composite score, the WOMAC function and stiffness subscale, the Visual Analogue Score of pain, objective physical function tests (the 30 s chair stand, 40- m fast paced walk test, the Timed up and go test) and the EuroQol-5D (EQ-5D). All outcomes will be evaluated at baseline, and 16, 26 and 52 weeks. All analyses will be conducted on an intention to-treat basis using linear mixed regression models. DISCUSSION: This paper presents the rationale, design, method and operational aspects of the trial. The findings will determine whether IA DPT, an inexpensive and simple injection, is a safe and effective non-surgical option for KOA. The results can be translated directly to clinical practice, with potentially substantial impact to patient care. TRIAL REGISTRATION: The trial ( ChiCTR-IPC-15006617 ) is registered under Chinese Clinical Trials Registry on 17th June 2015. PMID- 29764448 TI - Small bowel lymphoma presenting as inguinal hernia: case report and literature review. AB - BACKGROUND: Inguinal hernia is one of the most common benign pathologies that primarily affects men. Primary gastrointestinal non-Hodgkin's lymphoma (PGI NHL) is the most common type of extranodal lymphoma. This study reports a rare case in which these two conditions co-exist. CASE PRESENTATION: An 85-year-old male complained of bowel movement pattern change, abdominal distension and loss of weight, without vomiting but with nausea. A computed tomographic scan of the abdomen showed a small bowel obstruction caused by a migration of a small bowel loop in the right inguinal canal, with a clinically non-reducible inguinal hernia. The patient underwent surgery. The histopathological report showed small bowel large B cell non-Hodgkin's lymphoma. CONCLUSION: When the diagnosis of the contents of an inguinal hernia is not well-established, surgery should be performed as soon as possible to ensure the cure of the disease and the correct diagnosis of the contents. PMID- 29764449 TI - Primo software as a tool for Monte Carlo simulations of intensity modulated radiotherapy: a feasibility study. AB - BACKGROUND: IMRT provides higher dose conformation to the target and dose sparing to surrounding tissues than 3DCRT. Monte Carlo method in Medical Physics is not a novelty to approach dosimetric problems. A new PENELOPE based code named PRIMO recently was published. The most intriguing features of PRIMO are the user friendly approach, the stand-alone property and the built-in definition of different linear accelerators models. Nevertheless, IMRT simulations are not yet implemented. METHODS: A Varian Trilogy with a Millennium120 MLC and a Varian Novalis with 120HD MLC were studied. A RW3 multi-slab phantom was irradiated with Gafchromic films inserted between slabs. An Expression 10000XL scanner (Seiko Epson Corp., Nagano, Japan) was used to digitalize the films. PTW-Verisoft software using the global Gamma Function (2%, 2 mm) was used to compare simulated and experimental results. The primary beam parameters were adjusted to best match reference data previously obtained in a water phantom. Static MLC simulations were performed to validate the MLC models in use. Two Dynamic IMRT preliminary tests were performed with leaves moving with constant and variable speed. A further test of an in phantom delivery of a real IMRT field allowed simulating a clinical-like MLC modulation. RESULTS: Simulated PDD, X- and Y-profiles in reference conditions showed respectively 100.0%, 100.0% and 99.4% of Gamma points < 1 (2%, 2 mm). Static MLC simulations showed 100.0% of Gamma points < 1 with the 120HD MLC and 99.1% with the Millennium compared with the scanned images. The fixed speed test showed 99.5 and 98.9% of Gamma points < 1 respectively with two different MLC configuration-sampling algorithms when the 120HD MLC was used. The higher modulation MLC motion simulation showed 99.1% of Gamma points < 1 with respect to the experimental. This result depends on the number of the fields to reproduce the MLC motion, as well as calculation time. The clinical-like simulation showed 96.2% of Gamma points < 1 using the same analysis conditions. CONCLUSIONS: The numerical model of the Varian Trilogy and Novalis in the PRIMO software was validated. The algorithms to simulate MLC motion were considered reliable. A clinical-like procedure was successfully simulated. PMID- 29764450 TI - Evaluation of target dose inhomogeneity in breast cancer treatment due to tissue elemental differences. AB - BACKGROUND: Monte Carlo simulations were run to estimate the dose variations generated by thedifference arising from the chemical composition of the tissues. METHODS: CT datasets of five breast cancer patients were selected. Mammary gland was delineated as clinical target volume CTV, as well as CTV_lob and CTV_fat, being the lobular and fat fractions of the entire mammary gland. Patients were planned for volumetric modulated arc therapy technique, optimized in the Varian Eclipse treatment planning system. CT, structures and plans were imported in PRIMO, based on Monte Carlo code Penelope, to run three simulations: AdiMus, where the adipose and muscle tissues were automatically assigned to fat and lobular fractions of the breast; Adi and Mus, where adipose and muscle, respectively were assigned to the whole mammary gland. The specific tissue density was kept identical from the CT dataset. Differences in mean doses in the CTV_lob and CTV_fat structures were evaluated for the different tissue assignments. Differences generated by the tissue composition and estimated by Acuros dose calculations in Eclipse were also analysed. RESULTS: From Monte Carlo simulations, the dose in the lobular fraction of the breast, when adipose tissue is assigned in place of muscle, is overestimated by 1.25 +/- 0.45%; the dose in the fat fraction of the breast with muscle tissue assignment is underestimated by 1.14 +/- 0.51%. Acuros showed an overestimation of 0.98 +/- 0.06% and an underestimation of 0.21 +/- 0.14% in the lobular and fat portions, respectively. Reason of this dissimilarity resides in the fact that the two calculations, Monte Carlo and Acuros, differently manage the range of CT numbers and the material assignments, having Acuros an overlapping range, where two tissues are both present in defined proportions. CONCLUSION: Although not clinically significant, the dose deposition difference in the lobular and connective fat fraction of the breast tissue lead to an improved knowledge of the possible dose distribution and homogeneity in the breast radiation treatment. PMID- 29764451 TI - Phenotypic and genotypic characterization of Thai isolates of Plasmodium falciparum after an artemisinin resistance containment project. AB - BACKGROUND: In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone(r), a combination of atovaquone-proguanil (ATQ PG), has been used to cease artemisinin pressure in some areas along Thai Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before. RESULTS: One hundred and nine of P. falciparum isolates collected from Thai-Cambodia border from Chanthaburi and Trat provinces during 1988-2016 were used in this study. Of these, 58 isolates were collected after the containment. These parasite isolates were characterized for in vitro antimalarial sensitivities including chloroquine (CQ), quinine (QN), mefloquine (MQ), piperaquine (PPQ), artesunate (AS), dihydroartemisinin (DHA), ATQ and PG and genetic markers for drug resistance including the Kelch13 (k13), Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1) and cytochrome b (cytb) genes. Mean CQ, QN, MQ, PPQ and AS IC50s of the parasite isolates collected from 2009 to 2016 exhibited significantly higher than those of parasites collected before 2009. Approximately 57% exhibited in vitro MQ resistance. Approximately 94% of the isolates collected from 2009 to 2016 contained the pfmdr1 184F allele. Mutations of the k13 gene were detected in approximately 90% of the parasites collected from 2009 to 2016 which were significantly higher than the parasite isolates collected before. No ATQ resistant genotype and phenotype of P. falciparum were found among the isolates collected after the containment project. CONCLUSIONS: Although the containment project had been implemented in this area, the expansion of artemisinin-resistant parasites did not decline. In addition, reduced sensitivity of the partner drugs of ACT including MQ and PPQ were identified. PMID- 29764452 TI - Risk factors for Korean women to develop an isthmocele after a cesarean section. AB - BACKGROUND: The increase in number of cesarean section (CS) operations has resulted in an increase in cases of isthmocele development. The objective of this study is to determine the risk factors for isthmocele development after CS. METHODS: Isthmocele measurements were taken for 404 women with a history of at least one low transverse CS. The following potential risk factors were investigated: patient's age at CS, cause of CS, weeks of gestation at CS, premature rupture of membrane (PROM), phase of labor, type suture (single/double layer), operation time, uterine flexion (anteversion/retroversion), and blood transfusion during operation. A transvaginal ultrasound was carried out to examine the isthmocele in the uterus after CS, including the shape of the isthmocele, residual myometrial thickness, depth and width of isthmocele, cervical thickness, location of the isthmocele, and clinical characteristics. RESULTS: In our study population, the isthmocele had a prevalence of 73.8%. Most isthmocele had a triangular (65.4%) or semicircular shape (10.4%). The presence of an isthmocele was significantly associated with repeat CS, premature rupture of membrane (PROM), short operation time, and extent of cervix dilatation at CS. The risk of isthmocele was low in women who had placenta previa totalis (PPT), twin, a long operation time, or a transfusion during the operation. CONCLUSIONS: In our study, isthmocele development was significantly associated with repeat CS, PROM, a short operation time, and the extent of cervix dilatation at CS. Therefore, PROM prevention and a more careful uterine closure are needed to reduce the risk of developing an isthmocele after CS. PMID- 29764454 TI - Screening a repurposing library, the Medicines for Malaria Venture Stasis Box, against Schistosoma mansoni. AB - BACKGROUND: The development of new treatments against schistosomiasis is imperative but lacks commercial interest. Drug repurposing represents a suitable strategy to identify potential treatments, which have already unblocked several essential steps along the drug development path, hence reducing costs and timelines. Promoting this approach, the Medicines for Malaria Venture (MMV) recently distributed a drug repurposing library of 400 advanced lead candidates (Stasis Box). METHODS: All 400 compounds were initially tested in vitro against the larval stage of Schistosoma mansoni at 10 MUM. Hits progressed to screening on adult worms and were further characterised for IC50, cytotoxicity and selectivity. Ten lead compounds were tested in mice harbouring a chronic S. mansoni infection. RESULTS: Eleven of the 37 compounds active on the larval stage were also highly active on adult worms in vitro (IC50 = 2.0-7.5 MUM). IC50 values on adult S. mansoni decreased substantially in the presence of albumin (7.5-123.5 MUM). Toxicity to L6 and MRC cells was moderate. A moderate worm burden reduction of 51.6% was observed for MMV690534, while the other 9 compounds showed low activity. None of the in vivo results were statistically significant (P > 0.05). CONCLUSIONS: Phenotypic screening of advanced lead compounds is a simple and resource-low method to identify novel anthelminthics. None of the promising hits of the Stasis Box identified in vitro against S. mansoni yielded acceptable worm burden reductions in vivo, which might be due to the high plasma protein binding. Since the in vitro hits interfere with different drug targets, they might provide a starting point for target based screening and structure-activity relationship studies. PMID- 29764456 TI - A scoping review of reporting 'Ethical Research Practices' in research conducted among refugees and war-affected populations in the Arab world. AB - BACKGROUND: Ethical research conduct is a cornerstone of research practice particularly when research participants include vulnerable populations. This study mapped the extent of reporting ethical research practices in studies conducted among refugees and war-affected populations in the Arab World, and assessed variations by time, country of study, and study characteristics. METHODS: An electronic search of eight databases resulted in 5668 unique records published between 2000 and 2013. Scoping review yielded 164 eligible articles for analyses. RESULTS: Ethical research practices, including obtaining institutional approval, access to the community/research site, and informed consent/assent from the research participants, were reported in 48.2, 54.9, and 53.7% of the publications, respectively. Institutional approval was significantly more likely to be reported when the research was biomedical in nature compared to public health and social (91.7% vs. 54.4 and 32.4%), when the study employed quantitative compared to qualitative or mixed methodologies (61.7% vs. 26.8 and 42.9%), and when the journal required a statement on ethical declarations (57.4% vs. 27.1%). Institutional approval was least likely to be reported in papers that were sole-authored (9.5%), when these did not mention a funding source (29.6%), or when published in national journals (0%). Similar results were obtained for access to the community site and for seeking informed consent/assent from study participants. CONCLUSIONS: The responsibility of inadequacies in adherence to ethical research conduct in crisis settings is born by a multitude of stakeholders including funding agencies, institutional research boards, researchers and international relief organizations involved in research, as well as journal editors, all of whom need to play a more proactive role for enhancing the practice of ethical research conduct in conflict settings. PMID- 29764455 TI - Nerve trauma of the lower extremity: evaluation of 60,422 leg injured patients from the TraumaRegister DGU(r) between 2002 and 2015. AB - BACKGROUND: Nerve lesions are well known reasons for reduced functional capacity and diminished quality of life. By now only a few epidemiological studies focus on lower extremity trauma related nerve injuries. This study reveals frequency and characteristics of nerve damages in patients with leg trauma in the European context. METHODS: Sixty thousand four hundred twenty-two significant limb trauma cases were derived from the TraumaRegister DGU(r) between 2002 and 2015. The TR DGU is a multi- centre database of severely injured patients. We compared patients with additional nerve injury to those with intact neural structures for demographic data, trauma mechanisms, concomitant injuries, treatment and outcome parameters. RESULTS: Approximately 1,8% of patients with injured lower extremities suffer from additional nerve trauma. These patients were younger (mean age 38,1 y) and more likely of male sex (80%) compared to the patients without nerve injury (mean age 46,7 y; 68,4% male). This study suggests the peroneal nerve to be the most frequently involved neural structure (50,9%). Patients with concomitant nerve lesions generally required a longer hospital stay and exhibited a higher rate for subsequent rehabilitation. Peripheral nerve damage was mainly a consequence of motorbike (31,2%) and car accidents (30,7%), whereas leg trauma without nerve lesion most frequently resulted from car collisions (29,6%) and falls (29,8%). CONCLUSION: Despite of its low frequency nerve injury remains a main cause for reduced functional capacity and induces high socioeconomic expenditures due to prolonged rehabilitation and absenteeism of the mostly young trauma victims. Further research is necessary to get insight into management and long term outcome of peripheral nerve injuries. PMID- 29764457 TI - Video-mediastinoscopy assisted fish bone extraction and superior Medistinal abscess debridement. AB - BACKGROUND: Mediastinum abscess caused by sharp esophageal foreign body perforation usually needs surgical treatment, and the surgical procedures vary according to size of perforation and scope of abscess, etc. For special case with small esophageal mucosal crevasse and focal abscess confined to mediastinum, minimally invasive surgery with guidance of video-mediastinoscopy would be an alternative method, however, application of video-mediastinoscopy in this life threatening situation was rarely reported. CASE PRESENTATION: One patient with detention of fish bone stuck in the esophagus developed systemic inflammatory response syndrome. Computed tomography results revealed that two high-density foreign bodies migrated extraluminally and caused abscess confined in the mediastinum. Multidisplinary collaborative efforts of anesthesiology, gastroenterology and thoracic surgery were made to optimize the therapeutic process. By taking advantages of wide working channel and better exposure of video-mediastinoscopy, two sharp fish bones were removed with minimal risk of injuring adjacent important tissues, furthermore, complete debridement of the abscess and precise drainage tube indwelling was achieved simultaneously. Postoperative comprehensive therapy including anti-infection and nutrition support guaranteed a smooth transition of perioperative period. CONCLUSION: This is the first report on application of video-mediastinoscopy in removing two fish bones that migrated extraluminally and debridement of the abscess caused by esophagus perforation with minimal injury risk, which offer a safe and effective minimal invasive method for specific cases. PMID- 29764453 TI - AMPA-ergic regulation of amyloid-beta levels in an Alzheimer's disease mouse model. AB - BACKGROUND: Extracellular aggregation of the amyloid-beta (Abeta) peptide into toxic multimers is a key event in Alzheimer's disease (AD) pathogenesis. Abeta aggregation is concentration-dependent, with higher concentrations of Abeta much more likely to form toxic species. The processes that regulate extracellular levels of Abeta therefore stand to directly affect AD pathology onset. Studies from our lab and others have demonstrated that synaptic activity is a critical regulator of Abeta production through both presynaptic and postsynaptic mechanisms. AMPA receptors (AMPA-Rs), as the most abundant ionotropic glutamate receptors, have the potential to greatly impact Abeta levels. METHODS: In order to study the role of AMPA-Rs in Abeta regulation, we used in vivo microdialysis in an APP/PS1 mouse model to simultaneously deliver AMPA and other treatments while collecting Abeta from the interstitial fluid (ISF). Changes in Abeta production and clearance along with inflammation were assessed using biochemical approaches. IL-6 deficient mice were utilized to test the role of IL-6 signaling in AMPA-R-mediated regulation of Abeta levels. RESULTS: We found that AMPA-R activation decreases in ISF Abeta levels in a dose-dependent manner. Moreover, the effect of AMPA treatment involves three distinct pathways. Steady-state activity of AMPA-Rs normally promotes higher ISF Abeta. Evoked AMPA-R activity, however, decreases Abeta levels by both stimulating glutamatergic transmission and activating downstream NMDA receptor (NMDA-R) signaling and, with extended AMPA treatment, acting independently of NMDA-Rs. Surprisingly, we found this latter, direct AMPA pathway of Abeta regulation increases Abeta clearance, while Abeta production appears to be largely unaffected. Furthermore, the AMPA dependent decrease is not observed in IL-6 deficient mice, indicating a role for IL-6 signaling in AMPA-R-mediated Abeta clearance. CONCLUSION: Though basal levels of AMPA-R activity promote higher levels of ISF Abeta, evoked AMPA-R signaling decreases Abeta through both NMDA-R-dependent and -independent pathways. We find that evoked AMPA-R signaling increases clearance of extracellular Abeta, at least in part through enhanced IL-6 signaling. These data emphasize that Abeta regulation by synaptic activity involves a number of independent pathways that together determine extracellular Abeta levels. Understanding how these pathways maintain Abeta levels prior to AD pathology may provide insights into disease pathogenesis. PMID- 29764458 TI - Cone beam computed tomography in implant dentistry: recommendations for clinical use. AB - BACKGROUND: In implant dentistry, three-dimensional (3D) imaging can be realised by dental cone beam computed tomography (CBCT), offering volumetric data on jaw bones and teeth with relatively low radiation doses and costs. The latter may explain why the market has been steadily growing since the first dental CBCT system appeared two decades ago. More than 85 different CBCT devices are currently available and this exponential growth has created a gap between scientific evidence and existing CBCT machines. Indeed, research for one CBCT machine cannot be automatically applied to other systems. METHODS: Supported by a narrative review, recommendations for justified and optimized CBCT imaging in oral implant dentistry are provided. RESULTS: The huge range in dose and diagnostic image quality requires further optimization and justification prior to clinical use. Yet, indications in implant dentistry may go beyond diagnostics. In fact, the inherent 3D datasets may further allow surgical planning and transfer to surgery via 3D printing or navigation. Nonetheless, effective radiation doses of distinct dental CBCT machines and protocols may largely vary with equivalent doses ranging between 2 to 200 panoramic radiographs, even for similar indications. Likewise, such variation is also noticed for diagnostic image quality, which reveals a massive variability amongst CBCT technologies and exposure protocols. For anatomical model making, the so-called segmentation accuracy may reach up to 200 MUm, but considering wide variations in machine performance, larger inaccuracies may apply. This also holds true for linear measures, with accuracies of 200 MUm being feasible, while sometimes fivefold inaccuracy levels may be reached. Diagnostic image quality may also be dramatically hampered by patient factors, such as motion and metal artefacts. Apart from radiodiagnostic possibilities, CBCT may offer a huge therapeutic potential, related to surgical guides and further prosthetic rehabilitation. Those additional opportunities may surely clarify part of the success of using CBCT for presurgical implant planning and its transfer to surgery and prosthetic solutions. CONCLUSIONS: Hence, dental CBCT could be justified for presurgical diagnosis, preoperative planning and peroperative transfer for oral implant rehabilitation, whilst striving for optimisation of CBCT based machine-dependent, patient-specific and indication-oriented variables. PMID- 29764459 TI - Health-related quality of life by allergy symptoms in elementary school students. AB - BACKGROUND: Globally, allergic diseases are very common in childhood and may affect children's quality of life. This study aimed to explore health-related quality of life of elementary school students with allergy symptoms using the EQ 5D-Y and to examine the validity and feasibility of the EQ-5D-Y. METHODS: The study subjects were the students within 50 elementary schools which voluntarily participated in research project. In this sample population, the EQ-5D-Y questionnaire was self-administered by the students, and demographic and health information were collected from the student's parents. The parents' information was used to investigate the proportion of students with allergic symptoms (wheezing, runny or blocked nose, and itchy rash) in the past 12 months. In addition, we analyzed the correlation of symptom reporting and EQ-5D-Y including EQ-VAS. RESULTS: The overall return was 9117 responses, of which 198 (2.2%) lacked responses on the EQ-5D-Y dimension and 1258 (13.8%) on the VAS score. There were significant differences in symptom reporting in all EQ-5D-Y dimensions between groups with or without allergic symptoms. Particularly, there was a large difference in reporting rates in 'having pain or discomfort' and 'feeling worried, sad or unhappy' dimensions. As the number of allergic symptoms increased, in all dimensions also the problem reporting rate tended to increase. CONCLUSIONS: As expected, the presence of allergic symptoms is inversely correlated with the quality of life of children. The EQ-5D-Y instrument proved to be useful in terms of feasibility and construct validity in assessing the quality of life of Korean elementary school students. PMID- 29764461 TI - Characterization of a new apple luteovirus identified by high-throughput sequencing. AB - BACKGROUND: 'Rapid Apple Decline' (RAD) is a newly emerging problem of young, dwarf apple trees in the Northeastern USA. The affected trees show trunk necrosis, cracking and canker before collapse in summer. In this study, we discovered and characterized a new luteovirus from apple trees in RAD-affected orchards using high-throughput sequencing (HTS) technology and subsequent Sanger sequencing. METHODS: Illumina NextSeq sequencing was applied to total RNAs prepared from three diseased apple trees. Sequence reads were de novo assembled, and contigs were annotated by BLASTx. RT-PCR and 5'/3' RACE sequencing were used to obtain the complete genome of a new virus. RT-PCR was used to detect the virus. RESULTS: Three common apple viruses and a new luteovirus were identified from the diseased trees by HTS and RT-PCR. Sequence analyses of the complete genome of the new virus show that it is a new species of the genus Luteovirus in the family Luteoviridae. The virus is graft transmissible and detected by RT-PCR in apple trees in a couple of orchards. CONCLUSIONS: A new luteovirus and/or three known viruses were found to be associated with RAD. Molecular characterization of the new luteovirus provides important information for further investigation of its distribution and etiological role. PMID- 29764460 TI - Benign and severe early-life seizures: a round in the first year of life. AB - BACKGROUND: At the onset, differentiation between abnormal non-epileptic movements, and epileptic seizures presenting in early life is difficult as is clinical diagnosis and prognostic evaluation of the various seizure disorders presenting at this age. Seizures starting in the first year of life including the neonatal period might have a favorable course, such as in infants presenting with benign familial neonatal epilepsy, febrile seizures simplex or acute symptomatic seizures. However, in some cases, the onset of seizures at birth or in the first months of life have a dramatic evolution with severe cerebral impairment. Seizure disorders starting in early life include the "epileptic encephalopathies", a group of conditions characterized by drug resistant seizures, delayed developmental skills, and intellective disability. This group of disorders includes early infantile epileptic encephalopathy also known as Ohtahara syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, infantile spasms syndrome (also known as West syndrome), severe myoclonic epilepsy in infancy (also known as Dravet syndrome) and, myoclonic encephalopathies in non-progressive disorder. Here we report on seizures manifesting in the first year of life including the neonatal period. Conditions with a benign course, and those with severe evolution are presented. At this early age, clinical identification of seizures, distinction of each of these disorders, type of treatment and prognosis is particularly challenging. The aim of this report is to present the clinical manifestations of each of these disorders and provide an updated review of the conditions associated with seizures in the first year of life. PMID- 29764462 TI - Empirical and conceptual investigation of de-implementation of low-value care from professional and health care system perspectives: a study protocol. AB - BACKGROUND: A considerable proportion of interventions provided to patients lacks evidence of their effectiveness. This implies that patients may receive ineffective, unnecessary, or even harmful care. Thus, in addition to implementing evidence-based practices, there is also a need to abandon interventions that are not based on best evidence, i.e., low-value care. However, research on de implementation is limited, and there is a lack of knowledge about how effective de-implementation processes should be carried out. The aim of this project is to explore the phenomenon of the de-implementation of low-value health care practices from the perspective of professionals and the health care system. METHODS: Theories of habits and developmental learning in combination with theories of organizational alignment will be used. The project's work will be conducted in five steps. Step 1 is a scoping review of the literature, and Step 2 has an explorative design involving interviews with health care stakeholders. Step 3 has a prospective design in which workplaces and professionals are shadowed during an ongoing de-implementation. In Step 4, a conceptual framework for de-implementation will be developed based on the previous steps. In Step 5, strategies for de-implementation are identified using a co-design approach. DISCUSSION: This project contributes new knowledge to implementation science consisting of empirical data, a conceptual framework, and strategy suggestions on de-implementation of low-value care. The professionals' perspectives will be highlighted, including insights into how they make decisions, handle de implementation in daily practice, and what consequences it has on their work. Furthermore, the health care system perspective will be considered and new knowledge on how de-implementation can be understood across health care system levels will be obtained. The theories of habits and developmental learning can also offer insights into how context triggers and reinforces certain behaviors and how factors at the individual and the organizational levels interact. The project employs a solution-oriented perspective by developing a framework for de implementation of low-value practices and suggesting practical strategies to improve de-implementation processes at all levels of the health care system. The framework and the strategies can thereafter be evaluated for their validity and impact in future studies. PMID- 29764463 TI - LncMAPK6 drives MAPK6 expression and liver TIC self-renewal. AB - BACKGROUND: Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn't been explored. METHODS: Online available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. RESULTS: Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. CONCLUSION: MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation. PMID- 29764464 TI - Daytime and nighttime casein supplements similarly increase muscle size and strength in response to resistance training earlier in the day: a preliminary investigation. AB - BACKGROUND: Casein protein consumed before sleep has been suggested to offer an overnight supply of exogenous amino acids for anabolic processes. The purpose of this study was to compare supplemental casein consumed earlier in the day (DayTime, DT) versus shortly before bed (NightTime, NT) on body composition, strength, and muscle hypertrophy in response to supervised resistance training. METHODS: Thirteen males participated in a 10-week exercise and dietary intervention while receiving 35 g casein daily. Isocaloric diets provided 1.8 g protein/kg body weight. RESULTS: Both groups increased (p < 0.05) in lean soft tissue (DT Pre: 58.3 +/- 10.3 kg; DT Post: 61.1 +/- 11.1 kg; NT Pre: 58.3 +/- 8.6 kg; NT Post: 60.3 +/- 8.2 kg), cross-sectional area (CSA, DT Pre: 3.4 +/- 1.5 cm2; DT Post: 4.1 +/- 1.7 cm2; NT Pre: 3.3 +/- 1.6 cm2; NT Post: 3.7 +/- 1.6 cm2) and strength in the leg press (DT Pre: 341 +/- 87.3 kg; DT Post: 421.1 +/- 94.0 kg; NT Pre: 450.0 +/- 180.3 kg; NT Post: 533.9 +/- 155.4 kg) and bench press (DT Pre: 89.0 +/- 27.0 kg; DT Post: 101.0 +/- 24.0 kg; NT Pre 100.8 +/- 32.4 kg; NT Post: 109.1 +/- 30.4 kg) with no difference between groups in any variable (p > 0.05). CONCLUSIONS: Both NT and DT protein consumption as part of a 24-h nutrition approach are effective for increasing strength and hypertrophy. The results support the strategy of achieving specific daily protein levels versus specific timing of protein ingestion for increasing muscle mass and performance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03352583 . PMID- 29764465 TI - Traditional knowledge and cultural importance of Borassus aethiopum Mart. in Benin: interacting effects of socio-demographic attributes and multi-scale abundance. AB - BACKGROUND: Eliciting factors affecting distribution of traditional knowledge (TK) and cultural importance of plant resources is central in ethnobiology. Socio demographic attributes and ecological apparency hypothesis (EAH) have been widely documented as drivers of TK distribution, but their synergistic effect is poorly documented. Here, we focused on Borassus aethiopum, a socio-economic important agroforestry palm in Africa, analyzing relationships between the number of use reports and cultural importance on one hand, and informant socio-demographic attributes (age category and gender) on the other hand, considering the EAH at multi-scale contexts. Our hypothesis is that effects of socio-demographic attributes on use-reports and cultural importance are shaped by both local (village level) and regional (chorological region level) apparency of study species. We expected so because distribution of knowledge on a resource in a community correlates to the versatility in the resource utilization but also connections among communities within a region. METHODS: Nine hundred ninety-two face-to-face individual semi-structured interviews were conducted in six villages of low versus high local abundance of B. aethiopum spanning three chorological regions (humid, sub-humid and semi-arid) also underlying a gradient of increasing distribution and abundance of B. aethiopum. Number of use-reports and score of importance of uses of B. aethiopum were recorded in six use-categories including medicine, food, handcraft, construction, firewood, and ceremonies and rituals. Data were analyzed using Poisson and ordered logistic models. RESULTS: Informants listed 121 uses for B. aethiopum: medicine (66 uses), handcraft (16 uses), food (16 uses), construction (12 uses), firewood (6 uses), and ceremonies and rituals (5 uses); but food use was the most culturally important use (2.45 +/- 0.03), followed by construction (0.61 +/- 0.03), medicinal (0.57 +/- 0.03) and handcraft (0.56 +/- 0.03), firewood (0.29 +/- 0.02), and ceremonies and rituals (0.03 +/- 0.01). Food use was the most important for women who were specialized in hypocotyls and fruits collection for commercialization. Men valued more the species for handcrafting, construction, and medicine. The number of use-reports was significantly dependent on age category and gender, and differences between age categories (young, adult, and old) in particular were dependent upon local and regional apparency. In particular, discrepancies among age categories were higher in areas of low abundance and distribution, which may be linked to different speed in the process of knowledge acquisition. In areas of low abundance, the species past abundance was also found instrumental in understanding current knowledge distribution. CONCLUSION: Findings suggest that studies aiming at understanding relationship between current TK and cultural importance of a resource on one hand and socio-demographic attributes on the other hand should consider the resource current local and regional apparency but further its local past abundance. The study also confirms that B. aethiopum is a socio-economic important species in Benin. PMID- 29764466 TI - Validity of shoe-type inertial measurement units for Parkinson's disease patients during treadmill walking. AB - BACKGROUND: When examining participants with pathologies, a shoe-type inertial measurement unit (IMU) system with sensors mounted on both the left and right outsoles may be more useful for analysis and provide better stability for the sensor positions than previous methods using a single IMU sensor or attached to the lower back and a foot. However, there have been few validity analyses of shoe type IMU systems versus reference systems for patients with Parkinson's disease (PD) walking continuously with a steady-state gait in a single direction. Therefore, the purpose of this study is to assess the validity of the shoe-type IMU system versus a 3D motion capture system for patients with PD during 1 min of continuous walking on a treadmill. METHODS: Seventeen participants with PD successfully walked on a treadmill for 1 min. The shoe-type IMU system and a motion capture system comprising nine infrared cameras were used to collect the treadmill walking data with participants moving at their own preferred speeds. All participants took anti-parkinsonian medication at least 3 h before the treadmill walk. An intraclass correlation coefficient analysis and the associated 95% confidence intervals were used to evaluate the validity of the resultant linear acceleration and spatiotemporal parameters for the IMU and motion capture systems. RESULTS: The resultant linear accelerations, cadence, left step length, right step length, left step time, and right step time showed excellent agreement between the shoe-type IMU and motion capture systems. CONCLUSIONS: The shoe-type IMU system provides reliable data and can be an alternative measurement tool for objective gait analysis of patients with PD in a clinical environment. PMID- 29764468 TI - Development and implementation of a geographical area categorisation method with targeted performance indicators for nationwide EMS in Finland. AB - BACKGROUND: In Finland, hospital districts (HD) are required by law to determine the level and availability of Emergency Medical Services (EMS) for each 1-km2 sized area (cell) within their administrative area. The cells are currently categorised into five risk categories based on the predicted number of missions. Methodological defects and insufficient instructions have led to incomparability between EMS services. The aim of this study was to describe a new, nationwide method for categorising the cells, analyse EMS response time data and describe possible differences in mission profiles between the new risk category areas. METHODS: National databases of EMS missions, population and buildings were combined with an existing nationwide 1-km2 hexagon-shaped cell grid. The cells were categorised into four groups, based on the Finnish Environment Institute's (FEI) national definition of urban and rural areas, population and historical EMS mission density within each cell. The EMS mission profiles of the cell categories were compared using risk ratios with confidence intervals in 12 mission groups. RESULTS: In total, 87.3% of the population lives and 87.5% of missions took place in core or other urban areas, which covered only 4.7% of the HDs' surface area. Trauma mission incidence per 1000 inhabitants was higher in core urban areas (42.2) than in other urban (24.2) or dispersed settlement areas (24.6). The results were similar for non-trauma missions (134.8, 93.2 and 92.2, respectively). Each cell category had a characteristic mission profile. High energy trauma missions and cardiac problems were more common in rural and uninhabited cells, while violence, intoxication and non-specific problems dominated in urban areas. CONCLUSION: The proposed area categories and grid-based data collection appear to be a useful method for evaluating EMS demand and availability in different parts of the country for statistical purposes. Due to a similar rural/urban area definition, the method might also be usable for comparison between the Nordic countries. PMID- 29764467 TI - Association of IL17RC and COL6A1 genetic polymorphisms with susceptibility to ossification of the thoracic posterior longitudinal ligament in Chinese patients. AB - BACKGROUND: In our previous whole-genome sequencing study of 30 unrelated northern Chinese Han patients, we identified six single nucleotide polymorphisms (SNPs) in the interleukin 17 receptor C (IL17RC) and collagen type VI alpha1 chain (COL6A1) genes that were potentially associated with thoracic ossification of the posterior longitudinal ligament (T-OPLL). To determine whether these six SNPs are associated with susceptibility to T-OPLL in the northern Chinese Han population, we performed a case-control association study to confirm specific susceptible loci in the expanded samples. METHODS: The six SNPs in the IL17RC and COL6A1 genes were analyzed in 200 northern Chinese individuals (100 patients and 100 control subjects) using the Sequenom system. RESULTS: The genotype distributions and allele frequencies of each SNP in the control and patient groups were compared. rs201153092, rs13051496, rs199772854, rs76999397, and rs189013166 showed potential pathogenic loci for T-OPLL in the northern Chinese Han population, whereas rs151158105 did not. At the genotype level, the differences in the genotype frequencies of rs201153092, rs13051496, rs199772854, rs76999397, and rs189013166 between T-OPLL cases and controls reached statistical significance. CONCLUSIONS: To the best of our knowledge, this is the first association study of susceptibility genes in Han Chinese patients with T-OPLL. The results revealed five SNPs in the IL17RC and COL6A1 genes that represented potentially pathogenic mutations in patients with T-OPLL. PMID- 29764469 TI - Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/beta-catenin-Lin28/let7-PDK1 cascade. AB - BACKGROUND: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. METHODS: Gene expression pattern of NPC cells were used to test associations between Chibby and beta-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, beta-Catenin, and PDK1 by immunostaining. RESULTS: We observed that Chibby, a beta-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/beta-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/beta-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/beta-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/beta Catenin signaling and PDK1. CONCLUSIONS: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/beta-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment. PMID- 29764470 TI - Joint-preserving palliative surgery using self-locking screws of intramedullary nail and percutaneous cementoplasty for proximal humeral metastasis in the advanced cancer patients. AB - BACKGROUND: We introduced a palliative joint-preserving surgery using proximal self-locking screws of intramedullary (IM) nail and percutaneous cementoplasty (PC) in patients with proximal humeral metastases, including the head and neck, and evaluated the outcome of the surgical method. METHODS: Twenty-three patients (mean age = 63.0 +/- 11.8 years, M:F = 14:9) had IM nailing with a self-locking screw system and PC for the treatment of humeral head and neck metastases. Usually, three proximal locking screws were inserted after IM nailing, and 20.9 +/- 8.0 ml of polymethylmethacrylate (PMMA) bone cement was injected in the perimetal osteolytic area. RESULTS: Regional anesthesia with interscalene block was performed in 87.0% (20/23), and the duration of surgery (from anesthesia to awakening) was approximately 40-55 min. Red blood cell was not transfused intra- and/or postoperatively in 65.2% (15/23). The localized preoperative pain (visual analog scale (VAS), 8.2 +/- 3.1) was gradually decreased at postoperative 1 week (VAS, 4.9 +/- 2.1) and at 6 weeks (VAS, 2.9 +/- 2.1) (P < 0.001). Among nine patients who underwent F-18-FDG PET/CT, the proximal humeral metastasis around PC showed improved, stable, and aggravated states in five (55.6%), three (33.3%), and one patient (11.1%), respectively. Meanwhile, 88.8% (8/9) of patients showed aggravation at the naive bone metastasis area. CONCLUSION: The selection of the self-locking screw type of the IM nail and PC was helpful in preventing fixation failure for joint-preserving palliative surgery in the proximal humeral metastasis. PMID- 29764471 TI - Inhaled nitric oxide as a rescue therapy in a preterm neonate with severe pulmonary hypertension: a case report. AB - BACKGROUND: Inhaled nitric oxide (iNO) has been approved for the treatment of persistent pulmonary hypertension of the newborn (PPHN) in term and near-term newborns. Its role in the management of persistent pulmonary hypertension in preterm infants is not clear. Although guidelines do not exist, some studies have shown that iNO could be used as a rescue therapy in preterm neonate with severe pulmonary hypertension. CASE PRESENTATION: We describe the case of a preterm neonate, born at 30 + 1 weeks of gestation, with hypoxic respiratory failure not responding to maximal conventional therapy. On the third day of life echocardiography showed severe pulmonary hypertension with right to left shunt and therapy with iNO was started. We achieved a rapid improvement in clinical conditions and pulmonary pressure normalized after 42 h of treatment. CONCLUSIONS: Moving on a case by case basis, treatment with iNO should be considered as a rescue therapy in preterm newborns with acute hypoxic respiratory failure caused by severe pulmonary hypertension. PMID- 29764473 TI - Modularising ontology and designing inference patterns to personalise health condition assessment: the case of obesity. AB - BACKGROUND: The public health initiatives for obesity prevention are increasingly exploiting the advantages of smart technologies that can register various kinds of data related to physical, physiological, and behavioural conditions. Since individual features and habits vary among people, the design of appropriate intervention strategies for motivating changes in behavioural patterns towards a healthy lifestyle requires the interpretation and integration of collected information, while considering individual profiles in a personalised manner. The ontology-based modelling is recognised as a promising approach in facing the interoperability and integration of heterogeneous information related to characterisation of personal profiles. RESULTS: The presented ontology captures individual profiles across several obesity-related knowledge-domains structured into dedicated modules in order to support inference about health condition, physical features, behavioural habits associated with a person, and relevant changes over time. The modularisation strategy is designed to facilitate ontology development, maintenance, and reuse. The domain-specific modules formalised in the Web Ontology Language (OWL) integrate the domain-specific sets of rules formalised in the Semantic Web Rule Language (SWRL). The inference rules follow a modelling pattern designed to support personalised assessment of health condition as age- and gender-specific. The test cases exemplify a personalised assessment of the obesity-related health conditions for the population of teenagers. CONCLUSION: The paper addresses several issues concerning the modelling of normative concepts related to obesity and depicts how the public health concern impacts classification of teenagers according to their phenotypes. The modelling choices regarding the ontology-structure are explained in the context of the modelling goal to integrate multiple knowledge-domains and support reasoning about the individual changes over time. The presented modularisation pattern enhances reusability of the domain-specific modules across various health care domains. PMID- 29764472 TI - High species diversity of trichostrongyle parasite communities within and between Western Canadian commercial and conservation bison herds revealed by nemabiome metabarcoding. AB - BACKGROUND: Many trichostrongylid nematode species are reported to infect bison, some of which are major causes of disase and production loss in North American bison herds. However, there is little information on the species distribution and relative abundance of these parasites in either commercial or conservation herds. This is largely because trichostrongylid nematode species cannot be distinguished by visual microscopic examination of eggs present in feces. Consequently, we have applied ITS2 rDNA nemabiome metabarcoding to describe the trichostrongyle parasite species diversity in 58 bison production groups derived from 38 commercial North American plains bison (Bison bison bison) herds from across western Canada, and two bison conservation herds located in Elk Island National Park (EINP) [plains bison and wood bison (Bison bison athabascae)] and one in Grasslands National Park (GNP) (plains bison). RESULTS: We report much higher infection intensities and parasite species diversity in commercial bison herds than previously reported in beef cattle herds grazing similar latitudes. Predominant trichostrongyle parasite species in western Canadian commercial bison herds are those commonly associated with Canadian cattle, with Ostertagia ostertagi being the most abundant followed by Cooperia oncophora. Combined with high fecal egg counts in many herds, this is consistent with significant clinical and production-limiting gastrointestinal parasitism in western Canadian bison herds. However, Haemonchus placei was the most abundant species in five of the production groups. This is both surprising and important, as this highly pathogenic blood-feeding parasite has not been reported at such abundance, in any livestock species, at such northerly latitudes. The presence of Trichostrongylus axei as the most abundant parasite in four herds is also unusual, relative to cattle. There were striking differences in parasite communities between the EINP and commercial bison herds. Most notably, Orloffia bisonis was the predominant species in the wood bison herd despite being found at only low levels in all other herds surveyed. CONCLUSIONS: This study represents the most comprehensive description of parasite communities in North American bison to date and illustrates the power of deep amplicon sequencing as a tool to study species diversity in gastrointestinal nematode communities. PMID- 29764474 TI - Acute blindness as a presenting sign of childhood endemic Burkitt's lymphoma in Cameroon: a case report. AB - BACKGROUND: Endemic Burkitt's lymphoma is found predominantly in malaria holoendemic zones, typically in the tropical rain forest of Africa. It usually presents as an extra-nodal tumour in children and young adults with predilection for jaws and soft tissues of the abdomen. Clinical features depend on the primary tumour site, extent of the disease and histologic subtype. Acute blindness as a presentation sign is rare. CASE PRESENTATION: A 13 year old African female presented to our facility with a 3 week history of painful abdominal distention, and loss of vision of the left eye. On examination, there was a huge abdominopelvic mass, left breast mass and complete blindness of the left eye associated with mydriatic pupils non-responsive to light. An abdominal ultrasound showed a huge hypoechoic mass arising from the pelvis and protruding into the abdomen. The jaws, teeth and maxilla were all normal. A fine needle aspiration done was negative for malignant cells. A presumptive diagnosis of Burkitt's lymphoma was made on clinical grounds and abdominal ultrasound findings. The patient was immediately placed on chemotherapy and responded well to treatment with remission of the tumour but persistence of left eye blindness. CONCLUSION: Acute blindness can be the presenting sign of Burkitt's lymphoma in a patient with neither jaw nor maxillary swelling. Primary healthcare providers in low income settings require a high index of suspicion when faced with such atypical presentations. This emphasizes the need for thorough physical examination, and when possible, the clinical utility of ultrasonography for suspicious abdominal masses in the absence of state-of the art diagnostic tools for early diagnosis and treatment, which is critical for survival and to improve quality of life. PMID- 29764475 TI - A potential gliovascular mechanism for microglial activation: differential phenotypic switching of microglia by endothelium versus astrocytes. AB - BACKGROUND: Activation of microglia can result in phenotypic and functional diversity. However, the pathways that trigger different states of microglial activation remain to be fully understood. Here, we hypothesized that after injury, astrocytes and endothelium may contribute to a gliovascular switch for microglial activation. METHODS: Astrocytes or cerebral endothelial cells were subjected to oxygen glucose deprivation, then conditioned media were transferred to microglia. The release of TNFalpha, IL-1beta, IL-10, and IGF-1 was measured using ELISA. Surface markers of CD11b, CD45, CD86, and MHC class II were detected by flow cytometry. mRNA expression of iNOS, CD86, CD206, Arginase1, and transcription factors was measured using real-time PCR. Microglial function including migration and phagocytosis was assessed. Dendritogenesis was determined by counting the number of primary dendrites, secondary dendrites, and dendritic ends in the neurons exposed to either endothelial- or astrocyte-activated microglia. RESULTS: Exposure to conditioned media from oxygen-glucose-deprived cerebral endothelial cells or oxygen-glucose-deprived astrocytes activated microglia into different forms. The endothelium converted ramified microglia into amoeboid shapes; increased the release of TNFalpha, IL-1beta, and IL-10; decreased IGF-1; upregulated iNOS expression; and inhibited microglial migration and phagocytosis. In contrast, astrocytes increased microglial production of IGF 1, upregulated CD206 expression, and enhanced microglial phagocytosis. These opposing effects of the endothelium versus astrocyte crosstalk partly mirror potentially deleterious versus potentially beneficial microglial phenotypes. Consistent with this idea, endothelial-activated microglia were neurotoxic, whereas astrocyte-activated microglia did not affect neuronal viability but instead promoted neuronal dendritogenesis. CONCLUSION: These findings provide proof of concept that endothelial cells and astrocytes provide differing signals to microglia that influence their activation states and suggest that a gliovascular switch may be involved in the balance between beneficial versus deleterious microglial properties. PMID- 29764477 TI - Meta-analysis of the prevalence of tuberculosis in diabetic patients and its association with cigarette smoking in African and Asian countries. AB - OBJECTIVE: This systematic review and meta-analysis was undertaken to estimate the prevalence of tuberculosis in diabetic patients and to determine the effect of cigarette smoking. RESULTS: A total of 15 studies was included in the meta analysis. The pooled overall prevalence of tuberculosis in diabetes was 4.72% (95% CI 3.62-5.83%). In sub-group analyses, the prevalence was 5.13% (95% CI 4.34 5.92%) in Africa, followed by 4.16% (95% CI 2.9-5.4%) in Asia. The odd ratio of tuberculosis among diabetes patients was 7.6 (95% CI 1.46-39) in cigarette smokers as compared to nonsmokers. Publication bias was detected based on graphic asymmetry of fun-nel plots, Begg's and Egger's tests (p < 0.05). Tuberculosis is a common co-morbidity in diabetic patients. Tuberculosis-diabetes co-morbidity is significantly higher in cigarette smokers. PMID- 29764478 TI - Improved symptomatic, functional, and fluoroscopic outcomes following serial "series of three" double-balloon dilation for cricopharyngeus muscle dysfunction. AB - BACKGROUND: Cricopharyngeus muscle dysfunction (CPMD) is a common cause of dysphagia. We employ a progressive series of three double-balloon dilations separated by 4-6 weeks between procedures as a primary treatment option. The purpose of this study was to evaluate subjective, functional and objective improvement in swallowing after three serial dilations for CPMD. METHODS: We retrospectively evaluated patients between June 1, 2014, and June 30, 2016, who underwent a series of three double-balloon dilations for CPMD. Pre- and post dilation Eating Assessment Tool-10 (EAT-10), Functional Oral Intake Scale (FOIS), pharyngeal constriction ratio, pharyngeal area, and pharyngoesophageal segment (PES) opening were compared. RESULTS: Seventeen patients with CPMD underwent serial double-balloon dilation procedures separated by one month. Mean age of the cohort was 73.5 (SD +/- 13.3) years, and 53% were female. The mean EAT-10 improved from 24.7 (SD +/- 7.8) to 15.9 (SD +/- 10.2) [p = 0.0021]. Mean FOIS improved from 5.4 (SD +/- 1.4) pre- to 6.3 (SD +/- 0.9) post-treatment (p = 0.017). Mean UES opening increased from 1.05 (SD +/- 0.34) cm to 1.48 (SD +/- 0.41) cm (p = 0.0003) in the anteroposterior fluoroscopic view and from 0.58 (SD +/- 0.18) to 0.76 (SD +/- 0.30) cm (p = 0.018) in the lateral view. Pharyngeal constriction ratio (PCR), a surrogate measure of pharyngeal strength, improved from 0.49 (SD +/- 0.37) to 0.24 (SD +/- 0.15) (p = 0.015), however pharyngeal area (PA) was unchanged. CONCLUSIONS: A progressive series of three double balloon dilations for cricopharyngeus muscle dysfunction resulted in improved patient reported dysphagia symptom scores and objective fluoroscopic swallowing parameters. PMID- 29764476 TI - Traumatic brain injury in Uganda: exploring the use of a hospital based registry for measuring burden and outcomes. AB - OBJECTIVE: Lack of data on traumatic brain injuries (TBI) hinders the appreciation of the true magnitude of the TBI burden. This paper describes a scientific approach for hospital based systematic data collection in a low-income country. The registry is based on the evaluation framework for injury surveillance systems which comprises a four-step approach: (1) identifying characteristics that assess a surveillance system, (2) review of the identified variables based on adopted specific, measurable, assignable, realistic, and time related criteria, (3) assessment of the proposed variables and system characteristics by an expert panel, and (4) development and application of a rating system. RESULTS: The electronic hospital-based TBI registry is designed through a collaborative approach to capture comprehensive, yet context specific, information on each TBI case, from the time of injury until death or discharge from the hospital. It includes patients' demographics, pre-hospital and hospital assessment and care, TBI causes, injury severity, and patient outcomes. The registry in Uganda will open the opportunity to replicate the process in other similar context and contribute to a better understanding of TBI in these settings, and feed into the global agenda of reducing deaths and disabilities from TBI in low-and middle-income countries. PMID- 29764479 TI - Effect of FTO rs9939609 variant on insulin resistance in obese female adolescents. AB - OBJECTIVES: FTO rs9939609 variant has been shown to be associated with insulin resistance in Caucasian children. However, studies in Asia show inconsistent findings. We investigated the association between FTO rs9939609 polymorphisms and insulin resistance in obese female adolescents in Indonesia, a genetically distinct group within Asia. RESULTS: A total of 78 obese female adolescents participated in this study. The risk allele (A) frequency of FTO rs9939609 variant in Indonesian obese female adolescence was 44.2%. The frequency of insulin resistance was higher in the subjects with AA (54.6%) or AT (59.6%) than the subject with TT genotype (50%), but did not statistically different (p = 0.81 and p = 0.47, respectively). The insulin resistance rate was also higher in the risk allele (A) than the non-risk allele (T) subjects (0.58 vs. 0.55), but did not statistically different (p = 0.75). There was no association between FTO rs9939609 variant and body mass index, fasting glucose level, fasting insulin level, homeostatic model assessment of insulin resistance, and waist circumference (p > 0.05). In conclusion, FTO rs9939609 variant may not be associated with insulin resistance in Indonesian obese female adolescents. A multicenter study with a larger sample size is needed to clarify these findings. PMID- 29764480 TI - A stepped approach for the management of symptomatic internal derangement of the temporomandibular joint. AB - BACKGROUND: Internal derangement is the clinical and pathological condition of disc displacement of the temporomandibular joint. Management of these cases involve conservative and surgical treatment options. Minimally invasive surgical procedures namely arthrocentesis and arthroscopy are promising techniques in the management of internal derangement. However patient selection algorithms, indications for minimally invasive procedures and details of the techniques should be further studied for safe and cost effective management of these cases. This manuscript aims to retrospectively analyze the significance of a stepped surgical treatment approach (arthrocentesis under local anaesthesia as the first line of treatment, followed by arthroscopic lysis and lavage under general anaesthesia in unresolving cases) of internal derangement with or without osteoarthritis. METHODS: This is a retrospective cohort study. Case notes of 1414 patients that were managed with a standard protocol were reviewed. Appropriate inclusion and exclusion criteria were set. Thirty-three patients were eligible for inclusion. Parameters recorded were pain-free inter-incisal opening, spontaneous pain, pain on function, difficulty on chewing, and perceived disability on jaw movements. Pre-operative and post-operative (at the end of the follow up period) pain free maximum interincisal opening values were compared with paired t test and the subjective parameters were evaluated with Chisquare analysis. Treatment outcome and success rate according to American Association of Oral and Maxillofacial Surgeons were descriptively shown. RESULTS: Interincisal opening values increased, and the number of patients with severe or medium rated subjective parameters were reduced at discharge. These improvements were found to be statistically significant. Clinical (Wilkes) staging of internal derangement pre-operatively and at discharge remained either unchanged or was lower. Treatment outcome and success according to American Association of Oral and Maxillofacial Surgeons criteria was 94%. CONCLUSION: The stepped approach for the management of symptomatic internal derangement with or without osteoarthritis is a successful treatment strategy with favourable therapeutic outcomes. PMID- 29764481 TI - A total pleural covering of absorbable cellulose mesh prevents pneumothorax recurrence in patients with Birt-Hogg-Dube syndrome. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is a recently recognized inherited multiple cystic lung disease causing recurrent pneumothoraces. Similarly to the lesions in patients with lymphangioleiomyomatosis (LAM), the pulmonary cysts are innumerable and widely dispersed and cannot all be removed. We recently described a total pleural covering (TPC) that covers the entire visceral pleura with oxidized regenerated cellulose (ORC) mesh. TPC successfully prevented the recurrence of pneumothorax in LAM patients. The purpose of this study was to evaluate the effect of an ORC pleural covering on pneumothorax recurrence in BHDS patients. RESULTS: This retrospective study enrolled a total of 81 pneumothorax patients with the diagnosis of BHDS who underwent 90 covering surgeries from January 2010 to August 2017 at Tamagawa Hospital. During the first half of the study period, a lower pleural covering (LPC) which covered the affected area with ORC mesh was mainly used to treat 38 pneumothoraces. During the second half of the study period, TPC was primarily performed for 52 pneumothoraces. All the thoracoscopic surgeries were successfully performed without serious complications (>= Clavien-Dindo grade III). The median follow-up periods after LPC/TPC were 66/34 months, respectively. Pneumothorax recurrence rates after LPC at 2.5/5/7.5 years postoperatively were 5.4/12/42%, respectively; none of the patients who had underwent TPC developed postoperative pneumothorax recurrence (P = 0.032). CONCLUSIONS: TPC might be an effective option for surgical treatment of intractable pneumothorax in patients with BHDS. PMID- 29764483 TI - Impact of type 2 diabetes mellitus on short-term and long-term outcomes of patients with esophageal squamous cell cancer undergoing resection: a propensity score analysis. AB - BACKGROUND: The association between type 2 diabetes mellitus (T2DM) and the risk of esophageal cancer remains unclear. The present study aimed to evaluate the impact of T2DM on short-term outcomes and long-term survival in patients with esophageal squamous cell cancer (ESCC). METHODS: The present retrospective study included 862 patients diagnosed with ESCC between January 2001 and December 2010. Among them, 280 patients had T2DM. A 1:1 propensity score-matched cohort consisting of 280 patients with and 280 without T2DM was selected from the 862 patients. The associations between T2DM and clinicopathologic characteristics were assessed using the chi2 or Fisher's exact test. Survival of ESCC patients with and without T2DM was calculated by using the Kaplan-Meier method and compared by using the Cox regression model between the two groups. RESULTS: The occurrence rate of anastomotic leakage was significantly higher in patients with T2DM than in those without T2DM (P < 0.001). In the subgroup with weight loss rate <= 5.05%, ESCC patients with T2DM had a significant longer overall survival than did those without T2DM (P = 0.003), whereas in the subgroup with weight loss rate > 5.05%, the patients without T2DM showed a longer survival (P = 0.001). Univariate and multivariate analysis results showed that T2DM was not an independent prognostic factor for patient survival. CONCLUSIONS: Type 2 diabetes mellitus is not an independent prognostic factor in patients with ESCC. However, the combination of T2DM with severe weight loss would be a predictor of poor prognosis. PMID- 29764482 TI - Healthcare costs and utilization associated with high-risk prescription opioid use: a retrospective cohort study. AB - BACKGROUND: Previous studies on high-risk opioid use have only focused on patients diagnosed with an opioid disorder. This study evaluates the impact of various high-risk prescription opioid use groups on healthcare costs and utilization. METHODS: This is a retrospective cohort study using QuintilesIMS health plan claims with independent variables from 2012 and outcomes from 2013. We included a population-based sample of 191,405 non-elderly adults with known sex, one or more opioid prescriptions, and continuous enrollment in 2012 and 2013. Three high-risk opioid use groups were identified in 2012 as (1) persons with 100+ morphine milligram equivalents per day for 90+ consecutive days (chronic users); (2) persons with 30+ days of concomitant opioid and benzodiazepine use (concomitant users); and (3) individuals diagnosed with an opioid use disorder. The length of time that a person had been characterized as a high-risk user was measured. Three healthcare costs (total, medical, and pharmacy costs) and four binary utilization indicators (the top 5% total cost users, the top 5% pharmacy cost users, any hospitalization, and any emergency department visit) derived from 2013 were outcomes. We applied a generalized linear model (GLM) with a log-link function and gamma distribution for costs while logistic regression was employed for utilization indicators. We also adopted propensity score weighting to control for the baseline differences between high-risk and non high-risk opioid users. RESULTS: Of individuals with one or more opioid prescription, 1.45% were chronic users, 4.81% were concomitant users, and 0.94% were diagnosed as having an opioid use disorder. After adjustment and propensity score weighting, chronic users had statistically significant higher prospective total (40%), medical (3%), and pharmacy (172%) costs. The increases in total, medical, and pharmacy costs associated with concomitant users were 13%, 7%, and 41%, and 28%, 21% and 63% for users with a diagnosed opioid use disorder. Both total and pharmacy costs increased with the length of time characterized as high risk users, with the increase being statistically significant. Only concomitant users were associated with a higher odds of hospitalization or emergency department use. CONCLUSIONS: Individuals with high-risk prescription opioid use have significantly higher healthcare costs and utilization than their counterparts, especially those with chronic high-dose opioid use. PMID- 29764484 TI - Selection of candidates for surgery as local therapy among early-stage small cell lung cancer patients: a population-based analysis. AB - BACKGROUND: Surgery and radiotherapy are considered local therapies for small cell lung cancer (SCLC). The present study aimed to select candidates for surgery as local therapy among patients with stage I or II SCLC, based on the eighth edition of the TNM classification for lung cancer. METHODS: Patients diagnosed with SCLC between 2004 and 2013 were selected from the Surveillance, Epidemiology, And End Results database. The TNM stage of SCLC in these patients was re-classified according to the eighth edition of the TNM classification for lung cancer. Patients with stage I or II SCLC were included in the present study. Overall survival (OS) and lung cancer-specific survival (LCSS) were separately compared in the different TNM stages between patients who received surgery and radiotherapy as local therapy. Multivariate analysis was applied to evaluate multiple factors associated with survival. RESULTS: Among the 2129 patients included in the present study, 387 (18.2%) received surgery, 1032 (48.5%) underwent radiotherapy as local therapy, 154 (7.2%) underwent surgery and radiotherapy, and 556 (26.1%) did not undergo either surgery or radiotherapy. Among patients with T1-2N0 (tumor size <= 50 mm without positive lymph nodes) disease, patients who underwent surgery had higher 5-year OS and LCSS rates than patients who received radiotherapy (T1N0: 46.0% vs. 23.8%, P < 0.001, and 58.4% vs. 36.4%, P < 0.001, respectively; T2N0: 42.6% vs. 24.7%, P = 0.004, and 48.8% vs. 31.3%, P = 0.011, respectively). Multivariate analysis results revealed that surgery was associated with low risk of death. However, among T3N0 or T1-2N1 (stage IIB) SCLC patients, patients who underwent surgery did not have higher 5 year OS and LCSS rates than patients who received radiotherapy (T3N0: 16.2% vs. 26.5%, P = 0.085, and 28.7% vs. 30.9%, P = 0.372, respectively; T1-2N1: 20.3% vs. 29.0%, P = 0.146, and 25.6% vs. 35.5%, P = 0.064, respectively). CONCLUSIONS: Based on the assumption that the overwhelming majority of stage I or II SCLC patients who underwent surgery or radiotherapy also received certain types of systemic therapy, only patients with T1-2N0 SCLC may benefit from surgery as local therapy. Patients with T3N0 or T1-2N1 SCLC may consider radiotherapy as local therapy. PMID- 29764486 TI - Editorial announcement regarding title change of Chinese Journal of Cancer to Cancer Communications. PMID- 29764487 TI - Effect of induction chemotherapy with cisplatin, fluorouracil, with or without taxane on locoregionally advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis. AB - BACKGROUND: Available data in the literature comparing different induction chemotherapy (IC) regimens on locoregionally advanced nasopharyngeal carcinoma (NPC) are scarce. The purpose of the present study was to evaluate the outcomes of locoregionally advanced NPC patients who were treated with taxane, cisplatin and 5-fluorouracil (TPF) or cisplatin and 5-fluorouracil (PF) as IC followed by concurrent chemoradiotherapy (CCRT). METHODS: In total, 1879 patients with locoregionally advanced NPC treated with IC and CCRT from a prospectively maintained database were included in the present observational study. We compared overall survival (OS), disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival, using the propensity score method. RESULTS: In total, 1256 patients received TPF or PF as IC backbone. The TPF group showed significantly better OS (hazard ratio [HR], 0.660; 95% confidence interval [CI] 0.442-0.986; P = 0.042), DSS (HR, 0.624; 95% CI 0.411 0.947; P = 0.027) and DMFS (HR, 0.589; 95% CI 0.406-0.855; P = 0.005) compared with the PF group in multivariable analyses. Propensity score matching identified 294 patients in each cohort and confirmed that TPF was associated with significantly improved 5-year OS (88.1% vs. 80.7%; P = 0.042), DSS (88.5% vs. 80.7%; P = 0.021) and DMFS (87.9% vs. 78.6%; P = 0.012) rates compared with the PF group. There were no significant differences in locoregional relapse-free survival before or after matching. CONCLUSIONS: In our study, IC with the TPF regimen combined with CCRT showed improved long-term survival for the patients with locoregionally advanced NPC compared with the PF regimen. However, a prospective randomized clinical trial to validate these findings is necessary. PMID- 29764485 TI - The role of inflammation in the development of epilepsy. AB - Epilepsy, a neurological disease characterized by recurrent seizures, is often associated with a history of previous lesions in the nervous system. Impaired regulation of the activation and resolution of inflammatory cells and molecules in the injured neuronal tissue is a critical factor to the development of epilepsy. However, it is still unclear as to how that unbalanced regulation of inflammation contributes to epilepsy. Therefore, one of the goals in epilepsy research is to identify and elucidate the interconnected inflammatory pathways in systemic and neurological disorders that may further develop epilepsy progression. In this paper, inflammatory molecules, in neurological and systemic disorders (rheumatoid arthritis, Crohn's, Type I Diabetes, etc.) that could contribute to epilepsy development, are reviewed.Understanding the neurobiology of inflammation in epileptogenesis will contribute to the development of new biomarkers for better screening of patients at risk for epilepsy and new therapeutic targets for both prophylaxis and treatment of epilepsy. PMID- 29764490 TI - Efficacy of the hypoxia-activated prodrug evofosfamide (TH-302) in nasopharyngeal carcinoma in vitro and in vivo. AB - BACKGROUND: Tumor hypoxia is considered an important factor in metastasis and disease relapse. Evofosfamide is a hypoxia-activated prodrug that selectively targets the hypoxic regions of solid tumors. As hypoxia-inducible factor-1alpha (HIF-1alpha) is overexpressed in nasopharyngeal carcinoma (NPC) tissues, we performed the present study to evaluate the efficacy profile of evofosfamide in NPC. METHODS: We evaluated the efficacy of evofosfamide as a single agent or combined with cisplatin (DDP) in the NPC cell lines CNE-2, HONE-1 and HNE-1, and in nude mouse xenograft tumor models. RESULTS: Evofosfamide exhibited hypoxia selective cytotoxicity in NPC cell lines, with 50% inhibition concentration (IC50) values of 8.33 +/- 0.75, 7.62 +/- 0.67, and 0.31 +/- 0.07 MUmol/L under hypoxia in CNE-2, HONE-1 and HNE-1 cells, respectively. The sensitization ranged from ninefold to greater than 300-fold under hypoxia compared with normoxia controls. The combination of evofosfamide with DDP had a synergistic effect on cytotoxicity in the NPC cell lines by combination index values assessment. Cell cycle G2 phase was arrested after treated with 0.05 MUmol/L evofosfamide under hypoxia. Histone H2AX phosphorylation (gammaH2AX) (a marker of DNA damage) expression increased while HIF-1alpha expression suppressed after evofosfamide treatment under hypoxic conditions. In the HNE-1 NPC xenograft models, evofosfamide exhibited antitumor activity both as a single agent and combined with DDP. Hypoxic regions in xenograft tissue were reduced after both evofosfamide monotherapy and combined therapy with DDP. CONCLUSIONS: Our results present preclinical evidence for targeting the selective hypoxic portion of NPC by evofosfamide as a single agent and combined with DDP and provide rationale for the potential clinical application of evofosfamide for the treatment of nasopharyngeal carcinoma. PMID- 29764488 TI - Interventions to improve physical activity among socioeconomically disadvantaged groups: an umbrella review. AB - BACKGROUND: People from socioeconomically disadvantaged population groups are less likely to be physically active and more likely to experience adverse health outcomes than those who are less disadvantaged. In this umbrella review we examined across all age groups, (1) the effectiveness of interventions to improve physical activity among socioeconomically disadvantaged groups, (2) the characteristics of effective interventions, and (3) directions for future research. METHODS: PubMed/MEDLINE and Scopus were searched up to May 2017 to identify systematic reviews reporting physical activity interventions in socioeconomically disadvantaged populations or sub-groups. Two authors independently conducted study screening and selection, data extraction (one author, with data checked by two others) and assessment of methodological quality using the 'Assessment of Multiple Systematic Reviews' scale. Results were synthesized narratively. RESULTS: Seventeen reviews met our inclusion criteria, with only 5 (30%) reviews being assessed as high quality. Seven (41%) reviews focused on obesity prevention and an additional four focused on multiple behavioural outcomes. For pre school children, parent-focused, group-based interventions were effective in improving physical activity. For children, school based interventions and policies were effective; few studies focused on adolescents and those that did were generally not effective; for adults, there was mixed evidence of effectiveness but characteristics such as group-based interventions and those that focused on physical activity only were associated with effectiveness. Few studies focused on older adults. Across all ages, interventions that were more intensive tended to be more effective. Most studies reported short-term, rather than longer-term, outcomes and common methodological limitations included high probability of selection bias, low response rates, and high attrition. CONCLUSIONS: Interventions can be successful at improving physical activity among children from socioeconomically disadvantaged groups, with evidence for other age groups weak or inconclusive. More high-quality studies in this population group are needed, which adopt strategies to increase recruitment rates and reduce attrition, report longer term outcomes, and provide adequate intervention details, to allow determination of the characteristics of effective interventions. We recommend that the benefits of physical activity be recognised more broadly than obesity prevention in future studies, as this may have implications for the design and appeal of interventions. PMID- 29764489 TI - miR-MaGiC improves quantification accuracy for small RNA-seq. AB - OBJECTIVE: Many tools have been developed to profile microRNA (miRNA) expression from small RNA-seq data. These tools must contend with several issues: the small size of miRNAs, the small number of unique miRNAs, the fact that similar miRNAs can be transcribed from multiple loci, and the presence of miRNA isoforms known as isomiRs. Methods failing to address these issues can return misleading information. We propose a novel quantification method designed to address these concerns. RESULTS: We present miR-MaGiC, a novel miRNA quantification method, implemented as a cross-platform tool in Java. miR-MaGiC performs stringent mapping to a core region of each miRNA and defines a meaningful set of target miRNA sequences by collapsing the miRNA space to "functional groups". We hypothesize that these two features, mapping stringency and collapsing, provide more optimal quantification to a more meaningful unit (i.e., miRNA family). We test miR-MaGiC and several published methods on 210 small RNA-seq libraries, evaluating each method's ability to accurately reflect global miRNA expression profiles. We define accuracy as total counts close to the total number of input reads originating from miRNAs. We find that miR-MaGiC, which incorporates both stringency and collapsing, provides the most accurate counts. PMID- 29764492 TI - Mineral trioxide aggregate affects cell viability and induces apoptosis of stem cells from human exfoliated deciduous teeth. AB - BACKGROUND: Mineral trioxide aggregate (MTA) is widely used for pulp-capping procedures in permanent teeth and as a gold standard material in endodontics. The aim of the study was to investigate the effect of MTA on cell viability and apoptosis when MTA is directly in contact with Stem Cells from Human Exfoliated Deciduous Teeth (SHEDs). METHODS: MTA was mixed and coated in the bottom of a 24 well plate. SHEDs collected and cultured from normal exfoliated human deciduous teeth (passages 3-4) were seeded on square cover glasses. The glasses with seeded SHEDs were incubated in the plates with or without MTA coating. They were divided into four groups: MTA direct contact, direct control, MTA indirect contact, and indirect control. After 1, 2 and 3 days of culturing, cell morphology was observed and cell viability was assessed by the WST-1 cell cytotoxicity assay. TUNEL assay, immunofluorescent labeling and western blot analysis were used to study the effects of MTA on SHEDs apoptosis. RESULTS: MTA impaired cell viability of SHEDs in 1, 2 and 3 days, and the effect of direct contact was more severe. Cell apoptosis with positive Annexin V and TUNEL staining was noted when there was direct contact with MTA. Western blot analysis revealed that Bcl-2 and Bcl-xL decreased after SHEDs were in contact with MTA. CONCLUSIONS: This study shows that direct contact with 1 week post-set MTA significantly decreases the viability of SHEDs and induced cell apoptosis. The results suggest that there is a possible cytotoxic effect of pulp tissue when there is direct contact with MTA. Different responses would be expected due to the strong alkaline characteristics of fresh mixed MTA. PMID- 29764493 TI - Nasopharyngeal brushing: a convenient and feasible sampling method for nucleic acid-based nasopharyngeal carcinoma research. AB - BACKGROUND: Tissue specimens for nasopharyngeal carcinoma (NPC) research are scarce because of sampling difficulties. Previous studies have suggested non invasive nasopharyngeal brushing as an effective sampling method for NPC diagnosis. The present study aimed to evaluate the feasibility of nasopharyngeal brushing in the acquisition of NPC nucleic acids for research. METHODS: Nasopharyngeal brushing samples were acquired from 24 healthy individuals and 48 NPC patients. Tissues from 48 NPC and 18 nasopharyngitis patients were collected by endoscopic biopsy. The expression levels of tumor suppressor genes (TSGs) and Epstein-Barr virus (EBV)-encoded microRNAs as well as EBV DNA copy number were measured by quantitative polymerase chain reaction in both types of samples. RESULTS: Among six TSGs examined, the expression levels of two genes were significantly decreased in nasopharyngeal brushing and tissue samples from NPC patients as compared with those from healthy/nasopharyngitis individuals. Four EBV-encoded microRNAs, mir-bart1-5p, mir-bart5, mir-bart6-5p, and mir-bart17-5p, were significantly up-regulated in both NPC brushing and tissue samples compared with those from healthy/nasopharyngitis controls (P < 0.001). EBV DNA was significantly increased in both nasopharyngeal brushing samples (P < 0.001) and tissue samples (P < 0.001) from NPC patients in comparison with those from healthy controls. CONCLUSIONS: Nasopharyngeal brushing can obtain sufficient tumoral materials for the analysis of viral nucleic acid, including EBV-encoded microRNAs and EBV DNA. For the detection of TSG expression, nasopharyngeal brushings was feasible but inferior to tissue samples. This study confirms nasopharyngeal brushing as an applicable sampling method that can aid in nucleic acid-based NPC research. PMID- 29764494 TI - Precision medicine becomes reality-tumor type-agnostic therapy. AB - Precision medicine just witnessed two breakthroughs in oncology in 2017. Pembrolizumab (Keytruda), Merck's anti-programmed cell death-1 (PD-1) monoclonal antibody (mAb), received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high (MSI-H) or deficient DNA mismatch repair (dMMR). Shortly after, nivolumab (Opdivo), Bristol-Myers Squibb's anti-PD-1 mAb, gained an accelerated approval in August 2017 for adult and pediatric patients with MSI H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy. These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated, and therefore established a precedent for tumor type-agnostic therapy. In the 2017 American Society for Clinical Oncology annual meeting, larotrectinib (LOXO-101), Loxooncology's oral, potent, and selective inhibitor of tropomyosin receptor kinases (TRK), demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase (NTRK)-fusion proteins in adult and pediatric patients. Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features: (a) biomarker-based, well-defined rare patient population; (b) exceptionally high clinical efficacy, e.g., near 40% overall response rate (ORR) for pembrolizumab across 15 tumor types with MSI H/dMMR and 75% ORR for larotrectinib across more than 12 tumor types with NTRK fusion proteins; (c) durable responses lasting at least 6 months with complete responses observed; and (d) parallel development in adult and pediatric populations. With increasing accessibility to genetic analysis tools such as next generation sequencing, tumor type-agnostic therapy has become a reality, both during clinical development and in clinical practice. Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine. PMID- 29764495 TI - Cancer mortality in Serbia, 1991-2015: an age-period-cohort and joinpoint regression analysis. AB - BACKGROUND: As the result of dramatic political changes, civil wars, and a long term refugee crisis from the end of the last to beginning of this century, the population of Serbia has experienced significant health problems. The aim of this study was to assess cancer mortality trends in Serbia. METHODS: This nationwide study was carried out to analyze cancer mortality in Serbia during 1991-2015 using official data. The age-standardized mortality rates (per 100,000) were calculated by direct standardization, using the world standard population by Segi. The average annual percent change (AAPC) and corresponding 95% confidence interval (CI) were computed using joinpoint regression analysis. Age-period cohort analysis was performed to address the possible underlying reasons for the observed temporal trends. RESULTS: Over the 25-year study period, there were 466,075 cancer deaths (266,043 males and 200,032 females) in Serbia. Overall cancer mortality increased between 1991 and 2009 in both males (by + 0.9% per year) and females (by + 0.8% per year) and has been decreasing since then, by - 0.9% annually in both sexes. For almost all major cancers except stomach cancer, cancer mortality in Serbia demonstrated upward trends during the study period. The largest increases were noted in lung cancer among females (AAPC = + 3.7, 95% CI 3.5-3.9) and prostate cancer in males (AAPC = + 1.9, 95% CI 1.4-2.3). CONCLUSIONS: After two decades of increase, cancer mortality rates are finally declining in Serbia. Despite this, these rates place Serbia among the countries with the highest cancer mortality in the world. PMID- 29764491 TI - Does a low FODMAPs diet reduce symptoms of functional abdominal pain disorders? A systematic review in adult and paediatric population, on behalf of Italian Society of Pediatrics. AB - BACKGROUND: Despite the rising of the Functional Gastrointestinal Disorders (FGIDs)' incidence in the last years, the etio-pathogenesis of FGIDs remains unclear. The diet seems to play an important role in these disorders. Indeed, at least two thirds of adult patients with Irritable Bowel Syndrome (IBS) and of children with FGIDs perceive their GI symptoms to be food-related. In particular, in the last years, more interest has been focused in the low Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyol (FODMAPs) diet. AIMS: To provide a systematic review on the efficacy of a low FODMAPs diet in reducing symptoms associated with functional abdominal pain disorders. METHODS: Cochrane Library, MEDLINE (via Pubmed), and EMBASE databases from inception to June 2017 were searched. We included randomized controlled trials (RCTs), prospective and retrospective studies, systematic reviews and meta-analyses, reporting the efficacy of the FODMAPs diet intervention in FGIDs patients. RESULTS: Nineteen studies were eligible. A FODMAPs-restricted diet is beneficial in 12/13 intervention trials. The low FODMAPs diet improves overall GI symptoms, especially abdominal pain and bloating. In children, only one study reported positive results of a low FODMAPs diet. No effect was found for the lactose free diet whilst fructose-restricted diet was effective in 3/4 studies. The duration of the intervention was very different among the studies, ranging from 2 days to 16 months, and from 3 and 9 weeks for the RCTs. The majority of the trials presented differences in symptoms scoring scales, diet, food diaries, and food frequencies questionnaire. CONCLUSIONS: The FODMAPs-restricted diet may be an effective dietary intervention for reducing IBS symptoms in adults. In children, there are promising data, although only one randomized double-blind study exists and further data are needed to better clarify the role of FODMAPs and fructose restricted diet in IBS. The current evidence does not support the use of a lactose-restricted diet in children with FGIDs. PMID- 29764496 TI - Reporting quality of randomized controlled trials in otolaryngology: review of adherence to the CONSORT statement. AB - BACKGROUND: Randomized controlled trials are the gold standard in medical and surgical research to assess the efficacy of therapeutic interventions. The reporting of these trials should be of high quality to allow readers' appropriate interpretation and application. METHODS: The objectives of our study were to assess the extent to which the recent Otolaryngology - Head and Neck Surgery (ORL HNS) randomized control trials in the top nine journals and in the top Canadian journal comply with the Consolidated Standards of Reporting Trials (CONSORT) statement, and to identify the CONSORT items most in need of improvement. Based on the impact factor and circulation number of 2014, the top nine Otolaryngology journals and the top Canadian Otolaryngology journal were selected and were searched to identify RCTs published in English and between 2010 and 2014. Two authors independently reviewed and extracted data using a standardized data extraction form constructed with the help of a medical librarian. Our outcome was to assess the adherence of articles reporting to the CONSORT items. Descriptive statistics were used. RESULTS: One hundred and eighty-two Otolaryngologic RCTs were identified in the top nine international journals and in the top Canadian journal. The inter-rater reliability between two raters was 0.32. The extent of adherence to CONSORT Statement ranged from 25 to 93.5% with a mean of 59.0% and a median of 59.4%. Only 6.5% of RCTs described the individual responsible for enrolling and assigning subjects and method of randomization; 32.4% reported the estimated effect size and precision; 40.6% reported a sample size calculation and 32.4% mentioned external validity or implications of the findings. CONCLUSION: Findings revealed that the reporting of RCTs in the top nine ORL-HNS journals and in the top Canadian ORL-HNS journal is suboptimal. The quality of reporting can be improved by addressing the three CONSORT items found most deficient in this study namely, sample size calculations, estimated effect size and precision, and external validity. PMID- 29764497 TI - Activated prothrombin complex concentrate to reverse the factor Xa inhibitor (apixaban) effect before emergency surgery: a case series. AB - BACKGROUND: The lack of an antidote against factor Xa inhibitors in case of major bleeding or need for urgent surgery is a concern to clinicians. Guidelines on managing major bleeding in patients under anticoagulation with a factor Xa inhibitor suggest several hemostatic agents to reverse the effect, but there is no consensus regarding the choice of drug or appropriate dose. The ability of prothrombin complex concentrate, activated prothrombin complex concentrate, and recombinant factor VIIa to reverse the effect of factor Xa inhibitors has been evaluated in animal studies, in vitro studies, and healthy volunteers, but not yet in randomized clinical studies. CASE PRESENTATION: We report a consecutive case series of patients under factor Xa inhibitor (apixaban) treatment who received activated prothrombin complex concentrate to reverse the anticoagulation effect before emergency cardiovascular surgery. Patient 1, a 63-year-old white man, was operated with replacement of the aortic valve; patient 2, a 65-year-old white man, underwent heart transplantation; patient 3, a 68-year-old white man, was operated for acute type A aortic dissection. They all received activated prothrombin complex concentrate 25 IU/kg immediately before surgery. In two of the cases, the global coagulation assay thromboelastometry (ROTEMTM) was performed before and after administering activated prothrombin complex concentrate. The ROTEMTM clotting time was reduced from 1900 seconds to 740 seconds and from 1482 to 807 seconds, respectively, after administering a dose of 25 IU/kg activated prothrombin complex concentrate. The apixaban concentration before reversal was within the range considered to be the therapeutic level in all cases. No bleeding complications occurred during surgery, but one case was complicated with bleeding postoperatively. No thromboembolic complications were observed during or after surgery. CONCLUSIONS: Activated prothrombin complex concentrate 25 IU/kg reversed the anticoagulation effect of apixaban effectively and safely before emergency cardiovascular surgery. PMID- 29764498 TI - Talimogene Laherparepvec combined with anti-PD-1 based immunotherapy for unresectable stage III-IV melanoma: a case series. AB - BACKGROUND: Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved as an intratumoral therapy for treating unresectable stage IIIB-IV metastatic melanoma. The mechanisms of action for T-VEC and checkpoint inhibitor are highly complementary. Recent studies have shown that combining checkpoint inhibitor therapy with T-VEC injection can lead to improved response rates for stage IIIB IV melanoma patients. METHODS: We reviewed 10 consecutive cases of stage IIIC to stage IVM1b melanoma patients that received T-VEC plus checkpoint inhibitor(s) therapy (pembrolizumab, ipilimumab/nivolumab, or nivolumab) treated between June 2016 and August 2017 at the Cleveland Clinic with a median follow-up of 7 months (range: 4 to 13 months). Responses of injected (on-target) and uninjected (off target) lesions were evaluated according to RECIST 2.0. RESULTS: The overall response rate for on-target lesions was 90%, with 6 patients experiencing a complete response in injected lesions. Two patients had off-target lesions, which were completely resolved after treatment. Blood samples were tested for 3 complete responders and 2 partial responders. CD4:CD8 ratio and frequencies of circulating PD1+ CD4 and CD8 T cells were elevated in complete responders but not partial responders. One patient died due to causes unrelated to melanoma and one patient died of progression of the disease. CONCLUSION: Our data suggest that combining checkpoint inhibitor(s) with T-VEC injection may provide a synergistic efficacy for patients with unresectable melanoma. We observed a better overall response rate and complete response rate compared to published studies on similar therapeutic regimens. PMID- 29764500 TI - The role of initial 18F-FDG PET/CT in the management of patients with suspected extramedullary plasmocytoma. AB - BACKGROUND: Extramedullary plasmacytoma (EMP) is a plasma cell malignancy that originates in soft tissues without evidence of systemic spread, and its management differs from other plasma cell neoplasms. The purpose of the present study was to evaluate the role of initial 18F-FDG PET/CT in the management of patients with clinical suspected EMP. METHODS: 18F-FDG PET/CT scans performed in 21 patients (M/F = 12/9, mean age 51.1 +/- 15.3 years) with clear suspicion of EMP from 2006 to 2015 were analysed retrospectively. The detection of new lesions and the change in treatment were evaluated. RESULTS: PET/CT detected new lesions in 38.1% (8/21) of patients with 17 lesions, and lymph nodes were the most common site, accounting for 70.6% (12/17) of all lesions, followed by bone (n = 2), and less frequently, breast (n = 1), lung (n = 1), and stomach (n = 1). These findings resulted in treatment changes in 7 patients with EMP. Among these, 4 patients had major treatment changes and 3 patients had minor changes. Of the 21 patients, progression to MM was observed in 8 patients (8/21, 38.1%). In univariate analysis, tumour size > 4 cm and partial response (PR) after treatment were significant prognostic factors for Progression-free survival (PFS). CONCLUSIONS: Our data indicated that 18F-FDG PET/CT is helpful in the detection of additional lesions throughout the body, including lymph node involvement and distant additional lesion, which may have resulted in treatment change. PMID- 29764499 TI - Gestational diabetes is associated with change in the gut microbiota composition in third trimester of pregnancy and postpartum. AB - BACKGROUND: Imbalances of gut microbiota composition are linked to a range of metabolic perturbations. In the present study, we examined the gut microbiota of women with gestational diabetes mellitus (GDM) and normoglycaemic pregnant women in late pregnancy and about 8 months postpartum. METHODS: Gut microbiota profiles of women with GDM (n = 50) and healthy (n = 157) pregnant women in the third trimester and 8 months postpartum were assessed by 16S rRNA gene amplicon sequencing of the V1-V2 region. Insulin and glucose homeostasis were evaluated by a 75 g 2-h oral glucose tolerance test during and after pregnancy. RESULTS: Gut microbiota of women with GDM was aberrant at multiple levels, including phylum and genus levels, compared with normoglycaemic pregnant women. Actinobacteria at phylum level and Collinsella, Rothia and Desulfovibrio at genus level had a higher abundance in the GDM cohort. Difference in abundance of 17 species-level operational taxonomic units (OTUs) during pregnancy was associated with GDM. After adjustment for pre-pregnancy body mass index (BMI), 5 of the 17 OTUs showed differential abundance in the GDM cohort compared with the normoglycaemic pregnant women with enrichment of species annotated to Faecalibacterium and Anaerotruncus and depletion of species annotated to Clostridium (sensu stricto) and to Veillonella. OTUs assigned to Akkermansia were associated with lower insulin sensitivity while Christensenella OTUs were associated with higher fasting plasma glucose concentration. OTU richness and Shannon index decreased from late pregnancy to postpartum regardless of metabolic status. About 8 months after delivery, the microbiota of women with previous GDM was still characterised by an aberrant composition. Thirteen OTUs were differentially abundant in women with previous GDM compared with women with previous normoglycaemic pregnancy. CONCLUSION: GDM diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with normoglycaemic pregnant women, and 8 months after pregnancy, differences in the gut microbiota signatures are still detectable. The gut microbiota composition of women with GDM, both during and after pregnancy, resembles the aberrant microbiota composition reported in non-pregnant individuals with type 2 diabetes and associated intermediary metabolic traits. PMID- 29764501 TI - EYA4 inhibits hepatocellular carcinoma growth and invasion by suppressing NF kappaB-dependent RAP1 transactivation. AB - BACKGROUND: Our previous studies demonstrated that eyes absent homolog 4 (EYA4), a member of the eye development-related EYA family in Drosophila, is frequently methylated and silenced in hepatocellular carcinoma (HCC) specimens and associated with shorter survival. The current work aimed to explore the mechanisms through which EYA4 functions as a tumor suppressor in HCC. METHODS: Stable EYA4-expressing plasmid (pEYA4) transfectants of the human HCC cell lines Huh-7 and PLC/PRF/5 (PLC) were established. Xenografts tumors were established via subcutaneous injection of the stable transfectants into BALB/c nude mice. Tissue samples were obtained from 75 pathologically diagnosed HCC patients. Quantitative real-time polymerase chain reaction, Western blotting and immunohistochemistry were performed to determine the expression of EYA4 in cell lines, xenografts and clinical specimens. The cell proliferation, colony formation, invasiveness and tumor formation of stable transfectants were studied. A gene expression microarray was utilized to screen genes regulated by EYA4 expression. The effect of EYA4 on nuclear factor-kappaB (NF-kappaB)/RAS-related protein 1 (RAP1) signaling was demonstrated through the co-transfection of pEYA4 and Flag-tagged RAS-related protein 1A gene-expressing plasmid (Flag-RAP1A), functional studies, chromatin immunoprecipitation, immunofluorescence staining and cellular ubiquitination assay. RESULTS: The restoration of EYA4 expression in HCC cell lines suppressed cell proliferation, inhibited clonogenic outgrowth, reduced cell invasion and restrained xenograft tumor growth, and Flag-RAP1A reversed the suppressive effects of pEYA4 in vitro. Activation of NF-kappaB with tumor necrosis factor-alpha (TNF-alpha) increased the binding of p65 to the RAP1A gene promoter and up-regulated RAP1 protein expression. The inhibition of NF kappaB with BAY 11-7085 and p65 siRNA successfully blocked TNF-alpha-induced RAP1 up-regulation. EYA4 antagonized the TNF-alpha-induced phosphorylation and ubiquitination of inhibitor of NF-kappaBalpha (IkappaBalpha) as well as the nuclear translocation and transactivation of p65, resulting in repressed NF kappaB activity and RAP1 expression. Blocking the serine/threonine phosphatase activity of EYA4 with calyculin A notably abrogated its suppressive effect on NF kappaB activity. In addition, EYA4 expression was inversely correlated with IkappaBalpha/RAP1 activity in clinical HCC specimens. CONCLUSION: Our findings provide a functional and mechanistic basis for identifying EYA4 as a bona fide tumor suppressor that disrupts aberrant activation of the NF-kappaB/RAP1 signaling pathway and thus orchestrates a physiological impediment to HCC growth and invasion. PMID- 29764503 TI - Bacteriological profile of neonatal sepsis and antibiotic susceptibility pattern of isolates admitted at Kanti Children's Hospital, Kathmandu, Nepal. AB - OBJECTIVE: Neonatal sepsis is a major cause of morbidity and mortality of newborns (< 1 month of age). Septicemia and drug resistance is a predominant issue for neonatal death in Nepal. This study is intended to find bacteriological profile of neonatal sepsis and antibiotic susceptibility pattern of the isolates from neonates at Kanti Children's Hospital, Kathmandu, Nepal. RESULTS: Out of 350 suspected cases of neonatal sepsis, 59 (16.9%) cases showed positive blood culture. The prevalent of positive blood culture with different neonatal risk factors (sex, age, birth weight, gestational age, and delivery mode) showed highest positive bacterial growth in male (52.3%); 3 or above 3 days age (71.2%); low birth weight (62.7%); preterm gestational age (31.4%); and caesarean delivery mode (63.3%). Among positive cases, the bacteriological profile was found highest for Staphylococcus aureus (35.6%) followed by Klebsiella pneumoniae (15.3%). The most sensitive and resistive antibiotics among Gram-positive isolates were gentamicin (93%) and ampicillin (78%), respectively. Meropenem and imipenem showed highest 100% effective and cefotaxime was least (28%) sensitive among Gram negative isolates. This concludes broad ranges of bacteria are associated with neonatal sepsis and revealed variation in antibiotic susceptibility pattern among bacterial isolates. PMID- 29764502 TI - Decreased macrophage inflammatory protein (MIP)-1alpha and MIP-1beta increase the risk of developing nasopharyngeal carcinoma. AB - BACKGROUND: The association of circulating inflammation markers with nasopharyngeal carcinoma (NPC) is still largely unclear. This study aimed to comprehensively explore the relationship between circulating cytokine levels and the subsequent risk of NPC with a two-stage epidemiologic study in southern China. METHODS: The serum levels of 33 inflammatory cytokines were first measured in a hospital-based case-control study (150 NPC patients and 150 controls) using multiplex assay platforms. Marker levels were categorized into two or more groups based on the proportion of sample measurements that was above the lower limit of detection. Odds ratios (ORs) and 95% confidence intervals (CIs) relating the serum marker concentration to the risk of NPC were computed by multivariable logistic regression models. The associations were validated in 60 patients with NPC and 120 controls in a subsequent nested case-control study within a NPC screening trial. Potential interactions between serum cytokines and Epstein-Barr virus (EBV) relating to the risk of NPC were assessed using a likelihood ratio test. RESULTS: The levels of serum macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the highest categories were associated with a decreased risk of NPC in both the case-control study (MIP-1alpha: OR = 0.49, 95% CI = 0.26-0.95; MIP-1beta: OR = 0.47, 95% CI = 0.22-1.00) and the nested case-control study (MIP 1alpha: OR = 0.13, 95% CI = 0.03-0.62; MIP-1beta: OR = 0.20, 95% CI = 0.04-0.94), compared with those in the lowest categories. Furthermore, individuals with lower levels of these two cytokine markers who were EBV seropositive presented with a largely higher risk of NPC compared with patients with higher levels who were EBV seronegative in both the case-control study (MIP-1alpha: OR = 16.28, 95% CI = 7.11-37.23; MIP-1beta: OR = 12.86, 95% CI = 5.9-28.05) and the nested case control study (MIP-1alpha: OR = 86.12, 95% CI = 10.58-701.03; MIP-1beta: OR = 115.44, 95% CI = 13.92-957.73). CONCLUSIONS: Decreased preclinical MIP-1alpha and MIP-1beta levels might be associated with a subsequently increased risk of NPC. More mechanistic studies are required to fully understand this finding. PMID- 29764504 TI - Long-term outcomes of endoscopic submucosal dissection for high-grade dysplasia and early-stage carcinoma in the colorectum. AB - BACKGROUND: Colorectal carcinomas (CRCs) arise from premalignant precursors in an adenoma-carcinoma sequence, in which adenoma with high-grade dysplasia (HGD) and early-stage carcinoma are defined as advanced neoplasia. A limited number of studies have evaluated the long-term outcomes of endoscopic submucosal dissection (ESD) for advanced colorectal neoplasia. This study aimed to assess the efficacy and safety of ESD for advanced colorectal neoplasia as well as the long-term outcomes, including local recurrence and metastasis. METHODS: We analyzed data collected from 610 consecutive patients with 616 advanced colorectal neoplasia lesions treated with ESD between January 2007 and December 2013. Clinical, endoscopic, and histological data were collected over a median follow-up period of 58 months to determine tumor stage and type, resection status, complications, tumor recurrence, and distant metastasis. RESULTS: The overall rates of en bloc resection, histological complete resection, and major complications were 94.3%, 89.4%, and 2.3%, respectively. Hybrid ESD was an independent factor of piecemeal resection. Tumor location in the colon was associated with increased risk of ESD related complications. During the follow-up period, all patients remained free of metastasis. However, local recurrence occurred in 4 patients (0.8%); piecemeal resection was a risk factor. CONCLUSIONS: ESD is effective and safe for resection of advanced colorectal neoplasia, with a high en bloc resection rate and favorable long-term outcomes. ESD is indicated for the treatment of HGD and early stage CRC to obtain curative resection and reduce local recurrence rate. PMID- 29764505 TI - Xenograft tumors derived from malignant pleural effusion of the patients with non small-cell lung cancer as models to explore drug resistance. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions show dramatic responses to specific tyrosine kinase inhibitors (TKIs); however, after 10-12 months, secondary mutations arise that confer resistance. We generated a murine xenograft model using patient-derived NSCLC cells isolated from the pleural fluid of two patients with NSCLC to investigate the mechanisms of resistance against the ALK- and EGFR-targeted TKIs crizotinib and osimertinib, respectively. METHODS: Genotypes of patient biopsies and xenograft tumors were determined by whole exome sequencing (WES), and patients and xenograft-bearing mice received targeted treatment (crizotinib or osimertinib) accordingly. Xenograft mice were also treated for prolonged periods to identify whether the development of drug resistance and/or treatment responses were associated with tumor size. Finally, the pathology of patients biopsies and xenograft tumors were compared histologically. RESULTS: The histological characteristics and chemotherapy responses of xenograft tumors were similar to the actual patients. WES showed that the genotypes of the xenograft and patient tumors were similar (an echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) gene fusion (patient/xenograft: CTC15035EML4-ALK) and EGFR L858R and T790M mutations (patient/xenograft: CTC15063EGFR L858R, T790M)). After continuous crizotinib or osimertinib treatment, WES data suggested that acquired ALK E1210K mutation conferred crizotinib resistance in the CTC15035EML4-ALK xenograft, while decreased frequencies of EGFR L858R and T790M mutations plus the appearance of v RAF murine sarcoma viral oncogene homolog B (BRAF) G7V mutations and phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (PIK3C2A) A86fs frame shift mutations led to osimertinib resistance in the CTC15063EGFR L858R, T790M xenografts. CONCLUSIONS: We successfully developed a new method of generating drug resistance xenograft models from liquid biopsies using microfluidic technology, which might be a useful tool to investigate the mechanisms of drug resistance in NSCLC. PMID- 29764506 TI - Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study. AB - BACKGROUND: 5-Fluorouracil (5-FU) and capecitabine-associated cardiotoxicity ranging from asymptomatic electrocardiography (ECG) abnormalities to severe myocardial infarction has been reported in a number of studies, but such cardiotoxicity in Chinese patients with malignant diseases has not been investigated to date. In the present study, we aimed to prospectively evaluate the incidence rates and clinical manifestations of 5-FU- and capecitabine associated cardiotoxicity in cancer patients recruited from multiple centers in China. METHODS: Among the 527 patients who completed the study, 196 received 5-FU based chemotherapy and 331 received capecitabine-based chemotherapy as either first-line or adjuvant therapy. Adverse events were reported during the treatment and up to 28 days of follow-up. Outcome measures included ECG, myocardial enzymes, cardiac troponin, brain natriuretic peptide and echocardiography. Univariate analysis and logistic regression were performed for subgroup analysis and identification of significant independent variables that are associated with cardiotoxicity of both agents. RESULTS: In total, 161 of 527 patients (30.6%) experienced cardiotoxicity. The incidence rate of cardiotoxicity was 33.8% (112/331) in the capecitabine group, which was significantly higher than the rate of 25% (49/196) in the 5-FU group (P = 0.0042). 110/527 patients (20.9%) suffered arrhythmia, 105/527 (19.9%) developed ischemic changes, while only 20/527 patients (3.8%) presented heart failure and 6/527 patients (1.1%) had myocardial infarction. Pre-existing cardiac disease, hypertension, capecitabine-based chemotherapy and duration of treatment were identified as significant risk factors associated with cardiotoxicity. The odds ratio were 15.7 (prior history of cardiac disease versus no history), 1.86 (capecitabine versus 5-FU), 1.06 (5-8 versus 1-4 chemotherapy cycles) and 1.58 (hypertension versus no hypertension), respectively. CONCLUSIONS: Cardiotoxicity induced by fluoropyrimidines in the Chinese population may be underestimated in clinical practice. Close monitoring of patients is recommended, especially for those patients at high risk for cardiotoxicity. Possible risk factors are duration of treatment, capecitabine based chemotherapy, pre-existing cardiac diseases and hypertension. Trial registration This study was initiated on January 22, 2014 and has been retrospectively registered with the registration number ChiCTR1800015434. PMID- 29764508 TI - Adipose-derived stem cells for treatment of chronic ulcers: current status. AB - Chronic ulcers remain a difficult challenge in healthcare systems. While treatment options are limited, stem cells may be a novel alternative. Adipose derived stem cells (ADSC) have become increasingly popular compared with bone marrow-derived stem cells as they are far easier to harvest. To summarize the current status of treating chronic ulcers with ADSC, this systematic review includes all clinical trials on the subject from PubMed and EmBase, as well as all registered clinical trials on ClinicalTrials.Gov. A total of nine clinical trials and fourteen registered trials were included. The studies were significantly different in terms of study design and patient population, and the overall quality of the studies was low to moderate. Despite the overall low study quality and the significant differences between the studies, some conclusions were consistent: ADSCs are safe, improve the healing of chronic ulcers, and reduce pain. As these results are consistent despite the shortcomings of the studies, they appear to highlight the efficacy of ADSCs in the treatment of chronic ulcers. Larger numbers of higher quality studies are needed to determine the precise role of ADSCs in treating chronic leg ulcers. PMID- 29764507 TI - Aldolase A promotes proliferation and G1/S transition via the EGFR/MAPK pathway in non-small cell lung cancer. AB - BACKGROUND: Our previous study demonstrated that aldolase A (ALDOA) is overexpressed in clinical human lung squamous cell carcinoma and that ALDOA promotes epithelial-mesenchymal transition and tumorigenesis. The present study aimed to explore the function of ALDOA in the modulation of non-small cell lung cancer (NSCLC) proliferation and cell cycle progression and the potential mechanism. METHODS: ALDOA was knocked down by short hairpin RNA in H520 and H1299 cells. ALDOA was overexpressed with vectors carrying the full-length ALDOA sequence in H1299 and H157 cells. The proliferation capacities were assessed with immunohistochemical staining, Cell Counting Kit-8 and colony formation assays. The cell cycle distribution was examined by flow cytometry, and molecular alterations were determined by western blotting. Cell synchronization was induced with nocodazole. The stability of cyclin D1 mRNA was tested. The pyruvate kinase M2 and ALDOA protein distributions were examined. Aerobic glycolysis was evaluated with Cell Titer-Glo assay, glucose colorimetric assay and lactate colorimetric assay. RESULTS: ALDOA knockdown inhibited the proliferation and G1/S transition in H520 cells. Conversely, ALDOA overexpression promoted the proliferation and G1/S transition in H157 cells. The cell cycle synchronization assay showed that ALDOA expression increased in the G1 phase and G1/S transition. Furthermore, ALDOA knockdown reduced cyclin D1 expression by regulating epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) pathway. Similar results were found in H1299 and H157 cells. The inhibition of mitogen activated protein kinase kinase 1/2 prompted the nuclear distribution of ALDOA. Additionally, ALDOA knockdown reduced nuclear distribution of PKM2, the extracellular lactate and intracellular adenosine triphosphate concentrations and elevated the extracellular glucose concentration. CONCLUSIONS: ALDOA contributed to activation of the EGFR/MAPK pathway, thus promoting cyclin D1 expression and enhancing proliferation and G1/S transition in NSCLC. Additionally, ALDOA facilitated NSCLC aerobic glycolysis. PMID- 29764509 TI - Ultrasound-guided fine needle aspiration of retropharyngeal lymph nodes after radiotherapy for nasopharyngeal carcinoma: a novel technique for accurate diagnosis. AB - BACKGROUND: Enlarged retropharyngeal lymph nodes (RLNs) are very common in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy. The most suitable treatment option for enlarged RLNs depends on the pathological results. However, RLN sampling is difficult and imminent in the clinic setting. We recently developed a novel minimally invasive technique termed endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for sampling RLN tissues sufficient for pathological or cytological diagnosis. METHODS: We enrolled 30 post-radiotherapy patients with NPC with suspected RLN metastasis detected via magnetic resonance imaging (MRI). The EUS probe was introduced into the nasopharynx via the nostrils, and EUS was then used to scan the retropharyngeal space and locate the RLN in the anterior carotid sheath. EUS-FNA was subsequently performed. The safety and efficacy of using EUS-FNA to sample the RLN tissues were assessed. RESULTS: Strips of tissue were successfully sampled from all patients using EUS-FNA. Of the 30 patients, 23 were confirmed to have cancer cells in the biopsied tissues via pathology or cytology examinations with 1 EUS FNA biopsy session. The seven cases without confirmed cancer cells were subsequently reanalyzed by using another EUS-FNA biopsy session, and two more cases were confirmed possessing cancer cells. The other five patients without confirmed cancer cells were closely followed with MRI every month for 3 months. After follow-up for 3 months, three patients were still considered cancer-free due to the presence of RLNs with stable or shrinking diameters. The rest two patients who showed progressive disease underwent a third EUS-FNA biopsy procedure and were further confirmed to be cancer cell-positive. In the whole cohort reported here, the EUS-FNA procedure was not associated with any severe complications. CONCLUSION: EUS-FNA is a safe and effective diagnostic approach for sampling tissues from the RLNs in patients with suspected recurrent NPC. PMID- 29764510 TI - Optimizing the diagnosis of pelvic lymph node metastasis in bladder cancer using computed tomography and magnetic resonance imaging. PMID- 29764511 TI - High serum levels of pregenomic RNA reflect frequently failing reverse transcription in hepatitis B virus particles. AB - BACKGROUND: Hepatocytes infected by hepatitis B virus (HBV) produce different HBV RNA species, including pregenomic RNA (pgRNA), which is reverse transcribed during replication. Particles containing HBV RNA are present in serum of infected individuals, and quantification of this HBV RNA could be clinically useful. METHODS: In a retrospective study of 95 patients with chronic HBV infection, we characterised HBV RNA in serum in terms of concentration, particle association and sequence. HBV RNA was detected by real-time PCR at levels almost as high as HBV DNA. RESULTS: The HBV RNA was protected from RNase and it was found in particles of similar density as particles containing HBV DNA after fractionation on a Nycodenz gradient. Sequencing the epsilon region of the RNA did not reveal mutations that would preclude its binding to the viral polymerase before encapsidation. Specific quantification of precore RNA and pgRNA by digital PCR showed almost seven times lower ratio of precore RNA/pgRNA in serum than in liver tissue, which corresponds to poorer encapsidation of this RNA as compared with pgRNA. The serum ratio between HBV DNA and HBV RNA was higher in genotype D as compared with other genotypes. CONCLUSIONS: The results suggest that HBV RNA in serum is present in viral particles with failing reverse transcription activity, which are produced at almost as high rates as viral particles containing DNA. The results encourage further studies of the mechanisms by which these particles are produced, the impact of genotype, and the potential clinical utility of quantifying HBV RNA in serum. PMID- 29764512 TI - Mutational analysis of two residues in the DYRK homology box of the protein kinase DYRK1A. AB - OBJECTIVE: Dual specificity tyrosine phosphorylation-regulated kinases (DYRK) contain a characteristic sequence motif (DYRK homology box, DH box) that is located N-terminal of the catalytic domain and supports the autophosphorylation of a conserved tyrosine during maturation of the catalytic domain. Two missense mutations in the DH box of human DYRK1B were recently identified as causative of a rare familiar form of metabolic syndrome. We have recently shown that these amino acid exchanges impair maturation of the kinase domain. Here we report the characterization of DYRK1A point mutants (D138P, K150C) that correspond to the pathogenic DYRK1B variants (H90P, R102C). RESULTS: When expressed in HeLa cells, DYRK1A-D138P and K150C showed no significant difference from wild type DYRK1A regarding the activating tyrosine autophosphorylation or catalytic activity towards exogenous substrates. However, both DYRK1A variants were underphosphorylated on tyrosine when expressed in a bacterial cell free in vitro translation system. These results suggest that D138 and K150 participate in the maturation of the catalytic domain of DYRK1A albeit the mutation of these residues is compensated under physiological conditions. PMID- 29764513 TI - Cellular therapy with human autologous adipose-derived adult cells of stromal vascular fraction for alopecia areata. AB - BACKGROUND: Most common forms of hair loss (alopecia) are caused by aberrant hair follicle cycling and changes in hair follicle morphology. However, current treatments for alopecia do not specifically target these processes. Adipose derived stromal vascular cells (ADSVCs) that can be harvested from fat cells are one of the latest breakthroughs in the aesthetic field. The potential use of stem cell-based therapies (SCBT) for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions, which can be applied to prevent hair loss. This study aimed to present clinical cases of SCBT for the treatment of alopecia areata by transplantation of ADSVCs in the scalp. METHODS: Twenty patients (9 women and 11 men) were recruited to our retrospectively registered study. After lipoaspiration, autologous ADSVCs were generated and characterized before the injection of 4-4.7 * 106 cells into the scalp of the patient. Hair regeneration was assessed by three clinical tests: the pull test, hair quality, and hair density. RESULTS: All patients experienced hair regeneration, increased hair growth and decreased pull test 3 and 6 months after the treatment with ADSVCs [hair density (85.1 +/- 8.7 vs 121.1 +/- 12.5 hair/cm2, P < 0.0001), hair diameter (60.5 +/- 1.8 vs 80.8 +/- 2.4MU, P < 0.0001) and pull-test values (4.4 +/- 0.3 vs 0.8 +/- 0.2, P < 0.0001), untreated versus 6 months post-operative)]. Significant variation was observed between men and women only for hair diameter. No significant differences were observed with age. CONCLUSIONS: The obtained results prove the efficacy and the safety of the treatment, and satisfaction of the patients confirm the quality of the results. PMID- 29764514 TI - Integrative analysis of gene expression profiles reveals specific signaling pathways associated with pancreatic duct adenocarcinoma. AB - BACKGROUND: Pancreatic duct adenocarcinoma (PDAC) remains a major health problem because conventional cancer treatments are relatively ineffective against it. Microarray studies have linked many genes to pancreatic cancer, but the available data have not been extensively mined for potential insights into PDAC. This study attempted to identify PDAC-associated genes and signaling pathways based on six microarray-based profiles of gene expression in pancreatic cancer deposited in the gene expression omnibus database. METHODS: Pathway network methods were used to analyze core pathways in six publicly available pancreatic cancer gene (GSE71989, GSE15471, GSE16515, GSE32676, GSE41368 and GSE28735) expression profiles. Genes potentially linked to PDAC were assessed for potential impact on survival time based on data in The Cancer Genome Atlas and International Cancer Genome Consortium databases, and the expression of one candidate gene (CKS2) and its association with survival was examined in 102 patients with PDAC from our hospital. Effects of CKS2 knockdown were explored in the PDAC cell lines BxPC-3 and CFPAC-1. RESULTS: The KEGG signaling pathway called "pathway in cancer" may play an important role in pancreatic cancer development and progression. Five genes (BIRC5, CKS2, ITGA3, ITGA6 and RALA) in this pathway were significantly associated with survival time in patients with PDAC. CKS2 was overexpressed in PDAC samples from our hospital, and higher CKS2 expression in these patients was associated with shorter survival time. CKS2 knockdown substantially inhibited PDAC cell proliferation in vitro. CONCLUSIONS: Analysis integrating existing microarray datasets allowed identification of the "pathway in cancer" as an important signaling pathway in PDAC. This integrative approach may be powerful for identifying genes and pathways involved in cancer. PMID- 29764515 TI - Long-term outcome of a moderately hypofractionated, intensity-modulated radiotherapy approach using an endorectal balloon for patients with localized prostate cancer. AB - BACKGROUND: Technical advances in radiotherapy delivery have simultaneously enabled dose escalation and enhanced bladder and rectal sparing. However, the optimal radiation fractionation regimen for localized prostate cancer is unclear. Laboratory and clinical evidence suggest that hypofractionation may improve the therapeutic ratio of radiotherapy. We report our institutional outcomes using moderately hypofractionated, intensity-modulated radiotherapy (IMRT), and an endorectal balloon, with emphasis on long-term biochemical control and treatment related adverse events in patients with localized prostate cancer. METHODS: Between January 1997 and April 2004, 596 patients with cT1-T3 prostate cancer underwent IMRT using a moderate hypofractionation regimen (76.70 Gy at 2.19 Gy/fraction) with an endorectal balloon. Using D'Amico classification, 226 (37.9%), 264 (44.3%), and 106 (17.8%) patients had low-, intermediate-, or high risk disease, respectively. The majority of intermediate- and high-risk patients received androgen deprivation therapy. Biochemical relapse-free survival (bRFS) was evaluated using 2005 Phoenix criteria and estimated using the Kaplan-Meier method. RESULTS: The median follow-up was 62 months. Overall 5- and 10-year bRFS rates were 92.7% and 87.7%. For low-, intermediate-, and high-risk patients, the 5-year bRFS rates were 96.9%, 93.3%, and 82.0%, respectively; the 10-year bRFS rates were 91.4%, 89.3%, and 76.2%, respectively. Prostate-specific antigen, Gleason score, and T stage were significant predictors of bRFS (all P < 0.01). The 5-year rates of severe (>= Grade 3) adverse events were very low: 1.2% for gastrointestinal events and 1.1% for genitourinary events. CONCLUSIONS: Long-term outcomes after moderately hypofractionated IMRT are encouraging. Moderate hypofractionation represents a safe, efficacious, alternative regimen in the treatment of localized prostate cancer. PMID- 29764516 TI - Somatic mutation landscape of a meningioma and its pulmonary metastasis. AB - BACKGROUND: Extracranial metastasis (ENM) of meningiomas is extremely rare, and typically occurs several years after a primary tumor is diagnosed. However, the genetic changes underlying ENM events have not yet been investigated. CASE PRESENTATION: A 58-year-old male patient was sent to the emergency room of our hospital because of a sudden fall. Magnetic resonance imaging detected a mass at the right frontal sagittal sinus. He underwent tumor resection and recovered well, but post-operative computed tomography revealed three lumps on the right side of his chest. Thoracic surgery was performed to remove two of the lumps. Pathological findings revealed that the brain and lung tumors were grade I meningiomas. The patient received no additional radiation or chemotherapy post surgery, and there was no sign of tumor recurrence in the brain or progression of the remaining lump in the chest 1 year after surgery. We performed whole exome sequencing of the patient's blood, primary brain tumor, and lung metastatic tumor tissues to identify somatic genetic alterations that had occurred during ENM. This revealed that a frameshift deletion of the neurofibromin 2 gene likely drove formation of the meningioma. Surprisingly, we found that the brain tumor was relatively homogeneous and contained only one dominant clone; both the pulmonary metastasis and the original brain tumor were derived from the same clone, and no obvious additional driver mutations were detected in the metastatic tumor. CONCLUSION: Although ENM of meningiomas is very rare, brain tumor cells appear to be more adaptable to tissue microenvironments outside of the central nervous system than was commonly thought. PMID- 29764517 TI - New insights from the widening homogeneity perspective to target intratumor heterogeneity. AB - Precision medicine has shed new light on the treatment of heterogeneous cancer patients. However, intratumor heterogeneity strongly constrains the clinical benefit of precision medicine. Thus, rethinking therapeutic strategies from a different facet within the precision medicine framework will not only diversify clinical interventions, but also provide an avenue for precision medicine. Here, we explore the current approaches for targeting intratumor heterogeneity and their limitations. Furthermore, we propose a theoretical strategy with a "homogenization" feature based on iatrogenic evolutionary selection to target intratumor heterogeneity. PMID- 29764518 TI - A novel nomogram individually predicting disease-specific survival after D2 gastrectomy for advanced gastric cancer. AB - BACKGROUND: Few studies have shown nomograms that may predict disease-specific survival (DSS) probability after curative D2 gastrectomy for advanced gastric cancer (AGC), particularly among Chinese patients. This study sought to develop an elaborative nomogram that predicts long-term DSS for AGC in Chinese patients. METHODS: A retrospective study was conducted on 6753 AGC patients undergoing D2 gastrectomy between January 1, 2000 and December 31, 2012 from three large medical hospitals in China. We assigned patients from Sun Yat-sen University Cancer Center to the training set, and patients from the First Affiliated Hospital of China Medical University and Tianjin Medical University Cancer Hospital to two separate external validation sets. A multivariate survival analysis was performed using Cox proportional hazards regression model in a training set, and a nomogram was constructed. Harrell's C-index was used to evaluate discrimination and calibration plots were used to validate similarities between survival probabilities predicted by the nomogram model and actual survival rates in two validation sets. RESULTS: The multivariate Cox regression model identified age, tumor size, location, Lauren classification, lymphatic/venous invasion, depth of invasion, and metastatic lymph node ratio as covariates associated with survival. In the training set, the nomogram exhibited superior discrimination power compared with the 8th American Joint Committee on Cancer TNM classification (Harrell's C-index, 0.82 vs. 0.74; P < 0.001). In two validation sets, the nomogram's discrimination power was also excellent relative to TNM classification (C-index, 0.83 vs. 0.75 and 0.81 vs. 0.74, respectively; P < 0.001 for both). After calibration, the nomogram produced survival predictions that corresponded closely with actual survival rate. CONCLUSIONS: The established nomogram was able to predict 3-, 5-, and 10-year DSS probabilities for AGC patients. Validation revealed that this nomogram exhibited excellent discrimination and calibration capacity, suggesting its clinical utility. PMID- 29764520 TI - Investigation of a typhoid fever epidemic in Moyale Sub-County, Kenya, 2014-2015. AB - AIM: Typhoid fever is a vaccine-preventable bacterial disease that causes significant morbidity and mortality throughout Africa. This paper describes an upsurge of typhoid fever cases in Moyale Sub-County (MSC), Kenya, 2014-2015. METHODS: We conducted active hospital and health facility surveillance and laboratory and antimicrobial sensitivity testing for all patients presenting with headache, fever, stomach pains, diarrhea, or constipation at five MSC health facilities between December 2014 and January 2015. We also conducted direct observation of the residential areas of the suspected cases to assess potential environmental exposures and transmission mechanisms. Demographic, clinical, and laboratory data were entered into, and descriptive statistics were calculated with, MS Excel. RESULTS: A total of 317 patients were included in the study, with mean age 24 +/- 8.1 years, and 51% female. Of the 317 suspect cases, 155 (49%) were positive by Widal antigen reaction test. A total of 188 (59%) specimens were subjected to culture and sensitivity testing, with 71 (38%) culture positive and 54 (76%), 43 (60%), and 33 (46%) sensitive to ceftriaxone, cefuroxime, and ciprofloxacin, respectively. Environmental assessments through direct observations showed that commercial and residential areas had limited (1) clean water sources, (2) latrines, and (3) hygiene stations for street food hawkers and their customers. CONCLUSIONS: Typhoid fever is endemic in MSC and causes significant disease across age and sex groups. The local health department should develop policies to (1) assure community access to potable water and hygiene stations and (2) vaccinate specific occupations, such as food and drink handlers, against typhoid. PMID- 29764519 TI - Plasmodium yoelii infection inhibits murine leukaemia WEHI-3 cell proliferation in vivo by promoting immune responses. AB - BACKGROUND: Leukaemia is a malignant leukocyte disorder with a high fatality rate, and current treatments for this disease are unsatisfactory. Therefore, new therapeutic strategies for leukaemia must be developed. Malaria parasite infection has been shown to be effective at combating certain neoplasms in animal experiments. This study is to demonstrate the anti-leukaemia activity of malaria parasite Plasmodium yoelii (P. yoelii) infection,. METHODS: In this study, the proportion of CD3, CD19, CD11b and Mac-3 cells was analysed by flow cytometry; the levels of IFN-gamma and TNF-alpha in individual serum samples were measured by enzyme-linked immunosorbent assay, and the phagocytic activity of macrophages and natural killer (NK) cell activity were measured by flow cytometry. RESULTS: We found that P. yoelii infection significantly attenuated the growth of WEHI-3 cells in mice. In addition, tumor cell infiltration into the murine liver and spleen was markedly reduced. We also demonstrated that malaria parasite infection elicited anti-leukaemia activity by promoting immune responses, including increasing the surface markers of T cells (CD3) and B cells (CD19); decreasing the surface markers of monocytes (CD11b) and macrophages (Mac-3); inducing the secretion of IFN-gamma and TNF-alpha; and increasing NK cell and macrophage activity. CONCLUSIONS: Malaria parasite infection significantly decreases the number of myeloblasts and inhibits neoplasm proliferation in mice. In addition, malaria parasite infection inhibits murine leukaemia by promoting immune responses. PMID- 29764523 TI - The history and scope of neuropsychiatry. PMID- 29764522 TI - Treatment-resistant depression and peripheral C-reactive protein. AB - BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest. PMID- 29764524 TI - A qualitative examination of the factors related to the development and maintenance of insomnia in cancer survivors. AB - OBJECTIVE: Insomnia is underrecognized and inadequately managed, with close to 60% of cancer survivors experiencing insomnia at some point in the treatment trajectory. The objective of this study was to further understand predisposing, precipitating, and perpetuating factors in the development and maintenance of insomnia in cancer survivors. METHOD: A heterogeneous sample of 63 patients who had completed active treatment was recruited. Participants were required to have a score >7 on the Insomnia Severity Index and meet the diagnostic criteria for insomnia disorder. Open-ended, semistructured interviews were conducted to elicit participants' experiences with sleep problems. An a priori set of codes and a set of codes that emerged from the data were used to analyze the data.ResultThe mean age of the sample was 60.5 years, with 30% identifying as non-white and 59% reporting their sex as female. The cancer types represented were heterogeneous with the two most common being breast (30%) and prostate (21%). Participants described an inherited risk for insomnia, anxious temperament, and insufficient ability to relax as predisposing factors. Respondents were split as to whether they classified their cancer diagnosis as the precipitating factor for their insomnia. Participants reported several behaviors that are known to perpetuate problems with sleep including napping, using back-lit electronics before bed, and poor sleep hygiene. One of the most prominent themes identified was the use of sleeping medications. Participants reported that they were reluctant to take medication but felt that it was the only option to treat their insomnia and that it was encouraged by their doctors.Significance of resultsInsomnia is a prevalent, but highly treatable, disorder in cancer survivors. Patients and provider education is needed to change individual and organizational behaviors that contribute to the development and maintenance of insomnia and increase access to evidence-based nonpharmacological interventions. PMID- 29764525 TI - Development of understanding of DOHaD concepts in students during undergraduate health professional programs in Japan and New Zealand. AB - Evidence in support of the Developmental Origins of Health and Disease (DOHaD) hypothesis has reached the level where it can appropriately be used to inform practice. DOHaD informed interventions supporting primary noncommunicable disease risk reduction should target the pre- and periconceptional periods, pregnancy, lactation, childhood and adolescence. Such interventions are dependent on a health workforce (including dietitians, nurses, midwives, doctors, and nutrition teachers), that has a deep understanding of DOHaD concepts. This study assessed development of awareness of DOHaD concepts during undergraduate health professional training programs. Using a cross-sectional design, a standardized questionnaire was completed by Year 1-4 undergraduate students studying nutrition in Japan (n=309) and Year 1-3 nursing students in New Zealand (n=151). On entry to undergraduate study, most students had no awareness of the terms 'DOHaD' or 'First 1000 Days'. While awareness reached 60% by Year 3 in courses that included DOHaD-related teaching, this remains inadequate. More than 95% of Year 1 undergraduates in both countries demonstrated an appreciation of associations between maternal nutrition and fetal health. However, awareness of associations between parental health status and/or nutritional environment and later-life health was low. While levels of awareness increased across program years, overall awareness was less than optimal. These results indicate evidence of some focus on DOHaD-related content in curricula. We argue that DOHaD principles should be one pillar around which health training curricula are built. This study indicates a need for the DOHaD community to engage with faculties in curriculum development. PMID- 29764526 TI - Cannabinoid signalling in embryonic and adult neurogenesis: possible implications for psychiatric and neurological disorders. AB - Cannabinoid signalling modulates several aspects of brain function, including the generation and survival of neurons during embryonic and adult periods. The present review intended to summarise evidence supporting a role for the endocannabinoid system on the control of neurogenesis and neurogenesis-dependent functions. Studies reporting participation of cannabinoids on the regulation of any step of neurogenesis and the effects of cannabinoid compounds on animal models possessing neurogenesis-dependent features were selected from Medline. Qualitative evaluation of the selected studies indicated that activation of cannabinoid receptors may change neurogenesis in embryonic or adult nervous systems alongside rescue of phenotypes in animal models of different psychiatric and neurological disorders. The text offers an overview on the effects of cannabinoids on central nervous system development and the possible links with psychiatric and neurological disorders such as anxiety, depression, schizophrenia, brain ischaemia/stroke and Alzheimer's disease. An understanding of the mechanisms by which cannabinoid signalling influences developmental and adult neurogenesis will help foster the development of new therapeutic strategies for neurodevelopmental, psychiatric and neurological disorders. PMID- 29764521 TI - Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer. AB - Cancer cells often upregulate nutrient transporters to fulfill their increased biosynthetic and bioenergetic needs, and to maintain redox homeostasis. One nutrient transporter frequently overexpressed in human cancers is the cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT). SLC7A11 promotes cystine uptake and glutathione biosynthesis, resulting in protection from oxidative stress and ferroptotic cell death. Recent studies have unexpectedly revealed that SLC7A11 also plays critical roles in glutamine metabolism and regulates the glucose and glutamine dependency of cancer cells. This review discusses the roles of SLC7A11 in regulating the antioxidant response and nutrient dependency of cancer cells, explores our current understanding of SLC7A11 regulation in cancer metabolism, and highlights key open questions for future studies in this emerging research area. A deeper understanding of SLC7A11 in cancer metabolism may identify new therapeutic opportunities to target this important amino acid transporter for cancer treatment. PMID- 29764527 TI - An outbreak of haemorrhagic fever with renal syndrome linked with mountain recreational activities in Zagreb, Croatia, 2017. AB - In 2017 Zagreb faced the largest outbreak of haemorrhagic fever with renal syndrome (HFRS) to date. We investigated to describe the extent of the outbreak and identify risk factors for infection. We compared laboratory-confirmed cases of Hantavirus infection in Zagreb residents with the onset of illness after 1 January 2017, with individually matched controls from the same household or neighbourhood. We calculated adjusted matched odds ratios (amOR) using conditional logistic regression. During 2017, 104 cases were reported: 11-81 years old (median 37) and 71% (73) male. Compared with 104 controls, cases were more likely to report visiting Mount Medvednica (amOR 60, 95% CI 6-597), visiting a forest (amOR 46, 95% CI 4.7-450) and observing rodents (amOR 20, 95% CI 2.6 159). Seventy per cent of cases (73/104) had visited Mount Medvednica prior to infection. Among participants who had visited Mount Medvednica, cases were more likely to have drunk water from a spring (amOR 22, 95% CI 1.9-265), observed rodents (amOR 17, 95% CI 2-144), picked flowers (amOR 15, 95% CI 1.2-182) or cycled (amOR 14, 95% CI 1.6-135). Our study indicated that recreational activity around Mount Medvednica was associated with HFRS. We recommend enhanced surveillance of the recreational areas during an outbreak. PMID- 29764529 TI - Host community heterogeneity and the expression of host specificity in avian haemosporidia in the Western Cape, South Africa. AB - Similar patterns of parasite prevalence in animal communities may be driven by a range of different mechanisms. The influences of host heterogeneity and host parasite interactions in host community assemblages are poorly understood. We sampled birds at 27 wetlands in South Africa to compare four hypotheses explaining how host community heterogeneity influences host specificity in avian haemosporidia communities: the host-neutral hypothesis, the super-spreader hypothesis, the host specialist hypothesis and the heterogeneity hypothesis. A total of 289 birds (29%) were infected with Plasmodium, Haemoproteus and/or Leucocytozoon lineages. Leucocytozoon was the most diverse and generalist parasite genus, and Plasmodium the most conservative. The host-neutral and host specialist hypotheses received the most support in explaining prevalence by lineage (Leucocytozoon) and genus (Plasmodium and Haemoproteus), respectively. We observed that haemosporidian prevalence was potentially amplified or reduced with variation in host and/or parasitic taxonomic levels of analysis. Our results show that Leucocytozoon host abundance and diversity was influential to parasite prevalence at varying taxonomic levels, particularly within heterogeneous host communities. Furthermore, we note that prevalent mechanisms of infection can potentially act as distinct roots for shaping communities of avian haemosporidia. PMID- 29764528 TI - Symptomatic myocardial bridging: a frequently occurring coronary variation can cause severe myocardial ischaemia in affected children with underlying cardiac conditions. AB - Myocardial bridging is a congenital coronary artery anomaly in which the coronary artery has a partly "tunnelled" intramyocardial course. This tunnelling leads to compression of the affected vessel segment during ventricular systole. It is considered to be a benign variation of the norm in about 25% of the population caused by an aberrancy of embryologic coronary development. The bridging is also thought to cause severe cardiac conditions in a few of those affected. The series of six young patients presented here is the largest series so far to report on symptomatic myocardial bridging in children with different underlying heart diseases. All patients recently presented to our centre with signs of myocardial ischaemia. They subsequently underwent coronary angiography, which revealed myocardial bridging of the ramus interventricularis anterior. In all patients, therapy with beta blockers was started to reduce heart rate and myocardial contractility. beta Blocker treatment was also given in order to prolong diastole and improve coronary artery blood flow. Two patients underwent surgical exposure of the involved coronary segment: a 2-year-old boy because of recurrent, severe myocardial ischaemia in combination with a reduction of general health, changes in ST-segments, and the presence of a dilative cardiomyopathy; and a 13-year-old girl because of evidence of myocardial ischaemia during exercise testing after surviving sudden cardiac death. Surgery was successful and recovery was complete and uneventful. The presented series shows that myocardial bridging can be symptomatic and may require urgent treatment and even surgical intervention in early childhood in rare cases. PMID- 29764530 TI - Influence of maternal adiposity, preterm birth and birth weight centiles on early childhood obesity in an Indigenous Australian pregnancy-through-to-early childhood cohort study. AB - Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother-child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women. PMID- 29764531 TI - Syllables and inflectional morphemes in early Finnish readers: evidence from eye movements. AB - Finnish is a language with simple syllable structure but rich morphology. It was investigated whether syllables or morphemes are preferred processing units in early reading. To this end, Finnish first- and second-grade children read sentences with embedded inflected target words while their eye-movements were registered. The target words were either in essive or inessive/adessive (i.e., locative) case. The target words were either non-hyphenated, or had syllable congruent or syllable-incongruent hyphenation. For the locatives, the syllable incongruent hyphenation coincided with the morpheme boundary, but this was not the case for the essives. It was shown that the second-graders were slowed down by hyphenation to a larger extent than first-graders. However, there was no slowdown in gaze duration for either age group when the syllable-incongruent hyphen was morpheme-congruent. These findings suggest that Finnish readers already utilize morpheme-level information during the first grade. PMID- 29764532 TI - CJEM Debate Series: #PoCUS-All physicians practicing emergency medicine should be competent in the use of point-of-care ultrasound. PMID- 29764533 TI - New frontiers in Canadian atrial fibrillation management. PMID- 29764534 TI - Geriatric emergency medicine: Research priorities to respond to "The Silver Boom". PMID- 29764535 TI - The other side of the curtain. PMID- 29764536 TI - Adding value to scholarship in residency: Supporting and inspiring future emergency medicine research in Canada. PMID- 29764537 TI - There are no shortcuts: A focus on POCUS. PMID- 29764538 TI - The first step in an exciting journey. PMID- 29764540 TI - [2018 National consensus on cardiopulmonary resuscitation training in China]. AB - OBJECTIVE: To promote the technical training and scientific popularization of cardiopulmonary resuscitation (CPR) in China, the Cardiopulmonary Resuscitation Specialized Committee of Chinese Research Hospital Association combined with the Science Popularization Branch of the Chinese Medical Association wrote "2018 National consensus on cardiopulmonary resuscitation training in China". The formation was based on the general outline about "2016 National consensus on cardiopulmonary resuscitation in China", and to implement the important strategies included the "three pre" policy, prevention, precognition, and pre warning, before the cardiac arrest (CA); the "three modernization" methods, standardized, diversified and individualized, during the CA; and the "three life" strategies, the rebirth, the extra and the extended, after the CA; and also combined with the concrete National conditions and clinical practice of China area. The document summarized the evidence of published science about CPR training till now, and recommend the establishment of "the CPR Training Triangle" according to the Chinese National conditions. The bases of the triangle were system, training and person, the core of which was CPR science. The main contents were: (1) The "three training" policy for CPR training: the cultivation of a sound system, which included professional credibility, extensive mobilization and continuous driving force, and the participation of the whole people and continuous improvement; the cultivation of scientific guidelines, which included scientific content, methods and thinking; and the cultivation of a healthy culture, which included the enhancement of civic quality, education of rescue scientifically, and advocate of healthy life. (2) The "three training" program of CPR training: training professional skills, which included standard, multiple, and individual skills; training multidimensional, which included time, space, and human; and training flexible, including problem, time, and innovation oriented. (3) The "three party" direction of CPR training, the application for achievement translation, which included scientific translations, skill propagators, and cultural advocates; the precision disseminators, which included accurate communication sources, channels, and dissemination of the audience; and theoretical innovation guides, which included scientific, popular science and communication theory. That integrated the wisdom of scholars, melt the thought of genius, and created the act of envoy for Chinese and foreign CPR training. The training program should be suitable for different trainee, no matter who is trainer or trainee. The release of the expert consensus on the 2018 CPR training will make the National CPR education into the new training era with definite direction, clear target and fully standard of China. PMID- 29764541 TI - [Tianjin characteristics of integrated traditional Chinese and Western medicine in first aid medical system]. AB - OBJECTIVE: Tianjin, as the earliest city to open up, the exchange of Chinese and Western cultures also started earlier. Therefore, today's emergency medicine system with integrated features of Chinese and Western medicine is formed. Professor Wang Jinda, who works in Tianjin First Center Hospital, makes the theory of "treating bronchitis and treating diseases" and "three methods of three syndromes" for the treatment of severe diseases such as sepsis. The surgical aspect is the treatment of acute abdomen with the combination of Chinese and Western medicine which is proposed by Academician Wu Xianzhong who worked in Tianjin Nankai Hospital. In the aspect of acupuncture and moxibustion, Professor Guo Yi, who works in Tianjin University of Traditional Chinese Medicine, provides the twelve Jing points blood-letting therapy for cerebral diseases such as stroke. Professor Liu Xinqiao from the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine also conducts in-depth studies on brain protection after cardiopulmonary resuscitation (CPR). He proposes the importance of traditional Chinese medicine in addition to mild hypothermia and neuroprotective agents. The author summarized these achievements, in light of which looked forward to the future and proposed the concept of establishing a multi-specialist collaboration and an emergency center with obvious characteristics of integrated Chinese and Western medicine, which would pave the way for the development of integrated Chinese and Western medicine first aid. PMID- 29764539 TI - Effect of Chronic Social Stress on Prenatal Transfer of Antitetanus Immunity in Captive Breeding Rhesus Macaques (Macaca mulatta). AB - Because tetanus can cause significant morbidity and mortality in NHP, colonywide vaccination with tetanus toxoid is recommended for outdoor breeding colonies of rhesus macaques, with primary immunizations commonly given to infants at 6 mo of age followed by booster vaccines every 10 y. Maternal antibodies are thought to offer protective immunity to infants younger than 6 mo. However, historical colony data from the Yerkes National Primate Research Center show a higher incidence of tetanus among infants (<= 6 mo old) born to subordinate dams. Whether this higher incidence of infantile tetanus is due to a higher incidence of trauma among subordinate animals or is a stress-induced impairment of maternal antibody protection is unknown. Studies in other NHP species suggest that chronic exposure to social stressors interferes with the receptor-mediated transplacental transfer of IgG. Therefore, the primary aim of this study was to determine whether chronic stress associated with social subordination impairs prenatal transfer of antitetanus immunity in breeding female rhesus macaques. Subjects included 26 high- and 26 low-ranking adult female rhesus macaques that were nearly 5 or 10 y after their initial immunization and their nonimmunized infants. We hypothesized that infants born to subordinate dams that were nearly 10 y after immunization would have the lowest infant-to-dam antibody ratios and thus would be at greatest risk for infection. Results revealed no significant intergroup differences in infant antitetanus IgG levels. However, infant-to-dam IgG ratios against tetanus were significantly lower among subordinate animals compared with dominant macaques, after accounting for the number of years since the dam's initial vaccination. In addition, higher maternal hair cortisol levels predicted lower infantto-dam tetanus toxoid IgG ratios. Together, these findings suggest that chronic social stress in female rhesus macaques may hamper the prenatal transfer of antitetanus immunity to offspring. PMID- 29764542 TI - [Unfractionated heparin ameliorates lipopolysaccharide induced expressions of nitric oxide and reactive oxygen species in renal microvascular endothelial cells]. AB - OBJECTIVE: To observe the effect of heparin on the cellular morphology and the expressions of nitric oxide (NO) and reactive oxygen species (ROS) in renal microvascular endothelial cells (RMVECs) stimulated by lipopolysaccharide (LPS). METHODS: The three step gradient screen method was used to primarily culture rat RMVECs, and the 3rd and 4th generation cells with excellent growth were collected. The cells were divided into blank control group, 10 mg/L LPS treatment group and 2.5, 5, 10 kU/L heparin pretreatment groups (the corresponding dose of heparin was given 0.5 hour before LPS stimulation). The morphology of the cells at 24 hours after LPS stimulation was observed by transmission electron microscope, the expression of ROS in RMVECs was determined by immunofluorescence at 5, 15, 30, 45 minutes after LPS stimulation, and the expression of NO in RMVECs was determined by nitrate reductase method. RESULTS: (1) In blank control group, the RMVECs membrane was intact, and the mitochondria and endoplasmic reticulum in cells were clearly visible. The nuclear membrane was complete, and nucleolus was obvious. Cell bubble deformation was obvious at 24 hours after LPS stimulation, especially in the mitochondria and cell membrane. After 10 kU/L heparin pretreatment, the vacuolar degeneration of organelles was significantly reduced, and the cell membrane morphology was stable. (2) The increases in ROS and NO in RMVECs could be detected at 5 minutes after LPS stimulation, showed an increase tendency with time prolongation, ROS expression peaked at 30 minutes, NO expression peaked at 45 minutes, which showed significant differences as compared with those of blank control group [30-minute ROS (mean density): 76.2+/-5.8 vs. 1.5+/-0.1, 45-minute NO (MUmol/L): 70.3+/-8.6 vs. 1.8+/-0.1, both P < 0.01]. The expression of ROS and NO production in RMVECs were significantly reduced by heparin, showed a decrease tendency with heparin dose elevation, and the most obvious effect was 10 kU/L of heparin, with significant difference as compared with those of LPS treatment group [30-minute ROS (mean density): 16.8+/-1.7 vs. 76.2+/-5.8, 45-minute NO (MUmol/L): 11.8+/-8.6 vs. 70.3+/-8.6, both P < 0.01]. CONCLUSIONS: Unfractionated heparin ameliorates LPS induced expressions of NO and ROS in RMVECs and protects the cell morphology. The effect of 10 kU/L heparin is most obvious. PMID- 29764543 TI - [Experimental research on individual-specific rapid potassium supplementation strategy for fatal severe hypokalemia]. AB - OBJECTIVE: To explore the effectiveness and safety of the individual-specific rapid potassium supplementation strategy, and to provide experimental basis for treating fatal severe hypokalemia. METHODS: An acute fatal severe hypokalemia model was reproduced in 20 healthy adult Japanese big ear white rabbits with half lethal dose (LD50) of barium chloride (BaCl2) solution 168 mg*5 mL-1*kg-1. The rabbits were divided into conventional potassium supplementation group and individual-specific rapid potassium supplementation group according to random number table method with 10 rabbits in each group. All the animals were injected with 3% KCl through the auricular marginal veins by a micro-injection pump, and the target plasma potassium concentration was 4 mmol/L. The rabbits in conventional potassium supplementation group were administered continuously potassium infusion at the standard infusion rate of 0.4 mmol*kg-1*h-1. And those in the individual-specific rapid potassium supplementation group were treated in two steps: first, a loading dose of potassium was rapidly injected within 5 minutes, and this step was repeated until the plasma potassium concentration increased to 3.5 mmol/L; second, a sustaining dose of potassium infusion was continued at the rate of 0.4 mmol*kg-1*h-1 after the increase in plasma potassium concentration. The changes in electrocardiogram, blood pressure, respiratory rate (RR), plasma potassium concentration, urine potassium concentration, urine volume, potassium content in extracellular fluid (ECF) and other parameters were monitored. The potassium supplementation, potassium excretion and potassium cross cell status were recorded. Adverse reactions and 7-day death were observed. RESULTS: Since the BaCl2 administration, the plasma potassium concentration of all experimental rabbits were significantly lower than baseline at 0.5 hour, which was decreased below 2.5 mmol/L at 2.0 hours when the ventricular arrhythmias appeared, indicating the reproduction of fatal severe hypokalemia model was successful. There was no significant difference in gender, weight, baseline heart rate (HR), RR, mean arterial pressure (MAP), blood gas analysis or K+, Na+, Cl- levels between the two groups. Compared with baseline levels, MAP was significantly decreased and RR was significantly increased before potassium supplementation in both groups, but the parameters were improved significantly and restored to the baseline after potassium supplementation. There was no significant difference in MAP or RR during potassium supplementation between the two groups. The amount of potassium supplementation in two groups showed no significant differences. However, compared with the conventional potassium supplementation group, in the individual-specific rapid potassium supplementation group, the increase in plasma potassium concentration, urine potassium concentration, and the increase in potassium content in ECF were significantly increased [the increase in plasma potassium concentration (mmol/L): 2.40+/-0.33 vs. 1.51+/-0.75, urine potassium concentration (mmol/L): 164.94+/-18.07 vs. 108.35+/-19.67, the increase in potassium content in ECF (mmol): 1.17+/-0.16 vs. 0.73+/-0.35], the duration of potassium infusion was shortened (hours: 2.1+/-0.7 vs. 4.7+/-1.4), the total urine volume, renal excretion of potassium, and the amount of transcellular potassium shift were significantly decreased [total urine volume (mL): 6.40+/-1.78 vs. 13.60+/-4.69, renal excretion of potassium (mmol): 1.04+/-0.26 vs. 1.46+/-0.51, amount of transcellular potassium shift (mmol): 1.39+/-0.21 vs. 1.84+/-0.62], the duration of arrhythmia was shortened (minutes: 19.60+/-8.92 vs. 71.80+/-9.84), with statistically significant differences (all P < 0.05). Hyperkalemia did not occur in both groups. The rabbits of the individual specific rapid potassium supplementation group were all alive, while 4 died in the conventional potassium supplementation group, and statistically significant difference was found between the two groups (P < 0.01). CONCLUSIONS: These data demonstrate that the individual-specific rapid potassium supplementation strategy can shorten the time for correcting hypokalemia, which is a better option to reverse life-threatening arrhythmia caused by severe hypokalemia, with a high rescue success rate. The process of potassium supplement is safe and effective. PMID- 29764544 TI - [Effects of peroxisome proliferator-activated receptor gamma-toll-like receptor 4 tumor necrosis factor-alpha targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress]. AB - OBJECTIVE: To investigate the potential effects and mechanism on peroxisome proliferator-activated receptor gamma-toll-like receptor 4-tumor necrosis factor alpha (PPARgamma-TLR4-TNF-alpha) targeted pathway on hyperglycemia induced myocardium inflammation and oxidative stress. METHODS: Thirty-two Japanese healthy adult rabbits were randomly divided into four groups with 8 rabbits in each group: normal control group (NC group), diabetes mellitus group (DM group), diabetes mellitus + pioglitazone 4 mg*kg-1*d-1 and 8 mg*kg-1*d-1 groups (DM+PGZ 4 mg and 8 mg groups). DM model was reproduced by alloxan of 150 mg/kg through auricular vein injection. On the same day of successful DM model reproduction, the diabetic rabbits were fed with corresponding dose of pioglitazone in DM+PGZ 4 mg and 8 mg groups, but the rabbits in NC group were not challenged. After 8 weeks of feeding, venous blood of left jugular vein bifurcation and myocardium tissue were harvested respectively for the determination of inflammation and oxidative stress parameters. TNF-alpha, interleukin-1 (IL-1), adiponectin (ADP), nitric oxide (NO) and total nitric oxide synthase (NOS) levels were determined by enzyme linked immunosorbent assay (ELISA), myeloperoxidase (MPO) activity was determined by colorimetric method, superoxide dismutase (SOD) activity was determined by hydroxylamine method, malondialdehyde (MDA) was determined by thiobarbituric acid colorimetric method, and catalase (CAT) activity was determined by UV spectrophotometry method. In addition, the mRNA expressions of TNF-alpha and TLR4 were determined by real-time quantitate reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: (1) IL-1 and TNF-alpha in serum and myocardium of model rabbits were significantly increased, ADP was significantly decreased, and the mRNA expressions of TNF-alpha and TLR4 in myocardium were significantly increased, indicating a significant inflammatory reaction. The inflammatory reaction in pioglitazone intervention groups was significantly reduced, TNF-alpha and IL-1 levels in serum and myocardium of DM+PGZ 4 mg and 8 mg groups were significantly decreased as compared with those of DM group [serum: TNF-alpha (ng/L) was 268.33+/-46.57, 261.34+/-33.73 vs. 331.40+/-69.05, myocardium: TNF-alpha (ng/L) was 144.72+/-26.90, 139.59+/-14.59 vs. 177.48+/ 27.40; serum: IL-1 (ng/L) was 24.40+/-2.56, 23.35+/-3.13 vs. 30.08+/-5.44, myocardium: IL-1 (ng/L) was 21.26+/-2.85, 20.54+/-2.75 vs. 24.78+/-3.60, all P < 0.05], and ADP levels were significantly increased [serum (MUg/L): 19.64+/-8.85, 20.54+/-7.47 vs. 15.45+/-3.06, myocardium (MUg/L): 10.31+/-2.22, 11.49+/-3.42 vs. 7.76+/-1.77, all P < 0.05], and the mRNA expressions of TNF-alpha and TLR4 in myocardium were significantly decreased (TNF-alpha mRNA: 0.15+/-0.05, 0.14+/-0.06 vs. 0.25+/-0.09; TLR4 mRNA: 0.57+/-0.17, 0.40+/-0.18 vs. 0.75+/-0.35, all P < 0.05). (2) Oxidative stress in serum and myocardium of model rabbits was significantly increased, SOD, NO, and total NOS levels were significantly decreased while the serum CAT and MDA levels were significantly increased without effect on MPO. Compared with the DM group, SOD and NO levels in serum and myocardium were significantly increased in DM+PGZ 4 mg and 8 mg groups [serum: SOD (U/L) was 571.39+/-40.85, 609.28+/-54.47 vs. 535.10+/-37.08, myocardium: SOD (U/mg) was 55.74+/-8.12, 53.60+/-9.87 vs. 42.26+/-12.34; serum: NO (MUmol/L) was 2.95+/-0.51, 2.99+/-0.43 vs. 2.03+/-0.78, myocardium: NO (nmol/mg) was 1.95+/ 0.37, 2.11+/-0.26 vs. 1.56+/-0.33, all P < 0.05], the serum MDA levels were significantly decreased (MUmol/L: 20.11+/-2.34, 19.70+/-2.02 vs. 23.07+/-3.06, both P < 0.05), while no significant effect on CAT. There was no significant difference in parameter of inflammatory and oxidative stress between the two pioglitazone intervention groups. CONCLUSIONS: 4 mg*kg-1*d-1 pioglitazone could activate PPARgamma-TLR4-TNF-alpha targeted pathway, thus inhibit inflammatory and oxidative stress factors expression, and down-regulate hyperglycemia induced myocardium inflammatory and oxidative stress level, but the effect did not show a dose dependent manner. PMID- 29764546 TI - [Effect of pyrrolidine dithiocarbamate on oxidative stress and mitochondrial function of lung tissue in mice with acute lung injury]. AB - OBJECTIVE: To investigate the effects of pyrrolidine dithiocarbamate (PDTC) on oxidative stress and mitochondrial function of lung tissue in mice with acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: Forty female Balb/c mice were randomly divided into normal saline (NS) control group, LPS model group, PDTC group, and PDTC+LPS group, with 10 mice in each group. The model of mice with ALI was reproduced by intraperitoneal injection of 15 mg/kg LPS. PDTC was administered intraperitoneally with 50 mg/kg PDTC 1 hour before LPS treatment in the PDTC+LPS group. The mice in NS control group was given intraperitoneal injection of 0.1 mL NS only, and those in PDTC group was given intraperitoneal injection of 50 mg/kg PDTC only. The mice were sacrificed at 24 hours after model reproduction, and the lung tissues were harvested. The total antioxidant capacity (T-AOC) of lung tissue was measured by spectrophotometric kits. The content of malondialdehyde (MDA) was determined by thiobarbituric acid reactive substances assay. The protein expressions of superoxide dismutases (SOD1, SOD2) and catalase (CAT) in lung tissue were determined by Western Blot. Mitochondria from mouse lungs were isolated, and adenosine triphosphate (ATP) synthesis was measured with a luciferase/luciferin-based approach. The mitochondrial membrane potential (DeltaPsim) was estimated by using Rhodamine. The mRNA expressions of mitochondrial uncoupling proteins (UCPs) were determined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: LPS stimulation could significantly increase oxidative stress in lung tissue of mice and lead to mitochondrial dysfunction. The results showed that the protein expressions of T-AOC and SOD1 were decreased, the level of MDA was increased, the ATP synthesis was decreased in the mitochondrial, the DeltaPsim was decreased, and the mRNA expression of UCP2 was decreased. However, there was no significant change in the expressions of SOD2, CAT in lung tissue and UCP1, UCP3 in the mitochondria. Pretreatment with PDTC could obviously alleviate the increase in LPS-induced oxidative stress in lung tissue and mitigate mitochondrial dysfunction. Compared with the LPS model group, T-AOC in lung tissue of PDTC+LPS group was significantly increased (U/g: 0.35+/-0.08 vs. 0.31+/-0.07), the level of MDA was significantly decreased (MUmol/mg: 13.29+/-1.13 vs. 17.54+/-1.72), the protein expression of SOD1 was significantly upregulated (SOD1 protein: 1.13+/ 0.11 vs. 0.71+/-0.09), ATP synthesis was significantly increased in the mitochondrial (MUmol/mg: 49.23+/-5.42 vs. 36.92+/-2.21), DeltaPsim was significantly increased (mV: 226.03+/-11.69 vs. 194.86+/-7.79), and the mRNA expression of UCP2 was significantly increased (2-DeltaDeltaCt: 0.88+/-0.06 vs. 0.73+/-0.04). The differences were statistically significant (all P < 0.05). In lung tissue of normal mice, PDTC treatment also had the effect of anti-oxidizing, reducing oxidative stress and promoting ATP synthesis in the mitochondrial. Compared with the NS control group, the level of T-AOC (U/g: 0.49+/-0.09 vs. 0.43+/-0.06) and the protein expressions of SOD2 and CAT (SOD2 protein: 1.33+/ 0.08 vs. 1.00+/-0.11, CAT protein: 1.39+/-0.08 vs. 1.00+/-0.11), and ATP synthesis in the mitochondrial of PDTC group was significantly increased (MUmol/mg: 61.53+/-4.92 vs. 53.33+/-3.20), MDA was significantly decreased (MUmol/mg: 10.27+/-1.25 vs. 12.27+/-1.36), with statistical differences, but had no effect on the protein expression of SOD1 in lung tissue and DeltaPsim and UCPs mRNA expressions in mitochondrion. CONCLUSIONS: LPS can induce ALI in mice, increased oxidative stress in lung tissue, and induce mitochondrial dysfunction by inhibiting ATP synthesis. PDTC pretreatment has anti-oxidative effect on LPS induced ALI, and can mitigate mitochondrial dysfunction. PMID- 29764545 TI - [Effects of N-butylphthalide on the expressions of ZO-1 and claudin-5 in blood brain barrier of rats with acute carbon monoxide poisoning]. AB - OBJECTIVE: To explore the effects of N-butylphthalide on the expressions of ZO-1 and claudin-5 in blood-brain barrier (BBB) in rats with acute carbon monoxide (CO) poisoning. METHODS: A total of 144 adult healthy male Sprague-Dawley (SD) rats were randomly divided into normal control group, CO poisoning group, and NBP treatment group, with 48 rats in each group. The acute CO poisoning model was reproduced in hyperbaric oxygen chamber, and all model rats were given hyperbaric oxygen therapy once daily. The rats in the normal control group were free to breathe fresh air. The rats in NBP treatment group were administered orally NBP 60 mg/kg twice a day at 2 hours after poisoning until death. The rats in normal control group and CO poisoning group were treated with equal amount of pure olive oil. Four rats were sacrificed from each group at 1, 3, 7, 14 days after model reproducing, respectively. The changes in ultrastructure of BBB were observed under transmission electron microscope. The expressions of ZO-1 and claudin-5 proteins were determined by immunofluorescence staining and Western Blot. The localization of the two target proteins was observed by immunofluorescence double staining. The correlation between the two proteins was analyzed by linear regression. RESULTS: The ultrastructure of BBB was normal in normal control group, some ZO-1 and a large number of claudin-5 positive cells were observed. The ultrastructure of BBB was seriously injured, ZO-1 and claudin-5 positive cells in brain tissue were significantly decreased, and the expressions of ZO-1 and claudin-5 proteins in brain tissue at 1 day after poisoning in CO poisoning group were significantly lower than those of normal control group (ZO-1 protein: 3.38+/-0.30 vs. 24.50+/-5.62, claudin-5 protein: 11.38+/-0.93 vs. 46.35+/-6.88, both P < 0.05), and although gradually restored, they were maintained at relatively lower levels until 14 days as compared with those in normal control group (ZO-1 protein: 10.35+/-0.80 vs. 24.63+/-3.57, claudin-5 protein: 32.35+/ 3.11 vs. 46.43+/-7.20, both P < 0.05). NBP treatment could significantly alleviate the ultrastructure injury of BBB induced by acute CO poisoning, the amount of ZO-1 and claudin-5 positive cells in brain tissue were significantly increased, as well as the expressions of ZO-1 and claudin-5 proteins were significantly increased, which were significantly higher than those of CO poisoning group from 1 day and 3 days on, respectively (1-day ZO-1 protein: 7.57+/-0.69 vs. 3.38+/-0.30, 3-day claudin-5 protein: 20.46+/-1.42 vs. 11.43+/ 0.86, both P < 0.05), and which showed an increase tendency with time prolongation. The results of immunofluorescence double staining showed that ZO-1 and claudin-5 proteins could not only coexist in the same cell, but also could be expressed separately in different cells. Linear regression analysis showed the positive correlation between the expressions of ZO-1 and claudin-5 proteins in brain tissue of rats with acute CO poisoning (R2 = 0.917, P = 0.022). CONCLUSIONS: NBP could markedly improve the ultrastructure and functional integrity of BBB through up-regulating the expressions of ZO-1 and claudin-5 proteins, and then reduce brain damage caused by CO poisoning. PMID- 29764547 TI - [Comparison of lung protection for hydrochloric acid or oleic acid induced rat acute respiratory distress syndrome models pretreated with penehyclidine]. AB - OBJECTIVE: To compare the lung protection roles of intraperitoneal pre-injection with penehyclidine for two kinds of rat models with pulmonary and extrapulmonary acute respiratory distress syndrome (ARDSp and ARDSexp). METHODS: Forty healthy adult Sprague-Dawley (SD) rats were randomly divided into five groups (each n = 8): the rats in sham group received only tracheotomy; the ARDS rat models were reproduced by intratracheal inhalation of 0.1 mol/L hydrochloric acid (HCl) 2 mL/kg to simulate ARDSexp (HCl group) and 0.15 mL/kg oleic acid (OA) intravenous injection to simulate ARDSp (OA group) after tracheotomy; and the rats in two intervention groups were intraperitoneal injected with penehyclidine 0.5 mg/kg. All rats were received mechanical ventilation immediately after model reproduction. Carotid arterial blood was collected 4 hours after model reproduction for determining the arterial partial pressure of oxygen (PaO2), and oxygenation index (PaO2/FiO2) was calculated. Carotid venous blood and lung tissues were harvested, and the levels of myeloperoxidase (MPO), interleukin-8 (IL-8) and nuclear factor-kappaB (NF-kappaB) in serum and lung tissue were determined by enzyme linked immunosorbent assay (ELISA). Pulmonary pathology was observed under optical microscope, and pathological score of Smith was calculated. RESULTS: Under optical microscope, a large number of inflammatory cells infiltration in lung tissue, obvious alveolar collapse, fibrous exudation in alveolar and alveolar hyaline were found in HCl group. In OA group, however, microvascular congestion and interstitial pulmonary edema were the main pathological changes, with alveolar structure being kept relatively intact. Compared with sham group, pathological score of Smith in HCl and OA groups were increased, oxygenation was lowered, and inflammatory factors levels in serum and lung tissue were increased with levels in lung tissue being higher than those in serum, without significant difference between the two models. When pretreated with penehyclidine, however, pathological injury induced by HCl or OA was alleviated, and pathological score of Smith was also decreased as compared with that of corresponding model groups (5.48+/-1.76 vs. 9.69+/-2.02, 3.97+/-2.14 vs. 8.71+/-2.18, both P < 0.05), PaO2/FiO2 was raised significantly [mmHg (1 mmHg = 0.133 kPa): 323+/-55 vs. 211+/-27, 307+/-56 vs. 207+/-31, both P < 0.05], the inflammatory factors levels in serum and lung tissue were obviously decreased [MPO (MUg/L): 11.91+/-1.55 vs. 14.82+/-1.25, 12.75+/-1.16 vs. 16.97+/-2.06 in serum, 25.80+/-3.36 vs. 35.18+/-4.01, 24.23+/-1.24 vs. 33.94+/-1.43 in lung tissue; IL-8 (ng/L): 358+/-30 vs. 459+/-25, 377+/-38 vs. 427+/-34 in serum, 736+/ 53 vs. 866+/-51, 701+/-53 vs. 809+/-39 in lung tissue; NF-kappaB (ng/L): 483+/-68 vs. 632+/-73, 514+/-83 vs. 685+/-78 in serum, 984+/-75 vs. 1 217+/-123, 944+/-90 vs. 1 163+/-105 in lung tissue; all P < 0.05]. But all parameters above were similar between the two pretreatment groups (all P > 0.05). CONCLUSIONS: Inflammatory cell infiltration and alveolar collapse mainly happened in HCl induced ARDSp, while pulmonary interstitial edema and hemorrhage was mostly seen in ARDSexp rats induced by OA intravenous injection. There was no significant difference in oxygenation and inflammatory response between the two models of rats. Pre-intraperitoneal injection of penehyclidine equally improved oxygenation state, inhibited lung inflammation response, and reduced lung injury in the two kinds of ARDS, but there was no difference in protective role between two models pretreated with penehyclidine. PMID- 29764548 TI - [Effects of different core temperatures after heat strike on serum inflammatory cytokines and multiple organ dysfunction syndrome in rats]. AB - OBJECTIVE: To observe the effect of different core temperatures (Tc) after heat strike on serum inflammatory cytokines and multiple organ dysfunction syndrome (MODS) in rat. METHODS: 120 male Sprague-Dawley (SD) rats were randomly divided into normal control group (n = 30) and heat strike group (n = 90). The rats in heat strike group were put into simulated thermal climate animal module after adaptive training. The module temperature was raised to 39 centigrade in 30 minutes with 65% humidity. The rats ran simultaneously at 15 m/min, on the slope of 0 degree angle, 8 minutes each time, 2 minutes interval, and the heat strike time was 90 minutes. After the rats came out of the module, rectal temperature, which was Tc value, was recorded. The rats died or Tc < 41 centigrade during the experiment were excluded, the remaining 73 rats were divided into three subgroups: 41.0-41.9 centigrade (n = 38), 42.0-42.9 centigrade (n = 26), and >=43.0 centigrade (n = 9). The rats in the normal control group were reared at temperature of (25+/-2) centigrade, and humidity of (55+/-5)%. At 0 hour and 24 hours after the rats came out of the module, femoral artery blood was collected to determine serum interleukins (IL-1alpha, IL-1beta, IL-17), tumor necrosis factor-alpha(TNF-alpha) andgamma-interferon (IFN-gamma) by enzyme-linked immunosorbent assay (ELISA). The cardiac troponin I (cTnI), MB isoenzyme of creatine kinase (CK-MB), serum creatinine (SCr), blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels were determined by automatic biochemical analyzer. The incidence of MODS and the number of accumulative organs within 24 hours of the rats in different Tc of heat strike group were compared and analyzed. RESULTS: The serum inflammatory cytokines and biochemical parameters at 0 hour after heat strike were significant higher than those of the normal control group, and showed a time dependence. Further analysis showed that the inflammatory response and organ dysfunction in rats were increased gradually with the increase in Tc of rats. Compared with the normal control group, at 24 hours after heat strike, inflammatory cytokines in Tc>=43.0 centigrade rats were increased obviously [IL-1alpha (ng/L): 13.56+/-2.07 vs. 2.24+/-0.62, IL-1beta (ng/L): 17.11+/-1.90 vs. 7.40+/-1.52, IL-17 (ng/L): 17.00+/-1.41 vs. 6.00+/-1.78, TNF-alpha (ng/L): 16.78+/-1.79 vs. 7.27+/-1.74, IFN gamma (ng/L): 21.11+/-2.09 vs. 10.43+/-2.31], and the biochemical parameters were also increased obviously [cTnI (ng/L): 50.78+/-6.67 vs. 20.53+/-3.09, CK-MB (U/L): 62.89+/-3.82 vs. 22.00+/-3.01, SCr (MUmol/L): 149.22+/-4.35 vs. 92.53+/ 8.32, BUN (nmol/L): 55.22+/-1.99 vs. 19.10+/-2.02, ALT (U/L): 388.33+/-4.97 vs. 100.23+/-10.61, AST (U/L): 361.22+/-6.53 vs. 97.67+/-10.54, all P < 0.01]. The incidence of MODS within 24 hours in the heat strike group was 54.79% (40/73), and the higher the Tc, the higher the incidence of MODS, and the more insulted organs [the incidence of MODS in 41.0-41.9 centigrade, 42.0-42.9 centigrade, and >=43.0 centigrade subgroups was 36.84% (14/38), 65.38% (17/26), 100.00% (9/9), and the organ involvement rate was 12.17% (37/304), 23.08% (48/208), and 48.61% (35/72), respectively, when 8 organs or systems were calculated for each rat, both P < 0.01]. CONCLUSIONS: The higher the Tc of heat strike rats, the stronger the inflammatory reaction and the more serious the damage of tissue, and the more extensive damage of the organs. PMID- 29764549 TI - [Clinical verification of vancomycin population pharmacokinetics in patients with augmented renal clearance]. AB - OBJECTIVE: To evaluate the predictive value and to verify the clinical effect of JPKD-vancomycin for the trough concentration of vancomycin in patients with augmented renal clearance (ARC), and to provide a reference for clinical individualized drug therapy. METHODS: A retrospective analysis was conducted. The clinical data of 48 adult patients with ARC using vancomycin and monitoring steady-state trough concentration of vancomycin admitted to Suzhou Hospital Affiliated to Nanjing Medical University from July 2013 to July 2017 were collected. A combination of classical Vancomycin Calculator software and JPKD vancomycin software was used. Based on the individual conditions of patients [gender, age, height, weight, serum creatinine (SCr), disease status], Vancomycin Calculator software was used to obtain the recommended regimen and its steady state trough concentration, and then JPKD-vancomycin software was used to predict the steady-state trough concentration of initial regimen. If the regimen was adjusted during the treatment, JPKD-vancomycin software was used to predict the steady-state trough concentration of the adjusted regimen. The measured values of steady-state trough concentration were recorded. The weight deviation between predicted concentration and measured concentration (WRES) was calculated. WRES < 30% was considered as good prediction, and the predictive value of JPKD vancomycin software was evaluated for vancomycin trough concentration. RESULTS: Forty-eight patients with ARC were enrolled, of whom 24 patients had adjusted the dosing regimen during the treatment. The initial concentration of blood samples was 48, after adjusting the dosage regimen, 24 blood samples were collected. The initial and adjusted daily dose of vancomycin was (2 000+/-500) mg/d and (2 500+/ 600) mg/d, respectively, and the initial trough concentrations and adjusted trough concentrations was (8.4+/-7.3) mg/L and (9.1+/-4.3) mg/L, respectively. Only 14.6% and 25.0% of initial and adjusted trough concentrations reached the target range (10-20 mg/L) without significant difference (P > 0.05). The WRES value of adjusted trough concentrations predicted by JPKD-vancomycin software was significantly lower than that of initial regimen [10.6% (3.0%, 16.4%) vs. 14.3% (10.5%, 38.2%), P < 0.05], and the percentage of WRES < 30% also tended to increase [95.8% (23/24) vs. 70.8% (34/48), P < 0.05]. The well predictive rate of JPKD-vancomycin software for vancomycin trough concentration was 79.2% (57/72), but there were 15 patients with WRES > 30%. CONCLUSIONS: JPKD-vancomycin software has good predictive value for the vancomycin trough concentration of ARC patients, especially for the trough concentration after adjusting the treatment regimen. JPKD-vancomycin can provide a reference for the design of clinical individualized application of vancomycin. PMID- 29764550 TI - [Predictive value of central venous-to-arterial carbon dioxide partial pressure difference for fluid responsiveness in septic shock patients: a prospective clinical study]. AB - OBJECTIVE: To evaluate the accuracy of central venous-to-arterial carbon dioxide partial pressure difference (Pcv-aCO2) before and after rapid rehydration test (fluid challenge) in predicting the fluid responsiveness in patients with septic shock. METHODS: A prospective observation was conducted. Forty septic shock patients admitted to medical intensive care unit (ICU) of Peking Union Medical College Hospital from October 2015 to June 2017 were enrolled. All of the patients received fluid challenge in the presence of invasive hemodynamic monitoring. Heart rate (HR), blood pressure, cardiac index (CI), Pcv-aCO2 and other physiological variables were recorded at 10 minutes before and immediately after fluid challenge. Fluid responsiveness was defined as an increase in CI greater than 10% after fluid challenge, whereas fluid non-responsiveness was defined as no increase or increase in CI less than 10%. The correlation between Pcv-aCO2 and CI was explored by Pearson correlation analysis. Receiver operating characteristic (ROC) curves were established to evaluate the discriminatory abilities of baseline and the changes after fluid challenge in Pcv-aCO2 and other physiological variables to define the fluid responsiveness. The patients were separated into two groups according to the initial value of Pcv-aCO2. The cut-off value of 6 mmHg (1 mmHg = 0.133 kPa) was chosen according to previous studies. The discriminatory abilities of baseline and the change in Pcv-aCO2 (DeltaPcv aCO2) were assessed in each group. RESULTS: A total of 40 patients were finally included in this study. Twenty-two patients responded to the fluid challenge (responders). Eighteen patients were fluid non-responders. There was no significant difference in baseline physiological variable between the two groups. Fluid challenge could increase CI and blood pressure significantly, decrease HR notably and had no effect on Pcv-aCO2 in fluid responders. In non-responders, blood pressure was increased significantly and CI, HR, Pcv-aCO2 showed no change after fluid challenge. Pcv-aCO2 was comparable in responders and non-responders. In 40 patients, CI and Pcv-aCO2 was inversely correlated before fluid challenge (r = -0.391, P = 0.012) and the correlation between them weakened after fluid challenge (r = -0.301, P = 0.059). There was no significant correlation between the changes in CI and Pcv-aCO2 after fluid challenge (r = -0.164, P = 0.312). The baseline Pcv-aCO2 and DeltaPcv-aCO2 could not discriminate between responders and non-responders, with the area under ROC curve (AUC) of 0.50 [95% confidence interval (95%CI) = 0.32-0.69] and 0.51 (95%CI = 0.33-0.70), respectively. HR and blood pressure before fluid challenge and their changes after fluid challenge showed very poor discriminative performances. Before fluid challenge, 16 patients had a Pcv-aCO2 > 6 mmHg. Their mean CI was significantly lower and Pcv-aCO2 was significantly higher than that in 24 patients whose Pcv-aCO2 <= 6 mmHg [n = 24; CI (mL*s-1*m-2): 48.3+/-11.7 vs. 65.0+/-18.3, P < 0.01; Pcv-aCO2 (mmHg): 8.4+/ 1.9 vs. 2.9+/-2.8, P < 0.01]. Pcv-aCO2 was decreased significantly after fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg and their DeltaPcv-aCO2 was notably different as compared with the patients whose baseline Pcv-aCO2 <= 6 mmHg (mmHg: -3.8+/-3.4 vs. 0.9+/-2.9, P < 0.01). 68.8% (11/16) patients responded to the fluid challenge in patients with an initial Pcv-aCO2 > 6 mmHg. The AUC of the baseline Pcv-aCO2 and DeltaPcv-aCO2 to define fluid responsiveness was 0.85 (95%CI = 0.66-1.00) and 0.84 (95%CI = 0.63-1.00), respectively, and the positive predictive value was 1 when the cut-off value was 8.0 mmHg and -4.2 mmHg, respectively. 45.8% (11/24) patients responded to the fluid challenge in patients whose baseline Pcv-aCO2 <= 6 mmHg. There was no predictive value of baseline Pcv aCO2 and DeltaPcv-aCO2 on fluid responsiveness. CONCLUSIONS: Pcv-aCO2 and its change cannot serve as a surrogate of the change in cardiac output to define the response to fluid challenge in septic shock patients whose baseline Pcv-aCO2 <= 6 mmHg, while the predictive values of baseline Pcv-aCO2 and the change in Pcv-aCO2 are presented in patients with the initial value of Pcv-aCO2 > 6 mmHg. Clinical Trial Registration: Clinical Trials, NCT01941472. PMID- 29764551 TI - [Predictive values of different critical scoring systems for survival rate after discharge in critically ill patients supported by extracorporeal membrane oxygenation]. AB - OBJECTIVE: To determine the predictive values of different critical scoring systems for survival rate after discharge in critically ill patients supported by extracorporeal membrane oxygenation (ECMO). METHODS: The clinical data of 34 critically ill patients supported by ECMO admitted to Department of Emergency of the First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People's Hospital) from July 2015 to September 2017 were retrospectively analyzed. The general information and the worst values of vital signs and related pathophysiological indicators within 12 hours before ECMO treatment of patients were collected, and sequential organ failure assessment (SOFA), multiple organs dysfunction score (MODS), simplified acute physiology score II (SAPS II), and acute physiology and chronic health evaluation IV (APACHE IV) scores were calculated. The patients were divided into survival group and non-survival group according to 28-day survival after hospital discharge. General clinical characteristics and aforementioned scores were compared between the two groups. Scoring systems for predicting prognosis were assessed by using the receiver operating characteristic (ROC) curve. The Kaplan-Meier method was used to depict the surviving curve. RESULTS: Thirty-four patients were finally enrolled, 13 of whom were dead at the follow-up period of 28 days after hospital discharge, and 21 survived. Duration of ECMO support in non-survival group was significantly shorter than that in survival group (hours: 101.4+/-7.8 vs. 134.4+/-12.6), SOFA, SAPS II, and APACHE IV scores were significantly higher than those of survival group (SOFA score: 10.6+/-3.6 vs. 8.8+/-3.3, SAPS II score: 38.7+/-14.3 vs. 31.8+/-12.5, APACHE IV score: 46.5+/-15.5 vs. 38.1+/-11.3, all P < 0.05). There was no significant difference in gender, age, body mass index (BMI), vital signs or related pathophysiological indicators within 12 hours before ECMO treatment, or MODS score between the two groups. ROC curve analysis showed that the area under ROC curve (AUC) of SAPS II score for predicting 28-day survival rate was the highest, which was significantly higher than that of SOFA, MODS, and APACHE IV score (0.880 vs. 0.694, 0.654, 0.682, all P < 0.05). When the best cut-off value of SAPS II score was 43, the sensitivity was 81.2%, and the specificity was 77.9%. Kaplan-Meier survival analysis showed that 28-day survival rate after hospital discharge in patients with SAPS II score < 43 (n = 18) was significantly higher than that in patients with SAPS II score >= 43 (n = 16; chi2 = 2.444, P = 0.018). CONCLUSIONS: Four critical scoring systems of SOFA, MODS, SAPS II and APACHE IV have been proved to have good prognostic ability to predict 28-day survival after hospital discharge in critically ill patients supported by ECMO. Among them, SAPS II score system has more accurate prediction value. PMID- 29764552 TI - [Construction of death early-warning model for patients with septic myocardial depression: a retrospective analysis of 129 patients]. AB - OBJECTIVE: To explore the death risk factors of septic myocardial depression (SMD) and their predictive effect, and to set up a death early-warning model. METHODS: A retrospective analysis was conducted. The patients with SMD admitted to emergency department and rescue room of Beilun Branch of the First Affiliated Hospital of Zhejiang University Medical College from January 2015 to November 2017 were enrolled. The patients were divided into survival group and non survival group according to 28-day outcome, and the gender, age, and the initial examination parameters [white blood cell (WBC) count, neutrophil (Neut) count, activated partial thromboplastin time (APTT), procalcitonin (PCT), D-dimer, C reactive protein (CRP), cardiac troponin I (cTnI), N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left atrium diameter (LAD)] of both groups were compared. Binary logistic regression analysis was conducted on the factors with statistically significant difference analyzed in univariate analysis, and death early-warning model was set up subsequently. For parameters in early-warning model after variable screening, receiver operating characteristic curve (ROC) was applied to evaluate the predictive effect of death. RESULTS: A total of 129 patients were enrolled, 34 patients died within 28 days with the mortality of 26.4%. Univariate analysis showed that the PCT, cTnI and NT-proBNP in non-survival group were significantly higher than those of the survival group. However, there was no statistical difference in gender, age, WBC, Neut, APTT, D-dimer, CRP, LVEF, LVEDD or LAD between the two groups. Logistic stepwise regression analysis showed that PCT and cTnI were the independent factors influencing the death of patients with SMD [PCT: odds ratio (OR) =1.495, 95% confidence interval (95%CI) = 1.192-1.876, P = 0.001; cTnI: OR = 11.154, 95%CI = 5.709-17.264, P = 0.004], and the death early-warning model was logP = 3.737+0.402*PCT+2.412*cTnI. According to the statistics of Homser-Lemeshow, the effect of this model was good (chi2 = 6.258, P = 0.617). The analysis of ROC displayed that the area under ROC curve (AUC) of the combination of PCT and cTnI for predicting the prognosis of SMD patients was 0.851, and it was significantly higher than that of PCT and cTnI alone (0.738 and 0.719, respectively, both P < 0.05). When the combination of PCT and cTnI was 0.26, the sensitivity was 79.97%, the specificity was 87.01%, the positive predictive value was 71.3%, and the negative predictive value was 91.7%. CONCLUSIONS: PCT and cTnI are independent factors influencing the death of SMD patients. The combination of PCT and cTnI has predictive value for the prognosis of SMD patients. The death early-warning model of SMD patients can be used to predict the prognosis of SMD patients. PMID- 29764553 TI - [Interposed abdominal pulling-pressing cardiopulmonary resuscitation improve the resuscitation effect for patients with cardiac arrest]. AB - OBJECTIVE: To study the impact of interposed abdominal pulling-pressing cardiopulmonary resuscitation (IAPP-CPR) for patients with cardiac arrest (CA). METHODS: A prospective study was conducted. A total of 122 CA patients admitted to Department of Emergency of Shandong Provincial Mining Industry Group Company Central Hospital from July 2013 to December 2017 were enrolled. They were divided into standard cardiopulmonary resuscitation (S-CPR) group (n = 62) and IAPP-CPR group (n = 60) according to order of admission. The patients in S-CPR group received external cardiac compression, open airway, endotracheal intubation, mechanical ventilation, routine drug rescue, and defibrillation when ventricular fibrillation was found. And the patients in IAPP-CPR group received the IAPP-CPR on the basis of the routine chest compression. During the relaxation period, the patients were subjected to abdominal lifting and compressing with amplitude of 4 5 cm, frequency of 100 times/min, and the time ratio of lifting to compressing was 1:1. The data of demographics and clinical signs of patients were collected. The markers of respiratory and circulatory performance of all patients after CPR were determined. The rates of restoration of spontaneous circulation (ROSC), successful resuscitation, and the prognosis were recorded. With the success of CRP as the dependent variable, the factors with statistical significance showed by univariate analysis were used as the independent variable to carry out two classification Logistic regression analysis for screening the influence factors of CPR success. Receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of various factors on the success of CPR. RESULTS: 122 patients were enrolled in the analysis. Compared with the S-CPR group, heart rate (HR), mean arterial pressure (MAP), arterial partial pressure of oxygen (PaO2), and end-tidal carbon dioxide partial pressure (PETCO2) were significantly increased at 30 minutes after CPR in IAPP-CPR group [HR (bpm): 66.3+/-11.5 vs. 53.1+/-12.6, MAP (mmHg, 1 mmHg = 0.133 kPa): 65.4+/-6.5 vs. 53.2+/-5.4, PaO2 (mmHg): 77.7+/-11.8 vs. 61.8+/-14.3, PETCO2 (mmHg): 45.5+/-9.6 vs. 31.8+/-8.2, all P < 0.05], and arterial partial pressure of carbon dioxide (PaCO2) and lactic acid (Lac) were significantly lowered [PaCO2 (mmHg): 46.7+/-6.2 vs. 57.9+/-9.5, Lac (mmol/L): 2.1+/-1.5 vs. 4.4+/-2.2, both P < 0.05]. The time of CA to ROSC in IAPP-CPR group was significantly shorter than that in S-CPR group (minutes: 6.3+/ 1.8 vs. 11.2+/-1.4, P < 0.05), the ROSC rate and CPR success rate were significantly higher than those in S-CPR group [ROSC rate: 61.7% (37/60) vs. 43.5% (27/62), CPR success rate: 40.0% (24/60) vs. 21.0% (13/62), both P < 0.05], and 24-hour survival rate and survival and discharge rate of patients were significantly higher than those in the S-CPR group [24-hour survival rate: 46.7% (28/60) vs. 29.0% (18/62), survival and discharge rate: 20.0% (12/60) vs. 11.3% (7/62), both P < 0.05]. Logistic regression analysis showed that PaO2, PaCO2 and PETCO2 were the factors that affect the success of CPR [PaO2: beta= -3.76, odds ratio (OR) = 0.23, 95% confidence interval (95%CI) = 0.12-0.86, P = 0.031; PaCO2: beta= 1.41, OR = 4.09, 95%CI = 1.70-9.82, P = 0.002, PETCO2: beta= 0.78, OR = 2.18, 95%CI = 1.42-3.35, P = 0.000]. ROC curve analysis showed that the above three factors had good predictive value for the success of CPR. The predictive value of PaCO2 and PETCO2 were better, the area under ROC curve (AUC) was 0.93 and 0.92, respectively, when the cut-off values was 46.7 mmHg and 48.8 mmHg, the sensitivity was 92.0%, 88.0%, respectively, and the specificity was both 94.3%. CONCLUSIONS: PaO2, PaCO2 and PETCO2 are the factors that influence the success of CPR. PaCO2 and PETCO2 have great value in predicting the success of CPR. Compared with the S-CPR group, IAPP-CPR group results in better hemodynamic and pulmonary ventilation effects, and remarkably improve ROSC and successful resuscitation. IAPP-CPR has obvious clinical value for CA patients. PMID- 29764554 TI - [Efficacy and safety of nalbuphine on analgesia of patients in intensive care unit]. AB - OBJECTIVE: To analyze the efficacy and safety of nalbuphine in patients with sedative analgesia in intensive care unit (ICU). METHODS: A prospective observation was conducted. The adult patients with mild and moderate analgesia in general ICU of the First Affiliated Hospital of Zhengzhou University from January to November in 2017 were enrolled, and they were divided into nalbuphine group and sufentanil group in proper order. The nabobrown group was given 40 mg nabobrown, the sufentanil group was given 0.1 mg sufentanil, both of which were injected with 50 mL normal saline for continuous intravenous infusion in micro pump. Infusion speed was checked according to pain level. The analgesic target was critical-care pain observation tool (CPOT) score < 2. The change in hemodynamics of patients in both groups were observed, and CPOT score and Richmond agitation-sedation scale (RASS) score were recorded before and l, 3, 5, 12, 24 hours after administration. The analgesic and sedative effects of two drugs were evaluated. RESULTS: A total of 141 patients were enrolled, including 71 patients in nalbuphine group and 70 in sufentanil group. There was no significant difference in general data including gender, age, body weight, acute physiology and chronic health evaluation II (APACHE II) or pain source, as well as baseline hemodynamics parameter between the two groups. At 1 hour and 3 hours after administration, nalbuphine had no effect on blood pressure, but the heart rate was decreased slightly, while the heart rate and blood pressure of the sufentanil group were decreased obviously. The two drugs could make the heart rate and blood pressure fluctuate obviously with the time of medication, but there was no statistical difference between the two drugs. The two drugs had no significant effect on pulse oxygen saturation (SpO2) during analgesia. The average dosage of nalbuphine was 0.03 (0.02, 0.05) mg*kg-1*h-1 in the nalbuphine group, and the patient was satisfied with the analgesic effect until 3 hours after the use of the drug, and CPOT score was significantly decreased as compared with that before administration [1.0 (1.0, 2.0) vs. 3.0 (2.0, 4.0), P < 0.01], and the sedative effect was increased, RASS score was significantly lower than that before administration [0 (0, 1.0) vs. 1.0 (1.0, 2.0), P < 0.01]. No patients in naporphine group were treated with sufentanil due to unsatisfactory analgesia. The average dosage was 0.11 (0.06, 0.14) MUg*kg-1*h-1 in the sufentanil group, the patient was satisfied with the analgesic effect until 5 hours after administration, and the CPOT score was significantly lower than that before administration [1.0 (1.0, 2.0) vs. 4.0 (3.0, 6.0), P < 0.01], and the sedative effect was significantly increased, RASS score was significantly lower than that before administration [0 (-1.0, 0) vs. 2.0 (1.0, 2.0), P < 0.01]. The scores of CPOT and RASS in the sufentanil group were significantly higher than those of the naporphine group before use, so the decrease in the CPOT and RASS scores of the two drugs was further analyzed, which indicated the decrease in CPOT score of naporphine group was significantly lower than that in sufentanil group from 3 hours on [1.0 (0, 2.0) vs. 2.0 (1.0, 3.0), P < 0.05], and the decrease in RASS score of naporphine group was significantly lower than that in sufentanil group from 1 hour on [0 (0, 1.0) vs. 1.0 (0, 2.0), P < 0.01]. It suggested that naporphine could achieve sustained and stable analgesic effect and avoid excessive sedation caused by sufentanil. CONCLUSIONS: Naporphine had a sustained and stable analgesic effect on patients with mild and moderate ICU analgesia. The onset time of naporphine was equivalent to sufentanil, and it had a certain sedative effect and less influence on hemodynamics. PMID- 29764555 TI - [Role of noninvasive mechanical ventilation in patients with severe avian influenza A (H7N9) complicated with acute respiratory distress syndrome]. AB - OBJECTIVE: Human infection with avian influenza A (H7N9) is an acute contagious respiratory disease. Acute respiratory distress syndrome (ARDS) is a common complication in patients with severe avian influenza A (H7N9), for whom mechanical ventilation (MV) is an important supportive method. A patient, suffered from severe avian influenza A (H7N9) and complicated with ARDS, was admitted to the Second Affiliated Hospital of Guizhou Medical University in January 2017. With very intensive care for oxygenation, respiration and consciousness, and monitoring, she was successfully cured by comprehensive managements, among which noninvasive mechanical ventilation (NIV) was the major respiratory support method. The result demonstrate that, in patients with conscious state, satisfied expectoration ability and relatively good cooperation, and with close observation of oxygenation and respiratory rate, NIV may be accepted as an effective method for patient with ARDS caused by severe avian influenza A (H7N9). PMID- 29764556 TI - [Extra longtime continuous chest compression to rescue cardiopulmonary arrest: a case report and the literature review]. AB - OBJECTIVE: The new cardiopulmonary resuscitation (CPR) guideline emphasize the importance of chest compression, which was considered as the first step to CPR. The duration for CPR is usually limited to 30 minutes. With the development of new technology and evidence-based medicine, the success of extra longtime CPR has become possible, which is of great significance to some patients with cardiac arrest (CA), but the time limit has not been determined. On February 23rd in 2016, a 76-year-old female patient with respiratory and cardiac arrest who was on the third day after transurethral resection of bladder tumor (TUR-BT) was admitted to the intensive care unit of the General Hospital of Fushun Mining Bureau. On the basis of the comprehensive treatment measures such as ventilator support ventilation, physical cooling with ice cap, 1 mg adrenaline for intravenous injection, low molecular heparin of 5 000 U for subcutaneous injection, and the continuous chest compression were carried out in a timely and effective manner for 125 minutes, which make the patient recover to sinus rhythm and her brain function recovered well without any sequelae, and follow-up of the patient in 1 year showed well. The key to success or failure of CPR depend on the patient's condition. If the patients in healthy, single cause, a good response to the resuscitation, the pulsation of the large artery can be seen now and then during the rescue, and the recovery of the spontaneous breathing, CPR should be kept on. In the process of CPR, individualized assessment of the disease progression without the 30-minute time limit, may benefit the patients in maximum. In the future clinical practice, we should actively explore more favorable evidence, so that CA patients can be rescued more. PMID- 29764557 TI - [Development and application of disposable constant volume and negative pressure drainage device]. AB - OBJECTIVE: The common negative pressure drainage bottle used in the vacuum sealing drainage (VSD) cannot quantitative and automatically cut off. Excessive drainage damages the negative pressure source, causes drainage interruption, so once drainage was continuously performed, medical staff need to closely observe drainage bottle calibration. It was also important to known whether there was a large amount of fresh blood sucked out during continuous drainage because it could lose too much blood. To solve these two problems, we designed a kind of negative pressure drainage device, which volume was constant, with the function of automatic cutting off continuous drainage. It can not only prevent drainage fluid flowing back to the negative pressure source and cause drainage interruption, but also prevent massive blood loss from continued drainage after the hemorrhage. We could benefit from this device, which possess many advantages, such as simple structure, security and reliability. It is worthy promoting in the clinical work. PMID- 29764558 TI - [Progress of epidemiology and outcome for sepsis]. AB - OBJECTIVE: Sepsis is an uncontrolled host's response to infection and leads to life-threatening organ dysfunction. Traditional prognostic indicators for short term mortality, such as intensive care unit (ICU) mortality, hospital mortality, cannot reveal the real and final outcome of sepsis patients. Sepsis patients remain high mortality even several years after hospital discharge, at the same time the quality of life, and the cognitive function were also damaged at varying degrees. Nowadays, studies about long-term quality of life for sepsis were still sparse and further study was still needed. This article aims to explore the epidemiology, short-term and long-term outcome so that it can provide some reference for assessment and intervention of long-term outcome of sepsis. PMID- 29764559 TI - [Application of targeted temperature management in the treatment of cardiac arrest in adult patients]. AB - OBJECTIVE: Cardiac arrest (CA) is a fatal condition with low resuscitation rate and high mortality rate. Most of the survivors have neurological sequelae affecting their quality of life. Targeted temperature management (TTM) has been suggested by a number of studies to increase the survival rate and improve neurological outcome of CA. It is highly recommended by the International Liaison Committee on Resuscitation (ILCOR) for unconscious patients after resuscitation. In this review, we discuss the pathological mechanism of brain injury in CA and applications of TTM in adults with CA, with the aim of providing valuable information for clinical application. PMID- 29764560 TI - [Discussion of the implementation of MIMIC database in emergency medical study]. AB - OBJECTIVE: To introduce Medical Information Mart for Intensive Care (MIMIC) database and elaborate the approach of critically emergent research with big data based on the feature of MIMIC and updated studies both domestic and overseas, we put forward the feasibility and necessity of introducing medical big data to research in emergency. Then we discuss the role of MIMIC database in emergency clinical study, as well as the principles and key notes of experimental design and implementation under the medical big data circumstance. The implementation of MIMIC database in emergency medical research provides a brand new field for the early diagnosis, risk warning and prognosis of critical illness, however there are also limitations. To meet the era of big data, emergency medical database which is in accordance with our national condition is needed, which will provide new energy to the development of emergency medicine. PMID- 29764561 TI - MiR-204 acts as a potential therapeutic target in acute myeloid leukemia by increasing BIRC6-mediated apoptosis. AB - Acute myeloid leukemia (AML) is one of the most common hematological malignancies all around the world. MicroRNAs have been determined to contribute various cancers initiation and progression, including AML. Although microRNA-204 (miR 204) exerts anti-tumor effects in several kinds of cancers, its function in AML remains unknown. In the present study, we assessed miR-204 expression in AML blood samples and cell lines. We also investigated the effects of miR-204 on cellular function of AML cells and the underlying mechanisms of the action of miR 204. Our results showed that miR-204 expression was significantly downregulated in AML tissues and cell lines. In addition, overexpression of miR-204 induced growth inhibition and apoptosis in AML cells, including AML5, HL-60, Kasumi-1 and U937 cells. Cell cycle analysis further confirmed an augmentation in theapoptotic subG1 population by miR-204 overexpression. Mechanistically, baculoviral inhibition of apoptosis protein repeat containing 6 (BIRC6) was identified as a direct target of miR-204. Enforcing miR-204 expression increased the luciferase activity and expression of BIRC6, as well as p53 and Bax expression. Moreover, restoration of BIRC6 reversed the pro-apoptotic effects of miR-204 overexpression in AML cells. Taken together, this study demonstrates that miR-204 causes AML cell apoptosis by targeting BIRC6, suggesting miR-204 may play an anti carcinogenic role in AML and function as a novel biomarker and therapeutic target for the treatment of this disease. [BMB Reports 2018; 51(9): 444-449]. PMID- 29764562 TI - Osteoclast-derived SLIT3 is a coupling factor linking bone resorption to bone formation. AB - We identified osteoclast-derived SLIT3 as a new coupling factor using fractionated secretomics. Coupling links bone resorption to bone formation. SLIT3 stimulated the recruitment and proliferation of osteoblasts into bone remodeling sites via activation of beta-catenin. Autocrine signaling by SLIT3 also inhibited bone resorption by suppressing the fusion and differentiation of pre-osteoclasts. All mice lacking Slit3 or its receptor Robo1 showed an osteopenic phenotype with low bone formation and high bone resorption. A small truncated recombinant SLIT3 protein increased bone mass in an osteopenic mouse model. These results suggest that SLIT3 is a novel therapeutic target in metabolic bone diseases. [BMB Reports 2018; 51(6): 263-264]. PMID- 29764563 TI - Deubiquitinase USP35 as a novel mitotic regulator via maintenance of Aurora B stability. AB - Aurora B is an important kinase involved in dynamic cellular events in mitosis. Aurora B activity is controlled by several post-translational modifications (PTMs). Among them, E3 ubiquitin ligase-mediated ubiquitination plays crucial roles in controlling the relocation and degradation of Aurora B. Aurora B, ubiquitinated by different E3 ligases, moves to the exact site for its mitotic function during metaphase-anaphase transition and is then degraded for cell cycle progression at the end of mitosis. However, how the stability of Aurora B is maintained until its degradation has been poorly understood. Recently, we have found that USP35 acts as a deubiquitinating enzyme (DUB) for Aurora B and affects its stability during cell division, thus being involved in the regulation of mitosis. In this review, we discuss the USP35-mediated deubiquitination of Aurora B and the regulation of mitotic progression by USP35. [BMB Reports 2018; 51(6): 261-262]. PMID- 29764564 TI - Mitochondria-mediated defense mechanisms against pathogens in Caenorhabditis elegans. AB - Mitochondria are crucial organelles that generate cellular energy and metabolites. Recent studies indicate that mitochondria also regulate immunity. In this review, we discuss key roles of mitochondria in immunity against pathogen infection and underlying mechanisms, focusing on discoveries using Caenorhabditis elegans. Various mitochondrial processes, including mitochondrial surveillance mechanisms, mitochondrial unfolded protein response (UPRmt), mitophagy, and reactive oxygen species (ROS) production, contribute to immune responses and resistance of C. elegans against pathogens. Biological processes of C. elegans are usually conserved across phyla. Thus, understanding the mechanisms of mitochondria-mediated defense responses in C. elegans may provide insights into similar mechanisms in complex organisms, including mammals. [BMB Reports 2018; 51(6): 274-279]. PMID- 29764567 TI - [Features and management of very early onset inflammatory bowel disease]. AB - Inflammatory bowel disease (IBD) is a chronic nonspecific intestinal inflammatory disease of unknown etiology. This disease includes three main types: Crohn′s disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBD U). IBD is frequently presented in adults, but in recent years, there is a rising incidence in pediatric populations. Very early onset IBD (VEO-IBD) is a fraction of pediatric IBD, but they have exclusive phenotypic and genetic characteristics such that they are accompanied by severe disease course and resistance to conventional therapy. The purpose of this review is to provide a contemporary overview of the clinical features, pathogenesis, and management of VEO-IBD. PMID- 29764565 TI - Cancer stem cell metabolism: target for cancer therapy. AB - Increasing evidence suggests that cancer stem cell (CSC) theory represents an important mechanism underlying the observed failure of existing therapeutic modalities to fully eradicate cancers. In addition to their more established role in maintaining minimal residual disease after treatment and forming the new bulk of the tumor, CSCs might also critically contribute to tumor recurrence and metastasis. For this reason, specific elimination of CSCs may thus represent one of the most important treatment strategies. Emerging evidence has shown that CSCs have a different metabolic phenotype to that of differentiated bulk tumor cells, and these specific metabolic activities directly participate in the process of CSC transformation or support the biological processes that enable tumor progression. Exploring the role of CSC metabolism and the mechanism of the metabolic plasticity of CSCs has become a major focus in current cancer research. The targeting of CSC metabolism may provide new effective therapies to reduce the risk of recurrence and metastasis. In this review, we summarize the most significant discoveries regarding the metabolism of CSCs and highlight recent approaches in targeting CSC metabolism. [BMB Reports 2018; 51(7): 319-326]. PMID- 29764568 TI - [Effect of early application of recombinant human erythropoietin on white matter development in preterm infants]. AB - OBJECTIVE: To evaluate the effect of early application of recombinant human erythropoietin (rhEPO) on white matter development in preterm infants using fractional anisotropy (FA) of magnetic resonance diffusion tensor imaging (DTI). METHODS: A total of 81 preterm infants with gestational age ≤32 weeks, birth weight <1 500 g, and hospitalization within 24 hours after birth were randomly divided into rhEPO group (42 infants) and control group (39 infants). The infants in the rhEPO group were administered rhEPO, while those in the control group were given the same volume of normal saline. The preterm infants of both groups took examinations of head magnetic resonance imaging, diffusion-weighted imaging, and DTI at the corrected gestational age of 35-37 weeks. FA was calculated for the regions of interest in both groups. RESULTS: There was no significant difference in the incidence of intracranial hemorrhage, periventricular leukomalacia, focal cerebral white matter damage (CWMD), and extensive CWMD between rhEPO and control groups (P>0.05). Compared with the control group, the rhEPO group showed higher FA values at the posterior limb of the internal capsule, the splenium of the corpus callosum, frontal white matter, and occipital white matter (P<0.05). There was no significant difference in FA values at the parietal white matter, thalamus, lenticular nucleus, and caudate nucleus between the two groups (P>0.05). CONCLUSIONS: Early application of rhEPO has a neuroprotective effect on white matter development in preterm infants. PMID- 29764566 TI - Laminopathies; Mutations on single gene and various human genetic diseases. AB - Lamin A and its alternative splicing product Lamin C are the key intermediate filaments (IFs) of the inner nuclear membrane intermediate filament. Lamin A/C forms the inner nuclear mesh with Lamin B and works as a frame with a nuclear shape. In addition to supporting the function of nucleus, nuclear lamins perform important roles such as holding the nuclear pore complex and chromatin. However, mutations on the Lamin A or Lamin B related proteins induce various types of human genetic disorders and diseases including premature aging syndromes, muscular dystrophy, lipodystrophy and neuropathy. In this review, we briefly overview the relevance of genetic mutations of Lamin A, human disorders and laminopathies. We also discuss a mouse model for genetic diseases. Finally, we describe the current treatment for laminopathies. [BMB Reports 2018; 51(7): 327 337]. PMID- 29764569 TI - [Combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases in neonates]. AB - OBJECTIVE: To study the combined effect of gestational age and birth weight on metabolites related to inherited metabolic diseases (IMD). METHODS: A total of 3 381 samples ruled out of IMD by follow-up were randomly selected from 38 931 newborns who participated in the neonatal IMD screening during 2014-2016. The 3 381 neonates were categorized into seven groups according to their gestational age and birth weight: extremely preterm appropriate-for-gestational age (AGA) group (n=12), preterm small-for-gestational age (SGA) group (n=18), preterm AGA group (n=219), preterm large-for-gestational age (LGA) group (n=18), full-term SGA group (n=206), full-term AGA group (n=2 677), and full-term LGA group (n=231). Heel blood samples were collected from each group on postnatal days 3-7 after adequate breastfeeding. Levels of 17 key IMD-related metabolic indices in dried blood spots were measured using tandem mass spectrometry. Spearman′s correlation analysis was used to investigate the relationships between 17 IMD related metabolic indices and their influencing factors, while covariance analysis was used to compare the metabolic indices between these groups. RESULTS: After adjusting the influencing factors such as physiological and pathological status, compared with the full-term AGA group, the extremely preterm AGA, preterm SGA, and preterm AGA groups had significantly reduced levels of leucine?isoleucine?hydroxyproline and valine (P<0.05); the preterm AGA group had a significantly decreased ornithine level (P<0.05); the extremely preterm AGA and preterm AGA groups had a significantly reduced proline level (P<0.05). Besides, the phenylalanine level in the extremely preterm AGA and preterm AGA groups, the methionine level in the preterm SGA group, and the tyrosine level in the preterm AGA group all significantly increased (P<0.05). The increased levels of free carnitine, acetylcarnitine, and propionylcarnitine were found in the preterm SGA and preterm AGA groups. The oleylcarnitine level also significantly increased in the preterm SGA group (P<0.05). Most carnitine indices showed significant differences between the SGA group and the AGA/LGA group in both preterm and full term infants (P<0.05). CONCLUSIONS: Low gestational age and low birth weight may result in abnormal results in IMD screening. Therefore, gestational age and birth weight should be considered to comprehensively judge the abnormal results in IMD screening. PMID- 29764570 TI - [Kaup index in 16 887 singleton neonates with a gestational age of 27-42 weeks in Shenzhen, China]. AB - OBJECTIVE: To study the Kaup index (KI), an index used to evaluate body burliness and nutritional status, of neonates with a gestational age (GA) of 27-42 weeks at birth, and to establish the percentile curves of KI. METHODS: Cross-sectional cluster sampling was performed from April 2013 to September 2015 to select 16 887 singleton neonates with a GA of 27-42 weeks in two hospitals in Shenzhen, China. Body weight and body length were measured to calculate KI. The percentile curves of KI were plotted in these neonates. RESULTS: Mean KIs and corresponding standard deviations were obtained for singleton neonates with a gestational age of 27-42 weeks (in male, female, and mixed groups), and the 3rd-97th percentile curves of KI were plotted. The singleton neonates with a GA of 27 weeks had the lowest 50th percentile value of KI, and KI gradually increased with GA. Boys had a higher 50th percentile value of KI than girls in each GA group. In all groups except the 33-week GA group, boys had a higher mean KI than girls, and there was a significant difference in the mean KI between boys and girls in the GA groups of 34 and 36-40 weeks (P<0.05). CONCLUSIONS: KI of neonates at birth increases with GA, suggesting that body density and body burliness increase with GA. Boys have better body burliness than girls at birth. The percentile curves of KI plotted for singleton neonates with a GA of 27-42 weeks (in male, female, and mixed groups) can provide a reference for evaluating the body burliness and nutritional status of neonates at birth in Shenzhen. PMID- 29764571 TI - [Efficiency of electrocardiogram monitor for positioning the catheter tip in peripherally inserted central catheter placement in neonates]. AB - OBJECTIVE: To study the efficiency of electrocardiogram (ECG) monitor for positioning the catheter tip in the placement of peripherally inserted central catheter (PICC) in neonates. METHODS: A total of 160 neonates who were admitted to the neonatal intensive care unit (NICU) from January 2015 to December 2017 and underwent the PICC placement via the veins of upper extremity were enrolled. They were randomly divided into an observation group and a control group, with 80 neonates in each group. The neonates in the control group were given body surface measurement and postoperative X-ray localization, while those in the observation group were given body surface measurement, ECG localization, and postoperative X ray localization. The two groups were compared in terms of general information, one-time success rate of PICC placement, and time spent on PICC placement. RESULTS: There were no significant differences between the two groups in sex composition, gestational age, age in days at the time of PICC placement, disease type, and site of puncture (P>0.05). Compared with the control group, the observation group had a significantly higher one-time success rate of PICC placement (95% vs 79%; P<0.05) and a significantly shorter time spent on PICC placement (P<0.05). Localization under an ECG monitor during PICC placement had a sensitivity of 97% and a specificity of 100%. CONCLUSIONS: During the PICC placement in neonates, the use of ECG monitor to determine the position of catheter tip can improve the one-time success rate of placement and reduce the time spent on placement. PMID- 29764572 TI - [A single-center study on the incidence and mortality of preterm infants from 2006 to 2016]. AB - OBJECTIVE: To investigate the incidence and mortality rates of preterm infants and the main causes of death. METHODS: The basic information of preterm infants was collected from their medical records and admission/discharge records to analyze the incidence and mortality rates of preterm infants and the causes of their death. RESULTS: There were 76 812 neonates born in the Xuzhou Maternal and Child Health Hospital from January 2006 to December 2016, among whom 5 585 (7.27%) were preterm infants. The incidence rate of preterm infants tended to increase over these years (P<0.001). The overall mortality rate was 5.01% (280/5 585), and the mortality rate tended to decrease over these years (P<0.001). The mortality rate increased with the reductions in birth weight and gestational age (P<0.001). The top four causes of death in preterm infants were respiratory distress syndrome (44.3%), severe asphyxia (12.9%), neonatal malformation (4.3%), and pulmonary hemorrhage (2.9%) respectively. With the increase in birth weight, there were significant reductions in the constituent ratios of death due to respiratory distress syndrome and severe asphyxia (P<0.001). CONCLUSIONS: The incidence rate of preterm infants tended to increase and their mortality rate tended to decrease from 2006 to 2016. The mortality rate of preterm infants is associated with gestational age and birth weight. Respiratory distress syndrome and severe asphyxia are the main causes of death in preterm infants. PMID- 29764573 TI - [Clinical and laboratory characteristics of juvenile myelomonocytic leukemia]. AB - OBJECTIVE: To study the clinical and laboratory characteristics of juvenile myelomonocytic leukemia (JMML). METHODS: The clinical characteristics and laboratory results were retrospectively analyzed in 10 children with newly diagnosed JMML. They were compared with those of 28 children with myelodysplastic syndrome (MDS) and 44 children with chronic myeloid leukemia (CML). RESULTS: Compared with the children with CML or MDS, the children with JMML had significantly higher rates of skin rashes, ecchymosis, and lymphadenectasis, a significantly lower serum cholinesterase (ChE) level, and a significantly higher fetal hemoglobin level (P<0.05). The white blood cell count of children with JMML was significantly higher than that of children with MDS, but significantly lower than that of children with CML (P<0.05). In addition, the myeloid/erythroid ratio and rate of dyshaematopoiesis were significantly lower in children with JMML than those in children with CML or MDS. The children with JMML had a significantly higher expression of mature monocyte marker CD14 than those with CML or MDS (P<0.05). The levels of myeloid markers CD33, CD11b, CD13, and CD15 in children with JMML were significantly higher than those in children with MDS, but significantly lower than those in children with CML (P<0.05). The levels of CD2 and CD7 in children with JMML were higher than those in children with CML, but lower than those in children with MDS (P<0.05). CONCLUSIONS: Skin rashes, ecchymosis, lymphadenectasis, and ChE reduction are more common in children with JMML than in those with CML or MDS, while dyshaematopoiesis is less common. In addition, CD14 level increases significantly in children with JMML. PMID- 29764574 TI - [Clinical effect and mechanism of hemoperfusion in treatment of children with severe abdominal Henoch-Schonlein purpura]. AB - OBJECTIVE: To study the clinical effect and mechanism of hemoperfusion (HP) in the treatment of children with severe abdominal Henoch-Schonlein purpura (HSP). METHODS: A total of 24 children with severe abdominal HSP were divided into two groups: conventional treatment and HP (n=12 each). Ten healthy children who underwent physical examination were enrolled as the control group. Before and after treatment, chemiluminescence was used to measure the serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α); thiobarbituric acid colorimetry was used to measure the plasma level of malondialdehyde (MDA); the hydroxylamine method was used to measure the plasma level of superoxide dismutase (SOD); chemical colorimetry was used to measure the plasma level of total anti-oxidant capability (T-AOC). RESULTS: Compared with the control group, the conventional treatment and HP groups had significantly higher IL-6, TNF-α, and MDA levels and significantly lower SOD and T-AOC levels before treatment (P<0.05), but there were no significant differences between the conventional treatment and HP groups (P>0.05). After treatment, the conventional treatment and HP groups had significant reductions in IL-6, TNF-α, and MDA levels and significant increases in SOD and T-AOC levels (P<0.05). The HP group had significantly greater changes than the conventional treatment group; however, there were still significant differences in these indices between the HP and control groups (P<0.05). Compared with the HP group, the conventional treatment group had a significantly lower percentage of children with disappearance of digestive tract symptoms at 4 days after treatment and significantly longer time to disappearance of rash and digestive tract symptoms (P<0.05). Compared with the conventional treatment group, the HP group had a significantly lower amount of glucocorticoid used during treatment and a significantly lower percentage of children who experienced hematuria and/or proteinuria within 6 months of the disease course (P<0.05). There were no significant differences between the two groups in length of hospital stay and recurrence rates of rash and abdominal pain within 6 months of the disease course. CONCLUSIONS: HP can reduce the amount of glucocorticoid used during treatment and the incidence rate of kidney injury in children with severe abdominal HSP, possibly by eliminating IL-6, TNF-α, and MDA. PMID- 29764575 TI - [Association between overweight/obesity in parents and autism spectrum disorders in offspring]. AB - OBJECTIVE: To study the association between overweight/obesity in parents before maternal pregnancy and the development of autism spectrum disorders (ASD) in offspring. METHODS: A total of 36 children who were diagnosed with ASD (ASD group) and 72 normal children matched for sex and age (control group) were enrolled. A questionnaire survey was performed to collect the general information, including body height and body weight of parents before maternal pregnancy and maternal weight gain during pregnancy. Univariate and multivariate logistic regression analyses were used to investigate the association between overweight/obesity in parents before maternal pregnancy and ASD in offspring. RESULTS: The ASD group had a significantly higher detection rate of overweight/obesity in the father than the control group (56% vs 32%; P=0.018) before maternal pregnancy. The univariate and multivariate logistic regression analyses showed that overweight/obesity of the father before maternal pregnancy was a risk factor for ASD in offspring (OR=2.66 and 2.58 respectively; P<0.05). CONCLUSIONS: Overweight/obesity of the father before maternal pregnancy is an independent risk factor for ASD in offspring, and therefore, it is important for the father to control his body mass index within the normal range before maternal pregnancy. PMID- 29764576 TI - [NIPBL gene mutations in two children with Cornelia de Lange syndrome]. AB - Both children (one boy and one girl) experienced disease onset in infancy and visited the hospital due to growth retardation. They had unusual facies including thick hair, arched and confluent eyebrows, long and curly eyelashes, short nose, and micrognathia. Patient 1 had congenital heart disease (atrial septal defect and pulmonary stenosis) and special dermatoglyph (a single palmar crease). Patient 2 had cleft palate and moderate-to-severe deafness. Clinical features suggested Cornelia de Lange syndrome in both children. High-throughput sequencing was used to detect the seven known pathogenic genes of Cornelia de Lange syndrome, i.e., the NIPBL, SMC1A, SMC3, HDAC8, RAD21, EP300, and ANKRD11 genes. Sanger sequencing was used to analyze and verify gene mutations. Both patients were found to have novel mutations in the NIPBL gene. One patient had a frameshift mutation in exon 45, c.7834dupA, which caused early termination of translation and produced truncated protein p.R2612fsX20. The other patient had a nonsense mutation, c.505C>T, which caused a premature stop codon and produced truncated protein Q169X. Such mutations were not found in their parents or 50 unrelated healthy individuals. PMID- 29764577 TI - [Current status of exclusive breastfeeding for the second child and factors influencing exclusive breastfeeding in the context of the universal two-child policy]. AB - OBJECTIVE: To investigate the current status of exclusive breastfeeding for the second child in the context of the universal two-child policy and the factors influencing exclusive breastfeeding. METHODS: A self-designed questionnaire for the current status of breastfeeding and related factors influencing breastfeeding for the second child were used to survey 836 mothers with a second child, who were selected by cluster sampling, in Quzhou, Zhejiang, China. RESULTS: A total of 680 usable questionnaires were obtained. The rate of exclusive breastfeeding for the second child was significantly lower than for the first child (34.9% vs 42.2%; P<0.05). The univariate analysis revealed that there were significant differences between the exclusive and non-exclusive breastfeeding groups in the mother′s age, education background, occupation and time of maternity leave, mode of delivery of the first child, sex of the first child, feeding pattern of the first child, mode of delivery of the second child, whether the second child was admitted to the intensive care unit, whether the father supported breastfeeding, and whether the grandmother/maternal grandmother supported breastfeeding (P<0.05). The multivariate logistic regression analysis showed that artificial feeding+partial breastfeeding for the first child (OR=12.286, P<0.05), cesarean section for the second child (OR=1.724, P<0.05), and having no breastfeeding support from the maternal grandmother (OR=1.651, P<0.05) were main factors for influencing exclusive breastfeeding. CONCLUSIONS: The current status of exclusive breastfeeding for the second child is not optimistic in the context of the universal two-child policy. Education about breastfeeding should be taken seriously at the birth of the first child, the rate of cesarean section should be reduced, and the family members should support exclusive breastfeeding, in order to improve the status of exclusive breastfeeding. PMID- 29764578 TI - [Protective effect of astrocyte exosomes on hypoxic-ischemic neurons]. AB - OBJECTIVE: To study the effect of astrocyte exosomes on hypoxic-ischemic neurons. METHODS: Rat astrocytes were cultured in vitro, and differential centrifugation was used to obtain the exosomes from the cell supernatant. Transmission electron microscopy, Nanosight, and Western blot were used for the identification of exosomes. BCA method was used to measure the concentration of exosomes. Rat neurons were cultured in vitro and then divided into control group, exosome group, oxygen glucose deprivation (OGD) group, and OGD+exosome group (n=3 each). The OGD and OGD+exosome groups were cultured in glucose-free medium under the hypoxic condition. The exosome and OGD+exosome groups were treated with exosomes at a final concentration of 22 μg/mL. The control and OGD groups were given an equal volume of phosphate-buffered saline. ELISA was used to measure the level of lactate dehydrogenase (LDH) in neurons. The terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling was used to measure the apoptotic index of neurons. RESULTS: The identification of exosomes showed that the exosomes extracted by differential centrifugation had the features of exosomes. Compared with the control and exosome groups, the OGD group had significant increases in LDH level and apoptotic index (P<0.05). Compared with the OGD group, the OGD+exosome group had significant reductions in LDH level and apoptotic index (P<0.05). CONCLUSIONS: The exosomes from astrocytes have a protective effect on neurons with hypoxic-ischemic injury. PMID- 29764579 TI - [Dynamic expression and role of SUMO-modified C/EBPα in preterm rats with bronchopulmonary dysplasisa induced by hyperoxia exposure]. AB - OBJECTIVE: To study the expression of SUMO-modified CCAAT enhancer binding protein α (C/EBPα) in preterm rat model of bronchopulmonary dysplasisa (BPD) induced by hyperoxia exposure and its role. METHODS: Eighteen preterm rats were randomly divided into an air group and a hyperoxia group (n=9 each). The model of BPD was prepared in preterm rats exposed to hyperoxia. The rats from the two groups were sacrificed on postnatal days 4, 7 and 14 respectively (3 rats at each time) and lung tissues were harvested. Periodic acid Schiff (PAS) staining was used to observe the differentiation of rat lung tissues. Ki67 expression was detected by immunohistochemistry. Western blot was used to measure the protein expression of small ubiquitin-related modifier 1(SUMO1) and C/EBPα. A co-immunoprecipitation assay was performed to measure the protein expression of SUMO-modified C/EBPα. RESULTS: Compared with the air group, the hyperoxia group showed a decreased glycogen content in the lung tissue on postnatal day 4, and an increased content on postnatal days 7 and 14. Over the time of hyperoxia exposure, the hyperoxia group showed an increased expression of Ki67 in the lung tissue compared with the air group at all time points. Compared with the air group, the protein expression of C/EBPα increased on postnatal day 4 and decreased on postnatal days 7 and 14 in the hyperoxia group (P<0.05). The hyperoxia group had significantly upregulated expression of SUMO1 and SUMO-modified C/EBPα compared with the air group at all time points (P<0.05). In the hyperoxia group, the protein expression of SUMO-modified C/EBPα was positively correlated with the glycogen content (r=0.529, P<0.05) and the expression of Ki67 (r=0.671, P<0.05). CONCLUSIONS: Hyperoxia may induce over-proliferation and differentiation disorders of alveolar epithelial cells in preterm rat model of BPD, possibly through an increased expression of SUMO-modified C/EBP&alpha. PMID- 29764580 TI - [Effect of rhubarb on neonatal rats with bronchopulmonary dysplasia induced by hyperoxia]. AB - OBJECTIVE: To study the effect of rhubarb on neonatal rats with bronchopulmonary dysplasia (BPD) induced by hyperoxia. METHODS: A total of 64 rats (postnatal day 4) were randomly divided into four groups: air control, rhubarb control, hyperoxia model, and hyperoxia+rhubarb (n=16 each). The rats in the hyperoxia model and hyperoxia+rhubarb groups were exposed to hyperoxia (60% O2) to establish a BPD model. The rats in the rhubarb control and hyperoxia+rhubarb groups were given rhubarb extract suspension (600 mg/kg) by gavage daily. The pathological changes of lung tissue were evaluated by hematoxylin-eosin staining on postnatal days 14 and 21. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) were measured by spectrophotometry. The mRNA and protein expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were determined by RT-PCR and Western blot respectively. RESULTS: The hyperoxia model group showed reduced alveolar number, increased alveolar volume, and simplified alveolar structure, which worsened over the time of exposure to hyperoxia. These pathological changes were significantly reduced in the hyperoxia+rhubarb group. On postnatal days 14 and 21, compared with the air control and rhubarb control groups, the hyperoxia model group had significantly reduced radical alveolar count (RAC), significantly reduced activity of SOD in the lung tissue, and significantly increased content of MDA and mRNA and protein expression levels of TNF-α and IL-6 (P<0.05). Compared with the hyperoxia model group, the hyperoxia+rhubarb group had significantly increased RAC, significantly increased activity of SOD in the lung tissue, and significantly reduced content of MDA and mRNA and protein expression levels of TNF-α and IL-6 (P<0.05). CONCLUSIONS: Rhubarb may play a protective role in rats with BPD induced by hyperoxia through inhibiting inflammatory response and oxidative stress. PMID- 29764582 TI - [Research advances in the role of aptamers in the diagnosis and targeted therapy of pediatric cancer]. AB - Aptamers are single-stranded DNA or RNA which are isolated from synthesized random oligonucleotide library in vitro via systematic evolution of ligands by exponential enrichment (SELEX) and can bind to metal ions, small molecules, carbohydrates, lipids, proteins, and others targets with high affinity and specificity. Aptamers have the advantages of simple preparation, good thermal stability, and low immunogenicity and have great potential in the medical fields such as molecular imaging, biosensing, early diagnosis of diseases, and targeted therapy. Aptamer technology may be useful for early diagnosis and targeted therapy of pediatric cancer, and may avoid the side effects of conventional chemotherapy, such as growth and development disorders and long-term organ dysfunction. This article reviews the latest research advances in the selection and application of aptamers for pediatric cancer. PMID- 29764581 TI - [Clinical application of minimal residual disease detection in childhood acute leukemia]. AB - In recent years, great progress has been made in the treatment outcome of childhood acute leukemia with the improvement of chemotherapy regimens and the introduction of risk-stratified therapy; however, minimal residual disease (MRD) is still a difficult problem which affects the prognosis of acute leukemia. MRD influences the selection of chemotherapy regimens and recurrence risk stratification, and meanwhile, it can be used for prognostic prediction. At present, flow cytometry and polymerase chain reaction are mainly used for MRD detection. The next-generation sequencing also plays an important role in MRD detection, especially in MRD detection after stem cell transplantation. This article reviews the methodology and significance of MRD detection in childhood acute leukemia. PMID- 29764583 TI - [Syndromic Hirschsprung′s disease and its mode of inheritance]. AB - Hirschsprung′s disease (HSCR) is one of the major causes of chronic incomplete intestinal obstruction in children. HSCR is considered a type of neurocristopathy caused by no colonization of ganglion cells on some parts of the bowel wall due to abnormal termination of the migration of vagal neural cells during embryonic development. This disease can be classified into different types according to the length of the affected intestinal canal. Most HSCR patients present with single deformity, but some HSCR patients are affected by other deformities, which constitutes syndromic HSCR, such as congenital central hypoventilation syndrome, Fryns syndrome, and cartilage-hair hypoplasia syndrome. Most syndromes have abnormal genetic material. An adequate knowledge of syndromic HSCR is of vital importance for accurate diagnosis and prognostic evaluation. This article reviews the clinical manifestations, genetic basis, and genetic modes of different types of syndromic HSCR. PMID- 29764584 TI - [Preliminary Study on the Effect of Adipocytes on the Biological Behaviors of?Lung Adenocarcinoma A549 Cells in Tumor Microenvironment]. AB - BACKGROUND: Adipocytes in the tumor microenvironment may provide the metabolic fuel or signal transduction through media and other means to promote a variety of malignant proliferation and invasion, of tumor cells, but their role in lung cancer progression is still unclear. The purpose of this study was to investigate the effect of adipocytes on lung cancer cell biology. METHODS: 3T3-L1 pre adipocytes were induced into mature adipocytes. The cell morphology was observed by microscopy and Oil Red O staining. MTT assay, colony formation assay, wound healing and Transwell methods were used to detect lung cancer cell proliferation, migration and invasion ability. The content of triglyceride in cells was determined by colorimetry. RESULTS: The morphology of lung adenocarcinoma A549 cells became more slender after co-culture with mature adipocytes, and the proliferation and cloning ability were significantly enhanced (P<0.05). In addition, mature adipocytes can also promote the migration ability (P<0.05), invasion ability (P<0.01) and accumulation of intracellular lipid (P<0.05) of A549 cells. CONCLUSIONS: These findings suggested that adipocytes in tumor microenvironment can promote the proliferation, migration and invasion of lung adenocarcinoma A549 cells, which may be related to lipid metabolism. PMID- 29764585 TI - [Construction of EZH2 Knockout Animal Model by CRISPR/Cas9 Technology]. AB - BACKGROUND: It has been proven that CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9) system was the modern gene-editing technology through the constitutive expression of nucleases Cas9 in the mammalian, which binds to the specific site in the genome mediated by single guide RNA (sgRNA) at desired genomic loci. The aim of this study is that the animal model of EZH2 gene knockout was constructed using CRISPR/Cas9 technology. METHODS: In this study, we designed two single-guide RNAs targeting the Exon3 and Exon4 of EZH2 gene. Then, their gene-targeting efficiency were detected by SURVEYOR assay. The lentivirus was perfused into the lungs of mice by using a bronchial tube and detected by immunohistochemistry and qRT-PCR. RESULTS: The experimental results of NIH-3T3 cells verify that the designed sgEZH2 can efficiently effect the cleavage of target DNA by Cas9 in vitro. The immunohistochemistry and qRT-PCR results showed that the EZH2 expression in experimental group was significantly decreased in the mouse lung tissue. CONCLUSIONS: The study successfully designed two sgRNA which can play a knock-out EZH2 function. An EZH2 knockout animal model was successfully constructed by CRISPR/Cas9 system, and it will be an effective animal model for studying the functions and mechanisms of EZH2. PMID- 29764586 TI - [Relationship between FGFR1 Gene Regulation of Circulating Tumor Cells and Clinical Features of Non-small Cell Lung Cancer]. AB - BACKGROUND: The methods of detection for recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) have hysteresis and one-sidedness. This study summarizes the relationship between the circulating tumor cell (CTC) in peripheral blood, expression of fibroblast growth factor receptor 1 (FGFR1) and clinic pathological features in 30 patients with NSCLC so as to provide new ideas for the detection of tumor recurrence and metastasis. METHODS: To analyze the clinical data and CTC detection data of 30 cases of NSCLC in Department of Thoracic Surgery, Peking Union Medical College Hospital from November 2016 to June 2017. RESULTS: Data analysis showed that the positive rate of CTC in peripheral blood was remarkably correlated with the smoking history (P=0.016). There was no significant correlation among the pathological type and CTC positive rate and the expression of FGFR1 (P=0.202, P=0.806). There was no significant difference in the expression of FGFR1 in different type CTC cells (P=0.094). CONCLUSIONS: The positive rate of CTC was significantly correlated with the smoking history of patients with NSCLC. There was no significant difference in CTC classification and FGFR1 expression in different pathological types of NSCLC. There was no significant difference in the expression of FGFR1 between different types of CTCs. We look forward to a larger sample size and inclusion of follow-up data to arrive at more clinically relevant conclusions about CTC and FGFR1 gene expression. PMID- 29764587 TI - [Role of PD 0332991 on the Proliferation and Apoptosis of Vascular Endothelial Cells]. AB - BACKGROUND: Angiogenesis is an important process in the development of tumor. PD 0332991, a cell cycle inhibitor, can specifically inhibit CD4/6 phosphorylation and cell cycle progression. In xeongraft mice models, PD 0332991 treated mice had significantly decreased angiogenesis and vascular density compared with the control group, but the mechanism remains unknown. The purpose of this study is to investigate the role and molecular mechanism of PD 0332991 on vascular endothelial cells. METHODS: EA.hy926 cells, a kind of vascular endothelial cell, were used as the research model. The effects of PD 0332991 on the activity and proliferation of EA.hy926 cells were detected by the MTT, EdU assays. Wound healing assays and transwell assays were used to determine the effects of PD 0332991 on the mobility of EA.hy926. The influence of PD 0332991 on cell cycle and apoptosis of endothelial cells was tested by flow cytometry, and the Western blot was applied to observe the expression of cell cycle related proteins in EA.hy926 cells treated by PD 0332991. RESULTS: PD 0332991 significantly inhibited the proliferation and mobility of EA.hy926 cells, caused cell cycle arrest and apoptosis. At the same time, PD 0332991 inhibited the expression of CDK4/6 and phosphorylation of Rb, and thus inhibited the cell cycle progression of EA.hy926 cells. CONCLUSIONS: PD 0332991 can inhibit the proliferation and activity of endothelial cells and induces apoptosis. PMID- 29764589 TI - [Influence of Different Therapies on EGFR Mutants by Circulating Cell-free DNA of Lung Adenocarcinoma and Prognosis]. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutation is closely related to the EGFR-TKI target treatment and prognosis of lung adenocarcinoma patients. The mutation status of EGFR is limited by tissue detection. The purpose of this study was to investigate the difference of EGFR mutants in plasmacirculating cell-free DNA (cfDNA) obtained from patients with non-small cell lung cancer (NSCLC) in three groups: pre-therapy, after traditional chemotherapy and targeted therapy. The aim of this study was to analyze whether the plasma cfDNA could effectively determine the EGFR mutations and monitor the drug resistant gene T790M, as well as its prognostic prediction value in patients with targeted therapy. METHODS: ARMS (amplification refractory mutation system) PCR was used to detect EGFR mutations in 107 (50 of pre-therapy, 29 after traditional chemotherapy and 28 after targeted therapy) cases of paired plasma and tumor tissue specimens, followed by comparing their concordance. The sensitivity, specificity and the prognostic value of plasma cfDNA detection were also observed. RESULTS: The total rate of EGFR mutation was 56% (60/107) in all plasma samples and 77.6% (83/107) in corresponding tumor tissues. Completely the same mutants and wild-type EGFR were found in 68.2% cases of paired specimens. The sensitivity of plasma cfDNA detection was 72.3% and the specificity was up to 100%. Patients were sub-categorized according to therapy. The results showed that the highest consistent rate of cfDNA and tumor tissues was found in the group of pre-therapy (74%, 37/50). Whereas, the lowest consistent rate was observed in the targeted therapy group (57.1%, 16/28). It indicated that the targeted treatment could change the EGFR status in plasma cfDNA. Further analyses on inconsistent cases in this group revealed that 50% of them were compound EGFR mutations with T790M. Thereby, it suggested that targeted therapy might induce the emergence of drug resistance gene T790M. This speculation was confirmed by survival analyses. Based on plasma cfDNA results, patients with T790M mutant had significantly worse progression-free survival (PFS) and overall survival (OS). CONCLUSIONS: For EGFR testing, ARMS-PCR on plasma cfDNA is a promising methodology with the highest specificity and effective sensitivity. It is useful for EGFR testing in patients before treatment, especially the late-stage patients. Simultaneously, plasma cfDNA could be used to monitor the drug resistant mutation, T790M status and predict prognosis after targeted therapy. PMID- 29764590 TI - [Characteristics of Ventricular Function in Pulmonary Hypertension Patients ?with Different Shape of Interventricular Septum:?Preliminary Study with Cardiac Magnetic Resonance Imaging]. AB - BACKGROUND: To study the characteristics of ventricular function in Pulmonary Hypertension (PH) Patients with different shape of Interventricular Septum (IVS) by cardiac magnetic resonance (CMR). METHODS: 36 PH patients diagnosed by right heart catheterization accepted CMR. According to the morphology of IVS, the patients were divided into two groups: the non-deformation group (10 patients) and the deformation group (26 patients). The ventricular function parameters were as follows: RV and LV end-diastolic volume index (EDVI), end-systolic volume index (ESVI), stroke volume index (SVI), cardiac index (CI), ejection fraction (EF), and myocardial mass index (MMI). RESULTS: ANOVA analysis showed that the differences of RVEDVI, RVESVI, RVSVI, RVCI, RVEF, RVMMI, LVEDVI, LVESVI, LVSVI and LVCI were significant among the three groups. Compared with control group, RVSVI (P=0.017), RVEF (P<0.001), LVEDVI (P=0.048) and LVSVI (P=0.015) decreased in IVS non-deformation group. Compared with IVS non-deformation group, RVEDVI (P<0.001), RVESVI (P<0.001), RVCI (P=0.002) and RVMMI (P=0.017) were increased in IVS deformation group; while RVEF (P=0.001), LVEDVI (P=0.003), LVSVI (P<0.001) and LVCI (P=0.029) were decreased. Compared with the control group, RVEDVI (P<0.001), RVESVI (P<0.001), RVCI (P=0.004) and RVMMI (P=0.003) were increased in the IVS deformation group, while RVEF (P<0.001), LVEDVI (P<0.001), LVESVI (P<0.001), LVSVI (P<0.001), LVCI (P<0.001) were decreased. CONCLUSIONS: Ventricular function is different in PH Patients with different IVS shape. The IVS shape can represent the changes of ventricular function in PH patients. PMID- 29764588 TI - [Correlations between Ape1/Ref-1, ICAM-1 and IL-17A Levels in Serum and Radiation Pneumonitis for Local Advanced Non-small Cell Lung Cancer Patients]. AB - BACKGROUND: The main manifestations of radiation pneumonitis are injury of alveolar epithelial and endothelial cells, abnormal expression of cytokines, abnormal proliferation of fibroblasts and synthesis of fibrous matrix. The occurrence of radiation pneumonitis is associated with multiplecytokine level abnormality. These cytokines can also be used as bio-markers to predict the occurrence of radiation pneumonitis. This study was to evaluate the correlation between the change of apurinic/apyrimidinic endonuclease 1/redox factor-1 (Ape1/Ref-1), intercellular adhesion molecules 1 (ICAM-1) and interleukin-17A (IL 17A) before and after radiotherapy and radiation pneumonitis for local advanced non-small cell lung cancer (NSCLC) patients with concurrent chemoradiotherapy. METHODS: NSCLC patients (68 cases) were treated with concurrent radiotherapy and chemotherapy, every patient's normal tissue were controlled with a same radation dose. 68 local advanced NSCLC patients with concurrent chemoradiotherapy were detected the levels of Ape1/Ref-1, ICAM-1 and IL-17A in serum by ELISA before radiotherapy and in the 14th week after radiotherapy. Acute and advanced radiation pulmonary injury was graded according to Radiation Therapy Oncology Group/European Organization For Research and Treatment (RTOG/EORTC) diagnostic and grading criteria. Grade 2 or more radiation pneumonitis was taken as the main end point. RESULTS: Eighteen cases out of 68 developed radiation pneumonitis, 50 of 68 cases have no radiation pneumonia development. There was no significant change of Ape1/Ref-1 levels before and after radiotherapy in radiation pneumonitis group (P>0.05). There was no significant change of Ape1/Ref-1 concentration in serum after radiotherapy between radiation pneumonitis group and non-radiation pneumonitis group (P>0.05). Compared with before radiotherapy, upregulation degree of ICAM-1 levels in radiation pneumonitis group was significantly higher than that in non- radiation pneumonitis group (P<0.05). There was no significant change of IL-17A concentration before and after radiotherapy in radiation pneumonitis group, but after radiotherapy IL-17A concentration in serum were remarkably higher than that in non-radiation pneumonitis group (P<0.05). Correlation analysis found that the change of ICAM-1 before and after radiotherapy has no obvious correlation with the incidence of radiation pneumonitis, and IL-17A change has obvious correlation with the incidence of radiation pneumonitis. CONCLUSIONS: On the basis of strictly controlling radiation dose on normal tissue, IL-17A in serum could be the predictive factors of radiation pneumonitis for local advanced NSCLC patients with concurrent chemoradiotherapy. PMID- 29764591 TI - [Clinical Analysis of Small Cell Lung Cancer with Bone Marrow Metastases]. AB - BACKGROUND: Small cell lung cancer (SCLC) is highly malignant and prone to bone marrow metastasis in early stage, but its related reports are limited. This study analyzed the clinical feature, laboratory examination, treatment and prognosis of SCLC patients with bone marrow metastasis. METHODS: The clinical data of 26 SCLC patients with bone marrow metastasis were analyzed retrospectively. Prognostic factors were evaluated. RESULTS: The median age of 26 patients was 57 years and the median time from diagnosis of SCLC to confirmed bone marrow metastases was 8 d. Most patients (96.2%) were accompanied by other organ metastases. The most common laboratory abnormalities were elevated lactate dehydrogenase in 19 cases (73.1%), thrombocytopenia and elevated alkaline phosphatase respectively in 11 cases (42.3%) and anemia in 7 cases (26.9%). Twenty patients had received chemotherapy and the remaining 6 patients had not. Of this group, 16 patients received at least 2 cycles of chemotherapy after the diagnosis of bone marrow metastasis. The median survival time was 15.7 wk (0.1 wk-82.9 wk) after diagnosis of bone marrow metastasis. The survival of patients with chemotherapy was significantly better than that of those without chemotherapy (chi2=33.768, P<0.001). Multivariate analysis showed that no chemotherapy was independent poor prognostic factors (P<0.05). CONCLUSIONS: The SCLC patients with bone marrow metastasis have short survival, whereas chemotherapy can extend the survival of patients. PMID- 29764592 TI - [Analysis of the First Diagnosis Symptom and Its Influencing Factors in 500 Patients with Lung Cancer]. AB - BACKGROUND: As the morbidity and mortality in lung cancer keep raising, we are here to discuss the effect of clinical features especially the initial symptomon on diagnosis and follow-up treatment of newly diagnosed lung cancer patients. METHODS: The clinical features of the 500 patients with lung cancer in our hospital from March, 2017 to May, 2017 were analyzed retrospectively, including the initial symptom, stage, biomarkers, pathology, etc. RESULTS: There were 266 famle (53.3%), 372 adenocarcinoma (74.4%), 285 smokers (58%), status score of most patients (98.2%) was 0-1. 58.2% (n=291) of all the patients got biomarkers test, of which epidermal growth factor receptor (EGFR) mutations was 61.2%(178/291), anaplasticlymphoma kinase (ALK) fusion gene positive was 4.1% (12/291). Smoking status, initial symptom, pathological typing, TNM staging and EGFR mutation were the main factors affecting follow-up treatment. CONCLUSIONS: Patients with typical symptoms have shorter diagnosis time. Smoking status, lung cancer-related symptoms, pathology, TNM staging and EGFR mutation status are the main factors that affect the follow-up treatment. PMID- 29764593 TI - [Stereotactic Body Radiotherapy for Centrally Located Non-small Cell Lung Cancer]. AB - A few study has proven that about 90% of local control rates might be benefit from stereotactic body radiotherapy (SBRT) for patients with medically inoperable stage I non-small cell lung cancer (NSCLC), it is reported SBRT associated overall survival and tumor specific survival is comparable with those treated with surgery. SBRT has been accepted as the first line treatment for inoperable patients with peripheral located stage I NSCLC. However, the role of SBRT in centrally located lesions is controversial for potential toxic effects from the adjacent anatomical structure. This paper will review the definition, indication, dose regimens, dose-volume constraints for organs at risk, radiation technology, treatment side effect of centrally located NSCLC treated with SBRT and stereotactic body proton therapy. PMID- 29764595 TI - [Advances in Antiangiogenic Treatment of Advanced Non-squamous Non-small Cell Lung Cancer in 2017 ASCO and WCLC]. PMID- 29764594 TI - [Research Progress of KRAS Mutation in Non-small Cell Lung Cancer]. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80%-85% of all patients with lung cancer, the majority of patients with lung cancer at the time of diagnosis is in the advanced stage. The development of target therapy based on has changed the mode of treatment in patients with advanced NSCLC. In NSCLC, epidermal growth factor receptor mutation (EGFR) fusion with echinoderm microtubule-associated protein like4-anaplastic lymphoma kinase (EML4-ALK) has been shown to be a powerful biomarker. It is well known that KRAS is also NSCLC one of the most common mutations in oncogenes, although more than 20 years ago KRAS mutation was found in NSCLC. At present, although there are many drugs used to treat NSCLC patients with KRAS mutation, there is no selective or specific inhibitor for the direct elimination of KRAS activity. NSCLC patients with KRAS mutation have poor responsiveness to most systemic therapy. However, individualized therapy for activated signaling pathways with targeted drugs has a good effect on the prognosis of NSCLC patients with KRAS mutation. In addition, the prognostic and predictive role of KRAS mutation in NSCLC remains unclear. In this review, we focus on the research progress of NSCLC with KRAS mutation, including molecular biology, clinicopathological features, prognosis and prediction of KRAS mutation, which will help to improve the understanding of NSCLC in KRAS mutation.?. PMID- 29764597 TI - Frequent attendance and the concordance between PHQ screening and GP assessment in the detection of common mental disorders. PMID- 29764598 TI - Molecular subtypes might affect chemotherapy-induced peripheral neuropathy in breast cancer patients receiving neoadjuvant chemotherapy. PMID- 29764596 TI - [A Case Report of Advanced Lung Adenocarcinoma Harboring KRAS Mutation ?Treated with Anlotinib]. AB - In recent years, the number of advanced non-small cell lung cancer (NSCLC) patients has gradually increased, and the treatment methods have also been significantly increased. However, there are no standard treatment plans at home and abroad for third-line and above patients who are refractory to targeted therapy epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) or chemotherapy. The clinical treatment effect is also not satisfactory. Anlotinib is a novel TKI targeting the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR) and c-Kit. ALTER0303 trail, phase III study has demonstrated that Anlotinib significantly prolonged overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients as 3rd line treatment.Here we report a case of advanced lung adenocarcinoma harboring KRAS mutation treated with Anlotinib.?. PMID- 29764599 TI - The revised guideline on consultation-liaison psychiatry of the Netherlands Psychiatric Association. PMID- 29764600 TI - Emotion regulation in the context of depression and unhealthy eating styles: A response to Paans et al. (2018). PMID- 29764601 TI - Adolescent habitual caffeine consumption and hemodynamic reactivity during rest, psychosocial stress, and recovery. AB - OBJECTIVE: Most adolescents regularly consume caffeine. Whereas observational studies have suggested that coffee may be cardio-protective, pharmacological experimentation with adults shows that caffeine at dietary doses increases blood pressure, thereby implicating regular caffeine consumption as a potential source of harm for cardiovascular health. The present study was in response to the dearth of caffeine research among younger consumers. It was hypothesised that compared to the consumption of little or no caffeine, adolescents who habitually consume caffeine have overall higher blood pressure and increased vascular resistance. METHOD: Using a quasi-experimental design, continuous measurements of blood pressure, cardiac output, and total peripheral resistance were taken non invasively from adolescents (n = 333) aged 14-15 years and 18-19 years who reported "low", "moderate", or "high" levels of caffeine intake. Measurements were conducted when participants generally had negligible or low systematic caffeine levels while at rest, during stress, and during recovery from stress. RESULTS: Whereas habitual caffeine consumption did not predict blood pressure level, higher caffeine intake was associated with modestly increased vascular resistance during all phases of the experiment (i.e., at rest, during stress, and during recovery from stress). CONCLUSIONS: Present findings are important because they suggest that early exposure to caffeine may lead to persistent increases in vascular resistance, which in turn is an acknowledged risk factor for the development of hypertension. These results highlight the need for further studies of adolescents to determine the robustness of any persistent caffeine-related hemodynamic effects, and the implications such effects could have for long-term cardiovascular health. PMID- 29764602 TI - Psychiatric disorders among people living with HIV/AIDS in IRAN: Prevalence, severity, service utilization and unmet mental health needs. AB - BACKGROUND: HIV and psychiatric disorders are closely correlated and are accompanied by some similar risk factors. OBJECTIVE: The aim of this study was to assess psychiatric comorbidity and health service utilization for mental problems among people living with HIV/AIDS in Iran. METHODS: A total of 250 cases were randomly selected from a large referral center for HIV treatment and care in Tehran, Iran. Psychiatric disorders in the past 12 months including mood, anxiety, and substance use disorders were assessed through face-to-face interview, using a validated Persian translation of the Composite International Diagnostic Interview (CIDI v2.1). Severity of psychiatric disorders, social support, socio-economic status, service utilization and HIV-related indicators were assessed. RESULTS: Participants consisted of 147 men and 103 women. Psychiatric disorders were found in 50.2% (95% confidence interval: 43.8-56.6) of the participants. Major depressive disorder was the most prevalent diagnosis (32.1%), followed by substance use disorders (17.1%). In bivariate analysis, psychiatric disorders were significantly higher among male gender, single and unemployed individuals and those with lower social support. In multivariate regression analysis, only social support was independently associated with psychiatric disorders. Among those with a psychiatric diagnosis, 41.1% had used a health service for mental problems and 53% had received minimally adequate treatment. CONCLUSION: The findings of the study highlight the importance of mental health services in the treatment of people living with HIV/AIDS. PMID- 29764603 TI - Neuroticism predicts all-cause mortality over 19-years: The moderating effects on functional status, and the angiotensin-converting enzyme. AB - OBJECTIVE: To examine if the personality traits neuroticism, extraversion, and openness to experience are related to all-cause mortality in older adults over a follow-up period of 19 years. METHODS: Participants were a locally representative sample of 417 older adults (M +/- SD = 84.55 +/- 8.62 years). Statistical significance levels for hazard ratios were estimated having adjusted for age, sex, education, income, depressive illness, and personality traits. RESULTS: A significant effect was observed for neuroticism with each 1 SD increase in neuroticism associated with a 14% increased risk in all-cause mortality (p = 0.031: 95% CI, 1.01-1.28). Following the trichotomization of neuroticism, the hazard for those >1 SD above the mean was significantly greater than the average range (HR = 1.59; p = 0.001; 95% CI, 1.19-2.11). Examination of potential mechanisms revealed that neuroticism significantly moderated the effects of functional status (HRinteration = 1.09; p = 0.018; 95% CI = 1.02-1.17), and the angiotensin-converting enzyme (ACE; HRinteration = 0.88; p = 0.031; 95% CI = 0.79 0.99) on mortality. As such, for each 1 SD increase in neuroticism, the effect rate on all-cause mortality increased by 9% for functional status, and decreased by 12% for ACE. CONCLUSIONS: Findings suggest that neuroticism is associated with all-cause mortality in older age. Specifically, persons higher in neuroticism are at a distinctly greater risk of all-cause mortality. Both functional status, and the angiotensin-converting enzyme provide two potential mechanisms of effect in the association between neuroticism and mortality. PMID- 29764604 TI - Self-reported interoceptive deficits in eating disorders: A meta-analysis of studies using the eating disorder inventory. AB - OBJECTIVE: An impairment of the ability to sense the physiological condition of the body - interoception - has long been proposed as central to the onset and maintenance of eating disorders. More recent attention to this topic has generally indicated the presence of interoceptive deficits in individuals with an eating disorder diagnosis; however, possible links with specific diagnosis, BMI, age, illness duration, depression, and alexithymia remain unclear from individual studies. This meta-analysis aimed to provide a necessary quantitative overview of self-reported interoceptive deficits in eating disorder populations, and the relationship between these deficits and the previously mentioned factors. METHODS: Using a random effects model, our meta-analysis assessed the magnitude of differences in interoceptive abilities as measured using the Eating Disorder Inventory in 41 samples comparing people with eating disorders (n = 4308) and healthy controls (n = 3459). Follow-up and moderator analysis was conducted, using group comparisons and meta-regressions. RESULTS: We report a large pooled effect size of 1.62 for eating disorders with some variation between diagnostic groups. Further moderator analysis showed that BMI, age and alexithymia were significant predictors of overall effect size. CONCLUSION: This meta-analysis is the first to confirm that large interoceptive deficits occur in a variety of eating disorders and crucially, in those who have recovered. These deficits may be useful in identifying and distinguishing eating disorders. Future research needs to consider both objective and subjective measures of interoception across different types of eating disorders and may fruitfully examine interoception as a possible endophenotype and target for treatment. PMID- 29764605 TI - Perception matters: Stressful life events increase breast cancer risk. AB - OBJECTIVE: The relationship between psychological stress and breast cancer risk is unclear. The present study sought to understand how stressfulness appraisal of salient Life Events (LEs) influences breast cancer risk. METHODS: A case-control design was used and included 664 female cases identified through the Cancer Surveillance Program of Orange County, CA and 203 female population-based controls. A LE questionnaire determined if events occurred prior to breast cancer diagnosis and if these events were considered to be stressful or not. Multivariate unconditional logistic regression was used to calculate ORs while adjusting for known breast cancer covariates. RESULTS: Cumulative adverse LEs perceived as stressful were associated with increased breast cancer risk in a dose response fashion (OR = 1.63, 95% CI = 1.00-2.66, Ptrend = 0.045). Conversely, events perceived as non-stressful did not have a significant impact on breast cancer risk. Previous personal illness was directly related to increased breast cancer risk, whether perceived as stressful (OR = 2.84, 95% CI = 1.96-4.11) or non-stressful (OR = 3.47, 95% CI = 1.34-8.94). Abortion and relocation were observed to have a protective effect on breast cancer risk only when reported as stressful (OR = 0.54, 95% CI = 0.32-0.92; OR = 0.63, 95% CI = 0.43-0.93, respectively). Pre/Peri-menopausal women who were nulliparous or who had their first child at >=30 years of age were especially prone to the effects of appraised stress on increased breast cancer risk. CONCLUSIONS: This study underscores the importance of stressfulness appraisal when determining the effect of major LEs on breast cancer risk. Our results support incorporating assessments of perceived stressfulness in future epidemiological investigation of this topic. PMID- 29764607 TI - The impact of loneliness and relationship quality on life satisfaction: A longitudinal dyadic analysis in persons with physical disabilities and their partners. AB - OBJECTIVE: Persons with physical disabilities and their caregiving partners are at an increased risk of experiencing reduced life satisfaction. One potential explanation for this trend may be the potentially harmful effects of loneliness and poor relationship quality which this population often experience. To date, little is known about how the perceptions of loneliness and relationship quality affect life satisfaction in the disability and caregiving setting, furthermore the directionality of effect is not well understood. In this study, we investigate the actor and partner effects, and the reciprocal effects of loneliness and relationship quality on life satisfaction. METHODS: The analyses are based on longitudinal dyadic data from a Swiss community survey of persons with spinal cord injury (SCI) and their partners (n = 246). We employed mixed effects modelling to explore standardized (beta) and unstandardized (B) actor and partner effects, and used cross-lagged path analysis to explore reciprocal effects. RESULTS: Loneliness was more prevalent in persons with SCI than in their caregiving partners. In caregiving partners, we found significant negative actor effects of loneliness (beta = -0.20 (-0.31, -0.10)) and positive actor effects of relationship quality (beta = 0.15 (0.04, 0.26)) on life satisfaction, and significant partner effects of relationship quality on wellbeing. In persons with SCI, only the negative actor effect of loneliness was significant (beta = -0.30 ( 0.41, -0.18)). Over time, loneliness demonstrated reciprocal associations with life satisfaction. CONCLUSION: The findings of our study highlight the importance of reducing loneliness and strengthening relationship quality to improve life satisfaction in partnerships of persons coping with disability. PMID- 29764606 TI - Sex and family history of cardiovascular disease influence heart rate variability during stress among healthy adults. AB - OBJECTIVE: Studies of sex differences in heart rate variability (HRV) typically have not accounted for the influence of family history (FH) of cardiovascular disease (CVD). This study evaluated sex differences in HRV response to speech stress among men and women (age range 30-49 years) with and without a documented FH of CVD. METHODS: Participants were 77 adults (mean age = 39.8 +/- 6.2 years; range: 30-49 years; 52% female) with positive FH (FH+, n = 32) and negative FH (FH-, n = 45) of CVD, verified with relatives of participants. Cardiac activity for all participants was recorded via electrocardiogram during a standardized speech stress task with three phases: 5-minute rest, 5-minute speech, and 5 minute recovery. Outcomes included time domain and frequency domain indicators of HRV and heart rate (HR) at rest and during stress. Data were analyzed with repeated measures analysis of variance, with sex and FH as between subject variables and time/phase as a within subject variable. RESULTS: Women exhibited higher HR than did men and greater HR reactivity in response to the speech stress. However, women also exhibited greater HRV in both the time and frequency domains. FH+ women generally exhibited elevated HRV, despite the elevated risk of CVD associated with FH+. CONCLUSIONS: Although women participants exhibited higher HR at rest and during stress, women (both FH+ and FH-) also exhibited elevated HRV reactivity, reflecting greater autonomic control. Thus, enhanced autonomic function observed in prior studies of HRV among women is also evident among FH+ women during a standardized stress task. PMID- 29764608 TI - The endoscopic endonasal approach for the treatment of juvenile angiofibromas. AB - BACKGROUND AND OBJECTIVES: Juvenile angiofibroma (JA) is a benign tumour, for which the treatment of choice is surgery. It may be associated with significant morbidity because of its anatomical location and its locally destructive growth pattern. Severe haemorrhage constitutes a high risk in JA and its surgical management can be complex. The management of JA remains a challenge. The objective of this study was to review a series of patients with JA treated via the endonasal/endoscopic approach. MATERIAL AND METHODS: Medical records of patients operated for JA were reviewed. MAIN OUTCOME MEASURES: tumour stage, intraoperative blood loss, complications and persistence/recurrence rates. RESULTS: A total of 30 male patients and one female were included. The mean age was 17 years. Using the Radkowski classification, one JA was classified as stage I, 5 stage IIA, 9 stage IIB, 4 stage IIC, 10 stage IIIA and 2 stage IIIB. Thirty nine percent of the JA was classified as advanced stage JA (IIIA and IIIB). The mean blood loss was 1.156mL Except in one case, no significant complications were observed. Tumour persistence/recurrence was observed in 2 JA (6%), at the end of the follow-up. Mean postoperative follow-up time was 86 months. CONCLUSIONS: This retrospective study supports the notion that endonasal endoscopic approaches for a JA are a feasible option associated with good long-term results. PMID- 29764609 TI - Relationship between automation trust and operator performance for the novice and expert in spacecraft rendezvous and docking (RVD). AB - Operator trust in automation is a crucial factor influencing its use and operational performance. However, the relationship between automation trust and performance remains poorly understood and requires further investigation. The objective of this paper is to explore the difference in trust and performance on automation-aided spacecraft rendezvous and docking (RVD) between the novice and the expert and to investigate the relationship between automation trust and performance as well. We employed a two-factor mixed design, with training skill (novice and expert) and automation mode (manual RVD and automation aided RVD) serving as the two factors. Twenty participants, 10 novices and 10 experts, were recruited to conduct six RVD tasks for two automation levels. After the tasks, operator performance was recorded by the desktop hand-held docking training equipment. Operator trust was also measured by a 12-items questionnaire at the beginning and end of each trial. As a result, automation narrowed the performance gap significantly between the novice and the expert, and the automation trust showed a marginally significant difference between the novice and the expert. Furthermore, the result demonstrated that the attitude angle control error of the expert was related to the total trust score, whereas other automation performance indicators were not related to the total score of trust. However, automation performance was related to the dimensions of trust, such as entrust, harmful, and dependable. PMID- 29764610 TI - The effect of steering-system linearity, simulator motion, and truck driving experience on steering of an articulated tractor-semitrailer combination. AB - Steering systems of trucks consist of many linkages, which introduce nonlinearities that may negatively affect steering performance. Nowadays, it is possible to equip steering systems with actuators that provide artificial steering characteristics. However, before new steering systems are deployed in real vehicles, evaluation in a safe and controlled simulator environment is recommended. A much-debated question is whether experiments need to be performed in a motion-base simulator or whether a fixed-base simulator suffices. Furthermore, it is unknown whether simulator-based tests can be validly conducted with a convenience sample of university participants who have not driven a truck before. We investigated the effect of steering characteristic (i.e., nonlinear vs. linear) on drivers' subjective opinions about the ride and the steering system, and on their objective driving performance in an articulated tractor semitrailer combination. Thirty-two participants (12 truck drivers and 20 university drivers) each completed eight 5.5-min drives in which the simulator's motion system was either turned on or off and the steering model either resembled a linear (i.e., artificial) or nonlinear (i.e., realistic) system. Per drive, participants performed a lane-keeping task, merged onto the highway, and completed four overtaking manoeuvers. Results showed that the linear steering system yielded less subjective and objective steering effort, and better lane keeping performance, than the nonlinear system. Consistent with prior research, participants drove a wider path through curves when motion was on compared to when motion was off. Truck drivers exhibited higher steering activity than university drivers, but there were no significant differences between the two groups in lane keeping performance and steering effort. We conclude that for future truck steering systems, a linear system may be valuable for improving performance. Furthermore, the results suggest that on-centre evaluations of steering systems do not require a motion base, and should not be performed using a convenience sample of university students. PMID- 29764611 TI - Regenerative braking failures in battery electric vehicles and their impact on the driver. AB - A unique feature of battery electric vehicles (BEV) is their regenerative braking system (RBS) to recapture kinetic energy in deceleration maneuvers. If such a system is triggered via gas pedal, most deceleration maneuvers can be executed by just using this pedal. This impacts the driving task as different deceleration strategies can be applied. Previous research has indicated that a RBS failure leading to a sudden reduced deceleration represents an adverse event for BEV drivers. In the present study, we investigated such a failure's impact on the driver's evaluation and behavior. We conducted an experiment on a closed-off test track using a modified BEV that could temporarily switch off the RBS. One half of the 44 participants in the study received information about an upcoming RBS failure whereas the other half did not. While 91% of the drivers receiving prior information noticed the RBS failure, only 48% recognized it in the "uniformed" group. In general, the failure and the perception of its occurrence influenced the driver's evaluation and behavior more than receiving prior information. Nevertheless, under the tested conditions, drivers kept control and were able to compensate for the RBS failure. As the participants drove quite simple maneuvers in our experiment, further studies are needed to validate our findings using more complex driving settings. Given that RBS failures could have severe consequences, appropriate information and warning strategies for drivers are necessary. PMID- 29764612 TI - The effect of a novel square-profile hand rim on propulsion technique of wheelchair tennis players. AB - The purpose of this study was to investigate the effect of a square-profile hand rim (SPR) on propulsion technique of wheelchair tennis players. Eight experienced wheelchair tennis players performed two sets of three submaximal exercise tests and six sprint tests on a wheelchair ergometer, once with a regular rim (RR) and once with a SPR. Torque and velocity were measured continuously and power output and timing variables were calculated. No significant differences were found in propulsion technique between the RR and SPR during the submaximal tests. When sprinting with the racket, the SPR showed a significantly lower overall speed (9.1 vs. 9.8 m s-1), maximal speed (10.5 vs. 11.4 m s-1), and maximal acceleration (18.6 vs. 10.9 m s-2). The SPR does not seem to improve the propulsion technique when propelling a wheelchair with a tennis racket in the hand. However, the results gave input for new hand rim designs for wheelchair tennis. PMID- 29764613 TI - The joint use of resilience engineering and lean production for work system design: A study in healthcare. AB - Although lean production (LP) has been increasingly adopted in healthcare systems, its benefits often fall short of expectations. This might be partially due to the failure of lean to account for the complexity of healthcare. This paper discusses the joint use of principles of LP and resilience engineering (RE), which is an approach for system design inspired by complexity science. Thus, a framework for supporting the design of socio-technical systems, which combines insights from LP and RE, was developed and tested in a system involving a patient flow from an emergency department to an intensive care unit. Based on this empirical study, as well as on extant theory, eight design propositions that support the framework application were developed. Both the framework and its corresponding propositions can contribute to the design of socio-technical systems that are at the same time safe and efficient. PMID- 29764614 TI - Use and physiological responses of portable dynamic office workstations in an occupational setting - A field study. AB - OBJECTIVE: The aim of this study was to investigate the use of two types of dynamic workstations (Deskbike, activeLife Trainer) and their effects on physiological activation in an occupational setting. METHODS: 30 employees were given access to the devices for 28 days. Frequency and duration of borrowing and use was recorded by a Chipcard-system. Physiological activation (energy expenditure, heart rate) while working in a seated position and using the workstations was measured with the activity tracker Fitbit Charge HR. RESULTS: Participants used dynamic workstations on 40% of their working days for an average of 54.3 +/- 23.9 min per day. Energy expenditure and heart rate increased significantly while using the workstations compared to working seated. The Deskbike was used more frequently and resulted in greater heart rate elevation. CONCLUSION: Both types of dynamic workstations were used by the employees and had positive effects on physiological activation. The implementation of either type can be recommended. PMID- 29764615 TI - Comfort evaluation of a subject-specific seating interface formed by vibrating grains. AB - Sitting is the most common posture for work in offices, and spinal cord injury (SCI) patients who are wheelchair dependent spend 10.6 h per day seated in wheelchairs. Thus, the comfort of subject-specific interfaces is increasingly important for the well-being of patients and office workers. This paper introduces a new method of forming a subject-specific interface, based on vibrating grains. Twenty subjects (10 females and 10 males) participated in the sitting test. Interface comfort was evaluated using the pressure distribution and subjective rating methods. Five seating interface types were compared. The results showed that compared with a flat interface, the interfaces formed by vibrating grains had a significantly reduced peak contact pressure (PeakCP) (by more than 58.03%), and that PeakCP was highly correlated with the comfort rating (R = -0.533) and discomfort rating(R = -0.603). This new method shows promise for guiding the future development of customized seating interfaces. PMID- 29764616 TI - Uncertainty in monetary cost estimates for assessing working postures using inclinometry, observation or self-report. AB - OBJECTIVE: To assess uncertainty in cost estimates for collecting posture data by inclinometry, observations and self-report. METHOD: In a study addressing physical workloads at a paper mill, costs were calculated for measuring postures of twenty-eight workers during three shifts. Uncertainty in costs was assessed for all three methods as the range between an assumed best case (lowest cost) and worst case (highest cost) using scenario analysis. RESULTS: The cost for observation was larger, but also more uncertain (?16506 and ?89552 in the best and worst case, respectively) than that of inclinometry (?7613 - ?45896). Self report costs were both lower and less uncertain (?3743 - ?23368). CONCLUSIONS: The extent of uncertainty in cost estimates implies that observation could be less expensive than inclinometry, e.g., in a scenario where experienced observers could use existing software, while inclinometers would have to be purchased. We propose adding uncertainty assessments to cost estimates when selecting a method for measuring working postures, and offer guidance in how to proceed in a specific setting. PMID- 29764617 TI - Evaluation of commercially available seat suspensions to reduce whole body vibration exposures in mining heavy equipment vehicle operators. AB - As mining vehicle operators are exposed to high level of Whole body vibration (WBV) for prolonged periods of time, approaches to reduce this exposure are needed for the specific types of exposures in mining. Although various engineering controls (i.e. seat suspension systems) have been developed to address WBV, there has been lack of research to systematically evaluate these systems in reducing WBV exposures in mining heavy equipment vehicle settings. Therefore, this laboratory-based study evaluated the efficacy of different combinations of fore-aft (x-axis), lateral (y-axis), and vertical (z-axis) suspensions in reducing WBV exposures. The results showed that the active vertical suspension more effectively reduced the vertical vibration (~50%; p's < 0.0001) as compared to the passive vertical suspension (10%; p's < 0.11). The passive fore-aft (x-axis) and lateral (y-axis) suspension systems did not attenuate the corresponding axis vibration (p's > 0.06) and sometimes amplified the floor vibration, especially when the non-vertical vibration was predominant (p's < 0.02). These results indicate that there is a critical need to develop more effective engineering controls including better seat suspensions to address non-vertical WBV exposures, especially because these non-vertical WBV exposures can increase risks for adverse health effects including musculoskeletal loading, discomfort, and impaired visual acuity. PMID- 29764618 TI - Investigating daily fatigue scores during two-week offshore day shifts. AB - OBJECTIVES: This study examined daily scores of fatigue and circadian rhythm markers over two-week offshore day shift periods. METHODS: A prospective cohort study among N = 60 offshore day-shift workers working two-week offshore shifts was conducted. Offshore day shifts lasted from 07:00 - 19:00 h. Fatigue was measured objectively with pre- and post-shift scores of the 3-minute psychomotor vigilance tasks (PVT-B) parameters (reaction times, number of lapses, errors and false starts) and subjectively with pre- and post-shift Karolinska Sleepiness Scale (KSS) ratings. Evening saliva samples were collected on offshore days 2,7 and 13 to measure circadian rhythm markers such as dim-light melatonin onset times and cortisol. Generalized and linear mixed model analyses were used to examine daily fatigue scores over time. RESULTS: Complete data from N = 42 offshore day shift workers was analyzed. Daily parameters of objective fatigue, PVT-B scores (reaction times, average number of lapses, errors and false starts), remained stable over the course of the two-week offshore day shifts. Daily subjective post-shift fatigue scores significantly increased over the course of the two-week offshore shifts. Each day offshore was associated with an increased post-shift subjective fatigue score of 0.06 points (95%CI: .03 - .09 p < .001). No significant statistical differences in subjective pre-shift fatigue scores were found. Neither a circadian rhythm phase shift of melatonin nor an effect on the pattern and levels of evening cortisol was found. CONCLUSION: Daily parameters of objective fatigue scores remained stable over the course of the two week offshore day shifts. Daily subjective post-shift fatigue scores significantly increased over the course of the two-week offshore shifts. No significant changes in circadian rhythm markers were found. Increased post-shift fatigue scores, especially during the last days of an offshore shift, should be considered and managed in (offshore) fatigue risk management programs and fatigue risk prediction models. PMID- 29764619 TI - Effects of unexpected visual motion on postural sway and motion sickness. AB - Motion sickness is thought to occur when the brain's assumptions about incoming sensory information do not match the actual signals received. These signals must involve the vestibular system for motion sickness to occur. In this paper, we describe an experiment in which subjects experienced unexpected visual motions, or perturbations, as they navigated a virtual environment (VE) while standing and wearing a head mounted display (HMD) or while viewing a monitor. We found that postural instability, as measured by a balance board, increased with time only when perturbations were present. HMD users exhibited greater sway when exposed to visual perturbations than did monitor users. Yet motion sickness increased only when an HMD was used and occurred with or without participants undergoing perturbations. These results suggest that the postural instability which is generated by unexpected visual perturbation does not necessarily increase the likelihood of motion sickness in a virtual environment. PMID- 29764621 TI - Erratum to "The possible protective role of pumpkin seed oil in an animal model of acid aspiration pneumonia: Light and electron microscopic study Acta Histochemica 119 (2017) 161-171". PMID- 29764620 TI - Hand forces exerted by long-term care staff when pushing wheelchairs on compliant and non-compliant flooring. AB - Purpose-designed compliant flooring and carpeting have been promoted as a means for reducing fall-related injuries in high-risk environments, such as long-term care. However, it is not known whether these surfaces influence the forces that long-term care staff exert when pushing residents in wheelchairs. We studied 14 direct-care staff who pushed a loaded wheelchair instrumented with a triaxial load cell to test the effects on hand force of flooring overlay (vinyl versus carpet) and flooring subfloor (concrete versus compliant rubber [brand: SmartCells]). During straight-line pushing, carpet overlay increased initial and sustained hand forces compared to vinyl overlay by 22-49% over a concrete subfloor and by 8-20% over a compliant subfloor. Compliant subflooring increased initial and sustained hand forces compared to concrete subflooring by 18-31% when under a vinyl overlay. In contrast, compliant flooring caused no change in initial or sustained hand forces compared to concrete subflooring when under a carpet overlay. PMID- 29764623 TI - Pancreatic cancer: A critical review of dietary risk. AB - Pancreatic cancer is a deadly disease. It is estimated that about 90% of pancreatic cancer cases are due to environmental risk factors. Among these, approximately 50% of pancreatic cancer cases may be attributed to diet, which is largely modifiable. Given this large attribution to diet, there have been numerous epidemiological studies assessing the risk of various dietary factors on the incidence of pancreatic cancer. However, many of these studies present conflicting and/or inconclusive findings. The objective of this review is two fold: (a) to summarize the current evidence on the association between various dietary factors and the risk of developing pancreatic cancer and (b) to discuss what additional studies are needed to better elucidate the role of diet as a potential risk factor for pancreatic cancer. We summarized the evidence by using data primarily from meta-analyses and pooled analysis when available, focusing on the most studied nutrients, foods, and dietary patterns. We observed that, while the association between individual nutrients and pancreatic cancer risk have been heavily studied, the evidence is mostly conflicting and inconclusive. In contrast, the evidence of certain associations among dietary patterns and pancreatic cancer risk is clearer, has more power, and is less conflicting. Therefore, we propose a shift in the focus of nutritional epidemiological research with regards to pancreatic cancer risk. We discourage further epidemiological research studies that focus on single nutrients, whereas we strongly encourage additional studies that investigate how a combination of diet and other lifestyle factors may promote or prevent pancreatic carcinogenesis. PMID- 29764622 TI - Absolute CBV for the differentiation of recurrence and radionecrosis of brain metastases after gamma knife radiotherapy: a comparison with relative CBV. AB - AIM: To investigate the efficiency of absolute cerebral blood volume (CBV) in the differentiation of tumour recurrence (TR) and radionecrosis (RN) in brain metastases (BM) and to evaluate the performance of absolute CBV compared to relative CBV (rCBV). MATERIALS AND METHODS: Between March 2015 and June 2017, 46 patients with BM underwent quantitative dynamic susceptibility contrast perfusion weighted imaging (DSC-PWI) because new enhancement had been demonstrated in irradiated lesions after gamma knife radiotherapy. The patients were assigned to either the TR group or RN group on the basis of MR perfusion follow-up or histopathological outcome. Absolute CBV of lesions (CBVlesion) and contralateral normal appearing white matter (CBVNAWM) in both groups were obtained. Mean rCBV were calculated as CBVlesion/CBVNAWM, which was equal to rCBV using traditional DSC-PWI. RESULTS: CBVlesion of TR alone was significantly higher than the other parameters in both groups (p<0.001, separately). CBVlesion had smaller interobserver difference than CBVNAWM and rCBV (p<0.001, separately). Although CBVlesion significantly correlated with rCBV (r=0.914, p<0.001) and both had a similar specificity (96%) in differential diagnosis, CBVlesion had a higher sensitivity (96.9% versus 90.9%) to predict the treatment outcome. The best cut off value of CBVlesion was 21.8 ml/100 g. CONCLUSION: Quantitative DSC-PWI is a powerful method for the assessment of radiosurgically treated brain metastases. Absolute CBV has higher diagnostic efficiency than rCBV, which enables an absolute quantification of the regional CBV and prediction of tumour response. These advantages promote the intra- and inter-patient quantitative image comparison across different institutions. PMID- 29764624 TI - Hydrolyzed proteins from herring and salmon rest raw material contain peptide motifs with angiotensin-I converting enzyme inhibitors and resulted in lower urine concentrations of protein, cystatin C and glucose when fed to obese Zucker fa/fa rats. AB - The use of angiotensin-I converting enzyme (ACE) inhibitors is a common strategy for treating kidney disease. Several amino acid sequences with ACE inhibiting activity are identified in filet and rest raw material from various species of fish, and fish protein hydrolysates could be of interest for possible treatment or prevention of kidney disease. Therefore, we hypothesized that protein hydrolysates from rest raw material from herring and salmon contained ACE inhibiting motifs, and could beneficially affect typical markers for kidney function in an obesity rat model prone to developing renal failure. We identified 81 and 49 peptide sequences with known ACE inhibiting activity in herring and salmon protein hydrolysates from rest raw material, respectively. To investigate the effects of fish protein hydrolysates on markers of kidney function, obese Zucker fa/fa rats consumed diets with 25% of protein from herring (HER) or salmon (SAL) protein hydrolysate from rest raw material and 75% of protein from casein/whey, or 100% protein from casein/whey (CAS) for 4 weeks. Rats fed HER or SAL diets had lower urine concentrations (relative to creatinine) of protein, cystatin C and glucose when compared to rats fed CAS diets, with no differences between groups for serum concentrations of protein, creatinine and cystatin C. To conclude, protein hydrolysates from herring and salmon rest raw material contained several peptide sequences with known ACE inhibiting activities, and resulted in lower urine concentrations of proteins, cystatin C and glucose when fed to obese Zucker rats. PMID- 29764625 TI - Recognition of phenylthiocarbamide (PTC) in taste test is related to blood group B phenotype, females, and risk of developing food allergy: a cross-sectional Brazilian-based study. AB - Anti-nutritional factors, including hemagglutinins, are natural substances that reduce nutritional bioavailability and/or generate adverse physiological effects. Most are bitter toxic compounds, but present chemo-protective properties at low concentrations. Responses to phenylthiocarbamide (PTC) allow for an evaluation of humans' perception of bitter taste, a perception that has evolutionary advantages. Therefore, we hypothesized that relationships between food preference, dietary exposures and disease risk could reflect possible associations not only with the recognition threshold for the bitter taste of PTC, but also with ABO/Rh blood group phenotypes. To test this hypothesis, 375 volunteers of both genders, aged 16-49 years, were recruited. Data were obtained from laboratory tests and questionnaires. PTC test followed literature; blood typing used commercially available sera. Allele frequencies calculated from phenotypes were: T=0.51, t=0.49 (PTC); IA=0.22, IB=0.08, i=0.70 (ABO); D=0.57, d=0.43 (Rh). Associations with the recognition threshold for bitter taste were found for blood group B, females, and risk of developing food allergy for bitter taste at PTC dilution 1 (the highest concentration) (OR=3.862; 95%CI=1.387 10.756; p=0.016); for each more diluted PTC solution, the chance of food allergy fell 25.2% (95%CI = 0.764-0.836), while for each more concentrated solution the chance of food allergy increased 20.1% (p=0.000). There were also nominally significant differences among PTC tasting, ABO/Rh, genders and age-groups in relation to food preferences. Results demonstrated that the ability to recognize PTC in taste test is related to blood group B, females, and risk of developing food allergy, thus confirming the research hypothesis, and presenting original and important associations. PMID- 29764626 TI - 25-Hydroxvitamin D concentrations are not lower in children with bronchial asthma, atopic dermatitis, obesity, or attention-deficient/hyperactivity disorder than in healthy children. AB - Vitamin D (vitD) is involved in immune regulation, and its receptor has been identified in several tissues including lung, adipose tissue, brain, and skin. Based on these observations, it has been suggested that vitD has an essential role not only in bone metabolism but also in other diseases such as atopic dermatitis (AD), bronchial asthma (BA), attention-deficit/hyperactivity disorder (ADHD), and obesity because the affected tissues express vitD receptors. Furthermore, obesity, AD, and BA are regarded as inflammatory diseases. Therefore, we hypothesized that vitD concentrations are lower in children with AD, BA, ADHD, and obesity compared to healthy children. We measured 25 hydroxyvitamin D concentrations in 235 children (60% boys, age 9.3+/-1.7years) with obesity, BA, AD, or ADHD and compared them to those of 3352 children from a healthy population. Additionally, parathyroid hormone was measured in the children with obesity, ADHD, BA, and AD. VitD concentrations were not lower in children with obesity, ADHD, BA, and AD compared to healthy children. In multiple regression analyses adjusted to migration background, time period of blood sample, age, and sex, VitD levels correlated significantly with the severity of AD measured by SCORing Atopic Dermatitis index and attention deficit measured by Conners questionnaire in ADHD. VitD levels were not linked to hyperactivity in ADHD, the severity of BA measured as forced expiration volume in the first second, or body mass index standard deviation score. Parathyroid hormone was not associated with the activity of any analyzed disease. In conclusion, most of our findings do not support the hypothesis that vitD is involved in the pathogenesis of these entities. PMID- 29764627 TI - Dietary factors influence the association of cyclin D2 polymorphism rs11063069 with the risk of metabolic syndrome. AB - The relationship of CCND2 gene variation, rs11063069 with metabolic syndrome (MetS) modulates by dietary factors but enough data are not available on this issue. So, the hypothesis, which assumes that dietary factors modulate the relationship of CCND2 polymorphisms with the risk of MetS was investigated in our study. Subjects of this nested case-control study were selected from participants of the Tehran Lipid and Glucose Study. Each case (n=974) was pair-matched individually with a control by age, sex and the follow-up duration. Dietary patterns were determined using factor analysis. CCND2 rs11063069 was genotyped by the ARMS-polymerase chain reaction analysis. Two dietary patterns were extracted: the healthy dietary pattern (HDP) and the Western dietary pattern; among G allele carriers, being in the highest quartiles of HDP score decreased risk of MetS (OR, Q1:3.01 [1.95-6.15], Q4:0.88 [0.39-1.78], P trend=.001), compared with those in the lowest quartile. In addition, the consumption of some vegetables, red-yellow vegetable (tomatoes, squash and carrots) and fruits by G allele carriers could decrease the risk of high fasting plasma glucose (P interaction=.003), low HDL-C (P interaction=.03) and high blood pressure (P interaction=.01) respectively. No significant interaction was observed in this study between nutrients (macronutrients, zinc, magnesium and iron) and CCND2 rs11063069 in relation to MetS or its components in this study. Our findings showed that by promoting adherence to HDP and increasing intake of some vegetables and fruits, the risk of MetS or its components reduced in G allele carriers; these associations were not observed in the AA genotype group. PMID- 29764628 TI - National preceptor development program (PDP): Influential evidence and theory. The first of a 3-part series. AB - INTRODUCTION: Priority #3 of the Canadian Experiential Education Project for Pharmacy provided evidence-based guidance for the design and implementation of a national approach to preceptor development. In this first article (of three), findings from the project and recommendations to achieve a high-quality preceptor development program (PDP) are presented. METHODS: A multi-method approach including detailed semi-structured interviews, classic literature review, and advisory committee feedback was employed. The research team performed an integrated analysis of all data to achieve the objectives of Priority #3. RESULTS: Fifteen formal interviews, 167 articles and two stakeholder meetings informed findings. Experiential Education programs exhibited commonality in content and usually delivered programs online using modules or live lectures. Not all programs required preceptor education despite it being mandated by academic accreditors. Academics' perceptions varied regarding pharmacists' baseline knowledge, skills and attitudes prior to engaging in the preceptor role. A national approach to a PDP was desired if jurisdictional content was accommodated. Copious interprofessional literature of generally fair quality did not identify superior preceptor development approaches although there were numerous descriptions of interventions. Only 29 articles measured educational outcomes. Outcomes included satisfaction rates, self-efficacy and perceived knowledge, skill retention, skill implementation and participation rates. DISCUSSION AND CONCLUSIONS: Twelve recommendations were identified to guide successful development of a national PDP. In the absence of good evidence, adult educational theory provided a basis for an effective PDP. Findings from Priority #3 may be relevant not only to pharmacy in Canada but other health professions and counterparts in other western nations with similar approaches to professional education. PMID- 29764629 TI - An open randomized controlled study comparing an online text-based scenario and a serious game by Belgian and Swiss pharmacy students. AB - INTRODUCTION: To compare online learning tools, looped, branch serious game (SG) and linear text-based scenario (TBS), among a sample of Belgian and Swiss pharmacy students. METHODS: Open randomized controlled study. The lesson was based on the case of a benign cough in a healthy child. A randomized sample of 117 students: only the Swiss students had attended a previous lecture on coughs. Participation rate, pre- and post-experience Likert scales and students' clinical knowledge were measured. RESULTS: Our primary hypothesis was demonstrated: students favored the SG even if navigation was rated as more complex, and students who performed the SG better understood the aim of pharmacist triage in case of cough. The influence of the SG appeared to be linked to the presence of a previous lecture in the curriculum. DISCUSSION AND CONCLUSION: SG and TBS are effective to teach pharmacist triage. Higher SG complexity should be used to teach the aim of pharmacist triage in the case of a specific disease and could be an alternative to simulated patients. A simpler TBS does not require a previous lecture and a debriefing to be fully effective. PMID- 29764630 TI - Faculty motivations to use active learning among pharmacy educators. AB - INTRODUCTION: Faculty motivations to use active learning have been limited to surveys evaluating faculty perceptions within active learning studies. Our objective in this study was to evaluate the relationship between faculty intrinsic motivation, extrinsic motivation, and demographic variables and the extent of active learning use in the classroom. METHODS: An online survey was administered to individual faculty members at 137 colleges and schools of pharmacy across the United States. The survey assessed intrinsic and extrinsic motivations, active learning strategies, classroom time dedicated to active learning, and faculty development resources. Bivariate associations and multivariable stepwise linear regression were used to analyze the results. RESULTS: In total, 979 faculty members completed the questionnaire (23.6% response rate). All motivation variables were significantly correlated with percent active learning use (p < 0.001). Intrinsic motivation demonstrated the highest correlation (r = 0.447) followed by current extrinsic motivations (r = 0.245) and ideal extrinsic motivations (r = 0.291). Variables associated with higher intrinsic motivation included the number of resources used (r = 0.233, p < 0.001) and the number of active learning methods used in the last year (r = 0.259, p < 0.001). Years of teaching experience was negatively associated with intrinsic motivation (r = -0.177, p < 0.001). Regression analyses confirmed the importance of intrinsic and extrinsic motivations in predicting active learning use. DISCUSSION AND CONCLUSIONS: Our results suggest that faculty members who are intrinsically motivated to use active learning are more likely to dedicate additional class time to active learning. Furthermore, intrinsic motivation may be positively associated with encouraging faculty members to attend active learning workshops and supporting faculty to use various active learning strategies in the classroom. PMID- 29764631 TI - Introduction to surgical and perioperative clinical pharmacy for third-year pharmacy students: A pilot study of an elective course. AB - INTRODUCTION: The objective of this study was to implement and assess an elective course that exposes pharmacy students to clinical pharmacy in the surgical and perioperative setting. METHODS: A blended-design elective that included synchronous and asynchronous learning was developed and offered to third-year pharmacy students. Students' knowledge and perception regarding clinical topics in perioperative pharmacy was assessed using pre- and post-course assessments, online quizzes, a journal club, and course assignments. Knowledge of pharmacy operations was assessed using course assignments and reflective journal entries. RESULTS: Pre- and post-course assessment improvement was seen in the categories of perioperative optimization of pharmacotherapy (29.1-70.1%, p=0.006), common surgical complications (45.8-91.7%, p = 0.001), and anesthetic agents (25-71.9%, p <0.001). Overall, the course was successful in increasing clinical pharmacy knowledge and was well received by students. Course evaluations were completed by 100% of students, and all rated the course as "excellent." Students demonstrated mastery of course content, though the course may not have provided optimal exposure to operating room/post-anesthesia care unit operations. DISCUSSION AND CONCLUSIONS: Students agreed that the course was valuable and helped them develop new skills otherwise not developed by the curriculum; this conclusion was supported by objective assessment data. A team-teaching model allowed for minimal resources to operate the course. Moving forward, an early lecture addressing perioperative operations may supplement an area the course was lacking. Additionally, a longer duration of operating room shadowing may provide requested opportunities for observation of direct patient care. PMID- 29764632 TI - Development and impact of a simplified approach to didactic powerpoint presentations performed in a drug information course. AB - INTRODUCTION: To describe multimedia presentation development and assess impact of use on student and educator performance in a drug information course. METHODS: Slides were modified from bullet-point format to simplified pictorial format and three-slide handouts became outlined Word documents. Student performance, via exam scores and class average, and educator evaluation scores were compared between 2013 and 2014. RESULTS: Presentation revision resulted in a similar number of slides per presentation and smaller handout packets. Class average and final exam scores decreased (86.65% vs. 85.91%, p = 0.222; 84.88% vs. 84.08%, p = 0.053) while midterm exam scores improved (85.81% vs. 87.80%, p = 0.007). Assessment of teacher effectiveness (scale of 1 = strongly disagree to 5 = strongly agree) rose from a median of 3-4 (p = 0.06). CONCLUSION: Simplifying presentations provided anecdotal value but did not impact student performance nor student perception of educator effectiveness. PMID- 29764633 TI - National preceptor development program (PDP) prototype. The third of a 3-part series. AB - INTRODUCTION: Preceptor development is critical to successful delivery of experiential learning. Although many preceptor development programs exist, a more individualized approach to training is needed. To accomplish this a national preceptor development program should be considered based on the continuing professional development model. A detailed prototype for this program has been described. METHODS: In this final installment of the series, the twelve evidence based recommendations from the first installment were utilized to construct a prototype for a preceptor development program. Over a three-month period, investigators experimented with different designs and models before approving the final prototype. RESULTS: The prototype took the form of an electronic learning platform. Several categories were integral to the design and included sections entitled preceptor spotlight, mentorship, global outreach, choose your own adventure, continuing professional development, feedback, virtual online community, highlights/advertisements, what's new, competency assessment, and frequently asked questions. A graphic was developed to depict the process by which a preceptor would navigate through the web-based learning platform. DISCUSSION: The authors purposefully maintained a creative and unlimited vision for preceptor development. This conceptual model is intended to spark discussion and augment, refine, or develop entirely innovative ideas to meet preceptor needs. Development of a preceptor development platform could foster improved competency performance, enhanced interest in learning, and promote continuing professional development. CONCLUSION: With a greater focus on experiential education in pharmacy, the need for a national preceptor development resource is only expected to increase. PMID- 29764634 TI - First generation college students demographic, socio-economic status, academic experience, successes, and challenges at pharmacy schools in the United States. AB - INTRODUCTION: Identify the demographic, socio-economic status, academic performance, and challenges of first generation college students (FGCS) enrolled in pharmacy schools. Investigate students' perception on the strengths of available resources to support FGCS during their tenure in pharmacy school. METHODS: About 342 FGCS and 248 non-FGCS (NFGCS) from 24 pharmacy schools participated in an online anonymous survey that evaluated students' demographics and socio-economic background, commitment to the pharmacy profession, strength of institutional support, and school experience. Students' responses were analyzed using t-tests for continuous variables and chi-square tests for categorical variables. RESULTS: FGCS in pharmacy school are predominantly Caucasians (57.9%) and female (69%). About 15.5% of them come from families living below the federal poverty level; 2.5 times higher than their NFGCS counterparts (6%). While 35.6% of NFGCS come from families earning more than $100,000 per year, only 9.1% of FGCS belong to this group. No statistical difference between the grade point average of FGCS and NFGCS was found. DISCUSSION AND CONCLUSIONS: Although most FGCS come from a lower socio-economic background and experience many challenges throughout their tenure in pharmacy school, they still achieve academically as well as their NFGCS counterpart. The United States is rapidly becoming a more racially and ethnically diverse nation, therefore, it is critical that new strategies be designed to bring a stronger representation of minority groups in the field of pharmacy for the years to come. PMID- 29764635 TI - Ten year experience with student pharmacist research within a health system and education center. AB - INTRODUCTION: Skills gained from research experience allow student pharmacists to evolve as practitioners, innovators and perpetual learners in an increasingly complex healthcare environment. Data published regarding pharmacy resident research are focused on external dissemination rates and research programs. Little is published regarding student research. METHODS: This descriptive study was a five-year before and after comparison between the existing co-curricular model and a new longitudinal, 12-month research advanced pharmacy practice experience (L-APPE) model for student pharmacist research. The objective was to describe the development and transition to the L-APPE and compare the models in external dissemination rates and preceptor-classified impact on patient care. Preceptors were surveyed to characterize the impact on the health care institution. RESULTS: Over a ten-year period, 65 fourth year students engaged in research. From 2006-2011, 28 students (43.4% of student cohort) completed co curricular research projects. From 2011-2016, 37 students (40.2% of student cohort) completed the L-APPE. The number of national poster presentations increased 6-fold with the L-APPE, from 6 (21.4%) to 36 (97.3%) (p < 0.01). Combined posters and peer reviewed publications had a 350% higher occurrence (RR 4.5, 95% CI 1.9-10.9; p < 0.01). Preceptors classified L-APPE projects 1.5 times more often as leading to a change or affirmation of a practice model or prescribing pattern (83.3% vs 57.1%; p = 0.03). DISCUSSION AND CONCLUSIONS: The L APPE research model increased external dissemination rates and resulted in more meaningful practice model or prescribing pattern benefits. Additional study of pharmacy student research is warranted. PMID- 29764636 TI - Longitudinal evaluation of student professionalism throughout the professional didactic curriculum of a pharmacy program. AB - INTRODUCTION: The purpose of this study is to evaluate longitudinal changes in professionalism of pharmacy students across the curriculum using a validated instrument that minimizes ceiling effect. METHODS: The Professionalism Assessment Tool (PAT) was administered to first, second, and third year PharmD students twice throughout the first and second professional year (P1 and P2) and three times throughout the third professional year (P3). RESULTS: Longitudinal increases in all five domains of professionalism of the PAT were noted as students progressed through each year of the didactic curriculum. Most demographic categories (sex, age, employment in a pharmacy, and number of other degrees held) of respondents did not affect self-assessment results. Two demographic categories, the number of student organizations and age group, had statistically significant impact on self-reported professionalism. CONCLUSIONS: This pilot study showed longitudinal improvement in student self-assessment of professionalism over the course of the didactic curriculum at one school. Self assessment of pharmacy student professionalism increased over the course of the didactic curriculum and was not affected by most demographics. PMID- 29764637 TI - Association between physical activity and grade point average among a cohort of pharmacy students in didactic years. AB - INTRODUCTION: The physical activity (PA) behavior and its association with academic performance has not been examined among professional pharmacy (PharmD) students in didactic years. METHODS: A survey was administered to a cohort of PharmD students at University of Houston that collected information related to each student's PA and grade point average (GPA). Correlation analyses and multiple regression were performed to evaluate factors associated with GPA. RESULTS: The response rate was 58.1%. Stepwise multiple regression indicated that learning capacity and gender were major predictors for GPA. There was no significant association between PA and GPA. DISCUSSION AND CONCLUSIONS: Higher learning capacity and lower body mass index (BMI) were associated with higher GPA in PharmD students in their didactic years. Strategies such as engaging students in moderate to vigorous PA may enhance learning capacity and lower BMI; this may further positively influence students' GPA. In addition to an emphasis on academic competence, pharmacy education that can better incorporate exercise would help students establish regular PA behaviors. This may improve their health outcomes and facilitate future patient counseling practices. PMID- 29764638 TI - Health literacy of student pharmacists. AB - INTRODUCTION: The primary purpose of this study was to assess the health literacy levels of doctorate of pharmacy students. A secondary objective was to determine if a correlation exists between age, degree prior to pharmacy school, work experience, and health literacy status among these students. METHODS: Participants were first year doctorate of pharmacy students at an accredited college of pharmacy in the Southwestern United States. The design was cross sectional. Health literacy scores were collected using the Newest Vital Sign (NVS) in English. Health literacy was dichotomized with a score of 0-3 indicating inadequate and 4-6 indicating adequate. A two sample t-test or Fisher's exact test was used to compare cofactors between health literacy groups. RESULTS: Of the 72 first year students, 64 (88.9%) participated. The median NVS score was 5 (lower quartile 5, upper quartile 6). Nearly 90% of students (n = 57) obtained a score of ''always adequate literacy.'' Student age, having a degree before pharmacy school, nor healthcare work experience were significantly different between the two groups. DISCUSSION: If students enter pharmacy school with a high level of health literacy, they may have difficulties relating to and appropriately educating patients with low health literacy. Knowing this information, we can tailor our teaching about health literacy in curriculums to include strategies that assist students to understand what patients with low heath literacy may experience when interacting with the healthcare system. CONCLUSIONS: Nearly all student pharmacists in the study displayed high health literacy and no correlations to collected characteristics were noted. PMID- 29764639 TI - Web-based versus face-to-face interprofessional team encounters with standardized patients. AB - BACKGROUND: Challenges exist in developing interprofessional education (IPE) activities including coordinating schedules and obtaining appropriate space for teams to work. Virtual worlds have been explored as a means to overcome some of these challenges. We sought to develop a web-based interprofessional team interaction with a standardized patient (SP), as compared to a face-to-face SP interaction, focusing on the competency area of interprofessional communication. INTERPROFESSIONAL EDUCATION ACTIVITY: Interprofessional teams of students were randomized to complete a web-based or face-to-face SP encounter. The web-based encounter was conducted via video conference that students accessed using their own electronic device. Interprofessional communication was evaluated by faculty observers and the SPs. Participants of the web-based encounter also completed a perceptions questionnaire. DISCUSSION: Interprofessional communication was rated as average/above average by the authors and SPs. Perceptions of the web-based encounter were mixed with not all students willing to complete such an encounter again despite finding it enjoyable and a positive learning experience. The need for adequate preparation was identified, including the opportunity to review the patient case before the encounter. IMPLICATIONS: The web-based SP encounter afforded students the opportunity to utilize communication technology to provide patient-centered care while collaborating as an interprofessional team. Video conferencing presents an opportunity to bypass some logistical challenges in scheduling IPE experiences and can be implemented as a co-curricular activity, avoiding course revisions. Additional studies are needed to further explore student and patient perspectives and clarify when, and with what level of trainees, the experiences are most valuable. PMID- 29764640 TI - Development, implementation, and impact of a collaborative junior faculty engagement and professional growth program: The Young Faculty Leadership Initiative. AB - PURPOSE: To develop, implement, and evaluate the effect of a faculty engagement and professional growth program targeted at junior faculty members. EDUCATIONAL ACTIVITY: A faculty engagement and growth program based on adult learning theory was piloted in a clinical sciences department. Effect of the model was evaluated using a pre/post-survey evaluating faculty output and work engagement using the Utrecht Work Engagement Scale (UWES). FINDINGS: Average number of publications/projects with cross-campus collaboration increased (0.58 versus 1.25, P = 0.03, 95%CI 0.059-1.264). Involvement in national/state organizations, number of accepted poster presentations, and grants submitted and/or funded all increased (p>0.05). Total UWES score increased (4.13 vs. 4.495 p = 0.21) with the greatest subscale increase in vigor (3.833 vs 4.347, P = 0.1). SUMMARY: A faculty engagement and growth program targeting junior faculty members using adult learning theory as a framework may provide a novel and economic way for schools to support the development of these critical team members. PMID- 29764641 TI - Student preparation time for traditional lecture versus team-based learning in a pharmacotherapy course. AB - BACKGROUND AND PURPOSE: Determine how much time students spent preparing for traditional lecture versus team-based learning (TBL) for a pharmacotherapy course and determine if time spent in each pedagogy was within stated expectations for the course. EDUCATIONAL ACTIVITY AND SETTING: Instructors used a combination of traditional lecture and TBL to deliver material. Before each lecture, instructors recorded the amount of time students spent preparing for each method using a one question clicker-response survey. FINDINGS: Instructors delivered 16 hours of TBL, 32 hours of traditional lecture, and eight hours of a mix of TBL and traditional lecture. The median of students completing the survey each week was 89. A large percentage of the class (40.9%) did not prepare for traditional lecture while only 3.4% did not prepare for TBL. About 61% of students spent between 30 min and two hours preparing for a two-hour TBL session and only 10% spent more than three hours preparing. DISCUSSION AND SUMMARY: Results of this project show students spend little time preparing for traditional lectures without in-class accountability, which may give students the perception that TBL requires too much preparation time. PMID- 29764642 TI - Journal Club Standardization Tool: Helping participants get the JIST. AB - BACKGROUND AND PURPOSE: Clinical pharmacy practice relies on the ability to critically evaluate clinical trials and apply their findings to patient care. The development of these skills begins in pharmacy school, develops during residency programs, and continues to mature while practicing clinical pharmacy. The purpose of this analysis was to evaluate student attitudes and perceptions following implementation of the Journal Interpretation Summary Tool (JIST) into a pharmacy curriculum. EDUCATIONAL ACTIVITY AND SETTING: The "journal club" is an activity implemented in many curricula with the intent to hone these skills. The JIST is a standardized template aimed at improving the consistency of a journal review by organizing major elements of a trial, allowing the facilitator and participants to navigate through key information and guide the journal club discussion. FINDINGS: Implementation of JIST resulted in an increased level of confidence for a majority of students (63.3%) when conducting and critically evaluating a journal article. More than 80% of students reported they were better able to critically evaluate a published article using JIST, and 91.9% reported JIST provided structure to the journal club process. DISCUSSION AND SUMMARY: JIST provides the appropriate level of guidance and structure, particularly for the novice pharmacy student or pharmacist. The use of a standardized tool for journal club evaluation may lead to further improvements in applying literature to practice and other skills surrounding the critique of medical literature. PMID- 29764643 TI - Exploring an integrated curriculum in pharmacy: Educators' perspectives. AB - BACKGROUND AND PURPOSE: Lack of consensus regarding the benefits of an integrated curriculum, and ambiguity concerning what is being integrated within a pharmacy curriculum exists, but how an integrated curriculum is viewed, epistemologically, and subsequently incorporated into teaching practice has not been investigated. This study explores how educators conceptualize, experience and enact curricula integration both pedagogically and organizationally. EDUCATIONAL ACTIVITY AND SETTING: In-depth qualitative interviews with faculty members purposively sampled for maximum variation in disciplinary background and teaching experience were undertaken at a single site. Interviews addressed two research questions: how pharmacy educators understand an integrated curriculum and educators' experiences of it. FINDINGS AND DISCUSSION: Analysis of the interview data suggests four essential meanings of integration: integration as a method for organizing teaching and learning; integration as enacted by self and others; integration as tension between conflicting knowledge domains; and integration as an impossible concept to apply to teaching practice. Analysis suggests that integration is an abstract rather than enacted concept and although integration is viewed as learner-centered, integration is complex and associated with a loss of in-depth learning. SUMMARY: Differences in how faculty members conceptualize the purpose and effects of integration mean that the level and type of integration reported varied. A clearer understanding of the rationale for change, and methods for better applying theory of integration to teaching practice, may be needed to achieve curriculum standards required by bodies accrediting undergraduate pharmacy programs. PMID- 29764644 TI - Influence of an ambulatory care elective on career interest and perception of ambulatory care practice. AB - BACKGROUND AND PURPOSE: Ambulatory care is a growing area of pharmacy practice. Previous studies have shown that an ambulatory care elective course may improve student understanding and interest in ambulatory care, but it is unknown if an elective course may impact a student's intended career choice. The purpose of this study is to assess the impact of an ambulatory care elective on student understanding of ambulatory care pharmacy practice, career interest, and interest in residency training. EDUCATIONAL ACTIVITY AND SETTING: A three-credit-hour ambulatory care elective course was offered to pharmacy students in their third professional year of a four-year program at a private school of pharmacy in Fall 2015. All students in their third year of pharmacy school, including those enrolled in an ambulatory care elective course, were surveyed electronically at the beginning and end of the fall semester. Elective student responses were compared to non-elective student responses, and student responses were compared pre- versus post-semester within each group. FINDINGS: Twenty-five of 72 non elective students and 13 of 14 elective students responded to both surveys. Significantly more elective students felt they understood the daily responsibilities (p=0.003) and the role of the ambulatory care pharmacist (p = 0.001) in comparison to non-elective students post-semester. Interest in residency training or a career in ambulatory care pharmacy was not significantly different among groups pre- or post-semester. SUMMARY: An ambulatory care elective course increased perceived understanding of ambulatory care pharmacy but did not have a significant impact on student interest in residency training or a career in ambulatory care. PMID- 29764645 TI - Design and short-term impact of an event to promote careers in clinical pharmacy. AB - BACKGROUND AND PURPOSE: There is a role for local pharmacy organizations to promote clinical pharmacy and increase awareness to both potential and current pharmacy students. The Greater Milwaukee College of Clinical Pharmacy (GMCCP) chapter sought to promote clinical pharmacy amongst current and prospective pharmacy students to increase the knowledge, awareness, and interest in clinical pharmacy. EDUCATIONAL ACTIVITY AND SETTING: Subcommittee members designed programming to introduce the basics of clinical pharmacy. Students from three schools of pharmacy and more than 40 colleges in the region were invited to the event. Didactic and discussion-based content was developed. Pharmacists from GMCCP were solicited as presenters, along with a current pharmacy student and resident. Participants were asked to complete pre-event and post-event surveys to assess their awareness of and interest in clinical pharmacy. Volunteer pharmacists were also surveyed after the event. FINDINGS: Twenty-eight individuals attended the event. Nineteen students completed both the pre- and post-survey. The comparison between median score pre- and post-event was analyzed with the Wilcoxon Signed-Rank test. Students' awareness and knowledge of clinical pharmacy improved after attending the event. Students' interest in a career in clinical pharmacy also increased after attending the event. Nine of the thirteen volunteer breakout session pharmacists (69%) responded to the post-event survey. The majority strongly agreed that participants were interested in learning about their area of practice and asked meaningful questions appropriate for their area of practice. DISCUSSION AND CONCLUSIONS: The Exploring Careers in Clinical Pharmacy event increased awareness of clinical pharmacy career choices available within the profession of pharmacy. Local, regional, and national pharmacy organizations may consider utilizing the diverse talent of their membership and collaborate with colleges of pharmacy or other organizations to impact the knowledge, awareness, and interest in clinical pharmacy as a future career choice for pre-pharmacy and current pharmacy students. PMID- 29764647 TI - A Preceptor competency framework for pharmacists. Part 2 of a 3-part series. AB - BACKGROUND: Pharmacy faculties in Canada are transitioning to the doctor of pharmacy degree which will require approximately one-third of curricula contact time in experiential education. Preceptors will be responsible for delivering this experiential component and many have received little or no training in how to be an effective educator. Although training is mandated through accreditation standards, competencies to serve as a foundation for preceptor development have yet to be created. The objectives of this review were to develop core competencies of an effective preceptor and to identify performance indicators to guide preceptor growth METHODS: A literature review of teaching competencies from pharmacy, medicine, nursing, and higher education was completed. Competencies and performance indicators were extracted and analyzed for recurring themes. A framework was proposed and refined through consultation with Canadian and United States pharmacy stakeholder groups. RESULTS: Six-hundred and thirty-nine articles were identified through the review, of which only eight articles directly addressed preceptor competencies and/or related performance indicators. These articles were reviewed in detail. Regardless of discipline, several recurring themes emerged. Themes were collated and culminated in nine competencies and supporting performance indicators for preceptors. Competencies address important interpersonal, professional, and educational knowledge, skills, and attitudes of an effective educator. IMPLICATIONS: Defining competence and its performance indicators is essential to help preceptors effectively fulfill their professional responsibility of developing competent graduates. The competencies and performance indicators should be further refined through stakeholder engagement. This framework could be foundational to national preceptor development program, preceptor recruitment, and quality assurance programs. PMID- 29764646 TI - Association between attendance and overall academic performance on a module within a professional pharmacy degree. AB - BACKGROUND AND PURPOSE: As the higher education (HE) classroom begins to adopt newer internet-based technologies, the relationship between attendance and performance needs to be re-evaluated, particularly for professional degree courses such as pharmacy. In the present study, we aimed to establish if an association exists between attendance at all timetabled classes and academic performance, in a Clinical Pharmacology and Therapeutics (CPT) module, as part of the Master of Pharmacy (MPharm) degree course at Ulster University. EDUCATIONAL ACTIVITY AND SETTING: Data on attendance, final examination and coursework performance were collected over two academic years (2013-14 and 2014-15) of the CPT module at Ulster. In total 67 students were analysed. The MPharm degree at Ulster University implements an attendance policy, both as a pastoral support tool and to reinforce the need for professional conduct as a pharmacist. FINDINGS: Student (2013-14 and 2014-15, n = 35 and 32, respectively) attendance on the module across both year groups was approximately 80%. We observed positive, and statistically significant relationships between attendance and performance on the examination, and especially in the coursework elements of the module. Student failure (below 40%) in the final examination was linked to attendance below an 80% threshold in nine of 12 cases. Reasons for not attending class varied, but illness was unquestionably the most commonly cited extenuation. DISCUSSION: Taken together, these data confirm a convincing association between student attendance and academic achievement. SUMMARY: Our studies promote the use of attendance monitoring policies for professional degree courses such as pharmacy. PMID- 29764648 TI - Rapid evolution to host plant resistance by an invasive herbivore: soybean aphid (Aphis glycines) virulence in North America to aphid resistant cultivars. AB - Preventing rapid evolution of herbivores to plant traits that confer resistance is an area of active research for applied entomologists. The subfield of insect resistance management (IRM) uses elements of population genetics and ecology to prevent increases in the frequency of virulent (i.e. resistant) sub-populations of an insect pest. Efforts to delay such an increase include using highly lethal toxins (i.e., a high dose), combining multiple resistance traits in one cultivar (i.e., pyramids), and using susceptible plants (i.e. a refuge) within or near plantings of the resistant crop. Even if fully implemented, theoretical models suggest that IRM plans for asexually-reproducing insects (e.g. aphids) cannot limit the frequency of resistance to provide sustainable use of a pest-resistant cultivar. We discuss how feeding by conspecifics aphids induces susceptibility such that a "within plant" refuge is created, allowing both virulent and avirulent (i.e. susceptible) populations to persist. We use the soybean aphid (Aphis glycines Matsumura), and the rapid occurrence of virulence in the US to resistant cultivars of soybean (Glycine max). We describe how feeding by A. glycines on soybeans alters the quality of the plant as a host. These systemic changes to the plants' physiology allow avirulent A. glycines to thrive on resistant cultivars. We explore how the induction of susceptibility by a herbivore can slow an increase in the frequency of virulent populations to resistant host plants. We suggest that a within plant refuge, combined with standard IRM practices, can allow for sustainable use of plant resistance to asexually-reproducing insect pests. PMID- 29764649 TI - The biology and prevalence of fungal diseases in managed and wild bees. AB - Managed and wild bees, whether solitary or social have a plethora of microbial associations that vary in their influence on the health of the bees. In this review, we summarise our current knowledge of aspects of the biology and ecology of bee associated fungi. The biology of bees that fungi are associated with are described, and the likely influences on fungal transmission are discussed. There is a clear disparity in research on fungi associated with managed compared to wild bees, leaving gaps in our understanding of fungal pathogen epidemiology. Translocation of bees to meet global pollination needs will increase exposure of bees to exotic pathogens. Thus, filling these gaps is an important step towards mitigating the impact of fungal diseases in bees. PMID- 29764650 TI - Feedbacks between nutrition and disease in honey bee health. AB - Declines in honey bee health have been attributed to multiple interacting environmental stressors; among the most important are forage/nutrition deficits and parasites and pathogens. Recent studies suggest poor honey bee nutrition can exacerbate the negative impacts of infectious viral and fungal diseases, and conversely, that common honey bee parasites and pathogens can adversely affect bee nutritional physiology. This sets up the potential for harmful feedbacks between poor nutrition and infectious disease that may contribute to spiraling declines in bee health. We suggest that improving bees' nutritional resilience should be a major goal in combating challenges to bee health; this approach can buffer bees from other environmental stressors such as pathogen infection. PMID- 29764651 TI - Recently identified bee viruses and their impact on bee pollinators. AB - Bees are agriculturally and ecologically important plant pollinators. Recent high annual losses of honey bee colonies, and reduced populations of native and wild bees in some geographic locations, may impact the availability of affordable food crops and the diversity and abundance of native and wild plant species. Multiple factors including viral infections affect pollinator health. The majority of well characterized bee viruses are picorna-like RNA viruses, which may be maintained as covert infections or cause symptomatic infections or death. Next generation sequencing technologies have been utilized to identify additional bee-infecting viruses including the Lake Sinai viruses and Rhabdoviruses. In addition, sequence data is instrumental for defining specific viral strains and characterizing associated pathogenicity, such as the recent characterization of Deformed wing virus master variants (DWV-A, DWV-B, and DWV-C) and their impact on bee health. PMID- 29764652 TI - Genetics and physiology of Varroa mites. AB - Varroa destructor is the primary biological threat to domesticated honey bee colonies in much of the world, impacting host fitness both directly and by transmitting RNA viruses. Genomic, proteomic, and functional-genetic resources provide a framework for Varroa biology. When coupled with physiological analyses of development, host finding, and reproduction, these resources reveal general traits of arthropods and offer new strategies for mite control. Efforts to develop novel controls are focused on efficacy, efficient delivery, and the avoidance of both host impacts and the swift evolution of resistance by mites. PMID- 29764653 TI - Interaction effects of different drivers of wild bee decline and their influence on host-pathogen dynamics. AB - Wild bee decline is a multi-factorial problem, yet it is crucial to understand the impact of a single driver. Hereto the interaction effects of wild bee decline with multiple natural and anthropogenic stressors need to be clear. This is also true for the driver 'pathogens', as stressor induced disturbances of natural host pathogen dynamics can unbalance settled virulence equilibria. Invasive species, bee domestication, habitat loss, climate changes and insecticides are recognized drivers of wild bee decline, but all influence host-pathogen dynamics as well. Many wild bee pathogens have multiple hosts, which relaxes the host-density limitation of virulence evolution. In conclusion, disturbances of bee-pathogen dynamics can be compared to a game of Russian roulette. PMID- 29764654 TI - Drivers of colony losses. AB - Over the past decade, in some regions of the world, honey bee (Apis mellifera L.) colonies have experienced rates of colony loss that are difficult for beekeepers to sustain. The reasons for losses are complex and interacting, with major drivers including Varroaand related viruses, pesticides, nutrition and beekeeper practices. In these endeavors it has also become apparent that defining a dead colony, and singling out the effects of specific drivers of loss, is not so straightforward. Using the class of neonicotinoid pesticides as an example we explain why quantifying risk factor impact at the colony level is at times elusive and in some cases unpractical. In this review, we discuss the caveats of defining and quantifying dead colonies. We also summarize the current leading drivers of colony losses, their interactions and the most recent research on their effects on colony mortality. PMID- 29764656 TI - Rapid evolution of aphid pests in agricultural environments. AB - Aphids constitute a major group of crop pests that inflict serious damages to plants, both directly by ingesting phloem and indirectly as vectors of numerous diseases. In response to intense and repeated human-induced pressures, such as insecticide treatments, the use of resistant plants and biological agents, aphids have developed a series of evolutionary responses relying on adaptation and phenotypic plasticity. In this review, we highlight some remarkable evolutionary responses to anthropogenic pressures in agroecosystems and discuss the mechanisms underlying the ecological and evolutionary success of aphids. We outline the peculiar mode of reproduction, the polyphenism for biologically important traits and the diverse and flexible associations with microbial symbionts as key determinants of adaptive potential and pest status of aphids. PMID- 29764655 TI - Effects of the gut parasite Nosema ceranae on honey bee physiology and behavior. AB - The common and widespread parasite Nosema ceranae is considered a major threat to the Western honey bee at both the individual and colony levels. Several studies demonstrated that infection by this parasite may affect physiology, behavior, and survival of honey bees. N. ceranae infection impairs midgut integrity and alters the energy demand in honey bees. The infection can also significantly suppress the bee immune response and modify pheromone production in worker and queen honey bees leading to precocious foraging. However, the presence of N. ceranae is not systematically associated with colony weakening and honey bee mortality. This variability depends upon parasite or host genetics, nutrition, climate or interactions with other stressors such as environmental contaminants or other parasites. PMID- 29764657 TI - Does host plant adaptation lead to pesticide resistance in generalist herbivores? AB - Most herbivorous arthropods feed on one or a few closely related plant species; however, certain insect and mite species have a greatly expanded host range. Several of these generalists also show a remarkable propensity to evolve resistance to chemical pesticides. In this review, we ask if the evolution of mechanisms to tolerate the diversity of plant secondary metabolites that generalist herbivores encounter, has pre-adapted them to resist synthetic pesticides. Critical examination of the evidence suggests that a generalist life style per se is not a predictor of rapid resistance evolution to pesticides. Rather the prevalence of pesticide resistance in generalist herbivores probably reflects their economic importance as pests and thus the strong selection imposed by intensive pesticide use. PMID- 29764658 TI - Transgenerational effects of insecticides-implications for rapid pest evolution in agroecosystems. AB - Although pesticides are a major selective force in driving the evolution of insect pests, the evolutionary processes that give rise to insecticide resistance remain poorly understood. Insecticide resistance has been widely observed to increase with frequent and intense insecticide exposure, but can be lost following the relaxation of insecticide use. One possible but rarely explored explanation is that insecticide resistance may be associated with epigenetic modifications, which influence the patterning of gene expression without changing underlying DNA sequence. Epigenetic modifications such as DNA methylation, histone modifications, and small RNAs have been observed to be heritable in arthropods, but their role in the context of rapid evolution of insecticide resistance remain poorly understood. Here, we discuss evidence supporting how: firstly, insecticide-induced effects can be transgenerationally inherited; secondly, epigenetic modifications are heritable; and thirdly, epigenetic modifications are responsive to pesticide and xenobiotic stress. Therefore, pesticides may drive the evolution of resistance via epigenetic processes. Moreover, insect pests primed by pesticides may be more tolerant of other stress, further enhancing their success in adapting to agroecosystems. Resolving the role of epigenetic modifications in the rapid evolution of insect pests has the potential to lead to new approaches for integrated pest management as well as improve our understanding of how anthropogenic stress may drive the evolution of insect pests. PMID- 29764659 TI - Mechanisms of aphid adaptation to host plant resistance. AB - Host-plant resistant (HPR) crops can play a major role in preventing insect damage, but their durability is limited due to insect adaptation. Research in basal plant resistance provides a framework to investigate adaptation against HPR. Resistance and adaptation are predicted to follow the gene-for-gene and zigzag models of plant defense. These models also highlight the importance of insect effectors, which are small molecules that modulate host plant defense signaling. We highlight research in insect adaptation to plant resistance, and then draw parallels to virulence adaptation. We focus on virulent biotype evolution within the Aphididae, since this group has the highest number of described virulent biotypes. Understanding how virulence occurs will lead to more durable insect management strategies and enhance food production and security. PMID- 29764660 TI - Genomic mechanisms of sympatric ecological and sexual divergence in a model agricultural pest, the European corn borer. AB - The European corn borer, Ostrinia nubilalis, is a model species for elucidating mechanisms underlying adaptively differentiated subpopulations in the face of reciprocal gene flow, and is a major pest of cultivated maize in North America and Eurasia. Strains are characterized by different pheromone communication systems in combination with voltinism strains that are adapted to distinct local climate and photoperiod through adjustments in diapause traits. However, only partial barriers to inter-strain hybridization exist in areas of sympatry. Recent research shows that genes governing important strain-specific isolating traits are disproportionately located on the Z-chromosome. Furthermore, co-adapted combinations of some of these genes are non-recombining due to location within a large chromosomal inversion, and assist in maintaining strain integrity despite hybridization. PMID- 29764661 TI - Interactions between pesticides and pathogen susceptibility in honey bees. AB - There exist a variety of factors that negatively impact the health and survival of managed honey bee colonies, including the spread of parasites and pathogens, loss of habitat, reduced availability or quality of food resources, climate change, poor queen quality, changing cultural and commercial beekeeping practices, as well as exposure to agricultural and apicultural pesticides both in the field and in the hive. These factors are often closely intertwined, and it is unlikely that a single stressor is driving colony losses. There is a growing consensus, however, that increasing prevalence of parasites and pathogens are among the most significant threats to managed bee colonies. Unfortunately, improper management of hives by beekeepers may exacerbate parasite populations and disease transmission. Furthermore, research continues to accumulate that describes the complex and largely harmful interactions that exist between pesticide exposure and bee immunity. This brief review summarizes our progress in understanding the impact of pesticide exposure on bees at the individual, colony, and community level. PMID- 29764662 TI - Biological and genetic features of introduced aphid populations in agroecosystems. AB - In agroecosystems, introduced aphids that reproduce by obligate parthenogenesis (OP) show strong biased representation of a few genotypes (superclones), whereas species with cyclical parthenogenesis (CP) exhibit the opposite trend with many unique genotypes. We analyzed the biological and genetic features of 23 different aphid species introduced in different geographic areas and climates, finding putative superclones in about 60% of them. We have examined the proximal causes for aphid establishment and spread after their introduction, and found that OP, host availability, and phenotypic plasticity are among the main variables underpinning the ability of aphids to succeed in new geographic areas, which may explain the high potential for invasion in this group of pest insects. PMID- 29764663 TI - Tropilaelaps mite: an emerging threat to European honey bee. AB - The risk of transmission of honey bee parasites has increased substantially as a result of trade globalization and technical developments in transportation efficacy. Great concern over honey bee decline has accelerated research on newly emerging bee pests and parasites. These organisms are likely to emerge from Asia as it is the only region where all 10 honey bee species co-occur. Varroa destructor, an ectoparasitic mite, is a classic example of a pest that has shifted from A. cerana, a cavity nesting Asian honey bee to A. mellifera, the European honey bee. In this review, we will describe the potential risks to global apiculture of the global expansion of Tropilaelaps mercedesae, originally a parasite of the open-air nesting Asian giant honey bee, compared to the impact of V. destructor. PMID- 29764664 TI - Agriculture sows pests: how crop domestication, host shifts, and agricultural intensification can create insect pests from herbivores. AB - We argue that agriculture as practiced creates pests. We use three examples (Corn leafhopper, Dalbulus maidis; Western corn rootworm, Diabrotica virgifera virgifera; Cotton fleahopper, Pseudatomoscelis seriatus) to illustrate: firstly, how since its origins, agriculture has proven conducive to transforming selected herbivores into pests, particularly through crop domestication and spread, and agricultural intensification, and; secondly, that the herbivores that became pests were among those hosted by crop wild relatives or associates, and were pre adapted either as whole species or component subpopulations. Two of our examples, Corn leafhopper and Western corn rootworm, illustrate how following a host shift to a domesticated host, emergent pests 'hopped' onto crops and rode expansion waves to spread far beyond the geographic ranges of their wild hosts. Western corn rootworm exemplifies how an herbivore-tolerant crop was left vulnerable when it was bred for yield and protected with insecticides. Cotton fleahopper illustrates how removing preferred wild host plants from landscapes and replacing them with crops, allows herbivores with flexible host preferences to reach pest level populations. We conclude by arguing that in the new geological epoch we face, the Anthropocene, we can improve agriculture by looking to our past to identify and avoid missteps of early and recent farmers. PMID- 29764665 TI - Rapid evolution in insect pests: the importance of space and time in population genomics studies. AB - Pest species in agroecosystems often exhibit patterns of rapid evolution to environmental and human-imposed selection pressures. Although the role of adaptive processes is well accepted, few insect pests have been studied in detail and most research has focused on selection at insecticide resistance candidate genes. Emerging genomic datasets provide opportunities to detect and quantify selection in insect pest populations, and address long-standing questions about mechanisms underlying rapid evolutionary change. We examine the strengths of recent studies that stratify population samples both in space (along environmental gradients and comparing ancestral vs. derived populations) and in time (using chronological sampling, museum specimens and comparative phylogenomics), resulting in critical insights on evolutionary processes, and providing new directions for studying pests in agroecosystems. PMID- 29764666 TI - Relevance of wild and managed bees for human well-being. AB - Wild and managed bees provide pollination services to both crops and wild plants, and a variety of other services from which humans benefit. We summarize the most important and recent findings on bees as providers of provisioning, regulating and cultural ecosystem services. With comprehensive literature searches, we first identified ten important bee species for global pollination of crops, which include wild and managed honey bees, bumble bees, orchard-, cucumber- and longhorn bees. We second summarized bee-dependent ecosystem services to show how bees substantially contribute to food security, medical resources, soil formation or spiritual practices, highlighting their wide range of benefits for human well being and to identify future research needs. PMID- 29764667 TI - Bacterial pathogens of bees. AB - Pollination is an indispensable ecosystem service provided by many insects, especially by wild and managed bee species. Hence, reports on large scale honey bee colony losses and on population declines of many wild bees were alarming and resulted in increased awareness of the importance of bee health and increased interest in bee pathogens. To serve this interest, this review will give a comprehensive overview on bacterial bee pathogens by covering not only the famous pathogens (Paenibacillus larvae, Melissococcus plutonius), but also the orphan pathogens which have largely been neglected by the scientific community so far (spiroplasmas) and the pathogens which were only recently discovered as being pathogenic to bees (Serratia marcescens, Lysinibacillus sphaericus). PMID- 29764669 TI - Editorial overview: Ecology: Ecological adaptation in agroecosystems: novel opportunities to integrate evolutionary biology and agricultural entomology. PMID- 29764670 TI - Editorial overview: Parasites/parasitoids/biological control: Bee health in the modern age: a major concern. PMID- 29764668 TI - The role of the gut microbiome in health and disease of adult honey bee workers. AB - The role of the gut microbiome in animal health has become increasingly evident. Unlike most other insects, honey bees possess a highly conserved and specialized core gut microbiome, which consists of nine bacterial species and is acquired mostly through social transmission. Five of these species are ubiquitous in honey bees and are also present in bumble bees. Recent studies have shown that the bee gut microbiome plays a role in metabolism, immune function, growth and development, and protection against pathogens. Disruption of the gut microbiome has also been shown to have detrimental effects on bee health. Overall, evidence suggests that the gut microbiome plays an important role in bee health and disease. PMID- 29764672 TI - The global voice of diabetes. PMID- 29764671 TI - Stroke type and severity in patients with subclinical atrial fibrillation: An analysis from the Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT). AB - BACKGROUND: The Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial (ASSERT) demonstrated that subclinical atrial fibrillation (SCAF) was associated with a 2.5-fold increased risk of stroke. However, the absolute stroke rate was only 1.7% per year and fewer than 20% patients with stroke had SCAF in the preceding 30 days. This raises the possibility that SCAF is merely a risk marker for stroke rather than the cause. Systematic characterization of stroke subtypes among patients with SCAF would help clarify this issue. METHODS: All ischemic strokes that occurred in the ASSERT trial were blindly adjudicated by stroke neurologists, classified as cortical versus subcortical, and subtyped using modified TOAST criteria. Stroke severity was measured using the modified Rankin Score. RESULTS: Of the 44 participants who had an ischemic stroke, 14 had SCAF before stroke. Among patients with SCAF who had stroke, 57% of strokes (n = 8) were judged to be cardioembolic, 36% to be lacunar (n = 5), and 7% (n = 1) to be large artery disease. However, of 5 patients who had SCAF detected within 30 days before their index stroke, 4 patients had a cardioembolic stroke. The average duration of SCAF in these 4 patients was 6.0 +/- 6.1 h/d. The modified Rankin score at 30 days was similar between patients with (2.7 +/- 2.3) and without SCAF (2.3 +/- 2.0; P = .68). CONCLUSIONS: In patients with SCAF and stroke, SCAF seems probably causal in many cases; however, in more than 40%, it seems to be acting only as a risk marker. PMID- 29764673 TI - Comparison between thromboelastography and conventional coagulation test: Should we abandon conventional coagulation tests in polytrauma patients? AB - INTRODUCTION: TEG provides an in-vivo assessment of viscoelastic clot strength in whole blood compared with CCT, which may not reflect the influence of platelets. The aim of this study was to compare TEG vs. CCT in trauma patients stratified by mechanism of injury (MOI) and pre-existing coagulation status. METHODS: A retrospective, observational study of 230 polytrauma patients admitted to a University Hospital Level 1 Trauma Center, with TEG and CCT on admission stratified by MOI: multiple trauma (MT), isolated traumatic brain injury (TBI) or MT+TBI. Statistical analysis included correlation between TEG and CCT in all groups and a subgroup analysis of anticoagulated patients. Data were analyzed with ANOVA, Spearman and lineal regression when appropriate. Statistical significance was accepted at P<0.05. RESULTS: TEG was normal in 28.7%, hypercoagulable in 68.3%, hypocoagulable in 7%. There was no difference in TEG status among the groups. The coagulation status was not affected by age, ISS or shock. The CCT were abnormal in 63.6% of patients with normal TEG. Normal or hypercoagulable-TEG was found in 21/23 patients on Coumadin who had elevated INR and in 10/11 patients on NOAC. An analysis of the 23 patients on Coumadin stratified by INR showed a normal or hypercoagulable-TEG in 21/23 patients. Only 2 patients had a hypocoagulable-TEG. Mortality was 5.2% (58.3% severe TBI). CONCLUSIONS: TEG is more useful than CCT in polytrauma patients, including patients on anticoagulants. TBI could increase the incidence of hypercoagulability in trauma. CCT are not useful from the standpoint of treatment. PMID- 29764674 TI - Surgical management of patients with Eagle syndrome. AB - OBJECTIVE: Eagle syndrome, a spectrum of disease resulting from an elongated styloid process and/or calcified stylohyoid ligament, lacks standardized recommendations regarding indications for surgical intervention and approach. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care institution. SUBJECTS: Patients treated surgically for Eagle syndrome between January 2011 and June 2017. METHODS: Patients were diagnosed with Eagle syndrome based on thorough clinical workup and assessment. The primary outcome was improvement in pain severity following surgery, with complete resolution of pain being considered clinically meaningful. Wilcoxon rank-sum tests and Fisher's exact were used to compare numerical and categorical variables, respectively. RESULTS: Twenty-one patients were diagnosed with Eagle syndrome and underwent surgical resection of the styloid process. Patients most often complained of neck pain (81%), throat pain (62%), and ear pain (48%). Among these patients, 57% of procedures featured a transcervical approach, while the remaining 43% were transoral. The vast majority (90%) of patients experienced improvement in pain severity from a median of 6.0 before surgery to 0.0 afterwards (p < 0.01) as 62% experienced complete resolution. Using multivariable linear regression to model changes in pain severity, neck pain (beta = -1.69, p < 0.01) and jaw pain (beta = -0.93, p = 0.03) predicted greater relief, while headache (beta = 0.82, p = 0.04) predicted an inferior response. Adverse events were uncommon and typically resolved within three months, with 24% experiencing first bite syndrome and 19% reporting numbness. CONCLUSIONS: Transcervical and transoral styloidectomy are effective treatments for Eagle syndrome with minimal adverse effects. Patients with classic symptoms of neck or jaw pain benefit most from surgery. PMID- 29764675 TI - Extracorporeal membrane oxygenation support in a patient with pheochromocytoma stress myocardyopathy. PMID- 29764676 TI - Effect of plantarflexion resistance of an ankle-foot orthosis on ankle and knee joint power during gait in individuals post-stroke. AB - Plantarflexion resistance of an ankle-foot orthosis (AFO) plays an important role to prevent foot-drop, but its impact on push-off has not been well investigated in individuals post-stroke. The aim of this study was to investigate the effect of plantarflexion resistance of an articulated AFO on ankle and knee joint power of the limb wearing the AFO in individuals post-stroke. Gait analysis was performed on 10 individuals with chronic stroke using a Vicon 3-dimensional motion capture system and a Bertec split-belt instrumented treadmill. They walked on the treadmill under 4 plantarflexion resistance levels (S1 < S2$75,000 were more likely to have a parent report receipt of a provider recommendation than children living below poverty. Children with a provider recommendation were twice as likely to be vaccinated than those without. CONCLUSIONS: This study affirms the importance of provider recommendation for influenza vaccination among children. Ensuring that parents of all children receive a provider recommendation may improve vaccination coverage. PMID- 29764683 TI - The assessment of cost effectiveness and the effectiveness of cost assessment in cardiothoracic surgery. PMID- 29764682 TI - Oral lesions as presenting feature of childhood Sjogren syndrome. PMID- 29764680 TI - The parasite-derived rOv-ASP-1 is an effective antigen-sparing CD4+ T cell dependent adjuvant for the trivalent inactivated influenza vaccine, and functions in the absence of MyD88 pathway. AB - Vaccination remains the most cost-effective biomedical approach for controlling influenza disease. In times of pandemics, however, these vaccines cannot be produced in sufficient quantities for worldwide use by the current manufacturing capacities and practices. What is needed is the development of adjuvanted vaccines capable of inducing an adequate or better immune response at a decreased antigen dose. Previously we showed that the protein adjuvant rOv-ASP-1 augments influenza-specific antibody titers and survival after virus challenge in both young adult and old-age mice when administered with the trivalent inactivated influenza vaccine (IIV3). In this study we show that a reduced amount of rOv-ASP 1, with 40-times less IIV3 can also induce protection. Apparently the potency of the rOv-ASP-1 adjuvanted IIV3 vaccine is independent of the IIV3-specific Th1/Th2 associated antibody responses, and independent of the presence of HAI antibodies. However, CD4+ T helper cells were indispensable for the protection. Further, rOv ASP-1 with or without IIV3 elicited the increased level of various chemokines, which are known chemoattractant for immune cells, into the muscle 4 h after immunization, and significantly induced the recruitment of monocytes, macrophages and neutrophils into the muscles. The recruited monocytes had higher expression of the activation marker MHCII on their surface as well as CXCR3 and CCR2; receptors for IP-10 and MCP-1, respectively. These results show that the rOv-ASP 1 adjuvant allows substantial antigen sparing of IIV3 by stimulating at the site of injection the accumulation of chemokines and the recruitment of immune cells that can augment the activation of CD4+ T cell immune responses, essential for the production of antibody responses. Protection elicited by the rOv-ASP-1 adjuvanted IIV3 vaccine also appears to function in the absence of MyD88 signaling. Future studies will attempt to delineate the precise mechanisms by which the rOv-ASP-1 adjuvanted IIV3 vaccine works. PMID- 29764681 TI - Plasmid pcDNA3.1-s11 constructed based on the S11 segment of grass carp reovirus as DNA vaccine provides immune protection. AB - Although some commercial vaccines against grass carp reovirus (GCRV) are available, given the many varieties of GCRV and limited types of vaccines, the disease caused by GCRV remains a major problem, which leads to economic losses in grass carp aquaculture. A reovirus strain (GCRV-HN14) was recently isolated from local diseased fish in our laboratory. The S11 segment of GCRV-HN14 was speculated to encode the virus capsid protein VP35. In our study, the S11 segment was cloned into the eukaryotic expression vector pcDNA3.1(+) to construct the recombinant plasmid pcDNA3.1-s11, which was then transfected into CIK cells, and the VP35 protein was successfully expressed. Grass carp was immunized with pcDNA3.1-s11, and the in vivo distribution and expression of the pcDNA3.1-s11 plasmids were analyzed by PCR and Western blot. Recombinant plasmids were detected in the blood, liver, spleen, kidney, and muscle. However, protein expression could only be detected in the muscle. The immune protection of the pcDNA3.1-s11 plasmid in grass carp was evaluated using a series of experiments. Results showed that the population of white blood cells significantly increased at 1, 7, and 14 days post-immunization (dpi) and reached a peak with (9.58 +/- 0.72) * 107/ml at 7 dpi (P < 0.01 or P < 0.05). The percentage of neutrophils reached a peak with (24.13 +/- 2.38)% at 7 dpi (P < 0.01), whereas the lymphocytes peaked with (93.30 +/- 4.71)% at 14 dpi (P < 0.05). Serum antibody levels were significantly enhanced in immunized fish at 14, 21, and 28 dpi (P < 0.01). The mRNA expression levels of type I interferon, immunoglobulin M, Toll like receptor 22, and major histocompatibility complex class I were significantly up-regulated in the head kidney and spleen of immunized fish (P < 0.05). Grass carp immunized with pcDNA3.1-s11 exhibited a higher survival percentage (70.4% 73.3%) than the controls (5%-13%). Overall, as a DNA vaccine, the pcDNA3.1-s11 plasmid could induce immune protection against GCRV. PMID- 29764684 TI - Does septal myectomy reduce risk of sudden cardiac death in patients with hypertrophic cardiomyopathy? PMID- 29764685 TI - Does cramming work? Impact of National Web-Based Thoracic Surgery Curriculum login frequency on thoracic surgery in-training exam performance. AB - OBJECTIVE: Web-based curricula provide login data that can be advantageously used to characterize and analyze study habits. We sought to compare thoracic surgical trainee In-Training Examination percentiles with regard to their study habits (ie, cramming), as characterized by curriculum login frequency to the national Web-based Thoracic Surgery Curriculum. Furthermore, we then aimed to characterize the curriculum login frequency of trainees as stratified by their performance on the In-Training Examination and their improvement on the In-Training Examination over subsequent years. METHODS: We performed a retrospective review of trainees who accessed the curriculum before the 2014 In-Training Examination, with curriculum login data collected from site analytics. Scores were compared between trainees who crammed (>=30% increase in logins in the month before the In Training Examination) and those who did not. Trainees were stratified on the basis of 2014 In-Training Examination percentile and improvement in percentile from 2013 to 2014 into high, medium, and low scorers and improvers. RESULTS: Of 256 trainees who took the 2014 In-Training Examination, 63 (25%) met criteria as crammers. Crammers increased total study sessions immediately before the In Training Examination (P < .001), but without impact on 2014 In-Training Examination percentile (P = .995) or year-to-year improvement (P = .234). Stratification by In-Training Examination percentile demonstrated that highest scoring trainees used the curriculum more frequently in the final month than medium-range scorers (P = .039). When stratified by extent of year-to-year improvement, those who improved the most accessed the curriculum significantly more often in the last month compared with baseline (P = .040). Moreover, those with greatest improvement logged in more in the final month than those with least improvement (P = .006). CONCLUSIONS: Increasing the frequency of study periods on the national Web-based thoracic surgery curriculum before the In-Training Examination may have a unique benefit to trainees who initially score low to allow them to significantly improve their subsequent year In-Training Examination performance. PMID- 29764686 TI - Comparison of transcatheter versus surgical aortic valve implantation in high risk patients: A nationwide study in France. AB - OBJECTIVE: To compare the clinical outcomes and direct costs at 5 years between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) using real-world evidence. METHODS: We performed a nationwide longitudinal study using data from the French Hospital Information System from 2009 to 2015. We matched, inside hospitals, 2 cohorts of adults who underwent TAVI or SAVR during 2010 on propensity score based on patient characteristics. Outcomes analysis included mortality, morbidity, and total costs and with a maximum 60-month follow-up. Clinical outcomes were compared between cohorts using hazard ratios (HRs) estimated from a Cox proportional hazards model for all-cause death, and from Fine and Gray's competing risk model for morbidity. RESULTS: Based on a cohort of 1598 patients (799 in each group) from 27 centers, a higher risk of death was observed after 1 year with TAVI compared with SAVR (16.8% vs 12.8%, respectively; HR, 1.33; 95% confidence interval [CI], 1.02-1.72) and was sustained up to 5 years (52.4% vs 37.2%; HR, 1.56; 95% CI, 1.33-1.84). At 5 years, the risk of stroke was increased (HR, 1.64; 95% CI, 1.07-2.54) as was myocardial infarction (HR, 2.30; 95% CI, 1.12-4.69) and pacemaker implantation (HR, 2.40; 95% CI, 1.81-3.17) after TAVI. The hospitalization costs per patient at 5 years were ?69,083 after TAVI and ?55,687 after SAVR (P < .001). CONCLUSIONS: In our study, high-risk patients harbored a greater risk of mortality and morbidity at 5 years after TAVI compared with those who underwent SAVR and higher hospitalizations costs. Those results should encourage caution before expanding the indications of TAVI. PMID- 29764687 TI - Intraoperative aortic root pressure study for quantitative assessment of aortic regurgitation during valve-sparing root replacement: A preliminary report. PMID- 29764689 TI - Patient-Identified Needs Related to Seeking a Diagnosis in the Emergency Department. AB - STUDY OBJECTIVE: Although diagnosis is a valuable tool for health care providers, and often the reason patients say they are seeking care, it may not serve the same needs for patients as for providers. The objective of this study is to explore what patients specifically want addressed when seeking a diagnosis at their emergency department (ED) visit. We propose that understanding these needs will facilitate a more patient-centered approach to acute care delivery. METHODS: This qualitative study uses semistructured telephone interviews with participants recently discharged from the ED of a large urban academic teaching hospital to explore their expectations of their ED visit and postdischarge experiences. RESULTS: Thirty interviews were analyzed. Many participants reported wanting a diagnosis as a primary reason for seeking emergency care. When further asked to identify the functions of a diagnosis, they described wanting an explanation for their symptoms, treatment and guidance for symptoms, and clear communication about testing, treatment, and diagnosis. For many, a diagnosis was viewed as a necessary step toward achieving these goals. CONCLUSION: Although diagnosis may not be a feasible outcome of every acute care visit, addressing the needs associated with seeking a diagnosis may be achievable. Reframing acute care encounters to focus on addressing specific patient needs, and not just identifying a diagnosis, may lead to more effective transitions home and improved patient outcomes. PMID- 29764688 TI - Bridgehead Effects and Role of Adaptive Evolution in Invasive Populations. AB - Biological invasions are a major threat to biodiversity, agriculture, and human health. Invasive populations can be the source of additional new introductions, leading to a self-accelerating process whereby invasion begets invasion. This phenomenon, coined bridgehead effect, has been proposed to stem from the evolution of higher invasiveness in a primary introduced population. There is, however, no conclusive evidence that the success of bridgehead populations stems from the evolution of increased invasiveness. Instead, we argue that a high frequency of secondary introductions can be explained by increased abundance in the bridgehead region or the topology of human transport networks. We outline the type of evidence and experiments that are needed to demonstrate adaptive evolution and higher invasion success of introduced populations. PMID- 29764690 TI - Inter-ray variation in metatarsal strength properties in humans and African apes: Implications for inferring bipedal biomechanics in the Olduvai Hominid 8 foot. AB - When measured as a ratio of mean midshaft diameter to bone length, the OH 8 fossil hominin foot exhibits a metatarsal (Mt) robusticity pattern of 1 > 5 > 3 > 4 > 2, which differs from the widely perceived "common" modern human pattern (1 > 5 > 4 > 3 > 2); African apes generally exhibit a third pattern (1 > 2 > 3 > 4 > 5). Largely because of the relative ranking of Mt2 and Mt5, OH 8 metatarsals structurally resemble the pattern exhibited by bipedal humans more than the pattern of quadrupedal and climbing African apes. Considering only these three phenotypes, however, discounts the potentially important functional implications of variation in modern human (and African ape) metatarsal robusticity patterns, suggesting that they are not useful for interpreting the specific biomechanics of a bipedal gait in fossils (i.e., whether it was modern human-like or not). Using computed tomography scans to quantify metatarsal midshaft cross-sectional geometry in a large sample of Homo (n=130), Gorilla (n=44) and Pan (n=80), we documented greater variation in metatarsal robusticity patterns than previously recognized in all three groups. While apes consistently show a 1 > 2 > 3 > 4 > 5 pattern in our larger sample, there does not appear to be a similarly precise single "common" human pattern. Rather, human metatarsals converge towards a 1 > 4/5 > 2/3 pattern, where metatarsals 4 and 5, and metatarsals 2 and 3, often "flip" positions relative to each other depending on the variable examined. After reassessing what a "common" human pattern could be based on a larger sample, the previously described OH 8 pattern of 1 > 5 > 3 > 4 > 2 is only observed in some humans (<6%) and almost never in apes (<0.5%). Although this suggests an overall greater similarity to (some) humans than to any ape in loading of the foot, the relatively rare frequency of these humans in our sample underscores potential differences in loading experienced by the medial and lateral columns of the OH 8 foot compared to modern humans. PMID- 29764691 TI - Overview of Silk Fibroin Use in Wound Dressings. AB - Recently, biomimetic wound dressings were introduced as potential replacements for treating skin injuries. Although there are some clinically available skin replacements, the range of wound types and locations necessitates a broader range of options for the clinic. Natural polymeric-based dressings are of central interest in this area due to their outstanding biocompatibility, biodegradability, low toxicity, and non-allergenic nature. Among them, silk fibroin (SF) has exceptional characteristics as a wound dressing. SF-based dressings can also be used as carriers for delivering drugs, growth factors, and bioactive agents to the wound area, while providing appropriate support for complete healing. In this review, we describe recent advances in the development of SF-based wound dressings for skin regeneration. PMID- 29764694 TI - Angina severity, therapeutic choices and outcome in patients with diabetes mellitus. PMID- 29764692 TI - Combined high dose rate brachytherapy and external beam radiotherapy for clinically localised prostate cancer. AB - PURPOSE: To report the clinical outcomes and treatment-related toxicities after combined high-dose-rate (HDR) brachytherapy (BRT) with external beam radiotherapy (EBRT) for patients with clinically localised high-risk prostate cancer. MATERIAL AND METHODS: Between 2008 and 2012, three hundred and three consecutive patients with organ-confined high-risk prostate cancer were treated with definitive radiotherapy consisting of HDR-BRT followed by supplemental EBRT. The transrectal 3D-ultrasound-based HDR-BRT boost consisted of two single-fraction implants of 10.5 Gy, prescribed to the 90% of the gland (D90), for a total physical dose of 21.0 Gy delivered to the prostatic gland. EBRT was delivered with conventional fractionation, prescribing 45.0 Gy to the prostatic gland and seminal vesicles. Biochemical failure was defined according to the Phoenix Consensus Criteria, genitourinary (GU)/gastrointestinal (GI) toxicity was evaluated using the Common Toxicity Criteria for Adverse Events (version 3.0). RESULTS: The median follow-up was 71.6 months. The 7-year overall survival, biochemical control and metastasis free-survival rates for the entire cohort were 85.7%, 88.3% and 93.8%, respectively. Androgen deprivation therapy was initiated prior to treatment for 92.7% of patients with a median duration of 12 months. Toxicity was scored per event with late Grade 2, 3 and 4 GU adverse events and was found to be 15.3%, 2.2% and 0.3%, respectively. Late Grade 2 GI toxicity accounted for 0.3% with no instances of Grade 3 or higher late adverse events. CONCLUSION: HDR-BRT with supplemental EBRT results in low biochemical relapse-free survival rates associated with a very low incidence of higher-grade late adverse events. PMID- 29764693 TI - Prospective cohort studies of dietary vitamin B6 intake and risk of cause specific mortality. AB - BACKGROUND & AIMS: Vitamin B6 has been postulated to play an important role in determining chronic diseases. However, few studies have evaluated associations between dietary vitamin B6 and cause-specific mortality comprehensively. METHODS: We investigated the associations between vitamin B6 from diet and risk of all cause, and cause-specific mortality in 134,480 participants from the Shanghai Men's Health Study (2002-2014) and Shanghai Women's Health Study (1997-2014). The median follow-up periods for men and women were 10.3 and 16.2 years, respectively. We estimated hazard ratio (HR) and 95% confidence interval (CI) using Cox proportional hazards models. RESULTS: After adjustment for suspected confounders, the multivariable-adjusted HRs for the highest versus lowest quintiles for total, CVD, stroke and CHD mortality among men were 0.83 (95%CI = 0.76, 0.90), 0.73 (95%CI = 0.63, 0.85), 0.71 (95%CI = 0.58, 0.88), 0.66 (95%CI = 0.47, 0.91), accordingly. Women with the highest intake had significantly 17% (HR = 0.83; 95% CI = 0.77, 0.90), 20% (HR = 0.80; 95% CI = 0.70, 0.92), and 28% (HR = 0.72; 95% CI = 0.59, 0.86) lower risks of total, CVD and stroke mortality compared with those of women with lowest vitamin B6 intake. No significant association was observed between dietary vitamin B6 and cancer mortality both among men and women. CONCLUSIONS: In the current study with two prospective Chinese cohorts, high dietary vitamin B6 consumption was inversely associated with risk of all-cause and CVD mortality. PMID- 29764695 TI - Non-HDL-C levels and residual cardiovascular risk: Do population-specific precision approaches offer any advantages? PMID- 29764696 TI - Anthropometric measures in the risk assessment of obese individuals. PMID- 29764697 TI - Strokes, cholesterol and statins: When mortality is an endpoint. PMID- 29764698 TI - Translucency thresholds for dental materials. AB - OBJECTIVE: To determine the translucency acceptability and perceptibility thresholds for dental resin composites using CIEDE2000 and CIELAB color difference formulas. METHODS: A 30-observer panel performed perceptibility and acceptability judgments on 50 pairs of resin composites discs (diameter: 10mm; thickness: 1mm). Disc pair differences for the Translucency Parameter (DeltaTP) were calculated using both color difference formulas (DeltaTP00 ranged from 0.11 to 7.98, and DeltaTPab ranged from 0.01 to 12.79). A Takagi-Sugeno-Kang (TSK) Fuzzy Approximation was used as fitting procedure. From the resultant fitting curves, the 95% confidence intervals were estimated and the 50:50% translucency perceptibility and acceptability thresholds (TPT and TAT) were calculated. Differences between thresholds were statistically analyzed using Student t tests (alpha=0.05). RESULTS: CIEDE2000 50:50% TPT was 0.62 and TAT was 2.62. Corresponding CIELAB values were 1.33 and 4.43, respectively. Translucency perceptibility and acceptability thresholds were significantly different using both color difference formulas (p=0.01 for TPT and p=0.005 for TAT). CIEDE2000 color difference formula provided a better data fit than CIELAB formula. SIGNIFICANCE: The visual translucency difference thresholds determined with CIEDE2000 color difference formula can serve as reference values in the selection of resin composites and evaluation of its clinical performance. PMID- 29764699 TI - Potentially inapropriate prescribing in patients on dialysis using STOPP-START criteria. PMID- 29764700 TI - [Airway management in Ludwig's angina - a challenge: case report]. PMID- 29764701 TI - A combination of skeletal deformations of the dorsal mandible and temporomandibular region detected in orthopantomograms of patients with neurofibromatosis type 1 indicates an associated ipsilateral plexiform neurofibroma. AB - PURPOSE: Neurofibromatosis type 1 (NF1) is a tumour suppressor syndrome and also a bone disease. In the craniofacial region, local skeletal deformities have been recorded in patients with NF1. Obvious syndrome-related alterations of the jaws are particularly conspicuous in the mandible. Here we aimed to analyse the mandibular alterations of NF1-affected individuals from orthopantomograms (OPGs). MATERIALS AND METHODS: This study analyses 358 OPGs of 358 patients (mean age, 34.63 years; range, 12.57-69.13 years). The OPGs of 179 patients of Caucasian origin with NF1 were investigated (mean age, 34.84 years; range, 12.83-68.89 years; 44.13% male, 55.86% female). The radiographic findings were compared to those obtained from OPGs of sex- and age-matched controls. RESULTS: Characteristic deformations of the bone regions of interest occur in NF1 patients, especially in patients with plexiform neurofibroma of trigeminal nerve. These findings are always one-sided. The co-occurrence of several skeletal deformations can be expected with very high probability in this patient group. CONCLUSION: The radiological sign of the unilateral deformed mandible should be included in the diagnostic criteria for NF1. In addition to the diagnostic value in this syndrome, these findings are important for avoiding surgical complications in planned interventions in this region. PMID- 29764702 TI - A novel neuromodulation technique for the rehabilitation of balance and gait: A case study. AB - Cranial-nerve non-invasive neuromodulation (CN-NINM) through the tongue has been proposed as an adjuvant intervention to improve efficacy of rehabilitation. However, CN-NINM effects have only been explored in multiple sclerosis and stroke populations. In this report we used CN-NINM during a 2-week (2 * 1.5 h sessions daily) physiotherapy program for the rehabilitation of a 57 y/o woman presenting with balance and gait impairments after a surgical resection of a fourth ventricular ependymoma. Clinical and instrumented balance and gait assessments showed improved performance in all tests and without adverse effects This study shows the beneficial effects and feasibility of combined physiotherapy and CN NINM in this patient. PMID- 29764703 TI - Efficacy and safety of Fingolimod therapy in multi-ethnic Malaysian patients with relapsing remitting multiple sclerosis: A longitudinal observational study. PMID- 29764706 TI - Atrial fibrillation and ischemic events with rivaroxaban in patients with stable coronary artery disease (AFIRE): Protocol for a multicenter, prospective, randomized, open-label, parallel group study. AB - BACKGROUND: In atrial fibrillation (AF) patients with coronary artery disease (CAD), anticoagulants are commonly used in combination with antiplatelet drugs. However, dual therapy can increase the risk of bleeding, and the potential therapeutic benefits must be weighed against this. Therefore, it is recommended that dual therapy is only used for a limited time, and that monotherapy with anticoagulants should start from 1 year after percutaneous coronary intervention (PCI). However, there is a lack of evidence on the use of monotherapy, in particular with direct oral anticoagulants, in this group of patients. METHODS: The AFIRE Study is a multicenter, prospective, randomized, open-label, parallel group study conducted in patients aged >=20 years with non-valvular AF (NVAF) and CAD. Patients who have undergone PCI or coronary artery bypass graft at least 1 year prior to enrollment, or those without significant coronary lesions requiring PCI (>=50% stenosis), will be included. Approximately 2200 participants will be randomized to receive either rivaroxaban monotherapy or rivaroxaban plus an antiplatelet drug (aspirin, clopidogrel, or prasugrel). The primary efficacy endpoints are the composite of cardiovascular events (stroke, non-central nervous system embolism, myocardial infarction, and unstable angina pectoris requiring revascularizations) and all-cause mortality. The primary safety endpoint is major bleeding as defined by the International Society on Thrombosis and Haemostasis criteria. CONCLUSIONS: This study will be the first to assess the efficacy and safety of rivaroxaban monotherapy in NVAF patients with stable CAD. PMID- 29764705 TI - Downregulation of RFX1 predicts poor prognosis of patients with small hepatocellular carcinoma. AB - OBJECTIVE: Regulatory factor X1 (RFX1) deletion has been reported to be correlated with poor prognosis of some types of cancer. The present study aimed to investigate the prognostic value of RFX1 in HCC, especially in small hepatocellular carcinoma. METHODS: Immunohistochemical assay was used to investigate RFX1 expression in 221 HCC tissues and another validation cohort of 71 small HCC samples. We also performed in vitro experiments to investigate if RFX1 regulated invasive capacity of HCC cells and expression of epithelial mesenchymal transition (EMT) markers. RESULTS: We found that RFX1 expression was significantly lower in HCC tissues compared to the corresponding non-tumor tissues. Further survival analysis suggested that the downregulation of RFX1 correlated with poor prognosis and a high recurrence risk in HCC patients, particularly in small HCC patients. Furthermore, another validation cohort of small HCC samples confirmed that downregulation of RFX1 in HCC tissues predicted high recurrence risk and poor prognosis for early stage HCC patients. In vitro studies suggested that knocking down RFX1 facilitated HCC cell invasion, while overexpression of RFX1 reduced the invasion of HCC cells. Western blot assays also indicated that RFX1 regulated expression of some EMT markers. Knocking down RFX1 decreased E-cadherin and increased vimentin expression, while RFX1 overexpression enhanced E-cadherin and decreased vimentin expression. CONCLUSIONS: Our study demonstrated that RFX1 downregulation is a new predictive marker of high recurrence risk and poor prognosis of HCC; It has potential to help guide treatment for postoperative HCC patients, especially for small HCC patients. PMID- 29764707 TI - Mid-term outcomes from a multicenter study: Is TEVAR safe for ascending aortic dissection? AB - OBJECTIVES: This study aims to report mid-term follow-up outcomes of a series of TAAD patients treated with TEVAR in China. BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has been used to treat type A aortic dissection (TAAD) for years. However, by comparing public reports, their outcomes which were based on different sample sizes show inconsistency. METHODS: Between January 2001 and December 2015, there were 56 patients with TAAD received TEVAR identified in 5 medical centers. The morphology changes and early and late outcomes were recorded and analyzed. RESULTS: 56 patients (aged 38 to 80) with TAAD received TEVAR. The average follow-up period was 39.92 +/- 34.42 months (ranging from 11 to 140 months). 54 (96.43%) cases were technically successful. 1 patient died on day 2 after TEVAR because of stent graft migration during the procedure. There were 7 early events (within 30 days), including sudden death (1), cerebral infarction (3), stent graft migration (1), new dissection (1) and respiratory failure (1). The 30-day overall survival rate was 92.9%. 27 late events occurred during the follow-up: retrograde dissection (8), endoleak (5), coronary artery stenosis (3), cerebral infarction (3), new dissection (2), multiple organ dysfunction syndrome (1), left ventricular pseudoaneurysm (1), stent graft migration (1), respiratory failure (1), supraventricular tachycardia (1) and pericardial effusion (1). The 5 year overall survival rate of this study was 80.9% and this rate reached 98.2% if aorta-related deaths were excluded. CONCLUSIONS: TEVAR could be an effective alternative for high-risk patients. However, issues resulted from postoperative complications still call for attention. PMID- 29764709 TI - Editor's Choice - Influence of Proximal Aortic Neck Diameter on Durability of Aneurysm Sealing and Overall Survival in Patients Undergoing Endovascular Aneurysm Repair. Real World Data from the Gore Global Registry for Endovascular Aortic Treatment (GREAT). AB - OBJECTIVES: Aortic neck diameter is an independent anatomical feature that is poorly understood, yet potentially linked to proximal seal failure and adverse outcome following standard EVAR. The aim of this study was to assess whether large proximal aortic neck (LAN) diameter is associated with adverse outcome using prospectively collected individual patient data from The Global Registry for Endovascular Aortic Treatment (GREAT). METHODS: A total of 3166 consecutive patients, from 78 global centres, receiving Gore Excluder stent grafts for infrarenal abdominal aortic aneurysm repair between 2011 and 2017 were included. Patient demographics, biometrics, operative details, and clinical outcome were analysed. Patients were divided into two groups: normal baseline proximal aortic neck (NAN) diameter (<25 mm on computed tomography aortography), and LAN (>=25 mm). Clinical follow up (including imaging) was available for 76.5% of patients 5 years post-intervention. Primary endpoints analysed were Type IA endoleak and any aortic re-intervention up to 5 years post-procedure. A composite endpoint of Type IA endoleak, re-intervention, aortic rupture, or aortic related mortality was also assessed. RESULTS: A total of 1977 (62.4%) patients were classified NAN and 1189 (37.6%) were LAN. Immediate technical success was achieved in 3164 out of 3166 (>99.9%) of cases. Freedom from Type IA endoleak was achieved in 99.3% at 1 year and 97.3% at 5 years (lower in LAN vs. NAN: 96.8% [CI 93.7-98.4] vs. 98.6% [CI 94.5-99.6], p = .007). Freedom from aortic re-intervention was 93.7% at 1 year and 83.2% at 5 years (78.6% [CI 66.0-87.0] LAN vs. 86.0% [CI 81.8-89.3] NAN, p = .11). Freedom from primary composite endpoint was 95.9% at 1 year and 84.9% at 5 years (81.3% [CI 69.2-89.0] LAN vs. 87.0% [CI 81.6-91.0] NAN, p = .066). Five year survival was lower in the LAN group; 64.6% (CI 50.1-75.7) vs. 76.5% (CI 70.7-81.3), p = .03). CONCLUSION: LAN is associated with delayed Type IA endoleak occurrence and lower overall survival. PMID- 29764708 TI - Histological assessment & use of immunohistochemical markers for detection of dysplasia in Barrett's esophageal mucosa. AB - BACKGROUND: Histological assessment of dysplasia in Barrett's esophagus (BE) has high inter-observer variability. Hence, use of ancillary markers for early detection of dysplasia in BE is an important clinical question. METHODS: In this retrospective study consecutive cases of BE (n = 59), over a period of 4 years were included. Hematoxylin and eosin stained sections were reviewed independently by 3 senior qualified pathologists, who graded the dysplasia according to the Vienna Classification system and inter-observer agreement was analysed using the Kappa statistics. Subsequently Alpha-Methyl Acyl-CoA Racemase (AMACR), p53, CyclinD1, beta-catenin, H2AX and M30 immunohistochemical (IHC) stains were examined on the following disease categories: BE with no dysplasia [NFD] (45), BE with indefinite for dysplasia (IFD) (4), low grade dysplasia (LGD) (3), high grade dysplasia (HGD) (2) and in adenocarcinomas (5). H score was calculated by adding up products of different grades of stain distribution and stain intensities (range of scores 0-300). RESULTS: Among the 3 pathologists, overall agreement was poor (k 0.06; 95% CI -0.089 to 0.145), with highest disagreement noted for differentiating the LGD and IFDs (k = 0.21). After revising the histological criteria, the kappa improved to 0.53. Among the IHC stains performed, p53, beta-catenin, H2AX and M30 stains were significantly useful to differentiate between IFD and LGD (P values: 0.04, 0.004, 0.05 & 0.04, respectively). AMACR and beta-catenin stains though were up-regulated in HGD/adenocarcinomas than in other categories, their expression were not statistically different between the IFD and LGDs. CONCLUSIONS: A detail histological scoring system may bring uniformity in histological interpretation of dysplasia in BE. Using a combined panel of IHC stains seems helpful in detection of dysplasia in BE, especially to differentiate the IFD and LGD changes in BE. PMID- 29764710 TI - A systematic review to explore the feasibility of a behavioural sleep intervention for insomnia in children with neurodevelopmental disorders: A transdiagnostic approach. AB - Children with neurodevelopmental disorders (NDD) are at high risk for sleep problems, especially insomnia. It is currently not known whether behavioural sleep interventions developed for typically developing (TD) children are effective for children with NDD, and if interventions need to be modified for each diagnostic group. The aim of this systematic review was to identify and evaluate commonalities, trends in outcomes, and the methodological quality of parent-delivered behavioural sleep interventions for children with NDD, specifically Attention-Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Cerebral Palsy, and Fetal Alcohol Spectrum Disorder. Nine databases were searched. A total of 40 studies met eligibility criteria. The majority of studies were conducted with ASD and ADHD populations. Common sleep problems were evident across the NDD populations. The most frequently reported included bedtime resistance, night-waking, early morning awakening, and co sleeping. The most common interventions used were implementation of healthy sleep practices, reinforcement, graduated extinction, and faded bedtime. All studies reported at least one behavioural treatment component as effective. Commonalities across NDD populations, as well as the TD population, for both sleep problems reported and behavioural interventions implemented, suggest the feasibility of developing a transdiagnostic behavioural sleep intervention suitable for children with a range of NDD. PMID- 29764711 TI - Does lipid peroxidation and oxidative DNA damage differ in cryopreserved semen samples from young, adult and aged Nellore bulls? AB - The aims of this study were to evaluate cryopreserved semen of Nellore bulls of different ages and verify whether sperm quality declines with advancing age and whether lipid peroxidation and DNA damage are involved in this process. For this purpose, 40 Nellore bulls were divided into three age groups: Young, aged 1.8-2 years (n = 9); Adult, aged 3.5-7.0 years (n = 19); and Seniors, aged 8.0-14.3 years (n = 12). Three ejaculates were collected from each bull, cryopreserved and evaluated for various parameters including membrane integrity, mitochondrial potential (FITC-PSA and JC1), lipid peroxidation (C-11BODIPY 581 / 591) and oxidative DNA damage (8OHdG) using flow cytometry. The thawed semen of senior bulls was characterized by a low percentage of motile sperm (33.7 +/- 6.1%), higher damage to the plasma and acrosomal membrane (37.5 +/- 9.8%), and low mitochondrial potential (29.1 +/- 13.8%), as well as higher percentages of peroxidated cells (53.6 +/- 12.2%) and DNA damage (44.1 +/- 11.0%; P < 0.05). Lipid peroxidation was negatively correlated with motility (r = -0.35, P < 0.0002), average mitochondrial potential (r = -0.42; P < 0.0001) and showed a positive correlation with membrane injury and oxidative DNA damage (r = 039; P = 0.0003). Young bulls presented superior thawed sperm quality, possibly due to greater resistance to oxidative stress and, consequently, to cryopreservation. In conclusion, the sperm quality of bull semen declines with advancing age and is strongly associated with increased oxidative damage to both the plasma membrane and DNA. PMID- 29764712 TI - The tail in tropical hair ewes (Ovis aries) that are in estrus is used as a proceptive signal and favors ram' copulation. AB - Two experiments were performed to determine if the tail has a role: 1) in proceptive behavior, and 2) in facilitating copulation in hair sheep. The movements and position of the tail of estrous and non-estrous ewes in response to male courtship were compared in the first study. In the second study, the courtship of rams and mating behavior directed towards tailed or tail-docked, in estrus or diestrus ewes, were compared. Both experiments were conducted with restrained ewes during 3 min assessment periods. In Experiment 1, tail movements occurred in short episodes in response to physical contact of the male, but the rest of the time the tail of non-estrous ewes was drawn inward to the body, while in estrous ewes it simply hung naturally straight downward. Ewes in estrus had many tail moving episodes (P <0.001) with more movements per episode (P <0.001), that were of greater amplitude (P <0.001) and greater elevation in angle from the body (P <0.001) than in non-estrus ewes. In Experiment 2, ejaculation latencies with non-estrous ewes were longer than with estrous ewes (P <0.0001), and rams had more attempts to mount (P = 0.008), and more completed mounts (P = 0.0003) in non-estrous than estrous ewes. In addition, rams ejaculated more times (P <0.0001), and had a greater ejaculations/(mounts + ejaculations) ratio in estrous than non-estrous ewes (P <0.0001). More rams also had anal intromissions in docked than in intact tail-ewes (P = 0.0002). In conclusion, movements and position of the tail of estrous ewes is a primary component of the proceptive behavior that facilitates mating and serves as a physical barrier to avoid anal intromissions in hair sheep. PMID- 29764713 TI - Utility of GRACE and ACUITY-HORIZONS risk scores to guide dual antiplatelet therapy in Korean patients with acute myocardial infarction undergoing drug eluting stenting. AB - BACKGROUND: Dual antiplatelet therapy (DAPT) is recommended in patients receiving drug-eluting stents (DES). However, bleeding risk should be weighed against ischemic risk. Utility of GRACE risk score and ACUITY-HORIZONS bleeding risk score was assessed in patients with acute myocardial infarction (MI) according to use of P2Y12 blocker. METHODS: From the Korea Acute Myocardial Infarction Registry-National Institute of Health database, 7791 patients with acute MI receiving DES were divided into ticagrelor (n=1554) and clopidogrel (n=6237) groups. Propensity-matched 12-month mortality and bleeding event rates were compared according to GRACE and ACUITY-HORIZONS scores. Patients who received thrombolysis, prasugrel or anticoagulants, or who discontinued or switched DAPT were excluded. RESULTS: In all patients, high-risk patients more often received clopidogrel. After propensity score matching (n=1553 in each group), 12-month mortality was not different, but TIMI major bleeding rate was higher with ticagrelor (2.8% vs. 1.4%, p=0.007). On subgroup analysis, 12-month mortality was lower with ticagrelor in patients with high (>140) compared to low-to-moderate risk GRACE score (5.1% vs. 7.9%, p=0.04). When combined with ACUITY-HORIZONS bleeding score, 12-month mortality was lower with ticagrelor in patients with high GRACE score but without very high (>=20) ACUITY-HORIZONS score (2.4% vs. 5.3%, p=0.03). CONCLUSIONS: In patients with acute MI receiving DES, GRACE and ACUITY-HORIZONS scores may help guide DAPT. In patients with high GRACE score, a more potent P2Y12 blocker may be considered, particularly in the subset not at very high risk of bleeding. PMID- 29764714 TI - Bronchoscopic resection of a tracheobronchial leiomyoma in a pregnant patient. AB - Flexible bronchoscopy, therapeutic bronchoscopy and other procedures requiring anesthesia are generally avoided in pregnancy and postponed until after delivery if possible. We report a case of a parturient with an abnormal chest radiograph and mild obstructive symptoms of unknown etiology. At bronchoscopy, a tumor associated with post-obstructive suppuration was found and excised using electrocautery snare and cryotherapy, for restoration of airway patency. Coordination between pulmonary, obstetric, anesthesia, neonatology and thoracic surgery services was essential in ensuring success and the safety of the mother and fetus. PMID- 29764704 TI - Current understanding of neuroinflammation after traumatic brain injury and cell based therapeutic opportunities. AB - Traumatic brain injury (TBI) remains a major cause of death and disability worldwide. Increasing evidence indicates that TBI is an important risk factor for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. Despite improved supportive and rehabilitative care of TBI patients, unfortunately, all late phase clinical trials in TBI have yet to yield a safe and effective neuroprotective treatment. The disappointing clinical trials may be attributed to variability in treatment approaches and heterogeneity of the population of TBI patients as well as a race against time to prevent or reduce inexorable cell death. TBI is not just an acute event but a chronic disease. Among many mechanisms involved in secondary injury after TBI, emerging preclinical studies indicate that posttraumatic prolonged and progressive neuroinflammation is associated with neurodegeneration which may be treatable long after the initiating brain injury. This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell based therapies that target neuroinflammation and promote functional recovery after TBI. PMID- 29764717 TI - Mitochondrial damage and cytoskeleton reorganization in human dermal fibroblasts exposed to artificial visible light similar to screen-emitted light. AB - BACKGROUND: Artificial visible light is everywhere in modern life. Social communication confronts us with screens of all kinds, and their use is on the rise. We are therefore increasingly exposed to artificial visible light, the effects of which on skin are poorly known. OBJECTIVE: The purpose of this study was to model the artificial visible light emitted by electronic devices and assess its effect on normal human fibroblasts. METHODS: The spectral irradiance emitted by electronic devices was optically measured and equipment was developed to accurately reproduce such artificial visible light. Effects on normal human fibroblasts were analyzed on human genome microarray-based gene expression analysis. At cellular level, visualization and image analysis were performed on the mitochondrial network and F-actin cytoskeleton. Cell proliferation, ATP release and type I procollagen secretion were also measured. RESULTS: We developed a device consisting of 36 LEDs simultaneously emitting blue, green and red light at distinct wavelengths (450 nm, 525 nm and 625 nm) with narrow spectra and equivalent radiant power for the three colors. A dose of 99 J/cm2 artificial visible light was selected so as not to induce cell mortality following exposure. Microarray analysis revealed 2984 light-modulated transcripts. Functional annotation of light-responsive genes revealed several enriched functions including, amongst others, the "mitochondria" and "integrin signaling" categories. Selected results were confirmed by real-time quantitative PCR, analyzing 24 genes representing these two categories. Analysis of micro-patterned culture plates showed marked fragmentation of the mitochondrial network and disorganization of the F-actin cytoskeleton following exposure. Functionally, there was considerable impairment of cell growth and spread, ATP release and type I procollagen secretion in exposed fibroblasts. CONCLUSION: Artificial visible light induces drastic molecular and cellular changes in normal human fibroblasts. This may impede normal cellular functions and contribute to premature skin aging. The present results extend our knowledge of the effects of the low-energy wavelengths that are increasingly used to treat skin disorders. PMID- 29764715 TI - The State of Adherence to HIV Care in Black Women. AB - The purpose of this systematic review was to assess the state of adherence to HIV care such as HIV medication and appointment adherence among Black women in the United States. After a systematic search of CINAHL, PubMed, EMBASE, and clinicialtrials.gov, 26 studies and two ongoing trials met inclusion criteria. Psychosocial factors such as intersectional stigmas and depression were among the salient factors associated with adherence-to-care behaviors in women living with HIV (WLWH). In addition, interpersonal factors such as social support and the patient-provider relationship were frequently associated with adherence-to-care behaviors. No culturally relevant interventions for Black WLWH were found in the literature, but one ongoing trial that was developed specifically for Black WLWH seemed promising. Considering the dearth of tailored interventions, more gender specific and culturally relevant interventions are urgently needed to improve adherence-to-care behaviors and optimize health outcomes for Black WLWH. PMID- 29764716 TI - Individualized-Targeted Computerized Cognitive Training to Treat HIV-Associated Neurocognitive Disorder: An Interim Descriptive Analysis. PMID- 29764718 TI - Metabolic syndrome associates with left atrial dysfunction. AB - BACKGROUND AND AIMS: Obesity and metabolic syndrome (MetS) are risk factors of atrial fibrillation (AF), but limited data exist on their effect on left atrial (LA) function. The aim of the study was to evaluate the effects of cardiac, hepatic and intra-abdominal ectopic fat depots and cardiometabolic risk factors on LA function in non-diabetic male subjects. METHODS AND RESULTS: Myocardial and hepatic triglyceride contents were measured with 1.5T 1H-magnetic resonance spectroscopy and LA and left ventricular function, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), epicardial and pericardial fat by magnetic resonance imaging (MRI) in 33 men with MetS and 40 men without MetS. LA volumes were assessed using a novel three-chamber orientation based MRI approach. LA ejection fraction (EF) was lower in MetS patients than in the control group (44 +/- 7.7% in MetS vs. 49 +/- 8.6% in controls, p = 0.013) without LA enlargement, indicating LA dysfunction. LA EF correlated negatively with waist circumference, body mass index, SAT, VAT, fasting serum insulin, and homeostasis model assessment of insulin resistance index, and positively with fasting serum high density lipoprotein cholesterol. VAT was the best predictor of reduced LA EF. CONCLUSIONS: MetS associates with subclinical LA dysfunction. Multiple components of MetS are related to LA dysfunction, notably visceral obesity and insulin resistance. Further studies are needed to elucidate the role of mechanical atrial remodeling in the development of AF. PMID- 29764719 TI - Potential use of bitter melon (Momordica charantia) derived compounds as antidiabetics: In silico and in vivo studies. AB - Momordica charantia (bitter lemon) belongs to the cucurbitaceae family which has been extensively used in traditional medicines for the cure of various ailments such as cancer and diabetes. The underlying mechanism of M. charantia to maintain glycemic control was investigated. GLP-1 and DPP-4 gene modulation by M. charantia (5-20% inclusion in rats diet) was investigated in vivo by RT-PCR and possible compounds responsible for diabetic action predicted through in silico approach. Phytochemicalss previously characterized from M. charantia were docked into glucacon like peptide-1 receptor (GLP-1r), dipeptidyl peptidase (DPP4) and Takeda-G-protein-receptor-5 (TGR5) predicted using Autodock Vina. The results of the in silico suggests momordicosides D (ligand for TGR5), cucurbitacin (ligand for GLP-1r) and charantin (ligand for DPP-4) as the major antidiabetic compounds in bitter lemon leaf. M. charantia increased the expression of GLP-1 by about 295.7% with concomitant decreased in expression of DPP-4 by 87.2% with 20% inclusion in rat's diet. This study suggests that the mechanism underlying the action of these compounds is through activation of TGR5 and GLP-1 receptor with concurrent inhibition of DPP4. This study confirmed the use of this plant in diabetes management and the possible bioactive compounds responsible for its antidiabetic property are charantin, cucurbitacin and momordicoside D and all belong to the class of saponins. PMID- 29764720 TI - Altered somatosensory processing in Parkinson's disease and modulation by dopaminergic medications. AB - BACKGROUND: Somatosensory abnormalities contribute to the pathophysiology of Parkinson's disease (PD). The goal of this study was to identify abnormalities in the tactile-evoked activation of the somatosensory and motor cortices in PD, and in a sensorimotor circuit that traverses both of these cortical loci. The second goal was to investigate the impact of dopaminergic medication on these measures. METHODS: Individuals with PD (n = 10, age 61 +/- 8 years) and aged-matched controls (n = 11, age 52.3 +/- 10.4 years) were studied. PD subjects were studied on and off dopaminergic medications. Using high-resolution functional magnetic resonance, imaging data was acquired over the primary somatosensory and motor cortices during passively delivered, computer-automated tactile stimulation of digits 2 and 5 of the more affected hand in PD and the analogous hand in controls. Short and long-latency afferent inhibition (SAI, LAI) were assessed via median nerve stimulation followed by transcranial magnetic stimulation over the motor cortical representation of the first dorsal interosseous muscle. RESULTS: Compared to controls, PD subjects demonstrated diminished activation within the somatosensory cortex, reduced LAI and normal SAI, of which all were insensitive to dopaminergic medications. In addition to improving motor symptoms, dopaminergic medications reduced the hyperactivity observed within primary motor cortex in PD. CONCLUSIONS: Somatosensory processing is deficient in PD. Reduction in tactile-evoked activation within primary motor cortex may contribute to improvement in motor symptoms with dopaminergic medications. PMID- 29764722 TI - Middle-ear disease in children with cleft palate. AB - OBJECTIVE: The objective of this review is to summarize all aspects of middle ear diseases in children with cleft palate (CP). METHODS: PubMed, Scopus, The Cumulative Index to Nursing and Allied Health Literature (CINAHL) and The Cochrane Library were searched for English-language randomized control trials (RCTs), meta-analyses, systematic reviews and observational studies published through 31st July 2017. RESULTS: Epidemiology and pathogenesis of middle ear diseases in children with cleft palate have been discussed in this review. Methods of Evaluation, CP surgeries, complications and follow up have been detailed for the same. CONCLUSION: Evaluation of middle-ear disease in children with CP begins at birth by a newborn hearing screen. Tympanometry and otoscopy helps screen for middle-ear disease during follow-up visits. Ventilation tube may be placed when indicated based on the patient's clinical course and presentation. Long-term follow up should be provided to look for the development of cholesteatoma. PMID- 29764721 TI - Robust, Transient Neural Dynamics during Conscious Perception. AB - While neuroscientific research on perceptual awareness has traditionally focused on the spatial and temporal localizations of neural activity underlying conscious processing, recent development suggests that the dynamic characteristics of spatiotemporally distributed neural activity contain important clues about the neural computational mechanisms underlying conscious processing. Here, we summarize recent progress. PMID- 29764724 TI - Woman with headache and retro-orbital pain. PMID- 29764723 TI - Frailty Assessment to Help Predict Patients at Risk of Delirium When Consulting the Emergency Department. AB - BACKGROUND: Delirium is underdiagnosed in seniors at emergency departments (EDs) even though it is a frequent complication and is associated with functional and cognitive decline. As frailty is an independent predictor of adverse events in seniors, screening for frailty in EDs may help identify those at risk of delirium. OBJECTIVES: To assess if screening older patients for frailty in EDs could help identify those at risk of delirium. METHODOLOGY: This study was part of the multicenter prospective cohort INDEED study. Patients aged >= 65 years, initially free of delirium, with an ED stay >= 8 h were followed up to 24 h after ward admission. Frailty was assessed at baseline using the Clinical Frailty Scale; seniors with a score >= 5/7 were considered frail. Their delirium status was assessed twice daily using the Confusion Assessment Method. RESULTS: Among the 335 included patients, delirium occurred in 20/70 frail (28.6%) patients and in 20/265 (7.6%) robust ones. After adjusting for age and sex, the risk of delirium during ED stay was 3.13 (95% confidence interval 1.60-6.21) times higher in frail than in robust patients. Time between arrival to the ED and the incidence of delirium was also shorter for frail patients than for the robust ones (adjusted hazard ratio 2.44, 95% confidence interval 1.26-4.74). CONCLUSION: Increased frailty is associated with increased delirium during ED stays. Screening for frailty at emergency triage could help ED professionals identify seniors at higher risk of delirium. PMID- 29764725 TI - Approaches to sleep in severely brain damaged patients: Opposite or complementary? Reply to "Sleep and Circadian Rhythms in Severely Brain-Injured Patients - A Comment". PMID- 29764726 TI - [Diagnosing bipolar depression in primary care: Keys to the diagnostic challenge]. PMID- 29764727 TI - The Spring of Systems Biology-Driven Breeding. AB - Genetics and molecular biology have contributed to the development of rationalized plant breeding programs. Recent developments in both high-throughput experimental analyses of biological systems and in silico data processing offer the possibility to address the whole gene regulatory network (GRN) controlling a given trait. GRN models can be applied to identify topological features helping to shortlist potential candidate genes for breeding purposes. Time-series data sets can be used to support dynamic modelling of the network. This will enable a deeper comprehension of network behaviour and the identification of the few elements to be genetically rewired to push the system towards a modified phenotype of interest. This paves the way to design more efficient, systems biology-based breeding strategies. PMID- 29764729 TI - Epilepsy South Africa celebrates its 50th anniversary. PMID- 29764728 TI - Adaptation to Phosphate Scarcity: Tips from Arabidopsis Roots. AB - Phosphorus (P) availability is a limiting factor for plant growth and development. Root tip contact with low Pi media triggers diverse changes in the root architecture of Arabidopsis thaliana. The most conspicuous among these modifications is the inhibition of root growth, which is triggered by a shift from an indeterminate to a determinate root growth program. This phenomenon takes place in the root tip and involves a reduction in cell elongation, a decrease in cell proliferation, and the induction of premature cell differentiation, resulting in meristem exhaustion. Here, we review recent findings in the root response of A. thaliana to low Pi availability and discuss the cellular and genetic basis of the inhibition of root growth in Pi-deprived seedlings. PMID- 29764730 TI - Molecular detection of the human pathogen Rickettsia parkeri strain Atlantic rainforest in Amblyomma ovale ticks in Argentina. AB - Human rickettsioses caused by Rickettsia parkeri strain Atlantic rainforest in Brazil motivated the analysis of Amblyomma ovale ticks in Misiones province, a similar ecological region in northeastern Argentina. During 2010-2017, 393 A. ovale ticks were collected from domestic and wild animals and from vegetation, and 177 were pooled for rickettsial detection by PCR targeting the gltA, ompA and ompB genes. A sample consisting of a pool of two A. ovale adults collected on Nasua nasua was positive for Rickettsia parkeri strain Atlantic rainforest. Since the Atlantic rainforest areas in Brazil share environmental characteristics with Misiones province, the transmission cycle of R. parkeri strain Atlantic rainforest observed in Brazil should be extrapolated to Argentina, where awareness on the possibility of occurrence of rickettsiosis cases caused by this strain should be raised. PMID- 29764731 TI - How much is enough in rehabilitation? High running workloads following lower limb muscle injury delay return to play but protect against subsequent injury. AB - OBJECTIVES: Examine the influence of rehabilitation training loads on return to play (RTP) time and subsequent injury in elite Australian footballers. DESIGN: Prospective cohort study. METHODS: Internal (sessional rating of perceived exertion: sRPE) and external (distance, sprint distance) workload and lower limb non-contact muscle injury data was collected from 58 players over 5 seasons. Rehabilitation periods were analysed for running workloads and time spent in 3 rehabilitation stages (1: off-legs training, 2: non-football running, 3: group football training) was calculated. Multi-level survival analyses with random effects accounting for player and season were performed. Hazard ratios (HR) and 95% confidence intervals (CI) for each variable were produced for RTP time and time to subsequent injury. RESULTS: Of 85 lower limb muscle injuries, 70 were rehabilitated to RTP, with 30 cases of subsequent injury recorded (recurrence rate=11.8%, new site injury rate=31.4%). Completion of high rehabilitation workloads delayed RTP (distance: >49,775m [reference: 34,613-49,775m]: HR 0.12, 95%CI 0.04-0.36, sRPE: >1266AU [reference: 852-1266AU]: HR 0.09, 95%CI 0.03 0.32). Return to running within 4days increased subsequent injury risk (3-4days [reference: 5-6 days]: HR 25.88, 95%CI 2.06-324.4). Attaining moderate-high sprint distance (427-710m) was protective against subsequent injury (154-426m: [reference: 427-710m]: HR 37.41, 95%CI 2.70-518.64). CONCLUSIONS: Training load monitoring can inform player rehabilitation programs. Higher rehabilitation training loads delayed RTP; however, moderate-high sprint running loads can protect against subsequent injury. Shared-decision making regarding RTP should include accumulated training loads and consider the trade-off between expedited RTP and lower subsequent injury risk. PMID- 29764732 TI - A severe hemojuvelin mutation leading to late onset of HFE2-hemochromatosis. PMID- 29764734 TI - Can the contralateral limb be used as a control during the growing period in a rodent model? AB - The contralateral limb is often used as a control in various clinical, forensic and anthropological studies. However, no studies have been performed to determine if the contra-lateral limb is a suitable control during the bone development period. The aim of this study was to determine the bilateral symmetry of growing rat tibiae in terms of geometric shape, mechanical strength and bone morphological parameters with developmental stages. Left and right tibias of 18 male Sprague-Dawley rats at 4, 8 and 12 weeks of age were scanned with micro-CT for bone-morphometric evaluation and for 3D deviation analysis to quantify the geometric shape variations between left and right tibiae. Overall tibial lengths and curvatures were also measured, and bone mechanical strength was investigated using three-point bending tests. Deviation distributions between bilateral tibiae remained below 0.5 mm for more than 80% of the geometry for all groups. Tibial lengths, longitudinal tibial curvatures, bone-morphometric parameters and mechanical strengths changed significantly during the growing period but kept a strong degree of symmetry between bilateral tibiae. These results suggest that bilateral tibiae can be considered symmetrical in nature and that contralateral limb can be used as a control during the growing period in different experimental scenarios. PMID- 29764733 TI - Genetic polymorphism of sterol transporters in children with future gallstones. AB - BACKGROUND & AIMS: Gallstone disease is related to hypersecretion of cholesterol in bile, and low serum phytosterol levels. We examined how genetic polymorphisms of sterol transporters affect childhood cholesterol metabolism trait predicting adult gallstone disease. PATIENTS AND METHODS: In retrospective controlled study, we determined D19H polymorphism of ABCG8 gene, genetic variation at Niemann-Pick C1-like 1 (NPC1L1) gene locus (rs41279633, rs17655652, rs2072183, rs217434 and rs2073548), and serum cholesterol, noncholesterol sterols and lipids in children affected by gallstones decades later (n = 66) and controls (n = 126). RESULTS: In childhood, phytosterols were lower (9.7%-23.4%) in carriers of risk allele 19H compared to 19D homozygotes. Lowest campesterol/cholesterol tertile consisted of 1.9-times more future gallstone subjects, and 3.7-times more 19H carriers than highest one. Campesterol/cholesterol-ratio was highest in 19D homozygote controls, but ~11% lower in gallstone 19D homozygotes and ~25% lower among gallstone and control carriers of 19H. Gallstone subjects with alleles CC of rs41279633 and TT of rs217434 of NPC1L1 had ~18% lower campesterol/cholesterol ratio compared to mutation carriers. CONCLUSIONS: Risk trait of cholesterol metabolism (low phytosterols) in childhood favouring cholesterol gallstone disease later in adulthood is influenced by risk variant 19H of ABCG8 and obviously also other factors. NPC1L1 variants have minor influence on noncholesterol sterols. PMID- 29764735 TI - Risk factors for acute pancreatitis in patients with accidental hypothermia. AB - BACKGROUND: Pancreatic damage is commonly observed as a consequence of accidental hypothermia (core body temperature below 35 degrees C). We aimed to investigate the risk factors for pancreatic damage and the causal relationship in patients with accidental hypothermia. METHODS: This retrospective, single-center, observational case-control study was conducted in the emergency department of a tertiary care medical center. We investigated patients who were admitted for accidental hypothermia over a course of ten years (January 2008 to December 2017). RESULTS: Of the 138 enrolled patients, 70 had elevated serum amylase levels (51%). We observed a correlation between initial core body temperature and serum amylase level (Spearman's rank correlation coefficient -0.302, p < 0.001). Patients who developed acute pancreatitis had a significantly lower initial core body temperature than those who did not develop it (odds ratio = 0.76; 95% confidence interval [CI] = 0.61-0.94; p = 0.011). Receiver operating characteristic analysis showed that a body temperature lower than 28.5 degrees C at the time of visit was predictive of acute pancreatitis (area under the curve = 0.71, 95% CI = 0.54-0.88, sensitivity = 0.67, specificity = 0.69, p = 0.017). CONCLUSIONS: We concluded that an initial core body temperature lower than 28.5 degrees C was a risk factor for acute pancreatitis in accidental hypothermia cases. In such situations, careful follow-up is necessary. PMID- 29764736 TI - Time to successful completion of simulated pediatric lumbar puncture in lateral vs seated position: Comparison in novice providers. PMID- 29764737 TI - A comparison of head injuries in male and female lacrosse participants seen in US emergency departments from 2005 to 2016. AB - INTRODUCTION: In the United States there has been a large increase in participation in lacrosse for both males and females. The purpose of this study was to analyze the number of head injuries, injury rates (calculated using the reported number of participants) and types of head injuries that are seen in emergency departments in the United States. METHODS: We compared injuries between male and female lacrosse participants. This was a retrospective study using a publicly available database produced by the US Consumer Product Safety Commission and information about lacrosse participation from US Lacrosse. RESULTS: A linear regression was performed and showed a positive correlation between number of head injuries to males and time from 2002 to 2010 (R2 = 0.823; p = 0.001). While the number of injuries to the head in female lacrosse participants was not significant. There was a negative correlation between the number of head injuries to males from 2010 to 2016 (R2 = 0.800; p = 0.007), but again, there was no significance for female injury count (R2 = 0.417; p = 0.117). Other significant differences between head injuries in males and females included the mechanism of injury and the type of injury recorded. CONCLUSION: The most recent data from 2010 to 2016, suggest that both males and females have had a decrease in injury rate. However the total number of female head injuries is not significantly decreasing and as the sport continues to grow there will likely be more total head injuries and visits to the emergency department. PMID- 29764738 TI - Gastrocardiac syndrome: A forgotten entity. AB - Symptomatic bradycardia due to gastric distension is a rarely reported entity in the field of medicine. The mechanism of gastrointestinal distention that contributes to bradycardia is complex. A 75-year-old female with recurrent episodes of dizziness in the setting of gastric distension was found to have severe sinus bradycardia which resolved upon resolution of gastric distension. No structural or functional abnormality of heart was found. The patient was treated with permanent pacemaker implantation due to recurrent episodes of dizziness in the setting of sinus bradycardia. PMID- 29764739 TI - Maternal obesity alters the expression of embryonic regulatory transcripts in the preimplantation ovine conceptus. AB - The influence of exposure to overfeeding-induced maternal obesity around the time of conception on early embryogenesis was examined in the day 14 ovine conceptus. The relative abundance of FGFR2 and DNMT1 was influenced by maternal obesity status and conceptus sex, and the abundance of PPARG and PTGS2 transcripts was greater in male conceptuses regardless of the obesity status of the ewe. These observations demonstrated that short-term exposure to maternal obesity impacts early conceptus transcript patterning. PMID- 29764740 TI - Are computed tomography 3D measurements of the upper airways in mouth-breathing children in agreement with the ENT clinical diagnosis of obstruction? AB - INTRODUCTION: Imaging studies have hystorically been used to support the clinical otorhinolaryngological evaluation of the upper respiratory tract for the diagnosis of obstructive causes of oral breathing. OBJECTIVE: The objective of this study was to compare 3D volumetric measurements of nasal cavity, nasopharynx and oropharynx of obstructed mouth-breathing children with measurements of non obstructed mouth-breathing children. METHODS: This retrospective study included 25 mouth-breathing children aged 5-9 years evaluated by otorhinolaryngological clinical examination, flexible nasoendoscopy and full-head multi-slice computed tomography. Tomographic volumetric measurements and dichotomic otorhinolaryngological diagnosis (obstructed vs. non-obstructed) in three anatomical regions (the nasal cavity, nasopharynx and oropharynx) were compared and correlated. An independent sample t-test was used to assess the association between the 3D measurements of the upper airways and the otorhinolaryngological diagnosis of obstruction in the three anatomical regions. Inter- and intra observer intraclass correlation coefficients were used to evaluate the reliability of the 3D measurements. RESULTS: The intra-class correlation coefficients ranged from 0.97 to 0.99. An association was found between turbinate hypertrophy and nasal cavity volume reduction (p<0.05) and between adenoid hyperplasia and nasopharynx volume reduction (p<0.001). No association was found between palatine tonsil hyperplasia and oropharynx volume reduction. CONCLUSIONS: (1) The nasal cavity volume was reduced when hypertrophic turbinates were diagnosed; (2) the nasopharynx was reduced when adenoid hyperplasia was diagnosed; and (3) the oropharynx volume of mouth-breathing children with tonsil hyperplasia was similar to that of non-obstructed mouth-breathing children. The adoption of the actual anatomy of the various compartments of the upper airway is an improvement to the evaluation method. PMID- 29764741 TI - Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. AB - New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1 MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Abeta levels in mice in an acute treatment regimen. PMID- 29764742 TI - Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors. AB - The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a 17a) as well as their dehydrate dihydrofuran derivatives (11b-17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81 nM, respectively. However, all the dehydrate derivatives lose the SGLT2 inhibitory activity, with inhibition percentage no more than 66.5% at the concentration of 0.5 MUM, which might because of the configuration inversion at C-2 of glucose. In conclusion, the present study improves understanding of the SAR of SGLT2 inhibitors, and provided more information that could be applied to design new molecules. PMID- 29764744 TI - Effective gene silencing activity of prodrug-type 2'-O-methyldithiomethyl siRNA compared with non-prodrug-type 2'-O-methyl siRNA. AB - Small interfering RNAs (siRNAs) are an active agent to induce gene silencing and they have been studied for becoming a biological and therapeutic tool. Various 2' O-modified RNAs have been extensively studied to improve the nuclease resistance. However, the 2'-O-modified siRNA activities were often decreased by modification, since the bulky 2'-O-modifications inhibit to form a RNA-induced silencing complex (RISC). We developed novel prodrug-type 2'-O-methyldithiomethyl (MDTM) siRNA, which is converted into natural siRNA in an intracellular reducing environment. Prodrug-type 2'-O-MDTM siRNAs modified at the 5'-end side including 5'-end nucleotide and the seed region of the antisense strand exhibited much stronger gene silencing effect than non-prodrug-type 2'-O-methyl (2'-O-Me) siRNAs. Furthermore, the resistances for nuclease digestion of siRNAs were actually enhanced by 2'-O-MDTM modifications. Our results indicate that 2'-O-MDTM modifications improve the stability of siRNA in serum and they are able to be introduced at any positions of siRNA. PMID- 29764743 TI - Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines. AB - The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines. PMID- 29764745 TI - Can results from a Japanese pulmonary hypertension registry have an impact on Western guidelines? PMID- 29764746 TI - Appropriateness and clinical outcome of chest computed tomography without intravenous contrast: A study conducted in Pakistan. AB - BACKGROUND: Chest computed tomography (CT), including high-resolution CT (HRCT), has become an integral part of modern healthcare. It enables the physician to arrive at a diagnosis using a noninvasive approach. Our practice has shown that various chest CT scans without intravenous (IV) contrast, including HRCT, have no proper clinical indication. For the same reason, we have assessed the appropriateness of chest CT without IV contrast based on the evidence-based American College of Radiology (ACR) appropriateness criteria. METHODS: Chest CT scans without IV contrast were reviewed to evaluate if the examination was based upon the evidence-based ACR appropriateness criteria. All clinical indications, positive physical examination findings, laboratory test findings, and radiological records submitted at the time of chest CT were reviewed. RESULTS: Of 1205 CT scans, 538 (44.6%) were considered "inappropriate," 367 (30.4%) were considered "appropriate," and 300 (24.8%) were considered "may be appropriate." CT scans were performed on 241 (20.0%) patients with no clinical history, whereas 148 (12.3%) examinations in patients aged < 40 years were performed with no positive physical finding. Positive results that affected the management were 4.43 times more likely to be considered appropriate than inappropriate (adjusted odds ratio, 4.43; 95% confidence interval, 1.81-10.87). CONCLUSIONS: This study showed a high percentage of chest CT scans without IV contrast examinations not meeting the ACR appropriateness criteria. Chest CT is a valuable tool for evaluation of chest diseases only in the presence of adequate detailed history and physical examination. PMID- 29764747 TI - Correlation between clinical features, high-resolution computed tomography findings, and a visual scoring system in patients with pneumonia due to Mycoplasma pneumoniae. AB - BACKGROUND: Mycoplasma pneumoniae (MP) is the primary cause of community-acquired pneumonia. We aimed to evaluate the correlation between clinical features, with special reference to hypoxemia and the total affected area obtained using high resolution computed tomography (HRCT). METHODS: Medical records of MP pneumonia patients > 15 years of age at Kyorin University Hospital between January 2006 and November 2013 were reviewed retrospectively and compared to patients with Streptococcus pneumoniae pneumonia, diagnosed between January 2013 and September 2014. RESULTS: We identified 65 and 32 patients with MP- and S. pneumoniae pneumonia, respectively. HRCT data were available for 42 and 32 patients with MP- and S. pneumoniae pneumonia, respectively. Data were available for all hypoxemic patients. Hypoxemia was significantly higher in patients with S. pneumoniae (14/32, p = 0.008) than those with MP (5/39). Total visual score on HRCT correlated significantly with hypoxemia in both groups, but showed significantly higher scores with MP- than with S pneumoniae pneumonia in hypoxemic patients. MP pneumonia showed significant positive correlation between the total visual score and serum inflammatory markers (C-reaction protein [r = 0.43, p = 0.025] and lactate dehydrogenase [r = 0.466, p = 0.016]). In both groups, individual scores in the middle and lower lung fields were significantly higher than in the upper field, suggesting zonal predominance. CONCLUSIONS: This study provides the first evidence that the total affected area on lung HRCT was more with MP compared to S. pneumoniae pneumonia in hypoxemic patients and positively correlated with hypoxemia and serum inflammatory markers. PMID- 29764748 TI - Anticancer drug treatment for advanced lung cancer with interstitial lung disease. AB - Interstitial lung disease (ILD) is a risk factor for lung cancer development and is frequently observed in patients with lung cancer. Individuals with ILD have been excluded from most prospective clinical trials of lung cancer therapies because of the risk of ILD acute exacerbation. Thus, the optimal anticancer drug treatment for such patients has yet to be established. Tyrosine kinase inhibitors are avoided for the treatment of advanced non-small cell lung cancer (NSCLC) with ILD because of the concern of acute exacerbation, and information on the effects of immune-checkpoint inhibitors is limited in these patients. Only three prospective single-arm studies of cytotoxic chemotherapies for advanced lung cancer with ILD have been reported. Based on the results of these studies and those of retrospective analyses, carboplatin and either paclitaxel or nab paclitaxel are often selected in daily clinical practice for patients with NSCLC and ILD, whereas platinum plus etoposide is selected for those with small cell lung cancer and ILD. Although the antitumor activity of first-line platinum-based chemotherapy appears similar in advanced lung cancer patients with and without ILD, its impact on overall survival of the former patients is limited. The risks and benefits of chemotherapy must therefore be carefully explained before treatment initiation, and careful follow-up is necessary for such patients, especially those with the usual interstitial pneumonia pattern, a risk factor for chemotherapy-related exacerbation. Prospective clinical studies with large patient populations are still required to establish the appropriate treatments for advanced lung cancer with ILD. PMID- 29764750 TI - Patient-oriented optimal depth of conscious sedation using midazolam during flexible bronchoscopy: A prospective open-labeled single-arm trial. AB - BACKGROUND: The British Thoracic Society guidelines for diagnostic flexible bronchoscopy (FB) in adults recommend that intravenous sedation should be offered to patients undergoing bronchoscopy. However, it is difficult to determine the adequate depth of sedation for each patient because of inter-individual variability. METHODS: This prospective, open-label, single-arm study was conducted in patients undergoing routine bronchus examination with FB. All patients underwent FB under local anesthesia and conscious sedation, with initial administration of 0.03 mg/kg midazolam. The sedation level during FB was objectively assessed using the Ramsay sedation score (RSS). Two hours after the procedure, patients completed a questionnaire about its efficacy and adverse effects using a visual analog scale (VAS). Receiver operating characteristic (ROC) curve analyses were performed to determine the optimal RSS that could improve the subjective efficacy indicated by the VAS. RESULTS: This study enrolled 110 consecutive patients between September 2008 and February 2012. The median total amount of midazolam administered was 1.65 mg per patient. In an analysis of ROC curves between RSS and VAS, the area under the ROC curve for an RSS of 4 against the others was 0.66 (95% CI: 0.54 to 0.77, p = 0.014). The area under the ROC curve was not shown to be statistically significant for RSSs other than 4. CONCLUSIONS: The optimal depth of conscious sedation during FB for conventional examination was achieved at an RSS of 4. The patients' subjective evaluations indicated that a deep level of conscious sedation does not seem necessary for FB. PMID- 29764751 TI - Needle wash solution cultures following EBUS-TBNA with or without endobronchial intubation. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure with a high diagnostic yield in lesions adjacent to the airways. However, complications associated with EBUS TBNA, such as mediastinitis, have recently been reported. Oral bacteria contamination in punctured lymph nodes can cause severe infections. In the current study, we investigated whether endobronchial intubation using EBUS-TBNA can prevent oral bacterial contamination of punctured lymph nodes. METHODS: We retrospectively evaluated 80 patients (102 lymph nodes) who had undergone EBUS TBNA and divided them two groups: Group A comprised 60 patients who had undergone EBUS-TBNA with endobronchial intubation and Group B consisted of 20 patients who had undergone EBUS-TBNA without endobronchial intubation. The patients' medical records were examined and the two groups were compared using the unpaired Student's t-test. RESULTS: EBUS-TBNA needle wash cultures were positive in only two Group A cases (3.3%), but in all 20 Group B cases (100%) (P < 0.05). Except for one case of Mycobacterium tuberculosis, all bacterial isolates yielded typical oropharyngeal commensal flora. Fever (>= 38.0 degrees C) was observed in six Group A cases (10%) and two Group B cases (10%; P = 0.526). This was treated by cooling, a single administration of non-steroidal anti-inflammatory drugs, and/or antibiotic therapy. Fever was not associated with any clinical features, including malignancy in punctured lesions, number of punctures, echo features, simultaneous peripheral biopsy, additional oral prophylactic antibiotics, or positive needle wash cultures. CONCLUSIONS: Endobronchial intubation may prevent contamination by oropharyngeal commensal bacteria. PMID- 29764749 TI - Prognosis of chronic pulmonary aspergillosis in patients with pulmonary non tuberculous mycobacterial disease. AB - BACKGROUND: Pulmonary non-tuberculous mycobacterial disease (PNTM) is a known risk factor for chronic pulmonary aspergillosis (CPA). However, few studies have focused on the prognosis of PNTM-associated CPA. In the present investigation, we aimed to elucidate the clinical course and prognostic factors of CPA in patients with PNTM. METHODS: We retrospectively investigated the medical records of 62 patients with CPA and a history of PNTM who were admitted to Kinki-chuo Chest Medical Center between 2010 and 2015. Co-morbidities, causative microorganisms, radiological findings, and outcomes were evaluated. RESULTS: The patients' median age was 69.5 years, and the median follow-up period was 4.2 years. The major underlying diseases, other than PNTM and CPA, were old pulmonary tuberculosis, chronic obstructive pulmonary disease, and interstitial pneumonia. The most common causative NTM species were Mycobacterium avium complex (MAC; 37 patients; 59.7%) and Mycobacterium kansasii (20 patients; 32.3%). Survival was 83% after 1 year and 61% after 5 years. Use of systemic corticosteroids (hazard ratio: 3.32, 95% confidence interval: 1.23-9.51; P=0.00177) and C-reactive protein levels >= 5.0 mg/dL (hazard ratio: 8.96, 95% confidence interval: 2.15-62.9; P=0.0014) at the time of CPA diagnosis were associated with increased over-all mortality. CONCLUSIONS: CPA frequently developed in patients with MAC and M. kansasii PNTM. The treatment course of PNTM was not associated with all-cause mortality. However, systemic corticosteroid use and high CRP levels were negative prognostic factors of CPA in patients with PNTM. Since the prognosis is poor, early diagnosis and treatment of CPA are important in patients with PNTM. PMID- 29764752 TI - Successful treatment by pembrolizumab in a patient with end-stage renal disease with advanced non-small cell lung cancer and high PD-L1 expression. AB - We report a 66-year-old Japanese male with end-stage renal disease (ESRD) and advanced non-small cell lung cancer (NSCLC) who was on hemodialysis. The patient harbored high programmed death ligand 1 (PD-L1) expression and was successfully treated with pembrolizumab. Laboratory examination upon diagnosis showed elevated serum creatinine (6.58 mg/dL). We administered pembrolizumab (200 mg/body) and repeated every 3 weeks. His renal dysfunction gradually progressed, hemodialysis was initiated after eight courses of pembrolizumab, and the antitumor effect was maintained at five months after hemodialysis initiation. Therefore, pembrolizumab can be administered for patients with ESRD and advanced NSCLC, who harbor high PD L1 expression, during preparation for hemodialysis. PMID- 29764753 TI - Incidental diagnosis of pulmonary embolism during routine convex endobronchial ultrasound. PMID- 29764754 TI - Detection of methicillin-resistant coagulase-negative staphylococci harboring the class A mec complex by MALDI-TOF mass spectrometry. AB - The aim of this study was to test the identification of methicillin resistance in coagulase-negative staphylococci by routine matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). SCCmec cassettes of type II, III and VIII encode a small peptide called PSM-mec in the vicinity of mecA. It is visible at m/z 2415 during MALDI-TOF MS of whole cells of Staphylococcus aureus. In view of the fact that psm-mec has been identified in methicillin-resistant coagulase-negative staphylococci, we evaluated a collection of clinical coagulase-negative staphylococci, that contained 77.03% of methicillin-resistant isolates, for the presence of the structural gene encoding PSM-mec and the appearance of the corresponding signal during mass spectroscopy. In MALDI-TOF MS spectra, 89.65% of the strains that harbored the gene yielded the correct signal, corresponding to a sensitivity of 0.897 and a specificity of 1.0. However, regarding detection of methicillin resistance, i. e. considering all resistant strains as positive regardless of the presence of the gene, the overall sensitivity of the test decreased to 0.285, due to the fact that only 29.43% of all resistant isolates contained psm-mec. In conclusion, the presence of the signal in MALDI-TOF MS quickly indicates methicillin-resistance in coagulase negative staphylococci but its absence does not indicate susceptibility to methicillin. PMID- 29764755 TI - Investigations on small molecule inhibitors targeting the histone H3K4 tri methyllysine binding PHD-finger of JmjC histone demethylases. AB - Plant homeodomain (PHD) containing proteins are important epigenetic regulators and are of interest as potential drug targets. Inspired by the amiodarone derivatives reported to inhibit the PHD finger 3 of KDM5A (KDM5A(PHD3)), a set of compounds were synthesised. Amiodarone and its derivatives were observed to weakly disrupt the interactions of a histone H3K4me3 peptide with KDM5A(PHD3). Selected amiodarone derivatives inhibited catalysis of KDM5A, but in a PHD-finger independent manner. Amiodarone derivatives also bind to H3K4me3-binding PHD fingers from the KDM7 subfamily. Further work is required to develop potent and selective PHD finger inhibitors. PMID- 29764758 TI - Reality testing of the efficacy of tDCS on auditory hallucinations in schizophrenia. PMID- 29764756 TI - Straightforward hit identification approach in fragment-based discovery of bromodomain-containing protein 4 (BRD4) inhibitors. AB - A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 * 3200 compounds in total). Screening of the resulting sets using TSA, followed by re-testing at several concentrations, counter-screen, and TR-FRET assay resulted in 18 confirmed hits. Compounds derived from the initial fragment set showed better hit rate as compared to the other two sets. Finally, building dose-response curves revealed three compounds with IC50 = 1.9-7.4 MUM. For these compounds, binding sites and conformations in the BRD4 (4UYD) have been determined by docking. PMID- 29764759 TI - Development and validation of the client engagement and service use scale: A pilot study. AB - Specialized treatment for first episode psychosis offers clients a menu of services coordinated within a specialized treatment team. To enhance the impact of these services, promoting engagement and preventing early treatment drop-out is critical. However, engagement is poorly tracked and typically quantified through proxy variables such as session attendance, medication adherence, or working alliance. The aim of this study is to introduce and pilot a new measure of engagement for first episode psychosis coordinated specialty care, the Client Engagement and Service Use Scale (CENSUS). The CENSUS was evaluated for reliability and validated against the Service Engagement Scale and an appointment count for a small sample (N = 10) of first episode clients. The measure was also evaluated for acceptability by a consumer advocacy group. Clinicians achieved high inter-rater reliability after minimal training. CENSUS items demonstrated medium to large correlations with other measures of engagement. Feedback from the consumer group emphasized that clinicians should ask questions in a way that is nonjudgmental and successfully elicits authentic client feedback about their service preferences. This pilot study yielded preliminary evidence of reliability and validity, suggesting that the CENSUS is a useful and novel tool for tracking and differentiating degrees of client engagement across multiple intervention components and for facilitating structured discussions regarding clients' service utilization and preferences. PMID- 29764757 TI - Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition. AB - Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4 yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity. PMID- 29764760 TI - Altered predictive capability of the brain network EEG model in schizophrenia during cognition. AB - The study of the mechanisms involved in cognition is of paramount importance for the understanding of the neurobiological substrates in psychiatric disorders. Hence, this research is aimed at exploring the brain network dynamics during a cognitive task. Specifically, we analyze the predictive capability of the pre stimulus theta activity to ascertain the functional brain dynamics during cognition in both healthy and schizophrenia subjects. Firstly, EEG recordings were acquired during a three-tone oddball task from fifty-one healthy subjects and thirty-five schizophrenia patients. Secondly, phase-based coupling measures were used to generate the time-varying functional network for each subject. Finally, pre-stimulus network connections were iteratively modified according to different models of network reorganization. This adjustment was applied by minimizing the prediction error through recurrent iterations, following the predictive coding approach. Both controls and schizophrenia patients follow a reinforcement of the secondary neural pathways (i.e., pathways between cortical brain regions weakly connected during pre-stimulus) for most of the subjects, though the ratio of controls that exhibited this behavior was statistically significant higher than for patients. These findings suggest that schizophrenia is associated with an impaired ability to modify brain network configuration during cognition. Furthermore, we provide direct evidence that the changes in phase-based brain network parameters from pre-stimulus to cognitive response in the theta band are closely related to the performance in important cognitive domains. Our findings not only contribute to the understanding of healthy brain dynamics, but also shed light on the altered predictive neuronal substrates in schizophrenia. PMID- 29764763 TI - Direct recovery of mangostins from Garcinia mangostana pericarps using cellulase assisted aqueous micellar biphasic system with recyclable surfactant. AB - The alpha- and gamma-mangostins from Garcinia mangostana pericarps (GMP) exhibit antioxidant, anti-bacterial, anti-inflammatory and anti-tumor properties. The extraction yields alpha- and gamma-mangostins are often limited by the presence of the GMP cell walls. Therefore, the extraction and recovery of mangostins from GMP with an Aspergillus niger cellulase-assisted aqueous micellar biphasic system (CA-AMBS) was developed for enhanced yield of mangostins. Effects of the concentration of cellulase, the incubation time and the temperature of the system on the recovery of mangostins were investigated. The optimum condition for the recovery of alpha- and gamma-mangostins was obtained with the addition of 0.5% (w/w) cellulase incubated at 40 degrees C for 2 h. High log partition coefficients of alpha-mangostins (log Kalpha 4.79 +/- 0.02) and gamma-mangostins (log Kgamma 4.02 +/- 0.02) were achieved. High yields of alpha-mangostins (73.4%) and gamma-mangostins (14.0%) were obtained from the micelle-rich bottom phase with final concentrations of 3.67 mg/mL and 0.70 mg/mL, respectively. The back extraction of mangostins was performed with the addition of 30% (w/w) of isopropanol and 0.05 M of KCl at pH 9 to the bottom phase of the CA-AMBS. The yields of the alpha- and gamma-mangostins from GMP were considerably enhanced with the CA-AMBS and the direct recovery of mangostins was demonstrated without additional downstream processing steps. PMID- 29764762 TI - Analysis of Plasma Albumin, Vitamin D, and Apolipoproteins A and B as Predictive Coronary Risk Biomarkers in the REGICOR Study. AB - INTRODUCTION AND OBJECTIVES: New biomarkers could improve the predictive capacity of classic risk functions. The aims of this study were to determine the association between circulating levels of apolipoprotein A1 (apoA1), apolipoprotein B (apoB), albumin, and 25-OH-vitamin D and coronary events and to analyze whether these biomarkers improve the predictive capacity of the Framingham-REGICOR risk function. METHODS: A case-cohort study was designed. From an initial cohort of 5404 individuals aged 35 to 74 years with a 5-year follow up, all the participants who had a coronary event (n = 117) and a random group of the cohort (subcohort; n = 667) were selected. Finally, 105 cases and 651 individuals representative of the cohort with an available biological sample were included. The events of interest were angina, fatal and nonfatal myocardial infarction and coronary deaths. RESULTS: Case participants were older, had a higher proportion of men and cardiovascular risk factors, and showed higher levels of apoB and lower levels of apoA1, apoA1/apoB ratio, 25-OH-vitamin D and albumin than the subcohort. In multivariate analyses, plasma albumin concentration was the only biomarker independently associated with coronary events (HR, 0.73; P = .002). The inclusion of albumin in the risk function properly reclassified a significant proportion of individuals, especially in the intermediate risk group (net reclassification improvement, 32.3; P = .048). CONCLUSIONS: Plasma albumin levels are inversely associated with coronary risk and improve the predictive capacity of classic risk functions. PMID- 29764764 TI - Microbial fuel cells equipped with an iron-plated carbon-felt anode and Shewanella oneidensis MR-1 with corn steep liquor as a fuel. AB - A single chamber type microbial fuel cell (MFC) with 100 mL of chamber volume and 50 cm2 of air-cathode was developed in this study wherein a developed iron-plated carbon-felt anode and Shewanella oneidensis MR-1 were used. The performance of the iron-plated carbon-felt anode and the possibility of corn steep liquor (CSL) as a fuel, which was the byproduct of corn wet milling and contained lactic acid, was investigated here. MFCs equipped with iron-plated or non-plated carbon-felt anodes exhibited maximum current densities of 443 or 302 mA/m2 using 10 g/L of reagent-grade lactic acid, respectively. In addition, using centrifuged CSL without insoluble ingredients or non-centrifuged CSL as a fuel, the maximum current densities of the MFCs with iron-plated carbon-felt anode were 321 or 158 mA/m2, respectively. This report demonstrated the effect of iron-plated carbon felt anode for electricity generation of MFC using S. oneidensis MR-1 and the performance of CSL as a fuel. PMID- 29764761 TI - Reference values for muscle strength: a systematic review with a descriptive meta analysis. AB - BACKGROUND: Muscle strength is an important component of health. OBJECTIVE: To describe and evaluate the studies which have established the reference values for muscle strength on healthy individuals and to synthesize these values with a descriptive meta-analysis approach. METHODS: A systematic review was performed in MEDLINE, LILACS, and SciELO databases. Studies that investigated the reference values for muscle strength of two or more appendicular/axial muscle groups of health individuals were included. Methodological quality, including risk of bias was assessed by the QUADAS-2. Data extracted included: country of the study, sample size, population characteristics, equipment/method used, and muscle groups evaluated. RESULTS: Of the 414 studies identified, 46 were included. Most of the studies had adequate methodological quality. Included studies evaluated: appendicular (80.4%) and axial (36.9%) muscles; adults (78.3%), elderly (58.7%), adolescents (43.5%), children (23.9%); isometric (91.3%) and isokinetic (17.4%) strength. Six studies (13%) with similar procedures were synthesized with meta analysis. Generally, the coefficient of variation values that resulted from the meta-analysis ranged from 20.1% to 30% and were similar to those reported by the original studies. The meta-analysis synthesized the reference values of isometric strength of 14 muscle groups of the dominant/non-dominant sides of the upper/lower limbs of adults/elderly from developed countries, using dynamometers/myometer. CONCLUSIONS: Most of the included studies had adequate methodological quality. The meta-analysis provided reference values for the isometric strength of 14 appendicular muscle groups of the dominant/non-dominant sides, measured with dynamometers/myometers, of men/women, of adults/elderly. These data may be used to interpret the results of the evaluations and establish appropriate treatment goals. PMID- 29764765 TI - Easy reuse of magnetic cross-linked enzyme aggregates of lipase B from Candida antarctica to obtain biodiesel from Chlorella vulgaris lipids. AB - In this work, magnetic cross-linked enzyme aggregates (mCLEAs) of CALB (lipase B from Candida antarctica) were prepared and characterized. Moreover, a method for an easy, sustainable and economic extraction of lipids from nitrogen-starved cells of Chlorella vulgaris var L3 was developed. Then, the extracted lipids (oils and free fatty acids, FFAs) were converted to biodiesel using mCLEAs and chemical acid catalysis. Among several lipid extraction methods, saponification was selected given the amount of wet microalgal biomass it can process per unit of time, its low market value, and because it allows for the use of less toxic solvents. A biodiesel conversion of 80.2 +/- 4.4% was obtained by chemical catalysis (1 h at 100 degrees C) using FFAs and methanol as the alkyl donor. However, a biodiesel conversion of more than 90% (3 h at 30 degrees C) was obtained using mCLEAs and methanol. Both chemical and enzymatic catalysts gave biodiesel with similar fatty acid alkyl ester (FAAE) composition. Methanol, at 15% (v/v) or higher concentration, caused a decrease of lipase activity and a concomitant increase in the size of mCLEA aggregates (up to 2 MUm), as measured by dynamic light scattering (DLS). The magnetic character of the novel biocatalyst permits its easy recovery and reuse, for at least ten consecutive catalytic cycles (retaining 90% of the initial biodiesel conversion), using mild reaction conditions and environmentally-friendly solvents. PMID- 29764766 TI - Efficient monooxygenase-catalyzed piceatannol production: Application of cyclodextrins for reducing product inhibition. AB - Piceatannol is a rare, costly plant-based stilbene derivative and exhibits various health-enhancing properties. Recently, we demonstrated that piceatannol could be produced from resveratrol through site-selective hydroxylation using Escherichia coli cells expressing the monooxygenase HpaBC. However, piceatannol production ceased at approximately 25 mM, even when sufficient levels of the substrate resveratrol remained in the reaction mixture. In this study, we found that high concentrations (>20-25 mM) of piceatannol significantly inhibited the HpaBC-catalyzed reaction. Cyclodextrins (CDs) reportedly encapsulate various hydrophobic compounds. We found that the addition of beta-CD or gamma-CD to the reaction mixture reduced the inhibition caused by the product piceatannol. The effects of beta-CD on piceatannol production were more pronounced than those of gamma-CD at high concentrations of the substrate resveratrol and CDs. The production of piceatannol reached 49 mM (12 g L-1) in the presence of beta-CD, a level twice that achieved in the absence of beta-CD. The technique described here might be applicable to the bioproduction of other stilbenes and structurally related compounds. PMID- 29764767 TI - A Systematic Review of Mobile Produce Markets: Facilitators and Barriers to Use, and Associations with Reported Fruit and Vegetable Intake. AB - BACKGROUND: Diet-related chronic diseases are a major public health burden. There is growing awareness that disparities in healthful food access contribute to disparities in health. Mobile produce markets (MPMs) have emerged as a strategy to improve fruit and vegetable access and consumption, particularly among low income, minority, and other vulnerable populations (eg, older adults and children) in food desert neighborhoods. OBJECTIVE: This review examined research on MPMs in the United States and specifically aimed to assess the relationship between MPM use and fruit and/or vegetable intake, and facilitators and barriers related to MPM use within a social ecological framework. METHODS: A systematic review of the literature consistent with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was conducted. Articles published through December 2017 were identified using the following databases: Web of Science, PubMed, Agricola, and CAB Abstracts. MPM studies published in English and in peer-reviewed journals were eligible for inclusion if they were based on primary research of MPMs in the United States, included results, and if MPMs were analyzed separately from other market venues and sold predominantly fruits and/or vegetables. A total of 24 studies were identified for inclusion, which varied in study types as follows: quantitative (n=15), qualitative (n=3), and mixed methods (n=6). RESULTS: An association was found between MPM use and higher reported fruit and/or vegetable intake, although existing studies that measured fruit and vegetable intake were not rigorous in study design (eg, lack of control group, use of convenience sample, small sample size). MPM location was the most commonly cited facilitator of MPM use. Other institutional factors (eg, nutrition education), as well as policy factors (eg, food-assistance programs), community factors (eg, market site liaisons), interpersonal factors (eg, socializing at market), and intrapersonal factors (eg, awareness of the benefits of fruit and/or vegetable intake) were identified. CONCLUSIONS: MPMs offer a promising strategy to improve access to fruits and vegetables and may further support healthful-food purchasing and consumption through food-assistance incentives and enticements for consumers (eg, opportunities for social networking and nutrition education). Future research on MPMs would benefit from more rigorous experimental designs, such as including a control group, and examining multiple levels within a social ecological framework. PMID- 29764769 TI - Comparison of computed tomography with magnetic resonance imaging for imaging based clinical target volume contours in cervical cancer brachytherapy. AB - PURPOSE: To compare CT- and MRI-based brachytherapy (BT) target volumes for patients with advanced cervical cancer so as to identify those who benefit most from MRI-based planning. We also studied how the natural mobility of the organ at risks (OARs) affects the given doses. METHODS AND MATERIALS: Subjects were 60 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB-IVA cervical cancer. The CT high-risk clinical target volume (HR-CTV) was first delineated, then the MRI HR-CTV, with volume discrepancies calculated by subtraction. The DICE coefficient (DC) of similarity was calculated from a superimposition of the volumes. Maximum doses delivered to D2cc of OARs in CT and MRI plans were compared; the effect of time on the natural mobility was analyzed. RESULTS: The mean HR-CTVs and the maximum doses given to OARs in CT- and MRI based planes were similar. Multivariate analysis showed that deep infiltration affecting the uterine corpus and bowel loops adjacent to the cervix were the factors significantly impacting on the volume discrepancy between CT and MRI HR CTV (p = 0.001, p = 0.045) and on the DC (p = 0.005, p = 0.028). Univariate analysis demonstrated that the FIGO stage had a significant impact on DC (p = 0.022). Patients with bowel loops adjacent to the cervix had lower body mass indices (p = 0.003). The median difference between the doses given in CT- and MRI based plans, caused by mobility, were 0.5 Gy, 0.3 Gy, and 0.45 Gy per fraction for the rectum, bladder and sigmoid, respectively. No correlation of observed uncertainties and time between image acquisitions was detected. CONCLUSIONS: CT- or MRI-based scans at BT are adequate for OAR dose-volume histograms analysis. Cervical cancer patients with deep infiltration affecting the uterine corpus, a low body mass index with bowel loops adjacent to the cervix and an FIGO Stage III IVA benefit most from MRI-based planning of BT. PMID- 29764770 TI - Haploidentical stem cell transplantation-bone marrow vs peripheral blood. AB - Hematopoietic stem cells may be obtained by collection of bone marrow, mobilization and collection of peripheral blood stem cells or umbilical cord blood. Transplantation of peripheral blood hematopoietic cells has increased due to faster engraftment and practicability in both the related, unrelated or haploidentical setting. We reviewed the question of which stem cell source - bone marrow (BM) or peripheral blood (PBSC) - is the most suitable for individuals undergoing haploidentical stem cell transplantation. BM or PBSC could be safely used as allograft sources for haploidentical transplantation with good outcomes and acceptable rates of GVHD and graft failure. Prospective randomized studies are needed to evaluate the effect of PB vs BM in haploidentical settings. PMID- 29764771 TI - External stent in laparoscopic pyeloplasty: The K-wire technique. AB - The majority of surgeons leave internal stents following laparoscopic pyeloplasty, which necessitates a second anaesthetic for removal. A novel technique of placing external nephro-ureteric stents, thus obviating a second procedure for retrieval, is shown in this video bank. As demonstrated in the video, a Kirschner wire (K-wire) is used to thread the stent in place. Although, there are few reports of using externalised stents in laparoscopic pyeloplasty, it is believed that this technique has not been previously described. So far this technique has been used in 22 patients without any stent-related complications. The technique is feasible, safe and reproducible. It obviates the need for a further anaesthetic and avoids potential risks of another procedure. Secondary benefits include avoiding another hospital admission. PMID- 29764772 TI - Dizziness and (Fear of) Falling in The Elderly: A Few Facts. PMID- 29764768 TI - Hydroxylase Activity of ASPH Promotes Hepatocellular Carcinoma Metastasis Through Epithelial-to-Mesenchymal Transition Pathway. AB - Over-expression of aspartyl (asparagynal)-beta-hydroxylase (ASPH) contributes to hepatocellular carcinoma (HCC) invasiveness, but the role of ASPH hydroxylase activity in this process remains to be defined. As such, the current study investigated the role of ASPH hydroxylase activity in downstream signalling of HCC tumorgenesis and, specifically, metastasis development. Over-expression of wild-type ASPH, but not a hydroxylase mutant, promoted HCC cell migration in vitro, as well as intrahepatic and distant metastases in vivo. The enhanced migration and epithelial to mesenchymal transition (EMT) activation was notably absent in response to hydroxylase activity blockade. Vimentin, a regulator of EMT, interacted with ASPH and likely mediated the effect of ASPH hydroxylase activity with cell migration. The enhanced hydroxylase activity in tumor tissues predicted worse prognoses of HCC patients. Collectively, the hydroxylase activity of ASPH affected HCC metastasis through interacting with vimentin and regulating EMT. As such, ASPH might be a promising therapeutic target of HCC. PMID- 29764773 TI - Cochlear Implant Electrode Array From Partial to Full Insertion in Non-Human Primate Model. AB - OBJECTIVES: To determine the feasibility of progressive insertion (two sequential surgeries: partial to full insertion) of an electrode array and to compare functional outcomes. MATERIAL AND METHODS: 8 normal-hearing animals (Macaca fascicularis (MF)) were included. A 14 contact electrode array, which is suitably sized for the MF cochlea was partially inserted (PI) in 16 ears. After 3 months of follow-up revision surgery the electrode was advanced to a full insertion (FI) in 8 ears. Radiological examination and auditory testing was performed monthly for 6 months. In order to compare the values a two way repeated measures ANOVA was used. A p-value below 0.05 was considered as statistically significant. IBM SPSS Statistics V20 was used. RESULTS: Surgical procedure was completed in all cases with no complications. Mean auditory threshold shift (ABR click tones) after 6 months follow-up is 19 dB and 27 dB for PI and FI group. For frequencies 4, 6, 8, 12, and 16 kHz in the FI group, tone burst auditory thresholds increased after the revision surgery showing no recovery thereafter. Mean threshold shift at 6 months of follow- up is 19.8 dB ranging from 2 to 36dB for PI group and 33.14dB ranging from 8 to 48dB for FI group. Statistical analysis yields no significant differences between groups. CONCLUSION: It is feasible to perform a partial insertion of an electrode array and progress on a second surgical time to a full insertion (up to 270o). Hearing preservation is feasible for both procedures. Note that a minimal threshold deterioration is depicted among full insertion group, especially among high frequencies, with no statistical differences. PMID- 29764774 TI - The Natural History of Asymptomatic Deep Pars Tensa Retraction. AB - OBJECTIVES: The aim of this study was to quantify the natural behavior of asymptomatic deep pars tensa retraction in both adults and children. MATERIALS AND METHODS: Asymptomatic pars tensa retraction pockets that contacted the promontory were included. Persistently symptomatic pars tensa retraction, pars tensa retraction that did not contact the promontory, patients with attic retraction pockets and patients with cholesteatoma were excluded. Patients were followed up annually and were eliminated from the study if they required active intervention or recovered so that their ears were persistently ventilated with no contact of the tympanic membrane to the promontory. Outcome variables included surgical intervention, surgical intervention for cholesteatoma, and spontaneous improvement and were studied using the life table method. RESULTS: In total, 64 children and 25 adults were enrolled, of whom 19 children and five adults required intervention and five children and two adults developed pars tensa cholesteatomas. No significant difference was observed between children and adults. In total, three children, but no adults, developed attic cholesteatomas without progression of the pars tensa disease. Furthermore, the ears of 20 children, but not even one adult ear, returned to normal over the 10-year study period. DISCUSSION: Most retracted adult ears did not change. Over 10 years, the most common finding in children was the return of their ears to normal. Ear of all children recovered during the second decade. Deterioration to form cholesteatoma was not influenced by age. Attic cholesteatoma without the progression of pars tensa disease was observed in children, but not in adults. PMID- 29764775 TI - Predicting Round Window Visibility During Cochlear Implantation Using High Resolution CT Scan. AB - OBJECTIVES: To predict round window niche (RWN) visibility using high-resolution computed tomography (HRCT). MATERIALS AND METHODS: We retrospectively reviewed the pre-surgical axial HRCT scan of 110 patients who underwent cochlear implantation and compared the CT visibility of RWN with the intraoperative findings by reviewing the operative notes and replaying the surgical video recording. The shape of RWN was determined using the HRCT slice with maximum RWN visibility. Accordingly, it was classified as the O-shaped or C-shaped RWN. Based on the surgical view, RWN visibility was classified as clearly visible or difficult to visualize. Radiological findings were correlated with the surgical view. RESULTS: Seventy-six cases (69%) showed clear RWN visibility; of them, 66 correlated with the HRCT finding C-shaped RWN. Of the other 34 cases (31%) with difficult RWN visualization, 26 correlated with the HRCT finding O-shaped RWN. The sensitivity and specificity of the HRCT finding in predicting the difficulty in visualization of RWN were 79.4% and 86.8%, respectively. CONCLUSION: The RWN shape on HRCT can be a simple and useful method in predicting RWN visibility through posterior tympanotomy approach in cochlear implantation. PMID- 29764776 TI - Vestibulo-Cochlear Function After Cochlear Implantation in Patients With Meniere's Disease. AB - OBJECTIVES: To measure the auditory (pure tone audiometry and word recognition scores) and vestibular (video head impulse test and vestibular myogenic potentials) outcomes in patients diagnosed with Meniere's disease (MD) who underwent cochlear implantation. MATERIAL AND METHODS: This prospective study included 23 cochlear implant users with MD and 29 patients diagnosed with far advanced otosclerosis (the control group). RESULTS: The preoperative mean pure tone average thresholds were 99 and 122.5 dB for the Meniere's and control groups, respectively. Word recognition scores after cochlear implant yielded a median of 80% and 72% for the Meniere's and control groups, respectively. Semicircular canal gain was not observed to vary post implantation (mean variation for lateral, posterior, and anterior plane was 0, 0.03, and 0, respectively). The mean ocular and cervical myogenic potentials asymmetry varied as 9.65% and 18.39%, respectively. CONCLUSIONS: The auditory performance improved in patients with MD similar to the general cochlear implant population. No major dysfunction of otolithic or semicircular canal function was demonstrated after the implantation surgery. PMID- 29764777 TI - Comparison of Social Interaction between Cochlear-Implanted Children with Normal Intelligence Undergoing Auditory Verbal Therapy and Normal-Hearing Children: A Pilot Study. AB - OBJECTIVE: A cochlear implant is a device that helps hearing-impaired children by transmitting sound signals to the brain and helping them improve their speech, language, and social interaction. Although various studies have investigated the different aspects of speech perception and language acquisition in cochlear implanted children, little is known about their social skills, particularly Persian-speaking cochlear-implanted children. Considering the growing number of cochlear implants being performed in Iran and the increasing importance of developing near-normal social skills as one of the ultimate goals of cochlear implantation, this study was performed to compare the social interaction between Iranian cochlear-implanted children who have undergone rehabilitation (auditory verbal therapy) after surgery and normal-hearing children. MATERIALS AND METHODS: This descriptive-analytical study compared the social interaction level of 30 children with normal hearing and 30 with cochlear implants who were conveniently selected. The Raven test was administered to the both groups to ensure normal intelligence quotient. The social interaction status of both groups was evaluated using the Vineland Adaptive Behavior Scale, and statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 21. RESULTS: After controlling age as a covariate variable, no significant difference was observed between the social interaction scores of both the groups (p > 0.05). In addition, social interaction had no correlation with sex in either group. CONCLUSION: Cochlear implantation followed by auditory verbal rehabilitation helps children with sensorineural hearing loss to have normal social interactions, regardless of their sex. PMID- 29764778 TI - Lower Beclin-1 mRNA Levels in Pediatric Compared With Adult Patients With Otitis Media With Effusion. AB - OBJECTIVES: The role of autophagy in the pathophysiology of otitis media with effusion (OME) remains unclear, particularly regarding the difference between pediatric and adult patients. The present study analyzed the expression levels of autophagy-associated mRNAs in effusion fluids obtained from pediatric and adult patients with OME. MATERIALS AND METHODS: Middle ear fluid samples were collected from 76 pediatric patients and 41 adult patients with OME, and the levels of mRNAs encoding autophagy-related genes were measured using real-time reverse transcription-polymerase chain reaction. The relationships between the levels of autophagy-associated mRNAs and the frequency of ventilation tube insertion, the characteristics of middle ear fluid, and the results of bacterial culture were analyzed. RESULTS: Autophagy-associated mRNAs were present in the effusion fluid of all patients. The level of Beclin-1 mRNA was significantly lower in pediatric than in adult patients, regardless of the frequency of surgery or fluid characteristics (p < 0.05). CONCLUSION: Autophagy-associated mRNAs were expressed in effusion fluids of both pediatric and adult patients with OME. However, the level of Beclin-1 mRNA was significantly lower in the effusion fluid of pediatric than adult patients. PMID- 29764779 TI - Patients Over 60 Years of Age Have Poor Prognosis in Facial Nerve Decompression Surgery with Preserved Ossicular Chain. AB - OBJECTIVE: We report our retrospective study of the recovery rate of auditory ossicles preserved facial nerve decompression surgery via the transmastoid approach in cases of both an electroneurography score of < 10% and a Yanagihara score of <=8 in Bell's palsy and Ramsay Hunt syndrome. MATERIALS AND METHODS: We retrospectively reviewed 47 patients who we were able to follow-up for more than 6 months following the onset of palsy. The recovery rate was defined by the Japan Society for Facial Nerve Research or the Yanagihara score. RESULTS: Twelve months after palsy onset, the recovery rate was 48.8% (20/41) for all patients, 65.2% (15/23) for patients with Bell's palsy, and 27.8% (5/18) for patients with Ramsay Hunt syndrome. Comparing the clinical efficacy of surgical treatment at 12 months after palsy onset, we observed a statistically significant effect of age. Comparing the Yanagihara scores of patients aged < 60 years with those of patients aged >=60 years revealed that patients aged >=60 years had significant poor prognosis, particularly in patients with Ramsay Hunt syndrome, which showed a very low recovery rate (14.3%). We also analyzed six other factors, but none showed statistical significance. CONCLUSION: The clinical efficacy of surgical treatment of Ramsay Hunt syndrome was inferior to that of Bell's palsy, which is consistent with previous reports. There was a statistically significant difference in the Yanagihara score between patients aged < 60 years and those aged >=60 years. Particularly, patients with Ramsay Hunt syndrome aged >=60 years have a very low recovery rate. PMID- 29764780 TI - What is the Required Frequency of MRI Scanning in the Wait and Scan Management? AB - The wait and scan policy is being increasingly used as the first measure after the diagnosis of a vestibular schwannoma (VS) using magnetic resonance imaging (MRI). As part of the European Academy of Otology and Neuro-Otology (EAONO) position statement on VS, the frequency of imaging has been studied in the literature. Among 163 studies, 29 fulfilled the inclusion criteria and were scored using the Grading of Recommendations, Assessment, Development, and Evaluation system. Because tumor growth rate during the first 5 years of follow up is predictive of further growth during the upcoming years, a protocol for wait and scan is useful for centers dealing with this condition. The EAONO proposal is that after the initial diagnosis by MRI, a first new MRI would take place after 6 months, annually for 5 years, and then every other year for 4 years, followed by a lifelong MRI follow-up every 5 years. The first early MRI is to screen for fast growing tumors, and the lifelong follow-up with tapered intervals is to detect late repeated growth. PMID- 29764781 TI - EAONO position statement on Vestibular Schwannoma: Imaging Assessment Question: How should growth of Vestibular Schwannoma be defined? AB - The relevance of defining the growth of vestibular schwannoma (VS) is that any significant VS growth may impact treatment strategy. A conservative treatment strategy is often proposed as a primary treatment option in the management of VS. Several authors have demonstrated that a significant proportion of VSs do not grow, and those that do, usually grow slowly. Surgical and/or radiosurgical treatment options may be offered to the patient according to the VS growth. Therefore, defining the VS growth is a determinant in managing treatment strategies. A comprehensive literature search was performed to examine the definition of tumor growth for VS. The literature review was conducted using PubMed and Embase databases dated back to 20 years (1995-2015) and was updated until February 2015. VS growth should be measured on contrast-enhanced T1 weighted images. Although there the overall quality of the present studies is low, all highlight a significant VS growth of > 2 mm, and/or 1.2 cm3, and/or 20% change in volume, and/or the square of the product of the 2 orthogonal diameters. We suggest that VS growth should instead change management strategies when a 3-mm increase in diameter on two consecutive MRI scans are performed 1 year apart. PMID- 29764782 TI - EAONO Position Statement on Vestibular Schwannoma: Imaging Assessment. What are the Indications for Performing a Screening MRI Scan for a Potential Vestibular Schwannoma? PMID- 29764784 TI - Sneezing and Perilymphatic Fistula of the Round Window: Case Report and Systematic Review of the Literature. AB - The goal of the present study was to describe a case of perilymphatic fistula (PLF) of the round window (RW) that occurred after sneezing, along with a review of the literature. We report a case of PLF of RW, which was provoked by sneezing, and its consequent medical and surgical treatments. With respect to the review of the literature, articles were initially selected based on their titles or abstracts, followed by methodological evaluation. The patient underwent an explorative tympanotomy (ET) with packaging of RW with the pericondrium, following which the patient's complaints regarding vertigo and imbalance disappeared, but the severe sensorineural hearing loss persisted. For the literature review, five references were selected. These studies showed a great variety in the clinical presentation and healing of symptoms. Sneezing represents a rare but well-recognized cause of PLF, as reported in our case. The correct selection of patients who should undergo ET and an early surgical repair of PLF are mandatory for better outcomes, especially in case of hearing. PMID- 29764783 TI - An Analysis of The Parameters Used In Speech ABR Assessment Protocols. AB - The aim of this study was to assess the parameters of choice, such as duration, intensity, rate, polarity, number of sweeps, window length, stimulated ear, fundamental frequency, first formant, and second formant, from previously published speech ABR studies. To identify candidate articles, five databases were assessed using the following keyword descriptors: speech ABR, ABR-speech, speech auditory brainstem response, auditory evoked potential to speech, speech-evoked brainstem response, and complex sounds. The search identified 1288 articles published between 2005 and 2015. After filtering the total number of papers according to the inclusion and exclusion criteria, 21 studies were selected. Analyzing the protocol details used in 21 studies suggested that there is no consensus to date on a speech-ABR protocol and that the parameters of analysis used are quite variable between studies. This inhibits the wider generalization and extrapolation of data across languages and studies. PMID- 29764785 TI - Balloon Eustachian Tuboplasty: Systematic Review of Long-term Outcomes and Proposed Indications. AB - Balloon Eustachian tuboplasty (BET) aims to improve the function of the Eustachian tube (ET). The objective of this study was to review the long-term outcome of BET and present the process and results of outlining indications for BET by the Finnish Otosurgical Society. The literature review is based on a database search performed in May 2017. The search resulted in 100 individual articles, which were screened for relevance. Five articles fulfilled the inclusion criteria (follow-up >=12 months). Five additional articles (follow-up, 6-11 months) were analyzed to obtain supportive information. The proposed BET indications were constituted in the 2016 annual meeting of the Finnish Otosurgical Society. The workshop included a review of the Eustachian tube physiology, middle ear aeration mechanisms, and BET outcome studies. Thereafter, the members of the Society first voted and then discussed 14 cases in order to conclude whether BET was indicated in each case, and subsequently, a consensus statement on the indications for BET was outlined. The long-term follow-up studies were heterogeneous regarding the Eustachian tube dysfunction (ETD) definition, patient selection, follow-up duration, additional treatments, and outcome measures. The current, but limited, evidence suggests that BET is effective in the long-term. However, more long-term studies with uniform criteria and outcome measures as well as placebo-controlled studies are needed. The proposed indications for BET by the Finnish Otosurgical Society include chronic bothersome symptoms referring to ETD, ETD-related symptoms when pressure changes rapidly, or recurring serous otitis media. With the current evidence, we suggest treating only adults with BET. PMID- 29764786 TI - Instability in Patients with CANVAS: Can Computerized Dynamic Posturography Help in Diagnosis? AB - OBJECTIVE: To describe the pattern of dynamic posturography or its role in diagnosis in patients with cerebellar ataxia with neuropathy and vestibular arreflexia syndrome (CANVAS). MATERIALS AND METHODS: We present and describe posturographic data of four patients diagnosed with the CANVAS syndrome in a tertiary hospital. RESULTS: In all patients, the average balance score was diminished. Two patients presented a pattern of visual dependence. The other two showed misuse of three posturography sensory information (visual, vestibular and propioceptive information), specially null use of vestibular information, deterioration of somatosensory input, and poor use of strategies, particularly in conditions 5 and 6. CONCLUSIONS: If there is misuse of somatosensory information in sensory organization test (SOT) in a patient with bilateral vestibular deficit, a possibility of CANVAS should be considered. The SOT provides valuable information, because it evaluates sensory inputs influence the maintenance of balance. PMID- 29764787 TI - Myringoplasty Quality Control Is Necessary: Comparison of Surgical Results of Two Consecutive Series in A Single Institution. AB - OBJECTIVE: The aim of this study was to evaluate and compare myringoplasty results from two different consecutive series conducted at the Kuopio University Hospital during a four-decade period. MATERIALS AND METHODS: We reviewed 315 patients (a total of 338 ears) who underwent myringoplasty at Kuopio University Hospital between the years 1986 and 2012. The results from this series were compared with those form a previously published series of 404 patients who underwent myringoplasty between 1970 and 1985 at the same institution. RESULTS: Myringoplasty was considered to be successful whenever the tympanic membrane remained closed without atelectasis. The results were analyzed at the 1- and 3 year follow-up. The overall success rate after 1 year was 82.8% compared with 88% in the previous series. The success rate after 3 years was 87.4%. The best closure rate after 1 year (85.7%) was achieved with fascia grafts (n=272) and perichondrium (85.7%, n=14). The closure rate of 61.9% with the perichondrium/cartilage graft (n=21) and 71.0% with the fat graft (n=31) was statistically significantly lower (p < 0.05) compared with that with the fascia graft. The postoperative air-bone gap (0.5-4 kHz) was < 10 dB(HL) in 56.2% and < 20 dB(HL) in 79.6% cases compared with 61% and 87%, respectively, in previous series. CONCLUSION: Myringoplasty is a safe procedure with a reasonably high success rate. We observed a slight deterioration in the overall results compared with the previous series. This study highlights the importance of systematic quality control and the results and the need for follow-up of the learning curve after the introduction of new surgical techniques and materials. PMID- 29764788 TI - Periosteal Flap in Cochlear Implantation, How I Do It? AB - This clinical report describes and evaluates a novel periosteal flap design. This technique was applied in 26 patients who underwent cochlear implantation surgery at two tertiary referral centers. No complications were observed during or after the surgery. Additionally, there was no evidence of device migration, wound infection, wound hematoma, or delayed wound healing. Notably, the mastoid emissary vein was intact in all cases. In conclusion, this modified anterior based periosteal flap is a safe procedure and is aimed at avoiding mastoid emissary vein bleeding and allowing complete repositioning of the periosteum over the implanted device. PMID- 29764789 TI - Eosinophilic Otitis Media Treated with Anti-IgE Monoclonal Antibodies and A Bone Conduction Implant. AB - Eosinophilic otitis media (EOM) are intractable otitis media characterized by highly viscous secretions containing eosinophils in the middle ear. They are resistant to conventional medication and surgery. This condition occurs primarily in patients with bronchial asthma or allergic rhinitis and is often complicated by rhinosinusitis. Systemic and topical steroid therapies are effective treatments. However, long-term steroid therapy is often limited by a high risk of serious adverse effects. The use of topical steroids and otorrhea are bothersome when wearing hearing aids. Here, we report a case of intractable otitis media due to EOM. Otorrhea was controlled with topical steroids. Bone conduction hearing was stable for an extended period with anti-IgE monoclonal antibodies (omalizumab). An implantable bone conduction hearing aid was used for rehabilitation of conductive hearing loss. PMID- 29764790 TI - A Case of Inverted Papilloma of The Mastoid Cavity After Cholesteatoma Surgery. AB - An inverted papilloma is a benign neoplasm that occurs exclusively in the sinonasal cavity; an inverted papilloma involving the mastoid cavity is extremely rare. We present the case of a patient with an inverted papilloma of the mastoid cavity secondary to cholesteatoma surgery. No case that occurred after acquired cholesteatoma has been reported in literature. A 39-year-old female who was diagnosed with cholesteatoma was treated with a modified radical mastoidectomy in 1988. After recurrence, the patient underwent a canal wall down mastoidectomy in 2006. Four years later, the patient complained of right ear fullness; an examination determined that the right ear canal wall was nearly obliterated by a soft tissue mass. Surgery determined that a papilloma-like mass filled the mastoid cavity. The tumor was surgically resected by revision canal wall down mastoidectomy with canaloplasty. Histologically, it was determined to be an inverted papilloma. There has been no evidence of recurrence to date. PMID- 29764791 TI - Giant Cell Tumor of the Temporal Bone and Skull Base: A Case Report. AB - Giant cell tumor (GCT) is a benign tumor that originates from undifferentiated mesenchymal cells of the bone marrow. The cranium as well as temporal bone is a rare location for GCTs. Despite its benign nature, GCT may be locally aggressive and has the potential to recur locally. Furthermore, GCT may give rise to pulmonary metastases (~1%) in addition to causing local bone destruction. Surgical excision is the treatment of choice for patients with GCT. We describe the case of a 56-year-old female who presented with headache and hearing loss with extensive GCT, which originated in the squamous part of the temporal bone and extended into the left mandibular fossa and middle ear. She was treated by total resection of the tumor using left temporal craniotomy approach. In this article, we present a case of temporal bone GCT with its clinical features as well as a review of the related literature. PMID- 29764792 TI - Otitis Media with Effusion Revealing Underlying Meningioma. AB - Otitis media with effusion (OME) is a very common condition in the current clinical practice. Usually idiopathic, it may sometimes be the consequence of primary diseases. Extracranial meningioma is rare, and even more when involving the ear and temporal bone. We report a case of temporal meningioma spreading to the middle ear and mastoid presenting as an OME. The diagnosis relies on a thorough imaging evaluation with computed tomography and magnetic resonance imaging. This short report aims to warn the otolaryngologist of this rare situation to prevent any delay in diagnosing and managing such a condition. PMID- 29764793 TI - Evaluation of the Ovarian Reserve in Adolescents with Hashimoto's Thyroiditis Using Serum Anti-Mullerian Hormone Levels AB - Objective: This study aims to evaluate ovarian reserve in adolescent girls with Hashimoto's thyroiditis (HT) by assessment of serum anti-Mullerian hormone (AMH) levels. It was hypothesized that HT decreases ovarian reserve and AMH levels are lower in the HT group. Methods: Thirty HT patients, aged between 10-18 years, and 30 healthy girls as the control group were enrolled in this cross-sectional study. The mean serum AMH levels of the groups were compared using the Mann Whitney U test. Results: There was no statistically significant difference between the patient and the control groups in terms of serum AMH levels. There was a negative correlation between serum AMH and thyroid stimulating hormone (TSH) levels and no correlation between serum AMH and anti-thyroid peroxidase (anti-TPO) or anti-thyroglobulin (anti-Tg) antibody levels. Conclusion: Our results show that ovarian reserve of adolescent girls, as measured by serum AMH levels, is not affected by HT. Autoimmune damage to the ovaries may take time and the adolescent period may be too early to see these effects. Follow up of the patients for reproductive abnormalities and initiation of prospective studies is recommended. PMID- 29764794 TI - An eHealth Capabilities Framework for Graduates and Health Professionals: Mixed Methods Study. AB - BACKGROUND: The demand for an eHealth-ready and adaptable workforce is placing increasing pressure on universities to deliver eHealth education. At present, eHealth education is largely focused on components of eHealth rather than considering a curriculum-wide approach. OBJECTIVE: This study aimed to develop a framework that could be used to guide health curriculum design based on current evidence, and stakeholder perceptions of eHealth capabilities expected of tertiary health graduates. METHODS: A 3-phase, mixed-methods approach incorporated the results of a literature review, focus groups, and a Delphi process to develop a framework of eHealth capability statements. RESULTS: Participants (N=39) with expertise or experience in eHealth education, practice, or policy provided feedback on the proposed framework, and following the fourth iteration of this process, consensus was achieved. The final framework consisted of 4 higher-level capability statements that describe the learning outcomes expected of university graduates across the domains of (1) digital health technologies, systems, and policies; (2) clinical practice; (3) data analysis and knowledge creation; and (4) technology implementation and codesign. Across the capability statements are 40 performance cues that provide examples of how these capabilities might be demonstrated. CONCLUSIONS: The results of this study inform a cross-faculty eHealth curriculum that aligns with workforce expectations. There is a need for educational curriculum to reinforce existing eHealth capabilities, adapt existing capabilities to make them transferable to novel eHealth contexts, and introduce new learning opportunities for interactions with technologies within education and practice encounters. As such, the capability framework developed may assist in the application of eHealth by emerging and existing health care professionals. Future research needs to explore the potential for integration of findings into workforce development programs. PMID- 29764796 TI - Predicting the Reasons of Customer Complaints: A First Step Toward Anticipating Quality Issues of In Vitro Diagnostics Assays with Machine Learning. AB - BACKGROUND: Vendors in the health care industry produce diagnostic systems that, through a secured connection, allow them to monitor performance almost in real time. However, challenges exist in analyzing and interpreting large volumes of noisy quality control (QC) data. As a result, some QC shifts may not be detected early enough by the vendor, but lead a customer to complain. OBJECTIVE: The aim of this study was to hypothesize that a more proactive response could be designed by utilizing the collected QC data more efficiently. Our aim is therefore to help prevent customer complaints by predicting them based on the QC data collected by in vitro diagnostic systems. METHODS: QC data from five select in vitro diagnostic assays were combined with the corresponding database of customer complaints over a period of 90 days. A subset of these data over the last 45 days was also analyzed to assess how the length of the training period affects predictions. We defined a set of features used to train two classifiers, one based on decision trees and the other based on adaptive boosting, and assessed model performance by cross-validation. RESULTS: The cross-validations showed classification error rates close to zero for some assays with adaptive boosting when predicting the potential cause of customer complaints. Performance was improved by shortening the training period when the volume of complaints increased. Denoising filters that reduced the number of categories to predict further improved performance, as their application simplified the prediction problem. CONCLUSIONS: This novel approach to predicting customer complaints based on QC data may allow the diagnostic industry, the expected end user of our approach, to proactively identify potential product quality issues and fix these before receiving customer complaints. This represents a new step in the direction of using big data toward product quality improvement. PMID- 29764798 TI - Development of a Web Portal for Physical Activity and Symptom Tracking in Oncology Patients: Protocol for a Prospective Cohort Study. AB - BACKGROUND: Significant benefits accrue from increasing physical activity levels in people with a history of cancer. Physical activity levels can be increased using behavioral change interventions in this population. Access to Web portals and provision of activity monitors to provide feedback may support behavior change by encouraging patient engagement in physical therapy. The Web portal evaluated in this study will provide a system to monitor physical activity and sleep, for use by both clinician and patient, along with symptom and health related quality of life tracking capabilities. OBJECTIVE: The aim of this study was to outline a protocol for a feasibility study focused on a Web-based portal that provides activity monitoring and personalized messaging to increase physical activity in people with cancer. METHODS: Using a longitudinal cohort design, people with cancer will be serially allocated to 3 intervention cohorts of 20 participants each and followed for 10 weeks. Cohort 1 will be provided a wearable activity monitor and access to a Web-based portal. Cohort 2 will receive the same content as Cohort 1 and in addition will receive a weekly activity summary message. Cohort 3 will receive the same content as Cohorts 1 and 2 and in addition will receive a personalized weekly coaching message. Feasibility of the use of the portal is the primary outcome. RESULTS: Results are expected in early 2018. Outcome measures will include goal attainment and completion rate. CONCLUSIONS: This study will provide information about the feasibility of investigating eHealth initiatives to promote physical activity in people with cancer. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9586. PMID- 29764797 TI - Public Attitudes Toward Guided Internet-Based Therapies: Web-Based Survey Study. AB - BACKGROUND: Internet interventions have been proposed to improve the accessibility and use of evidence-based psychological treatments. However, little is known about attitudes toward such treatments, which can be an important barrier to their use. OBJECTIVE: This study aimed to (1) determine attitudes toward guided internet interventions, (2) assess its acceptability compared with other internet-based formats, and (3) explore predictors of acceptance. METHODS: A convenience-sample Web-based survey (N=646) assessed attitudes toward guided internet therapies (ie, perceived usefulness and helpfulness, and advantage relative to face-to-face therapy), preferences for delivery modes (ie, e preference: guided internet interventions, unguided internet interventions, or videoconferencing psychotherapy), and potential predictors of attitudes and preferences: sociodemographics, help-seeking-related variables, attachment style, and perceived stress. RESULTS: Although most participants perceived internet interventions as useful or helpful (426/646, 65.9%), a few indicated their advantage relative to face-to-face therapy (56/646, 8.7%). Most participants preferred guided internet interventions (252/646, 39.0%) over videoconferencing psychotherapy (147/646, 22.8%), unguided internet interventions (124/646, 19.2%), and not using internet interventions (121/646, 18.8%; missing data: 1/646, 0.2%). Attachment avoidance and stress were related to e-preference (all P<.05). Moreover, preference for therapist-guided internet interventions was higher for individuals who were aware of internet-based treatment (chi26=12.8; P=.046). CONCLUSIONS: Participants assessed therapist-guided internet interventions as helpful, but not equivalent to face-to-face therapies. The vast majority (523/646, 81.0%) of the participants were potentially willing to use internet based approaches. In lieu of providing patients with only one specific low intensity treatment, implementation concepts should offer several options, including guided internet interventions, but not limited to them. Conversely, our results also indicate that efforts should focus on increasing public knowledge about internet interventions, including information about their effectiveness, to promote acceptance and uptake. PMID- 29764799 TI - Perceptions of Existing Wearable Robotic Devices for Upper Extremity and Suggestions for Their Development: Findings From Therapists and People With Stroke. AB - BACKGROUND: Advances in wearable robotic technologies have increased the potential of these devices for rehabilitation and as assistive devices. However, the utilization of these devices is still limited and there are questions regarding how well these devices address users' (therapists and patients) needs. OBJECTIVE: The aims of this study were to (1) describe users' perceptions about existing wearable robotic devices for the upper extremity; (2) identify if there is a need to develop new devices for the upper extremity and the desired features; and (3) explore obstacles that would influence the utilization of these new devices. METHODS: Focus groups were held to collect data. Data were analyzed thematically. RESULTS: A total of 16 participants took part in the focus group discussions. Our analysis identified three main themes: (1) "They exist, but..." described participants' perceptions about existing devices for upper extremity; (2) "Indeed, we need more, can we have it all?" reflected participants' desire to have new devices for the upper extremity and revealed heterogeneity among different participants; and (3) "Bumps on the road" identified challenges that the participants felt needed to be taken into consideration during the development of these devices. CONCLUSIONS: This study resonates with previous research that has highlighted the importance of involving end users in the design process. The study suggests that having a single solution for stroke rehabilitation or assistance could be challenging or even impossible, and thus, engineers should clearly identify the targeted stroke population needs before the design of any device for the upper extremity. PMID- 29764800 TI - Mindfulness-Based Symptom and Stress Management Apps for Adults With Chronic Lung Disease: Systematic Search in App Stores. AB - BACKGROUND: Up to 70% of lung cancer survivors are affected by chronic obstructive pulmonary disease (COPD), a common, debilitating, comorbid disease. Lung cancer and COPD are both characterized by symptoms such as breathlessness, fatigue, and psychological distress. These distressing chronic symptoms are exacerbated by stress and detract from an individual's quality of life. OBJECTIVE: The aim of this study was to identify and evaluate evidence-based, commercially available apps for promoting mindfulness-based strategies among adults with a COPD or lung cancer history (ie, chronic lung disease). METHODS: For this review, an interdisciplinary research team used 19 keyword combinations in the search engines of Google and iOS app stores in May 2017. Evaluations were conducted on the apps' (1) content, (2) usability heuristics, (3) grade-level readability, and (4) cultural sensitivity. RESULTS: The search resulted in 768 apps (508 in iOS and 260 in Google stores). A total of 9 apps met the inclusion criteria and received further evaluation. Only 1 app had below an eighth-grade reading level; the ninth one did not have enough text to calculate a readability score. None of the 9 apps met the cultural sensitivity evaluation criteria. CONCLUSIONS: This systematic review identified critical design flaws that may affect the ease of using the apps in this study. Few mobile apps promote mindfulness-based strategies among adults with chronic lung disease (ie, COPD or lung cancer or both), but those that exist, overall, do not meet the latest scientific evidence. Recommendations include more stringent regulation of health related apps, use of evidence-based frameworks and participatory design processes, following evidence-based usability practices, use of culturally sensitive language and images, and ensuring that content is written in plain language. PMID- 29764795 TI - Mapping of Crowdsourcing in Health: Systematic Review. AB - BACKGROUND: Crowdsourcing involves obtaining ideas, needed services, or content by soliciting Web-based contributions from a crowd. The 4 types of crowdsourced tasks (problem solving, data processing, surveillance or monitoring, and surveying) can be applied in the 3 categories of health (promotion, research, and care). OBJECTIVE: This study aimed to map the different applications of crowdsourcing in health to assess the fields of health that are using crowdsourcing and the crowdsourced tasks used. We also describe the logistics of crowdsourcing and the characteristics of crowd workers. METHODS: MEDLINE, EMBASE, and ClinicalTrials.gov were searched for available reports from inception to March 30, 2016, with no restriction on language or publication status. RESULTS: We identified 202 relevant studies that used crowdsourcing, including 9 randomized controlled trials, of which only one had posted results at ClinicalTrials.gov. Crowdsourcing was used in health promotion (91/202, 45.0%), research (73/202, 36.1%), and care (38/202, 18.8%). The 4 most frequent areas of application were public health (67/202, 33.2%), psychiatry (32/202, 15.8%), surgery (22/202, 10.9%), and oncology (14/202, 6.9%). Half of the reports (99/202, 49.0%) referred to data processing, 34.6% (70/202) referred to surveying, 10.4% (21/202) referred to surveillance or monitoring, and 5.9% (12/202) referred to problem-solving. Labor market platforms (eg, Amazon Mechanical Turk) were used in most studies (190/202, 94%). The crowd workers' characteristics were poorly reported, and crowdsourcing logistics were missing from two-thirds of the reports. When reported, the median size of the crowd was 424 (first and third quartiles: 167-802); crowd workers' median age was 34 years (32-36). Crowd workers were mainly recruited nationally, particularly in the United States. For many studies (58.9%, 119/202), previous experience in crowdsourcing was required, and passing a qualification test or training was seldom needed (11.9% of studies; 24/202). For half of the studies, monetary incentives were mentioned, with mainly less than US $1 to perform the task. The time needed to perform the task was mostly less than 10 min (58.9% of studies; 119/202). Data quality validation was used in 54/202 studies (26.7%), mainly by attention check questions or by replicating the task with several crowd workers. CONCLUSIONS: The use of crowdsourcing, which allows access to a large pool of participants as well as saving time in data collection, lowering costs, and speeding up innovations, is increasing in health promotion, research, and care. However, the description of crowdsourcing logistics and crowd workers' characteristics is frequently missing in study reports and needs to be precisely reported to better interpret the study findings and replicate them. PMID- 29764801 TI - Assessing Unmet Information Needs of Breast Cancer Survivors: Exploratory Study of Online Health Forums Using Text Classification and Retrieval. AB - BACKGROUND: Patient education materials given to breast cancer survivors may not be a good fit for their information needs. Needs may change over time, be forgotten, or be misreported, for a variety of reasons. An automated content analysis of survivors' postings to online health forums can identify expressed information needs over a span of time and be repeated regularly at low cost. Identifying these unmet needs can guide improvements to existing education materials and the creation of new resources. OBJECTIVE: The primary goals of this project are to assess the unmet information needs of breast cancer survivors from their own perspectives and to identify gaps between information needs and current education materials. METHODS: This approach employs computational methods for content modeling and supervised text classification to data from online health forums to identify explicit and implicit requests for health-related information. Potential gaps between needs and education materials are identified using techniques from information retrieval. RESULTS: We provide a new taxonomy for the classification of sentences in online health forum data. 260 postings from two online health forums were selected, yielding 4179 sentences for coding. After annotation of data and training alternative one-versus-others classifiers, a random forest-based approach achieved F1 scores from 66% (Other, dataset2) to 90% (Medical, dataset1) on the primary information types. 136 expressions of need were used to generate queries to indexed education materials. Upon examination of the best two pages retrieved for each query, 12% (17/136) of queries were found to have relevant content by all coders, and 33% (45/136) were judged to have relevant content by at least one. CONCLUSIONS: Text from online health forums can be analyzed effectively using automated methods. Our analysis confirms that breast cancer survivors have many information needs that are not covered by the written documents they typically receive, as our results suggest that at most a third of breast cancer survivors' questions would be addressed by the materials currently provided to them. PMID- 29764802 TI - Overcoming Barriers to HIV Prevention and Healthcare Among Sub-Saharan African Migrants in Spain. PMID- 29764804 TI - NHS's greatest achievement after 70 years: The BMJ shortlist. PMID- 29764805 TI - David Oliver: Should advance care planning enter the mainstream? PMID- 29764803 TI - Effectiveness of a Combined Web-Based and Ecological Momentary Intervention for Incoming First-Year University Students: Protocol for a 3-Arm Randomized Controlled Trial. AB - BACKGROUND: Alcohol use among university students is common, and those who drink often choose to drink heavily (ie, 4 or more drinks per session for women or 5 or more for men). Web-based interventions (WBIs), in which students complete assessments and receive personalized feedback about their alcohol use, and ecological momentary interventions (EMIs), which use mobile devices as a method of delivering intervention information, are 2 methods that have had some success in reducing alcohol use among university students. OBJECTIVE: The aim of this study was to investigate the effectiveness of a combined WBI and EMI intervention to reduce alcohol use among university students. METHODS: The study is a 3-arm randomized controlled trial. Participants will be randomized into either a WBI+EMI condition, a WBI-only condition, or an assessment-only control. Our sample will consist of first-year university students, recruited through 5 residential colleges at the University of Otago, New Zealand. All participants will complete an online survey at baseline (ie, before Orientation Week); those in the WBI-only and WBI+EMI conditions will immediately receive personalized feedback (ie, the WBI), whereas participants in the assessment-only condition will receive no feedback. In addition, participants randomized into the WBI+EMI, but not those in the WBI-only or assessment-only groups, will receive 8 Orientation Week (2 per day on nights with large social events) and 6 academic year EMIs (delivered fortnightly). Participants in all conditions will complete brief surveys at the end of the first and second semester and report their weekend alcohol use fortnightly throughout each semester via ecological momentary assessments. RESULTS: The primary hypothesis is that participants in the WBI+EMI group will consume significantly fewer drinks during weekends in their first semester at university compared with WBI-only and assessment-only groups. Secondary hypotheses are that, when compared with the WBI-only and assessment only groups, the WBI+EMI group will report consuming fewer drinks during Orientation Week, report experiencing fewer negative alcohol-related consequences after first semester, and report lower Alcohol Use Disorder Identification Test Consumption scores following their first semester. CONCLUSIONS: This study adds to a growing body of work investigating the utility of WBIs and EMIs in curbing alcohol consumption. In addition, the study will help to inform policy approaches aimed at curbing alcohol consumption and alcohol-related harm in university students. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000015246; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374104&isReview= rue (Archived by WebCite at http://www.webcitation.org/6z9jRLTz6). REGISTERED REPORT IDENTIFIER: RR1-10.2196/10164. PMID- 29764808 TI - 9/11 Firefighters at Risk for Multiple Myeloma. AB - The largest study to date of responders to the World Trade Center attacks in New York, NY, on 9/11 reports that exposed firefighters have roughly twice the risk of developing multiple myeloma precursor disease as the general population. Moreover, firefighters who go on to develop multiple myeloma exhibit a younger age of onset and more aggressive disease than is typical. PMID- 29764807 TI - Predicting the Presence of Oral Squamous Cell Carcinoma Using Commonly Dysregulated MicroRNA in Oral Swirls. AB - Oral swirls are a noninvasive, rapidly collected source of salivary microRNA (miRNA) potentially useful in the early detection of disease states, particularly oral squamous cell carcinoma (OSCC). The aim of this study was to predict the presence of OSCC using a panel of OSCC-related dysregulated miRNA found in oral swirls, identified jointly in data from formalin-fixed paraffin-embedded (FFPE) and fresh-frozen specimens. Next-generation sequencing (NGS) was used to determine miRNA fold changes in FFPE OSCC specimens relative to histologically normal epithelium. These data were placed with NGS of fresh-frozen tissue data of The Cancer Genome Atlas database to select a panel of commonly dysregulated miRNA. This panel was then analyzed by RT-qPCR in RNA extracted from oral swirls collected from 30 patients with OSCC and 30 controls. Upregulation of miR-31 and miR-21 and downregulation of miR-99a, let-7c, miR-125b, and miR-100 were found between OSCC and controls in both FFPE and fresh-frozen samples. These miRNAs were studied in a training set of 15 OSCC versus 15 control oral swirls to develop a dysregulation score [AUC, 0.95; 95% confidence interval (CI), 0.88 1.03] and classification tree. A test cohort of 15 OSCC versus 15 control oral swirls yielded a dysregulation score AUC of 0.86 (95% CI, 0.79-1.00) with the classification tree identifying 100% (15/15) of OSCC and 67% (10/15) of controls. This study debuts the use of OSCC-associated miRNA, commonly dysregulated in both FFPE and frozen specimens, in oral swirls to indicate the presence of OSCC with high accuracy. Cancer Prev Res; 11(8); 491-502. (c)2018 AACR. PMID- 29764806 TI - Temporal Efficacy of a Sulforaphane-Based Broccoli Sprout Diet in Prevention of Breast Cancer through Modulation of Epigenetic Mechanisms. AB - Breast cancer is the most common cancer and the second leading cause of cancer related death among women. An important risk factor for breast cancer is individual genetic background, which is initially generated early in human life, for example, during the processes of embryogenesis and fetal development in utero Bioactive dietary components such as sulforaphane (SFN), an isothiocyanate from cruciferous vegetables including broccoli sprouts (BSp), cabbage, and kale, has been shown to reduce the risk of developing many common cancers through regulation of epigenetic mechanisms. Our study indicates a prenatal/maternal BSp dietary treatment exhibited maximal preventive effects in inhibiting breast cancer development compared with postnatal early-life and adult BSp treatments in two transgenic mouse models that can develop breast cancer. Postnatal early-life BSp treatment starting prior to puberty onset showed protective effects in prevention of breast cancer but was not as effective as the prenatal/maternal BSp treatment. However, adulthood-administered BSp diet did not reduce mammary tumorigenesis. Our results suggest that the prenatal/maternal BSp bioactive natural plant product may impact early embryonic development by regulating global differential gene expression through affecting epigenetic profiles resulting in differential susceptibility to breast cancer later in life. These results suggest that a temporal exposure to epigenetic-modulating dietary components such as cruciferous vegetables could be a key factor for maximizing chemopreventive effects on human breast cancer. This study may lead to translational breast cancer chemopreventive potential by appropriate administration of key dietary components leading to early breast cancer prevention in humans. Cancer Prev Res; 11(8); 451-64. (c)2018 AACR. PMID- 29764810 TI - GMC's wellbeing review aims to tackle doctors' workplace stresses. PMID- 29764812 TI - Hunger strikes in UK detention centres: injustice provokes desperate protests. PMID- 29764811 TI - In This Issue: May. PMID- 29764813 TI - Real-time continuous glucose monitoring improves glycaemic variability and neonatal outcomes in pregnant women with type 1 diabetes. PMID- 29764814 TI - Scotland to target junk food promotions to cut childhood obesity. PMID- 29764809 TI - Temperature-induced physiological stress and reproductive characteristics of the migratory seahorse Hippocampus erectus during a thermal stress simulation. AB - Inshore-offshore migration occurs frequently in seahorse species, either because of prey opportunities or because they are driven by reproduction, and variations in water temperature may dramatically change migratory seahorse behavior and physiology. The present study investigated the behavioral and physiological responses of the lined seahorse Hippocampus erectus under thermal stress and evaluated the potential effects of different temperatures on its reproduction. The results showed that the thermal tolerance of the seahorses was time dependent. Acute thermal stress (30 degrees C, 2-10 h) increased the basal metabolic rate (breathing rate) and the expression of stress response genes (Hsp genes) significantly and further stimulated seahorse appetite. Chronic thermal treatment (30 degrees C, 4 weeks) led to a persistently higher basal metabolic rate, higher stress response gene expression and higher mortality rates, indicating that the seahorses could not acclimate to chronic thermal stress and might experience massive mortality rates due to excessively high basal metabolic rates and stress damage. Additionally, no significant negative effects on gonad development or reproductive endocrine regulation genes were observed in response to chronic thermal stress, suggesting that seahorse reproductive behavior could adapt to higher-temperature conditions during migration and within seahorse breeding grounds. In conclusion, this simulation experiment indicates that temperature variations during inshore-offshore migration have no effect on reproduction, but promote significantly high basal metabolic rates and stress responses. Therefore, we suggest that the observed high tolerance of seahorse reproduction is in line with the inshore-offshore reproductive migration pattern of lined seahorses.This article has an associated First Person interview with the first author of the paper. PMID- 29764815 TI - Eliminate "toxic" trans fats from food by 2023, WHO urges. PMID- 29764817 TI - Sons must abide by decision not to allow their father to have a nasogastric at home. PMID- 29764816 TI - Consider funding social care like the NHS, say policy experts. PMID- 29764818 TI - Necrotising scleritis, keratitis and uveitis in primary antiphospholipid syndrome. AB - Ocular manifestations of antiphospholipid syndrome typically include thromboembolic and neuro-ophthalmic complications. In this report we present a case of inflammation of the ocular coats in a patient diagnosed with antiphospholipid syndrome 16 years prior. We discuss management of the case and the possible aetiology of the rare association. PMID- 29764819 TI - Penetrating trauma causing cerebrospinal fluid leak without nerve root damage. AB - A 19-year-old man with a stab injury to the lower back presented with no focal neurology or haemodynamic instability. He complained of a headache that was improved by lying flat and underwent imaging to look for damage to local structures. He was found to have air in his intraspinal space. Initially this case was managed conservatively; however, 2 weeks after discharge, he presented with cerebrospinal fluid leak from his wound. This was managed with neurosurgical intervention and watertight closure of fascia. There were no further complications. PMID- 29764820 TI - Unexplained bruising: a developing story. AB - We present the case of a 10-month-old male infant who presented to accident and emergency with unexplained bruising of the ear. Initial blood tests showed no clotting or platelet abnormalities and non-accidental injury investigation commenced. He was subsequently reviewed by the dermatology team who suggested the diagnosis of acute haemorrhagic oedema of infancy presumably triggered by a viral or bacterial infection, and the clinical findings fit this diagnosis. PMID- 29764821 TI - Atopic dermatitis complicated by severe impetigo in a Syrian refugee infant. AB - We present the case of a 3-month-old infant with atopic dermatitis who developed severe impetigo. The child was born to Syrian refugees shortly after they arrived in Canada. The case demonstrates the rapid and nearly complete resolution of dramatic skin findings after a course of hydrocortisone ointment and oral antibiotics with adjuvant measures. For resettled refugees, access to family physicians and local language proficiency are common barriers that negatively impact their health and healthcare. We discuss some aspects of how the healthcare model in one Canadian city addresses these issues in the context of this case. The case also raises questions about the burden of dermatological conditions in refugees while in transit and in countries of resettlement. The few reports that exist suggest that some conditions may be relatively common and that the epidemiology warrants additional investigation. PMID- 29764822 TI - Numb chin syndrome: an ominous sign of mandibular metastasis. AB - A 51-year-old woman a known case of stage 2 breast carcinoma in 2006 and underwent left mastectomy performed in the same year presented with bilateral lower limb pain suggestive of spinal pathology, and left chin numbness, both of 2 weeks' duration. Examination revealed left mandibular hypoesthesia without any other sign or symptoms. Orthopantomogram was unremarkable apart from mild alveolar bone expansion at tooth 36 area, which was extracted 3 months earlier. Subsequently, a full-body positron emission tomography contrast enhanced computer tomography revealed hypermetabolic lesions of her axial (excluding skull) and appendicular skeleton. In the head and neck region, left mandibular foramen and oropharynx bilaterally showed increased metabolism suggestive of tumour metastasis. The diagnosis was numb chin syndrome secondary to mandibular metastasis. Apart from supportive treatment, she was started on palliative chemotherapy and radiotherapy. At the time of discharge, there were no active complaints other than the aforementioned hypoesthesia. PMID- 29764823 TI - Spontaneous closure of branchial sinus of the pyriform fossa. AB - Management of third and fourth branchial cleft anomalies are similar. These anomalies should be suspected in a child with recurrent low-anterior neck abscess. Investigations in the form of cross-sectional studies and examination of the pharynx under anaesthesia will facilitate diagnosis and resolution of abscess. Spontaneous closure of the pyriform sinus can occur following conservative management with antibiotic treatment and abscess drainage. This emphasise the role of second-look prior to implementing endoscopic cauterisation or surgery. PMID- 29764824 TI - Achieving Full Neurological Recovery in Snakebite using Best Supportive Care. AB - A 29-year-old woman presented to a community hospital in Sierra Leone 2 hours after being bitten by an unknown snake. On arrival, she was agitated though alert, however deteriorated into respiratory arrest. There was no local availability of antivenom. The patient remained in respiratory arrest undergoing best supportive care in a low-resource setting for 2 hours 55 minutes before returning to spontaneous ventilation. She went on to make a full neurological recovery. Though spontaneous recovery following snakebite envenoming is rare, this case showcases that good communication and basic manoeuvres can have a hugely positive impact on patient outcome. Alongside this, it highlights the need for staff and community engagement and implementation of local protocols in order to improve confidence and achieve consistent practice. PMID- 29764825 TI - Sudden hemichorea and frontal lobe syndrome: a rare presentation of unbalanced polycythaemia vera. AB - Polycythaemia vera (PV) is an haematological neoplasm that frequently presents neurological symptoms. However, chorea is a rare complication of this disease, occurring in less than 5% of the patients. Cognitive impairment related to PV unbalanced is also a rare complication, and it can improve with proper treatment. We present a 96-year-old-man with acute-onset hemichorea and frontal lobe syndrome with no vascular pathology in the basal ganglia or frontal region. A clear relationship was observed between the onset of involuntary movements and the cognitive impairment and worsening of haematological parameters in the patient. After causal and symptomatic treatment, the patient's clinical status improved. In the elderly, PV must be considered as a cause of acute chorea and sudden cognitive impairment, as early diagnosis leads to effective treatment and prevention of complications. PMID- 29764826 TI - Systemic sclerosis: severe pulmonary arterial hypertension and pericardial effusion at diagnosis. AB - A 51-year-old female patient with a recent hospital admission reported to the emergency room (ER) with progressive worsening of fatigue, dyspnoea and chest discomfort. She had been recently admitted and discharged with the diagnosis of pericarditis and medicated with non-steroidal anti-inflammatory drugs and diuretics. She returned to the ER with persisting symptoms. Echocardiography was repeated and showed signs of elevated right ventricular systolic pressure and a slightly increased moderate/severe pericardial effusion without signs of cardiac tamponade. The patient was admitted and further evaluation confirmed an underlying case of advanced systemic sclerosis with skin, vascular, pulmonary and cardiac involvement. The patient was referred to specialised consults in autoimmune pathology and pulmonary arterial hypertension. She was started on bosentan and corticosteroids, presenting a favourable clinical evolution although symptoms of exertional dyspnoea persist. PMID- 29764827 TI - Not so mass effect? Finding of a remarkable 'incidentaloma' in a teenager with neurofibromatosis. AB - A 13-year-old boy with neurofibromatosis type 1 presented to the emergency department twice in a fortnight with moderate intermittent abdominal pain, radiating to the back and associated with nausea and vomiting. He examined as a well child with a soft abdomen and minimal tenderness. A history of constipation was identified but he failed to respond to a trial of laxatives. Subsequent ultrasound abdomen demonstrated a large mass surrounding the porta hepatis. MRI further characterised a focal, non-aggressive lesion extending from his liver, encapsulating his pancreas, portal vessels and laterally displacing his spleen and left kidney. Biopsy performed at a specialist cancer treatment hospital of our reference later confirmed this to be a benign neurofibroma of a size not previously reported in the literature. He will be managed conservatively with surveillance imaging and the potential for chemotherapy should the lesion continue to grow. PMID- 29764828 TI - Medically managed coronary artery aneurysm without concomitant stenosis. AB - Coronary artery aneurysms (CAAs) are relatively rare with an incidence varying from 1.4% to 5.3% of patients undergoing coronary angiography. Studies suggest that management of CAA can be guided by the absence or presence of significant coronary artery stenosis, with most concluding that CAA associated with stenosis of >=70% should be managed surgically or with percutaneous intervention. However, given the paucity of cases described in the literature and lack of randomised control trials, no consensus exists on the natural history, prognosis or management of CAAs without significant concomitant stenosis. We present a case of medically managed atherosclerotic CAA without significant stenosis that was found to no longer be present on coronary angiography performed 11 years after initial diagnosis. PMID- 29764829 TI - Role of dynamic MRI in occult cervical canal stenosis. PMID- 29764830 TI - Palatal tremor as a manifestation of posterior circulation haemorrhagic stroke. PMID- 29764831 TI - Prosopometamorphopsia secondary to a left splenium of the corpus callosum infarct. PMID- 29764832 TI - Large bowel obstruction in a 27-year-old woman caused by a sigmoid faecal bolus. AB - A 27-year-old woman presented to the emergency department with a 24-hour history of severe left iliac fossa pain associated with vomiting. She reported a history of ovarian cysts and was provisionally diagnosed with a ruptured ovarian cyst and admitted under the obstetrics and gynaecology team for further investigation. 24 hours later, she became haemodynamically unstable with increasing abdominal distention and developed a metabolic acidosis. A CT scan revealed large bowel obstruction (LBO) secondary to a faecal bolus in the sigmoid colon with appearances suggestive of adult-onset Hirschsprung's disease. She underwent an emergency laparotomy and decompressive transverse colotomy and was admitted to the intensive care unit overnight. After discharge, she presented again with small bowel obstruction (SBO) which resolved with conservative management. A follow-up colonoscopy and biopsies showed no anatomical abnormalities to account for the LBO and were inconclusive for Hirschsprung's disease. PMID- 29764834 TI - Immigration detention in the UK damages health and frustrates healthcare. PMID- 29764835 TI - Infrapatellar fat pad resection during total knee arthroplasty: yet another reason for? PMID- 29764833 TI - Early prosthetic valve endocarditis after transcatheter aortic valve implantation using St Jude Medical Portico valve. AB - An 87-year-old woman presented to the emergency department with a 2-week history of progressively worsening shortness of breath, fever and generalised myalgia. She underwent a transcatheter Portico aortic valve implantation for severe symptomatic aortic stenosis 3 months prior to this presentation. Examination revealed a temperature of 40 degrees C and a systolic murmur in the aortic area. Inflammatory markers were elevated, and blood cultures were positive for methicillin-sensitive Staphylococcus aureus A possible diagnosis of infective endocarditis was made as one major and one minor criterion in the modified Duke criteria were fulfilled. Subsequent transoesophageal echocardiography (TOE) demonstrated vegetation attached to the prosthetic valve stent frame at the level of the left ventricular outflow tract. She was started on a prolonged course of intravenous antibiotics, and follow-up TOE, 4 weeks later, confirmed resolution of the vegetation. She was discharged home after prolonged hospital stay. PMID- 29764836 TI - Subcellular Localization of Antigen in Keratinocytes Dictates Delivery of CD4+ T cell Help for the CTL Response upon Therapeutic DNA Vaccination into the Skin. AB - In a mouse model of therapeutic DNA vaccination, we studied how the subcellular localization of vaccine protein impacts antigen delivery to professional antigen presenting cells and efficiency of CTL priming. Cytosolic, membrane-bound, nuclear, and secretory versions of ZsGreen fluorescent protein, conjugated to MHC class I and II ovalbumin (OVA) epitopes, were expressed in keratinocytes by DNA vaccination into the skin. ZsGreen-OVA versions reached B cells in the skin draining lymph node (dLN) that proved irrelevant for CTL priming. ZsGreen-OVA versions were also actively transported to the dLN by dendritic cells (DC). In the dLN, vaccine proteins localized to classical (c)DCs of the migratory XCR1+ and XCR- subtypes, and-to a lesser extent-to LN-resident cDCs. Secretory ZsGreen OVA induced the best antitumor CTL response, even though its delivery to cDCs in the dLN was significantly less efficient than for other vaccine proteins. Secretory ZsGreen-OVA protein proved superior in CTL priming, because it led to in vivo engagement of antigen-loaded XCR1+, but not XCR1-, cDCs. Secretory ZsGreen-OVA also maximally solicited CD4+ T-cell help. The suboptimal CTL response to the other ZsGreen-OVA versions was improved by engaging costimulatory receptor CD27, which mimics CD4+ T-cell help. Thus, in therapeutic DNA vaccination into the skin, mere inclusion of helper epitopes does not ensure delivery of CD4+ T-cell help for the CTL response. Targeting of the vaccine protein to the secretory route of keratinocytes is required to engage XCR1+ cDC and CD4+ T-cell help and thus to promote CTL priming. Cancer Immunol Res; 6(7); 835-47. (c)2018 AACR. PMID- 29764839 TI - Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A. AB - We analyzed DNA from polymorphonuclear (PMN) cells, monocytes, B cells, and T cells of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Three lineage categories were defined: myeloid (PMN with or without monocytes), myelolympho-B (myeloid and B cells), and multipotent (myeloid, B and T cells). Six individuals with aberrant patterns were excluded from analysis. Ninety-four had a single mutation (56 in DNMT3A, 24 in TET2, 7 in other genes [JAK2, ASXL1, CBL or TP53]). Fourteen had multiple mutations. The lineage restriction patterns of single DNMT3A- or TET2-mutated individuals were different. The proportion of myeloid restricted mutations was higher for TET2 (54.2%, 13 of 24) than for DNMT3A (23.2%, 13 of 56) (P < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P < .05). Importantly, 0% (0 of 24) of the individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20 of 56) for DNMT3A (P < .01). The clone size predicted multipotent pattern for DNMT3A suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations. PMID- 29764838 TI - A common TCN1 loss-of-function variant is associated with lower vitamin B12 concentration in African Americans. PMID- 29764840 TI - How I diagnose and treat venous thromboembolism in sickle cell disease. AB - The incidence of venous thromboembolism (VTE) in adult patients with sickle cell disease (SCD) is high. However, overlapping features between the clinical presentation of VTE and SCD complications and a low index of suspicion for thrombosis can influence patient management decisions. VTE in SCD can therefore present management challenges to the clinical hematologist. Herein, we present 3 distinct clinical vignettes that are representative of our clinical practice with SCD patients. These vignettes are discussed with specific reference to the hypercoagulable state in SCD patients, recent VTE diagnosis and anticoagulant therapy guidelines from the general population, and evaluation of the risk of bleeding as a result of long-term exposure to anticoagulant therapy. We examine current diagnostic and treatment options, highlight limitations of the existing clinical prognostic models that offer personalized guidance regarding the duration of anticoagulation, and propose a clinical approach to guide the decision to extend anticoagulation beyond 3 months. PMID- 29764837 TI - IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties. AB - Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-kappaB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4+ T-helper cell response. IL22 is an effector molecule secreted by CD4+ and gammadelta T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8+ T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC+CCSP+ stem cells. Thus, we conclude that IL22 promotes Kras mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells. Cancer Immunol Res; 6(7); 788-97. (c)2018 AACR. PMID- 29764841 TI - Genetic Targeting of Organ-Specific Blood Vessels. AB - RATIONALE: Organs of the body require vascular networks to supply oxygen and nutrients and maintain physiological function. The blood vessels of different organs are structurally and functionally heterogeneous in nature. To more precisely dissect their distinct in vivo function in individual organs, without potential interference from off-site targets, it is necessary to genetically target them in an organ-specific manner. OBJECTIVE: The objective of this study was to generate a genetic system that targets vascular endothelial cells in an organ- or tissue-specific manner and to exemplify the potential application of intersectional genetics for precise, target-specific gene manipulation in vivo. METHODS AND RESULTS: We took advantage of 2 orthogonal recombination systems, Dre rox and Cre-loxP, to create a genetic targeting system based on intersectional genetics. Using this approach, Cre activity was only detectable in cells that had expressed both Dre and Cre. Applying this new system, we generated a coronary endothelial cell-specific Cre (CoEC-Cre) and a brain endothelial cell-specific Cre (BEC-Cre). Through lineage tracing, gene knockout and overexpression experiments, we demonstrated that CoEC-Cre and BEC-Cre efficiently and specifically target blood vessels in the heart and brain, respectively. By deletion of vascular endothelial growth factor receptor 2 using BEC-Cre, we showed that vascular endothelial growth factor signaling regulates angiogenesis in the central nervous system and also controls the integrity of the blood-brain barrier. CONCLUSIONS: We provide 2 examples to illustrate the use of intersectional genetics for more precise gene targeting in vivo, namely manipulation of genes in blood vessels of the heart and brain. More broadly, this system provides a valuable strategy for tissue-specific gene manipulation that can be widely applied to other fields of biomedical research. PMID- 29764842 TI - Role of the hepcidin-ferroportin axis in pathogen-mediated intracellular iron sequestration in human phagocytic cells. AB - Upon infection, pathogen and host compete for the same iron pool, because this trace metal is a crucial micronutrient for all living cells. Iron dysregulation in the host is strongly associated with poor outcomes in several infectious diseases, including tuberculosis, AIDS, and malaria, and inefficient iron scavenging by pathogens severely affects their virulence. Hepcidin is the master regulator of iron homeostasis in vertebrates, responsible for diminishing iron export from macrophages during iron overload or infection. Hepcidin regulation in hepatocytes is well characterized and mostly dependent on interleukin-6 signaling during inflammation, although in myeloid cells, hepcidin induction and the mechanisms leading to intracellular iron regulation remain elusive. Here we show that activation of different Toll-like receptors (TLRs) by their respective ligands leads to increased iron sequestration in macrophages. By measuring the transcriptional levels of iron-related proteins (eg, hepcidin, ferroportin, and ferritin), we observed that TLR signaling can induce intracellular iron sequestration in macrophages through 2 independent but redundant mechanisms. Interestingly, TLR2 ligands or infection with Listeria monocytogenes lead to direct ferroportin transcriptional downregulation, whereas TLR4 ligands, such as lipopolysaccharide, induce hepcidin expression. Infection with Mycobacterium bovis Bacillus Calmette-Guerin promotes intracellular iron sequestration through both hepcidin upregulation and ferroportin downregulation. This is the first study in which TLR1-9-mediated iron homeostasis in human macrophages was evaluated, and the outcome of this study elucidates the mechanism of iron dysregulation in macrophages during infection. PMID- 29764844 TI - Second-look laparostomy for perforated gangrenous gastric volvulus to prevent total gastrectomy. AB - A 42-year-old Caucasian woman presented to the emergency department with severe upper abdominal pain and vomiting. Clinically, she was septic, and abdominal examination suggested peritonitis. Following immediate resuscitation, the patient was stabilised and underwent urgent contrast-enhanced CT of the abdomen and pelvis. This revealed a mesenteroaxial gastric volvulus with traction on the mesentery and a small volume of free fluid. She underwent laparotomy revealing gangrenous gastric fundus perforation complicated by persistent intraoperative hypotension. This mandated a damage-control approach for the patient's safety entailing a limited-sleeve gastrectomy and laparostomy formation. Stabilisation in the intensive care unit allowed for a safer return to the operating room. On second look 24 hours later, previously ischaemic non-viable-looking portions of the stomach had recovered their blood supply. The patient was discharged 31 days postoperatively after recovering from the operations, postoperative wound infections and pleural effusions. PMID- 29764845 TI - Endoscopic diagnosis of a goblet cell carcinoid tumour of the appendix. AB - Primary malignancies of the appendix are rare. Of these, less than 5% are goblet cell carcinoid (GCC) tumours. The majority of GCC present with findings of acute appendicitis or advanced peritoneal spread. We describe a rare presentation of GCC as subtle mucosal abnormality of the appendiceal orifice seen on colonoscopy performed for iron-deficiency anaemia. Biopsies were interpreted as adenocarcinoma; however, final surgical pathology confirmed GCC of the appendix with caecal involvement. The patient recovered well from surgery, anaemia resolved and follow-up did not show metastatic disease. PMID- 29764847 TI - A mysterious postoperative rash. AB - This case report describes the development of a rash in a patient admitted with large bowel obstruction secondary to carcinoma of the sigmoid colon. The patient underwent a Hartmann's procedure and right hemicolectomy for a metastatic deposit at the terminal ileum. On postoperative day 3, the patient developed a bullous haemorrhagic rash on the thighs, flanks and abdomen, associated with a sharp drop in platelet count. Suspicion of heparin-induced skin necrosis was raised, and prophylactic enoxaparin was switched to fondaparinux. Skin biopsy results later confirmed the diagnosis. Clinical suspicion of heparin-induced skin necrosis is essential and should prompt a switch between prophylactic agents, in order to prevent potentiation of this life-threatening side effect. PMID- 29764843 TI - Poorly cytotoxic terminally differentiated CD56negCD16pos NK cells accumulate in Kenyan children with Burkitt lymphomas. AB - Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and Plasmodium falciparum malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya. We defined 5 subsets based on CD56 and CD16 expression, including CD56negCD16pos We found that licensed and terminally differentiated perforin-expressing CD56negCD16pos NK cells accumulated in eBL children, particularly in those with high EBV loads (45.2%) compared with healthy children without (6.07%) or with (13.5%) malaria exposure (P = .0007 and .002, respectively). This progressive shift in NK cell proportions was concomitant with fewer CD56dimCD16pos cells. Despite high MIP-1beta expression, CD56negCD16pos NK cells had diminished cytotoxicity, with lower expression of activation markers NKp46, NKp30, and CD160 and the absence of TNF-alpha. Of note, the accumulation of poorly cytotoxic CD56negCD16pos NK cells resolved in long-term eBL survivors. Our study demonstrates impaired NK cell-mediated immunosurveillance in eBL patients but with the potential to restore a protective NK cell repertoire after cancer treatment. Characterizing NK cell dysfunction during coinfections with malaria and EBV has important implications for designing immunotherapies to improve outcomes for children diagnosed with eBL. PMID- 29764846 TI - Non-operative management of an isolated lateral collateral ligament injury in an adolescent patient and review of the literature. AB - We present a rare case of isolated traumatic pure ligamentous rupture of the lateral collateral ligament of the knee in an adolescent high-level footballer managed non-operatively with a good functional outcome and return to sport in 4 months. PMID- 29764848 TI - Case of drug-induced interstitial lung disease secondary to adalimumab. AB - We report a rare case of drug-induced intestinal lung disease (ILD) secondary to adalimumab, a tumour necrosis factor alpha-receptor blocker. A 52-year-old smoker with ankylosing spondylitis, treated with adalimumab, presented with progressive breathlessness. A high resolution CT chest demonstrated predominantly upper-zone patchy ground glass changes and small bilateral pleural effusions. Bronchoscopy and bronchoalveolar lavage showed no evidence of infection or malignant cells and an echocardiogram was normal. The working diagnosis was that of possible adalimumab-induced ILD. Adalimumab was subsequently stopped. The patient's breathlessness and cough improved on cessation of the drug. A further CT chest several months later showed resolution of the ground glass changes. Adalimumab induced ILD is rare. We review the literature surrounding this and discuss the diagnostic challenges. This case highlights the importance of considering the possibility of drug-induced lung disease in patients taking adalimumab. PMID- 29764850 TI - Paediatric osteofibrous dysplasia-like adamantinoma with classical radiological findings. PMID- 29764849 TI - 10-year-old with concha bullosa pyogenic mucocele. AB - A 10-year-old girl presented with episodes of migraine. A nasal mass was found randomly during work-up. Interpreted as an osteoma, the mass was removed during endoscopic surgery. However, the histopathological examination turned out to be a pyomucocele in the right middle turbinate, which is an extremely rare yet benign condition in children. PMID- 29764851 TI - Inflammatory myofibroblastic tumour: an unusual presentation including small bowel obstruction and palpable abdominal mass. AB - A 41-year-old man with no medical history presented with 2 weeks of nausea, vomiting, a new palpable abdominal mass, constipation and a 14kgweight loss. On admission, CT abdomen and pelvis demonstrated a 6.9*3.7 cm soft-tissue abdominal mass deep to and invading the lower anterior abdominal wall with tethering of the urinary bladder and potential involvement of the urachus. Subsequently, a biopsy demonstrated a low-grade spindle cell neoplasm compatible with inflammatory myofibroblastic tumour with immunostain positive for smooth muscle actin and desmin and negative for CD21, CD117, DOG-1, TKE-1, mdm2, CD34 and ALK. One week following admission, he underwent en bloc excision of the mass including abdominal wall (umbilicus, portions of rectus sheath and muscle), bladder dome, right colon and a segment of small bowel. Final pathology of the mass confirmed an inflammatory myofibroblastic tumour, and his postoperative course was uneventful. PMID- 29764852 TI - Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma. AB - Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient derived xenografts of GBM, that the combination treatment reduces tumor growth, and that triple therapy involving the clinically validated compounds panobinostat, OTX015, and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivoConclusions: Overall, these results warrant clinical testing of this novel, efficacious combination therapy. Clin Cancer Res; 24(16); 3941-54. (c)2018 AACR. PMID- 29764853 TI - Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab Paclitaxel in Patients with Relapsed or Refractory Solid Tumors. AB - Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072-80. (c)2018 AACR. PMID- 29764854 TI - Preclinical Antitumor Activity of a Novel Anti-c-KIT Antibody-Drug Conjugate against Mutant and Wild-type c-KIT-Positive Solid Tumors. AB - Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti-c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.Experimental Design: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.Results: LOP628 exhibited potent antiproliferative activity on c-KIT-positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system.Conclusions: The preclinical findings suggest that the c-KIT-directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT-positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297-308. (c)2018 AACR. PMID- 29764855 TI - Magnetic Resonance Imaging of Tumor-Associated Macrophages: Clinical Translation. AB - Purpose: Tumor-associated macrophages (TAMs) in malignant tumors have been linked to tumor aggressiveness and represent a new target for cancer immunotherapy. As new TAM-targeted immunotherapies are entering clinical trials, it is important to detect and quantify TAM with noninvasive imaging techniques. The purpose of this study was to determine if ferumoxytol-enhanced MRI can detect TAM in lymphomas and bone sarcomas of pediatric patients and young adults.Experimental Design: In a first-in-patient, Institutional Review Board-approved prospective clinical trial, 25 pediatric and young adult patients with lymphoma or bone sarcoma underwent ferumoxytol-enhanced MRI. To confirm ferumoxytol enhancement, five pilot patients (two lymphoma and three bone sarcoma) underwent pre- and postcontrast MRI. Subsequently, 20 patients (10 lymphoma and 10 bone sarcoma) underwent ferumoxytol-enhanced MRI 24 to 48 hours after i.v. injection, followed by tumor biopsy/resection and macrophage staining. To determine if ferumoxytol MRI can differentiate tumors with different TAM content, we compared T2* relaxation times of lymphomas and bone sarcomas. Tumor T2* values of 20 patients were correlated with CD68+ and CD163+ TAM quantities on histopathology.Results: Significant ferumoxytol tumor enhancement was noted on postcontrast scans compared with precontrast scans (P = 0.036). Bone sarcomas and lymphomas demonstrated significantly different MRI enhancement and TAM density (P < 0.05). Within each tumor group, T2* signal enhancement on MR images correlated significantly with the density of CD68+ and CD163+ TAM (P < 0.05).Conclusions: Ferumoxytol-enhanced MRI is immediately clinically applicable and could be used to stratify patients with TAM-rich tumors to immune-targeted therapies and to monitor tumor response to these therapies. Clin Cancer Res; 24(17); 4110-8. (c)2018 AACR. PMID- 29764856 TI - TP53, STK11, and EGFR Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma. AB - Purpose: By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed.Experimental Design: We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow cytometry, and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and PD-L1 expression, and a public clinical database was used to validate the results obtained.Results: We showed that distinct combinations of STK11, EGFR, and TP53 mutations were major determinants of the tumor immune profile (TIP) and of the expression of PD L1 by malignant cells. Indeed, the presence of TP53 mutations without co occurring STK11 or EGFR alterations (TP53-mut/STK11-EGFR-WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T-cell density and PD-L1 expression. In this tumor subtype, pathways related to T-cell chemotaxis, immune cell cytotoxicity, and antigen processing were upregulated. Finally, a prolonged progression-free survival (PFS: HR = 0.32; 95% CI, 0.16 0.63, P < 0.001) was observed in anti-PD-1-treated patients harboring TP53 mut/STK11-EGFR-WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression.Conclusions: Our study reveals that different combinations of TP53, EGFR, and STK11 mutations, together with PD L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Clin Cancer Res; 24(22); 5710-23. (c)2018 AACR. PMID- 29764858 TI - Distinct regulation of Snail in two muscle lineages of the ascidian embryo achieves temporal coordination of muscle development. AB - The transcriptional repressor Snail is required for proper differentiation of the tail muscle of ascidian tadpole larvae. Two muscle lineages (B5.1 and B6.4) contribute to the anterior tail muscle cells, and are consecutively separated from a transcriptionally quiescent germ cell lineage at the 16- and 32-cell stages. Concomitantly, cells of these lineages begin to express Tbx6.b (Tbx6-r.b) at the 16- and 32-cell stages, respectively. Meanwhile, Snail expression begins in these two lineages simultaneously at the 32-cell stage. Here, we show that Snail expression is regulated differently between these two lineages. In the B5.1 lineage, Snail was activated through Tbx6.b, which is activated by maternal factors, including Zic-r.a. In the B6.4 lineage, the MAPK pathway was cell autonomously activated by a constitutively active form of Raf, enabling Zic-r.a to activate Snail independently of Tbx6.b As a result, Snail begins to be expressed at the 32-cell stage simultaneously in these two lineages. Such shortcuts might be required for coordinating developmental programs in embryos in which cells become separated progressively from stem cells, including germline cells. PMID- 29764857 TI - Lineage-guided Notch-dependent gliogenesis by Drosophila multi-potent progenitors. AB - Macroglial cells in the central nervous system exhibit regional specialization and carry out region-specific functions. Diverse glial cells arise from specific progenitors in specific spatiotemporal patterns. This raises an interesting possibility that glial precursors with distinct developmental fates exist that govern region-specific gliogenesis. Here, we have mapped the glial progeny produced by the Drosophila type II neuroblasts, which, like vertebrate radial glia cells, yield both neurons and glia via intermediate neural progenitors (INPs). Distinct type II neuroblasts produce different characteristic sets of glia. A single INP can make both astrocyte-like and ensheathing glia, which co occupy a relatively restrictive subdomain. Blocking apoptosis uncovers further lineage distinctions in the specification, proliferation and survival of glial precursors. Both the switch from neurogenesis to gliogenesis and the subsequent glial expansion depend on Notch signaling. Taken together, lineage origins preconfigure the development of individual glial precursors with involvement of serial Notch actions in promoting gliogenesis. PMID- 29764862 TI - Correction: Transglutaminase 2 Is a Direct Target Gene of YAP-TAZ-Response. PMID- 29764859 TI - Activation of Nrf2 Is Required for Normal and ChREBPalpha-Augmented Glucose Stimulated beta-Cell Proliferation. AB - Patients with both major forms of diabetes would benefit from therapies that increase beta-cell mass. Glucose, a natural mitogen, drives adaptive expansion of beta-cell mass by promoting beta-cell proliferation. We previously demonstrated that a carbohydrate response element-binding protein (ChREBPalpha) is required for glucose-stimulated beta-cell proliferation and that overexpression of ChREBPalpha amplifies the proliferative effect of glucose. Here we found that ChREBPalpha reprogrammed anabolic metabolism to promote proliferation. ChREBPalpha increased mitochondrial biogenesis, oxygen consumption rates, and ATP production. Proliferation augmentation by ChREBPalpha required the presence of ChREBPbeta. ChREBPalpha increased the expression and activity of Nrf2, initiating antioxidant and mitochondrial biogenic programs. The induction of Nrf2 was required for ChREBPalpha-mediated mitochondrial biogenesis and for glucose stimulated and ChREBPalpha-augmented beta-cell proliferation. Overexpression of Nrf2 was sufficient to drive human beta-cell proliferation in vitro; this confirms the importance of this pathway. Our results reveal a novel pathway necessary for beta-cell proliferation that may be exploited for therapeutic beta cell regeneration. PMID- 29764863 TI - Extracorporeal Photochemotherapy Drives Monocyte-to-Dendritic Cell Maturation to Induce Anticancer Immunity. AB - Extracorporeal photochemotherapy (ECP) is a cancer immunotherapy for cutaneous T cell lymphoma (CTCL) operative in more than 350 centers worldwide. Although its efficacy and favorable safety profile have driven its widespread use, elucidation of its underlying mechanism has been difficult. In this study, we identify the principal contributors to the anticancer immunotherapeutic effects of ECP, with the goal of enhancing potency and broadening applicability to additional malignancies. First, we scaled down the clinical ECP leukocyte-processing device to mouse size. Second, we used that miniaturized device to produce a cellular vaccine that regularly initiated therapeutic antimelanoma immunity. Third, we individually subtracted key factors from either the immunizing inoculum or the treated animal to ascertain their contribution to the in vivo antimelanoma response. Platelet-signaled monocyte-to-dendritic cell (DC) differentiation followed by sorting/processing/presentation of tumor antigens derived from internalized apoptotic tumor cells were absolute requirements. As in clinical ECP, immunogenic cell death of tumor cells was finely titrated by DNA cross linkage mediated by photoactivated 8-methoxypsoralen (8-MOPA). ECP-induced tumor loaded DC were effective immunotherapeutic agents only if they were spared exposure to 8-MOPA, indicating that healthy DC are required for ECP. Infusion of responder T cells into naive tumor-challenged mice established the protective role of stimulated T-cell antitumor immunity. Collectively, these results reveal that selective antitumor effects of ECP are initiated by tumor antigen-loaded, ECP-induced DC, which promote potent collaboration between CD4 and CD8 tumor specific T cells. These mechanistic insights suggest potential therapeutic applicability of ECP to solid tumors in addition to CTCL.Significance: These findings identify principal cellular contributors to the anticancer immunotherapeutic impact of ECP and suggest this treatment may be applicable to a broad spectrum of immunogenic malignancies. Cancer Res; 78(14); 4045-58. (c)2018 AACR. PMID- 29764860 TI - Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A. AB - Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A. PMID- 29764865 TI - HP1gamma Promotes Lung Adenocarcinoma by Downregulating the Transcription Repressive Regulators NCOR2 and ZBTB7A. AB - Lung adenocarcinoma is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma promoting histone methylation reader protein show that heterochromatin protein 1gamma (HP1gamma; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human lung adenocarcinoma, and that high HP1gamma mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. In vivo depletion of HP1gamma reduced K-RasG12D-driven lung adenocarcinoma and lengthened survival of mice bearing K-RasG12D-induced lung adenocarcinoma. HP1gamma and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma cells. HP1gamma directly repressed expression of the transcription repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1gamma-depleted lung adenocarcinoma cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high HP1gamma mRNA levels in lung adenocarcinoma samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1gamma and its reader activity in lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma-promoting mechanism in which HP1gamma downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes.Significance: Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1gamma leads to activation of protumorigenic genes in lung adenocarcinoma. Cancer Res; 78(14); 3834-48. (c)2018 AACR. PMID- 29764864 TI - Targeting the Hsp40/Hsp70 Chaperone Axis as a Novel Strategy to Treat Castration Resistant Prostate Cancer. AB - Castration-resistant prostate cancer (CRPC) is characterized by reactivation of androgen receptor (AR) signaling, in part by elevated expression of AR splice variants (ARv) including ARv7, a constitutively active, ligand binding domain (LBD)-deficient variant whose expression has been correlated with therapeutic resistance and poor prognosis. In a screen to identify small-molecule dual inhibitors of both androgen-dependent and androgen-independent AR gene signatures, we identified the chalcone C86. Binding studies using purified proteins and CRPC cell lysates revealed C86 to interact with Hsp40. Pull-down studies using biotinylated-C86 found Hsp40 present in a multiprotein complex with full-length (FL-) AR, ARv7, and Hsp70 in CRPC cells. Treatment of CRPC cells with C86 or the allosteric Hsp70 inhibitor JG98 resulted in rapid protein destabilization of both FL-AR and ARv, including ARv7, concomitant with reduced FL-AR- and ARv7-mediated transcriptional activity. The glucocorticoid receptor, whose elevated expression in a subset of CRPC also leads to androgen-independent AR target gene transcription, was also destabilized by inhibition of Hsp40 or Hsp70. In vivo, Hsp40 or Hsp70 inhibition demonstrated single-agent and combinatorial activity in a 22Rv1 CRPC xenograft model. These data reveal that, in addition to recognized roles of Hsp40 and Hsp70 in FL-AR LBD remodeling, ARv lacking the LBD remain dependent on molecular chaperones for stability and function. Our findings highlight the feasibility and potential benefit of targeting the Hsp40/Hsp70 chaperone axis to treat prostate cancer that has become resistant to standard antiandrogen therapy.Significance: These findings highlight the feasibility of targeting the Hsp40/Hsp70 chaperone axis to treat CRPC that has become resistant to standard antiandrogen therapy. Cancer Res; 78(14); 4022 35. (c)2018 AACR. PMID- 29764866 TI - LRRC15 Is a Novel Mesenchymal Protein and Stromal Target for Antibody-Drug Conjugates. AB - Progress in understanding tumor stromal biology has been constrained in part because cancer-associated fibroblasts (CAF) are a heterogeneous population with limited cell-type-specific protein markers. Using RNA expression profiling, we identified the membrane protein leucine-rich repeat containing 15 (LRRC15) as highly expressed in multiple solid tumor indications with limited normal tissue expression. LRRC15 was expressed on stromal fibroblasts in many solid tumors (e.g., breast, head and neck, lung, pancreatic) as well as directly on a subset of cancer cells of mesenchymal origin (e.g., sarcoma, melanoma, glioblastoma). LRRC15 expression was induced by TGFbeta on activated fibroblasts (alphaSMA+) and on mesenchymal stem cells. These collective findings suggested LRRC15 as a novel CAF and mesenchymal marker with utility as a therapeutic target for the treatment of cancers with LRRC15-positive stromal desmoplasia or cancers of mesenchymal origin. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) directed against LRRC15, and it demonstrated robust preclinical efficacy against LRRC15 stromal-positive/cancer-negative, and LRRC15 cancer positive models as a monotherapy, or in combination with standard-of-care therapies. ABBV-085's unique mechanism of action relied upon the cell-permeable properties of MMAE to preferentially kill cancer cells over LRRC15-positive CAF while also increasing immune infiltrate (e.g., F4/80+ macrophages) in the tumor microenvironment. In summary, these findings validate LRRC15 as a novel therapeutic target in multiple solid tumor indications and support the ongoing clinical development of the LRRC15-targeted ADC ABBV-085.Significance: These findings identify LRRC15 as a new marker of cancer-associated fibroblasts and cancers of mesenchymal origin and provide preclinical evidence for the efficacy of an antibody-drug conjugate targeting the tumor stroma. Cancer Res; 78(14); 4059-72. (c)2018 AACR. PMID- 29764867 TI - Fibrin Stiffness Mediates Dormancy of Tumor-Repopulating Cells via a Cdc42-Driven Tet2 Epigenetic Program. AB - Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here, we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2. Tet2 epigenetically activated cell-cycle-inhibiting genes p21 and p27 to induce dormancy, but also caused downregulation of integrin beta3 to maintain dormancy. This stiffness-mediated dormancy was recapitulated in mouse models for both murine and primary human melanoma TRCs. These data identify an epigenetic program directed by mechanics, which drives highly tumorigenic TRCs to enter dormancy in a stiff mechanical environment.Significance: A mechanics-directed epigenetic program enables tumor-repopulating cells to enter dormancy in a stiff mechanical environment. Cancer Res; 78(14); 3926-37. (c)2018 AACR. PMID- 29764868 TI - Systematic review of rehabilitation intervention outcomes of adult and paediatric patients with infectious encephalitis. AB - OBJECTIVE: Although a range of rehabilitation interventions have been applied to restore function after infectious encephalitis, there is a lack of literature summarising the benefits of these interventions. This systematic review aims to synthesise current scientific knowledge on outcome measures following rehabilitative interventions among children and adults with infectious encephalitis, with a specific focus on the influence of the age, sex, baseline status and intervention type. SEARCH STRATEGY: Five scholarly databases (MEDLINE, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials), three sources of grey literature (Google, Google Scholar and Grey Matters) and reference lists of included publications were systematically searched. Literature published before 15 December 2017 and focused on patients with infectious encephalitis in any rehabilitation setting were included. Quality assessment was completed using the Downs and Black rating scale. RESULTS: Of the 12 737 reference titles screened, 20 studies were included in this review. All of the studies had sample sizes of less than 25 patients and received a score of less than 15 out of 31 points on the Downs and Black rating scale. Findings showed a variety of interventions has been applied to alleviate sequelae from infectious encephalitis, including using cognitive therapy (nine studies), behavioural therapy (five studies), physical therapy (two studies) or two or more therapies (four studies). There was inconclusive evidence on the effect of sex, age and baseline functional abilities on outcomes. Due to clinical and methodological heterogeneity between studies, meta-analyses were not performed. CONCLUSION: Evidence suggests the potential for a beneficial effect of rehabilitation interventions in patients with infectious encephalitis. Future research is required to identify all effect modifiers and to determine the effect of time in the natural course of recovery. An enhanced set of known effect modifiers will support the process of future evaluation of a client-centred rehabilitation intervention. TRIAL REGISTRATION NUMBER: CRD42015029217. PMID- 29764869 TI - Tele-UPCAT: study protocol of a randomised controlled trial of a home-based Tele monitored UPper limb Children Action observation Training for participants with unilateral cerebral palsy. AB - INTRODUCTION: A new rehabilitative approach, called UPper Limb Children Action Observation Training (UPCAT), based on the principles of action observation training (AOT), has provided promising results for upper limb rehabilitation in children with unilateral cerebral palsy (UCP). This study will investigate if a new information and communication technology platform, named Tele-UPCAT, is able to deliver AOT in a home setting and will test its efficacy on children and young people with UCP. METHODS AND ANALYSIS: A randomised, allocation concealed (waitlist control) and evaluator-blinded clinical trial with two investigative arms will be carried out. The experimental group will perform AOT at home for 3 weeks using a customised Tele-UPCAT system where they will watch video sequences of goal-directed actions and then complete the motor training of the same actions. The control group will receive usual care for 3 weeks, which may include upper limb training. They will be offered AOT at home after 3 weeks. Twenty-four children with UCP will be recruited for 12 participants per group. The primary outcome will be measured using Assisting Hand Assessment. The Melbourne Assessment 2, ABILHAND, Participation and Environment Measure-Children and Youth and Cerebral Palsy Quality of Life Questionnaire will be included as secondary measures. Quantitative measures from sensorised objects and participants worn Actigraphs GXT3+ will be analysed. The assessment points will be the week before (T0) and after (T1) the period of AOT/standard care. Further assessments will be at T1 plus, the week after the AOT period for the waitlist group and at 8 weeks (T2) and 24 weeks (T3) after AOT training. ETHICS AND DISSEMINATION: The trial has been approved by the Tuscany Paediatric Ethics Committee (169/2016). Publication of all outcomes will be in peer-reviewed journals and conference presentations. TRIAL REGISTRATION: NCT03094455. PMID- 29764870 TI - Physicians' attitudes towards the media and peer-review selection of the 'best cancer doctor': comparison of two different selection methods. AB - OBJECTIVES: The choice of doctor is an important issue for patients with cancer, and the reputation of the doctor is the single most important factor for patients to choose a doctor. Media are providing information about the 'best cancer doctor', but they vary widely in their selection methodology. We investigated cancer physicians' attitudes towards the selection of the 'best cancer doctor' by the media, by comparing two different selection methodologies: selection by media personnel or selection through peer-review system. DESIGN: Nationwide, cross sectional survey. SETTING: National Cancer Center and 12 Regional Cancer Centers across Korea. PARTICIPANTS: A total of 680 cancer care physicians participated in the survey (75.5% participation rate), and two were excluded due to incomplete response. MAIN OUTCOME MEASURES: Physicians' opinions on the credibility, fairness, validity, helpfulness to patients, their intention to use the information and helpfulness to improve the quality of cancer care of the two different methods. RESULTS: Only a few physicians believed that the selection method of the 'best cancer doctor' by the media personnel was credible (9.1%), fair (6.1%) or valid (10.0%). In contrast, the majority agreed that the peer selection method of the 'best doctor' is credible (74.7%), fair (64.7%) and valid (67.4%). More physicians believed the latter methods would be useful for patients when selecting their doctor (38.5% vs 82.2%) and may lead to improvement of the quality of cancer care from the perspective of the healthcare system (12.6% vs 59.8%). The need for ensuring objectiveness and transparency was also raised. CONCLUSION: Physicians showed different attitudes towards two different selection methods. Regulations or guidelines for selecting the 'best cancer doctor' and for disclosing the information should be considered in order to control the quality of the information and to protect the customers. PMID- 29764871 TI - Balance and mobility training at home using Wii Fit in children with cerebral palsy: a feasibility study. AB - OBJECTIVES: To investigate whether balance and mobility training at home using Wii Fit is feasible and can provide clinical benefits. DESIGN: Single-group, pre post intervention study. SETTING: Participants' home. PARTICIPANTS: 20 children with cerebral palsy (6-12 years). INTERVENTION: Participants undertook 8 weeks of home-based Wii Fit training in addition to usual care. MAIN MEASURES: Feasibility was determined by adherence, performance, acceptability and safety. Clinical outcomes were strength, balance, mobility and participation measured at baseline (preintervention) and 8 weeks (postintervention). RESULTS: The training was feasible with 99% of training completed; performance on all games improved; parents understood the training (4/5), it did not interfere in life (3.8/5), was challenging (3.9/5) and would recommend it (3.9/5); and there were no injurious falls. Strength increased in dorsiflexors (Mean Difference (MD) 2.2 N m, 95% CI 1.1 to 3.2, p<0.001), plantarflexors (MD 2.2 N m, 95% CI 1.3 to 3.1, p<0.001) and quadriceps (MD 7.8 N m, 95% CI 5.2 to 10.5, p<0.001). Preferred walking speed increased (MD 0.25 m/s, 95% CI 0.09 to 0.41, p<0.01), fast speed increased (MD 0.24 m/s, 95% CI 0.13 to 0.35, p<0.001) and distance over 6 min increased (MD 28 m, 95% CI 10 to 45, p<0.01). Independence in participation increased (MD 1.4 out of 40, 95% CI 0.0 to 2.8, p=0.04). CONCLUSIONS: Balance and mobility training at home using Wii Fit was feasible and safe and has the potential to improve strength and mobility, suggesting that a randomised trial is warranted. TRIAL REGISTRATION NUMBER: ACTRN12616001362482. PMID- 29764872 TI - Development and testing of the Youth Alcohol Norms Survey (YANS) instrument to measure youth alcohol norms and psychosocial influences. AB - OBJECTIVES: This study aimed to develop and validate an online instrument to: (1) identify common alcohol-related social influences, norms and beliefs among adolescents; (2) clarify the process and pathways through which proalcohol norms are transmitted to adolescents; (3) describe the characteristics of social connections that contribute to the transmission of alcohol norms; and (4) identify the influence of alcohol marketing on adolescent norm development. SETTING: The online Youth Alcohol Norms Survey (YANS) was administered in secondary schools in Western Australia PARTICIPANTS: Using a 2-week test-retest format, the YANS was administered to secondary school students (n=481, age=13-17 years, female 309, 64.2%). PRIMARY AND SECONDARY OUTCOME MEASURES: The development of the YANS was guided by social cognitive theory and comprised a systematic multistage process including evaluation of content and face validity. A 2-week test-retest format was employed. Exploratory factor analysis was conducted to determine the underlying factor structure of the instrument. Test retest reliability was examined using intraclass correlation coefficient (ICC) and Cohen's kappa. RESULTS: A five-factor structure with meaningful components and robust factorial loads was identified, and the five factors were labelled as 'individual attitudes and beliefs', 'peer and community identity', 'sibling influences', 'school and community connectedness' and 'injunctive norms', respectively. The instrument demonstrated stability across the test-retest procedure (ICC=0.68-0.88, Cohen's kappa coefficient=0.69) for most variables. CONCLUSIONS: The results support the reliability and factorial validity of this instrument. The YANS presents a promising tool, which enables comprehensive assessment of reciprocal individual, behavioural and environmental factors that influence alcohol-related norms among adolescents. PMID- 29764873 TI - Individual, maternal and household risk factors for anaemia among young children in sub-Saharan Africa: a cross-sectional study. AB - OBJECTIVE: Anaemia affects the majority of children in sub-Saharan Africa (SSA). Previous studies of risk factors for anaemia have been limited by sample size, geography and the association of many risk factors with poverty. In order to measure the relative impact of individual, maternal and household risk factors for anaemia in young children, we analysed data from all SSA countries that performed haemoglobin (Hb) testing in the Demographic and Health Surveys. DESIGN AND SETTING: This cross-sectional study pooled household-level data from the most recent Demographic and Health Surveys conducted in 27 SSA between 2008 and 2014. PARTICIPANTS: 96 804 children age 6-59 months. RESULTS: The prevalence of childhood anaemia (defined as Hb <11 g/dL) across the region was 59.9%, ranging from 23.7% in Rwanda to 87.9% in Burkina Faso. In multivariable regression models, older age, female sex, greater wealth, fewer household members, greater height-for-age, older maternal age, higher maternal body mass index, current maternal pregnancy and higher maternal Hb, and absence of recent fever were associated with higher Hb in tested children. Demographic, socioeconomic factors, family structure, water/sanitation, growth, maternal health and recent illnesses were significantly associated with the presence of childhood anaemia. These risk factor groups explain a significant fraction of anaemia (ranging from 1.0% to 16.7%) at the population level. CONCLUSIONS: The findings from our analysis of risk factors for anaemia in SSA underscore the importance of family and socioeconomic context in childhood anaemia. These data highlight the need for integrated programmes that address the multifactorial nature of childhood anaemia. PMID- 29764874 TI - Resuming anticoagulants after anticoagulation-associated intracranial haemorrhage: systematic review and meta-analysis. AB - OBJECTIVE: To determine the adverse outcomes following resumption of anticoagulation in patients with anticoagulation-associated intracranial haemorrhage (ICH). DESIGN: We performed a systematic review and meta-analysis in this clinical population. The Preferred Reporting Items for Systemic Reviews and Meta-Analyses statement was followed, and two authors independently assessed eligibility of all retrieved studies and extracted data. DATA SOURCES: Medline, Embase and the Cochrane Central Register of Controlled Trials, from inception to February 2017. ELIGIBILITY CRITERIA AND OUTCOMES: Randomised controlled trials or cohort studies that recruited adults who received oral anticoagulants at the time of ICH occurrence and survived after the acute phase or hospitalisation were searched. Primary outcomes, including long-term mortality, recurrent ICH and thromboembolic events. Secondary outcomes were the frequency of resuming anticoagulant therapy and related factors. RESULTS: We included 12 cohort studies (no clinical trials) involving 3431 ICH participants. The pooled frequency of resuming anticoagulant therapy was 38% (95% CI 32% to 44%), but this was higher in participants with prosthetic heart valves, subarachnoid haemorrhage or dyslipidaemia. There was no evidence that resuming anticoagulant therapy was associated with higher long-term mortality (pooled relative risk (RR) 0.60, 95% CI 0.30 to 1.19; p=0.14) or ICH recurrence (pooled RR 1.14, 95% CI 0.72 to 1.80; p=0.57). Resumption of anticoagulation was associated with significantly fewer thromboembolic events (pooled RR 0.31, 95% CI 0.23 to 0.42; p<0.001). In a subgroup of patients with atrial fibrillation, resuming anticoagulant therapy was associated with fewer long-term mortality (pooled RR 0.27, 95% CI 0.20 to 0.37, p<0.001). CONCLUSIONS: Based on these observational studies, resuming anticoagulant therapy after anticoagulation-associated ICH has beneficial effects on long-term complications. Clinical trials are needed to substantiate these findings. PROSPERO REGISTRATION NUMBER: CRD42017063827. PMID- 29764875 TI - Efficacy and safety of GHX02 in the treatment of acute bronchitis: protocol of a phase II, double-blind, randomised placebo-controlled trial. AB - INTRODUCTION: Acute bronchitis is a self-limiting infection of the large airways; cough is the primary symptom, usually lasting for about 3 weeks. Annually, approximately 5% of adults develop acute bronchitis, and its economic burden is substantial. There are also problems of antibiotic abuse in public health systems and symptomatic therapies are commonly prescribed, for which there is insufficient supporting evidence. GHX02 contains four herbs originating from gwaruhaengryeon-hwan, which has been used in the treatment of patients with acute bronchitis in Korea. The objective is to compare the GHX02 and placebo in terms of efficacy and safety, and to determine the appropriate dosage. METHODS AND ANALYSIS: We planned a phase II, multicentre, dose-finding, double-blind, randomised placebo-controlled trial of two different doses of GHX02 compared with placebo. A total of 150 patients, aged 19-75 years, with a Bronchitis Severity Score (BSS) >=5 due to acute bronchitis starting within 2 weeks of study enrolment will be recruited from three university-affiliated hospitals across Korea. Participants will be stratified into three patterns using the Korean Standard Tool of Pattern Identifications of Cough and Sputum and randomly assigned to either a high-dose GHX02 group (1920 mg/day), standard-dose GHX02 group (960 mg/day) or placebo group according to a 1:1:1 allocation ratio. Patients will take medications three times daily for 7 days, with two visiting days. The primary outcome measure is a change in BSS from day 0 to day 7. The secondary outcomes are the Questionnaire of Clinical Symptoms of Cough and Sputum, Leicester Cough Questionnaire, frequency of coughing fits, Integrative Medicine Outcome Scale, Integrative Medicine Patient Satisfaction Scale and withdrawal rate of patients with exacerbation. Safety will be assessed by adverse events, vital signs and laboratory examinations. ETHICS AND DISSEMINATION: The study has been approved by our Institutional Review Board (No. DJDSKH-17-DR-14). The trial results will be disseminated via peer-reviewed journals and the Clinical Research Information Service. TRIAL REGISTRATION NUMBER: NCT03310385; Pre-results. PMID- 29764876 TI - Integrated versus nOn-integrated Peripheral inTravenous catheter. Which Is the most effective systeM for peripheral intravenoUs catheter Management? (The OPTIMUM study): a randomised controlled trial protocol. AB - INTRODUCTION: Peripheral intravenous catheters (PIVCs) are frequently used in hospitals. However, PIVC complications are common, with failures leading to treatment delays, additional procedures, patient pain and discomfort, increased clinician workload and substantially increased healthcare costs. Recent evidence suggests integrated PIVC systems may be more effective than traditional non integrated PIVC systems in reducing phlebitis, infiltration and costs and increasing functional dwell time. The study aim is to determine the efficacy, cost-utility and acceptability to patients and professionals of an integrated PIVC system compared with a non-integrated PIVC system. METHODS AND ANALYSIS: Two arm, multicentre, randomised controlled superiority trial of integrated versus non-integrated PIVC systems to compare effectiveness on clinical and economic outcomes. Recruitment of 1560 patients over 2 years, with randomisation by a centralised service ensuring allocation concealment. Primary outcomes: catheter failure (composite endpoint) for reasons of: occlusion, infiltration/extravasation, phlebitis/thrombophlebitis, dislodgement, localised or catheter-associated bloodstream infections. SECONDARY OUTCOMES: first time insertion success, types of PIVC failure, device colonisation, insertion pain, functional dwell time, adverse events, mortality, cost-utility and consumer acceptability. One PIVC per patient will be included, with intention-to-treat analysis. Baseline group comparisons will be made for potentially clinically important confounders. The proportional hazards assumption will be checked, and Cox regression will test the effect of group, patient, device and clinical variables on failure. An as-treated analysis will assess the effect of protocol violations. Kaplan-Meier survival curves with log-rank tests will compare failure by group over time. Secondary endpoints will be compared between groups using parametric/non-parametric techniques. ETHICS AND DISSEMINATION: Ethical approval from the Royal Brisbane and Women's Hospital Human Research Ethics Committee (HREC/16/QRBW/527), Griffith University Human Research Ethics Committee (Ref No. 2017/002) and the South Metropolitan Health Services Human Research Ethics Committee (Ref No. 2016-239). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12617000089336. PMID- 29764877 TI - Efficacy of practising Tai Chi for older people with mild dementia: protocol for a randomised controlled study. AB - INTRODUCTION: Many studies suggest that Tai Chi exercise is a safe and appropriate mind-body exercise for older people and effectively slows down age related cognitive decline. A set of bespoke Tai Chi exercise named 'Cognition Protecting Tai Chi' (CPT) has been created for older people with cognitive impairments by the research team of geriatricians, neurologists, rehabilitation specialists, experts of sports medicine and experienced practitioners of traditional Chinese medicine. This trial is designed to evaluate its effects on cognitive function, behaviour/moods, risk of falls and activities of daily living of the participants with mild dementia. METHODS AND ANALYSIS: A randomised controlled study will be conducted. Eighty participants with mild dementia will be recruited and randomly allocated to an intervention group and a control group. The intervention group will practice the CPT exercise three times a week for 20 min each time under the guidance of professional therapists. The control group will continue receiving their routine treatments. The duration of this study will be 10 months. All participants will be assessed with a battery of neuropsychological and functional evaluations, which include Mini Mental State Examination, Montreal Cognitive Assessment, the WHO-University of California Los Angeles-Auditory Verbal Learning test (WHO-UCLA-AVLT), Trail Making Test (TMT), Geriatric Depression Scale, Neuropsychological Inventory and Barthel Index, at the baseline, 5 and 10 months during the study period. Fall incident will also be recorded. The primary outcome will be the WHO-UCLA-AVLT delayed recall score. The secondary outcome will be the TMT score. ETHICS AND DISSEMINATION: This study has been approved by the ethical review committee of the Beijing Geriatric Hospital (protocol number: 2015-021). Informed consent will be obtained from all participants or their guardians. The authors intend to submit the findings of the study to peer-reviewed journals or academic conferences to be published. TRIAL REGISTRATION NUMBER: ChiCTR-INR-16009872; Pre-results. PMID- 29764878 TI - Association between an individual housing-based socioeconomic index and inconsistent self-reporting of health conditions: a prospective cohort study in the Mayo Clinic Biobank. AB - OBJECTIVE: Using surveys to collect self-reported information on health and disease is commonly used in clinical practice and epidemiological research. However, the inconsistency of self-reported information collected longitudinally in repeated surveys is not well investigated. We aimed to investigate whether a socioeconomic status based on current housing characteristics, HOUsing-based SocioEconomic Status (HOUSES) index linking current address information to real estate property data, is associated with inconsistent self-reporting. STUDY SETTING AND PARTICIPANTS: We performed a prospective cohort study using the Mayo Clinic Biobank (MCB) participants who resided in Olmsted County, Minnesota, USA, at the time of enrolment between 2009 and 2013, and were invited for a 4-year follow-up survey (n=11 717). PRIMARY AND SECONDARY OUTCOME MEASURES: Using repeated survey data collected at the baseline and 4 years later, the primary outcome was the inconsistency in survey results when reporting prevalent diseases, defined by reporting to have 'ever' been diagnosed with a given disease in the baseline survey but reported 'never' in the follow-up survey. Secondary outcome was the response rate for the 4-year follow-up survey. RESULTS: Among the MCB participants invited for the 4-year follow-up survey, 8508/11 717 (73%) responded to the survey. Forty-three per cent had at least one inconsistent self reported disease. Lower HOUSES was associated with higher inconsistency rates, and the association remained significant after pertinent characteristics such as age and perceived general health (OR=1.46; 95% CI 1.17 to 1.84 for the lowest compared with the highest HOUSES decile). HOUSES was also associated with lower response rate for the follow-up survey (56% vs 77% for the lowest vs the highest HOUSES decile). CONCLUSION: This study demonstrates the importance of using the HOUSES index that reflects current SES when using self-reporting through repeated surveys, as the HOUSES index at baseline survey was inversely associated with inconsistent self-report and the response rate for the follow-up survey. PMID- 29764879 TI - Quest for certainty regarding early discharge in paediatric low-risk febrile neutropenia: a multicentre qualitative focus group discussion study involving patients, parents and healthcare professionals in the UK. AB - OBJECTIVES: A systematic review of paediatric low-risk febrile neutropenia found that outpatient care is safe, with low rates of treatment failure. However, this review, and a subsequent meta-ethnography, suggested that early discharge of these patients may not be acceptable to key stakeholders. This study aimed to explore experiences and perceptions of patients, parents and healthcare professionals involved in paediatric febrile neutropenia care in the UK. SETTING: Three different centres within the UK, purposively selected from a national survey on the basis of differences in their service structure and febrile neutropenia management. PARTICIPANTS: Thirty-two participants were included in eight focus group discussions. PRIMARY OUTCOMES: Experiences and perceptions of paediatric febrile neutropenia care, including possible future reductions in therapy. RESULTS: Participants described a quest for certainty, in which they attempted to balance the uncertainty involved in understanding, expressing and negotiating risk with the illusion of certainty provided by strict protocols. Participants assessed risk using both formal and informal stratification tools, overlaid with emotional reactions to risk and experiences of risk within other situations. The benefits of certainty provided by protocols were counterbalanced by frustration at their strict constraints. The perceived benefits and harms of previous inpatient care informed participants' appraisals of future treatment strategies. CONCLUSIONS: This study highlighted the previously underestimated harms of admission for febrile neutropenia and the paternalistic nature of decision making, along with the frustrations and challenges for all parties involved in febrile neutropenia care. It demonstrates how the same statistics, generated by systematic reviews, can be used by key stakeholders to interpret risk differently, and how families in particular can view the harms of therapeutic options as different from the outcomes used within the literature. It justifies a reassessment of current treatment strategies for these children and further exploration of the potential to introduce shared decision making. PMID- 29764880 TI - Digital breast tomosynthesis plus synthesised images versus standard full-field digital mammography in population-based screening (TOSYMA): protocol of a randomised controlled trial. AB - INTRODUCTION: Development of digital breast tomosynthesis (DBT) provides a technology that generates three-dimensional data sets, thus reducing the pitfalls of overlapping breast tissue. Observational studies suggest that the combination of two-dimensional (2D) digital mammography and DBT increases diagnostic accuracy. However, because of duplicate exposure, this comes at the cost of an augmented radiation dose. This undesired adverse impact can be avoided by using synthesised 2D images reconstructed from the DBT data (s2D).We designed a diagnostic superiority trial on a high level of evidence with the aim of providing a comparison of screening efficacy parameters resulting from DBT+s2D versus the current screening standard 2D full-field digital mammography (FFDM) in a multicentre and multivendor setting on the basis of the quality-controlled, population-based, biennial mammography screening programme in Germany. METHODS AND ANALYSIS: 80 000 women in the eligible age 50-69 years attending the routine mammography screening programme and willing to participate in the TOSYMA trial will be assigned by 1:1 randomisation to either the intervention arm (DBT+s2D) or the control arm (FFDM) during a 12-month recruitment period in screening units of North Rhine-Westphalia and Lower Saxony. State cancer registries will provide the follow-up of interval cancers.Primary endpoints are the detection rate of invasive breast cancers at screening examination and the cumulative incidence of interval cancers in the 2 years after a negative examination. Secondary endpoints are the detection rate of ductal carcinoma in situ and of tumour size T1, the recall rate for assessment, the positive predictive value of recall and the cumulative 12-month incidence of interval cancers. An adaptive statistical design with one interim analysis provides the option to modify the design. ETHICS AND DISSEMINATION: This protocol has been approved by the local medical ethical committee (2016-132-f-S). Results will be submitted to international peer reviewed journals. TRIAL REGISTRATION: NCT03377036; Pre-results. PMID- 29764881 TI - Protocol for an economic evaluation of WHO STOPS childhood obesity stepped-wedge cluster randomised controlled trial. AB - INTRODUCTION: Prevention of overweight and obesity in childhood is a priority because of associated acute and chronic conditions in childhood and later in life, which place significant burden on health systems. Evidence suggests prevention should engage a range of actions and actors and target multiple levels. The Whole of Systems Trial Of Prevention Strategies for childhood obesity (WHO STOPS) will evaluate the outcomes of a novel systems-based intervention that aims to engage whole communities in a locally led multifaceted response. This paper describes the planned economic evaluation of WHO STOPS and examines the methodological challenges for economic evaluation of a complex systems-based intervention. METHODS AND ANALYSIS: Economic evaluation alongside a stepped-wedge cluster randomised controlled trial in regional and rural communities in Victoria, Australia. Cost-effectiveness and cost-utility analyses will provide estimates of the incremental cost (in $A) per body mass index unit saved and quality adjusted life year gained. A Markov cohort model will be employed to estimate healthcare cost savings and benefits over the life course of children. The dollar value of community resources harnessed for the community-led response will be estimated. Probabilistic uncertainty analyses will be undertaken to test sensitivity of results to plausible variations in all trial-based and modelled variables. WHO STOPS will also be assessed against other implementation considerations (such as sustainability and acceptability to communities and other stakeholders). ETHICS AND DISSEMINATION: The trial is registered by the Australian New Zealand Clinical Trials Registry (ACTRN12616000980437). Full ethics clearances have been received for all methods described below: Deakin University's Human Research Ethics Committee 2014-279, Deakin University's Human Ethics Advisory Group-Health (HEAG-H) HEAG-H 194_2014, HEAG-H 17 2015, HEAG-H 155_2014, HEAG-H 197_2016, HEAG-H 118_2017, the Victorian Department of Education and Training 2015_002622 and the Catholic Archdiocese of Ballarat. Trial findings (including economic evaluation) will be published in peer-reviewed journals and presented at international conferences. Collected data and analyses will be made available in accordance with journal policies and study ethics approvals. Results will be presented to relevant government authorities with an interest in cost effectiveness of these types of interventions. TRIAL REGISTRATION NUMBER: ACTRN12616000980437; Pre-results. PMID- 29764882 TI - Postnatal depression and intimate partner violence: a nationwide clinic-based cross-sectional study in Malaysia. AB - INTRODUCTION: An estimated 13% of women in the postnatal period suffer from postnatal depression (PND) worldwide. In addition to underprivileged women, women who are exposed to violence are at higher risk of PND. This study aimed to investigate the relationship between intimate partner violence (IPV) and PND in Malaysia. METHODS: This survey was conducted as a nationwide cross-sectional study using a cluster sampling design. Probable PND was assessed using a self administered Edinburgh Postnatal Depression Scale (EPDS). Demographic profiles and IPV were assessed using a locally validated WHO Multicountry Study on Women's Health and Life Events Questionnaire that was administered in a face-to-face interview. An EPDS total score of 12 or more and/or a positive tendency to self harm were used to define PND. RESULTS: Out of 6669 women, 5727 respondents were successfully interviewed with a response rate of 85.9%. The prevalence of probable PND was 4.4% (95% CI 2.9 to 6.7). The overall prevalence of IPV was 4.9% (95% CI 3.8 to 6.4). Among the women in this group, 3.7% (95% CI 2.7 to 5.0), 2.6% (95% CI 1.9 to 3.5) and 1.2% (95% CI 0.9 to 1.7) experienced emotional, physical and sexual violence, respectively. Logistic regression analysis revealed that women who were exposed to IPV were at 2.3 times the risk for probable PND, with an adjusted OR (aOR) of 2.34 (95% CI 1.12 to 4.87). Other factors for PND were reported emotional violence (aOR 3.79, 95% CI 1.93 to 7.45), unplanned pregnancy (aOR 3.32, 95% CI 2.35 to 4.69), lack of family support during confinement (aOR 1.79, 95% CI 1.12 to 2.87), partner's use of alcohol (aOR 1.59, 95% CI 1.07 to 2.35) or being from a household with a low income (aOR 2.99; 95% CI 1.63 to 5.49). CONCLUSIONS: Exposure to IPV was significantly associated with probable PND. Healthcare personnel should be trained to detect and manage both problems. An appropriate referral system and support should be made available. PMID- 29764883 TI - Comparison of indoor temperatures of homes with recommended temperatures and effects of disability and age: an observational, cross-sectional study. AB - OBJECTIVES: We examine if temperatures in winter in English homes meet the recommendation of being at least 18 degrees C at all times. We analyse how many days meet this criterion and calculate the hours per day and night being at/above 18 degrees C. These metrics are compared between households with occupants aged above 64 years or having a long-term disability (LTD) and those younger and without disability. DESIGN: Cross-sectional, observational. SETTING: England. PARTICIPANTS: 635 households. OUTCOMES MEASURES: (1) Mean temperatures, (2) proportion of days of the measurement period meeting the criterion, (3) average hours at/above 18 degrees C, (4) average hours at night at/above 18 degrees C. RESULTS: Mean winter temperatures in the bedroom were MBR=18.15 degrees C (SD=2.51), the living room MLR=18.90 degrees C (SD=2.46) and the hallway MHall=18.25 degrees C (SD=2.57).The median number of days meeting the criterion was 19-31%. For the living room, more days meet the criterion in the group with a LTD (Mdisability=342 vs Mno_disability=301, 95% CI 8 to 74), and with someone over 64 years present (Mabove64=341, Mbelow65=301 95%, CI 8 to 74).The median number of hours/day meeting the criterion was 13-17. In the living room, households with a disability had more hours at 18 degrees C (Mdisability=364, Mno_disability=297, 95% CI 17 to 83) as did the older age group (Mabove64=347, Mbelow65=296, 95% CI 18 to 84). In the hallway, more hours met the criterion in households with a disability (Mdisability=338, Mno_disability=302, 95% CI 3 to 70).247 homes had at least nine hours of at least 18 degrees C at night; no effect of age or disability. CONCLUSIONS: Many households are at risk of negative health outcomes because of temperatures below recommendations. PMID- 29764884 TI - Association between secondhand smoke exposure and hypertension in never smokers: a cross-sectional survey using data from Korean National Health and Nutritional Examination Survey V, 2010-2012. AB - OBJECTIVES: Secondhand smoke (SHS) exposure is associated with cardiovascular disease. This study aims to determine the association between SHS exposure estimated by questionnaire and hypertension in Korean never smokers. SETTING: Korean National Health and Nutrition Examination Survey (KNHANES) V was conducted from 2010 to 2012. PARTICIPANTS: We selected the never smokers aged over 20 years who answered the question about the SHS exposure. PRIMARY AND SECONDARY MEASURES: SHS exposure in both the home and work place was estimated using a self-reporting questionnaire. We investigated the association between SHS exposure and hypertension by using multivariate analysis. And we evaluated the mean systolic and diastolic blood pressure values according to SHS exposure after adjusting for possible confounding factors. All analyses were stratified by women and men. RESULTS: There were 10 532 (women 8987 and men 1545) never smokers. We divided the subjects into three groups according to the amount of SHS exposure: none group I, <2 hour/day-group II and >=2 hour/day-group III. Using multivariate analysis, hypertension was more commonly associated with group III than group I in women (adjusted OR 1.50, 95% CI 1.00 to 2.04, p=0.011). Adjusted mean systolic and diastolic blood pressure values in women who were not taking antihypertensive medication were significantly elevated in group III by 2.3 and 1.7 mm Hg, respectively. CONCLUSION: SHS exposure is significantly associated with hypertension in women never smokers. PMID- 29764885 TI - Compliance with current VTE prophylaxis guidelines and risk factors linked to complications of VTE prophylaxis in medical inpatients: a prospective cohort study in a Spanish internal medicine department. AB - OBJECTIVES: To evaluate the degree of compliance with the current guidelines regarding venous thromboembolism (VTE) prophylaxis in medical patients during admission and to identify risk factors linked to complications of VTE prophylaxis. DESIGN: Prospective cohort study. SETTING: The Internal Medicine Department of the University Hospital of Santiago de Compostela (tertiary referral hospital). PARTICIPANTS: A total of 396 hospitalised, elderly patients who did not undergo surgery and had no active or previous oral anticoagulation or low molecular weight heparin (LMWH) treatment (during the previous year) and who received VTE prophylaxis during admission. PRIMARY AND SECONDARY OUTCOME MEASURES: The degree of compliance with the current guidelines was estimated by calculating PADOVA and IMPROVE indexes in all cases. We analysed the development of the following complications: major and minor bleeding, major and minor haematoma and decrease of platelet count. RESULTS: We found that VTE prophylaxis was correctly indicated in 88.4% of patients. We found two (0.5%) cases with major bleeding, 17 (4.3%) with minor bleeding, 30 (7.6%) with decreased platelet count, 29 (7.3%) with major haematoma and 82 (20.7%) with minor haematoma. After multivariate logistic regression analysis, the presence of major haematomas was linked to obesity (OR 4.1; 95% CI 1.8 to 9.2, p=0.001), concomitant antiplatelet treatment (OR 2.7; 95% CI 1.1 to 6.5, p=0.03) and enoxaparin use (OR 3.5; 95% CI 1.1 to 10.9, p=0.029), and the presence of minor haematomas was associated with PADOVA index <4 points (OR 3.1; 95% CI 1.5 to 6.4, p=0.003) and diabetes mellitus (OR 2; 95% CI 1.1 to 3.7, p=0.031). CONCLUSIONS: Complications during VTE prophylaxis in elderly hospitalised medical patients are frequent even with correct application of current guidelines. The main factors linked to haematomas were obesity and concomitant antiplatelet treatment, the presence of which should lead physicians to exercise extreme caution. The use of tinzaparin for VTE prophylaxis in these patients could have a better safety profile. PMID- 29764886 TI - Association between dipstick proteinuria and hearing impairment in health check ups among Japanese workers: a cross-sectional study. AB - OBJECTIVE: Prevention of hearing impairment is important because it is difficult to recover from it. Epidemiological studies have examined the risk factors for hearing impairment; however, the association between dipstick proteinuria and hearing impairment has not been previously examined. This study aimed to clarify the association between dipstick proteinuria and hearing impairment. DESIGN: Cross-sectional study. SETTING: Office and factory workers from all over Japan. PARTICIPANTS: The total number of subjects was 7005. All were employees of the same company. Of these, we recruited 6192 subjects who underwent dipstick urine test and hearing test by audiometry in annual health check-ups (mean age 44.9 years, men 88.3%). PRIMARY OUTCOMES: Hearing tests were performed at two frequencies (1 kHz, 4 kHz) as prescribed by law in Japan. We defined the inability of subjects to respond to 30 dB at 1 kHz and/or 40 dB at 4 kHz as overall moderate hearing impairment. In addition, we defined moderate hearing impairment at 1 kHz (4 kHz) as an abnormal finding at 1 kHz (4 kHz). We examined the associations between degree of dipstick proteinuria and hearing impairment after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, serum creatinine level and history of noisy work environment. RESULTS: Overall moderate hearing impairment was noted in 324 subjects (5.2%). Of these, 107 subjects (1.7%) had moderate hearing impairment at 1 kHz and 278 subjects (4.5%) at 4 kHz. Dipstick proteinuria was significantly associated with overall moderate hearing impairment, as well as moderate hearing impairment at both 1 kHz and 4 kHz. The prevalence of overall moderate hearing impairment among subjects with proteinuria >=2+ was 23.5%, while that among subjects without proteinuria was 5.2% (p<0.01). CONCLUSIONS: Dipstick proteinuria was associated with moderate hearing impairment in Japanese workers. PMID- 29764887 TI - How effective and cost-effective are behaviour change interventions in improving the prescription and use of antibiotics in low-income and middle-income countries? A protocol for a systematic review. AB - INTRODUCTION: Antibiotic resistance endangers effective prevention and treatment of infections, and places significant burden on patients, families, communities and healthcare systems. Low-income and middle-income countries (LMICs) are especially vulnerable to antibiotic resistance, owing to high infectious disease burden, and limited resources for treatment. High prevalence of antibiotic prescription and use due to lack of provider's knowledge, prescriber's habits and perceived patient needs further exacerbate the situation. Interventions implemented to address the inappropriate prescription and use of antibiotics in LMICs must address different determinants of antibiotic resistance through sustainable and scalable interventions. The aim of this protocol is to provide a comprehensive overview of the methods that will be used to identify and appraise evidence on the effectiveness and cost-effectiveness of behaviour change interventions implemented in LMICs to improve the prescription and use of antibiotics. METHODS AND ANALYSIS: Two databases (Web of Science and PubMed) will be searched based on a strategy developed in consultation with an essential medicines and health systems researcher. Additional studies will be identified using the same search strategy in Google Scholar. To be included, a study must describe a behaviour change intervention and use an experimental design to estimate effectiveness and/or cost-effectiveness in an LMIC. Following systematic screening of titles, abstracts and keywords, and full-text appraisal, data will be extracted using a customised extraction form. Studies will be categorised by type of behaviour change intervention and experimental design. A meta-analysis or narrative synthesis will be conducted as appropriate, along with an appraisal of quality of studies using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) checklist. ETHICS AND DISSEMINATION: No individual patient data are used, so ethical approval is not required. The systematic review will be disseminated in a peer-reviewed journal and presented at a relevant international conference. PROSPERO REGISTRATION NUMBER: CRD42017075596. PMID- 29764888 TI - Assessment of thyroid cancer risk associated with radiation dose from personal diagnostic examinations in a cohort study of US radiologic technologists, followed 1983-2014. AB - OBJECTIVE: To assess whether personal medical diagnostic procedures over life, but particularly those associated with exposure in adulthood, were associated with increased thyroid cancer risk. DESIGN: Participants from the US Radiologic Technologists Study, a large, prospective cohort, were followed from the date of first mailed questionnaire survey completed during 1983-1989 to the earliest date of self-reported diagnosis of thyroid cancer or of any other cancer than non melanoma skin cancer (NMSC) in any of three subsequent questionnaires up to the last in 2012-2014. SETTING: US nationwide, occupational cohort. PARTICIPANTS: US radiologic technologists with exclusion of: those who reported a previous cancer apart from NMSC on the first questionnaire; those who reported a cancer with an unknown date of diagnosis on any of the questionnaires; and those who did not respond to both the first questionnaire and at least one subsequent questionnaire. PRIMARY OUTCOME MEASURE: We used Cox proportional hazards models with age as timescale to compute HRs and 95% CI for thyroid cancer in relation to cumulative 5-year lagged diagnostic thyroid dose. RESULTS: There were 414 self reported thyroid cancers (n=275 papillary) in a cohort of 76 415 persons. Cumulative thyroid dose was non-significantly positively associated with total (excess relative risk/Gy=2.29 (95% CI -0.91 to 7.01, p=0.19)) and papillary thyroid cancer (excess relative risk/Gy=4.15 (95% CI -0.39, 11.27, p=0.08)) risk. These associations were not modified by age at, or time since, exposure and were independent of occupational exposure. CONCLUSION: Our study provides weak evidence that thyroid dose from diagnostic radiation procedures over the whole of life, in particular associated with exposure in adulthood, influences adult thyroid cancer risk. PMID- 29764889 TI - Autologous Stem Cells in Achilles Tendinopathy (ASCAT): protocol for a phase IIA, single-centre, proof-of-concept study. AB - INTRODUCTION: Achilles tendinopathy (AT) is a cause of pain and disability affecting both athletes and sedentary individuals. More than 150 000 people in the UK every year suffer from AT.While there is much preclinical work on the use of stem cells in tendon pathology, there is a scarcity of clinical data looking at the use of mesenchymal stem cells to treat tendon disease and there does not appear to be any studies of the use of autologous cultured mesenchymal stem cells (MSCs) for AT. Our hypothesis is that autologous culture expanded MSCs implanted into an area of mid-portion AT will lead to improved pain-free mechanical function. The current paper presents the protocol for a phase IIa clinical study. METHODS AND ANALYSIS: The presented protocol is for a non-commercial, single-arm, open-label, phase IIa proof-of-concept study. The study will recruit 10 participants and will follow them up for 6 months. Included will be patients aged 18-70 years with chronic mid-portion AT who have failed at least 6 months of non operative management. Participants will have a bone marrow aspirate collected from the posterior iliac crest under either local or general anaesthetic. MSCs will be isolated and expanded from the bone marrow. Four to 6 weeks after the harvest, participants will undergo implantation of the culture expanded MSCs under local anaesthetic and ultrasound guidance. The primary outcome will be safety as defined by the incidence rate of serious adverse reaction. The secondary outcomes will be efficacy as measured by patient-reported outcome measures and radiological outcome using ultrasound techniques. ETHICS AND DISSEMINATION: The protocol has been approved by the National Research Ethics Service Committee (London, Harrow; reference 13/LO/1670). Trial findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT02064062. PMID- 29764890 TI - Marathon Kids UK: study design and protocol for a mixed methods evaluation of a school-based running programme. AB - INTRODUCTION: Schools are promising settings for physical activity promotion; however, they are complex and adaptive systems that can influence the quality of programme implementation. This paper presents an evaluation of a school-based running programme (Marathon Kids). The aims of this study are (1) to identify the processes by which schools implement the programme, (2) identify and explain the contextual factors affecting implementation and explications of effectiveness and (3) examine the relationship between the level of implementation and perceived outcomes. METHODS: Using a realist evaluation framework, a mixed method single group before-and-after design, strengthened by multiple interim measurements, will be used. Year 5 (9-10 years old) pupils and their teachers will be recruited from six state-funded primary schools in Leicestershire, UK.Data will be collected once prior to implementation, at five discrete time points during implementation and twice following implementation. A weekly implementation log will also be used. At time point 1 (TP1) (September 2016), data on school environment, teacher and pupil characteristics will be collected. At TP1 and TP6 (July 2017), accelerometry, pupil self-reported physical activity and psychosocial data (eg, social support and intention to be active) will be collected. At TP2, TP3 and TP5 (January, March and June 2017), observations will be conducted. At TP2 and TP5, there will be teacher interviews and pupil focus groups. Follow-up teacher interviews will be conducted at TP7 and TP8 (October 2017 and March 2018) and pupil focus group at TP8. In addition, synthesised member checking will be conducted (June 2018) with a mixed sample of schools. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained through Loughborough University Human Participants Ethics Subcommittee (R16-P032 & R16 P116). Findings will be disseminated via print, online media and dissemination events as well as practitioner and/or research journals. PMID- 29764891 TI - Developing a complex intervention to support timely engagement with palliative care for patients with advanced cancer in primary and secondary care in the UK: a study protocol. AB - INTRODUCTION: For patients with advanced cancer, timely access to palliative care can improve quality of life and enable patients to participate in decisions about their end-of-life care. However, in a UK population of 2500 patients who died from cancer, one-third did not receive specialist palliative care, and of those who did, the duration of involvement was too short to maximise the benefits. Initiating a conversation about palliative care is challenging for some health professionals and patients often have unmet information needs and misconceptions about palliative care. We will work closely with patients and health professionals to develop a patient decision aid and health professional training module designed to facilitate a timely and informed conversation about palliative care. METHODS AND ANALYSIS: This study is being conducted over 24 months from November 2017 to October 2019 and follows the UK Medical Research Council framework for developing complex interventions and the International Patient Decision Aids Guideline. The Ottawa Decision Support Framework underpins the study. The Supporting Timely Engagement with Palliative care (STEP) intervention will be developed though an iterative process informed by interviews and focus groups with patients with advanced cancer, oncologists, general practitioners and palliative care doctors. An expert panel will also review each iteration. The expert panel will consist of a patient representative with experience of palliative care, health professionals who are involved in advanced cancer care decision-making, a medical education expert and the National Council for Palliative Care director of transformation. The feasibility and acceptability of the decision aid and doctor training will be tested in oncology and general practice settings. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the Office for Research Ethics Committees Northern Ireland (ORECNI), approval reference 17/NI/0249. Dissemination and knowledge transfer will be conducted via publications, national bodies and networks, and patient and family groups. PMID- 29764893 TI - Correction: Diagnostic accuracy study of three alcohol breathalysers marketed for sale to the public. PMID- 29764894 TI - Correction: Is the weekend effect really ubiquitous? A retrospective clinical cohort analysis of 30-day mortality by day of week and time of day using linked population data from New South Wales, Australia. PMID- 29764892 TI - Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. AB - INTRODUCTION: Preliminary evidence supports the beneficial role of physical activity on prostate cancer outcomes. This phase III randomised controlled trial (RCT) is designed to determine if supervised high-intensity aerobic and resistance exercise increases overall survival (OS) in patients with metastatic castrate-resistant prostate cancer (mCRPC). METHODS AND ANALYSIS: Participants (n=866) must have histologically documented metastatic prostate cancer with evidence of progressive disease on androgen deprivation therapy (defined as mCRPC). Patients can be treatment-naive for mCRPC or on first-line androgen receptor-targeted therapy for mCRPC (ie, abiraterone or enzalutamide) without evidence of progression at enrolment, and with no prior chemotherapy for mCRPC. Patients will receive psychosocial support and will be randomly assigned (1:1) to either supervised exercise (high-intensity aerobic and resistance training) or self-directed exercise (provision of guidelines), stratified by treatment status and site. Exercise prescriptions will be tailored to each participant's fitness and morbidities. The primary endpoint is OS. Secondary endpoints include time to disease progression, occurrence of a skeletal-related event or progression of pain, and degree of pain, opiate use, physical and emotional quality of life, and changes in metabolic biomarkers. An assessment of whether immune function, inflammation, dysregulation of insulin and energy metabolism, and androgen biomarkers are associated with OS will be performed, and whether they mediate the primary association between exercise and OS will also be investigated. This study will also establish a biobank for future biomarker discovery or validation. ETHICS AND DISSEMINATION: Validation of exercise as medicine and its mechanisms of action will create evidence to change clinical practice. Accordingly, outcomes of this RCT will be published in international, peer-reviewed journals, and presented at national and international conferences. Ethics approval was first obtained at Edith Cowan University (ID: 13236 NEWTON), with a further 10 investigator sites since receiving ethics approval, prior to activation. TRIAL REGISTRATION NUMBER: NCT02730338. PMID- 29764896 TI - Correction: Is exercise-based cardiac rehabilitation effective? A systematic review and meta-analysis to re-examine the evidence. PMID- 29764895 TI - Correction: Values and preferences of women living with HIV who are pregnant, postpartum or considering pregnancy on choice of antiretroviral therapy during pregnancy. PMID- 29764900 TI - Celebrating 35 Years of the AJNR: May 1983 edition. PMID- 29764897 TI - Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion. AB - BACKGROUND: T-wave inversion (TWI) is common in patients with cardiomyopathy. However, up to 25% of athletes of African/Afro-Caribbean descent (black athletes) and 5% of white athletes also have TWI of unclear clinical significance despite comprehensive clinical evaluation and long-term follow-up. The aim of this study was to determine the diagnostic yield from genetic testing, beyond clinical evaluation, when investigating athletes with TWI. METHODS: We investigated 50 consecutive asymptomatic black and 50 white athletes 14 to 35 years of age with TWI and a normal echocardiogram who were referred to a UK tertiary center for cardiomyopathy and sports cardiology. Subjects underwent exercise testing, 24 hour ambulatory ECG, signal-averaged ECG, cardiac magnetic resonance imaging, and a blood-based analysis of a comprehensive 311-gene panel for cardiomyopathies and ion channel disorders associated with TWI, including hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, long-QT syndrome, and Brugada syndrome. RESULTS: In total, 21 athletes (21%) were diagnosed with cardiac disease on the basis of comprehensive clinical investigations. Of these, 8 (38.1%) were gene positive (myosin binding protein C[ MYBPC3], myosin heavy chain 7 [ MYH7], galactosidase alpha [ GLA], and actin alpha, cardiac muscle 1 [ ACTC1] genes) and 13 (61.9%) were gene negative. Of the remaining 79 athletes (79%), 2 (2.5%) were gene positive (transthyretin [ TTR] and sodium voltage-gated channel alpha subunit 5 [ SCN5A] genes) in the absence of a clinical phenotype. The prevalence of newly diagnosed cardiomyopathy was higher in white athletes compared with black athletes (30.0% versus 12%; P=0.027). Hypertrophic cardiomyopathy accounted for 90.5% of all clinical diagnoses. All black athletes and 93.3% of white athletes with a clinical diagnosis of cardiomyopathy or a genetic mutation capable of causing cardiomyopathy exhibited lateral TWI as opposed to isolated anterior or inferior TWI; the genetic yield of diagnoses from lateral TWI was 12.3%. CONCLUSIONS: Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice. PMID- 29764898 TI - Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis. AB - BACKGROUND: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. METHODS: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. RESULTS: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). beta-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. CONCLUSIONS: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction. PMID- 29764902 TI - Secular trend, seasonality and effects of a community-based intervention on neonatal mortality: follow-up of a cluster-randomised trial in Quang Ninh province, Vietnam. AB - BACKGROUND: Little is know about whether the effects of community engagement interventions for child survival in low-income and middle-income settings are sustained. Seasonal variation and secular trend may blur the data. Neonatal mortality was reduced in a cluster-randomised trial in Vietnam where laywomen facilitated groups composed of local stakeholders employing a problem-solving approach for 3 years. In this analysis, we aim at disentangling the secular trend, the seasonal variation and the effect of the intervention on neonatal mortality during and after the trial. METHODS: In Quang Ninh province, 44 communes were allocated to intervention and 46 to control. Births and neonatal deaths were assessed in a baseline survey in 2005, monitored during the trial in 2008-2011 and followed up by a survey in 2014. Time series analyses were performed on monthly neonatal mortality data. RESULTS: There were 30 187 live births and 480 neonatal deaths. The intervention reduced the neonatal mortality from 19.1 to 11.6 per 1000 live births. The reduction was sustained 3 years after the trial. The control areas reached a similar level at the time of follow-up. Time series decomposition analysis revealed a downward trend in the intervention areas during the trial that was not found in the control areas. Neonatal mortality peaked in the hot and wet summers. CONCLUSIONS: A community engagement intervention resulted in a lower neonatal mortality rate that was sustained but not further reduced after the end of the trial. When decomposing time series of neonatal mortality, a clear downward trend was demonstrated in intervention but not in control areas. TRIAL REGISTRATION NUMBER: ISRCTN44599712, Post-results. PMID- 29764901 TI - The Histone Demethylase KDM5 Is Essential for Larval Growth in Drosophila. AB - Regulated gene expression is necessary for developmental and homeostatic processes. The KDM5 family of transcriptional regulators are histone H3 lysine 4 demethylases that can function through both demethylase-dependent and independent mechanisms. While loss and overexpression of KDM5 proteins are linked to intellectual disability and cancer, respectively, their normal developmental functions remain less characterized. Drosophila melanogaster provides an ideal system to investigate KDM5 function, as it encodes a single ortholog in contrast to the four paralogs found in mammalian cells. To examine the consequences of complete loss of KDM5, we generated a null allele of Drosophila kdm5, also known as little imaginal discs (lid), and show that it is essential for viability. Animals lacking KDM5 show a dramatically delayed larval development that coincides with decreased proliferation and increased cell death in wing imaginal discs. Interestingly, this developmental delay is independent of the well characterized Jumonji C (JmjC) domain-encoded histone demethylase activity of KDM5, suggesting key functions for less characterized domains. Consistent with the phenotypes observed, transcriptome analyses of kdm5 null mutant wing imaginal discs revealed the dysregulation of genes involved in several cellular processes, including cell cycle progression and DNA repair. Together, our analyses reveal KDM5 as a key regulator of larval growth and offer an invaluable tool for defining the biological activities of KDM5 family proteins. PMID- 29764905 TI - Dynamics of sister chromatids through the cell cycle: Together and apart. AB - When and how sister chromatid resolution occurs after DNA replication is a fundamental question. Stanyte et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201801157) used CRISPR/Cas9 technology to label and track genomic loci in live cells throughout the cell cycle, shedding light on how replication is linked to mitotic sister chromatid organization. PMID- 29764904 TI - Aberrant MRP14 expression in thyroid follicular cells mediates chemokine secretion through the IL-1beta/MAPK pathway in Hashimoto's thyroiditis. AB - Myeloid-related protein 14 (MRP14) is responsible for inflammatory reactions. However, the correlation between MRP14 and Hashimoto's thyroiditis (HT) is still not clear. In this study, we examined the status of MRP14 in thyroid tissues and sera of HT patients and explored the mechanism of IL-1beta-mediated regulation of MRP14 expression, as well as the effects of MRP14 on pro-inflammatory chemokine secretion in thyroid follicular cells (TFCs), to elucidate the role of MRP14 in HT development. Our results showed dramatically increased MRP14 expression in thyroid tissues and sera from HT patients. In addition, IL-1beta significantly promoted the expression of MRP14 in TFCs, which was mediated by activation of the MAPK/NF-kappaB signalling pathway. More importantly, IL-1beta induced the secretion of the chemokines GRO-2, CXCL9 and CCL22, which was dependent on the regulation of MRP14 in TFCs. Therefore, these findings suggested that under pro inflammatory conditions, TFCs secreted chemokines with the help of MRP14 regulation, which might suggest a potential pathological mechanism of lymphocyte infiltration into the thyroid gland in HT. PMID- 29764906 TI - EB1 traps STIM1 and regulates local store-operated Ca2+ entry. AB - STIM1 activates store-operated Ca2+ entry when Ca2+ in the endoplasmic reticulum (ER) is depleted. In this issue, Chang et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201711151) demonstrate that EB1 traps STIM1 at dynamic contacts between the ER and microtubule plus ends, delaying STIM1 translocation to ER-plasma membrane junctions and preventing Ca2+ overload. PMID- 29764903 TI - Vitamin D supplementation does not improve CVD risk factors in vitamin D insufficient subjects. AB - OBJECTIVE: Low serum 25(OH)D levels are associated with cardiovascular disease (CVD) and some of its risk factors. However, in interventional studies, the effects of vitamin D supplementation have been uncertain, possibly due to inclusion of vitamin D-sufficient subjects. Our aim was therefore to examine effects of vitamin D supplementation on CVD risk factors in vitamin D insufficient subjects. DESIGN: Double-blinded randomized controlled trial. METHODS: A 4-month interventional study with high-dose vitamin D (100,000 IU loading dose, followed by 20,000 IU/week) or placebo with measurements of blood pressure, lipids (total-, LDL- and HDL-cholesterol, triglycerides, apolipoproteins A1 and B), and glucose metabolism parameters (blood glucose, HbA1c, serum human receptors for advanced glycation end products (sRAGE), insulin, C-peptide and HOMA-IR). RESULTS: A total of 422 subjects with mean serum 25(OH)D level 34 nmol/L were included, with 411 subjects completing the study. Serum 25(OH)D levels increased with 56 nmol/L and decreased with 4 nmol/L in the vitamin D and placebo group, respectively. We found no statistically significant differences between the two groups in any of the measured CVD risk factors, except for a minor increase in sRAGE in the vitamin D group. Stratified analyses of subjects with low baseline serum 25(OH)D levels alone, or combined with blood pressure, lipid and HOMA-IR values above the median for the cohort, did not skew the results in favour of vitamin D supplementation. CONCLUSION: Supplementation with vitamin D in subjects with baseline vitamin D insufficiency does not improve CVD risk factor profile. PMID- 29764907 TI - Mortality in acromegaly decreased in the last decade: a systematic review and meta-analysis. AB - OBJECTIVE: To compare the acromegaly mortality rates with those expected for the general population from studies published before and after 2008. METHODS: We performed a systematic review and included observational studies in which the number of deaths observed in acromegaly was compared with the expected mortality for the general population mortality observed/expected (O/E). The following electronic databases were used as our data sources: EMBASE, MEDLINE and LILACS. From the observed and expected deaths, we recalculated all standardized mortality ratios (SMR) and their respective confidence intervals (95% CI), which were plotted in a meta-analysis using the software RevMan 5.3. RESULTS: We identified 2303 references, and 26 studies fulfilled our eligibility criteria. From the 17 studies published before 2008, the mortality in acromegaly was increased, while from the nine studies published after 2008, the mortality was not different from the general population (SMR: 1.35, CI: 0.99-1.85). In six studies where somatostatin analogs (SAs) were used as adjuvant treatment, acromegaly mortality was not increased (SMR: 0.98, CI: 0.83-1.15), whereas in series including only patients treated with surgery and/or radiotherapy, mortality was significantly higher (SMR: 2.11; CI: 1.54-2.91). In studies published before and after 2008, the mortality was not increased in patients who achieved biochemical control, while it was higher in those with active disease. Cancer has become a leader cause of deaths in acromegaly patients in the last decade, period in which life expectancy improved. CONCLUSION: Mortality in acromegaly is normalized with biochemical control and decreased in the last decade with the more frequent use of SAs as adjuvant therapy. Increased life expectancy has been associated with more deaths due to cancer. PMID- 29764910 TI - Using Quality Improvement to Tackle Unwarranted Practice Variation. PMID- 29764908 TI - MANAGEMENT OF ENDOCRINE DISEASE: Which metabolic procedure? Comparing outcomes in sleeve gastrectomy and Roux-en Y gastric bypass. AB - Obesity and its associated comorbidities have become one of the largest challenges for health care in the near future. Conservative therapy for obesity and related comorbidities has a very high failure rate and poor long-term results. Similarly, the conservative and medical management of the majority of metabolic diseases such as type 2 diabetes mellitus are only able to slow down disease progression but have no causal effect on the disease process. Obesity surgery has evolved as a highly effective therapy for severe obesity achieving long-lasting weight loss. Furthermore, several studies have demonstrated the beneficial effects of obesity surgery on reduction of overall mortality, reduction of cardiovascular events and superior control of obesity-related diseases such as type 2 diabetes mellitus, dyslipidemia and also the non alcoholic steatohepatitis compared to medical therapy. Based on these findings, the term 'metabolic surgery' with the focus on treating metabolic diseases independent of body weight has been coined. Of great interest are recent studies that show that even existing complications of metabolic diseases such as diabetic nephropathy or the non-alcoholic steatohepatitis can be reversed by metabolic surgery. Although metabolic surgery has proven to be a safe and effective treatment for obesity, resolution of comorbidities and enhancing quality of life, it is still uncertain and unclear, which surgical procedure is the most effective to achieve these metabolic effects. The aim of this review is to compare the effects of the two currently most widely used metabolic operations, the Roux-en-Y gastric bypass and the sleeve gastrectomy in the treatment of obesity and its related comorbidities. PMID- 29764909 TI - Ohio Pediatric Asthma Repository: Opportunities to Revise Care Practices to Decrease Time to Physiologic Readiness for Discharge. AB - BACKGROUND: Large-scale, multisite studies in which researchers evaluate patient- and systems-level factors associated with pediatric asthma exacerbation outcomes are lacking. We sought to investigate patient-level risks and system-level practices related to physiologic readiness for discharge (PRD) in the prospective Ohio Pediatric Asthma Repository. METHODS: Participants were children ages 2 to 17 years admitted to an Ohio Pediatric Asthma Repository hospital for asthma exacerbation. Demographics, disease characteristics, and individual hospital practices were collected. The primary outcome was PRD timing (hours from admission or emergency department [ED] presentation until the first 4-hour albuterol spacing). RESULTS: Data for 1005 participants were available (865 ED presentations). Several nonstandard care practices were associated with time to PRD (P < .001). Continuous pulse oximetry was associated with increased time to PRD (P = .004). ED dexamethasone administration was associated with decreased time to PRD (P < .001) and less ICU admittance and intravenous steroid use (P < .0001). Earlier receipt of chest radiograph, antibiotics, and intravenous steroids was associated with shorter time to PRD (P < .05). Care practices associated with shorter time to PRD varied markedly by hospital. CONCLUSIONS: Substantial variation in care practices for inpatient asthma treatment exists among children's hospital systems in Ohio. We found several modifiable, system level factors and therapies that contribute to PRD that warrant further investigation to identify the best and safest care practices. We also found that there was no standardized measure of exacerbation severity used across the hospitals. The development of such a tool is a critical gap in current practice and is needed to enable definitive comparative effectiveness studies of the management of acute asthma exacerbation. PMID- 29764911 TI - A DEAL for open access: The negotiations between the German DEAL project and publishers have global implications for academic publishing beyond just Germany. PMID- 29764912 TI - Mitochondrial PITRM1 peptidase loss-of-function in childhood cerebellar atrophy. AB - OBJECTIVE: To identify the genetic basis of a childhood-onset syndrome of variable severity characterised by progressive spinocerebellar ataxia, mental retardation, psychotic episodes and cerebellar atrophy. METHODS: Identification of the underlying mutations by whole exome and whole genome sequencing. Consequences were examined in patients' cells and in yeast. RESULTS: Two brothers from a consanguineous Palestinian family presented with progressive spinocerebellar ataxia, mental retardation and psychotic episodes. Serial brain imaging showed severe progressive cerebellar atrophy. Whole exome sequencing revealed a novel mutation: pitrilysin metallopeptidase 1 (PITRM1) c.2795C>T, p.T931M, homozygous in the affected children and resulting in 95% reduction in PITRM1 protein. Whole genome sequencing revealed a chromosome X structural rearrangement that also segregated with the disease. Independently, two siblings from a second Palestinian family presented with similar, somewhat milder symptoms and the same PITRM1 mutation on a shared haplotype. PITRM1T931M carrier frequency was 0.027 (3/110) in the village of the first family evaluated, and 0/300 among Palestinians from other locales. PITRM1 is a mitochondrial matrix enzyme that degrades 10-65 amino acid oligopeptides, including the mitochondrial fraction of amyloid-beta peptide. Analysis of peptide cleavage activity by the PITRM1T931M protein revealed a significant decrease in the degradation capacity specifically of peptides >=40 amino acids. CONCLUSION: PITRM1T931M results in childhood-onset recessive cerebellar pathology. Severity of PITRM1-related disease may be affected by the degree of impairment in cleavage of mitochondrial long peptides. Disruption and deletion of X linked regulatory segments may also contribute to severity. PMID- 29764915 TI - Remote physiological monitoring in an austere environment: a future for battlefield care provision? AB - Wearable technologies are making considerable advances into the mainstream as they become smaller and more user friendly. The global market for such devices is forecasted to be worth over US$5 billion in 2018, with one in six people owning a device. Many professional sporting teams use self-monitoring to assess physiological parameters and work rate on the pitch, highlighting the potential utility for military command chains. As size of device reduces and sensitivity improves, coupled with remote connectivity technology, integration into the military environment could be relatively seamless. Remote monitoring of personnel on the ground, giving live updates on their physiological status, would allow commanders or medical officers the ability to manage their soldiers appropriately and improve combat effectiveness. This paper explores a proof of concept for the use of a self-monitoring system in the austere high altitude environment of the Nepalese Himalayas, akin to those experienced by modern militaries fighting in remote locations. It also reviews, in part, the historical development of remote monitoring technologies. The system allowed for physiological recordings, plotted against GPS position, to be remotely monitored in Italy. Examples of the data recorded are given and the performance of the system is discussed, including limitations, potential areas of development and how systems like this one could be integrated into the military environment. PMID- 29764914 TI - Less cholesterol means better tumor killing for cytotoxic T9 cells. AB - In this issue, Ma et al. (https://doi.org/10.1084/jem.20171576) show that removal of cholesterol from CD8 T cells during type 9 differentiation increases their IL 9 production, persistence in vivo, and cytolytic function against tumors by preventing SUMOylation of liver X receptors. PMID- 29764916 TI - Adults with intellectual disabilities experience shame that leads to psychological distress and mental illness that requires assessment and treatment. PMID- 29764913 TI - Mapping and characterizing N6-methyladenine in eukaryotic genomes using single molecule real-time sequencing. AB - N6-Methyladenine (m6dA) has been discovered as a novel form of DNA methylation prevalent in eukaryotes; however, methods for high-resolution mapping of m6dA events are still lacking. Single-molecule real-time (SMRT) sequencing has enabled the detection of m6dA events at single-nucleotide resolution in prokaryotic genomes, but its application to detecting m6dA in eukaryotic genomes has not been rigorously examined. Herein, we identified unique characteristics of eukaryotic m6dA methylomes that fundamentally differ from those of prokaryotes. Based on these differences, we describe the first approach for mapping m6dA events using SMRT sequencing specifically designed for the study of eukaryotic genomes and provide appropriate strategies for designing experiments and carrying out sequencing in future studies. We apply the novel approach to study two eukaryotic genomes. For green algae, we construct the first complete genome-wide map of m6dA at single-nucleotide and single-molecule resolution. For human lymphoblastoid cells (hLCLs), it was necessary to integrate SMRT sequencing data with independent sequencing data. The joint analyses suggest putative m6dA events are enriched in the promoters of young full-length LINE-1 elements (L1s), but call for validation by additional methods. These analyses demonstrate a general method for rigorous mapping and characterization of m6dA events in eukaryotic genomes. PMID- 29764917 TI - The path to VICTORy - a beginner's guide to success using commercial research antibodies. AB - Commercial research antibodies are crucial tools in modern cell biology and biochemistry. In the USA some $2 billion a year are spent on them, but many are apparently not fit-for-purpose, and this may contribute to the 'reproducibility crisis' in biological sciences. Inadequate antibody validation and characterization, lack of user awareness, and occasional incompetence amongst suppliers have had immense scientific and personal costs. In this Opinion, I suggest some paths to make the use of these vital tools more successful. I have attempted to summarize and extend expert views from the literature to suggest that sustained routine efforts should made in: (1) the validation of antibodies, (2) their identification, (3) communication and controls, (4) the training of potential users, (5) the transparency of original equipment manufacturer (OEM) marketing agreements, and (5) in a more widespread use of recombinant antibodies (together denoted the 'VICTOR' approach). PMID- 29764919 TI - SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways. AB - Sulfation and desulfation pathways represent highly dynamic ways of shuttling, repressing and re-activating steroid hormones, thus controlling their immense biological potency at the very heart of endocrinology. This theme currently experiences growing research interest from various sides, including, but not limited to, novel insights about phospho-adenosine-5'-phosphosulfate synthase and sulfotransferase function and regulation, novel analytics for steroid conjugate detection and quantification. Within this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including chronic inflammatory diseases and steroid-dependent cancers. PMID- 29764920 TI - Right Heart Failure-Unrecognized Cause of Cardiorenal Syndrome. PMID- 29764918 TI - A feed-forward relay integrates the regulatory activities of Bicoid and Orthodenticle via sequential binding to suboptimal sites. AB - The K50 (lysine at amino acid position 50) homeodomain (HD) protein Orthodenticle (Otd) is critical for anterior patterning and brain and eye development in most metazoans. In Drosophila melanogaster, another K50HD protein, Bicoid (Bcd), has evolved to replace Otd's ancestral function in embryo patterning. Bcd is distributed as a long-range maternal gradient and activates transcription of a large number of target genes, including otd Otd and Bcd bind similar DNA sequences in vitro, but how their transcriptional activities are integrated to pattern anterior regions of the embryo is unknown. Here we define three major classes of enhancers that are differentially sensitive to binding and transcriptional activation by Bcd and Otd. Class 1 enhancers are initially activated by Bcd, and activation is transferred to Otd via a feed-forward relay (FFR) that involves sequential binding of the two proteins to the same DNA motif. Class 2 enhancers are activated by Bcd and maintained by an Otd-independent mechanism. Class 3 enhancers are never bound by Bcd, but Otd binds and activates them in a second wave of zygotic transcription. The specific activities of enhancers in each class are mediated by DNA motif variants preferentially bound by Bcd or Otd and the presence or absence of sites for cofactors that interact with these proteins. Our results define specific patterning roles for Bcd and Otd and provide mechanisms for coordinating the precise timing of gene expression patterns during embryonic development. PMID- 29764922 TI - Introduction to the Thematic Review Series on Extracellular Vesicles: a focus on the role of lipids. PMID- 29764921 TI - Fibroblast Growth Factor-23 and Risks of Cardiovascular and Noncardiovascular Diseases: A Meta-Analysis. AB - Background Fibroblast growth factor-23 (FGF-23) has been hypothesized to play a role in the increased risk of cardiovascular disease in patients with CKD.Methods We identified prospective studies reporting associations between FGF-23 concentration and risk of cardiovascular events. Maximally adjusted risk ratios (RRs) were extracted for each outcome and scaled to a comparison of the top versus bottom third of the baseline FGF-23 concentration, and the results aggregated.Results Depending on the assay used, median FGF-23 concentrations were 43-74 RU/ml and 38-47 pg/ml in 17 general population cohorts; 102-392 RU/ml in nine cohorts of patients with CKD not requiring dialysis; and 79-4212 RU/ml and 2526-5555 pg/ml in eight cohorts of patients on dialysis. Overall, comparing participants in the top and bottom FGF-23 concentration thirds, the summary RRs (95% confidence intervals [95% CIs]) were 1.33 (1.12 to 1.58) for myocardial infarction, 1.26 (1.13 to 1.41) for stroke, 1.48 (1.29 to 1.69) for heart failure, 1.42 (1.27 to 1.60) for cardiovascular mortality, and 1.70 (1.52 to 1.91) for all-cause mortality. The summary RR for noncardiovascular mortality, calculated indirectly, was 1.52 (95% CI, 1.28 to 1.79). When studies were ordered by average differences in FGF-23 concentration between the top and bottom thirds, there was no trend in RRs across the studies.Conclusions The similarly-sized associations between increased FGF-23 concentration and cardiovascular (atherosclerotic and nonatherosclerotic) and noncardiovascular outcomes, together with the absence of any exposure-response relationship, suggest that the relationship between FGF-23 and cardiovascular disease risk may be noncausal. PMID- 29764925 TI - The acid test for pH-dependent gating in cloned HV1 channels. PMID- 29764924 TI - Normalized neutral lipid quantitation by flow cytometry. AB - Interest in measuring tissue lipids has increased as the link between fat-laden tissues and metabolic disease has become obvious; however, linking disease to a specific cell type within a tissue has been hampered by methodological limitations. Flow cytometry (FC) has been used to assess relative lipid levels in cells. Unfortunately, its usefulness is limited because comparisons between samples generated over several hours is problematic. We show that: 1) in lipophilic fluorophore stained cells, fluorescence intensity measured by FC reflects lipid levels; 2) this technique can be used to assess lipid levels in a mixed cell population; 3) normalizing to a control condition can decrease experiment-to-experiment variation; and 4) fluorescence intensity increases linearly with lipid levels. This allows triacylglycerol (TG) mass to be estimated in mixed cell populations comparing cells with known fluorescence and TG levels. We exploited this strategy to estimate lipid levels in monocytes within a mixed population of cells isolated from human blood. Using this strategy, we also confirmed that perilipin (PLIN)1 increases TG accumulation by ectopically expressing fluorescently tagged PLIN1 in Huh7 cells. In both examples, biochemically assaying for TG in specific cell populations is problematic due to limited cell numbers and isolation challenges. Other advantages are discussed. PMID- 29764923 TI - Extracellular vesicles: lipids as key components of their biogenesis and functions. AB - Intercellular communication has been known for decades to involve either direct contact between cells or to operate via circulating molecules, such as cytokines, growth factors, or lipid mediators. During the last decade, we have begun to appreciate the increasing importance of intercellular communication mediated by extracellular vesicles released by viable cells either from plasma membrane shedding (microvesicles, also named microparticles) or from an intracellular compartment (exosomes). Exosomes and microvesicles circulate in all biological fluids and can trigger biological responses at a distance. Their effects include a large variety of biological processes, such as immune surveillance, modification of tumor microenvironment, or regulation of inflammation. Extracellular vesicles can carry a large array of active molecules, including lipid mediators, such as eicosanoids, proteins, and nucleic acids, able to modify the phenotype of receiving cells. This review will highlight the role of the various lipidic pathways involved in the biogenesis and functions of microvesicles and exosomes. PMID- 29764926 TI - Search for a prognostic biomarker in multiple sclerosis: a step in the right direction? PMID- 29764929 TI - Scaffolding our systems? Patients and families 'reaching in' as a source of healthcare resilience. PMID- 29764928 TI - Ovarian steroid dependence of endoplasmic reticulum stress involvement in endometrial cell apoptosis during the human endometrial cycle. AB - Endoplasmic reticulum (ER) stress is a common cellular stress response that enhances apoptosis to trigger cell death. However, recent studies have shown that estrogen suppresses apoptosis by inhibiting ER stress in some cell types, suggesting that ER stress-induced apoptosis is regulated by ovarian steroid hormones. In endometrial cells, ER stress may also be controlled by ovarian steroid hormones and could be involved in apoptosis induction during the menstrual cycle. To test this hypothesis, we elucidate whether ER stress is regulated by ovarian steroid hormones in human endometrial cells and if it is involved in apoptosis induction. Specifically, we sought to determine the effects of estrogen and progesterone on the PERK/eIF2alpha/ATF4/CHOP pathway, a pro apoptotic pathway mediated by ER stress. Our results show that ER stress maker GRP78 expression was increased in human endometrial Ishikawa and endometrial stromal cells (ESCs) treated with tunicamycin. Addition of estrogen decreased tunicamycin-induced GRP78 expression. In contrast, progesterone treatment increased GRP78 in estrogen-treated Ishikawa and ESCs, which significantly increased CHOP expression through phosphorylation of eIF2alpha and upregulation of ATF4. This upregulation was accompanied by an increased apoptosis induction. The progesterone-induced increase in apoptosis was reversed by either mifepristone (progesterone receptor modulator) or salubrinal (ER stress inhibitor). Furthermore, our in vivo results also showed that GRP78, CHOP expression and apoptosis were significantly increased in endometrial cells during the secretory phase as well as by in vitro treatment with progesterone. In conclusion, our results suggest that estrogen inhibits ER stress in human endometrial cells. This inhibition is reversed by progesterone during the secretory phase, and this is directly involved in apoptosis induction. PMID- 29764930 TI - Closure of large bore 9 F arterial puncture sites with the AngioSeal STS device in acute stroke patients after intravenous recombinant tissue plasminogen activator (rt-PA). AB - PURPOSE: This retrospective analysis was performed to evaluate whether large bore 9 F puncture sites can be safely closed with the 8 F AngioSeal STS device after endovascular stroke procedures in patients who did or did not receive recombinant tissue plasminogen activator (rt-PA). METHODS: Out of 161 consecutive endovascular stroke procedures we identified 72 patients who met the inclusion criteria, of whom 46 received rt-PA before the endovascular procedure and 26 did not. All groin complications such as major haemorrhage, failure of the device to close the puncture site, delayed haemorrhage, acute lower extremity ischaemia or necessary vascular surgery as well as infections were recorded. RESULTS: Only one patient had delayed groin haemorrhage after closure of the 9 F puncture site with the AngioSeal STS device. There was no significant difference in complications between patients with or without rt-PA treatment. CONCLUSION: The 8 F AngioSeal STS seems to be safe and efficient to close 9 F femoral artery puncture sites, even under active rt-PA thrombolysis. PMID- 29764927 TI - Identification of Genes Related to Cold Tolerance and a Functional Allele That Confers Cold Tolerance. AB - Cold stress is a major factor limiting rice (Oryza sativa) production worldwide, especially at the seedling and booting stages. The identification of genes associated with cold tolerance (CT) in rice is important for sustainable food production. Here, we report the results of a genome-wide association study to identify the genetic loci associated with CT by using a 1,033-accession diversity panel. We identified five CT-related genetic loci at the booting stage. Accessions carrying multiple cold-tolerant alleles displayed a higher seed setting rate than did accessions that had no cold-tolerant alleles or carried a single allele. At the seedling stage, eight genetic loci related to CT have been identified. Among these, LOC_Os10g34840 was identified as the candidate gene for the qPSR10 genetic locus that is associated with CT in rice seedlings. A single nucleotide polymorphism (SNP), SNP2G, at position 343 in LOC_Os10g34840 is responsible for conferring CT at the seedling stage in rice. Further analysis of the haplotype network revealed that SNP2G was present in 80.08% of the temperate japonica accessions but only 3.8% of the indica ones. We used marker-assisted selection to construct a series of BC4F3 near-isogenic lines possessing the cold tolerant allele SNP2G When subjected to cold stress, plants carrying SNP2G survived better as seedlings and showed higher grain weight than plants carrying the SNP2A allele. The CT-related loci identified here and the functional verification of LOC_Os10g34840 will provide genetic resources for breeding cold tolerant varieties and for studying the molecular basis of CT in rice. PMID- 29764931 TI - High rates of variation in HLA-DQ2/DQ8 testing for coeliac disease: results from an RCPAQAP pilot program. AB - AIM: Coeliac disease(CD) is a highly prevalent, gluten-dependent, autoimmune enteropathy. While the diagnosis is based on serological and histological criteria, genotyping of the human leucocyte antigens (HLA) DQ2 and DQ8 has been shown to have substantial clinical utility, especially in excluding the diagnosis in patients who do not carry either antigen. As a result, HLA genotyping is now being performed by more laboratories and has recently become one of the most frequently requested genetic tests in Australia. To date, there has been little scrutiny on the accuracy and reporting of results by laboratories new to HLA typing. In response to clinician feedback that identified potentially clinically significant discrepancies in HLA typing results, the Royal College of Pathologists of Australasia Quality Assurance Programs (RCPAQAP) undertook a pilot study to assess laboratory performance in the detection of HLA-DQ2/DQ8 and their associated HLA-DQA1 and HLA-DQB1 alleles. METHODS: DNA was extracted from 5 patients and sent to 10 laboratories for external quality assurance (EQA) testing. Laboratories were assessed for reporting in genotyping, interpretation and methodology. RESULTS: Our findings showed that at least 80% of laboratories underperform with respect to recommended guidelines for HLA typing and reporting for CD, with 40% of laboratories failing to provide any clinical interpretation or full genotyping data. This suboptimal level of reporting may lead to ambiguities for downstream clinical interpretation that may compromise patient management. CONCLUSIONS: These findings highlight the importance of adherence to standardised guidelines for optimal performance and reporting of HLA results and substantiate the need for EQA and proficiency testing for laboratories providing this service. PMID- 29764932 TI - Distribution of mast cell subtypes in interstitial cystitis: implications for novel diagnostic and therapeutic strategies? AB - AIMS: To identify the presence and geographical distribution of mast cell (MC) subtypes: MCT (tryptase positive-chymase negative) and MCTC (tryptase positive chymase positive) in bladder tissue. METHODS: Bladder tissue was obtained from patients with painful bladder syndrome/interstitial cystitis (n=14) and normal histology from University Hospital Southampton tissue bank. Sequential tissue slices were immunohistochemically stained for MC subtypes using anti-MC tryptase (for MCT and MCTC) and anti-MC chymase (for MCTC). Stained sections were photographed, and positively stained MCs were quantified using ImageJ. Data were analysed using descriptive statistics and individual paired t-tests. RESULTS: There was a significant difference in the density of MCs between each layer of the disease bladder, with the greatest accumulation within the detrusor (p<0.001). There was a significant increase in MCTC subtype in the lamina (p=0.009) in painful bladder syndrome/interstitial cystitis. CONCLUSIONS: Our results suggest that mastocytosis is present within all layers of disease bladder, especially the muscle layer. The varying increase in MC subtypes in the lamina and mucosa may explain the variability in painful bladder syndrome/interstitial cystitis symptoms. A high influx of MCTC in the mucosa of individuals who also had ulceration noted within their diagnostic notes may be of the Hunner's ulcer subclassification. These findings suggest a relationship between the pathogenesis of MC subtypes and the clinical presentation of painful bladder syndrome/interstitial cystitis. A cohort study would further elucidate the diagnostic and/or therapeutic potential of MCs in patients with painful bladder syndrome/interstitial cystitis. PMID- 29764933 TI - Discovery of peroxisome proliferator-activated receptor alpha (PPARalpha) activators with a ligand-screening system using a human PPARalpha-expressing cell line. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARalpha is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARalpha activators are often used to treat patients with dyslipidemia. To discover additional PPARalpha activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator-responsive elements (PPREs) and tetracycline-regulated expression of full-length human PPARalpha to quantify the effects of chemical ligands on PPARalpha activity. Using the established cell-based PPARalpha activator screening system to screen a library of >12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPARalpha agonists. One of the hit compounds, a 1H-pyrazolo[3,4 b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up regulated PPARalpha transcriptional activity, leading to PPARalpha target gene expression both in vitro and in vivo Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPARalpha ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4 b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPARalpha to manage dyslipidemia. PMID- 29764934 TI - Structure-specific recognition protein-1 (SSRP1) is an elongated homodimer that binds histones. AB - The histone chaperone complex facilitates chromatin transcription (FACT) plays important roles in DNA repair, replication, and transcription. In the formation of this complex, structure-specific recognition protein-1 (SSRP1) heterodimerizes with suppressor of Ty 16 (SPT16). SSRP1 also has SPT16-independent functions, but how SSRP1 functions alone remains elusive. Here, using analytical ultracentrifugation (AUC) and small-angle X-ray scattering (SAXS) techniques, we characterized human SSRP1 and that from the amoeba Dictyostelium discoideum and show that both orthologs form an elongated homodimer in solution. We found that substitutions in the SSRP1 pleckstrin homology domain known to bind SPT16 also disrupt SSRP1 homodimerization. Moreover, AUC and SAXS analyses revealed that SSRP1 homodimerization and heterodimerization with SPT16 (resulting in FACT) involve the same SSRP1 surface, namely the PH2 region, and that the FACT complex contains only one molecule of SSRP1. These observations suggest that SSRP1 homo- and heterodimerization might be mutually exclusive. Moreover, isothermal titration calorimetry analyses disclosed that SSRP1 binds both histones H2A-H2B and H3-H4 and that disruption of SSRP1 homodimerization decreases its histone binding affinity. Together, our results provide evidence for regulation of SSRP1 by homodimerization and suggest a potential role for homodimerization in facilitating SPT16-independent functions of SSRP1. PMID- 29764935 TI - The disorderly conduct of Hsc70 and its interaction with the Alzheimer's-related Tau protein. AB - Hsp70 chaperones bind to various protein substrates for folding, trafficking, and degradation. Considerable structural information is available about how prokaryotic Hsp70 (DnaK) binds substrates, but less is known about mammalian Hsp70s, of which there are 13 isoforms encoded in the human genome. Here, we report the interaction between the human Hsp70 isoform heat shock cognate 71-kDa protein (Hsc70 or HSPA8) and peptides derived from the microtubule-associated protein Tau, which is linked to Alzheimer's disease. For structural studies, we used an Hsc70 construct (called BETA) comprising the substrate-binding domain but lacking the lid. Importantly, we found that truncating the lid does not significantly impair Hsc70's chaperone activity or allostery in vitro Using NMR, we show that BETA is partially dynamically disordered in the absence of substrate and that binding of the Tau sequence GKVQIINKKG (with a KD = 500 nm) causes dramatic rigidification of BETA. NOE distance measurements revealed that Tau binds to the canonical substrate-binding cleft, similar to the binding observed with DnaK. To further develop BETA as a tool for studying Hsc70 interactions, we also measured BETA binding in NMR and fluorescent competition assays to peptides derived from huntingtin, insulin, a second Tau-recognition sequence, and a KFERQ like sequence linked to chaperone-mediated autophagy. We found that the insulin C peptide binds BETA with high affinity (KD < 100 nm), whereas the others do not (KD > 100 MUm). Together, our findings reveal several similarities and differences in how prokaryotic and mammalian Hsp70 isoforms interact with different substrate peptides. PMID- 29764936 TI - Attachment of phosphorylcholine residues to pneumococcal teichoic acids and modification of substitution patterns by the phosphorylcholine esterase. AB - The bacterial lung pathogen Streptococcus pneumoniae has a unique nutritional requirement for exogenous choline and attaches phosphorylcholine (P-Cho) residues to the GalpNAc moieties of its teichoic acids (TAs) in its cell wall. Two phosphorylcholine transferases, LicD1 and LicD2, mediate the attachment of P-Cho to the O-6 positions of the two GalpNAc residues present in each repeating unit of pneumococcal TAs (pnTAs), of which only LicD1 has been determined to be essential. At the molecular level, the specificity of the P-Cho attachment to pnTAs by LicD1 and LicD2 remains still elusive. Here, using detailed structural analyses of pnTAs from a LicD2-deficient strain, we confirmed the specificity in the attachment of P-Cho residues to pnTA. LicD1 solely transfers P-Cho to alpha-d GalpNAc moieties, whereas LicD2 attaches P-Cho to beta-d-GalpNAc. Further, we investigated the role of the pneumococcal phosphorylcholine esterase (Pce) in the modification of the P-Cho substitution pattern of pnTAs. To clarify the specificity of Pce-mediated P-Cho hydrolysis, we evaluated different concentrations and pH conditions for the treatment of pneumococcal lipoteichoic acid with purified Pce. We show that Pce can hydrolyze both P-Cho residues of the terminal repeat of the pnTA chain and almost all P-Cho residues bound to beta-d GalpNAc in vitro However, hydrolysis in vivo was restricted to the terminal repeat. In summary, our findings indicate that LicD1 and LicD2 specifically transfer P-Cho to alpha-d-GalpNAc and beta-d-GalpNAc moieties, respectively, and that Pce removes distinct P-Cho substituents from pnTAs. PMID- 29764937 TI - Cyclin-dependent kinase 1 (CDK1) and CDK2 have opposing roles in regulating interactions of splicing factor 3B1 with chromatin. AB - Splicing factor 3B1 (SF3B1) is a core splicing protein that stabilizes the interaction between the U2 snRNA and the branch point in the mRNA target during splicing. SF3B1 is heavily phosphorylated at its N terminus and a substrate of cyclin-dependent kinases (CDKs). Although SF3B1 phosphorylation coincides with splicing catalysis, the functional significance of SF3B1 phosphorylation is largely undefined. Here, we show that SF3B1 phosphorylation follows a dynamic pattern during cell cycle progression that depends on CDK activity. SF3B1 is known to interact with chromatin, and we found that SF3B1 maximally interacts with nucleosomes during G1/S and that this interaction requires CDK2 activity. In contrast, SF3B1 disassociates from nucleosomes at G2/M, coinciding with a peak in CDK1-mediated SF3B1 phosphorylation. Thus, CDK1 and CDK2 appear to have opposing roles in regulating SF3B1-nucleosome interactions. Importantly, these interactions were modified by the presence and phosphorylation status of linker histone H1, particularly the H1.4 isoform. Performing genome-wide analysis of SF3B1-chromatin binding in synchronized cells, we observed that SF3B1 preferentially bound exons. Differences in SF3B1 chromatin binding to specific sites, however, did not correlate with changes in RNA splicing, suggesting that the SF3B1-nucleosome interaction does not determine cell cycle-dependent changes to mRNA splicing. Our results define a cell cycle stage-specific interaction between SF3B1 and nucleosomes that is mediated by histone H1 and depends on SF3B1 phosphorylation. Importantly, this interaction does not seem to be related to SF3B1's splicing function and, rather, points toward its potential role as a chromatin modifier. PMID- 29764939 TI - The importance of a halotyrosine dehalogenase for Drosophila fertility. AB - The ability of iodotyrosine deiodinase to salvage iodide from iodotyrosine has long been recognized as critical for iodide homeostasis and proper thyroid function in vertebrates. The significance of its additional ability to dehalogenate bromo- and chlorotyrosine is less apparent, and none of these functions could have been anticipated in invertebrates until recently. Drosophila, as most arthropods, contains a deiodinase homolog encoded by CG6279, now named condet (cdt), with a similar catalytic specificity. However, its physiological role cannot be equivalent because Drosophila lacks a thyroid and its associated hormones, and no requirement for iodide or halotyrosines has been reported for this species. We have now applied CRISPR/Cas9 technology to generate Drosophila strains in which the cdt gene has been either deleted or mutated to identify its biological function. As previously shown in larvae, expression of cdt is primarily limited to the fat body, and we now report that loss of cdt function does not enhance sensitivity of the larvae to the toxic effects of iodotyrosine. In adult flies by contrast, expression is known to occur in testes and is detected at very high levels in this tissue. The importance of cdt is most evident in the decrease in fertility observed when either males or females carry a deletion or mutation of cdt Therefore, dehalogenation of a halotyrosine appears essential for efficient reproduction in Drosophila and likely contributes to a new pathway for controlling viability in arthropods. PMID- 29764938 TI - Redistribution of SERCA calcium pump conformers during intracellular calcium signaling. AB - The conformational changes of a calcium transport ATPase were investigated with molecular dynamics (MD) simulations as well as fluorescence resonance energy transfer (FRET) measurements to determine the significance of a discrete structural element for regulation of the conformational dynamics of the transport cycle. Previous MD simulations indicated that a loop in the cytosolic domain of the SERCA calcium transporter facilitates an open-to-closed structural transition. To investigate the significance of this structural element, we performed additional MD simulations and new biophysical measurements of SERCA structure and function. Rationally designed in silico mutations of three acidic residues of the loop decreased SERCA domain-domain contacts and increased domain domain separation distances. Principal component analysis of MD simulations suggested decreased sampling of compact conformations upon N-loop mutagenesis. Deficits in headpiece structural dynamics were also detected by measuring intramolecular FRET of a Cer-YFP-SERCA construct (2-color SERCA). Compared with WT, the mutated 2-color SERCA shows a partial FRET response to calcium, whereas retaining full responsiveness to the inhibitor thapsigargin. Functional measurements showed that the mutated transporter still hydrolyzes ATP and transports calcium, but that maximal enzyme activity is reduced while maintaining similar calcium affinity. In live cells, calcium elevations resulted in concomitant FRET changes as the population of WT 2-color SERCA molecules redistributed among intermediates of the transport cycle. Our results provide novel insights on how the population of SERCA pumps responds to dynamic changes in intracellular calcium. PMID- 29764941 TI - The trypanosome-specific protein CIF3 cooperates with the CIF1 protein to promote cytokinesis in Trypanosoma brucei. AB - Cytokinesis, the terminal step in cell division, in the protist human pathogen Trypanosoma brucei occurs along the longitudinal axis from the anterior tip of the new flagellum attachment zone (FAZ) toward the posterior cell tip. This process is regulated by a signaling cascade composed of the Polo-like kinase homolog TbPLK, the Aurora B kinase homolog TbAUK1, and the trypanosome-specific CIF1-CIF2 protein complex. However, the regulatory mechanism and the signaling pathway for this unusual mode of cytokinesis remain poorly understood. Here, we report another trypanosome-specific protein assembly, the CIF1-CIF3 complex, and its essential role in cytokinesis initiation. Through biochemical and genetic approaches, we demonstrate that CIF3 interacts with CIF1 in a TbPLK-dependent manner and maintains CIF1 localization at the new FAZ tip. Conversely, CIF1 maintains CIF3 stability at the new FAZ tip. We further show that TbPLK is required for CIF3 localization and that CIF3 is necessary for targeting TbAUK1 to the new FAZ tip during anaphase. These results suggest that two trypanosome specific CIF1-containing protein complexes cooperate with the evolutionarily conserved Polo-like kinase and Aurora B kinase to promote cytokinesis in T. brucei. PMID- 29764940 TI - The tetrameric structure of sialic acid-synthesizing UDP-GlcNAc 2-epimerase from Acinetobacter baumannii: A comparative study with human GNE. AB - Sialic acid presentation on the cell surface by some pathogenic strains of bacteria allows their escape from the host immune system. It is one of the major virulence factors. Bacterial biosynthesis of sialic acids starts with the conversion of UDP-GlcNAc to UDP and ManNAc by a hydrolyzing 2-epimerase. Here, we present the crystal structure of this enzyme, named NeuC, from Acinetobacter baumannii The protein folds into two Rossmann-like domains and forms dimers and tetramers as does the epimerase part of the bifunctional UDP-GlcNAc 2 epimerase/ManNAc kinase (GNE). In contrast to human GNE, which showed only the closed conformation, the NeuC crystals contained both open and closed protomers in each dimer. Substrate soaking changed the space group from C2221 to P212121 In addition to UDP, an intermediate-like ligand was seen bound to the closed protomer. The UDP-binding mode in NeuC was similar to that in GNE, although a few side chains were rotated away. NeuC lacks the CMP-Neu5Ac-binding site for allosteric inhibition of GNE. However, the two enzymes as well as other NeuC homologues (but not SiaA from Neisseria meningitidis) appear to be common in tetrameric organization. The revised two-base catalytic mechanism may involve His 125 (Glu-134 in GNE), as suggested by mutant activity analysis. PMID- 29764942 TI - Could Positive Feedback Enable Bacterial Pheromone Signaling To Coordinate Behaviors in Response to Heterogeneous Environmental Cues? AB - Pheromone signaling (PS) underlies many important bacterial behaviors, yet its ecological functions remain unresolved. Because pheromone-mediated behaviors require high cell density, the term "quorum sensing" is widely used to describe and make sense of PS. However, while this term has unified and popularized the field, bacterial PS clearly has roles beyond census taking, and the complexities of PS circuits indicate broader functional capacities. Two common features of bacterial PS are its regulation in response to environmental conditions and positive-feedback loops. Combined, these could enable PS to coordinate quorum dependent group behaviors in response to heterogeneous environmental cues. Particularly in PS systems where positive feedback is strong, cells that are relatively far from a stimulatory environment could be recruited to a group response. Testing this model will benefit from in situ examination of relevant environmental cues and PS outputs in cells across populations, with and without positive feedback, in heterogeneous environments. PMID- 29764943 TI - Microscopic and Molecular Evidence of the First Elasmobranch Adomavirus, the Cause of Skin Disease in a Giant Guitarfish, Rhynchobatus djiddensis. AB - Only eight families of double-stranded DNA (dsDNA) viruses are known to infect vertebrate animals. During an investigation of papillomatous skin disease in an elasmobranch species, the giant guitarfish (Rhynchobatus djiddensis), a novel virus, distinct from all known viral families in regard to particle size, morphology, genome organization, and helicase phylogeny was discovered. Large inclusion bodies containing 75-nm icosahedral viral particles were present within epithelial cell nuclei in the proliferative skin lesions. Deep metagenomic sequencing revealed a 22-kb circular dsDNA viral genome, tentatively named guitarfish "adomavirus" (GAdoV), with only distant homology to two other fish viruses, Japanese eel endothelial cell-infecting virus (JEECV) and a recently reported marbled eel virus. Phylogenetic analysis of the helicase domain places the guitarfish virus in a novel clade that is equidistant between members of the Papillomaviridae and Polyomaviridae families. Specific PCR, quantitative PCR, and in situ hybridization were used to detect, quantify, and confirm that GAdoV DNA was localized to affected epithelial cell nuclei. Changes in the viral titer, as well as the presence of a hybridization signal, coincided with the progression and then final resolution of gross and microscopic lesions. The results indicate that GAdoV is the causative agent of the proliferative skin lesions.IMPORTANCE Cartilaginous fish, including the sharks and rays, evolved from ancestral fish species at least 400 million years ago. Even though they are the descendants of one of the most ancient vertebrate lineages, reports of viral diseases in these species are rare and poorly documented. Deep sequencing revealed a highly divergent virus, tentatively named guitarfish adomavirus, that is distantly related to known papillomaviruses and polyomaviruses. Out of the eight predicted viral genes, only the helicase could be identified as viral by sequence homology searches (BLAST), exemplifying the difficulties of discovering novel viruses within seas of unidentifiable "dark matter" associated with deep sequencing data. The novel adomavirus represents the first viral genome shown to cause clinical disease in a cartilaginous fish species, the giant guitarfish. Our findings demonstrate that emerging fish viruses are fertile ground to expand our understanding of viral evolution in vertebrates. PMID- 29764944 TI - RECON-Dependent Inflammation in Hepatocytes Enhances Listeria monocytogenes Cell to-Cell Spread. AB - The oxidoreductase RECON is a high-affinity cytosolic sensor of bacterium-derived cyclic dinucleotides (CDNs). CDN binding inhibits RECON's enzymatic activity and subsequently promotes inflammation. In this study, we sought to characterize the effects of RECON on the infection cycle of the intracellular bacterium Listeria monocytogenes, which secretes cyclic di-AMP (c-di-AMP) into the cytosol of infected host cells. Here, we report that during infection of RECON-deficient hepatocytes, which exhibit hyperinflammatory responses, L. monocytogenes exhibits significantly enhanced cell-to-cell spread. Enhanced bacterial spread could not be attributed to alterations in PrfA or ActA, two virulence factors critical for intracellular motility and intercellular spread. Detailed microscopic analyses revealed that in the absence of RECON, L. monocytogenes actin tail lengths were significantly longer and there was a larger number of faster-moving bacteria. Complementation experiments demonstrated that the effects of RECON on L. monocytogenes spread and actin tail lengths were linked to its enzymatic activity. RECON enzyme activity suppresses NF-kappaB activation and is inhibited by c-di-AMP. Consistent with these previous findings, we found that augmented NF kappaB activation in the absence of RECON caused enhanced L. monocytogenes cell to-cell spread and that L. monocytogenes spread correlated with c-di-AMP secretion. Finally, we discovered that, remarkably, increased NF-kappaB-dependent inducible nitric oxide synthase expression and nitric oxide production were responsible for promoting L. monocytogenes cell-to-cell spread. The work presented here supports a model whereby L. monocytogenes secretion of c-di-AMP inhibits RECON's enzymatic activity, drives augmented NF-kappaB activation and nitric oxide production, and ultimately enhances intercellular spread.IMPORTANCE To date, bacterial CDNs in eukaryotes are solely appreciated for their capacity to activate cytosolic sensing pathways in innate immunity. However, it remains unclear whether pathogens that actively secrete CDNs benefit from this process. Here, we provide evidence that secretion of CDNs leads to enhancement of L. monocytogenes cell-to-cell spread. This is a heretofore-unknown role of these molecules and suggests L. monocytogenes may benefit from their secretion in certain contexts. Molecular characterization revealed that, surprisingly, nitric oxide was responsible for the enhanced spread. Pathogens act to prevent nitric oxide production or, like L. monocytogenes, they have evolved to resist its direct antimicrobial effects. This study provides evidence that intracellular bacterial pathogens not only tolerate nitric oxide, which is inevitably encountered during infection, but can also capitalize on the changes this pleiotropic molecule enacts on the host cell. PMID- 29764945 TI - A Mechanism of Unidirectional Transformation, Leading to Antibiotic Resistance, Occurs within Nasopharyngeal Pneumococcal Biofilm Consortia. AB - Streptococcus pneumoniae acquires genes for resistance to antibiotics such as streptomycin (Str) or trimethoprim (Tmp) by recombination via transformation of DNA released by other pneumococci and closely related species. Using naturally transformable pneumococci, including strain D39 serotype 2 (S2) and TIGR4 (S4), we studied whether pneumococcal nasopharyngeal transformation was symmetrical, asymmetrical, or unidirectional. Incubation of S2Tet and S4Str in a bioreactor simulating the human nasopharynx led to the generation of SpnTet/Str recombinants. Double-resistant pneumococci emerged soon after 4 h postinoculation at a recombination frequency (rF) of 2.5 * 10-4 while peaking after 8 h at a rF of 1.1 * 10-3 Acquisition of antibiotic resistance genes by transformation was confirmed by treatment with DNase I. A high-throughput serotyping method demonstrated that all double-resistant pneumococci belonged to one serotype lineage (S2Tet/Str) and therefore that unidirectional transformation had occurred. Neither heterolysis nor availability of DNA for transformation was a factor for unidirectional transformation given that the density of each strain and extracellular DNA (eDNA) released from both strains were similar. Unidirectional transformation occurred regardless of the antibiotic-resistant gene carried by donors or acquired by recipients and regardless of whether competence-stimulating peptide-receptor cross talk was allowed. Moreover, unidirectional transformation occurred when two donor strains (e.g., S4Str and S19FTmp) were incubated together, leading to S19FStr/Tmp but at a rF 3 orders of magnitude lower (4.9 * 10-6). We finally demonstrated that the mechanism leading to unidirectional transformation was due to inhibition of transformation of the donor by the recipient.IMPORTANCE Pneumococcal transformation in the human nasopharynx may lead to the acquisition of antibiotic resistance genes or genes encoding new capsular variants. Antibiotics and vaccines are currently putting pressure on a number of strains, leading to an increase in antibiotic resistance and serotype replacement. These pneumococcal strains are also acquiring virulence traits from vaccine types via transformation. In this study, we recapitulated multiple-strain colonization with strains carrying a resistance marker and selected for those acquiring resistance to two or three antibiotics, such as would occur in the human nasopharynx. Strains acquiring dual and triple resistance originated from one progenitor, demonstrating that transformation was unidirectional. Unidirectional transformation was the result of inhibition of transformation of donor strains. Unidirectional transformation has implications for the understanding of acquisition patterns of resistance determinants or capsule-switching events. PMID- 29764946 TI - Comparative Genomics Reveals the Core Gene Toolbox for the Fungus-Insect Symbiosis. AB - Modern genomics has shed light on many entomopathogenic fungi and expanded our knowledge widely; however, little is known about the genomic features of the insect-commensal fungi. Harpellales are obligate commensals living in the digestive tracts of disease-bearing insects (black flies, midges, and mosquitoes). In this study, we produced and annotated whole-genome sequences of nine Harpellales taxa and conducted the first comparative analyses to infer the genomic diversity within the members of the Harpellales. The genomes of the insect gut fungi feature low (26% to 37%) GC content and large genome size variations (25 to 102 Mb). Further comparisons with insect-pathogenic fungi (from both Ascomycota and Zoopagomycota), as well as with free-living relatives (as negative controls), helped to identify a gene toolbox that is essential to the fungus-insect symbiosis. The results not only narrow the genomic scope of fungus insect interactions from several thousands to eight core players but also distinguish host invasion strategies employed by insect pathogens and commensals. The genomic content suggests that insect commensal fungi rely mostly on adhesion protein anchors that target digestive system, while entomopathogenic fungi have higher numbers of transmembrane helices, signal peptides, and pathogen-host interaction (PHI) genes across the whole genome and enrich genes as well as functional domains to inactivate the host inflammation system and suppress the host defense. Phylogenomic analyses have revealed that genome sizes of Harpellales fungi vary among lineages with an integer-multiple pattern, which implies that ancient genome duplications may have occurred within the gut of insects.IMPORTANCE Insect guts harbor various microbes that are important for host digestion, immune response, and disease dispersal in certain cases. Bacteria, which are among the primary endosymbionts, have been studied extensively. However, fungi, which are also frequently encountered, are poorly known with respect to their biology within the insect guts. To understand the genomic features and related biology, we produced the whole-genome sequences of nine gut commensal fungi from disease-bearing insects (black flies, midges, and mosquitoes). The results show that insect gut fungi tend to have low GC content across their genomes. By comparing these commensals with entomopathogenic and free-living fungi that have available genome sequences, we found a universal core gene toolbox that is unique and thus potentially important for the insect-fungus symbiosis. This comparative work also uncovered different host invasion strategies employed by insect pathogens and commensals, as well as a model system to study ancient fungal genome duplication within the gut of insects. PMID- 29764949 TI - Toward an Improved Meningococcal Serogroup B Assay. AB - Because of diverse sequences and differential expression of surface structures on individual invasive Neisseria meningitidis serogroup B (MenB) strains, predicting the efficacy of MenB vaccines using traditional human serum bactericidal assays (hSBA) is impractical. The meningococcal antigen surface expression (MEASURE) assay uses flow cytometry to quantitate the expression of factor H binding proteins (fHbp) contained in the bivalent rLP2086 MenB vaccine. To date, experience with MEASURE has been lacking, and in a long-awaited article, McNeil et al. (mBio 9:e00036-18, https://doi.org/10.1128/mBio.00036-18), provide detailed mapping of a cross-reactive antibody binding epitope and explore the potential utility of MEASURE in predicting the susceptibility of individual MenB strains to antibody-mediated killing. Remaining questions center around why some strains with high fHbp expression are nonsusceptible to anti-fHbp antibody killing. Consideration of alternative methods, such as a standardized enzyme linked immunosorbent assay (ELISA), might offer a more readily available and reproducible assay for wider use. PMID- 29764948 TI - Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections. AB - Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.IMPORTANCE Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms. PMID- 29764947 TI - Biological Roles Played by Sphingolipids in Dimorphic and Filamentous Fungi. AB - Filamentous and dimorphic fungi cause invasive mycoses associated with high mortality rates. Among the fungal determinants involved in the establishment of infection, glycosphingolipids (GSLs) have gained increased interest in the last few decades. GSLs are ubiquitous membrane components that have been isolated from both filamentous and dimorphic species and play a crucial role in polarized growth as well as hypha-to-yeast transition. In fungi, two major classes of GSLs are found: neutral and acidic GSLs. Neutral GSLs comprise glucosylceramide and galactosylceramide, which utilize Delta4-Delta8-9-methyl-sphingadienine as a sphingoid base, linked to a C16-18 fatty acid chain, forming ceramide, and to a sugar residue, such as glucose or galactose. In contrast, acidic GSLs include glycosylinositol phosphorylceramides (GIPCs), composed of phytosphingosine attached to a long or very long fatty acid chain (C18-26) and to diverse and complex glycan groups via an inositol-phosphate linker. GIPCs are absent in mammalian cells, while fungal glucosylceramide and galactosylceramide are present but diverge structurally from their counterparts. Therefore, these compounds and their biosynthetic pathways represent potential targets for the development of selective therapeutic strategies. In this minireview, we discuss the enzymatic steps involved in the production of fungal GSLs, analyze their structure, and address the role of the currently characterized genes in the biology and pathogenesis of filamentous and dimorphic fungi. PMID- 29764951 TI - Predictable Phenotypes of Antibiotic Resistance Mutations. AB - Antibiotic-resistant bacteria represent a major threat to our ability to treat bacterial infections. Two factors that determine the evolutionary success of antibiotic resistance mutations are their impact on resistance level and the fitness cost. Recent studies suggest that resistance mutations commonly show epistatic interactions, which would complicate predictions of their stability in bacterial populations. We analyzed 13 different chromosomal resistance mutations and 10 host strains of Salmonella enterica and Escherichia coli to address two main questions. (i) Are there epistatic interactions between different chromosomal resistance mutations? (ii) How does the strain background and genetic distance influence the effect of chromosomal resistance mutations on resistance and fitness? Our results show that the effects of combined resistance mutations on resistance and fitness are largely predictable and that epistasis remains rare even when up to four mutations were combined. Furthermore, a majority of the mutations, especially target alteration mutations, demonstrate strain-independent phenotypes across different species. This study extends our understanding of epistasis among resistance mutations and shows that interactions between different resistance mutations are often predictable from the characteristics of the individual mutations.IMPORTANCE The spread of antibiotic-resistant bacteria imposes an urgent threat to public health. The ability to forecast the evolutionary success of resistant mutants would help to combat dissemination of antibiotic resistance. Previous studies have shown that the phenotypic effects (fitness and resistance level) of resistance mutations can vary substantially depending on the genetic context in which they occur. We conducted a broad screen using many different resistance mutations and host strains to identify potential epistatic interactions between various types of resistance mutations and to determine the effect of strain background on resistance phenotypes. Combinations of several different mutations showed a large amount of phenotypic predictability, and the majority of the mutations displayed strain-independent phenotypes. However, we also identified a few outliers from these patterns, illustrating that the choice of host organism can be critically important when studying antibiotic resistance mutations. PMID- 29764950 TI - CagY-Dependent Regulation of Type IV Secretion in Helicobacter pylori Is Associated with Alterations in Integrin Binding. AB - Strains of Helicobacter pylori that cause ulcer or gastric cancer typically express a type IV secretion system (T4SS) encoded by the cag pathogenicity island (cagPAI). CagY is an ortholog of VirB10 that, unlike other VirB10 orthologs, has a large middle repeat region (MRR) with extensive repetitive sequence motifs, which undergo CD4+ T cell-dependent recombination during infection of mice. Recombination in the CagY MRR reduces T4SS function, diminishes the host inflammatory response, and enables the bacteria to colonize at a higher density. Since CagY is known to bind human alpha5beta1 integrin, we tested the hypothesis that recombination in the CagY MRR regulates T4SS function by modulating binding to alpha5beta1 integrin. Using a cell-free microfluidic assay, we found that H. pylori binding to alpha5beta1 integrin under shear flow is dependent on the CagY MRR, but independent of the presence of the T4SS pili, which are only formed when H. pylori is in contact with host cells. Similarly, expression of CagY in the absence of other T4SS genes was necessary and sufficient for whole bacterial cell binding to alpha5beta1 integrin. Bacteria with variant cagY alleles that reduced T4SS function showed comparable reduction in binding to alpha5beta1 integrin, although CagY was still expressed on the bacterial surface. We speculate that cagY-dependent modulation of H. pylori T4SS function is mediated by alterations in binding to alpha5beta1 integrin, which in turn regulates the host inflammatory response so as to maximize persistent infection.IMPORTANCE Infection with H. pylori can cause peptic ulcers and is the most important risk factor for gastric cancer, the third most common cause of cancer death worldwide. The major H. pylori virulence factor that determines whether infection causes disease or asymptomatic colonization is the type IV secretion system (T4SS), a sort of molecular syringe that injects bacterial products into gastric epithelial cells and alters host cell physiology. We previously showed that recombination in CagY, an essential T4SS component, modulates the function of the T4SS. Here we found that these recombination events produce parallel changes in specific binding to alpha5beta1 integrin, a host cell receptor that is essential for T4SS-dependent translocation of bacterial effectors. We propose that CagY-dependent binding to alpha5beta1 integrin acts like a molecular rheostat that alters T4SS function and modulates the host immune response to promote persistent infection. PMID- 29764953 TI - Fighting Antibiotic-Resistant Klebsiella pneumoniae with "Sweet" Immune Targets. AB - Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen. PMID- 29764952 TI - SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition. AB - Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects are exerted primarily through this pathway. Our results demonstrate that SAMHD1 activation, but not transcriptional upregulation or protein induction, is the predominant mechanism of HIV-1 restriction induced by type I, type II, and type III IFN signaling in macrophages. Furthermore, SAMHD1 activation presents a pharmacologically actionable target through which HIV-1 infection can be subverted.IMPORTANCE Our experimental results demonstrate that SAMHD1 dephosphorylation at threonine-592 represents a central mechanism of HIV-1 restriction that is common to the three known families of IFNs. While IFN types I and II were potent inhibitors of HIV-1, type III IFN showed modest to undetectable activity. Regulation of SAMHD1 by IFNs involved changes in phosphorylation status but not in protein levels. Phosphorylation of SAMHD1 in macrophages occurred at least in part via CDK1. Tyrosine kinase inhibitors similarly induced SAMHD1 dephosphorylation, which protects macrophages from HIV-1 in a SAMHD1-dependent manner. SAMHD1 is a critical restriction factor regulating HIV-1 infection of macrophages. PMID- 29764955 TI - The new normal of structure/function studies in the era of CRISPR/Cas9. AB - Major advances in gene-editing technologies have enabled the rapid dissection of proteins in complex biological systems, facilitating biological experiments to complement biochemical studies with purified components. In this editorial, we highlight CRISPR/Cas9-based strategies to rapidly manipulate endogenous genes - strategies that have already transformed functional studies of proteins in metazoan systems. We further describe emerging tools using a catalytically dead version of Cas9 (dCas9) that do not cleave DNA, but can alter gene expression and/or local chromatin states, edit single nucleotide bases, and permit the visualization of specific genomic loci. Looking to the not-too-distant future, CRISPR/Cas9-based methodologies promise to lead to discoveries of new biology, opening the door for bold new synthetic biology platforms. PMID- 29764954 TI - Survey of UK horse owners' knowledge of equine arboviruses and disease vectors. AB - Increased globalisation and climate change have led to concern about the increasing risk of arthropod-borne virus (arbovirus) outbreaks globally. An outbreak of equine arboviral disease in northern Europe could impact significantly on equine welfare, and result in economic losses. Early identification of arboviral disease by horse owners may help limit disease spread. In order to determine what horse owners understand about arboviral diseases of horses and their vectors, the authors undertook an open, cross sectional online survey of UK horse owners. The questionnaire was distributed using social media and a press release and was active between May and July 2016. There were 466 respondents, of whom 327 completed the survey in full. High proportions of respondents correctly identified photographic images of biting midges (71.2 per cent) and mosquitoes (65.4 per cent), yet few were aware that they transmit equine infectious diseases (31.4 per cent and 35.9 per cent, respectively). Of the total number of respondents, only 7.4 per cent and 16.2 per cent correctly named a disease transmitted by biting midges and mosquitoes, respectively. Only 13.1 per cent and 12.5 per cent of participants identified specific clinical signs of African horse sickness (AHS) and West Nile virus (WNV), respectively. This study demonstrates that in the event of heightened disease risk educational campaigns directed towards horse owners need to be implemented, focussing on disease awareness, clinical signs and effective disease prevention strategies. PMID- 29764956 TI - Spotlight on the transglutaminase 2 gene: a focus on genomic and transcriptional aspects. AB - The type 2 isoenzyme is the most widely expressed transglutaminase in mammals displaying several intra- and extracellular activities depending on its location (protein modification, modulation of gene expression, membrane signalling and stabilization of cellular interactions with the extracellular matrix) in relation to cell death, survival and differentiation. In contrast with the appreciable knowledge about the regulation of the enzymatic activities, much less is known concerning its inducible expression, which is altered in inflammatory and neoplastic diseases. In this context, we first summarize the gene's basic features including single-nucleotide polymorphism characterization, epigenetic DNA methylation and identification of regulatory regions and of transcription factor-binding sites at the gene promoter, which could concur to direct gene expression. Further aspects related to alternative splicing events and to ncRNAs (microRNAs and lncRNAs) are involved in the modulation of its expression. Notably, this important gene displays transcriptional variants relevant for the protein's function with the occurrence of at least seven transcripts which support the synthesis of five isoforms with modified catalytic activities. The different expression of the TG2 (type 2 transglutaminase) variants might be useful for dictating the multiple biological features of the protein and their alterations in pathology, as well as from a therapeutic perspective. PMID- 29764957 TI - Examining perceptions about IQOS heated tobacco product: consumer studies in Japan and Switzerland. AB - OBJECTIVE: To examine consumer perceptions, attitudes and behaviours regarding the heated tobacco product, IQOS, as well as to document the product's marketing strategies to determine its potential for appealing to youth and young adults. METHOD: Truth Initiative, in collaboration with Flamingo, collected qualitative data via: (1) expert interviews, (2) semiotic analysis of IQOS packing and marketing materials, and (3) 12 focus groups with adults in Switzerland (ages 19 44 years; June 6-9, 2016) and Japan (ages 20-39 years; June 22-24, 2016) (n=68 for both groups). RESULTS: Expert interviews and IQOS packing and marketing analyses revealed the product is being marketed as a clean, chic and pure product, which resonated very well in Japan given the strong cultural values of order, cleanliness, quality and respect for others. Focus groups results indicated Japanese IQOS users used the product for socialising with non-smokers. Focus group participants in both Japan and Switzerland reported lower levels of satisfaction with the product relative to combustible cigarettes, although many found the product packaging to be appealing. While participants identified several benefits and barriers related to IQOS, few reported any potential health benefits of use compared with combustible tobacco products. CONCLUSION: IQOS was marketed as a sophisticated, high tech and aspirational product. Because youth and young adults are more interested in such product positioning, this approach raises some concern about youth appeal. This research shows cultural factors appeared to affect the appeal of this messaging, indicating that prevalence and uptake data will likely not be similar from country to country. PMID- 29764958 TI - Diabetes mellitus and latent tuberculosis infection: baseline analysis of a large UK cohort. AB - : We conducted a cross-sectional analysis of baseline data from a UK cohort study which enrolled participants at risk of latent tuberculosis infection (LTBI, defined as a positive result for either of the two interferon gamma release assays). Binomial regression with a log link was used to estimate crude and adjusted prevalence ratios (PRs) and 95% CIs for the relationship between diabetes mellitus (DM) and LTBI. Adjusted for age, sex, ethnicity, body mass index and the presence of other immunocompromising conditions, DM was associated with a 15% higher prevalence of LTBI (adjusted PR=1.15, 95% CI 1.02 to 1.30, p=0.025). TRIAL REGISTRATION NUMBER: PREDICT is registered on clinicaltrials.gov (NCT01162265). PMID- 29764959 TI - A Targeted RNAi Screen Reveals Drosophila Female-Sterile Genes That Control the Size of Germline Stem Cell Niche During Development. AB - Adult stem cells maintain tissue homeostasis. This unique capability largely depends on the stem cell niche, a specialized microenvironment, which preserves stem cell identity through physical contacts and secreted factors. In many cancers, latent tumor cell niches are thought to house stem cells and aid tumor initiation. However, in developing tissue and cancer it is unclear how the niche is established. The well-characterized germline stem cells (GSCs) and niches in the Drosophila melanogaster ovary provide an excellent model to address this fundamental issue. As such, we conducted a small-scale RNAi screen of 560 individually expressed UAS-RNAi lines with targets implicated in female fertility. RNAi was expressed in the soma of larval gonads, and screening for reduced egg production and abnormal ovarian morphology was performed in adults. Twenty candidates that affect ovarian development were identified and subsequently knocked down in the soma only during niche formation. Feminization factors (Transformer, Sex lethal, and Virilizer), a histone methyltransferase (Enhancer of Zeste), a transcriptional machinery component (Enhancer of yellow 1), a chromatin remodeling complex member (Enhancer of yellow 3) and a chromosome passenger complex constituent (Incenp) were identified as potentially functioning in the control of niche size. The identification of these molecules highlights specific molecular events that are critical for niche formation and will provide a basis for future studies to fully understand the mechanisms of GSC recruitment and maintenance. PMID- 29764962 TI - Canadian Rheumatology Association Meeting, February 21-24, 2018. Introduction, Abstracts, Author Index. AB - The 73rd Annual Meeting of The Canadian Rheumatology Association (CRA) was held at the JW Marriott Parq Vancouver, Vancouver, British Columbia, Canada, February 21-24, 2018. The program consisted of presentations covering original research, symposia, awards, and lectures. PMID- 29764960 TI - A Genomic Region Containing REC8 and RNF212B Is Associated with Individual Recombination Rate Variation in a Wild Population of Red Deer (Cervus elaphus). AB - Recombination is a fundamental feature of sexual reproduction, ensuring proper disjunction, preventing mutation accumulation and generating new allelic combinations upon which selection can act. However it is also mutagenic, and breaks up favorable allelic combinations previously built up by selection. Identifying the genetic drivers of recombination rate variation is a key step in understanding the causes and consequences of this variation, how loci associated with recombination are evolving and how they affect the potential of a population to respond to selection. However, to date, few studies have examined the genetic architecture of recombination rate variation in natural populations. Here, we use pedigree data from ~ 2,600 individuals genotyped at ~ 38,000 SNPs to investigate the genetic architecture of individual autosomal recombination rate in a wild population of red deer (Cervus elaphus). Female red deer exhibited a higher mean and phenotypic variance in autosomal crossover counts (ACC). Animal models fitting genomic relatedness matrices showed that ACC was heritable in females ([Formula: see text] = 0.12) but not in males. A regional heritability mapping approach showed that almost all heritable variation in female ACC was explained by a genomic region on deer linkage group 12 containing the candidate loci REC8 and RNF212B, with an additional region on linkage group 32 containing TOP2B approaching genome-wide significance. The REC8/RNF212B region and its paralogue RNF212 have been associated with recombination in cattle, mice, humans and sheep. Our findings suggest that mammalian recombination rates have a relatively conserved genetic architecture in both domesticated and wild systems, and provide a foundation for understanding the association between recombination loci and individual fitness within this population. PMID- 29764963 TI - Reducing Missed Opportunities for Influenza Vaccination in Patients with Rheumatoid Arthritis: Evaluation of a Multisystem Intervention. AB - OBJECTIVE: To assess a multimodal intervention for reducing missed opportunities for outpatient influenza vaccination in individuals with rheumatoid arthritis (RA). METHODS: Patients with RA were enrolled from a single center and each rheumatology outpatient visit was tracked for missed opportunities for influenza vaccination, defined as a visit in which an unvaccinated patient without contraindications remained unvaccinated or lacked documentation of vaccine recommendation in the electronic medical record (EMR). Providers then received a multimodal intervention consisting of an education session, EMR alerts, and weekly provider-specific e-mail reminders. Missed opportunities before and after the intervention were compared, and the determinants of missed opportunities were analyzed. RESULTS: A total of 228 patients with RA were enrolled (904 preintervention visits) and 197 returned for at least 1 postintervention visit (721 postintervention visits). The preintervention frequency of any missed opportunities for influenza vaccination was 47%. This was reduced to 23% postintervention (p < 0.001). Among those vaccinated, the relative hazard for influenza vaccination post- versus preintervention period was 1.24 (p = 0.038). Younger age, less frequent office visits, higher erythrocyte sedimentation rate, and negative attitudes about vaccines were each independently associated with missed opportunities preintervention. Postintervention, these factors were no longer associated with missed opportunities; however, the intervention was not as effective in non-Hispanic black patients, non-English speakers, those residing outside of the New York City metropolitan area, and those reporting prior adverse reactions to vaccines. CONCLUSION: Improved uptake of influenza vaccination in patients with RA is possible using a multimodal approach. Certain subgroups may need a more potent intervention for equivalent efficacy. PMID- 29764961 TI - Genome-Wide Search for Quantitative Trait Loci Controlling Important Plant and Flower Traits in Petunia Using an Interspecific Recombinant Inbred Population of Petunia axillaris and Petunia exserta. AB - A major bottleneck in plant breeding has been the much limited genetic base and much reduced genetic diversity in domesticated, cultivated germplasm. Identification and utilization of favorable gene loci or alleles from wild or progenitor species can serve as an effective approach to increasing genetic diversity and breaking this bottleneck in plant breeding. This study was conducted to identify quantitative trait loci (QTL) in wild or progenitor petunia species that can be used to improve important horticultural traits in garden petunia. An F7 recombinant inbred population derived between Petunia axillaris and P. exserta was phenotyped for plant height, plant spread, plant size, flower counts, flower diameter, flower length, and days to anthesis in Florida in two consecutive years. Transgressive segregation was observed for all seven traits in both years. The broad-sense heritability estimates for the traits ranged from 0.20 (days to anthesis) to 0.62 (flower length). A genome-wide genetic linkage map consisting of 368 single nucleotide polymorphism bins and extending over 277 cM was searched to identify QTL for these traits. Nineteen QTL were identified and localized to five linkage groups. Eleven of the loci were identified consistently in both years; several loci explained up to 34.0% and 24.1% of the phenotypic variance for flower length and flower diameter, respectively. Multiple loci controlling different traits are co-localized in four intervals in four linkage groups. These intervals contain desirable alleles that can be introgressed into commercial petunia germplasm to expand the genetic base and improve plant performance and flower characteristics in petunia. PMID- 29764964 TI - Cardiovascular (CV) Risk after Initiation of Abatacept versus TNF Inhibitors in Rheumatoid Arthritis Patients with and without Baseline CV Disease. AB - OBJECTIVE: To evaluate the cardiovascular safety of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients with and without underlying cardiovascular disease (CVD). METHODS: We identified RA patients with and without baseline CVD who initiated ABA or TNFi by using data from 2 large US insurance claims databases: Medicare (2008-2013) and Truven MarketScan (2006-2015). After stratifying by baseline CVD, ABA initiators were 1:1 propensity score (PS) matched to TNFi initiators to control for > 60 baseline covariates. Cox proportional hazards regression estimated the HR and 95% CI for a composite endpoint of CVD including myocardial infarction, stroke/transient ischemic stroke, or coronary revascularization in the PS-matched cohorts. HR from 2 databases were combined through an inverse variance-weighted fixed-effects model. RESULTS: We included 6102 PS-matched pairs of ABA and TNFi initiators from Medicare and 6934 pairs from MarketScan. Of these, 35.3% in Medicare and 14.0% in MarketScan had baseline CVD. HR (95% CI) for composite CVD in the overall ABA group versus TNFi was 0.67 (0.55-0.81) in Medicare and 1.08 (0.83-1.41) in MarketScan with the combined HR of 0.79 (0.67-0.92). Among patients with baseline CVD, the HR (95% CI) was 0.71 (0.55-0.92) in Medicare and 1.02 (0.68-1.51) in MarketScan, with the combined HR of 0.79 (0.64-0.98). CONCLUSION: In this large cohort of publicly or privately insured patients with RA in the United States, ABA was associated with a 20% reduced risk of CVD versus TNFi. While this observational study is subject to potential residual confounding, our results were consistent in patients with baseline CVD. PMID- 29764965 TI - Effect of Treat-to-target Strategies Aiming at Remission of Arterial Stiffness in Early Rheumatoid Arthritis: A Randomized Controlled Study. AB - OBJECTIVE: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI <= 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI <= 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness. RESULTS: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV. CONCLUSION: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.]. PMID- 29764966 TI - Risk Factors for Intraarticular Heterotopic Bone Formation in the Temporomandibular Joint in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: Intraarticular corticosteroid (IAC) injections are often used to treat temporomandibular joint (TMJ) arthritis associated with juvenile idiopathic arthritis (JIA). One potential complication of IA therapy is heterotopic bone formation (HBF). The purpose of our study was to evaluate risk factors for HBF development in children with JIA who received IA therapy for TMJ arthritis. METHODS: This was a retrospective study of children with JIA who had received >= 1 IAC injection into the TMJ. Survival regression analysis was performed to identify risk factors for the development of HBF. RESULTS: There were 238 children included, of whom 33 (14%) developed HBF. No cases of HBF were diagnosed prior to the initial injection. Univariate analysis revealed that the risk factors for development of HBF were the total number of injections received into the TMJ and age at diagnosis of JIA, while the length of time from diagnosis of JIA to the first injection was inversely associated with the risk of HBF formation. The total number of injections was no longer significant following adjusted survival models. Children with HBF had increased physical examination evidence of acute or chronic changes, namely decreased maximal incisal opening and increased likelihood of jaw deviation. CONCLUSION: HBF within the TMJ is relatively common in patients with JIA receiving IAC injections for TMJ arthritis. Future prospective studies are required to delineate the risks posed by the injections themselves as opposed to the underlying disease activity, as well as to evaluate alternative forms of local therapy to the TMJ. PMID- 29764967 TI - High Disease Activity Is Associated with Self-reported Depression and Predicts Persistent Depression in Early Rheumatoid Arthritis: Results from the Ontario Best Practices Research Initiative. AB - OBJECTIVE: We sought to determine if initial high disease activity or changes in disease activity contribute to persistent depression in early rheumatoid arthritis (ERA). We also determined if disease activity and depression is modified by sex. METHODS: Depression was ascertained by self-report among patients enrolled in the Ontario Best Practices Research Initiative. The association between baseline disease activity, measured by the Clinical Disease Activity Index (CDAI), and persistent depression was evaluated with multivariate regression models, and effect modification by sex was tested. A general estimating equation assessed the association between change in CDAI over time and risk of depression. RESULTS: The sample of 469 ERA subjects was predominantly female (73%). At baseline, the prevalence of depression was 26%, and 23% reported persistent depression. After adjusting for potential confounders, higher baseline CDAI was associated with both baseline and persistent depression (OR 1.03, 95% CI 1.01-1.05). Female sex was an effect modifier of this relationship (OR 1.04, 95% CI 1.01-1.06). Maintaining a moderate or high CDAI score over 2 years also increased the risk of future depression. CONCLUSION: Depression in ERA is common and initial high disease activity is associated with the probability of depression and its persistence. This risk seems particularly modified in women with active disease and represents an area for targeted focus and screening. Future studies in ERA are needed to determine if intervening during the "window of opportunity" to control disease activity has the potential to mitigate the development and maintenance of adverse mental health outcomes, including depression. PMID- 29764968 TI - How to prevent and manage radiation-induced coronary artery disease. AB - Radiation-induced coronary heart disease (RICHD) is the second most common cause of morbidity and mortality in patients treated with radiotherapy for breast cancer, Hodgkin's lymphoma and other prevalent mediastinal malignancies. The risk of RICHD increases with radiation dose. Exposed patients may present decades after treatment with manifestations ranging from asymptomatic myocardial perfusion defects to ostial, triple-vessel disease and sudden cardiac death. RICHD is insidious, with a long latency and a tendency to remain silent late into the disease course. Vessel involvement is often diffuse and is preferentially proximal. The pathophysiology is similar to that of accelerated atherosclerosis, characterised by the formation of inflammatory plaque with high collagen and fibrin content. The presence of conventional risk factors potentiates RICHD, and aggressive risk factor management should ideally be initiated prior to radiation therapy. Stress echocardiography is more sensitive and specific than myocardial perfusion imaging in the detection of RICHD, and CT coronary angiography shows promise in risk stratification. Coronary artery bypass grafting is associated with higher risks of graft failure, perioperative complications and all-cause mortality in patients with RICHD. In most cases, the use of drug-eluting stents is preferable to surgical intervention, bare metal stenting or balloon angioplasty alone. PMID- 29764969 TI - Cardiovascular phenotype and prognosis of patients with heart failure induced by cancer therapy. AB - OBJECTIVE: This study compared the clinical features, cardiac structure and function evaluated by echocardiography, cardiopulmonary response to exercise and long-term clinical outcomes between patients with heart failure (HF) induced by cancer therapy (CTHF) and heart failure not induced by cancer therapy (NCTHF). METHODS: We evaluated 75 patients with CTHF and 894 with NCTHF who underwent clinically indicated cardiopulmonary exercise testing, and followed these individuals for a median of 4.5 (3.0-5.8) years, during which 187 deaths and 256 composite events (death, heart transplantation and left ventricular (LV) assistant device implantation) occurred. RESULTS: Compared with NCTHF, patients with CTHF were younger, with lower prevalence of cardiovascular comorbidities, higher LV ejection fraction (LVEF), but similar global longitudinal strain. LV diastolic function (higher E/e' ratio) and compliance (higher end-diastolic pressure/LV end-diastolic volume index ratio) were worse in CTHF and were both associated with adverse outcomes. Despite a favourable clinical profile, peak VO2 and VE/VCO2 slope were similarly impaired in CTHF and NCTHF. In multivariable Cox regression analysis including clinical characteristics, cardiopulmonary exercise testing variables and LVEF, CTHF was associated with a significantly higher risk of death (HR 2.64; 95% CI 1.53 to 4.55; p=0.001) and composite events (HR 1.79; 95% CI 1.10 to 2.91; p=0.019) compared with NCTHF. CONCLUSIONS: CTHF is characterised by a distinct clinical profile, better LVEF but worse LV diastolic properties, and similarly impaired global longitudinal strain, functional capacity and ventilatory efficiency. Accounting for differences in clinical characteristics, CTHF was associated with worse long-term prognosis than NCTHF. PMID- 29764970 TI - Reinforcement signaling of punishment versus relief in fruit flies. AB - Painful events establish opponent memories: cues that precede pain are remembered negatively, whereas cues that follow pain, thus coinciding with relief are recalled positively. How do individual reinforcement-signaling neurons contribute to this "timing-dependent valence-reversal?" We addressed this question using an optogenetic approach in the fruit fly. Two types of fly dopaminergic neuron, each comprising just one paired cell, indeed established learned avoidance of odors that preceded their photostimulation during training, and learned approach to odors that followed the photostimulation. This is in striking parallel to punishment versus relief memories reinforced by a real noxious event. For only one of these neuron types, both effects were strong enough for further analyses. Notably, interfering with dopamine biosynthesis in these neurons partially impaired the punishing effect, but not the relieving after-effect of their photostimulation. We discuss how this finding constraints existing computational models of punishment versus relief memories and introduce a new model, which also incorporates findings from mammals. Furthermore, whether using dopaminergic neuron photostimulation or a real noxious event, more prolonged punishment led to stronger relief. This parametric feature of relief may also apply to other animals and may explain particular aspects of related behavioral dysfunction in humans. PMID- 29764971 TI - Retrieval and sleep both counteract the forgetting of spatial information. AB - Repeatedly studying information is a good way to strengthen memory storage. Nevertheless, testing recall often produces superior long-term retention. Demonstrations of this testing effect, typically with verbal stimuli, have shown that repeated retrieval through testing reduces forgetting. Sleep also benefits memory storage, perhaps through repeated retrieval as well. That is, memories may generally be subject to forgetting that can be counteracted when memories become reactivated, and there are several types of reactivation: (i) via intentional restudying, (ii) via testing, (iii) without provocation during wake, or (iv) during sleep. We thus measured forgetting for spatial material subjected to repeated study or repeated testing followed by retention intervals with sleep versus wake. Four groups of subjects learned a set of visual object-location associations and either restudied the associations or recalled locations given the objects as cues. We found the advantage for restudied over retested information was greater in the PM than AM group. Additional groups tested at 5 min and 1-wk retention intervals confirmed previous findings of greater relative benefits for restudying in the short-term and for retesting in the long-term. Results overall support the conclusion that repeated reactivation through testing or sleeping stabilizes information against forgetting. PMID- 29764972 TI - Separate functional properties of NMDARs regulate distinct aspects of spatial cognition. AB - N-methyl-d-aspartate receptors (NMDARs) at excitatory synapses are central to activity-dependent synaptic plasticity and learning and memory. NMDARs act as ionotropic and metabotropic receptors by elevating postsynaptic calcium concentrations and by direct intracellular protein signaling. In the forebrain, these properties are controlled largely by the auxiliary GluN2 subunits, GluN2A and GluN2B. While calcium conductance through NMDAR channels and intracellular protein signaling make separate contributions to synaptic plasticity, it is not known if these properties individually influence learning and memory. To address this issue, we created chimeric GluN2 subunits containing the amino-terminal domain and transmembrane domains from GluN2A or GluN2B fused to the carboxy terminal domain of GluN2B (termed ABc) or GluN2A ATD (termed BAc), respectively, and expressed these mutated GluN2 subunits in transgenic mice. Expression was confirmed at the mRNA level and protein subunit translation and translocation into dendrites were observed in forebrain neurons. In the spatial version of the Morris water maze, BAc mice displayed signs of a learning deficit. In contrast, ABc animals performed similarly to wild-types during training, but showed a more direct approach to the goal location during a long-term memory test. There was no effect of ABc or BAc expression in a nonspatial water escape task. Since background expression is predominantly GluN2A in mature animals, the results suggest that spatial learning is more sensitive to manipulations of the amino terminal domain and transmembrane domains (calcium conductance) and long-term memory is regulated more by the carboxy-terminal domain (intracellular protein signaling). PMID- 29764973 TI - A complex mTOR response in habituation paradigms for a social signal in adult songbirds. AB - Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra finches. These colonial songbirds learn the unique song of individuals, which helps establish and maintain mate and other social bonds, and informs appropriate behavioral interactions with specific birds. We leveraged prior work demonstrating behavioral habituation for individual songs, and extended the molecular framework correlated with this behavior by investigating the mechanistic Target of Rapamycin (mTOR) signaling cascade. We hypothesized that mTOR may contribute to habituation because it integrates a variety of upstream signals and enhances associative learning, and it crosstalks with another cascade previously associated with habituation, ERK/ZENK. To begin probing for a possible role for mTOR in song recognition learning, we used a combination of song playback paradigms and bidirectional dysregulation of mTORC1 activation. We found that mTOR demonstrates the molecular signatures of a habituation mechanism, and that its manipulation reveals the complexity of processes that may be invoked during nonassociative learning. These results thus expand the molecular targets for habituation studies and raise new questions about neural processing of complex natural signals. PMID- 29764974 TI - Dissociable contributions of the amygdala to the immediate and delayed effects of emotional arousal on memory. AB - Emotional arousal enhances memory encoding and consolidation leading to better immediate and delayed memory. Although the central noradrenergic system and the amygdala play critical roles in both effects of emotional arousal, we have recently shown that these effects are at least partly independent of each other, suggesting distinct underlying neural mechanisms. Here we aim to dissociate the neural substrates of both effects in 70 female participants using an emotional memory paradigm to investigate how neural activity, as measured by fMRI, and a polymorphism in the alpha2B-noradrenoceptor vary for these effects. To also test whether the immediate and delayed effects of emotional arousal on memory are stable traits, we invited back participants who were a part of a large-scale behavioral memory study ~3.5 yr ago. We replicated the low correlation of the immediate and delayed emotional enhancement of memory across participants (r = 0.16) and observed, moreover, that only the delayed effect was, to some degree, stable over time (r = 0.23). Bilateral amygdala activity, as well as its coupling with the visual cortex and the fusiform gyrus, was related to the preferential encoding of emotional stimuli, which is consistent with affect-biased attention. Moreover, the adrenoceptor genotype modulated the bilateral amygdala activity associated with this effect. The left amygdala and its coupling with the hippocampus was specifically associated with the more efficient consolidation of emotional stimuli, which is consistent with amygdalar modulation of hippocampal consolidation. PMID- 29764975 TI - Development of mnemonic discrimination during childhood. AB - The present study examined mnemonic discrimination in 5- and 6-yr-old children, 8 and 9-yr-old children, 11- and 12-yr-old children, and young adults. Participants incidentally encoded pictorial stimuli and subsequently judged whether targets (i.e., repeated stimuli), lures (i.e., mnemonically related stimuli), and foils (i.e., novel stimuli) were old, similar, or new. Compared to older age groups, younger children were more likely to (1) incorrectly identify lures as "old" (rather than "similar") and (2) fail to recognize lures altogether, especially when lures were more mnemonically distinct from targets. These results suggest age-related improvements in pattern separation and pattern completion during childhood. PMID- 29764976 TI - HIV/AIDS in Syria and the response of the National AIDS Program during the war. PMID- 29764977 TI - Knowledge on human papillomavirus among transgender women in Colombia. PMID- 29764978 TI - The Hfq chaperone helps the ribosome mature. PMID- 29764979 TI - The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. AB - The MiT-TFE family of basic helix-loop-helix leucine-zipper transcription factors includes four members: TFEB, TFE3, TFEC, and MITF Originally described as oncogenes, these factors play a major role as regulators of lysosome biogenesis, cellular energy homeostasis, and autophagy. An important mechanism by which these transcription factors are regulated involves their shuttling between the surface of lysosomes, the cytoplasm, and the nucleus. Such dynamic changes in subcellular localization occur in response to nutrient fluctuations and various forms of cell stress and are mediated by changes in the phosphorylation of multiple conserved amino acids. Major kinases responsible for MiT-TFE protein phosphorylation include mTOR, ERK, GSK3, and AKT In addition, calcineurin de-phosphorylates MiT TFE proteins in response to lysosomal calcium release. Thus, through changes in the phosphorylation state of MiT-TFE proteins, lysosome function is coordinated with the cellular metabolic state and cellular demands. This review summarizes the evidence supporting MiT-TFE regulation by phosphorylation at multiple key sites. Elucidation of such regulatory mechanisms is of fundamental importance to understand how these transcription factors contribute to both health and disease. PMID- 29764980 TI - Interplay of cell-cell contacts and RhoA/MRTF-A signaling regulates cardiomyocyte identity. AB - Cell-cell and cell-matrix interactions guide organ development and homeostasis by controlling lineage specification and maintenance, but the underlying molecular principles are largely unknown. Here, we show that in human developing cardiomyocytes cell-cell contacts at the intercalated disk connect to remodeling of the actin cytoskeleton by regulating the RhoA-ROCK signaling to maintain an active MRTF/SRF transcriptional program essential for cardiomyocyte identity. Genetic perturbation of this mechanosensory pathway activates an ectopic fat gene program during cardiomyocyte differentiation, which ultimately primes the cells to switch to the brown/beige adipocyte lineage in response to adipogenesis inducing signals. We also demonstrate by in vivo fate mapping and clonal analysis of cardiac progenitors that cardiac fat and a subset of cardiac muscle arise from a common precursor expressing Isl1 and Wt1 during heart development, suggesting related mechanisms of determination between the two lineages. PMID- 29764983 TI - Is there a nocebo response that results from disease awareness campaigns and advertising in Australia, and can this effect be mitigated? AB - Direct-to-consumer advertising is banned in Australia, and instead pharmaceutical companies use disease awareness campaigns as a strategy to raise public awareness of conditions for which the company produces a treatment. This practice has been justified by promoting individual autonomy and public health, but it has attracted criticism regarding medicalisation of normal health and ageing, and exaggeration of the severity of the condition in question, imbalanced reporting of risks and benefits, and damaging the patient-clinician relationship. While there are benefits of disease awareness promotion, there is another possible adverse consequence that has not yet been rigorously considered: the possibility of inducing a nocebo response via the campaign. We will discuss the creation of a nocebo response in this context. PMID- 29764982 TI - SUPERMAN regulates floral whorl boundaries through control of auxin biosynthesis. AB - Proper floral patterning, including the number and position of floral organs in most plant species, is tightly controlled by the precise regulation of the persistence and size of floral meristems (FMs). In Arabidopsis, two known feedback pathways, one composed of WUSCHEL (WUS) and CLAVATA3 (CLV3) and the other composed of AGAMOUS (AG) and WUS, spatially and temporally control floral stem cells, respectively. However, mounting evidence suggests that other factors, including phytohormones, are also involved in floral meristem regulation. Here, we show that the boundary gene SUPERMAN (SUP) bridges floral organogenesis and floral meristem determinacy in another pathway that involves auxin signaling. SUP interacts with components of polycomb repressive complex 2 (PRC2) and fine-tunes local auxin signaling by negatively regulating the expression of the auxin biosynthesis genes YUCCA1/4 (YUC1/4). In sup mutants, derepressed local YUC1/4 activity elevates auxin levels at the boundary between whorls 3 and 4, which leads to an increase in the number and the prolonged maintenance of floral stem cells, and consequently an increase in the number of reproductive organs. Our work presents a new floral meristem regulatory mechanism, in which SUP, a boundary gene, coordinates floral organogenesis and floral meristem size through fine-tuning auxin biosynthesis. PMID- 29764981 TI - Mice with endogenous TDP-43 mutations exhibit gain of splicing function and characteristics of amyotrophic lateral sclerosis. AB - TDP-43 (encoded by the gene TARDBP) is an RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS). However, how TARDBP mutations trigger pathogenesis remains unknown. Here, we use novel mouse mutants carrying point mutations in endogenous Tardbp to dissect TDP-43 function at physiological levels both in vitro and in vivo Interestingly, we find that mutations within the C-terminal domain of TDP-43 lead to a gain of splicing function. Using two different strains, we are able to separate TDP-43 loss- and gain-of-function effects. TDP-43 gain-of-function effects in these mice reveal a novel category of splicing events controlled by TDP-43, referred to as "skiptic" exons, in which skipping of constitutive exons causes changes in gene expression. In vivo, this gain-of-function mutation in endogenous Tardbp causes an adult onset neuromuscular phenotype accompanied by motor neuron loss and neurodegenerative changes. Furthermore, we have validated the splicing gain-of function and skiptic exons in ALS patient-derived cells. Our findings provide a novel pathogenic mechanism and highlight how TDP-43 gain of function and loss of function affect RNA processing differently, suggesting they may act at different disease stages. PMID- 29764984 TI - Parallel Evolution of Common Allelic Variants Confers Flowering Diversity in Capsella rubella. AB - Flowering time is an adaptive life history trait. Capsella rubella, a close relative of Arabidopsis thaliana and a young species, displays extensive variation for flowering time but low standing genetic variation due to an extreme bottleneck event, providing an excellent opportunity to understand how phenotypic diversity can occur with a limited initial gene pool. Here, we demonstrate that common allelic variation and parallel evolution at the FLC locus confer variation in flowering time in C. rubella. We show that two overlapping deletions in the 5' untranslated region (UTR) of C. rubella FLC, which are associated with local changes in chromatin conformation and histone modifications, reduce its expression levels and promote flowering. We further show that these two pervasive variants originated independently in natural C. rubella populations after speciation and spread to an intermediate frequency, suggesting a role of this parallel cis-regulatory change in adaptive evolution. Our results provide an example of how parallel mutations in the same 5' UTR region can shape phenotypic evolution in plants. PMID- 29764986 TI - Phytochrome B Requires PIF Degradation and Sequestration to Induce Light Responses across a Wide Range of Light Conditions. AB - Phytochrome B (phyB) inhibits the function of phytochrome-interacting factors (PIFs) by inducing their degradation and sequestration, but the relative physiological importance of these two phyB activities is unclear. In an analysis of published Arabidopsis thaliana phyB mutations, we identified a point mutation in the N-terminal half of phyB (phyBG111D) that abolishes its PIF sequestration activity without affecting its PIF degradation activity. We also identified a point mutation in the phyB C-terminal domain, which, when combined with a deletion of the C-terminal end (phyB990G767R), does the opposite; it blocks PIF degradation without affecting PIF sequestration. The resulting phyB proteins, phyB990G767R and phyBG111D, are equally capable of inducing light responses under continuous red light. However, phyBG111D, which exhibits only the PIF degradation activity, induces stronger light responses than phyB990G767R under white light with prolonged dark periods (i.e., diurnal cycles). In contrast, phyB990G767R, which exhibits only the PIF sequestration activity, induces stronger light responses in flickering light (a condition that mimics sunflecks). Together, our results indicate that both of these separable phyB activities are required for light responses in varying light conditions. PMID- 29764985 TI - Responses to Systemic Nitrogen Signaling in Arabidopsis Roots Involve trans Zeatin in Shoots. AB - Plants face temporal and spatial variation in nitrogen (N) availability. This includes heterogeneity in soil nitrate (NO3-) content. To overcome these constraints, plants modify their gene expression and physiological processes to optimize N acquisition. This plasticity relies on a complex long-distance root shoot-root signaling network that remains poorly understood. We previously showed that cytokinin (CK) biosynthesis is required to trigger systemic N signaling. Here, we performed split-root experiments and used a combination of CK-related mutant analyses, hormone profiling, transcriptomic analysis, NO3- uptake assays, and root growth measurements to gain insight into systemic N signaling in Arabidopsis thaliana By comparing wild-type plants and mutants affected in CK biosynthesis and ABCG14-dependent root-to-shoot translocation of CK, we revealed an important role for active trans-zeatin (tZ) in systemic N signaling. Both rapid sentinel gene regulation and long-term functional acclimation to heterogeneous NO3- supply, including NO3- transport and root growth regulation, are likely mediated by the integration of tZ content in shoots. Furthermore, shoot transcriptome profiling revealed that glutamate/glutamine metabolism is likely a target of tZ root-to-shoot translocation, prompting an interesting hypothesis regarding shoot-to-root communication. Finally, this study highlights tZ-independent pathways regulating gene expression in shoots as well as NO3- uptake activity in response to total N deprivation. PMID- 29764988 TI - You've made the diagnosis of functional neurological disorder: now what? AB - Patients with functional neurological disorders (FND)/conversion disorder commonly present to outpatient clinics. FND is now a 'rule in' diagnosis based on neurological examination findings and semiological features. While neurologists may be more comfortable diagnosing patients with FND, there is only limited guidance as to how to conduct follow-up outpatient visits. Using clinical vignettes, we provide practical suggestions that may help guide clinical encounters including how to: (1) explore illness beliefs openly; (2) enquire longitudinally about predisposing vulnerabilities, acute precipitants and perpetuating factors that may be further elucidated over time; (3) facilitate psychotherapy engagement by actively listening for potentially unhelpful or maladaptive patterns of thoughts, behaviours, fears or psychosocial stressors that can be reflected back to the patient and (4) enquire about the fidelity of individual treatments and educate other providers who may be less familiar with FND. These suggestions, while important to individualise, provide a blueprint for follow-up FND clinical care. PMID- 29764987 TI - Rapid and Dynamic Alternative Splicing Impacts the Arabidopsis Cold Response Transcriptome. AB - Plants have adapted to tolerate and survive constantly changing environmental conditions by reprogramming gene expression The dynamics of the contribution of alternative splicing (AS) to stress responses are unknown. RNA-sequencing of a time-series of Arabidopsis thaliana plants exposed to cold determines the timing of significant AS changes. This shows a massive and rapid AS response with coincident waves of transcriptional and AS activity occurring in the first few hours of temperature reduction and further AS throughout the cold. In particular, hundreds of genes showed changes in expression due to rapidly occurring AS in response to cold ("early AS" genes); these included numerous novel cold responsive transcription factors and splicing factors/RNA binding proteins regulated only by AS. The speed and sensitivity to small temperature changes of AS of some of these genes suggest that fine-tuning expression via AS pathways contributes to the thermo-plasticity of expression. Four early AS splicing regulatory genes have been shown previously to be required for freezing tolerance and acclimation; we provide evidence of a fifth gene, U2B"-LIKE Such factors likely drive cascades of AS of downstream genes that, alongside transcription, modulate transcriptome reprogramming that together govern the physiological and survival responses of plants to low temperature. PMID- 29764992 TI - Aurora B opposes PP1 function in mitosis by phosphorylating the conserved PP1 binding RVxF motif in PP1 regulatory proteins. AB - Protein phosphatase 1 (PP1) is a highly conserved protein phosphatase that performs most of the serine- and threonine-dephosphorylation reactions in eukaryotes and opposes the actions of a diverse set of serine and threonine (Ser Thr) protein kinases. PP1 gains substrate specificity through binding to a large number (>200) of regulatory proteins that control PP1 localization, activity, and interactions with substrates. PP1 recognizes the well-characterized RVxF binding motif that is present in many of these regulatory proteins, thus generating a multitude of distinct PP1 holoenzymes. We showed that a subset of the RVxF binding motifs, in which x is a phosphorylatable amino acid (RV[S/T]F), was phosphorylated specifically during mitosis and that this phosphorylation event abrogated the interaction of PP1 with the regulatory protein. We determined that this phosphorylation was primarily governed by the mitotic protein kinase Aurora B and that high phosphorylation site stoichiometry of these sites maintained the phosphorylation of PP1 substrates during mitosis by disrupting the assembly of PP1 holoenzymes. We generated an antibody that recognizes the phosphorylated form of the RV[S/T]F motif (RVp[S/T]F) and used it to identify known PP1 regulatory proteins (KNL1, CDCA2, and RIF1) and multiple proteins that could potentially act as PP1 binding partners (UBR5, ASPM, SEH1, and ELYS) governed by this mechanism. Together, these data suggest a general regulatory mechanism by which the coordinated activities of Aurora B and PP1 control mitotic progression. PMID- 29764989 TI - Global assessment of its network dynamics reveals that the kinase Plk1 inhibits the phosphatase PP6 to promote Aurora A activity. AB - Polo-like kinase 1 (Plk1) is an essential protein kinase that promotes faithful mitotic progression in eukaryotes. The subcellular localization and substrate interactions of Plk1 are tightly controlled and require its binding to phosphorylated residues. To identify phosphorylation-dependent interactions within the Plk1 network in human mitotic cells, we performed quantitative proteomics on HeLa cells cultured with kinase inhibitors or expressing a Plk1 mutant that was deficient in phosphorylation-dependent substrate binding. We found that many interactions were abolished upon kinase inhibition; however, a subset was protected from phosphatase opposition or was unopposed, resulting in persistent interaction of the substrate with Plk1. This subset includes phosphoprotein phosphatase 6 (PP6), whose activity toward Aurora kinase A (Aurora A) was inhibited by Plk1. Our data suggest that this Plk1-PP6 interaction generates a feedback loop that coordinates and reinforces the activities of Plk1 and Aurora A during mitotic entry and is terminated by the degradation of Plk1 during mitotic exit. Thus, we have identified a mechanism for the previously puzzling observation of the Plk1-dependent regulation of Aurora A. PMID- 29764990 TI - IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. AB - Obesity or a high-fat diet represses the endoribonuclease activity of inositol requiring enzyme 1alpha (IRE1alpha), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. We found that IRE1alpha was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1alpha processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR 34 families, such that IRE1alpha promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1alpha and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor alpha (PPARalpha) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1alpha deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1alpha maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1alpha-UPR pathway under acute ER stress. PMID- 29764993 TI - SMAD3 gene rs12901499 polymorphism increased the risk of osteoarthritis. AB - A growing body of evidence suggested that smad family member 3 gene rs12901499 polymorphism was associated with the risk of osteoarthritis. However, the results of previous studies were conflicting. In the present study, we assessed whether smad family member 3 gene rs12901499 polymorphism was associated with the risk of osteoarthritis by the meta-analysis. We searched in the databases of PubMed, Embase, and CNKI. Pooled odds ratios and 95% confidence intervals were calculated. Seven papers involving 11 studies (5344 cases and 9080 controls) analyzed the association between smad family member 3 gene rs12901499 polymorphism and osteoarthritis risk. This meta-analysis confirmed that smad family member 3 gene rs12901499 polymorphism increased the risk of osteoarthritis. Stratification analysis of ethnicity found that rs12901499 polymorphism increased the risk of osteoarthritis among both Asians and Caucasians [G vs A: Asians, OR and 95%CI, 1.34(1.07, 1.69), P=0.012; Caucasians, OR and 95%CI, 1.21(1.13, 1.29), P<0.001]. In addition, subgroup analysis by type of osteoarthritis revealed that smad family member 3 gene rs12901499 polymorphism was correlated with the increased risk of hip osteoarthritis, but not associated with knee osteoarthritis. Sensitivity analysis did not draw different findings. In conclusion, this meta-analysis indicates that smad family member 3 gene rs12901499 polymorphism increased the risk of osteoarthritis. PMID- 29764991 TI - A DGKzeta-FoxO-ubiquitin proteolytic axis controls fiber size during skeletal muscle remodeling. AB - Skeletal muscle rapidly remodels in response to various stresses, and the resulting changes in muscle mass profoundly influence our health and quality of life. We identified a diacylglycerol kinase zeta (DGKzeta)-mediated pathway that regulated muscle mass during remodeling. During mechanical overload, DGKzeta abundance was increased and required for effective hypertrophy. DGKzeta not only augmented anabolic responses but also suppressed ubiquitin-proteasome system (UPS)-dependent proteolysis. We found that DGKzeta inhibited the transcription factor FoxO that promotes the induction of the UPS. This function was mediated through a mechanism that was independent of kinase activity but dependent on the nuclear localization of DGKzeta. During denervation, DGKzeta abundance was also increased and was required for mitigating the activation of FoxO-UPS and the induction of atrophy. Conversely, overexpression of DGKzeta prevented fasting induced atrophy. Therefore, DGKzeta is an inhibitor of the FoxO-UPS pathway, and interventions that increase its abundance could prevent muscle wasting. PMID- 29764994 TI - Associations between occupational exposure to benzene, toluene and xylene and risk of lung cancer in Montreal. AB - BACKGROUND: Benzene, toluene and xylene (BTX) are aromatic hydrocarbons with inconclusive evidence of lung carcinogenicity. The aim of this research was to assess the associations between occupational exposures to BTX agents and lung cancer. METHODS: In a population-based case-control study of lung cancer, occupational histories were obtained and exposures were assessed by experts. Unconditional multivariate logistic regression was used to estimate ORs and 95% CIs, among men, between various metrics of occupational exposure to BTX and lung cancer, while adjusting for established and possible risk factors. RESULTS: Considerable overlap was found between occupational exposure to BTX, where the majority of exposed participants were exposed to all three chemicals. Lung cancer was associated with exposure to benzene (OR=1.35; 95% CI 0.99 to 1.84), toluene (OR=1.31; 95% CI 0.99 to 1.74) and xylene (OR=1.44; 95% CI 1.03 to 2.01). While these results were adjusted for smoking and other recognised and possible lung cancer risk factors, they were not mutually adjusted among the three BTX agents. CONCLUSIONS: Our study provides suggestive evidence that occupational exposure to one or more of the BTX agents may be associated with lung cancer. PMID- 29764995 TI - Retraction for Zehorai and Seger, "Beta-Like Importins Mediate the Nuclear Translocation of Mitogen-Activated Protein Kinases". PMID- 29764996 TI - Retraction for Plotnikov et al., "Nuclear Extracellular Signal-Regulated Kinase 1 and 2 Translocation Is Mediated by Casein Kinase 2 and Accelerated by Autophosphorylation". PMID- 29764997 TI - Root-exuded coumarin shapes the root microbiome. PMID- 29765000 TI - Harnessing bistability for directional propulsion of soft, untethered robots. AB - In most macroscale robotic systems, propulsion and controls are enabled through a physical tether or complex onboard electronics and batteries. A tether simplifies the design process but limits the range of motion of the robot, while onboard controls and power supplies are heavy and complicate the design process. Here, we present a simple design principle for an untethered, soft swimming robot with preprogrammed, directional propulsion without a battery or onboard electronics. Locomotion is achieved by using actuators that harness the large displacements of bistable elements triggered by surrounding temperature changes. Powered by shape memory polymer (SMP) muscles, the bistable elements in turn actuate the robot's fins. Our robots are fabricated using a commercially available 3D printer in a single print. As a proof of concept, we show the ability to program a vessel, which can autonomously deliver a cargo and navigate back to the deployment point. PMID- 29765001 TI - Opinion: Reproducibility failures are essential to scientific inquiry. PMID- 29764999 TI - Targetable BET proteins- and E2F1-dependent transcriptional program maintains the malignancy of glioblastoma. AB - Competitive BET bromodomain inhibitors (BBIs) targeting BET proteins (BRD2, BRD3, BRD4, and BRDT) show promising preclinical activities against brain cancers. However, the BET protein-dependent glioblastoma (GBM)-promoting transcriptional network remains elusive. Here, with mechanistic exploration of a next-generation chemical degrader of BET proteins (dBET6), we reveal a profound and consistent impact of BET proteins on E2F1- dependent transcriptional program in both differentiated GBM cells and brain tumor-initiating cells. dBET6 treatment drastically reduces BET protein genomic occupancy, RNA-Pol2 activity, and permissive chromatin marks. Subsequently, dBET6 represses the proliferation, self renewal, and tumorigenic ability of GBM cells. Moreover, dBET6-induced degradation of BET proteins exerts superior antiproliferation effects compared to conventional BBIs and overcomes both intrinsic and acquired resistance to BBIs in GBM cells. Our study reveals crucial functions of BET proteins and provides the rationale and therapeutic merits of targeted degradation of BET proteins in GBM. PMID- 29765003 TI - Passive Versus Active Circuit During Invasive Mechanical Ventilation in Subjects With Amyotrophic Lateral Sclerosis. AB - BACKGROUND: Until recently, it has been considered essential to maintain the use of a double-limb circuit in patients with amyotrophic lateral sclerosis (ALS) to avoid rebreathing expired air during invasive mechanical ventilation. Currently, life-sustaining home ventilators can work with a single, lighter circuit that is easier to manage. Our aim was to evaluate the effectiveness and safety of a single-limb circuit with intentional leaks (passive circuit) in comparison with a circuit with an expiratory valve (active circuit), in subjects with ALS who use invasive home ventilation. METHODS: We conducted a retrospective single-center study. The enrolled subjects were divided into 2 groups according to the type of exhalation port. The aim of the study was to compare arterial blood gases; nocturnal oxygen saturation recordings; and the occurrence of adverse events, both clinical and technical events. In addition, we compared the rate of mortality and unplanned hospital admissions that occurred within a year after discharge from the hospital. RESULTS: Forty-three subjects were included in our study: 23 who used a passive circuit and 20 who used an active circuit. No significant difference in nocturnal and diurnal gas exchanges was detected. The incidence of adverse events was significantly higher in the active circuit group (85% in active circuit vs 30% in passive circuit, P < .001). However, by splitting the adverse events into 2 categories, clinical and technical, the technical events were significantly more frequent in the active circuit group. None of these events led to hospital admission or death. CONCLUSIONS: The passive circuit was shown to be as effective and safe as the active circuit during home invasive ventilation in the subjects with amyotrophic lateral sclerosis. A future randomized controlled study is necessary to confirm these results and to extend indications to other pathologies. PMID- 29765004 TI - A Comparison of the Adjustable Ranges of Inspiratory Pressurization During Pressure Controlled Continuous Mandatory Ventilation of 5 ICU Ventilators. AB - BACKGROUND: Faster inspiratory pressurization can improve patient-ventilator synchrony and reduce the patient's work of breathing during pressure controlled continuous mandatory (PC-CMV) ventilation. The characteristics of the pressurization ramp settings are not standardized across ventilators from different manufacturers. We performed a bench test of 5 models of ICU ventilators to examine the effects of pressurization ramp settings on the actual pressurization. METHODS: A twin-bellows lung model was used, in which one bellow simulates inspiratory muscle activity and the other simulates an adult normal lung model. We made the inspiratory effort by changing the tidal volume of the inspiratory muscle bellow. The effect of pressurization ramp settings on the performance of each ventilator was examined at 3 inspiratory effort levels (ie, none, ordinary, and strong). The pressurization ramp was set at 4 or 5 evenly divided steps from the minimum to maximum for each ventilator. The following parameters were measured: tidal volume, mean airway pressure, maximal inspiratory flow, time to maximal flow, and pressure-time products at 0.3 s (PTP0.3) and 0.5 s (PTP0.5) from the beginning of inspiration. PTP0.3 and PTP0.5 indicated levels of inspiratory pressurization. RESULTS: A proportional increase in PTP0.3 and PTP0.5 was observed with an increase in the pressurization ramp settings of the recent models of ventilators. PTP0.3 and PTP0.5 at ordinary and strong effort levels were similar in the recent models of ventilators. The actual adjustable ranges of PTP0.3 and PTP0.5 associated with change in the pressurization ramp settings differed between the 5 ventilators. CONCLUSIONS: The adjustable ranges of the pressurization were largely different among the different types of ventilators. The actual absolute inspiratory pressurization during PC-CMV varied between the different ventilators even at similar pressurization ramp settings. Users should be mindful of the differences in the pressurization ramp settings. PMID- 29765005 TI - Heart Rate Recovery, Physical Activity Level, and Functional Status in Subjects With COPD. AB - BACKGROUND: A normal heart rate reflects the balance between the sympathetic and parasympathetic autonomic nervous system. When the difference between heart rate at the end of an exercise test and after 1 min of recovery, known as the 1-min heart rate recovery, is <= 12 beats/min, this may indicate an abnormal delay. We sought to compare physical activity patterns and subjects' functional status with COPD with or without delayed 1-min heart rate recovery after the 6-min walk test (6MWT). METHODS: 145 subjects with COPD (78 men, median [interquartile range (IQR)] age 65 [60-73] y, body mass index 25 [21-30] kg/m2, FEV1 45 +/- 15% predicted) were underwent the following assessments: spirometry, 6MWT, functional status, and physical activity in daily life (PADL). A delayed heart rate recovery of 1 min was defined as <= 12 beats/min. RESULTS: Subjects with delayed 1-min heart rate recovery walked a shorter distance in the 6MWT compared to subjects without delayed heart rate recovery (median [IQR] 435 [390-507] m vs 477 [425 515] m, P = .01; 81 [71-87] vs 87 [79-98]% predicted, P = .002). Regarding PADL, subjects with delayed heart rate recovery spent less time in the standing position (mean +/- SD 185 +/- 89 min vs 250 +/- 107 min, P = .002) and more time in sedentary positions (472 +/- 110 min vs 394 +/- 129 min, P = .002). Scores based on the self-care domain of the London Chest Activity of Daily Living questionnaire and the activity domain of the Pulmonary Functional Status and Dyspnea questionnaire were also worse in the group with delayed heart rate recovery (6 +/- 2 points vs 5 +/- 2 points; P = .039 and 29 +/- 24 points vs 19 +/- 17 points; P = .037, respectively). CONCLUSIONS: Individuals with COPD who exhibit delayed 1-min heart rate recovery after the 6MWT exhibited worse exercise capacity as well as a more pronounced sedentary lifestyle and worse functional status than those without delayed heart rate recovery. Despite its assessment simplicity, heart rate recovery after the 6MWT can be further explored as a promising outcome in COPD. PMID- 29765006 TI - Exosomes and extracellular vesicles: the path forward. AB - Over the course of the past several decades, the concept that extracellular vesicles, exosomes and microvesicles, operate as cellular "housekeepers" and as agents for communication between and among cells and tissues, has emerged into one of the most promising yet vexing problems facing the biomedical community. Already, extracellular vesicles from biological fluids are being used for diagnostic purposes and hopes abound for their use as therapeutic agents. However, the most basic mechanistic questions surrounding their biogenesis and function in cellular and tissue homeostasis remain largely unexplored. In this issue of Essays in Biochemistry, the rise of a new intercellular communications pathway is considered from many perspectives-cell biology, physiology, and pathophysiology. PMID- 29765007 TI - From intra- to extracellular vesicles: extracellular vesicles in developmental signalling. AB - Signalling from cell-to-cell is fundamental for determining differentiation and patterning. This communication can occur between adjacent and distant cells. Extracellular vesicles (EVs) are membrane-based structures thought to facilitate the long-distance movement of signalling molecules. EVs have recently been found to allow the transport of two major developmental signalling pathways: Hedgehog and Wnt. These signalling molecules undergo crucial post-translational lipid modifications, which anchor them to membranes and impede their free release into the extracellular space. Preparation of these ligands in EVs involves intracellular vesicle sorting in an endocytosis-dependent recycling process before secretion. In the present review, we discuss the most recent advances with regard to EV involvement in developmental signalling at a distance. We focus on the role of the protein complexes involved in EV genesis, and provide a comprehensive perspective of the contribution of these complexes to intracellular vesicle sorting of developmental signals for their extracellular secretion, reception and transduction. PMID- 29765008 TI - Housing Assistance and Child Health: A Systematic Review. AB - CONTEXT: Given a large and consistent literature revealing a link between housing and health, publicly supported housing assistance programs might play an important role in promoting the health of disadvantaged children. OBJECTIVE: To summarize and evaluate research in which authors examine housing assistance and child health. DATA SOURCES: PubMed, Web of Science, PsycInfo, and PAIS (1990 2017). STUDY SELECTION: Eligible studies were required to contain assessments of public housing, multifamily housing, or vouchers in relation to a health outcome in children (ages 0-21); we excluded neighborhood mobility interventions. DATA EXTRACTION: Study design, sample size, age, location, health outcomes, measurement, program comparisons, analytic approach, covariates, and results. RESULTS: We identified 14 studies, including 4 quasi-experimental studies, in which authors examined a range of health outcomes. Across studies, the relationship between housing assistance and child health remains unclear, with ~40% of examined outcomes revealing no association between housing assistance and health. A sizable proportion of observed relationships within the quasi experimental and association studies were in favor of housing assistance (50.0% and 37.5%, respectively), and negative outcomes were less common and only present among association studies. LIMITATIONS: Potential publication bias, majority of studies were cross-sectional, and substantial variation in outcomes, measurement quality, and methods to address confounding. CONCLUSIONS: The results underscore a need for rigorous studies in which authors evaluate specific housing assistance programs in relation to child outcomes to establish what types of housing assistance, if any, serve as an effective strategy to reduce disparities and advance equity across the lifespan. PMID- 29765010 TI - 13 Things Pediatricians Should Know (and Do) About 13 Reasons Why. PMID- 29765009 TI - Parent-Provider Communication of HPV Vaccine Hesitancy. AB - : : media-1vid110.1542/5754332185001PEDS-VA_2017-2312Video Abstract OBJECTIVES: To prevent human papillomavirus (HPV)-related cancers, providers must effectively communicate with HPV vaccine-hesitant parents. Here, we developed a typology characterizing parent-provider communication around HPV vaccine hesitancy. METHODS: We audio-recorded 43 visits with unvaccinated adolescents at 6 pediatric clinics in Dallas, Texas in which parents were undecided about HPV vaccination. We qualitatively coded how parents verbally expressed hesitancy (assertive response, asking a question, or expressing concern) and whether providers responded with acquiescence (agree to defer vaccination) and/or persistence (continue discussion). We described the frequency of parent and provider communication codes and same-day vaccination. RESULTS: Among the 43 visits, 37 parents expressed hesitancy >=1 times in many ways. Assertive responses were most common (27 visits), followed by questions (16 visits), and concerns (12 visits). When the first expression of hesitancy was a question or concern, 71% and 75% of adolescents, respectively, received same-day vaccinations, whereas 33% of adolescents who received an initial assertive response were vaccinated. Providers responded with only persistence in 18 visits, a mix of acquiescence and persistence in 13 visits, and only acquiescence in 6 visits. When providers only used persistence, 17 of 18 adolescents were vaccinated; when providers responded with only acquiescence, no adolescents received the vaccine. CONCLUSIONS: Our exploratory analysis reveals that providers engaging hesitant parents and addressing their concerns can lead to same-day HPV vaccination. Data reveal that even parents making assertive statements are amenable to influence by providers. Our findings reveal an important missed opportunity when providers simply acquiesce to parental hesitation. PMID- 29765011 TI - Fluorometric 'switch-on' detection of heparin based on a system composed of rhodamine-labeled chitosan oligosaccharide lactate, and graphene oxide. AB - A novel fluorescence 'Switch on' for the detection of heparin based on the RhB COL/GO system was achieved. A strong fluorescence dye, Rhodamine B, was modified by chitosan oligosaccharide lactate (COL), which plays a major role in the formation of a positively charged RhB-COL complex. RhB-COL was soluble and stable in solution, which was characterized by using Fourier transform infrared spectroscopy and x-ray photoelectron spectroscopy. GO sheets quenched the fluorescence intensity of RhB-COL due to electron transfer from RhB to the GO surface. The decrease in fluorescence intensity of RhB-COL with increasing GO concentration was recorded using a Cary Eclipse fluorescence spectrophotometer. On the other hand, the addition of heparin replaced GO to bind with the RhB-COL surface via an electrostatic and noncovalent bond due to the abundant negative charge, which resulted in recovery of the fluorescence intensity. This RhB-COL/GO system possessed high selectivity and good sensitivity for the detection of heparin compared to other biomolecules, such as glycine, D-glucose, hyaluronic acid, L-glutamic acid, and ascorbic acid. The linear response toward heparin was measured over the range, 0-1.8 U . ml-1, with a low detection limit of 0.04 U . ml-1. The satisfactory sensing performance of RhB-COL/GO for heparin supports new 'switch-on' sensor applications in heparin-related biomedical detection. PMID- 29764998 TI - Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. AB - Hemispheric asymmetry is a cardinal feature of human brain organization. Altered brain asymmetry has also been linked to some cognitive and neuropsychiatric disorders. Here, the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium presents the largest-ever analysis of cerebral cortical asymmetry and its variability across individuals. Cortical thickness and surface area were assessed in MRI scans of 17,141 healthy individuals from 99 datasets worldwide. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Regionally, asymmetries of cortical thickness and/or surface area were found in the inferior frontal gyrus, transverse temporal gyrus, parahippocampal gyrus, and entorhinal cortex. These regions are involved in lateralized functions, including language and visuospatial processing. In addition to population-level asymmetries, variability in brain asymmetry was related to sex, age, and intracranial volume. Interestingly, we did not find significant associations between asymmetries and handedness. Finally, with two independent pedigree datasets (n = 1,443 and 1,113, respectively), we found several asymmetries showing significant, replicable heritability. The structural asymmetries identified and their variabilities and heritability provide a reference resource for future studies on the genetic basis of brain asymmetry and altered laterality in cognitive, neurological, and psychiatric disorders. PMID- 29765012 TI - Copolymer based multifunctional conducting polymer film for fluorescence sensing of glucose. AB - A simple, rapid and effective fluorescence sensing platform has been fabricated using a fluorescent conducting polymer surface. For this purpose, a rhodamine based electroactive monomer (RDC) and a functional group containing monomer (SNS) have been copolymerized to develop a conducting polymer based sensor platform having a fluorescence and enzyme-binding surface on ITO electrode. The proposed fluorescence sensing mechanism for detection of glucose is related to the consumption of dissolved oxygen at the double layer of the electrode which is fluorescence quenching agent by glucose-GOx reaction. Concentration of glucose was investigated quantitatively from 0.05 to 1 mM via fluorescence signal measurement. This novel approach could be adapted for the production of various rapid and effective fluorescence sensing platforms for glucose. PMID- 29765013 TI - A new tool for detection of extracellular traps. AB - Extracellular traps ejected by various immune cells (neutrophils, macrophages, eosinophils and mast cells) have several immune functions, either protective against pathogens or deleterious in some autoimmune or inflammatory disorders. Since their first description in 2004, the mechanisms of extracellular traps formation have been extensively investigated though still not fully understood. We describe here a new tool for the detection of extracellular traps by fluorescence microscopy in a single-step staining protocol, which does not require any wash. The approach uses the GreenGloTM DNA dye, which can differentiate between nuclear DNA and extracellular DNA (extracellular traps) released from cells using different fluorescence excitation wavelengths. GreenGloTM staining is suitable for adherent and non-adherent cells and is expected to be extendable to extracellular traps from other cells types (i.e. eosinophils, mast cells and monocytes). PMID- 29765014 TI - Steroid Receptor Coactivator-Interacting Protein (SIP) Suppresses Myocardial Injury Caused by Acute Pancreatitis. AB - BACKGROUND Steroid receptor coactivator-interacting protein (SIP) inhibits the activation of nuclear factor-kappa B (NF-kappaB) by interacting with p65. The occurrence of acute pancreatitis (AP) is closely associated with pro-inflammatory response. The present study aimed to investigate the role of SIP on myocardial injury caused by AP. MATERIAL AND METHODS Rat pancreatic acinar tumor cell line AR42J cells were treated with caerulein to establish AP cell models. The levels of TNF-alpha, IL-6, cTnI, CK-MB, and LDH1 were detected by ELISA assay. The mRNA and protein expression levels of SIP, p-p65, and p65 were detected by qRT-PCR and western blot analysis, respectively. Next, the AP cell models were non transfected or transfected with SIP plasmids or SIP siRNA. ELISA assay was also performed to test the levels of TNF-alpha, IL-6, cTnI, CK-MB, and LDH1. Moreover, qRT-PCR and western blot analysis were performed to measure the mRNA and protein expression levels of SIP, p-p65, and p65, respectively. RESULTS Caerulein upregulated the levels of TNF-alpha, IL-6, cTnI, CK-MB, and LDH1. These upregulations were reduced by SIP plasmids and promoted by SIP siRNA, respectively. Caerulein also increased the mRNA and protein expression levels of p-p65. However, the increases were attenuated by SIP plasmids and enhanced by SIP siRNA, respectively. CONCLUSIONS In conclusion, the results suggested that SIP may inhibit the inflammatory response by deactivating p65, thus reducing the myocardial damage caused by AP. PMID- 29765015 TI - Reduction of Blood Pressure Following After Renal Artery Adventitia Stripping During Total Nephroureterectomy: Potential Effect of Renal Sympathetic Denervation. AB - BACKGROUND Catheter-based renal sympathetic denervation has been reported to be effective for treatment resistance hypertension in Australia and Europe. However, in the blinded SYMPLICITY HTN-3 trial, renal denervation did not achieve a significant decrease in blood pressure (BP) in comparison to sham controls. There have been various discussions on the factors that influenced this result. CASE REPORT Two men on antihypertensive therapy underwent unilateral radical nephroureterectomy for cancer of the renal pelvis. When the renal artery adventitia was stripped and cauterized just before renal artery ligation, the measured BP of the 2 men increased after stripping adventitia and decreased gradually after cauterization of the renal artery. This was presumably due to removal of renal artery sympathetic nerves, similar to the mechanism of catheter based renal sympathetic denervation, although anesthesia, fluid infusion, and/or mesenteric traction may have had an influence. CONCLUSIONS A similar strategy involving thoracolumbar sympathectomy was reported about 50 years ago. The clinically significant blood pressure reduction in these patients suggests renal denervation is effective. PMID- 29765016 TI - B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation. AB - B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation. Conversely, little is known about how de novo deposition of DNA methylation affects B cell fate and function. Here we show that genetic deletion of the de novo DNA methyltransferases Dnmt3a and Dnmt3b (Dnmt3-deficient) in mouse B cells results in normal B cell development and maturation, but increased cell activation and expansion of the germinal center B cell and plasma cell populations upon immunization. Gene expression is mostly unaltered in naive and germinal center B cells, but dysregulated in Dnmt3-deficient plasma cells. Differences in gene expression are proximal to Dnmt3-dependent DNA methylation and chromatin changes, both of which coincide with E2A and PU.1-IRF composite binding motifs. Thus, de novo DNA methylation limits B cell activation, represses the plasma cell chromatin state, and regulates plasma cell differentiation. PMID- 29765017 TI - Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. AB - The International Stem Cell Initiative compared several commonly used approaches to assess human pluripotent stem cells (PSC). PluriTest predicts pluripotency through bioinformatic analysis of the transcriptomes of undifferentiated cells, whereas, embryoid body (EB) formation in vitro and teratoma formation in vivo provide direct tests of differentiation. Here we report that EB assays, analyzed after differentiation under neutral conditions and under conditions promoting differentiation to ectoderm, mesoderm, or endoderm lineages, are sufficient to assess the differentiation potential of PSCs. However, teratoma analysis by histologic examination and by TeratoScore, which estimates differential gene expression in each tumor, not only measures differentiation but also allows insight into a PSC's malignant potential. Each of the assays can be used to predict pluripotent differentiation potential but, at this stage of assay development, only the teratoma assay provides an assessment of pluripotency and malignant potential, which are both relevant to the pre-clinical safety assessment of PSCs. PMID- 29765018 TI - Tracking HIV-1 recombination to resolve its contribution to HIV-1 evolution in natural infection. AB - Recombination in HIV-1 is well documented, but its importance in the low diversity setting of within-host diversification is less understood. Here we develop a novel computational tool (RAPR (Recombination Analysis PRogram)) to enable a detailed view of in vivo viral recombination during early infection, and we apply it to near-full-length HIV-1 genome sequences from longitudinal samples. Recombinant genomes rapidly replace transmitted/founder (T/F) lineages, with a median half-time of 27 days, increasing the genetic complexity of the viral population. We identify recombination hot and cold spots that differ from those observed in inter-subtype recombinants. Furthermore, RAPR analysis of longitudinal samples from an individual with well-characterized neutralizing antibody responses shows that recombination helps carry forward resistance conferring mutations in the diversifying quasispecies. These findings provide insight into molecular mechanisms by which viral recombination contributes to HIV 1 persistence and immunopathogenesis and have implications for studies of HIV transmission and evolution in vivo. PMID- 29765019 TI - Relationship between circulating vascular endothelial growth factor and its soluble receptor in patients with hemorrhagic fever with renal syndrome. AB - Hemorrhagic fever with renal syndrome (HFRS) is characterized by endothelial dysfunction with capillary leakage without obvious cytopathology in the capillary endothelium. The aim of the study was to analyze the kinetics of vascular endothelial growth factor (VEGF) and its soluble receptor (sVEGFR-2) in HFRS patients infected with Dobrava (DOBV) or Puumala virus (PUUV). VEGF and sVEGFR-2 levels were measured in daily plasma and urine samples of 73 patients with HFRS (58 with PUUV, 15 with DOBV) and evaluated in relation to clinical and laboratory variables. In comparison with the healthy controls, initial samples (obtained in the first week of illness) from patients with HFRS had higher plasma and urine VEGF levels, whereas sVEGFR-2 levels were lower in plasma but higher in urine. VEGF levels did not differ in relation to hantavirus species, viral load, or the severity of HFRS. The comparison of VEGF dynamics in plasma and urine showed the pronounced secretion of VEGF in urine. Significant correlations were found between daily VEGF/sVEGFR-2 levels and platelet counts, as well as with diuresis: the correlations were positive for plasma VEGF/sVEGFR-2 levels and negative for urine levels. In addition, patients with hemorrhagic manifestations had very high plasma and urine VEGF, together with high urine sVEGFR-2. Measuring the local secretion of sVEGFR-2 in urine might be a useful biomarker for identifying HFRS patients who will progress to severe disease. PMID- 29765020 TI - Changes in genome organization of parasite-specific gene families during the Plasmodium transmission stages. AB - The development of malaria parasites throughout their various life cycle stages is coordinated by changes in gene expression. We previously showed that the three dimensional organization of the Plasmodium falciparum genome is strongly associated with gene expression during its replication cycle inside red blood cells. Here, we analyze genome organization in the P. falciparum and P. vivax transmission stages. Major changes occur in the localization and interactions of genes involved in pathogenesis and immune evasion, host cell invasion, sexual differentiation, and master regulation of gene expression. Furthermore, we observe reorganization of subtelomeric heterochromatin around genes involved in host cell remodeling. Depletion of heterochromatin protein 1 (PfHP1) resulted in loss of interactions between virulence genes, confirming that PfHP1 is essential for maintenance of the repressive center. Our results suggest that the three dimensional genome structure of human malaria parasites is strongly connected with transcriptional activity of specific gene families throughout the life cycle. PMID- 29765021 TI - Prospective surveillance for influenza. virus in Chinese swine farms. AB - Pork production in China is rapidly increasing and swine production operations are expanding in size and number. However, the biosecurity measures necessary to prevent swine disease transmission, particularly influenza. viruses (IAV) that can be zoonotic, are often inadequate. Despite this risk, few studies have attempted to comprehensively study IAV ecology in swine production settings. Here, we present environmental and animal sampling data collected in the first year of an ongoing five-year prospective epidemiological study to assess IAV ecology as it relates to swine workers, their pigs, and the farm environment. From March 2015 to February 2016, we collected 396 each of environmental swab, water, bioaerosol, and fecal/slurry samples, as well as 3300 pig oral secretion samples from six farms in China. The specimens were tested with molecular assays for IAV. Of these, 46 (11.6%) environmental swab, 235 (7.1%) pig oral secretion, 23 (5.8%) water, 20 (5.1%) bioaerosol, and 19 (4.8%) fecal/slurry specimens were positive for influenza. by qRT-PCR. Risk factors for IAV detection among collected samples were identified using bivariate logistic regression. Overall, these first year data suggest that IAV is quite ubiquitous in the swine production environment and demonstrate an association between the different types of environmental sampling used. Given the mounting evidence that some of these viruses freely move between pigs and swine workers, and that mixing of these viruses can yield progeny viruses with pandemic potential, it seems imperative that routine surveillance for novel IAVs be conducted in commercial swine farms. PMID- 29765022 TI - Tissue and cellular rigidity and mechanosensitive signaling activation in Alexander disease. AB - Glial cells have increasingly been implicated as active participants in the pathogenesis of neurological diseases, but critical pathways and mechanisms controlling glial function and secondary non-cell autonomous neuronal injury remain incompletely defined. Here we use models of Alexander disease, a severe brain disorder caused by gain-of-function mutations in GFAP, to demonstrate that misregulation of GFAP leads to activation of a mechanosensitive signaling cascade characterized by activation of the Hippo pathway and consequent increased expression of A-type lamin. Importantly, we use genetics to verify a functional role for dysregulated mechanotransduction signaling in promoting behavioral abnormalities and non-cell autonomous neurodegeneration. Further, we take cell biological and biophysical approaches to suggest that brain tissue stiffness is increased in Alexander disease. Our findings implicate altered mechanotransduction signaling as a key pathological cascade driving neuronal dysfunction and neurodegeneration in Alexander disease, and possibly also in other brain disorders characterized by gliosis. PMID- 29765023 TI - Symmetry mismatch-driven perpendicular magnetic anisotropy for perovskite/brownmillerite heterostructures. AB - Grouping different transition metal oxides together by interface engineering is an important route toward emergent phenomenon. While most of the previous works focused on the interface effects in perovskite/perovskite heterostructures, here we reported on a symmetry mismatch-driven spin reorientation toward perpendicular magnetic anisotropy in perovskite/brownmillerite heterostructures, which is scarcely seen in tensile perovskite/perovskite heterostructures. We show that alternately stacking perovskite La2/3Sr1/3MnO3 and brownmillerite LaCoO2.5 causes a strong interface reconstruction due to symmetry discontinuity at interface: neighboring MnO6 octahedra and CoO4 tetrahedra at the perovskite/brownmillerite interface cooperatively relax in a manner that is unavailable for perovskite/perovskite interface, leading to distinct orbital reconstructions and thus the perpendicular magnetic anisotropy. Moreover, the perpendicular magnetic anisotropy is robust, with an anisotropy constant two orders of magnitude greater than the in-plane anisotropy of the perovskite/perovskite interface. The present work demonstrates the great potential of symmetry engineering in designing artificial materials on demand. PMID- 29765024 TI - Diffusion markers of dendritic density and arborization in gray matter predict differences in intelligence. AB - Previous research has demonstrated that individuals with higher intelligence are more likely to have larger gray matter volume in brain areas predominantly located in parieto-frontal regions. These findings were usually interpreted to mean that individuals with more cortical brain volume possess more neurons and thus exhibit more computational capacity during reasoning. In addition, neuroimaging studies have shown that intelligent individuals, despite their larger brains, tend to exhibit lower rates of brain activity during reasoning. However, the microstructural architecture underlying both observations remains unclear. By combining advanced multi-shell diffusion tensor imaging with a culture-fair matrix-reasoning test, we found that higher intelligence in healthy individuals is related to lower values of dendritic density and arborization. These results suggest that the neuronal circuitry associated with higher intelligence is organized in a sparse and efficient manner, fostering more directed information processing and less cortical activity during reasoning. PMID- 29765025 TI - Functionalized boron nitride membranes with ultrafast solvent transport performance for molecular separation. AB - Pressure-driven, superfast organic solvent filtration membranes have significant practical applications. An excellent filtration membrane should exhibit high selectivity and permeation in aqueous and organic solvents to meet increasing industrial demand. Here, we report an amino functionalized boron nitride (FBN) based filtration membrane with a nanochannel network for molecular separation and permeation. This membrane is highly stable in water and in several organic solvents and shows high transport performance for solvents depending on the membranes' thickness. In addition, the FBN membrane is applicable for solute screening in water as well as in organic solvents. More importantly, the FBN membranes are very stable in acidic, alkaline and oxidative media for up to one month. The fast-flow rate and good separation performance of the FBN membranes can be attributed to their stable networks of nanochannels and thin laminar structure, which provide the membranes with beneficial properties for practical separation and purification processes. PMID- 29765026 TI - Hematopoietic stem cells can differentiate into restricted myeloid progenitors before cell division in mice. AB - Hematopoietic stem cells (HSCs) continuously replenish all blood cell types through a series of differentiation steps and repeated cell divisions that involve the generation of lineage-committed progenitors. However, whether cell division in HSCs precedes differentiation is unclear. To this end, we used an HSC cell-tracing approach and Ki67RFP knock-in mice, in a non-conditioned transplantation model, to assess divisional history, cell cycle progression, and differentiation of adult HSCs. Our results reveal that HSCs are able to differentiate into restricted progenitors, especially common myeloid, megakaryocyte-erythroid and pre-megakaryocyte progenitors, without undergoing cell division and even before entering the S phase of the cell cycle. Additionally, the phenotype of the undivided but differentiated progenitors correlated with the expression of lineage-specific genes and loss of multipotency. Thus HSC fate decisions can be uncoupled from physical cell division. These results facilitate a better understanding of the mechanisms that control fate decisions in hematopoietic cells. PMID- 29765027 TI - Polygenic pleiotropy and potential causal relationships between educational attainment, neurobiological profile, and positive psychotic symptoms. AB - Event-related potential (ERP) components have been used to assess cognitive functions in patients with psychotic illness. Evidence suggests that among patients with psychosis there is a distinct heritable neurophysiologic phenotypic subtype captured by impairments across a range of ERP measures. In this study, we investigated the genetic basis of this "globally impaired" ERP cluster and its relationship to psychosis and cognitive abilities. We applied K-means clustering to six ERP measures to re-derive the globally impaired (n = 60) and the non globally impaired ERP clusters (n = 323) in a sample of cases with schizophrenia (SCZ = 136) or bipolar disorder (BPD = 121) and healthy controls (n = 126). We used genome-wide association study (GWAS) results for SCZ, BPD, college completion, and childhood intelligence as the discovery datasets to derive polygenic risk scores (PRS) in our study sample and tested their associations with globally impaired ERP. We conducted mediation analyses to estimate the proportion of each PRS effect on severity of psychotic symptoms that is mediated through membership in the globally impaired ERP. Individuals with globally impaired ERP had significantly higher PANSS-positive scores (beta = 3.95, P = 0.005). The SCZ-PRS was nominally associated with globally impaired ERP (unadjusted P = 0.01; R2 = 3.07%). We also found a significant positive association between the college-PRS and globally impaired ERP (FDR-corrected P = 0.004; R2 = 6.15%). The effect of college-PRS on PANSS positivity was almost entirely (97.1%) mediated through globally impaired ERP. These results suggest that the globally impaired ERP phenotype may represent some aspects of brain physiology on the path between genetic influences on educational attainment and psychotic symptoms. PMID- 29765028 TI - DOT1L inhibition attenuates graft-versus-host disease by allogeneic T cells in adoptive immunotherapy models. AB - Adoptive T-cell therapy is a promising therapeutic approach for cancer patients. The use of allogeneic T-cell grafts will improve its applicability and versatility provided that inherent allogeneic responses are controlled. T-cell activation is finely regulated by multiple signaling molecules that are transcriptionally controlled by epigenetic mechanisms. Here we report that inhibiting DOT1L, a histone H3-lysine 79 methyltransferase, alleviates allogeneic T-cell responses. DOT1L inhibition reduces miR-181a expression, which in turn increases the ERK phosphatase DUSP6 expression and selectively ameliorates low avidity T-cell responses through globally suppressing T-cell activation-induced gene expression alterations. The inhibition of DOT1L or DUSP6 overexpression in T cells attenuates the development of graft-versus-host disease, while retaining potent antitumor activity in xenogeneic and allogeneic adoptive immunotherapy models. These results suggest that DOT1L inhibition may enable the safe and effective use of allogeneic antitumor T cells by suppressing unwanted immunological reactions in adoptive immunotherapy. PMID- 29765030 TI - Early Cambrian origin of the shelf sediment mixed layer. AB - The mixed layer of modern oceans is a zone of fully homogenized sediment resulting from bioturbation. The mixed layer is host to complex biogeochemical cycles that directly impact ecosystem functioning, affecting ocean productivity and marine biodiversity. The timing of origin of the mixed layer has been controversial, with estimates ranging from Cambrian to Silurian, hindering our understanding of biogeochemical cycling and ecosystem dynamics in deep time. Here we report evidence from the Global Stratotype Section and Point (GSSP) of the basal Cambrian in the Burin Peninsula of Newfoundland, Canada, showing that a well-developed mixed layer of similar structure to that of modern marine sediments was established in shallow marine settings by the early Cambrian (approximately 529 million years ago). These findings imply that the benthos significantly contributed to establishing new biogeochemical cycles during the Cambrian explosion. PMID- 29765031 TI - Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. AB - Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with "Huntington's Disease Signaling" identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets. PMID- 29765029 TI - The CRISPR tool kit for genome editing and beyond. AB - CRISPR is becoming an indispensable tool in biological research. Once known as the bacterial immune system against invading viruses, the programmable capacity of the Cas9 enzyme is now revolutionizing diverse fields of medical research, biotechnology, and agriculture. CRISPR-Cas9 is no longer just a gene-editing tool; the application areas of catalytically impaired inactive Cas9, including gene regulation, epigenetic editing, chromatin engineering, and imaging, now exceed the gene-editing functionality of WT Cas9. Here, we will present a brief history of gene-editing tools and describe the wide range of CRISPR-based genome targeting tools. We will conclude with future directions and the broader impact of CRISPR technologies. PMID- 29765032 TI - PCGF5 is required for neural differentiation of embryonic stem cells. AB - Polycomb repressive complex 1 (PRC1) is an important regulator of gene expression and development. PRC1 contains the E3 ligases RING1A/B, which monoubiquitinate lysine 119 at histone H2A (H2AK119ub1), and has been sub-classified into six major complexes based on the presence of a PCGF subunit. Here, we report that PCGF5, one of six PCGF paralogs, is an important requirement in the differentiation of mouse embryonic stem cells (mESCs) towards a neural cell fate. Although PCGF5 is not required for mESC self-renewal, its loss blocks mESC neural differentiation by activating the SMAD2/TGF-beta signaling pathway. PCGF5 loss-of function impairs the reduction of H2AK119ub1 and H3K27me3 around neural specific genes and keeps them repressed. Our results suggest that PCGF5 might function as both a repressor for SMAD2/TGF-beta signaling pathway and a facilitator for neural differentiation. Together, our findings reveal a critical context-specific function for PCGF5 in directing PRC1 to control cell fate. PMID- 29765033 TI - An epizootic of Chlamydia psittaci equine reproductive loss associated with suspected spillover from native Australian parrots. AB - Chlamydia psittaci is an avian pathogen capable of spill-over infections to humans. A parrot C. psittaci strain was recently detected in an equine reproductive loss case associated with a subsequent cluster of human C. psittaci infections. In this study, we screened for C. psittaci in cases of equine reproductive loss reported in regional New South Wales, Australia during the 2016 foaling season. C. psittaci specific-PCR screening of foetal and placental tissue samples from cases of equine abortion (n = 161) and foals with compromised health status (n = 38) revealed C. psittaci positivity of 21.1% and 23.7%, respectively. There was a statistically significant geographical clustering of cases ~170 km inland from the mid-coast of NSW (P < 0.001). Genomic analysis and molecular typing of C. psittaci positive samples from this study and the previous Australian equine index case revealed that the equine strains from different studs in regional NSW were clonal, while the phylogenetic analysis revealed that the C. psittaci strains from both Australian equine disease clusters belong to the parrot-associated 6BC clade, again indicative of spill-over of C. psittaci infections from native Australian parrots. The results of this work suggest that C. psittaci may be a more significant agent of equine reproductive loss than thought. A range of studies are now required to evaluate (a) the exact role that C. psittaci plays in equine reproductive loss; (b) the range of potential avian reservoirs and factors influencing infection spill-over; and PMID- 29765035 TI - Efficacy of a respiratory syncytial virus vaccine candidate in a maternal immunization model. AB - Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Maternal immunization is an option to increase maternal antibody levels and protect infants from infection. Here we assess the efficacy of virus-like particle (VLP) vaccine candidates containing stabilized pre-fusion (pre-F) or post-fusion (post-F) conformations of the RSV F protein and the attachment RSV G protein in a maternal immunization model using cotton rats. VLP vaccines containing RSV F and G proteins strongly boost pre-existing RSV immunity in dams preventing their perinatal drop in immunity. Boosting is stronger for the pre-F VLP than for the post-F VLP or purified subunit F protein vaccines, giving an advantage on mothers' protection. VLP immunization of dams provides significant protection to pups from RSV challenge and reduced pulmonary inflammation. Collectively, our results show that a VLP vaccine with RSV F and G proteins is safe and effective for maternal and adult vaccination. PMID- 29765034 TI - Solvent-assisted programming of flat polymer sheets into reconfigurable and self healing 3D structures. AB - It is extremely challenging, yet critically desirable to convert 2D plastic films into 3D structures without any assisting equipment. Taking the advantage of solvent-induced bond-exchange reaction and elastic-plastic transition, shape programming of flat vitrimer polymer sheets offers a new way to obtain 3D structures or topologies, which are hard for traditional molding to achieve. Here we show that such programming can be achieved with a pipette, a hair dryer, and a bottle of solvent. The polymer used here is very similar to the commercial epoxy, except that a small percentage of a specific catalyst is involved to facilitate the bond-exchange reaction. The programmed 3D structures can later be erased, reprogrammed, welded with others, and healed again and again, using the same solvent-assisted technique. The 3D structures can also be recycled by hot pressing into new sheets, which can still be repeatedly programmed. PMID- 29765036 TI - A CRISPRi screen in E. coli reveals sequence-specific toxicity of dCas9. AB - High-throughput CRISPR-Cas9 screens have recently emerged as powerful tools to decipher gene functions and genetic interactions. Here we use a genome-wide library of guide RNAs to direct the catalytically dead Cas9 (dCas9) to block gene transcription in Escherichia coli. Using a machine-learning approach, we reveal that guide RNAs sharing specific 5-nucleotide seed sequences can produce strong fitness defects or even kill E. coli regardless of the other 15 nucleotides of guide sequence. This effect occurs at high dCas9 concentrations and can be alleviated by tuning the expression of dCas9 while maintaining strong on-target repression. Our results also highlight the fact that off-targets with as little as nine nucleotides of homology to the guide RNA can strongly block gene expression. Altogether this study provides important design rules to safely use dCas9 in E. coli. PMID- 29765038 TI - Quantifying climate feedbacks in polar regions. AB - The concept of feedback is key in assessing whether a perturbation to a system is amplified or damped by mechanisms internal to the system. In polar regions, climate dynamics are controlled by both radiative and non-radiative interactions between the atmosphere, ocean, sea ice, ice sheets and land surfaces. Precisely quantifying polar feedbacks is required for a process-oriented evaluation of climate models, a clear understanding of the processes responsible for polar climate changes, and a reduction in uncertainty associated with model projections. This quantification can be performed using a simple and consistent approach that is valid for a wide range of feedbacks, offering the opportunity for more systematic feedback analyses and a better understanding of polar climate changes. PMID- 29765040 TI - Dynamics of a qubit while simultaneously monitoring its relaxation and dephasing. AB - Decoherence originates from the leakage of quantum information into external degrees of freedom. For a qubit, the two main decoherence channels are relaxation and dephasing. Here, we report an experiment on a superconducting qubit where we retrieve part of the lost information in both of these channels. We demonstrate that raw averaging the corresponding measurement records provides a full quantum tomography of the qubit state where all three components of the effective spin 1/2 are simultaneously measured. From single realizations of the experiment, it is possible to infer the quantum trajectories followed by the qubit state conditioned on relaxation and/or dephasing channels. The incompatibility between these quantum measurements of the qubit leads to observable consequences in the statistics of quantum states. The high level of controllability of superconducting circuits enables us to explore many regimes from the Zeno effect to underdamped Rabi oscillations depending on the relative strengths of driving, dephasing, and relaxation. PMID- 29765037 TI - Novel triple-reassortant influenza viruses in pigs, Guangxi, China. AB - Considered a "mixing vessel" for influenza viruses, pigs can give rise to new influenza virus reassortants that can threaten humans. During our surveillance of pigs in Guangxi, China from 2013 to 2015, we isolated 11 H1N1 and three H3N2 influenza A viruses of swine origin (IAVs-S). Out of the 14, we detected ten novel triple-reassortant viruses, which contained surface genes (hemagglutinin and neuraminidase) from Eurasian avian-like (EA) H1N1 or seasonal human-like H3N2, matrix (M) genes from H1N1/2009 pandemic or EA H1N1, nonstructural (NS) genes from classical swine, and the remaining genes from H1N1/2009 pandemic. Mouse studies indicate that these IAVs-S replicate efficiently without prior adaptation, with some isolates demonstrating lethality. Notably, the reassortant EA H1N1 viruses with EA-like M gene have been reported in human infections. Further investigations will help to assess the potential risk of these novel triple-reassortant viruses to humans. PMID- 29765041 TI - Nanographenes as electron-deficient cores of donor-acceptor systems. AB - Conjugation of nanographenes (NGs) with electro-active molecules can establish donor-acceptor pi-systems in which the former generally serve as the electron donating moieties due to their electronic-rich nature. In contrast, here we report a series of reversed donor-acceptor structures are obtained by C-N coupling of electron-deficient perchlorinated NGs with electron-rich anilines. Selective amination at the vertexes of the NGs is unambiguously shown through X ray crystallography. By varying the donating ability of the anilino groups, the optical and assembly properties of donor-acceptor NGs can be finely modulated. The electron-deficient concave core of the resulting conjugates can host electron rich guest molecules by intermolecular donor-acceptor interactions and gives rise to charge-transfer supramolecular architectures. PMID- 29765039 TI - STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. AB - Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/beta-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through beta catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal epithelial transition (MET) activity of etoposide, which suppresses the EMT/beta catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear beta-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy. PMID- 29765042 TI - Abnormal band bowing effects in phase instability crossover region of GaSe1-xTe x nanomaterials. AB - Akin to the enormous number of discoveries made through traditional semiconductor alloys, alloying selected 2D semiconductors enables engineering of their electronic structure for a wide range of new applications. 2D alloys have been demonstrated when two components crystallized in the same phase, and their bandgaps displayed predictable monotonic variation. By stabilizing previously unobserved compositions and phases of GaSe1-xTe x at nanoscales on GaAs(111), we demonstrate abnormal band bowing effects and phase instability region when components crystallize in different phases. Advanced microscopy and spectroscopy measurements show as tellurium is alloyed into GaSe, nanostructures undergo hexagonal to monoclinic and isotropic to anisotropic transition. There exists an instability region (0.56 < x < 0.67) where both phases compete and coexist, and two different bandgap values can be found at the same composition leading to anomalous band bowing effects. Results highlight unique alloying effects, not existing in single-phase alloys, and phase engineering routes for potential applications in photonic and electronics. PMID- 29765043 TI - Programmable sequential mutagenesis by inducible Cpf1 crRNA array inversion. AB - Mutations and genetic alterations are often sequentially acquired in various biological and pathological processes, such as development, evolution, and cancer. Certain phenotypes only manifest with precise temporal sequences of genetic events. While multiple approaches have been developed to model the effects of mutations in tumorigenesis, few recapitulate the stepwise nature of cancer evolution. Here we describe a flexible sequential mutagenesis system, Cpf1 Flip, with inducible inversion of a single crRNA array (FlipArray), and demonstrate its application in stepwise mutagenesis in murine and human cells. As a proof-of-concept, we further utilize Cpf1-Flip in a pooled-library approach to model the acquisition of diverse resistance mutations to cancer immunotherapy. Cpf1-Flip offers a simple, versatile, and controlled approach for precise mutagenesis of multiple loci in a sequential manner. PMID- 29765044 TI - Ambipolar ferromagnetism by electrostatic doping of a manganite. AB - Complex-oxide materials exhibit physical properties that involve the interplay of charge and spin degrees of freedom. However, an ambipolar oxide that is able to exhibit both electron-doped and hole-doped ferromagnetism in the same material has proved elusive. Here we report ambipolar ferromagnetism in LaMnO3, with electron-hole asymmetry of the ferromagnetic order. Starting from an undoped atomically thin LaMnO3 film, we electrostatically dope the material with electrons or holes according to the polarity of a voltage applied across an ionic liquid gate. Magnetotransport characterization reveals that an increase of either electron-doping or hole-doping induced ferromagnetic order in this antiferromagnetic compound, and leads to an insulator-to-metal transition with colossal magnetoresistance showing electron-hole asymmetry. These findings are supported by density functional theory calculations, showing that strengthening of the inter-plane ferromagnetic exchange interaction is the origin of the ambipolar ferromagnetism. The result raises the prospect of exploiting ambipolar magnetic functionality in strongly correlated electron systems. PMID- 29765045 TI - Hybrid nanostructured particles via surfactant-free double miniemulsion polymerization. AB - Double emulsions are complex fluid systems, in which droplets of a dispersed liquid phase contain even smaller dispersed liquid droplets. Particularly, water in-oil-in-water double emulsions provide significant advantages over simple oil in-water emulsions for microencapsulation, such as carrier of both aqueous and oily payloads and sustained release profile. However, double emulsions are thermodynamically unstable systems consisting typically of relatively large droplets. Here we show that nanoscale water-in-oil-in-water double emulsions can be prepared by adding a silica precursor polymer, hyperbranched polyethoxysiloxane, to the oil phase without any additional surfactants. The resulting double miniemulsions are transformed to robust water@SiO2@polymer@SiO2 nanocapsules via conversion of the precursor to silica and polymerization of the oil phase. Other intriguing nanostructures like nanorattles and Janus-like nanomushrooms can also be obtained by changing preparation conditions. This simple surfactant-free double miniemulsion polymerization technique opens a promising avenue for mass production of various complex hybrid nanostructures that are amenable to numerous applications. PMID- 29765046 TI - Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer. AB - The principle factors underlying gastric cancer (GC) development and outcomes are not well characterized resulting in a paucity of validated therapeutic targets. To identify potential molecular targets, we analyze gene expression data from GC patients and identify the nuclear receptor ESRRG as a candidate tumor suppressor. ESRRG expression is decreased in GC and is a predictor of a poor clinical outcome. Importantly, ESRRG suppresses GC cell growth and tumorigenesis. Gene expression profiling suggests that ESRRG antagonizes Wnt signaling via the suppression of TCF4/LEF1 binding to the CCND1 promoter. Indeed, ESRRG levels are found to be inversely correlated with Wnt signaling-associated genes in GC patients. Strikingly, the ESRRG agonist DY131 suppresses cancer growth and represses the expression of Wnt signaling genes. Our present findings thus demonstrate that ESRRG functions as a negative regulator of the Wnt signaling pathway in GC and is a potential therapeutic target for this cancer. PMID- 29765047 TI - Tip60-mediated lipin 1 acetylation and ER translocation determine triacylglycerol synthesis rate. AB - Obesity is characterized by excessive fatty acid conversion to triacylglycerols (TAGs) in adipose tissues. However, how signaling networks sense fatty acids and connect to the stimulation of lipid synthesis remains elusive. Here, we show that homozygous knock-in mice carrying a point mutation at the Ser86 phosphorylation site of acetyltransferase Tip60 (Tip60 SA/SA ) display remarkably reduced body fat mass, and Tip60 SA/SA females fail to nurture pups to adulthood due to severely reduced milk TAGs. Mechanistically, fatty acids stimulate Tip60 dependent acetylation and endoplasmic reticulum translocation of phosphatidic acid phosphatase lipin 1 to generate diacylglycerol for TAG synthesis, which is repressed by deacetylase Sirt1. Inhibition of Tip60 activity strongly blocks fatty acid-induced TAG synthesis while Sirt1 suppression leads to increased adiposity. Genetic analysis of loss-of-function mutants in Saccharomyces cerevisiae reveals a requirement of ESA1, yeast ortholog of Tip60, in TAG accumulation. These findings uncover a conserved mechanism linking fatty acid sensing to fat synthesis. PMID- 29765050 TI - Ratchet-free solid-state inertial rotation of a guest ball in a tight tubular host. AB - Dynamics of molecules in the solid state holds promise for connecting molecular behaviors with properties of bulk materials. Solid-state dynamics of [60]fullerene (C60) is controlled by intimate intermolecular contacts and results in restricted motions of a ratchet phase at low temperatures. Manipulation of the solid-state dynamics of fullerene molecules is thus an interesting yet challenging problem. Here we show that a tubular host for C60 liberates the solid state dynamics of the guest from the motional restrictions. Although the intermolecular contacts between the host and C60 were present to enable a tight association with a large energy gain of -14 kcal mol-1, the dynamic rotations of C60 were simultaneously enabled by a small energy barrier of +2 kcal mol-1 for the reorientation. The solid-state rotational motions reached a non-Brownian, inertial regime with an extremely rapid rotational frequency of 213 GHz at 335 K. PMID- 29765048 TI - Sensible heat has significantly affected the global hydrological cycle over the historical period. AB - Globally, latent heating associated with a change in precipitation is balanced by changes to atmospheric radiative cooling and sensible heat fluxes. Both components can be altered by climate forcing mechanisms and through climate feedbacks, but the impacts of climate forcing and feedbacks on sensible heat fluxes have received much less attention. Here we show, using a range of climate modelling results, that changes in sensible heat are the dominant contributor to the present global-mean precipitation change since preindustrial time, because the radiative impact of forcings and feedbacks approximately compensate. The model results show a dissimilar influence on sensible heat and precipitation from various drivers of climate change. Due to its strong atmospheric absorption, black carbon is found to influence the sensible heat very differently compared to other aerosols and greenhouse gases. Our results indicate that this is likely caused by differences in the impact on the lower tropospheric stability. PMID- 29765049 TI - Emergent superconductivity in an iron-based honeycomb lattice initiated by pressure-driven spin-crossover. AB - The discovery of iron-based superconductors (FeSCs), with the highest transition temperature (Tc) up to 55 K, has attracted worldwide research efforts over the past ten years. So far, all these FeSCs structurally adopt FeSe-type layers with a square iron lattice and superconductivity can be generated by either chemical doping or external pressure. Herein, we report the observation of superconductivity in an iron-based honeycomb lattice via pressure-driven spin crossover. Under compression, the layered FePX3 (X = S, Se) simultaneously undergo large in-plane lattice collapses, abrupt spin-crossovers, and insulator metal transitions. Superconductivity emerges in FePSe3 along with the structural transition and vanishing of magnetic moment with a starting Tc ~ 2.5 K at 9.0 GPa and the maximum Tc ~ 5.5 K around 30 GPa. The discovery of superconductivity in iron-based honeycomb lattice provides a demonstration for the pursuit of transition-metal-based superconductors via pressure-driven spin-crossover. PMID- 29765051 TI - Concurrent and orthogonal gold(I) and ruthenium(II) catalysis inside living cells. AB - The viability of building artificial metabolic pathways within a cell will depend on our ability to design biocompatible and orthogonal catalysts capable of achieving non-natural transformations. In this context, transition metal complexes offer unique possibilities to develop catalytic reactions that do not occur in nature. However, translating the potential of metal catalysts to living cells poses numerous challenges associated to their biocompatibility, and their stability and reactivity in crowded aqueous environments. Here we report a gold mediated C-C bond formation that occurs in complex aqueous habitats, and demonstrate that the reaction can be translated to living mammalian cells. Key to the success of the process is the use of designed, water-activatable gold chloride complexes. Moreover, we demonstrate the viability of achieving the gold promoted process in parallel with a ruthenium-mediated reaction, inside living cells, and in a bioorthogonal and mutually orthogonal manner. PMID- 29765053 TI - Ambient ammonia synthesis via palladium-catalyzed electrohydrogenation of dinitrogen at low overpotential. AB - Electrochemical reduction of N2 to NH3 provides an alternative to the Haber-Bosch process for sustainable, distributed production of NH3 when powered by renewable electricity. However, the development of such process has been impeded by the lack of efficient electrocatalysts for N2 reduction. Here we report efficient electroreduction of N2 to NH3 on palladium nanoparticles in phosphate buffer solution under ambient conditions, which exhibits high activity and selectivity with an NH3 yield rate of ~4.5 MUg mg-1Pd h-1 and a Faradaic efficiency of 8.2% at 0.1 V vs. the reversible hydrogen electrode (corresponding to a low overpotential of 56 mV), outperforming other catalysts including gold and platinum. Density functional theory calculations suggest that the unique activity of palladium originates from its balanced hydrogen evolution activity and the Grotthuss-like hydride transfer mechanism on alpha-palladium hydride that lowers the free energy barrier of N2 hydrogenation to *N2H, the rate-limiting step for NH3 electrosynthesis. PMID- 29765054 TI - Resolution of superluminal signalling in non-perturbative cavity quantum electrodynamics. AB - Recent technological developments have made it increasingly easy to access the non-perturbative regimes of cavity quantum electrodynamics known as ultrastrong or deep strong coupling, where the light-matter coupling becomes comparable to the bare modal frequencies. In this work, we address the adequacy of the broadly used single-mode cavity approximation to describe such regimes. We demonstrate that, in the non-perturbative light-matter coupling regimes, the single-mode models become unphysical, allowing for superluminal signalling. Moreover, considering the specific example of the quantum Rabi model, we show that the multi-mode description of the electromagnetic field, necessary to account for light propagation at finite speed, yields physical observables that differ radically from their single-mode counterparts already for moderate values of the coupling. Our multi-mode analysis also reveals phenomena of fundamental interest on the dynamics of the intracavity electric field, where a free photonic wavefront and a bound state of virtual photons are shown to coexist. PMID- 29765055 TI - Stable isotopes in water vapor and rainwater over Indian sector of Southern Ocean and estimation of fraction of recycled moisture. AB - Stable Hydrogen and Oxygen isotopic composition of water vapor, rainwater and surface seawater show a distinct trend across the latitude over the Southern Indian Ocean. Our observations on isotopic composition of surface seawater, water vapor and rainwater across a transect covering the tropical Indian Ocean to the regions of the Southern Ocean showed a strong latitudinal dependency; characterized by the zonal process of evaporation and precipitation. The sampling points were spread across diverse zones of SST, wind speed and rainfall regimes. The observed physical parameters such as sea surface temperature, wind speed and relative humidity over the oceanic regions were used in a box model calculation across the latitudes to predict the isotopic composition of water vapor under equilibrium and kinetic conditions, and compared with results from isotope enabled global spectral model. Further, we obtained the average fraction of recycled moisture across the oceanic transect latitudes as 13.4 +/- 7.7%. The values of recycled fraction were maximum at the vicinity of the Inter Tropical Convergence Zone (ITCZ), while the minimum values were recorded over the region of subsidence and evaporation, at the Northern and Southern latitudes of the ITCZ. These estimates are consistent with the earlier reported recyling values. PMID- 29765052 TI - Coherent X-rays reveal the influence of cage effects on ultrafast water dynamics. AB - The dynamics of liquid water feature a variety of time scales, ranging from extremely fast ballistic-like thermal motion, to slower molecular diffusion and hydrogen-bond rearrangements. Here, we utilize coherent X-ray pulses to investigate the sub-100 fs equilibrium dynamics of water from ambient conditions down to supercooled temperatures. This novel approach utilizes the inherent capability of X-ray speckle visibility spectroscopy to measure equilibrium intermolecular dynamics with lengthscale selectivity, by measuring oxygen motion in momentum space. The observed decay of the speckle contrast at the first diffraction peak, which reflects tetrahedral coordination, is attributed to motion on a molecular scale within the first 120 fs. Through comparison with molecular dynamics simulations, we conclude that the slowing down upon cooling from 328 K down to 253 K is not due to simple thermal ballistic-like motion, but that cage effects play an important role even on timescales over 25 fs due to hydrogen-bonding. PMID- 29765056 TI - Anatomy of a fumarolic system inferred from a multiphysics approach. AB - Fumaroles are a common manifestation of volcanic activity that are associated with large emissions of gases into the atmosphere. These gases originate from the magma, and they can provide indirect and unique insights into magmatic processes. Therefore, they are extensively used to monitor and forecast eruptive activity. During their ascent, the magmatic gases interact with the rock and hydrothermal fluids, which modify their geochemical compositions. These interactions can complicate our understanding of the real volcanic dynamics and remain poorly considered. Here, we present the first complete imagery of a fumarolic plumbing system using three-dimensional electrical resistivity tomography and new acoustic noise localization. We delineate a gas reservoir that feeds the fumaroles through distinct channels. Based on this geometry, a thermodynamic model reveals that near-surface mixing between gas and condensed steam explains the distinct geochemical compositions of fumaroles that originate from the same source. Such modeling of fluid interactions will allow for the simulation of dynamic processes of magmatic degassing, which is crucial to the monitoring of volcanic unrest. PMID- 29765058 TI - Linguistic measures of chemical diversity and the "keywords" of molecular collections. AB - Computerized linguistic analyses have proven of immense value in comparing and searching through large text collections ("corpora"), including those deposited on the Internet - indeed, it would nowadays be hard to imagine browsing the Web without, for instance, search algorithms extracting most appropriate keywords from documents. This paper describes how such corpus-linguistic concepts can be extended to chemistry based on characteristic "chemical words" that span more than traditional functional groups and, instead, look at common structural fragments molecules share. Using these words, it is possible to quantify the diversity of chemical collections/databases in new ways and to define molecular "keywords" by which such collections are best characterized and annotated. PMID- 29765057 TI - Critical amino acids for the insecticidal activity of Vip3Af from Bacillus thuringiensis: Inference on structural aspects. AB - Vip3 vegetative insecticidal proteins from Bacillus thuringiensis are an important tool for crop protection against caterpillar pests in IPM strategies. While there is wide consensus on their general mode of action, the details of their mode of action are not completely elucidated and their structure remains unknown. In this work the alanine scanning technique was performed on 558 out of the total of 788 amino acids of the Vip3Af1 protein. From the 558 residue substitutions, 19 impaired protein expression and other 19 substitutions severely compromised the insecticidal activity against Spodoptera frugiperda. The latter 19 substitutions mainly clustered in two regions of the protein sequence (amino acids 167-272 and amino acids 689-741). Most of these substitutions also decreased the activity to Agrotis segetum. The characterisation of the sensitivity to proteases of the mutant proteins displaying decreased insecticidal activity revealed 6 different band patterns as evaluated by SDS-PAGE. The study of the intrinsic fluorescence of most selected mutants revealed only slight shifts in the emission peak, likely indicating only minor changes in the tertiary structure. An in silico modelled 3D structure of Vip3Af1 is proposed for the first time. PMID- 29765059 TI - Postnatal Microstructural Developmental Trajectory of Corpus Callosum Subregions and Relationship to Clinical Factors in Very Preterm Infants. AB - Our objectives were to define the microstructural developmental trajectory of six corpus callosum subregions and identify perinatal clinical factors that influence early development of these subregions in very preterm infants. We performed a longitudinal cohort study of very preterm infants (32 weeks gestational age or younger) (N = 36) who underwent structural MRI and diffusion tensor imaging serially at four time points - before 32, 32, 38, and 52 weeks postmenstrual age. We divided the corpus callosum into six subregions, performed probabilistic tractography, and used linear mixed effects models to evaluate the influence of antecedent clinical factors on its microstructural growth trajectory. The genu and splenium demonstrated the most rapid developmental maturation, exhibited by a steep increase in fractional anisotropy. We identified several factors that favored greater corpus callosum microstructural development, including advancing postmenstrual age, higher birth weight, and college level or higher maternal education. Bronchopulmonary dysplasia, low 5-minute Apgar scores, caffeine therapy/apnea of prematurity and male sex were associated with reduced corpus callosum microstructural integrity/development over the first six months after very preterm birth. We identified a unique postnatal microstructural growth trajectory and associated clinical factor profile for each of the six corpus callosum subregions that is consistent with the heterogeneous functional role of these white matter subregions. PMID- 29765061 TI - Chemical and structural analysis on magnetic tunnel junctions using a decelerated scanning electron beam. AB - Current information technology relies on the advancement of nanofabrication techniques. For instance, the latest computer memories and hard disk drive read heads are designed with a 12 nm node and 20 nm wide architectures, respectively. With matured nanofabrication processes, a yield of such nanoelectronic devices is typically up to about 90%. To date the yield has been compensated with redundant hardware and software error corrections. In the latest memories, approximately 5% redundancy and parity bits for error corrections are used, which increase the total production cost of the devices. This means the yield directly affects the device costs. It is hence critical to increase the yield in nanofabrication. In this paper, we have applied our recently developed method to image buried interfaces in combination with chemical analysis to evaluate magnetic tunnel junctions and have revealed their different magnetoresistance ratios caused by the presence of materials formed at the junction edges. The formation of these materials can be avoided by optimising the junction patterning process to remove residual carbon introduced from resist. Our imaging method with chemical analysis have demonstrated a significant potential for the improvement of junction performance, resulting in higher yields. This can be used as a quality assurance tool in a nanoelectronic device production line. PMID- 29765060 TI - Iron-specific Signal Separation from within Heavy Metal Stained Biological Samples Using X-Ray Microtomography with Polychromatic Source and Energy Integrating Detectors. AB - Biological samples are frequently stained with heavy metals in preparation for examining the macro, micro and ultra-structure using X-ray microtomography and electron microscopy. A single X-ray microtomography scan reveals detailed 3D structure based on staining density, yet it lacks both material composition and functional information. Using a commercially available polychromatic X-ray source, energy integrating detectors and a two-scan configuration labelled by their energy- "High" and "Low", we demonstrate how a specific element, here shown with iron, can be detected from a mixture with other heavy metals. With proper selection of scan configuration, achieving strong overlap of source characteristic emission lines and iron K-edge absorption, iron absorption was enhanced enabling K-edge imaging. Specifically, iron images were obtained by scatter plot material analysis, after selecting specific regions within scatter plots generated from the "High" and "Low" scans. Using this method, we identified iron rich regions associated with an iron staining reaction that marks the nodes of Ranvier along nerve axons within mouse spinal roots, also stained with osmium metal commonly used for electron microscopy. PMID- 29765062 TI - Publisher Correction: Chitosan nanoparticles functionalized with beta cyclodextrin: a promising carrier for botanical pesticides. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29765063 TI - Long non-coding RNA expression patterns in lung tissues of chronic cigarette smoke induced COPD mouse model. AB - Long non-coding RNAs (lncRNAs) have critical regulatory roles in protein-coding gene expression. Aberrant expression profiles of lncRNAs have been observed in various human diseases. In this study, we investigated transcriptome profiles in lung tissues of chronic cigarette smoke (CS)-induced COPD mouse model. We found that 109 lncRNAs and 260 mRNAs were significantly differential expressed in lungs of chronic CS-induced COPD mouse model compared with control animals. GO and KEGG analyses indicated that differentially expressed lncRNAs associated protein coding genes were mainly involved in protein processing of endoplasmic reticulum pathway, and taurine and hypotaurine metabolism pathway. The combination of high throughput data analysis and the results of qRT-PCR validation in lungs of chronic CS-induced COPD mouse model, 16HBE cells with CSE treatment and PBMC from patients with COPD revealed that NR_102714 and its associated protein-coding gene UCHL1 might be involved in the development of COPD both in mouse and human. In conclusion, our study demonstrated that aberrant expression profiles of lncRNAs and mRNAs existed in lungs of chronic CS-induced COPD mouse model. From animal models perspective, these results might provide further clues to investigate biological functions of lncRNAs and their potential target protein-coding genes in the pathogenesis of COPD. PMID- 29765064 TI - Non-alcoholic fatty liver disease incidence, remission and risk factors among a general Chinese population with a 6-year follow-up. AB - This study aimed to investigate the incidence, remission and risk factors of non alcoholic fatty liver disease (NAFLD) among a general population with a 6-year follow-up. In total, 691 individuals from the general population in Jilin, China aged 20-75 years participated in two independent cross-sectional surveys carried out in 2007 and 2013. After excluding patients with alcoholism, viral hepatitis and other liver diseases, 646 individuals were finally enrolled in our study. Of the 646 subjects, 512 did not have NAFLD at baseline, while 134 did. Of the 512 individuals without NAFLD at baseline, 188 (36.7%) developed NAFLD during the six year follow-up period. The baseline body mass index (BMI, OR = 1.49, 1.36-1.64), high-density lipoprotein cholesterol level(HDL-C) (OR = 0.35, 0.16-0.76) and weight gain (OR = 1.22, 1.16-1.29) were independent predictors for NAFLD incidence. Of the 134 subjects with NAFLD at baseline, 33 (24.6%) had no evidence of NAFLD after 6 years. Males (OR = 4.85, 1.98-11.92) and baseline BMI levels (OR = 0.81, 0.70-0.94) were associated with NAFLD remission. Among the general population, the incidence of NAFLD mainly depended on baseline weight and weight gain. Subjects with mild baseline weights and male subjects were prone to NAFLD remission. PMID- 29765065 TI - The Fate of Lipid Biosignatures in a Mars-Analogue Sulfur Stream. AB - Past life on Mars will have generated organic remains that may be preserved in present day Mars rocks. The most recent period in the history of Mars that retained widespread surface waters was the late Noachian and early Hesperian and thus possessed the potential to sustain the most evolved and widely distributed martian life. Guidance for investigating late Noachian and early Hesperian rocks is provided by studies of analogous acidic and sulfur-rich environments on Earth. Here we report organic responses for an acid stream containing acidophilic organisms whose post-mortem remains are entombed in iron sulphates and iron oxides. We find that, if life was present in the Hesperian, martian organic records will comprise microbial lipids. Lipids are a potential sizeable reservoir of fossil carbon on Mars, and can be used to distinguish between different domains of life. Concentrations of lipids, and particularly alkanoic or "fatty" acids, are highest in goethite layers that reflect high water-to-rock ratios and thus a greater potential for habitability. Goethite can dehydrate to hematite, which is widespread on Mars. Mars missions should seek to detect fatty acids or their diagenetic products in the oxides and hydroxides of iron associated with sulphur-rich environments. PMID- 29765066 TI - Loss of CENP-F Results in Dilated Cardiomyopathy with Severe Disruption of Cardiac Myocyte Architecture. AB - Centromere-binding protein F (CENP-F) is a very large and complex protein with many and varied binding partners including components of the microtubule network. Numerous CENP-F functions impacting diverse cellular behaviors have been identified. Importantly, emerging data have shown that CENP-F loss- or gain-of function has critical effects on human development and disease. Still, it must be noted that data at the single cardiac myocyte level examining the impact of CENP F loss-of-function on fundamental cellular behavior is missing. To address this gap in our knowledge, we analyzed basic cell structure and function in cardiac myocytes devoid of CENP-F. We found many diverse structural abnormalities including disruption of the microtubule network impacting critical characteristics of the cardiac myocyte. This is the first report linking microtubule network malfunction to cardiomyopathy. Importantly, we also present data demonstrating a direct link between a CENP-F single nucleotide polymorphism (snp) and human cardiac disease. In a proximate sense, these data examining CENP F function explain the cellular basis underlying heart disease in this genetic model and, in a larger sense, they will hopefully provide a platform upon which the field can explore diverse cellular outcomes in wide-ranging areas of research on this critical protein. PMID- 29765067 TI - Wildfire smoke impacts activity and energetics of wild Bornean orangutans. AB - Indonesia's peatlands experience frequent and intense wildfires, producing hazardous smoke with consequences for human health, yet there is a lack of research into adverse effects on wildlife. We evaluated the effects of smoke on the activity and energy balance of Bornean orangutans (Pongo pygmaeus wurmbii) in a peat swamp forest at the Tuanan Research Station, Central Kalimantan. We collected behavioural data and urine samples from four adult flanged males before, during, and after wildfires between March 2015 and January 2016. During fires, particulate matter (PM10) concentrations were hazardous. Orangutans increased rest time during and after the smoke period, and decreased travel time and distance and increased fat catabolism post-smoke. The increase in post-smoke ketones was not related to changes in caloric intake and was likely due to an increase in energy expenditure, possibly related to immune response. Results show that wildfire smoke negatively affects orangutan condition, and sustained research is needed to assess the magnitude of the threat to the long-term viability of this Critically Endangered species. PMID- 29765070 TI - Ecosystem functions including soil organic carbon, total nitrogen and available potassium are crucial for vegetation recovery. AB - The effects of biodiversity on ecosystem functions have been extensively studied, but little is known about the effects of ecosystem functions on biodiversity. This knowledge is important for understanding biodiversity-ecosystem functioning relationships. Desertification reversal is a significant global challenge, but the factors that play key roles in this process remain unclear. Here, using data sampled from areas undergoing desertification reversal, we identify the dominant soil factors that play a role in vegetation recovery with ordinary least squares and structural equation modelling. We found that ecosystem functions related to the cycling of soil carbon (organic C, SOC), nitrogen (total N, TN), and potassium (available K, AK) had the most substantial effects on vegetation recovery. The effects of these ecosystem functions were simultaneously influenced by the soil clay, silt and coarse sand fractions and the soil water content. Our findings suggest that K plays a critical role in ecosystem functioning and is a limiting factor in desertification reversal. Our results provide a scientific basis for desertification reversal. Specifically, we found that plant biodiversity may be regulated by N, phosphorus (P) and K cycling. Collectively, biodiversity may respond to ecosystem functions, the conservation and enhancement of which can promote the recovery of vegetation. PMID- 29765068 TI - Linking cervicovaginal immune signatures, HPV and microbiota composition in cervical carcinogenesis in non-Hispanic and Hispanic women. AB - While high-risk human papillomavirus (HPV) infection is a well-established risk factor for cervical cancer, there are likely other factors within the local microenvironment that contribute to cervical carcinogenesis. Here we investigated relationships between HPV, vaginal pH, vaginal microbiota (VMB) composition, level of genital immune mediators and severity of cervical neoplasm. We enrolled women with low- and high-grade cervical dysplasia (LGD, HGD), invasive cervical carcinoma (ICC), and healthy controls. HPV16, HPV45, HPV58, and HPV31 were the most prevalent in our cohort with HPV16 and HPV31 genotypes more prevalent in Hispanics. Vaginal pH was associated with ethnicity and severity of cervical neoplasm. Lactobacillus dominance decreased with the severity of cervical neoplasm, which correlated with elevated vaginal pH. Hispanic ethnicity was also associated with decreased Lactobacillus dominance. Furthermore, Sneathia was enriched in all precancerous groups, ICC, abnormal pH and Hispanic origin. Patients with ICC, but not LGD and HGD, exhibited increased genital inflammatory scores and elevated specific immune mediators. Notably, IL-36gamma was significantly associated with ICC. Our study revealed local, host immune and microbial signatures associated with cervical carcinogenesis and provides an initial step to understanding the complex interplay between mucosal inflammation, HPV persistence and the VMB. PMID- 29765069 TI - De novo characterization of Phenacoccus solenopsis transcriptome and analysis of gene expression profiling during development and hormone biosynthesis. AB - The cotton mealybug Phenacoccus solenopsis is a devastating pest of cotton causing tremendous loss in the yield of crops each year. Widespread physiological and biological studies on P. solenopsis have been carried out, but the lack of genetic information has constrained our understanding of the molecular mechanisms behind its growth and development. To understand and characterize the different developmental stages, RNA-Seq platform was used to execute de-novo transcriptome assembly and differential gene expression profiling for the eggs, first, second, third instar and adult female stages. About 182.67 million reads were assembled into 93,781 unigenes with an average length of 871.4 bp and an N50 length of 1899 bp. These unigenes sequences were annotated and classified by performing NCBI non redundant (Nr) database, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Clusters of Orthologous Groups (COG), Gene ontology (GO), the Swiss-Prot protein database (Swiss-Prot), and nearest related organism Acyrthosiphon pisum (pea aphid) database. To get more information regarding the process of metamorphosis, we performed a pairwise comparison of four developmental stages and obtained 29,415 differentially expressed genes. Some of the differentially expressed genes were associated with functional protein synthesis, anti-microbial protection, development and hormone biosynthesis. Functional pathway enrichment analysis of differentially expressed genes showed the positive correlation with specific physiological activities of each stage, and these results were confirmed by qRT PCR experiments. This study gives a valuable genomics resource of P. solenopsis covering all its developmental stages and will promote future studies on biological processes at the molecular level. PMID- 29765071 TI - Effects of cold acclimation and dsRNA injections on Gs1l gene splicing in Drosophila montana. AB - Alternative splicing, in which one gene produce multiple transcripts, may influence how adaptive genes respond to specific environments. A newly produced transcriptome of Drosophila montana shows the Gs1-like (Gs1l) gene to express multiple splice variants and to be down regulated in cold acclimated flies with increased cold tolerance. Gs1l's effect on cold tolerance was further tested by injecting cold acclimated and non-acclimated flies from two distantly located northern and southern fly populations with double stranded RNA (dsRNA) targeting Gs1l. While both populations had similar cold acclimation responses, dsRNA injections only effected the northern population. The nature of splicing expression was then investigated in the northern population by confirming which Gs1l variants are present, by comparing the expression of different gene regions and by predicting the protein structures of splices using homology modelling. We find different splices of Gs1l not only appear to have independent impacts on cold acclimation but also elicit different effects in populations originating from two very different environments. Also, at the protein level, Gs1l appears homologous to the human HDHD1A protein and some splices might produce functionally different proteins though this needs to be verified in future studies by measuring the particular protein levels. Taken together, Gs1l appears to be an interesting new candidate to test how splicing influences adaptations. PMID- 29765072 TI - Notoginsenoside R1 inhibits vascular smooth muscle cell proliferation, migration and neointimal hyperplasia through PI3K/Akt signaling. AB - Restenosis caused by neointimal hyperplasia significantly decreases long-term efficacy of percutaneous transluminal angioplasty (PTA), stenting, and by-pass surgery for managing coronary and peripheral arterial diseases. A major cause of pathological neointima formation is abnormal vascular smooth muscle cell (VSMC) proliferation and migration. Notoginsenoside R1 (NGR1) is a novel saponin that is derived from Panax notoginseng and has reported cardioprotective, neuroprotective and anti-inflammatory effects. However, its role in modulating VSMC neointima formation remains unexplored. Herein, we report that NGR1 inhibits serum-induced VSMC proliferation and migration by regulating VSMC actin cytoskeleton dynamics. Using a mouse femoral artery endothelium denudation model, we further demonstrate that systemic administration of NGR1 had a potent therapeutic effect in mice, significantly reducing neointimal hyperplasia following acute vessel injury. Mechanistically, we show that NGR1's mode of action is through inhibiting the activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling. Taken together, this study identified NGR1 as a potential therapeutic agent for combating restenosis after PTA in cardiovascular diseases. PMID- 29765075 TI - Possible causes of data model discrepancy in the temperature history of the last Millennium. AB - Model simulations and proxy-based reconstructions are the main tools for quantifying pre-instrumental climate variations. For some metrics such as Northern Hemisphere mean temperatures, there is remarkable agreement between models and reconstructions. For other diagnostics, such as the regional response to volcanic eruptions, or hemispheric temperature differences, substantial disagreements between data and models have been reported. Here, we assess the potential sources of these discrepancies by comparing 1000-year hemispheric temperature reconstructions based on real-world paleoclimate proxies with climate model-based pseudoproxies. These pseudoproxy experiments (PPE) indicate that noise inherent in proxy records and the unequal spatial distribution of proxy data are the key factors in explaining the data-model differences. For example, lower inter-hemispheric correlations in reconstructions can be fully accounted for by these factors in the PPE. Noise and data sampling also partly explain the reduced amplitude of the response to external forcing in reconstructions compared to models. For other metrics, such as inter-hemispheric differences, some, although reduced, discrepancy remains. Our results suggest that improving proxy data quality and spatial coverage is the key factor to increase the quality of future climate reconstructions, while the total number of proxy records and reconstruction methodology play a smaller role. PMID- 29765074 TI - Two-fluid, hydrodynamic model for spherical electrolyte systems. AB - Spatial interaction effects between charge carriers in ionic systems play a sizable role beyond a classical Maxwellian description. We develop a nonlocal, two-fluid, hydrodynamic theory of charges and study ionic plasmon effects, i.e. collective charge oscillations in electrolytes. Ionic spatial dispersion arises from both positive and negative charge dynamics with an impact in the (far )infrared. Despite highly classical parameters, nonlocal quenching of up to 90% is observed for particle sizes spanning orders of magnitude. Notably, the ionic system is widely tunable via ion concentration, mass and charge, in contrast to solid metal nanoparticles. A nonlocal soft plasmonic theory for ions is relevant for biological and chemical systems bridging hard and soft matter theory and allowing the investigation of non-classical effects in electrolytes in full analogy to solid metal particles. The presented semi-classical approach allows studying plasmonic photo-catalysis introducing nonlocal aspects into electrolyte metal interactions. PMID- 29765073 TI - Oncotically Driven Control over Glycocalyx Dimension for Cell Surface Engineering and Protein Binding in the Longitudinal Direction. AB - Here we present a simple technique for re-directing reactions on the cell surface to the outermost region of the glycocalyx. Macromolecular crowding with inert polymers was utilized to reversibly alter the accessibility of glycocalyx proteoglycans toward cell-surface reactive probes allowing for reactivity control in the longitudinal direction ('z'-direction) on the glycocalyx. Studies in HUVECs demonstrated an oncotically driven collapse of the glycocalyx brush structure in the presence of crowders as the mechanism responsible for re directing reactivity. This phenomenon is consistent across a variety of macromolecular agents including polymers, protein markers and antibodies which all displayed enhanced binding to the outermost surface of multiple cell types. We then demonstrated the biological significance of the technique by increasing the camouflage of red blood cell surface antigens via a crowding-enhanced attachment of voluminous polymers to the exterior of the glycocalyx. The accessibility to Rhesus D (RhD) and CD47 proteins on the cell surface was significantly decreased in crowding-assisted polymer grafting in comparison to non-crowded conditions. This strategy is expected to generate new tools for controlled glycocalyx engineering, probing the glycocalyx structure and function, and improving the development of cell based therapies. PMID- 29765076 TI - Resveratrol significantly improves the fertilisation capacity of bovine sex sorted semen by inhibiting apoptosis and lipid peroxidation. AB - The aim of this study was to test the effects of five different concentrations (0, 10-3, 10-4, 10-5, and 10-6 M) of resveratrol (Res) supplementation in bull sperm washing and fertilisation medium on levels of reactive oxygen species (ROS), phosphatidylserine (PS) externalisation, mitochondrial membrane potential (Deltapsim), ATP and malondialdehyde (MDA), acrosomal integrity, blastocyst rate, and blastocyst quality after in vitro fertilisation (IVF). The results for sex sorted sperm from three bulls showed: (1) ROS and MDA levels in 10-3 M and 10-4 M Res groups were significantly lower than those of controls (P < 0.05); (2) the percentage of viable sperm, percentage of sperm with high Deltapsim, and the ATP content in 10-3 M and 10-4 M Res groups were significantly higher than those of controls (P < 0.05); (3) the percentage of viable sperm with acrosomal integrity, and the blastocyst percentage and quality of the 10-4 M Res group were significantly higher than those of controls (P < 0.05). In conclusion, 10-4 M Res supplementation in washing and fertilisation medium of sex-sorted bull sperm significantly decreased ROS, PS externalisation, and MDA, and protected mitochondrial function and acrosomal integrity, thereby increasing blastocyst percentage and quality following IVF. PMID- 29765077 TI - Homotypic endothelial nanotubes induced by wheat germ agglutinin and thrombin. AB - Endothelial barrier formation is maintained by intercellular communication through junctional proteins. The mechanisms involved in maintaining endothelial communication subsequent to barrier disruption remain unclear. It is known that low numbers of endothelial cells can be interconnected by homotypic actin-driven tunneling nanotubes (TNTs) which could be important for intercellular transfer of information in vascular physiology. Here we sought insight into the triggers for TNT formation. Wheat germ agglutinin, a C-type lectin and known label for TNTs, unexpectedly caused striking induction of TNTs. A succinylated derivative was by contrast inactive, suggesting mediation by a sialylated protein. Through siRNA mediated knockdown we identified that this protein was likely to be CD31, an important sialylated membrane protein normally at endothelial cell junctions. We subsequently considered thrombin as a physiological inducer of endothelial TNTs because it reduces junctional contact. Thrombin reduced junctional contact, redistributed CD31 and induced TNTs, but its effect on TNTs was CD31-independent. Thrombin-induced TNTs nevertheless required PKCalpha, a known mediator of thrombin-dependent junctional remodelling, suggesting a necessity for junctional proteins in TNT formation. Indeed, TNT-inducing effects of wheat germ agglutinin and thrombin were both correlated with cortical actin rearrangement and similarly Ca2+-dependent, suggesting common underlying mechanisms. Once formed, Ca2+ signalling along TNTs was observed. PMID- 29765078 TI - TDP-43 regulation of stress granule dynamics in neurodegenerative disease relevant cell types. AB - Stress granules (SGs) are cytoplasmic foci that form in response to various external stimuli and are essential to cell survival following stress. SGs are studied in several diseases, including ALS and FTD, which involve the degeneration of motor and cortical neurons, respectively, and are now realized to be linked pathogenically by TDP-43, originally discovered as a component of ubiquitin-positive aggregates within patients' neurons and some glial cells. So far, studies to undercover the role of TDP-43 in SGs have used primarily transformed cell lines, and thus rely on the extrapolation of the mechanisms to cell types affected in ALS/FTD, potentially masking cell specific effects. Here, we investigate SG dynamics in primary motor and cortical neurons as well as astrocytes. Our data suggest a cell and stress specificity and demonstrate a requirement for TDP-43 for efficient SG dynamics. In addition, based on our in vitro approach, our data suggest that aging may be an important modifier of SG dynamics which could have relevance to the initiation and/or progression of age related neurodegenerative diseases. PMID- 29765079 TI - Determination of flumequine enantiomers and 7-hydroxyflumequine in water and sediment by chiral HPLC coupled with hybrid quadrupole-time-of-flight mass spectrometer. AB - A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for simultaneous enantiomeric analysis of flumequine and its metabolite 7 hydroxyflumequine in water and sediment had been developed based on the separation method. Sediment samples were extracted with ACN and EDTA-Mcllvaine buffer solution (40:60, v/v) then were enriched and cleaned-up by Cleanert PEP solid-phase extraction cartridges. The extract solvent, solid cartridges, mobile phase ratios, and chiral separation column were all optimized to reach high sensitivity and selectivity, good peak shape, and satisfactory resolution. The results showed that the calibration curves of flumequine enantiomers and 7 hydroxyflumequine were linear in the range of 1.0 to 200.0 ug/L with correlation coefficients of 0.9822-0.9988, the mean recoveries for both the enantiomers ranged from 69.9-84.6% with relative standard deviations (RSDs) being 13.1% or below. The limits of detection (LODs) for both flumequine enantiomers were 2.5 ug/L and 5.0 ug/kg in water and sediment samples, whereas the limits of quantification (LOQs) were 8.0 ug/L and 15.0 ug/kg, respectively. While the LODs for 7-hydroxyflumequine were 3.2 ug/L in water samples and 7.0 ug/kg in sediment samples. The proposed method will be extended for studies on the degradation kinetics and environmental behaviors and providing additional information for reliable risk assessment of these chiral antibiotics. PMID- 29765080 TI - Distinguishing mirtrons from canonical miRNAs with data exploration and machine learning methods. AB - Mirtrons are non-canonical microRNAs encoded in introns the biogenesis of which starts with splicing. They are not processed by Drosha and enter the canonical pathway at the Exportin-5 level. Mirtrons are much less evolutionary conserved than canonical miRNAs. Due to the differences, canonical miRNA predictors are not applicable to mirtron prediction. Identification of differences is important for designing mirtron prediction algorithms and may help to improve the understanding of mirtron functioning. So far, only simple, single-feature comparisons were reported. These are insensitive to complex feature relations. We quantified miRNAs with 25 features and showed that it is impossible to distinguish the two miRNA species using simple thresholds on any single feature. However, when using the Principal Component Analysis mirtrons and canonical miRNAs are grouped separately. Moreover, several methodologically diverse machine learning classifiers delivered high classification performance. Using feature selection algorithms we found features (e.g. bulges in the stem region), previously reported divergent in two classes, that did not contribute to improving classification accuracy, which suggests that they are not biologically meaningful. Finally, we proposed a combination of the most important features (including Guanine content, hairpin free energy and hairpin length) which convey a specific pattern, crucial for identifying mirtrons. PMID- 29765081 TI - New birthweight percentiles by sex and gestational age in Southern China and its comparison with the INTERGROWTH-21st Standard. AB - We first showed the sex- and gestational age (week)-specific birthweight distributions from primiparous and multiparous mothers. Birthweight percentiles were created by using the Lambda Mu Sigma (LMS) method. We established the birthweight percentiles in Southern China and provide clinicians and researchers with up-to-date population norms of birthweight percentiles. Then we use the data from Birth Certificate System between Jan 1st, 2017 and Oct 31st, 2017, which included 1,245,364 live births to calculate SGA and LGA ratio by these three birthweight references- the new INTERGROWTH-21st standard, China's 2015 research standard and our birthweight percentiles. The overall prevalence of SGA estimated by our standards, the China's 2015 research standards and INTERGROWTH-21st standards, were 10.21%, 12.93% and 7.98%, respectively, whereas the overall prevalence of LGA was 9.88%, 4.48% and 8.37%, respectively. PMID- 29765082 TI - Pretreatment drug resistance in a large countrywide Ethiopian HIV-1C cohort: a comparison of Sanger and high-throughput sequencing. AB - Baseline plasma samples of 490 randomly selected antiretroviral therapy (ART) naive patients from seven hospitals participating in the first nationwide Ethiopian HIV-1 cohort were analysed for surveillance drug resistance mutations (sDRM) by population based Sanger sequencing (PBSS). Also next generation sequencing (NGS) was used in a subset of 109 baseline samples of patients. Treatment outcome after 6- and 12-months was assessed by on-treatment (OT) and intention-to-treat (ITT) analyses. Transmitted drug resistance (TDR) was detected in 3.9% (18/461) of successfully sequenced samples by PBSS. However, NGS detected sDRM more often (24%; 26/109) than PBSS (6%; 7/109) (p = 0.0001) and major integrase strand transfer inhibitors (INSTI) DRMs were also found in minor viral variants from five patients. Patients with sDRM had more frequent treatment failure in both OT and ITT analyses. The high rate of TDR by NGS and the identification of preexisting INSTI DRMs in minor wild-type HIV-1 subtype C viral variants infected Ethiopian patients underscores the importance of TDR surveillance in low- and middle-income countries and shows added value of high throughput NGS in such studies. PMID- 29765085 TI - Submarine canyons represent an essential habitat network for krill hotspots in a Large Marine Ecosystem. AB - Submarine canyon systems are ubiquitous features of marine ecosystems, known to support high levels of biodiversity. Canyons may be important to benthic-pelagic ecosystem coupling, but their role in concentrating plankton and structuring pelagic communities is not well known. We hypothesize that at the scale of a large marine ecosystem, canyons provide a critical habitat network, which maintain energy flow and trophic interactions. We evaluate canyon characteristics relative to the distribution and abundance of krill, critically important prey in the California Current Ecosystem. Using a geological database, we conducted a census of canyon locations, evaluated their dimensions, and quantified functional relationships with krill hotspots (i.e., sites of persistently elevated abundance) derived from hydro-acoustic surveys. We found that 76% of krill hotspots occurred within and adjacent to canyons. Most krill hotspots were associated with large shelf-incising canyons. Krill hotspots and canyon dimensions displayed similar coherence as a function of latitude and indicate a potential regional habitat network. The latitudinal migration of many fish, seabirds and mammals may be enhanced by using this canyon-krill network to maintain foraging opportunities. Biogeographic assessments and predictions of krill and krill-predator distributions under climate change may be improved by accounting for canyons in habitat models. PMID- 29765084 TI - Hepatoprotective effects of Auricularia cornea var. Li. polysaccharides against the alcoholic liver diseases through different metabolic pathways. AB - The present work was designed to evaluate the antioxidation and hepatoprotective effects of Auricularia cornea var. Li. polysaccharides (APS) and enzymatic extractable APS (EAPS) on the acute alcohol-induced alcoholic liver diseases (ALD). The in vitro antioxidant activities demonstrated that both APS and EAPS had strong reducing power and potential effects on scavenging reactive oxygen species. The in vivo mice experiments showed that the pretreatment with APS or EAPS showed potential hepatoprotective effects on the ALD possibly by increasing the antioxidant activities, reducing the lipid peroxidation, improving the alcohol metabolism, inhibiting the expression levels of inflammatory mediators and preventing the alcohol-induced histopathological alterations. In addition, the fourier-transform infrared (FT-IR), 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and gas chromatography (GC) had been analyzed to obtained the primarily characteristics. The results indicated that abundant xylose and glucose contents probably had potential effects on possessing the bioactivities. The findings suggested that the A. cornea var. Li. might be considered as promising natural resource on exploring clinical drugs for the prevention and treatment with ALD and its complications. PMID- 29765083 TI - Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease. AB - Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin 10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-alpha (TNF-alpha) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF alpha and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD. PMID- 29765086 TI - Fabrication and characterization of a scalable surface textured with pico-liter oil drops for mechanistic studies of bacteria-oil interactions. AB - Texturing a large surface with oily micro-drops with controlled size, shape and volume provides an unprecedented capability in investigating complex interactions of bacteria, cells and interfaces. It has particular implications in understanding key microbial processes involved in remediation of environmental disasters, such as Deepwater Horizon oil spill. This work presents a development of scalable micro-transfer molding to functionalize a substrate with oily drop array to generate a microcosm mimicking bacteria encountering a rising droplet cloud. The volume of each drop within a large "printed" surface can be tuned by varying base geometry and area with characteristic scales from 5 to 50 MUm. Contrary to macroscopic counterparts, drops with non-Laplacian shapes, i.e. sharp corners, that appears to violate Young-Laplacian relationship locally, are produced. Although the drop relaxes into a spherical cap with constant mean curvature, the contact line with sharp corners remains pinned. Relaxation times from initial to asymptotic shape require extraordinarily long time (>7 days). We demonstrate that non-Laplacian drops are the direct results of self-pinning of contact line by nanoparticles in the oil. This technique has been applied to study biofilm formation at the oil-water interface and can be readily extended to other colloidal fluids. PMID- 29765088 TI - Performance boost for primary magnesium cells using iron complexing agents as electrolyte additives. AB - Aqueous Mg battery technology holds significant appeal, owing to the availability of raw materials, high power densities and the possibility of fast mechanical recharge. However, Mg batteries have so far been prone to decreased capacity due to self-corrosion of the anodes from the electrochemical redeposition of impurities, such as Fe, which results in parasitic cathodically active sites on the discharging anode. This work demonstrates that by adding Fe3+-complexing agents like Tiron or salicylate to the aqueous electrolyte of an Mg battery, it was possible to prevent the redeposition of Fe impurities and subsequent self corrosion of the anode surface, thereby boosting battery performance. To prevent detrimental fouling of anode surface by Mg(OH)2, employed Fe3+-complexing agents must also form soluble complexes with Mg2+ of moderate stability. The interplay of these requirements predetermines the improvement of operating voltage and utilization efficiency. PMID- 29765087 TI - FABRICA: A Bioreactor Platform for Printing, Perfusing, Observing, & Stimulating 3D Tissues. AB - We are introducing the FABRICA, a bioprinter-agnostic 3D-printed bioreactor platform designed for 3D-bioprinted tissue construct culture, perfusion, observation, and analysis. The computer-designed FABRICA was 3D-printed with biocompatible material and used for two studies: (1) Flow Profile Study: perfused 5 different media through a synthetic 3D-bioprinted construct and ultrasonically analyzed the flow profile at increasing volumetric flow rates (VFR); (2) Construct Perfusion Study: perfused a 3D-bioprinted tissue construct for a week and compared histologically with a non-perfused control. For the flow profile study, construct VFR increased with increasing pump VFR. Water and other media increased VFR significantly while human and pig blood showed shallow increases. For the construct perfusion study, we confirmed more viable cells in perfused 3D bioprinted tissue compared to control. The FABRICA can be used to visualize constructs during 3D-bioprinting, incubation, and to control and ultrasonically analyze perfusion, aseptically in real-time, making the FABRICA tunable for different tissues. PMID- 29765089 TI - E-cigarettes can emit formaldehyde at high levels under conditions that have been reported to be non-averse to users. AB - E-cigarette aerosol emission studies typically focus on benchmarking toxicant levels versus those of cigarettes. However, such studies do not fully account for the distinct chemical makeup of e-liquids and their unique properties. These approaches often conclude that there are fewer and lower levels of toxins produced by e-cigarettes than by cigarettes. In 2015, we reported the discovery of new hemiacetals derived from the reaction of formaldehyde and the e-liquid solvents. The main finding was that they constituted a significant proportion of potentially undetected formaldehyde. Moreover, unlike gaseous formaldehyde, the hemiacetals reside in the aerosol particulate phase, and thus are capable of delivering formaldehyde more deeply into the lungs. However, the findings were criticized by those claiming that some of the results were obtained under conditions that are averse to vapers. A "reinvestigation" of our study was recently published addressing this latter issue. However, this reinvestigation ignored major details, including no mention of the formaldehyde hemiacetals. Herein, we isolated both gaseous formaldehyde and formaldehyde hemiacetals at an intermediate power level claimed, in the "reinvestigation", to be relevant to "non-averse," "normal" usage. The results were that both gaseous formaldehyde and formaldehyde from hemiacetals were produced at levels above OSHA workplace limits. PMID- 29765091 TI - Metagenomic profiling for assessing microbial diversity and microbial adaptation to degradation of hydrocarbons in two South African petroleum-contaminated water aquifers. AB - Biodegradation of hydrocarbons by indigenous populations of microorganisms found in petroleum-contaminated water sources represents one of the primary mechanisms by which petroleum and other hydrocarbon pollutants are eliminated from the aquatic environment. The identification of these microorganisms, which have capabilities to convert the majority of toxic hydrocarbons into compounds that are less harmful for end-users, is therefore crucial for bioremediation purposes. The aim of this study was to profile the microbial diversity of two South African petroleum-contaminated water aquifer sites and to determine the microbial adaptation to hydrocarbon degradation using a metagenomics approach. The sequenced samples revealed that protozoa (62.04%) were found to be the most dominant group, followed by fungi (24.49%), unknown (12.87%), and finally other sequences such as Animalia and plantae which were <(0.10%) domains in the first oil-polluted aquifer site. In the second site, protozoa (61.90%), unknown (16.51%), fungi (11.41%) in that order. According to the classification at the genus level, the dominant group was Naegleria (15.21%), followed by Vorticella (6.67%) as the only ciliated protozoan genus, other species such as Arabidopsis (2.97%), Asarum (1.84%) Populus (1.04%) were significantly low and drastically lower in the first site. Regarding the second site, the dominant group was Naegleria (18.29%) followed by Colpoda (9.86%) with the remainder of the genera representing <2%. Overall results demonstrated the ability of various groups of microorganisms to adapt and survive in petroleum oil-polluted water sites regardless of their respective distributions and this can be explored further for their role in bioremediation and environmental management. PMID- 29765090 TI - A rightward saccade to an unexpected stimulus as a marker for lateralised visuospatial attention. AB - The human brain is lateralised to the right for visuospatial attention, particularly when reorienting attention to unexpected stimuli. However, the developmental characteristics of lateralisation remain unclear. To address this question, we devised a saccade task applicable for both adults and children. To assess the utility of this system, we investigated the correlation between line bisection test performance and the saccade task for 54 healthy adult volunteers. Participants followed a visual target that jumped 10 times, alternating between two fixed positions across the midline with a constant pace. In both the rightward and leftward directions, saccadic reaction time (RT) to the target jump decreased and reached a plateau from the first to the tenth jumps. Furthermore, we obtained the time required for reorienting in the contralateral hemisphere using the corrected value of the first RT. We found that longer corrected RTs in the rightward saccade were associated with greater deviation to the left in the line bisection task. This correlation was not observed for leftward saccades. Thus, corrected RTs in rightward saccades reflected the strength of individual hemispheric lateralisation. In conclusion, the rightward saccade task provides a suitable marker for lateralised visuospatial attention, and for investigating the development of lateralisation. PMID- 29765092 TI - Pilot-scale study on catalytic ozonation of bio-treated dyeing and finishing wastewater using recycled waste iron shavings as a catalyst. AB - A pilot scale reactor with an effective volume of 2.93 m3 was built in-situ and run in both batch and continuous modes to investigate the removal for organic pollutants in bio-treated dyeing and finishing wastewater by heterogeneous catalytic ozonation under neutral pH with waste iron shavings as a catalyst. Experimental results showed that both running modes were able to reduce the chemical oxygen demand (COD) from 132-148 mg/L to a level below the discharge criteria (<80 mg/L) within 15-30 mins under several conditions. Specifically, significantly organic removal was observed with COD, soluble COD (sCOD) and dissolved organic carbon (DOC) decreased from the initial 165, 93 and 76 mg/L to 54, 28 and 16 mg/L respectively, when treated by 10.2 g-O3/min of ozone dosage at a hydraulic retention time of 30 mins under continuous mode. 80% proteins and 85% polysaccharides were removed with a decrease in their contribution to sCOD from 69% to 43%. Mineralization as well as conversion of high molecular organic compounds was observed through Gas Chromatography-Mass Spectrometer (GC-MS) & Liquid Chromatography-Mass Spectrometer (LC-MS) analysis, which led to a decrease of inhibitory effect from 29% to 25%, suggesting a reduction in the acute toxicity. PMID- 29765093 TI - Accurate and fiducial-marker-free correction for three-dimensional chromatic shift in biological fluorescence microscopy. AB - Correction of chromatic shift is necessary for precise registration of multicolor fluorescence images of biological specimens. New emerging technologies in fluorescence microscopy with increasing spatial resolution and penetration depth have prompted the need for more accurate methods to correct chromatic aberration. However, the amount of chromatic shift of the region of interest in biological samples often deviates from the theoretical prediction because of unknown dispersion in the biological samples. To measure and correct chromatic shift in biological samples, we developed a quadrisection phase correlation approach to computationally calculate translation, rotation, and magnification from reference images. Furthermore, to account for local chromatic shifts, images are split into smaller elements, for which the phase correlation between channels is measured individually and corrected accordingly. We implemented this method in an easy-to use open-source software package, called Chromagnon, that is able to correct shifts with a 3D accuracy of approximately 15 nm. Applying this software, we quantified the level of uncertainty in chromatic shift correction, depending on the imaging modality used, and for different existing calibration methods, along with the proposed one. Finally, we provide guidelines to choose the optimal chromatic shift registration method for any given situation. PMID- 29765095 TI - The high efficient catalytic properties for thermal decomposition of ammonium perchlorate using mesoporous ZnCo2O4 rods synthesized by oxalate co-precipitation method. AB - Mesoporous ZnCo2O4 rods have been successfully prepared via oxalate co precipitation method without any template. The nano-sized spinel crystallites connected together to form mesoporous structure by annealing homogeneous complex oxalates precursor at a low rate of heating. It is found that the low anneal rate plays an important role for the formation of mesoporous ZnCo2O4 rods. The effects of the heat temperature on the phase, morphology and catalytic properties of the products were studied. The XRD, SEM TEM, and N2 absorption/desorption have been done to obtain compositional and morphological information as well as BET surface area of the as-prepared sample. Catalytic activities of mesoporous ZnCo2O4 rods toward the thermal decomposition of ammonium perchlorate (AP) were investigated with differential scanning calorimetry (DSC) and thermogravimetry (TG) techniques. The results show that the addition of ZnCo2O4 rods to AP dramatically reduces the decomposition temperature. The ZnCo2O4 rods annealed at 250 degrees C possesses much larger specific area and exhibits excellent catalytic activity (decrease the high decomposition temperature of AP by 162.2 degrees C). The obtained mesoporous ZnCo2O4 rods are promising as excellent catalyst for the thermal decomposition of AP. PMID- 29765097 TI - Bion in Brazil: Supervisions and Commentaries, edited by Jose Americo Junqueria de Mattos, Gisele de Mattos Brito, and Howard B. Levine, Karnac, London, 2017, 262pp. PMID- 29765094 TI - The cell wall hydrolase Pmp23 is important for assembly and stability of the division ring in Streptococcus pneumoniae. AB - Bacterial division is intimately linked to synthesis and remodeling of the peptidoglycan, a cage-like polymer that surrounds the bacterial cell, providing shape and mechanical resistance. The bacterial division machinery, which is scaffolded by the cytoskeleton protein FtsZ, includes proteins with enzymatic, structural or regulatory functions. These proteins establish a complex network of transient functional and/or physical interactions which preserve cell shape and cell integrity. Cell wall hydrolases required for peptidoglycan remodeling are major contributors to this mechanism. Consistent with this, their deletion or depletion often results in morphological and/or division defects. However, the exact function of most of them remains elusive. In this work, we show that the putative lysozyme activity of the cell wall hydrolase Pmp23 is important for proper morphology and cell division in the opportunistic human pathogen Streptococcus pneumoniae. Our data indicate that active Pmp23 is required for proper localization of the Z-ring and the FtsZ-positioning protein MapZ. In addition, Pmp23 localizes to the division site and interacts directly with the essential peptidoglycan synthase PBP2x. Altogether, our data reveal a new regulatory function for peptidoglycan hydrolases. PMID- 29765096 TI - Temporal changes in immune cell composition and cytokines in response to chemoradiation in rectal cancer. AB - We measured systemic changes in the immune response in 92 patients receiving preoperative chemoradiation therapy (CRT) and subsequent surgery for rectal cancer. The peripheral blood was sampled five times from the onset of CRT until surgery. Lymphocytes decreased continuously during CRT but increased after CRT. The increased lymphocyte population was predominantly CD8+ T lymphocytes, which accounted for a significantly larger proportion in patients without residual lymph node metastasis than in those with residual lymph node metastasis. Neutrophils and monocytes decreased during the initial two weeks of CRT but were maintained or increased afterwards. Neutrophil and monocyte counts were significantly lower in patients with a pCR (pathologic complete response) than in those without a pCR two weeks after CRT began but not at the initiation of CRT. All cytokines showed dramatic changes one month after the termination of CRT. Cytokines related to the antitumour immune response increased, and those related to tumour progression decreased. The predictive value of cytokines was not clear. In short, we observed that immune components in peripheral blood are affected by CRT and show dynamic changes over time. We identified biomarker candidates to predict the pathologic response in the future. PMID- 29765098 TI - Author Correction: Rancher-reported efficacy of lethal and non-lethal livestock predation mitigation strategies for a suite of carnivores. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29765099 TI - One novel representation of DNA sequence based on the global and local position information. AB - One novel representation of DNA sequence combining the global and local position information of the original sequence has been proposed to distinguish the different species. First, for the sufficient exploitation of global information, one graphical representation of DNA sequence has been formulated according to the curve of Fermat spiral. Then, for the consideration of local characteristics of DNA sequence, attaching each point in the curve of Fermat spiral with the related mass has been applied based on the relationships of neighboring four nucleotides. In this paper, the normalized moments of inertia of the curve of Fermat spiral which composed by the points with mass has been calculated as the numerical description of the corresponding DNA sequence on the first exons of beta-global genes. Choosing the Euclidean distance as the measurement of the numerical descriptions, the similarity between species has shown the performance of proposed method. PMID- 29765100 TI - Non-thermal plasma treatment improves chicken sperm motility via the regulation of demethylation levels. AB - The quality of avian semen is an important economic trait in poultry production. The present study examines the in vitro effects of non-thermal dielectric barrier discharge plasma on chicken sperm to determine the plasma conditions that can produce the optimum sperm quality. Exposure to 11.7 kV of plasma for 20 s is found to produce maximum sperm motility by controlling the homeostasis of reactive oxygen species and boosting the release of adenosine triphosphate and respiratory enzyme activity in the mitochondria. However, prolonged exposure or further increase in plasma potential impairs the sperm quality in a time- and dose-dependent manner. Optimal plasma treatment of sperm results in upregulated mRNA and protein expression of antioxidant defense-related and energetic metabolism-related genes by increasing their demethylation levels. However, 27.6 kV of plasma exerts significant adverse effects. Thus, our findings indicate that appropriate plasma exposure conditions improve chicken sperm motility by regulating demethylation levels of genes involved in antioxidant defense and energetic metabolism. PMID- 29765101 TI - Favipiravir (T-705) protects against Nipah virus infection in the hamster model. AB - Nipah and Hendra viruses are recently emerged bat-borne paramyxoviruses (genus Henipavirus) causing severe encephalitis and respiratory disease in humans with fatality rates ranging from 40-75%. Despite the severe pathogenicity of these viruses and their pandemic potential, no therapeutics or vaccines are currently approved for use in humans. Favipiravir (T-705) is a purine analogue antiviral approved for use in Japan against emerging influenza strains; and several phase 2 and 3 clinical trials are ongoing in the United States and Europe. Favipiravir has demonstrated efficacy against a broad spectrum of RNA viruses, including members of the Paramyxoviridae, Filoviridae, Arenaviridae families, and the Bunyavirales order. We now demonstrate that favipiravir has potent antiviral activity against henipaviruses. In vitro, favipiravir inhibited Nipah and Hendra virus replication and transcription at micromolar concentrations. In the Syrian hamster model, either twice daily oral or once daily subcutaneous administration of favipiravir for 14 days fully protected animals challenged with a lethal dose of Nipah virus. This first successful treatment of henipavirus infection in vivo with a small molecule drug suggests that favipiravir should be further evaluated as an antiviral treatment option for henipavirus infections. PMID- 29765102 TI - The effects of cannabidiol on impulsivity and memory during abstinence in cigarette dependent smokers. AB - Acute nicotine abstinence in cigarette smokers results in deficits in performance on specific cognitive processes, including working memory and impulsivity which are important in relapse. Cannabidiol (CBD), the non-intoxicating cannabinoid found in cannabis, has shown pro-cognitive effects and preliminary evidence has indicated it can reduce the number of cigarettes smoked in dependent smokers. However, the effects of CBD on cognition have never been tested during acute nicotine withdrawal. The present study therefore aimed to investigate if CBD can improve memory and reduce impulsivity during acute tobacco abstinence. Thirty, non-treatment seeking, dependent, cigarette smokers attended two laboratory-based sessions after overnight abstinence, in which they received either 800 mg oral CBD or placebo (PBO), in a randomised order. Abstinence was biologically verified. Participants were assessed on go/no-go, delay discounting, prose recall and N-back (0-back, 1-back, 2-back) tasks. The effects of CBD on delay discounting, prose recall and the N-back (correct responses, maintenance or manipulation) were null, confirmed by a Bayesian analysis, which found evidence for the null hypothesis. Contrary to our predictions, CBD increased commission errors on the go/no-go task. In conclusion, a single 800 mg dose of CBD does not improve verbal or spatial working memory, or impulsivity during tobacco abstinence. PMID- 29765103 TI - Identification of a flagellar protein implicated in the gravitaxis in the flagellate Euglena gracilis. AB - Flagellated cells are of great evolutionary importance across animal and plant species. Unlike higher plants, flagellated cells are involved in reproduction of macro-algae as well as in early diverging land plants. Euglena gracilis is an emerging flagellated model organism. The current study reports that a specific calmodulin (CaM2) involved in gravitaxis of E. gracilis interacts with an evolutionary conserved flagellar protein, EgPCDUF4201. The subsequent molecular analysis showed clearly that EgPCDUF4201 is also involved in gravitaxis. We performed subcellular localization of CaM2 using immunoblotting and indirect immunofluorescence. By employing yeast two-hybrid screen, EgPCDUF4201 was identified as an interaction partner of CaM2. The C-terminus of EgPCDUF4201 is responsible for the interaction with CaM2. Silencing of N- and C-terminus of EgPCDUF4201 using RNAi resulted in an impaired gravitaxis. Moreover, indirect immunofluorescence assay showed that EgPCDUF4201 is a flagella associated protein. The current study specifically addressed some important questions regarding the signal transduction chain of gravitaxis in E. gracilis. Besides the fact that it improved the current understanding of gravity sensing mechanisms in E. gracilis, it also gave rise to several interesting research questions regarding the function of the domain of unknown function 4201 in flagellated cells. PMID- 29765104 TI - Falls and Recurrent Falls among Adults in A Multi-ethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study. AB - We evaluated the rate and risk factors associated with falls and recurrent falls in a multi-ethnic Asian population. 10,009 participants aged >=40 years (mean[SD] age = 58.9[10.4] years) underwent clinical examinations and completed interviewer administered questionnaires. Participants who self-reported at least one fall or >=2 falls in past 12 months were defined as fallers and recurrent fallers, respectively. Age-standardized rates for falls and recurrent falls were 13.8% (95%CI, 13.1-14.6%) and 4.6% (95%CI, 4.2-5.1%), respectively. Multivariable analyses showed older age (OR = 1.20; 95%CI, 1.11-1.30), female gender (OR = 1.79; 95%CI, 1.54-2.07), diabetes (OR = 1.22; 95%CI, 1.07-1.40), cardiovascular disease (CVD, OR = 1.37; 95%CI, 1.14-1.65), >=3 systemic comorbidities (OR = 1.35; 95%CI, 1.09-1.67), lower European Quality of Life-5 Dimensions (EQ-5D) score (OR = 1.36; 95%CI, 1.29-1.44), alcohol consumption (OR = 1.41, 95%CI, 1.11 1.78) and presenting visual impairment (VI, OR = 1.23; 95%CI, 1.02-1.47) were associated with falls. For recurrent falls, female gender (OR = 2.27; 95%CI, 1.75 2.94), diabetes (OR = 1.28; 95%CI, 1.03-1.61), CVD (OR = 2.00; 95%CI, 1.53-2.62), >=3 systemic comorbidities (OR = 1.69; 95%CI, 1.19-2.39), lower EQ-5D score (OR = 1.47; 95%CI, 1.35-1.59), living in 1-2 room public flat (OR = 1.57; 95%CI, 1.05 2.33), monthly income <2000 Singapore Dollar (OR = 1.62; 95%CI, 1.13-2.31), alcohol consumption (OR = 1.81, 95%CI, 1.23-2.66) and presenting VI (OR = 1.34; 95%CI, 1.01-1.79) were significant risk factors. These findings will be useful for the formulation of fall prevention programs. PMID- 29765105 TI - Neural predisposing factors of postoperative delirium in elderly patients with femoral neck fracture. AB - Elderly adults are more likely to develop delirium after major surgery, but there is limited knowledge of the vulnerability for postoperative delirium. In this study, we aimed to identify neural predisposing factors for postoperative delirium and develop a prediction model for estimating an individual's probability of postoperative delirium. Among 57 elderly participants with femoral neck fracture, 25 patients developed postoperative delirium and 32 patients did not. We preoperatively obtained data for clinical assessments, anatomical MRI, and resting-state functional MRI. Then we evaluated gray matter (GM) density, fractional anisotropy, and the amplitude of low-frequency fluctuation (ALFF), and conducted a group-level inference. The prediction models were developed to estimate an individual's probability using logistic regression. The group-level analysis revealed that neuroticism score, ALFF in the dorsolateral prefrontal cortex, and GM density in the caudate/suprachiasmatic nucleus were predisposing factors. The prediction model with these factors showed a correct classification rate of 86% using a leave-one-out cross-validation. The predicted probability computed from the logistic model was significantly correlated with delirium severity. These results suggest that the three components are the most important predisposing factors for postoperative delirium, and our prediction model may reflect the core pathophysiology in estimating the probability of postoperative delirium. PMID- 29765107 TI - Space-Wave Routing via Surface Waves Using a Metasurface System. AB - We introduce the concept of a metasurface system able to route space waves via surface waves. This concept may be used to laterally shift or modulate the beam width of scattered waves. The system is synthesized based on a momentum transfer approach using phase-gradient metasurfaces. The concept is experimentally verified in an "electromagnetic periscope". Additionally, we propose two other potential applications namely a beam expander and a multi-wave refractor. PMID- 29765106 TI - The mitochondrial genome of the oribatid mite Paraleius leontonychus: new insights into tRNA evolution and phylogenetic relationships in acariform mites. AB - Bilaterian mitochondrial (mt) genomes are circular molecules that typically contain 37 genes. To date, only a single complete mitogenome sequence is available for the species-rich sarcoptiform mite order Oribatida. We sequenced the mitogenome of Paraleius leontonychus, another species of this suborder. It is 14,186 bp long and contains 35 genes, including only 20 tRNAs, lacking tRNA Gly and tRNA Tyr . Re-annotation of the mitogenome of Steganacarus magnus increased the number of mt tRNAs for this species to 12. As typical for acariform mites, many tRNAs are highly truncated in both oribatid species. The total number of tRNAs and the number of tRNAs with a complete cloverleaf-like structure in P. leontonychus, however, clearly exceeds the numbers previously reported for Sarcoptiformes. This indicates, contrary to what has been previously assumed, that reduction of tRNAs is not a general characteristic for sarcoptiform mites. Compared to other Sarcoptiformes, the two oribatid species have the least rearranged mt genome with respect to the pattern observed in Limulus polyphemus, a basal arachnid species. Phylogenetic analysis of the newly sequenced mt genome and previously published data on other acariform mites confirms paraphyly of the Oribatida and an origin of the Astigmata within the Oribatida. PMID- 29765108 TI - Voltage-dependent Ca2+ channels promote branching morphogenesis of salivary glands by patterning differential growth. AB - Branching morphogenesis is a crucial part of early developmental processes in diverse organs, but the detailed mechanism of this morphogenic event remains to be elucidated. Here we introduce an unknown mechanism leading to branching morphogenesis using mouse embryonic organotypic cultures with time-lapse live imaging. We found spatially expressed L-type voltage-dependent Ca2+ channels (VDCCs) in the peripheral layers of developing epithelial buds and identified the VDCCs as a core signaling mediator for patterning branching architecture. In this process, differential growth in peripheral layers by VDCC-induced ERK activity promoted cleft formation through an epithelial buckling-folding mechanism. Our findings reveal an unexpected role of VDCCs in developmental processes, and address a fundamental question regarding the initial process of branching morphogenesis. PMID- 29765109 TI - Microvascular fractal dimension predicts prognosis and response to chemotherapy in glioblastoma: an automatic image analysis study. AB - The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients. PMID- 29765110 TI - Mast cells contribute to Enterovirus 71 infection-induced pulmonary edema in neonatal mice. AB - Enterovirus (EV) 71 infection has been widely acknowledged as the leading cause of severe hand, foot and mouth disease (HFMD), which may rapidly lead to fatal pulmonary edema. In this study, we established a mouse model for EV71 infection exhibiting high incidence of severe symptoms with pulmonary edema. Mast cells (MCs) accumulation, activation and allergic inflammation were found in the brains, lungs and skeletal muscle of mice after EV71 infection, especially in the lungs of mice. Levels of histamine, platelet-activating factor (PAF), interleukin (IL)-4, IL-5, IL-13, tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and noradrenaline (NA) were increased in EV71-infected lungs. In addition, EV71 infection reduced the number of pulmonary T cells, dendritic cells (DCs) and monocytes, and increased the number of lung eosinophils, Tregs and MCs. MCs number and tryptase expression in target organs or tissues posed a trend towards an increase from control to severe mice. There were positive correlations between MCs number in the brains (r = 0.701, P = 0.003), lungs (r = 0.802, P < 0.0001), skeletal muscles (r = 0.737, P = 0.001) and mean clinical score. Thus, our results suggested that MCs contributed to the pulmonary edema during EV71 infection. PMID- 29765112 TI - Structure-guided Discovery of Dual-recognition Chemibodies. AB - Small molecules and antibodies each have advantages and limitations as therapeutics. Here, we present for the first time to our knowledge, the structure guided design of "chemibodies" as small molecule-antibody hybrids that offer dual recognition of a single target by both a small molecule and an antibody, using DPP-IV enzyme as a proof of concept study. Biochemical characterization demonstrates that the chemibodies present superior DPP-IV inhibition compared to either small molecule or antibody component alone. We validated our design by successfully solving a co-crystal structure of a chemibody in complex with DPP IV, confirming specific binding of the small molecule portion at the interior catalytic site and the Fab portion at the protein surface. The discovery of chemibodies presents considerable potential for novel therapeutics that harness the power of both small molecule and antibody modalities to achieve superior specificity, potency, and pharmacokinetic properties. PMID- 29765111 TI - New insights into apoptosome structure and function. AB - The apoptosome is a platform that activates apical procaspases in response to intrinsic cell death signals. Biochemical and structural studies in the past two decades have extended our understanding of apoptosome composition and structure, while illuminating the requirements for initiator procaspase activation. A number of studies have now provided high-resolution structures for apoptosomes from C. elegans (CED-4), D. melanogaster (Dark), and H. sapiens (Apaf-1), which define critical protein interfaces, including intra and interdomain interactions. This work also reveals interactions of apoptosomes with their respective initiator caspases, CED-3, Dronc and procaspase-9. Structures of the human apoptosome have defined the requirements for cytochrome c binding, which triggers the conversion of inactive Apaf-1 molecules to an extended, assembly competent state. While recent data have provided a detailed understanding of apoptosome formation and procaspase activation, they also highlight important evolutionary differences with functional implications for caspase activation. Comparison of the CARD/CARD disks and apoptosomes formed by CED-4, Dark and Apaf-1. Cartoons of the active states of the CARD-CARD disks, illustrating the two CED-4 CARD tetrameric ring layers (CED4a and CED4b; top row) and the binding of 8 Dronc CARDs and between 3 4 pc-9 CARDs, to the Dark and Apaf-1 CARD disk respectively (middle and lower rows). Ribbon diagrams of the active CED-4, Dark and Apaf-1 apoptosomes are shown (right column). PMID- 29765113 TI - Plasma "bullet" with hollow structure: formation and evolution. AB - Since the plasma "bullet" and ring shape were discovered by Teschke and coworkers in 2005, the hollow structure of the plasma "bullet" has been a hot topic as an important phenomenon. Clearing the mechanism back on the phenomenon is very important to research and application of atmospheric pressure plasma jet (APPJ). Although a lot of discussions on the generation and evolution of the hollow structure have been conducted in past years, there is a substantial divergence between the experimental researcher and the numerical simulation researcher. The former considers that the Penning effect has a main contribution, because the presence of impurities enables the Penning process to occur at the gas flow/air interface. On the contrary, numerical simulation claims that the Penning effect is not so decisive to the formation of hollow structure. Based on our previous work, this paper aims to clear the debatable topic by setting the special experiments. After comparing and analyzing the phenomena and mechanism, a better comprehension is reached on the contribution of the Penning effect to the hollow structure. We also give a promising conclusion for forming the hollow structure of plasma jet in the end of paper. PMID- 29765114 TI - Evaluation of the utility of a rapid test for syphilis at a sexually transmitted disease clinic in Buenos Aires, Argentina. AB - Even though syphilis can be easily diagnosed by simple and low-cost laboratory methods, it continues to be an important health problem. Rapid tests (RT) for the detection of treponemal antibodies can facilitate earlier diagnosis, access to treatment and linkage to care. The aim of this study was to analyse the usefulness of the incorporation of a RT in the detection of patients infected with T. pallidum in a sexually-transmitted disease (STD) clinic. Between March and December 2015, a syphilis RT was offered to patients who spontaneously attended the clinic. Conventional serology testing was additionally indicated to every participant. The RT for syphilis was offered to 1887 patients, of whom 31.1% agreed to get tested. VDRL test was performed in 84.0% of patients that were also tested with syphilis RT, with a significantly higher frequency observed among participants with reactive RT (94.3% vs. 79.8%, p < 0.001). These results showed that 33.7% of the participants were reactive for the RT and 27.0% were reactive for the VDRL test. Both tests were reactive in 24.9% and non-reactive in 64.3%. A high prevalence of active syphilis was detected in patients attending the clinic. The use of a syphilis RT had a positive impact, which in combination with the VDRL test increased the number of patients that were effectively diagnosed. PMID- 29765116 TI - Passing on the electrons. PMID- 29765115 TI - Collective gradient sensing in fish schools. AB - Throughout the animal kingdom, animals frequently benefit from living in groups. Models of collective behaviour show that simple local interactions are sufficient to generate group morphologies found in nature (swarms, flocks and mills). However, individuals also interact with the complex noisy environment in which they live. In this work, we experimentally investigate the group performance in navigating a noisy light gradient of two unrelated freshwater species: golden shiners (Notemigonuscrysoleucas) and rummy nose tetra (Hemigrammus bleheri). We find that tetras outperform shiners due to their innate individual ability to sense the environmental gradient. Using numerical simulations, we examine how group performance depends on the relative weight of social and environmental information. Our results highlight the importance of balancing of social and environmental information to promote optimal group morphologies and performance. PMID- 29765118 TI - IFN-lambdas inhibit Hantaan virus infection through the JAK-STAT pathway and expression of Mx2 protein. AB - Hantaan virus (HTNV), member of the newly defined Hantaviridae family, within the order Bunyavirales, can cause a hemorrhagic fever with renal syndrome with high fatality rates in humans. However, no specific antiviral agents are currently available for HTNV infection approved by the US Food and Drug Administration. Although interferon lambdas (IFN-lambdas) have been shown to induce an antiviral state against HTNV, the molecular mechanisms remain to be determined. In this study, we found that IFN-lambdas exerted its anti-HTNV effect by activating Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway mediated antiviral immunity in A549 cells. Simultaneously, IFN-lambdas downregulated suppressor of cytokine signaling proteins, which are the known negative feedback regulators of the JAK-STAT signaling pathway. Additionally, we demonstrated the role of IFN-lambdas-induced myxovirus resistance 2 (Mx2, also known as MxB) protein as a potential inhibitor for HTNV infection. These findings indicate that IFN-lambdas play an important role in cellular defenses against HTNV infection at an early stage and that human Mx2 may represent a potential therapeutic target for HTNV infection. PMID- 29765117 TI - Risk of poisoning in children and adolescents with ADHD: a systematic review and meta-analysis. AB - Poisoning, a subtype of physical injury, is an important hazard in children and youth. Individuals with ADHD may be at higher risk of poisoning. Here, we conducted a systematic review and meta-analysis to quantify this risk. Furthermore, since physical injuries, likely share causal mechanisms with those of poisoning, we compared the relative risk of poisoning and injuries pooling studies reporting both. As per our pre-registered protocol (PROSPERO ID CRD42017079911), we searched 114 databases through November 2017. From a pool of 826 potentially relevant references, screened independently by two researchers, nine studies (84,756 individuals with and 1,398,946 without the disorder) were retained. We pooled hazard and odds ratios using Robust Variance Estimation, a meta-analytic method aimed to deal with non-independence of outcomes. We found that ADHD is associated with a significantly higher risk of poisoning (Relative Risk = 3.14, 95% Confidence Interval = 2.23 to 4.42). Results also indicated that the relative risk of poisoning is significantly higher than that of physical injuries when comparing individuals with and without ADHD (Beta coefficient = 0.686, 95% Confidence Interval = 0.166 to 1.206). These findings should inform clinical guidelines and public health programs aimed to reduce physical risks in children/adolescents with ADHD. PMID- 29765119 TI - Elucidation of inhibitory effects on metastatic sentinel lymph nodes of breast cancer during One-Step Nucleic Acid Amplification. AB - One-step nucleic acid amplification (OSNA) is an established method for intraoperative diagnosis of breast cancer metastasis in sentinel lymph nodes, based on quantification of CK19 mRNA, specific to breast epithelial cells. Inhibitors interfere with the PCR amplification process of PCR. Thus, OSNA, based on gene amplification without RNA purification, might be impacted by numerous factors persisting in a sample, and thereby potentially acting as PCR inhibitors. However, neither the characteristics of breast cancers showing inhibitory effects during OSNA, nor any of the possible inhibitors, have as yet been identified. Inhibitory effects detected during OSNA in 72 metastatic lymph nodes and the patients' clinicopathological features were examined. Left-over OSNA samples were analyzed with mass spectrometry to identify proteins possibly acting as inhibitors. Most tumors showed inhibitory effects, though to varying degrees. Large tumor, young age and high tumor-infiltrating lymphocyte counts were related to stronger inhibitory effects. Proteome analysis revealed elevations in RPB9 protein and EIF2 signaling upregulation in samples showing strong inhibitory effects. Tumors showing strong inhibitory effects had clinically relevant characteristics, including large size and extensive tumor-infiltrating lymphocyte involvement. Identifying inhibitors in OSNA might provide new insights into breast cancer biology as well as advancing the current technology. PMID- 29765122 TI - Australian budget delivers for science facilities and medical research. PMID- 29765121 TI - How science will suffer as US pulls out of Iran nuclear deal. PMID- 29765123 TI - Distant galaxy formed stars only 250 million years after the Big Bang. PMID- 29765120 TI - Oncological Outcome of Primary and Secondary Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-analysis. AB - Conflicting results of survival outcomes for primary and secondary muscle invasive bladder cancer (MIBC) have been reported in previous studies. Primary MIBC is defined as presentation of muscle-invasive disease at initial diagnosis while secondary MIBC presumes that non-muscle invasive disease later progressed to MIBC. Due to the varying reports, we conducted a systematic review and meta analysis to compare survival outcomes between the two groups. Relevant studies were retrieved from Medline, Embase, the Cochrane Library, and Scopus using a comprehensive search approach. Cancer-specific survival (CSS) was the outcome measure. A total of 14 studies involving 4,075 cases were included. Patients with secondary MIBC were significantly correlated with worse CSS in model I (pooled HR: 1.29, 95% CI: 1.07-1.56, P = 0.008). The results of sensitivity analyses indicated that the omission of any single study each time did not have a significant impact on the combined risk estimates. Egger's test suggested no publication bias among these studies. The European Organization for Research and Treatment of Cancer (EORTC) risk score offers the possibility of stratifying the secondary MIBC patients into different risk groups. In high-risk NMIBC, timely radical cystectomy should be considered. Further study is required to assess the multimodal therapy in both high-risk NMIBC and secondary MIBC patients as well as to evaluate genetic and molecular drivers of tumor induction, promotion, and progression. PMID- 29765124 TI - Evidence of illegal emissions of ozone-depleting chemicals. PMID- 29765125 TI - Regeneration. PMID- 29765126 TI - Wikipedia's top-cited scholarly articles - revealed. PMID- 29765127 TI - Sacked Japanese biologist gets chance to retrain at Crick institute. PMID- 29765128 TI - Aluminium producers promise a cleaner smelting pot. PMID- 29765131 TI - Neuroimaging model predicts time of symptom onset in sporadic AD. PMID- 29765129 TI - Intrauterine smoke exposure deregulates lung function, pulmonary transcriptomes, and in particular insulin-like growth factor (IGF)-1 in a sex-specific manner. AB - Prenatal exposure to tobacco smoke is a significant risk-factor for airway disease development. Furthermore, the high prevalence of pregnant smoking women requires the establishment of strategies for offspring lung protection. Therefore, we here aimed to understand the molecular mechanism of how prenatal smoke exposure affects fetal lung development. We used a mouse model recapitulating clinical findings of prenatally exposed children, where pregnant mice were exposed to smoke until c-section or spontaneous delivery, and offspring weight development and lung function was monitored. Additionally, we investigated pulmonary transcriptome changes in fetal lungs (GD18.5) by mRNA/miRNA arrays, network analyses and qPCR. The results demonstrated that prenatally exposed mice showed intrauterine and postnatal growth retardation, and impaired lung function. 1340 genes and 133 miRNAs were found to be significantly dysregulated by in utero smoke exposure, and we identified Insulin-like growth factor 1 (Igf1) as a top hierarchical node in a network analysis. Moreover, Igf1 mRNA was increased in female murine offspring and in prenatally exposed children. These findings suggest that prenatal smoking is associated with a dysregulation of several genes, including Igf1 in a sex-specific manner. Thus, our results could represent a novel link between smoke exposure, abberant lung development and impaired lung function. PMID- 29765133 TI - BAT 'talks' to muscles. PMID- 29765132 TI - Stars of neurology meet at AAN 2018. PMID- 29765134 TI - Low-protein diet in cancer: ready for prime time? PMID- 29765130 TI - Copy number variants implicate cardiac function and development pathways in earthquake-induced stress cardiomyopathy. AB - The pathophysiology of stress cardiomyopathy (SCM), also known as takotsubo syndrome, is poorly understood. SCM usually occurs sporadically, often in association with a stressful event, but clusters of cases are reported after major natural disasters. There is some evidence that this is a familial condition. We have examined three possible models for an underlying genetic predisposition to SCM. Our primary study cohort consists of 28 women who suffered SCM as a result of two devastating earthquakes that struck the city of Christchurch, New Zealand, in 2010 and 2011. To seek possible underlying genetic factors we carried out exome analysis, genotyping array analysis, and array comparative genomic hybridization on these subjects. The most striking finding was the observation of a markedly elevated rate of rare, heterogeneous copy number variants (CNV) of uncertain clinical significance (in 12/28 subjects). Several of these CNVs impacted on genes of cardiac relevance including RBFOX1, GPC5, KCNRG, CHODL, and GPBP1L1. There is no physical overlap between the CNVs, and the genes they impact do not appear to be functionally related. The recognition that SCM predisposition may be associated with a high rate of rare CNVs offers a novel perspective on this enigmatic condition. PMID- 29765135 TI - Invisible light inside the natural blind spot alters brightness at a remote location. AB - The natural blind spot in the visual field has been known as a large oval region that cannot receive any optical input because it corresponds to the retinal optic disk containing no rod/cone-photoreceptors. Recently, stimulation inside the blind spot was found to enhance, but not trigger, the pupillary light reflex. However, it is unknown whether blind-spot stimulation also affects visual perception. We addressed this question using psychophysical brightness-matching experiments. We found that a test stimulus outside the blind spot was judged as darker when it was accompanied by a consciously unexperienced blue oval inside the blind spot; moreover, the pupillary light reflex was enhanced. These findings suggested that a photo-sensitive mechanism inside the optic disk, presumably involving the photopigment melanopsin, contributes to our image-forming vision and provides a 'reference' for calibrating the perceived brightness of visual objects. PMID- 29765137 TI - Neurobiological similarities between RA and fibromyalgia. PMID- 29765136 TI - Detection of malaria sporozoites expelled during mosquito sugar feeding. AB - Malaria is a severe disease of global importance transmitted by mosquitoes of the genus Anopheles. The ability to rapidly detect the presence of infectious mosquitoes able to transmit malaria is of vital importance for surveillance, control and elimination efforts. Current methods principally rely on large-scale mosquito collections followed by labour-intensive salivary gland dissections or enzyme-linked immunosorbent (ELISA) methods to detect sporozoites. Using forced salivation, we demonstrate here that Anopheles mosquitoes infected with Plasmodium expel sporozoites during sugar feeding. Expelled sporozoites can be detected on two sugar-soaked substrates, cotton wool and Whatman FTA cards, and sporozoite DNA is detectable using real-time PCR. These results demonstrate a simple and rapid methodology for detecting the presence of infectious mosquitoes with sporozoites and highlight potential laboratory applications for investigating mosquito-malaria interactions. Our results indicate that FTA cards could be used as a simple, effective and economical tool in enhancing field surveillance activities for malaria. PMID- 29765138 TI - Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. AB - PURPOSE: To systematically investigate the longer-term clinical and health economic impacts of genomic sequencing for rare-disease diagnoses. METHODS: We collected information on continuing diagnostic investigation, changes in management, cascade testing, and parental reproductive outcomes in 80 infants who underwent singleton whole-exome sequencing (WES). RESULTS: The median duration of follow-up following result disclosure was 473 days. Changes in clinical management due to diagnostic WES results led to a cost saving of AU$1,578 per quality-adjusted life year gained, without increased hospital service use. Uninformative WES results contributed to the diagnosis of non-Mendelian conditions in seven infants. Further usual diagnostic investigations in those with ongoing suspicion of a genetic condition yielded no new diagnoses, while WES data reanalysis yielded four. Reanalysis at 18 months was more cost-effective than every 6 months. The parents of diagnosed children had eight more ongoing pregnancies than those without a diagnosis. Taking the costs and benefits of cascade testing and reproductive service use into account, there was an additional cost of AU$8,118 per quality-adjusted life year gained due to genomic sequencing. CONCLUSION: These data strengthen the case for the early use of genomic testing in the diagnostic trajectory, and can guide laboratory policy on periodic WES data reanalysis. PMID- 29765139 TI - Is universal tumor testing for Lynch syndrome cost-effective? It depends! PMID- 29765140 TI - Comment on "Resistance training alone reduces systolic and diastolic blood pressure in prehypertensive and hypertensive individuals: meta-analysis". PMID- 29765141 TI - Polyoma virus-associated carcinomas of the urologic tract: a clinicopathologic and molecular study. AB - In recent years, there has been increased interest in carcinomas of the urologic tract, that demonstrate association with the polyoma virus BK arising in immunosuppressed individuals, though the nature of this association is uncertain. To begin to understand this phenomenon, we reviewed the clinical, morphological, and immunohistochemical features of 11 carcinomas of the urologic tract, mainly urothelial (N = 9) and collecting duct carcinomas (N = 2), occurring during immunosuppression, and expressing polyoma virus T-antigen by immunohistochemistry. These were compared to a control group of carcinomas (N = 8), also arising during immunosuppression, but without T-antigen expression. A subset of both groups were also studied by hybrid capture-based DNA sequencing, probing not only for 479 cancer-related human genes, but also for polyoma and other viral sequences. Polyoma T-antigen-expressing tumors arose in 7 males and 4 females, at a median age of 66, and were aggressive, high-grade tumors with more than 1 variant morphologic pattern identified in 81% of cases, and a majority (73%) presenting at high stage category (>pT3). Diffuse polyoma T-antigen staining was seen in 91% of cases, with co-localization of aberrant p53 staining in 89%. Sequencing detected a lower number of deleterious mutations among T antigen-expressing cases (average 1.62; 1/8 with TP53 mutation) compared to control cases (average 3.5, 2/4 with TP53 mutation). Only BK virus was detected with clonal integration and breakpoints randomly distributed across the human and viral genomes in 5/5 of the polyoma T-antigen-expressing carcinomas, and in none of the controls (0/4). In summary, these findings identify aggressive clinicopathologic features of polyoma T-antigen-expressing carcinomas, document BK as the strain involved, and associate BK viral integration with T-antigen expression and p53 aberrancy. While the apparent randomness of viral insertion sites is functionally unclear, the differing rates of mutations between T-antigen expressing and control cases is intriguing. PMID- 29765142 TI - Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement. AB - Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-kappaB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-kappaB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma. PMID- 29765143 TI - Other immunomodulatory agent-related lymphoproliferative diseases: a single center series of 72 biopsy-confirmed cases. AB - Ongoing development of new drugs, as well as novel indications in the treatment of autoimmune diseases leads to the increasing use of immunomodulatory and immunosuppressive drugs. Immunomodulatory agent-related lymphoproliferative disorders are a known and potentially life threatening complication of chronic administration of these drugs, but are less well characterized compared with post transplant lymphoproliferative disorders. The heterogeneous drug targets, various underlying disease indications, different drug combinations used and relatively low incidence render data collection and interpretation difficult. In this retrospective paper, we describe the clinicopathological characteristics of a larger single-center series of 72 immunomodulatory agent-related lymphoproliferative disorder cases. We divided the cases according to the therapy, administered in the year preceding diagnosis of a lymphoproliferative disorder, in an immunosuppressive drug, an immunomodulatory drug and a combination of immunosuppressive and immunomodulatory drugs group. We observed differences in "time to lymphoproliferative disorder development" with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive-only (p = 0.0031). The proportion of malignant cases in patients receiving immunomodulatory therapy was, however, also significantly lower when compared with the immunosuppressive treated cases (43 vs 88%; p = 0.0184). The immunomodulatory/suppressive agent-related lymphoproliferative disorders were less often associated with the Epstein-Barr virus (EBV) (31 vs 66%; p = 1.829e-05) and the lymphoproliferative disorders incidence in the first year after immunomodulatory/immunosuppressive therapy initiation was lower (18 vs 41%; p = 0.04151)-compared with a published series of 140 post-transplant lymphoproliferative disorder cases from the same center. However, a similar histopathological spectrum from nondestructive, to polymorphic and monomorphic lesions as in post-transplant lymphoproliferative disorders is observed. With increasing use of immunosuppressive and especially immunomodulatory therapy, a higher incidence of immunomodulatory/suppressive agent-related lymphoproliferative disorders is to be expected. Life-long awareness for development of immunomodulatory/suppressive agent-related lymphoproliferative disorders with clinical follow-up and timely biopsies of suspicious lesions is required since these lymphoproliferative disorders arise both early after therapy initiation and many years later. Histopathological confirmation and correct classification is necessary to guide therapy and EBV ISH should be a part of routine pathological diagnostics. PMID- 29765145 TI - Optimizing radiotherapy for intermediate-risk localized disease. PMID- 29765146 TI - Do dietary calcium and vitamin D matter in men with prostate cancer? AB - Active surveillance (AS) is an attractive alternative to immediate treatment for men with low-risk prostate cancer. Thus, the identification of environmental factors that promote the progression of indolent disease towards aggressive stages is critical to optimize clinical management. Epidemiological studies suggest that calcium-rich diets contribute to an increased risk of developing prostate cancer and that vitamin D reduces this risk. However, the potential effect of these nutrients on the progression of early-stage prostate tumours is uncertain, as studies in this setting are scarce and have not provided unambiguous conclusions. By contrast, the results of a preclinical study from our own group demonstrate that a diet high in calcium dose-dependently accelerated the progression of early-stage prostate tumours and that dietary vitamin D prevented this effect. The extent to which the conclusions of preclinical and epidemiological studies support a role for calcium and vitamin D and the relevance of monitoring and adjustment of calcium and/or vitamin D intake in patients on AS require further investigation. PMID- 29765144 TI - Mind Wandering and Task-Focused Attention: ERP Correlates. AB - Previous studies looking at how Mind Wandering (MW) impacts performance in distinct Focused Attention (FA) systems, using the Attention Network Task (ANT), showed that the presence of pure MW thoughts did not impact the overall performance of ANT (alert, orienting and conflict) performance. However, it still remains unclear if the lack of interference of MW in the ANT, reported at the behavioral level, has a neurophysiological correspondence. We hypothesize that a distinct cortical processing may be required to meet attentional demands during MW. The objective of the present study was to test if, given similar levels of ANT performance, individuals predominantly focusing on MW or FA show distinct cortical processing. Thirty-three healthy participants underwent an EEG high density acquisition while they were performing the ANT. MW was assessed following the ANT using an adapted version of the Resting State Questionnaire (ReSQ). The following ERP's were analyzed: pN1, pP1, P1, N1, pN, and P3. At the behavioral level, participants were slower and less accurate when responding to incongruent than to congruent targets (conflict effect), benefiting from the presentation of the double (alerting effect) and spatial (orienting effect) cues. Consistent with the behavioral data, ERP's waves were discriminative of distinct attentional effects. However, these results remained true irrespective of the MW condition, suggesting that MW imposed no additional cortical demand in alert, orienting, and conflict attention tasks. PMID- 29765147 TI - Systemic treatments for high-risk localized prostate cancer. AB - The majority of patients with prostate cancer who later develop lethal metastatic disease have high-risk localized disease at presentation, emphasizing the importance of effective treatment strategies at this stage. Multimodal treatment approaches that combine systemic and local therapies offer a promising strategy for improving the clinical outcomes of patients with high-risk localized prostate cancer. Combinations of neoadjuvant and adjuvant chemotherapy, hormonal therapy, or chemohormonal therapy are considered to be the standard of care in most solid tumours and should be investigated in the future for the treatment of prostate cancer to improve patient outcomes. However, although the combination of androgen deprivation therapy and radiotherapy is a standard of care in high-risk localized or locally advanced prostate cancer, the benefit of chemotherapy or chemohormonal therapy has yet to be demonstrated outside of the metastatic setting. Moreover, the benefit of neoadjuvant and/or adjuvant systemic therapies in combination with radical prostatectomy has not been proved. The development of next-generation hormonal agents, which have been approved for the treatment of castration resistant prostate cancer, offers further therapeutic possibilities that are being assessed in early-phase clinical trials. PMID- 29765148 TI - Cancer subtype identification using somatic mutation data. AB - BACKGROUND: With the onset of next-generation sequencing technologies, we have made great progress in identifying recurrent mutational drivers of cancer. As cancer tissues are now frequently screened for specific sets of mutations, a large amount of samples has become available for analysis. Classification of patients with similar mutation profiles may help identifying subgroups of patients who might benefit from specific types of treatment. However, classification based on somatic mutations is challenging due to the sparseness and heterogeneity of the data. METHODS: Here we describe a new method to de sparsify somatic mutation data using biological pathways. We applied this method to 23 cancer types from The Cancer Genome Atlas, including samples from 5805 primary tumours. RESULTS: We show that, for most cancer types, de-sparsified mutation data associate with phenotypic data. We identify poor prognostic subtypes in three cancer types, which are associated with mutations in signal transduction pathways for which targeted treatment options are available. We identify subtype-drug associations for 14 additional subtypes. Finally, we perform a pan-cancer subtyping analysis and identify nine pan-cancer subtypes, which associate with mutations in four overarching sets of biological pathways. CONCLUSIONS: This study is an important step toward understanding mutational patterns in cancer. PMID- 29765149 TI - MASAN: a novel staging system for prognosis of patients with oesophageal squamous cell carcinoma. AB - BACKGROUND: Oesophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers worldwide. Treatment of ESCC is in progress through accurate staging and risk assessment of patients. The emergence of potential molecular markers inspired us to construct novel staging systems with better accuracy by incorporating molecular markers. METHODS: We measured H scores of 23 protein markers and analysed eight clinical factors of 77 ESCC patients in a training set, from which we identified an optimal MASAN (MYC, ANO1, SLC52A3, Age and N stage) signature. We constructed MASAN models using Cox PH models, and created MASAN-staging systems based on k-means clustering and minimum-distance classifier. MASAN was validated in a test set (n = 77) and an independent validation set (n = 150). RESULTS: MASAN possessed high predictive accuracies and stratified ESCC patients into three prognostic groups that were more accurate than the current pTNM-staging system for both overall survival and disease-free survival. To facilitate clinical utilisation, we also constructed MASAN-SI staging systems based on staining indices (SI) of protein markers, which possessed similar prognostic performance as MASAN. CONCLUSION: MASAN provides a good alternative staging system for ESCC prognosis with a high precision using a simple model. PMID- 29765150 TI - Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers. AB - BACKGROUND: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208. RESULTS: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208. CONCLUSIONS: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents. PMID- 29765151 TI - Apatorsen plus docetaxel versus docetaxel alone in platinum-resistant metastatic urothelial carcinoma (Borealis-2). AB - BACKGROUND: A randomised study to assess the addition of apatorsen, an antisense oligonucleotide that inhibits Hsp27 expression, to docetaxel in patients with metastatic urothelial carcinoma (mUC) relapsed after prior platinum-based chemotherapy. METHODS: Multicentre, phase II study with 1:1 randomisation to apatorsen (three loading doses at 600 mg intravenous followed by weekly doses) plus docetaxel (75 mg/m2 intravenous every 21 days) (A/D) or docetaxel alone. Overall survival (OS) was the primary end point with a P value <0.1 (one-sided) being positive. Progression-free survival (PFS), objective response rate (ORR), safety, and effect of Hsp27 levels on outcomes were secondary end points. RESULTS: Patients randomised to A/D (n = 99) had improved OS compared to docetaxel alone (n = 101): HR: 0.80, 80% CI: 0.65-0.98, P = 0.0784, median 6.4 vs 5.9 months. PFS and ORR were similar in both arms. A/D had more incidence of sepsis and urinary tract infections. Patients with baseline Hsp27 levels <5.7 ng/mL had improved OS compared to those with levels >=5.7 ng/mL. Patients with a decline or <=20.5% increase in Hsp27 from baseline benefited more from A/D than those with >20.5% increase. CONCLUSIONS: A/D met its predefined OS end point in patients with platinum-refractory mUC in this phase II trial. This trial is hypothesis generating requiring further study before informing practice. PMID- 29765152 TI - Illusory body ownership of an invisible body interpolated between virtual hands and feet via visual-motor synchronicity. AB - Body ownership can be modulated through illusory visual-tactile integration or visual-motor synchronicity/contingency. Recently, it has been reported that illusory ownership of an invisible body can be induced by illusory visual-tactile integration from a first-person view. We aimed to test whether a similar illusory ownership of the invisible body could be induced by the active method of visual motor synchronicity and if the illusory invisible body could be experienced in front of and facing away from the observer. Participants observed left and right white gloves and socks in front of them, at a distance of 2 m, in a virtual room through a head-mounted display. The white gloves and socks were synchronized with the observers' actions. In the experiments, we tested the effect of synchronization, and compared this to a whole-body avatar, measuring self localization drift. We observed that visual hands and feet were sufficient to induce illusory body ownership, and this effect was as strong as using a whole body avatar. PMID- 29765153 TI - COX-2 mediates pro-tumorigenic effects of PKCepsilon in prostate cancer. AB - The pro-oncogenic kinase PKCepsilon is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCepsilon-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCepsilon overexpression acts synergistically with Pten loss to promote NF-kappaB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCepsilon from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCepsilon, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCepsilon expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-kappaB pathway and its target gene COX2 as PKCepsilon effectors, and highlight the potential of PKCepsilon as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer. PMID- 29765154 TI - The cancer-associated microprotein CASIMO1 controls cell proliferation and interacts with squalene epoxidase modulating lipid droplet formation. AB - Breast cancer is a leading cause of cancer-related death in women. Small open reading frame (sORF)-encoded proteins or microproteins constitute a new class of molecules often transcribed from presumed long non-coding RNA transcripts (lncRNAs). The translation of some of these sORFs has been confirmed, but their cellular function and importance remains largely unknown. Here, we report the identification and characterization of a novel microprotein of 10 kDa, which we named Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1). CASIMO1 RNA is overexpressed predominantly in hormone receptor-positive breast tumors. Its knockdown leads to decreased proliferation in multiple breast cancer cell lines. Its loss disturbs the organization of the actin cytoskeleton, leads to inhibition of cell motility, and causes a G0/G1 cell cycle arrest. The proliferation phenotype upon overexpression is observed only with CASIMO1 protein expression, but not with a non-translatable mutant attributing the effects to the sORF-derived protein rather than a lncRNA function. CASIMO1 microprotein interacts with squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis and a known oncogene in breast cancer. Overexpression of CASIMO1 leads to SQLE protein accumulation without affecting its RNA levels and increased lipid droplet clustering, while knockdown of CASIMO1 decreased SQLE protein abundance and ERK phosphorylation downstream of SQLE. Importantly, SQLE knockdown mimicked the CASIMO1 knockdown phenotype and in turn SQLE overexpression fully rescued the effect of CASIMO1 knockdown. These findings establish CASIMO1 as the first functional microprotein that plays a role in carcinogenesis and is implicated in the cell lipid homeostasis. PMID- 29765156 TI - gammadeltaTCR regulates production of interleukin-27 by neutrophils and attenuates inflammatory arthritis. AB - gammadelta T cells have been implicated in inflammatory diseases as an important link between the innate and adaptive immune responses, however, their role in inflammatory arthritis remain unclear. To define the contribution of gammadelta T cells in the pathogenesis of inflammatory arthritis, we performed gene transfer of IL-23 in B10.RIII mice to establish joint inflammation in the presence or absence of gammadelta T cells. We demonstrated that gammadelta T cell blockade has a protective effect on arthritis incidence and severity by preventing neutrophil accumulation in the blood, spleen and bone marrow as well as by reducing neutrophil infiltration into the joints. Furthermore, our data demonstrate that absence of gammadelta T cells was associated with an increase of IL-27 levels produced by neutrophils and dendritic cells, and systemic IL-27 expression also prevents IL-23-induced inflammatory arthritis and limits neutrophil expansion. Collectively our findings reveal an immunomodulatory effect of gammadelta T cells on neutrophils associated with IL-27 synthesis and secretion and indicate a novel link between IL-27 and the modulation of gammadelta T cells and neutrophils that can be targeted in the treatment of inflammatory arthritis. PMID- 29765157 TI - Retinal findings in a patient with mutations in ABCC6 and ABCA4. PMID- 29765158 TI - Stepping outside the comfort zone of membrane contact site research. PMID- 29765160 TI - Author Correction: Effects of adolescent alcohol consumption on the brain and behaviour. AB - In the initially published version of this article, the following sentence was incorrect: "Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adolescence are generally not evident or are less pronounced than after comparable alcohol exposure in adulthood". The sentence should have read: "Studies that have compared equivalent exposures to alcohol in adolescent and adult animals have found that the effects of alcohol exposure during adulthood are generally not evident or are less pronounced than after comparable alcohol exposure in adolescence". The sentence has been corrected in the HTML and PDF versions of the article. PMID- 29765159 TI - Transition to chronic pain: opportunities for novel therapeutics. PMID- 29765162 TI - Scrutinizing spliceosomes. PMID- 29765161 TI - Expanding the BLUP alphabet for genomic prediction adaptable to the genetic architectures of complex traits. AB - Improvement of statistical methods is crucial for realizing the potential of increasingly dense genetic markers. Bayesian methods treat all markers as random effects, exhibit an advantage on dense markers, and offer the flexibility of using different priors. In contrast, genomic best linear unbiased prediction (gBLUP) is superior in computing speed, but only superior in prediction accuracy for extremely complex traits. Currently, the existing variety in the BLUP method is insufficient for adapting to new sequencing technologies and traits with different genetic architectures. In this study, we found two ways to change the kinship derivation in the BLUP method that improve prediction accuracy while maintaining the computational advantage. First, using the settlement under progressively exclusive relationship (SUPER) algorithm, we substituted all available markers with estimated quantitative trait nucleotides (QTNs) to derive kinship. Second, we compressed individuals into groups based on kinship, and then used the groups as random effects instead of individuals. The two methods were named as SUPER BLUP (sBLUP) and compressed BLUP (cBLUP). Analyses on both simulated and real data demonstrated that these two methods offer flexibility for evaluating a variety of traits, covering a broadened realm of genetic architectures. For traits controlled by small numbers of genes, sBLUP outperforms Bayesian LASSO (least absolute shrinkage and selection operator). For traits with low heritability, cBLUP outperforms both gBLUP and Bayesian LASSO methods. We implemented these new BLUP alphabet series methods in an R package, Genome Association and Prediction Integrated Tool (GAPIT), available at http://zzlab.net/GAPIT . PMID- 29765155 TI - Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. AB - The programmed death protein 1 (PD-1) and its ligand (PD-L1) represent a well characterized immune checkpoint in cancer, effectively targeted by monoclonal antibodies that are approved for routine clinical use. The regulation of PD-L1 expression is complex, varies between different tumor types and occurs at the genetic, transcriptional and post-transcriptional levels. Copy number alterations of PD-L1 locus have been reported with varying frequency in several tumor types. At the transcriptional level, a number of transcriptional factors seem to regulate PD-L1 expression including HIF-1, STAT3, NF-kappaBeta, and AP-1. Activation of common oncogenic pathways such as JAK/STAT, RAS/ERK, or PI3K/AKT/MTOR, as well as treatment with cytotoxic agents have also been shown to affect tumoral PD-L1 expression. Correlative studies of clinical trials with PD 1/PD-L1 inhibitors have so far shown markedly discordant results regarding the value of PD-L1 expression as a marker of response to treatment. As the indications for immune checkpoint inhibition broaden, understanding the regulation of PD-L1 in cancer will be of utmost importance for defining its role as predictive marker but also for optimizing strategies for cancer immunotherapy. Here, we review the current knowledge of PD-L1 regulation, and its use as biomarker and as therapeutic target in cancer. PMID- 29765163 TI - Polyunsaturated fatty acid status at birth, childhood growth, and cardiometabolic risk: a pooled analysis of the MEFAB and RHEA cohorts. AB - BACKGROUND/OBJECTIVES: Polyunsaturated fatty acid (PUFA) status during pregnancy has been suggested to influence offspring obesity and cardiometabolic health. We assessed whether prenatal PUFA exposure is associated with rapid infant growth, childhood BMI, and cardiometabolic profile. SUBJECTS/METHODS: In the Dutch MEFAB (n = 266) and Greek RHEA (n = 263) cohorts, we measured n-3 and n-6 PUFA concentrations in cord blood phospholipids, which reflect fetal exposure in late pregnancy. We defined rapid infant growth from birth to 6 months of age as an increase in weight z-score >0.67. We analyzed body mass index (BMI) as continuous and in categories of overweight/obesity at 4 and 6 years. We computed a cardiometabolic risk score at 6-7 years as the sum of waist circumference, non high-density lipoprotein cholesterol and blood pressure z-scores. Associations of PUFAs with child health outcomes were assessed using generalized linear models for binary outcomes and linear regression models for continuous ones after adjusting for important covariates, and for the pooled estimates, a cohort indicator. RESULTS: In pooled analyses, we found no association of PUFA levels with rapid infant growth, childhood BMI (beta per SD increase in the total n-3:n 6 PUFA ratio = -0.04 SD; 99% CI: -0.15, 0.06; P = 0.65 at 4 years, and -0.05 SD; 99% CI: -0.18, 0.08; P = 0.78 at 6 years), and overweight/obesity. We also found no associations for clustered cardiometabolic risk and its individual components. The results were similar across cohorts. CONCLUSIONS: Our findings suggest that PUFA concentrations at birth are not associated with later obesity development and cardiometabolic risk in childhood. PMID- 29765164 TI - Intake of polyunsaturated fatty acids and risk of preclinical and clinical type 1 diabetes in children-a systematic review and meta-analysis. AB - BACKGROUND/OBJECTIVES: The association between the intake of polyunsaturated fatty acids (PUFAs) and the risk of preclinical and clinical type 1 diabetes (T1D) in children has generated conflicting results. Thus, we aimed to evaluate the definite effects of PUFAs on the risk of preclinical and clinical T1D. SUBJECTS/METHODS: Three databases were systematically searched up to July 18, 2017 to identify relevant observational studies, without language restriction. Any study included should report the risk of preclinical or clinical T1D in children with PUFAs supplementation compared with the controls, and report relative risks (RRs) or odds ratios (ORs) or provide data for estimation. Pooled RRs (or ORs) with 95% confidence intervals (CI) were calculated using random effects models irrespective of statistical heterogeneity assessed by I2 statistic. RESULTS: We identified seven studies (three prospective cohort studies and four case-control studies) on PUFAs intake during pregnancy or during early life in children. The pooled RR between the risk of preclinical T1D and n-3 PUFAs supplementation against controls was 0.98 (95%CI, 0.85-1.13), with no heterogeneity. The results were similar after the intake during pregnancy, but not during early life in children (pooled RR, 0.45; 95%CI, 0.21-0.96; P = 0.039). N-3 PUFAs supplementation was not associated with a significant reduction in the risk of clinical T1D in children (pooled RR, 0.87; 95%CI, 0.71-1.08), with substantial heterogeneity(I2 = 64.7%). No association was also found between n-6 PUFAs intake and the risk of preclinical (1.07; 0.97-1.017) or clinical T1D (1.05; 0.92-1.20) in children. CONCLUSIONS: The result of the meta-analysis does not support that n-3 or n-6 PUFAs supplementation in children affects the overall risk of preclinical or clinical T1D. However, n-3 PUFAs intake in early life might reduce the risk of preclinical T1D. Therefore, this finding should be verified by more and well-designed prospective research in the future. PMID- 29765165 TI - Detection of cytomegalovirus DNA in fecal samples in the diagnosis of enterocolitis after allogeneic stem cell transplantation. AB - BACKGROUND: Cytomegalovirus enterocolitis is a rare but potentially life threatening complication after allogeneic stem cell transplantation. Its early diagnosis and treatment are essential for a successful outcome. OBJECTIVE: To determine the potential benefit of fecal CMV DNA detection in the diagnosis of CMV colitis among stem cell transplant recipients. STUDY DESIGN: Biopsies from the lower gastrointestinal tract, taken during 69 episodes of diarrhea, were compared with fecal samples previously examined for CMV DNA in 45 patients after allogeneic stem cell transplantation. RESULTS: Six confirmed cases of CMV colitis were observed, with 16 out of 69 (23%) fecal samples proving positive for CMV DNA. Only one positive sample correlated with histologically confirmed CMV colitis, and 15 samples were evaluated as false positive. These results provide a 16.7% sensitivity and 76.2% specificity in the diagnosis of CMV enterocolitis. CONCLUSION: The examination of fecal samples for the presence of CMV DNA has very low potential in the diagnosis of CMV enterocolitis after allogeneic stem cell transplantation; therefore, a biopsy of the gastrointestinal mucosa is still warranted for correct diagnosis. PMID- 29765166 TI - Diagnosis of retrocochlear lesions with emphasis on expansion of the cerebellopontine angle. AB - The correct diagnosis of CPA tumours is a relatively common issue in both neurological and ENT practice, the omission of which can have serious consequences for the patient. Properly set clinical guidelines and diagnostic protocols are key aspects of good clinical practice. In the case of CPA tumours, two options are available: the first is diagnosis with the help of an ABR as the primary tool for determining the group of patients with a possible tumour; the second is an MRI scan of the posterior cranial fossa. With an appropriately set diagnostic protocol in place, and despite the 40% chance of failure of the ABR to detect tumours less than or equal to 1 cm, similar treatment results can be achieved with much higher cost efficacy in case of primary ABR testing. PMID- 29765167 TI - The mineral content of the hard dental tissue of mesiodens. AB - OBJECTIVE: Mesiodens is the most common form of supernumerary tooth mainly located between the maxillary central incisors. Its etiology is not completely understood but both genetic and environmental factors are assumed. The degree of mineralization and inorganic element content in hard tooth tissues is poorly understood as well as is the durability and suitability for allo- and auto transplantation. Therefore aim of this study was to examine the content of inorganic elements. MATERIALS AND METHODS: This study included 26 mesiodens teeth and 26 normal central incisor teeth as controls. All specimens were prepared for SEM/EDS analysis which was aimed at specific sites on the enamel, dentine and cementum in order to evaluate the weight percentage and ratio of important inorganic elements. RESULTS: and Conclusion. The results showed that there was a difference in the weight percentage of selected inorganic elements (calcium, phosphorus, oxygen, carbon, magnesium and sodium) in all three types of dental hard tissues but the differences were mostly expressed in the cementum tissue. The statistical analysis showed that the differences were marginally significant especially for calcium and phosphorus values and ratio in the enamel and dentine. The carbon and magnesium content in all three hard tissues showed the most differences, but overall, the hard tissues mineral content of the mesiodens did not differs significantly from healthy teeth. PMID- 29765168 TI - Mucosal delivery systems of antihypertensive drugs: A practical approach in general practice. AB - Patients who are unable to receive oral medication (p.o.) are a major problem in outpatient settings, especially in home health care systems. Mucosal administration of drugs offers an alternative to the oral route, especially when the parenteral mode cannot be used. There are three main pathways of mucosal administration: sublingual/buccal, intranasal and rectal. We discuss the possibility of mucosal delivery of antihypertensive drugs. Perindopril arginine and Amlodipine besylate are registered in the EU as orodispersible tablets for oromucosal delivery, however, they are not available in all countries. For this reason, we describe other drugs suitable for mucosal delivery: Captopril and Nitrendipine in the sublingual system and Metoprolol tartrate, Propranolol and Furosemide by the transrectal route. Based on the published data and common clinical practice we discuss the use of mucosal delivery systems of all these antihypertensive drugs with special attention to their pharmacokinetics. We illustrate this mini-review with a case report of the prolonged-term use of mucosal delivery of sublingual Captopril and Nitrendipine combined with rectal Metoprolol tartrate and Furosemide in a patient with severe hypertension unable to receive medication p.o. This is also a report on the first human use of Furosemide-containing suppositories as well as prolonged-term transmucosal administration of these four drugs, describing a practical approach leading to successful control of severe hypertension with four antihypertensive drugs delivered via the mucosal route. The treatment was effective and without side effects; however, the long-term safety and efficacy of such therapy must be confirmed by randomized clinical trials. PMID- 29765169 TI - M1/M2 macrophage polarization in human obese adipose tissue. AB - Obesity and insulin resistance are closely associated with chronic inflammation in adipose tissue, where macrophages play an important role. Adipose tissue macrophages can be divided into two main phenotypes: the classical M1 macrophages and alternatively activated macrophages M2. M1 macrophages produce pro inflammatory cytokines (TNF-alpha, interleukin IL-6 and MCP-1) and thus contribute to the development of insulin resistance. On the other hand, M2 macrophages, anti-inflammatory, are involved in the maintenance of tissue homeostasis and are typical in the adipose tissue of slender individuals. Macrophages can also play a role in the pathogenesis of other serious illnesses such as cardiovascular diseases or cancer. This article reviews the latest data on macrophage polarization in adipose tissue. PMID- 29765170 TI - BK virus-induced renal allograft nephropathy. AB - BK virus nephropathy (BKVN) is a serious opportunistic infection threatening renal function especially during the first year after transplantation. Its incidence is now on the rise and is closely related to the level of the recipient's immune system inhibition. This is more intensive with current trends in transplantation medicine, where more potent immunosuppressive protocols are used and more aggressive antirejection therapy is applied. In the absence of BK virus (BKV) specific therapy and limited treatment options for advanced BKVN, active screening of BKV replication and subsequent preemptive adjustment of immunosuppression are essential measures to prevent BKVN. However, it remains unclear how to modify immunosuppressive protocols as well as how to address initial stages of BKV replication. This comprehensive review summarizes the currently applied and not completely uniform procedures for the detection, prophylaxis and therapy of BKV replication and BKVN. The pitfalls brought by reduced immunosuppression, as a typical response to a significant viral replication or a developed BKVN, are also mentioned, particularly in the form of graft rejection. The paper also outlines the authors' experiences, and lists currently ongoing studies on the subject. The perspectives of new, especially immune-based, procedures in the treatment of complications associated with BKV infections are highlighted. Different views on the management of patients indicated for kidney re-transplantation whose previous graft failed because of BKVN are also discussed. PMID- 29765171 TI - Risks and protective factors for triple negative breast cancer with a focus on micronutrients and infections. AB - Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) with a poor prognosis. Second, patients cannot benefit from targeted therapy, except for those with BRCA1/2 mutations, for whom poly (ADP-ribose) polymerase (PARP) inhibition therapy using olaparib has recently been approved. As global priorities continue to be epidemiological analysis of BC risk factors and early diagnosis, this review focuses on the risks and protective factors associated with TNBC. A PubMed keyword search for new knowledge on the risks and protective factors for TNBC was carried out. We also found statistical information from current online databases concerning the estimated incidence, prevalence and mortality worldwide of this cancer. Traditional risk factors for BC and TNBC are those related to reproduction such as the age of menarche, age of first birth, parity, breastfeeding and age at menopause. Attention needs to be paid to familial BC, weight control, alcohol consumption and regular physical activity. Epidemiological studies on TNBC provide evidence for protective factors such as regular consumption of soya, seafood, green tea, folic acid and vitamin D. Potential risk factors may include night work and viral infectious agents like human papillomavirus (HPV) and Epstein-Barr virus (EBV). Droplet digital methylation-specific PCR (ddMSP) is a possible new screening method for detection of BC including TNBC. Further research is necessary to validate these new factors. PMID- 29765173 TI - Hemodiafiltration and plasma levels of axitinib in a patient with metastatic renal clear cell carcinoma. AB - BACKGROUND: The standard treatment for metastatic renal cancer is based on vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTor) inhibitors. Compared to other advanced tumors, the treatment of renal cancer is highly affected by impaired renal function; therefore, patients with severe renal insufficiency, including patients on hemodialysis, are generally excluded from clinical trials. CASE REPORT: In the present manuscript we present the case of a renal cancer patient who underwent bilateral nephrectomy and received two lines of treatment. We hypothesized that axitinib, a tyrosine kinase inhibitor, would have a similar plasma concentration to patients without hemodialysis and that the levels before and after hemodiafiltration will not differ significantly, as observed in other targeted therapies. CONCLUSION: The observed axitinib concentrations were at least an order of magnitude lower than expected based on the literature and measurements in other patients. The present case report indicates a potential risk of axitinib underdosing in patients on hemodiafiltration with the standard dose; therefore, drug dosage may need to be corrected based on the plasma levels of axitinib. PMID- 29765172 TI - Dietary sucrose regulates the expression of the Cd36 gene in hepatic tissue of rats with obesity and Non Alcoholic Fatty Liver Disease (NAFLD). AB - AIM: To evaluate the mRNA expression levels of Cd36 in adipose and hepatic tissues, in rats with NAFLD after the consumption of sucrose for 10 and 20 weeks. METHODS: Twenty Wistar rats, all nearly 21 days old were divided into two experimental groups (NAFLD-10 and NAFLD-20), that received a standard diet (2014 Teklad Global) plus 30% sucrose in their drinking water for 10 and 20 weeks and the control groups (C Groups). Variables such as body weight, food intakes, and serum parameters were measured. Adipose and hepatic tissues were extirpated; some tissue was preserved in formalin and some at -70 degrees C until analysis. Histological analysis was carried out, and the Cd36 mRNA expression levels were determined. RESULTS: The rats in the NAFLD-10 and NAFLD-20 groups showed a significative increase in abdominal fat, triglycerides, free fatty acids, insulin, AST, ALT, uric acid and HOMA index; as well as changes in the cellular dynamics in adipose tissue, (adipocytes hypertrophic: >1500 um2) with respect to the control groups (P<0.05). The histological analysis showed development of mild portal hepatitis in rats of the NAFLD-10 group and grade 1 hepatic steatosis with mild portal inflammation in rats of the NAFLD-20 group. Finally, Cd36 mRNA expression levels were significantly increased in hepatic tissue after 10 (1.5 fold) and 20 (3.5-fold) weeks of sucrose ingestion (P<0.05). CONCLUSION: mRNA expression is a molecular mechanism involved in the development of NAFLD associated with obesity in rats consuming sucrose. However, there was increased Cd36 mRNA expression only in hepatic tissue while in hypertrophic adipose tissue mRNA levels remained unchanged. PMID- 29765174 TI - Treatment of retinal capillary hemangioma using 810 nm infrared laser. AB - AIM: Presentation of the efficacy of infrared laser for the treatment of retinal capillary hemangioma (RCH). METHODS: The treatment and follow-up of nine eyes (fourteen tumors of different sizes and localizations) in seven patients (five children) with RCH. Infrared diode laser (810 nm) was used for modified transpupillary thermotherapy (TTT) in long exposition mode and power between 200 and 1200 mW with a beam diameter of 2 mm (indirect ophthalmoscope, +28 D or +40 D lens) or 0.5 mm-3 mm (slit-lamp) depending on the diameter and localisation of the hemangioma. RESULTS: We achieved complete destruction of the tumor with flat chorioretinal atrophic scar in all cases. Only one tumor regrowth was observed and re-treatment in this case was necessary. Treatment was combined with brachytherapy in a one case. There was one serious complication- total exudative retinal detachment, causing permanent deterioration in visual acuity despite pars plana vitrectomy (PPV). Other complications such as haze and vitreal hemorrhage were transient. The final best corrected visual acuity (BCVA) ranged from 20/20 to counting fingers at 2 feet. CONCLUSION: Infrared laser can be considered an acceptable therapeutic option for RCH especially for centrally localized lesions. We believe that the role of this therapy will increase in the future. PMID- 29765175 TI - The impact of walking speed on interlimb coordination in individuals with Parkinson's disease. AB - [Purpose] Interlimb coordination can be affected by the symptoms associated with Parkinson's disease and may result in an increased risk of falls. The purpose of the current study was to compare changes in interlimb coordination in individuals with Parkinson's disease to healthy older adults while systematically manipulating walking speed. [Subjects and Methods] Participants walked on a treadmill while systematically increasing and decreasing the walking speed between 0.22 and 1.30 m/s. Kinematic data were collected by means of a three dimensional motion capture system. Dependent variables included the phase relation between arm and leg movements as well as between pelvic and thoracic rotation. [Results] Compared to healthy controls, an increased variability in relative phase between left and right arm swing, and smaller amplitude with arm, leg as well as less variability for the phase relation between thoracic and pelvic rotations were shown in individuals with Parkinson's disease. [Conclusion] The increased variability of phase relation between left and right arm swing may be related to the reduced out-of-phase forcing of the arm movements at the shoulders as a result of axial rigidity in Parkinson's disease. It deserves further investigation whether the improvement of the coordination between arms could result in the normalization of parkinsonian gait. PMID- 29765177 TI - New estimation model of the initial lower limb angle to improve angle estimation during the extension phase of standing-up movement. AB - [Purpose] An estimation model of the knee and ankle joint angles during the extension phase was proposed in the previous study. However, it had limited use because of the fixed initial lower limb angle before standing up. This study aimed to propose a new estimation model of the initial lower limb angle to improve the angle estimation during extension phase. [Subjects and Methods] Seven healthy male volunteers were enrolled. The new estimation model approximated the initial lower limb angle using a force sensor plate that measured the plantar pressure of the subjects. The estimated angle and force were compared to those obtained by a motion capture system and force plate. [Results] The new estimation model of initial lower limb angle showed no significant difference compared with the true values obtained by motion capture, except for the subject who had a greater foot-pressure measurement error compared with the force plate measurement, with maximum errors of 5.98 degrees and 6.31 degrees , respectively. [Conclusion] The proposed model in this study can estimate the initial lower limb angle before standing and can be applied to the angle estimation model during the extension phase of the standing-up movement. PMID- 29765178 TI - Gender difference in factors affecting the medial longitudinal arch height of the foot in healthy young adults. AB - [Purpose] Medial longitudinal arch (MLA) height is associated with various injuries and diseases and gender differences, if any. This study aimed to examine factors affecting the MLA height associated with gender differences in healthy subjects with no orthopedic disorders. [Subjects and Methods] This study included 36 healthy adults (19 males, 17 females; mean age, 21.8 +/- 3.6 years; body mass index, 21.1 +/- 2.0 kg/m2). Their height, body weight, foot length, muscle strength of the tibialis posterior muscle (TPM), toe-gripping strength, hallux valgus angle, inversion microdactylia angle, angle of leg-heel alignment, femoro tibial angle, and navicular height were measured. Correlation between the ratio of arch height and other measurement parameters was examined. [Results] In females, the ratio of arch height was significantly positively correlated with muscle strength of the TPM and toe-gripping strength and negatively correlated with the hallux valgus angle and the leg-heel alignment, whereas in males, only a positive correlation between the ratio of arch height and muscle strength of the TPM was observed. [Conclusion] These results reveal that etiological mechanisms determining MLA height are different between males and females. Overall, the present results indicate that further studies identifying causes of MLA height variation must include gender-based analysis. PMID- 29765179 TI - Is early treatment for mild adolescent idiopathic scoliosis superior over the traditional 'watch & wait' approach? A case report with long-term follow-up. AB - [Purpose] To present a case of the complete correction of mild suspected adolescent idiopathic scoliosis in support of the argument that early aggressive treatment is superior to the traditional 'watch & wait' approach. [Subject and Methods] A 9-year-old female presented with a 14 degrees thoracic curve indicative of early adolescent idiopathic scoliosis. The parents consented to immediate and early treatment with the SpineCor dynamic and corrective scoliosis brace. The brace was worn 20 hours per day and check-ups were performed every three months. [Results] The patient achieved complete correction of the thoracic curve within 9-months. The child was followed for 4.5 years until she approached near cessation of skeletal growth (Risser sign grade 4) at the age of 14 years, 4 months. The patient's spine remained straight throughout the follow-up. [Conclusion] This report as well as others suggests that the SpineCor bracing system is a unique and effective intervention for mild scoliosis. Further, this case illustrates an ideal outcome and supports the argument that initiating treatment at the earliest indication of suspected idiopathic scoliosis should offer superior outcomes versus the traditional 'watch & wait' approach. Last, radiation exposures associated with radiography for scoliosis treatment and management are negligible and not harmful. PMID- 29765176 TI - Impairments of postural control, functional performance and strength in morbidly obese patients awaiting bariatric surgery in comparison to healthy individuals. AB - [Purpose] There is a lack of information evaluating specific markers of performance in patients awaiting bariatric surgery. We aimed to assess the postural control, functional performance, strength and endurance performance for morbidly obese patients awaiting bariatric surgery compared to lean controls. [Subjects and Methods] All parameters were assessed by modified Y-balance test, timed-up-and-go-test, maximum strength testing on resistance exercise equipment and cardio-pulmonary exercise testing on a cycle ergometer in 10 morbidly obese patients awaiting bariatric surgery and 10 age- and sex-matched lean controls. [Results] It was found that significant differences existed for overall modified Y-balance test in morbidly obese patients awaiting bariatric surgery versus lean controls (0.37 +/- 0.03 vs. 0.47 +/- 0.02 cm.cm-1), timed-up-and-go-test (9.33 +/ 1.23 vs. 7.85 +/- 1.73 sec) and several variables of cardio-pulmonary exercise testing. Overall absolute strength expressed in kilogram was similar, yet when relativized to body weight strength differences were notable (0.4 +/- 0.17 vs. 0.83 +/- 0.32 kg.kg-1). [Conclusion] The results of this study demonstrate the need for comprehensive functional assessment prior to surgery with an identified demand for subsequent tailored physical training prescription that should begin before surgery. PMID- 29765180 TI - Effects of circular gait training on balance, balance confidence in patients with stroke: a pilot study. AB - [Purpose] This study aimed to investigate the effects of circular gait training on balance and balance confidence in patients with stroke. [Subjects and Methods] Fifteen patients with stroke were randomly divided into either the circular gait training (CGT) group (n=8) or the straight gait training (SGT) group (n=7). Both groups had conventional therapy that adhered to the neurodevelopmental treatment (NDT) approach, for 30 min. In addition, the CGT group performed circular gait training, and the SGT group practiced straight gait training for 30 min. Each intervention was applied for 1 h, 5 days a week, for 2 weeks. Berg Balance Scale (BBS), Timed Up and Go (TUG) test, and Activities-specific Balance Confidence (ABC) scale were used to test balance and balance confidence. [Results] After the intervention, both groups showed significant increases in balance and balance confidence. Significant improvements in the balance of the CGT group compared with the SGT group were observed at post-assessment. [Conclusion] This study showed that circular gait training significantly improves balance in patients with stroke. PMID- 29765181 TI - Assessment of leg muscle activity using toe tapping in patients with Parkinson's disease: comparison of two types of toe tapping. AB - [Purpose] This study investigates two types of toe tapping, i.e., "closed," with both feet on the floor, and "open," in which the foot does not touch the ground, and evaluates their usefulness in combination with monitoring of muscle activity during toe tapping. [Subjects and Methods] The study enrolled 11 patients with Parkinson's disease (PD) and 9 controls (Controls). The tibialis anterior (TA) and gastrocnemius (GS) muscle activity during toe tapping was measured using surface electromyography. [Results] In closed tapping, the minima in GS activation with the first tap was significantly higher in patients with PD than in Controls. In open tapping, the coefficient of variation (CV) of local maxima in TA activation was significantly higher in patients with PD than in Controls. In both types of tapping, the CV of extrema in GS activities increased with disease duration, but this may be due to the long-term administration of Levodopa, which itself tends to cause excessive GS activities. [Conclusion] Closed tapping is suitable for the assessment of GS activity and can detect excessive activities, which is observed as visible movement. Open tapping, on the other hand, is suitable for assessment of TA activity. PMID- 29765182 TI - Influence of ankle dorsiflexion range of motion on heel-rise time during gait. AB - [Purpose] The purpose of this study was to examine the correlation between weight bearing (WB) and non-WB ankle dorsiflexion (DF) range of motion (ROM) and ankle movement during gait, including heel-rise time and ankle DF at heel-rise. [Subjects and Methods] Thirty healthy male subjects were recruited for this study. Ankle DF ROM of both feet was measured under the WB and non-WB conditions. Heel-rise time and ankle DF at heel-rise in both feet during gait were measured using a motion analysis system. Pearson product moment correlations were used to identify correlation ankle DF ROM and ankle movement during gait. [Results] Heel rise time and ankle DF at heel rise were significantly correlated with WB ankle DF ROM. However, no correlations were found between ankle movement during gait and non-WB ankle DF ROM. [Conclusion] These findings demonstrate that WB ankle DF ROM measurements can be used to predict heel-rise time and ankle DF at heel-rise. PMID- 29765183 TI - The effect of chest expansion exercise with TENS on gait ability and trunk control in chronic stroke patients. AB - [Purpose] The purpose of this study was to investigate the effect of chest expansion exercise with transcutaneous electrical nerve stimulation (TENS) on gait ability and trunk control of patient with stroke. [Subjects and Methods] The subjects were divided into 7 in the chest expansion exercise with TENS group (experimental group) and 7 in the chest expansion exercise with placebo TENS (control group). The gait ability and trunk contol were measured using Six-Minute Walk Test, Tinetti gait index and Trunk impairment scale (TIS). [Results] Both the experimental group and the control group showed significant improvement in the Six-Minute Walk Test, Tinetti gait index, and TIS total score. The dynamic sitting balance and coordination of TIS showed significant improvement only in the experimental group. In comparison between the two groups, the experimental group showed a more significant improvement in Tinetti gait index and TIS total score than the control group. [Conclusion] This study showed that chest expansion exercise with TENS was an effective method for improving gait ability and trunk control in chronic stroke patients. PMID- 29765184 TI - The effect of respiratory exercise on trunk control, pulmonary function, and trunk muscle activity in chronic stroke patients. AB - [Purpose] This study aims to identify the effect of respiratory exercise on trunk control, pulmonary function, and trunk muscle activity in chronic stroke patients. [Subjects and Methods] The study included 24 chronic stroke patients who were randomly assigned, 12 each, to the experimental and control groups, and received neurodevelopmental treatment. Moreover, the experimental group underwent respiratory exercise. In each patient, the trunk control was measured using the Trunk Impairment Scale (TIS); muscle activity of the trunk, through the surface electromyogram; and pulmonary function, using the pneumatometer. [Results] The intragroup comparison showed significant differences in TIS, Forced vital capacity (FVC), Forced expiratory volume at one second (FEV1), Rectus Abdominis (RA), Internal Oblique (IO) and External Oblique (EO) in the experimental group. The intergroup comparison showed that the differences in TIS, FVC, FEV1, RA, IO and EO within the experimental group appeared significant relative to the control group. [Conclusion] Based on these results, this study proved that respiratory exercise was effective in improving trunk control, pulmonary function, and trunk muscle activity in patients with chronic stroke. PMID- 29765185 TI - The immediate effects of taping therapy on knee pain and depression in patients with degenerative arthritis. AB - [Purpose] This study aims to identify the immediate effects of taping therapy on knee pain and depression among patients with degenerative arthritis. [Subjects and Methods] In total, 32 patients with degenerative arthritis were randomly assigned to one of two groups: the experimental group that underwent taping therapy and the control group that underwent regular treatment (16 patients per group). In the experimental group, therapeutic tape was wrapped all around the knee joint. Pain and depression were measured using the visual analogue scale (VAS) and the Beck Depression Inventory (BDI), respectively. [Results] The intra group comparison showed significant differences in VAS and BDI for the experimental group. The intergroup comparison showed that the differences in VAS and BDI within the experimental group appeared significant relative to the control group. [Conclusion] It was observed that taping therapy showed an immediate effect in decreasing knee pain and depression among patients with degenerative arthritis. PMID- 29765186 TI - Effect of the frequency of therapy on the performance of activities of daily living in children with cerebral palsy. AB - [Purpose] This study investigated the frequency effect of physical and occupational therapy on activities of daily living performance in children with cerebral palsy. [Subjects and Methods] A total of 162 children with cerebral palsy who attended a convalescent or rehabilitation center for disabled individuals or a special school for physical disabilities in South Korea participated in this study. The Pediatric Evaluation Disability Inventory was used to collect data on activities of daily living performance according to physical therapy frequency based on neurodevelopmental therapy for 1 year. [Results] The relationships between physical therapy frequency and activities of daily living performance (mobility, social function, and total functional skill) and between occupational therapy frequency and activities of daily living performance (social function and total functional skill) were significant. There was no significant difference in activities of daily living performance according to physical therapy frequency. The difference in the activities of daily living performance according to occupational therapy frequency was significant for social function. [Conclusion] Intensive occupational therapy was more effective in improving activities of daily living performance in children with cerebral palsy. In particular, their social function further improved with intensive physical therapy. PMID- 29765187 TI - Gross motor skill development of kindergarten children in Japan. AB - [Purpose] The purposes of this study were to assess and explore the gender-based differences in gross motor skill development of 5-year-old Japanese children. [Subjects and Methods] This cross-sectional study recruited 60 healthy 5-year-old (third-year kindergarten, i.e., nencho) children (34 boys, 26 girls) from one local private kindergarten school in Otawara city, Tochigi Prefecture, Japan. Gross motor skills, including six locomotor and six object control skills, were assessed using the test of gross motor development, second edition (TGMD-2). All subjects performed two trials of each gross motor skill, and the performances were video-recorded and scored. Assessment procedures were performed according to the standardized guidelines of the TGMD-2. [Results] The majority of subjects had an average level of overall gross motor skills. Girls had significantly better locomotor skills. Boys had significantly better object control skills. [Conclusion] The gross motor skill development of 5-year-old Japanese children involves gender-based differences in locomotor and object control skills. This study provided valuable information that can be used to establish normative references for the gross motor skills of 5-year-old Japanese children. PMID- 29765188 TI - Influence of peripheral magnetic stimulation of soleus muscle on H and M waves. AB - [Purpose] This study evaluated the effects of repetitive peripheral magnetic stimulation of the soleus muscle on spinal cord and peripheral motor nerve excitability. [Subjects and Methods] Twelve healthy adults (mean age 22 years) who provided written informed consent were administered repetitive peripheral magnetic stimulation for 10 min. Pre-and post-stimulation latencies and amplitudes of H- and M-waves of the soleus muscle were measured using electromyography and compared using paired t-tests. [Results] Pre- and post stimulation latencies (28.3 +/- 3.3 vs. 29.1 +/- 1.3 ms, respectively) and amplitudes (35.8 +/- 1.3 vs. 35.8 +/- 1.1 mV, respectively) of H-waves were similar. Pre-stimulation latencies of M-waves were significantly higher than post stimulation latencies (6.1 +/- 2.2 vs. 5.0 +/- 0.9 ms, respectively), although pre- and post-stimulation amplitudes were similar (12.2 +/- 1.4 vs. 12.2 +/- 1.3 mV, respectively). Motor neuron excitability, based on the excitability of motor nerves and peripheral nerve action, was increased by M-waves following magnetic stimulation. [Conclusion] The lack of effect of magnetic stimulation on the amplitude and latency of the H-reflex suggests that magnetic stimulation did not activate sensory nerve synapses of alpha motor neurons in the spinal cord. However, because motor nerves were stimulated together with sensory nerves, the increased H-wave amplitude may have reflected changes in peripheral rather than in alpha motor nerves. PMID- 29765190 TI - Evaluating equilibrium in anterior cruciate ligament reconstruction. AB - [Purpose] The purpose of this review was to summarize available methods and equipment which are administered to evaluate the balance in anterior cruciate ligament reconstruction. [Subjects and Methods] A literature search was performed and reviewed using the narrative approach. This study reviewed English articles concerning balance assessment methods in anterior cruciate ligament reconstruction subjects from 1985 to 2015 using the following key words: Anterior Cruciate Ligament Injury, Anterior Cruciate Ligament Reconstruction, Postural Control, Equilibrium, Balance and Stability. [Results] This review included 44 studies out of 117 initially retrieved articles. These articles were discussed in balance measurement procedure without comparing the effect of various surgical, medical or rehabilitation approaches. [Conclusion] Biodex and EquiTest, functional dynamic tests are of choice in the evaluation and tracking of anterior cruciate ligament reconstruction subjects. Force plate parameters provide information regarding strategies of static postural control and is not sensitive enough to challenge postural control system in physical activities. PMID- 29765191 TI - Alleviation of posttraumatic dizziness by restoration of the cervical lordosis: a CBP(r) case study with a one year follow-up. AB - [Purpose] To present the successful treatment of posttraumatic dizziness and neck pains that were initiated in a patient following a whiplash event. [Subject and Methods] A 46 year old male suffered a whiplash event that initiated neck pain and dizziness symptoms. The patient had many positive orthopedic findings and demonstrated a forward head posture and cervical hypolordosis. The patient was treated by Chiropractic BioPhysics(r) technique including cervical extension traction, extension exercises and spinal manipulative therapy initially three times a week for 16-weeks, and once a month thereafter. [Results] The patient had a resolution of daily dizziness and neck pain with a concomitant reduction of forward head translation and increase in cervical lordosis. The postural measures were further improved after one year of mostly home-care. [Conclusion] The cervical spine alignment may be an important biomarker for those with dizziness. The correction of cervical lordosis may be an essential requirement for superior clinical outcomes for those with posttraumatic dizziness. PMID- 29765189 TI - Effect of Capacitive and Resistive electric transfer on changes in muscle flexibility and lumbopelvic alignment after fatiguing exercise. AB - [Purpose] This study aimed to clarify the effects of Capacitive and Resistive electric transfer (CRet) on changes in muscle flexibility and lumbopelvic alignment after fatiguing exercise. [Subjects and Methods] Twenty-two healthy males were assigned into either the CRet (n=11) or control (n=11) group. Fatiguing exercise and CRet intervention were applied at the quadriceps muscle of the participants' dominant legs. The Ely test, pelvic tilt, lumbar lordosis, and superficial temperature were measured before and after exercise and for 30 minutes after intervention. Statistical analysis was performed using one-way analysis of variance, with Tukey's post-hoc multiple comparison test to clarify within-group changes and Student's t-test to clarify between-group differences. [Results] The Ely test and pelvic tilt were significantly different in both groups after exercise, but there was no difference in the CRet group after intervention. Superficial temperature significantly increased in the CRet group for 30 minutes after intervention, in contrast to after the exercise and intervention in the control group. There was no significant between-group difference at any timepoint, except in superficial temperature. [Conclusion] CRet could effectively improve muscle flexibility and lumbopelvic alignment after fatiguing exercise. PMID- 29765193 TI - Re: JSLS. 2017 Jul-Sep; 21(3): e2017.00043. DOI: 10.4293/JSLS.2017.00043. Endoscopic Pilonidal Sinus Treatment: Long-Term Results of a Prospective Series. PMID- 29765192 TI - Pinch aperture proprioception: reliability and feasibility study. AB - [Purpose] To establish the reliability and feasibility of a novel pinch aperture device to measure proprioceptive joint position sense. [Subjects and Methods] Reliability of the pinch aperture device was assessed in 21 healthy subjects. Following familiarization with a 15 degrees target position of the index finger and thumb, subjects performed 5 trials in which they attempted to actively reproduce the target position without visual feedback. This procedure was repeated at a testing session on a separate date, and the between-session intraclass correlation coefficient (ICC) was calculated. In addition, extensor tendon vibration was applied to 19 healthy subjects, and paired t-tests were conducted to compare performance under vibration and no-vibration conditions. Pinch aperture proprioception was also assessed in two individuals with known diabetic neuropathy. [Results] The pinch aperture device demonstrated excellent reliability in healthy subjects (ICC 0.88, 95% confidence interval 0.70-0.95). Tendon vibration disrupted pinch aperture proprioception, causing subjects to undershoot the target position (18.1 +/- 2.6 degrees vs. 14.8 degrees +/- 0.76, p<0.001). This tendency to undershoot the target position was also noted in individuals with diabetic neuropathy. [Conclusion] This study describes a reliable, feasible, and functional means of measuring finger proprioception. Further research should investigate the assessment and implications of pinch aperture proprioception in neurological and orthopedic populations. PMID- 29765194 TI - Somatotype, the risk of hydroxychloroquine retinopathy, and safe daily dosing guidelines. AB - Purpose: The aim of this study was to determine whether somatotype influences the risk of hydroxychloroquine (HC) retinopathy (HCR) and whether dosing by real body weight (RBW), ideal body weight (IBW), or the lesser of these better predicts the risk of HCR. Patients and methods: A total of 565 patients taking HC for whom height and weight were recorded and a sensitive ancillary testing modality was used including 10-2 visual fields, spectral domain optical coherence tomography, fundus autofluorescence imaging, and multifocal electroretinography were enrolled. Body mass index (BMI) was compared for patients without and with HCR. Logistic regression models of age, cumulative dose, and daily dosing based on RBW, IBW, or lesser of these were compared. Area under the curve (AUC) of receiver operating characteristic plots was used to assess the diagnostic accuracy of RBW, IBW, and lesser of these guidelines for safe dosing. Probability plots for the risk of retinopathy versus BMI were compared for the different recommended guidelines on safe dosing. Results: A total of 41 patients had HCR. The median BMI was 27.6 (interquartile range [IQR] 24.3, 32.6) and 24.0 (IQR 21.0, 31.6) for patients without and with HCR (P=0.0102), respectively. AUC for univariate receiver operating characteristic plots of retinopathy versus dosing by RBW, IBW, and lesser of these was 0.71, 0.72, and 0.76, respectively. AUC for multivariate receiver operating characteristic plots of retinopathy versus models incorporating gender, age, cumulative dose, and BMI and differing by including dosing by RBW, IBW, and lesser of these was 0.82, 0.82, and 0.83, respectively. For all of the multivariate logistic models, the risk of retinopathy was higher for lower BMIs. Conclusion: Short, asthenic women are at higher risk for HCR. The 2011 American Academy of Ophthalmology (AAO) guidelines are safer for short, obese women. The 2016 AAO guidelines are safer for short, asthenic patients. Choosing daily dosing based on the lesser of the RBW and IBW guidelines is safer for all patients. PMID- 29765195 TI - Use of a novel extended blink test to evaluate the performance of two polyvinylpyrrolidone-containing, silicone hydrogel contact lenses. AB - Background: Sustained digital display viewing reduces eye blink frequency and tear film stability. To retain water and preserve a smooth optical surface, contact lens manufacturers have integrated the humectant polyvinylpyrrolidone (PVP) into silicone hydrogel contact lenses. In this study, extended blink time (EBT) was used to assess visual stability over a prolonged blink interval of two PVP-containing silicone hydrogel lenses, samfilcon A (SAM) and senofilcon A (SEN). Materials and methods: This randomized, bilateral, masked, crossover study assessed lens performance in ten subjects after 16 hours of wear. EBT, ie, the time elapsed between cessation of blinking and blur-out of a threshold letter on the acuity chart, was measured. At the end of the wear period, subjects reported duration of computer use and rated visual quality (VQ) and comfort while wearing the assigned lens, and the investigator evaluated lens surface wetting characteristics. Each lens was removed and immediately weighed to determine total water content. Results: EBTs were 10.42 seconds for SAM and 8.04 seconds for SEN (p = 0.015). Subjective ratings of VQ after 16 hours of wear were 84.6 for SAM and 74.4 for SEN (p = 0.049). Comfort ratings were 85.9 for SAM and 80.2 for SEN (p > 0.05). Median times of computer use were 6-8 hours for both lens types. Post blink, 70.0% of SAM and 30.0% of SEN lenses were completely wet (p = 0.021). Total water content after wear was 43.7% for SAM and 35.5% for SEN (p < 0.001). Conclusion: EBT measurement indicated more stable vision with the PVP-containing SAM polymer compared with the PVP-containing SEN polymer. The SAM polymer also demonstrated better surface wetting and maintained higher water content after a prolonged period of wear. EBT can be valuable in assessing vision stability of patients after hours of computer use. PMID- 29765196 TI - Optical coherence tomography retinal nerve fiber layer analysis in eyes with long axial lengths. AB - Purpose: To evaluate the relationship between axial length (AL) and retinal nerve fiber layer (RNFL) profile and to characterize differences in optical coherence tomography RNFL of myopic glaucomatous eyes compared to nonglaucomatous eyes. Methods: Retrospective chart review of 170 eyes of 89 subjects with optical biometry and optical coherence tomography RNFL assessment was conducted. Results: Temporal RNFL thickness showed no association with AL in either glaucomatous or nonglaucomatous eyes. Nasal thinning was most strongly associated with glaucoma in myopic eyes. Both myopic glaucomatous and nonglaucomatous eyes had a mean RNFL thickness of 16-22 um thinner than mean RNFL thickness of normal AL eyes. Conclusion: An average of 16-22 um thinning of RNFL compared to nomogram can be tolerated in patients with long AL. Prominent nasal thinning likely represents changes from axial elongation. Temporal RNFL thinning in those with long AL tends to be mild, and significant thinning should raise suspicion for glaucoma. PMID- 29765197 TI - Impact of conjunctival autograft on pterygium treatment: evaluation of related symptoms and patients' satisfaction after surgery. AB - Purpose: Pterygium is a fibrovascular condition of the ocular surface that can cause a broad range of irritative and visual symptoms. Controversy exists regarding pterygium mechanisms, management, surgical techniques, adjuvant approaches and impact on patients' quality of life. We performed a retrospective survey focused on the impact of pterygium-related symptoms before surgery and patients' satisfaction after excision surgery followed by conjunctival autograft transplantation with fibrin glue, based on patients' subjective reporting. Methods: All patients underwent surgery consisting of the extensive removal of the pterygium fibrovascular tissue, followed by autologous conjunctival graft fixed with fibrin glue to cover the bare scleral area. A total of 500 patients were contacted by phone call and invited to participate in the study answering a brief two-question survey. First, to grade overall intensity of symptoms related to pterygium before surgical intervention, such as pain, irritation, tearing, red eye, photophobia, burning and foreign body sensation, using a scale from 0 to 10 (0 asymptomatic and 10 very severe symptoms). Results were categorized as mild (0 3), moderate (4-7) and severe (8-10). Then, patients were asked about their satisfaction with the surgery outcome, also using a scale from 0 to 10 (ranging from dissatisfied to fully satisfied). Results: Patients' mean age was 41.5+/ 12.31 (min 18/max 83) years old and the mean of days after surgery was 1,493+/ 552.7 (min 711/max 2,702). Symptoms were referred to as severe (70.2%), moderate (25.2%) and mild (4.6%). After surgery, most patients were fully satisfied and the mean grade was 9.6; 1% (0-3), 2.4% (4-7) and 96.6% (8-10). Women presented a higher score of symptoms compared to men (P<0.01) but similar satisfaction rates. Conclusions: The present study shows that pterygium greatly impacts on patients' quality of life and that excision surgery using conjunctival autograft transplantation and fibrin glue improved symptoms with high rates of satisfaction. PMID- 29765198 TI - Management of post-LASIK dry eye: a multicenter randomized comparison of a new multi-ingredient artificial tear to carboxymethylcellulose. AB - Purpose: To compare the efficacy and safety of a preservative-free, multi ingredient formulation of carboxymethylcellulose 0.5%, hyaluronic acid 0.1%, and organic osmolytes (CMC-HA), to preservative-free carboxymethylcellulose 0.5% (CMC) in the management of postoperative signs and symptoms of dry eye following laser-assisted in situ keratomileusis (LASIK). Methods: This was a double-masked, randomized, parallel-group study conducted in 14 clinical centers in Canada and Australia. Subjects with no more than mild dry eye instilled CMC-HA or CMC for 90 days post-LASIK. Ocular Surface Disease Index(c) (OSDI; primary efficacy measure), corneal staining, tear break-up time (TBUT), Schirmer's test, acceptability/tolerability surveys, and visual acuity were assessed at screening and days 2, 10, 30, 60, and 90 post-surgery. Safety analyses included all enrolled. Results: A total of 148 subjects (CMC-HA, n=75; CMC, n=73) were enrolled and assigned to receive treatment, and 126 subjects completed the study without any protocol violations. Post-LASIK, dry eye signs/symptoms peaked at 10 days. OSDI scores for both groups returned to normal with no differences between treatment groups at day 90 (P=0.775). Corneal staining, Schirmer's test, TBUT, and survey results were comparable. Higher mean improvements in uncorrected visual acuity were observed in the CMC-HA group at all study visits, reaching statistical significance at day 30 (P=0.013). Both treatments were well tolerated. Conclusion: CMC-HA-containing artificial tears relieved post-LASIK ocular dryness as well as CMC alone, and demonstrated incremental benefit in uncorrected vision, with a favorable safety profile. Results support use of CMC HA eye drops to reduce signs and symptoms of ocular dryness post-LASIK. PMID- 29765199 TI - The development of a reference database with the Topcon 3D OCT-1 Maestro. AB - Importance: The paper presents the range for measurements taken with a new spectral domain optical coherence tomography (OCT) device to establish a reference database for discrimination purposes. Objective: To report the range of thickness values for the new Topcon Maestro 3D OCT device with 2 scan size settings: the 12*9 mm wide field and 6*6 mm scans. Design: Prospective, multicenter cohort study conducted at 7 clinical sites across the USA. Setting: Primary eyecare clinics within academic, hospital, and private practice locations. Participants: Healthy volunteers; all enrolled participants underwent a complete ophthalmological examination to confirm healthy ocular status prior to being enrolled in the study. Main outcome measure: Average and 1st, 5th, 95th, and 99th percentile ranges for OCT parameters Early Treatment Diabetic Retinopathy Study macula full retinal thickness, ganglion cell + inner plexiform layer thickness (GCL + IPL), ganglion cell complex (GCC) thickness, circumpapillary retinal nerve fiber layer (cpRNFL) thickness. Results: Three hundred and ninety-nine eyes of 399 subjects were included in the analysis. Mean (SD) age was 46.3 (16.3) years (range 18-88 years). Forty-three percent of the subjects were male. Mean (SD) measurements (in MUm) for the 12*9 mm wide scan were as follows: foveal thickness=237.079 (20.899), GCL + IPL=71.363 (5.924), GCC=105.949 (8.533), cpRNFL=104.720 (11.829); measurements for the 6*6 mm scans were as follows: foveal thickness=234.000 (20.657), GCL + IPL=71.726 (5.880), GCC=106.698 (9.094), cpRNFL=104.036 (11.341). Conclusion: The overall normal thickness values reported with Topcon 3D OCT-1 Maestro were like those studies with OCT from different manufactures. The reference limits at the 1st, 5th, 95th, and 99th percentile points establish the thresholds for the quantitative comparison of the cpRNFL and the macula in the human retina to a database of known healthy subjects. PMID- 29765201 TI - Deposition and transport of linezolid mediated by a synthetic surfactant Synsurf(r) within a pressurized metered dose inhaler: a Calu-3 model. AB - Background: Previous studies in our laboratory demonstrated that a synthetic peptide containing lung surfactant enhances the permeability of chemical compounds through bronchial epithelium. The purpose of this study was to test two formulations of Synsurf(r) combined with linezolid as respirable compounds using a pressurized metered dose inhaler (pMDI). Methods: Aerosolization efficiency of the surfactant-drug microparticles onto Calu-3 monolayers as an air interface culture was analyzed using a Next Generation ImpactorTM. Results: The delivered particles and drug dose showed a high dependency from the preparation that was aerosolized. Scanning electron microscopy imaging allowed for visualization of the deposited particles, establishing them as liposomal-type structures (diameter 500 nm to 2 MUm) with filamentous features. Conclusion: The different surfactant drug combinations allow for an evaluation of the significance of the experimental model system, as well as assessment of the formulations providing a possible noninvasive, site-specific, delivery model via pMDI. PMID- 29765200 TI - Efficacy and safety of the CRTh2 antagonist AZD1981 as add-on therapy to inhaled corticosteroids and long-acting beta2-agonists in patients with atopic asthma. AB - Objectives: To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA), in patients with persistent asthma with an allergic component. Patients and methods: In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]). The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV1) averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety. Results: In total, 1,140 patients (99.7%) received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID) vs placebo was not statistically significant (0.02 L, P=0.58), preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups. Conclusion: In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety profile. This clinical study is registered with ClinicalTrials.gov (NCT01197794). PMID- 29765202 TI - Inhibition of human prostate cancer (PC-3) cells and targeting of PC-3-derived prostate cancer stem cells with koenimbin, a natural dietary compound from Murraya koenigii (L) Spreng. AB - Background: Inhibition of prostate cancer stem cells (PCSCs) is an efficient curative maintenance protocol for the prevention of prostate cancer. The objectives of this study were to assess the efficiency of koenimbin, a major biologically active component of Murraya koenigii (L) Spreng, in the suppression of PC-3 cells and to target PC-3-derived cancer stem cells (CSCs) through apoptotic and CSC signaling pathways in vitro. Materials and methods: The antiproliferative activity of koenimbin was examined using MTT, and the apoptotic detection was carried out by acridine orange/propidium iodide (AO/PI) double staining and multiparametric high-content screening (HCS) assays. Caspase bioluminescence assay, reverse transcription polymerase chain reaction (RT-PCR), and immunoblotting were conducted to confirm the expression of apoptotic associated proteins. Cell cycle analysis was investigated using flow cytometry. Involvement of nuclear factor-kappa B (NF-kappaB) was analyzed using HCS assay. AldefluorTM and prostasphere formation examinations were used to evaluate the impact of koenimbin on PC-3 CSCs in vitro. Results: Koenimbin remarkably inhibited cell proliferation in a dose-dependent manner. Koenimbin induced nuclear condensation, formation of apoptotic bodies, and G0/G1 phase arrest of PC 3 cells. Koenimbin triggered the activation of caspase-3/7 and caspase-9 and the release of cytochrome c, decreased anti-apoptotic Bcl-2 and HSP70 proteins, increased pro-apoptotic Bax proteins, and inhibited NF-kappaB translocation from the cytoplasm to the nucleus, leading to the activation of the intrinsic apoptotic pathway. Koenimbin significantly (P<0.05) reduced the aldehyde dehydrogenase-positive cell population of PC-3 CSCs and the size and number of PC 3 CSCs in primary, secondary, and tertiary prostaspheres in vitro. Conclusion: Koenimbin has chemotherapeutic potential that may be employed for future treatment through decreasing the recurrence of cancer, resulting in the improvement of cancer management strategies and patient survival. PMID- 29765204 TI - Research as an event: a novel approach to promote patient-focused drug development. AB - Patient groups are increasingly engaging in research to understand patients' preferences and incorporate their perspectives into drug development and regulation. Several models of patient engagement have emerged, but there is little guidance on how to partner with patient groups to engage the disease community. Our group has been using an approach to engage patient groups that we call research as an event. Research as an event is a method for researchers to use a community-centered event to engage patients in their own environment at modest incremental cost. It is a pragmatic solution to address the challenges of engaging patients in research to minimize patients' frustration, decrease the time burden, and limit the overall cost. The community, the event, and the research are the three components that constitute the research as an event framework. The community represents a disease-specific community. The event is a meeting of common interest for patients and other stakeholders, such as a patient advocacy conference. The research describes activities in engaging the community for the purpose of research. Research as an event follows a six-step approach. A case study is used to demonstrate the six steps followed by recommendations for future implementation. PMID- 29765203 TI - Identification of novel drug targets in bovine respiratory disease: an essential step in applying biotechnologic techniques to develop more effective therapeutic treatments. AB - Background: Bovine Respiratory Disease (BRD) is a major problem in cattle production which causes substantial economic loss. BRD has multifactorial aetiologies, is multi-microbial, and several of the causative pathogens are unknown. Consequently, primary management practices such as metaphylactic antimicrobial injections for BRD prevention are used to reduce the incidence of BRD in feedlot cattle. However, this poses a serious threat in the form of development of antimicrobial resistance and demands an urgent need to find novel interventions that could reduce the effects of BRD drastically and also delay/prevent bacterial resistance. Materials and methods: We have employed a subtractive genomics approach that helps delineate essential, host-specific, and druggable targets in pathogens responsible for BRD. We also proposed antimicrobials from FDA green and orange book that could be repositioned for BRD. Results: We have identified 107 putative targets that are essential, selective and druggable. We have also confirmed the susceptibility of two BRD pathogens to one of the proposed antimicrobials - oxytetracycline. Conclusion: This approach allows for repositioning drugs known for other infections to BRD, predicting novel druggable targets for BRD infection, and providing a new direction in developing more effective therapeutic treatments for BRD. PMID- 29765205 TI - Patterns of persistence with pharmacological treatment among patients with current depressive episode and their impact on long-term outcome: a naturalistic study with 5-year follow-up. AB - Background: The aim of the study was to describe and compare the patterns of medication persistence among patients with unipolar depression (UD) or bipolar depression in a 5-year follow-up, and explore their impact on long-term outcome. Patients and methods: A total of 333 eligible patients with current major depressive episode were observed and followed up from the first index prescription for 5 years. Lack of persistence or treatment interruption was defined as a gap of at least 2 consecutive months without taking any medication. Time to lack of persistence in the first (TLP1) and the second (TLP2) episode of treatment, number of visits before the first treatment interruption (NV) and number of treatment interruptions (NTI) were measured. Results: During the 5-year follow-up, nearly 50% of patients experienced at least two times of treatment interruption. Pattern of medication persistence did not significantly differ between UD and bipolar disorder (BD) patients. TLP1 was positively associated with TLP2. Shorter TLP1 predicted a higher possibility of subsequent visits because of recurrence or relapse and more NTI meant a lower likelihood of achieving full remission in the fifth year for both UD and BD patients. For UD patients, shorter TLP1 or less NV predicted a lower chance of achieving remission, while for BD patients, shorter TLP1 meant an earlier subsequent visit and more NTI predicted a lower possibility of achieving remission. Conclusion: Pattern of medication persistence was similar but its impact on the long-term outcome was quite different between UD and BD. PMID- 29765206 TI - Cross-cultural validation of the educational needs assessment tool into Chinese for use in severe knee osteoarthritis. AB - Background: Patient education is an integral part of the management of osteoarthritis. The educational needs assessment tool (ENAT) was developed in the UK to help direct needs-based patient education in rheumatic diseases. Aim: The aim of the study was to adapt and validate the ENAT into Chinese, for use in severe knee osteoarthritis (KOA). Methods: This cross-cultural validation study took two phases: 1) adaptation of the ENAT into Chinese (CENAT) and 2) validation of the CENAT. The Construct validity was determined using factor analysis and criterion-related validity by comparing data from CENAT with data from different self-efficacy scales: patient-physician interactions scale (PEPPI-10), self efficacy for rehabilitation outcome scale (SER), and the self-efficacy for exercise scale (SEE). Results: The sample comprised 196 patients, with mean age 63.6+/-8.7 years, disease duration was11.5 years, and 57.1% were female. The CENAT was found to have high internal consistency. The CENAT had weak correlations with the Chinese versions of PEPPI r=0.40, SER r=0.40, and SEE r=0.39. There were no correlations with age r=-0.03 or disease duration r=-0.11. Conclusion: The ENAT translated well into Chinese and has evidence of validity in KOA. Future studies will further inform its usefulness in clinics, community, and online settings. PMID- 29765207 TI - Adherence to antihyperglycemic medications and glucagon-like peptide 1-receptor agonists in type 2 diabetes: clinical consequences and strategies for improvement. AB - Adherence to antihyperglycemic medications is often suboptimal in patients with type 2 diabetes, and this can contribute to poor glycemic control, increased hospitalization, and the development of diabetic complications. Reported adherence rates to antihyperglycemics vary widely among studies, and this may be related to differences in methodology for measuring adherence, patient populations, and other factors. Poor adherence may occur regardless of the specific regimen used and whether therapy is oral or injectable, and can be especially common in chronic, asymptomatic conditions, such as type 2 diabetes. More convenient drug-administration regimens and advances in formulations and delivery devices are among strategies shown to improve adherence to antihyperglycemic therapy, especially for injectable therapy. This is exemplified by technological developments made in the drug class of glucagon-like peptide 1 receptor agonists, which are a focus of this narrative review. Dulaglutide, albiglutide, and prolonged-release exenatide have an extended duration of action and can be administered once weekly, whereas such agents as liraglutide require once-daily administration. The convenience of once-weekly versus once-daily administration is associated with better adherence in real-world studies involving this class of agent. Moreover, provision of a user-friendly delivery device has been shown to overcome initial resistance to injectable therapy among patients with type 2 diabetes. This suggests that recent innovations in drug formulation (eg, ready-to-use formulations) and delivery systems (eg, single-dose prefilled pens and hidden, ready-attached needles) may be instrumental in encouraging patient acceptance. For physicians who aim to improve their patients' adherence to antihyperglycemic medications, it is thus important to consider the patient's therapeutic experience (treatment frequency, drug formulation, delivery device). Better adherence, powered by recent technological advances in the delivery of glucagon-like peptide 1-receptor agonists, may thus lead to improved clinical outcomes in type 2 diabetes. PMID- 29765208 TI - Primary nonadherence to chronic disease medications: a meta-analysis. AB - Background: Medication nonadherence is a global problem that requires urgent attention. Primary nonadherence occurs when a patient consults with a medical doctor, receives a referral for medical therapy but never fills the first dispensation for the prescription medication. Nonadherence to chronic disease medications costs the USA ~$290 billion (USD) every year in avoidable health care costs. In Canada, it is estimated that 5.4% of all hospitalizations are due to medication nonadherence. Objectives: The objective of this study was to quantify the extent of primary nonadherence for four of the most common chronic disease medications. The second objective was to identify factors associated with primary nonadherence to chronic disease medications. Materials and methods: We conducted an extensive systematic literature review of eight databases with a wide range of keywords. We identified relevant articles for primary nonadherence to antihypertensives, lipid-lowering agents, hypoglycemics, and antidepressants. After further screening and assessment of methodologic quality, relevant data were extracted and analyzed using a random-effects model. Results: Twenty-four articles were included for our meta-analysis after full review and assessment for risk of bias. The pooled primary nonadherence rate for the four chronic disease medications was 14.6% (95% CI: 13.1%-16.2%). Primary medication nonadherence was higher for lipid-lowering medications among the four chronic disease medications assessed (20.8%; 95% CI: 16.0%-25.6%). The rates in North America (17.0%; 95% CI: 14.4%-19.5%) were twice those from Europe (8.5%; 95% CI: 7.1%-9.9%). The absence of social support (20%; 95% CI: 14.4%-26.6%) was the most common sociodemographic variable associated with chronic disease medication primary nonadherence. Conclusion: Evidence suggests that a considerable percentage of patients do not initially fill their medications for treatable chronic diseases or conditions. This represents a major health care problem that can be successfully addressed. Efforts should be directed toward proper medication counseling, patient social support, and clinical follow-up, especially when the indications for the prescribed medication aim to provide primary prevention. PMID- 29765209 TI - Using the Frailty Assessment for Care Planning Tool (FACT) to screen elderly chronic kidney disease patients for frailty: the nurse experience. AB - Purpose: Recent evidence supports the prognostic significance of frailty for functional decline and poor health outcomes in patients with chronic kidney disease. Yet, despite the development of clinical tools to screen for frailty, little is known about the experiential impact of screening for frailty in this setting. The Frailty Assessment for Care Planning Tool (FACT) evaluates frailty across 4 domains: mobility, function, social circumstances, and cognition. The purpose of this qualitative study was as follows: 1) explore the nurse experience of screening for frailty using the FACT tool in a specialized outpatient renal clinic; 2) determine how, if at all, provider perceptions of frailty changed after implementation of the frailty screening tool; and 3) determine the perceived factors that influence uptake and administration of the FACT screening tool in a specialized clinical setting. Methods: A semi-structured interview of 5 nurses from the Nova Scotia Health Authority, Central Zone Renal Clinic was conducted. A grounded theory approach was used to generate thematic categories and analysis models. Results: Four primary themes emerged in the data analysis: "we were skeptical", "we made it work", "we learned how", and "we understand". As the renal nurses gained a sense of confidence in their ability to implement the FACT tool, initial barriers to implementation were attenuated. Implementation factors - such as realistic goals, clear guidelines, and ongoing training - were important factors for successful uptake of the frailty screening initiative. Conclusion: Nurse participants reported an overall positive experience using the FACT method to screen for frailty and indicated that their understanding of the multiple dimensions and subtleties of "frailty" were enhanced. Future nurse-led FACT screening initiatives should incorporate those factors identified as being integral to program success: realistic goals, clear guidelines, and ongoing training. Adopting the evaluation of frailty as a priority within clinical departments will encourage sustainability. PMID- 29765210 TI - Percutaneous kyphoplasty combined with zoledronic acid infusion in the treatment of osteoporotic thoracolumbar fractures in the elderly. AB - Objective: We studied the efficacy of zoledronic acid (ZOL) infusion on radiographic and clinical outcomes after percutaneous kyphoplasty (PKP) for elderly patients with osteoporotic thoracolumbar fractures (osteoporotic vertebral compression fractures [OVCFs]). Materials and methods: We retrospectively analyzed 95 elderly patients (age >65 years) with OVCF. All patients were followed up for 2 years. Thirty-two patients were treated with only once-yearly 5 mg ZOL infusion (ZOL group), 34 patients with only PKP (PKP group) and 29 patients received ZOL infusion 3 days after PKP (PKP+ZOL group). Results: There were no significant differences in the patients' age, gender, body mass index, lumbar spine bone mineral density T-scores, baseline of Visual Analog Scale scores and Oswestry Disability Index scores (P>0.05). The postoperative vertebral heights of patients with OVCF after PKP and PKP+ZOL were 23.70+/-3.03 and 24.30+/-3.13 mm, respectively, which were significantly higher than that of patients in ZOL group (P<0.05). The reduction in degrees of kyphotic deformity in the PKP and PKP+ZOL groups were corrected to 8.4 degrees and 8.7 degrees . The bone mineral density T-scores of patients with OVCF in the ZOL group and PKP+ZOL group were significantly higher than that in the PKP group (P<0.05). The Visual Analog Scale and the Oswestry Disability Index scores of the PKP+ZOL and PKP groups were significantly lower than those of the ZOL group (P<0.05). The incidence of recompression vertebral fracture (RVF) in the PKP group was 14.7%, but there was no patient with RVF in the PKP+ZOL group (P<0.05). Conclusion: Once yearly 5 mg ZOL infusion combined with PKP could provide beneficial effects in elderly osteoporotic patients with OVCF. PMID- 29765212 TI - The effect of conjugated linoleic acid on oxidative stress and matrix metalloproteinases 2 and 9 in patients with COPD. AB - Background: Natural antioxidants in foods may be used in prevention and treatment of oxidative stress and inflammation in COPD. Therefore, this study aimed to evaluate the effect of conjugated linoleic acid (CLA) supplement as natural antioxidants on oxidative stress levels, and MMP2 and MMP9 serum levels in COPD patients. Materials and methods: This clinical trial study was conducted on 90 (supplement group=45 and control group=45) COPD patients in Ardabil city, Iran, in 2015. After obtaining written consent, general information was collected from each patient using a validated and reliable questionnaire. Supplement group received 3.2 g of CLA and those in the control group were given 3.2 g of placebo for 6 weeks on a daily basis. Fasting blood samples were taken from all of the patients for testing of malondialdehyde (MDA), MMP2, and MMP9 levels at the beginning and end of the study. Data were analyzed using Kolmogorov-Smirnov test, independent samples t-test, paired sample t-test, chi-square test, and ANOVA. Results: There were no significant differences between the two groups with regard to mean age, smoking status, and serum level of MDA at the beginning of the study. In the supplement group, the serum level of MDA decreased significantly at the end of the 6th week compared to that in the beginning of the study (p=0.0004), while in the placebo group, the difference was found to be insignificant. The serum level of MMP9 decreased significantly in the supplement group, while in the placebo group its level increased significantly as compared to that at the beginning of the study (p<0.05). The serum levels of MMP2 indicated no significant differences between the two groups neither at the beginning nor at the end of the study. Conclusion: These findings indicated that CLA supplementation may be helpful for COPD patients through inhibiting the production of oxidative stress and controlling MMP9 serum levels. PMID- 29765211 TI - Usability and acceptability of technology for community-dwelling older adults with mild cognitive impairment and dementia: a systematic literature review. AB - Background: The objective of this review was to obtain an overview of the technologies that have been explored with older adults with mild cognitive impairment and dementia (MCI/D), current knowledge on the usability and acceptability of such technologies, and how people with MCI/D and their family carers (FCs) were involved in these studies. Materials and methods: Primary studies published between 2007 and 2017 that explored the use of technologies for community-dwelling people with MCI/D were identified through five databases: MEDLINE, PsycINFO, Embase, AMED, and CINAHL. Twenty-nine out of 359 papers met the criteria for eligibility. We used the Mixed Methods Appraisal Tool for quality assessment. Results: A wide range of technologies was presented in the 29 studies, sorted into four domains: 1) safe walking indoors and outdoors; 2) safe living; 3) independent living; and 4) entertainment and social communication. The current state of knowledge regarding usability and acceptability reveals that even if researchers are aware of these concepts and intend to measure usability and acceptability, they seem difficult to assess. Terms such as "user friendliness" and "acceptance" were used frequently. User participation in the 29 studies was high. Persons with MCI/D, FCs, and staff/other older adults were involved in focus groups, workshops, and interviews as part of the preimplementation process. Conclusion: Research regarding technologies to support people with MCI/D seems optimistic, and a wide range of technologies has been evaluated in homes with people with MCI/D and their FCs. A major finding was the importance of including people with MCI/D and their FCs in research, in order to learn about required design features to enhance usability and acceptability. Surprisingly, very few studies reported on the consequences of technology use with regard to quality of life, occupational performance, or human dignity. PMID- 29765213 TI - Health status in patients with COPD treated with roflumilast: two large noninterventional real-life studies: DINO and DACOTA. AB - Purpose: DINO and DACOTA were prospective, noninterventional studies assessing the health status and quality of life of patients with COPD newly treated with roflumilast 500 MUg once-daily add-on therapy. Patients and methods: Patients were evaluated over 6 months. Clinical COPD questionnaire (CCQ) and COPD assessment test (CAT) scores were recorded at baseline and after 3 and 6 months. In DACOTA, post-bronchodilator FEV1 was recorded at each time point. Results: Of 5,462 and 3,645 patients recruited into DINO and DACOTA, respectively, 3,274 patients in DINO and 916 patients in DACOTA completed the 6-month visit. Almost all patients had severe or very severe airway obstruction; mean baseline CCQ total score was 3.9 in DINO and 3.7 in DACOTA. Overall, 33.8% of patients in DACOTA and 30.6% in DINO discontinued treatment prematurely. Significant and clinically relevant improvements in CCQ total scores were observed in both studies (mean change from baseline of 1.36 in DINO and 0.91 in DACOTA at Month 6 [all P<0.001]). Changes in CAT total score from baseline to Month 6 indicated that the average clinical impact of COPD was reduced from a severe (score: 21-30) to a moderate (score: 11-20) impairment. In DACOTA, mean change in post bronchodilator FEV1 was 202 mL (P<0.001). Diarrhea, nausea, and weight decrease were the most frequently reported adverse drug reactions. Conclusion: In real life clinical practice, roflumilast treatment as an add-on therapy is associated with clinically relevant improvements in health status and quality of life. PMID- 29765214 TI - Tiotropium inhibits methacholine-induced extracellular matrix production via beta catenin signaling in human airway smooth muscle cells. AB - Background: Airway remodeling is an important feature of chronic obstructive pulmonary disease (COPD) that is associated with disease severity and irreversible airflow limitation. An extensive alteration of the extracellular matrix (ECM) surrounding the airway smooth muscle (ASM) bundle is one of the pathological manifestations of airway remodeling, which contributes to the decline in lung function. Tiotropium, a long-acting inhaled muscarinic receptor antagonist, has been confirmed to play a role in preventing airway remodeling including ECM deposition beyond bronchodilation in vivo, but the relationship between ASM cell (ASMC) relaxation and ECM production remains unclear. Purpose: In this study, we attempted to investigate the influence of tiotropium on ECM production by ASMCs and the underlying mechanism. Methods: Tiotropium was added 30 minutes before the addition of methacholine to primary cultured human ASMCs. Protein expression was analylized by Western Blot and mRNA abundance was determined by real-time PCR. Results: We found that tiotropium reduced collagen I protein expression, and the mRNA abundance of collagen I, fibronectin, and versican. beta-catenin signaling was inactivated by inhibiting glycogen synthase kinase 3beta (GSK3beta) phosphorylation in this process. Tiotropum inhibited the amount of active beta-catenin and its transcription activity. Furthermore, overexpression of active beta-catenin by adenoviruses carrying the S33Y mutant resisted the suppressive effect of tiotropium on collagen I protein expression. However, silencing beta-catenin by specific small interfering RNA enhanced the negative effect of tiotropium. Conclusion: These findings suggest that relaxation of ASMCs by tiotropium can prevent ECM production through beta-catenin signaling. PMID- 29765215 TI - In vivo investigation on the chronic hepatotoxicity induced by intraperitoneal administration of 10-nm silicon dioxide nanoparticles. AB - Background: Silicon dioxide (silica) nanoparticles (SDNPs) are widely used in nanotechnology and medicine, but these nanomaterials may carry a high risk for human health while little is known about their toxicity. Methods: We investigated the alterations in morphometry, biochemistry, hematology, histology of liver tissue and gene expression of drug-metabolizing enzymes induced by 10-nm SDNPs. Healthy male Wistar albino rats were exposed to 20, 35 and 50 repeated injections of SDNPs (2 mg/kg body weight). Whole blood, serum and plasma samples were used for hematological and biochemical analyses, whereas liver biopsies were processed for histopathological and gene expression alterations. Results: In comparison with control rats, exposure to SDNPs lowered the body weight gain and liver index and increased the counts of white blood cells and platelets, but lowered the platelet larger cell ratio and plateletcrit. Levels of alkaline phosphatase, lactate dehydrogenase, low-density lipids, procalcitonin, aspartate aminotransferase and alanine aminotransferase, as well as potassium, phosphorus and iron concentrations, were increased. Histopathology revealed that SDNPs could induce hydropic degeneration, sinusoidal dilatation, hyperplasia of Kupffer cells, karyopyknosis and infiltration of inflammatory cells in the liver. SDNPs reduced the expression of 12 genes of drug-metabolizing enzymes significantly (p<0.05). Conclusion: These results suggest that SDNPs could cause alterations in morphometry, biochemistry, hematology, liver tissues and the expression of drug metabolizing enzyme genes. PMID- 29765217 TI - Allergy to chlorpromazine and valproic acid following carbamazepine hypersensitivity in a patient with an HLA-B*4601 allele. AB - A 73-year-old man, exhibiting psychomotor excitement after traumatic brain injury, developed allergic cutaneous eruptions and hepatic inflammation that did not resolve after the cessation of carbamazepine (CBZ). Fusing maculopapular erythema was observed in the face, neck, presternal region, and bilaterally in the forearms and feet. A drug-induced lymphocyte stimulation test revealed hypersensitivity to chlorpromazine (CPZ) and valproic acid (VPA), as well as to CBZ. The allergic reaction with eosinophilia to CPZ and VPA was suspected to have emerged following CBZ hypersensitivity, since previous treatment with CPZ and VPA prior to the introduction of CBZ had not been associated with adverse reactions earlier in the course of treatment. Recent studies have indicated linkages between severe CBZ hypersensitivity - but not mild CBZ hypersensitivity - and specific leukocyte antigens, HLA-B*1502 and HLA-A*3101, in Asian and European populations. The present case exhibited the HLA-B*4601 allele, which is associated with a high relative risk for the development of CBZ-induced maculopapular eruptions in Japanese and Han Chinese populations. Although cross hypersensitivity among aromatic compounds, including CBZ and CPZ, is well established, data regarding CBZ allergy-associated hypersensitivity to VPA are limited. In the present case, a cutaneous allergy to mianserin (a tetracyclic antidepressant) was also observed later in the course of treatment, suggesting additional cross-reactivity exists among aromatic psychotropic drugs. Thus, the association between the HLA-B*4601 allele and allergic reactions to VPA, aromatic psychotropic drugs, and CBZ should be further examined in future studies. PMID- 29765218 TI - The effects of Maras powder use on patients with migraine. AB - Background: It is accepted that smoking often triggers migraine. However, studies evaluating the relationship between the use of smokeless tobacco and migraine are limited, and there is no clear consensus on the subject. In this study, it was aimed to evaluate the relationship between migraine and Maras powder, which is the most common smokeless tobacco in Turkey. Subjects and methods: The study included a total of 600 subjects, consisting of 300 patients (aged >18 years) diagnosed with a migraine according to the International Headache Society (IHS ICHD-3 Beta) criteria after presenting at Sutcu Imam University Medical Faculty Neurology Policlinic with the complaint of headache between July 2016 and December 2016 and a control group of 300 individuals with similar features of age, gender, and educational level. A questionnaire was administered to each patient to record the status of smoking or using Maras powder. Results: In the migraine patient group, 16.4% smoked and 9.7% used Maras powder. In the control group, the rate of smoking was 8.5% and the rate of Maras powder use was 11.86%. In males diagnosed with a migraine, the use of Maras powder was found to be at a higher rate than smoking (p<0.001). The Visual Pain Score and the headache frequency values were higher in those who smoked or used Maras powder than in non users (p<0.001). The Fagerstrom Test for Nicotine Dependence Smokeless Tobacco results of the patients diagnosed with migraine and who used Maras powder were found to be higher than of those who smoked (Fagerstrom Test for Nicotine Dependence; p<0.001). When patients were evaluated according to the Migraine Disability Assessment Scale, the majority of migraine patients were seen to be at stages 1 and 2, and one in every three patients who used Maras powder cigarette and one in every two patients who smoked had headaches of a severity which affected their daily activities (p<0.001). Conclusion: Smoking or the use of Maras powder increases the frequency and severity of migraines in a similar way. Therefore, Maras powder must be included in the scope of the fight against tobacco and people should be warned about this issue. PMID- 29765216 TI - Dysfunction of various organelles provokes multiple cell death after quantum dot exposure. AB - Quantum dots (QDs) are different from the materials with the micrometer scale. Owing to the superiority in fluorescence and optical stability, QDs act as possible diagnostic and therapeutic tools for application in biomedical field. However, potential threats of QDs to human health hamper their wide utilization in life sciences. It has been reported that oxidative stress and inflammation are involved in toxicity caused by QDs. Recently, accumulating research unveiled that disturbance of subcellular structures plays a magnificent role in cytotoxicity of QDs. Diverse organelles would collapse during QD treatment, including DNA damage, endoplasmic reticulum stress, mitochondrial dysfunction and lysosomal rupture. Different forms of cellular end points on the basis of recent research have been concluded. Apart from apoptosis and autophagy, a new form of cell death termed pyroptosis, which is finely orchestrated by inflammasome complex and gasdermin family with secretion of interleukin-1 beta and interleukin-18, was also summarized. Finally, several potential cellular signaling pathways were also listed. Activation of Toll-like receptor-4/myeloid differentiation primary response 88, nuclear factor kappa-light-chain-enhancer of activated B cells and NACHT, LRR and PYD domains-containing protein 3 inflammasome pathways by QD exposure is associated with regulation of cellular processes. With the development of QDs, toxicity evaluation is far behind its development, where specific mechanisms of toxic effects are not clearly defined. Further studies concerned with this promising area are urgently required. PMID- 29765220 TI - Children with autism spectrum disorders and selective mutism. AB - Background: It has been suggested that autism spectrum disorder (ASD) might be a "comorbid" condition in selective mutism (SM). Methods: In this retrospective study, we examined medical records of children with SM diagnosis (n=97) at a medical center specializing in assessment of ASD. Results: Mean age for onset of SM symptoms was 4.5 years and mean age at SM diagnosis was 8.8 years. SM was more common among girls (boy:girl ratio=2.7:1). We found that 63% of the study group had an ASD (no gender difference). The SM group with combined ASD had later onset of symptoms, higher age at diagnosis, more often a history of speech delay, and a higher proportion of borderline IQ or intellectual disability. Conclusion: The results highlight the risk of overlap between ASD and SM. PMID- 29765219 TI - Estimated prevalence and incidence of diagnosed ADHD and health care utilization in adults in Sweden - a longitudinal population-based register study. AB - Background: Although the worldwide prevalence of attention-deficit/hyperactivity disorder (ADHD) in adults is estimated to be between 2% and 5%, it is considered to be underdiagnosed. This register study explored the prevalence of diagnosed ADHD and incidence of newly diagnosed ADHD in Swedish adults over time, and assessed comorbidities and pharmacologic treatment. Methods: National Patient Register data were used to estimate the overall prevalence of adults (>=18 years) with a registered ADHD diagnosis from 2006 to 2011, and the incidence of newly registered diagnoses from 2007 to 2011. Data from the Prescribed Drug Register were used to estimate the mean dose of the most frequently prescribed ADHD medication. Results: The estimated annual prevalence (N=44,364) of diagnosed ADHD increased from 0.58 per 1,000 persons in 2006 to 3.54 per 1,000 persons in 2011. The estimated annual incidence of newly diagnosed ADHD (N=24,921) increased from 0.39 per 1,000 persons to 0.90 per 1,000 persons between 2007 and 2011. At least one comorbidity was diagnosed in 52.6% of adults with ADHD (54.0% of newly diagnosed adults), with anxiety, substance use disorders, and depression being the most common. Among all adults with ADHD, 78.9% (65.7% of newly diagnosed adults) were prescribed ADHD medication and one-third were prescribed more than one add-on medication. Osmotic release oral system methylphenidate was the most commonly used medication. The mean daily dose was 51.5 mg, and was significantly higher in males, patients with substance use disorders, patients with drug holidays, and patients with at least one add-on medication. The most frequent concomitant medications were anxiolytics and hypnotics. Conclusion: In Sweden, the number of adults diagnosed with ADHD increased between 2006 and 2011, and the majority of patients were prescribed ADHD-specific medication. Over one-half of patients had psychiatric comorbidities; one-third were prescribed more than one add-on medication. Consumption of pharmacologic ADHD medication was high in specific patient subpopulations. PMID- 29765223 TI - Efficacy of denosumab in two cases with multiple-system atrophy and osteoporosis. AB - Background: Multiple-system atrophy (MSA) is an alpha-synucleinopathy with a very aggressive course and poor prognosis, which lacks efficient treatment. Thus, MSA represents a serious health and social problem. Progressive stridor and acute laryngeal obstruction likely occur in MSA; however, little is known about the bone metabolism or efficacy of bone absorption drugs, such as denosumab, in osteoporosis with MSA. Case presentation and methods: Two male patients with osteoporosis in MSA presented to our institution (at 54 and 68 years of age). Denosumab was started after the diagnosis of osteoporosis in MSA, and the therapy was continued for 18-24 months. Results: Lumbar and hip bone mineral density showed a 3.5% and 0.6% increase at 24 months or a 10.3% and 3.2% increase at 18 months, respectively. Bone turnover markers were also improved in the two cases during follow-up. No fractures or other complications were recorded during the observation period. Conclusion: This is the first study describing osteoporosis in two patients with MSA being treated by osteoporotic treatment. Based on our findings, it can be concluded that denosumab may be an effective therapy for osteoporosis in MSA. PMID- 29765221 TI - Surgical treatment of an esophageal bronchogenic cyst with massive upper digestive tract hematoma without esophagectomy: a case report and the review of the literature. AB - Esophageal bronchogenic cysts are extremely rare. Here we report a case of massive upper digestive tract hematoma and bronchogenic cyst mimicking aortic dissection that was safely removed without esophagectomy. A 30-year-old man was referred to our hospital for the treatment of a mediastinal cystic tumor located in the submucosa of the distal esophagus. His chief complaints were dysphagia > 1 week and severe persistent upper abdominal pain mimicking aortic dissection with constant vomiting for 1 day after gastroscopy examination. The serum level of carbohydrate antigen (CA)199 was > 1,000 U/mL and CA125 was 4,816 U/mL. Hemoglobin levels decreased from 122 g/L to 85 g/L in 5 days. Imaging examinations detected a huge hematoma of the gastric wall. Preoperative diagnosis was difficult. Although the pain indicated a possible aortic dissection, the abnormal levels of tumor biomarkers suggested malignancy. The patient underwent left thoracotomy. The cyst showed an exophytic lesion connected to the esophageal wall at the level of the gastroesophageal junction. Muddy brown contents were obtained by aspiration of the mass intraoperatively. Because enucleation could not be performed, esophageal myotomy in the distal esophagus and partial resection of the cyst were selected. Histopathological examination indicated a bronchogenic cyst of the esophagus. At a follow-up visit 3 months later, the patient had no signs of disease recurrence or any complaints. Postoperative tumor biomarkers returned to normal range. The present report summarizes the clinical details of the case and reviews the literature in order to improve the accuracy of diagnosis. PMID- 29765222 TI - Improving adherence to gout therapy: an expert review. AB - Gout is the most common form of inflammatory arthritis and is a considerable burden to patients and health care systems worldwide. Despite its clinical, economic, and social impact, patient persistence and adherence to prescribed urate-lowering therapies (ULT), ranging from 20% to 70%, is considered to be among the poorest of all chronic conditions. The majority of gout patients consequently receive suboptimal benefits of their prescribed pharmacotherapies. As gout is associated with several comorbidities along with an increased risk of premature mortality, achieving improved outcomes through adherence to ULT is crucial. Adherence to medication is complex and multidimensional and includes a combination of treatment-, patient-, and physician-related factors. This review explores the factors related to ULT adherence with the overall aim of helping health care providers better understand the barriers to adherence. Several interventions targeting pharmacists, nurses, and patients are being investigated to improve adherence. Furthermore, enhanced awareness and understanding of the need to treat-to-target in order to improve patient outcomes is needed among health care professionals. Greater understanding of the multidimensional nature of non-adherence can help physicians to treat gout more effectively and empower patients to improve self-management of this long-term disease. PMID- 29765224 TI - Statins use and risk of new-onset diabetes in hypertensive patients: a population based retrospective cohort study in Yinzhou district, Ningbo city, People's Republic of China. AB - Background: Reports have suggested that statin use is associated with an increased incidence of type 2 diabetes mellitus (T2DM). Guidelines suggested that statins should be prescribed in hypertensive patients for primary prevention. However, there were very few studies on the risk of T2DM associated with statin use among patients with hypertension in mainland People's Republic of China. Purpose: To determine the association between statin use and new-onset diabetes mellitus among patients with hypertension in mainland People's Republic of China. Patients and methods: We performed a retrospective cohort study of hypertensive patients using the Yinzhou regional health care database from January 1, 2010, to August 31, 2016. Patients aged 30-90 years old without T2DM were eligible for inclusion. We identified new statin initiators and nonusers by using prescription records of inpatients and outpatients. Multivariate Cox model and propensity score methods were used to adjust potential confounders, including age, sex, body mass index, comorbidities, lifestyle characteristics, and baseline antihypertensive drug use. The risk of incident T2DM among statin initiators compared to nonusers was estimated by the Cox proportional hazards model. Propensity scores for statin use were then developed using logistic regression, statin initiators were matched 1:1 with nonusers according to propensity scores with the nearest neighbor matching method within 0.2 caliper width, and Cox regression was again conducted. Results: Among 67,993 patients (21,551 statin initiators; 46,442 nonusers), the unadjusted incidence rate of incident T2DM was higher in statin initiators than nonusers (25.68 versus 14.19 events/1,000 person years; adjusted hazard ratio: 1.55; 95% confidence interval: 1.44-1.66). After propensity score 1:1 matching (19,818 statin initiators; 19,818 nonusers), baseline characteristics between 2 groups were balanced except that the nonusers group was 0.53 years older on average (P<0.001). Then statin use was still associated with a significant increased risk for T2DM in the matched cohort (adjusted hazard ratio: 1.54; 95% confidence interval: 1.41-1.67). Subgroup analyses also demonstrated similar findings. Conclusion: Our study indicated an association between statin use and an increased risk of new-onset diabetes mellitus. It provides better understanding of statin and new-onset diabetes mellitus association among hypertensive patients in real-word setting. As an observational study, our findings were prone to unmeasured confounding and bias. PMID- 29765225 TI - Increased risk of adverse drug events secondary to bevacizumab treatment in patients with advanced or metastatic breast cancer: a meta-analysis of randomized controlled trials. AB - Background: Several clinical trials have shown an increased risk of hypertension with bevacizumab when added to chemotherapy in different types of malignancy; however, the risks of other significant adverse events besides hypertension, specifically in breast cancer, have not been completely elucidated. This study was conducted with the aim, primarily, to assess the overall incidence and risk of common toxicities associated with bevacizumab in patients with advanced or metastatic breast cancer and, secondarily, to descriptively review study results concerning a potential correlation between bevacizumab-induced hypertension and its efficacy for breast cancer treatment. Methods: We carried out a meta-analysis of relevant randomized controlled trials (RCTs) identified from a database search (Cochrane Library and PubMed) and, additionally, by reviewing previous reviews and meta-analyses. Overall incidence rates, odds ratios (ORs), and 95% confidence intervals (CIs) were assessed with the random- or fixed-effect models, depending on the level of heterogeneity across the included trials. The primary clinical outcomes were high-grade adverse events commonly reported with bevacizumab therapy. Results: We included 6,260 patients with advanced-stage breast cancer from 12 RCTs in the meta-analysis. Five types of high-grade (Grade 3 or 4) adverse drug events were identified as being correlated with bevacizumab treatment versus alternative treatment with statistical significance: hypertension (OR 5.67, 95% CI 3.02-10.65), proteinuria (OR 10.09, 95% CI 4.79 21.27), bleeding (OR 3.45, 95% CI 2.25-5.30), cardiac toxicity (OR 2.15, 95% CI 1.29-3.59), and neutropenic fever (OR 1.51, 95% CI 1.15-2.00). The prognostic value of bevacizumab-induced hypertension for its antitumor efficacy among patients with breast cancer remains controversial, with mixed results presented in the five retrospective studies that were identified from our additional literature search. Conclusion: The addition of bevacizumab to anticancer therapy was associated with a significant increase in the risk of high-grade adverse events, including hypertension, proteinuria, bleeding, cardiac toxicity, and neutropenic fever among patients with advanced-stage breast cancer. Although several retrospective studies suggested a predictive importance of hypertension secondary to bevacizumab therapy, the role of elevated blood pressure as a prognostic biomarker for its antitumor efficacy remains controversial, and further prospective trials are required to confirm such a correlation. PMID- 29765226 TI - Whole-body computed tomography in trauma patients: optimization of the patient scanning position significantly shortens examination time while maintaining diagnostic image quality. AB - Background: The study was conducted to compare examination time and artifact vulnerability of whole-body computed tomographies (wbCTs) for trauma patients using conventional or optimized patient positioning. Patients and methods: Examination time was measured in 100 patients scanned with conventional protocol (Group A: arms positioned alongside the body for head and neck imaging and over the head for trunk imaging) and 100 patients scanned with optimized protocol (Group B: arms flexed on a chest pillow without repositioning). Additionally, influence of two different scanning protocols on image quality in the most relevant body regions was assessed by two blinded readers. Results: Total wbCT duration was about 35% or 3:46 min shorter in B than in A. Artifacts in aorta (27 vs 6%), liver (40 vs 8%) and spleen (27 vs 5%) occurred significantly more often in B than in A. No incident of non-diagnostic image quality was reported, and no significant differences for lungs and spine were found. Conclusion: An optimized wbCT positioning protocol for trauma patients allows a significant reduction of examination time while still maintaining diagnostic image quality. PMID- 29765228 TI - Role of miR-613 as a tumor suppressor in glioma cells by targeting SOX9. AB - Background and objectives: MicroRNA-613 (miR-613), a novel cancer-related microRNA, has been shown to be responsible for the inhibition of tumor development and progression in various cancers. We aimed to investigate the biological function and regulatory mechanisms of miR-613 in gliomas. Materials and methods: miR-613 expression were detected by qRT-PCR assays in glioma tissues and cell lines. Cell Counting Kit-8 (CCK-8) assay, colony formation analysis, wound healing and transwell invasion assays were performed to evaluate cell proliferation, colony formation, migration and invasion abilities. Luciferase reporter assays, qRT-PCR and Western blot were performed to explore the potential targets of miR-613. Xenograft mice model was established to evaluate the effect of miR-613 in vivo. Result: The expression levels of miR-613 were significantly downregulated in the glioma tissues and cell lines, and the decreased level was significantly negatively associated with the overall disease-free survival of the patients. Functionally, ectopic expression of miR-613 in glioma cells suppressed the proliferation, colony formation, and migration and invasion of the cells. The sex-determining region Y-box 9 (SOX9) was identified as a direct functional target of miR-613, and its expression was inversely correlated with miR-613 expression in glioma tissues. Moreover, rescue of SOX9 could partially reverse the inhibitory effects of miR-613 on glioma cell proliferation, colony formation, migration, and invasion. Importantly, miR-613 also suppressed tumor growth in vivo by targeting SOX9. Conclusion: Taken together, these findings demonstrate that miR-613 functions as a tumor suppressor in glioma cells by directly targeting SOX9. PMID- 29765227 TI - Age-gender distribution of coronary artery calcium score in a black African population in Ghana. AB - Background: Distribution of coronary artery calcium (CAC) has been determined in different heterogeneous populations in the Multi-Ethnic Study of Atherosclerosis (MESA). Based on findings showing that geography and culture can influence CAC scoring beyond traditional race groups, we determined the distribution of CAC in a homogenous black African population to provide an initial basis for a larger CAC score study in Africa. Methods and results: This is a preliminary study using computed tomography to determine the CAC scores within a black African population who were referred to our center. Other information on patients were recorded through a combination of one-on-one interviews and medical records. A total of 170 patients were involved in our study, including 60.6% males, with an average age of 53.9 +/- 9.2 years. The majority (78.8%) had a zero calcium score, with patients within the age group of 55-64 years dominating the non-zero calcium score population. Males were found to have higher calcium levels compared to females, and coronary artery calcification and prevalence steadily rose with the increasing age. However, P-values of 0.328 and <0.001 were observed with distribution of CAC according to gender and age, respectively. Conclusion: Findings from this study showed that the distribution of CAC was markedly affected by the age of our study population, which will be more apparent in a larger study. PMID- 29765230 TI - Clinical and radiological characteristics of central pulmonary adenocarcinoma: a comparison with central squamous cell carcinoma and small cell lung cancer and the impact on treatment response. AB - Purpose: The proportion of central pulmonary adenocarcinoma (ADC) in central-type lung cancer has been gradually increasing due to the overall increasing incidence of pulmonary ADC. But the clinical and radiological characteristics of central ADCs remain unclear. In this study, we compared the clinical and radiological characteristics of central ADCs with those of small cell lung cancers (SCLCs) and squamous cell carcinomas (SQCCs) and investigated the impact of these characteristics on patients' treatment response. Patients and methods: The medical records of 302 consecutive patients with central lung cancer from July 2014 to September 2016 were retrospectively reviewed. There were 99 patients with ADC, 95 with SQCC and 108 with SCLC. Computed tomography images were interpreted by two radiologists. Treatment response was determined by Response Evaluation Criteria In Solid Tumors 1.1. Results: Univariate analyses found that younger age, female sex, no history of smoking, higher levels of carcinoembryonic antigen (CEA), contralateral hilum lymphadenopathy, contralateral lung metastasis, pleural nodules and pleural metastasis to the interlobular fissure were significantly correlated with central ADC. Multivariate logistic regression analyses revealed that compared with central SQCC, female sex, younger age, no history of smoking, higher levels of CEA and contralateral hilum lymphadenopathy were the significantly independent indicators of central pulmonary ADC. Furthermore, compared with central SCLC, younger age, higher levels of CEA and cytokeratin 19 fragment (Cyfra21-1), lower levels of neuron-specific enolase, pleural nodules and lack of vascular involvement were significantly associated with central ADC. In 85 central ADC patients who received first-line platinum based chemotherapy, both univariate and multivariate logistic regression analyses revealed that pulmonary emphysema had a negative correlation with treatment response (odds ratio=8.04, p=0.02). Conclusion: Our study revealed that central pulmonary ADCs exhibited more aggressive clinical and radiological characteristics. Pulmonary emphysema was an independent and negative indicator for treatment response of central ADC. PMID- 29765229 TI - The genetic association between iNOS and eNOS polymorphisms and gastric cancer risk: a meta-analysis. AB - Objective: There are a number of susceptible factors for an increased risk of gastric cancer. Nitric oxide (NO) is considered to be associated with the development of a range of cancers. In particular, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) are known to play a central role in the production of NO. Published studies relating to the association between eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms and the risk of gastric cancer risk are conflicting and inconclusive and require further analysis. Materials and methods: This study involved a meta-analysis of case control studies relating to eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms published prior to January 2018. Literature searches were carried out in PubMed, Embase, Web of Science, the Cochrane Library databases, and the Chinese National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of association based on genotype data. Results: A total of 1,356 cases and 1,791 controls were included from nine case-control studies involving eNOS rs1799983 (G894T), rs2070744 (T-786C), and iNOS rs2297518 (C150T) polymorphisms. Data analysis indicated that iNOS rs2297518 was a risk factor for Helicobacter pylorus-positive gastric cancer when compared with H. pylorus-negative gastric cancer (p=0.003, OR [95% CI] =2.19 [1.31-3.66]). In addition, the allelic, dominant, and recessive models of eNOS rs2070744 were significantly associated with a risk of gastric cancer (allelic model: p<0.00001, OR [95% CI] =0.23 [0.16-0.34]; dominant model: p<0.00001, OR [95% CI] =0.25 [0.15-0.42]; recessive model: p<0.00001, OR [95% CI] =0.16 [0.08-0.30]). No association was identified between eNOS rs1799983 and the risk of gastric cancer (p>0.05). Conclusion: iNOS rs2297518 and eNOS rs2070744 polymorphisms may represent susceptible factors for gastric cancer. PMID- 29765231 TI - Low circulating total adiponectin, especially its non-high-molecular weight fraction, represents a promising risk factor for colorectal cancer: a meta analysis. AB - Aim: The principal goal of this meta-analysis is to test the hypothesis that circulating total adiponectin or certain fractions may represent a promising biological candidate in modulating the risk of colorectal cancer. Methods: The processes of paper identification, paper selection and data extraction were accomplished independently by two authors. Effect-size estimates were expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI). A total of 31 papers including 48 qualified studies (7,554 patients with colorectal cancer and 9,798 controls) were meta-analyzed. Results: Pooling all studies found that circulating total adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: -0.76 ug/mL, 95% CI: -1.20 to -0.32, p=0.001), with significant heterogeneity (I2: 94.2%) and low publication bias (Egger's p=0.336). By adiponectin fractions, the difference in high-molecular weight (HMW) adiponectin was comparable between the two groups (WMD: -0.22 ug/mL, 95% CI: -0.70 to 0.25, p=0.350), while non-HMW adiponectin was significantly lower in patients with colorectal cancer than in controls (WMD: -0.27 ug/mL, 95% CI: -0.35 to -0.19, p<0.001), with marginal heterogeneity (I2: 52.3%). Subgroup analysis revealed that effect-size estimates were heterogeneous when grouping studies by cancer subtype, region, study design, matching status, gender and obesity. Further meta-regression analysis indicated that age and gender were significant potential sources of heterogeneity. The results showed the studied subgroups were not subject to publication bias (Egger's p<0.1). Conclusion: Our data collectively indicate that low circulating total adiponectin, especially its non-HMW fraction, represents a promising risk factor for colorectal cancer. Further studies are needed to explore underlying mechanisms. PMID- 29765232 TI - Prognostic factors for operable biliary tract cancer: serum levels of lactate dehydrogenase, a strong association with survival. AB - Background: Biliary tract cancers (BTCs) are uncommon but fatal, with a low 5 year survival rate after surgical resection. This study was designed to investigate the prognostic factors for operable BTC. Methods: Baseline demographics at diagnosis were retrospectively evaluated in 341 BTC patients undergoing radical surgery at The First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2015. The association between prognostic factors and overall survival (OS) was determined by multivariate analysis using the Cox proportional hazards regression model. Results: Our study showed that 341 patients were included in the analysis, of which 166 (48.7%) were males and 175 (51.3%) were females. Older age, depth of tumor invasion, positive surgical margin, lower hemoglobin, and higher lactic dehydrogenase (LDH) were associated with significantly worse OS using multivariate analysis. In the entire cohort, the estimate of median OS in patients with LDH <271 U/L was 36.291 months (95% CI; 30.989-41.594 months), and 30.736 months (95% CI; 19.154-42.318 months) in patients with LDH >=271 U/L (adjusted HR-1.505, 95% CI; 1.009-2.245, P = 0.045). Moreover, it was investigated whether serum LDH retained its significance as a prognostic marker in BTC subgroups separately. The results showed that LDH was prognostic in patients with distal bile duct (DBD) carcinoma undergoing radical surgery (HR-2.452, 95% CI; 1.167-5.152, P = 0.018). However, there were no statistical differences between LDH and OS in multivariate analysis in the other three individual subgroups except for DBD carcinoma. This may be due to the limited number of patients in the study, indicating that a greater number of patients may be required for statistical significance. Conclusion: Older age, depth of tumor invasion, positive surgical margin status, lower hemoglobin levels, and elevated serum LDH level are associated with poor survival in operable BTC patients. Serum LDH level is a cost-effective prognostic biomarker in patients with operable BTC and especially DBD carcinoma. PMID- 29765233 TI - Patterns of local failures and suggestions for reduction of clinical target volume for nasopharyngeal carcinoma patients without cervical lymph node metastasis. AB - Background: To demonstrate the robustness of clinical target volume delineation for nasopharyngeal carcinoma (NPC) patients, this study makes a detailed analysis of the initial irradiated dose of the recurrent site and local failure patterns after intensity-modulated radiation therapy (IMRT). Based on this analysis, further improvement of delineation recommendations may be made in order to improve the quality-of-life in NPC, without decreasing the local control and survival rate. Methods: In total, 382 newly diagnosed non-metastatic NPC patients were retrospectively enrolled, receiving elective neck irradiation to levels II, III, and VA. For patients with local failure, the location and extent of local failures were transferred to the pretreatment planning computed tomography (CT) for dosimetric analysis. The dose of radiation received by GTVr (gross tumor volume of recurrence) was calculated and analyzed with dose-volume histogram (DVH). Failures were classified as: "in field" if 95% of GTVr was within the 95% isodose, "marginal" if 20%-95% of GTVr was within the 95% isodose, or "outside" if less than 20% of GTVr was inside the 95% isodose. Results: With a median follow-up time of 61.3 months, 12 patients developed local recurrence (10 cases available). The 5-year overall survival, local relapse-free survival, regional relapse-free survival, distant metastasis failure-free survival, and disease-free survival were 87.8%, 95.2%, 99.1%, 93.3%, and 82.5%, respectively. Dose conformity with IMRT was excellent, and the recurrence was mainly within 3 years after the first treatment. The dosimetric analysis showed that seven failures were classified as "in-field", two failures as "marginal", and only one failure as "out-field". Most local relapse sites located just the same site of primary tumor and most anatomic sites were at low risk of concurrent bilateral tumor invasion. Conclusions: IMRT with elective neck irradiation provides excellent local control for NPC patients without cervical lymph node metastasis. In-field failures are the main patterns for local recurrence, and the radioresistant subvolumes within the gross tumor volume are needed to be identified. This study proposed suggestions for reduction of target volume during IMRT treatment for NPC patients. PMID- 29765235 TI - Fatal hemoptysis in patients with advanced esophageal cancer treated with apatinib. AB - Targeted therapy is commonly used for treating advanced malignant tumors. Compared with cytotoxic drugs, targeted drugs have the characteristics of good curative results, less adverse effects, and convenient oral administration. Hence, they are especially suitable for patients with cancer who are not able to tolerate chemotherapy. Anti-angiogenic therapy can achieve the objective by inhibiting the formation of new blood vessels in tumors. Apatinib is a novel tyrosine kinase inhibitor targeting the intracellular domain of vascular endothelial growth factor receptor-2. It has been proven to be effective and safe in treating patients with gastric carcinoma and gastroesophageal junction carcinoma. So far, no reports are available on the treatment of esophageal cancer with apatinib. Two patients with advanced esophageal cancer were treated with oral apatinib because of their poor physical condition. After treatment, the dyspnea symptoms disappeared and quality of life significantly improved. Chest computed tomography showed massive necrosis of tumor tissues in each patient. The tumors significantly reduced and a cavity was formed locally in each patient. However, both patients died of massive hemoptysis, probably due to the rupture of the bronchial artery eroded by tumors. The results indicated that apatinib was effective in treating some patients with advanced esophageal cancer, and adverse effects were controllable. However, doctors should choose appropriate candidates according to apatinib's indications. In addition, the use of apatinib should be carefully controlled for patients with esophageal cancer, especially in those with large vessels and trachea or bronchus eroded by tumor, so as to avoid or reduce the occurrence of fatal hemorrhage. PMID- 29765234 TI - Perioperative chemotherapy with pemetrexed and cisplatin for pulmonary large-cell neuroendocrine carcinoma: a case report and literature review. AB - Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is associated with poor prognosis, and its treatment strategy is still controversial, especially regarding chemotherapy regimens. Case report: We present the case of a 49-year-old Chinese male with primary pulmonary LCNEC treated with neoadjuvant and adjuvant chemotherapy with cisplatin plus pemetrexed. A suspected quasi circular mass in the left lower pulmonary lobe and an enlarged mediastinal lymph node were found. The patient was diagnosed with adenocarcinoma with neuroendocrine differentiation based on computerized tomography-guided percutaneous lung biopsy. An EGFR gene mutation test showed negative results. Cisplatin and pemetrexed were administered as the neoadjuvant chemotherapy regimen. The primary lesion had reduced markedly, and the enlarged mediastinal lymph node had disappeared after two cycles of neoadjuvant chemotherapy. A left lower lobectomy and mediastinal lymph node dissection were performed. The lesion was confirmed as LCNEC based on postoperative histopathological analysis and immunohistochemical results. The patient underwent four cycles of adjuvant chemotherapy with cisplatin and pemetrexed for a month postoperatively, followed by postoperative adjuvant radiotherapy. The patient was still alive after a follow-up of 24 months, with no evidence of tumor recurrence. Conclusion: Cisplatin combined with pemetrexed is effective and safe for patients with pulmonary LCNEC. PMID- 29765237 TI - Comparative genomic analysis of multidrug-resistant Streptococcus pneumoniae isolates. AB - Introduction: Multidrug resistance in Streptococcus pneumoniae has emerged as a serious problem to public health. A further understanding of the genetic diversity in antibiotic-resistant S. pneumoniae isolates is needed. Methods: We conducted whole-genome resequencing for 25 pneumococcal strains isolated from children with different antimicrobial resistance profiles. Comparative analysis focus on detection of single-nucleotide polymorphisms (SNPs) and insertions and deletions (indels) was conducted. Moreover, phylogenetic analysis was applied to investigate the genetic relationship among these strains. Results: The genome size of the isolates was ~2.1 Mbp, covering >90% of the total estimated size of the reference genome. The overall G+C% content was ~39.5%, and there were 2,200 2,400 open reading frames. All isolates with different drug resistance profiles harbored many indels (range 131-171) and SNPs (range 16,103-28,128). Genetic diversity analysis showed that the variation of different genes were associated with specific antibiotic resistance. Known antibiotic resistance genes (pbps, murMN, ciaH, rplD, sulA, and dpr) were identified, and new genes (regR, argH, trkH, and PTS-EII) closely related with antibiotic resistance were found, although these genes were primarily annotated with functions in virulence as well as carbohydrate and amino acid transport and metabolism. Phylogenetic analysis unambiguously indicated that isolates with different antibiotic resistance profiles harbored similar genetic backgrounds. One isolate, 14-LC.ER1025, showed a much weaker phylogenetic relationship with the other isolates, possibly caused by genomic variation. Conclusion: In this study, although pneumococcal isolates had similar genetic backgrounds, strains were diverse at the genomic level. These strains exhibited distinct variations in their indel and SNP compositions associated with drug resistance. PMID- 29765238 TI - Higher baseline viral diversity correlates with lower HBsAg decline following PEGylated interferon-alpha therapy in patients with HBeAg-positive chronic hepatitis B. AB - Background: Viral diversity seems to predict treatment outcomes in certain viral infections. The aim of this study was to evaluate the association between baseline intra-patient viral diversity and hepatitis B surface antigen (HBsAg) decline following PEGylated interferon-alpha (Peg-IFN-alpha) therapy. Patients and methods: Twenty-six HBeAg-positive patients who were treated with Peg-IFN alpha were enrolled. Nested polymerase chain reaction (PCR), cloning, and sequencing of the hepatitis B virus S gene were performed on baseline samples, and normalized Shannon entropy (Sn) was calculated as a measure of small hepatitis B surface protein (SHBs) diversity. Multiple regression analysis was used to estimate the association between baseline Sn and HBsAg decline. Results: Of the 26 patients enrolled in the study, 65.4% were male and 61.5% were infected with hepatitis B virus genotype B. The median HBsAg level at baseline was 4.5 log10 IU/mL (interquartile range: 4.1-4.9) and declined to 3.0 log10 IU/mL (interquartile range: 1.7-3.9) after 48 weeks of Peg-IFN-alpha treatment. In models adjusted for baseline alanine aminotransferase (ALT) and HBsAg, the adjusted coefficients (95% CI) for DeltaHBsAg and relative percentage HBsAg decrease were -1.3 (-2.5, -0.2) log10 IU/mL for higher SHBs diversity (Sn>=0.58) patients and -26.4% (-50.2%, -2.5%) for lower diversity (Sn<0.58) patients. Further analysis showed that the "a" determinant upstream flanking region and the first loop of the "a" determinant (nucleotides 341-359, 371-389, and 381-399) were the main sources of higher SHBs diversity. Conclusion: Baseline intra patient SHBs diversity was inverse to HBsAg decline in HBeAg-positive chronic hepatitis B (CHB) patients receiving Peg-IFN-alpha monotherapy. Also, more sequence variations within the "a" determinant upstream flanking region and the first loop of the "a" determinant were the main sources of the higher SHBs diversity. PMID- 29765236 TI - Methicillin-resistant Staphylococcus aureus bacteremia among liver transplant recipients: epidemiology and associated risk factors for morbidity and mortality. AB - Bacteremia due to Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), complicates the clinical course of liver transplantation and is associated with high morbidity and mortality. Intravascular catheters had been reported to be the most frequent source of MRSA bacteremia. Among bacteremic liver recipients, 26.3%-100% of S. aureus were MRSA. Previous studies identified pre-transplant and post-transplant acquired S. aureus carriage, greater severity of liver disease, hepatocellular carcinoma and infection with immuno-modulatory viruses as predictors of S. aureus bacteremia in liver recipients. MRSA bacteremia accompanied by pneumonia and abdominal infections was related to mortality. Vancomycin, as well as daptomycin, is a first-line antibiotic for MRSA bacteremia. The purpose of this review is to better understand the characteristics of MRSA bacteremia by summarizing the epidemiology and antimicrobial resistance of S. aureus, the primary source, and related risk factors for morbidity and mortality of MRSA bacteremia. We have also explored the diagnostic, therapeutic and preventive measures for MRSA bacteremia to improve the outcomes of liver recipients. PMID- 29765239 TI - The clinical significance of silent mutations with respect to ciprofloxacin resistance in MRSA. AB - Background: The aim of this study was to investigate the genotypic differences between different sequence type MRSA isolates, especially focusing on silent rpoB474 mutations and the relationship between such mutations and ciprofloxacin resistance. Methods: Seventy-nine MRSA isolates were obtained for antibiotic susceptibility tests and molecular study. Results: Among these isolates, we found that the MIC50, MIC90, and minimum inhibitory concentration (MIC) range of ciprofloxacin were much higher for the isolates without the rpoB474 mutation than for isolates with the rpoB474 mutation. A total of 87.5% of the isolates with the rpoB474 mutation were susceptible to ciprofloxacin, but none of the isolates without the rpoB474 mutation were susceptible to ciprofloxacin. For 27 MRSA isolates without rpo474 silent mutation but with gyrA86/126 silent mutation, all of them belonged to SCCmec III, and had high ciprofloxacin MIC levels. For another 44 MRSA isolates with rpo474 silent mutation but without gyrA86/126 silent mutation, all of them showed low ciprofloxacin MIC levels, all of them belonged to either SCCmec IV or V. Furthermore, MRSA ciprofloxacin resistance was found to be associated with the mutations gyrA S84L/parC S80F or gyrA S84L, and S85P/parC S80Y. Conclusion: Most occurrences of this rpoB474 silent mutation were found in community acquired-MRSA (CA-MRSA) isolates with susceptibility to most antibiotics, especially for ciprofloxacin and vice versa. Thus, this mutation may help to differentiate the different microbiologic characteristics of MRSA clinical isolates. PMID- 29765240 TI - Seasonality of cellulitis: evidence from Google Trends. AB - Introduction: According to our clinical experience, cellulitis is common in summer; however, very few studies have mentioned this trend. Methods: Using Google Trends, we analyzed the monthly data of Google searches for "cellulitis" from 31 countries on 6 continents. Results: Seasonality explained 34%-92% of the variability in search volume, with peaks occurring in summer months. Conclusion: The analyses offered new insights into the epidemiology of cellulitis on national and international scales. Clinical data are needed to validate the Internet search data. PMID- 29765241 TI - Prevalence of antibiotic prescription in southern Italian outpatients: real-world data analysis of socioeconomic and sociodemographic variables at a municipality level. AB - Purpose: The aim of this study was to analyze the geographic variation in systemic antibiotic prescription at a regional level and to explore the influence of socioeconomic and sociodemographic variables. Methods: This study was a retrospective analysis of reimbursement pharmacy records in the outpatient settings of Italy's Campania Region in 2016. Standardized antibiotic prescription rates were calculated at municipality and Local Health Unit (LHU) level. Antibiotic consumption was analyzed as defined daily doses (DDD)/1000 inhabitants per day (DID). Logistic regression was performed to evaluate the association between antibiotic prescription and sociodemographic and socioeconomic determinants at a municipality level. Results: The average antibiotic prevalence rate was 46.8%. At LHU level, the age-adjusted prevalence rates ranged from 41.1% in Benevento to 51.0% in Naples2. Significant differences were found among municipalities, from 15.2% in Omignano (Salerno LHU [Sa-LHU]) to 61.9% in Moschiano (Avellino [Av-LHU]). The geographic distribution also showed significant differences in terms of antibiotic consumption, from 6.7 DID in Omignano to 41.6 in San Marcelino (Caserta [Ce-LHU]). Logistic regression showed that both municipality type and average annual income level were the main determinants of antibiotic prescription. Urban municipalities were more than eight times as likely to have antibiotic high prevalence rates compared to rural municipalities (adjusted odds ratio [OR]: 8.62; 95% confidence interval [CI]: 4.06-18.30, P<0.001). Low average annual income level municipalities were more than eight times as likely to have antibiotic high prevalence rates compared to high average annual income level municipalities (adjusted OR: 8.48; 95% CI: 3.45 20.81, P<0.001). Conclusion: We provide a snapshot of Campania's antibiotic consumption, evidencing the impact of both socioeconomic and sociodemographic factors on the prevalence of antibiotic prescription. The observed intraregional variability underlines the lack of shared therapeutic protocols and the need for careful monitoring. Our results can be useful for decision makers to plan educational interventions, thus optimizing health resources and improving rational drug use. PMID- 29765242 TI - Claims-based proxies of patient instability among commercially insured adults with schizophrenia. AB - Objective: Schizophrenia (Sz) patients are among the highest utilizers of hospital-based services. Prevention of relapse is in part a treatment goal in order to reduce hospital admissions. However, predicting relapse is a challenge, particularly for payers and disease management firms with only access to claims data. Understandably, such organizations have had little success predicting relapse. A tool that allows payers to identify patients at elevated risk of relapse could facilitate targeted interventions prior to relapse and avoid rehospitalization. In this study, a series of proxy measures of patient instability, calculated from claims data were examined for their utility in identifying Sz patients at elevated risk of relapse. Methods: Aetna claims were used to assess the relationship between instability of Sz patients and valence and magnitude of antipsychotic (AP) medication change during a 2-year period. Six proxies of instability including hospital admissions, emergency department visits, medication utilization patterns, and use of outpatient services were identified. Results were replicated using claims data from Truven MarketScan(r). Results: Patients who switched AP ingredient had the highest overall instability at the point of switch and the second steepest decline in instability following switch. Those who changed to a long-acting injectable AP showed the second highest level of instability and the steepest decrease in instability following the change. Patients augmented with a second AP showed the smallest increase in instability, up to the switch. Results were directionally consistent between the two data sets. Conclusion: Using claims-based proxy measures to estimate instability may provide a viable method to better understand Sz patient markers of change in disease severity. Also, such proxies could be used to identify those individuals with the greatest need for treatment modification preventing relapse, improving patient outcomes, and reducing the burden of illness. PMID- 29765243 TI - Reexploring 5-methoxyindole-2-carboxylic acid (MICA) as a potential antidiabetic agent. AB - 5-Methoxyindole-2-carboxylic acid (MICA) is a potent hypoglycemic agent that inhibits gluconeogenesis in the liver. It is also a well-known inhibitor of mitochondrial dihydrolipoamide dehydrogenase. MICA was extensively studied in the 1960s and 1970s and was once tested for its antidiabetic effect in diabetic Chinese hamsters, whereby MICA was shown to exhibit pronounced glucose-lowering ability while also leading to increased rate of death of the diabetic animals. Since then, MICA's potential ability in lowering blood glucose in diabetes has never been revisited. In my opinion, MICA should be comprehensively reexplored for its antidiabetic properties in a variety of rodent diabetes models. For a given animal model, its dose-dependent effect and the effects of different routes of administrations as well as its synergistic effects with other glucose-lowering drugs should also be investigated. More studies in the future on this chemical may provide novel insights into its role as an antidiabetic agent. PMID- 29765245 TI - The epidemiology of outpatient pain treatment in pediatrics. AB - Background: There is limited real-world, population-level data on the prevalence and treatment of pain in children. An understanding of pediatric pain conditions and its management can help inform provider education, treatment guidelines, and design of pediatric pain studies. Therefore, in this study, we aimed to describe the prevalence of conditions associated with acute and chronic pain in pediatric patients and to characterize pediatric pain treatment with nonsteroidal anti inflammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, opioids (immediate release or extended release), antidepressants, topical analgesics, anticonvulsants, and other therapies based on a large, real-world sample. Materials and methods: In this cohort study, we used administrative claims data from the Truven Health MarketScan(r) Research Databases, which contain data regarding demography, prescription, diagnosis, and procedure performed. Descriptive statistics were used to assess the prevalence of various conditions associated with pediatric pain and to estimate the proportion of patients who received various analgesic and nonanalgesic treatments. All analyses were stratified according to demographics. Results: This study included data on more than 30 million pediatric patients from throughout the US. Overall, among patients with commercial insurance, surgery was the most common pain-related diagnosis, followed by orthopedic conditions, malignancies, trauma, and genetic conditions. For patients with Medicaid, surgery was also the most common diagnosis, followed by traumatic injury, orthopedic conditions, malignancies, and genetic conditions. These diagnoses varied by age, with most showing higher prevalence in older children. Treatment varied substantially by condition, and many children (more than 50% for most of the conditions evaluated) did not receive any prescription pain treatments. For patients with either commercial insurance or Medicaid who were using prescription opioids, immediate-release opioids were the most commonly used analgesic treatment for pain. Overall, prescription pain treatments were more common in the Medicaid population. Extended-release opioids were rarely used. Conclusion: The types of pain treatments varied substantially by condition and age of the patient, with the highest prevalence of use in older children. PMID- 29765244 TI - An echo to Choosing Wisely(r) in Switzerland. AB - Background: Inspired by the US Choosing Wisely(r), in 2016 the Swiss Society of General Internal Medicine released a list of five treatments or diagnostic tests used in the hospital and considered unnecessary based on not improving patient care and adding to health care costs. These "Smarter Medicine" recommendations were implemented in the Department of Internal Medicine, Uster Hospital, in August 2016. They were supported by lectures and weekly email communications. We analyzed the number of blood draws before and after implementation of the recommendation aimed at reducing blood tests. Methods: This retrospective analysis was conducted in the Department of Internal Medicine, Uster Hospital, Canton of Zurich, Switzerland. Patients hospitalized in the 3 months before and after implementation were analyzed. Results: A total of 2023 hospitalizations were analyzed. There was a significant decrease in the number of blood draws after introduction of the recommendation: before implementation, the median number of blood draws per patient was 4 (interquartile range [IQR], 2-7); after implementation, the median was 4 (IQR, 2-6; P = 0.002). Indeed, since 46% of the patients in the first group had more than four blood tests, this ratio decreased to 39% after implementation. Discussion: Inappropriate blood draws may lead to anemia, patient discomfort and false-positive results. The simple and low-cost interventions used to implement "Smarter Medicine" have changed physician behavior by reducing the number of blood orders. These results are promising. Whether such recommendations will impact patient and clinical outcomes remains unknown; hence, further studies are needed to clarify this issue. PMID- 29765247 TI - Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer. AB - Background: Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. Methods: A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Results: Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P=0.000; Spearman =0.650, P=0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. Conclusion: We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC. PMID- 29765246 TI - Efficacy of opioids versus placebo in chronic pain: a systematic review and meta analysis of enriched enrollment randomized withdrawal trials. AB - Introduction: Opioids have been used for millennia for the treatment of pain. However, the long-term efficacy of opioids to treat chronic non-cancer pain continues to be debated. To evaluate opioids' efficacy in chronic non-cancer pain, we performed a meta-analysis of published clinical trials for MU-opioid receptor agonists performed for US Food and Drug Administration approval. Methods: MEDLINE and Cochrane trial register were searched for enriched enrollment randomized withdrawal studies (before June 2016). Selection criteria included: adults, >=10 subjects per arm, any chronic pain condition, double-blind treatment period lasting >=12 weeks, and all MU-agonist opioids approved in the USA. Results: Fifteen studies met criteria. Opioid efficacy was statistically significant (p<0.001) versus placebo for pain intensity (standardized mean difference: -0.416), >=30% and >=50% improvement in pain (risk difference: 0.166 and 0.137), patient global impression of change (0.163), and patient global assessment of study medication (0.194). There were minor benefits on physical function and no effect on mental function. Conclusion: Opioids are efficacious in the treatment of chronic non-cancer pain for up to 3 months in randomized controlled trials. This should be considered, alongside data on opioid safety, in the use of opioids for the treatment of chronic pain. PMID- 29765248 TI - Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative-intent surgery for hepatocellular carcinoma: experience from a developing country. AB - Purpose: The aim of the study was to evaluate a prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on long-term survival of cirrhotic and noncirrhotic hepatocellular cancer (HCC) patients managed by a curative-intent liver surgery in a developing country. Patients and methods: During the study period between November 1, 2001, and December 31, 2012, 109 patients underwent potentially curative hepatectomy for HCC. Data were retrospectively reviewed from the prospectively collected database. The median follow-up was 25 months. NLR was estimated by dividing an absolute neutrophil count by an absolute lymphocyte count from the differential blood count. Receiver operating characteristic curve was constructed to assess the ability of NLR to predict long-term outcomes and to determine an optimal cutoff value for all patients group, the subgroup with cirrhosis, and the subgroup without cirrhosis. The optimal cutoff values were 1.28, 1.28, and 2.09, respectively. Results: The overall 3- and 5-year survival rates were 49% and 45%, respectively, for low NLR group and 38% and 26%, respectively, for high NLR group. The difference was statistically significant (p=0.015). Overall survival was similar between low and high NLR groups in patients with cirrhosis; no difference was found between the groups (p=0.124). In patients without cirrhosis, low NLR group had longer overall survival compared with high NLR group (p=0.015). Univariate analysis identified four factors as significant predictors of long-term survival: cirrhosis, Child-Pugh score, platelet count, and NLR. On multivariate analysis, only platelet count and NLR were independent prognostic factors of long-term survival. Conclusion: Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed. PMID- 29765249 TI - Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2- metastatic breast cancer? AB - Background: Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (MBC) accounts for 73% of all MBCs. Endocrine therapy (ET) is the basis of first-line (1L) therapy for patients with HR+/HER2- MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS) compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS) benefit to date. We reviewed studies of HR+/HER2- MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL). Methods: The Embase(r), Medline(r), and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2- MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs), observational, and retrospective studies were included. Results: Seventy-nine RCTs were identified: 58 (73%) in the 1L+ setting and 21 (27%) in second-line or greater settings. PFS hazard ratios (HRs) were reported in 61 (77%) studies; 31 (39%) reported significant PFS improvements. OS was reported in 44 (41%) studies; 12 (15%) reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8%) studies (1 Phase II; 5 Phase III). Patients with HER2- MBC received, on average, >=5 lines of therapy, with no consistent treatment pathway. Baseline characteristics, prior therapies, and the type and number of post-progression therapies significantly impacted OS. PFS, response rates, and HRQoL decreased with each line of therapy (EuroQol 5 Dimensions: 0.78 1L vs. 0.70 post-progression). Conclusion: Few RCTs in HR+/HER2- MBC have demonstrated significant improvements in OS. Factors other than choice of 1L therapy impact OS, including post-progression therapies, which cannot be controlled in RCTs. This study emphasizes the importance of PFS improvement in 1L treatment of HR+/HER2- MBC. PMID- 29765250 TI - Genetic variants in the exon region of versican predict survival of patients with resected early-stage hepatitis B virus-associated hepatocellular carcinoma. AB - Background: The upregulated expression of versican (VCAN) promotes the proliferation, invasion, and metastasis of various types of human cancer cells, including hepatocellular carcinoma (HCC) cells. Patients and methods: In this study, genetic variants in the exon region of VCAN were genotyped by DNA sequencing. Prognostic values of VCAN exon single nucleotide polymorphisms (SNPs) were assessed by Kaplan-Meier with the log-rank test, and uni- and multivariate Cox proportional hazard regression model. Results: A total of 111 patients with resected hepatitis B virus-associated early-stage HCC were collected for genotyping VCAN exon SNPs using Sanger DNA sequencing. Haplotype analysis was performed using Haploview 4.2. Survival data were analyzed using Kaplan-Meier curves and Cox proportional hazards regression analyses. The rs2652098, rs309559, rs188703, rs160278, and rs160277 SNPs were significantly associated with overall patient survival (p<0.001, p=0.012, p=0.010, p=0.007, and p=0.007, respectively). Patients carrying the TAGTG haplotype had a poorer prognosis than those with the most common CGAAT haplotype, after adjusting for tumor size, tumor capsule, and regional invasion (adjusted hazard ratio [HR] =2.06, 95% CI: 1.27-3.34, p=0.003). Meanwhile, patients with the TAGTG haplotype and a larger tumor size or an incomplete tumor capsule had an increased risk of death, compared with the others (adjusted HR =3.00, 95% CI: 1.67-5.36, p<0.001; and adjusted HR = 1.99, 95% CI = 1.12-3.55, p = 0.02, respectively). The online database mining analysis showed that upregulated VCAN expression in HCC tissues was associated with a poor overall survival of 148 HCC patients. Conclusion: Genetic variants in the exon region of VCAN were associated with overall survival in patients with resected early-stage hepatitis B virus-associated HCC, and may be a potential prognostic biomarker. PMID- 29765251 TI - Genetic variants of ALDH2-rs671 and CYP2E1-rs2031920 contributed to risk of hepatocellular carcinoma susceptibility in a Chinese population. AB - Objective: Acetaldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been associated with hepatocellular carcinoma (HCC) susceptibility and prognosis. The polymorphisms ALDH2 rs671 and CYP2E1 rs2031920 are reportedly correlated with the prevalence of HCC in other countries. The aim of this study was to investigate associations between ALDH2 and CYP2E1, and HCC susceptibility in a population of Guangxi, southern China, an area with a high incidence of HCC. Patients and methods: The study cohort included 300 HCC cases, 292 healthy controls for HCC susceptibility analysis, and another 20 HCC cases and 10 healthy controls for ascertainment. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. Results: The study results demonstrated that mutant genotypes of ALDH2 (G/A and A/A) led to significant differences in HCC susceptibility, as compared with the wild genotype (G/G) with the same C1/C1 genotype in non-drinking individuals (adjusted P=0.010, OR=0.20, 95% CI=0.06-0.68). The mutant genotypes of CYP2E1 (C1/C2 and C2/C2) brought about significant differences in HCC susceptibility, as compared with the wild genotype (C1/C1) and the same G/G genotype (adjusted P=0.025, OR=0.42, 95% CI=0.20-0.90). Drinking plays a role in HCC susceptibility in the same G/G genotype individuals (adjusted P=0.004, OR=0.32, 95% CI=0.15-0.69), but had no impact when combined with CYP2E1 for analysis (all P>0.05). Conclusion: These results suggest that the mutant genotypes of ALDH2 and CYP2E1 may be protective factors for HCC susceptibility in Guangxi province, China. PMID- 29765252 TI - Triple-negative and HER2-overexpressing breast cancer cell sialylation impacts tumor microenvironment T-lymphocyte subset recruitment: a possible mechanism of tumor escape. AB - Introduction: Breast cancers develop different patterns of sialylation to modulate their tumor-infiltrating lymphocyte (TIL) environment. We studied the relationship between alpha-2,6 sialyltransferases and the TIL in different breast cancer molecular subgroups. Materials and methods: Immunohistochemical preparations were made from 39 luminal (LUM), 13 human epidermal growth factor receptor 2-overexpressing (HER2) and 47 triple-negative (TN) breast carcinomas. Targeted proteins included ST6Gal-I, ST6Gal-II, ST6GalNac-I, CD8, CD4 and granzyme-B in both cytotoxic T lymphocytes and NK lymphocytes (CTL/NK). Results: CTL/NK populations were significantly more frequent in TN than LUM (P <0.001). TN showed a lower level of ST6Gal-I expression than LUM or HER2 (both P > 0.001). ST6GalNac-I expression was lower in LUM than in TN or HER2 (P = 0.002 and P = 0.02, respectively). In HER2, a significant association was found between a low level of ST6Gal-I expression and a high TIL level. In TN, a significant association was observed between a high level of ST6Gal-II expression and a high TIL level. Conclusion: An increase in infiltrating lymphocytes could be influenced by low expression of ST6Gal-I in HER2 and by high expression of ST6Gal II in TN breast cancers. Thus, targeting these sialylation pathways could modulate the levels of TIL. PMID- 29765253 TI - Use of histamine H2 receptor antagonists and outcomes in patients with heart failure: a nationwide population-based cohort study. AB - Background: Histamine H2 receptor activation promotes cardiac fibrosis and apoptosis in mice. However, the potential effectiveness of histamine H2 receptor antagonists (H2RAs) in humans with heart failure is largely unknown. We examined the association between H2RA initiation and all-cause mortality among patients with heart failure. Methods: Using Danish medical registries, we conducted a nationwide population-based active-comparator cohort study of new users of H2RAs and proton pump inhibitors (PPIs) after first-time hospitalization for heart failure during the period 1995-2014. Hazard ratios (HRs) for all-cause mortality and hospitalization due to worsening of heart failure, adjusting for age, sex, and time between heart failure diagnosis and initiation of PPI or H2RA therapy, index year, comorbidity, cardiac surgery, comedications, and socioeconomic status were computed based on Cox regression analysis. Results: Our analysis included 42,902 PPI initiators (median age 78 years, 46% female) and 3,296 H2RA initiators (median age 76 years, 48% female). Mortality risk was lower among H2RA initiators than PPI initiators after 1 year (26% vs 31%) and 5 years (60% vs 66%). In multivariable analyses, the 1-year HR was 0.80 (95% CI, 0.74-0.86) and the 5-year HR was 0.85 (95% CI, 0.80-0.89). These findings were consistent after propensity score matching and for ischemic and nonischemic heart failure, as for sex and age groups. The rate of hospitalization due to worsening of heart failure was lower among H2RA initiators than PPI initiators. Conclusion: In patients with heart failure, H2RA initiation was associated with 15%-20% lower mortality than PPI initiation. PMID- 29765254 TI - STUMP, a surprise finding in a large fibroid uterus in a 20-year-old woman. AB - We report on a case of a 20-year-old nulliparous woman with menorrhagia associated with a smooth muscle tumor of uncertain malignant potential (STUMP) that was responsive to Goserelin. This case details the investigation and management of a young woman who desires ongoing fertility preservation. STUMP is a rare uterine tumor with a paucity of literature available regarding management and subsequent malignant potential, particularly in the case of a patient who desires fertility preservation. PMID- 29765255 TI - Distribution of pomalidomide into semen of healthy male subjects after multiple doses. AB - Objective: To assess whether pomalidomide can distribute into human semen and its duration in human semen. Method: A phase 1, randomized, double-blind, placebo controlled study (CC-4047-CP-006) was conducted to evaluate the safety, tolerability, and pharmacokinetics of pomalidomide (CC-4047) following multiple daily doses in healthy male subjects. Semen samples were collected on Day -1 and 4 hours after dosing on Day 4 to quantify the pomalidomide concentrations in ejaculate after multiple oral doses of pomalidomide. Result: Our study showed that pomalidomide was present in male subjects' semen samples, and the average amount of pomalidomide in a single ejaculate 4 hours after dosing was less than 0.0022% of the daily 2 mg dose. There was a good correlation between the semen concentrations and the plasma concentrations, suggesting that the plasma concentration may be the main driving force for the distribution of pomalidomide into the seminal reservoirs. Simulation results suggest that pomalidomide was undetectable in semen 48 hours after stopping dosing. Conclusion: Based on the results from this study, the pomalidomide prescribing information approved by the US Food and Drug Administration includes a statement that "pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 4 weeks after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm." PMID- 29765256 TI - Grazoprevir/elbasvir for the treatment of adults with chronic hepatitis C: a short review on the clinical evidence and place in therapy. AB - Chronic hepatitis C virus (HCV) infection impacts approximately 71 million people and approximately 400,000 deaths are attributed to HCV-related liver disease annually worldwide. Mainstay of treatment for over 25 years has been pegylated interferon until the advent of protease inhibitors, which has led to all-oral HCV treatment regimens that have changed the outlook of hepatitis C treatment. Grazoprevir/elbasvir provides high rates of efficacy and tolerability and is an all-oral once daily treatment option for HCV infection. Efficacy of grazoprevir/elbasvir has been proven in patients with cirrhosis, patients who have previously failed treatment with peginterferon and ribavirin (RBV), patients with end-stage renal disease and patients with HIV co-infection. Data have shown a high barrier to resistance despite the presence of resistance-associated substitutions. Grazoprevir/elbasvir represents a very promising regimen for treatment of HCV infection. This review provides a summary of pharmacology, efficacy, and safety of grazoprevir/elbasvir for the treatment of HCV infection. PMID- 29765257 TI - Spotlight on certolizumab pegol in the treatment of axial spondyloarthritis: efficacy, safety and place in therapy. AB - Certolizumab pegol (CZP) is a pegylated humanized tumor necrosis factor-alpha inhibitor (TNFi) approved for the treatment of ankylosing spondylitis (AS) in the USA and for AS and non-radiographic axial spondyloarthritis (nr-axSpA) in Europe and in some Latin American countries. CZP lacks Fc region, preventing complement fixation and cytotoxicity mediated by antibody; CZP does not actively cross the placenta, unlike other TNFi. RAPID-axSpA study is a Phase III trial conducted in patients with AS and nr-axSpA as double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Of a total of 325 patients recruited, 107 patients were assigned to placebo and 218 patients to CZP (111 to CZP 200 mg Q2W, 107 to CZP 400 mg Q4W). Improvements in axial involvement, joint involvement, enthesitis and quality of life were reported in patients treated with CZP. Safety profile was like that reported for other TNFi in axSpA patients. In this article, we summarized the pharmacology and we reviewed the efficacy and tolerability of this drug for the treatment of axSpA. Some special considerations of CZP during pregnancy are included. CZP, the latest TNFi to be approved, showed efficacy in all manifestations of AS and nr-axSpA. PMID- 29765259 TI - Shadowing emergency medicine residents by medical education specialists to provide feedback on non-medical knowledge-based ACGME sub-competencies. AB - Objective: Non-medical knowledge-based sub-competencies (multitasking, professionalism, accountability, patient-centered communication, and team management) are challenging for a supervising emergency medicine (EM) physician to evaluate in real-time on shift while also managing a busy emergency department (ED). This study examines residents' perceptions of having a medical education specialist shadow and evaluate their nonmedical knowledge skills. Methods: Medical education specialists shadowed postgraduate year 1 and postgraduate year 2 EM residents during an ED shift once per academic year. In an attempt to increase meaningful feedback to the residents, these specialists evaluated resident performance in selected non-medical knowledge-based Accreditation Council of Graduate Medical Education (ACGME) sub-competencies and provided residents with direct, real-time feedback, followed by a written evaluation sent via email. Evaluations provided specific references to examples of behaviors observed during the shift and connected these back to ACGME competencies and milestones. Results: Twelve residents participated in this shadow experience (six post graduate year 1 and six postgraduate year 2). Two residents emailed the medical education specialists ahead of the scheduled shadow shift requesting specific feedback. When queried, five residents voluntarily requested their feedback to be included in their formal biannual review. Residents received milestone scores and narrative feedback on the non-medical knowledge-based ACGME sub-competencies and indicated the shadow experience and subsequent feedback were valuable. Conclusion: Medical education specialists who observe residents over the course of an entire shift and evaluate non-medical knowledge-based skills are perceived by EM residents to provide meaningful feedback and add valuable information for the biannual review process. PMID- 29765260 TI - Attitude and perception of undergraduate medical students toward the problem based learning in Chitwan Medical College, Nepal. AB - Background: Problem-based learning (PBL) was introduced into Basic Medical Sciences early in the 1980s at Tribhuvan University (TU), Nepal, followed by other universities where didactic lecture method was still followed as the main teaching strategy. Despite gaining its popularity worldwide as integrated teaching learning method, PBL is not given importance in Nepal. This study aimed to assess the attitude and perceptions of undergraduate medical students regarding learning outcomes of PBL and to know their views about role and qualities of effective tutors for its successful implementation. Methods: This descriptive study was based on a self-administered questionnaire. The first part of the questionnaire measured students' perception and attitude toward benefits of PBL and the second part measured students' perception about role of PBL tutor. Bachelor of Medicine and Bachelor of Surgery (MBBS) first year (2014/2015 academic year) students at Chitwan Medical College, TU, were asked to express their opinions about the importance of learning outcomes by rating each statement on a five-point Likert scale and the responses were combined into three categorical variables: "agree" (strongly agree plus agree), "neutral", and "disagree" (strongly disagree plus disagree). Data were analyzed using SPSS version 21.0. Results: Approximately 85.5% participants agreed that PBL is an interesting method of teaching learning. Most of them (86.7%) accepted that PBL is an interactive and a mutual learning method and improves self-directed learning (83.2%). Although 78% had recommended it better than lecture, many (54.2%) pointed it out as a time-consuming method. The participants were also highly rated (80.5%) to the statement - the tutor's role in enhancing the constructive active learning and maintaining good intra-personal behavior. Conclusion: Student's attitude toward PBL was positive. They highly appreciated the roles of a tutor as facilitators and motivators for proper activities in PBL session. PBL sessions were considered effective in improving students professional knowledge and refining problem-solving and self-directed learning skills along with enriching teamwork experience. PMID- 29765258 TI - Psychological interventions for behavioral adjustments in diabetes care - a value based approach to disease control. AB - Psychological aspects of a person, such as the personal value and belief systems, cognition and emotion, form the basis of human health behaviors, which, in turn, influence self-management, self-efficacy, quality of life, disease control and clinical outcomes in people with chronic diseases such as diabetes mellitus. However, psychological, psychosocial and behavioral interventions aimed at these groups of patients have yielded inconsistent effects in terms of clinical outcomes in clinical trials. This might have been due to differing conceptualization of health behavioral theories and models in the interventions. Assimilating different theories of human behavior, this narrative review attempts to demonstrate the potential modulatory effects of intrinsic values on cognitive and affective health-directed interventions. Interventions that utilize modification of cognition alone via education or that focuses on both cognitive and emotional levels are hardly adequate to initiate health-seeking behavior and much less to sustain them. People who are aware of their own personal values and purpose in life would be more motivated to practice good health-related behavior and persevere in them. PMID- 29765261 TI - Depression in medical students: current insights. AB - Medical students are exposed to multiple factors during their academic and clinical study that have been shown to contribute to high levels of depression, anxiety, and stress. The purpose of this article was to explore the issue of depression in the medical student population, including prevalence, causes, and key issues, along with suggestions for early identification and support from one medical school in New Zealand. After establishing that the prevalence of depression is higher for medical students than the general population, the key issues explored include assessment used in the program, characteristics of the student population (such as Type A personality and perfectionism), resilience, selection procedures, students' motivation, and the nature of the clinical environment. This review includes several recommendations to improve students' psychological health such as positioning well-being within an overarching comprehensive workplace wellness model and integrating peer and faculty-led support into the day-to-day running of the institution. It also highlights the advantages of the addition of a well-being curriculum, as skills to prevent and manage distress and depression are relevant in supporting the competencies required by medical practitioners. It concludes that medical schools need wide ranging strategies to address the complexities associated with the particular student population attracted to medicine and calls for educators to act, by noticing opportunities where they can introduce such initiatives into their medical programs. PMID- 29765262 TI - A new Notomastus (Annelida, Capitellidae) species from Korean waters, with genetic comparison based on three gene markers. AB - Notomastus koreanussp. n., collected from the sublittoral muddy bottom of Korean waters, is described as a new species. The Korean new species closely resembles N. torquatus Hutchings & Rainer, 1979 in the chaetal arrangement and the details of abdominal segments, but differs in the position of genital pores and the absence of eyes. DNA sequences (mtCOI, 16S rRNA, and histone H3) of the new species were compared with all the available sequences of Notomastus species in the GenBank database. Three genes showed significant genetic differences between the new species and its congeners (COI: 51.2%, 16S: 38.1-47.3%, H3: 3.7-9.3%). This study also includes a comprehensive comparison of the new Korean Notomastus species with its most closely similar species, based on the morphological and genetic results. PMID- 29765263 TI - First observations of the bigfin squid Magnapinna sp. in the Colombian Southern Caribbean. AB - Herein, first observations are reported of Magnapinna squids in the Colombian Southern Caribbean. Two specimens were observed by Remote Operated Vehicles (ROV) during exploratory drilling surveys for hydrocarbons at 1,883 and 2,294 m depth. These are the first observations of specimens of Magnapinna in the Southern Caribbean. Resumen La primera observacion del calamar Magnapinna sp. en el caribe sur colombiano. Dos especimenes de calamares de aleta grande fueron observados con submarino de operacion remota (ROV) durante un proyecto de perforacion exploratoria de hidrocaburos a profundidades de 1,883 y de 2,294 m, respectivamente. Estas son las primeras observaciones de especimenes de Magnapinna en el Caribe Sur. PMID- 29765264 TI - Coping with loss of ability vs. emotional control and self-esteem in women after mastectomy. AB - Aim: Does coping with the loss of ability depend on self-esteem and emotional control? Background: Persons who experience losses in two dimensions, i.e. health and ability can deal with the loss by physical therapy, and also by mental and socio-professional rehabilitation. But far and foremost, it is the personality of the person who experiences the loss that matters most. Materials and methods: The study included 37 patients after mastectomy. They were divided into two groups according to the time elapsed from cancer diagnosis. The study was conducted using the Questionnaire on Coping With Ability Loss (P. Wolski), Self-Esteem Loss (M. Rosenberg,) and the Courtauld Emotional Control Scale - CECS. Results: In Group I, the higher level of acceptance in the QCAL test, the higher self-esteem. The more depression experienced by individuals, the lower is their level of self esteem or the less depression experienced, the higher the self-esteem. In Group II, the higher the level of depression, the lower the level of anger. The greater the struggle, the lower level of anger. The lower the level of depression and struggle, the higher the level of emotion control. Conclusions: Women diagnosed no longer than five years back do not differ from those diagnosed further back in terms of copying with the loss of ability, self-esteem and emotional control. PMID- 29765266 TI - James F. Thornton, MD. PMID- 29765267 TI - Facial Mohs Reconstruction. PMID- 29765265 TI - Is volumetric modulated arc therapy with constant dose rate a valid option in radiation therapy for head and neck cancer patients? AB - Background: Intensity-modulated radiotherapy (IMRT) improves dose distribution in head and neck (HN) radiation therapy. Volumetric-modulated arc therapy (VMAT), a new form of IMRT, delivers radiation in single or multiple arcs, varying dose rates (VDR-VMAT) and gantry speeds, has gained considerable attention. Constant dose rate VMAT (CDR-VMAT) associated with a fixed gantry speed does not require a dedicated linear accelerator like VDR-VMAT. The present study explored the feasibility, efficiency and delivery accuracy of CDR-VMAT, by comparing it with IMRT and VDR-VMAT in treatment planning for HN cancer. Methods and materials: Step and shoot IMRT (SS-IMRT), CDR-VMAT and VDR-VMAT plans were created for 15 HN cancer patients and were generated by Pinnacle3 TPS (v 9.8) using 6 MV photon energy. Three PTVs were defined to receive respectively prescribed doses of 66 Gy, 60 Gy and 54 Gy, in 30 fractions. Organs at risk (OARs) included the mandible, spinal cord, brain stem, parotids, salivary glands, esophagus, larynx and thyroid. SS-IMRT plans were based on 7 co-planar beams at fixed gantry angles. CDR-VMAT and VDR-VMAT plans, generated by the SmartArc module, used a 2 arc technique: one clockwise from 182 degrees to 178 degrees and the other one anti-clockwise from 178 degrees to 182 degrees . Comparison parameters included dose distribution to PTVs (Dmean, D2%, D50%, D95%, D98% and Homogeneity Index), maximum or mean doses to OARs, specific dose-volume data, the monitor units and treatment delivery times. Results: Compared with SS-IMRT, CDR-VMAT significantly reduced the maximum doses to PTV1 and PTV2 and significantly improved all PTV3 parameters, except D98% and D95%. It significantly spared parotid and submandibular glands and was associated with a lower Dmean to the larynx. Compared with VDR-VMAT, CDR-VMAT was linked to a significantly better Dmean, to the PTV3 but results were worse for the parotids, left submandibular gland, esophagus and mandible. Furthermore, the Dmean to the larynx was also worse. Compared with SS-IMRT and VDR-VMAT, CDR-VMAT was associated with higher average monitor unit values and significantly shorter average delivery times. Conclusions: CDR-VMAT appeared to be a valid option in Radiation Therapy Centers that lack a dedicated linear accelerator for volumetric arc therapy with variable dose-rates and gantry velocities, and are unwilling or unable to sanction major expenditure at present but want to adopt volumetric techniques. PMID- 29765268 TI - Approach to the Post Mohs Patient. AB - This article discusses the often unique patient presentations and management challenges of the post Mohs resection surgical patient. This includes social, economic, and health issues. Anesthesia considerations and pre- and postoperative care are also discussed in this article. PMID- 29765270 TI - Simplifying Lip Reconstruction: An Algorithmic Approach. AB - The authors provide an overview of lip reconstruction after Mohs surgery based on the senior author's practice. Lip reconstruction offers unique challenges to preserve not only lip function but also aesthetics. Lip reconstruction must take into consideration the three anatomical layers that comprise the lip and defects that involve the mucosa, the muscle, the skin or more than one layer will help determine the modality of repair. The authors offer an algorithm based on defect location, tissue involvement, and severity of defect to simplify an often complex decision-making process. PMID- 29765269 TI - Mohs Micrographic Surgery: Development, Technique, and Applications in Cutaneous Malignancies. AB - Mohs micrographic surgery (MMS) is a specialized technique for treating skin malignancies that offers the highest cure rate by allowing histological evaluation of the entire peripheral and deep margins. MMS also maximally preserves as much uninvolved, normal adjacent tissue as possible, allowing for the best cosmetic and functional outcomes. When used for appropriate indications, this technique is also more cost-effective than other treatment modalities. In this article, the authors will discuss the development of MMS, the steps involved in this procedure, and the indications for this technique. They will also review the use of MMS for basal cell carcinoma, squamous cell carcinoma, melanoma in situ, and some less common skin malignancies. PMID- 29765271 TI - Approach to Reconstruction of Nasal Defects. AB - The nose is the most central and anterior projecting facial feature. Therefore, the presence of a defect is easily noticeable to the untrained eye. Return of the defect to the original form is an achievable end goal of reconstruction, necessitating appropriate reformation of three-dimensional geometry, proper establishment of symmetry, and excellent color and texture match to the adjacent structures. Regarding its physiological importance, disruption of the normal function may cause respiratory obstruction and contribute to patient distress. To achieve successful repair, preoperative preparation must consider the location, the layers involved, and the size of the defect. Prompt and well-organized repair minimizes the occurrence of progressive necrosis and severe late-stage deformity. Here the authors provide a framework to approach various nasal defects and provide a review of the novel ideologies and techniques. The workhorse of nasal repair, the forehead flap, is discussed independently due to the breadth of innovation. PMID- 29765272 TI - Approach to Reconstruction of Cheek Defects. AB - The cheek is the largest facial unit with a prominent position on the face. Trauma, burns, and the resection of skin cancers constitute common sources of injury, potentially resulting in defects that, through natural healing, produce noticeable scarring. Surgical repair focuses on the reformation of three dimensional geometries, proper establishment of symmetry, and the minimization of color and texture discrepancies to the surrounding. Defects located in this region may extend to the orbital, nasal, or buccal units and cause unique structural and functional disturbances. Furthermore, without appropriate repair, full-thickness defects involving the buccal mucosa may result in oral dysfunction. In this article, the authors provide a framework to approach various cheek defects and provide a review of the host of ideologies and techniques. PMID- 29765273 TI - Scalp and Forehead Reconstruction. AB - Reconstructing the scalp and forehead is a challenging endeavor frequently undertaken by facial plastic and reconstructive surgeons. There are many anatomical factors to be considered in this area, including multiple neurovascular structure present that should be identified and preserved. Hair morphology and physiology should be considered, and trichophytic techniques should be incorporated into incision planning and closure. The reconstructive ladder must be used when considering options in reconstructing scalps and forehead defects. This article reviews reconstructive options including secondary intention, primary closure, skin grafting, allografts, tissue expanders, and local, regional, and free tissue transfers, among others in the surgical management of forehead and scalp defects. The reconstructive surgeon should be familiar with these techniques and be able to use them when indicated, based on the size, shape, and location of defects. PMID- 29765276 TI - Delivering Multimedia Education in Clinical Biochemistry. PMID- 29765274 TI - Review of Eyelid Reconstruction Techniques after Mohs Surgery. AB - Mohs micrographic surgery achieves high cure rates while preserving healthy tissue making it the optimal treatment for skin cancer. The goals of eyelid reconstruction after Mohs surgery include restoring eyelid structure and function while attaining acceptable aesthetic results. Given the variety of eyelid defects encountered after Mohs surgery, a thorough understanding of the complex eyelid anatomy as well as an in-depth knowledge of the numerous reconstructive techniques available are required to accomplish these reconstructive goals. In this article, the authors review eyelid anatomy and discuss a variety of techniques used for the reconstruction of defects involving the periocular region. PMID- 29765275 TI - Tristemma hirtum and Five Other Cameroonian Edible Plants with Weak or No Antibacterial Effects Modulate the Activities of Antibiotics against Gram Negative Multidrug-Resistant Phenotypes. AB - In order to contribute to the fight against infectious diseases, the in vitro antibacterial activity and the antibiotic-potentiating effects of Tristemma hirtum and five other Cameroonian edible plants have been evaluated against Gram negative multidrug-resistant (MDR) phenotypes. The microdilution method was used to evaluate the bacterial susceptibility of the extracts and their combination to common antibiotics. The phytochemical screening of the extracts was carried out according to standard methods. Phytochemical analysis of the extracts revealed the presence of alkaloids, triterpenes, steroids, and polyphenols, including flavonoids in most of the tested extracts. The entire tested extracts showed moderate (512 MUg/mL <= MIC <= 2048 MUg/mL) to weak (MIC > 2048 MUg/mL) antibacterial activities against the tested bacteria. Furthermore, extracts of leaf of Tristemma hirtum and pericarps of Raphia hookeri (at their MIC/2 and MIC/4) strongly potentiated the activities of all antibiotics used in the study, especially those of chloramphenicol (CHL), ciprofloxacin (CIP), kanamycin (KAN), and tetracycline (TET) against 70% (7/10) to 100% (10/10) of the tested MDR bacteria, with the modulating factors ranging from 2 to 128. The results of this study suggest that extracts from leaves of Tristemma hirtum and pericarps of Raphia hookeri can be sources of plant-derived products with antibiotic modifying activity. PMID- 29765278 TI - Arise Sir Bio-Informatician a Proposal for a New Advanced Practitioner in Laboratory Medicine. PMID- 29765277 TI - Case-of-the-Week: Connected, Collaborative Clinical Chemistry. PMID- 29765279 TI - Summary of Training in Laboratory Diagnosis of Autoimmune Diseases. PMID- 29765280 TI - Estimating Systematic Error of Measurement Procedures of Lipid Quantities. PMID- 29765281 TI - Foreword from the new editor-in-chief. PMID- 29765283 TI - Integration of multigene panels for the diagnosis of hereditary retinal disorders using Next Generation Sequencing and bioinformatics approaches. AB - In recent years, Next-Generation Sequencing (NGS) opened a new way for the study of pathogenic mechanisms and for molecular diagnosis of inherited disorders. In the present work, we focused our attention on the inherited retinal dystrophies (IRDs), a group of specific disorders of the retina, displaying a very high clinical and genetic heterogeneity, whose genetic diagnosis is not easily feasible. It represents a paradigmatic example for the integration of clinical and molecular examination toward precision medicine. In this paper, we discuss the use of targeted NGS resequencing of selected gene panels in a cohort of patients affected by IRDs. We tested the hypothesis to apply a selective approach based on a careful clinical examination. By this approach we reached a 66% overall detection rate for pathogenic variants, with a 52% diagnostic yield. Reduction of the efforts for validation and classification of variants is a clear advantage for the management of genetic testing in a clinical setting. PMID- 29765282 TI - Next-generation sequencing approach for the diagnosis of human diseases: open challenges and new opportunities. AB - The rapid evolution and widespread use of next generation sequencing (NGS) in clinical laboratories has allowed an incredible progress in the genetic diagnostics of several inherited disorders. However, the new technologies have brought new challenges. In this review we consider the important issue of NGS data analysis, as well as the interpretation of unknown genetic variants and the management of the incidental findings. Moreover, we focus the attention on the new professional figure of bioinformatics and the new role of medical geneticists in clinical management of patients. Furthermore, we consider some of the main clinical applications of NGS, taking into consideration that there will be a growing progress in this field in the forthcoming future. PMID- 29765287 TI - The IFCC Curriculum - phase 1. PMID- 29765285 TI - Anemia and thrombocytopenia in the cohort of HIV-infected adults in northwest Ethiopia: a facility-based cross-sectional study. AB - Background: Anemia and thrombocytopenia are frequent hematological abnormalities in patients with human immunodeficiency virus (HIV) infection and have been associated with increased morbidity and mortality. However, there is a paucity of data on the prevalence and correlates of these hematological abnormalities among HIV infected adults in Ethiopia. The aim of this study was to determine the prevalence and correlates of anemia and thrombocytopenia in a cohort of HIV-1 infected adults in northwest Ethiopia. Methods: A total of 320 HIV-infected adults were enrolled into the study, from March 2016 to July 2016. Sociodemographic and clinical characteristics of the study participants were recorded. Blood samples were collected from each patient to determine hematological and immunological parameters. A binary logistic regression model was fitted to identify factors associated with each hematological abnormality. The odds ratio with a 95% confidence interval was calculated. A p-value <0.05 was considered statistically significant. Results: Out of 320 HIV-1 positive participants, 203 (63.4%) were female. Overall, anemia was found in 25% (95% CI: 20.23 - 29.8%) of the study participants, of whom 2.5% (n=2) had severe and 21.2% (n=17) had moderate anemia. About 83.8% (67/80) anemic patients were on highly active antiretroviral therapy (HAART) for a minimum of six months, and 31 of them were receiving Zidovudine (AZT)-based HAART regimen. Multivariable logistic regression analysis showed that being HAART-naive (AOR= 5.5, 95% CI: 1.5-19.9) and having CD4 count below 200 cells/ul (AOR= 2.4, 95% CI: 1.3-4.9) were independent and significant predictors of anemia. Thrombocytopenia was noted in 6.3% (95% CI: 3.58-8.9%) of the study participants. Sixty percent of thrombocytopenic (n=12) subjects were over the age of 40 years. Conclusion: We found an overall high prevalence of anemia in the cohort of HIV-infected adults in northwest Ethiopia. HAART naive subjects and those with CD4 count less than 200 cells/ul were found to be at higher risk for developing anemia. This data has an important implication for management of hematological abnormalities in HIV patients and highlights the need for early initiation of HAART to reduce the burden of anemia. PMID- 29765288 TI - Serum ferritin as a biomarker of polycythemia vera? PMID- 29765284 TI - Influence of serum leptin levels and Q223R leptin receptor polymorphism on clinical characteristic of patients with rheumatoid arthritis from Western Mexico. AB - Objective: The aim of the present study was to evaluate the possible association between the Q223R Leptin receptor (LEPR) polymorphism (A>G; rs1137101) and leptin levels in patients with rheumatoid arthritis (RA) from Western Mexico. Methods: A cross-sectional study was performed with 70 RA patients and 74 controls subject (CS). Disease activity was evaluated using DAS28 score, the Q223R LEPR polymorphism was determined by the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) and serum leptin levels, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) were quantified. Results: RA patients had significant high serum leptin levels compared with CS; leptin levels correlated strongly with body composition measures, but not with inflammatory markers, disease evolution, and activity. The genotype and allele frequencies of the Q223R LEPR polymorphism were not associated with RA. Similarly, leptin levels did not differ between Q223R LEPR genotypes. Conclusion: The LEPR Q223R polymorphism was not associated with RA risk in patients from Mexican population, even though high levels of serum leptin were present and these could explain the low weight observed in RA patients when they were compared to control subjects. However, the serum leptin levels did not correlate with inflammatory markers, severity and disease evolution. PMID- 29765286 TI - Reference intervals for a complete blood count on an automated haematology analyser Sysmex XN in healthy adults from the southern metropolitan area of Barcelona. AB - Background: The examination of peripheral blood is routinely used as a basic test in daily medical practice. Reliable reference intervals are necessary to avoid misdiagnoses, and the establishment of those intervals is an important task for clinical laboratories.The aim of the present study was to establish the reference intervals for complete blood count (CBC) on a Sysmex XN haematology analyser in healthy adults from the southern metropolitan area of Barcelona (Spain). Methods: A total of 213 apparently healthy adults who received a general health examination at Hospital Universitari de Bellvitge were recruited to this study. Blood samples collected in K3EDTA tubes were analysed on a Sysmex XN. Statistically relevant gender based partition was assessed, outliers removed, and the reference intervals calculated in concordance with Clinical and Laboratory Standards Institute (CLSI) EP28-A3C guidelines. Results: The CBC reference intervals were established in 191 adults (64 men and 127 women) who fulfilled all of the inclusion criteria. Significant gender-dependent differences in red blood cells, haematocrit, haemoglobin and platelets were found. The rest of the CBC reference intervals were obtained from the overall data. Conclusions: We report CBC reference intervals established on a Sysmex XN analyser, a widely used automated analyser for which reference intervals were previously lacking in the literature. However, these reference intervals we recommend should be validated by individual laboratories for the local population as recommended by CLSI. PMID- 29765289 TI - Hemotherapy with New Blood Products. PMID- 29765290 TI - Extended Half-Life Factor VIII and Factor IX Preparations. AB - In the last couple of years, several extended half-life factor VIII and factor IX preparations were intensively studied and gained approval. In order to extend half-lives, techniques like fusion to protein conjugates (Fc part of IgG1 or albumin), chemical modification (PEGylation), and protein sequence modification are implemented. With these techniques, it is possible to extend half-lives of factor IX products 4- to 6- fold, while half-life extension of factor VIII products is limited to 1.5- to 2-fold due to their interaction with von Willebrand factor. Nevertheless, both extended half-life factor VIII and IX products have improved and facilitated prophylactic factor replacement therapy in hemophilia A and B, respectively. Extended half-life factor concentrates pose challenges to coagulation laboratories because accurate therapy monitoring is not possible with all factor activity assays currently used. PMID- 29765291 TI - The Potential Close Future of Hemophilia Treatment - Gene Therapy, TFPI Inhibition, Antithrombin Silencing, and Mimicking Factor VIII with an Engineered Antibody. AB - Summary Hemophilia is one of the best researched monogenic diseases. Hemophilia A will affect approximately 1:5,000 male live births. In recent decades, great progress has been made with the introduction of recombinant proteins in the 1990s for therapy and prophylaxis, securing adequate availability and, with the introduction of the prophylaxis concept, reducing the negative impact of hemophilia on morbidity (especially arthropathy). Despite this progress, there are still challenges to overcome to secure adequate prophylaxis and treatment: for the time being, causal pharmacological hemophilia prophylaxis and therapy requires repeated i.v. application on a regular basis. Although this approach leads to a reduced comorbidity, it does not yet represent an optimized approach with continuous reversal of the hemophilic defect, which would be the ideal solution. This review summarizes the very new treatment strategies for the treatment of hemophilia A and B. PMID- 29765292 TI - Platelet Additive Solutions: A Review of the Latest Developments and Their Clinical Implications. AB - Summary Platelet additive solutions (PASs) have undergone many reformulations in order to further improve platelet storage. Studies of platelets stored in PAS-F (containing acetate, magnesium and potassium as key constituents) showed that platelets may be stored for 13 days with recovery and survival outcomes that are equal or even superior to 7-day stored platelets in plasma. Clinically, patients transfused with platelets in PAS have fewer allergic reactions, while for febrile reactions data are conflicting. Transfusion-related acute lung injury (TRALI) occurs less frequently if PAS is used for buffy coat-derived platelets, but for apheresis platelets there is no difference. For PAS-B and PAS-C, corrected count increments (CCIs) are lower than for platelets stored in plasma, but for PAS-E (like PAS-F also with acetate, magnesium and potassium but with additional phosphate), though limited data is available in the literature, the CCIs seem to be comparable to those observed for platelets in plasma. With platelets in PAS, there is an accumulated dilution effect of anticoagulant and PAS as well as a loss of number and function (due to storage and/or pathogen inactivation treatment) of platelets, of which it is not clear how this impacts clinical outcomes of patients undergoing massive transfusion. Worst-case in vitro studies, where the entire plasma fraction is replaced by supernatant of platelets in PAS, do show an effect on the ability of reconstituted whole blood to clot, but in a more realistic scenario, functional clotting parameters are not different. In this review, recent laboratory and clinical data are discussed, focusing on studies published after 2010. PMID- 29765293 TI - Recurrent Bleedings in Newborn: A Factor VII Deficiency Case Report. AB - Background: Major hemorrhages in newborns can be caused by several conditions, and knowledge of the differential diagnosis is essential in order to ensure prompt recognition and appropriate treatment. Case Report: We describe the case of a male newborn experiencing recurrent hemorrhages from the first days of life. Laboratory findings showed normal platelet count, hepatic function, and C reactive protein. Coagulation tests detected an isolated prothrombin time (PT) prolongation and severe factor VII (FVII) deficiency. Conclusion: Inherited FVII deficiency is a rare autosomal recessive bleeding disorder. Clinical presentation is heterogeneous, and bleeding severity is not directly related to FVII levels. Acute bleeding episodes can be treated with human plasma-derived FVII (pdFVII) or recombinant activated FVII (rFVIIa). In case of severe deficiency, prophylaxis must be evaluated. Awareness of this condition is crucial in order to establish prompt diagnosis and treatment. PMID- 29765294 TI - Which Infectious Blood Donors Could Be Identified by the Donor History Questionnaire? - Comparison of Blood Donors Infected with HIV or HCV with Notified Cases from General Population in Germany. AB - Background: Potential risks for transfusion-transmissible infections are identified by donor history questionnaires (DHQs), and donors with higher risks are deferred from donation. We assessed to which extent the currently used DHQs support the identification of infections among blood donors. Methods: Between 2006 and 2013, we analyzed data from notified HIV and HCV cases in the general population and positive blood donors in Germany. Logistic regressions were used to identify relevant infection risks. We estimated the possible effect of improved capture of risk factors for donor selection by calculation of population attributable fractions (PAF). Results: Risky sexual contacts - MSM as well as heterosexual contacts - were the most prominent infection risks among HIV infected donors. Whereas MSM contacts were significantly less reported by donors than by cases from the general population, 58% of donors disclosed heterosexual risks compared to 26% of notified cases. The complete identification of heterosexual risk contacts might prevent acceptance of 53% of HIV-infected donors. HCV-infected donors were more likely to report heterosexual exposure, imprisonment, and piercing/tattoo than notified HCV cases. Improved recording of piercing/tattoo could prevent acceptance of 16% of HCV-infected donors. Conclusion: Donor selection should be improved with special attention to the identification of (hetero)sexual risk factors, invasive procedures (piercing/tattoo and imprisonment) applying well-designed DHQs, effective donor education, and confidential environment in all steps of the selection process. PMID- 29765295 TI - Incentives for Blood Donation: A Discrete Choice Experiment to Analyze Extrinsic Motivation. AB - Background: Demographic trends affect size and age structure of populations. One of the consequences will be an increasing need for blood products to treat age related diseases. Donation services rely on voluntariness and charitable motivation. It might be questioned whether there will be sufficient blood supply with voluntary donation. The present study focused on elicitation of preferences for incentives and aimed to contribute to the discussion on how to increase donation rates. Methods: A self-administered discrete choice experiment (DCE) was applied. Respondents were repeatedly asked to choose between hypothetical blood donation centers. In case of reluctance to receiving incentives a none-option was included. Random parameter logit (RPL) and latent class models (LCM) were used for analysis. Results: The study sample included 416 college students from the US and Germany. Choice decisions were significantly influenced by the characteristics of the donation center in the DCE. Incentives most preferred were monetary compensation, paid leave, and blood screening test. LCM identified subgroups with preference heterogeneity. Small subgroups indicated moderate to strong aversion to incentives. Conclusion: The majority of the sample positively responded to incentives and indicated a willingness to accept incentives. In face of future challenges, the judicious use and appropriate utilization of incentives might be an option to motivate potential donors and should be open to discussion. PMID- 29765297 TI - Group Analysis in FieldTrip of Time-Frequency Responses: A Pipeline for Reproducibility at Every Step of Processing, Going From Individual Sensor Space Representations to an Across-Group Source Space Representation. AB - An important aim of an analysis pipeline for magnetoencephalographic (MEG) data is that it allows for the researcher spending maximal effort on making the statistical comparisons that will answer his or her questions. The example question being answered here is whether the so-called beta rebound differs between novel and repeated stimulations. Two analyses are presented: going from individual sensor space representations to, respectively, an across-group sensor space representation and an across-group source space representation. The data analyzed are neural responses to tactile stimulations of the right index finger in a group of 20 healthy participants acquired from an Elekta Neuromag System. The processing steps covered for the first analysis are MaxFiltering the raw data, defining, preprocessing and epoching the data, cleaning the data, finding and removing independent components related to eye blinks, eye movements and heart beats, calculating participants' individual evoked responses by averaging over epoched data and subsequently removing the average response from single epochs, calculating a time-frequency representation and baselining it with non stimulation trials and finally calculating a grand average, an across-group sensor space representation. The second analysis starts from the grand average sensor space representation and after identification of the beta rebound the neural origin is imaged using beamformer source reconstruction. This analysis covers reading in co-registered magnetic resonance images, segmenting the data, creating a volume conductor, creating a forward model, cutting out MEG data of interest in the time and frequency domains, getting Fourier transforms and estimating source activity with a beamformer model where power is expressed relative to MEG data measured during periods of non-stimulation. Finally, morphing the source estimates onto a common template and performing group-level statistics on the data are covered. Functions for saving relevant figures in an automated and structured manner are also included. The protocol presented here can be applied to any research protocol where the emphasis is on source reconstruction of induced responses where the underlying sources are not coherent. PMID- 29765296 TI - Peripartum Haemorrhage: Haemostatic Aspects of the New German PPH Guideline. AB - Summary Peripartum haemorrhage remains one of the main causes of maternal mortality world-wide. The German, Austrian and Swiss Societies of Gynaecology and Obstetrics have updated the current guidelines for the treatment of peripartum haemorrhage together with the German Society of Anaesthesiology and Intensive Care Medicine and the Society of Thrombosis and Haemostasis Research. The recommendations have been the result of a thorough review of the available scientific literature and a consensus process involving all members of the guideline group. A key element of the anaesthesiological and haemostatic management is the development of a multidisciplinary standard operating procedure combining surgical as well as medical and haemostatic treatments depending on the severity of bleeding. The guideline underscores the value of clinical and laboratory diagnostics of peripartum haemorrhage as early as possible, even pre emptively. This allows for an early identification of causes of bleeding and a specific treatment. The guideline comprises evidence-based recommendations for the use of uterotonics, tranexamic acid and blood products such as factor concentrates, fresh frozen plasma, platelet concentrates, packed red blood cells, recombinant activated factor VII and desmopressin. In addition, recommendations for blood conservation strategies involving the use of cell salvage, permissive hypotension and transfusion triggers are given. PMID- 29765298 TI - Real-Time Tracking of Selective Auditory Attention From M/EEG: A Bayesian Filtering Approach. AB - Humans are able to identify and track a target speaker amid a cacophony of acoustic interference, an ability which is often referred to as the cocktail party phenomenon. Results from several decades of studying this phenomenon have culminated in recent years in various promising attempts to decode the attentional state of a listener in a competing-speaker environment from non invasive neuroimaging recordings such as magnetoencephalography (MEG) and electroencephalography (EEG). To this end, most existing approaches compute correlation-based measures by either regressing the features of each speech stream to the M/EEG channels (the decoding approach) or vice versa (the encoding approach). To produce robust results, these procedures require multiple trials for training purposes. Also, their decoding accuracy drops significantly when operating at high temporal resolutions. Thus, they are not well-suited for emerging real-time applications such as smart hearing aid devices or brain computer interface systems, where training data might be limited and high temporal resolutions are desired. In this paper, we close this gap by developing an algorithmic pipeline for real-time decoding of the attentional state. Our proposed framework consists of three main modules: (1) Real-time and robust estimation of encoding or decoding coefficients, achieved by sparse adaptive filtering, (2) Extracting reliable markers of the attentional state, and thereby generalizing the widely-used correlation-based measures thereof, and (3) Devising a near real-time state-space estimator that translates the noisy and variable attention markers to robust and statistically interpretable estimates of the attentional state with minimal delay. Our proposed algorithms integrate various techniques including forgetting factor-based adaptive filtering, l1 regularization, forward-backward splitting algorithms, fixed-lag smoothing, and Expectation Maximization. We validate the performance of our proposed framework using comprehensive simulations as well as application to experimentally acquired M/EEG data. Our results reveal that the proposed real-time algorithms perform nearly as accurately as the existing state-of-the-art offline techniques, while providing a significant degree of adaptivity, statistical robustness, and computational savings. PMID- 29765299 TI - Src Kinase Dependent Rapid Non-genomic Modulation of Hippocampal Spinogenesis Induced by Androgen and Estrogen. AB - Dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from an axon terminal at the synapse. Memories are stored in synapses which consist of spines and presynapses. Rapid modulations of dendritic spines induced by hippocampal sex steroids, including dihydrotestosterone (DHT), testosterone (T), and estradiol (E2), are essential for synaptic plasticity. Molecular mechanisms underlying the rapid non-genomic modulation through synaptic receptors of androgen (AR) and estrogen (ER) as well as its downstream kinase signaling, however, have not been well understood. We investigated the possible involvement of Src tyrosine kinase in rapid changes of dendritic spines in response to androgen and estrogen, including DHT, T, and E2, using hippocampal slices from adult male rats. We found that the treatments with DHT (10 nM), T (10 nM), and E2 (1 nM) increased the total density of spines by ~1.22 to 1.26-fold within 2 h using super resolution confocal imaging of Lucifer Yellow-injected CA1 pyramidal neurons. We examined also morphological changes of spines in order to clarify differences between three sex steroids. From spine head diameter analysis, DHT increased middle- and large-head spines, whereas T increased small- and middle-head spines, and E2 increased small-head spines. Upon application of Src tyrosine kinase inhibitor, the spine increases induced through DHT, T, and E2 treatments were completely blocked. These results imply that Src kinase is essentially involved in sex steroid-induced non-genomic modulation of the spine density and morphology. These results also suggest that rapid effects of exogenously applied androgen and estrogen can occur in steroid-depleted conditions, including "acute" hippocampal slices and the hippocampus of gonadectomized animals. PMID- 29765300 TI - Detection of DNA Double Strand Breaks by gammaH2AX Does Not Result in 53bp1 Recruitment in Mouse Retinal Tissues. AB - Gene editing is an attractive potential treatment of inherited retinopathies. However, it often relies on endogenous DNA repair. Retinal DNA repair is incompletely characterized in humans and animal models. We investigated recruitment of the double stranded break (DSB) repair complex of gammaH2AX and 53bp1 in both developing and mature mouse neuroretinas. We evaluated the immunofluorescent retinal expression of these proteins during development (P07 P30) in normal and retinal degeneration models, as well as in potassium bromate induced DSB repair in normal adult (3 months) retinal explants. The two murine retinopathy models used had different mutations in Pde6b: the severe rd1 and the milder rd10 models. Compared to normal adult retina, we found increased numbers of gammaH2AX positive foci in all retinal neurons of the developing retina in both model and control retinas, as well as in wild type untreated retinal explant cultures. In contrast, the 53bp1 staining of the retina differed both in amount and character between cell types at all ages and in all model systems. There was strong pan nuclear staining in ganglion, amacrine, and horizontal cells, and cone photoreceptors, which was attenuated. Rod photoreceptors did not stain unequivocally. In all samples, 53bp1 stained foci only rarely occurred. Co localization of 53bp1 and gammaH2AX staining was a very rare event (< 1% of gammaH2AX foci in the ONL and < 3% in the INL), suggesting the potential for alternate DSB sensing and repair proteins in the murine retina. At a minimum, murine retinal DSB repair does not appear to follow canonical pathways, and our findings suggests further investigation is warranted. PMID- 29765301 TI - The Additional Contribution of White Matter Hyperintensity Location to Post stroke Cognitive Impairment: Insights From a Multiple-Lesion Symptom Mapping Study. AB - White matter hyperintensities (WMH) are common in acute ischemic stroke patients. Although WMH volume has been reported to influence post-stroke cognition, it is still not clear whether WMH location, independent of acute ischemic lesion (AIL) volume and location, contributes to cognitive impairment after stroke. Here, we proposed a multiple-lesion symptom mapping model that considers both the presence of WMH and AIL to measure the additional contribution of WMH locations to post stroke cognitive impairment. Seventy-six first-ever stroke patients with AILs in the left hemisphere were examined by Montreal Cognitive Assessment (MoCA) at baseline and 1 year after stroke. The association between the location of AIL and WMH and global cognition was investigated by a multiple-lesion symptom mapping (MLSM) model based on support vector regression (SVR). To explore the relative merits of MLSM over the existing lesion-symptom mapping approaches with only AIL considered (mass-univariate VLSM and SVR-LSM), we measured the contribution of the significant AIL and/or WMH clusters from these models to post-stroke cognitive impairment. In addition, we compared the significant WMH locations identified by the optimal SVR-MLSM model for cognitive impairment at baseline and 1 year post stroke. The identified strategic locations of WMH significantly contributed to the prediction of MoCA at baseline (short-term) and 1 year (long term) after stroke independent of the strategic locations of AIL. The significant clusters of WMH for short-term and long-term post-stroke cognitive impairment were mainly in the corpus callosum, corona radiata, and posterior thalamic radiation. We noted that in some regions, the AIL clusters that were significant for short-term outcome were no longer significant for long-term outcome, and interestingly more WMH clusters in these regions became significant for long-term outcome compared to short-term outcome. This indicated that there are some regions where local WMH burden has larger impact than AIL burden on the long-term post-stroke cognitive impairment. In consequence, SVR-MLSM was effective in identifying the WMH locations that have additional impact on post-stroke cognition on top of AIL locations. Such a method can also be applied to other lesion-behavior studies where multiple types of lesions may have potential contributions to a specific behavior. PMID- 29765303 TI - ADNP, a Microtubule Interacting Protein, Provides Neuroprotection Through End Binding Proteins and Tau: An Amplifier Effect. PMID- 29765302 TI - The Role of Actin Cytoskeleton in Dendritic Spines in the Maintenance of Long Term Memory. AB - Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such alterations induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. This is especially intriguing as the half-life of most of the proteins that underlie such changes is usually in the range of hours to days and these proteins may change their location over time. In this review we describe studies that indicate the involvement of dendritic spines in memory formation and its maintenance. These studies show that learning leads to changes in the number and morphology of spines. Disruption in spines morphology or manipulations that lead to alteration in their number after consolidation are associated with impairment in memory maintenance. We further ask how changes in dendritic spines morphology, induced by learning and reputed to encode memory, are maintained to preserve long term memory. We propose a mechanism, based on studies described in the review, whereby the actin cytoskeleton and its regulatory proteins involved in the initial alteration in spine morphology induced by learning are also essential for spine structural stabilization that maintains long-term memory. In this model glutamate receptors and other synaptic receptors activation during learning leads to the creation of new actin cytoskeletal scaffold leading to changes in spines morphology and memory formation. This new actin cytoskeletal scaffold is preserved beyond actin and its regulatory proteins turnover and dynamics by active stabilization of the level and activity of actin regulatory proteins within these memory spines. PMID- 29765305 TI - Commentary: Nicotinic Acetylcholine Receptor alpha9 and alpha10 Subunits Are Expressed in the Brain of Mice. PMID- 29765306 TI - Microglial Activation Is Modulated by Captopril: in Vitro and in Vivo Studies. AB - The renin-angiotensin system (RAS) is an important peripheral system involved in homeostasis modulation, with angiotensin II (Ang II) serving as the main effector hormone. The main enzyme involved in Ang II formation is angiotensin-converting enzyme (ACE). ACE inhibitors (ACEIs) such as captopril (Cap) are predominantly used for the management of hypertension. All of the components of the RAS have also been identified in brain. Centrally located hormones such as Ang II can induce glial inflammation. Moreover, in Alzheimer's disease (AD) models, where glial inflammation occurs and is thought to contribute to the propagation of the disease, increased levels of Ang II and ACE have been detected. Interestingly, ACE overexpression in monocytes, migrating to the brain was shown to prevent AD cognitive decline. However, the specific effects of captopril on glial inflammation and AD remain obscure. In the present study, we investigated the effect of captopril, given at a wide concentration range, on inflammatory mediators released by lipopolysaccharide (LPS)-treated glia. In the current study, both primary glial cells and the BV2 microglial cell line were used. Captopril decreased LPS-induced nitric oxide (NO) release from primary mixed glial cells as well as regulating inducible NO synthase (iNOS) expression, NO, tumor necrosis factor-alpha (TNF-alpha) and induced interleukin-10 (IL-10) production by BV2 microglia. We further obtained data regarding intranasal effects of captopril on cortical amyloid beta (Abeta) and CD11b expression in 5XFAD cortex over three different time periods. Interestingly, we noted decreases in Abeta burden in captopril-treated mice over time which was paralleled by increased microglial activation. These results thus shed light on the neuroprotective role of captopril in AD which might be related to modulation of microglial activation. PMID- 29765307 TI - A Novel Integrative Mechanism in Anxiolytic Behavior Induced by Galanin 2/Neuropeptide Y Y1 Receptor Interactions on Medial Paracapsular Intercalated Amygdala in Rats. AB - Anxiety is evoked by a threatening situation and display adaptive or defensive behaviors, found similarly in animals and humans. Neuropeptide Y (NPY) Y1 receptor (NPYY1R) and Galanin (GAL) receptor 2 (GALR2) interact in several regions of the limbic system, including the amygdala. In a previous study, GALR2 enhanced NPYY1R mediated anxiolytic actions on spatiotemporal parameters in the open field and elevated plus maze, involving the formation of GALR2/NPYY1R heteroreceptor complexes in the amygdala. Moreover, the inclusion of complementary ethological parameters provides a more comprehensive profile on the anxiolytic effects of a treatment. The purpose of the current study is to evaluate the anxiolytic effects and circuit activity modifications caused by coactivation of GALR2 and NPYY1R. Ethological measurements were performed in the open field, the elevated plus-maze and the light-dark box, together with immediate early gene expression analysis within the amygdala-hypothalamus periaqueductal gray (PAG) axis, as well as in situ proximity ligation assay (PLA) to demonstrate the formation of GALR2/NPYY1R heteroreceptor complexes. GALR2 and NPYY1R coactivation resulted in anxiolytic behaviors such as increased rearing and head-dipping, reduced stretch attend postures and freezing compared to single agonist or aCSF injection. Neuronal activity indicated by cFos expression was decreased in the dorsolateral paracapsular intercalated (ITCp-dl) subregion of the amygdala, ventromedial hypothalamic (VMH) nucleus and ventrolateral part of the periaqueductal gray (vlPAG), while increased in the perifornical nucleus of the hypothalamus (PFX) following coactivation of GALR2 and NPYY1R. Moreover, an increased density of GALR2/NPYY1R heteroreceptor complexes was explicitly observed in ITCp-dl, following GALR2 and NPYY1R coactivation. Besides, knockdown of GALR2 was found to reduce the density of complexes in ITCp-dl. Taken together, these results open up the possibility that the increased anxiolytic activity demonstrated upon coactivation of NPYY1R and GALR2 receptor was related to actions on the ITCp-dl. GALR2-NPYY1R heteroreceptor complexes may inhibit neuronal activity, by also modifying the neuronal networks of the hypothalamus and the PAG. These results indicate that GALR2/NPYY1R interactions in medial paracapsular intercalated amygdala can provide a novel integrative mechanism in anxiolytic behavior and the basis for the development of heterobivalent agonist drugs targeting GALR2/NPYY1R heteromers, especially in the ITCp-dl of the amygdala for the treatment of anxiety. PMID- 29765308 TI - Diverse Long-Range Axonal Projections of Excitatory Layer 2/3 Neurons in Mouse Barrel Cortex. AB - Excitatory projection neurons of the neocortex are thought to play important roles in perceptual and cognitive functions of the brain by directly connecting diverse cortical and subcortical areas. However, many aspects of the anatomical organization of these inter-areal connections are unknown. Here, we studied long range axonal projections of excitatory layer 2/3 neurons with cell bodies located in mouse primary somatosensory barrel cortex (wS1). As a population, these neurons densely projected to secondary whisker somatosensory cortex (wS2) and primary/secondary whisker motor cortex (wM1/2), with additional axon in the dysgranular zone surrounding the barrel field, perirhinal temporal association cortex and striatum. In three-dimensional reconstructions of 6 individual wS2 projecting neurons and 9 individual wM1/2-projecting neurons, we found that both classes of neurons had extensive local axon in layers 2/3 and 5 of wS1. Neurons projecting to wS2 did not send axon to wM1/2, whereas a small subset of wM1/2 projecting neurons had relatively weak projections to wS2. A small fraction of projection neurons solely targeted wS2 or wM1/2. However, axon collaterals from wS2-projecting and wM1/2-projecting neurons were typically also found in subsets of various additional areas, including the dysgranular zone, perirhinal temporal association cortex and striatum. Our data suggest extensive diversity in the axonal targets selected by individual nearby cortical long-range projection neurons with somata located in layer 2/3 of wS1. PMID- 29765309 TI - Computer Vision Evidence Supporting Craniometric Alignment of Rat Brain Atlases to Streamline Expert-Guided, First-Order Migration of Hypothalamic Spatial Datasets Related to Behavioral Control. AB - The rat has arguably the most widely studied brain among all animals, with numerous reference atlases for rat brain having been published since 1946. For example, many neuroscientists have used the atlases of Paxinos and Watson (PW, first published in 1982) or Swanson (S, first published in 1992) as guides to probe or map specific rat brain structures and their connections. Despite nearly three decades of contemporaneous publication, no independent attempt has been made to establish a basic framework that allows data mapped in PW to be placed in register with S, or vice versa. Such data migration would allow scientists to accurately contextualize neuroanatomical data mapped exclusively in only one atlas with data mapped in the other. Here, we provide a tool that allows levels from any of the seven published editions of atlases comprising three distinct PW reference spaces to be aligned to atlas levels from any of the four published editions representing S reference space. This alignment is based on registration of the anteroposterior stereotaxic coordinate (z) measured from the skull landmark, Bregma (beta). Atlas level alignments performed along the z axis using one-dimensional Cleveland dot plots were in general agreement with alignments obtained independently using a custom-made computer vision application that utilized the scale-invariant feature transform (SIFT) and Random Sample Consensus (RANSAC) operation to compare regions of interest in photomicrographs of Nissl stained tissue sections from the PW and S reference spaces. We show that z aligned point source data (unpublished hypothalamic microinjection sites) can be migrated from PW to S space to a first-order approximation in the mediolateral and dorsoventral dimensions using anisotropic scaling of the vector-formatted atlas templates, together with expert-guided relocation of obvious outliers in the migrated datasets. The migrated data can be contextualized with other datasets mapped in S space, including neuronal cell bodies, axons, and chemoarchitecture; to generate data-constrained hypotheses difficult to formulate otherwise. The alignment strategies provided in this study constitute a basic starting point for first-order, user-guided data migration between PW and S reference spaces along three dimensions that is potentially extensible to other spatial reference systems for the rat brain. PMID- 29765310 TI - Economic Holobiont: Influence of Parasites, Microbiota and Chemosignals on Economic Behavior. AB - The article is a perspective on utilization of microorganisms and chemosignals in studying human economic behavior. Research in biological roots of economic development has already confirmed that parasitic pressure influenced the creation and development of cultural norms and institutions. However, other effects of microorganisms on human groups and individual decision-making and behavior are heavily understudied. The perspective discusses how parasitic infections, sexually transmitted organisms and microbiota (i.e., "human holobiont") could causally influence risk-seeking behavior, impulsivity, social dominance, empathy, political views and gender differences. As a case study, the parasite Toxoplasma gondii and its influence on economic preferences, personal characteristics and human appearance are examined. I also briefly review how chemosignals influence decision-making, particularly in the social preferences domain. I mention some predictions that arise from the paradigm of economic holobiont for the economic science. The conclusion summarizes limitations of the discussed findings and the stated speculations. PMID- 29765311 TI - Altered Sense of Body Ownership and Agency in Posttraumatic Stress Disorder and Its Dissociative Subtype: A Rubber Hand Illusion Study. AB - Traumatic experiences have been linked to the development of altered states of consciousness affecting bodily perception, including alterations in body ownership and in sense of agency, the conscious experience of the body as one's own and under voluntary control. Severe psychological trauma and prolonged distress may lead to posttraumatic stress disorder (PTSD). Together, symptoms of derealization and, related specifically to the sense of body ownership and agency, of depersonalization (where parts of the body or the entire body itself is perceived as detached and out of control), constitute the dissociative subtype (PTSD+DS). In this study, we explored the Rubber Hand Illusion, an experimental paradigm utilized to manipulate sense of body ownership in PTSD (n = 4) and PTSD+DS (n = 6) as compared to healthy controls (n = 7). Perceived finger location and self-report questionnaires were used as behavioral and subjective measures of the illusion, respectively. In addition, the correlation between the illusion's effect and sense of agency as a continuous feeling of controlling one's own body movements was explored. Here, a lower illusion effect was observed in the PTSD as compared to the control group after synchronous stimulation for both the proprioceptive drift and subjectively perceived illusion. Moreover, by both proprioceptive drift and by subjective ratings, the PTSD+DS group showed a response characterized by high variance, ranging from a very strong to a very weak effect of the illusion. Finally, sense of agency showed a trend toward a negative correlation with the strength of the illusion as subjectively perceived by participants with PTSD and PTSD+DS. These findings suggest individuals with PTSD may, at times, maintain a rigid representation of the body as an avoidance strategy, with top-down cognitive processes weakening the impact of manipulation of body ownership. By contrast, the response elicited in PTSD+DS appeared to be driven by either an increased vulnerability to manipulation of embodiment or by a dominant top-down cognitive representation of the body, with disruption of multisensory integration processes likely in both cases. Taken together, these findings further our understanding of bodily consciousness in PTSD and its dissociative subtype and highlight the supportive role played by sense of agency for the maintenance of body ownership. PMID- 29765304 TI - Chloride Homeostasis in Neurons With Special Emphasis on the Olivocerebellar System: Differential Roles for Transporters and Channels. AB - The intraneuronal ionic composition is an important determinant of brain functioning. There is growing evidence that aberrant homeostasis of the intracellular concentration of Cl- ([Cl-]i) evokes, in addition to that of Na+ and Ca2+, robust impairments of neuronal excitability and neurotransmission and thereby neurological conditions. More specifically, understanding the mechanisms underlying regulation of [Cl-]i is crucial for deciphering the variability in GABAergic and glycinergic signaling of neurons, in both health and disease. The homeostatic level of [Cl-]i is determined by various regulatory mechanisms, including those mediated by plasma membrane Cl- channels and transporters. This review focuses on the latest advances in identification, regulation and characterization of Cl- channels and transporters that modulate neuronal excitability and cell volume. By putting special emphasis on neurons of the olivocerebellar system, we establish that Cl- channels and transporters play an indispensable role in determining their [Cl-]i and thereby their function in sensorimotor coordination. PMID- 29765312 TI - Associations Between Daily Mood States and Brain Gray Matter Volume, Resting State Functional Connectivity and Task-Based Activity in Healthy Adults. AB - Numerous studies have shown differences in the functioning in the areas of the frontal-limbic circuitry between depressed patients and controls. However, current knowledge on frontal-limbic neural substrates of individual differences in mood states in everyday life in healthy individuals is scarce. The present study investigates anatomical, resting-state, and functional neural correlates of daily mood states in healthy individuals. We expected to observe associations between mood and the frontal-limbic circuitry and the default-mode network (DMN). A total of 42 healthy adults (19 men, 23 women; 34 +/- 1.2 years) regularly followed for behavior and psychosocial functioning since age of 6, underwent a functional magnetic resonance imaging scan, and completed a daily diary of mood states and related cognitions for 5 consecutive days. Results showed that individuals with smaller left hippocampal gray matter volumes experienced more negative mood and rumination in their daily life. Greater resting-state functional connectivity (rsFC) within the DMN, namely between posterior cingulate cortex (PCC) and medial prefrontal cortex regions as well as between PCC and precuneus, was associated with both greater negative and positive mood states in daily life. These rsFC results could be indicative of the role of the DMN regional functioning in emotional arousal, irrespective of valence. Lastly, greater daily positive mood was associated with greater activation in response to negative emotional stimuli in the precentral gyri, previously linked to emotional interference on cognitive control. Altogether, present findings might reflect neural mechanisms underlying daily affect and cognition among healthy individuals. PMID- 29765314 TI - Underlying Mechanisms of Cooperativity, Input Specificity, and Associativity of Long-Term Potentiation Through a Positive Feedback of Local Protein Synthesis. AB - Long-term potentiation (LTP) is a specific form of activity-dependent synaptic plasticity that is a leading mechanism of learning and memory in mammals. The properties of cooperativity, input specificity, and associativity are essential for LTP; however, the underlying mechanisms are unclear. Here, based on experimentally observed phenomena, we introduce a computational model of synaptic plasticity in a pyramidal cell to explore the mechanisms responsible for the cooperativity, input specificity, and associativity of LTP. The model is based on molecular processes involved in synaptic plasticity and integrates gene expression involved in the regulation of neuronal activity. In the model, we introduce a local positive feedback loop of protein synthesis at each synapse, which is essential for bimodal response and synapse specificity. Bifurcation analysis of the local positive feedback loop of brain-derived neurotrophic factor (BDNF) signaling illustrates the existence of bistability, which is the basis of LTP induction. The local bifurcation diagram provides guidance for the realization of LTP, and the projection of whole system trajectories onto the two parameter bifurcation diagram confirms the predictions obtained from bifurcation analysis. Moreover, model analysis shows that pre- and postsynaptic components are required to achieve the three properties of LTP. This study provides insights into the mechanisms underlying the cooperativity, input specificity, and associativity of LTP, and the further construction of neural networks for learning and memory. PMID- 29765313 TI - Can Tai Chi and Qigong Postures Shape Our Mood? Toward an Embodied Cognition Framework for Mind-Body Research. AB - Dynamic and static body postures are a defining characteristic of mind-body practices such as Tai Chi and Qigong (TCQ). A growing body of evidence supports the hypothesis that TCQ may be beneficial for psychological health, including management and prevention of depression and anxiety. Although a variety of causal factors have been identified as potential mediators of such health benefits, physical posture, despite its visible prominence, has been largely overlooked. We hypothesize that body posture while standing and/or moving may be a key therapeutic element mediating the influence of TCQ on psychological health. In the present paper, we summarize existing experimental and observational evidence that suggests a bi-directional relationship between body posture and mental states. Drawing from embodied cognitive science, we provide a theoretical framework for further investigation into this interrelationship. We discuss the challenges involved in such an investigation and propose suggestions for future studies. Despite theoretical and practical challenges, we propose that the role of posture in mind-body exercises such as TCQ should be considered in future research. PMID- 29765315 TI - Challenges in Reproducibility, Replicability, and Comparability of Computational Models and Tools for Neuronal and Glial Networks, Cells, and Subcellular Structures. AB - The possibility to replicate and reproduce published research results is one of the biggest challenges in all areas of science. In computational neuroscience, there are thousands of models available. However, it is rarely possible to reimplement the models based on the information in the original publication, let alone rerun the models just because the model implementations have not been made publicly available. We evaluate and discuss the comparability of a versatile choice of simulation tools: tools for biochemical reactions and spiking neuronal networks, and relatively new tools for growth in cell cultures. The replicability and reproducibility issues are considered for computational models that are equally diverse, including the models for intracellular signal transduction of neurons and glial cells, in addition to single glial cells, neuron-glia interactions, and selected examples of spiking neuronal networks. We also address the comparability of the simulation results with one another to comprehend if the studied models can be used to answer similar research questions. In addition to presenting the challenges in reproducibility and replicability of published results in computational neuroscience, we highlight the need for developing recommendations and good practices for publishing simulation tools and computational models. Model validation and flexible model description must be an integral part of the tool used to simulate and develop computational models. Constant improvement on experimental techniques and recording protocols leads to increasing knowledge about the biophysical mechanisms in neural systems. This poses new challenges for computational neuroscience: extended or completely new computational methods and models may be required. Careful evaluation and categorization of the existing models and tools provide a foundation for these future needs, for constructing multiscale models or extending the models to incorporate additional or more detailed biophysical mechanisms. Improving the quality of publications in computational neuroscience, enabling progressive building of advanced computational models and tools, can be achieved only through adopting publishing standards which underline replicability and reproducibility of research results. PMID- 29765318 TI - Utility of a Novel Three-Dimensional and Dynamic (3DD) Cell Culture System for PK/PD Studies: Evaluation of a Triple Combination Therapy at Overcoming Anti-HER2 Treatment Resistance in Breast Cancer. AB - Background: Emergence of Human epidermal growth factor receptor 2 (HER2) therapy resistance in HER2-positive (HER2+) breast cancer (BC) poses a major clinical challenge. Mechanisms of resistance include the over-activation of the PI3K/mTOR and Src pathways. This work aims to investigate a novel combination therapy that employs paclitaxel (PAC), a mitotic inhibitor, with everolimus (EVE), an mTOR inhibitor, and dasatinib (DAS), an Src kinase inhibitor, as a modality to overcome resistance. Methods: Static (two dimensional, 2D) and three-dimensional dynamic (3DD) cell culture studies were conducted using JIMT-1 cells, a HER2+ BC cell line refractory to HER2 therapies. Cell viability and caspase-3 expression were examined after JIMT-1 cell exposure to agents as monotherapy or in combination using a 2D setting. A pharmacokinetic/pharmacodynamic (PK/PD) combination study with PAC+DAS+EVE was conducted over 3 weeks in a 3DD setting. PAC was administered into the system via a 3 h infusion followed by the addition of a continuous infusion of EVE+DAS 24 h post-PAC dosing. Cell counts and caspase 3 expression were quantified every 2 days. A semi-mechanistic PK/PD model was developed using the 2D data and scaled up to capture the 3DD data. The final model integrated active caspase-3 as a biomarker to bridge between drug exposures and cancer cell dynamics. Model fittings were performed using Monolix software. Results: The triple combination significantly induced caspase-3 activity in the 2D cell culture setting. In the 3DD cell culture setting, sequential dosing of PAC then EVE+DAS showed a 5-fold increase in caspase-3 activity and 8.5-fold decrease in the total cell number compared to the control. The semi-mechanistic PK/PD models fit the data well, capturing the time-course profiles of drug concentrations, caspase-3 expression, and cell counts in the 2D and 3DD settings. Conclusion: A novel, sequential triple combination therapeutic regimen was successfully evaluated in both 2D and 3DD in vitro cell culture systems. The efficacy of this combination at inhibiting the cellular proliferation and re growth of HER2/mTOR resistant cell line, JIMT-1, is demonstrated. A biomarker linked PK/PD model successfully captured all time-course data. The latter can be used as a modeling platform for a direct translation from 3DD in vitro settings to the clinic. PMID- 29765317 TI - Sodium Tanshinone IIA Sulfonate Decreases Cigarette Smoke-Induced Inflammation and Oxidative Stress via Blocking the Activation of MAPK/HIF-1alpha Signaling Pathway. AB - Aberrant activation of hypoxia-inducible factor (HIF)-1alpha is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1alpha-induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1alpha expression in vivo and in vitro, and pretreatment with HIF-1alpha siRNA reduced CSE-induced elevation of TNF-alpha, IL-1beta, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1alpha expression. It indicated that STS inhibits CSE induced HIF-1alpha expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1alpha protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1alpha signaling, and may be a novel strategy for the treatment of COPD. PMID- 29765319 TI - Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy. AB - Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and mildly decreased liver fibrosis, but exhibited no effect on hepatic steatosis/macrovesicular vacuolation. In conclusion, we found the progression of NASH hepatic steatosis/macrovesicular vacuolation, and inflammation eventually lead to hepatocyte death and fibrosis. Life style change and current pharmacotherapies in development may be effective in treating NASH, but their effects on NASH-induced fibrosis may be mild. Since fibrosis is known to be an independent risk for decompensated cirrhosis, cardiovascular events, and mortality, our study suggests that effective anti-fibrosis therapy should be an essential component of the combined pharmacotherapy for advanced NASH. PMID- 29765320 TI - Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice. AB - Mechanisms of pain resolution are largely unclear. Increasing evidence suggests that specialized pro-resolving mediators (SPMs), derived from fish oil docosahexaenoic acid (DHA), promote the resolution of acute inflammation and potently inhibit inflammatory and neuropathic pain. In this study, we examined the analgesic impact of DHA and DHA-derived SPMs in a mouse model of post operative pain induced by tibial bone fracture (fPOP). Intravenous perioperative treatment with DHA (500 MUg), resolvin D1 (RvD1, 500 ng) and maresin 1 (MaR1, 500 ng), 10 min and 24 h after the surgery, delayed the development of fPOP (mechanical allodynia and cold allodynia). In contrast, post-operative intrathecal (IT) administration of DHA (500 MUg) 2 weeks after the surgery had no effects on established mechanical and cold allodynia. However, by direct comparison, IT post-operative treatment (500 ng) with neuroprotectin D1 (NPD1), MaR1, and D-resolvins, RvD1 and RvD5, but not RvD3 and RvD4, effectively reduced mechanical and cold allodynia. ELISA analysis showed that perioperative DHA treatment increased RvD1 levels in serum and spinal cord samples after bone fracture. Interestingly, sham surgery resulted in transient allodynia and increased RvD1 levels, suggesting a correlation of enhanced SPM levels with acute pain resolution after sham surgery. Our findings suggest that (1) perioperative treatment with DHA is effective in preventing and delaying the development of fPOP and (2) post-treatment with some SPMs can attenuate established fPOP. Our data also indicate that orthopedic surgery impairs SPM production. Thus, DHA and DHA-derived SPMs should be differentially supplemented for treating fPOP and improving recovery. PMID- 29765321 TI - Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy. AB - There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFkappaB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury. PMID- 29765316 TI - Noradrenergic Dysfunction in Alzheimer's and Parkinson's Diseases-An Overview of Imaging Studies. AB - Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD. PMID- 29765323 TI - Up-Down Reader: An Open Source Program for Efficiently Processing 50% von Frey Thresholds. AB - Most pathological pain conditions in patients and rodent pain models result in marked alterations in mechanosensation and the gold standard way to measure this is by use of von Frey fibers. These graded monofilaments are used to gauge the level of stimulus-evoked sensitivity present in the affected dermal region. One of the most popular methods used to determine von Frey thresholds is the up-down testing paradigm introduced by Dixon for patients in 1980 and by Chapman and colleagues for rodents in 1994. Although the up-down method is very accurate, leading to its widespread use, defining the 50% threshold from primary data is complex and requires a relatively time-consuming analysis step. We developed a computer program, the Up-Down Reader (UDReader), that can locate and recognize handwritten von Frey assessments from a scanned PDF document and translate these measurements into 50% pain thresholds. Automating the process of obtaining the 50% threshold values negates the need for reference tables or Microsoft Excel formulae and eliminates the chance of a manual calculation error. Our simple and straightforward method is designed to save research time while improving data collection accuracy and is freely available at https://sourceforge.net/projects/updownreader/ or in supplementary files attached to this manuscript. PMID- 29765324 TI - Evodiamine, a Novel NOTCH3 Methylation Stimulator, Significantly Suppresses Lung Carcinogenesis in Vitro and in Vivo. AB - Lung cancer is a leading cause of cancer-related deaths worldwide. NOTCH3 signaling is mainly expressed in non-small cell lung carcinoma (NSCLC), and has been proposed as a therapeutic target of NSCLC. While, few agents for preventing or treating NSCLC via targeting NOTCH3 signaling are used in modern clinical practice. Evodiamine (EVO), an alkaloid derived from Euodiae Fructus, possesses low toxicity and has long been shown to exert anti-lung cancer activity. However, the underlying anti-lung cancer mechanisms of EVO are not yet fully understood. In this study, we explored the involvement of NOTCH3 signaling in the anti-lung cancer effects of EVO. Urethane-induced lung cancer mouse model and two NSCLC cell models, A549 and H1299, were used to evaluate the in vivo and in vitro anti lung cancer action of EVO. A DNA methyltransferase inhibitor was employed to investigate the role of NOTCH3 signaling in the anti-lung cancer effects of EVO. Results showed that EVO potently reduced tumor size and tumor numbers in mice, and inhibited NOTCH3 in the tumors. EVO also dramatically reduced cell viability, induced G2/M cell cycle arrest, inhibited cell migration and reduced stemness in cultured NSCLC cells. Mechanistic studies showed that EVO potently inhibited NOTCH3 signaling by activation of DNMTs-induced NOTCH3 methylation. Importantly, inhibition of NOTCH3 methylation in NSCLC cells diminished EVO's anti-NSCLC effects. Collectively, EVO, a novel NOTCH3 methylation stimulator, exerted potent anti-lung cancer effects partially by inhibiting NOTCH3 signaling. These findings provide new insight into the EVO's anti-NSCLC action, and suggest a potential role of EVO in lung cancer prevention and treatment. PMID- 29765322 TI - Therapeutic Potential of Ginsenosides as an Adjuvant Treatment for Diabetes. AB - Ginseng, one of the oldest traditional Chinese medicinal herbs, has been used widely in China and Asia for thousands of years. Ginsenosides extracted from ginseng, which is derived from the roots and rhizomes of Panax ginseng C. A. Meyer, have been used in China as an adjuvant in the treatment of diabetes mellitus. Owing to the technical complexity of ginsenoside production, the total ginsenosides are generally extracted. Accumulating evidence has shown that ginsenosides exert antidiabetic effects. In vivo and in vitro tests revealed the potential of ginsenoside Rg1, Rg3, Rg5, Rb1, Rb2, Rb3, compound K, Rk1, Re, ginseng total saponins, malonyl ginsenosides, Rd, Rh2, F2, protopanaxadiol (PPD) and protopanaxatriol (PPT)-type saponins to treat diabetes and its complications, including type 1 diabetes mellitus, type 2 diabetes mellitus, diabetic nephropathy, diabetic cognitive dysfunction, type 2 diabetes mellitus with fatty liver disease, diabetic cerebral infarction, diabetic cardiomyopathy, and diabetic erectile dysfunction. Many effects are attributed to ginsenosides, including gluconeogenesis reduction, improvement of insulin resistance, glucose transport, insulinotropic action, islet cell protection, hepatoprotective activity, anti-inflammatory effect, myocardial protection, lipid regulation, improvement of glucose tolerance, antioxidation, improvement of erectile dysfunction, regulation of gut flora metabolism, neuroprotection, anti angiopathy, anti-neurotoxic effects, immunosuppression, and renoprotection effect. The molecular targets of these effects mainly contains GLUTs, SGLT1, GLP 1, FoxO1, TNF-alpha, IL-6, caspase-3, bcl-2, MDA, SOD, STAT5-PPAR gamma pathway, PI3K/Akt pathway, AMPK-JNK pathway, NF-kappaB pathway, and endoplasmic reticulum stress. Rg1, Rg3, Rb1, and compound K demonstrated the most promising therapeutic prospects as potential adjuvant medicines for the treatment of diabetes. This paper highlights the underlying pharmacological mechanisms of the anti-diabetic effects of ginsenosides. PMID- 29765325 TI - Mequindox-Induced Kidney Toxicity Is Associated With Oxidative Stress and Apoptosis in the Mouse. AB - Mequindox (MEQ), belonging to quinoxaline-di-N-oxides (QdNOs), is a synthetic antimicrobial agent widely used in China. Previous studies found that the kidney was one of the main toxic target organs of the QdNOs. However, the mechanisms underlying the kidney toxicity caused by QdNOs in vivo still remains unclear. The present study aimed to explore the molecular mechanism of kidney toxicity in mice after chronic exposure to MEQ. MEQ led to the oxidative stress, apoptosis, and mitochondrial damage in the kidney of mice. Meanwhile, MEQ upregulated Bax/Bcl-2 ratio, disrupted mitochondrial permeability transition pores, caused cytochrome c release, and a cascade activation of caspase, eventually induced apoptosis. The oxidative stress mediated by MEQ might led to mitochondria damage and apoptosis in a mitochondrial-dependent apoptotic pathway. Furthermore, upregulation of the Nrf2-Keap1 signaling pathway was also observed. Our findings revealed that the oxidative stress, mitochondrial dysfunction, and the Nrf2-Keap1 signaling pathway were associated with the kidney apoptosis induced by MEQ in vivo. PMID- 29765326 TI - Descriptions of Adverse Drug Reactions Are Less Informative in Forums Than in the French Pharmacovigilance Database but Provide More Unexpected Reactions. AB - Background: Social media have drawn attention for their potential use in Pharmacovigilance. Recent work showed that it is possible to extract information concerning adverse drug reactions (ADRs) from posts in social media. The main objective of the Vigi4MED project was to evaluate the relevance and quality of the information shared by patients on web forums about drug safety and its potential utility for pharmacovigilance. Methods: After selecting websites of interest, we manually evaluated the relevance of the content of posts for pharmacovigilance related to six drugs (agomelatine, baclofen, duloxetine, exenatide, strontium ranelate, and tetrazepam). We compared forums to the French Pharmacovigilance Database (FPVD) to (1) evaluate whether they contained relevant information to characterize a pharmacovigilance case report (patient's age and sex; treatment indication, dose and duration; time-to-onset (TTO) and outcome of the ADR, and drug dechallenge and rechallenge) and (2) perform impact analysis (nature, seriousness, unexpectedness, and outcome of the ADR). Results: The cases in the FPVD were significantly more informative than posts in forums for patient description (age, sex), treatment description (dose, duration, TTO), and outcome of the ADR, but the indication for the treatment was more often found in forums. Cases were more often serious in the FPVD than in forums (46% vs. 4%), but forums more often contained an unexpected ADR than the FPVD (24% vs. 17%). Moreover, 197 unexpected ADRs identified in forums were absent from the FPVD and the distribution of the MedDRA System Organ Classes (SOCs) was different between the two data sources. Discussion: This study is the first to evaluate if patients' posts may qualify as potential and informative case reports that should be stored in a pharmacovigilance database in the same way as case reports submitted by health professionals. The posts were less informative (except for the indication) and focused on less serious ADRs than the FPVD cases, but more unexpected ADRs were presented in forums than in the FPVD and their SOCs were different. Thus, web forums should be considered as a secondary, but complementary source for pharmacovigilance. PMID- 29765327 TI - Cardiovascular Adaptive Homeostasis in Exercise. AB - Adaptive Homeostasis has been defined as, "The transient expansion or contraction of the homeostatic range in response to exposure to sub-toxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events." (Davies, 2016). I propose that one of the most significant examples of adaptive homeostasis may be the adaptation of the cardiovascular system to exercise training. In particular, endurance type training involves the generation of increased levels of free radicals such as ubisemiquinone, superoxide, nitric oxide, and other (non-radical) reactive oxygen species such as hydrogen peroxide (H2O2), in a repetitive manner, typically several times per week. As long as the training intensity and duration are sub-maximal and not exhaustive these reactive species do not cause damage, but rather activate signal transduction pathways to induce mitochondrial biogenesis-the foundation of increased exercise endurance. Particularly important are the NFkappaB and Nrf2 signal transduction pathways which respond to reactive oxygen and nitrogen species generated during exercise. As with other examples of adaptive homeostasis the effects are transient, lasting only as long as the training is maintained. Unfortunately, the ability to adapt to exercise training declines with age, perhaps as a result of impaired Nrf2 and NFkappaB signaling, as does adaptive homeostasis capacity in general. Since this is an Hypothesis/Theory Paper and not a review, I have not tried to provide a comprehensive discussion of all the literature relating to exercise adaptation and the cardiovascular system. Rather, I have attempted to develop the Hypothesis or Theory that adaptive homeostasis is the foundation for adaptation of the cardiovascular system to exercise training, largely based on work from my own laboratory, that of close collaborators, and that of key contributors over a period of almost 40 years. PMID- 29765328 TI - Long-Term Consumption of Cuban Policosanol Lowers Central and Brachial Blood Pressure and Improves Lipid Profile With Enhancement of Lipoprotein Properties in Healthy Korean Participants. AB - Metabolic syndrome is closely associated with higher risk of hypertension, cardiovascular disease (CVD), diabetes and stroke. The aim of the present study was to investigate the long-term effects of policosanol supplementation on blood pressure (BP) and the lipid profile in healthy Korean participants with pre hypertension (systolic 120-139 mmHg, diastolic 85-89 mmHg). This randomized, double-blinded, and placebo-controlled trial included 84 healthy participants who were randomly assigned to three groups receiving 10 mg of policosanol, 20 mg of policosanol, or placebo for 24 weeks. The BP, lipid profile, and anthropometric factors were measured pre- and post-intervention and then compared. Based on an average of three measurements of brachial BP, the policosanol 20 mg group showed the most significant reduction in average systolic BP (SBP) from 138 +/- 12 mmHg at week 0 to 126 +/- 13 mmHg at week 24 (p < 0.0001). The policosanol 20 mg group also showed significant reductions in aortic SBP and DBP up to 9% (p = 0.00057) and 8% (p = 0.004), respectively compared with week 0. Additionally, blood renin and aldosterone levels were significantly reduced in the policosanol 20 mg group up to 63% (p < 0.01) and 42% (p < 0.05), respectively, at week 24. For the blood lipid profile, the policosanol 10 mg and 20 mg groups showed significant reductions in total cholesterol (TC) of around 8% (p = 0.029) and 13% (p = 0.0004), respectively, at week 24 compared with week 0. Serum HDL-C level significantly increased up to 16% and 12% in the policosanol 10 mg (p = 0.002) and 20 mg (p = 0.035) group, respectively. The study results suggest that long term policosanol consumption simultaneously reduces peripheral BP as well as aortic BP accompanied by elevation of HDL-C and % HDL-C in TC in a dose-dependent manner. PMID- 29765330 TI - Glial Cells Are Involved in ANG-II-Induced Vasopressin Release and Sodium Intake in Awake Rats. AB - It is known that circulating angiotensin II (ANG-II) acts on the circumventricular organs (CVOs), which partially lack a normal blood-brain barrier, to stimulate pressor responses, vasopressin (AVP), and oxytocin (OT) secretion, as well as sodium and water intake. Although ANG-II type 1 receptors (AT1R) are expressed in neurons and astrocytes, the involvement of CVOs glial cells in the neuroendocrine, cardiovascular and behavioral responses induced by central ANG II remains to be further elucidated. To address this question, we performed a set of experiments combining in vitro studies in primary hypothalamic astrocyte cells (HACc) and in vivo intracerebroventricular (icv) microinjections into the lateral ventricle of awake rats. Our results showed that ANG-II decreased glutamate uptake in HACc. In addition, in vivo studies showed that fluorocitrate (FCt), a reversible glial inhibitor, increased OT secretion and mean arterial pressure (MAP) and decreased breathing at rest. Furthermore, previous FCt decreased AVP secretion and sodium intake induced by central ANG-II. Together, our findings support that CVOs glial cells are important in mediating neuroendocrine and cardiorespiratory functions, as well as central ANG-II-induced AVP release and salt-intake behavior in awake rats. In the light of our in vitro studies, we propose that these mechanisms are, at least in part, by ANG-II induced astrocyte mediate reduction in glutamate extracellular clearance. PMID- 29765329 TI - The Role of Macrophages in Acute and Chronic Wound Healing and Interventions to Promote Pro-wound Healing Phenotypes. AB - Macrophages play key roles in all phases of adult wound healing, which are inflammation, proliferation, and remodeling. As wounds heal, the local macrophage population transitions from predominantly pro-inflammatory (M1-like phenotypes) to anti-inflammatory (M2-like phenotypes). Non-healing chronic wounds, such as pressure, arterial, venous, and diabetic ulcers indefinitely remain in inflammation-the first stage of wound healing. Thus, local macrophages retain pro inflammatory characteristics. This review discusses the physiology of monocytes and macrophages in acute wound healing and the different phenotypes described in the literature for both in vitro and in vivo models. We also discuss aberrations that occur in macrophage populations in chronic wounds, and attempts to restore macrophage function by therapeutic approaches. These include endogenous M1 attenuation, exogenous M2 supplementation and endogenous macrophage modulation/M2 promotion via mesenchymal stem cells, growth factors, biomaterials, heme oxygenase-1 (HO-1) expression, and oxygen therapy. We recognize the challenges and controversies that exist in this field, such as standardization of macrophage phenotype nomenclature, definition of their distinct roles and understanding which phenotype is optimal in order to promote healing in chronic wounds. PMID- 29765333 TI - Beneficial Effects of Elderly Tailored Mediterranean Diet on the Proteasomal Proteolysis. AB - Aging is a multifactorial process characterized by the accumulation of proteins undergoing oxidative modifications, either due to enhanced levels of oxidative stress or due to their decreased clearance; both facts are related to the establishment of chronic inflammatory processes. These processes are directly associated with functional and structural modifications of a key cellular component, namely the proteasome. In this study, levels of oxidized proteins, along with proteasome and immunoproteasome composition and activity on a selected group of 120 elderly volunteers were analyzed before and after the administration of a specific dietary protocol, based on an elderly tailored Mediterranean diet (the "NU-AGE diet"). A significant negative correlation between levels of oxidized/carbonylated proteins and proteasome function was confirmed, both before and after intervention. Furthermore, it was demonstrated that subgroups of non frail subjects and women receive a greater benefit after the intervention, concerning specifically the proteasome content and activity. These data highlight the putative beneficial effects of Mediterranean diet on the major cellular proteolytic mechanism, the proteasome, in elderly people. PMID- 29765334 TI - High-Frequency Electrical Modulation of the Superior Ovarian Nerve as a Treatment of Polycystic Ovary Syndrome in the Rat. AB - The polycystic ovary syndrome (PCOS) is the most prevalent ovarian pathology in women, with excessive sympathetic activity in the superior ovarian nerve (SON) playing an important role in inducing the PCOS symptoms in the rats and humans. Our previous studies have shown that surgical transection of the SON can reverse the disease progression, prompting us to explore the effect of the kilohertz frequency alternating current (KHFAC) modulation as a method of reversible non surgical suppression of the nerve activity in the rodent model of PCOS. 56 animals were randomly allocated to three groups: the Control group (n = 18), the PCOS group (n = 15), and the PCOS + KHFAC group (n = 23). The physiological, anatomical, and biochemical parameters of ovarian function were evaluated during the progression of the experimentally-induced PCOS and during long-term KHFAC modulation applied for 2-3 weeks. The KHFAC modulation has been able to reverse the pathological changes in assessed PCOS parameters, namely the irregular or absent estrous cycling, formation of ovarian cysts, reduction in the number of corpora lutea, and ovarian norepinephrine concentration. The fertility capacity was similar in the PCOS and the PCOS + KHFAC groups, indicating the safety of KHFAC modulation approach. In summary, these results suggest that the KHFAC modulation approach of suppressing the SON activity could become a useful treatment modality for PCOS and potentially other pathological ovarian conditions. PMID- 29765331 TI - High pH-Sensitive Store-Operated Ca2+ Entry Mediated by Ca2+ Release-Activated Ca2+ Channels in Rat Odontoblasts. AB - Odontoblasts play a crucial role in dentin formation and sensory transduction following the application of stimuli to the dentin surface. Various exogenous and endogenous stimuli elicit an increase in the intracellular free calcium concentration ([Ca2+]i) in odontoblasts, which is mediated by Ca2+ release from intracellular Ca2+ stores and/or Ca2+ influx from the extracellular medium. In a previous study, we demonstrated that the depletion of Ca2+ stores in odontoblasts activated store-operated Ca2+ entry (SOCE), a Ca2+ influx pathway. However, the precise biophysical and pharmacological properties of SOCE in odontoblasts have remained unclear. In the present study, we examined the functional expression and pharmacological properties of Ca2+ release-activated Ca2+ (CRAC) channels that mediate SOCE and evaluated the alkali sensitivity of SOCE in rat odontoblasts. In the absence of extracellular Ca2+, treatment with thapsigargin (TG), a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, induced an increase in [Ca2+]i. After [Ca2+]i returned to near-resting levels, the subsequent application of 2.5 mM extracellular Ca2+ resulted in an increase in [Ca2+]i which is a typical of SOCE activation. Additionally, application of 2 methylthioadenosine diphosphate trisodium salt (2-MeSADP), a P2Y1,12,13 receptor agonist, or carbachol (CCh), a muscarinic cholinergic receptor agonist, in the absence of extracellular Ca2+, induced a transient increase in [Ca2+]i. The subsequent addition of extracellular Ca2+ resulted in significantly higher [Ca2+]i in 2-MeSADP- or CCh-treated odontoblasts than in untreated cells. SOCE, that is activated by addition of extracellular Ca2+ in the TG pretreated odontoblasts was then suppressed by Synta66, BTP2, or lanthanum, which are CRAC channel inhibitors. Treatment with an alkaline solution enhanced SOCE, while treatment with HC030031, a TRPA1 channel antagonist, inhibited it. The amplitude of SOCE at pH 9 in the presence of HC030031 was higher than that at pH 7.4 in the absence of HC030031. These findings indicate that CRAC channel-mediated alkali sensitive SOCE occurs in odontoblasts. SOCE is mediated by P2Y and muscarinic cholinergic receptors, which are activated by endogenous ligands in odontoblasts. PMID- 29765332 TI - Galectin-9 Expression Predicts Favorable Clinical Outcome in Solid Tumors: A Systematic Review and Meta-Analysis. AB - Background and Objective: Galectin-9 (Gal-9) is one of the galectin family members which are known as proteins with beta-galactoside-binding affinity. Accumulative evidence suggest that Gal-9 plays multifaceted roles in tumor biology. However, the prognostic significance of Gal-9 in solid cancer patients remains controversial. The objective of the study was to clarify the prognostic significance of Gal-9 in solid tumors via meta-analysis. Methods: We searched PubMed, Embase and the Cochrane library for studies that report the correlation between Gal-9 expression and prognosis or clinicopathological parameters in solid cancer patients from inception to October 2017, with no language restriction. We calculated pooled hazard ratio (HR) and 95% confidence interval (CI) to investigate the prognostic significance of Gal-9 expression in solid tumors. We also calculated Odds ratio (OR) to explore the association between Gal-9 expression and clinicopathological features. Results: We included Fourteen studies with 2326 patients in our meta-analysis. The synthetic results revealed that high Gal-9 expression indicated improved overall survival (OS; HR = 0.70, 95% CI = 0.51-0.71, P = 0.006) but had no correlation with disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 0.85, 95% CI = 0.51-1.41, P = 0.527) in solid tumors. In stratified analyses, high Gal-9 expression was significantly correlated with improved OS in hepatocellular carcinoma and colon cancer and with improved DFS/RFS in gastric cancer and non-small cell lung cancer. In addition, ethnicity and the method of data extraction didn't affect the positive prognostic values of high Gal-9 expression. Moreover, high Gal-9 expression was significantly correlated with a smaller depth of invasion (TI/TII vs. TIII/TIV, OR = 2.80, 95% CI = 1.97-3.96, P < 0.001), an earlier histopathological stage (I/II vs. III/IV, OR = 3.00, 95% CI = 2.04-4.42, P < 0.001), negative lymph node metastasis (Presence vs. Absence, OR = 0.47, 95% CI = 0.25-0.89, P = 0.020) and negative distal tumor metastasis (Presence vs. Absence, OR = 13.85, 95% CI = 3.50 54.76, P < 0.001). Conclusion: Gal-9 expression indicates beneficial outcome in patients with solid tumors and is correlated with the pathogenesis of solid tumors. Gal-9 may serve as a prognostic biomarker and an emerging therapeutic target against solid tumors. PMID- 29765336 TI - The Red Blood Cells on the Move! PMID- 29765335 TI - Heart Rate Variability During a Joint Attention Task in Toddlers With Autism Spectrum Disorders. AB - Background: Autism Spectrum Disorders (ASD) are a heterogeneous group of neurodevelopmental disorders featuring early impairments in social domain, with autonomic nervous system (ANS) unbalance possibly representing a useful marker for such disturbances. Impairments in joint attention (JA) are one of the earliest markers of social deficits in ASD. In this study, we assessed the feasibility of using wearable technologies for characterizing the ANS response in ASD toddlers during the presentation of JA stimuli. Methods: Twenty ASD toddlers and 20 age- and gender-matched typically developed (TD) children were recorded at baseline and during a JA task through an unobtrusive chest strap for electrocardiography (ECG). Specific algorithms for feature extraction, including Heart Rate (HR), Standard Deviation of the Normal-to-Normal Intervals (SDNN), Coefficient of Variation (CV), pNN10 as well as low frequency (LF) and high frequency (HF), were applied to the ECG signal and a statistical comparison between the two groups was performed. Results: As regards the single phases, SDNN (p = 0.04) and CV (p = 0.021) were increased in ASD at baseline together with increased LF absolute power (p = 0.034). Moreover, CV remained higher in ASD during the task (p = 0.03). Considering the phase and group interaction, LF increased from baseline to task in TD group (p = 0.04) while it decreased in the ASD group (p = 0.04). Conclusions: The results of this study indicate the feasibility of characterizing the ANS response in ASD toddlers through a minimally obtrusive tool. Our analysis showed an increased SDNN and CV in toddlers with ASD particularly at baseline compared to TD and lower LF during the task. These findings could suggest the possibility of using the proposed approach for evaluating physiological correlates of JA response in young children with ASD. PMID- 29765337 TI - Plethysmographic Loops: A Window on the Lung Pathophysiology of COPD Patients. AB - Plethysmographic alveolar pressure-flow (Palv-F) loops contain potentially relevant information about the pathophysiology of chronic obstructive pulmonary disease (COPD), but no quantitative analysis of these loops during spontaneous breathing has ever been performed. The area of the loop's inspiratory (Ains) and expiratory portion (Aexp), and the difference between the end-expiratory and end inspiratory alveolar pressure (DeltaPalv) were measured in 20 young, 20 elderly healthy subjects, and 130 stable COPD patients. Ains and DeltaPalv increased by 55 and 78% from young to elderly subjects, and by 107 and 122% from elderly subjects to COPD patients, reflecting changes in mechanical heterogeneity, lung units recruitment/derecruitment, and possibly air trapping occurring with aging and/or obstructive disease. Aexp increased by 38% from young to elderly subjects, and by 198% from elderly subjects to COPD patients, consistent with the additional contribution of tidal expiratory flow-limitation, which occurs only in COPD patients and affects Aexp only. In COPD patients, Aexp and DeltaPalv showed a significant negative correlation with VC, FEV1, IC, and a significant positive correlation with RV/TLC. The results suggest that the analysis of plethysmographic Palv-F loops provides an insight of the pathophysiological factors, especially tidal expiratory flow-limitation, that affect lung function in COPD patients. PMID- 29765339 TI - Can "Model Projects of Need-Adapted Care" Reduce Involuntary Hospital Treatment and the Use of Coercive Measures? AB - Intensive outpatient models of need-adapted psychiatric care have been shown to reduce the length of hospital stays and to improve retention in care for people with severe mental illnesses. In contrast, evidence regarding the impact of such models on involuntary hospital treatment and other coercive measures in inpatient settings is still sparse, although these represent important indicators of the patients' wellbeing. In Germany, intensive models of care still have not been routinely implemented, and their effectiveness within the German psychiatric system is only studied in a few pioneering regions. An innovative model of flexible, assertive, need-adapted care established in Berlin, Germany, in 2014, treating unselected 14% of the catchment area's patients, was evaluated on the basis of routine clinical data. Records of n = 302 patients diagnosed with severe mental disorders, who had been hospitalized at least once during a 4-year observational period, were analyzed in a retrospective individual mirror-image design, comparing the 2 years before and after inclusion in the model project regarding the time spent in hospital, the number and duration of involuntary hospital treatments and the use of direct coercive interventions like restraint or isolation. After inclusion to the project, patients spent significantly less time in hospital. Among patients treated on acute wards and patients with a diagnosis of psychosis, the number of patients subjected to provisional detention due to acute endangerment of self or others decreased significantly, as did the time spent under involuntary hospital treatment. The number of patients subjected to mechanical restraint, but not to isolation, on the ward decreased significantly, while the total number of coercive interventions remained unchanged. Findings suggest some potential of intensive models of need-adapted care to reduce coercive interventions in psychiatry. However, results must be substantiated by evidence from randomized-controlled trials and longer observation periods. PMID- 29765340 TI - Inconclusive Evidence in Support of the Dopamine Hypothesis of Psychosis: Why Neurobiological Research Must Consider Medication Use, Adjust for Important Confounders, Choose Stringent Comparators, and Use Larger Samples. PMID- 29765338 TI - Psychotherapeutic Treatment for Anorexia Nervosa: A Systematic Review and Network Meta-Analysis. AB - Background: The aim of the study was a systematic review of studies evaluating psychotherapeutic treatment approaches in anorexia nervosa and to compare their efficacy. Weight gain was chosen as the primary outcome criterion. We also aimed to compare treatment effects according to service level (inpatient vs. outpatient) and age group (adolescents vs. adults). Methods:The data bases PubMed, Cochrane Library, Web of Science, Cinahl, and PsychInfo were used for a systematic literature search (until Feb 2017). Search terms were adapted for data base, combining versions of the search terms anorexia, treat*/therap* and controlled trial. Studies were selected using pre-defined in- and exclusion criteria. Data were extracted by two independent coders using piloted forms. Network-meta-analyses were conducted on all RCTs. For a comparison of service levels and age groups, standard mean change (SMC) statistics were used and naturalistic, non-randomized studies included. Results: Eighteen RCTs (trials on adults: 622 participants; trials on adolescents: 625 participants) were included in the network meta-analysis. SMC analyses were conducted with 38 studies (1,164 participants). While family-based approaches dominate interventions for adolescents, individual psychotherapy dominates in adults. There was no superiority of a specific approach. Weight gains were more rapid in adolescents and inpatient treatment. Conclusions: Several specialized psychotherapeutic interventions have been developed and can be recommended for AN. However, adult and adolescent patients should be distinguished, as groups differ in terms of treatment approaches considered suitable as well as treatment response. Future trials should replicate previous findings and be multi-center trials with large sample sizes to allow for subgroup analyses. Patient assessment should include variables that can be considered relevant moderators of treatment outcome. It is desirable to explore adaptive treatment strategies for subgroups of patients with AN. Identifying and addressing maintaining factors in AN remains a major challenge. PMID- 29765341 TI - Multiple Frames of Reference Are Used During the Selection and Planning of a Sequential Joint Action. AB - Co-actors need to anticipate each other's actions to successfully perform joint actions. The frames of reference (FOR) used to simulate a co-actor's action could impact what information is anticipated. We hypothesized that co-actor's would adopt their co-actor's body-centered FOR, even when they do not share the same spatial orientation, so that they could anticipate body-related aspects of their co-actor's task. Because it might be beneficial to plan joint actions based on environment and body-centered information, we hypothesized that individuals would utilize multiple FORs during response planning. To test these hypotheses, participants performed a sequential aiming task where the goal was to move a wooden dowel to one of four potential targets as quickly and accurately as possible. A cue was presented at the beginning of each trial that was either 25, 50, or 75% valid. Following the cue presentation, the first person to act (initiator) placed the wooden dowel, anywhere they liked, in the workspace. Then, the finisher performed their aiming movement from the location that the initiator had placed the dowel. The key dependent measure was the dowel placement of the initiator because it provided an index of how much the initiator attempted to facilitate the efficient performance of the finisher. The results revealed that individuals adopted an allocentric FOR (dowel placement was more biased toward cued locations as cue validity increased) and partially adopted their co-actor's body-centered FOR (dowel placement was biased toward the finisher's body, but not toward the co-actor's contralateral space). In conclusion, multiple FORs can be used to anticipate both body- and environment-related information of a co-actor's task. It may be difficult, however, for individuals to fully adopt their co actor's body-centered FOR when they have differing orientations. PMID- 29765342 TI - Mind Control: How Parasites Manipulate Cognitive Functions in Their Insect Hosts. AB - Neuro-parasitology is an emerging branch of science that deals with parasites that can control the nervous system of the host. It offers the possibility of discovering how one species (the parasite) modifies a particular neural network, and thus particular behaviors, of another species (the host). Such parasite-host interactions, developed over millions of years of evolution, provide unique tools by which one can determine how neuromodulation up-or-down regulates specific behaviors. In some of the most fascinating manipulations, the parasite taps into the host brain neuronal circuities to manipulate hosts cognitive functions. To name just a few examples, some worms induce crickets and other terrestrial insects to commit suicide in water, enabling the exit of the parasite into an aquatic environment favorable to its reproduction. In another example of behavioral manipulation, ants that consumed the secretions of a caterpillar containing dopamine are less likely to move away from the caterpillar and more likely to be aggressive. This benefits the caterpillar for without its ant bodyguards, it is more likely to be predated upon or attacked by parasitic insects that would lay eggs inside its body. Another example is the parasitic wasp, which induces a guarding behavior in its ladybug host in collaboration with a viral mutualist. To exert long-term behavioral manipulation of the host, parasite must secrete compounds that act through secondary messengers and/or directly on genes often modifying gene expression to produce long-lasting effects. PMID- 29765343 TI - Questionnaire-Based Maladaptive Decision-Coping Patterns Involved in Binge Eating Among 1013 College Students. AB - Binge Eating Disorder (BED), considered a public health problem because of its impact on psychiatric, physical, and social functioning, merits much attention given its elevation to an independent diagnosis in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Similar with substance use disorders, some neuropsychological and personality constructs are potentially implicated in the onset and development of BED, in which poor decision-making has been suggested to facilitate overeating and BED. The objective of this study was to investigate the associations between decision-coping patterns, monetary decision-making, and binge-eating behavior in young adults. A sample of 1013 college students, equally divided into binge-eating and non-binge-eating groups according to the scores on the Binge Eating Scale (BES), were administered multiple measures of decision-making including the Melbourne Decision-Making Questionnaire (MDMQ), the Delay-discounting Test (DDT), and the Probability Discounting Test (PDT). Compared with the non-binge-eating group, the binge eating group displayed elevated scores on maladaptive decision-making patterns including Procrastination, Buck-passing, and Hypervigilance. Logistic regression model revealed that only Procrastination positively predicted binge eating. These findings suggest that different dimensions of decision-making may be distinctly linked to binge eating among young adults, with Procrastination putatively identified as a risk trait in the development of overeating behavior, which might promote a better understanding of this disorder. PMID- 29765344 TI - Centeredness Theory: Understanding and Measuring Well-Being Across Core Life Domains. AB - Background: Centeredness Theory (CT) is proposed as a new mental health paradigm that focuses on well-being at a systems-level, across the core life domains of the self, the family unit, relationships, community, and work. The current studies aimed to validate the psychometric properties of a new scale that measures CT against existing well-being and mental health measures. Methods: Study 1 included 488 anonymous online respondents (46% females, 28% males, 25% unknown with median age between 31 and 35 years) across 38 countries who completed the CT scale. Study 2 included 49 first-year psychology students (90% females, mean age of 19 years) from Sydney Australia that completed the CT scale and other well-being and mental health questionnaires at baseline and 2-weeks follow-up. Results: Exploratory and confirmatory factor analyses resulted in a refined 60-item CT scale with five domains, each with four sub-domains. The CT scale demonstrated good internal consistency reliability and test-retest reliability, and showed evidence of convergent validity against other well-being measures (e.g., COMPAS-W Wellbeing Scale, SWLS scale, and Ryff's Psychological Well-being scale). Conclusions: The CT scale appears to be a reliable measure of well-being at a systems-level. Future studies need to confirm these findings in larger heterogeneous samples. PMID- 29765345 TI - ExGUtils: A Python Package for Statistical Analysis With the ex-Gaussian Probability Density. AB - The study of reaction times and their underlying cognitive processes is an important field in Psychology. Reaction times are often modeled through the ex Gaussian distribution, because it provides a good fit to multiple empirical data. The complexity of this distribution makes the use of computational tools an essential element. Therefore, there is a strong need for efficient and versatile computational tools for the research in this area. In this manuscript we discuss some mathematical details of the ex-Gaussian distribution and apply the ExGUtils package, a set of functions and numerical tools, programmed for python, developed for numerical analysis of data involving the ex-Gaussian probability density. In order to validate the package, we present an extensive analysis of fits obtained with it, discuss advantages and differences between the least squares and maximum likelihood methods and quantitatively evaluate the goodness of the obtained fits (which is usually an overlooked point in most literature in the area). The analysis done allows one to identify outliers in the empirical datasets and criteriously determine if there is a need for data trimming and at which points it should be done. PMID- 29765346 TI - Auditory Emotion Word Primes Influence Emotional Face Categorization in Children and Adults, but Not Vice Versa. AB - In order to assess how the perception of audible speech and facial expressions influence one another for the perception of emotions, and how this influence might change over the course of development, we conducted two cross-modal priming experiments with three age groups of children (6-, 9-, and 12-years old), as well as college-aged adults. In Experiment 1, 74 children and 24 adult participants were tasked with categorizing photographs of emotional faces as positive or negative as quickly as possible after being primed with emotion words presented via audio in valence-congruent and valence-incongruent trials. In Experiment 2, 67 children and 24 adult participants carried out a similar categorization task, but with faces acting as visual primes, and emotion words acting as auditory targets. The results of Experiment 1 showed that participants made more errors when categorizing positive faces primed by negative words versus positive words, and that 6-year-old children are particularly sensitive to positive word primes, giving faster correct responses regardless of target valence. Meanwhile, the results of Experiment 2 did not show any congruency effects for priming by facial expressions. Thus, audible emotion words seem to exert an influence on the emotional categorization of faces, while faces do not seem to influence the categorization of emotion words in a significant way. PMID- 29765347 TI - How Deep Is Your SNARC? Interactions Between Numerical Magnitude, Response Hands, and Reachability in Peripersonal Space. AB - Spatial, physical, and semantic magnitude dimensions can influence action decisions in human cognitive processing and interact with each other. For example, in the spatial-numerical associations of response code (SNARC) effect, semantic numerical magnitude facilitates left-hand or right-hand responding dependent on the small or large magnitude of number symbols. SNARC-like interactions of numerical magnitudes with the radial spatial dimension (depth) were postulated from early on. Usually, the SNARC effect in any direction is investigated using fronto-parallel computer monitors for presentation of stimuli. In such 2D setups, however, the metaphorical and literal interpretation of the radial depth axis with seemingly close/far stimuli or responses are not distinct. Hence, it is difficult to draw clear conclusions with respect to the contribution of different spatial mappings to the SNARC effect. In order to disentangle the different mappings in a natural way, we studied parametrical interactions between semantic numerical magnitude, horizontal directional responses, and perceptual distance by means of stereoscopic depth in an immersive virtual reality (VR). Two VR experiments show horizontal SNARC effects across all spatial displacements in traditional latency measures and kinematic response parameters. No indications of a SNARC effect along the depth axis, as it would be predicted by a direct mapping account, were observed, but the results show a non-linear relationship between horizontal SNARC slopes and physical distance. Steepest SNARC slopes were observed for digits presented close to the hands. We conclude that spatial numerical processing is susceptible to effector-based processes but relatively resilient to task-irrelevant variations of radial-spatial magnitudes. PMID- 29765349 TI - The Influence of Parental Control and Parent-Child Relational Qualities on Adolescent Internet Addiction: A 3-Year Longitudinal Study in Hong Kong. AB - This study investigated how parental behavioral control, parental psychological control, and parent-child relational qualities predicted the initial level and rate of change in adolescent internet addiction (IA) across the junior high school years. The study also investigated the concurrent and longitudinal effects of different parenting factors on adolescent IA. Starting from the 2009/2010 academic year, 3,328 Grade 7 students (Mage = 12.59 +/- 0.74 years) from 28 randomly selected secondary schools in Hong Kong responded on a yearly basis to a questionnaire measuring multiple constructs including socio-demographic characteristics, perceived parenting characteristics, and IA. Individual growth curve (IGC) analyses showed that adolescent IA slightly decreased during junior high school years. While behavioral control of both parents was negatively related to the initial level of adolescent IA, only paternal behavioral control showed a significant positive relationship with the rate of linear change in IA, suggesting that higher paternal behavioral control predicted a slower decrease in IA. In addition, fathers' and mothers' psychological control was positively associated with the initial level of adolescent IA, but increase in maternal psychological control predicted a faster drop in IA. Finally, parent-child relational qualities negatively and positively predicted the initial level and the rate of change in IA, respectively. When all parenting factors were considered simultaneously, multiple regression analyses revealed that paternal behavioral control and psychological control as well as maternal psychological control and mother-child relational quality were significant concurrent predictors of adolescent IA at Wave 2 and Wave 3. Regarding the longitudinal predicting effects, paternal psychological control and mother-child relational quality at Wave 1 were the two most robust predictors of later adolescent IA at Wave 2 and Wave 3. The above findings underscore the importance of the parent child subsystem qualities in influencing adolescent IA in the junior high school years. In particular, these findings shed light on the different impacts of fathering and mothering which are neglected in the scientific literature. While the findings based on the levels of IA are consistent with the existing theoretical models, findings on the rate of change are novel. PMID- 29765348 TI - Numerical Affordance Influences Action Execution: A Kinematic Study of Finger Movement. AB - Humans represent symbolic numbers as oriented from left to right: the mental number line (MNL). Up to now, scientific studies have mainly investigated the MNL by means of response times. However, the existing knowledge on the MNL can be advantaged by studies on motor patterns while responding to a number. Cognitive representations, in fact, cannot be fully understood without considering their impact on actions. Here we investigated whether a motor response can be influenced by number processing. Participants seated in front of a little soccer goal. On each trial they were visually presented with a numerical (2, 5, 8) or a non-numerical ($) stimulus. They were instructed to kick a small ball with their right index toward a frontal soccer goal as soon as a stimulus appeared on a screen. However, they had to refrain from kicking when number five was presented (no-go signal). Our main finding is that performing a kicking action after observation of the larger digit proved to be more efficient: the trajectory path was shorter and lower on the surface, velocity peak was anticipated. The smaller number, instead, specifically altered the temporal and spatial aspects of trajectories, leading to more prolonged left deviations. This is the first experimental demonstration that the reaching component of a movement is influenced by number magnitude. Since this paradigm does not require any verbal skill and non-symbolic stimuli (array of dots) can be used, it could be fruitfully adopted to evaluate number abilities in children and even preschoolers. Notably, this is a self-motivating and engaging task, which might help children to get involved and to reduce potential arousal connected to institutional paper-and-pencil examinations. PMID- 29765350 TI - Cognitive and Personality Components Underlying Spoken Idiom Comprehension in Context. An Exploratory Study. AB - In this exploratory study, we investigated whether and to what extent individual differences in cognitive and personality variables are associated with spoken idiom comprehension in context. Language unimpaired participants were enrolled in a cross-modal lexical decision study in which semantically ambiguous Italian idioms (i.e., strings with both a literal and an idiomatic interpretation as, for instance, break the ice), predictable or unpredictable before the string offset, were embedded in idiom-biasing contexts. To explore the contributions of different cognitive and personality components, participants also completed a series of tests respectively assessing general speed, inhibitory control, short term and working memory, cognitive flexibility, crystallized and fluid intelligence, and personality. Stepwise regression analyses revealed that online idiom comprehension was associated with the participants' working memory, inhibitory control and crystallized verbal intelligence, an association modulated by idiom type. Also personality-related variables (State Anxiety and Openness to Experience) were associated with idiom comprehension, although in marginally significant ways. These results contribute to the renewed interest on how individual variability modulates language comprehension, and for the first time document contributions of individual variability on lexicalized, high frequency multi-word expressions as idioms adding new knowledge to the existing evidence on metaphor and sarcasm. PMID- 29765351 TI - Multiscale Information Transfer in Functional Corticomuscular Coupling Estimation Following Stroke: A Pilot Study. AB - Recently, functional corticomuscular coupling (FCMC) between the cortex and the contralateral muscle has been used to evaluate motor function after stroke. As we know, the motor-control system is a closed-loop system that is regulated by complex self-regulating and interactive mechanisms which operate in multiple spatial and temporal scales. Multiscale analysis can represent the inherent complexity. However, previous studies in FCMC for stroke patients mainly focused on the coupling strength in single-time scale, without considering the changes of the inherently directional and multiscale properties in sensorimotor systems. In this paper, a multiscale-causal model, named multiscale transfer entropy, was used to quantify the functional connection between electroencephalogram over the scalp and electromyogram from the flexor digitorum superficialis (FDS) recorded simultaneously during steady-state grip task in eight stroke patients and eight healthy controls. Our results showed that healthy controls exhibited higher coupling when the scale reached up to about 12, and the FCMC in descending direction was stronger at certain scales (1, 7, 12, and 14) than that in ascending direction. Further analysis showed these multi-time scale characteristics mainly focused on the beta1 band at scale 11 and beta2 band at scale 9, 11, 13, and 15. Compared to controls, the multiscale properties of the FCMC for stroke were changed, the strengths in both directions were reduced, and the gaps between the descending and ascending directions were disappeared over all scales. Further analysis in specific bands showed that the reduced FCMC mainly focused on the alpha2 at higher scale, beta1 and beta2 across almost the entire scales. This study about multi-scale confirms that the FCMC between the brain and muscles is capable of complex and directional characteristics, and these characteristics in functional connection for stroke are destroyed by the structural lesion in the brain that might disrupt coordination, feedback, and information transmission in efferent control and afferent feedback. The study demonstrates for the first time the multiscale and directional characteristics of the FCMC for stroke patients, and provides a preliminary observation for application in clinical assessment following stroke. PMID- 29765352 TI - Optimal Hematoma Volume Cut Points to Predict Functional Outcome After Basal Ganglia and Thalamic Hemorrhages. AB - Background: Basal ganglia hemorrhage (BG-ICH) and thalamic hemorrhage (TH-ICH) have been historically grouped into a single "deep" hemorrhage group in prior studies. We aimed to assess whether BG-ICH and TH-ICH have different optimal hematoma volume cut points in predicting functional outcome. Methods: Patients with BG-ICH and TH-ICH with no preexisting disabilities who were enrolled in a single-center intracerebral hemorrhage (ICH) cohort study were studied. The hematoma volume of patients who achieved modified Rankin Scale (mRS) of <=2 and <=3 at 3 months were compared between BG-ICH and TH-ICH groups. Receiver operating characteristic (ROC) curves were created to determine the optimal hematoma volume cut points in predicting 3-month mRS of <=2 and <=3 for BG-ICH and TH-ICH groups. Results: A total of 135 (81 BG-ICH and 54 TH-ICH) patients were studied. The hematoma volume among those with 3-month mRS <= 2 (BG-ICH: 9.5 +/- 5.4 cm3 vs. TH-ICH: 5.1 +/- 4.9 cm3, p = 0.01) and 3-month mRS <= 3 (BG-ICH: 14.2 +/- 13.4 cm3 vs. TH-ICH: 4.7 +/- 4.1 cm3, p = 0.001) were smaller in TH-ICH than BG-ICH. The area under the ROC curve in predicting mRS <= 2 was 0.838 for BG ICH (optimal hematoma volume cut point: 18.0 cm3, sensitivity 72.1%, specificity 95.0%) and 0.802 for TH-ICH (optimal hematoma volume cut point: 4.6 cm3, sensitivity 83.8%, specificity 70.6%); and in predicting mRS <= 3 was 0.826 for BG-ICH (optimal hematoma volume cut point: 28.8 cm3, sensitivity 71.4%, specificity 93.8%) and 0.902 for TH-ICH (optimal hematoma volume cut point: 5.5 cm3, sensitivity 92.9%, specificity 76.9%). Conclusion: TH-ICH have smaller optimal hematoma volume cut points than BG-ICH in predicting functional outcome. PMID- 29765353 TI - Fentanyl Induces Cerebellar Internal Granular Cell Layer Apoptosis in Healthy Newborn Pigs. AB - Background: Opioids like fentanyl are regularly used in neonates for analgesia and sedation. So far, they have been reported to be safe and eligible to use. The cerebellum has become a focus of neurodevelopmental research within the last years, as it is known to play an important role in long-lasting motor, cognitive, and other behavioral changes. The cerebellar cortex is of major importance in the coordinative role of the cerebellum and highly vulnerable to injury and impaired growth. Objective: This study was performed to evaluate the apoptotic effect of intravenous fentanyl infusion on the cerebellum in healthy newborn pigs. Methods: Thirteen healthy pigs (= LMC > leaf gas exchange > leaf area in both stages. This sequence of changes in maize responding to soil water deficit and related critical thresholds may be better indicators of damage classification and drought monitoring. PMID- 29765380 TI - The Complete Plastome Sequences of Seven Species in Gentiana sect. Kudoa (Gentianaceae): Insights Into Plastid Gene Loss and Molecular Evolution. AB - The chloroplast (cp) genome is useful in the study of phylogenomics, molecular dating, and molecular evolution. Gentiana sect. Kudoa is a predominantly alpine flowering plant that is valued for its contributions to medicine, ecology, and horticulture. Previous evolutionary studies showed that the plastid gene loss pattern and intra-sectional phylogenetics in sect. Kudoa are still unclear. In this study, we compared 11 Gentiana plastomes, including 7 newly sequenced plastomes from sect. Kudoa, to represent its three serious: ser. Ornatae, ser. Verticillatae, and ser. Monanthae. The cp genome sizes of the seven species ranged from 137,278 to 147,156 bp. The plastome size variation mainly occurred in the small single-copy and long single-copy regions rather than the inverted repeat regions. Compared with sect. Cruciata, the plastomes in ser. Ornatae and ser. Verticillatae had lost approximately 11 kb of sequences containing 11 ndh genes. Conversely, far fewer losses were observed in ser. Monanthae. The phylogenetic tree revealed that sect. Kudoa was not monophyletic and that ser. Monanthae was more closely related to other sections rather than sect. Kudoa. The molecular dating analysis indicated that ser. Monanthae and sect. Kudoa diverged around 8.23 Ma. In ser. Ornatae and ser. Verticillatae, the divergence occurred at around 0.07-1.78 Ma. The nucleotide diversity analysis indicated that the intergenic regions trnH-psbA, trnK-trnQ, ycf3-trnS and rpl32-trnL constituted divergence hotspots in both sect. Kudoa and Gentiana, and would be useful for future phylogenetic and population genetic studies. PMID- 29765382 TI - The Plant Phenology Ontology: A New Informatics Resource for Large-Scale Integration of Plant Phenology Data. AB - Plant phenology - the timing of plant life-cycle events, such as flowering or leafing out - plays a fundamental role in the functioning of terrestrial ecosystems, including human agricultural systems. Because plant phenology is often linked with climatic variables, there is widespread interest in developing a deeper understanding of global plant phenology patterns and trends. Although phenology data from around the world are currently available, truly global analyses of plant phenology have so far been difficult because the organizations producing large-scale phenology data are using non-standardized terminologies and metrics during data collection and data processing. To address this problem, we have developed the Plant Phenology Ontology (PPO). The PPO provides the standardized vocabulary and semantic framework that is needed for large-scale integration of heterogeneous plant phenology data. Here, we describe the PPO, and we also report preliminary results of using the PPO and a new data processing pipeline to build a large dataset of phenology information from North America and Europe. PMID- 29765383 TI - FISH-Based Markers Enable Identification of Chromosomes Derived From Tetraploid Thinopyrum elongatum in Hybrid Lines. AB - Tetraploid Thinopyrum elongatum, which has superior abiotic stress tolerance characteristics, and exhibits resistance to stripe rust, powdery mildew, and Fusarium head blight, is a wild relative of wheat and a promising source of novel genes for wheat improvement. Currently, a high-resolution Fluorescence in situ hybridization (FISH) karyotype of tetraploid Th. elongatum is not available. To develop chromosome-specific FISH-based markers, the hexaploid Trititrigia 8801 and two accessions of tetraploid Th. elongatum were characterized by different repetitive sequences probes. We found that all E-genome chromosomes could be unambiguously identified using a combination of pSc119.2, pTa535, pTa71, and pTa713 repeats, and the E-genome chromosomes of the wild accessions and the partial amphiploid failed to exhibit any significant variation in the probe hybridization patterns. To verify the validation of these markers, the chromosome constitution of eight wheat- Th. elongatum hybrid derivatives were analyzed. We revealed that these probes could quickly detect wheat and tetraploid Th. elongatum chromosomes in hybrid lines. K16-712-1-2 was a 1E (1D) chromosome substitution line, K16-681-4 was a 2E disomic chromosome addition line, K16-562-3 was a 3E, 4E (3D, 4D) chromosome substitution line, K15-1033-8-2 contained one 4E, two 5E, and one 4ES?1DL Robertsonian translocation chromosome, and four other lines carried monosomic 4E, 5E, 6E, and 7E chromosome, respectively. Furthermore, the E-genome specific molecular markers analysis corresponded perfectly with the FISH results. The developed FISH markers will facilitate rapid identification of tetraploid Th. elongatum chromosomes in wheat improvement programs and allow appropriate alien chromosome transfer. PMID- 29765385 TI - Optimizing Winter Wheat Resilience to Climate Change in Rain Fed Crop Systems of Turkey and Iran. AB - Erratic weather patterns associated with increased temperatures and decreasing rainfall pose unique challenges for wheat breeders playing a key part in the fight to ensure global food security. Within rain fed winter wheat areas of Turkey and Iran, unusual weather patterns may prevent attaining maximum potential increases in winter wheat genetic gains. This is primarily related to the fact that the yield ranking of tested genotypes may change from one year to the next. Changing weather patterns may interfere with the decisions breeders make about the ideotype(s) they should aim for during selection. To inform breeding decisions, this study aimed to optimize major traits by modeling different combinations of environments (locations and years) and by defining a probabilistic range of trait variations [phenology and plant height (PH)] that maximized grain yields (GYs; one wheat line with optimal heading and height is suggested for use as a testing line to aid selection calibration decisions). Research revealed that optimal phenology was highly related to the temperature and to rainfall at which winter wheat genotypes were exposed around heading time (20 days before and after heading). Specifically, later winter wheat genotypes were exposed to higher temperatures both before and after heading, increased rainfall at the vegetative stage, and reduced rainfall during grain filling compared to early genotypes. These variations in exposure to weather conditions resulted in shorter grain filling duration and lower GYs in long-duration genotypes. This research tested if diversity within species may increase resilience to erratic weather patterns. For the study, calculated production of a selection of five high yielding genotypes (if grown in five plots) was tested against monoculture (if only a single genotype grown in the same area) and revealed that a set of diverse genotypes with different phenologies and PHs was not beneficial. New strategies of progeny selection are discussed: narrow range of variation for phenology in families may facilitate the discovery and selection of new drought-resistant and avoidant wheat lines targeting specific locations. PMID- 29765384 TI - The Hydrophobin-Like OmSSP1 May Be an Effector in the Ericoid Mycorrhizal Symbiosis. AB - Mutualistic and pathogenic plant-colonizing fungi use effector molecules to manipulate the host cell metabolism to allow plant tissue invasion. Some small secreted proteins (SSPs) have been identified as fungal effectors in both ectomycorrhizal and arbuscular mycorrhizal fungi, but it is currently unknown whether SSPs also play a role as effectors in other mycorrhizal associations. Ericoid mycorrhiza is a specific endomycorrhizal type that involves symbiotic fungi mostly belonging to the Leotiomycetes (Ascomycetes) and plants in the family Ericaceae. Genomic and RNASeq data from the ericoid mycorrhizal fungus Oidiodendron maius led to the identification of several symbiosis-upregulated genes encoding putative SSPs. OmSSP1, the most highly symbiosis up-regulated SSP, was found to share some features with fungal hydrophobins, even though it lacks the Pfam hydrophobin domain. Sequence alignment with other hydrophobins and hydrophobin-like fungal proteins placed OmSSP1 within Class I hydrophobins. However, the predicted features of OmSSP1 may suggest a distinct type of hydrophobin-like proteins. The presence of a predicted signal peptide and a yeast based signal sequence trap assay demonstrate that OmSSP1 is secreted. OmSSP1 null mutants showed a reduced capacity to form ericoid mycorrhiza with Vaccinium myrtillus roots, suggesting a role as effectors in the ericoid mycorrhizal interaction. PMID- 29765387 TI - Photosynthetic Characteristics and Chloroplast Ultrastructure of Summer Maize Response to Different Nitrogen Supplies. AB - Maize (Zea mays L.) is the important crop over the world. Nitrogen (N) as necessary element affects photosynthetic characteristics and grain yield of summer maize. In this study, N0 (0 kg N ha-1), N1 (129 kg N ha-1), N2 (185 kg N ha-1), and N3 (300 kg N ha-1) was conducted using hybrid 'ZhengDan958' at Dawenkou research field (36 degrees 11'N, 117 degrees 06'E, 178 m altitude) in the North China Plain to explore the effects of N rate on photosynthetic characteristics and chloroplast ultrastructure. Gas exchange parameters, chlorophyll fluorescence parameters, leaf area index (LAI), chlorophyll SPAD value, chloroplast ultrastructure, dry matter weight and grain yield were measured. At physiological maturity stage, dry matter weight and grain yield of N2 increased by 33-52% (P <= 0.05) and 6-32% (P <= 0.05), respectively, compared with other treatments. During the growing from silking (R1) to milk (R3) stage, LAI of N0 and N1 were 35-38% (P <= 0.05) and 9-23% (P <= 0.05) less than that of N2, respectively. Chlorophyll SPAD value of N0 and N1 were 13-22% (P <= 0.05) and 5-11% (P <= 0.05) lower than that of N2. There was no significant difference in LAI and chlorophyll SPAD value between N2 and N3 during the period from R1 to R3 (P > 0.05). The net photosynthetic rate (Pn), maximal quantum efficiency of PSII (Fv/Fm) and quantum efficiency of PSII (PhiPSII) were higher with the increase of N rate up to N2 (P <= 0.05), and those of N3 were significantly less than N2 (P <= 0.05). In compared with N2, the chloroplast configuration of N0 and N1 became elliptical, almost circular or irregular. The membrane of chloroplast and thylakoid resolved with growing stage, and the number of chloroplast per cell and lamellae per grana decreased under N0 and N1 treatment (P <= 0.05). Under N0 and N1 treatments, summer maize had more negative photosynthetic characteristics. The more number of osmium granule and vesicle and the larger gap between lamellae were shown in N3. Therefore, N2 treatment, 185 kg N ha-1, is the appropriate application rate for grain yield, photosynthesis and chloroplast ultrastructure. PMID- 29765388 TI - Changes of Vegetation Distribution in the East Dongting Lake After the Operation of the Three Gorges Dam, China. AB - Water regime is regarded as the primary factor influencing the vegetation distribution in natural wetland ecosystems. However, the effect of water regime change induced by large-scale hydraulic engineering on vegetation distribution is still unclear. In this study, multi-temporal TM/ETM+/OLI images and hydrological data from 1995 to 2015 were used to elucidate how the change in water regime influenced the vegetation distribution in the East Dongting Lake (EDTL), especially after the operation of the Three Gorges Dam (TGD) in 2003. Using unsupervised and supervised classification methods, three types of land cover were identified in the study area: Water and Mudflat, Grass, and Reed and Forest. Results showed that the total vegetation area in EDTL increased by approximately 78 km2 during 1995-2015. The areas of Reed and Forest and Grass exhibited a contrasting trend, dramatic increase in Reed and Forest but sharp decrease in Grass, particularly after the operation of TGD. The lowest distribution elevations of Grass and Reed and Forest decreased by 0.61 and 0.52 m, respectively. As a result of water level variation, submergence duration increased at 20-21 m and 28 m elevations (1-13 days), but significantly decreased at 22-27 m and 29-30 m elevations (-3 to -31 days). The submergence duration of Grass and Reed and Forest was 246 and 177 days, respectively. This study indicated that wetland vegetation pattern significantly changed after the operation of TGD, mainly as a result of changes in submergence condition. Submergence duration might be an effective indicator to predict the shift of vegetation distribution in EDTL, and which could provide scientific guidance for vegetation restoration and wetland management in this lake. PMID- 29765386 TI - Design of a Type-1 Diabetes Vaccine Candidate Using Edible Plants Expressing a Major Autoantigen. AB - Type-1 diabetes (T1D) is a metabolic disease involving the autoimmune destruction of insulin-producing pancreatic beta cells. It is often diagnosed by the detection of autoantibodies, typically those recognizing insulin itself or the 65 kDa isoform of glutamic acid decarboxylase (GAD65). Oral insulin can be used to induce systemic immunological tolerance and thus prevent or delay the onset of T1D, suggesting that combination treatments with other autoantigens such as GAD65 could be even more successful. GAD65 has induced oral tolerance and prevented T1D in preclinical studies but it is difficult to produce in sufficient quantities for clinical testing. Here we combined edible plant systems, namely spinach (Spinacia oleracea cv Industra) and red beet (Beta vulgaris cv Moulin Rouge), with the magnICON(r) expression system to develop a safe, cost-effective and environmentally sustainable platform for the large-scale production of GAD65. The superior red beet platform was extensively characterized in terms of recombinant protein yields and bioequivalence to wild-type plants, and the product was tested for its ability to resist simulated gastric digestion. Our results indicate that red beet plants are suitable for the production of a candidate oral vaccine based on GAD65 for the future preclinical and clinical testing of T1D immunotherapy approaches. PMID- 29765389 TI - Homoeologous Chromosomes From Two Hordeum Species Can Recognize and Associate During Meiosis in Wheat in the Presence of the Ph1 Locus. AB - Understanding the system of a basic eukaryotic cellular mechanism like meiosis is of fundamental importance in plant biology. Moreover, it is also of great strategic interest in plant breeding since unzipping the mechanism of chromosome specificity/pairing during meiosis will allow its manipulation to introduce genetic variability from related species into a crop. The success of meiosis in a polyploid like wheat strongly depends on regular pairing of homologous (identical) chromosomes and recombination, processes mainly controlled by the Ph1 locus. This means that pairing and recombination of related chromosomes rarely occur in the presence of this locus, making difficult wheat breeding trough the incorporation of genetic variability from related species. In this work, we show that wild and cultivated barley chromosomes associate in the wheat background even in the presence of the Ph1 locus. We have developed double monosomic wheat lines carrying two chromosomes from two barley species for the same and different homoeology chromosome group, respectively. Genetic in situ hybridization revealed that homoeologous Hordeum chromosomes recognize each other and pair during early meiosis in wheat. However, crossing over does not occur at any time and they remained always as univalents during meiosis metaphase I. Our results suggest that the Ph1 locus does not prevent chromosome recognition and pairing but crossing over between homoeologous. The role of subtelomeres in chromosome recognition is also discussed. PMID- 29765390 TI - Preclinical Evaluation of the NeVaTM Stent Retriever: Safety and Efficacy in the Swine Thrombectomy Model. AB - Background: A novel stent retriever device with an enhanced radial force profile, enlarged offset openings, and a closed distal end has been developed. Objective: Evaluate the safety and effectiveness of the NeVaTM thrombectomy device in animal model of thrombo-occlusive disease. Materials and Methods: Seven swine were used in safety and efficacy studies. Thrombo-occlusive disease was modeled using 4 emboli morphologies; 2 distinct models of autologous whole blood thrombi, plasma enriched thrombi, and Onyx(r) emboli. A total of 35 vascular occlusions and retrievals were performed using emboli of variable sizes. Pre- and post-modified thrombolysis in cerebral ischemia (mTICI) scores, number of retrievals, and the presence of angiographic complications were recorded. In the safety study, a total of 6 clot retrievals were completed and the vascular territory examined grossly and harvested for histopathological evaluation. A semiquantitative vasospasm study was performed. Radial force testing was performed on NeVaTM and control devices for comparison. Results: Near-full or full reperfusion (mTICI 2b/3) was achieved in 34/35 occlusions after a mean of 1.2 passes. Full reperfusion (TICI 3) was achieved in 17/17 of whole blood clot occlusions (ranging between 10 and 20 mm) after a mean of 1.06 passes. The rate of mTICI 2b/3 reperfusion was 10/11 (mean, 1.6 passes) and 5/5 (mean, 1.0 passes) for Onyx(r) and plasma-enriched clot emboli, respectively. Histopathological vessel injury and vasospasm scores were comparable to predicate studies. Radial force curves demonstrated increased expansive radial force and similar compressive radial force compared to predicate devices. Conclusions: Our preclinical results support the use of the NeVaTM device in a clinical trial to determine if this novel design improves upon current stent retriever outcomes. PMID- 29765392 TI - Carotid Stenting for Treatment of Symptomatic Carotid Webs: A Single-Center Case Series. AB - Background and Purpose: Carotid webs are an increasingly recognized cause of acute is-chemic stroke, particularly in younger adults. The optimal medical and surgical strategies for managing these lesions have not been well established. We report a single-center case series of carotid stenting for treatment of symptomatic carotid webs. Materials and Methods: Consecutive patients undergoing stent placement for treatment of symptomatic carotid webs were included. Carotid webs were defined as a thin intraluminal filling defect along the posterior wall of the carotid bulb just beyond the carotid bifurcation on CTA. Data were collected on demographic characteristics, antiplatelet management, clinical presentation, imaging findings, treatment characteristics, complications, and stroke recurrence rates. Descriptive statistics are reported. Results: A total of 4 patients were treated. Their mean age was 44 years (range 30-50). Three patients were female and 1 was male. All patients were symptomatic presenting with ipsilateral transient ischemic attacks or stroke. Patients were placed on dual antiplatelet therapy with ticagrelor and aspirin prior to the procedure. There were no ischemic or hemorrhagic complications. Three patients had postoperative bradycardia, 1 of whom required atropine immediately following stenting. No patients had recurrent ischemic events. Conclusions: Stent placement for treatment of carotid webs can be performed safely. Further studies are needed to confirm our findings. PMID- 29765391 TI - Abciximab (ReoPro) Dosing Strategy for the Management of Acute Intraprocedural Thromboembolic Complications during Pipeline Flow Diversion Treatment of Intracranial Aneurysms. AB - Background: Flow diversion with the Pipeline embolization device (PED) is an effective neuro-endovascular method and increasingly accepted for the treatment of cerebral aneurysms. Acute in situ thrombosis is a known complication of PED procedures. There is limited experience in the flow diversion literature on the use of abciximab (ReoPro) for the management of acute thrombus formation in PED cases. Methods: Data were collected retrospectively on patients who received intra-arterial (IA) ReoPro with or without subsequent intravenous (IV) infusion during PED flow diversion treatment of intracranial aneurysms. Results: A total of 30 cases in patients with a mean age of 56.7 years (range 36-84) and a mean aneurysm size of 8.6 mm (range 2-25) were identified to have intraprocedural thromboembolic complications during PED treatment. IA ReoPro was administered in all cases, with 20 cases receiving increments of 5-mg boluses and 10 cases receiving a 0.125 mg/kg IA bolus (half cardiac dosing). Complete or partial recanalization was achieved in 100% of the cases. IV ReoPro infusion at 0.125 MUg/kg/min for 12 h was administered postprocedurally in 22 cases with a residual thrombus. Postprocedurally, 18 patients were transitioned from clopidogrel (Plavix) to prasugrel (Effient). The majority of the cases (23/30; 77%) were discharged home. Periprocedural intracranial hemorrhage was noted in 2 cases (7%) and radiographic infarct was noted in 4 cases (13%), with an overall mortality of 0% at the time of initial discharge. Clinical follow-up was available for 28/30 patients. The average duration of follow-up was 11.7 months, at which time 23/28 (82%) of the patients had a modified Rankin Scale score of 0. Conclusions: IA ReoPro administration is an effective and safe rescue strategy for the management of acute intraprocedural thromboembolic complications during PED treatment. Using a dosing strategy of either 5-mg increments or a 0.125 mg/kg IA bolus (half cardiac dosing) can provide high rates of recanalization with low rates of hemorrhagic complications and long-term morbidity. PMID- 29765393 TI - Support of New Triage Protocol among Acute Stroke Care Providers. AB - Objective: We conducted an online survey to gauge the acceptance of sending acute stroke patients with suspected large vessel occlusion (LVO) directly to an endovascular-capable hospital (ECH) even if that means bypassing a closer alteplase-capable hospital (ACH) without endovascular capability. Methods: The survey was composed of two cases of acute stroke, one with cortical symptoms suggestive of LVO and the other without. In each case, responders were asked to choose between triaging to a closer ACH or an ECH that is further away and to provide an opinion regarding the maximum extra travel time they would tolerate if they chose the ECH. The survey was sent electronically to national groups of neurologists, emergency department (ED) physicians, emergency medical service (EMS) directors, and stroke coordinators. Results: There were 320 responders from 44 states, most of them with 10 years or more of experience. Most of the responders, 72.5%, chose ECH for the LVO case, while 56% chose ACH for the non LVO case. There were marked differences in responses by specialty: neurology strongly supported ECH for LVO and strongly supported ACH for non-LVO, most ED and EMS chose ECH for both cases, and stroke coordinators were the least supportive of bypassing ACH. Almost all groups agreed on 30 min as the acceptable extra transfer time to ECH. Conclusion: Among the survey responders, there is a broad acceptance of the idea of bypassing ACH and going straight to ECH when LVO is suspected; however, there is less agreement on triaging patients with non-LVO stroke. PMID- 29765394 TI - Mechanical Thrombectomy in Elderly Stroke Patients with Mild-to-Moderate Baseline Disability. AB - Background: The number of elderly patients suffering from ischemic stroke is rising. Randomized trials of mechanical thrombectomy (MT) generally exclude patients over the age of 80 years with baseline disability. The aim of this study was to understand the efficacy and safety of MT in elderly patients, many of whom may have baseline impairment. Methods: Between January 2015 and April 2017, 96 patients >=80 years old who underwent MT for stroke were selected for a chart review. The data included baseline characteristics, time to treatment, the rate of revascularization, procedural complications, mortality, and 90-day good outcome defined as a modified Rankin Scale (mRS) score of 0-2 or return to baseline. Results: Of the 96 patients, 50 had mild baseline disability (mRS score 0-1) and 46 had moderate disability (mRS score 2-4). Recanalization was achieved in 84% of the patients, and the rate of symptomatic hemorrhage was 6%. At 90 days, 34% of the patients had a good outcome. There were no significant differences in good outcome between those with mild and those with moderate baseline disability (43 vs. 24%, p = 0.08), between those aged <=85 and those aged > 85 years (40.8 vs. 26.1%, p = 0.19), and between those treated within and those treated beyond 8 h (39 vs. 20%, p = 0.1). The mortality rate was 38.5% at 90 days. The Alberta Stroke Program Early CT Score (ASPECTS) and the National Institutes of Health Stroke Scale (NIHSS) predicted good outcome regardless of baseline disability (p < 0.001 and p = 0.009, respectively). Conclusion: Advanced age, baseline disability, and delayed treatment are associated with sub-optimal outcomes after MT. However, redefining good outcome to include return to baseline functioning demonstrates that one-third of this patient population benefits from MT, suggesting the real-life utility of this treatment. PMID- 29765395 TI - Progressive Neurological Decline with Deep Bilateral Imaging Changes: A Protean Presentation of Dural Arteriovenous Fistulae. AB - Intracranial dural arteriovenous fistulae (DAVF) within the deep cerebral vasculature are diagnostically challenging because of their variable clinical presentation and typical bilateral neuroimaging findings mimicking inflammatory, infectious, and metabolic processes. Increasingly, reports have emerged highlighting the diagnostic and treatment challenges of these lesions and their associated high morbidity and rapid clinical deterioration when untreated. We describe here a case series of 4 patients with deep cerebral DAVF who presented with impaired arousal or memory and behavioral changes. In all patients, the initial differential diagnosis included metabolic, inflammatory, infectious, or neoplastic disease, with an eventual correct diagnosis obtained after catheter angiography had demonstrated arterialization of the deep venous structures, including the vein of Galen. All patients were successfully treated with endovascular embolization, with 1 patient requiring additional surgical treatment. We review the contemporary diagnostic evaluation and management of DAVF within the deep cerebral vasculature. With rapid diagnosis and treatment, a favorable outcome is possible. PMID- 29765396 TI - Acute In-Stent Thrombosis after Carotid Angioplasty and Stenting: A Case Report and Literature Review. AB - Background: Based on the results of a recent randomized controlled trial, carotid artery stenting (CAS) was regarded as a relatively safe, less invasive treatment of internal carotid artery stenosis. However, cerebral thromboembolic events are the most common complications of CAS. Especially acute stent thrombosis following CAS will be fatal without prompt diagnosis and revascularization. Case Report: We report a case of acute stent thrombosis in whom carotid revascularization was performed successfully via arterial thrombolysis and balloon postdilation. A 79 year-old man with hypertension was hospitalized for an episode of transient ischemic attack. Computed tomography angiography revealed subtotal occlusion in the left carotid artery. Aspirin (100 mg) and clopidogrel (75 mg) were administered daily for 5 days before the procedure. CAS was performed under local anesthesia. The first postprocedural angiogram showed the stent looked good. However, a repeat angiogram showed in-stent thrombosis 2 min after withdrawal of the cerebral protection filter. Interestingly, the patient presented no neurologic deficit. After an additional 2,000 U of heparin had been administered intravenously, a microcatheter (SL-14; Boston Scientific, USA) was positioned to the in-stent thrombosis. Next, a total dose of 10 mg of recombinant tissue plasminogen activator was injected into the thrombus via the microcatheter within 10 min, which led to partial recanalization with antegrade flow. However, complete occlusion of the lesion occurred 5 min later. Under the guidance of angiography roadmap, a protection filter (Emboshield NAV6; Abbott Vascular, USA) was deployed at the distal part of the stent and redilation of the stent was performed with a 5 * 30 mm balloon (Viatrac 14 Plus; Abbott Vascular) at 14 atm. Finally, carotid revascularization was performed successfully, proven by postprocedural angiogram. Conclusion: Acute carotid stent thrombosis (ACST) can have devastating effects on the survival of the patient. For ACST when the stent does not fully adhere to the blood vessel, a mechanical approach should be a feasible solution to the problem. PMID- 29765397 TI - LVIS Jr Device for Y-Stent-Assisted Coil Embolization of Wide-Neck Intracranial Aneurysms: A Multicenter Experience. AB - Background and Purpose: Complex wide-neck intracranial aneurysms are challenging to treat. We report a multicenter experience using the LVIS Jr stent for "Y stent"-assisted coiling embolization of wide-neck bifurcation aneurysms. Methods: Seven centers provided retrospective data on patients who underwent Y-stenting. Technical complications, immediate posttreatment angiographic results, clinical outcomes, and imaging follow-up were assessed. Results: Thirty patients/aneurysms were treated: 15 basilar tip, 8 middle cerebral artery, 4 anterior communicating artery, 1 pericallosal, and 2 posterior inferior cerebellar artery aneurysms. The mean aneurysm size was 11 mm and the mean dome-to-neck ratio was 1.3 mm. Twenty four aneurysms were unruptured and treated electively, and 6 were acutely ruptured. Fifty-eight LVIS Jr stents were successfully deployed without any technical issue. One pro-cedural and transient in-stent thrombosis resolved with the intravenous infusion of a glycoprotein IIb/IIIa inhibitor. Five periprocedural complications (within 30 days) occurred: 2 periprocedural neurological complications (1 small temporal stroke that presented with transient aphasia and 1 posterior cerebral artery infarct) and 3 nonneurological periprocedural complications (2 retroperitoneal hematomas, and 1 patient developed a disseminated intravascular coagulopathy). One permanent complication (3.3%) directly related to Y-stenting was reported in the patient who suffered the posterior cerebral artery infarct. Immediate complete obliteration (Raymond Roy Occlusion Classification [RROC] I-II) was achieved in 26 cases (89.6%). Twenty-four patients had clinical and imaging follow-up (mean 5.2 months). Complete angiographic occlusion (RROC I-II) was observed in 23 patients (96%). A good functional outcome with a modified Rankin Scale score <=2 was achieved in 26 cases. Conclusions: In this multicenter case series, Y-stent-assisted coiling of wide-neck aneurysms with the LVIS Jr device was feasible and relatively safe. Follow-up imaging demonstrated very low recanalization rates. PMID- 29765399 TI - A Seasonal Time-Series Model Based on Gene Expression Programming for Predicting Financial Distress. AB - The issue of financial distress prediction plays an important and challenging research topic in the financial field. Currently, there have been many methods for predicting firm bankruptcy and financial crisis, including the artificial intelligence and the traditional statistical methods, and the past studies have shown that the prediction result of the artificial intelligence method is better than the traditional statistical method. Financial statements are quarterly reports; hence, the financial crisis of companies is seasonal time-series data, and the attribute data affecting the financial distress of companies is nonlinear and nonstationary time-series data with fluctuations. Therefore, this study employed the nonlinear attribute selection method to build a nonlinear financial distress prediction model: that is, this paper proposed a novel seasonal time series gene expression programming model for predicting the financial distress of companies. The proposed model has several advantages including the following: (i) the proposed model is different from the previous models lacking the concept of time series; (ii) the proposed integrated attribute selection method can find the core attributes and reduce high dimensional data; and (iii) the proposed model can generate the rules and mathematical formulas of financial distress for providing references to the investors and decision makers. The result shows that the proposed method is better than the listing classifiers under three criteria; hence, the proposed model has competitive advantages in predicting the financial distress of companies. PMID- 29765398 TI - Epidemiology of Intracranial Hemorrhage Associated with Oral Anticoagulants in Spain: Trends in Anticoagulation Complications Registry - The TAC 2 Study. AB - Objective: Patients receiving treatment with oral anticoagulants (OACs) are at risk of intracranial hemorrhage (ICH). In this study, we describe the epidemiological and clinical characteristics of patients receiving OACs who experience ICH and compare those receiving vitamin K antagonists (ICH-VKAs) with those receiving direct OACs (ICH-DOACs). Methods: We performed a national, multicenter, descriptive, observational, retrospective study of all adult patients receiving OACs who were admitted to the neurology department with ICH over a 1-year period. The study population was divided into 2 groups (ICH-VKAs and ICH-DOACs). Epidemiological, clinical, radiological, and therapy-related variables, as well as functional outcome, were compared at 3 months. A total of 366 cases were included (331 ICH-VKAs, 35 ICH- DOACs). Results: The crude annual incidence of OAC-induced ICH was 3.8 (95% CI, 2.78-3.41) per 100,000 inhabitants/year. The mean (+/- SD) age was greater for ICH-DOACs (81.5 +/- 8.3 vs. 77.7 +/- 8.3 years; p = 0.012). The median (IQR) volume of the hemorrhage was lower for ICH-DOACs (11 [30.8] vs. 25 [50.7] mL; p = 0.03). The functional independence rate at 3 months (modified Rankin Scale, mRS < 3) was similar in both groups, although stroke-related mortality was greater in ICH-VKAs (40 vs. 72.7%; p = 0.02). The most frequently indicated poststroke antithrombotic therapy was DOACs (38.7%). Conclusion: We found that the incidence of OAC-induced ICH was greater than in previous studies. Hemorrhage volume and mortality were lower in ICH-DOACs than in ICH-VKAs. After stroke, DOACs were the most frequently indicated antithrombotic treatment. PMID- 29765400 TI - Single-Trial Evoked Potential Estimating Based on Sparse Coding under Impulsive Noise Environment. AB - Estimating single-trial evoked potentials (EPs) corrupted by the spontaneous electroencephalogram (EEG) can be regarded as signal denoising problem. Sparse coding has significant success in signal denoising and EPs have been proven to have strong sparsity over an appropriate dictionary. In sparse coding, the noise generally is considered to be a Gaussian random process. However, some studies have shown that the background noise in EPs may present an impulsive characteristic which is far from Gaussian but suitable to be modeled by the alpha stable distribution (1 < alpha <= 2). Consequently, the performances of general sparse coding will degrade or even fail. In view of this, we present a new sparse coding algorithm using p-norm optimization in single-trial EPs estimating. The algorithm can track the underlying EPs corrupted by alpha-stable distribution noise, trial-by-trial, without the need to estimate the alpha value. Simulations and experiments on human visual evoked potentials and event-related potentials are carried out to examine the performance of the proposed approach. Experimental results show that the proposed method is effective in estimating single-trial EPs under impulsive noise environment. PMID- 29765401 TI - Mixed-Effects Modeling of Neurofeedback Self-Regulation Performance: Moderators for Learning in Children with ADHD. AB - Introduction: Neurofeedback (NF) has gained increasing popularity as a training method for children and adults with attention deficit hyperactivity disorder (ADHD). However, it is unclear to what extent children learn to regulate their brain activity and in what way NF learning may be affected by subject- and treatment-related factors. Methods: In total, 48 subjects with ADHD (age 8.5-16.5 years; 16 subjects on methylphenidate (MPH)) underwent 15 double training sessions of NF in either a clinical or a school setting. Four mixed-effects models were employed to analyze learning: training within-sessions, across sessions, with continuous feedback, and with transfer in which performance feedback is delayed. Results: Age and MPH affected the NF performance in all models. Cross-session learning in the feedback condition was mainly moderated by age and MPH, whereas NF learning in the transfer condition was mainly boosted by MPH. Apart from IQ and task types, other subject-related or treatment-related effects were unrelated to NF learning. Conclusion: This first study analyzing moderators of NF learning in ADHD with a mixed-effects modeling approach shows that NF performance is moderated differentially by effects of age and MPH depending on the training task and time window. Future studies may benefit from using this approach to analyze NF learning and NF specificity. The trial name Neurofeedback and Computerized Cognitive Training in Different Settings for Children and Adolescents With ADHD is registered with NCT02358941. PMID- 29765402 TI - TLR4-NF-kappaB Signal Involved in Depressive-Like Behaviors and Cytokine Expression of Frontal Cortex and Hippocampus in Stressed C57BL/6 and ob/ob Mice. AB - Studies found that elevated levels of cytokines such as interleukin- (IL-) 1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) are closely associated with the pathogenesis of depression. Obesity providing a low-grade inflammation state was proposed to be implicated in susceptibility to depression in obesity. However, the alterations of cytokines and the TLR4-NF-kappaB signal in the brain of normal weight and obese mice under stress have not been fully elucidated. This study used chronic unpredictable mild stress (CUMS) to induce a depressive-like behavior in an animal model and examine depressive-like behaviors, memory changes, and serum corticosterone levels, as well as the expressions of cytokines and NF-kappaB in the frontal cortex and hippocampus. We aimed to observe the role of neuroinflammation in susceptibility to depression in obesity under CUMS. In addition, we investigated the protective effect of inhibiting the TLR4-NF-kappaB signal. Our results demonstrated that CUMS induced depressive-like behavior and spatial memory damage, higher level of serum corticosterone, and overexpression of cytokines and NF-kappaB in the frontal cortex and hippocampus in both C57BL/6 and ob/ob mice. ob/ob mice displayed serious behavioral disorder and higher levels of IL-1beta, IL-6, TNF-alpha, and NF-kappaB. Our results concluded that a hyperactive TLR4-NF-kappaB signal and higher level of cytokines are involved in susceptibility to depression in stressed obese mice. PMID- 29765403 TI - Effect of Maternal Administration of Edible Bird's Nest on the Learning and Memory Abilities of Suckling Offspring in Mice. AB - Although human brains continue developing throughout the underage developmental stages, the infancy period is considered the most important one for the whole life. It has been reported that sialic acid from edible bird's nest (EBN) can facilitate the development of brain and intelligence. In this study, by oral administration of EBN to female mice during the pregnancy or lactation period, the effects of EBN on the levels of sialic acid in mouse milk were determined using high-performance liquid chromatography (HPLC). Furthermore, the spatial learning performances of their offspring were assessed using the Morris water maze test. Additionally, cerebral malondialdehyde (MDA), superoxide dismutase (SOD), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) in cubs nursed by the female mice given the EBN homogenate were examined, while BDNF immunohistochemical staining and neuron count in hippocampi were investigated as well. These results showed that administration with EBN in maternal mice during pregnancy or lactation period can improve the learning and memory functions in their offspring, possibly by increasing the activities of SOD and ChAT and, at the meantime, decreasing the levels of MDA and activities of AChE. Moreover, BDNF levels for CA1, CA2, and CA3 regions in hippocampi and the numbers of dyed neurons in CA1, CA2, CA3, and DG regions among the offspring were significantly enhanced due to the intake of EBN by the maternal mice. We concluded that maternal administration of EBN during the pregnancy and lactation periods can improve the spatial learning performances in the offspring. PMID- 29765404 TI - Meta-Analysis of the Association between Vitamin D Receptor Polymorphisms and the Risk of Autoimmune Thyroid Disease. AB - The association between vitamin D receptor (VDR) polymorphisms (rs731236, rs1544410, rs2228570, and rs7975232) and the risk of autoimmune thyroid disease (AITD) had been investigated in previous studies. However, the results of these studies remained controversial. Thus, a meta-analysis was performed to derive a more precise conclusion. All related articles were systematically searched by PubMed, Embase, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI). The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association. The overall results indicated that VDR rs731236 and rs2228570 polymorphisms were significantly associated with a reduced risk of AITD. However, a stratification analysis based on clinical types showed that VDR rs731236 and rs2228570 polymorphisms were associated only with a reduced risk of HT. A stratification analysis by ethnicity showed that VDR rs731236 polymorphism was significantly associated with a reduced risk of AITD in Asian and African populations. VDR rs2228570 polymorphism was associated with a reduced risk of AITD in Asian populations. VDR rs1544410 polymorphism was associated with a reduced risk of AITD in European and African populations, but with an increased risk of AITD in Asian populations. VDR rs7975232 polymorphism was significantly associated with an increased risk of AITD in African populations. In conclusion, the present study suggested that VDR rs731236, rs1544410, rs2228570, and rs7975232 polymorphisms were significantly associated with AITD risk. However, more well-designed studies should be performed to verify the current results. PMID- 29765405 TI - Recent Progress of Fabrication of Cell Scaffold by Electrospinning Technique for Articular Cartilage Tissue Engineering. AB - As a versatile nanofiber manufacturing technique, electrospinning has been widely employed for the fabrication of tissue engineering scaffolds. Since the structure of natural extracellular matrices varies substantially in different tissues, there has been growing awareness of the fact that the hierarchical 3D structure of scaffolds may affect intercellular interactions, material transportation, fluid flow, environmental stimulation, and so forth. Physical blending of the synthetic and natural polymers to form composite materials better mimics the composition and mechanical properties of natural tissues. Scaffolds with element gradient, such as growth factor gradient, have demonstrated good potentials to promote heterogeneous cell growth and differentiation. Compared to 2D scaffolds with limited thicknesses, 3D scaffolds have superior cell differentiation and development rate. The objective of this review paper is to review and discuss the recent trends of electrospinning strategies for cartilage tissue engineering, particularly the biomimetic, gradient, and 3D scaffolds, along with future prospects of potential clinical applications. PMID- 29765408 TI - The Interaction between Bmal1 and Per2 in Mouse BMSC Osteogenic Differentiation. AB - The circadian clock is a system that controls endogenous time of organisms, and it regulates the physiology and behavior of bodies. The transcription factors Brain and Muscle ARNT-like Protein 1 (BMAL1) and Period2 (Per2) are components of the circadian clock, and they play vital roles in circadian clock function. Both Bmal1-/- mice and Per2-/- mice display obvious bone volume changes. In this study, we inhibited the expression of Bmal1 in bone marrow-derived mesenchymal stem cells (BMSCs) using a lentiviral vector harboring RNAi sequences, which increased the osteogenic differentiation capability of BMSCs. We also suppressed Per2 gene expression using an adenovirus vector harboring RNAi sequences, and similarly, the osteogenic differentiation ability of BMSCs was enhanced. Furthermore, when both Bmal1 and Per2 gene expression was suppressed in BMSCs by lentiviral and adenoviral interference, the osteogenic differentiation capability was stronger than that in BMSCs following single-gene inhibition. Our data support that both Bmal1 and Per2 play negative roles in BMSC osteogenic differentiation and that Bmal1 and Per2 have a synergistic effect on the osteogenic differentiation of BMSCs. PMID- 29765407 TI - Effects of Transplanted Heparin-Poloxamer Hydrogel Combining Dental Pulp Stem Cells and bFGF on Spinal Cord Injury Repair. AB - Spinal cord injury (SCI) is one of serious traumatic diseases of the central nervous system and has no effective treatment because of its complicated pathophysiology. Tissue engineering strategy which contains scaffolds, cells, and growth factors can provide a promising treatment for SCI. Hydrogel that has 3D network structure and biomimetic microenvironment can support cellular growth and embed biological macromolecules for sustaining release. Dental pulp stem cells (DPSCs), derived from cranial neural crest, possess mesenchymal stem cell (MSC) characteristics and have an ability to provide neuroprotective and neurotrophic properties for SCI treatment. Basic fibroblast growth factor (bFGF) is able to promote cell survival and proliferation and also has beneficial effect on neural regeneration and functional recovery after SCI. Herein, a thermosensitive heparin poloxamer (HP) hydrogel containing DPSCs and bFGF was prepared, and the effects of HP-bFGF-DPSCs on neuron restoration after SCI were evaluated by functional recovery tests, western blotting, magnetic resonance imaging (MRI), histology evaluation, and immunohistochemistry. The results suggested that transplanted HP hydrogel containing DPSCs and bFGF had a significant impact on spinal cord repair and regeneration and may provide a promising strategy for neuron repair, functional recovery, and tissue regeneration after SCI. PMID- 29765406 TI - The Differentiation Balance of Bone Marrow Mesenchymal Stem Cells Is Crucial to Hematopoiesis. AB - Bone marrow mesenchymal stem cells (BMSCs), the important component and regulator of bone marrow microenvironment, give rise to hematopoietic-supporting stromal cells and form hematopoietic niches for hematopoietic stem cells (HSCs). However, how BMSC differentiation affects hematopoiesis is poorly understood. In this review, we focus on the role of BMSC differentiation in hematopoiesis. We discussed the role of BMSCs and their progeny in hematopoiesis. We also examine the mechanisms that cause differentiation bias of BMSCs in stress conditions including aging, irradiation, and chemotherapy. Moreover, the differentiation balance of BMSCs is crucial to hematopoiesis. We highlight the negative effects of differentiation bias of BMSCs on hematopoietic recovery after bone marrow transplantation. Keeping the differentiation balance of BMSCs is critical for hematopoietic recovery. This review summarises current understanding about how BMSC differentiation affects hematopoiesis and its potential application in improving hematopoietic recovery after bone marrow transplantation. PMID- 29765409 TI - A Novel Secretory Vesicle from Deer Antlerogenic Mesenchymal Stem Cell Conditioned Media (DaMSC-CM) Promotes Tissue Regeneration. AB - Multipotent stem cells have the capacity to generate terminally differentiated cell types of each lineage; thus, they have great therapeutic potential for a wide variety of diseases. The most widely available stem cells are derived from human tissues, and their use for therapeutic application is limited by their high cost and low productivity. Herein, we report that conditioned media of mesenchymal stem cells (MSCs) isolated from deer antlers enhanced tissue regeneration through paracrine action via a combination of secreted growth factors and cytokines. Notably, DaMSC-conditioned media (DaMSC-CM) enhanced hair regeneration by activating the Wnt signaling pathway. In addition, DaMSC-CM had regenerative potential in damaged skin tissue through induction of skin regeneration-related genes. Remarkably, we identified round vesicles derived from DaMSC-CM, with an average diameter of ~120 nm that were associated with hair follicle formation, suggesting that secretory vesicles may act as paracrine mediators for modulation of local cellular responses. In addition, these secretory vesicles could regulate the expression of Wnt-3a, Wnt-10b, and lymphoid enhancer-binding factor-1 (LEF-1), which are related to tissue renewal. Thus, our findings demonstrate that the use of DaMSC-CM as a unique natural model for rapid and complete tissue regeneration has possible application for therapeutic development. PMID- 29765410 TI - Comparison of Regenerative Tissue Quality following Matrix-Associated Cell Implantation Using Amplified Chondrocytes Compared to Synovium-Derived Stem Cells in a Rabbit Model for Cartilage Lesions. AB - Known problems of the autologous chondrocyte implantation motivate the search for cellular alternatives. The aim of the study was to test the potential of synovium derived stem cells (SMSC) to regenerate cartilage using a matrix-associated implantation. In an osteochondral defect model of the medial femoral condyle in a rabbit, a collagen membrane was seeded with either culture-expanded allogenic chondrocytes or SMSC and then transplanted into the lesion. A tailored piece synovium served as a control. Rabbit SMSC formed typical cartilage in vitro. Macroscopic evaluation of defect healing and the thickness of the regenerated tissue did not reveal a significant difference between the intervention groups. However, instantaneous and shear modulus, reflecting the biomechanical strength of the repair tissue, was superior in the implantation group using allogenic chondrocytes (p < 0.05). This correlated with a more chondrogenic structure and higher proteoglycan expression, resulting in a lower OARSI score (p < 0.05). The repair tissue of all groups expressed comparable amounts of the collagen types I, II, and X. Cartilage regeneration following matrix-associated implantation using allogenic undifferentiated synovium-derived stem cells in a defect model in rabbits showed similar macroscopic results and collagen composition compared to amplified chondrocytes; however, biomechanical characteristics and histological scoring were inferior. PMID- 29765411 TI - Skin-Derived Stem Cells for Wound Treatment Using Cultured Epidermal Autografts: Clinical Applications and Challenges. AB - The human skin fulfills important barrier, sensory, and immune functions-all of which contribute significantly to health and organism integrity. Widespread skin damage requires immediate treatment and coverage because massive skin loss fosters the invasion of pathogens, causes critical fluid loss, and may ultimately lead to death. Since the skin is a highly immunocompetent organ, autologous transplants are the only viable approach to permanently close a widespread skin wound. Despite the development of tissue-saving autologous transplantation techniques such as mesh and Meek grafts, treatment options for extensive skin damage remain severely limited. Yet, the skin is also a rich source of stem and progenitor cells. These cells promote wound healing under physiological conditions and are potential sources for tissue engineering approaches aiming to augment transplantable tissue by generating cultured epidermal autografts (CEAs). Here, we review autologous tissue engineering strategies as well as transplantation products based on skin-derived stem cells. We further provide an overview of clinical trial activities in the field and discuss relevant translational and clinical challenges associated with the use of these products. PMID- 29765413 TI - Human Urine-Derived Stem Cells: Potential for Cell-Based Therapy of Cartilage Defects. AB - Stem cell therapy is considered an optimistic approach to replace current treatments for cartilage defects. Recently, human urine-derived stem cells (hUSCs), which are isolated from the urine, are studied as a promising candidate for many tissue engineering therapies due to their multipotency and sufficient proliferation activities. However, it has not yet been reported whether hUSCs can be employed in cartilage defects. In this study, we revealed that induced hUSCs expressed chondrogenic-related proteins, including aggrecan and collagen II, and their gene expression levels were upregulated in vitro. Moreover, we combined hUSCs with hyaluronic acid (HA) and injected hUSCs-HA into a rabbit knee joint with cartilage defect. Twelve weeks after the injection, the histologic analyses (HE, toluidine blue, and Masson trichrome staining), immunohistochemistry (aggrecan and collagen II), and histologic grade of the sample indicated that hUSCs-HA could stimulate much more neocartilage formation compared with hUSCs alone, pure HA, and saline, which only induced the modest cartilage regeneration. In this study, we demonstrated that hUSCs could be a potential cell source for stem cell therapies to treat cartilage-related defects in the future. PMID- 29765412 TI - Neural Stem Cell-Conditioned Medium Ameliorated Cerebral Ischemia-Reperfusion Injury in Rats. AB - Introduction: Our previous study suggested that NSC-CM (neural stem cell conditioned medium) inhibited cell apoptosis in vitro. In addition, many studies have shown that neurotrophic factors and microparticles secreted into a conditioned medium by NSCs had neuroprotective effects. Thus, we hypothesized that NSC-CM had the capacity of protecting against cerebral I/R injury. Methods: Adult male Sprague-Dawley rats receiving middle cerebral artery occlusion surgery as an animal model of cerebral I/R injury were randomly assigned to two groups: the control group and NSC-CM-treated group. 1.5 ml NSC-CM or PBS (phosphate buffer saline) was administrated slowly by tail vein at 3 h, 24 h, and 48 h after ischemia onset. Results: NSC-CM significantly ameliorated neurological defects and reduced cerebral infarct volume, accompanied by preserved mitochondrial ultrastructure. In addition, we also found that NSC-CM significantly inhibited cell apoptosis in the ischemic hemisphere via improving the expression of Bcl-2 (B-cell lymphoma-2). Conclusion: NSC-CM might be an alternative and effective therapeutic intervention for ischemic stroke. PMID- 29765415 TI - Human Recombinant Peptide Sponge Enables Novel, Less Invasive Cell Therapy for Ischemic Stroke. AB - Bone marrow stromal cell (BMSC) transplantation has the therapeutic potential for ischemic stroke. However, it is unclear which delivery routes would yield both safety and maximal therapeutic benefits. We assessed whether a novel recombinant peptide (RCP) sponge, that resembles human collagen, could act as a less invasive and beneficial scaffold in cell therapy for ischemic stroke. BMSCs from green fluorescent protein-transgenic rats were cultured and Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion (MCAo). A BMSC-RCP sponge construct was transplanted onto the ipsilateral intact neocortex 7 days after MCAo. A BMSC suspension or vehicle was transplanted into the ipsilateral striatum. Rat motor function was serially evaluated and histological analysis was performed 5 weeks after transplantation. The results showed that BMSCs could proliferate well in the RCP sponge and the BMSC-RCP sponge significantly promoted functional recovery, compared with the vehicle group. Histological analysis revealed that the RCP sponge provoked few inflammatory reactions in the host brain. Moreover, some BMSCs migrated to the peri-infarct area and differentiated into neurons in the BMSC-RCP sponge group. These findings suggest that the RCP sponge may be a promising candidate for animal protein-free scaffolds in cell therapy for ischemic stroke in humans. PMID- 29765414 TI - Developmental Pathways Pervade Stem Cell Responses to Evolving Extracellular Matrices of 3D Bioprinted Microenvironments. AB - Developmental studies and 3D in vitro model systems show that the production and engagement of extracellular matrix (ECM) often precede stem cell differentiation. Yet, unclear is how the ECM triggers signaling events in sequence to accommodate multistep process characteristic of differentiation. Here, we employ transcriptome profiling and advanced imaging to delineate the specificity of ECM engagement to particular differentiation pathways and to determine whether specificity in this context is a function of long-term ECM remodeling. To this end, human mesenchymal stem cells (hMSCs) were cultured in 3D bioprinted prisms created from ECM proteins and associated controls. We found that exogenous ECM provided in 3D microenvironments at early time points impacts on the composition of microenvironments at later time points and that each evolving 3D microenvironment is uniquely poised to promote stem cell differentiation. Moreover, 2D cultures undergo minimal ECM remodeling and are ill-equipped to stimulate pathways associated with development. PMID- 29765417 TI - Zinc Promotes Adipose-Derived Mesenchymal Stem Cell Proliferation and Differentiation towards a Neuronal Fate. AB - Zinc is an essential element required for cell division, migration, and proliferation. Under zinc-deficient conditions, proliferation and differentiation of neural progenitors are significantly impaired. Adipose-derived mesenchymal stem cells (AD-MSCs) are multipotent stem cells that can differentiate into neurons. The aim of this study was to evaluate the effect of zinc on AD-MSC proliferation and differentiation. We initially examined the effect of zinc on stem cell proliferation at the undifferentiated stage. AD-MSCs showed high proliferation rates on day 6 in 30 MUM and 100 MUM of ZnCl2. Zinc chelation inhibited AD-MSC proliferation via downregulation of ERK1/2 activity. We then assessed whether zinc was involved in cell migration and neurite outgrowth during differentiation. After three days of neuronal differentiation, TUJ-1-positive cells were observed, implying that AD-MSCs had differentiated into early neuron or neuron-like cells. Neurite outgrowth was increased in the zinc-treated group, while the CaEDTA-treated group showed diminished, shrunken neurites. Furthermore, we showed that zinc promoted neurite outgrowth via the inactivation of RhoA and led to the induction of neuronal gene expression (MAP2 and nestin) in differentiated stem cells. Taken together, zinc promoted AD-MSC proliferation and affected neuronal differentiation, mainly by increasing neurite outgrowth. PMID- 29765418 TI - Isolation and Characterisation of Mesenchymal Stem Cells from Rat Bone Marrow and the Endosteal Niche: A Comparative Study. AB - Within bone, mesenchymal stromal cells (MSCs) exist within the bone marrow stroma (BM-MSC) and the endosteal niche, as cells lining compact bone (CB-MSCs). This study isolated and characterised heterogeneous MSC populations from each niche and subsequently investigated the effects of extensive cell expansion, analysing population doublings (PDs)/cellular senescence, colony-forming efficiencies (CFEs), MSC cell marker expression, and osteogenic/adipogenic differentiation. CB MSCs and BM-MSCs demonstrated similar morphologies and PDs, reaching 100 PDs. Both populations exhibited consistent telomere lengths (12-17 kb), minimal senescence, and positive telomerase expression. CB-MSCs (PD15) had significantly lower CFEs than PD50. CB-MSCs and BM-MSCs both expressed MSC (CD73/CD90/CD105); embryonic (Nanog) and osteogenic markers (Runx2, osteocalcin) but no hematopoietic markers (CD45). CB-MSCs (PD15) strongly expressed Oct4 and p16INK4A. At early PDs, CB-MSCs possessed a strong osteogenic potency and low potency for adipogenesis, whilst BM-MSCs possessed greater overall bipotentiality for osteogenesis and adipogenesis. At PD50, CB-MSCs demonstrated reduced potency for both osteogenesis and adipogenesis, compared to BM-MSCs at equivalent PDs. This study demonstrates similarities in proliferative and mesenchymal cell characteristics between CB-MSCs and BM-MSCs, but contrasting multipotentiality. Such findings support further comparisons of human CB-MSCs and BM-MSCs, facilitating selection of optimal MSC populations for regenerative medicine purposes. PMID- 29765420 TI - A Feasible Method of Angiogenesis Assessment in Gastric Cancer Using 3D Microvessel Density. AB - Background: Cancer stem cell (CSC) promotes angiogenesis which plays an important role in tumor occurrence, growth, and metastasis. Accurately, quantifying the tumor vasculature can help understanding CSC characteristics and improve cancer diagnosis, therapy planning, and evaluation. The objective of this study is to present a method for improved angiogenesis assessment. Methods: We proposed a three-dimensional microvessel density (3D MVD) to evaluate tumor angiogenesis and tested it in animal models. Six male Balb/c nude mice were divided into normal group and tumor group. The mice in tumor group were orthotopically implanted human gastric cancer, cell line BGC-823. The phase-contrast images were collected at Shanghai Synchrotron Radiation Facility BL13W beamline, which has much higher soft-tissue contrast and spatial resolution than conventional X-ray. After volume reconstruction and vessel extraction, the 3D models of the angiogenesis were established for MVD calculation. Results: The results showed that the proposed 3D MVD is positively correlated with the pathological changes of the microvessels. It took the advantage of high resolution of the phase-contrast imaging and added three-dimensional information to the existing MVD measure. Conclusions: Our study presents a feasible approach for better understanding of tumor angiogenesis. It may provide doctors and scientists a better tool for cancer investigation and improving medical outcomes. PMID- 29765419 TI - Low Magnitude of Compression Enhances Biosynthesis of Mesenchymal Stem Cells towards Nucleus Pulposus Cells via the TRPV4-Dependent Pathway. AB - Mesenchymal stem cell- (MSC-) based therapy is regarded as a promising tissue engineering strategy to achieve nucleus pulposus (NP) regeneration for the treatment of intervertebral disc degeneration (IDD). However, it is still a challenge to promote the biosynthesis of MSC to meet the requirement of NP regeneration. The purpose of this study was to optimize the compressive magnitude to enhance the extracellular matrix (ECM) deposition towards discogenesis of MSCs. Thus, we constructed a 3D culture model for MSCs to bear different magnitudes of compression for 7 days (5%, 10%, and 20% at the frequency of 1.0 Hz for 8 hours/day) using an intelligent and mechanically active bioreactor. Then, the underlying mechanotransduction mechanism of transient receptor potential vanilloid 4 (TRPV4) was further explored. The MSC-encapsulated hybrids were evaluated by Live/Dead staining, biochemical content assay, real-time PCR, Western blot, histological, and immunohistochemical analysis. The results showed that low-magnitude compression promoted anabolic response where high-magnitude compression induced the catabolic response for the 3D-cultured MSCs. The anabolic effect of low-magnitude compression could be inhibited by inhibiting TRPV4. Meanwhile, the activation of TRPV4 enhanced the biosynthesis analogous to low magnitude compression. These findings demonstrate that low-magnitude compression promoted the anabolic response of ECM deposition towards discogenesis for the 3D cultured MSCs and the TRPV4 channel plays a key role on mechanical signal transduction for low-magnitude compressive loading. Further understanding of this mechanism may provide insights into the development of new therapies for MSC based NP regeneration. PMID- 29765416 TI - Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review. AB - Knee osteoarthritis (OA) is a chronic degenerative disorder which could be distinguished by erosion of articular cartilage, pain, stiffness, and crepitus. Not only aging-associated alterations but also the metabolic factors such as hyperglycemia, dyslipidemia, and obesity affect articular tissues and may initiate or exacerbate the OA. The poor self-healing ability of articular cartilage due to limited regeneration in chondrocytes further adversely affects the osteoarthritic microenvironment. Traditional and current surgical treatment procedures for OA are limited and incapable to reverse the damage of articular cartilage. To overcome these limitations, cell-based therapies are currently being employed to repair and regenerate the structure and function of articular tissues. These therapies not only depend upon source and type of stem cells but also on environmental conditions, growth factors, and chemical and mechanical stimuli. Recently, the pluripotent and various multipotent mesenchymal stem cells have been employed for OA therapy, due to their differentiation potential towards chondrogenic lineage. Additionally, the stem cells have also been supplemented with growth factors to achieve higher healing response in osteoarthritic cartilage. In this review, we summarized the current status of stem cell therapies in OA pathophysiology and also highlighted the potential areas of further research needed in regenerative medicine. PMID- 29765424 TI - Public Awareness on Cord Blood Banking in Saudi Arabia. AB - Background: In the last decade, cord blood (CB) has proven to be a valuable source of hematopoietic stem cells for transplantation to treat many hematological disorders. Since then, many CB banks have been established worldwide. Our aim was to estimate the level of public awareness of CB banking in Saudi Arabia. Study Design and Methods: A self-administered questionnaire of 22 multiple choices was conveniently distributed, consisting of demographics, awareness measure, attitude toward banking preference, and donation for research data. Results: A total of 1146 participants have completed the questionnaire. The majority were young female 19-25 years old (26%), who are college graduates (57%) with middle class socioeconomic status (82%). The subjective assessment of the overall knowledge was inadequate (66%). For the objective assessment, 12 questions were asked about CB source, collection, storage, and usage. Only half of the subjects (52%) knew that CB is a source of stem cells. More than half did not know the main use of CB. About half did not know about the method of collection nor the condition of storing. Conclusion: This study shows a high lack of knowledge about CB banking. More than half of the subjects were unaware of CB banking and its uses. However, most subjects are accepting CB storage, which anticipates great impact and efficacy on educational programs. Moreover, the data demonstrated that health professionals were not the source of knowledge. We recommend having comprehensive educational campaigns with clear information about CB banking to facilitate positive perspectives towards donation and scientific research. PMID- 29765423 TI - Comparison of Teratoma Formation between Embryonic Stem Cells and Parthenogenetic Embryonic Stem Cells by Molecular Imaging. AB - With their properties of self-renewal and differentiation, embryonic stem (ES) cells hold great promises for regenerative therapy. However, teratoma formation and ethical concerns of ES cells may restrict their potential clinical applications. Currently, parthenogenetic embryonic stem (pES) cells have attracted the interest of researchers for its self-renewing and pluripotent differentiation while eliciting less ethic concerns. In this study, we established a model with ES and pES cells both stably transfected with a double fusion reporter gene containing renilla luciferase (Rluc) and red fluorescent protein (RFP) to analyze the mechanisms of teratoma formation. Transgenic Vegfr2 luc mouse, which expresses firefly luciferase (Fluc) under the promoter of vascular endothelial growth factor receptor 2 (Vegfr2-luc), was used to trace the growth of new blood vessel recruited by transplanted cells. Bioluminescence imaging (BLI) of Rluc/Fluc provides an effective tool in estimating the growth and angiogenesis of teratoma in vivo. We found that the tumorigenesis and angiogenesis capacity of ES cells were higher than those of pES cells, in which VEGF/VEGFR2 signal pathway plays an important role. In conclusion, pES cells have the decreased potential of teratoma formation but meanwhile have similar differentiating capacity compared with ES cells. These data demonstrate that pES cells provide an alternative source for ES cells with the risk reduction of teratoma formation and without ethical controversy. PMID- 29765422 TI - The Effect of Pulsatile Flow on bMSC-Derived Endothelial-Like Cells in a Small Sized Artificial Vessel Made by 3-Dimensional Bioprinting. AB - Replacement of small-sized vessels is still challenging. This study is aimed at investigating the possibility of small-sized artificial vessels made by 3 dimensional bioprinting and the effect of pulsatile flow on bMSC-derived endothelial-like cells. Cells were harvested from rabbit bone marrow and primary cultured with or without growth factors. Endothelial differentiation was confirmed by the Matrigel tube formation assay, Western blot, and qRT-PCR. In addition, embedment of endothelial-like cells in an artificial vessel was made by 3-dimensional bioprinting, and the pulsatile flow was performed. For pumped and nonpumped groups, qRT-PCR was performed on CD31 and VE-cadherin gene expression. Endothelial-like cells showed increased gene expression of CD31 and VE-cadherin, and tube formation is observed at each week. Endothelial-like cells grow well in a small-sized artificial vessel made by 3-dimensional bioprinting and even express higher endothelial cell markers when they undergo pulsatile flow condition. Moreover, the pulsatile flow condition gives a positive effect for cell observation not only on the sodium alginate hydrogel layer but also on the luminal surface of the artificial vessel wall. We have developed an artificial vessel, which is a mixture of cells and carriers using a 3-dimensional bioprinting method, and applied pulsatile flow using a peristaltic pump, and we also demonstrated cell growth and differentiation into endothelial cells. This study suggests guidelines regarding a small-sized artificial vessel in the field of tissue engineering. PMID- 29765421 TI - Retention and Functional Effect of Adipose-Derived Stromal Cells Administered in Alginate Hydrogel in a Rat Model of Acute Myocardial Infarction. AB - Background: Cell therapy for heart disease has been proven safe and efficacious, despite poor cell retention in the injected area. Improving cell retention is hypothesized to increase the treatment effect. In the present study, human adipose-derived stromal cells (ASCs) were delivered in an in situ forming alginate hydrogel following acute myocardial infarction (AMI) in rats. Methods: ASCs were transduced with luciferase and tested for ASC phenotype. AMI was inducted in nude rats, with subsequent injection of saline (controls), 1 * 106 ASCs in saline or 1 * 106 ASCs in 1% (w/v) alginate hydrogel. ASCs were tracked by bioluminescence and functional measurements were assessed by magnetic resonance imaging (MRI) and 82rubidium positron emission tomography (PET). Results: ASCs in both saline and alginate hydrogel significantly increased the ejection fraction (7.2% and 7.8% at 14 days and 7.2% and 8.0% at 28 days, resp.). After 28 days, there was a tendency for decreased infarct area and increased perfusion, compared to controls. No significant differences were observed between ASCs in saline or alginate hydrogel, in terms of retention and functional salvage. Conclusion: ASCs improved the myocardial function after AMI, but administration in the alginate hydrogel did not further improve retention of the cells or myocardial function. PMID- 29765425 TI - Production of Adult Human Synovial Fluid-Derived Mesenchymal Stem Cells in Stirred-Suspension Culture. AB - The chondrogenic potential of synovial fluid-derived mesenchymal stem cells (SF MSCs) supports their use in cartilage regeneration strategies. However, their paucity in synovial fluid necessitates their proliferation in culture to generate clinically relevant quantities. Here it was determined that 125 mL stirred suspension bioreactors utilizing Cytodex-3 microcarrier beads represent a viable platform for the proliferation of these cells. During the inoculation phase, a bead loading of 2 g/L, an inoculation ratio of 4.5 cells/bead, and continuous agitation at 40 rpm in a medium with 5% serum resulted in high cell attachment efficiencies and a subsequent overall cell fold expansion of 5.7 over 8 days. During the subsequent growth phase, periodic addition of new microcarriers and fresh medium increased culture longevity, resulting in a 21.3 cell fold increase over 18 days in the same vessel without compromising the defining characteristics of the cells. Compared to static tissue culture flasks, a bioreactor-based bioprocess requires fewer handling steps, is more readily scalable, and for the same cell production level, has a lower operating cost as it uses approximately half the medium. Therefore, stirred suspension bioreactors incorporating microcarrier technology represent a viable and more efficient platform than tissue culture flasks for the generation of SF-MSCs in culture. PMID- 29765427 TI - Adipose-Derived Mesenchymal Stem Cells in the Use of Cartilage Tissue Engineering: The Need for a Rapid Isolation Procedure. AB - Mesenchymal stem cells (MSCs) have shown much promise with respect to their use in cartilage tissue engineering. MSCs can be obtained from many different tissue sources. Among these, adipose tissue can provide an abundant source of adipose derived mesenchymal stem cells (ADMSCs). The infrapatellar fat pad (IFP) is a promising source of ADMSCs with respect to producing a cartilage lineage. Cell isolation protocols to date are time-consuming and follow conservative approaches that rely on a long incubation period of 24-48 hours. The different types of ADMSC isolation techniques used for cartilage repair will be reviewed and compared with the view of developing a rapid one-step isolation protocol that can be applied in the context of a surgical procedure. PMID- 29765430 TI - Tobacco Dependence Treatment Grants: A Collaborative Approach to the Implementation of WHO Tobacco Control Initiatives. AB - The number of global tobacco-related deaths is projected to increase from about 6 million to 8 million annually by 2030, with more than 80% of these occurring in low- and middle-income countries (LMICs). The World Health Organization Framework Convention on Tobacco Control (FCTC) came into force in 2005 and Article 14 relates specifically to the treatment of tobacco dependence. However, LMICs, in particular, face several barriers to implementing tobacco dependence treatment. This paper is a descriptive evaluation of a novel grant funding mechanism that was initiated in 2014 to address these barriers. Global Bridges. Healthcare Alliance for Tobacco Dependence Treatment aims to create and mobilize a global network of healthcare professionals and organizations dedicated to advancing evidence-based tobacco dependence treatment and advocating for effective tobacco control policy. A 2014 request for proposals (RFP) focused on these goals, particularly in LMICs, where funding for this work had been previously unavailable. 19 grants were awarded by Global Bridges to organizations in low- and middle-income countries across all six WHO regions. Virtually all focused on developing a tobacco dependence treatment curriculum for healthcare providers, while also influencing the political environment for Article 14 implementation. As a direct result of these projects, close to 9,000 healthcare providers have been trained in tobacco dependence treatment and an estimated 150,000 patients have been offered treatment. Because most of these projects are designed with a "train-the-trainer" component, two years of grant funding has been a tremendous catalyst for accelerating change in tobacco dependence treatment practices throughout the world. In order to foster such exponential growth and continue to maintain the impact of these projects, ongoing financial, educational, and professional commitments are required. PMID- 29765428 TI - Autophagy in Stem Cell Biology: A Perspective on Stem Cell Self-Renewal and Differentiation. AB - Autophagy is a highly conserved cellular process that degrades modified, surplus, or harmful cytoplasmic components by sequestering them in autophagosomes which then fuses with the lysosome for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis, as well as for remodeling during normal development. Impairment of this process has been implicated in various diseases, in the pathogenic response to bacterial and viral infections, and in aging. Pluripotent stem cells, with their ability to self-replicate and to give rise to any specialized cell type, are very valuable resources for cell-based medical therapies and open a number of promising avenues for studying human development and disease. It has been suggested that autophagy is vital for the maintenance of cellular homeostasis in stem cells, and subsequently more in-depth knowledge about the regulation of autophagy in stem cell biology has been acquired recently. In this review, we describe the most significant advances in the understanding of autophagy regulation in hematopoietic and mesenchymal stem cells, as well as in induced pluripotent stem cells. In particular, we highlight the roles of various autophagy activities in the regulation of self-renewal and differentiation of these stem cells. PMID- 29765432 TI - Utility and safety of three-dimensional contrast low-dose dobutamine echocardiography in the evaluation of myocardial viability early after an acute myocardial infarction. AB - Introduction: The aim of the study was to determine the utility and safety of three-dimensional contrast low-dose dobutamine echocardiography (3DCLDDE) in the evaluation of myocardial viability early after ST-elevation myocardial infarction (STEMI). Material and methods: We prospectively evaluated a group of 100 consecutive patients. Myocardial viability was assessed using dobutamine echocardiography in 76 patients with segmental wall motion abnormalities, including 37 patients evaluated using 3DCLDDE and 39 patients evaluated using a standard low-dose dobutamine echocardiography protocol (LDDE), alternately. Results: Single ventricular ectopic beats were observed during the test in 1 (2.5%, 1, p = 1) patient in the 3DCLDDE group, while pain (1, p = 1) dyspnea (1, p = 1), single ventricular beats (2, p = 1), and complex ventricular arrhythmia (2, p = 0.49) were noted in 4 (10%) patients in the LDDE group. Five-year survival was 89% in the 3DCLDDE group and 87% in the LDDE group. Conclusions: 3DCLDDE and LDDE are equally safe and useful in patients after STEMI. PMID- 29765431 TI - Skin perfusion pressure for the prediction of wound healing in critical limb ischemia: a meta-analysis. AB - Introduction: The purpose of this meta-analysis was to determine the value and efficacy of skin perfusion pressure (SPP) for the prediction of wound healing in patients with critical limb ischemia. Material and methods: Medline, Cochrane, EMBASE, and Google Scholar databases were searched from inception until December 31, 2014 using combinations of the following keywords: skin perfusion pressure, limb ischemia, wound healing, prediction. Randomized controlled trials, 2-arm prospective studies, and retrospective studies that measured SPP in patients with limb ischemia were included. The outcome was the sensitivity and specificity of SPP for the prediction of wound healing. Results: Five studies were included in the meta-analysis. The mean patient age ranged from 62.2 to 71.5 years, and the majority were male. The pooled sensitivity of SPP for the prediction of wound healing was 79.9% using 30 mm Hg as the cut-off, 67.1% using 40 mm Hg, and 76.1% for all included studies (95% CI: 73.9-84.9%, 55.8-76.8%, and 70.7-80.8%, respectively). The pooled specificity was 78.2% using 30 mm Hg, 84.2% using 40 mm Hg, and 82.1% for all included studies (95% CI: 61.5-89.0%, 74.0-90.9%, 73.7 88.3%, respectively). Conclusions: Skin perfusion pressure can accurately predict wound healing in patients with critical limb ischemia. PMID- 29765429 TI - The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant. AB - Preponderance of proinflammatory signals is a characteristic feature of all acute and resulting long-term morbidities of the preterm infant. The proinflammatory actions are best characterized for bronchopulmonary dysplasia (BPD) which is the chronic lung disease of the preterm infant with lifelong restrictions of pulmonary function and severe consequences for psychomotor development and quality of life. Besides BPD, the immature brain, eye, and gut are also exposed to inflammatory injuries provoked by infection, mechanical ventilation, and oxygen toxicity. Despite the tremendous progress in the understanding of disease pathologies, therapeutic interventions with proven efficiency remain restricted to a few drug therapies with restricted therapeutic benefit, partially considerable side effects, and missing option of applicability to the inflamed brain. The therapeutic potential of mesenchymal stromal cells (MSCs)-also known as mesenchymal stem cells-has attracted much attention during the recent years due to their anti-inflammatory activities and their secretion of growth and development-promoting factors. Based on a molecular understanding, this review summarizes the positive actions of exogenous umbilical cord-derived MSCs on the immature lung and brain and the therapeutic potential of reprogramming resident MSCs. The pathomechanistic understanding of MSC actions from the animal model is complemented by the promising results from the first phase I clinical trials testing allogenic MSC transplantation from umbilical cord blood. Despite all the enthusiasm towards this new therapeutic option, the caveats and outstanding issues have to be critically evaluated before a broad introduction of MSC-based therapies. PMID- 29765433 TI - Left ventricular structural and functional changes evaluated by echocardiography and two-dimensional strain in patients with sickle cell disease. AB - Introduction: Patients with sickle cell disease have increased left ventricular size, which is not usually accompanied by changes in systolic function indexes. We assessed echocardiographic abnormalities present in patients with sickle cell anemia (SCA) and compared echocardiographic parameters to other sickle cell diseases (OSCD). Material and methods: A blind cross-sectional study with 60 patients with SCA and 16 patients with OSCD who underwent transthoracic echocardiography was performed. Results: Echocardiographic findings were: left atrial volume index 47.7 +/-11.5 ml/m2 in SCA group and 31.7 +/-8.42 ml/m2 in OSCD group (p < 0.001); left ventricular diastolic diameter index 3.47 +/-0.37 cm/m2 in SCA group and 2.97 +/-0.41 cm/m2 in OSCD group (p < 0.001); left ventricular systolic diameter index 2.12 +/-0.31 cm/m2 in SCA group and 1.86 +/ 0.28 cm/m2 in OSCD group (p < 0.001). There were no differences in the left ventricular ejection fraction: 68.2 +/-6.69% in SCA group and 67.1 +/-6.21% in OSCD group (p = 0.527). The ratio between mitral E wave and mean mitral annulus e' wave velocities was higher in the SCA group (7.72 +/-1.54 vs. 6.70 +/-1.65; p = 0.047). Mitral A wave correlated significantly with hemoglobin levels (r = 0.340; p = 0.032). Conclusions: There was an increase of left ventricular and left atrial sizes in patients with SCA, compared to patients with OSCD, without changes in systolic or diastolic function in both groups. This could be due to the hyperkinetic state due to the more severe anemia in the SCA subjects. PMID- 29765426 TI - Current Therapeutic Strategies for Stem Cell-Based Cartilage Regeneration. AB - The process of cartilage destruction in the diarthrodial joint is progressive and irreversible. This destruction is extremely difficult to manage and frustrates researchers, clinicians, and patients. Patients often take medication to control their pain. Surgery is usually performed when pain becomes uncontrollable or joint function completely fails. There is an unmet clinical need for a regenerative strategy to treat cartilage defect without surgery due to the lack of a suitable regenerative strategy. Clinicians and scientists have tried to address this using stem cells, which have a regenerative potential in various tissues. Cartilage may be an ideal target for stem cell treatment because it has a notoriously poor regenerative potential. In this review, we describe past, present, and future strategies to regenerate cartilage in patients. Specifically, this review compares a surgical regenerative technique (microfracture) and cell therapy, cell therapy with and without a scaffold, and therapy with nonaggregated and aggregated cells. We also review the chondrogenic potential of cells according to their origin, including autologous chondrocytes, mesenchymal stem cells, and induced pluripotent stem cells. PMID- 29765435 TI - Mortality of adult intensive care units in Turkey using the APACHE II and SOFA systems (outcome assessment in Turkish intensive care units). AB - Introduction: The aim of this study was to evaluate intensive care unit (ICU) performance using risk-adjusted ICU mortality rates nationally, assessing patients who died or had been discharged from the ICU. For this purpose, this study analyzed the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) databases, containing detailed clinical and physiological information and mortality of mixed critically ill patients in a medical ICU at secondary and tertiary referral ICUs in Turkey. Material and methods: A total of 690 adult intensive care units in Turkey were included in the study. Among 690 ICUs evaluated, 39.7% were secondary and 60.3% were tertiary ICUs. A total of 4188 patients were enrolled in this study. Intensive care units of ministry, university, and private hospitals were evaluated all over Turkey. During the study period, clinical data that were collected concurrently for each patient contained demographic details and the diagnostic category leading to ICU admission. APACHE II and SOFA scores following ICU admission were calculated and recorded. Patients were followed up for outcome data until death or ICU discharge. Results: The mean age of patients was 68.8 +/ 19 and 54% of them were male. The mean APACHE II score was 20 +/-8.7. The ICUs' mortality rate was 46.3%, and mean predicted mortality was 37.2% for APACHE II. The standardized mortality ratio was 1.28 (95% confidence interval: 1.21-1.31). Conclusions: There was a wide difference in outcome for patients admitted to different ICUs and severity of illness using risk adjustment methods. The high mortality rate in patients could be related to comorbid diseases, high mechanical ventilation rates and older ages. PMID- 29765436 TI - Anti-thyroid antibodies, parietal cell antibodies and tissue transglutaminase antibodies in patients with autoimmune thyroid disease. AB - Introduction: The co-existence of tissue-specific autoantibodies in autoimmune thyroid disease (ATD) is well established. The published prevalence of anti parietal cell antibodies (PC-Ab) is 20-25%, and that of celiac antibodies is 2 5%. The goal of this study was to determine the prevalence of PC-Ab and anti tissue transglutaminase antibodies (tTG-Ab) in patients with ATD and to evaluate the correlation between anti-thyroid antibodies and the other antibodies. Material and methods: The files of 120 Israeli Jews and Arabs with ATD were evaluated for anti-thyroglobulin antibodies (Tg-Ab), anti-thyroid peroxidase antibodies (TPO-Ab), PC-Ab and tTG-Ab. For patients with positive PC-Ab and/or tTG-Ab, upper gastrointestinal (GI) endoscopy results were recorded. Gastrin levels were collected in patients with positive PC-Ab. Results: Twelve (10%) males and 108 (90%) females were evaluated, of whom 93.33% had Hashimoto's thyroiditis. Thirty-four (28.3%) subjects had positive PC-Ab. This rate was not affected by gender, ethnicity or thyroid disease. Abnormal gastroscopy findings were documented in 95.2% of the upper GI endoscopies. The mean gastrin level in this subgroup was 660.4 pg/ml. Five of 114 tTG-Ab tests were positive (4.4%). All were females with Hashimoto's thyroiditis. Rates were equal among Jews and Arabs. Higher TPO-Ab levels were associated with higher risk for PC-Ab positivity (p = 0.027), but not tTG-positivity. Higher Tg-Ab levels were not associated with higher levels of other antibodies. Conclusions: Considering the frequency of PC Ab and tTG-Ab positivity in ATD, checking for the presence of these two entities should be an integral part of the workup of this disease. PMID- 29765434 TI - Risk factors and prognostic role of an electrical storm in patients after myocardial infarction with an implanted ICD for secondary prevention. AB - Introduction: The aim of our study was to determine the risk factors for electrical storm (ES) and to assess the impact of ES on the long-term prognosis in patients after myocardial infarction (MI) with an implantable cardioverter defibrillator (ICD) for secondary prevention of sudden cardiac death (SCD). Material and methods: We retrospectively analyzed 416 patients with coronary artery disease after MI who had an implanted ICD for secondary prevention of SCD. Fifty (12%) patients had one or more incidents of an electrical storm - the ES (+) group. We matched the reference group of 47 patients from 366 ES (-) patients. Results: We analyzed 3,408 episodes of ventricular arrhythmias: 3,148 ventricular tachyarrhythmic episodes in the ES (+) group (including 187 episodes of ES) and 260 in the ES (-) group. Multivariate logistic regression showed that inferior wall MI (RR = 3.98, 95% CI: 1.52-10.41) and the absence of coronary revascularization (RR = 2.92, 95% CI: 1.18-7.21) were independent predictors of ES (p = 0.0014). During 6-year observation of 97 patients, there were 39 (40%) deaths: 25 (50%) subjects in the ES (+) group and 14 (30%) in the ES (-) group (p = 0.036). Independent predictors of death were: the occurrence of ES (HR = 1.93), older age (HR = 1.06), and lower left ventricular ejection fraction (HR = 0.95) (for all p < 0.001). Conclusions: Electrical storm in patients after MI with ICD for secondary prevention is a relatively common phenomenon and has a negative prognostic significance. Myocardial infarction of the inferior wall and the absence of coronary revascularization are predisposing factors for the occurrence of an ES. PMID- 29765438 TI - Decline in ovarian reserve may be an undiagnosed reason for unexplained infertility: a cohort study. AB - Introduction: Unexplained infertility refers to the absence of a definable cause for a couple's failure to achieve pregnancy. Reproductive aging plays a role in pathogenesis of unexplained infertility. We investigated the results of ovarian reserve tests in unexplained infertility. Material and methods: The patients were divided into two groups: unexplained infertility (n = 148) and male factor infertility (n = 112). Follicle-stimulating hormone, estradiol, inhibin b levels and anti-Mullerian hormone levels were evaluated. Antral follicle count and ovarian volume measurements were performed. Results: The demographic variables were comparable. Follicle-stimulating hormone levels were higher in the unexplained infertility group than the male factor infertility group, although this difference did not reach statistical significance (p = 0.071). Estradiol levels, inhibin b concentrations and ovarian volume showed no difference between groups. However, antral follicle count was significantly lower in the unexplained infertility group than the male factor infertility group (p = 0.023). The median anti-Mullerian hormone concentrations were significantly lower in the unexplained infertility group 1.42 (0.4-6.2) than in the male factor infertility group (2.04 (0.64-8.2); p = 0.001). Conclusions: Although anti-Mullerian hormone values and antral follicle count were higher than the low thresholds, a statistically significant decline of ovarian reserve in the unexplained infertility group was found in the present study. This might be an undiagnosed reason for unexplained infertility. PMID- 29765437 TI - Evaluation of ovarian reserve in women with overt or subclinical hypothyroidism. AB - Introduction: Thyroid dysfunction is among the most common autoimmune disorders in women of reproductive age. Previous studies have shown the association between autoimmune thyroid disease (AITD) and infertility. Anti-Mullerian hormone (AMH) is secreted by granulosa cells and is a useful marker for assessment of ovarian reserve. In the present study, we sought to evaluate the ovarian reserves of women with autoimmune thyroid disorder by measurement of AMH values. Material and methods: This prospective study included women with newly diagnosed AITD aged between 20 and 40 years. Patients were divided into three groups: subclinical hypothyroidism (SCH, n = 21), overt hypothyroidism (OH, n = 21) and controls (CG, n = 32). Study parameters included serum free T4, free T3, thyroid-stimulating hormone, anti-thyroglobulin, anti-thyroid peroxidase antibodies, follicle stimulating hormone, luteinizing hormone, estradiol and AMH concentrations measured in the early follicular phase. Antral follicle count (AFC) was assessed with ultrasound. Body mass index (BMI) and waist circumference of the patients were noted. Results: No significant difference was found among SCH, OH and CG in regard to ovarian reserves measured by AMH values (p = 0.19) and AFC (p = 0.80). A significant negative correlation was found between AMH and BMI (r = -0.382, p = 0.001). Anti-Mullerian hormone and waist circumference (r = -0.330, p = 0.004) were also negatively correlated. Conclusions: Although AMH values were not significantly different among groups, AMH values were lower in OH and SCH patients, indicating a possible need for close monitoring of these patients. PMID- 29765439 TI - Radiographic features of anatomic relationship between impacted third molar and inferior alveolar canal on coronal CBCT images: risk factors for nerve injury after tooth extraction. AB - Introduction: The present study was aimed to identify the radiographic signs between impacted third molar root and inferior alveolar canal (IAC) on cone-beam CT (CBCT) images as risk factors and prognostic predictors associated with inferior alveolar nerve (IAN) damage following tooth removal. Material and methods: A retrospective clinical study was performed involving 136 patients with 257 impacted lower third molars from January 2013 to December 2014. The neurosensory function of the lower lip and chin was subjectively evaluated and assessed by neurosensory tests before and after surgery. The preoperative CBCT data were retrieved and analyzed to identify the radiographic signs associated with postoperative IAN injury. Results: The overall incidence of IAN injury in our patient cohort was 13.2%. Multiple radiographic features on coronal CBCT images including contact between IAC and root, IAC position relative to root, IAC shape and cortication status were found to be significantly associated with IAN damage (p < 0.05, chi2 test). Furthermore, buccolingual position, teardrop/dumbbell shape and cortication status of IAC were identified as independent prognostic predictors for IAN damage. Conclusions: Our findings indicate that radiographic signs including direct contact between IAC and root, buccal/lingual IAC position relative to root, teardrop/dumbbell shape and cortication absence of the IAC on presurgical CBCT images are associated with high risk of IAN injury and postoperative neurosensory disturbance. PMID- 29765441 TI - Suspected unexpected and other adverse reactions to antiretroviral drugs used as post-exposure prophylaxis of HIV infection - five-year experience from clinical practice. AB - Introduction: With increased use of antiretroviral drugs (ARVs) in HIV uninfected persons, proper reporting on suspected unexpected serious adverse reactions (SUSARs) and continued insight into adverse drug reactions (ADRs) are needed for adequate information on safety of ARVs in such populations. Material and methods: Medical documentation of persons receiving ARVs after non-occupational HIV exposure (non-occupational post-exposure prophylaxis - nPEP) during 5 successive years (2009-2013) was evaluated by two HIV physicians. Adverse drug reactions s and SUSARs were defined according to international standards. In statistical analyses Cox proportional hazard models were used to identify independent predictors of developing a first ADR. Results: In total 375 persons received nPEP with the following indications: needle stick (43%), unprotected sexual intercourse (17%), rape (10%) and first aid (10%). In 84 (22%) cases the source patient was HIV positive or an active injecting drug user. In total 170 ADRs were reported. One hundred thirty-nine persons had only 1 ADR. The most frequent first ADRs were gastrointestinal disorders (22%), followed by general symptoms (9%), hypersensitivity reactions (1.6%) and CNS symptoms (1.3%). The remaining events represented less than 1% of all patients. Eight (2.1%) patients developed a SUSAR. In multivariate analyses only age at first visit to the clinic was an independent predictor of developing an ADR (HR = 1.17, 95% CI: 1.03-1.34; p = 0.02). Conclusions: In our observations ADRs in reaction to nPEP were frequent yet usually mild events, mostly occurring in the first 2 weeks and rarely causing discontinuation. The only significant factor increasing the risk of ADR was age. SUSARs were rare, transient and clinically insignificant. PMID- 29765440 TI - Prevalence of bacteria and fungi in samples of cornea preservation fluid. AB - Introduction: Recipients of corneal transplants are at risk of healthcare associated infections, which, apart from other causes of surgical site infections, may also occur as a result of the transfer of infected corneal tissue. In this study we assessed the risk of bacterial and fungal infections based on the results of routine microbiological testing of cornea preservation fluid samples. Material and methods: We examined a total of 725 samples of corneal preservation fluid, obtained during a period of 3 years (2011-2013). Corneal preservation fluid samples were cultured and identified in accordance with standard microbiological methods. Results: The analysis comprised 725 samples of corneal preservation fluid, of which 32 (4.4%) samples tested positively in microbiological cultures. In total, 34 strains of bacteria and fungi were cultured. Gram-positive bacteria, Gram-negative bacteria and fungi comprised 85.3%, 8.8% and 5.9% of these strains, respectively. Analysis of the susceptibility of the cultured bacterial isolates to gentamicin was also performed, as this antibiotic is present in the composition of corneal preservation fluid. Among the cultured bacterial strains, 10 (33.3%) were resistant to gentamicin. None of the 32 patients who received a cornea stored in preservation fluid contaminated with bacteria and/or fungi demonstrated infectious complications in the surgical site within 1 year following cornea transplantation. Conclusions: We postulate that perioperative antibiotic prophylaxis in cornea transplant recipients is important in preventing bacterial infections derived from the donor cornea. We believe that the addition of an antifungal agent to commercially available cornea preservation fluids should also be considered. PMID- 29765442 TI - Hepatitis C coinfection adversely affects the life expectancy of people living with HIV in northwestern Poland. AB - Introduction: Hepatitis C (HCV) infection adversely affects survival among people living with HIV, increasing mortality risk due to liver-related causes. In Poland HCV is found among ~30% of HIV infected individuals, with only a small percentage successfully treated for this coinfection. This study aimed to analyze the HCV associated influence on the life expectancy among HIV/HCV coinfected patients from northwestern Poland. Material and methods: Longitudinal data of 701 (368 HIV monoinfected and 368 HIV/HCV coinfected) patients were investigated to assess the life expectancy and survival after HIV diagnosis. Kaplan-Meier and Cox analyses were used to assess the mortality risk in both unadjusted and multivariate models. Effect plots indicate the adjusted hazard ratio for HCV-associated survival. Results: Overall mortality was significantly higher among HCV coinfected (22.52%) compared to HIV monoinfected (10.32%) cases (p < 0.001, OR = 2.52 (95% CI: 1.65-3.85)), with shorter life expectancy among HIV/HCV infected patients (median: 55.4 (IQR: 42.8-59.1) years) compared to HIV monoinfection (median 72.7 (IQR: 60.4-76.8) years, univariate HR = 4.15 (95% CI: 2.7-6.38), p < 0.0001, adjusted HR = 2.32 (95% CI: 1.47-3.65), p < 0.0001). After HIV diagnosis, HCV adversely influenced the survival after 15 years of follow-up, with a strengthened impact in the subsequent 5 years (univariate HR = 1.57 (95% CI: 1.05 2.34) p = 0.026 for the 20-year survival time point, adjusted HR = 2.21 (95% CI: 1.18-4.13), p = 0.013). Conclusions: Among patients living with HIV, HCV coinfection is associated with a median life expectancy decrease of 17.3 years and low probability of surviving until the age of 65 years. In the era of directly acting anti-HCV drugs, treatment scale-up and immediacy of treatment are advisable in this cohort. PMID- 29765444 TI - Sequentiality of treatment in the rheumatoid arthritis drug programme in the years 2009-2014. AB - Approximately 1% of the population suffers from rheumatoid arthritis (RA) worldwide (0.45% in Poland). The therapy consists of the use of disease-modifying antirheumatic drugs (DMARDs). Biologics are used in the form of the drug programme. Analysis of the NHF database demonstrated the sequence of conversion between drugs and time spent in a single treatment. In 2009, the patients would start the following treatments: adalimumab 5.8%; etanercept 14.4%; infliximab 23.1%; leflunomide 53.6%; rituximab 3%. After the first year 16% of patients changed therapy or abstained, and in the second year this situation affected 65% of patients. The following percentages maintained the same treatment in the last 6 years: infliximab 4%; adalimumab 15%; etanercept 21%; leflunomide on prescription was continued by 70%. Patients remain too long on the same therapy when it is inefficient. Achieving remission or low disease activity (DAS28 < 2.6) should take place within 6 months of starting therapy. PMID- 29765445 TI - Augmented reality in neurosurgery. AB - Neurosurgery is a medical specialty that relies heavily on imaging. The use of computed tomography and magnetic resonance images during preoperative planning and intraoperative surgical navigation is vital to the success of the surgery and positive patient outcome. Augmented reality application in neurosurgery has the potential to revolutionize and change the way neurosurgeons plan and perform surgical procedures in the future. Augmented reality technology is currently commercially available for neurosurgery for simulation and training. However, the use of augmented reality in the clinical setting is still in its infancy. Researchers are now testing augmented reality system prototypes to determine and address the barriers and limitations of the technology before it can be widely accepted and used in the clinical setting. PMID- 29765443 TI - Management of cardiac hemochromatosis. AB - Iron-overload syndromes may be hereditary or acquired. Patients may be asymptomatic early in the disease. Once heart failure develops, there is rapid deterioration. Cardiac hemochromatosis is characterized by a dilated cardiomyopathy with dilated ventricles, reduced ejection fraction, and reduced fractional shortening. Deposition of iron may occur in the entire cardiac conduction system, especially the atrioventricular node. Cardiac hemochromatosis should be considered in any patient with unexplained heart failure. Screening for systemic iron overload with serum ferritin and transferin saturation should be performed. If these tests are consistent with iron overload, further noninvasive and histologic confirmation is indicated to confirm organ involvement with iron overload. Cardiac magnetic resonance imaging is superior to other diagnostic tests since it can quantitatively assess myocardial iron load. Therapeutic phlebotomy is the therapy of choice in nonanemic patients with cardiac hemochromatosis. Therapeutic phlebotomy should be started in men with serum ferritin levels of 300 MUg/l or more and in women with serum ferritin levels of 200 MUg/l or more. Therapeutic phlebotomy consists of removing 1 unit of blood (450 to 500 ml) weekly until the serum ferritin level is 10 to 20 MUg/l and maintenance of the serum ferritin level at 50 MUg/l or lower thereafter by periodic removal of blood. Phlebotomy is not a treatment option in patients with anemia (secondary iron-overload disorders) nor in patients with severe congestive heart failure. In these patients, the treatment of choice is iron chelation therapy. PMID- 29765446 TI - Inhibitory effect of PDGF-BB and serum-stimulated responses in vascular smooth muscle cell proliferation by hinokitiol via up-regulation of p21 and p53. AB - Introduction: Vascular smooth muscle cell (VSMC) proliferation plays a major role in the progression of vascular diseases. In the present study, we established the efficacy and the mechanisms of action of hinokitiol, a tropolone derivative found in Chamaecyparis taiwanensis, Cupressaceae, in relation to platelet-derived growth factor-BB (PDGF-BB) and serum-dependent VSMC proliferation. Material and methods: Primary cultured rat VSMCs were pre-treated with hinokitiol and then stimulated by PDGF-BB (10 ng/ml) or serum (10% fetal bovine serum). Cell proliferation and cytotoxicity were determined using the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide assay and lactose dehydrogenase assay, respectively. The degree of DNA synthesis was evaluated by BrdU-incorporation measurements and observed using confocal microscopy. Immunoblotting was utilized to determine the protein level of p-extracellular signal-regulated kinase (ERK) 1/2, p-Akt, p-phosphoinositide 3-kinase (PI3K), p-Janus kinase 2 (JAK2), p-p53, and p21Cip1. The promoter activity of p21 and p53 activity were measured by dual luciferase reporter assay. Results: Treatment with hinokitiol (1-10 MUM) inhibited PDGF-BB and serum-induced VSMC proliferation and DNA synthesis in a concentration-dependent manner. Cytotoxicity was not observed in hinokitiol treated VSMCs at the studied concentrations. Pre-incubation of VSMCs with hinokitiol did not alter PDGF-BB-induced phosphorylation of ERK1/2, Akt, PI3K or JAK2. Interestingly, hinokitiol induced promoter activity of p21 and p21 protein expression in VSMCs. Furthermore, hinokitiol augmented p53 protein phosphorylation and subsequently led to enhanced p53 activity. Conclusions: These data suggest that the anti-proliferative effects of hinokitiol in VSMCs may be mediated by activation of p21 and p53 signaling pathways, and it may contribute to the prevention of vascular diseases associated with VSMC proliferation. PMID- 29765447 TI - MicroRNA-141 inhibits proliferation of gastric cardia adenocarcinoma by targeting MACC1. AB - Introduction: Abnormal expression of microRNAs (miRNAs) contributes to cancer development through regulating proliferation, apoptosis and drug resistance in cancer cells. The present study was designed to explore the effect and mechanism of miR-141 on gastric cardia adenocarcinoma (GCA). Material and methods: Forty one paired GCA tissues and adjacent normal tissues were obtained from GCA patients never treated by chemotherapy or radiotherapy. QRT-PCR was used to detect the expression level of miR-141 in GCA. Effects of miR-141 on cell proliferation and apoptosis were detected in vitro. Western blot analysis was used to determine the downstream targets of miR-141. Results: In the present study, our data showed that miR-141 was significantly decreased and correlated with advanced TNM stage and lymph node metastases in GCA. In addition, we found that miR-141 could inhibit cell proliferation and induce cell apoptosis in AGS cells. Moreover, MACC1 was predicted as a possible target of miR-141. The luciferase reporter assay proved that miR-141 could suppress MACC1 directly by binding to its 3'-UTR. Further studies showed that miR-141 influenced the MEK/ERK and p38 MAPK signaling pathways. Conclusions: Our findings demonstrated that miR 141 expression was associated with GCA progression. MACC1, working as one possible target of miR-141, may contribute to the process. MiR-141 is expected to be a potential therapeutic target for the treatment of GCA patients. PMID- 29765448 TI - Overexpressed HO-1 is associated with reduced STAT3 activation in preeclampsia placenta and inhibits STAT3 phosphorylation in placental JEG-3 cells under hypoxia. AB - Introduction: Inadequate trophoblast invasion and placentation are widely believed to contribute to preeclampsia, and multiple lines of evidence indicate the involvement of hypoxia in preeclampsia. However, the molecular mechanisms underlying the association of placental hypoxia with preeclampsia are not clear. Material and methods: The present study focused on the role in preeclampsia of heme oxygenase 1 (HO-1), which is an inducible isoform of HO in response to hypoxia, via examining the expression of HO-1 and the expression and phosphorylation (Tyr705) of Signal transducer and activator of transcription (STAT) 3 in preeclamptic placentas via the immunohistochemical method, western blotting assay and RT-qPCR method. Then we investigated the regulation by HO-1 of the expression and phosphorylation of STAT3 in human placental choriocarcinoma JEG-3 cells under hypoxia. Results: There was upregulation of HO-1 at both mRNA (1.506 +/-0.08347 (N = 37) vs. 1.000 +/-0.08854 (N = 31), p < 0.0001) and protein (0.630 +/-0.155 (N = 35) vs. 0.310 +/-0.052, 0.630 +/-0.155 (N = 35), p < 0.001) levels and a reduced level of STAT3 phosphorylation (Tyr 705) in the preeclamptic placental tissues, compared to normal placental tissues (0.143 +/-0.027 (N = 35) vs. 0.194 +/-0.028 (N = 35), p < 0.01). Also, in vitro experiments demonstrated that HO-1 was markedly promoted by hypoxia in human placental choriocarcinoma JEG 3 cells, 6 or 12 h post treatment (p < 0.05 or p < 0.01). However, the STAT3 phosphorylation (Tyr 705) was attenuated by sustained hypoxia (p < 0.01). Moreover, it was demonstrated that HO-1 overexpression significantly inhibited the hypoxia-promoted STAT3 phosphorylation (Tyr 705). Conclusions: HO-1 was overexpressed in PE placenta, in association with reduced STAT3 phosphorylation (Tyr 705). HO-1 inhibits the STAT3 phosphorylation in placental JEG-3 cells under hypoxia. Thus, we speculate that overexpressed HO-1 might contribute to the reduced STAT3 phosphorylation (Tyr 705) and the pathogenesis of preeclampsia. PMID- 29765449 TI - Effects of single and combined low frequency electromagnetic fields and simulated microgravity on gene expression of human mesenchymal stem cells during chondrogenesis. AB - Introduction: Low frequency electromagnetic fields (LF-EMF) and simulated microgravity (SMG) have been observed to affect chondrogenesis. A controlled bioreactor system was developed to apply LF-EMF and SMG singly or combined during chondrogenic differentiation of human mesenchymal stem cells (hMSCs) in 3D culture. Material and methods: An external motor gear SMG bioreactor was combined with magnetic Helmholtz coils for EMF (5 mT; 15 Hz). Pellets of hMSCs (+/-TGF beta3) were cultured (P5) under SMG, LF-EMF, LF-EMF/SMG and control (1 g) conditions for 3 weeks. Sections were stained with safranin-O and collagen type II. Gene expression was evaluated by microarray and real-time polymerase chain reaction analysis. Results: Simulated microgravity application significantly changed gene expression; specifically, COLXA1 but also COL2A1, which represents the chondrogenic potential, were reduced (p < 0.05). Low frequency electromagnetic fields application showed no gene expression changes on a microarray basis. LF-EMF/SMG application obtained significant different expression values from cultures obtained under SMG conditions with a re-increase of COL2A1, therefore rescuing the chondrogenic potential, which had been lowered by SMG. Conclusions: Simulated microgravity lowered hypertrophy but also the chondrogenic potential of hMSCs. Combined LF-EMF/SMG provided a rescue effect of the chondrogenic potential of hMSCs although no LF-EMF effect was observed under optimal conditions. The study provides new insights into how LF-EMF and SMG affect chondrogenesis of hMSCs and how they generate interdependent effects. PMID- 29765450 TI - Lutein prevents osteoarthritis through Nrf2 activation and downregulation of inflammation. AB - Introduction: Osteoarthritis is an inflammatory disorder associated with oxidative stress and apoptosis leading to cartilage destruction and impairment of cartilage formation. In the present study, we studied the protective effect of lutein against monosodium iodoacetate (MIA)-induced osteoarthritis in primary chondrocyte cells. Material and methods: Oxidative stress was determined through testing antioxidant status, reactive oxygen species levels and lipid peroxide content. Also, Nrf2 expression and its downstream target genes HO-1 and NQO-1 were determined. Inflammation was analyzed through NF-kappaB, COX-2 and pro inflammatory cytokines (IL-6, TNF-alpha, IL-1beta). In addition, the effects of MIA and lutein on mitochondrial membrane potential and caspase-3 levels were analyzed. Results: The results showed that lutein treatment significantly increased the cell viability of chondrocytes and offered significant cytoprotection by enhancing the antioxidant defense mechanisms and reducing oxidative stress (reactive oxygen species and lipid peroxidation). Lutein treatment showed anti-inflammatory effects by downregulating inflammatory proteins (NF-kappaB, COX-2) and pro-inflammatory cytokines (IL-6, TNF-alpha, IL 1beta). Lutein reduced MIA-induced apoptosis through maintaining mitochondrial membrane potential and downregulating caspase-3 activity. Conclusions: The present study shows significant cytoprotection offered by lutein against MIA induced oxidative stress, inflammation and apoptosis by the modulatory effect of NF-kappaB and Nrf2 activation. PMID- 29765451 TI - Sequencing of exons 4, 5, 12 of COCH gene in patients with postlingual sensorineural hearing loss accompanied by vestibular lesion. AB - Introduction: Mutations at the DFNA9 locus on chromosome 14q12 are the third most common form of DFNA hearing loss, which is clinically characterized by late onset (in adulthood) progressive sensorineural hearing loss accompanied by vestibular dysfunction. The aim of the study was to search for COCH gene mutations (P51S, V66G, G87W, G88E, V104del, I109N, W117R, A119T, M512T, C542Y) in patients with severe or profound sensorineural hearing loss accompanied by a vestibular lesion. Material and methods: The study was based on a group of 30 patients. Qualification criteria comprised the presence of progressive postlingual, severe to profound sensorineural hearing loss with tinnitus, early age of sensorineural hearing loss onset, before the 40th year of life, and a positive family history of early onset hearing loss. All patients were diagnosed with peripheral vestibular lesions. Results: The authors did not find P51S, V66G, G87W, G88E, V104del, I109N, W117R, A119T, M512T, or C542Y mutations in the COCH gene in the tested group (no differences were found in the nucleotide sequences of exomes 4, 5 and 12 when compared to the published cDNA sequence of the COCH gene). Conclusions: No cochlin mutations were found in the group of patients with severe to profound sensorineural hearing impairment accompanied by a vestibular lesion. The COCH gene needs further exploration and analysis of genotype-phenotype correlations. PMID- 29765452 TI - Effects and potential mechanism of atorvastatin treatment on Lp-PLA2 in rats with dyslipidemia. AB - Introduction: The effects of statins on lipoprotein-associated phospholipase A2 (Lp-PLA2) are controversial, and the present study aimed to investigate whether atorvastatin could reduce Lp-PLA2 in rats with dyslipidemia. Material and methods: A high-fat and high-cholesterol diet was prescribed to produce a dyslipidemia model. Thereafter, low-dose atorvastatin (5 mg/kg/day), high-dose atorvastatin (20 mg/kg/day) or saline (without-treatment group) was prescribed for 14 days. At 6 weeks after dyslipidemia model establishment and 14 days of atorvastatin treatment, fasting venous blood was drawn for biochemical analysis. Between-group differences and Pearson correlation analysis were conducted. Results: Compared to the normal-control group, fasting plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were significantly increased in dyslipidemia groups, while plasma nitric oxide (NO) levels were significantly decreased with attendant elevation of plasma C-reactive protein (CRP) and rho-associated kinase 1 (ROCK1) levels (p < 0.05). At 14 days of atorvastatin treatment, compared to the without-treatment group, plasma levels of TC and LDL-C in the high-dose group were significantly reduced (p < 0.05); and compared to low-dose and without-treatment groups, NO up-regulation (1.8 +/-1.1 MUmol/l), and CRP (-0.8 +/-0.4 ng/ml), ROCK1 (-124 +/-65 mmol/l) and Lp-PLA2 ( 3.8 +/-1.2 ng/ml) reduction were more significant in the high-dose group (p < 0.05). Pearson correlation analysis showed that TC (r = 0.365), LDL-C (r = 0.472), CRP (r = 0.501) and ROCK1 (r = 0.675) were positively correlated with Lp PLA2, while NO (r = -0.378) and atorvastatin (r = -0.511) were negatively correlated with Lp-PLA2. Conclusions: Atorvastatin treatment is beneficial for reducing the Lp-PLA2 level in rats with dyslipidemia, which may be related to reduced ROCK1 expression in a dose-dependent manner. PMID- 29765453 TI - Therapeutic inhibition of CXC chemokine receptor 2 by SB225002 attenuates LPS induced acute lung injury in mice. AB - Introduction: Sustained neutrophilic infiltration is known to contribute to organ damage, such as acute lung injury (ALI). CXC chemokine receptor 2 (CXCR2) is the major receptor regulating inflammatory neutrophil recruitment in acute and chronic inflamed tissues. The purpose of this study was to investigate the functional relevance of the CXCR2 inhibitor SB225002 in LPS-induced acute lung injury. Material and methods: Male C57BL/6 mice were randomly divided into the following four experimental groups (n = 10 per group): untreated group (control group, Ctr); LPS-treated ALI group (LPS group, LPS); LPS + PBS-treated group (LPS + PBS); and SB225002-treated ALI group (LPS + SB225002). Twenty-four hours after treatment, the blood, bronchoalveolar lavage fluid (BALF), and lung tissue were collected and wet/dry ratio, protein concentration, myeloperoxidase (MPO) activity, neutrophil infiltration, and inflammatory cytokine secretion in lung tissue were measured. The pathologic changes in the lungs were examined using optical microscopy. Survival rates were recorded at 120 h in all four groups, in other experiments. Results: Histology findings revealed that the SB225002-treated group had significantly milder lung injury compared to the LPS-induced ALI and the PBS-treated control groups. Treatment with SB225002 significantly attenuated LPS-induced lung injury and suppressed the inflammatory responses in damaged lung tissue. Compared to the PBS-treated control group, treatment with SB225002 dramatically decreased the lung wet/dry ratio, protein concentration, and infiltration of neutrophils in lung tissue. Therefore, SB225002 treatment appeared to inhibit the production of inflammatory cytokines and increase survival time compared to the PBS-treated control group. Conclusions: Together, these data demonstrated that inhibition of CXCR2 signaling by SB225002 could ameliorate LPS-induced acute lung injury, by reducing neutrophil recruitment and vascular permeability. SB225002 may be further developed as a potential novel treatment for LPS-induced ALI. PMID- 29765454 TI - The effects of ketamine and thiopental used alone or in combination on the brain, heart, and bronchial tissues of rats. AB - Introduction: We compared the side effects of ketamine and thiopental used alone and of a ketamine/thiopental combination dose on the brain,heart, and bronchial tissues of rats. Material and methods: Three groups received intraperitoneal injections of 30 mg/kg ketamine (K-30); 15 mg/kg thiopental (T-15); or of both in combination (KTSA). These doses were doubled in another set of study groups (K 60, T-30, and KTA groups, respectively). Optimal anesthesia duration was examined in all groups. Results: Anesthesia did not occur with 30 mg/kg ketamine or 15 mg/kg thiopental. However, when used alone ketamine and thiopental led to oxidative stress in the striatum, heart, and bronchial tissues. Conversely, combined administration of anesthetics and subanesthetic doses were found not to create oxidative stress in any of these areas. The highest level of adrenaline in blood samples collected from the tail veins was measured in the KTA-60, and the lowest amount in the T-30. Creatine kinase activity was highest in the KTA-60 group (p < 0.001). When we compared for all 5 groups to untreated control group; the creatine kinase-MB activities were significiantly different in K-30, T-15 and T-30 (p < 0.001). Conclusions: The studied doses of ketamine led to oxidative stress by increasing the amount of adrenaline. Thiopental increased oxidative stress with decreases in adrenaline. A longer anesthetic effect with minimal adverse events may be achieved by ketamine and thiopental in combination. PMID- 29765457 TI - High lncRNA HULC expression is associated with poor prognosis and promotes tumor progression by regulating epithelial-mesenchymal transition in prostate cancer. AB - Introduction: Recently, increasing evidence has shown that long non-coding RNAs (lncRNAs) play critical roles in tumor progression and development. However, the expression pattern and biological function of lncRNA HULC (highly upregulated in liver cancer) in prostate cancer (PCa) remain largely unclear. Material and methods: The expression of lncRNA HULC in 53 paired PCa tissues and cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR). The chi2 test was used to explore the association of lncRNA HULC expression with clinicopathologic features. Kaplan-Meier analysis was used to detect the association between HULC expression and overall survival of PCa patients. Furthermore, the function of HULC in cell growth and metastasis was detected in PCa cells. Results: Our data showed that HULC expression was upregulated in PCa tissues and cell lines compared to adjacent non-tumor tissues and the normal prostate cell line RWPE-1 (p < 0.05). High HULC expression was positively associated with advanced clinicopathologic features and poor overall survival (OS) for PCa patients (p < 0.05). HULC inhibition suppressed PCa cell growth and metastasis both in vitro and in vivo (p < 0.05). Furthermore, HULC knockdown reduced N-cadherin and vimentin expression and increased E-cadherin expression in PCa cells (p < 0.05). Conclusions: Our data suggested that lncRNA HULC might play oncogenic roles in PCa progression, which provided a novel therapeutic strategy for PCa patients. PMID- 29765455 TI - Ringer's lactate solution enhances the inflammatory response during fluid resuscitation of experimentally induced haemorrhagic shock in rats. AB - Introduction: Hemorrhagic shock leads to systemic oxygen deficit (hypoxaemia) that results in systemic inflammatory response syndrome (SIRS), a recognised cause of late mortality in this case. The aim of this study was to analyse the impact of fluid resuscitation, using two Ringer solutions, on the microcirculation changes that take place during experimentally induced haemorrhagic shock. Material and methods: A model of the rat cremaster muscle was used to assess microcirculation in vivo. The experimental groups (n = 10 each) included: control (CTRL); shock (HSG); Ringer's acetate (RAG); and Ringer's lactate (RLG). Microhaemodynamic parameters were measured during the experiment. Results: A statistically significantly higher level of leukocytes, both those attached to the endothelium and those located in the extravascular space (p < 0.05), was reported in the lactate Ringer (LR) group compared with the AR group. There were significant differences in the activity of A3 arterioles compared with A1 and A2 arterioles. Ringer's lactate solution seemed to the inflammation response during fluid resuscitation from haemorrhagic shock. A3 arterioles are likely to play a role as a pre-capillary sphincter in the skeletal muscle. Conclusions: The present study revealed that fluid resuscitation with Ringer's lactate solution exacerbates inflammation in the skeletal muscle. It is worth noting that Ringer's acetate solution reduces local inflammation and could therefore be recommended as the "first line" crystalloid of the fluid resuscitation during haemorrhagic shock. PMID- 29765456 TI - Indomethacin-induced gastric damage in rats and the protective effect of donkey milk. AB - Introduction: Indomethacin is an anti-inflammatory drug with clearly known side effects on gastric mucosa. New treatment and side effect prevention methods are being studied. Donkey milk, as a nutritional support, has recently come into the spotlight with its anti-oxidant features, high antibody content and low allergenic properties. In this study, we investigated donkey milk's possible protective effect against acute gastric mucosal damage by indomethacin. Material and methods: Four groups, each composed of 8 rats, were created. Rats in the first and third groups were fed with standard rat chow, while those in the second and fourth groups were additionally fed with 25 mg/kg of donkey milk per day via nasogastric gavage. On the 11th day gastric mucosal damage was induced by oral administration of 30 mg/kg of indomethacin to the rats in groups 3 and 4. Six h later all rats were sacrificed and their stomachs were removed for macroscopic and microscopic evaluation as well as biochemical examination of glutathione (GSH) and malondialdehyde (MDA) levels. Tumor necrosis factor-alpha (TNF-alpha) expression in the gastric mucosa was evaluated immunohistochemically. Results: In the donkey milk-indomethacin group, total area of erosion and degree of linear ulceration were significantly lower than in the standard food-indomethacin group (p < 0.05). Also, GSH levels were increased and MDA levels were decreased significantly in this group. Tumor necrosis factor-alpha expression was more prevalent and stronger in the gastritis group, while lower expression was observed in the donkey milk group. Conclusions: Donkey milk was observed to have significant protective effects against gastric damage induced by indomethacin. PMID- 29765458 TI - Analysis of Web-based learning methods in emergency medicine: randomized controlled trial. AB - Introduction: In medical education, Web-based learning is increasingly used as a complement to practical classes. The objective of the study was to perform a comparative analysis of three different forms of e-learning course on emergency medicine in terms of an indicator of knowledge growth and students' satisfaction. Material and methods: For the purpose of the study, we developed and implemented a tool in the form of an online course: A - non-animated presentation, B - video, C - interactive video. The participants were undergraduate students of emergency medicine and nursing (n = 106). A pre-test and a post-test were carried out, and the resulting data were analyzed using parametric tests (t-test, ANOVA, post hoc). Final questionnaires assessing six parameters of satisfaction were also evaluated. Results: A significant increase in knowledge in the experimental group which used an interactive video was observed (p = 0.04). Moreover, the number of replays of learning material was the highest in group C (2.09 +/-2.48). The level of post-course satisfaction turned out to be comparable in all three groups (p = 0.62). Conclusions: The study allowed the interactive course to be identified as the most effective method of distance learning among selected ones. Due to the limitations of the study, we conclude that there is a need for further studies on the effectiveness of e-learning in emergency medicine. PMID- 29765459 TI - The number of strata in propensity score stratification for a binary outcome. AB - Introduction: Non-interventional and other observational studies have become important in medical research. In such observational, non-randomized studies, groups usually differ in some baseline covariates. Propensity scores are increasingly being used in the statistical analysis of these studies. Stratification, also called subclassification, based on propensity scores is one of the possible methods. There is the quasi-standard of using five strata. In this paper we focus on a binary outcome and evaluate the above-mentioned standard of using five strata. Material and methods: Bias and power for different numbers of strata are investigated with a simulation study. The methods are illustrated using data from a study where patients with diabetes mellitus and triple vessel disease undergoing coronary artery bypass surgery with and without previous percutaneous coronary intervention were compared. Results: We show that more than five strata can be more powerful and give less biased results. However, using more than ten strata hardly gives any further benefit. Conclusions: When applying a stratification, more than five strata may be preferable, especially because of increased power. Our simulation study does not show a clear winner; hence a useful strategy could be to work with five as well as with ten strata. PMID- 29765460 TI - The role of intestinal microbiota in the pathogenesis of NAFLD: starting points for intervention. AB - In recent years, close links between intestinal microbiota and host metabolism have been recognized. Intestinal bacteria can participate in the extraction of calories from food, and circulation of bacterial products, in particular lipopolysaccharides (LPS), is responsible for the "metabolic endotoxemia", which contributes to insulin resistance and its complications, such as non-alcoholic fatty liver disease (NAFLD). Indeed, qualitative and quantitative intestinal dysbiotic changes have been clearly documented in NAFLD patients, and several mechanisms by which the intestinal microbiota can directly promote liver fat deposition, inflammation and fibrosis have also been described. Consistently, although with some differences concerning type and proportion of results, experimental and clinical studies are quite concordant in demonstrating beneficial effects of probiotic and/or prebiotic therapy in NAFLD. Although some physiopathological bases have been produced, major doubts still remain concerning how and when to intervene. Indeed, most of the available works were performed with mixtures of probiotics and/or prebiotics, and a baseline assessment of dysbiosis aimed at selecting the best candidates for treatment and predicting response has not been performed in any of the clinical studies in NAFLD. While future research is expected to solve these issues, the particularly favorable safety profile suggests that probiotic/prebiotic therapy could already be "tested" in NAFLD patients on an individual basis, at least once all the measures recommended by the latest guidelines have failed. PMID- 29765463 TI - The Effects of Curtain Airbag on Occupant Kinematics and Injury Index in Rollover Crash. AB - Background: Occupant injuries in rollover crashes are associated with vehicle structural performance, as well as the restraint system design. For a better understanding of the occupant kinematics and injury index in certain rollover crash, it is essential to carry out dynamic vehicle rollover simulation with dummy included. Objective: This study focused on effects of curtain airbag (CAB) parameters on occupant kinematics and injury indexes in a rollover crash. Besides, optimized parameters of the CAB were proposed for the purpose of decreasing the occupant injuries in such rollover scenario. Method and Material: The vehicle motion from the physical test was introduced as the input for the numerical simulation, and the 50% Hybrid III dummy model from the MADYMO database was imported into a simulation model. The restraint system, including a validated CAB module, was introduced for occupant kinematics simulation and injury evaluation. TTF setting, maximum inflator pressure, and protection area of the CAB were analysed. Results: After introducing the curtain airbag, the maximum head acceleration was reduced from 91.60 g to 49.52 g, and the neck Mx and neck Fz were reduced significantly. Among these CAB parameters, the TTF setting had the largest effect on the head acceleration which could reduce 8.6 g furthermore after optimization. The neck Fz was decreased from 3766.48 N to 2571.77 N after optimization of CAB protection area. Conclusions: Avoiding hard contact is critical for the occupant protection in the rollover crashes. The simulation results indicated that occupant kinematics and certain injury indexes were improved with the help of CAB in such rollover scenario. Appropriate TTF setting and inflator selection could benefit occupant kinematics and injury indexes. Besides, it was advised to optimize the curtain airbag thickness around the head contact area to improve head and neck injury indexes. PMID- 29765462 TI - Development of a New Intelligent Joystick for People with Reduced Mobility. AB - Despite the diversity of electric wheelchairs, many people with physical limitations and seniors have difficulty using their standard joystick. As a result, they cannot meet their needs or ensure safe travel. Recent assistive technologies can help to give them autonomy and independence. This work deals with the real-time implementation of an artificial intelligence device to overcome these problems. Following a review of the literature from previous work, we present the methodology and process for implementing our intelligent control system on an electric wheelchair. The system is based on a neural algorithm that overcomes problems with standard joystick maneuvers such as the inability to move correctly in one direction. However, this implies the need for an appropriate methodology to map the position of the joystick handle. Experiments on a real wheelchair are carried out with real patients of the Mohamed Kassab National Institute Orthopedic, Physical and Functional Rehabilitation Hospital of Tunis. The proposed intelligent system gives good results compared to the use of a standard joystick. PMID- 29765461 TI - Anticancer Properties of Essential Oils and Other Natural Products. AB - Essential oils are secondary metabolites with a key-role in plants protection, consisting primarily of terpenes with a volatile nature and a diverse array of chemical structures. Essential oils exhibit a wide range of bioactivities, especially antimicrobial activity, and have long been utilized for treating various human ailments and diseases. Cancer cell prevention and cytotoxicity are exhibited through a wide range of mechanisms of action, with more recent research focusing on synergistic and antagonistic activity between specific essential oils major and minor components. Essential oils have been shown to possess cancer cell targeting activity and are able to increase the efficacy of commonly used chemotherapy drugs including paclitaxel and docetaxel, having also shown proimmune functions when administered to the cancer patient. The present review represents a state-of-the-art review of the research behind the application of EOs as anticancer agents both in vitro and in vivo. Cancer cell target specificity and the use of EOs in combination with conventional chemotherapeutic strategies are also explored. PMID- 29765464 TI - Renin-angiotensin-aldosterone inhibition improves right ventricular function: a meta-analysis. AB - The benefits of inhibiting the renin-angiotensin-aldosterone system (RAAS) are well established for left ventricular dysfunction, but remain unknown for right ventricular (RV) dysfunction. The aim of the current meta-analysis is to investigate the role of RAAS inhibition on RV function in those with or at risk of RV dysfunction. Medline, PubMed, EMBASE and Cochrane Libraries were systematically searched and 12 studies were included for statistical synthesis, comprising 265 RAAS inhibition treatment patients and 265 placebo control patients. The treatment arm showed a trend towards increased RV ejection fraction (weighted mean difference (WMD)=0.95, 95% CI -0.12 to 2.02, p=0.08) compared with the control arm. Subgroup analysis demonstrated a trend towards improvement in RV ejection fraction in patients receiving angiotensin receptor blockers compared with control (WMD=1.11, 95% CI -0.02 to 2.26, p=0.06), but not in the respective comparison for ACE inhibitors (WMD=0.07, 95% CI -2.74 to 2.87, p>0.05). No differences were shown between the two groups with regard to maximal oxygen consumption, RV end-systolic volume, RV end-diastolic volume, duration of cardiopulmonary exercise testing, and resting and maximal heart rate. Mild adverse drug reactions were common but evenly distributed between the treatment and control groups. The current meta-analysis highlights that there may be a role for RAAS inhibition, particularly treatment with angiotensin receptor blockers, in those with or at risk of RV dysfunction. However, further confirmation will be required by larger prospective trials. PMID- 29765465 TI - The development or worsening of hypertension after transcatheter aortic valve replacement (TAVR) improves short-term and long-term patient outcomes. AB - Objectives: In patients with symptomatic aortic valve disease who are at intermediate to high risk for open surgical aortic valve replacement, transcatheter aortic valve replacement (TAVR) decreases overall mortality and improves quality of life. Hypertension (HTN) after TAVR has been associated with improved cardiac function and short-term survival but its effect on survival over 1 year is unclear. Our study aims to evaluate the effect of HTN following TAVR on short-term and long-term clinical and echocardiographic outcomes. Methods: A retrospective chart review case-control study of 343 consecutive patients who underwent TAVR between August 2012 and November 2016 was performed to elucidate the relationship between HTN and post-TAVR outcomes. Results: 193 patients who underwent TAVR (56.2%) developed or had a worsening of their HTN after TAVR. The development of post-TAVR HTN was associated with a significantly better overall survival at 1 year (89% vs 67%, p<0.001) and 2 years (72% vs 46%, p=0.002). Patients with increased blood pressure also had a significant lower in hospital cardiovascular mortality (1% vs 12%, p<0.001). However, the development or worsening of their HTN after TAVR was associated with an increase in heart failure (HF) exacerbations and diuretic use. Conclusions: The development or worsening of HTN after TAVR is associated with improved overall survival despite an increase in postprocedural HF exacerbations and antihypertensive medication utilisation. The outcomes of this study could be important in postoperative management of patients who underwent TAVR. PMID- 29765466 TI - Anodic oxidation of bisamides from diaminoalkanes by constant current electrolysis. AB - In general, bisamides derived from diamines and involving 3 and 4 methylene groups as spacers between the two amide functionalities behave similar to monoamides upon anodic oxidation in methanol/LiClO4 because both types undergo majorly mono- and dimethoxylations at the alpha-position to the N atom. However, in cases where the spacer contains two methylene groups only the anodic process leads mostly to CH2-CH2 bond cleavage to afford products of type RCONHCH2OCH3. Moreover, upon replacing LiClO4 with Et4NBF4 an additional fragmentation type of product was generated from the latter amides, namely RCONHCHO. Also, the anodic process was found to be more efficient with C felt as the anode, and in a mixture of 1:1 methanol/acetonitrile co-solvents. PMID- 29765467 TI - Two novel blue phosphorescent host materials containing phenothiazine-5,5-dioxide structure derivatives. AB - Two novel D-A bipolar blue phosphorescent host materials based on phenothiazine 5,5-dioxide: 3-(9H-carbazol-9-yl)-10-ethyl-10H-phenothiazine-5,5-dioxide (CEPDO) and 10-butyl-3-(9H-carbazol-9-yl)-10H-phenothiazine-5,5-dioxide (CBPDO) were synthesized and characterized. The photophysical, electrochemical and thermal properties were systematically investigated. CEPDO and CBPDO not only have a high triplet energy but also show a bipolar behavior. Moreover, their fluorescence emission peaks are in the blue fluorescence region at 408 nm and the fluorescence quantum efficiency (Phi) of CEPDO and CBPDO were 62.5% and 59.7%, respectively. Both CEPDO and CBPDO showed very high thermal stability with decomposition temperatures (Td) of 409 and 396 degrees C as well as suitable HOMO and LUMO energy levels. This preferable performance suggests that CEPDO and CBPDO are alternative bipolar host materials for the PhOLEDs. PMID- 29765468 TI - Methyl isocyanide as a convertible functional group for the synthesis of spirocyclic oxindole gamma-lactams via post-Ugi-4CR/transamidation/cyclization in a one-pot, three-step sequence. AB - The synthesis of spiro[indoline-3,2'-pyrrole]-2,5'(1'H)-diones and spiro[indoline 3,2'-pyrrolidine]-2,5'-diones, via a post-Ugi-domino transamidation/cyclization sequential process, has been achieved in three sequential steps utilizing a one pot reaction protocol. The variation in carboxylic acid substrates allows for the generation of new chiral racemic quaternary carbon centers under basic conditions providing molecular diversity and a small library of spirocyclic oxindoles. PMID- 29765469 TI - An efficient and facile access to highly functionalized pyrrole derivatives. AB - A straightforward and one-pot synthesis of pyrrolo[3,4-c]pyrrole-1,3-diones via Ag(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with N-alkyl maleimide, followed by readily complete oxidation with DDQ, has been successfully developed. Further transformation with alkylamine/sodium alkoxide alcohol solution conveniently afforded novel polysubstituted pyrroles in good to excellent yields. This methodology for highly functionalized pyrroles performed well over a broad scope of substrates. It is conceivable that this efficient construction method for privileged pyrrole scaffolds could deliver more active compounds for medicinal chemistry research. PMID- 29765470 TI - Electrochemically modified Corey-Fuchs reaction for the synthesis of arylalkynes. The case of 2-(2,2-dibromovinyl)naphthalene. AB - The electrochemical reduction of 2-(2,2-dibromovinyl)naphthalene in a DMF solution (Pt cathode) yields selectively 2-ethynylnaphthalene or 2 (bromoethynyl)naphthalene in high yields, depending on the electrolysis conditions. In particular, by simply changing the working potential and the supporting electrolyte, the reaction can be directed towards the synthesis of the terminal alkyne (Et4NBF4) or the bromoalkyne (NaClO4). This study allowed to establish that 2-(bromoethynyl)naphthalene can be converted into 2 ethynylnaphthalene by cathodic reduction. PMID- 29765471 TI - Volatiles from three genome sequenced fungi from the genus Aspergillus. AB - The volatiles emitted by agar plate cultures of three genome sequenced fungal strains from the genus Aspergillus were analysed by GC-MS. All three strains produced terpenes for which a biosynthetic relationship is discussed. The obtained data were also correlated to genetic information about the encoded terpene synthases for each strain. Besides terpenes, a series of aromatic compounds and volatiles derived from fatty acid and branched amino acid metabolism were identified. Some of these compounds have not been described as fungal metabolites before. For the compound ethyl (E)-hept-4-enoate known from cantaloupe a structural revision to the Z stereoisomer is proposed. Ethyl (Z) hept-4-enoate also occurs in Aspergillus clavatus and was identified by synthesis of an authentic standard. PMID- 29765472 TI - Development of novel cyclic NGR peptide-daunomycin conjugates with dual targeting property. AB - Cyclic NGR peptides as homing devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13- but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free epsilon-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide-daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property. PMID- 29765473 TI - Local energy decomposition analysis of hydrogen-bonded dimers within a domain based pair natural orbital coupled cluster study. AB - The local energy decomposition (LED) analysis allows for a decomposition of the accurate domain-based local pair natural orbital CCSD(T) [DLPNO-CCSD(T)] energy into physically meaningful contributions including geometric and electronic preparation, electrostatic interaction, interfragment exchange, dynamic charge polarization, and London dispersion terms. Herein, this technique is employed in the study of hydrogen-bonding interactions in a series of conformers of water and hydrogen fluoride dimers. Initially, DLPNO-CCSD(T) dissociation energies for the most stable conformers are computed and compared with available experimental data. Afterwards, the decay of the LED terms with the intermolecular distance (r) is discussed and results are compared with the ones obtained from the popular symmetry adapted perturbation theory (SAPT). It is found that, as expected, electrostatic contributions slowly decay for increasing r and dominate the interaction energies in the long range. London dispersion contributions decay as expected, as r-6. They significantly affect the depths of the potential wells. The interfragment exchange provides a further stabilizing contribution that decays exponentially with the intermolecular distance. This information is used to rationalize the trend of stability of various conformers of the water and hydrogen fluoride dimers. PMID- 29765475 TI - Mechanochemistry of nucleosides, nucleotides and related materials. AB - The application of mechanical force to induce the formation and cleavage of covalent bonds is a rapidly developing field within organic chemistry which has particular value in reducing or eliminating solvent usage, enhancing reaction rates and also in enabling the preparation of products which are otherwise inaccessible under solution-phase conditions. Mechanochemistry has also found recent attention in materials chemistry and API formulation during which rearrangement of non-covalent interactions give rise to functional products. However, this has been known to nucleic acids science almost since its inception in the late nineteenth century when Miescher exploited grinding to facilitate disaggregation of DNA from tightly bound proteins through selective denaturation of the latter. Despite the wide application of ball milling to amino acid chemistry, there have been limited reports of mechanochemical transformations involving nucleoside or nucleotide substrates on preparative scales. A survey of these reactions is provided, the majority of which have used a mixer ball mill and display an almost universal requirement for liquid to be present within the grinding vessel. Mechanochemistry of charged nucleotide substrates, in particular, provides considerable benefits both in terms of efficiency (reducing total processing times from weeks to hours) and by minimising exposure to aqueous conditions, access to previously elusive materials. In the absence of large quantities of solvent and heating, side-reactions can be reduced or eliminated. The central contribution of mechanochemistry (and specifically, ball milling) to the isolation of biologically active materials derived from nuclei by grinding will also be outlined. Finally non-covalent associative processes involving nucleic acids and related materials using mechanochemistry will be described: specifically, solid solutions, cocrystals, polymorph transitions, carbon nanotube dissolution and inclusion complex formation. PMID- 29765476 TI - Developmental trends of theta-beta interelectrode power correlation during resting state in normal children. AB - The possibility that power-to-power (theta-beta) frequency coupling increases during development was analyzed. Three minutes of spontaneous EEG in an open eyes condition were recorded in a sample of 160 subjects ranging from 6 to 26 years old. Theta (4-7 Hz) and beta band (15-20 Hz) power was calculated in a trial-by trial basis. Inter-electrode power correlations (IPC) were computed in each subject as the correlation between the power of two frequency bands recorded in two electrodes. An increase in theta-beta IPC with age was obtained. IPCs were higher when theta was seeded in posterior regions than in anterior or central regions. Moreover, the significant correlations between each individual IPC and age were calculated, making it possible to draw IPC versus age correlation maps in order to capture the IPC development topography. An increase was found in significant correlations in the left hemisphere compared to the right hemisphere. There were no differences in the inter-hemispheric versus intra-hemispheric IPC maturation spatial patterns. An increase in power-to-power-frequency coupling in theta-beta occurs during development, suggesting an increase in functional connectivity with age. Frequency coupling between theta and beta rhythms would be one of the mechanisms facilitating integration of long distance functional networks during development. PMID- 29765474 TI - On the design principles of peptide-drug conjugates for targeted drug delivery to the malignant tumor site. AB - Cancer is the second leading cause of death affecting nearly one in two people, and the appearance of new cases is projected to rise by >70% by 2030. To effectively combat the menace of cancer, a variety of strategies have been exploited. Among them, the development of peptide-drug conjugates (PDCs) is considered as an inextricable part of this armamentarium and is continuously explored as a viable approach to target malignant tumors. The general architecture of PDCs consists of three building blocks: the tumor-homing peptide, the cytotoxic agent and the biodegradable connecting linker. The aim of the current review is to provide a spherical perspective on the basic principles governing PDCs, as also the methodology to construct them. We aim to offer basic and integral knowledge on the rational design towards the construction of PDCs through analyzing each building block, as also to highlight the overall progress of this rapidly growing field. Therefore, we focus on several intriguing examples from the recent literature, including important PDCs that have progressed to phase III clinical trials. Last, we address possible difficulties that may emerge during the synthesis of PDCs, as also report ways to overcome them. PMID- 29765478 TI - Neuroelectric responses of sportsmen and sedentaries under cognitive stress. AB - Stress and anxiety are states which sportsmen are continuously exposed to. Our study aimed to evaluate neuroelectrical peripheral and central nervous system responses of sportsmen (SPR) and sedentary individuals (SED) during concentration grid test (CGT) employed under time pressure. Forty three SPR and 33 SED participated in the study. Neuroelectrical responses were simultaneously obtained during baseline and CGT. All responses were observed to increase under stress in both SED and SPR. The SPR's stress related peripheral responses were lower than SED's. When central values were evaluated a stress related increase according to baseline was observed in all frequency powers in all of the participants. Statistical comparison of increase rates revealed a significantly greater increase in beta in SED compared to SPR. Beta has been associated to alertness and cortical arousal. As SED exhibit greater beta increase under stress compared to SPR their state of cortical arousal and alertness may be interpreted to be higher than SPR. However the SPR's weak increase in beta and their lower peripheral responses taken together may imply that they are better in stress management. In fact according to their performance scores the SPR's higher level of performance under stress compared to SED shows that they are better at maintaining and focusing their attention under stress than SED. PMID- 29765477 TI - Detecting epileptic seizure with different feature extracting strategies using robust machine learning classification techniques by applying advance parameter optimization approach. AB - Epilepsy is a neurological disorder produced due to abnormal excitability of neurons in the brain. The research reveals that brain activity is monitored through electroencephalogram (EEG) of patients suffered from seizure to detect the epileptic seizure. The performance of EEG detection based epilepsy require feature extracting strategies. In this research, we have extracted varying features extracting strategies based on time and frequency domain characteristics, nonlinear, wavelet based entropy and few statistical features. A deeper study was undertaken using novel machine learning classifiers by considering multiple factors. The support vector machine kernels are evaluated based on multiclass kernel and box constraint level. Likewise, for K-nearest neighbors (KNN), we computed the different distance metrics, Neighbor weights and Neighbors. Similarly, the decision trees we tuned the paramours based on maximum splits and split criteria and ensemble classifiers are evaluated based on different ensemble methods and learning rate. For training/testing tenfold Cross validation was employed and performance was evaluated in form of TPR, NPR, PPV, accuracy and AUC. In this research, a deeper analysis approach was performed using diverse features extracting strategies using robust machine learning classifiers with more advanced optimal options. Support Vector Machine linear kernel and KNN with City block distance metric give the overall highest accuracy of 99.5% which was higher than using the default parameters for these classifiers. Moreover, highest separation (AUC = 0.9991, 0.9990) were obtained at different kernel scales using SVM. Additionally, the K-nearest neighbors with inverse squared distance weight give higher performance at different Neighbors. Moreover, to distinguish the postictal heart rate oscillations from epileptic ictal subjects, and highest performance of 100% was obtained using different machine learning classifiers. PMID- 29765479 TI - Protective effects of evodiamine in experimental paradigm of Alzheimer's disease. AB - Evodiamine, a major component of Evodia rutaecarpa, has been reported to possess various pharmacological activities, including anti-inflammatory, antioxidative stress, and neuroprotective effects. Our previous study has shown that the potential effects of evodiamine on the learning and memory impairments in the transgenic mouse model of Alzheimer's disease (AD). The present study was designed to investigate neuroprotective mechanism and therapeutic potential of evodiamine against intracerebroventricular streptozotocin (ICV-STZ)-induced experimental sporadic Alzheimer's disease in mice. STZ was injected twice intracerebroventrically (3 mg/kg ICV) on alternate days (day 1 and day 3) in mice. Daily oral administration with evodiamine (50 or 100 mg/kg per day) starting from the first dose of STZ for 21 days showed an improvement in STZ induced cognitive deficits as assessed by novel object recognition and Morris water maze test. Evodiamine significantly decreased STZ induced elevation in acetylcholinesterase activity and malondialdehyde level, and significantly increased STZ induced reduction in glutathione activities and superoxide dismutase activities in the hippocampus compared to control. Furthermore, evodiamine inhibited significantly glial cell activation and neuroinflammation (TNF-alpha, IL-1beta, and IL-6 levels) in the hippocampus. Moreover, evodiamine increased the activity of AKT/GSK-3beta signalling pathway and inhibited the activity of nuclear factor kappaB. In summary, our study suggests that evodiamine can be a novel therapeutic agent for the management of sporadic AD. PMID- 29765481 TI - Weak periodic signal detection by sine-Wiener-noise-induced resonance in the FitzHugh-Nagumo neuron. AB - Based on the FitzHugh-Nagumo (FHN) neuron model subjected to sine-Wiener (SW) noise, impacts of SW noise on weak periodic signal detection are investigated by calculating response measure Q for characterizing synchronization between the input signal and the output temporal activities of the neuron. It is numerically demonstrated that the response measure Q can achieve the optimal value under appropriate and moderate intensity or correlation time of SW noise, suggesting the occurrence of SW-noise-induced stochastic resonance. Furthermore, the optimal value of Q is sensitive to correlation time. Consequently, the correlation time of SW noise has a great influence on the performance of signal detection in the FHN neuron. PMID- 29765482 TI - Fatigue-life distributions for reaction time data. AB - The family of fatigue-life distributions is introduced as an alternative model of reaction time data. This family includes the shifted Wald distribution and a shifted version of the Birnbaum-Saunders distribution. Although the former has been proposed as a way to model reaction time data, the latter has not. Hence, we provide theoretical, mathematical and practical arguments in support of the shifted Birnbaum-Saunders as a suitable model of simple reaction times and associated cognitive mechanisms. PMID- 29765483 TI - Mitochondrial T16189C Polymorphism Is Associated with Metabolic Syndrome in the Mexican Population. AB - Genetic factors, such as the mitochondrial DNA (mtDNA) T16189C polymorphism, have been associated with metabolic syndrome (MetS), but this association has not been studied in Mexico to date. The aim of the present study was to determine whether this polymorphism contributes to MetS in the Mexican population. We recruited 100 unrelated volunteer subjects who were divided into 2 groups: with MetS (MetS group) and without MetS (control group). All subjects were genotyped for the mtDNA T16189C polymorphism by polymerase chain reaction and sequencing. The mitochondrial T16189C polymorphism was detected in 24 (24%) of 100 subjects analyzed. The frequency of the mtDNA T16189C polymorphism was higher in the MetS group with 21 (32.3%) of 65 testing positive compared to 3 (8.5%) of 35 in the control group, indicating that this polymorphism is a probable risk factor for MetS in the Mexican population (odds ratio 5.0909, 95% CI 1.3977-18.5424, P = 0.0136). Our results may contribute to early diagnosis of MetS, which is essential for establishing changes in early stages of the disease to avoid further complications and pathologies, thereby preventing the development of type 2 diabetes and cardiovascular disease in Mexico. PMID- 29765484 TI - Successful embolization of a enterocutaneous fistula tract with Onyx 34 following low anterior resection for rectal cancer. AB - Enterocutaneous fistulas (ECFs) can be one of the complications found after surgical intervention for rectal cancer. Interventional modalities consisting of surgical, endoscopic, and radiological methods are often implemented to treat postoperative symptomatic complications. We present the case of 61-year-old Caucasian man who presented to us with a recent diagnosis of rectal cancer that had invaded the levators as well as anteriorly into the prostate, and who underwent low anterior resection with a diverting loop ileostomy. The patient was found to have a persistent presacral abscess due to an ECF tract. This case highlights the off-label use of ethylene-vinyl alcohol copolymer dissolved in dimethyl sulfoxide (Onyx 34) to seal an ECF. PMID- 29765480 TI - Effect of spike-timing-dependent plasticity on stochastic burst synchronization in a scale-free neuronal network. AB - We consider an excitatory population of subthreshold Izhikevich neurons which cannot fire spontaneously without noise. As the coupling strength passes a threshold, individual neurons exhibit noise-induced burstings. This neuronal population has adaptive dynamic synaptic strengths governed by the spike-timing dependent plasticity (STDP). However, STDP was not considered in previous works on stochastic burst synchronization (SBS) between noise-induced burstings of sub threshold neurons. Here, we study the effect of additive STDP on SBS by varying the noise intensity D in the Barabasi-Albert scale-free network (SFN). One of our main findings is a Matthew effect in synaptic plasticity which occurs due to a positive feedback process. Good burst synchronization (with higher bursting measure) gets better via long-term potentiation (LTP) of synaptic strengths, while bad burst synchronization (with lower bursting measure) gets worse via long term depression (LTD). Consequently, a step-like rapid transition to SBS occurs by changing D, in contrast to a relatively smooth transition in the absence of STDP. We also investigate the effects of network architecture on SBS by varying the symmetric attachment degree [Formula: see text] and the asymmetry parameter [Formula: see text] in the SFN, and Matthew effects are also found to occur by varying [Formula: see text] and [Formula: see text]. Furthermore, emergences of LTP and LTD of synaptic strengths are investigated in details via our own microscopic methods based on both the distributions of time delays between the burst onset times of the pre- and the post-synaptic neurons and the pair correlations between the pre- and the post-synaptic instantaneous individual burst rates (IIBRs). Finally, a multiplicative STDP case (depending on states) with soft bounds is also investigated in comparison with the additive STDP case (independent of states) with hard bounds. Due to the soft bounds, a Matthew effect with some quantitative differences is also found to occur for the case of multiplicative STDP. PMID- 29765485 TI - Spontaneous hemoperitoneum resulting from segmental arterial mediolysis. AB - Segmental arterial mediolysis is a rare but potentially life-threatening arteropathy of medium to large arteries that can be managed with endovascular treatment for patients who are hemodynamically unstable. We present a case of segmental arterial mediolysis in a 73-year-old woman who developed spontaneous hemoperitoneum in the emergency department after initially presenting with unrelated upper respiratory complaints. Her initial computed tomography revealed an aneurysm arising off the right hepatic artery. She was taken to the interventional radiology suite for embolization and multiple aneurysms along the right hepatic artery were identified that had the appearance of segmental arterial mediolysis. She initially stabilized but then developed acute renal failure and had a decrease in hemoglobin on postprocedure day 2. She was taken back to the angiography suite where multiple small left gastric and left hepatic trunk aneurysms were identified, with a small area of extravasation evident. The vessel was coiled from the liver to the origin of the left gastric artery. She was discharged and had a follow-up angiogram 2 months later, which showed interval development of an aneurysm to the distal right hepatic artery. PMID- 29765487 TI - An Analysis of Pediatric Scar Progression Over Time. AB - Objective: The advances in surgical approaches for a pyloromyotomy have all focused on creating smaller incisions from a right upper quadrant now to a laparoscopic umbilical incision. A key assumption is that the final scar retains the size of the original incision as the child matures. Our case reports on a family with several members, now adults, with the same surgery and same surgeon who had the right upper quadrant incision as infants to elucidate the extent of how infantile scars grow over time, significantly exceeding the original incision. Methods: We evaluated the various pyloromyotomy scars of our newborn patient, his maternal grandmother, and his two maternal twin aunts. One aunt (#1) was of normal stature, whereas her twin (#2) never went through a full vertical growth phase due to being stunted by Cornelia de Lange syndrome. For each member, we compared the length of the original incision with the current scar length to determine how much the scar has grown over time. Results: Significant scar growth was seen in the grandmother and aunt 1. In contrast aunt 2's scar did not grow significantly due to her stunted vertical growth from Cornelia de Lange syndrome. Conclusions: This case supports the notion that surgical incisions in infants grow more substantially than realized with age, resulting in larger scars than anticipated. Our findings suggest the reason why the laparoscopic pyloromyotomy has been popularized due to its incisions being so small that they continue to present a cosmetic advantage over time. PMID- 29765486 TI - Use of Hyaluronic Acid-Based Biological Bilaminar Matrix in Wound Bed Preparation: A Case Series. AB - Objective: Hyalomatrix, a matrix that consists of esterified hyaluronic acid, covered with a removable, semipermeable silicone top layer, was used to generate granulation tissue in a series of 12 serious, surgical wounds of different etiologies. Methods: Many defects showed exposed muscle, tendons, and/or bone. After thorough debridement, the matrix was applied, in a number of cases, combined with negative pressure wound therapy. Results: All wounds developed granulation tissue in and on top of the matrix. Nine wounds were then closed with a split skin autograft. There was no graft failure, and all wounds showed complete reepithelialization. Three wounds healed by secondary intention and also reached complete healing. Conclusion: This case series shows a strong trend for Hyalomatrix to play an important role in supporting wound healing in complex, surgical wounds. PMID- 29765488 TI - Morinda citrifolia L. Leaf Extract Protects against Cerebral Ischemia and Osteoporosis in an In Vivo Experimental Model of Menopause. AB - We aimed to determine the protective effects against cerebral ischemia and osteoporosis of Morinda citrifolia extract in experimental menopause. The neuroprotective effect was assessed by giving M. citrifolia leaf extract at doses of 2, 10, and 50 mg/kg BW to the bilateral ovariectomized (OVX) rats for 7 days. Then, they were occluded in the right middle cerebral artery (MCAO) for 90 minutes. The neurological score, brain infarction volume, oxidative stress status, and ERK1/2 and eNOS activities were assessed 24 hours later. M. citrifolia improved neurological score, brain infarction, and brain oxidative stress status in the cortex of OVX rats plus the MCAO. No changes in ERK 1/2 signal pathway and NOS expression were observed in this area. Our data suggested that the neuroprotective effect of the extract might occur partly via the improvement of oxidative stress status in the cortex. The antiosteoporotic effect in OVX rats was also assessed after an 84-day intervention of M. citrifolia. The serum levels of calcium, osteocalcin, and alkaline phosphatase and osteoblast density in the tibia were increased, but the density of osteoclast was decreased in OVX rats which received the extract. Therefore, the current data suggested that the extract possessed antiosteoporotic effect by increasing bone formation but decreasing bone resorption. PMID- 29765490 TI - Antiaging of Cucurbitane Glycosides from Fruits of Momordica charantia L. AB - Methanol extracts of Momordica charantia L. fruits are extensively studied for their antiaging activities. A new cucurbitane-type triterpenoid (1) and nine other known compounds (2-10) were isolated, and their structures were determined according to their spectroscopic characteristics and chemical derivatization. Biological evaluation was performed on a K6001 yeast bioassay system. The results indicated that all the compounds extended the replicative lifespan of K6001 yeast significantly. Compound 9 was used to investigate the mechanism involved in the increasing of the lifespan. The results indicated that this compound significantly increases the survival rate of yeast under oxidative stress and decreases ROS level. Further study on gene expression analysis showed that compound 9 could reduce the levels of UTH1 and SKN7 and increase SOD1 and SOD2 gene expression. In addition, it could not extend the lifespan of the yeast mutants of Uth1, Skn7, Sod1, and Sod2. These results demonstrate that compound 9 exerts antiaging effects via antioxidative stress and regulation of UTH1, SKN7, SOD1, and SOD2 yeast gene expression. PMID- 29765489 TI - Gallic Acid-L-Leucine Conjugate Protects Mice against LPS-Induced Inflammation and Sepsis via Correcting Proinflammatory Lipid Mediator Profiles and Oxidative Stress. AB - The pathology of endotoxin LPS-induced sepsis is hallmarked by aberrant production of proinflammatory lipid mediators and nitric oxide (NO). The aim of the present study was to determine whether the new product gallic acid-L-leucine (GAL) conjugate could ameliorate the LPS-induced dysregulation of arachidonic acid metabolism and NO production. We first investigated the effects of GAL conjugate on the expression of proinflammatory enzymes and the production of proinflammatory NO and lipid mediators in mouse macrophage cell line RAW264.7, primary peritoneal macrophages, and mouse model. Western blot analyses revealed that GAL attenuated LPS-induced expression of iNOS, COX-2, and 5-LOX in a concentration-dependent manner. Consistently, probing NO-mediated fluorescence revealed that GAL antagonized the stimulatory effect of LPS on iNOS activity. By profiling of lipid mediators with ESI-MS-based lipidomics, we found that GAL suppressed LPS-induced overproduction of prostaglandin E2, prostaglandin F2, leukotriene B4, and thromboxane B2. We further discovered that GAL might exhibit anti-inflammatory activities by the following mechanisms: (1) suppressing LPS induced activation of MAP kinases (i.e., ERK1/2, JNK, and p38); (2) reducing the production of reactive oxygen species (ROS); and (3) preventing LPS-induced nuclear translocation of transcription factors NF-kappaB and AP-1. Consequently, GAL significantly decreased the levels of COX-2 and iNOS expression and the plasma levels of proinflammatory lipid mediators in LPS-treated mice. GAL pretreatment enhanced the survival of mice against LPS-induced endotoxic shock. Taken together, our results suggest that GAL may be a potential anti-inflammatory drug for the treatment of endotoxemia and sepsis. PMID- 29765491 TI - Interplay of Oxidative Stress, Inflammation, and Autophagy: Their Role in Tissue Injury of the Heart, Liver, and Kidney. PMID- 29765492 TI - Editorial: Oxidative Stress in the Critically Ill Patients: Pathophysiology and Potential Interventions. PMID- 29765493 TI - Long-Term Exercise Protects against Cellular Stresses in Aged Mice. AB - The current study examined the effect of aging and long-term wheel-running on the expression of heat shock protein (HSP), redox regulation, and endoplasmic reticulum (ER) stress markers in tibialis anterior (T.A.) and soleus muscle of mice. Male mice were divided into young (Y, 3-month-old), old-sedentary (OS, 24 month-old), and old-exercise (OE, 24-month-old) groups. The OE group started voluntary wheel-running at 3 months and continued until 24 months of age. Aging was associated with a higher thioredoxin-interacting protein (TxNiP) level, lower thioredoxin-1 (TRX-1) to TxNiP ratio-a determinant of redox regulation and increased CHOP, an indicator of ER stress-related apoptosis signaling in both muscles. Notably, GRP78, a key indicator of ER stress, was selectively elevated in T.A. Long-term exercise decreased TxNiP in T.A. and soleus muscles and increased the TRX-1/TxNiP ratio in soleus muscle of aged mice. Inducible HSP70 and constituent HSC70 were upregulated, whereas CHOP was reduced after exercise in soleus muscle. Thus, our data demonstrated that aging induced oxidative stress and activated ER stress-related apoptosis signaling in skeletal muscle, whereas long-term wheel-running improved redox regulation, ER stress adaptation and attenuated ER stress-related apoptosis signaling. These findings suggest that life-long exercise can protect against age-related cellular stress. PMID- 29765494 TI - The Oxidant-Antioxidant Equilibrium and Inflammatory Process Indicators after an Exercise Test on the AlterG Antigravity Treadmill in Young Amateur Female Athletes. AB - The AlterG antigravity treadmill allows running with a considerable weight reduction. Physical exercise practiced on this treadmill is an innovative method supporting the treatment of injuries in sports and rehabilitation of patients. The aim of the study was to investigate the effect of a 30 min run on the AlterG treadmill with 80% body weight reduction comparing the effect to the similar effort on the classic treadmill on the redox equilibrium and the activity of selected lysosomal enzymes and a serine protease inhibitor in the blood of amateur minor female volleyball players. Venous blood samples were taken before the exercise and 30 minutes and 24 hours after its completion. The obtained results were analysed using Tukey's test and Pearson's linear correlations were calculated. 24 h after the running test on classic treadmill, the erythrocytic superoxide dismutase activity was higher than before and 30 min after it, as well as compared to the run on AlterG treadmill (p < 0.001). The erythrocytic conjugated diene concentration 24 h after the exercise on the classic treadmill was meaningly higher compared to that after the exercise on the AlterG treadmill (p < 0.001). The cathepsin D activity was significantly lower after the exercise in AlterG conditions compared to the baseline value and that measured after the exercise on classic treadmill (p < 0.001). It seems that the exercise on the AlterG treadmill keeps the oxidant-antioxidant equilibrium and stabilizes lysosomal membranes in young, physically active women in contrast to the exercise on the classic treadmill. This trial is registered with CTRI/2018/01/011344. PMID- 29765495 TI - Effect of the Antioxidant Lipoic Acid in Aortic Phenotype in a Marfan Syndrome Mouse Model. AB - Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgDeltaloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture. PMID- 29765496 TI - Long Noncoding RNAs in Yeast Cells and Differentiated Subpopulations of Yeast Colonies and Biofilms. AB - We summarize current knowledge regarding regulatory functions of long noncoding RNAs (lncRNAs) in yeast, with emphasis on lncRNAs identified recently in yeast colonies and biofilms. Potential regulatory functions of these lncRNAs in differentiated cells of domesticated colonies adapted to plentiful conditions versus yeast colony biofilms are discussed. We show that specific cell types differ in their complements of lncRNA, that this complement changes over time in differentiating upper cells, and that these lncRNAs target diverse functional categories of genes in different cell subpopulations and specific colony types. PMID- 29765497 TI - Di-2-pyridylhydrazone Dithiocarbamate Butyric Acid Ester Exerted Its Proliferative Inhibition against Gastric Cell via ROS-Mediated Apoptosis and Autophagy. AB - Diversified biological activities of dithiocarbamates have attracted widespread attention; improving their feature or exploring their potent action of mechanism is a hot topic in medicinal research. Herein, we presented a study on synthesis and investigation of a novel dithiocarbamate, DpdtbA (di-2-pyridylhydrazone dithiocarbamate butyric acid ester), on antitumor activity. The growth inhibition assay revealed that DpdtbA had important antitumor activity for gastric cancer (GC) cell lines (IC50 = 4.2 +/- 0.52 MUM for SGC-7901, 3.80 +/- 0.40 MUM for MGC 803). The next study indicated that growth inhibition is involved in ROS generation in mechanism; accordingly, the changes in mitochondrial membrane permeability, apoptotic genes, cytochrome c, bax, and bcl-2 were observed, implying that the growth inhibition of DpdtbA is involved in ROS-mediated apoptosis. On the other hand, the upregulated p53 upon DpdtbA treatment implied that p53 could also mediate the apoptosis. Yet the excess generation of ROS induced by DpdtbA led to cathepsin D translocation and increase of autophagic vacuoles and LC3-II, demonstrating that autophagy was also a contributor to growth inhibition. Further investigation showed that DpdtbA could induce cell cycle arrest at the G1 phase. This clearly indicated the growth inhibition of DpdtbA was via triggering ROS formation and evoking p53 response, consequently leading to alteration in gene expressions that are related to cell survival. PMID- 29765498 TI - Edaravone Improves Septic Cardiac Function by Inducing an HIF-1alpha/HO-1 Pathway. AB - Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia inducible factor- (HIF-) 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO-) 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP) with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp.) before CLP and intraperitoneal injection of the HIF-1alpha antagonist, ME (15 mg/kg), after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1alpha, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1alpha by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1alpha/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction. PMID- 29765499 TI - Effect of Heat Stress on Sperm DNA: Protamine Assessment in Ram Spermatozoa and Testicle. AB - Sperm DNA fragmentation is considered one of the main causes of male infertility. The most accepted causes of sperm DNA damage are deleterious actions of reactive oxygen species (ROS), defects in protamination, and apoptosis. Ram sperm are highly prone to those damages due to the high susceptibility to ROS and to oxidative stress caused by heat stress. We aimed to evaluate the effects of heat stress on the chromatin of ejaculated and epididymal sperm and the activation of apoptotic pathways in different cell types in ram testis. We observed higher percentages of ejaculated sperm with increased chromatin fragmentation in the heat stress group; a fact that was unexpectedly not observed in epididymal sperm. Heat stress group presented a higher percentage of spermatozoa with DNA fragmentation and increased number of mRNA copies of transitional protein 1. Epididymal sperm presented greater gene expression of protamine 1 on the 30th day of the spermatic cycle; however, no differences in protamine protein levels were observed in ejaculated sperm and testis. Localization of proapoptotic protein BAX or BCL2 in testis was not different. In conclusion, testicular heat stress increases ram sperm DNA fragmentation without changes in protamination and apoptotic patterns. PMID- 29765500 TI - Mito-TEMPO Alleviates Renal Fibrosis by Reducing Inflammation, Mitochondrial Dysfunction, and Endoplasmic Reticulum Stress. AB - Background: Renal fibrosis is a common pathological symptom of chronic kidney disease (CKD). Many studies support that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are implicated in the pathogenesis of CKD. In our study, we investigated the benefits and underlying mechanisms of Mito-TEMPO on renal fibrosis in 5/6 nephrectomy mice. Methods: Mice were randomly divided into five groups as follows: control group, CKD group, CKD + Mito-TEMPO (1 mg.kg 1.day-1) group, CKD + Mito-TEMPO (3 mg.kg-1.day-1) group, and Mito-TEMPO group (3 mg.kg-1.day-1). Renal fibrosis was evaluated by PAS, Masson staining, immunohistochemistry, and real-time PCR. Oxidative stress markers such as SOD2 activity and MDA level in serum and isolated mitochondria from renal tissue were measured by assay kits. Mitochondrial superoxide production was evaluated by MitoSOX staining and Western blot. Mitochondrial dysfunction was assessed by electron microscopy and real-time PCR. ER stress-associated protein was measured by Western blot. Results: Impaired renal function and renal fibrosis were significantly improved by Mito-TEMPO treatment. Furthermore, inflammation cytokines, profibrotic factors, oxidative stress markers, mitochondrial dysfunction, and ER stress were all increased in the CKD group. However, these effects were significantly ameliorated in the Mito-TEMPO treatment group. Conclusions: Mito-TEMPO ameliorates renal fibrosis by alleviating mitochondrial dysfunction and endoplasmic reticulum stress possibly through the Sirt3-SOD2 pathway, which sheds new light on prevention of renal fibrosis in chronic kidney disease. PMID- 29765502 TI - The Phenolic Components of Gastrodia elata improve Prognosis in Rats after Cerebral Ischemia/Reperfusion by Enhancing the Endogenous Antioxidant Mechanisms. AB - Pharmacological or spontaneous thrombolysis in ischemic stroke triggers an outbreak of reactive oxygen species and results in neuron death. Nrf2-mediated antioxidation in cells has been proved as a pivotal target for neuroprotection. This research reports that phenolic components of Gastrodia elata Blume (PCGE), a traditional Chinese medicine, can alleviate the pathological lesions in the penumbra and hippocampus by increasing the survival of neurons and astrocytes and improve neurofunction and cognition after reperfusion in a rat model of middle cerebral artery occlusion. LDH assay indicated that pretreatment of cells with PCGE (25 MUg/ml) for 24 h significantly reduced H2O2-induced cell death in astrocytes and SH-SY5Y cells. Western blot showed that the nucleus accumulation of Nrf2 and the expression of cellular HO-1 and NQO-1, two of Nrf2 downstream proteins, were increased in both cells. BDNF, an Nrf2-dependent neurotrophic factor, was also upregulated by PCGE in astrocytes. These results illustrated that PCGE can reduce the cerebral ischemia/reperfusion injury and improve prognosis by remedying the cell damage within affected tissues. The protective effects of PCGE seem to be via activation of a Nrf2-mediated cellular defense system. Therefore, PCGE could be a therapeutic candidate for ischemic stroke and other oxidative stress associated neurological disorders. PMID- 29765501 TI - Peroxisomal Acyl-CoA Oxidase Type 1: Anti-Inflammatory and Anti-Aging Properties with a Special Emphasis on Studies with LPS and Argan Oil as a Model Transposable to Aging. AB - To clarify appropriateness of current claims for health and wellness virtues of argan oil, studies were conducted in inflammatory states. LPS induces inflammation with reduction of PGC1-alpha signaling and energy metabolism. Argan oil protected the liver against LPS toxicity and interestingly enough preservation of peroxisomal acyl-CoA oxidase type 1 (ACOX1) activity against depression by LPS. This model of LPS-driven toxicity circumvented by argan oil along with a key anti-inflammatory role attributed to ACOX1 has been here transposed to model aging. This view is consistent with known physiological role of ACOX1 in yielding precursors of specialized proresolving mediators (SPM) and with characteristics of aging and related disorders including reduced PGC1-alpha function and improvement by strategies rising ACOX1 (via hormonal gut FGF19 and nordihydroguaiaretic acid in metabolic syndrome and diabetes conditions) and SPM (neurodegenerative disorders, atherosclerosis, and stroke). Delay of aging to resolve inflammation results from altered production of SPM, SPM improving most aging disorders. The strategic metabolic place of ACOX1, upstream of SPM biosynthesis, along with ability of ACOX1 preservation/induction and SPM to improve aging-related disorders and known association of aging with drop in ACOX1 and SPM, all converge to conclude that ACOX1 represents a previously unsuspected and currently emerging antiaging protein. PMID- 29765503 TI - Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB. AB - Age-associated diseases such as neurodegenerative and cardiovascular disorders are characterized by increased oxidative stress associated with autophagy dysfunction. Oleuropein aglycone (OA), the main polyphenol found in olive oil, was recently characterized as an autophagy inducer and a promising agent against neurodegeneration. It is presently unknown whether OA can have beneficial effects in a model of cardiac stress characterized by autophagy dysfunction. Here, we explored the effects of OA in cardiomyocytes with overexpression of monoamine oxidase-A (MAO-A). This enzyme, by degrading catecholamine and serotonin, produces hydrogen peroxide (H2O2), which causes oxidative stress, autophagic flux blockade, and cell necrosis. We observed that OA treatment counteracted the cytotoxic effects of MAO-A through autophagy activation, as displayed by the increase of autophagic vacuoles and autophagy-specific markers (Beclin1 and LC3 II). Moreover, the decrease in autophagosomes and the increase in autolysosomes, indicative of autophagosome-lysosome fusion, suggested a restoration of the defective autophagic flux. Most interestingly, we found that the ability of OA to confer cardioprotection through autophagy induction involved nuclear translocation and activation of the transcriptional factor EB (TFEB). Our data provide strong evidence of the beneficial effects of OA, suggesting its potential use as a nutraceutical agent against age-related pathologies involving autophagy dysfunction, including cardiovascular diseases. PMID- 29765504 TI - Polyphenolic Compounds, Antioxidant, and Cardioprotective Effects of Pomace Extracts from Feteasca Neagra Cultivar. AB - Grape pomace is a potential source of natural antioxidant agents. Phenolic compounds and antioxidant and cardioprotective properties of fresh and fermented pomace extracts obtained from Vitis vinifera L. red variety Feteasca neagra grown in Romania in 2015 were investigated. Grape pomace extracts total phenolic index, total tannins, total anthocyanins, proanthocyanidins, flavan-3-ol monomers, stilbenes, and DPPH free radical scavenger were measured. The effect of a seven day pretreatment with grape pomace extracts on the isoprenaline-induced infarct like lesion in rats was assessed by ECG monitoring, serum levels of creatine kinase, aspartate transaminase, and alanine transaminase. Total serum oxidative status, total antioxidant response, oxidative stress index, malondialdehyde, total thiols, and nitric oxide have been also assessed. Higher phenolic content and antioxidant activity were found in fermented pomace extracts when compared to fresh pomace extracts. Pretreatment with grape pomace extracts significantly improved cardiac and oxidative stress parameters. In conclusion, Feteasca neagra pomace extracts had a good in vitro antioxidant activity due to an important phenolic content. In vivo, the extracts had cardioprotective effects against isoprenaline-induced infarct-like lesion by reducing oxidative stress, fresh pomace extracts having a better effect. PMID- 29765506 TI - 6'-O-Galloylpaeoniflorin Attenuates Cerebral Ischemia Reperfusion-Induced Neuroinflammation and Oxidative Stress via PI3K/Akt/Nrf2 Activation. AB - 6'-O-galloylpaeoniflorin (GPF), a galloylated derivative of paeoniflorin isolated from peony root, has been proven to possess antioxidant potential. In this present study, we revealed that GPF treatment exerted significant neuroprotection of PC12 cells following OGD, as evidenced by a reduction of oxidative stress, inflammatory response, cellular injury, and apoptosis in vitro. Furthermore, treatment with GPF increased the levels of phosphorylated Akt (p-Akt) and nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as promoted Nrf2 translocation in PC12 cells, which could be inhibited by Ly294002, an inhibitor of phosphoinositide 3-kinase (PI3K). In addition, Nrf2 knockdown or Ly294002 treatment significantly attenuated the antioxidant, anti-inflammatory, and antiapoptotic activities of GPF in vitro. In vivo studies indicated that GPF treatment significantly reduced infarct volume and improved neurological deficits in rats subjected to CIRI, as well as decreased oxidative stress, inflammation, and apoptosis, which could be inhibited by administration of Ly294002. In conclusion, these results revealed that GPF possesses neuroprotective effects against oxidative stress, inflammation, and apoptosis after ischemia-reperfusion insult via activation of the PI3K/Akt/Nrf2 pathway. PMID- 29765505 TI - Inhibition of Protein Aggregation by Several Antioxidants. AB - Amyloid fibril formation is a shared property of all proteins; therefore, model proteins can be used to study this process. We measured protein aggregation of the model amyloid-forming protein stefin B in the presence and absence of several antioxidants. Amyloid fibril formation by stefin B was routinely induced at pH 5 and 10% TFE, at room temperature. The effects of antioxidants NAC, vitamin C, vitamin E, and the three polyphenols resveratrol, quercetin, and curcumin on the kinetics of fibril formation were followed using ThT fluorescence. Concomitantly, the morphology and amount of the aggregates and fibrils were checked by transmission electron microscopy (TEM). The concentration of the antioxidants was varied, and it was observed that different modes of action apply at low or high concentrations relative to the binding constant. In order to obtain more insight into the possible mode of binding, docking of NAC, vitamin C, and all three polyphenols was done to the monomeric form of stefin B. PMID- 29765507 TI - Ex Vivo Cardiotoxicity of Antineoplastic Casiopeinas Is Mediated through Energetic Dysfunction and Triggered Mitochondrial-Dependent Apoptosis. AB - Casiopeinas are a group of copper-based antineoplastic molecules designed as a less toxic and more therapeutic alternative to cisplatin or Doxorubicin; however, there is scarce evidence about their toxic effects on the whole heart and cardiomyocytes. Given this, rat hearts were perfused with Casiopeinas or Doxorubicin and the effects on mechanical performance, energetics, and mitochondrial function were measured. As well, the effects of Casiopeinas triggered cell death were explored in isolated cardiomyocytes. Casiopeinas III Ea, II-gly, and III-ia induced a progressive and sustained inhibition of heart contractile function that was dose- and time-dependent with an IC50 of 1.3 +/- 0.2, 5.5 +/- 0.5, and 10 +/- 0.7 MUM, correspondingly. Myocardial oxygen consumption was not modified at their respective IC50, although ATP levels were significantly reduced, indicating energy impairment. Isolated mitochondria from Casiopeinas-treated hearts showed a significant loss of membrane potential and reduction of mitochondrial Ca2+ retention capacity. Interestingly, Cyclosporine A inhibited Casiopeinas-induced mitochondrial Ca2+ release, which suggests the involvement of the mitochondrial permeability transition pore opening. In addition, Casiopeinas reduced the viability of cardiomyocytes and stimulated the activation of caspases 3, 7, and 9, demonstrating a cell death mitochondrial dependent mechanism. Finally, the early perfusion of Cyclosporine A in isolated hearts decreased Casiopeinas-induced dysfunction with reduction of their toxic effect. Our results suggest that heart cardiotoxicity of Casiopeinas is similar to that of Doxorubicin, involving heart mitochondrial dysfunction, loss of membrane potential, changes in energetic metabolites, and apoptosis triggered by mitochondrial permeability. PMID- 29765508 TI - miR-200a Modulates the Expression of the DNA Repair Protein OGG1 Playing a Role in Aging of Primary Human Keratinocytes. AB - Oxidative DNA damage accumulation may induce cellular senescence. Notably, senescent cells accumulate in aged tissues and are present at the sites of age related pathologies. Although the signaling of DNA strand breaks has been extensively studied, the role of oxidative base lesions has not fully investigated in primary human keratinocyte aging. In this study, we show that primary human keratinocytes from elderly donors are characterized by a significant accumulation of the oxidative base lesion 8-OH-dG, impairment of oxidative DNA repair, and increase of miR-200a levels. Notably, OGG1-2a, a critical enzyme for 8-OH-dG repair, is a direct target of miR-200a and its expression levels significantly decrease in aged keratinocytes. The 8-OH-dG accumulation displays a significant linear relationship with the aging biomarker p16 expression during keratinocyte senescence. Interestingly, we found that miR 200a overexpression down-modulates its putative target Bmi-1, a well-known p16 repressor, and up-regulates p16 itself. miR-200a overexpression also up-regulates the NLRP3 inflammasome and IL-1beta expression. Of note, primary keratinocytes from elderly donors are characterized by NRPL3 activation and IL-1beta secretion. These findings point to miR-200a as key player in primary human keratinocyte aging since it is able to reduce oxidative DNA repair activity and may induce several senescence features through p16 and IL-1beta up-regulation. PMID- 29765510 TI - Correlation between metabolic syndrome and sleep apnea. AB - The so-called "metabolic syndrome" (MS), constitutes a cluster of metabolic and cardiovascular abnormalities, including fasting glucose, blood pressure, triglycerides, high density lipoprotein cholesterol (HDL-C), and waist circumference that arise from insulin resistance. Obstructive sleep apnea (OSA) syndrome is characterized by recurrent episodes of partial or complete obstruction of the upper airway, involving cessation or significant decreased airflow, with intermittent hypoxemia, frequent arousals from sleep and recurrent oxyhemoglobin desaturations that interfere with normal sleep patterns generating difficulty falling asleep, unrefreshing sleep and loud snoring. The relation between these two entities is known as "Syndrome Z", and there is no question about the impact of these risk factors on health and disease. This clinical condition presents a growing epidemic Worldwide, affecting approximately 60% of the general population with both MS and OSA due to the constant increase of body mass index in humans. This article presents evidence-based data that focuses on the direct relationship between MS and OSA. PMID- 29765511 TI - Immunohistochemical analysis of RHAMM expression in normal and neoplastic human tissues: a cell cycle protein with distinctive expression in mitotic cells and testicular germ cells. AB - Expression of Receptor for Hyaluronic Acid Mediated Motility (RHAMM) increases cellular motility and RHAMM overexpression promotes invasive phenotype and metastasis of cancer cells. RHAMM has been suggested as a biomarker for poor prognosis in several tumor types, including lung, breast, colorectal, gastric, pancreatic ductal, and ovarian cancers. RNA studies showed restricted RHAMM expression in normal tissues, but its protein expression data in tissues were limited. In light of its potential as a prognostic marker and a therapeutic target, we performed immunohistochemical analysis to systematically characterize RHAMM expression in normal and neoplastic human tissues. Among 29 normal adult tissues, RHAMM protein showed restricted expression and was observed in the thymus, lymph node/tonsil, small intestine, colon, skin, bone marrow, placenta, and testis. The cellular distribution patterns of RHAMM in these normal tissues were consistent with RHAMM being a G2/M cell cycle protein, and this was further supported in comparison to the expression of cyclin B2, another G2/M protein. However, unlike the subcellular localization of cyclin B2, RHAMM decorated mitotic spindles in both anaphase and metaphase. RHAMM expression in tumor tissues is variable; and higher RHAMM protein expression is associated with histologically higher-grade tumors in general. Distinct from its expression in somatic tissues, RHAMM showed diffuse, strong, stage-specific expression in the spermatocyte stage of germ cells in adult testis. The neoplastic counterpart, spermatocytic tumor, also showed strong RHAMM expression. This unique expression in testis suggests that RHAMM may function during normal testicular germ cell maturation. PMID- 29765509 TI - Resveratrol-Induced Downregulation of NAF-1 Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine via the ROS/Nrf2 Signaling Pathways. AB - NAF-1 (nutrient-deprivation autophagy factor-1), which is an outer mitochondrial membrane protein, is known to play important roles in calcium metabolism, antiapoptosis, and antiautophagy. Resveratrol, a natural polyphenolic compound, is considered as a potent anticancer agent. Nevertheless, the molecular mechanisms underlying the effects of resveratrol and NAF-1 and their mediation of drug resistance in pancreatic cancer remain unclear. Here, we demonstrate that resveratrol suppresses the expression of NAF-1 in pancreatic cancer cells by inducing cellular reactive oxygen species (ROS) accumulation and activating Nrf2 signaling. In addition, the knockdown of NAF-1 activates apoptosis and impedes the proliferation of pancreatic cancer cells. More importantly, the targeting of NAF-1 by resveratrol can improve the sensitivity of pancreatic cancer cells to gemcitabine. These results highlight the significance of strategies that target NAF-1, which may enhance the efficacy of gemcitabine in pancreatic cancer therapy. PMID- 29765512 TI - DHX9 regulates production of hepatitis B virus-derived circular RNA and viral protein levels. AB - Hepatitis B virus (HBV) infection, which is a major health concern worldwide, can lead to liver cirrhosis and hepatocellular carcinoma. Although current nucleos(t)ide analogs efficiently inhibit viral reverse transcription and viral DNA load clinically, episomal viral covalently closed circular DNA (cccDNA) minichromosomes and transcripts from cccDNA continue to be expressed over the long term. We hypothesized that, under these conditions, viral transcripts may have biological functions involved in pathogenesis. Here, we show that the host protein DExH-box helicase 9 (DXH9) is associated with viral RNAs. We also show that viral-derived circular RNA is produced during HBV replication, and the amount is increased by knockdown of the DHX9 protein, which, in turn, results in decreased viral protein levels but does not affect the levels of HBV DNA. These phenomena were observed in the HBV-producing cell culture model and HBV mini circle model mimicking HBV cccDNA, as well as in human primary hepatocytes infected with HBV. Based on these results, we conclude that, in HBV infection, the RNA binding factor DHX9 is a novel regulator of viral circular RNA and viral protein levels. PMID- 29765515 TI - Cancer cell-selective, clathrin-mediated endocytosis of aptamer decorated nanoparticles. AB - Lung cancer is the leading cause of cancer mortality worldwide, resulting in 88% deaths of all diagnosed patients. Hence, novel therapeutic modalities are urgently needed. Single-stranded oligonucleotide-based aptamers (APTs) are excellent ligands for tumor cell targeting. However, the molecular mechanisms underlying their internalization into living cells have been poorly studied. Towards the application of APTs for active drug targeting to cancer cells, we herein studied the mechanism underlying S15-APT internalization into human non small cell lung cancer A549 cells. We thus delineated the mode of entry of a model nanomedical system based on quantum dots (QDs) decorated with S15-APTs as a selective targeting moiety for uptake by A549 cells. These APT-decorated QDs displayed selective binding to, and internalization by target A549 cells, but not by normal human bronchial epithelial BEAS2B, cervical carcinoma (HeLa) and colon adenocarcinoma CaCo-2 cells, hence demonstrating high specificity. Flow cytometric analysis revealed a remarkably low dissociation constant of S15-APTs decorated QDs to A549 cells (Kd = 13.1 +/- 1.6 nM). Through the systematic application of a series of established inhibitors of known mechanisms of endocytosis, we show that the uptake of S15-APTs proceeds via a classical clathrin-dependent receptor-mediated endocytosis. This cancer cell-selective mode of entry could possibly be used in the future to evade plasma membrane-localized multidrug resistance efflux pumps, thereby overcoming an important mechanism of cancer multidrug resistance. PMID- 29765513 TI - 20(S)-protopanaxadiol regio-selectively targets androgen receptor: anticancer effects in castration-resistant prostate tumors. AB - We have explored the effects of 20(S)-protopanaxadiol (aPPD), a naturally derived ginsenoside, against androgen receptor (AR) positive castration resistant prostate cancer (CRPC) xenograft tumors and have examined its interactions with AR. In silico docking studies for aPPD binding to AR, alongside transactivation bioassays and in vivo efficacy studies were carried out in the castration resistant C4-2 xenograft model. Immunohistochemical (IHC) and Western blot analyses followed by evaluation of AR, apoptotic, cell cycle and proliferative markers in excised tumors was performed. The growth of established CRPC tumors was inhibited by 53% with aPPD and a corresponding decrease in serum PSA was seen compared to controls. The IHC data revealed that Ki-67 was significantly lower for aPPD treated tumors and was associated with elevated p21 and cleaved caspase 3 expression, compared to vehicle treatment. Furthermore, aPPD decreased AR protein expression in xenograft tumors, while significantly upregulating p27 and Bax protein levels. In vitro data supporting this suggests that aPPD binds to and significantly inhibits the N-terminal or the DNA binding domains of AR. The AR androgen binding site docking score for androgen (dihydrotestosterone) was -11.1, while that of aPPD was -7.1. The novel findings described herein indicate aPPD potently inhibits PCa in vivo partly via inhibition of a site on the AR N terminal domain. This manifested as cell cycle arrest and concurrent induction of apoptosis via an increase in Bax, cleaved-caspase-3, p27 and p21 expression. PMID- 29765514 TI - Wnt5a-induced cell migration is associated with the aggressiveness of estrogen receptor-positive breast cancer. AB - Elevated expression of Wnt5a is associated with malignancy, cell invasion, and metastasis. The role of Wnt5a expression in breast cancer remains elusive. We investigated the significance of Wnt5a expression in breast cancer. The relationship between Wnt5a expression and clinicopathologic factors was assessed in invasive breast cancer (n = 178) resected at Hiroshima University Hospital between January 2011 and February 2014. Wnt5a was expressed in 69 of 178 cases (39%) of invasive breast cancer and correlated strongly with estrogen receptor (ER) expression (P < 0.001). Wnt5a expression in ER-positive breast cancer correlated significantly with lymph node metastasis, nuclear grade, and lymphatic invasion. The recurrence-free survival was shorter in breast cancer patients with Wnt5a expression than in those without (P = 0.024). The migratory capacity of ER positive breast cancer cells increased with constitutive expression of Wnt5a and decreased with Wnt5a knockdown. DNA microarray analysis identified activated leukocyte cell adhesion molecule (ALCAM) as the primary gene induced by Wnt5a. ALCAM was expressed in 69% of Wnt5a-positive but only 27% of Wnt5a-negative cancers (kappa = 0.444; P < 0.001). The inhibition of ALCAM reversed the enhanced migratory effect of Wnt5a, confirming the importance of this protein in the migration of ER-positive breast cancer cells. Wnt5a expression is related to high malignancy and a poor prognosis in ER-positive breast cancer. We suspect that Wnt5a expression increases the malignancy of breast cancer by increasing the migratory capacity of cancer cells through the induction of ALCAM expression. PMID- 29765516 TI - Selective dissociation between LSD1 and GFI1B by a LSD1 inhibitor NCD38 induces the activation of ERG super-enhancer in erythroleukemia cells. AB - Lysine-specific demethylase 1 (LSD1) is a histone modifier for transcriptional repression involved in the regulation of hematopoiesis. We previously reported that a LSD1 inhibitor NCD38 induces transdifferentiation from erythroid lineage to granulomonocytic lineage and exerts anti-leukemia effect through de-repression of the specific super-enhancers of hematopoietic regulators including ERG in a human erythroleukemia cell line, HEL. However, the mechanistic basis for this specificity of NCD38 has remained unclear. Herein, we report major partners associated with LSD1 and clarify the mechanism in HEL cells. Proteome analysis identified 54 candidate proteins associated with LSD1, including several transcription factors such as GFI1B and RUNX1 as well as BRAF-histone deacetylase complex (BHC) components such as CoREST, HDAC1, and HDAC2. NCD38 selectively disrupted the interaction of LSD1 with GFI1B but not with RUNX1, CoREST, HDAC1 and HDAC2. Erg was downregulated in murine erythroid progenitors with prominent upregulation of Gfi1b. NCD38 induced ERG and attenuated an erythroid marker CD235a in HEL while this attenuation was mimicked by the lentiviral overexpression of ERG. The ERG super-enhancer contained the conserved binding motif of GFI1B and was actually occupied by GFI1B. NCD38 dissociated LSD1 and CoREST but not GFI1B from the ERG super-enhancer. Collectively, the selective separation of LSD1 from GFI1B by NCD38 restores the ERG super-enhancer activation and consequently upregulates ERG expression, inducing the transdifferentiation linked to the anti-leukemia effect. PMID- 29765517 TI - Targeting the mevalonate pathway is a novel therapeutic approach to inhibit oncogenic FoxM1 transcription factor in human hepatocellular carcinoma. AB - Dysregulation of cell metabolism is a hallmark of cancer. The mevalonate pathway in lipid metabolism has been implicated as a potential target of cancer therapy for hepatocellular carcinoma (HCC). The role of the Forkhead Box M1 (FoxM1) transcription factor in HCC development has been well documented, however, its involvement in cancer metabolism of HCC has not been fully determined. Here, we hypothesized that FoxM1 is involved in the mevalonate pathway of cholesterol biosynthesis in HCC. Inhibition of the mevalonate pathway by statins, inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR), resulted in reduced expression of FoxM1 and increased cell death in human hepatoma cells. Re-exposure of mevalonate, a product of HMGCR, restored these effects. Likewise, knockdown of HMGCR reduced FoxM1 expression, indicating that FoxM1 expression was regulated by the mevalonate pathway in HCC. Mechanistically, protein geranylgeranylation was found to be responsible for FoxM1 expression and geranylgeranylated proteins, including RhoA, Rac1 or Cdc42, were shown to be involved in this process. In surgically resected human HCC tissues, the gene expression of FoxM1 had a positive correlation with that of the mevalonate pathway-related genes, such as HMGCR or sterol regulatory element-binding protein 2 (SREBP2). Furthermore, the gene expression of FoxM1 along with that of HMGCR or SREBP2 defined prognosis of HCC patients, suggesting the clinical significance of the mevalonate-FoxM1 pathway in human HCC. Our data indicate that FoxM1 links the mevalonate pathway to oncogenic signals in HCC. Thus, we propose a novel therapeutic approach to inhibit FoxM1 by targeting the mevalonate pathway for HCC. PMID- 29765518 TI - Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation. AB - Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors. Late generation tumors showed higher incidence of lymph node metastases than early generation tumors in three models (ED-15, HL-16, LA-19), and the increased metastatic propensity was associated with increased tumor growth rate, increased microvascular density, and increased expression of angiogenesis-related and cancer stem cell-related genes. Furthermore, late generation tumors showed decreased fraction of pimonidazole-positive tissue (i.e., decreased fraction of hypoxic tissue) in two models (HL-16, LA-19) and decreased fraction of collagen-I positive tissue (i.e., less extensive extracellular matrix) in two models (ED-15, HL-16). This study showed that serially transplanted PDXs may not necessarily mirror the donor patients' diseases, and consequently, proper use of serially transplanted PDX models in translational cancer research requires careful molecular monitoring of the models. PMID- 29765519 TI - Long noncoding RNAs are associated with metabolic and cellular processes in the jejunum mucosa of pre-weaning calves in response to different diets. AB - Long noncoding RNAs (lncRNAs) emerged as important regulatory component of mechanisms involved in gene expression, chromatin modification and epigenetic processes, but they are rarely annotated in the bovine genome. Our study monitored the jejunum transcriptome of German Holstein calves fed two different milk diets using transcriptome sequencing (RNA-seq). To identify potential lncRNAs within the pool of unknown transcripts, four bioinformatic lncRNA prediction tools were applied. The intersection of the alignment-free lncRNA prediction tools (CNCI, PLEK and FEELnc) predicted 1,812 lncRNA transcripts concordantly comprising a catalogue of 1,042 putative lncRNA loci expressed in the calves' intestinal mucosa. Nine lncRNA loci were differentially expressed (DE lncRNAs) between both calf groups. To elucidate their biological function, we applied a systems biology approach that combines weighted gene co-expression network analysis with functional enrichment and biological pathway analysis. Four DE lncRNAs were found to be strongly correlated with a gene network module (GNM) enriched for genes from canonical pathways of remodeling of epithelial adherens junction, tight junction and integrin signaling. Another DE lncRNA was strongly correlated with a GNM enriched for genes associated with energy metabolism and maintaining of cellular homeostasis with a focus on mitochondrial processes. Our data suggest that these DE lncRNAs may play potential regulatory roles in modulating biological processes associated with energy metabolism pathways and cellular signaling processes affecting the barrier function of intestinal epithelial cells of calves in response to different feeding regimens in the pre weaning period. PMID- 29765520 TI - Histogram analysis parameters of dynamic contrast-enhanced magnetic resonance imaging can predict histopathological findings including proliferation potential, cellularity, and nucleic areas in head and neck squamous cell carcinoma. AB - Our purpose was to analyze possible associations between histogram analysis parameters of dynamic contrast-enhanced magnetic resonance imaging DCE MRI and histopathological findings like proliferation index, cell count and nucleic areas in head and neck squamous cell carcinoma (HNSCC). 30 patients (mean age 57.0 years) with primary HNSCC were included in the study. In every case, histogram analysis parameters of Ktrans, Ve, and Kep were estimated using a mathlab based software. Tumor proliferation index, cell count, and nucleic areas were estimated on Ki 67 antigen stained specimens. Spearman's non-parametric rank sum correlation coefficients were calculated between DCE and different histopathological parameters. KI 67 correlated with Ktrans min (p = -0.386, P = 0.043) and s Ktrans skewness (p = 0.382, P = 0.045), Ve min (p = -0.473, P = 0.011), Ve entropy (p = 0.424, P = 0.025), and Kep entropy (p = 0.464, P = 0.013). Cell count correlated with Ktrans kurtosis (p = 0.40, P = 0.034), Ve entropy (p = 0.475, P = 0.011). Total nucleic area correlated with Ve max (p = 0.386, P = 0.042) and Ve entropy (p = 0.411, P = 0.030). In G1/2 tumors, only Ktrans entropy correlated well with total (P =0.78, P =0.013) and average nucleic areas (p = 0.655, P = 0.006). In G3 tumors, KI 67 correlated with Ve min (p = 0.552, P = 0.022) and Ve entropy (p = 0.524, P = 0.031). Ve max correlated with total nucleic area (p = 0.483, P = 0.049). Kep max correlated with total area (p = -0.51, P = 0.037), and Kep entropy with KI 67 (p = 0.567, P = 0.018). We concluded that histogram-based parameters skewness, kurtosis and entropy of Ktrans, Ve, and Kep can be used as markers for proliferation activity, cellularity and nucleic content in HNSCC. Tumor grading influences significantly associations between perfusion and histopathological parameters. PMID- 29765521 TI - Long term deficiency of vitamin D in germ cell testicular cancer survivors. AB - Background: Cisplatin-based chemotherapy significantly improved the survival of patients with germ cell testicular cancer. However, long term side effects of chemotherapy have non-negligible impact on the quality of life of these young patients, who have a long life expectancy after being successfully treated. Materials and Methods: 25-OH vitamin D, testosterone, FSH and LH of patients with testicular cancer were retrospectively evaluated and for each patient clinical information were collected. The tissue of 52 patients with germ cell tumors was analyzed for VDR expression by immunohistochemistry. The serum 25-OH vitamin D and VDR expression were correlated to the patients 'clinical characteristics. Results: 25-OH vitamin D was analyzed in 82 patients. Insufficient (< 30 ng/ml) levels were detected in 65%-85%, mild deficient (< 20 ng/ml) in 25%-36% and severe deficient (< 10 ng/ml) in 6%-18% of the patients over a median follow-up of 48 months. No difference in serum 25-OH vitamin D was detected over the follow up time points. No correlation with histology, stage and type of treatment was found. The 25-OH vitamin D levels were not correlated to testosterone, FSH and LH levels. Interestingly, the expression of VDR was much higher in non seminoma than in seminoma tissue. Conclusions: Patients with testicular cancer have reduced vitamin D levels after the treatment of the primary cancer. Since long term hypovitaminosis D leads to high risk of fractures, infertility and cardiovascular diseases, we envision that vitamin D should be regularly checked in patients with testicular cancer and replaced if needed. PMID- 29765522 TI - Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma. AB - Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a rare and devastating malignancy, and preclinical studies are needed to evaluate potential therapeutic regimens. Here, we examined the antitumor effects of cisplatin (CDDP), etoposide (ETP) and irinotecan (CPT-11) and their combinations on GEP-NEC using three small-cell GEP-NEC cell lines (pancreatic NEC, A99; esophageal NEC, TYUC-1; duodenum NEC, TCC-NECT-2). In vitro studies were conducted using cell viability assays. In vivo experiments were conducted in mice inoculated with A99 or TCC-NECT-2 and treated with no agent, CDDP, CDDP+ETP (EP) or CDDP+CPT-11 (IP). TYUC-1 was the most susceptible to all agents, whereas A99 was refractory. Classical isobolograms showed synergism in both the EP and IP combinations for the three cell lines. In the TCC-NECT-2 mouse model, the IP regimen showed a significant antitumor effect, and CDDP alone showed a marginal effect compared to the control. In contrast, no effect was detected in the A99 model, probably because A99 was established from a metastatic tumor after chemotherapy with EP. Gene expression analysis of the ATP-binding cassette transporters revealed that ATP binding cassette subfamily B member1 (ABCB1) was conspicuously expressed in A99, and ABCB1 and ATP binding cassette subfamily C member2 (ABCC2) were deficient in TYUC-1, which might explain a part of different CDDP susceptibilities between cell lines. These preclinical models indicate that CDDP is a key agent, and IP regimen might be a reasonable option, although its efficacy is moderate. Our data on the platinum-based regimen will be useful as reference information in developing new agents for GEP-NEC. PMID- 29765523 TI - Overexpressing TPTE2 (TPIP), a homolog of the human tumor suppressor gene PTEN, rescues the abnormal phenotype of the PTEN-/- mutant. AB - One possible approach to normalize mutant cells that are metastatic and tumorigenic, is to upregulate a functionally similar homolog of the mutated gene. Here we have explored this hypothesis by generating an overexpressor of TPTE2 (TPIP), a homolog of PTEN, in PTEN-/- mutants, the latter generated by targeted mutagenesis of a human epithelial cell line. Overexpression of TPTE2 normalized phenotypic changes associated with the PTEN mutation. The PTEN-/- -associated changes rescued by overexpressing TPTE2 included 1) accelerated wound healing in the presence or absence of added growth factors (GFs), 2) increased division rates on a 2D substrate in the presence of GFs, 3) adhesion and viability on a 2D substrate in the absence of GFs, 4) viability in a 3D Matrigel model in the absence of GFs and substrate adhesion 5) loss of apoptosis-associated annexin V cell surface binding sites. The results justify further exploration into the possibility that upregulating TPTE2 by a drug may reverse metastatic and tumorigenic phenotypes mediated in part by a mutation in PTEN. This strategy may also be applicable to other tumorigenic mutations in which a homolog to the mutated gene is present and can substitute functionally. PMID- 29765525 TI - Clinical characteristics of non-small cell lung cancer harboring mutations in exon 20 of EGFR or HER2. AB - Unlike common epidermal growth factor receptor gene (EGFR) mutations that confer sensitivity to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC), mutations in exon 20 of either EGFR or the human EGFR2 gene (HER2) are associated with insensitivity to EGFR-TKIs, with treatment options for patients with such mutations being limited. Clinical characteristics, outcome of EGFR-TKI or nivolumab treatment, and the presence of coexisting mutations were reviewed for NSCLC patients with exon-20 mutations of EGFR or HER2 as detected by routine application of an amplicon-based next-generation sequencing panel. Between July 2013 and June 2017, 206 patients with pathologically confirmed lung cancer were screened for genetic alterations including HER2 and EGFR mutations. Ten patients harbored HER2 exon-20 insertions (one of whom also carried an exon-19 deletion of EGFR), and 12 patients harbored EGFR exon-20 mutations. Five of the 13 patients with EGFR mutations were treated with EGFR-TKIs, two of whom manifested a partial response, two stable disease, and one progressive disease. Among the seven patients treated with nivolumab, one patient manifested a partial response, three stable disease, and three progressive disease, with most (86%) of these patients discontinuing treatment as a result of disease progression within 4 months. The H1047R mutation of PIK3CA detected in one patient was the only actionable mutation coexisting with the exon-20 mutations of EGFR or HER2. Potentially actionable mutations thus rarely coexist with exon-20 mutations of EGFR or HER2, and EGFR-TKIs and nivolumab show limited efficacy in patients with such exon-20 mutations. PMID- 29765524 TI - Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy). AB - CfDNA samples from colon (mCRC) and non-small cell lung cancers (NSCLC) (CIRCAN cohort) were compared using three platforms: droplet digital PCR (ddPCR, Biorad); BEAMing/OncoBEAMTM-RAS-CRC (Sysmex Inostics); next-generation sequencing (NGS, Illumina), utilizing the 56G oncology panel (Swift Biosciences). Tissue biopsy and time matched cfDNA samples were collected at diagnosis in the mCRC cohort and during 1st progression in the NSCLC cohort. Excellent matches between cfDNA/FFPE mutation profiles were observed. Detection thresholds were between 0.5-1% for cfDNA samples examined using ddPCR and NGS, and 0.03% with BEAMing. This high level of sensitivity enabled the detection of KRAS mutations in 5/19 CRC patients with negative FFPE profiles. In the mCRC cohort, comparison of mutation results obtained by testing FFPE to those obtained by testing cfDNA by ddPCR resulted in 47% sensitivity, 77% specificity, 70% positive predictive value (PPV) and 55% negative predictive value (NPV). For BEAMing, we observed 93% sensitivity, 69% specificity, 78% PPV and 90% NPV. Finally, sensitivity of NGS was 73%, specificity was 77%, PPV 79% and NPV 71%. Our study highlights the complementarity of different diagnostic approaches and variability of results between OncoBEAMTM-RAS-CRC and NGS assays. While the NGS assay provided a larger breadth of coverage of the major targetable alterations of 56 genes in one run, its performance for specific alterations was frequently confirmed by ddPCR results. PMID- 29765526 TI - Esophageal cancer cells resistant to T-DM1 display alterations in cell adhesion and the prostaglandin pathway. AB - Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate that specifically targets HER2 thanks to its antibody component trastuzumab. In spite of responses to this novel agent, acquired resistance to treatment remains a major obstacle. Prolonged in vitro exposure of the gastroesophageal junction cancer cell line OE 19 to T-DM1, in the absence or presence of ciclosporin A resulted in the selection of two resistant cell lines to T-DM1. T-DM1-resistant cells presented an increased expression of adhesion genes, altered spreading and higher sensitivity to anoikis than parental cells. A resistant cell line showed decreased adhesion strength, increased migration speed and increased sensitivity to RhoA inhibition. Genes involved in the prostaglandin pathway were deregulated in resistant models. Addition of prostaglandin E2 to T-DM1 partially restored its cytotoxic activity in resistant models. This work demonstrates that T-DM1 resistance may be associated with alterations of cell adhesion and the prostaglandin pathway, which might constitute novel therapeutic targets. PMID- 29765527 TI - LpMab-23-recognizing cancer-type podoplanin is a novel predictor for a poor prognosis of early stage tongue cancer. AB - Purpose: We report that the reactivity of a novel monoclonal antibody LpMab-23 for human cancer-type podoplanin (PDPN) is a predictor for a poor prognosis of tongue cancer. Patients and Methods: The association between LpMab-23-recognizing cancer-type PDPN expression and clinical/pathological features were analyzed on 60 patients with stage I and II tongue cancer treated with transoral resection of the primary tumor. Results: In the mode of invasion, the LpMab-23-dull/negative cases were significantly larger in cases with low-grade malignancies and without late cervical lymph node metastasis, than in cases with high-grade malignancies and the metastasis. In the high-grade malignant cases, LpMab-23-positive cases were significantly larger than LpMab-23-dull/negative cases. The Kaplan-Meier curves of the five-year metastasis-free survival rate (MFS) were significantly lower in the LpMab-23 positive patients than in LpMab-23 dull/negative patients. The LpMab-23-dull/negative cases showed the highest MFS in all of the clinical/pathological features and particularly, the MFS of the LpMab-23 positive cases decreased to less than 60% in the first year. In the Cox proportional hazard regression models a comparison of the numbers of LpMab-23 dull/negative with positive cases showed the highest hazard ratio with statistical significance in all of the clinical/pathological features. Conclusions: LpMab-23 positive cases may be considered to present a useful predictor of poor prognosis for early stage tongue cancer. PMID- 29765528 TI - Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells. AB - Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines. We demonstrated that metformin as a single agent, especially at high concentrations produced significant reductions in viability and proliferation only in Daudi and SUDHL-4 cell lines with associated alterations in mitochondrial oxidative and glycolytic metabolism. As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110delta- PI3K inhibitor). Co-treating KPUM-UH1 and SUDHL-4 cells with 10 mM of metformin resulted in 1.4 fold and 8.8 fold decreases, respectively, in IC-50 values of Venetoclax. By contrast, 3-fold and 10 fold reduction in IC-50 values of BAY 1143572 in Daudi and Jeko-1 cells respectively was seen in the presence of 10 mM of metformin. No change in IC-50 value for Idelalisib was observed across cell lines. These data suggest that although metformin is not a potent single agent, targeting cancer metabolism with similar but more effective drugs in novel combination with either bcl-2 or CDK9 inhibitors warrants further exploration. PMID- 29765530 TI - Mean platelet volume as a predictive marker for venous thromboembolism in patients treated for Hodgkin lymphoma. AB - Mean platelet volume (MPV) is reported to be associated with the risk of venous thromboembolism (VTE) and mortality in patients with cancer. We sought to determine the association of MPV with symptomatic VTE occurrence in patients treated for newly diagnosed Hodgkin lymphoma (HL) and their outcomes. We retrospectively studied 167 consecutive adult patients treated with HL. During first-line treatment 12 (7.2%) patients developed VTE and 14 (8%) died within the observation period. The pre-chemotherapy values of MPV were significantly lower in VTE patients than those without (p=0.0343). Patients with MPV<=25th percentile (6.8 fl) had an increased risk of VTE occurrence (p=0.0244). In multivariate analysis, MPV<=25th percentile (OR 2.21; 95%CI 1.07-4.57, p=0.033), advanced stage (OR 2.08; 95%CI 1.06-4.07, p=0.033) and bulky disease (OR 2.23; 95%CI 1.16 4.31, p=0.016) were significant factors for developing VTE. Only the impact of MPV<=25th percentile on VTE-free survival rates was found. VTE occurred in 43% (n=3) of the high-risk patients of the Thrombosis Lymphoma (ThroLy) score and in 17% (n=2) of the high-risk of the Khorana Risk Score (KRS). Neither the KRS nor the ThroLy score could identify patients at a high risk of VTE with a high degree of accuracy. We expanded the ThroLy score with the addition of the MPV<=25th percentile to more accurately identify HL patients with a higher risk of VTE. Our study indicates that the pre-chemotherapy MPV value, while of no use as an overall prognosis predictor, may still represent a useful prognostic marker for a significant VTE risk especially when incorporated into VTE-risk assessment models. PMID- 29765529 TI - MYC gene amplification is a rare event in atypical fibroxanthoma and pleomorphic dermal sarcoma. AB - Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are rare malignancies typically occurring in elderly patients and predominantly located in skin regions exposed to UV-light. Thus, a role of UV-radiation-induced damage for AFX and PDS tumorigenesis has been postulated. MYC gene amplification has been demonstrated as a distinctive feature of radiation-induced angiosarcoma. In order to investigate whether chronic exposure to UV-light might also lead to MYC copy number changes, 51 AFX and 24 PDS samples were retrospectively analyzed for MYC amplification by fluorescence in situ hybridization using a MYC and a CEP8 gene probe. Of the 44 analyzable AFX samples, one case showed MYC amplification (defined as a MYC/CEP8 ratio >=2.0), whereas 13 cases demonstrated low level copy number gains (defined as MYC/CEP8 ratio >= 1.2-< 2.0). MYC amplification was seen in an AFX sample of extraordinary tumor thickness of 17.5 mm (vs. median 3.25 mm for all samples). Of the 24 PDS cases, five specimen demonstrated MYC low level copy number gains. Immunohistochemically, neither the AFX nor the PDS cases showed MYC protein expression. In summary, these findings rule out that MYC amplification is a major genetic driver in the process of AFX or PDS tumorigenesis. However, MYC amplification may occur as a late event during AFX development and hence might only be detectable in advanced, thick lesions. PMID- 29765531 TI - Comparison of coronary artery bypass grafting and percutaneous coronary intervention in patients with heart failure with reduced ejection fraction and multivessel coronary artery disease. AB - Aims: To compare coronary artery bypass grafting (CABG) with percutaneous coronary interventions (PCI) in patients with heart failure with reduced ejection fraction (HFrEF) and multivessel coronary artery disease. Methods: 1213 patients were selected from institutional databases, 761 and 452 in CABG and PCI group respectively. Only the subjects with left ventricle ejection fraction <= 35% and multivessel coronary artery disease were included to the study. The primary outcome measure was long-term all-cause death, the secondary outcomes were recurrent myocardial infarction, urgent repeat revascularization and stroke. Propensity Score-Based Adjusted Survival Curves were used for revascularization methods comparison. Results: Survival rates were similar in both groups (HR, 0.91; 95% CI, 0.65-1.28; p=0.59). Recurrent myocardial infarction was observed significantly less often in the CABG group (HR, 0.44; 95% CI, 0.26-0.74; p=0.002). Repeat urgent revascularization was less frequent in the CABG group (HR, 0.50; 95% CI, 0.30-0.84; p=0.008). The rate of stroke did not differ between the groups (HR, 1.17; 95% CI, 0.62-2.22; p=0.62). Conclusions: In patients with HFrEF and multivessel CAD revascularization both with CABG and PCI resulted in similar survival rates. PCI is associated with increased risk of recurrent MI and urgent repeat revascularization, whereas the risk of stroke is similar in both methods. PMID- 29765532 TI - Chemopreventive activity of celastrol in drug-resistant human colon carcinoma cell cultures. AB - Celastrol (tripterine) a pentacyclic triterpenoid extracted from the roots of Tripterygium wilfordii Hook f., exhibits potent antioxidant and anti-inflammatory activity and also exerts important anti-cancer effects, as induction of apoptosis and lowering the level of drug resistance of several cancers. Increased level of cellular resistance to cytostatic drugs is typical for colorectal cancers, and largely determines the failure of chemotherapy for this tumor. The purpose of our research was to evaluate the chemopreventive effect of celastrol on cultures of colon cancer cells resistant to doxorubicin (LOVO/DX). With the use of flow cytometry we have shown that celastrol reduces the cell size of the SP (side population; subpopulation of cancer cells enriched with cancer stem cells), increases frequency of apoptosis and binds to Pgp protein in cell membranes inhibiting its transport function. The inhibition of the Pgp transport function has been shown to increase the accumulation of rhodamine-123 and standard cytostatic- doxorubicin in LOVO/DX cells. Our results prove that celastrol exhibits significant chemopreventive and chemosensitizing activities on drug resistant colon cancer cells. Celastrol appears to be a good candidate for adjuvant medicine that can improve the effectiveness of standard cytostatic therapy in humans. PMID- 29765533 TI - GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer risk in Polish nonsmokers. AB - Glutathione S-transferase (GST) enzymes are responsible for cellular detoxification of many carcinogens and are important anticancer elements. This study assessed potential relationships between GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer (CRC) risk in Polish nonsmokers. We also analyzed the influence of GST gene polymorphisms on CRC clinical and histopathological features. Our study included 197 CRC patients and 104 healthy controls. GSTM1, GSTT1, and GSTP1 polymorphisms were evaluated using qPCR. Polymorphism frequencies observed in our control group corresponded to those in other European populations. The GSTM1 null and GSTT1 null genotypes were observed with similar frequencies in both CRC patients and controls (GSTM1 null: 46.7% vs. 45.2%; GSTT1 null: 15.7% vs. 20.2%). GSTP1 Ile/Ile, Ile/Val, and Val/Val genotype frequencies were respectively 42.1%, 48.2%, and 9.6% in patients and 48.1%, 42.3%, and 9.6% in controls. GSTT1 polymorphism correlated with higher tumor grade in CRC patients, and the GSTM1 null/null genotype was associated with more frequent metastasis to lymph nodes (pN classification). Our results suggest that GST gene polymorphisms may influence CRC tumor grade and stage. PMID- 29765534 TI - BI2536 induces mitotic catastrophe and radiosensitization in human oral cancer cells. AB - BI2536 has been developed as a potential therapeutic agent for various cancers but not in oral cancer cells. Since BI2536 exhibits mitosis-regulating activity which are the most radiosensitive, we hypothesized that BI2536 might modulate the radiosensitivity of oral cancer cells. Human normal fibroblasts, oral cancer SAS, and OECM1 cells were treated with BI2536 (0-50 nM) and/or radiation (0-4 Gy). MTT assay, Liu's staining, flow cytometry, clonogenic assay, Annexin V/propidium iodide (PI) staining, western blot analysis, and small interfering RNA knockdown experiments were used to assess cell viability, morphology, cell cycle progression, radiation survival, and expression of regulatory proteins in vitro. Male BALB/c nude mice implanted with SAS cells were used to examine the effects of BI2536 in vivo. Treatment with BI2536 preferentially inhibited the viability of SAS and OECM1 cells, but not the normal fibroblasts. Morphological examination and Annexin V/PI staining of BI2536-treated oral cancer cells showed mitotic catastrophe and apoptosis. A DNA histogram revealed BI2536 induced G2/M and upregulation of phosphorylated H3 indicating accumulation in the M phase. BI2536 modulated the expression of PLK1, cell division control protein (Cdc)2, Cdc20, Cdc25c, adenomatous polyposis coli 3, and cyclin B1. At 10 nM, BI2536 exhibited low cytotoxicity, effectively induced mitotic catastrophe, and more importantly, sensitized oral cancer cells to radiotherapy. The animal study showed that BI2536 (10 mg/kg) + radiation (2 Gy) resulted in stronger tumor inhibition than that associated with radiation alone. Our findings showed that BI2536 could be an effective radiosensitizer both in vitro and in vivo. PMID- 29765535 TI - Effects of CB2 and TRPV1 receptors' stimulation in pediatric acute T lymphoblastic leukemia. AB - T-Acute Lymphoblastic Leukemia (T-ALL) is less frequent than B-ALL, but it has poorer outcome. For this reason new therapeutic approaches are needed to treat this malignancy. The Endocannabinoid/Endovanilloid (EC/EV) system has been proposed as possible target to treat several malignancies, including lymphoblastic diseases. The EC/EV system is composed of two G-Protein Coupled Receptors (CB1 and CB2), the Transient Potential Vanilloid 1 (TRPV1) channel, their endogenous and exogenous ligands and enzymes. CB1 is expressed mainly in central nervous system while CB2 predominantly on immune and peripheral cells, therefore we chose to selectively stimulate CB2 and TRPV1. We treated T-ALL lymphoblasts derived from 4 patients and Jurkat cells with a selective agonist at CB2 receptor: JWH-133 [100 nM] and an agonist at TRPV1 calcium channel: RTX [5 uM] at 6, 12 and 24 hours. We analyzed the effect on apoptosis and Cell Cycle Progression by a cytofluorimetric assays and evaluated the expression level of several target genes (Caspase 3, Bax, Bcl-2, AKT, ERK, PTEN, Notch-1, CDK2, p53) involved in cell survival and apoptosis, by Real-Time PCR and Western Blotting. We observed a pro-apoptotic, anti-proliferative effect of these compounds in both primary lymphoblasts obtained from patients with T-ALL and in Jurkat cell line. Our results show that both CB2 stimulation and TRPV1 activation, can increase the apoptosis in vitro, interfere with cell cycle progression and reduce cell proliferation, indicating that a new therapeutic approach to T-cell ALL might be possible by modulating CB2 and TRPV1 receptors. PMID- 29765536 TI - Predicting hepatocellular carcinoma through cross-talk genes identified by risk pathways. AB - Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer with poor survival rate and high mortality. Despite efforts on the mechanism of HCC, new molecular markers are needed for exact diagnosis, evaluation and treatment. Here, we combined transcriptome of HCC with networks and pathways to identify reliable molecular markers. Through integrating 249 differentially expressed genes with syncretic protein interaction networks, we constructed a HCC-specific network, from which we further extracted 480 pivotal genes. Based on the cross talk between the enriched pathways of the pivotal genes, we finally identified a HCC signature of 45 genes, which could accurately distinguish HCC patients with normal individuals and reveal the prognosis of HCC patients. Among these 45 genes, 15 showed dysregulated expression patterns and a part have been reported to be associated with HCC and/or other cancers. These findings suggested that our identified 45 gene signature could be potential and valuable molecular markers for diagnosis and evaluation of HCC. PMID- 29765537 TI - STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells. AB - Although several studies established that unlike normal B cells chronic lymphocytic leukemia (CLL) cells metabolize fatty acids (FA), how CLL cells internalize FA is poorly understood. Because in various cell types CD36 facilitates FA uptake, we wondered whether a similar mechanism is operative CLL. We found that CD36 levels are higher in CLL cells than in normal B cells, and that small interfering RNA, CD36 neutralizing antibodies or sulfosuccinimidyl oleate (SSO) that inhibits CD36 significantly reduced the oxygen consumption of CLL cells incubated with FA. Because CD36 is oeverexpressed and STAT3 is constitutively activated in CLL cells, we wondered whether STAT3 induces CD36 expression. Sequence analysis identified putative STAT3 binding sites in the CD36 gene promoter. Chromatin immunoprecipitation and an electrophoretic mobility shift assay revealed that STAT3 binds to the CD36 gene promoter. A luciferase assay and STAT3-small hairpin RNA, that significantly decreased the levels of CD36 in CLL cells, established that STAT3 activates the transcription of the CD36 gene. Furthermore, SSO induced a dose-dependent apoptosis of CLL cells. Taken together, our data suggest that STAT3 activates CD36 and that CD36 facilitates FA uptake in CLL cells. Whether CD36 inhibition would provide clinical benefits in CLL remains to be determined. PMID- 29765539 TI - CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity. AB - CRM1/XPO1 (CRM1) is a nuclear export chaperone that mediates the export of proteins essential to growth regulation and tumor suppression. Its overexpression in tumors was found to be associated with poor prognosis. Selective inhibitors of nuclear export are in phase I and II clinical trials for several tumor types. Our aim was to investigate CRM1 expression in pancreatic adenocarcinoma (PAC) and its relationship to survivin expression and the proliferative activity. Sections of tissue microarray containing 76 formalin fixed and paraffin embedded PAC were stained by immunohistochemistry (IHC) for CRM1, survivin, and Cyclin A. Expression levels of CRM1 and survivin and the proliferative activity, the S phase fraction (SPF) in tumor cells, were determined using a quantitative digital image analysis solution (OTMIAS). Sixty-six of the 76 (86%) PAC showed positive staining for CRM1, and 10 (14%) were completely negative. The mean CRM1 expression levels ranged from 0.3 to 53 units and the median from 0.3 to 45 units. There was significant positive correlation between the mean and median expression levels of CRM1 in tumor cells and the mean and median levels of survivin (p<0.001). Moreover, there was positive correlation between the mean and median CRM1 levels in tumor cells and the SPF (p=0.013). Our results show that CRM1 is expressed in a significant proportion of PAC, and increased CRM1 levels correlates with increased survivin levels and increased proliferative activity. PMID- 29765538 TI - Prognostic value of the DNA integrity index in patients with malignant lung tumors. AB - Introduction: Lung cancer survival remains poor in the western world due to late presentation in most cases, leading to difficulty of treatment in these advanced and metastatic patients. Therefore, the development of a robust biomarker for prognosis and to monitor treatment response and relapse would be of great benefit. The use of Alu repeats and DNA Integrity Index has been shown to hold both diagnostic and prognostic value, and as it is obtained from the plasma of patients, it can serve as a non-invasive tool for routine monitoring. This study evaluates the efficiency of this technique in malignant lung cancer patients. Methods: Plasma samples were collected from 48 patients, consisting of 29 lung cancer patients and 19 non-cancer controls. Alu repeat ratio and confounders were measured. Results: Observations showed a higher Alu repeat ratio amongst the cancer group compared to controls (p=0.035), mean Alu ratio 0.38 (range 0.01 0.93) and 0.22 (0.007-0.44) respectively, ROC curve analysis AUC 0.61 (p=0.22). Analysis by staging was more promising, whereby a higher DNA Integrity Index was seen in advanced cases compared to both early stage and controls, p<0.0001; AUC: 0.92 (P=0.0002) and p=0.0006, AUC - 0.88 (p=0.0007) respectively, however no significant difference was observed in the early stage compared to controls. Short term survival data also showed a DNA Integrity Index of >0.5 to be associated with poorer overall survival p=0.03. Conclusion: The results of this study show a potential use of Alu repeats ratios for prognostic purposes in the advanced setting for lung cancer patients. PMID- 29765540 TI - Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer? AB - Glioblastoma is the most aggressive brain tumor with poor overall survival bellow 2 years. The natural compounds with anti-cancer properties, are thus gaining attention for possible adjuvant GBM treatment. In various cancer models Enterolobium contortisiliquum Trypsin Inhibitor (EcTI) proved to have anti-cancer effects. Here, we investigated the EcTI effects on GBM U87 cells and on mesenchymal stem cells (MSC) compared to their direct coculture (MSC/U87). MSC are present in tumor stroma, modulating GBM cells phenotype, and also represent potential drug delivery vehicle due to their tumor tropism. We showed that in p53 wild type U87 cells, metabolic activity was less affected by EcTI as in MSC monocuture, but the metabolic rate of mixed coculture was significantly reduced at lower EcTI concentration. Under coculture condition, EcTI potentiated MSC induced cell cycle arrest, possible due to highly increased p53, p21 and lower D1 expression, but there was no effect on apoptosis. Accordingly, in the coculture EcTI also enhanced Ca2+ signalling mediated via bradykinin receptor 2, being associated with nitric oxide release that highly impaired proliferation and invasion. The mechanism did not seem to involve changes in cell adhesion but rather it down-regulated the beta1 integrin signaling with associated p-FAK in U87 cells, both supporting inhibition of invasion. Finally, some cytokines were down-regulated, indicating that EcTI inhibition of signalling might be mediated by cytokines. In conclusion, these results indicate that in cocultured MSC/U87 cells EcTI impairs the metabolic activity, proliferation, and reduced invasion, possibly associated with observed cytokines secretion. In this context, we confirmed that the plant derived protein potentiated the anticancer effects, induced by MSC, as represented by GBM U87 cell line. PMID- 29765541 TI - The effect of antiviral therapy on serum lipid profiles in chronic hepatitis C. AB - Background: Low lipid profile is associated with hepatitis C virus (HCV) infection. Chronic HCV infection is the main cause of liver injury and serum lipid levels during antiviral treatment. We aimed to evaluate the effect of antiviral treatment on the change of lipid profiles during HCV treatment. Methods: Total 863 patients who complete the interferon-based therapy in Kaohsiung Medical University Hospital were included in this study. The lipid profile measured and evaluated in baseline and after 6 months of the treatment. Results: Sustained virological response (SVR) was achieved in 81.2% of all patients. The baseline triglycerides (TG) levels in the SVR group and non SVR groups were similar. The TG levels at 6 months after cessation of the treatment was significantly elevated in SVR group (102.9+/-57.0 mg/dL, p=0.0001) but did not elevated in non SVR group (94.5+/-45.6 mg/dL, p=0.690) compared with baseline TG levels. After adjusting patients by four indexes for fibrosis (FIB4) in cut off point 3.25, serum TG levels significantly increased in low FIB4 group (103.2+/-57.9 mg/dL, p=0.0001) but not in high FIB4 group (98.1+/-49.6 mg/dL, p=0.095) after 6 months end of the treatment. Serum TG level was increased greater in patients who had low FIB4 score and patients who achieved SVR (baseline 89.1+/-34.8 mg/dL; 6 months after treatment 104.3+/-59.3 mg/dL, paired T test p=0.0001). Conclusion: The clearance of the HCV RNA is the main determinant of the increase of lipids after PegIFN/RBV treatment. However advanced fibrosis also has an effect in increase of lipids after the treatment. PMID- 29765542 TI - SMAR1 inhibits Wnt/beta-catenin signaling and prevents colorectal cancer progression. AB - Reduced expression of Scaffold/Matrix Attachment Region Binding Protein 1 (SMAR1) is associated with various cancers resulting in poor prognosis of the diseases. However, the precise underlying mechanism elucidating the loss of SMAR1 requires ongoing study. Here, we show that SMAR1 is highly downregulated during aberrant Wnt3a signaling due to proteasomal degradation and predicted poor prognosis of colorectal cancer. However, substitution mutation (Arginine and Lysine to Alanine) in the D-box elements of SMAR1 viz. "RCHL" and "RQRL" completely abrogated its proteasomal degradation despite Wnt3a activity. SMAR1 inhibited Wnt/beta-catenin signaling by recruiting Histone deacetylase-5 to beta-catenin promoter resulting in reduced cell migration and invasion. Consequently, reduced tumor sizes in in-vivo NOD-SCID mice were observed that strongly associated with suppression of beta-catenin. However, loss of SMAR1 led to enriched H3K9 Acetylation in the beta-catenin promoter that further increased Wnt/beta-catenin signaling activities and enhanced colorectal cancer progression drastically. Using docking and isothermal titration calorimetric studies we show that small microbial peptides viz. AT-01C and AT-01D derived from Mycobacterium tuberculosis mask the D-box elements of SMAR1. These peptides stabilized SMAR1 expression that further inhibited metastatic SW480 colorectal cancer cell migration and invasion. Drastically reduced subcutaneous tumors were observed in in-vivo NOD-SCID mice upon administration of these peptides (25 mg/kg body weight) intraperitoneally. Taken together our structural studies, in-vitro and in-vivo results strongly suggest that the D-box elements of SMAR1 represent novel druggable targets, where the microbial peptides hold promise as novel colorectal cancer therapeutics. PMID- 29765543 TI - IgG4-related kidney disease: the effects of a Rituximab-based immunosuppressive therapy. AB - IgG4-related disease (IgG4-RD) is a recently recognized disorder, characterized by elevated serum IgG4 concentrations, dense tissue infiltration of IgG4-positive plasma cells and storiform fibrosis. Treatment is usually based on steroids, however, relapses and long-term adverse effects are frequent. We prospectively studied 5 consecutive patients with histologically-proven IgG4-RD and renal involvement, treated with an extended Rituximab protocol combined with steroids. Two doses of intravenous cyclophosphamide were added in 4 patients. Five patients with IgG-RD were investigated: three had tubulointerstitial nephritis (TIN), while two had retroperitoneal fibrosis (RPF). In the patients with TIN, renal biospy was repeated after 1 year. In the patients with TIN, estimated glomerular filtration rate (eGFR) at 12 months increased from 9 to 24 ml/min per 1.73 m2; IgG/IgG4 decreased from 3,236/665 to 706/51 mg/dl; C3/C4 increased from 49/6 to 99/27 mg/dl; CD20+ B-cells decreased from 8.7% to 0.5%; Regulatory T-cells decreased from 7.2% to 2.5%. These functional and immunologic changes persisted at 24 months and in two patients at 36 months. A repeat renal biopsy in the patients with TIN showed a dramatic decrease in interstitial plasma cell infiltrate with normalization of IgG4/IgG positive plasma cells. The patients with RPF showed a huge regression of retroperitoneal tissue. In this sample of patients with aggressive IgG4-RD and renal involvement, treatment aimed at depleting B cells and decreasing antibody and cytokine production was associated with a substantial, persistent increase in eGFR, and a definite improvement in immunologic, radiologic and histological parameters. PMID- 29765544 TI - Comparison of infectivity and spread between HSV-1 and HSV-2 based oncolytic viruses on tumor cells with different receptor expression profiles. AB - Herpes simplex virus (HSV) is one of the many viruses that have been modified or adapted for oncolytic purposes. There are two serotypes of HSV, HSV-1 and HSV-2. The majority of oncolytic HSVs, including T-VEC which has recently been approved by the US Food and Drug Administration (FDA) for clinical use in treating late stage melanoma patients, are derived from HSV-1. Recently, we and others have developed several HSV-2 based oncolytic viruses. During our in vitro characterization of oncolytic viruses developed from both serotypes (Baco-1 from HSV-1 and FusOn-H2 from HSV-2), we noticed there is a subpopulation of cancer cells in which both viruses could infect but only FusOn-H2 could spread from cell to cell on monolayers. This observation prompted us to investigate the virus receptor expression profiles in these and other tumor cells. Our data show the following: 1) This subpopulation of tumor cells only express nectin-2, not the other two major receptors (HVEM or nectin-1). 2) Baco-1 grows to a higher titer than FusOn-H2 in this subpopulation of tumor cells, but the latter kills these tumor cells more efficiently than the former. 3) FusOn-H2 is effective at treating tumors formed from these tumor cells while Baco-1 is completely ineffective. Our results suggest that this subpopulation of tumor cells may be intrinsically resistant to the therapeutic effect of a HSV-1 based oncolytic virus but they remain sensitive to a HSV-2 based virotherapy. PMID- 29765545 TI - Multi-institution analysis of racial disparity among African-American men eligible for prostate cancer active surveillance. AB - There is a significant controversy on whether race should be a factor in considering active surveillance for low-risk prostate cancer. To address this question, we analyzed a multi-institution database to assess racial disparity between African-American and White-American men with low risk prostate cancer who were eligible for active surveillance but underwent radical prostatectomy. A retrospective analysis of prospectively collected clinical, pathologic and oncologic outcomes of men with low-risk prostate cancer from seven tertiary care institutions that underwent radical prostatectomy from 2003-2014 were used to assess potential racial disparity. Of the 333 (14.8%) African-American and 1923 (85.2%) White-American men meeting active surveillance criteria, African-American men were found to be slightly younger (57.5 vs 58.5 years old; p = 0.01) and have higher BMI (29.3 v 27.9; p < 0.01), pre-op PSA (5.2 v 4.7; p < 0.01), and maximum percentage cancer on biopsy (15.1% v 13.6%; p < 0.01) compared to White-American men. Univariate and multivariate analysis demonstrated similar rates of upgrading, upstaging, positive surgical margin, and biochemical recurrence between races. These results suggest that single institution studies recommending more stringent AS enrollment criteria for AA men with a low-risk prostate cancer may not capture the complete oncologic landscape due to institutional variability in cancer outcomes. Since all seven institutions demonstrated no significant racial disparity, current active surveillance eligibility should not be modified based upon race until a prospective study has been completed. PMID- 29765546 TI - Proteomic screening identifies the zonula occludens protein ZO-1 as a new partner for ADAM12 in invadopodia-like structures. AB - The epithelial mesenchymal transition (EMT) is a key process for cancer cell invasion and migration. This complex program whereby epithelial tumor cells loose polarity and acquire mesenchymal phenotype is driven by the regulation of cell cell adhesion and cell-substrate interactions. We recently described the association of ADAM12 with EMT and we now use immunoprecipitation and proteomic approaches to identify interacting partners for ADAM12 during EMT. We identify twenty proteins that are involved in molecular mechanisms associated with adhesion/invasion processes. Integrative network analyses point out the zonula occludens protein ZO-1, as a new potential partner for ADAM12. In silico screening demonstrates that ZO-1 and ADAM12 are coexpressed in breast cancer cell lines sharing EMT signature. We validate the interaction between ZO-1 and ADAM12 in invasive breast cancer cell lines and show that ZO-1 and ADAM12 co-localize in actin- and cortactin-rich structures. Silencing either ADAM12 or ZO-1 inhibits gelatin degradation demonstrating that both proteins are required for matrix degradation. We further show that matrix metalloprotease 14, known to mediate degradation of collagen in invadopodia-like structures interacts with ZO-1. Depletion of PKCepsilon that regulates the recruitment of ADAM12 and ZO-1 to cell membranes induces a decrease in ADAM12 and ZO-1 at invadopodia-like structures and degradation activity. Together our data provide evidence for a new interaction between ADAM12, a mesenchymal marker induced during TGF-beta dependent EMT and ZO-1, a scaffolding protein expressed in tight junctions of epithelial cells, both proteins being redistributed at the invadopodia-like structures of mesenchymal invasive cells to promote PKCepsilon-dependent matrix degradation. PMID- 29765547 TI - Signature program: a platform of basket trials. AB - Investigating targeted therapies can be challenging due to diverse tumor mutations and slow patient accrual for clinical studies. The Signature Program is a series of 8 phase 2, agent-specific basket protocols using a rapid study start up approach involving no predetermined study sites. Each protocol evaluated 1 agent (buparlisib, dovitinib, binimetinib, encorafenib, sonidegib, BGJ398, ceritinib, or ribociclib) in patients with solid or hematologic malignancies and an actionable mutation. The primary endpoint of each study was the clinical benefit rate (ie, complete or partial response, or stable disease) at 16 weeks. A total of 192 individual sites were opened in the United States, with a median start-up time of 3.6 weeks. The most common tumor types among the 595 treated patients were colorectal (9.2%), non-small cell lung adenocarcinoma (9.1%), and ovarian (8.4%). Frequent genetic alterations were in PIK3CA, RAS, p16, and PTEN. Overall, 30 partial or complete responses were observed with 6 compounds in 16 tumor types. The Signature Program presents a unique and successful approach for rapid signal finding across multiple tumors and allowed various agents to be evaluated in patients with rare alterations. Incorporating these program features in conventional studies could lead to improved trial efficiencies and patient outcomes. PMID- 29765548 TI - Transformation of mouse T cells requires MYC and AKT activity in conjunction with inhibition of intrinsic apoptosis. AB - Peripheral T-cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by excessive proliferation of transformed mature T cells. The number and nature of genetic aberrations required and sufficient for transformation of normal T cells into lymphomas is unknown. Here, using a combinatorial in vitro-approach, we demonstrate that overexpression of MYC together with activated AKT in conditions of inhibition of intrinsic apoptosis rapidly resulted in transformation of mature mouse T cells with a frequency approaching 100%. Injection of transformed cells into mice resulted in rapid development of aggressive T cell lymphoma, characterized by spread to several organs, destruction of tissue architecture and rapid death of the animals. TcR-sequencing revealed a polyclonal repertoire of tumor cells indicating that co-expression of MYC, activated AKT and BCLXL is sufficient for tumor transformation and do not require acquisition of additional genetic events. When analyzing cells with inducible expression we found that proliferation of transformed T cells required sustained expression of both MYC and AKT. AKT exerted a dual function as it inhibited induction of, and promoted exit from, cellular quiescence and contributed to inhibion of apoptosis. Downregulation of AKT and/or MYC together with BCLXL resulted in rapid and complete elimination of cells through induction of apoptotic cell death. PMID- 29765549 TI - Deregulation of methylation of transcribed-ultra conserved regions in colorectal cancer and their value for detection of adenomas and adenocarcinomas. AB - Expression of Transcribed Ultraconserved Regions (T-UCRs) is often deregulated in cancer. The present study assesses the expression and methylation of three T-UCRs (Uc160, Uc283 and Uc346) in colorectal cancer (CRC) and explores the potential of T-UCR methylation in circulating DNA for the detection of adenomas and adenocarcinomas. Expression levels of Uc160, Uc283 and Uc346 were lower in neoplastic tissues from 64 CRC patients (statistically significant for Uc160, p<0.001), compared to non-malignant tissues, while methylation levels displayed the inverse pattern (p<0.001, p=0.001 and p=0.004 respectively). In colon cancer cell lines, overexpression of Uc160 and Uc346 led to increased proliferation and migration rates. Methylation levels of Uc160 in plasma of 50 CRC, 59 adenoma patients, 40 healthy subjects and 12 patients with colon inflammation or diverticulosis predicted the presence of CRC with 35% sensitivity and 89% specificity (p=0.016), while methylation levels of the combination of all three T UCRs resulted in 45% sensitivity and 74.3% specificity (p=0.013). In conclusion, studied T-UCRs' expression and methylation status are deregulated in CRC while Uc160 and Uc346 appear to have a complicated role in CRC progression. Moreover their methylation status appears a promising non-invasive screening test for CRC, provided that the sensitivity of the assay is improved. PMID- 29765550 TI - MTBP inhibits the Erk1/2-Elk-1 signaling in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the prognosis of HCC patients, especially those with metastasis, remains extremely poor. This is partly due to unclear molecular mechanisms underlying HCC metastasis. Our previous study indicates that MDM2 Binding Protein (MTBP) suppresses migration and metastasis of HCC cells. However, signaling pathways regulated by MTBP remain unknown. To identify metastasis-associated signaling pathways governed by MTBP, we have performed unbiased luciferase reporter-based signal array analyses and found that MTBP suppresses the activity of the ETS domain transcription factor Elk-1, a downstream target of Erk1/2 MAP kinases. MTBP also inhibits phosphorylation of Elk-1 and decreases mRNA expression of Elk 1 target genes. Reduced Elk-1 activity is caused by inhibited nuclear translocation of phosphorylated Erk1/2 (p-Erk) by MTBP and subsequent inhibition of Elk-1 phosphorylation. We also reveal that MTBP inhibits the interaction of p Erk with importin-7/RanBP7 (IPO7), an importin family member which shuttles p-Erk into the nucleus, by binding to IPO7. Moreover, high levels of MTBP in human HCC tissues are correlated with cytoplasmic localization of p-Erk1/2. Our study suggests that MTBP suppresses metastasis, at least partially, by down-modulating the Erk1/2-Elk-1 signaling pathway, thus identifying a novel regulatory mechanism of HCC metastasis by regulating the subcellular localization of p-Erk. PMID- 29765551 TI - Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer. AB - The PI3Kalpha signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2), decreased function in tumor suppressors (e.g. PTEN) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kalpha/delta(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC50 increases, respectively) compared with parental control cell lines. In addition, mechanistic analysis revealed that MAP3K1 disruption enhances AKT phosphorylation and downstream signaling and reduces sensitivity to AZD5363 mediated pathway inhibition. This appears to be a consequence of deficient MAP3K1 JNK signaling increasing IRS1 stability and therefore promoting IRS1 binding to p85, resulting in enhanced PI3Kalpha activity. Using 3D-MCF10A-PI3KalphaH1047R models, we found that MAP3K1 depletion increased overall acinar volume and counteracted AZD5363-mediated reduction of acinar growth due to enhanced proliferation and reduced apoptosis. Furthermore, in vivo efficacy studies revealed that MAP3K1-deficient MCF7 tumors were less sensitive to AKT inhibitor treatment, compared with parental MCF7 tumors. Our study provides mechanistic and in vivo evidence indicating a role for MAP3K1 as a tumor suppressor gene at least in the context of PIK3CA-mutant backgrounds. Further, our work predicts that MAP3K1 mutational status may be considered as a predictive biomarker for efficacy in PI3K pathway inhibitor trials. PMID- 29765552 TI - Higher enterococcus counts indicate a lower risk of colorectal adenomas: a prospective cohort study. AB - Intestinal bacteria play an important role in human health. This prospective cohort study aimed to investigate the relationship between the abundance of different intestinal bacteria and the risk of developing colorectal cancer (CRC). Fecal samples from CRC patients (n = 157) were collected at the start of the study wherein patients subsequently underwent endoscopy to remove polyps. Gut bacteria were isolated by using specific culture methods and the fecal counts of various bacteria were quantified by reverse-transcription-quantitative-PCR (RT qPCR) assays. The obtained data were subjected to cohort analysis in relation to the incidence of colorectal adenomas after 4 years of intervention. No relationship was detected between the counts of major intestinal bacteria and the incidence of colorectal adenomas. However, interestingly, a significant negative correlation was noted between colorectal adenoma incidence and the counts of bacteria grown on Columbia blood agar base (COBA) (P = 0.007). The risk ratio of colorectal adenomas was 0.58 (95% CI: 0.35-0.96) in the group with the highest bacterial count compared to the lowest. Bacteria grown on COBA were more abundant in older patients, non-smoking patients, and patients with a lower body mass index. The RT-qPCR results revealed a significantly lower colorectal adenoma incidence in subjects with higher enterococcal count as compared to subjects with a lower count, with a risk ratio of 0.47 (95% CI: 0.30-0.76). Correlation of a higher enterococci count with a lower risk of CRC development suggests that certain Enterococcus strains may have adenoma suppressive effects. PMID- 29765553 TI - Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer. AB - We previously reported the establishment of several types of long-term estrogen depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy. PMID- 29765554 TI - Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model. AB - Temozolomide (TMZ) chemotherapy for glioblastoma (GBM) is generally well tolerated at standard doses but it can cause side effects. GBMs overexpress microRNA-21 and microRNA-10b, two known oncomiRs that promote cancer development, progression and resistance to drug treatment. We hypothesized that systemic injection of antisense microRNAs (antagomiR-21 and antagomiR-10b) encapsulated in cRGD-tagged PEG-PLGA nanoparticles would result in high cellular delivery of intact functional antagomiRs, with consequent efficient therapeutic response and increased sensitivity of GBM cells to lower doses of TMZ. We synthesized both targeted and non-targeted nanoparticles, and characterized them for size, surface charge and encapsulation efficiency of antagomiRs. When using targeted nanoparticles in U87MG and Ln229 GBM cells, we showed higher uptake-associated improvement in sensitivity of these cells to lower concentrations of TMZ in medium. Co-inhibition of microRNA-21 and microRNA-10b reduced the number of viable cells and increased cell cycle arrest at G2/M phase upon TMZ treatment. We found a significant increase in expression of key target genes for microRNA-21 and microRNA-10b upon using targeted versus non-targeted nanoparticles. There was also significant reduction in tumor volume when using TMZ after pre-treatment with loaded nanoparticles in human GBM cell xenografts in mice. In vivo targeted nanoparticles plus different doses of TMZ showed a significant therapeutic response even at the lowest dose of TMZ, indicating that preloading cells with antagomiR-21 and antagomiR-10b increases cellular chemosensitivity towards lower TMZ doses. Future clinical applications of this combination therapy may result in improved GBM response by using lower doses of TMZ and reducing nonspecific treatment side effects. PMID- 29765555 TI - A protein folding molecular imaging biosensor monitors the effects of drugs that restore mutant p53 structure and its downstream function in glioblastoma cells. AB - Misfolding mutations in the DNA-binding domain of p53 alter its conformation, affecting the efficiency with which it binds to chromatin to regulate target gene expression and cell cycle checkpoint functions in many cancers, including glioblastoma. Small molecule drugs that recover misfolded p53 structure and function may improve chemotherapy by activating p53-mediated senescence. We constructed and optimized a split Renilla luciferase (RLUC) complementation molecular biosensor (NRLUC-p53-CRLUC) to determine small molecule-meditated folding changes in p53 protein. After initial evaluation of the biosensor in three different cells lines, we engineered endogenously p53P98L mutant (i.e. not affecting the DNA-binding domain) Ln229 glioblastoma cells, to express the biosensor containing one of four different p53 proteins: p53wt, p53Y220C, p53G245S and p53R282W. We evaluated the consequent phenotypic changes in these four variant cells as well as the parental cells after exposure to PhiKan083 and SCH529074, drugs previously reported to activate mutant p53 folding. Specifically, we measured induced RLUC complementation and consequent therapeutic response. Upon stable transduction with the p53 biosensors, we demonstrated that these originally p53P98L Ln229 cells had acquired p53 cellular phenotypes representative of each p53 protein expressed within the biosensor fusion protein. In these engineered variants we found a differential drug response when treated with doxorubicin and temozolomide, either independently or in combination with PhiKan083 or SCH529074. We thus developed a molecular imaging complementation biosensor that mimics endogenous p53 function for use in future applications to screen novel or repurposed drugs that counter the effects of misfolding mutations responsible for oncogenic structural changes in p53. PMID- 29765556 TI - Antibody-assisted target identification reveals afatinib, an EGFR covalent inhibitor, down-regulating ribonucleotide reductase. AB - Afatinib, used for the first-line treatment of non-small-cell lung carcinoma (NSCLC) patients with distinct epidermal growth factor receptor (EGFR) mutations, inactivates EGFR by mimicking ATP structure and forming a covalent adduct with EGFR. We developed a method to unravel potential targets of afatinib in NSCLC cells through immunoprecipitation of afatinib-labeling proteins with anti afatinib antiserum and mass spectrometry analysis. Ribonucleotide reductase (RNR) is one of target proteins of afatinib revealed by this method. Treatment of afatinib at 10-100 nM potently inhibited intracellular RNR activity in an in vitro assay using permeabilized PC-9 cells (formerly known as PC-14). PC-9 cells treated with 10 MUM afatinib displayed elevated markers of DNA damage. Long-term treatment of therapeutic concentrations of afatinib in PC-9 cells caused significant decrease in protein levels of RNR subunit M2 at 1-10 nM and RNR subunit M1 at 100 nM. EGFR-null Chinese hamster ovary (CHO) cells treated with afatinib also showed similar effects. Afatinib repressed the upregulation of RNR subunit M2 induced by gemcitabine. Covalent modification with afatinib resulting in inhibition and protein downregulation of RNR underscores the therapeutic and off-target effects of afatinib. Afatinib may serve as a lead compound of chemotherapeutic drugs targeting RNR. This method can be widely used in the identification of potential targets of other covalent drugs. PMID- 29765557 TI - Coffee consumption and risk of myocardial infarction: a dose-response meta analysis of observational studies. AB - Background: Previous epidemiological studies have provided inconsistent conclusions on the effect of coffee consumption in the development of myocardial infarction (MI). The aim of the study was to evaluate the influence of coffee consumption and its potential dose-response patterns on the risk of developing MI. Materials and Methods: Three databases were searched for evidence of eligible studies. A random-effects model was used to pool the fully adjusted odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Dose-response analysis was performed to show the effect of each cup increased in daily coffee drinking on the risk of MI. Results: Seventeen studies involving 233,617 participants were included in our study. The association between coffee consumption and risk of MI did not show statistical significance when pooling the outcome data for the coffee consumption categories of 1~2 vs. < 1 cup per day (OR = 1.06, 95% CI: 0.94-1.19) and 2~3 vs. < 1 cup per day (OR = 1.07, 95% CI: 0.94 1.23). Compared with < 1 cup, daily drinking of 3~4 cups and > 4 cups of coffee were significantly associated with the risk of MI, and the pooled ORs (95% CIs) were 1.40 (1.11-1.77) and 1.48 (1.22-1.79), respectively. The dose-response analysis showed a "J-shaped" curve relationship of the risk of MI with coffee consumption. Conclusions: Daily drinking of more than three cups of coffee was associated with a significantly increased risk of MI. This positive association was only found in men but not in women. The impact of gender on this association should be further evaluated. PMID- 29765558 TI - The fallopian tube microbiome: implications for reproductive health. AB - Objective: There is a paucity of data characterizing the microbiota of the female upper genital tract, which controversially is described as a sterile site. We examine whether the fallopian tube harbours an endogenous microbial community. Design: This prospective study collected from women undergoing total hysterectomy or salpingectomy-oophorectomy. Setting: Private hospital gynaecology department. Patients: Fallopian tubes were collected from women diagnosed with benign disease or for prophylaxis. Interventions: Samples were interrogated for the presence of microbial DNA using a next generation sequencing technology approach to exploit the V5 to V9 regions of the 16S rRNA gene. Main outcome measures: The fallopian tube microbiota was characterized using traditional culture techniques and next generation sequencing. Results: Bacteria were isolated from 50% of cultured samples, and 100% of samples returned positive PCR results. Only 68% of the culture isolates could be confidently identified using automated diagnostic equipment in a clinical microbiology laboratory. Monomicrobial communities were identified only for cultured isolates (50%). Pyrosequencing revealed that all communities were polymicrobial. Lactobacillus spp. were not present in all groups, nor were they the most dominant isolates. Distinct differences in the microbial communities were evident for left compared to right fallopian tubes, ampulla versus isthmus, pre- and post- menopausal tissue, and in secretory phase fallopian tubes with and without Mirena intrauterine devices in situ (all p < 0.05). Conclusion: The female upper genital tract is not sterile. Distinct microbial community profiles in the fallopian tubes of healthy women suggest that this genital tract site supports an endogenous microbiota. PMID- 29765559 TI - Patients with high serum substance P levels previously to liver transplantation for hepatocellular carcinoma have higher risk of one-year liver transplantation mortality. AB - Purpose: Substance P is a tachykinins family member with inflammatory effects. Higher circulating levels of substance P have been found in patients with liver diseases and in patients with higher severity of liver diseases. The objective of this study was to determine whether serum levels of substance P levels, prior to liver transplantation (LT) for hepatocellular carcinoma (HCC) are associated with one-year LT mortality. Material and Methods: In this observational retrospective unicenter study were included patients with LT for HCC. Serum levels of substance P were measured before LT. The end-point of the study was one-year mortality after LT. Results: We found that one-year survivor patients (n = 127) showed a lower age in liver donors (p = 0.03) and lower levels of serum substance P levels (p = 0.003) than non-survivor patients (n = 15). Logistic regression analysis showed that serum levels of substance P (levels) were associated with one-year mortality (Odds Ratio = 1.011; 95% CI = 1.004-1.018; p = 0.002) controlling for the age of the LT donor. Conclusions: We believe that our study is the first study reporting data on circulating levels of substance P previously to LT for HCC, and an association between elevated levels of serum substance P before LT and mortality during the first year of LT. PMID- 29765560 TI - Transarterial chemoembolization as a substitute to radiofrequency ablation for treating Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma. AB - Background and Aim: Transarterial chemoembolization (TACE) is the standard procedure for treating Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC). However, it is often carried out in the treatment of BCLC stage 0/A HCC for various reasons. This study aimed to elucidate the prognosis for BCLC stage 0/A HCC patients treated with TACE or with radiofrequency ablation (RFA). Materials and Methods: The prognosis of 242 BCLC stage 0/A HCC patients within Milan criteria who underwent initially TACE or RFA were retrospectively analyzed using propensity score matching analysis. Results: The analyses of baseline patient characteristics revealed that the maximum tumor size and the proportion of BCLC stage A patients were significantly higher in patients treated with TACE than in those treated with RFA (P<0.001 and 0.047, respectively). After adjusting these factors using propensity score matching (1:3 matching), patients treated with TACE (n=32) and those treated with RFA (n=96) were further analyzed. The local recurrence rate was significantly higher in the TACE group than in the RFA group (P<0.001). However, the overall survival (OS) in HCC patients treated with TACE was comparable to that in HCC patients treated with RFA (1 year, 93.5 vs. 95.8%; 3 years, 75.4 vs. 85.8%; 5 years, 61.8 vs. 70.7%; P=0.196). Multivariate analyses followed by univariate analyses revealed that serum bilirubin level (P=0.032), serum albumin level (P=0.008), HBV-DNA (P=0.013), and tumor number (P=0.021) were independent predictors of OS. Conclusion: TACE can substitute RFA at least in some patients with BCLC 0/A HCC. PMID- 29765561 TI - A pilot study of peptide vaccines for VEGF receptor 1 and 2 in patients with recurrent/progressive high grade glioma. AB - Object: Early-phase clinical studies of glioma vaccines have shown feasibility and encouraging preliminary clinical activity. A vaccine that targets tumor angiogenesis factors in glioma microenvironment has not been reported. Therefore, we performed a pilot study to evaluate the safety and immunogenicity of a novel vaccination targeting tumor angiogenesis with synthetic peptides for vascular endothelial growth factor (VEGF) receptor epitopes in patients with recurrent/progressive high grade gliomas. Methods: Eight patients received intranodal vaccinations weekly at a dose of 2mg/kg bodyweight 8 times. T lymphocyte responses against VEGF receptor (VEGFR) epitopes were assessed by enzyme linked immunosorbent spot assays. Results: This treatment was well tolerated in patients. The first four vaccines induced positive immune responses against at least one of the targeted VEGFR epitopes in the peripheral blood mononuclear cells in 87.5% of patients. The median overall survival time in all patients was 15.9 months. Two achieved progression-free status lasting at least 6 months. Two patients with recurrent GBM demonstrated stable disease. Plasma IL-8 level was negatively correlated with overall survival. Conclusion: These data demonstrate the safety and immunogenicity of VEGFR peptide vaccines targeting tumor vasculatures in high grade gliomas. PMID- 29765564 TI - Correction: Diagnostic and prognostic utilities of humoral fibulin-3 in malignant pleural mesothelioma: Evidence from a meta-analysis. AB - [This corrects the article DOI: 10.18632/oncotarget.14712.]. PMID- 29765563 TI - Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review. AB - Pancreatic cancer has a dismal prognosis particularly in patients presenting with unresectable tumors. We performed a bibliometric analysis of clinical trials for pancreatic cancer conducted between 2014-2016 focusing on patients that presented with unresectable (locally advanced or metastatic) tumors. We discuss a range of studies that employed FOLFIRINOX, the gemcitabine + nab-paclitaxel combination and studies that used molecularly-targeted therapy. Major areas of focus have been dual targeting of EGFR and VEGFR, immunotherapy or a multimodal approach - combining chemotherapy with radiotherapy. We also point out the need for molecular selection for low prevalence subtypes. Key insights sourced from these pivotal trials should improve clinical outcomes for this devastating cancer. PMID- 29765565 TI - The rediscovery of the social side of medicine: philosophy and value of the International Classification of Functioning, Disability and Health (ICF). AB - Medicine is at risk of sliding into a sole repair service for the malfunction of organs. But the patients' hope and confidence towards doctors practicing this repair work go far beyond that: after acute medical treatment many patients suffer from chronic impairments due to the natural course of the disease or as a result of medical interventions. Despite resulting handicaps, patients aim at participating in family and social life, retaining a workplace and receiving support to remain a valued member of the family and the community. Doctors should therefore not only concentrate on the natural science and technological part of medicine, but also consider the background of their patients, their involvement in life situations including environmental and personal factors, as these may influence functioning and disability as facilitators or barriers. Health Insurances Companies must organize, finance and control the achievements of the post-acute treatment process with the goal of participation. "Public Health" must combine and assess individual views to prepare reasonable population based social, economic and political decisions. The philosophy and structure of the International Classification of Functioning, Disability and Health (ICF) is supporting this attitude of medicine, to complement the International Classification of Diseases (ICD) as a basis for health reports. PMID- 29765562 TI - A myriad of roles of miR-25 in health and disease. AB - Small non-coding RNAs including microRNAs (miRNAs) have been recently recognized as important regulators of gene expression. MicroRNAs play myriads of roles in physiological processes as well as in the pathogenesis of a number of diseases by translational repression or mRNA destabilization of numerous target genes. The miR-106b-25 cluster is highly conserved in vertebrates and consists of three members including miR-106b, miR-93 and miR-25. MiR-106b and miR-93 share the same seed sequences; however, miR-25 has only a similar seed sequence resulting in different predicted target mRNAs. In this review, we specifically focus on the role of miR-25 in healthy and diseased conditions. Many of miR-25 target mRNAs are involved in biological processes such as cell proliferation, differentiation, and migration, apoptosis, oxidative stress, inflammation, calcium handling, etc. Therefore, it is no surprise that miR-25 has been reported as a key regulator of common cancerous and non-cancerous diseases. MiR-25 plays an important role in the pathogenesis of acute myocardial infarction, left ventricular hypertrophy, heart failure, diabetes mellitus, diabetic nephropathy, tubulointerstitial nephropathy, asthma bronchiale, cerebral ischemia/reperfusion injury, neurodegenerative diseases, schizophrenia, multiple sclerosis, etc. MiR-25 is also a well-described oncogenic miRNA playing a crucial role in the development of many tumor types including brain tumors, lung, breast, ovarian, prostate, thyroid, oesophageal, gastric, colorectal, hepatocellular cancers, etc. In this review, our aim is to discuss the translational therapeutic role of miR-25 in common diseased conditions based on relevant basic research and clinical studies. PMID- 29765566 TI - Efficacy of combination of Viola odorata, Rosa damascena and Coriandrum sativum in prevention of migraine attacks: a randomized, double blind, placebo-controlled clinical trial. AB - Background: Migraine is the second most common type of headache after tension headaches. In Iranian traditional medicine several herbal drugs are used for the treatment of headache. Including, a product of Iranian traditional medicine, a combination of Viola odorata L. flowers, Rosa damascena L. flowers and Coriandrum sativum L. fruits. Objective: To determine the effectiveness of a combination of Viola odorata flowers, Rosa damascene flowers and Coriandrum sativum fruits on severity, duration and frequency of migraine headaches. Methods: This randomized, double blind, placebo-controlled clinical trial was performed on 88 patients who had migraine and visited Besat Neurology Clinic No. 4 at Kerman University of Medical Sciences, Kerman, Iran, from September 2016 to march 2017. Patients were randomly divided into the intervention (n=44) or placebo group (n=44). The intervention group received a product of Iranian traditional medicine, a combination of Viola odorata L. flowers, Rosa damascena L. flowers and Coriandrum sativum L. fruits in 500 mg capsules three times a day and propranolol 20mg tablet twice a day, and the control group received placebo capsules (500mg) three times a day and propranolol 20mg tablet twice a day for four weeks. Patients were asked to report the frequency, duration and severity of their headaches in designed forms at home. Then at the end of the 2nd and 4th weeks of treatment, patients were followed for clinical efficacy. Results: In terms of duration, frequency and severity of headaches between the two groups of herbal medicine and placebo, the behavior of the two protocols was changed over time (p<0.001). During the 4 weeks, the time and drug interactions, were significant (p <0.001). In other words, the pattern of changes to the two protocols over time, was different. Also, at the end of the 4th week, there was a significant difference between the two groups (p<0.001). Conclusion: The study findings suggest that the Iranian traditional product combination of Viola odorata flowers, Rosa damascena flowers and Coriandrum sativum fruits may be effective in improving headaches in patients with migraine. Clinical trial registration: The trial was registered at the Iranian registry of clinical trials (IRCT: www.irct.ir) with registered NO. IRCT 2016110830776N1. Funding: The authors received no financial support for the research, authorship, and/or publication of this article. PMID- 29765567 TI - Effects of multimodal communication program on patients with chronic aphasia: a single-subject A-B-A design study. AB - Background and aim: Aphasia as a common consequence of stroke, is an acquired neurologic communication disorder that can affect symbol language processing. Different types of intervention approaches have been introduced. Multimodal Communication Program (MCP) is a new augmentative alternative communication approach in chronic aphasia. The aim of this study was to investigate the effect of MCP on communication skills of patients with chronic aphasia. Methods: This prospective, single subject, A-B-A design study was done during 2016 in Semnan, Iran. Participants were two patients with severe aphasia with a single left hemisphere stroke. Three phases, including baseline, intervention and follow-up were administered. The patients received nine-hour intervention, over 10 working days. Results: Three different scores were calculated for each patient: verbal efforts, the frequency of each modality and the accuracy of switching between modalities and the reaction time. The frequency of verbal modality increased for both patients. They could switch between modalities more successfully than before the intervention. The results for the reaction time, however were challenging. The onset reaction time decreased for patient 1, and increased during switching between modalities, and patient 2 showed the opposite. Conclusion: The MCP can improve the communication skills in patients with chronic post stroke aphasia. However, some factors, such as reduction of the patients' reaction time is probably related to the amount of allocated resources during intervention. Trial registration: The trial was registered at IRCT center with ID: IRCT2016032325194N3. Funding: The study was financed by Semnan University of Medical Sciences (Grant no.: A-10-333-3). PMID- 29765568 TI - Relationship between tooth value and skin color in patients visiting Royal Medical Services clinics of Jordan. AB - Background: Facial and dental aesthetics are becoming of great concern for patients, especially for the younger generation. Tooth color matching and selection is considered a vital element in order to create an attractive beautiful smile. The importance of tooth color matching is to adjust tooth colors to obtain a good match with adjacent teeth and the skin. This is considered a challenge especially if adjacent teeth were lost or records of patients' teeth color were not available. Objective: The aim of this study was to determine the relationship between skin complexion and tooth value in a Jordanian population. Methods: A cross-sectional study of 520 individuals who were randomly selected and belonging to different age groups, ranging from 15-65 years, with equal sex distribution. These patients visited the dental clinics at different Jordanian military hospitals. The study was carried out over a period of one year from 2015 to 2016. The randomly selected sample was examined by one researcher. Shade of the middle third of the labial surface of central incisor was determined visually using VITA tooth guide, 3D-MASTER shade guide. Tooth shades were divided into two categories according to their value. The skin complexion was identified using Fitzpatrick skin type test, and was categorized into two categories (fair and dark). Data were statistically analyzed using Epi Info version 6. Results: A statistically significant tooth shade value difference was discovered among subjects of different skin color (p<0.0001). Individuals with dark skin tend to have lighter teeth, while individuals with light skin tend to have darker teeth. Out of the 304 participants that were with dark complexion 274 (90%) have light teeth, and only 30 (10%) were with dark teeth. Out of the 216 participants with light complexion 172 (80%) have dark teeth and only 44 (20%) have light teeth. Conclusion: Within the limitation of this study, there was an inverse relation between skin complexion and tooth value among a Jordanian population. Thus, considering the skin complexion when choosing tooth shades is helpful in achieving a pleasing good-looking smile, yet further investigations in this field must be carried out. PMID- 29765569 TI - Bolton discrepancy in an Iranian population and its relation with maxillary lateral incisors' size. AB - Background: Bolton's two main ratios describing the proportional size of upper and lower teeth, could contribute to estimating the excess or deficiency of tooth size necessary to obtain an ideal occlusion. However, the mean Bolton values are not the same among different societies. Determining the prevalence of tooth size deviations from population-specific Bolton indices might help local orthodontists to have a more concise treatment plan. Objective: The study aimed to define the prevalence of clinically significant tooth size discrepancies (TSD) in an Iranian population and to evaluate the influence of lateral incisors' size on this discrepancy. Methods: This cross-sectional study was conducted on study casts of orthodontic patients attending Imam Reza Dental Clinic from September 2008 to December 2016. The sample comprised of 150 randomly selected pre-treatment study casts (64 males and 86 females from 17 to 28). The mesiodistal diameter of all permanent teeth from the first molar on the right to the first molar on the left was measured using 2 similar digital calipers, and Bolton analysis was calculated. Subjective visual estimation of Bolton discrepancy was also performed. SPSS v18.0, Wilcoxon signed ranks test, Pearson correlation and Receiver Operating Characteristic (ROC) curve analysis were used for statistical analysis. A p<0.05 was considered statistically significant. Results: In the sample group, 34.7% had anterior Bolton index (ABI) and 20.7% had total Bolton index (TBI) greater than 2 Standard Deviations (2SDs) of Bolton's means, and about half of them required correction of the ABI considering the actual size of discrepancies (mm). The sensitivity of estimating clinically significant tooth size discrepancy more than 2SDs of Bolton's ABI and the visual judgment was 96.0% and a cut-off point of -0.12mm was obtained. Conclusion: Bolton's analysis should be routinely performed in all orthodontic patients, and visual estimation of TSD would be suggested as a screening method in the first visit prior to measurements and set-ups. PMID- 29765570 TI - Relationship between self-care behaviors and health literacy among elderly women in Iran, 2015. AB - Background and aim: Self-care is a basic concept in health promotion, regarding the importance of health literacy as a key factor in self-care. This study aimed to identify the relationship between self-care behaviors and health literacy among elderly women in Iran. Methods: This descriptive and analytic study was performed between October and December 2015. A total of 360 participants were selected from elderly women referred to health centers. Data was collected by test of functional health literacy in adults (S-TOFHLA) and a checklist for assessment of self-care behaviors, and health information seeking. Data were analyzed by SPSS software (version 22) with One-Way Analysis of Variance, and the Pearson correlation coefficient, t-test and regression test. Results: The mean score of functional health literacy was 41.30+/-6.29. Of the participants, 73.6% had inadequate health literacy, 20.8% borderline health literacy, and 5.6% enough health literacy. The mean score of health information seeking was 1.791. Also, 31.9% of elderly women had poor self-care behaviors, 56.9% moderate, and 11.1% high. A significant difference was observed in mean score of health literacy between different levels of self-care (F=30.087, p<0.001). Based on regression analysis, health literacy and health information seeking predicted 19.9% of the variance of self-care behaviors. Conclusion: This study highlights the necessity of promoting health literacy and attention to its influencing factors to improve self-care ability of elderly women. In conclusion, Planning interventions to improve health literacy is essential for health promotion among elderly women. PMID- 29765572 TI - The predictors of earthquake preparedness in Tehran households. AB - Background: The high risk of an earthquake happening and the harmful consequences that it leaves, besides the unsuccessful policies for preparing the community for mitigation, suggested that social factors should be considered more in this regard. Social trust is an influencing factor that can have significant impact on people's behavior. Objective: To determine the relationship of the influencing factors on the preparedness of Tehran households against earthquake. Methods: This was a cross-sectional study with 369 participants (February to April 2017) involved through stratified random sampling from selected urban districts of Tehran. The Persian version of an 'Intention to be prepared' measurement tool and a standard checklist of earthquake preparedness behaviors were used. The tool was evaluated for internal consistency and test-retest reliability in a pilot study (Cronbach's alpha =0.94 and Intra Class Correlation Coefficient =0.92). Results: Multivariate linear regression analysis showed that social trust is the most important predictor for the preparedness mean of changes in Tehran (R2=0.109, p<0.001, beta: 0.187 for the Preparedness behavior; R2=0.117, beta: 0.298, p<0.001 for Intention to be prepared; and R2=0.142, beta: 0.345, p<0.001 for the Perceived preparedness). Conclusion: The relationship between social trust and preparedness dimensions suggested that changing a social behavior is not possible through considering only individual characteristics of community members and not their social networks relations. The programs and policies which try to enhance the social trust in general, may be able to increase public preparedness against earthquakes in the future. PMID- 29765573 TI - The relationship between emotional intelligence with administrators' performance at Mashhad University of Medical Sciences. AB - Background: The leadership of an organization requires specific features to adapt to changes and to survive and grow in new environments, and emotional intelligence is one of the most important attributes that can help leaders and managers respond to these changes. Objective: This study aimed to determine the relationship between emotional intelligence with administrators' performance at Mashhad University of Medical Sciences, Mashhad, Iran. Methods: This cross sectional study was conducted on 100 basic and middle managers of Mashhad University of Medical Sciences, Mashhad, Iran who were selected by census method in 2016. The instrument of data collecting was the "Inventory Shrinkage", and the "Organizational performance evaluation forms". The data were analyzed by SPSS version 16 using descriptive statistics and Spearman correlation. Results: The results showed there was a significant negative correlation between emotional intelligence and organizational performance in administrators (r=-0.214, p=0.032). The findings also showed that among the components of emotional intelligence and administrators' performance, only components of empathy, was there a significant negative correlation (r=-0.199, p=0.047). Also, there was no statistically significant relationship between emotional intelligence and demographic variables such as work experience, age, marital status and education level (p>0.05). There was no significant relationship between organizational performance and demographic variables, either (p>0.05). But between the components of emotional intelligence, only for social skills and work place of administrators, a significant positive correlation was confirmed (r=0.203, p=0.043). Conclusions: The results of this study showed that there was a negative and significant correlation between the components of emotional intelligence and administrators' performance of Mashhad University of Medical Sciences administrators, only in the empathy component. PMID- 29765571 TI - Relationship between health literacy and knowledge among patients with hypertension in Isfahan province, Iran. AB - Background: Hypertension is usually symptomless, and is not seriously attended until it causes some chronic complications. Individuals' skills in understanding and applying information about health subjects may have a substantial impact on patients' behavior and health. Objective: to determine the relationship between health literacy and knowledge among patients with hypertension in Isfahan province, Iran. Methods: This cross-sectional study was conducted on 700 patients with hypertension selected according to multistage random and quota types in Isfahan province (Iran). Data collection tools included Health Literacy for Iranian Adults (HELIA) and Hypertension Knowledge Level Scale (HK-LS), which were completed by patients. Data were analyzed by SPSS version 23 using Pearson's correlation, one way ANOVA, and Independent-samples t-test. The significance level was set at 0.05. Results: The mean (SD) of participants' age was 60.58+/ 11.14 years. Results showed that the relationship between age and health literacy (r=-0.354, p<0.001) and knowledge (r=-0.129, p<0.001) was statistically significant. More than three quarters of participants (75.5%) are inadequate and partially adequate of health literacy. There was a significant correlation between the blood pressure knowledge and the mean score of health literacy (r=0.0407, p<0.001). Conclusion: The present study confirmed that the majority of the patients with hypertension had inadequate health literacy and there was a significant correlation between the blood pressure knowledge and the mean score of health literacy. Therefore, adequate education should be provided in health centers to increase the health literacy and knowledge about hypertension in hypertensive people. So it is suggested that future studies will be conducted on the use of various educational media in hypertensive people. PMID- 29765574 TI - Psychometric properties of self-assessment clinical competency questionnaire in baccalaureate nursing students. AB - Background: One of the main challenges of nursing student education is the lack of clinical competence that reduces the quality of patients care. Measuring the clinical competency of undergraduate nursing students is effective in curriculum developing, planning, and learning evaluation. Objective: To validate self assessment clinical competence questionnaire of undergraduate nursing students. Methods: This was a cross-sectional study at Baqiyatallah University of Medical Sciences in Tehran, Iran, 2015-2016. The original version of the self-assessment questionnaire for baccalaureate nursing graduates was translated to Persian by the World Health Organization's (WHO) method. The psychometric evaluation of the questionnaire was conducted on 300 nursing students. The participants were selected by convenience sampling. The tool validity was confirmed by exploratory factor analyses. The reliability was investigated by internal consistency and test-retest. Results: Cronbach's alpha coefficient was 0.96 (0.82-0.91). Intraclass correlation coefficient (ICC) was 0.98 (0.88-0.99). Five factors were extracted by analysis of clinical competency tool of undergraduate nursing students. The factors included technical competence, advanced competence, ethical competence, care management and safety competence. Conclusions: The Persian version of the clinical competence assessment tool has acceptable psychometric characteristics in the Iranian nursing students' community. This questionnaire can be used as a valid tool in planning and research management areas. PMID- 29765575 TI - Association of serum testosterone and dehydroepiandrosterone sulfate with rheumatoid arthritis: a case control study. AB - Background: It is supposed that hypoandrogenism may be involved in the pathogenesis of rheumatoid arthritis (RA). Testosterone and dehydroepiandrosterone sulfate (DHEAs) levels decrease in body fluids of patients with RA. Objective: The aim of this study was to determine the association of serum testosterone and DHEAs with RA. Methods: This case-control study was conducted on 59 patients with RA and 61 healthy gender- and age-matched controls at Qazvin University of Medical Sciences, Qazvin, Iran, in 2014. Serum free testosterone and DHEAs levels were measured and compared between two groups. Serum testosterone levels lower than 0.029 ng/ml in females and 2.49 ng/ml in males were considered as abnormal. DHEAs levels lower than 18.9 MUg/dl in females and 88.9 MUg/dl in males were considered as abnormal. Data were analyzed using independent sample T-test, Chi-square test, and logistic regression analysis by SPSS software, version 19. Results: The mean testosterone level in females of the control group was significantly higher than females in the case group. The mean DHEAs in the control group was significantly higher than the case group. Abnormal testosterone and DHEAs level in the case group was significantly higher than the control group. Logistic regression analysis showed independent association only between DHEAs levels and RA, after adjusting for age and gender (OR: 0.966, 95% CI: 0.953-0.979; p<0.001). Conclusion: With regard to the results, abnormal testosterone and DHEAs level in patients with RA was significantly higher than the control group. This shows the anti-inflammatory effects of gonadal and adrenal androgens in RA. PMID- 29765576 TI - A trend analysis of surgical operations under a global payment system in Tehran, Iran (2005-2015). AB - Background: Global payment system is a first example of per-case payment system that contains 60 commonly used surgical operations for which payment is based on the average cost per case in Iran. Objective: The aim of the study was to determine the amount of reduction, increase or no change in the trend of global operations. Methods: In this retrospective longitudinal study, data on the 60 primary global surgery codes was gathered from Tehran Health Insurance Organization within the ten-year period of 2005-2015 separately, for each month. Out of 60 surgery codes, only acceptable data for 46 codes were available based on the insurance documents sent by medical centers. A quantitative analysis of time series through Regression Analysis Model using STATA software v.11 was performed. Results: Some global surgery codes had an upward trend and some were downwards. Of N Codes, N83, N20, N28, N63, and N93 had an upward trend (p<0.05) and N32, N43, N81 and N90 showed a significant downward trend (p<0.05). Similarly, all H Codes except for H18 had a significant upward trend (p<0.000). As such, K Codes including K45, K56 and K81 had an increasing movement. S Codes also experienced both increasing and decreasing trends. However, none of the O Codes changed according to time. Other global surgical codes like C61, E07, M51, L60, J98 (p<0.000), I84 (p<0.031) and I86 (p<0.000) shown upward and downward trends. Total global surgeries trend was significantly upwards (B=24.26109, p<0.000). Conclusion: The varying trend of global surgeries can partly reflect the behavior of service providers in order to increase their profits and minimize their costs. PMID- 29765577 TI - Perception of family caregivers about barriers of leisure in care of individuals with chronic psychiatric disorders: a qualitative study. AB - Background: Family caregivers of individuals with chronic psychiatric disorders play an important role in the management of the patient's conditions, which interferes with other activities of daily living, work, social and leisure activities. Objective: This study was conducted in an Iranian context to explore the perception of family caregivers about barriers of leisure in care of individuals with chronic psychiatric disorders. Methods: The current qualitative study was conducted on the basis of conventional content analysis. Participants were 15 family caregivers of individuals with chronic psychiatric disorders who were selected by Purposeful sampling method between July 2016 and March 2017 in Tehran, Iran. The data was collected via in-depth semi-structured interviews. The interviews were tape recorded, written and transcribed. Then, data were analyzed by inductive content analysis method. Results: Data analysis led to extraction of 3 main categories and 10 sub categories. Obstacles to leisure-time of family caregivers have been placed in three main categories which are patient-related factors (Resentment from psychological problems, Resentment from behavioral problems, Need for continuous monitoring and access), caregiver-related factors (Physical harm, Psychosocial harm, Temporal stress, Accumulation of responsibilities, Concerns), and community-related factors (Feeling of sympathy and rejection, Social stigma). Conclusion: Understanding the barriers of leisure in this group of family caregivers has contributed to understanding the family caregivers' perception in this area and regarding their leisure, it can provide a broader perspective to mental health therapists, rehabilitation managers and policy makers for understanding the needs, addressing the challenges and barriers of this group of family caregivers. PMID- 29765578 TI - Lipid-lowering drugs (statins) and peripheral neuropathy. AB - Background and aim: Peripheral neuropathy is a disorder with often unknown causes. Some drugs, including statins, are proposed to be among the causes of peripheral neuropathy. This study aimed at evaluating this condition by electrodiagnostic study among patients who had received statins. Methods: This case-control study was conducted in Shiraz, Iran in 2015, and included 39 patients aged 35-55 who had received statins for at least 6 months, and 39 healthy matched controls. Using electrodiagnosis, the sensory and motor wave features (amplitude, latency and nerve conduction velocity) of the peripheral nerves (Median, Ulnar, Tibial, Sural, and Peroneal) were evaluated among the subjects. Data were analyzed using SPSS software and p<0.05 was considered statistically significant. Results: Regarding the occurrence of neuropathy, there were no significant differences in any of the definitions presented for peripheral neuropathy. However, the difference was close to significance for one definition [2 abnormalities in 2 nerves (p=0.055)]. Regarding mean values of the features, significant differences were observed in two features: amplitude of the peroneal motor nerve (p=0.048) and amplitude of the sural sensory nerve (p=0.036). Conclusion: Since statins are widely used, awareness regarding their side-effects would lead to better treatment. Even though no significant differences were found between the groups regarding the occurrence of peripheral neuropathy, there were significant differences in amplitudes of the sural sensory response and the peroneal motor response. This indicates the involvement of peripheral nerves. Therefore, we recommend that patients and physicians should be informed about the possible symptoms of this condition. PMID- 29765579 TI - Antagonistic effect of isolated probiotic bacteria from natural sources against intestinal Escherichia coli pathotypes. AB - Background: Probiotics are live microorganisms which are beneficial bacteria that are normal flora of the digestive system which, in determined amounts, show beneficial effects on host health, and can balance gastrointestinal microflora. Digestive tract diseases such as diarrhea are one of the major causes of child mortality in developing countries. Different pathotypes of Escherichia coli cause diarrhea that affects children, therefore reduction of these colonization strains in humans or animals can decline gastrointestinal disorders such as diarrhea. Objective: The aim of this study was to determine the antimicrobial effect of probiotic bacterial strains isolated from different natural sources against 4 pathotypes of pathogenic E. coli using disk and well diffusion methods. Methods: This cross-sectional study was conducted from December 2013 to July 2014 on Martyr Chamran University in Ahwaz city. A total of 13 probiotic colonies isolated from 20 samples of traditional dairy products including yogurt, cheese and milk, and 20 samples of vegetables including carrots and cabbages (red and white), of which 5 isolates were selected to determine the antimicrobial effect against 4 Escherichia coli pathotypes, randomly. The antimicrobial effect was evaluated using two methods: disk diffusion and well diffusion tests and measuring growth inhibition zones of probiotics against 4 pathotypes of pathogenic E. coli. Results: Obtained results showed growth inhibition effects of all 5 probiotic strains against Escherichia coli pathotypes in both used methods. But in comparison Lactobacillus plantarum had higher growth inhibitory effects in both methods. Conclusion: results of this study demonstrated high antimicrobial effect of probiotic bacteria against pathogenic Escherichia coli strains. It indicated a positive and beneficial role of probiotics in human health and prevention of illness. PMID- 29765580 TI - Predictive factors associated with mortality and discharge in intensive care units: a retrospective cohort study. AB - Background and aim: Accurate prediction of prognosis of patients admitted to intensive care units (ICUs) is very important for the clinical management of the patients. The present study aims to identify independent factors affecting death and discharge in ICUs using competing risk modeling. Methods: This retrospective cohort study was conducted on enrolling 880 patients admitted to emergency ICU in Namazi hospital, Shiraz University of Medical Sciences, Shiraz, Iran during 2013 2015. The data was collected from patients' medical records using a researcher made checklist by a trained nurse. Competing risk regression models were fitted for the factors affecting the occurrence of death and discharge in ICU. Data analysis was conducted using STATA 13 and R 3.3.3 software. Results: Among these patients, 682 (77.5%) were discharged and 157 (17.8%) died in the ICU. The patients' mean +/- SD age was 48.90+/-19.52 yr. Among the study patients, 45.57% were female and 54.43% were male. In the competing risk model, age (Sub distribution Hazard Ratio (SHR)) =1.02, 95% CI: 1.007-1.032), maximum heart rate (SHR=1.009, 95% CI: 1.001-1.019), minimum sodium level (SHR=1.035, 95% CI: 1.007 1.064), PH (SHR=7.982, 95% CI: 1.259-50.61), and bilirubin (SHR=1.046, 95% CI: 1.015-1.078) increased the risk of death, while maximum sodium level (SHR=0.946, 95% CI: 0.908-0.986) and maximum HCT (SHR=0.938, 95% CI: 0.882-0.998) reduced the risk of death. Conclusion: In conclusion, the results of this study revealed several variables that were effective in ICU length of stay (LOS). The variables that independently influenced time-to-discharge were age, maximum systolic blood pressure, minimum HCT, maximum WBC, and urine output, maximum HCT and Glasgow coma score. The results also showed that age, maximum heart rate, maximum sodium level, PH, urine output, and bilirubin, minimum sodium level and maximum HCT were the predictors of death. Furthermore, our findings indicated that the competing risk model was more appropriate than the Cox model in evaluating the predictive factors associated with the occurrence of death and discharge in patients hospitalized in ICUs. Hence, this model could play an important role in managers' and clinicians' decision-making and improvement of the standard of care in ICUs. PMID- 29765581 TI - The antimicrobial activity of probiotic bacteria Escherichia coli isolated from different natural sources against hemorrhagic E. coli O157:H7. AB - Background: Diarrheal diseases have been seen in all geographical areas throughout the world. Therefore, considering treatment, could be deemed a necessary action. Objective: The aim of this study was to determine the antimicrobial effect of probiotic bacterial strains isolated from different natural sources against 2 pathotypes of pathogenic E. coli. Methods: This cross sectional study of Martyr Chamran University of Ahvaz was carried out from December 2013 to July 2014. A total of 13 probiotic colonies isolated from 20 samples of traditional dairy products including (yogurt, cheese, milk) and 20 samples of vegetables including carrots and cabbages (red and white) of which 5 isolates were selected to evaluate the antimicrobial effect against 2 Escherichia coli pathotypes, randomly. Antimicrobial effect was evaluated using two methods: disk diffusion and well diffusion tests and measuring growth inhibition zones of probiotics against 2 pathotypes of pathogenic E. coli. Results: Obtained results showed growth inhibition effects of all 5 probiotic strains against Escherichia coli pathotypes in both used methods. All selected strains showed considerable antimicrobial effect on Escherichia coli O157:H7 strain, but had no inhibitory effect against Enterohemorrhagic Escherichia coli. Conclusion: This study demonstrated considerable antimicrobial effect against E. coli O157:H7 strain. Due to this, characteristic and similar antimicrobial effects of probiotics bacteria, increasing use of the probiotics as a natural and modern method for prevention of different diseases is recommended. PMID- 29765582 TI - Demographic determinants of obesity, and adherence to dietary and physical activity guidelines among 4 to 6-year-old children in Behbahan city, southwest Iran, 2016. AB - Background and aim: The world is experiencing an alarming increase in prevalence of childhood obesity. The aim of this study was to determine the demographic determinants of obesity and adherence to dietary and physical activity guidelines among children aged 4 to 6 years old in Behbahan city, southwest Iran, in 2016. Methods: This cross-sectional study was conducted on 120 preschool children aged 4 to 6 years old in Behbahan city, southwest Iran, in 2016. Multi-stage random sampling was done. The weight and height of the children were measured with standard methods. The demographic and behavioral factors data were collected in self report questionnaires which were completed by the children's mothers. The Chi-square test, Independent-samples t-tests, One-way analysis of variances and logistic regression analysis were used for data analysis. SPSS software (version 22) was employed. Results: This study showed that 88.3% of the children did not meet the guideline of 5 servings per day of fruit and vegetables. Only 2.5% met the guideline of 60 minutes of structured physical activity every day. Sex and mother's occupation status were associated with adhering to screen time guideline. This study found a significant difference in the mean of screen time between sexes. Boys were more likely to meet the screen time guideline. A significant association between adhering to physical activity guidelines and mother's occupation status was revealed. Significant statistical relationship between demographic factors and BMI categories was not illustrated. Demographic covariates were not significantly related to adherence to dietary and physical activity guidelines. Conclusion: In preventive programs of obesity among 4 to 6 year-old children key lifestyle behaviors and demographic factors need to be considered. PMID- 29765583 TI - Effect of diet on blood viscosity in healthy humans: a systematic review. AB - Background: Increased whole blood viscosity is associated with increased risk of morbidity and mortality of several life-threatening diseases, including cardiovascular and cerebrovascular disease. The effect of diet on human health has been indicated in many studies, and a health dietary pattern can reduce the incidence of several chronic diseases. Objective: The aim of this systematic review was to assess the effect of diet on blood viscosity and related parameters such as haematocrit (HCT). Methods: This systematic review was carried out in 2017. MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from inception to 2 May 2017. We selected and included randomized clinical trials (RCTs) in the study. The inclusion criteria were articles that describe the effect of any types of local and traditional diet on blood viscosity in apparently healthy individuals. Results: Three randomized controlled trials were included in this systematic review. Different diets were used in the included trials. In one study, ingested dried-bonito broth (DBB) for four weeks, significantly reduced the blood passage time in the intervention group from 55.4+/-3.4 to 47.6+/-2.0 sec (mean +/- SEM, p<0.05) compared with no significant change in the placebo group. Another study has shown significantly increased blood fluidity score in a vegetarian group in contrast to the control group after six weeks. In the last study, plasma viscosity was significantly decreased in a group which used onion-olive-oil capsules compared to the placebo group, with a highly significant difference between the two groups (p=0.0015). Conclusions: Our components of food diets may decrease blood viscosity in health status. Better and expanded methodology may improve our results. PMID- 29765584 TI - Nursing managers attitude toward spirituality and spiritual care in Khorasan Razavi Province hospitals in 2016. AB - Background and aim: Spiritual care is an important part of nursing practice that seems to provide comprehensive care to patients. Nursing manager's attention to the spiritual dimension is one of the most important aspects affecting human health. Therefore, the aim of this study was to determine nursing managers' attitude to spirituality and spiritual care in hospitals in Khorasan Razavi Province in 2016. Methods: In this cross-sectional study, 110 management nurses (8 matrons, 37 supervisors and 65 head nurses) of hospitals in Khorasan Razavi Province (2016) were recruited for the study. Data were collected using a Spirituality & Spiritual Care Rating Scale (SSCRS) questionnaire in two parts, demographic information and questions related to the research objectives. Data were collected and analyzed using SPSS 16 software and doing descriptive (frequency, mean, standard deviation) and inferential statistics (independent samples t-test, ANOVA) and considering levels of significance (p<0.05). Results: The results showed mean and standard deviation in management nursing attitude to spirituality (4.01+/-0.35) and spiritual care (4.03+/-0.78). The result showed significant differences between the attitude to spirituality and spiritual care and gender, age and work experience in nursing management (p<0.05). Conclusions: Management nursing has high level attitude to spirituality and spiritual care. Therefore, providing the perfect platform to provide this care, and for nurses to implement it in hospitals is recommended. PMID- 29765585 TI - A Study of the Effects of Daily Physical Activity on Memory and Attention Capacities in College Students. AB - This study evaluated the relationship between daily physical activity (DPA) and memory capacity, as well as the association between daily activity and attention capacity, in college students in Taiwan. Participants (mean age = 20.79) wore wearable trackers for 106 days in order to collect DPA. These data were analyzed in association with their memory and attention capacities, as assessed using the spatial span test (SST) and the trail making test (TMT). The study showed significant negative correlations between memory capacity, time spent on the attention test (TSAT), calories burnt, and very active time duration (VATD) on the day before testing (r = -0.272, r = -0.176, r = 0.289, r = 0.254, resp.) and during the week prior to testing (r = -0.364, r = -0.395, r = 0.268, r = 0.241, resp.). The calories burnt and the VATD per day thresholds, which at best discriminated between normal-to-good and low attention capacity, were >=2283 calories day-1, >=20 minutes day-1 of very high activity (VHA) on the day before testing, or >=13,640 calories week-1, >=76 minutes week-1 of VHA during the week prior to testing. Findings indicated the short-term effects that VATD and calories burnt on the day before or during the week before testing significantly and negatively associated with memory and attention capacities of college students. PMID- 29765587 TI - Variation in the degree of reciprocal herkogamy affects the degree of legitimate pollination in a distylous species. AB - Distyly is a widespread floral polymorphism characterized by the flowers within a population showing reciprocal placement of the anthers and stigma. Darwin hypothesizes that distyly evolves to promote precise pollen transfer between morphs. Primula chungensis exhibits two types of anther heights, and these two types of anthers show pollen of two different size classes. To understand whether the stigma could capture more pollen grains from the anthers of the pollen donor as the separation between the stigma of pollen receiver and the anther of pollen donor decreased, the present research assessed the source of the pollen load in a series of open-pollinated flowers with continuous variation of style lengths. Individuals with continuous variation of style length were tagged, and the selected flowers in the tagged plants were emasculated the day before dehiscence. The stigma of the emasculated flowers was fixed in fuchsin gel at the end of blooming. We assessed the pollen sources on each stigma by taking photos under a microscope and measured the diameter of each conspecific pollen grain with ImageJ. We found that a shorter distance from the stigmas to the anthers of a pollen donor gave the flower a higher capacity to receive pollen from those anthers. Our result provides a new evidence that distyly could promote the pollen transfer between morphs, which is consistent with Darwin's hypothesis of disassortative pollination. An alternative hypothesis for the evolution of distyly (e.g. selfing avoidance) might also be true, but less likely, because self-incompatibility would greatly avoid self-fertilization for many distylous species. PMID- 29765586 TI - Design of a Clinical Decision Support System for Fracture Prediction Using Imbalanced Dataset. AB - More than 1 billion people suffer from chronic respiratory diseases worldwide, accounting for more than 4 million deaths annually. Inhaled corticosteroid is a popular medication for treating chronic respiratory diseases. Its side effects include decreased bone mineral density and osteoporosis. The aims of this study are to investigate the association of inhaled corticosteroids and fracture and to design a clinical support system for fracture prediction. The data of patients aged 20 years and older, who had visited healthcare centers and been prescribed with inhaled corticosteroids within 2002-2010, were retrieved from the National Health Insurance Research Database (NHIRD). After excluding patients diagnosed with hip fracture or vertebrate fractures before using inhaled corticosteroid, a total of 11645 patients receiving inhaled corticosteroid therapy were included for this study. Among them, 1134 (9.7%) were diagnosed with hip fracture or vertebrate fracture. The statistical results showed that demographic information, chronic respiratory diseases and comorbidities, and corticosteroid-related variables (cumulative dose, mean exposed daily dose, follow-up duration, and exposed duration) were significantly different between fracture and nonfracture patients. The clinical decision support systems (CDSSs) were designed with integrated genetic algorithm (GA) and support vector machine (SVM) by training and validating the models with balanced training sets obtained by random and cluster-based undersampling methods and testing with the imbalanced NHIRD dataset. Two different objective functions were adopted for obtaining optimal models with best predictive performance. The predictive performance of the CDSSs exhibits a sensitivity of 69.84-77.00% and an AUC of 0.7495-0.7590. It was concluded that long-term use of inhaled corticosteroids may induce osteoporosis and exhibit higher incidence of hip or vertebrate fractures. The accumulated dose of ICS and OCS therapies should be continuously monitored, especially for patients with older age and women after menopause, to prevent from exceeding the maximum dosage. PMID- 29765588 TI - DNA barcoding a taxonomically complex hemiparasitic genus reveals deep divergence between ploidy levels but lack of species-level resolution. AB - DNA barcoding is emerging as a useful tool not only for species identification but also for studying evolutionary and ecological processes. Although plant DNA barcodes do not always provide species-level resolution, the generation of large DNA barcode data sets can provide insights into the mechanisms underlying the generation of species diversity. Here, we study evolutionary processes in taxonomically complex British Euphrasia (Orobanchaceae), a group with multiple ploidy levels, frequent self-fertilization, young species divergence and widespread hybridization. We use a phylogenetic approach to investigate the colonization history of British Euphrasia, followed by a DNA barcoding survey and population genetic analyses to reveal the causes of shared sequence variation. Phylogenetic analysis shows Euphrasia have colonized Britain from mainland Europe on multiple occasions. DNA barcoding reveals that no British Euphrasia species has a consistent diagnostic sequence profile, and instead, plastid haplotypes are either widespread across species, or are population specific. The partitioning of nuclear genetic variation suggests differences in ploidy act as a barrier to gene exchange, while the divergence between diploid and tetraploid ITS sequences supports the polyploids being allotetraploid in origin. Overall, these results show that even when lacking species-level resolution, analyses of DNA barcoding data can reveal evolutionary patterns in taxonomically complex genera. PMID- 29765589 TI - Non-union of the trapezium: rare consequence of a rare injury. AB - Fractures of the trapezium are rare and easily missed. As these injuries are often imperceptible on plain radiographs, diagnosis in the ED setting is challenging. We report a case of an isolated fracture of the trapezium which was picked up as a non-union 5 months after the injury following persistence of symptoms. PMID- 29765590 TI - A case of rhabdomyolysis after kidney transplantation successfully managed with intensive continuous dialysis. AB - Rhabdomyolysis is characterized by muscle cell death which can result in acute kidney injury from pigment nephropathy. We present a patient who developed rhabdomyolysis immediately after deceased donor kidney transplantation surgery and was managed with continuous renal replacement therapy that resulted in successful salvage of the kidney allograft. Patients who develop acute kidney failure requiring renal replacement therapy generally have a poor prognosis. It is worth noting that while continuous veno-venous hemofiltration (CVVHF) offers greater volume support and continuous clearance compared to hemodialysis (HD), recent studies have demonstrated no clinically significant improvement in clinical outcome between the two. Perhaps CVVHF is a better modality compared to HD in this setting to prevent further insult from pigment nephropathy to an allograft. A combination of early diagnosis and intensive continuous renal replacement therapy can be used for allograft salvage in a patient with rhabdomyolysis in the immediate post-kidney transplant period. PMID- 29765591 TI - A case of periorbital necrotizing fasciitis rapidly progressing to severe multiorgan failure. AB - Periorbital necrotizing fasciitis (PNF) is a severe suppurative infection of the subcutaneous tissue and underlying fascia of the periorbital region. Typically, the course of PNF is milder and has a better prognosis than that of necrotizing fasciitis in other parts of the body. As such, this disease is thought to be associated with a significantly smaller risk of morbidity and mortality. Nevertheless, it is a rare and devastating condition that can lead to disfigurement, blindness and death. Early recognition is critical to improved patient outcomes. Here, we describe a case of PNF in a 60-year-old male that rapidly progressed to widespread systemic involvement and severe multiorgan failure requiring ventilatory, cardiovascular and renal support. Treatment included broad-spectrum antibiotics, intravenous immunoglobulin and surgical debridement. This case highlights the life-threatening nature of PNF, as demonstrated by rapid progression to multiorgan dysfunction and the need of an urgent surgical intervention. PMID- 29765592 TI - An unusual cause for small bowel obstruction as a complication of an ileostomy formation. AB - Ileostomy formation is a fundamental component in the surgical management of many gastrointestinal diseases and like all intra-abdominal surgeries, small bowel obstruction is a recognized complication. In this paper we discuss a case of a 44 year-old female who previously had a loop ileostomy for slow bowel transit in the presence of spinal bifida. She presented for subsequent total colectomy because of ongoing pain due to chronic colonic dilation. At surgery, the stoma was not revised and the efferent loop was divided at the peritoneal level of the anterior abdominal wall. Six days postoperatively, the patient developed a small bowel obstruction as a result of the remnant efferent loop within the anterior abdominal wall, forming a cystic mass compressing the ileostomy, requiring surgical intervention. As far as we are aware, this is the first case of small bowel obstruction described due to this unusual etiology. PMID- 29765593 TI - Appendico ilial knotting: a rare cause of small bowel obstruction. AB - Small bowel obstruction (SBO) is one of the most common acute surgical conditions that needs immediate innervation to prevent the morbidity and mortality associated with it. The common causes of SBO are different in developed and developing nations. Well-versed knowledge of the rare causes of SBO including its option of management is necessary. In this article, we present a case of an acute SBO secondary to Appendico-ileal knotting. The diagnostic difficulty and the options of management are discussed. PMID- 29721314 TI - Preliminary investigation of deoxyoligonucleotide binding to ribonuclease A using mass spectrometry: An attempt to develop a lab experience for undergraduates. AB - Deoxyoligonucleotide binding to bovine pancreatic ribonuclease A (RNase A) was investigated using electrospray ionization ion-trap mass spectrometry (ESI-IT MS). Deoxyoligonucleotides included CCCCC (dC 5) and CCACC (dC 2AC 2). This work was an attempt to develop a biochemistry lab experience that would introduce undergraduates to the use of mass spectrometry for the analysis of protein-ligand interactions. Titration experiments were performed using a fixed RNase A concentration and variable deoxyoligonucleotide concentrations. Samples at equilibrium were infused directly into the mass spectrometer under native conditions. For each deoxyoligonucleotide, mass spectra showed one-to-one binding stoichiometry, with marked increases in the total ion abundance of ligand bound RNase A complexes as a function of concentration, but the accurate determination of dC 5 and dC 2AC 2 dissociation constants was problematic. PMID- 26925222 TI - Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / DICER1 syndrome: a unique variant of the two-hit tumor suppression model. AB - Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition, DICER1 syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of DICER1-associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific "hotspot" codons within the RNase IIIb domain of DICER 1, combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing DICER1 mutations and sought correlations with clinical phenotypes. Over 70% have inherited or de novo germline LOF mutations, most of which truncate the DICER1 open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing DICER1 mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of DICER1 syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in DICER1-associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development. PMID- 29765596 TI - An evolutionary perspective on night terrors. AB - Night terrors, also known as sleep terrors, are an early childhood parasomnia characterized by screams or cries, behavioral manifestations of extreme fear, difficulty waking and inconsolability upon awakening. The mechanism causing night terrors is unknown, and a consistently successful treatment has yet to be documented. Here, we argue that cultural practices have moved us away from an ultimate solution: cosleeping. Cosleeping is the norm for closely related primates and for humans in non-Western cultures. In recent years, however, cosleeping has been discouraged by the Western medical community. From an evolutionary perspective, cosleeping provides health and safety benefits for developing children. We discuss night terrors, and immediate and long-term health features, with respect to cosleeping, room-sharing and solitary sleeping. We suggest that cosleeping with children (>=1-year-old) may prevent night terrors and that, under certain circumstances, cosleeping with infants (<=11-months-old) is preferable to room-sharing, and both are preferable to solitary sleeping. PMID- 29765598 TI - Crystallography and the development of therapeutic medicines. AB - Advances in crystallography and cryo-EM promise to further enhance the proud role crystallography has played in the development of new medicines. PMID- 29765597 TI - Cancer cell transmission via the placenta. AB - Cancer cells have a parasitic propensity in the primary host but their capacity to transit between individuals is severely restrained by two factors: a lack of a route for viable cell transfer and immune recognition in allogeneic, secondary recipients. Several examples of transmissible animal cancers are now recognised. In humans, the only natural route for transmission is via the haemochorial placenta which is permissive for cell traffic. There are three special examples of this occurring in utero: maternal to foetus, intraplacental twin to twin leukaemias and choriocarcinoma-extra-embryonic cells to mother. We discuss the rare circumstances under which such transmission occurs. PMID- 29765599 TI - Interactions that know no boundaries. AB - Diffuse scattering provides evidence that variations are correlated across molecular boundaries in macromolecular crystals. PMID- 29765600 TI - Multi-model imaging of the interaction of nanomaterials with cells. AB - A multi-model X-ray imaging approach was implemented to probe the interaction of nanomaterials with a mammalian cell in three dimensions. With further developments, this approach could have an impact on nanomedicine and nanotoxicology. PMID- 29765601 TI - Survey and analysis of crystal polymorphism in organic structures. AB - With the intention of producing the most comprehensive treatment of the prevalence of crystal polymorphism among structurally characterized materials, all polymorphic compounds flagged as such within the Cambridge Structural Database (CSD) are analysed and a list of crystallographically characterized organic polymorphic compounds is assembled. Classifying these structures into subclasses of anhydrates, salts, hydrates, non-hydrated solvates and cocrystals reveals that there are significant variations in polymorphism prevalence as a function of crystal type, a fact which has not previously been recognized in the literature. It is also shown that, as a percentage, polymorphic entries are decreasing temporally within the CSD, with the notable exception of cocrystals, which continue to rise at a rate that is a constant fraction of the overall entries. Some phenomena identified that require additional scrutiny include the relative prevalence of temperature-induced phase transitions among organic salts and the paucity of polymorphism in crystals with three or more chemical components. PMID- 29765602 TI - Protein crystal lattices are dynamic assemblies: the role of conformational entropy in the protein condensed phase. AB - Until recently, the occurrence of conformational entropy in protein crystal contacts was considered to be a very unlikely event. A study based on the most accurately refined protein structures demonstrated that side-chain conformational entropy and static disorder might be common in protein crystal lattices. The present investigation uses structures refined using ensemble refinement to show that although paradoxical, conformational entropy is likely to be the major factor in the emergence and integrity of the protein condensed phase. This study reveals that the role of shape entropy and local entropic forces expands beyond the onset of crystallization. For the first time, the complete pattern of intermolecular interactions by protein atoms in crystal lattices is presented, which shows that van der Waals interactions dominate in crystal formation. PMID- 29765604 TI - Deciphering mineralogical changes and carbonation development during hydration and ageing of a consolidated ternary blended cement paste. AB - To understand the main properties of cement, a ubiquitous material, a sound description of its chemistry and mineralogy, including its reactivity in aggressive environments and its mechanical properties, is vital. In particular, the porosity distribution and associated sample carbonation, both of which affect cement's properties and durability, should be quantified accurately, and their kinetics and mechanisms of formation known both in detail and in situ. However, traditional methods of cement mineralogy analysis (e.g. chemical mapping) involve sample preparation (e.g. slicing) that can be destructive and/or expose cement to the atmosphere, leading to preparation artefacts (e.g. dehydration). In addition, the kinetics of mineralogical development during hydration, and associated porosity development, cannot be examined. To circumvent these issues, X-ray diffraction computed tomography (XRD-CT) has been used. This allowed the mineralogy of ternary blended cement composed of clinker, fly ash and blast furnace slag to be deciphered. Consistent with previous results obtained for both powdered samples and dilute systems, it was possible, using a consolidated cement paste (with a water-to-solid ratio akin to that used in civil engineering), to determine that the mineralogy consists of alite (only detected in the in situ hydration experiment), calcite, calcium silicate hydrates (C-S-H), ettringite, mullite, portlandite, and an amorphous fraction of unreacted slag and fly ash. Mineralogical evolution during the first hydration steps indicated fast ferrite reactivity. Insights were also gained into how the cement porosity evolves over time and into associated spatially and time-resolved carbonation mechanisms. It was observed that macroporosity developed in less than 30 h of hydration, with pore sizes reaching about 100-150 um in width. Carbonation was not observed for this time scale, but was found to affect the first 100 um of cement located around macropores in a sample cured for six months. Regarding this carbonation, the only mineral detected was calcite. PMID- 29765603 TI - Three-dimensional ultrastructural imaging reveals the nanoscale architecture of mammalian cells. AB - Knowledge of the interactions between nanomaterials and large-size mammalian cells, including cellular uptake, intracellular localization and translocation, has greatly advanced nanomedicine and nanotoxicology. Imaging techniques that can locate nanomaterials within the structures of intact large-size cells at nanoscale resolution play crucial roles in acquiring this knowledge. Here, the quantitative imaging of intracellular nanomaterials in three dimensions was performed by combining dual-energy contrast X-ray microscopy and an iterative tomographic algorithm termed equally sloped tomography (EST). Macrophages with a size of ~20 um that had been exposed to the potential antitumour agent [Gd@C82(OH)22] n were investigated. Large numbers of nanoparticles (NPs) aggregated within the cell and were mainly located in phagosomes. No NPs were observed in the nucleus. Imaging of the nanomedicine within whole cells advanced the understanding of the high-efficiency antitumour activity and the low toxicity of this agent. This imaging technique can be used to probe nanomaterials within intact large-size cells at nanometre resolution uniformly in three dimensions and may greatly benefit the fields of nanomedicine and nanotoxicology. PMID- 29765605 TI - Pressure-induced coherent sliding-layer transition in the excitonic insulator Ta2NiSe5. AB - The crystal structure of the excitonic insulator Ta2NiSe5 has been investigated under a range of pressures, as determined by the complementary analysis of both single-crystal and powder synchrotron X-ray diffraction measurements. The monoclinic ambient-pressure excitonic insulator phase II transforms upon warming or under a modest pressure to give the semiconducting C-centred orthorhombic phase I. At higher pressures (i.e. >3 GPa), transformation to the primitive orthorhombic semimetal phase III occurs. This transformation from phase I to phase III is a pressure-induced first-order phase transition, which takes place through coherent sliding between weakly coupled layers. This structural phase transition is significantly influenced by Coulombic interactions in the geometric arrangement between interlayer Se ions. Furthermore, upon cooling, phase III transforms into the monoclinic phase IV, which is analogous to the excitonic insulator phase II. Finally, the excitonic interactions appear to be retained despite the observed layer sliding transition. PMID- 29765606 TI - A new MR-SAD algorithm for the automatic building of protein models from low resolution X-ray data and a poor starting model. AB - Determining macromolecular structures from X-ray data with resolution worse than 3 A remains a challenge. Even if a related starting model is available, its incompleteness or its bias together with a low observation-to-parameter ratio can render the process unsuccessful or very time-consuming. Yet, many biologically important macromolecules, especially large macromolecular assemblies, membrane proteins and receptors, tend to provide crystals that diffract to low resolution. A new algorithm to tackle this problem is presented that uses a multivariate function to simultaneously exploit information from both an initial partial model and low-resolution single-wavelength anomalous diffraction data. The new approach has been used for six challenging structure determinations, including the crystal structures of membrane proteins and macromolecular complexes that have evaded experts using other methods, and large structures from a 3.0 A resolution F1 ATPase data set and a 4.5 A resolution SecYEG-SecA complex data set. All of the models were automatically built by the method to Rfree values of between 28.9 and 39.9% and were free from the initial model bias. PMID- 29765607 TI - Internal protein motions in molecular-dynamics simulations of Bragg and diffuse X ray scattering. AB - Molecular-dynamics (MD) simulations of Bragg and diffuse X-ray scattering provide a means of obtaining experimentally validated models of protein conformational ensembles. This paper shows that compared with a single periodic unit-cell model, the accuracy of simulating diffuse scattering is increased when the crystal is modeled as a periodic supercell consisting of a 2 * 2 * 2 layout of eight unit cells. The MD simulations capture the general dependence of correlations on the separation of atoms. There is substantial agreement between the simulated Bragg reflections and the crystal structure; there are local deviations, however, indicating both the limitation of using a single structure to model disordered regions of the protein and local deviations of the average structure away from the crystal structure. Although it was anticipated that a simulation of longer duration might be required to achieve maximal agreement of the diffuse scattering calculation with the data using the supercell model, only a microsecond is required, the same as for the unit cell. Rigid protein motions only account for a minority fraction of the variation in atom positions from the simulation. The results indicate that protein crystal dynamics may be dominated by internal motions rather than packing interactions, and that MD simulations can be combined with Bragg and diffuse X-ray scattering to model the protein conformational ensemble. PMID- 29765608 TI - Isomerism in double-pillared-layer coordination polymers - structures and photoreactivity. AB - The existence of isomerism in coordination polymeric structures offers opportunities to understand structure-function relationships. Herein the serendipitous isolation is reported of two isomeric double-pillared-layer coordination polymeric structures arising from two different types of carboxyl ate bonding of benzene-1,4-di-carboxyl-ate ligands to zinc(II), which constitutes a new type of structural isomerism. The different bonding modes not only alter the shape and size of the pores, but also the nature of interpenetration and photoreactivity. Although two trans,cis,trans-bpeb ligands with conjugated olefin bonds are aligned in close proximity in both of the structures, one isomer undergoes a double [2 + 2] cyclo-addition reaction and the second isomer only offers an incomplete single cyclo-addition product. This work demonstrates how small changes in the structural connectivity can have an impact on the overall structural, physical and chemical properties of such materials. PMID- 29765609 TI - Electron crystallography with the EIGER detector. AB - Electron crystallography is a discipline that currently attracts much attention as method for inorganic, organic and macromolecular structure solution. EIGER, a direct-detection hybrid pixel detector developed at the Paul Scherrer Institut, Switzerland, has been tested for electron diffraction in a transmission electron microscope. EIGER features a pixel pitch of 75 * 75 um2, frame rates up to 23 kHz and a dead time between frames as low as 3 us. Cluster size and modulation transfer functions of the detector at 100, 200 and 300 keV electron energies are reported and the data quality is demonstrated by structure determination of a SAPO-34 zeotype from electron diffraction data. PMID- 29765611 TI - Intermolecular correlations are necessary to explain diffuse scattering from protein crystals. AB - Conformational changes drive protein function, including catalysis, allostery and signaling. X-ray diffuse scattering from protein crystals has frequently been cited as a probe of these correlated motions, with significant potential to advance our understanding of biological dynamics. However, recent work has challenged this prevailing view, suggesting instead that diffuse scattering primarily originates from rigid-body motions and could therefore be applied to improve structure determination. To investigate the nature of the disorder giving rise to diffuse scattering, and thus the potential applications of this signal, a diverse repertoire of disorder models was assessed for its ability to reproduce the diffuse signal reconstructed from three protein crystals. This comparison revealed that multiple models of intramolecular conformational dynamics, including ensemble models inferred from the Bragg data, could not explain the signal. Models of rigid-body or short-range liquid-like motions, in which dynamics are confined to the biological unit, showed modest agreement with the diffuse maps, but were unable to reproduce experimental features indicative of long-range correlations. Extending a model of liquid-like motions to include disorder across neighboring proteins in the crystal significantly improved agreement with all three systems and highlighted the contribution of intermolecular correlations to the observed signal. These findings anticipate a need to account for intermolecular disorder in order to advance the interpretation of diffuse scattering to either extract biological motions or aid structural inference. PMID- 29765610 TI - X-ray and cryo-EM structures of inhibitor-bound cytochrome bc1 complexes for structure-based drug discovery. AB - Cytochrome bc1, a dimeric multi-subunit electron-transport protein embedded in the inner mitochondrial membrane, is a major drug target for the treatment and prevention of malaria and toxoplasmosis. Structural studies of cytochrome bc1 from mammalian homologues co-crystallized with lead compounds have underpinned structure-based drug design to develop compounds with higher potency and selectivity. However, owing to the limited amount of cytochrome bc1 that may be available from parasites, all efforts have been focused on homologous cytochrome bc1 complexes from mammalian species, which has resulted in the failure of some drug candidates owing to toxicity in the host. Crystallographic studies of the native parasite proteins are not feasible owing to limited availability of the proteins. Here, it is demonstrated that cytochrome bc1 is highly amenable to single-particle cryo-EM (which uses significantly less protein) by solving the apo and two inhibitor-bound structures to ~4.1 A resolution, revealing clear inhibitor density at the binding site. Therefore, cryo-EM is proposed as a viable alternative method for structure-based drug discovery using both host and parasite enzymes. PMID- 29765613 TI - Basic lifestyle advice to individuals at high risk of type 2 diabetes: a 2-year population-based diabetes prevention study. The DE-PLAN intervention in the HUNT Study, Norway. AB - Objective: Among individuals at high risk for diabetes identified through a population survey, we performed an intervention study with basic lifestyle advice aiming to prevent diabetes. Research design and methods: Among 50 806 participants in the HUNT3 Survey (2006-2008), 5297 individuals with Finnish Diabetes Risc Score (FINDRISC >=15 were invited to an oral glucose tolerance test (OGTT) and an education session with lifestyle advice, and 2634 (49.7%) attended. Among them, 2380 people without diabetes were included in the prevention study with repeated examinations and education sessions after 6, 12, and 24 months. We examined participation, diabetes incidence, glycemia, and adiposity during follow up. Results: Of 2380 participants, 1212 (50.9%) participated in >=3 of the four examinations. Diabetes was detected in 3.5%, 3.1%, and 4.0% of individuals at the 6-month, 12-month, and 24-month examinations, respectively, indicating a 10.3% 2 year diabetes incidence. Mean (95% CI) increases from baseline to 2-year follow up were 0.30 (0.29 to 0.32) percentage points (3.3 (3.2 to 3.5) mmol/mol) for Hemoglobin A1c, 0.13 (0.10 to 0.16) mmol/L for fasting serum-glucose, 0.46 (0.36 to 0.56) mmol/L for 2-hour OGTT s-glucose, 0.30 (0.19 to 0.40) kg/m2 forbody mass index (BMI) (all p<0.001) and -0.5 (-0.9 to -0.2) cm for waist circumference (p=0.004), with broadly similar estimates by baseline age, sex, education, depressive symptoms, BMI, physical activity, and family history of diabetes. Only 206 (8.7%) participants had evidence of >5% weight loss during follow-up; their fasting and 2-hour s-glucose did not increase, and HbA1c increased less than in other participants. Conclusion: Basic lifestyle advice given to high-risk individuals during three group sessions with 6-month intervals was not effective in reducing 2-year diabetes risk. PMID- 29765612 TI - Crystal structures of Lymphocytic choriomeningitis virus endonuclease domain complexed with diketo-acid ligands. AB - The Arenaviridae family, together with the Bunyaviridae and Orthomyxoviridae families, is one of the three negative-stranded RNA viral families that encode an endonuclease in their genome. The endonuclease domain is at the N-terminus of the L protein, a multifunctional protein that includes the RNA-dependent RNA polymerase. The synthesis of mRNA in arenaviruses is a process that is primed by capped nucleotides that are 'stolen' from the cellular mRNA by the endonuclease domain in cooperation with other domains of the L protein. This molecular mechanism has been demonstrated previously for the endonuclease of the prototype Lymphocytic choriomeningitis virus (LCMV). However, the mode of action of this enzyme is not fully understood as the original structure did not contain catalytic metal ions. The pivotal role played by the cap-snatching process in the life cycle of the virus and the highly conserved nature of the endonuclease domain make it a target of choice for the development of novel antiviral therapies. Here, the binding affinities of two diketo-acid (DKA) compounds (DPBA and L-742,001) for the endonuclease domain of LCMV were evaluated using biophysical methods. X-ray structures of the LCMV endonuclease domain with catalytic ions in complex with these two compounds were determined, and their efficacies were assessed in an in vitro endonuclease-activity assay. Based on these data and computational simulation, two new DKAs were synthesized. The LCMV endonuclease domain exhibits a good affinity for these DKAs, making them a good starting point for the design of arenavirus endonuclease inhibitors. In addition to providing the first example of an X-ray structure of an arenavirus endonuclease incorporating a ligand, this study provides a proof of concept that the design of optimized inhibitors against the arenavirus endonuclease is possible. PMID- 29765614 TI - Bivalirudin versus heparin in primary PCI: clinical outcomes and cost analysis. AB - Background: The evidence for benefits of bivalirudin over heparin has recently been challenged. We aimed to analyse the safety and cost-effectiveness following reintroduction of heparin instead of bivalirudin as the standard anticoagulation for primary percutaneous coronary intervention (PPCI) in a high-volume centre. Methods and results: This analysis was an open-label, prospective registry including all patients admitted to our centre for PPCI from April 2014 to April 2016. Heparin was reintroduced as standard anticoagulant in April 2015. During the 2 years, 1291 patients underwent a PPCI, 662 in the Bivalirudin protocol period (Cohort B) and 629 in the Heparin protocol period (Cohort H). Baseline and procedural characteristics were not significantly different, except for a higher use of thromboaspiration and femoral access in the earlier Cohort B. Glycoprotein 2b3a (Gp2b3a) antagonists were used in 24% of the patients in Cohort B versus 28% in Cohort H (P<0.01). We did not observe any differences in death at 180 days (11.03% in Cohort B vs 11.29% in Cohort H)(HR 95% CI 0.98 (0.72 to 1.33), P=0.88). The incidence of any bleeding complications at 30 days did not differ between the two periods (21.9% vs 21.9%, P=0.99). The cost related to the anticoagulants amounted to L246 236 in Cohort B versus L4483 in Cohort H (L324 406 vs L102 347 when adding Gp2b3a antagonists). Conclusion: We did not find clinically relevant changes in patient outcomes, including bleeding complications with reintroduction of heparin in our PPCI protocol. However, the use of heparin was associated with a major reduction in treatment costs. PMID- 29765615 TI - Prognostic significance of repeated brain natriuretic peptide measurements after percutaneous transluminal septal myocardial ablation in patients with drug refractory hypertrophic obstructive cardiomyopathy. AB - Objectives: To evaluate whether repeated brain natriuretic peptide (BNP) measurements after percutaneous transluminal septal myocardial ablation (PTSMA) provide prognostic information regarding the response to PTSMA in patients with drug-refractory hypertrophic obstructive cardiomyopathy (HOCM). Background: Plasma BNP levels are associated with clinical outcomes in patients with HOCM. However, the prognostic value of plasma BNP level changes before and after PTSMA remains unclear. Methods: We measured the plasma BNP levels serially before and after PTSMA, and evaluated the relationship between the changes in plasma BNP levels and clinical improvement in 47 patients. The patients were assigned to two groups based on the reduction in the New York Heart Association class >=1 (good responder) or <1 (poor responder) before and after PTSMA. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status. Results: The plasma BNP levels gradually decreased after PTSMA, although the levels plateaued 3 months until 12 months after PTSMA. Although the plasma BNP levels and resting left ventricular outflow tract peak pressure gradient before PTSMA were comparable between the groups, the ratio of the BNP levels before and after PTSMA in the good responder group was significantly lower than that in the poor responder group (0.43 (range, 0.24-0.68) vs 0.78 (range, 0.62-0.93), p=0.002). The KCCQ score changes in the good responder group were significantly higher than those in the poor responder group. Conclusions: The plasma BNP level ratio was associated with long-term clinical improvement of heart failure after PTSMA for drug-refractory HOCM. PMID- 29765616 TI - Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort. AB - Objective: Corticosteroids are a mainstay of SLE treatment; however, cumulative steroid exposure may lead to organ damage. This study aimed to quantify the risk of new diabetes, hypertension, cataracts, osteoporosis and avascular necrosis that is attributable to cumulative corticosteroid exposure in SLE. Methods: Using data from the Hopkins Lupus Cohort, a longitudinal study of lupus activity, organ damage and quality of life in patients with SLE, five matched case-control analyses nested within a prospectively enrolled SLE cohort were performed. Two randomly selected controls were matched to each case using incidence-density sampling from defined risk sets. Attributable risk was calculated for steroid exposure (dose and duration, separately). Cumulative steroid dose was modelled as a four-level categorical variable using clinically relevant thresholds: 0 g (no exposure); >0 and <3.65 g (<10 mg/day for a year); >=3.65 g and <18.25 g (1-5 years at 10 mg/day); and >=18.25 g (>5 years at 10 mg/day). Results: Eligible cases were identified for diabetes (n=42), hypertension (n=79), cataract (n=132), osteoporosis (n=118) and avascular necrosis (n=38). The unadjusted OR for a one category increase in cumulative steroid exposure ranged from 1.157 (cataract (0.889 to 1.506); p=0.2779) to 2.183 (avascular necrosis (1.162 to 4.103); p=0.0153). After adjusting for confounding variables, a one-category increase in the cumulative steroid dose was significantly associated with risk of cataract (OR (95% CI) 1.855 (1.190 to 2.892); p=0.0064) and osteoporosis (OR (95% CI) 1.604 (1.067 to 2.412); p=0.0232). ORs for avascular necrosis, diabetes and hypertension suggested a moderately increased risk (not significant). Duration of steroid exposure was not associated with any of the outcomes. The proportion of risk attributable to steroid exposure after adjustment for covariates was 0.711 for cataract and 0.540 for osteoporosis. Conclusions: Cumulative steroid exposure was associated with an increased risk of cataract and osteoporosis in patients with SLE. Trial registration number: NCT01616472. PMID- 29765618 TI - Mediastinal monophasic synovial sarcoma with pericardial extension causing hemodynamic instability. AB - A 46-year-old man presented with mass on chest x-ray along with a 6-month history of weight loss, dyspnea and cough. He was hypotensive and an echocardiogram showed large extra-cardiac mass compressing the right ventricular outflow tract resulting in features of cardiac tamponade. Chest computed tomography revealed a mediastinal mass invading the pericardium adjacent to right ventricular outflow tract. Biopsy of the mass confirmed primary monophasic synovial sarcoma. Chemotherapy and radiotherapy along with anti-inflammatories were given as surgery was too high risk due to the location of the tumour and pericardial involvement. Patient responded briefly to the treatment with improvement in hemodynamic parameters but over next weeks he became less responsive to treatment with increasing size. He died 2 months after treatment commenced. PMID- 29765617 TI - Accelerated model of lupus autoimmunity and vasculopathy driven by toll-like receptor 7/9 imbalance. AB - Objectives: Activation of endosomal toll-like receptor (TLR)7 or TLR9 has been proposed as a critical step for the initiation and development of SLE. Traditional spontaneous lupus models normally introduce multiple risk alleles, thereby adding additional confounding factors. In the induced lupus models, the role of TLR9 remains unclear. In the present study, we explored the role of an imbalance between TLR7 and TLR9 pathways in the pathogenesis of lupus and its associated vasculopathy using the imiquimod model in TLR9 KO/B6 background. Methods: Wild type (WT) and Tlr9-/- mice were epicutaneously treated with imiquimod cream 5% on both ears three times per week for indicated times. At euthanasia, mice were analysed for organ involvement, endothelium-dependent vasorelaxation, serum autoantibodies, and innate and adaptive immune responses. Results: Compared with the lupus-like phenotype that develops in imiquimod treated WT mice, Tlr9-/- mice exposed to imiquimod have increased severity of autoimmunity features and inflammatory phenotype that develops at earlier stages. These abnormalities are characterised by enhanced TLR7 expression and immune activation, increased immune complex deposition, Th1 T cells and dendritic cell kidney infiltration and significant impairments in endothelial function. Modulation of TLR7 expression was observed in the Tlr9-/- mice. Conclusions: These findings further underscore the protective role of TLR9 in TLR7-driven autoimmunity and also in the development of vasculopathy, further strengthening the importance of tightly manipulating TLRs in putative therapeutic strategies. This study provides a new model of accelerated lupus phenotype driven by danger associated molecular patterns. PMID- 29765620 TI - Reducing language to rhythm: Amazonian Bora drummed language exploits speech rhythm for long-distance communication. AB - Many drum communication systems around the world transmit information by emulating tonal and rhythmic patterns of spoken languages in sequences of drumbeats. Their rhythmic characteristics, in particular, have not been systematically studied so far, although understanding them represents a rare occasion for providing an original insight into the basic units of speech rhythm as selected by natural speech practices directly based on beats. Here, we analyse a corpus of Bora drum communication from the northwest Amazon, which is nowadays endangered with extinction. We show that four rhythmic units are encoded in the length of pauses between beats. We argue that these units correspond to vowel-to vowel intervals with different numbers of consonants and vowel lengths. By contrast, aligning beats with syllables, mora or only vowel length yields inconsistent results. Moreover, we also show that Bora drummed messages conventionally select rhythmically distinct markers to further distinguish words. The two phonological tones represented in drummed speech encode only few lexical contrasts. Rhythm thus appears to crucially contribute to the intelligibility of drummed Bora. Our study provides novel evidence for the role of rhythmic structures composed of vowel-to-vowel intervals in the complex puzzle concerning the redundancy and distinctiveness of acoustic features embedded in speech. PMID- 29765619 TI - Contrasting ecological roles of non-native ungulates in a novel ecosystem. AB - Conservation has long focused on preserving or restoring pristine ecosystems. However, understanding and managing novel ecosystems has grown in importance as they outnumber pristine ecosystems worldwide. While non-native species may be neutral or detrimental in pristine ecosystems, it is possible that even notorious invaders could play beneficial or mixed roles in novel ecosystems. We examined the effects of two long-established non-native species-Philippine deer (Rusa marianna) and feral pigs (Sus scrofa)-in Guam, Micronesia, where native vertebrate frugivores are functionally absent leaving forests devoid of seed dispersers. We compared the roles of deer and pigs on seedling survival, seed dispersal and plant community structure in limestone karst forests. Deer, even at low abundances, had pronounced negative impacts on forest communities by decreasing seedling and vine abundance. By contrast, pigs showed no such relationship. Also, many viable seeds were found in pig scats, whereas few were found in deer scats, suggesting that pigs, but not deer, provide an ecosystem function-seed dispersal-that has been lost from Guam. Our study presents a discrepancy between the roles of two non-native species that are traditionally managed as a single entity, suggesting that ecological function, rather than identity as a non-native, may be more important to consider in managing novel systems. PMID- 29765621 TI - Biofilm inhibition and pathogenicity attenuation in bacteria by Proteus mirabilis. AB - Biofilms play an important role in the antibiotic resistance of encased bacteria, and biofilm formation is regulated by quorum sensing (QS). Inhibiting the QS system may, therefore, degrade the integrity of a biofilm and expose the bacterial pathogens within it to the deleterious effects of molecules such as antibiotics. Moreover, the use of QS inhibitors (QSIs) may provide a novel approach for treating bacterial infections of aquacultures. In the present study, the bacterium Proteus mirabilis was identified as a potential producer of QSIs. Varying concentrations (0.1-1.1%) of filtrates prepared from the culture of P. mirabilis inhibited biofilm formation by the pathogens Pseudomonas aeruginosa, Vibrio harveyi and Staphylococcus aureus by as much as 58.9%, 41.5% and 41.9%, respectively. These filtrates as well as the crude aqueous extracts prepared from them increased the sensitivities of pathogens to the inhibitory effects of kanamycin. The filtrates also showed pathogenicity attenuation potential in P. aeruginosa by decreasing the production of virulence factors. Moreover, the filtrates did not influence the planktonic growth of these pathogens. The results indicate that P. mirabilis may act as a non-specific (or broad-spectrum) inhibitor of biofilm formation that will help control infectious diseases that adversely affect the aquaculture industry. PMID- 29765623 TI - Theoretical investigation of Banert cascade reaction. AB - Computational inside of Banert cascade reaction for triazole formation is studied with B3LYP/6-31G(d,p) level of theory. The reaction proceeds mainly by SN2 initial chloride displacement rather than SN2'-type attack. Furthermore, according to the rate of reaction calculation, SN2 displacement is much faster than SN2' displacement in the order of 8. The [3,3]-sigmatropic rearrangement for the conversion of propargyl azide into triazafulvene has been proved as the rate determining step having highest activation energy parameter. Solvent effect on total course of reaction has been found negligible. Furthermore, effects of different density functional theory functionals and functional groups on activation energies of [3,3]-sigmatropic rearrangement of propargyl azide were also studied. BHHLYP, omegaB97XD, M062X and BMK calculated DeltaG? are consistent with B3LYP. PMID- 29765624 TI - Generalized transformations and coordinates for static spherically symmetric general relativity. AB - We examine a static, spherically symmetric solution of the empty space field equations of general relativity with a non-orthogonal line element which gives rise to an opportunity that does not occur in the standard derivations of the Schwarzschild solution. In these derivations, convenient coordinate transformations and dynamical assumptions inevitably lead to the Schwarzschild solution. By relaxing these conditions, a new solution possibility arises and the resulting formalism embraces the Schwarzschild solution as a special case. The new solution avoids the coordinate singularity associated with the Schwarzschild solution and is achieved by obtaining a more suitable coordinate chart. The solution embodies two arbitrary constants, one of which can be identified as the Newtonian gravitational potential using the weak field limit. The additional arbitrary constant gives rise to a situation that allows for generalizations of the Eddington-Finkelstein transformation and the Kruskal-Szekeres coordinates. PMID- 29765622 TI - Are monkeys intuitive Aristotelians? Associations between target size and vertical target position in long-tailed macaques. AB - Different hypotheses have been put forward to explain the interaction between size perception and spatial position. To explore the evolutionary roots of these phenomena, we tested long-tailed macaques' performance in a two-choice discrimination task on a touchscreen and contrasted two hypotheses. First, a hierarchy association in which large objects are associated with top positions, due to a link between power, dominance and importance with top position. Second, a naive Aristotelian association in which large objects are associated with bottom positions, due to the experience that larger objects are heavier and thus more likely to be found at the bottom. Irrespective of training regime (positively reinforcing the small (Touch-Small) or large (Touch-Large) stimulus), the monkeys had a bias to touch the bottom compared to the top location. Individuals in the Touch-Small group took significantly longer to acquire the task, but subsequently made fewer mistakes. When presented with two stimuli of equal medium size, the Touch-Large group had a clear bias to touch the lower stimulus, while the Touch-Small group touched both locations at equal rates. Our findings point to an innate bias towards larger stimuli and a natural preference for the lower position, while the extent of interaction between size and position depends on executive control requirements of a task. PMID- 29765625 TI - Does it actually feel right? A replication attempt of the rounded price effect. AB - How does the roundedness of prices affect product evaluations? The 'rounded price effect' postulates that depending on the context, rounded or non-rounded prices increase the purchase likelihood of consumers. The study presented here is a replication attempt of these findings and the proposed mediation of the effect through a sense of 'feeling right' when evaluating the product. p-Curve analysis and the R-Index are used to assess the robustness of the originally reported statistics since original data were not available. A pre-registered replication of study 5 from the original article was conducted in a sample of N=588 participants. For both the original product and one alternative product neither an interaction between price roundedness and context, nor a mediation through 'a sense of feeling right' was found. Our results suggest that the effect is either smaller than originally reported or contingent on other, not investigated factors. Further studies might investigate contingencies in larger samples. PMID- 29765627 TI - In situ epoxide generation by dimethyldioxirane oxidation and the use of epichlorohydrin in the flow synthesis of a library of beta-amino alcohols. AB - The flow coupling of epichlorohydrin with substituted phenols, while efficient, limits the nature of the epoxide available for the development of focused libraries of beta-amino alcohols. This limitation was encountered in the production of analogues of 1-(4-nitrophenoxy)-3-((2-((4 (trifluoromethyl)pyrimidin-2-yl)amino)ethyl)amino)propan-2-ol 1, a potential antibiotic lead. The in situ (flow) generation of dimethyldoxirane (DMDO) and subsequent flow olefin epoxidation abrogates this limitation and afforded facile access to structurally diverse beta-amino alcohols. Analogues of 1 were readily accessed either via (i) a flow/microwave hybrid approach, or (ii) a sequential flow approach. Key steps were the in situ generation of DMDO, with olefin epoxidation in typically good yields and a flow-mediated ring opening aminolysis to form an expanded library of beta-amino alcohols 1 and 10a-18g, resulting in modest (11a, 21%) to excellent (12g, 80%) yields. Alternatively flow coupling of epichlorohydrin with phenols 4a-4m (22%-89%) and a Bi(OTf)3 catalysed microwave ring opening with amines afforded a select range of beta-amino alcohols, but with lower levels of aminolysis regiocontrol than the sequential flow approach. PMID- 29765628 TI - Deep cultural ancestry and human development indicators across nation states. AB - How historical connections, events and cultural proximity can influence human development is being increasingly recognized. One aspect of history that has only recently begun to be examined is deep cultural ancestry, i.e. the vertical relationships of descent between cultures, which can be represented by a phylogenetic tree of descent. Here, we test whether deep cultural ancestry predicts the United Nations Human Development Index (HDI) for 44 Eurasian countries, using language ancestry as a proxy for cultural relatedness and controlling for three additional factors-geographical proximity, religion and former communism. While cultural ancestry alone predicts HDI and its subcomponents (income, health and education indices), when geographical proximity is included only income and health indices remain significant and the effect is small. When communism and religion variables are included, cultural ancestry is no longer a significant predictor; communism significantly negatively predicts HDI, income and health indices, and Muslim percentage of the population significantly negatively predicts education index, although the latter result may not be robust. These findings indicate that geographical proximity and recent cultural history-especially communism-are more important than deep cultural factors in current human development and suggest the efficacy of modern policy initiatives is not tightly constrained by cultural ancestry. PMID- 29765626 TI - A focused library synthesis and cytotoxicity of quinones derived from the natural product bolinaquinone. AB - Bolinaquinone is a natural product that is a structurally complex, cytotoxic sesquiterpene quinone. A scaffold simplification and focused library approach using a microwave-assisted Suzuki coupling gave 32 bolinaquinone analogues with good-to-excellent cytotoxicity profiles. Mono-arylbenzoquinones, Library A, were preferentially toxic towards BE2-C (neuroblastoma) cells with growth inhibition (GI50) values of 4-12 uM; only the 3,4-dimethoxyphenyl 23 and 3-biphenyl 28 variants were broad-spectrum active-HT29 (colon carcinoma), U87 and SJ-G2 (glioblastoma), MCF-7 (breast carcinoma), A2780 (ovarian carcinoma), H460 (lung carcinoma), A431 (skin carcinoma), Du145 (prostate carcinoma), BE2-C (neuroblastoma), MIA (pancreatic carcinoma) and SMA (spontaneous murine astrocytoma). Library B with a second aryl moiety exhibited broad-spectrum cytotoxicity with MCF-7 cells' GI50 values of 5.6 +/- 0.7 and 5.1 +/- 0.5 uM for 2,5-dimethoxy-3-(naphthalene-1-yl)-6-(naphthalene-3-yl) 33 and 2,5-dimethoxy-3 (biaryl-2-yl)-6-(naphthalene-3-yl) 36, respectively. Similar potencies were also noted with 2,5-dimethoxy-3,6-diphenyl 30 against A2780 (GI50 = 5.9 +/- 0.0 uM) and with 2,5-dimethoxy-3-(biaryl-3-yl)-6-(naphthalene-3-yl) 37 against HT29 (GI50 = 5.4 +/- 0.4 uM), while the 3,4-dimethoxy mono-aryl analogue 23 exhibited good levels of activity against A2780 (GI50 = 3.8 +/- 0.75 uM), the neuroblastoma cell line BE2-C (GI50 = 3 +/- 0.35 uM) and SMA (GI50 = 3.9 +/- 0.54 uM). Introduction of the amino-substituted Library C gave 2-(naphthalen-1-yl)-5-(naphthalen-3-yl) 3,6-bis(propylamino) 43, with excellent activity against HT29 (0.08 +/- 0.0 uM), MCF-7 (0.17 +/- 0.1 uM), A2780 (0.14 +/- 0.1 uM), A431 (0.11 +/- 0.0 uM), Du145 (0.16 +/- 0.1 uM), BE2-C (0.08 +/- 0.0 uM) and MIA (0.1 +/- 0.0 uM). PMID- 29765629 TI - Reliability modelling and analysis of a multi-state element based on a dynamic Bayesian network. AB - This paper presents a quantitative reliability modelling and analysis method for multi-state elements based on a combination of the Markov process and a dynamic Bayesian network (DBN), taking perfect repair, imperfect repair and condition based maintenance (CBM) into consideration. The Markov models of elements without repair and under CBM are established, and an absorbing set is introduced to determine the reliability of the repairable element. According to the state transition relations between the states determined by the Markov process, a DBN model is built. In addition, its parameters for series and parallel systems, namely, conditional probability tables, can be calculated by referring to the conditional degradation probabilities. Finally, the power of a control unit in a failure model is used as an example. A dynamic fault tree (DFT) is translated into a Bayesian network model, and subsequently extended to a DBN. The results show the state probabilities of an element and the system without repair, with perfect and imperfect repair, and under CBM, with an absorbing set plotted by differential equations and verified. Through referring forward, the reliability value of the control unit is determined in different kinds of modes. Finally, weak nodes are noted in the control unit. PMID- 29765630 TI - Photocatalytic degradation of sulfamethazine in aqueous solution using ZnO with different morphologies. AB - In this study, photocatalytic experiments of 20 mg l-1 sulfamethazine (SMN) in aqueous solution containing ZnO with different morphologies, tetra-needle-like ZnO (T-ZnO), flower-like ZnO (F-ZnO) and nanoparticles ZnO (P-ZnO), were performed. The results indicated that photocatalytic degradation of SMN was effective and followed the pseudo-first-order reaction, but the degree of SMN mineralization showed obvious differences using ZnO with different shapes. After 12 h irradiation, 86%, 71% and 50% of the initial total organic carbon was eliminated in SMN suspension containing T-ZnO, F-ZnO and P-ZnO, respectively. The release ratio of sulfur was close to 100% in the presence of T-ZnO, but reached to 86% and 67% in the presence of F-ZnO and P-ZnO, respectively. The release ratio of nitrogen was about 76%, 63% and 40% using T-ZnO, F-ZnO and P-ZnO as photocatalyst, respectively. The morphology of ZnO played an important role in determining its catalytic activity. Seven intermediates were observed and identified in the UV/T-ZnO reaction system by LC-MS/MS analysis, and a possible degradation pathway was proposed. PMID- 29765631 TI - Environmentally friendly and breathable wet-laid hydroentangled nonwovens for personal hygiene care with excellent water absorbency and flushability. AB - Developing wet-laid papers with a good wet strength remains a longstanding challenge in the papermaking industry. In this study, hydroentanglement, a mechanical bonding technique is developed to consolidate the wet-laid fibre web. The results indicate that wet tensile strength, ductile stretching property, softness, air permeability and water absorbency of the wet-laid fibre web are significantly improved by hydroentanglement. In addition, the abrasion test shows that the dusting off rate of wet-laid fibre web can be effectively reduced through hydroentanglement. Moreover, the disintegration experiment proves that wet-laid hydroentangled nonwovens could be easily dispersed when compared with conventional carded hydroentangled nonwovens. Therefore, the new wet-laid hydroentangled nonwovens can maintain excellent performance in a wet state, showing a great potential for personal hygiene applications. PMID- 29765632 TI - Determination of carcinogenic herbicides in milk samples using green non-ionic silicone surfactant of cloud point extraction and spectrophotometry. AB - A new cloud point methodology was successfully used for the extraction of carcinogenic pesticides in milk samples as a prior step to their determination by spectrophotometry. In this work, non-ionic silicone surfactant, also known as 3 (3-hydroxypropyl-heptatrimethylxyloxane), was chosen as a green extraction solvent because of its structure and properties. The effect of different parameters, such as the type of surfactant, concentration and volume of surfactant, pH, salt, temperature, incubation time and water content on the cloud point extraction of carcinogenic pesticides such as atrazine and propazine, was studied in detail and a set of optimum conditions was established. A good correlation coefficient (R2 ) in the range of 0.991-0.997 for all calibration curves was obtained. The limit of detection was 1.06 ug l-1 (atrazine) and 1.22 ug l-1 (propazine), and the limit of quantitation was 3.54 ug l-1 (atrazine) and 4.07 ug l-1 (propazine). Satisfactory recoveries in the range of 81-108% were determined in milk samples at 5 and 1000 ug l-1, respectively, with low relative standard deviation, n = 3 of 0.301-7.45% in milk matrices. The proposed method is very convenient, rapid, cost-effective and environmentally friendly for food analysis. PMID- 29765633 TI - Differential arthropod responses to warming are altering the structure of Arctic communities. AB - The Arctic is experiencing some of the fastest rates of warming on the planet. Although many studies have documented responses to such warming by individual species, the idiosyncratic nature of these findings has prevented us from extrapolating them to community-level predictions. Here, we leverage the availability of a long-term dataset from Zackenberg, Greenland (593 700 specimens collected between 1996 and 2014), to investigate how climate parameters influence the abundance of different arthropod groups and overall community composition. We find that variation in mean seasonal temperatures, winter duration and winter freeze-thaw events is correlated with taxon-specific and habitat-dependent changes in arthropod abundances. In addition, we find that arthropod communities have exhibited compositional changes consistent with the expected effects of recent shifts towards warmer active seasons and fewer freeze-thaw events in NE Greenland. Changes in community composition are up to five times more extreme in drier than wet habitats, with herbivores and parasitoids generally increasing in abundance, while the opposite is true for surface detritivores. These results suggest that species interactions and food web dynamics are changing in the Arctic, with potential implications for key ecosystem processes such as decomposition, nutrient cycling and primary productivity. PMID- 29765634 TI - Noise-induced transitions and shifts in a climate-vegetation feedback model. AB - Motivated by the extremely important role of the Earth's vegetation dynamics in climate changes, we study the stochastic variability of a simple climate vegetation system. In the case of deterministic dynamics, the system has one stable equilibrium and limit cycle or two stable equilibria corresponding to two opposite (cold and warm) climate-vegetation states. These states are divided by a separatrix going across a point of unstable equilibrium. Some possible stochastic scenarios caused by different externally induced natural and anthropogenic processes inherit properties of deterministic behaviour and drastically change the system dynamics. We demonstrate that the system transitions across its separatrix occur with increasing noise intensity. The climate-vegetation system therewith fluctuates, transits and localizes in the vicinity of its attractor. We show that this phenomenon occurs within some critical range of noise intensities. A noise-induced shift into the range of smaller global average temperatures corresponding to substantial oscillations of the Earth's vegetation cover is revealed. Our analysis demonstrates that the climate-vegetation interactions essentially contribute to climate dynamics and should be taken into account in more precise and complex models of climate variability. PMID- 29765637 TI - The cosmic spiderweb: equivalence of cosmic, architectural and origami tessellations. AB - For over 20 years, the term 'cosmic web' has guided our understanding of the large-scale arrangement of matter in the cosmos, accurately evoking the concept of a network of galaxies linked by filaments. But the physical correspondence between the cosmic web and structural engineering or textile 'spiderwebs' is even deeper than previously known, and also extends to origami tessellations. Here, we explain that in a good structure-formation approximation known as the adhesion model, threads of the cosmic web form a spiderweb, i.e. can be strung up to be entirely in tension. The correspondence is exact if nodes sampling voids are included, and if structure is excluded within collapsed regions (walls, filaments and haloes), where dark-matter multistreaming and baryonic physics affect the structure. We also suggest how concepts arising from this link might be used to test cosmological models: for example, to test for large-scale anisotropy and rotational flows in the cosmos. PMID- 29765636 TI - Vibrational spectroscopy of metal methanesulfonates: M = Na, Cs, Cu, Ag, Cd. AB - In this work, we have used a combination of vibrational spectroscopy (infrared, Raman and inelastic neutron scattering) and periodic density functional theory to investigate six metal methanesulfonate compounds that exhibit four different modes of complexation of the methanesulfonate ion: ionic, monodentate, bidentate and pentadentate. We found that the transition energies of the modes associated with the methyl group (C-H stretches and deformations, methyl rock and torsion) are essentially independent of the mode of coordination. The SO3 modes in the Raman spectra also show little variation. In the infrared spectra, there is a clear distinction between ionic (i.e. not coordinated) and coordinated forms of the methanesulfonate ion. This is manifested as a splitting of the asymmetric S-O stretch modes of the SO3 moiety. Unfortunately, no further differentiation between the various modes of coordination: unidentate, bidentate etc ... is possible with the compounds examined. While it is likely that such a distinction could be made, this will require a much larger dataset of compounds for which both structural and spectroscopic data are available than that available here. PMID- 29765638 TI - Porous polymer coatings on metal microneedles for enhanced drug delivery. AB - We present a simple method to coat microneedles (MNs) uniformly with a porous polymer (PLGA) that can deliver drugs at high rates. Stainless steel (SS) MNs of high mechanical strength were coated with a thin porous polymer layer to enhance their delivery rates. Additionally, to improve the interfacial adhesion between the polymer and MNs, the MN surface was modified by plasma treatment followed by dip coating with polyethyleneimine, a polymer with repeating amine units. The average failure load (the minimum force sufficient for detaching the polymer layer from the surface of SS) recorded for the modified surface coating was 25 N, whereas it was 2.2 N for the non-modified surface. Calcein dye was successfully delivered into porcine skin to a depth of 750 um by the porous polymer-coated MNs, demonstrating that the developed MNs can pierce skin easily without deformation of MNs; additional skin penetration tests confirmed this finding. For visual comparison, rhodamine B dye was delivered using porous-coated and non coated MNs in gelatin gel which showed that delivery with porous-coated MNs penetrate deeper when compared with non-coated MNs. Finally, lidocaine and rhodamine B dye were delivered in phosphate-buffered saline (PBS) medium by porous polymer-coated and non-coated MNs. For rhodamine B, drug delivery with the porous-coated MNs was five times higher than that with the non-coated MNs, whereas 25 times more lidocaine was delivered by the porous-coated MNs compared with the non-coated MNs. PMID- 29765635 TI - Poor neuro-motor tuning of the human larynx: a comparison of sung and whistled pitch imitation. AB - Vocal imitation is a hallmark of human communication that underlies the capacity to learn to speak and sing. Even so, poor vocal imitation abilities are surprisingly common in the general population and even expert vocalists cannot match the precision of a musical instrument. Although humans have evolved a greater degree of control over the laryngeal muscles that govern voice production, this ability may be underdeveloped compared with control over the articulatory muscles, such as the tongue and lips, volitional control of which emerged earlier in primate evolution. Human participants imitated simple melodies by either singing (i.e. producing pitch with the larynx) or whistling (i.e. producing pitch with the lips and tongue). Sung notes were systematically biased towards each individual's habitual pitch, which we hypothesize may act to conserve muscular effort. Furthermore, while participants who sung more precisely also whistled more precisely, sung imitations were less precise than whistled imitations. The laryngeal muscles that control voice production are under less precise control than the oral muscles that are involved in whistling. This imprecision may be due to the relatively recent evolution of volitional laryngeal motor control in humans, which may be tuned just well enough for the coarse modulation of vocal-pitch in speech. PMID- 29765639 TI - Structure and phylogeography of two tropical predators, spinner (Stenella longirostris) and pantropical spotted (S. attenuata) dolphins, from SNP data. AB - Little is known about global patterns of genetic connectivity in pelagic dolphins, including how circumtropical pelagic dolphins spread globally following the rapid and recent radiation of the subfamily delphininae. In this study, we tested phylogeographic hypotheses for two circumtropical species, the spinner dolphin (Stenella longirostris) and the pantropical spotted dolphin (Stenella attenuata), using more than 3000 nuclear DNA single nucleotide polymorphisms (SNPs) in each species. Analyses for population structure indicated significant genetic differentiation between almost all subspecies and populations in both species. Bayesian phylogeographic analyses of spinner dolphins showed deep divergence between Indo-Pacific, Atlantic and eastern tropical Pacific Ocean (ETP) lineages. Despite high morphological variation, our results show very close relationships between endemic ETP spinner subspecies in relation to global diversity. The dwarf spinner dolphin is a monophyletic subspecies nested within a major clade of pantropical spinner dolphins from the Indian and western Pacific Ocean populations. Population-level division among the dwarf spinner dolphins was detected-with the northern Australia population being very different from that in Indonesia. In contrast to spinner dolphins, the major boundary for spotted dolphins is between offshore and coastal habitats in the ETP, supporting the current subspecies-level taxonomy. Comparing these species underscores the different scale at which population structure can arise, even in species that are similar in habitat (i.e. pelagic) and distribution. PMID- 29765640 TI - Vascularization of the trachea in the bottlenose dolphin: comparison with bovine and evidence for evolutionary adaptations to diving. AB - The rigid structure of the mammalian trachea is functional to maintain constant patency and airflow during breathing, but no gas exchange takes place through its walls. The structure of the organ in dolphins shows increased rigidity of the tracheal cartilaginous rings and the presence of vascular lacunae in the submucosa. However, no actual comparison was ever made between the size and capacity of the vascular lacunae of the dolphin trachea and the potentially homologous structures of terrestrial mammals. In the present study, the extension of the lacunae has been compared between the bottlenose dolphin and the bovine, a closely related terrestrial Cetartiodactyla. Our results indicate that the extension of the blood spaces in the submucosa of dolphins is over 12 times larger than in the corresponding structure of the bovines. Furthermore, a microscopic analysis revealed the presence of valve-like structures in the walls of the cetacean lacunae. The huge difference in size suggests that the lacunae are not merely a product of individual physiological plasticity, but may constitute a true adaptive evolutionary character, functional to life in the aquatic environment. The presence of valve-like structures may be related to the regulation of blood flow, and curtail excessive compression under baric stress at depth. PMID- 29765641 TI - Combined morphological and phylogenomic re-examination of malawimonads, a critical taxon for inferring the evolutionary history of eukaryotes. AB - Modern syntheses of eukaryote diversity assign almost all taxa to one of three groups: Amorphea, Diaphoretickes and Excavata (comprising Discoba and Metamonada). The most glaring exception is Malawimonadidae, a group of small heterotrophic flagellates that resemble Excavata by morphology, but branch with Amorphea in most phylogenomic analyses. However, just one malawimonad, Malawimonas jakobiformis, has been studied with both morphological and molecular phylogenetic approaches, raising the spectre of interpretation errors and phylogenetic artefacts from low taxon sampling. We report a morphological and phylogenomic study of a new deep-branching malawimonad, Gefionella okellyi n. gen. n. sp. Electron microscopy revealed all canonical features of 'typical excavates', including flagellar vanes (as an opposed pair, unlike M. jakobiformis but like many metamonads) and a composite fibre. Initial phylogenomic analyses grouped malawimonads with the Amorphea-related orphan lineage Collodictyon, separate from a Metamonada+Discoba clade. However, support for this topology weakened when more sophisticated evolutionary models were used, and/or fast evolving sites and long-branching taxa (FS/LB) were excluded. Analyses of ' FS/LB' datasets instead suggested a relationship between malawimonads and metamonads. The 'malawimonad+metamonad signal' in morphological and molecular data argues against a strict Metamonada+Discoba clade (i.e. the predominant concept of Excavata). A Metamonad+Discoba clade should therefore not be assumed when inferring deep-level evolutionary history in eukaryotes. PMID- 29765643 TI - Ultrasound-assisted synthesis of N235-impregnated resins for vanadium (V) adsorption. AB - N235-impregnated resins were prepared using XAD-16HP macroporous adsorption resins as support with and without ultrasonic irradiation to evaluate the effects of ultrasound impregnation (UI) on the preparation and adsorption characteristics of the resins. The results show that the impregnation ratio of the solvent impregnated resins (SIRs) prepared by ultrasound impregnation method (SIRs-UI) increases obviously but their adsorption capacity for V(V) just slightly increases and the utilization rate of the extractant decreases with the augmentation of ultrasound power. This may be caused by the fact that more extractant can enter into the deeper pores of the resins under high ultrasound intensity, but these extractants cannot effectively react with V(V). The impregnation equilibrium time of SIRs-UI can be obviously shortened in comparison to that of the SIRs prepared by conventional impregnation method (SIRs-CI) (3 min versus 240 min) due to the cavitation effect evoked by ultrasound. Ultrasonic irradiation may cause more N235 desorbed from the pores of the resin at low N235 content, resulting in lower adsorption capacity for V(V) than that of SIRs-CI, but the adsorption capacity is inverse at higher N235 content. N235 may be distributed more homogeneously in the pores of XAD-16HP with ultrasonic irradiation, thus, SIRs-UI presents higher adsorption capacity and stronger stability than SIRs-CI. This study manifests that ultrasound-assistant impregnation method may be a potential and promising technique for the preparation of SIRs. PMID- 29765642 TI - Glucocorticoids modulate gastrointestinal microbiome in a wild bird. AB - It has recently been hypothesized that stress exposure (e.g. via glucocorticoid secretion) may dysregulate the bacterial gut microbiome, a crucial 'organ' in animal health. However, whether stress exposure (e.g. via glucocorticoid secretion) affects the bacterial gut microbiome of natural populations is unknown. We have experimentally altered the basal glucocorticoid level (corticosterone implants) in a wild avian species, the yellow-legged gull Larus michahellis, to assess its effects on the gastrointestinal microbiota. Our results suggest underrepresentation of several microbial taxa in the corticosterone-implanted birds. Importantly, such reduction included potentially pathogenic avian bacteria (e.g. Mycoplasma and Microvirga) and also some commensal taxa that may be beneficial for birds (e.g. Firmicutes). Our findings clearly demonstrate a close link between microbiome communities and glucocorticoid levels in natural populations. Furthermore, they suggest a beneficial effect of stress in reducing the risk of infection that should be explored in future studies. PMID- 29765645 TI - Accelerated degradation of polyetheretherketone and its composites in the deep sea. AB - The performance of polymer composites in seawater, under high hydrostatic pressure (typically few tens of MPa), for simulating exposures at great depths in seas and oceans, has been little studied. In this paper, polyetheretherketone (PEEK) and its composites reinforced by carbon fibres and glass fibres were prepared. The seawater environment with different seawater hydrostatic pressure ranging from normal pressure to 40 MPa was simulated with special equipment, in which the seawater absorption and wear behaviour of PEEK and PEEK-based composites were examined in situ. The effects of seawater hydrostatic pressure on the mechanical properties, wear resistance and microstructure of PEEK and its composites were focused on. The results showed that seawater absorption of PEEK and its composites were greatly accelerated by increased hydrostatic pressure in the deep sea. Affected by seawater absorption, both for neat PEEK and composites, the degradation on mechanical properties, wear resistance and crystallinity were induced, the degree of which was increasingly serious with the increase of hydrostatic pressure of seawater environment. There existed a good correlation in an identical form of exponential function between the wear rate and the seawater hydrostatic pressure. Moreover, the corresponding mechanisms of the effects of deep-sea hydrostatic pressure were also discussed. PMID- 29765644 TI - Identification of potent chromone embedded [1,2,3]-triazoles as novel anti tubercular agents. AB - A series of 20 novel chromone embedded [1,2,3]-triazoles derivatives were synthesized via an easy and convenient synthetic procedure starting from 2 hydroxy acetophenone. The in vitro anti-mycobacterial evaluation studies carried out in this work reveal that seven compounds exhibit significant inhibition against Mycobacterium tuberculosis H37Rv strain with MIC in the range of 1.56 12.5 ug ml-1. Noticeably, compound 6s was the most potent compound in vitro with a MIC value of 1.56 ug ml-1. Molecular docking and chemoinformatics studies revealed that compound 6s displayed drug-like properties against the enoyl-acyl carrier protein reductase of M. tuberculosis further establishing its potential as a potent inhibitor. PMID- 29765646 TI - Towards the fluorogenic detection of peroxide explosives through host-guest chemistry. AB - Two dansyl-modified beta-cyclodextrin derivatives (1 and 2) have been synthesized as host-guest sensory systems for the direct fluorescent detection of the peroxide explosives diacetone diperoxide (DADP) and triacetone triperoxide (TATP) in aqueous media. The sensing is based on the displacement of the dansyl moiety from the cavity of the cyclodextrin by the peroxide guest resulting in a decrease of the intensity of the fluorescence of the dye. Both systems showed similar fluorescent responses and were more sensitive towards TATP than DADP. PMID- 29765648 TI - Graphene platelets enhanced pressureless- sintered B4C ceramics. AB - B4C ceramics with different contents of graphene platelets (GPL) were synthesized by a pressureless process in Ar atmosphere. The influences of GPL on mechanical properties, thermal conductivity and electrical resistivity of the B4C ceramics were investigated. Mechanical properties ran up to optimal condition with hardness of 29.1 GPa, bending strength of 383.9 GPa and fracture toughness of 5.72 MPa m1/2 with 0.8 wt% GPL separately. Thermal conductivity and electrical resistivity reached extreme values of 26.35 W m-1 k-1 and 0.1 Omega cm-1. Performances of the ceramics were mainly affected by the generation of non functional-GPL and the result indicated that a large amount of non-functional-GPL could contribute to poorer overall performance. Meanwhile, two particular pullout mechanisms concerning toughness enhancing was discussed in detail. PMID- 29765647 TI - Controlled fluorescence quenching by antibody-conjugated graphene oxide to measure tau protein. AB - We report an ultrasensitive immunoassay for tau protein-a key marker of Alzheimer's disease. This sensing platform relies on graphene oxide (GO) surfaces conjugated with anti-human tau antibody to provide quantitative binding sites for the tau protein. The GO quenches standard fluorescein isothiocyanate labelled tau (tau-FITC) when tau protein and tau-FITC are both present and compete for the binding sites. This change in fluorescence signal can be used to quantitate tau protein. In contrast with traditional enzyme-linked immunosorbent assay (ELISA), our method does not require enzyme-linked secondary antibodies for protein recognition nor does it require an enzyme substrate for optical signal generation. This requires fewer reagents and has less systematic error than the antigen-antibody recognition steps in ELISA. Our method has a tau protein detection limit of 0.14 pmol ml-1 in buffer. This approach could be developed into a promising biosensor for the detection of tau protein and may be useful in the clinical diagnosis of tau-induced neurodegeneration syndromes. PMID- 29765649 TI - Dietary specialization is linked to reduced species durations in North American fossil canids. AB - How traits influence species persistence is a fundamental question in ecology, evolution and palaeontology. We test the relationship between dietary traits and both species duration and locality coverage over 40 million years in North American canids, a clade with considerable ecomorphological disparity and a dense fossil record. Because ecomorphological generalization-broad resource use-may enable species to withstand disturbance, we predicted that canids of average size and mesocarnivory would exhibit longer durations and wider distributions than specialized larger or smaller species. Second, because locality coverage might reflect dispersal ability and/or survivability in a range of habitats, we predicted that high coverage would correspond with longer durations. We find a nonlinear relationship between species duration and degree of carnivory: species at either end of the carnivory spectrum tend to have shorter durations than mesocarnivores. Locality coverage shows no relationship with size, diet or duration. To test whether generalization (medium size, mesocarnivory) corresponds to an adaptive optimum, we fit trait evolution models to previously generated canid phylogenies. Our analyses identify no single optimum in size or diet. Instead, the primary model of size evolution is a classic Cope's Rule increase over time, while dietary evolution does not conform to a single model. PMID- 29765650 TI - In situ investigations of the phase change behaviour of tungsten oxide nanostructures. AB - This study uses two in situ techniques to investigate the geometry and phase change behaviour of bundled ultrathin W18O49 nanowires and WO3 nanoparticles. The in situ X-ray diffraction (XRD) results have shown that the phase transition of WO3 nanoparticles occurs in sequence from monoclinic (room temperature) -> orthorhombic (350 degrees C) -> tetragonal (800 degrees C), akin to bulk WO3; however, W18O49 nanowires remain stable as the monoclinic phase up to 500 degrees C, after which a complete oxidation to WO3 and transformation to the orthorhombic beta-phase at 550 degrees C is observed. The in situ Raman spectroscopy investigations have revealed the Raman peak downshifts as the temperature increases, and have identified the 187.6 cm-1 as the fingerprint band for the phase transition from gamma- to beta-phase of the WO3 nanoparticle. Furthermore, WO3 nanoparticles exhibit the gamma- to beta-phase conversion at 275 degrees C, which is about 75 degrees C lower than the relaxation temperature of 350 degrees C for the monoclinic gamma-W18O49 nanowires. These new fundamental understandings on the phase transition behaviour offer important guidance for the design and development of tungsten oxide-based nanodevices by defining their allowed operating conditions. PMID- 29765651 TI - Surrogate modelling for the prediction of spatial fields based on simultaneous dimensionality reduction of high-dimensional input/output spaces. AB - Time-consuming numerical simulators for solving groundwater flow and dissolution models of physico-chemical processes in deep aquifers normally require some of the model inputs to be defined in high-dimensional spaces in order to return realistic results. Sometimes, the outputs of interest are spatial fields leading to high-dimensional output spaces. Although Gaussian process emulation has been satisfactorily used for computing faithful and inexpensive approximations of complex simulators, these have been mostly applied to problems defined in low dimensional input spaces. In this paper, we propose a method for simultaneously reducing the dimensionality of very high-dimensional input and output spaces in Gaussian process emulators for stochastic partial differential equation models while retaining the qualitative features of the original models. This allows us to build a surrogate model for the prediction of spatial fields in such time consuming simulators. We apply the methodology to a model of convection and dissolution processes occurring during carbon capture and storage. PMID- 29765652 TI - Cell wall microstructure, pore size distribution and absolute density of hemp shiv. AB - This paper, for the first time, fully characterizes the intrinsic physical parameters of hemp shiv including cell wall microstructure, pore size distribution and absolute density. Scanning electron microscopy revealed microstructural features similar to hardwoods. Confocal microscopy revealed three major layers in the cell wall: middle lamella, primary cell wall and secondary cell wall. Computed tomography improved the visualization of pore shape and pore connectivity in three dimensions. Mercury intrusion porosimetry (MIP) showed that the average accessible porosity was 76.67 +/- 2.03% and pore size classes could be distinguished into micropores (3-10 nm) and macropores (0.1-1 um and 20-80 um). The absolute density was evaluated by helium pycnometry, MIP and Archimedes' methods. The results show that these methods can lead to misinterpretation of absolute density. The MIP method showed a realistic absolute density (1.45 g cm 3) consistent with the density of the known constituents, including lignin, cellulose and hemi-cellulose. However, helium pycnometry and Archimedes' methods gave falsely low values owing to 10% of the volume being inaccessible pores, which require sample pretreatment in order to be filled by liquid or gas. This indicates that the determination of the cell wall density is strongly dependent on sample geometry and preparation. PMID- 29765653 TI - Environment-friendly wood fibre composite with high bonding strength and water resistance. AB - With the growing depletion of wood-based materials and concerns over emissions of formaldehyde from traditional wood fibre composites, there is a desire for environment-friendly binders. Herein, we report a green wood fibre composite with specific bonding strength and water resistance that is superior to a commercial system by using wood fibres and chitosan-based adhesives. When the mass ratio of solid content in the adhesive and absolute dry wood fibres was 3%, the bonding strength and water resistance of the wood fibre composite reached the optimal level, which was significantly improved over that of wood fibre composites without adhesive and completely met the requirements of the Chinese national standard GB/T 11718-2009. Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) characterizations revealed that the excellent performance of the binder might partly be due to the amide linkages and hydrogen bonding between wood fibres and the chitosan-based adhesive. We believe that this strategy could open new insights into the design of environment friendly wood fibre composites with high bonding strength and water resistance for multifunctional applications. PMID- 29765654 TI - Membrane-assisted extraction of monoterpenes: from in silico solvent screening towards biotechnological process application. AB - This work focuses on the process development of membrane-assisted solvent extraction of hydrophobic compounds such as monoterpenes. Beginning with the choice of suitable solvents, quantum chemical calculations with the simulation tool COSMO-RS were carried out to predict the partition coefficient (logP) of (S) (+)-carvone and terpinen-4-ol in various solvent-water systems and validated afterwards with experimental data. COSMO-RS results show good prediction accuracy for non-polar solvents such as n-hexane, ethyl acetate and n-heptane even in the presence of salts and glycerol in an aqueous medium. Based on the high logP value, n-heptane was chosen for the extraction of (S)-(+)-carvone in a lab-scale hollow-fibre membrane contactor. Two operation modes are investigated where experimental and theoretical mass transfer values, based on their related partition coefficients, were compared. In addition, the process is evaluated in terms of extraction efficiency and overall product recovery, and its biotechnological application potential is discussed. Our work demonstrates that the combination of in silico prediction by COSMO-RS with membrane-assisted extraction is a promising approach for the recovery of hydrophobic compounds from aqueous solutions. PMID- 29765655 TI - Adsorption behaviour of hydrogarnet for humic acid. AB - Discharge of humic acid (HA) in aqueous environments is a key health and aesthetic issue. The present work investigates the use of hydrogarnet as a novel adsorbent for HA. Hydrogarnet was hydrothermally synthesized with different solvents to control the chemical composition. Hydrogarnet with three types of chemical compositions had better adsorption properties for HA than hydrogarnet with a single chemical composition. Controlling the chemical composition of hydrogarnet increased the number of hydroxyl groups and the overall binding energy of the system, leading to changes in the zeta potential. The enhancement of these adsorption properties is related to the increased numbers of hydroxyl groups on the surface and their diverse binding energies. PMID- 29765656 TI - The rise and fall of an ancient Adelie penguin 'supercolony' at Cape Adare, Antarctica. AB - We report new discoveries and radiocarbon dates on active and abandoned Adelie penguin (Pygoscelis adeliae) colonies at Cape Adare, Antarctica. This colony, first established at approximately 2000 BP (calendar years before present, i.e. 1950), is currently the largest for this species with approximately 338 000 breeding pairs, most located on low-lying Ridley Beach. We hypothesize that this colony first formed after fast ice began blocking open-water access by breeding penguins to the Scott Coast in the southern Ross Sea during a cooling period also at approximately 2000 BP. Our results suggest that the new colony at Cape Adare continued to grow, expanding to a large upper terrace above Ridley Beach, until it exceeded approximately 500 000 breeding pairs (a 'supercolony') by approximately 1200 BP. The high marine productivity associated with the Ross Sea polynya and continental shelf break supported this growth, but the colony collapsed to its present size for unknown reasons after approximately 1200 BP. Ridley Beach will probably be abandoned in the near future due to rising sea level in this region. We predict that penguins will retreat to higher elevations at Cape Adare and that the Scott Coast will be reoccupied by breeding penguins as fast ice continues to dissipate earlier each summer, restoring open-water access to beaches there. PMID- 29765657 TI - Facile fabrication of microfluidic surface-enhanced Raman scattering devices via lift-up lithography. AB - We describe a facile and low-cost approach for a flexibly integrated surface enhanced Raman scattering (SERS) substrate in microfluidic chips. Briefly, a SERS substrate was fabricated by the electrostatic assembling of gold nanoparticles, and shaped into designed patterns by subsequent lift-up soft lithography. The SERS micro-pattern could be further integrated within microfluidic channels conveniently. The resulting microfluidic SERS chip allowed ultrasensitive in situ SERS monitoring from the transparent glass window. With its advantages in simplicity, functionality and cost-effectiveness, this method could be readily expanded into optical microfluidic fabrication for biochemical applications. PMID- 29765658 TI - Nest size is predicted by female identity and the local environment in the blue tit (Cyanistes caeruleus), but is not related to the nest size of the genetic or foster mother. AB - The potential for animals to respond to changing climates has sparked interest in intraspecific variation in avian nest structure since this may influence nest microclimate and protect eggs and offspring from inclement weather. However, there have been relatively few large-scale attempts to examine variation in nests or the determinates of individual variation in nest structure within populations. Using a set of mostly pre-registered analyses, we studied potential predictors of variation in the size of a large sample (803) of blue tit (Cyanistes caeruleus) nests across three breeding seasons at Wytham Woods, UK. While our pre-registered analyses found that individual females built very similar nests across years, there was no evidence in follow-up (post hoc) analyses that their nest size correlated to that of their genetic mother or, in a cross-fostering experiment, to the nest where they were reared. In further pre-registered analyses, spatial environmental variability explained nest size variability at relatively broad spatial scales, and especially strongly at the scale of individual nest boxes. Our study indicates that nest structure is a characteristic of individuals, but is not strongly heritable, indicating that it will not respond rapidly to selection. Explaining the within-individual and within-location repeatability we observed requires further study. PMID- 29765659 TI - Self-assembly behaviours of peptide-drug conjugates: influence of multiple factors on aggregate morphology and potential self-assembly mechanism. AB - Peptide-drug conjugates (PDCs) as self-assembly prodrugs have the unique and specific features to build one-component nanomedicines. Supramolecular structure based on PDCs could form various morphologies ranging from nanotube, nanofibre, nanobelt to hydrogel. However, the assembly process of PDCs is too complex to predict or control. Herein, we investigated the effects of extrinsic factors on assembly morphology and the possible formation of nanostructures based on PDCs. To this end, we designed a PDC consisting of hydrophobic drug (S)-ketoprofen (Ket) and valine-glutamic acid dimeric repeats peptide (L-VEVE) to study their assembly behaviour. Our results showed that the critical assembly concentration of Ket-L-VEVE was 0.32 mM in water to form various nanostructures which experienced from micelle, nanorod, nanofibre to nanoribbon. The morphology was influenced by multiple factors including molecular design, assembly time, pH and hydrogen bond inhibitor. On the basis of experimental results, we speculated the possible assembly mechanism of Ket-L-VEVE. The pi-pi stacking interaction between Ket molecules could serve as an anchor, and hydrogen bonded-induced beta-sheets and hydrophilic/hydrophobic balance between L-VEVE peptide play structure directing role in forming filament-like or nanoribbon morphology. This work provides a new sight to rationally design and precisely control the nanostructure of PDCs based on aromatic fragment. PMID- 29765660 TI - Behavioural responses of spinner dolphins to human interactions. AB - There is increasing evidence that whale and dolphin watching activities have detrimental effects on targeted cetacean populations. In Egypt, spinner dolphins regularly occur in the resting areas of Samadai, Satayah and Qubbat'Isa reefs. In water human interactions with dolphins are regulated with a time-area closure system at Samadai, unregulated at Satayah and non-existent at Qubbat'Isa. This provided an ideal experimental setting to advance our understanding of the effects of tourism on a species highly sensitive to disturbances. Our study confirmed that the intensity and duration of interactions, and therefore, dolphin exposure to tourism, differed among the study sites. Compared with the Qubbat'Isa control site, behavioural reactions to boats and swimmers at the two tourism sites suggested that dolphin rest was disrupted, especially around the middle of the day and especially at Satayah, where dolphin tourism is unregulated. Our results indicate also that the dolphin protection measures at Samadai reduce the level of disturbance. We recommend that similar measures be implemented at other dolphin tourism locations, and that no new operations be initiated until the long term impacts on dolphin populations are better understood. Our experience emphasizes the need to adopt precautionary approaches in research and management of whale and dolphin watching. PMID- 29765661 TI - Testing the assumptions of the pyrodiversity begets biodiversity hypothesis for termites in semi-arid Australia. AB - Fire shapes the composition and functioning of ecosystems globally. In many regions, fire is actively managed to create diverse patch mosaics of fire-ages under the assumption that a diversity of post-fire-age classes will provide a greater variety of habitats, thereby enabling species with differing habitat requirements to coexist, and enhancing species diversity (the pyrodiversity begets biodiversity hypothesis). However, studies provide mixed support for this hypothesis. Here, using termite communities in a semi-arid region of southeast Australia, we test four key assumptions of the pyrodiversity begets biodiversity hypothesis (i) that fire shapes vegetation structure over sufficient time frames to influence species' occurrence, (ii) that animal species are linked to resources that are themselves shaped by fire and that peak at different times since fire, (iii) that species' probability of occurrence or abundance peaks at varying times since fire and (iv) that providing a diversity of fire-ages increases species diversity at the landscape scale. Termite species and habitat elements were sampled in 100 sites across a range of fire-ages, nested within 20 landscapes chosen to represent a gradient of low to high pyrodiversity. We used regression modelling to explore relationships between termites, habitat and fire. Fire affected two habitat elements (coarse woody debris and the cover of woody vegetation) that were associated with the probability of occurrence of three termite species and overall species richness, thus supporting the first two assumptions of the pyrodiversity hypothesis. However, this did not result in those species or species richness being affected by fire history per se. Consequently, landscapes with a low diversity of fire histories had similar numbers of termite species as landscapes with high pyrodiversity. Our work suggests that encouraging a diversity of fire-ages for enhancing termite species richness in this study region is not necessary. PMID- 29765662 TI - New Guinea bone daggers were engineered to preserve social prestige. AB - Bone daggers were once widespread in New Guinea. Their purpose was both symbolic and utilitarian; they functioned as objects of artistic expression with the primary function of stabbing and killing people at close quarters. Most daggers were shaped from the tibiotarsus of cassowaries, but daggers shaped from the femora of respected men carried greater social prestige. The greater cross sectional curvature of human bone daggers indicates superior strength, but the material properties of cassowary bone are unknown. It is, therefore, uncertain whether the macrostructure of human bone daggers exists to compensate for inferior material properties of human femora or to preserve the symbolic value of a prestigious object. To explore this question, we used computed tomography to examine the structural mechanics of 11 bone daggers, 10 of which are museum accessioned objects of art. We found that human and cassowary bones have similar material properties and that the geometry of human bone daggers results in higher moments of inertia and a greater resistance to bending. Data from finite-element models corroborated the superior mechanical performance of human bone daggers, revealing greater resistance to larger loads with fewer failed elements. Taken together, our findings suggest that human bone daggers were engineered to preserve symbolic capital, an outcome that agrees well with the predictions of signalling theory. PMID- 29765663 TI - Categorizing experience-based foraging plasticity in mites: age dependency, primacy effects and memory persistence. AB - Behavioural plasticity can be categorized into activational (also termed contextual) and developmental plasticity. Activational plasticity allows immediate contextual behavioural changes, whereas developmental plasticity is characterized by time-lagged changes based on memory of previous experiences (learning). Behavioural plasticity tends to decline with age but whether this holds true for both plasticity categories and the effects of first-in-life experiences is poorly understood. We tackled this issue by assessing the foraging plasticity of plant-inhabiting predatory mites, Amblyseius swirskii, on thrips and spider mites following age-dependent prey experience, i.e. after hatching or after reaching maturity. Juvenile and young adult predator females were alternately presented thrips and spider mites, for establishing 1st and 2nd prey in-life experiences, and tested, as gravid females, for their foraging plasticity when offered both prey species. Prey experience by juvenile predators resulted in clear learning effects, which were evident in likelier and earlier attacks on familiar prey, and higher proportional inclusion of familiar prey in total diet. First prey-in-life experience by juvenile but not adult predators resulted in primacy effects regarding attack latency. Prey experience by adult predators resulted mainly in prey-unspecific physiological changes, with easy-to-grasp spider mites providing higher net energy gains than difficult-to-grasp thrips. Prey experience by juvenile, but not adult, predators was adaptive, which was evident in a negative correlation between attack latencies and egg production. Overall, our study provides key evidence that similar experiences by juvenile and adult predators, including first-in-life experiences, may be associated with different types of behavioural plasticity, i.e. developmental and activational plasticity. PMID- 29765664 TI - Determination of cyanide in bamboo shoots by microdiffusion combined with ion chromatography-pulsed amperometric detection. AB - A practical method for the determination of cyanide in bamboo shoots has been developed using microdiffusion preparation integrated with ion chromatography pulsed amperometric detection (IC-PAD). Cyanide was released from bamboo shoots after Conway cell microdiffusion, and then analysed by IC-PAD. In comparison with the previously reported methods, derivatization and ion-pairing agent addition were not required in this proposed microdiffusion combined with IC-PAD method. The microdiffusion parameters were optimized including hydrolysis systems, temperature, time, and so on. Under the optimum conditions, the linear range of the calibration curve for cyanide was 0.2-200.0 ug kg-1 with satisfactory correlation coefficients of 0.9996 and the limit of detection was 0.2 ug kg-1 (S/N = 3). The spiked recovery range was from 92.8 to 98.6%. The intra-day and inter-day relative standard deviations of cyanide were 2.7-14.9% and 3.0-18.3%, respectively. This method was proved to be convenient in operation with high sensitivity, precision and accuracy, and was successfully applied in the determination of cyanide in bamboo shoot samples. PMID- 29765665 TI - Morphometric assessment of pterosaur jaw disparity. AB - Pterosaurs were a successful group of Mesozoic flying reptiles. They were the first vertebrate group to achieve powered flight and varied enormously in morphology and ecology, occupying a variety of niches and developing specialized feeding strategies. Ecomorphological principles suggest this variation should be reflected by great morphological diversity in the lower jaw, given that the mandible served as the primary apparatus for prey acquisition. Here we present the first study of mandibular shape disparity in pterosaurs and aim to characterize major aspects of variation. We use a combination of geometric morphometric approaches, incorporating both outline analysis using elliptical Fourier analysis and semi-landmark approaches. Our results show that morphological convergence is prevalent and many pterosaurs, belonging to diverse dietary groups and subclades, overlap in morphospace and possessed relatively simple 'rod-shaped' jaws. There is no clear trend of size distributions in pterosaur mandibular morphospace, and larger forms are widely distributed. Additionally, there is limited functional signal within pterosaur lower jaw morphospace. Instead, the development of a large anterior ventral crest represents the major component of disparity. This suggests that a socio-sexual trait was a key driver for innovation in pterosaur lower jaw shape. PMID- 29765666 TI - Straightforward and precise approach to replicate complex hierarchical structures from plant surfaces onto soft matter polymer. AB - The surfaces of plant leaves are rarely smooth and often possess a species specific micro- and/or nano-structuring. These structures usually influence the surface functionality of the leaves such as wettability, optical properties, friction and adhesion in insect-plant interactions. This work presents a simple, convenient, inexpensive and precise two-step micro-replication technique to transfer surface microstructures of plant leaves onto highly transparent soft polymer material. Leaves of three different plants with variable size (0.5-100 um), shape and complexity (hierarchical levels) of their surface microstructures were selected as model bio-templates. A thermoset epoxy resin was used at ambient conditions to produce negative moulds directly from fresh plant leaves. An alkaline chemical treatment was established to remove the entirety of the leaf material from the cured negative epoxy mould when necessary, i.e. for highly complex hierarchical structures. Obtained moulds were filled up afterwards with low viscosity silicone elastomer (PDMS) to obtain positive surface replicas. Comparative scanning electron microscopy investigations (original plant leaves and replicated polymeric surfaces) reveal the high precision and versatility of this replication technique. This technique has promising future application for the development of bioinspired functional surfaces. Additionally, the fabricated polymer replicas provide a model to systematically investigate the structural key points of surface functionalities. PMID- 29765667 TI - A novel non-sequencing approach for rapid authentication of Testudinis Carapax et Plastrum and Trionycis Carapax by species-specific primers. AB - A novel non-sequencing approach was developed to detect short DNA fragments (ca 100 bp) for rapid authentication of two natural products, namely Testudinis Carapax et Plastrum and Trionycis Carapax, based on the difference in mitochondrial genome. Five specifically designed primer reactions were established to target species for reliable identification of their commercial products. They were confirmed to have a high level of inter-species-specificity and good intra-species stability. The limit of detection was estimated to be 1 ng of genomes for all of five assays. Also, the validation results demonstrated that the raw materials and processed products in addition to some of the highly processed products can be conveniently authenticated with good sensitivity and precision by this newly proposed approach. Especially, when reference sample mixtures were assayed, these primer sets have still performed well but not the prevailing COI barcoding technology. These could assist in the discrimination and identification of other animal-derived medicines for their form of raw material, the pulverized and the complex. PMID- 29765668 TI - Applicability of Taylor's hypothesis in thermally driven turbulence. AB - In this paper, we show that, in the presence of large-scale circulation (LSC), Taylor's hypothesis can be invoked to deduce the energy spectrum in thermal convection using real-space probes, a popular experimental tool. We perform numerical simulation of turbulent convection in a cube and observe that the velocity field follows Kolmogorov's spectrum (k-5/3). We also record the velocity time series using real-space probes near the lateral walls. The corresponding frequency spectrum exhibits Kolmogorov's spectrum (f-5/3), thus validating Taylor's hypothesis with the steady LSC playing the role of a mean velocity field. The aforementioned findings based on real-space probes provide valuable inputs for experimental measurements used for studying the spectrum of convective turbulence. PMID- 29765669 TI - Entrainment in the master equation. AB - The master equation plays an important role in many scientific fields including physics, chemistry, systems biology, physical finance and sociodynamics. We consider the master equation with periodic transition rates. This may represent an external periodic excitation like the 24 h solar day in biological systems or periodic traffic lights in a model of vehicular traffic. Using tools from systems and control theory, we prove that under mild technical conditions every solution of the master equation converges to a periodic solution with the same period as the rates. In other words, the master equation entrains (or phase locks) to periodic excitations. We describe two applications of our theoretical results to important models from statistical mechanics and epidemiology. PMID- 29765670 TI - Family ties: the multilevel effects of households and kinship on the networks of individuals. AB - Among social mammals, humans uniquely organize themselves into communities of households that are centred around enduring, predominantly monogamous unions of men and women. As a consequence of this social organization, individuals maintain social relationships both within and across households, and potentially there is conflict among household members about which social ties to prioritize or de emphasize. Extending the logic of structural balance theory, I predict that there will be considerable overlap in the social networks of individual household members, resulting in a pattern of group-level reciprocity. To test this prediction, I advance the Group-Structured Social Relations Model, a generalized linear mixed model that tests for group-level effects in the inter-household social networks of individuals. The empirical data stem from social support interviews conducted in a community of indigenous Nicaraguan horticulturalists, and model results show high group-level reciprocity among households. Although support networks are organized around kinship, covariates that test predictions of kin selection models do not receive strong support, potentially because most kin-directed altruism occurs within households, not between households. In addition, the models show that households with high genetic relatedness in part from children born to adulterous relationships are less likely to assist each other. PMID- 29765671 TI - Epigenetic and genetic variation among three separate introductions of the house sparrow (Passer domesticus) into Australia. AB - Invasive populations are often associated with low levels of genetic diversity owing to population bottlenecks at the initial stages of invasion. Despite this, the ability of invasive species to adapt rapidly in response to novel environments is well documented. Epigenetic mechanisms have recently been proposed to facilitate the success of invasive species by compensating for reduced levels of genetic variation. Here, we use methylation sensitive amplification fragment length polymorphism and microsatellite analyses to compare levels of epigenetic and genetic diversity and differentiation across 15 sites in the introduced Australian house sparrow population. We find patterns of epigenetic and genetic differentiation that are consistent with historical descriptions of three distinct, introductions events. However unlike genetic differentiation, epigenetic differentiation was higher among sample sites than among invasion clusters, suggesting that patterns of epigenetic variation are more strongly influenced by local environmental stimuli or sequential founder events than the initial diversity in the introduction population. Interestingly, we fail to detect correlations between pairwise site comparisons of epigenetic and genetic differentiation, suggesting that some of the observed epigenetic variation has arisen independently of genetic variation. We also fail to detect the potentially compensatory relationship between epigenetic and genetic diversity that has been detected in a more recent house sparrow invasion in Africa. We discuss the potential for this relationship to be obscured by recovered genetic diversity in more established populations, and highlight the importance of incorporating introduction history into population-wide epigenetic analyses. PMID- 29765672 TI - Large-scale fabrication of porous YBO3 hollow microspheres with tunable photoluminescence. AB - Hollow lanthanide-doped compounds are some of the most popular materials for high performance luminescent devices. However, it is challenging to find an approach that can fabricate large-scale and well-crystallized lanthanide-doped hollow structures and that is facile, efficient and of low cost. In this study, YBO3: Eu3+/Tb3+ hollow microspheres were fabricated by using a novel multi-step transformation synthetic route for the first time with polystyrene spheres as the template, followed by the combination of a facile homogeneous precipitation method, an ion-exchange process and a calcination process. The results show that the as-obtained YBO3: Eu3+/Tb3+ hollow spheres have a uniform morphology with an average diameter of 1.65 um and shell thickness of about 160 nm. When used as luminescent materials, the emission colours of YBO3: Eu3+/Tb3+ samples can be tuned from red, through orange, yellow and green-yellow, to green by simply adjusting the relative doping concentrations of the activator ions under the excitation of ultraviolet light, which might have potential applications in fields such as light display systems and optoelectronic devices. PMID- 29765673 TI - Success of sky-polarimetric Viking navigation: revealing the chance Viking sailors could reach Greenland from Norway. AB - According to a famous hypothesis, Viking sailors could navigate along the latitude between Norway and Greenland by means of sky polarization in cloudy weather using a sun compass and sunstone crystals. Using data measured in earlier atmospheric optical and psychophysical experiments, here we determine the success rate of this sky-polarimetric Viking navigation. Simulating 1000 voyages between Norway and Greenland with varying cloudiness at summer solstice and spring equinox, we revealed the chance with which Viking sailors could reach Greenland under the varying weather conditions of a 3-week-long journey as a function of the navigation periodicity Deltat if they analysed sky polarization with calcite, cordierite or tourmaline sunstones. Examples of voyage routes are also presented. Our results show that the sky-polarimetric navigation is surprisingly successful on both days of the spring equinox and summer solstice even under cloudy conditions if the navigator determined the north direction periodically at least once in every 3 h, independently of the type of sunstone used for the analysis of sky polarization. This explains why the Vikings could rule the Atlantic Ocean for 300 years and could reach North America without a magnetic compass. Our findings suggest that it is not only the navigation periodicity in itself that is important for higher navigation success rates, but also the distribution of times when the navigation procedure carried out is as symmetrical as possible with respect to the time point of real noon. PMID- 29765674 TI - Photocatalytic degradation properties of alpha-Fe2O3 nanoparticles for dibutyl phthalate in aqueous solution system. AB - The phthalate ester compounds in industrial wastewater, as kinds of environmental toxic organic pollutants, may interfere with the body's endocrine system, resulting in great harm to humans. In this work, the photocatalytic degradation properties of dibutyl phthalate (DBP) were investigated using alpha-Fe2O3 nanoparticles and H2O2 in aqueous solution system. The optimal parameters and mechanism of degradation were discussed by changing the morphology and usage amount of catalysts, the dosage of H2O2, pH value and the initial concentration of DBP. Hollow alpha-Fe2O3 nanoparticles showed the highest degradation efficiency when 30 mg of catalyst and 50 ul of H2O2 were used in the DBP solution with the initial concentration of 13 mg l-1 at pH = 6.5. When the reaction time was 90 min, DBP was degraded 93% for the above optimal parameters. The photocatalytic degradation mechanism of DBP was studied by the gas chromatography mass spectrometry technique. The result showed that the main degradation intermediates of DBP were ortho-phthalate monobutyl ester, methyl benzoic acid, benzoic acid, benzaldehyde, and heptyl aldehyde when the reaction time was 2 h. DBP and its intermediates were almost completely degraded to CO2 and H2O in 12 h in the alpha-Fe2O3/ H2O2/UV system. PMID- 29765677 TI - Drivers of temporal beta diversity of a benthic community in a seasonally hypoxic fjord. AB - Global expansion of oxygen-deficient (hypoxic) waters will have detrimental effects on marine life in the Northeast Pacific Ocean (NEP) where some of the largest proportional losses in aerobic habitat are predicted to occur. However, few in situ studies have accounted for the high environmental variability in this region while including natural community-assembly dynamics. Here, we present results from a 14-month deployment of a benthic camera platform tethered to the VENUS cabled observatory in the seasonally hypoxic Saanich Inlet. Our time series continuously recorded natural cycles of deoxygenation and reoxygenation that allowed us to test whether a community from the NEP showed hysteresis in its recovery compared to hypoxia-induced decline, and to address the processes driving temporal beta diversity under variable states of hypoxia. Using high frequency ecological time series, we reveal (i) differences in the response and recovery of the epibenthic community are rate-limited by recovery of the sessile species assemblage; (ii) both environmental and biological processes influence community assembly patterns at multiple timescales; and (iii) interspecific processes can drive temporal beta diversity in seasonal hypoxia. Ultimately, our results illustrate how different timescale-dependent drivers can influence the response and recovery of a marine habitat under increasing stress from environmental change. PMID- 29765678 TI - A new large squalodelphinid (Cetacea, Odontoceti) from Peru sheds light on the Early Miocene platanistoid disparity and ecology. AB - The South Asian river dolphin (Platanista gangetica) is the only extant survivor of the large clade Platanistoidea, having a well-diversified fossil record from the Late Oligocene to the Middle Miocene. Based on a partial skeleton collected from the Chilcatay Formation (Chilcatay Fm; southern coast of Peru), we report here a new squalodelphinid genus and species, Macrosqualodelphis ukupachai. A volcanic ash layer, sampled near the fossil, yielded the 40Ar/39Ar age of 18.78 +/- 0.08 Ma (Burdigalian, Early Miocene). The phylogenetic analysis places Macrosqualodelphis as the earliest branching squalodelphinid. Combined with several cranial and dental features, the large body size (estimated body length of 3.5 m) of this odontocete suggests that it consumed larger prey than the other members of its family. Together with Huaridelphis raimondii and Notocetus vanbenedeni, both also found in the Chilcatay Fm, this new squalodelphinid further demonstrates the peculiar local diversity of the family along the southeastern Pacific coast, possibly related to their partition into different dietary niches. At a wider geographical scale, the morphological and ecological diversity of squalodelphinids confirms the major role played by platanistoids during the Early Miocene radiation of crown odontocetes. PMID- 29765676 TI - Using virtual reality to estimate aesthetic values of coral reefs. AB - Aesthetic value, or beauty, is important to the relationship between humans and natural environments and is, therefore, a fundamental socio-economic attribute of conservation alongside other ecosystem services. However, beauty is difficult to quantify and is not estimated well using traditional approaches to monitoring coral-reef aesthetics. To improve the estimation of ecosystem aesthetic values, we developed and implemented a novel framework used to quantify features of coral reef aesthetics based on people's perceptions of beauty. Three observer groups with different experience to reef environments (Marine Scientist, Experienced Diver and Citizen) were virtually immersed in Australian's Great Barrier Reef (GBR) using 360 degrees images. Perceptions of beauty and observations were used to assess the importance of eight potential attributes of reef-aesthetic value. Among these, heterogeneity, defined by structural complexity and colour diversity, was positively associated with coral-reef-aesthetic values. There were no group-level differences in the way the observer groups perceived reef aesthetics suggesting that past experiences with coral reefs do not necessarily influence the perception of beauty by the observer. The framework developed here provides a generic tool to help identify indicators of aesthetic value applicable to a wide variety of natural systems. The ability to estimate aesthetic values robustly adds an important dimension to the holistic conservation of the GBR, coral reefs worldwide and other natural ecosystems. PMID- 29765675 TI - Leishmania naiffi and Leishmania guyanensis reference genomes highlight genome structure and gene evolution in the Viannia subgenus. AB - The unicellular protozoan parasite Leishmania causes the neglected tropical disease leishmaniasis, affecting 12 million people in 98 countries. In South America, where the Viannia subgenus predominates, so far only L. (Viannia) braziliensis and L. (V.) panamensis have been sequenced, assembled and annotated as reference genomes. Addressing this deficit in molecular information can inform species typing, epidemiological monitoring and clinical treatment. Here, L. (V.) naiffi and L. (V.) guyanensis genomic DNA was sequenced to assemble these two genomes as draft references from short sequence reads. The methods used were tested using short sequence reads for L. braziliensis M2904 against its published reference as a comparison. This assembly and annotation pipeline identified 70 additional genes not annotated on the original M2904 reference. Phylogenetic and evolutionary comparisons of L. guyanensis and L. naiffi with 10 other Viannia genomes revealed four traits common to all Viannia: aneuploidy, 22 orthologous groups of genes absent in other Leishmania subgenera, elevated TATE transposon copies and a high NADH-dependent fumarate reductase gene copy number. Within the Viannia, there were limited structural changes in genome architecture specific to individual species: a 45 Kb amplification on chromosome 34 was present in all bar L. lainsoni, L. naiffi had a higher copy number of the virulence factor leishmanolysin, and laboratory isolate L. shawi M8408 had a possible minichromosome derived from the 3' end of chromosome 34. This combination of genome assembly, phylogenetics and comparative analysis across an extended panel of diverse Viannia has uncovered new insights into the origin and evolution of this subgenus and can help improve diagnostics for leishmaniasis surveillance. PMID- 29765679 TI - The bat-bird-bug battle: daily flight activity of insects and their predators over a rice field revealed by high-resolution Scheimpflug Lidar. AB - We present the results of, to our knowledge, the first Lidar study applied to continuous and simultaneous monitoring of aerial insects, bats and birds. It illustrates how common patterns of flight activity, e.g. insect swarming around twilight, depend on predation risk and other constraints acting on the faunal components. Flight activity was monitored over a rice field in China during one week in July 2016, using a high-resolution Scheimpflug Lidar system. The monitored Lidar transect was about 520 m long and covered approximately 2.5 m3. The observed biomass spectrum was bimodal, and targets were separated into insects and vertebrates in a categorization supported by visual observations. Peak flight activity occurred at dusk and dawn, with a 37 min time difference between the bat and insect peaks. Hence, bats started to feed in declining insect activity after dusk and stopped before the rise in activity before dawn. A similar time difference between insects and birds may have occurred, but it was not obvious, perhaps because birds were relatively scarce. Our observations are consistent with the hypothesis that flight activity of bats is constrained by predation in bright light, and that crepuscular insects exploit this constraint by swarming near to sunset/sunrise to minimize predation from bats. PMID- 29765681 TI - Salishicetus meadi, a new aetiocetid from the late Oligocene of Washington State and implications for feeding transitions in early mysticete evolution. AB - Living baleen whales, or Mysticeti, lack teeth and instead feed using keratinous baleen plates to sieve prey-laden water. This feeding strategy is profoundly different from that of their toothed ancestors, which processed prey using the differentiated dentition characteristic of mammals. The fossil record of mysticetes reveals stem members that include extinct taxa with dentition, illuminating the morphological states that preceded the loss of teeth and the subsequent origin of baleen. The relationships among stem mysticetes, including putative clades such as Mammalodontidae and Aetiocetidae, remain debatable. Aetiocetids are among the more species-rich clade of stem mysticetes, and known only from fossil localities along the North Pacific coastline. Here, we report a new aetiocetid, Salishicetus meadi gen. et sp. nov, from the late Oligocene of Washington State, USA. Salishicetus preserves a near-complete lower dentition with extensive occlusal wear, indicating that it processed prey using shearing cheek teeth in the same way as its stem cetacean ancestors. Using a matrix with all known species of aetiocetids, we recover a monophyletic Aetiocetidae, crownward of a basal clade of Mammalodontidae. The description of Salishicetus resolves phylogenetic relationships among aetiocetids, which provides a basis for reconstructing ancestral feeding morphology along the stem leading to crown Mysticeti. PMID- 29765680 TI - The relationship between substrate morphology and biological performances of nano silver-loaded dopamine coatings on titanium surfaces. AB - Biomedical device-associated infection (BAI) and lack of osseointegration are the main causes of implant failure. Therefore, it is imperative for implants not only to depress microbial activity and biofilm colonization but also to prompt osteoblast functions and osseointegration. As part of the coating development for implants, the interest of in vitro studies on the interaction between implant substrate morphology and the coating's biological performances is growing. In this study, by harnessing the adhesion and reactivity of bioinspired polydopamine, nano-silver was successfully anchored onto micro/nanoporous as well as smooth titanium surfaces to analyse the effect of substrate morphology on biological performances of the coatings. Compared with the smooth surface, a small size of nano-silver and high silver content was found on the micro/nanoporous surface. More mineralization happened on the coating on the micro/nanoporous structure than on the smooth surface, which led to a more rapid decrease of silver release from the micro/nanoporous surface. Antimicrobial tests indicated that both surfaces with resulting coating inhibit microbial colonization on them and growth around them, indicating that the coating eliminates the shortcoming of the porous structure which render the implant extremely susceptible to BAI. Besides, the multiple osteoblast responses of nano silver-loaded dopamine coatings on both surfaces, i.e. attachment, proliferation and differentiation, have deteriorated, however the mineralized surfaces of these coatings stimulated osteoblast proliferation and differentiation, especially for the micro/nanoporous surface. Therefore, nano-silver-loaded dopamine coatings on micro/nanoporous substratum may not only reduce the risk of infection but also facilitate mineralization during the early post-operative period and then promote osseointegration owing to the good osteoblast-biocompatibility of the mineralized surface. These results clearly highlight the influence of the substrate morphology on the biological performances of implant coating. PMID- 29765682 TI - Effects of the inclusion of a mixed Psychrotrophic bacteria strain for sewage treatment in constructed wetland in winter seasons. AB - Constructed wetlands (CWs) have been used globally in wastewater treatment for years. CWs represent an efficient ecological system which is both energy-saving and low in investment for construction and operational cost. In addition, CWs also have the advantage of being easy to operate and maintain. However, the operation of CWs at northern latitudes (both mid and high) is sometimes quite demanding, due to the inhibitory effect of low temperatures that often occur in winter. To evaluate the wastewater treatment performance of a culture of mixed Psychrotrophic bacteria strains in an integrated vertical-flow CW, the removal rates of ammonia nitrogen (NH3-N), chemical oxygen demand (COD), nitrite nitrogen [Formula: see text], nitrate nitrogen [Formula: see text] and total phosphorus (TP) were quantified at different bacterial dosages to determine the best bacterial dosage and establish kinetic degradation models of the mixed strains. The bacterial culture was made up of Psychrobacter TM-1, Sphingobacterium TM-2 and Pseudomonas TM-3, mixed together at a volume/volume ratio of 1 : 1 : 1 (at bacterial suspension concentrations of 4.4 * 109 ml-1). Results showed that the organic pollutants (nitrogen and phosphorus) in the sewage could be efficiently removed by the culture of mixed Psychrotrophic bacteria. The optimal dosage of this mixed bacteria strain was 2.5%, and the treatment efficiency of COD, NH3-N, [Formula: see text], [Formula: see text], total nitrogen and TP were stable at 91.8%, 91.1%, 88.0%, 93.8%, 94.8% and 95.2%, respectively, which were 1.5, 2.0, 2.1, 1.5, 2.2 and 1.3 times those of the control group. In addition, a pseudo first-order degradation model was a good fit for the degradation pattern observed for each of these pollutants. PMID- 29765683 TI - Preparation of Cu-ZSM-5 catalysts by chemical vapour deposition for catalytic wet peroxide oxidation of phenol in a fixed bed reactor. AB - Cu-ZSM-5 catalysts were prepared by chemical vapour deposition for catalytic wet peroxide oxidation (CWPO) of phenol in a fixed bed reactor. Firstly, Cu-ZSM-5 catalysts with Cu loading of 0.5, 2, and 6 wt% were prepared and characterized by X-ray diffraction (XRD), N2 adsorption-desorption and X-ray photoelectron spectra (XPS). The characterization results demonstrated that CuO was uniformly dispersed on ZSM-5 with slight effect on the structure properties of the support. Then, several variables, such as the copper loading, reaction temperature, catalyst bed height and feed flow rate were investigated in the CWPO of phenol in aqueous solution at high concentration (1000 ppm). Compared with the catalyst prepared by the impregnation method, the Cu-ZSM-5 prepared by chemical vapour deposition has a better capacity of further oxidizing the intermediate organic products into carbon dioxide and water with less metal loading. Based on the Cu-ZSM-5 catalyst with Cu loading of 6 wt%, complete removal of phenol and a high TOC reduction (around 70%) have been achieved at the temperature of 80 degrees C feed flow rate of 2 ml min-1 and catalyst bed height of 3 cm. Moreover, this catalyst maintained high catalytic activity after three runs with high phenol conversion (94%) under this optimum operating condition. Finally, the reaction mechanism was studied based on the intermediates detected by high-performance liquid chromatography (HPLC). PMID- 29765684 TI - Clawed forelimbs allow northern seals to eat like their ancient ancestors. AB - Streamlined flippers are often considered the defining feature of seals and sea lions, whose very name 'pinniped' comes from the Latin pinna and pedis, meaning 'fin-footed'. Yet not all pinniped limbs are alike. Whereas otariids (fur seals and sea lions) possess stiff streamlined forelimb flippers, phocine seals (northern true seals) have retained a webbed yet mobile paw bearing sharp claws. Here, we show that captive and wild phocines routinely use these claws to secure prey during processing, enabling seals to tear large fish by stretching them between their teeth and forelimbs. 'Hold and tear' processing relies on the primitive forelimb anatomy displayed by phocines, which is also found in the early fossil pinniped Enaliarctos. Phocine forelimb anatomy and behaviour therefore provide a glimpse into how the earliest seals likely fed, and indicate what behaviours may have assisted pinnipeds along their journey from terrestrial to aquatic feeding. PMID- 29765685 TI - Discrepancies in the spiking threshold and frequency sensitivity of nocturnal moths explainable by biases in the canonical auditory stimulation method. AB - The auditory stimulation method used in experiments on moth A cell(s) is generally believed to be adequate to characterize the encoding of bat echolocation signals. The stimulation method hosts, though, several biases. Their compounded effects can explain a range of discrepancies between the reported electrophysiological recordings and significantly alter the current interpretation. To test the hypothesis that the bias may significantly alter our current understanding of the moth's auditory transducer characteristics, papers using the same auditory stimulation method and reporting on either spiking threshold or spiking activity of the moth's A cells were analysed. The consistency of the reported data was assessed. A range of corrections issued from best practices and theoretical background were applied to the data in an attempt to re-interpret the data. We found that it is not possible to apply a posteriori corrections to all data and bias. However the corrected data indicate that the A cell's spiking may (i) be independent of the repetition rate, (ii) be maximum when detecting long and low-intensity pulses and (iii) steadily reduce as the bat closes on the moth. These observations raise the possibility that a fixed action pattern drives the moths' erratic evasive manoeuvres until the final moment. In depth investigations of the potential bias also suggest that the auditory transducer's response may be constant for a larger frequency range than thought so far, and provide clues to explain the negative taxis in response to the searching bats' calls detection. PMID- 29765686 TI - Phylogeography of hydrothermal vent stalked barnacles: a new species fills a gap in the Indian Ocean 'dispersal corridor' hypothesis. AB - Phylogeography of animals provides clues to processes governing their evolution and diversification. The Indian Ocean has been hypothesized as a 'dispersal corridor' connecting hydrothermal vent fauna of Atlantic and Pacific oceans. Stalked barnacles of the family Eolepadidae are common associates of deep-sea vents in Southern, Pacific and Indian oceans, and the family is an ideal group for testing this hypothesis. Here, we describe Neolepas marisindica sp. nov. from the Indian Ocean, distinguished from N. zevinae and N. rapanuii by having a tridentoid mandible in which the second tooth lacks small elongated teeth. Morphological variations suggest that environmental differences result in phenotypic plasticity in the capitulum and scales on the peduncle in eolepadids. We suggest that diagnostic characters in Eolepadidae should be based mainly on more reliable arthropodal characters and DNA barcoding, while the plate arrangement should be used carefully with their intraspecific variation in mind. We show morphologically that Neolepas specimens collected from the South West Indian Ridge, the South East Indian Ridge and the Central Indian Ridge belong to the new species. Molecular phylogeny and fossil evidence indicated that Neolepas migrated from the southern Pacific to the Indian Ocean through the Southern Ocean, providing key evidence against the 'dispersal corridor' hypothesis. Exploration of the South East Indian Ridge is urgently required to understand vent biogeography in the Indian Ocean. PMID- 29765687 TI - Machine learning methods for locating re-entrant drivers from electrograms in a model of atrial fibrillation. AB - Mapping resolution has recently been identified as a key limitation in successfully locating the drivers of atrial fibrillation (AF). Using a simple cellular automata model of AF, we demonstrate a method by which re-entrant drivers can be located quickly and accurately using a collection of indirect electrogram measurements. The method proposed employs simple, out-of-the-box machine learning algorithms to correlate characteristic electrogram gradients with the displacement of an electrogram recording from a re-entrant driver. Such a method is less sensitive to local fluctuations in electrical activity. As a result, the method successfully locates 95.4% of drivers in tissues containing a single driver, and 95.1% (92.6%) for the first (second) driver in tissues containing two drivers of AF. Additionally, we demonstrate how the technique can be applied to tissues with an arbitrary number of drivers. In its current form, the techniques presented are not refined enough for a clinical setting. However, the methods proposed offer a promising path for future investigations aimed at improving targeted ablation for AF. PMID- 29765688 TI - Advances in synthetic gauge fields for light through dynamic modulation. AB - Photons are weak particles that do not directly couple to magnetic fields. However, it is possible to generate a photonic gauge field by breaking reciprocity such that the phase of light depends on its direction of propagation. This non-reciprocal phase indicates the presence of an effective magnetic field for the light itself. By suitable tailoring of this phase, it is possible to demonstrate quantum effects typically associated with electrons, and, as has been recently shown, non-trivial topological properties of light. This paper reviews dynamic modulation as a process for breaking the time-reversal symmetry of light and generating a synthetic gauge field, and discusses its role in topological photonics, as well as recent developments in exploring topological photonics in higher dimensions. PMID- 29765689 TI - A new archaic baleen whale Toipahautea waitaki (early Late Oligocene, New Zealand) and the origins of crown Mysticeti. AB - A new genus and species of extinct baleen whale ?Toipahautea waitaki (Late Oligocene, New Zealand) is based on a skull and associated bones, from the lower Kokoamu Greensand, about 27.5 Ma (local upper Whaingaroan Stage, early Chattian). The upper jaw includes a thin, elongate and apparently toothless maxilla, with evidence of arterial supply for baleen. Open sutures with the premaxilla suggest a flexible (kinetic) upper jaw. The blowhole is well forward. The mandible is bowed laterally and slightly dorsally; unlike the Eomysticetidae, there are no mandibular alveoli, and the coronoid process is tapered and curved laterally. Jaw structure is consistent with baleen-assisted gulp-feeding. The age of early Chattian makes ?Toipahautea a very early, if not the oldest named, toothless and baleen-bearing mysticete, suggesting that the full transition from toothed to baleen-bearing probably occurred in the Early Oligocene. Late Oligocene mysticetes vary considerably in jaw form and kinesis, tooth form and function, and development of baleen, implying a wide range of raptorial, suctorial and filter-feeding behaviour. More study may elucidate the function of jaws, teeth and baleen in terms of opportunist/generalist feeding, as in modern gray whales, versus specialized feeding. We here propose that early mysticetes, when transitioned from toothed to baleen-bearing, were generalists and opportunists instead of specializing in any forms of feeding strategies. In addition, two different phylogenetic analyses placed ?Toipahautea either in a polytomy including crown Mysticeti, or immediately basal to the crown, and above ?Eomysticetidae in both cases. Because the ?Toipahautea waitaki holotype is an immature individual, it may plot more basally in phylogeny than its true position. PMID- 29765690 TI - Digested sludge-derived three-dimensional hierarchical porous carbon for high performance supercapacitor electrode. AB - Digested sludge, as the main by-product of the sewage sludge anaerobic digestion process, still contains considerable organic compounds. In this protocol, we report a facile method for preparing digested sludge-derived self-doped porous carbon material for high-performance supercapacitor electrodes via a sustainable pyrolysis/activation process. The obtained digested sludge-derived carbon material (HPDSC) exhibits versatile O-, N-doped hierarchical porous framework, high specific surface area (2103.6 m2 g-1) and partial graphitization phase, which can facilitate ion transport, provide more storage sites for electrolyte ions and enhance the conductivity of active electrode materials. The HPDSC-based supercapacitor electrodes show favourable energy storage performance, with a specific capacitance of 245 F g-1 at 1.0 A g-1 in 0.5 M Na2SO4; outstanding cycling stability, with 98.4% capacitance retention after 2000 cycles; and good rate performance (211 F g-1 at 11 A g-1). This work provides a unique self-doped three-dimensional hierarchical porous carbon material with a favourable charge storage capacity and at the same time finds a high value-added and environment friendly strategy for disposal and recycling of digested sludge. PMID- 29765691 TI - Sexual phenotype drives variation in endocrine responses to social challenge in a quasi-clonal animal. AB - In many species, males tend to behave more aggressively than females and female aggression often occurs during particular life stages such as maternal defence of offspring. Though many studies have revealed differences in aggression between the sexes, few studies have compared the sexes in terms of their neuroendocrine responses to contest experience. We investigated sex differences in the endocrine response to social challenge using mangrove rivulus fish, Kryptolebias marmoratus. In this species, sex is determined environmentally, allowing us to produce males and hermaphrodites with identical genotypes. We hypothesized that males would show elevated androgen levels (testosterone and 11-ketotestosterone) following social challenge but that hermaphrodite responses might be constrained by having to maintain both testicular and ovarian tissue. To test this hypothesis, we staged fights between males and between hermaphrodites, and then compared contest behaviour and hormone responses between the sexes. Hermaphrodites had significantly higher oestradiol but lower 11-ketotestosterone than males before contests. Males took longer to initiate contests but tended to fight more aggressively and sustain longer fights than hermaphrodites. Males showed a dramatic post-fight increase in 11-ketotestosterone but hermaphrodites did not. Thus, despite being genetically identical, males and hermaphrodites exhibit dramatically different fighting strategies and endocrine responses to contests. PMID- 29765692 TI - The cascading pathogenic consequences of Sarcoptes scabiei infection that manifest in host disease. AB - Sarcoptic mange, caused by the parasitic mite Sarcoptes scabiei, causes a substantive burden of disease to humans, domestic animals and wildlife, globally. There are many effects of S. scabiei infection, culminating in the disease which hosts suffer. However, major knowledge gaps remain on the pathogenic impacts of this infection. Here, we focus on the bare-nosed wombat host (Vombatus ursinus) to investigate the effects of mange on: (i) host heat loss and thermoregulation, (ii) field metabolic rates, (iii) foraging and resting behaviour across full circadian cycles, and (iv) fatty acid composition in host adipose, bone marrow, brain and muscle tissues. Our findings indicate that mange-infected V. ursinus lose more heat to the environment from alopecia-affected body regions than healthy individuals. Additionally, mange-infected individuals have higher metabolic rates in the wild. However, these metabolic demands are difficult to meet, because infected individuals spend less time foraging and more time inactive relative to their healthy counterparts, despite being outside of the burrow for longer. Lastly, mange infection results in altered fatty acid composition in adipose tissue, with increased amounts of omega-6 acids, and decreased amounts of omega-3 acids, a consequence of chronic cutaneous inflammation and inhibition of anti-inflammatory responses. These findings highlight the interactions of mange-induced physiological and behavioural changes, and have implications for the treatment and rehabilitation of infected individuals. PMID- 29765693 TI - Homophily, heterophily and the diversity of messages among decision-making individuals. AB - To better understand the intriguing mechanisms behind cooperation among decision making individuals, we study the simple yet appealing use of preplay communication or cheap talk in evolutionary games, when players are able to choose strategies based on whether an opponent sends the same message as they do. So when playing games, in addition to pure cooperation and defection, players have two new strategies in this setting: homophilic (respectively, heterophilic) cooperation which is to cooperate (respectively, defect) only with those who send the same message as they do. We reveal the intrinsic qualities of individuals playing the two strategies and show that under the replicator dynamics, homophilic cooperators engage in a battle of messages and will become dominated by whichever message is the most prevalent at the start, while populations of heterophilic cooperators exhibit a more harmonious behaviour, converging to a state of maximal diversity. Then we take Prisoner's Dilemma (PD) as the base of the cheap-talk game and show that the hostility of heterophilics to individuals with similar messages leaves no possibility for pure cooperators to survive in a population of the two, whereas the one-message dominance of homophilics allows for pure cooperators with the same tag as the dominant homophilics to coexist in the population, demonstrating that homophilics are more cooperative than heterophilics. Finally, we generalize an existing convergence result on population shares associated with weakly dominated strategies to a broadly applicable theorem and complete previous research on PD games with preplay communication by proving that the frequencies of all types of cooperators, i.e. pure, homophilic and heterophilic, converge to zero in the face of defectors. This implies homophily and heterophily cannot facilitate the long-term survival of cooperation in this setting, which urges studying cheap-talk games under other reproduction dynamics. PMID- 29765695 TI - Influence of high altitude on the burning behaviour of typical combustibles and the related responses of smoke detectors in compartments. AB - The effect of altitude on typical combustible burning and related smoke detector response signals was investigated by comparison experiments at altitudes of 40 m and 3650 m based on EN54 standard tests. Point-type light scattering photoelectric smoke detectors and ionization smoke detectors were used for four kinds of EN54 fire tests, including two kinds of smouldering fires with wood (test fire no. 2 in EN54 standard or TF2) and cotton (TF3), and two kinds of flaming fires with polyurethane (TF4) and n-heptane (TF5). First, the influence of altitude or ambient pressure on mass loss for smouldering combustion (TF2 or TF3) was insignificant, while a significant decrease in the mass burning rate was found for flaming tests (TF4 and TF5) as reported in our previous studies. Second, for photoelectric smoke detectors in flaming fire tests, the effect of altitude was similar to that of the burning rate, whereas for the ionization smoke detectors, the response signal at high altitudes was shown to be 'enhanced' by the detection principle of the ionization chamber, leading to an even larger value than at normal altitude for smouldering conditions. Third, to provide a reference for smoke detector design in high-altitude areas, the differences between signal speed in rising and peak values at two locations are discussed. Also, relationship between ion chamber signals and smoke optical densities are presented by utilization of an ionization smoke detector and smoke concentration meter. Moreover, a hierarchical diagram is illustrated to provide a better understanding of the effects of altitude on combustible burning behaviour and the mechanisms of detector response. PMID- 29765694 TI - Development of an intravascular ultrasound elastography based on a dual-element transducer. AB - The ability to measure the elastic properties of plaques and vessels would be useful in clinical diagnoses, particularly for detecting a vulnerable plaque. This study demonstrates the feasibility of the combination of intravascular ultrasound (IVUS) and acoustic radiation force elasticity imaging for detecting the distribution of stiffness within atherosclerotic arteries ex vivo. A dual frequency IVUS transducer with two elements was used to induce the propagation of the shear wave (by the 8.5 MHz pushing element) which could be simultaneously monitored by the 31 MHz imaging element. The wave-amplitude image and the wave velocity image were reconstructed by measuring the peak displacement and wave velocity of shear wave propagation, respectively. System performance was verified using gelatin phantoms. The phantom results demonstrate that the stiffness differences of shear modulus of 1.6 kPa can be distinguished through the wave amplitude and wave-velocity images. The stiffness distributions of the atherosclerotic aorta from a rabbit were obtained, for which the values of peak displacement and the shear wave velocity were 3.7 +/- 1.2 um and 0.38 +/- 0.19 m s-1 for the lipid-rich plaques, and 1.0 +/- 0.2 um and 3.45 +/- 0.45 m s-1 for the arterial walls, respectively. These results indicate that IVUS elasticity imaging can be used to distinguish the elastic properties of plaques and vessels. PMID- 29765696 TI - Behavioural divergence during biological invasions: a study of cane toads (Rhinella marina) from contrasting environments in Hawai'i. AB - Invasive species must deal with novel challenges, both from the alien environment and from pressures arising from range expansion per se (e.g. spatial sorting). Those conditions can create geographical variation in behaviour across the invaded range, as has been documented across regions of Australia invaded by cane toads; range-edge toads are more exploratory and willing to take risks than are conspecifics from the range-core. That behavioural divergence might be a response to range expansion and invasion per se, or to the different environments encountered. Climate differs across the cane toads' invasion range from the wet tropics of Queensland to the seasonally dry climates of northwestern Western Australia. The different thermal and hydric regimes may affect behavioural traits via phenotypic plasticity or through natural selection. We cannot tease apart the effects of range expansion versus climate in an expanding population but can do so in a site where the colonizing species was simultaneously released in all suitable areas, thus removing any subsequent phase of range expansion. Cane toads were introduced to Hawai'i in 1932; and thence to Australia in 1935. Toads were released in all major sugarcane-growing areas in Hawai'i within a 12-month period. Hence, Hawai'ian cane toads provide an opportunity to examine geographical divergence in behavioural traits in a climatically diverse region (each island has both wet and dry sides) in the absence of range expansion subsequent to release. We conducted laboratory-based behavioural trials testing exploration, risk-taking and response to novelty using field-caught toads from the wet and dry sides of two Hawai'ian islands (Oahu and Hawai'i). Toads from the dry side of Oahu had a higher propensity to take risks than did toads from the dry side of Hawai'i. Toads from Oahu were also more exploratory than were conspecifics from the island of Hawai'i. However, toads from wet versus dry climates were similar in all behaviours that we scored, suggesting that founder effects, genetic drift, or developmentally plastic responses to ecological factors other than climate may have driven behavioural divergence between islands. PMID- 29765697 TI - Analytical model of the feto-placental vascular system: consideration of placental oxygen transport. AB - The placenta is a transient vascular organ that enables nutrients and blood gases to be exchanged between fetal and maternal circulations. Herein, the structure and oxygen diffusion across the trophoblast membrane between the fetal and maternal red blood cells in the feto-placental vasculature system in both human and mouse placentas are presented together as a functional unit. Previous models have claimed that the most efficient fetal blood flow relies upon structures containing a number of 'conductive' symmetrical branches, offering a path of minimal resistance that maximizes blood flow to the terminal villi, where oxygen diffusion occurs. However, most of these models have disregarded the actual descriptions of the exchange at the level of the intermediate and terminal villi. We are proposing a 'mixed model' whereby both 'conductive' and 'terminal' villi are presumed to be present at the end of single (in human) or multiple (in mouse) pregnancies. We predict an optimal number of 18 and 22 bifurcation levels in the human and the mouse placentas, respectively. Wherever possible, we have compared our model's predictions with experimental results reported in the literature and found close agreement between them. PMID- 29765699 TI - Feasibility and effects of a home-based intervention using activity trackers on achievement of individual goals, quality of life and motor performance in patients with paediatric cancer. AB - Objectives: Supervised exercise interventions during inpatient care are feasible. The objective was to evaluate the usability of activity trackers and centralised monitoring to conduct a home-based exercise intervention during cancer treatment. The primary endpoint and confirmatory analysis was achievement of individual goals for daily steps, compared (A) in the intervention group (IG) over time and (B) between the IG and control group (CG). Secondary endpoints included achievement of goals for active minutes and effects on motor performance and health-related quality of life (hrQoL). Methods: Forty patients treated for paediatric cancer (14.7+/-3.9 years) were included. The IG received a 6-8 week intervention during acute treatment (T1) and a 2-week intervention in transition to aftercare (T2). The CG only received the intervention at T2. Baseline tests to assess motor performance and physical activity were conducted prior to every intervention. Results: In the primary confirmatory analysis, the IG significantly improved achievement of individual step goals (p=0.04) whereas group analyses did not reveal significant differences. Achievement of active minutes remained low (p=0.23). IG scored higher in hrQoL than CG (p<0.01) and percentage of children scoring below normative value in strength tests was higher in CG. Of all participants, 94% rated the intervention as meaningful and 80% as motivational. Conclusions: Results of this study indicate that this intervention for home stays with centralised supervision is feasible and leads to increased achievement of individual step goals. Despite the positive effects on hrQoL, further strategies are needed to increase positive effects on motor performance. PMID- 29765698 TI - The epidemiology of hepatitis C virus in Pakistan: systematic review and meta analyses. AB - To characterize hepatitis C virus (HCV) epidemiology in Pakistan and estimate the pooled mean HCV antibody prevalence in different risk populations, we systematically reviewed all available records of HCV incidence and/or prevalence from 1989 to 2016, as informed by the Cochrane Collaboration Handbook. This systematic review was reported following the PRISMA guidelines. Populations were classified into six categories based on the risk of exposure to HCV infection. Meta-analyses were performed using DerSimonian and Laird random-effects models with inverse variance weighting. The search identified one HCV incidence study and 341 prevalence measures/strata. Meta-analyses estimated the pooled mean HCV prevalence at 6.2% among the general population, 34.5% among high-risk clinical populations, 12.8% among populations at intermediate risk, 16.9% among special clinical populations, 55.9% among populations with liver-related conditions and 53.6% among people who inject drugs. Most reported risk factors in analytical epidemiologic studies related to healthcare procedures. Pakistan is enduring an HCV epidemic of historical proportions-one in every 20 Pakistanis is infected. HCV plays a major role in liver disease burden in this country, and HCV prevalence is high in all-risk populations. Most transmission appears to be driven by healthcare procedures. HCV treatment and prevention must become a national priority. PMID- 29765700 TI - Study of the measurement and predictive validity of the Functional Movement Screen. AB - Objective: The aim of the study was to evaluate the reported measurement capabilities and predictive validity of the Functional Movement Screen (FMS) for injury. Methods: This was a prospective observational longitudinal study of 24 male footballers from a single team in England, alongside analysis of an existing database over one season (September 2015-May 2016). A preseason FMS was carried out with scores recorded by an experienced assessor and derived, retrospectively, from the three-dimensional movement data that were simultaneously captured. The assessor scores were compared with the photogrammetric system to determine measurement validity, and predictive validity was quantified by assessing sensitivity and specificity (cut-off score of 14). Results: The real-time assessor score matched the photogrammetric score awarded for one of the participants, was higher than the photogrammetric system for 22 participants and was lower than the photogrammetric system in 1 participant. There was no discernible relationship between FMS scores and the competencies required to be met as per the rules articulated for the allocation of a score. A higher number of total injuries were associated with higher FMS scores, whether determined through real-time assessment or codification of kinematic variables. Additionally, neither method of score determination was able to prospectively identify players at risk of serious injury. Conclusion: The FMS does not demonstrate the properties essential to be considered as a measurement scale and has neither measurement nor predictive validity. A possible reason for these observations could be the complexity in the instructions associated with the scale. Further work on eliminating redundancies and improving the measurement properties is recommended. PMID- 29765701 TI - Subjects with cardiovascular disease or high disease risk are more sedentary and less active than their healthy peers. AB - Objectives: We investigated differences in objectively measured sedentary behaviour (SB) and physical activity (PA) levels in subjects with cardiovascular disease (CVD) diagnosis or high CVD risk compared with healthy controls. Methods: The present study includes a subsample (n=1398, Health 2011 Study) of participants, who attended health examinations and wore a triaxial accelerometer (>=4 days). Patients with CVD were identified and CVD risk was calculated for others using Framingham Risk Score (FRS). Participants were categorised into groups: FRS<10%; FRS=10%-30%; FRS>30%/CVD. Raw acceleration data were analysed with mean amplitude deviation (MAD) and angle for posture estimation (APE). MAD corresponding to intensity of PA was converted to metabolic equivalents (MET) and categorised to light (1.5-2.9 METs) and moderate to vigorous PA (MVPA>=3.0 METs). APE recognises SB and standing. Results: Daily accumulated time of >30 s MVPA bouts was higher in FRS<10% group (46 min) than in FRS>30%/CVD group (29 min) (p<0.001). FRS>30%/CVD group were more sedentary, their mean daily number of >10 min SB bouts (13.2) was higher than in FRS <10% group (11.5) (p=0.002). Conclusion: Number and accumulated times of SB and PA bouts differed between the CVD risk groups. Causative research is required to assess the importance of SB and PA in prevention and rehabilitation of CVDs. PMID- 29765702 TI - Is radiographic progression in radiographic axial spondyloarthritis related to matrix metalloproteinase degradation of extracellular matrix? AB - Background: Radiographic axial spondyloarthritis (r-axSpA) is associated with extracellular matrix (ECM) remodelling of affected tissues. We investigated whether there was a relationship between biomarkers of ECM remodelling and 2-year radiographic progression in r-axSpA. Methods: Patients from the Outcome in Ankylosing Spondylitis International Study (OASIS) were included if they had serum, clinical and spinal radiographic assessments available at baseline and 2 years later. Two readers independently scored the radiographs according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The average score was used. Type I, V and VI collagen metabolites (C1M, C5M and C6M) and citrullinated and matrix metalloproteinase-degraded vimentin (VICM) were assessed in serum by ELISAs. The relationship between serum biomarkers and 2-year radiographic progression was investigated using linear regression analyses adjusted for potential confounders. Interactions were tested. Results: Patients included (n=122) had a mean age of 45 years (SD 12), 70% were male and 82% were human leucocyte antigen-B27 positive. The mean 2-year mSASSS progression was 2.1 (2.9) units. Only C1M was significantly associated with mSASSS progression (beta=0.01, 95% CI 0.00 to 0.03). The effect disappeared after adjustment for confounders. C5M, C6M and VICM showed no relationship with mSASSS progression. Conclusion: We did not find evidence that degradation of ECM is related to radiographic progression in patients with r-axSpA. PMID- 29765704 TI - Crystal structure of N,N'-dibenzyl-3,3'-di-meth-oxy-benzidine. AB - The title compound, (systematic name: N,N'-dibenzyl-3,3'-dimeth-oxy-1,1'-biphenyl 4,4'-di-amine), C28H28N2O2, was synthesized by the reduction of a Schiff base prepared via a condensation reaction between o-dianisidine and benzaldehyde under acidic conditions. The mol-ecule lies on a crystallographic inversion centre so that the asymmetric unit contains one half-mol-ecule. The biphenyl moiety compound is essentially planar. Two intra-molecular N-H?O hydrogen bonds occur. The dihedral angle between the terminal phenyl and phenyl-ene rings of a benzidine unit is 48.68 (6) degrees . The methyl-ene C atom of the benzyl group is disordered over two sets of sites, with occupancy ratio 0.779 (18):0.221 (18). In the crystal, mol-ecules are connected by hydrogen bonding between o dianisidine O atoms and H atoms of the terminal benzyl groups, forming a one dimensional ladder-like structure. In the data from DFT calculations, the central biphenyl showed a twisted conformation. PMID- 29765703 TI - Effects of baricitinib on radiographic progression of structural joint damage at 1 year in patients with rheumatoid arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs. AB - Background: Baricitinib was efficacious in a 24-week phase III study in patients with rheumatoid arthritis (RA) and an inadequate response to conventional synthetic disease-modifying anti rheumatic drugs (DMARDs) (csDMARDs) (RA-BUILD). Objectives: To evaluate radiographic progression of structural joint damage in RA BUILD patients over 48 weeks of baricitinib treatment in the long-term extension study, RA-BEYOND. Methods: In RA-BUILD, patients were randomised to placebo, baricitinib 2 mg or 4 mg once daily, with rescue possible from week 16. Patients completing RA-BUILD and entering RA-BEYOND continued to receive the baricitinib dose received at the end of RA-BUILD. Patients receiving placebo were switched to baricitinib 4 mg in RA-BEYOND. Joint damage was measured using the van der Heijde modified total Sharp score. To account for missing scores and scores obtained after rescue, switch or discontinuation of study drug, data were analysed using (1) linear extrapolation (LE) and (2) observed/last observation carried forward (LOCF). The observed/LOCF method used all available observed data, including after rescue or switch, with patients analysed according to original treatment assignment. Results: Using LE, radiographic progression at 24 and 48 weeks was statistically significantly lower for both baricitinib 2 or 4 mg compared with placebo. Only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomised to placebo using observed/LOCF at week 48. Conclusions: Once daily oral baricitinib inhibited radiographic progression of structural joint damage in patients with an inadequate response or intolerance to csDMARDs over 48 weeks. The most robust benefit was seen for the 4 mg dose. PMID- 29765705 TI - Crystal structure of bromido(eta6-1-isopropyl-4-methylbenzene)(7-oxocyclohepta 1,3,5-trien-1-olato-kappa2O,O')osmium. AB - In the title compound, [OsBr(C10H14)(C7H5O2)], the central OsII ion is ligated by a hexa-haptic eta6p-cymene ring, a Br- ligand and two O atoms of a chelating tropolonate group. The p-cymene ligand presents more than one conformation, giving rise to a discrete disorder, which was modelled with two different orientations with occupancy values of 0.561 (15) and 0.439 (15). The crystal packing features C-H?O and C-H?Br hydrogen bonding. Aromatic pi-pi stacking inter actions are also observed between adjacent non-benzenoid aromatic tropolone rings. PMID- 29765706 TI - Crystal structure of silver [(propane-1,3-diyl-dinitrilo-kappa2N,N')-tetra acetato-kappa4O,O',O'',O''']chromate(III) from synchrotron X-ray data. AB - The asymmetric unit of the title compound, Ag[Cr(C11H14N2O8)].3H2O, contains one [Cr(1,3-pdta)]- anion [1,3-pdta is (propane-1,3-diyldi-nitrilo)-tetra-acetate], one Ag+ cation and three water mol-ecules. The Cr3+ ion is coordinated to the four O and two N atoms of the 1,3-pdta ligand, displaying a distorted octa-hedral geometry. The mean Cr-N and Cr-O bond lengths are 2.0727 (17) and 1.9608 (15) A, respectively. The conformations of the chelate rings were found to be envelope for the glycinates and twist-boat for the six-membered di-amine (T) ring. The Ag+ cation is surrounded by six O atoms from three non-coordinated carbonyl O atoms of neighbouring 1,3-pdta groups and three water mol-ecules. The crystal structure is stabilized by inter-molecular hydrogen bonding involving the water O-H group as donor and the carboxyl O atom as acceptor. PMID- 29765707 TI - Crystal structure of the tri-ethyl-ammonium salt of 3-[(4-hy-droxy-3-meth-oxy phen-yl)(4-hy-droxy-2-oxo-2H-chromen-3-yl)meth-yl]-2-oxo-2H-chromen-4-olate. AB - The reaction between 3,3'-[(3-meth-oxy-4-hy-droxy-phen-yl)methanedi-yl]bis-(4-hy droxy-2H-chromen-2-one) and tri-ethyl-amine in methanol yielded the title compound tri-ethyl-ammonium 3-[(4-hy-droxy-3-meth-oxy-phen-yl)(4-hy-droxy-2-oxo 2H-chromen-3-yl)meth-yl]-2-oxo-2H-chromen-4-olate, C6H16N+.C26H17O8- or (NHEt3)+(C26H17O8)-, which crystallized directly from its methano-lic mother liquor. The non-deprotonated coumarol substituent shares its H atom with the deprotonated coumarolate substituent in a short negative charge-assisted hydrogen bond in which the freely refined H atom is moved from its parent O atom towards the acceptor O atom, elongating the covalent O-H bond to 1.18 (3) A. The respective H atom can therefore be described as being shared by two alcohol O atoms, culminating in the formation of an eight-membered ring. PMID- 29765708 TI - Crystal structure of octa-kis-(4-meth-oxy-pyridinium) bis-(4-meth-oxy-pyridine kappaN)tetra-kis-(thio-cyanato-kappaN)ferrate(III) bis-[(4-meth-oxypyri-dine kappaN)pentakis-(thio-cyanato-kappaN)ferrate(III)] hexa-kis-(thio-cyanato kappaN)ferrate(III) with iron in three different octa-hedral coordination environments. AB - The crystal structure of the title salt, (C6H8NO)8[Fe(NCS)4(C6H7NO)2][Fe(NCS)5(C6H7NO)]2[Fe(NCS)6], comprises three negatively charged octa-hedral FeIII complexes with different coordination environments in which the FeIII atoms are coordinated by a different number of thio-cyanate anions and 4-meth-oxy-pyridine ligands. Charge balance is achieved by 4-meth-oxy-pyridinium cations. The asymmetric unit consists of three FeIII cations, one of which is located on a centre of inversion, one on a twofold rotation axis and one in a general position, and ten thio-cyanate anions, two 4 meth-oxy-pyridine ligands and 4-meth-oxy-pyridinium cations (one of which is disordered over two sets of sites). Beside to Coulombic inter-actions between organic cations and the ferrate(III) anions, weak N-H?S hydrogen-bonding inter actions involving the pyridinium N-H groups of the cations and the thio-cyanate S atoms of the complex anions are mainly responsible for the cohesion of the crystal structure. PMID- 29765709 TI - Syntheses, spectroscopy, and crystal structures of 3-(4-bromo-phen-yl)-1,5-di phenyl-formazan and the 3-(4-bromo-phen-yl)-1,5-di-phenyl-verdazyl radical and the crystal structure of the by-product 5-anilino-3-(4-bromo-phen-yl)-1-phenyl-1H 1,2,4-triazole. AB - The title compounds, C19H15BrN4, C20H16BrN4 and C20H15BrN4, are nitro-gen-rich organic compounds that are related by their synthesis. The verdazyl radical, in which stacking leads to anti-ferromagnetic inter-actions, was reported previously [Iwase et al. (2013 ?). Phys. Rev. B, 88, 184431]. For this compound, improved structural data and spectroscopic data are presented. The other two compounds have been crystallized for the first time and form stacks of dimers, roughly along the a-axis direction of the crystal. The formazan mol-ecule shows signs of rapid intra-molecular H-atom exchange typical for this class of compounds and spectroscopic data are provided in addition to the crystal structure. The triazole compound appears to be a side-product of the verdazyl synthesis. PMID- 29765710 TI - Design of new anti-Alzheimer drugs: ring-expansion synthesis and synchrotron X ray diffraction study of dimethyl 4-ethyl-11-fluoro-1,4,5,6,7,8-hexa-hydro azonino[5,6-b]indole-2,3-di-carboxyl-ate. AB - The title compound, C20H23FN2O4, is the product of a ring-expansion reaction from a seven-membered fluorinated hexa-hydro-azepine to a nine-membered azonine. The nine-membered azonine ring of the mol-ecule adopts a chair-boat conformation. The C=C and C-N bond lengths [1.366 (3) and 1.407 (3) A, respectively] indicate the presence of conjugation within the enamine CH2-C=C-N-CH2 fragment. The substituent planes at the C=C double bond of this fragment are twisted by 16.0 (3) degrees as a result of steric effects. The amine N(Et) N atom has a trigonal pyramidal configuration (sum of the bond angles = 346.3 degrees ). The inter planar angle between the two carboxyl-ate substituents is 60.39 (8) degrees . In the crystal, mol-ecules form zigzag chains along [010] by inter-molecular N-H?O hydrogen-bonding inter-actions, which are further packed in stacks toward [100]. The title azonino-indole might be considered as a candidate for the design of new Alzheimer drugs. PMID- 29765711 TI - Crystal structures and Hirshfeld surface analyses of bis-[N,N-bis-(2-meth-oxy-eth yl)di-thio-carbamato-kappa2S,S']di-n-butyl-tin(IV) and [N-(2-meth-oxy-eth-yl)-N methyl-dithio-carbamato-kappa2S,S']tri-phenyl-tin(IV). AB - The crystal and mol-ecular structures of the two title organotin di-thio carbamate compounds, [Sn(C4H9)2(C7H14NO2S2)2], (I), and [Sn(C6H5)3(C5H10NOS2)], (II), are described. Both structures feature asymmetrically bound di-thio carbamate ligands leading to a skew-trapezoidal bipyramidal geometry for the metal atom in (I) and a distorted tetra-hedral geometry in (II). The complete mol ecule of (I) is generated by a crystallographic twofold axis (Sn site symmetry 2). In the crystal of (I), mol-ecules self-assemble into a supra-molecular array parallel to (10-1) via methyl-ene-C-H?O(meth-oxy) inter-actions. In the crystal of (II), supra-molecular dimers are formed via pairs of weak phenyl-C-H?pi(phen yl) contacts. In each of (I) and (II), the specified assemblies connect into a three-dimensional architecture without directional inter-actions between them. Hirshfeld surface analyses confirm the importance of H?H contacts in the mol ecular packing of each of (I) and (II), and in the case of (I), highlight the importance of short meth-oxy-H?H(but-yl) contacts between layers. PMID- 29765712 TI - Crystal structure of hexa-kis-(dimethyl sulfoxide-kappaO)cobalt(II) bis-[tri chlorido-(quinoline-kappaN)cobaltate(II)]. AB - There are few reports that describe crystal structures of compounds containing cobalt complexed to either dimethyl sulfoxide (Me2SO) or quinoline (C9H7N). The title compound, [Co(C2H6OS)6][CoCl3(C9H7N)]2, is a cobalt salt in which the metal ion is complexed to both Me2SO and quinoline. In particular, we observed that anhydrous cobalt(II) chloride reacts with quinoline in Me2SO to form a salt that is to be formulated as [CoII(Me2SO)6]2+{[CoIICl3quinoline]2-}. The CoII atom in the cation portion of this mol-ecule lies on a inversion center and is bound to the O atoms of six Me2SO moieties in an octa-hedral configuration, while the CoII atom in the anion is attached to three chloride ligands and one quinoline moiety in a tetra-hedral arrangement. PMID- 29765714 TI - Synthesis, crystal structure and computational studies of a new Schiff base compound: (E)-4-bromo-2-eth-oxy-6-{[(2-meth-oxy-phen-yl)imino]meth-yl}phenol. AB - The title compound, C16H16BrNO3, which shows enol-imine tautomerism, crystallizes in the monoclinic P21/c space group. All non-H atoms of the mol-ecule are nearly coplanar, with a maximum deviation of 0.274 (3) A. In the crystal, mol-ecules are held together by weak C-H?O, pi-pi and C-H?pi inter-actions. The E/Z isomerism and enol/keto tautomerism energy barriers of the compound have been calculated by relaxed potential energy surface scan calculations with DFT methods. To observe the changes in the aromatic ring, HOMA aromaticity indexes were calculated during the scan process. Total energy and HOMA change curves were obtained to visualize results of the scan calculations. PMID- 29765713 TI - Different packing motifs of isomeric (E)-N'-(halo-phenyl-methyl-idene)-N-methyl-2 (thio-phen-2-yl)acetohydrazides controlled by C-H?O inter-actions. AB - The crystal structures of three isomeric (E)-N'-(chloro-phenyl-methyl-idene)-N methyl-2-(thio-phen-2-yl)acetohydrazides (C14H13ClN2OS) are described, with the Cl atom in ortho (I), meta (III) and para (IV) positions in the benzene ring. The ortho-bromo derivative (II) (C14H13BrN2OS), which is isostructural with its chloro congener (I), is also reported. Mol-ecules (I)-(III) have similar conformations, which approximate to l-shapes, as indicated by their N-C-C-Ct (t = thio-phene) torsion angles of -90.1 (3), -91.44 (18) and -90.7 (9) degrees , respectively. The conformation of (IV) is different, with an equivalent torsion angle of -170.75 (11) degrees corresponding to a more extended shape for the mol ecule. The thio-phene ring in each structure features 'flip' rotational disorder. The packing for (I) and (II) features inversion dimers, linked by pairs of C-H?O inter-actions, which generate R22(14) loops. In the crystal of (III), [010] C(8) chains arise, with adjacent mol-ecules linked by pairs of C-H?O hydrogen bonds. The packing for (IV) features unusually short C-H?O inter-actions arising from an H atom attached to the benzene ring (H?O = 2.18 A), which lead to C(9) [301] chains. Hirshfeld fingerprint percentage contact contributions are similar for the four title compounds. PMID- 29765715 TI - Crystal structure and Hirshfeld surface analysis of (E)-4-{[2-(4-hy-droxy-benzo yl)hydrazin-1-yl-idene]meth-yl}pyridin-1-ium nitrate. AB - The asymmetric unit of the title aroyl hydrazone Schiff base salt, C13H12N3O2+.N O3-, consists of one mol-ecular cation in the keto tautomeric form, adopting an E configuration with respect to the azomethine bond, and one nitrate anion. The two units are linked via an N-H?O hydrogen bond. The mol-ecule overall is non-planar, with the pyridinium and benzene rings being inclined to each other by 4.21 (4) degrees . In the crystal, cations and anions are linked via inter-molecular O-H?O and bifurcated N-H?O hydrogen bonds, forming a two-dimensional network parallel to (101). These networks are further linked by C-H?O hydrogen bonds, forming slabs parallel to (101). The slabs are linked by offset pi-pi inter-actions, involving the benzene and pyridinium rings of adjacent slabs [inter-centroid distance = 3.610 (2) A], forming a three-dimensional structure. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H?O/O?H (45.1%), H?H (19.3%), H?C/C?H (14.5%), H?N/N?H (7.9%) and C?C (6.0%) inter-actions. PMID- 29765716 TI - Synthesis and crystal structure of deca-carbon-yl(MU3-3,7-di-thia-nonane-1,9-di thiol-ato)bis-(MU2-propane-1,3-di-thiol-ato)nickel(II)tetra-iron(II) di-chloro methane disolvate. AB - The title compound,, [Fe4Ni(C3H6S2)2(C7H14S4)(CO)10].2CH2Cl2, is reported as a biomimic model for the active site of [FeFe]-hydrogenases. Bis(2-mercaptoeth-yl) 1,3-propane-dithio ether nickel(II) was firstly introduced into [Fe2(C3H6S2)(CO)5] as an S-containing ligand. It coordinates with two [Fe2(C3H6S2)(CO)5] groups, and a five-metal core complex is formed. The Fe2S2 core is in a butterfly conformation. The Fe-Fe distances in the [Fe2(C3H6S2)(CO)5] groups are 2.5126 (6) and 2.5086 (7) A. The distances between the adjacent Fe and Ni atoms are 3.5322 (1) and 3.5143 (1) A. There are intra molecular C-H?O and C-H?S contacts present in the complex. In the crystal, the five metal cores are linked via C-H?O hydrogen bonds, forming columns lying parallel to (110). The di-chloro-methane solvent mol-ecules are each partially disordered over two positions and only one is linked to the five-metal core complex by a C-H?O hydrogen bond. PMID- 29765717 TI - Crystal structures of (E)-1-naphthaldehyde oxime and (E)-phenanthrene-9 carbaldehyde oxime. AB - The aldoximes C11H9NO (I) and C15H11NO (II), synthesized in ca 90% yield, by treatment of 1-naphthaldehyde or phenanthrene-9-carbaldehyde, respectively, with hydroxyl-amine hydro-chloride and sodium carbonate, have been characterized by IR, 1H, 13C and DEPT-135 NMR spectroscopies, and also by single-crystal X-ray diffraction analysis. The mol-ecules of (I) and (II) are conformationally similar, with the aldoxime substituent groups lying outside the planes of the naphthalene or phenanthrene rings, forming dihedral angles with them of 23.9 (4) and 27.9 (6) degrees , respectively. The crystal structures of both (I) and (II) are similar with a single inter-molecular O-H?N hydrogen-bonding inter-action, giving rise to the formation of one-dimensional polymeric chains extending along the 21 (b) screw axes in each. PMID- 29765718 TI - Crystal structure of (E)-1,2-bis-(6-bromo-9-hexyl-9H-carbazol-3-yl)ethene. AB - The title compound, C38H40Br2N2, crystallizes in the triclinic space group P-1 with two mol-ecules in a unit cell. The two carbazole groups are nearly coplanar, making a dihedral angle of 16.90 (5) degrees , and are bridged by vinyl. The crystal structure features pi-pi and C-H?pi inter-actions and C-H?Br short contacts. PMID- 29765719 TI - 2,2'-Bipyridin-1'-ium 1-oxide bromide monohydrate. AB - The title compound 2,2'-bipyridin-1'-ium 1-oxide bromide crystallizes as a monohydrate, C10H9N2+.Br-.H2O. Structural disorder is observed due to the fact that protonation, as well as oxidation, of the N atoms of 2,2'-bi-pyridine occurs at either of the N atoms. The disorder extends to the remainder of the cation, with a refined occupancy rate of 0.717 (4) for the major moiety. An intra molecular N-H?O hydrogen bond forces the bi-pyridine unit into an s-cis conformation. Each pair of neighbouring 2,2'-bipyridin-1'-ium ions forms a dimeric aggregate by hydrogen bonds between their respective N-O and the N-H functions. These dimers and hydrogen-bonding inter-actions with bromide ions and the water mol-ecule give rise to a complex supra-molecular arrangement. PMID- 29765720 TI - Crystal structures of methyl 3,5-di-bromo-4-cyano-benzoate and methyl 3,5-di bromo-4-iso-cyano-benzoate. AB - The title crystals, C9H5Br2NO2, are the first reported 2,6-dihalophenyl cyanide isocyanide pair that have neither three- nor two-dimensional isomorphism. Both crystals contain contacts between the carbonyl O atom and a Br atom. In the crystal of the cyanide, R22(10) inversion dimers form based on C=N?Br contacts, a common packing feature in this series of crystals. In the isocyanide, the corresponding N=C?Br contacts are not observed. Instead, the iso-cyano C atom forms contacts with the meth-oxy C atom. RNC was refined as a two-component pseudo-merohedral twin. PMID- 29765721 TI - Crystal structure of dimethyl 1-oxo-2,4-di-phenyl-1,2-dihydronaphthalene-2,3-di carboxyl-ate. AB - In the title compound, C26H20O5, a 1,2-di-hydro-naphthalene derivative, the cyclo hexa-1,3-diene ring of the 1,2-di-hydro-naphthalene ring system adopts a half chair conformation. The mean plane of the 1,2-di-hydro-napthalene ring system makes dihedral angles of 86.23 (6) and 64.80 (7) degrees with two phenyl rings. The carbonyl O atom attached to the di-hydro-naphthalene ring system deviates from the mean plane of the 1,2-di-hydro-naphthalene ring system by 0.618 (1) A. In the crystal, the mol-ecules are linked into layers parallel to the bc plane via two kinds of C-H?O inter-actions, one of which forms a C(10) chain motif running along the c-axis direction and the other forms an R22(6) ring motif. Adjacent layers are further connected by C-H?pi and offset pi-pi inter-actions [centroid-centroid distance = 3.6318 (9) A]. PMID- 29765722 TI - Synthesis and crystal structures of (2E)-1,4-bis-(4-chloro-phen-yl)but-2-ene-1,4 dione and (2E)-1,4-bis-(4-bromo-phen-yl)but-2-ene-1,4-dione. AB - The mol-ecular structure of (2E)-1,4-bis-(4-chloro-phen-yl)but-2-ene-1,4-dione [C16H10Cl2O2, (1)] is composed of two p-chlorophenyl rings, each bonded on opposite ends to a near planar 1,4-trans enedione moiety [-C(=O)-CH=CH-(C=O)-] [r.m.s. deviation = 0.003 (1) A]. (2E)-1,4-Bis(4-bromo-phen-yl)but-2-ene-1,4 dione [C16H10Br2O2, (2)] has a similar structure to (1), but with two p bromophenyl rings and a less planar enedione group [r.m.s. deviation = 0.011 (1) A]. Both mol-ecules sit on a center of inversion, thus Z' = 0.5. The dihedral angles between the ring and the enedione group are 16.61 (8) and 15.58 (11) degrees for (1) and (2), respectively. In the crystal, mol-ecules of (1) exhibit C-Cl?Cl type I inter-actions, whereas mol-ecules of (2) present C-Br?Br type II inter-actions. van der Waals-type inter-actions contribute to the packing of both mol-ecules, and the packing reveals face-to-face ring stacking with similar inter planar distances of approximately 3.53 A. PMID- 29765723 TI - Two CuII complexes of 3,4,5-tri-methyl-1H-pyrazole. AB - The crystal structure of complexes of 3,4,5-tri-methyl-1H-pyrazole with CuCl2.2H2O and Cu(NO3)2.2.5H2O are presented, namely di-MU-chlorido bis[chloridobis(3,4,5-trimethyl-1H-pyrazole-kappaN2)copper(II)], [Cu2Cl4(C6H10N2)4] (1) and aquatetrakis(3,4,5-trimethyl-1H-pyrazole kappaN2)copper(II) dinitrate, [Cu(C6H10N2)4(H2O)](NO3)2 (2), and compared to the previously determined structures for 3-methyl-1H-pyrazole and 3,5-di-methyl-1H pyrazole. CuCl2 forms a 2:1 ligand-to-metal chloride-bridged complex with 3,4,5 tri-methyl-1H-pyrazole, with a square-pyramidal coordination geometry about each copper(II) center. Similarly to the previously obtained 3,5-di-methyl-1H-pyrazole complex with CuCl2, the pyrazole ligands are cis to each other, with two chloride ions bridging the two copper(II) centers, and a terminal chloride ion occupying the axial position. Cu(NO3)2 forms a 4:1 ligand-to-metal complex with 3,4,5-tri methyl-1H-pyrazole that is also arranged in a square-pyramidal geometry about CuII. The newly obtained copper(II) complex has the same coordination geometry as the 3,5-di-methyl-1H-pyrazole complex, including an axial water mol-ecule, two nitrate ions hydrogen-bonded to the water mol-ecule, and four pyrazole ligands in the equatorial plane, suggesting that similar steric forces are at play in the formation of these complexes. PMID- 29765724 TI - Crystal structures of two 2,3-diaryl-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-ones. AB - The syntheses and crystal structures of 2,3-bis-[3-(tri-fluoro-meth-yl)phen-yl] 2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-m-CF3; C22H13F6NOS) (1) and 2,3-bis (4-methyl-phen-yl)-2,3-di-hydro-4H-1,3-benzo-thia-zin-4-one (di-p-CH3; C22H19NOS) (2) are reported. Each structure is racemic: the asymmetric unit of 2 consists of two mol-ecules. In both 1 and 2, the six-membered 1,3-thia-zine ring is close to an envelope conformation with the chiral C atom forming the flap. In 1, the 2 aryl group is pseudo-equatorial, while in 2 it is pseudo-axial. In 1, the pendant aryl rings form a V shape with an inter-centroid distance of 3.938 (3) A and an acute dihedral angle of 48.3 (2) degrees between them. Both CF3 groups are disordered over two orientations in 0.687 (19):0.313 (19) and 0.667 (16):0.33 (16) ratios. In each of the independent mol-ecules of 2, the aryl rings are almost orthogonal to each other [dihedral angles = 85.50 (12) and 86.07 (11) degrees ]. In both structures, the chiral C atom and the O atoms participate in C H?O-type hydrogen bonding between symmetry-related mol-ecules of 1 or the independent enanti-omers in 2, forming chains along the c-axis direction in 1 and the b-axis direction in 2. Additionally, in 1, pi-pi contacts of both face-to face and edge-to-face type, as well as pi-H?O and pi-H?F inter-actions are observed. In 2, a racemic mixture of mol-ecules forms layers in the ac plane linked by weak pi-pi and C-H?pi inter-actions. PMID- 29765725 TI - Crystal structure and Hirshfeld surface analysis of 7-eth-oxy-5-methyl-2-(pyridin 3-yl)-11,12-di-hydro-5,11-methano-[1,2,4]triazolo[1,5-c][1,3,5]benzoxadiazo-cine. AB - The title compound, C19H19N5O2, was prepared by the reaction of 3-amino-5 (pyridin-3-yl)-1,2,4-triazole with acetone and 2-hy-droxy-3-eth-oxy-benzaldehyde. It crystallizes from ethanol in a tetra-gonal space group, with one mol-ecule in the asymmetric unit. The 1,2,4-triazole five-membered ring is planar (maximum deviation = 0.0028 A). The pyridine and phenyl rings are also planar with maximum deviations of 0.0091 and 0.0094 A, respectively. In the crystal, N-H?N hydrogen bonds link the mol-ecules into supra-molecular chains propagating along the c axis direction. Hirshfeld surface analysis and two-dimensional fingerprint plots have been used to analyse the inter-molecular inter-actions present in the crystal. PMID- 29765726 TI - (4-Nitro-phen-yl)methyl 2,3-di-hydro-1H-pyrrole-1-carboxyl-ate: crystal structure and Hirshfeld analysis. AB - In the title compound, C12H12N2O4, the di-hydro-pyrrole ring is almost planar (r.m.s. deviation = 0.0049 A) and is nearly coplanar with the adjacent C2O2 residue [dihedral angle = 4.56 (9) degrees ], which links to the 4-nitro-benzene substituent [dihedral angle = 4.58 (8) degrees ]. The mol-ecule is concave, with the outer rings lying to the same side of the central C2O2 residue and being inclined to each other [dihedral angle = 8.30 (7) degrees ]. In the crystal, supra-molecular layers parallel to (10-5) are sustained by nitro-benzene-C H?O(carbon-yl) and pyrrole-C-H?O(nitro) inter-actions. The layers are connected into a three-dimensional architecture by pi(pyrrole)-pi(nitro-benzene) stacking [inter-centroid separation = 3.7414 (10) A] and nitro-O?pi(pyrrole) inter actions. PMID- 29765727 TI - Reinvestigation of the crystal structure of N-(4-chloro-benzyl-idene)-2-hy-droxy aniline: a three-dimensional structure containing O-H?N, O-H?O and C-H?pi(arene) hydrogen bonds. AB - The mol-ecule of the title compound, C13H10ClNO, (I), which contains an intra molecular O-H?N hydrogen bond, is almost planar: the dihedral angle between the two aryl rings is only 3.31 (9) degrees . The mol-ecules of (I) are linked into sheets by two C-H?pi(arene) hydrogen bonds and the sheets are linked into a three dimensional structure by O-H?O hydrogen bonds. Comparisons are made with the structures of a number of related compounds. PMID- 29765728 TI - Different mol-ecular conformations in the crystal structures of three 5-nitro imidazolyl derivatives. AB - The crystal structures of (E)-1-methyl-5-nitro-1H-imidazole-2-carbaldehyde O benzyl-oxime, C12H12N4O3, (I), (E)-1-methyl-5-nitro-1H-imidazole-2-carb-alde-hyde O-(4-fluoro-benz-yl) oxime, C12H11FN4O3, (II), and (E)-1-methyl-5-nitro-1H imidazole-2-carbaldehyde O-(4-bromo-benz-yl) oxime, C12H11BrN4O3, (III), are described. The dihedral angle between the ring systems in (I) is 49.66 (5) degrees and the linking Nm-C-C=N (m = methyl-ated) bond shows an anti conformation [torsion angle = 175.00 (15) degrees ]. Compounds (II) and (III) are isostructural [dihedral angle between the aromatic rings = 8.31 (5) degrees in (II) and 5.34 (15) degrees in (III)] and differ from (I) in showing a near-syn conformation for the Nm-C-C=N linker [torsion angles for (II) and (III) = 17.64 (18) and 8.7 (5) degrees , respectively], which allows for the occurrence of a short intra-molecular C-H?N contact. In the crystal of (I), C-H?N hydrogen bonds link the mol-ecules into [010] chains, which are cross-linked by very weak C-H?O bonds into (100) sheets. Weak aromatic pi-pi stacking inter-actions occur between the sheets. The extended structures of (II) and (III) feature several C-H?N and C H?O hydrogen bonds, which link the mol-ecules into three-dimensional networks, which are consolidated by aromatic pi-pi stacking inter-actions. Conformational energy calculations and Hirshfeld fingerprint analyses for (I), (II) and (III) are presented and discussed. PMID- 29765729 TI - Crystal structure and Hirshfeld surface analysis of the naturally occurring cassane-type diterpenoid, 6beta-cinnamoyl-7beta-hy-droxy-vouacapen-5alpha-ol. AB - The title compound, C29H36O5, a cassane-type diterpenoid {systematic name: (4aR,5R,6R,6aS,7R,11aS,11bR)-4a,6-dihy-droxy-4,4,7,11b-tetra-methyl 1,2,3,4,4a,5,6,6a,7,11,11a,11b-dodeca-hydro-phenanthro[3,2-b]furan-5-yl 3-phenyl prop-2-enoate}, was isolated from a medicinally important plant, Caesalpinia pulcherrima (Fabaceae). In the mol-ecule, three cyclo-hexane rings are trans fused and adopt chair, chair and half-chair conformations. In the crystal, mol ecules are linked via O-H?O hydrogen bonds, forming a tape structure along the b axis direction. The tapes are further linked into a double-tape structure through C-H?pi inter-actions. The Hirshfeld surface analysis indicates that the contributions to the crystal packing are H?H (65.5%), C?H (18.7%), O?H (14.5%) and C?O (0.3%). PMID- 29765730 TI - Synthesis and structure of an aryl-tellurenium(II) cation; [4-tert-butyl-2,6-bis (1-pentyl-1H-benz-imidazol-2-yl-kappaN3)phenyl-kappaC1]tellurium(II) (1,4 dioxane)tri-iodido-mercurate(II). AB - In the title salt, (C34H41N4Te)[HgI3(C4H8O2)], the aryl-tellurenium [C34H41N4Te]+ cations and [HgI3(dioxane)]- anions are linked by a short inter-action between the Te atom and one of the I-atom donors of the anion, as well as through weak C H?I inter-actions. The geometry around the Te atom is T-shaped with the coordination comprising a C atom of the central aromatic ring and two N atom donors of the benzimidazolyl moiety. The Te-N bond lengths are almost equal [2.232 (3) and 2.244 (3) A], while the Te-C bond length is 2.071 (4) A. The N-Te N bond angle is 150.68 (11) degrees . The HgII atom of the anion is coordinated by iodide ions from three sides and the fourth coordination site is occupied by an O atom of the solvent mol-ecule (dioxane). Thus, it attains a trigonal pyrimidal geometry, with O-Hg-I angles ranging of 90.76 (8) and 96.76 (7) degrees and I-Hg-I angles ranging from 112.41 (1) to 125.10 (1) degrees . The cations and anions are involved in numerous weak pi-pi stacking inter-actions involving both the central phenyl ring and two inversion-related benzimidazole moieties, which propagate in the a-axis direction. In addition, there are numerous C-H?I inter-actions between the cations and anions, which link them into a complex three-dimensional array. PMID- 29765731 TI - Crystal structure and Hirshfeld surface analysis of (E)-4-chloro-N-{2-[2-(4-nitro benzyl-idene)hydrazin-1-yl]-2-oxoeth-yl}benzene-sulfonamide N,N-di-methyl formamide monosolvate. AB - The asymmetric unit of the title compound, C15H13ClN4O5S.C3H7NO, contains one mol ecule each of the Schiff base and the solvent di-methyl-formamide. The hydrazone group adopts an E configuration about the C=N bond. The dihedral angle between the two aromatic rings is 86.58 (2) degrees . In the crystal, pairs of N-H?O hydrogen bonds between centrosymmetrically related mol-ecules generates rings with an R22(10) graph-set motif. The dimers are further linked via N-H?O and C H?O hydrogen bonds, leading to the formation of R33(11) ring motifs. C-H?pi inter actions are also observed. The inter-molecular inter-actions in the crystal structure were qu-anti-fied and analysed using Hirshfeld surface analysis, which indicates that the most significant contacts in packing are O?H/H?O (31.3%), followed by H?H (25.4%) and C?H/H?C (13.0%). PMID- 29765734 TI - Crystal structure and DFT study of (E)-4-[({4-[(pyri-din-2-yl-methyl-idene)amino] phen-yl}amino)-meth-yl]phenol. AB - In the title Schiff base compound, C19H17N3O, the configuration about the C=N bond is E. The mol-ecule is non-planar, with the phenolic and pyridine rings being inclined to the central benzene ring by 56.59 (4) and 15.13 (14) degrees , respectively. In the crystal, mol-ecules are linked by pairs of O-H?N hydrogen bonds, forming inversion dimers. The dimers are connected to neighbouring dimers by N-H?O hydrogen bonds and C-H?pi inter-actions, forming layers parallel to the bc plane. The layers are linked by offset pi-pi inter-actions [inter-centroid distance = 3.779 (2) A], forming a three-dimensional supra-molecular structure. Quantum chemical calculations of the mol-ecule are in good agreement with the solid-state structure. PMID- 29765733 TI - Elaboration, structural study and validation of a new NASICON-type structure, Na0.72(Cr0.48,Al1.52)(Mo2.77,Al0.23)O12. AB - The title compound, sodium chromium/aluminium molybdenum/aluminium dodeca-oxide, Na0.72Cr0.48Al1.74Mo2.77O12, was prepared by solid-state reaction. Its crystal structure is related to NaSICON-type compounds. The framework is built up from M1O6 (M1 = Cr/Al) octa-hedra and M2O4 (M2 = Mo/Al) tetra-hedra inter-connected by corners. The three-dimensional framework contains cavities in which sodium cations are located. Two validation models (BVS and CHARDI) were used to confirm the proposed structural model. The mobility of Na+ ions in the structure has been investigated by theoretical means. PMID- 29765732 TI - Crystal structure and conformational analysis of doxorubicin nitrate. AB - Crystal structure determination of doxorubicin nitrate, (DoxH)NO3, systematic name (7S,9S)-7-{[(2R,4S,5S,6S)-4-azaniumyl-5-hy-droxy-6-methyl-oxan-2-yl]-oxy} 6,9,11-trihy-droxy-9-(2-hy-droxy-acet-yl)-4-meth-oxy-8,10-di-hydro-7H-tetra-cen 5,12-dione nitrate, shows two formula units present in the asymmetric unit. In the crystal lattice, hydrogen-bonded pairs of (DoxH+) cations and segregation of the aglycone and sugar moieties are observed. Inspection of mol-ecular overlays reveals that the conformation of (DoxH)NO3 resembles that of DNA-inter-calated, but not of protein-docked (DoxH)+. The structure was refined as a two-component twin. PMID- 29765735 TI - (1R,2S,5R)-5-Methyl-2-[2-(4-nitro-phen-yl)propan-2-yl]cyclo-hexyl 2-(4-meth-oxy phen-yl)-2,5-di-hydro-1H-pyrrole-1-carboxyl-ate: crystal structure and Hirshfeld analysis. AB - In the title compound, C28H34N2O5, the adjacent ester and nitro-benzene substituents are connected via an intra-molecular methyl-ene-C-H?pi(nitrobenzene) inter-action and the mol-ecule approximates to a U-shape. The di-hydro-pyrrole ring (r.m.s. deviation = 0.003 A) is almost co-planar with the carboxyl-ate residue [Cm-N-C1-Oc (m = methine, c = carbox-yl) torsion angle = 1.8 (4) degrees ] but is orthogonal to the 4-meth-oxy-benzene ring [dihedral angle = 84.34 (17) degrees ]. In the crystal, methyl-ene-C-H?O(carbon-yl) inter-actions lead to linear supra-molecular chains along the b-axis direction, which pack without directional inter-actions between them. The analysis of the calculated Hirshfeld surface points to the importance of weak inter-atomic H?H, O?H/H?O and C?H/H?C contacts in the crystal. PMID- 29765736 TI - Crystal structure of 2-isopropyl-4-meth-oxy-5-methyl-phenyl 4-methyl-benzene sulfonate. AB - The title compound, C18H22O4S, an hemisynthetic product, was obtained by the tosyl-ation reaction of the naturally occurring meroterpene p-meth-oxy-thymol. The mol-ecule comprises a tetra-substitued phenyl ring linked to a toluene sulfonate through one of its O atoms. In the crystal, C-H?O and C-H?pi inter actions link the mol-ecules, forming a three-dimensional network. PMID- 29765737 TI - Crystal structure and Hirshfeld surface analysis of di-aqua-bis-(N,N-di-ethyl nicotinamide-kappaN1)bis-(2,4,6-tri-methyl-benzoato-kappaO)manganese(II). AB - In the title centrosymmetric complex, [Mn(C10H11O2)2(C10H14N2O)2(H2O)2], the MnII cation is located on an inversion centre. The four O atoms form a slightly distorted square-planar arrangement around the MnII cation, and the distorted octa-hedral coordination is completed by two pyridine N atoms at distances of 2.3289 (15) A. The dihedral angle between the planar carboxyl-ate group and the adjacent benzene ring is 87.73 (16) degrees , while the benzene and pyridine rings are oriented at a dihedral angle of 43.03 (8) degrees . In the crystal, the water mol-ecules are involved in both intra-molecular (to the non-coordinating carboxyl-ate O atom) and inter-molecular (to the amide carbonyl O atom) O-H?O hydrogen bonds. The latter lead to the formation of layers parallel to (100). These layers are further linked via weak C-H?O hydrogen bonds, resulting in a three-dimensional supra-molecular network. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H?H (70.0%), H?O/O?H (15.5%) and H?C/C?H (14.0%) inter-actions. One of the ethyl groups of the di-ethyl-nicotinamide ligand is disordered over two sets of sites, with an occupancy ratio of 0.282 (10):0.718 (10). PMID- 29765738 TI - Crystal structure and Hirshfeld analysis of trans-bis-(5-fluoro-indoline-2,3 dione 3-oximato-kappa2O2,N3)-trans-bis-(pyridine-kappaN)copper(II). AB - The reaction in methanol of CuII acetate monohydrate with 5-fluoro-isatin 3-oxime deprotonated with KOH in a 1:2 molar ratio and recrystallization from pyridine yielded the title compound, [Cu(C8H4FN2O2)2(C5H5N)2]. In the centrosymmetric complex, the anionic form of the isatin oxime acts as a kappa2N,O donor, building five-membered metallarings. The CuII cation is sixfold coordinated in a slightly distorted octa-hedral environment by two trans, equatorial, anionic isatin derivatives and two trans pyridine ligands in axial positions. The complexes are linked by hydrogen bonding into a three-dimensional network, which is also stabilized by pi-pi stacking inter-actions [centroid-to-centroid distance = 3.7352 (9) A] and C-H?pi contacts. The Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H?H (31.80%), H?C (24.30%), H?O (15.20%) and H?F (10.80%). This work is the second report in the literature of a crystal structure of a coordination compound with isatin 3-oxime ligands (coordination chemistry). PMID- 29765739 TI - Crystal structure of catena-poly[[di-iodidomer-cury(II)]-MU-2,2'-di-thio-bis (pyridine N-oxide)-kappa2O:O']. AB - The title compound, [HgI2(C10H8N2O2S2)] n , a one-dimensional coordination polymer with HgI2 units and 2,2'-di-thio-bis-(pyridine N-oxide) spacer ligands in an alternating fashion, forms helical chains running along the b axis in the crystal. Within a single coordination polymer strand, the axially chiral 2,2'-di thio-bis-(pyridine N-oxide) ligands are homochiral, but the enanti-omeric conformation is present in adjacent strands. Within a coordination polymer strand, the iodido ligands point towards the centroids of the aromatic rings of the pyridine N-oxide moieties in the coordination sphere of HgII. Moreover, intra strand C-H?O and C-H?I inter-actions, and inter-strand short S?I and S?O contacts are observed. PMID- 29765740 TI - Crystal structure and Hirshfeld surface analysis of bis-(2,6-di-amino-pyridinium) tetra-chlorido-cobaltate(II). AB - In the title mol-ecular salt, (C5H8N3)2[CoCl4], the cations are protonated at their pyridine N atoms and the anion is an almost regular tetra-hedron. The crystal structure consists of alternating inorganic layers, built from tetra chlorido-cobaltate anions, and organic layers formed by protonated cations of 2,6 di-amino-pyridinium. The crystal packing is governed by C/N-H?Cl hydrogen-bonding inter-actions between the organic and the inorganic ions and Cl?Cl inter-actions. Moreover, the cations show a pi-pi stacking inter-action [inter-centroid distance = 3.763 (2) A]. The prevalence of these inter-actions is illustrated by an analysis of the three-dimensional Hirshfeld surface and by two-dimensional fingerprint plots. PMID- 29765741 TI - Crystal structure and Hirshfeld surface analysis of 3-cyano-phenyl-boronic acid. AB - In the title compound, C7H6BNO2, the mean plane of the -B(OH)2 group is twisted by 21.28 (6) degrees relative to the cyano-phenyl ring mean plane. In the crystal, mol-ecules are linked by O-H?O and O-H?N hydrogen bonds, forming chains propagating along the [101] direction. Offset pi-pi and B?pi stacking inter actions link the chains, forming a three-dimensional network. Hirshfeld surface analysis shows that van der Waals inter-actions constitute a further major contribution to the inter-molecular inter-actions, with H?H contacts accounting for 25.8% of the surface. PMID- 29765742 TI - Crystal structure of diaphorin methanol monosolvate isolated from Diaphorina citri Kuwayama, the insect vector of citrus greening disease. AB - The title compound C22H39NO9.CH3OH [systematic name: (S)-N-((S)-{(2S,4R,6R)-6 [(S)-2,3-di-hydroxy-prop-yl]-4-hy-droxy-5,5-di-methyl-tetra-hydro-2H-pyran-2 yl}(hy-droxy)meth-yl)-2-hy-droxy-2-[(2R,5R,6R)-2-meth-oxy-5,6-dimeth-yl-4-methyl ene-tetra-hydro-2H-pyran-2-yl]acetamide methanol monosolvate], was isolated from the Asian citrus psyllid, Diaphorina citri Kuwayama, and crystallizes in the space group P21. 'Candidatus Profftella armatura' a bacterial endosymbiont of D. citri, biosynthesizes diaphorin, which is a hybrid polyketide-nonribosomal peptide comprising two highly substituted tetra-hydro-pyran rings joined by an N acyl aminal bridge [Nakabachi et al. (2013 ?). Curr. Biol.23, 1478-1484]. The crystal structure of the title compound establishes the complete relative configuration of diaphorin, which agrees at all nine chiral centers with the structure of the methanol monosolvate of the di-p-bromo-benzoate derivative of pederin, a biogenically related compound whose crystal structure was reported previously [Furusaki et al. (1968 ?). Tetra-hedron Lett.9, 6301-6304]. Thus, the absolute configuration of diaphorin is proposed by analogy to that of pederin. PMID- 29765743 TI - Crystal structure of aqua-chlorido-(nitrato-kappa2O,O')[1-(pyridin-2-yl-kappaN)-2 (pyridin-2-yl-methyl-idene-kappaN)hydrazine-kappaN2]manganase(II). AB - The search for novel manganese(II) compounds having inter-esting magnetic properties, using 1-(pyridin-2-yl)-2-(pyridin-2-yl-methyl-idene)hydrazine (HL) as a tridendate ligand, led to the preparation of the title mononuclear material, [MnCl(NO3)(C11H10N4)(H2O)], and the determination of its structure by XRD. The asymmetric unit comprises a discrete mol-ecule in which the cation MnII is hepta coordinated. The environment around the cation is an almost perfect penta-gonal bipyramid. The base is defined by the two N atoms of the pyridine rings, the N atom of the imino function of the ligand and the two O atoms of the chelating bidentate nitrate ligand. The apical positions are occupied by a Cl atom and a water mol-ecule. In the crystal, there are numerous hydrogen bonds of the types Ow-H?ONO2 and C-H?ONO2, which generate layers parallel to the bc plane in which the ligands in the axial positions point into the inter-layer space. These axial ligands give rise to hydrogen bonds of the types Ow-H?ONO2, Ow-H?Cl, N-H?Cl and C H?Cl, leading to a three-dimensional framework. The chain bridging the two pyridine rings is disordered over two sets of sites in a 0.53 (2):0.47 (2) ratio. PMID- 29765744 TI - Spontaneous resolution and crystal structure of (2S)-2-(3-nitro-phen-yl)-3-phenyl 2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one; crystal structure of rac-2-(4-nitro phen-yl)-3-phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one. AB - The crystal structures of isomeric rac-2-(4-nitro-phen-yl)-3-phenyl-2,3,5,6-tetra hydro-4H-1,3-thia-zin-4-one (C16H14N2O3S) (1) and (2S)-2-(3-nitro-phen-yl)-3 phenyl-2,3,5,6-tetra-hydro-4H-1,3-thia-zin-4-one (C16H14N2O3S) (2) are reported here. While 1 crystallizes in a centrosymmetric space group, the crystal of 2 chosen for data collection has mol-ecules only with (2S) chirality. This is the result of spontaneous resolution during crystallization, as the synthesis produces a racemic mixture. A crystal with (2R) mol-ecules was also found in the same crystallization vial (structure factors available). The six-membered thia zine ring in both 1 and 2 displays an envelope conformation with the S atom forming the flap. The aryl rings in both structures adopt an approximate V shape with angles between their planes of 46.97 (14) degrees in 1 and 58.37 (10) degrees in 2. In both structures, the mol-ecules form layers in the ab plane. Within such a layer in 1, one of the O atoms of the nitro-phenyl group accepts a C-H?O hydrogen bond from the CH group at position 5 of the thia-zine ring of a mol-ecule of opposite chirality, forming chains along the a-axis direction. Each of the thia-zine rings also participate in C-H?O bonds with the same carbon atom as above, resulting in chains along the b-axis direction, albeit of monochiral type. Adjacent layers are consolidated along the c-axis direction by pairs of parallel hydrogen bonds (C-H?O type) between the nitro-phenyl groups of enanti omers. In 2, the two C-H?O hydrogen bonds contribute to chain formation along the b-axis direction. Weak edge-to-face inter-actions between the aryl groups of neighbouring mol-ecules in 1, and C-H?pi inter-actions between a thia-zine ring CH group and a phenyl group of a neighboring mol-ecule in 2 are also observed. PMID- 29765745 TI - Crystal structure of 2-oxopyrrolidin-3-yl 4-(2-phenyl-diazen-1-yl)benzoate. AB - In the title compound, C17H15N3O3, the plane of the pyrrolidone ring is inclined at an angle of 59.791 (2) degrees to that of the azo-benzene segment, which adopts a configuration close to planar. In the crystal, mol-ecules are oriented pairwise by (2-oxopyrrolidin-3-yl)-oxy moieties at an angle of 76.257 (3) degrees , linked by hydrogen bonds and pi-stacking inter-actions, forming zigzag supra molecular chains parallel to [010] further linked via additional C-H?pi inter actions. PMID- 29765746 TI - Crystal structure of [2,13-bis-(acetamido)-5,16-dimethyl-2,6,13,17-tetra-aza-tri cyclo-[16.4.0.07,12]docosane-kappa4N]silver(II) dinitrate from synchrotron X-ray data. AB - The asymmetric unit of the title compound, [Ag(C24H46N6O2)](NO3)2 [C24H46N6O2 is (5,16-dimethyl-2,6,13,17-tetra-aza-tri-cyclo-[16.4.0.07,12]docosane-2,13-di yl)diacetamide, L], consists of one independent half of the [Ag(C24H46N6O2)]2+ cation and one nitrate anion. The Ag atom, lying on an inversion centre, has a square-planar geometry and the complex adopts a stable trans-III conformation. Inter-estingly, the two O atoms of the pendant acetamide groups are not coordinated to the AgII ion. The longer distance of 2.227 (2) A for Ag N(tertiary) compared to 2.134 (2) A for Ag-N(secondary) may be due to the effects of the attached acetamide group on the tertiary N atom. Two nitrate anions are very weakly bound to the AgII ion in the axial sites and are further connected to the ligand of the cation by N-H?O hydrogen bonds. The crystal packing is stabilized by hydrogen-bonding inter-actions among the N-H donor groups of the macrocycle and its actetamide substituents, and the O atoms of the nitrate anions and of an acetamide group as the acceptor atoms. PMID- 29765747 TI - Crystal structure of (20S)-21-[4-(2-hy-droxy-propan-2-yl)-1H-1,2,3-triazol-4-yl] 20-(4-methyl-pent-yl)-5-pregnen-3beta-ol with an unknown solvate. AB - In the title cholesterol analogue, [systematic name: (3S,8S,9S,10R,13S,14S,17R) 17-{(S)-1-[4-(2-hy-droxy-propan-2-yl)-1H-1,2,3-triazol-1-yl]-6-methyl-heptan-2 yl}-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetra-deca-hydro-1H-cyclo penta-[a]phenanthren-3-ol] C32H53N3O2, a new chain, including an inter-mediate triazole and a tertiary hydroxyl group in the terminal position, has been added at position 20 inducing a change in its stereochemistry. In the crystal, mol ecules are linked by O-H?O and O-H?N hydrogen bonds, forming layers lying parallel to (-201) and enclosing R44(36) ring motifs. The isopropyl group is disordered about two positions with a refined occupancy ratio of 0.763 (5):0.237 (5). A region of disordered electron density was corrected for using the SQUEEZE routine in PLATON (Spek (2015). Acta Cryst. C71, 9-18). The given chemical formula and other crystal data do not take into account the unknown solvent mol ecule(s). PMID- 29765748 TI - Crystal structure of (2-{[(8-aminona-phthalen-1-yl)imino]-meth-yl}-4,6-di-tert butyl-phenolato-kappa3N,N',O)bromido-nickel(II). AB - The title compound, [NiBr(C25H29N2O)], contains an NiII atom with a slightly distorted square-planar coordination environment defined by one O and two N atoms from the 2-{[(8-aminona-phthalen-1-yl)imino]-meth-yl}-4,6-di-tert-butyl-phenolate ligand and a bromide anion. The Ni-O and Ni-N bond lengths are slightly longer than those observed in the phenyl backbone counterpart, which can be attributed to the larger steric hindrance of the naphthyl group in the structure of the title compound. The mol-ecule as a whole is substanti-ally distorted, with both the planar naphthalene-1,8-di-amine and imino-meth-yl-phenolate substitutents rotated against the NiN2OBr plane by 38.92 (7) and 37.22 (8) degrees , respectively, giving the mol-ecule a twisted appearance. N-H?Br hydrogen bonds and N-H?C(pi) contacts connect the mol-ecules into dimers, and additional C-H?Br contacts, C-H?pi inter-actions, and an offset stacking inter-action between naphthyl units inter-connect these dimers into a three-dimensional network. PMID- 29765749 TI - Naloxegol hydrogen oxalate displaying a hydrogen-bonded layer structure. AB - In the salt (5alpha,6alpha)-6-[(2,5,8,11,14,17,20-hepta-oxadocosan-22-yl)-oxy] 3,14-dihy-droxy-17-(prop-2-en-1-yl)-4,5-ep-oxy-morphinan-17-ium hydrogen oxalate, C34H54NO11+.C2HO4- the polyether unit of the naloxegol cation adopts the shape of a squashed open letter 'O'. In the crystal, the hydrogen oxalate anions are linked into a chain by O-H?O hydrogen bonds. Each naloxegol unit is hydrogen bonded to three hydrogen oxalate ions via two O-H?O and one N-H?O inter-actions. The resulting hydrogen-bonded two-dimensional layer structure is 3,5-connected and has the 3,5 L50 topology. PMID- 29765750 TI - Crystal structures and anti-oxidant capacity of (E)-5-benz-yloxy-2-{[(4-chloro phen-yl)imino]-meth-yl}phenol and (E)-5-benz-yloxy-2-({[2-(1H-indol-3-yl)eth yl]iminium-yl}meth-yl)phenolate. AB - The title Schiff base compounds, C20H16ClNO2 (I) and C24H22N2O2 (II), were synthesized via the condensation reaction of 2-amino-4-chloro-phenol for (I), and 2-(2,3-di-hydro-1H-indol-3-yl)ethan-1-amine for (II), with 4-benz-yloxy-2-hy droxy-benzaldehyde. In both compounds, the configuration about the C=N imine bond is E. Neither mol-ecule is planar. In (I), the central benzene ring makes dihedral angles of 49.91 (12) and 53.52 (11) degrees with the outer phenyl and chloro-phenyl rings, respectively. In (II), the central benzene ring makes dihedral angles of 89.59 (9) and 72.27 (7) degrees , respectively, with the outer phenyl ring and the mean plane of the indole ring system (r.m.s. deviation = 0.011 A). In both compounds there is an intra-molecular hydrogen bond forming an S(6) ring motif; an O-H?O hydrogen bond in (I), but a charge-assisted N+-H?O- hydrogen bond in (II). In the crystal of (I), mol-ecules are linked by C-H?pi inter-actions, forming slabs parallel to plane (001). In the crystal of (II), mol ecules are linked by pairs of N-H?O hydrogen bonds, forming inversion dimers. The dimers are linked by C-H?O hydrogen bonds, C-H?pi inter-actions and a weak N-H?pi inter-action, forming columns propagating along the a-axis direction. The anti oxidant capacity of the synthesized compounds was determined by cupric reducing anti-oxidant capacity (CUPRAC) for compound (I) and by 2,2-picrylhydrazyl hydrate (DPPH) for compound (II). PMID- 29765751 TI - Crystal structures of two new 3-(2-chloro-eth-yl)-r(2),c(6)-diarylpiperidin-4 ones. AB - The syntheses and crystal structures of 3-(2-chloro-eth-yl)-r-2,c-6-di-phenyl piperidin-4-one, C19H20ClNO, (I), and 3-(2-chloro-eth-yl)-r-2,c-6-bis-(4-fluoro phen-yl)piperidin-4-one, C19H18ClF2NO, (II), are described. The piperidone ring adopts a chair conformation in (I), whereas a slightly distorted chair conformation is formed in (II). The dihedral angle between the mean plane of the phenyl rings is 59.1 (1) degrees in (I) and 76.1 (1) degrees in (II). The crystal packing features weak inter-molecular N-H?O hydrogen bonds in each structure. PMID- 29765752 TI - Synthesis, crystal structure and catalytic activity in reductive amination of di chlorido-(eta6-p-cymene)(2'-di-cyclo-hexyl-phosphanyl-2,6-di-meth-oxy-biphen-yl kappaP)ruthenium(II). AB - The title compound, [RuCl2(C10H14)(C26H35O2P)] (I), crystallizes in the monoclinic space group P21/c with two crystallographically independent mol-ecules (A and B) in the asymmetric unit. The geometries of both mol-ecules are very similar and distinguished only by the twist angles of the two benzene rings in the phosphine substituents [89.54 (14) and 78.36 (14) degrees for mol-ecules A and B, respectively]. The Ru atoms have classical pseudo-tetra-hedral piano-stool coordination environments. The conformation of each mol-ecule is stabilized by intra-molecular C-H?O and C-H?Cl hydrogen bonds and C-H?pi inter-actions. The two mol-ecules are linked by a C-H?Cl hydrogen bond. In the crystal, the mol-ecules are further linked by C-H? pi inter-actions, forming -A-B-A-B- chains propagating along the a-axis direction. Complex I is an active catalyst for reductive amination reaction. The catalytic activity of this complex can be explained by the lability of the p-cymene ligand, which can be replaced by two-electron ligands such as CO or amine. PMID- 29765753 TI - (E)-1,3-Bis(anthracen-9-yl)prop-2-en-1-one: crystal structure and DFT study. AB - The title compound, C31H20O, was synthesized using a Claisen-Schmidt condensation. The enone group adopts an s-trans conformation and the anthracene ring systems are twisted at angles of 85.21 (19) and 83.98 (19) degrees from the enone plane. In the crystal, mol-ecules are connected into chains along [100] via weak C-H?pi inter-actions. The observed band gap of 3.03 eV is in excellent agreement with that (3.07 eV) calculated using density functional theory (DFT) at the B3LYP/6-311++G(d,p) level. The Hirshfeld surface analysis indicates a high percentage of C?H/H?C (41.2%) contacts in the crystal. PMID- 29765754 TI - Synthesis and crystal structures of 2-bromo-1,3-di-methyl-imidazolium iodides. AB - Attempts at direct bromination of 1,3-di-methyl-imidazolium salts were futile. The title compounds, 2-bromo-1,3-di-methyl-imidazolium iodide chloro-form 0.33 solvate, C5H8BrN2+.I-.0.33CHCl3, 2-bromo-1,3-di-methyl-imidazolium iodide di chloro-methane hemisolvate, C5H8BrN2+.I-.0.5CH2Cl2, and 2-bromo-1,3-di-methyl imidazolium iodide hemi(diiodide), C5H8BrN2+.I-.0.5I2, were obtained by methyl ation of 2-bromo-1-methyl-imidazole. They crystallized as CHCl3, CH2Cl2 or I2 solvates/adducts. The Br atom acts as a sigma-hole to accept short C-Br?I inter actions. C-H?I hydrogen bonds are observed in each structure. PMID- 29765755 TI - Crystal structure of bis-(diiso-propyl-ammonium) cis-di-iodido-bis-(oxolato kappa2O1,O2)stannate(IV). AB - In the title compound, (iPr2NH2)2[SnI2(C2O4)2], which was prepared by reacting ( i Pr2NH2+)2.C2O42- with SnI4 in a 2:1 molar ratio in a mixed ethanol-aceto nitrile solvent, the Sn atom is coordinated by two chelating oxalate ions and two iodide ions, with the latter in a cis configuration. In the crystal, the cations are linked to the anions by N-H?O and bifurcated N-H?(O,O) hydrogen bonds, generating [10-1] chains. PMID- 29765756 TI - Effect of counter-ion on packing and crystal density of 5,5'-(3,3'-bi[1,2,4-oxa diazole]-5,5'-di-yl)bis-(1H-tetra-zol-1-olate) with five different cations. AB - In energetic materials, the crystal density is an important parameter that affects the performance of the material. When making ionic energetic materials, the choice of counter-ion can have detrimental or beneficial effects on the packing, and therefore the density, of the resulting energetic crystal. Presented herein are a series of five ionic energetic crystals, all containing the dianion 5,5'-(3,3'-bi[1,2,4-oxa-diazole]-5,5'-di-yl)bis-(1H-tetra-zol-1-olate), with the following cations: hydrazinium (1) (2N2H5+.C6N12O42-), hydroxyl-ammonium (2) 2NH4O+.C6N12O42- [Pagoria et al.. (2017). Chem. Heterocycl. Compd, 53, 760-778; included for comparison], di-methyl-ammonium (3) (2C2H8N+.C6N12O42-), 5-amino-1H tetra-zol-4-ium (4) (2CH4N5+.C6N12O42-.4H2O), and amino-guanidinium (5) (2CH7N4+.C6N12O42-). Both the supra-molecular inter-actions and the sterics of the cation play a role in the density of the resulting crystals, which range from 1.544 to 1.873 Mg m-1. In 5, the tetra-zolate ring is disordered over two positions [occupancy ratio 0.907 (5):0.093 (5)] due to a 180 degrees rotation in the terminal tetra-zole rings. PMID- 29765757 TI - Crystal structure of calcium perchlorate anhydrate, Ca(ClO4)2, from laboratory powder X-ray diffraction data. AB - The crystal structure of calcium perchlorate anhydrate was determined from laboratory X-ray powder diffraction data. The title compound was obtained by heating hydrated calcium perchlorate [Ca(ClO4)2.xH2O] at 623 K in air for 12 h. It crystallizes in the ortho-rhom-bic space group Pbca and is isotypic with Ca(AlD4)2. The asymmetric unit contains one Ca, two Cl and eight O sites, all on general sites (Wyckoff position 8c). The crystal structure consists of isolated ClO4- tetra-hedra and Ca2+ cations. The Ca2+ cation is coordinated by eight O atoms of eight symmetry-related ClO4- tetra-hedra within a distorted square-anti prismatic environment. PMID- 29765758 TI - Crystal structure of De-hydro-dieugenol B methyl ether, a neolignan from Nectandra leucantha Nees and Mart (Lauraceae). AB - In the title compound, C21H24O4 (systematic name: 4,5'-diallyl-2,2',3'-tri-meth oxy-diphenyl ether), the aromatic rings lie almost perpendicular to each other [dihedral angle = 85.96 (2) degrees ]. The allyl side chains show similar configurations, with Car-C-C=C (ar = aromatic) torsion angles of -123.62 (12) and -115.54 (12) degrees . A possible weak intra-molecular C-H?O inter-action is observed. In the crystal, mol-ecules are connected by two C-H?O hydrogen bonds, forming undulating layers lying parallel to the bc plane. Weak C-H?pi and pi-pi stacking inter-actions also occur. PMID- 29765759 TI - Crystal structures of 5,12-dimethyl-1,4,8,11-tetra-aza-cyclo-tetra-decane cobalt(III) mono-phenyl-acetyl-ide and bis-phenyl-acetyl-ide. AB - Reported in this contribution are the synthesis and crystal structures of new mono- and bis-phenyl-acetyl-ides based on CoIII(DMC) (DMC is 5,12-dimethyl 1,4,8,11-tetra-aza-cyclo-tetra-deca-ne). Chlorido-(5,12-dimethyl-1,4,8,11-tetra aza-cyclo-tetra-deca-ne)(phenyl-ethyn-yl)cobalt(III) chloride-aceto-nitrile methanol (1/1/1), [Co(C8H5)Cl(C12H28N4)]Cl.CH3CN.CH3OH, 1, and (5,12-dimethyl 1,4,8,11-tetra-aza-cyclo-tetra-deca-ne)bis-(phenyl-ethyn-yl)cobalt(III) tri fluoro-methane-sulfonate-di-chloro-methane (2/1), [Co(C8H5)2(C12H28N4)]2(CF3SO3)2.CH2Cl2, 2, were prepared under weak-base conditions in satisfactory yields. Single-crystal X-ray diffraction studies revealed that both 1 and 2 adopt a pseudo-octa-hedral symmetry in which the Cl-Co C angles of 1 and C-Co-C of 2 range from 177.7 (2) to 178.0 (2) degrees and from 177.67 (9) to 179.67 (9) degrees , respectively. In both structures, the CoIII metal center is coordinated in the equatorial plane by four N atoms, in which the N-Co-N angles range from 85.6 (3) to 94.4 (3) degrees . The structure of 1 features two crystallographically independent mol-ecules in its triclinic cell (Z' = 2), which are related to each other by pseudo-monoclinic symmetry. The crystal investigated was twinned by a symmetry operator of the approximate double volume C-centered cell (180 degrees rotation around [201] of the actual triclinic cell), with a refined twin ratio of 0.798 (3) to 0.202 (3). Both methanol solvent mol-ecules in 1 are disordered, the major occupancy rates refined to 0.643 (16) and 0.357 (16). Compound 2 also contains two mol-ecules in the asymmetric unit, together with two tri-fluoro-methane-sulfonate anions [of which one is disordered; occupancy values of 0.503 (16) and 0.497 (16)] and a disordered di-chloro-methane [occupancy values of 0.545 (12) and 0.455 (12)]. PMID- 29765760 TI - 2-Oxo-2H-chromen-7-yl 4-tert-butyl-benzoate. AB - In the title compound, C20H18O4, the benzoate ring is oriented at an acute angle of 33.10 (12) degrees with respect to the planar (r.m.s deviation = 0.016 A) coumarin ring system. An intra-molecular C-H?O hydrogen bond closes an S(6) ring motif. In the crystal, C-H?O contacts generate infinite C(6) chains along the b axis direction. Also present are pi-pi stacking inter-actions between neighbouring pyrone and benzene rings [centroid-centroid distance = 3.7034 (18) A] and C=O?pi inter-actions [O?centroid = 3.760 (3) A]. The data obtained from quantum chemical calculations performed on the title compound are in good agreement with the observed structure, although the calculated C-O-C-C torsion angle between the coumarin ring system and the benzoate ring (129.1 degrees ) is somewhat lower than the observed value [141.3 (3) degrees ]. Hirshfeld surface analysis has been used to confirm and qu-antify the supra-molecular inter actions. PMID- 29765761 TI - Crystal structures of two isotypic lanthanide(III) complexes: tri-aqua-[2,6-di acetyl-pyridine bis-(benzoyl-hydrazone)]methano-llanthanide(III) trichloride methanol disolvates (LnIII = Tb and Dy). AB - The title lanthanide complexes, [Ln(DAPBH2)(CH3OH)(H2O)3]Cl3.2CH3OH [LnIII = Tb and Dy; DAPBH2 = 2,6-di-acetyl-pyridine bis-(benzoyl-hydrazone), C23H21N5O2], are isotypic. The central lanthanide ions are nine-coordinate, being ligated by three N and two O atoms from the penta-dentate DAPBH2 ligand, and four O atoms from the coordinated methanol mol-ecule and three coordinated water mol-ecules. The coordination geometry of the lanthanide ion is a distorted capped square anti prism. In the crystals, the various components are linked by O-H?Cl, N-H?Cl and O H?O hydrogen bonds, forming three-dimensional supra-molecular frameworks. Within the frameworks, there are C-H?Cl and C-H?O hydrogen bonds and offset pi-pi inter actions (inter-centroid distance ca 3.81 A). PMID- 29765762 TI - Tris[2,2,6,6-tetra-methyl-8-(tri-methyl-sil-yl)benzo[1,2-d;4,5-d']bis-(1,3-di thiol)-4-yl]methanol diethyl ether monosolvate. AB - The title compound, a tri-aryl-methanol, C46H64OS12Si31, was synthesized via li thia-tion of tris-2,2,6,6-tetra-methyl-benzo[1,2-d;4,5-d']bis-[1,3]di-thiol-4-yl methanol, 2, and electrophilic quenching with tri-methyl-silyl chloride. The current crystal structure reveals information about the reactivity of this compound and compares well with the structure reported for the unsubstituted parent compound 2 [Driesschaert et al. (2012 ?). Eur. J. Org. Chem.33, 6517 6525]. The title compound 1 forms mol-ecular propellers and crystallizes in P [Formula: see text], featuring an unusually long Si-Car bond of 1.910 (3) A. Moreover, the geometry at the central quaternary carbon is rather trigonal pyramidal than tetra-hedral due to vast intra-molecular stress. One tri-methyl silyl group is disordered over two positions in a 0.504 (4):0.496 (4) ratio and one S atom is disordered over two positions in a 0.509 (7):0.491 (7) ratio. The contribution of disordered diethyl ether solvent mol-ecule(s) was removed using the PLATON SQUEEZE (Spek, 2015 ?) solvent masking procedure. These solvent mol ecules are not considered in the given chemical formula and other crystal data. PMID- 29765763 TI - Crystal structure and catalytic activity of tetra-kis-(MU2-ethyl 2,6-di-tert butyl-4-methyl-phenyl phos-phato-kappa2O:O')bis-(ethyl 2,6-di-tert-butyl-4-methyl phenyl phosphato-kappa2O,O')dilutetium n-heptane disolvate. AB - The title complex, [Lu2(C17H28O4P)6].2C7H16, was formed in the reaction between potassium 2,6-di-tert-butyl-4-methyl-phenyl ethyl phosphate, [K(2,6- t Bu2-4 MeC6H2-O)(EtO)PO2], and LuCl3(H2O)6 in water, followed by vacuum drying and recrystallization from heptane. Its crystal structure has triclinic (P [Formula: see text]) symmetry at 120 K. The lutetium tris-(phosphate) complex has a binuclear [Lu2(MU-OPO)4] core and the organophosphate ligand exhibits kappa2O,O' terminal and MU2-kappa1O:kappa1O' bridging coordination modes with the LuIII ion being sixfold coordinated. The complex is of inter-est as a precatalyst in the acrylo-nitrile polymerization process and displays good catalytic activity under mild conditions. PMID- 29765764 TI - Crystal structure of 2,3-bis-(4-methyl-phen-yl)benzo[g]quinoxaline. AB - The title compound, C26H20N2, was obtained during a search for new pi-extended ligands with the potential to generate efficient phosphors with iridium(III) for organic light-emitting devices (OLEDs). The benzoquinoxaline ring system is almost planar (r.m.s. deviation = 0.076 A). A pseudo-twofold rotation axis runs through the midpoints of the C2-C3 and C9-C10 bonds. The two phenyl rings are twisted relative to the benzoquinoxaline ring system, making dihedral angles of 53.91 (4) and 36.86 (6) degrees . In the crystal, C-H?pi (arene) inter-actions link the mol-ecules, but no pi-pi inter-actions between aromatic rings are observed. PMID- 29765765 TI - Cs[Tf2N]: a second polymorph with a layered structure. AB - The structural determination of the ionic liquid, caesium bis-[(tri-fluoro-meth yl)sulfon-yl]imide or poly[[MU4-bis-[(tri-fluoro-meth-yl)sulfon yl]imido]caesium(I)], Cs[N(SO2CF3)2] or Cs[Tf2N], reveals a second polymorph that also crystallizes in a layer structure possessing monoclinic P21/c symmetry at 120 K instead of C2/c for the known polymorph [Xue et al. (2002 ?). Solid State Sci.4, 1535-1545]. The caesium ions in the cationic layers are coordinated by the sulfonyl groups of the bis-triflimide mol-ecules from anion layers while the tri fluoro-methyl groups are oriented in the opposite direction, forming a non-polar surface separating the layers. The layer direction is (100). PMID- 29765766 TI - Crystal structure of (-)-(5R,7R,8S,9R,10S)-8-methyl-7-[(5R)-3-methyl-2-oxooxolan 3-en-5-yl]-1-aza-6-oxatri-cyclo-[8.3.0.05,9]tridecan-13-one monohydrate. AB - The title compound, C17H23NO4.H2O, is an epimer of the natural tetra-cyclic alkaloid isosaxorumamide which consists of a fused 5-7-5 tricyclic core and a di hydro-furan-one substituent. The terminal di-hydro-furan ring is essentially planar with a maximum deviation of 0.0273 (14) A from the mean plane and oxolane, azepane and pyrrolidine rings in the tricyclic ring system adopt twist, twist chair and envelope forms, respectively. In the crystal, the amide and water mol ecules are linked by O-H?O hydrogen bonds, forming a tape structure running along the b-axis direction. The tapes are further connected by C-H?O inter-actions into a three-dimensional architecture. PMID- 29765767 TI - Crystal water as the mol-ecular glue for obtaining different co-crystal ratios: the case of gallic acid tris-caffeine hexa-hydrate. AB - The crystal structure of the hexa-hydrate co-crystal of gallic acid and caffeine, C7H6O5.3C8H10N4O2.6H2O or GAL3CAF.6H2O, is a remarkable example of the importance of hydrate water acting as structural glue to facilitate the crystallization of two components of different stoichiometries and thus to compensate an imbalance of hydrogen-bond donors and acceptors. The water mol-ecules provide the additional hydrogen bonds required to form a crystalline solid. Whereas the majority of hydrogen bonds forming the inter-molecular network between gallic acid and caffeine are formed by crystal water, only one direct classical hydrogen bond between two mol-ecules is formed between the carb-oxy-lic oxygen of gallic acid and the carbonyl oxygen of caffeine with d(D?A) = 2.672 (2) A. All other hydrogen bonds either involve crystal water or utilize protonated carbon atoms as donors. PMID- 29765768 TI - Crystal structure of 3-[2-(1,3-thia-zol-2-yl)diazen-1-yl]pyridine-2,6-di-amine monohydrate. AB - In the title hydrated azo compound, C8H8N6S.H2O, the two aromatic groups are close to coplanar with the dihedral angle between the mean planes of the thia zole and pyridine rings being 2.9 (2) degrees . The organic mol-ecule adopts an E configuration with respect to the double bond of the azo bridge. In the crystal, mol-ecules are linked by (amine)N-H?N(pyridine), (amine)N-H?O(water) and (water)O H?N(thia-zole) hydrogen bonds along with pi-pi inter-actions involving pairs of thia-zole rings and pairs of pyridine rings. The plane-to-plane distance between two parallel mol-ecules is 3.7856 (4) A and corresponds to the length of the a axis. In this way, a layer structure parallel to (010) is formed. The layers are linked by weak C-H?S hydrogen bonds, eventually resulting in a three-dimensional network. PMID- 29765769 TI - Synthesis and crystallographic characterization of [2,2-bis-(eta5-penta-methyl cyclo-penta-dien-yl)-3,4-bis(tri-methyl-sil-yl)-2-zircona-furan-5-one kappaO5]triisobutyl-aluminium. AB - The crystal structure of the title zwitterionic zirconocene complex containing a furan-one unit, [AlZr(C10H15)2(C4H9)3(C9H18O2Si2)], is reported. On reacting a zircona-furan-one with two equivalents of HAl(i-Bu)2, disproportionation of the Lewis acid results in the formation of a triiso-butyl-aluminium fragment, Al(i Bu)3, which coordinates to the exocyclic carbonyl O atom of the zircona-furan-one ring. Single-crystal X-ray diffraction reveals that the zircona-furan-one ring remains intact with coordination of the aluminium to the exocyclic O atom. One of the i-butyl groups is disordered over two sets of sites, with an occupancy ratio of 0.731 (3):0.269 (3). PMID- 29765771 TI - Reduction in nephrotoxicities using short hydration for chemotherapy containing cisplatin: a consecutive analysis of 467 patients with thoracic malignancies. AB - Background: Conventional hydration (CH) in chemotherapy containing cisplatin (CDDP) has been recommended to prevent renal toxicity. Although an increasing number of studies have demonstrated the feasibility of short hydration (SH), few large studies have reported the superiority of SH, compared with CH, in terms of nephrotoxicities. Methods: We conducted a consecutive retrospective analysis of 467 patients who had been treated with chemotherapy including CDDP. Statistical analyses were performed to evaluate the risk factors for nephrotoxicities. The following factors were included in the analyses: age, sex, performance status (PS), concomitant thoracic radiotherapy, CDDP dose, magnesium supplementation, baseline creatinine values and method of hydration. Results: The patients' characteristics were as follows: male/female, 323/144 patients; median age (range), 62 (27-69) years; PS 0/1/2/3, 238/217/10/2 patients and SH/CH, 111/356 patients. The proportion of patients requiring a CDDP dose reduction in the SH group was 6.3%, while that in the CH group was 12.9%. Patients who discontinued CDDP because of nephrotoxicities accounted for 0.9% of the patients in the SH group and 2.2% of the patients in the CH group. After CDDP-based chemotherapy, a creatinine increase of more than grade 1 was observed in 14.4% and 33.1% of the patients in the SH and CH groups, respectively. A logistic regression analysis revealed a significantly lower incidence of grade 1 or higher creatinine toxicity after the first cycle of chemotherapy in the SH group (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). Conclusions: SH resulted in a significantly lower incidence of nephrotoxicity. PMID- 29765770 TI - Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers. AB - Polybrominated diphenyl ethers (PBDEs) are a pervasive class of brominated flame retardants that are present in the environment at particularly high levels, especially in the United States. Their environmental stability, propensity for bioaccumulation, and known potential for neurotoxicity has evoked interest regarding their effects on the developing nervous system. Exposure to PBDEs has been strongly associated with neurodevelopmental disorders. However, the details of their mechanistic roles in such disorders are incompletely understood. Here, we report the effects of one of the most prevalent congeners, BDE-47, and its hydroxylated metabolites on the maturation and function of embryonic rat cortical neurons. Prolonged exposure to 6OH-BDE-47 produces the strongest effects amongst the parent BDE-47 congener and its tested hydroxylated metabolites. These effects include: i) disruption of transcriptional responses to neuronal activity, ii) dysregulation of multiple genes associated with neurodevelopmental disorders, and intriguingly, iii) altered expression of several subunits of the developmentally relevant BAF (Brg1-associated factors) chromatin remodeling complex, including the key subunit BAF170. Taken together, our data indicate that persistent exposure to 6OH-BDE-47 may interfere with neurodevelopmental chromatin remodeling mechanisms and gene transcription programs, which in turn are likely to interfere with downstream processes such as synapse development and overall functional maturity of neurons. Results from this study have identified a novel aspect of 6OH-BDE-47 toxicity and open new avenues to explore the effects of a ubiquitous environmental toxin on epigenetic regulation of neuronal maturation and function. PMID- 29765772 TI - Nutrition in patients with cancer: a new area for medical oncologists? A practising oncologist's interdisciplinary position paper. PMID- 29765773 TI - Optimising the use of cetuximab in the continuum of care for patients with metastatic colorectal cancer. AB - The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in combination with chemotherapy is a standard of care in the first-line treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC) and has demonstrated efficacy in later lines. Progressive disease (PD) occurs when tumours develop resistance to a therapy, although controversy remains about whether PD on a combination of chemotherapy and targeted agents implies resistance to both components. Here, we propose that some patients may gain additional clinical benefit from the reuse of cetuximab after having PD on regimens including cetuximab in an earlier treatment line. We conducted a non-systematic literature search in PubMed and reviewed published and ongoing clinical trials, focusing on later-line cetuximab reuse in patients with mCRC. Evidence from multiple studies suggests that cetuximab can be an efficacious and tolerable treatment when continued or when fit patients with mCRC are retreated with it after a break from anti-EGFR therapy. Furthermore, on the basis of available preclinical and clinical evidence, we propose that longitudinal monitoring of RAS status may identify patients suitable for such a strategy. Patients who experience progression on cetuximab plus chemotherapy but have maintained RAS wt tumour status may benefit from continuation of cetuximab with a chemotherapy backbone switch because they have probably developed resistance to the chemotherapeutic agents rather than the biologic component of the regimen. Conversely, patients whose disease progresses on cetuximab-based therapy due to drug-selected clonal expansion of RAS-mutant tumour cells may regain sensitivity to cetuximab following a defined break from anti-EGFR therapy. Looking to the future, we propose that RAS status determination at disease progression by liquid, needle or excisional biopsy may identify patients eligible for cetuximab continuation and rechallenge. With this approach, treatment benefit can be extended, adding to established continuum-of-care strategies in patients with mCRC. PMID- 29765775 TI - Potential impact of introducing the pneumococcal conjugate vaccine into national immunisation programmes: an economic-epidemiological analysis using data from India. AB - Pneumococcal pneumonia causes an estimated 105 000 child deaths in India annually. The planned introduction of the serotype-based pneumococcal conjugate vaccine (PCV) is expected to avert child deaths, but the high cost of PCV relative to current vaccines provided under the Universal Immunization Programme has been a concern. Cost-effectiveness studies from high-income countries are not readily comparable because of differences in the distribution of prevalent serotypes, population and health systems. We extended IndiaSim, our agent-based simulation model representative of the Indian population and health system, to model the dynamics of Streptococcus pneumoniae. This enabled us to evaluate serotype and overall disease dynamics in the context of the local population and health system, an aspect that is missing in prospective evaluations of the vaccine. We estimate that PCV13 introduction would cost approximately US$240 million and avert US$48.7 million in out-of-pocket expenditures and 34 800 (95% CI 29 600 to 40 800) deaths annually assuming coverage levels and distribution similar to DPT (diphtheria, pertussis and tetanus) vaccination (~77%). Introducing the vaccine protects the population, especially the poorest wealth quintile, from potentially catastrophic expenditure. The net-present value of predicted money-metric value of insurance for 20 years of vaccination is US$160 000 (95% CI US$151 000 to US$168 000) per 100 000 under-fives, and almost half of this protection is for the bottom wealth quintile (US$78 000; 95% CI 70 800 to 84 400). Extending vaccination to 90% coverage averts additional lives and provides additional financial risk protection. Our estimates are sensitive to immunity parameters in our model; however, our assumptions are conservative, and if willingness to pay per years of life lost averted is US$228 or greater, then introducing the vaccine is more cost-effective than our baseline (no vaccination) in more than 95% of simulations. PMID- 29765776 TI - What is the impact of water sanitation and hygiene in healthcare facilities on care seeking behaviour and patient satisfaction? A systematic review of the evidence from low-income and middle-income countries. AB - Patient satisfaction with healthcare has clear implications on service use and health outcomes. Barriers to care seeking are complex and multiple and delays in seeking care are associated with significant morbidity and mortality. We sought to assess the relationship between water, sanitation and hygiene (WASH) provision in healthcare facilities (HCF) and patient satisfaction/care seeking behaviour in low-income and middle-income countries. Pubmed and Medline Ovid were searched using a combination of search terms. 984 papers were retrieved and only 21 had a WASH component warranting inclusion. WASH was not identified as a driver of patient satisfaction but poor WASH provision was associated with significant patient dissatisfaction with infrastructure and quality of care. However, this dissatisfaction was not sufficient to stop patients from seeking care in these poorly served facilities. With specific regard to maternal health services, poor WASH provision was the reason for women choosing home delivery, although providers' attitudes and interpersonal behaviours were the main drivers of patient dissatisfaction with maternal health services. Patient satisfaction was mainly assessed via questionnaires and studies reported a high risk of courtesy bias, potentially leading to an overestimation of patient satisfaction. Patient satisfaction was also found to be significantly affected by expectation, which was strongly influenced by patients' socioeconomic status and education. This systematic review also highlighted a paucity of research to describe and evaluate interventions to improve WASH conditions in HCF in low-income setting with a high burden of healthcare-associated infections. Our review suggests that improving WASH conditions will decrease patience dissatisfaction, which may increase care seeking behaviour and improve health outcomes but that more rigorous research is needed. PMID- 29765774 TI - How shall we treat early triple-negative breast cancer (TNBC): from the current standard to upcoming immuno-molecular strategies. AB - Triple-negative breast cancer (TNBC) is a long-lasting orphan disease in terms of little therapeutic progress during the past several decades and still the standard of care remains chemotherapy. Experimental discovery of molecular signatures including the 'BRCAness' highlighted the innate heterogeneity of TNBC, generating the diversity of TNBC phenotypes. As it contributes to enhancing genomic instability, it has widened the therapeutic spectrum of TNBC. In particular, unusual sensitivity to DNA damaging agents was denoted in patients with BRCA deficiency, suggesting therapeutic benefit from platinum and poly(ADP ribose) polymerase inhibitors. However, regardless of enriched chemosensitivity and immunogenicity, majority of patients with TNBC still suffer from dismal clinical outcomes including early relapse and metastatic spread. Therefore, efforts into more precise and personalised treatment are critical at this point. Accordingly, the advance of multiomics has revealed novel actionable targets including PI3K-Akt-mTOR and epidermal growth factor receptor signalling pathways, which might actively participate in modulating the chemosensitivity and immune system. Also, TNBC has long been considered a potential protagonist of immunotherapy in breast cancer, supported by abundant tumour-infiltrating lymphocytes and heterogeneous tumour microenvironment. Despite that, earlier studies showed somewhat unsatisfactory results of monotherapy with immune checkpoint inhibitors, consistently durable responses in responders were noteworthy. Based on these results, further combinatorial trials either with other chemotherapy or targeted agents are underway. Incorporating immune molecular targets into combination as well as refining the standard chemotherapy might be the key to unlock the future of TNBC. In this review, we share the current and upcoming treatment options of TNBC in the framework of scientific and clinical data, especially focusing on early stage of TNBC. PMID- 29765778 TI - Reflections on family medicine and primary healthcare in sub-Saharan Africa. PMID- 29765777 TI - Patterns of authorship on community health workers in low-and-middle-income countries: an analysis of publications (2012-2016). AB - Introduction: Studies of authorship provide a barometer of local research capacity and ownership of research, considered key to defining appropriate research priorities, developing contextualised responses to health problems and ensuring that research informs policy and practice. This paper reports on an analysis of patterns of research authorship of the now substantial literature on community health workers (CHWs) in low-and-middle-income countries (LMICs) for the 5-year period: 2012-2016. Methods: A search of five databases identified a total of 649 indexed publications reporting on CHWs in LMICs and meeting the inclusion criteria. The country, region and income classification of studies, affiliations (country, organisation) of lead (first) and last authors, proportions of all authors locally affiliated, programme area (eg, maternal child health) and funding source were extracted. Results: The 649 papers reported experiences from 51 countries, 55% from middle-income countries (MICs) and 32% from low-income countries (LICs), with the remaining 13% multicountry studies. Overall, 47% and 54% of all the papers had a high-income country (HIC) lead and last author, respectively. Authorship followed three patterns: (1) a concentrated HIC pattern, with US-based authors numerically dominating LIC-based and multicountry studies; (2) an MIC pattern of autonomy, with a handful of countries India, South Africa and Brazil, in particular-leading >70% of their CHW publications and (3) a pattern of unevenness among LICs in their lead authorship of publications varying from 14% (Malawi) to 54% (Uganda). Region, programme area and funding source were all associated with the distribution of authorship across country income categories. Conclusion: The findings in this analysis mirror closely that of other authorship studies in global health. Collectively these provide a common message-that investments in global health programmes in the Millennium Development Goal era may have benefited health but not necessarily capacity for knowledge generation in LMICs. PMID- 29765779 TI - Effect of Timing of Initial Cataract Surgery, Compliance to Amblyopia Therapy on Outcomes of Secondary Intraocular Lens Implantation in Chinese Children: A Retrospective Case Series. AB - Purpose: As a secondary analysis, we reassess the association of initial congenital cataract surgery times, compliance to amblyopia therapy, and visual outcomes for a long-term follow-up in a secondary IOL implantation. Methods: Retrospective review of records of all infants with congenital cataracts who underwent secondary IOL implantation in the Eye and ENT Hospital of Fudan University from January 1, 2001, to December 31, 2007, and the minimum follow-up period was 5 years. Multiple regression analysis was used and the possible confounding factors were also analyzed to assess the effect on visual outcome. Results: A total of 110 patients (male: 59.1%) were included. The median (min max) age at cataract extraction and IOL implantation was 7.5 (3.0-15.0) and 35.0 (22.0-184.0) months, respectively, and the average follow-up period was 99.3 +/- 23.6 months. The median (min-max) BCVA at final follow-up was 0.20 (0.01-1.00). Compliance to amblyopia therapy was none, poor, and good in 21.8%, 24.5%, and 53.6%, respectively. Postoperative BCVA [logMAR, median (min-max) 0.70 (0.00 2.00)] linearly decreased with increasing cataract extraction time (per month) (beta = 0.04, 95% CI: 0.03-0.06, p < 0.0001) in multivariable models with laterality and compliance to amblyopia therapy adjusted. Good compliance to amblyopia therapy was associated with better BCVA (logMAR) at last follow-up (beta = -0.40, 95% CI = -0.53 to -0.27, p < 0.0001) with laterality, opacity type, and extraction time adjusted. Conclusions: For Chinese infants with congenital cataract, an earlier primary congenital cataract surgery at an age of 3 to 15 months is associated with a better visual outcome. Good compliance to amblyopia therapy was also significant to visual outcome. PMID- 29765780 TI - Outcomes and Complications of Scleral-Fixated Intraocular Lens Combined with Ahmed Tube Surgery. AB - Background: To evaluate the outcome and complications of transscleral suture fixated posterior chamber intraocular lens (PCIOL) implantation combined with Ahmed glaucoma valve (AGV) surgery in Asian eyes. Design: This was a retrospective study that included 22 eyes from 22 participants. The surgeries were performed at Singapore's National University Hospital. Participants underwent an Ahmed tube surgery, together with transscleral suture-fixated posterior chamber intraocular lens. Main Outcome Measures: Complete success was defined as 6 <= intraocular pressure (IOP) <= 21 mmHg without medications at the last follow-up visit, with no reoperation required and no progression to no perception of light (NPL). Results: At the last follow-up, there was a significant reduction in mean IOP (22.4 +/- 6.5 mmHg versus 13.9 +/- 3.9 mmHg; p < 0.001) and mean number of intraocular pressure-lowering medications (2.45 +/- 1.30 versus 0.05 +/- 0.21; p < 0.001). There was no significant change in visual acuity [1.43 +/- 1.21 (LogMAR) versus 1.09 +/- 1.31 (p = 0.204)]. Sixteen eyes (72.7%) achieved complete success. The 3 commonest complications were bullous keratopathy, choroidal detachment, and displacement of intraocular lens. Conclusion and Relevance: This technique showed good success for intraocular pressure control and vision preservation. Postoperative complications were relatively common although most were self-limiting. Patients at increased risk of trabeculectomy failure may be suitable for this procedure. PMID- 29765782 TI - Biosimilars Have Arrived: Rituximab. AB - A biosimilar is a biologic product that is highly similar to a licensed biologic ("originator") such that there are no clinically meaningful differences in safety, purity, or potency between the biosimilar and the originator. As patent protection and data exclusivity for the biologic rituximab expire, several potential biosimilars to rituximab are in development, which could soon lead to the availability of numerous rituximab biosimilars. Biosimilars are evaluated using thorough and rigorous analyses of the potential biosimilar versus the originator biological to confirm similar structure, function, and clinical efficacy as well as safety. Approval of a biosimilar is based upon the totality of the evidence demonstrating similarity to the originator. An understanding of the process of the interchangeable designation of a biosimilar is important in the context of patient outcomes. We conducted an analysis of the properties and benefits of rituximab in the treatment of inflammatory diseases, the development and approval of biosimilars, and the potential benefits of rituximab biosimilars. PubMed and ClinicalTrials.gov databases were searched for "biosimilar" and "rituximab" and regulatory and pharmaceutical company web pages were screened regarding biosimilars in development and specific guidelines developed for the approval of biosimilars. The results indicate that, at present, six rituximab biosimilar candidates are undergoing comparative clinical development, and two were recently approved in the European Union. Our analysis indicates rituximab biosimilars are expected to have a continuing role in treating inflammatory conditions such as rheumatoid arthritis. PMID- 29765781 TI - Bactericidal and Cytotoxic Activities of Polyphenol Extracts from Solanum tuberosum spp. tuberosum and spp. andigena Cultivars on Escherichia coli and Human Neuroblastoma SH-SY5Y Cells In Vitro. AB - Potatoes (Solanum tuberosum L.) are a good source of dietary antioxidant polyphenols. This study investigated the potential antioxidant, bactericidal, and cytotoxic activities in vitro of the phenolic compounds present in tubers of one S. tuberosum spp. tuberosum (Summerside), and three S. tuberosum spp. andigena (landraces Moradita, Waicha, and Santa Maria) cultivars. Both the content of phenolic acids, chlorogenic acids (CGAs) being the most abundant, and the antioxidant activity were higher in extracts from skin than from flesh. Extracts from Moradita flesh and Summerside skin showed bactericidal activity against Escherichia coli ATCC 25922 but failed to inhibit pathogenic E. coli O157. Both extracts lack pigmentation but do contain 5-CGA, caffeic, and ferulic acids. Positive control with gentamicin and commercial 5-CGA resulted in a complete inhibition of bacterial growth. In addition, all potato extracts and commercial 5 CGA diminished dose-dependently human neuroblastoma SH-SY5Y cell viability. Skin extracts were more potent than flesh extracts. Among flesh extracts, Moradita was the most potent. Together, our results suggest that Moradita flesh could provide a desirable source of important health-promoting substances. Findings indicate that the biological activity of potato extracts is a combination of various bioactive compounds and contribute to the revalorization of potato as a functional food. PMID- 29765783 TI - Multiorgan Failure and Refractory Lactic Acidosis due to Pasteurella multocida Septicemia in a Patient with No Animal Exposure. AB - Introduction: Pasteurella multocida is a gram-negative coccobacillus pathogenic to animals. It can cause infection in humans by a bite, scratch, or lick from a cat or dog. P. multocida can cause a variety of infections in humans, including cellulitis, osteomyelitis, endocarditis, peritonitis, and septic shock. Case Presentation: A 56-year-old male presented to our hospital with a 2-day history of fever, abdominal pain, nausea, and vomiting. He denied exposure to cats, dogs or other pets. He had severe respiratory distress requiring ventilator support, profound septic shock requiring multiple vasopressors, severe lactic acidosis, and renal failure requiring emergent hemodialysis. Blood cultures confirmed the presence of P. multocida. The patient subsequently died of cardiopulmonary arrest due to multiorgan failure with refractory shock. Conclusion: P. multocida septicemia can lead to septic shock. Early identification of this organism may decrease mortality. Although our patient had no known cat or dog exposure, physicians should enquire about a history of animal exposure when a patient presents with an infection with no obvious cause. PMID- 29765784 TI - Use of the Tei Index in the Conservative Management of TRAP Sequence Pregnancies Diagnosed during the Periviable Period: A Case Series. AB - Twin Reverse Arterial Perfusion (TRAP) Sequence is a rare complication of monochorionic pregnancies. Without intervention, the viable pump twin in a case of TRAP Sequence may develop high output cardiac failure leading to an intrauterine fetal demise. We present 3 cases of TRAP Sequence pregnancy diagnosed during the second or third trimesters of pregnancy. There are minimal sonographic tools for the guidance of a fetal therapeutic interventional procedure during the second trimester or timing of delivery during the third trimester to reduce morbidity and mortality of a viable fetus. Tei index may be a useful sonographic tool in the management of TRAP Sequence during the second or third trimester of pregnancy. PMID- 29765785 TI - Spondylocostal Dysostosis: A Literature Review and Case Report with Long-Term Follow-Up of a Conservatively Managed Patient. AB - Introduction: Patients with spondylocostal dysostosis (SCD) have congenital spine and rib deformities associated with frequently severe thoracic insufficiency and respiratory compromise. The literature is largely composed of case reports and small cohorts, and there is little information regarding adults with this condition. In this report, we describe the natural history of a conservatively treated patient and include quality-of-life issues such as childbearing, athletic participation, and occupational selection. Case Presentation: We present a patient with SCD who was conservatively treated by a single physician from birth for 31 years. Our patient was capable of a reasonably good quality of life through adulthood, including participation in gymnastics and employment. At age 18, she became pregnant and subsequently terminated the pregnancy due to obstetrical concerns for compromised respiration. She has had intermittent respiratory complaints and occasionally experiences dyspnea with exertion, but this only has limited her during certain activities in the past three years. Currently, she takes naproxen for chronic back pain with periodic exacerbations. Discussion: Other cases in the literature have described adult SCD patients who have received nonoperative treatment and achieved a wide range of functional outcomes. This provides some limited evidence to suggest that select patients with SCD may be treated conservatively and achieve a reasonable quality of life. However, close clinical follow-up with these patients is recommended, particularly early on, considering the high rates of infant morbidity and mortality. Chest physiotherapy and early pulmonary care have been associated with favorable outcomes in infancy. Surgery to increase thoracic volume and correct scoliosis has been shown in some cases to improve respiratory function. Treatment depends on the degree of thoracic insufficiency and quality of life. The natural history of SCD remains largely unknown, but some patients are capable of relatively favorable life spans, employment, and participation in athletics. PMID- 29765786 TI - Nasal Septal Perforation in Propylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. AB - Here, we present the case of a 29-year-old woman with nasal septal perforation and positive myeloperoxidase- (MPO-) anti-neutrophil cytoplasmic antibody (ANCA). She had been diagnosed with Graves' disease and had been treated with propylthiouracil (PTU) for 14 months. A biopsy of the nasal septum revealed an infiltration of inflammatory cells, with no evidence of malignancy or granulomatous change. Because of the use of PTU, destructive nasal lesion, and positive MPO-ANCA, she was diagnosed with drug-induced ANCA-associated vasculitis (AAV) and was treated with prednisolone and methotrexate after the cessation of PTU. Although PTU is known to be the medicine that induces drug-induced AAV, the manifestation of nasal septal perforation in drug-induced AAV is poorly identified. This is the rare case of drug-induced AAV which manifested only nasal septal perforation. PMID- 29765787 TI - Liver Failure and Conjugated Hyperbilirubinemia in a Preterm Neonate: Role of Early IVIG and Exchange Transfusion. AB - Neonatal liver failure (NLF) is a rare diagnosis but carries with it significant risks of mortality and morbidity. Common etiologies for NLF include metabolic causes, gestational alloimmune liver disease (GALD or neonatal hemochromatosis), and viral infections. We report a case of liver failure in a premature infant with abnormal iron profile within 48 hours of birth. Lack of accepted guidelines for the initial management of severe jaundice with a high direct component in the first week after birth made treatment challenging. The infant underwent intensive phototherapy along with four exchange transfusions (ET) and two courses of intravenous immunoglobulins (IVIG). The clinical goals were to keep total bilirubin values <= 20 mg/dL in this premature neonate and to minimize the risk of bilirubin-induced neurologic dysfunction and decompensated liver failure. Abnormal iron studies and later magnetic resonance imaging were suggestive of GALD. Liver functions improved over time with normal neurodevelopmental assessment at 3 years of age. To conclude, in infants with NLF soon after birth, earlier consideration of IVIG/ET in the first few days may be beneficial. Larger multicenter data analyses are required to formulate treatment guidelines and indications for phototherapy, ET, and IVIG in sick neonates with NLF. PMID- 29765788 TI - Early Pulmonary Interstitial Emphysema in Preterm Neonates-Respiratory Management and Case Report in Nonventilated Very Low Birth Weight Twins. AB - Early pulmonary interstitial emphysema in extreme preterm neonates is closely linked with respiratory distress syndrome and exposure to mechanical ventilation. In severe cases, maintaining adequate gas exchange aiming to avoid further lung damage and other neonatal morbidities associated with systemic/pulmonary hypoperfusion, prolonged hypoxia, and respiratory acidosis can be challenging and requires in-depth knowledge into the pathophysiology of the disease. Herein, we report on very low birth weight twins who developed early pulmonary interstitial emphysema during noninvasive respiratory support. We further review the current evidence from the literature, specifically addressing on possible preventive measures and the respiratory management options of this acute pulmonary disease in high-risk neonates. PMID- 29765789 TI - Pharmacokinetics of Hydroxyprogesterone Caproate and its Primary Metabolites during Pregnancy. AB - Objective To measure pharmacokinetics of hydroxyprogesterone caproate (OHPC) and its major metabolites throughout pregnancy. Study Design Thirty women were prescribed OHPC for recurrent preterm birth prevention. Three cohorts of subjects had blood drawn for 7 consecutive days at one of three times: cohort 1 ( n = 6) after the first dose (weeks 16-20), cohort 2 ( n = 8) between weeks 24 and 28, and cohort 3 ( n = 16) between weeks 32 and 36. We measured serum trough levels after week 1 in cohort 1 or after two consecutive weekly doses in cohorts 2 and 3. In 10 subjects, we estimated OHPC terminal half-life at 28 days after their last dose. Results In cohorts 1, 2, and 3, the areas under curve (ng * h/mL) for OHPC were 571.4 +/- 195.2, 1,269.6 +/- 285.0, and 1,268.0 +/- 511.6, respectively. Maximum OHPC levels (ng/mL) were 5.0 +/- 1.5, 12.5 +/- 3.9, and 12.3 +/- 4.9, respectively. The areas under the curve for mono-hydroxylated metabolites were 208.5 +/- 92.4, 157.1 +/- 64.6, and 211.2 +/- 113.1, and maximum concentrations were 1.9 +/- 0.7, 1.5 +/- 0.7, and 1.8 +/- 1.0, respectively. Di hydroxylated metabolite levels were significantly lower than mono-hydroxylated metabolites. Estimated terminal half-life of OHPC was 16.3 +/- 3.6 days and 19.7 +/- 6.2 days for the mono-hydroxylated metabolites. Conclusion After the first injection, OHPC maximum serum level was approximately half steady-state level. Measurable metabolites of unknown activity were detected. PMID- 29765790 TI - Direct Posterior Bipolar Cervical Facet Radiofrequency Rhizotomy: A Simpler and Safer Approach to Denervate the Facet Capsule. AB - Radiofrequency cervical rhizotomy has been shown to be effective for the relief of chronic neck pain, whether it be due to soft tissue injury, cervical spondylosis, or post-cervical spine surgery. The target and technique have traditionally been taught using an oblique approach to the anterior lateral capsule of the cervical facet joint. The goal is to position the electrode at the proximal location of the recurrent branch after it leaves the exiting nerve root and loops back to the cervical facet joint. The standard oblique approach to the recurrent nerve requires the testing of both motor and sensory components to verify the correct position and ensure safety so as to not damage the slightly more anterior nerve root. Bilateral lesions require the repositioning of the patient's neck. Poorly positioned electrodes can also pass anteriorly and contact the nerve root or vertebral artery. The direct posterior approach presented allows electrode positioning over a broader expanse of the facet joint without risk to the nerve root or vertebral artery. Over a four-year period, direct posterior radiofrequency ablation was performed under fluoroscopic guidance at multiple levels without neuro-stimulation testing with zero procedural neurologic events even as high as the C2 spinal segment. The direct posterior approach allows either unipolar or bipolar lesioning at multiple levels. Making a radiofrequency lesion along the larger posterior area of the facet capsule is as effective as the traditional target point closer to the nerve root but technically easier, allowing bilateral access and safety. The article will review the anatomy and innervation of the cervical facet joint and capsule, showing the diffuse nerve supply extending into the capsule of the facet joint that is more extensive than the recurrent medial sensory branches that have been the focus of radiofrequency lesioning. PMID- 29765791 TI - Cutaneous Leukocytoclastic Vasculitis Following Influenza Vaccination in Older Adults: Report of Bullous Purpura in an Octogenarian after Influenza Vaccine Administration. AB - The influenza vaccination is recommended annually for protection against influenza infection. Adults over 65 years of age are especially vulnerable to complications from influenza infection; in addition, they constitute the largest group of influenza vaccination recipients each year. Cutaneous leukocytoclastic vasculitis involves inflammation of small vessel walls by neutrophils. An 88-year old man with a history of idiopathic pulmonary fibrosis who developed bullous cutaneous leukocytoclastic vasculitis 14 days after receiving the influenza vaccine is described and the characteristics of influenza-associated cutaneous leukocytoclastic vasculitis in older individuals are reviewed. PMID- 29765793 TI - Myocardial Infarction in a Young Cocaine User with Atrial Myxoma: What is the Central Cause? AB - The differential diagnosis of myocardial infarction in patients with a number of potential causes can be challenging, especially when there is no angiographic evidence of coronary obstruction. We describe a case of extensive anterior ST elevation myocardial infarction in a young male smoker who had a left atrial myxoma and a history of cocaine use 10 hours before the event. Clinical reasoning during a myocardial infarction investigation should be oriented by the probability of the causal relationship between the ischemic event and each factor present in the clinical context. PMID- 29765792 TI - Stereotactic MRI-guided Adaptive Radiation Therapy (SMART) for Locally Advanced Pancreatic Cancer: A Promising Approach. AB - Locally advanced pancreatic cancer (LAPC) is characterized by poor prognosis and low response durability with standard-of-care chemotherapy or chemoradiotherapy treatment. Stereotactic body radiation therapy (SBRT), which has a shorter treatment course than conventionally fractionated radiotherapy and allows for better integration with systemic therapy, may confer a survival benefit but is limited by gastrointestinal toxicity. Stereotactic MRI-guided adaptive radiation therapy (SMART) has recently gained attention for its potential to increase treatment precision and thus minimize this toxicity through continuous real-time soft-tissue imaging during radiotherapy. The case presented here illustrates the promising outcome of a 69-year-old male patient with LAPC treated with SMART with daily adaptive planning and respiratory-gated technique. PMID- 29765795 TI - Inverse proximity effect in semiconductor Majorana nanowires. AB - We study the influence of the inverse proximity effect on the superconductivity nucleation in hybrid structures consisting of semiconducting nanowires placed in contact with a thin superconducting film and discuss the resulting restrictions on the operation of Majorana-based devices. A strong paramagnetic effect for electrons entering the semiconductor together with spin-orbit coupling and van Hove singularities in the electronic density of states in the wire are responsible for the suppression of superconducting correlations in the low-field domain and for the reentrant superconductivity at high magnetic fields in the topologically nontrivial regime. The growth of the critical temperature in the latter case continues up to the upper critical field destroying the pairing inside the superconducting film due to either orbital or paramagnetic mechanism. The suppression of the homogeneous superconducting state near the boundary between the topological and non-topological regimes provides the conditions favorable for the Fulde-Ferrel-Larkin-Ovchinnikov instability. PMID- 29765794 TI - Femoral Access for Central Venous Port System Implantation. AB - Totally implanted venous access port (TIVAP) systems provide adequate quality of care and life, especially for oncology patients. Long-term vascular access is very important and easy to perform, but in some clinical situations, if patients have a superior caval system occlusion, femoral insertion may be the only option. We present a case of a 70-year-old colorectal adenocarcinoma patient diagnosed with subclavian vein hypoplasia. Her care team decided intraoperatively to implant a port system by the right femoral access. The patient was included in an active surveillance program with regular follow-ups and has had no complications by the end of 2017. This uncommon surgical approach provided this cancer patient with an opportunity to realize a chemotherapy program with optimal quality of life. PMID- 29765796 TI - Circular dichroism of chiral Majorana states. AB - Background: Majorana states in condensed matter devices may be of a localized nature, such as in hybrid semiconductor/superconductor nanowires, or chirally propagating along the edges such as in hybrid 2D quantum-anomalous Hall/superconductor structures. Results: We calculate the circular dichroism due to chiral Majorana states in a hybrid structure made of a quantum-anomalous Hall insulator and a superconductor. The optical absorption of chiral Majorana states is characterized by equally spaced absorption peaks of both positive and negative dichroism. In the limit of a very long structure (a 2D ribbon) peaks of a single sign are favored. Conclusion: Circular-dichroism spectroscopy of chiral Majorana states is suggested as a relevant probe for these peculiar states of topological matter. PMID- 29765797 TI - Electrodeposition of reduced graphene oxide with chitosan based on the coordination deposition method. AB - The electrodeposition of graphene has drawn considerable attention due to its appealing applications for sensors, supercapacitors and lithium-ion batteries. However, there are still some limitations in the current electrodeposition methods for graphene. Here, we present a novel electrodeposition method for the direct deposition of reduced graphene oxide (rGO) with chitosan. In this method, a 2-hydroxypropyltrimethylammonium chloride-based chitosan-modified rGO material was prepared. This material disperses homogenously in the chitosan solution, forming a deposition solution with good dispersion stability. Subsequently, the modified rGO material was deposited on an electrode through codeposition with chitosan, based on the coordination deposition method. After electrodeposition, the homogeneous, deposited rGO/chitosan films can be generated on copper or silver electrodes or substrates. The electrodeposition method allows for the convenient and controlled creation of rGO/chitosan nanocomposite coatings and films of different shapes and thickness. It also introduces a new method of creating films, as they can be peeled completely from the electrodes. Moreover, this method allows for a rGO/chitosan film to be deposited directly onto an electrode, which can then be used for electrochemical detection. PMID- 29765798 TI - Heterostuctures of 4-(chloromethyl)phenyltrichlorosilane and 5,10,15,20-tetra(4 pyridyl)-21H,23H-porphine prepared on Si(111) using particle lithography: Nanoscale characterization of the main steps of nanopatterning. AB - Nanostructures of 4-(chloromethyl)phenyltrichlorosilane (CMPS) were used as a foundation to attach and grow heterostructures of porphyrins and organosilanes. A protocol was developed with particle lithography using steps of immersion in organosilane solutions to selectively passivate the surface of Si(111) with octadecyltrichlorosilane (OTS). A methyl-terminated matrix was chosen to direct the growth of CMPS nanostructures to fill the uncovered sites of Si(111) to enable spatial confinement of the surface reaction. Silica spheres with a diameter of 500 nm were used as a surface mask to prepare nanoscopic holes within the OTS matrix film. Next, the samples were immersed in solutions of CMPS dissolved in toluene or bicyclohexane. Nanostructures of CMPS formed within the nanoholes, to furnish spatially selective sites for binding porphyrins. The samples were then characterized with AFM to evaluate the height and morphology of the CMPS nanostructures that had formed within the nanoholes of OTS. The samples were then refluxed in a porphyrin solution for selective binding to produce heterostructures. The attachment of porphyrins was evidenced by increases in the height and width of the CMPS nanopatterns. The measurements of size indicate that multiple layers of porphyrins were added. Through each step of the surface reaction the surrounding matrix of OTS showed minimal areas of nonspecific adsorption. The AFM studies provide insight into the mechanism of the self polymerization of CMPS as a platform for constructing porphyrin heterostructures. PMID- 29765799 TI - A novel copper precursor for electron beam induced deposition. AB - A fluorine free copper precursor, Cu(tbaoac)2 with the chemical sum formula CuC16O6H26 is introduced for focused electron beam induced deposition (FEBID). FEBID with 15 keV and 7 nA results in deposits with an atomic composition of Cu:O:C of approximately 1:1:2. Transmission electron microscopy proved that pure copper nanocrystals with sizes of up to around 15 nm were dispersed inside the carbonaceous matrix. Raman investigations revealed a high degree of amorphization of the carbonaceous matrix and showed hints for partial copper oxidation taking place selectively on the surfaces of the deposits. Optical transmission/reflection measurements of deposited pads showed a dielectric behavior of the material in the optical spectral range. The general behavior of the permittivity could be described by applying the Maxwell-Garnett mixing model to amorphous carbon and copper. The dielectric function measured from deposited pads was used to simulate the optical response of tip arrays fabricated out of the same precursor and showed good agreement with measurements. This paves the way for future plasmonic applications with copper-FEBID. PMID- 29765800 TI - Surface characterization of nanoparticles using near-field light scattering. AB - The effect of nanoparticle surface coating characteristics on colloidal stability in solution is a critical parameter in understanding the potential applications of nanoparticles, especially in biomedicine. Here we explored the modification of the surface of poly(ethylene glycol)-coated superparamagnetic iron oxide nanoparticles (PEG-SPIOs) with the synthetic pseudotannin polygallol via interpolymer complexation (IPC). Changes in particle size and zeta potential were indirectly assessed via differences between PEG-SPIOs and IPC-SPIOs in particle velocity and scattering intensity using near-field light scattering. The local scattering intensity is correlated with the distance between the particle and waveguide, which is affected by the size of the particle (coating thickness) as well as the interactions between the particle and waveguide (related to the zeta potential of the coating). Therefore, we report here the use of near-field light scattering using nanophotonic force microscopy (using a NanoTweezerTM instrument, Halo Labs) to determine the changes that occurred in hydrated particle characteristics, which is accompanied by an analytical model. Furthermore, we found that altering the salt concentration of the suspension solution affected the velocity of particles due to the change of dielectric constant and viscosity of the solution. These findings suggest that this technique is suitable for studying particle surface changes and perhaps can be used to dynamically study reaction kinetics at the particle surface. PMID- 29765801 TI - Atomistic modeling of tribological properties of Pd and Al nanoparticles on a graphene surface. AB - Background: The frictional properties of nanoparticles have been studied to gain insight into the fundamental origin of sliding friction. Results: Using molecular dynamics we investigate frictional properties of aluminum and palladium nanoparticles deposited on a graphene layer. We study the time evolution of the total momentum of the system, the total and potential energies, the temperature, the velocity and position of the center of mass, the dimensions of the nanoparticle, and the friction and substrate forces acting on the particle. We also study how the friction force depends on the nanoparticle-graphene contact area and the temperature. Conclusion: The tribological properties of nanoparticles strongly depend on the materials. The particles move in an irregular (saw-like) manner. The averaged friction force depends nearly linearly on the contact area and non-monotonously on temperature. We observe ordered crystalline domains of atoms at the bottom surface of the metal particles, but the peaks of radial distribution function are blurred indicating that the nanoparticles are amorphous or polycrystalline. PMID- 29765803 TI - The electrical conductivity of CNT/graphene composites: a new method for accelerating transmission function calculations. AB - We present a new universal method to accelerate calculations of transmission function and electrical conductance of 2D materials, the supercell of which may contain hundreds or thousands of atoms. The verification of the proposed method is carried out by exemplarily calculating the electrical characteristics of graphene and graphane films. For the first time, we calculated the transmission function and electrical conductance of pillared graphene, composite film of carbon nanotubes (CNTs)/graphene. The electrical conductance of different models of this material was calculated in two mutually perpendicular directions. Regularities in resistance values were found. PMID- 29765802 TI - Computational exploration of two-dimensional silicon diarsenide and germanium arsenide for photovoltaic applications. AB - The properties of bulk compounds required to be suitable for photovoltaic applications, such as excellent visible light absorption, favorable exciton formation, and charge separation are equally essential for two-dimensional (2D) materials. Here, we systematically study 2D group IV-V compounds such as SiAs2 and GeAs2 with regard to their structural, electronic and optical properties using density functional theory (DFT), hybrid functional and Bethe-Salpeter equation (BSE) approaches. We find that the exfoliation of single-layer SiAs2 and GeAs2 is highly feasible and in principle could be carried out experimentally by mechanical cleavage due to the dynamic stability of the compounds, which is inferred by analyzing their vibrational normal mode. SiAs2 and GeAs2 monolayers possess a bandgap of 1.91 and 1.64 eV, respectively, which is excellent for sunlight harvesting, while the exciton binding energy is found to be 0.25 and 0.14 eV, respectively. Furthermore, band-gap tuning is also possible by application of tensile strain. Our results highlight a new family of 2D materials with great potential for solar cell applications. PMID- 29765804 TI - Proximity effect in a two-dimensional electron gas coupled to a thin superconducting layer. AB - There have recently been several experiments studying induced superconductivity in semiconducting two-dimensional electron gases that are strongly coupled to thin superconducting layers, as well as probing possible topological phases supporting Majorana bound states in such setups. We show that a large band shift is induced in the semiconductor by the superconductor in this geometry, thus making it challenging to realize a topological phase. Additionally, we show that while increasing the thickness of the superconducting layer reduces the magnitude of the band shift, it also leads to a more significant renormalization of the semiconducting material parameters and does not reduce the challenge of tuning into a topological phase. PMID- 29765805 TI - Artifacts in time-resolved Kelvin probe force microscopy. AB - Kelvin probe force microscopy (KPFM) has been used for the characterization of metals, insulators, and semiconducting materials on the nanometer scale. Especially in semiconductors, the charge dynamics are of high interest. Recently, several techniques for time-resolved measurements with time resolution down to picoseconds have been developed, many times using a modulated excitation signal, e.g., light modulation or bias modulation that induces changes in the charge carrier distribution. For fast modulation frequencies, the KPFM controller measures an average surface potential, which contains information about the involved charge carrier dynamics. Here, we show that such measurements are prone to artifacts due to frequency mixing, by performing numerical dynamics simulations of the cantilever oscillation in KPFM subjected to a bias-modulated signal. For square bias pulses, the resulting time-dependent electrostatic forces are very complex and result in intricate mixing of frequencies that may, in some cases, have a component at the detection frequency, leading to falsified KPFM measurements. Additionally, we performed fast Fourier transform (FFT) analyses that match the results of the numerical dynamics simulations. Small differences are observed that can be attributed to transients and higher-order Fourier components, as a consequence of the intricate nature of the cantilever driving forces. These results are corroborated by experimental measurements on a model system. In the experimental case, additional artifacts are observed due to constructive or destructive interference of the bias modulation with the cantilever oscillation. Also, in the case of light modulation, we demonstrate artifacts due to unwanted illumination of the photodetector of the beam deflection detection system. Finally, guidelines for avoiding such artifacts are given. PMID- 29765806 TI - Formation mechanisms of boron oxide films fabricated by large-area electron beam induced deposition of trimethyl borate. AB - Boron-containing materials are increasingly drawing interest for the use in electronics, optics, laser targets, neutron absorbers, and high-temperature and chemically resistant ceramics. In this article, the first investigation into the deposition of boron-based material via electron beam-induced deposition (EBID) is reported. Thin films were deposited using a novel, large-area EBID system that is shown to deposit material at rates comparable to conventional techniques such as laser-induced chemical vapor deposition. The deposition rate and stoichiometry of boron oxide fabricated by EBID using trimethyl borate (TMB) as precursor is found to be critically dependent on the substrate temperature. By comparing the deposition mechanisms of TMB to the conventional, alkoxide-based precursor tetraethyl orthosilicate it is revealed that ligand chemistry does not precisely predict the pathways leading to deposition of material via EBID. The results demonstrate the first boron-containing material deposited by the EBID process and the potential for EBID as a scalable fabrication technique that could have a transformative effect on the athermal deposition of materials. PMID- 29765807 TI - Formation and development of nanometer-sized cybotactic clusters in bent-core nematic liquid crystalline compounds. AB - Two homologue achiral bent-core liquid crystals (LCs), BCN66 and BCN84, in their nematic phases are studied by dielectric spectroscopy in the frequency range 10 Hz-10 MHz. In each of these compounds, two relaxation processes are identified and assigned to (i) collective dynamics of molecules in nanometer-sized cybotactic clusters and (ii) individual molecular relaxations, in the ascending order of frequency of the probe field. The temperature and the bias electric field dependence of the dielectric strength and relaxation frequency for these processes are shown to give rise to sharpness in cluster boundaries, increased size and volume fraction in the LC nematic phase. The effect of the bias field on the LC cell is similar to reducing its temperature; both variables increase the cluster size and volume fraction and give rise to sharp cluster boundaries. The findings confirm that dielectric spectroscopy is a powerful and an extremely useful technique to provide a deeper understanding of the mechanism of cybotactic cluster formation in the isotropic liquid and the nematic phase of LCs as a function of temperature and the bias field. PMID- 29765808 TI - Induced smectic phase in binary mixtures of twist-bend nematogens. AB - The investigation of liquid crystal (LC) mixtures is of great interest in tailoring material properties for specific applications. The recent discovery of the twist-bend nematic phase (NTB) has sparked great interest in the scientific community, not only from a fundamental viewpoint, but also due to its potential for innovative applications. Here we report on the unexpected phase behaviour of a binary mixture of twist-bend nematogens. A binary phase diagram for mixtures of imino-linked cyanobiphenyl (CBI) dimer and imino-linked benzoyloxy-benzylidene (BB) dimer shows two distinct domains. While mixtures containing less than 35 mol % of BB possess a wide temperature range twist-bend nematic phase, the mixtures containing 55-80 mol % of BB exhibit a smectic phase despite that both pure compounds display a Iso-N-NTB-Cr phase sequence. The phase diagram shows that the addition of BB of up to 30 mol % significantly extends the temperature range of the NTB phase, maintaining the temperature range of the nematic phase. The periodicity, obtained by atomic force microscopy (AFM) imaging, is in the range of 6-7 nm. The induction of the smectic phase in the mixtures containing 55-80 mol % of BB was confirmed using polarising optical microscopy (POM), differential scanning calorimetry (DSC) and X-ray diffraction. The origin of the intercalated smectic phase was unravelled by combined spectroscopic and computational methods and can be traced to conformational disorder of the terminal chains. These results show the importance of understanding the phase behaviour of binary mixtures, not only in targeting a wide temperature range but also in controlling the self-organizing processes. PMID- 29765809 TI - Ag2WO4 nanorods decorated with AgI nanoparticles: Novel and efficient visible light-driven photocatalysts for the degradation of water pollutants. AB - To develop efficient and stable visible-light-driven (VLD) photocatalysts for pollutant degradation, we synthesized novel heterojunction photocatalysts comprised of AgI nanoparticle-decorated Ag2WO4 nanorods via a facile method. Various characterization techniques, including XRD, SEM, TEM, EDX, and UV-vis DRS were used to investigate the morphology and optical properties of the as-prepared AgI/Ag2WO4 catalyst. With AgI acting as the cocatalyst, the resulting AgI/Ag2WO4 heterostructure shows excellent performance in degrading toxic, stable pollutants such as rhodamine B (RhB), methyl orange (MO) and para-chlorophenol (4-CP). The high performance is attributed to the enhanced visible-light absorption properties and the promoted separation efficiency of charge carriers through the formation of the heterojunction between AgI and Ag2WO4. Additionally, AgI/Ag2WO4 exhibits durable stability. The active species trapping experiment reveals that active species (O2*- and h+) dominantly contribute to RhB degradation. The AgI/Ag2WO4 heterojunction photocatalyst characterized in this work holds great potential for remedying environmental issues due to its simple preparation method and excellent photocatalytic performance. PMID- 29765810 TI - Construction of a synthetic Araneus ventricosus dragline silk gene multimer and its expression in Escherichia coli. AB - One of the most representative core gene sequence of Araneus ventricosus dragline silk protein partial cDNA monomer (JN857964.2) was selected and multimerized using a "head-to-tail" strategy by compatible but nonregenerable sites at both ends resulting in a concatemer of 16 contiguous monomers. This concatemer was cloned into pET-28a(+) expression vector and transformed into Escherichia coli. A 52.6 kDa silk protein was successfully expressed and detected by SDS-PAGE and confirmed by Western blotting. A maximum yield of the silk protein was expressed with 7.06 mM IPTG after 5 h incubation. This is the first report on the construction and overexpression of a A. ventricosus dragline silk multimeric gene construct and the results from our study will provide a reference point for further exploration and development of large-scale production of spider silk protein. PMID- 29765812 TI - Enhanced production and purification of recombinant surface array protein (Sap) for use in detection of Bacillus anthracis. AB - Surface array protein (Sap) can be an important biomarker for specific detection of Bacillus anthracis, which is released by the bacterium during its growth in culture broth. In the present work, we have cloned and expressed Sap in Escherichia coli. The culture conditions and cultivation media were optimized and used in batch fermentation process for scale up of Sap in soluble form. The recombinant Sap was purified employing affinity chromatography followed by diafiltration. The final yield of purified protein was 20 and 46 mg/l of culture during shake flasks and batch fermentation, respectively. The protein purity and its reactivity were confirmed employing SDS-PAGE and Western blot, respectively. The antibodies raised against purified Sap were evaluated by Western blotting for detection of Sap released by B. anthracis. Our results showed that the Sap could be a novel marker for detection and confirmation of B. anthracis. PMID- 29765811 TI - Comparative genome analysis of Bacillus velezensis reveals a potential for degrading lignocellulosic biomass. AB - Genomes of 24 sequenced Bacillus velezensis strains were characterized to identity shared and unique genes of lignocellulolytic enzymes and predict potential to degrade lignocellulose. All 24 strains had genes that encoded lignocellulolytic enzymes, with potential to degrade cellulose and hemicelluloses. Several lignocellulosic genes related to cellulose degradation were universally present, including one GH5 (endo-1,4-beta-glucanase), one GH30 (glucan endo-1,6-beta-glucosidase), two GH4 (6-phospho-beta-glucosidase, 6 phospho-alpha-glucosidase), one GH1 (6-phospho-beta-galactosidase), one GH16 (beta-glucanase) and three GH32 (two sucrose-6-phosphate hydrolase and levanase). However, in the absence of gene(s) for cellobiohydrolase, it was predicted that none of the 24 strains would be able to directly hydrolyse cellulose. Regarding genes for hemicellulose degradation, four GH43 (1,4-beta-xylosidase; except strain 9912D), one GH11 (endo-1,4-beta-xylanase), three GH43 (two arabinan endo 1,5-alpha-L-arabinosidase and one arabinoxylan arabinofuranohydrolase), two GH51 (alpha-N-arabinofuranosidase), one GH30 (glucuronoxylanase), one GH26 (beta mannosidase) and one GH53 (arabinogalactan endo-1,4-beta-galactosidase) were present. In addition, two PL1 (pectate lyase) and one PL9 (pectate lyase) with potential for pectin degradation were conserved among all 24 strains. In addition, all 24 Bacillus velezensis had limited representation of the auxiliary activities super-family, consistent with a limited ability to degrade lignin. Therefore, it was predicted that for these bacteria to degrade lignin, pretreatment of lignocellulosic substrates may be required. Finally, based on in silico studies, we inferred that Bacillus velezensis strains may degrade a range of polysaccharides in lignocellulosic biomasses. PMID- 29765813 TI - Isolation and characterization of fusarium wilt resistance gene analogs in radish. AB - The resistance gene analog (RGA)-based marker strategy is an effective supplement for current marker reservoir of radish disease-resistance breeding. In this study, we identified RGAs based on the conserved nucleotide-binding site (NBS) and S-receptor-like kinase (SRLK) domains. A total of 68 NBS-RGAs and 46 SRLK RGAs were isolated from two FW-resistant radish inbred lines, B2 and YR31, and one susceptible line, YR15. A BLASTx search revealed that the NBS-RGAs contained six conserved motifs (i.e., P loop, RNBS-A, Kinase-2, RNBS-B, RNBS-C, and GLPL) and the SRLK-RGAs, contained two conserved motifs (i.e., G-type lectin and PAN AP). A phylogenetic analysis indicated that the NBS-RGAs could be separated into two classes (i.e., toll/interleukin receptor and coiled-coil types), with six subgroups, and the SRLK-RGAs were divided into three subgroups. Moreover, we designed RGA-specific markers from data-mining approach in radish databases. Based on marker analysis, 24 radish inbred lines were clustered into five main groups with a similarity index of 0.44 and showing genetic diversity with resistance variation in those radish inbred lines. The development of RGA specific primers would be valuable for marker-assisted selection during the breeding of disease-resistant radish cultivars. PMID- 29765815 TI - In vitro investigation of antimicrobial activities of ethnomedicinal plants against dental caries pathogens. AB - The study aimed to evaluate the antimicrobial activity of medicinal plant extracts against the bacterial pathogens prominent in dental caries. A total of 20 plant species (herbs, shrubs and trees) belonging to 18 genera and 15 families were documented for dental caries. Antimicrobial activity of solvent extracts and essential oil from plants were determined by zone of inhibition on the growth of Streptococcus mutans (MTCC 497) and Lactobacillus acidophilus (MTCC 10307) using the agar well diffusion method. The results of in vitro antimicrobial assay prove that methanol is more successful in the extraction of phytochemicals from plant samples than aqueous solvent, as methanol extracts show higher antimicrobial activity than aqueous extracts against both the test pathogens. Methanol extracts of Nigella sativa, Psidium guajava and Syzygium aromaticum were the most effective among all 20 plant samples and have potent inhibitory activity against both dental caries pathogens with minimum inhibitory concentration of 0.2 mg mL- 1. N. sativa seed methanol extract was more effective with 22.3 mm zone of inhibition at 0.2 mg mL- 1 against S. mutans (MTCC 497), while L. acidophilus (MTCC 10307) was more sensitive to S. aromaticum bud methanol extract at 11.3 mm zone of inhibition at concentration 0.1 mg mL- 1. Essential oil extracted from plants also possesses strong antimicrobial activity for both test pathogens, with a minimum inhibitory concentration range of 0.05-0.16 mg mL- 1. Syzygium aromaticum bud essential oil at 0.05 mg mL- 1 was most active against S. mutans (MTCC 497). Plant extracts viewing antimicrobial activity with minimum inhibitory concentration show the efficacy of the plant products that could be considered as a good indicator of prospective plants for discovering new antimicrobial agents against dental caries pathogens. The findings of this study provide a lead to further polyherbal formulations for the treatment of dental caries malaise. PMID- 29765814 TI - Designing of phenol-based beta-carbonic anhydrase1 inhibitors through QSAR, molecular docking, and MD simulation approach. AB - Tuberculosis (Tb) is an airborne infectious disease caused by Mycobacterium tuberculosis. Beta-carbonic anhydrase 1 (beta-CA1) has emerged as one of the potential targets for new antitubercular drug development. In this work, three dimensional quantitative structure-activity relationships (3D-QSAR), molecular docking, and molecular dynamics (MD) simulation approaches were performed on a series of natural and synthetic phenol-based beta-CA1 inhibitors. The developed 3D-QSAR model (r2 = 0.94, q2 = 0.86, and pred_r2 = 0.74) indicated that the steric and electrostatic factors are important parameters to modulate the bioactivity of phenolic compounds. Based on this indication, we designed 72 new phenolic inhibitors, out of which two compounds (D25 and D50) effectively stabilized beta-CA1 receptor and, thus, are potential candidates for new generation antitubercular drug discovery program. PMID- 29765816 TI - Bioconversion of lignite humic acid by white-rot fungi and characterization of products. AB - Lignite humic acids (LHAs) were sequentially separated from lignite with aqueous NaOH and HCl and biotreated by an isolated fungus WF8. The liquid product (LP), residues (RS) and LHAs were analyzed using a Fourier transform infrared spectrometer (FTIR) and a proton nuclear magnetic resonance (1H NMR). Three main enzymes in WF8 (i.e., lignin peroxidase, manganese peroxidase and laccase) were also measured and analyzed with and without LHAs. The results show that LHAs can induce the ligninolytic enzymes. The oxidation and hydrogenation reactions proceeded to some extent, aromaticity in LHAs and carboxyl in LP decreased, and LHAs were converted into simpler LP via biochemical reactions by WF8. PMID- 29765818 TI - Targeted Epidural Blood Patch Treatment for Refractory Spontaneous Intracranial Hypotension in China. AB - Objective An epidural blood patch (EBP) is the mainstay of treatment for refractory spontaneous intracranial hypotension (SIH). We evaluated the treatment efficacy of targeted EBP in refractory SIH. Methods All patients underwent brain magnetic resonance imaging (MRI) with contrast and heavily T2-weighted spine MRI. Whole spine computed tomography (CT) myelography with non-ionic contrast was performed in 46 patients, and whole spine MR myelography with intrathecal gadolinium was performed in 119 patients. Targeted EBPs were placed in the prone position one or two vertebral levels below the cerebrospinal fluid (CSF) leaks. Repeat EBPs were offered at 1-week intervals to patients with persistent symptoms, continued CSF leakage, or with multiple leakage sites. Results Brain MRIs showed pachymeningeal enhancement in 127 patients and subdural hematomas in 32 patients. One hundred fifty-two patients had CSF leakages on heavily T2 weighted spine MRIs. CSF leaks were also detected on CT and MR myelography in 43 and 111 patients, respectively. Good recovery was achieved in all patients after targeted EBP. No serious complications occurred in patients treated with targeted EBP during the 1 to 7 years of follow-up. Conclusions Targeted and repeat EBPs are rational choices for treatment of refractory SIH caused by CSF leakage. PMID- 29765817 TI - Solid-state fermentation of oil palm frond petiole for lignin peroxidase and xylanase-rich cocktail production. AB - In current practice, oil palm frond leaflets and stems are re-used for soil nutrient recycling, while the petioles are typically burned. Frond petioles have high commercialization value, attributed to high lignocellulose fiber content and abundant of juice containing free reducing sugars. Pressed petiole fiber is the subject of interest in this study for the production of lignocellulolytic enzyme. The initial characterization showed the combination of 0.125 mm frond particle size and 60% moisture content provided a surface area of 42.3 m2/g, porosity of 12.8%, and density of 1.2 g/cm3, which facilitated fungal solid-state fermentation. Among the several species of Aspergillus and Trichoderma tested, Aspergillus awamori MMS4 yielded the highest xylanase (109 IU/g) and cellulase (12 IU/g), while Trichoderma virens UKM1 yielded the highest lignin peroxidase (222 IU/g). Crude enzyme cocktail also contained various sugar residues, mainly glucose and xylose (0.1-0.4 g/L), from the hydrolysis of cellulose and hemicellulose. FT-IR analysis of the fermented petioles observed reduction in cellulose crystallinity (I900/1098), cellulose-lignin (I900/1511), and lignin hemicellulose (I1511/1738) linkages. The study demonstrated successful bioconversion of chemically untreated frond petioles into lignin peroxidase and xylanase-rich enzyme cocktail under SSF condition. PMID- 29765819 TI - Complications in Salvage Surgery for Nasal and Paranasal Malignant Tumors Involving the Skull Base. AB - Objective Nasal and paranasal malignant tumors invading the skull base are rare and poorly studied. We evaluated postoperative complications in patients undergoing salvage surgery for such tumors. Design Retrospective study. Setting Kobe University Hospital. Participants Among 48 patients who underwent surgery for tumors involving the skull base between 1993 and 2015, 21 patients had squamous cell carcinoma, 13 had olfactory neuroblastoma, 5 had adenocarcinoma, 2 had sarcoma, 2 had adenoid cystic carcinoma, and 1 each had malignant melanoma, poorly differentiated carcinoma, undifferentiated carcinoma, myoepithelial carcinoma, and malignant peripheral nerve sheath tumor. Prior to skull base surgery, radiotherapy, chemoradiotherapy (CRT), particle radiotherapy, chemotherapy, or surgery were applied in 3, 15, 4, 5, and 3 patients, respectively. Main Outcome Measures Main outcome measures were postoperative complications in patients who underwent skull base surgery after concomitant CRT and/or particle therapy. Results Major postoperative complications were observed in 14 surgical procedures (29%; 2 patients with cerebral herniation, 3 with cerebrospinal fluid leakages, 3 with meningitis, 1 with hydrocephalus, 6 with epidural abscesses, 2 with local infections, and 2 with partial flap necrosis). Four patients developed >=2 complications. One patient died of postoperative lung infarction. Three (16.7%) of 18 patients without prior treatment and 9 (50%) of 18 patients who underwent preoperative radiotherapy/CRT had severe postoperative complications. Two (50%) of four patients treated with particle radiotherapy had postoperative complications. Conclusions CRT or particle radiotherapy were significantly associated with a high risk of severe postoperative complications after skull base surgery. Meticulous care should be taken in patients treated with radiotherapy/particle therapy prior to skull base surgery. PMID- 29765820 TI - A Comparative Analysis of Endoscopic-Assisted Transoral and Transnasal Approaches to Parapharyngeal Space: A Cadaveric Study. AB - Background Surgical resection of parapharyngeal space (PPS) tumors is very challenging. An endoscopic-assisted surgical approach to this region requires detailed and precise anatomic knowledge. The main purpose of this study is to describe and compare the detailed anatomy of the PPS via transnasal transpterygoid (TP) and endoscopic-assisted transoral (TO) approaches. Materials and Methods Six fresh injected cadaver heads (12 sides) were prepared for dissection of the PPS via TP and TO approaches. Computed tomography (CT) with image-based navigation (Navigation System II; Stryker, Kalamazoo, Michigan, United States) was used to identify bony structures around the PPS. Results TP and TO approaches could both expose the detailed anatomical structures in the PPS. The TP approach can provide a direct route to the upper PPS, but it is limited inferiorly by the hard palate and laterally by the medial and lateral pterygoid muscles. However, the TO approach can provide a direct route to the lower PPS, but it is difficult to expose the area around the Eustachian tube. The styloglossus and stylopharyngeus muscles could be considered as the safe anterior boundary of the parapharyngeal internal carotid artery (ICA) with the TO approach. Dissection between the stylopharyngeus muscle and the superior pharyngeal constrictor muscle provides direct access to the parapharyngeal ICA. Conclusion The TP and TO approaches provide new strategies to manage lesions in the PPS. The important neurovascular structures of the PPS could be identified with these approaches. The endoscopic-assisted TO approach can provide direct access to the parapharyngeal ICA. PMID- 29765821 TI - Potential Surgical Exposure of the Parapharyngeal Internal Carotid Artery by Endonasal, Transoral, and Transcervical Approaches. AB - Objectives Endoscopic and endoscopic-assisted approaches to the parapharyngeal space have been reported; however, their potential for vascular exposure has not been previously assessed. This study aims to compare the potential exposure and control of the parapharyngeal internal carotid artery (ppICA) via various approaches. Design and Main Outcome Measures Ten cadaveric specimens were dissected bilaterally, exposing the ppICA via endonasal, transoral, and transcervical approaches. Length of the exposed vessel and potential control were assessed (feasibility and time required to place an encircling suture). Results Endoscopic transoral and transcervical-transmandibular approaches expose a significantly longer segment of the ppICA (6.89 and 7.09 cm) than the transoral and endonasal approaches. Vascular control was achieved via endoscopic-endonasal, endoscopic-transoral, and open techniques in 121.6, 64.8, and 5.2 seconds, respectively. Conclusion Histopathology, goals of surgery, and familiarity of the surgeon with each technique may ultimately determine the choice of approach; however, this study suggests that exposure of the ppICA by endoscopic-assisted transoral approach is comparable to that of a transcervical-transmandibular approach. Vascular control was feasible under elective circumstances. However, the difficulty varied widely, potentially reflecting the challenges of controlling an injured ppICA. However, one must note that active bleeding obscures the surgical field in ways that may impair ppICA control. Furthermore, the results may not reflect clinical scenarios where tumor distorts the surgical field. Nonetheless, the study suggests that, in properly selected patients, the endoscopic-assisted transoral approach avoids problems associated with unsightly scars, mandibular osteotomy, and facial nerve manipulation, whereas, the transcervical-transmandibular approach offers the swiftest vascular control. PMID- 29765822 TI - Minimally Invasive Surgery for Resection of Parapharyngeal Space Tumors. AB - Background Surgical removal of parapharyngeal space tumors (PPST) poses challenges due to the complex anatomy of the region. PPSTs are routinely resected by a transcervical approach using blind finger dissection. Large PPSTs or those located high at the skull base, often require transmandibular or infratemporal fossa approaches, associated with considerable morbidity. Objective Here, we describe an approach for PPST removal that comprises transcervical endoscopic, with or without transoral robotic technique. Materials and Methods We retrospectively studied the demographic, clinical, surgical, and outcome data of 11 consecutive patients who underwent PPST excision between June 2013 and July 2017 at our center. Patients either underwent a transcervical endoscopic procedure ( n = 4), a transoral robotic procedure ( n = 2) or a combination of the two procedures ( n = 5). Results Complete tumor excision was achieved in all cases, with no intra-, peri-, or postoperative complications. Final histopathologic findings demonstrated pleomorphic adenoma for seven patients, cavernous hemangioma for one patient, and malignant tumors for three patients. The average tumor size was 44.22 +/- 31.9 cm 3 (range: 7.5-111 cm 3 ). At follow up (range: 3-42 months), there was no evidence of recurrence. Conclusions The approach described provides improved visualization and safe vascular control with minimum tumor stress, preventing the need for blind finger dissection, and allowing complete tumor removal while minimizing tumor spillage, nerve injury, and blood loss, maintaining excellent cosmetic and functional results. This approach could be utilized for the removal of large benign PPST, or small PPST located high. PMID- 29765823 TI - The Natural Growth Rate of Residual Juvenile Angiofibroma. AB - Objectives Examine the postoperative growth rate of residual juvenile angiofibroma (JA) in a large series of patients relative to pediatric growth parameters and other prognostic factors. Establish an algorithm for postoperative surveillance of patients with JA. Design Retrospective case series. Setting Tertiary referral academic center. Participants Pediatric patients undergoing surgical resection of JA between September 2005 and June 2015. Main Outcome Measures Postoperative recurrence and tumor growth rates. Results Thirty-eight patients were identified with a mean follow-up of 24.1 months. Sixty-eight percent (26/34) of patients achieved gross total resection, and 32% (12/38) had persistent postoperative disease. Of those with postoperative residual tumor, all had preoperative skull base involvement and residual blood supply from the internal carotid artery following embolization. Sixty-seven percent (8/12) of patients with postoperative residual tumor demonstrated radiographic stability of disease with scans being completed approximately every 6 months. Radiographic rates of disease progression ranged from 4.1 to 9.22 mm/year. Conclusions Patients with preoperative skull base involvement and residual vascularity following preoperative embolization are more likely to have residual postoperative disease, and a longer postoperative follow-up is warranted in these patients. Progression of residual disease occurred approximately 7.5 months postoperatively. Younger patients may be more likely to need further intervention for postoperative residual disease, and postoperative imaging at 6-month intervals appears appropriate. PMID- 29765824 TI - Changing Trends in the Management of Esthesioneuroblastoma: Irish and International Perspectives. AB - Objectives Evaluation of the changing trends in esthesioneuroblastoma in an Irish context and review of management options nationally to clarify the best current therapeutic approach by comparing with international research on this uncommon malignancy. Design Retrospective review. Setting Tertiary referral center. Participants All patients presenting with esthesioneuroblastoma in Beaumont hospital or on the National Cancer Registry of Ireland between 1994 and 2013. Main Outcome Measures Recurrence-free and overall survival. Results During the study period, 32 cases of esthesioneuroblastoma were diagnosed (0.4 per million per year). Average age at diagnosis was 57 years; however, two cases were under 20. The majority (62.5%) were male. Patients predominantly presented with epistaxis or nasal congestion (73%), while two cases were identified incidentally on radiological investigations. Twenty-seven cases underwent primary surgical management (two post neo-adjuvant treatment) with seventeen requiring bifrontal craniotomy. Twenty-four of these received postoperative radiation therapy. Overall, 5-year survival was 65%. Kadish A/B patients exhibited 100% 5 year disease-specific survival versus 54% in Kadish C/D ( p = 0.011). Hyams grade I/II patients exhibited 75% 5-year disease-specific survival versus 63% in Hyams grade III/IV ( p = 0.005). Patients treated endoscopically exhibited 100% 5-year disease-specific survival versus 51% in those treated via an open approach ( p = 0.102). Conclusions Many controversies exist in the diagnosis and management of this condition. Despite this, results from Irish data are mostly concordant with the international literature. The rising incidence of this disease may represent improved pathological recognition. An increasing number of esthesioneuroblastoma cases are being successfully treated via endoscopic surgery. PMID- 29765825 TI - Early-Career Surgical Practice for Cerebellopontine Angle Tumors in the Era of Radiosurgery. AB - We analyzed the outcomes of patients with large cerebellopontine angle (CPA) tumors treated by a skull-base team in which two surgeons (one neurosurgeon and one otological surgeon) were in the beginning of their careers (<40 years old). Data of patients operated on between April 2012 and March 2016 were reviewed. All factors related to surgical training were considered. Thirty-one patients had vestibular schwannomas, while 26 had meningiomas. Mean tumor diameter was 30.6 mm (range, 23-49 mm) for schwannomas and 35 mm (range, 22-51 mm) for meningiomas. Satisfactory postoperative facial nerve function (House-Brackmann's grade I or II) was achieved in 20 (64.5%) schwannoma patients and 21 (80.7%) meningioma patients. Gross total and near-total resections (residual tumor < 5 mm) were achieved in 21 (67.7%) and 9 (29%) schwannoma patients, respectively. Gross total resection (Simpson's grade II) was achieved in 18 (69.2%) meningioma patients. In both groups, the retrosigmoid approach was the most common approach. Regarding surgical training of the two younger surgeons, during the residency period, they attended high-volume centers for CPA tumors. Application of microsurgical techniques was systematically applied from the beginning of their personal series in every intracranial pathology case. During the first 2 years of the series, they were supervised by more experienced surgeons and followed a stepwise sharing of increasingly difficult surgical phases; by comparing results of this period with the last 2 years of the series, where they acquired a complete autonomy, no relevant difference was detected. Our results suggest that young surgeons may achieve good results even at the beginning of their careers, if specific conditions related to training and mentorship are met. PMID- 29765826 TI - Rates and Locations of Regional Metastases in Sinonasal Malignancies: The Mayo Clinic Experience. AB - Objectives The objective of this study was to identify factors that may influence the rate and location of regional metastasis in sinonasal malignancies (SNMs). Design This is a retrospective review. Setting This study was set at the single-institution tertiary referral center. Participants A total of 299 patients were treated for SNMs from 1994 to 2014. Main Outcome Measures The main outcome measures were incidence and distribution of regional metastases. Results Several histologic subtypes were treated, with squamous cell carcinoma (28.4%), esthesioneuroblastoma (18.1%), and mucosal melanoma (12.4%) being the most common. Of the 299 patients, 59 (19.7%) developed a regional metastasis, either at presentation or during follow-up. Higher cumulative incidence of regional metastases was significantly associated with histologic type ( p <=0.001) and invasion of the dura ( p = 0.005), infratemporal fossa ( p = 0.036), orbit ( p = 0.020), or palate ( p = 0.016). Ipsilateral level II lymph nodes were the most commonly involved nodes. Contralateral regional metastases were associated with higher risk histologic types ( p = 0.005) and dural invasion ( p = 0.008). Parotid metastases were associated with invasion of the facial soft tissue ( p = 0.028), and retropharyngeal metastases were associated with invasion of the pterygoid plates and musculature ( p = 0.030). Conclusion Histologic type of SNM appears to be the most important factor in predicting the rate of regional metastases. Histologic type and invasion of certain neighboring structures may help define which lymphatic basins are at highest risk for metastasis. PMID- 29765827 TI - A Cross-sectional Survey of the North American Skull Base Society: Current Practice Patterns of Vestibular Schwannoma Evaluation and Management in North America. AB - Background Very few studies have examined vestibular schwannoma (VS) management trends across centers and between providers. The objective of this study is to examine current practice trends, variance in treatment philosophies, and nuanced or controversial aspects of VS care across North America. Methods This is a cross-sectional survey of North American Skull Base Society (NASBS) members who report regular involvement in VS care. Results A total of 57 completed surveys were returned. Most respondents claimed to have over 20 years of experience and the majority reported working in an academic practice with an affiliated otolaryngology and/or neurosurgery residency program. Sixty-three percent of respondents claimed to evaluate VS patients in clinic with both an otolaryngologist and neurosurgeon involved. Eighty-six percent of respondents claimed to operate on VS with both an otolaryngologist and neurosurgeon involved, while only 18% of neurosurgeons and 9% of otolaryngologists performed surgery alone. There was a wide range in the number of cases evaluated at each center annually. Similarly, there was wide variation in the number of patients treated with microsurgery and radiation at each center. Additional details regarding management preferences for microsurgery, stereotactic radiosurgery, stereotactic radiotherapy, and conservative observation are presented. Conclusion VS management practices vary between providers and centers. Overall, most centers employ a multidisciplinary approach to management with collaboration between otolaryngology and neurosurgery. Overall, survey responses concur with previous studies suggesting a shift toward conservatism in management. PMID- 29765829 TI - Injury of the Carotid Artery during Endoscopic Endonasal Surgery: Surveys of Skull Base Surgeons. AB - Objectives This study aimed to review endoscopic skull base surgeon experience with internal carotid artery (ICA) injuries during endoscopic endonasal surgery (EES) to provide an estimate of the incidence of ICA injury, the associated factors and identify the best training modalities for the management of this complication. Design Anonymous electronic survey of past participants at a well established endoscopic skull base surgery course and a global online community of skull base surgeons. Main Outcome Measures Relative incidence of ICA injuries during EES, associated anatomic and intraoperative factors, and surgeon experience. Results At least 20% of surgeons in each surveyed population experienced a carotid artery injury. Reported carotid artery injuries were most common during tumor exposure and removal (48%). The parasellar carotid artery was the most commonly injured segment (39%). Carotid artery injuries were more common in high-volume surgeons, but only statistically significant in one of the two populations. Attendance at a skull base course or courses did not change the incidence of carotid artery injury in either surveyed population. In both surveys, respondents preferred live surgeries or active (not computer simulated) training models. Conclusions ICA injury is underreported and most common when manipulating the parasellar carotid artery for exposure and tumor dissection. Given the high morbidity and mortality associated with these injuries, vascular injury management should be prioritized and taught in a graduated approach by modern endoscopic skull base courses. PMID- 29765828 TI - A Cross-sectional Survey of the North American Skull Base Society on Vestibular Schwannoma, Part 2: Perioperative Practice Patterns of Vestibular Schwannoma in North America. AB - Introduction Perioperative care of vestibular schwannoma (VS) patients is extremely variable across surgeons and institutions making practice patterns difficult to standardize. No data currently exist detailing this practice variability. Methods The North American Skull Base Society membership was electronically surveyed regarding perioperative care of surgically operated VS patients. Results There were 87 respondents to the survey. Surgical positioning, surgical approach utilized, and perioperative medical adjuncts are quite variable. However, of those performing retrosigmoid approaches, 49% perform this in the supine position, while 33% use a park-bench position with only 2% using the sitting position. In those performing translabyrinthine approaches, 86% perform this in supine position. Although the use of neuromonitoring appears to be standard of care (98%), other than the seventh nerve, there is substantial variability between respondents regarding monitoring of additional cranial nerves. Postoperative antibiotics are used by 65%, postoperative steroids 81%, and postoperative chemical deep vein thrombosis prophylaxis in 68% of survey respondents. Conclusion Although the perioperative adjuncts to VS surgery are variable, there does appear to be a trend in common practice. Therefore, making surgeons aware of these trends may lead to standardized practice or alternatively trials of these variances to instruct which truly improve patient outcomes. PMID- 29765830 TI - Long-Term Facial Nerve Outcomes after Microsurgical Resection of Vestibular Schwannomas in Patients with Preoperative Facial Nerve Palsy. AB - Objectives This study aimed at evaluating facial nerve outcomes in vestibular schwannoma patients presenting with preoperative facial nerve palsy. Design A retrospective review. Setting Single-institution cohort. Participants Overall, 368 consecutive patients underwent vestibular schwannoma resection. Patients with prior microsurgery or radiosurgery were excluded. Main Outcome Measures Incidence, House-Brackmann grade. Results Of 368 patients, 9 had confirmed preoperative facial nerve dysfunction not caused by prior treatment, for an estimated incidence of 2.4%. Seven of these nine patients had Koos grade 4 tumors. Mean tumor diameter was 3.0 cm (range: 2.1-4.4 cm), and seven of nine tumors were subtotally resected. All nine patients were followed up clinically for >= 6 months. Of the six patients with a preoperative House-Brackmann grade of II, two improved to grade I, three were stable, and one patient worsened to grade III. Of the three patients with grade III or worse, all remained stable at last follow-up. Conclusions Preoperative facial nerve palsy is rare in patients with vestibular schwannoma; it tends to occur in patients with relatively large lesions. Detailed long-term outcomes of facial nerve function after microsurgical resection for these patients have not been reported previously. We followed nine patients and found that eight (89%) of the nine patients had either stable or improved facial nerve outcomes after treatment. Management strategies varied for these patients, including rates of subtotal versus gross-total resection and the use of stereotactic radiosurgery in patients with residual tumor. These results can be used to help counsel patients preoperatively on expected outcomes of facial nerve function after treatment. PMID- 29765831 TI - Quality of Life before and after Endoscopic Pituitary Surgery as Measured by the Short-Form-36. AB - Objectives/Hypotheses To assess quality of life (QOL) after transnasal, endoscopic pituitary surgery using the 36-item short form (SF-36) instrument. Design Retrospective review was used for this study. Setting The study was conducted in a tertiary academic medical center. Participants Patients who underwent endoscopic, transnasal, transsphenoidal surgery for pituitary adenomas between January 1, 2007 and July 1, 2016 and completed preoperative and postoperative SF-36 surveys. Main Outcome Measures SF-36 survey data as measured by its eight domains (physical functioning, physical role functioning, emotional role functioning, energy/fatigue, emotional well-being, social functioning, pain, and general health). Results There were 18 preoperative, 13 short-term (2 weeks or less after surgery) postoperative, and 14 longer term (>2 weeks after surgery) postoperative surveys. There was no significant difference between preoperative and long-term postoperative SF-36 scores across domains ( p > 0.05). In comparing short-term postoperative and preoperative scores, tumor size was positively associated with emotional well-being ( p = 0.049) and general health scores ( p = 0.031), while visual changes preoperatively were positively associated with general health scores ( p = 0.046). Compared with standard U.S. general population summary data, these patients scored lower preoperatively in all domains except for emotional role functioning and pain ( p < 0.05). Postoperatively, patients improved to baseline general population data scores with the exception of the physical role functioning domain ( p < 0.0001). Conclusion Patients undergoing endoscopic, transnasal, transsphenoidal surgery for pituitary adenomas had lower QOL in six of eight domains preoperatively, but improved to baseline values on the long run after surgery in seven of eight domains. This suggests that minimally invasive pituitary surgery has a restorative role in general QOL as measured by the SF-36. PMID- 29765832 TI - Tracking Effects of Exercise on Neuronal Plasticity. PMID- 29765834 TI - Control of the Cell Cycle in Adult Neurogenesis and its Relation with Physical Exercise. AB - In the adult brain the neurogenesis is mainly restricted to two neurogenic regions: newly generated neurons arise at the subventricular zone (SVZ) of the lateral ventricle and at the subgranular zone of the hippocampal subregion named the dentate gyrus. The hippocampus is involved in learning and memory paradigms and the generation of new hippocampal neurons has been hypothesized to be a pivotal form of plasticity involved in the process. Moreover the dysregulation of hippocampal adult neurogenesis has been recognized and could anticipate several varieties of brain disease such as Alzheimer disease, epilepsy and depression. Over the last few decades numerous intrinsic, epigenetic and environmental factors have been revealed to deeply influence the process of adult neurogenesis, although the underlying mechanisms remain largely unknown. Growing evidence indicates that physical exercise represents one of the main extrinsic factor able to profoundly increase hippocampal adult neurogenesis, by altering neurochemistry and function of newly generated neurons. The present review surveys how neurogenesis can be modulated by cell cycle kinetics and highlights the putative role of the cell cycle length as a key component of the beneficial effect of running for hippocampal adult neurogenesis, both in physiological conditions and in the presence of defective neurogenesis. PMID- 29765833 TI - How the Body Talks to the Brain; Peripheral Mediators of Physical Activity Induced Proliferation in the Adult Hippocampus. AB - In the hippocampal dentate gyrus, stem cells maintain the capacity to produce new neurons into adulthood. These adult-generated neurons become fully functional and are incorporated into the existing hippocampal circuit. The process of adult neurogenesis contributes to hippocampal functioning and is influenced by various environmental, hormonal and disease-related factors. One of the most potent stimuli of neurogenesis is physical activity (PA). While the bodily and peripheral changes of PA are well known, e.g. in relation to diet or cardiovascular conditions, little is known about which of these also exert central effects on the brain. Here, we discuss PA-induced changes in peripheral mediators that can modify hippocampal proliferation, and address changes with age, sex or PA duration/intensity. Of the many peripheral factors known to be triggered by PA, serotonin, FGF-2, IGF-1, VEGF, beta-endorphin and adiponectin are best known for their stimulatory effects on hippocampal proliferation. Interestingly, while age negatively affects hippocampal proliferation per se, also the PA-induced response to most of these peripheral mediators is reduced and particularly the response to IGF-1 and NPY strongly declines with age. Sex differences per se have generally little effects on PA-induced neurogenesis. Compared to short term exercise, long term PA may negatively affect proliferation, due to a parallel decline in FGF-2 and the beta-endorphin receptor, and an activation of the stress system particularly during conditions of prolonged exercise but this depends on other variables as well and remains a matter of discussion. Taken together, of many possible mediators, serotonin, FGF 2, IGF-1, VEGF, beta-endorphin and adiponectin are the ones that most strongly contribute to the central effects of PA on the hippocampus. For a subgroup of these factors, brain sensitivity and responsivity is reduced with age. PMID- 29765837 TI - Running Improves Pattern Separation during Novel Object Recognition. AB - Running increases adult neurogenesis and improves pattern separation in various memory tasks including context fear conditioning or touch-screen based spatial learning. However, it is unknown whether pattern separation is improved in spontaneous behavior, not emotionally biased by positive or negative reinforcement. Here we investigated the effect of voluntary running on pattern separation during novel object recognition in mice using relatively similar or substantially different objects.We show that running increases hippocampal neurogenesis but does not affect object recognition memory with 1.5 h delay after sample phase. By contrast, at 24 h delay, running significantly improves recognition memory for similar objects, whereas highly different objects can be distinguished by both, running and sedentary mice. These data show that physical exercise improves pattern separation, independent of negative or positive reinforcement. In sedentary mice there is a pronounced temporal gradient for remembering object details. In running mice, however, increased neurogenesis improves hippocampal coding and temporally preserves distinction of novel objects from familiar ones. PMID- 29765838 TI - Downstream Consequences of Exercise Through the Action of BDNF. AB - Physical exercise produces many beneficial responses in the brain, which affect cognitive function, blood flow, neurogenesis and resistance to injury. However, the exact mechanisms whereby exercise produces an induction in the brain are not well understood. A significant consequence is the induction of growth factors, such as Brain-derived Neurotrophic Factor (BDNF). Cognitive decline that occurs with aging, as well as progression of neurodegenerative diseases, are strongly correlated with decreases in BDNF. In this article, we discuss the properties of neurotrophins and the mechanisms that can account for the ability of exercise to promote brain plasticity through BDNF. PMID- 29765839 TI - Hormetic effects by exercise on hippocampal neurogenesis with glucocorticoid signaling. AB - Exercise enhances adult hippocampal neurogenesis (AHN), although the exact nature of how this happens remains controversial. The beneficial effects of exercise vary depending upon the exercise condition, especially intensity. Most animal studies, however, have used wheel running, which only evaluates running distance (exercise volume) and does not consider intensity. In our rat model, we have found that exercise-induced neurogenesis varies depending on the intensity of the exercise and have found that exercise-enhanced neurogenesis is more pronounced with mild exercise than with moderate and/or intense exercise. This may be due, at least in part, to increased glucocorticoid (CORT) secretion. To test this hypothesis, we used our special exercise model in mice, with and without a stress response, based on the lactate threshold (LT) in which moderate exercise above the LT increases lactate and adrenocorticotropic hormone (ACTH) release, while mild exercise does not. Adult male C57BL/6J mice were subjected to two weeks of exercise training and AHN was measured with a 5-Bromo-2-deoxyuridine (BrdU) pre injection and immunohistochemistry. The role of glucocorticoid signaling was examined using intrapertioneal injections of antagonists for the glucocorticoid receptor (GR), mifepristone, and the mineralocorticoid receptor (MR), spironolactone. We found that, while mild exercise increased AHN without elevating CORT blood levels, both MR and GR antagonists abolished mild-exercise induced AHN, but did not affect AHN under intense exercise. This suggests a facilitative, permissive role of glucocorticoid and mineralocorticoid receptors in AHN during mild exercise (234/250). PMID- 29765835 TI - Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction Like Behavior. AB - The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction. PMID- 29765836 TI - The Benefits of Exercise on Structural and Functional Plasticity in the Rodent Hippocampus of Different Disease Models. AB - In this review, the benefits of physical exercise on structural and functional plasticity in the hippocampus are discussed. The evidence is clear that voluntary exercise in rats and mice can lead to increases in hippocampal neurogenesis and enhanced synaptic plasticity which ultimately result in improved performance in hippocampal-dependent tasks. Furthermore, in models of neurological disorders, including fetal alcohol spectrum disorders, traumatic brain injury, stroke, and neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease exercise can also elicit beneficial effects on hippocampal function. Ultimately this review highlights the multiple benefits of exercise on hippocampal function in both the healthy and the diseased brain. PMID- 29765842 TI - Activity-Dependent Inhibitory Synaptogenesis in Cerebellar Cultures. AB - Inhibitory synapses on Purkinje cell somata in organotypic cerebellar cultures derived from newborn mice were increased after chronic exposure post explantation to agents that enhance neuronal activity. Inhibitory synaptogenesis was reduced in similar cultures after continuous blockade of spontaneous neuronal discharges. By contrast, excitatory synapses developed fully in the absence of neuronal activity. The reduction of inhibitory synaptogenesis was prevented by the simultaneous application of activity blocking agents and neurotrophins BDNF or NT 4, which are TrkB receptor ligands, but not with NT-3, a TrkC receptor ligand. The effect of endogenous neurotrophins was evaluated by continuously exposing cerebellar cultures to antibodies to BDNF and NT-4, which caused a significant reduction in the development of inhibitory Purkinje cell axosomatic synapses. These combined results indicated a role for TrkB receptors in activity-dependent inhibitory synaptogenesis. This concept was supported by the promotion of inhibitory synaptogenesis by specific antibody activation of TrkB receptors. PMID- 29765843 TI - Interactions Between Microglia and Newly Formed Hippocampal Neurons in Physiological and Seizure-Induced Inflammatory Environment. AB - Adult hippocampal neurogenesis is modulated by physiological and pathological stimuli, including seizures and inflammation. Here, we describe stable interactions between microglia and newborn neurons using two-photon and confocal microscopy. On 3 weeks-old neurons, these interactions exhibit preferences for distal dendrites under physiological conditions. Conversely, after status epilepticus, ramified microglia, in particular, interact more with the proximal dendrites of new neurons. No such differences were found on 6 weeks-old neurons. Our study demonstrates regional and temporal specificity of the interactions between newborn neurons and microglia during a critical period for homeostasis and synaptic integration. PMID- 29765845 TI - Live-Imaging of Myelin in Animal Models and in Human. PMID- 29765844 TI - Increased Inhibition in Non-Primary Motor Areas of String-Instrument Players: A Preliminary Study with Paired-Pulse Transcranial Magnetic Stimulation. AB - Background: The muscle representations in non-primary motor area (NPMA) are located in the dorsal premotor area (PMd) and in the border region between the premotor area and the supplementary motor area (SMA). Objective: We characterized the plasticity of intracortical inhibitory and excitatory circuits in muscle representations in primary motor cortex (M1) and in NPMA related to acquired fine motor skills. We compared local cortical inhibition and facilitation balance in M1 and in NPMA between control subjects (n = 6) and right-handed string instrument players (n = 5). Methods: Navigated transcranial magnetic stimulation (TMS) was used to compare motor thresholds (MTs), motor evoked potentials (MEPs), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in non-dominant hand muscle representations in M1 and NPMA. Results: String instrument players showed reduced SICI in M1 in the actively used left hand abductor digiti minimi (ADM) muscle representation at 3 ms inter-stimulus interval (ISI) with a conditioning stimulus (CS) intensity of 80% of MT and increased SICI in NPMA in ADM representation at 2 ms ISI and CS intensity of 50% of MT in comparison with controls. No differences between string-instrument players and controls were found for the SICI in the left hand opponens pollicis (OP) muscle representation, which is a muscle not intensively trained in string instrument players. Conclusions: These preliminary results indicate that the stronger inhibition in motor representations outside M1 in string-instrument players may be crucial when accurate movements of single muscles must be performed. In contrast, weaker inhibition in M1 in string-instrument players may benefit the performance of fast finger movements. PMID- 29765840 TI - Synaptic Failure: Focus in an Integrative View of ALS. AB - From early description by Charcot, the classification of the Amyotrophic Lateral Sclerosis (ALS) is evolving from a subtype of Motor Neuron (MN) Disease to be considered rather a multi-systemic, non-cell autonomous and complex neurodegenerative disease. In the last decade, the huge amount of knowledge acquired has shed new insights on the pathological mechanisms underlying ALS from different perspectives. However, a whole vision on the multiple dysfunctional pathways is needed with the inclusion of information often excluded in other published revisions. We propose an integrative view of ALS pathology, although centered on the synaptic failure as a converging and crucial player to the etiology of the disease. Homeostasis of input and output synaptic activity of MNs has been proved to be severely and early disrupted and to definitively contribute to microcircuitry alterations at the spinal cord. Several cells play roles in synaptic communication across the MNs network system such as interneurons, astrocytes, microglia, Schwann and skeletal muscle cells. Microglia are described as highly dynamic surveying cells of the nervous system but also as determinant contributors to the synaptic plasticity linked to neuronal activity. Several signaling axis such as TNFalpha/TNFR1 and CX3CR1/CX3CL1 that characterize MN microglia cross talk contribute to synaptic scaling and maintenance, have been found altered in ALS. The presence of dystrophic and atypical microglia in late stages of ALS, with a decline in their dynamic motility and phagocytic ability, together with less synaptic and neuronal contacts disrupts the MN-microglia dialogue, decreases homeostatic regulation of neuronal activity, perturbs "on/off" signals and accelerates disease progression associated to impaired synaptic function and regeneration. Other hotspot in the ALS affected network system is the unstable neuromuscular junction (NMJ) leading to distal axonal degeneration. Reduced neuromuscular spontaneous synaptic activity in ALS mice models was also suggested to account for the selective vulnerability of MNs and decreased regenerative capability. Synaptic destabilization may as well derive from increased release of molecules by muscle cells (e.g. NogoA) and by terminal Schwann cells (e.g. semaphorin 3A) conceivably causing nerve terminal retraction and denervation, as well as inhibition of re-connection to muscle fibers. Indeed, we have overviewed the alterations on the metabolic pathways and self regenerative capacity presented in skeletal muscle cells that contribute to muscle wasting in ALS. Finally, a detailed footpath of pathologic changes on MNs and associated dysfunctional and synaptic alterations is provided. The oriented motivation in future ALS studies as outlined in the present article will help in fruitful novel achievements on the mechanisms involved and in developing more target-driven therapies that will bring new hope in halting or delaying disease progression in ALS patients. PMID- 29765847 TI - Advances in Intravital Non-Linear Optical Imaging of the Central Nervous System in Rodents. AB - Purpose of review: Highly coordinated cellular interactions occur in the healthy or pathologic adult rodent central nervous system (CNS). Until recently, technical challenges have restricted the analysis of these events to largely static modes of study such as immuno-fluorescence and electron microscopy on fixed tissues. The development of intravital imaging with subcellular resolution is required to probe the dynamics of these events in their natural context, the living brain. Recent findings: This review focuses on the recently developed live non-linear optical imaging modalities, the core principles involved, the identified technical challenges that limit their use and the scope of their applications. We highlight some practical applications for these modalities with a specific attention given to Experimental Autoimmune Encephalomyelitis (EAE), a rodent model of a chronic inflammatory disease of the CNS characterized by the formation of disseminated demyelinating lesions accompanied by axonal degeneration. Summary: We conclude that label-free nonlinear optical imaging combined to two photon imaging will continue to contribute richly to comprehend brain function and pathogenesis and to develop effective therapeutic strategies. PMID- 29765846 TI - Imaging Myelination In Vivo Using Transparent Animal Models. AB - Myelination by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system is essential for nervous system function and health. Despite its importance, we have a relatively poor understanding of the molecular and cellular mechanisms that regulate myelination in the living animal, particularly in the CNS. This is partly due to the fact that myelination commences around birth in mammals, by which time the CNS is complex and largely inaccessible, and thus very difficult to image live in its intact form. As a consequence, in recent years much effort has been invested in the use of smaller, simpler, transparent model organisms to investigate mechanisms of myelination in vivo. Although the majority of such studies have employed zebrafish, the Xenopus tadpole also represents an important complementary system with advantages for investigating myelin biology in vivo. Here we review how the natural features of zebrafish embryos and larvae and Xenopus tadpoles make them ideal systems for experimentally interrogating myelination by live imaging. We outline common transgenic technologies used to generate zebrafish and Xenopus that express fluorescent reporters, which can be used to image myelination. We also provide an extensive overview of the imaging modalities most commonly employed to date to image the nervous system in these transparent systems, and also emerging technologies that we anticipate will become widely used in studies of zebrafish and Xenopus myelination in the near future. PMID- 29765850 TI - Imaging Central Nervous System Demyelination and Remyelination by Positron Emission Tomography. AB - Positron Emission Tomography (PET), an imaging technique based on the injection of radiotracers directed against specific biological targets within brain tissues, within brain tissues, is a specific and sensitive technique which offers the unique opportunity to quantify myelin dynamics in the central nervous system. Several stilbene and benzothiazole derivatives have been repurposed to image myelin by PET. In demyelinating and dysmyelinating models, selected radiotracers were shown to reliably quantify demyelination and remyelination, allowing a translational approach in humans. A pilot study in subjects with active relapsing MS using PET and the most available benzothiazole derivative, [11C]PIB, supported the hypothesis that this technique is able to quantify myelin content in multiple sclerosis (MS) lesions and to capture dynamic demyelination and remyelination over time. This study highlighted for the first time in vivo the prognostic value of individual profiles of remyelination on the disease course. In future, the clinical application of myelin PET will be pushed forward thanks to the availability of novel fluorinated tracers for myelin, together with the setting up of non invasive quantification procedures and the use of powerful PET-MR systems. This will enable to address in vivo critical unanswered questions about the pathogenesis of remyelination, and to measure the efficacy of emerging promyelinating drugs in early-phase therapeutic trials. PMID- 29765841 TI - Serotonergic Neuroplasticity in Alcohol Addiction. AB - Alcohol addiction is a debilitating disorder producing maladaptive changes in the brain, leading drinkers to become more sensitive to stress and anxiety. These changes are key factors contributing to alcohol craving and maintaining a persistent vulnerability to relapse. Serotonin (5-Hydroxytryptamine, 5-HT) is a monoamine neurotransmitter widely expressed in the central nervous system where it plays an important role in the regulation of mood. The serotonin system has been extensively implicated in the regulation of stress and anxiety, as well as the reinforcing properties of all of the major classes of drugs of abuse, including alcohol. Dysregulation within the 5-HT system has been postulated to underlie the negative mood states associated with alcohol use disorders. This review will describe the serotonergic (5-HTergic) neuroplastic changes observed in animal models throughout the alcohol addiction cycle, from prenatal to adulthood exposure. The first section will focus on alcohol-induced 5-HTergic neuroadaptations in offspring prenatally exposed to alcohol and the consequences on the regulation of stress/anxiety. The second section will compare alterations in 5-HT signalling induced by acute or chronic alcohol exposure during adulthood and following alcohol withdrawal, highlighting the impact on the regulation of stress/anxiety signalling pathways. The third section will outline 5-HTergic neuroadaptations observed in various genetically-selected ethanol preferring rat lines. Finally, we will discuss the pharmacological manipulation of the 5-HTergic system on ethanol- and anxiety/stress-related behaviours demonstrated by clinical trials, with an emphasis on current and potential treatments. PMID- 29765851 TI - Stimulation Mapping of Myelinated Tracts in Awake Patients. AB - For a long time, although the functional anatomy of human cortex has extensively been studied, subcortical white matter tracts have received little consideration. Recent advances in tractography have opened the door to a non-invasive investigation of the subcortical fibers in vivo. However, this method cannot study directly the function of the bundles. Interestingly, for the first time in the history of cognitive neurosciences, direct axonal electrostimulation (DES) mapping of the neural pathways offers the unique opportunity to investigate the function of the connectomal anatomy. Indeed, this technique is able to perform real-time anatomo-functional correlations in awake patients who undergo brain surgery, especially at the level of the subcortical fibers. Here, the aim is to review original data issued from DES of myelinated tracts in adults, with regard to the functional connectivity mediating the sensorimotor, visuo-spatial, language, cognitive and emotional functions, as well as the interactions between these different sub-networks, leading ultimately to explore consciousness. Therefore, axonal stimulation is a valuable tool in the field of connectomics, that is, the map of neural connections, in order to switch from the traditional localizationist view of brain processing to a networking model in which cerebral functions are underpinned by the dynamic interactions of large-scale distributed and parallel sub-circuits. Such connectomal account should integrate the anatomic constraint represented by the subcortical fascicles. Indeed, post-lesional neuroplasticity is possible only on the condition that the white matter fibers are preserved, to allow communication and temporal synchronization among delocalized inter-connected networks. PMID- 29765852 TI - Adult Neurogenesis in Injury-Induced Self-Repair: Use It or Lose It. AB - One of the most hotly pursued topics in neuroscience and therapeutic medicine is the use of stem cells in the adult brain. Growing in parallel to this emerging field is the recognition that the adult brain is indeed capable of generating new cells. While neurogenesis was understood to be restricted to a few areas, recent studies suggest that damage to the adult brain can trigger neurogenesis even in regions outside of these specific areas. This finding raises the possibility that neurons born in response to perturbation in the brain may be involved in the recovery of function in the damaged adult brain. The key is understanding how to cultivate these newborn cells, because they do not remain viable if they are not accepted into the damaged network of interconnected neurons which support specific functions. From a birth site, undifferentiated precursor cells or neurons undergo migration and differentiation. Many factors influence the safe journey of migrating cells and their survival after maturation at their destination. This review will present evidence from ring dove studies that an activity-dependent mechanism underlies the survival of adult newborn neurons and establishment of their functionality. This evidence includes: [1] unique electrophysiological properties or specific connectivity associated with various type of neurons involved in ring dove coo behavior and reproductive function, [2] emergence of electrophysiological properties and specific projection neurons emanating from newborn neurons after hypothalamic lesion, and finally [3] collective behavioral analyses of social stimulations suggesting that sensorimotor events contribute to the integration of new neurons and reinstatement of function. PMID- 29765848 TI - MRI and M/EEG studies of the White Matter Development in Human Fetuses and Infants: Review and Opinion. AB - Already during the last trimester of gestation, functional responses are recorded in foetuses and preterm newborns, attesting an already complex cerebral architecture. Then throughout childhood, anatomical connections are further refined but at different rates and over asynchronous periods across functional networks. Concurrently, infants gradually achieve new psychomotor and cognitive skills. Only the recent use of non-invasive techniques such as magnetic resonance imaging (MRI) and magneto- and electroencephalography (M/EEG) has opened the possibility to understand the relationships between brain maturation and skills development in vivo. In this review, we describe how these techniques have been applied to study the white matter maturation. At the structural level, the early architecture and myelination of bundles have been assessed with diffusion and relaxometry MRI, recently integrated in multi-compartment models and multi parametric approaches. Nevertheless, technical limitations prevent us to map major developmental mechanisms such as fibers growth and pruning, and the progressive maturation at the bundle scale in case of mixing trajectories. At the functional level, M/EEG have been used to record different visual, somatosensory and auditory evoked responses. Because the conduction velocity of neural impulses increases with the myelination of connections, major changes in the components latency are observed throughout development. But so far, only a few studies have related structural and functional markers of white matter myelination. Such multi modal approaches will be a major challenge in future research, not only to understand normal development, but also to characterize early mechanisms of pathologies and the influence of fetal and perinatal interventions on later outcome. PMID- 29765849 TI - Magnetic Resonance of Myelin Water: An in vivo Marker for Myelin. AB - Myelin is critical for healthy brain function. An accurate in vivo measure of myelin content has important implications for understanding brain plasticity and neurodegenerative diseases. Myelin water imaging is a magnetic resonance imaging method which can be used to visualize myelination in the brain and spinal cord in vivo. This review presents an overview of myelin water imaging data acquisition and analysis, post-mortem validation work, findings in both animal and human studies and a brief discussion about other MR techniques purported to provide in vivo myelin content. Multi-echo T2 relaxation approaches continue to undergo development and whole-brain imaging time now takes less than 10 minutes; the standard analysis method for this type of data acquisition is a non-negative least squares approach. Alternate methods including the multi-flip angle gradient echo mcDESPOT are also being used for myelin water imaging. Histological validation studies in animal and human brain and spinal cord tissue demonstrate high specificity of myelin water imaging for myelin. Potential confounding factors for in vivo myelin water fraction measurement include the presence of myelin debris and magnetization exchange processes. Myelin water imaging has successfully been used to study animal models of injury, applied in healthy human controls and can be used to assess damage and injury in conditions such as multiple sclerosis, neuromyelitis optica, schizophrenia, phenylketonuria, neurofibromatosis, niemann pick's disease, stroke and concussion. Other quantitative magnetic resonance approaches that are sensitive to, but not specific for, myelin exist including magnetization transfer, diffusion tensor imaging and T1 weighted imaging. PMID- 29765856 TI - Regulation of Adult Neurogenesis 2.0 - Beyond Signaling Pathways and Transcriptional Regulators. PMID- 29765855 TI - The Acute Effects of Aerobic Exercise on the Functional Connectivity of Human Brain Networks. AB - Although there is promising evidence that regular physical activity could counteract age-related decline in cognitive and brain function, the mechanisms for this neuroprotection remain unclear. The acute effects of exercise can provide insight into the mechanisms by which the brain adapts to habitual exercise by reflecting transient modulations of systems that would subsequently accumulate long-term adaptations through repeated training sessions. However, methodological limitations have hindered the mechanistic insight gained from previous studies examining acute exercise effects on the human brain. In the current study, we tested the plasticity of functional brain networks in response to a single stimulus of aerobic exercise using resting-state functional connectivity analyses. In a sample of healthy younger (N = 12; age = 23.2 years; 6 females) and older adults (N = 13; age = 66.3 years; 6 females), we found that 30 minutes of moderate-intensity aerobic cycling selectively increased synchrony among brain regions associated with affect and reward processing, learning and memory, and in regions important for attention and executive control. Importantly, these changes did not occur when the same participants completed a passive, motor-driven control condition. Our results suggest that these transient increases in synchrony serve as a possible avenue for systematically investigating the effects of various exercise parameters on specific brain systems, which may accelerate mechanistic discoveries about the benefits of exercise on brain and cognitive function. PMID- 29765854 TI - Exercise in a Pill: The Latest on Exercise-Mimetics. AB - There is increasing evidence that an active lifestyle benefits both body and brain. However, not everyone may be able to exercise due to disease, injury or aging-related frailty. Identification of cellular targets activated by physical activity may lead to the development of new compounds that can, to some extent, mimic systemic and central effects of exercise. This review will focus on factors relevant to energy metabolism in muscle, such as the 5' adenosine monophosphate activated protein kinase (AMPK) - sirtuin (SIRT1) - Peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1alpha) pathway, and the molecules affecting it. In particular, putative exercise-mimetics such as AICAR, metformin, and GW501516 will be discussed. Moreover, plant-derived polyphenols such as resveratrol and (-)epicatechin, with exercise-like effects on the body and brain will be evaluated. PMID- 29765853 TI - The Effects of Acute Exercise on Mood, Cognition, Neurophysiology, and Neurochemical Pathways: A Review. AB - A significant body of work has investigated the effects of acute exercise, defined as a single bout of physical activity, on mood and cognitive functions in humans. Several excellent recent reviews have summarized these findings; however, the neurobiological basis of these results has received less attention. In this review, we will first briefly summarize the cognitive and behavioral changes that occur with acute exercise in humans. We will then review the results from both human and animal model studies documenting the wide range of neurophysiological and neurochemical alterations that occur after a single bout of exercise. Finally, we will discuss the strengths, weaknesses, and missing elements in the current literature, as well as offer an acute exercise standardization protocol and provide possible goals for future research. PMID- 29765858 TI - Neural Stem Cell Activation and the Role of Protein Synthesis. AB - Adult neural stem cells are generated at embryonic stages by entering a quiescent state that allows their retention into adulthood and thereby maintenance of life long brain homeostasis. Thus, a tight balance between the quiescence and activation state is instrumental to meet the brain demands for a specific cell type at the correct numbers, at a given time and position. Protein synthesis is the most energy-consuming process within the cell and, not surprisingly, it occurs at low rates in quiescent stem cells. This way quiescent cells adjust to energy constraints and avoid their premature depletion. Stem cell activation is characterized by upregulation of protein synthesis followed by cell division and differentiation. The role of such upregulation as causative or rather a consequence of the activation remains elusive. Here we summarize recent findings connecting stem cell activation to the regulation of protein synthesis, particularly focusing on embryonic and adult neural stem cells of the ventricular zone. PMID- 29765857 TI - DNA Methylation and Adult Neurogenesis. AB - The role of DNA methylation in brain development is an intense area of research because the brain has particularly high levels of CpG and mutations in many of the proteins involved in the establishment, maintenance, interpretation, and removal of DNA methylation impact brain development and/or function. These include DNA methyltransferase (DNMT), Ten-Eleven Translocation (TET), and Methyl CpG binding proteins (MBPs). Recent advances in sequencing breadth and depth as well the detection of different forms of methylation have greatly expanded our understanding of the diversity of DNA methylation in the brain. The contributions of DNA methylation and associated proteins to embryonic and adult neurogenesis will be examined. Particular attention will be given to the impact on adult hippocampal neurogenesis (AHN), which is a key mechanism contributing to brain plasticity, learning, memory and mood regulation. DNA methylation influences multiple aspects of neurogenesis from stem cell maintenance and proliferation, fate specification, neuronal differentiation and maturation, and synaptogenesis. In addition, DNA methylation during neurogenesis has been shown to be responsive to many extrinsic signals, both under normal conditions and during disease and injury. Finally, crosstalk between DNA methylation, Methyl-DNA binding domain (MBD) proteins such as MeCP2 and MBD1 and histone modifying complexes is used as an example to illustrate the extensive interconnection between these epigenetic regulatory systems. PMID- 29765860 TI - The Role of Lipid Metabolism for Neural Stem Cell Regulation. AB - Neural stem/progenitor cells (NSPCs) give rise to billions of cells during development and are critical for proper brain formation. The finding that NSPCs persist throughout adulthood has challenged the view that the brain has poor regenerative abilities and raised hope for stem cell-based regenerative therapies. For decades there has been a strong movement towards understanding the requirements of NSPCs and their regulation, resulting in the discovery of many transcription factors and signaling pathways that can influence NSPC behavior and neurogenesis. However, the role of metabolism for NSPC regulation has only gained attention recently. Lipid metabolism in particular has been shown to influence proliferation and neurogenesis, offering exciting new possible mechanisms of NSPC regulation, as lipids are not only the building blocks of membranes, but can also act as alternative energy sources and signaling entities. Here I review the recent literature examining the role of lipid metabolism for NSPC regulation and neurogenesis. PMID- 29765862 TI - Genomic Imprinting and the Regulation of Postnatal Neurogenesis. AB - Most genes required for mammalian development are expressed from both maternally and paternally inherited chromosomal homologues. However, there are a small number of genes known as "imprinted genes" that only express a single allele from one parent, which is repressed on the gene from the other parent. Imprinted genes are dependent on epigenetic mechanisms such as DNA methylation and post translational modifications of the DNA-associated histone proteins to establish and maintain their parental identity. In the brain, multiple transcripts have been identified which show parental origin-specific expression biases. However, the mechanistic relationship with canonical imprinting is unknown. Recent studies on the postnatal neurogenic niches raise many intriguing questions concerning the role of genomic imprinting and gene dosage during postnatal neurogenesis, including how imprinted genes operate in concert with signalling cues to contribute to newborn neurons' formation during adulthood. Here we have gathered the current knowledge on the imprinting process in the neurogenic niches. We also review the phenotypes associated with genetic mutations at particular imprinted loci in order to consider the impact of imprinted genes in the maintenance and/or differentiation of the neural stem cell pool in vivo and during brain tumour formation. PMID- 29765863 TI - Autophagy and Adult Neurogenesis: Discoveries Made Half a Century Ago Yet in their Infancy of being Connected. AB - Within the brain, the physiological and pathological functions of autophagy in development and throughout the lifespan are being elucidated. This review summarizes recent in vitro and in vivo results that are defining the role of autophagy-related genes during the process of adult neurogenesis. We also discuss the need for future experiments to determine the molecular mechanism and functional significance of autophagy in the different neural stem cell populations and throughout the stages of adult neurogenesis. PMID- 29765864 TI - Non-canonical post-transcriptional RNA regulation of neural stem cell potential. AB - Adult brain structures and complexity emerge from a single layer of neuroepithelial cells that early during the development give rise to neural stem cells (NSCs). NSCs persist in restricted regions of the postnatal brain where they support neurogenesis throughout life thus allowing brain plasticity and adaptation. NSC regulation involves a precise coordination of intrinsic and extrinsic mechanisms that finely modulate the neurogenic process. Here we will discuss new mechanisms of post-transcriptional gene regulation that act in the embryonic and adult brain to regulate NSC maintenance and differentiation. In our recent work we found that the RNAaseIII Drosha not only regulates microRNA production, but also directly affects the stability of mRNAs and thereby controls proteome composition. This non-canonical (miRNA-independent) function of Drosha is central in the maintenance and fate choices made by adult hippocampal NSCs in the healthy brain. We found that Drosha targets the mRNA of the gliogenic transcription factor Nuclear Factor I/B and thereby blocks its expression in the NSCs. In the absence of Drosha, NSCs aberrantly differentiate into oligodendrocytes and are lost leading to an impairment of neurogenesis. Overall these findings reveal an unprecedented Drosha-mediated post-transcriptional mechanism for the regulation of hippocampal NSC potential. PMID- 29765859 TI - miRNA-Mediated Regulation of Adult Hippocampal Neurogenesis; Implications for Epilepsy. AB - Hippocampal neural stem/progenitor cells (NSPCs) proliferate and differentiate to generate new neurons across the life span of most mammals, including humans. This process takes place within a characteristic local microenvironment where NSPCs interact with a variety of other cell types and encounter systemic regulatory factors. Within this microenvironment, cell intrinsic gene expression programs are modulated by cell extrinsic signals through complex interactions, in many cases involving short non-coding RNA molecules, such as miRNAs. Here we review the regulation of gene expression in NSPCs by miRNAs and its possible implications for epilepsy, which has been linked to alterations in adult hippocampal neurogenesis. PMID- 29765867 TI - Tongue reshaping: a new surgical method to prevent self-sucking in dairy cows. AB - Self-sucking behaviors lead to substantial milk loss and inflammation of the udder and teats among dairy cows. Both conservative and surgical approaches are available to prevent such behavior; however, the current methods are limited by variable efficacy and risk of complications. The objective of the present study was to evaluate a new minimally invasive technique for reshaping of the tongue to prevent self-sucking. The current technique was performed on five mixed breed dairy cows aged 4-6 years and with a mean weight 320 kgs. Reshaping of the normal contour of the tongue was achieved by the application of multiple interrupted inverting sutures to the ventral surface to prevent the tongue from forming "U" shape. Post-operative approach included antiseptic mouth wash with povidone iodine solution twice daily and recording the healing process and complications. The mean operative time was 12+/-1 minutes. No complications except superficial pressure wounds from 3rd up to 10th day post-operative were observed. At three months follow up all treated cows had stopped self-sucking. One-shot tongue reshaping is an easy, minimally invasive, effective, and time-saving procedure for the treatment of self-sucking among dairy cows, with the advantage of causing little tissue damage. PMID- 29765866 TI - Effects of endosulfan isomers on cytokine and nitric oxide production by differentially activated RAW 264.7 cells. AB - Endosulfan is an organochlorine insecticide comprised of two isomers: endosulfan alpha and endosulfan-beta. Endosulfan exposure has been shown to elevate some inflammatory factors, such as nitric oxide (NO) and tumor necrosis factor (TNF), in animals or cultures of animal cells. Because the two endosulfan isomers can vary in their biological activities, the goal of this study was to determine if individual endosulfan isomers differentially impact production of NO or TNF by the mouse macrophage cell RAW 264.7 at non-cytotoxic levels. We found elevated TNF with exposure to endosulfan-alpha (not endosulfan-beta), but only at concentrations that were cytotoxic (>=100 MUM), whereas neither endosulfan isomer altered baseline levels of NO at any concentration up to 300 MUM. In interferon (IFN)-gamma-activated cultures, NO levels were significantly suppressed by either endosulfan isomer at 10 MUM (the lowest concentration examined), whereas only endosulfan-beta significantly lowered TNF levels at non-cytotoxic concentrations. In lipopolysaccharide (LPS)-activated cultures, both endosulfan isomers significantly reduced NO, but not TNF, at non-cytotoxic concentrations. These results suggest that the endosulfan isomers have some capacity to alter inflammatory responses differentially, particularly with IFN-gamma stimulation. PMID- 29765865 TI - A protocatechuate biosensor for Pseudomonas putida KT2440 via promoter and protein evolution. AB - Robust fluorescence-based biosensors are emerging as critical tools for high throughput strain improvement in synthetic biology. Many biosensors are developed in model organisms where sophisticated synthetic biology tools are also well established. However, industrial biochemical production often employs microbes with phenotypes that are advantageous for a target process, and biosensors may fail to directly transition outside the host in which they are developed. In particular, losses in sensitivity and dynamic range of sensing often occur, limiting the application of a biosensor across hosts. Here we demonstrate the optimization of an Escherichia coli-based biosensor in a robust microbial strain for the catabolism of aromatic compounds, Pseudomonas putida KT2440, through a generalizable approach of modulating interactions at the protein-DNA interface in the promoter and the protein-protein dimer interface. The high-throughput biosensor optimization approach demonstrated here is readily applicable towards other allosteric regulators. PMID- 29765861 TI - Mitochondrial Metabolism-Mediated Regulation of Adult Neurogenesis. AB - The life-long generation of new neurons from radial glia-like neural stem cells (NSCs) is achieved through a stereotypic developmental sequence that requires precise regulatory mechanisms to prevent exhaustion or uncontrolled growth of the stem cell pool. Cellular metabolism is the new kid on the block of adult neurogenesis research and the identity of stage-specific metabolic programs and their impact on neurogenesis turns out to be an emerging research topic in the field. Mitochondrial metabolism is best known for energy production but it contains a great deal more. Mitochondria are key players in a variety of cellular processes including ATP synthesis through functional coupling of the electron transport chain and oxidative phosphorylation, recycling of hydrogen carriers, biosynthesis of cellular building blocks, and generation of reactive oxygen species that can modulate signaling pathways in a redox-dependent fashion. In this review, I will discuss recent findings describing stage-specific modulations of mitochondrial metabolism within the adult NSC lineage, emphasizing its importance for NSC self-renewal, proliferation of neural stem and progenitor cells (NSPCs), cell fate decisions, and differentiation and maturation of newborn neurons. I will furthermore summarize the important role of mitochondrial dysfunction in tissue regeneration and ageing, suggesting it as a potential therapeutic target for regenerative medicine practice. PMID- 29765868 TI - Retrobulbar steatitis and meningitis/empyema secondary to right otitis media, right otitis interna and an inflammatory polyp in a cat. AB - The purpose was to describe a case of retrobulbar steatitis and meningitis in a cat caused by otitis media, otitis interna and an inflammatory polyp in the middle ear. Investigations included ophthalmic and neurological examinations, haematology and biochemistry, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and aerobic, anaerobic bacterial and fungal culture of material from the middle ear. A 6-year-old female neutered domestic-short-haired cat presented with right-sided exophthalmos and resistance to retropulsion. Anisocoria, reduced corneal sensation and oculocephalic movements and low Schirmer tear test (STT1) were found. An MRI revealed the right external ear canal and tympanic bulla to be fluid filled with presence of a thickened contrast enhancing mucosa. Contrast enhancement extended into the calvarium, as marked thickening and contrast enhancement of the pachymeninges, and further rostrally through the right orbital fissure into the orbit. The retrobulbar tissues were swollen, resulting in mild exophthalmos. Enrichment culture of material from the middle ear revealed Klebsiella pneumonia susceptible to marbofloxacin. The cat underwent a total ear canal ablation with removal of the cartilaginous cuff at the external auditory meatus and local debridement and curettage. A polypoid structure was removed from the middle ear. No bulla osteotomy was performed. Horner's syndrome was present immediately following surgery. The cat received a course of systemic dexamethasone (1mg/cat SID/3 weeks) tapered off and marbofloxacin (2mg/kg SID/2 weeks). Follow up at 120 days showed no recurrence of the symptoms. The Horner's syndrome and low STT1 had resolved and returned to normal values respectively. This case highlights the importance of MRI in the investigation of retrobulbar diseases. MRI is a useful tool for the evaluation of the extent of the lesion and the appearance of adjacent structures in which additional potentially life-threatening abnormalities, such as meningitis, can be seen. PMID- 29765869 TI - Nutritional secondary hyperparathyroidism in two ponies. AB - Nutritional secondary hyperparathyroidism (NSH) is uncommon in horses. Aim of this report is evaluate an alternative therapeutic approach and provide more information on the diagnostic procedures, through detailed microscopic findings of the bone lesions pony with NSH. Administration of tiludronate along with a balanced diet can be used in a treatment protocol for ponies with NSH. This case report suggests that tiludronate can be used to ameliorate the clinical signs of NSH. PMID- 29765870 TI - Low starting dosage of infliximab with possible escalating dosage in psoriatic arthritis gives the same treatment results as standard dosage of adalimumab or etanercept: results from the nationwide Icelandic ICEBIO registry. AB - Objective: To explore differences in response to a low dosage regimen of infliximab with an escalating dosage in comparison to a standard dosage of etanercept and adalimumab in patients with psoriatic arthritis (PsA). Methods: Biologically naive PsA patients who were beginning anti-TNF-alpha therapy were selected from the ICEBIO registry. Demographics and clinical differences were compared in four treatment groups: infliximab <4 mg/kg; infliximab >4 mg/kg; etanercept or adalimumab at baseline and on follow-up (6 and 12 months, last visit). The Kruskal-Wallis rank sum test was used for comparison of the groups and the Wilcoxon test to compare the two infliximab dosage regimens. Results: One hundred and eighty-five patients (61% female) were identified; 84 patients received infliximab, 66 etanercept, and 35 adalimumab. A total of 19% of the patients treated with infliximab escalated their dosage >=4 mg/kg. No significant differences were observed at baseline in respect to visual analog scale (VAS) pain, VAS fatigue, Health Assessment Questionnaire, C-reactive protein (CRP), numbers of swollen or tender joints, or Disease Activity Score (DAS) 28-CRP values. A similar treatment response was observed in all four treatment groups on follow-up. Conclusion: In respect to treatment effects, a low dosage of infliximab with possible escalating dosage is acceptable for the majority of PsA patients who are in need of biological treatment. PMID- 29765871 TI - Optimizing medicine use for people who are homebound: an evaluation of a pilot domiciliary Medicine Use Review (dMUR) service in England. AB - Background: As global life expectancy increases, older people with chronic diseases are being required to manage multiple and complex medicine regimes. However, polypharmacy raises the risk of medicine-related problems and preventable hospital admissions. To improve medicine use, English community pharmacies are commissioned to deliver Medicines Use Reviews (MURs), which are typically delivered from the pharmacy. People who are homebound rarely receive the service. This paper describes the uptake and impact of a pilot project that seeks to provide domiciliary Medicines Use Reviews (dMURs). Methods: Participating pharmacists collected data on their dMUR activity over a 12-month period. Outcome measures (eg, adherence, side-effects, pharmacist assessment of preventable hospital admissions) were recorded. Pharmacists were also invited to submit written testimonies of their experiences of undertaking dMURs. Results: Out of 433 possible pharmacies eligible to take part in the pilot, 186 pharmacies expressed an interest, and 91 actively engaged in providing the dMUR service. The total number of dMURs performed were 1092 (mean number performed by each pharmacy was 12). Two thirds of patients reported problems and concerns about side-effects and missed doses regarding their medicines. Pharmacists' assessment to prevent hospital admissions found that over one-third of the dMURs had contributed towards preventing either a possible or likely emergency hospital admission. Twelve pharmacists' testimonies were submitted providing context of the problems patients faced with medicines. Discussion: dMURs are feasible and improve patient medicines use. The results indicate that dMUR potentially prevents hospital admissions and readmissions. dMURs offer an opportunity to support the self-care agenda and ensure homebound patients can successfully manage their medicines. PMID- 29765872 TI - Effect of Caregiver Driven Robot-Assisted In-Ward Training in Subacute Stroke Patients: A Case Series. AB - Objective: To evaluate the effect of caregiver driven robot-assisted in-ward training in subacute stroke patients. Methods: A retrospective evaluation was performed for patients treated with caregiver driven robot-assisted in-ward training to retain gait function from June 2014 and December 2016. All patients received more than 2 weeks of caregiver driven robot-assisted in-ward training after undergoing conventional programs. The robot was used as a sitting device, a standing frame, or a high-walker depending on functional status of the patient. Patients were evaluated before and after robot training. Patient records were assessed by Korean version of Modified Barthel Index (K-MBI), Functional Independence Measure (FIM), and Functional Ambulation Category (FAC). Results: Initially, patients used the robot as a sitting device (n=6), a standing frame (n=7), or a partial body-weight support high-walker (n=2). As patient functions were improved, usage level of the robot was changed to the next level. At the end of the treatment, the robot was used as a sitting device (n=1), a standing frame (n=6), or high-walker (n=8). Scores of K-MBI (Delta17.47+/-10.72) and FIM (Delta19.80+/-12.34) were improved in all patients. Conclusion: Patients' usage level of the robot and functional scores were improved. Therefore, performing additional caregiver driven robot-assisted in-ward training is feasible and beneficial for subacute stroke patients. PMID- 29765874 TI - Predictive Variables for Sonographically Guided Corticosteroid Injection in Mild to-Moderate Carpal Tunnel Syndrome. AB - Objective: To assess the predictive variables after sonographically guided corticosteroid injection in carpal tunnel syndrome. Methods: A prospective, observational study was carried out on 25 wrists of 20 consecutive patients with carpal tunnel syndrome, confirmed by the American Association of Neuromuscular and Electrodiagnostic Medicine criteria, which includes clinical history, symptoms, and evidence of slowing of distal median nerve conduction. Visual analogue scale (VAS) and Boston Carpal Tunnel Questionnaire (BCTQ) were asked to the patients before and 4 weeks after the procedure. On a basis of VAS difference before and after the procedure, we divided the patients into two groups: more than 50% of VAS improving (good response group) and less than 50% of VAS improving (poor response group). Also, nerve conduction studies and ultrasound evaluations were performed prior to sonographically guided corticosteroid injection and at 4 weeks after the procedure. The cross-sectional area (CSA) of median nerve at maximal swelling point around wrist was measured by manual tracing using ultrasonography. With assessments mentioned above, we tried to assess predictive variables for prognosis after sonographically guided corticosteroid injection in carpal tunnel syndrome. Results: The CSA of median nerve at wrist measured before the procedure was significantly larger in good response group than in poor response group. Furthermore, the CSA of median nerve at wrist, symptom severity scale of BCTQ, motor/sensory latency and sensory amplitude were correlated with VAS improving. Conclusion: The CSA of median nerve at wrist is the strongest predictive value for sonographically guided corticosteroid injection in mild-to-moderate carpal tunnel syndrome. PMID- 29765873 TI - Characteristics of Cricopharyngeal Dysphagia After Ischemic Stroke. AB - Objective: To evaluate the characteristics of cricopharyngeal dysfunction (CPD), the frequency, and correlation with a brain lesion in patients with first-ever ischemic stroke, and to provide basic data for developing a therapeutic protocol for dysphagia management. Methods: We retrospectively reviewed the medical records of a series of subjects post-stroke who underwent a videofluoroscopic swallowing study (VFSS) from January 2009 to December 2015. VFSS images were recorded on videotape and analyzed. CPD was defined as the retention of more than 25% of residue in the pyriform sinus after swallowing. The location of the brain lesion was assessed using magnetic resonance imaging. Results: Among the 262 dysphagic patients with first-ever ischemic stroke, 15 (5.7%) showed CPD on the VFSS. Patients with an infratentorial lesion had a significantly higher proportion of CPD than those with a supratentorial lesion (p=0.003), and lateral medullary infarction was identified as the single independent predictor of CPD (multivariable analysis: odds ratio=19.417; confidence interval, 5.560-67.804; p<0.0001). Compared to patients without CPD, those with CPD had a significantly prolonged pharyngeal transit time, lower laryngeal elevation, and a higher pharyngeal constriction ratio and functional dysphagia scale score. Conclusion: Overall, the results support the notion that an impaired upper esopharyngeal opening is likely related to the specific locations of brain lesions. The association of CPD with lateral medullary infarction can be explained based on the regulation of the pharyngolaryngeal motor system by the motor neurons present in the dorsal nucleus ambiguus. Overall, the results reveal the relation between CPD and the problems in the pharyngeal phase as well as the severity of dysphagia. PMID- 29765875 TI - Clinical and Biomechanical Effects of Low-Dye Taping and Figure-8 Modification of Low-Dye Taping in Patients With Heel Pad Atrophy. AB - Objective: To investigate and compare the effect of low-dye taping (LDT) and figure-8 modification of LDT (MLDT) on peak plantar pressure and heel pain in patients with heel pad atrophy. Methods: There were reviewed 32 feet of 19 patients who have been diagnosed with heel pad atrophy who were enrolled in this study. The patients were diagnosed with heel pad atrophy with clinical findings, and loaded heel pad thickness measured by ultrasonography. At the first visit, patients were taught how to do LDT and MLDT. They were instructed to do daily living with barefoot, LDT and MLDT at least one time per day. Patients performed pedobarography with barefoot, LDT and MLDT within 2 weeks. The severity of heel pain was also checked with the visual analogue scale (VAS) during daily living with barefoot, LDT and MLDT. Results: VAS of hindfoot were significantly decreased after LDT and MLDT (p<0.01). Peak plantar pressure under hindfoot were also decreased after LDT and MLDT (p<0.01). The effect of MLDT in decreasing peak plantar pressure of hindfoot (p<0.01) and pain relief (p=0.001) was better than the effect of LDT. Conclusion: The LDT technique is clinically useful for pain management and reducing peak plantar pressure of hindfoot in patients with heel pad atrophy. MLDT is more effective than LDT in reducing peak plantar pressure and heel pain in patients with heel pad atrophy. PMID- 29765876 TI - Effects of Repetitive Peripheral Magnetic Stimulation on Patients With Acute Low Back Pain: A Pilot Study. AB - Objective: To investigate the effects of real repetitive peripheral magnetic stimulation (rPMS) treatment compared to sham rPMS treatment on pain reduction and functional recovery of patients with acute low back pain. Methods: A total of 26 patients with acute low back pain were randomly allocated to the real rPMS group and the sham rPMS group. Subjects were then administered a total of 10 treatment sessions. Visual analogue scale (VAS) was assessed before and after each session. Oswestry Disability Index (ODI) and Roland-Morris Disability Questionnaire (RMDQ) were employed to assess functional recovery at baseline and after sessions 5 and 10. Results: Real rPMS treatment showed significant pain reduction immediately after each session. Sustained and significant pain relief was observed after administering only one session in the real rPMS group. Significant functional improvement was observed in the real rPMS group compared to that in the sham rPMS group after sessions 5 and 10 based on ODI and after session 5 based on RMDQ. Conclusion: Real rPMS treatment has immediate effect on pain reduction and sustained effect on pain relief for patients with acute low back pain compared to sham rPMS. PMID- 29765877 TI - Gender-Related Differences in Reliability of Thorax, Lumbar, and Pelvis Kinematics During Gait in Patients With Non-specific Chronic Low Back Pain. AB - Objective: To evaluate test-retest reliability of trunk kinematics relative to the pelvis during gait in two groups (males and females) of patients with non specific chronic low back pain (NCLBP) using three-dimensional motion capture system. Methods: A convenience sample of 40 NCLBP participants (20 males and 20 females) was evaluated in two sessions. Participants were asked to walk with self selected speed and kinematics of thorax and lumbar spine were captured using a 6 infrared-cameras motion-analyzer system. Peak amplitude of displacement and its measurement errors and minimal detectable change (MDC) were then calculated. Results: Intraclass correlation coefficients (ICCs) were relatively constant but small for certain variables (lower lumbar peak flexion in female: inter-session ICC=0.51 and intra-session ICC=0.68; peak extension in male: inter-session ICC=0.67 and intra-session ICC=0.66). The measurement error remained constant and standard error of measurement (SEM) difference was large between males (generally <=4.8 degrees ) and females (generally <=5.3 degrees ). Standard deviation (SD) was higher in females. In most segments, females exhibited higher MDCs except for lower lumbar sagittal movements. Conclusion: Although ICCs were sufficiently reliable and constant in both genders during gait, there was difference in SEM due to difference in SD between genders caused by different gait disturbance in chronic low back pain. Due to the increasing tendency of measurement error in other areas of men and women, attention is needed when measuring lumbar motion using the method described in this study. PMID- 29765878 TI - Effects of Very High Stimulation Frequency and Wide-Pulse Duration on Stimulated Force and Fatigue of Quadriceps in Healthy Participants. AB - Objective: To determine the effect of very high stimulation frequency (150 and 200 Hz) with wide pulse duration versus 50 Hz with wide pulse duration on stimulated force and fatigue of quadriceps femoris in healthy participants. Methods: Thirty-four healthy participants underwent fatigue test using three stimulation frequency conditions (50, 150, and 200 Hz) with pulse duration of 0.9 ms. Normalized force values at the end of each fatigue protocol and curve fitting patterns were compared among stimulated frequencies. Results: Very high stimulation frequency (150 and 200 Hz) conditions showed a trend of having more decline in normalized stimulated force during fatigue test compared to a low stimulation frequency at 50 Hz. However, the difference was not statistically significant. Responder group showed the same slope of a linear fitting pattern, implying the same pattern of muscle fatigue among three stimulation frequency conditions (-3.32 in 50 Hz, -2.88 in 150 Hz, and -3.14 in 200 Hz, respectively). Conclusion: There were high inter-subject variations in the response to different frequency stimulation conditions. However, very high stimulation frequency generated the same fatigue pattern as the low stimulation frequency in the responder group. Further research is needed to explore the mechanism involved. PMID- 29765880 TI - Pressure Relieving Effect of Adding a Pelvic Well Pad to a Wheelchair Cushion in Individuals With Spinal Cord Injury. AB - Objective: To identify the pressure relieving effect of adding a pelvic well pad, a firm pad that is cut in the ischial area, to a wheelchair cushion on the ischium. Methods: Medical records of 77 individuals with SCI, who underwent interface pressure mapping of the buttock-thigh area, were retrospectively reviewed. The pelvic well pad is a 2.5-cm thick firm pad and has a cut in the ischial area. Expecting additional pressure relief, it can be inserted under a wheelchair cushion. Subjects underwent interface pressure mapping in the subject's wheelchair utilizing the subject's pre-existing pressure relieving cushion and subsequently on a combination of a pelvic well pad and the cushion. The average pressure, peak pressure, and contact area of the buttock-thigh were evaluated. Results: Adding a pelvic well pad, under the pressure relieving cushion, resulted in a decrease in the average and peak pressures and increase in the contact area of the buttock-thigh area when compared with applying only pressure relieving cushions (p<0.05). The mean of the average pressure decreased from 46.10+/-10.26 to 44.09+/-9.92 mmHg and peak pressure decreased from 155.03+/ 48.02 to 131.42+/-45.86 mmHg when adding a pelvic well pad. The mean of the contact area increased from 1,136.44+/-262.46 to 1,216.99+/-255.29 cm2. Conclusion: When a pelvic well pad was applied, in addition to a pre-existing pressure relieving cushion, the average and peak pressures of the buttock-thigh area decreased and the contact area increased. These results suggest that adding a pelvic well pad to wheelchair cushion may be effective in preventing a pressure ulcer of the buttock area. PMID- 29765879 TI - Quantitative Measurement of Muscle Atrophy and Fat Infiltration of the Supraspinatus Muscle Using Ultrasonography After Arthroscopic Rotator Cuff Repair. AB - Objective: To investigate the utility of ultrasonography to objectively examine morphological changes (i.e., muscle atrophy and fatty infiltration) of the supraspinatus muscle. Methods: Thirty-four patients were prospectively enrolled in this study. The degrees of muscle atrophy and fat infiltration were measured using ultrasonography 3-4 months after arthroscopic supraspinatus tendon repair. Shoulder function (i.e., shoulder active range of motion, visual analogue scale, and constant score) was examined. Using the symmetricity of the muscles in the human body, the degrees of morphological changes of the supraspinatus muscle were quantitatively measured. The associations between the morphological changes of the supraspinatus muscle and shoulder function were identified. Results: There were statistically significant differences in the cross-sectional area (CSA) and echogenicity between the surgery and non-surgery sides (p<0.001). The CSA ratio, which represents the degree of muscle atrophy, was associated with shoulder forward flexion, external rotation, and constant score; however, the echogenicity ratio, which represents the degree of fat infiltration, was not associated with shoulder function after surgery. Conclusion: This study demonstrated that shoulder function could be predicted by evaluating the morphological changes of the supraspinatus muscle using ultrasonography and that objective evaluation is possible through quantitative measurement using the symmetricity of the human body. PMID- 29765881 TI - Determinants of Hip and Femoral Deformities in Children With Spastic Cerebral Palsy. AB - Objective: To find factors affecting hip and femoral deformities in children with spastic cerebral palsy (CP) by comparing various clinical findings with imaging studies including plain radiography and computed tomography (CT) imaging. Methods: Medical records of 709 children with spastic CP who underwent thorough baseline physical examination and functional assessment between 2 to 6 years old were retrospectively reviewed. Fifty-seven children (31 boys and 26 girls) who had both plain radiography of the hip and three-dimensional CT of the lower extremities at least 5 years after baseline examination were included in this study. Results: The mean age at physical examination was 3.6 years (SD=1.6; range, 2-5.2 years) and the duration of follow-up imaging after baseline examination was 68.4 months (SD=22.0; range, 60-124 months). The migration percentage correlated with motor impairment and the severity of hip adductor spasticity (R1 angle of hip abduction with knee flexion). The femoral neck and shaft angle correlated with the ambulation ability and severity of hip adductor spasticity (R1 and R2 angles of hip abduction with both knee flexion and extension). Conclusion: Hip subluxation and coxa valga deformity correlated with both dynamic spasticity and shortening of hip adductor muscles. However, we found no correlation between femoral deformities such as femoral anteversion, coxa valga, and hip subluxation. PMID- 29765882 TI - Relationship Between Functional Level and Muscle Thickness in Young Children With Cerebral Palsy. AB - Objective: To investigate the relationship between functional level and muscle thickness (MT) of the rectus femoris (RF) and the gastrocnemius (GCM) in young children with cerebral palsy (CP). Methods: The study participants were comprised of 26 children (50 legs) with spastic CP, aged 3-6 years, and 25 age-matched children with typical development (TD, 50 legs). The MT of the RF, medial GCM, and lateral GCM was measured with ultrasound imaging. The functional level was evaluated using the Gross Motor Function Measurement-88 (GMFM-88), Gross Motor Function Classification System (GMFCS), and based on the mobility area of the Korean version of the Modified Barthel Index (K-MBI). The measurement of spasticity was evaluated with the Modified Ashworth Scale (MAS). Results: We note that the height, weight, body mass index, and MT of the RF, and the medial and lateral GCM were significantly higher in the TD group (p<0.05). There was a direct relationship between MT of the RF and medial GCM and the GMFM-88, GMFCS, and mobility scores of the K-MBI in individuals with early CP. In addition, we have noted that there was a direct relationship between MT of the lateral GCM and the GMFM-88 and GMFCS. Although there was a tendency toward lower MT with increasing MAS ratings in the knee and ankle, the correlation was not statistically significant. Conclusion: In young children with CP, MT of the RF and GCM was lower than in age-matched children with TD. Furthermore, it is noted with confidence that a significant positive correlation existed between MT and functional level as evaluated using the GMFM-88, GMFCS, and mobility area of K MBI. PMID- 29765883 TI - The Validity of Two Neuromotor Assessments for Predicting Motor Performance at 12 Months in Preterm Infants. AB - Objective: To evaluate the validity of the Test of Infant Motor Performance (TIMP) and general movements (GMs) assessment for predicting Alberta Infant Motor Scale (AIMS) score at 12 months in preterm infants. Methods: A total of 44 preterm infants who underwent the GMs and TIMP at 1 month and 3 months of corrected age (CA) and whose motor performance was evaluated using AIMS at 12 months CA were included. GMs were judged as abnormal on basis of poor repertoire or cramped-synchronized movements at 1 month CA and abnormal or absent fidgety movement at 3 months CA. TIMP and AIMS scores were categorized as normal (average and low average and >5th percentile, respectively) or abnormal (below average and far below average or <5th percentile, respectively). Correlations between GMs and TIMP scores at 1 month and 3 months CA and the AIMS classification at 12 months CA were examined. Results: The TIMP score at 3 months CA and GMs at 1 month and 3 months CA were significantly correlated with the motor performance at 12 months CA. However, the TIMP score at 1 month CA did not correlate with the AIMS classification at 12 months CA. For infants with normal GMs at 3 months CA, the TIMP score at 3 months CA correlated significantly with the AIMS classification at 12 months CA. Conclusion: Our findings suggest that neuromotor assessment using GMs and TIMP could be useful to identify preterm infants who are likely to benefit from intervention. PMID- 29765885 TI - Comparison of Second and Third Editions of the Bayley Scales in Children With Suspected Developmental Delay. AB - Objective: To compare the scores of the Bayley Scales of Infant Development second edition (BSID-II) and the third edition, Bayley-III, in children with suspected developmental delay and to determine the cutoff score for developmental delay in the Bayley-III. Methods: Children younger than 42 months (n=62) with suspected developmental delay who visited our department between 2014 and 2015 were assessed with both the BSID-II and Bayley-III tests. Results: The mean Bayley-III Cognitive Language Composite (CLC) score was 5.8 points higher than the mean BSID-II Mental Developmental Index (MDI) score, and the mean Bayley-III Motor Composite (MC) score was 7.9 points higher than the mean BSID-II Psychomotor Developmental Index (PDI) score. In receiver operating characteristic (ROC) analysis of a BSID-II MDI score <70, Bayley-III CLC scores showed a cutoff of 78.0 (96.6% sensitivity and 93.9% specificity). In ROC analysis of a BSID-II PDI score <70, the Bayley-III MC score showed a cutoff of 80. Conclusion: There was a strong correlation between the BSID-II and Bayley-III in children with suspected developmental delay. The Bayley-III identified fewer children with developmental delay. The recommended cutoff value for developmental delay increased from a BSID-II score of 70 to a Bayley-III CLC score of 78 and Bayley III MC score of 80. PMID- 29765884 TI - Visual Evoked Potential in Children With Developmental Disorders: Correlation With Neurodevelopmental Outcomes. AB - Objective: To investigate the neurodevelopmental outcomes in children with developmental disorder according to visual evoked potential (VEP) results. Methods: We retrospectively analyzed children who visited our Department of Pediatric Rehabilitation Medicine with a chief complaint of developmental disability from January 2001 to July 2015. Of the 549 medical records reviewed, 322 children younger than 42 months who underwent both Bayley Scales of Infant and Toddler Development second edition (BSID-II) and VEP studies were enrolled. We compared the development of 182 children with normal VEP latency and 140 children with delayed VEP latency results using the BSID-II results. The Mann Whitney U-test was used to analyze the differences between the two groups. Results: There were no significant differences in baseline characteristics between the two groups. The delayed VEP latency group showed a significant delay in BSID-II index scores and developmental quotients compared with the normal VEP latency group. In addition, a comparative analysis of developmental quotients of mental and psychomotor domains according to age (younger than 12 months, 12-23 months, and 24-42 months) revealed significantly lower values in children with delayed VEP latency compared to children with normal VEP latency, younger than 12 months and from 12 to 23 months. Conclusion: Children with delayed VEP latency showed more developmental delay than children with normal VEP latency. It is suggested that VEP can be easily applied to children with suspected developmental delay when physicians have concerns about visual impairment. Furthermore, it is proposed that VEP results could provide an insight into children's development and serve as early indicators for consultation with an ophthalmologist for the existing problem. PMID- 29765886 TI - Reference Value for Infrapatellar Branch of Saphenous Nerve Conduction Study: Cadaveric and Clinical Study. AB - Objective: To determine the optimal stimulation and recording site for infrapatellar branch of saphenous nerve (IPBSN) conduction studies by a cadaveric study, and to confirm that obtained location is practically applicable to healthy adults. Methods: Twelve lower limbs from six cadavers were studied. We defined the optimal stimulation site as the point IPBSN exits the sartorius muscle and the distance or ratio were measured on the X- and Y-axis based on the line connecting the medial and lateral poles of the patella. We defined the optimal recording site as the point where the terminal branch met the line connecting inferior pole of patella and tibial tuberosity, and measured the distance from the inferior pole. Also, nerve conduction studies were performed with obtained location in healthy adults. Results: In optimal stimulation site, the mean value of X-coordinate was 55.50+/-6.10 mm, and the ratio of the Y-coordinate to the thigh length was 25.53%+/-5.40%. The optimal recording site was located 15.92+/ 1.83 mm below the inferior pole of patella. In our sensory nerve conduction studies through this location, mean peak latency was 4.11+/-0.30 ms and mean amplitude was 4.16+/-1.49 uV. Conclusion: The optimal stimulation site was located 5.0-6.0 cm medial to medial pole of the patella and 25% of thigh length proximal to the X-axis. The optimal recording site was located 1.5-2.0 cm below inferior pole of patella. We have also confirmed that this location is clinically applicable. PMID- 29765887 TI - Validation of Korean Version of the London Chest Activity of Daily Living Scale in Patients With Chronic Obstructive Pulmonary Disease. AB - Objective: To translate the English version of the London Chest Activity of Daily Living scale (LCADL) into a Korean version and to determine the reliability and validity of the Korean version in patients with chronic obstructive pulmonary disease (COPD). Methods: The English version of LCADL was translated into Korean and back-translated into English. Subsequently, the back-translated version was reviewed and compared with the original, and thus the final K-LCADL was obtained. To evaluate the validation of the K-LCADL, patients simultaneously completed a pulmonary function test, a 6-Minute Walk Test (6MWT), and questionnaires, including the modified Medical Research Council (mMRC) dyspnea scale, the Korean version of the St. George's Respiratory Questionnaire (K-SGRQ), the Korean version of the COPD Assessment Test (K-CAT), and the Korean version of the EuroQoL-5 Dimensions (K-EQ-5D). To assess test-retest reliability, the K-LCADL was again administered to the same patients within 2 weeks from initial assessment. Results: A total of 94 patients participated in the present study. The total K-LCADL score was positively correlated with the K-SGRQ (r=0.802, p<0.001), the mMRC dyspnea scale (r=0.603, p<0.001), and the K-CAT score (r=0.714, p<0.001), and negatively correlated with the K-EQ-5D (r=-0.764, p<0.001), 6MWT (r=-0.635, p<0.001), forced expiratory volume in one second 1 (r= 0.416, p=0.002), and forced vital capacity (r=-0.397, p=0.023). Intraclass correlation coefficient of the K-LCADL was 0.951 (p<0.001). Conclusion: The K LCADL is a reliable and valid questionnaire for evaluating limitation of activities of daily living in patients with COPD. PMID- 29765888 TI - Disability Measurement for Korean Community-Dwelling Adults With Stroke: Item Level Psychometric Analysis of the Korean Longitudinal Study of Ageing. AB - Objective: To investigate the psychometric properties of the activities of daily living (ADL) instrument used in the analysis of Korean Longitudinal Study of Ageing (KLoSA) dataset. Methods: A retrospective study was carried out involving 2006 KLoSA records of community-dwelling adults diagnosed with stroke. The ADL instrument used for the analysis of KLoSA included 17 items, which were analyzed using Rasch modeling to develop a robust outcome measure. The unidimensionality of the ADL instrument was examined based on confirmatory factor analysis with a one-factor model. Item-level psychometric analysis of the ADL instrument included fit statistics, internal consistency, precision, and the item difficulty hierarchy. Results: The study sample included a total of 201 community-dwelling adults (1.5% of the Korean population with an age over 45 years; mean age=70.0 years, SD=9.7) having a history of stroke. The ADL instrument demonstrated unidimensional construct. Two misfit items, money management (mean square [MnSq]=1.56, standardized Z-statistics [ZSTD]=2.3) and phone use (MnSq=1.78, ZSTD=2.3) were removed from the analysis. The remaining 15 items demonstrated good item fit, high internal consistency (person reliability=0.91), and good precision (person strata=3.48). The instrument precisely estimated person measures within a wide range of theta (-4.75 logits < theta < 3.97 logits) and a reliability of 0.9, with a conceptual hierarchy of item difficulty. Conclusion: The findings indicate that the 15 ADL items met Rasch expectations of unidimensionality and demonstrated good psychometric properties. It is proposed that the validated ADL instrument can be used as a primary outcome measure for assessing longitudinal disability trajectories in the Korean adult population and can be employed for comparative analysis of international disability across national aging studies. PMID- 29765889 TI - Amount of Weight-Bearing During Tilt Table Inclination, With Neutral and Unilateral Knee Flexion Postures. AB - Objective: To analyze the amount of weight-bearing during tilt table increments, with a review of neutral and unilateral knee flexion postures. Methods: There were 17 healthy participants enrolled in this study. The subjects were tilted from 10 degrees to 90 degrees , and their body weight was measured at each 10 degrees increment. In the first test, both plantar pressures, with the subjects in neutral posture, were recorded. During the second and third tests, the angle of inclination was thus recorded and increased, with the subjects in unilateral knee flexion posture; flexion was maintained at 25 degrees by attaching a cylindrical support to the tilt table at the level of the popliteal fossa. Results: The study was divided into two types of postures: neutral and unilateral knee flexion. The percentage of body weight (%BW) between each leg during neutral posture was noted as not being statistically significant. The %BW of one side during tilt table inclination was significantly different between the two postures at 10 degrees to 80 degrees (p<0.05). The weight during unilateral knee flexion posture was lower as analyzed, regardless of tilt table inclination compared with that in neutral posture. We note that fifty percent of the ratio of %BW was noted at 33.12 degrees and 38.76 degrees in neutral and flexion postures, respectively. Conclusion: The unilateral knee flexion could induce the effect of decreased body weight compared with non-flexion side. The results of this study will help in setting a safe and quantitative percentage of weight bearing on the lower extremity during tilt training. PMID- 29765890 TI - Intraoperative Monitoring of Hypoglossal Nerve Using Hypoglossal Motor Evoked Potential in Infratentorial Tumor Surgery: A Report of Two Cases. AB - The hypoglossal nerve (CN XII) may be placed at risk during posterior fossa surgeries. The use of intraoperative monitoring (IOM), including the utilization of spontaneous and triggered electromyography (EMG), from tongue muscles innervated by CN XII has been used to reduce these risks. However, there were few reports regarding the intraoperative transcranial motor evoked potential (MEP) of hypoglossal nerve from the tongue muscles. For this reason, we report here two cases of intraoperative hypoglossal MEP monitoring in brain surgery as an indicator of hypoglossal deficits. Although the amplitude of the MEP was reduced in both patients, only in the case 1 whose MEP was disappeared demonstrated the neurological deficits of the hypoglossal nerve. Therefore, the disappearance of the hypoglossal MEP recorded from the tongue, could be considered a predictor of the postoperative hypoglossal nerve deficits. PMID- 29765891 TI - Botulinum Toxin Injection in the Treatment of Postextubation Dysphagia: A Case Report. AB - Prolonged intubation is known to bring on postextubation dysphagia (PED) in some patients. We have noted that there were some studies to investigate specific type and pattern of PED, which showed large variety of different swallowing abnormalities as mechanisms of PED that are multifactorial. There are several options of treatment in accordance with the management of these abnormalities. A botulinum toxin (BoT) injection into the upper esophageal sphincter (UES) can improve swallowing functions for patients with this disorder, by working to help the muscle relax. In this case, the conventional treatment was not effective in patients with PED, whereas the BoT injection made a great improvement for these patients. This study suggests that the UES pathology could be the main cause of PED. PMID- 29765892 TI - Botulinum Toxin-A Injection in the Treatment of Spasticity in a Infantile-Onset Neurodegeneration With Brain Iron Accumulation: A Case Report. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is a neurodegenerative disorder characterized by iron accumulation in the globus pallidus (GP) of the brain (neurodegeneration with brain iron accumulation [NBIA]), which is characterized by dystonia and spasticity resulting in postural difficulties. A 33 month-old boy was admitted with a pronounced gait disturbance. Marked hypertonicity in the patient's both calf muscles was noted, resulting in waddling with repeated slip-falls. NBIA was suspected by high T2 intensity in the GP on brain MRI, then it was confirmed by detecting PANK2 mutation. Botulinum toxin-A injection was administered to both calf muscles. After 2 weeks, a decrease in spasticity and an increase in range of motion were observed, and consequently, an increase in the patient's gait stability with both heels touching the ground, enabling him to walk straight independently. A definitive treatment for NBIA has not been established, and a symptomatic therapy is currently the mainstay of treatment in this case. This is the first case report of botulinum toxin injection for treatment of gait disturbance caused by spasticity in an infantile onset PKAN. PMID- 29765893 TI - Successful Management of Acquired Tracheomalacia of Patients With Amyotrophic Lateral Sclerosis: A Report of Three Cases. AB - Tracheomalacia is characterized by weakness of the tracheal walls and supporting cartilage. It results in dynamic compression of the airway, where the cross sectional area of the trachea is reduced by expiratory compression. Acquired tracheomalacia results from complications associated with the use of endotracheal or tracheostomy tubes. In this report, we present three cases of patients with amyotrophic lateral sclerosis (ALS) successfully treated for tracheomalacia, including one case where the patient underwent surgery for combined tracheoesophageal fistula. We discuss the appropriate management strategies for tracheomalacia in patients with ALS. Through these case reports, we note the results of ALS patients who will have tracheostomy, and who are therefore at risk of sustaining a long term high cuff pressure, this study provides an evaluation for tracheomalacia and therapeutic management which should be considered for improving patient care outcomes. PMID- 29765894 TI - In Reply: Comment on "Effect of Extracorporeal Shockwave Therapy Versus Intra articular Injections of Hyaluronic Acid for the Treatment of Knee Osteoarthritis". PMID- 29765896 TI - Comparison of the shaping ability of novel thermally treated reciprocating instruments. AB - Objectives: The present study aimed to evaluate the shaping ability of 2 thermally treated nickel-titanium reciprocating systems in simulated curved canals. Materials and Methods: Forty simulated canals were prepared to apical size 25 using Reciproc Blue R25 (VDW) and WaveOne Gold Primary (Dentsply Sirona) instruments. Standard pre- and post-preparation images were taken and superimposed. The removal of resin material was measured at 5 standard points: the canal orifice, halfway between the canal orifice and the beginning of the curve, the beginning of the curve, the apex of the curve, and the end-point of the simulated canal. The data were analysed using the independent sample t-test with a 5% significance threshold. Results: The canals in which Reciproc Blue R25 was used showed a significantly greater widening than those in which WaveOne Gold was used at 4 of the 5 measurement points (p < 0.05). The Reciproc Blue R25 instrument removed significantly more resin from the inner aspect of the curve at 2 of the 5 points and similar amounts at the remaining 3 points. At the 2 apical points, there was no significant difference between the Reciproc Blue R25 and WaveOne Gold Primary instruments. Conclusion: Both instruments respected the original canal anatomy; however, WaveOne Gold resulted in a more conservative shape with less transportation. PMID- 29765895 TI - Effect of smear layer deproteinization on bonding of self-etch adhesives to dentin: a systematic review and meta-analysis. AB - Objectives: The aim of this systematic review was to critically analyze previously published studies of the effects of dentin surface pretreatment with deproteinizing agents on the bonding of self-etch (SE) adhesives to dentin. Additionally, a meta-analysis was conducted to quantify the effects of the above mentioned surface pretreatment methods on the bonding of SE adhesives to dentin. Materials and Methods: An electronic search was performed using the following databases: Scopus, PubMed and ScienceDirect. The online search was performed using the following keywords: 'dentin' or 'hypochlorous acid' or 'sodium hypochlorite' and 'self-etch adhesive.' The following categories were excluded during the assessment process: non-English articles, randomized clinical trials, case reports, animal studies, and review articles. The reviewed studies were subjected to meta-analysis to quantify the effect of the application time and concentration of sodium hypochlorite (NaOCl) and hypochlorous acid (HOCl) deproteinizing agents on bonding to dentin. Results: Only 9 laboratory studies fit the inclusion criteria of this systematic review. The results of the meta analysis revealed that the pooled average microtensile bond strength values to dentin pre-treated with deproteinizing agents (15.71 MPa) was significantly lower than those of the non-treated control group (20.94 MPa). Conclusions: In light of the currently available scientific evidence, dentin surface pretreatment with deproteinizing agents does not enhance the bonding of SE adhesives to dentin. The HOCl deproteinizing agent exhibited minimal adverse effects on bonding to dentin in comparison with NaOCl solutions. PMID- 29765898 TI - Periodontal healing following non-surgical repair of an old perforation with pocket formation and oral communication. AB - Iatrogenic perforations negatively impact the outcome of endodontic treatments. Studies on prognostic factors showed that perforations in the coronal third of the root with periodontal pocket formation have an unfavorable prognosis. A 36 year-old female was referred for endodontic evaluation of tooth #13 with a history of an iatrogenic perforation, happened 3 years ago. There was a sinus tract associated with perforation, 10 mm probing on the mesial and mesio-palatal, bleeding on probing, radiolucent lesion adjacent to the perforation and complete resorption of the interdental bone between teeth #13 and #12. After the treatment options were discussed, she chose to save the tooth. The tooth was accessed under rubber dam isolation, the perforation site was cleaned and disinfected using 0.5% sodium hypochlorite and sealed with calcium-enriched mixture cement. Eighteen months after treatment the tooth was functional and asymptomatic. The probing depths were normal without bleeding on probing. Radiographically, the interdental crestal bone formed between teeth #13 and #12. Despite all negative prognostic factors in this case (i.e., perforations in the coronal third, pocket formation, and radiolucent lesion), healing was unexpectedly achieved via non-surgical repair of the perforation. Further research on biological aspects of healing in the periodontium following iatrogenic perforations are recommended. PMID- 29765899 TI - The effect of continuous application of MDP-containing primer and luting resin cement on bond strength to tribochemical silica-coated Y-TZP. AB - Objectives: This study investigated the effect of continuous application of 10 methacryloyloxydecyldihydrogen phosphate (MDP)-containing primer and luting resin cement on bond strength to tribochemical silica-coated yttria-stabilized tetragonal zirconia polycrystal (Y-TZP). Materials and Methods: Forty bovine teeth and Y-TZP specimens were prepared. The dentin specimens were embedded in molds, with one side of the dentin exposed for cementation with the zirconia specimen. The Y-TZP specimen was prepared in the form of a cylinder with a diameter of 3 mm and a height of 10 mm. The bonding surface of the Y-TZP specimen was sandblasted with silica-coated aluminium oxide particles. The forty tribochemical silica-coated Y-TZP specimens were cemented to the bovine dentin (4 groups; n = 10) with either an MDP-free primer or an MDP-containing primer and either an MDP-free resin cement or an MDP-containing resin cement. After a shear bond strength (SBS) test, the data were analyzed using 1-way analysis of variance and the Tukey test (alpha = 0.05). Results: The group with MDP-free primer and resin cement showed significantly lower SBS values than the MDP-containing groups (p < 0.05). Among the MDP-containing groups, the group with MDP-containing primer and resin cement showed significantly higher SBS values than the other groups (p < 0.05). Conclusions: The combination of MDP-containing primer and luting cement following tribochemical silica coating to Y-TZP was the best choice among the alternatives tested in this study. PMID- 29765901 TI - Statistical notes for clinical researchers: simple linear regression 1 - basic concepts. PMID- 29765897 TI - Anatomical analysis of the resected roots of mandibular first molars after failed non-surgical retreatment. AB - Objectives: Understanding the reason for an unsuccessful non-surgical endodontic treatment outcome, as well as the complex anatomy of the root canal system, is very important. This study examined the cross-sectional root canal structure of mandibular first molars confirmed to have failed non-surgical root canal treatment using digital images obtained during intentional replantation surgery, as well as the causative factors of the failed conventional endodontic treatments. Materials and Methods: This study evaluated 115 mandibular first molars. Digital photographic images of the resected surface were taken at the apical 3 mm level and examined. The discolored dentin area around the root canal was investigated by measuring the total surface area, the treated areas as determined by the endodontic filling material, and the discolored dentin area. Results: Forty 2-rooted teeth showed discolored root dentin in both the mesial and distal roots. Compared to the original filled area, significant expansion of root dentin discoloration was observed. Moreover, the mesial roots were significantly more discolored than the distal roots. Of the 115 molars, 92 had 2 roots. Among the mesial roots of the 2-rooted teeth, 95.7% of the roots had 2 canals and 79.4% had partial/complete isthmuses and/or accessory canals. Conclusions: Dentin discoloration that was not visible on periapical radiographs and cone-beam computed tomography was frequently found in mandibular first molars that failed endodontic treatment. The complex anatomy of the mesial roots of the mandibular first molars is another reason for the failure of conventional endodontic treatment. PMID- 29765900 TI - Effect of various bleaching treatments on shear bond strength of different universal adhesives and application modes. AB - Objectives: The aim of this in vitro study was to evaluate the bond strength of 2 universal adhesives used in different application modes to bleached enamel. Materials and Methods: Extracted 160 sound human incisors were used for the study. Teeth were divided into 4 treatment groups: No treatment, 35% hydrogen peroxide, 16% carbamid peroxide, 7.5% carbamid peroxide. After bleaching treatments, groups were divided into subgroups according to the adhesive systems used and application modes (n = 10): 1) Single Bond Universal, etch and rinse mode; 2) Single Bond Universal, self-etch mode; 3) Gluma Universal, etch and rinse mode; 4) Gluma Universal, self-etch mode. After adhesive procedures nanohybrid composite resin cylinders were bonded to the enamel surfaces. All specimens were subjected to shear bond strength (SBS) test after thermocycling. Data were analyzed using a 3-way analysis of variance (ANOVA) and Tukey post hoc test. Results: No significant difference were found among bleaching groups (35% hydrogen peroxide, 16% carbamid peroxide, 7.5% carbamid peroxide, and no treatment groups) in the mean SBS values. There was also no difference in SBS values between Single Bond Universal and Gluma Universal at same application modes, whereas self-etch mode showed significantly lower SBS values than etch and rinse mode (p < 0.05). Conclusions: The bonding performance of the universal adhesives was enhanced with the etch and rinse mode application to bleached enamel and non-bleached enamel. PMID- 29765902 TI - Comparison of light-transmittance in dental tissues and dental composite restorations using incremental layering build-up with varying enamel resin layer thickness. AB - Objectives: To evaluate and compare light-transmittance in dental tissues and dental composite restorations using the incremental double-layer technique with varying layer thickness. Materials and Methods: B1-colored natural teeth slabs were compared to dental restoration build-ups with A2D and B1E-colored nanofilled, supra-nanofilled, microfilled, and microhybrid composites. The enamel layer varied from 0.3, 0.5, or 1.2 mm thick, and the dentin layer was varied to provide a standardized 3.7 mm overall sample thickness (n = 10). All increments were light-cured to 16 J/cm2 with a multi-wave LED (Valo, Ultradent). Using a spectrophotometer, the samples were irradiated by an RGB laser beam. A voltmeter recorded the light output signal to calculate the light-transmittance through the specimens. The data were analyzed using 1-way analysis of variance followed by the post hoc Tukey's test (p = 0.05). Results: Mean light-transmittance observed at thicker final layers of enamel were significantly lower than those observed at thinner final layers. Within 1.2 mm final enamel resin layer (FERL) thickness, all composites were similar to the dental tissues, with exception of the nanofilled composite. However, within 0.5 mm FERL thickness, only the supra nanofilled composite showed no difference from the dental tissues. Within 0.3 mm FERL thickness, none of the composites were similar to the dental tissues. Conclusions: The supra-nanofilled composite had the most similar light transmittance pattern when compared to the natural teeth. However, for other composites, thicker FERL have a greater chance to match the light-transmittance of natural dental tissues. PMID- 29765903 TI - Effect of ultrasonic agitation on push-out bond strength and adaptation of root end filling materials. AB - Objectives: This study evaluated the effect of ultrasonic agitation of mineral trioxide aggregate (MTA), calcium silicate-based cement (CSC), and Sealer 26 (S26) on adaptation at the cement/dentin interface and push-out bond strength. Materials and Methods: Sixty maxillary canines were divided into 6 groups (n = 10): MTA, S26, and CSC, with or without ultrasonic activation (US). After obturation, the apical portions of the teeth were sectioned, and retrograde cavities were prepared and filled with cement by hand condensation. In the US groups, the cement was activated for 60 seconds: 30 seconds in the mesio-distal direction and 30 seconds in the buccal-lingual direction, using a mini Irrisonic insert coupled with the ultrasound transducer. After the materials set, 1.5-mm thick sections were obtained from the apexes. The presence of gaps and the bond between cement and dentin were analyzed using low-vacuum scanning electron microscopy. Push-out bond strength was measured using a universal testing machine. Results: Ultrasonic agitation increased the interfacial adaptation of the cements. The S26 US group showed a higher adaptation value than MTA (p < 0.05). US improved the push-out bond strength for all the cements (p < 0.05). Conclusions: The US of retrograde filling cements enhanced the bond to the dentin wall of the root-end filling materials tested. PMID- 29765904 TI - Cyclic fatigue resistance, torsional resistance, and metallurgical characteristics of M3 Rotary and M3 Pro Gold NiTi files. AB - Objectives: To evaluate the mechanical properties and metallurgical characteristics of the M3 Rotary and M3 Pro Gold files (United Dental). Materials and Methods: One hundred and sixty new M3 Rotary and M3 Pro Gold files (sizes 20/0.04 and 25/0.04) were used. Torque and angle of rotation at failure (n = 20) were measured according to ISO 3630-1. Cyclic fatigue resistance was tested by measuring the number of cycles to failure in an artificial stainless steel canal (60 degrees angle of curvature and a 5-mm radius). The metallurgical characteristics were investigated by differential scanning calorimetry. Data were analyzed using analysis of variance and the Student-Newman-Keuls test. Results: Comparing the same size of the 2 different instruments, cyclic fatigue resistance was significantly higher in the M3 Pro Gold files than in the M3 Rotary files (p < 0.001). No significant difference was observed between the files in the maximum torque load, while a significantly higher angular rotation to fracture was observed for M3 Pro Gold (p < 0.05). In the DSC analysis, the M3 Pro Gold files showed one prominent peak on the heating curve and 2 prominent peaks on the cooling curve. In contrast, the M3 Rotary files showed 1 small peak on the heating curve and 1 small peak on the cooling curve. Conclusions: The M3 Pro Gold files showed greater flexibility and angular rotation than the M3 Rotary files, without decrement of their torque resistance. The superior flexibility of M3 Pro Gold files can be attributed to their martensite phase. PMID- 29765905 TI - The effect of thermocycling on the degree of conversion and mechanical properties of a microhybrid dental resin composite. AB - Objective: The purpose of this study was to investigate the degree of conversion (DC) and mechanical properties of a microhybrid Filtek Z250 (3M ESPE) resin composite after aging. Method: The specimens were fabricated using circular molds to investigate Vickers microhardness (Vickers hardness number [VHN]) and DC, and were prepared according to ISO 4049 for flexural strength testing. The initial DC (%) of discs was recorded using attenuated total reflectance-Fourier transforming infrared spectroscopy. The initial VHN of the specimens was measured using a microhardness tester under a load of 300 g for 15 seconds and the flexural strength test was carried out with a universal testing machine (crosshead speed, 0.5 mm/min). The specimens were then subjected to thermocycling in 5 degrees C and 55 degrees C water baths. Properties were assessed after 1,000-10,000 cycles of thermocycling. The surfaces were evaluated using scanning electron microscopy (SEM). Data were analyzed using 1-way analysis of variance followed by the Tukey honest significant difference post hoc test. Results: Statistical analysis showed that DC tended to increase up to 4,000 cycles, with no significant changes. VHN and flexural strength values significantly decreased upon thermal cycling when compared to baseline (p < 0.05). However, there was no significant difference between initial and post-thermocycling VHN results at 1,000 cycles. SEM images after aging showed deteriorative changes in the resin composite surfaces. Conclusions: The Z250 microhybrid resin composite showed reduced surface microhardness and flexural strength and increased DC after thermocycling. PMID- 29765907 TI - Attenuated Bacteria as Immunotherapeutic Tools for Cancer Treatment. AB - The use of attenuated bacteria as cancer therapeutic tools has garnered increasing scientific interest over the past 10 years. This is largely due to the development of bacterial strains that maintain good anti-tumor efficacy, but with reduced potential to cause toxicities to the host. Because of its ability to replicate in viable as well as necrotic tissue, cancer therapy using attenuated strains of facultative anaerobic bacteria, such as Salmonella, has several advantages over standard treatment modalities, including chemotherapy and radiotherapy. Despite some findings suggesting that it may operate through a direct cytotoxic effect against cancer cells, there is accumulating evidence demonstrating that bacterial therapy acts by modulating cells of the immune system to counter the growth of the tumor. Herein, we review the experimental evidence underlying the success of bacterial immunotherapy against cancer and highlight the cellular and molecular alterations in the peripheral immune system and within the tumor microenvironment that have been reported following different forms of bacterial therapy. Our improved understanding of these mechanisms should greatly aid in the translational application of bacterial therapy to cancer patients. PMID- 29765909 TI - Shiga Toxin-Producing Escherichia coli Infection in Jonkoping County, Sweden: Occurrence and Molecular Characteristics in Correlation With Clinical Symptoms and Duration of stx Shedding. AB - Shiga toxin-producing Escherichia coli (STEC) cause bloody diarrhea (BD), hemorrhagic colitis (HC), and even hemolytic uremic syndrome (HUS). In Nordic countries, STEC are widely spread and usually associated with gastrointestinal symptoms and HUS. The objective of this study was to investigate the occurrence of STEC in Swedish patients over 10 years of age from 2003 through 2015, and to analyze the correlation of critical STEC virulence factors with clinical symptoms and duration of stx shedding. Diarrheal stool samples were screened for presence of stx by real-time PCR. All STEC isolates were characterized by DNA microarray assay and PCR to determine serogenotypes, stx subtypes, and presence of intimin gene eae and enterohaemolysin gene ehxA. Multilocus sequencing typing (MLST) was used to assess phylogenetic relationships. Clinical features were collected and analyzed using data from the routine infection control measures in the county. A total of 14,550 samples were enrolled in this 12-years period study, and 175 (1.2%) stools were stx positive by real-time PCR. The overall incidence of STEC infection was 4.9 cases per 100,000 person-years during the project period. Seventy-five isolates, with one isolate per sample were recovered, among which 43 were from non-bloody stools, 32 from BD, and 3 out of the 75 STEC positive patients developed HUS. The presence of stx2 in both stools and isolates were associated with BD (p = 0.008, p = 0.05), and the presence of eae in isolates was related to BD (p = 0.008). The predominant serogenotypes associated with BD were O157:H7, O26:H11, O121:H19, and O103:H2. Isolates from HUS were O104:H4 and O98: H21 serotypes. Phylogenetic analysis revealed our strains were highly diverse, and showed close relatedness to HUS-associated STEC collection strains. In conclusion, the presence of stx2 in stool was related to BD already at the initial diagnostic procedure, thus could be used as risk predictor at an early stage. STEC isolates with stx2 and eae were significantly associated with BD. The predominant serotypes associated with BD were O157:H7, O26:H11, O121:H19, and O103:H2. Nevertheless, the pathogenic potential of other serotypes and genotypes should not be neglected. PMID- 29765908 TI - The Subgingival Microbiome of Periodontal Pockets With Different Probing Depths in Chronic and Aggressive Periodontitis: A Pilot Study. AB - Periodontitis is a kind of infectious disease initiated by colonization of subgingival periodontal pathogens, which cause destruction of tooth-supporting tissues, and is a predominant threat to oral health as the most common cause of loss of teeth. The aim of this pilot study was to characterize the subgingival bacterial biodiversity of periodontal pockets with different probing depths in patients with different forms of periodontitis. Twenty-one subgingival plaque samples were collected from three patients with chronic periodontitis (ChP), three patients with aggressive periodontitis (AgP) and three periodontally healthy subjects (PH). Each patient with periodontitis was sampled at three sites, at different probing depths (PDs, one each at 4 mm, 5-6 mm, and >= 7 mm). Using 16S rRNA gene high-throughput sequencing and bioinformatic analysis, we found that subgingival communities in health and periodontitis samples largely differed. Meanwhile, Acholeplasma, Fretibacterium, Porphyromonas, Peptococcus, Treponema_2, Defluviitaleaceae_UCG_011, Filifactor, and Mycoplasma increased with the deepening of the pockets in ChP, whilst only Corynebacterium was negatively associated with PD. In AgP, Corynebacterium and Klebsiella were positively associated with PD, while Serratia, Pseudoramibacter, Defluviitaleaceae_UCG_011, and Desulfobulbus were negatively associated with PD. And among these two groups, Corynebacterium shifted differently. Moreover, in subgingival plaque, the unweighted UniFrac distances between samples from pockets with different PD in the same patients were significantly lower than those from pockets within the same PD category from different patients. This study demonstrated the shift of the subgingival microbiome in individual teeth sites during disease development. Within the limitation of the relative small sample size, this pilot study shed new light on the dynamic relationship between the extent of periodontal destruction and the subgingival microbiome. PMID- 29765910 TI - A Promising IFN-Deficient System to Manufacture IFN-Sensitive Influenza Vaccine Virus. AB - Interferon (IFN)-sensitive and replication-incompetent influenza viruses are likely to be the alternatives to inactivated and attenuated virus vaccines. Some IFN-sensitive influenza vaccine candidates with modified non-structural protein 1 (NS1) are highly attenuated in IFN-competent hosts but induce robust antiviral immune responses. However, little research has been done on the manufacturability of these IFN-sensitive vaccine viruses. Here, RIG-I-knockout 293T cells were used to package the IFN-sensitive influenza A/WSN/33 (H1N1) virus expressing the mutant NS1 R38A/K41A. We found that the packaging efficiency of the NS1 R38A/K41A virus in RIG-I-knockout 293T cells was much higher than that in 293T cells. Moreover, the NS1 R38A/K41A virus almost lost its IFN antagonist activity and could no longer replicate in A549, MDCK, and Vero cells after 3-6 passages. This indicated that the replication of NS1 R38A/K41A virus is limited in conventional cells. Therefore, we further established a stable Vero cell line expressing the wild-type (WT) NS1 of the WSN virus, based on the Tet-On 3G system. The NS1 R38A/K41A virus was able to steadily propagate in this IFN-deficient cell line for at least 20 passages. In a mouse model, the NS1 R38A/K41A virus showed more than a 4-log reduction in lung virus titers compared to the WT virus at 3 and 5 days post infection. Furthermore, we observed that the NS1 R38A/K41A virus triggered high-level of IFN-alpha/beta production in lung tissues and was eliminated from the host in a relatively short period of time. Additionally, this virus induced high-titer neutralizing antibodies against the WT WSN, A/Puerto Rico/8/1934 (PR8), or A/California/04/2009 (CA04) viruses and provided 100% protection against the WT WSN virus. Thus, we found that the replication of the NS1 R38A/K41A virus was limited in IFN-competent cells and mice. We also presented a promising IFN-deficient system, involving a RIG-I-knockout 293T cell line to package the IFN-sensitive vaccine virus and a stable Vero cell line expressing NS1 to propagate the IFN-sensitive vaccine virus. The IFN-deficient system is applicable for the manufacture of IFN-sensitive vaccine virus. PMID- 29765911 TI - Immunization With Skp Delivered on Outer Membrane Vesicles Protects Mice Against Enterotoxigenic Escherichia coli Challenge. AB - Outer membrane vesicles (OMVs) are promising vaccine components because they combine antigen and adjuvant in a single formulation. Detoxified Salmonella enterica strains that express penta-acylated lipid A retain OMV immunogenicity but with reduced reactogenicity. We have previously shown that a recombinant form of the enterotoxigenic Escherichia coli (ETEC) 17 kilodalton protein (Skp) protects mice in a pulmonary challenge model, when fused to the glutathione-S transferase (GST) epitope and combined with cholera toxin. Here we compared directly the efficacy of expressing Skp in detoxified Salmonella OMVs to GST-Skp for their ability to protect mice against ETEC challenge. We observed that the display of Skp on OMVs, in the absence of exogenous adjuvant, protects the mice as well as the recombinant GST-Skp with adjuvant, showing that we can achieve protection when antigen and adjuvant are administered as a single formulation. Collectively, these data demonstrate the utility of using OMVs for the expression and display of antigens for use in vaccine development and validate previously published work demonstrating that immunization with Skp is efficacious in protecting mice against ETEC challenge. PMID- 29765906 TI - Epstein-Barr Virus and Human Papillomaviruses Interactions and Their Roles in the Initiation of Epithelial-Mesenchymal Transition and Cancer Progression. AB - Oncoviruses are implicated in around 20% of all human cancers including both solid and non-solid malignancies. Epstein-Barr virus (EBV) and human papillomaviruses (HPVs) are the most common oncoviruses worldwide. Currently, it is well established that onco-proteins of EBV (LMP1, LMP2A, and EBNA1) and high risk HPVs (E5 and E6/E7) play an important role in the initiation and/or progression of several human carcinomas, including cervical, oral, and breast. More significantly, it has been recently pointed out that viral onco-proteins of EBV and high-risk HPVs can be co-present and consequently cooperate to initiate and/or amplify epithelial-mesenchymal transition (EMT), which is the hallmark of cancer progression and metastasis. This could occur by beta-catenin, JAK/STAT/SRC, PI3k/Akt/mTOR, and/or RAS/MEK/ERK signaling pathways, which onco proteins of EBV and HPVs share. This review presents the most recent advances related to EBV and high-risk HPVs onco-proteins interactions and their roles in the progression of human carcinomas especially oral and breast via the initiation of EMT. PMID- 29765913 TI - Survival analysis of an orthodontic bracket bond subjected to cyclic tensile and shear forces. AB - OBJECTIVES: The objective of this study was to evaluate the use of survival analysis in cyclic fatigue testing in orthodontic bracket bonding. MATERIALS AND METHODS: We used 100 extracted bovine lower incisors (50 orthodontic brackets and 50 eyelet brackets). Each set of brackets was further divided by etching technique (25 total-etch and 25 self-etch). Cyclic fatigue testing was performed at a crosshead speed of 2 mm/min using an up-and-down method. Kaplan-Meier survival data analyses and Cox regression analyses were performed. RESULTS: Survival analysis proved to be a simple methodology and revealed that the etching technique was not a statistically significant predictor for survival of orthodontic bracket bonding with either tensile or shear cyclic forces at P > 0.05. In tensile cyclic loading, high mechanical loading after controlling for the etching technique is a statistically significant predictor for lower survival of the orthodontic bracket bond at P < 0.001. CONCLUSIONS: Both etching techniques (total-etch and self-etch) are equally efficient in bonding orthodontic brackets. High mechanical loading is an important predictor of bond failure when applying tensile cyclic forces. Finally, survival analysis is a simpler alternative method to analyze orthodontic bracket bonding subjected to cyclic tensile and shear forces and gives similar results to other complicated methods. PMID- 29765914 TI - Nonsurgical treatment and stability of an adult with a severe anterior open-bite malocclusion. AB - OBJECTIVES: A skeletal anterior open-bite is a challenging malocclusion for the orthodontist due to the difficulty and instability of correction. Treatment options for the adult patient include extractions, anterior extrusion with intermaxillary elastics, posterior intrusion using skeletal anchorage, occlusal adjustment, and orthognathic surgery. Patient compliance plays a key role in posttreatment stability. The present case report demonstrates the orthodontic treatment of an adult patient who presented with a complex open-bite malocclusion. MATERIALS AND METHODS: Treatment involved the placement of four miniscrews to assist intrusion of maxillary molars by applying posterior vertical maxillary elastics and extrusion of the anterior segments using anterior vertical interarch elastics. RESULTS: Ideal intercuspation was successfully achieved and good stability was maintained during 3 years following treatment. CONCLUSION: The intrusion of the maxillary molars with miniscrews is an interesting option in selected cases of skeletal anterior open bite. The retention protocol should be specific in these cases. PMID- 29765912 TI - Oncolytic adenovirus Ad657 for systemic virotherapy against prostate cancer. AB - Background: Human species C adenovirus serotype 5 (Ad5) is the archetype oncolytic adenovirus and has been used in the vast majority of preclinical and clinical tests. While Ad5 can be robust, species C Ad6 has lower seroprevalence, side effects, and appears to be more potent as a systemic therapy against a number of tumors than Ad5. Historically, there have only been four species C human adenoviruses: serotypes 1, 2, 5, and 6. More recently a new species C adenovirus, Ad57, was identified. Ad57 is most similar to Ad6 with virtually all variation in their capsid proteins occurring in the hypervariable regions (HVRs) of their hexon proteins. Most adenovirus neutralizing antibodies target the HVRs on adenoviruses. This led us to replace the hexon HVRs in Ad6 with those from Ad57 to create a new virus called Ad657 and explore this novel species C platform's utility as an oncolytic virus. Methods: The HVR region from Ad57 was synthesized and used to replace the Ad6 HVR region by homologous recombination in bacteria generating a new viral platform that we call Ad657. Replication competent Ad5, Ad6, and Ad657 were compared in vitro and in vivo for liver damage and oncolytic efficacy against prostate cancers after single intravenous treatment in mice. Results: Ad5, Ad6, and Ad657 had similar in vitro oncolytic activity against human prostate cancer cells. Ad5 provoked the highest level of liver toxicity after intravenous injection and Ad657 caused the least damage in mice. Previous data demonstrated that Ad6 was superior to Ad5 at killing distant subcutaneous prostate cancer tumors in mouse models after a intravenous injection. Given this, Ad657 was compared to the Ad6 benchmark virus by single intravenous injection into mice bearing subcutaneous human DU145 prostate cancers. Under these conditions, Ad657 first infected the liver and then reached distant tumors. Both Ad6 and Ad657 mediated significant delays in tumor growth and extension of survival with Ad6 mediating higher efficacy. Conclusions: These data suggest that Ad657 may have utility as a local or systemic oncolytic virotherapy for prostate cancers. These data also lay the foundation for serotype switching with oncolytic species C Ads. PMID- 29765915 TI - Association between muscle activity and overjet in class II malocclusion with surface electromyography. AB - OBJECTIVES: The aim of the study was to assess the association and correlation between the overjet and muscle activity (the masseter and temporalis muscles) in patient with Class II malocclusion in different genders using surface electromyography (sEMG). MATERIALS AND METHODS: The overjet (measured clinically) and electromyographical activity (rest, chew, post chew rest, clench and post clench rest) of the masseter and temporalis muscle of class II malocclusion patient were assessed in 18 patients (3 males and 15 females) from the School of Dental Science, Hospital University Sains Malaysia. RESULTS: The results were compared by simple linear regression test to evaluate the association between overjet and muscle activity in different genders. Class II malocclusion patients with increased overjet group showed significant association with masseter muscle activity on chewing stage (P = 0.005, F = 6.081 and adj-R2 = 0.473). Left temporalis muscle in class II malocclusion showed a significant linear association (P = 0.014, F = 0.812 and adj-R2= -0.034) with gender during clench. CONCLUSION: In conclusion, class II malocclusion patient with increased overjet can affect masticatory muscle function and as well as clench force may differ in gender. PMID- 29765916 TI - An assessment of job satisfaction: A cross-sectional study among orthodontists of Saudi Arabia. AB - AIM OF THE STUDY: The main objective of the present study was to investigate the level of job satisfaction among professional orthodontists in relation to some significant intrinsic and extrinsic factors that generally affect their performance. MATERIALS AND METHODS: A cross-sectional study was conducted among orthodontists working in the Kingdom of Saudi Arabia using an online survey questionnaire through Survey Monkey. A total of 161 responses were received; among those, 57.8% of the respondents were Saudi and 42.2% were non-Saudi. RESULTS: On an overall satisfaction basis, a majority of orthodontists (80.7%) were satisfied with orthodontics as their profession irrespective of their gender. Only 4.4% showed dissatisfaction, whereas the remaining 14.9% were moderately satisfied with orthodontics as a profession. In-depth analysis revealed that a majority of the respondents (56.2%) showed reservations over having ample time for their family life. 52.8% of the respondents strongly agreed that they are assigned significant paperwork. Likewise, 66.5% of the orthodontists showed moderate to dissatisfaction over time adherence by the patients. CONCLUSION: The findings of the present investigations depicted a higher level of passion and commitment among the male and female respondents for the profession in spite of the fact that they do not have adequate time for their personal life. The working efficiency of orthodontists may be significantly enhanced by sparing them from too much paperwork and ensuring that their patients appear on time. PMID- 29765917 TI - Dentoskeletal effects of the forsusTM fatigue resistance device in the treatment of class II malocclusion: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of this systematic review and meta-analysis is to quantitatively compare previous studies that evaluated skeletal and dentoalveolar effects of the ForsusTM Fatigue Resistance Device (FRD) in the treatment of Class II malocclusion with a matched untreated control group. MATERIALS AND METHODS: Four electronic searches PubMed, Web of Science, Cochrane Library, and Science Direct that were limited to articles on human studies comparing the effect of Forsus appliance with a matched control group in the treatment of Class II malocclusion from the year (2000-2017). An additional manual search was carried out by examining the references of the included articles, SEARCH terms included; Forsus and Class II malocclusion. The quality of the included studies was assessed using the modified methodological score for clinical trials. The data were analyzed using Michael Borenstein's Comprehensive Meta-Analysis Software (V3.3.070, Biostat, Inc., US). RESULTS: Seven studies were included comprising 273 participants (Forsus group = 142; control group = 131). The results indicated a statistical significant skeletal effect of the Forsus appliance on increasing the occlusal plane only (P < 0.001). The results also indicated a statistical significant (P < 0.001) dentoalveolar effects of the Forsus appliance on the following outcomes; protruding, proclining, and intruding lower incisors; retroclining upper incisors, distalizing and intruding upper molars, as well as reducing overjet and overbite. CONCLUSIONS: The ForsusTM showed positive effects on the maxillary incisors and first molars as well as overjet and overbite. However, multiple negative effects were reported on the occlusal plane and lower incisors that need to be considered when using such appliance in treating Class II malocclusion. PMID- 29765918 TI - Comparative tomographic study of the maxillary central incisor collum angle between Class I, Class II, division 1 and 2 patients. AB - INTRODUCTION: It has been reported that Class II, division 2 maxillary central incisors frequently demonstrate increased collum angles, which indicates an excessive palatal "bend" of the crown. However, evidence supporting such observation is mostly derived from radiographic studies. OBJECTIVE: The objective of this study was to evaluate and compare the collum angle of maxillary central incisors in Class I, Class II, division 1, and Class II, division 2 cases using cone-beam computed tomography. MATERIALS AND METHODS: Forty-eight consecutive orthodontic cases (16 Class I, 16 Class II, division 1, and 16 Class II, division 2 malocclusion) with cone-beam computed tomography as part of their initial diagnostic records were evaluated. Cross-sections including maxillary right and left central incisors were used to calculate the angulation between the crown and root long axes (collum angle). Comparisons between groups were performed using analysis of variance for multiple and post-hoc Tukey for paired analyses. RESULTS: Mean collum angle observed in Class II, division 2 cases was significantly larger (5.2 +/- 1.3 degrees ) than the ones obtained for Class I (1.1 +/- 4.2 degrees ) (P = 0.034) or Class II, division 1 cases (0.1 +/- 0.7 degrees ) (P = 0.014). CONCLUSIONS: Our findings suggest that Class II, division 2 individuals demonstrate accentuated lingual inclination of the maxillary central incisor crown compared to the other types of malocclusion studied here. Such morphological feature indicates the need for better tooth movement planning, especially in regard to root palatal torqueing of the maxillary central incisors. PMID- 29765919 TI - Assessing the validity of ITK-SNAP software package in measuring the volume of upper airway spaces secondary to rapid maxillary expansion. AB - INTRODUCTION: The purpose of this study is to evaluate the validity of a free access software package (ITK-SNAP) in segmenting and measuring the volume of upper airway spaces secondary to rapid maxillary expansion (RME). MATERIALS AND METHODS: Sixteen participants who required RME were recruited for this study. Preoperative (T1) and 6-month postoperative (T2) cone-beam computed tomographic scans of all participants were analyzed. OnDemand3D software packages was used for superimposition and orientation of the images, while ITK-SNAP software was used to measure the volume of airway spaces. At week one (W1), all volumetric measurements were carried out by one examiner and repeated after 1 week (W2). Paired t-test, the interclass correlation coefficient, and Dahlberg coefficients of reliability were used to assess the reproducibility. RESULTS: Student's t-test showed no significant difference between the W1 and W2 set of measurements (P > 0.05). Coefficients of reliability were above 95% and intraclass correlation coefficient ranged from 0.99 to 1.000, which altogether confirmed the satisfactory reproducibility of the measurements. CONCLUSIONS: ITK-SNAP software package is a reliable and cost-effective method to segment and measure upper airway changes subsequent to RME. PMID- 29765920 TI - Space creation for a missing central incisor using functional and fixed appliances. AB - Children with an overjet of more than 6 mm are three times more likely to receive trauma to their upper incisors than children with an average overjet. This could be complicated with avulsion of permanent incisor and with space loss for the tooth. Functional appliances are usually used to treat Class II skeletal pattern and increased overjet in growing patients. The following is a case in which the Twin Block functional appliance was used, while its classic design was modified to treat a Class II skeletal problem and to open a space for a missing maxillary central incisor. PMID- 29765921 TI - Therapeutic Approaches to Atrophic Vaginitis in Postmenopausal Women: A Systematic Review with a Network Meta-analysis of Randomized Controlled Trials. AB - Objectives: Atrophic vaginitis (AV), which is common in postmenopausal women, is characterized by vaginal dryness, dyspareunia, and discomfort. There are a variety of therapeutic agents for the treatment of AV, besides hormone replacement therapy. We performed this systematic review to compare the effectiveness of various therapies for symptom improvement in AV patients. Methods: We searched the Cochrane Library, EMBASE, MEDLINE, and other literature (Google Scholar, Web of Science, and hand search) for studies published between January 2010 and March 2015. AV was evaluated by the following outcomes: vaginal pH, dyspareunia, vaginal dryness, or cytological change (endometrial thickness, percentages of superficial cells and parabasal cells). They measured treatment efficacy with various outcomes pertaining to AV symptoms. Results: Meta-analysis suggested that ospemifene was effective against dyspareunia, vaginal dryness, endometrial thickness, and percentage changes in superficial and parabasal cells. Vaginal pH was most affected by soy isoflavone vaginal gel. Ospemifene was effective for AV symptoms. Conclusions: This systematic review compared the effects of several therapeutic agents on symptoms of AV through a network meta analysis. This study provides objective evidence for clinical treatment and efficacy management in AV. PMID- 29765922 TI - Effect of Herbal Medicine on Vaginal Epithelial Cells: A Systematic Review and Meta-analysis. AB - Objectives: The present meta-analysis aimed to assess the effect of the herbal medicine on the vaginal epithelial cells (VECs) among the menopausal subjects. Methods: The literature related to VECs exposed to various herbal medicines in menopausal women were searched on three databases, MEDLINE (1966-August 2017), Scopus (1990-August 2017) and Cochrane Library (Cochrane Central Register of Controlled Trials; 2014). Results: Totally, the meta-analysis was conducted on 11 randomised controlled trials. Based on the findings, the standardized mean difference (SMD) of maturation value (MV) was observed to be elevated by 0.48% (95% interval confidence [CI], 0.108-0.871; P = 0.012), as well as the heterogeneity was high (I2 = 84%; P < 0.001). The MV revealed a significant increase in soy group (SMD, 0.358; 95% CI, 0.073-0.871; P = 0.014) compared to the control group. Conclusions: The herbal medicines exhibited a statistically significant effect on the VECs. A significant effect on the VECs was also found in the subgroup analysis of the patients, who received soy. However, further and extensive studies are required to achieve reliable outcomes. PMID- 29765923 TI - Insomnia with Musculoskeletal Pain in Postmenopause: Associations with Symptoms, Mood, and Quality of Life. AB - Objectives: To investigate the relationship between insomnia (INS) combined with chronic musculoskeletal pain (MSP) in postmenopausal women and its characteristics regarding MSP, menopausal and mood symptoms, sleep and quality of life (QOL). Methods: A cross-sectional control study in 4 groups of postmenopausal women: control (n = 15), MSP (n = 15), INS (n =15) and INS + MSP (n = 17). Sixty-two participants completed questionnaires and had blood collected, and 43 underwent polysomnography. Results: INS was associated with increased anxiety (P = 0.04) and sleep fragmentation (P = 0.02); worse MSP severity (P = 0.00), MSP interference with daily function (P = 0.00), higher pain intensity at midday (P = 0.02) and menopausal symptoms (P = 0.00); and reduced QOL (P = 0.00). MSP was associated with increased anxiety (P = 0.02) and menopausal symptoms (P = 0.00), and reduced QOL (P = 0.05). In the whole sample, depression symptoms were higher but no statistical differences were found between groups (P = 0.47). Worse QOL was associated with both higher depressive symptoms (P = 0.01) and worse pain interference (P = 0.02). Conclusions: INS + MSP was related to higher menopausal and anxiety symptoms, more sleep fragmentation and complaints of MSP severity and interference, more pain sites and worse QOL. The presence of INS was associated to more MSP. Sleep management is essential in women who have developed chronic MSP. PMID- 29765924 TI - The Effect of Short-term Treatment with Fennel on Lipid Profile in Postmenopausal Women: A Randomized Controlled Trial. AB - Objectives: The present trial aimed to assess the effects of Fennel (Foeniculum vulgare Mill.) on lipid profiles. Methods: In this double blind, randomized and placebo-controlled trial, sixty eligible postmenopausal women were randomly assigned into the fennel and placebo groups. Total blood cholesterol, cholesterol fractions, and triglycerides were tested at the baseline, and after three-month follow-up. Results: There was no significant difference in triglyceride (P = 0.679), total cholesterol (P = 0.103), low-density lipoprotein cholesterol (LDL C; P = 0.146) and high-density lipoprotein cholesterol (HDL-C; P = 0.266) levels between the two groups. In addition, in both groups, a paired t.test showed no significant difference in all mentioned parameters, except for HDL-C, indicating significant borderline improvement (P = 0.052) in the fennel group. Conclusions: The fennel group revealed a very slight positive change in LDL-C, triglyceride and HDL-C. Further studies with longer durations, higher doses, and larger sample sizes are recommended to validate the results. PMID- 29765925 TI - Decline in Pulmonary Function Tests after Menopause. AB - Objectives: Menopause is the permanent cessation of menstruation resulting from the loss of ovarian follicular activity. There is limited and conflicting evidence for an association between lung function and menopause. The purpose of this study is to evaluate Pulmonary Function Test (PFT) in postmenopausal women. Methods: Digital Spirometer was used to measure PFTs in premenopausal (n = 49) and postmenopausal (n = 46) women. Results: Significant decline in many PFT parameters was observed. Conclusions: Menopausal status is associated with low lung function. PMID- 29765926 TI - Sexual Disharmony in Menopausal Women and Their Husband: A Qualitative Study of Reasons, Strategies, and Ramifications. AB - Objectives: The goal of this study was to explore perceptions and experiences of general practitioners and midwives during sexual dialogue with menopausal women. Methods: In a descriptive exploratory qualitative study, 13 midwives and 12 general practitioners were selected using a semi-structured interview and purposive sampling method. Data analysis was conducted using qualitative content analysis adopted by Graneheim and Lundman. Results: Through data analysis "sexual disharmony" emerged as a central theme, which included three categories of reasons, strategies, and ramifications of sexual disharmony. Reasons for sexual disharmony included subcategories of aging and health related-problems, marital problems, and stereotypical perceptions regarding menopause and sexuality and daily concerns. Strategies used by couples to address sexual disharmony consisted of changing roles and values, pretending to reach orgasm, suppressing sexual desire, meeting sexual needs of husbands in accordance with religious rules, seeking help of peers, seeking friends or traditional medicine and health providers, seeking a help charmer, engaging in sex with other women to fulfill sexual needs, pretending to be moody to alleviate sexual tension. Sexual disharmony may lead to spending money on a prostitute instead of engaging in sex out of wedlock or a surge in social pathologies such as sexually transmitted disease. Conclusions: Healthcare providers must be aware of various sexual behavior of menopausal women and their husbands when they detect sexual disharmony in their patients. Results of this study can facilitate development of restricted guidelines for sexual discussion with menopausal women. PMID- 29765927 TI - Comparing the Pattern of Menopausal Symptoms, Concern and Attitudes in Urban and Rural Postmenopausal Iranian Women. AB - Objectives: Although hormonal changes during menopause are inevitable in this period, the severity of the menopausal symptoms can be controlled. Accepting menopause and having a positive attitude toward it can also help. Given the results of previous studies, and since environmental factors affect the pattern of menopausal symptoms the present study was conducted to compare the pattern of menopausal symptoms, concern and attitudes in urban and rural postmenopausal women. Methods: This cross-sectional study was conducted on urban and rural postmenopausal women residing in and around Tabriz, Iran. Cluster sampling was used to select the subjects. The data collection tools used included a demographic questionnaire to assess women's experiences during menopause. Results: This study examined 544 urban and rural postmenopausal women between March and September 2015. The women had a mean age of 51.8 +/- 3.1. After adjusting the basic variables, the mean scores of menopausal symptoms and their subscales showed significantly higher scores in the physical and psychological subscales in the urban women, while the rural women had significantly higher scores in the concern subscale. Conclusions: Rural women were significantly different from urban women in terms of menopausal symptoms, concern and attitudes. Hot flushes, a common menopausal symptom, and decreased sexual desire were more common in the urban women; in contrast, the rural women experienced more concern about menopause and its consequences. PMID- 29765928 TI - Aromatherapy for Sexual Problems in Menopausal Women: A Systematic Review and Meta-analysis. AB - Objectives: The aim of the present systematic review and meta-analysis is the exploration of the potential evidence of the effectiveness of aromatherapy products on the sexual function of menopausal women. Methods: From inception to December 2017, the search process was performed using the MEDLINE and Scopus databases and the Cochrane Library regarding the trials on the effectiveness of herbal-medicine aromatherapy on the sexual function of menopausal women. Results: Three of the trials comprise suitable data for inclusion in the meta-analysis. According to the meta-analysis, it is possible to improve the standardized mean difference (SMD) of the sexual desire up to 0.56 in the aromatherapy group compared with the control group (SMD = 0.56; P < 0.001; heterogeneity; I2 = 42%; P = 0.141). According to one of the trials, the serum-estrogen level of two different doses did not change in the neroli oil inhalation group compared with the almond-oil group. Conclusions: Both aromatherapy with neroli oil or lavender (monopreparation) and combined-oil aromatherapy with lavender, fennel, geranium, and rose significantly improved human sexual function; however, a significant change of the serum-estrogen level was not detected. The findings of the present review should be presented cautiously because of the corresponding limitations such as the lack of a standardized tool, the lack of intention-to-treat reporting, the low study amount, and the short-term follow-up. PMID- 29765929 TI - Gonadotropin-releasing Hormone Agonist Plus Aromatase Inhibitor in the Treatment of Uterine Leiomyoma in Near Menopause Patient: A Case Series Study. AB - Objectives: There are many drugs for of symptomatic fibroids. Gonadotropin releasing hormone (GnRH) agonists are the well known drugs. Also, aromatase inhibitors are effective. All published studies surveyed the effect of one of these two drugs. In this study as the first study decided to evaluate the effectiveness of the combination of GnRH agonists + aromatise inhibitor on the uterine fibroids. Methods: A cross-sectional prospective case series study was performed on 10 known cases of uterine fibroids late perimenopause, at least 3 myomas >5 cm, abnormal uterine bleeding and anemia due to fibroids, candidate for hysterectomy, no tendency to surgery. A single dose of Diphereline 11.25 mg, SR plus 2.5 mg of Letrozole daily for 4 weeks with add-back therapy + calcium carbonate were used. The second dose of Diphereline 11.25 mg, SR was used 3 months after the first injection. The patients were followed until 3 years. Results: The mean age of the study group was 49.90 +/- 1.66. The mean fibroid size reduced from 15.05 +/- 57.20 cm to 13.56 +/- 39.39 cm (P = 0.012) and fibroid volume reduced from 72.78 +/- 110.6 to 50.96 +/- 64.2 (P = 0.116). There was no signification changes in the serum level of hormones at the end of six months. Eight cases were menopause at the end of the study and hypoestrogenism symptoms did not happened in none of the cases until the end of 24 months. Except in one case, there was no need to do surgery on others. Conclusions: Combination of Diphereline + Letrozole probably could prevent surgery in cases that have multiple fibroids, perimenopause, anemic and candidate for surgery. PMID- 29765930 TI - Effect of Fennel on the Health Status of Menopausal Women: A Systematic and Meta analysis. AB - Objectives: The aim of the present study is the systematic and critical investigation of the effectiveness of fennel on the climacteric symptoms among menopausal females. Methods: A search of the trials studying the effect of fennel on menopausal females was conducted in 2017 using the MEDLINE and Scopus databases and the Cochrane Library with the following keywords: fennel, Foeniculum vulgare, and menopause. Results: Fennel combined with officinalis is more effective in the attenuating of sleep disorders compared to Citalopram. The comparison of these two groups regarding the mean bone mineral density and bone mineral content (P = 0.14, P = 0.504); the total hip femoral (P = 0.42, P = 0.66); the trochanter (P = 0.075, P = 0.07); the intertrochanter (P = 0.84, P = 0.93); and the femoral neck (P = 0.43, P = 0.64) did not show any significant statistical differences; however, a statistically significant difference regarding the vasomotor symptoms (P < 0.01) was found. The other significant differences are related to the values of the total cholesterol (P = 0.103); low density lipoprotein cholesterol, or LDL-C (P = 0.104); high-density lipoprotein cholesterol, or HDL-C (P = 0.266); triglyceride (P = 0.679); body weight (P = 0.212); body mass index (P = 0.041); waist and hip circumferences (P = 0.365); and fat distribution (P = 0.337) between the two groups. The standardized mean difference (SMD) values of sexual activity (SMD = 0.638; P < 0.001), and maturation value (SMD = 0.601; P = 0.003) are highly significant among the fennel treated women compared with the placebo group. Conclusions: According to the findings of the present study, fennel is important in the relieving of vasomotor symptoms, vaginal itching, dryness, dyspareunia, sexual function, sexual satisfaction, and sleep distribution. PMID- 29765931 TI - Decreased Breg/Th17 Ratio Improved the Prognosis of Patients with Ulcerative Colitis. AB - Objective: To investigate the effects of regulatory B (Breg) cells and T helper 17 (Th17) cells on pathogenesis of ulcerative colitis, explore the clinical significance of Breg/Th17 ratio on the prognosis of ulcerative colitis, and provide the theoretical basis for the targeted therapy, diagnosis, and prognosis of the disease. Methods: Peripheral blood and colonic mucosa were collected from patients with ulcerative colitis. Hematoxylin-eosin staining was used to observe the pathological changes of colonic mucosa. Flow cytometry was utilized to analyze the percentages of Breg cells and Th17 cells. Real-time fluorescent quantitative polymerase chain reaction and immunohistochemistry were applied to determine the expression of Breg cells-related cytokines IL-10 and Th17 cell transcription factor RORgammaT. Enzyme-linked immunosorbent assay was employed to detect serum IL-10 and IL-17 levels. Results: The colonic mucosa of ulcerative colitis patients presented massive inflammatory cell infiltration and hemorrhagic necrosis. The number of Breg cells and Th17 cells, the gene expressions of IL-10 and RORgammaT, and serum levels of IL-10 and IL-17 all increased in peripheral blood. Compared with nonremission group, the remission group showed that the percentage of Breg cells reduced, the percentage of Th17 cells increased, and thus the B10/Th17 ratio was significantly decreased in peripheral blood. In addition, serum IL-10 levels diminished, IL-17 levels increased, and thus IL 10/IL-17 ratio was remarkably reduced in remission group. B10/Th17 ratio and IL 10/IL-17 ratio were positively correlated with the severity of disease. Conclusions: Breg and Th17 cells participate in the occurrence and development of ulcerative colitis. B10/Th17 ratio and IL-10/IL-17 ratio can be used as prognostic markers for ulcerative colitis. This provides a theoretical basis for design of targeted treatment and prognosis assessment of the disease. PMID- 29765932 TI - Fluid Overload and Renal Angina Index at Admission Are Associated With Worse Outcomes in Critically Ill Children. AB - Objectives: We investigated the association of fluid overload and oxygenation in critically sick children, and their correlation with various outcomes (duration of ventilation, ICU stay, and mortality). We also assessed whether renal angina index (RAI) at admission can predict mortality or acute kidney injury (AKI) on day 3 after admission. Design and setting: Prospective study, pediatric intensive care in a tertiary hospital. Duration: June 2013-June 2014. Patients: Patients were included if they needed invasive mechanical ventilation for >24 h and had an indwelling arterial catheter. Patients with congenital heart disease or those who received renal replacement therapy (RRT) were excluded. Methods: Oxygenation index, fluid overload percent (daily, cumulative), RAI at admission and pediatric logistic organ dysfunction (PELOD) score were obtained in all critically ill children. KDIGO classification was used to define AKI, using both creatinine and urine output criteria. Admission data for determination of RAI included the use of vasopressors, invasive mechanical ventilation, percent fluid overload, and change in kidney function (estimated creatinine clearance). Univariable and multivariable approaches were used to assess the relations between fluid overload, oxygenation index and clinical outcomes. An RAI cutoff >8 was used to predict AKI on day 3 of admission and mortality. Results: One hundred and two patients were recruited. Fluid overload predicted oxygenation index in all patients, independent of age, gender and PELOD score (p < 0.05). Fluid overload was associated with longer duration of ventilation (p < 0.05), controlled for age, gender, and PELOD score. Day-3 AKI rates were higher in patients with a RAI of 8 or more, and higher areas under the RAI curve had better prediction rates for Day-3 AKI. An RAI <8 had high negative predictive values (80-95%) for Day-3 AKI. RAI was better than traditional markers of pediatric severity of illness (PELOD) score for prediction of AKI on day 3. Conclusions: This study emphasizes that positive fluid balance adversely affects intensive care in critically ill children. Further, the RAI prediction model may help optimize treatment and improve clinical prediction of AKI. PMID- 29765933 TI - A Pilot Study of Inhaled CO Therapy in Neonatal Hypoxia-Ischemia: Carboxyhemoglobin Concentrations and Brain Volumes. AB - Objective: The objective of this pilot study was to start evaluating the efficacy and the safety (i.e., carboxyhemoglobin concentration of carbon monoxide (CO)) as a putative neuroprotective therapy in neonates. Study Design: Neonatal C57BL/6 mice were exposed to CO at a concentration of either 200 or 250 ppm for a period of 1 h. The pups were then sacrificed at 0, 10, 20, 60, 120, 180, and 240 min after exposure to either concentration of CO, and blood was collected for analysis of carboxyhemoglobin. Following the safety study, 7-day-old pups underwent a unilateral carotid ligation. After recovery, the pups were exposed to a humidified gas mixture of 8% oxygen and 92% nitrogen for 20 min in a hypoxia chamber. One hour after the hypoxia exposure, the pups were randomized to one of two groups: air (HI+A) or carbon monoxide (HI+CO). An inhaled dose of 250 ppm of CO was administered to the pups for 1 h per day for a period of 3 days. At 7 days post-injury, the pups were sacrificed and the brains analyzed for cortical and hippocampal volumes. Results: CO exposure at 200 and 250 ppm produced a peak carboxyhemoglobin concentration of 21.52 +/- 1.18% and 27.55 +/- 3.58%, respectively. The carboxyhemoglobin concentrations decreased rapidly, reaching control concentrations by 60 min post exposure. At 14 days of age (7 days post injury), the HI+CO (treated with 1 h per day of 250 ppm of CO for 3 days post injury) had significant preservation of the ratio of ipsilateral to contralateral cortex (median 1.07, 25% 0.97, 75% 1.23, n = 10) compared the HI+A group (p < 0.05). Conclusion: CO exposure of 250 ppm did not reach carboxyhemoglobin concentrations which would induce acute neurologic abnormalities and was effective in preserving cortical volumes following hypoxic-ischemic injury. PMID- 29765934 TI - Autoimmune Gastritis in the Pediatric Age: An Underestimated Condition Report of Two Cases and Review. AB - Background: Diagnosis of pediatric autoimmune gastritis (AIG) in children is important due to poor outcome and risk of malignancy. This condition is often underestimated in the clinico-pathologic diagnostic work-up, leading to delayed time-to-diagnosis. To increase the awareness of this condition in the pediatric population, we present two cases encountered at our institution, discuss their clinical, biological, and histological presentations in relation with evidence from the literature, and propose an algorithm for diagnosis and follow-up of AIG in children. Case presentation: Two patients (12 and 17 years old) presented with iron deficiency anemia and negative family history for autoimmune disorders. In both cases, the final diagnosis of autoimmune gastritis was delayed until pathological examination of endoscopic gastric biopsies showed atrophy of oxyntic glands. Helicobacter pylori search was negative. Follow up biopsies revealed persistent disease. Literature review on this condition shows unclear etiology and poor long term outcome in some patients because of increased risk of malignancy. Conclusions: AIG should be considered in the differential diagnosis of iron deficiency anemia in the pediatric population.Standardized clinico pathologic work-up is mandatory. Endoscopic follow-up should be performed due to the risk of malignancy. PMID- 29765935 TI - Experiences During a Psychoeducational Intervention Program Run in a Pediatric Ward: A Qualitative Study. AB - Hospitalization, despite its duration, is likely to result in emotional, social, and academic costs to school-age children and adolescents. Developing adequate psychoeducational activities and assuring inpatients' own class teachers' collaboration, allows for the enhancement of their personal and emotional competences and the maintenance of a connection with school and academic life. These educational programs have been mainly designed for patients with long stays and/or chronic conditions, in the format of Hospital Schools, and typically in pediatric Hospitals. However, the negative effects of hospitalization can be felt in internments of any duration, and children hospitalized in smaller regional hospitals should have access to actions to maintain the connection with their daily life. Thus, this investigation aims to present a psychoeducational intervention program theoretically grounded within the self-regulated learning (SRL) framework, implemented along 1 year in a pediatric ward of a regional hospital to all its school-aged inpatients, regardless of the duration of their stay. The program counts with two facets: the psychoeducational accompaniment and the linkage to school. All the 798 school-aged inpatients (Mage = 11.7; SDage = 3.71; Mhospital stay = 4 days) participated in pedagogical, leisure nature, and SRL activities designed to train transversal skills (e.g., goal-setting). Moreover, inpatients completed assigned study tasks resulting from the linkage between the students' own class teachers and the hospital teacher. The experiences reported by parents/caregivers and class teachers of the inpatients enrolling in the intervention allowed the researchers to reflect on the potential advantages of implementing a psychoeducational intervention to hospitalized children and adolescents that is: individually tailored, focused on leisure playful theoretically grounded activities that allow learning to naturally occur, and designed to facilitate school re-entry after hospital discharge. Parents/caregivers highlighted that the program helped in the preparation for surgery and facilitated the hospitalization process, aided in the distraction from the health condition, promoted SRL competences, and facilitated the communication and linkage with school life. Class teachers emphasized the relevance of the program, particularly in the liaison between hospital and school, in the academic and psycho-emotional and leisure-educational support provided, and in smoothing the school re-entry. PMID- 29765936 TI - Parental Socioeconomic Status and Weight Faltering in Infants in Japan. AB - Background: Previous studies in the UK and Denmark found no significant association between low socioeconomic status (SES) and weight faltering. However, to our knowledge, there are no studies from other developed countries. We examined the association between parental SES and weight faltering in infants up to 1.5 years of age, and investigated whether the inequalities changed between 2001 and 2010 in Japan. Methods: We used data from two Japanese population-based birth cohorts started in 2001 (n = 34,594) and 2010 (n = 21,189). Parental SES was assessed as household income and parental education when the infant was 6 months old. Weight faltering was defined as the slowest weight gaining in 5% of all children in each cohort. Logistic regression analyses were conducted with adjustment for covariates. The relative index of inequality was used to assess relative impact of parental SES on weight faltering. Results: Infants in the lowest quartile of household income were 1.29 (95% confidence interval [CI]: 1.10, 1.52) and 1.27 (95% CI: 1.03, 1.56) times more likely to experience weight faltering than those in the highest income quartile both in the 2001 and 2010 cohorts, respectively. The relative index of inequality for household income was 1.66 (95% CI: 1.36, 1.96) in 2001 and 1.86 (95% CI: 1.42, 2.31) in 2010. Conclusions: Infants from lower income families have a greater risk of weight faltering in Japan. Additionally, the income-related inequalities in weight faltering did not change between the two cohorts. Social policies to address maldistribution of weight faltering due to household income are needed. PMID- 29765937 TI - Conceptual DFT Study of the Local Chemical Reactivity of the Colored BISARG Melanoidin and Its Protonated Derivative. AB - This computational study assessed eight fixed RSH (range-separated hybrid) density functionals that include CAM-B3LYP, LC-omegaPBE, M11, MN12SX, N12SX, omegaB97, omegaB97X, and omegaB97XD related to the Def2TZVP basis sets together with the SMD solvation model in the calculation the molecular structure and reactivity properties of the BISARG intermediate melanoidin pigment (5-(2-(E)-(Z) 5-[(2-furyl)methylidene]-3-(4-acetylamino-4-carboxybutyl)-2-imino-1,3 dihydroimidazol-4-ylideneamino(E)-4-[(2-furyl)methylidene]-5-oxo-1H-imidazol-1 yl)-2-acetylaminovaleric acid) and its protonated derivative, BISARG(p). The chemical reactivity descriptors for the systems were calculated via the Conceptual Density Functional Theory. The choice of active sites applicable to nucleophilic, electrophilic as well as radical attacks were made by linking them with Fukui functions indices, electrophilic and nucleophilic Parr functions, and the condensed Dual Descriptor Deltaf(r). The study found the MN12SX and N12SX density functionals to be the most appropriate in predicting the chemical reactivity of the molecular systems under study starting from the knowledge of the HOMO, LUMO, and HOMO-LUMO gap energies. PMID- 29765938 TI - Utilizing Benzotriazole and Indacenodithiophene Units to Construct Both Polymeric Donor and Small Molecular Acceptors to Realize Organic Solar Cells With High Open Circuit Voltages Beyond 1.2 V. AB - Devolopment of organic solar cells with high open-circuit voltage (VOC) and power conversion efficiency (PCE) simutaniously plays a significant role, but there is no guideline how to choose the suitable photovoltaic material combinations. In our previous work, we developed "the Same-Acceptor-Strategy" (SAS), by utilizing the same electron-accepting segment to construct both polymeric donor and small molecular acceptor. In this study, we further expend SAS to use both the same electron-accepting and electron-donating units to design the material combination. The p-type polymer of PIDT-DTffBTA is designed by inserting conjugated bridge between indacenodithiophene (IDT) and fluorinated benzotriazole (BTA), while the n-type small molecules of BTAx (x = 1, 2, 3) are obtained by introducing different end-capped groups to BTA-IDT-BTA backbone. PIDT-DTffBTA: BTAx (x = 1-3) based photovolatic devices can realize high VOC of 1.21-1.37 V with the very small voltage loss (0.55-0.60 V), while only the PIDT-DTffBTA: BTA3 based device possesses the enough driving force for efficient hole and electron transfer and yields the optimal PCE of 5.67%, which is among the highest value for organic solar cells (OSCs) with a VOC beyond 1.20 V reported so far. Our results provide a simple and effective method to obtain fullerene-free OSCs with a high VOC and PCE. PMID- 29765939 TI - Comparing the Relative Interfacial Affinity of Soft Colloids With Different Crosslinking Densities in Pickering Emulsions. AB - Pickering emulsions prepared by various kinds of soft colloids such as the poly(N isopropylacrylamide) (PNIPAM)-based microgels, have been studied for decades in order to fabricate stimuli-responsive emulsions. It has been generally viewed that the interfacial properties of the microgel monolayers and the emulsion stability are dominated by the softness or deformability of the microgel particles. However, there is still no convenient way to characterize the adsorption/desorption energy of the microgels at the interface although this is an essential topic for microgel-stabilized emulsions. This paper presents a novel method for directly comparing the relative interfacial affinity of microgel particles with comparable size but different crosslinking densities, therefore, different softness at the oil/water interface. Typical micron-sized PNIPAM-based microgels were synthesized and used in this study. With advanced fluorescent labeling techniques, we are capable of distinguishing different kinds of microgels in a Pickering emulsion. During vigorous agitation, particles with higher adsorption energy are more likely to be found at the oil/water interface instead of the loosely adsorbed counterparts. By counting the ratio of interfacial area occupied by two microgels, the interfacial affinity of them can be compared. It is found that interfacial affinity of microgels is not only dependent on the softness but also strongly correlated with the core-shell morphology of the microgels, especially the outmost collapsed polymer layer at the interface. This result is consistent with the interfacial morphology model proposed by other researchers. The understanding of the stabilization of such Pickering emulsions can help us to design and develop responsive Pickering emulsions with better controlled stability. PMID- 29765940 TI - A Comparative Survey of Methods for Remote Heart Rate Detection From Frontal Face Videos. AB - Remotely measuring physiological activity can provide substantial benefits for both the medical and the affective computing applications. Recent research has proposed different methodologies for the unobtrusive detection of heart rate (HR) using human face recordings. These methods are based on subtle color changes or motions of the face due to cardiovascular activities, which are invisible to human eyes but can be captured by digital cameras. Several approaches have been proposed such as signal processing and machine learning. However, these methods are compared with different datasets, and there is consequently no consensus on method performance. In this article, we describe and evaluate several methods defined in literature, from 2008 until present day, for the remote detection of HR using human face recordings. The general HR processing pipeline is divided into three stages: face video processing, face blood volume pulse (BVP) signal extraction, and HR computation. Approaches presented in the paper are classified and grouped according to each stage. At each stage, algorithms are analyzed and compared based on their performance using the public database MAHNOB-HCI. Results found in this article are limited on MAHNOB-HCI dataset. Results show that extracted face skin area contains more BVP information. Blind source separation and peak detection methods are more robust with head motions for estimating HR. PMID- 29765941 TI - Nano- and Micro-Patterned S-, H-, and X-PDMS for Cell-Based Applications: Comparison of Wettability, Roughness, and Cell-Derived Parameters. AB - Polydimethylsiloxane (PDMS) is a promising biomaterial for generating artificial extracellular matrix (ECM) like patterned topographies, yet its hydrophobic nature limits its applicability to cell-based approaches. Although plasma treatment can enhance the wettability of PDMS, the surface is known to recover its hydrophobicity within a few hours after exposure to air. To investigate the capability of a novel PDMS-type (X-PDMS) for in vitro based assessment of physiological cell properties, we designed and fabricated plane as well as nano- and micrometer-scaled pillar-patterned growth substrates using the elastomer types S-, H- and X-PDMS, which were fabricated from commercially available components. Most importantly, we compared X-PDMS based growth substrates which have not yet been investigated in this context with H- as well as well-known S PDMS based substrates. Due to its applicability to fabricating nanometer-sized topographic features with high accuracy and pattern fidelity, this material may be of high relevance for specific biomedical applications. To assess their applicability to cell-based approaches, we characterized the generated surfaces using water contact angle (WCA) measurement and atomic force microscopy (AFM) as indicators of wettability and roughness, respectively. We further assessed cell number, cell area and cellular elongation as indirect measures of cellular viability and adhesion by image cytometry and phenotypic profiling, respectively, using Calcein and Hoechst 33342 stained human foreskin fibroblasts as a model system. We show for the first time that different PDMS types are differently sensitive to plasma treatment. We further demonstrate that surface hydrophobicity changes along with changing height of the pillar-structures. Our data indicate that plane and structured X-PDMS shows cytocompatibility and adhesive properties comparable to the previously described elastomer types S- and H-PDMS. We conclude that nanometer-sized structuring of X-PDMS may serve as a powerful method for altering surface properties toward production of biomedical devices for cell based applications. PMID- 29765943 TI - Juvenile Xanthogranuloma in a Pediatric Patient with Langerhans Cell Histiocytosis. AB - Purpose: To report a case of juvenile xanthogranuloma that simulated a chalazion and to discuss the association between juvenile xanthogranuloma and Langerhans cell histiocytosis. Method: Case report and review of literature. Results: A 13 year-old boy with a prior history of Langerhans cell histiocytosis was referred to our clinic for a possible chalazion. The patient had undergone treatment for Langerhans cell histiocytosis 10 years prior. The patient underwent an excisional biopsy. Histopathology revealed a proliferation of histiocytes and lymphocytes with Touton giant cells, consistent with a diagnosis of juvenile xanthogranuloma. Conclusions: Though the relationship between Langerhans cell histiocytosis and juvenile xanthogranuloma has yet to be fully elucidated, juvenile xanthogranuloma should be included in the differential diagnosis for any former Langerhans cell histiocytosis patient presenting with a new cutaneous lesion. PMID- 29765942 TI - Malpractice Litigation in Ocular Oncology. AB - Aims: The aim of this study was to report and analyze the causes and outcomes of ocular oncology malpractice litigation. Methods: The WestLaw(r) database was reviewed for all litigation related to ophthalmology in the United States from 1930 to 2014. All ocular oncology cases were included in this analysis and compared to other ophthalmic subspecialties. Results: Sixteen ocular oncology malpractice cases were included in this study. Overall, 56.3% of the cases were resolved in favor of the defendant. A total of 62.5% of cases were resolved via jury verdict, with 30.0% resulting in plaintiff verdicts with mean adjusted awards of USD 511,244.48, comparable to ophthalmology as a whole. Three cases (18.8%) resulted in settlements with mean adjusted indemnities of USD 828,928.14. A total of 87.5% of cases alleged insufficient intervention resulting in loss of vision and/or death. The most common clinical entities were uveal melanoma (31.3%), retinoblastoma (12.5%), and sebaceous cell carcinoma (12.5%). Conclusions: Ocular oncology malpractice litigation was relatively rare and outcomes generally favored defendants; however, unlike other subspecialties in ophthalmology, blindness or premature death were common to all cases, highlighting both the importance of prompt diagnosis and treatment and the difficulty inherent in diagnosing ocular malignancies. PMID- 29765944 TI - Uveal Melanoma: 5-Year Update on Incidence, Treatment, and Survival (SEER 1973 2013). AB - Purpose: To analyze trends in incidence, treatment, and survival of uveal melanoma in the United States from 1973 to 2013 using the Surveillance, Epidemiology, and End Results database. Materials and Methods: Patients were identified using International Classification of Disease for Oncology codes: C69.3 (choroid), C69.4 (ciliary body and iris), and C69.2 (retina). Trends in age adjusted incidence, treatment (surgery or radiation), and 5-year relative survival were calculated. Results: There were 4,999 cases of uveal melanoma. The majority (97.8%) were reported by hospital inpatient/outpatient clinics. Histopathologic confirmation was available in 67.8%. The mean age-adjusted incidence was 5.2 per million (95% CI 5.0-5.4). When the incidence was standardized for race, a small but statistically significant (p < 0.05) annual percentage change of 0.5% was detected in Whites. There was a decline in patients treated with surgery alone (94.2% from 1973 to 1975 vs. 24.7% from 2012 to 2013). A corresponding increase was observed in radiation as primary treatment selection (1.3% from 1973 to 1975 vs. 68.3% from 2012 to 2013). No change in the 5-year relative survival (80.9%) was observed. Conclusions: The age-adjusted incidence of uveal melanoma has remained stable with a minor increase in Whites. Despite a shift towards globe-preserving treatment, there has not been a concomitant improvement in survival. PMID- 29765946 TI - Radiation Retinopathy 47 Years following Brachytherapy for Retinoblastoma. AB - A 50-year-old female who had undergone enucleation in the left eye and brachytherapy in the right eye for retinoblastoma at the age of 2 years was diagnosed with nonproliferation radiation retinopathy 47 years following the initial treatment. The patient had noticed black spots in her vision (scotomas) that interfered with reading. New onset of microaneurysms and lipid exudation threatening the foveola was noted on examination of the right eye. Initial visual acuity (VA) was 20/25. Optical coherence tomography showed no evidence of macular edema, but parafoveal lipid exudation was present. On fluorescein angiography, no sign of neovascularization or macular ischemia was observed. Direct focal treatment of microaneurysms was performed to prevent progression of the radiation retinopathy and vision loss. At 18 months' follow-up following focal laser, VA remained stable at 20/25 and there was a regression of the retinopathy. PMID- 29765945 TI - Atypical Fibroxanthoma of the Bulbar Conjunctiva: A Unique Case Describing the Pathology, Clinical Presentation, and Management. AB - Background/Aims: Atypical fibroxanthoma is an uncommon tumor that usually occurs in the skin of the head and neck of the elderly with significant sun exposure. We describe a unique case featuring a rare ocular surface conjunctival tumor (atypical fibroxanthoma) and provide insight on its characteristic clinical features, surgical management, and histology. Methods: A 71-year-old male fisherman with no pertinent ocular history presented to an academic center with a rapidly enlarging bulbar conjunctival mass in the right perilimbal region for the past several months. The patient underwent surgical excisional biopsy with cryotherapy, adjuvant alcohol, and amniotic membrane transplantation. Results: Pathology specimen illustrated an atypical spindle cell tumor with inflammatory cells, increased mitotic activity, cytologic atypia, and positive diffuse staining with CD163 and CD10 consistent with an atypical fibroxanthoma. Conclusion: Atypical fibroxanthoma is an extremely rare ocular surface tumor that may simulate conjunctival or ocular surface squamous neoplasia. While this lesion typically pursues a benign clinical course, it may recur or rarely metastasize. Thus it should be treated aggressively with excisional biopsy, cryotherapy, absolute alcohol, and/or amniotic membrane transplantation. PMID- 29765947 TI - Leser-Trelat Syndrome in a Male with Breast Carcinoma and Eyelid Basal Cell Carcinoma. AB - Purpose: Leser-Trelat syndrome consists of appearance of a solid tumor-like carcinoma breast, colon, or stomach following eruption of multiple seborrheic keratoses (SK) of the skin. We present an unusual and possibly the first case report of Leser-Trelat syndrome in a male patient with a history of mastectomy for breast carcinoma who presented to us with a second malignancy in the form of basal cell carcinoma (BCC) of the lower eyelid. Procedure: A 75-year-old male presented in 2014 with a history of modified radical mastectomy for infiltrating ductal carcinoma of the left breast which was performed 11 years prior to the day of presentation. Breast carcinoma was diagnosed following eruption of multiple SK at the same time. In the previous 3 years he noted a nodulo-ulcerative growth over the lateral aspect of the right lower eyelid which was clinically diagnosed as BCC. Mass excision under frozen section control and lid reconstruction was performed. Diagnosis of BCC was confirmed on histopathological examination of the excised specimen. Results and Conclusions: Though a previously unobserved entity, our case supports the importance of Leser-Trelat sign and its relevance to affected individuals, as early recognition and prompt treatment of a low-stage cancer offers good prognosis. PMID- 29765948 TI - Congenital Orbital Rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is the most common malignant tumor of the orbit in children, but it is rarely present at birth. We report a large congenital orbital RMS with intracranial extension in a newborn baby. A newborn baby girl was referred to our hospital due to severe right-eye exophthalmia. Imaging studies showed an orbital mass with intracranial extension. Treatment was started with a course of neoadjuvant chemotherapy followed by right orbital exenteration and intracranial resection of the tumor. Histologic examination of the mass showed undifferentiated malignant small-cell tumor. Immunohistochemical study proved it to be RMS. The patient was categorized as intermediate-risk RMS and chemotherapy was continued accordingly with VAC regimen. In spite of treatment, the infant developed intracranial recurrence at the age of 6 months and died 1 month later. Congenital orbital RMS has a poor prognosis. Reconstruction surgery should be deferred due to high rate of recurrence and low chance of survival. A multidisciplinary approach might increase the survival of these patients. PMID- 29765950 TI - Early Neuroblastic and Astrocytic Differentiation Demonstrated Immunohistochemically in a Small Intraocular Medulloepithelioma. AB - Purpose: To investigate the source of fibrous astrocytes and neuroblasts in a small ciliary body medulloepithelioma appearing as a leukocoria in a 3-week-old baby girl. Methods: Histopathologic and immunohistochemical studies included Alcian blue, periodic acid-Schiff, and antisera for the detection of S100 protein, CD99, glial fibrillary acidic protein (GFAP), CRX, NeuN, neurofilaments, synaptophysin, desmin, and myogenin. Results: A small, nonteratoid ciliary body medulloepithelioma with collections of Alcian blue+ mucoplysaccharides was present in the enucleated globe. The retinal mass displayed multilaminar dysplastic rosettes that were CRX+, NeuN-, and synaptophysin-. Intraretinal neurofilaments and scattered NeuN+ neurocytes were also identified. At the base of the retinal mass ribbons and pseudopapillae of CRX+, NeuN- medullary epithelium were found. The latter developed from an S100+ and weakly CD99+ monolayer of premedullary epithelium. GFAP+ fibrous astrocytes and NeuN- neuroblasts streamed from the medullary epithelium. Conclusions: A multilaminar medullary epithelium and a precursor monolayer of premedullary epithelium were both identified. Neuroblasts and fibrous astrocytes were determined to arise separately from the medullary epithelium. The early stage of tumorigenesis afforded by a small tumor provided the opportunity to discover morphologic and immunohistochemical evidence for these differentiations. PMID- 29765949 TI - A 20-Year Retrospective Review of Retinoblastoma at Two Tertiary Academic Hospitals in Johannesburg, South Africa. AB - Aim: This paper presents a 20-year review of retinoblastoma in Johannesburg, South Africa, aiming to better characterize the disease in this sub-Saharan setting. Methods: The study represents a retrospective case series of retinoblastoma patients presenting to Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital between January 1, 1992, and December 31, 2011. Results: The total number of cases identified was 282, with 245 meeting the study inclusion criteria. Retinoblastoma comprised 6.9% of the total pediatric oncology presentations; 65.3% were unilateral, 34.3% bilateral, and 0.4% trilateral. The overall male-to-female ratio was 1.08. The mean age at presentation overall was 32.6 months (median 28.0), in the unilateral group 39.4 months (median 33.0), and in the bilateral group 19.7 months (median 17.0). The mean delay to presentation overall was 7.0 months (median 4.0). The most frequent presenting symptoms were leukocoria (37.1%) and proptosis (34.7%). The distribution of disease stages at presentation (International Retinoblastoma Staging System) was 1.6% stage 0, 24.1% stage I, 27.8% stage II, 16.3% stage III, and 25.3% stage IV. 26.5% defaulted care. The 5-year Kaplan-Meier survival estimate was 57.7% overall. Conclusion: This study shows that delayed presentation and refusal of therapy remains a significant barrier to effective treatment in this African setting. PMID- 29765951 TI - Advanced Midzonal Iris Pigment Epithelial Cyst Managed by Aspiration Deflation. AB - Background: There are several cysts that can occur in the iris. The midzonal (retroiridic) iris pigment epithelial (IPE) cyst is important because it can simulate melanoma of the ciliary body. However, it is frequently asymptomatic and requires no treatment. Methods: A 37-year-old asymptomatic woman with visual acuity of 20/20 in each eye was found to have an elevated mass behind the left iris, presumed to be melanoma, and was referred for management. On our examination, there was a typical midzonal IPE cyst in the left eye (OS), requiring observation without intervention. After 4 years, she developed progressive visual loss to 20/40 OS and cyst enlargement was noted, obstructing most of the visual axis and causing partial lens subluxation. Translimbal fine needle aspiration deflation with a 30-G needle was performed. Results: Immediately at aspiration, the cyst demonstrated collapse, disappearing behind the iris stroma, and the lens subluxation resolved. Visual acuity returned to 20/20 OS and has remained stable without recurrence for 3 years. Conclusion: Although most midzonal IPE cysts are asymptomatic, this case showed progressive enlargement with visual loss and was managed with translimbal aspiration. Symptomatic midzonal IPE cysts can be deflated with translimbal aspiration rather than more aggressive surgical excision. PMID- 29765952 TI - Malignant Orbital Meningioma Originating from the Frontal Lobe. AB - Purpose of the Study: Orbital meningiomas are typically benign tumors, most commonly originating from the dura of the sphenoid wing or the optic nerve sheath. Procedures: We describe an unusual case of a malignant meningioma originating from the frontal lobe that ultimately produced orbital and distant metastases. Results and Conclusions: Orbital invasion by the meningioma was preceded by multiple incomplete resections, which may have facilitated access to the orbit. The present case serves to remind clinicians that surgical resection of aggressive, recurrent frontal lobe meningiomas may facilitate subsequent penetration of surrounding structures, particularly by tumors that demonstrate bone-destructive properties. PMID- 29765953 TI - Response to "Comparison of Gene Expression Profiling and Chromosome 3 Analysis by Fluorescent in situ Hybridization and Multiplex Ligation Probe Amplification in Fine-Needle Aspiration Biopsy Specimens of Uveal Melanoma". PMID- 29765954 TI - An Unusual Presentation of Esthesioneuroblastoma in a Young Pregnant Female. AB - Background: Esthesioneuroblastoma is a rare neuroepithelial tumor arising from the olfactory epithelium in the cribriform plate or nasal cavity. It accounts for 1-5% of cases of malignant neoplasms of the nasal cavity. Methods: A 20-year-old pregnant female presented with painful loss of vision in both eyes, on imaging diagnosed as meningioma. There was a progressive increase in pain along with diminution of vision to the extent of complete loss of vision in the right eye. Results: In view of increasing proptosis with progressive complete loss of vision in the left eye also, she consulted the neurosurgery department at a tertiary care hospital where a follow-up of contrast-enhanced computerised tomography was made. Histopathology of fluid obtained after craniotomy showed esthesioneuroblastoma. In view of intracranial space-occupying lesion applying pressure on the optic nerve, intravenous methylprednisolone (1 g, IV stat X 3 days) was given. She underwent extensive radiotherapy but died within 3 months of diagnosis. Conclusion: This case highlights the progressive and fatal course of olfactory neuroblastoma. As it can present with the complex symptoms related to ocular and nasal sites, timely referral of patients presenting with visual symptoms along with nasal involvement (frequent epistaxis) to otorhinolaryngologists is very important. PMID- 29765955 TI - Pediatric Multiple Endocrine Neoplasia Type 2B: Clinicopathological Correlation of Perilimbal Mucosal Neuromas and Treatment of Secondary Open-Angle Glaucoma. AB - Ocular findings of multiple endocrine neoplasia type 2B (MEN 2B) include prominent corneal nerves, mucosal neuromas of the conjunctiva, glaucoma, and dry eyes. A 15-year-old girl with MEN 2B presents with advanced secondary open-angle glaucoma and bilateral perilimbal masses. High-resolution optical coherence tomography (HR-OCT) of the perilimbal lesions showed normal epithelial thickness and subepithelial lobular areas of mixed reflectivity, which correlates well with histopathologic findings of benign mucosal neuromas. The patient underwent bilateral gonioscopy-assisted transluminal trabeculotomy (GATT) in both eyes, which achieved adequate intraocular pressure control at short-term follow-up. To the authors' knowledge, this is the first report correlating HR-OCT and histopathologic findings in benign mucosal neuroma associated with MEN 2B, and the first description of secondary open-angle glaucoma associated with MEN 2B treated with GATT. PMID- 29765956 TI - Transcriptomic Profiling of Zebrafish Hair Cells Using RiboTag. AB - The zebrafish inner ear organs and lateral line neuromasts are comprised of a variety of cell types, including mechanosensitive hair cells. Zebrafish hair cells are evolutionarily homologous to mammalian hair cells, and have been particularly useful for studying normal hair cell development and function. However, the relative scarcity of hair cells within these complex organs, as well as the difficulty of fine dissection at early developmental time points, makes hair cell-specific gene expression profiling technically challenging. Cell sorting methods, as well as single-cell RNA-Seq, have proved to be very informative in studying hair cell-specific gene expression. However, these methods require that tissues are dissociated, the processing for which can lead to changes in gene expression prior to RNA extraction. To bypass this problem, we have developed a transgenic zebrafish model to evaluate the translatome of the inner ear and lateral line hair cells in their native tissue environment; the Tg(myo6b:RiboTag) zebrafish. This model expresses both GFP and a hemagglutinin (HA) tagged rpl10a gene under control of the myo6b promoter (myo6b:GFP-2A-rpl10a 3xHA), resulting in HA-tagged ribosomes expressed specifically in hair cells. Consequently, intact zebrafish larvae can be used to enrich for actively translated hair cell mRNA via an immunoprecipitation protocol using an antibody for the HA-tag (similar to the RiboTag mice). We demonstrate that this model can be used to reliably enrich for actively translated zebrafish hair cell mRNA. Additionally, we perform a global hair cell translatome analysis using RNA-Seq and show enrichment of known hair cell expressed transcripts and depletion of non hair cell expressed transcripts in the immunoprecipitated material compared with mRNA extracted from whole fish (input). Our results show that our model can identify novel hair cell expressed genes in intact zebrafish, without inducing changes to gene expression that result from tissue dissociation and delays during cell sorting. Overall, we believe that this model will be highly useful for studying changes in zebrafish hair cell-specific gene expression in response to developmental progression, mutations, as well as hair cell damage by noise or ototoxic drug exposure. PMID- 29765957 TI - Genetic Insights Into Frailty: Association of 9p21-23 Locus With Frailty. AB - Frailty is a complex aging phenotype associated with increased vulnerability to disability and death. Understanding the biological antecedents of frailty may provide clues to healthy aging. The genome-wide association study hotspot, 9p21 23 region, is a risk locus for a number of age-related complex disorders associated with frailty. Hence, we conducted an association study to examine whether variations in 9p21-23 locus plays a role in the pathogenesis of frailty in 637 community-dwelling Ashkenazi Jewish adults aged 65 and older enrolled in the LonGenity study. The strongest association with frailty (adjusted for age and gender) was found with the SNP rs518054 (odds ratio: 1.635, 95% CI = 1.241-2.154; p-value: 4.81 * 10-04) intergenic and located between LOC105375977 and C9orf146. The prevalence of four SNPs (rs1324192, rs7019262, rs518054, and rs571221) risk alleles haplotype in this region was significantly higher (compared with other haplotypes) in frail older adults compared with non-frail older adults (29.7 vs. 20.8%, p = 0.0005, respectively). Functional analyses using in silico approaches placed rs518054 in the CTCF binding site as well as DNase hypersensitive region. Furthermore, rs518054 was found to be in an enhancer site of NFIB gene located downstream. NFIB is a transcription factor that promotes cell differentiation during development, has antiapoptotic effect, maintains stem cell populations in adult tissues, and also acts as epigenetic regulators. Our study found novel association of SNPs in the regulatory region in the 9p21-23 region with the frailty phenotype; signifying the importance of this locus in aging. PMID- 29765959 TI - Outcome of 5-Year Treatment of Neovascular Age-Related Macular Degeneration With Intravitreal Anti-VEGF Using "Treat and Extend" Regimen. AB - Objective: The aim of this study is twofold. First, to evaluate the long-term outcome of anti-vascular endothelial growth factor (anti-VEGF) treatment in a clinical setting using the "treat-and-extend regimen" (TER) in patients with neovascular age-related macular degeneration (nAMD). Second, to determine the proportion of patients treated with anti-VEGF with good visual acuity (VA), i.e., vision sufficient to maintain a high level of independence. Design: We conducted a single center retrospective review of patients with treatment-naive nAMD who were treated with anti-VEGF. Patients were treated with anti-VEGF intravitreal injections according to the TER. Patients started treatment with monthly injections of either bevacizumab (1.25 mg/0.05 mL) or ranibizumab (0.5 mg/0.05 mL) until there were no signs present of choroidal neovascularization (CNV) activity. CNV activity was determined from fundus examination and SD-OCT imaging. Follow-up administration of intravitreal injections was extended by 2-week intervals, up to a total of 14 weeks, provided no signs of CNV activity were detected. In some patients, the first treatment was replaced with aflibercept (2 mg/0.05 mL). Participants: On the basis of the inclusion criterion for the study, that patients had to be treated for 5 years, a total of 101 patients were included in the study. In all patients, one eye was treated for a 5-year period, and thus we studied 101 eyes. Measurements: Best corrected VA was analyzed at baseline and each year during the 5-year follow-up. Results: VA improved initially after year 1 of the treatment. VA decreased in the subsequent 4 years of treatment, but remained significantly higher from year 1 to year 3 of the treatment compared to baseline values. Patients with good VA followed a similar trend: the proportion increased in the first year, and thereafter gradually decreased during the course of the 5-year follow up. At year 5, the number of patients with good VA decreased to baseline values. Conclusion: TER with anti VEGF for nAMD treatment prevents long-term severe visual loss in real-world setting and maintains patients' VA at levels sufficient to ensure independence. PMID- 29765960 TI - Lichen Planopilaris with Pustules: A Diagnostic Challenge. AB - Introduction: Lichen planopilaris (LPP) is a lymphocytic primary cicatricial alopecia presenting with scarring hair loss and variable degrees of perifollicular erythema and scaling. Pustules are infrequent and may mimic folliculitis decalvans (FD) and other forms of neutrophilic alopecia. We present a series of LPP cases with pustules and discuss the importance of differentiating them from primary neutrophilic folliculitis. Materials and Methods: Demographic, clinical, histopathological, and follow-up data of 13 cases of LPP with pustules followed at the Department of Dermatology of the University of Sao Paulo Medical School were described. Results: Seven females and 6 males were included. Onset of signs and symptoms ranged from 23 to 61 years of age. Previous diagnoses were FD in 3 patients, pityriasis amiantacea in 2 cases, and folliculitis keloidalis nuchae in 1 case. Other 7 cases presented typical clinical features of LPP. Discussion: There is limited data concerning LPP with pustules. Our analysis shows that LPP should be considered a differential diagnosis in patients with refractory folliculitis. Cautious examination of the entire scalp with dermoscopy and/or reevaluation after a course of antibiotics can avoid misdiagnosis. Further studies are required to establish the etiology of pustules in the setting of LPP. PMID- 29765961 TI - Efinaconazole 10% Topical Solution: Case Review of Onychomycosis Patients Who Were Completely Cured at Week 24. AB - Background: Clinical studies with topical onychomycosis agents typically involve daily application over 48 weeks. Some patients are cured earlier; however, individual data are limited. Objective: The aim of this study was to assess baseline demographics/disposition of onychomycosis patients completely cured at week 24 following daily efinaconazole treatment. Methods: We conducted a week-24 case review of 2 identical, multicenter, randomized, double-blind, vehicle controlled studies on 1,655 patients with mild-to-moderate onychomycosis. Patients were randomized (3:1) to efinaconazole 10% solution or vehicle, once daily for 48 weeks, with a 4-week post-treatment follow-up. Complete cure was defined as 0% clinical involvement of the target toenail and mycological cure (negative KOH examination and fungal culture). Results: Overall, 19 patients had clear nails (0% clinical involvement) at week 24, and 13 (68%) were completely cured. Patients were predominantly younger (17/19 aged <65 years), female (12/19), and with recent disease (6/12). No patient had disease recurrence over the subsequent 28 weeks. Complete cure appeared independent of baseline severity. Two patients with moderate disease had clear nails by week 12, and 1 experienced recurrence. Conclusions: Efinaconazole 10% topical solution has been shown to be an effective and well-tolerated treatment for onychomycosis. Our case review highlights that some patients (typically those having faster growing, shorter nails) might expect complete cure within 24 weeks. Continued treatment appears to prevent recurrence. PMID- 29765958 TI - Current Perspectives on Opisthorchiasis Control and Cholangiocarcinoma Detection in Southeast Asia. AB - Similar to bile duct cancer or cholangiocarcinoma (CCA) in the western world, opisthorchiasis-associated CCA in Southeast Asia is an aggressive cancer with high mortality rates. It is known to cause a significant health burden in the opisthorchiasis region in Thailand and possibly throughout mainland Southeast. To reduce this health burden, a comprehensive prevention and control program for opisthorchiasis, as well as CCA, is required. In this review, our aim is to provide a brief update of the current situation regarding the natural history of opisthorchiasis and health burden of CCA in Southeast Asia. A comprehensive approach to tackling these issues being implemented in Thailand under the "Cholangiocarcinoma Screening and Care Program" is described. This comprehensive program consists of a three stage prevention and patient care program. The primary prevention component involves opisthorchiasis screening using a new and sensitive urine assay. The secondary prevention component involves screening for CCA and periductal fibrosis, with suspected CCA patients following the protocol for confirmation and appropriate treatment. Due to the eco-epidemiology of opisthorchiasis-induced CCA, the anticipated impacts and outcomes of the program include short-, medium-, and the long-term goals for the reduction of CCA incidence. To achieve long-term sustainable impacts, concerted efforts to raise social awareness and participating action by general public, non-government organizations, and government agencies are necessary. The strategic plans developed for this program can be expanded for use in other endemic areas as well as being a model for use in other chronic diseases. PMID- 29765962 TI - Value of Eponyms in Dermato-Trichological Nomenclature. AB - Traditionally, syndromes have been named after the physician who originally identified the condition. These are referred to as eponymous syndromes. Nevertheless, the term eponym is to be regarded in a broader sense, since - by definition - an eponym is a person, place, or thing after whom or which something is named. Accordingly, some eponymous syndromes do not refer to the physician who originally reported the condition, but alternatively to the indicator patient, a geographic location, or a historical, literary, or mythological context. The recent past has seen a shift towards naming conditions descriptively by symptoms rather than eponymously. When the syndrome name is formed as an abbreviation from the initial letters of the symptoms, it is referred to as an acronym. The use of acronyms has become particularly popular and is often taught as mnemonic device or used as mental checklist. However, the use of eponyms confers historical, literary, and cultural information that reaches beyond and therefore conveys the dignity of a broader educational background and understanding. PMID- 29765963 TI - Alopecic and Aseptic Nodules of the Scalp: First Report in South America and Second in America. AB - Alopecic and aseptic nodules of the scalp, also named pseudocysts of the scalp, are a relatively new, little-known, and for sure underdiagnosed disease. It affects mostly young men and is characterized by a solitary or a few dome-shaped nodules accompanied by nonscarring alopecia, deep inflammatory infiltration in the skin biopsy specimen, and, in most cases, granulomas. It has a good response to doxycycline, intralesional corticosteroids, or drainage/aspiration of the lesion. We present a case report and a summary of the published cases. PMID- 29765964 TI - A Rare Syndrome Resembling Scleroderma: Huriez Syndrome. AB - Huriez syndrome, also referred to as "sclerotylosis," is a rare autosomal dominant genodermatosis characterized by the triad of congenital scleroatrophy of the distal extremities, palmoplantar keratoderma, and hypoplastic nails. The development of aggressive squamous cell carcinoma (SCC) arising in the scleroatrophic area is also a distinctive feature of the syndrome. Early diagnosis is important due to the early onset, mostly in the third to fourth decades of life, and aggressive progress of SCC, which occurs in around 15% of affected individuals. Our patient had palmoplantar keratoderma, scleroatrophy of the hands, and hypoplastic nails. Her mother and father had a second-degree blood relation. Two of her siblings had similar complaints and findings. She showed no sign of actinic keratosis or SCC, and was called for regular follow-ups. With this case, we want to emphasize that Huriez syndrome is a rare genodermatosis, mimicking scleroderma-like acrosclerosis, and early diagnosis is critical for recognizing and preventing the development of SCC. PMID- 29765965 TI - Dermoscopy of Yellow Concretions on Axillary Hair. PMID- 29765966 TI - Further Clinical Evidence for the Effect of IGF-1 on Hair Growth and Alopecia. AB - Observations on the Laron syndrome originally offered the opportunity to explore the effect of insulin-like growth factor 1 (IGF-1) deficiency on human hair growth and differentiation. According to its expression in the dermal hair papilla, IGF-1 is likely involved in reciprocal signaling. It has been shown to affect follicular proliferation, tissue remodeling, and the hair growth cycle, as well as follicular differentiation, identifying IGF-1 signaling as an important mitogenic and morphogenetic regulator in hair follicle biology. Of all the cytokines or growth factors that have been postulated to play a role in hair follicles, ultimately IGF-1 is known to be regulated by androgens. Accordingly, dermal papillary cells from balding scalp follicles were found to secrete significantly less IGF-1 than their counterparts from nonbalding scalp follicles. Herein, hypotrichosis in primary growth hormone deficiency, and a lack of response of female and male androgenetic-type alopecia to treatment with topical minoxidil and oral finasteride in patients who had undergone surgical resection of the pituitary gland, provide further evidence for an effect of IGF-1 on hair growth and alopecia. PMID- 29765967 TI - Nail Pyogenic Granuloma following Treatment with Blinatumomab. PMID- 29765968 TI - Histopathological Evidence of the Efficacy of Percutaneous Ethanol Injection in the Treatment of Axillary Osmidrosis: A Promising New Procedure. AB - Axillary osmidrosis (AO) is a common disease, affecting patients psychologically and influencing their quality of life. The medical approach to AO remains controversial, ranging from conservative medical to surgical choices. We describe the successful treatment of AO and axillary hyperhidrosis (AH) using percutaneous ethanol injection (PEI) in a 30-year-old patient with AO and AH who did not respond to topical and systemic medication. We also describe the clinical efficacy of PEI by presenting our experience with histopathological evidence of necrosis of the sweat glands. PMID- 29765969 TI - Cutaneous Leishmaniasis: A Case Involving the Scalp - Clinical and Videodermoscopic Findings. AB - Cutaneous leishmaniasis (CL) is a worldwide infectious disease caused by flagellate protozoa of the genus Leishmania. In America, the species most commonly responsible for CL are L. mexicana and L. brasiliensis. Usually, in America, it is transmitted by sand flies mainly of the genus Lutzomyia and Psychodopygus. CL most commonly affects exposed areas and is characterized by an erythematous infiltrated and ulcerated papular or nodular lesion. We report a 28 year-old male, with a 6-month history and a previous trip to the forest in the south of Mexico. He presented with an asymptomatic erythematous plaque on his scalp, with slow and progressive nodular lesions with central crusted ulceration, with a raised and well-defined border. On videodermoscopy, we observed erythematous gummy lesions, yellowish scabs, and white star, dotted, hairpin, and glomerular patterns of vessels. PMID- 29765970 TI - Clinical Description of Frontal Fibrosing Alopecia with Concomitant Lichen Planopilaris. PMID- 29765971 TI - Alopecia Areata in a Dog: Clinical, Dermoscopic and Histological Features. AB - Alopecia areata (AA)-like disease is characterized by multifocal patchy hair loss in humans, rodents, dogs, and horses. Remarkable similarities between human and nonhuman AA cases have been reported in terms of clinical presentation, histology, and immune mechanisms of the disease. Canine AA-like lesions most often consist of well-demarcated alopecic patches, frequently but not only involving the face and the head, which extend to the ear pinnae and legs. In some cases, hair loss can have a more generalized distribution. As in humans, hair regrowth is most commonly spontaneous in canine AA-like disease and the resistant cases usually respond to glucocorticoids or cyclosporine treatment. Diagnosis of AA in veterinary medicine relies on presentation, histopathology, and immunohistochemistry and on regrowth following therapy. This case report describes the first dermoscopic evaluation of AA-like disease in a dog with a clinical presentation of symmetrical hair loss. PMID- 29765972 TI - Reflectance Confocal Microscopy as New Diagnostic Tool in Folliculotropic Mycosis Fungoides. AB - We present a case of folliculotropic mycosis fungoides (FMF), a variant of cutaneous T-cell lymphoma which particularly affects hair follicles. FMF can imitate a wide variety of otherwise benign dermatoses, so it poses major diagnostic obstacles both for the dermatologist as well as the dermatopathologist. In our case, in vivo reflectance confocal microscopy (RCM) was very important for guiding the skin biopsy site selection. For this reason, RCM can reduce the number of unsuccessful histopathological examinations and increase the diagnostic accuracy for different skin dermatoses. PMID- 29765973 TI - Complete Regrowth of Beard Hair with Ruxolitinib in an Alopecia Universalis Patient. AB - While most alopecia areata (AA) cases resolve spontaneously, the more severe types of AA, alopecia totalis (AT) and alopecia universalis (AU), can be highly resistant to therapy. We report on a 33-year-old ultraorthodox Jewish man with an 11-year history of AA that resulted in complete loss of the scalp and body hair 7 years ago. Previous treatments with intralesional and systemic corticosteroids had only partial and temporary effects. The patient was treated with ruxolitinib, 20 mg twice daily, resulting in complete growth of the beard after 4 months of treatment. The beard has a special significance for ultraorthodox Jews, and loss of the beard hair can have marked social and psychological consequences in AA patients. The Janus kinase (JAK) inhibitors have recently emerged as an effective treatment modality in AA, including the more severe forms, such as AT or AU. This report highlights the beneficial effects of the JAK inhibitors, especially in populations where the hair has a special importance due to cultural and religious backgrounds. PMID- 29765974 TI - Diving under Nail Plate. PMID- 29765975 TI - Relationship of SNP rs2645429 in Farnesyl-Diphosphate Farnesyltransferase 1 Gene Promoter with Susceptibility to Lung Cancer. AB - Background and Purpose: The mevalonate pathway is one of the major metabolic pathways that use acetyl-CoA to produce sterols and isoprenoids. These compounds can be effective in the growth and development of tumors. One of the enzymes involved in the mevalonate pathway is FDFT1. Different variants of this gene are involved in the risk of suffering various diseases. The present study examined the relationship between FDFT1 rs2645429 polymorphism and the risk of nonsmall cell lung cancer (NSCLC) in a population from southern Iran. Method: The genotypes of rs2645429 polymorphism of FDFT1 gene were examined in 95 samples: 34 patients with NSCLC and 61 healthy individuals by RFLP method. Results: The results of this study indicated that C allele of this polymorphism was effectively associated with the risk of NSCLC in the Iranian population (p value = 0.023; OR = 2.71; 95% CI = 1.12-6.59) and CC genotype has significant relation with susceptibility to NSCLC (p value = 0.029; OR = 3.02; 95% CI = 1.09-8.39). This polymorphism is located in the promoter region FDFT1 gene, and CC genotype may increase the activity of this promoter. This study also found a significant relationship between C allele and metastatic status. C allele was more common in NSCLC patients. (p = 0.04). Conclusion: C allele of FDFT1 rs2645429 polymorphism gene can be a risk factor for NSCLC, whereas T allele probably has a low protective role. PMID- 29765976 TI - Differential Expression Profiling of Long Noncoding RNA and mRNA during Osteoblast Differentiation in Mouse. AB - Long noncoding RNAs (lncRNAs) are emerging as an important controller affecting metabolic tissue development, signaling, and function. However, little is known about the function and profile of lncRNAs in osteoblastic differentiation in mice. Here, we analyzed the RNA-sequencing (RNA-Seq) datasets obtained for 18 days in two-day intervals from neonatal mouse calvarial pre-osteoblast-like cells. Over the course of osteoblast differentiation, 4058 mRNAs and 3948 lncRNAs were differentially expressed, and they were grouped into 12 clusters according to the expression pattern by fuzzy c-means clustering. Using weighted gene coexpression network analysis, we identified 9 modules related to the early differentiation stage (days 2-8) and 7 modules related to the late differentiation stage (days 10-18). Gene ontology and KEGG pathway enrichment analysis revealed that the mRNA and lncRNA upregulated in the late differentiation stage are highly associated with osteogenesis. We also identified 72 mRNA and 89 lncRNAs as potential markers including several novel markers for osteoblast differentiation and activation. Our findings provide a valuable resource for mouse lncRNA study and improves our understanding of the biology of osteoblastic differentiation in mice. PMID- 29765977 TI - Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine. AB - Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with q value < 0.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis. PMID- 29765978 TI - Factors Affecting the Presence of Adequately Iodized Salt at Home in Wolaita, Southern Ethiopia: Community Based Study. AB - Background: Universal use of iodized salt is a simple and inexpensive method to prevent and eliminate iodine deficiency disorders like mental retardation. However, little is known about the level of adequately iodized salt consumption in the study area. Therefore, the study was aimed at assessing the proportion of households having adequately iodized salt and associated factors in Wolaita Sodo town and its peripheries, Southern Ethiopia. Methods: A cross-sectional study was conducted from May 10 to 20, 2016, in 441 households in Sodo town and its peripheries. Samples were selected using the systematic sampling technique. An iodometric titration method (AOAC, 2000) was used to analyze the iodine content of the salt samples. Data entry and analysis were done using Epi Info version 3.5.1 and SPSS version 16, respectively. Result: The female to male ratio of the respondents was 219. The mean age of the respondents was 30.2 (+/-7.3 SD). The proportion of households having adequately iodized salt was 37.7%, with 95% CI of 33.2% to 42.2%. Not exposing salt to sunlight with [OR: 3.75; 95% CI: 2.14, 6.57], higher monthly income [OR: 3.71; 95% CI: 1.97-7.01], and formal education of respondents with [OR: 1.75; 95% CI: 1.14, 2.70] were found associated with the presence of adequately iodized salt at home. Conclusion: This study revealed low levels of households having adequately iodized salt in Wolaita Sodo town and its peripheries. The evidence here shows that there is a need to increase the supply of adequately iodized salt to meet the goal for monitoring progress towards sustainable elimination of IDD. PMID- 29765979 TI - Influence of Material Selection on the Marginal Accuracy of CAD/CAM-Fabricated Metal- and All-Ceramic Single Crown Copings. AB - This study evaluated the marginal accuracy of CAD/CAM-fabricated crown copings from four different materials within the same processing route. Twenty stone replicas of a metallic master die (prepared upper premolar) were scanned and divided into two groups. Group 1 (n = 10) was used for a pilot test to determine the design parameters for best marginal accuracy. Group 2 (n = 10) was used to fabricate 10 specimens from the following materials with one identical CAD/CAM system (GAMMA 202, Wissner GmbH, Goettingen, Germany): A = commercially pure (cp) titanium, B = cobalt-chromium alloy, C = yttria-stabilized zirconia (YSZ), and D = leucite-reinforced glass-ceramics. Copings from group 2 were evaluated for the mean marginal gap size (MeanMG) and average maximum marginal gap size (AMaxMG) with a light microscope in the "as-machined" state. The effect of the material on the marginal accuracy was analyzed by multiple pairwise comparisons (Mann Whitney, U-test, alpha = 0.05, adjusted by Bonferroni-Holmes method). MeanMG values were as follows: A: 46.92 +/- 23.12 MUm, B: 48.37 +/- 29.72 MUm, C: 68.25 +/- 28.54 MUm, and D: 58.73 +/- 21.15 MUm. The differences in the MeanMG values proved to be significant for groups A/C (p = 0.0024), A/D (p = 0.008), and B/C (p = 0.0332). AMaxMG values (A: 91.54 +/- 23.39 MUm, B: 96.86 +/- 24.19 MUm, C: 120.66 +/- 32.75 MUm, and D: 100.22 +/- 10.83 MUm) revealed no significant differences. The material had a significant impact on the marginal accuracy of CAD/CAM-fabricated copings. PMID- 29765980 TI - Aerobic Interval Training Regulated SIRT3 Attenuates High-Fat-Diet-Associated Cognitive Dysfunction. AB - Cognitive dysfunction is an important complicated disease in obesity. Exercise ameliorates obesity and the related cognitive dysfunction. However, the underlying mechanism is still unclear. In this study, we investigated whether aerobic interval training (AIT) could attenuate high-fat-diet- (HFD-) associated cognitive dysfunction and the possible mechanism of SIRT3-MnSOD pathway. C57BL/6 wild-type (WT) mice and SIRT3 knockout (KO) mice were randomized into control (Con) or HFD group with or without AIT training for 6 weeks. The spatial learning and memory ability were impaired in HFD group compared to the control group. The levels of mitochondrial protein acetylation were increased in the hippocampus of HFD group. The acetylation level of antioxidative MnSOD was increased as well. As a result, the ROS and MDA levels were significantly increased, which leads to the neuron apoptosis in the hippocampus. SIRT3 deficiency further aggravated HFD induced cognitive dysfunction and susceptibility to oxidative stress injury. However, AIT upregulated neuron SIRT3 expression and decreased the acetylation of MnSOD. The hippocampus neuron oxidative stress and apoptosis were both decreased compared to untrained HFD group, which finally improved cognitive function of HFD mice. Collectively, AIT attenuates HFD-associated cognitive dysfunction through SIRT3 upregulation and improvement of antioxidative MnSOD activity. PMID- 29765982 TI - Time Course of Detection of Human Male DNA from Stained Blood Sample on Various Surfaces by Loop Mediated Isothermal Amplification and Polymerase Chain Reaction. AB - This study explores determining the sex of humans from blood stains taken from different surfaces and compares the time course of detection with the conventional PCR, Conventional Loop Mediated Isothermal Amplification (LAMP), and LAMP-Lateral Flow Dipstick (LFD). For the DNA templates, 7 male and 7 female blood stained samples were extracted and added to LAMP and PCR reaction solution to amplify the SRY gene. The DNA samples were extracted from the following blood stained materials: cloth, wood, clay, and tile. Then, the samples were stored at room temperature for 1, 7, 30, and 60 day(s). After the DNA amplification, the gel electrophoresis process was applied to detect LAMP product. The LFD was combined with the LAMP to detect LAMP product on the male cloth samples. For the male samples, the time course of detection on the first and seventh days indicated positive for both LAMP and PCR products on all the surfaces while no DNA amplification was found on any of the female samples. On day 30, positive LAMP product was still found on all the male samples. However, it had faded on the tiles. Moreover, all the male samples, which had tested positive for PCR product, were blurred and unclear. On day 60, LAMP product was still found on all the male samples. Conversely, the PCR method resulted in no bands showing for any of the male samples. However, the LAMP-LFD method detected product on all the male samples of cloth. The results show that the LAMP is an effective, practical, and reliable molecular-biological method. Moreover, the LFD can increase the efficiency and sensitivity of the LAMP, making it more suitable for field studies because gel electrophoresis apparatus is not required. PMID- 29765981 TI - Correlation between Allergic Rhinitis and Laryngopharyngeal Reflux. AB - Background and Objectives: Laryngopharyngeal reflux (LPR) exhibits nonspecific clinical presentations, and these symptoms may be associated with other conditions such as allergies, including allergic rhinitis and laryngitis. However, there is a gap in the literature regarding the correlation of laryngopharyngeal reflux with allergic rhinitis/laryngitis. Hence, the aim of this study is to explore the correlation between these two conditions. Patients and Methods: A total of 126 patients with suggestive manifestations of laryngopharyngeal reflux were included in this study. Patients were classified into LPR positive and negative groups based on the results of a 24-hour oropharyngeal pH monitoring system while allergic rhinitis status was assessed with the score for allergic rhinitis (SFAR). The results of the two groups were compared regarding the SFAR score Correlation between the pH results and SFAR score was explored Results: The LPR positive group demonstrated significantly higher SFAR scores compared to the negative LPR group (p < 0.0001). In addition, the Ryan score was significantly correlated with the SFAR total score and its symptomatology-related items (r ranged between 0.35 and 0.5). Conclusion. It seems that laryngopharyngeal reflux increases patients' self-rating of allergic manifestations. It appears that there is an association between laryngopharyngeal reflux and allergic rhinitis/laryngitis. PMID- 29765983 TI - A Clinical Study of Toxication Caused by Carbamazepine Abuse in Adolescents. AB - Carbamazepine is known to produce the side effect of euphoria. As such, it lends itself to being a drug of abuse, particularly in the adolescent population. This retrospective study evaluated carbamazepine abuse, treatment course, and associated morbidity in Chinese adolescents. The median dose of carbamazepine resulting in overdose was 2,000 mg (800-5,000). Patients were largely from urban rural fringe areas (76.47%, 52.94%) with school performance within the last 1/3 range and (52.94%) unsupervised by parents. 35.29% experienced an obvious sense of euphoria. All patients had nervous system symptoms, 6 (35.29%) cases developed coma (GCS < 8), and 5 (29.41%) cases experienced convulsion. Four cases were treated with hemodialysis. The incidence rate in young patients with repeat carbamazepine use and without the supervision of parents was higher than that in first-time users (5/7 versus 4/10), but the difference was not significant. The toxic dose of repeat users was 3428 +/- 1035 mg, significantly higher than that of 1470 +/- 646 mg in first-time users (P = 0.001). Carbamazepine can produce a sense of euphoria, which is more likely to lead to its abuse and overdose in adolescents. To prevent carbamazepine abuse and overdose will be critical in educating at-risk adolescents and preventing associated morbidities in the future. PMID- 29765984 TI - JAZF1 Inhibits Adipose Tissue Macrophages and Adipose Tissue Inflammation in Diet Induced Diabetic Mice. AB - Background: Juxtaposed with another zinc finger gene 1 (JAZF1) affects gluconeogenesis, insulin sensitivity, lipid metabolism, and inflammation, but its exact role in chronic inflammation remains unclear. This study aimed to examine JAZF1 overexpression in vivo on adipose tissue macrophages (ATMs). Methods: Mouse models of high-fat diet- (HFD-) induced insulin resistance were induced using C57BL/6J and JAZF1-overexpressing (JAZF1-OX) mice. The mice were randomized (8 10/group) to C57BL/6J mice fed regular diet (RD) (NC group), C57BL/6J mice fed HFD (HF group), JAZF1-OX mice fed RD (NJ group), and JAZF1-OX mice fed HFD (HJ group). Adipose tissue was harvested 12 weeks later. ATMs were evaluated by flow cytometry. Inflammatory markers were evaluated by ELISA. Results: JAZF1-OX mice had lower blood lipids, blood glucose, body weight, fat weight, and inflammatory markers compared with HF mice (all P < 0.05). JAZF1 overexpression decreased ATM number and secretion of proinflammatory cytokines. JAZF1 overexpression decreased total CD4+ T cells, active T cells, and memory T cells and increased Treg cells. JAZF1 overexpression downregulated IFN-gamma and IL-17 levels and upregulated IL 4 levels. JAZF1 overexpression decreased MHCII, CD40, and CD86 in total ATM, CD11c+ ATM, and CD206+ ATM. Conclusions: JAZF1 limits adipose tissue inflammation by limiting macrophage populations and restricting their antigen presentation function. PMID- 29765985 TI - Effects of Afternoon Nap Deprivation on Adult Habitual Nappers' Inhibition Functions. AB - Multiple studies have established the effects of afternoon naps on cognition. However, relatively few studies have investigated the domain of executive functions. Moreover, the effects of napping on inhibition are far from conclusive. The present study employed adult habitual nappers to investigate the effects of afternoon nap deprivation on response-based inhibition assessed by a Go/No-go task and stimulus-based inhibition assessed by a Flanker task and on alertness assessed by a psychomotor vigilance test (PVT) and the Karolinska Sleepiness Scale (KSS). The results showed that afternoon nap deprivation significantly decreased participants' accuracy and reaction speed for the Go/No go task but not for the Flanker task. In addition, participants' alertness was significantly impaired after nap deprivation in terms of increased subjective sleepiness and worse PVT performance. Task-specific effects of napping on inhibition were demonstrated. The implications of the results are discussed. PMID- 29765986 TI - Advanced Glycation End Products Enhance Murine Monocyte Proliferation in Bone Marrow and Prime Them into an Inflammatory Phenotype through MAPK Signaling. AB - Objective: Increased monocytes, particularly the inflammatory subset, are associated with accelerated atherosclerosis in diabetes through thus far incompletely defined mechanisms. The present study tested the hypothesis that advanced glycation end products (AGEs) promote bone marrow monocytes to proliferate and drive them into an inflammatory phenotype. Methods and Results: In vivo, AGEs (25 mg/kg i.p. for 7 days) increased proportions of CD115+ monocytes and the inflammatory subset, the CD115+Ly6Chigh cells, in murine bone marrow (flow cytometry analysis (FCM)), and enhanced gene expression of proinflammatory cytokines (IL-1beta and TNF-alpha) but only slightly upregulated mRNA expression of anti-inflammatory cytokine (IL-10) (real-time PCR) in monocytes. In vitro, when the monocytes were treated with different dosages of AGEs (50, 150, and 300 MUg/mL), we found that proliferation (CCK8) but not apoptosis (FCM) of the monocytes was induced; the mRNA expressions of proinflammatory cytokines (IL-1beta and TNF-alpha) and GM-CSF were upregulated in a dose-dependent manner while mRNA levels of IL-10 and M-CSF were changed much less in monocytes (real-time PCR). Furthermore, AGEs (300 MUg/mL) significantly enhanced the expression of Ki67 in monocytes (immunofluorescence staining (IF)), and this dose of AGEs markedly increased secretion of GM-CSF but not that of M CSF (ELISA). For a pathway study, the monocytes were stimulated by 300 MUg/mL AGEs for different periods of time (0, 15, 30, and 120 min) and the activation of the MAPK pathway was tested (FCM); the results showed the p38 and ERK pathways were activated but not JNK signaling. Pretreatment with an inhibitor of p38 (SB203580) or ERK (U0126) attenuated AGE-induced gene expression of proinflammatory cytokines and GM-CSF (real-time PCR), as well as reversing AGE induced Ki67 expression (IF). Conclusions: AGEs promote bone marrow monocytes to proliferate and drive them into an inflammatory phenotype through p38 and ERK activation. PMID- 29765987 TI - Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index. AB - Aim: To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods: A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT). Results: Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (DeltaGlu0-30 <= 0) and 30 had a nonpositive insulin response (DeltaIns0-30 <= 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index >= 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (p < 0.05), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (p < 0.05). Conclusions: These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (DeltaGlu0 30 <= 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (DeltaIns0-30 <= 0) had a higher risk for future one. PMID- 29765988 TI - Genetic Variability of the Glucose-Dependent Insulinotropic Peptide Gene Is Involved in the Premature Coronary Artery Disease in a Chinese Population with Type 2 Diabetes. AB - Background: Glucose-dependent insulinotropic polypeptide (GIP) is closely related to diabetes and obesity, both of which are confirmed to increase the risk of coronary artery disease (CAD). Our study aimed to investigate whether the polymorphisms in GIP genes could affect the risk of cardiovascular disease in type 2 diabetic patients in the Chinese Han population. Methods: We selected and genotyped two haplotype-tagging single nucleotide polymorphisms (tag-SNPs) (rs2291725 C>T, rs8078510 G>A) of GIP gene based on CHB data in HapMap Phase II database (r2 < 0.8). The case-control study of Chinese Han population involved 390 diabetic patients with CAD as positive group and 276 diabetic patients without CAD as control group. Allele and genotype frequencies were compared between the two groups. Results: In dominant inheritance model, the carriers of T/T or T/C had a lower risk of CAD (OR = 0.635, 95% CI = 0.463-0.872, p = 0.005), even after adjustment other CAD risk factors (gender, age, BMI, smoking status, dyslipidemia, hypertension history, and diabetic duration) (OR' = 0.769, 95% CI' = 0.626-0.945, p' = 0.013). The allele A at rs8078510 was associated with decreased risk of CAD (OR = 0.732, p = 0.039). p = 0.018 in subgroup analysis, individuals with higher BMI (>=24 kg/m2) had increased risk for CAD when carrying C/C at rs2291725 (OR' = 1.291, 95% CI' = 1.017-1.639, p' = 0.036). In age < 55 men and age < 65 women, the carriers of allele C at rs2291725 had a higher risk of CAD than noncarriers (OR = 1.627, p = 0.015). Carriers of allele G in rs8078510 had higher susceptibility to CAD (OR = 2.049, 95% = CI 1.213-3.463, p = 0.007). p = 0.004; in addition, allele G in rs8078510 would bring higher CAD risk to the carriers who ever smoked (OR = 1.695, 95% CI = 1.080-2.660, p = 0.021). Conclusion: The genetic variability of GIP gene is associated with CAD and it may play a role in the premature CAD in the Chinese Han population with type 2 diabetes. PMID- 29765989 TI - Corrigendum to "Dendritic Cells and Leishmania Infection: Adding Layers of Complexity to a Complex Disease". AB - [This corrects the article DOI: 10.1155/2016/3967436.]. PMID- 29765991 TI - Immune Response and Evasion Mechanisms of Plasmodium falciparum Parasites. AB - Malaria causes approximately 212 million cases and 429 thousand deaths annually. Plasmodium falciparum is responsible for the vast majority of deaths (99%) than others. The virulence of P. falciparum is mostly associated with immune response evading ability. It has different mechanisms to evade both Anopheles mosquito and human host immune responses. Immune-evading mechanisms in mosquito depend mainly on the Pfs47 gene that inhibits Janus kinase-mediated activation. Host complement factor also protects human complement immune attack of extracellular gametes in Anopheles mosquito midgut. In the human host, evasion largely results from antigenic variation, polymorphism, and sequestration. They also induce Kupffer cell apoptosis at the preerythrocytic stage and interfere with phagocytic functions of macrophage by hemozoin in the erythrocytic stage. Lack of major histocompatibility complex-I molecule expression on the surface red blood cells also avoids recognition by CD8+ T cells. Complement proteins could allow for the entry of parasite into the red blood cell. Intracellular survival also assists the escape of malarial parasite. Invading, evading, and immune response mechanisms both in malaria vector and human host are critical to design appropriate vaccine. As a result, the receptors and ligands involved in different stages of malaria parasites should be elucidated. PMID- 29765990 TI - Immunosuppressive Role of Myeloid-Derived Suppressor Cells and Therapeutic Targeting in Lung Cancer. AB - Lung cancer is the leading cause of cancer death worldwide due to its late diagnosis and poor outcome. Immunotherapy is becoming more and more encouraging and promising in lung cancer therapy. Myeloid-derived suppressor cells (MDSCs) are the main tumor suppressor factors, and the treatment strategy of targeting MDSCs is gradually emerging. In this review, we summarize what is currently known about the role of MDSCs in lung cancer. In view of the emerging importance of MDSCs in lung cancer, the treatment of targeting MDSCs will be useful to the control of the development and progression of lung cancer. However, the occurrence, metastasis, and survival of cancer is the result of multiple factors and multiple mechanisms, so combined treatments using different strategies will become the major therapy method for lung cancer in the future. PMID- 29765993 TI - Investigating PIK3R3 and ATp2A1 Genes Expressions in Ventilator-Associated Pneumonia Patients Admitted to the Intensive Care Unit of Masih Daneshvari Hospital in 2016. AB - Background: Infectious diseases such as ventilator- associated pneumonia (VAP) are one of the serious problems in intensive care units (ICU) of hospitals. To date, there has been no appropriate clinical and diagnostic marker for early detection of this disease. In this study, expression of PIK3R3 and ATp2A1 genes in patients with VAP were assessed to be used as biomarkers to identify and confirm the disease. Methods: This study was conducted by using peripheral blood samples of 60 individuals, including 30 patients with VAP and 30 healthy volunteers. First, the peripheral blood samples were taken and then RNA was extracted and converted into cDNA. Finally, the assessment of genes was performed by Real-time PCR. Results: In peripheral blood samples, 46.6% and 30% were positive for PIK3R3 expression in patients and healthy groups, respectively. The ATp2A1 expression in patients and healthy controls were found 40% and 23.3%, respectively. Comparing the DeltaCT obtained for the PIK3R3 and ATp2A1 genes showed statistically significant differences between the two groups of patients and healthy subjects (p=0.042, p=0.036). Conclusion: ATp2A1 and PIK3R3 may be used as biomarkers for early detection of VAP disease. However, further studies are required. PMID- 29765992 TI - Serological Immunoglobulin-Free Light Chain Profile in Myasthenia Gravis Patients. AB - Background: Serological levels of free immunoglobulin light chains (FLCs), produced in excess of heavy chains during synthesis of immunoglobulins by plasma cells, can be considered a direct marker of B cell activity in different systemic inflammatory-autoimmune conditions and may represent a useful predictor of rituximab (RTX) therapeutic efficacy, as reported for rheumatoid arthritis and systemic lupus erythematosus. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction with antibodies (abs) targeting the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK), inducing muscle weakness and excessive fatigability. As MG course may be remarkably variable, we evaluated the possible use of FLCs as biomarkers of disease activity. Subjects and Methods: We assessed FLC levels in 34 sera from 17 AChR-MG and from 13 MuSK MG patients, in comparison with 20 sera from patients with systemic autoimmune rheumatic diseases and 18 from healthy blood donors, along with titers of specific auto-abs and IgG subclass distribution. Results: We found a statistically significant increase in free kappa chains in both AChR- and MuSK-MG patients, while free lambda chain levels were increased only in AChR-MG. We also observed a significant reduction of both free kappa and lambda chains in 1/4 MuSK MG patients along with specific abs titer, two months after RTX treatment. Conclusions: From our data, FLCs appear to be a sensitive marker of B cell activation in MG. Further investigations are necessary to exploit their potential as reliable biomarkers of disease activity. PMID- 29765994 TI - Heterologous Expression, Purification, and Characterization of the HspX, Ppe44, and EsxV Proteins of Mycobacterium tuberculosis. AB - Background: Subunit vaccines are appropriate vaccine candidates for the prevention of some infections. In this study, three immunogenic proteins of Mycobacterium tuberculosis, including HspX, Ppe44, and EsxV as a new construction, were expressed alone and as a fusion protein to develop a new vaccine candidate against tuberculosis infection. Methods: To make the fusion protein, the three genes were linked together by AEAAAKEAAAKA linkers and inserted into pET21b and pET32b vectors. Escherichia coli (E. coli) Top10 cells were transformed with the plasmid, and the purified plasmid was used to transform E. coli BL21 cells. Protein expression was induced with IPTG. After optimizing protein expression, the recombinant proteins were purified by Ni-NTA chromatography. Protein purification was confirmed by SDS-PAGE and Western blotting with an anti-poly histidine-peroxidase monoclonal antibody against the 6His-tags at the proteins' C termini. Results: Directional cloning was confirmed by polymerase chain reaction (PCR), restriction enzyme digestion, and sequencing. The highest expression of the tri-fusion protein and HspX were obtained by the addition of 0.2 mM of IPTG to E. coli BL-21 cells at 37 degrees C and 18 h of incubation. For Ppe44 and EsxV, the optimum expression conditions were 18 degrees C and 16 h of incubation. SDS-PAGE and Western blots confirmed that the desired proteins were produced. Conclusion: The three desired proteins and the fusion protein were successfully expressed and the conditions for optimum expression determined. These recombinant proteins will be evaluated as vaccine candidates against tuberculosis. Further studies are needed to evaluate the abilities of these proteins to induce strong immunological responses. PMID- 29765996 TI - An In vitro Study on Curcumin Delivery by Nano-Micelles for Esophageal Squamous Cell Carcinoma (KYSE-30). AB - Background: The incidence of esophageal squamous cell carcinoma (ESCC) is increasing, causing catastrophic health burdens on communities. Curcumin has shown promise as a therapeutic agent in the treatment of colon, colorectal, pancreatic, and esophageal cancers but it has very poor bioavailability. The application of nano-carriers as drug delivery systems increases curcumin's bioavailability. Cyclin D1 is overexpressed in ESCC and curcumin may change its expression. Methods: In this study, the effect of SinaCurcumin(r), a novel nano micelle product containing 80 mg curcumin, on the growth of KYSE-30 cells and expression of cyclin D1, was investigated. Paclitaxel and Carboplatin served as reference drugs. Results: Nano-curcumin increased cell cytotoxicity, decreased IC50, and down-regulated of cyclin D1. However, treatment of cells with nano curcumin might result in multidrug resistance. Conclusion: Nano-curcumin suppressed proliferation of KYSE-30 cells and expression of cyclin D1 although its use in combination with other chemotherapeutic agents requires further testing. PMID- 29765995 TI - Effects of Oral Dosage of Lead Acetate II on Osteocalcin Gene Expression in Rat Mesenchymal Stem Cells. AB - Background: Lead (Pb) is a heavy metal that has devastating effects on many animal tissues. In this study we investigated the effects of orally-dosed lead acetate II on osteocalcin gene (osteocalcin) expression in mesenchymal stem cells grown in an osteogenic medium. Osteocalcin is an abundant bone matrix differentiation protein. Methods: Twelve male Wistar rats were divided into three groups of four rats each. Two groups were fed orally with 50 or 100 ppm of lead acetate II with libitum feed and water for two months. The control group was fed with libitum feed and water only. Rats were euthanized and femoral bone marrow mesenchymal stem cells (BM-MSCs) were extracted. The cells were cultured in osteogenic medium and osteocalcin expression was determined by real-time PCR. Results: Real-time PCR showed that osteocalcin expression was significantly less in the BM-MSCs of rats that received 100 ppm of lead acetate II than in the BM MSCs of the other groups (P<0.05), and that osteocalcin expression was less in the BM-MSCs of the group that received 50 ppm of lead acetate II than in the control group. Conclusion: Doses of 50 and 100 ppm of lead acetate II in rats caused a significant decrease in osteocalcin expression in BM-MSCs grown in osteogenic medium. PMID- 29765997 TI - Effects of Oral Probiotic Feeding on Toll-Like Receptor Gene Expression of the Chicken's Cecal Tonsil. AB - Background: It was proposed that probiotics may influence immune system through direct or indirect exposure. Direct exposure is mostly mediated by surface receptors. Toll-like receptors (TLRs) are conserved molecular sensors which could be triggered via some pathogen associated structures, hence, modulate the immune responses. This study was conducted to elucidate the impact of lactobacillus acidophilus as a common probiotic on the expression level of TLRs in the chicken's cecal tonsil. Methods: Thirty one-day-old chicken were selected and separated into three groups as probiotic-fed, dairy-fed and control. In addition to commercial powder supply, each chicken in the probiotic-fed group received 109 CFU/Kg of L. acidophilus daily. While, chickens in the dairy-fed group were provided with commercial powder feed and sterile dairy milk. After 14 and 21 days of oral feeding the cecal tonsil was removed and the expression of TLR2, TLR4 and TLR5 were examined by real-time PCR. Results: At the age of 14-day, there was a slight upregulation in the expression levels of TLR2 (118.9%), TLR4 (129.6%) and TLR5 (123.7%) of the cecal tonsil in the probiotic-fed group; however, these alterations were not statistically significant. At the age of 21-day, a non significant downregulation was observed in TLR expression level of both dairy-fed (TLR2, 85%; TLR4, 79.5%; and TLR5, 86.5%) and probiotic-fed (TLR2, 88.8%; TLR4, 81%; and TLR5, 87.2%) groups in comparison to controls. Conclusion: The findings revealed that although the probiotic supplementation could be useful but it did not significantly affect innate immunity state through alteration of TLRs. PMID- 29765998 TI - Cloning, Expression, Purification and CD Analysis of Recombinant Human Betatrophin. AB - Background: Betatrophin is a member of the angiopoietin-like (ANGPTL) family that has been implicated in both triglyceride and glucose metabolism. The physiological functions and molecular targets of this protein remain largely unknown; hence, a purified available protein would aid study of the exact role of betatrophin in lipid or glucose metabolism. Methods: In this study, we cloned the full-length cDNA of betatrophin from a human liver cDNA library. Betatrophin was expressed in the pET-21b-E. coli Bl21 (DE3) system and purified by immobilized metal-affinity chromatography and ion-exchange chromatography. Results: Circular dichroism spectroscopy revealed alpha-helix as the major regular secondary structure in recombinant betatrophin. Conclusion: The production method is based on commonly available resources; therefore, it can be readily implemented. PMID- 29765999 TI - Genetic Variability of Antigen B8/1 among Echinococcus granulosus Isolates from Human, Cattle, and Sheep in Fars Province, Southern Iran. AB - Background: Cystic echinococcosis (CE), known as hydatid cyst, is a zoonotic parasitic infection caused by the larval stage of Echinococcus granulosus (E. granulosus). Antigen B, the major component of hydatid cyst fluid, is encoded by members of a multigene family. The present study aimed to evaluate the genetic diversity of the gene encoding antigen B8/1 (EgAgB8/1) among the main intermediate hosts of E. granulosus. Methods: Twenty-eight hydatid cyst isolates (10 sheep, 9 human, and 9 cattle) were collected in Fars province, Iran. DNA was extracted from each cyst and PCR, followed by DNA sequencing was used to identify potential EgAgB8/1 sequence variation and polymorphism. A phylogenetic tree was constructed using MEGA 7.0 software and the maximum likelihood method. Results: Using EgAgB8/1 primers, an approximately 315 bp band was amplified from all the isolates. The PCR products were sequenced, and the sequences were deposited in GenBank (accession numbers, KY709266-KY709293). The polymorphism variation among the isolates was 0.0, while intra-species variation within the isolates and related sequences in GenBank was 0.5-1%. Analysis of the phylogenetic tree revealed that the isolates from humans, sheep, and cattle all cluster in one group and are homologous to the EgAgB8/1 M1 allele. Conclusion: Findings of this study revealed close similarity between the EgAgB8/1 of human, sheep, and cattle E. granulosus isolates. However, differences were found between the EgAgB8/1 sequences in our study and those reported from other CE endemic areas. Whether such similarities and differences exist in other subunits AgB subunits require further study. PMID- 29766000 TI - Vitamin D3 Induces Gene Expression of Ox-LDL Scavenger Receptors in Streptozotocin-Induced Diabetic Rat Aortas: New Insight into the Role of Vitamin D in Diabetic Atherosclerosis. AB - Background: Several lines of evidence suggest that oxidized LDL (Ox-LDL) scavenger receptors play a crucial role in the genesis and progression of diabetic atherosclerosis. This study aimed to elucidate the effect of vitamin D3 on gene expression of lectin-like oxidized LDL receptor-1 (LOX-1), scavenger receptor-A (SR-A), Cluster of Differentiation 36 (CD36), and Cluster of Differentiation 68 (CD68) as the main Ox-LDL receptors in streptozotocin (STZ) induced diabetic rat aortas. Methods: Eighteen Sprague-Dawley rats were randomly divided into three groups of six rats each. Two rats died during the study so five rats from each group were analyzed at the study's end. Diabetes was induced in overnight starved rats in two of the groups by intraperitoneal injections of 60 mg/kg of STZ. The vitamin D3/diabetic group then received weekly intraperitoneal injections of 5000 IU/kg of vitamin D3 dissolved in cottonseed oil for four weeks, diabetic controls received cottonseed oil, and healthy controls received sterile saline weekly for the same period. At the end of the four-week study period the animals were killed and the aortas were collected to examine the mRNA expression using real-time polymerase chain reaction (RT-PCR). Results: SR-A and CD36 mRNA expression were significantly greater in the vitamin D3/diabetic rats than in both the diabetic control and healthy control rats. CD68 and LOX-1 expression were greater in the vitamin D3/diabetic rats than in the diabetic control and healthy control rats, respectively. Conclusion: Vitamin D3 may increase the risk of diabetic atherosclerosis by inducing scavenger receptors expression. PMID- 29766001 TI - Production of Recombinant Streptavidin and Optimization of Refolding Conditions for Recovery of Biological Activity. AB - Background: Streptavidin is a protein produced by Streptomyces avidinii with strong biotin-binding ability. The non-covalent, yet strong bond between these two molecules has made it a preferable option in biological detection systems. Due to its extensive use, considerable attention is focused on streptavidin production by recombinant methods. Methods: In this study, streptavidin was expressed in Escherichia coli (E. coli) BL21 (DE3) pLysS cells and purified by affinity chromatography. Various dialysis methods were employed to enable the protein to refold to its natural form and create a strong bond with biotin. Results: Streptavidin was efficiently expressed in E. coli. Streptavidin attained its natural form during the dialysis phase and the refolded protein bound biotin. The addition of proline or arginine to the dialysis buffer resulted in a refolded streptavidin with greater affinity for biotin than refolding in dialysis buffer with no added amino acids. Conclusion: Dialysis of recombinant streptavidin in the presence of arginine or proline resulted in proper refolding of the protein. The recombinant dialyzed streptavidin bound biotin with affinity as great as that of a commercial streptavidin. PMID- 29766002 TI - Influence of Vitamin D Receptor Gene Polymorphisms on Response to Pegylated Interferon in Chronic Hepatitis B Egyptian Patients. AB - Background: We explored the effect of vitamin D receptor gene (VDR) polymorphisms in response to PEG-IFN treatment in Egyptian chronic hepatitis B (CHB) patients. Methods: Two hundred hepatitis B virus (HBV) patients (42.3+/-10.7 years) on PEG IFN alpha-2a (180 ug /kg for 48 weeks) and one hundred control subjects (37.3 +/ 12 years) were enrolled in the study. Vitamin D levels and hepatitis B surface antigen (HBsAg) expression were assessed by ELISA. VDR polymorphisms FokI T>C (rs 10735810), BsmI A>G (rs 1544410), ApaI (rs7975253), and TaqI C>T (rs 731236), were genotyped using real-time PCR. Results: Hepatitis B virus patients expressed significantly greater AST (p=< 0.00001) and ALT (P=< 0.00001), and significantly less vitamin D (P=0.01), than control subjects. Patients with Ff or ff alleles of the FokI single-nucleotide polymorphism (SNP), bb alleles of BsmI SNP, or TT alleles of the Taq1 single nucleotide polymorphisms (SNP) showed greater response to PEG-IFN therapy than those with the FF (P=0.02 and P=0.0002), Bb (P=0.023), or Tt/tt alleles (P=0.01 and P=0.004 respectively). Logistic stepwise regression showed that HBV DNA (r: 0.910, P< .00001), FokI SNP polymorphism (r: 0.919, (P=0.037) and bAt haplotype (r: .926, (P=0.043) are independent factors that determine PEG-IFN treatment response in the HBV-infected patients. Conclusion: VDR gene polymorphisms may be used as treatment response predictors in HBV patients receiving PEG-IFN. FokI SNP and bAt haplotype are independent factors that that can be used to determine PEG-IFN treatment responses in HBV-infected patients. PMID- 29766003 TI - The Status of Nitric Oxide and its Backup, Heme Oxygenase 1, in Thromboangiitis Obliterans. AB - Background: Until recently, a gene polymorphism in the promoter region of endothelial nitric oxide synthase has been suggested as a risk factor for thromboangiitis obliterans (TAO) development. The aim of this study was to compare the metabolites of nitric oxide (NO) and its backup, heme-oxygenase-1 (HMOX1), between TAO patients and those of a smoking control group matched by race, age, sex, and smoking habits. Methods: Twenty-four male Caucasian TAO patients and 20 male Caucasian controls enrolled in the study. Their smoking habits were matched based on the serum cotinine levels of 17 of the TAO patients and the 20 controls. A colorimetric kit was used to measure NO, and an enzyme linked immunosorbent assay kit was used to measure cotinine and HMOX1 levels. Results: The mean serum level of NO metabolites in the TAO group was significantly less than in the controls (p = 0.03) and also significantly less in the patients with below-knee amputations than in non-amputees (p= 0.018). Also, HMOX1 was significantly greater in the TAO patients than in the controls (p= 0.01). No significant correlation was found between NO and HMOX1 (p = 0.054). Conclusion: Nitric oxide may play a pivotal role in TAO development and its outcome. However, the intact HMOX1 pathway may demonstrate the unique role of NO, which cannot be compensated for by HMOX1 and whose absence may make patients susceptible to developing TAO. In addition, another pathway besides NO, with influence on vascular tone and hemostasis, might be involved in TAO development, such as the autonomic nervous system. Further studies are suggested regarding these issues. PMID- 29766004 TI - Oral Administration of Zataria multiflora Extract Decreases IL-17 Expression in Perennial Allergic Rhinitis. AB - Background: Rhinitis, which occurs most commonly as allergic rhinitis and affects 20% of the world's population, is a major health care burden causing significant morbidity. Considering the high prevalence of allergic rhinitis and anti inflammatory effects of thyme, a favorite condiment, we performed a randomized clinical trial to determine whether thyme can relieve allergic rhinitis symptoms and affect the expression of TH17- and T-regulatory cell- (Treg) related cytokines IL-17, TGF-beta, FOXP3, and IL-10. Methods: Thirty patients with allergic rhinitis symptoms and positive skin prick test for common aero allergens were randomly assigned to experimental or control groups. The experimental group received thyme or Zataria multiflora (ZM) extracts and the control group received placebo for two months. Expression of IL-17, TGF-beta, FOXP3, and IL-10 was evaluated in all subjects by real-time PCR before and after intervention. Results: After treatment IL-17 expression was significantly less in the ZM group than in controls (p<0.05), while TGF-beta, FOXP3, and IL-10, expression were not significantly changed. Conclusion: Given the significant effect of thyme in reducing symptoms of allergic rhinitis and decrease IL-17 gene expression and because allergic rhinitis is a multifactorial disease, the administration of thyme extract along with conventional treatments may benefit allergic rhinitis sufferers. PMID- 29766005 TI - The Enhancement of the Pasteurella's Bacterin by Propolis Extracts. AB - Background: Pasteurella multocida continues to pose a danger to prone farm and wild animals all over the world. Chemotherapeutic treatments are progressively losing their effectiveness, last for long time, and cost a lot of money, as well as being toxic to human consumers. Therefore, clearing the way for immunization as a big-wheel alternative against the economic grain. Yet, the vaccines available in the market do not confer the necessary protection against the pathogen. The integration of the well adjuvanted killed vaccine with the attenuated vaccines proved to offer an effective protection to the host animals. However, the bare use of the killed bacterin to provide protection from the possible harm of the live attenuated vaccine was doubtful. Methods: In the present study, propolis extracts were used to ameliorate the immunogenicity of the Pasteurella bacterin. The cellular and humoral activities were assessed for the different bacterin formulations. Results: Propolis extracts adjuvants proved to broaden and extend the IgG potency, as well as to induce a unique mucosal protection against the bacterium. Simultaneously it offered an anti-inflammatory effect that increased the tolerability to the bacterin. While the cellular activity was relatively reduced with propolis extracts. Conclusion: These results confirm the effectiveness of the formulation of the bacterin with propolis to offer a potent homologous primary protection to the animals against the long-life use of the attenuated Pasteurella vaccines. PMID- 29766008 TI - Diagnostic Utility of Chest Radiography in Predicting Long-Standing Systemic Arterial Hypertension. AB - Purpose: To investigate the association between aortic arch width on frontal chest radiography and systemic hypertension. Methods: A total of 200 consecutive patients were included. Relationships between aortic arch width measurement on chest radiography and blood pressure measurement were investigated using Student's t -tests and Fisher's exact tests. Results: Twenty-five patients were normotensive (< 130/90 mmHg), and 175 were hypertensive. Using cut-off values, 136 patients had an aortic arch width >= 3.5 cm, and 65 had an aortic arch width >= 4 cm. We found a significant relationship between aortic arch width and hypertension (p < 0.001) as well between aortic arch width cut-off values of 3.5 cm and 4 cm and hypertension (p < 0.001 and p < 0.005, respectively). An aortic arch width >= 3.5 cm was associated with a positive likelihood ratio (LR) of 2.3, negative LR of 0.39, sensitivity of 73, specificity of 68, positive predictive value of 94, negative predictive value of 26.6, pretest odds of 7, posttest odds of 16, and posttest probability of 94%. An aortic arch width >= 4 cm was associated with a positive LR of 4.50, negative LR of 0.70, sensitivity of 36, specificity of 92, positive predictive value of 97, negative predictive value of 17, pretest odds of 7, posttest odds of 31.5, and posttest probability of 97%. Conclusions: Aortic arch width measurement on chest radiography can be used to predict the presence of long-standing systemic arterial hypertension. PMID- 29766009 TI - Persistent Buttock Claudication after Endovascular Abdominal Aortic Aneurysm Repair. AB - We describe the successful surgical treatment of a 71-year-old man affected by right buttock claudication after a right internal iliac artery (IIA) coil embolization as an adjunct to endovascular iliac artery aneurysm repair. Computed tomography angiography revealed extensive aortoiliac calcifications and thrombus in the vessel walls. Despite patency of the contralateral IIA and preservation of right distal collateral flow through ipsilateral hypogastric branches, the symptom was persistent and disabling. The high-risk patient underwent an "open" repair of the infrarenal abdominal aneurysm with removal of the entire stent graft and concomitant revascularization of the right IIA. Post-operative recovery was uneventful, and the patient remained asymptomatic during a 30-month follow up. This case underscores the importance of considering all potential solutions, including open surgery, to preserve pelvic inflow after aortoiliac stent grafting, particularly for high-risk patients with vulnerable plaque and higher risk of thrombus embolization. PMID- 29766007 TI - Autoimmunity in the Abdominal Aortic Aneurysm and its Association with Smoking. AB - Smoking increases the risk of abdominal aortic aneurysm (AAA) in both humans and mice, although the underlying mechanisms are not completely understood. An adventitial aortic antigen, AAAP-40, has been partially sequenced. It has motifs with similarities to all three fibrinogen chains and appears to be connected in evolution to a large family of proteins called fibrinogen-related proteins. Fibrinogen may undergo non-enzymatic nitration, which may result from exposure to nitric oxide in cigarette smoke. Nitration of proteins renders them more immunogenic. It has recently been reported that anti-fibrinogen antibody promotes AAA development in mice. Also, anti-fibrinogen antibodies are present in patients with AAA. These matters are reviewed in the overall context of autoimmunity in AAA. The evidence suggests that smoking amplifies an auto-immune reaction that is critical to the pathogenesis of AAA. PMID- 29766006 TI - Interaction Between Air Pollutants and Pollen Grains: The Role on the Rising Trend in Allergy. AB - Asthma and allergic diseases cases have risen in recent decades. Plant pollen is considered as the main aeroallergen causing allergic reactions. According to available data, urban residents experience more respiratory allergies than rural residents mainly due to the interaction between chemical air pollutants and pollen grains. PMID- 29766011 TI - Use of Iliac Branch Device for Endovascular Treatment for Abdominal Aorta Aneurysm with Small Diameter Neck. AB - We present the case of a 78-year-old woman with a 4.5-cm symptomatic abdominal aortic aneurysm with a small diameter (13-mm diameter) infrarenal aortic neck who underwent endovascular treatment using an iliac branch device as a bifurcated aortic stent-graft. PMID- 29766010 TI - Single-stage Endovascular Treatment of a Penetrating Aortic Ulcer with a Concomitant "Isolated" Iliac Aneurysm. AB - Penetrating aortic ulcer (PAU) is an acute aortic syndrome that can proceed to life-threatening aortic dissection or even aortic rupture. Isolated iliac aneurysms are relatively rare and often asymptomatic due to their deep pelvic location but are frequently associated with high mortality with rupture. We report a case of a 68-year-old man with a symptomatic penetrating ulcer in the descending aorta and an asymptomatic right iliac aneurysm involving the common and internal iliac arteries. The patient was successfully treated by endovascular repair in a single-stage manner using stent grafts in the descending aorta and right common iliac artery after coil embolization of the right internal iliac artery. Follow-up imaging showed complete resolution of the PAU and exclusion of the right iliac aneurysm without endoleak. Aggressive endovascular treatment for a symptomatic PAU with an asymptomatic isolated iliac aneurysm is feasible and allows complete treatment of vascular pathology at a single time. PMID- 29766013 TI - The Tricky Art of Managing Infectious Complications of Addiction: Dr. Paul Sax Interviews Dr. Alysse Wurcel. PMID- 29766012 TI - Page for the General Public. PMID- 29766014 TI - Experience with Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome in a Large Urban HIV Clinic in the United States: Case Series and Literature Review. AB - In 2010, a new entity, characterized by the classical signs and symptoms of Kaposi sarcoma herpesvirus-associated multicentric Castleman's disease (KSHV-MCD) in the absence of pathologic evidence of MCD, was described in individuals living with HIV. This syndrome was named KSHV inflammatory cytokine syndrome (KICS). It carries mortality rates of up to 60%. To date, there are no standard therapies. Treatment regimens studied in clinical trials for MCD disease are used in cases of KICS. PMID- 29766016 TI - A Healthcare Model for the World's Most Remote and Impoverished: Dr. Paul Sax Interviews Dr. Rajesh Panjabi. PMID- 29766015 TI - A Mycoses Study Group International Prospective Study of Phaeohyphomycosis: An Analysis of 99 Proven/Probable Cases. AB - Background: Phaeohyphomycosis is infection caused by dematiaceous, or darkly pigmented, fungi. The spectrum of disease is broad, and optimal therapy remains poorly defined. The Mycoses Study Group established an international case registry of patients with proven/probable phaeohyphomycosis with the goal of improving the recognition and management of these infections. Methods: Patients from 18 sites in 3 countries were enrolled from 2009-2015. Cases were categorized as local superficial, local deep (pulmonary, sinus, osteoarticular infections), and disseminated infections. End points were clinical response (partial and complete) and all-cause mortality at 30 days and end of follow-up. Results: Of 99 patients, 32 had local superficial infection, 41 had local deep infection, and 26 had disseminated infection. The most common risk factors were corticosteroids, solid organ transplantation, malignancy, and diabetes. Cultures were positive in 98% of cases. All-cause mortality was 16% at 30 days and 33% at end of follow-up, and 18 of 26 (69%) with dissemination died. Itraconazole was most commonly used for local infections, and voriconazole was used for more severe infections, often in combination with terbinafine or amphotericin B. Conclusions: Phaeohyphomycosis is an increasingly recognized infection. Culture remains the most frequently used diagnostic method. Triazoles are currently the drugs of choice, often combined with other agents. Further studies are needed to develop optimal therapies for disseminated infections. PMID- 29766017 TI - Outcomes According to Discharge Location for Persons Who Inject Drugs Receiving Outpatient Parenteral Antimicrobial Therapy. AB - Background: Opioid use disorder poses a significant public health risk. Persons who inject drugs (PWID) suffer from high mortality and morbidity secondary to serious infectious diseases, often requiring prolonged courses of outpatient parenteral antibiotics. The goal of this study was to determine the outcomes of PWID discharged to home or to a skilled nursing or rehabilitation facility (SNF/rehab) with parenteral antibiotic treatment under an outpatient parenteral antimicrobial therapy (OPAT) program. Methods: This is a retrospective observational study. The study population was identified via hospital and OPAT databases using substance use disorder diagnoses and confirmed through chart review. The study population included hospitalized PWID with injection drug use in the preceding 2 years who were discharged between 2010 and 2015 to complete at least 2 weeks of parenteral antibiotics and monitored by the OPAT program. Retrospective chart review was used to describe patient characteristics and outcomes. Results: Fifty-two patients met inclusion criteria, 21 of whom were discharged to home and 31 were discharged to a SNF/rehab. Of the patients discharged to home, 17 (81%) completed their planned antibiotic courses without complication. Twenty (64%) patients discharged to a SNF/rehab completed the antibiotic courses without complication. Six (11%) patients had line infections, 6 (11%) had injection drug use relapse, and 12 (23%) required readmission. Conclusions: Persons who inject drugs discharged home were not more likely to have complications than those discharged to a SNF/rehab. Home OPAT may be a safe discharge option in carefully selected patients. PMID- 29766018 TI - Usefulness of Simultaneous Screening for HIV- and Hepatitis C-Specific Antibodies and Hepatitis B Surface Antigen by Capillary-Based Multiplex Immunochromatographic Rapid Test to Strengthen Prevention Strategies and Linkage to Care in Childbearing-Aged Women Living in Resource-Limited Settings. AB - Childbearing-aged women (n = 266) attending a gynecological clinic in Chad were subjected to multiplex immunochromatographic rapid test for HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV). Ten (3.7%) and 8 (3.0%) were seropositive for HIV and HCV, respectively, and 20 (7.5%) for HBV surface antigen, allowing diagnosis of chronic viral infections in 1 of 7 (14.3%) women. PMID- 29766019 TI - Abacavir Use and Risk for Myocardial Infarction and Cardiovascular Events: Pooled Analysis of Data From Clinical Trials. AB - Background: Some observational studies and randomized controlled trials (RCTs) have suggested an association between abacavir (ABC) use and myocardial infarction (MI), whereas others have not. Methods: This pooled analysis of 66 phase II-IV RCTs estimates exposure-adjusted incidence rates (IRs) and relative rates (RRs) of MI and cardiovascular events (CVEs) in participants receiving ABC- and non-ABC-containing combination antiretroviral therapy (cART). The primary analysis of MI included ABC-randomized trials with >=48-week follow-up. Sensitivity analyses of MI and CVEs included non-ABC-randomized and <48-week follow-up trials. Results: In 66 clinical trials, 13 119 adults (75% male, aged 18-85 years) were on ABC-containing cART and 7350 were not. Exposure-adjusted IR for MI was 1.5 per 1000 person-years (PY; 95% confidence interval [CI], 0.67 3.34) in the ABC-exposed group and 2.18 per 1000 PY (95% CI, 1.09-4.40) in the unexposed group. The IR for CVEs was 2.9 per 1000 PY (95% CI, 2.09-4.02) in the exposed group and 4.69 per 1000 PY (95% CI, 3.40-6.47) in the unexposed group with studies of >=48 weeks of follow-up, with an RR of 0.62 (95% CI, 0.39-0.98). The inclusion of nonrandomized and shorter-duration trials did not significantly change the RR for MI or coronary artery disease. Conclusions: This pooled analysis found comparable IRs for MI and CVEs among ABC-exposed and -unexposed participants, suggesting no increased risk for MI or CVEs following ABC exposure in a clinical trial population. Modifiable risk factors for MI and CVEs should be addressed when prescribing ART. PMID- 29766020 TI - Amelioration of Muscle and Nerve Pathology in LAMA2 Muscular Dystrophy by AAV9 Mini-Agrin. AB - LAMA2-related muscular dystrophy (LAMA2 MD) is the most common and fatal form of early-onset congenital muscular dystrophies. Due to the large size of the laminin alpha2 cDNA and heterotrimeric structure of the protein, it is challenging to develop a gene-replacement therapy. Our group has developed a novel adeno associated viral (AAV) vector carrying the mini-agrin, which is a non-homologous functional substitute for the mutated laminin alpha2. A significant therapeutic effect in skeletal muscle was observed in our previous study using AAV serotype 1 (AAV1). In this investigation, we examined AAV9 vector, which has more widespread transduction than AAV1, to determine if the therapeutic effects could be further improved. As expected, AAV9-mini-agrin treatment offered enhanced therapeutic effects over the previously used AAV1-mini-agrin in extending mouse lifespan and improvement of muscle pathology. Additionally, overexpression of mini-agrin in peripheral nerves of dyw/dyw mice partially amended nerve pathology as evidenced by improved motor function and sensorimotor processing, partial restoration of myelination, partial restoration of basement membrane via EM examination, as well as decreased regeneration of Schwann cells. In conclusion, our studies indicate that overexpression of mini-agrin into dyw/dyw mice offers profound therapeutic effects in both skeletal muscle and nervous system. PMID- 29766021 TI - Transduction Patterns of Adeno-associated Viral Vectors in a Laser-Induced Choroidal Neovascularization Mouse Model. AB - Adeno-associated virus (AAV) vector is a promising platform technology for ocular gene therapy. Recently clinical successes to treat choroidal neovascularization (CNV) in wet type age-related macular degeneration have been reported. However, because pathologic conditions of the retina may alter the tropism of viral vectors, it is necessary to evaluate the transduction efficiency of different serotypes of AAV vectors in the retinas with CNVs. Here, we show the patterns and efficacy of transduction of AAV2, -5, and -8 vectors in a laser-induced CNV mouse model. C57BL/6J mice were subjected to unilateral laser photocoagulation on the right eye to induce CNV 5 days prior to intravitreal injection of AAV2, -5, and 8 capsids expressing EGFP. Transduction was increased around CNV lesions for all AAV capsid types, and AAV2 resulted in the highest transduction efficiency. In the absence of CNV, the AAV2 vector transduced ganglion and inner nuclear layer (INL) cells, and AAV5 and AAV8 transduced only a small proportion of cells in the retinal ganglion cell layer. CNV increased AAV2 vector expression throughout the retina and in and around CNVs; the transduced cells included retinal ganglion cells, Muller cells, cells from the INL and outer nuclear layer (ONL), photoreceptors, and retinal pigment epithelium (RPE) cells. Inflammatory cells and endothelial cells in CNVs were also transduced by AAV2. AAV5 and AAV8 were transduced in retinal ganglion, Muller, INL, ONL, and RPE cells in a localized pattern, and only endothelial cells at the surface of CNV lesions showed EGFP expression. Taken together, CNV formation resulted in enhanced transduction of AAV2, -5, and -8, and AAV2 exhibited the highest transduction efficiency in cells in CNV lesions. PMID- 29766022 TI - Influence of Pre-existing Anti-capsid Neutralizing and Binding Antibodies on AAV Vector Transduction. AB - Pre-existing immunity to adeno-associated virus (AAV) is highly prevalent in humans and can profoundly impact transduction efficiency. Despite the relevance to AAV-mediated gene transfer, relatively little is known about the fate of AAV vectors in the presence of neutralizing antibodies (NAbs). Similarly, the effect of binding antibodies (BAbs), with no detectable neutralizing activity, on AAV transduction is ill defined. Here, we delivered AAV8 vectors to mice carrying NAbs and demonstrated that AAV particles are taken up by both liver parenchymal and non-parenchymal cells; viral particles are then rapidly cleared, without resulting in transgene expression. In vitro, imaging of hepatocytes exposed to AAV vectors pre-incubated with either NAbs or BAbs revealed that virus is taken up by cells in both cases. Whereas no successful transduction was observed when AAV was pre-incubated with NAbs, an increased capsid internalization and transgene expression was observed in the presence of BAbs. Accordingly, AAV8 vectors administered to mice passively immunized with anti-AAV8 BAbs showed a more efficient liver transduction and a unique vector biodistribution profile compared to mice immunized with NAbs. These results highlight a virtually opposite effect of neutralizing and binding antibodies on AAV vectors transduction. PMID- 29766023 TI - Adeno-associated Virus Genome Population Sequencing Achieves Full Vector Genome Resolution and Reveals Human-Vector Chimeras. AB - Recombinant adeno-associated virus (rAAV)-based gene therapy has entered a phase of clinical translation and commercialization. Despite this progress, vector integrity following production is often overlooked. Compromised vectors may negatively impact therapeutic efficacy and safety. Using single molecule, real time (SMRT) sequencing, we can comprehensively profile packaged genomes as a single intact molecule and directly assess vector integrity without extensive preparation. We have exploited this methodology to profile all heterogeneic populations of self-complementary AAV genomes via bioinformatics pipelines and have coined this approach AAV-genome population sequencing (AAV-GPseq). The approach can reveal the relative distribution of truncated genomes versus full length genomes in vector preparations. Preparations that seemingly show high genome homogeneity by gel electrophoresis are revealed to consist of less than 50% full-length species. With AAV-GPseq, we can also detect many reverse-packaged genomes that encompass sequences originating from plasmid backbone, as well as sequences from packaging and helper plasmids. Finally, we detect host-cell genomic sequences that are chimeric with inverted terminal repeat (ITR) containing vector sequences. We show that vector populations can contain between 1.3% and 2.3% of this type of undesirable genome. These discoveries redefine quality control standards for viral vector preparations and highlight the degree of foreign products in rAAV-based therapeutic vectors. PMID- 29766025 TI - Isoliquiritigenin Inhibits IL-1beta-Induced Production of Matrix Metalloproteinase in Articular Chondrocytes. AB - Osteoarthritis (OA) is a major joint disease in which inflammatory cytokine interleukin-1beta (IL-1beta) and matrix metalloproteinases (MMPs) play a pivotal role. Isoliquiritigenin has been reported to have anti-inflammation activity. In this study, the effect of isoliquiritigenin on IL-1beta-induced production of matrix metalloproteinase and nuclear factor kappaB (NF-kappaB) activation was analyzed. We treated primary cultured articular chondrocytes with isoliquiritigenin and the expressions of MMPs were analyzed on mRNA and protein level. The phosphorylation of IkappaBa and p65 was analyzed to detect NF-kappaB activation. We also used in vivo model by treating mice with isoliquiritigenin and detecting the level of MMPs. IL-1beta induced NF-kappaB activation and MMP-1, MMP-3, MMP-9, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 production on chondrocytes. A 10-MUM isoliquiritigenin treatment significantly inhibited IL-1beta-induced NF-kappaB activation and these MMPs production on chondrocytes. Injecting isoliquiritigenin into rat knee joint also inhibited IL-1beta-induced NF-kappaB activation and MMPs production in articular cartilage. Isoliquiritigenin treatment inhibited IL-1beta induced MMPs production and NF-kappaB activation both in vitro and in vivo, suggesting a potential therapeutic role of isoliquiritigenin to treat osteoarthritis. PMID- 29766024 TI - Integrating HDAd5/35++ Vectors as a New Platform for HSC Gene Therapy of Hemoglobinopathies. AB - We generated an integrating, CD46-targeted, helper-dependent adenovirus HDAd5/35++ vector system for hematopoietic stem cell (HSC) gene therapy. The ~12 kb transgene cassette included a beta-globin locus control region (LCR)/promoter driven human gamma-globin gene and an elongation factor alpha-1 (EF1alpha) mgmtP140K expression cassette, which allows for drug-controlled increase of gamma globin-expressing erythrocytes. We transduced bone marrow lineage-depleted cells from human CD46-transgenic mice and transplanted them into lethally irradiated recipients. The percentage of gamma-globin-positive cells in peripheral blood erythrocytes in primary and secondary transplant recipients was stable and greater than 90%. The gamma-globin level was 10%-20% of adult mouse globin. Transgene integration, mediated by a hyperactive Sleeping Beauty SB100x transposase, was random, without a preference for genes. A second set of studies was performed with peripheral blood CD34+ cells from mobilized donors. 10 weeks after transplantation of transduced cells, human cells were harvested from the bone marrow and differentiated ex vivo into erythroid cells. Erythroid cells expressed gamma-globin at a level of 20% of adult alpha-globin. Our studies suggest that HDAd35++ vectors allow for efficient transduction of long-term repopulating HSCs and high-level, almost pancellular gamma-globin expression in erythrocytes. Furthermore, our HDAd5/35++ vectors have a larger insert capacity and a safer integration pattern than currently used lentivirus vectors. PMID- 29766026 TI - Development of Intrathecal AAV9 Gene Therapy for Giant Axonal Neuropathy. AB - An NIH-sponsored phase I clinical trial is underway to test a potential treatment for giant axonal neuropathy (GAN) using viral-mediated GAN gene replacement (https://clinicaltrials.gov/ct2/show/NCT02362438). This trial marks the first instance of intrathecal (IT) adeno-associated viral (AAV) gene transfer in humans. GAN is a rare pediatric neurodegenerative disorder caused by autosomal recessive loss-of-function mutations in the GAN gene, which encodes the gigaxonin protein. Gigaxonin is involved in the regulation, turnover, and degradation of intermediate filaments (IFs). The pathologic signature of GAN is giant axonal swellings filled with disorganized accumulations of IFs. Herein, we describe the development and characterization of the AAV vector carrying a normal copy of the human GAN transgene (AAV9/JeT-GAN) currently employed in the clinical trial. Treatment with AAV/JeT-GAN restored the normal configuration of IFs in patient fibroblasts within days in cell culture and by 4 weeks in GAN KO mice. IT delivery of AAV9/JeT-GAN in aged GAN KO mice preserved sciatic nerve ultrastructure, reduced neuronal IF accumulations and attenuated rotarod dysfunction. This strategy conferred sustained wild-type gigaxonin expression across the PNS and CNS for at least 1 year in mice. These results support the clinical evaluation of AAV9/JeT-GAN for potential therapeutic outcomes and treatment for GAN patients. PMID- 29766027 TI - Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice. AB - Viral gene delivery is showing great promise for treating retinal disease. Although subretinal vector delivery has mainly been used to date, intravitreal delivery has potential advantages if low retinal transduction efficiency can be overcome. To this end, we investigated the effects of co-injection of glycosaminoglycan-degrading enzymes, singly or in combination, with AAV2 as a method of increasing retinal transduction. Experiments using healthy mice demonstrated that these enzymes enhance retinal transduction. We found that heparinase III produced the greatest individual effect, and this was enhanced further by combination with hyaluronan lyase. In addition, this optimized AAV2 enzyme combination led to a marked improvement in transduction in retinas with advanced retinal degeneration compared with AAV2 alone. Safety studies measuring retinal function by flash electroretinography indicated that retinal function was unaffected in the acute period and at least 12 months after enzyme treatment, whereas pupillometry confirmed that retinal ganglion cell activity was unaffected. Retinal morphology was not altered by the enzyme injection. Collectively these data confirm the efficacy and safety of this intravitreal approach in enhancing retinal transduction efficiency by AAV in rodents. Translating this method into other species, such as non-human primates, or for clinical applications will have challenges and require further studies. PMID- 29766028 TI - A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model. AB - The CRISPR-based technology has revolutionized genome editing in recent years. This technique allows for gene knockout and evaluation of function in cell lines in a manner that is far easier and more accessible than anything previously available. Unfortunately, the ability to extend these studies to in vivo syngeneic murine cell line implantation is limited by an immune response against cells transduced to stably express Cas9. In this study, we demonstrate that a non integrating lentiviral vector approach can overcome this immune rejection and allow for the growth of transduced cells in an immunocompetent host. This technique enables the establishment of a von Hippel-Lindau (VHL) gene knockout RENCA cell line in BALB/c mice, generating an improved model of immunocompetent, metastatic renal cell carcinoma (RCC). PMID- 29766029 TI - Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy. AB - Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities. PMID- 29766030 TI - Cre Recombinase Mediates the Removal of Bacterial Backbone to Efficiently Generate rSV40. AB - Gene therapy has been shown to be a feasible approach to treat inherited disorders in vivo. Among the currently used viral vector systems, adeno associated virus (AAV) vectors are the most advanced and have been applied in patients successfully. An important drawback of non-integrating AAV vectors is their loss of expression upon cell division, while repeating systemic administration lacks efficacy due to the induction of neutralizing antibodies. In addition, a significant percentage of the general population is not eligible for AAV-mediated gene therapy due to pre-existing immunity. Development of additional viral vectors may overcome this hurdle. Simian virus 40 (SV40)-derived vectors have been reported to transduce different tissues, including the liver, and prevalence of neutralizing antibodies in the general population is very low. This renders recombinant SV40 (rSV40) vector an interesting candidate for effective (re-)administration. Clinical use of SV40 vectors is in part hampered by less advanced production methods compared to AAVs. To optimize the production of rSV40 and make it better suitable for clinical practice, we developed a production system that relies on Cre recombinase-mediated removal of the bacterial plasmid backbone. PMID- 29766031 TI - A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates. AB - Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed gene therapy in a mouse model of a fatal pediatric leukodystrophy. In light of recent success with profiling diversified natural AAV capsid repertoires and the understanding of AAV capsid sequence-structure-function relationship, such a combinatory approach to AAV capsid development is expected to further improve vector targeting and expand the vector toolbox for therapeutic gene delivery. PMID- 29766032 TI - Serum-free Erythroid Differentiation for Efficient Genetic Modification and High Level Adult Hemoglobin Production. AB - In vitro erythroid differentiation from primary human cells is valuable to develop genetic strategies for hemoglobin disorders. However, current erythroid differentiation methods are encumbered by modest transduction rates and high baseline fetal hemoglobin production. In this study, we sought to improve both genetic modification and hemoglobin production among human erythroid cells in vitro. To model therapeutic strategies, we transduced human CD34+ cells and peripheral blood mononuclear cells (PBMCs) with lentiviral vectors and compared erythropoietin-based erythroid differentiation using fetal-bovine-serum containing media and serum-free media. We observed more efficient transduction (85%-93%) in serum-free media than serum-containing media (20%-69%), whereas the addition of knockout serum replacement (KSR) was required for serum-free media to promote efficient erythroid differentiation (96%). High-level adult hemoglobin production detectable by electrophoresis was achieved using serum-free media similar to serum-containing media. Importantly, low fetal hemoglobin production was observed in the optimized serum-free media. Using KSR-containing, serum-free erythroid differentiation media, therapeutic adult hemoglobin production was detected at protein levels with beta-globin lentiviral transduction in both CD34+ cells and PBMCs from sickle cell disease subjects. Our in vitro erythroid differentiation system provides a practical evaluation platform for adult hemoglobin production among human erythroid cells following genetic manipulation. PMID- 29766033 TI - Use of Key Performance Indicators to Improve Milestone Assessment in Semi-Annual Clinical Competency Committee Meetings. AB - Background: The Accreditation Council for Graduate Medical Education's Next Accreditation System requires residency programs to semiannually submit composite milestone data on each resident's performance. This report describes and evaluates a new assessment review procedure piloted in our departmental Clinical Competency Committee (CCC) semi-annual meeting in June 2016. Methods: A modified Delphi technique was utilized to develop key performance indicators (KPI) linking milestone descriptors to clinical practice. In addition, the CCC identified six specific milestone sub-competencies that would be prescored with objective data prior to the meeting. Each resident was independently placed on the milestones by 3 different CCC faculty members. Milestone placement data of the same cohort of 42 residents (Clinical Anesthesia Years 1-3) were collected to calculate inter rater reliability of the assessment procedures before and after the implemented changes. A survey was administrated to collect CCC feedback on the new procedure. Results: The procedure assisted in reducing meeting time from 8 to 3.5 hours. Survey of the CCC members revealed positive perception of the procedure. Higher inter-rater reliability of the milestone placement was obtained using the implemented KPIs (Intraclass correlation coefficient [ICC] single measure range: before=.53-.94, after=.74-.98). Conclusion: We found the new assessment procedure beneficial to the efficiency and transparency of the assessment process. Further improvement of the procedure involves refinement of KPIs and additional faculty development on KPIs to allow non-CCC faculty to provide more accurate resident evaluations. PMID- 29766034 TI - How to Write Well-Defined Learning Objectives. AB - Writing effective learning objectives is a necessary skill in academic medicine. Learning objectives are clearly written, specific statements of observable learner behavior or action that can be measured upon completion of an educational activity. They are the foundation for instructional alignment whereby the learning objectives, assessment tools, and instructional methods mutually support the desired learning outcome. This review article describes the essential components of a learning objective and provides practical tips on writing well defined learning objectives. PMID- 29766035 TI - Using the Teaching Perspectives Inventory as an Introduction to a Residents-as Teachers Curriculum. AB - Objective: The Anesthesiology Milestone Project includes a milestone for assessing the teaching attributes of residents within the competency of Practice based Learning and Improvement. We intend to develop a Residents-as-Teachers educational curriculum to assist our residents in successfully achieving this milestone. The goal of this study is to identify the specific teaching perspectives and intentions of our residents and to promote residents' comprehension of their own teaching philosophy. Methods: We invited our residents to complete the Teaching Perspective Inventory (TPI) and a follow-up survey to gather information regarding dominant and recessive teaching perspectives, their intended career pathway, and their view of the importance of understanding teaching perspectives. Results: The two most common dominant teaching perspectives are apprenticeship and nurturing for residents who are planning a career in both academic medicine and private practice. A greater percentage of residents planning an academic career agree that identifying their teaching perspective is beneficial to their role as a clinical educator, compared to those anticipating a career in private practice. Conclusions: Based on this pilot data, our Residents-as-Teachers curriculum will include instruction of educational strategies specifically designed towards the apprenticeship and nurturing perspectives. PMID- 29766036 TI - Simulation-based Airway Management Training for Anesthesiologists - A Brief Review of its Essential Role in Skills Training for Clinical Competency. AB - In clinical practice, failure of proper airway management can lead to significant patient morbidity and mortality. Difficult airway management comprises a fundamental skill set for anesthesiologists and has long been recognized as one of the most challenging skills. Simulation-based training is an essential technique to establish and maintain technical and nontechnical skills for airway management. We review the evidence-based utility of simulation-based training for anesthesiologists to accquire technical and nontechnical airway mangement skills. Limitations and challenges of simulation training for airway management and the key role of instructional skills mandate thoughtful and well-designed programs of simulation-based training to assure optimal educational outcomes. Simulation and clinical training should be developed as complementary techniques in an integrated parallel instructional design paradigm to ensure effective development of technical and nontechnical airway management skill for anesthesiologists. Evidence-based educational outcomes favoring simulation-based airway training are highlighted. PMID- 29766037 TI - International Elective Opportunities in United States Anesthesia Residency Programs. AB - Background: Global health is a recognized component of medical education and is increasingly included in residency programs. International electives have the potential to improve global health training by providing exposure to different populations and the challenges of health disparities. The objective of this study was to describe international elective opportunities in US anesthesiology residency training programs, including an assessment the types of programs offered and the obstacles to providing this type of training. Methods: An electronic survey was sent to 122 anesthesiology programs. The survey defined an international experience as "a time in which a current US anesthesiology resident traveled outside of the US to pursue a healthcare-related experience." Details describing international opportunities were collected. Responses were stratified by geographic region, program size, and by the availability of international electives. The websites of all surveyed programs were then reviewed to determine specific mention of international or global health programs. These results were compared to the survey responses. Results: In the website review, 33.6% of programs' websites described international electives for residents. Among all surveyed programs, 56 (45.9%) completed surveys were returned, with 39 (69.6%) of these programs offering international electives. Not all programs with electives described the offering on their websites. There was no relationship between program size or location and the availability of an elective. At most programs with international electives, at least 4 residents participated annually. Funding was the primary barrier to providing international electives. Perceptions of international electives were generally positive. Conclusions: A large proportion of US anesthesia residency programs offer international electives, and perceptions of global health in anesthesiology are positive. This is consistent with developments in global health in other subspecialty fields. PMID- 29766038 TI - Frontal Eye Field Inactivation Reduces Saccade Preparation in the Superior Colliculus but Does Not Alter How Preparatory Activity Relates to Saccades of a Given Latency. AB - A neural correlate for saccadic reaction times (SRTs) in the gap saccade task is the level of low-frequency activity in the intermediate layers of the superior colliculus (iSC) just before visual target onset: greater levels of such preparatory iSC low-frequency activity precede shorter SRTs. The frontal eye fields (FEFs) are one likely source of iSC preparatory activity, since FEF preparatory activity is also inversely related to SRT. To better understand the FEF's role in saccade preparation, and the way in which such preparation relates to SRT, in two male rhesus monkeys, we compared iSC preparatory activity across unilateral reversible cryogenic inactivation of the FEF. FEF inactivation increased contralesional SRTs, and lowered ipsilesional iSC preparatory activity. FEF inactivation also reduced rostral iSC activity during the gap period. Importantly, the distributions of SRTs generated with or without FEF inactivation overlapped, enabling us to conduct a novel population-level analyses examining iSC preparatory activity just before generation of SRT-matched saccades. When matched for SRTs, we observed no change during FEF inactivation in the relationship between iSC preparatory activity and SRT-matched saccades across a range of SRTs, even for the occasional express saccade. Thus, while our results emphasize that the FEF has an overall excitatory influence on preparatory activity in the iSC, the communication between the iSC and downstream oculomotor brainstem is unaltered for SRT-matched saccades. PMID- 29766039 TI - Beneficial Outcome of Urethane Treatment Following Status Epilepticus in a Rat Organophosphorus Toxicity Model. AB - The efficacy of benzodiazepines to terminate electrographic status epilepticus (SE) declines the longer a patient is in SE. Therefore, alternative methods for ensuring complete block of SE and refractory SE are necessary. We compared the ability of diazepam and a subanesthetic dose of urethane to terminate prolonged SE and mitigate subsequent pathologies. Adult Sprague Dawley rats were injected with diisopropylfluorophosphate (DFP) to induce SE. Rats were administered diazepam (10 mg/kg, ip) or urethane (0.8 g/kg, s.c.) 1 h after DFP-induced SE and compared to rats that experienced uninterrupted SE. Large-amplitude and high frequency spikes induced by DFP administration were quenched for at least 46 h in rats administered urethane 1 h after SE onset as demonstrated by cortical electroencephalography (EEG). By contrast, diazepam interrupted SE but seizures with high power in the 20- to 70-Hz band returned 6-10 h later. Urethane was more effective than diazepam at reducing hippocampal neurodegeneration, brain inflammation, gliosis and weight loss as measured on day 4 after SE. Furthermore, rats administered urethane displayed a 73% reduction in the incidence of spontaneous recurrent seizures after four to eight weeks and a 90% reduction in frequency of seizures in epileptic rats. By contrast, behavioral changes in the light/dark box, open field and a novel object recognition task were not improved by urethane. These findings indicate that in typical rodent SE models, it is the return of SE overnight, and not the initially intense 1-2 h of SE experience, that is largely responsible for neurodegeneration, accompanying inflammation, and the subsequent development of epilepsy. PMID- 29766040 TI - The Midline Axon Crossing Decision Is Regulated through an Activity-Dependent Mechanism by the NMDA Receptor. AB - Axon guidance in vertebrates is controlled by genetic cascades as well as by intrinsic activity-dependent refinement of connections. Midline axon crossing is one of the best studied pathfinding models and is fundamental to the establishment of bilaterally symmetric nervous systems. However, it is not known whether crossing requires intrinsic activity in axons, and what controls that activity. Further, a mechanism linking neuronal activity and gene expression has not been identified for axon pathfinding. Using embryonic zebrafish, we found that the NMDA receptor (NMDAR) NR1.1 subunit (grin1a) is expressed in commissural axons. Pharmacological inhibition of grin1a, hypoxia exposure reduction of grin1a expression, or CRISPR knock-down of grin1a leads to defects in midline crossing. Inhibition of neuronal activity phenocopies the effects of grin1a loss on midline crossing. By combining pharmacological inhibition of the NMDAR with optogenetic stimulation to precisely restore neuronal activity, we observed rescue of midline crossing. This suggests that the NMDAR controls pathfinding by an activity dependent mechanism. We further show that the NMDAR may act, via modulating activity, on the transcription factor arxa (mammalian Arx), a known regulator of midline pathfinding. These findings uncover a novel role for the NMDAR in controlling activity to regulate commissural pathfinding and identify arxa as a key link between the genetic and activity-dependent regulation of midline axon guidance. PMID- 29766043 TI - Erratum: Dash et al., Poly (ADP-Ribose) Polymerase-1 (PARP-1) Induction by Cocaine Is Post-Transcriptionally Regulated by miR-125b (eNeuro July/August 2017, 4(4) e0089-17.2017 1-16 https://doi.org/10.1523/ENEURO.0089-17.2017). AB - [This corrects the article DOI: 10.1523/ENEURO.0089-17.2017.][This corrects the article DOI: 10.1523/ENEURO.0089-17.2017.]. PMID- 29766044 TI - Filter-Based Phase Shifts Distort Neuronal Timing Information. AB - Filters are widely used for the modulation, typically attenuation, of amplitudes of different frequencies within neurophysiological signals. Filters, however, also induce changes in the phases of different frequencies whose amplitude is unmodulated. These phase shifts cause time lags in the filtered signals, leading to a disruption of the timing information between different frequencies within the same signal and between different signals. The emerging time lags can be either constant in the case of linear phase (LP) filters or vary as a function of the frequency in the more common case of non-LP (NLP) filters. Since filters are used ubiquitously online in the early stages of data acquisition, the vast majority of neurophysiological signals thus suffer from distortion of the timing information even prior to their sampling. This distortion is often exacerbated by further multiple offline filtering stages of the sampled signal. The distortion of timing information may cause misinterpretation of the results and lead to erroneous conclusions. Here we present a variety of typical examples of filter induced phase distortions and discuss the evaluation and restoration of the timing information underlying the original signal. PMID- 29766041 TI - Report on the National Eye Institute's Audacious Goals Initiative: Creating a Cellular Environment for Neuroregeneration. AB - The cellular environment of the CNS is non-permissive for growth and regeneration. In the retina, transplantation of stem cells has been limited by inefficient survival and integration into existing circuits. In November 2016, as part of the National Eye Institute's Audacious Goals Initiative (AGI), a diverse collection of investigators gathered for a workshop devoted to articulating the gaps in knowledge, barriers to progress, and ideas for new approaches to understanding cellular environments within the retina and how these environments may be manipulated. In doing so, the group identified the areas of (1) retinal and optic nerve glia, (2) microglia and inflammation, and the (3) extracellular matrix (ECM) and retinal vasculature as key to advancing our understanding and manipulation of the retinal microenvironments. We summarize here the findings of the workshop for the broader scientific community. PMID- 29766042 TI - BC RNA Mislocalization in the Fragile X Premutation. AB - Fragile X premutation disorder is caused by CGG triplet repeat expansions in the 5' untranslated region of FMR1 mRNA. The question of how expanded CGG repeats cause disease is a subject of continuing debate. Our work indicates that CGG repeat structures compete with regulatory BC1 RNA for access to RNA transport factor hnRNP A2. As a result, BC1 RNA is mislocalized in vivo, as its synapto dendritic presence is severely diminished in brains of CGG-repeat knock-in animals (a premutation mouse model). Lack of BC1 RNA is known to cause seizure activity and cognitive dysfunction. Our working hypothesis thus predicted that absence, or significantly reduced presence, of BC1 RNA in synapto-dendritic domains of premutation animal neurons would engender cognate phenotypic alterations. Testing this prediction, we established epileptogenic susceptibility and cognitive impairments as major phenotypic abnormalities of CGG premutation mice. In CA3 hippocampal neurons of such animals, synaptic release of glutamate elicits neuronal hyperexcitability in the form of group I metabotropic glutamate receptor-dependent prolonged epileptiform discharges. CGG-repeat knock-in animals are susceptible to sound-induced seizures and are cognitively impaired as revealed in the Attentional Set Shift Task. These phenotypic disturbances occur in young-adult premutation animals, indicating that a neurodevelopmental deficit is an early-initial manifestation of the disorder. The data are consistent with the notion that RNA mislocalization can contribute to pathogenesis. PMID- 29766045 TI - Post-stroke Intranasal (+)-Naloxone Delivery Reduces Microglial Activation and Improves Behavioral Recovery from Ischemic Injury. AB - Ischemic stroke is the leading cause of disability, and effective therapeutic strategies are needed to promote complete recovery. Neuroinflammation plays a significant role in stroke pathophysiology, and there is limited understanding of how it affects recovery. The aim of this study was to characterize the spatiotemporal expression profile of microglial activation and whether dampening microglial/macrophage activation post-stroke facilitates the recovery. For dampening microglial/macrophage activation, we chose intranasal administration of naloxone, a drug that is already in clinical use for opioid overdose and is known to decrease microglia/macrophage activation. We characterized the temporal progression of microglia/macrophage activation following cortical ischemic injury in rat and found the peak activation in cortex 7 d post-stroke. Unexpectedly, there was a chronic expression of phagocytic cells in the thalamus associated with neuronal loss. (+)-Naloxone, an enantiomer that reduces microglial activation without antagonizing opioid receptors, was administered intranasally starting 1 d post-stroke and continuing for 7 d. (+)-Naloxone treatment decreased microglia/macrophage activation in the striatum and thalamus, promoted behavioral recovery during the 14-d monitoring period, and reduced neuronal death in the lesioned cortex and ipsilateral thalamus. Our results are the first to show that post-stroke intranasal (+)-naloxone administration promotes short-term functional recovery and reduces microglia/macrophage activation. Therefore, (+)-naloxone is a promising drug for the treatment of ischemic stroke, and further studies should be conducted. PMID- 29766046 TI - Deletion of Tsc2 in Nociceptors Reduces Target Innervation, Ion Channel Expression, and Sensitivity to Heat. AB - The mechanistic target of rapamycin complex 1 (mTORC1) is known to regulate cellular growth pathways, and its genetic activation is sufficient to enhance regenerative axon growth following injury to the central or peripheral nervous systems. However, excess mTORC1 activation may promote innervation defects, and mTORC1 activity mediates injury-induced hypersensitivity, reducing enthusiasm for the pathway as a therapeutic target. While mTORC1 activity is required for full expression of some pain modalities, the effects of pathway activation on nociceptor phenotypes and sensory behaviors are currently unknown. To address this, we genetically activated mTORC1 in mouse peripheral sensory neurons by conditional deletion of its negative regulator Tuberous Sclerosis Complex 2 (Tsc2). Consistent with the well-known role of mTORC1 in regulating cell size, soma size and axon diameter of C-nociceptors were increased in Tsc2-deleted mice. Glabrous skin and spinal cord innervation by C-fiber neurons were also disrupted. Transcriptional profiling of nociceptors enriched by fluorescence-associated cell sorting (FACS) revealed downregulation of multiple classes of ion channels as well as reduced expression of markers for peptidergic nociceptors in Tsc2-deleted mice. In addition to these changes in innervation and gene expression, Tsc2 deleted mice exhibited reduced noxious heat sensitivity and decreased injury induced cold hypersensitivity, but normal baseline sensitivity to cold and mechanical stimuli. Together, these data show that excess mTORC1 activity in sensory neurons produces changes in gene expression, neuron morphology and sensory behavior. PMID- 29766050 TI - Severe dysphagia requiring gastrostomy following cervical spine fracture fixation. AB - Background: The incidence of severe dysphagia requiring gastrostomy tube (GT) placement following operative fixation of traumatic cervical spine fractures is unknown. Risk factors for severe dysphagia are not well identified and GT placement is often delayed due to the belief that it will resolve quickly. We hypothesized that patient and clinical factors could be used to predict severe dysphagia requiring GT placement in this population. Methods: A retrospective multicenter review of all adult patients requiring operative fixation of cervical spine fractures was performed. Data on demographics, injury severity score, presence of spinal cord injury, operative approach, presence of severe traumatic brain injury, and the need and timing of tracheostomy and GT were collected. The timing, number and results of formal speech, and language pathology examinations were also recorded. Results: 243 patients underwent cervical spine fixation for traumatic fractures, of which 72 (30%) required GT placement. Patients requiring gastrostomy were significantly older, 54 versus 45 years (p=0.002), and had higher injury severity scores at 24 versus 18 (p<0.0001). Tracheostomy was strongly associated with severe dysphagia; GT was required in 83% of patients who underwent tracheostomy versus 5% of those who did not require tracheostomy. 50% of patients underwent tracheostomy and GT on the same day after injury, with the remaining patients having an average of 9 days delay between procedures. The need for gastrostomy placement was also higher in patients undergoing combined operative approach versus anterior or posterior approach alone (p=0.02). There were no GT-related complications. Conclusions: Severe dysphagia requiring GT placement occurs commonly (30%) in patients who undergo operative fixation of cervical spine fractures. Gastrostomy placement was delayed in 50%. Tracheostomy was strongly associated with the need for GT placement. Earlier GT placement, especially in patients requiring tracheostomy, would improve patient care and disposition. PMID- 29766047 TI - A Transient Dopamine Signal Represents Avoidance Value and Causally Influences the Demand to Avoid. AB - While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid. PMID- 29766049 TI - Interleukin 1alpha-Deficient Mice Have an Altered Gut Microbiota Leading to Protection from Dextran Sodium Sulfate-Induced Colitis. AB - Inflammatory bowel diseases (IBD) are a group of chronic inflammatory disorders of the intestine, with as-yet-unclear etiologies, affecting over a million people in the United States alone. With the emergence of microbiome research, numerous studies have shown a connection between shifts in the gut microbiota composition (dysbiosis) and patterns of IBD development. In a previous study, we showed that interleukin 1alpha (IL-1alpha) deficiency in IL-1alpha knockout (KO) mice results in moderate dextran sodium sulfate (DSS)-induced colitis compared to that of wild type (WT) mice, characterized by reduced inflammation and complete healing, as shown by parameters of weight loss, disease activity index (DAI) score, histology, and cytokine expression. In this study, we tested whether the protective effects of IL-1alpha deficiency on DSS-induced colitis correlate with changes in the gut microbiota and whether manipulation of the microbiota by cohousing can alter patterns of colon inflammation. We analyzed the gut microbiota composition in both control (WT) and IL-1alpha KO mice under steady state homeostasis, during acute DSS-induced colitis, and after recovery using 16S rRNA next-generation sequencing. Additionally, we performed cohousing of both mouse groups and tested the effects on the microbiota and clinical outcomes. We demonstrate that host-derived IL-1alpha has a clear influence on gut microbiota composition, as well as on severity of DSS-induced acute colon inflammation. Cohousing both successfully changed the gut microbiota composition and increased the disease severity of IL-1alpha-deficient mice to levels similar to those of WT mice. This study shows a strong and novel correlation between IL-1alpha expression, microbiota composition, and clinical outcomes of DSS-induced colitis. IMPORTANCE Here, we show a connection between IL-1alpha expression, microbiota composition, and clinical outcomes of DSS-induced colitis. Specifically, we show that the mild colitis symptoms seen in IL-1alpha-deficient mice following administration of DSS are correlated with the unique gut microbiota compositions of the mice. However, when these mice are exposed to WT microbiota by cohousing, their gut microbiota composition returns to resemble that of WT mice, and their disease severity increases significantly. As inflammatory bowel diseases are such common diseases, with limited effective treatments to date, there is a great need to better understand the interactions between microbiota composition, the immune system, and colitis. This study shows correlation between microbiota composition and DSS resistance; it may potentially lead to the development of improved probiotics for IBD treatment. PMID- 29766048 TI - Phasic Stimulation of Midbrain Dopamine Neuron Activity Reduces Salt Consumption. AB - Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviors, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organizing motivated behaviors. PMID- 29766052 TI - Fellowship training in Acute Care Surgery: from inception to current state. AB - Recognizing the need for urgent and emergent surgical care across America, the American Association for the Surgery of Trauma developed and implemented, and oversees, the Acute Care Surgery Fellowship Training Program. Now in its 10th year, the fellowship has become an established post-General Surgery Fellowship Training Program, with 20 approved programs and 82 fellows trained. Consistent with the desire to have this non-Accreditation Council for Graduate Medical Education (ACGME) fellowship one with the highest standards, several educational improvements have occurred since its origin. The following is an account of the background and evolution of what has become a significant educational contribution to surgery. PMID- 29766053 TI - Necrotizing soft tissue infection of the chest wall. PMID- 29766051 TI - Does diabetes type increase the odds of venous thromboembolism following traumatic injury? AB - Background: Venous thromboembolism (VTE) remains a clinically significant complication after trauma even though screening and prophylaxis strategies for at risk patients have substantially reduced incidence. Our study sought to determine if diabetes, a condition that promotes thrombi formation, is associated with developing a VTE in trauma patients. Methods: The registries of 2 level I and a level II trauma centers were retrospectively reviewed for consecutively admitted trauma patients over a 6-year period. Demographics, VTE risk factors, injury characteristics, and VTE incidence were univariately compared between patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and no diabetes. Stepwise logistic regression was performed to identify independent predictors of VTE; results were further stratified by age (<65 and >=65 years) and presented as adjusted ORs (AOR). Results: Of the 26 934 total patients, 779 (2.9%) had IDDM, 2052 (7.6%) had NIDDM, and the remaining 89.5% were without diabetes. VTE incidence was 3.6%, 2.4%, and 2.2%, in IDDM, NIDDM, and non-diabetes, respectively (p=0.02). After adjustment for established and significant risk factors, neither IDDM (AOR=1.43, 95% CI 0.95 to 2.15, p=0.09) nor NIDDM (AOR=1.03, 95% CI 0.75 to 1.40, p=0.88) was associated with increased odds of developing a VTE. Patients >=65 years developed VTE more frequently than those <65 years (2.5% vs 2.1%, p=0.04). Among patients <65 years, IDDM was significantly predictive of VTE (AOR=1.86, 95% CI 1.01-3.41, p=0.045), but NIDDM was not. For patients >=65 years, neither type of diabetes was predictive of VTE. Conclusions: VTE incidence was ~2 times higher among injured patients <65 years with IDDM versus no diabetes. Overall, we did not find an increased risk of VTE in patients with any diabetes. Additional studies are needed before a recommendation on VTE screening or prophylaxis in IDDM can be made. Level of evidence: Level III, therapeutic/care management. PMID- 29766054 TI - The world is getting smaller.... PMID- 29766055 TI - Water slide injuries in Jamaica. AB - Background: Patients are presented in this study to describe injuries, each of which have not been previously described in the literature, as a result of a specific mechanism of injury on a water slide. Some of these injuries are potentially fatal and are usually the result of a very high energy mechanism of injury. All injuries occurred in a 6-week time span in the summer of 2015. Method: Injuries arising from water slides and their definitive treatment were documented. All of the cases presented to Saint Ann's Bay Hospital in Saint Ann's Bay, Jamaica. The mechanism of injury was analyzed with a view to implement preventative measures. Results: Three cases had open book pelvic injuries and one of them also had a vaginal tear. All of the open book injuries occurred after the patron's thighs violently abducted despite adhering to the recommended starting position that suggested patrons cross their legs. The fourth case was of a 25 year-old man who sustained a posterior shoulder dislocation as a result of his arms flailing despite attempting to adhere to the rule recommending that the patron place his arms across his chest. The final case was of a 14-year-old boy who was involved in an atypical collision injury, resulting in the boy sustaining a displaced distal femoral fracture. Conclusions: Modern water slides will expose patrons to more frequent and severe injuries from atypical mechanisms of injuries. Risk factors for injury must be factored into preventative measures. Improved surveillance strategies to monitor these injuries are suggested. PMID- 29766057 TI - Isolated prehospital hypotension correlates with injury severity and outcomes in patients with trauma. AB - Objective: Patients normotensive in the trauma bay despite documented prehospital hypotension may not be recognized as significantly injured. The purpose of this study was to determine whether isolated prehospital hypotension portends poor outcomes and correlates with injury severity. Methods: Prospective cohort study conducted at a level 1 university trauma center. The lowest recorded prehospital systolic blood pressure (SBP) and the first recorded SBP on hospital arrival were used to divide patients into either the normotensive (NP) or hypotensive (HP) group. Patients who failed to achieve normotension on hospital arrival were excluded. Hypotension was defined as SBP<=110 mmHg. Results: Compared to NP (n=206), HP (n=81) had lower Glasgow Coma Scores both prehospital (12.81+/-0.44 vs 14.38+/-0.13) and at hospital admission (12.78+/-0.47 vs 14.37+/-0.14). Injury Severity Score positively correlated with prehospital hypotension (HP 12.27+/ 1.12 vs NP 9.22+/-0.49). Prehospital hypotension positively correlated with intensive care unit (ICU) admission (HP 56.79% vs NP 22.82%), ICU length of stay (LOS) (HP 3.23+/-0.71 vs NP 0.71+/-0.17), hospital LOS (HP 8.58+/-1.39 vs NP 4.86+/-0.33), ventilator days (HP 3.38+/-1.20 vs NP 0.27+/-0.08 days), and repeat hypotensive episodes during their hospital stay (HP 81.71% vs NP 38.16%). HP also required more packed red blood cells in the first 24 hours after admission (22% vs 6%). Significance was set at p<0.05. Conclusions: Isolated prehospital hypotension in patients in the trauma and emergency department correlates with increased injury severity and portends worse outcomes despite a normal blood pressure reading at admission. Prehospital hypotension must be given heavy consideration in triage, as these patients may be transiently hypotensive and appear less critical than their true status. Level of Evidence: Level II, Prognostic study. PMID- 29766056 TI - New device for temporary hemorrhage control in penetrating injuries to the ventricles. AB - Background: The best way to control hemorrhage from cardiac injuries is through digital occlusion followed by suture. However, this is difficult to accomplish in the emergency department (ED) setting. Generally, temporary control is obtained in advance of definitive treatment in the operating room. Despite safety and efficacy concerns, balloon Foley catheter insertion through the injury is still an option following ED thoracotomies. We developed a new device for temporary hemorrhage control in cardiac injuries and compared it to the Foley. Methods: 6 adult swine (n=6) underwent full-thickness (1.5 cm) injury along the longitudinal axis of the right ventricle (RV). After 5 s of bleeding, hemorrhage control was attempted with either the device or the Foley, and blood loss quantified. Subsequently, the wound was sutured and mean arterial pressure was restored to baseline with lactated Ringer's infusion. Subsequently, another injury 2 cm apart in the same ventricle was managed with apparatus not employed in the first injury. The same followed in the LV totaling 4 injuries per animal, 2 in each ventricle. Intraoperative echocardiogram, laboratory test and final wound sizes assessed. Results: The device resulted in less bleeding than the Foley; RV 58.7+/ 11.3 vs 147.7+/-30.9 mL, LV 81.7+/-11.9 vs 187.5+/-40.3 mL (p<0.05). Percent change in tricuspid regurgitation was less with the device than FO, 66.6% vs 400%. Mitral regurgitation increased 16% with Foley, but remained unchanged with the device. Changes in stroke volume and LV ejection fraction were less with the device than with Foley; SV 2.09% vs 12.48%, left ventricular ejection fraction 0.46% vs 5.45%. Foley insertion enlarged the wounds. Platelet count, complete blood count, prothrombin time, activated prothrombin time and fibrinogen decreased, whereas troponin and lactate increased compared with baseline, underscoring the magnitude of shock. Conclusions: Cardiac hemorrhage was effectively controlled with the new device. The low-profile collapsible blocking membrane interfered less with cardiac function than did the balloon of the Foley, an important asset in the context of shock. PMID- 29766058 TI - Prospective observational study of point-of-care creatinine in trauma. AB - Background: Patients with trauma are at risk for renal dysfunction from hypovolemia or urological injury. In austere environments, creatinine values are not available to guide resuscitation. A new portable device, the Stat Sensor Point-of-care (POC) Whole Blood Creatinine Analyzer, provides accurate results in <30 s and requires minimal training. This device has not been evaluated in trauma despite the theoretical benefit it provides. The purpose of this study is to determine the clinical impact of the POC device in trauma. Methods: 40 patients with trauma were enrolled in a prospective observational study. One drop of blood was used for creatinine determination on the Statsensor POC device. POC creatinine results were compared to the laboratory. Turnaround time (TAT) for POC and laboratory methods was calculated as well as time elapsed to CT scan if applicable. Results: Patients (n=40) were enrolled between December 2014 and March 2015. POC creatinine values were similar to laboratory methods with a mean bias of 0.075+/-0.27 (p=0.08). Mean analytical TATs for the POC measurements were significantly faster than the laboratory method (11.6+/-10.0 min vs 78.1+/-27.9 min, n=40, p<0.0001). Mean elapsed time before arrival at the CT scanner was 52.9+/-34.2 min. Conclusions: The POC device reported similar creatinine values to the laboratory and provided significantly faster results. POC creatinine testing is a promising development for trauma practice in austere environments and workup of a subset of stable patients with trauma. Further study is warranted to determine clinical impact, both in hospital-based trauma and austere environments. PMID- 29766059 TI - Abdominal vascular trauma. AB - Abdominal vascular trauma, primarily due to penetrating mechanisms, is uncommon. However, when it does occur, it can be quite lethal, with mortality ranging from 20% to 60%. Increased early mortality has been associated with shock, acidosis, hypothermia, coagulopathy, free intraperitoneal bleeding and advanced American Association for the Surgery of Trauma Organ Injury Scale grade. These patients often arrive at medical centers in extremis and require rapid surgical control of bleeding and aggressive resuscitation including massive transfusion protocols. The most important factor in survival is surgical control of hemorrhage and restoration of appropriate perfusion to the abdominal contents and lower extremities. These surgical approaches and the techniques of definitive vascular repair can be quite challenging, particularly to the inexperienced surgeon. This review hopes to describe the most common abdominal vascular injuries, their presentation, outcomes, and surgical techniques to control and repair such injuries. PMID- 29766061 TI - Acute traumatic abdominal wall herniation with evisceration. PMID- 29766060 TI - Impact of MRI on changing management of the cervical spine in blunt trauma patients with a 'negative' CT scan. AB - Background: Owing to the potential risks associated with missed injury, many blunt trauma patients with suspected cervical spine injury undergo some form of imaging technique which has progressed from primarily using plain radiography to relying on CT. Recently, studies have shown that in certain situations, adding MRI may improve the diagnostic accuracy over solely relying on CT. Methods: Retrospective study of 3468 adult blunt trauma patients at a level I trauma center of which 94 with an initial negative CT scan underwent subsequent MRI. These 94 patients were classified as reliable or unreliable for examination; coded as either having a positive or negative MRI result; and assessed for a change in management. Results: Of the 94 patients in the study population, 69 (73.4%) were deemed reliable and 25 (26.6%) deemed unreliable for examination. Overall, 65 (69.1%) patients had a positive MRI result-49 (71.0%) reliable and 16 (64.0%) unreliable-with some patients testing positive for more than one finding. There was no significant difference in positive MRI rates between reliable and unreliable patients. None of the 29 patients who had negative MRI had a change in management, while 31 of the 65 (47.7%) patients with positive MRI did have a change in management of either continued cervical collar immobilization or neck surgery. Conclusions: The use of CT scans should be continued as the primary imaging technique for patients with suspected cervical spine injuries. In cases where obtundation or clinical suspicion exists for a false-negative CT scan, MRI should be considered as a supplement and should not be rejected solely based on the negative result of the CT. Level of evidence: Level IV. PMID- 29766062 TI - Through the looking glass: early non-invasive imaging in TBI predicts the need for interventions. AB - Background: Early diagnosis and treatment of traumatic brain injury (TBI) lead to better outcomes. It is difficult to predict which patients benefit from specialised centres, leading to over triage or delay in definitive care. We propose that a non-invasive test comprising optic nerve sheath ultrasound, transcranial Doppler and quantitative papillary reactivity is feasible, correlates with CT findings and may allow for accurate early identification of TBI. Methods: A 1-year, prospective observation study evaluated a low-risk, non invasive method of assessing brain injury. Patients underwent a non-invasive neurological examination for trauma, including the above assessments. Data from the three examinations were collected within 6 hours of injury and at 24 hours, and were analysed. Demographics, haemodynamic data, imaging results and short term outcomes/interventions were recorded. Results: Trauma patients over the age of 18 years, with a Glascow coma scale (GCS) of <12 or CT evidence of TBI, and intubated were included (N=100). These were divided into +CT (n=49) and -CT groups (n=51) according to the Marshall CT classification of TBI. The +CT group was older, with worse GCS and higher lactate (p=0.008, p=0.001 and p=0.01) but were otherwise well matched. The +CT group included all TBI types, with 96% of the patients having more than one type of TBI. Pulsatility index and neurologic pupillary index were predictive of a +CT (p=0.04, p=0.02). Area under the receiver-operating curve for the logistic regression model for the prediction of positive radiographic findings was r=0.718. Finally, we suggest a preliminary scoring heuristic for predicting a positive radiological finding in a patient with TBI. Conclusions: The proposed examination is a feasible, non-invasive tool that may have clinical utility in the early prediction of TBI. If validated, it may improve trauma triage for the brain-injured patient. Further studies are warranted to validate this model. PMID- 29766063 TI - Response to mass casualty events: from the battlefield to the Stop the Bleed campaign. AB - In the aftermath of a number of episodes of mass casualty events, we must be reminded of how important it is to be prepared and to reflect on the knowledge accumulated over the past 15 years of war in Iraq and Afghanistan. PMID- 29766065 TI - Massive intrapericardial and intrathoracic hemorrhage secondary to unusual injuries causing cardiopulmonary arrest. PMID- 29766066 TI - Potential benefit of early operative utilization of low profile, partial resuscitative endovascular balloon occlusion of the aorta (P-REBOA) in major traumatic hemorrhage. PMID- 29766064 TI - Hospital-based violence intervention programs targeting adult populations: an Eastern Association for the Surgery of Trauma evidence-based review. AB - Background: Violent injury and reinjury take a devastating toll on distressed communities. Many trauma centers have created hospital-based violent injury prevention programs (HVIP) to address psychosocial, educational, and mental health needs of injured patients that may contribute to reinjury. Objectives: To evaluate the overall effectiveness of HVIPs for violent injury prevention. We performed an evidence-based review to answer the following population, intervention, comparator, outcomes (PICO) question: Are HVIPs attending to adult patients (age 18+) treated for intentional injury more effective than the usual care at preventing: intentional violent reinjury and/or death; arrest and/or incarceration; substance abuse and/or mental issues; job and/or school attainment? Data sources: PubMed, Web of Science, Google Scholar, and the Cochrane Library were queried for salient articles by a professional librarian on two separate occasions, and related articles were identified from references. Study eligibility criteria participants interventions: Eligible studies examined adult patients treated for intentional injury in a hospital-based violence prevention program compared to a control group. Study appraisal and synthesis methods: We used the Grading of Recommendations Assessment, Development, and Evaluation methodology to assess the breadth and quality of the evidence. Results: 71 articles were identified. After discarding duplicates, reviews, and those articles that did not address our PICO questions, we ultimately reviewed 10 articles. We found insufficient evidence to recommend adult-focused HVIP interventions. Limitations: There was a relative paucity of data, and available studies were limited by self-selection bias and small sample sizes. Conclusions: We make no recommendation with respect to adult-focused HVIP interventions. PMID- 29766067 TI - Creation of the first Hartford Consensus compliant elementary school in the USA. AB - Background: The Hartford Consensus established a framework for minimizing deaths due to mass shootings, specifically eliminating preventable deaths due to limb exsanguination. Two major principles defined within this framework are (1) redefining the first responder role and (2) the ubiquitous availability of proper training in application of hemorrhage control techniques, including tourniquets. We hypothesized that this hemorrhage control posture could be fully translated into an elementary school. Methods: Following institutional review board approval, all teachers at a prekindergarten through 8th grade elementary school underwent short, intensive instruction on their role as a first responder, as well as indications and proper technique for hemorrhage control and tourniquet application for limb exsanguination. All teachers self-reported their confidence in their role as a first responder as well as tourniquet application indications and technique before and after instruction. Following instruction, teachers were evaluated on proper tourniquet application technique on a simulated limb to assess competence. Results: 26 elementary school teachers and 2 administrative staff underwent training. All reported low confidence in their role as a first responder and in tourniquet application indication and technique before training. Following training, all teachers reported high confidence. Testing demonstrated all teachers were competent in the tourniquet application technique. Following training, each classroom was equipped with a purpose-made commercial tourniquet, and a dedicated hemorrhage control bag was placed in the school's central administrative office. Conclusions: All teachers were successfully trained to act as first responders and in correct hemorrhage control techniques, which was verified by testing. This is the first elementary school to universally adopt a hemorrhage control posture to eliminate preventable deaths from limb exsanguination advocated by the Hartford Consensus. PMID- 29766068 TI - Retrospective comparison of postoperative infection and bone union between late and immediate intramedullary nailing of Gustilo grades I, II, and IIIA open tibial shaft fractures. AB - Background: The optimal method of skeletal stabilization is still controversial. Therefore, we examined the clinical outcomes associated with late (L) versus immediate intramedullary nailing (IMN). Methods: This was a retrospective comparative study of trauma registry data from an emergency medical care center (university hospital). We examined 85 open tibial shaft fractures (85 patients) treated with L or immediate (I) IMN from January 2004 to December 2010. The L and I groups comprised 37 (33 men, 4 women) and 48 (44 men, 4 women) patients, respectively. The postoperative infection rate, time to bone union, and delayed union/non-union were evaluated. Results: The mean ages at the time of trauma in the L and I groups were 41.8 (18-79) and 42.0 (18-71) years, respectively; the mean follow-up periods were 15.0 (6-39) and 18.3 (8-36) months, respectively. A higher rate of postoperative infection was found in the L group than in the I group (p=0.004). Superficial/deep infection developed at a higher rate in the L group than in the I group (p=0.042 and 0.045, respectively). Among patients with Gustilo grade IIIA fractures, postoperative infection occurred at a higher rate in the L group than in the I group (p=0.008). However, the delayed union rate, non-union rate, and time to bone union were not significantly different between the groups. Conclusions: Gustilo grade IIIA fractures had a high infection rate, which is likely due to various factors, including pin-site infection after external fixation. We think that I IMN is safer than L IMN, and it should be the treatment of choice. Level of evidence: Retrospective comparative study, level III. PMID- 29766069 TI - Pre-emptive administration of fibrinogen concentrate contributes to improved prognosis in patients with severe trauma. AB - Background: Patients with severe trauma often present with critical coagulopathy, resulting in impaired hemostasis, massive hemorrhage, and a poor survival prognosis. The efficacy of hemostatic resuscitation in correcting coagulopathy and restoring tissue perfusion has not been studied. We assessed a novel approach of pre-emptive administration of fibrinogen concentrate to improve critical coagulopathy in patients with severe trauma. Methods: We retrospectively compared blood transfusion volumes and survival prognosis between three groups of patients with trauma, with an Injury Severity Score (ISS) >=26 over three consecutive periods: group A, no administration of fibrinogen concentrate; group B, administration of 3 g of fibrinogen concentrate after evaluation of trauma severity and a plasma fibrinogen level <1.5 g/L; group C, pre-emptive administration of 3 g of fibrinogen concentrate immediately on patient arrival based on prehospital information, including high-severity injury or assessed need for massive transfusion before measurement of fibrinogen. Results: ~56% of patients with an ISS >=26 and transfused with red blood cell concentrates >=10 units, had hypofibrinogenemia (fibrinogen <1.5 g/L) on arrival. Patients who received fibrinogen concentrate in group C showed significantly higher fibrinogen levels after treatment with this agent than those in group B (2.41 g/L vs 1.88 g/L; p=0.01). Although no significant difference was observed in blood transfusion volumes between the groups, the 30-day survival of patients in group C (all, and those with an ISS >=26) was significantly better than in group A (p<0.05). The 48-hour mortality rate in patients with an ISS >=26 was significantly lower in group C than in group A (8.6% vs 22.9%; p=0.005). Further, among patients with an ISS >=41, the overall mortality was significantly lower in group C than in group A (20% vs 50%; p=0.02). Conclusion: Pre-emptive administration of fibrinogen concentrate for patients with trauma with critical coagulopathy may contribute to improved survival. Level of evidence: Level IV. PMID- 29766071 TI - Case of intracranial penetration of a metallic pipe through the orbit. PMID- 29766070 TI - Vasopressin analog terlipressin attenuates kidney injury in hemorrhagic shock. AB - Background: In hemorrhagic shock (HS), volume replacement with crystalloid solution can restore the hemodynamic status and decrease mortality. However, it can also lead to tissue edema and pulmonary congestion, as well as increasing vascular permeability. Here, we analyzed the effects that resuscitation with lactated Ringer's solution (LRS) or administration of the vasopressin analog terlipressin has on renal function in a porcine model of HS. Methods: Using pressure-controlled bleeding, we induced pigs to HS, maintaining mean arterial pressure (MAP) at 40 mm Hg for 30 min. Animals were divided into 4 groups: sham (anesthesia only); shock-only (HS induction); shock+LRS (HS induction and subsequent resuscitation with LRS at 3 times the volume of blood removed); and shock+Terli (HS induction and subsequent bolus administration of 2 mg of terlipressin). Parameters were evaluated at baseline, then at 30, 60, and 120 min after treatment (T30, T60, and T120, respectively). Animals were euthanized at T60 or T120. Results: Both treatments restored MAP to baseline values. At T30 and T60, creatinine clearance was highest in shock+LRS pigs, whereas it was highest in shock+Terli pigs at T120. Both treatments initially induced hyponatremia, although urinary excretion of all ions was higher in shock+LRS pigs at T30. Both treatments restored Na-K-2Cl cotransporter expression, whereas only terlipressin restored aquaporin 2 expression. Both treatments also prevented HS-induced acute tubular necrosis. Expression of the vasopressin receptors V1a and V2 was highest in shock-only pigs. At T120, V1a expression was lowest in shock+LRS pigs. Discussion: Terlipressin might be useful for preventing HS-induced acute kidney injury. PMID- 29766072 TI - Outcome of femoral fractures care as a measure of trauma care between level I and level II trauma systems in Israel. AB - Background: Our hypothesis in this study was that the outcome of patients with femur fractures would be favorable in a level I trauma center (LITC). Methods: A prospective multicenter cohort study. 5 LITC and 6 regional (level II) trauma centers (RTCs) were enrolled to participate in the study. A total of 238 patients suffering from a femoral fracture were recruited to the study. 125 patients were treated in LITCs and 113 in RTCs. Data were extracted from the emergency medical services ambulances, emergency department records, patient hospitalization and discharge records, operating room records, and the national trauma registry (for LITCs). A study questionnaire was administered to all participating patients at discharge, 6 weeks and 6 months postoperatively. The following parameters were studied: mechanism of injury, time from injury to the hospital, Injury Severity Score, classification of femoral fracture, additional injuries, medical history, time to surgery, implant type, skill level of the surgical team, type of anesthesia, length of stay and intensive care unit (ICU) stay, postoperative and intraoperative complications and mortality. Results: There was a significant difference in the modality of patient transfer between the 2 study groups-with the LITC receiving more patients transported by helicopters or medical intensive care. Time to surgery from admission was shorter in the LITC. Length of stay, ICU stay, and mortality were similar. In the LITCs, 47% of the procedures were performed by residents without the supervision of an attending surgeon, and in the RTCs 79% of the procedures were performed with an senior orthopaedic surgeon. Intraoperative and immediate complication rates were similar among the 2 groups. Conclusions: A femoral shaft fracture can be successfully treated in an LITC and RTC in the state of Israel. Both research and policy implementation works are required. Also, a more detailed outcome analysis and triage criteria for emergency are desired. Level of evidence: II. PMID- 29766073 TI - Novel method of delivery of continuous positive airway pressure for apnea testing during brain death evaluation. AB - Background: There are several methods for apnea testing for the evaluation of neurological death, including oxygen via T-piece, oxygen cannula inserted into the endotracheal tube, and continuous positive airway pressure (CPAP). Lung suitability for transplantation is determined in part by the partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2; P:F) ratio. We hypothesized that delivery of CPAP during apnea testing using a novel method would improve post-test P:F ratios. Methods: A retrospective review was performed at a level I trauma center for all patients undergoing apnea testing from 2010 to 2016. The CPAP system used a flow-inflating bag and was made available in 2012. It was used at the discretion of the clinician. Patients were classified as having an apnea test by CPAP or by non-CPAP method (T-piece, oxygen cannula in endotracheal tube, etc). The two groups were compared for baseline characteristics and the primary outcome of postapnea test P:F ratio. Results: During the study period, 145 patients underwent apnea testing; 67 patients by the CPAP method and 78 by non-CPAP method. There were no significant differences in demographics, mechanism of brain injury, pneumonia rate, smoking status, or antibiotic usage between the two groups. The pretest P:F ratio was similar between groups, but the CPAP group had significantly higher post-test P:F ratio (304 vs 250, p=0.02). There were no reported complications arising from CPAP use. Conclusions: We describe a novel method of delivering CPAP by a flow-inflating bag during examination for brain death. This method led to improved oxygenation, P:F ratios, and may decrease barotrauma. The flow-inflating bag was inexpensive, easily implemented, and without adverse effects. Multicentered, prospective trials are needed to elicit significant benefit in lung donation and transplantation. Level of evidence: Level IV, diagnostic tests. PMID- 29766074 TI - Risk factors for extubation failure at a level I trauma center: does the specialty of the intensivist matter? AB - Introduction: Extubation failure in critically ill patients is associated with higher morbidity and mortality. Although predictors of failed extubation have been previously determined in intensive care unit (ICU) cohorts, relatively less attention has been directed toward this issue in patients with trauma. The aim of this study was to identify predictors of extubation failure among patients with trauma in a multidisciplinary ICU setting. Methods: A prospective observational study of extubation failures (EF) was conducted at an American College of Surgeons level I trauma center over 3 years (2011-2013). Case-control patients (CC) were then compared with the study group (EF) with respect to demographic/clinical characteristics and outcomes. Failure of extubation was defined as reintubation within 72 hours following planned extubation. Results: 7830 patients were admitted to the trauma service and 1098 (14%) underwent mechanical ventilation. 63 patients met inclusion criteria for the EF group and 63 comprised the CC group. The overall rate of extubation failure was 5.7% and mean time to reintubation was 13.0 hours. Groups (EF vs CC) were similar for Injury Severity Score (21 vs 21), Glasgow Coma Scale at extubation (11 vs 10), number of comorbidities (1.5 vs 1.7), injury mechanism (blunt 79% vs 74%), and body mass index (27.9 vs 27.2). In addition, groups were similar with respect to weaning protocol compliance (84% vs 89%, p=0.57). EF group had significantly increased ICU length of stay (LOS) (15.7 vs 7.4 days, p<0.001), ventilator days (13.3 vs 4.8, p<0.001), and mortality (9.5% vs 0%, p=0.03). Multiple regression analysis identified that EF was associated with increased odds of: (1) temperature >38 degrees C at time of extubation (OR 5.9, 95% CI 1.7 to 20.8), and (2) non-surgeon intensivist consultation (OR 24.2, 95% CI 5.5 to 105.9). Conclusions: Extubation failure is associated with increased LOS, ventilator days, and mortality in patients with trauma. Fever at time of extubation is associated with extubation failure, and the presence of such should give pause in the decision to extubate. Non-surgeon intensivist involvement increases risk of extubation failure, and a surgical critical care service may be most appropriate for the management of ventilated patients with trauma. Level of evidence: III, Prognostic and epidemiological. PMID- 29766075 TI - Surgical intensivist and global critical care: is there a role? PMID- 29766076 TI - Management of diaphyseal tibial fractures by plate fixation with absolute or relative stability: a retrospective study of 45 patients. AB - Background: Fixation of diaphyseal tibial fractures by plates is not considered the best option due to complications that may eventually arise; however, if principles of stability and proper surgical techniques are used, it is possible to obtain fracture consolidation without major risks. Methods: We conducted a cross-sectional observational descriptive study by retrospectively analyzing medical records of patients with diaphyseal tibial fractures that were treated with plates from the period between June 2011 and June 2014 at San Jose and Susana Lopez Hospitals in the city of Popayan, Colombia. 3 treatment groups were created and analyzed according to the type of fracture (Association Osteosynthesis/Osteosynthesis Trauma Association AO/OTA): group I: simple fractures 42A/B, absolute stability; group II: simple fractures 42A/B, Minimally Invasive Plate Osteosynthesis (MIPO) technique, relative stability; group III: multifragmentary fractures 42C, MIPO technique, relative stability. A descriptive analysis of patients, fracture consolidation time, and complications in each group were performed. Results: 45 patients with tibial fractures treated with osteosynthesis plates were analyzed. Group I: 14 patients, 42A (n=13) and 42B (n=1), had an average consolidation time of 16.38 (SD=1.98) and 14 weeks, respectively. In group II: 19 patients, out of which 18 achieved fracture consolidation (42A n=15 and 42B n=3) with an average time of 17.4 (SD=3.33) and 17.3 weeks (SD=6.11), respectively. Finally, in group III: 12 patients all with 42C fractures with a consolidation time of 16.86 (SD=2.93) weeks. The average fracture consolidation time for all 44 patients was 16.86 weeks (SD 2.93). Conclusions: Osteosynthesis plates are an alternative to intramedullary nailing for diaphyseal tibial fractures and their outcomes can be favorable as long as the management of soft tissues and the proper principle of stability are taken into account. Level of evidence: IV. PMID- 29766077 TI - Impact thromboelastometry (ITEM) for point-of-injury detection of trauma-induced coagulopathy: a pilot study. AB - Background: Acute coagulopathy of trauma is associated with high mortality and extensive use of blood products. Hemostatic resuscitation, the early administration of blood products with higher ratios of procoagulant components, may improve trauma outcomes in select cases, but can also worsen outcome if inappropriately used. Evolving approaches to hemostatic resuscitation utilize viscoelastic tests to provide a more rational basis for choosing blood component therapy regimens, but these tests are logistically rigorous. We hypothesized that coagulopathy could be detected by the failure of blood clots to remain intact when subjected to a predefined impact force. Methods: We aim to develop a point of-injury test for coagulopathy. We created coagulopathic blood using an ex vivo normal saline (NS) dilution model and allowed blood of varying dilutions to clot, then examined the behavior of the clotted blood when subjected to a uniform gravitationally induced sheer force. Results: Clots created from coagulopatic blood (diluted to <=50% with NS) failed under gravitational challenge at a significantly higher rate than non-coagulopathic blood dilutions. Discussion: Impact thromboelastometry (ITEM) represents a simple, logistically lean method for detecting dilutional coagulopathy that may facilitate detection of trauma induced coagulopathy. ITEM may thus function as a point-of-injury or point-of care screening test for the presence of coagulopathy. Level of evidence: Diagnostic studies, Level IV. PMID- 29766078 TI - Prehospital tranexamic acid: what is the current evidence? AB - Many trauma systems are examining whether to implement prehospital tranexamic acid (TXA) protocols since hemorrhage remains the leading cause of potentially preventable early trauma mortality, and early in-hospital administration of TXA within 3 hours of injury is associated with reduced mortality. But robust evidence regarding the efficacy of prehospital administration of the antifibrinolytic drug TXA on trauma outcomes is lacking. This review examines the current evidence available regarding prehospital TXA efficacy in both military and civilian trauma, and updates available evidence regarding in-hospital TXA efficacy in trauma. PMID- 29766079 TI - Rib fixation: Who, What, When? AB - Rib fractures are among the most common traumatic injury found in ~20% of all patients who suffer thoracic trauma. The majority of these are a result of a blunt mechanism and are often associated with other traumatic injuries. The most common associated injury is lung contusion. Rib fractures impart an increased morbidity and mortality with the highest mortality associated with a flail chest in the elderly population. Flail chest is defined radiographically as 3 or more consecutive ribs fractured in 2 or more places. This often translates to a clinical flail which is associated with paradoxical chest wall movement during respiratory cycles. The mainstay of treatment has been pain control and respiratory support with positive pressure ventilation. However, over the past 2 decades, there has been mounting evidence to suggest that open reduction and internal fixation of ribs benefits patients. The indications remain confined to the most severely injured patients with flail chest or chronic non-unions; however, there remains debate whether or not less severely injured patients would benefit as well. This article will review the current evidence and provide proposed indications based on available evidence and current expert opinion. PMID- 29766082 TI - Trauma advanced practice provider programme development in an academic setting to optimize care coordination. AB - Background: Benchmark data from the Trauma Quality Improvement Program (TQIP) identified an opportunity for improvement in our trauma programme. Our unexpected return to the intensive care unit (ICU) was found to be higher than the national averages and we also noticed that our readmission rate had increased. We chose to address these complications as continuous quality improvement projects. It was hypothesized that restructuring the workflow of the trauma advanced practice providers (APPs) to focus on the delivery of comprehensive clinical care would decrease return to ICU and readmission rates of trauma patients. Methods: The development of the APP programme occurred from 2012 to 2014. First, APP daily shifts were extended to mirror the resident physicians' coverage. Second, the APPs' original job description was expanded from 'task-oriented' workflow to providing comprehensive clinical care. Third, the APPs were involved in the evaluation and decision-making process for transferring trauma patients from the ICU. Finally, the APPs implemented a new discharge process that included all information in a standardized format and a follow-up phone call 24-48 hours after discharge. The trauma registry at our verified, academic level I trauma center was use to assess our ICU and hospital readmission rates during the time we instituted the new APP workflow programme. Results: In 2012, our ICU readmission rate was 5.7% (TQIP=1.9%) but then decreased to 4.4% in 2013 (TQIP=2.5%) and 2.1% in 2014 (TQIP=2.8%). Our hospital readmission rate was 2.0% in 2012 but then decreased to 1.38% and 0.96% over the next 2 years. Conclusions: After extending the APP service coverage, implementing a comprehensive clinical care model and standardizing the discharge process, our unplanned return to ICU rates have decreased to below the TQIP national average and hospital readmission rates have also decreased by half. Level of evidence: III. PMID- 29766081 TI - Comprehensive approach to the management of the patient with multiple rib fractures: a review and introduction of a bundled rib fracture management protocol. AB - Rib fractures are common among patients sustaining blunt trauma, and are markers of severe bodily and solid organ injury. They are associated with high morbidity and mortality, including multiple pulmonary complications, and can lead to chronic pain and disability. Clinical and radiographic scoring systems have been developed at several institutions to predict risk of complications. Clinical strategies to reduce morbidity have been studied, including multimodal pain management, catheter-based analgesia, pulmonary hygiene, and operative stabilization. In this article, we review risk factors for morbidity and complications, intervention strategies, and discuss experience with bundled clinical pathways for rib fractures. In addition, we introduce the multidisciplinary rib fracture management protocol used at our level I trauma center. PMID- 29766083 TI - Prognostic predictors of early mortality from exsanguination in adult trauma: a Malaysian trauma center experience. AB - Background: Trauma mortality due to exsanguination is the second most common cause of death. The objective of this study is to investigate the predictors for early death from exsanguination. Methods: A prognostic study was done to identify predictors of early mortality due to exsanguination. Data were extracted from our Trauma Surgery Registry database of Sultanah Aminah Hospital, Johor Bahru, Malaysia. All patients who were treated from May 1, 2011 to April 31, 2014 by the trauma team were included. Adult trauma patients included from the Trauma Surgery Registry were divided into two groups for analysis: early death from exsanguination and death from non-exsanguination/survivors. Univariate and multivariate analysis was performed to look for significant predictors of death from exsanguination. Variables analyzed were demography, mechanism of injury, organ injury scale, physiological parameters (systolic blood pressure (SBP), respiratory rate, heart rate, temperature), Glasgow Coma Scale (GCS), Revised Trauma Score (RTS), New Injury Severity Score (NISS), Trauma and Injury Severity Score (TRISS) and cause of death. Results: A total of 2208 patients with an average age of 36 (+/-16) years were included. Blunt trauma was the majority with 90.5%, followed by penetrating injuries (9.2%). The overall mortality is 239 out of 2208 (10.8%). Seventy-eight patients (32.6%) died due to central nervous system injury, 69 due to sepsis (28.9%) and 58 due to exsanguination (24.3%). After multivariate analysis, age (OR 1.026 (1.009 to 1.044), p=0.002), SBP (OR 0.985 (0.975 to 0.995), p=0.003) and temperature (OR 0.203 (0.076 to 0.543), p=0.001) were found to be the significant physiological parameters. Intra abdominal injury and NISS were significant anatomic mortality predictors from exsanguination (p<0.001). Patients with intra-abdominal injury had four times higher risk of mortality from exsanguination (OR 3.948 (2.331 to 6.686), p<0.001). Discussion: In a Malaysian trauma center, age, SBP, core body temperature, intra-abdominal injury and NISS were significant predictors of early death from exsanguination. Level of evidence: II. PMID- 29766084 TI - Effects of mechanism of injury and patient age on outcomes in geriatric rib fracture patients. AB - Background: Patients older than 65 years have 2-5 times higher mortality if they sustain >=2 rib fractures compared to younger adults. As a result, our level I trauma center guidelines suggest that older adults with rib fractures be admitted to the intensive care unit for the first 24 hours. In this study, we evaluated the outcomes associated with these guidelines. Methods: We retrospectively reviewed all patients aged >=65 years in our Trauma Registry who sustained rib fractures from January 2008 to March 2015. Data included demographics, comorbidities, injuries, length of intensive care and hospital stay (LOS), ventilator days, analgesic used, morbidity, mortality, and disposition. Results: 97 patients aged >=65 years with at least one rib fracture and an Abbreviated Injury Score of <=2 for other regions were admitted. Falls caused 58% of the injuries, while motor vehicle collisions (MVC) accounted for 33%. Overall mortality was 4%. Patients who fell had a median hospital LOS that was 0.5 to 1 day longer than in those who suffered other mechanisms of injury or were involved in an MVC respectively. Patients aged >=70 years had a median LOS of 4 days, twice that of those aged 65 to 69 years. Of the 87 patients with more than one rib fracture, 59 (68%) were not admitted directly to the intensive care unit (ICU) from the emergency department as recommended by our guidelines. 6 of these 59 patients (9%) were later transferred to the ICU and 2 of these patients expired. Conclusions: Although overall compliance with the geriatric rib fracture guideline was low, both mortality and hospital LOS were low in this group. This suggests that the guideline could be modified to reduce ICU resource usage without compromising patient outcomes. Level of evidence: Level III, retrospective cohort study. PMID- 29766086 TI - Advocacy efforts in trauma and acute care surgery: learning to walk. PMID- 29766085 TI - An update on nonoperative management of the spleen in adults. AB - Many patients with blunt splenic injury are considered for nonoperative management and, with proper selection, the success rate is high. This paper aims to provide an update on the treatments and dilemmas of nonoperative management of splenic injuries in adults and to offer suggestions that may improve both consensus and patient outcomes. PMID- 29766080 TI - Open abdomen critical care management principles: resuscitation, fluid balance, nutrition, and ventilator management. AB - The term "open abdomen" refers to a surgically created defect in the abdominal wall that exposes abdominal viscera. Leaving an abdominal cavity temporarily open has been well described for several indications, including damage control surgery and abdominal compartment syndrome. Although beneficial in certain patients, the act of keeping an abdominal cavity open has physiologic repercussions that must be recognized and managed during postoperative care. This review article describes these issues and provides guidelines for the critical care physician managing a patient with an open abdomen. PMID- 29766087 TI - Damage control laparotomy trial: design, rationale and implementation of a randomized controlled trial. AB - Background: Damage control laparotomy (DCL) is an abbreviated operation intended to prevent the development of hypothermia, acidosis, and coagulopathy in seriously injured patients. The indications for DCL have since been broadened with no high-quality data to guide treatment. For patients with an indication for DCL, we aim to determine the effect of definitive laparotomy on patient morbidity. Method: This is a pragmatic, parallel-group, randomized controlled pilot trial. Emergent laparotomy is defined as admission directly to the operating room from the emergency department within 90 min of arrival. DCL indications excluded from the study include packing of the liver or retroperitoneum, abdominal compartment syndrome prophylaxis, to expedite interventional radiology for hemorrhage control, and the need for ongoing transfusions and/or continuous vasopressor support. When a surgeon determines a DCL is indicated, the patient will be screened for inclusion and exclusion criteria. Patients with any indication for DCL that is not excluded are eligible for randomization. Patients will be randomized intraoperatively to DCL (control) or definitive fascial closure of the laparotomy (intervention). The primary outcome will be major abdominal complication or death within 30 days. Major abdominal complication is a composite outcome including fascial dehiscence, organ/space surgical site infection, enteric suture line failure, and unplanned reopening of the abdomen. Outcomes will be compared using both frequentist and Bayesian statistics. Discussion: In patients with an indication for DCL, this trial will determine the effect of definitive laparotomy on major abdominal complications and death and will inform clinicians on the risks and benefits of this procedure. Regardless of the study outcome, the results will improve the quality of care provided to injured patients. Trial registration number: NCT02706041. PMID- 29766088 TI - Protecting study participants in emergency research: is community consultation before trial commencement enough? AB - Background: This article presents the results of a community consultation (CC) process completed in Toronto, Ontario, using a random digit dialling technique, on the attitudes and perceptions of the public toward the use of exception from informed consent when conducting emergency research involving the use of massive blood transfusions. Methods: In 2012, our hospital conducted a CC, using a random digit dialling technique, to elicit the attitudes and perceptions of the public toward the use of an exemption from informed consent for an upcoming clinical trial. A total of 500 participants from high violent crime areas were interviewed as part of this consultation. Results: The response rate for the telephone survey was 54%. Participants indicated a personal acceptance rate of 76%, acceptance of the justification for the exception to consent at 81%, thatthe study would meet the best interest of patients and the community at 81% and that youth (between 15 and 18 years) could be enrolled at 71%. When offered, no participant requested an opt-out wrist band to avoid being enrolled in this study. Discussion: The use of violent crime neighborhoods to locate at risk communities was not effective in identifying the appropriate community of interest for this study. Though only representing a small subpopulation from a large Canadian city, the attitudes noted here is suggestive that Canadians may have a similar level of acceptance as the US based on published studies. However, given the resources needed to undertake this process and that in the end it did not elicit any useful feedback or recommendations for enhancing the safety of participants, the future use of phone surveys as a means of engaging communities should be reconsidered. Level of evidence Level V: This is a retrospective subanalysis of a CC using a randomized phone dialling technique from a site prior to the start of the Pragmatic Randomized Optimal Platelet and Plasma Ratios Trial. The CC was not designed specifically for research purposes and as such reflect only a case study from a single center. Trial registration number: Pre-result, NCT01545232. PMID- 29766089 TI - Staying connected: Service-specific orientation can be successfully achieved using a mobile application for onboarding care providers. AB - Communicating service-specific practice patterns, guidelines, and provider information to a new team of learners that rotate frequently can be challenging. Leveraging individual and healthcare electronic resources, a mobile device platform was implemented into a newly revised resident onboarding process. We hypothesized that offering an easy-to-use mobile application would improve communication across multiple disciplines as well as improve provider experiences when transitioning to a new rotation. A mobile platform was created and deployed to assist with enhancing communication within a trauma service and its resident onboarding process. The platform had resource materials such as: divisional policies, Clinical Practice Guidelines (CMGs), and onboarding manuals along with allowing for the posting of divisional events, a divisional directory that linked to direct dialing, text or email messaging, as well as on-call schedules. A mixed methods study, including an anonymous survey, aimed at providing information on team member's impressions and usage of the mobile application was performed. Usage statistics over a 3-month period were analyzed on those providers who completed the survey. After rotation on the trauma service, trainees were asked to complete an anonymous, online survey addressing both the experience with, as well as the utility of, the mobile app. Thirty of the 37 (81%) residents and medical students completed the survey. Twenty-five (83%) trainees stated that this was their first experience rotating on the trauma service and 6 (20%) were from outside of the health system. According to those surveyed, the most useful function of the app were access to the directory (15, 50%), the divisional calendar (4, 13.3%), and the on-call schedules (3, 10%). Overall, the app was felt to be easy to use (27, 90%) and was accessed an average of 7 times per day (1-50, SD 9.67). Over half the survey respondents felt that the mobile app was helpful in completing their everyday tasks (16, 53.3%). Fifteen (50%) of the respondents stated that the app made the transition to the trauma service easier. Twenty-five (83.3%) stated it was valuable knowing about departmental events and announcements, and 17 (56.7%) felt more connected to the division. The evolution of mobile technology is rapidly becoming fundamental in medical education and training. We found that integrating a service-specific mobile application improved the learner's experience when transitioning to a new service and was a valuable onboarding instrument. Level of evidence IV. PMID- 29766091 TI - Update in sepsis guidelines: what is really new? AB - Sepsis remains a highly lethal entity resulting in more than 200 000 deaths in the USA each year. The in-hospital mortality approaches 30% despite advances in critical care during the last several decades. The direct health care costs in the USA exceed $24 billion dollars annually and continue to escalate each year especially as the population ages. The Surviving Sepsis Campaign published their initial clinical practice guidelines for the management of severe sepsis and septic shock in 2004. Updated versions were published in 2008, 2012 and most recently in 2016 following the convening of the Third International Consensus Definitions Task Force. This task force was convened by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine to address prior criticisms of the multiple definitions used clinically for sepsis-related illnesses. In the 2016 guidelines, sepsis is redefined by the taskforce as a life threatening organ dysfunction caused by a dysregulated host response to infection. In addition to using the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score to more rapidly identify patients with sepsis, the task force also proposed a novel scoring system to rapidly screen for patients outside the ICU who are at risk of developing sepsis: the 'quickSOFA' (qSOFA) score. To date, the largest reductions in mortality have been associated with early identification of sepsis, initiation of a 3-hour care bundle and rapid administration of broad-spectrum antibiotics. The lack of progress in mortality reduction in sepsis treatment despite extraordinary investment of research resources underscores the variability in patients with sepsis. No single solution is likely to be universally beneficial, and sepsis continues to be an entity that should receive high priority for the development of precision health approaches for treatment. PMID- 29766092 TI - Defining burden and severity of disease for emergency general surgery. AB - As general surgery trainees continue to enter specialty practice at a high rate, fewer and fewer are caring for emergency general surgery (EGS) patients. Thus EGS has become one of the cornerstones of the practice of acute care surgery. With the centralization of this area of surgical care in many areas of the country, a clear understanding of the issues associated with this becomes vital. Understanding the public health implications with respect to burden of care and cost will allow for appropriate planning and resource allocation in the future. In addition, the development of validated severity modeling will help with risk stratification in future study of these diseases. PMID- 29766090 TI - Impact of circle of Willis anatomy in traumatic blunt cerebrovascular injury related stroke. AB - Background: Cerebral vascular anatomy, specifically the circle of Willis (COW), plays an unstudied role in the development of stroke after blunt cerebrovascular injury (BCVI; carotid and vertebral). Variant anatomy is very common, and certain variants such as persistent fetal circulation (enlarged posterior communicating artery) may improve collateralization between the anterior (carotid) and posterior (vertebral) circulations. Identifying patients at increased stroke risk may allow tailored anticoagulation, the mainstay of therapy. This study constitutes the first attempt to identify vascular anatomy patterns associated with stroke, with the hypothesis that normal anatomy would protect against stroke. Study design: Radiographic images from patients with BCVI-related stroke from 2005 to 2014 were identified. Patients with stroke were compared with injury matched, non-stroke controls. Normal COW anatomy is defined as the presence of all vessels without hypoplasia. Results: Of 457 patients BCVI, 22 (4.8%) BCVI related patients with stroke and matched controls were reviewed. 9 (41%) patients with stroke and 2 (9%) controls had normal COW anatomy (OR=7.1, 95% CI 1.28 to 33.3). Persistent fetal-type circulation was found in 6 controls and 1 patient with stroke, resulting in a 7.9-fold decreased risk of stroke with this variant (OR=0.13, 95% CI 0.003 to 1.26). Conclusions: Cerebral vascular anatomy has a role in BCVI-related stroke. Normal anatomy is not protective; however, the increased collateral flow provided by a persistent fetal-type enlarged posterior communicating artery is likely protective. The identification of high-risk patients may eventually allow for more tailored treatment. Prospective, multi institutional trials are needed to further reduce the incidence BCVI-related stroke. Level of evidence: Prognostic and epidemiological, level III. PMID- 29766093 TI - The history of Harborview Medical Center and the Washington State Trauma System. AB - Harborview Medical Center serves as the sole adult and pediatric level I trauma center for Washington State, and its faculty have led efforts to develop comprehensive systems of trauma care across the country. The Washington State trauma system is an inclusive system that was developed based on data-driven decisions to distribute resources based on population need. This article seeks to explore the history of Harborview Medical Center and the development of the Washington State trauma system to identify the guiding principles and lessons learned, which can facilitate system development for a host of time-sensitive medical conditions. PMID- 29766095 TI - Lower extremity compartment syndrome. AB - Lower extremity compartment syndrome is a devastating complication if not rapidly diagnosed and properly managed. The classic symptoms of compartment syndrome can be deceiving as they occur late. Any concern for compartment syndrome based on mechanism, or the presence of pain in the affected extremity, should prompt a compartment pressure check. Both absolute compartment pressures above 30 mm Hg and a pressure differential of less than 30 mm Hg are used to make the diagnosis. The treatment goal is first to save the patient's life and second to salvage the affected limb. Fasciotomy is the only accepted treatment of compartment syndrome and should be performed quickly after the diagnosis is made. Outcomes after fasciotomy are best when there is no delay in treatment. PMID- 29766096 TI - Specialization in acute care surgery in low-income and middle-income countries. AB - Traumatic injuries represent the highest portion of surgical conditions worldwide, and the groups most vulnerable to these injuries are disproportionately in low-income and middle-income countries (LMICs). It is in this context that we recognize and propose an urgent opportunity for developing and strengthening the field of acute care surgery (ACS) in LMICs. In this article, we will briefly review the history and advantages of ACS as a specialty and recognize the unique opportunity and benefit it may have in LMICs. PMID- 29766094 TI - Evolution of the operative management of colon trauma. AB - For any trauma surgeon, colon wounds remain a relatively common, yet sometimes challenging, clinical problem. Evolution in operative technique and improvements in antimicrobial therapy during the past two centuries have brought remarkable improvements in both morbidity and mortality after injury to the colon. Much of the early progress in management and patient survival after colon trauma evolved from wartime experience. Multiple evidence-based studies during the last several decades have allowed for more aggressive management, with most wounds undergoing primary repair or resection and anastomosis with an acceptably low suture line failure rate. Despite the abundance of quality evidence regarding management of colon trauma obtained from both military and civilian experience, there remains some debate among institutions regarding management of specific injuries. This is especially true with respect to destructive wounds, injuries to the left colon, blunt colon trauma and those wounds requiring colonic discontinuity during an abbreviated laparotomy. Some programs have developed data-driven protocols that have simplified management of destructive colon wounds, clearly identifying those high-risk patients who should undergo diversion, regardless of mechanism or anatomic location. This update will describe the progression in the approach to colon injuries through history while providing a current review of the literature regarding management of the more controversial wounds. PMID- 29766098 TI - REBOA in hemorrhagic shock: a unique non-responder? PMID- 29766097 TI - Identifying chronic heavy alcohol use in emergency general surgery patients: a pilot study. AB - Background: Chronic heavy alcohol (CHA) use has been associated with perioperative complications. Emergency general surgery (EGS) patients are not routinely screened for CHA. If screened, it is usually for hazardous use of alcohol, using a survey such as the Alcohol Use Disorders Identification Test (AUDIT). This study screened EGS patients for CHA use using serum carbohydrate deficient transferrin (%dCDT) level, a biomarker that has been validated as an indicator for CHA use, as well as the AUDIT. The purpose of this study was to determine the percent of EGS patients with CHA (as indicated by elevated %dCDT), and the relationship between %dCDT and AUDIT. Secondary aims included comparing the characteristics of EGS patients with and without CHA use, and evaluating the association of CHA use with negative clinical outcomes. Methods: EGS patients aged 21 and older admitted to the general surgery inpatient service of a tertiary hospital from July 2014 to June 2016 were invited to participate in this study. %dCDT levels above 1.7% were considered positive for CHA use, as were AUDIT scores >=8. Results: 195 EGS patients were screened for inclusion and 91 (46.7%) agreed to participate. 14 (15.4%) were positive for hazardous alcohol use on AUDIT and 5 (5.5%) were positive for CHA by %dCDT. Positive predictive value of AUDIT for CHA was 21.4%. There was no correlation between positive scores on AUDIT and %dCDT. Discussion: Identifying at risk patients early on in their hospital course may allow clinicians to institute treatments to mitigate and/or circumvent complications in such patients. This pilot study determined that 17.6% of participating EGS patients were positive for some type of alcohol misuse, but only 5.5% had CHA. Further research is needed to determine whether routine use of %dCDT would be beneficial in reducing perioperative complications in this patient population. Level of evidence: III (diagnostic test). PMID- 29766099 TI - CT scan incidental findings in trauma patients: does it impact hospital length of stay? AB - Background: CT scans are heavily relied on for assessment of solid organ injuries complementing clinical examination. These CT scans could also reveal pathologies not related to trauma called incidental findings. We aimed to evaluate the frequency of these findings and their outcome on hospital services. Methods: A retrospective chart review of prospectively collected data of the emergency department's trauma database from January 2005 to December 2011 to evaluate incidental findings on CT scans on trauma admissions. These incidental findings were divided into three classes: class 1-minor degenerative, non-degenerative, normal variants or congenital finding that does not require further investigation or workup; class 2-findings not requiring urgent intervention with scheduled outpatient follow-up and class 3-all findings that require urgent evaluation/further investigation during the same hospital admission. One-year follow-up was done to review hospital length of stay, trauma clinic follow-up and post-trauma surgery. Results: Of 1000 charts reviewed, 957 were selected after 43 patients were excluded due to incomplete documentation. Of the 957 patients, 385 (40%) were found to have incidental findings. A total of 560 incidental findings were found on the CT scan reports with one-third of patients having multiple findings (144 patients, 37.4%). The largest number of incidental findings were in class 2. The incidental group had significantly longer length of stay after adjusted multivariate analysis (8.7+/-0.48 vs 6.7+/-0.55, p=0.005). Conclusion: The incidental findings are commonly found during CT imaging in trauma centers and our rate was 40%. Appropriate documentation, communication and follow-up of those findings is necessary. A classification system for these findings practiced nationwide will aid in categorizing the urgency of continued follow-up. This also will help decrease the length of hospital stay and healthcare cost. Level of evidence: Level 4. PMID- 29766101 TI - Methodology to reliably measure preventable trauma death rate. AB - This article describes a methodology to establish a trauma preventable death rate (PDR) in a densely populated county in the USA. Harris County has >4 million residents, encompasses a geographic area of 1777 square miles and includes the City of Houston, Texas. Although attempts have been made to address a national PDR, these studies had significant methodological flaws. There is no national consensus among varying groups of clinicians for defining preventability or documenting methods by which preventability is determined. Furthermore, although trauma centers routinely evaluate deaths within their hospital for preventability, few centers compare across regions, within the prehospital arena and even fewer have evaluated trauma deaths at non-trauma centers. Comprehensive population-based data on all trauma deaths within a defined region would provide a framework for effective prevention and intervention efforts at the regional and national levels. The authors adapted a military method recently used in Southwest Asia to determine the potential preventability of civilian trauma deaths occurring across a large and diverse population. The project design will allow a data-driven approach to improve services across the entire spectrum of trauma care, from prevention through rehabilitation. PMID- 29766100 TI - Trauma resource designation: an innovative approach to improving trauma system overtriage. AB - Background: Effective triage of injured patients is often a balancing act for trauma systems. As healthcare reimbursements continue to decline,1 innovative programs to effectively use hospital resources are essential in maintaining a viable trauma system. The objective of this pilot intervention was to evaluate a new triage model using 'trauma resource' (TR) as a new category in our existing Tiered Trauma Team Activation (TA) approach with hopes of decreasing charges without adversely affecting patient outcome. Methods: Patients at one Level II Trauma Center (TC) over seven months were studied. Patients not meeting American College of Surgeons criteria for TA were assigned as TR and transported to a designated TC for expedited emergency department (ED) evaluation. Such patients were immediately assessed by a trauma nurse, ED nurse, and board-certified ED physician. Diagnostic studies were ordered, and the trauma surgeon (TS) was consulted as needed. Demographics, injury mechanism, time to physician evaluation, time to CT scan, time to disposition, hospital length of stay (LOS), and in-hospital mortality were analyzed. Results: Fifty-two of the 318 TR patients were admitted by the TS and were similar to TA patients (N=684) with regard to gender, mean Injury Severity Score, mean LOS and in-hospital mortality, but were older (60.4 vs 47.2 years, p<0.0001) and often involved in a fall injury (52% vs 35%, p=0.0170). TR patients had increased door to physician evaluation times (11.5 vs 0.4 minutes, p<0.0001) and increased door to CT times (76.2 vs 25.9 minutes, p<0.0001). Of the 313 TR patients, 52 incurred charges totaling US$253 708 compared with US$1 041 612 if patients had been classified as TA. Conclusions: Designating patients as TR prehospital with expedited evaluation by an ED physician and early TS consultation resulted in reduced use of resources and lower hospital charges without increase in LOS, time to disposition or in hospital mortality. Level of evidence: Level II. PMID- 29766102 TI - Antifibrinolytics in a rural trauma state: assessing the opportunities. AB - Background: Tranexamic acid (TXA) has demonstrated improved mortality among trauma patients. However, recent evidence from urban US trauma centers has failed to show a benefit among the civilian population. TXA in rural states has not been evaluated. This study aimed to evaluate the current use of TXA in the rural trauma population. Methods: A retrospective observational review at a level 1 trauma center based in a rural environment. Records were reviewed for TXA indications. TXA indication was defined as: systolic blood pressure <90 mm Hg, blood transfusion, or with a clinical concern for ongoing bleeding. Patients were ineligible if the time since injury was >3 hours. Results: 400 patients were evaluated. 54% of patients met indications for TXA. 14% of these received TXA. 30.4% with an indication for TXA were ineligible due to arrival beyond 3 hours from time of injury. 135 patients arrived as transfers, 265 from the scene. There was no difference in TXA indications between scene and transfers (73 vs 144, p=1). Transfers were more likely to arrive beyond the 3-hour window (59 vs 7, p=0.001). Mortality for patients treated with TXA was 12.5%. This was not significantly different from patients not treated with TXA (19%). Discussion: In a rural system, long transfers exclude most patients from treatment with TXA. A multicenter rural trauma center study will be needed to better define the optimal use of TXA in rural populations. Level of evidence: Level IV data: therapeutic/care management. PMID- 29766103 TI - Characterizing the gut microbiome in trauma: significant changes in microbial diversity occur early after severe injury. AB - Background: Recent studies have demonstrated the vital influence of commensal microbial communities on human health. The central role of the gut in the response to injury is well described; however, no prior studies have used culture independent profiling techniques to characterize the gut microbiome after severe trauma. We hypothesized that in critically injured patients, the gut microbiome would undergo significant compositional changes in the first 72 hours after injury. Methods: Trauma stool samples were prospectively collected via digital rectal examination at the time of presentation (0 hour). Patients admitted to the intensive care unit (n=12) had additional stool samples collected at 24 hours and/or 72 hours. Uninjured patients served as controls (n=10). DNA was extracted from stool samples and 16S rRNA-targeted PCR amplification was performed; amplicons were sequenced and binned into operational taxonomic units (OTUs; 97% sequence similarity). Diversity was analyzed using principle coordinates analyses, and negative binomial regression was used to determine significantly enriched OTUs. Results: Critically injured patients had a median Injury Severity Score of 27 and suffered polytrauma. At baseline (0 hour), there were no detectable differences in gut microbial community diversity between injured and uninjured patients. Injured patients developed changes in gut microbiome composition within 72 hours, characterized by significant alterations in phylogenetic composition and taxon relative abundance. Members of the bacterial orders Bacteroidales, Fusobacteriales and Verrucomicrobiales were depleted during 72 hours, whereas Clostridiales and Enterococcus members enriched significantly. Discussion: In this initial study of the gut microbiome after trauma, we demonstrate that significant changes in phylogenetic composition and relative abundance occur in the first 72 hours after injury. This rapid change in intestinal microbiota represents a critical phenomenon that may influence outcomes after severe trauma. A better understanding of the nature of these postinjury changes may lead to the ability to intervene in otherwise pathological clinical trajectories. Level of evidence: III. Study type: Prognostic/epidemiological. PMID- 29766104 TI - Correlating abdominal pain and intra-abdominal injury in patients with blunt abdominal trauma. AB - Background: A thorough history and physical examination in patients with blunt abdominal trauma (BAT) is important to safely exclude clinically significant intra-abdominal injury (IAI). We seek to evaluate a correlation between self reported abdominal pain, abdominal tenderness on examination and IAI discovered on CT or during exploratory laparotomy. Methods: This retrospective analysis assessed patients with BAT >=13 years old who arrived to the emergency department following BAT during the 23-month study period. Upon arrival, the trauma team examined all patients. Only those who underwent an abdominal and pelvic CT scan were included. Patients were excluded if they were unable to communicate or lacked documentation, had obvious evidence of extra-abdominal distracting injuries, had a positive drug or alcohol screen, had a Glasgow Coma Scale <=13, or had a positive pregnancy screening. The primary objective was to assess the agreement between self-reported abdominal pain and abdominal tenderness on examination and IAI noted on CT or during exploratory laparotomy. Results: Among the 594 patients included in the final analysis, 73.1% (n=434) had no self reported abdominal pain, 64.0% (n=384) had no abdominal tenderness on examination, and 22.2% (n=132) had positive CT findings suggestive of IAI. Among the 352 patients who had no self-reported abdominal pain and no abdominal tenderness on examination, a significant number of positive CT scan results (14%, n=50) were still recorded. Furthermore, a small but clinically significant portion of these 50 patients underwent exploratory laparotomy (1.1%, n=4). All four of these patients ultimately underwent a splenectomy and all were completed on hospital day one. Conclusion: Lack of abdominal pain and tenderness in patients with BAT with non-distracting injuries was associated with a small portion of patients who underwent a splenectomy. Patients with BAT without abdominal pain or tenderness may need a period of observation or CT scan to rule out IAI prior to discharge home. Level of evidence: Level III, therapeutic/care management. PMID- 29766105 TI - Pitfalls in the management of peripheral vascular injuries. AB - Over the past 65+ years, most civilian peripheral vascular injuries have been managed by trauma surgeons with training or experience in vascular repair or ligation. This is appropriate as the in-hospital trauma team is immediately available, and there are often other injuries present in the victim. The pitfall to avoid during evaluation of the patient in the emergency center is a missed diagnosis. In the patient without 'hard' signs of a peripheral vascular injury, a careful history (bleeding), physical examination including measurement of ankle brachial (ABI) or brachial-brachial index and liberal use of CT arteriography depending on an ABI <0.9 should essentially make the diagnosis if an arterial injury is present. At operation, one pitfall is to limit skin preparation and draping, thereby eliminating the option of removing the greater saphenous vein if needed as a conduit from either the groin or ankle of an uninjured lower extremity. Another pitfall is to make a full longitudinal incision directly over a large pulsatile hematoma. Rather, separate shorter longitudinal incisions should be made to obtain proximal and distal vascular control before entering the hematoma. The failure to recognize patients who should be managed initially with insertion of a temporary intraluminal shunt is a major pitfall as well. Not following time-proven and results-proven 'fine techniques' of operative repair is another major pitfall. Such techniques include the following: use of small angioaccess vascular clamps or silastic vessel loops; passage of proximal and distal Fogarty catheters; administration of regional or systemic heparin during complex repairs; an open anastomosis technique; and completion arteriography after a complex arterial repair in a lower extremity. Avoiding pitfalls should allow for success in peripheral vascular repair, particularly since most patients are young with non-diseased vessels. PMID- 29766106 TI - Clinical indicators of hemorrhagic shock in pregnancy. AB - Background: Several hemodynamic parameters have been promoted to help establish a rapid diagnosis of hemorrhagic shock, but they have not been well validated in the pregnant population. In this study, we examined the association between three measures of shock and early blood transfusion requirements among pregnant trauma patients. Methods: This study included 81 pregnant trauma patients admitted to a level 1 trauma center (2010-2015). In separate logistic regression models, we tested the relationship between exposure variables-initial systolic blood pressure (SBP), shock index (SI), and rate over pressure evaluation (ROPE)-and the outcome of transfusion of blood products within 24 hours of admission. To test the predictive ability of each measure, we used receiver operating characteristic (ROC) curves. Results: A total of 10% of patients received blood products in the patient cohort. No patients had an initial SBP<=90, so the SBP measure was excluded from analysis. We found that patients with SI>1 were significantly more likely to receive blood transfusions compared with patients with SI<1 (OR 10.35; 95% CI 1.80 to 59.62), whereas ROPE>3 was not associated with blood transfusion compared with ROPE<=3 (OR 2.92; 95% CI 0.28 to 30.42). Furthermore, comparison of area under the ROC curve for SI (0.68) and ROPE (0.54) suggested that SI was more predictive than ROPE of blood transfusion. Conclusion: We found that an elevated SI was more closely associated with early blood product transfusion than SBP and ROPE in injured pregnant patients. Level of evidence: Prognostic, level III. PMID- 29766108 TI - TSACO first anniversary: life is good. PMID- 29766107 TI - Life-threatening perioperative anesthetic complications: major issues surrounding perioperative morbidity and mortality. AB - Perioperative morbidity and mortality related to anesthesia involves multiple factors. Patient characteristics and comorbidities play a role in many of these events, highlighting the importance of preoperative screening. While optimization of patient comorbidities is not always possible, having data regarding those comorbidities can prove life-saving. Equipment and medication considerations also enter into untoward outcomes such as anesthetic interventions outside of the traditional operating room where resources are sometimes lacking and haste creates errors. Ultimately, when surgeons and anesthesiologists cooperate in patient care, communicating concisely but thoroughly, patients are more likely to do well. The language of surgeons is that of diagnosis requiring a surgical intervention, while anesthesiologists are discussing patient comorbidities impacted by anesthetic medications, positive pressure ventilation, neuraxial techniques, ramifications of patient positioning, effects of opiates and so on. Because all of the considerations combine in determining outcomes, it is incumbent on both surgeons and anesthesiologists to understand those elements leading to severe morbid events as well as death. This review touches on many of the most important factors. PMID- 29766109 TI - Endovascular stent graft repair of an abdominal gunshot with liver and aortic injuries. PMID- 29766110 TI - Skiers and snowboarders have improved short-term outcomes with immediate fixation of tibial plateau fractures. AB - Background: Tibial plateau fractures (TPFs) are frequently associated with motor vehicle accidents, auto-pedestrian crashes and falls. However, hospitals near ski resorts commonly treat TPF resulting from skiing. The soft tissue envelope and original mechanism of injury are important determinants in the decision to proceed with immediate or delayed fixation of the fracture. Our objective was to assess whether immediate (<=24 hours) versus delayed (>24 hours) open reduction internal fixation (ORIF) affected in-hospital outcomes among snow sport participants. Methods: This was a retrospective study of patients with isolated TPF who were injured while skiing or snowboarding and treated at a Level III Trauma Center that serves four major ski resorts between 2010 and 2013. Clinical characteristics and in-hospital outcomes were obtained from an existing trauma database. Imaging was reviewed to classify the fracture as high (Schatzker IV-VI) or low (Schatzker I-III) energy. Differences in clinical characteristics and outcomes between immediate and delayed ORIF patients were analyzed with chi2 and Wilcoxon two-sample tests. These analyses were also performed in the high-energy and low-energy fracture populations. Results: ORIF was performed on 119 snow sport patients, 93 (78%) immediately. Patients had a median age of 49 years (range 19-70) and were predominantly male (66%). Forty percent sustained a high energy TPF. No differences were observed between the demographic characteristics, injury severity, Schatzker scores or time from injury to hospital arrival for patients treated immediately versus delayed treatment. Compared with delayed fixation, patients treated immediately had less compartment syndrome (3% vs 27%), needed fewer fasciotomies (6% vs 31%) and had a shorter length of stay (3 vs 6.5 days), p<0.05 for all. These results persisted in the stratified analysis of high energy fracture patients. Discussion: Treating patients immediately led to more favorable in-hospital outcomes compared with delayed treatment, even among the patients with a high-energy fracture. Level of evidence: Level IV, Therapeutic/Care Management. PMID- 29766111 TI - Seasonal Variation of Trauma in Western Massachusetts: Fact or Folklore? AB - Background: Previous studies have demonstrated a significant relationship between weather or seasons and total trauma admissions. We hypothesized that specific mechanisms such as penetrating trauma, motor vehicle crashes, and motorcycle crashes (MCCs) occur more commonly during the summer, while more falls and suicide attempts during winter. Methods: A retrospective review of trauma admissions to a single Level I trauma center in Springfield, Massachusetts from 01/2010 through 12/2015 was performed. Basic demographics including age, Injury Severity Score (ISS), and length of stay were collected. Linear regression analysis was used to test the association between monthly admission rates and season, year, injury class, and mechanism of injury, and whether seasonal variation trends were different according to injury class or mechanism. Results: A total of 8886 admissions had a mean age of 44.6 and mean ISS of 11.9. Regression analysis showed significant seasonal variation in blunt compared with penetrating trauma (p<0.001), MCC (p<0.001), and falls (p=0.002). In addition, seasonal variation differed according to injury class or mechanism. There were significantly lower rates of MCCs in winter compared with all other seasons and conversely higher rates of total falls in winter compared with other seasons. Discussion: A significant seasonal variation in blunt trauma, MCC, and falls was observed. This has potential ramifications for resource allocation, including trauma prevention programs geared toward mechanisms of injury with significant seasonal variation. Level of evidence: Retrospective Review, Level IV. PMID- 29766113 TI - Faster on-scene times associated with decreased mortality in Helicopter Emergency Medical Services (HEMS) transported trauma patients. AB - Background: The 'Golden Hour' emphasizes the importance of rapidly providing definitive care to trauma patients. Dispatch time, defined as the time it takes the Helicopter Emergency Medical Service (HEMS) to dispatch from their base and reach the patient, and on-scene time, defined as the time spent with the patient prior to departure to a trauma center, can impact how quickly the patient will reach definitive care. We evaluated HEMS dispatch and on-scene times by investigating the survival rates among patients transported by air to a level 1 trauma center. We hypothesize that longer HEMS dispatch and on-scene times are associated with worse patient outcomes. Methods: A retrospective, single institution analysis was performed on patients transported by HEMS. Inclusion criteria were air transported patients aged 18 years and above admitted to a level 1 trauma center from January 1, 2005 to January 1, 2015. Total dispatch time and on-scene times were divided into five incremental groups and mortality data were analyzed. Mortality was defined as death during initial hospital admission. A Pearson's correlation was used to analyze relationship between dispatch times, on-scene times, and mortality. Simple binary logistic regression was used to run a multivariate analysis on confounding variables of Injury Severity Score (ISS), gender, age, and Glasgow Coma Scale. Results: There was a strong positive linear correlation between HEMS on-scene time and mortality, R=0.962, p=0.038. Additionally, there was a positive trend between HEMS dispatch time and mortality. ISS was found to be a significant confounder of mortality in our cohort with on-scene times >20 min, with mortality increasing by 7.5% for every 0.1 increase in ISS score (p=0.01). Conclusion: Longer HEMS on-scene and dispatch times appeared to be associated with increased mortality in trauma patients. However, those with higher ISS require longer on-scene times, increasing mortality. Regardless, efforts should focus on reducing on-scene and dispatch times. Level of evidence and study type: Level III; Therapeutic/Care Management. PMID- 29766114 TI - Cecal volvulus with necrosis following deceased-donor renal transplantation. PMID- 29766112 TI - Derivation and validation of a two-biomarker panel for diagnosis of ARDS in patients with severe traumatic injuries. AB - Background: Acute respiratory distress syndrome (ARDS) is common after severe traumatic injuries but is underdiagnosed and undertreated. We hypothesized that a panel of plasma biomarkers could be used to diagnose ARDS in severe trauma. To test this hypothesis, we derived and validated a biomarker panel in three independent cohorts and compared the diagnostic performance to clinician recognition of ARDS. Methods: Eleven plasma biomarkers of inflammation, lung epithelial and endothelial injury were measured in a derivation cohort of 439 severe trauma patients. ARDS status was analyzed by two-investigator consensus, and cases were required to meet Berlin criteria on intensive care unit (ICU) day 1. Controls were subjects without ARDS during the first 4 days of study enrollment. A multivariable logistic regression model was used to generate probabilities for ARDS. A reduced model with the top two performing markers was then tested in two independent validation cohorts. To assess clinical diagnosis of ARDS, medical records in the derivation cohort were systematically searched for documentation of ARDS diagnosis made by a clinical provider. Results: Among 11 biomarkers, the combination of the endothelial injury marker angiopoietin-2 (Ang-2) and the lung epithelial injury marker receptor for advanced glycation endproducts (RAGE) provided good discrimination for ARDS in the derivation cohort (area under the curve (AUC)=0.74 (95% CI 0.67 to 0.80). In the validation cohorts, the AUCs for this model were 0.70 (0.61 to 0.77) and 0.78 (0.71 to 0.84). In contrast, provider assessment demonstrated poor diagnostic accuracy for ARDS, with AUC of 0.55 (0.51 to 0.60). Discussion: A two-biomarker panel consisting of Ang-2 and RAGE performed well across multiple patient cohorts and outperformed clinical providers for diagnosing ARDS in severe trauma. Clinical application of this model could improve both diagnosis and treatment of ARDS in patients with severe trauma. Level of evidence: Diagnostic study, level II. PMID- 29766115 TI - Case report and literature review of the outcome following reimplantation of the arm. AB - : The following case report and literature review will detail the management of a traumatic amputation of the arm in a 12-year-old boy. Compared with lower limbs, upper limb prosthesis usually results in significant suboptimal function by any measure. While the literature lacks high-quality evidence with regard to functional outcomes following proximal amputations of the upper limb, especially in children, it is known that children generally have superior functional outcomes compared with their adult counterparts. The mechanism of injury, transportation of the amputated part, type of ischemia, timing of surgery, surgical techniques/factors and postoperative rehabilitation will be discussed as factors affecting outcome of reimplantation. LEVEL OF EVIDENCE: V. PMID- 29766117 TI - Predictive factors of mortality after colectomy in ischemic colitis: an ACS-NSQIP database study. AB - Background: Surgical intervention for ischemic colitis is associated with significant postoperative morbidity and mortality. Predictive factors of adverse outcomes have been reported in the literature, but are based on small sample populations. We sought to identify risk factors for mortality after emergent colectomy for ischemic colitis using a clinical outcomes database. Methods: The American College of Surgeons National Surgical Quality Improvement Project database was queried from 2010 to 2015 to identify emergent colectomies performed for ischemic colitis using Current Procedural Terminology and International Classification of Diseases, Ninth Revision codes. Univariate and multivariate logistic regression analysis was used to identify independent risk factors associated with increased risk of mortality. Results: A total of 4548 patients undergoing emergent colectomies for ischemic colitis were identified. Overall, 30 day postoperative mortality was 25.3%. On univariate analysis, preoperative risk factors associated with a higher rate of mortality include dyspnea, functional status, ventilator dependency, history of chronic obstructive pulmonary disease, ascites, congestive heart failure exacerbation, hypertension, dialysis dependency, cancer, open wounds, chronic steroids, weight loss >10%, transfusions within 72 hours before surgery, septic shock and duration from hospital admission to surgery. Factors that were significant for mortality on logistic regression analysis include elderly age, poor functional status, multiple comorbidities, septic shock, blood transfusion, acute renal failure and the duration of time from hospital admission to surgery. Conclusions: Postoperative morbidity and mortality rates for ischemic colitis remain significantly high. Identification of risk factors may help patient selection for surgical interventions, and make informed decisions with patients and family members. Although it is certainly challenging, early diagnosis and prompt surgical intervention for patients with ischemic colitis may improve outcomes. Study type and level of evidence: Therapeutic/care management, level II. PMID- 29766116 TI - Emergency general surgery in pregnancy. AB - It is often that the acute care surgeon will be called on to evaluate the pregnant patient with abdominal pain. Most of the diagnostic and management decisions regarding pregnant patients will follow the usual tenets of surgery; however, there are important differences in the pregnant patient to be aware of to avoid pitfalls which can lead to complications for both mother and fetus. This review hopes to describe the most common emergencies facing the surgeon caring for the pregnant patient and the latest management options. PMID- 29766119 TI - Geospatial relationship of road traffic crashes and healthcare facilities with trauma surgical capabilities in Nairobi, Kenya: defining gaps in coverage. AB - Background: Road traffic injuries (RTIs) are a cause of significant morbidity and mortality in low- and middle-income countries. Access to timely emergency services is needed to decrease the morbidity and mortality of RTIs and other traumatic injuries. Our objective was to describe the distribution of roadtrafficcrashes (RTCs) in Nairobi with the relative distance and travel times for victims of RTCs to health facilities with trauma surgical capabilities. Methods: RTCs in Nairobi County were recorded by the Ma3route app from May 2015 to October 2015 with latitude and longitude coordinates for each RTC extracted using geocoding. Health facility administrators were interviewed to determine surgical capacity of their facilities. RTCs and health facilities were plotted on maps using ArcGIS. Distances and travel times between RTCs and health facilities were determined using the Google Maps Distance Matrix API. Results: 89 percent (25/28) of health facilities meeting inclusion criteria were evaluated. Overall, health facilities were well equipped for trauma surgery with 96% meeting WHO Minimal Safety Criteria. 76 percent of facilities performed greater than 12 of three pre-selected 'Bellweather Procedures' shown to correlate with surgical capability. The average travel time and distance from RTCs to the nearest health facilities surveyed were 7 min and 3.4 km, respectively. This increased to 18 min and 9.6 km if all RTC victims were transported to Kenyatta National Hospital (KNH). Conclusion: Almost all hospitals surveyed in the present study have the ability to care for trauma patients. Treating patients directly at these facilities would decrease travel time compared with transfer to KNH. Nairobi County could benefit from formally coordinating the triage of trauma patients to more facilities to decrease travel time and potentially improve patient outcomes. Level of evidence: III. PMID- 29766118 TI - Preinjury ASA score as an independent predictor of readmission after major traumatic injury. AB - Background: Patients with trauma have a high predisposition for readmission after discharge. Unplanned solicitation of medical services is a validated quality of care indicator and is associated with considerable economic costs. While the existing literature emphasizes the severity of the injury, there is heterogeneity in defining preinjury health status. We evaluate the validity of the American Society of Anesthesiologists (ASA) Physical Status score as an independent predictor of readmission and compare it to the Charlson Comorbidity Index (CCI). Methods: This is a single center, retrospective cohort study based on adult patients (>18 years of age) with trauma admitted to the Ottawa Hospital from January 1, 2004 to November 1, 2014. A multivariate logistic regression model is used to control for confounding and assess individual predictors. Outcome is readmission to hospital within 30 days, 3 months and 6 months. Results: A total of 4732 adult patients were included in this analysis. Readmission rates were 6.5%, 9.6% and 11.8% for 30 days, 3 months and 6 months, respectively. Higher preinjury ASA scores demonstrated significantly increased risk of readmission across all levels in a dose-dependent manner for all time frames. The effect of preinjury ASA scores on readmission is most striking at 30 days, with patients demonstrating a 2.81 (1.88-4.22, P<0.0001), 3.59 (2.43-5.32, P<0.0001) and 7.52 (4.72-11.99, P<0.0001) fold odds of readmission for ASA class 2, 3 and 4, respectively, as compared with healthy ASA class 1 patients. The ASA scores outperformed the CCI at 30 days and 3 months. Conclusions: The preinjury ASA score is a strong independent predictor of readmission after traumatic injury. In comparison to the CCI, the preinjury ASA score was a better predictor of readmission at 3 and 6 months after a major traumatic injury. Level of Evidence: Prognostic and Epidemiological Study, Level III. PMID- 29766120 TI - Emergency department management of patients with rib fracture based on a clinical practice guideline. AB - Background: Clinical practice guidelines (CPGs) have the ability to increase efficiency and standardize care. A CPG based on forced vital capacity (FVC) for rib fractures was developed as a tool for triage of these patients. The objectives of this study were to assess the efficacy and compliance of physicians with this rib fracture CPG. Methods: Patients >18 that were discharged from an urban level 2 trauma center emergency department (ED) between the dates of January 1, 2014, to December 31, 2016, were eligible for the study. Demographics, mechanism, outcomes and FVC were abstracted by review of the electronic medical record. Compliance with the CPG was examined, and comparisons were made between patients successfully discharged and patients who returned. Results: 455 patients met were identified during the study period. 233 were eligible after exclusions. 64% of the cohort was male with median age of 53 years. Falls were the most common mechanism (59.6%). The median number of rib fractures was 2 and median FVC 2500 mL. 28 (12.0%) of the 233 returned to the ED after discharge. The groups were well matched with no significant differences. The most common reason for return was pain (95%). Adjusted analysis showed that increasing age (adjusted OR (AOR) 0.968) and FVC (AOR 0.999) were independent predictors. Adherence with the CPG was good for hemothorax/pneumothorax and bilateral fractures (96%), but lagged with the number of fractures (74%). Conclusions: This study confirms that the rib fracture CPG is safe and an FVC of 1500 mL is a safe criterion for discharging patients with rib fractures. Interestingly, it appears that older age is protective. More work needs to be done on effective pain control to decrease return to ED visits using this CPG. Level of evidence: IV. Type of study: Therapeutic. PMID- 29766121 TI - Current outcomes of blunt open pelvic fractures: how modern advances in trauma care may decrease mortality. AB - Background: Open pelvic fracture, caused by a blunt mechanism, is an uncommon injury with a high mortality rate. In 2008, evidence-based algorithm for managing pelvic fractures in unstable patients was published by the Western Trauma Association (WTA). The use of massive transfusion protocols has become widespread as has the availability and use of pelvic angiography. The purpose of this study was to evaluate the outcome of open pelvic fractures in association with related advances in trauma care. Methods: A retrospective review was performed, at an American College of Surgeon verified level I trauma center, of patients with blunt open pelvic fractures from January 2010 to April 2016. The WTA algorithm, including massive transfusion protocol, and pelvic angiography were uniformly used. Data collected included injury severity score, demographic data, transfusion requirements, use of pelvic angiography, length of stay, and disposition. Data were compared with a similar study from 2005. Results: During the study period, 1505 patients with pelvic fractures were analyzed; 87 (6%) patients had open pelvic fractures. Of these, 25 were from blunt mechanisms and made up the study population. Patients in both studies had similar injury severity scores, ages, Glasgow Coma Scale, and gender distributions. Use of angiography was higher (44% vs. 16%; P=0.011) and mortality was lower (16% vs. 45%; P=0.014) than in the 2005 study. Conclusions: Changes in trauma care for patients with open blunt pelvic fracture include the use of an evidence-based algorithm, massive transfusion protocols and increased use of angioembolization. Mortality for open pelvic fractures has decreased with these advances. Level of evidence: Level IV. PMID- 29766122 TI - Spontaneous splenic rupture due to marginal zone lymphoma. PMID- 29766124 TI - Routine repeat head CT may not be necessary for patients with mild TBI. AB - Background: Routine repeat cranial CT (RHCT) is standard of care for CT-verified traumatic brain injury (TBI). Despite mixed evidence, those with mild TBI are subject to radiation and expense from serial CT scans. Thus, we investigated the necessity and utility of RHCT for patients with mild TBI. We hypothesized that repeat head CT in these patients would not alter patient care or outcomes. Methods: We retrospectively studied patients suffering from mild TBI (Glasgow Coma Scale (GCS) score 13-15) and treated at the R Adams Cowley Shock Trauma Center from November 2014 through January 2015. The primary outcome was the need for surgical intervention. Outcomes were compared using paired Student's t-test, and stratified by injury on initial CT, GCS change, demographics, and presenting vital signs (mean +/- SD). Results: Eighty-five patients met inclusion criteria with an average initial GCS score=14.6+/-0.57. Our center sees about 2800 patients with TBI per year, or about 230 per month. This includes patients with concussions. This sample represents about 30% of patients with TBI seen during the study period. Ten patients required operation (four based on initial CT and others for worsening GCS, headaches, large unresolving injury). There was progression of injury on repeat CT scan in only two patients that required operation, and this accompanied clinical deterioration. The mean brain Abbreviated Injury Scale (AIS) score was 4.8+/-0.3 for surgical patients on initial CT scan compared with 3.4+/-0.6 (P<0.001) for non-surgical patients. Initial CT subdural hematoma size was 1.1+/-0.6 cm for surgical patients compared with 0.49+/-0.3 cm (P=0.05) for non-surgical patients. There was no significant difference between intervention groups in terms of other intracranial injuries, demographics, vital signs, or change in GCS. Overall, 75 patients that did not require surgical intervention received RHCT. At $340 per CT, $51 000 was spent on unnecessary imaging ($367 000/year, extrapolated). Discussion: In an environment of increased scrutiny on healthcare expenditures, it is necessary to question dogma and eliminate unnecessary cost. Our data questions the use of routine repeat head CT scans in every patient with anatomic TBI and suggests that clinically stable patients with small injury can simply be followed clinically. Level of evidence: Level III. PMID- 29766123 TI - Orthopaedic traumatology: fundamental principles and current controversies for the acute care surgeon. AB - Multiply injured patients with fractures are co-managed by acute care surgeons and orthopaedic surgeons. In most centers, orthopaedic surgeons definitively manage fractures, but preliminary management, including washouts, splinting, reductions, and external fixations, may be performed by selected acute care surgeons. The acute care surgeon should have a working knowledge of orthopaedic terminology to communicate with colleagues effectively. They should have an understanding of the composition of bone, periosteum, and cartilage, and their reaction when there is an injury. Fractures are usually fixed urgently, but some multiply injured patients are better served with a damage control strategy. Extremity compartment syndrome should be suspected in all critically injured patients with or without fractures and a low threshold for compartment pressure measurements or empiric fasciotomy maintained. Acute care surgeons performing rib fracture fixation and other chest wall injury reconstructions should follow the principles of open fracture reduction and stabilization. PMID- 29766125 TI - Trauma Early Mortality Prediction Tool (TEMPT) for assessing 28-day mortality. AB - Background: Prior mortality prediction models have incorporated severity of anatomic injury quantified by Abbreviated Injury Severity Score (AIS). Using a prospective cohort, a new score independent of AIS was developed using clinical and laboratory markers present on emergency department presentation to predict 28 day mortality. Methods: All patients (n=1427) enrolled in an ongoing prospective cohort study were included. Demographic, laboratory, and clinical data were recorded on admission. True random number generator technique divided the cohort into derivation (n=707) and validation groups (n=720). Using Youden indices, threshold values were selected for each potential predictor in the derivation cohort. Logistic regression was used to identify independent predictors. Significant variables were equally weighted to create a new mortality prediction score, the Trauma Early Mortality Prediction Tool (TEMPT) score. Area under the curve (AUC) was tested in the validation group. Pairwise comparison of Trauma Injury Severity Score (TRISS), Revised Trauma Score, Glasgow Coma Scale, and Injury Severity Score were tested against the TEMPT score. Results: There was no difference between baseline characteristics between derivation and validation groups. In multiple logistic regression, a model with presence of traumatic brain injury, increased age, elevated systolic blood pressure, decreased base excess, prolonged partial thromboplastin time, increased international normalized ratio (INR), and decreased temperature accurately predicted mortality at 28 days (AUC 0.93, 95% CI 0.90 to 0.96, P<0.001). In the validation cohort, this score, termed TEMPT, predicted 28-day mortality with an AUC 0.94 (95% CI 0.92 to 0.97). The TEMPT score preformed similarly to the revised TRISS score for severely injured patients and was highly predictive in those having mild to moderate injury. Discussion: TEMPT is a simple AIS-independent mortality prediction tool applicable very early following injury. TEMPT provides an AIS-independent score that could be used for early identification of those at risk of doing poorly following even minor injury. Level of evidence: Level II. PMID- 29766126 TI - Factor VIIa administration in traumatic brain injury: an AAST-MITC propensity score analysis. AB - Background: Recombinant factor VIIa (rFVIIa) has been used off-label as an adjunct in the reversal of warfarin therapy and management of hemorrhage after trauma. Only a handful of these reports are rigorous studies, from which results regarding safety and effectiveness have been mixed. There remains no clear consensus as to the role of rFVIIa in traumatic brain injury (TBI). Methods: Eleven level 1 trauma centers provided clinical data and head CT scans of patients with a Glasgow Coma Scale (GCS) score of <=13 and radiographic evidence of TBI. A propensity score (PS) to receive rFVIIa in those surviving >=2 days was calculated for each patient based on patient demographics, comorbidities, physiology, Injury Severity Score, admission GCS score, and treatment center. Patients receiving rFVIIa within 24 hours of admission were matched to patients who did not receive rFVIIa for outcomes assessment. Subgroup analysis evaluated patients with primary head injury with PS matching. Results: There were 4284 patient observations; 129 received rFVIIa. Groups were comparable after matching. No differences in mortality or morbidity were found. Improvement in GCS score from admission to discharge was less among those receiving rFVIIa (5.5 vs. 2.4; P value 0.001); however, there was no difference in average GCS score at discharge. No significant differences in outcomes were identified in patients with isolated TBI receiving rFVIIa. Discussion: rFVIIa in early management of TBI is not associated with a decreased risk of mortality or morbidity, and may negatively impact recovery and functional status at discharge in the severely injured patient with polytrauma. Level of evidence: Level III. Study type: Therapeutic/care management. PMID- 29766127 TI - Grey's Anatomy effect: television portrayal of patients with trauma may cultivate unrealistic patient and family expectations after injury. AB - Background: Expectations of the healthcare experience may be influenced by television dramas set in the hospital workplace. It is our perception that the fictional television portrayal of hospitalization after injury in such dramas is misrepresentative. The purpose of this study was to compare trauma outcomes on television dramas versus reality. Methods: We screened 269 episodes of Grey's Anatomy, a popular medical drama. A television (TV) registry was constructed by collecting data for each fictional trauma portrayed in the television series. Comparison data for a genuine patient cohort were obtained from the 2012 National Trauma Databank (NTDB) National Program Sample. Results: 290 patients composed of the TV registry versus 4812 patients from NTDB. Mortality was higher on TV (22% vs 7%, P<0.0001). Most TV patients went straight from emergency department (ED) to operating room (OR) (71% vs 25%, P<0.0001). Among TV survivors, a relative minority were transferred to long-term care (6% vs 22%, P<0.0001). For severely injured (Injury Severity Score >=25) survivors, hospital length of stay was less than 1 week for 50% of TV patients versus 20% in NTDB (P<0.0001). Conclusions: Trauma patients as depicted on television dramas typically go from ED to OR, and survivors usually return home. Television portrayal of rapid functional recovery after major injury may cultivate false expectations among patients and their families. Level of evidence: Level III. PMID- 29766128 TI - A multi-decade joinpoint analysis of firearm injury severity. AB - Background: Non-fatal firearm injuries constitute approximately 70% of all firearm trauma injuries in the United States. Patterns of severity of these injuries are poorly understood. We analyzed the overall, age-, sex- and intent specific temporal trends in the injury severity of firearm hospitalizations from 1993 to 2014. Methods: We assessed temporal trends in the severity of patients hospitalized for firearm using Nationwide Inpatient Sample (NIS) data over a 22 year period. Firearm hospitalization was identified using assault (E965x), unintentional (E922x), intentional self-harm (E955x), legal (E970) and undetermined (E985x) International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9) codes. Injury severity was measured using the computed New Injury Severity Score (NISS). We used survey weighted means, SD and annual percent change (APC), and joinpoint regression to analyze temporal trends. Results: A weighted total of 648 662 inpatient admissions for firearm injury were analyzed. Firearm injury severity demonstrated a significant annual increase of 1.4% (95% CI=1.3 to 1.6), and was driven by annual increases among young adults (APC=1.4%, 95% CI=1.3 to 1.5), older adults (APC=1.5%, 95% CI=1.3 to 1.6), female (APC=1.5%, 95% CI=1.3 to 1.6) and male (APC=1.4%, 95% CI=1.3 to 1.6) hospitalizations. The annual increase among assault/legal injuries was 1.4% (95% CI=1.3 to 1.5), similar to unintentional (APC=1.4%, 95% CI=1.3 to 1.6), intentional self-harm (APC=1.5%, 95% CI=1.4 to 1.6) and undetermined (APC=1.4%, 95% CI=1.3 to 1.6). Conclusions: The severity of hospitalized firearm injuries increased significantly from 1993 to 2014. This annual increase reflects a move towards hospitalization of more serious injuries, and outpatient management of less serious injuries across the board, suggesting a mounting burden on the US healthcare system. Level of evidence: Level IV. PMID- 29766129 TI - Is thromboelastography (TEG)-based resuscitation better than empirical 1:1 transfusion? AB - : Thomboelastography (TEG) is a whole blood measure of coagulation which was originally described in the 1950s. However, it has only been in the last few decades that assays have become accessible and viable as a point-of-care test. Following the observation that hemorrhagic shock is associated with an intrinsic coagulopathy, TEG has been used as a method of diagnosing specific coagulation defects in order to direct individualized blood products resuscitation. An alternative transfusion strategy is the administration of fixed ratio products, a paradigm borne out of military experience. It is unknown which strategy is superior and this topic was debated at the 36th Annual Point/Counterpoint Acute Care Surgery Conference. The following article summarizes the discussants points of view along with a summary of the evidence. Level of evidence: Level III. PMID- 29766130 TI - Resuscitative endovascular balloon occlusion of the aorta: rupture risk and implications for blind inflation. AB - Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a torso hemorrhage control technique. To expedite deployment, inflation is frequently performed as a blind technique with minimal imaging, which carries a theoretical risk of aortic injury. The objective of this study was to examine the relationship between balloon inflation, deformation and the risk of aortic rupture. Methods: Compliant balloon catheters were incrementally inflated in segments of cadaveric swine aorta. Serial longitudinal and circumferential measurements were recorded, along with the incidence of aortic rupture. Results: Fourteen cadaveric swine aorta segments were tested with mean (+/-SD) baseline aortic diameter (mm) of 14.2+/-3.4. Rupture occurred in three aortas. The mean baseline diameters (mm) of the aortic segments that were ruptured were significantly smaller than those that did not rupture (8.9+/-1.2 vs 15.6+/-1.9; P<0.001). The maximal circumferential stretch ratios were significantly higher in the aorta segments that ruptured compared with those that did not (1.9+/-0.1 vs 1.5+/-0.1; P<0.001). The maximal amount of balloon longitudinal deformation was 80 mm (116% longer than the intended working length). Conclusions: Inflation of aortic balloon catheters carries an inherent risk of aortic injury, which may be minimized through an understanding of the intrinsic characteristics of the aorta and compliant balloons. Smaller diameter aortic segments undergoing overinflation, particularly beyond a circumferential stretch ratio of 1.8, are at risk of aortic rupture. Level of evidence: Level II. PMID- 29766131 TI - Does intracranial pressure management hurt more than it helps in traumatic brain injury? AB - : Traumatic brain injury (TBI) is the leading cause of death after traumatic injury. Raised intracranial pressure (ICP) is particularly associated with poor TBI outcomes, prompting clinicians to monitor this parameter, using it to guide therapies aimed at reducing pressures. Despite this approach being recommended by several bodies such as the Brain Trauma Foundation and the American College of Surgeons, the evidence demonstrating that ICP-guided therapy improves outcome is limited. The topic was debated at the 36th Annual Point/Counterpoint Acute Care Surgery Conference and the following article summarizes the discussants points of view along with a summary of the evidence. Level of evidence: Level III. PMID- 29766132 TI - Red cell distribution width predicts out of hospital outcomes in critically ill emergency general surgery patients. AB - Introduction: Red cell distribution width (RDW) is associated with mortality and bloodstream infection risk in critically ill patients. We hypothesized that an increase in RDW at hospital discharge in critically ill patients who received emergency general surgery (EGS) would be associated with increased mortality after hospital discharge. Methods: We performed a two-center observational study of patients treated in medical and surgical intensive care units. We studied 1567 patients, who received critical care between 1998 and 2012 who underwent EGS and survived hospitalization. The exposure of interest was RDW within 24 hours of hospital discharge and categorized a priori in quintiles as <=13.3%, 13.3% to 14.0%, 14.0% to 14.7%, 14.7% to 15.8%, 15.8% to 17.0% and >17.0%. The primary outcome was 90-day all-cause mortality. Adjusted ORs were estimated by multivariable logistic regression models with inclusion of covariate terms for age, race, gender, Deyo-Charlson Index, sepsis and number of organs with acute failure. Results: The cohort patients were 51.4% male and 23.2% non-white. 23.9% had sepsis and the mean age was 58 years. 90-day postdischarge mortality was 6.8%. Patients with a discharge RDW 15.8% to 17.0% or RDW >17.0% have an adjusted OR of 90-day postdischarge mortality of 3.64 (95% CI 1.04 to 12.68; p=0.043) or 4.58 (95% CI 1.32 to 15.93; p=0.02), respectively, relative to patients with a discharge RDW <=13.3%. Further, patients with a discharge RDW >=15.8 have an adjusted OR of 30-day hospital readmission of 2.12 (95% CI 1.17 to 3.83; p=0.013) relative to patients with a discharge RDW <=13.3%. Conclusions: In EGS patients requiring critical care who survive hospitalization, an elevated RDW at the time of discharge is a robust predictor of all-cause patient mortality and hospital readmission after discharge. Level of evidence: Level II, prognostic retrospective study. PMID- 29766133 TI - Trauma Transitional Care Coordination: protecting the most vulnerable trauma patients from hospital readmission. AB - Background: Unplanned hospital readmissions increase healthcare costs and patient morbidity. We hypothesized that a program designed to reduce trauma readmissions would be effective. Methods: A Trauma Transitional Care Coordination (TTCC) program was created to support patients at high risk for readmission. TTCC interventions included call to patient (or caregiver) within 72 hours of discharge to identify barriers to care, complete medication reconciliation, coordination of appointments, and individualized problem solving. Information on all 30-day readmissions was collected. 30-day readmission rates were compared with center-specific readmission rates and population-based, risk-adjusted rates of readmission using published benchmarks. Results: 260 patients were enrolled in the TTCC program from January 2014 to September 2015. 30.8% (n=80) of enrollees were uninsured, 41.9% (n=109) reported current substance abuse, and 26.9% (n=70) had a current psychiatric diagnosis. 74.2% (n=193) attended outpatient trauma appointments within 14 days of discharge. 96.3% were successfully followed. Only 6.6% (n=16) of patients were readmitted in the first 30 days after discharge. This was significantly lower than both center-specific readmission rates before start of the program (6.6% vs. 11.3%, P=0.02) and recently published population based trauma readmission rates (6.6% vs. 27%, P<0.001). Discussion: A nursing-led TTCC program successfully followed patients and was associated with a significant decrease in 30-day readmission rates for patients with high-risk trauma. Targeted outpatient support for these most vulnerable patients can lead to better utilization of outpatient resources, increased patient satisfaction, and more consistent attainment of preinjury level of functioning or better. Level of evidence: Level IV. PMID- 29766135 TI - Joint statement from the American College of Surgeons Committee on Trauma (ACS COT) and the American College of Emergency Physicians (ACEP) regarding the clinical use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). PMID- 29766134 TI - Protocol for a randomized trial of the effect of timing of cholecystectomy during initial admission for predicted mild gallstone pancreatitis at a safety-net hospital. AB - Background: There is evidence-based consensus for laparoscopic cholecystectomy during index admission for predicted mild gallstone pancreatitis, defined by the absence of organ failure and of local or systemic complications. However, the optimal timing for surgery within that admission is controversial. Early cholecystectomy may shorten hospital length of stay (LOS) and increase patient satisfaction. Alternatively, it may increase operative difficulty and complications resulting in readmissions. Methods: This trial is a single-center randomized trial of patients with predicted mild gallstone pancreatitis comparing laparoscopic cholecystectomy with intraoperative cholangiogram (IOC) at index admission within 24 hours of presentation versus after clinical resolution on clinical and patient-reported outcomes (PROs). The primary endpoint is 30-day LOS (hours) after initial presentation, which includes the index admission and readmissions. Secondary outcomes are conversion to open, complications, time from admission to cholecystectomy, initial hospital LOS, number of procedures within 30 days, 30-day readmissions, and PROs (change in Gastrointestinal Quality-of Life Index). Discussion: The primary goal of this research is to obtain the least biased estimate of effect of timing of cholecystectomy for mild gallstone pancreatitis on clinical and PROs; the results of this trial will be used to inform patient care locally as well as to design future multicenter effectiveness and implementation trials. This trial will provide data regarding PROs including health-related quality of life that can be used in cost-utility and cost effectiveness analyses. Trial registration number: NCT02806297, ClinicalTrials.gov. PMID- 29766136 TI - Can necrotizing soft tissue infection be reliably diagnosed in the emergency department? AB - : Necrotizing soft tissue infections (NSTIs) are associated with a high mortality and require prompt recognition and treatment, consisting of aggressive surgical debridement and critical care support. Diagnosis is a key step, which is generally made in the operating room (OR), but the decision to debride requires guidance. This is frequently made on clinical grounds, but NSTI can be occult in presentation and several other infective processes can mimic NSTI. It is unknown whether the various scoring systems described in the literature can enable clinicians to reliably diagnose NSTI in the emergency department, rather than the OR. The topic was debated at the 36thAnnual Point/Counterpoint Acute Care Surgery Conference and the following article summarizes the discussants points of view along with a summary of the evidence. Level of evidence: Level III. PMID- 29766137 TI - After the embo: predicting non-hemorrhagic indications for splenectomy after angioembolization in patients with blunt trauma. AB - Background: Successful non-operative management (NOM) of blunt splenic trauma is enhanced with splenic angioembolization (SAE). Patients may still require splenectomy post-SAE for splenic infarction/necrosis. Prior studies have used white blood cell count (WBC), platelet count (PLT), and PLT:WBC ratio after splenectomy to predict complications, but none have evaluated these findings prior to splenectomy in patients who have undergone SAE. Changes in these values may indicate clinically significant splenic infarction, facilitating management of these patients. Methods: Patients admitted to an American College of Surgeons verified level 1 trauma center from January 2007 to August 2017 who underwent SAE were identified. Patients with successful NOM after SAE (SAE/NOM) were compared with those requiring splenectomy (SAE/SPLEN). Data included demographics, splenic injury grade, Injury Severity Score (ISS), time to SAE and splenectomy, intensive care unit and hospital length of stay (LOS), and complete blood count. Lab values were analyzed immediately post-SAE (time 1) and day 5 post-SAE (or day of discharge) for SAE/NOM patients and day of SPLEN for SAE/SPLEN patients (time 2). Data were analyzed using Mann-Whitney U, chi2 tests, and receiver operating characteristic (ROC) curves with significance attributed to P<0.05. Results: Of 124 patients undergoing SAE, 16 (13%) later required SPLEN for infarction/necrosis at a median of 5 days post-SAE (IQR: 3-10 days). SAE/SPLEN and SAE/NOM patients did not differ by age, gender, ISS, or grade of splenic injury. SAE/SPLEN patients had longer hospital LOS (23 vs. 10 days, P<0.001). WBC, PLT, and PLT:WBC ratio did not differ between the groups at time 1. At time 2, WBC was higher and PLT:WBC ratio was lower in SAE/SPLEN patients. Using ROC curves at time 2, the area under the curve was 0.90 (P<0.001) for WBC and 0.71 (P<0.007) for PLT:WBC ratio. Discussion: Patients requiring splenectomy for clinically significant infarction/necrosis after SAE develop leukocytosis and decreased PLT:WBC ratio when compared with SAE/NOM patients. Monitoring these parameters allows more prompt diagnosis and operative intervention. Level of evidence: Therapeutic/care management, level III. PMID- 29766139 TI - Necrotizing fasciitis following abdominal gunshot wound. PMID- 29766140 TI - Multidisciplinary damage control management of life-threatening carotid blowout syndrome. PMID- 29766138 TI - Risk stratification tools in emergency general surgery. AB - The use of risk stratification tools (RST) aids in clinical triage, decision making and quality assessment in a wide variety of medical fields. Although emergency general surgery (EGS) is characterized by a comorbid, physiologically acute patient population with disparately high rates of perioperative morbidity and mortality, few RST have been explicitly examined in this setting. We examined the available RST with the intent of identifying a tool that comprehensively reflects an EGS patients perioperative risk for death or complication. The ideal tool would combine individualized assessment with relative ease of use. Trauma Scoring Systems, Critical Care Scoring Systems, Surgical Scoring Systems and Track and Trigger Models are reviewed here, with the conclusion that Emergency Surgery Acuity Score and the American College of Surgeons National Surgical Quality Improvement Programme Universal Surgical Risk Calculator are the most applicable and appropriate for EGS. PMID- 29766141 TI - Brown-Sequard syndrome. PMID- 29766142 TI - Improving life expectancy: A 'broken neck' doesn't have to be a terminal diagnosis for the elderly. AB - Background: Elderly patients with cervical spine fractures require optimal care. Treatment with a cervical collar or halo instead of surgical fixation may increase mortality. This investigation intends to describe the life expectancy after injury and evaluate the impact of surgical intervention on mortality. Methods: Patients >=65 years, with traumatic cervical spine fractures without cord injury were identified in the 1995-2009 California Office of Statewide Health and Planning database. Those with halo placement or surgical spine fixation were identified. Primary outcome was death, studied at the initial admission, 30 days, 1 year, and the entire study period. Univariate and multivariate regressions were performed to identify predictors of death. Kaplan Meier survival curves were used to describe life expectancy after injury. Results: 10 938 patients were identified. Mortality rate was 10% during the initial admission, 28% at 1 year and 50% during the entire study period. A halo was placed in 14% of patients and 12% underwent surgical fixation. Mortality rates during the initial admission were 11% for patients without an intervention, 7% with halo placement and 6% with surgical fixation; at 1 year, these increased to 30%, 26% and 19%, respectively. At 1 year, more than one in four patients above 75 years of age will die.At 1 year spine fixation, female gender and admission to a trauma center predicted a lower risk of death at 1 year (OR 0.59, 0.68; p<0.001 and OR 0.89; p=0.02, respectively). Having a complication, fall mechanism, and traumatic brain injury (OR 1.84, 1.33, 1.37; p<0.001, respectively) were predictors of a higher risk of death. Halo use had no impact on death at 1 year (OR 0.98; p=0.77). Discussion: Mortality rates after cervical spine fracture in the elderly is high. Surgical fixation is associated with improved survival; remaining true after adjusting for age and comorbidities; suggesting that surgical fixation may improve outcomes in the elderly. Level of evidence: Level IV. PMID- 29766143 TI - When should screening of pediatric trauma patients for adult behaviors start? AB - Background: Care of patients with trauma is not only limited to the sustained physical injuries but also requires addressing social issues, such as substance abuse and interpersonal violence, which are responsible for trauma-related recidivism. This study investigates whether there are age-related variations in these problematic social behaviors to analyze whether there is an age cut-off at which point adolescents should be screened for adult social behaviors. Methods: Retrospective review of patients with trauma aged 12-21 admitted to an urban Level 1 adult and pediatric trauma center between February 2013 and April 2016. Demographics, mechanisms of injury, Injury Severity Score, outcomes, toxicology and social history evaluations were abstracted from the electronic medical record. Results: 756 patients were admitted during the 39-month period. Most patients were male (73.9%) without significant variation by age. The mechanisms of injury varied by age (p<0.001) with the incidence of sports and bicycle injuries decreasing and the incidence of motor vehicle/motorcycle crashes, assaults and gunshot injuries increasing with increasing patient age. In a logistic regression, risks of positive toxicology tests, injuries due to violence as well as overall use of drugs, tobacco and alcohol also significantly increased with age starting with the youngest age included in the study. Conclusions: As pediatric trauma patients get older, they have increasing risks of social issues typically associated with adults. Our study underscores the need to evaluate and address these issues even in young adolescents. Level of evidence: Level IV epidemiological. PMID- 29766144 TI - Novel application of an old technique: the use of external to internal carotid artery transposition in trauma. PMID- 29766146 TI - The effect of resveratrol on oxidative stress in the liver and serum of a rat model of polycystic ovary syndrome: An experimental study. AB - Background: Studies of oxidative status in polycystic ovarian syndrome (PCOS) patients are limited with inconsistent results. The effects of resveratrol as a natural antioxidant on oxidative status in PCOS aren't clear. Objective: This study evaluated effects of resveratrol on oxidative stress in the liver and serum of the PCOS rats. Materials and Methods: Fifteen female Wistar rats (3 wk old) were divided into 3 groups (n=5/each e): Control group, PCO-Control group, and PCO-Resveratrol group. For induction of polycystic ovary phenotype, testosterone enanthate 10 mg/kg was injected for 35 days subcutaneously. Then, resveratrol 10 mg/kg was injected intraperitoneally for 28 days to rats of the PCO-Resveratrol group. Ovarian sections were stained with hematoxylin/eosin. The serum glucose and insulin and the levels of malondialdehyde (MDA) and total antioxidant capacity (TAC) in serum and liver were measured. Results: Control animals showed normal ovarian morphology and PCO-Control animals exhibited cystic follicles. There were no significant differences in liver TAC between groups. The serum MDA (p=0.034), and homeostatic model assessment insulin resistance (HOMA-IR) (p=0.014) levels in PCO-Control rats were higher than the controls. The liver MDA in PCO-Control rats was more than that of controls (p=0.001). The HOMA-IR (p=0.008) and serum MDA (p=0.006) levels in PCO-Control rats were more than those of PCO-Resveratrol rats (p=0.008). In PCO-Resveratrol group, serum TAC was higher than that of PCO-Control group (p=0.022) and liver MDA was more than controls (p=0.01). Conclusion: Results indicated that the induction of PCOS in rats increased lipid peroxidation and insulin resistance and resveratrol improved these complications. PMID- 29766145 TI - Basic and clinical genetic studies on male infertility in Iran during 2000-2016: A review. AB - The male factor contributes to 50% of infertility. The cause of male infertility is idiopathic and could be congenital or acquired. Among different factors which are involved in idiopathic male infertility, genetic factors are the most prevalent causes of the disease. Considering, the high prevalence of male infertility in Iran and the importance of genetic factors in the accession of it, in this article we reviewed the various studies which have been published during the last 17 yr on the genetic basis of male infertility in Iran. To do this, the PubMed and Scientific information database (SID) were regarded for the most relevant papers published in the last 17 yr referring to the genetics of male factor infertility using the keywords ''genetics'', "cytogenetic", ''male infertility", and "Iranian population". Literatures showed that among the Iranian infertile men Yq microdeletion and chromosomal aberrations are two main factors that intervene in the genetics of male infertility. Also, protamine deficiency (especially P2) is shown to have an influence on fertilization rate and pregnancy outcomes. The highest rate of sperm DNA damages has been found among the asthenospermia patients. In several papers, the relation between other important factors such as single gene mutations and polymorphisms with male infertility has also been reported. Recognition of the genetic factors that influence the fertility of Iranian men will shed light on the creation of guidelines for the diagnosis, consultation, and treatment of the patients." PMID- 29766147 TI - The non-preventive effects of human menopausal gonadotropins on ovarian tissues in Nandrolone decanoate-treated female rats: A histochemical and ultra-structural study. AB - Background: The follicular growth and development may be affected by abused drugs. Nandrolone decanoate (ND) as an anabolic androgenic steroid can damage the morphological and functional features of the ovary and may lead to reproductive failure. Objective: This study was designed to evaluate the effects of synchronized and non-synchronized administration of Human Menopausal Gonadotropins (hMG) with ND on ovarian tissue and level of sex hormones in the adult female rat. Materials and Methods: Forty adult female Sprague Dawley rats were divided into eight groups. The five experimental groups received 3 and/or 10 mg/kg of ND synchronized and non-synchronized with 10 IU of hMG and hMG alone. The two shams and control groups received solvents of ND and hMG. The animals' serum levels of Follicle-stimulating hormone, Luteinizing hormone, progesterone and estrogen and the weight, volume and dimensions of the ovaries were measured. The ovaries were prepared for apoptosis assessment and morphological study. Results: The ovarian volume and sex hormones in the experimental groups were decreased, but ovarian weight and dimensions didn't change. The rate of apoptosis was increased in the experimental groups as follows; a low and high dose of ND synchronized with hMG 48.80+/-18.70 and 65.20+/-14.20 respectively vs. Sham 1, 33.20+/-17.80, a low and high dose of ND non-synchronized with hMD 55.80+/-17.20 and 75.20+/-14.30 respectively vs. Sham 2, 31.60+/-32.40 groups, p?0.01. Follicular and stromal cells were damaged in the experimental groups except for the hMG group. Conclusion: Administration of ND decreased the serum level of Luteinizing hormone, Follicle-stimulating hormone, progesterone and estrogen and damaged ovarian tissue irreversibly and irreparably and hMG cannot prevent the destruction of the follicles in the adult female rats. This can be a serious warning to women who abuse ND. PMID- 29766148 TI - Endogenous luteinizing hormone concentration and IVF outcome during ovarian stimulation in fixed versus flexible GnRH antagonist protocols: An RCT. AB - Background: Luteinizing hormone (LH) is essential for normal follicular development and oocyte maturation. In particular, fluctuations of LH during the follicular phase have a significant impact on morphological and functional changes of the oocyte and determine its meiotic status and ability to be fertilized. Objective: This prospective randomized controlled trial examined effects of endogenous follicular phase LH levels on oocyte maturity and IVF outcomes in fixed vs. flexible in vitro fertilization. Materials and Methods: Normo-ovulatory women age <39 yr (n=213) were randomized to fixed or flexible gonadotrophin-releasing hormone (GnRH) antagonist protocols. Follicular phase LH, estradiol, and progesterone profiles were measured. Oocytes retrieved, implantation rate, and pregnancy rate were compared between the two groups. Results: LH profiles were similar in both protocols. A lower trend of LH values at the end of ovarian stimulation correlated significantly with a higher pregnancy rate, regardless of protocol (p=0.02). Estradiol levels were statistically different with respect to time points within treatment groups (p<0.0001), but not between groups (p=0.43), or pregnancy outcomes (p=0.2595). Progesterone profiles were similar between groups. No differences were found in retrieved oocytes numbers, fertilization rate or embryos obtained. Significantly, younger age and a higher number of antral follicles were correlated with positive results. Conclusion: Fixed and flexible GnRH antagonist protocols did not produce an oscillation of endogenous LH values correlated to the outcome of ovarian stimulation. PMID- 29766149 TI - Alteration in CatSper1 and 2 genes expression, sperm parameters and testis histology in varicocelized rats. AB - Background: CatSper gene, a member of cation channel sperm family, has an essential role in sperm motility and male fertility. Following varicocele, sperm parameters especially sperm movement decreases. For this reason, we hypothesized that CatSper gene expression might be reduced after varicocele induction in an animal model. Objective: The aim of this study was to evaluate the expression of CatSper 1 and 2 genes, sperm parameters and testis histology following varicocele induction. Materials and Methods: A total of 30 Wistar male rats were randomly divided into three following groups (n=10/ each): control, sham, and varicocele group. Experimental varicocele was induced by partial ligation of the left renal vein. The epididymal sperm parameters, CatSper1 and 2 genes expression, and testes histology were studied two months after varicocele induction. Results: Our results revealed that motility (32.73+/-16.14%), morphology (48.80+/-17%) and viability (31.23+/-9.82%) of sperms significantly reduced following varicocele induction. In addition, we showed a significant decrease in the number of spermatogonia (43.63+/-5.31) and seminiferous tubules diameters (190.51+/-19.23 mm) in experimental varicocele rats. The level of CatSper1 and 2 genes expression evaluated using real-time polymerase chain reaction was significantly downregulated 2 months after varicocele induction. Conclusion: Our data indicated that experimental varicocele has deleterious effects on sperm parameters, testis structure as well as the expression of CatSper 1 and 2 genes. PMID- 29766150 TI - Psychometrics properties of the Iranian version of fertility quality of life tool: A cross- sectional study. AB - Background: Clinical measurement of quality of life (QoL) for assessing reproductive problems should be considered as a standard investigation at the initial and continuing medical consultations with infertile people. Objective: The purpose of this study was comprehensive testing the psychometric properties of the Iranian version of fertility quality of life (FertiQoL). Materials and Methods: This cross-sectional study was conducted on300 women referred to infertility clinic. After linguistic validation, a semi-structured interview was conducted to assess face validity. Consequently exploratory factor analysis was performed to indicate the scale constructs. Discriminate validity was assessed using the known groups comparison. Convergent validity was evaluated by assessing the correlation between similar content on the 12-Item Short Form Health Survey (SF12), Hospital Anxiety and Depression Scale and FertiQol. In addition, reliability analysis was carried out with internal consistency. Results: The reliability of the Iranian version of the FertiQoL was satisfactory in all dimensions (0.77-0.83). Six factors (emotional, mind/body, relational, social, environmental, and tolerability) were extracted from the results of exploratory factor analysis. Discrimination validity showed that FertiQoL can differentiate between female patients with differing duration of infertility and number of children. Moreover, the results of convergent validity showed a favorable correlation between the related dimensions of SF12 (0.43-0.68), Hospital Anxiety and Depression Scale (0.47-0.52) and FertiQoL. Conclusion: The Iranian version of FertiQoL is valid and reliable for assessing infertility problems and the effects of treatment on QoL of infertile patients referred for diagnosis and treatment at infertility clinic. PMID- 29766152 TI - Undesired effect of excessive betamethasone administration during pregnancy: A rare case. AB - Background: Postpartum bilateral femoral neck fracture (BFNF) is a rare condition. We here report a case of BFNF due to excessive corticosteroid consumption, twin pregnancy, immobility, and vitamin D deficiency. Case: This is a report of a 32-yr-old woman with bilateral femoral insufficiency fracture five days after emergency cesarean section due to preterm labor, twin pregnancy, and the history of a previous cesarean section at 33 wk. Antenatal repeated courses of betamethasone injections for fetal lung maturity, daily oral use of prednisolone for the history of miscarriage, immobilization, and vitamin D deficiency were the important contributing factors in her past medical history and lab investigations. The bone mineral density examination showed low bone density for the expected age. Conclusion: Clinicians, who deal with pregnant women, should consider the diagnosis of bilateral femoral insufficiency fracture in any pregnant women with pelvic pain. Awareness of risk factors of BFNF might help to reduce the rate of this complication. PMID- 29766151 TI - The effect of supernatant product of adipose tissue derived mesenchymal stem cells and density gradient centrifugation preparation methods on pregnancy in intrauterine insemination cycles: An RCT. AB - Background: One of the most important involved factors in pregnancy occurrence following intrauterine insemination (IUI) is semen sample preparation. Recently, supernatant product of adipose tissue derived mesenchymal stem cells (SPAS) method has been shown to improve semen parameters. Objective: To compare the effect of preparation methods in order to IUI, SPAS and density gradient centrifugation (DGC). Materials and Methods: This trial was done on 80 couples with male factor infertility who attend jihad daneshgahi infertility treatment center of Qom province, undergoing ovarian stimulation and IUI cycle. Various semen parameters including motility, count, DNA fragmentation and capacitation were evaluated before and after preparation. The effect of semen preparation methods and influence of various semen parameters on pregnancy occurrence were examined. Results: The overall clinical pregnancy rate was 17.5% per patient with no miscarriage. The pregnancy rate for DGC and SPAS were 5% (2 of 40) and 30% (12 of 40) respectively. Since there is no significant difference in improving motion parameters between two groups (except recovery of total number of motile spermatozoa), it seems that these parameters alone are not sufficient to predict IUI pregnancy outcome whereas in samples with >25 million motile spermatozoa in inseminate, there was a clear trend for a higher pregnancy rate for the sample processed using SPAS. Conclusion: Considering SPAS as a new and effective method leading to provide a combination of various improved semen parameters, is expected in near future. PMID- 29766154 TI - Endowing CuTCNQ with a new role: a high-capacity cathode for K-ion batteries. AB - Herein, copper-tetracyanoquinodimethane (CuTCNQ) with phase-I kinetics character has been proposed as an effective cathode for potassium-ion batteries. In a voltage range of 2-4.1 V (vs. K+/K), both cuprous cations (Cu+) and organic anions (TCNQ-) are electrochemically active, and they render a three-electron redox mechanism, thereby enabling CuTCNQ to yield a high specific discharge capacity of 244 mA h g-1. Even after 50 cycles, the discharge capacity of 170 mA h g-1 is retained at 50 mA g-1. In addition, when the current density is elevated to 1000 mA g-1, the discharge capacity is still maintained at 125 mA h g-1. These test data are among the best results reported for high-potential cathodes of potassium-ion batteries. PMID- 29766153 TI - A bioorthogonal turn-on fluorescent strategy for the detection of lysine acetyltransferase activity. AB - Lysine acetylation plays vital roles in the regulation of fundamental cellular processes, which is mediated by lysine acetyltransferases (KATs). Developing chemical biology probes for KAT activity detection is of important value in providing improved understanding of their biological functions. We reported a panel of "turn-on" fluorescent probes for sensitive and selective detection of KAT enzymatic activity through a simple mix-and-read format. Combined with bioorthogonal substrate labelling and click chemistry, these probes produced strong "turn-on" fluorescent signals in response to KAT-mediated acylation process. This chemical biology strategy diversifies the assay toolboxes to investigate functions and mechanisms of acetyltransferase enzymes. PMID- 29766155 TI - High-temperature thermoelectric transport behavior of the Al/gamma-Al2O3 interface: impact of electron and phonon scattering at nanoscale metal-ceramic contacts. AB - The thermoelectric transport properties of a metal-ceramic interface based on Al and gamma-Al2O3 are explored by employing the non-equilibrium Green's function formalism (NEGF) coupled with density functional theory (DFT). However, to acquire the phonon thermal conductance, the parameterized ReaxFF potential is utilized for computing the intrinsic force constants of propagating phonons across the interface. Several interfacial electronic properties such as the charge transfer, the potential barrier, and the atomic orbital overlap are critically analyzed based on the DFT derived results of the electrostatic difference potential, the electron density difference, and the spin-polarized density of states in the fully relaxed structure of the interface. Within the NEGF framework, both the electron and phonon transmission coefficients are estimated for the variations of bias voltage and temperature gradient across the interface. The strong orbital overlap and the scattering of electrons and phonons at the nanometer-size interface suppress the lattice thermal conductivity significantly compared to the electron transport, which in turn enhances the thermoelectric performance of the Al/Al2O3 composite, in contrast to the bulk material of Al. Moreover, a steep rise of power factor induced by the increased transmission of charge carriers with temperature improves the energy conversion efficiency of the material. The present findings could pave the way for developing thermoelectric materials based on metal-ceramic composites. PMID- 29766156 TI - Copper-catalyzed selective radical-radical cross-coupling for C-S bond formation: an access to alpha-alkylthionitriles. AB - A new protocol for C-S bond formation was developed by selective cross-coupling between a thiyl radical and an isobutyronitrile radical. Using this strategy, a series of valuable alpha-alkylthionitrile derivatives were synthesized from basic starting materials. Preliminary mechanistic investigation was performed by EPR and XAFS, revealing that the transient thiyl radical could be stabilized by a copper catalyst to a persistent one. Therefore, on the basis of the persistent radical effect, selective radical-radical cross-coupling between the thiyl radical and the isobutyronitrile radical was achieved successfully in this work. PMID- 29766157 TI - Dual-acting antitumor Pt(iv) prodrugs of kiteplatin with dichloroacetate axial ligands. AB - With the aim to obtain dual acting drugs able to target both nuclear DNA and mitochondria, Pt(iv) kiteplatin derivatives having dichloroacetate (DCA) ligands in axial positions have been synthesized. The rather fast hydrolysis (t1/2 of ca. 1 h) and reduction (by ascorbic acid) of these Pt(iv) derivatives did not impede a potent pharmacological effect on tumor cells. Moreover, similarly to kiteplatin, also the Pt(iv)-DCA compounds proved to be capable of overcoming oxaliplatin-resistance, which is particularly important in view of the fact that metastatic colorectal cancer is the third most common cancer in males and the second in females. The possible role of DCA released by the Pt(iv) compounds in eliciting the antiproliferative activity has also been investigated. Pt(iv)-DCA compounds determine a substantial increase of ROS production, blockage of oxidative phosphorylation, hypopolarization of the mitochondrial membrane, and caspase-3/7 mediated apoptotic cell death. PMID- 29766158 TI - Study of oxygen evolution reaction on amorphous Au13@Ni120P50 nanocluster. AB - The pursuit of catalysts to promote effective water oxidization to produce oxygen has become a research subject of high priority for water splitting. Here, first principles calculations are employed to study the water-splitting oxygen evolution reaction (OER) on ~1.5 nm diameter Au13@Ni120P50 core-shell nanoclusters. Water splitting to produce oxygen proceeds in four intermediate reaction steps (OH*, O*, OOH* and O2). Adsorption configurations and adsorption energies for the species involved in OER on both Au13@Ni120P50 cluster and Ni12P5(001) supported by Au are presented. In addition, thermodynamic free energy diagrams and kinetic potential energy changes are systematically discussed. We show that the third intermediate reaction (O* reacting with H2O to produce OOH*) of the four elementary steps is the reaction-determining step, which accords with previous results. Also, the catalytic performance of OER for Au13@Ni120P50 is better than that for Ni12P5(001) supported by Au in terms of reactive overpotential (0.74 vs. 1.58 V) and kinetic energy barrier (2.18 vs. 3.17 eV). The optimal kinetic pathway for OER is further explored carefully for the Au13@Ni120P50 cluster. The low thermodynamic overpotential and kinetic energy barrier make Au13@Ni120P50 promising for industrial applications as a good OER electrocatalyst candidate. PMID- 29766159 TI - A tunable THz absorber consisting of an elliptical graphene disk array. AB - Herein, we present an adjustable absorber consisting of a periodically patterned elliptical graphene disk array, which absorbs in the THz region. When a circularly polarized light beam illuminates this structure, its absorption spectrum displays two absorption peaks, which originate from the F-P resonance of the fundamental graphene edge plasmon mode along the major and minor axes of the elliptical graphene disk. The position of these two absorption peaks can be modulated by changing the Fermi level of graphene. Furthermore, both absorption bands can merge into one broadband by changing the length of the major and minor axes. The full width at half maximum (FWHM) of the broadband can reach up to 3.52 THz. In addition, by changing the incident elliptically polarized light, the peak ratio between the two absorption bands can also be tuned to convert the double band absorption to single-band absorption. PMID- 29766161 TI - Phonon-mediated stabilization and softening of 2D transition metal carbides: case studies of Ti2CO2 and Mo2CO2. AB - Two-dimensional transition metal carbides (MXenes) exhibit excellent thermodynamic stability, mechanical strength and flexibility, which make them promising candidates in flexible devices and reinforcements in nanocomposites. However, the dynamic stability may intrinsically determine the preferred adsorption sites of functional groups in MXenes and lead to premature failure under finite strain before approaching the elastic limits. It is found interestingly that different adsorption sites of the functional groups correspond to the different phonon stabilities and adsorption energies of MXenes, which can be attributed to different hybridization characteristics between the metal-d and O-pz states and delocalized electron behaviors around the metal atoms. Although both Ti2CO2 and Mo2CO2 possess high ideal strengths and superior flexibility, the premature phonon instabilities appear unexpectedly in distinct manners before approaching their elastic limits. An in-depth exploration of the soft modes and deformed electronic structures reveals that a continuously decreasing gap-opening at the Gamma point in Ti2CO2 increases after in-plane phonon instability due to the pseudo Jahn-Teller effect, differing from the out-of-plane phonon instability and semiconductor-metal transition under biaxial tension observed in MoS2. Although Mo2CO2 shows similar failure modes to graphene under uniaxial/biaxial tensions, the band crossings around the Fermi level are found to be responsible for its metallic character and elastic/phonon instabilities by modifying the elastic energy or electronic band energy, different from the gap opening appearing in graphene. Our results shed light onto the profound effect of the phonon instability on the preferable structure and strengths of MXenes, providing theoretical guidance on designing flexible MXene devices, raising a great challenge to the conventional strengthening theory by simply counting bonds. PMID- 29766160 TI - On the relationship between the structural and volumetric properties of solvated metal ions in O-donor solvents using new structural data in amide solvents. AB - The structures of the N,N-dimethylformamide (dmf), N,N-dimethylacetamide (dma), and N,N-dimethylpropionamide (dmp) solvated strontium and barium ions have been determined in solution using large angle X-ray scattering and EXAFS spectroscopy. The strontium ion has a mean coordination number (CN) between 6.2 and 6.8, and the barium ion has a mean CN between 7.1 and 7.8 in these amide solvents. The non integer numbers indicates that equilibria between different coordination numbers and geometries exist in these systems. Structural information of the alkali, alkaline earth, and selected transition metal and lanthanoid(iii) ions, and the halide ions in water, methanol, ethanol, dimethylsulfoxide, formamide, dmf and dma has been combined with previously reported standard partial molar volumes, V0. The ionic radii and charge densities (charge/ionic volume), and corresponding V0 values have been used to gain information on the relationship between structural and volumetric properties. For the structure-breaking ions, i.e. the alkali metal and halide ions, there is an almost linear relationship between the ionic radius and V0. On the other hand, for the structure-making ions, here the alkaline earth, transition metal and lanthanoid(iii) ions, a linear relationship is observed between the charge density and V0. Solvents with a well-defined bulk structure through hydrogen bonding, specifically, water, methanol and ethanol, will be more contracted through solvation than aprotic solvents, as the space between the solvent molecules is lost as a result of the hydrogen bonding. In this respect, methanol stands out as the most compressed solvent participating in solvation compared to its bulk structure. PMID- 29766162 TI - Fe-Si networks and charge/discharge-induced phase transitions in Li2FeSiO4 cathode materials. AB - Structural phase transitions of electrode materials are responsible for poor reversibility during charge/discharge cycling in Li-ion batteries. Using previously developed structural databases, we investigate a structural landscape for LixFeSiO4 systems at x = 1. Starting with low-energy Li2FeSiO4 crystal structures, we explore the crystal structures of the material in different states of charge. The as-prepared Li2FeSiO4 materials adopt low energy structures characterized by two-dimensional (2D) Fe-Si networks. After the removal of one Li per formula unit to form LiFeSiO4, the structures with three-dimensional (3D) diamond-like Fe-Si networks become more energetically favorable without a significant impact on the charge capacity, which agrees with previous experimental and theoretical work. However, we reveal that the structure with a 3D diamond-like Fe-Si network can further transform into a new structure at x = 1. And the Li atom is hard to reinsert into these new structures. Consequently the system is prevented from returning to the Li2FeSiO4 state. We believe that the formation of this new structure plays an important role in the loss of reversible capacity of Li2FeSiO4 electrode materials. PMID- 29766163 TI - Synchronous synthesis of Kirkendall effect induced hollow FeSe2/C nanospheres as anodes for high performance sodium ion batteries. AB - In this work, we have developed a simple and facile method to synchronously synthesize hollow FeSe2/C nanospheres using the Kirkendall effect. When evaluated as an anode for SIBs, the hollow FeSe2/C nanospheres exhibit a high discharge capacity retention of 474.1 mA h g-1 at 0.05 A g-1 (based on the calculation of FeSe2), which is very close to the theoretical capacity of FeSe2 (~500 mA h g-1). Meanwhile, hollow FeSe2/C also has a superior rate capability of 364.5 and 316.5 mA h g-1 even at 2.0 and 5.0 A g-1, respectively. The high performance of the hollow FeSe2/C nanospheres can be ascribed to the unique carbon coated hollow nanostructure. PMID- 29766164 TI - Electron transfer-induced reduction of organic halides with amines. AB - Reduction of a variety of organo halides was examined by using amines as a sacrificial hydrogen source. UV light-induced reduction of vinyl and aryl halides with triethylamine proceeded smoothly to give the corresponding reduced products. High temperature heating also caused the reduction and DABCO (1,4 diazabicyclo[2.2.2]octane) also served as a good reducing reagent. PMID- 29766165 TI - Effects of EPA and lipoic acid supplementation on circulating FGF21 and the fatty acid profile in overweight/obese women following a hypocaloric diet. AB - FGF21 has emerged as a key metabolism and energy homeostasis regulator. Dietary supplementation with eicosapentaenoic acid (EPA) and/or alpha-lipoic acid (LIP) has shown beneficial effects on obesity. In this study, we evaluated EPA and/or LIP effects on plasma FGF21 and the fatty acid (FA) profile in overweight/obese women following hypocaloric diets. At the baseline, FGF21 levels were negatively related to the AST/ALT ratio and HMW adiponectin. The weight loss did not cause any significant changes in FGF21 levels, but after the intervention FGF21 increased in EPA-supplemented groups compared to non-EPA-supplemented groups. EPA supplementation decreased the plasma n-6-PUFA content and increased n-3-PUFAs, mainly EPA and DPA, but not DHA. In the LIP-alone supplemented group a decrease in the total SFA and n-6-PUFA content was observed after the supplementation. Furthermore, EPA affected the desaturase activity, lowering Delta4D and raising Delta5/6D. These effects were not observed in the LIP-supplemented groups. Besides, the changes in FGF21 levels were associated with the changes in EPA, n-3 PUFAs, Delta5/6D, and n-6/n-3 PUFA ratio. Altogether, our study suggests that n-3 PUFAs influence FGF21 levels in obesity, although the specific mechanisms implicated remain to be elucidated. PMID- 29766166 TI - Hamiltonian replica exchange simulations of glucose oxidase adsorption on charged surfaces. AB - The Hamiltonian replica exchange Monte Carlo (H-REMC) algorithm was applied to study protein adsorption and its performance was compared with that of the temperature replica exchange Monte Carlo (T-REMC). Comparisons indicate that the simulation results are consistent but the computational efficiency is improved for H-REMC. H-REMC could accurately and efficiently identify the preferred orientations of glucose oxidase (GOx) on charged surfaces; different preferential GOx orientations on different surfaces and solution conditions could be spotted with a much fewer number of simulation runs. On positively charged surfaces, when electrostatic interactions dominate, the negatively charged GOx can be easily adsorbed with the "standing" orientation for which the substrate-binding domain is accessible to substrates. As the surface charge densities decrease and ionic strengths increase, there is an increasing contribution from the van der Waals (vdW) interactions, and thus more possible orientations appear. When the vdW interactions dominate, the unfavorable "front-lying" becomes the preferred orientation for which the substrate-binding domain is blocked by the surface. On negatively charged surfaces, though GOx has a net charge of -30 e under physiological conditions, the charged groups are unevenly distributed over the protein surface; the positive potential regions in the "back" of GOx enable the protein to be adsorbed on negatively charged surfaces with the "back-lying" orientation. The H-REMC provides an alternative method to accurately and efficiently probe the lowest-energy orientation of proteins adsorbed on surfaces for biotechnological applications. PMID- 29766167 TI - Ab initio calculation of energy levels of trivalent lanthanide ions. AB - The energy levels of Ln3+ ions are known to be only slightly dependent on the ion environment. This allows one to predict the spectra of f-f transitions in Ln3+ complexes using group theory and simple semiempirical models: Russell-Saunders scheme for spin-orbit coupling, ligand-field theory for the splitting of the electronic levels, and Judd-Ofelt parameterization for reproducing the intensity of f-f transitions. Nevertheless, a fully ab initio computational scheme employing no empirical parameterization and suitable for any asymmetrical environment of Ln3+ would be instructive. Here we present such a scheme based on the multireference SA-CASSCF/XMCQPDT2/SO-CASSCF (state-averaged complete active space SCF, quasi-degenerate perturbation theory, and spin-orbit CASSCF) approach for trivalent lanthanide ions from Ce3+ (4f1) to Yb3+ (4f13). To achieve the most accurate results, we analyse the factors that influence the accuracy of the calculation: basis set size, state averaging scheme, effect of the low-spin states on the energy gap between the high-spin states (e.g., effect of triplets on the septet-quintet gaps in f6 or f8 configurations), and radial and angular correlations in the 4f shell. Our calculated energy levels agree well with the experimental values. We have shown that low-lying highest-spin and second-highest spin states are reproduced very well, while for higher-lying states the accuracy of the calculation decreases. The procedure was verified by calculating optical emission spectra of NaYF4:Eu,Tb; YAG:Eu,Tb; and Tb(acac)3bpm (bpm is 2,2' bipyridine, acac is acetylacetonate, and YAG is yttrium aluminium garnet). For these compounds ligand-field induced electric-dipole transition intensities were calculated. PMID- 29766168 TI - Inelastic neutron scattering study of the lattice dynamics of the homologous compounds (PbSe)5(Bi2Se3)3m (m = 1, 2 and 3). AB - We report on the inelastic response of the homologous compounds (PbSe)5(Bi2Se3)3m for m = 1, 2 and 3 followed in a broad temperature range (50-500 K) using high resolution powder inelastic neutron scattering experiments. These results are complemented by low-temperature measurements of the specific heat (2-300 K). The evolution of the anisotropic crystal structure of these compounds with varying m, built from alternate Pb-Se and mBi-Se layers, only weakly influences the generalized phonon density of states. In all the three compounds, intense inelastic signals, likely mainly associated with the dynamics of the Pb atoms, are observed in the 4.5-6 meV low-energy range. The response of these low-energy modes to temperature variations indicates a conventional quasi-harmonic behavior over the whole temperature range investigated. The modes located above 8 meV show a minor temperature effect regardless of the value of m. The low-energy excess of vibrational modes manifests itself in the low-temperature specific heat as a pronounced peak in the Cp(T)/T3 data near 10 K. The lack of significant anharmonicity beyond that associated with the thermal expansion of the lattice suggests that the inherent disorder in the monoclinic unit cell and scattering at interlayer interfaces are the most important ingredients that limit the heat transport in this series of compounds. PMID- 29766169 TI - A new anthraquinoid ligand for the iron-catalyzed hydrosilylation of carbonyl compounds at room temperature: new insights and kinetics. AB - The reaction of 1-((2-(pyridin-2-yl)ethyl)amino)anthraquinone with either Fe(HMDS)2 or Li(HMDS)/FeCl2 allowed the preparation of a new anthraquinoid-based iron(ii) complex active in the hydrosilylations of carbonyls. The new complex Fe(2)2 was characterized by single-crystal X-ray diffraction, infrared spectroscopy, NMR, and high resolution mass spectrometry (electrospray ionization). Superconducting quantum interference device (SQUID) magnetometry established no spin crossover behavior with an S = 2 state at room temperature. This complex was determined to be an effective catalyst for the hydrosilylation of aldehydes and ketones, exhibiting turnover frequencies of up to 63 min-1 with a broad functional group tolerance by just using 0.25 mol% of the catalyst at room temperature, and even under solvent-free conditions. The aldehyde hydrosilylation makes it one of the most efficient first-row transition metal catalysts for this transformation. Kinetic studies have proven first-order dependences with respect to acetophenone and Ph2SiH2 and a fractional order in the case of the catalyst. PMID- 29766170 TI - Design of a wearable device for real-time screening of urinary tract infection and kidney disease based on smartphone. AB - In this study, we developed a novel wearable and low-cost device for qualitative screening of glucose (GLU), leukocytes (LEU), and nitrite (NIT) and for semi quantitative analysis of blood (BLD) and proteins (PRO) in the urine samples. The device can be attached to a diaper, and the results can be read by an app. The main functions of the device can be divided into sample collection, valve closing, and pad saturation; the recorded times for valve closing and pad saturation at four corners and pad saturation at the central parts are pseudo medians (Hodges-Lehmann estimator) of 3.55 (95% WCI, 3.45-3.72), 6.5 (95% WCI, 6 7), and 6 (95% WCI, 5.5-6.5) minutes, respectively. The RGB values in the reagent pads remain stable from 20 min to 480 min, which satisfies the requirement of regular diaper-wearing time. Pre-diagnostic results indicate high accuracy with good accuracy for the app recognition of five biomarkers in the urine samples, which makes it a promising tool for screening diseases, especially for the elderly healthcare. PMID- 29766171 TI - Electron donor and acceptor functionalized dithienylethenes: effects of charge density on photochromic properties. AB - Electron-donating triphenylamine and/or electron-withdrawing pyromellitic diimide (PMDI) are functionalized on dithienylethene (DTE) and three novel photochromic materials have been designed and successfully synthesized. All the compounds display reversible photochromism due to the molecular switching between ring closed isomers upon UV light irradiation and ring-open isomers upon exposure to visible light. Thus they can be applied as an anti-counterfeiting ink. Moreover, the study of the photoswitching kinetics reveals that both the ring-closing and ring-opening reactions are first-order reactions. Further charge population analysis discovers that the electron densities of the substituents at the DTE core have a dramatic influence on the photochromic properties. The incorporation of electron-donating triphenylamine groups at the alpha-position of the thiophene rings in the DTE unit facilitates the ring-closing reaction upon UV light irradiation. In contrast, the substitution of an electron-withdrawing PMDI unit in the DTE unit is beneficial to the ring-opening reaction upon irradiation of visible light. This work may help to understand the photochromism of DTE derivatives and provide a pathway for designing DTE-based photochromes with more or less sensitivity to UV or visible light. PMID- 29766172 TI - Effect of conformational flexibility on photophysics of bis-coumarins. AB - The fluorescence intensity of bis-coumarins linked via CONH and COO functionalities are shown to exhibit a strong dependance on solvent polarity. The presence of the intramolecular hydrogen bond between the C[double bond, length as m-dash]O oxygen atom of coumarin and amide-NH moieties reduces the number of thermodynamically populated conformations in both ground and electronically excited states and an anti-arrangement of coumarin units is favored. Additionally, the rigidity of the linker raises the barrier to the conical intersection with the ground state, and in non-polar solvents strong fluorescence is observed. Although changing the CONH linking position from 3-7' to 3-6', does not remarkably affect the photophysics, replacement with a flexible ester linker allows the molecule a greater degree of conformational freedom due to the absence of the intramolecular hydrogen bonding interaction. The photophysical effect of this is the appearance of two fluorescence bands, the relative intensity and spectral positions of which are sensitive to the environment. Theoretical explorations of the excited-state potential energy surfaces performed with the aid of the ADC(2) ab initio electronic structure theory method revealed an exceptional wealth of concomitant photophysical processes. In particular, two channels for radiationless deactivation of the excited state were found; the first is related to the inter-ring twist of the coumarin units, and the second is associated with the excited-state intramolecular proton-transfer (ESIPT) from the CONH linker to the coumarin core. PMID- 29766173 TI - A manganese porphyrin-alpha-cyclodextrin conjugate as an artificial enzyme for the catalytic epoxidation of polybutadiene. AB - We describe a manganese porphyrin-alpha-cyclodextrin conjugate as a catalyst for the epoxidation of cis-polybutadiene with trans-epoxide preference, which is a reverse stereoselectivity as compared to normal porphyrin catalysts. A clamp-like mechanism is proposed based on a combination of circular dichroism analysis, molecular modeling, and a series of epoxidation experiments. PMID- 29766174 TI - Efficient nitrogen fixation to ammonia on MXenes. AB - Active catalysts for nitrogen fixation (N2-fixation) have been widely pursued through constant efforts for industrial applications. Here, we report a family of catalysts, MXenes (M2X: M = Mo, Ta, Ti, and W; X = C and N), for application in N2-fixation based on density functional theory calculations. We find that the catalytic performance of MXenes strongly depends on the reaction energy in each reaction step. More exothermic steps lead to higher catalytic performance in the course of N2-fixation. We show that the reaction energy in N2-fixation is strongly affected by the charge transfer: (1) if N atoms gain more electrons in a step, the reaction is exothermic with a larger reaction energy; (2) if N atoms lose electrons in a step, the reaction is endothermic in general. We further show that Mo2C and W2C are highly active for N2-fixation due to their exothermic reactions and strong charge transfer, which may be applicable in the chemical engineering industry. PMID- 29766175 TI - Bismuth as a versatile cation for luminescence in coordination polymers from BiX3/4,4'-bipy: understanding of photophysics by quantum chemical calculations and structural parallels to lanthanides. AB - Coordination polymers (CPs) with bismuth(iii) as a connectivity centre have been prepared from BiX3 (X = Cl-I) and 4,4'-bipyridine (bipy) in order to implement Bi based luminescence. The products were obtained via different synthetic routes such as solution chemistry, melt syntheses or mechanochemical reactions. Five neutral and anionic 1D-CPs are presented that show a chemical parallel to trivalent lanthanides forming isostructural or closely related 1D-CPs, of which five additional compounds are described. Bi3+ proves to be a versatile cation for luminescence resulting from energy transfer processes between a metal and a ligand in the presented CPs. Quantum chemical calculations were carried out to investigate Bi3+-participation in the luminescence processes. The calculated results allow an assignment of the bright transitions composed of mainly metal-to ligand-charge transfer (MLCT) character. These results show that Bi3+ can form strongly luminescent coordination compounds with N-donor ligands. PMID- 29766176 TI - Modelling absorption and emission of a meso-aniline-BODIPY based dye with molecular mechanics. AB - Absorption and emission spectra of 8-(4-dimethylaminophenyl)-1,3,5,7-tetramethyl BODIPY have been calculated using Coupled Cluster (CC) approaches, Time-Dependent Density Functional Theory (TD-DFT) and a QM-informed MM approach. In the case of TD-DFT calculations solvent effects were included using the linear-response (LR), corrected linear response (cLR) and state specific (SS) Polarizable Continuum Model (PCM). We show that range-separated functionals give results in reasonable agreement with coupled cluster methods but both tend to overestimate excitation energies. Furthermore, we show that the SS-PCM approach is unable to provide a quantitative description of solvent effects in these systems, especially for the highly challenging charge-separated charge-transfer state. In contrast, the QM informed MM approach gives results in good agreement with experiment and we propose a scheme which can be used to directly compare theoretically obtained spectra with experimental ones. PMID- 29766177 TI - Redox-active, pyrene-based pristine porous organic polymers for efficient energy storage with exceptional cyclic stability. AB - A novel class of pyrene-based conjugated porous organic polymers having an N containing network was developed by employing Buchwald-Hartwig coupling for supercapacitor energy storage. The pristine polymer was found to exhibit a specific capacitance of 456 F g-1 at 0.5 A g-1 current density with excellent long-term cyclic stability. PMID- 29766178 TI - Ab initio calculations on the ground and excited electronic states of neutral and charged palladium monoxide, PdO0,+,. AB - Multi-reference configuration interaction and coupled cluster calculations were carried out for the ground and several low-lying excited electronic states for PdO, PdO+, and PdO-. Spin-orbit coupling, core-correlation effects, and large correlation-consistent basis sets were employed. We report bond lengths, spectroscopic constants, energetics, and potential energy curves for all of the considered states. Our calculations settle the assignment for the previously recorded peaks of the experimental PdO- photoelectron spectrum. We found that the spin-orbit effects mix considerably the Lambda-S states of PdO, changing dramatically the order of its low-lying electronic states. The ground states of these species were found to be 4Sigma- for PdO+, 3Sigma- for PdO, and 2Pi for PdO . Going from PdO to PdO+, the electron detaches from a sigma orbital which is localized on the metal. Going from PdO to PdO-, the additional electron attaches a pi orbital, which is more localized on oxygen. For PdO- we found six electronic states bound with respect to PdO. PMID- 29766179 TI - Piperidinium ionic liquids as electrolyte solvents for sustained high temperature supercapacitor operation. AB - The synthesis and physicochemical properties of a series of non-flammable, thermally stable alkyl ether containing piperidinium ionic liquid electrolytes, containing lithium bis(trifluoromethanesulfonyl)imide, are described along with the superior performance of a lithium-ion supercapacitor containing a piperidinium electrolyte compared to a standard carbonate-based electrolyte at 100 degrees C. PMID- 29766180 TI - A nitrocellulose membrane-based integrated microfluidic system for bacterial detection utilizing magnetic-composite membrane microdevices and bacteria specific aptamers. AB - Bacteria such as Acinetobacter baumannii (AB) can cause serious infections, resulting in high mortality if not diagnosed early and treated properly; there is consequently a need for rapid and accurate detection of this bacterial species. Therefore, we developed a new, nitrocellulose-based microfluidic system featuring AB-specific aptamers capable of automating the bacterial detection process via the activity of microfluidic devices composed of magnetic-composite membranes. Electromagnets were used to actuate these microfluidic devices such that the entire diagnostic process could be conducted in the integrated microfluidic system within 40 minutes with a limit of detection as low as 450 CFU per reaction for AB. Aptamers were used to capture AB in complex samples on nitrocellulose membranes, and a simple colorimetric assay was used to estimate bacterial loads. Given the ease of use, portability, and sensitivity of this aptamer-based microfluidic system, it may hold great promise for point-of-care diagnostics. PMID- 29766185 TI - The curcumin derivative WZ35 activates ROS-dependent JNK to suppress hepatocellular carcinoma metastasis. AB - Tumor metastasis is the leading cause of cancer death; due to the progress made in the elucidation of the mechanism of cancer cell metastasis, there is hope for patients with severe stages of cancer. Curcumin, as a novel anti-cancer drug, has been applied in cancer therapy; however, the toxicity of curcumin hinders its application. Herein, we constructed a novel derivative, WZ35, and evaluated its metastatic inhibition properties in vitro and in vivo. CCK-8 assay was performed to evaluate the tumor suppressive activity of WZ35. Cell apoptosis was detected by flow cytometry analysis. Transwell cell migration assay and RTCA were used to detect cell migration in mock and WZ35-treated cells. Western blotting was performed to analyze molecular alteration with different treatments. In this study, we found that curcumin and its derivative WZ35 could dramatically suppress proliferation, invasion, and migration of the hepatocellular HCCLM3, HepG2, and Huh7 cancer cells. Moreover, the cancer cell metastatic markers MMP-2, MMP-9, and N-cadherin were decreased, and E-cadherin was up-regulated. In addition, our data show that WZ35 promotes ROS-dependent JNK activation that is essential for WZ35 caused cell metastasis suppression. Moreover, the NAC and JNK inhibitor SP600125 could dramatically reverse WZ35-caused MMP-2, MMP-9, and N-cadherin reduction and E-cadherin up-regulation. We have also found that WZ35 exhibits powerful anti metastasis activity of HCCLM3 in vivo. In conclusion, our data indicated that WZ35 could be a candidate for the treatment of metastatic liver cancer patients. PMID- 29766190 TI - Toxicity assessment and mechanistic investigation of engineered monoclinic VO2 nanoparticles. AB - Growing interest in monoclinic VO2 nanoparticles (NPs) among consumers and the industries of window coatings, solar sensors etc. has brought particular attention to their safety concerns. The toxicity of this new class of nanomaterials in bacterial ecosystems has not yet been evaluated. The degree of crystallinity is a significant parameter that determines the performance of materials. However, the previously reported methods for toxicity assessment have neglected its influence. In this work, we systematically evaluated the toxicity of VO2 NPs with different degrees of crystallinity to four typical bacterial strains and studied the influence of physicochemical properties and aging treatment on their antibacterial effect. The results showed that the toxicity of VO2 nanoparticles was very low. Interestingly, we found that antibacterial properties of VO2 NPs were dependent on both bacterial strains and VO2 particle properties. In addition, the highly crystalline VO2 NPs were more toxic than normal and industrial VO2 particles. We attribute the crystallinity-related toxicity to the dissolved vanadium, the physical interactions between the bacteria and particles, and the generation of reactive oxygen species, as supported by our experimental results and theoretical calculation. PMID- 29766191 TI - Palladium mediated deallylation in fully aqueous conditions for native chemical ligation at aspartic and glutamic acid sites. AB - An efficient native chemical ligation approach at Asp and Glu sites is reported applying a hydrazide precursor, as a peptide thioester, and allyl protection at the side chain of Asp and Glu. The allyl protection was efficiently removed, after the ligation step, using the water-soluble palladium complex [Pd(allyl)Cl]2 and glutathione within a few minutes under fully aqueous conditions. PMID- 29766192 TI - Mixed carboxylic-sulfonic anhydride in reaction with imines: a straightforward route to water-soluble beta-lactams via a Staudinger-type reaction. AB - The first example of employing a mixed carboxylic-sulfonic anhydride in reaction with imines is reported. Unlike its well-studied isostere homophthalic anhydride, benzo[c][1,2]oxathiin-3(4H)-one 1,1-dioxide gave no product of a formal [4 + 2] cycloaddition and only followed an alternative reaction pathway toward beta lactams, presumably, via a formal [2 + 2] cycloaddition (a Staudinger-type reaction). Optimized reaction conditions involve the use of triethylamine as a base promoter, which also allows isolating the product beta-lactam benzene sulfonic acids as respective triethylammonium salts by conventional column chromatography. The reaction shows some preference to trans-isomer formation; pure diastereomers can be isolated in some cases. PMID- 29766193 TI - Electrostatics and Soft Matter: a Themed Collection in memory of Per Linse. PMID- 29766194 TI - Comparison of riboflavin-derived flavinium salts applied to catalytic H2O2 oxidations. AB - A series of flavinium salts, 5-ethylisoalloxazinium, 5-ethylalloxazinium, and 1,10-ethylene-bridged alloxazinium triflates, were prepared from commercially available riboflavin. This study presents a comparison between their optical and redox properties, and their catalytic activity in H2O2 oxidations of sulfide, tertiary amine, and cyclobutanone. Reflecting the difference between the pi conjugated ring structures, the flavinium salts displayed very different redox properties, with reduction potentials in the order of: 5-ethylisoalloxazinium > 5 ethylalloxazinium > 1,10-ethylene-bridged alloxazinium. A comparison of their catalytic activity revealed that 5-ethylisoalloxazinium triflate specifically oxidises sulfide and cyclobutanone, and 5-ethylalloxazinium triflate smoothly oxidises tertiary amine. 1,10-Bridged alloxazinium triflate, which can be readily obtained from riboflavin in large quantities, showed moderate catalytic activity for the H2O2 oxidation of sulfide and cyclobutanone. PMID- 29766195 TI - Cascade double isocyanide insertion and C-N coupling of 2-iodo-2'-isocyano-1,1' biphenyls. AB - A palladium-catalyzed double isocyanide insertion using 2-iodo-2'-isocyano-1,1' biphenyls followed by copper-catalyzed intramolecular C-N coupling, delivering a unique heterocyclic structure containing both phenanthridine and carbazole scaffolds, has been developed. In this cascade process, four chemical bonds, including two C-C, one C-O, and one C-N bonds are formed consecutively without isolating an intermediate. The strategy of using a functionalized isocyanide in double insertion provides a quick approach for constructing heterocyclic systems with high bond-forming efficiency. PMID- 29766196 TI - Gold-catalyzed C5-alkylation of indolines and sequential oxidative aromatization: access to C5-functionalized indoles. AB - A novel protocol for the synthesis of C5-alkylated indole derivatives via a gold catalyzed reaction of indolines with diazo compounds and subsequent oxidative aromatization has been developed. C-H bond functionalization selectively occurs at the C5-position of indolines without a directing group. The experimental operation is simple and the whole process can be manipulated in one-pot. PMID- 29766197 TI - Selenoprotein W as a molecular target of d-amino acid oxidase is regulated by d amino acid in chicken neurons. AB - Selenoprotein W (SelW) is an important member of the avian selenoprotein family. It is well known for its important role in protecting neurons from oxidative stress during neuronal development. d-Amino acid (d-serine), as a neurotransmitter in the central nervous system (CNS), can mediate neurotoxicity. d-Amino acid oxidase (DAAO) is responsible for regulating the d-serine levels in cells. However, the correlation between SelW and DAAO is not clear yet. To investigate the regulations between SelW and DAAO, chicken embryo monolayer neurons were treated with d-serine and/or Se. In this study, we predicted molecular binding between SelW and DAAO. These results showed that the 9-16, 18, 41-47 and 66 residues of SelW could combine with the DAAO, which suggested that chicken SelW might be the target of DAAO. We determined the DAAO activity and the mRNA expression of SelW in in vitro cultured chicken embryo primitive neuron cells. d-Serine influenced the activity of DAAO and, moreover, a significant increase in the mRNA expression of SelW was found in neurons treated with Se. Notably, we also observed changes in the expression of SelW and DAAO when neurons were treated with various concentrations of d-serine and Se. In conclusion, these data suggest that d-serine could regulate the mRNA expression of SelW by interfering with the activity of DAAO in chicken embryo neurons. PMID- 29766198 TI - Aquaporins in cancer development: opportunities for bioinorganic chemistry to contribute novel chemical probes and therapeutic agents. AB - Aquaporins (AQPs) are membrane proteins allowing permeation of water, glycerol & hydrogen peroxide across biomembranes, and playing an important role in water homeostasis in different organs, exocrine gland secretion, urine concentration, skin moisturization, fat metabolism and neural signal transduction. Notably, a large number of studies showed that AQPs are closely associated with cancer biological functions and expressed in more than 20 human cancer cell types. Furthermore, AQP expression is positively correlated with tumour types, grades, proliferation, migration, angiogenesis, as well as tumour-associated oedema, rendering these membrane channels attractive as both diagnostic and therapeutic targets in cancer. Recent developments in the field of AQPs modulation have identified coordination metal-based complexes as potent and selective inhibitors of aquaglyceroporins, opening new avenues in the application of inorganic compounds in medicine and chemical biology. The present review is aimed at providing an overview on AQP structure and function, mainly in relation to cancer. In this context, the exploration of coordination metal compounds as possible inhibitors of aquaporins may open the way to novel chemical approaches to study AQP roles in tumour growth and potentially to new drug families. Thus, we describe recent results in the field and reflect upon the potential of inorganic chemistry in providing compounds to modulate the activity of "elusive" membrane targets as the aquaporins. PMID- 29766200 TI - Highly enantioselective synthesis of alpha-tertiary chiral amino acid derivatives through rhodium-catalyzed asymmetric arylation of cyclic N-sulfonyl alpha ketimino esters. AB - By employing an easily available, exceptionally simple sulfur-olefin ligand, a highly enantioselective rhodium-catalyzed arylation of cyclic N-sulfonyl alpha ketimino esters with arylboronic acids has been developed. The reaction allows facile access to a wide range of alpha,alpha-gem-diaryl substituted chiral amino esters in excellent yields with extremely high enantioselectivities (uniformly 98 99% ee). The synthetic utility of this approach was highlighted by the efficient synthesis of a series of interesting molecules including unique chiral spirocycles bearing 2,3-dihydrobenzofuran and 1H-isoindole skeletons. PMID- 29766199 TI - Promoter free allylation of trichloroacetimidates with allyltributylstannanes under thermal conditions to access the common 1,1'-diarylbutyl pharmacophore. AB - 1,1'-Diarylbutyl groups are a common pharmacophore found in many biologically active small molecules. To access these systems under mild conditions, the reaction of diarylmethyl trichloroacetimidates with allyltributylstannanes was explored. Simply heating allyltributylstannane with the trichloroacetimidate resulted in substitution of the imidate with an allyl group. Unlike other methods used to access these systems, no strong base, transition metal catalyst, Bronsted acid or Lewis acid promoter was required to affect the transformation. Conversions are best with electron rich benzylic trichloroacetimidate systems, where excellent yields are achieved just by refluxing the reactants together in nitromethane. PMID- 29766201 TI - Selenium deficiency inhibits differentiation and immune function and imbalances the Th1/Th2 of dendritic cells. AB - Selenium (Se) deficiency inhibits immune cell differentiation, affects immune response, and leads to cellular and humoral immune dysfunction. However, the impact of Se deficiency on the differentiation and Th1/Th2 balance of dendritic cells is still unclear. In this study, we replicated a model of Se-deficient chickens by feeding the chickens with a low-Se diet (i.e., the content of Se is 0.008 mg per kg diet). On this basis, we explored the effect of Se deficiency on the differentiation of chicken dendritic cells by induction culture of peripheral blood monocyte cells. We induced chicken dendritic cells by incubating mononuclear cells with a 100 ng mL-1 recombinant chicken granulocyte-macrophage colony-stimulating factor and 20 ng mL-1 recombinant chicken IL-4 for total 7 days. The results showed that Se deficiency decreased the expression of cell surface markers including CD11c, CD40, CD86, and MHC II. Furthermore, we analyzed the cytokine profiles using real-time quantitative PCR and ELISA. The results indicated that Se deficiency inhibited the expression of selenoproteins and changed the secretion of IL-10, IL-12p40, and IFN-gamma. Additionally, Se deficiency weakened the ability of dendritic cells to stimulate the proliferation of mixed allogeneic lymphocytes. In conclusion, Se deficiency suppressed the differentiation and immune function of chicken dendritic cells by down-regulating the expression of CD11c, CD40, CD86, MHC II, and selenoproteins. The result also showed that the Th1/Th2 imbalance was induced by enhancing the secretion of Th1 type cytokine IL-12p40 and IFN-gamma and reducing that of Th2-type cytokine IL 10. Our findings contribute to understanding the mechanism of Se deficiency in the differentiation and immune function of chicken dendritic cells. PMID- 29766202 TI - Photochemical device for selective detection of phenol in aqueous solutions. AB - We demonstrate that a lab-on-a-chip device (hereafter termed a photochemical phenol sensor) that integrates a photocatalytic long-period fiber grating (PLPFG), fiber Bragg grating (FBG), polymer membrane, ultraviolet (UV) visible light, and microchannels can be exploited to selectively detect phenol in aqueous solutions. The novel PLPFG consisted of a thinned long-period fiber grating (LPFG) and a UV-visible-light-driven Er3+:YAlO3/SiO2/TiO2 (EYST) coating. The polymer membrane with high phenol permselectivity was synthesized using PEBA2533 doped with beta-cyclodextrin and was wrapped around the EYST surface, thus forming a microchannel between the membrane and PLPFG to enable the injection and outflow of standard analytes. Subsequently, a Z-shaped microchannel in a PMMA plate was fabricated and employed as a storage chamber for phenol analytes. To realize the EYST photocatalyst, UV-visible-light was irradiated using a tapered UV optical array. Thereafter, to eliminate the effect of temperature on the device, a FBG sensor as a temperature-compensating element was presented. To demonstrate the sensitivity and selectivity of the proposed device, we investigated the effects of the EYST coating's thickness, phenol-based analytes and temperature on the sensitivity and accuracy of the device for measuring phenol concentrations. The results of our present study suggest that the photochemical sensor is effective over a wide range of concentrations (7.5 MUg L 1 to 100 mg L-1), pH values (2.0 to 14.0), and temperatures (10 to 48 degrees C) for selective detection of phenol in aqueous solutions. Thus, the proposed lab-on a-chip device may be useful for accurate determination of phenol concentrations in real samples. PMID- 29766203 TI - A general autocatalytic route toward silica nanospheres with ultrasmall sized and well-dispersed metal oxide nanoparticles. AB - A facile and efficient approach for the synthesis of metal ions@silica nanospheres is proposed by using an intramolecular autocatalytic route. By the rational selection of reactants, metal ions@silica nanospheres can be obtained via successive spontaneous reactions under near neutral conditions. After thermal treatment, spherical silica equipped with ultrasmall and highly dispersed metal oxides nanoparticles was obtained. PMID- 29766204 TI - Adiponectin administration alleviates DSS-induced colonic inflammation in Caco-2 cells and mice. AB - BACKGROUND: Adiponectin, a protein hormone produced by adipose tissues, exhibits anti-inflammatory functions in various models. This study was investigated the effects of adiponectin on dextran sodium sulfate (DSS)-colonic injury, inflammation, apoptosis, and intestinal barrier dysfunction in Caco-2 cell and mice. MATERIALS AND METHODS: The results showed that DSS caused inflammatory response and intestinal barrier dysfunction in vitro and in vivo. Adiponectin injection alleviated colonic injury and rectal bleeding in mice. Meanwhile, adiponectin downregulated colonic IL-1beta and TNF-alpha expressions and regulated apoptosis relative genes to attenuate DSS-induced colonic inflammation and apoptosis. Adiponectin markedly reduced serum lipopolysaccharide concentration, a biomarker for intestinal integrity, and enhanced colonic expression of tight junctions (ZO-1 and occludin). The in vitro data further demonstrated that adiponectin alleviated DSS-induced proinflammatory cytokines production and the increased permeability in Caco-2 cells. CONCLUSION: Adiponectin plays a beneficial role in DSS-induced inflammation via alleviating apoptosis and improving intestinal barrier integrity. PMID- 29766205 TI - [Effective nutritional supplements or pharmaceuticals : How can they be classified and used?] AB - Health awareness is increasing in the population, which means that more and more dietary supplements are being bought. These are very similar to well known medicines and sometimes indistinguishable both for healthcare professionals as well as for the consumer. Unclear legal terms and missing maximum quantities and substance lists contribute to this. Both product groups are subject to completely different legal norms and have different market access procedures and risk assessment systems. They also differ in purpose. Thus, medicines are used to cure, alleviate and prevent disease. In contrast dietary supplements should complement the normal diet. Whether this is always necessary and useful is contentiously discussed. Last but not least, there is also a great deal of controversy over the amounts of nutrients added in food supplements. European rules on the use of nutritional supplements for nutrition and health claims in foodstuffs are intended to protect consumers from misleading and false promises; however, numerous competition procedures show that further action is needed in this respect. PMID- 29766206 TI - Sustainable partnerships for NCD prevention: implications for public health. PMID- 29766207 TI - Risks and prevention of surgical fires : A systematic review. AB - Surgically induced fire is a life-threatening hazard; this topic has received little attention, although only 3 factors, the so-called fire triad, are needed for surgical fires to occur: an oxidizer, fuel and an ignition source. This systematic review aims to determine the impact of each component and to delegate every staff member an area of responsibility, thus ensuring patient health through prevention or protection. The trial was registered in Prospero CRD42018082656. A database search of eligible, preferably evidence-based studies was conducted. The Robins-I tool for assessing the risk of bias revealed a moderate risk of bias. Due to insufficient data, the main findings of these studies could not be summarized through a quantitative synthesis; therefore, a qualitative synthesis is outlined. The results are summarized according to the roles of the fire triad and discussed. (1) Role of the oxidizer: oxygen is the key component of the triad. Safe oxygen delivery is important. An oxygen-enriched environment (ORE) is caused by draping and is preferably prevented by suctioning. Fuel characteristics are affected by varying oxygen concentrations. (2) Role of the ignition source: electrocauterization is the most common ignition source, followed by lasers. Less common ignition sources include fiberoptic cables and preparative solutions, petrol or acetone. (3) Role of the fuel: surgical drapes are one of the most common fuels for surgical fires followed by the patient's hair and skin. Skin preparation solutions are among the less common fuels. Many fire-resistant materials have been tested that do not remain fire resistant in ORE. It was concluded that the main problem is defining the real extent of this hazard. Exact numbers and exact condition protocols are needed; therefore, standardized registration of every fire and future studies with much evidence are needed. Immediate prevention consists of close attention to patient safety to prevent surgical fires from happening. PMID- 29766208 TI - [Adequate anti-infective treatment : Importance of individual dosing and application]. AB - Sepsis-induced changes in pharmacokinetic parameters are a well-known problem in intensive care medicine. Dosing of antibiotics in this setting is therefore challenging. Alterations to the substance-specific kinetics of anti-infective substances have an effect on the distribution and excretion processes in the body. Increased clearance and an increased distribution volume (Vd) and particularly compromized organ function with reduced antibiotic elimination are often encountered in patients with sepsis. Renal replacement treatment, which is frequently used in intensive care medicine, represents a substantial intervention in this system. Current international guidelines recommend individualized dosing strategies and adaptation of doses according to measured serum levels and pharmacokinetic/pharmacodynamic (PK/PD) parameters as concepts to optimize anti infective therapy in the critically ill. Likewise, the recommendation to adjust the administration form of beta-lactam antibiotics to prolonged or continuous infusion can be found increasingly more often in the literature. This article reviews the background of the individual dosing in intensive care patients and their applicability to the clinical routine. PMID- 29766211 TI - [Ethanol injection for ablation of persistent bile leaks]. PMID- 29766210 TI - Re: The article "Detrusor pressures in urodynamic studies during voiding in women". PMID- 29766212 TI - [Artery-first approach for partial pancreatoduodenectomy]. PMID- 29766209 TI - Is cannabis a risk factor for suicide attempts in men and women with psychotic illness? AB - OBJECTIVE: To investigate whether recent cannabis use by men and women with psychotic disorders was associated with increased risk of suicide attempt, and to determine associated factors, stratified by sex. METHODS: Data from 1065 men and 725 women interviewed in the Australian national survey of psychosis were analysed to model separately, for each sex, the impact of daily, casual or no past-year cannabis use and other risk factors including age, on a past-year suicide attempt. RESULTS: In the past year, 168 (9.4%) participants attempted suicide. Unadjusted analyses showed daily cannabis users of both sexes had significantly increased odds of attempting suicide compared to non-users. After adjusting for confounding factors, this relationship was no longer significant. Depression had the strongest association with attempting suicide for both sexes. Sex differences in other risk factors were observed. In post hoc analysis, daily cannabis use was associated with higher odds of attempting suicide in older men compared to non-users; this was not found in younger men or women. CONCLUSIONS: Associations between past-year cannabis use and suicide attempts were confounded by other factors (depression, loneliness, homelessness and hallucinations). The possibility of greater risk of suicidal behaviour with regular cannabis use for older men should be considered. PMID- 29766213 TI - Purpuric rash and right infectious endocarditis. PMID- 29766214 TI - Caution for chlorhexidine gluconate use for oral care: insufficient data. PMID- 29766215 TI - The prevalence of burnout. PMID- 29766217 TI - Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability. AB - Glutamate is the most abundant neurotransmitter of the central nervous system, as the majority of neurons use glutamate as neurotransmitter. It is also well known that this neurotransmitter is not restricted to synaptic clefts, but found in the extrasynaptic regions as ambient glutamate. Extrasynaptic glutamate originates from spillover of synaptic release, as well as from astrocytes and microglia. Its concentration is magnitudes lower than in the synaptic cleft, but receptors responding to it have higher affinity for it. Extrasynaptic glutamate receptors can be found in neuronal somatodendritic location, on astroglia, oligodendrocytes or microglia. Activation of them leads to changes of neuronal excitability with different amplitude and kinetics. Extrasynaptic glutamate is taken up by neurons and astrocytes mostly via EAAT transporters, and astrocytes, in turn metabolize it to glutamine. Extrasynaptic glutamate is involved in several physiological phenomena of the central nervous system. It regulates neuronal excitability and synaptic strength by involving astroglia; contributing to learning and memory formation, neurosecretory and neuromodulatory mechanisms, as well as sleep homeostasis.The extrasynaptic glutamatergic system is affected in several brain pathologies related to excitotoxicity, neurodegeneration or neuroinflammation. Being present in dementias, neurodegenerative and neuropsychiatric diseases or tumor invasion in a seemingly uniform way, the system possibly provides a common component of their pathogenesis. Although parts of the system are extensively discussed by several recent reviews, in this review I attempt to summarize physiological actions of the extrasynaptic glutamate on neuronal excitability and provide a brief insight to its pathology for basic understanding of the topic. PMID- 29766216 TI - Impact of angiotensin-converting enzyme inhibitors or receptor blockers on post ICU discharge outcome in patients with acute kidney injury. AB - PURPOSE: Acute kidney injury (AKI) is associated with the activation of the renin angiotensin system. Whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) improve outcome in patients recovering from AKI remains unexplored. The purpose was to investigate the association between prescription of ACEi/ARB at intensive care unit (ICU) discharge and 1-year outcome in patients recovering from AKI. METHODS: Association between ACEi/ARB and 1-year mortality rate was explored in 1551 patients discharged from 21 European ICUs in an observational cohort. One-year all-cause mortality after ICU discharge was the primary endpoint. AKI was defined using the kidney disease improvement global outcome definition. Propensity score matching was used to consider the probability to receive ACEi/ARB at ICU discharge and included chronic heart failure, ACEi/ARB on ICU admission, Charlson Comorbidity Index, age, diabetes mellitus, chronic kidney disease, estimated glomerular filtration rate and arterial blood pressure at ICU discharge vasopressors and renal replacement therapy. RESULTS: Overall, 1-year mortality was 28 and 15% in patients with AKI (n = 611, 39%) and without AKI (n = 940), respectively. In patients with AKI, unadjusted, adjusted and propensity-score matched 1-year mortality rates were lower in patients treated with ACEi/ARB at ICU discharge [HR of 0.55 (0.35-0.89), HR of 0.45 (0.27-0.75), and HR of 0.48 (0.27-0.85, p < 0.001), respectively]. These results were consistent across sensitivity analysis. No association was observed in patients without AKI. CONCLUSIONS: In patients discharged alive from the ICU after experiencing AKI, ACEi/ARB prescription at discharge is associated with a decrease in 1-year mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01367093. Registered on 6 June 2011. PMID- 29766218 TI - QTL mapping and epistatic interaction analysis of field resistance to sudden death syndrome (Fusarium virguliforme) in soybean. AB - KEY MESSAGE: Two interactive quantitative trait loci (QTLs) controlled the field resistance to sudden death syndrome (SDS) in soybean. The interaction between them was confirmed. Sudden death syndrome (SDS), caused by Fusarium virguliforme, is a major disease of soybean [Glycine max (L.) Merr.] in the United States. Breeding for soybean resistance to SDS is the most cost-effective method to manage the disease. The objective of this study was to identify and characterize quantitative trait loci (QTLs) underlying field resistance to SDS in a recombinant inbred line population from the cross GD2422 * LD01-5907. This population was genotyped with 1786 polymorphic single nucleotide polymorphisms (SNPs) using SoySNP6 K iSelect BeadChip and evaluated for SDS resistance in a naturally infested field. Four SDS resistance QTLs were mapped on Chromosomes 4, 8, 12 and 18. The resistant parent, LD01-5907, contributed the resistance alleles for the QTLs on Chromosomes 8 and 18 (qSDS-8 and qSDS-18), while the other parent, GD2422, provided the resistance alleles for the QTLs on Chromosomes 4 and 12 (qSDS-4 and qSDS-12). The minor QTL on Chromosome 12 (qSDS-12) is novel. The QTL on Chromosomes 8 and 18 (qSDS-8 and qSDS-18) overlapped with two soybean cyst nematode resistance-related loci, Rhg4 and Rhg1, respectively. A significant interaction between qSDS-8 and qSDS-18 was detected by disease incidence. Individual effects together with the interaction effect explained around 70% of the phenotypic variance. The epistatic interaction of qSDS-8 and qSDS-18 was confirmed by the field performance across multiple years. Furthermore, the resistance alleles at qSDS-8 and qSDS-18 were demonstrated to be recessive. The SNP markers linked to these QTLs will be useful for marker-assisted breeding to enhance the SDS resistance. PMID- 29766220 TI - Reinhard Niessner and Andreas Schaffer: Organic trace analysis. PMID- 29766219 TI - Association study of genetic variants in estrogen metabolic pathway genes and colorectal cancer risk and survival. AB - Although studies have investigated the association of genetic variants and the abnormal expression of estrogen-related genes with colorectal cancer risk, the evidence remains inconsistent. We clarified the relationship of genetic variants in estrogen metabolic pathway genes with colorectal cancer risk and survival. A case-control study was performed to assess the association of single-nucleotide polymorphisms (SNPs) in ten candidate genes with colorectal cancer risk in a Chinese population. A logistic regression model and Cox regression model were used to calculate SNP effects on colorectal cancer susceptibility and survival, respectively. Expression quantitative trait loci (eQTL) analysis was conducted using the Genotype-Tissue Expression (GTEx) project dataset. The sequence kernel association test (SKAT) was used to perform gene-set analysis. Colorectal cancer risk and rs3760806 in SULT2B1 were significantly associated in both genders [male: OR = 1.38 (1.15-1.66); female: OR = 1.38 (1.13-1.68)]. Two SNPs in SULT1E1 were related to progression-free survival (PFS) [rs1238574: HR = 1.24 (1.02 1.50), P = 2.79 * 10-2; rs3822172: HR = 1.30 (1.07-1.57), P = 8.44 * 10-3] and overall survival (OS) [rs1238574: HR = 1.51 (1.16-1.97), P = 2.30 * 10-3; rs3822172: HR = 1.53 (1.67-2.00), P = 2.03 * 10-3]. Moreover, rs3760806 was an eQTL for SULT2B1 in colon samples (transverse: P = 3.6 * 10-3; sigmoid: P = 1.0 * 10-3). SULT2B1 expression was significantly higher in colorectal tumor tissues than in normal tissues in the Cancer Genome Atlas (TCGA) database (P < 1.0 * 10 4). Our results indicated that SNPs in estrogen metabolic pathway genes confer colorectal cancer susceptibility and survival. PMID- 29766223 TI - Does Wildfire Open a Policy Window? Local Government and Community Adaptation After Fire in the United States. AB - Becoming a fire adapted community that can coexist with wildfire is envisioned as a continuous, iterative process of adaptation, but it is unclear how communities may pursue adaptation. Experience with wildfire and other natural hazards suggests that disasters may open a "window of opportunity" leading to local government policy changes. We examined how destructive wildfire affected progress toward becoming fire adapted in eight locations in the United States. We found that community-level adaptation following destructive fires is most common where destructive wildfire is novel and there is already government capacity and investment in wildfire regulation and land use planning. External funding, staff capacity, and the presence of issue champions combined to bring about change after wildfire. Locations with long histories of destructive wildfire, extensive previous investment in formal wildfire regulation and mitigation, or little government and community capacity to manage wildfire saw fewer changes. Across diverse settings, communities consistently used the most common tools and actions for wildfire mitigation and planning. Nearly all sites reported changes in wildfire suppression, emergency response, and hazard planning documents. Expansion in voluntary education and outreach programs to increase defensible space was also common, occurring in half of our sites, but land use planning and regulations remained largely unchanged. Adaptation at the community and local governmental level therefore may not axiomatically follow from each wildfire incident, nor easily incorporate formal approaches to minimizing land use and development in hazardous environments, but in many sites wildfire was a focusing event that inspired reflection and adaptation. PMID- 29766222 TI - Cisplatin increases the number of enterochromaffin cells containing substance P in rat intestine. AB - We previously reported that cisplatin potentiated ileal 5-hydroxytryptamine (5 HT) metabolism and caused pathological changes with an inflammatory response in the delayed phase (72 h) after administration to rats. In the present study, we further investigated the time-dependent effect of cisplatin on ileal 5-HT metabolism and the effects of combining cisplatin and anti-inflammatory drugs on ileal tryptophan hydroxylase expression and pica (the consumption of non nutritive materials such as kaolin). Cyclooxygenase-2 (COX-2) expression was significantly increased at 24 h after cisplatin (5 mg/kg, intraperitoneal) administration. Cisplatin significantly increased ileal 5-HT content at 48 h after administration and the number of L-tryptophan hydroxylase-expressing cells (i.e., enterochromaffin cells) in the ileal mucosa within 24 h after administration. It also caused a significant increase in the number of substance P-expressing cells. Immunohistochemical double staining revealed that most of the enterochromaffin cells contained substance P. Neither daily treatment with dexamethasone (1 mg/kg, subcutaneous) nor meloxicam (3 mg/kg, subcutaneous), a selective COX-2 inhibitor, affected the cisplatin-induced increase in the number of enterochromaffin cells. Meloxicam had no effect on cisplatin-induced pica, although dexamethasone almost completely inhibited it. This study demonstrated that cisplatin administration induced COX-2 expression and increased the number of enterochromaffin cells in the acute phase (i.e., within 24 h). However, COX-2 expression in the ileum seems to have little direct effect on the mechanism of the induction of enterochromaffin cells and pica. PMID- 29766221 TI - Tracking emerging mycotoxins in food: development of an LC-MS/MS method for free and modified Alternaria toxins. AB - Mycotoxins produced by Alternaria fungi are ubiquitous food contaminants, but analytical methods for generating comprehensive exposure data are rare. We describe the development of an LC-MS/MS method covering 17 toxins for investigating the natural occurrence of free and modified Alternaria toxins in tomato sauce, sunflower seed oil, and wheat flour. Target analytes included alternariol (AOH), AOH-3-glucoside, AOH-9-glucoside, AOH-3-sulfate, alternariol monomethyl ether (AME), AME-3-glucoside, AME-3-sulfate, altenuene, isoaltenuene, tenuazonic acid (TeA), tentoxin (TEN), altertoxin I and II, alterperylenol, stemphyltoxin III, altenusin, and altenuic acid III. Extensive optimization resulted in a time- and cost-effective sample preparation protocol and a chromatographic baseline separation of included isomers. Overall, adequate limits of detection (0.03-9 ng/g) and quantitation (0.6-18 ng/g), intermediate precision (9-44%), and relative recovery values (75-100%) were achieved. However, stemphyltoxin III, AOH-3-sulfate, AME-3-sulfate, altenusin, and altenuic acid III showed recoveries in wheat flour below 70%, while their performance was stable and reproducible. Our pilot study with samples from the Austrian retail market demonstrated that tomato sauces (n = 12) contained AOH, AME, TeA, and TEN in concentrations up to 20, 4, 322, and 0.6 ng/g, while sunflower seed oil (n = 7) and wheat flour samples (n = 9) were contaminated at comparatively lower levels. Interestingly and of relevance for risk assessment, AOH-9-glucoside, discovered for the first time in naturally contaminated food items, and AME-3-sulfate were found in concentrations similar to their parent toxins. In conclusion, the established multi-analyte method proved to be fit for purpose for generating comprehensive Alternaria toxin occurrence data in different food matrices. Graphical abstract ?. PMID- 29766224 TI - Stable and Enriched Cenarchaeum symbiosum and Uncultured Betaproteobacteria HF1 in the Microbiome of the Mediterranean Sponge Haliclona fulva (Demospongiae: Haplosclerida). AB - Sponges harbor characteristic microbiomes derived from symbiotic relationships shaping their lifestyle and survival. Haliclona fulva is encrusting marine sponge species dwelling in coralligenous accretions or semidark caves of the Mediterranean Sea and the near Atlantic Ocean. In this work, we characterized the abundance and core microbial community composition found in specimens of H. fulva by means of electron microscopy and 16S amplicon Illumina sequencing. We provide evidence of its low microbial abundance (LMA) nature. We found that the H. fulva core microbiome is dominated by sequences belonging to the orders Nitrosomonadales and Cenarchaeales. Seventy percent of the reads assigned to these phylotypes grouped in a very small number of high-frequency operational taxonomic units, representing niche-specific species Cenarchaeum symbiosum and uncultured Betaproteobacteria HF1, a new eubacterial ribotype variant found in H. fulva. The microbial composition of H. fulva is quite distinct from those reported in sponge species of the same Haliclona genus. We also detected evidence of an excretion/capturing loop between these abundant microorganisms and planktonic microbes by analyzing shifts in seawater planktonic microbial content exposed to healthy sponge specimens maintained in aquaria. Our results suggest that horizontal transmission is very likely the main mechanism for symbionts' acquisition by H. fulva. So far, this is the first shallow water sponge species harboring such a specific and predominant assemblage composed of these eubacterial and archaeal ribotypes. Our data suggests that this symbiotic relationship is very stable over time, indicating that the identified core microbial symbionts may play key roles in the holobiont functioning. PMID- 29766225 TI - Potential Common Pathogenic Pathways for the Left Ventricular Noncompaction Cardiomyopathy (LVNC). AB - Ventricular trabeculation and compaction are two essential morphogenetic events for generating a functionally competent ventricular wall. A significant reduction in trabeculation is usually associated with hypoplastic wall and ventricular compact zone deficiencies, which commonly leads to embryonic heart failure and early embryonic lethality. In contrast, the arrest of ventricular wall compaction (noncompaction) is believed to be causative to the left ventricular noncompaction (LVNC), a genetically heterogeneous disorder and the third most common cardiomyopathy among pediatric patients. After critically reviewing recent findings from genetically engineered mouse models, we suggest a model which proposes that defects in myofibrillogenesis and polarization in trabecular cardiomyocytes underly the common pathogenic mechanism for ventricular noncompaction. PMID- 29766226 TI - Cutoffs of Short-Term Heart Rate Variability Parameters in Brazilian Adolescents Male. AB - A low heart rate variability (HRV) has been associated with cardiovascular risk factors in adolescents. However, no cut-off points are known for HRV parameters in this age group, making it difficult to use in clinical practice. Thus, the aims of the current study were to establish cutoffs of HRV parameters and to examine their association with cardiovascular risk in Brazilian adolescents male. For this reason, this cross-sectional study included 1152 adolescent boys (16.6 +/- 1.2 years old). HRV measures of time (SD of all RR intervals, root mean square of the squared differences between adjacent normal RR intervals, and the percentage of adjacent intervals over 50 ms), frequency domains [low (LF) and high (HF) frequency], and Poincare plot (SD1, SD2 and SD1/SD2 ratio) were assessed. Cardiovascular risk was assessed by sum of abdominal obesity, high blood pressure, overweight, and low physical activity level. The proposed cutoffs showed moderate to high sensitivity, specificity, and area under curve values (p < 0.05). HRV frequency parameters were statistically superior when compared to time-domain and Poincare plot parameters. The binary logistic regression analysis indicated that all proposed HRV cutoffs were independently associated with a clustering of cardiovascular risk factors, with greater magnitude of HF and SD1/SD2 ratio (two or more risk factors: OR = 3.59 and 95% CI 1.76-7.34). In conclusion, proposed HRV cutoffs have moderate to high sensitivity in detecting of the cardiovascular risk factor and HRV frequency-domain were better discriminants of cardiovascular risk than time-domain and Poincare plot parameters. PMID- 29766228 TI - Relationship Between Visceral Obesity and Postoperative Inflammatory Response Following Minimally Invasive Esophagectomy. AB - BACKGROUND: Esophagectomy for esophageal cancer is one of the most invasive surgeries. However, the factors influencing postoperative systemic inflammatory response following esophagectomy have not been elucidated. Recently, visceral fat has been shown to play an important role in both chronic and acute inflammation. In this study, we assessed the relationship between visceral obesity and postoperative inflammatory response following minimally invasive esophagectomy (MIE). METHODS: Visceral fat area (VFA) was measured using computed tomography in 152 patients undergoing MIE for esophageal cancer. We assessed perioperative serum C-reactive protein (CRP) levels preoperatively and on postoperative days (PODs) 1-5 and analyzed the relationship between VFA and perioperative serum CRP levels. RESULTS: VFA was positively associated with preoperative serum CRP level (P < 0.001). Univariate analysis revealed that VFA was significantly associated with increased serum CRP levels on PODs 1-5 (P < 0.001 for each day), whereas multivariate analysis revealed that it was independently associated with increased serum CRP levels on PODs 1-4 (P = 0.033, 0.035, 0.001, and 0.006, respectively). Similar results were observed in patients who did not have postoperative infectious complications, such as pneumonia, anastomotic leak, and surgical site infection. VFA was not an independent risk factor for the occurrence of these postoperative infectious complications. CONCLUSIONS: Visceral obesity might be associated with chronic inflammation in patients with esophageal cancer and promote postoperative inflammatory response following MIE. PMID- 29766227 TI - Noncontrast computed tomography factors predictive of extracorporeal shock wave lithotripsy outcomes in patients with pancreatic duct stones. AB - PURPOSE: To assess the usefulness of factors unique to NCCT for the prediction of ESWL outcomes in patients with pancreatic duct stones. MATERIALS AND METHODS: We retrospectively evaluated 148 patients with multiple PDS who had undergone ESWL therapy. All patients received an examination for NCCT both before and after ESWL. The following parameters were measured and recorded: patient characteristics including sex and age; NCCT parameters including mean stone length, mean stone volumes before and after ESWL, mean value of CT attenuation, standard deviation of CT attenuation, variation coefficient of CT attenuation, skin-to-stone distance, and pancreatic duct diameter; ESWL outcome indexes including stone clearance rate calculated using the formula [Formula: see text], and the number of ESWL sessions. All patients were divided into groups based on their SCR: A group (SCR >= 90%), B group (SCR between 50% and 90%), and C group (SCR < 50%). Analysis of variance was used among the three groups to evaluate the potential predictors of SCR, and a receiver-operating curve was established to determine the optimal cutoff value. RESULTS: ANOVA analysis revealed that MSD was the only significant predictor for SCR (p < 0.05), and ROC indicated an optimal cutoff value of +1000.45 HU, with a sensitivity up to 78.0% and specificity of 48.6%. Stones with MSD lower than +1000.45 HU had higher SCR (69.3%) than that of higher-density ones (59.6%). Pearson correlation analysis and histogram indicated a significant positive correlation between ESWL No. and MSL (r = 0.536), MSD (r = 0.250), SDSD (r = 0.247), and PDD (r = 0.227), all values being p < 0.01. CONCLUSION: MSD is the optimal predictor of ESWL efficacy, and PDS with lower MSD had a better clearance rate with fewer fragmentation sessions. PMID- 29766229 TI - Clinical Status and Treatment of Liver Metastasis of Differentiated Thyroid Cancer Using Tyrosine Kinase Inhibitors. AB - BACKGROUND: Treatment of patients with liver metastasis of differentiated thyroid carcinoma (DTC) has not been sufficiently defined, because liver metastasis of DTC has been described mostly as case reports. Additionally, such patients are considered end-of-treatment responders. A relatively new approach using tyrosine kinase inhibitors (TKIs) may provide opportunities to manage systemic metastasis. This study aims to define the clinical features of DTC patients with liver metastasis and evaluate the benefits of TKIs. METHODS: We retrospectively analyzed clinical features of 29 patients (mean age 67.8 years) diagnosed with liver metastasis of DTC at our institution between January 1981 and May 2017. RESULTS: All patients had distant metastasis at other organ sites upon diagnosis of liver metastasis; 41% of them developed new metastasis afterward. Management after diagnosis of liver metastasis comprised palliative care (48%), radioactive iodine therapy (28%), and TKI therapy (24%). The median survival after diagnosis of liver metastasis was only 4.8 months. Survival rates were significantly better in patients with performance statuses between 0 and 2 on the Eastern Cooperative Oncology Group scale at diagnosis of liver metastasis (n = 22, 76%) treated with TKI compared to those who were not (P = 0.017; log-rank test; hazard ratio 0.19). One-year survival rates were 71.4 and 26.7% for patients treated with or without TKI, respectively. CONCLUSIONS: Patients with liver metastasis had poor clinical prognosis. When other distant metastases existed at diagnosis of liver metastasis, TKI therapy was considered an effective therapeutic option for patients with liver metastasis of DTC. PMID- 29766230 TI - Vasa vasorum of the failed aorto-coronary venous grafts. AB - PURPOSE: This study was designed to investigate the distribution of vasa vasorum in walls of failed aorto-coronary venous grafts. METHODS: Fifty-one diseased venous grafts harvested from 39 patients underwent qualitative histological evaluation. The morphology of the grade of the pathological changes and the extent of the vascularisation were examined, and related to the length of the interval between the primary surgery and the explantation. The obtained results were placed into five groups, substantially differing one from the other in morphology and vascularisation. RESULTS: The intervals between grafts implantation and explantation ranged from 1 day to 35 years. The onset of arterialization of the graft media was observed on average at 1 month after bypass implantation. During this same time period massive intimal hyperplasia and atherosclerosis occurred. Vasa vasorum proliferation from the adventitia to the outer layers of the media was first apparent between 7 and 24 months after implantation. Proliferation of the vasa vasorum throughout the entire atherosclerotic media and hyperplastic intima continued for a much longer time interval. CONCLUSION: No correlation between neoangiogenesis and age, sex or type of bypassed coronary branch was proven. Regarding the given findings, the authors believe that changes in hemodynamic conditions and endothelial trauma are primarily responsible for the development of graft disease and that vasa vasorum proliferation is only a secondary reaction to the structural changes of the graft wall. To what extent the frequently present pre-existing intimal hyperplasia of venous bypass grafts play in the development of graft disease remains questionable. PMID- 29766231 TI - Available bone morphology and status of neural structures in the mandibular interforaminal region: three-dimensional analysis of anatomical structures. AB - PURPOSE: This study aimed to clarify the size and morphology of the mandible and to determine state of neural structures for the planning of the dental implantation using cone-beam computerized tomography (CBCT). METHODS: Of the 252 patients, CBCT images of 48 selected patients were evaluated. The bone height and width were measured and the type of the mental portion of the inferior alveolar canal, the anterior loop length (ALL), the location of the incisive canal and lingual foramen were identified with cross-sectional and multiplane reformatted CBCT images. According to buccal and lingual concavities, the shape of the mandible is classified as type A, B and C. RESULTS: Bone widths of males were significantly higher than female (p < 0.05). The thickest part of the alveolar bone was measured in the middle triple zone (d line) and the thinnest part was measured in the area near the alveolar crest (b line). The most seen type of mandible was type B (45.8%) that mandible was concave on the buccal side. Bone heights had a tendency to increase towards to the anterior mandible, and bone height in male patients was slightly but not significantly greater than that in female patients. ALL was 4.2 +/- 1.2 mm and visible incisive canal length on CBCT was 9.7 +/- 3.8 mm. CONCLUSION: CBCT assessment of morphological features of the alveolar bone and locations of nerve canals and foramina in the anterior-premolar region of mandible represent useful practical anatomical information about the interforaminal region. This information is the guide to the dentist before implant surgery. PMID- 29766232 TI - Waning and boosting: on the dynamics of immune status. AB - The aim is to describe the distribution of immune status (as captured by antibody level) on the basis of a within-host submodel for continuous waning and occasional boosting. Inspired by Feller's fundamental work and the more recent delay equation formulation of models for the dynamics of physiologically structured populations, we derive, for given force of infection, a linear renewal equation. The solution is obtained by generation expansion, with the generation number corresponding to the number of times the individual became infected. Our main result provides a precise characterization of the stable distribution of immune status. PMID- 29766233 TI - Environmental Drivers Controlling Bacterial and Archaeal Abundance in the Sediments of a Mediterranean Lagoon Ecosystem. AB - The environmental factors controlling the abundance of Bacteria and Archaea in lagoon ecosystems are poorly understood. Here, an integrated physico-chemical, biogeochemical, and microbiological survey was applied in the Sacca di Goro lagoon (Po River Delta, Italy) to investigate the variation of bacterial and archaeal abundance, as assessed by Fluorescence In Situ Hybridization, along winter and summer environmental gradients. We hypothesised that bacterial and archaeal cells respond differentially to physico-chemical parameters of the sediment, which can be manifested in variations of total cells number. Our results suggest that Archaea are an important component of microbial communities (up to 20%) and they are also quite constant along the sediment depth investigated, while Bacteria tend to decrease in the subsurface sediments. The abiotic (i.e. temperature, ammonium, pH) and trophic parameters (i.e. chlorophyll a) explain differentially the variations of bacterial and archaeal distribution, and raise interesting questions about the ecological significance of the microbial composition in this area. PMID- 29766235 TI - Localized pain-causing JAK2-V617F-positive myeloproliferation with normal peripheral blood values. PMID- 29766234 TI - The severe cytokine release syndrome in phase I trials of CD19-CAR-T cell therapy: a systematic review. AB - CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive results in treating acute lymphoblastic leukemia (B-ALL), chronic lymphoblastic leukemia (B-CLL), and B-cell non-Hodgkin lymphoma (B-NHL) over the past few years. Meanwhile, the cytokine release syndrome (CRS), which could be moderate or even life-threatening, has emerged as the most significant adverse effect in the clinical course of this novel targeting immunotherapy. In this systematic review, we analyzed the incidence of severe CRS in 19 clinical trials selected from studies published between 2010 and 2017. The pooled severe CRS proportion was 29.3% (95% confidence interval [CI] 12.3-49.1%) in B-ALL, 38.8% (95%CI 12.9 67.6%) in B-CLL, and 19.8% (95%CI 4.2-40.8%) in B-NHL. In the univariate meta regression analysis, the proliferation of CD19-CAR-T cell in vivo was correlated with the severe CRS. Specifically, total infusion cell dose contributed to the severe CRS occurring in B-ALL patients but not in B-CLL or B-NHL patients. Tumor burden was strongly associated with the severity of CRS in B-ALL. Besides, post HSCT CD19 CAR-T cell infusion represented lower severe CRS incidence. Further investigations into the risk factors of CRS in B-CLL and B-NHL are needed. PMID- 29766236 TI - Ethnicity-specific impact of HLA I/II genotypes on the risk of inhibitor development: data from Korean patients with severe hemophilia A. AB - Inhibitor development is the most serious complication in patients with hemophilia. We investigated association of HLA genotypes with inhibitor development in Korean patients with severe hemophilia A (HA). HLA genotyping was done in 100 patients with severe HA including 27 patients with inhibitors. The allele frequencies between inhibitor-positive and inhibitor-negative patients were compared. HLA class I alleles were not associated with the inhibitor status. In HLA class II, DRB1*15 [n = 100, odds ratio (OR) 0.217, P = 0.028] and DPB1*05:01 [OR 0.461, P = 0.026] were negatively associated with inhibitor development. In a subgroup of patients with intron 22 inversion, C*07:02 was positively associated with inhibitor development [n = 30, OR 5.500, P = 0.043]. In the subgroup of patients without intron 22 inversion, the negative association between DPB1*05:01 and inhibitor development was reinforced [n = 70, OR 0.327, P = 0.010], and positive association of DRB1*13:02 and DPB1*04:01 with inhibitor development was identified [OR 3.059, P = 0.037 for both]. Previously reported risk alleles were not consistently associated with inhibitor risk in our series. This study demonstrated the profile of HLA alleles associated with inhibitor risk in Korean patients with severe HA was different from that in patients of other ethnicities, which needs to be considered in risk assessment and management. PMID- 29766238 TI - Mitteilungen DGKFO. PMID- 29766237 TI - Correction to: Stent placement in patients with acute subarachnoid haemorrhage: when is it justified? AB - In the original version of this article one author name was published incorrectly: Tanja Ddjurdjevic has been corrected to Tanja Djurdjevic. PMID- 29766241 TI - Cellulase production by white-rot basidiomycetous fungi: solid-state versus submerged cultivation. AB - White-rot basidiomycetous (WRB) fungi are a group of wood-decaying fungi that are known to be endowed with the ability to secrete enzymes that can catalyze decomposition of a range of plant cell wall polysaccharides, including cellulose and lignin. Expression of these enzymes is induced by the substrate and the enzyme yields obtained depend on the growth of the fungi and thus the mode of cultivation. In order to exploit WRB fungi for local enzyme production for converting lignocellulosic materials in biorefinery processes, the fungi can principally be cultivated in either solid-state (SSC) or submerged cultivation (SmC) systems. In this review, we quantitatively assess the data available in the literature on cellulase production yields by WRB fungi cultivated by SSC or SmC. The review also assesses cellulolytic enzyme production rates and enzyme recovery when WRB fungi are cultivated on different biomass residues in SSC or SmC systems. Although some variation in cellulase production yields have been reported for certain substrates, the analysis convincingly shows that SmC is generally more efficient than SSC for obtaining high cellulase production yields and high cellulase production rates on the substrate used. However, the cultivation method also affects the enzyme activity profile obtained, and the resulting enzyme titers and significant dilution of the enzymes usually occurs in SmC. The review also highlights some future approaches, including sequential cultivations and co-cultivation of WRB fungi for improved enzyme expression, as well as on-site approaches for production of enzyme blends for industrial biomass conversion. The quantitative comparisons made have implications for selection of the most appropriate cultivation method for WRB fungi for attaining maximal cellulase production. PMID- 29766242 TI - Inactivation of deubiquitinase CYLD enhances therapeutic antibody production in Chinese hamster ovary cells. AB - Chinese hamster ovary (CHO) cells are promising host engineering cells for industry manufacturing of therapeutic antibodies. However, cell death due to apoptosis remains a huge challenge to augment antibody production, and developing CHO cells with enhanced anti-apoptosis and proliferation ability is fundamental for cell line development and high-yielding bioprocesses. Deubiquitinase cylindromatosis (CYLD) has been proved to be a tumor suppressor by negatively regulating NF-kappaB and Wnt/beta-catenin signaling pathways. Its mutation or deletion is a common chromosome variation in several types of cancers. Here, we engineered CHO CYLD-/- cells by CRISPR-Cas9 editing technology. These cells displayed stronger cell proliferation and anti-apoptosis ability compared to parental cells. Three antibody expression plasmid kits were transiently transfected into these cells. Our data showed that inactivation of CYLD increased the highest titers of rituximab, Herceptin, and one bispecific antibody by 105, 63, and 228%, respectively. Reversely, overexpression of CYLD could promote cell apoptosis, whereas inhibiting cell proliferation and antibody production. Furthermore, inhibition of CYLD in CHO cells stably expressing an IgG antibody (CHO-IgG) achieved about 50% increase in product titer compared to parental cells. Meanwhile, inhibition of CYLD did not affect the quality of antibody. Thus, our data demonstrated that inactivation of CYLD could promote CHO cell proliferation, anti-apoptosis ability, and subsequent antibody production, suggesting that CYLD is a potential functional target for CHO cell engineering. PMID- 29766240 TI - Pulmonary Thermal Ablation Enables Long Chemotherapy-Free Survival in Metastatic Colorectal Cancer Patients. AB - BACKGROUND: Chemotherapy (ct) is the preferred treatment option in metastatic colorectal cancer (mCRC). The objective of the study was to determine the overall survival (OS), disease-free survival (DFS) and ct-free survival (CFS) of pulmonary thermal ablation (TA) and its place in the treatment of mCRC. PATIENTS AND METHODS: All consecutive patients treated (over 11 years) with percutaneous TA for lung metastasis of colorectal origin were reviewed. All sequences of treatments were considered. We determined the OS, DFS and CFS of pulmonary TA. RESULTS: Two hundred and nine patients underwent 323 TA procedures for 630 lung metastases. Majority of the metastases (71.5%) were unilateral with a median diameter of 10 mm (2-46). A single metastasis was treated in 95 patients (45.5%), and 2-8 in 114 patients (54.5%). One hundred and thirty-two patients (63.2%) had only a single procedure, 77 patients (36.8%) had 2-5 procedures. Following the first TA (n = 209), 125 patients (59.8%) resumed ct. Sixty-four out of the 126 patients presenting lung progression were treated again with TA. The median CFS was 12.2 months (95% CI: 10.3-17.7). Patients with no extra-pulmonary metastases showed a statistically better CFS than those who had extra-pulmonary metastases with a median of 20.9 and 9.2 months, respectively (p < 0.001). Median follow-up and OS were 50 and 67.6 months, respectively. CONCLUSION: This study demonstrates, for the first time, that TA enables a CFS of 12.2 months that extended to 20.9 months in patients who presented with lung-only metastases. TA is a viable option for a pause in the therapy of mCRCs. PMID- 29766239 TI - 90Y Resin Microspheres Radioembolization for Colon Cancer Liver Metastases Using Full-Strength Contrast Material. AB - OBJECTIVES: To assess safety and efficacy of 90Y resin microspheres administration using undiluted non-ionic contrast material (UDCM) {100% Omnipaque 300 (Iohexol)} in both the "B" and "D" lines. MATERIALS AND METHODS: We reviewed all colorectal cancer liver metastases patients treated with 90Y resin microspheres radioembolization (RAE) from 2009 to 2017. As of April 2013, two experienced operators started using UDCM (study group) instead of standard sandwich infusion (control group). Occurrence of myelosuppression (leukopenia, neutropenia, erythrocytopenia or/and thrombocytopenia), stasis, nontarget delivery (NTD), median fluoroscopy radiation dose (FRD), median infusion time (IT), liver progression-free (LPFS) and overall survivals (OS) was evaluated. Complications within 6 months post-RAE were reported according to CTCAE v3.0 criteria. RESULTS: Study and control groups comprised 23(28%) and 58(72%) patients, respectively. Median follow-up was 9.1 months. There was no statistically significant difference in myelosuppression incidence within 6 months post-RAE between groups. Median FRD and IT for study and control groups were 44.6 vs. 97.35 Gy/cm2 (p = 0.048) and 31 vs. 39 min (p = 0.006), respectively. A 38% lower stasis incidence in study group was not significant (p = 0.34). NTD occurred in 1/27(4%) study vs. 5/73(7%) control group procedures (p = 1). Grade 1-2 and grade 3-4 toxicities between study and control group patients were 36%(8/22) vs. 45%(26/58), p = 0.61 and 9%(2/22) vs. 16%(9/58), p = 0.72, respectively. There was no difference in LPFS and OS between groups. CONCLUSION: Administration of 90Y resin microspheres using UDCM in both lines is safe and effective, resulting in lower fluoroscopy radiation dose and shorter infusion time, without evidence of myelosuppression or increased stasis incidence. PMID- 29766243 TI - A proteomic analysis of ferulic acid metabolism in Amycolatopsis sp. ATCC 39116. AB - The pseudonocardiate Amycolatopsis sp. ATCC 39116 is used for the biotechnical production of natural vanillin from ferulic acid. Our laboratory has performed genetic modifications of this strain previously, but there are still many gaps in our knowledge regarding its vanillin tolerance and the general metabolism. We performed cultivations with this bacterium and compared the proteomes of stationary phase cells before ferulic acid feeding with those during ferulic acid feeding. Thereby, we identified 143 differently expressed proteins. Deletion mutants were constructed and characterized to analyze the function of nine corresponding genes. Using these mutants, we identified an active ferulic acid beta-oxidation pathway and the enzymes which constitute this pathway. A combined deletion mutant in which the beta-oxidation as well as non-beta-oxidation pathways of ferulic acid degradation were deleted was unable to grow on ferulic acid as the sole source of carbon and energy. This mutant differs from the single deletion mutants and was unable to grow on ferulic acid. Furthermore, we showed that the non-beta-oxidation pathway is involved in caffeic acid degradation; however, its deletion is complemented even in the double deletion mutant. This shows that both pathways can complement each other. The beta-oxidation deletion mutant produced significantly reduced amounts of vanillic acid (0.12 instead of 0.35 g/l). Therefore, the resulting mutant could be used as an improved production strain. The quinone oxidoreductase deletion mutant (DeltaytfG) degraded ferulic acid slower at first but produced comparable amounts of vanillin and significantly less vanillyl alcohol when compared to the parent strain. PMID- 29766244 TI - Copy number of ArsR reporter plasmid determines its arsenite response and metal specificity. AB - The key component in bacteria-based biosensors is a transcriptional reporter employed to monitor induction or repression of a reporter gene corresponding to environmental change. In this study, we made a series of reporters in order to achieve highly sensitive detection of arsenite. From these reporters, two biosensors were developed by transformation of Escherichia coli DH5alpha with pLHPars9 and pLLPars9, consisting of either a high or low copy number plasmid, along with common elements of ArsR-luciferase fusion and addition of two binding sequences, one each from E. coli and Acidithiobacillus ferrooxidans chromosome, in front of the R773 ArsR operon. Both of them were highly sensitive to arsenite, with a low detection limit of 0.04 MUM arsenite (~ 5 MUg/L). They showed a wide dynamic range of detection up to 50 MUM using high copy number pLHPars9 and 100 MUM using low copy number pLLPars9. Significantly, they differ in metal specificity, pLLPars9 more specific to arsenite, while pLHPars9 to both arsenite and antimonite. The only difference between pLHPars9 and pLLPars9 is their copy numbers of plasmid and corresponding ratios of ArsR to its binding promoter/operator sequence. Therefore, we propose a working model in which DNA bound-ArsR is different from its free form in metal specificity. PMID- 29766245 TI - [18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery. AB - PURPOSE: Medullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [18F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection. METHODS: A group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse. RESULTS: Primary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02). CONCLUSION: This study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success. PMID- 29766246 TI - Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy. AB - AIM: The purpose of this study was to investigate the diagnostic performance of 68Ga-PSMA-11 PET/CT in the evaluation of bone metastases in metastatic prostate cancer (PC) patients scheduled for radionuclide therapy in comparison to [18F]sodium fluoride (18F-NaF) PET/CT. METHODS: Sixteen metastatic PC patients with known skeletal metastases, who underwent both 68Ga-PSMA-11 PET/CT and 18F NaF PET/CT for assessment of metastatic burden prior to radionuclide therapy, were analysed retrospectively. The performance of both tracers was calculated on a lesion-based comparison. Intensity of tracer accumulation of pathologic bone lesions on 18F-NaF PET and 68Ga-PSMA-11 PET was measured with maximum standardized uptake values (SUVmax) and compared to background activity of normal bone. In addition, SUVmax values of PET-positive bone lesions were analysed with respect to morphologic characteristics on CT. Bone metastases were either confirmed by CT or follow-up PET scan. RESULTS: In contrast to 468 PET-positive lesions suggestive of bone metastases on 18F-NaF PET, only 351 of the lesions were also judged positive on 68Ga-PSMA-11 PET (75.0%). Intensity of tracer accumulation of pathologic skeletal lesions was significantly higher on 18F-NaF PET compared to 68Ga-PSMA-11 PET, showing a median SUVmax of 27.0 and 6.0, respectively (p < 0.001). Background activity of normal bone was lower on 68Ga PSMA-11 PET, with a median SUVmax of 1.0 in comparison to 2.7 on 18F-NaF PET; however, tumour to background ratio was significantly higher on 18F-NaF PET (9.8 versus 5.9 on 68Ga-PSMA-11 PET; p = 0.042). Based on morphologic lesion characterisation on CT, 18F-NaF PET revealed median SUVmax values of 23.6 for osteosclerotic, 35.0 for osteolytic, and 19.0 for lesions not visible on CT, whereas on 68Ga-PSMA-11 PET median SUVmax values of 5.0 in osteosclerotic, 29.5 in osteolytic, and 7.5 in lesions not seen on CT were measured. Intensity of tracer accumulation between18F-NaF PET and 68Ga-PSMA-11 PET was significantly higher in osteosclerotic (p < 0.001) and lesions not visible on CT (p = 0.012). CONCLUSION: In comparison to 68Ga-PSMA-11 PET/CT, 18F-NaF PET/CT detects a higher number of pathologic bone lesions in advanced stage PC patients scheduled for radionuclide therapy. Our data suggest that 68Ga-PSMA-11 PET should be combined with 18F-NaF PET in PC patients with skeletal metastases for restaging prior to initiation or modification of therapy. PMID- 29766247 TI - Current status of wrist imaging in juvenile idiopathic arthritis. AB - Wrist involvement occurs in about one-quarter of patients diagnosed with juvenile idiopathic arthritis (JIA), increasing to 40% 5 years after diagnosis. The imaging appearances, both for active inflammation and permanent change, differ from those seen in adult rheumatoid arthritis; therefore, a child-specific approach is crucial for correct assessment. In this review article, we provide an update on the current status for imaging wrist JIA, with a focus on evidence based practice. PMID- 29766248 TI - Imaging of the knee in juvenile idiopathic arthritis. AB - In juvenile idiopathic arthritis (JIA), imaging is increasingly used in clinical practice. In this paper we discuss imaging of the knee, the clinically most commonly affected joint in JIA. In the last decade, a number of important steps have been made in the development of imaging outcome measures in children with JIA knee involvement. Ultrasound is undergoing a fast validation process, which should be accomplished within the next few years. The validation processes of MRI as an imaging biomarker for clinical trials in the JIA knee are at an advanced stage, with important data available on the feasibility, reliability and validity of the Juvenile Arthritis MRI Scoring system. Moreover, both US and MRI data are emerging on the normal appearance of the growing knee joint. PMID- 29766249 TI - Imaging of temporomandibular joint abnormalities in juvenile idiopathic arthritis with a focus on developing a magnetic resonance imaging protocol. AB - Inflammation and damage in the temporomandibular joint (TMJ) often develop without clinical symptoms but can lead to severe facial growth abnormalities and impaired health-related quality of life, making early diagnosis of TMJ changes crucial to identify. Inflammatory and osteochondral changes detectable through magnetic resonance imaging (MRI) occur in TMJs of approximately 40% of children with juvenile idiopathic arthritis (JIA), and no other imaging modality or physical method of examination can reliably detect these changes. Therefore contrast-enhanced MRI is the diagnostic standard for diagnosis and interval monitoring of JIA. However the specific usage of MRI for TMJ arthritis is not standardized at present. There is a recognized need for a consensus effort toward standardization of an imaging protocol with required and optional sequences to improve detection of pathological changes and shorten study time. Such a consensus imaging protocol is important for providing maximum information with minimally necessary sequences in a way that allows inter-site comparison of results of clinical trials and improved clinical management. In this paper we describe the challenges of TMJ imaging and present expert-panel consensus suggestions for a standardized TMJ MRI protocol. PMID- 29766250 TI - Juvenile idiopathic arthritis - the role of imaging from a rheumatologist's perspective. AB - Alongside recent advances in treatment strategies for juvenile idiopathic arthritis (JIA), paediatric rheumatologists have taken increasing interest in the use of imaging. Magnetic resonance imaging (MRI) and musculoskeletal ultrasound, by providing more detailed information on disease activity than clinical examination and conventional radiography (CR), have become helpful diagnostic and managerial tools. The growing skeleton, however, with changing appearances over time, is still challenging in the establishment of valid scoring systems for pathological changes. Defining child- and age-specific reference standards is therefore a highly prioritized issue. The aim of this article is to raise awareness among radiologists of the substantial role that imaging can play to optimize the management of JIA patients and to describe the state-of-the-art validation process of imaging as an outcome measure. A closer collaboration between radiologists and pediatric rheumatologists is crucial to define a scheduled workflow for imaging in JIA. PMID- 29766251 TI - Imaging of the hip in juvenile idiopathic arthritis. AB - Hip involvement is common and estimated to occur in approximately 35-63% of children with juvenile idiopathic arthritis (JIA). It is more prevalent in the aggressive systemic subtypes, with irreversible changes occurring as early as within 5 years of diagnosis. Whilst clinical parameters and joint examination can be useful for assessing disease severity, subclinical disease is known to exist and delayed treatment may herald a lifetime of disability and pain. Early recognition of JIA changes is therefore crucial in determining treatment options. Validated scoring systems in the radiologic assessment of the hip for clinical drug trials may inform treatment outcomes, although robust tools for analysis are still lacking. This review article details the modalities utilised for imaging the hip in children with JIA with particular efforts focused upon reliability and validity in their assessment of joint disease. We conclude with a short literature review on the potential future techniques being developed for hip joint imaging in JIA. PMID- 29766255 TI - ? PMID- 29766253 TI - Update on imaging in juvenile idiopathic arthritis. PMID- 29766257 TI - The impact of exercise on sleep (time, quality, and disturbance) in patients with rheumatoid arthritis: a study protocol for a pilot randomised controlled trial. AB - : Poor sleep is an issue for people with rheumatoid arthritis (RA), which may curtail their ability to function appropriately and reduce their activity levels. This paper describes a protocol for a pilot randomised controlled trial of an aerobic exercise intervention compared with exercise advice designed to improve sleep in people with RA. Objectives are to obtain reliable estimates regarding recruitment rates, participant retention and protocol adherence and to generate potential effect size estimates for a main trial. Participants will be identified from an existing database held at a University Hospital and in person at weekly rheumatology clinics. Participants meeting the inclusion criteria will be randomised into an intervention or control group. Those in the intervention group will participate in an 8-week walking-based exercise intervention consisting of 28 walking sessions, with 1 session per week being supervised by a trained physiotherapist, spread over a maximum of 8 weeks (2-5 times/week), while those in the control group will receive advice on the benefits of exercise for people with RA. Results will provide data for efficient recruitment and data collection, to determine if a larger, statistically powered main trial could be generalised to a multi-centre rheumatoid arthritis population. Given recent information that sleep is commonly reduced in people with RA and that physical activity and exercise profiles are lower, this study will contribute data to the field of exercise and sleep that is currently lacking and importantly will include people with RA in the study process prior to any fully powered trial. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03140995 (April 25th, 2017). PMID- 29766256 TI - Monogenic systemic lupus erythematosus: insights in pathophysiology. AB - Systemic lupus erythematosus (SLE) is a complex disease with different genetic, immunologic, and environmental factors contributing to the pathogenesis. Monogenic SLE could help us understand the main phases of immune dysregulation in SLE. The aim of this review is to summarize the current knowledge on monogenic SLE with the implications of the respective genes on disease pathogenesis. A comprehensive literature search on monogenic SLE was conducted utilizing the Cochrane Library and MEDLINE/PubMed databases. The main affected pathways in disease pathogenesis are identified as follows: complement system, apoptosis, nucleic acid degradation, nucleic acid sensing, self-tolerance, and type I interferon production. Further studies on monogenic SLE can make precision medicine possible for SLE by increasing our understanding of disease pathogenesis. PMID- 29766258 TI - Treatment of osteochondral defects with a combination of bone grafting and AMIC technique. AB - INTRODUCTION: Osteochondral defects of the knee may cause functional impairment of young and sportively active patients. Different surgical treatment options have been proposed using either one or two step procedures. The aim of the current study was to evaluate mid-term outcomes of combined bone grafting with autologous matrix-associated chondrogenesis (AMIC) for the treatment of large osteochondral defects. MATERIALS AND METHODS: 15 Patients with osteochondrosis dissecans of the medial femoral condyle grade III or IV according to ICRS classification were treated with a single step surgical procedure combining bone grafting and the AMIC procedure. Mean defect size was 4.98 cm2 (+/- 3.02) and patients were examined at 6, 12 weeks, 6 and 12 month and at mean final follow-up of 49 months (36-61). Patients were evaluated using VAS, IKDC, KOOS, Lysholm, Tegner activity scores and psychological and physical health assessed using the SF 12. MRI evaluation was performed at final follow-up using the MOCART score. RESULTS: Pain had significantly decreased at final follow-up (7.2 +/- 1.4 vs. 2.4 +/- 2.6) compared to preoperative baseline. All functional scores had improved significantly throughout the follow-up period (IKDC from 36.6 +/- 20.6 vs. 72.2 +/- 18.7; KOOS 50.0 +/- 18.9 vs. 81.7 +/- 13.9; LYSHOLM 39.3 +/- 19.5 vs. 79.8 +/ 15.1). SF12 evaluation showed a significant increase in physical component summary (PCS) (31.2 +/- 11.1 preoperative vs. 46.3 +/- 9.9 at final follow-up), while mental component summary (MCS) remained stable (51.8 +/- 8.9 vs. 57.3 +/- 3.3). MOCART score revealed a mean overall score of 77 +/- 15 at final follow-up. Integration to the adjacent cartilage was complete in 79%, incomplete in 21%. Defect filling was complete in 64%, incomplete in 36%. CONCLUSION: Significant improvement of knee function and restoration of homogenous cartilage morphology could be achieved with simultaneous AMIC procedure and bone grafting in 2/3 of all patients with large osteochondral lesions at 4 years postoperatively. PMID- 29766259 TI - A telephone outcall program to support caregivers of people diagnosed with cancer: utility, changes in levels of distress, and unmet needs. AB - PURPOSE: To evaluate the utility of a telephone outcall program for cancer caregivers and to examine longitudinal changes in their distress levels and supportive care needs. METHODS: As part of the PROTECT trial, caregivers assigned to the intervention arm (N = 108) received three telephone outcalls from a Cancer Council 13 11 20 nurse at three time points (7-10 days post-randomization, 1 and 4 months later). During each call, caregivers were screened for distress using the Distress Thermometer (range: 0-10) then six supportive care issues were raised for discussion. Participants completed a utility survey 1 month post intervention. RESULTS: The outcall program was highly acceptable and perceived as beneficial by caregivers. Overall, 95% reported it was worth their time to take part in the outcall program and 82% stated that the program was very relevant to them. Level of distress and impact of distress decreased over time (p = 0.0031, p < 0.0001, respectively). Average call duration decreased over time (p < 0.0001) and was longer for female than male caregivers (p = 0.0009). The frequency of caregivers discussing issues related to psychological distress (p = 0.0003), health literacy (p < 0.0001), financial (p = 0.0014), and practical concerns (p = 0.0121) decreased over time. Psychological distress was more often discussed by female than male caregivers (p = 0.0153), and family issues more often by younger (< 55 years) than older caregivers (p = 0.0071). CONCLUSIONS: Utility of this outcall program was high. Caregivers' level of distress and unmet needs decreased over time. Gender and age differences emerged, which warrants the need for tailored support. Further research is necessary to identify the best method of improving access to 13 11 20 services for caregivers. PMID- 29766260 TI - Supportive care priorities of low-income Latina breast cancer survivors. AB - PURPOSE: This study investigated the supportive care needs of a sample of low income Latina breast cancer survivors. METHODS: Ninety-nine Spanish-speaking breast cancer survivors who self-identified as Latina and reported an income below the US Census Bureau low-income threshold were recruited from the oncology clinic of a major public safety net hospital. Eligible participants completed the supportive care needs survey (SCNS-SF34) and a demographic questionnaire. RESULTS: Ninety-three percent of respondents had unmet needs. The majority of frequently reported unmet needs involved (1) access to and delivery of health related information and (2) physical function. These findings appear to contrast with those of other studies of supportive care needs in heterogeneous cancer survivors, most of which describe psychological concerns as most urgent. CONCLUSIONS: Participants espoused information-related needs with a higher frequency than many other samples of cancer survivors. This study population may also require a particularly high level of assistance with overcoming participation restrictions. Further research is needed to understand these discrepancies and to address unmet needs across all domains. PMID- 29766261 TI - Comprehensive evaluation of autohydrogenotrophic membrane biofilm reactor treating OTC-enriched water medium. AB - In the recent years, there has been considerable debate about the potential impacts of antibiotics present in various environments on the public health and ecology. Oxytetracycline (OTC) is one of tetracycline antibiotic group used for growth and treatment of animals and humans. In this study, OTC and nitrate (NO3 N) were simultaneously reduced using a hydrogen-based membrane biofilm reactor (H2-MBfR). The system successfully accomplished OTC and nitrate removals. The fluxes of OTC and NO3-N were 8.96 mg OTC/m2 day and 1100 mg N/m2 day, respectively. On the other hand, the fluxes of H2 utilized for OTC and NO3-N reductions were calculated as maximum values of 1.71 and 395 mg H2/m2 day, respectively. The concentrations of transformation products of OTC formed at ppb levels. The dominant species in all the experimental periods with OTC biodegradation referred to Naxibacter sp., Uncultured Beta proteobacterium, Janthinobacterium sp. and Alicycliphilus denitrificans in autotrophic biofilm community degrading OTC. PMID- 29766262 TI - In Defense of Lady Windermere Syndrome. AB - Defense of Lady Windermere Syndrome (LWS) provides a critical analysis of its proposed pathogenesis, evidence supporting a causal role of volitional cough suppression, pathogenesis of M. avium complex (MAC) superimposition, a defense of the eponym, and cites a possible contribution of LWS to the bronchiectasis population. PMID- 29766263 TI - [Oral anticoagulation : Current overview and perioperative management in ophthalmic surgery]. AB - Antithrombotic treatment with oral anticoagulants and antiplatelet agents can increase the risk for perioperative bleeding. In contrast to other surgical fields, the optimal perioperative management in ophthalmic surgery has not yet been exactly defined and, thus, is not standardized. In this contribution, we provide an overview of currently available oral anticoagulants and discuss potential strategies for the management of these agents in different ophthalmic surgical procedures. PMID- 29766264 TI - [Registry-based research in ophthalmology]. AB - Medical registries and registry studies are frequently used for health services research as they represent a valuable means of capturing real-life data. Registry studies are particularly suitable for rare diseases for which epidemiological population-based or randomized controlled clinical studies are difficult. The are many examples of successful medical registries that have not only contributed to both epidemiological and clinical research, but which have also improved health service delivery. Only few ophthalmological medical registries are currently available. For non-infectious uveitis in children and adolescents with juvenile idiopathic arthritis (JIA), a rare disease entity, there is a need for data on, e.g., treatment, long-term outcomes, and risk factors for progression. The advantages for this disease of a registry with uveitis module from which numerous scientific publications and guidelines have been derived has been proven. Thus, we use the example of non-infectious uveitis to discuss the benefits of registries for other areas of ophthalmology. PMID- 29766265 TI - Surgery for subependymal giant cell astrocytomas in children with tuberous sclerosis complex. AB - OBJECTIVE: Subependymal giant cell astrocytomas (SEGAs) are low-grade intraventricular glial tumors that develop in 10-15% of patients with tuberous sclerosis complex; they often cause hydrocephalus and are potentially accessible to a surgical treatment. Our aim is to evaluate morbidity and results after surgery in symptomatic and asymptomatic patients. METHOD: We present a retrospective series of 18 pediatric patients operated on for SEGA between 2006 and 2016 at our institution. We reviewed surgical indications, preoperative clinical and radiologic data, surgical management, and clinical and radiological follow-up. RESULTS: Mean age at surgery was 10.7 years. The surgical decision was based on clinical signs of raised intracranial pressure due to hydrocephalus in 8 and on radiological findings without any clinical signs in the other 10 patients (increased in SEGA volume with or without ventricular enlargement). Surgical treatment consisted in a frontal trans-ventricular microsurgical approach in 17 patients and an endoscopic approach in 1. External ventricular drainage was placed in all the patients but 1. Ventriculoperitoneal shunting (VPS) became necessary in 6 patients, all of them presenting with a preoperative active hydrocephalus. Morbidity appeared very low with meningitis occurring in 1 patient. Resection was complete in 15 children with no recurrence during a mean follow-up of 5.25 years and incomplete in 3 requiring a second surgery. CONCLUSION: Surgery of SEGA represents a very effective treatment with low morbidity and no mortality in the present series. In patients operated before the onset of clinical signs of hydrocephalus, internal VPS could be avoided whereas in others, an additional shunt surgery became necessary. This gives arguments in favor of a regular MRI surveillance in tuberous sclerosis complex patients with SEGA in order to best propose resective surgery once a growth of tumor and/or ventricular size have been confirmed but before raised intracranial pressure occurs. PMID- 29766266 TI - [Syncope and fitness to drive]. AB - Although medical students are rarely instructed in traffic medicine in Germany, they are obliged to inform their patients about their fitness to drive after having become a medical doctor. This article gives an overview on the fitness to drive for patients with syncope by referring to the driving license regulation and the current guidelines released by the department of traffic. The driving license regulation distinguishes between group 1 and group 2 drivers. Group 1 drivers drive vehicles with a total weight less than 3.5 t, whereas group 2 drivers drive vehicles with a total weight above 3.5 t or provide commercial passenger transport. Since patients with syncope may suffer from different serious illnesses, the first approach is to clarify the cause of syncope. If no treatable cause of syncope (e. g., pacemaker, aortic valve replacement) is found, drivers of group 1 are not fit to drive for 6 months after a second unexplained syncope, whereas in this situation, drivers of group 2 are not fit to drive permanently. If, however, syncopes occur in conditions which cannot be expected to occur while driving (e. g. venipuncture, defecation, micturition) fitness to drive will persist. Syncope due to ventricular tachycardia in ischemic heart disease and reduced left ventricular ejection fraction are in general treated with an implantable cardioverter-defibrillator (ICD). Group 2 drivers with an ICD are normally unfit to drive. Group 1 drivers with an ICD are fit to drive when no syncope or adequate shock occurred within the last three months. PMID- 29766267 TI - [Syncopes and channelopathies]. AB - Syncope can be the first manifestation of cardiac channelopathies, namely Brugada syndrome, long QT syndrome, short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). Patients affected by these rare diseases are at increased risk for sudden cardiac death due to ventricular tachyarrhythmias and require specific therapy and follow-up. As syncope is common in the general population, only few cases are caused by an underlying channelopathy. Nevertheless, the diagnosis should be considered in young patients with structurally normal hearts, especially if the history of syncope is typical for an arrhythmogenic cause, in the presence of characteristic echocardiogram (ECG) patterns, and if there is a family history of channelopathies or sudden cardiac death. On the other hand, syncope plays an important role in the management of patients with diagnosed channelopathies, as they may indicate an increased risk for sudden cardiac death. The predictive value and consequences for treatment vary between the different channelopathies. However, data on this issue are scarce due to the low prevalence of these diseases. This review highlights typical findings in the medical history and diagnostic tests that may point towards an underlying channelopathy in patients with syncope. It also discusses the prognostic and therapeutic implications of a history of syncope in patients with known channelopathies. PMID- 29766268 TI - Electrocardiographic and echocardiographic findings in muscular dystrophy patients with heart failure. AB - Cardiac involvement in muscular dystrophy (MD) is known to cause heart failure (HF). However, little is known about the differences in electrocardiographic and echocardiographic findings between MD patients with and without the experience of hospitalization for HF. We retrospectively identified 95 MD patients (mean age at diagnosis of MD 41.1 +/- 18.7 years; males 64.2%), including nine (9.4%) patients who were hospitalized for HF (the HF group) and 86 (90.6%) patients who were not (the non-HF group) during the follow-up period (16.7 +/- 12.2 years). The HF group had a significantly wider QRS duration (126.0 +/- 37.6 vs. 98.1 +/- 16.7 ms, p < 0.001) and QTc interval (454.6 +/- 50.5 vs. 409.5 +/- 23.6 ms, p < 0.001) at the time of HF hospitalization than the non-HF group. The HF group also had a significantly lower left ventricular (LV) ejection fraction (35.4 +/- 19.2 vs. 62.5 +/- 11.3%, p < 0.001) and significantly larger diastolic LV dimension (64 +/ 2 vs. 45 +/- 1 mm, p < 0.001) and left atrial diameter (38 +/- 12 vs. 29 +/- 6 mm, p = 0.003) at the time of HF hospitalization than the non-HF group. In the HF group, the QRS duration was significantly wider at the time of HF hospitalization than at the initial electrocardiogram before the development of HF (129.8 +/- 30.7 vs. 119.0 +/- 33.3 ms, p = 0.018). This study suggests that HF occurs in MD patients with electrocardiographic and echocardiographic abnormalities. Early recognition of abnormal findings during a regular electrocardiographic or echocardiographic follow-up may be useful for identifying cardiac involvement in MD. PMID- 29766269 TI - Antimalarial activity and metabolism of dihydroartemisinin-derived dimer. AB - The dihydroartemisinin-derived dimer (DHA dimer) was synthesized, and its antimalarial activities were evaluated both in vitro and in vivo. The dimer IC50 value of 0.51 +/- 0.12 nM in vitro was significantly lower than that of DHA at 1.81 +/- 0.70 nM. The dimer ED50 values were 0.44 +/- 0.03 and 0.18 +/- 0.03 mg/(kg.day) in vivo for intragastric (i.g.) and intravenous (i.v.) groups, respectively, to Plasmodium yoelii rodent malaria. It also performed better relative to those of DHA which had ED50 values of 0.76 +/- 0.03 mg/(kg.day) (i.g.) and 0.32 +/- 0.03 mg/(kg.day) (i.v.). Moreover, the recrudescence rate, negative conversion rate, and cure rate of the dimer showed superior performance. Furthermore, the metabolites and major metabolic pathways of the dimer in rats were preliminarily investigated using the HPLC-HRMSn method. Twenty-seven metabolites, including DHA, 11 metabolites of DHA, and 15 other novel metabolites, were detected in rats after i.g. administration of dimer. The metabolic pathways of the 15 novel metabolites were inferred: deoxygenation, hydroxylation, and hydroxylation with dehydration. PMID- 29766270 TI - Parasitological and molecular diagnostic of a clinical Babesia caballi outbreak in Southern Romania. AB - Equine piroplasmosis (EP) is a tick-borne disease of equids caused by Babesia caballi and/or Theileria equi, which is endemic in many tropical and temperate areas of the world. However, clinical outbreaks of EP in Romania during the last decades have not been reported Therefore, the aim of this paper is (i) to describe a clinical B. caballi outbreak in horses on several farms in Southern Romania using a diagnostic and therapeutic approach and (ii) the molecular diagnostic of EP in an endemic area of Romania. In the first case, a 10-month-old stallion male was presented with lethargy, anorexia, fever (40.9 degrees C), pale mucosal/mucous/membranes and a marked anemia. In the subsequent weeks, three horses from other farms located in the same area, displayed similar clinical signs. B. caballi was diagnosed in all the horses based on Giemsa-stained blood smears and the diagnosis was further confirmed by polymerase chain reaction (PCR), using a single-round and multiplex PCR and sequencing. All four horses were treated with imidocarb dipropionate, at a dose rate of 2.2 mg/kg body weight (two injections at 48 h apart), and all horses clinically recovered within 24-48 h, post-treatment. This report presents the first molecularly characterized B. caballi outbreak in Romania in clinically affected horses, confirmed by DNA sequencing. PMID- 29766271 TI - Obstructive sleep apnea and cerebral white matter change: a systematic review and meta-analysis. AB - Obstructive sleep apnea (OSA) can cause sleep fragmentation and intermittent hypoxemia, which are linked to oxidative stress. White matter changes (WMCs) representing cerebrovascular burden and are at risk factor for oxidative ischemic injury. The current study explores the mutual relationships between OSA and WMCs. We performed a systematic review of electronic databases for clinical studies investigating OSA and WMCs. Random-effects models were used for pooled estimates calculation. A total of 22 studies were included in the meta-analysis. The results revealed a significantly higher prevalence rate of WMCs [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.52-2.80, p < 0.001] and significantly higher severity of WMCs (Hedges' g = 0.23, 95% CI 0.06-0.40, p = 0.009) in the patients with OSA than in controls. Furthermore, the results revealed a significantly higher apnea-hypopnea index (Hedges' g = 0.54, 95% CI 0.31-0.78, p < 0.001) and significantly higher prevalence rate of moderate-to-severe OSA (OR 2.86, 95% CI 1.44-5.66, p = 0.003) in the patients with WMCs than in controls, however there was no significant difference in the prevalence rate of mild OSA between the patients with WMCs and controls (OR 0.71, 95% CI 0.20-2.54, p = 0.603). OSA was associated with a higher prevalence and more severe WMCs, and the patients with WMCs had an increased association with moderate-to-severe OSA. Future large-scale randomized controlled trials with a longitudinal design are essential to further evaluate treatment in patients with OSA. PMID- 29766272 TI - Blood pressure is normal, but is the heart? AB - BACKGROUND: There is no detailed strain analysis of cardiac functions in treated hypertensive pediatric patients. The aim of this study was to evaluate the cardio protective effects of different drug classes in treated pediatric hypertensive patients. METHODS: Sixty non-obese-treated hypertensive patients with preserved left ventricular (LV) systolic function and 45 age-, sex-, and body mass index matched healthy subjects underwent clinical evaluation, including 24-h ambulatory blood pressure monitoring, standard echocardiographic examination, tissue Doppler imaging, and two-dimensional Speckle Tracking Echocardiography. The patients were divided into two subgroups based on the effects of the drugs on the Renin Angiotensin Aldosterone System. The subgroup hypertension (HT) 1 received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and HT 2 subgroup received calcium channel blocker, beta-blocker, or diuretics. RESULTS: There was no difference between the two groups and subgroups with respect to clinical, demographic, ABPM, ventricular volumes, ejection fraction, and tissue Doppler imaging (TDI) parameters. For patients and controls, respectively, global longitudinal strain was - 18.70 +/- 3.41 versus - 21.01 +/- 3.82 (P < 0.001), and global radial strain was 40.6 +/- 9.8 versus 54.8 +/- 12.8 (P = 0.004). Peak LV twist and peak LV torsion were not significantly different. The patient subgroup analyses with each other revealed no difference in systolic and diastolic myocardial deformation properties. CONCLUSIONS: Strain parameters were reduced in all treated hypertensive children compared to normotensive children, and the various cardiac mechanic parameters were similarly abnormal no matter what type of antihypertensive agent was used. PMID- 29766273 TI - [Preventing and treating medication overuse headache]. PMID- 29766275 TI - Implementing Cough Reflex Testing in a Clinical Pathway for Acute Stroke: A Pragmatic Randomised Controlled Trial. AB - Silent aspiration is common after stroke and can lead to subsequent pneumonia. While standard bedside dysphagia assessments are ineffective at predicting silent aspiration, cough reflex testing (CRT) has shown promise for identifying patients at risk of silent aspiration. We investigated the impact of CRT on patient and service outcomes when embedded into a clinical pathway. 488 acute stoke patients were randomly allocated to receive either CRT or standard care (i.e. bedside assessment). Primary outcomes included confirmed pneumonia within 3 months post stroke and length of acute inpatient stay. Secondary outcomes related to the feasibility of implementing a CRT pathway and clinician and patient satisfaction. There was a non-significant reduction in pneumonia rates by 2.2% points in the CRT group (OR 0.32, 95% CI 0.06-1.62). There was a non-significant difference of 0.7 days (95% CI - 0.29 to 1.71 days) in length of stay between the standard care group and the CRT group. The CRT took on average 3 min longer to complete (p < 0.01) and resulted in a significant 6.7% increase in videofluoroscopic referrals (p = 0.02); however, these results are clinically insignificant. High patient and clinician satisfaction with CRT was found, with clinicians reporting additional knowledge and confidence in decision making for dysphagia management. Post hoc subgroup analyses according to stroke types were conducted and revealed no significant differences in pneumonia rates after adjustment for multiple comparisons. In conclusion, it was possible to implement a CRT pathway with minimal increases in clinician resources. While clinicians perceived CRT as beneficial in clinical decision making, the efficacy of CRT for reducing pneumonia rates in acute stroke remains to be established.Clinical Trial Registration-URL: http://www.anzctr.org.au . Unique identifier: ACTRN12616000724471. PMID- 29766277 TI - Dexmedetomidine as an adjuvant during general anesthesia. PMID- 29766276 TI - Anti-ganglionic AChR antibodies in Japanese patients with motility disorders. AB - BACKGROUND: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). METHODS: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. RESULTS: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. CONCLUSIONS: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders. PMID- 29766280 TI - Novel insights into nucleoamino acids: biomolecular recognition and aggregation studies of a thymine-conjugated L-phenyl alanine. AB - This article deals with the synthesis in solid phase and characterization of a nucleoamino amide, based on a phenylalaninamide moiety which was N-conjugated to a thymine nucleobase. In analogy to the natural nucleobase-amino acid conjugates, endowed with a wide range of biological properties, the nucleoamino amide interacts with single-stranded nucleic acids as verified in DNA- and RNA-binding assays conducted by CD and UV spectroscopies. These technologies were used to show also that this conjugate binds serum proteins altering significantly their secondary structure, as evidenced by CD and UV using BSA as a model. The biomolecular recognition seems to rely on the ability of the novel compound to bind aromatic and heteroaromatic moieties in protein and nucleic acids, not hindered by its propensity to self-assemble in aqueous solution, behavior suggested by dynamic light scattering (DLS) and CD spectroscopy in concentration- and temperature-dependent experiments. Finally, the high stability in human serum concurs to define the picture of the nucleoamino amide: this enzymatically stable drug candidate could interfere with protein and single-stranded nucleic acid driven biological processes, particularly those associated with mRNA poly(A) tail, and its self-assembling nature, in analogy to other L-Phe-based systems, discloses new scenarios in drug delivery technology. PMID- 29766279 TI - Current and potential distribution of the ectomycorrhizal fungus Suillus lakei ((Murrill) A.H. Sm. & Thiers) in its invasion range. AB - Suillus lakei is an ectomycorrhizal fungus native to North America and known in Europe, South America, and New Zealand. This contribution aims to illustrate the worldwide biogeography of S. lakei based on sporocarp records. Species distribution modeling was used to assess the suitable niche distribution of S. lakei, based on the climatic variables as well as distribution of its ectomycorrhizal partner, Douglas fir. In general, distribution of suitable niches of S. lakei greatly overlaps with the distribution of Douglas fir in North America. By spatial distribution modeling, we found that the precipitation of the coldest quarters, isothermality, and annual mean temperature are important factors influencing the potential distribution of S. lakei. Nevertheless, the most crucial factor limiting expansion of S. lakei in its invasion range is Douglas fir occurrence. This factor reached an 86.4% contribution for the S. lakei species distribution model. Additionally, we compare the aboveground and belowground presence of S. lakei based on surveys in the field. Our study shows that even extremely low abundance of ectomycorrhizas can open the possibility of using an ectomycorrhiza survey for their quantification as a good indicator of the presence of S. lakei in field conditions. Both sporocarps and ectomycorrhizas occurred only in gardens, where Douglas fir seedlings were outplanted at the beginning of the 1990s as an ornamental plant. Presumably, international trade of ornamental plants was one possible route of introduction of S. lakei to Poland. PMID- 29766278 TI - Adenomatous ductal proliferation/hyperplasia in the parotid gland associated without any other pathological lesions; a report and survey of the literatures. AB - Adenomatous ductal proliferation/hyperplasia (ADP/H) is a rare hyperplastic condition of the salivary gland. It is mostly associated with other salivary gland pathologies such as tumors and inflammations, and is incidentally found in tissue sections during histopathological examinations of those diseases. Herein, we report a case of ADP/H in the parotid gland not associated with any other pathological lesions, and present a review of the literature on this condition. A 60-year-old Japanese female complained of swelling on the left side of parotid region. Clinical examination revealed a swelling on the lower lobe of the left parotid gland. The lesion was firm but non-tender and was not attached to adjacent structures. A clinical diagnosis of benign salivary gland tumor was reached, and surgical excision was performed under general anesthesia. Histopathological examination revealed an intact parotid gland capsule with isomorphic and basaloid cells within scanty cytoplasm. In addition, an admixture of hyperplasia and proliferation of the intercalated ducts, the presence of zymogen granules, the absence of solid nests, and a peripheral palisaded arrangement of the cells were observed. Based on these findings, a diagnosis of ADP/H was confirmed. ADP/H is a non-tumorous lesion; therefore, tumor involvement should be ruled out before the diagnosis is reached. PMID- 29766281 TI - Sex and gender differences in schizophrenic psychoses-a critical review. AB - Many sex and gender differences in schizophrenic psychoses have been reported, but few have been soundly replicated. A stable finding is the later age of onset in women compared to men. Gender differences in symptomatology, comorbidity, and neurocognition seem to reflect findings in the general population. There is increasing evidence for estrogens being psychoprotective in women and for hypothalamic-pituitary-gonadal dysfunction in both sexes.More methodologically sound, longitudinal, multi-domain, interdisciplinary research investigating both sex (biological) and gender (psychosocial) factors is required to better understand the different pathogenesis and etiologies of schizophrenic psychoses in women and men, thereby leading to better tailored treatments and improved outcomes. PMID- 29766282 TI - Parameters of pulse wave velocity: determinants and reference values assessed in the population-based study LIFE-Adult. AB - AIMS AND BACKGROUND: Parameters of arterial stiffness such as pulse wave velocity (PWV) were recently proposed as independent risk factors of cardiovascular events. We analyse three PWV parameters in the large population-based study LIFE Adult to identify risk factors, normal and reference values. METHODS AND RESULTS: Brachial-ankle (ba), brachial-femoral (bf) and carotid-femoral (cf) PWV assessment was performed using Vicorder device. 8509 participants aged 19-80 were analysed. PWV parameters were moderately correlated (r(ba/bf) = 0.6, r(ba/cf) = 0.46, r(bf/cf) = 0.59). Age and blood pressure are the dominant determinants of PWV parameters explaining > 18% of variability. Sex was only relevant for bfPWV and cfPWV. All further analysed cardiovascular and other risk factors are of minor importance. We provide age-dependent percentiles for the population (reference values) and for the subgroup of normotonic individuals. All percentiles show a strong increase with age. The difference between normotonic and all individuals is small for younger age groups but increases up to 1 m/s for elderly subjects. CONCLUSION: Our study confirms and further underpins the strong impact of age and blood pressure on arterial stiffness and the relatively weak contribution of other factors, supporting an independent role of arterial stiffness in cardiovascular disease development. Age-dependent reference and normal values were provided on the basis of the so far largest study sample facilitating the implementation of PWV assessment in clinical practice. Due to better compliance, handling and stronger association with age and blood pressure, baPWV could serve as an alternative to cfPWV. Follow-up data are required to estimate the clinical significance of specified PWV cut-offs. PMID- 29766283 TI - Should we treat any sleep apnea in patients with atrial fibrillation? PMID- 29766284 TI - Sodium levels during hospitalization with acute myocardial infarction are markers of in-hospital mortality: Soroka acute myocardial infarction II (SAMI-II) project. AB - OBJECTIVE: Abnormalities in sodium homeostasis are common in hospitalized patients. Hyponatremia upon admission is a poor prognostic marker in acute myocardial infarction (AMI) patients. However, little is known about the association between changes in sodium levels and in-hospital mortality. We delineated changes in sodium levels and studied the association of such changes with in-hospital mortality of AMI patients. METHODS: Retrospective analysis of AMI patients hospitalized for > 6 days. Sodium levels throughout the 6-day post admission were divided into five equally sized groups (quintiles = Q) and thereafter categorized as follows: Q1 (< 135 mEq/L), Q2-Q4 (135-140 mEq/L, reference group), and Q5 (>=141 mEq/L). PRIMARY OUTCOME: in-hospital mortality. RESULTS: A total of 8306 patients (10,416 admissions) were included (mean age 67.8 +/- 14.0 years, 33.4% women, 45.5% STEMI). In-hospital mortality was 6.6%. Q1 and Q5 upon admission were both related to higher risk for in-hospital mortality, compared with the reference group (OR 1.47 and OR 1.33, respectively, p < 0.001 each). Q1 was more frequent in non-survivors throughout the entire study period, while the prevalence of Q5 levels was similar in survivors and non survivors upon admission carrying increasing mortality risk thereafter: for Q1 consistent OR 1.50, while for Q5 it, increased from OR 1.32 upon admission to OR 1.90 on the sixth day, p < 0.001. CONCLUSIONS: Low and high sodium levels are associated with increased risk for in-hospital mortality in patients with AMI. The risk is unchanged for hyponatremia, while it consistently increases for increased sodium levels. PMID- 29766286 TI - Attenuation of the association between sugar-sweetened beverages and diabetes risk by adiposity adjustment: a secondary analysis of national health survey data. AB - PURPOSE: While weight gain and obesity are the dominant factors, dietary sugar and specifically sugar-sweetened beverages (SSB) has been implicated in causing type 2 diabetes (T2DM). We assessed how much of the apparent effect of SSB is explained by adiposity, but not captured by adjustment for BMI, which is a poor index of body fat. METHODS: We examined data from 5187 adults (mean age 50.8 years, SD = 16.4, 172 (3.3%) T2DM), from the Scottish Health Survey 2003 and 2008 2010 databases. Logistic regression was used to assess the association between SSB consumption and T2DM (non-insulin treated) and its attenuation (reduction in odds ratios, ORs), after entering published anthropometric indices of adiposity into the regression model, adjusted for age, sex, social class, education, smoking, alcohol consumption and physical activity. RESULTS: Compared with low SSB categories ("less often/never", once/week or 1-3 times/month), the OR without adiposity adjustment for having T2DM in high SSB consumers (2-3, 4-5, >= 6/day) was 2.56 (95% CI 1.12-5.83; p = 0.026). That OR was marginally changed by adjusting for BMI (+ 4.3%), WC (+ 5.5%) or total body fat (- 4.3%), but greatly attenuated by adjusting for estimated %body fat (- 23.4%). These indices had similar influences on the associations between SSB and T2DM combining known T2DM patients with unknown HbA1c > 6.5%, > 48 mmol/mol. CONCLUSIONS: Associations between SSB and T2DM are attenuated more markedly by adjustment with estimated %body fat than with BMI, indicating an adiposity effect not captured using BMI. Future research should employ best available estimates of adiposity. PMID- 29766287 TI - Reply to ZT Lopez-Ixta. PMID- 29766285 TI - Impact of left ventricular hypertrophy on myocardial injury in patients with ST segment elevation myocardial infarction. AB - BACKGROUND: Left ventricular hypertrophy (LVH) has been suggested as a determinant of outcome in patients with ST-segment elevation myocardial infarction (STEMI). However, available data are inconclusive and the underlying mechanisms remain unclear. Therefore, the aim of this study was to evaluate the impact of LVH on myocardial injury and clinical outcome in a large multicenter STEMI population. METHODS: Cardiovascular magnetic resonance was performed in 795 patients within 10 days after STEMI to assess left ventricular (LV) mass and parameters of myocardial injury. Gender-specific cutoff values of indexed LV mass were used to define LVH (67 g/m2 for men and 61 g/m2 for women). Rates of major adverse cardiac events (MACE) were determined at 12-month follow-up. RESULTS: LVH was present in 438 patients (55%) and associated with a significantly larger infarct size [18.3% of LV mass (%LV) versus 14.0%LV; p < 0.01], a lower myocardial salvage index (47.8 versus 54.4; p < 0.01), larger extent of microvascular obstruction (0.4 versus 0%LV; p < 0.01) and lower LV ejection fraction (47.9 versus 53.2%; p < 0.01) compared to STEMI patients without LVH. The effect of LVH on LV ejection fraction, infarct size and myocardial salvage index remained statistically significant after adjustment for baseline characteristics (p < 0.01 for all). MACE rates at 12 months were numerically higher in patients with versus without LVH without reaching statistical significance (7.5 versus 5.6%; p = 0.32). CONCLUSION: In STEMI patients, LVH is associated with more pronounced structural and functional alterations in CMR imaging as an indicator for adverse clinical outcomes in STEMI survivors. PMID- 29766288 TI - Letter to the editor regarding Pluymen et al.'s paper: Early introduction of complementary foods and childhood overweight in breastfed and formula-fed infants in the Netherlands: the PIAMA birth cohort study. PMID- 29766289 TI - Comment on "Early introduction of complementary foods and childhood overweight in breastfed and formula-fed infants in the Netherlands: the PIAMA birth cohort study". PMID- 29766290 TI - Control, perceived control or self-efficacy as confounders in the relation between fruit and vegetable consumption and psychological disorders. PMID- 29766291 TI - Response to letters to the editor regarding our paper "Early introduction of complementary foods and childhood overweight in breastfed and formula-fed infants in the Netherlands: the PIAMA birth cohort study". PMID- 29766292 TI - Gut-derived lipopolysaccharides increase post-prandial oxidative stress via Nox2 activation in patients with impaired fasting glucose tolerance: effect of extra virgin olive oil. AB - PURPOSE: Post-prandial phase is characterized by enhanced oxidative stress but the underlying mechanism is unclear. We investigated if gut-derived lipopolysaccharide (LPS) is implicated in this phenomenon and the effect of extra virgin olive oil (EVOO) in patients with impaired fasting glucose (IFG). METHODS: This is a randomized cross-over interventional study including 30 IFG patients, to receive a lunch with or without 10 g of EVOO. Serum LPS, Apo-B48, markers of oxidative stress such as oxidized LDL (oxLDL) and soluble Nox2-derived peptide (sNox2-dp), a marker of nicotinamide-adenine-dinucleotide-phosphate oxidase isoform Nox2 activation, and plasma polyphenols were determined before, 60 and 120 min after lunch. RESULTS: In patients not given EVOO oxidative stress as assessed by sNox2-dp and oxLDL significantly increased at 60 and 120 min concomitantly with an increase of LPS and Apo-B48. In these patients, changes of LPS were correlated with Apo-B48 (Rs = 0.542, p = 0.002) and oxLDL (Rs = 0.463, p = 0.010). At 120 min, LPS (beta - 15.73, p < 0.001), Apo-B48 (beta - 0.14, p = 0.004), sNox2-dp (beta - 5.47, p = 0.030), and oxLDL (beta - 42.80, p < 0.001) significantly differed between the two treatment groups. An inverse correlation was detected between polyphenols and oxLDL (R - 0.474, p < 0.005). In vitro study showed that LPS, at the same concentrations found in the human circulation, up regulated Nox2-derived oxidative stress via interaction with Toll-like receptor 4. CONCLUSIONS: Post-prandial phase is characterized by an oxidative stress related inflammation potentially triggered by LPS, a phenomenon mitigated by EVOO administration. PMID- 29766293 TI - NMDA receptor subunits change in the prefrontal cortex of pure-opioid and multi drug abusers: a post-mortem study. AB - Addiction is a chronic relapsing disorder and is one of the most important issues in the world. Changing the level of neurotransmitters and the activities of their receptors, play a major role in the pathophysiology of substance abuse disorders. It is well-established that N-methyl-D-aspartate receptors (NMDARs) play a significant role in the molecular basis of addiction. NMDAR has two obligatory GluN1 and two regionally localized GluN2 subunits. This study investigated changes in the protein level of GluN1, GluN2A, and GluN2B in the prefrontal cortex of drug abusers. The medial prefrontal cortex (mPFC), lateral prefrontal cortex (lPFC), and orbitofrontal cortex (OFC) were dissected from the brain of 101 drug addicts brains and were compared with the brains of non-addicts (N = 13). Western blotting technique was used to show the alteration in NMDAR subunits level. Data obtained using Western blotting technique showed a significant increase in the level of GluN1 and GluN2B, but not in GluN2A subunits in all the three regions (mPFC, lPFC, and OFC) of men whom suffered from addiction as compared to the appropriate controls. These findings showed a novel role for GluN1, GluN2B subunits, rather than the GluN2A subunit of NMDARs, in the pathophysiology of addiction and suggested their role in the drug-induced plasticity of NMDARs. PMID- 29766295 TI - The impact of temporal contingencies between cue and target onset on spatial attentional capture by subliminal onset cues. AB - Prior research suggested that attentional capture by subliminal abrupt onset cues is stimulus driven. In these studies, reacting was faster when a searched-for target appeared at the location of a preceding abrupt onset cue compared to when the same target appeared at a location away from the cue (cueing effect), although the earlier onset of the cue was subliminal, because it appeared as one out of three horizontally aligned placeholders with a lead time that was too short to be noticed by the participants. Because the cueing effects seemed to be independent of top-down search settings for target features, the effect was attributed to stimulus-driven attentional capture. However, prior studies did not investigate if participants experienced the cues as useful temporal warning signals and, therefore, attended to the cues in a top-down way. Here, we tested to which extent search settings based on temporal contingencies between cue and target onset could be responsible for spatial cueing effects. Cueing effects were replicated, and we showed that removing temporal contingencies between cue and target onset did not diminish the cueing effects (Experiments 1 and 2). Neither presenting the cues in the majority of trials after target onset (Experiment 1) nor presenting cue and target unrelated to one another (Experiment 2) led to a significant reduction of the spatial cueing effects. Results thus support the hypothesis that the subliminal cues captured attention in a stimulus-driven way. PMID- 29766294 TI - Influence of dietary nitrate supplementation on local sweating and cutaneous vascular responses during exercise in a hot environment. AB - PURPOSE: We investigated the influence of inorganic nitrate ([Formula: see text]) supplementation on local sweating and cutaneous vascular responses during exercise in hot conditions. METHOD: Eight healthy, young subjects were assigned in a randomized, double-blind, crossover design to receive [Formula: see text] rich beetroot (BR) juice (140 mL/day, containing ~ 8 mmol of [Formula: see text]) and [Formula: see text]-depleted placebo (PL) juice (140 mL/day, containing ~ 0.003 mmol of [Formula: see text]) for 3 days. On day 3 of supplementation, subjects cycled at an intensity corresponding to 55% of [Formula: see text]O2max for 30 min in hot conditions (30 degrees C, 50% relative humidity). Chest and forearm sweat rate (SR) and skin blood flow (SkBF), were measured continuously. Cutaneous vascular conductance (CVC) was calculated by SkBF/mean arterial pressure (MAP). RESULTS: Prior to exercise, plasma [Formula: see text] (21 +/- 6 and 581 +/- 161 uM) and nitrite ([Formula: see text], 87 +/- 28 and 336 +/- 156 nM) concentrations were higher after BR compared to PL supplementation (P <= 0.011, n = 6). Oesophageal, mean skin, and mean body temperatures during exercise were not different between conditions. In addition, BR supplementation did not affect SR, SkBF, and CVC during exercise. A lower MAP was found after 30 min of exercise following BR supplementation (112 +/- 6 and 103 +/- 6 mmHg for PL and BR, respectively, P = 0.021). CONCLUSION: These results suggest that inorganic [Formula: see text] supplementation, which increases the potential for O2 independent NO production, does not affect local sweating and cutaneous vascular responses, but attenuates blood pressure in young healthy subjects exercising in a hot environment. PMID- 29766296 TI - Characterization of in vivo metabolites in rat urine following an oral dose of masitinib by liquid chromatography tandem mass spectrometry. AB - Masitinib (MST) is an orally administered drug that targets mast cells and macrophages, important cells for immunity, by inhibiting a limited number of tyrosine kinases. It is currently registered in Europe and USA for the treatment of mast cell tumors in dogs. AB Science announced that the European Medicines Agency has accepted a conditional marketing authorization application for MST to treat amyotrophic lateral sclerosis. In our work, we focused on studying in vivo metabolism of MST in Sprague-Dawley rats. Single oral dose of MST (33 mg kg-1) was given to Sprague-Dawley rats (kept in metabolic cages) using oral gavage. Urine was collected and filtered at 0, 6, 12, 18, 24, 48, 72 and 96 h from MST dosing. An equal amount of ACN was added to urine samples. Both organic and aqueous layers were injected into liquid chromatography-tandem mass spectrometry (LC-MS/MS) to detect in vivo phase I and phase II MST metabolites. The current work reports the identification and characterization of twenty in vivo phase I and four in vivo phase II metabolites of MST by LC-MS/MS. Phase I metabolic pathways were reduction, demethylation, hydroxylation, oxidative deamination, oxidation and N-oxide formation. Phase II metabolic pathways were the direct conjugation of MST, N-demethyl metabolites and oxidative metabolites with glucuronic acid. Part of MST dose was excreted unchanged in urine. The literature review showed no previous articles have been made on in vivo metabolism of MST or detailed structural identification of the formed in vivo phase I and phase II metabolites. PMID- 29766297 TI - Ultraviolet Light-Assisted Copper Oxide Nanowires Hydrogen Gas Sensor. AB - We fabricated copper oxide nanowires (CuO NWs) ultraviolet (UV) light-assisted hydrogen gas sensor. The fabricated sensor shows promising sensor response behavior towards 100 ppm of H2 at room temperature and elevated temperature at 100 degrees C when exposed to UV light (3.0 mW/cm2). One hundred-cycle device stability test has been performed, and it is found that for sample elevated at 100 degrees C, the UV-activated sample achieved stability in the first cycle as compared to the sample without UV irradiation which needed about 10 cycles to achieve stability at the initial stage, whereas the sample tested at room temperature was able to stabilize with the aid of UV irradiation. This indicates that with the aid of UV light, after some "warming up" time, it is possible for the conventional CuO NW sensor which normally work at elevated temperature to function at room temperature because UV source is speculated to play a dominant role to increase the interaction of the surface of CuO NWs and hydrogen gas molecules absorbed after the light exposure. PMID- 29766298 TI - K27/G34 versus K28/G35 in histone H3-mutant gliomas: A note of caution. PMID- 29766300 TI - Treatment of cardial submucosal tumors originating from the muscularis propria layer: submucosal tunneling endoscopic resection versus endoscopic submucosal excavation. AB - BACKGROUND AND AIMS: Submucosal tunneling endoscopic resection (STER) is increasingly used for the treatment of submucosal tumors (SMTs) originating from the muscularis propria layer; however, endoscopic submucosal excavation (ESE) is still performed in many hospitals for its low-skill and experience requirements. This study aimed to compare STER with ESE for cardial SMTs. METHODS: From March 2013 to February 2017, patients with cardial SMTs undergoing STER (n = 47) and ESE (n = 40) were retrospectively assessed. Clinicopathological, endoscopic, and complication data were compared between STER and ESE groups. RESULTS: The 87 enrolled patients included 31 females and 56 males, aged 48.2 +/- 9.8 years. Mean tumor size was 22.0 mm (range 5.0-80.0 mm) as evaluated by pathology. Demographic and lesion features were similar in both groups. Despite similar hospital stay duration and cost, ESE was superior to STER with reduced operation time (34 vs. 46 min, P = 0.013) and less clips required (3 vs. 5, P = 0.000). En bloc resection rates, complete resection rates, hospital stay duration, cost, complications, and hemoglobin levels were similar in both groups. Irregular shaped SMTs were more likely to achieve piecemeal resection in both STER and ESE groups (all P < 0.05). Meanwhile, the piecemeal resection rate was significantly higher for larger tumors in the STER group. CONCLUSION: Compared with ESE, STER does not show overt advantages for cardial SMTs. However, ESE is superior to STER for reduced operation time. Irregular tumor shape seems to be a risk factor for piecemeal resection in both STER and ESE. PMID- 29766299 TI - Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features. AB - Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT. PMID- 29766301 TI - Randomized clinical trial comparing laparoscopic hiatal hernia repair using sutures versus sutures reinforced with non-absorbable mesh. AB - BACKGROUND: Current literature is characterized by a discrepancy between reported symptomatic and radiological recurrent hiatal hernia's following primary repair. Crural augmentation using mesh is suggested to reduce recurrence rates. The aim of this trial is to analyze 1-year outcome of laparoscopic hiatal hernia repair using sutures versus sutures reinforced with non-absorbable mesh. METHODS: Between 2013 and 2016, 72 patients with an objectified hiatal hernia were randomized for primary repair using non-absorbable sutures and sutures reinforced with non-absorbable mesh. Data regarding the incidence of recurrent hiatal hernia, need for endoscopic dilatation or surgical reintervention, postoperative dysphagia and/or reflux symptoms, general health, and use of acid-suppressing medication were analyzed. RESULTS: 72 patients (n = 36 vs. n = 36) were included. One year after primary repair and repair using non-absorbable mesh, there were no differences in the number of recurrent hiatal hernia's demonstrated by barium swallow radiology (n = 4 [11.4%] vs. n = 6 [19.4%], p = 0.370) or upper gastrointestinal endoscopy (n = 5 [14.4%] vs. n = 5 [17.2%], p = 0.746), the number of surgical reinterventions (n = 2 [5.6%] vs. n = 1 [2.8%], p = 1.000), nor in chest pain and heartburn scores, with comparable dysphagia and satisfaction scores. Compared to the preoperative state, both groups demonstrated a comparable and significant reduction in chest pain score and Dakkak dysphagia score. CONCLUSIONS: Use of non-absorbable mesh to reinforce primary hiatal hernia repair results in equal hiatal hernia recurrence and symptomatic outcome compared to repair using sutures alone. During 1-year follow-up, there were no mesh related complications. Follow-up beyond 1 year needs to demonstrate whether these findings are sustained. PMID- 29766302 TI - Technique, safety, and feasibility of EUS-guided radiofrequency ablation in unresectable pancreatic cancer. AB - BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is a well-recognized local ablative technique applied in the treatment of different solid tumors. Intraoperative RFA has been used for non-metastatic unresectable pancreatic ductal adenocarcinoma (PDAC), showing increased overall survival in retrospective studies. A novel RFA probe has recently been developed, allowing RFA under endoscopic ultrasound (EUS) guidance. Aim of the present study was to assess the feasibility and safety of EUS-guided RFA for unresectable PDACs. METHODS: Patients with unresectable non-metastatic PDAC were included in the study following neoadjuvant chemotherapy. EUS-guided RFA was performed using a novel monopolar 18-gauge electrode with a sharp conical 1 cm tip for energy delivery. Pre- and post-procedural clinical and radiological data were prospectively collected. RESULTS: Ten consecutive patients with unresectable PDAC were enrolled. The procedure was successful in all cases and no major adverse events were observed. A delineated hypodense ablated area within the tumor was observed at the 30-day CT scan in all cases. CONCLUSIONS: EUS-guided RFA is a feasible and safe minimally invasive procedure for patients with unresectable PDAC. Further studies are warranted to demonstrate the impact of EUS-guided RFA on disease progression and overall survival. PMID- 29766303 TI - Comparison between laparoscopic and open Hartmann's reversal: results of a decade long multicenter retrospective study. AB - BACKGROUND: Hartmann's reversal is a challenging surgical procedure with significant postoperative morbidity rates. Various surgical methods have been suggested to lower the risk of postoperative complications. In this study, we aimed to compare the postoperative results between open and laparoscopic techniques for Hartmann's reversal. METHODS: A retrospective study of all patients who underwent Hartmann's reversal in five centers in central Israel between January 2004 and June 2015 was conducted. Medical charts were reviewed, analyzing preoperative and operative parameters and short-term postoperative outcomes. RESULTS: 260 patients were included in the study. 76 patients were operated laparoscopically with a conversion rate of 26.3% (20 patients). No differences were found between patients operated laparoscopically and those operated in an open technique regarding gender (p = 0.785), age (61.34 vs. 62.64, p = 0.521), body mass index (26.6 vs. 26.2, p = 0.948), Charlson index score (1.79 vs. 1.95, p = 0.667), and cause for Hartmann's procedure (neoplastic vs. non-neoplastic, p = 0.644). No differences were seen in average time from the Hartmann's procedure to reversal (204.89 vs. 213.60 days, p = 0.688) and in overall complication rate (46.4 vs. 46.5%, p = 1). The Clavien-Dindo score for distinguishing between minor (0-2 score, p = 1) and major complications (3-5 score, p = 0.675) failed to demonstrate an advantage to laparoscopy, as well as to average length of stay (10.91 days in the laparoscopic group vs. 11.72 days in the open group, p = 0.529). An analysis based on the intention-to-treat with laparoscopy, including converted cases in the laparoscopic group, showed similar results, including overall complication rate (48.6 vs. 45.6%, p = 0.68) and Clavien-Dindo score in both minor (p = 0.24) and major complications (p = 0.44). Length of stay (10.92 vs. 11.81 days, p = 0.45) was also similar between the two groups. CONCLUSION: In this series, a laparoscopic approach to Hartmann's reversal did not offer any short-term advantage when compared to an open surgical approach. PMID- 29766304 TI - Operative technique in robotic pancreaticoduodenectomy (RPD) at University of Illinois at Chicago (UIC): 17 steps standardized technique : Lessons learned since the first worldwide RPD performed in the year 2001. AB - BACKGROUND: Minimally invasive pancreaticoduodenectomy (MIPD) was introduced in the attempt to improve the outcomes of the open approach. Laparoscopic pancreaticoduodenectomy (LPD) was first reported by Gagner and Pomp (Surg Endosc 8:408-410, 1994). Unfortunately, due to its complexity and technical demand, LPD never reached widespread popularity. Since it was first performed by P. C. Giulianotti in 2001, Robotic PD (RPD) has been gaining ground among surgeons. MIPD is included as a surgical option in the latest NCCN Guidelines. However, lack of surgical standardization, however, has limited the reproducibility of MIPD and made the acquisition of the technique by other surgeons difficult. We provide an accurate description of our standardized step-by-step RDP technique. METHODS: We took advantage of our 15-year long experience and > 150 cases performed to provide a step-by-step guidance of our RPD standardized technique. The description includes practical "tips and tricks" to facilitate the learning curve and assist with the teaching/evaluation process. RESULTS: 17 surgical steps were identified as key components of the RPD procedure. The steps reflect the subdivision of the RPD into several parts which help to understand a strategy that takes into accounts specific anatomical landmarks and the demands of the robotic platform. CONCLUSIONS: Standardization is a key element of the learning curve of RPD. It can potentially provide consistent, reproducible results that can be more easily evaluated. Despite promising results, full acceptance of RPD as the 'gold standard' is still work in progress. Randomized-controlled trials with the application of a standardized technique are necessary to better define the role of RPD. PMID- 29766305 TI - Evaluation of VTE prophylaxis and the impact of alternate regimens on post operative bleeding and thrombotic complications following bariatric procedures. AB - BACKGROUND: Studies examining utilization and impact of venous thromboembolism (VTE) chemoprophylaxis for patients undergoing bariatric surgery are limited. Determination of the optimal prophylactic regimen to minimize complications is crucial. METHODS: The Cerner Health Facts database from 2003 to 2013 was queried using ICD-9 codes to identify patients undergoing laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB). VTE chemoprophylaxis regimens were divided into pre-operative alone (PreP), post-operative alone (PostP), both pre operative and post-operative (PPP), or no prophylaxis (NP). Specific chemoprophylaxis agents were compared. Comparisons in inpatient clinical outcomes were based on univariate analysis and multivariable logistic regression when appropriate. RESULTS: We identified 11,860 patients who underwent LSG and RYGB. 634 (5.35%) had PreP, 4593 (38.73%) had PostP, 2646 (22.31%) had PPP, and 3987 (33.62%) had NP. The overall rates of transfusion, DVT, and PE were 2.48, 0.27, and 0.18%, respectively. Patients without chemoprophylaxis had higher rate of DVT compared to any chemoprophylaxis (0.58 vs 0.11%, p < 0.0001), without any significant difference in PE rate. Patients with pre-operative chemoprophylaxis were more likely to receive transfusion compared to patients with post-operative prophylaxis alone (OR 1.98, 95% CI 1.28-3), without significant difference in having VTE. When examining heparin versus enoxaparin versus mixed regimen in the PostP group, mixed regimen was associated with increased transfusion requirements (p < 0.001). CONCLUSIONS: Bariatric surgical VTE chemoprophylaxis utilization is inconsistent. In this study, post-operative VTE chemoprophylaxis was associated with decreased VTE events compared to NP, while minimizing bleeding compared to PreP. Mixed therapy using heparin and enoxaparin was associated with more bleeding. PMID- 29766306 TI - Intraoperative conversion does not affect the oncological outcomes of minimally invasive esophagectomy for treatment of esophageal cancer. AB - BACKGROUND: The aim of this study is to summarize the causes and implications of intraoperative conversion from minimally invasive esophagectomy (MIE) to open thoracotomy, and to evaluate the effect on long-term survival. METHODS: There were 293 thoracoscopic esophagectomies for esophageal squamous cell carcinoma (ESCC) of the thoracic esophagus performed by the authors from September 2009 to August 2015. Totally, 257 patients were enrolled in this study. These patients were divided into two groups (those underwent complete MIE and those converted to open thoracotomy) and then compared. A standardized preoperative evaluation, as well as a postoperative method of following at a regular frequency were adopted for all of these patients. The clinicopathologic characteristics and the perioperative variables were retrospectively analyzed. Univariate and multivariate analyses were performed to identify prognostic factors. And the Kaplan-Meier method was used to compare survival differences. RESULTS: There were 231 patients (89.9%) underwent successful thoracoscopic esophagectomy (Group 1), and 26 cases (10.1%) required conversion to open procedure (Group 2). The majority of conversion (73.1%, 19/26) occurred in the initial 100 cases. No significant difference in background or clinicopathologic factors between the two groups was observed, but patients in Group 2 had significantly longer operative time and more operative blood loss. Among the 26 patients of Group 2, there were nine cases that need emergent conversion for various reasons. And the most common cause for emergent conversion was intraoperative bleeding. Univariate and multivariate analyses all demonstrated that intraoperative conversion did not significantly influence the overall or recurrence-free survival of these patients. CONCLUSIONS: Univariate analysis and multivariate Cox proportional hazard regression analysis indicated that intraoperative conversion did not significantly influence the OS and RFS rate of these patients. Our results demonstrated that the intraoperative conversion did not affect the long-term survival of patients underwent MIE for ESCC. PMID- 29766307 TI - The laparoscopic inguinal and diaphragmatic defect (LIDD) model: a validation study of a novel box trainer model. AB - BACKGROUND: Paediatric laparoscopic procedures are now becoming routine practice. Therefore, there is a need for simulated laparoscopic models to acquire part procedural competency prior to direct patient contact in a safe learning environment. For this reason, we chose two paediatric conditions; inguinal hernia (IH) and congenital diaphragmatic hernia (CDH), which were combined to create the laparoscopic inguinal and diaphragmatic defect (LIDD) model. Our aim was to assess this novel surgical simulation model by determining its construct and content validity. METHODS: A total of 107 participants completed the validation study: volunteer medical students (novices), surgical trainees (intermediate) and consultant surgeons (experts). Basic demographic data were collected. Subjects were shown a pre-recorded video of both exercises. The assessment exercise involved closing both the simulated inguinal or diaphragmatic hernial orifice. The task was assessed using a novel scoring system with a maximum score of 21 for IH model and 15 for the CDH. The content validity was assessed by a 6-point Likert scale of the expert group. RESULTS: 105/107 participants successfully completed the two exercises. Both aspects of the LIDD model revealed a statistical significance between the scores obtained by the three groups of subjects. Experts scored 20.3/21 for the IH and 14.8/15 for the CDH models which significantly higher than medical students (6.3/21 and 5.3/15; p < 0.05 for both) and trainees (11.2/21 and 9.3/15; p < 0.05 for both). Similarly, trainees performed significantly better than medical students in both models (p < 0.05). Therefore, the LIDD model was found to have a good construct validity. It was, however, unable to differentiate between the various levels of trainees in the intermediate group. Content validity from the experts revealed that there was a high score for the potential of both aspects of LIDD (4.8 and 4.8). There was also a high level of functional fidelity for task completion (4.0 and 4.0). CONCLUSIONS: We have demonstrated both the construct and content validity of the LIDD model for both laparoscopic IH and CDH repair. It was able to successfully differentiate between the expert, trainees and inexperienced laparoscopic surgeons. PMID- 29766308 TI - Robotic-assisted laparoscopic groin hernia repair: observational case-control study on the operative time during the learning curve. AB - BACKGROUND: Robotic groin hernia repair (r-TAPP) is demonstrating rapid adoption in the US. Barriers in Europe include: low availability of robotic systems to general surgeons, cost of robotic instruments, and the perception of longer operative time. METHODS: Patients undergoing r-TAPP in our start-up period were prospectively entered in the EuraHS database and compared to laparoscopic TAPP (l TAPP) performed by the same surgeon within the context of two other prospective studies. Operations were performed with the daVinci Xi robot and the primary endpoint was skin-to-skin operative time. RESULTS: Following proctoring in September 2016 by US surgeons, 50 r-TAPP (34 unilateral and 16 bilateral) procedures have been performed up to January 2017. Mean operative time for unilateral r-TAPP was 54 min, with a decrease from 63 min for the first tertile to 44 min for the third tertile. For unilateral l-TAPP, the mean operative time was 45 min. Mean operative time for bilateral r-TAPP was 78 min, with a decrease from 90 min for the first half to 68 min for the second half. For bilateral l TAPP, the mean operative time was 61 min. There were no intraoperative complications and no conversions to conventional laparoscopy or open surgery. The operation was performed as an outpatient in 67% of cases. Urinary retention requiring urinary catheterization was the only early postoperative complication noted in 5 patients (10.2%). At 4 week follow-up, 7 patients (14.3%) had an asymptomatic seroma, but no other complications were seen. CONCLUSION: Robotic TAPP was associated with a rapid reduction in operative time during our learning curve and afterwards the operative time to perform a robotic TAPP equals the operative time to perform a laparoscopic TAPP, both for unilateral and for bilateral groin hernia repairs. No complications related to the introduction of robotic-assisted laparoscopic groin hernia repair were observed. PMID- 29766310 TI - It's better to be lucky. AB - Presidential Address at the 2018 SAGES Annual Meeting Seattle, Washington, April 13, 2018. Working together, there is no limit to what SAGES teams can achieve with innovation, passion, persistence, and a little luck. The speech highlights several SAGES initiatives, and he recognizes their champions. PMID- 29766309 TI - Perioperative outcomes and anesthetic considerations of robotic bariatric surgery in a propensity-matched cohort of super obese and super-super obese patients. AB - BACKGROUND: The use of the robotic platform has not been well established in patients with super obesity (SO; body mass index, BMI >= 50) and super-super obesity (SSO, BMI >= 60). We aimed to determine safety and feasibility of robotic bariatric surgery in this cohort. METHODS: Review of a prospectively maintained database was performed of consecutive patients undergoing robotic bariatric surgery between 2015 and 2017. Propensity score analysis with 1:2 nearest neighbor matching was performed to control for baseline characteristics and procedure type. RESULTS: A propensity-matched cohort of 47 SO patients (median BMI 55.3, range 50.1-92.5) and 94 morbidly obese (MO; median BMI 41.8, range 35.1 48.8) patients were analyzed. After matching, there were no difference in baseline characteristics including age, American Society of Anesthesiologists (ASA) score, or preoperative comorbidities. Most patients in each group underwent sleeve gastrectomy (81% of SO patients versus 76% of MO patients) or Roux-en-Y gastric bypass (13% vs. 18%, respectively), p = 0.66. There were no differences in operative time, intraoperative complications, postoperative complications, or re-admissions between groups. Length of stay was slightly longer in the MO group (2.2 days, IQR 1.8-3.2 vs. 1.8 days, IQR 1.2-2.7; p = 0.01). A subset of SSO patients (n = 11, median BMI 67, range 60-92) was analyzed; there was no increase in operation time, and zero intraoperative complications, conversions to open, or postoperative complications in this subset. CONCLUSIONS: Robotic bariatric surgery can safely be performed on patients with SO or SSO with low perioperative morbidity and no increase in operating time. PMID- 29766311 TI - Monitoring scanner calibration using the image-derived arterial blood SUV in whole-body FDG-PET. AB - BACKGROUND: The current de facto standard for quantification of tumor metabolism in oncological whole-body PET is the standardized uptake value (SUV) approach. SUV determination requires accurate scanner calibration. Residual inaccuracies of the calibration lead to biased SUV values. Especially, this can adversely affect multicenter trials where it is difficult to ensure reliable cross-calibration across participating sites. The goal of the present work was the evaluation of a new method for monitoring scanner calibration utilizing the image-derived arterial blood SUV (BSUV) averaged over a sufficiently large number of whole-body FDG-PET investigations. Data of 681 patients from three sites which underwent routine 18F-FDG PET/CT or PET/MR were retrospectively analyzed. BSUV was determined in the descending aorta using a three-dimensional ROI concentric to the aorta's centerline. The ROI was delineated in the CT or MRI images and transferred to the PET images. A minimum ROI volume of 5 mL and a concentric safety margin to the aortic wall was observed. Mean BSUV, standard deviation (SD), and standard error of the mean (SE) were computed for three groups of patients at each site, investigated 2 years apart, respectively, with group sizes between 53 and 100 patients. Differences of mean BSUV between the individual groups and sites were determined. RESULTS: SD (SE) of BSUV in the different groups ranged from 14.3 to 20.7% (1.7 to 2.8%). Differences of mean BSUV between intra-site groups were small (1.1-6.3%). Only one out of nine of these differences reached statistical significance. Inter-site differences were distinctly larger (12.6-25.1%) and highly significant (P<0.001). CONCLUSIONS: Image-based determination of the group-averaged blood SUV in modestly large groups of whole-body FDG-PET investigations is a viable approach for ensuring consistent scanner calibration over time and across different sites. We propose this approach as a quality control and cross-calibration tool augmenting established phantom-based procedures. PMID- 29766313 TI - Correction to: Long-Term Prognostic Value of Coronary Computed Tomography Angiography. AB - The authors would like to note that this article published in Current Treatment Options in Cardiovascular Medicine journal is not showing Open Access on the website. Thus, the paper is still not available for free online. PMID- 29766312 TI - Posttraumatic Growth as a Response to Natural Disasters in Children and Adolescents. AB - PURPOSE OF REVIEW: This review examines factors thought to be associated with posttraumatic growth (PTG) (demographic variables, exposure, and family and social processes) among youth exposed to natural disasters, describes the relationship between PTG and posttraumatic stress, and discusses psychological processes (rumination and coping) linked to PTG. RECENT FINDINGS: Guided by PTG theory and the literature on PTG in adults, research has revealed relationships between PTG and child, environmental, and family and social factors among youth though the results are mixed. Youth's subjective exposure to disasters, their level of posttraumatic stress following the disaster, and the type of psychological processes they employ to cope with the disaster appear to be associated with PTG. Research has garnered preliminary support for PTG in children exposed to natural disasters but additional research is needed to fully explicate these relationships and to understand how these relationships change over time. PMID- 29766314 TI - Metastatic colon cancer derived from a diverticulum incidentally found at herniorrhaphy: a case report. AB - BACKGROUND: There are few reports of metastases from colon cancer to an inguinal hernia sac, and few reports of colon cancer originating in diverticula. We report a patient with carcinoma of the sigmoid colon arising in two diverticula, who presented with peritoneal seeding to an inguinal hernia sac, and a review of the literature. CASE PRESENTATION: A 55-year-old male underwent open herniorrhaphy for a left inguinal hernia. At operation, a nodule in the inguinal hernia sac was resected and histologic examination revealed adenocarcinoma, which was suspected to be a metastasis from a distant primary lesion. Postoperative evaluation included colonoscopy and positron emission tomography which showed two suspected lesions in sigmoid diverticula. Laparoscopic subtotal colectomy was performed, and pathology revealed adenocarcinoma in two sigmoid diverticula. CONCLUSIONS: If a nodule is found in an inguinal hernia sac, especially in older patients, peritoneal metastases should be considered. Resection of the nodule with histopathologic evaluation is essential. Colon cancer arising in a diverticulum should be considered as a possible site of the primary lesion. PMID- 29766317 TI - Comment on: "The effect of corticosteroid on postoperative early pain, renal colic and total analgesic consumption after uncomplicated and unstented ureteroscopy: a matched-pair analysis". PMID- 29766316 TI - Influence of harvest stage on the pharmacological effect of Angelica dahurica. AB - BACKGROUND: Baizhi (Angelica dahurica) has been widely used as a traditional Chinese herbal medicine, functional food and cosmetic product ingredient, mostly because of the high furanocoumarin compounds in roots. The cropping system of Baizhi with its unique summer dormancy feature, is easily affected by the transition of its growth stages. The aim of this study was to analyze the quantity (size, form and dry weight [DW]) and quality (antioxidant and furanocoumarin content) of taproot and lateral root from three growth stages of Baizhi; vegetative (V-stage), summer dormancy (S-stage) and bolting stage (B stage). RESULTS: Root length and diameter were lower at V-stage than the other two stages, and S-stage had higher lateral root to total root ratio. However, the highest root DW was observed at S-stage. Antioxidant activity was revealed by 2,2 diphenyl-L-picrylhydrazyl and Fe2+ chelating assay, and the content of six furanocoumarin compounds, including xanthotoxin, bergapten, oxypeucedanin, imperatorin, phellopterin and isoimperatorin, was analyzed by liquid chromatography. Although the antioxidant activity was less at S-stage than the other stages, furanocoumarin contents showed little variation. CONCLUSION: Considering the high DW and stable furanocoumarin composition, S-stage is the best harvest stage than the other stages because of its richer total pharmacological content. PMID- 29766315 TI - Validation and determination of nine PFCS in surface water and sediment samples using UPLC-QTOF-MS. AB - In this study, an analytical method for the routine determination of nine perfluorinated compounds (PFCs), using ultra performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer (UPLC-QTOF-MS), was developed, validated, and used for their assay in surface water and sediments. The method yielded good linearity with a correlation coefficient (R2) ranging between 0.991 and 0.999 for all the compounds investigated. Limits of detection (LOD) ranged between 0.02 and 0.08 ng/l, while the limit of quantification (LOQ) ranged from 0.065 to 0.261 ng/l. Recovery studies were carried out in replicate assays, and percentage recoveries ranged between 56 and 112% for the nine perfluorinated compounds investigated. The method was applied to determine levels of perflurooctanoic acid (PFOA) and PFOS in surface water and sediment samples collected along the Plankenburg River in Stellenbosch, South Africa. Samples were pre-treated, extracted, and cleaned up via offline solid-phase extraction (SPE) procedures, using hydrophilic-lipophilic balance (HLB) C-18 cartridges. Levels of PFOA and PFOS found in surface water ranged between (12.8 +/- 4.24 and 62.62 +/- 4.86 ng/l) and ( 8 days on vvECMO. 12 patients on ECMO for > 8 days were identified. Prior to transfer, patients underwent ECMO therapy for 18 +/- 9.5 days. Total time on ECMO was 60 +/- 46.6 days. 11/12 patients could be successfully weaned from ECMO, 7/12 in the first 28 days after transfer (8 +/- 8.8 ECMO-free days at day 28). In 7 patients, ECMO could be terminated after at least partial lung recovery, in 4 patients after salvage lung transplant. No patient died or needed re-initiation of ECMO therapy at day 28. In summary, weaning from vvECMO was feasible even after prolonged ECMO courses and salvage lung transplant could be avoided in most cases. Patients may benefit from transfer to a specialized ECMO center. PMID- 29766321 TI - Acute kidney injury after implantation of a left ventricular assist device: a comparison of axial-flow (HeartMate II) and centrifugal-flow (HeartWare HVAD) devices. AB - Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly being used to treat advanced, refractory chronic heart failure. Herein, we sought to determine the incidence of postoperative acute kidney injury (AKI) in axial-flow (HeartMate II; HM-II) and centrifugal-flow (HVAD) CF-LVAD recipients, as well as the effect of AKI on mortality. The study cohort comprised 520 patients who received a HM-II (n = 398) or HVAD (n = 122) at our center between November 2003 and March 2016. Their records were reviewed to determine the incidence of RIFLE defined AKI after LVAD implantation. We compared the perioperative characteristics, postoperative complications, and survival rates of the patients with and without AKI and differentiated the outcomes based on device type (HM-II or HVAD). Seventy-five patients (14.4%) developed AKI postoperatively. Patients with AKI after LVAD implantation had significantly reduced survival compared to patients without AKI (p = 0.01). Cox proportional hazards models showed that AKI was a significant independent predictor of mortality (HR = 1.54, p = 0.03). Preoperative mechanical circulatory support and prolonged cardiopulmonary bypass time were independent predictors of AKI. The incidence of AKI was similar for HM II and HVAD recipients (p = 0.25). There was no significant difference in AKI rates for the HM-II and HVAD recipients. Developing AKI adversely affected survival. PMID- 29766322 TI - MicroDAIMON study: Microcirculatory DAIly MONitoring in critically ill patients: a prospective observational study. AB - BACKGROUND: Until now, the prognostic value of microcirculatory alterations in critically ill patients has been mainly evaluated in highly selected subgroups. Aim of this study is to monitor the microcirculation daily in mixed group of Intensive Care Unit (ICU)-patients and to establish the association between (the evolution of) microcirculatory alterations and outcome. METHODS: This is a prospective longitudinal observational single-centre study in adult patients admitted to a 12-bed ICU in an Italian teaching hospital. Sublingual microcirculation was evaluated daily, from admission to discharge/death, using Sidestream Dark Field imaging. Videos were analysed offline to assess flow and density variables. Laboratory and clinical data were recorded simultaneously. A priori, a Microvascular Flow Index (MFI) < 2.6 was defined as abnormal. A binary logistic regression analysis was performed to evaluate the association between microcirculatory variables and outcomes; a Kaplan-Meier survival curve was built. Outcomes were ICU and 90-day mortality. RESULTS: A total of 97 patients were included. An abnormal MFI was present on day 1 in 20.6%, and in 55.7% of cases during ICU admission. Patients with a baseline MFI < 2.6 had higher ICU, in hospital and 90-day mortality (45 vs. 15.6%, p = 0.012; 55 vs. 28.6%, p = 0.035; 55 vs. 26%, p = 0.017, respectively). An independent association between baseline MFI < 2.6 and outcome was confirmed in a binary logistic analysis (odds ratio 4.594 [1.340-15.754], p = 0.015). A heart rate (HR) >= 90 bpm was an adjunctive predictor of mortality. However, a model with stepwise inclusion of mean arterial pressure < 65 mmHg, HR >= 90 bpm, lactate > 2 mmol/L and MFI < 2.6 did not detect significant differences in ICU mortality. In case an abnormal MFI was present on day 1, ICU mortality was significantly higher in comparison with patients with an abnormal MFI after day 1 (38 vs. 6%, p = 0.001), indicating a time-dependent significant difference in prognostic value. CONCLUSIONS: In a general ICU population, an abnormal microcirculation at baseline is an independent predictor for mortality. In this setting, additional routine daily microcirculatory monitoring did not reveal extra prognostic information. Further research is needed to integrate microcirculatory monitoring in a set of commonly available hemodynamic variables. Trial registration NCT 02649088, www.clinicaltrials.gov . Date of registration: 23 December 2015, retrospectively registered. PMID- 29766324 TI - A General LC-MS/MS Method for Monitoring Potential beta-Lactam Contamination in Drugs and Drug-Manufacturing Surfaces. AB - Penicillins and some non-penicillin beta-lactams may cause potentially life threatening allergic reactions. Thus, possible cross contamination of beta lactams in food or drugs can put people at risk. Therefore, when there is a reasonable possibility that a non-penicillin product could be contaminated by penicillin, the drug products are tested for penicillin contamination. Here, a sensitive and rapid method for simultaneous determination of multiple beta-lactam antibiotics using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Mass spectral acquisition was performed on a Q-Exactive HF mass spectrometer in positive ion mode with parallel reaction monitoring (PRM). The method was validated for seven beta-lactam antibiotics including one or two from each class and a synthetic intermediate. The quantification precision and accuracy at 200 ppb were in the range of +/- 1.84 to +/- 4.56 and - 5.20 to 3.44%, respectively. The limit of detection (LOD) was 0.2 ppb, and the limit of quantitation (LOQ) was 2 ppb with a linear dynamic range (LDR) of 2-2000 ppb for all eight beta-lactams. From various drug products, the recoveries of eight beta-lactams at 200 and 2 ppb ranged from 93.8 +/- 3.2 to 112.1 +/- 4.2% and 89.7 +/- 4.6 to 110.6 +/- 1.9%, respectively. The application of the method for detecting cross contamination of trace beta-lactams (0.2 ppb) and for monitoring facility surface cleaning was also investigated. This sensitive and fast method was fit-for-purpose for detecting and quantifying trace amount of beta-lactam contamination, monitoring cross contamination in manufacturing processes, and determining potency for regulatory purposes and for quality control. PMID- 29766323 TI - cGMP at the centre of attention: emerging strategies for activating the cardioprotective PKG pathway. AB - The nitric oxide (NO)-protein kinase G (PKG) pathway has been known for some time to be an important target for cardioprotection against ischaemia/reperfusion injury and heart failure. While many approaches for reducing infarct size in patients have failed in the past, the advent of novel drugs that modulate cGMP and its downstream targets shows very promising results in recent preclinical and clinical studies. Here, we review main aspects of the NO-PKG pathway in light of recent drug development and summarise potential cardioprotective strategies in which cGMP is the main player. PMID- 29766325 TI - Anthropometric outcomes of a motivational interviewing school-based randomized trial involving adolescents with overweight. AB - : Motivational interviewing (MI) is an effective method to promote weight loss that can be delivered by non-mental health providers. The aim of this study was to evaluate whether MI was superior to conventional counseling to improve the anthropometric outcomes of adolescents with obesity/overweight. It was a controlled cluster randomized trial with parallel design in a school setting. The study included two groups: Motivational Interviewing Group (MIG) and control group (Conventional Intervention Group, CIG). Students participated in three face to-face 30-min interviews, 3 months apart. Outcomes were BMI z-score, abdominal circumference, percentages of fat mass and muscle mass, and blood pressure. Sessions were coded with the Motivational Interviewing Treatment Integrity (MITI) manual. Mixed repeated-measures ANOVAs were used to assess the group versus time interaction. Effect sizes were calculated for each ANOVA with eta-squared measures (eta2). Eighty-three adolescents finished the protocol. While MIG participants showed a significant improvement in all anthropometric scores at 6 months, CIG participants showed an unfavorable change in those variables. CONCLUSION: Our results provide additional evidence of the short-term usefulness of a school-based MI intervention on anthropometric outcomes of adolescents with obesity/overweight, demonstrating that pediatricians can play an important role in the prevention and management of pediatric obesity. TRIAL REGISTRATION: The study is called IMAGINE and is registered in Clinicaltrials.gov with the number NCT02745795. What is Known: * Although MI has been recognized as an effective counseling style for behavioral change in weight loss, there are few reports about the anthropometric outcomes of interventions with adolescents being treated for obesity/overweight. * Our study showed significant positive changes in anthropometric variables (BMI z-score, abdominal circumference, percentage of fat mass, percentage of muscular mass, systolic and diastolic blood pressure) after only three face-to-face sessions over 6 months. What is New: * MI delivered by non-mental health providers in a school setting seems to have short-term usefulness in a program aiming the treatment of obese/overweight adolescents. PMID- 29766326 TI - The change in management of bronchiolitis in the intensive care unit between 2000 and 2015. AB - : This case-control study evaluated interventions for bronchiolitis in relation to time in the pediatric intensive care unit (PICU) during a 16-year surveillance period. Together, 105 infants aged < 12 months were treated for bronchiolitis in the PICU, and for them, we selected 210 controls admitted for bronchiolitis closest to cases. We collected data on treatments in the PICU, at the ward and in the emergency department for three periods: years 2000-2005, 2006-2010, and 2011 2015. Median hospital length of stay for PICU patients were 7 days (interquartile range 5-12), 5 days (4-8) and 8 days (4-12.5, p = 0.127), respectively. By time, the use of inhaled beta-agonist (68 vs. 44 vs. 38%, p = 0.019) and systemic corticosteroids (29 vs. 15 vs. 5%, p = 0.019) decreased, but that of racemic adrenaline (59 vs. 78 vs. 84%, p = 0.035) and hypertonic saline (0 vs. 0 vs. 54%, p < 0.001) inhalations increased in the PICU. Similar changes were seen at the ward. In the PICU, non-invasive ventilation therapies increased significantly, but intubation rates did not decline. CONCLUSION: Beta-agonists and systemic corticosteroids were used less by time in intensive care for infant bronchiolitis, but the use of hypertonic saline and racemic adrenaline increased, though their effectiveness has been questioned. What is Known: * Until now, studies have shown which treatments do not work in bronchiolitis, and so, there is no consensus how infants with bronchiolitis should be treated. In particular, there is no consensus on different interventions in intensive care for bronchiolitis. What is New: * During 2000-2015, treatments with inhaled beta agonists and systemic corticosteroids decreased but treatments with racemic adrenaline and hypertonic saline inhalations increased in intensive care for bronchiolitis. Similar changes were seen at the ward. Though non-invasive ventilation therapies increased, the intubation rate did not decline. PMID- 29766327 TI - Characterization of carfilzomib-resistant non-small cell lung cancer cell lines. AB - PURPOSE: We previously showed that carfilzomib (CFZ) has potent anti proliferative and cytotoxic activity in a broad range of lung cancer cell lines. Here we investigate possible mechanisms of CFZ acquired resistance in lung cancer cell lines. METHODS: CFZ-resistant non-small cell lung cancer (NSCLC) cell lines were developed by exposing A549 and H520 cells to stepwise increasing concentrations of CFZ. Resistance to CFZ and cross-resistance to bortezomib and other chemotherapy drugs was measured using the MTT assay. Cytotoxicity to CFZ was determined using a CytoTox assay. Western blot was used to measure apoptosis, autophagy, and drug efflux transporter-related proteins. Quantitative targeted whole transcriptome sequencing and quantitative RT-PCR was used to measure gene expression. Flow cytometry was used to analyze intracellular accumulation of doxorubicin. RESULTS: The CFZ IC50 value of the resistant cells increased versus parental lines (2.5-fold for A549, 122-fold for H520). Resistant lines showed reduced expression of apoptosis and autophagy markers and reduced death versus parental lines following CFZ treatment. Both resistant lines exhibited higher P glycoprotein (Pgp) gene (TempO-Seq(r) analysis, increased 1.2-fold in A549, > 9000-fold in H520) and protein expression levels versus parental lines. TempO Seq(r) analysis indicated other drug resistance pathways were upregulated. The resistant cell lines demonstrated less accumulation of intracellular doxorubicin, and were cross-resistant to other Pgp client drugs: bortezomib, doxorubicin, and paclitaxel, but not cisplatin. CONCLUSIONS: Upregulation of Pgp appears to be an important, but not the only, mechanism of CFZ resistance in NSCLC cell lines. PMID- 29766328 TI - Implementing a Standardized Social Networks Testing Strategy in a Low HIV Prevalence Jurisdiction. AB - Alternative HIV testing strategies are needed to engage individuals not reached by traditional clinical or non-clinical testing programs. A social networks recruitment strategy, in which people at risk for or living with HIV are enlisted and trained by community-based agencies to recruit individuals from their social, sexual, or drug-using networks for HIV testing, demonstrates higher positivity rates compared to other non-clinical recruitment strategies in some jurisdictions. During 2013-2015, a social networks testing protocol was implemented in Wisconsin to standardize an existing social networks testing program. Six community-based, non-clinical agencies with multiple sites throughout the state implemented the protocol over the 2-year period. Both quantitative and qualitative data were collected. The new positivity rate (0.49%) through social networks testing did not differ from that of traditional counseling, testing, and referral recruitment methods (0.48%). Although social networks testing did not yield a higher new positivity rate compared to other testing strategies, it proved to be successful at reaching high risk individuals who may not otherwise engage in HIV testing. PMID- 29766329 TI - Syringe Sharing in Drug Injecting Dyads: A Cross-Classified Multilevel Analysis of Social Networks. AB - We examined the association of dyadic-level factors with syringe sharing among people who inject drugs (PWID) in Kerman, Iran. In a cross-sectional study, we collected data on 329 drug-injecting dyads by individual face-to-face interviews. An injecting dyad was defined as 2 PWID who knew each other and injected drugs together during the last 6 months. If they reported at least 1 occasion of syringe sharing, the dyad was considered high-risk. Dyadic-level factors associated with syringe sharing were assessed using cross-classified multilevel logistic regression. The rate of syringe sharing was significantly higher for dyads who were more intimate (adjusted odds ratio [AOR] 4.5, CI 95%, 2.3-8.6), who had instrumental support (AOR 2.1, 95% CI 1.1-4.5), and who pooled money for drugs (AOR 4.1, 95% CI 2.0-8.3). The rate was lower in same-sex dyads (AOR 0.4, 95% CI 0.2-0.9) and in dyads who shared health information (AOR 0.5, 95% CI 0.2 0.9). Findings highlight close-peer influences on syringe-sharing behavior. PMID- 29766330 TI - Laser reduction of specific microorganisms in the periodontal pocket using Er:YAG and Nd:YAG lasers: a randomized controlled clinical study. AB - The objective of this study was to evaluate the microbiological and clinical outcomes following nonsurgical treatment by either scaling and root planing, combination of Nd:YAG and Er:YAG lasers, or by Er:YAG laser treatment alone. The study involved 60 patients with generalized chronic periodontitis, randomly assigned into one of three treatment groups of 20 patients. The first group received scaling and root planing by hand instruments (SRP group), the second group received Er:YAG laser treatment alone (Er group), and the third group received combined treatment with Nd:YAG and Er:YAG lasers (NdErNd group). Microbiological samples, taken from the periodontal pockets at baseline and 6 months after treatments, were assessed with PET Plus tests. The combined NdErNd laser (93.0%), followed closely by Er:YAG laser (84.9%), treatment resulted in the highest reduction of all bacteria count after 6 months, whereas SRP (46.2%) failed to reduce Treponema denticola, Peptostreptococcus micros, and Capnocytophaga gingivalis. Full-mouth plaque and bleeding on probing scores dropped after 6 months and were the lowest in both laser groups. The combination of NdErNd resulted in higher probing pocket depth reduction and gain of clinical attachment level (1.99 +/- 0.23 mm) compared to SRP (0.86 +/- 0.13 mm) or Er:YAG laser alone (0.93 +/- 0.20 mm) in 4-6 mm-deep pockets. Within their limits, the present results provide support for the combination of Nd:YAG and Er:YAG lasers to additionally improve the microbiological and clinical outcomes of nonsurgical periodontal therapy in patients with moderate to severe chronic periodontitis. PMID- 29766332 TI - Ecofriendly demulsification of water in oil emulsions by an efficient biodemulsifier producing bacterium isolated from oil contaminated environment. AB - OBJECTIVE: Water in oil emulsions increase oil processing costs and cause damage to refinery equipment which necessitates demulsification. Since chemical demulsifiers cause environmental pollution, biodemulsifiers have been paid more attention. This study aims to identify biodemulsifier-producing bacteria from petroleum contaminated environments. RESULTS: As a result, several biodemulsifier producing strains were found that Stenotrophomonas sp. strain HS7 (accession number: MF445088) which produced a cell associated biodemulsifier showed the highest demulsifying ratio, 98.57% for water in kerosene and 66.28% for water in crude oil emulsion after 48 h. 35 degrees C, pH 7, 48 h incubation and ammonium nitrate as nitrogen source were optimum conditions for biodemulsifier production. Furthermore, it was found that hydrophobic carbon sources like as liquid paraffin is not preferred as the sole carbon source while a combination of various carbon sources including liquid paraffin will increase demulsification efficiency of the biodemulsifier. CONCLUSIONS: The appropriate potential of this biodemulsifier strengthens the possibility of its application in industries especially petroleum industry. PMID- 29766331 TI - Complete nucleotide sequences and annotations of phi673 and phi674, two newly characterised lytic phages of Corynebacterium glutamicum ATCC 13032. AB - The genomes of two new lytic phages of Corynebacterium glutamicum ATCC 13032, phi673 and phi674, were sequenced and annotated (GenBank: MG324353, MG324354). Electron microscopy studies of both virions revealed that taxonomically they belong to the Siphoviridae family and have a polyhedral head with a width of 50 nm and a non-contractile tail with a length of 250 nm. The genomes of phi673 and phi674 consist of linear double-stranded DNA molecules with lengths of 44,530 bp (G+C = 51.1%) and 43,193 bp (G+C = 50.7%) and identical, protruding, cohesive 3' ends 13 nt in length. The level of identity between the phi673 and phi674 genomes is 85.2%. Two major structural proteins of each virion were separated via SDS PAGE and identified using peptide mass fingerprinting. Based on bioinformatic analysis, 56 and 54 ORFs were predicted for phi673 and phi674, respectively. Only 20 of the putative gene products of phi673 and 20 of phi674 could be assigned to known functions. Both genomes were divided into functional modules. Nine putative promoters in the phi673 genome and eight in the phi674 genome were predicted. One bidirectional Rho-independent transcription terminator was identified and experimentally confirmed in each phage genome. PMID- 29766333 TI - Treatment of donor cells with recombinant KDM4D protein improves preimplantation development of cloned ovine embryos. AB - Incomplete epigenetic reprogramming is one of the major factors affecting the development of embryos cloned by somatic cell nuclear transfer (SCNT). Histone 3 lysine 9 (H3K9) trimethylation has been identified as a key barrier to efficient reprogramming by SCNT. The aim of this study was to explore a method of downregulating H3K9me3 levels in donor cells by using histone lysine demethylase (KDM) protein. When sheep fetal fibroblast cells were treated with recombinant human KDM4D protein (rhKDM4D), the levels of H3K9 trimethylation and dimethylation were both significantly decreased. After SCNT, rhKDM4D-treated donor cells supported significantly higher percentage of cloned embryos developing into blastocysts as compared to non-treated control cells. Moreover, the blastocyst quality was also improved by rhKDM4D treatment of donor cells, as assessed by the total cell number in blastocysts and the expression of developmental genes including SOX2, NANOG and CDX2. These results indicate that treatment of donor cells with recombinant KDM4D protein can downregulate the levels of H3K9 trimethylation and dimethylation and improve the developmental competence of SCNT embryos. This strategy may be convenient to be used in KDM4 assisted SCNT procedure for improving the efficiency of cloning. PMID- 29766335 TI - Ticagrelor Versus Clopidogrel as Part of Dual or Triple Antithrombotic Therapy: a Systematic Review and Meta-Analysis. AB - PURPOSE: Clopidogrel is the standard P2Y12 receptor inhibitor used in patients requiring both antiplatelet therapy and oral anticoagulation (OAC). We investigated the safety and efficacy of ticagrelor as an alternative to clopidogrel in patients on OAC. METHODS: A systematic electronic literature search was performed in MEDLINE, EMBASE, and the Cochrane Library for randomised controlled studies that examined the relative safety and efficacy of clopidogrel versus ticagrelor among patients requiring therapy with antiplatelet agents plus OAC. RESULTS: Three randomised controlled trials were identified with a total of 5659 patients. The risk of clinically significant bleeding was significantly increased among patients on dual or triple antithrombotic therapy who received ticagrelor compared with patients on clopidogrel (OR 1.52, 95% CI 1.12 to 2.06, and OR 1.7, 95% CI 1.24 to 2.33, respectively). Among those on triple therapy, ticagrelor was associated with a significantly higher risk of major adverse cardiovascular events (MACE) compared to clopidogrel (OR 1.88, 95% CI 1.26 to 2.80). Patients who received dual therapy exhibited similar risk of MACE and stroke with ticagrelor versus clopidogrel (OR 1.14, 95% CI 0.83 to 1.56, and OR 0.42, 95% CI 0.10 to 1.74, respectively). CONCLUSION: The use of ticagrelor as part of dual or triple antithrombotic therapy is associated with significantly higher rates of clinically relevant haemorrhagic complications compared with clopidogrel. Among triple therapy-treated patients, the use of ticagrelor might increase thromboembolic and ischaemic cardiac events. PMID- 29766334 TI - A New modified anthropometric haller index obtained without radiological exposure. AB - To validate a new modified method for measuring the anthropometric Haller index (HI), obtained without radiological exposure. This new method was based on the use of a rigid ruler and of a 2.5 MHz ultrasound transducer for the assessment of latero-lateral and antero-posterior chest diameters, respectively. We enrolled 100 consecutive patients (mean age 67.9 +/- 14.5 years, 55% males), who underwent a two-plane CXR, for any clinical indication, over a four-month period. In all patients, the same radiologist calculated the conventional radiological HI (mean value 1.93 +/- 0.35) and the same cardiologist used the above described new technique to measure the modified HI (mean value 1.99 +/- 0.26). The Bland-Altman analysis showed tight limits of agreement (+ 0.37; - 0.51) between the two measurement methods, with a mild systematic overestimation of the new method as compared to the standard radiological HI. The Pearson's correlation analysis highlighted a strong correlation between the two methods (r = 0.81, p < 0.0001), while the Student's t test demonstrated a not statistically difference between the means (p = 0.12). The modified HI might allow a quick description of the chest conformation without radiological exposure and a more immediate comprehension of its possible influence on the cardiac kinetics and function, as assessed by echocardiography or other imaging modalities. PMID- 29766336 TI - Ischaemic Preconditioning Protects Cardiomyocytes from Anthracycline-Induced Toxicity via the PI3K Pathway. AB - PURPOSE: Anthracyclines cause chronic irreversible cardiac failure, but the mechanism remains poorly understood. Emerging data indicate that cardiac damage begins early, suggesting protective modalities delivered in the acute stage may confer prolonged benefit. Ischaemic preconditioning (IPC) activates the pro survival reperfusion injury salvage kinase (RISK) pathway which involves PI3 kinase and MAPK/ERK1/2. METHODS: We investigated whether simulated IPC (sIPC), in the form of a sublethal exposure to a hypoxic buffer simulating ischaemic conditions followed by reoxygenation, protects primary adult rat cardiomyocytes against anthracycline-induced injury. PI3-kinase and MAPK/ERK1/2 were inhibited using LY294002, and PD98059. The role of reactive oxygen species (ROS), mitochondrial membrane potential (Deltapsim) and mitochondrial permeability transition pore (mPTP) were also investigated in doxorubicin-treated cells. We further examined whether sIPC protected HeLa cancer cells from doxorubicin induced death. RESULTS: sIPC protected cardiomyocytes against doxorubicin-induced death (35.4 +/- 1.7% doxorubicin vs 14.7 +/- 1.5% doxorubicin + sIPC; p < 0.01). This protection was abrogated by the PI3-kinase inhibitor, LY294002, but not the MAPK/ERK1/2 inhibitor, PD98059. A ROS scavenger failed to rescue cardiomyocytes from doxorubicin toxicity, and no significant influence on Deltapsim or mPTP opening was identified after subjecting cells to a doxorubicin insult. Importantly, sIPC did not protect HeLa cancer cells from doxorubicin-induced death. CONCLUSION: sIPC is able to protect cardiomyocytes against anthracycline injury via a pathway involving PI3-kinase. This mechanism appears to be independent of ROS, changes to Deltapsim, and mPTP. Further investigation of the mechanism of sIPC-induced protection against anthracycline-injury is warranted. PMID- 29766338 TI - An unusual surgical indication for cerebral tuberculosis: status dystonicus. Case report. AB - Actual indications for surgery in tuberculosis are limited to obtaining a diagnosis, acquiring tissue for culture studies, treating hydrocephalus, aspiring a brain abscess, and reducing intracranial pressure in patients with multiple tuberculomas. Tuberculosis-related movement disorders are usually treated pharmacologically. We report on a child affected by post-tubercular generalized dystonia, who progressed to status dystonicus (SD) and underwent stereotactic bilateral pallidotomy. After surgery, SD resolved, and drugs were rapidly tapered. The successful reversal of SD and the motor improvement observed in our patient demonstrate the safety, feasibility, and clinical efficacy of pallidotomy in post-tuberculous-meningoencephalitis dystonia and SD. PMID- 29766337 TI - A phase I trial to determine safety and pharmacokinetics of ASLAN002, an oral MET superfamily kinase inhibitor, in patients with advanced or metastatic solid cancers. AB - Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was conducted to determine the safety and pharmacokinetics of ASLAN-002 in patients with advanced cancer. Methods Patients with advanced or metastatic solid tumours, who had progressed on standard therapy or for whom standard therapy was not known, were administered ASLAN-002 orally. The starting dose was 100 mg once daily (QD) with subsequent cohorts to receive doses of 200 mg QD, 300 mg QD, 450 mg QD, 600 mg QD, 300 mg twice daily (BID), 450 mg BID, and 600 mg BID. Results Forty patients were included across 7 dose cohorts. Cohort 8 (600 mg BID) was not opened due to the lack of appreciable pharmacokinetic (PK) differences between 300 mg BID and 450 mg BID and higher incidences of grade 3 or 4 adverse events (AE) in Cohort 7 (450 mg BID). Fifteen patients (37.5%) experienced a grade 3 or 4 AE. The most commonly reported AEs were nausea (55%), fatigue (47.5%) and constipation (30%). One dose limiting toxicity (DLT) of atrial fibrillation was observed with 450 mg BID. Conclusions ASLAN-002 is well tolerated at 300 mg BID and is the recommended dose for future phase II studies (RP2D). Clinical Trials Registry Number: NCT01721148 . PMID- 29766339 TI - Predicting factors for shunt-dependent hydrocephalus in patients with aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Chronic hydrocephalus after aneurysmal subarachnoid hemorrhage (SAH) is a major complication that leads to a medical burden and poor clinical outcomes. The aim of this study was to evaluate the predictive factors of shunt dependent hydrocephalus focusing on postoperative fever and infection. METHOD: A total of 418 patients were included in this study and the patient demographic features, radiologic findings, days of fever burden, and infection were compared between the shunt (n = 72) and no shunt group (n = 346). Days of fever burden was defined as the total number of days with the highest body temperature >= 38.0 degrees C each day from day 1 to day 14. Pneumonia, urinary tract infection (UTI), meningitis, and bacteremia were recorded in all patients. RESULTS: The independent predictive factors for shunt-dependent hydrocephalus were older age >= 65, microsurgical clipping, placement of extraventricular drainage (EVD), days of fever burden, and infection. The incidence of shunt dependency was 2.4% in the no fever burden patients (n = 123), 14.9% in the 1-3 days of fever burden patients (n = 161), 27.0% in the 4-6 days of fever burden patients (n = 74), and 41.7% in the >= 7 days of fever burden patients with statistical significance among groups (p < 0.001). CONCLUSION: The rate of shunt dependency increased proportionally as the days of fever burden increased. Older age (>= 65), microsurgical clipping, placement of EVD, days of fever burden, and infection were independent predictive factors for shunt dependency. Proper postoperative care for maintaining normal body temperature and preventing infectious disease can help reduce the rate of shunt dependency and improve clinical outcomes. PMID- 29766340 TI - The cholic acid extension study in Zellweger spectrum disorders: results and implications for therapy. AB - INTRODUCTION: Currently, no therapies are available for Zellweger spectrum disorders (ZSDs), a group of genetic metabolic disorders characterised by a deficiency of functional peroxisomes. In a previous study, we showed that oral cholic acid (CA) treatment can suppress bile acid synthesis in ZSD patients and, thereby, decrease plasma levels of toxic C27-bile acid intermediates, one of the biochemical abnormalities in these patients. However, no effect on clinically relevant outcome measures could be observed after 9 months of CA treatment. It was noted that, in patients with advanced liver disease, caution is needed because of possible hepatotoxicity. METHODS: An extension study of the previously conducted pretest-posttest design study was conducted including 17 patients with a ZSD. All patients received oral CA for an additional period of 12 months, encompassing a total of 21 months of treatment. Multiple clinically relevant parameters and markers for bile acid synthesis were assessed after 15 and 21 months of treatment. RESULTS: Bile acid synthesis was still suppressed after 21 months of CA treatment, accompanied with reduced levels of C27-bile acid intermediates in plasma. These levels significantly increased again after discontinuation of CA. No significant changes were found in liver tests, liver elasticity, coagulation parameters, fat-soluble vitamin levels or body weight. CONCLUSIONS: Although CA treatment did lead to reduced levels of toxic C27-bile acid intermediates in ZSD patients without severe liver fibrosis or cirrhosis, no improvement of clinically relevant parameters was observed after 21 months of treatment. We discuss the implications for CA therapy in ZSD based on these results. PMID- 29766342 TI - 15th International Coloproctology Meeting : Turin, April 17-18 2018. PMID- 29766341 TI - Sitz bath and keyhole deformity in benign anorectal disorders. PMID- 29766343 TI - Intraoperative check for enterocele in perineal stapled prolapse resection. PMID- 29766344 TI - From "Einfuhlung" to empathy: exploring the relationship between aesthetic and interpersonal experience. AB - Is there a relationship between aesthetic and interpersonal experience? This question is motivated not only by the fact that historically experiences of both kinds have often been accounted for in terms of "empathy", the English translation of the German term "Einfuhlung", but also by the fact that some contemporary theories refer to mechanisms underlying both aesthetic and interpersonal experience. In this Editorial introducing the special section titled "From 'Einfuhlung' to empathy: exploring the relationship between aesthetic and interpersonal experience", we briefly sketch these two motivations and the relationship between the different mechanisms that have been associated with both aesthetic and interpersonal experience. PMID- 29766346 TI - Polydopamine-based molecularly imprinting polymers on magnetic nanoparticles for recognition and enrichment of ochratoxins prior to their determination by HPLC. AB - A polydopamine-based molecularly imprinted polymer was deposited on the surface of magnetite (ferroferric oxide) nanoparticles (Fe3O4@PDA MIPs) and is shown to be an efficient and fairly specific sorbent for the extraction of various ochratoxins. The MIPs were characterized by IR spectroscopy and transmission electron microscopy. The adsorption capacities, evaluated through the langmuir adsorption isotherm model, are 1.8, 0.23 and 0.17 mg.g-1 for ochratoxin A, ochratoxin B and ochratoxin C, respectively. Parameters such as the amount of magnetic MIPs, pH value, time for ultrasonication, elution solvent and volume were optimized. Following desorption from the MIP with acetonitrile, the ochratoxins were quantified by HPLC with fluorometric detection. Under optimal experimental conditions, the calibration plots are linear in the range of 0.01 1.0 ng.mL-1 of OTA, 0.02-2.0 ng.mL-1 of OTB, and 0.002-0.2 ng.mL-1 of OTC. The LODs are between 1.8 and 18 pg.mL-1, and the recoveries from spiked samples are 71.0% - 88.5%, with RSDs of 2.3-3.8% in case of rice and wine samples. The MIPs can be re-used for at least 7 times. Graphical abstract Schematic of the preparation of a magnetic molecularly imprinted polymer based on self polymerization of dopamine in weakly alkaline solution. Ochratoxins are recognized owing to homologous cavities in the MIPs, and quantified by HPLC after desorption with acetonitrile. PMID- 29766345 TI - Visual function assessed by visually evoked potentials in optic pathway low-grade gliomas with and without neurofibromatosis type 1. AB - PURPOSE: To investigate the contribution of full-field transient pattern-reversal visually evoked potentials (PRVEP) on cross-sectional evaluations of visual function in patients with and without neurofibromatosis type 1 (NF1) affected by optic pathway low-grade gliomas (OPLGG). METHODS: Participants were children and adolescents referred for visual function evaluation and receiving treatment for OPLGG, linked (NF1-OPLGG) or not to NF1 (Non-NF1-OPLGG). An age-adjusted control group was included for comparison. Monocular full-field PRVEPs were recorded from each eye in accordance with ISCEV standards. Parameters of peak-to-peak P100 amplitude (uV) and P100 peak time (ms) were measured. Cutoff normative values obtained from controls for 15' and 60' check sizes were >= 9.0 uV for N75-P100 amplitude and <= 103.0 ms for P100 peak time. The association of age, gender, tumor resection and NF1 with P100 amplitude reduction and P100 peak time delay was explored by Firth logistic regression modeling. RESULTS: Participants were 30 patients (15 males, 60% Non-NF1) with ages from 3.6 to 19.9 years (mean +/- SD = 9.2 +/- 3.8 years; median = 8.4 years) and 19 controls (12 males) with ages from 3.7 to 19.9 years (mean +/- SD = 10.4 +/- 4.9 years; median = 9.5 years). Overall, 68% of tested eyes presented reduced P100 amplitudes for both check sizes (46% in the NF-1 and 83% in the Non-NF1) and delayed P100 for both check sizes (38% in NF1 and 89% in Non-NF1). Absence of NF1 adjusted for age, gender and tumor resection was significantly associated with marginally reduced P100 amplitude for 15' checks [odds ratio (OR): 6.26; 95% confidence interval (CI) = 0.96-40.94; p = 0.055]. CONCLUSIONS: Full-field PRVEP on cross-sectional evaluations contributed to detect visual dysfunction in two-thirds of patients with OPLGG by highlighting subclinical evidence of visual loss. Abnormalities were more frequent and more severe in OPLGG not linked to NF1 than in NF1-OPLGG; however, there was a difference in surgical management between these groups. PRVEP parameters may provide reliable evidence of visual pathway involvement in OPLGG, helping to hasten treatment before optic atrophy is detected. PMID- 29766347 TI - Towards Alternative Approaches for Coupling of a Soft Robotic Sleeve to the Heart. AB - Efficient coupling of soft robotic cardiac assist devices to the external surface of the heart is crucial to augment cardiac function and represents a hurdle to translation of this technology. In this work, we compare various fixation strategies for local and global coupling of a direct cardiac compression sleeve to the heart. For basal fixation, we find that a sutured Velcro band adheres the strongest to the epicardium. Next, we demonstrate that a mesh-based sleeve coupled to the myocardium improves function in an acute porcine heart failure model. Then, we analyze the biological integration of global interface material candidates (medical mesh and silicone) in a healthy and infarcted murine model and show that a mesh interface yields superior mechanical coupling via pull-off force, histology, and microcomputed tomography. These results can inform the design of a therapeutic approach where a mesh-based soft robotic DCC is implanted, allowed to biologically integrate with the epicardium, and actuated for active assistance at a later timepoint. This strategy may result in more efficient coupling of extracardiac sleeves to heart tissue, and lead to increased augmentation of heart function in end-stage heart failure patients. PMID- 29766348 TI - Simulating squirmers with multiparticle collision dynamics. AB - Multiparticle collision dynamics is a modern coarse-grained simulation technique to treat the hydrodynamics of Newtonian fluids by solving the Navier-Stokes equations. Naturally, it also includes thermal noise. Initially it has been applied extensively to spherical colloids or bead-spring polymers immersed in a fluid. Here, we review and discuss the use of multiparticle collision dynamics for studying the motion of spherical model microswimmers called squirmers moving in viscous fluids. PMID- 29766349 TI - Recent Developments in the Role of Coenzyme Q10 for Coronary Heart Disease: a Systematic Review. AB - PURPOSE OF REVIEW: This review examines recent randomized clinical trials evaluating the role of coenzyme Q10 (CoQ10) in the management of coronary heart disease. RECENT FINDINGS: CoQ10 is one of the most commonly used dietary supplements in the USA. Due to its antioxidant and anti-inflammatory effects, CoQ10 has been studied extensively for possible use in managing coronary heart disease. One of the most common applications of CoQ10 is to mitigate statin associated muscle symptoms (SAMS) based on the theory that SAMS are caused by statin depletion of CoQ10 in the muscle. Although previous studies of CoQ10 for SAMS have produced mixed results, CoQ10 appears to be safe. Because CoQ10 is a cofactor in the generation of adenosine triphosphate, supplementation has also recently been studied in patients with heart failure, which is inherently an energy deprived state. The Q-SYMBIO trial found that CoQ10 supplementation in patients with heart failure not only improved functional capacity, but also significantly reduced cardiovascular events and mortality. Despite these positive findings, a larger prospective trial is warranted to support routine use of CoQ10. Less impressive are the effects of CoQ10 on specific cardiovascular risk factors such as blood pressure, dyslipidemia, and glycemic control. Current evidence does not support routine use of CoQ10 in patients with coronary heart disease. Additional studies are warranted to fully determine the benefit of CoQ10 in patients with heart failure before including it in guideline-directed medical therapy. PMID- 29766350 TI - An Alternative Interpretation of the Linearly Weighted Kappa Coefficients for Ordinal Data. AB - When two (or more) observers are independently categorizing a set of observations, Cohen's kappa has become the most notable measure of interobserver agreement. When the categories are ordinal, a weighted form of kappa becomes desirable. The two most popular weighting schemes are the quadratic weights and linear weights. Quadratic weights have been justified by the fact that the corresponding weighted kappa is asymptotically equivalent to an intraclass correlation coefficient. This paper deals with linear weights and shows that the corresponding weighted kappa is equivalent to the unweighted kappa when cumulative probabilities are substituted for probabilities. A numerical example is provided. PMID- 29766352 TI - Correction to: Establishing a Reproducible Murine Animal Model of Single Anastomosis Duodenoileal Bypass with Sleeve Gastrectomy (SADl-S). AB - The first and last names of the authors were inverted in the original article. They are displayed correctly here. PMID- 29766351 TI - Comparative whole genome re-sequencing analysis in upland New Rice for Africa: insights into the breeding history and respective genome compositions. AB - BACKGROUND: Increasing rice demand is one of the consequences of the steadily improving socio-economic status of the African countries. New Rice for Africa (NERICA), which are interspecific hybrids between Asian and African rice varieties, are one of successful breeding products utilizing biodiversity across the two different rice crop species. Upland NERICA varieties (NU) exhibit agronomic traits of value for the harsh eco-geography, including shorter duration, higher yield and stress tolerance, compared to local African varieties. However, the molecular basis of the traits in NU varieties is largely unknown. RESULTS: Whole genome re-sequencing was performed of four NU lines (3, 4, 5, and 7) and for the parental Oryza sativa WAB56-104 and Oryza glaberrima CG14. The k mer analysis predicted large genomes for the four NU lines, most likely inherited from WAB56-104. Approximately 3.1, 0.10, and 0.40 million single nucleotide polymorphisms, multi nucleotide polymorphisms, and short insertions/deletions were mined between the parental lines, respectively. Integrated analysis with another four NU lines (1, 2, 8, and 9) showed that the ratios of the donor CG14 allelic sites in the NU lines ranged from 1.3 to 9.8%. High resolution graphical genotype indicated genome-level similarities and common genetic events during the breeding process: five xyloglucan fucosyltransferase from O. glaberrima were introgressed in common. Segregation of genic segments revealed potential causal genes for some agronomic traits including grain shattering, awnness, susceptibility to bacterial leaf bright, and salt tolerance. Analysis of unmapped sequences against the reference cultivar Nipponbare indicated existence of unique genes for pathogen and abiotic stress resistance in the NU varieties. CONCLUSIONS: The results provide understanding of NU genomes for rice improvement for Africa reinforcing local capacity for food security and insights into molecular events in breeding of interspecific hybrid crops. PMID- 29766353 TI - How Ethical Is Our Current Delivery of Care to Patients with Severe and Complicated Obesity? AB - Despite overwhelming evidence that bariatric interventions reduce morbidity and mortality and are cost-effective, access for affected patients is limited. We sought to describe the extent to which health policy makers and publically funded health services have an ethical obligation to provide bariatric care. We conducted a narrative review of the literature pertaining to the efficacy, safety, and cost-effectiveness of bariatric surgical interventions, in the context of the core principles of medical ethics. We found that in relation to autonomy (i.e., the right to self-determination), beneficence, non-maleficence, and justice (i.e., the obligation to provide fair and equitable treatment to all patients), the current provision of bariatric surgical care fell short of meeting internationally recognized medical ethical standards. These findings have important implications for government policy and healthcare resource allocation. Respecting the individual's right of self-determination, to do good, prevent harm, and provide equity in access to services is paramount, even when that individual is obese. PMID- 29766355 TI - Early functional MRI activation predicts motor outcome after ischemic stroke: a longitudinal, multimodal study. AB - An accurate prediction of long term outcome after stroke is urgently required to provide early individualized neurorehabilitation. This study aimed to examine the added value of early neuroimaging measures and identify the best approaches for predicting motor outcome after stroke. This prospective study involved 34 first ever ischemic stroke patients (time since stroke: 1-14 days) with upper limb impairment. All patients underwent baseline multimodal assessments that included clinical (age, motor impairment), neurophysiological (motor-evoked potentials, MEP) and neuroimaging (diffusion tensor imaging and motor task-based fMRI) measures, and also underwent reassessment 3 months after stroke. Bivariate analysis and multivariate linear regression models were used to predict the motor scores (Fugl-Meyer assessment, FMA) at 3 months post-stroke. With bivariate analysis, better motor outcome significantly correlated with (1) less initial motor impairment and disability, (2) less corticospinal tract injury, (3) the initial presence of MEPs, (4) stronger baseline motor fMRI activations. In multivariate analysis, incorporating neuroimaging data improved the predictive accuracy relative to only clinical and neurophysiological assessments. Baseline fMRI activation in SMA was an independent predictor of motor outcome after stroke. A multimodal model incorporating fMRI and clinical measures best predicted the motor outcome following stroke. fMRI measures obtained early after stroke provided independent prediction of long-term motor outcome. PMID- 29766354 TI - Image-based SPECT calibration based on the evaluation of the Fraction of Activity in the Field of View. AB - BACKGROUND: SPECT quantification is important for dosimetry in targeted radionuclide therapy (TRT) and the calibration of SPECT images is a crucial stage for image quantification. The current standardized calibration protocol (MIRD 23) uses phantom acquisitions to derive a global calibration factor in specific conditions. It thus requires specific acquisitions for every clinical protocols. We proposed an alternative and complementary image-based calibration method that allows to determine a calibration factor adapted to each patient, radionuclide, and acquisition protocol and that may also be used as an additional independent calibration. RESULTS: The proposed method relies on a SPECT/CT acquisition of a given region of interest and an initial whole-body (WB) planar image. First, the conjugate view of WB planar images is computed after scatter and attenuation correction. 3D SPECT images are reconstructed with scatter, attenuation, and collimator-detector response (CDR) corrections and corrected from apparent dead time. The field of view (FOV) of the SPECT image is then projected on the corrected WB planar image. The fraction of activity located in the area corresponding to the SPECT FOV is then calculated based on the counts on the corrected WB planar image. The Fraction of Activity in Field Of View (FAF) is then proposed to compute the calibration factor as the total number of counts in the SPECT image divided by this activity. Quantification accuracy was compared with the standard calibration method both with phantom experiments and on patient data. Both standard and image-based calibrations give good accuracy on large region of interest on phantom experiments (less than 7% of relative difference compared to ground truth). Apparent dead-time correction allows to reduce the uncertainty associated with standard calibration from 2.5 to 1%. The differences found between both methods were lower than the uncertainty range of the standard calibration (<3%). In patient data, although no ground truth was available, both methods give similar calibration factor (average difference 3.64%). CONCLUSIONS: A calibration factor may be computed directly from the acquired SPECT image providing that a WB planar image is also available and if both acquisitions are performed before biological elimination. This method does not require to perform phantom acquisition for every different acquisition conditions and may serve to double check the calibration with an independent factor. PMID- 29766357 TI - Enhancement of calcification by osteoblasts cultured on hydroxyapatite surfaces with adsorbed inorganic polyphosphate. AB - Inorganic polyphosphate has been expected to accelerate bone regeneration. However, there are limited evidences to prove that polyphosphate adsorbed on the surface of a hydroxyapatite plate enhances calcification of cultured osteoblasts. In this study, we examined the effect of polyphosphate adsorbed onto the surface of a hydroxyapatite plate on the attachment, proliferation, differentiation, and calcification of osteoblasts. After hydroxyapatite plates were soaked in solutions of polyphosphate, the plate surfaces were analyzed by scanning electron microscopy and toluidine blue staining to confirm adsorption of polyphosphate. The hydroxyapatite plates were further subjected to the measurements of surface roughness, water contact angle, and the binding capacity of calcium ions. Cell culture experiments were carried out using MC3T3-E1 pre-osteoblastic cells. It was found that soaking a hydroxyapatite plate in a polyphosphate solution gave rise to an increase in surface roughness and reduction in water contact angle in a concentration-dependent manner, suggesting the adsorption of polyphosphate onto the surface of a hydroxyapatite plate. It was further observed that surface adsorbed polyphosphate exhibited an inhibitory effect on cell adhesion and proliferation. In contrast, cell differentiation was promoted on hydroxyapatite plates with adsorbed polyphosphate, when assessed from expression of differentiation marker genes including alkaline phosphatase, osteopontin, and osteocalcin. In addition, calcification of the culture was enhanced on hydroxyapatite plates with relatively low density of adsorbed polyphosphate. Our results as a whole provided an evidence to show that there is a narrow window with regard to the surface density of adsorbed polyphosphate for the enhancement of osteoblast calcification. PMID- 29766356 TI - Endothelial cell loss and graft survival after penetrating keratoplasty for laser iridotomy-induced bullous keratopathy. AB - PURPOSE: To assess corneal endothelial cell loss after penetrating keratoplasty (PK) treatment for laser iridotomy (LI)-induced bullous keratopathy (BK). METHODS: A retrospective study conducted on consecutive patients who underwent PK between March 2000 and December 2011. Patients who had undergone more than 24 months of follow-up were included. Patients who underwent PK were subcategorized into two groups based on their diagnosis of BK prior to PK; PK was performed to treat either LI-BK or non LI-BK. The cell density of the central corneal endothelium and the graft survival were evaluated during follow-up. RESULTS: Corneal endothelial cell density decreased in a similar fashion in both the LI-BK and non LI-BK patients, though the cell density decreased significantly faster in the LI-BK group than in the non LI-BK group throughout the 108 months of the study (p = 0.026). The mean cell loss at 36 months for the LI-BK group was 57.7% vs. 63.2% for the non LI-BK, 76.9% vs. 70.1% at 72 months, and 85.6% vs. 72.0% at 108 months. No eye among 21 eyes in the LI-BK group (0%) had failed grafts, whereas 4 of 25 eyes in the non LI-BK group (16.0%) had failed grafts at 60 months (p = 0.114). CONCLUSIONS: The outcome of PK for BK secondary to LI was no worse than the outcome of PK for other types of BK. However, our long-term follow up after PK showed that cell density decreased faster in the LI-BK group than in the non LI-BK, suggesting that cell loss might be involved in the existence of LI prior to PK. PMID- 29766358 TI - Colorimetric detection of DNA at the nanomolar level based on enzyme-induced gold nanoparticle de-aggregation. AB - The authors describe a colorimetric method for the determination of DNA based on the deaggregation of gold nanoparticles (AuNPs) induced by exonuclease III (Exo III). DNA amplification is accomplished by Exo III to generate large quantities of the residual DNA. Residual DNA tethers onto the surfaces of AuNPs which prevents their aggregation. Hence, the color of the solution is red. However, in the absence of DNA, salt-induced aggregation is not prevented, and the bluish purple color of the aggregated AuNPs is observed. The ratio of absorbances at 525 and 625 nm increases up to 150 nM DNA concentrations, and the LOD is as low as 3.0 nM. It is shown that the presence of 300 nM concentrations of random DNA (with a mass up to 10-fold that of target DNA) does not interfere. The method was successfully applied to the analysis of DNA in spiked serum samples. The method is simple, reliable, and does not require complicated amplification steps and expensive instrumentation. Graphical abstract Schematic of a sensing strategy for DNA detection by exonuclease III-induced deaggregation of gold nanoparticles. DNA concentrations as low as 3 nM can be detected via colorimetric monitoring of the color change from red to purple-blue. PMID- 29766360 TI - RE: Evaluation of hyoscine N-butyl bromide efficacy on the prevention of catheter related bladder discomfort after transurethral resection of prostate: a randomized, double-blind control trial. PMID- 29766359 TI - Two types of ectopic Cushing syndrome or a continuum? Review. AB - BACKGROUND: Two types of ectopic Cushing syndrome (ECS) are described: ECS associated with aggressive neoplasms, and ECS with indolent and occult tumors, however, there is a lack of studies that thoroughly review their characteristics. METHODS: A systematic review was carried out on PUBMED of all the papers about the ECS, in order to better define the types of this subcategory of Cushing's syndrome, highlighting the differential aspects between these subgroups. RESULTS: It was found that in 50% of cases the prototypic "aggressive" ECS is caused by small cell lung carcinomas (SCLC). In these cases, the clinical presentation may be atypical, predominating the signs and symptoms derived from the protein catabolism. Cortisol and ACTH levels are extremely high, the clinical presentation is abrupt (< 3-6 months) and the tumor is usually advanced, being impossible a curative treatment. On the other hand, "indolent" ECS is mainly represented by carcinoid tumors (CT). In these cases the clinical presentation overlaps enormously with that of Cushing's disease (CD). Cortisol and ACTH levels are slightly elevated, the clinical presentation is progressive (> 6 months) and the prognosis is usually good, and a curative treatment is possible in about 75% of the cases. CONCLUSION: Although there is no absolute differentiation between the two extremes of ECS, a classification could be established in two groups, guided by its clinical and biochemical characteristics, and mainly by the type and stage of the ACTH-secreting tumor. However, a small percentage of tumors do not fit in this simple grouping, and may present both phenotypes or an intermediate one. PMID- 29766361 TI - Genetic dissection of the BRCA2 promoter and transcriptional impact of DNA variants. AB - PURPOSE: Promoter mutations may affect transcription and can be associated with human diseases. However, the promoters of the breast cancer (BC) genes are not regularly screened. Our goal was to investigate the BRCA2 promoter in order to study a possible correlation between impaired transcription and disease. METHODS: The proximal and core promoter of the BRCA2 gene was sequenced in 95 high-risk BC patients. A BRCA2-promoter insert [- 938 to + 312 from the transcription start site (TSS)] was generated and cloned into the firefly luciferase vector pGL4.10. Promoter variants and deletions were introduced by site-directed mutagenesis and quantified by Dual-Luciferase assays and semi-quantitative RT-PCR. RESULTS: Three different variants were detected in high-risk BC patients: rs3092989, rs206118, and rs563971900. Functional mapping of 13 overlapping deletions revealed four down-regulating segments (TSS positions): -59_-10del/udel3 (16% of activity of the wild-type construct), -104_-55del/udel4 (62%), -239_-190del/udel7 (39%), 464_-415/udel12 (78%), suggesting the presence therein of putative transcriptional activator motifs. Additionally, six microdeletions rendered luciferase overexpression: +32_+81del/udel1 (356%), -14_+36del/udel2 (180%), 194_-145del/udel6 (154%), -284_-235del/udel8 (168%), -329_-280del/udel9 (111%), and -509_-460del/udel13 (139%), which is indicative of repressor elements. Functional assays of 15 promoter variants (including those detected in patients) showed that ten of them significantly altered expression with seven up-regulating (113-163%) and three down-regulating (rs551887850_G, rs570548398_T, rs55880202_T; 72-83%) SNPs. Eight of them were located in an ENCODE-DNase Hypersensitive Cluster (TSS - 185 to + 105) where most active transcriptional motifs are known to be placed. CONCLUSIONS: BRCA2 expression is highly sensitive to promoter variations as most of them induced relevant changes. Moreover, we mapped critical regions of the BRCA2 promoter that may constitute potential targets for regulatory variants. Three SNPs moderately decreased luciferase activity, but confirmation of its potential pathogenicity requires further analysis. These data reinforce the need to screen the promoter regions of breast cancer genes with a view to discovering novel deleterious mutations. PMID- 29766362 TI - Exploration of tumour-infiltrating lymphocytes as a predictive biomarker for adjuvant endocrine therapy in early breast cancer. AB - PURPOSE: Tumour-infiltrating lymphocytes (TILs) have been shown to be prognostic for disease-free survival and predictive for the benefit of chemotherapy in patients with early breast cancer, but have not been studied for endocrine therapy. EXPERIMENTAL DESIGN: The number of CD8-positive TILs was assessed in a subcohort of 236 patients in the Intergroup Exemestane Study. AQ After 2-3 years of adjuvant tamoxifen, AQpatients were randomized between the schemes of continuation for 5 years on tamoxifen and switching to exemestane. The numbers of CD8-positive TILs were analysed for correlations with disease-free survival (DFS) and overall survival (OS). A similar analysis was performed on 2596 patients in the TEAM trial who were randomized between the sequential scheme and the exemestane monotherapy. RESULTS: In the first cohort, patients with low (below median) numbers of CD8-positive TILs had a univariate hazard ratio (HR) for DFS of 0.27 (95% CI 0.13-0.55) in favour of treatment with exemestane, whereas this benefit was not observed in patients with high numbers of CD8-positive TILs (HR 1.34, 95% CI 0.71-2.50, HR for interaction 5.02, p = 0.001). In the second cohort, patients with low numbers of CD8-positive TILs showed a benefit of exemestane treatment on recurrence-free survival (RFS HR 0.67, 95% CI 0.45-0.99), and not with above-median numbers of CD8-positive TILs (HR 0.86, 95% CI 0.59 1.26, HR for interaction 1.29, p = 0.36). CONCLUSIONS: This study is the first to propose the number of CD8-positive TILs as potential predictive markers for endocrine therapy, with the low presence of CD8-positive TILs associated to benefit for exemestane-inclusive therapy. However, treatment-by-marker interactions were only significant in one cohort, indicating the need for further validation. PMID- 29766363 TI - Palbociclib in highly pretreated metastatic ER-positive HER2-negative breast cancer. AB - PURPOSE: We aimed to investigate the role of palbociclib, a first-in-class cyclin dependent kinase 4 and 6 inhibitor, in postmenopausal women with highly pretreated endocrine therapy-resistant metastatic breast cancer (MBC). METHODS: Between 28 September 2015 and 14 March 2017, a compassionate use program was established in the University Hospitals Leuven in which 82 postmenopausal women with estrogen receptor-positive, HER2-negative MBC were included after at least four lines of systemic treatment. The efficacy and safety analysis was performed in 82 patients who had received at least one dose of palbociclib and who had at least 6-month follow-up at the data cut-off point. The primary objective was the evaluation of efficacy of the combination of palbociclib and endocrine therapy with clinical benefit as primary endpoint, defined as the absence of progressive disease and being on treatment for at least 6 months. Secondary objectives were the evaluation of toxicity and the identification of potential predictors for clinical benefit. RESULTS: The median age of the patients was 67.1 years (range 34.8-85.9) at the time of inclusion. The average duration of treatment was 5.6 months (range 1-19), with a median progression-free survival of 3.17 (95% CI 2.76 4.70) months. At the data cut-off point, 10 patients were still on treatment with palbociclib. In this highly pretreated setting, 34 patients experienced no progressive disease within 6 months, resulting in an overall clinical benefit rate (CBR) of 41.5%. 20.7% (17/82) showed stable disease for >= 9 months and 13.4% for >= 12 months. None of the investigated predicting factors were significantly associated with clinical benefit at 6 months. For 43.9% of the patients, treatment delay or dose reduction was indicated. CONCLUSIONS: Palbociclib in combination with endocrine therapy shows an unexpectedly high CBR and favorable safety profile in heavily pretreated endocrine-resistant estrogen receptor-positive, HER2-negative MBC patients. PMID- 29766364 TI - Binding of Cd(II), Pb(II), and Zn(II) to a type 1 metallothionein from maize (Zea mays). AB - Metallothioneins (MTs) are a family of ubiquitous, low-molecular-mass, cysteine rich proteins that play a significant role in maintaining intracellular metal homeostasis, eliminating metal toxification, and protecting cells against oxidative damages. Research activity on plant MTs, although known for 30 years, has only moderately increased in the past few years. In this study, a type 1 MT from maize (Zea mays) (ZmMT1) was successfully expressed in Escherichia coli strain BL21 (DE3). The UV absorption spectra recorded after the reconstitution of apo-ZmMT1 with different metals demonstrated that ZmMT1 can coordinate up to six Zn(II) ions, six Cd(II) ions, and even higher amounts of Pb(II). In addition, the general metal ion coordination abilities of ZmMT1 characterized by pH-dependent zinc-, lead- and cadmium-binding stability and by the competitive reaction with 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) were evaluated. Results showed that the affinity of metal ions for the recombinant form of ZmMT1 can be arranged as follows: Cd(II) > Pb(II) > Zn(II). The observation revealed that chelating agents, such as ethylene diamine tetraacetic acid (EDTA) and ATP, accelerate the oxidation of ZmMT1 in the following order: EDTA ? L-histidine > ATP ~ citrate. Meanwhile, commonly used buffers increase the reactivity of ZmMT1 with DTNB in the following order: PBS > Tris-HCl > HEPES. PMID- 29766365 TI - Iron overload prevents oxidative damage to rat brain after chlorpromazine administration. AB - The hypothesis tested is that Fe administration leads to a response in rat brain modulating the effects of later oxidative challenges such as chlorpromazine (CPZ) administration. Either a single dose (acute Fe overload) or 6 doses every second day (sub-chronic Fe overload) of 500 or 50 mg Fe-dextran/kg, respectively, were injected intraperitoneally (ip) to rats. A single dose of 10 mg CPZ/kg was injected ip 8 h after Fe treatment. DNA integrity was evaluated by quantitative PCR, lipid radical (LR.) generation rate by electron paramagnetic resonance (EPR), and catalase (CAT) activity by UV spectrophotometry in isolated brains. The maximum increase in total Fe brain was detected after 6 or 2 h in the acute and sub-chronic Fe overload model, respectively. Mitochondrial and nuclear DNA integrity decreased after acute Fe overload at the time of maximal Fe content; the decrease in DNA integrity was lower after sub-chronic than after acute Fe overload. CPZ administration increased LR. generation rate in control rat brain after 1 and 2 h; however, CPZ administration after acute or sub-chronic Fe overload did not affect LR. generation rate. CPZ treatment did not affect CAT activity after 1-4 h neither in control rats nor in acute Fe-overloaded rats. However, CPZ administration to rats treated sub-chronically with Fe showed increased brain CAT activity after 2 or 4 h, as compared to control values. Fe supplementation prevented brain damage in both acute and sub-chronic models of Fe overload by selectively activating antioxidant pathways. PMID- 29766367 TI - Extraterrestrial autonomic function. PMID- 29766368 TI - Systemic Contact Dermatitis. AB - Systemic contact dermatitis (SCD) traditionally refers to a skin condition where an individual who is cutaneously sensitized to an allergen will subsequently react to that same allergen or a cross reacting allergen via a different route. It occurs to allergens including metals, medications, and foods. The exact pathophysiology underlying this disease remains unknown, although it appears to be mediated by type 4 hypersensitivity reactions and possibly type 3 hypersensitivity reactions. The p-I concept (pharmacologic interaction with immunoreceptors) hypothesized that drugs are able to bind directly to a T cell receptor without first being presented by MHC (major histocompatibility complex) molecules and without prior metabolism, which would help explain why SCD can be seen on first exposure to medications. Nomenclature remains a challenge as SCD can be subcategorized using terms such as ACDS (allergic contact dermatitis syndrome) and its four clinical stages, Baboon syndrome, and SDRIFE (symmetrical drug-related intertriginous and flexural exanthema), which share many overlapping features. Food allergens may be responsible for uncontrolled or persistent symptoms in patients with contact dermatitis who do not respond to topical avoidance. With medications, symptoms may be induced by topical application versus systemic administration. Patch testing (PT) may be beneficial in diagnosing SCD caused by metals and many topical medications including corticosteroids, antimicrobials (ampicillin, bacitracin, erythromycin, neomycin, nystatin), NSAIDs (diclofenac, ibuprofen), anesthetics, and antihistamines (chlorphenamine, piperazine). Current treatment options include topical steroids and oral antihistamines for symptom relief and dietary avoidance to causative foods or metals. PMID- 29766369 TI - Nutritional Issues in Food Allergy. AB - Diet and nutrition play an important role in the development and management of food allergy. The diet of expectant mothers can have an effect on their offspring in terms of allergic outcomes. A host of confounding factors may influence this, with a maternal diet rich in fruits and vegetables, fish, vitamin D-rich foods associated with a lower risk of allergic disease in their children. More surprisingly, the consumption of milk and butter has also been shown to have a protective effect, especially in a farm environment. Similarly, the diet of the infant can also be important, not only in terms of breast feeding, but also the timing of the introduction of complementary foods, the diversity of the diet and the effect of individual foods on the development of allergy. One factor which has clearly been shown not to influence the development of food allergy is allergen avoidance by expectant mothers. In the infant diet, the manipulation of the gut microbiome to prevent the development of atopic disease is clearly an area which promises much, although studies have yet to provide a breakthrough in the prevention of atopic dermatitis. More concrete evidence of the value of diet in prevention has come from studies evaluating infant eating patterns which may protect gut health, through the consumption of large amounts of home-processed fruits and vegetables. The consumption of fish during the first year of life has also been shown to be protective. The importance of nutritional issues in children and adults who have a food allergy has become much more accepted in recent years. The primary allergenic foods in infancy and childhood, milk, egg, wheat and soy are also ones which are present in many foods and thus their avoidance can be problematic from a nutritional perspective. Thus, children with a food allergy can have their growth compromised through avoidance, especially pre-diagnosis, when foods may be excluded without any expert nutritional input. The management of a food allergy largely remains the exclusion of the offending food(s), but it is now clear that in doing so, children in particular can be at nutritional risk if insufficient attention is paid to the rest of the diet. Adults with food allergy are often thought not to need nutritional counselling; however, many will exclude a wide range of foods due to anxiety about trace exposure, or similar foods causing reactions. The avoidance of staple foods such as milk and wheat are common, but substitute foods very often do not have comparable nutritional profiles. Adults may also be more susceptible to on-line promotion of extreme nutritional regimes which can be extremely harmful. All food allergic individuals, whatever their age, should have a nutrition review to ensure they are consuming a healthy, balanced diet, and are not avoiding food groups unnecessarily. PMID- 29766366 TI - Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS) : Endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). AB - PURPOSE: Patients suffering from cardiovascular autonomic failure often develop neurogenic supine hypertension (nSH), i.e., high blood pressure (BP) in the supine position, which falls in the upright position owing to impaired autonomic regulation. A committee was formed to reach consensus among experts on the definition and diagnosis of nSH in the context of cardiovascular autonomic failure. METHODS: As a first and preparatory step, a systematic search of PubMed indexed literature on nSH up to January 2017 was performed. Available evidence derived from this search was discussed in a consensus expert round table meeting in Innsbruck on February 16, 2017. Statements originating from this meeting were further discussed by representatives of the American Autonomic Society and the European Federation of Autonomic Societies and are summarized in the document presented here. The final version received the endorsement of the European Academy of Neurology and the European Society of Hypertension. RESULTS: In patients with neurogenic orthostatic hypotension, nSH is defined as systolic BP >= 140 mmHg and/or diastolic BP >= 90 mmHg, measured after at least 5 min of rest in the supine position. Three severity degrees are recommended: mild, moderate and severe. nSH may also be present during nocturnal sleep, with reduced-dipping, non-dipping or rising nocturnal BP profiles with respect to mean daytime BP values. Home BP monitoring and 24-h-ambulatory BP monitoring provide relevant information for a customized clinical management. CONCLUSIONS: The establishment of expert-based criteria to define nSH should standardize diagnosis and allow a better understanding of its epidemiology, prognosis and, ultimately, treatment. PMID- 29766370 TI - Continuous Laminaribiose Production Using an Immobilized Bienzymatic System in a Packed Bed Reactor. AB - The first continuous production system of laminaribiose from sucrose and glucose in a bienzymatic reaction is reported in this study. Immobilized laminaribiose phosphorylase and sucrose phosphorylase were used in a packed bed reactor system comprising of a 3-cm glass column at 35 degrees C with a steady feeding flow rate of 0.1 ml/min. Factors affecting product formation including enzyme ratio, peal concept (both enzymes in one pearl or in separate pearls), and pearl size were studied. An enzyme ratio of 2:1 of laminaribiose phosphorylase (LP) to sucrose phosphorylase (SP) when encapsulated separately in bigger size peals resulted in higher concentration of product. Laminaribiose (0.4 g/(L h)) is produced in the optimized system at steady state. The reaction system proved to be operationally stable throughout 10 days of continuous processing. A half-life time of more than 9 days was observed for both biocatalysts. PMID- 29766372 TI - CARS 2018-Computer Assisted Radiology and Surgery Proceedings of the 32nd International Congress and Exhibition Berlin, Germany, June 20-23, 2018. PMID- 29766371 TI - Landsat phenological metrics and their relation to aboveground carbon in the Brazilian Savanna. AB - BACKGROUND: The quantification and spatially explicit mapping of carbon stocks in terrestrial ecosystems is important to better understand the global carbon cycle and to monitor and report change processes, especially in the context of international policy mechanisms such as REDD+ or the implementation of Nationally Determined Contributions (NDCs) and the UN Sustainable Development Goals (SDGs). Especially in heterogeneous ecosystems, such as Savannas, accurate carbon quantifications are still lacking, where highly variable vegetation densities occur and a strong seasonality hinders consistent data acquisition. In order to account for these challenges we analyzed the potential of land surface phenological metrics derived from gap-filled 8-day Landsat time series for carbon mapping. We selected three areas located in different subregions in the central Brazil region, which is a prominent example of a Savanna with significant carbon stocks that has been undergoing extensive land cover conversions. Here phenological metrics from the season 2014/2015 were combined with aboveground carbon field samples of cerrado sensu stricto vegetation using Random Forest regression models to map the regional carbon distribution and to analyze the relation between phenological metrics and aboveground carbon. RESULTS: The gap filling approach enabled to accurately approximate the original Landsat ETM+ and OLI EVI values and the subsequent derivation of annual phenological metrics. Random Forest model performances varied between the three study areas with RMSE values of 1.64 t/ha (mean relative RMSE 30%), 2.35 t/ha (46%) and 2.18 t/ha (45%). Comparable relationships between remote sensing based land surface phenological metrics and aboveground carbon were observed in all study areas. Aboveground carbon distributions could be mapped and revealed comprehensible spatial patterns. CONCLUSION: Phenological metrics were derived from 8-day Landsat time series with a spatial resolution that is sufficient to capture gradual changes in carbon stocks of heterogeneous Savanna ecosystems. These metrics revealed the relationship between aboveground carbon and the phenology of the observed vegetation. Our results suggest that metrics relating to the seasonal minimum and maximum values were the most influential variables and bear potential to improve spatially explicit mapping approaches in heterogeneous ecosystems, where both spatial and temporal resolutions are critical. PMID- 29766373 TI - Prostate segmentation in MRI using a convolutional neural network architecture and training strategy based on statistical shape models. AB - PURPOSE: Most of the existing convolutional neural network (CNN)-based medical image segmentation methods are based on methods that have originally been developed for segmentation of natural images. Therefore, they largely ignore the differences between the two domains, such as the smaller degree of variability in the shape and appearance of the target volume and the smaller amounts of training data in medical applications. We propose a CNN-based method for prostate segmentation in MRI that employs statistical shape models to address these issues. METHODS: Our CNN predicts the location of the prostate center and the parameters of the shape model, which determine the position of prostate surface keypoints. To train such a large model for segmentation of 3D images using small data (1) we adopt a stage-wise training strategy by first training the network to predict the prostate center and subsequently adding modules for predicting the parameters of the shape model and prostate rotation, (2) we propose a data augmentation method whereby the training images and their prostate surface keypoints are deformed according to the displacements computed based on the shape model, and (3) we employ various regularization techniques. RESULTS: Our proposed method achieves a Dice score of 0.88, which is obtained by using both elastic-net and spectral dropout for regularization. Compared with a standard CNN-based method, our method shows significantly better segmentation performance on the prostate base and apex. Our experiments also show that data augmentation using the shape model significantly improves the segmentation results. CONCLUSIONS: Prior knowledge about the shape of the target organ can improve the performance of CNN-based segmentation methods, especially where image features are not sufficient for a precise segmentation. Statistical shape models can also be employed to synthesize additional training data that can ease the training of large CNNs. PMID- 29766374 TI - Perceived importance of substance use prevention in juvenile justice: a multi level analysis. AB - BACKGROUND: Youth under juvenile justice (JJ) supervision are at high-risk of adverse outcomes from substance use, making prevention important. Few studies have examined prevention-related attitudes of JJ employees, yet such attitudes may be important for implementing prevention programs. Attitudes toward prevention may reflect individual characteristics and organizational contexts. METHODS: Mixed effects regression was used to analyze data from 492 employees in 36 sites participating in the Juvenile Justice-Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) cooperative agreement. JJ employees' perceived importance of substance use prevention was measured. Staff-level variables included attitudes, job type, and demographic characteristics. Site-level variables focused on use of evidence-based screening tools, prevention programs, and drug testing. RESULTS: On average, JJ employees rated substance use prevention as highly important (mean = 45.9, out of 50). JJ employees generally agreed that preventing substance use was part of their agency's responsibility (mean = 3.8 on scale ranging from 1 to 5). At the site level, 72.2% used an evidence-based screening tool, 22.2% used one or more evidence-based prevention program, and 47.2% used drug testing. Reported importance of prevention was positively associated with site-level use of screening tools and drug testing as well as staff-level attitudes regarding prevention being consistent with the agency's mission. CONCLUSIONS: The associations between screening and prevention attitudes suggest that commitment to identifying youth needs may result in greater openness to preventing substance use. Future efforts to implement substance use prevention within JJ agencies charged with supervising youth in the community may benefit from highlighting the fit between prevention and the agency's mission. PMID- 29766376 TI - Long-term etanercept retention patterns and factors associated with treatment discontinuation: a retrospective cohort study using Canadian claims-level data. AB - To examine 12-month retention rates over 6 years of etanercept patients in Canada, and to identify factors associated with treatment discontinuation. A retrospective cohort study was conducted using longitudinal prescription drug claims data from IQVIA Private Drug Plan database (PDP), Ontario Public Drug Plan database (OPDP), and Regie de l'assurance maladie du Quebec database (RAMQ). Between 07/2008 and 06/2010, bio-naive patients who initiated etanercept were identified and followed for 72 months. Twelve-month retention rates were estimated in one-year increments and factors associated with time to discontinuation over the 72-month period were identified using a Cox proportional hazards regression model. The study identified 4528 etanercept patients (61% female, 85% rheumatic diseases, and 15% psoriasis). Twelve-month etanercept retention rates increased significantly for patients following their first year on therapy (p < 0.0001), with 66% of patients retained at year 1 vs. 79, 82, 84, 83, and 79% at years 2, 3, 4, 5, and 6, respectively. 17.1% (n = 771) of patients were retained for the entire 72-month study. Patients with psoriasis were at increased risk (HR 1.199; p < 0.0001); while public drug coverage plan patients (OPDP HR 0.721; p < 0.0001 and RAMQ HR 0.537; p < 0.0001) were at decreased risk of treatment discontinuation. Twelve-month etanercept retention rates increased significantly for patients following their first year on therapy. Indication and drug coverage plan were associated with patients' time to etanercept discontinuation. With a better understanding of factors associated with retention, programs can be designed to address the specific needs of at-risk groups while supporting patients stable on therapy. PMID- 29766375 TI - Efficacy of adalimumab and infliximab in recalcitrant retinal vasculitis inadequately responsive to other immunomodulatory therapies. AB - The primary aim of the study was to evaluate the efficacy of tumor necrosis factor (TNF)-alpha blockers adalimumab (ADA) and infliximab (IFX) in refractory sight-threatening retinal vasculitis (RV) during a 12-month follow-up period. Secondary aims were to evaluate (i) any impact of concomitant conventional disease-modifying anti-rheumatic drugs (cDMARDs) and different lines of biologic therapy; (ii) any difference in terms of efficacy between ADA and IFX; (iii) consequences of biotherapies on the best-corrected visual acuity (BCVA); (iv) corticosteroid-sparing effect; and (vi) ocular complications during anti-TNF alpha treatment. Demographic, clinical, and therapeutic data were retrospectively collected from the medical records and statistically analyzed. Forty-eight patients (82 eyes) were recruited, 22 (45.8%) of which received IFX and 26 (54.2%) ADA. The percentages of patients achieving RV remission within 3 and 12 months were 54 and 86%, respectively. A significant decrease in RV detection was identified from baseline to 3-month (p < 0.0001) and 12-month (p < 0.0001) assessments and between 3-month and 12-month visits (p = 0.004). No differences were identified in terms of RV resolution between (i) patients undergoing monotherapy and those co-administered with cDMARDs at 3-month (p = 0.560) and 12 month (p = 0.611) follow-up; (ii) biologic-naive patients and those already exposed to other biologics at 3-month (p = 0.497) and 12-month (p > 0.99) visits; and (iii) patients treated with ADA and those treated with IFX (p = 0.357). During the study period, a statistically significant corticosteroid-sparing effect was observed (p = 0.0002), while BCVA values did not significantly change (p = 0.950). Anti-TNF-alpha monoclonal antibodies have proved excellent results in patients with recalcitrant sight-threatening RV. PMID- 29766378 TI - 2-Methacryloyloxyethyl phosphorylcholine (MPC)-polymer suppresses an increase of oral bacteria: a single-blind, crossover clinical trial. AB - OBJECTIVES: The biocompatible 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers, which mimic a biomembrane, reduce protein adsorption and bacterial adhesion and inhibit cell attachment. The aim of this study is to clarify whether MPC-polymer can suppress the bacterial adherence in oral cavity by a crossover design. We also investigated the number of Fusobacterium nucleatum, which is the key bacterium forming dental plaque, in clinical samples. MATERIALS AND METHODS: This study was a randomized, placebo-controlled, single-blind, crossover study, with two treatment periods separated by a 2-week washout period. We conducted clinical trial with 20 healthy subjects to evaluate the effect of 5% MPC-polymer mouthwash after 5 h on oral microflora. PBS was used as a control. The bacterial number in the gargling sample before and after intervention was counted by an electronic bacterial counter and a culture method. DNA amounts of total bacteria and F. nucleatum were examined by q-PCR. RESULTS: The numbers of total bacteria and oral streptcocci after 5 h of 5% MPC-polymer treatment significantly decreased, compared to the control group. Moreover, the DNA amounts of total bacteria and F. nucleatum significantly decreased by 5% MPC-polymer mouthwash. CONCLUSIONS: We suggest that MPC-polymer coating in the oral cavity may suppress the oral bacterial adherence. CLINICAL RELEVANCE: MPC-polymer can be a potent compound for the control of oral microflora to prevent oral infection. PMID- 29766377 TI - Resolution of femoral metaphyseal dysplasia in CINCA syndrome after long-term treatment with interleukin-1 blockade. AB - Chronic infantile neurological cutaneous articular (CINCA) syndrome is a rare autoinflammatory disorder driven by uncontrolled hypersecretion of interleukin (IL)-1, which can be clinically depicted by striking cutaneous, neurologic, and skeletal features. Little is known about the exact pathogenesis of CINCA bone disease, which mainly involves the knees. We report a 20-year-old CINCA patient, who was consecutively treated firstly with anakinra, started at 7 years, then with full dose canakinumab, started at 17 years, focusing on the typical bone abnormalities of the syndrome: the comparison of radiographs of knees performed at 7 and 20 years has shown the disappearance of a typical metaphyseal dysplasia occurring in the femurs of this CINCA patient, regularly treated with IL-1 blockade for a period of 13 years. A review of the medical literature reveals poor information on the skeletal response of CINCA syndrome to IL-1-inhibiting therapies. This contribution confirms the protean striking effects of IL-1 blockade in this peculiar autoinflammatory disorder, showing for the first time the reversal of the characteristic CINCA metaphyseal dysplasia over long-term treatment. PMID- 29766379 TI - Relative salience of syllable structure and syllable order in zebra finch song. AB - There is a rich history of behavioral and neurobiological research focused on the 'syntax' of birdsong as a model for human language and complex auditory perception. Zebra finches are one of the most widely studied songbird species in this area of investigation. As they produce song syllables in a fixed sequence, it is reasonable to assume that adult zebra finches are also sensitive to the order of syllables within their song; however, results from electrophysiological and behavioral studies provide somewhat mixed evidence on exactly how sensitive zebra finches are to syllable order as compared, say, to syllable structure. Here, we investigate how well adult zebra finches can discriminate changes in syllable order relative to changes in syllable structure in their natural song motifs. In addition, we identify a possible role for experience in enhancing sensitivity to syllable order. We found that both male and female adult zebra finches are surprisingly poor at discriminating changes to the order of syllables within their species-specific song motifs, but are extraordinarily good at discriminating changes to syllable structure (i.e., reversals) in specific syllables. Direct experience or familiarity with a song, either using the bird's own song (BOS) or the song of a flock mate as the test stimulus, improved both male and female zebra finches' sensitivity to syllable order. However, even with experience, birds remained much more sensitive to structural changes in syllables. These results help to clarify some of the ambiguities from the literature on the discriminability of changes in syllable order in zebra finches, provide potential insight on the ethological significance of zebra finch song features, and suggest new avenues of investigation in using zebra finches as animal models for sequential sound processing. PMID- 29766380 TI - Effects of Race Are Rarely Included in Clinical Prediction Models for Cardiovascular Disease. PMID- 29766381 TI - Impact of Drug Overdose Deaths on Solid Organ Transplantation in the United States. PMID- 29766383 TI - The Association of Food Insufficiency with Patient Activation Among Women Veterans Using Veterans Administration Healthcare: a Cross-Sectional Analysis. PMID- 29766385 TI - Highlights of Issue 6, 2018. PMID- 29766384 TI - Increased Functional MEG Connectivity as a Hallmark of MRI-Negative Focal and Generalized Epilepsy. AB - Epilepsy is one of the most prevalent neurological diseases with a high morbidity. Accumulating evidence has shown that epilepsy is an archetypical neural network disorder. Here we developed a non-invasive cortical functional connectivity analysis based on magnetoencephalography (MEG) to assess commonalities and differences in the network phenotype in different epilepsy syndromes (non-lesional/cryptogenic focal and idiopathic/genetic generalized epilepsy). Thirty-seven epilepsy patients with normal structural brain anatomy underwent a 30-min resting state MEG measurement with eyes closed. We only analyzed interictal epochs without epileptiform discharges. The imaginary part of coherency was calculated as an indicator of cortical functional connectivity in five classical frequency bands. This connectivity measure was computed between all sources on individually reconstructed cortical surfaces that were surface aligned to a common template. In comparison to healthy controls, both focal and generalized epilepsy patients showed widespread increased functional connectivity in several frequency bands, demonstrating the potential of elevated functional connectivity as a common pathophysiological hallmark in different epilepsy types. Furthermore, the comparison between focal and generalized epilepsies revealed increased network connectivity in bilateral mesio-frontal and motor regions specifically for the generalized epilepsy patients. Our study indicated that the surface-based normalization of MEG sources of individual brains enables the comparison of imaging findings across subjects and groups on a united platform, which leads to a straightforward and effective disclosure of pathological network characteristics in epilepsy. This approach may allow for the definition of more specific markers of different epilepsy syndromes, and increased MEG-based resting state functional connectivity seems to be a common feature in MRI-negative epilepsy syndromes. PMID- 29766382 TI - Reduced Effectiveness of Interruptive Drug-Drug Interaction Alerts after Conversion to a Commercial Electronic Health Record. AB - BACKGROUND: Drug-drug interaction (DDI) alerts in electronic health records (EHRs) can help prevent adverse drug events, but such alerts are frequently overridden, raising concerns about their clinical usefulness and contribution to alert fatigue. OBJECTIVE: To study the effect of conversion to a commercial EHR on DDI alert and acceptance rates. DESIGN: Two before-and-after studies. PARTICIPANTS: 3277 clinicians who received a DDI alert in the outpatient setting. INTERVENTION: Introduction of a new, commercial EHR and subsequent adjustment of DDI alerting criteria. MAIN MEASURES: Alert burden and proportion of alerts accepted. KEY RESULTS: Overall interruptive DDI alert burden increased by a factor of 6 from the legacy EHR to the commercial EHR. The acceptance rate for the most severe alerts fell from 100 to 8.4%, and from 29.3 to 7.5% for medium severity alerts (P < 0.001). After disabling the least severe alerts, total DDI alert burden fell by 50.5%, and acceptance of Tier 1 alerts rose from 9.1 to 12.7% (P < 0.01). CONCLUSIONS: Changing from a highly tailored DDI alerting system to a more general one as part of an EHR conversion decreased acceptance of DDI alerts and increased alert burden on users. The decrease in acceptance rates cannot be fully explained by differences in the clinical knowledge base, nor can it be fully explained by alert fatigue associated with increased alert burden. Instead, workflow factors probably predominate, including timing of alerts in the prescribing process, lack of differentiation of more and less severe alerts, and features of how users interact with alerts. PMID- 29766386 TI - Cognitive assessment in multiple sclerosis-an Italian consensus. AB - The aim of this consensus paper was to define the state of the art on cognitive assessment of persons with multiple sclerosis (PwMS), with the purpose of providing recommendations for the Italian centers involved in MS management. While there are no formal guidelines published regarding the assessment of cognitive function in MS, on the basis of an expert opinion meeting, held in Milan (Italy) on July 4, 2016, we report the recommendations of a panel of Italian experts including MS neurologists and neuropsychologists for the assessment and follow-up of cognitive function in adult MS subjects. PMID- 29766387 TI - Comparative morphological analysis of two parallel mycoheterotrophic transitions reveals divergent and convergent traits in the genus Pyrola (Pyroleae, Ericaceae). AB - The genus Pyrola includes species with different degree of mycoheterotrophy; some species possess individuals that rely on all carbon through their associations with fungi (full mycoheterotrophy, FM), whereas some species obtain carbon through both fungi and photosynthesis by itself (partial mycoheterotrophy, PM). To investigate how plant functional traits of photosynthesis and reproduction are related to the degree of mycoheterotrophy in the initial stage of the transition from PM to FM, we determined morphological traits in FM (or nearly FM) and PM species in two independent lineages, P. picta and P. japonica complexes. We used herbarium specimens and examined leaf number, leaf area, flower number, and scape length in FM or nearly FM species (P. aphylla and P. subaphylla) and PM species (P. picta s.l. and P. japonica). We found a leaf area reduction in FM (or nearly FM) species in both lineages, suggesting that this is a convergent trait. The number of flowers was not significantly different between FM (or nearly FM) and PM species in both lineages. On the other hand, differences in the variation between FM (or nearly FM) and PM species were found in some traits between the two lineages. The FM (or nearly FM) species in one lineage only possessed rudimentary leaves, whereas that in the other linage possessed a few small, ordinary leaves in addition to those with only rudimentary leaves. The scape length of the FM (or nearly FM) species was significantly longer than that of PM species in one lineage, whereas it was shorter in the other lineage. The different and common variations are divergent and convergent traits, respectively, that could be associated with the transition to FM in Pylora. In addition, shoots of both PM species occasionally lacked ordinary leaves, possibly indicating possession of these shoots is preadaptation for the transition to FM in Pyrola. PMID- 29766390 TI - Together We Make a Difference. PMID- 29766388 TI - Molecular Evolution of Metaplasia to Adenocarcinoma in the Esophagus. AB - Esophageal adenocarcinoma (EAC) develops from Barrett's esophagus (BE), a condition where the normal squamous epithelia is replaced by specialized intestinal metaplasia in response to chronic gastroesophageal acid reflux. In a minority of individuals, BE can progress to low- and high-grade dysplasia and eventually to intra-mucosal and then invasive carcinoma. BE provides researchers with a unique model to characterize the process by which a carcinoma arises from its precursor lesion. Molecular studies of BE have demonstrated that it is not simply a metaplastic tissue, but rather it harbors frequent alterations that are also present in dysplastic BE and in EAC. Both BE and EAC are characterized by loss of heterozygosity, aneuploidy, specific genetic mutations, and clonal diversity. Epigenetic abnormalities, primary alterations in DNA methylation, are also frequently seen in BE and EAC. Candidate gene and array-based approaches have demonstrated that numerous tumor suppressor genes exhibit aberrant promoter methylation, and some of these altered genes are associated with the neoplastic progression of BE. It has also been shown that the BE and EAC epigenomes are characterized by hypomethylation of intragenic and non-coding regions Recent studies have also provided new insight into the evolutionary forces underlying the molecular alterations seen in BE and EAC and into the molecular pathogenesis of EAC. PMID- 29766389 TI - The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion. AB - BACKGROUND: Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival. METHODS: A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986-May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database. RESULTS: Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39-40 degrees C. CONCLUSIONS: Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined. PMID- 29766391 TI - Medication-related problems among adult chronic kidney disease patients in a sub Saharan tertiary hospital. AB - BACKGROUND: Chronic kidney disease (CKD) patients are prone to medication-related problems (MRPs). Few studies address the clinical relevance of MRPs among CKD patients in sub-Saharan Africa. OBJECTIVE: To investigate the frequency and predictors of MRPs among adult CKD patients treated at a tertiary care facility in an urban sub-Saharan setting. SETTING: Kenyatta National Hospital in Nairobi, Kenya. METHOD: A cross-sectional study involving 60 adult patients with CKD was carried out. Data were collected through structured interviews and patient chart reviews between April 2016 and June 2016. MRPs identified from the collected data were classified according to Hepler and Strand classification. The frequencies of the identified MRPs were computed and logistic regression used to investigate the associations between the MRPs and covariates in the data. MAIN OUTCOME MEASURES: frequencies and predictors of MRPs. RESULTS: 271 MRPs were identified. The commonest MRPs were drug interactions (21.8%), indication without drug (18.1%) and medication non-adherence (15.5%). Compared to patients with CKD stage 3, patients with CKD stage 4 were 5.9 times more likely to have an improper drug selection and 4.7 times more likely to experience overdosage. Other significant predictors of MRPs were the number of medications per prescription and the number of comorbidities per patient. CONCLUSION: This study found a high frequency of MRPs among patients with chronic kidney disease receiving care in urban sub Saharan tertiary hospital settings. The predictors of MRPs among CKD patients in this setting are likely to be multifactorial and include the CKD stage, polypharmacy, and comorbidities. PMID- 29766392 TI - Excessive Glutamate Stimulation Impairs ACE2 Activity Through ADAM17-Mediated Shedding in Cultured Cortical Neurons. AB - The excitotoxicity of glutamate plays an important role in the progression of various neurological disorders via participating in inflammation and neuronal damage. In this study, we identified the role of excessive glutamate stimulation in the modulation of angiotensin-converting enzyme type 2 (ACE2), a critical component in the compensatory axis of the renin-angiotensin system (RAS). In primary cultured cortical neurons, high concentration of glutamate (100 uM) significantly reduced the enzymatic activity of ACE2. The elevated activity of ADAM17, a member of the 'A Disintegrin And Metalloprotease' (ADAM) family, was found to contribute to this glutamate-induced ACE2 down-regulation. The decrease of ACE2 activity could be prevented by pre-treatment with antagonists targeting ionotropic glutamate receptors. In addition, the glutamate-induced decrease in ACE2 activity was significantly attenuated when the neurons were co-treated with MitoTEMPOL or blockers that target oxidative stress-mediated signaling pathway. In summary, our study reveals a strong relationship between excessive glutamate stimulation and ADAM17-mediated impairment in ACE2 activity, suggesting a possible cross-talk between glutamate-induced excitotoxicity and dysregulated RAS. PMID- 29766393 TI - Linear feature projection-based real-time decoding of limb state from dorsal root ganglion recordings. AB - Proprioceptive afferent activities recorded by a multichannel microelectrode have been used to decode limb movements to provide sensory feedback signals for closed loop control in a functional electrical stimulation (FES) system. However, analyzing the high dimensionality of neural activity is one of the major challenges in real-time applications. This paper proposes a linear feature projection method for the real-time decoding of ankle and knee joint angles. Single-unit activity was extracted as a feature vector from proprioceptive afferent signals that were recorded from the L7 dorsal root ganglion during passive movements of ankle and knee joints. The dimensionality of this feature vector was then reduced using a linear feature projection composed of projection pursuit and negentropy maximization (PP/NEM). Finally, a time-delayed Kalman filter was used to estimate the ankle and knee joint angles. The PP/NEM approach had a better decoding performance than did other feature projection methods, and all processes were completed within the real-time constraints. These results suggested that the proposed method could be a useful decoding method to provide real-time feedback signals in closed-loop FES systems. PMID- 29766395 TI - Nonword repetition stimuli for Vietnamese-speaking children. AB - Nonword repetition (NWR) has been a widely used measure of language-learning ability in children with and without language disorders. Although NWR tasks have been created for a variety of languages, minimal attention has been given to Asian tonal languages. This study introduces a new set of NWR stimuli for Vietnamese. The stimuli include 20 items ranging in length from one to four syllables. The items consist of dialect-neutral phonemes in consonant-vowel (CV) and CVC sequences that follow the phonotactic constraints of the language. They were rated high on wordlikeness and have comparable position segments and biphone probabilities across stimulus lengths. We validated the stimuli with a sample of 59 typically developing Vietnamese-English bilingual children, ages 5 to 8. The stimuli exhibited the expected age and length effects commonly found in NWR tasks: Older children performed better on the task than younger children, and longer items were more difficult to repeat than shorter items. We also compared different scoring systems in order to examine the individual phoneme types (consonants, vowels, and tones) and composite scores (proportions of phonemes correct, with and without tone). The study demonstrates careful construction and validation of the stimuli, and future directions are discussed. PMID- 29766394 TI - Treatment of Eosinophilic Granulomatosis with Polyangiitis: A Review. AB - Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) is a rare type of anti-neutrophil cytoplasm antibody-associated vasculitis. Nevertheless, eosinophilic granulomatosis with polyangiitis stands apart because it has features of vasculitis and eosinophilic disorders that require targeted therapies somewhat different from those used for other anti-neutrophil cytoplasm antibody-associated vasculitides. Considerable advances have been made in understanding the underlying pathophysiology of eosinophilic granulomatosis with polyangiitis that have highlighted the key role of eosinophils and opened new therapeutic opportunities. Its conventional treatment relies mainly on agents that decrease inflammation: corticosteroids and immunosuppressant adjunction for severe manifestations. New therapeutic approaches are needed for refractory disease, relapses and issues associated with corticosteroid dependence, especially for asthma manifestations. Drugs under evaluation mostly target eosinophils and B cells. Results of low-evidence-based trials suggested possible efficacies of biologicals: B-cell-blocking rituximab and anti-immunoglobulin E omalizumab. Recently, the first large-scale randomised controlled trial on eosinophilic granulomatosis with polyangiitis proved the efficacy of anti interleukin-5 mepolizumab. That finding opens a new era in eosinophilic granulomatosis with polyangiitis management, with mepolizumab approval but also in future drug evaluations and trial designs for eosinophilic granulomatosis with polyangiitis. Additional studies are needed to determine which patients would benefit most from targeted therapies and achieve personalised treatment for patients with eosinophilic granulomatosis with polyangiitis. Herein, we review eosinophilic granulomatosis with polyangiitis characteristics and provide an overview of established and novel pharmacological agents. PMID- 29766396 TI - A novel evaluation of two related and two independent algorithms for eye movement classification during reading. AB - Nystrom and Holmqvist have published a method for the classification of eye movements during reading (ONH) (Nystrom & Holmqvist, 2010). When we applied this algorithm to our data, the results were not satisfactory, so we modified the algorithm (now the MNH) to better classify our data. The changes included: (1) reducing the amount of signal filtering, (2) excluding a new type of noise, (3) removing several adaptive thresholds and replacing them with fixed thresholds, (4) changing the way that the start and end of each saccade was determined, (5) employing a new algorithm for detecting PSOs, and (6) allowing a fixation period to either begin or end with noise. A new method for the evaluation of classification algorithms is presented. It was designed to provide comprehensive feedback to an algorithm developer, in a time-efficient manner, about the types and numbers of classification errors that an algorithm produces. This evaluation was conducted by three expert raters independently, across 20 randomly chosen recordings, each classified by both algorithms. The MNH made many fewer errors in determining when saccades start and end, and it also detected some fixations and saccades that the ONH did not. The MNH fails to detect very small saccades. We also evaluated two additional algorithms: the EyeLink Parser and a more current, machine-learning-based algorithm. The EyeLink Parser tended to find more saccades that ended too early than did the other methods, and we found numerous problems with the output of the machine-learning-based algorithm. PMID- 29766397 TI - Novel variant of unknown significance in MUTYH in a patient with MUTYH-associated polyposis: a case to reclassify. AB - MUTYH-associated polyposis (MAP) is a hereditary cancer syndrome that is caused by biallelic pathogenic variants in the MUTYH gene and should be evaluated for in patients with an attenuated colonic polyposis phenotype. Monoallelic pathogenic variants in MUTYH are associated with a moderate increased risk of colorectal cancer but not with the polyposis phenotype. We present a case of a patient presenting with multiple colonic adenomatous polyps, whose germline testing revealed a heterozygous pathogenic variant in MUTYH in exon 13, c.1187G > A (p.Gly396Asp) as well as a heterozygous variant of unknown significance (VUS) in MUTYH in exon 14, c.1379T > C (p.Leu460Ser). We interpret the VUS as pathogenic in light of the patient's phenotype; the fact that the VUS was in trans with a known pathogenic variant; and because all the in silico predictors suggested, it was likely to be deleterious. This case highlights the importance of a gastroenterologist recognizing the indication for genetic testing in a patient with greater than ten adenomas, the importance of a genetic counselor in interpretation of results, and is the first report of the specific variant in the literature with clinical information to suggest that it is likely pathogenic. PMID- 29766398 TI - Hepatosplenic T cell lymphoma: a unifying entity in a patient with hemolytic anemia, massive splenomegaly, and liver dysfunction. AB - Hepatosplenic T cell lymphoma (HSTCL) is a rare subtype of peripheral non-Hodgkin lymphoma, of which 20% of cases are associated with chronic immunosuppression. It often occurs in patients with inflammatory bowel disease treated with immunomodulating medications such a thiopurines or TNF-alpha inhibitors. Cytopenias are commonly seen but autoimmune hemolytic anemia (AIHA) is rare. Here we present a young male with longstanding ulcerative colitis on chronic azathioprine, exhibiting several rare features of HSTCL. He initially presented with refractory AIHA, thrombocytopenia, and massive splenomegaly, requiring splenectomy. Histologic examination of his spleen confirmed diagnosis of HSTCL. Approximately 3 months after diagnosis, he was found to have leukemic transformation, representing a secondary malignancy. PMID- 29766400 TI - Social media in the REI clinic: what do patients want? AB - PURPOSE: To elicit patient preferences for social media utilization and content in the infertility clinic. METHODS: This was a cross-sectional survey study conducted in three US fertility practices. Women presenting to the infertility clinic for an initial or return visit were offered an anonymous voluntary social media survey. The survey elicited patient perception of whether social media use in the infertility clinic is beneficial, and preferences regarding topics of interest. RESULTS: A total of 244 surveys were collected during the study period, of which 54.5% were complete. Instagram is a more popular platform than Twitter across all age groups. Use of both platforms varies by age, with patients >= 40 less likely to be active users. The majority of respondents felt that social media provided benefit to the patient experience in the infertility clinic (79.9%). "Education regarding infertility testing and treatment" and "Myths and Facts about infertility" were the most popular topics for potential posts, with 93.4 and 92.0% of patients endorsing interest respectively. The least popular topic was "Newborn photos and birth announcements," with only 47.4% endorsing interest. A little over half of respondents (56.3%) would feel comfortable with the clinic posting a picture of their infant. The vast majority of patients (96.2%) feel comfortable communicating electronically with their infertility clinic. CONCLUSION: Patients are interested in the use of social media as a forum for patient education and support in the infertility clinic. Patient preferences regarding post topics should be carefully considered. PMID- 29766401 TI - Penehyclidine Hydrochloride Decreases Pulmonary Microvascular Endothelial Inflammatory Injury Through a Beta-Arrestin-1-Dependent Mechanism. AB - Penehyclidine hydrochloride (PHC), a type of hyoscyamus drug, has both antimuscarinic and antinicotinic activities and retains potent central and peripheral anticholinergic activities. Compared with other hyoscyamine, the notable advantage of PHC is that it has few M2 receptor-associated cardiovascular side effects. Recent studies and clinical trials have suggested that treatment with penehyclidine hydrochloride may also possess good effects in the treatment of lung injury. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on pulmonary vascular endothelium. Since inflammatory reactions of the endothelium are signs of endothelial injury in the pathogenesis of lung injury, we determined the effects of penehyclidine hydrochloride on endothelial inflammatory injury in cultured human pulmonary microvascular endothelial cells (HPMVEC). Furthermore, human pulmonary microvascular endothelial cells were transfected with a shRNA-containing plasmid that specifically targets beta arrestin-1 mRNA, to test whether the effect of penehyclidine hydrochloride on lipopolysaccharide (LPS)-induced endothelial cell injury is dependent on its upregulation of beta-arrestin-1 or not. Penehyclidine hydrochloride reduced the inflammatory responses to LPS stimulation, as evidenced by reduced lactate dehydrogenase (LDH), tumor necrosis factor-alpha (TNF-alpha), and interleukelin-6 (IL-6) levels, as well as vascular cell adhesion molecule 1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) expressions. This was found to result from increased beta-arrestin-1 expression and decreased nuclear transcription factor-kappaB (NF-kappaB) activation. Expression of a shRNA containing plasmid that specifically targets beta-arrestin-1 mRNA nullified these effects of penehyclidine hydrochloride. The results indicate that penehyclidine hydrochloride exerts a protective effect on pulmonary microvascular endothelial inflammatory injury induced by LPS. We also demonstrate that this is due to its ability to increase beta-arrestin-1, which in turn inhibits NF-kappaB activation. PMID- 29766402 TI - Correction to: Gadolinium-Based Contrast Agent-Related Toxicities. AB - The name of the last author (as shown in the author listing on page 229) was incorrectly tagged during the journal production process, and so appears incorrectly in the PubMed record. The name should be indexed in PubMed as. PMID- 29766403 TI - Teacher Involvement Prevents Increases in Children's Depressive Symptoms: Bidirectional Associations in Elementary School. AB - There is accumulating evidence that social relationships can buffer the development of depression in childhood and adolescence. However, few studies have focused on teacher-child relationships in the elementary school years. In addition, research that has examined bidirectional relations between teacher involvement and depressive symptoms is virtually absent in this age period. The participants in this study were 570 children and 30 teachers from 15 elementary schools. Data on children's depressive symptoms (peer- and teacher-reports) and teacher involvement (teacher-reports) were collected in the fall and spring of Grade 2 and Grade 3 (four waves). As expected, negative cross-time effects of teacher involvement on depressive symptoms were found within grade 2 and 3. In addition, a negative cross-time effect of depressive symptoms on teacher involvement was found in grade 3 only. The results thus indicate the protective role of teacher involvement in the development of depressive symptoms but also suggest that teachers may become less involved over time when they perceive a child as more depressed. PMID- 29766404 TI - Assessing the safety of magnetic resonance imaging in cardiac device carriers. PMID- 29766405 TI - Syncope and autonomic failure in a middle-aged man. PMID- 29766406 TI - A giant hepatocellular carcinoma with uncommon features. PMID- 29766407 TI - An annotated list and molecular data on larvae of gryporhynchid tapeworms (Cestoda: Cyclophyllidea) from freshwater fishes in Africa. AB - An annotated list of larvae (metacestodes) of gryporhynchid tapeworms (Cestoda: Cyclophyllidea) from freshwater fishes in Africa is provided with numerous new host and geographical records. Newly collected materials from Burundi, Democratic Republic of the Congo, Kenya, Madagascar, Namibia, Senegal, South Africa, Sudan and Zimbabwe practically double the total number of species reported from African fish so far. We confirm the occurrence of 16 species (five unidentified to the species level and most likely representing new taxa) belonging to the genera Amirthalingamia Bray, 1974 (1 species), Cyclustera Fuhrmann, 1901 (2 species), Dendrouterina Fuhrmann, 1912 (1 species), Neogryporhynchus Baer & Bona, 1960 (1 species), Paradilepis Hsu, 1935 (4 species), Parvitaenia Burt, 1940 (5 species), and Valipora Linton, 1927 (2 species). Additionally, metacestodes of four unidentified species of Paradilepis and Parvitaenia are reported from fish for the first time. Rostellar hooks of all species are illustrated and their measurements are provided together with a host-parasite list. The molecular phylogenetic analysis based on partial LSU rDNA sequences offers the first insight into the internal phylogenetic relationships within the family. Together with the morphological observations, the present study provides a taxonomic baseline for future studies on this largely neglected, but widely distributed and relatively frequent, group of parasites of African fishes, including economically important cichlids like tilapias and cyprinids. PMID- 29766409 TI - Where youth matters-clinicopathologic characteristics and emerging trends in treatment and outcomes in young Irish women with breast cancer. AB - BACKGROUND: Young women with breast cancer (YWBC) represent 7-12% of breast cancer diagnoses and ostensibly have more biologically aggressive subtypes with higher relapse and mortality rates. We studied the clinical and pathological characteristics in YWBC and examined how outcomes and treatment have evolved. METHODS: YWBC were identified from pathology databases at two tertiary centers. Patients were divided into two cohorts: those diagnosed from 2000 to 2005 (C1) and from 2006 to 2015 (C2). Data were retrieved from clinical, radiology, and histology databases. Statistical analysis was performed using R(r) (V3.2.0). RESULTS: We identified 345 patients. Median age was 36 years (23-39 years). Mastectomy was performed in 232 patients (67.2%) and axillary lymph node clearance (ALNC) in 207 patients (60% [C1 82.7 vs. C2: 49.4%, p < 0.001]). One hundred-seventy patients (49%) were ER + HER2-, 88 (25.5%) were HER2+, and 58 (16.8%) were triple negative. Eighty patients (23.2%) received neoadjuvant therapy. Pathological complete response rates were statistically similar between C1 and C2 [C1 1 (0.9%) vs C2 16 (6.8%) p = 0.1]. Distant relapse occurred in 59 (19%) patients. There was a higher relapse rate (RR) in C1 [27 (32.1%) vs. 32 (15.7%), p < 0.002). HER2+ and ER+ HER2- patients in C1 had higher RRs than C2. Median overall survival in patients with metastatic disease was 29 months (range 2-119 months). CONCLUSION: Locally advanced disease was more prevalent in YWBC. Mastectomy and ALNC rates were high and most received multimodal treatment. The extent of axillary surgery declined over time. Outcomes were unchanged in triple negative patients. These remain a priority for research. PMID- 29766408 TI - Association between circulating levels of heat-shock protein 27 and aggressive periodontitis. AB - Heat-shock protein (Hsp) 27 is a major intracellular molecular chaperone and controller of intracellular responses to inflammatory signals. In the extracellular space, recombinant Hsp27 has been described to exert anti inflammatory activities. The aim of this study was to assess the association between circulating levels of Hsp27 and different types of periodontitis. Pro- and anti-inflammatory cytokines and the stress proteins Hsp27 and Hsp60 with proposed anti- and pro-inflammatory properties, respectively, were measured by two-site ELISA in the serum of patients with aggressive periodontitis (AgP, n = 30), chronic periodontitis (CP, n = 29) and periodontally healthy controls (H, n = 28). Furthermore, Hsp27 and Hsp60 levels were also measured longitudinally in 12 AgP patients at 6 time points up to 3 months after treatment. AgP patients had lower levels of Hsp27 compared to CP patients and healthy subjects (adjusted one way ANOVA, p < 0.001, followed by post hoc Tukey HSD comparisons), while no differences in levels of Hsp60 or cytokines between the three groups were detected. In CP patients and H subjects, the systemic Hsp27 levels correlated with Hsp60 (r = 0.43, p < 0.001; r = 0.59, p < 0.001, respectively) and with pro inflammatory cytokines TNF-alpha (r = 0.48, p < 0.001; r = 0.55, p < 0.001, respectively) and IL-6 (r = 0.44, p < 0.01). However, no such correlations were detected in AgP cases. No consistent temporal patterns of changes of Hsp27 concentration were detected across AgP patients following periodontal treatment. This study provides the first evidence that Hsp27 may be differentially expressed and regulated in AgP patients as compared with CP patients and healthy individuals. PMID- 29766411 TI - Gastrointestinal Stromal Tumors Risk of Recurrence Stratification by Tumor Volume is a Best Predictor Compared with Risk Based on Mitosis and Tumor Size. AB - PURPOSE: Gastrointestinal stromal tumors (GIST) have the potential to recur and metastasize. Several prognostic schemes have been developed, mostly based on the mitotic count, diameter, and tumor site. However, these systems are not precise enough. The research question was whether the tumor size determined by volumetry allows a better risk stratification than the traditional system, and our aim was to determine the value of tumor volumetry, a feasible and simple parameter, in the recurrence of GIST. METHODS: Seventy-four cases of GIST were studied. The cases presented with non-metastatic disease, which were resected and did not receive imatinib. We compared the clinico-pathologic features of the cases with recurrence against those with non-recurrence and compared the tumor volumetry against the classification system based on tumor size and mitosis. RESULTS: The median age was 58 years (range: 25 to 91 years). Half of the cases were presented in the stomach. The tumor size had a median of 8 cm (range of 1-30 cm). The median mitosis count for 50 HPF was 4 (range 0-92). During the period of study, 16 (21.6%) patients suffered recurrence. The significant differences were that patients with recurrence accounted for more deaths and the follow-up period was larger. The area under the curve (AUC) of the volumetry classification was superior to the AUC of the classification system based on tumor size and mitosis (NIH-criteria) (p = .05). CONCLUSION: Tumor volumetry calculated in the surgical specimen and/or pre-operative tomography was superior to the NIH consensus in stratifying the risk of recurrence in GIST. PMID- 29766410 TI - Complete concentric collapse at the soft palate in sleep endoscopy: what change is possible after UPPP in patients with CPAP failure? AB - PURPOSE: The aim of this work was to assess whether uvulopalatopharyngoplasty in patients with failure for positive airway pressure not only reduces the degree of obstructive sleep apnea but also to determine as well if it changes the collapse pattern of the soft palate and thereby fulfills the qualifications for implementing upper airway stimulation (UAS) as an adjunctive solution. METHOD: Fifteen patients with intolerance for positive airway pressure were included in this retrospective cohort study. Polygraphy and drug-induced sleep endoscopy were used in order to evaluate the reduction of the apnea-hypopnea index (AHI), as well as the change of collapse pattern at the soft palate level before and about 3 months after uvulopalatopharyngoplasty and tonsillectomy (TE-UPPP). RESULTS: In 93% of the patients, a postoperative change of the initially complete concentric palatal collapse pattern could be found during drug-induced sleep endoscopy. In one patient, no obstruction at all was seen at the soft palatal level. Only one patient still presented with a complete concentric collapse at velum level. AHI decreased from mean 34.7 events per hour to 20.2/h and oxygen desaturation index from 25.3 events per hour to 16.1/h. CONCLUSION: Patients seeking for positive airway pressure alternatives could not only benefit from reduction of AHI by TE UPPP postoperatively; additionally, by changing the collapse pattern at the soft palate, they might also fulfill criteria for upper airway stimulation (UAS) in case of persistent OSA of at least moderate degree. PMID- 29766412 TI - Cutaneous Large B Cell Lymphoma Involving the Duodenum and the Bile Duct: a Case Report. PMID- 29766413 TI - Dental plaque disclosure as an auxiliary method for infants' oral hygiene. AB - AIM: This was to evaluate the effectiveness of plaque disclosure as an auxiliary method for early childhoods' oral hygiene. METHODS: The study was performed with 20 mothers and their children (aged 6-36 months), members of a preventive programme, which two groups used one of two approaches: conventional oral hygiene/group I (tooth brushing) and plaque disclosure with subsequent oral hygiene/group II (tooth brushing with prior plaque disclosure). Ten mothers started the study in group I and the other 10 in group II, after one month interval they changed to be in the alternate group. Each group consisted of baseline and three additional visits at weekly intervals. The effectiveness of oral hygiene was assessed in a blind fashion by plaque quantity estimation, using the Green Vermilion index for smooth surfaces and the plaque thickness index for occlusal surfaces. Statistical comparisons were performed using repeated measures ANOVA/Fisher's post hoc test and paired t-test (p < 0.05). RESULTS: For smooth and occlusal surfaces at first and second visits, group II recorded significantly lower plaque indices when compared with group I. Additionally, when considering the mean dental plaque index of all visits, group II also presented lower plaque scores than group I. CONCLUSION: Dental plaque disclosure before toothbrushing helps mothers to enhance the effectiveness of early childhood oral hygiene. REGISTRATION NUMBER AND NAME OF TRIAL REGISTRY: RBR-7fyc7g; Avaliacao do Treinamento e de Metodos Auxiliares na Efetividade da Escovacao Dentaria Materna em Bebes. Where the full trial protocol can be accessed: http://www.ensaiosclinicos.gov . PMID- 29766414 TI - Oral health and oral health risk behaviour in children with and without externalising behaviour problems. AB - AIM: This was to study children with early detected externalising behaviour problems compared to matched controls regarding oral health, oral health risk behaviour and the parental evaluation of the child's oral health and dental care. METHODS: Children aged 10-13 years and with externalising behaviour problems, were compared to matched controls. Behavioural characteristics were based on the Strength and Difficulties Questionnaire. The children and their parents completed questionnaires regarding dental fear, tooth brushing, dietary habits and evaluation of oral health and dental care. Data on dental caries risk assessments, caries, behaviour management problems and dental trauma were obtained from dental files. RESULTS: There were no differences in caries prevalence in children with early detected externalising behaviour problems, compared to controls. However, the former group consumed more sweet drinks when thirsty and brushed their teeth fewer than twice daily; they also had more dental trauma in both dentitions and a higher risk range for dental fear, compared to controls. CONCLUSIONS: This study points out potential oral health risk factors in children with early-detected externalising behaviour problems. Although no difference in caries prevalence was observed, externalising behaviour may affect oral health. Therefore, dental professionals should support the families and the children to preserve dental health by offering increased prophylactic measures. There were no differences between children with externalising behaviour problems, compared with controls, regarding the parent evaluation of their child's dental health. However, more parents in the study group evaluated the dental care as poor or not functioning. PMID- 29766415 TI - Reliability and validity of a newly proposed classification system for categorisation of parental behaviour (CCPB) in the dental setting. AB - AIM: To evaluate the reliability and validity of a newly proposed classification system for categorisation of parental behaviour (CCPB) in the dental setting. METHODS: Parents of patients aged 5-14 years were included. 127 parents were evaluated and rated on two scales: Parental Cooperation Scale (PCS; 1-4) and CCPB (0-5) by two trained examiners during the initial interaction of the parent with the examiners at their first visit in the dental setting. Kappa Score measurement of agreement was used to assess the inter-rater reliability. Spearman's rho correlation was used to assess the correlations between PCS and CCPB. RESULTS: The Kappa score between independent raters was 0.774 (substantial agreement) and Spearman's rho correlation coefficient was 0.778, which was statistically significant (p < 0.001). CONCLUSIONS: The CCPB refers to the same domain as the PCS and was found to be a reliable tool to be used in future research. PMID- 29766416 TI - IgG4-Associated Adrenalis-a Case Report. AB - A 67-year-old man was adrenalectomized due to a tumor measuring 100 mm. Specimens revealed an inflammation with slight fibrosis and moderate infiltrates of lymphocytes and plasmacytes with immunoreactivity for IgG and IgG4 resulting in the diagnosis of an active IgG4-associated adrenalitis. To our knowledge, this is the first reported active adrenalitis of this type. It should be the precursor lesion of the adrenal calcifying fibrous tumor that was reported once before. PMID- 29766417 TI - The FTO Gene Is Associated with Growth and Omega-3/-6 Ratio in Asian Seabass. AB - Polymorphisms in the FTO gene are associated with obesity and body mass index in humans and livestock. Little information of whether FTO plays an important role in aquaculture fish species is available. We cloned and characterized the FTO gene in an economically important food fish species: Asian seabass (Lates calcarifer). The full-length cDNA of the gene is 3679 bp, containing an ORF of 1935 bp encoding 644 amino acids, a 216 bp 5' UTR and a 1538 bp 3' UTR. The gene consisted of nine exons and eight introns and was 117,679 bp in length. Phylogenetic analysis revealed that the gene in Asian seabass was closely related to those of Japanese flounder and Nile tilapia. Analysis of its expressions using qRT-PCR showed that it was expressed ubiquitously, but was higher in the liver, stomach and intestine. Comparative analysis of the genomic sequences of part of intron 1 of the gene among 10 unrelated individuals identified two SNPs. Analysis of associations between SNPs and traits (i.e. growth, oil content, omega-3 and -6 contents) in an F2 family demonstrated that the two SNPs were significantly associated with growth, oil content, omega-3 content and omega-3/-6 ratio. Altogether, our data suggest that the gene or/and its linked genes play an important role in growth and fatty acid synthesis, and that the SNPs associated with traits may be used as markers for selecting quicker growth and higher omega 3/-6 ratio at the fingerling stage. PMID- 29766418 TI - Partitioning of particulate matter and elements of suburban continental aerosols between fine and coarse modes. AB - The results presented in this work demonstrate for the first time a distribution of elements in the spectral analysis of aerosols in the suburban continental Balkan Peninsula. Samples were collected in the suburban area of Belgrade (Serbia) in the period from March 2012 till December 2013. Results presented here are from long-term measurements of masses of size-segregated aerosols and macro- and microelements in the range of PM0.27-16. The following elements were analyzed: Al, Ag, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Mo, Na, Ni, Pb, Sb, Ti, Tl, V, and Zn; levels of Be, Hg, and Se were under the detection limits in all samples. Average concentrations and time and seasonal variations of particulate matter (PM) as well as element contents and their percentage shares are given. The results showed the domination of particle content around the accumulation mode in the range of 0.53 < Dp < 1.06 MUm, but the fractional distribution of elements showed maximal average concentrations in different fractions depending on the origin of each element. Crustal elements (Al, Ca, Fe, Mg, Mn, Ti, etc.) dominated in coarse mode, while anthropogenic elements (As, Cd, Cu, Pb, Sb, etc.) were mainly distributed in fine mode fractions. Some elements, such are As and Ni, were detected in investigated aerosols only occasionally, while others, such as Ca, Fe, and Mg, were detected in all analyzed samples. The application of multivariate analysis (PCA) demonstrated the connection between the elements of similar origin, in fine fractions mainly of anthropogenic origin, while in coarse mode of crustal origin, indicating the resuspension with contribution of about 40%. The contents of some measured elements were compared with their contents in aerosols in some European suburban areas. PMID- 29766419 TI - Biomonitoring of chlorpyrifos exposure and health risk assessment among applicators on rice farms in Ghana. AB - Chlorpyrifos is a neurotoxic insecticide that is widely used in the agricultural sector of Ghana. The main objective of this study was to evaluate the levels of chlorpyrifos exposure and health risk among applicators (n = 21) on irrigated rice farms in Ghana, based on a typical application event. Pre- and post application urine samples (24-h) were collected from the applicators and analysed for 3,5,6-trichloro-2-pyridinol (TCP), using LC-MS/MS. The levels of chlorpyrifos absorbed dose with the applicators were estimated from the urinary TCP levels. Prior to application, the median absorbed dose of chlorpyrifos (background exposure) with the applicators was 0.2 MUg/kg/day (range 0.05 to 2 MUg/kg/day). Following application, the median absorbed dose of chlorpyrifos (application exposure) increased 30-fold to 6 MUg/kg/day (range 0.7 to 74 MUg/kg/day). The mean elimination half-life (t1/2) of chlorpyrifos was calculated to be 50 h. Hazard quotient (HQ) values (HQ > 1) obtained with the chronic (10 MUg/kg/day) and acute (100 MUg/kg/day) guideline values of the WHO suggested no risk of chronic or acute health effects, respectively, among both the median and 5% highly exposed groups. However, HQ values (HQ > 1) obtained with the chronic (0.3 MUg/kg/day) and acute (5 MUg/kg/day) guideline values of the USEPA suggested risk of chronic and acute health effects, respectively, among both the median and 5% highly exposed groups. The quantity of chlorpyrifos formulation applied, spraying duration, and the number of spray tanks applied significantly correlated with the absorbed dose levels of chlorpyrifos from application exposure. Therefore, these factors suggest means to reduce exposure and consequent health risk among the applicators. PMID- 29766420 TI - Exploring innovative techniques for identifying geochemical elements as fingerprints of sediment sources in an agricultural catchment of Argentina affected by soil erosion. AB - Identification of hot spots of land degradation is strongly related with the selection of soil tracers for sediment pathways. This research proposes the complementary and integrated application of two analytical techniques to select the most suitable fingerprint tracers for identifying the main sources of sediments in an agricultural catchment located in Central Argentina with erosive loess soils. Diffuse reflectance Fourier transformed in the mid-infrared range (DRIFT-MIR) spectroscopy and energy-dispersive X-ray fluorescence (EDXRF) were used for a suitable fingerprint selection. For using DRIFT-MIR spectroscopy as fingerprinting technique, calibration through quantitative parameters is needed to link and correlate DRIFT-MIR spectra with soil tracers. EDXRF was used in this context for determining the concentrations of geochemical elements in soil samples. The selected tracers were confirmed using two artificial mixtures composed of known proportions of soil collected in different sites with distinctive soil uses. These fingerprint elements were used as parameters to build a predictive model with the whole set of DRIFT-MIR spectra. Fingerprint elements such as phosphorus, iron, calcium, barium, and titanium were identified for obtaining a suitable reconstruction of the source proportions in the artificial mixtures. Mid-infrared spectra produced successful prediction models (R2 = 0.91) for Fe content and moderate useful prediction (R2 = 0.72) for Ti content. For Ca, P, and Ba, the R2 were 0.44, 0.58, and 0.59 respectively. PMID- 29766421 TI - Ecological efficiency in China and its influencing factors-a super-efficient SBM metafrontier-Malmquist-Tobit model study. AB - Ecological problem is one of the core issues that restrain China's economic development at present, and it is urgently needed to be solved properly and effectively. Based on panel data from 30 regions, this paper uses a super efficiency slack-based measure (SBM) model that introduces the undesirable output to calculate the ecological efficiency, and then uses traditional and metafrontier-Malmquist index method to study regional change trends and technology gap ratios (TGRs). Finally, the Tobit regression and principal component analysis methods are used to analysis the main factors affecting eco efficiency and impact degree. The results show that about 60% of China's provinces have effective eco-efficiency, and the overall ecological efficiency of China is at the superior middling level, but there is a serious imbalance among different provinces and regions. Ecological efficiency has an obvious spatial cluster effect. There are differences among regional TGR values. Most regions show a downward trend and the phenomenon of focusing on economic development at the expense of ecological protection still exists. Expansion of opening to the outside, increases in R&D spending, and improvement of population urbanization rate have positive effects on eco-efficiency. Blind economic expansion, increases of industrial structure, and proportion of energy consumption have negative effects on eco-efficiency. PMID- 29766399 TI - Consensus guidelines for the use and interpretation of angiogenesis assays. AB - The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference. PMID- 29766422 TI - Migration and leaching characteristics of base cation: indicating environmental effects on soil alkalinity in a karst area. AB - In karst areas, rock dissolution often results in the development of underground networks, which act as subterranean pathways for rapid water and nutrient (and possibly soil) loss during precipitation events. Loss of soluble nutrients degrades surface soils and decreases net primary productivity, so it is important to establish flow pathways and quantify nutrient loss during rainfall events of different magnitudes. We conducted a simulated rainfall experiment in karst and nonkarst areas to compare the concentration of nutrients in surface and subsurface flow water and effects on soil alkalinity in three lithologic soil formations under five different rainfall intensity treatments. Compared with the nonkarst area, the runoff in subsurface flows and the proportion of nutrient loss in the subsurface flow are larger in the karst area and less affected by rain intensity. The maximum loss loads of calcium (Ca2+) and magnesium (Mg2+) ions were 32.9 and 19.8 kg ha-1, respectively. With the estimate of base cation loss loads in the China southern karst area under the rainfall intensity of 45 mm h-1, more than 80% of the base cation loss load occurred in the limestone karst area. Although the alkalinity leaching value in nonkarst was similar to that in the karst area under simulated rainfall conditions, its impact on the ecological environment was quite different. PMID- 29766425 TI - Distribution of linear alkylbenzenes as a domestic sewage molecular marker in surface sediments of International Anzali Wetland in the southwest of the Caspian Sea, Iran. AB - Due to directly receiving high volume of untreated urban and industrial sewage and in turn transferring the pollutants to fish and back to humans, the International Anzali Wetland has been considered to be urgently registered in the Montreux Record. Hence, the present study was aimed to determine the spatial distribution of the linear alkylbenzenes (LABs) in surface sediments of the wetland and its sewage contamination situation. The surface sediments (sampling stations = 167) were collected from the western, eastern, southwest, and central regions of the wetland. The samples were extracted, fractioned, and then analyzed using gas chromatography-mass spectrometry (GC-MS). The concentration of LABs in the sediment samples revealed a range from 394.12 to 109,305.26 ng g-1 dw. The concentrations of SigmaLABs in the eastern region were significantly higher than that in the other regions. The occurrence of low ratio of internal to external isomers (I/E ratio) of LABs (from 0.65 to 1.30) and D% (from - 0.07 to 24.13) implied effluent row or poorly untreated sewage into the wetland. No correlation was observed between the detected LAB concentrations with total organic carbon (TOC) and grain size. Taken together, regional anthropogenic inputs are the controlling factors for the observed spatial distributions of ?LABs in the International Anzali Wetland. The findings suggested that LABs are powerful indicators to trace anthropogenic sewage contamination and also highlighted the necessity of sewage treatment plants to be founded around the International Anzali Wetland, especially in the vicinity of the eastern and central regions. PMID- 29766423 TI - Solid-liquid separation: an emerging issue in heavy metal wastewater treatment. AB - Solid-liquid separation (SLS) plays a dominant role in various chemical industries. Nowadays, low efficiency of SLS also become a significant problem in heavy metal (HM) wastewater treatment, affecting the effluent quality (HM concentration and turbidity) and overall process economy. In this context, we summarize here the occurrence of solids in HM wastewater, as well as typical SLS operations used in HM wastewater treatment, including sedimentation, flotation, and centrifugation. More important, this article reviews the improvement of the SLS operations by some technologies, including coagulation, flocculation, ballasted method, seeding method, granular sludge strategy, and external field enhancement. It is noted that abiological granular sludge strategy and magnetic field enhancement often possess higher SLS efficiency (faster settling velocity or shorter separation time) than other methods. Hence, the two strategies stand out as promising tools for improving SLS in HM wastewater treatment, but further research is required regarding scalability, economy, and reliability. PMID- 29766424 TI - Effect of titanium dioxide nanoparticles on the accumulation and distribution of arsenate in Daphnia magna in the presence of an algal food. AB - The impact of titanium dioxide nanoparticles (nano-TiO2) on the bioavailability of metals in aquatic filter-feeding organisms has rarely been investigated, especially in the presence of algae as a food source. In this study, we quantified the accumulation and subcellular distribution of arsenate (AsV) in Daphnia magna in the presence of nano-TiO2 and a green alga (Scenedesmus obliquus) food source. Results showed that S. obliquus significantly increased the accumulation of total arsenic (As) and titanium (Ti) in D. magna. The presence of this food source increased As in metal-sensitive fractions (MSF) and as biologically detoxified metals (BDM), while it decreased Ti levels in MSF but increased levels as BDM. The difference in the subcellular distribution of As and Ti demonstrates the dissociation of As from nano-TiO2 during digestion at subcellular partitioning irrespective of food availability. In turn, the presence of algae was shown to increase metal-based toxicity in D. magna due to the transfer of As from BMD to MSF. Furthermore, S. obliquus significantly increased the concentration of As and Ti in soluble fractions, indicating that As and nano TiO2 ingested by D. magna could be transferred more readily to their predators in the presence of S. obliquus. Our study shows the potential of algae to increase the toxicity and biomagnification of As V . Furthermore, it highlights food as an important factor in the toxicity assessment of nanomaterials and co-existing pollutants. PMID- 29766426 TI - Seasonal variations and relationships between environmental parameters and heavy metal concentrations in tissues of Crassostrea species and in its ambience from the tropical estuaries. AB - This study aimed to evaluate the relationship between physicochemical parameters and heavy metal (Cu, Ni, Pb, and Cd) concentrations from sediment, seawater, and its accumulation in tissues of oyster species (Crassostrea madrasensis and C. gryphoides) from the three sites (Chicalim Bay (CB), Nerul Creek (NC), Chapora Bay (ChB)) along the Goa coast (India). Results showed enrichment of Cu and Ni in sediment exceeding the effect range low (ERL) level. The higher concentrations of Cu and Ni in sediments and in suspended particulate matter (SPM) from all the study sites are indicative of severe contamination of estuarine and associated habitats. Moreover, particulate Ni (at all the sites), Cu (at NC and ChB), Pb (at NC), and Cd (at CB and NC) concentrations were recorded more than its total loadings in surface sediment. Concentration of Cu and Cd in oyster tissue was several folds higher than its concentration in ambience. Further, this study showed that the levels of metal in oysters and their ambient environment were higher during the monsoon season. Hence, the consumption of oysters needs to be considered carefully with respect to the health hazards posed by the elevated levels of metal contaminants in certain seasons. The present study concludes that metals associated with the particulate matter in water column are the main source of metal accumulation in oyster. It is also suggested that concentration of metal pollutants in coastal and estuarine water bodies should be monitored regularly to ensure the acceptable limits of metal concentrations. PMID- 29766427 TI - An improved export coefficient model to estimate non-point source phosphorus pollution risks under complex precipitation and terrain conditions. AB - To control non-point source (NPS) pollution, it is important to estimate NPS pollution exports and identify sources of pollution. Precipitation and terrain have large impacts on the export and transport of NPS pollutants. We established an improved export coefficient model (IECM) to estimate the amount of agricultural and rural NPS total phosphorus (TP) exported from the Luanhe River Basin (LRB) in northern China. The TP concentrations of rivers from 35 selected catchments in the LRB were used to test the model's explanation capacity and accuracy. The simulation results showed that, in 2013, the average TP export was 57.20 t at the catchment scale. The mean TP export intensity in the LRB was 289.40 kg/km2, which was much higher than those of other basins in China. In the LRB topographic regions, the TP export intensity was the highest in the south Yanshan Mountains and was followed by the plain area, the north Yanshan Mountains, and the Bashang Plateau. Among the three pollution categories, the contribution ratios to TP export were, from high to low, the rural population (59.44%), livestock husbandry (22.24%), and land-use types (18.32%). Among all ten pollution sources, the contribution ratios from the rural population (59.44%), pigs (14.40%), and arable land (10.52%) ranked as the top three sources. This study provides information that decision makers and planners can use to develop sustainable measures for the prevention and control of NPS pollution in semi-arid regions. PMID- 29766428 TI - Modeling and multi-objective optimization for ANAMMOX process under COD disturbance using hybrid intelligent algorithm. AB - Anaerobic ammonium oxidation (ANAMMOX) has been regarded as an efficient process to treat nitrogen-containing wastewater. However, the treatment process is not fully understood in terms of reaction mechanisms, process simulation, and control. In this paper, a multi-objective control strategy mixed soft-sensing model (MCSSM) is developed to systematically design the operating variations for multi-objective control by integrating the developed model, a least square support vector machine optimized with principal component analysis (PCA-LSSVM) and non-dominated sorting genetic algorithm-II (NSGA-II). The results revealed that the PCA-LSSVM model is a feasible and efficient tool for predicting the effluent ammonia nitrogen concentration ([Formula: see text]) and the total nitrogen removal concentration (C TN, rem ) with determination coefficients (R2) were 0.997 for [Formula: see text] and 0.989 for C TN, rem , and gives us the reasonable solutions in influent by using NSGA-II. To achieve a better removal effect, the influent pH should be kept between 7.50 and 7.52, the COD/TN ratio is suggested to maintain at 0.15 and the NH4+-N/NO2--N ratio is suggested to maintain at 0.61. The developed MCSSM approach and its general modeling framework have a high potential of applicability and guidance to bioprocess in wastewater treatment, and numerical models can be structured for predicting and optimization and experiments can be conducted for data acquisition and model establishment. PMID- 29766430 TI - Solid waste management of small island developing states-the case of the Seychelles: a systemic and collaborative study of Swiss and Seychellois students to support policy. AB - Solid waste management (SWM) is a significant challenge for the Seychelles. Waste generation, fueled by economic development and tourism, increases steadily, while landfilling continues to be the main disposal path, thus exacerbating the island nation's specific weaknesses. Due to the small scale of the Seychelles economy, there is little capital available to stimulate innovations in SWM and generate the knowledge for setting priorities and guiding SWM action. Students from ETH Zurich and UniSey conducted a transdisciplinary case study (tdCS) to fill this knowledge gap and gain insights into the obstacles and opportunities related to sustainable SWM. The tdCS approach allowed students to gain comprehensive and in depth knowledge about the SWM system required to set priorities for action and next steps. The government should streamline the different financial frameworks according to a clear principle (e.g., polluter pays principle). Specific biogenic waste streams represent a potential source of energy and fertilizers. Expanding the scope and densifying the network of collection points could help raise recycling rates of other waste fractions. Diverting biogenic waste and recycling more glass, metals, paper, and plastics would also significantly reduce landfilling rates. Regardless of future amounts of waste ending up on landfills, the latter must be reengineered before the surrounding environment suffers major adverse impacts. All these actions imply a government-driven approach which integrates the views of stakeholders and consumers alike. PMID- 29766429 TI - Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. AB - Cyclophosphamide (CP) is a common chemotherapeutic agent that is effective against a wide variety of tumors. The associated hepatotoxicity and nephrotoxicity, however, limit its therapeutic use. Naringin (NG) is a natural flavanone glycoside that has pharmacological and therapeutic activities, such as anti-inflammation, anti-apoptotic, and antioxidant properties. Therefore, the present study was undertaken to evaluate the protective effect of NG against CP induced hepatotoxicity and nephrotoxicity in rats. Rats were pre-treated with NG (50 and 100 mg/kg b.w.) for 7 days before administering a single dose of CP (200 mg/kg b.w.) on the seventh day. CP-induced hepatotoxicity and nephrotoxicity were associated with an increase in serum toxicity markers and a decrease in antioxidant enzyme activities. CP also induced inflammatory responses by increasing the levels of tumor necrosis factor-alpha (TNF-alpha), nuclear factor kappa B (NF-kappaB), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta), and activities of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX 2). Moreover, it activated the apoptotic and autophagic pathway by increasing cysteine aspartate-specific protease-3 (caspase-3) expression and light chain 3B (LC3B) level and also increased the expression of 8-hydroxy-2'-deoxyguanosine (8 OHdG), which is the marker of oxidative DNA damage. Pre-treatment with NG (50 and 100 mg/kg), however, significantly decreased serum toxicity markers, increased antioxidant enzyme activities, and regulated inflammation, apoptosis, autophagy, and oxidative DNA damage in hepatic and renal tissues. These results indicated that NG was an effective protectant against CP-induced hepatotoxicity and nephrotoxicity. PMID- 29766431 TI - The indoor-outdoor characteristics of water-soluble ion in PM2.5 in Tianjin wintertime. AB - The indoor and outdoor PM2.5 mass concentration, water-soluble ion by filter sampler was analyzed on December 3-21, 2015 during wintertime in Tianjin, China. The results indicate that high humidity conditions result in the accumulation of atmospheric pollutants and reduce atmosphere visibility. The I/O ratio for PM2.5 concentration in dormitory and lab are less than 1 in haze days. Indoor PM2.5 concentration increases rapidly with outdoor PM2.5 concentration increasing in haze days. The filtration factors of the dormitory and lab indicate nearly half of the outdoor PM2.5 enters indoor environment. The human activities in dormitory could cause more the formation of PM2.5 than those in lab. The concentration of SO42- is the highest ion in water-soluble ion for outdoor PM2.5. The SO42-, NO3-, NH4+, and Cl- are generated mainly by outdoor sources; however, the Na+, Ca2+, and Mg2+ are generated mainly by indoor sources. The NH4NO3, (NH4)2SO4, and NH4Cl accounts for 20.2~41.8%, 32.0~51.4%, and 6.4~10.6% of the total water-soluble ion in different indoor-outdoor environment. The total secondary aerosols including NH4NO3, (NH4)2SO4, and NH4Cl in PM2.5 are 28.3, 42.1, 28.2, 31.0, and 33.9% in outdoor environment for haze days, outdoor environment for non-haze days, dormitory for haze days, dormitory for non-haze days, and lab for haze days, respectively. PMID- 29766432 TI - Cl-initiated photo-oxidation reactions of methyl propionate in atmospheric condition. AB - Cl-initiated photo-oxidation reaction of methyl propionate was investigated experimentally using relative rate method. Gas chromatography/mass spectrometry (GC-MS) and GC/infrared spectroscopy (GC-IR) were used as analytical tools to follow the concentrations of reactants and products during reaction. The gas phase kinetics of methyl propionate with Cl atoms was measured over the temperature range of 263-363 K at 760 Torr in N2 atmosphere using C2H6 and C2H4 as reference compounds. The temperature-dependent rate coefficient for the reaction of methyl propionate with Cl atom was obtained as k(T) = [(3.25 +/- 1.23) * 10-16] T2 exp [- (33 +/- 4) / T] cm3 molecule-1 s-1. Theoretical calculations were also performed at CCSD(T)/cc-pVDZ//B3LYP/6-31G(d,p) level of theory, and the rate coefficients for H abstraction reactions were evaluated using canonical variational transition state theory (CVT/SCT) with interpolated single point energy (ISPE) method over the temperature range of 200-400 K. The rate coefficients over the studied temperature range yielded the Arrhenius expression k(T) = (7.22 * 10-16) T1.5 exp (466 / T) cm3 molecule-1 s-1. The reaction mechanism based on product analysis, thermochemistry, branching ratios, atmospheric implications, degradation pathways, and cumulative lifetime of methyl propionate is also presented in this manuscript. Graphical abstract ?. PMID- 29766436 TI - Effects of fouling on separation performance by forward osmosis: the role of specific organic foulants. AB - In this study, forward osmosis (FO) membranes and fouling solutions were systematically characterized to elucidate the effects of organic fouling on the rejection of two pharmaceutically active compounds, namely, sulfamethoxazole and carbamazepine. Municipal wastewater resulted in a more severe flux decline compared to humic acid and sodium alginate fouling solutions. This result is consistent with the molecular weight distribution of these foulant solutions. Liquid chromatography with organic carbon detection analysis shows that municipal wastewater consists of mostly low molecular weight acids and neutrals, which produce a more compact cake layer on the membrane surface. By contrast, humic acid and sodium alginate consist of large molecular weight humic substances and biopolymers, respectively. The results also show that membrane fouling can significantly alter the membrane surface charge and hydrophobicity as well as the reverse salt flux. In particular, the reverse salt flux of a fouled membrane was significantly higher than that under clean conditions. Although the rejection of sulfamethoxazole and carbamazepine by FO membrane was high, a discernible impact of fouling on their rejection could still be observed. The results show that size exclusion is a major rejection mechanism of both sulfamethoxazole and carbamazepine. However, they respond to membrane fouling differently. Membrane fouling results in an increase in sulfamethoxazole rejection while carbamazepine rejection decreases due to membrane fouling. PMID- 29766435 TI - Adsorption performance and mechanism of magnetic reduced graphene oxide in glyphosate contaminated water. AB - In this study, the magnetic reduced graphene oxide (RGO/Fe3O4), with easy separation and high adsorption performance, was prepared and used to treat glyphosate (GLY) contaminated water. GLY adsorption performance of RGO/Fe3O4 was investigated, and influences of pH, adsorption time, temperature, contaminant concentration, and competing anions were analyzed. Moreover, the adsorption mechanism was discussed in the light of several characterization methods, including scanning electron microscopy (SEM), energy dispersive spectrum (EDS), Fourier-transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS). The results demonstrated that the RGO/Fe3O4 presented a significant GLY adsorption capacity and acid condition was beneficial for this adsorption. The pseudo-second-order kinetic model and the Langmuir model correlated satisfactorily to the experimental data, indicating that this process was controlled by chemical adsorption and monolayer adsorption. Thermodynamic studies revealed that the adsorption of glyphosate onto RGO/Fe3O4 was spontaneous, endothermic, and feasible process. High temperatures were beneficial to GLY adsorption. The GLY adsorption mechanism of RGO/Fe3O4 was mainly attributed to hydrogen-bond interaction, electrostatic interaction, and coordination. Therefore, the RGO/Fe3O4 investigated in this research may offer an attractive adsorbent candidate for treatment of glyphosate contaminated water and warrant further study as a mechanism for glyphosate efficient removal. PMID- 29766434 TI - Comparative study on adsorption of crude oil and spent engine oil from seawater and freshwater using algal biomass. AB - Efficiency of a biosorbent prepared from the green macroalga Enteromorpha intestinalis biomass for decontamination of seawater and freshwater polluted by crude oil and engine spent oil was compared. The effect of different experimental conditions including contact time, pH, particle size, initial oil concentration, and biosorbent dose on the oil biosorption was studied in the batch method. The biosorbent was characterized by CHNOS, FTIR, and SEM analysis. The experimental data were well fitted to the pseudo-second-order kinetic model and the Langmuir adsorption isotherm model. Based on the obtained results, the adsorption of spent oil with higher viscosity was better than crude oil. The biosorption of oil hydrocarbons from seawater was more efficient than freshwater. The algal biomasses which are abundantly available could be effectively used as a low-cost and environmentally friendly adsorbent for remediation of oil spill in the marine environments or in the water and wastewater treatment. PMID- 29766433 TI - The role of heat shock protein 70 in oxidant stress and inflammatory injury in quail spleen induced by cold stress. AB - The aim of this study was to investigate the role of heat shock protein 70 (Hsp70) in oxidative stress and inflammatory damage in the spleen of quails which were induced by cold stress. One hundred ninety-two 15-day-old male quails were randomly divided into 12 groups and kept at 12 +/- 1 degrees C to examine acute and chronic cold stress. We first detected the changes in activities of antioxidant enzymes in the spleen tissue under acute and chronic cold stress. The activities of glutathione peroxidase (GSH-Px) fluctuated in acute cold stress groups, while they were significantly decreased (p < 0.05) after chronic cold stress. The activities of superoxide dismutase (SOD), inducible nitric oxide synthase (iNOS), and nitric oxide (NO) content were decreased significantly (p < 0.05) in both of the acute and chronic cold stress groups. Malondialdehyde (MDA) content was significantly increased (p < 0.05) under cold stress except the 0.5 h group of acute cold stress. Besides, histopathological analysis showed that quail's spleen tissue was inflammatory injured seriously in both the acute and chronic cold stress groups. Additionally, the inflammatory factors (cyclooxygenase-2 (COX-2), prostaglandin E synthase (PTGES), iNOS, nuclear factor kappa B (NF-kappaB), and tumor necrosis factor-a (TNF-alpha)) and Hsp70 mRNA levels were increased in both of the acute and chronic cold stress groups compared with the control groups. These results suggest that oxidative stress and inflammatory injury could be induced by cold stress in spleen tissues of quails. Furthermore, the increased expression of Hsp70 may play a role in protecting the spleen against oxidative stress and inflammatory damage caused by cold stress. PMID- 29766437 TI - Serum phosphate levels are related to all-cause, cardiovascular and COPD mortality in men. AB - Hyperphosphatemia has been associated with increased mortality in chronic kidney disease but the nature of such a relation in the general population is unclear. To investigate the association between phosphate (P) levels and all-cause and cause-specific mortality, we assessed two cohorts from the Rotterdam Study, with follow-up of 14.5 (RS-I) and 10.9 (RS-II) years until January 2012 with availability of fasting phosphate levels. Deaths were classified according to International Classification of Diseases into 7 groups: cardiovascular, cancer, infections, external, dementia, chronic lung diseases and other causes. Sex stratified Weibull and competing-risks models were adjusted for age, BMI and smoking. Hazard ratios are expressed per 1 mg/dL increase in phosphate levels. The total number of participants included 3731 (RS-I, 2154 women) and 2494 (RS II, 1361 women) subjects. The main outcome measures were all-cause and cause specific mortality. A significant positive association was found between phosphate and all-cause mortality in men (pooled HR (95% CI): 1.46 (1.26-1.69)) but not in women (0.90 (0.77-1.05)). In men, higher phosphate increased the risk for cardiovascular mortality (1.66 (1.29-2.14)), other causes (1.67 (1.16-2.40)) and chronic lung disease mortality (1.94 (1.02-3.72)), the latter driven by mortality due to chronic obstructive pulmonary disease (COPD) (4.44 (2.08-9.49)). No relations were found for mortality due to infections, cancer, dementia or external causes. In conclusion, serum P is associated with increased all-cause, cardiovascular and COPD mortality in men but not women. The association with COPD mortality is novel and needs further research on underlying mechanisms. PMID- 29766438 TI - Sexual orientation differences in outpatient psychiatric treatment and antidepressant usage: evidence from a population-based study of siblings. AB - In the past two decades, population-based health surveys have begun including measures of sexual orientation, permitting estimates of sexual orientation disparities in psychiatric morbidity and differences in treatment utilization. The present study takes advantage of the high-quality, comprehensive nationwide health registry data available in Sweden to examine whether psychiatric outpatient treatment for various diagnoses and antidepressant medication usage are greater in sexual minority individuals compared to their siblings. A longitudinal cohort study design was used with a representative random population based sample in Stockholm, Sweden. Registry-based health record data on all specialized outpatient health care visits and prescription drug use was linked to a sample of 1154 sexual minority individuals from the Stockholm Public Health Cohort and their siblings. The main outcomes were treatment due to psychiatric diagnoses retrieved from nationwide registry-based health records. In analyses accounting for dependency between siblings, gay men/lesbians had a greater likelihood of being treated for mood disorder [adjusted odds ratio (AOR) 1.77; 99% confidence intervals (CI) 1.00, 3.16] and being prescribed antidepressants (AOR 1.51; 99% CI 1.10, 2.07) compared to their siblings. Further, bisexual individuals had a greater likelihood of any outpatient psychiatric treatment (AOR 1.69; 99% CI 1.17, 2.45) and being prescribed antidepressants (AOR 1.48; 99% CI 1.07, 2.05) as well as a greater likelihood of being treated for a mood disorder (AOR 1.98; 99% CI 1.33, 2.95) compared to their siblings. No difference in anxiety or substance use disorder treatment was found between any sexual minority subgroup and their siblings. The potential role of familial confounding in psychiatric disorder treatment was not supported for more than half of the outcomes that were examined. Results suggest that sexual minority individuals are significantly more likely to be treated for certain psychiatric disorders compared to their siblings. Future research is needed to understand mechanisms other than familial factors that might cause the substantial treatment differences based on sexual orientation reported here. PMID- 29766439 TI - Translation and cross-cultural adaptation of eight pediatric PROMIS(r) item banks into Spanish and German. AB - PURPOSE: The Patient-Reported Outcome Measurement Information System (PROMIS(r)) is a National Institutes of Health (NIH)-funded initiative to develop reliable, valid, and normed item banks to measure health. We describe the first large-scale translation and cross-cultural adaptation effort to German and Spanish of eight pediatric PROMIS item banks: Physical activity (PAC), subjective well-being (SWB), experiences of stress (EOS), and family relations (FAM). METHODS: We utilized methods outlined in the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) PRO Translation Task Force recommendations. Ten professional translators performed a translatability assessment and generated forward translations. Forward Translations were compared within a country and cross-culturally to identify problems and to produce a consensus-derived version, which was then back translated, evaluated, and revised where necessary. Reconciled versions were evaluated in cognitive interviews with 126 children before finalization. RESULTS: Eight resulting pediatric PROMIS(r) item banks were translated: Two PAC banks (22 total items), three SWB banks (125 total items), two EOS banks (45 total items), and one FAM bank (47 total items). Up to 92% of all items raised no or only minor translation difficulties, 0-5.6% were difficult to translate. Up to 20% item revisions were necessary to ensure conceptual equivalence and comprehensibility. Cognitive interviews indicated that 91-94% of the final items were appropriate for children (8-17 years). CONCLUSIONS: German and Spanish translations of eight PROMIS Pediatric item banks were created for clinical trials and routine pediatric health care. Initial translatability assessment and rigorous translation methodology helped to ensure conceptual equivalence and comprehensibility. Next steps include cross-cultural validation and adaptation studies. PMID- 29766440 TI - Health-related quality of life of maltreated children and adolescents who attended a service center in Brazil. AB - PURPOSE: This study's aim was to evaluate the health-related quality of life (HRQoL) and associated factors of maltreated children and adolescents. METHODS: This cross-sectional study consisted of individuals between 8 and 17 years of age who were victims of maltreatment. The KIDSCREEN-52 was used to measure their HRQoL. Socioeconomic and demographic data were collected, as well as information about the type of abuse, type of perpetrator, and psychological support adherence. The Kruskal-Wallis test was used to analyze the scores of the KIDSCREEN-52 by the independent variables. RESULTS: One hundred and thirteen victims answered the questionnaire. Girls and adolescents had a lower overall HRQoL score (p < 0.05). Children who suffered from sexual abuse had a lowest score on the moods and emotions dimension than children who suffered from physical abuse (p < 0.05). There was a lowest score on the autonomy dimension among the children who suffered maltreatment by an extrafamilial perpetrator than those who were victimized by an intrafamilial perpetrator (p < 0.05). A lower score on the psychological well-being was observed among the children who adhered to the psychological support program provided by the service compared to those who terminated the service before completion (p < 0.05). CONCLUSIONS: Adolescents and girls were associated with lower HRQoL scores. There was no association between the overall HRQoL score and the characteristics of the maltreatment; however, the type of abuse and the victim's relationship with the perpetrator were only related to some dimensions. These findings may assist maltreatment care providers in planning strategies to reduce the consequences that violence may cause. PMID- 29766441 TI - Metabolomic analysis and biochemical changes in the urine and serum of streptozotocin-induced normal- and obese-diabetic rats. AB - Diabetes mellitus (DM) is a chronic disease that can affect metabolism of glucose and other metabolites. In this study, the normal- and obese-diabetic rats were compared to understand the diabetes disorders of type 1 and 2 diabetes mellitus. This was done by evaluating their urine metabolites using proton nuclear magnetic resonance (1H NMR)-based metabolomics and comparing with controls at different time points, considering the induction periods of obesity and diabetes. The biochemical parameters of the serum were also investigated. The obese-diabetic model was developed by feeding the rats a high-fat diet and inducing diabetic conditions with a low dose of streptozotocin (STZ) (25 mg/kg bw). However, the normal rats were induced by a high dose of STZ (55 mg/kg bw). A partial least squares discriminant analysis (PLS-DA) model showed the biomarkers of both DM types compared to control. The synthesis and degradation of ketone bodies, tricarboxylic (TCA) cycles, and amino acid pathways were the ones most involved in the variation with the highest impact. The diabetic groups also exhibited a noticeable increase in the plasma glucose level and lipid profile disorders compared to the control. There was also an increase in the plasma cholesterol and low-density lipoprotein (LDL) levels and a decline in the high-density lipoprotein (HDL) of diabetic rats. The normal-diabetic rats exhibited the highest effect of all parameters compared to the obese-diabetic rats in the advancement of the DM period. This finding can build a platform to understand the metabolic and biochemical complications of both types of DM and can generate ideas for finding targeted drugs. PMID- 29766445 TI - Complete Appendiceal Intussusception Associated with Endometriosis. PMID- 29766444 TI - Toward a More Sensitive Endpoint for Assessing Postoperative Complications in Patients with Inflammatory Bowel Disease: a Comparison Between Comprehensive Complication Index (CCI) and Clavien-Dindo Classification (CDC). AB - BACKGROUND: The comprehensive complication index (CCI) is a novel approach to evaluate complications. However, application of the CCI in inflammatory bowel disease (IBD) population is scarce and the difference between the CCI and the Clavien-Dindo classification (CDC) remains unknown. The aim of this study was to compare the CCI to the conventional CDC by applying the CCI among the IBD patients. METHODS: The data of 426 IBD patients who underwent surgery between September 1, 2015 and August 31, 2017 were collected. Univariate and multivariate analyses were conducted to identify risk factors for postoperative complications. The efficacy of CCI and CDC was compared using correlation analysis and logistic regression. Cumulative sum control (CUSUM) models were applied to monitor the CCI continuously. RESULTS: Totally, 297 complications occurred in 144 (33.8%) patients. The rate of severe complications (CDC grade >= III) was 12.9% and the mean CCI was 9.8 +/- 15.5. Preoperative glucocorticoids usage and previous abdominal surgery were related to higher CCI value (p = 0.002, p = 0.006, respectively) but not related to higher incidence of severe complications (CDC grade >= III) (p = 0.117, p = 0.177, respectively). In patients with multiple complications, the CCI demonstrated a stronger correlation with hospital stay (rho = 0.604, p < 0.001) than CDC (rho = 0.508, p < 0.001). Higher CCI value (p < 0.001, OR 1.161, 95% CI 1.093-1.234) and the CDC grade (p < 0.001, OR 3.811, 95% CI 2.283-6.362) were risk factors for prolonged LOS. In the CUSUM-CCI model of IBD surgery, a gradual decrease was observed over time. CONCLUSIONS: The CCI and the CDC are both risk factors for prolonged postoperative LOS after surgery for IBD patients. The CCI is more strongly correlated with postoperative LOS than is the conventional CDC. The CUSUM-CCI model is effective in monitoring surgical quality. PMID- 29766447 TI - Optimizing radionuclide protocols: Dotting our I's and crossing our T's. PMID- 29766446 TI - Prognostic Significance of Post-Operative Morbidity Severity Score After Potentially Curative D2 Gastrectomy for Carcinoma. AB - BACKGROUND: Survival and relapse after gastric cancer surgery are largely attributed to tumor biology and surgical radicality; yet, other prognostic factors have been reported, including respiratory sepsis and anastomotic leakage, but not global morbidity severity score (MSS). The hypothesis tested was that MSS would be associated with both disease-free (DFS) and overall survival (OS). METHODS: Consecutive 373 patients undergoing potentially curative surgery for gastric adenocarcinoma between 2004 and 2016 in a UK cancer network were studied. Complications were defined prospectively as any deviation from a pre-determined post-operative course within 30 days of surgery and classified according to the Clavien-Dindo severity classification (CDSC). Primary outcome measures were DFS and OS. RESULTS: Post-operative complications were identified in 127 (34.0%) patients, which was associated with 9 (2.4%) post-operative deaths. Five-year DFS and OS were 35.9 and 38.5% for patients with a post-operative complication compared with 59.5 and 61.5% in controls (p < 0.001, p = 0.001, respectively). On multivariable DFS analysis, post-operative morbidity [hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.06-2.50, p = 0.026] was independently associated with poor survival. On multivariable OS analysis, post-operative morbidity HR 2.25 (95% CI 1.04-4.85, p = 0.039) and CDSC HR 1.76 (95% CI 1.35-2.29, p < 0.001) were independently associated with poor survival. These associations were also observed in patients with TNM stage I and II disease with morbidity HR 7.06 (95% CI 1.89-26.38, p = 0.004) and CDSC HR 2.93 (95% CI 1.89-4.55, p < 0.001) offering independent prognostic value. CONCLUSION: Post-operative CDSC was an important independent prognostic factor after potentially curative gastrectomy for carcinoma associated with both DFS and OS. Prehabilitation strategies to minimize complications are warranted. PMID- 29766443 TI - The Impact of MDCT and Endoscopic Transpapillary Mapping Biopsy to Predict Longitudinal Spread of Extrahepatic Cholangiocarcinoma. AB - BACKGROUNDS: We aimed to investigate the diagnostic accuracy of multidetector-row computed tomography (MDCT), mapping biopsy, and other imaging modalities to predict the longitudinal extension and depth of invasion of extrahepatic cholangiocarcinoma at possible surgical ductal margins. METHODS: Of 102 patients with surgical resection of extrahepatic cholangiocarcinoma between January 2010 and October 2015, 32 evaluated by multidetector-row computed tomography (MDCT) performed before biliary drainage and mapping biopsy were enrolled. Mapping biopsies were performed at 74 sites to determine the resection point of the bile duct (at 74 possible surgical ductal margins). Diagnostic accuracy was evaluated by histopathology. RESULTS: The diagnostic accuracy of MDCT for longitudinal cancer spread was 79.7%, that of biopsy was 73.0%, and combining the two modalities showed highest accuracy (83.8%). The depth of tumor invasion could be predicted by combination of the ductal wall thickness and contrast enhancement on MDCT, that is, at 11 of 13 sites (84.6%) with submucosal invasion, ductal wall thickness was > 2.5 mm with high contrast enhancement. CONCLUSIONS: MDCT demonstrated highest accuracy of diagnosing longitudinal extension at possible surgical ductal margins in patients with extrahepatic cholangiocarcinoma. The depth of tumor invasion could be predicted by ductal wall thickness and contrast enhancement of MDCT. PMID- 29766442 TI - Rate of Improvement of Pain and Function in Mid-Portion Achilles Tendinopathy with Loading Protocols: A Systematic Review and Longitudinal Meta-Analysis. AB - BACKGROUND: Mid-portion Achilles tendinopathy is prevalent within both the athletic and non-athletic populations and loading protocols for Achilles tendinopathy are effective over time, though the rate of symptom change throughout rehabilitation is unknown. OBJECTIVE: The objective of this study was to determine the rate of change in pain and function over time in patients while completing a loading protocol for mid-portion Achilles tendinopathy. METHODS: A systematic review and longitudinal meta-analysis was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The databases PubMed, CINAHL (Ovid) and CINAHL (EBSCO) were searched for articles published from inception until 31 July, 2017. Our search focused on clinical trials and cohort studies examining changes in pain and function when completing a loading protocol for mid-portion Achilles tendinopathy. The primary outcome measure assessing pain and function was the Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire. RESULTS: A total of 31 separate cohorts (24 studies) were eligible, with follow-up ranging from 2 weeks to 6 months. The data were pooled to create the mean (standard deviation) of change from baseline at each time point. The data demonstrated an improvement in pain and function as early as 2 weeks that appeared to peak at 12 weeks with a mean (standard deviation) of 21.11 (6.61) points of change on the VISA-A. CONCLUSION: The improvement in pain and function during rehabilitation suggests future research should be directed toward investigating contributing mechanisms as tendon structure on imaging does not change within 2 weeks and muscular hypertrophy is not seen for at least 4 weeks following the inception of a loading protocol. Systematic Review Registry: PROSPERO registration number: CRD42017062737 ( https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=62737 ). PMID- 29766448 TI - Cross-sectional study on hospitalizations related to herpes zoster in an Italian region, 2008-2016. AB - INTRODUCTION: To assess the burden of herpes zoster (HZ) by analyzing HZ-related hospital admissions. METHODS: We conducted a population-based descriptive cross sectional study on all hospitalizations for HZ among the resident population admitted to all public and accredited private hospitals in the Veneto Region (north-east Italy) during the years 2008-2016. HZ hospitalizations were identified from the International Classification of Diseases codes in the hospital discharge records. RESULTS: During the period considered, we identified 3566 HZ-associated admissions, 194 (5.4%) of which were readmissions within 30 days. A complicated HZ diagnosis was mentioned for 44.4% of the patients admitted once and for 65.9% of those admitted twice. In the sample as a whole, 27.0% of patients had at least one comorbidity. Overall, our analysis revealed a gradual increase in hospitalizations with age for both genders, reaching a hospitalization rate for the population over 80 years old of 51.2 * 100,000 for males and 52.8 * 100,000 for females. The average hospitalization rate for HZ related conditions during the years 2008-2016 was 7.7 per 100,000 population. Postherpetic neuralgia was diagnosed in 8.2% of hospitalizations, with no difference between the genders. The estimated overall cost of HZ-related conditions was approximately ?2.7 million a year. CONCLUSIONS: This study suggests that the burden of HZ and its impact on quality of life are of critical relevance to public health decision-making. PMID- 29766449 TI - Value of an old school approach: safety and long-term success of radiofrequency current catheter ablation of atrioventricular nodal reentrant tachycardia in children and young adolescents. AB - PURPOSE: Radiofrequency current energy (RFC) ablation is still considered as the gold standard for atrioventricular nodal reentrant tachycardia (AVNRT). Success rates for AVNRT ablation vary irrespective of the ablation technology and strategy. This study aimed to access safety, efficacy, and long-term outcome of RFC catheter ablation for the treatment of AVNRT in children and adolescents aged < 19 years with special focus on modulation versus ablation of the AV nodal slow pathway (SP). METHODS: A total number of 1143 patients (pts) < 19 years were referred for invasive electrophysiological testing due to paroxysmal supraventricular tachycardia (SVT). RESULTS: Diagnosis of AVNRT was confirmed in 412 pts, and RFC-guided ablation was attempted in 386 pts (age 13.0 +/- 3.5 years). No permanent complications were observed. RFC application resulted in SP ablation in 171/386 (44.3%) and in SP modulation in 208/386 (53.9%) children, whereas attempts for RFC treatment failed in 7 pts. Follow-up was completed for 396/412 patients (96.1%). Within a mean follow-up period of 54.9 +/- 39.7 months, in 51/379 pts (13.5%) AVNRT recurrence was observed. The median time until tachycardia recurrence was 19.5 months. No difference for AVNRT recurrence was found comparing SP ablation versus SP modulation (p > 0.05), whereas the recurrence rate was significantly higher in patients with non-inducible SVT and therefore empiric SP treatment as compared to patients with inducible AVNRT (p = 0.01). CONCLUSIONS: RFC-guided ablation for AVNRT in children and adolescents is safe and leads to an acceptable long-term freedom from recurrences. SP modulation and SP ablation resulted in comparable acute and long-term success rates. Late AVNRT recurrences can occur even after years of freedom from tachycardia-related symptoms. PMID- 29766450 TI - Metrical congruency and kinematic familiarity facilitate temporal binding between musical and dance rhythms. AB - Although music and dance are often experienced simultaneously, it is unclear what modulates their perceptual integration. This study investigated how two factors related to music-dance correspondences influenced audiovisual binding of their rhythms: the metrical match between the music and dance, and the kinematic familiarity of the dance movement. Participants watched a point-light figure dancing synchronously to a triple-meter rhythm that they heard in parallel, whereby the dance communicated a triple (congruent) or a duple (incongruent) visual meter. The movement was either the participant's own or that of another participant. Participants attended to both streams while detecting a temporal perturbation in the auditory beat. The results showed lower sensitivity to the auditory deviant when the visual dance was metrically congruent to the auditory rhythm and when the movement was the participant's own. This indicated stronger audiovisual binding and a more coherent bimodal rhythm in these conditions, thus making a slight auditory deviant less noticeable. Moreover, binding in the metrically incongruent condition involving self-generated visual stimuli was correlated with self-recognition of the movement, suggesting that action simulation mediates the perceived coherence between one's own movement and a mismatching auditory rhythm. Overall, the mechanisms of rhythm perception and action simulation could inform the perceived compatibility between music and dance, thus modulating the temporal integration of these audiovisual stimuli. PMID- 29766451 TI - Early Hemolysis Within Human Intracerebral Hematomas: an MRI Study. AB - Early hemolysis occurs in the hematoma within 24 h in rat model of intracerebral hemorrhage (ICH). The present study investigated the prevalence of early hemolysis in ICH patients using MRI and the relationship between early hemolysis and perihematomal edema. Thirty ICH patients were prospectively enrolled within 24 h of onset. All patients had cranial CT on admission. Cranial MRI with T2 FLAIR-weighted imaging and T2*-weighted imaging were undertaken at days 1 and 14. The evolution of a non-hypointense lesion on T2*-weighted images and the relationship between the volume of that non-hypointense lesion and perihematomal edema volume were investigated. MRI images of 15 patients were analyzed. The median hematoma volume was 16.3 ml on admission. All patients underwent a baseline MRI within 24 h of ICH onset and showed a non-hypointense lesion within the hematoma on T2*-weighted images. The volume of non-hypointense lesion on T2* weighted image was 6.0 (8.9) ml at day 1 and 8.6 (17.3) ml at day 14. The absolute perihematomal edema volume was 16.0 (17.9) ml and 24.8 (27.5) ml at days 1 and 14, respectively. There was a linear correlation between non-hypointense T2* lesion and perihematomal edema volume at day 1 and day 14 (p < 0.01). Early hemolysis in the hematoma occurs in humans and contributes to the development of perihematomal edema. PMID- 29766453 TI - Comment on Microsurgical therapy of pituitary adenomas. PMID- 29766452 TI - A Novel Technique for Visualizing and Analyzing the Cerebral Vasculature in Rodents. AB - We introduce a novel protocol to stain, visualize, and analyze blood vessels from the rat and mouse cerebrum. This technique utilizes the fluorescent dye, DiI, to label the lumen of the vasculature followed by perfusion fixation. Following brain extraction, the labeled vasculature is then imaged using wide-field fluorescence microscopy for axial and coronal images and can be followed by regional confocal microscopy. Axial and coronal images can be analyzed using classical angiographic methods for vessel density, length, and other features. We also have developed a novel fractal analysis to assess vascular complexity. Our protocol has been optimized for adult rat, adult mouse, and neonatal mouse studies. The protocol is efficient, can be rapidly completed, stains cerebral vessels with a bright fluorescence, and provides valuable quantitative data. This method has a broad range of applications, and we demonstrate its use to study the vasculature in assorted models of acquired brain injury. PMID- 29766454 TI - Successful surgery of the hypothalamic region: Yes, we can! PMID- 29766455 TI - Consensus document on the progression and treatment response criteria in gastroenteropancreatic neuroendocrine tumors. AB - PURPOSE: Gastroenteropancreatic neuroendocrine tumors are a heterogeneous group of low incidence neoplasms characterized by a low proliferative activity and slow growth. Their response to targeted therapies is heterogeneous and often does not lead to tumor shrinkage. Thus, evaluation of the therapeutic response should differ from other kind of tumors. METHODS: To answer relevant questions about which techniques are best in the assessment of progression or treatment response a RAND/UCLA-based consensus process was implemented. Relevant clinical questions were listed followed by a systematic search of the literature. The expert panel answered all questions with recommendations, combining available evidence and expert opinion. Recommendations were validated through a questionnaire and a participatory meeting. RESULTS: Expert recommendations regarding imaging tools for tumor assessment and evaluation of progression were agreed upon. Available imaging techniques were reviewed and recommendations for best patient monitoring practice and the best way to evaluate treatment response were formulated. PMID- 29766456 TI - Prognostic role for the derived neutrophil-to-lymphocyte ratio in early breast cancer: a GEICAM/9906 substudy. AB - PURPOSE: Elevated markers of host inflammation, a hallmark of cancer, have been associated with worse outcomes in several solid tumors. Here, we explore the prognostic role of the derived neutrophil-to-lymphocyte ratio (dNLR), across different tumor subtypes, in patients with early breast cancer. PATIENTS AND METHODS: This was a retrospective analysis of 1246 patients with lymph node positive, operable early breast cancer enrolled in the GEICAM/9906 trial, a multicenter randomized phase 3 study evaluating adjuvant chemotherapy. dNLR was calculated as the ratio of neutrophils and the difference between total leukocytes and neutrophils in peripheral blood before chemotherapy. Disease-free survival (DFS) and overall survival were explored using a Cox proportional hazard analysis. RESULTS: The analysis comprised 1243 (99.8%) patients with dNLR data, with a median follow-up of 10 years. Data on intrinsic subtypes were available from 818 (66%) patients (luminal A 34%, luminal B 32%, HER2-enriched 21% and basal-like 9%). Median dNLR was 1.35 [interquartile range (IQR) 1.08-1.71]. In the whole population, dNLR was not prognostic after adjustment for clinico pathological factors. However, dNLR >= 1.35 was independently associated with worse DFS in the hormone receptor-negative/HER2+ population (HR 2.86; p = 0.038) and in patients with one to three lymph node metastases (HR 1.32, p = 0.032). There was a non-significant association with worse DFS in non-luminal and in HER2 enriched tumors (HR 1.40, p = 0.085 and HR 1.53, p = 0.067). No significant interaction was observed between the treatment arm and dNLR. CONCLUSION: Elevated dNLR appears to be an adverse prognostic factor in hormone receptor-negative early breast cancer. TRIAL REGISTRATION: EudraCT: 2005-003108-12 (retrospectively registered 28/06/2005). ClinicalTrials.gov Identifier: NCT00129922 (retrospectively registered 10/08/2005). Results of this study were presented in part at the 2016 ESMO conference October 7-11, 2016, Copenhagen, Denmark (oral presentation). PMID- 29766457 TI - Influence of age on variation in patterns of care in patients with rectal cancer in Catalonia (Spain). AB - BACKGROUND: Population ageing is a relevant concern in people diagnosed with rectal cancer. This study evaluates the adherence to clinical practice guidelines (CPGs) and patient outcomes in rectal cancer, with a particular focus on variation according to age. METHODS: This is a multicentre retrospective cohort study of all patients surgically treated for the first time for primary rectal cancer with curative intent in public hospitals in Catalonia during two study periods: first, with data from 2005 to 2007, and then with data from 2011 to 2012. We obtained the study data through a comprehensive review of patients' clinical records. Information on diagnosis, treatment and follow-up was collected and then compared with the relevant CPGs. We then performed a descriptive analysis of the categorical variables followed by a univariate and multivariate logistic regression analysis to calculate the odds ratio. Finally, we calculated the recurrence and death rates per person-year at 2 years' follow-up. RESULTS: In total, 3770 people were included in this study. The participants aged 70 and under were more likely to receive neoadjuvant therapy than those aged over 80 (2005/2007, 63 vs 17.4% p < 0.001; 2011/2012, 72 vs 41.1% p < 0.001); however, in the second study period there was less imbalance between the two groups in this regard, showing improved administration of neoadjuvant therapy in the elderly. The quality of surgery was suboptimal in a larger proportion of the elderly population, and the choice of surgical technique was dependent to some extent on the age of the participant. Recurrence and survival rates were significantly better in the second study period. CONCLUSIONS: Compared to younger patients, the most elderly were less likely to receive the recommended adjuvant treatment, laparoscopy and total mesorectal excision. However, we observed improved adherence to the recommended treatment regimen in the most elderly participants, resulting in decreased recurrence and increased survival rates in this population. PMID- 29766460 TI - Child with Progressive Hemiparesis: Think Beyond Neoplastic Disorders. PMID- 29766459 TI - Cognitive Functioning in Chiari Malformation Type I Without Posterior Fossa Surgery. AB - Chiari Malformation type I (CM-I) is a neurological disorder characterized by a displacement of the cerebellar tonsils through the foramen magnum into the spinal canal. Most research has focused on physical symptomatology but few studies include neuropsychological examinations. Moreover, although current research highlights the involvement of the cerebellum on higher cognitive functions, little is known about cognitive consequences associated with CM-I. The aim of this study is to analyze cognitive functioning between 39 CM-I patients and 39 healthy controls, matched by gender, age and years of education. Participants have been examined on a large battery of neuropsychological tests, including executive functioning, verbal fluency, spatial cognition, language, verbal memory, processing speed, facial recognition and theory of mind. Results show a poorer performance of the clinical group compared to the control group, even after controlling the effect of physical pain and anxious-depressive symptomatology. The findings suggest the presence of a generalized cognitive deficit associated with CM-I, which makes it necessary to focus attention not only on physical consequences, but also on cognitive ones. PMID- 29766462 TI - Disgust and fear: common emotions between eating and phobic disorders. AB - : Eating disorders (ED) are prevalent mental illnesses composed mainly of anorexia nervosa, bulimia nervosa and binge eating disorders. Anxiety disorders are another set of mental illnesses, with phobic disorder (PD) being the most prevalent disorder. ED and PD are highly comorbid. The aim of this study is to assess, in 131 individuals attending an outpatient clinic for different health issues, the level of fear related to situations generating avoidance such as in social anxiety and specific phobias according to the fear questionnaire (FQ), the level of disgust according to the disgust scale (DS-R) and the vulnerability towards ED according to the SCOFF scale to demonstrate that high levels of both fear and disgust increase the vulnerability towards ED. The study demonstrated that the level of disgust increased when fear increases (r = 0.377, p < 0.001 for the first part of the FQ; r = 0.225, p = 0.01 for the second part of the FQ). Moreover, individuals with vulnerability towards having an ED presented a higher level of disgust than individuals without this vulnerability (p = 0.009). Furthermore, individuals with vulnerability towards ED have a higher level of anxiety related to PD subtypes (p = 0.008 for agoraphobia; p = 0.001 for injection/blood phobia) as well as to social anxiety (p = 0.01), independently from having a depressive or another anxiety disorder. In the multivariate analysis, a history of psychiatric consultation has been the only significantly different parameter between individuals with or without vulnerability towards ED (p = 0.0439). Accordingly, fear and disgust are negative emotions that seem to be clinically associated which better explains the comorbidity of ED with PD. LEVEL OF EVIDENCE: Level III. Evidence obtained from well-designed cohort or case control analytic studies, preferably from more than one center or research group. PMID- 29766463 TI - Predictive factors for the outcomes of initial I-131 low-dose ablation therapy to Japanese patients with differentiated thyroid cancer. AB - OBJECTIVE: To identify prognostic factors associated with a low-iodine diet (LID) and the amount of remnant thyroid tissue in Japanese patients with differentiated thyroid cancer (DTC) who received initial I-131 remnant ablation (RAI) using a fixed low dose of I-131 (1110 MBq). PATIENTS AND METHODS: In this prospective study, we enrolled 45 patients. Patients were classified into a self-managed LID group and a strict LID group. We measured the urinary iodine concentration on the day of RAI after patients consumed LID for 2 weeks. Thyroid-stimulating hormone induced thyroglobulin (Tg) levels and I-131 uptake by the remnant thyroid tissue were also evaluated. A response-evaluation whole-body scan (WBS) was performed 6 8 months after RAI to determine the outcome of the therapy. RESULTS: Post-LID urinary iodine levels of the strict LID group tended to be lower than those of the self-managed LID group. Twenty-five cases (56%) showed absence of uptake, whereas 20 cases (44%) showed residual uptake on the response-evaluation WBS. There were no significant differences between "absence" and "residual" groups in urinary iodine concentrations and Tg levels (p = 0.253 and p = 0.234, respectively). However, significant differences were observed in I-131 uptake by the thyroid bed (p = 0.035). CONCLUSIONS: For patients following the current Japanese method of a 2-week LID, the urinary iodine concentration was not a predictive factor for the successful outcome of RAI. In contrast, low I-131 uptake by the thyroid bed, revealed by the scintigram after RAI, may serve as a favorable predictive factor. PMID- 29766458 TI - Cerebellar-Stimulation Evoked Prefrontal Electrical Synchrony Is Modulated by GABA. AB - Cerebellar-prefrontal connectivity has been recognized as important for behaviors ranging from motor coordination to cognition. Many of these behaviors are known to involve excitatory or inhibitory modulations from the prefrontal cortex. We used cerebellar transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) to probe cerebellar-evoked electrical activity in prefrontal cortical areas and used magnetic resonance spectroscopy (MRS) measures of prefrontal GABA and glutamate levels to determine if they are correlated with those potentials. Cerebellar-evoked bilateral prefrontal synchrony in the theta to gamma frequency range showed patterns that reflect strong GABAergic inhibitory function (r = - 0.66, p = 0.002). Stimulation of prefrontal areas evoked bilateral prefrontal synchrony in the theta to low beta frequency range that reflected, conversely, glutamatergic excitatory function (r = 0.66, p = 0.002) and GABAergic inhibitory function (r = - 0.65, p = 0.002). Cerebellar-evoked prefrontal synchronization had opposite associations with cognition and motor coordination: it was positively associated with working memory performance (r = 0.57, p = 0.008) but negatively associated with coordinated motor function as measured by rapid finger tapping (r = - 0.59, p = 0.006). The results suggest a relationship between regional GABA levels and interregional effects on synchrony. Stronger cerebellar-evoked prefrontal synchrony was associated with better working memory but surprisingly worse motor coordination, which suggests competing effects for motor activity and cognition. The data supports the use of a TMS-EEG-MRS approach to study the neurochemical basis of large-scale oscillations modulated by the cerebellar-prefrontal connectivity. PMID- 29766464 TI - Women's Preferences for Birthing Hospital in Denmark: A Discrete Choice Experiment. AB - BACKGROUND: Free choice of hospital has been introduced in many healthcare systems to accommodate patient preferences and incentivize hospitals to compete; however, little is known about what patients actually prefer. OBJECTIVES: This study assessed women's preferences for birthing hospital in Denmark by quantifying the utility and trade-offs of hospital attributes. METHODS: We conducted a discrete-choice experiment survey with 12 hypothetical scenarios in which women had to choose between three hospitals characterized by five attributes: continuity of midwifery care, availability of a neonatal intensive care unit (NICU), hospital services offered, level of specialization to handle rare events, and travel time. A random parameter logit model was used to estimate the utility and marginal willingness to travel (WTT) for improvements in other hospital attributes. RESULTS: A total of 517 women completed the survey. Significant preferences were expressed for all attributes (p < 0.01), with the availability of a NICU being the most important driver of women's preferences; women were willing to travel 30 more minutes (95% confidence interval 28-32) to reach a hospital with a highly specialized NICU. The subgroup analyses revealed differences in WTT, with substantial heterogeneity due to prior experience with giving birth and regarding risk attitude and health literacy. CONCLUSION: A high specialization level was the most influential factor for women without previous birth experience and for risk-averse individuals but not for women with a high health literacy score. Hence, more information about the woman's risk profile and services required could play a role in affecting hospital choice. PMID- 29766465 TI - Effects of fenoldopam on renal blood flow in hypertensive chronic kidney disease. AB - BACKGROUND AND AIM: The synthetic drug fenoldopam mesylate (FM) may have a renoprotective role, and a "renal dose" of 0.1 ug/kg/min intravenous (IV) infusion of FM has been reported as able to increase renal blood flow without affecting systemic blood pressure. But conclusive data are still lacking. We aimed to investigate by color-Doppler ultrasonography the effects of IV administration of FM at this dosage in hypertensive chronic kidney disease (CKD) patients, and verify whether it may induce any systemic hemodynamic alteration. METHODS: In 60 hypertensive CKD patients, we measured by duplex Doppler ultrasonography, at baseline and during infusion of 0.1 ug/kg/min of FM, the systolic and diastolic flow velocity (sampled at the renal hilum, intermediate section and origin of both renal arteries) and the intra-parenchymal renal resistive index (RRI) sampled on interlobular arteries of both kidneys. Patients were divided into four subgroups (I-IV) according to classification of National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-DOQI). RESULTS: Infusion of 0.1 ug/kg/min FM significantly decreased the RRI (0.73 +/- 0.05 vs. 0.65 +/- 0.06; p < 0.0001) and increased the systolic and diastolic flow velocities in all renal artery tracts examined. No single episode of systemic hypotension was observed. CONCLUSIONS: Very low-dose FM may significantly increase renal blood flow and exert a renal protective effect in hypertensive CKD patients. Infusion of FM at such low dosage appears also to be quite safe, even in CKD and hypertensive patients. PMID- 29766461 TI - The Effectiveness of Trimetazidine Treatment in Patients with Stable Angina Pectoris of Various Durations: Results from the CHOICE-2 Study. AB - INTRODUCTION: Trimetazidine (TMZ) has been shown to reduce angina symptoms and to increase exercise capacity in randomized clinical trials, but more extensive data would be useful to assess its effects in real-world clinical practice and in patients with different durations of disease. METHODS: CHOICE-2 was a Russian, multicenter, 6-month, open-label, prospective observational study that assessed the effect of adding TMZ modified release 35 mg bid to antianginal treatment in a real-world setting. The present analysis of CHOICE-2 results explored the effects of adding TMZ to background antianginal therapies with regard to the duration of stable angina. RESULTS: A total of 741 patients with known durations of disease were divided into four groups according to stable angina pectoris (AP) duration, ranging from less than 1 year to more than 9 years. Addition of TMZ led to a significant decrease in the frequency of angina attacks and in the use of short acting nitrates in all groups. In patients with recently diagnosed angina (AP duration < 1 year), the average number of angina attacks per week decreased significantly from 3.75 +/- 4.63 to 0.67 +/- 1.51 and in those with advanced disease (AP duration > 9 years) from 5.63 +/- 5.24 to 1.32 +/- 2.07. Angina-free walking distance also improved significantly. Addition of TMZ also improved patient well-being. Results were achieved rapidly (within 2 weeks), were maintained over 6 months, and were obtained in all patient groups regardless of angina duration. CONCLUSION: TMZ added to other antianginal therapies proved to be effective for reducing angina attacks and short-acting nitrate use, increasing angina-free walking distance, and improving patient well-being in a real-life setting, irrespective of angina duration, including patients with recently diagnosed angina. This provides an opportunity for intensification of treatment early on in the disease process, with the aim of decreasing angina burden and improving patient quality of life. FUNDING: Servier. TRIAL REGISTRATION: ISRCTN identifier ISRCTN65209863. PMID- 29766466 TI - Concurrent isolated IgG2-positive membranous nephropathy and malignant B-cell lymphoma. AB - A recent systematic review showed that hematological malignancy is often complicated by membranous nephropathy (MN). Histologically, the deposition of IgG subclasses other than IgG4 may imply secondary MN, such as malignancy-associated MN (M-MN). We describe a very rare case of concurrent isolated IgG2-positive MN and B-cell lymphoma. An 83-year-old woman was hospitalized at our institute for facial and lower extremity edema persisting for 2 months. Laboratory tests showed urinary protein level of 10.8 g/day, serum albumin level of 1.6 g/dl, and serum creatinine level of 2.34 mg/dl. Soon after diagnosis of nephrotic syndrome, treatment with corticosteroid was initiated, but it proved to be ineffective. Renal biopsy showed isolated IgG2-positive MN with highly infiltrated CD20 positive lymphoid cells in the kidney. Computed tomography revealed systemic lymphadenopathy, and aberrant B-cells with immunoglobulin light chain restriction were detected in peripheral blood and bone marrow, which led to the diagnosis of mature B-cell lymphoma. Although rituximab (375 mg/m2/week) was administered, the patient suddenly died from gastrointestinal bleeding on day 40 of hospitalization. It is, thus, necessary to consider hematological malignancy when a diagnosis of MN is made. Further studies are expected to elucidate the pathogenesis and to help establish the adequate treatment for this rare situation. PMID- 29766467 TI - Thrombotic microangiopathy on kidney biopsy in a patient with TAFRO syndrome. AB - TAFRO syndrome represents a characteristic constellation of symptoms comprising Thrombocytopenia, Anasarca, myeloFibrosis, Renal dysfunction, and Organomegaly, and is considered to be a clinicopathologic variant of idiopathic multicentric Castleman disease. A 51-year-old woman was admitted to the hospital complaining of abdominal distension. Findings on physical examination were indicative of anasarca. Computed tomography revealed mild splenomegaly, pericardial effusion, pleural effusion, ascites, and paraaortic lymphadenopathy. Blood tests showed thrombocytopenia, and urinalysis demonstrated hematuria, proteinuria, and worsening renal function. Kidney biopsy was performed and revealed thrombotic microangiopathy-like lesions with global sclerosis of 1 of the 16 glomeruli on light microscopy. The remaining glomeruli had a distinct lobular pattern, with mesangiolysis, double contours of the glomerular basement membranes, and marked endothelial swelling. Immunofluorescence studies for IgG, IgM, IgA, C1q, C3, C4, kappa-light chains, and lambda-light chains were indeterminate. Electron microscopy showed marked endothelial swelling. We made a diagnosis of TAFRO syndrome and started steroid treatment, following which her symptoms gradually improved. There are few reports describing renal pathology in a patient with TAFRO syndrome. PMID- 29766468 TI - Gemcitabine-induced thrombotic microangiopathy with nephrotic syndrome. AB - We encountered a case of gemcitabine (GEM)-induced secondary thrombotic microangiopathy (TMA) with nephrotic syndrome. Advanced pancreatic cancer with liver metastasis had originally been diagnosed. Renal biopsy showed focal reduplication of the glomerular basement membrane, endothelial cell swelling, and narrowed capillary lumens with fragmented erythrocytes and fibrin deposition, compatible with TMA. Regular monitoring of renal function during GEM treatment and discontinuation of treatment if acute kidney injury (AKI) might occur is crucial, because AKI combined with TMA is life-threatening. PMID- 29766469 TI - Proteinuric glomerulopathy in an adolescent with a distal partial trisomy chromosome 1. AB - We report a case of distal partial trisomy 1 from q32.1 to 41 that have exhibited proteinuric glomerulopathy. The patient was a 17-year-old adolescent with clinical features of low birth weight, mild mental retardation and mild deafness, from the birth. He exhibited non-nephrotic range proteinuria with the mild obesity since the age of sixteen. Image studies did not reveal morphological abnormalities of the kidneys. Renal biopsy findings showed no definitive evidence of primary glomerular diseases, and were characterized by a very low glomerular density, glomerulomegaly and focal effacement of podocyte foot processes. Therapies with dietary sodium restriction, body weight reduction and the administration of angiotensin receptor blocker markedly reduced his proteinuria. It was likely that mismatch between congenital reduction in the nephron number and catch-up growth of the whole body size played a major role in the development of glomerular hyperperfusion injury. At present, the direct contribution of genetic factors due to this chromosomal disorder to such a substantial reduction in the nephron number remains uncertain. PMID- 29766470 TI - Perinatal depression prevention through home visitation: a cluster randomized trial of mothers and babies 1-on-1. AB - Postpartum depression is highly prevalent in low-income women and has significant health effects on mother and child. This pilot study tested the effectiveness of the newly adapted Mothers and Babies (MB) 1-on-1 intervention. A cluster randomized trial was conducted with 8 programs using trained home visitors to deliver MB 1-on-1 and 6 delivering usual home visiting. One hundred twenty pregnant women not experiencing major depression were enrolled. Outcomes were assessed at baseline and 3- and 6-months postpartum. The rate of change in depressive and anxiety symptoms between groups was significant at 6 months, but not 3 months. No statistically significant differences between groups were found on secondary outcomes except perceptions of social support at 6 months. There was variability in use of MB skills, with fewer women using cognitive restructuring techniques. Although larger studies should be conducted, MB 1-on-1 appears promising in using home visitors to deliver a cognitive behavioral intervention to women at risk for postpartum depression. PMID- 29766471 TI - Self-control as measured by delay discounting is greater among successful weight losers than controls. AB - Long-term weight loss maintenance is likely to require strong self-control in order to sustain changes in behavior patterns. We, therefore, tested the hypothesis that those who have successfully maintained weight loss may have superior self-control compared to control participants. Self-control was assessed using a delay discounting task through a webbased assessment of members of the National Weight Control Registry (NWCR: N = 757; non-obese = 605; obese = 152) and control participants (Control N = 443; nonobese = 236; obese = 207) from Amazon's Mechanical Turk. Both NWCR members that were currently obese (t = 5.42, p < 0.001) and nonobese (t = 5.28, p < 0.001) discounted the future less than control participants with comparable weight statuses. These results are indicative of higher levels of self-control behaviors in individuals that have lost and successfully maintained weight loss. Thus, successful weight losers may exhibit stronger self-control, as measured through discounting of future rewards, However, further research is needed to determine whether strong selfcontrol enables individuals to succeed at weight loss maintenance or develops as a consequence. PMID- 29766472 TI - Epidemiology, management and outcome of varicella in pregnancy: a 20-year experience at the Tuscany Reference Centre for Infectious Diseases in Pregnancy. AB - Data from 215 pregnant women exposed to varicella and 276 with varicella observed at the Tuscany Reference Center for Infectious Diseases in Pregnancy, Florence, Italy, in the period 1997-2016 were retrospectively collected. The risk of developing varicella was lower in exposed women who received varicella zoster immunoglobulin compared with those who did not receive it [42% (21 of 50) vs 72% (13 of 18); p = 0.0263]. Typical congenital varicella syndrome was observed in 1.56% of fetuses/neonates born from pregnant women with varicella. PMID- 29766475 TI - Facing the Language-Memory Problem in the Study of Autobiographical Memory. AB - This paper discusses the problem of the role of language in autobiographical memory, that is barely considered in studies on autobiographical memories and narratives. As a matter of fact, most of the current studies on autobiographical memory confounded memory and narrative together. The present paper focuses on two main issues. Firstly, it debates how narratives contribute to the construction of autobiographical memories through self-other communication. Secondly, it reflects on how language and communication should be manipulated in studies about autobiographical memory. This paper is made of three sections: the first section discusses the role of language, particularly in the form of narrative, as a social tool by which autobiographical memories can be organised in a life story; the second section examines previous methods of investigation used in the study of autobiographical memories; finally, the third section proposes different methodological alternatives to overcome the problems emerging from our analysis of literature. PMID- 29766473 TI - MR imaging findings in some rare neurological complications of paediatric cancer. AB - : Neurological complications of paediatric cancers are a substantial problem. Complications can be primary from central nervous system (CNS) spread or secondary from indirect or remote effects of cancer, as well as cancer treatments such as chemotherapy and radiation therapy. In this review, we present the clinical and imaging findings of rare but important neurological complications in paediatric patients with cancer. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Paraneoplastic neurological syndromes, hyperviscosity syndrome, haemophagocytic lymphohistiocytosis and infection are found in the pre-treatment phase, while Trousseau's syndrome, posterior reversible encephalopathy syndrome and methotrexate neurotoxicity are found in the treatment phase; though some complications overlap between the pre-treatment and treatment phases. Hippocampal sclerosis, radiation induced tumour, radiation induced focal haemosiderin deposition and radiation-induced white matter injury are found in the post remission phase. With increasingly long survival after treatment, CNS complications have become more common. It is critical for radiologists to recognise neurological complications related to paediatric cancer or treatment. Magnetic resonance imaging (MRI) plays a significant role in the recognition and proper management of the neurological complications of paediatric cancer. TEACHING POINTS: * Neurological complications of paediatric cancer include various entities. * Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. * Radiologists should be familiar with clinical and imaging findings of neurological complications. * MRI features may be characteristic and lead to early diagnosis and proper treatments. PMID- 29766476 TI - [Admission to child and adolescent psychiatry: how do we provide for the right to a confidential advisor?] PMID- 29766474 TI - Masses of developmental and genetic origin affecting the paediatric craniofacial skeleton. AB - : Although rare, masses and mass-like lesions of developmental and genetic origin may affect the paediatric craniofacial skeleton. They represent a major challenge in clinical practice because they can lead to functional impairment, facial deformation and disfigurement. The most common lesions include fibrous dysplasia, dermoid cysts, vascular malformations and plexiform neurofibromas. Less common lesions include torus mandibularis and torus palatinus, cherubism, nevoid basal cell carcinoma syndrome, meningoencephalocele and nasal sinus tract. This article provides a comprehensive approach for the evaluation of children with masses or mass-like lesions of developmental and genetic origin affecting the craniofacial skeleton. Typical findings are illustrated and the respective roles of computed tomography (CT), cone beam CT (CBCT), magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) sequences and ultrasonography (US) are discussed for the pre-therapeutic assessment, complex treatment planning and post-treatment surveillance. Key imaging findings and characteristic clinical manifestations are reviewed. Pitfalls of image interpretation are addressed and how to avoid them. TEACHING POINTS: * Masses of developmental and genetic origin may severely impair the craniofacial skeleton. * Although rare, these lesions have characteristic imaging features. * CT, MRI and ultrasonography play a key role in their work-up. * Recognition of pivotal imaging pearls and diagnostic pitfalls avoids interpretation errors. PMID- 29766477 TI - [Long-term follow-up of psychogenic pseudosyncope]. AB - BACKGROUND: Patients with psychogenic pseudosyncope (PPS) are frequently seen by neurologists and psychiatrists. As of yet, there has been no follow-up study of patients with PPS after communicating the diagnosis. AIM: To determine the outcome of patients with psychogenic pseudosyncope (PPS) after communicatingthe diagnosis. METHOD: A retrospective cohort study of patients with PPS referred to a tertiary referral center for syncope from 2007 to 2015. We reviewed patient records, studying attack frequency, factors possibly affecting attack frequency, health care use and quality of life using questionnaires. We explored influences on absence of attack and attack frequency in the six months before follow-up for age, sex, level of education, duration until a diagnosis was made, probability of diagnosis, additional syncope and acceptance of diagnosis. RESULTS: 47 out 57 PPS cases could be traced, of these 35 (74%) participated. Twelve (34%) were attack free for at least six months. The median time from diagnosis to follow-up was 50 months (range 6-103 months). Communication and explanation of the diagnosis resulted in immediate reduction of attack frequency (p=0.007) from the month before diagnosis (median one attack, range 0-156) to the month afterwards (median one attack, range 0-16). In the six months before follow-up the number of admissions decreased from 19/35 to 0/35 (p = 0.002). Furthermore, the demand for somatic health care shifted to psychiatric care (p < 0.0001). Quality of life at follow-up (Short Form Health Survey 36; SF-36) showed lower scores for seven of the eight domains compared to matched Dutch control values. The quality of life was not significantly influenced by absence of attack. CONCLUSION: After communicating the diagnosis of PPS, attack frequency decreased and health care use shifted toward mental care. Low quality of life underlines the fact that PPS is a serious condition. Improvement of quality of life probably requires both a longer treatment and longer follow-up. PMID- 29766478 TI - [Time for cluster C personality disorders: state of the art]. AB - BACKGROUND: Compared to cluster B personality disorders, the assessment and treatment of people with obsessive-compulsive, dependent, and avoidant personality disorders (cluster C) is given little attention in the field of research and clinical practice. AIM: Presenting the current state of affairs in regard to cluster C personality disorders. METHOD: A systematic literature search was conducted using the main data bases. RESULTS: Cluster C personality disorders are present in approximately 3-9% of the general population. In about half of the cases of mood, anxiety, and eating disorders, there is co-morbid cluster C pathology. This has a major influence on the progression of symptoms, treatment effectiveness and potential relapse. There are barely any well conducted randomized studies on the treatment of cluster-C in existence. Open cohort studies, however, show strong, lasting treatment effects. CONCLUSION: Given the frequent occurrence of cluster C personality disorders, the burden of disease, associated societal costs and the prognostic implications in case of a co-morbid cluster C personality disorder, early detection and treatment of these disorders is warranted. PMID- 29766479 TI - [N-of-1 trials in child and adolescent psychiatry: a closer look at stimulants]. AB - BACKGROUND: An N-of-1 trial is a clinical trial studying the response of an individual to a particular intervention or different interventions in an objective, systematic way. AIM: To evaluate both the applications and the methodology of N-of-1 trials in child and adolescent psychiatry. METHOD: A systematic review using PubMed and Embase assessing N-of-1 trials published during the period 1986 - July 2016 with the following key-word: 'N-of-1'. RESULTS: 20 articles were included. All articles used N-of-1 trials to evaluate the effect of stimulant medications in children and adolescents with ADHD. Most articles recommended the use of the N-of-1 methodology in clinical practice, despite the large variation in methodology and in outcome interpretation of N-of 1 trials. The 20 articles didn't meet the current quality standards for N-of-1 trials. CONCLUSION: Despite the advantages of N-of-1 trials, the applications in child and adolescent psychiatry turn out to be rather limited and specific. N-of 1 trials have more to offer regarding both clinical practice and research in child and adolescent psychiatry. If the methodological recommendations are sufficiently met, N-of-1 trials could provide a useful and applicable tool for the child- and adolescent psychiatrist to offer individual patient care. PMID- 29766480 TI - [The therapeutic alliance in community mental health services]. AB - BACKGROUND: The treatment of severe mental illnesses is increasingly taking place in a domiciliary setting due to the deinstitutionalisation.
AIM: Theoretical reflection on the influence of home treatment on the therapeutic alliance.
METHOD: Qualitative review of possible effects of home treatment based on own experiences, the scientific literature, and recent handbooks on community mental health.
RESULTS: The therapeutic relationship appears to be an important general factor in the outcomes of community mental health approaches. The working alliance has a more egalitarian and reciprocal nature. It improved when the scope of treatment was defined by the needs of the client. Boundaries concerning both the extent of personal involvement of the caregiver and the autonomy of the client presented important challenges in a context that lacks formal professional boundaries such as those seen in a consultation room or a hospital.
CONCLUSION: Characteristic features of the therapeutic alliance during home treatment pose a challenge to the caregiver in terms of balancing interpersonal involvement and distance. The need to intervene in the personal life of the patient often causes ethical dilemmas. A dialectical form of intervision is proposed to explore the emotional involvement of the caregiver and to systematically reflect on possible ethical issues as a tool for daily practice. PMID- 29766481 TI - [Is psychiatry ready to let patients review their own files? Inventory of initial experiences]. AB - BACKGROUND: Dutch patients will be granted the right to digitally access their own medical records, an option already available to the patients at the University Medical Center Utrecht since 2015. AIM: To start a conversation about the development of readily accessible online patient records. METHODS Describe the experiences of a University department of psychiatry with an online patient portal, obtained through discussions and questionnaires. RESULTS: During the next few years three legal developments will enable patients to acquire direct, remote, digital access to their medical files. Immediate online review of medical records improves accessibility and empowers the patient. Some therapists experienced a change in patient interaction. Furthermore, during documentation psychiatrists took into account that patients could review the contents at a later point. CONCLUSION: Patients' accessibility of online records will influence the patient-therapist dynamic. More research on the patient perspective and a discussion among professionals are necessary to further streamline broad implementation of online patient portals. PMID- 29766482 TI - [Fragile X syndrome: new therapeutic strategies]. AB - BACKGROUND: Fragile X syndrome (fxs) is the most common hereditary cause of intellectual disability and autism spectrum disorders. Targeted treatment is currently lacking. In the past decades an enormous amount of knowledge has been obtained concerning the involved molecular pathways, introducing potential targets for disease modifying therapy.
AIM: To present an overview of the development of targeted treatment for fxs.
METHOD: Several important publications were collected and indexed.
RESULTS: While preclinical animal model studies with targeted interventions are promising, the translation to the clinic has been disappointing.
CONCLUSION: Targeted treatment for fxs is necessary and could be applied in other causes of autism spectrum disorders and intellectual disability. Factors relating to translation, study design and outcome measures are possibly contributing to the disappointing results. The clustering of patient care in a center of expertise is required to clinically implement future therapeutic strategies and to facilitate research. In addition, this improves patient care, one example being the recent medical guideline for children with fxs. PMID- 29766483 TI - [Autism or personality disorder in older adults? Guidelines for the differential diagnosis]. AB - Autism spectrum disorders and personality disorders are common, also in the elderly. Differential diagnosis is complex, especially if an undiagnosed autism spectrum disorder or personality disorder is suspected. We discuss two cases and conclude the article with suggestions for the differential diagnosis. PMID- 29766485 TI - Abstracts of the 105th Annual Congress of the Swiss Society of Surgery, held in Basel, Switzerland, 16 May - 18 May 2018. PMID- 29766484 TI - [The future of prevention of depression for adolescents: challenges and chances]. PMID- 29766486 TI - Risk communication in genetic counseling: Exploring uptake and perception of recurrence numbers, and their impact on patient outcomes. AB - Providing recurrence numbers is often considered a fundamental component of genetic counseling. We sought to fill knowledge gaps regarding how often patients actively seek recurrence numbers, and how they impact patient outcomes. We conducted a retrospective chart review at a clinic where patients routinely complete the Genetic Counseling Outcomes Scale (GCOS, measuring empowerment) pre (T1)/post (T2) appointment. Using analysis of covariance, we evaluated the effect on T2 GCOS score of: (1) receiving recurrence numbers and (2) patient perception of recurrence numbers. Recurrence numbers were a primary indication for 134/300 patients (45%). After counseling about etiology and risk-reducing strategies, 116 patients (39%) opted to receive recurrence numbers, with most (n = 64, 55%) perceiving the number to be lower than expected. There was no difference in T2 GCOS scores between those who: (1) received recurrence numbers vs those who did not, or (2) perceived the number to be lower than expected vs those with other perceptions. However, a subset of patients who did not receive recurrence numbers had larger increases in GCOS scores. Our data provide impetus to question the assumption that recurrence numbers should be routinely provided in genetic counseling, and show that in naturalistic practice, optimal patient outcomes are not contingent on receipt of recurrence numbers. PMID- 29766487 TI - Inhaled corticosteroids for bronchiectasis. AB - BACKGROUND: Bronchiectasis is being increasingly diagnosed and recognised as an important contributor to chronic lung disease in both adults and children in high and low-income countries. It is characterised by irreversible dilatation of airways and is generally associated with airway inflammation and chronic bacterial infection. Medical management largely aims to reduce morbidity by controlling the symptoms, reduce exacerbation frequency, improve quality of life and prevent the progression of bronchiectasis. This is an update of a review first published in 2000. OBJECTIVES: To evaluate the efficacy and safety of inhaled corticosteroids (ICS) in children and adults with stable state bronchiectasis, specifically to assess whether the use of ICS: (1) reduces the severity and frequency of acute respiratory exacerbations; or (2) affects long term pulmonary function decline. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL), the Cochrane Airways Group Register of trials, MEDLINE and Embase databases. We ran the latest literature search in June 2017. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing ICS with a placebo or no medication. We included children and adults with clinical or radiographic evidence of bronchiectasis, but excluded people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: We reviewed search results against predetermined criteria for inclusion. In this update, two independent review authors assessed methodological quality and risk of bias in trials using established criteria and extracted data using standard pro forma. We analysed treatment as 'treatment received' and performed sensitivity analyses. MAIN RESULTS: The review included seven studies, involving 380 adults. Of the 380 randomised participants, 348 completed the studies.Due to differences in outcomes reported among the seven studies, we could only perform limited meta-analysis for both the short-term ICS use (6 months or less) and the longer-term ICS use (> 6 months).During stable state in the short-term group (ICS for 6 months or less), based on the two studies from which data could be included, there were no significant differences from baseline values in the forced expiratory volume in the first second (FEV1) at the end of the study (mean difference (MD) -0.09, 95% confidence interval (CI) -0.26 to 0.09) and forced vital capacity (FVC) (MD 0.01 L, 95% CI -0.16 to 0.17) in adults on ICS (compared to no ICS). Similarly, we did not find any significant difference in the average exacerbation frequency (MD 0.09, 95% CI -0.61 to 0.79) or health-related quality of life (HRQoL) total scores in adults on ICS when compared with no ICS, though data available were limited. Based on a single non-placebo controlled study from which we could not extract clinical data, there was marginal, though statistically significant improvement in sputum volume and dyspnoea scores on ICS.The single study on long term outcomes (over 6 months) that examined lung function and other clinical outcomes, showed no significant effect of ICS on any of the outcomes. We could not draw any conclusion on adverse effects due to limited available data.Despite the authors of all seven studies stating they were double-blind, we judged one study (in the short duration ICS) as having a high risk of bias based on blinding, attrition and reporting of outcomes. The GRADE quality of evidence was low for all outcomes (due to non-placebo controlled trial, indirectness and imprecision with small numbers of participants and studies). AUTHORS' CONCLUSIONS: This updated review indicates that there is insufficient evidence to support the routine use of ICS in adults with stable state bronchiectasis. Further, we cannot draw any conclusion for the use of ICS in adults during an acute exacerbation or in children (for any state), as there were no studies. PMID- 29766489 TI - Phenotypic disparity of the elbow joint in domestic dogs and wild carnivores. AB - In this article, I use geometric morphometrics in 2D from a sample of 366 elbow joints to quantify phenotypic disparity in domestic dog breeds, in wild canids, and across the order Carnivora. The elbow joint is a well-established morphological indicator of forearm motion and, by extension, of functional adaptations toward locomotor or predatory behavior in living carnivores. The study of the elbow joint in domestic dogs allows the exploration of potential convergences between (i) pursuit predators and fast-running dogs, and (ii) ambush predators and fighting breeds. The results indicate that elbow shape disparity among domestic dogs exceeds than in wolves; it is comparable to the disparity of wild Caninae, but is significantly lower than the one observed throughout Canidae and Carnivora. Moreover, fast-running and fighting breeds are not convergent in elbow joint shape with extreme pursuit and ambush wild carnivores, respectively. The role of artificial selection and developmental constraints in shaping limb phenotypic disparity through the extremely fast evolution of the domestic dog is discussed in the light of this new evidence. PMID- 29766488 TI - Nanoemulsions and dermatological diseases: contributions and therapeutic advances. AB - Skin disease is one of the most common human diseases and affects between 30% and 70% of individuals, which requires a lot of attention to their treatments. The delivery of active pharmacological ingredients at the topical level is a challenge because of the difficulties in overcoming the mechanical barrier created by the skin and reaching greater depths, since delivery specificities are decisive for the degree of effectiveness. In this way, the nanoemulsions emerge as a potential system for the incorporation of active substances in the cells and for the controlled release of active principles. The present article intends to review the main treatments for which the nanoemulsions were used in the field of dermatology. In addition, it discusses the results and advantages over the other dermatological therapies that are being used. The results showed that the particle size in nanoemulsions increased the contact surface area, resulting in increased drug efficacy, even in comparison with other existing pharmaceutical formulations. In conclusion, it has been shown that nanoemulsions have a better performance in efficacy, safety, permeability profile, and bioavailability compared with other formulations studied. PMID- 29766491 TI - Rapid spread of a Wolbachia infection that does not affect host reproduction in Drosophila simulans cage populations. AB - Wolbachia endosymbionts that are maternally inherited can spread rapidly in host populations through inducing sterility in uninfected females, but some Wolbachia infections do not influence host reproduction yet still persist. These infections are particularly interesting because they likely represent mutualistic endosymbionts, spreading by increasing host fitness. Here, we document such a spread in the wAu infection of Drosophila simulans. By establishing multiple replicate cage populations, we show that wAu consistently increased from an intermediate frequency to near fixation, representing an estimated fitness advantage of around 20% for infected females. The effective population size in the cages was estimated from SNP markers to be around a few thousand individuals, precluding large effects of genetic drift in the populations. The exact reasons for the fitness advantage are unclear but viral protection and nutritional benefits are two possibilities. PMID- 29766490 TI - Emotional hyper-reactivity and cardiometabolic risk in remitted bipolar patients: a machine learning approach. AB - OBJECTIVE: Remitted bipolar disorder (BD) patients frequently present with chronic mood instability and emotional hyper-reactivity, associated with poor psychosocial functioning and low-grade inflammation. We investigated emotional hyper-reactivity as a dimension for characterization of remitted BD patients, and clinical and biological factors for identifying those with and without emotional hyper-reactivity. METHOD: A total of 635 adult remitted BD patients, evaluated in the French Network of Bipolar Expert Centers from 2010-2015, were assessed for emotional reactivity using the Multidimensional Assessment of Thymic States. Machine learning algorithms were used on clinical and biological variables to enhance characterization of patients. RESULTS: After adjustment, patients with emotional hyper-reactivity (n = 306) had significantly higher levels of systolic and diastolic blood pressure (P < 1.0 * 10-8 ), high-sensitivity C-reactive protein (P < 1.0 * 10-8 ), fasting glucose (P < 2.23 * 10-6 ), glycated hemoglobin (P = 0.0008) and suicide attempts (P = 1.4 * 10-8 ). Using models of combined clinical and biological factors for distinguishing BD patients with and without emotional hyper-reactivity, the strongest predictors were: systolic and diastolic blood pressure, fasting glucose, C-reactive protein and number of suicide attempts. This predictive model identified patients with emotional hyper reactivity with 84.9% accuracy. CONCLUSION: The assessment of emotional hyper reactivity in remitted BD patients is clinically relevant, particularly for identifying those at higher risk of cardiometabolic dysfunction, chronic inflammation, and suicide. PMID- 29766492 TI - Nivolumab versus ipilimumab in the treatment of advanced melanoma: a critical appraisal: ORIGINAL ARTICLE: Wolchok JD, Chiarion-Sileni V, Gonzalez R et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017; 377:1345-56. AB - AIM: To show whether either nivolumab in combination with ipilimumab or nivolumab monotherapy vs. ipilimumab monotherapy extends overall survival (OS) or progression-free survival (PFS) in adults with previously untreated, advanced melanoma. SETTING AND DESIGN: The trial was conducted at 137 sites in 21 countries. Randomization (n = 945; 1 : 1 : 1 ratio) was stratified according to metastasis stage, BRAF mutation status and programmed death ligand 1 status. STUDY EXPOSURE: Adults were randomized to one of the following: nivolumab plus ipilimumab every 3 weeks for four doses, followed by nivolumab every 2 weeks; nivolumab every 2 weeks plus placebo; or ipilimumab every 3 weeks for four doses plus placebo. Treatment was continued until progression, unacceptable toxicity or withdrawal. OUTCOMES: OS, PFS and objective response rate were determined. Patients were also assessed for adverse events. The primary end points of interest were OS and PFS, comparing either the nivolumab plus ipilimumab group or the nivolumab-only group with the patients treated with ipilimumab only. RESULTS: At 3 years, the OS rates were 58%, 52% and 34% for the nivolumab plus ipilimumab, the nivolumab monotherapy and the ipilimumab monotherapy groups, respectively. For the nivolumab plus ipilimumab group, the median OS was not reached at the time of analysis. For the nivolumab-only group, the median OS was 37.6 months, and the ipilimumab-only group had a median OS of 19.9 months. The hazard ratio for death was 0.55 [95% confidence interval (CI) 0.45-0.69; P < 0.001] comparing nivolumab plus ipilimumab with ipilimumab, and 0.65 (95% CI 0.53-0.80; P < 0.001) comparing nivolumab with ipilimumab. The PFS rates at 3 years were 39% for the nivolumab plus ipilimumab group, 32% for the nivolumab monotherapy group and 10% for the ipilimumab monotherapy group, with 95% CIs for the two nivolumab groups that did not overlap with that for ipilimumab alone. CONCLUSIONS: Among patients with advanced melanoma, significantly longer OS and PFS occurred with the combination of nivolumab plus ipilimumab or with nivolumab alone compared with ipilimumab alone. Furthermore, survival outcomes favoured the nivolumab containing groups over the ipilimumab group in subgroup analyses. PMID- 29766493 TI - Multidisciplinary management of periocular tumour excision repair. PMID- 29766494 TI - Digest: Demographic inferences accounting for selection at linked sites?. AB - Complex demography and selection at linked sites can generate spurious signatures of divergent selection. Unfortunately, many attempts at demographic inference consider overly simple models and neglect the effect of selection at linked sites. In this issue, Rougemont and Bernatchez (2018) applied an approximate Bayesian computation (ABC) framework that accounts for indirect selection to reveal a complex history of secondary contacts in Atlantic salmon (Salmo salar) that might explain a high rate of latitudinal clines in this species. PMID- 29766496 TI - Infant Motor Development in Autism Spectrum Disorder: A Synthesis and Meta analysis. AB - Studies of infant motor development in autism spectrum disorder (ASD) have increased in recent years. This article synthesized this literature through meta analysis to assess (a) whether infant motor ability differs in ASD relative to neurotypical controls; and (b) whether motor ability and communication are related in infants with ASD. Study 1 aggregated data from 1,953 infants with ASD (ages 3.0-42.0 months), and Study 2 included 890 infants with ASD (age 6.0-42.9 months). Study 1 revealed that infant motor ability differed significantly in ASD compared with neurotypical infants-this difference was robust to variation in measurement and design. Furthermore, this group difference amplified as age increased. Study 2 indicated that within ASD, infant motor ability and communication are related. PMID- 29766495 TI - iNEXT: a European facility network to stimulate translational structural biology. PMID- 29766497 TI - Hydraulic Conductivity Calibration of Logging NMR in a Granite Aquifer, Laramie Range, Wyoming. AB - In granite aquifers, fractures can provide both storage volume and conduits for groundwater. Characterization of fracture hydraulic conductivity (K) in such aquifers is important for predicting flow rate and calibrating models. Nuclear magnetic resonance (NMR) well logging is a method to quickly obtain near-borehole hydraulic conductivity (i.e., KNMR ) at high-vertical resolution. On the other hand, FLUTe flexible liner technology can produce a K profile at comparable resolution but requires a fluid driving force between borehole and formation. For three boreholes completed in a fractured granite, we jointly interpreted logging NMR data and FLUTe K estimates to calibrate an empirical equation for translating borehole NMR data to K estimates. For over 90% of the depth intervals investigated from these boreholes, the estimated KNMR are within one order of magnitude of KFLUTe . The empirical parameters obtained from calibrating the NMR data suggest that "intermediate diffusion" and/or "slow diffusion" during the NMR relaxation time may occur in the flowing fractures when hydraulic aperture are sufficiently large. For each borehole, "intermediate diffusion" dominates the relaxation time, therefore assuming "fast diffusion" in the interpretation of NMR data from fractured rock may lead to inaccurate KNMR estimates. We also compare calibrations using inexpensive slug tests that suggest reliable KNMR estimates for fractured rock may be achieved using limited calibration against borehole hydraulic measurements. PMID- 29766498 TI - Routine Language: Speech Directed to Infants During Home Activities. AB - Everyday activities are replete with contextual cues for infants to exploit in the service of learning words. Nelson's (1985) script theory guided the hypothesis that infants participate in a set of predictable activities over the course of a day that provide them with opportunities to hear unique language functions and forms. Mothers and their firstborn 13-month-old infants (N = 40) were video-recorded during everyday activities at home. Transcriptions and coding of mothers' speech to infants-time-locked to activities of feeding, grooming, booksharing, object play, and transition-revealed that the amount, diversity, pragmatic functions, and semantic content of maternal language systematically differed by activity. The activities of everyday life shape language inputs to infants in ways that highlight word meaning. PMID- 29766501 TI - Impact of gastrointestinal disease states on oral drug absorption - implications for formulation design - a PEARRL review. AB - OBJECTIVES: Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed. KEY FINDINGS: Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy. CONCLUSIONS: Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential. PMID- 29766502 TI - Frost and leaf-size gradients in forests: global patterns and experimental evidence. AB - Explanations of leaf size variation commonly focus on water availability, yet leaf size also varies with latitude and elevation in environments where water is not strongly limiting. We provide the first conclusive test of a prediction of leaf energy balance theory that may explain this pattern: large leaves are more vulnerable to night-time chilling, because their thick boundary layers impede convective exchange with the surrounding air. Seedlings of 15 New Zealand evergreens spanning 12-fold variation in leaf width were exposed to clear night skies, and leaf temperatures were measured with thermocouples. We then used a global dataset to assess several climate variables as predictors of leaf size in forest assemblages. Leaf minus air temperature was strongly correlated with leaf width, ranging from -0.9 to -3.2 degrees C in the smallest- and largest-leaved species, respectively. Mean annual temperature and frost-free period were good predictors of evergreen angiosperm leaf size in forest assemblages, but no climate variable predicted deciduous leaf size. Although winter deciduousness makes large leaves possible in strongly seasonal climates, large-leaved evergreens are largely confined to frost-free climates because of their susceptibility to radiative cooling. Evergreen leaf size data can therefore be used to enhance vegetation models, and to infer palaeotemperatures from fossil leaf assemblages. PMID- 29766499 TI - Optimal Timing of Physician Visits after Hospital Discharge to Reduce Readmission. AB - OBJECTIVE: To identify the optimal timing of in-person physician visit after hospital discharge to yield the largest reduction in readmission among elderly or chronically ill patients. DATA SOURCES/STUDY SETTING/EXTRACTION METHODS: We extracted insurance billing data on 620,656 admissions for any cause from 2002 to 2009 in Quebec, Canada. STUDY DESIGN: We used flexible survival models to estimate inverse probability weights for the precise timing (days) of in-person physician visit after discharge and weighted competing risk outcome models. PRINCIPAL FINDINGS: Readmission reduction associated with in-person physician visits (compared to none) was seen early after discharge, with 67.8 fewer readmissions per 1,000 discharges if physician visit occurred within 7 days (95 percent CI: 66.7-69.0), and 110.0 fewer readmissions within 21 days (95 percent CI: 108.2-111.7). The period of largest contribution to readmission reduction was seen in the first 10 days, while physician visits occurring later than 21 days after discharge did not further contribute to reducing hospital readmissions. Larger risk reductions were observed among patients in the highest morbidity level and for in-person follow-up with a primary care physician rather than a medical specialist. CONCLUSIONS: When provided promptly, postdischarge in-person physician visit can prevent many readmissions. The benefits appear optimal when such visit occurs within the first 10 days, or at least within the first 21 days of discharge. PMID- 29766500 TI - Konjac glucomannan octenyl succinate (KGOS) as an emulsifier for lipophilic bioactive nutrient encapsulation. AB - BACKGROUND: Konjac glucomannan octenyl succinate (KGOS) has excellent emulsification properties and can potentially be used in the food industry as an emulsifier, stabilizer and microcapsule wall material. In the present study, the in vitro digestion properties and emulsification capability and stability of KGOS were studied to evaluate the transport and encapsulation characteristics of KGOS with insoluble bioactive nutrients. RESULTS: Confocal scanning laser microscopy (CSLM) suggested that oil droplets could be encapsulated by KGOS into regular spheres. In vitro digestion properties showed that KGOS is effective for colon targeted transport. beta-Carotene was selected as a representative lipophilic bioactive compound to evaluate the emulsification characteristics of KGOS. The loading capacity of the 0.4 mg mL-1 KGOS solution for beta-carotene was 3.26%, and transmission electron microscopy suggested that the self-aggregate particles of KGOS/beta-carotene (KGOSC) were more uniform than KGOS. With a composition of 0.03% beta-carotene, 0.3% KGOS and 10% medium-chain triglycerides, the emulsification yield of the KGOSC nanoemulsion was more than 95%. After 30 days of storage, the particle size and polydispersity index of the KGOSC nanoemulsion were less than 5 nm and 0.5, respectively, and the sensitivity of KGOSC nanoemulsions to storage conditions decreased in the order temperature, oxygen and light. CONCLUSION: The results of this study suggested that KGOS is a good potential emulsifier and stabilizer for lipophilic bioactive nutrient encapsulation. (c) 2018 Society of Chemical Industry. PMID- 29766503 TI - Transcriptome Analysis of Potential miRNA Involved in Adipogenic Differentiation of C2C12 Myoblasts. AB - >Emerging evidence indicates that microRNA (miRNA) plays an important role in adipogenesis and disease pathogenesis. To investigate the miRNA involved in regulating different periods of adipogenesis, we performed a comprehensive study on microRNAome during the stimulation of adipogenesis by an adipogenic differentiation cocktail in C2C12 myoblasts at 0, 2, 4, and 7 days using the Solexa sequencing technology. In this study, we identified 52 differentially expressed (DE) miRNA. Functional annotation indicated that the target genes of DE miRNA were mostly enriched in adipogenic transdifferentiation and fat metabolism related pathways, including Wnt, mitogen-activated protein kinase (MAPK), and insulin signaling. The insulin signaling pathway was further analyzed for its close connections to Wnt and MAPK signaling pathways as well as for the containing of thymoma viral proto-oncogene-3 (Akt3) and glycogen synthase kinase 3 beta (Gsk3b), which were both target genes predicted by most DE miRNA. CLIP-seq (crosslinking-immunprecipitation and high-throughput sequencing) data showed that Akt3 was targeted by seven DE miRNA, including five upregulated (miR-203-3p, miR 181c-5p, miR-322-5p, miR-351-5p, and miR-181a-5p) and two downregulated (miR-15b 5p and miR-17-5p) ones. Likewise, Gsk3b was targeted by six DE miRNA, including four upregulated (miR-199a-3p, miR-126-5p, miR-26a-5p, and miR-101a-3p) and two downregulated (miR-150-5p and miR-140-3p) ones. Moreover, Akt3 could regulate the key transcription factor (TF) Foxo1, targeted by two downregulated miRNA (miR-96 5p and miR-183-5p). The expression levels of Akt3 and Gsk3b were downregulated, and TF Foxo1, which worked on the transcription axis of Pgc1a-Pparalpha-Rxrg Ppargamma to regulate adipogenesis, was upregulated. In conclusion, DE miRNA stimulated the adipogenesis of C2C12 myoblasts through the targeted insulin signaling pathway involving the genes Akt3, Gsk3b, and TF Foxo1. PMID- 29766504 TI - Indene Compounds Synthetically Derived from Vitamin D Have Selective Antibacterial Action on Helicobacter pylori. AB - Helicobacter pylori infects the human stomach and is closely linked with the development of gastric cancer. When detected, this pathogen can be eradicated from the human stomach using wide-spectrum antibiotics. However, year by year, H. pylori strains resistant to the antibacterial action of antibiotics have been increasing. The development of new antibacterial substances effective against drug-resistant H. pylori is urgently required. Our group has recently identified extremely selective bactericidal effects against H. pylori in (1R,3aR,7aR)-1 [(1R)-1,5-dimethylhexyl]octahydro-7a-methyl-4H-inden-4-one (VDP1) (otherwise known as Grundmann's ketone), an indene compound derived from the decomposition of vitamin D3 and proposed the antibacterial mechanism whereby VDP1 induces the bacteriolysis by interacting at least with PtdEtn (dimyristoyl phosphatidylethanolamine [di-14:0 PtdEtn]) retaining two 14:0 fatty acids of the membrane lipid constituents. In this study, we synthesized new indene compounds ((1R,3aR,7aR)-1-((2R,E)-5,6-dimethylhept-3-en-2-yl)-7a-methyloctahydro-4H-inden-4 one [VD2-1], (1R,3aR,7aR)-1-((S)-1-hydroxypropan-2-yl)-7a-methyloctahydro-1H inden-4-ol [VD2-2], and (1R,3aR,7aR)-7a-methyl-1-((R)-6-methylheptan-2 yl)octahydro-1H-inden-4-ol [VD3-1]) using either vitamin D2 or vitamin D3 as materials. VD2-1 and VD3-1 selectively disrupted the di-14:0 PtdEtn vesicles without destructing the vesicles of PtdEtn (dipalmitoyl-phosphatidylethanolamine) retaining two 16:0 fatty acids. In contrast, VD2-2, an indene compound lacking an alkyl group, had no influence on the structural stability of both PtdEtn vesicles. In addition, VD2-1 and VD3-1 exerted extremely selective bactericidal action against H. pylori without affecting the viability of commonplace bacteria. Meanwhile, VD2-2 almost forfeited the bactericidal effects on H. pylori. These results suggest that the alkyl group of the indene compounds has a crucial conformation to interact with di-14:0 PtdEtn of H. pylori membrane lipid constituents whereby the bacteriolysis is ultimately induced. PMID- 29766505 TI - Esophageal multimodal stimulation and sensation. AB - Esophageal mechanosensation describes the relationship between a mechanical stimulation of the esophageal wall, such as bag distension, and the reaction to the stimulation perceived or unperceived. When studying mechanosensation in esophageal disease, it is important to recognize that symptoms might be due to alterations at different levels of the neuromuscular system, such as alterations at the mechanoreceptor level or in the afferent mechanosensory pathways, or irregularities in the homeostatic state. One might ask if it is possible to provoke, record, and describe the multidimensional responses behind a mechanosensory experience? It is a complex system and, at a minimum, a multidisciplinary approach is needed to avoid erroneous conclusions. The multimodal study design, taking the mode, location, and parameters of stimulation into consideration, together with controlled recording of assessment parameters, is an approach that seems rational and valid. Gastrointestinal (GI) physicians of the 21th century need to have knowledge of advances in the evaluation of GI mechanical function and what provokes symptoms. Hereby, it is possible to fully appreciate the slowly emerging awareness of how GI pain symptoms should be explored and explained to patients. PMID- 29766506 TI - Unique causes of esophageal inflammation: a histopathologic perspective. AB - Gastroenterologists frequently perform endoscopic esophageal mucosal biopsies for pathologic diagnosis in patients experiencing symptoms of esophagitis. The more common causes of esophagitis diagnosed on esophageal mucosal biopsy include reflux esophagitis, eosinophilic esophagitis, and infectious esophagitis caused by Candida albicans, herpes simplex virus, and/or cytomegalovirus. However, there are several causes of esophagitis seen less frequently by pathologists that are very important to recognize. We discuss unique types of esophageal inflammation, including acute bacterial esophagitis, esophageal manifestations of dermatologic diseases, medication-induced esophageal injury, and sloughing esophagitis; and we review their clinical and histopathologic features. PMID- 29766507 TI - Abscisic acid prevents pollen abortion under high-temperature stress by mediating sugar metabolism in rice spikelets. AB - Heat stress at the pollen mother cell (PMC) meiotic stage leads to pollen sterility in rice, in which the reactive oxygen species (ROS) and sugar homeostasis are always adversely affected. This damage is reversed by abscisic acid (ABA), but the mechanisms underlying the interactions among the ABA, sugar metabolism, ROS and heat shock proteins in rice spikelets under heat stress are unclear. Two rice genotypes, Zhefu802 (a recurrent parent) and fgl (its near isogenic line) were subjected to heat stress of 40 degrees C after pre-foliage sprayed with ABA and its biosynthetic inhibitor fluridone at the meiotic stage of PMC. The results revealed that exogenous application of ABA reduced pollen sterility caused by heat stress. This was achieved through various means, including: increased levels of soluble sugars, starch and non-structural carbohydrates, markedly higher relative expression levels of heat shock proteins (HSP24.1 and HSP71.1) and genes related to sugar metabolism and transport, such as sucrose transporters (SUT) genes, sucrose synthase (SUS) genes and invertase (INV) genes as well as increased antioxidant activities and increased content of adenosine triphosphate and endogenous ABA in spikelets. In short, exogenous application of ABA prior to heat stress enhanced sucrose transport and accelerated sucrose metabolism to maintain the carbon balance and energy homeostasis, thus ABA contributed to heat tolerance in rice. PMID- 29766508 TI - Repair of lumbosacral fracture-luxation with bilateral twisted string-of-pearls locking plates. AB - OBJECTIVES: To describe a surgical technique using bilateral twisted string-of pearls locking plates for lumbosacral fracture-luxation in dogs and cats. MATERIALS AND METHODS: Twisted string-of-pearls locking plates were used to stabilise lumbosacral fracture-luxation between 2013 and 2017. Decompression of the cauda equina was achieved by dorsal laminectomy through a dorso-medial approach. Stabilisation was achieved using bilateral string-of-pearls plates attached to the lateral aspects of the vertebral body cranial to the fractured vertebra and the iliosacral joints. Reduction of the luxation was assessed under fluoroscopy. Outcome and complications were evaluated 24 hours, 6 weeks and 6 months postoperatively. RESULTS: Six animals (four dogs and two cats) were included. Five animals were presented with non-ambulatory paraparesis. Tail anaesthesia and severe lumbosacral pain was evident in all cases but one. Six weeks postoperatively, all animals improved to ambulation, and tail sensation recovered. The long-term clinical outcome was defined as excellent in five and satisfactory in the remaining case. CLINICAL SIGNIFICANCE: Bilateral twisted string-of-pearls locking plates can be associated with a satisfactory result in treating lumbosacral fracture-luxation. PMID- 29766509 TI - Acceleration and deceleration at constant speed: systematic modulation of motion perception by kinematic sonification. AB - Many domains of human behavior are based on multisensory representations. Knowledge about the principles of multisensory integration is useful to configure real-time movement information for the online support of perceptuomotor processes (motor perception, control, and learning). A powerful method for generating real time information is movement sonification. Remarkable evidence exists on movement acoustic real-time information being effective in behavioral domains (music training, motor rehabilitation, sports). Here, we investigate whether and how biological motion perception can be enhanced, substituted, or modulated by kinematic sonification, with a focus on pitch coding. We work with gross motor cyclic movements and investigate the effectiveness of pitch scaling and consistent transposition on audiovisual motor perception accuracy (Experiment A). Beyond that, a new kind of audiovisual stimulus with inconsistent pitch transposition is used to produce a directed modulation of the integrated audiovisual percept (Experiment B). Results from Experiment A indicate pitch being powerful for mediating kinematic information to enhance motor perception and substituting information between perceptual modalities, even exceeding visual performance. Beyond these findings, results from Experiment B indicate that visual estimations of movement velocity can be enhanced or reduced auditorily. Movement sonification used for reshaping intermodal adjustments should be a powerful new tool for subconsciously shaping human movement patterns in the future. PMID- 29766511 TI - Relevance of histology in the diagnosis of reflux esophagitis. AB - Reflux esophagitis is an important clinical diagnosis; however, the histologic findings can be nonspecific and overlap with other entities. Various benign changes can produce diagnostic difficulties for pathologists. In this review, the typical histologic findings of gastroesophageal reflux disease (GERD) of the esophagus are discussed, along with the issues relating to clinical correlation and technical aspects of endoscopic biopsies and specimen processing. The literature has been reviewed to discuss histologic definitions of GERD as well as current and developing controversies in the area of GERD. Histologic features are not entirely sensitive or specific for GERD. Awareness of these problems is essential; clinical and endoscopic information can be very useful in distinguishing GERD from other inflammatory lesions. PMID- 29766510 TI - Ineffectiveness of saxagliptin as a neuroprotective drug in 6-OHDA-lesioned rats. AB - OBJECTIVES: To determine whether the drug saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor which is utilized for the treatment of Diabetes Mellitus, has neuroprotective effects in the animal model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA) in rats. METHODS: Male Wistar rats (weighing 280 300 g) received a bilateral infusion of 6-OHDA in the substantia nigra. Twenty four hours later, they were treated with saxagliptin (1 mg/kg, p.o) once daily, for 21 days. The motor function was evaluated using the open field and rotarod (RT) tests. In addition, cognition was assessed with the novel object recognition test (ORT). After the evaluation of the behavioural tests, the animals were transcardially perfused to perform immunohistochemistry staining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc). KEY FINDINGS: Saxagliptin impaired the memory of animals in the sham group. CONCLUSIONS: Saxagliptin treatment did not exhibit neuroprotection and it did not improve the cognitive and motor deficits in the 6-OHDA model of PD. Interestingly, when saxagliptin was administered to the sham animals, a cognitive decline was observed. Therefore, this drug should be investigated as a possible treatment for PTSD. PMID- 29766512 TI - Structured radiology reporting on an institutional level-benefit or new administrative burden? AB - Significant technical advances have been made in radiology since the first discovery of X-rays. Diagnostic techniques have become more and more complex, workflows have been digitized, and data production has increased exponentially. However, the radiology report as the main method for communicating examination results has largely remained unchanged. Growing evidence supports that more structured radiology reports offer various benefits over conventional narrative reports. Various efforts have been made to further develop and promote structured reporting. However, regardless of the potential benefits, structured reporting has still not seen widespread implementation into the clinical routine. With recent technical advances, especially new research topics such as big data and machine learning, structured reporting could prove essential for the future of radiology. New interoperable solutions are needed to facilitate the implementation of template-based structured reporting into the clinical routine. PMID- 29766513 TI - Nurses' knowledge and attitudes about dementia care: Systematic literature review. AB - PURPOSE: To explore nurse's knowledge and attitudes toward the care of people with dementia. DESIGN AND METHODS: A systematic review informed by the PRISMA-P (preferred reporting items for systematic reviews and meta-analyses protocols) guidelines in four databases (CINAHL, PsyINFO, Pubmed, Cohrane, EMBASE) using keywords "attitudes," "behaviors," "dementia," "knowledge," and "nurses." Predetermined inclusion criteria were selected. The review was conducted between January 1 and December 30, 2017. FINDINGS: Sixteen quantitative studies, one qualitative, and two mixed methods studies were included. Nurses lack knowledge, communication skills, management strategies, and confidence in the provision of dementia care. Interventional studies suggested that knowledge and attitudes improved after training programs were implemented. PRACTICE IMPLICATION: This review contributes to care advancement and practice development through the reinforcement of organizational support and educational opportunities for nurses. PMID- 29766514 TI - Effect of catalytic subunit phosphorylation on the properties of SnRK1 from Phaseolus vulgaris embryos. AB - Legume seed development represents a high demand for energy and metabolic resources to support the massive synthesis of starch and proteins. However, embryo growth occurs in an environment with reduced O2 that forces the plant to adapt its metabolic activities to maximize efficient energy use. SNF1-related protein kinase1 (SnRK1) is a master metabolic regulator needed for cells adaptation to conditions that reduce energy availability, and its activity is needed for the successful development of seeds. In bean embryo extracts, SnRK1 can be separated by anion exchange chromatography into two pools: one where the catalytic subunit is phosphorylated (SnRK1-p) and another with reduced phosphorylation (SnRK1-np). The phosphorylation of the catalytic subunit produces a large increase in SnRK1 activity but has a minor effect in determining its sensitivity to metabolic inhibitors such as trehalose 6-P (T6P), ADP-glucose (ADPG), glucose 1-P (G1P) and glucose 6-P (G6P). In Arabidopsis thaliana, upstream activating kinases (SnAK) phosphorylate the SnRK1 catalytic subunit at T175/176, promoting and enhancing its activity. Recombinant Phaseolus vulgaris homologous to SnAK proteins (PvSnAK), can phosphorylate and activate the catalytic domains of the alpha-subunits of Arabidopsis, as well as the SnRK1-np pool purified from bean embryos. While the phosphorylation process is extremely efficient for catalytic domains, the phosphorylation of the SnRK1-np complex was less effective but produced a significant increase in activity. The presence of SnRK1-np could contribute to a quick response to unexpected adverse conditions. However, in addition to PvSnAK kinases, other factors might contribute to regulating the activation of SnRK1. PMID- 29766515 TI - Results of pneumatic dilation in treating achalasia: predictive factors. AB - Forced pneumatic dilatation (PD) of the cardia is one of the most consecrated therapeutic measures for esophageal achalasia. The procedure only achieved better standardization with the appearance of the Rigiflex balloon. Results and predictive factors of success and failure of PD are reviewed, right after the description of the main technical aspects of the procedure. The success rates, providing control of dysphagia for about 1 year from the procedure using the Rigiflex balloon, are quite satisfactory, with success in more than 75% of patients. It is generally observed that good responses sustained for more than 5 years appear in at least 40% of cases. However, approximately half of the patients submitted to PD require additional dilation and a subgroup of them will undergo surgical treatment to attain adequate control of dysphagia. PD is a method with a low rate of acute complications, with esophageal perforation, the most severe of them, not affecting more than 5% of the cases. The best results could be potentially obtained when predictive factors of success were considered before choosing PD as a therapeutic option, but prospective studies in this field are missing until now. PMID- 29766516 TI - Radiographic bone loss in a Scottish non-smoking type 1 diabetes mellitus population: A bitewing radiographic study. AB - BACKGROUND: The dental complications of uncontrolled diabetes include reduced salivary flow rate, candidiasis and periodontal manifestations. A recent meta analysis concluded that diabetes patients have a significantly higher severity, but not extent, of destructive periodontal disease than non-diabetics. The authors reported that most type-1 diabetes studies using dental radiographic data have not controlled for confounding factors such as smoking. The aim of this cross-sectional study was to compare radiographic alveolar bone loss between type 1 diabetes (T1DM) and non-diabetes (NDM) participants in a Scottish non-smoking population. METHODS: Digital bitewing radiographs for 174 Scottish adults never or ex-smoker (>5 years) participants (108 T1DM, 66 NDS), recruited from outpatient clinics throughout Greater Glasgow and Clyde, were included in the analysis. A single blinded, trained, and calibrated examiner recorded the radiographic bone loss seen on bitewing radiographs using the digital screen caliper (Screen Calliper ICONICO version 4.0 (Copyright (C) 2001-6 Iconico), New York). The bone loss was measured as the distance between the cemento-enamel junction (CEJ) and the deepest radiographic alveolar bone margin interproximally of each tooth. RESULTS: T1DM participants had more radiographic alveolar bone loss throughout the all teeth measured (median:1.27 mm versus 1.06 mm, P < 0.001) and more than a two-fold increase in the risk of having sites with >=2 mm periodontal destruction (OR = 2.297, 95%CI 1.058 to 4.986, P = 0.036) compared with non-diabetes subjects. CONCLUSIONS: Patients suffering from type 1 diabetes are at higher risk of periodontitis even when controlling for multiple possible confounding factors and this difference can be detected on routine dental radiographs at an early stage. These data confirm radiographically the previously reported association between T1DM and periodontal bone loss. PMID- 29766517 TI - Occupational fixed drug eruption with ipe wood. PMID- 29766519 TI - Lack of correspondence between the reactive proactive questionnaire and the impulsive premeditated aggression scale among forensic psychiatric outpatients. AB - The most studied bimodal classifications of aggressive behavior are the impulsive/premeditated distinction measured with the Impulsive Premeditated Aggression Scale and the reactive/proactive distinction measured with the Reactive Proactive Questionnaire. The terms of these classifications are often used interchangeably, assuming that reactive aggression is equivalent to impulsive aggression and that proactive aggressive behavior is the same as premeditated aggression. The correspondence or discrepancy between both aggression classifications/questionnaires, however, is understudied. Therefore, the current study investigated the correspondence between the RPQ and IPAS in a sample of 161 forensic psychiatric outpatients (FPOs) with severe aggressive behavior. Correlation analysis revealed a limited correspondence between the RPQ and IPAS. Cluster analyses derived three clusters from the RPQ as well as the IPAS: these clusters did not match in 60.3% of the cases. Furthermore, the notion that the RPQ measures trait aggression whereas the IPAS assesses state aggression could not be verified. The present study indicates that aggression subtypes as measured by use of the RPQ and IPAS correspond only partially and should not be used interchangeably. Furthermore, it was suggested that RPQ focuses more on actual aggressive behavior and the IPAS more on emotions and their regulation. Future research is needed to elucidate the applicability of both questionnaires in further detail. PMID- 29766520 TI - The role of electronic health records in clinical reasoning. AB - Electronic health records (eHRs) play an increasingly important role in documentation and exchange of information in multi-and interdisciplinary patient care. Although eHRs are associated with mixed evidence in terms of effectiveness, they are undeniably the health record form of the future. This poses several learning opportunities and challenges for medical education. This review aims to connect the concept of eHRs to key competencies of physicians and elaborates current learning science perspectives on diagnostic and clinical reasoning based on a theoretical framework of scientific reasoning and argumentation. It concludes with an integrative vision of the use of eHRs, and the special role of the patient, for teaching and learning in medicine. PMID- 29766518 TI - PLS, iPLS, GA-PLS models for soluble solids content, pH and acidity determination in intact dovyalis fruit using near-infrared spectroscopy. AB - BACKGROUND: Dovyalis species Dovyalis abyssinica Warb. and Dovyalis hebecarpa Warb. were introduced into Brazil, but the fruit quality of these species is not appropriate for fresh consumption due to their high titratable acidity (TA) and low soluble solids content (SSC). With the selection of new D. abyssinica clones with lower acidity and the hybridization of these two dovyalis species (D. abyssinica and D. hebecarpa) the fruit quality improved and the better physical chemical characteristics make them more suitable for fresh consumption. The objective of this study was to develop partial least squares (PLS) models using near infrared spectroscopy (NIRS) for the determination of SSC, TA and pH in intact dovyalis hybrid fruit (D. abyssinica Warb. * D. hebecarpa Warb.). RESULTS: The best SSC prediction model was developed with PLS regression (root mean square error of prediction (RMSEP ) of 0.71 degrees Brix, prediction data set (RP 2 ) of 0.74 and residual predictive deviation (RPD) of 2.82). Although interval PLS was tested, genetic algorithm PLS performed better for TA (RMSEP of 4.8 g kg-1 , RP 2 of 0.40, and RPD of 1.67), and for pH (RMSEP of 0.03, RP 2 of 0.90, and RPD of 6.67). CONCLUSION: NIRS can be used as a non-destructive method to determine quality parameters in intact dovyalis hybrid fruit. (c) 2018 Society of Chemical Industry. PMID- 29766521 TI - Current and future perspectives in the management of gastroesophageal reflux disease. AB - Although the prevalence of gastroesophageal reflux disease (GERD) used to be lower in East Asia as compared to Western countries, it has recently been increasing, most likely due to the socioeconomic development in the East. The prevalence of both GERD and functional gastrointestinal disorders (FGIDs) ranges between 10% and 25% worldwide and there are distinct subgroups of patients with overlapping of GERD and FGIDs. However, the true prevalence of an overlap between GERD and FGIDs can be determined only when a formal pathophysiological evaluation has been performed. Nocturnal reflux symptoms have a significant impact on patients' sleep quality and quality of life. Although proton pump inhibitors (PPIs) can improve both reflux and sleep-related symptoms, the relationship between nocturnal reflux events and sleep disturbance is not fully understood. GERD plays an important role in the pathogenesis of lung fibrosis, and PPIs or fundoplication may decrease the likelihood of pulmonary exacerbation or even improve pulmonary function. Refractory reflux symptoms without esophagitis have become one of the most common presentations of GERD in gastroenterology clinics. There are several new medical therapies, and endoscopic as well as laparoscopic techniques that have been increasingly used in these patients. The selection of options should be tailored and individualized based on the pathophysiology of refractory GERD. PMID- 29766522 TI - To honor and obey: Perceptions and disclosure of sexual assault among honor ideology women. AB - The overwhelming majority of rapes goes unreported. To better understand the sociocultural mechanisms behind why underreporting may occur, three studies (total n = 1,481) examine how women's endorsement of honor values influence the perceptions of rape. Using vignettes that varied the closeness of the perpetrator of a sexual assault (i.e., stranger, acquaintance, or husband), we found that women who endorse honor values of womanhood were less likely to label a forced sexual act as "rape" and to suggest that the victim discloses the rape to others, including to the police. This was especially true the closer the victim was to the perpetrator (e.g., husband vs. stranger). Our findings highlight the effects of honor values on perceived sexual assault and the consequences of disclosure, and may aid in understanding barriers to rape reporting and areas for intervention. PMID- 29766523 TI - A case of allergic contact dermatitis caused by Disperse Blue dye in ultrasound gel. PMID- 29766524 TI - A tool to assure the geographical origin of local food products (glasshouse tomatoes) using labeling with rare earth elements. AB - BACKGROUND: Trace element fingerprinting has been widely used for identification of provenance of regional food. In the case of products from conventional agriculture, it is expected that the elemental composition will comply with that of the commercially available substrate of the plants. Therefore, for products without a direct relationship with the regional soil the region-specific differences in elemental composition are no longer recognizable. The idea of this work is the labeling of tomatoes with rare earth elements (REE) in the ultra trace range for food authentication. RESULTS: Labeling of tomatoes was carried out either by watering the soil with Nd- and Er-spiked water or by adding these elements as solid oxides to the soil. In both cases enrichment of Nd and Er relative to the control group was detected in tomato fruits and leaves using inductively coupled plasma-mass spectrometry. Tomato plants rapidly absorb the dissolved REE from the irrigation water, and watering for a short period just before ripeness is sufficient to induce REE labels. CONCLUSION: Labeling with trace amounts of REE could potentially be used to assure the provenance of tomatoes of local origin and separate these from products of foreign origin. (c) 2018 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29766525 TI - Establishment and validation of microsampling techniques in wild rodents for ecotoxicological research. AB - Compounds and products in the biocide and plant protection sector can only be registered after formal risk assessment to ensure safety for users and the environment. In bird and mammal risk assessment, this is routinely done using generic focal species as models, which are of particular exposure risk. Such a species is the common vole (Microtus arvalis) due to its high food intake relative to the low body weight. For wild species, biological samples, data and hence realistic exposure estimations are particularly difficult to obtain. In recent years, advances have been made in the techniques related to serial microsampling of laboratory mice and rats that allow for a reduction in sampling volumes. Similar progress in wild species sampling is missing. This study presents a proof of concept to dose wild rodents with relevant compounds and to draw serial, low volume blood samples suitable for state-of-the art toxicokinetic analyses. For the first time, the jugular vein of common voles was used to administer compounds (two frequently used fungicidal components). This procedure and the following microsampling of blood (2 * 10 MUl six times within 24 hours) from the lateral tail vein did not affect body weight and mortality of voles. Samples were sufficient to detect dissipation patterns of the compounds from blood in toxicokinetic analysis. These results suggest that microsampling can be well translated from laboratory mice to wild rodent species and help to obtain realistic exposure estimates in wild rodents for ecotoxicological studies as well as to promote the 3R concept in studies with wild rodent species. PMID- 29766528 TI - Reflecting on the Past: A Content Analysis of Family Therapy Research from 2000 2015. AB - In this content analysis, researchers examine articles published from 2000 to 2015 in three family therapy journals, yielding a total of 948 empirical articles. The purpose is to provide an overview of the research being published, assess who is publishing, and investigate the current state of clinical effectiveness research in marriage and family therapy (MFT). Most first authors were affiliated with MFT programs and primarily included diversity and couples in their research. There was a significant increase of research on clinical process though the number of clinical outcome studies held steady. There were no significant changes with regard to research funding. Implications support the use of innovative research methods to provide evidence of clinical effectiveness. PMID- 29766527 TI - Exploring workplace TB interventions with foreign-born Latino workers. AB - BACKGROUND: Persons born outside the United States are more likely to be diagnosed with tuberculosis disease (TB) than native-born individuals. Foreign born Latinos at risk of TB may be difficult to reach with public health interventions due to cultural and institutional barriers. Workplaces employing large concentrations of foreign-born Latinos may be useful locations for TB interventions targeting this high-risk population. METHOD: This study used a two phase approach to investigate the feasibility of workplace TB interventions. The first phase investigated employer knowledge of TB and receptiveness to allowing TB interventions in their businesses through 5 structured interviews. The second phase investigated foreign-born workers' knowledge of TB and their receptiveness to receiving TB interventions in their places of employment through 12 focus groups stratified by gender and education. RESULTS: Phase 1: Only 1 of the 5 employers interviewed had a high level of knowledge about TB, and three had no knowledge other than that TB was a disease that involved coughing. They were receptive to workplace TB interventions, but were concerned about lost productivity and customers finding out if an employee had TB. Phase 2: There was no observed differences in responses between gender and between the bottom two education groups, so the final analysis took place between a gender-combined lower education group and higher education group. The higher education group tended to have knowledge that was more accurate and to view TB as a disease associated with poverty. The lower education group tended to have more misconceptions about TB and more often expressed concern that their employers would not support worksite interventions. CONCLUSIONS: The results from both phases indicate that more TB education is needed among both foreign-born Latino workers and their employers. Obstacles to implementing workplace TB interventions include knowledge, potential productivity loss, employer liability, and perceived customer response. PMID- 29766526 TI - QTc interval in takotsubo cardiomyopathy: How the activation of insular cortex interacts. PMID- 29766529 TI - Ephedrine-induced maculopapular rash. PMID- 29766530 TI - Population pharmacokinetics of tacrolimus in paediatric systemic lupus erythematosus based on real-world study. AB - WHAT IS KNOWN AND OBJECTIVES: Different population pharmacokinetics (PPK) models of tacrolimus have been established in various populations. However, the tacrolimus PPK model in paediatric systemic lupus erythematosus (PSLE) is still undefined. This study aimed to establish the tacrolimus PPK model in Chinese PSLE. METHODS: A total of nineteen Chinese patients with PSLE from real-world study were characterized with nonlinear mixed-effects modelling (NONMEM). The impact of demographic features, biological characteristics, and concomitant medications was evaluated. Model validation was assessed by bootstrap and prediction-corrected visual predictive check (VPC). RESULTS: A one-compartment model with first-order absorption and elimination was determined to be the most suitable model in PSLE. The typical values of apparent oral clearance (CL/F) and the apparent volume of distribution (V/F) in the final model were 2.05 L/h and 309 L, respectively. Methylprednisolone and simvastatin were included as significant. WHAT IS NEW AND CONCLUSION: The first validated tacrolimus PPK model in patients with PSLE is presented. PMID- 29766531 TI - Nonparametric analysis of dependently interval-censored failure time data. AB - Failure time studies based on observational cohorts often have to deal with irregular intermittent observation of individuals, which produces interval censored failure times. When the observation times depend on factors related to a person's failure time, the failure times may be dependently interval censored. Inverse-intensity-of-visit weighting methods have been developed for irregularly observed longitudinal or repeated measures data and recently extended to parametric failure time analysis. This article develops nonparametric estimation of failure time distributions using weighted generalized estimating equations and monotone smoothing techniques. Simulations are conducted for examination of the finite sample performance of proposed estimators. This research is motivated in part by the Toronto Psoriatic Arthritis Cohort Study, and the proposed methodology is applied to this study. PMID- 29766532 TI - Root-expressed phytochromes B1 and B2, but not PhyA and Cry2, regulate shoot growth in nature. AB - Although photoreceptors are expressed throughout all plant organs, most studies have focused on their function in aerial parts with laboratory-grown plants. Photoreceptor function in naturally dark-grown roots of plants in their native habitats is lacking. We characterized patterns of photoreceptor expression in field- and glasshouse-grown Nicotiana attenuata plants, silenced the expression of PhyB1/B2/A/Cry2 whose root transcripts levels were greater/equal to those of shoots, and by micrografting combined empty vector transformed shoots onto photoreceptor-silenced roots, creating chimeric plants with "blind" roots but "sighted" shoots. Micrografting procedure was robust in both field and glasshouse, as demonstrated by transcript accumulation patterns, and a spatially explicit lignin visual reporter chimeric line. Field- and glasshouse-grown plants with PhyB1B2, but not PhyA or Cry2, -blind roots, were delayed in stalk elongation compared with control plants, robustly for two field seasons. Wild type plants with roots directly exposed to FR phenocopied the growth of irPhyB1B2 blind root grafts. Additionally, root-expressed PhyB1B2 was required to activate the positive photomorphogenic regulator, HY5, in response to aboveground light. We conclude that roots of plants growing deep into the soil in nature sense aboveground light, and possibly soil temperature, via PhyB1B2 to control key traits, such as stalk elongation. PMID- 29766533 TI - A cross-sectional study on experiences of young adult carers compared to young adult noncarers: parentification, coping and resilience. AB - BACKGROUND: Most young carer studies on parentification, resilience and coping concentrated on child carers up to age 18 years, whereas the group of young adult caregivers (18-24 years) has been neglected. In our study, we focused on these young adult caregivers, who are in a life phase in which young people usually are distancing themselves from their families and are striving for autonomy and freedom. AIM: To explore young adult carers' perceptions of parentification, resilience and coping compared to young adult noncarers. DESIGN: Cross-sectional. METHODS: In 2014/2015, data were collected on 297 healthcare students from a school for vocational education and a university in the Netherlands. A fully structured questionnaire was used. Young adult carers were compared with young adult noncarers on parentification, resilience and coping. RESULTS: Fifty-six students identified themselves as a carer: 40 vocational education students and 16 university students. Carers scored significantly higher than noncarers on three out of six parentification dimensions. No differences were found for resilience and problem-focused coping behaviour, whereas results for emotion focused coping demonstrated a higher score for the carers compared to the noncarers. CONCLUSION: Although it is important to take care of the needs of all young carers, special attention should be given to those who are at the start of their adult lives, undergoing extensive changes and taking major decisions on study and career issues. Home-care professionals and school counsellors should be able to recognise this group and their needs and activate support from specialised services and significant others. PMID- 29766534 TI - Duodenoduodenostomy for obstruction of the sigmoid flexure of the duodenum in cattle. AB - OBJECTIVE: To describe clinical findings, surgical treatment, and outcome associated with duodenoduodenostomy for treatment of duodenal obstruction secondary to adhesions associated with the sigmoid flexure of the duodenum. STUDY DESIGN: Retrospective study (1996-2016). ANIMALS: Fourteen Holstein cattle. METHODS: Medical records of cows treated at 3 academic surgical referral centers with duodenoduodenostomy for duodenal obstruction secondary to adhesions associated with the sigmoid flexure of the duodenum were reviewed. Data that were collected included signalment, physical examination results, laboratory results, diagnostic findings, treatments, and survival to discharge. Owners were contacted for follow-up information. RESULTS: Affected cattle ranged in age from 4 months to 5 years. Electrolyte abnormalities, including severe hypochloremia, were present in all cases. Abnormalities included cranial duodenal distension without concurrent distension of the descending duodenum and palpable focal adhesions in the region of the sigmoid flexure of the duodenum. Duodenoduodenostomy involved a stapled (n = 11) or sutured (n = 3) side-to-side anastomosis between the cranial duodenum and descending duodenum. Thirteen of 14 cattle that were treated with duodenoduodenostomy survived to hospital discharge. Long-term follow-up was available in 8 cows, and 7 of those 8 survived for at least 1 year. CONCLUSION: Short- and long-term survival were favorable after duodenoduodenostomy in cattle with adhesions associated with the sigmoid flexure of the duodenum. CLINICAL SIGNIFICANCE: Duodenoduodenostomy results in acceptable survival and future productivity in cows with obstruction at the sigmoid flexure of the duodenum. PMID- 29766535 TI - Deceptively bland cutaneous angiosarcoma on the nose mimicking hemangioma-A clinicopathologic and immunohistochemical analysis. AB - BACKGROUND: We investigated 2 cases of deceptively bland cutaneous angiosarcoma (AS), which showed a uniform clinical presentation with a rapidly growing tumor on the nose. It remains unclear whether this was a primary cutaneous manifestation or a metastasis. Both tumors initially presented a high histologic overlap with a benign vascular tumor. The diagnosis was primarily based on the rapidly progressing clinical course and on the results of the staging procedures. METHODS: Immunohistochemical stains were performed for cytokeratin (AE1/AE3 and MNF116), CD31, ERG, CD34 (HPCA1/my10), D2-40/podoplanin, LYVE-1, Ki67, PHH3, alphaSMA (1A4), MYC, FOS-B, CAMTA-1, TFE-3, WT1, nestin, VEGFR-2(KDR), VEGFR 3(FLT4), HHV8. MYC amplification was also investigated by fluorescence in situ hybridization. RESULTS: The tumor cells were negative for MYC and revealed no D2 40/podoplanin expression. SMA-positive pericytes formed rims around the vessel. The proliferative activity (Ki-67) was elevated, in one case only in a later stage. DISCUSSION: Cutaneous ASs can be rather bland and may easily be mistaken for benign vascular tumors. Both cases presented a uniform clinical picture, which implied a malignant vascular tumor. In contrast, the cytomorphology of the endothelial cells and the immunohistochemical profile were not suspicious. We worked out subtle histological criteria, which should allow an early detection of such tumors. PMID- 29766536 TI - Using accelerated drug stability results to inform long-term studies in shelf life determination. AB - In the pharmaceutical industry, the shelf life of a drug product is determined by data gathered from stability studies and is intended to provide consumers with a high degree of confidence that the drug retains its strength, quality, and purity under appropriate storage conditions. In this paper, we focus on liquid drug formulations and propose a Bayesian approach to estimate a drug product's shelf life, where prior knowledge gained from the accelerated study conducted during the drug development stage is used to inform the long-term study. Classical and nonlinear Arrhenius regression models are considered for the accelerated conditions, and two examples are given where posterior results from the accelerated study are used to construct priors for a long-term stability study. PMID- 29766537 TI - Quantifying and estimating the predictive accuracy for censored time-to-event data with competing risks. AB - This paper focuses on quantifying and estimating the predictive accuracy of prognostic models for time-to-event outcomes with competing events. We consider the time-dependent discrimination and calibration metrics, including the receiver operating characteristics curve and the Brier score, in the context of competing risks. To address censoring, we propose a unified nonparametric estimation framework for both discrimination and calibration measures, by weighting the censored subjects with the conditional probability of the event of interest given the observed data. The proposed method can be extended to time-dependent predictive accuracy metrics constructed from a general class of loss functions. We apply the methodology to a data set from the African American Study of Kidney Disease and Hypertension to evaluate the predictive accuracy of a prognostic risk score in predicting end-stage renal disease, accounting for the competing risk of pre-end-stage renal disease death, and evaluate its numerical performance in extensive simulation studies. PMID- 29766538 TI - Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice. AB - Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21-day-old male Swiss mice at doses of 15 and 30 mg kg-1 daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240-1100 ng dl-1 ). CBD treatment induced a significant increase in the frequency of stages I-IV and V-VI of spermatogenesis, and a decrease in the frequency of stages VII-VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity. PMID- 29766539 TI - Block versus longitudinal integrated clerkships: students' views of rural clinical supervision. AB - CONTEXT: Medical students undertaking longitudinal integrated clerkships (LICs) train in multiple disciplines concurrently, compared with students in block rotations who typically address one medical discipline at a time. Current research suggests that LICs afford students increased access to patients and continuity of clinical supervision. However, these factors are less of an issue in rural placements where there are fewer learners. The aim of this study was to compare rural LIC and rural block rotation students' reported experiences of clinical supervision. METHODS: De-identified data from the 2015 version of the Australian national rural clinical schools (RCSs) exit survey was used to compare students in LICs with those in block rotations in relation to how they evaluate their clinical supervisors and how they rate their own clinical competence. RESULTS: Multivariate general linear modelling showed no association between placement type (LIC versus Block) and reported clinical supervision. The single independent predictor of positive perception of clinical supervisors was choosing an RCS as a first preference. There was also no association between placement type (LIC versus Block) and self-rated clinical competence. Instead, the clinical supervision score and male gender predicted more positive self-ratings of clinical competence. CONCLUSIONS: The quality of clinical supervision in block placements and LIC programmes in rural Australian settings was reported by students as equivalent. PMID- 29766540 TI - Gaps in predicting clinical doses for cannabinoids therapy: Overview of issues for pharmacokinetics and pharmacodynamics modelling. AB - Model-based prediction on clinical doses for cannabinoids therapy is beneficial in the clinical setting, especially for seriously ill patients with both altered pharmacokinetics and pharmacodynamic responses. The objective of this article is to review the currently available PK and/or PD models of Delta9 tetrahydrocannabinol (THC) and cannabidiol (CBD) and to highlight the major issues for modelling this complex therapeutic area. A systematic search was conducted in the electronic databases PubMed and EMBASE using the key words 'cannabis', 'cannabinoid', 'tetrahydrocannabinol', 'THC', 'cannabidiol', 'CBD', 'pharmacokinetic model', 'pharmacodynamics model' and their combinations. Twelve empirical PK and/or PD models for THC for humans were identified. Among them, ten were developed from data of healthy participants and two were from ill patients. Models for CBD were not found. Model-based prediction on appropriate doses for cannabinoids therapy for ill patients is currently limited due to insufficiency of relevant PK and PD data. High-quality PK and PD data of cannabinoids for patients with different illnesses is needed for model development. Mechanism based PK and PD models are promising for improved predictive dosing performance for ill and comorbid patients. PMID- 29766541 TI - Gold nanoparticles in ophthalmology. AB - Many research projects are underway to improve the diagnosis and therapy in ophthalmology. Indeed, visual acuity deficits affect 285 million people worldwide and different strategies are being developed to strengthen patient care. One of these strategies is the use of gold nanoparticles (GNP) for their multiple properties and their ability to be used as both diagnosis and therapy tools. This review exhaustively details research developing GNPs for use in ophthalmology. The toxicity of GNPs and their distribution in the eye are described through in vitro and in vivo studies. All publications addressing the pharmacokinetics of GNPs administered in the eye are extensively reviewed. In addition, their use as biosensors or for imaging with optical coherence tomography is illustrated. The future of GNPs for ophthalmic therapy is also discussed. GNPs can be used to deliver genes or drugs through different administration routes. Their antiangiogenic and anti-inflammatory properties are of great interest for different ocular pathologies. Finally, GNPs can be used to improve stereotactic radiosurgery, brachytherapy, and photothermal therapy because of their many properties. PMID- 29766542 TI - Cyberbullying prevention: Insight and recommendations from youths, parents, and paediatricians. AB - BACKGROUND: The purpose of this study was to identify injunctive norms for cyberbullying prevention among youths, parents, and primary care providers, as well as barriers to preventive behaviours. METHODS: Semi-structured interviews on the topic of cyberbullying were conducted with 29 adolescents, 13 paediatricians, and 15 parents recruited from 3 primary care sites. Transcripts were coded for themes related to various stakeholders' perceived roles in cyberbullying prevention and barriers to preventive behaviours. RESULTS: Participants reported perceptions that youths should intervene in the moment and get outside help for others. Fear of repercussions emerged as a significant barrier to these behaviours. Participants believed that parents should communicate with their children and monitor and supervise youths' online activities. Barriers included perception of priority and low parental efficacy or naivete. Participants believed that providers should provide education and resources and ask screening questions; the most frequently identified barrier to those behaviours was the perception of providers' role. CONCLUSIONS: Youths and providers may not be aware of their potential to prevent cyberbullying before it occurs. Educating youths, parents, and providers about cyberbullying prevention is warranted. PMID- 29766543 TI - Assessing preschoolers interactive behaviour: A validation study of the "Coding System for Mother-Child Interaction". AB - BACKGROUND: The preschool years are a period of great developmental achievements, which impact critically on a child's interactive skills. Having valid and reliable measures to assess interactive behaviour at this stage is therefore crucial. The aim of this study was to describe the adaptation and validation of the child coding of the Coding System for Mother-Child Interactions and discuss its applications and implications in future research and practice. METHODS: Two hundred twenty Portuguese preschoolers and their mothers were videotaped during a structured task. Child and mother interactive behaviours were coded based on the task. Maternal reports on the child's temperament and emotional and behaviour problems were also collected, along with family psychosocial information. RESULTS: Interrater agreement was confirmed. The use of child Cooperation, Enthusiasm, and Negativity as subscales was supported by their correlations across tasks. Moreover, these subscales were correlated with each other, which supports the use of a global child interactive behaviour score. Convergent validity with a measure of emotional and behavioural problems (Child Behaviour Checklist 1 1/2-5) was established, as well as divergent validity with a measure of temperament (Children's Behaviour Questionnaire-Short Form). Regarding associations with family variables, child interactive behaviour was only associated with maternal behaviour. CONCLUSIONS: Findings suggest that this coding system is a valid and reliable measure for assessing child interactive behaviour in preschool age children. It therefore represents an important alternative to this area of research and practice, with reduced costs and with more flexible training requirements. Attention should be given in future research to expanding this work to clinical populations and different age groups. PMID- 29766545 TI - Association of handgrip strength with various oral functions in 82- to 84-year old community-dwelling Japanese. AB - OBJECTIVE: The purpose of this study was to elucidate the associations between muscle strength and several oral functions in a large cohort of community dwelling, 82- to 84-year-old community-dwelling Japanese people. BACKGROUND DATA DISCUSSING THE PRESENT STATUS OF THE FIELD: Several studies have examined the relationships between physical performance and oral functions. However, no studies have investigated the associations of muscle strength with various objectively evaluated oral functional parameters in a large cohort of very old adults. MATERIALS AND METHODS: This study included 809 community-dwelling Japanese people (407 men and 402 women) aged 82-84 years. The oral functions examined were the maximal occlusal force, masticatory performance, stimulated salivary flow rate, repetitive saliva-swallowing test (RSST) score, tongue pressure and mouth-opening distance. Handgrip strength was measured, and its correlations with oral functions were assessed. Multiple linear and logistic regression analyses were performed to investigate the relationships between oral functions and handgrip strength. RESULTS: Multivariate analysis revealed that handgrip strength was correlated with not only the maximal occlusal force, masticatory performance and tongue pressure but also the RSST score and mouth opening distance after adjustment for sex, number of teeth, use of removable denture, periodontal condition, instrumental activities of daily living, body mass index. When we examine the elderly people whose handgrip strength is declining, we should predict that their various oral functions may be declining. CONCLUSION: Handgrip strength was related to various oral functions after adjustment for the number of teeth in this population of community-dwelling 82- to 84-year-old Japanese. PMID- 29766544 TI - Dipeptidyl peptidase-4 inhibitor use is associated with decreased risk of fracture in patients with type 2 diabetes: a population-based cohort study. AB - AIMS: The aim of this study was to investigate the putative link between dipeptidyl peptidase-4 inhibitor (DPP-4i) use and the risk of fracture in patients with type 2 diabetes. METHODS: This propensity-score-matched population based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP-4i as a second-line antidiabetic drug. The same number of matched non-DPP-4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause-specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP-4i use and overall and cause-specific fractures stratified by age and sex. RESULTS: Over a maximum follow-up period of 5 years, 340 DPP-4i users and 419 non-DPP-4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP-4i use significantly reduced the risk of all-cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74-0.99) and 0.75 (95% CI: 0.59 0.95), respectively. The aforementioned associations of DDP-4i use with fracture were sustained across sex and age stratifications. CONCLUSIONS: The results of this study supported the premise that DPP-4i usage is associated with a reduced risk of all-cause fractures and upper extremity fractures in patients with type 2 diabetes. PMID- 29766546 TI - Therapeutic interventions to lessen the psychosocial effect of vitiligo in children: A review. AB - Vitiligo commonly affects children, with half of affected individuals experiencing disease onset before the age of 20. Because childhood is a time of advancement in social and psychological development, understanding the extent of the effect of the disease and means of alleviation is crucial. Vitiligo has been shown to decrease children's quality of life, with greater distress in children with highly visible lesions and darker skin tones. This article reviews the literature regarding interventions that have been analyzed in children. Studies evaluating the effect of camouflage, cognitive behavioral therapy, psychological self-help tools, and support groups on the psychosocial aspects of vitiligo were included. The review highlights the ongoing need for studies to better understand the modalities described in this article, as well as others, such as skin dyes, bleaching creams, medical tattooing; week-long camps that cater to children with chronic skin disease; and biofeedback, that might have a role in preventing the psychosocial sequelae of childhood vitiligo. PMID- 29766547 TI - Potent and selective CC chemokine receptor 1 antagonists labeled with carbon-13, carbon-14, and tritium. AB - 1-(4-Fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2 methanesulfonyl-pyridin-4-ylmethyl)-amide (1) and its analogs (2) and (3) are potent CCR1 antagonists intended for the treatment of rheumatoid arthritis. The detailed syntheses of these 3 compounds labeled with carbon-13 as well as the preparation of (1) and (2) labeled with carbon-14, and (1) labeled with tritium, are described. PMID- 29766548 TI - Dermal non-neural granular cell tumor in a 3-year-old child. AB - Dermal non-neural granular cell tumors, also known as primitive polypoid granular cell tumors, are a rare group of distinct cutaneous non-neural granular cell tumors. Pediatric cases are rare, and to the best of our knowledge, we report the youngest patient with dermal non-neural granular cell tumors. PMID- 29766549 TI - Leukocytoclastic vasculitis associated with immunoglobulin A lambda monoclonal gammopathy of undetermined significance: A case report and review of previously reported cases. AB - Leukocytoclastic vasculitis is often associated with immunoglobulin (Ig)A deposition on the vascular walls. IgA-associated leukocytoclastic vasculitis comprises various underlying diseases. Hematological disorders that can be minor triggers include multiple myeloma and monoclonal gammopathy of undetermined significance. Here, we present the case of a 78-year-old woman with leukocytoclastic vasculitis associated with monoclonal gammopathy of undetermined significance of the IgA lambda chain. Oral steroid administration initially showed remission of vasculitis; however, the condition recurred after four attempts of treatment withdrawal. We also reviewed previous reports of 14 cases of IgA-associated leukocytoclastic vasculitis, of which 11 were associated with multiple myeloma and three with monoclonal gammopathy of undetermined significance. PMID- 29766550 TI - What advice is given to newly qualified doctors on Twitter? An analysis of #TipsForNewDocs tweets. AB - CONTEXT: Twitter is a social media platform on which users post very brief messages that can be rapidly communicated across wide geographical areas and audiences. Many doctors use Twitter for personal as well as professional communications and networking. The #TipsForNewDocs hashtag is used on Twitter to give advice to newly qualified doctors as they commence their careers. This study explores the nature and focus of such advice. METHODS: An analysis of Twitter activity containing the #TipsForNewDocs hashtag was performed using Symplur health care analytics software. Tweets sent during a peak 48-hour period in 2016 (immediately preceding the first day of work for newly qualified UK doctors) were studied. The geographical locations and professional backgrounds of participants were categorised and the content of tweets was subjected to thematic analysis. During 1 and 2 August 2016, 661 unique #TipsForNewDocs tweets were posted. A total of 621 (94.0%) were posted by people in the UK; 522 (79.0%) were posted by doctors, and the remainder by allied health care professionals and patients. RESULTS: The majority of included tweets focused on aspects of professional development, improving personal or professional knowledge, particularly tacit knowledge, and developing 'know-how'. These aspects of professional knowledge have previously been described as fundamental to professional education and training. However, a significant subset of tweets focused on accelerating socialisation into the profession, an essential step in joining a professional community. The tweets relating to socialisation were often humorous and colloquial in nature. CONCLUSIONS: Despite their brief and often jocular nature, #TipsForNewDocs tweets provided meaningful advice for newcomers to the profession, often focusing on tacit learning and professional socialisation. Hashtag-driven enquiries can be a valuable and time-efficient way of accessing and sharing tacitly held knowledge. Social media content analysis can provide valuable insights into key educational issues. PMID- 29766551 TI - Lower lip capillary malformation associated with lymphatic malformation without overgrowth: Part of the spectrum of CLAPO syndrome. AB - Characteristic lower lip capillary malformation of CLAPO syndrome (Capillary malformation of the lower lip, Lymphatic malformations of the face and neck, Asymmetry, and Partial or generalized Overgrowth) may also occur as an isolated lesion or with only minor anomalies, supporting the concept that there is a spectrum of abnormalities in CLAPO syndrome. Preliminary studies have demonstrated mosaic activating mutations in PIK3CA. PMID- 29766553 TI - Erythema multiforme after orf virus infection. AB - The case of a 6-year-old boy with multiple, target-shaped lesions and a crusted nodule on his right index finger is presented. Based on clinical findings and the patient's recent contact with sheep and goats, a diagnosis of orf disease associated with erythema multiforme was suspected. Microscopy studies confirmed the presence of parapoxvirus in the primary lesion. Orf-induced erythema multiforme is a rare complication of orf in children, possibly related to the presence of orf virus DNA in erythema multiforme lesions. PMID- 29766552 TI - Hand, foot, and mouth disease photolocalized to sunburn. AB - Hand, foot, and mouth disease is a common exanthem linked to infection with several non-polio enteroviruses. This case of an 11-year-old boy with an enteroviral infection limited to areas of sunburn is an atypical presentation of hand, foot, and mouth disease. Recognition of this unusual distribution will allow pediatricians and pediatric dermatologists to appropriately manage and counsel patients and parents. PMID- 29766554 TI - Primary cutaneous aspergillosis at the site of cyanoacrylate skin adhesive in a neonate. AB - Primary cutaneous aspergillosis is a rare but potentially life-threatening disease. We present the case of a premature infant who developed primary cutaneous aspergillosis with Aspergillus niger at the site of a skin abrasion that had been treated with a purple-colored cyanoacrylate product. The infection was treated successfully with gentle debridement of the cyanoacrylate product, followed by intravenous voriconazole and topical fluconazole. To our knowledge, this is the first reported case of primary cutaneous aspergillosis occurring at the site of cyanoacrylate-based skin adhesive. PMID- 29766556 TI - Case of S100-positive benign cephalic histiocytosis involving monocyte/macrophage lineage marker expression. PMID- 29766555 TI - Hand-foot-skin reaction related to use of the multikinase inhibitor sorafenib and hard orthotics. AB - Hand-foot-skin reaction is a distinct clinical condition arising in association with the use of multikinase inhibitors, including sorafenib. Because multikinase inhibitors are increasingly being used in children with cancer, recognition of this previously unfamiliar condition is of importance to pediatric dermatologists. We describe the diagnosis and successful treatment of a case of hand-foot-skin reaction in a child taking sorafenib for an unresectable desmoid tumor. PMID- 29766557 TI - Risk factors for ocular complications in periocular infantile hemangiomas. AB - BACKGROUND/OBJECTIVES: Infantile hemangiomas are the most common benign tumors of childhood. Although some children with periocular infantile hemangiomas do not require treatment, these lesions may result in amblyopia and visual impairment if not properly treated. We have attempted to characterize clinical features of periocular infantile hemangiomas that predict negative ocular outcomes and thus require prompt referral to an ophthalmologist and initiation of therapy. METHODS: This study included children with periocular infantile hemangiomas consecutively seen at Ann & Robert H. Lurie Children's Hospital of Chicago from January 1994 through December 2014. Only patients evaluated by both a dermatologist and an ophthalmologist were included. Medical records of patients who met inclusion criteria were reviewed. Ocular findings were reviewed for the presence of ptosis, refractive errors, strabismus, proptosis, and amblyopia. RESULTS: Ninety-six patients (74% female, median age of onset 0.48 months) were included. Periocular infantile hemangiomas larger than 1 cm in diameter, with a deep component, and with involvement of the upper eyelid were significantly associated with astigmatism (P = .002, P = .02, and P = .003, respectively) and amblyopia (P = .002, P = .02, and P = .04, respectively). Using logistic regression, diameter greater than 1 cm (odds ratio = 14.13, P = .01) and amblyopia (odds ratio = 21.00, P = .04) were the strongest predictors of astigmatism. Lower lid and medial and lateral canthal involvement were not predictive of ocular complications. CONCLUSION: Predictive factors for ocular complications in patients with periocular infantile hemangiomas are diameter greater than 1 cm, a deep component, and upper eyelid involvement, with size being the most consistent predictor. These patients should be promptly referred to an ophthalmologist, and treatment should be strongly considered. PMID- 29766559 TI - Case of anti-p200 pemphigoid accompanying uterine malignancy. PMID- 29766558 TI - A cure-rate model for Q-learning: Estimating an adaptive immunosuppressant treatment strategy for allogeneic hematopoietic cell transplant patients. AB - Cancers treated by transplantation are often curative, but immunosuppressive drugs are required to prevent and (if needed) to treat graft-versus-host disease. Estimation of an optimal adaptive treatment strategy when treatment at either one of two stages of treatment may lead to a cure has not yet been considered. Using a sample of 9563 patients treated for blood and bone cancers by allogeneic hematopoietic cell transplantation drawn from the Center for Blood and Marrow Transplant Research database, we provide a case study of a novel approach to Q learning for survival data in the presence of a potentially curative treatment, and demonstrate the results differ substantially from an implementation of Q learning that fails to account for the cure-rate. PMID- 29766560 TI - Further options for treating lipids in people with diabetes: targeting LDL cholesterol and beyond. AB - Diabetes is associated with increased cardiovascular disease (CVD) risk. Previous studies with statins have established that a 1 mmol/l reduction in LDL cholesterol reduces CVD events by 21% over 5 years in people with diabetes. More recently, trials in people with acute coronary syndromes showed that ezetimibe reduced CVD events by 6% at 5 years and achieved a LDL-cholesterol of 1.6 mmol/l with better results in people with Type 2 diabetes. Several novel lipid-lowering therapies have recently been developed. Most data have been accumulated with proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors, which reduce LDL cholesterol by 50-55%. A large CVD outcome trial with evolocumab, in which 40% of participants had diabetes, achieved a LDL-cholesterol of 0.8 mmol/l and showed a consistent 20% relative risk reduction within 2 years, including in people with diabetes. Trials to increase HDL-cholesterol using cholesterol ester transfer protein (CETP) inhibitors have generally underwhelmed. Although anacetrapib reduced coronary ischaemic events by 7% in a population with chronic CVD, more expansive CVD endpoints were not improved. The complex nature of CETP inhibitor trial outcomes means that these compounds are not being developed further. Trials targeting inflammation-associated lipids have been generally unsuccessful but recent data on the interleukin-1B receptor antagonist canakinumab have shown a reduction in acute coronary intervention, validating this target although at the cost of increased infections. The ability to achieve low LDL-cholesterol with off patent medications and the costs of novel therapies will confine the use of novel agents to subgroups of people at highest risk of CVD. PMID- 29766561 TI - Erythema nodosum arising during everolimus therapy for tuberous sclerosis complex. AB - Indications for everolimus and other drugs within the mammalian target of rapamycin inhibitor class have recently expanded to include tuberous sclerosis complex. Everolimus is generally well tolerated, but it is important for physicians to identify and manage associated cutaneous adverse effects. We report the first case of a child developing erythema nodosum while undergoing everolimus therapy. PMID- 29766564 TI - Personal oral hygiene and dental caries: A systematic review of randomised controlled trials. AB - OBJECTIVE: To conduct a systematic review of randomised trials assessing the association between personal oral hygiene and dental caries in the absence of the confounding effects of fluoride. BACKGROUND: Dental caries continues to affect close to 100% of the global population. There is a century-old conflict on whether dental caries is caused by poor oral hygiene or poorly formed teeth (ie, teeth with dental defects). Resolving this conflict is of significant public health importance as these two hypotheses on dental caries aetiology can lead to different prevention strategies. METHODS: A systematic search for randomised trials was conducted using predefined criteria in 3 databases. The impact of personal oral hygiene interventions on coronal dental caries incidence was evaluated using random-effects models. RESULTS: Three randomised studies involving a total of 743 participants were included. Personal oral hygiene interventions failed to influence the incidence of dental caries (Delta Decayed, Missing and Filled Surfaces (DFMS) = -0.11; 95% confidence interval: (-0.91, 0.69; P-value < .79)) despite meticulous deplaquing of teeth. There was no significant heterogeneity in the trial results (heterogeneity chi-squared = 1.88, P = .39). The findings were robust to sensitivity analyses, including consideration of the results of nonrandomised studies. CONCLUSION: Personal oral hygiene in the absence of fluorides has failed to show a benefit in terms of reducing the incidence of dental caries. PMID- 29766562 TI - Cutaneous fibrolipomatous hamartoma: Report of 2 cases with retrocalcaneal location. AB - Precalcaneal congenital fibrolipomatous hamartoma is an underreported benign entity that has been described in the literature under different names. We present two cases of unilateral fibrolipomatous hamartoma (FLH) appearing in a unique location: on the posterior aspect of the foot overlying the heel. We propose the term "FLH of the skin" as a more inclusive and less confusing term for this condition, thus allowing distinction with FLH arising from neural tissue. High-frequency ultrasonography appears to be a useful diagnostic tool that may avoid unnecessary biopsies for this condition. PMID- 29766563 TI - The effects of gestational diabetes mellitus on fetal growth and neonatal birth measures in an African cohort. AB - AIM: Fetal exposure to gestational diabetes mellitus (GDM) is said to alter fetal growth and increase the risk of macrosomia. However, little research on GDM exists in African populations. This study aimed to assess longitudinal fetal growth and neonatal birth measures among Black African babies exposed to GDM. METHODS: Pregnant women (Soweto, South Africa) enrolled into a cohort study were followed up with repeated fetal ultrasounds. At 24-28 weeks' gestation a 2-h 75 g oral glucose tolerance test was performed and GDM was diagnosed using the World Health Organization's 2013 criteria. Neonatal birth measures were assessed. RESULTS: The study involved 741 women; 83 (11.2%) with GDM and 658 (88.8%) without. A total of 4040 fetal ultrasounds were performed. GDM exposure was associated with an increase in fetal growth measures, especially abdominal circumference, which was already seen at 16-18 weeks' gestation. Male fetuses in particular, showed a significant association between GDM exposure and increased abdominal circumference (P = 0.009). Most women with GDM (66.3%) received management; all received diet therapy and 32.7% were prescribed medication. There was no difference in birth measures between the GDM-exposed and unexposed neonates. CONCLUSION: Repeated ultrasound measures identified the effects of GDM as early as 16-18 weeks' gestation, well before a diagnosis of GDM would usually be made. Sex differences in fetal growth were observed, with GDM-exposed male fetuses being more affected with larger abdominal circumferences than females. A low rate of macrosomia was observed compared with historical GDM populations. PMID- 29766565 TI - A retrospective observational study of people with Type 1 diabetes with self reported severe hypoglycaemia reveals high level of ambulance attendance but low levels of therapy change and specialist intervention. AB - AIM: To evaluate the impact of severe hypoglycaemia on NHS resources and overall glycaemic control in adults with Type 1 diabetes. METHODS: An observational, retrospective study of adults (aged >= 18 years) with Type 1 diabetes reporting one or more episodes of severe hypoglycaemia during the preceding 24 months in 10 NHS hospital diabetes centres in England and Wales. The primary outcome was healthcare resource utilization associated with severe hypoglycaemia. Secondary outcomes included demographic and clinical characteristics, diabetes control and pathway of care. RESULTS: Some 140 episodes of severe hypoglycaemia were reported by 85 people during the 2-year observation period. Ambulances were called in 99 of 140 (71%) episodes and Accident and Emergency attendance occurred in 26 of 140 (19%) episodes, whereas 29 of 140 (21%) episode required no immediate help from healthcare providers. Participants attended a median of 5 (range 0-58) diabetes clinic consultations during the observation period; 13% (70 of 552) of all consultations were severe hypoglycaemia-related. Of the HbA1c measurements recorded closest prior to severe hypoglycaemia (n = 119), only 7 of 119 measurements were < 48 mmol/mol (< 6.5%) and mean HbA1c was 70 (sd 19) mmol/mol (8.5%, sd 1.7%). Some 119 changes to diabetes treatment were recorded during the observation period (median/person 0;, range 0-11), of which 52 of 119 changes (44%) followed severe hypoglycaemic events. CONCLUSIONS: We observed a high level of ambulance service intervention but surprisingly low levels of hypoglycaemia follow-up, therapy change and specialist intervention in people self-reporting severe hypoglycaemia. These results suggest there may be important gaps in care pathways for people with Type 1 diabetes self-reporting severe hypoglycaemia. PMID- 29766566 TI - Case of generalized pustular psoriasis that might have progressed from terbinafine-induced acute generalized exanthematous pustulosis. PMID- 29766567 TI - Melatonin attenuates osteosarcoma cell invasion by suppression of C-C motif chemokine ligand 24 through inhibition of the c-Jun N-terminal kinase pathway. AB - Osteosarcoma, with its high metastatic potential, is the most prevalent malignant bone tumor in children and adolescents. Melatonin possesses multiple tumor suppressing properties for a myriad of tumors, but little is known about the effects of melatonin on osteosarcoma metastasis. In this study, we demonstrated that melatonin elicited very low cytotoxicity and significantly inhibited cellular motility, migration, and invasion in human osteosarcoma U2OS and HOS cells. Moreover, using RNA sequencing technology, we revealed that melatonin repressed C-C motif chemokine ligand 24 (CCL24) gene expression in U2OS cells. Manipulation of CCL24 levels influenced the motility of osteosarcoma cells as cell migration and invasion were enhanced by the addition of recombinant human CCL24 and attenuated by the silencing of CCL24. Moreover, melatonin increased and decreased the activation of extracellular signal-regulated kinase (ERK) 1/2 and c Jun N-terminal kinase (JNK) 1/2, respectively, in a dose-dependent manner in U2OS and HOS cells while exerting no evident influence on the level and activation of p38, Akt, FAK, steroid receptor coactivator, or Raf. In further functional experiments, the use of JNK inhibitors (SP600125 and DN-JNK) confirmed that the pharmaceutic inhibition of JNK augmented the melatonin-mediated CCL24 suppression and migration of U2OS cells. Overall, our results revealed that melatonin attenuated chemokine CCL24 levels through inhibition of the JNK pathway to hinder human osteosarcoma cell invasion, thereby highlighting the therapeutic potential of melatonin for osteosarcoma metastasis. PMID- 29766568 TI - Cord blood insulin, IGF-I, IGF-II, leptin, adiponectin and ghrelin, and their associations with insulin sensitivity, beta-cell function and adiposity in infancy. AB - AIM: Vulnerability to insulin resistance and Type 2 diabetes may originate in early life, but little is known about whether any perinatal biomarkers are predictive of later metabolic health. We sought to assess whether cord blood insulin, insulin-like growth factor (IGF)-I, IGF-II, leptin, adiponectin and ghrelin are associated with metabolic health indicators in infancy. METHODS: In a prospective singleton birth cohort, we assessed cord blood insulin, IGF-I, IGF II, leptin, adiponectin and ghrelin concentrations in relation to the homeostasis model assessment of insulin resistance (HOMA-IR), beta-cell function (HOMA-beta), fasting proinsulin-to-insulin ratio, BMIz-score, and the sum of triceps and subscapular skinfold thickness (an indicator of adiposity) in infants at age 1 year (n = 185). RESULTS: Adjusting for maternal and infant characteristics, one standard deviation (sd) increase in cord blood adiponectin was associated with an 11.1% (95% confidence interval 1.8-19.5%) decrease in HOMA-beta (P = 0.02) and a 13.6% (1.8-26.8%) increase in proinsulin-to-insulin ratio (P = 0.02), indicating worse beta-cell function in infants at age 1 year. One sd increase in cord blood insulin was associated with a 0.5 (0.1-1.0) mm increase in skinfold thickness (P = 0.01). One sd increase in cord blood ghrelin was associated with a 0.2 (0.02 0.3) decrease in BMIz-score (P = 0.02) and a 0.5 (0.1-0.9) mm decrease (P = 0.02) in skinfold thickness. Cord blood IGF-I and IGF-II were not associated with the observed metabolic health indicators at age 1 year. CONCLUSION: The study is the first to show that cord blood adiponectin may be negatively predictive of beta cell function, whereas cord blood ghrelin may be negatively predictive of adiposity in infancy. PMID- 29766569 TI - Differential roles of melatonin in plant-host resistance and pathogen suppression in cucurbits. AB - Since the 1950s, research on the animal neurohormone, melatonin, has focused on its multiregulatory effect on patients suffering from insomnia, cancer, and Alzheimer's disease. In plants, melatonin plays major role in plant growth and development, and is inducible in response to diverse biotic and abiotic stresses. However, studies on the direct role of melatonin in disease suppression and as a signaling molecule in host-pathogen defense mechanism are lacking. This study provides insight on the predicted biosynthetic pathway of melatonin in watermelon (Citrullus lanatus), and how application of melatonin, an environmental-friendly immune inducer, can boost plant immunity and suppress pathogen growth where fungicide resistance and lack of genetic resistance are major problems. We evaluated the effect of spray-applied melatonin and also transformed watermelon plants with the melatonin biosynthetic gene SNAT (serotonin N-acetyltransferase) to determine the role of melatonin in plant defense. Increased melatonin levels in plants were found to boost resistance against the foliar pathogen Podosphaera xanthii (powdery mildew), and the soil-borne oomycete Phytophthora capsici in watermelon and other cucurbits. Further, transcriptomic data on melatonin-sprayed (1 mmol/L) watermelon leaves suggest that melatonin alters the expression of genes involved in both PAMP-mediated (pathogen-associated molecular pattern) and ETI-mediated (effector-triggered immunity) defenses. Twenty-seven upregulated genes were associated with constitutive defense as well as initial priming of the melatonin-induced plant resistance response. Our results indicate that developing strategies to increase melatonin levels in specialty crops such as watermelon can lead to resistance against diverse filamentous pathogens. PMID- 29766570 TI - Melatonin improves endothelial function in vitro and prolongs pregnancy in women with early-onset preeclampsia. AB - Preeclampsia remains a leading cause of maternal and perinatal morbidity and mortality. There have been no material advances in the treatment of preeclampsia for nearly 50 years. Combining in vitro studies and a clinical trial, we aimed to determine whether melatonin could be a useful adjuvant therapy. In a xanthine/xanthine oxidase (X/XO) placental explant model, melatonin reduced oxidative stress (8-isoprostane) and enhanced antioxidant markers (Nrf2 translocation, HO-1), but did not affect explant production of anti-angiogenic factors (sFlt, sEng, activin A). In cultured HUVECs, melatonin mitigated TNFalpha induced vascular cell adhesion molecule expression and rescued the subsequent disruption to endothelial monolayer integrity but did not affect other markers for endothelial activation and dysfunction. In a phase I trial of melatonin in 20 women with preeclampsia, we assessed the safety and efficacy of melatonin on (i) preeclampsia progression, (ii) clinical outcomes, and (iii) oxidative stress, matching outcomes with recent historical controls receiving similar care. Melatonin therapy was safe for mothers and their fetuses. Compared to controls, melatonin administration extended the mean +/- SEM diagnosis to delivery interval by 6 +/- 2.3 days reduced the need for increasing antihypertensive medication on days 3-4 (13% vs 71%), days 6-7 (8% vs 51%), and at delivery (26% vs 75%). All other clinical and biochemical measures of disease severity were unaffected by melatonin. We have shown that melatonin has the potential to mitigate maternal endothelial pro-oxidant injury and could therefore provide effective adjuvant therapy to extend pregnancy duration to deliver improved clinical outcomes for women with severe preeclampsia. PMID- 29766571 TI - From UV to Near-Infrared Light-Responsive Metal-Organic Framework Composites: Plasmon and Upconversion Enhanced Photocatalysis. AB - The exploitation of photocatalysts that harvest solar spectrum as broad as possible remains a high-priority target yet grand challenge. In this work, for the first time, metal-organic framework (MOF) composites are rationally fabricated to achieve broadband spectral response from UV to near-infrared (NIR) region. In the core-shell structured upconversion nanoparticles (UCNPs)-Pt@MOF/Au composites, the MOF is responsive to UV and a bit visible light, the plasmonic Au nanoparticles (NPs) accept visible light, whereas the UCNPs absorb NIR light to emit UV and visible light that are harvested by the MOF and Au once again. Moreover, the MOF not only facilitates the generation of "bare and clean" Au NPs on its surface and realizes the spatial separation for the Au and Pt NPs, but also provides necessary access for catalytic substrates/products to Pt active sites. As a result, the optimized composite exhibits excellent photocatalytic hydrogen production activity (280 umol g-1 h-1 ) under simulated solar light, and the involved mechanism of photocatalytic H2 production under UV, visible, and NIR irradiation is elucidated. Reportedly, this is an extremely rare study on photocatalytic H2 production by light harvesting in all UV, visible, and NIR regions. PMID- 29766572 TI - Multiple superficial oral mucoceles after Mycoplasma-induced mucositis. AB - Oral mucoceles are lesions arising mainly from the minor salivary glands and are thought to occur after excretory duct trauma. We report a case of multiple superficial oral mucoceles on a child's labial mucosa after Mycoplasma pneumoniae mucositis. Mucoceles can mimic persistent or recurrent stomatitis and lead to potential errors in management. PMID- 29766573 TI - Asymmetrical Ladder-Type Donor-Induced Polar Small Molecule Acceptor to Promote Fill Factors Approaching 77% for High-Performance Nonfullerene Polymer Solar Cells. AB - In this work, an effectual strategy of constructing polar small molecule acceptors (SMAs) to promote fill factor (FF) of nonfullerene polymer solar cells (PSCs) is first reported. Three asymmetrical SMAs of IDT6CN, IDT6CN-Th, and IDT6CN-M, which own large dipole moments, are designed and synthesized. The PSCs based on three polar SMAs exhibit apparently higher FFs compared with their symmetrical analogues. The asymmetrical design strategy accompanied with side chain and end group engineering makes IDT6CN-Th- and IDT6CN-M-based nonfullerene PSCs achieve high power conversion efficiency with FFs approaching 77%. PMID- 29766574 TI - Metallic Graphene-Like VSe2 Ultrathin Nanosheets: Superior Potassium-Ion Storage and Their Working Mechanism. AB - Potassium-ion batteries (KIBs) are receiving increasing interest in grid-scale energy storage owing to the earth abundant and low cost of potassium resources. However, their development still stays at the infancy stage due to the lack of suitable electrode materials with reversible depotassiation/potassiation behavior, resulting in poor rate performance, low capacity, and cycling stability. Herein, the first example of synthesizing single-crystalline metallic graphene-like VSe2 nanosheets for greatly boosting the performance of KIBs in term of capacity, rate capability, and cycling stability is reported. Benefiting from the unique 2D nanostructure, high electron/K+ -ion conductivity, and outstanding pseudocapacitance effects, ultrathin VSe2 nanosheets show a very high reversible capacity of 366 mAh g-1 at 100 mA g-1 , a high rate capability of 169 mAh g-1 at 2000 mA g-1 , and a very low decay of 0.025% per cycle over 500 cycles, which are the best in all the reported anode materials in KIBs. The first principles calculations reveal that VSe2 nanosheets have large adsorption energy and low diffusion barriers for the intercalation of K+ -ion. Ex situ X-ray diffraction analysis indicates that VSe2 nanosheets undertake a reversible phase evolution by initially proceeding with the K+ -ion insertion within VSe2 layers, followed by the conversion reaction mechanism. PMID- 29766575 TI - Development of a novel humanoid-robot simulator for endoscope with pharyngeal reflex and real-life responses. PMID- 29766576 TI - Predictive factors of overall functioning improvement in patients with chronic schizophrenia and schizoaffective disorder treated with paliperidone palmitate and aripiprazole monohydrate. AB - BACKGROUND: Long-acting injectable (LAI) antipsychotics can improve medication adherence and reduce hospitalisation rates compared with oral treatments. Paliperidone palmitate (PAL) and aripiprazole monohydrate (ARI) LAI treatments were associated with improvements in global functioning in patients with schizophrenia. OBJECTIVE: The objective of this study was to assess the predictive factors of better overall functioning in patients with chronic schizophrenia and schizoaffective disorder treated with PAL and ARI. METHOD: Enrolled were 143 (97 males, 46 females, mean age 38.24 years, SD = 12.65) patients with a diagnosis of schizophrenia or schizoaffective disorder, whom we allocated in two groups (PAL and ARI treatments). We assessed global functioning, amount of oral medications, adherence to oral treatment, and number of hospitalisations before LAI introduction and at assessment time point. RESULTS: Longer treatment time with LAIs (p < .001), lower number of oral drugs (p < .001), and hospitalisations (p = .002) before LAI introduction, and shorter duration of illness (p = .038) predicted better Global Assessment of Functioning scores in the whole sample (R2 = 0.337). CONCLUSION: Early administration and longer duration of ARI or PAL treatments could play a significant role in improving global functioning of patients with schizophrenia and schizoaffective disorder. Better improvement in functioning could be achieved with ARI in young individuals with recent illness onset and PAL in patients at risk for recurrent hospitalisations. PMID- 29766577 TI - Mechanism of the Dehydrogenative Phenothiazination of Phenols. AB - The straightforward capture of oxidized phenothiazines with phenols under aerobic conditions represents a unique cross-dehydrogenative C-N bond-forming reaction in terms of operational simplicity. The mechanism of this cross-dehydrogenative N arylation of phenothiazines with phenols has been the object of debate, particularly regarding the order in which the substrates are oxidized and their potentially radical or cationic nature. Understanding the selective reactivity of phenols for oxidized phenothiazines is one of the key objectives of this study. The reaction mechanism is investigated in detail by utilizing electron paramagnetic resonance spectroscopy, cyclic voltammetry, radical trap experiments, kinetic isotope effects, and solvent effects. Finally, the key reaction steps are calculated by using density functional theory (DFT) and broken symmetry open-shell singlet DFT methods to unravel a unique biradical mechanism for the oxidative phenothiazination of phenols. PMID- 29766578 TI - Self-assembly of Fluorescent Dehydroberberine Enhances Mitochondria-Dependent Antitumor Efficacy. AB - Selective imaging and inducing mitochondrial dysfunction in tumor cells using mitochondria-targeting probes has become as a promising approach for cancer diagnosis and therapy. Here, we report the design of a fluorescent berberine analog, dehydroberberine (DH-BBR), as a new mitochondria-targeting probe capable of self-assembling into monodisperse organic nanoparticles (DTNPs) upon integration with a lipophilic counter anion, allowing for enhanced fluorescence imaging and treatment of tumors in living mice. X-ray crystallography revealed that the self-assembly process was attributed to a synergy of different molecular interactions, including pi-pi stacking, O???pi interaction and electrostatic interaction between DH-BBR and counter anions. We demonstrated that DTNPs could efficiently enter tumor tissue following intravenous injection and enhance mitochondrial delivery of DH-BBR via an electrostatic interaction driven anion exchange process. Selective accumulation in the mitochondria capable of emitting strong fluorescence and causing mitochondrial dysfunction was achieved, enabling efficient inhibition of tumor growth in living mice. This study demonstrates promise for applying lipophilic anions to control molecular self-assembly and tune antitumor activity of mitochondria-targeting probes, which can facilitate to improve cancer treatment in vivo. PMID- 29766579 TI - Memory complaints in amnestic Mild Cognitive Impairment: More prospective or retrospective? AB - OBJECTIVE: Patients with amnestic Mild Cognitive Impairment (aMCI), usually considered an early stage of Alzheimer's disease, have deficits not only in retrospective memory (RM), that is, recalling of past events, words or people, but also on prospective memory (PM), the cognitive ability of remembering to execute delayed intentions in the future. This study investigated whether patients with aMCI refer more PM complaints as compared with RM complaints, and whether this might depend upon short-term vs long-term items or time-based vs event-based tasks. METHODS: Patients with aMCI (n = 178) and healthy controls (n = 160) underwent the Prospective and Retrospective Memory Questionnaire (PRMQ), a 16-item instrument to appraise differences between PM and RM complaints, as well as a general mental state examination, a subjective memory complaints questionnaire, objective memory tests, and assessment of depressive symptoms and activities of daily living. RESULTS: Patients with aMCI reported more memory complaints evaluated with the PRMQ (total score = 44.3 +/- 10.8) as compared with controls (36.7 +/- 9.8, P < 0.001). Using a mixed effect repeated-measures analysis of covariance (ANCOVA) showed that participants generally referred more retrospective than prospective memory complaints. Patients with aMCI had significantly more complaints on short-term memory as compared with long-term memory, and more complaints in time-based (auto-initiated) as compared with event based tasks, than healthy controls. CONCLUSION: Patients with aMCI reported significantly more difficulties on short-term memory, presumably reflecting internal temporal lobe pathology typical of Alzheimer's disease, and more complaints on time-based tasks, which are cognitively very demanding, but did not seem particularly troubled regarding prospective memory. PMID- 29766580 TI - A 2D Conductive Organic-Inorganic Hybrid with Extraordinary Volumetric Capacitance at Minimal Swelling. AB - Rational design and synthesis of 2D organic-inorganic hybrid materials is important for transformative technological advances for energy storage. Here, a 2D conductive hybrid lamella and its intercalation properties for thin-film supercapacitors are reported. The 2D organic-inorganic hybrid lamella comprises periodically stacked 2D nanosheets with 11.81 A basal spacing, and is electronically conductive (605 S m-1 ). In contrast to the pre-existing organic based 2D materials, this material has extremely low gas-permeable porosity (16.5 m2 g-1 ) in contrast to the high ionic accessibility. All these structural features collectively contribute to the high capacitances up to 732 F cm-3 , combined with small structural swelling at as low as 4.8% and good stability. At a discharge time of 6 s, the thin-film intercalation electrode delivers an energy density of 24 mWh cm-3 , which universally outperforms the surface-dominant capacitive processes in porous carbons. PMID- 29766583 TI - Hollow TiNb2 O7 @C Spheres with Superior Rate Capability and Excellent Cycle Performance as Anode Material for Lithium-Ion Batteries. AB - TiNb2 O7 , with high charge/discharge voltage (1.65 V), long life span, and excellent reversibility has become a new anode material for lithium ion batteries in recent years. However, the inherent poor electronic conductivity strictly limits its practical applications. Herein, we report for the first time hollow TiNb2 O7 @C spheres, with carbon spheres as sacrificial template. The special hollow structure can effectively relieve the volume expansion during the repeated process of charging/discharging. The conductivity of hollow TiNb2 O7 spheres can be greatly improved by the carbon layers uniformly coated outside the surface of TiNb2 O7 spheres. Besides, the particle aggregation can be conspicuously suppressed by the uniformly coated carbon layers. As a result, hollow TiNb2 O7 @C spheres show a prominent charge/discharge capacity of 282.6/283.8 mAh g-1 after 100 cycles at 0.25 C (1 C=388 mA g-1 ), revealing the excellent cycle performance and high reversible capacity. Meanwhile, the charge/discharge capacity of 157.5 and 157.9 mAh g-1 can be maintained at 10 C after 10 cycles. The facial synthetic method can be extended to prepare various materials with volume expansion during repeated charging/discharging process. PMID- 29766581 TI - Corannulene-Incorporated AIE Nanodots with Highly Suppressed Nonradiative Decay for Boosted Cancer Phototheranostics In Vivo. AB - Fluorescent nanoparticles (NPs) based on luminogens with aggregation-induced emission characteristic (AIEgens), namely AIE dots, have received wide attention because of their antiquenching attitude in emission and reactive oxygen species (ROS) generation when aggregated. However, few reports are available on how to control and optimize their fluorescence and ROS generation ability. Herein, it is reported that enhancing the intraparticle confined microenvironment is an effective approach to advanced AIE dots, permitting boosted cancer phototheranostics in vivo. Formulation of a "rotor-rich" and inherently charged near-infrared (NIR) AIEgen with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [methoxy(polyethylene glycol)-2000] and corannulene-decorated PEG affords DSPE AIE dots and Cor-AIE dots, respectively. Compared to DSPE-AIE dots, Cor-AIE dots show 4.0-fold amplified fluorescence quantum yield and 5.4-fold enhanced ROS production, because corannulene provides intraparticle rigidity and strong interactions with the AIEgen to restrict the intramolecular rotation of AIEgen to strongly suppress the nonradiative decay and significantly facilitate the fluorescence pathway and intersystem crossing. Thus, it tremendously promotes phototheranostic efficacies in terms of NIR image-guided cancer surgery and photodynamic therapy using a peritoneal carcinomatosis-bearing mouse model. Collectively, it not only provides a novel strategy to advanced AIE dots for cancer phototheranostics, but also brings new insights into the design of superior fluorescent NPs for biomedical applications. PMID- 29766582 TI - Do community-dwelling Maori and Pacific peoples present with dementia at a younger age and at a later stage compared with NZ Europeans? AB - OBJECTIVE: Ethnicity may affect presentation to clinical services in people with dementia; however, no studies have examined this in Maori or Pacific peoples in New Zealand (NZ). Our objective was to examine the routinely collected clinical data from a memory assessment service in South Auckland to examine the presentation of dementia in the major NZ ethnic groups. METHODS: A total of 360 patients presenting to a memory service with a new diagnosis of dementia were included in this study. Demographic data (age, sex, and ethnicity) and dementia sub-type and severity were analyzed. RESULTS: There were 142 NZ European (mean age: 79.2, SD 7.4), 43 Maori (mean age: 70.2, SD 7.6), 126 Pacific (mean age: 74.3, SD 7.6), and 49 other ethnicities (mean age: 78.0, SD 8.5) presenting with a new diagnosis of dementia. After adjustment for gender and dementia subtype, Maori and Pacific patients were 8.5 and 5.3 years younger than NZ European patients (P < 0.0001). Pacific peoples tended to present with more advanced dementia (OR = 1.63, 95% CI: 0.98-2.70, P = 0.06) after adjustment for age and gender. There was little difference in the subtypes of dementia between ethnic groups. CONCLUSIONS: Maori and Pacific peoples with dementia presented to an NZ memory service at a younger age than NZ Europeans, and Pacific peoples presented with more advanced dementia. A population-based epidemiological study is critical to determine whether Maori and Pacific peoples have indeed a higher risk of developing dementia at a younger age. PMID- 29766584 TI - Direct Immunoassay for Facile and Sensitive Detection of Small Molecule Aflatoxin B1 based on Nanobody. AB - Aflatoxin B1 (AFB1 ), one of the most toxic mycotoxins, is classified as a group I carcinogen and ubiquitous in various foods and agriproducts. Thus, accurate and sensitive determination of AFB1 is of great significance to meet the criteria of food safety. Direct detection of AFB1 is difficult by monoclonal antibody (mAb) with large molecular size (~150 kD) since the target is too small to produce a detectable signal change. Herein, by combining the electrochemical properties of nanomaterials and the advantages of nanobodies, we developed a direct, highly selective and sensitive electrochemical immunosensor for small molecule detection. The proposed immunosensor had a wide calibration range of 0.01 to 100 ng mL-1 and a low detection limit of 3.3 pg mL-1 (S/N=3). Compared with the immunosensor prepared with mAb which was applied in the typical indirect immunoassay, the immunosensor in this work possessed two orders of magnitudes wider linear range and 10-fold more sensitivity. The as-obtained immunosensor was further successfully applied for sensing AFB1 in real samples. This proposed assay would provide a simple, highly sensitive and selective approach for the direct immunoassay of small molecule AFB1 , and is extendable to the development of direct immunosensing systems for other small molecules detection by coupling nanocarbon and nanobody. PMID- 29766586 TI - Awareness is related to reduced post-stimulus alpha power: a no-report inattentional blindness study. AB - Delineating the neural correlates of sensory awareness is a key requirement for developing a neuroscientific understanding of consciousness. A neural signal that has been proposed as a key neural correlate of awareness is amplitude reduction of 8-14 Hz alpha oscillations. Alpha oscillations are also closely linked to processes of spatial attention, providing potential alternative explanations for past results associating alpha oscillations with awareness. We employed a no report inattentional blindness (IB) paradigm with electroencephalography to examine the association between awareness and the power of 8-14 Hz alpha oscillations. We asked whether the alpha-power decrease commonly reported when stimuli are perceived is related to awareness, or other factors that commonly confound awareness investigations, specifically task-relevance and visual salience. Two groups of participants performed a target discrimination task at fixation while irrelevant non-salient shape probes were presented briefly in the left or right visual field. One group was explicitly informed of the peripheral probes at the commencement of the experiment (the control group), whereas the other was not told about the probes until halfway through the experiment (IB group). Consequently, the IB group remained unaware of the probes for the first half of the experiment. In all conditions in which participants were aware of the probes, there was an enhanced negativity in the event-related potential (the visual awareness negativity). Furthermore, there was an extended contralateral alpha-power decrease when the probes were perceived, which was not present when they failed to reach awareness. These results suggest alpha oscillations are intrinsically associated with awareness itself. PMID- 29766585 TI - Design of a New Fused-Ring Electron Acceptor with Excellent Compatibility to Wide Bandgap Polymer Donors for High-Performance Organic Photovoltaics. AB - Fused-ring electron acceptors (FREAs) have recently received intensive attention. Besides the continuing development of new FREAs, the demand for FREAs featuring good compatibility to donor materials is becoming more and more urgent, which is highly desirable for screening donor materials and achieving new breakthroughs. In this work, a new FREA is developed, ZITI, featuring an octacyclic dithienocyclopentaindenoindene central core. The core is designed by linking 2,7 dithienyl substituents and indenoindene with small methylene groups, in which the indeno[1,2-b]thiophene-2-(3-oxo-2,3-dihydro-1H-inden-1-ylidene)malononitrile part provides a large and unoccupied pi-surface. Most notably, ZITI possesses an excellent compatibility with commercially available polymer donors, delivering very high power conversion efficiencies of over 13%. PMID- 29766587 TI - All-Solution-Processed Metal-Oxide-Free Flexible Organic Solar Cells with Over 10% Efficiency. AB - All-solution-processing at low temperatures is important and desirable for making printed photovoltaic devices and also offers the possibility of a safe and cost effective fabrication environment for the devices. Herein, an all-solution processed flexible organic solar cell (OSC) using poly(3,4 ethylenedioxythiophene):poly-(styrenesulfonate) electrodes is reported. The all solution-processed flexible devices yield the highest power conversion efficiency of 10.12% with high fill factor of over 70%, which is the highest value for metal oxide-free flexible OSCs reported so far. The enhanced performance is attributed to the newly developed gentle acid treatment at room temperature that enables a high-performance PEDOT:PSS/plastic underlying substrate with a matched work function (~4.91 eV), and the interface engineering that endows the devices with better interface contacts and improved hole mobility. Furthermore, the flexible devices exhibit an excellent mechanical flexibility, as indicated by a high retention (~94%) of the initial efficiency after 1000 bending cycles. This work provides a simple route to fabricate high-performance all-solution-processed flexible OSCs, which is important for the development of printing, blading, and roll-to-roll technologies. PMID- 29766588 TI - Synthesis of Chlorotrifluoromethylated Pyrrolidines by Electrocatalytic Radical Ene-Yne Cyclization. AB - The stereoselective synthesis of chlorotrifluoromethylated pyrrolidines was achieved using anodically coupled electrolysis, an electrochemical process that combines two parallel oxidative events in a convergent and productive manner. The bench-stable and commercially available solids CF3 SO2 Na and MgCl2 were used as the functional group sources to generate CF3. and Cl. , respectively, via electrochemical oxidation, and the subsequent reaction of these radicals with the 1,6-enyne substrate was controlled with an earth-abundant Mn catalyst. In particular, the introduction of a chelating ligand allowed for the ene-yne cyclization to take place with high stereochemical control over the geometry of the alkene group in the pyrrolidine product. PMID- 29766589 TI - DNA aggregation induced by Mg2+ ions under different conditions. AB - Cations-induced DNA aggregation can modify the local structure of oligonucleotides and has potential applications in medicine and biotechnology. Here, we used atomic force microscopy to investigate lambda-DNA aggregation on Mg2+ -treated glass (Mg2+ /glass) and in Mg2+ solution. Atomic force microscopy topography images showed that some DNA fragments were slightly stacked together on 10 mM Mg2+ /glass and stacked stronger on >=50 mM Mg2+ /glass. They also showed that DNA aggregated stronger in Mg2+ solution than on Mg2+ /glass, ie, DNAs are strongly stacked and twisted at 10 mM Mg2+ , rolled together at 50 mM Mg2+ , and slightly aggregated to form small particles at 100 mM Mg2+ . At a specific condition, ie, heating lambda-DNA to 92 degrees C, cooling down to 75 degrees C, adding Mg2+ , and vortexing the resulting solution, DNA strongly aggregated and formed pancake-like shapes at 10 and 50 mM or a large aggregate at 100 mM Mg2+ solutions. Our results may be helpful for medical applications and gene therapy using cation-DNA technology. PMID- 29766590 TI - Automatic change detection and spatial attention: a visual mismatch negativity study. AB - Visual mismatch negativity (vMMN) is the electrophysiological correlate of automatic detection of unattended changes in the visual environment. However, vMMNs' relatedness to spatial attention has not been explicitly tested. Thus, the aim of the study was to investigate the effects of spatial attention on the vMMN event-related potential component. To this end, participants were instructed to fixate and attend to task-related stimuli. In an oddball sequence, offset stimuli were applied, i.e., from time-to time, the two sides of permanently presented objects disappeared. Distance between the task-related and unrelated events resulted in the typical finding of spatial attention; the amplitude of the N1 component was larger at the shorter distance between the two kinds of events. VMMN was elicited by the deviant vanishing parts, with no reliable effect of distance between the task-field and vMMN-related stimuli. In terms of the difference potentials, vMMN was followed by a positive posterior component in the 270-330 ms range. This positivity was much larger when the task-field was close to vMMN-related stimuli. The reappearance of the vanishing parts was also investigated. The reappearance of the whole objects after a deviant offset elicited vMMN but only when the task-field was close to the oddball sequence. We concluded that infrequently vanishing parts of objects are detected automatically. However, these deviant events initiate orientation only if the objects are close to the field of task-relevant events. Similarly, automatic registration of the rare but expected events are registered only in the visual field close to the focus of attention. PMID- 29766591 TI - Bilateral activations in operculo-insular area show temporal dissociation after peripheral electrical stimulation in healthy adults. AB - Interhemispheric transfer is necessary for sensory integration and coordination of body sides. We studied how somatosensory input from one body side may reach both body sides. First, we investigated with 17 healthy adults in which uni- and bilateral brain areas were involved in consecutive stages of automatic sensory processing of non-nociceptive peripheral stimulation. Somatosensory evoked fields (SEFs) to electrical stimulation were recorded with 306-channel magnetoencephalography in two conditions. First, SEFs were registered following sensory radial nerve (RN) stimulation to dorsal surface of the right hand and second, following median nerve (MN) stimulation at the right wrist. Cortical activations were located in contralateral postcentral gyrus after MN and RN stimulations and in bilateral operculo-insular area after RN stimulation. First component occurred earlier after MN than RN stimulation. Middle latency components had similar latencies with stronger activation in contralateral postcentral gyrus after MN than RN stimulation. Interestingly, long latency components located in bilateral operculo-insular area after RN stimulation showed latency difference between hemispheres, i.e. activation peaked earlier in contralateral than in ipsilateral side. Additional experiments comparing novel intracutaneous nociceptive, RN and MN electrical stimuli confirmed bilateral long latency activation elicited by each stimulus type and highlighted latency differences between hemispheres. Variations in activation of bilateral operculo insular areas may corroborate their role in pain network and in multisensory integration. Our findings imply that these areas present a relay station in multisensory stimulus detection. PMID- 29766593 TI - Carbohydrate knowledge, lifestyle and insulin: an observational study of their association with glycaemic control in adults with type 1 diabetes. AB - BACKGROUND: The ability to achieve optimal glycaemic control varies widely among individuals with type 1 diabetes. The present study aimed to explore the factors that are associated with optimal glycaemic control compared to suboptimal control. METHODS: An observational study design was used to explore the association of various factors with glycaemic control. Surveys were completed by individuals who attended the type 1 diabetes clinic at a tertiary hospital in New South Wales (NSW), Australia. Clinical and demographic information and attendance at dietary review were also collected. RESULTS: One hundred and three individuals completed the survey. Those with optimal control [glycated haemoglobin <=7.0% (53 mmol mol-1 )] had a significantly shorter mean (SD) duration of diabetes [10.1 (12.6) years versus 18.8 (12.8) years, P = 0.005), were less likely to omit basal and bolus insulin (18.2% versus 47.5%, P = 0.016; 36.4% versus 61.8%, P = 0.034, respectively), and were less likely to report low confidence in managing their diabetes (9.1% versus 35.4%, P = 0.017). Participants who were able to identify carbohydrate sources were significantly more likely to have attended dietary review in the past 12 months (60.5% versus 20.0%, P = 0.001). However, they were not more likely to have better glycaemic control. CONCLUSIONS: The present study identified that consistency in taking insulin and confidence in self-management was associated with better glycaemic control. An association was also found between recent dietary review and better carbohydrate knowledge, although this did not translate into better glycaemic control. Future investigation into the application of carbohydrate knowledge is required. PMID- 29766592 TI - Scoring the best deal: Quantity discounts and street price variation of diverted oxycodone and oxymorphone. AB - BACKGROUND: Diverted prescription opioids are significant contributors to drug overdose mortality. Street price has been suggested as an economic metric of the diverted prescription opioid black market. This study examined variables that may influence the street price of diverted oxycodone and oxymorphone. METHODS: A cross-sectional study was conducted utilizing data from the previously validated, crowdsourcing website StreetRx. Street price reports of selected oxycodone and oxymorphone products, between August 22, 2014 and June 30, 2016, were considered for analysis. Geometric means and 95% confidence intervals were calculated comparing prices per milligram of drug in US dollars. Univariate and multivariable regressions were used to examine the influence of dosage strength, drug formulation, and bulk purchasing on street price. RESULTS: A total of 5611 oxycodone and 1420 oxymorphone reports were analyzed. Across various dosages and formulations, geometric mean prices per milligram ranged between $0.12 and $1.07 for oxycodone and $0.73 and $2.90 for oxymorphone. For a 2-fold increase in dosage strength, there is a 24.0% (95% CI: -28.1%, -19.6%, P < 0.001) and a 22.5% (95% CI: -24.2%, -20.8%, P < 0.001) decrease on average in price per milligram for oxycodone and oxymorphone, respectively. Lower potency, high dosage strength, crush-resistant opioids, and those purchased in bulk were significantly cheaper. CONCLUSION: Street prices for diverted oxycodone and oxymorphone are influenced by multiple factors including potency, dosage, formulation, and bulk purchasing. Buyers who purchase large quantities of low potency, large dosage, crush resistant formulation prescription opioids can expect to achieve the lowest price. PMID- 29766594 TI - Residual Strain and Stress in Biocrystals. AB - The development of residual strains within a material is a valuable engineering technique for increasing the material's strength and toughness. Residual strains occur naturally in some biominerals and are an important feature that is recently highlighted in biomineral studies. Here, manifestations of internal residual strains detected in biominerals are reviewed. The mechanisms by which they develop, as well as their impact on the biominerals' mechanical properties, are described. The question as to whether they can be utilized in multiscale strengthening and toughening strategies for biominerals is discussed. PMID- 29766595 TI - Highly deficient alcohol health warning labels in a high-income country with a voluntary system. AB - INTRODUCTION AND AIMS: To examine the prevalence and design elements of the voluntary health warning labels and related industry initiatives on a purposive sample of alcoholic beverage containers sold in New Zealand (NZ), a country with no mandatory health warning labels. DESIGN AND METHODS: We selected a purposive (e.g. low-cost) sample of 59 local and imported beers, wines and ready-to-drink alcoholic beverage containers available in NZ in 2016-2017. We documented the occurrence, content, size, appearance and position of messages concerning drinking during pregnancy, drink-driving, other health effects and industry-led initiatives that could relate to warnings; and collected data about alcohol content, standard drinks, ingredients and energy information. RESULTS: A majority (80%) of the alcoholic beverage containers had a pregnancy-related warning, 73% had industry-led initiatives (e.g. advising 'responsible' consumption) and 19% had drink-driving/heavy machinery warnings. Warning labels were small, with the average area of pregnancy-related and drink-driving/heavy machinery pictograms being 45 and 36 mm2 , respectively (i.e. pea-size). The average heights of pregnancy-related and drink-driving text were 1.6 and 2.2 mm, respectively. Pregnancy-related pictograms occupied between an average of 0.13% (wine) and 0.21% (ready-to-drink) of the available surface area of the alcoholic beverage container (i.e. less than 1/400th of the available space). Drink-driving pictograms occupied an average of 0.12% (imported beer), and 0.13% (NZ beer) of the available surface area. DISCUSSION AND CONCLUSIONS: Voluntary recommendations in NZ appear to have been inadequate for producing health warnings on alcoholic beverage containers that are consistent with evidence-informed recommendations for effective labels. This finding suggests that mandatory standardised labelling outlining alcohol-related risks may be required to ensure adequate consumer information. PMID- 29766596 TI - Quality of life among women diagnosed with breast Cancer: A randomized waitlist controlled trial of commercially available mobile app-delivered mindfulness training. AB - OBJECTIVE: The primary objective was to evaluate the efficacy of commercially available mobile app-delivered mindfulness training (AMT), compared with waitlist control (WC), on quality of life (QOL) among women diagnosed with breast cancer. The secondary outcome was dispositional mindfulness. Enrollment, app utilization, and study completion are reported as feasibility objectives. METHODS: Women diagnosed with breast cancer <=5 years (n = 112) were randomized to AMT (n = 57) or WC (n = 55), over 8 weeks, with 4 weeks of follow-up. We conducted linear mixed effects models to examine group by observation interactions on QOL and dispositional mindfulness at baseline, during intervention (5-weeks), post intervention (9-weeks), and follow-up (12-weeks post-baseline). RESULTS: Participants assigned to AMT reported higher QOL, compared with those assigned to WC, from baseline through follow-up t(258.40) = 3.09, P < 0.01, 95% CI [2.71, 11.90]. Participants assigned to AMT also reported higher dispositional mindfulness, compared with those assigned to WC, from baseline through follow-up t(268.44) = 2.04, P = 0.04, 95% CI [0.01, 0.57]. App utilization data was obtained from 34 participants. Fewer participants assigned to AMT completed all study assessments, compared with participants assigned to WC, (chi21 = 7.07, P = 0.008). CONCLUSIONS: Findings suggest commercially available AMT may proffer some benefit to women seeking to enhance their QOL following breast cancer diagnosis. PMID- 29766598 TI - Dying at home in rural residential aged care: A mixed-methods study in the Snowy Monaro region, Australia. AB - Residential aged care (RAC) is a significant provider of end-of-life care for people aged 65 years and older. Rural residents perceive themselves as different to their urban counterparts. Most studies describing place of death (PoD) in RAC are quantitative and reflect an urban voice. Using a mixed-methods design, this paper examines the PoD of 80 RAC residents (15 short-stay residents who died in RAC during respite or during an attempted step-down transition from hospital to home, and 65 permanent residents), within the rural Snowy Monaro region, Australia, who died between 1 February 2015 and 31 May 2016. Death data were collected from local funeral directors, RAC facilities, one multi-purpose heath service and obituary notices in the local media. The outcome variable was PoD: RAC, local hospital or out-of-region tertiary hospital. For the permanent RAC residents, the outcome of interest was dying in RAC or dying in hospital. Cross tabulations by PoD and key demographic data were performed. Pearson Chi squared tests and exact p-values were used to determine if any of the independent variables were associated with PoD. Using an ethnographic approach, data were collected from 12 face-to-face, open-ended interviews with four RAC residents, with a life expectancy of <=6 months, and six family caregivers. Interviews were audio-recorded, transcribed and analysed thematically. Fifty-one (78.5%) of the permanent residents died in RAC; 21.5% died in hospital. Home was the initial preferred POD for most interviewed participants; most eventually accepted the transfer to RAC. Long-term residents considered RAC to be their "home"-a familiar place, and an important part of their rural community. The participants did not consider a transfer to hospital to be necessary for end-of-life care. Further work is required to explore further the perspectives of rural RAC residents and their families, and if transfers to hospital are avoidable. PMID- 29766597 TI - A functional assay for the clinical annotation of genetic variants of uncertain significance in Diamond-Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss-of-function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in-frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre-rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild-type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre-rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients. PMID- 29766600 TI - Effect of childhood adversities on alcohol problems is mainly mediated by depression. AB - BACKGROUND AND OBJECTIVES: We aimed to study how five childhood adversities and trauma (CAT) core domains: emotional abuse (EmoAb), physical abuse (PhyAb), sexual abuse (SexAb), emotional neglect (EmoNeg), physical neglect (PhyNeg), associate with alcohol problems (APs), and whether there are any gender differences in these associations. METHODS: Altogether, 690 adult participants drawn from the general population completed a mailed questionnaire, including the trauma and distress scale, as an indicator of CAT, and questions concerning sociodemographic background, depressive symptoms, and APs. RESULTS: In univariate analyses, male gender, middle age, divorced/separated marital status and lower education, frequency of use of alcohol, previous treatment for mental problems, as well as depressive symptoms and CAT domain scores were associated with APs. Of the CAT domains, females reported more EmoAb and SexAb than males, but there was no gender difference in other CAT domains and depressive symptoms. In multivariate analyses, when the effects of background characteristics were controlled, CAT sum and all its domains had indirect effects via depressive symptoms on APs with no significant direct effect except in females, in whom PhyAb and SexAb associated directly with APs even when the effects of other CAT domains were taken into account. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: All CAT domains associate extensively with APs. Generally, their effect on APs is mainly mediated via depressive symptoms. In females, PhyAb and SexAb also have a considerable direct effect on APs. In treating individuals with CAT experiences and alcohol problems, treatment of depression is also important. (Am J Addict 2018;XX:1-9). PMID- 29766599 TI - Randomized clinical trial to evaluate the effectiveness of enrofloxacin as a second-line antibiotic for treatment of acute Escherichia coli mastitis. AB - The objective of the present study was to evaluate the effectiveness of enrofloxacin (ERFX) as a second-line antibiotic for treatment of acute Escherichia coli (E. coli) mastitis. Forty-two cows with naturally occurring acute E. coli mastitis were enrolled. On the first day of treatment (day 0), empirically selected antibiotics (oxytetracycline: n = 32, kanamycin: n = 10) were administered. Although systemic signs improved in 10 cows (first-line group), the signs remained unchanged or worsened in 32 cows on day 1, including two cows that were found dead. The 30 surviving cows were randomly assigned to second-line groups constituting an ERFX group (n = 19) or a control group (n = 11) that was treated with other antibiotics. Response to each treatment was evaluated by measuring clinical signs from day 0 to day 3, subsequent quarter milk recovery, and the 60-day survival rate. Appetite on day 3 was significantly better in the ERFX group compared to the control group. No significant differences were observed in the 60-day survival rate or the subsequent milk recovery between the ERFX group and the control group. Thus, the use of ERFX as a second-line antibiotic for the treatment of acute E. coli mastitis could induce a rapid appetite recovery. PMID- 29766603 TI - Characterization of aerosol nitroaromatic compounds: Validation of an experimental method. AB - The analytical capabilities associated with the use of silylation reactions have been extended to a new class of organic molecules, nitroaromatic compounds (NACs). These compounds are a possible contributor to urban particulate matter of secondary origin which would make them important analytes due to their (1) detrimental health effects, (2) potential to affect aerosol optical properties, and (3) and usefulness for identifying PM2.5 from biomass burning. The technique is based on derivatization of the parent NACs by using N,O-bis-(trimethylsilyl) trifluoro acetamide, one of the most prevalent derivatization reagent for analyzing hydroxylated molecules, followed by gas chromatography-mass spectrometry using electron ionization (EI) and methane chemical ionization (CI). This method is evaluated for 32 NACs including nitrophenols, methyl-/methoxy nitrophenols, nitrobenzoic acids, and nitrobenzyl alcohols. Electron ionization spectra were characterized by a high abundance of ions corresponding to [M+ ] or [M+ - 15]. Chemical ionization spectra exhibited high abundance for [M+ + 1], [M+ - 15], and [M+ + 29] ions. Both EI and CI spectra exhibit ions specific to nitro group(s) for [M+ - 31], [M+ - 45], and [M+ - 60]. The strong abundance observed for [M+ ] (EI), [M+ - 15] (EI/CI), or [M+ + 1] (CI) ions is consistent with the high charge stabilizing ability associated with aromatic compounds. The combination of EI and CI ionization offers strong capabilities for detection and identification of NACs. Spectra associated with NACs, containing hydrogen, carbon, oxygen, and nitrogen atoms only, as silylated derivatives show fragment/adduct ions at either (a) odd or (b) even masses that indicate either (a) odd or (b) even number of nitro groups, respectively. Mass spectra associated with silylated NACs exhibited 3 distinct regions where characteristic fragmentation with a specific pattern associated with (1) ?OH and/or ?COOH groups, (2) ?NO2 group(s), and (3) benzene ring(s). These findings were confirmed with applications to chamber aerosol and ambient PM2.5 . PMID- 29766602 TI - Study of the effect of genotype-environment interaction on age at first calving and production traits in Nellore cattle using multi-trait reaction norms and Bayesian inference. AB - This study investigated the effects of genotype-environment interaction on yearling weight, age at first calving and post-weaning weight gain in Nellore cattle using multi-trait reaction norm models. The environmental gradient was defined as a function of the mean yearling weight of the contemporary groups. A first-order random regression sire model with four classes of residual variance was used in the analyses and Bayesian methods were applied to estimate the (co)variance components. The heritability estimates ranged from 0.284 to 0.547, 0.222 to 0.316 and 0.256 to 0.522 for yearling weight, age at first calving and post-weaning weight gain, respectively. The lowest genetic correlations between environment groups for each trait were 0.38, 0.02 and 0.04 for yearling weight, age at first calving and post-weaning weight gain, respectively. Differences in the correlation estimates were observed between traits in the same environments, with the magnitude of the estimates tending toward zero as the environment improved. The results highlight the importance of including genotype-environment interactions in genetic evaluation programs considering the differences observed between environmental groups not only in terms of heritability, but also of genetic correlations. PMID- 29766605 TI - What role does dopamine really play in tobacco addiction? PMID- 29766606 TI - Glutamic acid-related hydrazine reagent for the derivatization of carbonyl compounds. PMID- 29766601 TI - Functional high-intensity exercise training ameliorates insulin resistance and cardiometabolic risk factors in type 2 diabetes. AB - NEW FINDINGS: What is the central question of this study? Does short-duration, high-intensity exercise training that combines functional aerobic and resistance exercises into training sessions lasting 8-20 min benefit individuals with type 2 diabetes? What is the main finding and its importance? Functional high-intensity training improves insulin sensitivity and reduces cardiometabolic risk in individuals with type 2 diabetes. This type of exercise training may be an effective exercise mode for managing type 2 diabetes. The increase in insulin sensitivity addresses a key defect in type 2 diabetes. ABSTRACT: Functional high intensity training (F-HIT) is a novel fitness paradigm that integrates simultaneous aerobic and resistance training in sets of constantly varied movements, based on real-world situational exercises, performed at high-intensity in workouts that range from ~8 to 20 min per session. We hypothesized that F-HIT would be an effective exercise mode for reducing insulin resistance in type 2 diabetes (T2D). We recruited 13 overweight/obese adults (5 males, 8 females; 53 +/- 7 years; BMI 34.5 +/- 3.6 kg m-2 , means +/- SD) with T2D to participate in a 6-week (3 days week-1 ) supervised F-HIT programme. An oral glucose tolerance test was used to derive measures of insulin sensitivity. F-HIT significantly reduced fat mass (43.8 +/- 83.8 vs. 41.6 +/- 7.9 kg; P < 0.01), diastolic blood pressure (80.2 +/- 7.1 vs. 74.5 +/- 5.8; P < 0.01), blood lipids (triglyceride and VLDL, both P < 0.05) and metabolic syndrome z-score (6.4 +/- 4.5 vs. -0.2 +/- 5.2 AU; P < 0.001), and increased basal fat oxidation (0.08 +/- 0.03 vs. 0.10 +/- 0.04 g min-1 ; P = 0.05), and high molecular mass adiponectin (214.4 +/- 88.9 vs. 288.8 +/- 127.4 ng mL-1 ; P < 0.01). Importantly, F-HIT also increased insulin sensitivity (0.037 +/- 0.010 vs. 0.042 +/- 0.010 AU; P < 0.05). Increases in high molecular mass adiponectin and basal fat oxidation correlated with the change in insulin sensitivity (rho, 0.75, P < 0.05 and rho, 0.81, P < 0.01, respectively). Compliance with the training programme was >95% and no injuries or adverse events were reported. These data suggest that F-HIT may be an effective exercise mode for managing T2D. The increase in insulin sensitivity addresses a key defect in T2D and is consistent with improvements observed after more traditional aerobic exercise programmes in overweight/obese adults with T2D. PMID- 29766604 TI - Sodium nitroglycerin induces middle cerebral artery vasodilatation in young, healthy adults. AB - NEW FINDINGS: What is the central question of this study? Nitric oxide causes dilatation in peripheral vessels; however, whether nitric oxide affects basal cerebral artery dilatation has not been explored. What is the main finding and its importance? This study demonstrated that vasodilatation occurs in the right middle cerebral artery in response to exogenous nitric oxide. However, blood velocity decreased and, therefore, overall cerebral blood flow remained unchanged. This study provides new insight into the role of nitric oxide in cerebral blood flow control. ABSTRACT: Recent evidence indicates that basal cerebral conduit vessels dilate with hypercapnia, with a nitric oxide (NO) mechanism explaining one way in which parenchymal cerebral arterioles dilate. However, whether NO affects basal cerebral artery dilatation remains unknown. This study quantified the effect of an exogenous NO donor [sodium nitroglycerin (NTG); 0.4 mg sublingual spray] on the right middle cerebral artery (rMCA) cross sectional area (CSA), blood velocity and overall blood flow. Measures of vessel CSA (7 T magnetic resonance imaging) and MCA blood velocity (transcranial Doppler ultrasound) were made at baseline (BL) and after exogenous NTG or placebo (PLO) administration in young, healthy individuals (n = 10, two males, age range 20-23 years). The CSA increased in the rMCA [BL, 5.2 +/- 1.2 mm2 ; PLO, 5.4 +/- 1.5 mm2 ; NTG, 6.6 +/- 1.5 mm2 , P < 0.05; mean +/- SD]. Concurrently, rMCA blood velocity decreased from BL during NTG compared with PLO (BL, 67 +/- 10 cm s-1 ; PLO, 62 +/- 10 cm s-1 ; NTG, 59 +/- 9.3 cm s-1 , P < 0.05; mean +/- SD]. However, total MCA blood flow did not change with NTG or PLO [BL, 221 +/- 37.4 ml min-1 ; PLO, 218 +/- 35.0 ml min-1 ; NTG, 213 +/- 46.4 ml min-1 ). Therefore, exogenous NO mediates a dilatory response in the rMCA, but not in its downstream vascular bed. PMID- 29766608 TI - Effects of supplementary desalted mother liquor as replacement of commercial salt in diet for Thai native cattle on digestibility, energy and nitrogen balance, and rumen conditions. AB - Four Thai native cattle were used in a 4 * 4 Latin square design experiment to evaluate the availability of desalted mother liquor (DML) as replacement of salt in concentrate. Each cattle was assigned to one of the following concentrate feeding treatments: C1, 1% NaCl was added as salt; C2, 2% NaCl was added as salt; D1, 1% NaCl was replaced by DML; D2, 2% NaCl was replaced by DML, on a dry matter (DM) basis. The animals were fed rice straw and experimental concentrates (40:60) at 1.9% of body weight on a DM basis, daily. Acid detergent fiber expressed exclusive of residual ash (ADFom) digestibility in DML treatment was higher than salt treatment (p < .05) and D2 feeding showed the highest value (60.8%). There were no significant differences in blood metabolites, nitrogen retention, ruminal ammonia nitrogen, methane emission or energy efficiency among treatments. Molar percent of acetate on volatile fatty acids in rumen fluid 4 hr post-feeding tended to be higher in DML treatment than salt treatment (p = .08). The results indicated that adding DML could improve ADFom digestibility and salt could be replaced by DML up to 2% as NaCl in concentrate without adverse effects on nitrogen balance, rumen conditions, blood metabolites and methane emission. PMID- 29766609 TI - Effects of colostrum whey on immune function in the digestive tract of goats. AB - The objective of the present study is to examine whether colostrum whey can have an effect on immune function in goats digestive tract. Two milliliters of colostrum whey (colostrum group) or water (control group) were administrated orally to goats every day for 3 weeks. Blood was collected twice a week for 3 weeks to measure immunoglobulin A (IgA), interleukin 8 (IL-8), and IL-10. At the end of the experimental period, the parotid glands, oral mucosa, lingua, esophagus, jejunum, and ileum were collected for immunohistochemical detection of IgA, cathelicidin-7, and S100A8. The ratio of the length of IgA-positive mucosal surface in the esophagus to the total esophageal length was significantly greater in the colostrum group than in the control group. The number of IgA-positive cells in the labial gland and ileum in the colostrum group was significantly higher than that in the control group. There were no significant differences between the colostrum and control groups in the number of cathelicidin-7-positive cells in the jejunum and ileum and in the number of S100A8-positive cells in the lingua, jejunum, and ileum. These results suggest that colostrum stimulates the recruitment of plasma cells into the labial gland, which then secrete more IgA into the saliva. PMID- 29766610 TI - Sensitive and simultaneous quantitation of 6beta-hydroxycortisol and cortisol in human plasma by LC-MS/MS coupled with stable isotope dilution method. AB - CYP3A phenotyping provides a means for personalized drug therapy. We focused our attention on the plasma 6beta-hydroxycortisol (6beta-OHF) to cortisol ratio as an index for CYP3A phenotyping. In the present study, we developed a sensitive and reliable method for the simultaneous determination of 6beta-OHF and cortisol in human plasma using high-performance liquid chromatography/tandem mass spectrometry together with picolinylester derivatization or nonderivatization methods and 6beta-[9,11,12,12-2 H4 ]hydroxycortisol and [1,2,4,19-13 C4 ]cortisol as internal standards for in vivo CYP3A phenotyping in humans. The lower limits of quantification were 38.513 pg/mL for 6beta-OHF and 38.100 pg/mL for cortisol. The relative error and relative standard deviation of the lower limits of quantification were <5% for both methods. The intra-day and inter-day assay reproducibilities of the determined 6beta-OHF and cortisol concentrations were consistent with the actual amounts added as relative errors and relative standard deviations for both methods, which were <5.4% and <3.9%, respectively. Both methods were applied for the quantification of plasma 6beta-OHF and cortisol concentrations in healthy subjects taking oral contraceptives. The absolute concentrations and time course of 6beta-OHF and cortisol were found to be consistent when measured using the 2 methods. The ratio as an index for in vivo CYP3A activity decreased after 21 days of taking oral contraceptives for both methods. To the best of our knowledge, this is the first study reporting the detailed investigation of accuracy and precision in the simultaneous measurement of 6beta-OHF and cortisol in human plasma using liquid chromatography/tandem mass spectrometry coupled with stable isotope dilution method, which can be applied to CYP3A phenotyping. PMID- 29766611 TI - Drinking game participation and outcomes in a sample of Australian university students. AB - INTRODUCTION AND AIMS: Most drinking game (DG) research among university students has been conducted among USA college samples. The extent to which demographics and game type (e.g. team and sculling games) are linked to DG behaviours/consequences among non-USA students is not well understood. As such, the current study investigated characteristics of DG participation (and associated outcomes) among a sample of Australian university students. METHODS: University students (N = 252; aged 18-24 years; 67% female) who had consumed alcohol in the prior year completed an online survey. Measures included demographics, DG behaviours (lifetime, frequency and consumption) and gaming specific consequences. RESULTS: Most of the students reported lifetime DG participation (85%). Among those who played a DG in the prior 6 months (69%), most had experienced a negative gaming-specific consequence. While team games were the most popular DG played, regression analysis demonstrated that participation in games which encouraged consumption (e.g. sculling) were associated with increased alcohol consumption during play. In addition to being older, playing DGs more frequently, and consuming more alcohol while playing, participation in both consumption and dice games (e.g. 7-11, doubles) predicted more negative gaming-specific consequences. DISCUSSION AND CONCLUSIONS: DG participation is common among Australian university students, as it is in other parts of the world. The importance of game type is clear, particularly the risk of consumption games. Findings could help inform interventions to reduce participation in consumption games and identify students who might be especially at-risk for experiencing negative DG consequences. PMID- 29766612 TI - Visuomotor coordination and cortical connectivity of modular motor learning. AB - The ability to transfer sensorimotor skill components to new actions and the capacity to use skill components from whole actions are characteristic of the adaptability of the human sensorimotor system. However, behavioral evidence suggests complex limitations for transfer after combined or modular learning of motor adaptations. Also, to date, only behavioral analysis of the consequences of the modular learning has been reported, with little understanding of the sensorimotor mechanisms of control and the interaction between cortical areas. We programmed a video game with distorted kinematic and dynamic features to test the ability to combine sensorimotor skill components learned modularly (composition) and the capacity to use separate sensorimotor skill components learned in combination (decomposition). We examined motor performance, eye-hand coordination, and EEG connectivity. When tested for integrated learning, we found that combined practice initially performed better than separated practice, but differences disappeared after integrated practice. Separate learning promotes fewer anticipatory control mechanisms (depending more on feedback control), evidenced in a lower gaze leading behavior and in higher connectivity between visual and premotor domains, in comparison with the combined practice. The sensorimotor system can acquire motor modules in a separated or integrated manner. However, the system appears to require integrated practice to coordinate the adaptations with the skill learning and the networks involved in the integrated behavior. This integration seems to be related to the acquisition of anticipatory mechanism of control and with the decrement of feedback control. PMID- 29766614 TI - Noninferiority trials in oral medicine. PMID- 29766613 TI - Cortical Thickness Estimations of FreeSurfer and the CAT12 Toolbox in Patients with Alzheimer's Disease and Healthy Controls. AB - BACKGROUND AND PURPOSE: Automated cortical thickness (CT) measurements are often used to assess gray matter changes in the healthy and diseased human brain. The FreeSurfer software is frequently applied for this type of analysis. The computational anatomy toolbox (CAT12) for SPM, which offers a fast and easy-to use alternative approach, was recently made available. METHODS: In this study, we compared region of interest (ROI)-wise CT estimations of the surface-based FreeSurfer 6 (FS6) software and the volume-based CAT12 toolbox for SPM using 44 elderly healthy female control subjects (HC). In addition, these 44 HCs from the cross-sectional analysis and 34 age- and sex-matched patients with Alzheimer's disease (AD) were used to assess the potential of detecting group differences for each method. Finally, a test-retest analysis was conducted using 19 HC subjects. All data were taken from the OASIS database and MRI scans were recorded at 1.5 Tesla. RESULTS: A strong correlation was observed between both methods in terms of ROI mean CT estimates (R2 = .83). However, CAT12 delivered significantly higher CT estimations in 32 of the 34 ROIs, indicating a systematic difference between both approaches. Furthermore, both methods were able to reliably detect atrophic brain areas in AD subjects, with the highest decreases in temporal areas. Finally, FS6 as well as CAT12 showed excellent test-retest variability scores. CONCLUSION: Although CT estimations were systematically higher for CAT12, this study provides evidence that this new toolbox delivers accurate and robust CT estimates and can be considered a fast and reliable alternative to FreeSurfer. PMID- 29766617 TI - Gingival tissue reaction to direct adhesive restoration: A preliminary study. AB - INTRODUCTION: It is debated whether composite resin marginal/submarginal direct restoration can be usefully performed without inflammatory consequences. This histological study is the first human analysis aimed to compare, in the same tooth, the gingival tissue close to composite resin restorations with gingival tissue close to hard tissue. METHODS: Eight healthy patients with almost a residual strategic tooth needing endodontic therapy, and post-and-core restoration, then indirect prosthetic restoration, were selected. Direct margin relocation with composite resin was necessary to perform endodontic treatment. The crown lengthening with a secondary flap harvested was necessary to perform prosthetic rehabilitation. Three months after marginal relocation, the secondary flap was harvested, embedded in PMMA, 4-MUm sectioned, and stained to analyze the inflammation degree. RESULTS: All patients completed post-and-core reconstruction and the planned prosthetic therapy, maintaining the stringent hygienic protocol plan. The inflammation level comparison, slightly lower in gingiva close to the teeth (3.62 +/- 0.38) than in gingiva close to the composite (3.75 +/- 0.26), results in a p-value of 0.11 after Wilcoxon test. CONCLUSIONS: Results highlight a minimal, statistically not significant difference in the inflammation degree after margin relocation, conceivably due to patients, teeth and cases selection, together with adopted stringent methodological and supportive measures. PMID- 29766616 TI - Addressing unwarranted clinical variation: A rapid review of current evidence. AB - INTRODUCTION: Unwarranted clinical variation (UCV) can be described as variation that can only be explained by differences in health system performance. There is a lack of clarity regarding how to define and identify UCV and, once identified, to determine whether it is sufficiently problematic to warrant action. As such, the implementation of systemic approaches to reducing UCV is challenging. A review of approaches to understand, identify, and address UCV was undertaken to determine how conceptual and theoretical frameworks currently attempt to define UCV, the approaches used to identify UCV, and the evidence of their effectiveness. DESIGN: Rapid evidence assessment (REA) methodology was used. DATA SOURCES: A range of text words, synonyms, and subject headings were developed for the major concepts of unwarranted clinical variation, standards (and deviation from these standards), and health care environment. Two electronic databases (Medline and Pubmed) were searched from January 2006 to April 2017, in addition to hand searching of relevant journals, reference lists, and grey literature. DATA SYNTHESIS: Results were merged using reference-management software (Endnote) and duplicates removed. Inclusion criteria were independently applied to potentially relevant articles by 3 reviewers. Findings were presented in a narrative synthesis to highlight key concepts addressed in the published literature. RESULTS: A total of 48 relevant publications were included in the review; 21 articles were identified as eligible from the database search, 4 from hand searching published work and 23 from the grey literature. The search process highlighted the voluminous literature reporting clinical variation internationally; yet, there is a dearth of evidence regarding systematic approaches to identifying or addressing UCV. CONCLUSION: Wennberg's classification framework is commonly cited in relation to classifying variation, but no single approach is agreed upon to systematically explore and address UCV. The instances of UCV that warrant investigation and action are largely determined at a systems level currently, and stakeholder engagement in this process is limited. Lack of consensus on an evidence-based definition for UCV remains a substantial barrier to progress in this field. PMID- 29766618 TI - Successful treatment of cutaneous metastatic melanoma with high-dose intralesional interleukin-2 treatment combined with cryosurgery. PMID- 29766615 TI - Barriers and facilitators to smoking cessation in pregnancy and in the post partum period: The health care professionals' perspective. AB - OBJECTIVES: Health care professionals and the health care environment play a central role in protecting pregnant and post-partum women and their infants from smoking-related harms. This study aimed to better understand the health professional's perspective on how interactions between women, health care professionals, and the environment influence how smoking is managed. DESIGN: Semi structured interviews and focus groups. METHODS: Data were from 48 health care staff involved in antenatal or post-partum care at two UK sites, including midwives, obstetricians, health visitors, GPs, pharmacists, service commissioners, and Stop Smoking Service (SSS) advisors and managers. Thematic analysis was guided by a social-ecological framework (SEF). RESULTS: Themes were divided across three SEF levels and represented factors connected to the management of smoking in the health care context and the beliefs and behaviour of pregnant or post-partum smokers. Organizational level: Service reconfigurations, 'last resort' nicotine replacement therapy prescribing policies, and non mandatory training were largely negative factors. There were mixed views on opt out referral pathways and positive views on carbon monoxide monitoring. Interpersonal level: Protection of client-professional relationships often inhibited frank discussions about smoking, and weak interservice relationships affected SSS referral motivation and quality. Individual level: Professionals felt community midwives had primary responsibility for managing smoking, although midwives felt underskilled doing this. Midwives' perceived priority for addressing smoking was influenced by the demands from unrelated organizational initiatives. CONCLUSIONS: Opportunities to improve clinical support for pregnant smokers exist at organizational, interservice, and health care professional levels. Interactions between levels reflect the importance of simultaneously addressing different level-specific barriers to smoking cessation in pregnancy. Statement of contribution What is already known on this subject? Few health care professionals discuss smoking cessation support with pregnant or post-partum women. Identified health care professional-related barriers to supporting pregnant and post-partum women to stop smoking include deficits in knowledge and confidence, perceived lack of time, and concerns about damaging client relationships. There is currently a gap in understanding regarding the barriers and facilitators to supporting this group and how interactions between the health care environment and health care professionals influence the way smoking is addressed. What does this study add? This study identifies modifiable factors that can influence cessation support delivery to pregnant and post-partum women. These factors are mapped across organizational, interpersonal, and individual health care professional levels. Service structure, communication pathways, and policies appear to influence what cessation support is offered. Interpersonal and individual factors influence how this support is delivered. PMID- 29766619 TI - Universal infant health interventions and young adult outcomes. AB - Three recent studies have documented short- and long-run benefits of early infancy health interventions in Norway, Sweden, and Denmark: Universal nurse home visiting (NHV) and well-baby center care decreased infant mortality and positively impacted long-run survival (DK, S), morbidity (DK, N), and educational and labor market outcomes (N). Using Danish conscription data, this paper examines intermediate outcomes to assess both potential mechanisms and the importance of selective survival for the long-run health effects of NHV. We do not find strong effects of NHV for young adult's height or obesity status, but we find that NHV increases treated individuals' probability of emigration. As emigrants in our sample are positively selected and as they are not part of the samples used in long-run analyses, this finding suggests that the established long-run health benefits of NHV may be lower bounds. PMID- 29766621 TI - Prototyping Instruments for the Chemical Laboratory Using Inexpensive Electronic Modules. AB - Open-source electronics and programming can augment chemical and biomedical research. Currently, chemists can choose from a broad range of low-cost universal electronic modules (microcontroller boards and single-board computers) and use them to assemble working prototypes of scientific tools to address specific experimental problems and to support daily research work. The learning time can be as short as a few hours, and the required budget is often as low as 50 USD. Prototyping instruments using low-cost electronic modules gives chemists enormous flexibility to design and construct customized instrumentation, which can reduce the delays caused by limited access to high-end commercial platforms. PMID- 29766622 TI - Evaluating the implementation of confusion assessment method-intensive care unit using a quality improvement approach. AB - Quality improvement (QI) is a way through which health care delivery can be made safer and more effective. Various models of quality improvement methods exist in health care today. These models can help guide and manage the process of introducing changes into clinical practice. The aim of this project was to implement the use of a delirium assessment tool into three adult critical care units within the same hospital using a QI approach. The objective was to improve the identification and management of delirium. Using the Model for Improvement framework, a multidisciplinary working group was established. A delirium assessment tool was introduced via a series of educational initiatives. New local guidelines regarding the use of delirium assessment and management for the multidisciplinary team were also produced. Audit data were collected at 6 weeks and 5 months post-implementation to evaluate compliance with the use of the tool across three critical care units within a single hospital in London. At 6 weeks, in 134 assessment points out of a possible 202, the tool was deemed to be used appropriately, meaning that 60% of patients received timely assessment; 18% of patients were identified as delirious in audit one. Five months later, only 95 assessment points out of a possible 199 were being appropriately assessed (47%); however, a greater number (32%) were identified as delirious. This project emphasizes the complexity of changing practice in a large busy critical care centre. Despite an initial increase in delirium assessment, this was not sustained over time. The use of a QI model highlights the continuous process of embedding changes into clinical practice and the need to use a QI method that can address the challenging nature of modern health care. QI models guide changes in practice. Consideration should be given to the type of QI model used. PMID- 29766623 TI - Substitution-Inert Polynuclear Platinum Complexes That Inhibit the Activity of DNA Polymerase in Triplex-Forming Templates. AB - The formation of triple-helical DNA is implicated in the regulation of gene expression. The triplexes are, however, unstable under physiological conditions so that effective stabilizers for the triplex formation are needed. Herein, we describe a new strategy for the stabilization of such triplexes that is based on antitumor substitution-inert polynuclear platinum complexes (SI-PPCs). These compounds were previously shown to bind to DNA through the phosphate clamp-a discrete mode of DNA-ligand recognition distinct from the canonical intercalation and minor-groove binding. We have found that SI-PPCs efficiently inhibit DNA synthesis by DNA polymerase in sequences prone to the formation of pyrimidine- and purine-motif triplex DNAs. Moreover, the results suggest that SI-PPCs are able to induce the formation of triple-helical DNA between duplexes and strands that are not completely complementary to each other. Collectively, these data provide evidence that SI-PPCs are very efficient stabilizers of triple-stranded DNA that might exert their action by stabilizing higher-order structures such as triple-helical DNA. PMID- 29766620 TI - Insane in the apical membrane: Trafficking events mediating apicobasal epithelial polarity during tube morphogenesis. AB - The creation of cellular tubes is one of the most vital developmental processes, resulting in the formation of most organ types. Cells have co-opted a number of different mechanisms for tube morphogenesis that vary among tissues and organisms; however, generation and maintenance of cell polarity is fundamental for successful lumenogenesis. Polarized membrane transport has emerged as a key driver not only for establishing individual epithelial cell polarity, but also for coordination of epithelial polarization during apical lumen formation and tissue morphogenesis. In recent years, much work has been dedicated to identifying membrane trafficking regulators required for lumenogenesis. In this review we will summarize the findings from the past couple of decades in defining the molecular machinery governing lumenogenesis both in 3D tissue culture models and during organ development in vivo. PMID- 29766624 TI - Quantification of Interfacial pH Variation at Molecular Length Scales Using a Concurrent Non-Faradaic Reaction. AB - We quantified changes in interfacial pH local to the electrochemical double layer during electrocatalysis by using a concurrent non-faradaic probe reaction. In the absence of electrocatalysis, nanostructured Pt/C surfaces mediate the reaction of H2 with cis-2-butene-1,4-diol to form a mixture of 1,4-butanediol and n-butanol with selectivity that is linearly dependent on the bulk solution pH value. We show that kinetic branching occurs from a common surface-bound intermediate, ensuring that this probe reaction is uniquely sensitive to the interfacial pH value within molecular length scales of the surface. We used the pH-dependent selectivity of this reaction to track changes in interfacial pH during concurrent hydrogen oxidation electrocatalysis and found that the local pH value can vary dramatically (>3 units) relative to the bulk value even at modest current densities in well-buffered electrolytes. This study highlights the key role of interfacial pH variation in modulating inner-sphere electrocatalysis. PMID- 29766625 TI - The Important Role of the Byproduct Triphenylphosphine Oxide in the Magnesium(II) Catalyzed Enantioselective Reaction of Hemiacetals and Phosphorus Ylides. AB - By employing a simple in situ generated magnesium catalyst, a direct asymmetric reaction between hemiacetals and phosphorus ylides was achieved through a tandem Wittig-oxa-Michael reaction sequence. Enantioenriched chromans, isochromans, and tetrahydropyrans were obtained in good chemical yields, and (-)-erythrococcamide B was synthesized in enantioenriched form. The byproduct triphenylphosphine oxide was identified as a necessary additive for this process. PMID- 29766627 TI - A Cocatalyst that Stabilizes a Hydride Intermediate during Photocatalytic Hydrogen Evolution over a Rhodium-Doped TiO2 Nanosheet. AB - The hydrogen evolution reaction using semiconductor photocatalysts has been significantly improved by cocatalyst loading. However, there are still many speculations regarding the actual role of the cocatalyst. Now a photocatalytic hydrogen evolution reaction pathway is reported on a cocatalyst site using TiO2 nanosheets doped with Rh at Ti sites as one-atom cocatalysts. A hydride species adsorbed on the one-atom Rh dopant cocatalyst site was confirmed experimentally as the intermediate state for hydrogen evolution, which was consistent with the results of density functional theory (DFT) calculations. In this system, the role of the cocatalyst in photocatalytic hydrogen evolution is related to the withdrawal of photo-excited electrons and stabilization of the hydride intermediate species; the presence of oxygen vacancies induced by Rh facilitate the withdrawal of electrons and stabilization of the hydride. PMID- 29766626 TI - CO2 laser and photodynamic therapy: Study of efficacy in periocular BCC. AB - Basal cell carcinoma (BCC), the most common type of skin cancer in the world, usually arises in sun-exposed areas of the skin. The therapeutic approach to periocular BCC has changed in the last few years. Currently the treatment, considering the delicate localization of the disease, must not only ensure complete recovery from the neoplastic disease, but must also satisfy functional and aesthetic criteria. In this study we tried to evaluate the efficacy of CO2 laser and photodynamic therapy in periocular BCC. PMID- 29766628 TI - Health professional student education related to the prevention of falls in older people: A survey of universities in Australia and New Zealand. AB - OBJECTIVE: To determine the amount and nature of health professional education related to fall prevention for older adults in Australian and New Zealand universities. METHODS: Universities offering medicine, nursing and allied health courses were invited to complete an online survey enquiring about fall prevention course-related information: topics; delivery mode; and time dedicated. RESULTS: One hundred and five respondents, 11 disciplines and 43 universities completed the survey. Courses were primarily undergraduate level (90%) and delivered face to-face (93%). Time dedicated to fall prevention was usually one to three hours of lectures (>65% of courses) and 1-3+ hours of tutorials/practical sessions (>80% of courses). CONCLUSIONS: Survey results indicate that education of health professionals across a range of disciplines in Australia and New Zealand does include older adult fall prevention. Education of all health and exercise professionals about falls is vital given their critical role in the prevention and management of falls in our rapidly ageing population. PMID- 29766629 TI - Lower Activation Energy for Catalytic Reactions through Host-Guest Cooperation within Metal-Organic Frameworks. AB - Industrial synthesis is driven by a delicate balance of the value of the product against the cost of production. Catalysts are often employed to ensure product turnover is economically favorable by ensuring energy use is minimized. One method, which is gaining attention, involves cooperative catalytic systems. By inserting a flexible polymer into a metal-organic framework (MOF) host, the advantages of both components work synergistically to create a composite that efficiently fixes carbon dioxide to transform various epoxides into cyclic carbonates. The resulting material retains high yields under mild conditions with full reusability. By quantitatively studying the kinetic rates, the activation energy was calculated, for a physical mixture of the catalyst components to be about 50 % higher than that of the composite. Through the unification of two catalytically active components, a new opportunity opens up for the development of synergistic systems in multiple applications. PMID- 29766630 TI - Violence committed against nursing staff by patients in psychiatric outpatient settings. AB - Violence against nurses has increased particularly in psychiatric outpatient settings as psychiatric care shifts from being inpatient-based to being outpatient-based. Violence is a complex phenomenon that must be explored in different psychiatric nursing environments and settings. Violence in psychiatric outpatient settings should especially be explored as violence in this context has scarcely been examined. The aim of this systematic review was to elucidate violence committed against nursing staff by patients in adult psychiatric outpatient settings, based on reports from previous studies. A literature search was conducted in the CINAHL (EBSCO), Ovid MEDLINE, and PsycARTICLES (Ovid) databases. Fourteen studies emerged after the selection and quality assessment process. These studies indicated that violence in psychiatric outpatient settings is a multidimensional phenomenon comprising the reasons for, forms of, and consequences of violence. Reasons for violence could be related to the patient as well as to nursing staff. In psychiatric outpatient settings, verbal violence was the most common form of violence, and violence most frequently led to psychological consequences for nursing staff. The findings of this review highlight the importance of nursing staff developing skills and interventions for managing different kinds of violent situations. Given the multidimensional consequences of violence, attention must be given to the occupational well-being and coping ability of nursing staff at work. Furthermore, it would be worthwhile to compare cultural and intercountry differences of violent exposures in psychiatric outpatient settings. PMID- 29766631 TI - Pathological findings that contribute to tissue stiffness in the spleen of liver cirrhosis patients. AB - AIM: Spleen stiffness is increased in liver cirrhosis (LC). We attempted to characterize the pathological features of spleen in LC. METHODS: We compared pathological findings of resected spleen tissues of 28 LC patients and those of six healthy controls. In addition, we measured spleen stiffness before splenectomy by shear wave elastography in nine LC patients. After splenectomy, we examined the relationship between spleen stiffness and pathological findings. RESULTS: Passive congestion of the spleen was more frequently observed in LC patients than in controls (P < 0.01). The sinus was wider in LC patients than in controls (P < 0.01). In the spleens of the LC patients, diffuse alpha-smooth muscle actin (alphaSMA) expression of sinusoidal mesenchymal cells and deposition of collagen fibers on the perisinusoidal wall were observed. In nine LC patients whose spleen stiffness was examined, the width of the sinus increased along with spleen stiffness (r = 0.89, P < 0.01). Spleen stiffness was higher in the spleen tissues with diffuse alphaSMA expression of sinusoidal mesenchymal cells than in those with partial alphaSMA expression of sinusoidal mesenchymal cells (P = 0.01). The degree of fibrosis was higher in the LC patients with diffuse alphaSMA expression of the red pulp than in those with partial alphaSMA expression of the red pulp (P = 0.03). CONCLUSION: In the LC patients, spleen tissues showed passive congestion with a dilated sinus, diffuse alphaSMA expression of sinusoidal mesenchymal cells, and deposition of collagen fibers on the perisinusoidal wall. This contributed to spleen stiffness. PMID- 29766632 TI - Dynamic Ultralong Organic Phosphorescence by Photoactivation. AB - Smart materials with ultralong phosphorescence are rarely investigated and reported. Herein we report on a series of molecules with unique dynamic ultralong organic phosphorescence (UOP) features, enabled by manipulating intermolecular interactions through UV light irradiation. Our experimental data reveal that prolonged irradiation of single-component organic phosphors of PCzT, BCzT, and FCzT under ambient conditions can activate UOP with emission lifetimes spanning from 1.8 to 1330 ms. These phosphors can also be deactivated back to their original states with short-lived phosphorescence by UV irradiation for 3 h at room temperature or through thermal treatment. Additionally, the dynamic UOP was applied successfully for a visual anti-counterfeiting application. These findings may provide unique insight into dynamic molecular motion for optical processing and expand the scope of smart-response materials for broader applications. PMID- 29766633 TI - Empagliflozin as adjunct to insulin in Japanese participants with type 1 diabetes: Results of a 4-week, double-blind, randomized, placebo-controlled phase 2 trial. AB - AIMS: This phase 2, double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02702011) with 4 sites in Japan investigated the pharmacodynamics (PD), pharmacokinetics (PK) and safety profile of empagliflozin in Japanese participants with type 1 diabetes mellitus (T1DM) as adjunctive therapy to insulin. MATERIALS AND METHODS: Participants using multiple daily injections of insulin for >=12 months, with HbA1c of 7.5%-10.0%, entered a 2 week, open-label, placebo run-in period, followed by a 4-week, double-blind period during which participants were randomized 1:1:1:1 to receive empagliflozin 2.5 mg (n = 13), empagliflozin 10 mg (n = 12), empagliflozin 25 mg (n = 12) or placebo (n = 11). The primary objective was to assess the effect of empagliflozin vs placebo on urinary glucose excretion (UGE) after 7 days of treatment. RESULTS: PD: Empagliflozin resulted in a dose-dependent significant increase in 24-hour UGE compared with placebo (UGE placebo-corrected mean [95% confidence interval] change from baseline: 2.5 mg, 65.10 [43.29, 86.90] g/24 h; 10 mg, 81.19 [58.80, 103.58] g/24 h; 25 mg, 98.11 [75.91, 120.31] g/24 h). After 4 weeks of treatment, UGE increase was associated with improved glycaemic control, reduced body weight and decreased insulin needs. Empagliflozin treatment also resulted in dose dependent increases in serum ketone bodies and free fatty acids. PK: Plasma empagliflozin levels increased in a dose-dependent manner and peaked at 1.5 hours. In this short study, empagliflozin was well tolerated, with no increase in rate of hypoglycaemia and no diabetic ketoacidosis events reported. CONCLUSIONS: Based on this short-duration phase 2 study, the PK/PD profile of empagliflozin in Japanese participants with T1DM is comparable to that of non-Japanese participants. PMID- 29766634 TI - Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials. AB - AIMS: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established. MATERIALS AND METHODS: Subjects with inadequately controlled type 2 diabetes (drug-naive or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects. RESULTS: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects). CONCLUSIONS: In SUSTAIN 1 to 5, semaglutide induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor. PMID- 29766635 TI - Efficacy and safety of MK-1293 insulin glargine compared with originator insulin glargine (Lantus) in type 1 diabetes: A randomized, open-label clinical trial. AB - AIM: To compare the efficacy and safety of MK-1293 insulin glargine (Mk-Gla; 100 U/mL) with originator insulin glargine, Lantus (Sa-Gla), in people with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: This phase 3, randomized, active controlled, open-label, 52-week study (ClinicalTrials.gov NCT02059161) enrolled 508 people with T1DM (HbA1c <=11.0%; 97 mmol/mol) taking basal and prandial insulin. Participants were randomized 1:1 to once-daily Mk-Gla (n = 245) or Sa Gla (n = 263). Dose titration of basal insulin was by a pre-breakfast plasma glucose dosing algorithm. The primary efficacy objective was assessment of the non-inferiority of HbA1c change from baseline (margin of 0.40% [4.4 mmol/mol]) for Mk-Gla compared with Sa-Gla over 24 weeks. The primary safety objective was assessment of anti-insulin antibody development over 24 weeks. RESULTS: The least squares (LS) mean HbA1c change from baseline at week 24 was -0.62 (95% CI -0.79, 0.45)% (-6.8 [-8.7, -4.9] mmol/mol) and -0.66 (-0.82, -0.50)% (-7.2 [-9.0, -5.4] mmol/mol) for Mk-Gla and Sa-Gla. The LS mean HbA1c difference was 0.04 (-0.11, 0.19)% (0.4 [-1.2, 2.0] mmol/mol) for Mk-Gla minus Sa-Gla, meeting the primary and secondary objective criteria for non-inferiority and equivalence. Week 24 mean insulin glargine dose for Mk-Gla and Sa-Gla was 0.46 and 0.48 U/kg, respectively. Similarity of HbA1c response and basal insulin dose trajectory persisted over the 52 weeks. Safety and tolerability, including anti-insulin antibody responses, hypoglycaemia, adverse events and body weight, were similar between insulins over the 52-week study duration. CONCLUSIONS: Mk-Gla and Sa-Gla exhibited similar efficacy and safety over 52 weeks in people with T1DM. ClinicalTrials.gov: NCT02059161. PMID- 29766637 TI - Subtype-specific clinical and prognostic relevance of tumor-expressed F5 and regulatory F5 variants in breast cancer: the CoCaV study. AB - : Essentials The role of coagulation factor V (encoded by F5) in cancer pathogenesis is unknown. The clinical significance of tumor-expressed F5 was evaluated in breast cancer patient cohorts. F5 was expressed in human breast tumors, and the expression was higher than in normal tissue. High F5 expression was associated with aggressive tumors, but also with survival in breast cancer. SUMMARY: Background Tumor expression of certain coagulation factors has been linked to cancer progression. Single nucleotide polymorphisms (SNPs) in F5 (encoding the FV protein) have been found to be associated with breast cancer; however, the role of coagulation factor V (FV) in cancer pathogenesis remains undiscovered. Objectives We aimed to investigate the clinical significance of FV and the regulatory role of F5 gene variants in breast cancer. Patients/Methods A Scandinavian 503-sample breast cancer cohort and three public breast cancer datasets (GOBO, TCGA and KM plotter) were used to determine associations between F5 gene expression (tumor-specific), circulating FV, F5 SNPs, clinical characteristics and breast cancer survival. Immunohistochemistry (IHC) was used to detect FV antigen in tumors. Results F5 expression was 2-fold higher in breast tumors compared with normal tissue, and the presence of FV antigen in breast tumors was confirmed by IHC staining. F5 expression was increased in patients with hormone receptor negative tumors, triple negative tumors, HER2-enriched and basal-like tumors. In patients with basal tumors, high expression of F5 was associated with improved overall survival (hazard ratio, HR = 0.52, 95% confidence interval, 0.31-0.86). SNPs in F5 were associated with tumor size and luminal A tumors. The rs6427202-rs9332542 C-G haplotype, previously associated with breast cancer, displayed a cis-regulatory effect on F5 expression in tumors and plasma FV antigen levels. In silico mining supported this regulatory function. Conclusions FV was a possible marker of aggressive breast cancer, yet also a predictor of favorable outcome. Evaluation of FV expression may be clinically useful for prognosis and treatment decisions in aggressive breast cancer. PMID- 29766636 TI - Empagliflozin as add-on to linagliptin in a fixed-dose combination in Japanese patients with type 2 diabetes: Glycaemic efficacy and safety profile in a 52 week, randomized, placebo-controlled trial. AB - AIMS: This double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add-on to linagliptin (Lina) 5 mg (fixed-dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients. METHODS: The trial (40 sites; May 2015-March 2017) involved screening 433 adults (>=20 years) who were treatment-naive or were using one oral antidiabetic drug for >=12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%-10.0% after >=16 weeks of using Lina (pre-enrolment or during a 16-week, open-label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once-daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c >= 7.0% at Week 24 received Empa/Lina up-titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks. RESULTS: Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, -0.93% vs 0.21%; adjusted mean difference, 1.14%) and Week 52 (-1.16% vs 0.06%; adjusted mean difference, -1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin-associated events (eg, increased urination, increased blood ketones). There were no adjudication-confirmed diabetic ketoacidosis events or lower limb amputations. CONCLUSIONS: These results support the notion that empagliflozin-linagliptin in fixed-dose combination is a therapeutic option for Japanese patients with type 2 diabetes. PMID- 29766638 TI - Lethal and sublethal effects of chlorantraniliprole on Spodoptera cosmioides (Lepidoptera: Noctuidae). AB - BACKGROUND: The Spodoptera cosmioides (Walker, 1858) population has increased in Bacillus thuringiensis Berliner (Bt) soybean crops in Argentina. As there are no registered products for its control, the recommended insecticides for S. frugiperda are used. The aim of this study was therefore to determine the lethal concentration (LC) of chlorantraniliprole and its sublethal effects on the biological and reproductive functions of S. cosmioides, an emerging soybean pest in Argentina. RESULTS: An ingestion toxicity bioassay showed that chlorantraniliprole was active against larvae of the second instar, and after 48 h of exposure LC50 was 0.054 ug mL-1 H2 O. In the study of sublethal effect, chlorantraniliprole induced changes in the life cycle of exposed S. cosmioides, which required more time to complete all stages of development (larval, pupal and adult stages). Pupal weight was also higher in larvae exposed to sublethal concentrations of chlorantraniliprole. Adult fecundity was decreased: the number of eggs laid by each adult female moth, as compared with control females, was two (LC15 ) and eight (LC30 ) times lower. CONCLUSION: These results indicate that chlorantraniliprole has toxicity against S. cosmioides larvae. Sublethal effects on the biological and reproductive performance of this species can help optimize integrated pest management programs. (c) 2018 Society of Chemical Industry. PMID- 29766640 TI - Subclinical inflammation phenotypes and long-term outcomes after pediatric kidney transplantation. AB - The implementation of surveillance biopsies in pediatric kidney transplantation remains controversial. Surveillance biopsies detect subclinical injury prior to clinical dysfunction, which could allow for early interventions that prolong allograft survival. We conducted a single-center retrospective cohort study of 120 consecutive pediatric kidney recipients, of whom 103 had surveillance biopsies <=6 months posttransplant. We tested the hypothesis that subclinical inflammation (borderline or T cell-mediated rejection without clinical dysfunction) is associated with a 5-year composite endpoint of acute rejection and allograft failure. Overall, 36% of subjects had subclinical inflammation, which was associated with increased hazard for the composite endpoint (adjusted hazard ratio 2.89 [1.27, 6.57]; P < .01). Subjects with treated vs untreated subclinical borderline rejection had a lower incidence of the composite endpoint (41% vs 67%; P < .001). Subclinical vascular injury (subclinical inflammation with Banff arteritis score > 0) had a 78% incidence of the composite endpoint vs 11% in subjects with no major surveillance abnormalities (P < .001). In summary, we showed that subclinical inflammation phenotypes were prevalent in pediatric kidney recipients without clinical dysfunction and were associated with increased acute rejection and allograft failure. Once prospectively validated, our data would support implementation of surveillance biopsies as standard of care in pediatric kidney transplantation. PMID- 29766639 TI - Oxidation resistance 1 is a novel senolytic target. AB - The selective depletion of senescent cells (SCs) by small molecules, termed senolytic agents, is a promising therapeutic approach for treating age-related diseases and chemotherapy- and radiotherapy-induced side effects. Piperlongumine (PL) was recently identified as a novel senolytic agent. However, its mechanism of action and molecular targets in SCs was unknown and thus was investigated. Specifically, we used a PL-based chemical probe to pull-down PL-binding proteins from live cells and then mass spectrometry-based proteomic analysis to identify potential molecular targets of PL in SCs. One prominent target was oxidation resistance 1 (OXR1), an important antioxidant protein that regulates the expression of a variety of antioxidant enzymes. We found that OXR1 was upregulated in senescent human WI38 fibroblasts. PL bound to OXR1 directly and induced its degradation through the ubiquitin-proteasome system in an SC-specific manner. The knockdown of OXR1 expression by RNA interference significantly increased the production of reactive oxygen species in SCs in conjunction with the downregulation of antioxidant enzymes such as heme oxygenase 1, glutathione peroxidase 2, and catalase, but these effects were much less significant when OXR1 was knocked down in non-SCs. More importantly, knocking down OXR1 selectively induced apoptosis in SCs and sensitized the cells to oxidative stress caused by hydrogen peroxide. These findings provide new insights into the mechanism by which SCs are highly resistant to oxidative stress and suggest that OXR1 is a novel senolytic target that can be further exploited for the development of new senolytic agents. PMID- 29766642 TI - Arf1 and ER-mitochondrial tethering - a new trick for an old dog. AB - Endoplasmic reticulum (ER)-mitochondria tethering by the ERMES complex is critical for numerous mitochondrial functions in fungi. It was recently discovered that the GTPase Arf1, which regulates within Golgi vesicular trafficking also affects ER-mitochondrial tethering potentially through ERMES. In Candida albicans, Arf1 not only functions in vesicular trafficking and affects ERMES but also impacts reactive oxygen species generation, which is a key immune defense molecule. PMID- 29766641 TI - Tailoring the homing capacity of human Tregs for directed migration to sites of Th1-inflammation or intestinal regions. AB - Cell-based therapy with CD4+ FOXP3+ regulatory T cells (Tregs) is a promising strategy to limit organ rejection and graft-vs-host disease. Ongoing clinical applications have yet to consider how human Tregs could be modified to direct their migration to specific inflammation sites and/or tissues for more targeted immunosuppression. We show here that stable, homing-receptor-tailored human Tregs can be generated from thymic Tregs isolated from pediatric thymus or adult blood. To direct migration to Th1-inflammatory sites, addition of interferon-gamma and IL-12 during Treg expansion produced suppressive, epigenetically stable CXCR3+ TBET+ FOXP3+ T helper (Th)1-Tregs. CXCR3 remained expressed after injection in vivo and Th1-Tregs migrated efficiently towards CXCL10 in vitro. To induce tissue specific migration, addition of retinoic acid (RA) during Treg expansion induced expression of the gut-homing receptors alpha4beta7-integrin and CCR9. FOXP3+ RA Tregs had elevated expression of the functional markers latency-associated peptide and glycoprotein A repetitions predominant, increased suppressive capacity in vitro and migrated efficiently to healthy and inflamed intestine after injection into mice. Homing-receptor-tailored Tregs were epigenetically stable even after long-term exposure to inflammatory conditions, suppressive in vivo and characterized by Th1- or gut-homing-specific transcriptomes. Tailoring human thymic Treg homing during in vitro expansion offers a new and clinically applicable approach to improving the potency and specificity of Treg therapy. PMID- 29766643 TI - Does the apex optimization line matter for single-channel vaginal cylinder brachytherapy planning? AB - The objective of this study is to test the impact of the use of the apex optimization line for new vaginal cylinder (VC) applicators. New single channel VC applicators (Varian) that have different top thicknesses but the same diameters as the old VC applicators (2.0 cm diameter, 2.3, 2.6, 3.0, and 3.5 cm) were compared using phantom studies. Old VC applicator plans without the apex optimization line were also compared to the plans with an apex optimization line. The apex doses were monitored at 5 mm depth doses (eight points) where a prescription dose (Rx) of 6 Gy was prescribed. VC surface doses (eight points) were also analyzed. The new VC applicator plans without apex optimization line presented significantly lower 5-mm depth doses over the Rx (on average -31 +/- 7%, P < 0.00001) due to thicker VC tops (3.4 +/- 1.1 mm thicker with the range of 1.2-4.4 mm) than the old VC applicators. Old VC applicator plans also showed a statistically significant reduction (P < 0.00001) due to the Ir-192 source anisotropic effect at the apex region, but the percent reduction over the Rx was only -7 +/- 9%. However, by adding the apex optimization line to the new VC applicator plans, the plans improved 5-mm depth doses (-7 +/- 9% over Rx) that were not statistically different from old VC applicator plans (P = 0.923), along with apex VC surface doses (-22 +/- 10% over old VC vs -46 +/- 7% without using apex optimization line). The use of the apex optimization line is important in order to avoid significant additional cold doses (-24 +/- 2%) at the prescription depth (5 mm) of the apex, specifically for the new VC applicators that have thicker tops. A template-based vaginal cylinder planning reduced the intra- and inter-planner variations of manual generation of apex optimization line, along with treatment time. PMID- 29766644 TI - Evaluation of the influence of implant placement timing on the esthetic outcomes of single tooth implant treatment in the anterior maxilla: A retrospective study. AB - OBJECTIVES: The purpose of this retrospective study was to investigate the influence of implant placement timing on the esthetic outcomes for single implants in the anterior maxilla. MATERIALS AND METHODS: One hundred and ten patients (48 males; 62 females) who received a single-tooth implant after extraction either immediately (Type 1); after 4-8 weeks (Type 2); after 8-16 weeks (Type 3); or more than 16 weeks (Type 4) were evaluated in terms of esthetic outcomes after a mean post-placement interval of 26.3 months (range 12 116). Esthetic outcomes were measured using the Pink and White Esthetic Score (PES; WES). Stepwise regression analysis was performed to analyze the effect of timing of placement, as well as patient demographics and other clinical parameters on the esthetic outcomes. RESULTS: No statistically significantly differences in PES were found between the various treatment modalities with Type 1 implants (n = 33) scoring 10.58 +/- 1.65 (median: 11), followed by 10.36 +/- 2.09 (median: 10.5), 9.68 +/- 2.43 (median: 10), and 9.63 +/- 2.21 (median: 10) for Type 2 (n = 14), Type 3 (n = 19), and Type 4 (n = 44), respectively. For immediate implants, a trend towards better esthetic outcomes was observed when implant placement was done flaplessly in cases with intact buccal bone (Type 1A, median PES 11) as compared to cases with partial/complete missing buccal plates where a flap was raised (Type 1B, median PES 10). Overall, the only parameter that influenced esthetic outcomes (as measured by PES) was gender, with females having significantly superior results. The median WES was 8 and 96% of the crowns were deemed esthetically acceptable, with crowns placed by specialist prosthodontists yielding higher scores than those placed by general practitioners. CONCLUSIONS: Single tooth implants in the anterior maxilla showed satisfactory outcomes when measured with objective esthetic criteria. Timing of implant placement did not significantly influence the esthetic outcomes, although a trend towards better outcomes was seen with immediate implant placement as observed by higher median PES values. CLINICAL SIGNIFICANCE: Single tooth implant placement in the anterior maxilla is a predictable treatment modality for achieving acceptable esthetic outcomes regardless of the timing of placement. PMID- 29766645 TI - Synthesis, Cancer-Selective Antiproliferative and Apoptotic Effects of Some (+/-) Naringenin Cycloaminoethyl Derivatives. AB - Naringenin is a naturally occurring flavonoid and due to its broad spectrum of biological activities, including anticancer properties, has attracted scientific attention in recent years. To contribute to these studies, we synthesized some new (+/-)-naringenin cyclic aminoethyl derivatives, analyzed the cytotoxic and anti-proliferative properties of them via 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium bromide (MTT) assay, and mitochondrial apoptosis signaling response and gene expressions belong to caspase-3 depended apoptosis as biomarkers in both healthy and cancer cell lines. Our results suggest that some of our naringenin derivatives are potential anticancer agents with a selective death potential and targeting properties for mitochondrial apoptosis signaling against at least human cervix and breast cancer. PMID- 29766646 TI - Psychosocial variables and presence, severity and prognosis of plantar heel pain: A systematic review of cross-sectional and prognostic associations. AB - OBJECTIVE: Plantar heel pain (PHP) is often disabling, and persistent symptoms are common. Psychosocial variables are known to affect pain and disability but the association of these factors with PHP has yet to be established. The purpose of the present systematic review was to determine if psychosocial variables are associated with the presence, severity and prognosis of PHP. METHODS: A systematic review of the literature and qualitative synthesis was carried out. Electronic searches of MEDLINE, CINAHL, SPORTDiscus, PsycINFO and EMBASE were undertaken from the inception of the respective databases up to November 2017. Any study design incorporating measurements of psychosocial variables with participants with plantar heel pain were included. The quality of included articles was appraised using the Newcastle Ottawa Scale. RESULTS: Five articles from four studies were included in the review, with a total of 422 participants. Moderate-level evidence suggested a clinically unimportant association with the incidence of PHP and depression, anxiety and stress, and limited evidence suggested a clinically unimportant association with job dissatisfaction. Moderate level evidence suggested that there may also be an association between depression, anxiety, stress and catastrophization and PHP pain, and between depression, anxiety, stress, catastrophization and kinesiophobia and PHP function. We also found moderate-level evidence that a psychological disorder may be associated with a poorer outcome to shockwave therapy. CONCLUSION: In light of this review, the association of psychosocial variables and plantar heel pain cannot be ruled out. Given recommendations to adopt an individualized and stratified approach to other musculoskeletal conditions, clinicians should remain vigilant to their presence. PMID- 29766647 TI - Competing Mechanisms for Photocurrent Induced at the Monolayer-Multilayer Graphene Junction. AB - Graphene is characterized by demonstrated unique properties for potential novel applications in photodetection operated in the frequency range from ultraviolet to terahertz. To date, detailed work on identifying the origin of photoresponse in graphene is still ongoing. Here, scanning photocurrent microscopy to explore the nature of photocurrent generated at the monolayer-multilayer graphene junction is employed. It is found that the contributing photocurrent mechanism relies on the mismatch of the Dirac points between the monolayer and multilayer graphene. For overlapping Dirac points, only photothermoelectric effect (PTE) is observed at the junction. When they do not coincide, a different photocurrent due to photovoltaic effect (PVE) appears and becomes more pronounced with larger separation of the Dirac points. While only PTE is reported for a monolayer bilayer graphene junction in the literature, this work confirms the coexistence of PTE and PVE, thereby extending the understanding of photocurrent in graphene based heterojunctions. PMID- 29766648 TI - Synthesis of New Benzimidazole-1,2,3-triazole Hybrids as Tyrosinase Inhibitors. AB - A novel series of benzimidazole-1,2,3-triazole hybrids containing substituted benzyl moieties were designed, synthesized and evaluated for their inhibitory activity against mushroom tyrosinase. The results indicated that 2-(4-{[1-(3,4 dichlorobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6g) and 2 (4-{[1-(4-bromobenzyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-1H-benzimidazole (6h) exhibited effective inhibitory activity with IC50 values of 9.42 and 10.34 MUm, respectively, comparable to that of kojic acid as the reference drug (IC50 = 9.28 MUm). Kinetic study of compound 6g confirmed mixed-type inhibitory activity towards tyrosinase indicating that it can bind to free enzyme as well as enzyme substrate complex. Also, molecular docking analysis was performed to determine the binding mode of the most potent compounds (6g and 6h) in the active site of tyrosinase. Consequently, 6g and 6h derivatives might serve as promising candidates in cosmetics, medicine or food industry, and development of such compounds may be of an interest. PMID- 29766649 TI - Lysyl oxidase: A colorectal cancer biomarker of lung and hepatic metastasis. AB - BACKGROUND: Colorectal cancer (CRC) is a common and lethal disease in which distant metastasis remains the primary cause of death. Paradoxical roles of LOX have been reported in CRC, and the intracellular function of LOX has also recently been determined. Correlations of LOX expression and its intracellular localization with clinicopathological features in CRC patients remain largely unknown. The aim of the present study was to explore the potential roles of LOX in CRC. METHODS: LOX messenger RNA expression was assayed by quantitative PCR in eight paired normal mucosa and tumor tissues. Immunohistochemistry was conducted using tissue arrays to investigate LOX expression in 201 CRC patients. Regulation of LOX by YAP and TEAD4 was explored by YAP or TEAD4 short hairpin RNA interference in a LoVo cell line. RESULTS: LOX messenger RNA expression was elevated in some CRC specimens, and LOX nuclear localization was detected in CRC tumor tissues. LOX nuclear localization was found to correlate with lung/hepatic metastasis, elevated serum carcinoembryonic antigen concentration, and mucinous tumor type (P < 0.05). Nuclear LOX expression was found to be associated with poor overall and disease-free survival (P < 0.05), and postoperative lung/hepatic metastasis (P < 0.05). Knockdown of YAP or TEAD4 induced downregulation of LOX expression. CONCLUSIONS: LOX nuclear localization was significantly associated with poor survival in patients with CRC. Nuclear LOX expression was correlated with synchronous or postoperative lung/hepatic metastasis. LOX may prove to be a potential target gene of YAP and TEAD4. PMID- 29766650 TI - Social communication in bats. AB - Bats represent one of the most diverse mammalian orders, not only in terms of species numbers, but also in their ecology and life histories. Many species are known to use ephemeral and/or unpredictable resources that require substantial investment to find and defend, and also engage in social interactions, thus requiring significant levels of social coordination. To accomplish these tasks, bats must be able to communicate; there is now substantial evidence that demonstrates the complexity of bat communication and the varied ways in which bats solve some of the problems associated with their unique life histories. However, while the study of communication in bats is rapidly growing, it still lags behind other taxa. Here we provide a comprehensive overview of communication in bats, from the reasons why they communicate to the diversity and application of different signal modalities. The most widespread form of communication is the transmission of a signaller's characteristics, such as species identity, sex, individual identity, group membership, social status and body condition, and because many species of bats can rely little on vision due to their nocturnal lifestyles, it is assumed that sound and olfaction are particularly important signalling modes. For example, research suggests that secretions from specialized glands, often in combination with urine and saliva, are responsible for species recognition in several species. These olfactory signals may also convey information about sex and colony membership. Olfaction may be used in combination with sound, particularly in species that emit constant frequency (CF) echolocation calls, to recognize conspecifics from heterospecifics, yet their simple structure and high frequency do not allow much information of individual identity to be conveyed over long distances. By contrast, social calls may encode a larger number of cues of individual identity, and their lower frequencies increase their range of detection. Social calls are also known to deter predators, repel competitors from foraging patches, attract group mates to roost sites, coordinate foraging activities, and are used during courtship. In addition to sound, visual displays such as wing flapping or hovering may be used during courtship, and swarming around roost sites may serve as a visual cue of roost location. However, visual communication in bats still remains a poorly studied signal modality. Finally, the most common form of tactile communication known in bats is social grooming, which may be used to signal reproductive condition, but also to facilitate and strengthen cooperative interactions. Overall, this review demonstrates the rapid advances made in the study of bat social communication during recent years, and also identifies topics that require further study, particularly those that may allow us to understand adaptation to rapidly changing environmental conditions. PMID- 29766652 TI - Mucosal microflora in head and neck cancer patients. AB - OBJECTIVE: To analyse the tongue and buccal microflora prospectively in head and neck cancer patients treated with radiation therapy (RT). METHODS: In 33 dentate patients, microbial samples from the tongue and buccal mucosa were collected pretreatment, during treatment, and 6 months, 1 year and 2 years post-treatment. Microorganisms associated with oral health and oral disorders were analysed using cultivation technique. Oral mucositis was scored at the appointment during treatment. RESULTS: Compared with pretreatment, lactobacilli and Candida increased on the tongue, while streptococci and Neisseria decreased during treatment. Two years post-treatment, Neisseria and Prevotella were decreased and Candida increased. On the buccal mucosa, an increased growth of lactobacilli and increased detection frequencies of the opportunistic bacteria Staphylococcus aureus, Gram-negative enteric rods and enterococci were seen during treatment compared with pretreatment. Seventy per cent showed severe mucositis during treatment. Two years post-treatment the total count as well as streptococci, Neisseria and Fusobacterium nucleatum were decreased and lactobacilli increased compared with pretreatment. CONCLUSION: Despite improvements in treatment for cancer in the head and neck region, microorganisms associated with oral health decrease during treatment and mucosal pathogens increase. Two years post treatment, levels of acid-tolerant (lactobacilli and Candida) were increased, while acid-sensitive microorganisms (Neisseria and F. nucleatum) were decreased, plausibly due to persisting decreased salivary secretion rate. PMID- 29766651 TI - Adhesive/silane application effects on bond strength durability to a lithium disilicate ceramic. AB - OBJECTIVE: To test the effects of different adhesive protocols and silane application on the adhesive durability to a Lithium Disilicate reinforced glass ceramic. METHODS: Forty disks of 13 mm diameter (E.max Press) were used. After etching with 9.5% HF for 20 seconds, disks were randomly assigned into 4 groups according to the adhesive/silane protocol: silane application only (SIL); silane application followed by adhesive (SILXP-XP Bond); silane-containing adhesive (SBU ScotchBond Universal); silane application followed by silane-containing adhesive (SILSBU). Four resin composite cylinders of 1-mm diameter and 3-mm height were made on each ceramic disk and tested in shear. Specimens were stored in water for 24 hours or 12 months prior to testing. Results were statistically analyzed by two-way ANOVA and Tukey test. RESULTS: After 24 hours, the highest SBS values were observed for SILXP and SILSBU. However, after 12 months, SILXP and SILSBU presented a significant reduction in SBS, while the highest SBS were observed for SIL. For SBU, no significant reduction in SBS was observed, however, it showed the lowest SBS after 12 months. CONCLUSIONS: Regardless of the presence of silane in the composition of SBU, previous silane application is still recommended prior to cementation of Lithium Disilicate. CLINICAL SIGNIFICANCE: The application of silane as a separate step is recommended prior to cementation of Lithium Disilicate reinforced glass-ceramic, independent of the presence of silane within the universal adhesive solution. PMID- 29766653 TI - Organic psychosis: The pathobiology and treatment of delusions. AB - Organic or secondary psychosis can be seen in diverse conditions such as toxic/metabolic disorders, neurodegenerative disease, and stroke. Poststroke psychosis is a rare phenomenon, but its study has significantly contributed to the understanding of delusion formation. The evidence from case studies of patients with focal strokes shows that delusions develop following unilateral damage of the right hemisphere. The majority of patients with right hemisphere stroke do not develop delusions however, and advanced neuroimaging analysis has elucidated why this symptom develops in only a small proportion. Lesions of the right lateral prefrontal cortex or lesions with connectivity to this area correlate with delusional beliefs in this subgroup. Studies of patients with primary psychosis, for example schizophrenia, or under the influence of the psychotogenic drug ketamine, also show abnormal function of this area in relation to the severity of their abnormal beliefs. The conclusion of these studies is that the right lateral prefrontal cortex is 1 hub in a neural network which includes the basal ganglia and limbic system and receives inputs from midbrain dopamine neurones. In patients with schizophrenia, or at risk of psychosis, dopamine is dysregulated and evidence suggests that faulty dopamine signaling is the precursor of delusion formation. It is therefore likely that the mechanism of delusion formation is the same in both primary and secondary psychosis. This is consistent with the mainstay of treatment of both conditions being antipsychotic medication. However, antipsychotic medication in people with cerebrovascular disease should be avoided if at all possible. This is because epidemiological studies have found that antipsychotic use is associated with an increased risk of stroke and will thus compound the possibility of a further cerebrovascular accident. PMID- 29766654 TI - Prospective short-term feasibility study of perioperative suprapubic catheters in laparoscopic colectomy. AB - INTRODUCTION: Here we report a prospective study on whether a temporary suprapubic catheter (SPC) can be safely inserted as a substitute for transurethral balloon catheterization during laparoscopy-assisted colectomy. METHODS: Our subjects included 52 cases who gave informed consent to have an SPC inserted. These subjects were selected from cases who underwent laparoscopy assisted surgery for primary colorectal cancer from October 2014 to August 2015. RESULTS: An SPC was inserted into 45 of the original 52 cases. The median surgical duration was 220 min (range, 11-438 min), and the SPC insertion was performed at a median of 133 min (range, 9-384 min) after the start of surgery. Insertion required a median duration of 116 s. In one case (2.2%), the bladder was perforated by the paracentesis needle, and in two cases (4.4%), hematuria was observed at the time of insertion; however, surgery was completed without any incident in these three cases. Six of the remaining 42 cases (13.3%) demonstrated neither micturition desire nor independent urination on the day the catheter was clamped. In these cases, the clamp was released two to four times, and draining of an average of 586-mL urine, micturition desire, and independent urination were confirmed 2-4 days later. CONCLUSION: Transurethral balloon catheterization is a simple procedure that is commonly used on surgical patients, but it can cause pain, discomfort, and infection. In contrast, SPC insertion is a procedure that avoids crossing the urethra and its associated disadvantages. Here we were able to demonstrate that the procedure can be safely used in laparoscopic surgery patients. PMID- 29766655 TI - Pre-surgical, surgical and post-surgical experiences of weight loss surgery patients: a closer look at social determinants of health. AB - Using a novel qualitative approach, Photovoice, researchers assessed social, psychological, physical and economic barriers encountered by patients of weight loss surgery. Applying the Photovoice approach and Williams' theory of narrative reconstruction for qualitative interviewing, the research team set out to investigate the bariatric patient experience from pre-surgery to hospitalization to post-surgery. Fifteen participants were given digital cameras and asked to take photographs that represented their weight loss journeys. Photographs and qualitative interviews were used to theorize the role played by comorbidities, social determinants of health, provider communication experiences and understanding of insurance coverage in patient outcomes. Several themes emerged from the interviews and photographs including themes centred around: (i) racial/ethnic standards of beauty; (ii) gender expectations; (iii) comorbidities, depression/disordered eating and obesity discrimination and (iv) financial hardship impacting adherence. Photographs also illuminated the impact of hospital and state-wide policies on patient lives. Results suggest that Photovoice may be a useful adjunct to standard-of-care to help patients identify barriers, and to identify shortcomings in health services. Additional screening tools for gender- and income-related barriers (and concomitant referrals to support services) provide an opportunity to improve patient care and reduce post-operative readmissions. PMID- 29766656 TI - Microencapsulated rabbit adipose stem cells initiate tissue regeneration in a rabbit ear defect model. AB - Cell-based tissue engineering can promote cartilage tissue regeneration, but cell retention in the implant site post-delivery is problematic. Alginate microbeads containing adipose stem cells (ASCs) pretreated with chondrogenic media have been used successfully to regenerate hyaline cartilage in critical size defects in rat xiphoid suggesting that they may be used to treat defects in elastic cartilages such as the ear. To test this, we used microbeads made with low viscosity, high mannuronate medical grade alginate using a high electrostatic potential, and a calcium cross linking solution containing glucose. Microbeads containing rabbit ASCs (rbASCs) were implanted bilaterally in 3 mm critical size midcartilage ear defects of six skeletally mature male New Zealand White rabbits (empty defect; microbeads without cells; microbeads with cells; degradable microbeads with cells; and autograft). Twelve weeks post-implantation, regeneration was assessed by microCT and histology. Microencapsulated rbASCs cultured in chondrogenic media expressed mRNAs for aggrecan, Type II collagen, and Type X collagen. Histologically, empty defects contained fibrous tissue; microbeads without cells were still present in defects and were surrounded by fibrous tissue; nondegradable beads with rbASCs initiated cartilage regeneration; degradable microbeads with cells produced immature bone-like tissue, also demonstrated by microCT; and autografts appeared as normal auricular cartilage but were not fully integrated with the tissue surrounding the defect. Elastin, the hallmark of auricular cartilage, was not evident in the neocartilage. This delivery system offers the potential for regeneration of auricular cartilage, but vascularity of the treatment site and use of factors that induce elastin must be considered. PMID- 29766658 TI - Ampli: A Construction Set for Paperfluidic Systems. AB - The design and fabrication of reconfigurable, modular paperfluidics driven by a prefabricated reusable block library, asynchronous modular paperfluidic linear instrument-free (Ampli) block, are reported. The blocks are inspired by the plug and-play modularity of electronic breadboards that lower prototyping barriers in circuit design. The resulting biochemical breadboard is a paperfluidic construction set that can be functionalized with chemical, biological, and electrical elements. Ampli blocks can form standard paperfluidic devices without any external instrumentation. Furthermore, their modular nature enhances fluidics in ways that fixed devices cannot. The blocks' ability to start, stop, modify, and reverse reaction flows, reagents, and rates in real time is demonstrated. These enhancements allow users to increase colorimetric signals, fine tune reaction times, and counter check multiplexed diagnostics for false positives or negatives. The modular construction demonstrates that field-ready, distributed fabrication of paper analytical systems can be standardized without requiring the "black box" of craft and technique inherent in paper-based systems. Ampli assembly and point-of-care redesign extends the usability of paper analytical systems and invites user-driven prototyping beyond the lab setting demonstrating "Design for Hack" in diagnostics. PMID- 29766657 TI - Drug-drug interaction and doping: Effect of non-prohibited drugs on the urinary excretion profile of methandienone. AB - The potential consequences of drug-drug interactions on the excretion profile of the anabolic androgenic steroid methandienone (17beta-hydroxy-17alpha methylandrosta-1,4-dien-3-one) are discussed. More specifically, we have evaluated by in vitro and in vivo experiments the effects of 7 non-prohibited drugs (fluconazole, ketoconazole, itraconazole, miconazole, fluoxetine, paroxetine, and nefazodone) on the main metabolic pathways of methandienone. These are selected among those most commonly used by the athletes. The in vitro assays were based on the use of human liver microsomes, specific recombinant enzyme isoforms of cytochrome P450 and uridine 5'-diphospho-glucuronosyl transferase. The in vivo study was performed by analyzing urines collected after the oral administration of methandienone with and without the co-administration of ketoconazole. Methandienone and its metabolites were determined by liquid chromatography-mass spectrometry-based techniques after sample pretreatment including an enzymatic hydrolysis step (performed only for the investigation on phase II metabolism) and liquid/liquid extraction with t-butyl methyl-ether. The results from the in vitro experiments showed that the formation of the hydroxylated and dehydrogenated metabolites was significantly reduced in the presence of itraconazole, ketoconazole, miconazole and nefazodone, whereas the production of the 18-nor-hydroxylated metabolites and glucuronidation reactions was reduced significantly only in the presence of ketoconazole and miconazole. The analysis of the post-administration samples confirmed the in vitro observations, validating the hypothesis that drug-drug interaction may cause significant alterations in the metabolic profile of banned drugs, making their detection during doping control tests more challenging. PMID- 29766661 TI - Structure-Based Design of a Eukaryote-Selective Antiprotozoal Fluorinated Aminoglycoside. AB - Aminoglycosides (AG) are antibiotics that lower the accuracy of protein synthesis by targeting a highly conserved RNA helix of the ribosomal A-site. The discovery of AGs that selectively target the eukaryotic ribosome, but lack activity in prokaryotes, are promising as antiprotozoals for the treatment of neglected tropical diseases, and as therapies to read-through point-mutation genetic diseases. However, a single nucleobase change A1408G in the eukaryotic A-site leads to negligible affinity for most AGs. Herein we report the synthesis of 6' fluorosisomicin, the first 6'-fluorinated aminoglycoside, which specifically interacts with the protozoal cytoplasmic rRNA A-site, but not the bacterial A site, as evidenced by X-ray co-crystal structures. The respective dispositions of 6'-fluorosisomicin within the bacterial and protozoal A-sites reveal that the fluorine atom acts only as a hydrogen-bond acceptor to favorably interact with G1408 of the protozoal A-site. Unlike aminoglycosides containing a 6'-ammonium group, 6'-fluorosisomicin cannot participate in the hydrogen-bonding pattern that characterizes stable pseudo-base-pairs with A1408 of the bacterial A-sites. Based on these structural observations it may be possible to shift the biological activity of aminoglycosides to act preferentially as antiprotozoal agents. These findings expand the repertoire of small molecules targeting the eukaryotic ribosome and demonstrate the usefulness of fluorine as a design element. PMID- 29766662 TI - Bioproduction of Benzylamine from Renewable Feedstocks via a Nine-Step Artificial Enzyme Cascade and Engineered Metabolic Pathways. AB - Production of chemicals from renewable feedstocks has been an important task for sustainable chemical industry. Although microbial fermentation has been widely employed to produce many biochemicals, it is still very challenging to access non natural chemicals. Two methods (biotransformation and fermentation) have been developed for the first bio-derived synthesis of benzylamine, a commodity non natural amine with broad applications. Firstly, a nine-step artificial enzyme cascade was designed by biocatalytic retrosynthetic analysis and engineered in recombinant E. coli LZ243. Biotransformation of l-phenylalanine (60 mm) with the E. coli cells produced benzylamine (42 mm) in 70 % conversion. Importantly, the cascade biotransformation was scaled up to 100 mL and benzylamine was successfully isolated in 57 % yield. Secondly, an artificial biosynthesis pathway to benzylamine from glucose was developed by combining the nine-step cascade with an enhanced l-phenylalanine synthesis pathway in cells. Fermentation with E. coli LZ249 gave benzylamine in 4.3 mm concentration from glucose. In addition, one-pot syntheses of several useful benzylamines from the easily available styrenes were achieved, representing a new type of alkene transformation by formal oxidative cleavage and reductive amination. PMID- 29766660 TI - The deterioration of muscle mass and radiodensity is prognostic of poor survival in stage I-III colorectal cancer: a population-based cohort study (C-SCANS). AB - BACKGROUND: Muscle abnormalities such as low muscle mass and low muscle radiodensity are well known risk factors for unfavourable cancer prognosis. However, little is known in regard to the degree and impact of longitudinal changes in muscle mass and radiodensity within the context of cancer. Here, we explore the relationship between muscle wasting and mortality in a large population-based study of patients with non-metastatic colorectal cancer (CRC). METHODS: A total of 1924 patients with stage I-III CRC who underwent surgical resection in the Kaiser Permanente Northern California Health System were included. Muscle mass and radiodensity were quantified using computed tomography images obtained at diagnosis and after approximately 14 months. Cox proportional hazards models were used to estimate hazard ratios for all-cause mortality. RESULTS: The hazard ratio for all-cause mortality among patients with the largest deterioration in muscle mass (>=2 SD; >=11.4% loss from baseline), as compared with those who remained stable (+/-1 SD; 0.0 +/- 5.7%) was 2.15 [95% confidence interval (CI): 1.59-2.92; P < 0.001]. The hazard ratio for all-cause mortality among patients who experienced the largest deterioration in muscle radiodensity (>=2 SD; >=20.2% loss from baseline), as compared with those who remained stable (+/-1 SD; 0.0 +/- 10.1%) was 1.61 (95% CI: 1.20-2.15; P = 0.002). CONCLUSIONS: In patients with stage I-III CRC, muscle wasting is a risk factor for mortality, independent of change in body mass and other body composition parameters. PMID- 29766659 TI - Prognosis of patients with hepatocellular carcinoma treated with sorafenib: a comparison of five models in a large Canadian database. AB - Several systems (tumor-node-metastasis [TNM], Barcelona Clinic Liver Cancer [BCLC], Okuda, Cancer of the Liver Italian Program [CLIP], and albumin-bilirubin grade [ALBI]) were developed to estimate the prognosis of patients with hepatocellular carcinoma (HCC) mostly prior to the prevalent use of sorafenib. We aimed to compare the prognostic and discriminatory power of these models in predicting survival for HCC patients treated with sorafenib and to identify independent prognostic factors for survival in this population. Patients who received sorafenib for the treatment of HCC between 1 January 2008 and 30 June 2015 in the provinces of British Columbia and Alberta, and two large cancer centers in Toronto, Ontario, were included. Survival was assessed using the Kaplan-Meier method. Multivariate Cox regression was used to identify predictors of survival. The models were compared with respect to homogeneity, discriminatory ability, monotonicity of gradients, time-dependent area under the curve, and Akaike information criterion. A total of 681 patients were included. 80% were males, 86% had Child-Pugh class A, and 37% of patients were East Asians. The most common etiology for liver disease was hepatitis B (34%) and C (31%). In all model comparisons, CLIP performed better while BCLC and TNM7 performed less favorably but the differences were small. The utility of each system in allocating patients into different prognostic groups varied, for example, TNM poorly differentiated patients in advanced stages (8.7 months (m) (95% CI 6.5-11.5) versus 8.4 m (95% CI 7.0-9.6) for stages III and IV, respectively) while ALBI had excellent discrimination of early grades (15.6 m [95% CI 13.0-18.4] versus 8.3 m [95% CI 7.0-9.2] for grades 1 and 2, respectively). On multivariate analysis, hepatitis C, alcoholism, and prior hepatic resection were independently prognostic of better survival (P < 0.01). In conclusion, none of the prognostic systems was optimal in predicting survival in sorafenib-treated patients with HCC. Etiology of liver disease should be considered in future models and clinical trial designs. PMID- 29766663 TI - The effect of filtration method on the efficiency of environmental DNA capture and quantification via metabarcoding. AB - Environmental DNA (eDNA) is a promising tool for rapid and noninvasive biodiversity monitoring. eDNA density is low in environmental samples, and a capture method, such as filtration, is often required to concentrate eDNA for downstream analyses. In this study, six treatments, with differing filter types and pore sizes for eDNA capture, were compared for their efficiency and accuracy to assess fish community structure with known fish abundance and biomass via eDNA metabarcoding. Our results showed that different filters (with the exception of 20-MUm large-pore filters) were broadly consistent in their DNA capture ability. The 0.45-MUm filters performed the best in terms of total DNA yield, probability of species detection, repeatability within pond and consistency between ponds. However performance of 0.45-MUm filters was only marginally better than for 0.8 MUm filters, while filtration time was significantly longer. Given this trade off, the 0.8-MUm filter is the optimal pore size of membrane filter for turbid, eutrophic and high fish density ponds analysed here. The 0.45-MUm Sterivex enclosed filters performed reasonably well and are suitable in situations where on-site filtration is required. Finally, prefilters are applied only if absolutely essential for reducing the filtration time or increasing the throughput volume of the capture filters. In summary, we found encouraging similarity in the results obtained from different filtration methods, but the optimal pore size of filter or filter type might strongly depend on the water type under study. PMID- 29766664 TI - Tissue engineered nigrostriatal pathway for treatment of Parkinson's disease. AB - The classic motor deficits of Parkinson's disease are caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of their long-distance axonal projections that modulate the striatum. Current treatments only minimize the symptoms of this disconnection as there is no approach capable of replacing the nigrostriatal pathway. We are applying microtissue engineering techniques to create living, implantable constructs that mimic the architecture and function of the nigrostriatal pathway. These constructs consist of dopaminergic neurons with long axonal tracts encased within hydrogel microcolumns. Microcolumns were seeded with dopaminergic neuronal aggregates, while lumen extracellular matrix, growth factors, and end targets were varied to optimize cytoarchitecture. We found a 10-fold increase in axonal outgrowth from aggregates versus dissociated neurons, resulting in remarkable axonal lengths of over 6 mm by 14 days and 9 mm by 28 days in vitro. Axonal extension was also dependent upon lumen extracellular matrix, but did not depend on growth factor enrichment or neuronal end target presence. Evoked dopamine release was measured via fast scan cyclic voltammetry and synapse formation with striatal neurons was observed in vitro. Constructs were microinjected to span the nigrostriatal pathway in rats, revealing survival of implanted neurons while maintaining their axonal projections within the microcolumn. Lastly, these constructs were generated with dopaminergic neurons differentiated from human embryonic stem cells. This strategy may improve Parkinson's disease treatment by simultaneously replacing lost dopaminergic neurons in the substantia nigra and reconstructing their long-projecting axonal tracts to the striatum. PMID- 29766665 TI - Identification of the novel HLA-DRB1 allele, DRB1*14:183, in a Colombian umbilical cord blood bank donor. AB - HLA-DRB1*14:183 has two nucleotide changes from HLA-DRB1-13:44, D to E and F to Y. PMID- 29766667 TI - An SSP-PCR method for the rapid detection of disease-associated alleles HLA-A*29 and HLA-B*51. AB - HLA-A*29 and HLA-B*51 are associated with birdshot uveitis and Behcet's disease, respectively, and are used as a diagnostic criterion in patients with suspected disease, requiring their detection in diagnostic laboratories. While commercial tests for individual HLA alleles are available for other disease-associated HLA variants, no similar allele-specific assays are available for HLA-A*29 and HLA B*51. Here, we report sequence-specific priming-polymerase chain reaction (SSP PCR) methods for the detection of HLA-A*29 and HLA-B*51 using a single PCR reaction per allele. The assays were tested in 30 and 32 previously HLA-typed samples, respectively, representing >97% of HLA-A alleles and >93% of HLA-B alleles in a European population. A concordance of 100% was observed with previous typing results, validating these methods for use in a diagnostic or research context. PMID- 29766666 TI - Light at night disrupts nocturnal rest and elevates glucocorticoids at cool color temperatures. AB - Nighttime light pollution is quickly becoming a pervasive, global concern. Since the invention and proliferation of light-emitting diodes (LED), it has become common for consumers to select from a range of color temperatures of light with varying spectra. Yet, the biological impacts of these different spectra on organisms remain unclear. We tested if nighttime illumination of LEDs, at two commercially available color temperatures (3000 and 5000 K) and at ecologically relevant illumination levels affected body condition, food intake, locomotor activity, and glucocorticoid levels in zebra finches (Taeniopygia guttata). We found that individuals exposed to 5000 K light had higher rates of nighttime activity (peaking after 1 week of treatment) compared to 3000 K light and controls (no nighttime light). Birds in the 5000 K treatment group also had increased corticosterone levels from pretreatment levels compared to 3000 K and control groups but no changes in body condition or food intake. Individuals that were active during the night did not consequently decrease daytime activity. This study adds to the growing evidence that the spectrum of artificial light at night is important, and we advocate the use of nighttime lighting with warmer color temperatures of 3000 K instead of 5000 K to decrease energetic costs for avian taxa. PMID- 29766668 TI - Thermally Stable High-Performance Polymer Solar Cells Enabled by Interfacial Engineering. AB - Interfacial engineering plays an important role in determining the performance and stability of polymer solar cells (PSCs). In this study, thermally stable highly efficient PSCs are fabricated by incorporating a solution-processed cathode interfacial layer (CIL), including 4,4'-({[methyl(4 sulfonatobutyl)ammonio]bis(propane-3,1-diyl)}bis(dimethylammoniumdiyl))bis(butane 1-sulfonate) (MSAPBS) and polyethylenimine (PEI). For PSCs based on blends of poly{4,8-bis[5-(2-ethylhexyl)thiophen-2-yl]benzo[1,2-b;4,5-b']dithiophene-2,6 diyl-alt-[4-(2-ethylhexyl)-3fluorothieno[3,4-b]thiophene-2-carboxylate-2,6-diyl]} (PBDTTT-EFT) and [6,6]-phenyl C71 -butyric acid methyl ester (PC71 BM), the maximum power conversion efficiency (PCE) of inverted PSCs reaches 8.1 % and 7.2 % for MSAPBS and PEI CILs, respectively. The inverted PEI devices exhibit remarkable stability (lifetime >6000 h) under accelerated thermal aging (at 80 degrees C in ambient environment), which is much superior to that of the device with commonly used LiF CIL (lifetime~33 h). This stability represents the best result reported for PSCs. The promising results based on this strategy can stimulate further work on the development of novel CILs for PSCs and pave the way towards the realization of commercially viable PSCs with high performance and long-term stability. PMID- 29766669 TI - Eosinophils in voided urine smear. PMID- 29766670 TI - Identification of the novel HLA-B*15:18:01:04 in a Korean individual. AB - HLA-B*15:18:01:04 differs from HLA-B*15:18:01:02 by single nucleotide substitution at position 2176 (G > A). PMID- 29766671 TI - Point-of-care treatment of focal cartilage defects with selected chondrogenic mesenchymal stromal cells-An in vitro proof-of-concept study. AB - Due to the poor self-healing capacities of cartilage, innovative approaches are a major clinical need. The use of in vitro expanded mesenchymal stromal cells (MSCs) in a 2-stage approach is accompanied by cost-, time-, and personnel intensive good manufacturing practice production. A 1-stage intraoperative procedure could overcome these drawbacks. The aim was to prove the feasibility of a point-of-care concept for the treatment of cartilage lesions using defined MSC subpopulations in a collagen hydrogel without prior MSC monolayer expansion. We tested 4 single marker candidates (MSCA-1, W4A5, CD146, CD271) for their effectiveness of separating colony-forming units of ovine MSCs via magnetic cell separation. The most promising surface marker with regard to the highest enrichment of colony-forming cells was subsequently used to isolate a MSC subpopulation for the direct generation of a cartilage graft composed of a collagen type I hydrogel without the propagation of MSCs in monolayer. We observed that separation with CD271 sustained the highest enrichment of colony forming units. We then demonstrated the feasibility of generating a cartilage graft with an unsorted bone marrow mononuclear cell fraction and with a characterized CD271 positive MSC subpopulation without the need for a prior cell expansion. A reduced volume of 6.25% of the CD271 positive MSCs was needed to achieve the same results regarding chondrogenesis compared with the unseparated bone marrow mononuclear cell fraction, drastically reducing the number of nonrelevant cells. This study provides a proof-of-concept and reflects the potential of an intraoperative procedure for direct seeding of cartilage grafts with selected CD271 positive cells from bone marrow. PMID- 29766672 TI - Ribcage deformity and the altered breathing pattern in children with osteogenesis imperfecta. AB - AIM: Osteogenesis Imperfecta (OI) is a genetic disease characterized by bones fragility and progressive deformity. Life expectancy is reduced in the non-lethal most severe type III form before the age of 10 years. The main cause of death in OI is respiratory insufficiency resulting from impaired thoracic function worsened by ribcage deformity and scoliosis. METHODS: We used opto-electronic plethysmography to study chest geometry, the ventilatory, and the thoraco abdominal pattern at rest in supine position in children younger than 10 years. Radiographic measurements were used to describe spinal deformity. RESULTS: Eight severe OI (sOI), seven affected by other moderate forms (mOI), and nine healthy controls (CTR) were analyzed. sOI were characterized by Pectus carinatum (sternal angle: 165.2 degrees , CTR: 183.1 degrees ; P < 0.01), rapid and shallow breathing (RSBi: 267.4 L-1 min-1 , CTR: 150.7 L-1 min-1 ; P < 0.05) and reduced pulmonary rib cage contribution to tidal volume (5.1%, CTR: 14.6%; P < 0.001) that evolved with age approaching the paradoxical inspiratory inward movement previously found in adults. mOI showed almost normal ventilatory pattern (RSBi: 189.2-1 min-1 ) and absence of sternal deformity (sternal angle: 176.8 degrees ). Platyspondyly and kyphosis were common features in all OI children. CONCLUSION: An altered breathing pattern in severe OI is present since childhood and it worsens with age. This is caused by the combination of pectus carinatum, brittle ribs and spinal deformity that put the ribcage muscles in mechanical disadvantage. These results suggest that in severe OI the assessment of the respiratory function should start in early childhood in order to try to reduce the incidence of premature death. PMID- 29766674 TI - Assessment of airway inflammation and remodeling in children with severe asthma: The next challenge. PMID- 29766675 TI - Interactions between monocytes, mesenchymal stem cells, and implants evaluated using flow cytometry and gene expression. AB - Monocytes and mesenchymal stem cells (MSC) are evident at the implants during early healing. However, when coexisting, their interactions at different implants have not been determined. This study uses an in vitro system, consisting of monoculture and direct co-cultures of monocytes and MSC on screw-shaped machined and oxidized titanium implants in combination with scanning electron microscopy, enzyme-linked immunosorbent assay, flow cytometry, cell sorting, and quantitative polymerase chain reaction. The cell-specific adhesion and gene expression of monocytes and MSC was determined. After 24 hr, the coexistence of monocytes and MSC in co-culture led to equal proportions of adherent monocytes and MSC, irrespective of the implant type. In contrast, higher number of adherent monocytes than MSC was found on the oxidized implant in monoculture. Quantitative polymerase chain reaction analysis of fluorescent activated cell sorting-sorted cells revealed up-regulation of interleukin-1beta, in monocytes, and interleukin 1beta and C-X-C chemokine receptor type 4, in MSC, when the cell types coexisted compared with monocultures. Further, in co-culture, the expression of bone morphogenetic protein-2, stromal cell-derived factor 1, and integrin-beta1 was enhanced in the implant-adherent MSC, but not monocytes. It is concluded that during the first 24 hr in an in vitro static condition, the effect of co-culture of monocytes and MSC was more prominent than the effect of the implant surface properties. The results indicate that the coexistence of monocytes and MSC on an implant alters the adhesion and expression of some genes compared with when each cell type existed alone. Further, the results show that the gene expression of major growth and recruitment factors is mainly enhanced in the implant-adherent MSC in contrast to implant-adherent monocytes in co-culture. PMID- 29766676 TI - Identification of hospitalized tracheostomy and ventilator dependent patients in administrative data. AB - BACKGROUND: Patients with established tracheostomy and ventilator dependence are hospitalized more frequently and use more healthcare resources than other patients with complex chronic conditions. However, data to compare variation in hospitalization and resource use among patients in this population across the United States is deficient, partly due to the lack of structured methods to query national databases. AIM: Determine the best method for identifying the subset of children with established tracheostomy and ventilator dependence in Pediatric Health Information System (PHIS). HYPOTHESIS: A combination of identifiable characteristics coded in the PHIS database can be used to identify the population of patients with established tracheostomy and ventilator dependence who are admitted to the hospital. METHODS: This cross-sectional, retrospective cohort study used established methods to extract data from PHIS and assessed the sensitivity and specificity of an algorithm to identify patients with established tracheostomy and ventilator dependence as compared with a local registry of ventilator dependent patients. RESULTS: A newly created algorithm identified >90% of the 157 patients with established tracheostomy and ventilator dependence hospitalized at our organization during 2014. The sensitivity and specificity of the algorithm to identify these patients was 91% and 99%, respectively. CONCLUSIONS: This new algorithm can be used to reliably identify and further study healthcare utilization by this population of patients with established tracheostomy and ventilator dependence. In addition, future work can determine the applicability of this algorithm to other administrative datasets. PMID- 29766673 TI - Genomic characterization of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung cancer. AB - Single nucleotide polymorphisms (SNPs) may modulate individual susceptibility to carcinogens. We designed a genome-wide association study to characterize individuals presenting extreme phenotypes of high and low risk to develop tobacco induced non-small cell lung cancer (NSCLC), and we validated our results. We hypothesized that this strategy would enrich the frequencies of the alleles that contribute to the observed traits. We genotyped 2.37 million SNPs in 95 extreme phenotype individuals, that is: heavy smokers that either developed NSCLC at an early age (extreme cases); or did not present NSCLC at an advanced age (extreme controls), selected from a discovery set (n = 3631). We validated significant SNPs in 133 additional subjects with extreme phenotypes selected from databases including >39,000 individuals. Two SNPs were validated: rs12660420 (pcombined = 5.66 * 10-5 ; ORcombined = 2.80), mapping to a noncoding transcript exon of PDE10A; and rs6835978 (pcombined = 1.02 * 10-4 ; ORcombined = 2.57), an intronic variant in ATP10D. We assessed the relevance of both proteins in early stage NSCLC. PDE10A and ATP10DmRNA expressions correlated with survival in 821 stage I-II NSCLC patients (p = 0.01 and p < 0.0001). PDE10A protein expression correlated with survival in 149 patients with stage I-II NSCLC (p = 0.002). In conclusion, we validated two variants associated with extreme phenotypes of high and low risk of developing tobacco-induced NSCLC. Our findings may allow to identify individuals presenting high and low risk to develop tobacco-induced NSCLC and to characterize molecular mechanisms of carcinogenesis and resistance to develop NSCLC. PMID- 29766677 TI - Sleeping chILD: Neuroendocrine cell hyperplasia of infancy and polysomnography. AB - OBJECTIVES: Neuroendocrine cell hyperplasia of infancy (NEHI) is a children's interstitial and diffuse lung disease of unknown etiology that presents in infancy with characteristic findings of tachypnea, retractions, crackles, and hypoxemia. At the present, the mainstay of treatment is oxygen supplementation to normalize oxygen saturations and decrease work of breathing. There are characteristic pulmonary function, radiographic, and histologic findings, but polysomnography (PSG) data has not been reported. We sought to report PSG data and implications for management and treatment of NEHI patients. METHODS: A retrospective chart review was performed under a Colorado Institutional Review Board approved protocol for which consent was waived. Informatics for Integrating Biology and the Bedside was used to query the electronic medical record at Children's Hospital Colorado for patients with both a diagnosis of NEHI and a PSG. PSG was performed for clinical reasons. Routine sleep quality and respiratory parameters were recorded and analyzed. RESULTS: Of our 77 patients with NEHI, 14 (19%) children underwent PSG during the study period. Eight children met criteria for OSA and three met criteria for CSA. Ten patients had low oxygen saturations during a study, six had low sleep efficiency, and three had periodic limb movement disorder. CONCLUSIONS: Patients with NEHI may have sleep related breathing disorders that contribute to disrupted sleep, including obstructive and central sleep apnea, hypoxemia, decreased sleep efficiency, and increased periodic limb movement disorder. PSG should be considered as part of NEHI management, as it may lead to recognition of clinically significant sleep disordered breathing. PMID- 29766678 TI - Association between Bone Mineral Density and Albuminuria: Cross-Sectional Analysis of Data from the 2011 Korea National Health and Nutrition Examination Survey V-2. AB - BACKGROUND: Albuminuria is known to be independently associated with progression of renal and cardiovascular disease. However, little is known regarding the exact relationship between albuminuria and bone mineral density (BMD). The aim of this population-based study conducted in Korea was to identify the association between albuminuria and BMD. METHODS: We performed a cross-sectional analysis of data from the Korea National Health and Nutrition Examination Survey (KNHANES V-2) 2011. BMD was measured for total hip (TH), femur neck (FN), and lumbar spine (LS). Analysis of covariance was used to compare BMD levels between the groups at the TH, FN, and LS sites, after adjusting for age. Separate analyses were performed according to sex; women were divided into two groups according to menopausal status and each group was subdivided into three according to urine albumin-to-creatinine ratio (level 1, <30 mg/g; level 2, 30 to 299 mg/g; level 3, >=300 mg/g). RESULTS: Data on a total of 1,831 adults (857 men and 974 women) were analyzed. In postmenopausal women, after adjusting for age, BMD of TH tended to decrease as levels of albuminuria increased (0.767+/-0.117, 0.757+/-0.129, 0.752+/-0.118, respectively; P=0.040). However, there was no significant difference in BMD according to albuminuria level in premenopausal women and men. CONCLUSION: Level of albuminuria was closely related with BMD of TH in postmenopausal women, after adjusting for age, but there was no significant relationship between albuminuria and BMD in premenopausal women and men. PMID- 29766681 TI - Evaluation of Thyroid Hormone Levels and Urinary Iodine Concentrations in Koreans Based on the Data from Korea National Health and Nutrition Examination Survey VI (2013 to 2015). AB - No nationwide data have been published about thyroid hormone levels and urinary iodine concentrations (UICs) in Korea. The Korea Centers for Disease Control and Prevention and the Korean Thyroid Association established a project to evaluate the nationwide thyroid hormone profile and UICs in healthy Koreans as part of the Korea National Health and Nutrition Examination Survey (KNHANES) VI (2013 to 2015), a nationwide, cross-sectional survey of the Korean population that enrolled 7,061 individuals who were weighted to represent the entire Korean population. Based on the KNHANES VI, the geometric mean value of serum thyroid stimulating hormone was 2.16 mIU/L, and its reference interval was 0.59 to 7.03 mIU/L. The mean value of serum free thyroxine was 1.25 ng/dL, and its reference interval was 0.92 to 1.60 ng/dL. The median UIC in the Korean population was reported to be 294 MUg/L, corresponding to 'above requirements' iodine intake according to the World Health Organization recommendations. A U-shaped relationship of UIC with age was found. The prevalence of overt hyperthyroidism and overt hypothyroidism in the Korean population based on the KNHANES VI was 0.54% and 0.73%, respectively. PMID- 29766680 TI - C-Arm Computed Tomography-Assisted Adrenal Venous Sampling Improved Right Adrenal Vein Cannulation and Sampling Quality in Primary Aldosteronism. AB - BACKGROUND: Adrenal venous sampling (AVS) is a gold standard for subtype classification of primary aldosteronism (PA). However, this procedure has a high failure rate because of the anatomical difficulties in accessing the right adrenal vein. We investigated whether C-arm computed tomography-assisted AVS (C AVS) could improve the success rate of adrenal sampling. METHODS: A total of 156 patients, diagnosed with PA who underwent AVS from May 2004 through April 2017, were included. Based on the medical records, we retrospectively compared the overall, left, and right catheterization success rates of adrenal veins during the periods without C-AVS (2004 to 2010, n=32) and with C-AVS (2011 to 2016, n=124). The primary outcome was adequate bilateral sampling defined as a selectivity index (SI) >5. RESULTS: With C-AVS, the rates of adequate bilateral AVS increased from 40.6% to 88.7% (P<0.001), with substantial decreases in failure rates (43.7% to 0.8%, P<0.001). There were significant increases in adequate sampling rates from right (43.7% to 91.9%, P<0.001) and left adrenal veins (53.1% to 95.9%, P<0.001) as well as decreases in catheterization failure from right adrenal vein (9.3% to 0.0%, P<0.001). Net improvement of SI on right side remained significant after adjustment for left side (adjusted SI, 1.1 to 9.0; P=0.038). C-AVS was an independent predictor of adequate bilateral sampling in the multivariate model (odds ratio, 9.01; P<0.001). CONCLUSION: C-AVS improved the overall success rate of AVS, possibly as a result of better catheterization of right adrenal vein. PMID- 29766679 TI - Comparison of the Effects of Ezetimibe-Statin Combination Therapy on Major Adverse Cardiovascular Events in Patients with and without Diabetes: A Meta Analysis. AB - BACKGROUND: Ezetimibe-statin combination therapy has been found to reduce low density lipoprotein cholesterol levels and the risk of major adverse cardiovascular events (MACEs) in large trials. We sought to examine the differential effect of ezetimibe on MACEs when added to statins according to the presence of diabetes. METHODS: Randomized clinical trials with a sample size of at least 50 participants and at least 24 weeks of follow-up that compared ezetimibe-statin combination therapy with a statin- or placebo-controlled arm and reported at least one MACE, stratified by diabetes status, were included in the meta-analysis and meta-regression. RESULTS: A total of seven trials with 28,191 enrolled patients (mean age, 63.6 years; 75.1% men; 7,298 with diabetes [25.9%]; mean follow-up, 5 years) were analysed. MACEs stratified by diabetes were obtained from the published data (two trials) or through direct contact (five trials). No significant heterogeneity was observed among studies (I2=14.7%, P=0.293). Ezetimibe was associated with a greater reduction of MACE risk in subjects with diabetes than in those without diabetes (pooled relative risk, 0.84 vs. 0.93; P(heterogeneity)=0.012). In the meta-regression analysis, the presence of diabetes was associated with a greater reduction of MACE risk when ezetimibe was added to statins (beta=0.87, P=0.038). CONCLUSION: Ezetimibe-statin combination therapy was associated with greater cardiovascular benefits in patients with diabetes than in those without diabetes. Our findings suggest that ezetimibe-statin combination therapy might be a useful strategy in patients with diabetes at a residual risk of MACEs. PMID- 29766685 TI - Test-retest reliability of brain mitochondrial cytochrome-c-oxidase assessed by functional near-infrared spectroscopy. AB - Functional near-infrared spectroscopy (fNIRS) is a noninvasive method for measuring in vivo both hemodynamic and mitochondrial metabolic activities in brain cortical structures. Although the test-retest reliability of the hemodynamic measures, such as reflected by oxygenated (HbO2), deoxygenated (HHb) hemoglobin, and the tissue oxygenation index (TOI), has been previously reported to be good to excellent, the reliability of the metabolic signal indexed by oxidized cytochrome-c-oxidase (oxCCO) has not been reported. The present test retest study compared the reliability of the metabolic and hemodynamic signals in 10 healthy participants undergoing hypo- and hypercapnia challenges. The primary reliability measure was the intraclass correlation coefficient (ICC). Results of both hypo- and hypercapnia showed that the oxCCO signal (ICC = 0.876 / 0.757) had robust reliability comparable with that of the HbO2 (ICC = 0.841 / 0.801), HHb (ICC = 0.804 / 0.571), and TOI (ICC = 0.574 / 0.614) signals. These findings show that the oxCCO signal can be assessed by fNIRS with comparable reliability to the hemodynamic measures. We discuss the results in light of current interest in a mitochondrial metabolic marker derived from fNIRS. PMID- 29766683 TI - Star-Shaped Intense Uptake of 131I on Whole Body Scans Can Reflect Good Therapeutic Effects of Low-Dose Radioactive Iodine Treatment of 1.1 GBq. AB - BACKGROUND: After initial radioactive iodine (RAI) treatment in differentiated thyroid cancer patients, we sometimes observe a star-shaped region of intense uptake of 131I on whole body scans (WBSs), called a 'star artifact.' We evaluated the clinical implications of star artifacts on the success rate of remnant ablation and long-term prognosis. METHODS: Total 636 patients who received 131I dose of 1.1 GBq for the initial RAI therapy and who did not show distant metastasis at the time of diagnosis were retrospectively evaluated. A negative second WBS was used for evaluating the ablation efficacy of the RAI therapy. Among them, 235 patients (36.9%) showed a star artifact on their first WBS. RESULTS: In patients with first stimulated thyroglobulin (sTg) levels <=2 ng/mL, patients with star artifacts had a higher rate of negative second WBS compared with those without star artifacts (77.8% vs. 63.9%, P=0.044), and showed significantly higher recurrence-free survival (P=0.043) during the median 8.0 years (range, 1.0 to 10.0) of follow-up. The 5- and 10-year recurrence rates (5YRR, 10YRR) were also significantly lower in patients with star artifacts compared with those without (0% vs. 4.9%, respectively, P=0.006 for 5YRR; 0% vs. 6.4%, respectively, P=0.005 for 10YRR). However, ablation success rate or recurrence-free survival was not different among patients whose first sTg levels >2 ng/mL regardless of star artifacts. CONCLUSION: Therefore, star artifacts at initial RAI therapy imply a good ablation efficacy or a favorable long-term prognosis in patients with sTg levels <=2 ng/mL. PMID- 29766682 TI - Distinct Ultradian Rhythms in Plasma Clusterin Concentrations in Lean and Obese Korean Subjects. AB - BACKGROUND: Blood levels of many hormones show rhythmic fluctuations with variable duration of cycles. Clusterin/apolipoprotein J is a glycoprotein which is highly expressed in the plasma and has modulatory roles in immune and inflammatory reactions, neurobiology, lipid metabolism, and leptin signaling. In this study, we examined the diurnal fluctuations of plasma clusterin concentrations in lean and obese young men. METHODS: For the study, 14 subjects (five lean and five obese men; two lean and two obese women) were admitted to the research ward and blood samples were drawn every 30 minutes during light-on period (6:00 AM to 10:00 PM) and every hour during light-off period. RESULTS: Notably, plasma clusterin concentrations displayed a unique ultradian rhythm with five cycles a day in both men and women. During the light-on period, circulating clusterin levels showed fluctuating curves with 4 hours regular intervals with sharp peaks and troughs. In contrast, single oscillation curve during light-off exhibited a smoothened/lower peak and longer (8-hour) duration. In obese men, these cycles were phase-advanced by approximately 1 hour, and had reduced amplitude of fluctuating curves and blunted diurnal pattern. Cyclic fluctuations of plasma clusterin were preserved under fasting and unexpected meal condition, suggesting that rhythmic oscillations in plasma clusterin levels are not generated by meal-related cues. CONCLUSION: These findings firstly demonstrate a novel pattern of plasma clusterin fluctuations with extremely regular cycles. PMID- 29766686 TI - Multimodal approach in assessment of the response of breast cancer to neoadjuvant chemotherapy. AB - The ability for noninvasive visualization of functional changes of a tumor's oxygenation and circulatory system offers new advantages for prognosis and monitoring of the treatment efficacy. The results of breast cancer oxygen state study under chemotherapy action obtained by diffuse optical spectroscopy (DOS) in combination with Doppler ultrasonic imaging are presented. Complex use of optical and ultrasound methods gives complementary information about the size of the tumor node, peculiarities of its vascular bed, rate of its blood flow as well as oxygenation, and provide a picture of the tumor response to treatment. Comparison with tumor pathologic response allowed to identify differences in the changes of these parameters depending on the degree of pathological tumor response to chemotherapy. It was demonstrated that fourth and fifth degrees of therapeutic pathomorphism may be predicted by the increase of oxygen saturation level after the first cycle of chemotherapy. If the reduction or absence of the oxygen saturation dynamics is observed, first or second degree of pathological tumor response can be expected. Additional ultrasound investigation of the tumors may be useful for observation of the dynamics of tumor blood flow thereby for understanding the reasons of induced chemotherapy oxygenation changes. The proposed approach based on DOS and ultrasonography may be applied for monitoring of breast tumors under therapy and prediction of their sensitivity. PMID- 29766684 TI - Neuromyelitis Optica: Review and Utility of Testing Aquaporin-4 Antibody in Typical Optic Neuritis. AB - Neuromyelitis optica (NMO) is an autoimmune, inflammatory demyelinating disorder often leading to severe vision impairment and disability. The discovery of a diagnostic biomarker, the aquaporin-4 antibody (AQP4-IgG), transformed the clinical diagnosis and treatment of NMO and broadened the spectrum of disease [NMO spectrum disorders (NMOSD)]. Though the antibody is highly sensitive and specific to NMOSD, routine testing in patients with typical optic neuritis is considered controversial. This article will provide a brief review of NMOSD and highlight the pros and cons of routine testing in typical optic neuritis. PMID- 29766687 TI - Structured illumination to spatially map chromatin motions. AB - We describe a simple optical method that creates structured illumination of a photoactivatable probe and apply this method to characterize chromatin motions in nuclei of live cells. A laser beam coupled to a diffractive optical element at the back focal plane of an excitation objective generates an array of near diffraction-limited beamlets with FWHM of 340 +/- 30 nm, which simultaneously photoactivate a 7 * 7 matrix pattern of GFP-labeled histones, with spots 1.70 MUm apart. From the movements of the photoactivated spots, we map chromatin diffusion coefficients at multiple microdomains of the cell nucleus. The results show correlated motions of nearest chromatin microdomain neighbors, whereas chromatin movements are uncorrelated at the global scale of the nucleus. The method also reveals a DNA damage-dependent decrease in chromatin diffusion. The diffractive optical element instrumentation can be easily and cheaply implemented on commercial inverted fluorescence microscopes to analyze adherent cell culture models. A protocol to measure chromatin motions in nonadherent human hematopoietic stem and progenitor cells is also described. We anticipate that the method will contribute to the identification of the mechanisms regulating chromatin mobility, which influences most genomic processes and may underlie the biogenesis of genomic translocations associated with hematologic malignancies. PMID- 29766689 TI - Furan in roasted, ground and brewed coffee AB - Coffee is the most popular hot beverage in the world. The annual coffee production in 2010, 2014 and 2016 was 8.1, 9.0 and 9.3 million tons respectively. There are more than 100 coffee species, but only two of them: Arabica (Coffea arabica) and Robusta (Coffea canephora) have gained commercial importance. During roasting of green coffee beans not only desirable compounds are formed, that exert positive influence on the taste and flavour of coffee, but also small quantities of undesirable ones. Furan (C4H4O) is one of the latter.Furan is a volatile compound (boiling temp. of 31.4 oC) formed during thermal processing of food. The toxicity of furan has been well documented and it is classified as "possible human carcinogen" (Group 2B) by the International Agency for Research on Cancer. Various pathways have been reported for furan formation during food processing. It can be formed from carbohydrates, amino acids by their thermal degradation or thermal re-arrangement and by oxidation of ascorbic acid and polyunsaturated acids and carotenoids. High concentrations of furan have been reported in coffee, baked and roasted food and in food subjected to preserving in cans and jars. Furan levels in brewed coffee are typically near or below 120 MUg/L, but it can approach thousands MUg/kg in roasted whole beans or ground coffee. The highest concentration of furan in roasted coffee reaches the level of 7000 MUg/kg. Taking into account that coffee is the most popular hot drink, it becomes the main contributor to furan exposure from dietary sources for adults.In this article the published scientific papers concerned with the presence of furan in roasted non-brewed and brewed coffee have been reviewed. The formation mechanisms and occurrence of furan in coffee and the harmful influence of furan on the consumer health have been discussed. PMID- 29766688 TI - Assessing effects of pressure on tumor and normal tissue physiology using an automated self-calibrated, pressure-sensing probe for diffuse reflectance spectroscopy. AB - Diffuse reflectance spectroscopy (DRS) represents a quantitative, noninvasive, nondestructive means of assessing vascular oxygenation, vascularity, and structural properties. However, it is known that such measurements can be influenced by the effects of pressure, which is a major concern for reproducible and operator-independent assessment of tissues. Second, regular calibration is a necessary component of quantitative DRS to account for factors such as lamp decay and fiber bending. Without a means of reliably controlling for these factors, the accuracy of any such assessments will be reduced, and potentially biased. To address these issues, a self-calibrating, pressure-controlled DRS system is described and applied to both a patient-derived xenograft glioma model, as well as a set of healthy volunteers for assessments of oral mucosal tissues. It was shown that pressure had a significant effect on the derived optical parameters, and that the effects on the optical parameters were magnified with increasing time and pressure levels. These findings indicate that not only is it critical to integrate a pressure sensor into a DRS device, but that it is also important to do so in an automated way to trigger a measurement as soon as possible after probe contact is made to minimize the perturbation to the tissue site. PMID- 29766691 TI - Analysis of acrylamide, 3-monochloropropane-1,2-diol, its esters and glycidyl esters in carbohydrate-rich products available on the Polish market AB - Background: Carbohydrate-rich foods, such as breakfast products, snacks and biscuits because of its nutritional or sensory qualities are an inherent part of human diet. However, their production might contribute to the formation of acrylamide, 3-monochloropropane-1,2-diol (3-MCPD) and its esters and glycidyl esters. Objective: The aim of this work was to assess the levels of acrylamide, free and bound 3-MCPD and glycidyl esters in selected carbohydrate-rich, thermal processed products, present on the market in Poland in 2016-2017. Material and Methods: The survey involved 60 samples of snacks, breakfast products and biscuits. Acrylamide and free 3-MCPD was determined using modified QuEChERS approach. Analysis of 3-MCPD and glycidyl esters was based on the acid-catalysed method of sample preparation, derivatisation with PBA and GC-MS analysis. Results: Free 3-MCPD contents were within the values of 9.3-63.3 MUg kg-1, with the highest mean content for muesli (33.3 MUg kg-1), and the lowest for baby biscuits (11.7 MUg kg-1). The levels of bound 3-MCPD were higher (from 9.3 MUg kg 1 to 1500 MUg kg-1). The highest average content was observed for sugar free biscuits (599 MUg kg-1), whereas the lowest for breakfast cereals (50.2 MUg kg 1). Glycidyl esters were detected only in four samples with the highest content at the level of 28.8 MUg kg-1. The acrylamide levels varied from 195 to 1352 MUg kg-1, with the highest content for organic biscuit samples (913 MUg kg-1), and the lowest for muesli (348 MUg kg-1). Conclusions: Regular consumption of popular snacks such as potato chips, crackers and biscuits may result in risk to human health as the effect of high content of acrylamide or 3-MCPD. Due to a high level of these contaminants detected in some type of breakfast products, and products targeted for children, its consumption should be restricted, especially in younger population groups. PMID- 29766692 TI - The influence of preschool children's diets on the risk of lifestyle diseases. A pilot study AB - Background: A healthy diet in early life not only contributes to physical and intellectual development, but it can also reduce the risk of disease in adulthood. There is growing evidence to indicate that childhood diets are highly correlated with health in adult years. Eating habits formed in childhood persist in later life. Objective: The objective of this study was to evaluate the diets of preschool children aged 3 to 6 years and to identify statistical correlations between dietary factors and the risk of lifestyle diseases. Material and methods: The described survey was conducted based on the paper and pencil interviewing method. The study was conducted on 380 children from Lublin and Swietokrzyskie regions. The risk of lifestyle diseases in the studied population was evaluated based on the answers to 17 selected questions. The questionnaires were processed statistically in SPSS and Statistica programs. Results: Eating irregular meals increased the risk of lifestyle diseases, and the lower the number of meals per day, the greater the relevant risk (p=0.002). Children who did not eat regular breakfasts or afternoon teas and ate sweet and salty snacks were at significantly higher risk of lifestyle diseases. Consumption of milk and dairy product was an important predictor of lifestyle diseases. Children who did not drink milk every day were at significantly higher risk of developing lifestyle diseases than their peers who drank milk at least once a day (p<0.0001). Conclusions: Eating habits formed in childhood can contribute to the risk of lifestyle diseases in adulthood. Particularly dangerous are nutritional habits leading to overweight and obesity. Both children and parents require nutritional education to develop healthy eating habits. PMID- 29766690 TI - Garden nasturtium (Tropaeolum majus L.) - a source of mineral elements and bioactive compounds AB - The garden nasturtium (Tropaeolum majus L.) belongs to the family Tropaeolaceae. Native to South America it was brought to Europe in XVI century. It is a plant with numerous healing properties. Medicinal plants such as the garden nasturtium contain trace elements and bioactive compounds which can be easily absorbed by the human body. The flowers and other parts of the garden nasturtium are a good source of micro elements such as potassium, phosphorus, calcium and magnesium, and macro elements, especially of zinc, copper and iron. The essential oil, the extract from the flowers and leaves, and the compounds isolated from these elements have antimicrobial, antifungal, hypotensive, expectorant and anticancer effects. Antioxidant activity of extracts from garden nasturtium is an effect of its high content of compounds such as anthocyanins, polyphenols and vitamin C. Due to its rich phytochemical content and unique elemental composition, the garden nasturtium may be used in the treatment of many diseases for example the illnesses of the respiratory and digestive systems. High content of erucic acid in nasturtium seeds makes it possible to use its oil as treatment in adrenoleukodystrophy. It is also applied in dermatology because it improves the condition of skin and hair. More recently, the flowers of this species have been used as a decorative and edible element of some types of dishes. Aim of the review was to summarize available data concerning garden nasturtium Tropaeolum majus L. PMID- 29766693 TI - Food aversions and dietary preferences in pre-school children from Olsztyn AB - Background: The nutrition of pre-school children often does not follow the recommendations, and qualitatively and quantitatively limited selection of products in the diet shapes an attitude of aversion towards new products and dishes. The risk of deficiencies in many important nutrients emerges, particularly in vitamins and mineral components, which can affect the psychophysical development of the child and have an impact on nutritional status and health disorders in adulthood. Objective: Study of dietary preferences in pre school children and identify possible food aversions. Material and methods: Nutritional preferences of pre-school children in Olsztyn were examined using a questionnaire prepared in a graphic form, presenting images of 40 food products classified into 5 groups, and the acceptance level and knowledge of the product was established. Results: The values of Cole's index proving the proper nutritional status of pre-school children were obtained for about 87% of the examined group, excessive nutrition was observed in more than 4% of the examined group, about 2% of the group demonstrated obesity and mild malnutrition was observed in about 7% of the examined children. A high acceptance rate of sweets and fast-food products by children was observed. A high degree of preference for milk was recorded, as well as traditional and cognitive aversion for kefir. In the group of fruit and vegetables, both a high degree of preference and aversions to all indicated vegetables and fruit were observed. Taste determined the results, with high acceptance for the sweet taste and rejection or a neutral attitude towards sour and bitter products. Conclusions: Food aversions, by reducing the intake of food products, can result in nutritional deficiencies, affecting the psychosomatic development and cognitive abilities of the child. Traditional and cognitive food aversions was observed towards kefir, cheeses and most of vegetables. A high level of preference was observed in relation towards sweet and fast food products and a low acceptance level for selected vegetables, fruits and dairy products. PMID- 29766695 TI - Analysis of nutrition and nutritional status of haemodialysis patients AB - Background: Chronic kidney disease (CKD) is a common disease of civilization where nutrition is part of the treatment. Diet therapy is difficult as it is necessary to control the intake of: energy, protein and minerals - Na, K, Ca and P in the daily food rations (DFR). Objective: The aim of the study was to assess the nutritional status and diets of haemodialysis (HD) patients. Material and method: The study involved 141 haemodialysis patients, at the average age of 65.9. The patients were divided into groups taking into consideration their sex and diagnosis for diabetes. The information on the diets were collected using a 7 day dietary recall. In the DFRs the amount of energy and 22 nutrients were calculated. Obtained results were compared with requirements for HD patients. Results: Appropriate nutritional status (measured with BMI) was reported for majority of women (70.6%) and almost half of men, however, excessive weight was recognized in every third female patient and more than half male patients, and type I obesity was noted in 7.8% of men. The analysis of the results showed that diets of all examined patients were deficient in energy and protein (except women with diabetes), whereas the consumption of fat was appropriate in both groups of women. The recommendations with respect to the amount of cholesterol were met but dietary fibre was too low. Intake of vitamins B1, D, C, folates and Ca and Mg was lower and intake of vitamin B12 was higher than recommended. Conclusions: Assessment of the coverage of the demand on nutrients in HD patients should not be based on the analysis of their nutritional status (BMI) only but also on the analysis of diets, especially in case of diabetes. PMID- 29766694 TI - Analysis of the choice of food products and the energy value of diets of female middle- and long-distance runners depending on the self-assessment of their nutritional habits AB - Background: Properly balanced diet is especially important in the case of young athletes, as it influences not only their physical development, but also influences results obtained during trainings and competitions. Objective: The aim of the study was to assess the choice of food products and the energy value of diets of female middleand long-distance runners, depending on the self-assessment of their nutritional habits. Material and methods: The study was conducted in the group of 40 female middle- and long-distance runners, aged 15-25, who declared average diet (n=15, 37.5%) or outstanding diet (n=25, 62.5%). Participants conducted three-day dietary record of the consumed dishes and drunk beverages, that was based on the self-reported data. The choice of products, the energy value of diets as well as macronutrients intake were compared depending on the self-assessment of the nutritional habits. Results: Runners declaring outstanding diet were characterized by significantly lower intake of dairy beverages, than runners declaring average diet (p=0.0459), but simultaneously, by higher intake of mushrooms (p=0.0453). No difference of energy value of diets was stated between groups of runners depending on the self-assessment of their nutritional habits.Runners declaring outstanding diet were characterized by significantly lower intake of lactose, than runners declaring average diet (p=0.0119), but simultaneously, by higher intake of cholesterol (p=0.0307). Conclusions: The female middle- and long-distance runners analysed in the presented study do not assess the quality of their diet reliably, so they probably do not have the sufficient nutritional knowledge. There is a need to implement nutritional education among professional runners and their coaches, in order to improve the quality of diet of professional runners and, as a results maybe also to improve their sport results. PMID- 29766696 TI - Dietary practices and nutritional status in survivors of breast cancer AB - Background: Wrong dietary practices and excessive body mass may not only influence the risk of primary breast cancer but also the risk of its recurrence. Objective: Evaluation of dietary practices and identification of nutritional factors which may influence the risk of tumor recurrence in women with prior breast cancer. Materials and methods: The case-control study involved 108 women aged 50 years and older with history of breast cancer who were divided into two categories: women after completed cancer treatment with no recurrence for minimum 5 years (group I, n=82) and women with diagnosed breast cancer recurrence (group II, n=26). A control group (n=74) constituted of subjects with no breast cancer diagnosis. In every subject anthropometric measurements were taken and dietary practices were evaluated by means of an original questionnaire. Results: Average BMI and hip circumference values were higher in the group II than in the group I. In both study groups the percentage of high WHR values was significantly higher than in the control group. Women with history of cancer consumed significantly fewer vegetable and fruit and more refined cereals, dairy products, meat and cold cuts than women in the control group. Group I responders more often declared implementation and maintenance of changes in their diet after diagnosis of cancer than women from group II. Subjects with cancer history consumed more alcohol and more often used supplements than females in the control group. Conclusion: Avoiding overweight and obesity along with following the principles of a healthy diet seems to reduce the risk of both breast cancer incidence and its recurrence. PMID- 29766697 TI - The assessment of the nutritional value of meals consumed by patients with recognized schizophrenia AB - Background: As studies show, changes in diet - so important in the therapy of psychiatric disorders and related to changes in appetite and nutritional preferences, including avoiding of the consumption of specific groups of products and dishes - are much more frequent among patients affected by schizophrenia. Objective: The aim of the study was to assess the chosen nutritional habits, including the number and type of meals usually consumed during a day, snacking between meals and the energy value and content of the chosen nutrients in the diets of persons with recognized schizophrenia. Material and methods: The study was carried out in a group of 85 patients with recognized schizophrenia, and 70 healthy volunteers ranging in age from 18-65 years without mental or nutritional disorders. For the purpose of the study, we used a questionnaire containing questions on nutritional habits. A 24-hour diet recall was used in the quantitative nutritional assessment with the use of the computer program Dieta 5.0. Results: Female patients with recognized schizophrenia were having 3 meals a day significantly more frequently as compared to healthy women. They were also having an afternoon snack much more frequently as compared to the control group. The food rations of female patients were characterized by a significantly higher energy value and the content of most of the assessed nutrients as compared to the food rations of healthy women. The food rations of men with recognized schizophrenia were characterized by a much lower energy intake and the content of the majority of assessed nutrients as compared to the food rations of healthy men. In all compared groups, we observed an energetic structure of food rations with the breakdown by specific meals that was inconsistent with the applicable recommendations. Conclusions: Despite of differences between the nutritional value of the meals of patients with recognized schizophrenia and those of healthy subjects, it seems advisable to involve patients with recognized schizophrenia in the education of forming appropriate nutritional habits. PMID- 29766698 TI - Eating behaviours of primary school pupils from Slaskie, Malopolskie and Opolskie Voivodeships in Poland AB - Background: Nutrition is one of the major environmental factors affecting children's physical development and health, with nutrition mistakes made in early years of life having short- and long-term health consequences. Objective: This study has been aimed at evaluating eating behaviours of primary school pupils and determining whether there are relationships between pupils' eating habits and their area of residence. Material and methods: The study was conducted in primary schools located in the following voivodeships (administrative units) in Poland: Slaskie, Opolskie and Malopolskie, on a total sample of 1138 pupils. A survey specially designed for the purpose of this study was used to investigate the pupils' eating behaviours. The findings were then analysed with the use of MS Excel 2010 and Statistica 12.0 software. Results: According to the survey, 61.42% of pupils in our study ate the recommended number of meals daily. 72.74% reported eating breakfast daily, 66.17% stated they ate packed lunch/midmorning snack daily, 17.49% reported eating wholemeal bread more than once daily, whilst milk and natural yoghurt were consumed daily by 20.04% and 10.81% of pupils, respectively. Sweets and salty snacks were excluded from the diet of 2.2% and 3.08% of pupils respectively. 6.59% of pupils reported not eating fast food at all. Conclusions: The eating behaviours of primary school pupils differ. Regional variations in eating behaviours have been found to exist, revealing a correlation between the pupils' area of residence (voivodeship) and some eating behaviours. The largest number of healthy eating behaviours were reported by pupils from Malopolskie Voivodeship. PMID- 29766699 TI - Evaluation of health status of children attending primary schools with different organization of physical education lessons AB - Background: The mandatory swimming lesson in primary schools, equipped with swimming pools, was introduced without studying of its health-saving effectiveness. Objective: The purpose of this study was to evaluate the health status of pupils studying in schools with different organization of physical education lessons. Materials and Methods: Cross-sectional study was organized in two schools with different organization of physical education lessons. The experimental group (E) consisted of 408 children of 1-4 year of study (210 girls and 198 boys) who during one of the lessons of physical education were engaged in swimming in the school basin. Control group (C) consisted of 279 primary school children (210 girls and 156 boys) from a neighboring educational institution where all physical education lessons were organized in the gym. The health status was evaluated using classical method of complex assessment of the state of health with the subsequent assignment of each child to one of the health groups. Results: In result of evaluation of state of health there was established that among pupils from E group the proportion of boys with harmonious anthropometric parameters is higher (p<0.05), children from this group are stronger than C group (p<0.05). The prevalence of diseases of the musculoskeletal system and the eyes among pupils in E group was lower comparing to the C group (p<0.01). In the E group percentage of pupils assigned to health group I was significantly higher and lower for the II (children with some morpho-functional abnormalities) comparing to the C group. Conclusion: Organization of one mandatory swimming lesson per week in primary school has positive effect on health status of children. PMID- 29766700 TI - Health policy programs realised in Poland in 2016-2017 AB - Background: Health Policy Program (Program Polityki Zdrowotnej - PPZ) is a state policy tool for engaging local government units into the mechanism of granting provision of health services. Authors show areas in which self-governments most often took preventive health care actions and describe legislative changes in the Act on provision of health services. Objective: The aim of the article is to quantitative and qualitative statement of PPZ prepared in Poland in 2016 and 2017, as well as presenting changing legal situation in the scope of evaluation of these projects. Materials and methods: Authors use descriptive method, presenting changes of legal status. The article includes data available in the Bulletin of Public Information by The Agency for Health Technology Assessment. 590 programs were analyzed (239 from 2016 and 351 from 2017). Results: In 2016 - 67% of submitted programs were given a positive opinion and in 2017 - 71%. The most of positively evaluated PPZ submitted by local government units (53% in 2016; 47% in 2017) referred to prevention of infectious diseases by vaccines. On the basis of analyses conducted, significant differences were observed in the implementation of the PPZ in various regions of Poland. Conclusions: In the recent years a big improvement in the quality of planned self-government health programs is observed.It is suggested that due to the regulation defining the model of the health policy program and the model of the final report, this trend will continue. PMID- 29766702 TI - Cutaneous pili migrans in pediatric patients. PMID- 29766701 TI - New multi-targeting strategy in hair growth promotion: in vitro and in vivo studies. AB - BACKGROUND: Considering the importance of hair in our modern society and the impact of hair loss, the efforts of researchers are addressed to better understand the mechanisms behind the hair cycle regulation and dysregulation. Because hair loss is multifactorial, differenced and new approaches are required. In particular we addressed our attention to two recently identified targets in hair cycling and growth control: olfactory receptor and autophagy. The aim of the study was to evaluate: the possible pro-autophagic effect of N1-methylspermidine (a spermidine analogue) in vitro and, in a double blind clinical trial, the safety and efficacy of topical daily application of a lotion containing N1 methylspermidine and Sandalore(r). METHODS: Autophagic modulation by N1 methylspermidine was monitored in vitro by LC3 and p62 fluorescent signal cell line. Topical daily application of the lotion was tested in 60 male and female subjects with chronic telogen effluvium by means of non-invasive objective evaluation. RESULTS: The results obtained by in vitro tests showed the capacity of N1-methylspermidine to increase autophagic process while the clinical trials performed confirmed the safety and anti hair loss efficacy of the lotion reporting a reduction of hair loss (modified wash test) and hair growth stimulation as evaluated by hair density, hair shaft diameter, % of anagen hair and Hair Mass Index increase after 3 months of treatment. The lotion efficacy remained statistically significant for the above-mentioned parameters, with the exception of hair lost during wash, also 3 months after the end of treatment. CONCLUSIONS: Based on the obtained results, the daily use of the N1 methylspermidine and Sandalore(r)-based lotion is efficient to counteract hair loss and increase hair growth by a multifunctional targeting approach. PMID- 29766703 TI - Meyerson's phenomenon in melanoma: when a halo dermatitis hides a malignancy. PMID- 29766704 TI - Incomplete excision of basal cell carcinoma of the head region: analysis of 724 consecutive cases. PMID- 29766705 TI - Multiple granuloma faciale: a clinical finding from a dermoscopic point a view. PMID- 29766706 TI - Idiopathic follicular mucinosis: can dermoscopy be helpful? PMID- 29766707 TI - Squamous cell carcinoma developed after ingenol mebutate therapy: a possible consequence of the treatment? PMID- 29766708 TI - Axillary extramammary Paget's disease on lymphadenectomy scar for melanoma: an instance of immunocompromised district. PMID- 29766709 TI - Two sisters with neurofibromatosis type 1 and celiac disease. PMID- 29766710 TI - Bilateral elastofibroma dorsi. PMID- 29766711 TI - Multicentric reticulohistiocytosis and metastatic colon carcinoma: an uncommon neoplasm recurrence manifestation. PMID- 29766712 TI - Highly Sensitive Membrane-Based Pressure Sensors (MePS) for Real-Time Monitoring of Catalytic Reactions. AB - Functional, flexible, and integrated lab-on-chips, based on elastic membranes, are capable of fine response to external stimuli, so to pave the way for many applications as multiplexed sensors for a wide range of chemical, physical and biomedical processes. Here, we report on the use of elastic thin membranes (TMs), integrated with a reaction chamber, to fabricate a membrane-based pressure sensor (MePS) for reaction monitoring. In particular, the TM becomes the key-element in the design of a highly sensitive MePS capable to monitor gaseous species production in dynamic and temporally fast processes with high resolution and reproducibility. Indeed, we demonstrate the use of a functional MePS integrating a 2 MUm thick polydimethylsiloxane TM by monitoring the dioxygen evolution resulting from catalytic hydrogen peroxide dismutation. The operation of the membrane, explained using a diffusion-dominated model, is demonstrated on two similar catalytic systems with catalase-like activity, assembled into polyelectrolyte multilayers capsules. The MePS, tested in a range between 2 and 50 Pa, allows detecting a dioxygen variation of the MUmol L-1 s-1 order. Due to their structural features, flexibility of integration, and biocompatibility, the MePSs are amenable of future development within advanced lab-on-chips. PMID- 29766713 TI - Probing DNA Hybridization Equilibrium by Cationic Conjugated Polymer for Highly Selective Detection and Imaging of Single-Nucleotide Mutation. AB - Hybridization-based probes emerge as a promising tool for nucleic acid target detection and imaging. However, the single-nucleotide selectivity is still challenging because the specificity of hybridization reaction is typically low at room temperature. We disclose an effective and simple method for highly selective detection and in situ imaging of single-nucleotide mutation (SNM) by taking the advantages of the specific hybridization of short duplex and the signal amplifying effect of cationic conjugated polymer (CCP). Excellent discrimination of the nucleic acid strands only differing by single nucleotide was achieved enabling the sensitive detection of SNM at the abundance as low as 0.1%. Single molecule fluorescence resonance energy transfer (smFRET) study reveals that the presence of CCP enhances the perfect matched duplex and the mismatched duplex to a different extent, which can be an explanation for the high single-nucleotide selectivity. Due to the simple design of the probe and the stable brightness of CCP, highly selective mRNA in situ imaging was achieved in fixed cells. Melanoma cell line A375 with BRAF V600E point mutation exhibits higher FRET efficiency than liver cancer cell line HegG2 that was not reported having the mutation at this point. PMID- 29766714 TI - Outer Membrane Vesicle Proteome of Porphyromonas gingivalis Is Differentially Modulated Relative to the Outer Membrane in Response to Heme Availability. AB - Porphyromonas gingivalis is an anaerobic, Gram-negative oral pathogen associated with chronic periodontitis. P. gingivalis has an obligate requirement for heme, which it obtains from the host. Heme availability has been linked to disease initiation and progression. In this study we used continuous culture of the bacterium to determine the effect of heme limitation and excess on the P. gingivalis proteome. Four biological replicates of whole cell lysate (WCL) and outer membrane vesicle (OMV) samples were digested with trypsin and analyzed by tandem mass spectrometry and MaxQuant label-free quantification. In total, 1211 proteins were quantified, with 108 and 49 proteins significantly changing in abundance more than 1.5-fold ( p < 0.05) in the WCLs and OMVs, respectively. The proteins most upregulated in response to heme limitation were those involved in binding and transporting heme, whereas the four proteins most upregulated under the heme-excess condition constitute a putative heme efflux system. In general, the protein abundance ratios obtained for OMVs and WCLs agreed, indicating that changes to the OM protein composition are passed onto OMVs; however, 16 proteins were preferentially packaged into OMVs under one condition more than the other. In particular, moonlighting cytoplasmic proteins were preferentially associated with OMVs under heme excess. PMID- 29766715 TI - MoSe2 Dispersed in Stabilizing Surfactant Media: Effect of the Surfactant Type and Concentration on Electron Transfer and Catalytic Properties. AB - Layered transition metal dichalcogenides (TMDs) have gained attention from the scientific community because of their extended range of applications. Molybdenum diselenide (MoSe2) has been proven to be an efficient catalyst for the hydrogen evolution reaction (HER), having implications in the research of new catalysts for clean energy production. One way to produce large quantities of these materials involves the use of surfactants for liquid exfoliation. Herein, we investigate the effects of cationic, anionic, and nonionic surfactants within a concentration range on the heterogeneous electron transfer rates, electrocatalytic efficiency toward the HER of MoSe2, and on the stability of the dispersions. We found that surfactants can have a detrimental effect on the electrocatalytic properties of the material when used above a concentration threshold. In some cases, high surfactant levels also had a negative effect on the stability of the material. This report serves to gain an understanding on how the way TMDs are prepared, processed, and stabilized can have dramatic effects on their efficiency toward HER, one of their most popular applications, and how choosing the appropriate surfactant type and concentration is crucial to gain in stability without compromising the intrinsic properties of the material. PMID- 29766716 TI - Pick a Color MARIA: Adaptive Sampling Enables the Rapid Identification of Complex Perovskite Nanocrystal Compositions with Defined Emission Characteristics. AB - Recent advances in the development of hybrid organic-inorganic lead halide perovskite (LHP) nanocrystals (NCs) have demonstrated their versatility and potential application in photovoltaics and as light sources through compositional tuning of optical properties. That said, due to their compositional complexity, the targeted synthesis of mixed-cation and/or mixed-halide LHP NCs still represents an immense challenge for traditional batch-scale chemistry. To address this limitation, we herein report the integration of a high-throughput segmented flow microfluidic reactor and a self-optimizing algorithm for the synthesis of NCs with defined emission properties. The algorithm, named Multiparametric Automated Regression Kriging Interpolation and Adaptive Sampling (MARIA), iteratively computes optimal sampling points at each stage of an experimental sequence to reach a target emission peak wavelength based on spectroscopic measurements. We demonstrate the efficacy of the method through the synthesis of multinary LHP NCs, (Cs/FA)Pb(I/Br)3 (FA = formamidinium) and (Rb/Cs/FA)Pb(I/Br)3 NCs, using MARIA to rapidly identify reagent concentrations that yield user defined photoluminescence peak wavelengths in the green-red spectral region. The procedure returns a robust model around a target output in far fewer measurements than systematic screening of parametric space and additionally enables the prediction of other spectral properties, such as, full-width at half-maximum and intensity, for conditions yielding NCs with similar emission peak wavelength. PMID- 29766719 TI - Application of Cp2TiCl-Promoted Radical Cyclization: A Unified Strategy for the Syntheses of Iridoid Monoterpenes. AB - An expedient approach toward the unified total syntheses of (+)-iridomyrmecin, ( )-isoiridomyrmecin, (+)-7- epi-boschnialactone, (+)-teucriumlactone, and (-) dolichodial in chirally pure forms starting from readily available (+)-beta citronellene is delineated combining step economy and simplicity. Highlights include a Ti(III)-mediated reductive epoxide opening-cyclization for the construction of the core cyclopenta[ c]pyran skeleton of the iridoid lactones with complete diastereoselectivity for the newly created bridgehead stereogenic centers. Subsequent transformations facilitate a short access to (+) teucriumlactone and (-)-dolichodial and formal access to potentially other iridoids. PMID- 29766717 TI - Photocatalytic Oxidation of Sulfur Mustard and Its Simulant on BODIPY Incorporated Polymer Coatings and Fabrics. AB - Sulfur mustard is one of the most toxic chemical warfare agents worldwide. We report the use of 4,4-difluoro-4-bora-3a,4a-diaza- s-indacene (BODIPY) photosensitizers as a fast and effective sulfur mustard decontaminant and their incorporation into various polymer coatings and fabrics, including army combat uniform. These BODIPY-embedded materials are capable of generating singlet oxygen under visible light irradiation and effectively detoxifying sulfur mustard by converting it into nontoxic sulfoxides as the major products. The rate of decontamination is found to be affected by the photosensitizer structure and concentration as well as the excitation wavelength. The most effective BODIPY embedded self-decontamination material observed in this study shows a half-life of only 0.8 min. In comparison to the current methods, which use activated carbon as the adsorbent layer, these self-detoxifying coatings and fabrics provide constant destruction of and real-time protection against sulfur mustard. PMID- 29766718 TI - Synthesis of 6-Fluoroalkyl 6 H-Benzo[ c]chromenes via Visible-Light-Promoted Radical Addition/Cyclization of Biaryl Vinyl Ethers. AB - A novel visible-light-promoted cascade cyclization reaction for the synthesis of 6-fluoroalkyl 6 H-benzo[ c]chromenes has been successfully realized, which was initiated by intermolecular radical addition to biaryl vinyl ethers using easily available fluoroalkylated reagents BrCF2CO2Et or 2-bromo-2,2-difluoroamides as the sources of fluorinated radicals, followed by the cyclization onto an aromatic ring process. This protocol tolerated a wide range of functional groups and provided the desired products in moderate to good yields. PMID- 29766720 TI - Gradient Structure Design of Flexible Waterborne Polyurethane Conductive Films for Ultraefficient Electromagnetic Shielding with Low Reflection Characteristic. AB - Highly efficient electromagnetic shielding materials entailing strong electromagnetic wave absorption and low reflection have become an increasing requirement for next-generation communication technologies and high-power electronic instruments. In this study, a new strategy is employed to provide flexible waterborne polyurethane composite films with an ultra-efficient electromagnetic shielding effectiveness (EMI SE) and low reflection by constructing gradient shielding layers with a magnetic ferro/ferric oxide deposited on reduced graphene oxide (rGO@Fe3O4) and silver-coated tetraneedle like ZnO whisker (T-ZnO/Ag) functional nanoparticles. Because of the differences in density between rGO@Fe3O4 and T-ZnO/Ag, a gradient structure is automatically formed during the film formation process. The gradient distribution of rGO@Fe3O4 over the whole thickness range forms an efficient electromagnetic wave absorption network that endows the film with a strong absorption ability on the top side, while a thin layer of high-density T-ZnO/Ag at the bottom constructs a highly conductive network that provides an excellent electromagnetic reflection ability for the film. This specific structure results in an "absorb-reflect-reabsorb" process when electromagnetic waves penetrate into the composite film, leading to an excellent EMI shielding performance with an extremely low reflection characteristic at a very low nanofiller content (0.8 vol % Fe3O4@rGO and 5.7 vol % T-ZnO/Ag): the EMI SE reaches 87.2 dB against the X band with a thickness of only 0.5 mm, while the shielding effectiveness of reflection (SER) is only 2.4 dB and the power coefficient of reflectivity ( R) is as low as 0.39. This result means that only 39% of the microwaves are reflected in the propagation process when 99.9999998% are attenuated, which is the lowest value among the reported references. This composite film with remarkable performance is suitable for application in portable and wearable smart electronics, and this method offers an effective strategy for absorption-dominated EMI shielding. PMID- 29766721 TI - Policy Considerations for Mobile Biosensors. AB - Meeting policy requirements is essential for advancing molecular diagnostic devices from the laboratory to real-world applications and commercialization. Considering policy as a starting point in the design of new technology is a winning strategy. Rapid developments have put mobile biosensors at the frontier of molecular diagnostics, at times outpacing policymakers, and therefore offering new opportunities for breakthroughs in global health. In this Perspective we survey influential global health policies and recent developments in mobile biosensing in order to gain a new perspective for the future of the field. We summarize the main requirements for mobile diagnostics outlined by policy makers such as the World Health Organization (WHO), the World Bank, the European Union (EU), and the Food and Drug Administration (FDA). We then classify current mobile diagnostic technologies according to the manner in which the biosensor interfaces with a smartphone. We observe a trend in reducing hardware components and substituting instruments and laborious data processing steps for user-friendly apps. From this perspective we see software application developers as key collaborators for bridging the gap between policy and practice. PMID- 29766723 TI - Structure-Activity Relationships of Nitro-Substituted Aroylhydrazone Iron Chelators with Antioxidant and Antiproliferative Activities. AB - Aroylhydrazone iron chelators such as salicylaldehyde isonicotinoyl hydrazone (SIH) protect various cells against oxidative injury and display antineoplastic activities. Previous studies have shown that a nitro-substituted hydrazone, namely, NHAPI, displayed markedly improved plasma stability, selective antitumor activity, and moderate antioxidant properties. In this study, we prepared four series of novel NHAPI derivatives and explored their iron chelation activities, anti- or pro-oxidant effects, protection against model oxidative injury in the H9c2 cell line derived from rat embryonic cardiac myoblasts, cytotoxicities to the corresponding noncancerous H9c2 cells, and antiproliferative activities against the MCF-7 human breast adenocarcinoma and HL-60 human promyelocytic leukemia cell lines. Nitro substitution had both negative and positive effects on the examined properties, and we identified new structure-activity relationships. Naphthyl and biphenyl derivatives showed selective antiproliferative action, particularly in the breast adenocarcinoma MCF-7 cell line, where they exceeded the selectivity of the parent compound NHAPI. Of particular interest is a compound prepared from 2-hydroxy-5-methyl-3-nitroacetophenone and biphenyl-4 carbohydrazide, which protected cardiomyoblasts against oxidative injury at 1.8 +/- 1.2 MUM with 24-fold higher selectivity than SIH. These compounds will serve as leads for further structural optimization and mechanistic studies. PMID- 29766722 TI - Effects of Whole-Grain Rice and Wheat on Composition of Gut Microbiota and Short Chain Fatty Acids in Rats. AB - Diets rich in whole grain (WG) cereals bring lower disease risks compared with refined grain-based diets. We investigated the effects of polished rice (PR), refined wheat (RW), unpolished rice (UPR), and whole wheat (WW) on short-chain fatty acids (SCFAs) and gut microbiota in ileal, cecal, and colonic digesta of normal rats. Animals fed with UPR and WW diets exhibited higher total SCFA in cecal and colonic digesta compared with those fed with PR and RW diets. Wheat diets contributed higher total SCFA than rice diets. In cecal and colonic digesta, animals fed with UPR and WW diets demonstrated higher acetate and butyrate contents than those given PR and RW. Firmicutes were the dominant eumycota in rat ileum digesta (>92% abundance). Cecal and colonic digesta were dominated by Firmicutes, Verrucomicrobia, and Bacteroidetes. UPR and WW affected gut microbiota, decreasing the proportion of Firmicutes to Bacteroidetes. SMB53, Lactobacillus, and Faecalibacterium were the main bacterial genera in ileal digesta. Akkermansia was highest in cecal and colonic digesta. In the colonic digesta of rats, the relative abundance of Akkermansia in rats on wheat diets was higher than that in rats on rice diets ( P < 0.05). Thus, UPR and WW could modulate gut microbiota composition and increase the SCFA concentration. Wheat diet was superior to rice diet in terms of intestinal microbiota adjustment. PMID- 29766724 TI - Construction of Polycyclic beta-Ketoesters Using a Homoconjugate Addition/Decarboxylative Dieckmann Annulation Strategy. AB - The construction of arene-fused cyclic beta-ketoesters from 2-iodoaryl esters and 1,1-cyclopropane diesters is detailed. The synthetic method takes advantage of a CuI.SMe2-mediated homoconjugate addition followed by a decarboxylative Dieckmann cyclization to afford valuable polycyclic building blocks. Various iodoaryl esters and 1,1-cyclopropane diesters were evaluated, and the limitations of both reactions are discussed. Several mechanistic probes are detailed and synthetic applications are described. PMID- 29766725 TI - [The prevalence of type 2 diabetes mellitus in patients with autoimmune thyroiditis in hypothyroid stadium]. AB - INTRODUCTION: Autoimmune thyroiditis (AIT) and type 2 diabetes mellitus (DM2T) are the two most common endocrinological diseases worldwide. The relationship between T1DM and autoimmune thyreopathies is known and described, but the relationship between thyreopathies and diabetes type 2 is not clarified sufficiently through that studies manifest increasingly the connection between them. OBJECTIVE: Investigate the prevalence of DM2T in patients with AIT in hypothyroid stadium and compare with common population and investigate a possible association between thyroid and glucose metabolism parameters. MATERIAL AND METHODS: The group consisted of 100 patients (33 men and 67 women) with AIT without until now documented glucose metabolism disorder, average age 65.63 +/- 19.05 years. The control group (CG) consisted of 100 subjects without until now documented thyreopathy and glucose metabolism disorder (37 men and 63 women), average age 63.85 +/- 18.98 years. We realised venous blood sampling and determined thyroidal and glycid metabolism parameters. RESULTS: The study did not confirm higher prevalence of diabetes in patients with AIT [3 (3 %) vs 4 (4 %), p = 1]. There were no statistical significant differences between glycid metabolism parameters in patients with AIT and CG. Also no glycid metabolism parameters correlated to thyroidal parameters. CONCLUSION: We did not confirm higher prevalence of DM in patients with AIT.Key words: autoimmune thyroiditis - diabetes mellitus type 2. PMID- 29766726 TI - [Euthanasia and the good life: why euthanasia is (sometimes) ethical]. AB - In this paper I present the strongest argument, in my opinion, in favour of moral admissibility of euthanasia. In the introduction I briefly mention two important arguments in support of euthanasia - out of respect for autonomy and as a last act of grace, however I refuse them as insufficient. I propose a definition of both forms of assisted death: euthanasia and assisted suicide. I present the basic ideas underlying the theory of the good life and deal with hedonism in greater depth. I define a deprivation concept of the badness of death and, employing hedonism, I specifically describe when death is bad and when it is good. Next I present consequentialism and utilitarianism and show how it is possible to proceed from the reflections on the good life and badness of death toward the concrete normative conclusions about euthanasia. In conclusion I extend my reflections also to other theories of the good life, such as preferentialism or the theory of objective desire and the objective pluralistic theory. The paper arrives at the defense of the thesis that there exist situations in medical practice in which euthanasia presents a morally acceptable choice. Key words: concept of badness of death - consequentialism - deprivation - desire-fulfilment theory - euthanasia - hedonism - preferentialism - utilitarianism. PMID- 29766727 TI - [Human life as goodness: why euthanasia is morally unacceptable]. AB - The current discussion of the moral admissibility or inadmissibility of euthanasia should, in my opinion, consider the greatest possible number of the shared premises of the two opinion camps. That is why I followed a thesis in this paper that the question of the good life is the focus of ethical interest, as this is what connects the advocates and the opponents to euthanasia. In the first part of the paper I critically discuss the two main theories of the good life widely embraced among the advocates of euthanasia: hedonism and desire-fulfilment theory. My focus is to show that both of them are descriptively inadequate, not quite in agreement with the intuitions and ideas that we have about the good life. From this critique I proceed towards the objective theory of full-fledged human development known as the natural law theory. Within this framework I discuss in depth the nature of life as the objective goodness and go over to a brief criticism of utilitarianism, the theory dominating bioethics today; I derive several normative conclusions from the nature of the fundamental goods, leading to the conclusion that an innocent human life cannot be ended under any circumstances. The second part of this paper focuses on the current critique of the medical practice which, as physicians assert, adheres to the norm forbidding to end a patients life, while the actual practice is different. I undertake a detailed analysis of the possibility of distinguishing between the behaviours and classifying them under 1 of 2 categories: causing injury (including termination of life) and allowing injury to happen (including death). I am trying to show that it is possible to make this distinction. In the final part I briefly outline the method of supplying arguments in support of a thesis that there exists a moral asymmetry between the two categories of behaviour, so the moral admissibility of one (letting die) cannot form a basis for the moral admissibility of the other.Key words: allowing harm - consequentialism - desire fulfillment theory - doing harm - euthanasia - hedonism - natural law ethics - preferentialism - utilitarianism. PMID- 29766728 TI - [Euthanasia: legal comparison in selected European countries]. AB - This article deals with the subject of euthanasia (all its forms) and other end of-life decisions, such as assisted suicide, withdrawing and whithholding life sustaining treatments. Among other things, the article will also deal with the issue of the offense of Homicide by the Victims Request. Based on an empirical historical method, the article compares the various selected legal orders. From this analysis, it draws some conclusions that have an impact on ethical discourse. First of all, the terminology is defined in the article, which is very important in this area. Further, German law is being analysed, with emphasis on Nazi Germany. On that basis, the so-called reductio ad Hitlerum argument is rejected. Research continues and is followed by another states, the Netherlands, Belgium and Switzerland. By analysing them, the following ethical arguments used in euthanasia debates are examined: the argument of a slippery slope and the argument of respect for autonomy. Finally, the judgment of the European Court of Human Rights in the Pretty case is also analysed. On this case, we can demonstrate, how insufficient is argument of human dignity. The last part is dedicated to the Czech Republic and its legal order. Firstly, it focuses on the history of the legal regulation of euthanasia, but the main part deals with the current legal situation. In addition to the recent state of affairs, the bill of Death with dignity act is also being examined. At the end of the article it is pointed out that the Czech regulation is insufficient and changes are necessary. However, the proposed bill of Death with dignity act is not the right way to follow. Rather, it may be wise to adopt an amendment to the Penal Code that would introduce the offense of Homicide by the Victims Request.Key words: assisted suicide - euthanasia - Homicide by the Victims Request - medical futility - withdrawing and whithholding life-sustaining treatment. PMID- 29766729 TI - Cardiovascular risk of non-steroidal anti-inflammatory drugs. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) belong to the most widely used drugs. Results of recent large meta-analyses have shown that the cardiovascular risk of NSAIDs is more serious than originally believed and is not associated exclusively with coxibs; it is also increased when using so called traditional NSAIDs. Data obtained to date show the safest drugs of this class in terms of cardiovascular risk are naproxen and ibuprofen at low doses. The position of naproxen as the safest NSAID has been challenged by some more recent findings. The authors examine some results of meta-analyses and conclusions of regulatory agencies.Key words: cardiovascular risk - coxibs - diclofenac - ibuprofen - naproxen - non-steroidal anti-inflammatory drugs. PMID- 29766730 TI - [Splanchnic vein thrombosis]. AB - Splanchnic vein thrombosis (SVT) represents an unusual manifestation of venous thromboembolism. The etiological factors for SVT can be divided into local and systemic, frequently found concurrently. SVT can be the first presenting symptom in myeloproliferative neoplasms. SVT puts the patients affected in jeopardy of developing the intestinal infarction, impairing the liver function and portal hypertension development with the risk of potentially life-threatening gastrointestinal bleeding. The current guidelines emphasise the role of anticoagulation in acute splanchnic thrombosis. Considering the potentially fatal complications it is necessary to tailor the anticoagulant treatment individually. The duration of anticoagulant therapy is strongly dependent upon the risk evaluation of thrombosis recurrence. The article deals with the causes, diagnostic methods and aspects influencing the therapeutic strategy.Key words: anticoagulation - liver cirrhosis - portal hypertension - prothrombotic state - splanchnic vein thrombosis. PMID- 29766731 TI - [Current and prospective biologics and small molecules in the treatment of inflammatory bowel diseases]. AB - Crohns disease (CD) and ulcerative colitis (UC) belong to chronic inflammatory bowel diseases, which are induced by autoimmune processes. While CD is characterized by over-activity of Th1, ILC1, and MAIT cells, UC is mediated by exaggerated activities of Th2 and ILC2 cells and cytokines they produce. Knowledge of the pathogenesis enabled a rational therapy based mostly on biologics and small molecules. TNF is the principal proinflammatory cytokine in both diseases. Anti-TNF monoclonal antibodies, mostly infliximab or adalimumab were therefore introduced to their treatment. Approximately 50-70 % of CD and more than 33 % of UC patients respond to primary treatment only, which resulted in the development of other biologics and small molecules. Out of them, monoclonal antibodies targeting adhesive molecules (vedolizumab, etrolizumab) and p40 chains shared by IL12 and IL23 (ustekinumab) have been already in clinical practice. There are also other small molecules in clinical trials: mongersen, tafacitinib, and ozanimod. Mongersen supports immunosuppressive activity of TGFbeta; it has been tried for the treatment of CD. Tofacitinib inhibits activity of JAK kinases; it was shown to be effective in UC management. Ozanimod interferes with migrations of activated T cells to the site of inflammation and is a promising drug for the UC treatment.Key words: Crohns disease - mongersen - monoclonal antibodies - ozanimod - tofacitinib - ulcerative colitis. PMID- 29766732 TI - [Remission of the disease associated/related with immunoglobulin IgG4 accompanied by multiple lymphadenopathy after treatment with rituximab and dexamethasone: a case report]. AB - A disease associated with immunoglobulin IgG4 is a rare unit with very variable symptoms. We describe the course and treatment of the disease in a patient who presented with multiple lymphadenopathy and infiltrates in the area of the retroperitoneum and pelvis and signs of chronic sclerosing pancreatitis. The disease was clinically manifested by a significant loss of weight, but also by a loss of perception of taste and smell. The diagnosis was made based on a high amount of IgG4 expressing plasma cells in the sampled tissue and an increased concentration of immunoglobulins of type IgG and mainly subclass IG4. Rituximab in 475 mg/m2 dose was used in the treatment, the initial four doses of rituximab were administered at 14-day intervals, always with a one-off administration of a 40 mg dose of dexamethasone. According to FDG-PET/CT, only partial remission of the disease was reached after 4 applications of rituximab and dexamethasone. The patient recovered its sense of smell and taste. In another 4 cycles ritu-ximab was administered on day 1 of a 28-day cycle. On days 1 and 15 of the cycle dexamethasone at 40 mg and cyclophosphamide at 600 mg were administered by intravenous infusion. After the completion of 8 cycles of treatment based on rituximab and dexamethasone and with cyclophosphamide added in the second half of the treatment, the control FDG-PET/CT examination proved the complete remission. Before the treatment commencement the concentration of the subclass of immunoglobulin IgG4 was equal to 51.0 g/l, after the completion of the aforementioned treatment it dropped to 3.5 g/l. The patient tolerated the treatment without any adverse effects. Ritu-ximab, dexamethasone and cyclophosphamide induced the complete remission of this disease.Key words: IgG4 associated/releated disease - rituximab. PMID- 29766733 TI - [Hemophagocytic lymfohistiocytosis in adults: review and case report]. AB - Hemophagocytic lymfohistiocytosis (HLH) is rare, life-threatening condition, characterized by excessive activation of immune system with subsequent proinflammatory state resulting in multiorgan failure. Most frequently, it appears in infancy as a primary disorder caused by mutation of immune-regulatory genes. Increasingly, HLH is being diagnosed as a secondary - adult - form, which occurs as a result of aberrant immune response. Viral or bacterial systemic infections, malignancy with a predominance of lymphoproliferative disorders and autoimmune diseases are the most common triggers. Early diagnosis and initiation of therapy is crucial and increase the chance for recovery. HLH is usually presented as multisystem febrile illness, where an extensive differential diagnosis is needed. Diagnosis of HLH is defined by a combination of clinical and laboratory findings, eventually by a proof of specific mutation. The basic mechanism of therapy is an interruption of aberrant immune response by destruction and suppression of T-lymphocytes function. This is mostly achieved by corticosteroid and etoposide therapy. This review summarizes pathophysiology, diagnostics and therapy of HLH. Furthermore, a case-report of 22-years old patient with secondary HLH being manifested predominantly with acute respiratory failure is presented.Key words: acute respiratory failure - hemophagocytic lymphohistiocytosis - HLH-94 - macrophage activation syndrome - MODS. PMID- 29766734 TI - [More safe anticoagulant treatment - use of idarucizumab (Praxbind(r)): case reports from RE-VERSE AD study and clinical practice]. AB - RE-VERSE AD, a prospective multicentric cohort study, examined the effect of idarucizumab on 2 cohorts of patients anticoagulated with dabigatran - in cohort A in patients with uncontrollable or life threatening bleeding, in cohort B in patients who undergo acute surgery. Within the study patients were intravenously administered 5 g antidote divided into 2 doses per 2.5 g within 15 min to eliminate the anticoagulation effect of dabigatran. A series of case studies is presented to describe the use of idarucizumab within the RE-VERSE AD study and in clinical practice in the period of 2015-2016 at the University Hospital Hradec Kralove. The included examples illustrate the benefit of dabigatran as the only drug so far from the group of direct oral anticoagulants which has an antidote.Key words: antidote - bleeding - dabigatran - direct oral anticoagulants - DOAC - high risk of bleeding - idarucizumab - intervention. PMID- 29766735 TI - [A case of post-intubation tracheal stenosis mimicking bronchial asthma: case report]. AB - Postintubation tracheal stenosis (PITS) is one of the most frequent causes of lower airways obstruction. Usually, PITS is the consequence of prolonged intubation period, but may occur also after short-term intubation. Diagnosis may be difficult if stridor is not present and the post-extubation period is many years long. Bronchoscopy and CT scanning are the diagnostic gold standard. In some cases, lung function tests may also be helpful. Treatment options include conservative treatment, surgery and endoscopic methods. We present a case report of a 23 year old woman with exercise dyspnoea caused by PITS that was incorrectly treated for bronchial asthma during a 2-years long period. Key words: bronchoscopy - cardiopulmonary exercise testing - postintubation stenosis - tracheal stenosis. PMID- 29766736 TI - Spanish Consensus Document on Bariatric Endoscopy. Part 1. General considerations. AB - Obesity is a chronic multifactorial, incurable, recurrent, and progressive disease associated with significant physical and psychological complications, and considerable morbidity and mortality. For this reason, the assessment, management, and follow-up of obese patients should take place in the setting of a multidisciplinary unit equipped with adequate human and structural resources. Medical treatment using hygienic-dietary measures, while indispensable, may be insufficient, and surgery, which is reserved for severe or morbid obesity, is not exempt from complications neither is to the liking of many patients. In this context three situations may be considered where endoscopic treatment, used as a supplementary strategy with few complications, contributes to benefit obese patients: first, in a subgroup of patients with grade-II overweight or non-morbid obesity where medical therapy alone failed or needs supplementation. Second, in patients with morbid obesity when surgery is rejected, is contraindicated, or entails excessive risk. Finally, in patients with superobesity who need to lose weight before bariatric surgery in order to reduce surgery-related morbidity and mortality. In this regard, the Spanish Task Force on Bariatric Endoscopy (Grupo Espanol de Trabajo para el Tratamiento Endoscopico del Metabolismo y la Obesidad, GETTEMO) have developed this Consensus Document to serve as practical guidance for all professionals involved in the endoscopic management of obesity, and to facilitate establishing a minimum set of requirements for the proper functioning of a bariatric endoscopy unit. PMID- 29766737 TI - Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking. AB - AIM: The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants. METHODOLOGY: A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors. CONCLUSION: The virtual screening of commercially available compounds led to the identification of interesting new hit compounds. The most promising hit was confirmed to be a new allosteric inhibitor of wild type and T790M/L858R double mutant EGFR which was able to inhibit the growth of non-small-cell lung cancer cell lines. PMID- 29766739 TI - Lingual Thyroid Carcinoma: A Case Report and Review of Surgical Approaches in the Literature. AB - INTRODUCTION: Lingual thyroid cancer is a rare entity with a paucity of literature guiding methods of surgical treatment. Its location presents anatomic challenges with access and excision. OBJECTIVE: We present a case of T4aN1b classical variant papillary thyroid carcinoma of the lingual thyroid that was removed without pharyngeal entry. We also present a review of the literature of this rare entity and propose a treatment algorithm to provide safe and oncologic outcomes. FINDINGS: Our review of the literature found 28 case reports of lingual thyroid carcinoma that met search criteria. The trans-cervical/trans-hyoid approach was the most frequently used and provides safe oncologic outcomes. This was followed by the transoral approach and then lateral pharyngotomy. Complications reported across the series include 1 case of pharyngocutaneous fistula associated with mandibulotomy and postoperative respiratory distress requiring reintubation or emergent tracheostomy in 2 patients. CONCLUSION: The location of lingual thyroid carcinoma can be variable, and surgical management requires knowledge of adjacent involved structures to decrease the risk of dysphagia and airway compromise. In particular, for cases where there is extensive loss to swallowing mechanisms, laryngeal suspension can allow the patient to resume a normal diet after treatment. PMID- 29766740 TI - Factors Predictive of Postoperative Acute Respiratory Failure Following Inpatient Sinus Surgery. AB - OBJECTIVE: The impact of perioperative risk factors on outcomes following outpatient sinus surgery is well defined; however, risk factors and outcomes following inpatient surgery remain poorly understood. We aimed to define risk factors of postoperative acute respiratory failure following inpatient sinus surgery. METHODS: Utilizing data from the Nationwide Inpatient Sample Database from the years 2010 to 2014, we identified patients (>=18 years of age) with an Internal Classification of Disease, Ninth Revision, Clinical Modification (ICD-9 CM) procedure code of sinus surgery. We used multivariable logistic regression to identify risk factors of postoperative acute respiratory failure. RESULTS: We identified 4919 patients with a median age of 53 years. The rate of inpatient postoperative acute respiratory failure was 3.35%. Chronic sinusitis (57.7%) was the most common discharge diagnosis. The final multivariable logistic regression analysis suggested that pneumonia, bleeding disorder, alcohol dependence, nutritional deficiency, heart failure, paranasal fungal infections, and chronic kidney disease were associated with increased odds of acute respiratory failure (all P < .05). CONCLUSION: To our knowledge, this represents the first study to evaluate potential risk factors of acute respiratory failure following inpatient sinus surgery. Knowledge of these risk factors may be used for risk stratification. PMID- 29766741 TI - Simultaneous Intraoperative Measurement of Cadaver Ankle and Subtalar Joint Compression During Arthrodesis With Intramedullary Nail, Screws, and Tibiotalocalcaneal Plate. AB - BACKGROUND: Suboptimal tibiotalocalcaneal arthrodesis (TTCA) fusion rates may result from inadequate compression that increases motion and interferes with bony bridging. The aim of this study was to evaluate compressive forces at the ankle and subtalar joints with 3 contemporary TTCA constructs. METHODS: Thirty fresh frozen cadaveric lower extremity specimens were divided into 3 groups of 10 each: 3 partially threaded cannulated screws, hindfoot nail, and lateral plate. Specimens were mounted to a testing apparatus, and compression was independently measured at the tibiotalar and talocalcaneal interfaces. Statistical analysis included paired Student t tests, analysis of variance, and Tukey post hoc tests. RESULTS: Mean forces at the ankle joint for the screws, nail, and plate constructs were 331 +/- 86, 479 +/- 137, and 548 +/- 199 N, respectively, with plates providing significantly more compression than screws ( P < .01). Similarly, subtalar compressive forces demonstrated 319 +/- 105 N in the screws group, 466 +/- 125 N, in the nail group, and 513 +/- 181 N in the plate group, with plate compression greater than that achieved with screws ( P < .01). No differences were identified in compression between ankle and subtalar joints within specimens in any group. CONCLUSIONS: Lateral TTCA plates provided increased compressive forces at the ankle and subtalar joint compared with screws only constructs. Hindfoot nails did not demonstrate significant differences in either of these parameters compared with plates or screws in this study. CLINICAL RELEVANCE: Hindfoot nail and lateral plate options should be strongly considered when aiming to maximize compression in patients undergoing TTCA. PMID- 29766743 TI - Inclusive dietetic practice. PMID- 29766742 TI - Wound and Sural Nerve Complications of the Sinus Tarsi Approach for Calcaneus Fractures. AB - : Background The purpose of this study was to evaluate the optimal timing and measures of the sinus tarsi approach for calcaneus fractures to avoid iatrogenic injury of the sural nerve and to assess for wound complications. METHODS: A case series of 53 patients with calcaneus fractures treated by a single surgeon with the sinus tarsi approach was retrospectively analyzed. On the basis of the delay time from injury to surgery, patients were classified into 4 groups: immediate (0 3 days), early (4-6 days), intermediate (7-14 days), and late (14-18 days). All patients were followed for at least 1 year to observe wound conditions. The rate of wound complications and iatrogenic sural nerve injury was described. Incisions were classified into 2 groups: group A included patients with incisions extending posterior to the lateral malleolus, and group B included patients with incisions confined anterior to the lateral malleolus. The rates of nerve injury were compared between both groups. Forty-three patients with 52 Sanders type II fractures were included. RESULTS: The average time to surgery from injury was 8.8 days (range, 0-18 days). The overall postoperative rate of wound complications was 5.8% (3 of 52). In the immediate group, deep infections and wound necrosis were found in 2 of 8 fractures (25%). In the early group, 1 of 15 fractures developed superficial infection (6.7%). In the intermediate and late groups, no wound complication was identified. Iatrogenic sural nerve injury was recorded in 5 of 52 patients (9.6%). Group A had 33% (4 of 12) nerve injuries and group B had 2.5% (1 of 40) ( P = .009). In 70% of cases, a main branch of the sural nerve was directly under the incision. CONCLUSIONS: The sinus tarsi approach was generally effective and safe for calcaneus fractures. However, it was relatively risky to perform open reduction and internal fixation by the sinus tarsi approach within 6 days of injury. Because the sural nerve is in the vicinity of the approach, iatrogenic injury should be avoided by the use of careful planning and meticulous manipulations. Level of Evidence Therapeutic; Level III, comparative study. PMID- 29766744 TI - Psychometric Properties and Factor Structure of the German Version of the Clinician-Administered PTSD Scale for DSM-5. AB - The Clinician-Administered PTSD Scale (CAPS) is a widely used diagnostic interview for posttraumatic stress disorder (PTSD). Following fundamental modifications in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5), the CAPS had to be revised. This study examined the psychometric properties (internal consistency, interrater reliability, convergent and discriminant validity, and structural validity) of the German version of the CAPS-5 in a trauma-exposed sample ( n = 223 with PTSD; n =51 without PTSD). The results demonstrated high internal consistency (alphas = .65-.93) and high interrater reliability (ICCs = .81-.89). With regard to convergent and discriminant validity, we found high correlations between the CAPS severity score and both the Posttraumatic Diagnostic Scale sum score ( r = .87) and the Beck Depression Inventory total score ( r = .72). Regarding the underlying factor structure, the hybrid model demonstrated the best fit, followed by the anhedonia model. However, we encountered some nonpositive estimates for the correlations of the latent variables (factors) for both models. The model with the best fit without methodological problems was the externalizing behaviors model, but the results also supported the DSM-5 model. Overall, the results demonstrate that the German version of the CAPS-5 is a psychometrically sound measure. PMID- 29766745 TI - Incidence of Acute Kidney Injury in Patients Coinfected with HIV and Hepatitis C Virus Receiving Tenofovir Disoproxil Fumarate and Ledipasvir/Sofosbuvir in a Real World, Urban, Ryan White Clinic. AB - Ledipasvir/sofosbuvir (LDV/SOF), an antiviral treatment for hepatitis C virus (HCV), and tenofovir disoproxil fumarate (TDF), an antiretroviral for treating human immunodeficiency virus (HIV), may be coadministered in patients coinfected with these viruses. A drug interaction between LDV and TDF could increase TDF associated nephrotoxicity rates; however, there is minimal clinical evidence describing acute kidney injury (AKI) rates in this population. This study was conducted at a Ryan White-funded facility in Atlanta, Georgia, that cares for over 5,000 patients with AIDS. This retrospective cohort used chart review to assess occurrence of and risk factors for AKI in HIV/HCV-coinfected patients receiving LDV/SOF and antiretroviral therapy (ART). AKI rates were compared between TDF-containing and non-TDF-containing ART groups according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Additional evaluated risk factors for AKI included chronic kidney disease and use of boosted protease inhibitor-based ART. In the 117 included patients, the overall incidence of AKI was 27.3%. AKI occurred more frequently in the non-TDF group (13/86, 15.1% vs. 19/31, 61.3%, p < .001). All AKI was KDIGO stage 1. From multivariable logistic regression, the only independent predictor of AKI was treatment with non-TDF relative to TDF (adjusted odds ratio 6.51, 95% confidence interval 2.34-18.10, p < .001). In this real-world cohort of HIV/HCV-coinfected patients, KDIGO-defined AKI was common, but occurred less frequently in patients receiving TDF-based ART. Our study suggests that patients with normal baseline renal function can be safely treated with TDF and LDV/SOF without significant nephrotoxicity if renal function is closely monitored. PMID- 29766746 TI - Adolescent Victims Emerging From Cyberbullying. AB - Cyberbullying is a pervasive public health issue, affecting 10% to 50% of adolescents and resulting in significant negative health outcomes. Due to the relative newness of cyberbullying, there are many elements of the phenomenon that are not understood. Fifteen adolescents and young adults who had experienced cyberbullying as adolescents, participated in one-on-one, semi-structured interviews. A grounded theory and model, Emerging From Cyberbullying, was constructed to describe the process of being a victim of cyberbullying. The process began by Being Targeted and a cycle of Being Cyberbullied, Losing Oneself, and Attempting to Cope followed. Once out of the cycle, victims could begin the process of Resolving and Finding Oneself. This theory can be used to inform cyberbullying prevention efforts and adolescent providers can utilize this theory to understand the process of being a victim of cyberbullying, promote open discussions with adolescents about cyberbullying, and offer suggestions for effective methods to cope. PMID- 29766738 TI - The Role of Gene Editing in Neurodegenerative Diseases. AB - Neurodegenerative diseases (NDs), at least including Alzheimer's, Huntington's, and Parkinson's diseases, have become the most dreaded maladies because there are no precise diagnostic tools or definite treatments for these debilitating diseases. The increased prevalence and a substantial impact on the social economic and medical care of NDs propel governments to develop policies to counteract the impact. Although the etiologies of NDs are still unknown, growing evidence suggests that genetic, cellular, and circuit alternations may cause the generation of abnormal misfolded proteins, which uncontrolledly accumulate to damage and eventually overwhelm the protein-disposal mechanisms of these neurons, leading to a common pathological feature of NDs. If the functions and the connectivity can be restored, alterations and accumulated damages may improve. The gene-editing tools including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats-associated nucleases (CRISPR/CAS) have emerged as a novel tool not only for generating specific ND animal models for interrogating the mechanisms and screening potential drugs against NDs but also for the editing sequence-specific genes to help patients with NDs to regain function and connectivity. This review introduces the clinical manifestations of three distinct NDs and the applications of the gene-editing technology on these debilitating diseases. PMID- 29766747 TI - A Seat Around the Table: Participatory Data Analysis With People Living With Dementia. AB - The involvement of "people with experience" in research has developed considerably in the last decade. However, involvement as co-analysts at the point of data analysis and synthesis has received very little attention-in particular, there is very little work that involves people living with dementia as co analysts. In this qualitative secondary data analysis project, we (a) analyzed data through two theoretical lenses: Douglas's cultural theory of risk and Tronto's Ethic of Care, and (b) analyzed data in workshops with people living with dementia. The design involved cycles of presenting, interpreting, representing and reinterpreting the data, and findings between multiple stakeholders. We explore ways of involving people with experience as co-analysts and explore the role of reflexivity, multiple voicing, literary styling, and performance in participatory data analysis. PMID- 29766748 TI - Medical Cannabis for Pediatric Moderate to Severe Complex Motor Disorders. AB - A complex motor disorder is a combination of various types of abnormal movements that are associated with impaired quality of life (QOL). Current therapeutic options are limited. We studied the efficacy, safety, and tolerability of medical cannabis in children with complex motor disorder. This pilot study was approved by the institutional ethics committee. Two products of cannabidiol (CBD) enriched 5% oil formulation of cannabis were compared: one with 0.25% delta-9 tetrahydrocannabinol (THC) 20:1 group, the other with 0.83% THC 6:1 group. Patients aged 1 to 17 years (n = 25) with complex motor disorder were enrolled. The assigned medication was administered for 5 months. Significant improvement in spasticity and dystonia, sleep difficulties, pain severity, and QOL was observed in the total study cohort, regardless of treatment assignment. Adverse effects were rare and included worsening of seizures in 2 patients, behavioral changes in 2 and somnolence in 1. PMID- 29766749 TI - Enhanced Sternal Healing Through Platelet-Rich Plasma and Biodegradable Gelatin Hydrogel. AB - Platelet-rich plasma (PRP) contains numerous growth factors and promotes bone fracture healing. The aim of this study was to evaluate the effectiveness of the controlled release of PRP from biodegradable gelatin hydrogel for promoting healing in a rabbit ischemic sternal model. PRP was prepared from the whole blood of a Japanese white rabbit. Sixteen rabbits were randomized into four groups (each n = 4) and all underwent median sternotomy and bilateral internal thoracic artery removal. Before the sternum was closed, the following solutions were applied between the sternum incisions in three of the groups: 30 mg of gelatin hydrogel incorporating 300 MUL of phosphate-buffered saline, 300 MUL of a solution form of PRP, or 30 mg of gelatin hydrogel incorporating 300 MUL of PRP (PRP + Gel). The fourth group acted as a control. Sternal healing was evaluated by histology and microcomputed tomography 7 days after the intervention. The PRP + Gel group showed a significantly higher proportion of fibrosis within the fracture area (an indicator of sternal healing) than the other groups and a significantly higher mean intensity of osteocalcin. These results indicate that the controlled release of PRP from locally applied gelatin hydrogel was markedly effective in enhancing sternal healing in the early postoperative period. This novel therapy could potentially help prevent complications, such as deep sternal wound infection and could result in early postoperative ambulation after median sternotomy. PMID- 29766755 TI - The Role of Maternal Acceptance in Mediating Child Outcomes Among Substance Using Women Experiencing Intimate Partner Violence. AB - Intimate partner violence (IPV) is prevalent in the United States, and many women who experience IPV have children in their care. Substance use is common among this population and affects parenting behaviors such as maternal acceptance and child outcomes. Maternal experience of IPV affects a mother's ability to parent and interact with her child. Little is known about the combined influence of both maternal substance use and IPV on parenting behaviors and child problem behaviors. The current study examined differences in maternal acceptance and child internalizing and externalizing behaviors among mothers who reported experiencing IPV to mothers who never reported experiencing IPV. Results showed that mothers with a history of IPV reported lower rates of maternal acceptance and higher rates of child problem behaviors compared with those with no history of IPV. In addition, frequency of substance use moderated this relationship. This is the first study, to date, to examine the relationship between maternal acceptance and child problem behaviors among substance using mothers with a history of IPV and is a first step to understanding the parenting practices of this population. PMID- 29766752 TI - MRI-Guided Intravenous Alteplase for Stroke - Still Stuck in Time. PMID- 29766754 TI - Antiplatelet Therapy after Ischemic Stroke or TIA. PMID- 29766757 TI - A Comparison of Juror Decision Making in Race-Based and Sexual Orientation-Based Hate Crime Cases. AB - Several constructs have been identified as relevant to the juror decision-making process in hate crime cases. However, there is a lack of research on the relationships between these constructs and their variable influence across victim group. The purpose of the current study was to reexamine factors relevant to the juror decision-making process in hate crime cases within a structural model, and across victim group, to gauge the relative strength and explanatory power of various predictors. In the current study, 313 participants sentenced a perpetrator found guilty of a hate crime committed against either a Black man or a gay man; participants also responded to individual difference measures relevant to mock juror hate crime decision making, including prejudice toward the victim's social group. Using path analysis, we explored the role of juror prejudice on sentencing decisions in hate crime cases as well as similarities and differences based on the victimized group. Results indicated that, when the victim was a Black man, modern racism influenced sentencing both directly and indirectly through perpetrator blame attributions, explaining 18% of the variance in sentencing. In contrast, when the victim was a gay man, modern homophobia did not directly predict sentencing, and the overall model explained only 4% of the variance in sentencing, suggesting variables beyond juror prejudice may be better suited to explain juror decision making in sexual orientation-based hate crimes. The current study suggests that the role of juror prejudice in hate crime cases varies as a function of the victimized group and raises questions about the importance of juror prejudice in the sentencing of hate crime cases, particularly antigay prejudice. The importance of blame attributions, social dominance orientation, and juror beliefs regarding penalty enhancements for hate crime cases, as well as policy implications, are also addressed. PMID- 29766756 TI - Sexual and Nonsexual Homicide in Scotland: Is There a Difference? AB - While a number of previous studies have compared sexual homicides to nonlethal sexual offenses, there have been few studies comparing sexual and nonsexual homicides. This study examines whether sexual homicide offenders differ from nonsexual homicide offenders in Scotland regarding characteristics of the offender, the victim, and the homicide incident. Unlike previous studies, only homicides committed by males against females were examined. Data from a national police database were used to compare 89 male sexual homicide offenders who killed adult females with 306 male nonsexual homicide offenders who had also killed adult females using bivariate and multivariate (logistic regression) analyses. The findings revealed not only some similarities between the two groups, particularly regarding some victim variables, but also significant bivariate and multivariate differences. Sexual homicides appeared to be associated with indicators of instrumentality and sexual deviance. We conclude that sexual homicide offenders might be considered a distinct group of homicide offenders, more similar to sexual offenders than to other homicide offenders. PMID- 29766753 TI - Toxicity of pristine and paint-embedded TiO2 nanomaterials. AB - Little is known on the toxicity of nanomaterials in the user phase. Inclusion of nanomaterials in paints is a common nanotechnology application. This study focuses on the toxicity of dusts from sanding of paints containing nanomaterials. We compared the toxicity of titanium dioxide nanomaterials (TiO2NMs) and dusts generated by sanding boards coated with paints with different amounts of two different types of uncoated TiO2NMs (diameters:10.5 nm and 38 nm). Mice were intratracheally instilled with a single dose of 18, 54 and 162 ug of TiO2NMs or 54, 162 and 486 ug of sanding dusts. At 1, 3 and 28 days post-instillation, we evaluated pulmonary inflammation, liver histology and DNA damage in lung and liver. Pulmonary exposure to both pristine TiO2NMs and sanding dusts with different types of TiO2NMs resulted in dose-dependently increased influx of neutrophils into the lung lumen. There was no difference between the sanding dusts from the two paints. For all exposures but not in vehicle controls, mild histological lesions were observed in the liver. Pulmonary exposure to pristine TiO2NMs and paint dusts with TiO2NMs caused similar type of histological lesions in the liver. PMID- 29766758 TI - Anti-Inflammatory Peptide Attenuates Edema and Promotes BMP-2-Induced Bone Formation in Spine Fusion. AB - Recombinant human bone morphogenic protein-2 (BMP-2)-loaded absorbable collagen sponges (ACS) have been successfully used to enhance bone formation and to induce spinal fusion in humans. However, side effects, such as soft tissue edema and inflammation, have been reported. NEMO binding domain peptide (NBD) inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB), a central regulator of immune response. In this study, we investigated NBD's potential to reduce BMP-2-induced soft tissue inflammation without affecting BMP-2-mediated spinal fusion in rat. For evaluation of soft tissue inflammation, ACS containing BMP-2, BMP-2+NBD, NBD, or ACS only were implanted into intramuscular paraspinal sites of 32 rats. At day 2 postsurgery, edema formation at the implant sites was assessed using magnetic resonance imaging. T2 weighted relaxation time (T2-RT) values were increased in the BMP-2 group compared with BMP-2+NBD, NBD, and ACS groups. No difference in T2-RT values was detected between BMP-2+NBD versus NBD and ACS controls. Postsacrifice, histological analysis of the implant-surrounding zones showed increased mononuclear cell infiltration in the BMP-2 group compared with BMP-2+NBD and controls. The presence of BMP-2 increased relative NF-kappaB binding and gene expression of inflammatory markers, interleukin (IL)1beta, IL6, IL18, and chemokine ligand (CCL)2 and CCL3 compared with controls. In the BMP-2+NBD group, cytokine expression was blocked. No differences were found between BMP-2+NBD and control groups. For evaluation of spinal fusion, posterolateral intertransverse lumbar fusion procedures were performed on 16 rats. ACS were loaded with BMP-2 or BMP-2+NBD. After sacrifice at week 12, microcomputed tomographic assessment of the fusion site detected a higher bone volume and reduced trabecular spacing in the BMP-2+NBD group compared with BMP-2. Histological analysis did not show any differences in newly formed bone microarchitecture. In summary, addition of NBD to BMP-2-loaded ACS reduces BMP-2-induced soft tissue edema formation and mononuclear cell infiltration, diminishes NF-kappaB binding, and thus blocks transcription of NF-kappaB-regulated cytokines in rat. Furthermore, NBD stimulates bone formation in BMP-2-mediated spinal fusion, possibly through crosstalk of the NF-kappaB pathway with other pathways. The results of this study might provide the basis to develop new therapeutic bone grafting approaches with combinatory administration of BMP-2 and NBD for spinal fusion. PMID- 29766751 TI - Overcoming Challenges in Engineering Large, Scaffold-Free Neocartilage with Functional Properties. AB - Although numerous cartilage engineering methods have been described, few report generation of constructs greater than 4 cm2, which is the typical lesion size considered for cell-based therapies. Furthermore, current cell-based therapies only target focal lesions, while treatment of large nonisolated lesions remains an area of great demand. The objective of this study was to scale up fabrication of self-assembled neocartilage from standard sizes of 0.2 cm2 to greater than 8 cm2. Passaged sheep articular chondrocytes were self-assembled into 5 or 25-mm diameter scaffoldless neocartilage constructs. The 25-mm-diameter constructs grew up to 9.3 cm2 (areal scale-up of 23) and possessed properties similar to those of the 5-mm-diameter constructs; unfortunately, these large constructs were deformed and are unusable as a potential implant. A novel neocartilage fabrication strategy-employing mechanical confinement, a minute deadweight, and chemical stimulation (cytochalasin D, TGF-beta1, chondroitinase-ABC, and lysyl oxidase like 2 protein)-was found to successfully generate large (25-mm diameter) constructs with flat, homogeneous morphologies. Chemical stimulation increased collagen content and tensile Young's modulus 140% and 240% in the 25-mm-diameter constructs and 30% and 70% in the 5-mm-diameter constructs, respectively. This study not only demonstrated that exceedingly large self-assembled neocartilage can be generated with the appropriate combination of mechanical and chemical stimuli but also that its properties were maintained or even enhanced. PMID- 29766760 TI - Osteoinduction by Ex Vivo Nonviral Bone Morphogenetic Protein Gene Delivery Is Independent of Cell Type. AB - Ex vivo nonviral gene delivery of bone inductive factors has the potential to heal bone defects. Due to their inherent role in new bone formation, multipotent stromal cells (MSCs) have been studied as the primary target cell for gene delivery in a preclinical setting. The relative contribution of autocrine and paracrine mechanisms, and the need of osteogenic cells, remains unclear. This study investigates the contribution of MSCs as producer of transgenic bone morphogenetic proteins (BMPs) and to what extent the seeded MSCs participate in actual osteogenesis. Rat-derived MSCs or fibroblasts (FBs) were cotransfected with pBMP-2 and pBMP-6 or pBMP-7 via nucleofection. The bioactivity of BMP products was shown through in vitro osteogenic differentiation assays. To investigate their role in new bone formation, transfected cells were seeded on ceramic scaffolds and implanted subcutaneously in rats. Bone formation was assessed by histomorphometry after 8 weeks. As a proof of principle, we also investigated the suitability of bone marrow-derived mononuclear cells and the stromal vascular fraction isolated from adipose tissue for a one-stage gene delivery strategy. Bone formation was induced in all conditions containing cells overexpressing BMP heterodimers. Constructs seeded with FBs transfected with BMP 2/6 and MSCs transfected with BMP-2/6 showed comparable bone volumes, both significantly higher than controls. Single-stage gene delivery proved possible and resulted in some bone formation. We conclude that bone formation as a result of ex vivo BMP gene delivery can be achieved even without direct osteogenic potential of the transfected cell type, suggesting that transfected cells mainly function as a production facility for osteoinductive proteins. In addition, single-stage transfection and reimplantation of cells appeared feasible, thus facilitating future clinical translation of the method. PMID- 29766761 TI - Use of Home- and Community-Based Services in Taiwan's National 10-Year Long-Term Care Plan. AB - We aimed to understand the relationships between care recipients' profiles and home- and community-based services (HCBS use patterns. Data were from the 2010 to 2013 Long-Term Care Service Management System in Taiwan ( N = 78,205). We used latent class analysis and multinomial logistic regression analyses. Three HCBS use patterns were found. Care recipients who lived alone, lived in less urbanized areas, and had instrumental activities of daily living disabilities were more likely to be in the home-based personal care group. Those in the home-based personal and medical care group were more likely than others to have a primary caregiver. Care recipients who had poorer abilities at basic activities of daily living and cognitive function, better household income, and lived in a more urbanized area were more likely to be in the non-personal care multiple services group. The findings suggest that policymakers alleviate barriers to accessing various patterns of HCBS should be encouraged. PMID- 29766759 TI - The Role of Temporal Cues in Voluntary Stream Segregation for Cochlear Implant Users. AB - The role of temporal cues in sequential stream segregation was investigated in cochlear implant (CI) listeners using a delay detection task composed of a sequence of bursts of pulses (B) on a single electrode interleaved with a second sequence (A) presented on the same electrode with a different pulse rate. In half of the trials, a delay was added to the last burst of the otherwise regular B sequence and the listeners were asked to detect this delay. As a jitter was added to the period between consecutive A bursts, time judgments between the A and B sequences provided an unreliable cue to perform the task. Thus, the segregation of the A and B sequences should improve performance. The pulse rate difference and the duration of the sequences were varied between trials. The performance in the detection task improved by increasing both the pulse rate differences and the sequence duration. This suggests that CI listeners can use pulse rate differences to segregate sequential sounds and that a segregated percept builds up over time. In addition, the contribution of place versus temporal cues for voluntary stream segregation was assessed by combining the results from this study with those from our previous study, where the same paradigm was used to determine the role of place cues on stream segregation. Pitch height differences between the A and the B sounds accounted for the results from both studies, suggesting that stream segregation is related to the salience of the perceptual difference between the sounds. PMID- 29766762 TI - Typical visual-field locations enhance processing in object-selective channels of human occipital cortex. AB - Natural environments consist of multiple objects, many of which repeatedly occupy similar locations within a scene. For example, hats are seen on people's heads, while shoes are most often seen close to the ground. Such positional regularities bias the distribution of objects across the visual field: hats are more often encountered in the upper visual field, while shoes are more often encountered in the lower visual field. Here we tested the hypothesis that typical visual field locations of objects facilitate cortical processing. We recorded functional MRI while participants viewed images of objects that were associated with upper or lower visual field locations. Using multivariate classification, we show that object information can be more successfully decoded from response patterns in object-selective lateral occipital cortex (LO) when the objects are presented in their typical location (e.g., shoe in the lower visual field) than when they are presented in an atypical location (e.g., shoe in the upper visual field). In a functional connectivity analysis, we relate this benefit to increased coupling between LO and early visual cortex, suggesting that typical object positioning facilitates information propagation across the visual hierarchy. Together these results suggest that object representations in occipital visual cortex are tuned to the structure of natural environments. This tuning may support object perception in spatially structured environments. NEW & NOTEWORTHY In the real world, objects appear in predictable spatial locations. Hats, commonly appearing on people's heads, often fall into the upper visual field. Shoes, mostly appearing on people's feet, often fall into the lower visual field. Here we used functional MRI to demonstrate that such regularities facilitate cortical processing: Objects encountered in their typical locations are coded more efficiently, which may allow us to effortlessly recognize objects in natural environments. PMID- 29766763 TI - Force feedback delay affects perception of stiffness but not action, and the effect depends on the hand used but not on the handedness. AB - Interaction with an object often requires the estimation of its mechanical properties. We examined whether the hand that is used to interact with the object and their handedness affected people's estimation of these properties using stiffness estimation as a test case. We recorded participants' responses on a stiffness discrimination of a virtual elastic force field and the grip force applied on the robotic device during the interaction. In half of the trials, the robotic device delayed the participants' force feedback. Consistent with previous studies, delayed force feedback biased the perceived stiffness of the force field. Interestingly, in both left-handed and right-handed participants, for the delayed force field, there was even less perceived stiffness when participants used their left hand than their right hand. This result supports the idea that haptic processing is affected by laterality in the brain, not by handedness. Consistent with previous studies, participants adjusted their applied grip force according to the correct size and timing of the load force regardless of the hand that was used, the handedness, or the delay. This suggests that in all of these conditions, participants were able to form an accurate internal representation of the anticipated trajectory of the load force (size and timing) and that this representation was used for accurate control of grip force independently of the perceptual bias. Thus these results provide additional evidence for the dissociation between action and perception in the processing of delayed information. NEW & NOTEWORTHY Introducing delay to force feedback during interaction with an elastic force field biases the perceived stiffness of the force field. We show that this bias depends on the hand that was used for probing but not on handedness. At the same time, both left-handed and right-handed participants adjusted their applied grip force while using either their left or right hands in anticipation of the correct magnitude and timing despite the delay in load force. PMID- 29766764 TI - Local cortical activity of distant brain areas can phase-lock to the olfactory bulb's respiratory rhythm in the freely behaving rat. AB - An important unresolved question about neural processing is the mechanism by which distant brain areas coordinate their activities and relate their local processing to global neural events. A potential candidate for the local-global integration are slow rhythms such as respiration. In this study, we asked if there are modulations of local cortical processing that are phase-locked to (peripheral) sensory-motor exploratory rhythms. We studied rats on an elevated platform where they would spontaneously display exploratory and rest behaviors. Concurrent with behavior, we monitored whisking through electromyography and the respiratory rhythm from the olfactory bulb (OB) local field potential (LFP). We also recorded LFPs from dorsal hippocampus, primary motor cortex, primary somatosensory cortex, and primary visual cortex. We defined exploration as simultaneous whisking and sniffing above 5 Hz and found that this activity peaked at ~8 Hz. We considered rest as the absence of whisking and sniffing, and in this case, respiration occurred at ~3 Hz. We found a consistent shift across all areas toward these rhythm peaks accompanying behavioral changes. We also found, across areas, that LFP gamma (70-100 Hz) amplitude could phase-lock to the animal's OB respiratory rhythm, a finding indicative of respiration-locked changes in local processing. In a subset of animals, we also recorded the hippocampal theta activity and found that occurred at frequencies overlapped with respiration but was not spectrally coherent with it, suggesting a different oscillator. Our results are consistent with the notion of respiration as a binder or integrator of activity between brain regions. PMID- 29766766 TI - Recent advances in objectifying pain using neuroimaging techniques. AB - The pursuit of a physiological indicator of noxious stimulation is desirable as it has the potential to provide mechanistic information regarding acute pain and may ultimately improve pain management strategies. Currently, there are no specific neurophysiological markers of pain to evaluate treatments. Recent attempts to identify neural correlates of pain have focused on different neuroimaging modalities. The purpose of this review is to discuss common neuroimaging techniques and findings thus far. PMID- 29766768 TI - Distinct mechanisms explain the control of reach speed planning: evidence from a race model framework. AB - Previous studies have investigated the computational architecture underlying the voluntary control of reach movements that demands a change in position or direction of movement planning. Here we used a novel task in which subjects had to either increase or decrease the movement speed according to a change in target color that occurred randomly during a trial. The applicability of different race models to such a speed redirect task was assessed. We found that the predictions of an independent race model that instantiated an abort-and-replan strategy was consistent with all aspects of performance in the fast-to-slow speed condition. The results from modeling indicated a peculiar asymmetry, in that although the fast-to-slow speed change required inhibition, none of the standard race models was able to explain how movements changed from slow to fast speeds. Interestingly, a weighted averaging model that simulated the gradual merging of two kinematic plans explained behavior in the slow-to-fast speed task. In summary, our work shows how a race model framework can provide an understanding of how the brain controls different aspects of reach movement planning and help distinguish between an abort-and-replan strategy and merging of plans. NEW & NOTEWORTHY For the first time, a race model framework was used to understand how reach speeds are modified. We provide evidence that a fast-to-slow speed change required aborting the current plan and a complete respecification of a new plan, while none of the race models was able to explain an instructed increase of hand movement speed, which was instead accomplished by a merging of a new kinematic plan with the existing kinematic plan. PMID- 29766765 TI - Control of transitions between locomotor-like and paw shake-like rhythms in a model of a multistable central pattern generator. AB - The ability of the same neuronal circuit to control different motor functions is an actively debated concept. Previously, we showed in a model that a single multistable central pattern generator (CPG) could produce two different rhythmic motor patterns, slow and fast, corresponding to cat locomotion and paw shaking. A locomotor-like rhythm (~1 Hz) and a paw shake-like rhythm (~10 Hz) did coexist in our model, and, by applying a single pulse of current, we could switch the CPG from one regime to another (Bondy B, Klishko AN, Edwards DH, Prilutsky BI, Cymbalyuk G. In: Neuromechanical Modeling of Posture and Locomotion, 2016). Here we investigated the roles of slow intrinsic ionic currents in this multistability. The CPG is modeled as a half-center oscillator circuit comprising two reciprocally inhibitory neurons. Each neuron is equipped with two slow inward currents, a Na+ current ( INaS) and a Ca2+ current ( ICaS). ICaS inactivates much more slowly and at more hyperpolarized voltages than INaS. We demonstrate that INaS is the primary current driving the paw shake-like bursting. ICaS is crucial for the locomotor-like bursting, and it is inactivated during the paw shake-like activity. We investigate the sensitivity of the bursting regimes to perturbations, using a pulse of current to induce a switch from one regime to the other, and we demonstrate that the transition duration is dependent on pulse amplitude and application phase. We also investigate the modulatory roles of the strength of various currents on characteristics of these rhythms and show that their effects are regime specific. We conclude that a multistable CPG is physiologically plausible and derive testable predictions of the model. NEW & NOTEWORTHY Little is known about how a single central pattern generator could produce multiple rhythms. We describe a novel mechanism for multistability of bursting regimes with strongly distinct periods. The proposed mechanism emphasizes the role of intrinsic cellular dynamics over synaptic dynamics in the production of multistability. We describe how the temporal characteristics of multiple rhythms could be controlled by neuromodulation and how single pulses of current could produce a switch between regimes in a functional fashion. PMID- 29766767 TI - Neural architecture: from cells to circuits. AB - Circuit operations are determined jointly by the properties of the circuit elements and the properties of the connections among these elements. In the nervous system, neurons exhibit diverse morphologies and branching patterns, allowing rich compartmentalization within individual cells and complex synaptic interactions among groups of cells. In this review, we summarize work detailing how neuronal morphology impacts neural circuit function. In particular, we consider example neurons in the retina, cerebral cortex, and the stomatogastric ganglion of crustaceans. We also explore molecular coregulators of morphology and circuit function to begin bridging the gap between molecular and systems approaches. By identifying motifs in different systems, we move closer to understanding the structure-function relationships that are present in neural circuits. PMID- 29766769 TI - Movement vigor as a traitlike attribute of individuality. AB - A common aspect of individuality is our subjective preferences in evaluation of reward and effort. The neural circuits that evaluate these commodities influence circuits that control our movements, raising the possibility that vigor differences between individuals may also be a trait of individuality, reflecting a willingness to expend effort. In contrast, classic theories in motor control suggest that vigor differences reflect a speed-accuracy trade-off, predicting that those who move fast are sacrificing accuracy for speed. Here we tested these contrasting hypotheses. We measured motion of the eyes, head, and arm in healthy humans during various elementary movements (saccades, head-free gaze shifts, and reaching). For each person we characterized their vigor, i.e., the speed with which they moved a body part (peak velocity) with respect to the population mean. Some moved with low vigor, while others moved with high vigor. Those with high vigor tended to react sooner to a visual stimulus, moving both their eyes and arm with a shorter reaction time. Arm and head vigor were tightly linked: individuals who moved their head with high vigor also moved their arm with high vigor. However, eye vigor did not correspond strongly with arm or head vigor. In all modalities, vigor had no impact on end-point accuracy, demonstrating that differences in vigor were not due to a speed-accuracy trade-off. Our results suggest that movement vigor may be a trait of individuality, not reflecting a willingness to accept inaccuracy but demonstrating a propensity to expend effort. NEW & NOTEWORTHY A common aspect of individuality is how we evaluate economic variables like reward and effort. This valuation affects not only decision making but also motor control, raising the possibility that vigor may be distinct between individuals but conserved across movements within an individual. Here we report conservation of vigor across elementary skeletal movements, but not eye movements, raising the possibility that the individuality of our movements may be driven by a common neural mechanism of effort evaluation across modalities of skeletal motor control. PMID- 29766773 TI - Effects of a Structured Physical Activity Program on Habitual Physical Activity and Body Composition in Patients With Chronic Kidney Disease and in Kidney Transplant Recipients. AB - OBJECTIVES: In this study, we compared the effects of an individualized physical activity program on lifestyle, metabolic profile, body composition, and quality of life in kidney transplant recipients and patients with chronic kidney disease. MATERIALS AND METHODS: Our study included 24 kidney transplant recipients and 15 patients with chronic kidney disease at stage 3/4. Body composition (impedance spectroscopy) and habitual physical activity (accelerometry) assessed at baseline were used to prepare the individualized physical activity program. Participants received repeated training, which was supervised during the first 2 weeks, followed by short message service reminders. Measurements were repeated after 1 and 3 months. RESULTS: Time spent daily on physical activity and total energy expenditure increased in kidney transplant recipients (from 126 +/- 87 to 200 +/- 132 min/day [P = .001] and from 1.73 +/- 0.37 to 2.24 +/- 0.59 cal/min [P < .001]) and in patients with chronic kidney disease (from 79 +/- 78 to 109 +/- 114 min/day [P < .001] and from 1.5 +/- 0.5 to 1.92 +/- 0.47 cal/min [P < .001]). Adipose mass (40.8 +/- 11.5 vs 38.5 +/- 10.3 kg; P = .01), total body water (38.1 +/- 9.1 vs 37.3 +/- 9.7 L; P = .01), and fat tissue index (14.3 +/- 3.7 vs 13.5 +/- 3.1 kg/m2; P = .009) decreased significantly only in kidney transplant recipients. Body cell mass decreased in patients with chronic kidney disease. Significant changes of estimated glomerular filtration rates were observed in kidney transplant recipients. CONCLUSIONS: Increased physical activity achieved through structured exercise programs induced beneficial effects on metabolic profile and body composition in patients with chronic kidney disease, with even greater benefits in kidney transplant recipients. PMID- 29766774 TI - Factors Associated with Health Care Professionals' Attitude Toward the Presumed Consent System. AB - OBJECTIVES: This paper explores health care professionals' potential attitude toward organ donation if the presumed consent system were to be implemented in Malaysia, as well as factors associated with this attitude. MATERIALS AND METHODS: We used self-administered questionnaires to investigate the attitude of 382 health care professionals from the University of Malaya Medical Center between January and February 2014. The responses were analyzed using logistic regression. RESULTS: Of the 382 respondents, 175 (45.8%) stated that they would officially object to organ donation if the presumed consent system were to be implemented, whereas the remaining 207 (54.2%) stated that they would not object. The logistic regression showed that health care professionals from the Malay ethnic group were more likely to object than those from Chinese (adjusted odds ratio of 0.342; P = .001) and Indian and other (adjusted odds ratio of 0.341; P = .003) ethnic groups. Health care professionals earning 3000 Malaysian Ringgit or below were more likely to object than those earning above 3000 Malaysian Ringgit (adjusted odds ratio of 1.919; P = .006). Moreover, respondents who were initially unwilling to donate organs, regardless of the donation system, were more likely to object under the presumed consent system than those who were initially willing to donate (adjusted odds ratio of 2.765; P < .001). CONCLUSIONS: Health care professionals in Malaysia have a relatively negative attitude toward the presumed consent system, which does not encourage the implementation of this system in the country at present. To pave the way for a successful implementation of the presumed consent system, efforts should be initiated to enhance the attitude of health care professionals toward this system. In particular, these efforts should at most target the health care professionals who are Malay, earn a low income, and have a negative default attitude toward deceased donation. PMID- 29766775 TI - Deceased-Donor Smoking History Is Associated With Increased Recipient Mortality After Kidney Transplant: A Population-Cohort Study. AB - OBJECTIVES: Historical data have suggested that donor smoking is associated with detrimental clinical outcomes for recipients of kidneys from deceased donors. However, the effects of smoking status of a kidney donor on the outcomes of the recipient in a contemporary setting of immunosuppression and transplant practice have not yet been ascertained. MATERIALS AND METHODS: This retrospective, population-cohort study analyzed data of all deceased-donor kidney-alone transplant procedures performed in the United Kingdom between April 2001 and April 2013. Our study included 11?199 deceased-donor kidney allograft recipients, with median follow-up of 46 months posttransplant. RESULTS: In our cohort, 5280 deceased donors (47.1%) had a documented history of smoking. Deceased donors with versus those without smoking history were more likely to be younger (mean age of 48 vs 50 years; P < .001), be of white ethnicity (96.6% vs 95.3%; P < .001), and have brain death before donation (77.1% vs 74.9%; P = .006). On unadjusted survival analyses, overall patient survival was significantly shorter in patients who received kidney allografts from deceased donors with smoking history (hazard ratio of 1.12, 95% confidence interval, 1.00-1.25; P = .044). No significant association was seen for death-censored or overall graft survival. Our multivariate survival analyses showed that, after accounting for confounding factors, the effects of donor smoking status remained significant for patient survival (hazard ratio of 1.16, 95% CI, 1.03-1.29; P =.011) but not graft survival. CONCLUSIONS: This population-cohort study suggests that deceased-donor kidneys from smokers contribute to an increased risk of death for kidney allograft recipients. These study findings imply donor smoking history should be factored into the risk stratification decision for recipient selection to optimize decision making; however, further clarification and validation of these data are warranted. PMID- 29766771 TI - Five-Year Risk of Stroke after TIA or Minor Ischemic Stroke. AB - BACKGROUND: After a transient ischemic attack (TIA) or minor stroke, the long term risk of stroke and other vascular events is not well known. In this follow up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events. METHODS: We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk. RESULTS: A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke. CONCLUSIONS: In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years. (Funded by AstraZeneca and others.). PMID- 29766776 TI - BK Polyomavirus Immune Response With Stress on BK-Specific T Cells. AB - Polyomavirus-associated nephropathy is a pertinent cause of poor renal allograft survival. Absence of defensive immunity toward BK polyomavirus may favor the occurrence of BK polyomavirus-active infection and influence the progression to polyomavirus-associated nephropathy. Humoral immune responses may offer incomplete protection. In this review, available data on both humoral and cellular immunity were examined, with a concentration on BK polyomavirus-specific T cells; in addition, their roles in BK polyomavirus cellular immune response and immunotherapy were discussed. This traditional narrative review used PubMed and Medline searches for English language reports on BK polyomavirus immune response and BK-specific T cells published between January 1990 and November 2017. The search included the key words BK virus, BK polyomavirus, immune and response, and specific T cells. Monitoring BK polyomavirus-specific T cells has both therapeutic and prognostic value. Innovative cellular immunotherapy approaches, including development of vaccinations and infectious recombinant BK polyomavirus, could further contribute to the prevention of BK polyomavirus infection and related diseases. PMID- 29766777 TI - Administering RiaSTAP for Congenital Afibrinogenemia During Liver Transplant. AB - Liver transplant has occasionally been performed in the presence of congenital afibrinogenemia and has been rarely used to treat it. Historically, to safely manage coagulopathy during transplant, these patients have been administered a combination of fresh frozen plasma and cryoprecipitate. In this case report, we discuss the first reported use of recombinant fibrinogen to treat such a patient and the decision-making process considered to balance the thrombotic and hemorrhagic risks. PMID- 29766778 TI - The Effects of Polymorphism on Physicochemical Properties and Pharmacodynamics of Solid Drugs. AB - BACKGROUND: Nowadays, the polymorphism of solid materials plays important roles in pharmaceutical field, food industry, fine chemicals and so on. Due to the differences in crystal structure, different polymorphs of a given solid drug show different physicochemical characteristics, which may lead to different drug bioavailability and half-life of the drug. Studies about polymorphism of solid drugs have become an indispensable important component in dosage form design, approval, production and quality control of drugs. METHODS: In order to reveal the dissimilarity between polymorphs, the classification approach of polymorphism and the features of each category are outlined and discussed in this paper. The influence of polymorphism on physicochemical characteristics of solid drugs such as powder property, melting point, enthalpy of fusion, dissolution behavior and stability are discussed in detail. Furthermore, a variety of differences in drug bioavailability and curative effect of polymorphs are also summarized and discussed. RESULTS: Due to the differences in internal crystalline structure, different polymorphs of the same solid drugs generally show different physicochemical properties, including powder property, melting point, enthalpy of fusion, dissolution behavior and stability. Furthermore, different polymorphs of solid drugs often exert a diverse curative effect. CONCLUSION: As one of the significant factors to affect the quality and curative effect of solid drugs, polymorphism of drug substances has been investigated in the pharmaceutical field for over 50 years. Considerable studies indicate that comprehensive understanding of polymorphism is important for development, dosage form design, approval, production, quality control and curative effect of solid drugs. PMID- 29766779 TI - Technetium-99m-based Radiopharmaceuticals in Sentinel Lymph Node Biopsy: Gynecologic Oncology Perspective. AB - Technetium (99mTc)-radiolabeled colloids are popular tracers used to map lymphatic vessels and regional lymph nodes (LNs). The regional LN status is a significant determinant of cancer stage and patient prognosis, and strongly influences treatment. Regional LN dissection has become a part of surgical treatment. However, not all patients with LN involvement benefit from extensive lymphadenectomy in terms of prolonged survival. Moreover, overtreatment of patients with localized disease carries the unnecessary risk of complications. It is believed that sentinel LN biopsy (SLNB) allows to assess the involvement of the most representative LN of the lymphatic basin and to decide on radical LN dissection.99mTc is an easily available radionuclide emitting gamma rays. The value of 99mTc for diagnostic procedures is associated with its relatively short half-life that makes it safe both for patients and medical personnel. A colloid presenting specific physical and biological properties, including optimal particle size, is a carrier for the radionuclide. When administered at the tumor site, a radiocolloid is absorbed by the lymphatics, and the first LN that it gets trapped in is referred to as the sentinel LN (SLN). The radiopharmaceutical must reach the SLN relatively quickly, but its storage within the SLN, and the radionuclide's half-life must be long enough to enable intraoperative imaging and evaluation. SLNB is currently the gold standard in breast cancer and malignant melanoma diagnosis, and is under extensive investigation in gynecological cancers. Here, we provide a historical perspective of the SLN concept and the clinical relevance of SLNB in gynecologic oncology. Moreover, we review the technical aspects of the application of 99mTc-based radiopharmaceuticals in lymphoscintigraphy and intraoperative lymphatic mapping. PMID- 29766780 TI - Soft Biomaterial-based Nanocrystal in Pharmaceutical. AB - BACKGROUND AND OBJECTIVE: Bio-soft material, a class of derivatives of the natural or synthetic material, is getting more and more prevalent in biomedical researches and applications due to the advantages such as in-vivo biodegradation, good water solubility and designable targeting ability. With the presence of bio soft materials, the drug nanocrystal can be easily generated and aggregated in a feasible process. Given the promising application of the bio-soft material in biological and chemical research, it is valuable to discuss the crucial step in designing bio-soft materials and analyze the emerging properties of bio-soft materials. METHODS: A comprehensive literature survey in the field of bio-soft material development and analysis has been conducted. The collected data and figures were meticulously analyzed and interpreted. RESULTS: In this review, the details of bio-soft materials based nanocrystal were demonstrated in three sections with respect to different materials. In each section, the pros and cons for each bio-soft material and its derivatives were elaborately listed and discussed. CONCLUSION: The review enables an insightful discussion about the properties and the applications of existing biosoft material. It may contribute to the further researches about bio-soft material development and analysis. PMID- 29766781 TI - Similar and Distinct Mechanisms in the Protective Processes of Upper and Lower Gastrointestinal Tract. AB - Gastrointestinal (GI) mucosal integrity is based on the balance of aggressive and protective mechanisms. Mucosal damage may occur when the injurious factors become dominant or the mucosal defensive processes are impaired. The main target of the therapy against GI mucosal injury is the reduction of aggressive factors, however, the therapeutic possibilities for stimulation of mucosal defensive processes are rather limited. This overview focuses on the gastric and intestinal mucosal protective mechanisms and discusses the main targets that increase protective processes and increase the mucosal resistance to injurious stimuli at pre-epithelial, epithelial and sub-epithelial levels. PMID- 29766782 TI - Role of Oxidative Stress in Diabetic Retinopathy and the Beneficial Effects of Flavonoids. AB - Diabetic Retinopathy (DR) is one of the leading causes of decreased vision and blindness in developed countries. Diabetes-induced metabolic disorder is believed to increase oxidative stress in the retina. This results in deleterious change through dysregulation of cellular physiology that damages both neuronal and vascular cells. In this review, we first highlight the evidence of potential metabolic sources and pathways which increase oxidative stress that contribute to retinal pathology in diabetes. As oxidative stress is a central factor in the pathophysiology of DR, antioxidants therapy would be beneficial towards preventing the retinal damage. A number of experimental studies by our group and others showed that dietary flavonoids cause reduction in increased oxidative stress and other beneficial effects in diabetic retina. We then discuss the beneficial effects of the six major flavonoid families, such as flavanones, flavanols, flavonols, isoflavones, flavones and anthocyanins, which have been studied to improve retinal damage. Flavanoids, being known antioxidants, may ameliorate the retinal degenerative factors including apoptosis, inflammation and neurodegeneration in diabetes. Therefore, intake of potential dietary flavonoids would limit oxidative stress and thereby prevent the retinal damage, and subsequently the development of DR. PMID- 29766783 TI - Role of Formyl Peptide Receptors in Gastrointestinal Healing. AB - The wound healing and the barrier restoration of the gastrointestinal (GI) mucosa must be continuously ensured to allow homeostasis of the gastrointestinal tract and of all the surrounding tissues. Several lines of the evidence report a key role of innate immunity, and in particular of Pattern Recognition Receptors (PRRs), in controlling the homeostasis of GI tract by sensing commensal and pathogen bacteria, activating the immune response and regulating epithelial repair, thus guaranteeing the morphological and functional recovery of the injured tissue. We will discuss the role of a particular class of PRRs - the Formyl Peptide Receptors - in the homeostasis of GI mucosa. We here report the results of studies that strongly suggest the possibility that the activation of FPRs is crucial in the maintenance of homeostasis of the GI tract and provide indications of the potential clinical relevance of new treatment regimens involving FPR modulation for several GI disorders. PMID- 29766784 TI - Polyphenols, their Metabolites and Derivatives as Drug Leads. AB - In this non-comprehensive review, the potential of natural polyphenols as lead compounds for the design and synthesis of new molecules with potential application in several diseases was highlighted. Organic synthesis has been essential for the development of new analogues of naturally found polyphenols, providing a wide range of structural modifications for structure-activity relationship studies and improving or modulating the biological activity of the promising compounds. PMID- 29766770 TI - MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. AB - BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .). PMID- 29766785 TI - Pharmaceutical Strategies for Stabilizing Drug Nanocrystals. AB - BACKGROUND: Nanocrystallization technologies have been widely studied in recent years, as the formulation of drug nanocrystals solves problems of poor drug solubility and bioavailability. However, drug nanocrystals in the size range of 1 1000 nm usually need to be accompanied by stabilizers, such as polymers or surfactants, to enhance their stability. Despite their simplicity, improved dissolution rate, and enhanced bioavailability, the limited stability of nanocrystal formulations has prevented further development. OBJECTIVE: The most effective way to handle this instability is to use stabilizers. This paper reviews various factors to consider for the production of stable drug nanocrystals and provides suggestions to overcome the problems associated with instability, such as aggregation and Ostwald ripening. Through various examples of stabilizers acting via electrostatic and steric stabilization, this review highlights the scope of enhancing the stability of drug nanocrystals. CONCLUSION: Studies on stabilizers used in the production of drug nanocrystals are ongoing; various factors, such as the effect of zeta potential on the stability of drug nanosuspensions, have already been revealed. However, it is necessary to determine the most appropriate stabilizer experimentally based on the various mechanisms and factors have been reviewed since the possible interactions between each drug and stabilizer are diverse. PMID- 29766786 TI - Nanocrystals: The Preparation, Precise Control and Application Toward the Pharmaceutics and Food Industry. AB - Crystallization is a significant process employed to produce a wide variety of materials in pharmaceutical and food area. The control of crystal dimension, crystallinity, and shape is very important because they will affect the subsequent filtration, drying and grinding performance as well as the physical and chemical properties of the material. This review summarizes the special features of crystallization technology and the preparation methods of nanocrystals, and discusses analytical technology which is used to control crystal quality and performance. The crystallization technology applications in pharmaceutics and foods are also outlined. These illustrated examples further help us to gain a better understanding of the crystallization technology for pharmaceutics and foods. PMID- 29766788 TI - Microbial Genetic Screens for Monitoring Protein Misfolding Associated with Neurodegeneration: Tools for Identifying Disease-Relevant Genes and for Screening Synthetic and Natural Compound Libraries for the Discovery of Potential Therapeutics. AB - Neurodegenerative Diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of highthroughput assays for the identification of cellular factors and processes that are important mediators of NDassociated proteotoxicities. In addition, such systems have facilitated the discovery of synthetic and natural compounds with the ability to rescue the misfolding and the associated pathogenic effects of aggregation-prone proteins associated with NDs. This review outlines such available systems in bacteria and yeast, whose usage will likely accelerate the pre-clinical discovery process for effective drugs against a variety of NDs with high socioeconomic impact. PMID- 29766787 TI - Nanocrystal Technology as a Strategy to Improve Drug Bioavailability and Antitumor Efficacy for the Cancer Treatment. AB - BACKGROUND AND OBJECTIVE: Nanocrystal technology is an effective approach which can increase the dissolution rate of poorly water-soluble drugs by raising their saturation solubility, thus improving the drug bioavailability. With the development of nanocrystals, its preparation approaches have gradually matured, which can be generally divided into Bottom-up, Top-down and Combinative technologies. METHODS: A systematic literature review in the field of nanocrystal technology for the cancer treatment was scanned and collected data was detailedly analyzed and summarized. RESULTS: Over the past decade, several anticancer drug nanocrystals have been explored and evaluated in preclinical studies and clinical trials. This review mainly covers the utilizations of the nanocrystal technology in enhancing the saturation solubility of anticancer drugs associated with the increased bioavailability and anticancer efficacy. Preparation methods and characterizations of nanocrystals are also introduced in brief. In addition, one critical step in the formation of drug nanocrystals is selecting suitable stabilizers for the system. Many types of research are heading towards the role of the stabilizers in the final nanocrystals formulation. So we summed up several commonly used stabilizers in order to give a reference to the further study. At last, we discussed some considerations raised by the application of nanocrystal drugs for cancer treatment. CONCLUSION: This review is likely to enable a detailed insight on nanocrystal technology as a strategy to improve drug bioavailability and antitumor efficacy for the cancer treatment and be of particular interest to pharmaceutical industry. PMID- 29766789 TI - Metabolomics: A High-throughput Screen for Biochemical and Bioactivity Diversity in Plants and Crops. AB - Plants and crops contain a staggering diversity of compounds, many of which have pharmacological activity towards a variety of diseases. These properties have been exploited by traditional and modern medicine providing important sources of healthcare to this day. The contribution of natural products (such as plant derived) to the modern pharmacopeia is indeed significant; however, the process of identifying novel bioactive compounds from biological sources has been a central challenge in the discovery of natural products. The resolution of these challenges relied extensively on the use of hyphenated Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR)-based analytical technologies for the structural elucidation and annotation of novel compounds. Technical developments in instrumentation and data processing have fostered the development of the field of metabolomics which provides a wealth of tools with the huge potential for application in the process of drug/bioactive discovery from plant tissues. This manuscript provides an overview of the metabolomics toolbox available for the discovery of novel bioactive compounds and the integration of these tools in the bioprospection and drug discovery workflows. PMID- 29766790 TI - MALT Lymphoma, Stress Ulcer and Cholinergic Nerves from the Viewpoint of Bilateral and Unilateral Truncal Vagotomy and Substance P. AB - BACKGROUND: Vagal nerve plays an important role in the stomach function. The cholinergic nerves are the most abundantly distributed nerves in the gastric tissue. It has recently been reported that the vagal nerve is significantly related to both gastric cancer development and progression. However, its relation to the mesenchymal tumor, including MALT lymphoma, is not known. In this study, we investigated the effect of unilateral truncal vagotomy on gastric MALT lymphoma development by using Helicobacter heilmannii-infected mouse model as well as that of bilateral truncal vagotomy on stress-induced ulcer formation. METHODS: In the first part of this study, the distribution of the cholinergic nerves in the rat gastric mucosa and the effect of bilateral truncal vagotomy, as well as various kinds of agents acting on autonomic nerves in rats, were investigated by the histochemical and macroscopic method. In the second part, we employed MALT lymphoma formation in C57BL/6NCrl mice that were infected with Helicobacter heilmannii. A total of 38 infected mice underwent unilateral vagotomy under microscopy. The mice were randomized into 4 groups from which samples were collected; 2, 3, 4 and 6 months after infection. Both the anterior and posterior sides of the stomachs were sampled from each mouse for pathological and immunohistochemical analyses. RESULTS: The bilateral truncal vagotomy significantly suppressed the restraint-induced gastric ulcer formation in rats, while bethanechol, and 6-hydroxydopamine led to an increase of the gastric ulcer formation. In the unilateral truncal vagotomy study using MALT lymphoma, the thickness of the gastric mucosa was reduced in the vagotomized side compared to the non-vagotomized side. Furthermore, the gastric MALT lymphoma was more prominently found in the vagotomized anterior side of stomach compared with that in the non-vagotomized posterior side of stomach. Substance P-immunoreactive nerves markedly increased surrounding the MALT lymphoma and the neurokinin-1 receptor immunoreactive lymphocytes increased within the MALT lymphoma in the vagotomized side. In conclusion, vagotomy enhanced gastric MALT lymphoma development possibly through the substance P-neurokinin-1 receptor pathway. PMID- 29766792 TI - GABAA receptors: Various stoichiometrics of subunit arrangement in alpha1beta3 and alpha1beta3epsilon receptors. AB - GABAA receptors are members of the Cys-loop family of ligand-gated ion channels which mediate most inhibitory neurotransmission in the central nervous system. These receptors are pentameric assemblies of individual subunits, including alpha1-6, beta1-3, gamma1-3, delta, epsilon, pi, theta and rho1-3. The majority of receptors are comprised of alpha, beta and gamma or delta subunits. Depending on the subunit composition, the receptors are located in either the synapses or extrasynaptic regions. The most abundant receptors are alpha1betagamma2 receptors, which are activated and modulated by a variety of pharmacologically and clinically unrelated agents such as benzodiazepines, barbiturates, anaesthetics and neurosteroids, all of which bind at distinct binding sites located within the receptor complex. However, compared to alphabetagamma, the binary alphabeta receptors lack a benzodiazepine alpha-gamma2 interface. In pentameric alphabeta receptors, the third subunit is replaced with either an alpha1 or a beta3 subunit leading to two distinct receptors that differ in subunit stoichiometry, 2alpha:3beta or 3alpha:2beta. The consequence of this is that 3alpha:2beta receptors contain an alpha-alpha interface whereas 2alpha:3beta receptors contain a beta-beta interface. Apart from the replacement of gamma by alpha1 or beta3 in binary receptors, the incorporation of epsilon subunit into GABAA receptors might be more complicated. As the epsilon subunit is not only capable of substituting the gamma subunit, but also replacing the alpha/beta subunits, receptors with altered stoichiometry and different pharmacological properties are produced. The different subunit arrangement of the receptors potentially constructs novel binding sites which may become new targets of the current or new drugs. PMID- 29766791 TI - Immunometabolic changes in hepatocytes arising from obesity and the practice of physical exercise. AB - Over the recent years, a particular interest was shown towards understanding the roles of excessive hepatic fat accumulation and the development of obesity related diseases. While hepatic triacylglycerol accumulation seems to be a response to the systemic increase of insulin release, fatty acid metabolites contribute to the progression of non-alcoholic fatty liver disease (NAFLD) to non alcoholic steatohepatitis (NASH). It is widely accepted that NAFLD is a polygenic and multifactorial disease under the influence of critical behavioral factors such as overeating and sedentary lifestyles. The progression of the disease is proposed to include the accumulation of lipids in hepatocytes, but liver damage would be mainly initiated through an exaggerated activation of the immune system. This inflammatory response would be triggered by the increase in cytokine production followed by TLR-4 activation and NF-kB pathways. Interestingly, cytokines as IL-1ra, IL-4, IL-6 and IL-10 acts as anti-inflammatory in response to exercise and thus, could play an important role in the restoration liver functions in diseased conditions. Strategies of healthy life behaviors including nutrition and regular physical exercise are recommended to counteract the dreadful effects of NAFLD. To beyond the classical effect of exercise for increasing energy expenditure and/or inducing negative energy balance, exercise also prevents and reverses the effects of disorders related to the immunometabolic profile. This suggests that exercise prescription may be an attractive alternative for the prevention of obesity and NAFLD. Thus, this review seeks to shed light on the inflammatory pathways regulating the beneficial effects of physical activity on obesity and NAFLD. We will clarify how physical activity intervenes to normalize inflammatory processes and prevent obesity and NAFLD. Finally, the exercise interventions should be individualized to facilitate behavioral and cognitive strategies in order to promote long-term adherence. A multidisciplinary approach including lifestyles, diet and exercise training interventions is considered as a "best practice" and displays the strongest liver benefits when it occurs simultaneously with weight loss. PMID- 29766794 TI - Chitosan-coated C-phycocyanin Liposome for Extending the Neuroprotective Time Window Against Ischemic Brain Stroke. AB - The time window for neuroprotection during ischemic brain stroke is short, and hence, development of neuroprotectants is critical to extend this time window. This study sought to verify if muco-adhesive chitosan coating improves the neuroprotective potential of the pre-proven C-Phycocyanin-pertaining liposome (C Pc liposome). The use of chitosan-coated liposomes extended the neuroprotective time window by 6 h after occlusion, and further improved the neuroprotection efficiency of the C-Pc liposome in a rat Middle Cerebral Artery Occlusion (MCAO) model. Beneficial changes in mRNA expressions of antioxidants, inflammatory cytokines and glia scar proteoglycans were evident in the C-Pc liposomes. In addition, in the cultured astrocytes, the chitosan- coated C-Pc liposome expressed anti-oxidative activity without cytotoxicity. PMID- 29766793 TI - Engineering of Microbial Cell Factories for the Production of Plant Polyphenols with Health-Beneficial Properties. AB - Polyphenols form a group of important natural bioactive compounds with numerous ascribed healthbeneficial attributes (e.g. antioxidant, anti-inflammatory, anti microbial and tumor-suppressing properties). Some polyphenols can also be used as natural dyes or plastic precursors. Notwithstanding their relevance, production of most of these compounds still relies on extraction from plant material, which for most of it is a costly and an inefficient procedure. The use of microbial cell factories for this purpose is an emerging alternative that could allow a more efficient and sustainable production. The most recent advances in molecular biology and genetic engineering, combined with the ever-growing understanding of microbial physiology have led to multiple success stories. Production of multiple polyphenolic compounds or their direct precursors has been achieved not only in the common production hosts, such as Escherichia coli and Saccharomyces cerevisiae, but also in Corynebacterium glutamicum and Lactococcus lactis. However, boosting production of native compounds or introduction of heterologous biosynthetic pathways also brings certain challenges, such as the need to express, balance and maintain efficient precursor supply. This review will discuss the most recent advances in the field of metabolic engineering of microorganisms for polyphenol biosynthesis and its future perspectives, as well as outlines their potential health benefits and current production methods. PMID- 29766795 TI - Carboxymethyl-hexanoyl Chitosan Nanodroplets for Ultrasonic Imaging and Drug Delivery to Tumor. AB - INTRODUCTION: Although a great many strategies have been proposed for tumor targeted chemotherapy, current delivery methods of anticancer drugs present limited success with inevitable systemic toxicity. The aim of this study was to develop a new kind of theranostic carrier for targeted tumor therapy. METHODS: Prior to prepare CHC-PFP-DOX, carboxymethyl-hexanoyl chitosan (CHC) was synthesized by acylation of carboxymethyl chitosan. To develop CHC-PFP, perfluoropentane (PFP), an ultrasound gas precursor, was simultaneously encapsulated into the hydrophobic inner cores of pre-formulated CHC micelle in aqueous phase via using the oil in water (O/W) emulsion method. The size distribution and surface charges of these nanodroplets were measured and the morphology was observed by transmission electron microscopy (TEM). For ultrasound imaging application, in vitro model was established to evaluate the imaging of CHC-PFP-DOX under different concentration and mechanical index. After that, the anti-tumor effect of ultrasound combined with CHC-PFPDOX on ovarian cancer cells was investigated. RESULTS: The resulting CHC-PFP-DOX had a nano-sized particle structure, with hydrophobic anticancer DOX/PFP inner cores and a hydrophilic carboxymethyl chitosan polymer outer shell. The favorable nano-scaled size offers the potential to extravagate from veins and accumulate in tumor tissues via enhanced permeation and retention (EPR) effect. Additionally, CHC-PFP-DOX showed the ability to serve as ultrasound imaging agent at body temperature. Notably, it exhibited an ultrasound-triggered drug release profile through the external ultrasound irradiation. Further study demonstrated that ultrasound combined with CHC-PFP-DOX can improve the killing effect of chemotherapy for tumor. CONCLUSION: CHC-PFP-DOX holds great promise in simultaneous cancer-targeting ultrasound imaging and ultrasound- mediated delivery for cancer chemotherapy. PMID- 29766796 TI - Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure. AB - BACKGROUND: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium spp., we previously identified tyrosine betaine as a major constituent. METHODS: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies. RESULTS: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 uM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). CONCLUSIONS: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Abeta levels and, accordingly, with a higher risk for the onset of Alzheimer's disease. PMID- 29766797 TI - Anti-aging and Anti-aggregation Properties of Polyphenolic Compounds in C. elegans. AB - Polyphenols constitute a group of compounds that have been highly investigated for their beneficial effects against various pathologic and non-pathologic conditions and diseases. Among their multi-faceted properties, their anti-oxidant potential nominates them as ideal protective candidates for conditions characterized by elevated levels of oxidative stress, including aging and age related diseases. The nematode Caenorhabditis elegans is a multicellular model organism that is highly exploited in studies related to aging and age-associated pathologies. In this review, we will summarize studies where polyphenolic compounds have been tested for their anti-aging potential and their protective role against the progression of age-related diseases using C. elegans as their main model. PMID- 29766798 TI - High Level of Menaquinone-7 Production by Milking Menaquinone-7 with Biocompatible Organic Solvents. AB - BACKGROUND: The effect of milking menaquinone-7 (MK-7) with biocompatible organic solvents on MK-7 production in B. subtilis fermentation was studied. Periodic milking of MK-7 from the fermentation medium by n-hexane significantly enhanced the total MK-7 production ~ 1.7 fold at the end of 72 hours of fermentation (p < 0.05) as compared to the control medium. METHODS: Milking of MK-7 with a mixture of n-hexane phase modified with n-butanol was also explored. Although milking of MK-7 by a mixture of n-hexane and n-butanol (1:2, v/v), was found to be appropriate in terms of high extraction capacity, no significant increase in total MK-7 concentration was observed. Biocompatibility between the extraction solvents and B. subtilis was also examined. RESULTS AND CONCLUSION: The results indicated that the mixture of n-hexane and n-butanol exhibited some detrimental effects. However, n-hexane alone exhibited delayed toxicity starting at 84 hours of periodic milking and could, therefore, be considered as the most promising organic solvent for milking MK-7 in B. subtilis fermentation while enhancing the productivity of the system. PMID- 29766799 TI - Anticancer Activity of an Oplopanax elatus Stem Extract and Biologically Active Isolated Compounds. AB - BACKGROUND AND METHODS: Oplopanax elatus (Nakai) Nakai is used in folk medicine in China. In this study, the antiproliferative activity of an O. elatus fraction extracted by ethyl acetate (EF) was tested on human breast cancer MCF-7 cells, human colon cancer HCT-116 cells, and human stomach cancer AGS cells. The potential mechanism of antiproliferation was also investigated using an apoptosis assay. RESULTS: The results showed that the EF remarkably suppressed proliferation of human breast, stomach, and colon cancer cells. Further apoptosis tests by flow cytometry and immunoblot analyses showed the EF inhibited HCT-116 cell proliferation by inducing apoptosis. The bioassay-monitored fractionation of the EF resulted in the isolation of two polyacetylenes, falcarindiol (compound 1) and oplopandiol (compound 2), with falcarindiol possessing the strongest antiproliferative activity in colon cancer cells. CONCLUSION: Together, this study evaluated the anticancer activity of an O. elatus extract against human cancer cells, and provided the basis for further development of this herbal extract for the treatment of cancer. PMID- 29766800 TI - Antifungal Activity, Gas Chromatographic-Mass Spectrometric Analysis And in silico Study of Punica Granatum Peel Extracts Against Fluconazole Resistant Strains of Candida Species. AB - AIMS: Candida species is the common cause of opportunistic fungal infections all over the world with increased mortality and morbidity especially in immunosuppressed patients. Fluconazole is the first line therapy for candidiasis. The antifungal resistance pattern in high-risk patients is a major concern. The present study was aimed to assess the anticandidal activity of Punica granatum peel against fluconazole resistant Candida species isolated from HIV patients. MATERIALS & METHODS: Ethanol, chloroform, petroleum ether and aqueous extracts of the peel of P. granatum were evaluated against standard strains of Candida spp. and fluconazole resistant clinical isolates by agar diffusion and broth dilution techniques. The GC-MS analysis of the extracts was performed to identify the phytochemicals present in it. The predominant phytochemical was subjected to molecular docking study to determine its binding efficacy with lanosterol 14 alpha demethylase. RESULTS: P. granatum peel extracts showed excellent anticandidal activity with ethanol extract exhibiting the most inhibitory activity. C. albicans and C. krusei were the most inhibited and C. parapsilosis was the least inhibited species. The GC-MS analysis of the ethanol extract identified five predominant phytochemicals. On docking studies, the five phytochemicals showed a good binding to the lanosterol 14-alpha demethylase. CONCLUSION: The present study is the first report on the antifungal activity of various extracts of P. granatum against fluconazole resistant Candida isolates. Ethanol extract of P. granatum peel showed excellent anticandidal activity against fluconazole resistant Candida spp. Hence, it can be explored further to identify a potential drug candidate. PMID- 29766801 TI - Naringenin and its Nano-formulations for Fatty Liver: Cellular Modes of Action and Clinical Perspective. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease mainly caused by high-fat diets and sudden feed changes, vitamin and energy deficiency, and inflammatory processes. Fatty liver leads to cirrhosis, hepatocellular carcinoma as well as liver failure. Lifestyle-modifying such as weight loss and a healthy diet have an inverse correlation with the risk of fatty liver. The promising effect of a diet rich in vegetables and fruits against fatty liver has been evidenced by several empirical studies focused on flavonoids. Among naturally occurring flavonoids, naringenin is one of the most important flavonoids which can be isolated from some edible fruits, especially citrus species. METHODS: In the present review, we discuss the effects of naringenin and its nano-formulations against fatty liver disease and the proposed molecular mechanism of action. A large number of studies attributed to naringenin anti-inflammatory, antioxidant and insulin-like actions, as well as different types of effects on sex hormone metabolism and lipid metabolism. Naringenin loaded nanoparticles have been used to solve the limited stability, solubility, bioavailability and pharmacological activity of naringenin and, consequently, to improve its therapeutic effects. RESULTS AND DISCUSSION: Naringenin exerts diverse biological actions including the decrease of biomarkers of lipid peroxidation and protein carbonylation, increase of antioxidant defenses, scavenging of reactive oxygen species and modulation of signaling pathways related to fatty acid metabolism which can favor the oxidation of fatty acid, lower lipid accumulation in the liver and thereby prevent fatty liver. PMID- 29766802 TI - Endoplasmic Reticulum Stress Related Molecular Mechanisms in Nonalcoholic Fatty Liver Disease (NAFLD). AB - Non-alcoholic fatty liver disease (NAFLD) is a common public health issue and is considered a main drive for liver diseases. However, the basic mechanisms that trigger the development of NAFLD still remain somewhat elusive. Endoplasmic reticulum (ER) stress facilitates the unfolded protein response (UPR) and contributes to the etiology of steatosis, nonalcoholic steatohepatitis and ultimately hepatocarcinoma. Although ER stress may lead to a cascade of compensatory responses that help to restore ER homeostasis, cell survival and adaptation, prolonged ER stress is known to impose detrimental pathological outcome, involving insulin resistance, ectopic fat deposition, inflammation, apoptosis, and dysregulated autophagy. All of these processes are capable of provoking the onset and development of NAFLD. To this end, it is pertinent to understand the role of ER stress in the onset and progression of NAFLD for proper management of this devastating metabolic disease. Here in this review, we will summarize available information on the recent advances in the potential role for ER stress in the etiology of NAFLD. PMID- 29766803 TI - The Chemistry and Biological Effects of Thioflavones. AB - Thioflavone derivatives are the thio analogs of the core constituent of the natural product class of flavones. Based on the position and oxidation level of sulfur, they can be divided into three major categories: 4-thioflavones, 1 thioflavones and 1-thioflavones 1,1-dioxide. In recent years, great efforts have been made to develop an approach for the synthesis of thioflavones, especially 1- thioflavones with high functional group compatibility, high yields, low toxicity as well as proceeding under a mild condition, and a variety of synthetic protocols have been developed, the method of choice being dependent on the nature of substrates. As isosteric analogs of biologically active flavones, thioflavones also exhibit various pharmaceutical properties, such as antimicrobial, anticancer and neuroprotective activities. Replacement of the oxygen atom on flavone skeleton by a sulfur atom resulted in modified biological effects due in most part to the change of the structural properties. However, these varying effects depend on the substituents present and the test species. To provide a comprehensive vision of this class of compounds, this review primarily focuses on the structure, synthetic methods, biological properties as well as structure activity relationships of thioflavones. PMID- 29766804 TI - Cyclophilin A: A Predictive Biomarker of Carotid Stenosis in Cerebral Ischemic Stroke. AB - BACKGROUND: Cyclophilin A plays a pathogenic role in the development and progression of atherosclerosis, which can be assessed by measuring carotid intima media thickness. The primary aim of this study was to examine the interaction between plasma Cyclophilin A level and carotid intima-media thickness in patients with acute ischemic stroke. METHOD: Plasma concentration of Cyclophilin A was measured on admission in 66 consecutive patients who had been hospitalized for acute cerebral stroke and in 52 case-control subjects without a history of acute stroke. Subjects in both groups also underwent ultrasound B-mode imaging to measure the mean and maximum intima-media thickness of the carotid artery. Inflammatory biomarkers including high-sensitivity C-reactive protein and fibrinogen were also assessed. RESULTS: We found that the plasma concentration of Cyclophilin A was significantly higher in patients with acute ischemic stroke (p = 0.042). Increased Cyclophilin A was also correlated with carotid intima-media thickness in the patient group (p < 0.001). Among the risk factors for cerebral stroke examined in this study, only hypertension was significantly associated with plasma Cyclophilin A level. CONCLUSION: Increased plasma Cyclophilin A levels might be involved in the pathophysiology of acute ischemic stroke and Cyclophilin A might serve as a biomarker in risk assessment of acute stroke patients. PMID- 29766805 TI - A Novel Neuroimaging Model to Predict Early Neurological Deterioration After Acute Ischemic Stroke. AB - OBJECTIVE: In acute ischemic stroke, early neurological deterioration (END) may occur in up to one-third of patients. However, there is still no satisfying or comprehensive predictive model for all the stroke subtypes. We propose a practical model to predict END using magnetic resonance imaging (MRI). METHOD: Patients with anterior circulation infarct were recruited and they underwent an MRI within 24 hours of stroke onset. END was defined as an elevation of >=2 points on the National Institute of Health Stroke Scale (NIHSS) within 72 hours of stroke onset. We examined the relationships of END to individual END models, including: A, infarct swelling; B, small subcortical infarct; C, mismatch; and D, recurrence. RESULTS: There were 163 patients recruited and 43 (26.4%) of them had END. The END models A, B and C significantly predicted END respectively after adjusting for confounding factors (p=0.022, p=0.007 and p<0.001 respectively). In END model D, we examined all imaging predictors of Recurrence Risk Estimator (RRE) individually and only the "multiple acute infarcts" pattern was significantly associated with END (p=0.032). When applying END models A, B, C and D, they successfully predicted END (p<0.001; odds ratio: 17.5[95% confidence interval: 5.1- 60.8]), with 93.0% sensitivity, 60.0% specificity, 45.5% positive predictive value and 96.0% negative predictive value. CONCLUSION: The results demonstrate that the proposed model could predict END in all stroke subtypes of anterior circulation infarction. It provides a practical model for clinical physicians to select high-risk patients for more aggressive treatment to prevent END. PMID- 29766806 TI - Increased Serum Total Bile Acids can be Associated with a Small Hematoma Volume and Decreased Clinical Severity During Acute Intracerebral Hemorrhage. AB - BACKGROUND: The impact of Total Bile Acids (TBA) level on clinical outcomes after acute Intracerebral Hemorrhage (ICH) is still not understood. OBJECTIVE: We investigated whether admission TBA level is associated with hematoma volume, stroke clinical severity, and 3-month outcomes in acute ICH patients. METHODS: A total of 335 ICH patients were prospectively enrolled. Patients were divided into four groups, according to the quartiles of serum TBA level at the time of admission. Three-month outcomes were evaluated by interviews with patients or their family members. RESULTS: The median hematoma volumes for the quartiles of TBA level (Q1 to Q4) were 12.0, 12.3, 10.0, and 6.7 mL (P<0.001) and the median National Institutes of Health Stroke Scale (NIHSS) scores were 8, 8, 6, and 5 (P=0.002), respectively. In the adjusted models, patients in the highest quartile (Q4) had smaller hematoma volumes (P=0.039) and lower NIHSS scores (P=0.037) than patients in Q1. At three months follow-up, there were 136 patients with poor outcomes (defined as having modified Rankin Scale scores>=3) and 46 cases of all cause deaths. TBA level was not significantly associated with poor outcome nor all-cause death after adjusting for age, sex, hematoma volume, and baseline NIHSS(all P-trend>=0.380). CONCLUSIONS: Higher admission TBA was associated with smaller hematoma volume and decreased clinical severity, but not three month outcomes in patients with acute ICH. PMID- 29766807 TI - First Total Synthesis of omega-Phenyl Delta6 Fatty Acids and their Leishmanicidal and Anticancer Properties. AB - INTRODUCTION: The first total synthesis of omega-phenyl Delta6 fatty acids (FA) and their cytotoxicity (A549) and leishmanicidal (L. infantum) activities are described. The novel 16-phenyl-6-hexadecynoic acid (1) and the known 16 phenylhexadecanoic acid (2) were synthesized in 7-8 steps with overall yields of 46 % and 41 %, respectively. The syntheses of the unprecedented 10-phenyl-6 decynoic acid (3), 10-cyclohexyl-6-decynoic acid (4) and 10-(4-methoxyphenyl)-6 decynoic acid (5) was also performed in 3 steps with 73-76 % overall yields. The use of lithium acetylide coupling enabled the 4-step synthesis of 10-phenyl-6Z decenoic acid (6) with a 100 % cis-stereochemistry. The cytotoxicity of these novel FA was determined against A549 cells and L. infantum promastigotes and amastigotes. Among the omega-phenylated FA, the best cytotoxicity towards A549 was displayed by 1, with an IC50 of 18 +/- 1 MUM. On the other hand, among the C10 acids, the omega-cyclohexyl acid 4 presented the best cytotoxicity (IC50 = 40 +/- 2 MUM) towards A549. RESULTS: Based on caspase-3/7 studies neither of the FA induced apoptosis in A549, thus implying other mechanisms of cell death. CONCLUSION: The antileishmanial studies were performed with the top Leishmania donovani topoisomerase IB (LdTopIB) inhibitors, namely 1 and 2 (EC50 between 14 and 36 MUM, respectively), acids that did not stabilize the cleavage complexes between LdTopIB and DNA. Acids 1 and 2 displayed cytotoxicity towards L. infantum amastigotes (IC50 = 3-6 MUM) and L. infantum promastigotes (IC50 = 60- 70 MUM), but low toxicity towards murine splenocytes. Our results identified 1 as the optimum omega- phenylated acid of the series. PMID- 29766809 TI - Associations between Depressive Disorders and Inflammatory Rheumatic Diseases. AB - Depressive disorders, are not only common but also among the leading causes of disability worldwide. They are associated with increased incidences of various other diseases. It has been shown that in patients with autoimmune diseases, when depression coexists, the quality of life is worse and medical treatment and management is compromised. Depression-like symptoms, such as fatigue and disinterest are also common in inflammatory rheumatic diseases and often associated with poor quality of life. Medical therapy targeting inflammation results in alleviation of these symptoms in many patients. Interestingly, there is cumulating evidence suggesting potential roles of inflammatory cytokines in the pathogenesis of major depression. Effects of some of the biological agents used in rheumatic diseases have been studied on depressive disorders. Results have been controversial and further studies are needed in this area. These findings suggest associations between depression and inflammatory rheumatic diseases and raise the possibility that treatment of one of them might influence the outcome of the other. We have reviewed the current literature on associations between depression and inflammatory rheumatologic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome and ankylosing spondylitis. PMID- 29766808 TI - A Review on Plant Antimicrobials of Past Decade. AB - As per WHO reports, about three-quarters (65-80%) of the world's population seek plants or plant-derived natural products for various diseases. The slow discovery of new synthetic molecules and rising resistance in microbes against existing ones has triggered an alarm for speeding up the development process for new molecules. Traditional system(s) of medicine and plant resources has been foresighted again by researchers to circumvent the situation. This review represents various plant genera which, either as a whole plant or their parts, have been reported possessing antimicrobial properties during the last decade. Before 2007, literature is already well cited in various books and reviews. PMID- 29766810 TI - Mst1: Function and Mechanism in Brain and Myocardial Ischemia Reperfusion Injury. AB - Mammalian STE20-like kinase-1 (Mst1) is a generally expressed apoptosis-promoting kinase and a key bridgebuilder of apoptotic signaling in the etiology of tissue injury. Despite the fact that the biological function of Mst1 and its role in the cell's signalling network have yet to be determined, however, there is a lot of evidence that Mst1 plays an important role in cell death which results from tissue injury. Previous studies have shown that Mst1 is not only a target for some apoptosis- related molecules such as caspase 3 and P53, but also act as an activator of these proteinases to magnify apoptosis signal pathways. This article reviews the role of Mst1 in the signaling pathways which is related with the neuronal cell apoptosis or microglia activation following myocardial and brain injury. Therefore, this work contributes to better understanding of the pathological process of myocardial and brain injury. PMID- 29766811 TI - P2X7 Receptor-Associated Programmed Cell Death in the Pathophysiology of Hemorrhagic Stroke. AB - Hemorrhagic stroke is a life-threatening disease characterized by a sudden rupture of cerebral blood vessels, and cell death is widely believed to occur after exposure to blood metabolites or subsequently damaged cells. Recently, programmed cell death, such as apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis, has been demonstrated to play crucial roles in the pathophysiology of stroke. However, the detailed mechanisms of these novel kinds of cell death are still unclear. The P2X7 receptor, previously known for its cytotoxic activity, is an ATP-gated, nonselective cation channel that belongs to the family of ionotropic P2X receptors. Evolving evidence indicates that the P2X7 receptor plays a pivotal role in central nervous system pathology; genetic deletion and pharmacological blockade of the P2X7 receptor provide neuroprotection in various neurological disorders, including intracerebral hemorrhage and subarachnoid hemorrhage. The P2X7 receptor may regulate programmed cell death via (I) exocytosis of secretory lysosomes, (II) exocytosis of autophagosomes or autophagolysosomes during formation of the initial autophagic isolation membrane or omegasome, and (III) direct release of cytosolic IL-1beta secondary to regulated cell death by pyroptosis or necroptosis. In this review, we present an overview of P2X7 receptor- associated programmed cell death for further understanding of hemorrhagic stroke pathophysiology, as well as potential therapeutic targets for its treatment. PMID- 29766812 TI - Switching dipeptidyl peptidase-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 improves arterial stiffness evaluated by cardio-ankle vascular index in patients with type 2 diabetes: a pilot study AB - BACKGROUND: We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in type 2 diabetes mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients. METHODS: Nineteen T2DM patients who had received DPP 4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin. RESULTS: At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), ? glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (?CAVI), baseline serum levels of AGEs were significantly higher in the low ?CAVI group (high responder) than in the high one (low responder). ?AST and ?GTP were positively correlated with ?CAVI. CONCLUSION: The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin. PMID- 29766813 TI - Coreceptor Tropism and Maraviroc Sensitivity of Clonally Derived Ethiopian HIV-1C Strains Using an in-house Phenotypic Assay and Commonly Used Genotypic Methods. AB - OBJECTIVES: Genotypic Tropism Testing (GTT) tools are generally developed based on HIV-1 subtype B (HIV-1B) and used for HIV-1C as well but with a large discordance of prediction between different methods. We used an established phenotypic assay for comparison with GTT methods and for the determination of in vitro maraviroc sensitivity of pure R5-tropic and dual-tropic HIV-1C. METHODS: Plasma was obtained from 58 HIV-1C infected Ethiopians. Envgp120 was cloned into a luciferase tagged NL4-3 plasmid. Phenotypic tropism was determined by in house method and the V3 sequences were analysed by five GTT methods. In vitro maraviroc sensitivity of R5-tropic and dual-tropic isolates were compared in the TZMbl cell line. RESULTS: The phenotypes were classified as R5 in 92.4% and dual tropic (R5X4) in 7.6% of 79 clones. The concordance between phenotype and genotype ranged from 64.7% to 84.3% depending on the GTT method. Only 46.9% of the R5 phenotypes were predicted as R5 by all GTT tools while R5X4 phenotypes were predicted as X4 by four methods, but not by Raymond's method. All six tested phenotypic R5 clones, as well as five of six of dual tropic clones, showed a dose response to maraviroc. CONCLUSION: There is a high discordance between GTT methods, which underestimates the presence of R5 and overestimates X4 strains compared to a phenotypic assay. Currently available GTT algorithms should be further improved for tropism prediction in HIV-1C. Maraviroc has an in vitro activity against most HIV-1C viruses and could be considered as an alternative regimen in individuals infected with CCR5-tropic HIV-1C viruses. PMID- 29766814 TI - Effect of beta-D-mannuronic acid (M2000) on oxidative stress enzymes' gene using healthy donor peripheral blood mononuclear cells for evaluating the anti-aging property. AB - OBJECTIVE: This research aimed to study the anti-aging and anti-inflammatory effects of low and high doses of the beta-D-mannuronic (M2000) on gene expression of enzymes involved in oxidative stress (including SOD2, GST, GPX1, CAT, iNOS, and MPO) in peripheral blood mononuclear cells (PBMCs) of healthy donors under in vitro conditions. METHODS: The PBMCs were separated and the RNAs were then extracted and the cDNAs synthesized, and expression levels of the mentioned genes were detected by qRT-PCR. RESULTS: Our results indicated that the high dose of this drug could significantly reduce the expression level of the SOD2 gene compared to the lipopolysaccharide (LPS) group (p < 0.0001). Moreover, it was found that the high dose of this drug could significantly decrease the expression level of the GST gene compared to the LPS group (p < 0.0001). However, no significant reductions were observed in expression levels of the CAT and GPX1 genes compared to the LPS group. Furthermore, our data revealed that the level of iNOS and MPO gene expression was significantly reduced, in both doses of M2000, respectively, compared to the LPS group (p < 0.0001). CONCLUSION: This research showed that M2000 as a novel NSAID with immunosuppressive properties could modify oxidative stress through lowering expression levels of the SOD2, GST, iNOS, and MPO genes compared to the healthy expression levels, with a probable reduction of the risk of developing inflammatory diseases related to age and aging. PMID- 29766815 TI - Old and New Treatments for Pediatric Autoimmune Hepatitis. AB - BACKGROUND: Autoimmune hepatitis is a rare inflammatory disease of the liver that most frequently affects children and young adults. It is a multifactorial disease of unknown etiology, characteristically progressive in nature, and if left untreated, may lead to cirrhosis and terminal liver failure. It has been known for several decades now that immunosuppressive treatment convincingly alters the outcome of most patients with autoimmune hepatitis and as such it should be started as soon as diagnosis is made. Primary goals of treatment are: normalization of hepatocellular function, extinction of the hepatic necroinflammatory process, and maintenance of a stable remission, thus preventing progression to cirrhosis and its complications. This article aims to review old and new treatments for this rare chronic disorder, from the oldest and most frequently used treatment consisting of the association of prednisone and azathioprine, to alternative medical treatments, liver transplant and promising medical strategies currently under investigation. RESULT AND CONCLUSION: The review will focus on the efficacy and safety profile of each drug, as well as on the published clinical experience with them in pediatric patients with autoimmune hepatitis. PMID- 29766816 TI - A Systematic Review of the Literature of the Three Related Disease Entities Cheilitis Granulomatosa, Orofacial Granulomatosis and Melkersson - Rosenthal Syndrome. AB - BACKGROUND AND OBJECTIVE: Melkersson Rosenthal syndrome (MRS) is a rare disorder of unknown etiology and comprises the triad: orofacial edema, recurrent facial paralysis and lingua plicata. In the current literature confusing heterogeneity exists, mixing together the historically grown terms cheilitis granulomatosa or granulomatous cheilitis, Melkersson Rosenthal syndrome and the umbrella term Orofacial Granulomatosis (OFG). METHODS: We provide a systematic review comprising all three disease entities of orofacial granulomatosis using the computerized database "Pubmed Medline" entering the keywords "orofacial granulomatosis" (141 references), "Melkersson-Rosenthal syndrome" (207 references), "granulomatous cheilitis" or "cheilitis granulomatosa" (102 references) back to 1956. Full-text journals and case studies were included, and data synthesis was performed individually. RESULTS: Etiology remains unclear for all three disease entities. Etiological relatedness to chronic inflammatory bowel disease is under discussion and effectiveness was found for different treatments, e.g. local triamcinolone injections, antibiotics, surgical interventions, TNF alpha blockers or exclusive enteral nutrition. No randomized controlled trial concerning the therapy of orofacial granulomatosis was found. As a consequence, the therapeutic conclusion is drawn mainly from small case series, thus limiting the evidence of therapeutic interventions. CONCLUSION: OFG with the sub-entities MRS and cheilitis granulomatosa is an etiological obscure disease process with various possible therapeutic interventions potentially alleviating the disease course but to broaden treatment knowledge further study in randomized controlled trials is needed. PMID- 29766817 TI - Characteristics and Outcomes of Patients with Anti-Glomerular Basement Membrane Antibody Disease and Anti-Neutrophil Cytoplasmic Antibodies. AB - BACKGROUND: It is unclear whether patients with anti-glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCA), so called "double-positive" (DP), have a different clinical presentation and outcome compared to patients with anti-GBM antibody disease alone. This study describes the clinical and histologic characteristics as well as the patient and renal outcomes of DP patients at the University of Washington compared to patients with anti-GBM antibody disease alone. Methods: Adults admitted to the University of Washington and Harborview Medical Centers from 2000 to 2016 who had a kidney biopsy showing anti-GBM disease characterized by crescentic glomerulonephritis with strong linear staining of glomerular basement membranes for IgG by immunofluorescence were included. Subjects were classified into anti-GBM or DP based on serologic testing. Information on demographics, clinical presentation, biopsy findings, initial treatment, and rates of relapse and patient and renal survival were collected. Continuous and categorical variables were analyzed using the Mann-Whitney U and Fisher's exact tests, respectively. Results: There were 6 anti-GBM and 7 DP patients. Two patients were lost to follow-up after one year. There was no significant difference in clinical presentation or outcomes between the two groups. Two DP patients had greater than 50% global glomerulosclerosis. All the subjects developed ESRD. Two DP patients had a relapse while off immunosuppression. Two patients in each group died within 5 years of diagnosis. Conclusion: Two DP patients in our cohort had a relapse within 5 years of diagnosis. Multicenter studies are needed to determine whether DP patients have a higher relapse rate and need prolonged immunosuppression. PMID- 29766818 TI - Cell-Free Fetal DNA: A Novel Biomarker for Early Prediction of Pre-eclampsia and Other Obstetric Complications. AB - : Hypertensive disorder of pregnancy, especially Pre-eclampsia is one of the major causes of increased maternal and perinatal morbidity and mortality all over the world. Early prediction of pre-eclampsia is the need of modern obstetrics, as this can timely prevent the progress of disease as well as related fetal and maternal morbidity and mortality. In addition to the screening of fetal aneuploidies, Rhesus-D status, fetal sex, single gene disorders, the cell-free fetal Deoxyribonucleic acid (DNA) quantification has emerged out as a promising biomarker for prediction of pre-eclampsia. Hence, its use can help in the early prediction of hypertensive disorders of pregnancy, especially pre-eclampsia even before the appearance of symptoms. Furthermore, in future, it can also help in the determination of the complete DNA sequence of every gene of the fetus. The present review focuses on recent literature concerning the use of cell-free fetal DNA in early prediction of pre-eclampsia as well as for non-invasive prenatal genetic screening of fetus for various disorders. METHODS: The recent literature related to cell-free fetal DNA was searched from numerous English language journals and published peer-reviewed articles on Pubmed, Google Scholar, MEDLINE and various government agencies till 2016. PMID- 29766819 TI - Synthesis, In silico Molecular Docking and Pharmacokinetic Studies, In vitro Antimycobacterial and Antimicrobial Studies of New Imidozolones Clubbed with Thiazolidinedione. AB - BACKGROUND: A series of (E)-5-(4-((Z)-4-substitutedbenzylidene-2-thienylmethylene 5-oxo- 2-phenyl-4,5-dihydro-1H-imidazol-1-yl) benzylidene)thiazolidine-2,4-diones were synthesized and evaluated for antimycobacterial and antimicrobial activity. All these ligands were docked against protein (InhA) Enoyl-ACP reductase of the type II fatty acid syntase (FAS-II) system, (PDB ID: 4COD). OBJECTIVE: In this report, we have designed and synthesized azole scaffolds with good antitubercular activities as there is a real need to develop new candidates with less toxicity and more efficiency toward pathogen. The obtained antimycobacterial activity data have been validated in the terms of ligand-protein interaction and were also analyzed for ADME properties to determine their potential to build up as good oral drug candidates. METHODS: All the synthesized compounds have been established by elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. In vitro antimycobacterial activity was carried out against (M. tuberculosis) H37Rv strain using Lowenstein-Jensen medium and antimicrobial activity against two gram positive bacteria (S. aureus, S. pyogenes), two gram-negative bacteria (E. coli, P. aeruginosa) and three fungal species (C. albicans, A. niger, A. clavatus) using the broth microdilution method. In silico molecular docking studies were carried out using Glide (grid-based ligand docking) program incorporated in the Schrodinger molecular modeling package by Maestro 11.0 and ADME properties of synthesized compounds was performed using DruLito software. RESULTS: Compounds 3a, 3b, 3d, 3g, 3i and 3n exhibited promising antimicrobial activity whereas compound 3n showed very good antimycobacterial activity along with Gilde docking score (-8.864) and with the one violation in Lipinski's rule of five. CONCLUSION: The wet lab result for compound 3n along with Glide XP docking score and the calculated ADME parameters give the best choice for the preparation of new derivatives in order to improve antitubercular activity in future with more improved potency. PMID- 29766820 TI - Salient Aspects of PBP2A-inhibition; A QSAR Study. AB - BACKGROUND: Inhibition of penicillin binding protein 2A (PBP2A) represents a sound drug design strategy in combatting Methicillin resistant Staphylococcus aureus (MRSA). Considering the urgent need for effective antimicrobials in combatting MRSA infections, we have developed a statistically robust ensemble of molecular descriptors (1, 2, & 3-D) from compounds targeting PBP2A in vivo. METHODS: 37 (training set: 26, test set: 11) PBP2A-inhibitors were submitted for descriptor generation after which an unsupervised, non-exhaustive genetic algorithm (GA) was deployed for fishing out the best descriptor subset. Assignment of descriptors to a regression model was accomplished with the Partial Least Square (PLS) algorithm. At the end, an ensemble of 30 descriptors accurately predicted the ligand bioactivity, IC50 (R = 0.9996, R2 = 0.9992, R2 a = 0.9949, SEE =, 0.2297 Q2 LOO = 0.9741). RESULTS AND CONCLUSION: Inferentially, we noticed that the overall efficacy of this model greatly depends on atomic polarizability and negative charge (electron) density. Besides the formula derived, the high dimensional model also offers critical insights into salient cheminformatics parameter to note during hit-to-lead PBP2A-antagonist optimization. PMID- 29766821 TI - Docking and 3D QSAR Studies on Substituted Cyclobutylphenyl Quinoline Derivatives as Inhibitors of Bacterial DNA Gyrase. AB - BACKGROUND: Docking and 3D QSAR studies were performed on Inhibitor of Bacterial DNA gyrase to develop a predictive Common Pharmacophore Hypothesis (CPH). Molecular interaction and binding affinities of these analogues, differing with nucleotides and amino acids are studied are performed. METHODS: Biological activity is predicted by QSAR approach by relating the set of compounds. QSAR study was applied using PHASE, the docking studies were performed using Glide module and Prime/MM-GB/SA is used for free energy ligand binding calculations. RESULTS: We obtained high pred_r2 value (pred_r2= 0. 9239), suggesting a significant external predictive ability of the QSAR model. Mutant docking score is -9. 023. In Wild type docking it shows lower binding energy and binding affinity is a decrease so, docking score of wild most dock 26 molecule is - 6.093. Protein shows various sites for molecular interaction, so from MM-GBSA. CONCLUSION: In the present study, development of predictive hypothesis (CPH) for 4-substituted cyclobutylphenyl quinoline derivatives and CPH were generated and results were interpreted on a developed model containing five features gives good and predictive statistical significance. Docking studies explained hydrogen bonding, pi-pi stacking with deoxy-ribonucleotide and with Ala 1120 and positive charge with deoxyribonucleotide. MM-GBSA explains the binding affinity of most docked ligand with protein. PMID- 29766823 TI - Analysis of Toxicity Effects of Buspirone, Cetirizine and Olanzapine on Human Blood Lymphocytes: in Vitro Model. AB - BACKGROUND: The current study investigates the cytotoxicity mechanism of common drugs with piperazine ring such as cetirizine, olanzapine and buspirone on human lymphocytes. METHODS: The viability of lymphocytes, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, lysosomal integrity, content of glutathione and lipid peroxidation was determined. RESULTS: Buspirone and cetirizine showed more toxicity than olanzapine on human lymphocytes with an IC50 value of 200 ug/ml, after 6 h of incubation. Significant ROS formation, MMP collapse, lipid peroxidation, lysosomal damage and elevation of glutathione disulfide (GSSG) were observed in treated lymphocytes concentrations (4, 20, 40 ug/ml) of buspirone and cetirizine. CONCLUSION: Our results show the exposure of human lymphocytes with buspirone and cetirizine, which usually happens during the poisoning, triggers oxidative stress and organelle damages. Our study suggests that using antioxidants, mitochondrial and lysosomal protective agents can protect blood lymphocytes, from probable side effects of these highly consumed medications. PMID- 29766822 TI - 2, 5-Disubstituted Phthalimides: Design, Synthesis and Anticonvulsant Activity in scPTZ and MES Models. AB - INTRODUCTION: In this study, fifteen new 2,5-disubstituted analgouges of phthalimide were designed and synthesized using the appropriate synthetic route to evaluate anticonvulsant activity against the Maximal Electroshock (MES) and subcutaneous Pentylenetetrazole (scPTZ) compare to phenytoin as a positive control. The structures of the synthesized compounds were confirmed by FTIR, H NMR, C-NMR and MASS spectroscopy. METHODS: All the tested compounds were found to be effective in the PTZ model at dose of 60 mg/kg and most of the compounds showed protection against MES test indicative of their ability to inhibit the seizure spread at all dose ranges. Compound 3 illustrated the best efficacy among all compounds and showed more potency than phenytoin in clonic seizure and was potent as phenytoin in tonic seizure. RESULTS & DISCUSSION: Using a model of the Na channel, these derivatives were docked in the active site. Docking studies displayed that all synthesized compounds have more negative binding energy compare to reference drug and inhibition-constant less than phenytoin that means they can block the receptor more efficiently and usually form hydrophobic interactions or hydrogen bond interaction frequently with the domains I, II, III and rarely with domain IV. PMID- 29766825 TI - Anti-glioma effects of Caffeic acid phenethyl ester and Dasatinib combination therapy in an in vivo rat glioma model. AB - BACKGROUND: Caffeic acid phenethyl ester and Dasatinib in combination, when used in congruous proportions and durations, present an antitumor potential for glioma in vitro, suggesting a high therapeutic potential for glioma treatment. OBJECTIVE: In the present study, we addressed the question whether CAPE and Dasatinib target multiple pathways involved in tumor growth, proliferation and development on an in vivo rat model of glioma. METHODS: Expression analysis of proteins thought to be mediating proliferation, cell motility, angiogenesis, and invasion was carried out to delineate the antineoplastic action of CAPE and Dasatinib. RESULTS: CAPE and Dasatinib modulates the expression of proteins having potential interactive crosstalk with major oncogenic pathways involved in glioma progression. Our results showed that combination treatment modulates the expression of p53 in group co-administered with CAPE and Dasatinib after glioma induction in comparison to group induced with glioma only. EGFR and PCNA expression were significantly altered in the co-treated group in comparison to the glioma-induced group. The effects of CAPE and Dasatinib treatment were further evaluated on AKT pathway by Western blot analysis, the co-treated group showed a significant reduction in expression of AKT. The histopathological analysis further backed the antiproliferative and anti invasive effects of CAPE and Dasatinib. CONCLUSION: This study in totality suggests that the combinational therapy remarkably reduces the proliferation of glioma cells in vivo, suggesting that CAPE and Dasatinib therapy could be exploited for the management of gliomas without showing drug-related resistances and side effects, suggesting a high therapeutic potential of the therapy in glioma. PMID- 29766824 TI - Adipose-derived Mesenchymal Stem Cells in the Treatment of Obesity: A Systematic Review of Longitudinal Studies on Preclinical Evidence. AB - BACKGROUND: Obesity is an increasing global health problem, but its treatment is not yet optimal, especially in the long term. For this reason, preclinical studies have been conducted relating to a new therapeutic strategy for obesity based on adipose-derived mesenchymal stem cells (AD-MSCs). The aim of our systematic review is to summarize these findings deriving from the animal model in order to establish whether there is sufficient evidence to justify going forward to clinical studies. METHODS: Literature searches, study selection, methods and quality appraisal were performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were collated using a narrative approach. RESULTS: Of the 578 articles retrieved, seven studies met the inclusion criteria, and their analysis revealed several main findings. There was a strong evidence of the positive effect of AD-MSCs in obesity treatment in terms of body weight, glucose metabolism homeostasis, lipid profiles, non-alcoholic fatty liver disease and systemic inflammation. Moreover, there was recent evidence from a few studies for a significant effect of AD-MSCs transplantation on the improvement of obesity-related hormonal status, (i.e., leptin) and body composition patterns, though these investigations may need further replication. CONCLUSION: The effects of AD-MSCs transplantation on obesity, in terms of weight loss and obesityrelated diseases, are promising in animal models. In the future, further well-designed studies should be performed to understand the mechanism of action and to overcome some methodological limitations such as the small sample sizes and risk of bias evidenced in our systematic review, before moving forward to assess AD-MSCs as a potential strategy for human obesity management. PMID- 29766827 TI - Pain-Related Behavior and Brain Activation in a Cynomolgus Macaque Model of Postoperative Pain. AB - BACKGROUND: Inadequate postoperative pain management could lead to persistent pain and this is, in part, due to incomplete understanding of the mechanism of postoperative pain. Currently available rodent models may have limited translatability to clinical postoperative pain. Thus, a preclinical model of postoperative pain was developed in the cynomolgus macaque, a species that is phylogenetically closer to humans than rodents. METHOD: The presence of pressure hypersensitivity was assessed with non-noxious pressure applied proximally and distally (approximately 10 cm) to an abdominal incision in macaques. The effect of the opioid morphine (intramuscular, i.m.), the nonsteroidal anti-inflammatory drug diclofenac (i.m.) and the anticonvulsant pregabalin (i.m.) on pressure hypersensitivity was evaluated one and two days following surgery. Brain activation during non-noxious pressure stimulation was observed with functional magnetic resonance imaging. RESULTS: Hypersensitivity to non-noxious pressure applied proximally and distally (approximately 10 cm) to the incision was observed, lasting for up to seven days and three days, respectively, following surgery. Postoperative pressure hypersensitivity was attenuated with morphine but not with either diclofenac or pregabalin. Bilateral activation of the insular cortex and cingulate cortex was observed during non-noxious pressure stimulation proximal to the incision, which was attenuated with morphine. By contrast, pregabalin reduced only cingulate cortex activation. CONCLUSION: The lack of antinociceptive efficacy of pregabalin on postoperative pain could be due to the incomplete suppression of pressure-evoked brain activation. It is speculated that incomplete postoperative pain relief observed in general could be due to residual or persistent activity of key pain nuclei such as the insular cortex. The current macaque model could be used for further elaborating the mechanism of postoperative pain as well as confirming the efficacy of potential treatments for the management of postoperative pain. PMID- 29766826 TI - Analysis of babA, cagE and cagA genes in Helicobacter pylori from upper gastric patients in the north of Iran. AB - OBJECTIVE: Helicobacter pylori is a Gram-negative bacterium which has a serious effect on the up to half of the world's population and has been related to different gastric diseases. The goal of this study was to assess the frequency of babA, cagE and cagA genotypes among H. pylori strains isolated from gastric biopsies of endoscopic patients in the north of Iran. METHODS: The present study was performed on 90 strains of H. pylori isolated from patients with gastric diseases (Gastric ulcer (GU), Duodenal ulcer (DU), Gastritis (G), Non-ulcer dyspepsia (NUD) and Gastric adenocarcinoma (GC)). DNA was extracted from all isolated strains and PCR method was performed to detect the prevalence of babA, cagE and cagA genes using specific primers. RESULTS: Among 90 samples of H. pylori, babA, cagE, and cagA genes were detected in 42.2%, 30% and 82.2% of strains respectively. The statistical analysis showed that the prevalence of cagA gene in GU, G, DU, and NUD was significantly higher than other genes. Moreover, cagA, and babA2 genes was significantly more prevalent in GC patients compared to cagE gene. Our isolates exhibited 8 distinct arrangements of virulence patterns. The occurrence of cagA (35.6%) was the most prevalent pattern followed by cagA/babA2 (20%), and cagA/babA2/cagE (14.4%). CONCLUSION: In summary, as first report from Guilan province in the north of Iran, we showed significant association between the presence of babA2, cagE, and cagA genes in different types of gastric disorders. PMID- 29766828 TI - Protective Effects of Crocetin on Depression-like Behavior Induced by Immobilization in Rat. AB - BACKGROUND & OBJECTIVE: Crocetin, an active ingredient of saffron, has been recognized as a potent antioxidant. Plant extracts or their components may be useful in ameliorating the various diseases, including neurodegenerative disorders. This study investigated the effects of crocetin on oxidative damage induced by chronic restraint stress in the rat brain. For this reason, rats were kept in the restrainers for 1 hour every day, for 21 consecutive days. The animals were injected crocetin (20, 40, 60 mg/kg) or vehicle daily for 21 days. Findings showed that the immobility time significantly increased in the rodents subjected to the chronic stress compared with the normal group. However, the number of crossing beams in the rats submitted to the chronic stress significantly decreased versus the non-stress rats. Treatment with crocetin ameliorated the immobility time and the number of crossing in the chronic restraint stress rats versus the non-treated stress group. Crocetin also reverted the levels of MDA and GSH and also the activities of antioxidant enzymes to the normal levels in the stress groups. CONCLUSION: The present study suggests that crocetin may be useful for the management of depressantlike effects induced by chronic stress through decreasing oxidative damage in the brain. PMID- 29766829 TI - Acute Myeloid Leukemia: Diagnosis and Management Based on Current Molecular Genetics Approach. AB - BACKGROUND & OBJECTIVE: Acute Myeloid Leukemia (AML) is characterized by the accumulation of >=20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed. CONCLUSION: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients. PMID- 29766830 TI - Impact of Sphingolipid Mediators on the Determination of Cochlear Survival in Ototoxicity. AB - BACKGROUND AND OBJECTIVE: Sphingolipid metabolites, including ceramide, sphingosine, and their phosphorylates (ceramide-1-phosphonate [C1P] and sphingosine-1-phosphate [S1P]), regulate diverse cellular processes including apoptosis, the cell cycle, and cellular differentiation. Recent studies have shown that these sphingolipid metabolites are generated in response to ototoxic agents and play important roles in determining the fate of cochlear hair cells in ototoxic injury. METHODS: This review summarizes the current knowledge on the roles of sphingolipid mediators in cochlear ototoxicity. RESULTS: During ototoxicity, ceramide is mainly generated via sphingomyelinase in the cochlea through a ceramide/sphingomyelin cycle from sphingomyelin. The generated ceramide is converted to other sphingolipid mediators. Ceramide and sphingosine accelerate cochlear hair cell death induced by ototoxic agents, while, C1P and S1P, on the other hand, protect cochlear hair cells. Hair cell protection of S1P is mediated by S1P receptor subtype 2 (S1PR2). CONCLUSION: Sphingolipid mediators play important roles in cochlear hair cell survival or death in ototoxic injury. PMID- 29766831 TI - Phagocytosis and Motility in Human Neutrophils is Competent but Compromised by Pharmacological Inhibition of Ezrin Phosphorylation. AB - BACKGROUND AND OBJECTIVE: Ezrin links the cortical cytoskeleton to the plasma membrane and plays a role in regulating changes in cell shape. Recently, NSC668394 has been shown to inhibit a key step for its activity, i.e. phosphorylation at threonine 567. In neutrophils, another key regulatory step is the Ca2+-mediated cleavage of ezrin by calpain. METHODS: In this paper, we use NSC668394 as a pharmacological inhibitor to investigate the interplay between these two steps in regulating changes in neutrophil shape. RESULTS: NSC668394 reduced the amount of peripherally located ezrin in neutrophils, and increased Ca2+-dependent ezrin cleavage. Neutrophils with NSC668394-inhibited ezrin phosphorylation remained both phagocytic and chemotactically competent. However, phagocytosis was slightly impaired and chemotaxis could not be maintained over longer periods. The characteristic chemotactic morphology which neutrophils adopt was also aberrant. Although phosphorylation of ezrin plays a minor role in limiting the rapid changes in cell shape in neutrophils, inhibition of ezrin phosphorylation by NSC668394 prevented multiple and prolonged shape changes during extended chemotaxis. CONCLUSION: The susceptibility of prolonged chemotaxis to inhibition by NSC668394 may point to a useful target for anti inflammatory therapy. Inhibition of neutrophil chemotaxis towards chronically inflamed sites without compromising their ability to undergo phagocytosis is a much sought after the effect of anti-neutrophil therapy. PMID- 29766832 TI - NorthStar Perspectives for Actinium-225 Production at Commercial Scale. AB - OBJECTIVE: Actinium-225, and its daughter Bismuth-213, have great promise in Alpha Immuno Therapy (AIT) for treatment of various disease modalities. Unfortunately, current production levels of actinium-225 do not support broad use of either actinium-225 or bismuth-213 in development or use for disease treatment. Further, the current cost per millicurie is much too high to be sustainable long term. Resolution of both supply and cost issues allows clinical research to proceed through clinical trials and potentially produce one or more effective therapies for cancer or infectious diseases that could benefit the public. METHODS: NorthStar Medical Technologies, LLC, has investigated several routes that could lead to commercial scale production of actinium-225. RESULTS: This article will discuss those efforts and results to date. CONCLUSION: The outlook for future supplies of actinium-225 from multiple sources to support clinical needs is encouraging. PMID- 29766833 TI - Human MicroRNAs Expression Profiles in Influenza B Virus-Infected Cells based on Illumina MiSeq Platform. AB - BACKGROUND: Influenza B virus causes influenza-like illness in humans. MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression through mRNA degradation or translational repression. MiRNAs have evolved to regulate many cellular processes including the viral infection response. OBJECTIVE: This study aims to investigate the miRNA profiles of human cells infected with influenza B virus. METHODS: A549 cells were infected with influenza B viruses (MOI = 0.5). MiRNAs were extracted at 24 and 48 hours post-infection. MiRNAs were used to construct four DNA libraries: influenza Binfected and an uninfected control for both time points. Then high-throughput sequencing was performed using the Miseq platform (Illumina). Sequencing data were analyzed by Miseq reporter software. The miRNAs were categorized and counted based on the frequency of reads. All filtered contigs were aligned with data from miRbase. The relative expression of each miRNA between uninfected and influenza B-infected cells was calculated. RESULTS: There were 13 down-regulated miRNAs and 21 up-regulated miRNAs observed in influenza B infected cells at 24 hours post infection. At 48 hours post infection, 14 miRNAs were downregulated, whereas 8 miRNAs were up-regulated. CONCLUSION: This study suggested that miRNAs may play important roles in host gene regulation in response to viral infection. PMID- 29766834 TI - The issue of nutrition training in health professions. PMID- 29766836 TI - Untold stories: Cancer clinic waiting room. PMID- 29766835 TI - Are consumption of dairy products and physical activity independently related to bone mineral density of 6-year-old children? Longitudinal and cross-sectional analyses in a birth cohort from Brazil. AB - OBJECTIVE: To evaluate cross-sectional and longitudinal associations of consumption of dairy products and physical activity (PA) with bone mineral density (BMD). DESIGN: Cohort study with children from the 2004 Pelotas (Brazil) Birth Cohort. SETTING: Pelotas, a medium-sized Brazilian city. SUBJECTS: The study started in 2004 and mothers/children were interviewed/measured periodically from birth to age 6 years. PA was measured by maternal proxy at 4 and 6 years and by accelerometry at 6 years. Consumption of dairy products was measured using 24 h food recall (at 4 years) and FFQ (at 6 years). Total-body and lumbar-spine BMD (g/cm2) were measured by dual-energy X-ray absorptiometry. RESULTS: At 6 years, BMD was measured in 3444 children and 2636 children provided data on objectively measured PA by accelerometry. Consumption of dairy products at 4 years was associated with higher lumbar-spine BMD at 6 years in boys, while current consumption was positively associated with BMD in both sexes (P < 0.001). PA assessed by maternal report at 4 and 6 years of age was associated with higher BMD at 6 years in boys. PA assessed by accelerometry was positively related to total-body and lumbar-spine BMD in boys and lumbar-spine BMD in girls. We did not find evidence for an interaction between PA and consumption of dairy products on BMD. CONCLUSIONS: We observed positive and independent longitudinal and cross sectional associations between consumption of dairy products and PA with BMD in the total body and at the lumbar spine in young children. PMID- 29766838 TI - DMD mutation and LTBP4 haplotype do not predict onset of left ventricular dysfunction in Duchenne muscular dystrophy. AB - Cardiomyopathy develops in >90% of Duchenne muscular dystrophy (DMD) patients by the second decade of life. We assessed the associations between DMD gene mutations, as well as Latent transforming growth factor-beta-binding protein 4 (LTBP4) haplotypes, and age at onset of myocardial dysfunction in DMD. DMD patients with baseline normal left ventricular systolic function and genotyping between 2004 and 2013 were included. Patients were grouped in multiple ways: specific DMD mutation domains, true loss-of-function mutations (group A) versus possible residual gene expression (group B), and LTBP4 haplotype. Age at onset of myocardial dysfunction was the first echocardiogram with an ejection fraction <55% and/or shortening fraction <28%. Of 101 DMD patients, 40 developed cardiomyopathy. There was no difference in age at onset of myocardial dysfunction among DMD genotype mutation domains (13.7+/-4.8 versus 14.3+/-1.0 versus 14.3+/ 2.9 versus 13.8+/-2.5, p=0.97), groups A and B (14.4+/-2.8 versus 12.1+/-4.4, p=0.09), or LTBP4 haplotypes (14.5+/-3.2 versus 13.1+/-3.2 versus 11.0+/-2.8, p=0.18). DMD gene mutations involving the hinge 3 region, actin-binding domain, and exons 45-49, as well as the LTBP4 IAAM haplotype, were not associated with age of left ventricular dysfunction onset in DMD. PMID- 29766837 TI - Diet quality and depressive symptoms in adolescence: no cross-sectional or prospective associations following adjustment for covariates. AB - OBJECTIVE: Adolescence is a critical period for development of depression and understanding of behavioural risk factors is needed to support appropriate preventive strategies. We examined associations between adolescent diet quality and depressive symptoms, cross-sectionally and prospectively, in a large community cohort, adjusting for behavioural and psychosocial covariates. DESIGN: Prospective community-based cohort study (ROOTS). SETTING: Secondary schools in Cambridgeshire and Suffolk, UK. SUBJECTS: Study participants (n 603) who completed 4 d diet diaries at age 14 years and reported depressive symptoms (Moods and Feelings Questionnaire (MFQ)) at 14 and 17 years of age. RESULTS: Diet data were processed to derive a Mediterranean diet score (MDS) and daily servings of fruit and vegetables, and fish. At age 14 years, a negative association between fruit and vegetable intake and MFQ score was seen in the unadjusted cross sectional regression model (beta=-0.40; 95 % CI -0.71,-0.10), but adjustment for behavioural covariates, including smoking and alcohol consumption, attenuated this association. Fish intake and MDS were not cross-sectionally associated with MFQ score. No prospective associations were found between MDS, fruit and vegetable intake or fish intake and later MFQ score. CONCLUSIONS: Diet quality was not associated with depressive symptoms in mid-adolescence. Previously reported associations in this age range may be due to confounding. Further longitudinal studies are needed that investigate associations between adolescent diet and depression across different time frames and populations, ensuring appropriate adjustment for covariates. PMID- 29766839 TI - Status, quality and specific needs of Ebola virus diagnostic capacity and capability in laboratories of the two European preparedness laboratory networks EMERGE and EVD-LabNet. AB - From December 2013 to March 2016, West Africa experienced the largest Ebola virus (EBOV) outbreak to date, leading to a European-wide activation of laboratory preparedness and response. At the end of the outbreak, laboratories associated with the two European preparedness networks of expert laboratories EMERGE JA and EVD-LabNet were invited to participate in an assessment of the response of European laboratories to the EBOV outbreak, to identify learning points and training needs to strengthen future outbreak responses. Response aspects assessed included diagnostics, biorisk management and quality assurance. The overall coverage of EBOV diagnostics in the European Union/European Economic Area (EU/EEA) was found to be adequate although some points for quality improvement were identified. These included the need for relevant International Organization for Standardization (ISO) accreditation, the provision of EBOV external quality assessments (EQA) in periods where there is no emergency, facilitating access to controls and knowledge, biorisk management without compromising biosafety and a rapid public health response, and the need for both sustained and contingency funding for preparedness and response activities. PMID- 29766840 TI - Rubella infection in pregnancy and congenital rubella in United Kingdom, 2003 to 2016. AB - Rubella vaccination has been included in the United Kingdom's (UK) routine childhood schedule for nearly 30 years. The UK achieved World Health Organization (WHO) elimination status in 2016 and acute rubella infections are rare. In the period 2003-16, 31 rubella infections in pregnancy (0.23 per 100,000 pregnancies) were identified through routine surveillance, of which 26 were in women who were born abroad. Five of the 31 rubella infections led to congenital rubella syndrome in the infant and three had confirmed congenital rubella infection without congenital rubella syndrome. An additional seven babies were identified with congenital rubella syndrome, although rubella infection in pregnancy had not been reported. Place of birth was known for six of these seven mothers, all of whom were born outside the UK, and in five cases maternal infection was acquired abroad. WHO Europe has set targets for measles and rubella elimination and prevention of congenital rubella syndrome by 2015. Vaccination uptake and rubella immunity is high in the UK population and most infections in pregnancy since 2003 were acquired abroad and in unvaccinated women. Every contact with a health professional should be used to check that women are fully immunised according to UK schedule. PMID- 29766841 TI - Case-control study on risk factors for acute hepatitis E in Germany, 2012 to 2014. AB - BackgroundNotified cases of hepatitis E have increased 40-fold in the past 10 years in Germany. Food safety is a major concern as hepatitis E virus (HEV) RNA has been detected in ready-to-eat retail-level food products. The objective of this case-control study was to assess risk factors for autochthonous symptomatic hepatitis E and explore reasons for delays in diagnosis. Methods: Demographic, clinical and exposure data from notified hepatitis E cases and individually matched population controls were collected in semi-standardised telephone interviews. Conditional logistic regression analysis was used to calculate matched odds ratios (mOR) and population attributable fractions (PAF). Results: In total, 270 cases and 1,159 controls were included (mean age 53 years, 61% men in both groups). Associated with disease were: consumption of undercooked pork liver, pork, wild boar meat, frankfurters, liver sausage and raw vegetables; contact with waste water (occupational) and various host factors (mORs between 1.9 and 34.1, p value < 0.03). PAF for frankfurters and liver sausage were 17.6%, and 23.6%, respectively. There were statistically significant differences in the clinical presentation and hospitalisation proportion of acute hepatitis E in men and women. Diagnosis was preceded by more invasive procedures in 29.2% of patients, suggesting that hepatitis E was not immediately considered as a common differential diagnosis. Conclusions: Our study suggests that there are indeed sex specific differences in disease development and lends important epidemiological evidence to specific ready-to-eat pork products as a major source for autochthonous hepatitis E. A review of existing consumer recommendations and production methods may be indicated. PMID- 29766843 TI - Long-Term Prognostic Role of the Diagnostic Criteria for Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. AB - OBJECTIVES: The aim of this study was to evaluate the long-term prognostic role of the 2010 task force criteria (TFC)-based scoring in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). BACKGROUND: Categories of the 2010 TFC include the risk factors for cardiovascular mortality and sudden cardiac death in patients with ARVC/D. METHODS: Ninety patients with ARVC/D who met the definitive diagnosis of the 2010 TFC were retrospectively studied. ARVC/D risk score was calculated as the sum of major (2 points) and minor (1 point) criteria in all 6 subdivided categories of the TFC and was divided into tertile groups of scores; group A (4 to 6 points), group B (7 to 9 points), and group C (10 to 12 points). The primary endpoints were major adverse cardiovascular events: cardiovascular death, heart failure hospitalization, and sustained ventricular tachycardia or ventricular fibrillation. RESULTS: During the follow-up period of 10.2 +/- 7.1 years, 19 patients died because of cardiovascular causes, 28 patients were admitted because of worsened heart failure, and 47 patients experienced sustained ventricular tachycardia or ventricular fibrillation. Patients in groups B and C were at increased risk for major adverse cardiovascular events compared with those in group A (hazard ratio [HR]: 4.80; 95% confidence interval [CI]: 1.87 to 12.33; p = 0.001; and HR: 6.15; 95% CI: 2.20 to 17.21; p = 0.001, respectively). Patients in groups B and C were at increased risk for sustained ventricular tachycardia or ventricular fibrillation compared with those in group A (HR: 6.64; 95% CI: 2.00 to 22.03; p = 0.002; and HR: 9.18; 95% CI: 2.60 to 32.40; p = 0.001, respectively). CONCLUSIONS: Our study suggests that risk scoring based on the 2010 TFC is useful to predict major adverse cardiovascular events in patients with ARVC/D. PMID- 29766844 TI - Evidence Mounts That Severity of Disease Impacts the Prognosis for Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. PMID- 29766845 TI - Right Bundle Branch Block as a Potential Cause of Pacemaker Malfunction. PMID- 29766842 TI - Continuous low-dose antibiotic prophylaxis to prevent urinary tract infection in adults who perform clean intermittent self-catheterisation: the AnTIC RCT. AB - BACKGROUND: People carrying out clean intermittent self-catheterisation (CISC) to empty their bladder often suffer repeated urinary tract infections (UTIs). Continuous once-daily, low-dose antibiotic treatment (antibiotic prophylaxis) is commonly advised but knowledge of its effectiveness is lacking. OBJECTIVE: To assess the benefit, harms and cost-effectiveness of antibiotic prophylaxis to prevent UTIs in people who perform CISC. DESIGN: Parallel-group, open-label, patient-randomised 12-month trial of allocated intervention with 3-monthly follow up. Outcome assessors were blind to allocation. SETTING: UK NHS, with recruitment of patients from 51 sites. PARTICIPANTS: Four hundred and four adults performing CISC and predicted to continue for >= 12 months who had suffered at least two UTIs in the previous year or had been hospitalised for a UTI in the previous year. INTERVENTIONS: A central randomisation system using random block allocation set by an independent statistician allocated participants to the experimental group [once-daily oral antibiotic prophylaxis using either 50 mg of nitrofurantoin, 100 mg of trimethoprim (Kent Pharmaceuticals, Ashford, UK) or 250 mg of cefalexin (Sandoz Ltd, Holzkirchen, Germany); n = 203] or the control group of no prophylaxis (n = 201), both for 12 months. MAIN OUTCOME MEASURES: The primary clinical outcome was relative frequency of symptomatic, antibiotic treated UTI. Cost-effectiveness was assessed by cost per UTI avoided. The secondary measures were microbiologically proven UTI, antimicrobial resistance, health status and participants' attitudes to antibiotic use. RESULTS: The frequency of symptomatic antibiotic-treated UTI was reduced by 48% using prophylaxis [incidence rate ratio (IRR) 0.52, 95% confidence interval (CI) 0.44 to 0.61; n = 361]. Reduction in microbiologically proven UTI was similar (IRR 0.49, 95% CI 0.39 to 0.60; n = 361). Absolute reduction in UTI episodes over 12 months was from a median (interquartile range) of 2 (1-4) in the no-prophylaxis group (n = 180) to 1 (0-2) in the prophylaxis group (n = 181). The results were unchanged by adjustment for days at risk of UTI and the presence of factors giving higher risk of UTI. Development of antimicrobial resistance was seen more frequently in pathogens isolated from urine and Escherichia coli from perianal swabs in participants allocated to antibiotic prophylaxis. The use of prophylaxis incurred an extra cost of L99 to prevent one UTI (not including costs related to increased antimicrobial resistance). The emotional and practical burden of CISC and UTI influenced well-being, but health status measured over 12 months was similar between groups and did not deteriorate significantly during UTI. Participants were generally unconcerned about using antibiotics, including the possible development of antimicrobial resistance. LIMITATIONS: Lack of blinding may have led participants in each group to use different thresholds to trigger reporting and treatment-seeking for UTI. CONCLUSIONS: The results of this large randomised trial, conducted in accordance with best practice, demonstrate clear benefit for antibiotic prophylaxis in terms of reducing the frequency of UTI for people carrying out CISC. Antibiotic prophylaxis use appears safe for individuals over 12 months, but the emergence of resistant urinary pathogens may prejudice longer-term management of recurrent UTI and is a public health concern. Future work includes longer-term studies of antimicrobial resistance and studies of non antibiotic preventative strategies. TRIAL REGISTRATION: Current Controlled Trials ISRCTN67145101 and EudraCT 2013-002556-32. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 22, No. 24. See the NIHR Journals Library website for further project information. PMID- 29766847 TI - Advances in Clinical Electrophysiology: 2015 in Review. PMID- 29766846 TI - COCATS 4, the 2015 CCEP Advanced Training Statement, and the Transition From 12 to 24 Required Months of Electrophysiology Training: Rationale, Status, and Implications for the Future. PMID- 29766849 TI - Pulmonary Vein Nonconduction: A False Indicator of Durable Pulmonary Vein Isolation. PMID- 29766848 TI - The Timing and Frequency of Pulmonary Veins Unexcitability Relative to Completion of a Wide Area Circumferential Ablation Line for Pulmonary Vein Isolation. AB - OBJECTIVES: This study sought to assess loss of pulmonary vein (PV) excitability to pacing relative to the development of entrance block and the anatomic completion of the circumferential radiofrequency ablation (RFA) line. BACKGROUND: During encircling RFA for PV isolation (PVI), entrance block develops before anatomic completion of encirclement (early) in some patients. We hypothesized that early entrance block may be associated with loss of PV excitability to pacing. METHODS: In 30 patients undergoing PV isolation (age 61 +/- 10 years, 21 men), excitability to pacing was assessed at predefined PV sites when entrance block developed and after completion of the RFA line. RESULTS: Of 60 PV pairs, 37 developed entrance block early, with a gap >=10 mm in the RFA line. In only 35% of PV pairs in this subgroup, both PV sleeves captured, and all of the capturing PV pairs showed exit block (no conduction from PV to atrium) despite the presence of an excitable gap. In the remaining 23 PV pairs, entrance block did not occur until encircling RFA was anatomically complete. In 83% of these PV pairs, both sleeves captured with exit block (p < 0.001 compared with early block PVs). CONCLUSIONS: The majority of PV pairs develops entrance and exit block before complete anatomic encircling by RFA lesions. Early entrance block is frequently associated with loss of PV sleeve excitability, consistent with a spreading wave of injury or edema rather than a permanent conduction barrier. This may help to explain the significant rate of PV conduction recovery associated with the acute endpoints of entrance and exit block. PMID- 29766850 TI - Peri-Mitral Atrial Tachycardia Using the Marshall Bundle Epicardial Connections. AB - OBJECTIVES: The aim of this study was to determine whether re-entrant circuits were associated with the ligament of Marshall (LOM). BACKGROUND: Peri-mitral atrial tachycardias (PMATs) following pulmonary vein isolation (PVI) or mitral valve surgery are common. METHODS: Six PMATs involving epicardial circuits were identified from 38 patients. Of these, 4 PMATs involved the LOM (PMAT-LOM, mean cycle length 308 +/- 53 ms), as confirmed by the insertion of a 2-F electrode in the vein of Marshall (VOM). All patients underwent PVI and mitral isthmus ablation. The PMAT-LOMs were diagnosed based on left atrium (LA) activation maps that covered <90% of tachycardia cycle length (TCL), and a difference between the post-pacing interval and TCL that was: 1) <=20 ms at the VOM, the ridge between the left pulmonary vein and appendage, the anterior wall of the LA, and along the 6 to 11 o'clock direction of the mitral annulus; and 2) >20 ms at the distal coronary sinus (CS), the posterior wall of the LA, and the mitral isthmus ablation line (or noncapture). Catheter ablation was performed at the ridge for all PMAT-LOMs. RESULTS: Three tachycardias were successfully terminated at the ridge, which showed continuous fractionated potential lasting >100 ms, confirming the bidirectional block of Marshall bundle (MB)-LA connections. The remaining tachycardia required ablation for the CS-MB connections, confirming bidirectional block of CS-MB connections. CONCLUSIONS: PMAT-LOMs following PVI or valve surgery accounted for up to 11% of PMATs. The bidirectional block of either MB-LA or CS MB connections is required to eliminate PMAT-LOMs. PMID- 29766851 TI - Practice Variation in Triple Therapy for Patients With Both Atrial Fibrillation and Coronary Artery Disease: Insights From the ACC's National Cardiovascular Data Registry. AB - OBJECTIVES: The aim of this study was to test the hypothesis that in the United States substantial practice variation exists in triple therapy prescribing practices, unrelated to measured patient factors. BACKGROUND: Recent data have shown that the risk of bleeding on dual antiplatelet therapy and oral anticoagulation ("triple therapy") is high, although the optimal strategy for patients with atrial fibrillation and coronary artery disease remains unclear. METHODS: Using the PINNACLE (National Practice Innovation and Clinical Excellence) registry, we identified 79,875 unique patients with both atrial fibrillation/atrial flutter and myocardial infarction and/or coronary stenting within 12 months. Using triple therapy as a binary outcome variable, we created a mixed-effects logistic regression model with patient factors as fixed effects and practice site as a random effect. Patient factors included age, sex, diabetes, congestive heart failure, hypertension, peripheral arterial disease, prior stroke or transient ischemic attack, history of systemic embolization, and dyslipidemia. The model was assessed with a median odds ratio to assess practice variation after adjustment for patient factors. RESULTS: After adjustment for patient factors, significant practice variation was suggested by a median odds ratio of 2.78 (95% confidence interval: 2.33 to 3.23). In particular, this suggests that 2 randomly selected practices would differ in their likelihood of prescribing triple therapy for an identical patient by a factor of nearly 3. CONCLUSIONS: In the United States, there is substantial practice variation in prescribing triple therapy to eligible patients even after adjustment for patient clinical characteristics. These results suggest that opportunities exist to improve the quality of care of this sizable population. PMID- 29766852 TI - Practice Variation in Patients Eligible for Triple Therapy: Designing Systems to Assess Risk and Tailor Treatment. PMID- 29766853 TI - Net Clinical Benefit of Edoxaban for Stroke, Mortality, and Bleeding Risk: Modeling Projections for a European Population. AB - OBJECTIVES: The purpose of this study was to determine, in a model based on Europeans at risk of stroke by virtue of atrial fibrillation (AF), the net clinical benefit of edoxaban in the reduction of the risk of stroke, mortality, and of hemorrhage. BACKGROUND: Vitamin K antagonists (e.g., warfarin) are commonly underused because of such factors as fear of hemorrhage in patients with high-risk AF. The non-vitamin K antagonist oral anticoagulants are similarly or more effective than warfarin and have lower rates of serious hemorrhage. Although outcomes of the ENGAGE AF-TIMI 48 trial that compared the non-vitamin K antagonist oral anticoagulant edoxaban with warfarin and indicated similar efficacy and better safety compared with warfarin for stroke prevention in AF, the application of trial data to the general population is unknown. METHODS: This study modelled a treatment effect of edoxaban on the risks of thromboembolism, major bleeding, and death in a real-world population of patients with AF drawn from the Euro Heart Survey, and extrapolated this to the general European population. RESULTS: In those at high risk of stroke (CHA2DS2VASc >=2), edoxaban would need to be taken by 319 patients to prevent 1 thromboembolism, major bleeding event, or death compared with warfarin, and by 41 patients to prevent 1 thromboembolism or death compared with no treatment. These translate to demonstrating a net clinical benefit of 8.9 events saved per 1,000 patients with edoxaban 60 mg. Modeling these data to the population of Europe of 508 million, use of edoxaban 30 mg and 60 mg instead of warfarin would, respectively, prevent approximately 19,400 and 30,300 thromboembolic events, major bleeds, and deaths annually. CONCLUSIONS: Our modeling exercise suggests that the use of edoxaban for thromboprophylaxis in AF based on current guidelines could provide a profound benefit on rates of stroke, major bleeds, and deaths in European patients with AF. PMID- 29766854 TI - Practical Considerations of Mapping Persistent Atrial Fibrillation With Whole Chamber Basket Catheters. AB - OBJECTIVES: This study sought to evaluate basket catheter deployment, catheter tissue contact, and time-space stability of unipolar atrial electrograms (aEGMs) recorded in persistent atrial fibrillation (AF) patients. BACKGROUND: Panoramic mapping of human AF using multiple-electrode basket catheters may identify AF sources. Although clinical results using this technique are provocative, questions remain about its effectiveness. METHODS: Data were collected from patients (N = 25) undergoing catheter ablation for AF during the multicenter STARLIGHT (Signal Transfer of Atrial Fibrillation Data to Guide Human Treatment) trial (NCT01765075). Left and right aEGM signals were recorded using basket catheters during baseline AF, following ablation and during sinus rhythm. Data were analyzed for basket deployment, peak-to-peak voltage, and electrogram stability and organization. Electrogram stability and organization were evaluated via time-frequency analysis (TFA). RESULTS: Basket catheters displayed equatorial bunching when deployed in atria. Interspline spacing ranged from 1.7 to 64.0 mm in the right atrial and from 1.5 to 85.08 mm in the left atrial basket. Approximately one-third of mapping electrodes failed to demonstrate a median peak to-peak voltage >2* the low-voltage threshold. Time-space stability and organization was observed in 13 of 22 (59.09%) right atrial and 10 of 22 (45.45%) left atrial baskets. CONCLUSIONS: Despite poor deployment and a large number of low-voltage electrodes, stability and organization was observed in about one-half of the mapped patients. Although this study suggests that basket catheters have limitations for patient-specific AF mapping, concordant activation occurs in some persistent AF patients, which may be amenable to high-density mapping techniques. PMID- 29766855 TI - Atrial Mapping With Basket Catheters: A Basket Case? PMID- 29766856 TI - Procedural Success of Left Ventricular Lead Placement for Cardiac Resynchronization Therapy: A Meta-Analysis. AB - OBJECTIVES: The goal of this study was to assess the contemporary and historical success rates of transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy (CRT), their change over time, and the reasons for failure. BACKGROUND: In selected patients, CRT improves morbidity and mortality, but the placement of the LV lead can be technically challenging. METHODS: A literature search was used to identify all studies reporting success rates of LV lead placement for CRT via the coronary sinus (CS) route. A total of 164 studies were identified, and a meta-analysis was performed. RESULTS: The studies included 29,503 patients: 74% (95% confidence interval [CI]: 72% to 76%) were male; their mean age was 66 years (95% CI: 65 to 67); their mean New York Heart Association functional class was 2.8 (95% CI: 2.7 to 2.9); the mean LV ejection fraction was 26% (95% CI: 25% to 28%); and the mean QRS duration was 155 ms (95% CI: 150 to 160). The overall rate of failure of implantation of an LV lead was 3.6% (95% CI: 3.1 to 4.3). The rate of failure in studies commencing before 2005 was 5.4% (95% CI: 4.4% to 6.5%), and from 2005 onward it was 2.4% (95% CI: 1.9% to 3.1%; p < 0.001). Causes of failure (reported for 39% of failures) also changed over time. Failure to cannulate and navigate the CS decreased from 53% to 30% (p = 0.01), and the absence of any suitable, acceptable vein increased from 39% to 64% (p = 0.007). The proportion of leads in a lateral or posterolateral final position (reported for 26% of leads) increased from 66% to 82% (p = 0.004). CONCLUSIONS: The reported rate of failure to place an LV lead via the CS has decreased steadily over time. A greater proportion of failures in recent studies are due to coronary venous anatomy that is unsuitable for this technique. PMID- 29766772 TI - Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. AB - BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .). PMID- 29766858 TI - Moving Beyond Beta-Blockers and Amiodarone: The Use of Anti-Inflammatories to Treat Post-Cardiac Surgery Atrial Fibrillation. PMID- 29766857 TI - Colchicine for Prevention of Post-Operative Atrial Fibrillation: A Meta-Analysis. AB - OBJECTIVES: This study sought to investigate the efficacy and safety of colchicine for prevention of post-operative atrial fibrillation. BACKGROUND: Proinflammatory processes induced during cardiac surgery may contribute toward post-operative atrial fibrillation (AF). Colchicine is a potent anti-inflammatory agent, which may have a role in post-operative AF prevention. METHODS: We searched PubMed, EMBASE, Web of Science, CINAHL, ClinicalTrials.gov, and the Cochrane Library databases for randomized controlled trials (RCT) comparing colchicine versus placebo for prevention of post-operative AF. The main outcome measure of interest was the development of AF within 12 months after cardiac surgery. The overall risk ratio (RR) for the development of post-operative AF was computed using a random-effects model. RESULTS: Data analyzed from 3 randomized studies with a total of 912 patients, where 457 patients received colchicine and 455 patients received placebo, showed that perioperative colchicine therapy was associated with a reduced incidence of post-operative AF (RR: 0.65; 95% confidence interval [CI]: 0.46 to 0.91; p < 0.01). Although colchicine therapy was associated with increased incidence of gastrointestinal intolerance (RR: 2.20; 95% CI: 1.31 to 3.70; p = 0.003), it was not associated with early treatment discontinuation (RR: 1.37; 95% CI: 0.95 to 1.96; p = 0.09). CONCLUSIONS: In conclusion, current evidence suggests that colchicine therapy is efficacious for the prevention of post-operative AF, and may be considered as adjunctive prophylaxis. Further studies may be required to determine the optimal treatment protocol to reduce the incidence of gastrointestinal intolerance. PMID- 29766859 TI - Surgical Management of Implantation-Related Complications of the Subcutaneous Implantable Cardioverter-Defibrillator. AB - OBJECTIVES: This study assessed outcomes in patients in whom subcutaneous implantable cardioverter-defibrillator (S-ICD) therapy was continued after implantation-related complications, in order to avoid conversion to transvenous ICD therapy. BACKGROUND: Patients at risk for sudden cardiac death benefit from ICD therapy, despite a significant risk for complications. S-ICD has a similar complication rate as transvenous ICD therapy, but the absence of transvenous leads may hold long-term benefits, especially in young ICD patients. METHODS: In the largest single-center cohort available to date, S-ICD patients implanted between 2009 and 2015 were included. RESULTS: There were 123 patients at a median age of 40 years. During a median follow-up of 2 years, 10 patients (9.4%) suffered implant-related complications. There were 5 infections, 3 erosions, and 2 implant failures for which 21 surgical procedures were needed. In 9 of 10 patients, S-ICD therapy could be continued after intervention. In 6 patients, the period between extraction and reimplantation of the S-ICD system was bridged with a wearable cardioverter-defibrillator (WCD). The pulse generator was reimplanted at the original site in 5 patients and in 3 underneath the serratus anterior muscle. One patient was not reimplanted following extraction due to recurrent infections. Conversion to a transvenous ICD was not needed in any patient. CONCLUSIONS: In most patients with a complication, S-ICD therapy could be continued after intervention, avoiding the need to convert to a transvenous system. Bridging to recovery with a WCD and submuscular implantation of the pulse generator are effective treatment strategies to manage S-ICD complications. PMID- 29766862 TI - The Substrate in "Early Persistent" Atrial Fibrillation: Arrhythmia Induced, Risk Factor Induced, or From a Specific Fibrotic Atrial Cardiomyopathy? PMID- 29766863 TI - Global Survey of Esophageal Injury in Atrial Fibrillation Ablation: Characteristics and Outcomes of Esophageal Perforation and Fistula. AB - OBJECTIVES: This study sought to assess the incidence, operator demographics, clinical characteristics, procedural factors, and prognosis of esophageal perforation and fistula after atrial fibrillation ablation. BACKGROUND: Esophageal injury is a feared complication of atrial fibrillation ablation. METHODS: An Internet-based global survey soliciting anonymous information regarding esophageal perforation and fistula was emailed to 3,080 physicians. Detailed information regarding physician, patient, and procedural characteristics related to esophageal perforation with or without fistula was collected. RESULTS: The survey was completed by 405 of 3,080 physicians (13%). Responding physicians performed 191,215 atrial fibrillation ablations and esophageal perforation with or without fistula occurred in 31 patients (0.016%) with multiple ablation catheter types despite monitoring of esophageal position or temperature during ablation in 90% of patients. Among patients who present with esophageal perforation, death, or severe neurologic injury occurred more frequently in patients with greater body mass index (30.9 +/- 6.8 kg/m2 vs. 25.8 +/- 3.3 kg/m2; p = 0.03), and lower left ventricular ejection fraction (55.1 +/- 9.1% vs. 61.7 +/- 5.4%; p = 0.04). Among analyzed patients, atrial-esophageal fistula was seen in 72%, pericardial-esophageal fistula in 14%, and esophageal perforation without fistula in 14%. Mortality was 79% with atrial-esophageal fistula and 13% in esophageal perforation without atrial-esophageal fistula. CONCLUSIONS: Esophageal perforation is rare but continues to occur with multiple catheter types despite esophageal monitoring during ablation. The prognosis of esophageal perforation is substantially improved if diagnosed and treated before development of atrial esophageal fistula. An early surgical approach to esophageal perforation should be strongly considered regardless of evidence of fistula. PMID- 29766864 TI - Pre-Procedural Serum Atrial Natriuretic Peptide Levels Predict Left Atrial Reverse Remodeling After Catheter Ablation in Patients With Atrial Fibrillation. AB - OBJECTIVES: This study aimed to investigate the role of atrial natriuretic peptide (ANP) levels to predict left atrial (LA) reverse remodeling in atrial fibrillation (AF) patients. BACKGROUND: Although LA reverse remodeling after radiofrequency catheter ablation (RFCA) for AF was reported to be associated with favorable outcomes and improvement of LA and left ventricular function, the predictor has not been extensively evaluated. METHODS: This study included 104 consecutive patients who underwent RFCA for AF. All patients underwent multidetector computed tomography examination and laboratory tests, including measurement of ANP, plasma B-type natriuretic peptide (BNP), and high-sensitivity C-reactive protein (hs-CRP) levels before and 6 months after RFCA. The study population was divided according to the extent of the decrease in the LA volume index at follow-up; responders were defined as patients who exhibited a >=15% decrease in the LA volume index. RESULTS: At follow-up, 49 patients (47%) were classified as responders. Pre-procedural serum ANP and BNP levels were significantly higher in the responders than in the nonresponders (both p < 0.01). In the responders, a significant decrease was observed in the log ANP, log BNP, and log hs-CRP levels from baseline to follow-up (all p < 0.01). Multivariate linear regression analysis revealed that log ANP levels before RFCA and maintenance of sinus rhythm during follow-up were independent predictors of LA reverse remodeling (both p < 0.01). CONCLUSIONS: In this study, 47% of the patients exhibited LA reverse remodeling after RFCA for AF, with a concomitant improvement in serum ANP, BNP, and hs-CRP levels. The pre-procedural ANP level and maintenance of sinus rhythm were independently associated with LA reverse remodeling. PMID- 29766860 TI - Selective Ablation of the Ligament of Marshall Reduces the Prevalence of Ventricular Arrhythmias Through Autonomic Modulation in a Cesium-Induced Long QT Canine Model. AB - OBJECTIVES: The goal of this study was to investigate the effect of selective ablation of the ligament of Marshall (LOM) on ventricular arrhythmias (VAs). BACKGROUND: Previous studies have shown that selective stimulation of sympathetic elements of the LOM, the distal segment of the ligament of Marshall that extends beyond the left superior pulmonary vein (LOMLSPV), might induce VAs. METHODS: In protocol 1, the blood pressure and ventricular effective refractory period changes as a response to LOMLSPV stimulation and left stellate ganglion (LSG) stimulation were measured before and after LOMLSPV ablation in 8 anesthetized dogs. In protocol 2, a total of 24 dogs were randomly divided into group 1 (cesium alone, n = 8), group 2 (cesium combined with LSG stimulation, n = 8), and group 3 (cesium combined with LSG stimulation after LOMLSPV ablation, n = 8). Early afterdepolarization amplitude, VA prevalence, and the tachycardia threshold (measured according to the dose of cesium administered) were compared among the groups. RESULTS: In protocol 1, both LOMLSPV stimulation and LSG stimulation significantly increased blood pressure and shortened the ventricular effective refractory period, both of which were significantly attenuated by LOMLSPV ablation. In protocol 2, compared with group 1, the prevalence of VAs and the early afterdepolarization amplitudes were significantly augmented in group 2 and were maintained at a comparable level in group 3. Furthermore, the tachycardia threshold in group 2 (0.625 mmol/kg) was significantly lower than that noted in groups 1 and 3 (both 1.000 mmol/kg; p < 0.05). CONCLUSIONS: LOMLSPV ablation reduced the prevalence of the VAs induced by cesium in combination with LSG stimulation, and the antiarrhythmic effect may involve the blockade of the sympathetic conduit between the LSG and the ventricles. PMID- 29766861 TI - Persistent Atrial Fibrillation From the Onset: A Specific Subgroup of Patients With Biatrial Substrate Involvement and Poorer Clinical Outcome. AB - OBJECTIVES: This study sought to characterize the clinical characteristics, atrial substrate, and prognosis in a subgroup of patients with persistent atrial fibrillation (AF) from the onset (PsAFonset). BACKGROUND: Patients with AF frequently progress from trigger-driven paroxysmal arrhythmias to substrate dependent persistent arrhythmias. METHODS: Patients referred for persistent AF (PsAF) ablation were enrolled from 3 centers. Consecutive patients with PsAFonset (n = 129) were compared with patients with PsAF that progressed from paroxysmal AF (n = 231). In addition, 90 patients (30 patients with PsAFonset and 60 control subjects) were studied with noninvasive mapping to characterize the AF drivers. The degree of fractionation and endocardial voltages were assessed invasively. RESULTS: Patients with PsAFonset were younger (p = 0.047) and more obese (p < 0.001); there were more men (p = 0.034), more patients with hypertension (p = 0.044), and these patients had larger left (p < 0.05) and right atria (p < 0.05). Baseline AF cycle length was shorter in the PsAFonset group (p < 0.01); the degree of fractionation was higher (p < 0.001 for both atria), and the endocardial voltage was lower (p < 0.05 for both atria). Patients with PsAFonset had higher a number of re-entrant driver regions (p < 0.001) and extrapulmonary vein regions that had re-entrant drivers (p < 0.05), whereas control subjects displayed more focal driver regions (p = 0.029). The acute AF termination rate was lower in the PsAFonset group (42% vs. 81%; p < 0.001). During a mean follow up of 17 +/- 11 months from the last procedure, patients with PsAFonset had significantly higher AF, atrial tachycardia (AT), and AF/AT recurrence rates (p < 0.01). CONCLUSIONS: Patients with PsAFonset represent a distinct subgroup defined by specific demographics, underlying diffuse biatrial substrate disease, and worse clinical outcome. The findings highlight the importance of defining criteria for early detection of atrial substrate disease. PMID- 29766865 TI - Natriuretic Peptides for Predicting Left Atrial Reverse Remodeling After Atrial Fibrillation Ablation: Too Much of a Stretch? PMID- 29766866 TI - Safety of Catheter Ablation for Atrial Fibrillation in Patients With Prior Cerebrovascular Events. AB - OBJECTIVES: This study sought to report on the safety of catheter ablation for atrial fibrillation (AF) in patients with prior cerebrovascular events (CVEs), at a large-volume tertiary care center over the course of the past 15 years. BACKGROUND: Many patients with drug-refractory AF have a history of a prior CVE. These patients are considered to be at high procedural risk for catheter ablation but data are scant. METHODS: All consecutive patients undergoing AF ablation at the Cleveland Clinic were enrolled in a prospectively maintained data registry, which was used to identify patients with a prior CVE. Strict periprocedural anticoagulation protocols were in place. Extreme care was taken with sheath and catheter manipulation to prevent thrombus formation or air embolism. All thromboembolic and hemorrhagic events occurring periprocedurally and up to 3 months of follow-up were identified. RESULTS: Of 9,413 consecutive patients who underwent AF ablation, 247 patients with a prior CVE were identified (median age, 64 years; 40.1% female; median CHA2DS2-VASC score, 4). Anticoagulants used were warfarin (n = 192), dabigatran (n = 32), rivaroxaban (n = 15), and apixaban (n = 8). All patients received intravenous heparin before transseptal access (activated clotting time target during procedure, 350 to 400 seconds). The energy source was radiofrequency in 242 patients and cryoenergy in 5 patients. Acute procedural complications included 5 groin hematomas (1 requiring transfusion), 5 pericardial effusions with associated tamponade physiology in 2 (1 required pericardiocenthesis, 1 required surgery), and 1 arteriovenous fistula (managed conservatively). Importantly, none of the patients had a periprocedural thromboembolic event. CONCLUSIONS: Patients with a prior history of cerebrovascular events do not seem to be predisposed to a significant risk of clinical CVE recurrence when undergoing catheter ablation for AF without interruption of therapeutic anticoagulation. PMID- 29766868 TI - Outcomes Related to First-Degree Atrioventricular Block and Therapeutic Implications in Patients With Heart Failure. AB - The prevalence of first-degree atrioventricular block in the general population is approximately 4%, and it is associated with an increased risk of atrial fibrillation. Cardiac pacing for any indication in patients with first-degree heart block is associated with worse outcomes compared with patients with normal atrioventricular conduction. Among patients with heart failure, first-degree atrioventricular block is present in anywhere between 15% and 51%. Data from cardiac resynchronization therapy studies have shown that first-degree atrioventricular block is associated with an increased risk of mortality and heart failure hospitalization. Recent studies suggest that optimization of atrioventricular delay in patients with cardiac resynchronization therapy is an important target for therapy; however, the optimal method for atrioventricular resynchronization remains unknown. Understanding the role of first-degree atrioventricular block in the treatment of patients with heart failure will improve medical and device therapy. PMID- 29766867 TI - Radiofrequency Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation: Meta-Analysis of Quality of Life, Morbidity, and Mortality. AB - OBJECTIVES: The aim of this study was to perform a collaborative meta-analysis of published and unpublished quality-of-life, morbidity, and mortality data from randomized controlled trial comparisons of radiofrequency ablation (RFA) and antiarrhythmic drug therapy (AAD) in symptomatic atrial fibrillation. BACKGROUND: RFA is superior to AAD in decreasing recurrences of atrial fibrillation, but the effects on other clinical outcomes are not well established. METHODS: The primary investigators of eligible randomized controlled trials were invited to contribute standardized outcome data. Random-effects summary estimates were calculated as standardized mean differences and risk ratios with 95% confidence intervals for continuous and binary outcomes, respectively. Fixed effects were used in subgroup analyses. RESULTS: Twelve randomized controlled trials (n = 1,707 patients) were included. RFA led to greater improvements in 4 36-Item Short Form Health Survey areas and the symptom frequency score from baseline to 3 months. In all quality of-life metrics, there was a trend toward diminution of the differences between the 2 approaches with follow-up. There were 7 of 866 (5 in a study using phased RFA) and 0 of 704 strokes in the RFA and AAD arms, respectively (p = 0.02, Fisher exact test). Bleeding and mortality events were not significantly different between the 2 arms. There was high heterogeneity for hospitalizations, with decreased hospitalization risk with RFA when it was not first-line therapy (risk ratio: 0.34; 95% confidence interval: 0.24 to 0.46) and increased risk as first line therapy (risk ratio: 1.22; 95% confidence interval: 1.03 to 1.45). CONCLUSIONS: RFA demonstrates an early but nonsustained superiority over AAD for the improvement of quality of life. There are no obvious differences in other clinical outcomes, and the periprocedural stroke risk is non-negligible. PMID- 29766869 TI - Should the Aortic Root Be the Preferred Route for Ablation of Focal Atrial Tachycardia Around the AV Node?: Support From Intracardiac Echocardiography. AB - OBJECTIVES: The purpose of this study was to determine the optimal approach to focal atrial tachycardia originating from around the atrioventricular node. BACKGROUND: Focal atrial tachycardia (FAT) demonstrating earliest activation around the atrioventricular (AV) node during right atrial (RA) mapping has been eliminated by ablation at the RA para-Hisian region, from the left atrium (LA) or the noncoronary aortic cusp (NCC). However the optimal approach has not been determined. METHODS: We conducted a retrospective analysis of a consecutive series of 148 patients undergoing catheter ablation for FAT between 2006 and 2014 in our institution. RESULTS: Earliest activation was recorded in the peri-AV nodal region during RA mapping in 34 patients (23%). Of these, 7 patients (20.5%) had successful ablation at the RA septum, using either radiofrequency (n = 4) or cryoenergy (n = 3). Seven FATs (20.5%) were ablated from the LA at the region of the aortomitral continuity, and 20 patients (59%) had successful ablation in the NCC, including 1 patient with a recurrence after a temporarily successful cryoablation from the RA. The proportion of the 3 approaches in this series showed a significant temporal evolution and overall frequency favoring ablation in the NCC (p = 0.011 for time trend and 0.013 for actual vs. expected frequencies). Intracardiac echocardiography proved superior catheter stability with the NCC approach. There were 2 cases of atrioventricular block and 1 recurrence after RA ablation versus no complications or recurrent FAT with NCC and LA approaches. CONCLUSIONS: Most peri-AV nodal FATs can be safely and effectively ablated from the NCC. The strategy of preferential NCC approach avoids RA para-Hisian ablation with the accompanying risk of AV block. PMID- 29766870 TI - What Is the Optimal Approach to Ablation of Para-Hisian Atrial Tachycardias? PMID- 29766871 TI - Prospective Assessment of the Risk of Vasovagal Syncope During Driving. AB - OBJECTIVES: This study sought to estimate the likelihood of a motor vehicle accident causing serious risk or harm in patients with frequent vasovagal syncope, and compare this with international accident data. BACKGROUND: Recurrent vasovagal syncope poses a risk because of fainting while driving, but prospective, benchmarked estimates of this risk have not been reported. METHODS: Data were from the POST (Prevention of Syncope Trial)-1 and -2, which were multicenter randomized studies of patients with >=3 lifetime vasovagal syncope spells. POST-1 patients (reported in 2005) received metoprolol or placebo for <=1 year between 1998 and 2004; POST 2 patients received fludrocortisone or placebo for <=1 year between 2006 and 2011. Accident data were recovered from Internet reports from the United States, United Kingdom, and Canada. RESULTS: A total of 418 patients (age 38 +/- 17 years) had a median of 10 lifetime faints and a median of 3 faints in the previous year. Total follow-up time was 323 years, or 0.77 years per person. A total of 174 subjects fainted, having a total of 615 faints. Two patients fainted while driving, without fatality or injury, with a likelihood of 0.62% per person-year. The risk of serious harm or death was <0.0035% per person-year, and 0.0018% per faint. In the general U.S., U.K., and Canadian driving populations, the risk of serious harm or death was 0.067% per driver-year, and the risk of death was 0.009%. CONCLUSIONS: The estimated risk of serious harm or death was <0.0035% per person-year in highly symptomatic patients, less than the risk of serious harm or death in the general population. (A Randomized Clinical Trial of Fludrocortisone for Vasovagal Syncope: The Second Prevention of Syncope Trial [POST II]; NCT00118482). PMID- 29766872 TI - On the Road Again After Vasovagal Syncope? PMID- 29766873 TI - Cardiac Resynchronization Therapy With a Quadripolar Electrode Lead Decreases Complications at 6 Months: Results of the MORE-CRT Randomized Trial. AB - OBJECTIVES: The aim of this study was to test the hypothesis that a quadripolar left ventricular (LV) lead results in fewer LV lead-related events than a bipolar cardiac resynchronization therapy (CRT) system in a prospective randomized trial. BACKGROUND: Bipolar LV leads cannot be implanted at the optimal site in up to 10% of patients who need CRT, because of anatomic or technical challenges (pacing threshold, phrenic stimulation, or mechanical instability). METHODS: The MORE-CRT (More Options Available With a Quadripolar LV Lead Provide In-Clinic Solutions to CRT Challenges) trial enrolled 1,078 patients. Patients with indications for CRT defibrillator therapy were randomized into 2 groups in a 1:2 ratio: a group with a bipolar CRT lead system (the BiP group; any manufacturer) and a group with a quadripolar CRT system (the Quad group; Quartet LV lead). The primary endpoint was freedom from a composite endpoint of intraoperative and post-operative LV lead-related events at 6 months. RESULTS: A total of 1,074 of 1,078 patients (99%) were randomized and contributed to the primary endpoint. Freedom from the composite endpoint was significantly greater in the Quad than the BiP group (83.0% vs. 74.4%, p = 0.0002). The intraoperative component of the endpoint was met less frequently by Quad group patients (6.26% Quad vs. 12.1% BiP), whereas there was no difference for the post-operative component (7.1% Quad vs. 7.6% BiP). CONCLUSIONS: The Quartet LV system significantly reduced total LV lead related events at 6 months after implantation compared with a bipolar CRT system. The reduction in events demonstrates the superiority of this quadripolar technology to effectively manage CRT patients. (More Options Available With a Quadripolar LV Lead Provide In-Clinic Solutions to CRT Challenges [MORE-CRT]; NCT01510652). PMID- 29766874 TI - Rhythm Control Versus Rate Control and Clinical Outcomes in Patients With Atrial Fibrillation: Results From the ORBIT-AF Registry. AB - OBJECTIVES: The study sought to evaluate clinical outcomes in clinical practice with rhythm control versus rate control strategy for management of atrial fibrillation (AF). BACKGROUND: Randomized trials have not demonstrated significant differences in stroke, heart failure, or mortality between rhythm and rate control strategies. The comparative outcomes in contemporary clinical practice are not well described. METHODS: Patients managed with a rhythm control strategy targeting maintenance of sinus rhythm were retrospectively compared with a strategy of rate control alone in a AF registry across various U.S. practice settings. Unadjusted and adjusted (inverse-propensity weighted) outcomes were estimated. RESULTS: The overall study population (N = 6,988) had a median of 74 (65 to 81) years of age, 56% were males, 77% had first detected or paroxysmal AF, and 68% had CHADS2 score >=2. In unadjusted analyses, rhythm control was associated with lower all-cause death, cardiovascular death, first stroke/non central nervous system systemic embolization/transient ischemic attack, or first major bleeding event (all p < 0.05); no difference in new onset heart failure (p = 0.28); and more frequent cardiovascular hospitalizations (p = 0.0006). There was no difference in the incidence of pacemaker, defibrillator, or cardiac resynchronization device implantations (p = 0.99). In adjusted analyses, there were no statistical differences in clinical outcomes between rhythm control and rate control treated patients (all p > 0.05); however, rhythm control was associated with more cardiovascular hospitalizations (hazard ratio: 1.24; 95% confidence interval: 1.10 to 1.39; p = 0.0003). CONCLUSIONS: Among patients with AF, rhythm control was not superior to rate control strategy for outcomes of stroke, heart failure, or mortality, but was associated with more cardiovascular hospitalizations. PMID- 29766875 TI - Rate Control Versus Rhythm Control in the ORBIT-AF Registry: The Beat Goes On. PMID- 29766876 TI - Prevention of Coagulum Formation With Simultaneous Charge Delivery in Radiofrequency Ablation: A Canine Model. AB - OBJECTIVES: This study reports on a novel method to prevent coagulum formation by continuously delivering a negative charge to the catheter tip to repel negatively charged fibrinogen molecules during RF ablation. BACKGROUND: Radiofrequency (RF) ablation for cardiac arrhythmias is associated with a 70% incidence of coagulum formation on the catheter tip during ablation and a 10% incidence of thromboembolic events. Catheter tip thrombus can impede RF energy to the tissue, reducing efficacy and increasing procedure times. METHODS: A novel circuit was built to deliver a negative, fixed-offset, direct current-based charge using a 9 V battery, placed in parallel with an RF delivery unit during RF ablation. In in vivo canine experiments, standard ablation catheters were advanced into atria and ventricles under fluoroscopic guidance. The presence of thrombus with and without RF delivery was identified with intracardiac echocardiography. RESULTS: Scanning electron microscopy of the catheter tips showed clot coverage of the catheter tip to be 90% for noncharged catheters compared to 0% (p < 0.01) in negatively charged catheters. Volume of clot formed on the catheter tip decreased with increased amount of charge (140 +/- 5.3 arbitrary units with no charge vs. 0 arbitrary units with a 100-MUA current delivering negative charge, p < 0.01). Application of a negative charge did not affect the quality of the intracardiac electrogram or induce malignant ventricular arrhythmias. CONCLUSIONS: Negative charge delivery to ablation catheter tips and tissue during RF ablation is feasible and safe and can eliminate coagulum formation, potentially reducing thromboembolic complications. PMID- 29766877 TI - Eliminating Coagulum Formation With Charge Delivery During Radiofrequency Ablation: Negative May Be a Positive! PMID- 29766878 TI - Subcutaneous Implantable Cardioverter-Defibrillator and Left Ventricular Assist Device: A Safe and Effective Approach for Refractory Heart Failure. PMID- 29766879 TI - Atrioventricular Reciprocating Tachycardia Mediated by Twin Atrioventricular Nodes. PMID- 29766880 TI - Improving Outcomes of AF Ablation: Where Do We Focus? PMID- 29766881 TI - Competitive Sports Participation in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia: A Single Center's Early Experience. AB - OBJECTIVES: The study sought to determine the outcomes of continued sports participation in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). BACKGROUND: Patients with CPVT are at increased risk of sudden death with exertion. Currently, CPVT patients are advised disqualification from nearly all sports in accordance with expert opinion guidelines. However, we have approached this complex issue with a shared decision making model respecting a patient's and their family's right to be a competitive athlete following institution of comprehensive CPVT-directed treatment program. METHODS: A retrospective record review was performed on patients with CPVT who were >6 years of age at the time of initial evaluation to determine their athlete status and frequency/scope of subsequent CPVT-triggered events. RESULTS: Among 63 eligible patients with CPVT (34 females, mean age at diagnosis 16.6 +/- 12.9 years), 31 (49%) were athletes at some point in their life. Compared to the nonathletes, these athletes were significantly younger at diagnosis (11.8 +/- 6.6 years vs. 21.3 +/- 15.6 years; p = 0.003) and more symptomatic (21 [68%] vs. 13 [41%]; p = 0.04). Following diagnosis, 21 of 24 athletes (88%) continued competition. For these 21 athletes, 16 (76%) had experienced 32 CPVT-triggered events prior to diagnosis versus 57 events in 18 nonathletes (43%; p = 0.02). During follow-up, 3 events occurred in 3 of 21 athletes (14%) compared to 7 events in 6 of 42 nonathletes (14%, p = 1.00). No event resulted in death, and all received an adjustment in their CPVT therapy. CONCLUSIONS: Although sports participation is a risk taking behavior in undiagnosed and untreated CPVT, the risk may be acceptable for a well-treated and well-informed athlete following the diagnosis of CPVT. PMID- 29766882 TI - Catecholaminergic Polymorphic Ventricular Tachycardia: Activity as Tolerated? PMID- 29766883 TI - Comorbid Epilepsy and Developmental Disorders in Congenital Long QT Syndrome With Life-Threatening Perinatal Arrhythmias. AB - OBJECTIVES: Given the association of long QT syndrome (LQTS) and neurological disorders, we speculated that the more severe LQTS phenotype, perinatal LQTS, would exhibit more frequent comorbid neurodevelopmental anomalies than LQTS without perinatal arrhythmias (nonperinatal LQTS). BACKGROUND: Congenital LQTS with life-threatening perinatal arrhythmias (perinatal LQTS) has a poor life prognosis. METHODS: Twenty-one consecutive LQTS patients diagnosed before 1 year of age at our institution and 3 previously reported perinatal LQTS patients with neurological seizures were enrolled. In total, the clinical course was evaluated in 24 patients. RESULTS: Among 21 infantile LQTS patients, 5 of 6 with perinatal LQTS (83%) were diagnosed with epilepsy and 4 (67%) with developmental disorders, but none with nonperinatal LQTS were. The total development quotient by Kinder Infant Development Scale scores was 17 to 72 (median 67) in 5 epileptic perinatal LQTS. In the 8 perinatal LQTS patients with neurological disorders, including 3 previously reported cases, epileptic seizures occurred at 2 days to 2.5 years of age and 5 had developmental disorders. Mutations in these 8 patients were located in the transmembrane loop of KCNH2, and D3/S4-S5 linker, D4/S4, or the D4/S6 segment of SCN5A. CONCLUSIONS: A high comorbidity of neurodevelopmental anomalies was observed in perinatal LQTS. Mutations in patients with neurological comorbidities were in loci linked to LQTS with a severe cardiac phenotype. These observations indicate the possibility that neurological disorders in perinatal LQTS are manifested as neurological phenotypes associated with severe cardiac phenotypes, while we could not completely exclude another possibility that those were caused by a brain perfusion injury. PMID- 29766884 TI - Long QT Syndrome and Seizures. PMID- 29766886 TI - Implications of Frailty in Elderly Patients With Electrophysiological Conditions. AB - A growing number of complex older adults are referred for electrophysiological conditions and age alone is insufficient to guide management decisions such as implantable cardioverter-defibrillator (ICD) implantation or atrial fibrillation anticoagulation. The concept of frailty has emerged as a geriatric vital sign to gain insight into physiological reserve and prognostic risk beyond chronological age and comorbidities. To date, a number of published studies have evaluated frailty in patients with electrophysiological conditions. These studies collectively demonstrate that frail patients have an increased prevalence of atrial fibrillation, lower use of oral anticoagulation, higher risk of bleeding complications from oral anticoagulation, and higher risk of stroke and mortality. A paucity of studies have explored frailty in the setting of device implantation, with a signal suggesting that frail heart failure patients may have a lower likelihood of being considered for ICD and cardiac resynchronization therapy devices, and a higher risk of fatal and nonfatal events after ICD and cardiac resynchronization therapy implantation. Whether frailty modulates the risks and benefits of these devices is a critical knowledge gap for which further study is clearly warranted. PMID- 29766885 TI - Impact of Updated Diagnostic Criteria for Long QT Syndrome on Clinical Detection of Diseased Patients: Results From a Study of Patients Carrying Gene Mutations. AB - OBJECTIVES: In this study, we scored patients with long QT syndrome (LQTS) according to the different Schwartz diagnostic criteria from 1993, 2006, and 2011, and to examine the validation of the criteria in relevance to the frequency of LQTS-related gene mutation. BACKGROUND: Although updated diagnostic criteria have been used in clinical settings, few data exist regarding their impact on the diagnosis of LQTS. METHODS: We used a cohort of 132 patients who presented with prolonged QTc intervals and/or abnormal clinical history in cardiac screening and who underwent exercise stress testing. LQTS scores of >=3.5 points according to the 2006 and the 2011 criteria were considered to indicate a high probability of LQTS, as opposed to the 4 points used by the 1993 criteria. The 2011 criteria were updated by adding the evaluation of the recovery phase of exercise. RESULTS: The 2011 criteria significantly increased the number of high probability patients (n = 62) compared with the 1993 criteria (n = 32; p = 0.0002) or the 2006 criteria (n = 36; p = 0.0014). The percentage of mutation carriers in those with an intermediate score, which was rather high using the 1993 (53%) and 2006 criteria (53%), was greatly reduced with the 2011 criteria (15%, p = 0.0014 vs. the 1993 criteria, and p = 0.0013 vs. the 2006 criteria). Among 54 mutation carriers, the 1993, the 2006, and the 2011 criteria identified a high probability of carriers in 25 patients (46% sensitivity and 91% specificity), 27 patients (50% sensitivity and 88% specificity), and 48 patients (89% sensitivity and 82% specificity), respectively. CONCLUSIONS: The use of the 2011 criteria will facilitate the diagnosis of LQTS and will decrease the number of false negative results. PMID- 29766887 TI - Prevalence of Left Atrial Thrombus Detection by Transesophageal Echocardiography: A Comparison of Continuous Non-Vitamin K Antagonist Oral Anticoagulant Versus Warfarin Therapy in Patients Undergoing Catheter Ablation for Atrial Fibrillation. AB - OBJECTIVES: The purpose of this study is to determine whether patients on >=4 weeks of continuous non-vitamin K antagonist oral anticoagulant (NOAC) therapy require transesophageal echocardiography (TEE) before catheter ablation of atrial fibrillation (AF) or atrial flutter and to compare rates of left atrial (LA) thrombus and dense spontaneous echocardiographic contrast (SEC) in patients on NOAC versus warfarin therapy. BACKGROUND: The impact of NOAC therapy on the rates of LA thrombus detection by TEE in patients undergoing catheter ablation of AF is unknown. METHODS: Initial TEEs for 388 patients (median age, 65 years; 74% male) on >=4 weeks of continuous NOAC (n = 183) or warfarin therapy (n = 205) undergoing catheter ablation of AF and flutter were reviewed. RESULTS: After >=4 weeks of therapy, the prevalence of LA thrombus and LA thrombus/dense SEC among patients on NOACs was 4.4% and 6.0%, respectively, which was comparable with that of patients on warfarin. LA thrombus rates among patients on dabigatran, rivaroxaban, and apixaban were 5.4%, 4.8%, and 0%, respectively (p = 0.46). Predictors of LA thrombus were congestive heart failure (odds ratio [OR]: 5.38; 95% confidence interval [CI]: 1.79 to 16.2; p = 0.003); and persistent AF (OR: 3.27; 95% CI: 1.06 to 10.2; p = 0.040). CONCLUSIONS: Despite >=4 weeks of anticoagulation, the rate of LA thrombus in patients on NOACs before catheter ablation of AF or atrial flutter was 4.4%. This suggests that continuous NOAC therapy does not eliminate the need for TEE before catheter ablation of AF. PMID- 29766888 TI - Assessing Intracardiac Thrombus Before Atrial Fibrillation Ablation: Challenges Faced After Testing. PMID- 29766889 TI - Cardiac Resynchronization Therapy May Be Antiarrhythmic Particularly in Responders: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This study sought to study the effect of echocardiographic response to cardiac resynchronization therapy (CRT) on ventricular arrhythmias (VA). The effect of CRT-defibrillator on sustained VA was compared with implantable cardioverter-defibrillator (ICD)-only therapy. BACKGROUND: CRT is an effective adjunctive therapy in selected patients with advanced congestive heart failure, but its effect on VA remains controversial. METHODS: PubMed was searched to identify studies. For primary comparison, studies reporting incidence of VA in patients with congestive heart failure with CRT compared with ICD were included. For secondary comparison, studies reporting incidence of VA in echocardiographic responders compared with nonresponders were included. Studies reporting incidence of VA in CRT nonresponders before and after CRT upgrade from ICD were assessed for the third comparison. Inverse variance method in a random-effects model was used to combine effect sizes. RESULTS: Thirteen studies (4,631 subjects) were included in the primary meta-analysis. Patients with CRT had a significantly lower incidence of VA compared with patients with ICD only (odds ratio: 0.754; confidence interval: 0.594 to 0.959). Thirteen studies (n = 3,667) were included in the meta-analysis of VA in CRT responders versus nonresponders. Responders had a significantly lower risk of VA (odds ratio: 0.436; confidence interval: 0.323 to 0.589). Multivariate meta-regression showed that the percentage beta-blocker use and follow-up duration explained heterogeneity between the studies. Three studies were included in the comparison of VA in CRT nonresponders before and after upgrade from ICD. CRT nonresponders had an elevated risk of VA compared with ICD-only subjects (odds ratio: 1.497; confidence interval: 1.225 to 1.829). CONCLUSIONS: CRT may significantly reduce risk of VA compared with ICDs in patients who meet criteria for CRT. CRT responders have significant reduction in VA compared with nonresponders. CRT nonresponse might significantly increase risk of VA. PMID- 29766890 TI - Ventricular Arrhythmias: The Black Box of Cardiac Resynchronization Therapy? PMID- 29766891 TI - Randomized Comparison of Continuous Versus Intermittent Heparin Infusion During Catheter Ablation of Atrial Fibrillation. AB - OBJECTIVES: This study tested the hypothesis that continuous heparin infusions would be favorable for maintaining heparin concentrations during radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). BACKGROUND: Heparin infusions are essential for RFCA of AF. There is a paucity of data on the details for the optimal heparin infusion during RFCA of AF. METHODS: A total of 333 patients undergoing AF ablation were consecutively enrolled and randomized to intermittent or continuous heparin infusion. A heparin bolus of 100 U/kg was injected just prior to transseptal puncture. The heparin concentration necessary to maintain an optimal activated clotting time (ACT) (300 to 400 s) was determined and checked every 30 min during the procedure. The primary endpoint of the study was the frequency of the maintenance of an optimal intraprocedural ACT. RESULTS: The frequency of an optimal ACT in the continuous group was significantly higher than that in the intermittent group (64.0% vs. 57.6%, respectively, p < 0.01), whereas the total heparin level was significantly lower in the continuous group (13,162 +/- 4,634 U vs. 15,837 +/- 5,243 U, respectively, p < 0.01). The standard deviation of the ACT was significantly smaller in the continuous group than in the intermittent group (49 +/- 30 vs. 33 +/- 18, respectively, p < 0.01). Ninety-six patients had new oral anticoagulants (NOACs) before the procedure, and an optimal ACT at the first ACT check was less frequent than in patients taking warfarin (12.5% vs. 59.1%, respectively, p < 0.01). There were no significant differences in periprocedural bleeding or thromboembolic complications between the groups. CONCLUSIONS: During AF ablation, a continuous heparin infusion was superior to an intermittent heparin infusion for maintaining an optimal ACT range. (Randomized Comparison of Continuous and Intermittent Heparin Infusion During Catheter Ablation of Atrial Fibrillation [COHERE]; NCT01935557). PMID- 29766892 TI - Heparin Bolus or Infusion: Can We Draw a Conclusion? PMID- 29766893 TI - Chronic Intermittent Low-Level Stimulation of Tragus Reduces Cardiac Autonomic Remodeling and Ventricular Arrhythmia Inducibility in a Post-Infarction Canine Model. AB - OBJECTIVES: This study investigated whether chronic low-level tragus stimulation (LL-TS) inhibits cardiac sympathetic remodeling and reduces ventricular arrhythmia inducibility in a post-infarction canine model. BACKGROUND: Low-level vagal stimulation has been shown to suppress cardiac sympathetic activity, which plays an important role in ventricular arrhythmia after myocardial infarction (MI). Our previous studies reported a noninvasive approach to deliver vagal stimulation by transcutaneous stimulation at the tragus, where the auricular branch of the vagus nerve is located. METHODS: Twenty-two beagles were randomized to the normal control (n = 6), MI (left anterior descending coronary artery ligation without LL-TS [n = 8]), and TS (MI plus LL-TS [n = 8]) groups. LL-TS was delivered 2 h each day at 80% below the threshold which slowed sinus rate. RESULTS: At 2-month follow-up, LL-TS was found to significantly reduce ventricular arrhythmia inducibility (arrhythmia score: 1.8 +/- 0.8 vs. 3.6 +/- 0.7, p < 0.01, compared to the MI group), decreased left stellate ganglion (LSG) activity (frequency: 32 +/- 15 vs. 112 +/- 29 impulses/s; and amplitude: 0.15 +/- 0.12 mV vs. 0.38 +/- 0.12 mV, compared to MI group), and attenuated cardiac sympathetic remodeling induced by chronic MI. The nerve growth factor (NGF) protein was down-regulated, whereas the small conductance calcium-activated potassium channel type2 (SK2) protein was up-regulated in the LSG by chronic LL TS. CONCLUSIONS: Chronic LL-TS could reduce the ventricular arrhythmia inducibility, LSG neural activity and sympathetic neural remodeling in a post infarction canine model. Down-regulation of NGF protein and up-regulation of SK2 protein in the LSG contribute to the salutary effects of LL-TS. PMID- 29766894 TI - Prospective Evaluation of Implantable Cardioverter-Defibrillator Lead Function During and After Left Ventricular Assist Device Implantation. AB - OBJECTIVES: This study investigated the mechanism of lead malfunction by monitoring lead parameters throughout left ventricular assist device (LVAD) implantation. BACKGROUND: Implantable cardioverter-defibrillator (ICD) lead malfunction can occur after LVAD implantation. METHODS: ICD lead data were prospectively evaluated during and after LVAD implantation and at 12 pre specified intraoperative time points. RESULTS: We prospectively evaluated 32 patients with ICDs who underwent LVAD implantation, of whom 20 patients underwent serial testing at 12 intraoperative steps. Post-operative right ventricle (RV) sensing had decreased by >50% from baseline in 7 patients (22%), with RV sensing improving at 1 to 7 weeks in 2 patients (28.6%). Nine patients (28.1%) had >10 ohm (Omega) high-voltage (HV) impedance changes from baseline to final impedance. In all 5 patients with >50% decrease in RV sensing and all 7 patients with a >10 Omega HV impedance change who underwent intraoperative testing, changes were not detected until after weaning from cardiopulmonary bypass. Patients with decreased RV lead sensing >50% (n = 7) had lower glomerular filtration rates (48.7 +/- 21.9 ml/min/1.73 m2 vs. 68.4 +/- 22.5 ml/min/1.73 m2, respectively, p = 0.0489), were more likely to have undergone concomitant RVAD placement (42.9% vs. 0%, respectively, p = 0.0071), concomitant tricuspid valve surgery (57.1% vs. 16%, p = 0.0469), or to have had cardiac tamponade or unplanned return to the operating room (57.1% vs. 12%, p = 0.0258). CONCLUSIONS: ICD lead malfunction can occur following LVAD implantation but may improve over time. Intraoperative RV sensing and HV impedance changes were not detected until after weaning from cardiopulmonary bypass, suggesting the mechanism of RV lead malfunction may be related to LV unloading and concomitant leftward septal shift. A conservative approach is warranted in many patients with ICD parameter changes after LVAD implantation because parameter abnormalities may improve over time. (Implantable Cardioverter Defibrillator (ICD) Function During Ventricular Assist Device (VAD) Implantation; NCT01576562). PMID- 29766895 TI - Association of Body Mass Index With Care and Outcomes in Patients With Atrial Fibrillation: Results From the ORBIT-AF Registry. AB - OBJECTIVES: This study sought to determine the association between body mass index (BMI) and clinical outcomes among patients with prevalent atrial fibrillation (AF). BACKGROUND: Higher BMI is an independent risk factor for incident AF. However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear. METHODS: Patients with AF enrolled in the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry from June 2010 through August 2011 were stratified into BMI-based categories as normal weight, overweight, class I obese, class II obese, and class III obese. Unadjusted and adjusted Cox frailty models were constructed to assess the association of BMI with clinical outcomes over a 2-year follow-up. RESULTS: We evaluated 9,606 patients with AF (42% women; 78% overweight/obese) from 174 ORBIT participating practices in the United States. Higher BMI patients were younger and had a greater prevalence of diabetes, hypertension, and obstructive sleep apnea (OSA). Use of anticoagulation and rhythm control strategies was significantly greater among higher BMI patients. Rates for all cause mortality and thromboembolic events decreased in a near linear fashion across increasing BMI categories (p < 0.001). After multivariable adjustment, higher BMI was associated with lower risk for all-cause mortality with lowest risk among class I obese patients (hazard ratio [HR]: 0.65; 95% CI: 0.54 to 0.78); reference: normal weight). For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 7% lower. In contrast, BMI was not associated with adjusted risk for thromboembolic events and AF progression. CONCLUSIONS: Although AF patients with higher BMI were significantly younger, higher BMI in AF patients was associated with similar or better clinical outcomes. PMID- 29766896 TI - Mortality Paradox in Obesity and Atrial Fibrillation: True Clinical Phenomenon or Red Herring in Atrial Fibrillation Care? PMID- 29766897 TI - Clinical and Electrophysiologic Characteristics Before and After Radiofrequency Ablation of Sustained Slow Atrioventricular Nodal Pathway Conduction. AB - OBJECTIVES: This study examined the clinical and electrocardiographic characteristics and electrophysiologic determinants of sustained slow pathway conduction (SSPC) during sinus rhythm. BACKGROUND: SSPC during sinus rhythm in presence of dual atrioventricular (AV) nodal pathways has not been thoroughly studied. METHODS: We studied 30 consecutive patients (19 men), whose median age was 31 years (interquartile range: 22 to 48 years); their electrocardiograms revealed 2 different PR intervals during nearly identical sinus rates. We measured the short and long PR intervals and their differences and examined the electrophysiologic determinants of SSPC during slow pathway (SP) ablation in 12 patients. RESULTS: Among the 30 patients, 21 (70%) complained of major symptoms. The short and long PR intervals measured 202 +/- 42 ms and 472 +/- 110 ms, respectively, and their mean difference measured 270 +/- 101 ms. During electrophysiologic studies, dual AV nodal and SSPC were observed in all patients. A markedly prolonged refractory period (593 +/- 116 ms) and retrograde conduction block over the fast pathway (FP) were observed over a range of sinus cycle lengths (CLs). Ablation of the SP in 11 patients promoted FP conduction and shortened its effective refractory period from 593 +/- 116 ms to 288 +/- 90 ms. Over a median follow-up of 2 years (interquartile range: 1 to 3 years), all patients remained asymptomatic and without recurrences of SSPC or AV block. CONCLUSIONS: Two distinct PR intervals during sinus rhythm indicated the presence of dual AV nodal pathways. SSPC was promoted by a markedly impaired bidirectional conduction over the FP at critical sinus CL. SP ablation safely and effectively eliminated SSPC in symptomatic patients. PMID- 29766898 TI - Duality of AV Nodal Conduction: An Ongoing Saga. PMID- 29766899 TI - Meta-Analysis of Contemporary Atrial Fibrillation Ablation Strategies: Irrigated Radiofrequency Versus Duty-Cycled Phased Radiofrequency Versus Cryoballoon Ablation. AB - OBJECTIVES: Using data from published studies, we performed a comparison of the 3 most commonly used atrial fibrillation (AF) ablation technologies in terms of efficacy and procedural duration. BACKGROUND: Catheter ablation is an effective treatment of atrial fibrillation (AF). Until recently, it has been performed with point-by-point delivery of irrigated radiofrequency energy (IRF). Phased duty cycled radiofrequency (PRF) and cryoballoon ablation (CBA) have been introduced as alternatives to simplify AF ablation. METHODS: Electronic searches of 6 databases was performed, and eligible studies with IRF, PRF, or CBA as cohort arms were included. These ablation strategies were compared directly by using conventional frequentist meta-analysis and indirectly by using network meta analysis, with outcomes graded using rank probability analysis. RESULTS: Direct conventional meta-analysis using all available published data showed that PRF was associated with an apparently higher freedom from AF than IRF (66.4% vs. 58%, respectively, p = 0.007), whereas CBA was comparable with IRF (64.8% vs. 62%, respectively, p = 0.99). PRF was associated with shorter procedural time (p < 0.0001), whereas there was a trend toward shorter procedural time with CBA than with IRF (p = 0.10). Indirect network meta-analysis using all available published data showed that PRF was associated with higher freedom from AF than CBA and IRF (odds ratio: 1.51; 95% confidence interval [CI]: 1.12 to 1.92) while having the shortest procedural time (weighted mean difference: 40.8 min; 95% CI: -63.31 to 18.11). Rank probability analysis also suggested that PRF was superior to CBA in terms of efficacy and procedural duration. However, when the meta-analysis was repeated using randomized controlled trial data alone, IRF and PRF were comparable in terms of freedom from AF (p = 0.35) over a mean follow-up of 9 months, but PRF was associated with significantly shorter procedural time (p = 0.006). There was a higher freedom from AF with IRF than with CBA (p = 0.04) over a mean follow-up of 12 months, whereas both techniques demonstrated similar procedural time (p = 0.47). CONCLUSIONS: Although preliminary meta-analysis of pooled data suggested the highest efficacy with PRF, this was not replicated when analysis was limited to randomized data. Therefore, there was insufficient evidence to suggest that one ablation modality is more efficacious than another. However, there was a consistent reduction in procedural duration associated with PRF in all analyses. The present meta-analysis highlights the critical need for further randomized studies comparing available ablation technologies in terms of efficacy and safety. PMID- 29766900 TI - Focal-, Circular-, or Balloon-Based Atrial Fibrillation Ablation: How to Interpret the Data in a Rapidly Developing Field? PMID- 29766901 TI - Uhl's Anomaly: Cardiac Features and ICD Implantation. PMID- 29766902 TI - Aortic Intramural Hematoma After Catheter Ablation for Atrial Fibrillation. PMID- 29766903 TI - Pyopneumopericardium Secondary to Pericardioesophageal Fistula After Radiofrequency Ablation of Atrial Fibrillation. PMID- 29766904 TI - Channelopathies: Literacy and Competence. PMID- 29766905 TI - Rapid freezing of water under dynamic compression. AB - Understanding the behavior of materials at extreme pressures is a central issue in fields like aerodynamics, astronomy, and geology, as well as for advancing technological grand challenges such as inertial confinement fusion. Dynamic compression experiments to probe high-pressure states often encounter rapid phase transitions that may cause the materials to behave in unexpected ways, and understanding the kinetics of these phase transitions remains an area of great interest. In this review, we examine experimental and theoretical/computational efforts to study the freezing kinetics of water to a high-pressure solid phase known as ice VII. We first present a detailed analysis of dynamic compression experiments in which water has been observed to freeze on sub-microsecond time scales to ice VII. This is followed by a discussion of the limitations of currently available molecular and continuum simulation methods in modeling these experiments. We then describe how our phase transition kinetics models, which are based on classical nucleation theory, provide a more physics-based framework that overcomes some of these limitations. Finally, we give suggestions on future experimental and modeling work on the liquid-ice VII transition, including an outline of the development of a predictive multiscale model in which molecular and continuum simulations are intimately coupled. PMID- 29766906 TI - n-type Rashba spin splitting in a bilayer inorganic halide perovskite with external electric field. AB - Here, we investigated the Rashba effect of the CsPbBr3 bilayers under the external electric field (EEF) with first-principles calculations. For the PbBr2 terminated bilayer, we found that only electrons experience the Rashba splitting under EEF, while holes do not. Such an n-type Rashba effect can be ascribed to the surface relaxation effect that reverses the positions of the top valence bands. The n-type Rashba parameter can be tuned monotonically to the maximum of 0.88 eV A at EEF of 1.35 V nm-1 at which the sequence of top valence bands recover to the bulk style. During this process the p-type spins will not survive in this 2D CsPbBr3, that indeed reveals a new way for making advanced functional spintronic devices. PMID- 29766907 TI - Adenocarcinoma arising in a rectal duplication cyst with distant metastasis A case report and a review of the recent literature. AB - INTRODUCTION: Rectal duplication cysts are rare cystic lesions, arising from the hindgut and classified as congenital/developmental tumors of the presacral space. Their clinical presentation is nonspecific, the diagnosis remains difficult and their management is aided by a multidisciplinary evaluation. CASE REPORT: We report the case of a 55-year-old woman with a cystic mass located in the retrorectal space and identified incidentally on a CT scan. Following imaging studies, surgical resection by a posterior approach (Kraske procedure) was carried out and an adenocarcinoma arising in a duplication cyst of the rectum was present an uncommon case of a rectal duplication cyst with malignant transformation and distant metastasis, describe the clinical, radiologic and pathologic findings and discuss tidentified by microscopy. CONCLUSION: We phe embryological basis of rectal duplication cysts and the surgical anatomy of the presacral space. Key Words: Rectal adenocarcinoma, rectal duplication cyst, Retrorectal space. PMID- 29766909 TI - Backward glance o'er travel'd roads. PMID- 29766908 TI - The cover page. PMID- 29766910 TI - Founders of Indian Neurosciences: Professor Krishna Prasad Bhargava(5th October 1925- 16th August 1991). PMID- 29766911 TI - Evolution of concepts in the management of craniopharyngiomas: Lessons learnt from Prof. S.N. Bhagwati's article published in 1993. PMID- 29766912 TI - Widening the circle of service: The gift of academic neurosurgery. PMID- 29766913 TI - Telemedicine and neurosciences. AB - It is well documented that there is an acute shortage of neurologists and neurosurgeons in India and globally. Despite all efforts, it will be impossible to make available neurospecialists in all suburban and rural areas. Simultaneously, there has been an exponential increase in the growth and development of Information and Communication Technology (ICT). Plummeting costs and unbelievable sophistication in the availability of user-friendly mobile video conferencing devices is making distance meaningless. Geography has become History! Worldwide, the ultraconservative health care industry, in particular, the medical community, has been uniformly slow to adopt and embrace the use of ICT to extend their clinical reach. In the last decade, however, specialists in all branches of neurosciences are slowly accepting the inevitable that telemedicine must and will have to be incorporated into the core of the healthcare delivery system. This literature review summarizes the current use of telemedicine in different subspecialties of neurosciences. The author defines the growth and development of clinical telemedicine in India with special reference to Neurosciences and attempts to show the stellar role telemedicine has to play in enhancing the services provided by doctors. As clinicians regularly using technology, it should not be difficult for us to convince our patients that today a virtual remote consult and management can indeed effectively substitute for a physical face-to-face encounter. PMID- 29766915 TI - Parent vessel occlusion and revascularization: A dying art? PMID- 29766914 TI - Training residents and fellows in the procedure of diagnostic cervicocerebral angiography: Techniques to avoid complications. AB - We examine the problems arising when training residents/fellows (RFs) initiate the learning of diagnostic cervicocerebral angiography (DCCA) and describe the steps on how to facilitate the learning process while avoiding complications. The risk of permanent neurological deficit as a result of DCCA ranges from 0.3-0.5%. Factors that correlated with complications include the following: the history of cerebral infarction, infusion of a large amount of contrast medium, a prolonged fluoroscopic time (>80 min) and the efficiency of training received. These findings suggest that the neurological morbidity depends largely upon the technique of catheterization of the patient. In order to reduce the complications arising from the lack of training, a personalised mentorship with a careful supervision of trainees is necessary. To ensure a good patient outcome, a decreased procedural time, awareness of complications at every step of the procedure and their avoidance, as well as the provision of good quality images is necessary. A mentorship program with a close supervision of the RFs is also one of the prerequisites for obtaining a good result. PMID- 29766916 TI - What is the current role of bypass surgery in the management of cerebral aneurysms? PMID- 29766917 TI - High time we focus on sleep in amyotrophic lateral sclerosis! PMID- 29766919 TI - Relapsing-remitting multiple sclerosis: Blood-brain barrier permeability and intravascular leakage measurement by dynamic contrast-enhanced MRI and the extended Tofts linear model. PMID- 29766918 TI - Sleep in amyotrophic lateral sclerosis. PMID- 29766920 TI - Dynamic contrast-enhanced MRI perfusion in multiple sclerosis: Is this the way to go? PMID- 29766921 TI - Quantification of blood brain barrier using DCE MRI in multiple sclerosis - Technical issues and its possible role in routine clinical practice. PMID- 29766922 TI - Carpal tunnel syndrome: The precipitating risk factors. PMID- 29766923 TI - Carpal tunnel syndrome: The lessons learnt and the points often overlooked in its management. PMID- 29766924 TI - Management of brain-stem hemangioblastomas: Surgical skill versus technological advancements. PMID- 29766925 TI - Management of brain-stem hemangioblastomas: A bird's-eye view. PMID- 29766926 TI - New daily persistent headache: An evolving entity. AB - New daily persistent headache (NDPH) is characterized by an abrupt onset of headache that becomes a daily entity, is unremitting and continuous from the onset, and lasts for more than 3 months. Dr Walter Vanast first described NDPH in the year 1986. Originally, it was proposed as a chronic daily headache but it was placed under "other primary headaches" in the International Classification of Headache Disorder Second Edition (ICHD 2nd edition). However, with evolving literature and better understanding of its clinical characteristics, it was classified as a "chronic daily headache" in the ICHD 3rd edition beta. There are still many knowledge-gaps regarding the underlying cause, pathophysiology, natural history and treatment of NDPH. This review tries to revisit the entity and discusses the current status of understanding regarding NDPH. PMID- 29766750 TI - Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. AB - BACKGROUND: Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS: In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS: A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS: In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .). PMID- 29766927 TI - Microvascular decompression versus stereotactic radiosurgery as primary treatment modality for trigeminal neuralgia: A systematic review and meta-analysis of prospective comparative trials. AB - Objective: The current opinion among neurosurgeons regarding the selection between microvascular decompression (MVD) and gamma knife radiosurgery for trigeminal neuralgia is not based on clear evidence. In this meta-analysis, we have attempted to synthesize the findings of the prospective trials comparing the efficacy and complications of the two procedures as primary treatment modality for medically refractory trigeminal neuralgia. Materials and Methods: The authors performed a systematic review of PubMed for manuscripts comparing the efficacy or complications of MVD and stereotactic radiosurgery for medically refractory trigeminal neuralgia. The data of the identified studies was pooled and a meta analysis was done. Results: Five prospective studies fulfilling the eligibility criteria were identified. The mean age of the patients subjected to gamma knife therapy (GKT) was more than those who underwent MVD. The initial success rate in the pooled data with MVD was 96% (95% confidence interval [C.I.] 93.3%-98.6%) as compared to GKT which was 71.8% (95% C.I. 64.9%-78.7%) with the ratio of 1.309 (95% C.I. 1.217-1.409; P= <0.001). This superiority was sustained till the last follow up available in all the studies. Out of the complications common to both procedures, MVD had a lower rate of facial numbness, with a risk ratio of 0.481 (95% C.I. 0.297-0.778); and dysesthetic pain, with a risk ratio of 0.470 (95% C.I. 0.172-1.286). Conclusions: MVD seems to be more efficacious than GKT as a first line treatment for trigeminal neuralgia immediately as well as on a long term basis. However, the dilemma regarding the choice of treatment to be adopted still remains for special subgroups of patients, like the elderly patients and those in whom no vascular compression has been found during surgery. Further studies are needed for elucidating the unequivocal treatment plan under these circumstances. PMID- 29766928 TI - Parent artery sacrifice for ruptured aneurysms in acute and chronic phases: A systematic review. AB - Background: Experience with respect to parent vessel sacrifice (PVS) for unclippable/uncoilable ruptured aneurysms is limited. Objective: The aim of the present systematic review was to evaluate the risk of PVS for unclippable/uncoilable ruptured aneurysms. Materials and Methods: The PUBMED and SCIENCEDIRECT databases were searched using "parent vessel occlusion OR parent artery occlusion" AND "acute subarachnoid hemorrhage" till December 27, 2015, and 1 journal was searched from November 1995 to April 2016 for relevant results. Results: Out of a total of 19 eligible studies, 104 patients with 104 ruptured aneurysms were treated by PVS with or without bypass surgery. Unfavorable outcome [modified Rankin Score (mRS) 4-6] was reported in 14 (13.4%) acute phase patients, with a 9.6% mortality rate. Thirty (28.8%) patients developed ischemic complications and 3 (2.9%) developed bleeding complications. The complication rate was higher for PVS in the acute phase (38.0% vs. 12.0%; P= 0.015). The unfavorable clinical outcome was found to be significant in acute phase versus chronic phase (17.7% vs. 0%; P= 0.024). The risk of morbidity associated with distal vessel [posterior cerebral artery (PCA) + superior cerebellar artery (SCA) + posterior inferior cerebellar artery (PICA)] sacrifice was not lower than that associated with major vessel [internal carotid artery (ICA) + basilar artery (BA) + vertebral artery (VA)] sacrifice (P = 0.961). Conclusion: Complication and unfavorable outcome rates associated with PVS for acutely ruptured aneurysms are high. The risk of distal vessel sacrifice was not lower than major vessel sacrifice in the acute phase. PMID- 29766929 TI - Sleep disorders in amyotrophic lateral sclerosis: A questionnaire-based study from India. AB - Background: Amyotrophic lateral sclerosis (ALS) is a relatively rare neurological disorder affecting upper and lower motor neurons in the brain and spinal cord with survival for 3-5 years and rarely beyond 10 years. Sleep disturbances in ALS are underreported and undertreated and there is no related data from India. This study aimed to assess the frequency of sleep disorders in patients of ALS and their determinants. Methods: Patients with definite and probable ALS as per the El Escorial criteria were recruited from May 2014 to April 2016. Functional impairment, presence of sleep specific abnormalities and anxiety and depression were assessed using standardized questionnaires. Results: Forty patients with ALS (23 male; 17 female) with their median age at presentation being 58.5 years (range 44-75 years) and the median duration of illness being 18 months (range: 4 120 months) were includedin the study. Half of the patients had poor sleep quality, which was significantly worse across all components of Pittsburgh Sleep Quality Index (PSQI) compared to controls. Sleep disorders were observed in 70%, insomnia in 65%, sleep disordered breathing/hypoventilation in 52.5% and restless legs syndrome in 5% patients. Night time awakenings attributable to symptoms associated with ALS were noted in 85%, and anxiety and depression in 57.5% patients. Excessive daytime somnolence emerged as an independent predictor for the presence of sleep disorders in ALS patients on multivariate logistic regression [P = 0.043, odd's ratio (OR) 1.435; 95% confidence interval[CI] (1.011 2.036)]. Conclusion: This is the first study from India providing insight into the presence of sleep disorders in ALS. About half of the patients of ALS had a poor sleep quality and two-thirds suffered from sleep disturbances. PMID- 29766932 TI - Prognostic value of cerebrospinal fluid lactate in meningitis in postoperative neurosurgical patients. AB - Objective: To evaluate the prognostic usefulness of cerebrospinal fluid (CSF) lactate in postoperative bacterial meningitis (POBM) and to establish the optimal CSF lactate cut-off values in our population to identify POBM in neurosurgical patients. Patients and Methods: A prospective study of postoperative neurosurgical patients with presumed and established bacterial meningitis in the Department of Neurosurgery, NIMS, Hyderabad, India, from September 2012 to December 2014. The diagnostic and prognostic values of CSF lactate have been evaluated and compared with other well-established CSF markers. All the patients who have undergone intradural cranial surgery with features of meningism have been included. Results: The study included 37 patients. The CSF value of the first lumbar puncture (LP) was taken to evaluate the diagnostic value of CSF lactate. Twenty three corresponded to Group A, and 14 to Group B. The mean CSF lactate in Group A was 5.94 +/- 2.36, and in Group B 4.60 +/- 2.31. Subsequent LPs were performed and CSF analyzed to evaluate the prognostic value of CSF lactate. The CSF markers like neutrophil count (P = 0.003), CSF/blood glucose ratio (P = 0.012), CSF lactate (P = 0.024), lymphocyte count (P = 0.046), leukocyte count (P = 0.047) have shown their prognostic value in a descending order. CSF markers like the presence of red blood cells (P = 0.540) and proteins (P = 0.757) did not show prognostic significance. The decline in CSF lactate (content and concentration) after initiation of antibiotics correlated with subsidence of fever (P = 0.0001), decrease in neck rigidity (P = 0.022) and improvement in sensorium. They were also correlated improvement in CSF/blood glucose ratio and CSF white blood cell counts. Conclusions: In our study, CSF lactate was noted to have a dependable prognostic value in POBM. As routine CSF markers can be ambiguous in POBM, CSF lactate can be considered a better alternative for both establishing the diagnosis and prognostication. PMID- 29766931 TI - In vitro differentiation of neural cells from human adipose tissue derived stromal cells. AB - Background: Stem cells, including neural stem cells (NSCs), are endowed with self renewal capability and hence hold great opportunity for the institution of replacement/protective therapy. We propose a method for in vitro generation of stromal cells from human adipose tissue and their differentiation into neural cells. Materials and Methods: Ten grams of donor adipose tissue was surgically resected from the abdominal wall of the human donor after the participants' informed consents. The resected adipose tissue was minced and incubated for 1 hour in the presence of an enzyme (collagenase-type I) at 370C followed by its centrifugation. After centrifugation, the supernatant and pellets were separated and cultured in a medium for proliferation at 370C with 5% CO2 for 9-10 days in separate tissue culture dishes for generation of mesenchymal stromal cells (MSC). At the end of the culture, MSC were harvested and analyzed. The harvested MSC were subjected for further culture for their differentiation into neural cells for 5-7 days using differentiation medium mainly comprising of neurobasal medium. At the end of the procedure, culture cells were isolated and studied for expression of transcriptional factor proteins: orthodenticle homolog-2 (OTX-2), beta-III-tubulin (beta3-Tubulin), glial-fibrillary acid protein (GFAP) and synaptophysin-beta2. Results: In total, 50 neural cells-lines were generated. In vitro generated MSC differentiated neural cells' mean quantum was 5.4 +/- 6.9 ml with the mean cell count being, 5.27 +/- 2.65 * 103/MUl. All of them showed the presence of OTX-2, beta3-Tubulin, GFAP, synaptophysin-beta2. Conclusion: Neural cells can be differentiated in vitro from MSC safely and effectively. In vitro generated neural cells represent a potential therapy for recovery from spinal cord injuries and neurodegenerative disease. PMID- 29766930 TI - Measurement of the permeability, perfusion, and histogram characteristics in relapsing-remitting multiple sclerosis using dynamic contrast-enhanced MRI with extended Tofts linear model. AB - Objective: To investigate the application value of using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) with extended Tofts linear model for relapsing-remitting multiple sclerosis (RRMS) and its correlation with expanded disability status scale (EDSS) scores and disease duration. Materials and Methods: Thirty patients with multiple sclerosis (MS) underwent conventional magnetic resonance imaging (MRI) and DCE-MRI with a 3.0 Tesla MR scanner. An extended Tofts linear model was used to quantitatively measure MR imaging biomarkers. The histogram parameters and correlation among imaging biomarkers, EDSS scores, and disease duration were also analyzed. Results: The MR imaging biomarkers volume transfer constant (Ktrans), volume of the extravascular extracellular space per unit volume of tissue (Ve), fractional plasma volume (Vp), cerebral blood flow (CBF), and cerebral blood volume (CBV) of contrast enhancing (CE) lesions were significantly higher (P < 0.05) than those of nonenhancing (NE) lesions and normal-appearing white matter (NAWM) regions. The skewness of Ve value in CE lesions was more close to normal distribution. There was no significant correlation among the biomarkers with the EDSS scores and disease duration (P > 0.05). Conclusions: Our study demonstrates that the DCE-MRI with the extended Tofts linear model can measure the permeability and perfusion characteristic in MS lesions and in NAWM regions. The Ktrans, Ve, Vp, CBF, and CBV of CE lesions were significantly higher than that of NE lesions. The skewness of Ve value in CE lesions was more close to normal distribution, indicating that the histogram can be helpful to distinguish the pathology of MS lesions. PMID- 29766933 TI - Corticospinal tract changes in acute brainstem ischemic stroke patients: A diffusion kurtosis imaging study. AB - Purpose: The present study aimed to investigate the corticospinal tract (CST) changes in patients with brainstem ischemic stroke by using the diffusion kurtosis imaging (DKI) approach.. Materials and Methods: Twenty-one patients with brainstem stroke and 21 group-matched healthy controls underwent brain DKI with 3.0 T magnetic resonance imaging (MRI). The DKI was obtained by using three b values of 0, 1,000, 2,000 s/mm2 with 15 diffusion directions. Regions of interest (ROIs) were placed at four levels: the pons, posterior limb of the internal capsule (PLIC), corona radiata, and precentral gyrus. The DKI parameters, including fractional anisotropy (FA), mean diffusivity (MD), and mean kurtosis (MK) values, in these regions were measured from the contralateral to the ipsilateral side of patients and both the left and right sides of healthy controls at all the four selected levels. Results: The ipsilateral side of the ischemic lesion showed a decrease in FA and MD and an increase in MK when compared with the contralateral normal region at all the four selected levels with statistically differences (P < 0.05). At these four selected levels, there were no differences between the left and right sides in healthy controls with MD, FA, and MK (P > 0.05). The MD values of the contralateral side of the ischemic lesion in patients at the four selected levels were significantly higher than those in the corresponding side of the healthy controls (P < 0.05). Compared to the healthy controls, there was a decrease at the posterior limb of the internal capsule (PLIC) in FA of the contralateral side of the ischemic lesion in stroke patients (P < 0.05). However, no significant differences were observed for MK values between the groups (P > 0.05). Conclusion: The current results suggest that the DKI technique could identify the early microstructural changes along the motor pathway and that these changes were not limited to the ipsilateral side of the ischemic lesion; in fact, the contralateral changes also occurred, especially at the PLIC. PMID- 29766935 TI - Brain metastasis and their management: A current perspective. PMID- 29766934 TI - Spectrum of metastatic neoplasms of the brain: A clinicopathological study in a tertiary care cancer centre. AB - Background: While brain metastases (BM) are the most common causes of neurologic disorders in patients with known systemic malignancies, they can often be the initial manifestations of an undetected primary elsewhere. BM are major causes of morbidity and mortality in cancer patients. Aims: We describe a mixed population (data from both retrospective and prospective collection) having a BM from a solid tumor. We report the percentage distribution of the most frequent types of BM, confirming the data published in the literature. This paper may play a role in presenting the Southeast Asian reality compared with the Western countries. Setting: A tertiary-care cancer centre. Materials and Methods: Data for 4 years were retrieved from the records of the Department of Pathology of our institute. Hematolymphoid and meningeal tumors were excluded. Hematoxylin and eosin (H and E) stained slides were reviewed, and in cases with an unknown primary, immunohistochemistry (IHC) was advised. The panel of markers was chosen based on the histomorphology on H and E sections. IHC was done in cases with an unknown primary where paraffin blocks were available. Results: Lung cancer was found to be the most common primary malignancy (n = 30; 48.4%) followed by breast cancer (n = 13; 21%), colorectal cancer (n = 6; 9.6%), and skin cancer (melanoma) [n = 3; 4.8%]. Conclusion: The incidence of BM from lung and breast cancer was similar to that seen in the Western studies. However, BM from colorectal cancer and melanoma show a higher and lower incidence, respectively, in comparison with the Western literature. PMID- 29766936 TI - Risk factors, symptom severity and functional status among patients with carpel tunnel syndrome. AB - Background: Carpal tunnel syndrome refers to a constellation of symptoms resulting from compression of the median nerve at the wrist. The characteristic symptoms include pain and numbness in the hands. Aim: To identify the risk factors responsible for carpal tunnel syndrome, to identify the symptom severity as well as functional status of patients with carpal tunnel syndrome, and to determine the relationship between symptom severity and functional status among patients with carpal tunnel syndrome. Settings and Design: A non-experimental descriptive study was conducted. Materials and Methods: A semi-structured questionnaire was administered to assess the risk factors. Standardized questionnaires included the symptom severity scale (SSS) and functional status scale (FSS). Results: The risk factors assessed were the female gender (64%), premorbidities (75%), diabetes mellitus (53%), hypertension (25%), dyslipidemia (24%), osteoarthritis (8%), and impaired thyroid functions (10%). Fifty-one patients were overweight and 8 were obese. There was an association between symptom severity and presence of any of the premorbidities (chi2 = 5.80; P < 0.05). There was also an association between symptom severity and diabetes mellitus (chi2 = 13.62; P < 0.05). A positive correlation was also noted between the symptom severity and the functional status of patients with carpal tunnel syndrome (r = 0.705; P = 0.00). Conclusions: Prompt recognition, timely management, and avoidance of risk factors responsible for the manifestations of carpal tunnel syndrome have practical implications in the treatment of carpal tunnel syndrome. PMID- 29766937 TI - Enhanced resection of primary high-grade gliomas using a combination of intraoperative magnetic resonance imaging and intraoperative fluorescence (5 aminolevulinic acid): A single-centre experience. AB - Background: The extent of resection (EOR) of a tumor is a proven prognostic factor in patients undergoing surgery for suspected high grade glioma. A few recent publications have shown the importance of intraoperative magnetic resonance imaging (iMRI) with 5-aminolevulinic acid (5-ALA) fluorescence-guidance in order to maximally increase the EOR. Aim: The objective of our study was to calculate the effect on survival of patients with high grade gliomas of resection using both iMRI and 5-ALA fluorescence-guidance as intraoperative adjuncts. Methods: Thirty-seven patients with gadolinum-enhancing high gliomas on preoperative MRI undergoing surgical excision were included in a prospective study. Surgeries began under white-light conditions. Intermittently, a blue light filter was switched on to search for remaining tumor tissue not visible to the naked eye. When gross total resection (GTR) was thought to have been achieved, iMRI was done to check for any contrast-enhancing part left behind. Surgery was concluded or resumed based on the iMRI findings. Histopathological examination of the tumor tissue was done. All patients underwent immediate postoperative MRI at the end of the surgery to calculate the EOR. Results: Our results showed that out of the total of 37 patients, 17 patients died during the follow up period and 11 patients were still alive. The mean survival was 587.1 days and median survival was 491 days with a range of 342 to 943 days. When we compared these figures with the average survival in patients with a high grade glioma, i.e., 9 to 14 months, it showed that both the above mentioned modalities were very helpful in increasing the EOR, and in turn, the overall survival. Conclusions: The use of iMRI as well as fluorescence-guidance are appropriate methods to improve the extent of resection in surgery of contrast-enhancing gliomas. Best results can be achieved by the complementary use of both modalities. PMID- 29766938 TI - Surgery for high-grade gliomas using intraoperative MRI and fluorescence. PMID- 29766939 TI - Minimally invasive options for surgical management of adjacent segment disease of the lumbar spine. AB - Background: The incidence of adjacent segment disease (ASD) after lumbar spine surgery is a condition that has become increasingly common as the rate of lumbar spine surgery continues to rise. Minimally invasive techniques continue to be refined and offer an opportunity to treat ASD with minimal tissue disruption, lower blood loss, a shorter hospital stay, and decreased morbidity. The aim of this report is to describe the various minimally invasive options for ASD with a comprehensive review of the existing literature. Materials and Methods: A retrospective chart review of patients undergoing minimally invasive spine surgery (MIS) for ASD of the lumbar spine was conducted. Four basic techniques and their modifications were identified to address ASD. Illustrative cases, surgical techniques, and post-surgical outcomes are described. Results: Four MIS techniques were identified as common surgical methods to correct ASD. (1) Non instrumented discectomy, foraminotomy, or decompression, (2) anterior lumbar interbody fusion (ALIF), (3) transforaminal lumbar interbody fusion (TLIF), and (4) lateral lumbar interbody fusion (LLIF) were found to be MIS techniques that address ASD. ALIF and LLIF provide indirect decompression of the neural foramina, while TLIF provides direct decompression. The addition and removal of screws and rods can be combined with any of these techniques. Conclusions: MIS techniques provide decompression of the neural elements, stabilization, and, potentially, fusion for patients with ASD. These illustrated cases and the review of MIS surgical techniques can provide a comprehensive framework for addressing ASD. PMID- 29766940 TI - Melanotic intracranial epidermoid: Case report and description of a new subtype. AB - Intracranial epidermoids are generally seen as hypodense nonenhancing lesions on computed tomography scans; and, as T1 hypointense and T2 hyperintense lesions on magnetic resonance imaging (MRI). Unusual radiological findings have been reported earlier. The authors present the case of a 54-year old male patient who had prior intracranial surgery. On MRI, there was a thick peripheral mantle of diffusion restriction with a central core of brilliant T1 hyperintensity and very black T2 hypointensity. The peripheral mantle showing diffusion restriction was heterogeneously T1 hypointense and T2 hyperintense. At surgery, there was a typical pearly white epidermoid peripherally with a greenish-brown centre. Pathology showed abundant extracellular melanin which was also found in the basal layer. The authors present the first case of a melanin pigmented intracranial epidermoid in literature, describing a new histological subtype. PMID- 29766941 TI - Idiopathic inflammatory myopathies in adults: A comparative study of Bohan and Peter and European Neuromuscular Center 2004 criteria. AB - Background: Bohan and Peter criteria are widely used for the diagnosis of idiopathic inflammatory myopathies (IIMs). Recently, European Neuromuscular Center (ENMC) formulated criteria to identify subgroups of IIMs. Aim: To compare the two diagnostic criteria in adult IIMs. Materials and Methods: This was a retrospective review of case records of histologically confirmed IIMs in adults between January 2014 and May 2015. Both the Bohan and Peter, and ENMC 2004 criteria were applied in the same group of patients to subgroup the IIMs. Muscle biopsy was evaluated in all the four domains: muscle fiber, inflammatory, connective tissue, and vascular, with the basic panel of histological stains. Sporadic inclusion body myositis (s-IBM) was diagnosed using ENMC IBM diagnostic research criteria 2011. Results: During the study period, 69 patients fulfilled the ENMC criteria for IIMs including 16 patients with s-IBM. The subgrouping as per the ENMC criteria (53) was: dermatomyositis (DM) in 30; polymyositis (PM) in 2; immune-mediated necrotizing myopathy (IMNM) in 9; and nonspecific myositis (NM) in 12 patients, whereas subgrouping by the Bohan and Peter criteria was DM in 9 and PM with and without connective tissue disease (CTD) in 26 patients only. There was underdiagnosis of DM, as perifascicular atrophy is not recognized as a diagnostic histological feature, and overdiagnosis of PM with and without CTD due to poor characterization of histological features in PM by the Bohan and Peter criteria. Conclusions: Systematic evaluation of muscle biopsy according to the ENMC criteria with basic panel of histochemical stains improved the diagnostic yield of IIM significantly when compared to the Bohan and Peter criteria. PMID- 29766942 TI - Thalamus and Language: What do we know from vascular and degenerative pathologies. AB - Language is a complex cognitive task that is essential in our daily life. For decades, researchers have tried to understand the different role of cortical and subcortical areas in cerebral language representations and language processing. Language-related cortical zones are richly interconnected with other cortical regions (particularly via myelinated fibre tracts), but they also participate in subcortical feedback loops within the basal ganglia (caudate nucleus and putamen) and thalamus. The most relevant thalamic functions are the control and adaptation of cortico-cortical connectivity and bandwidth for information exchange. Despite having the knowledge of thalamic and basal ganglionic involvement in linguistic operations, the specific functions of these subcortical structures remain rather controversial. The aim of this study is to better understand the role of thalamus in language network, exploring the functional configuration of basal network components. The language specificity of subcortical supporting activity and the associated clinical features in thalamic involvement are also highlighted. PMID- 29766944 TI - Craniovertebral junction evaluation by computed tomography in asymptomatic individuals in the Indian population. AB - Background: The available literature on the anatomy and imaging of the craniovertebral junction (CVJ) focusses on the osteometric indices described for the detection of abnormal relationships between the components of CVJ. However, a knowledge of the normal osteometry of this region in the Indian population is critically important for the operating surgeon as it may influence the surgical technique as well as the choice, size and configurations of the implants. It is also important to determine whether critical differences exist between the osteometric data of Indians and the rest of the world for this part of the anatomy. Accordingly, the present study is an attempt to quantitate the osteometric indices for the anatomically normal CVJ in Indian subjects. Materials and Methods: We retrospectively studied the imaging data of 49 consecutive adult patients (31 males, 18 females) who underwent a computed tomographic (CT) angiogram for suspected vascular conditions unrelated to the craniovertebral junction. Several parameters related to the atlanto-dental relationship, foramen magnum, atlas and axis vertebrae were recorded, including the dimensions of the commonly instrumented bony regions and also the indices related to the CVJ bony relationships. The data was also compared between the two genders, statistically through the Student's t-test using the statistical program "R". Results: No patient had an atlanto dens interval >2.5 mm. The mean distance of the odontoid tip from the McRae line in this series was 5.11 mm and no patient had the odontoid tip above the McRae line. Female subjects had significantly smaller diameters of C1 lateral masses and odontoid screw trajectory length when compared to males. Additionally, in the Indian population, the length range of odontoid screw trajectory and the thickness of the narrowest part of the C2 pedicles was smaller with respect to similar data from other geographical regions. However, the rest of the parameters resembled the data from studies conducted on populations with other ethnicities. Conclusion: The osteometric parameters of the CVJ in the Indian population are largely similar to those described globally. However, there are some important differences too which can influence the design of surgical implants suited to the Indian population. PMID- 29766943 TI - Brain-stem hemangioblastomas: The seemingly innocuous lesion in a perilous location. AB - Introduction: Hemangioblastomas [75% sporadic, 25% with Von Hippel Lindau (VHL) disease] are highly vascular, benign lesions. The surgical nuances, management, and complication avoidance in brain-stem hemangioblastomas (BHs) have been studied. Material and Methods: Over 18 years, 27(mean age: 29 years; range 15-60 years) consecutive cases of BH underwent microsurgical excision. All patients were assessed clinico-radiologically for neurological deficits and screened for VHL disease. Outcome of the patients was based on Karnofsky Performance Status scale (KPS). Results: 12 out of 19 (70.4%) patients with hydrocephalus underwent a cerebrospinal fluid (CSF) diversion procedure. Lower cranial nerve palsy was present in 10 (37%) patients and motor weakness in 13 (48%). The tumours [mean size 3.34 +/- 1.06 cm, range: 1.4-5.5 cm; 11 solid, rest solid-cystic; 18 (66.7%) subpial and 9 (33.33%) intramedullary] were divided into four categories based on size: A: <2 cm (n = 5,18.5%); B: 2-3 cm (n = 10,37%); C: 3-4 cm (n = 6,22.2%); D: >4 cm (n = 6,22.2%). Their location was at posterior cervicomedullary junction (n = 12); pontomedullary junction (n = 7); pons (n = 3), medulla (n = 3) and ponto mesencephalic region (n = 2). Multiple flow voids were seen in >50% patients with tumour >2 cm. 5 patients had syringomyelia; and, 8 had diffuse cervical cord expansion. Two patients with a large vascular tumour underwent preoperative embolization. Six patients had VHL disease; one underwent bilateral adrenalectomy for refractory hypertension; and, the another, nephrectomy for renal cell carcinoma. Twenty-six patients underwent a midline suboccipital craniectomy; and, 1 with a cerebellopontine angle tumour, a retromastoid craniectomy. 15 patients underwent total excision; 10 patients, near-total (<10% remaining) excision, and 2 patients, a subtotal (>10% remaining)) excision. Three patients (2 with VHL disease) expired due to exsanguinating hemorrhage, spreading venous thrombosis and aspiration pneumonitis, respectively. At follow-up visit (median: 25 +/- interquartile range 2-56months), 17 patients had improved KPS, 4 remained in same status and 3 (recently operated, on tracheostomy) had worsened KPS. Conclusions: Significant improvement is achievable in neurological status in patients following successful extirpation of a brain-stem hemangioblastoma, despite a turbulent perioperative period. Leaving tumour capsule adherent to the brain-stem often helps in preserving brain-stem function. Postoperatively, the patients should be monitored for their respiratory and lower cranial nerve status to prevent aspiration pneumonitis. PMID- 29766945 TI - Proposed solution for dorsal internal carotid artery aneurysms: Suggestion of a novel new clip design. AB - Dorsal internal carotid artery (ICA) aneurysms are notorious for their high morbidity and mortality. They have an extremely fragile wall and have a high chance of rupture and clip slippage during the intraoperative and postoperative period. Strategies proposed to mitigate these problems encompass including part of the normal ICA wall in addition to neck of aneurysm in clip blades, as well as the use of encircling materials (silicon, cellulose, Weck's clip) over a clip. The Achilles' heel of the problem is to take an appropriate thickness of the normal ICA in clip blades. Too less or too much of this can spell disaster. This is easier said than done during an actual surgical procedure. So, in this difficult situation, is there any better method of clipping? We propose a fenestrated clip in which the clip blades are placed just at the beginning of fenestration and at right angles to the clip. This occludes the aneurysm taking part of the normal ICA wall in the clip blades. The fenestration hugs the ICA and prevents clip slippage. This has been explained with appropriate figures in the two and three-dimensional format. There cannot be a single stop solution for a complex disease like dorsal ICA aneurysm. The present proposed design is an attempt to provide a better clipping chance in these difficult aneurysms. Future work on this design can prove its usefulness. PMID- 29766946 TI - Department of Neurosurgery, Madurai Medical College and the development of neurosurgery in South Tamil Nadu. AB - The development of neurosurgery in South Tamil Nadu can be traced to the Department of Neurosurgery, Madurai Medical College and Government Rajaji Hospital, Madurai, Tamil Nadu, India. The hospital was established in the year 1940 and Madurai Medical College was started in 1954. Prof. M. Natarajan founded this department in September, 1963. This department has a Neurosurgery Residency Program that is 50 years old. The establishment of this department and its growth to its present stature is documented here. PMID- 29766948 TI - Methamphetamine-induced internal carotid artery vasospasm: A rapidly fatal stroke. PMID- 29766949 TI - Inadvertent stent placement in the persistent hypoglossal artery: A case for caution. PMID- 29766947 TI - A summary of some of the recently published, seminal papers in neurosciences. PMID- 29766950 TI - False localizing oculomotor nerve palsy after endovascular coiling of a posterior communicating artery aneurysm. PMID- 29766951 TI - Pigmented intramedullary spinal cord meningioma mimicking a nervous system infection: An unusual report and review of the literature. PMID- 29766952 TI - Magnetic resonance imaging and magnetic resonance spectroscopy in varicella zoster necrotizing encephalitis. PMID- 29766954 TI - Necklace body myopathy: A rare entity. PMID- 29766953 TI - The mysterious case of bilateral sensory neural hearing loss (superficial siderosis). PMID- 29766955 TI - Episodic ataxia in a child with senataxin mutation. PMID- 29766956 TI - Retracing the natural history of Dravet syndrome: Report and review of literature. PMID- 29766957 TI - A rare association of Gorlin-Goltz syndrome. PMID- 29766958 TI - Peripheral primitive neuroectodermal tumor of cauda equina: A report and review of literature. PMID- 29766959 TI - Trigeminal neuralgia caused by a venous angioma: The neuroimaging and surgical findings. PMID- 29766961 TI - Anaplastic astrocytoma and pituitary macroadenoma within the same patient: A rare case of intracranial collision tumor. PMID- 29766962 TI - Giant cell tumor at the clivus: Not an area 51. PMID- 29766960 TI - Primary spinal cord glioblastoma metastasizing to the cerebellum: A missed entity. PMID- 29766963 TI - Intracranial chondroma without meningeal attachment. PMID- 29766964 TI - Calvarial intraosseous leiomyoma: Another consideration in children with suspected esosinophilic granuloma. PMID- 29766965 TI - Hypersexuality following anterior communicating artery aneurysm rupture. PMID- 29766966 TI - Primary cerebellar agenesis in a normal man. PMID- 29766968 TI - Cortical hyperintensities: A rare magnetic resonance imaging finding in Wilson's disease. PMID- 29766967 TI - A novel cost-effective pillow for prevention of an occipital pressure sore. PMID- 29766969 TI - Sieve-like basal ganglia: A rare MRI presentation of vascular parkinsonism. PMID- 29766970 TI - Fetal meningocele manque. PMID- 29766971 TI - Persistent primitive trigeminal artery- a study of two cases. PMID- 29766972 TI - Eye in the brain. PMID- 29766973 TI - Large serpentine aneurysm of the anterior cerebral artery. PMID- 29766974 TI - An unusual cause of combined cauda equina and conus medullaris syndrome. PMID- 29766975 TI - Why do we need the humanities in medicine? PMID- 29766977 TI - Change in the natural profile of Duchenne muscular dystrophy with the judicious use of steroids. PMID- 29766976 TI - Current trends in the management of intracranial aneurysms and how neurosurgical residency programs in India are falling behind in this revolution. PMID- 29766978 TI - Wilder Penfield. The second career with other essays and addresses. PMID- 29766979 TI - Playing it cool: Characterizing social play, bout termination, and candidate play signals of juvenile and infant Tibetan macaques (Macaca thibetana). AB - Play behaviors and signals during playful interactions with juvenile conspecifics are important for both the social and cognitive development of young animals. The social organization of a species can also influence juvenile social play. We examined the relationships among play behaviors, candidate play signals, and play bout termination in Tibetan macaques (Macaca thibetana) during juvenile and infant social play to characterize the species play style. As Tibetan macaques are despotic and live in groups with strict linear dominance hierarchies and infrequent reconciliation, we predicted that play would be at risk of misinterpretation by both the individuals engaged in the play bout and by those watching, possibly leading to injury of the players. Animals living in such societies might need to frequently and clearly signal playful intent to play partners and other group members to avoid aggressive outcomes. We gathered video data on 21 individually-identified juvenile and infant macaques (one month to five years of age) from the Valley of the Wild Monkeys, Mt. Huangshan, China. We used all-occurrence sampling to record play behaviors and candidate play signals based on an ethogram. We predicted that play groups would use multiple candidate play signals in a variety of contexts and in association with the number of audience members in proximity to the players and play bout length. In the 283 playful interactions we scored, juvenile and infant macaques used multiple body and facial candidate play signals. Our data showed that juvenile and infant Tibetan macaques use a versatile repertoire of play behaviors and signals to sustain play. PMID- 29766980 TI - Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling. AB - BACKGROUND Microvascular endothelial inflammation and apoptosis are responsible for septic acute lung injury (ALI). Ripasudil is a novel Rho/Rho kinase (ROCK) inhibitor which shows therapeutic effects on several vascular diseases. The aim of this study was to investigate the protective effects and correlated molecular mechanisms of ripasudil on lipopolysaccharide- induced inflammation and apoptosis of pulmonary microvascular endothelial cells (PMVECs). MATERIAL AND METHODS Cultured PMVECs were exposed to lipopolysaccharide (LPS). Ripasudil at various concentrations was used to treat the cells. Several cells were also co administrated with the endothelial nitric oxide synthase (eNOS) inhibitor Nomega Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cell viability was assessed by MTT assay. Terminal dUTP transferase nick-end labeling (TUNEL) assay was used to detect the apoptosis. The colorimetric method was used to measure the activity of eNOS and ROCK2. Protein phosphorylation and expression were assessed by Western blotting. RESULTS Ripasudil attenuated the LPS-induced inflammation and apoptosis in PMVECs, which was reversed by L-NAME. Ripasudil suppressed ROCK2 activity and further increased the eNOS activity. Ripasudil treatment increased the phosphorylation of eNOS, increased the expression level of Bcl2, and decreased the expression level of active caspase3 in LPS-treated PMVECs. Moreover, the ripasudil treatment also inhibited the nuclear translocation of NF kappaB and further suppressed the levels of interleukin (IL) 6 and tumor necrosis factor (TNF) alpha. The co-treatment with L-NAME, however, impaired the anti apoptotic and anti-inflammatory effects of ripasudil on PMVECs without affecting ROCK2. CONCLUSIONS The novel ROCK2 inhibitor ripasudil suppressed LPS-induced apoptosis and inflammation in PMVECs by regulating the ROCK2/eNOS signaling pathway. PMID- 29766982 TI - Effect of dietary supplementation of xylanase on apparent ileal digestibility of nutrients, viscosity of digesta, and intestinal morphology of growing pigs fed corn and soybean meal based diet. AB - This study was to determine apparent ileal digestibility of acid detergent fiber (ADF), neutral detergent fiber (NDF), dry matter (DM), energy, organic matter (OM), crude ash, digesta viscosity, and gut morphology in nursery pigs fed diets containing xylanase (Lohmann Animal Nutrition GmbH, Cuxhaven, Germany). The diet (61% corn, 35% soybean meal, 1% poultry fat, and 3% minerals and vitamins) was mixed with 3 levels of xylanase (0, 700, and 1400 LXU/kg). Thirty-six barrows (17.6 +/- 3.3 kg) received one of 3 treatment diets based on a randomized complete block design with the initial body weight (BW) as a block. Pigs were individually housed and received experimental diets twice daily (0700 and 1700 h) at a fixed amount based on BW of pigs (0.09 * BW0.75 kg). Pigs were fed diets for 10 d, and chromium oxide (0.3%) was added to the diets from d 6 as an indigestible external marker. Pigs were euthanized at the end of d 10 for the collection of digesta and tissues. Jejunal digesta were centrifuged to measure viscosity using a viscometer (Brookfield Engineering Laboratories, Stoughton, MA). Diets and freeze-dried ileal digesta were used to measure ADF, NDF, and chromium to calculate apparent ileal digestibility of ADF and NDF. Villus height and crypt depth of jejunum were measured using a microscope (Fisher Scientific, Hampton, NH). Data were analyzed using polynomial contrasts in the MIXED procedure of SAS version 9.3 (SAS Inc., Cary, NC, USA). Morphological measurements and ileal ADF digestibility were not affected by increasing xylanase. However, increasing xylanase supplementation from 0 to 1400 LXU/kg enhanced ileal digestibility of NDF (P < 0.042, linear) from 27.9 to 40.3%, DM (P < 0.006, linear) from 55.4 to 64.6%, OM (P < 0.006, linear) from 59.2 to 67.7%, and energy (P < 0.003, linear) from 58.8 to 68.0%. Viscosity of jejunal digesta decreased (P < 0.023) in a non-linear manner from 2.9 to 2.5 centipoises (cP). In conclusion, the usage of xylanase in corn and soybean meal based pig diets linearly enhanced digestibility of nutrients and affected viscosity of digesta in a non-linear manner. PMID- 29766981 TI - [Improvement of the management of outpatient consultations by a direct automatic citation of interconsultations]. AB - OBJECTIVE: The delay caused to provide an appointment and the uncertainty of the expected waiting time, are cause for discontent in the patients. The object of this work was to improve the accessibility to the consultation of specialized attention in our health area, decreasing the average waiting time and reduce the number of claims for this reason. METHODS: To measure the quality of the service provided, 5 criteria were developed and evaluated, by means of a cross section, in December 2015 for all patients pending appointment in the Area. Likewise, the complaints and claims collected during the 6 months prior to this date were quantified. As an intervention, a new circuit was designed and implemented in the interconsultation process, protocolizing a direct and automatic citation system. This system also eliminated patients without an appointment, allowing prioritization in preferred cases. At the end of 2016, a new evaluation was made with the same methodology. For the statistical analysis, Student's t and Chisquare were used. RESULTS: In six months the number of patients without appointment was reduced from 4726 to 0. The average waiting time for external consultations improved from 63 to 44.2 days. Patients waiting more than 50 days increased from 41.5% to 74.8%. The number of complaints and claims due to appointment in external consultations decreased from 161 to 80. CONCLUSIONS: Accessibility has improved by reducing the average waiting time and eliminating the list of patients without an appointment, although the number of patients pending appointments for more than 50 days has increased. The number of complaints and claims has been halved. PMID- 29766983 TI - Myokine interleukin-15 expression profile is different in suckling and weaning piglets. AB - Interleukin-15 (IL-15) is a cytokine highly expressed in skeletal muscle. The objective of the present study was to investigate the development of muscle IL-15 expression in suckling piglets and in early weaning piglets (day 14) at each level, that is, mRNA, protein, and secretion. Eight litters (eight piglets per litter) of newborn healthy piglets (Large * White * Landrace) with a similar initial weight (1618.0 +/- 140.1 g) were chosen and divided into two groups. Group one used suckling piglets that were killed, respectively, at days 1, 7, 14, 21, and group two used early (day 14) weaning piglets that were killed respectively, at days 15, 17, 19, 21. In group one, IL-15 gene expression levels increased significantly (P < 0.05) along with increased body weight over time. IL 15 protein expression levels in piglets at day 21 of age were higher (P < 0.05) than those in piglets at other ages, and there was no difference (P > 0.05) among piglets at other ages. These findings indicated that increased IL-15 mRNA expression did not result in a corresponding increase of its protein expression. In group two, which used early weaning piglets from days 15-19, IL-15 mRNA and protein expression levels increased constantly (P < 0.05) and were higher (P < 0.05) than those in suckling piglets. Moreover, there was no gain of body weight (P > 0.05) compared with suckling piglets at day 14 of age. However, IL-15 protein expression levels in early weaning piglets at day 21 of age dropped significantly (P < 0.05) to the levels as suckling piglets at day 21 of age, while body weight increased (P < 0.05) markedly to the levels as suckling piglets at day 21 of age. In both groups, the serum IL-15 levels of piglets decreased significantly (P < 0.01) over time. Taken together, our results indicate that IL 15 expression differs in suckling piglets and in weaning piglets. It is speculated that IL-15 may play an important role in counteracting the effects of early weaning stress. PMID- 29766985 TI - Effects of dietary protein level on nutrients digestibility and reproductive performance of female mink (Neovison vison) during gestation. AB - The objective of this study was to determine whether nutrient digestibility and reproductive performance of pregnant mink (Neovison vison) were affected by different dietary protein levels. One hundred and twenty female mink were randomly assigned to four groups, receiving diets of fresh material with different protein levels. The dietary protein levels, expressed as percentage of dry matter (DM), were 32, 36, 40 and 44% respectively. These values corresponded to average 320, 360, 400 and 440 g protein/kg DM, respectively. Results were as follows. All of crude protein digestibility, nitrogen (N) intake, N retention increased along with dietary protein level increasing. Low protein level (32%) significantly reduced the above indicators (P < 0.05). DM digestibility and ether extract digestibility were not affected by dietary protein level. Results of mated females, barren females, kids per litter, live born kids per mated female, birth survival rate, and birth weight showed that mink achieved optimal reproductive performance when dietary protein level was 36%. In conclusion, dietary protein was anticipated to significantly influence some nutrients' utilization. Adopting the appropriate dietary protein level allow better reproduction performance. The most preferable reproductive performance was achieved when diet contained 275.5 g digestible protein per kg DM for female mink in gestation. PMID- 29766987 TI - Comment on "Effect of Extracorporeal Shockwave Therapy Versus Intra-articular Injections of Hyaluronic Acid for the Treatment of Knee Osteoarthritis". PMID- 29766984 TI - Towards the control of necrotic enteritis in broiler chickens with in-feed antibiotics phasing-out worldwide. AB - Poultry production has undergone a substantial increase compared to the livestock industries since 1970. However, the industry worldwide is now facing challenges with the removal of in-feed antibiotics completely or gradually, as the once well controlled poultry diseases have re-emerged to cause tremendous loss of production. Necrotic enteritis (NE) is one of the most important diseases which costs the industry over two billion dollars annually. In this paper, we review the progress on the etiology of NE and its control through dietary modifications, pre- and probiotics, short chain fatty acids, and vaccination. The other likely measures resulted in the most advances in the toxin characterization are also discussed. Vaccine strategies may have greater potential for the control of NE mainly due to clearer etiology of NE having been elucidated in recent years with the identification of necrotic enteritis toxin B-like (NetB) toxin. Therefore, the use of alternatives to in-feed antibiotics with a better understanding of the relationship between nutrition and NE, and limiting exposure to infectious agents through biosecurity and vaccination, might be a tool to reduce the incidence of NE and to improve gut health in the absence of in-feed antibiotics. More importantly, the combinations of different measures may achieve greater protection of birds against the disease. Among all the alternatives investigated, prebiotics, organic acids and vaccination have shown improved gastrointestinal health and thus, have potential for the control of NE. PMID- 29766986 TI - Effects of casein glycomacropeptide supplementation on growth performance, intestinal morphology, intestinal barrier permeability and inflammatory responses in Escherichia coli K88 challenged piglets. AB - Casein glycomacropeptide (CGMP) is a bioactive peptide derived from milk with multiple functions. This study was aimed at evaluating the effects of CGMP as a potential feed additive on growth performance, intestinal morphology, intestinal barrier permeability and inflammatory responses of Escherichia coli K88 (E. coli K88) challenged piglets. Eighteen weaning piglets were randomly assigned to three groups. Control group and K88 challenged group received a basal diet, and CGMP treated group received the basal diet supplemented with 1% of CGMP powder. The trail lasted for 12 days, K88 was orally administered to the piglets of K88 challenged group and CGMP treated group on days 8-10. The results showed that the diet containing 1% CGMP significantly alleviated the decrease in average daily gain (P < 0.05), increase in pathogenic bacteria amounts in intestinal contents (P < 0.05), intestinal morphology (P > 0.05) and barrier permeability damage (P < 0.05), and acute inflammatory response (P < 0.05) induced by E. coli K88 infection. In conclusion, CGMP supplementation in the diet protected the weaning piglets against E. coli K88 infection. PMID- 29766988 TI - Effects of dietary copper on elemental balance, plasma minerals and serum biochemical parameters of growing-furring male mink (Mustela vison). AB - The objectives of this study were to study the effects of different levels of dietary copper on copper and zinc balance, plasma minerals and serum biochemical parameters of mink in the growing-furring periods. One hundred and five standard dark male mink were randomly assigned to seven groups with the following dietary treatments: basal diet with no supplemental Cu (Control); basal diet supplemented with either 6, 12, 24, 48, 96, or 192 mg/kg Cu from copper sulfate, respectively. The average daily gain (ADG) linearly (P = 0.0026, P = 0.0006) responded to increasing levels of Cu; maximal growth was seen in the Cu24 group. Feed efficiency tended to improve with the increase of dietary copper level (linear P = 0.0010, quad, P = 0.0011). Fecal copper, urinary copper, retention copper responded in a linear (P < 0.05) fashion with increasing level of Cu. The effect of level of Cu was linear (P < 0.001) for plasma Cu concentration. The serum glutamic-oxalacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) activities were increased linearly (P < 0.05) with dose of Cu, but serum total protein (TP) and albumin (ALB) concentrations decreased linearly (P < 0.05) as dietary copper levels increased. Effect of level of Cu was linear (P < 0.001) for serum ceruloplasmin (CER) concentration or Cu-Zn superoxide dismutase (Cu-Zn SOD) activity. Supplemental dose of Cu linearly decreased serum triglyceride (TG) (P = 0.011) and total cholesterol (TC) (P = 0.007). Our results indicated that the activity of Cu-dependent enzymes was enhanced by increasing dietary Cu concentration and that supplementation of Cu in the diet of mink could alter the plasma lipid profile and copper concentration. PMID- 29766989 TI - Mycotoxins and the intestine. AB - Fungal biochemical pathways can yield various compounds that are not considered to be necessary for their growth and are thus referred to as secondary metabolites. These compounds have been found to have wide ranging biological effects and include potent poisons (mycotoxins). Mycotoxins invariably contaminate crops and (thus) animal feeds. The intestine is the key link between ingested mycotoxins and their detrimental effects on the animal. Effects on the intestine, or intestinal environment, and immune system have been reported with various mycotoxins. These effects are almost certainly occurring across species. Most, if not all, of the reported effects of mycotoxins are negative in terms of intestinal health, for example, decreased intestinal cell viability, reductions in short chain fatty acid (SCFA) concentrations and elimination of beneficial bacteria, increased expression of genes involved in promoting inflammation and counteracting oxidative stress. This challenge to intestinal health will predispose the animal to intestinal (and systemic) infections and impair efficient digestion and absorption of nutrients, with the associated effect on animal productivity. PMID- 29766990 TI - Correction: Chidamide and decitabine can synergistically induce apoptosis of Hodgkin lymphoma cells by up-regulating the expression of PU.1 and KLF4. AB - [This corrects the article DOI: 10.18632/oncotarget.20659.]. PMID- 29766991 TI - Response: Commentary: Analysis of SUMO1-conjugation at synapses. PMID- 29766992 TI - Effects of dietary threonine:lysine ratioes and sanitary conditions on performance, plasma urea nitrogen, plasma-free threonine and lysine of weaned pigs. AB - Two 21 d-experiments were conducted to determine the optimum standardized ileal digestible (SID) threonine:lysine ratio (Thr:Lys) for weaned piglets reared under clean (Exp. 1) or unclean (Exp. 2) sanitary conditions and fed antibiotic-free diets. In each experiment, 90 mixed-sex pigs (Duroc * [Yorkshire * Landrace]; initial BW 7.2 +/- 0.3 kg) were randomly assigned to 5 dietary treatments each with 6 replicates (3 pigs per pen). The dietary treatments were 5 graded levels of SID Thr:Lys (55, 59, 63, 67 and 71%). Diets were corn-wheat-soybean meal-based with a constant SID Lys of 1.18% that was set to be second limiting amino acid. In Exp. 1 and Exp. 2, plasma-free Thr increased (P = 0.05) with increasing dietary SID Thr:Lys. In Exp. 1, the SID Thr:Lys for gain-to-feed ratio (G:F) was optimized at 65%. In Exp. 2, the estimated optimal SID Thr:Lys for overall G:F was 66.5%. In conclusion, an average optimal SID Thr:Lys of 65 and 66.5% could be used to optimize feed efficiency for weaned pigs under clean and unclean sanitary conditions, respectively. PMID- 29766993 TI - Specialized protein products in broiler chicken nutrition: A review. AB - In poultry nutrition, most attention is given to protein products, due to the importance of protein as a major constituent of the biologically active compounds in the body. It also assists in the synthesis of body tissue, for that renovation and growth of the body. Furthermore, protein exists in form of enzymes and hormones which play important roles in the physiology of any living organism. Broilers have high dietary protein requirements, so identification of the optimum protein concentration in broiler diets, for either maximizing broiler performance or profit, requires more knowledge about birds' requirements for protein and amino acids and their effects on the birds' growth performance and development. It also requires knowledge about the protein sources available that can be used in poultry diets. The broad aim of this review is to highlight the importance of some of the available high-quality specialized protein products of both animal and plant origins which can be explored for feeding broiler chickens. Minimization of the concentration of anti-nutritional factors (ANFs) and supplementation with immunologically active compounds are the main focus of gut health-promoting broiler diets. These diet characteristics are influenced by feed ingredient composition and feed processing. The general hypothesis is that these protein products are highly digestible and devoid of or contain less ANFs. Feeding these products to broiler chicks, especially at an earlier age, can assist early gut development and digestive physiology, and improve broiler growth performance and immunity. PMID- 29766995 TI - Effects of protein sources for milk replacers on growth performance and serum biochemical indexes of suckling calves. AB - This study investigated the effects of protein sources for milk replacers on growth performance and serum biochemical indexes of suckling calves. Fifty Chinese Holstein bull calves with similar BW and age were randomly allocated to 5 groups (1 control and 4 treatments) of 10 calves in each group. Five types of milk replacers were designed to have the same level of energy and protein. The protein source for milk replacers of the control group was full milk protein (MP). The protein source of milk replacers of the 4 treatment groups was composed of MP and one vegetable protein (VP) (30 and 70% of total protein). The 4 types of VP were soybean protein concentrate (SP), hydrolyzed wheat protein (WP), peanut protein concentrate (PP), and rice protein isolate (RP). Results of the experiment showed: 1) there was no significant difference on average daily gain (ADG) and feed:gain ratio (F:G) among the MP, SP and RP groups (P > 0.05), whereas the ADG and F:G of the WP and PP groups were significantly lower compared with the MP group (P < 0.05); 2) there was not a significant difference in withers height, body length and heart girth among treatment groups compared with the MP group (P > 0.05). Thereby the 4 VP milk replacers had no adverse effects on body size of calves; 3) all groups showed no significant difference in the serum contents of urea nitrogen, total protein, albumin, globulin, beta hydroxybutyrate, growth hormone, insulin-like growth factor-1, and the ratio of albumin to globulin (A:G) (P > 0.05). In conclusion, SP or RP (accounts for 70% of the total protein) as calf milk replacers could substitute MP, whereas wheat gluten and PP had a significant adverse effect on growth performance in this experiment. PMID- 29766996 TI - Effects of dry dietary protein on digestibility, nitrogen-balance and growth performance of young male mink. AB - The experiment was to study the nutrient digestibility and metabolism performance of male minks, which were fed different protein level diets during growth period. Effects of protein quantity on growth and development of minks and feed conversion ratio (FCR) were also investigated. Sixty healthy male minks of 45 d were randomly allocated into six groups with ten replicates, which was one sable for each replicate. The minks in six groups were fed diets in which protein levels were 28, 30, 32, 34, 36 and 38%, respectively. The six groups were denoted as P28, P30, P32, P34, P36 and P38. After 2 wk, all minks were weighed, average daily gains (ADG) were calculated, and the digestibility values of nutrients were determined. The results indicated that digestibility of calcium, nitrogen of fence, nitrogen deposition, net protein utilization (NPU), and biological value of protein (BV) were similar (P > 0.05), however, nitrogen intake greatly varied among groups (P < 0.01). Compared with group P28, groups of P34, P36 and P38 showed significant difference (P < 0.01) in ADG and FCR. In conclusion, it was recommended that adding 34% protein to mink diet would optimize production parameters including ADG, digestibility of nutrition, and FCR, and negative result was observed when diet protein was lower than 28%. PMID- 29766994 TI - Responses of heat shock protein 70 and caspase-3/7 to dietary selenomethionine in juvenile white sturgeon. AB - An 8-week feeding trial was conducted to investigate the responses of juvenile white sturgeon (Acipenser transmontanus) to elevated dietary selenium (Se) based on the determination of the RNA/DNA ratio in muscle, heat shock protein 70 (Hsp70), and caspase-3/7 in muscle and/or liver tissues. Four semi-purified test diets were prepared by adding different levels of L-selenomethionine (0, 50, 100, and 200 mg/kg diet). The analytical determinations of total Se were 2.2, 19.7, 40.1, and 77.7 mg/kg diet. The sturgeon (initial body weight: 30 +/- 2 g; mean +/ SEM) were raised in indoor tanks provided with flow through freshwater (18-19 degrees C). There were three replicates for each dietary treatment with 25 fish per replicate. The liver and muscle tissues were collected at 4 and 8 weeks after feeding the test diets. A significant interaction between duration and levels of dietary Se exposures on RNA/DNA ratio in the muscle tissue was detected (P < 0.05). Although there was no significant main effect due to the duration of dietary Se exposures (i.e., 4 weeks versus 8 weeks) on muscle RNA/DNA ratio (P >= 0.05), the ratio was significantly decreased with increasing dietary Se levels. Significant main effects were caused by the duration and levels of dietary Se exposures on Hsp70 in both the muscle and liver tissues, with significant increases in Hsp70 due to a longer exposure (8 weeks) and higher levels (40.1 and 77.7 mg Se/kg diet) of dietary Se. The caspase-3/7 activity in the liver were significantly higher in fish fed the diets containing 40.1 and 77.7 mg Se/kg diet than those fed the other diets. The toxic thresholds of Se in the muscle were estimated to be 32.2 and 26.6 mg Se/kg for the depressed specific growth rate and the induced Hsp70 response in muscle, respectively. This result indicated that the Hsp70 response in muscle is a more sensitive biomarker than the SGR of sturgeon for evaluating Se toxicity in white sturgeon. Results of the current study suggest that a mechanism involved with the activation of stress protein production and apoptosis protects white sturgeon from the lethal effect of Se. PMID- 29766997 TI - Bioinformatic analysis of the ssc-miR-146b upstream promoter region. AB - Sus Scrofa microRNA-146b-5p (ssc-miR-146b) was found to be one of differentially expressional microRNAs (miRNA) in our previous study. Not only it is highly expressed but also it maintains the largest up-regulated differences on the expressional level at different time points in the small intestinal mucosa of weaned piglets. To further explore the regulation mechanism of microRNA-146b-5p (miR-146b) during the stressful progress in weaned piglets, the present study predicted the functions of the ssc-miR-146b upstream promoter region using biological analysis. The analytical results showed that ssc-miR-146b is an intergenic miRNA. The length of the promoter region of ssc-miR-146b was predicted to be 2,249 bp using the Ensemble database. The length of the CpG island in the ssc-miR-146b promoter region was found to be 167 bp and it was located from 464 to 630 bp. Twenty six binding sites of 9 transcription factors in the upstream promoter region, including the sites of genes such as Sp1, AP-1, MyoD, GATA etc, were discovered using different kinds of analytical software. The predictions of the CpG island and transcription factor binding sites provided significant information for further studying the transcriptional regulation mechanism of ssc miR-146b on the small intestinal injury due to weaning stress. PMID- 29766998 TI - Improving leadership and management education in medical school. PMID- 29766999 TI - Effects of applying lactic acid bacteria to the fermentation on a mixture of corn steep liquor and air-dried rice straw. AB - This study was to determine the fermentation quality of a mixture of corn steep liquor (CSL) (178 g/kg wet basis) and air-dried rice straw (356 g/kg wet basis) after being treated with inoculants of different types of lactic acid bacteria (LAB). The treatments included the addition of no LAB additive (control), which was deionized water; homo-fermentative LAB alone (hoLAB), which was Lactobacillus plantarum alone), and a mixture of homo-fermentative and hetero-fermentative LAB (he + hoLAB), which were L. plantarum, Lactobacillus casei, and Lactobacillus buchneri. The results showed that the inoculation of the mixture of CSL and air dried rice straw with he + hoLAB significantly increased the concentration of acetic acid and lactic acid compared with the control (P < 0.05). The addition of he + hoLAB effectively inhibited the growth of yeast in the silage. The concentration of total lactic acid bacteria in the he + hoLAB-treated silage was significant higher than those obtained in other groups (P < 0.05). The duration of the aerobic stability of the silages increased from 56 h to >372 h. The control group was the first to spoil, whereas the silage treated with he + hoLAB remained stable throughout the 372 h period of monitoring. The results demonstrated that the he + hoLAB could effectively improve the fermentation quality and aerobic stability of the silage. PMID- 29767000 TI - Differences of hormones involved in adipose metabolism and lactation between high and low producing Holstein cows during heat stress. AB - The experiment was conducted to evaluate hormonal involvement in the adipose metabolism and lactation between high and low producing dairy cows in a hot environment. Forty Holstein healthy cows with a similar parity were used and assigned into high producing group (average production 41.44 +/- 2.25 kg/d) and low producing group (average production 29.92 +/- 1.02 kg/d) with 20 cows in each group. Blood samples were collected from caudal vein to determine the difference of hormones related to adipose metabolism and lactation. The highest, lowest, and average temperature humidity index (THI), recorded as 84.02, 79.35 and 81.89, respectively, indicated that cows were at the state of high heat stress. No significant differences between high and low producing groups were observed in the levels of nonestesterified fatty acid (NEFA), beta-hydroxybutyrate (beta OHB), total cholesterol (TCHO), and insulin (INS) (P > 0.05). However, the very low density lipoprotein (VLDL), apolipoprotein B100 (apoB-100), high-density lipoprotein (HDL-C) and estrogen (E2) concentrations in high producing group were significantly higher than those of low producing group (P < 0.05). No significant differences between high and low producing groups were observed in the levels of prolactin (PRL) and progesterone (PROG) (P > 0.05), whereas high producing group had a rise in the insulin-like growth factor-1 (IGF-1) level compared with low producing group (P < 0.05). These results indicated that, during summer, high and low producing dairy cows have similar levels of lipid catabolism, but high producing dairy cows have advantages in outputting hepatic triglyceride (TG). PMID- 29767001 TI - Effects of dietary leucine supplementation on the gene expression of mammalian target of rapamycin signaling pathway and intestinal development of broilers. AB - This experiment was to investigate the effects of dietary leucine supplementation on the gene expression of mammalian target of rapamycin (mTOR) signaling pathway and intestinal development of broilers. A total of 384 one-day-old broilers were randomly assigned into 4 treatments with 6 replicates (16 broilers per replicate). Broilers in these treatment groups were offered the following diets with 1.37, 1.77, 2.17 and 2.57% of leucine. These diet treatments were named 1.37TM, 1.77TM, 2.17TM, and 2.57TM. The experiment lasted 21 days and all birds had free access to feed and water. Results indicated that there was no significant difference in body weight, average daily gain and average feed intake among all treatments (P > 0.05). The broiler duodenal villus height in 2.57TM was the lowest, but the highest occurred in 1.37TM on d 7 and 14 (P < 0.05). The villus height in the jejunum and ileum increased along with leucine level from 1.37 to 2.17%. The villus height of jejunum was significantly higher in 2.17TM than in 1.37TM on d 7 and 14, and the ratio of villus height to crypt depth (V:C) in the duodenum, jejunum and ileum increased significantly (P < 0.05) on d 21. The gene expression level of mTOR in the duodenum decreased with increasing leucine level and was higher in 1.37TM than in 2.57TM on d 7 and 14 (P < 0.05). On d 14 and 21 of the trial, the expression of S6K1 in the duodenum was higher in 1.37TM than in 2.57TM (P < 0.05), and the expression of mTOR, S6K1 in the jejunum and ileum increased with increasing leucine level form 1.37 to 2.17%, whereas a significant difference occurred between 1.37TM and 2.17TM (P < 0.05). In conclusion, the addition of leucine fails to enhance the growth performance of broilers. However, leucine can improve intestinal development by enhancing villus height and V:C ratio in the jejunum and ileum. Moreover, the expression of mTOR, S6K1 increased as the level of dietary leucine was elevated from 1.37 to 2.17%. PMID- 29767002 TI - Effects of dietary cellulose levels on the estimation of endogenous amino acid losses and amino acid digestibility for growing pigs. AB - Two experiments were conducted to investigate the effects of dietary cellulose levels on the determination of the ileal endogenous losses (IEL) of amino acids (AA), apparent ileal digestibility (AID) and standardized ileal digestibility (SID) of AA in corn-soybean meal diets for growing pigs. In the first experiment, 28 pigs (BW, 45.1 +/- 2.0 kg) that were fitted with simple T-cannulas at the distal ileum were fed 4 nitrogen-free diets consisting of 4 dietary cellulose levels (0, 3%, 6% and 9%) in a randomized complete block design. In the second experiment, 28 pigs (BW, 45.6 +/- 2.0 kg) fitted with simple T-cannulas at the distal ileum were fed 4 corn-soybean meal diets consisting of 4 dietary cellulose levels (0, 3%, 6% and 9%) in a randomized complete block design. There were 7 replicates per diet with 1 pig as a replicate in each treatment. Both experiments consisted of a 7-d adjustment period and a 2-d ileal digesta collection period on d 8 and 9. Chromic oxide was used as an indigestible marker to calculate IEL and digestibility of AA. The results showed that the IEL of AA for growing pigs was not influenced by dietary cellulose supplementation (P > 0.05). The AID of Thr, Ser, Glu, Cys, Ile, Tyr, Phe, Lys and His decreased with increasing cellulose supplementation levels for pigs fed corn-soybean meal diets (P < 0.05). The SID of Thr, Ser, Cys, Val, Ile, Tyr, Phe, Lys and His decreased with increasing cellulose supplementation levels in corn-soybean meal diets (P < 0.05). In summary, dietary cellulose levels had no effect on the estimation of IEL of AA for growing pigs. The AID and SID of most AA in corn-soybean meal diets decreased with increasing levels of dietary cellulose supplementation. PMID- 29767004 TI - Medical students' experiences of resuscitation: a medical student's perspective. PMID- 29767003 TI - Recent advances on the circadian gene PER2 and metabolic rhythm of lactation of mammary gland. AB - Due to regulation by circadian rhythm, the lactation of the mammary gland has rhythmicity. As one of prominent members of period protein family which regulates biological rhythms, PER2 plays an important role in developing the milk duct and maintaining the polarity and the morphology of the mammary epithelium; at the same time, it is also closely related with the metabolism of milk protein and milk fat. This paper summarized recent researches on PER2 gene and related researches on mammary gland development and metabolism to provide some information for the studies of the theory and technology on physiological functions of the mammary gland and milk quality control. PMID- 29767005 TI - Effect of indigenous fungi on ochratoxin A produced by two species of Penicillium. AB - Interaction between indigenous fungal strains in preventing ochratoxin A (OTA) production by Penicillium verrucosum and Penicillium nordicum was studied in 100 mL of Czapek yeast autolysate (CYA) medium in a 250-mL "U" shaped culture vessel in one end for 3 days. At the end of incubation period, test fungi inoculated and incubated at 27 +/- 2 degrees C for another 14 days to study the inhibition of OTA production was estimated by high performance liquid chromatography (HPLC). Total inhibition of OTA production was recorded with Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus ustus, Fusarium culmorum, Fusarium graminarium, Fusarium proliferatum, Penicillium chrysogenum, Penicillium expansum and Trichoderma viridae. A significant correlation coefficient (r) on growth (0.493, P <= 0.0003) and OTA production (0.785, P <= 0.0001) was observed between the tested Penicillium species and other co-existing fungi. In conclusion, the present investigation revealed that those indigenous fungi are necessary to minimize potential losses to the poultry farmer and toxicological hazards to the consumer as biological control agent in different foods and feeds. PMID- 29767006 TI - Effect of dietary supplementation with protease on growth performance, nutrient digestibility, intestinal morphology, digestive enzymes and gene expression of weaned piglets. AB - This study was conducted to investigate the effect of dietary protease supplementation on the growth performance, nutrient digestibility, intestinal morphology, digestive enzymes and gene expression in weaned piglets. A total of 300 weaned piglets (21 days of age Duroc * Large White * Landrace; initial BW = 6.27 +/- 0.45 kg) were randomly divided into 5 groups. The 5 diets were: 1) positive control diet (PC), 2) negative control diet (NC), and 3) protease supplementations, which were 100, 200, and 300 mg per kg NC diet. Results indicated that final BW, ADG, ADFI, crude protein digestibility, enzyme activities of stomach pepsin, pancreatic amylase and trypsin, plasma total protein, and intestinal villus height were higher for the PC diet and the supplementations of 200 and 300 mg protease per kg NC diet than for the NC diet (P < 0.05). Supplementations of 200 and 300 mg protease per kg NC diet significantly increased the ratio of villus height to crypt depth (VH:CD) of duodenum, jejunum and ileum compared with NC diet (P < 0.05). Feed to gain ratio, diarrhea index, blood urea nitrogen, and diamine oxidase were lower for the PC diet and supplementations of 200 and 300 mg protease per kg NC diet than for the NC diet (P < 0.05). Piglets fed the PC diet had a higher peptide transporter 1 (PepT1) mRNA abundance in duodenum than piglets fed the NC diet (P < 0.05), and supplementations of 100, 200 and 300 mg protease per kg NC diet increased the PepT1 mRNA abundance in duodenum (P < 0.05) comparing with the NC diet. Piglets fed the PC diet had a higher b0,+AT mRNA abundance in jejunum than piglets fed the NC diet (P < 0.05), and supplementations of 200 and 300 mg protease per kg NC diet increased the b0,+AT mRNA abundance in jejunum and ileum comparing with the NC diet (P < 0.05). In summary, dietary protease supplementation increases growth performance in weaned piglets, which may contribute to the improvement of intestinal development, protein digestibility, nutrient transport efficiency, and health status of piglets when fed low digestible protein sources. PMID- 29767007 TI - Nutritional evaluation of integral cassava root silages for growing pigs. AB - The experiment aimed at determining the nutritional value of integral cassava root silages with yogurt as inoculant or wastewater (manipueira) by liquid addition ensiling process. Eighteen crossbred piglets (Large White * Landrace), castrated males with an initial average weight of 50 kg were allocated in metabolism cages throughout 11-day trial duration (6 days for animal's adaptation to the cages and to the experimental diets, and 5 days of urine and faeces collection). The experimental design was a randomized block arrangement with 3 treatments and 6 replicates: basal diet (100%); mixture composed of 75% basal diet and 25% integral cassava root silage with yogurt as inoculant; a mixture composed of 75% of basal diet and 25% integral cassava root silage with wastewater. The silages with wastewater and yogurt presented the following values of apparent digestibility of dry matter 89.96% and 90.01%, apparent digestibility of crude protein of 60.67% and 66.43%, apparent digestibility of gross energy of 90.43% and 91.48%, gross energy metabolizability coefficients of 87.88% and 88.93%, digestible energy values of 3,705 and 3,783 kcal/kg on a dry matter (DM) basis, and metabolizable energy values of 3,600 and 3,676 kcal/kg DM, respectively. The results have demonstrated that integral cassava root silages with wastewater or yogurt have a high nutritional value and can be used as an alternative energy source in growing pig's diets. PMID- 29767008 TI - Progress in the biological function of alpha-enolase. AB - Alpha-enolase (ENO1), also known as 2-phospho-D-glycerate hydrolase, is a metalloenzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid in the glycolytic pathway. It is a multifunctional glycolytic enzyme involved in cellular stress, bacterial and fungal infections, autoantigen activities, the occurrence and metastasis of cancer, parasitic infections, and the growth, development and reproduction of organisms. This article mainly reviews the basic characteristics and biological functions of ENO1. PMID- 29767009 TI - Effects of metabolizable energy and crude protein levels on laying performance, egg quality and serum biochemical indices of Fengda-1 layers. AB - This study was conducted to investigate the effects of dietary ME and CP levels on laying performance, egg quality and serum biochemical indices of Fengda-1 layers. In a 2 * 3 factorial arrangement, 2,400 Fengda-1 layers (32 wk of age) were randomly assigned to 6 experimental diets with 2,650 and 2,750 kcal of ME/kg of diet, each containing 14.50%, 15.00% and 15.50% CP, respectively. Each dietary treatment was replicated 5 times, and feed and water were provided ad libitum. The trial lasted for 10 wk, including a 2-week acclimation period and an 8-week experimental period. Our results showed that ADFI decreased as the ME level of diet increased from 2,650 to 2,750 kcal/kg (P < 0.05). Layers fed diets with 2,750 kcal/kg ME exhibited higher mortality than those fed with 2,650 kcal/kg ME (P < 0.05). Birds fed with 14.50% and 15.00% CP had higher egg production (EP) and egg mass (EM) than those fed with 15.50% CP (P < 0.05). Yolk color increased as the ME level of the diet increased from 2,650 to 2,750 kcal/kg, however, the eggshell thickness decreased (P < 0.05). Serum concentrations of uric acid and triglyceride in layers fed diets with 2,750 kcal/kg ME were higher than those fed diets with 2,650 kcal/kg ME (P < 0.05). There was no significant interaction between ME and CP on laying performance, egg quality, or serum biochemical indices (P > 0.05). Based on the data under the experimental conditions, the optimal dietary ME and CP levels of Fengda-1 layers are 2,650 kcal/kg and 15.00% (33 to 41 wk of age). PMID- 29767010 TI - The influence of graded levels of available phosphorus on growth performance, muscle antioxidant and flesh quality of young grass carp (Ctenopharyngodon idella). AB - Growth, muscle composition, meat quality characteristics and antioxidant capacity in muscle of young grass carp (Ctenopharyngodon idella) (initial weight 282.9 +/- 3.3 g) fed graded levels of phosphorus (1.0, 2.5, 3.8, 5.6, 7.8 and 9.5 g/kg diet) for 8 wk were investigated. Results indicated that percentage weight gain, feed intake, feed efficiency, serum phosphorus and alkaline phosphatase were improved with optimal phosphorus supplementations (P < 0.05). Muscle protein content and water holding capacity were significantly elevated, while moisture, lipid and ash contents were significantly decreased with dietary phosphorus to a certain level (P < 0.05). The meat shear force value and hydroxyproline content were not influenced by different levels of phosphorus. Muscle anti-hydroxyl radical, superoxide dismutase, catalase, glutathione S-transferase activities and glutathione content were significantly improved (P < 0.05). Conversely, anti superoxide anion, glutathione reducase and glutathione peroxidase activities were decreased (P < 0.05) with dietary phosphorus to a certain level. These results indicated that suitable dietary phosphorus improved growth performance, meat quality and muscle antioxidant capacity. Dietary available phosphorus requirement of young grass carp for percentage weight gain was 4.0 g/kg diet. PMID- 29767012 TI - Corrigendum to "The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation". AB - [This corrects the article DOI: 10.1155/2017/8415205.]. PMID- 29767011 TI - Cassava chip (Manihot esculenta Crantz) as an energy source for ruminant feeding. AB - Cassava (Manihot esculenta Crantz) is widely grown in sub-tropical and tropical areas, producing roots as an energy source while the top biomass including leaves and immature stems can be sun-dried and used as cassava hay. Cassava roots can be processed as dried chip or pellet. It is rich in soluble carbohydrate (75 to 85%) but low in crude protein (2 to 3%). Its energy value is comparable to corn meal but has a relatively higher rate of rumen degradation. Higher levels of non protein nitrogen especially urea (1 to 4%) can be successfully incorporated in concentrates containing cassava chip as an energy source. Cassava chip can also be processed with urea and other ingredients (tallow, sulfur, raw banana meal, cassava hay, and soybean meal) to make products such as cassarea, cassa-ban, and cassaya. Various studies have been conducted in ruminants using cassava chip to replace corn meal in the concentrate mixtures and have revealed satisfactory results in rumen fermentation efficiency and the subsequent production of meat and milk. In addition, it was advantageous when used in combination with rice bran in the concentrate supplement. Practical home-made-concentrate using cassava chip can be easily prepared for use on farms. A recent development has involved enriching protein in cassava chips, yielding yeast fermented cassava chip protein (YEFECAP) of up to 47.5% crude protein, which can be used to replace soybean meal. It is therefore, recommended to use cassava chip as an alternative source of energy to corn meal when the price is economical and it is locally available. PMID- 29767013 TI - Inhibition of lipid oxidation in foods and feeds and hydroxyl radical-treated fish erythrocytes: A comparative study of Ginkgo biloba leaves extracts and synthetic antioxidants. AB - This study explored the effects of butylated hydroxytoluene (BHT) and ethoxyquin (EQ) and ethyl ether extracts, ethyl acetate extracts (EAE), acetone extracts, ethanol extracts and aqueous extracts of Ginkgo biloba leaves (EGbs) on lipid oxidation in a linoleic acid emulsion, fish flesh and fish feed and in hydroxyl radical (.OH)-treated carp erythrocytes. The linoleic acid, fish flesh and fish feed were incubated with BHT, EQ and EGbs at 45 degrees C for 8 d, respectively, except for the control group. The lipid oxidation in the linoleic acid emulsion, fish flesh and fish feed was then measured by the ferric thiocyanate method or thiobarbituric acid method. The carp erythrocytes were treated with BHT, EQ or EGbs in the presence of 40 MUmol/L FeSO4 and 20 MUmol/L H2O2 at 37 degrees C for 6 h, except for the control group. Oxidative stress and apoptosis parameters in carp erythrocytes were then evaluated by the commercial kit. The results showed that BHT, EQ and EGbs inhibited lipid oxidation in the linoleic acid emulsion, fish flesh and fish feed and .OH-induced phosphatidylserine exposure and DNA fragmentation (the biomarkers of apoptosis) in carp erythrocytes. Furthermore, BHT, EQ and EGbs decreased the generation of reactive oxygen species (ROS), inhibited the oxidation of cellular components and restored the activities of enzymatic antioxidants in .OH-treated carp erythrocytes. Of all examined EGbs, EAE showed the strongest effects. The effects of EAE on lipid oxidation in the linoleic acid emulsion and on superoxide anion and malonaldehyde levels, catalase activity and apoptosis in .OH-treated carp erythrocytes were equivalent to or stronger than those of BHT. Moreover, these results indicated that the inhibition order of EGbs on the generation of ROS and oxidation of cellular components in fish erythrocytes approximately agreed with that for the food and feed materials tested above. And, the antioxidative and anti-apoptotic effects of EGbs were positively correlated with their flavonoid content. Taken together, these results revealed that the fish erythrocyte system can be used as an experimental model to evaluate lipid oxidation in food and feed ingredients. The EAE can be used as a potential natural antioxidant or apoptosis inhibitor. The inhibition effects of EGbs on lipid oxidation and apoptosis may be due to the presence of flavonoid compounds. PMID- 29767015 TI - Effects of dietary nanocrystalline cellulose supplementation on growth performance, carcass traits, intestinal development and lipid metabolism of meat ducks. AB - The influence of nanocrystalline cellulose (NCC) supplementation on growth performance, carcass traits, intestinal development, and lipid metabolism was assessed in 600 one-day-old male meat ducks (Cherry Valley ducks) from 1 to 35 d of age. Diets were supplemented with 0, 200, 500, 800 and 1,500 mg/kg NCC during both the starter (1-14 d) and grower (15-35 d) phases. Each dietary treatment consisted of 8 replicate cages of 15 birds. Supplementation of NCC was associated with dose dependent increases in BW gain and feed intake (P < 0.01) during 1-14 d of age and in BW at 35 d of age. As NCC content increased, the percentage of breast meat weight (P < 0.05) and leg (with bone) weight (P < 0.05) linearly increased, while the percentage of abdominal fat weight (P < 0.01) linearly decreased in ducks at 35 d of age. Supplementation of NCC resulted in a dose dependent increase in the weight (P < 0.05) and density (P < 0.01) of the cecum. The percentage of total hepatic lipid content (P < 0.01) at 14 d of age and serum triglyceride (TG) concentration (P = 0.052) at 35 d of age linearly decreased with increasing of dietary NCC addition. In conclusion, inclusion of 1,500 mg/kg NCC in feed resulted in the greatest improvements in duck performance, intestinal development and lipid deposition. PMID- 29767016 TI - Monitoring the fibrolytic potential of microbial ecosystems from domestic and wild ruminants browsing tanniferous forages. AB - Although the rumen microbiome has been reported to synthesize a rich source of symbiotic enzymes (exocellulase, endocellulase, hemicellulase and cellobiase), the digestion of tropical C4 grasses and browses by ruminants is still limited. Therefore, this study aimed to unveil potential fibrolytic microbial ecosystems from giraffe, kudu, impala and consortia (A1 [giraffe + kudu], A2 [giraffe + impala], A3 [kudu + impala], and A4 [giraffe + kudu + impala]) browsing tanniferous plants, which can be used to improve forage utilization in domesticated goat. Crude protein enzyme extracts (CPZ) from fresh faecal samples were precipitated by 60% ammonium sulphate and assayed for exocellulase, endocellulase and hemicellulase by incubating with crystalline cellulose, carboxymethyl cellulose and xylan at 38 degrees C with optimum pH of 5.5 to 6.5 for 1, 2, and 48 h, respectively. Enzyme specific activities were defined as MUg of reducing sugar/mg CPZ. In vitro fermentation study was done by transferring 33 mL of fresh faecal inoculum into 67 mL of salivary buffer containing 1 g Acacia sieberiana and incubating for 72 h at 38 degrees C. Apparent degradability (APDeg), true degradability (TD), neutral detergent fibre degradability (NDFdeg), acid detergent fibre degradability (ADFdeg), microbial yield (MY), metabolizable energy (ME) and total gas emitted (Gas) were measured. Exocellulase activities were higher (P < 0.05) in all wild animals and consortia than those in goat except for A4. Minimal differences in hemicellulase activities (P < 0.05) were observed among goat and wild animals and consortia, while endocellulase activity was generally higher (P < 0.05) in goat than that in the rest of the systems. Apart from A3, TDeg, NDFdeg and ADFdeg were higher (P < 0.05) in all microbial ecosystems from wild animals and consortia than those in goat. Apparent degradability, MY and ME also varied (P < 0.05) among these systems. Giraffe, Kudu and A3 produced lower (P < 0.05) gas than the goat system. This study showed that microbial ecosystems from wild browsers (especially impala) and consortia possess a higher potential to digest tanniferous forage with less enteric gas production compared with domesticated goat, hence those microbiome could be exploited as microbial feed additives for improving digestibility and reducing enteric gas production in domesticated goat. Improvements of goat's digestibility will depend on the survival and establishment of microbial species in the rumen as well as their fibrolytic and symbiotic potential including tannin tolerance. PMID- 29767014 TI - Effects of weaning age on growth, nutrient digestibility and metabolism, and serum parameters in Hu lambs. AB - This study was conducted to investigate the effect of weaning age on growth performance, nutrient digestion and metabolism, and serological indicators, and to obtain an optimal weaning age in Hu lambs. Forty-eight newborn Hu lambs (birth weight, 2.53 +/- 0.14 kg) were randomly divided into 4 groups. The lambs in control group (ER) suckled their dams. The lambs in other three experimental groups were weaned on milk replacer at 10, 20, and 30 days of age (EW10, EW20, and EW30 groups), respectively. The results were as follows: 1) lambs in EW10 and EW30 groups had a lower (P < 0.05) ADG than those in ER group within 10 days post weaning; the weaned lambs began to show a higher (P < 0.05) ADG than those in ER group after 20 days post-weaning. 2) EW10 and EW20 groups had a higher (P < 0.05) creep feed intake than EW30 and ER groups from 15 to 60 days of age. 3) The apparent digestibility of dry matter, organic matter, gross energy, nitrogen, ether extract and phosphorus, and the deposition of nitrogen and phosphorus did not differ (P > 0.05) among groups; however, the apparent digestibility and deposition of calcium in early weaned lambs were lower (P < 0.05) than those in ewe-reared lambs. 4) The albumin content in EW30 group was lower (P < 0.05) than that in ER group; the globulin content in EW30 group was higher (P < 0.05) than that in other groups; the content of serum insulin-like growth factor-I in weaned lambs tended to increase compared with lambs in ER group. Finally, the growth rate of lambs decreased within 10 days post-weaning, but early weaning boosted creep feed intake, leading to better growth and health later in life. The Hu lambs can be weaned on milk replacer and creep feed at 10 days of age. PMID- 29767017 TI - The use of near infrared transmittance kernel sorting technology to salvage high quality grain from grain downgraded due to Fusarium damage. AB - The mycotoxins associated with specific Fusarium fungal infections of grains are a threat to global food and feed security. These fungal infestations are referred to as Fusarium Head Blight (FHB) and lead to Fusarium Damaged Kernels (FDK). Incidence of FDK >0.25% will lower the grade, with a tolerance of 5% FDK for export feed grain. During infestation, the fungi can produce a variety of mycotoxins, the most common being deoxynivalenol (DON). Fusarium Damaged Kernels have been associated with reduced crude protein (CP), lowering nutritional, functional and grade value. New technology has been developed using Near Infrared Transmittance (NIT) spectra that estimate CP of individual kernels of wheat, barley and durum. Our objective is to evaluate the technology's capability to reduce FDK and DON of downgraded wheat and ability to salvage high quality safe kernels. In five FDK downgraded sources of wheat, the lowest 20% CP kernels had significantly increased FDK and DON with the high CP fractions having decreased FDK and DON, thousand kernel weights (TKW) and bushel weight (Bu). Strong positive correlations were observed between FDK and DON (r = 0.90); FDK and grade (r = 0.62) and DON and grade (r = 0.62). Negative correlations were observed between FDK and DON with CP (r = -0.27 and -0.32); TKW (r = -0.45 and -0.54) and Bu (r = -0.79 and -0.74). Results show improved quality and value of Fusarium downgraded grain using this technology. PMID- 29767018 TI - Effect of ground corn cobs as a fiber source in total mixed ration on feed intake, milk yield and milk composition in tropical lactating crossbred Holstein cows. AB - The aim of this study was to evaluate the effect of ground corn cobs (GCC) as a sole fiber source in total mixed ration (TMR) on feed intake, milk yield and milk composition in tropical lactating crossbred Holstein cows. Four multiparous crossbreds Holstein Friesian dairy cows with an initial body weight (BW) of 415.5 +/- 26.20 kg were used in a 4 * 4 Latin square design. The dietary treatments of TMR contained a roughage-to-concentrate ratio of 40:60. The roughage source was used at different ratios of GCC to rice straw (RS) at 100:0, 82.5:17.5, 67.5:32.5, and 50:50 for TMR1 to TMR4, respectively. The results revealed significant improvements in intake of dry matter, protein, neutral detergent fiber (NDF) and metabolizable energy (ME) for TMR1 and TMR2 (P < 0.05), while the digestibility of nutrients was not altered by the treatments (P >= 0.05). Ground corn cobs was used for up to 100% of the total roughage without affecting milk production. Moreover, ruminal pH, temperature, ammonia-nitrogen (NH3-N) and volatile fatty acid (VFA) concentrations were not impacted by the treatments (P > 0.05). However, milk yield was significantly different among the GCC:RS ratios (P < 0.05) and was the highest in TMR1 and TMR2 (13.1 kg/d), while the milk compositions were not changed (P > 0.05). The results imply that using GCC as a whole roughage source significantly improved nutrients intake and milk yield in dairy cows raised in tropical areas. PMID- 29767020 TI - Estimation of herbage intake and digestibility of grazing sheep in Zhenglan Banner of Inner Mongolia by using n-alkanes. AB - To reveal the seasonal dynamics of herbage intake, diet composition and digestibility and clarify the relationship of those with herbage nutrient and botanical composition of grazing sheep in Zhenglan Banner of Inner Mongolia, the n-alkane technique was used to test in sheep grazed during June, August and December. The results showed that the sheep mainly ate Fringed sagebrush, Stipa krylovii and Carex in proportions of 33.5, 17.9 and 21.2%, respectively, in spring. In summer, the sheep consumed cleistogenes, Potentilla tanacetifolia, Thyme, etc; the intake of Fringed sagebrush, Carex and Stipa declined. In winter, Fringed sagebrush accounted for 50.1% of herbage intake, and the intakes of Cleistogenes and Stipa krylovii increased to 15.3 and 18.4%, respectively. Herbage intake by the sheep in spring was 1.8 kg DM/d, and digestibility was 71.4%. Herbage intake and digestibility decreased slightly to 1.7 kg DM/d and 68.4% during the summer, respectively and decreased significantly to 1.2 kg DM/d and 36.4% in winter. There were significant correlations between diet composition and CP content in winter, diet composition and botanical composition in summer. A highly positive correlation between herbage intake and digestibility was observed in grazing sheep. PMID- 29767021 TI - Dietary composition affects odour emissions from meat chickens. AB - Abatement of odour emissions has become an important consideration to agricultural industries, including poultry production. The link between diet and odour emissions was studied in two experiments using Ross 308 male meat chickens reared in specially designed chambers in a climate controlled room. In the first experiment, two treatments were compared using three replicates of two birds per chamber. Two wheat-soy based treatment diets were formulated with or without canola seed, an ingredient rich in sulfur amino acids. Treatment 1 (T1) had 13.39 MJ/kg ME (as fed) and used 60 g/kg canola seed without corn while Treatment 2 (T2) contained 12.90 MJ/kg ME (as fed) and used 150 g/kg corn without canola seed. In the second experiment, birds were assigned to three dietary treatments of five replicates with five birds per replicate (chamber). The basal starter, grower and finisher diets in the control group (SBM group) contained soybean meal in the range of 227-291 g/kg (as fed) as the main protein source. The other treatments (CM and MBM groups) contained either high levels of canola meal (174 190 g/kg) or meat meal (74-110 g/kg) at the expense of soybean meal. In both experiments, diets were isocaloric, isonitrogenous and contained similar digestible amino acid contents as per 2007 Aviagen Ross 308 guidelines. Emissions of odour were measured using Fourier transform infrared (FTIR) spectroscopy. In both experiments, major odorous compounds detected included 2,3-butanedione (diacetyl), 2-butanone, dimethyl disulfide, methyl mercaptan, ethyl mercaptan, 2 butanol, 3-methyl-butanal, phenol and m-cresol. In the first experiment, T1 (with canola seed) produced higher concentration of methyl mercaptan (P < 0.05) and lower diacetyl (P < 0.01) than T2. In the second experiment, methyl mercaptan emission was higher in SBM group (P = 0.01) and total elemental sulfur were higher in SBM and CM groups up to day 24 (P < 0.01). Results of these experiments indicated a direct link between diet and odour emissions from meat chickens. PMID- 29767019 TI - Effects of pantothenic acid on growth performance, slaughter performance, lipid metabolism, and antioxidant function of Wulong geese aged one to four weeks. AB - This experiment was conducted to study the effects of pantothenic acid on the growth performance, slaughter performance, lipid metabolism, and antioxidant function of one-to four-week-old Wulong geese and determine the appropriate supplemental level of pantothenic acid. A total of 360 one-day-old Wulong geese were randomly divided into 6 groups with 6 replicates per group and 10 geese (5 males and 5 females) per replicate. The geese in group I (control group) were fed a basal diet, and the geese in groups II to VI (experimental groups) were given the basal diet supplemented with 8, 15, 30, 60, and 120 mg/kg pantothenic acid, respectively. The experiment lasted for 4 weeks. Based on the results of unrelated comparative analysis, the body weight was the highest when the dietary pantothenic acid level was 27.57 mg/kg. When the dietary pantothenic acid level was 26.17 mg/kg, the average daily gain peaked. When the dietary pantothenic acid level was 15.50 mg/kg, the feed:gain ratio was the lowest. The percentage of abdominal fat in groups III and IV was significantly lower than that in group I (P < 0.05). The content of total cholesterol in serum in groups III to V was significantly lower than that in group I (P < 0.05). The triglyceride content in groups III and IV was significantly lower than that in group I (P < 0.01). The high-density lipoprotein-cholesterol content in group IV was significantly higher than that in group I (P < 0.05). The total antioxidant capacity of serum and liver in group IV was significantly higher than that in group I (P < 0.05). The malondialdehyde content in the liver in groups III and IV was significantly lower than that in group I (P < 0.05). Glutathione peroxidase activity in the serum in group IV was significantly higher than that in group I (P < 0.05). Glutathione peroxidase activity in the liver in groups IV and V was significantly higher than that in group I (P < 0.01). The addition of pantothenic acid in the diet of one to four-week-old Wulong geese significantly affected the growth performance, slaughter performance, lipid metabolism, and antioxidant function of the geese. In terms of economic benefits, the optimal supplemental level of pantothenic acid in one-to four-week-old geese was 15.50 mg/kg. PMID- 29767022 TI - The in vitro effect of lipopolysaccharide on proliferation, inflammatory factors and antioxidant enzyme activity in bovine mammary epithelial cells. AB - Lipopolysaccharide (LPS) was selected as a stimulus to investigate its effect on cell viability and oxidative stress in bovine mammary epithelial cells (BMEC) by detecting the cell relative growth rate (RGR), antioxidant indicators and inflammatory factors. This information was used to provide the theoretical basis for the establishment of a LPS-induced oxidative damage model. The experiment was divided into two parts. The first part used a two-factor experimental design to determine the appropriate incubation time of LPS by detecting the RGR. The third passage BMEC were divided into 24 groups with six replicates in each group. The first factor was LPS concentration, which was 0 (control), 0.1, 1.0 and 10.0 MUg/mL; the second factor was LPS incubation time (2, 4, 6, 8, 12 and 24 h). The optimum LPS incubation time was 6 h according to the results of the first part of the experiment. The second part of the experiment was conducted using a single factor experimental design, and the third-passage cells were divided into four groups with six replicates in each group. The cells were incubated with culture medium containing different concentrations of LPS (0 [control], 0.1, 1.0 and 10.0 MUg/mL) for 6 h to select the appropriate concentration of LPS to measure the antioxidant indicators and inflammatory factors. The results showed the RGR was significantly reduced as the concentration of LPS and the incubation time increased; the interaction between concentration and incubation time was also significant. The cells treated with 0.1 MUg/mL of LPS for 6 h had no significant difference in the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) (P > 0.05) compared with the cells in the control group. On the contrary, catalase (CAT) activity and malondialdehyde (MDA) content were markedly lower and higher, respectively, in the 0.1 MUg/mL LPS-treated group for 6 h compared with the control group (P < 0.05). The activities of GPx, CAT and SOD in the BMEC treated with 1.0 or 10.0 MUg/mL of LPS were significantly lower compared with the cells treated with 0.1 MUg/mL of LPS and cells in the control group after 6 h of incubation; however, the opposite trend was detected in MDA content. There was no significant (P > 0.05) difference between the 10.0 and 1.0 MUg/mL LPS-treated groups. Compared with the control group, interleukin-1, interleukin-6 and nitric oxide concentrations and the activity of inducible nitric oxide synthase in the 0.1 MUg/mL LPS-treated group significantly increased (P < 0.0001), but the levels of tumour necrosis factor did not significantly change (P > 0.05). All of observed indicators were higher in the 1.0 and 10.0 MUg/mL LPS treated groups (P < 0.0001) compared with the other groups, but there was no significant (P > 0.05) difference between the 1.0 and 10.0 MUg/mL LPS-treated groups. The results indicated that a concentration of 1.0 MUg/mL of LPS and an incubation time of 6 h were the optimum conditions necessary to induce oxidative stress in the BMEC and establish a model for oxidative damage. PMID- 29767023 TI - Hospital-based violence intervention: an emerging practice based on public health principles. PMID- 29767024 TI - Pyrosequencing investigation into the influence of Cu2+, Zn2+, Fe2+ and I- mixtures on fungal diversity and toxigenic fungal growth in a fermented liquid feed. AB - A L9(34) orthogonal experiment was conducted to evaluate the influence of 9 mixtures which consisted of Cu2+, Zn2+, Fe2+ and I- ions at different ion concentrations on fungal diversity and toxigenic fungal growth in a Bacillus subtilis-fermented liquid feed (FLF) using pyrosequencing. The maximal Chao estimator and Shannon index were achieved in the FLF with a mixture of Cu2+ (200 mg/kg), Zn2+ (160 mg/kg), Fe2+ (150 mg/kg) and I- (2.4 mg/kg). The minimal relative abundance of Aspergillus was achieved when a mixture of Cu2+ (200 mg/kg), Zn2+, Fe2+ and I- was added to the FLF. Compared with Zn2+, Fe2+ and I-, Cu2+ was the most important ion in inhibiting Aspergillus growth. Adding Zn2+ (160 mg/kg), Cu2+, Fe2+ and I- to the FLF minimized the relative abundance of Fusarium. It was Zn2+ instead of Cu2+ played a critical role in suppressing the growth of Fusarium. The proper use of the mixture of Cu2+, Zn2+, Fe2+ and I- in FLF contributes to inhibit the growth of mycotoxin-producing fungi during storage. The new findings of this study help farmers properly use the mixture of Cu2+, Zn2+, Fe2+ and I- to inhibit the growth of mycotoxin-producing fungi in the production of high quality FLF and alleviate mycotoxins damages to animals and humans. PMID- 29767025 TI - Effects of dietary protein levels on the long-term growth response and fitting growth models of gibel carp (Carassius auratus gibelio). AB - A 41-wk growth trial was conducted to evaluate the effects of dietary protein levels on the long-term growth response and fitting growth models of gibel carp (Carassius auratus gibelio) with an initial body weight of 1.85 +/- 0.17 g. The dietary protein levels were designed at 320 (P32), 360 (P36), 400 (P40), and 440 g/kg (P44), respectively. The growth curves of the gibel carp for each group were fitted and analyzed with four nonlinear regression models (Gompertz, logistic, von Bertalanffy and Richards). The final body weights (mean +/- SD) of the fish were 226 +/- 6, 231 +/- 7, 242 +/- 2, and 236 +/- 2 g for P32, P36, P40, and P44, respectively. Feed conversion ratio of P40 and P44 groups was significantly lower than that of P32 and P36 groups (P < 0.05). Productive protein value of P44 group was significantly lower than that of P32 and P36 groups, but not different from that of P40 group (P >= 0.05). The growth response of the gibel carp for each group was the best fitted by Richards model with the lowest Chi2, residual sum of squares and residual variance, then Gompertz and von Bertalanffy growth models, but the logistic model did not fit the data well justified by Chi2 values. The optimal protein level (400 g/kg) prolonged the stage of fast growth and predicted the highest asymptotic weight, which was close to the harvest size in practice. PMID- 29767026 TI - Graded levels of sugar syrup in broiler rations and its effect on growth performance and blood biochemical parameters. AB - Dietary energy for chickens normally includes cereal grains and fat. This innovative study investigated the effect of replacing part of the corn and fat in broiler chicken rations with graded levels of sugar syrup on growth performance and biochemical parameters. Experimental treatments consisted of feeding a corn soy basal diet alone, or with graded levels of sugar syrup in increments of 5%, 10% and 15%. All starter diets were isonitrogenous and isocaloric. Body weight gain and efficiency of feed utilization of chicks fed the control diet alone were not significantly (P < 0.05) different from chicks fed diets supplemented with either 5% or 15% sugar syrup. Supplementation of sugar syrup to broiler diets had no significant effect on blood glucose, creatinine, total protein, or liver enzymes. Adding 5% sugar syrup to broiler rations significantly decreased blood cholesterol and triglycerides in chickens fed the sugar syrup diet compared with birds fed the control diet. In conclusion, the results shows sugar syrup can be used in poultry ration to replace part of the corn as a source of energy. These results allowed the authors to recommend the safe usage of sugar syrup in broiler rations. PMID- 29767027 TI - Studying the effect of formic acid and potassium diformate on performance, immunity and gut health of broiler chickens. AB - Our trial was conducted to study the effects of formic acid (FA) and potassium di formate (KDF) in broiler ration on performance, carcass traits, blood biochemical, intestinal microbial load, histological picture of intestine and immune parameters of broilers. In this study 360 one-day-old broiler chicks were divided to 3 groups with 3 replicates of 40 chicks each. The trial continued for 35 days. The control group was fed only basal diet (G1). Group 2 (G2) were fed basal diet supplemented with FA (5 g/kg diet), and group 3 (G3) received basal diet supplemented with KDF (5 g/kg diet). The results showed that both FA and KDF significantly increased body weight gain (BWG), dressing percentage of broilers and significantly decreased feed conversion ratio (FCR) (P < 0.05). The highest percent of breast and thigh was observed in G3. The improvement in villus height was observed in G2 and G3 compared with the control one, and the highest was in G3. The results evidence that the using of FA or KDF in broiler feeds have significant effects on performance, immune parameters, and gut health without having any significant effects on blood biochemical. However, KDF is more effective than FA as little amount of FA reaches the small intestine due to metabolism and absorption, whereas KDF permits a proportion of FA to pass through the fore-gut intact and enter the small intestinal tract. In addition, FA has a strong odor and corrosiveness to gastrointestinal tract which limits its use. PMID- 29767028 TI - Nutrient profile and digestibility of tubers and agro-industrial coproducts determined using an in vitro model of swine. AB - Exploring and evaluating alternative feed ingredients to be used in swine diet is essential due to highly variable cost and limited availability of conventional feed ingredients. Tubers and agro-industrial coproducts could provide the basis for producing affordable swine feed. However, information on the nutritional value of these potential alternative feedstuffs is necessary while considering their use in swine feeding program. Four tubers (purple sweet potato [PSP], okinawan sweet potato, taro and cassava) and 3 coproducts (okara, wheat millrun [WMR] and barley brewers grain [BBG]) were analyzed for their proximate nutrients, starch, fibers and gross energy (GE) content. Two independent in vitro studies were carried out for tubers and coproducts to determine their nutrients digestibility using a 3-step enzymatic assay (which mimics the digestion occurring in the gastrointestinal tract of swine) with 9 replicates of each sample digested in 3 batches equally. All replicate samples were used to determine in vitro dry matter digestibility (IVDDM) while 2 replicates from each batch were used to determine in vitro GE digestibility (IVDGE). Among tubers, CP content was the highest in taro (8.8%) and the lowest in cassava (3.7%), while CP content among coproducts was the highest in okara (22.7%) and the lowest in WMR (11.8%). Ether extract content among tubers ranged from 1.1% to 2.8%. The GE content among tubers, ranged from 4,134 to 4,334 kcal/kg whereas among coproducts it ranged from 4,270 to 4,794 kcal/kg. Among tubers, IVDDM for PSP was significantly higher (86.8%, P < 0.001) than taro (70.3%). Among coproducts, IVDDM of okara (74.1%) was significantly higher (P < 0.05) than BBG (61.3%). In conclusion, both tubers and coproducts can be used as a partial substitute of conventional energy feedstuffs in swine diets as these are rich in GE and other nutrients and are fairly digestible. PMID- 29767029 TI - Effects of infusing milk precursors into the artery on rumen fermentation in lactating cows. AB - This experiment was conducted to investigate the effects of infusing milk precursors into the external pudic artery on rumen fermentation in lactating dairy cows. Eight multiparous Holstein cows were randomly assigned to Group A (experimental group) and Group B (control group) with 4 cows each. A 2 * 4 complex factor crossover design was used. Cows in Group A were fed corn straw as the only roughage, and cows in Group B were fed mixed roughage. The experiment was divided into two periods. In the first period, cows in Group A, received treatments: 1) a basal infusate as a control (CSC); 2) a milk fat precursor infusion including C16:0, C18:0, C18:1c9, C18:2c6, C18:3n3, acetic acid (CSF); 3) a milk protein precursor infusion including 16 amino acids (CSA); 4) the mixed infusion of milk fat and protein precursors (CSFA). And meanwhile, cows in Group B were infused the basal infusate as a control group. In the second period, the cows in both Groups A and B were crossed over, which cows in Group A were named as Group B and the cows originally in Group B were in Group A. The experimental results showed that cows in experimental group had higher ruminal pH compared with the control, and ruminal pH in CSC, CSF, CSA were significantly higher than those in their respective control group (P < 0.05). The concentration of ammonia nitrogen (NH3-N) was significantly higher in CSA and CSFA compared with Group B (P < 0.05). We also observed that the infusion of mixed amino acids significantly increased the bacterial protein (BCP) content in rumen (P < 0.05) and influenced the rumen acetic acid concentration as well as the acetic to propionic ratio (P < 0.05). Milk fat precursors infusion significantly affected butyric acid concentration (P < 0.05). In addition, the content of lipopolysaccharide (LPS) in CSA was significantly higher than that in the control group (P < 0.05). It is concluded that the milk precursors infused into external pudic artery caused feedback effects on ruminal fermentation under the corn straw roughage conditions. The milk protein precursor increased the ruminal pH, the contents of BCP and acetic acid, which adjust rumen fermentation and improve milk performance. PMID- 29767030 TI - Commentary: Sleep Deprivation Promotes Habitual Control over Goal-Directed Control: Behavioral and Neuroimaging Evidence. PMID- 29767031 TI - Utilization of autoclaved and fermented sesame (Sesamum indicum L.) seed meal in diets for Til-aqua natural male tilapia. AB - Current research emphasis has been on the reduction of feed cost by incorporating processed sesame seed meal in the diet of tilapia. Raw sesame (Sesamum indicum) seed was soaked and subjected to either autoclaving or fermentation, after which their oil contents were mechanically extracted. Graded levels of autoclaved (71.2, 165.5 and 296.3 g/kg designated as diets 1, 2 and 3, respectively) and fermented (71.0, 164.3 and 292.2 g/kg designated as diets 4, 5 and 6, respectively) sesame seed meal were included into fishmeal based diets for Til aqua natural male tilapia (NMT) fry (initial weight, 1.69 +/- 0.02 g). A diet without sesame seed meal served as the control. Diets were approximately iso nitrogenous (35% crude protein). Fish were fed 5 times their maintenance requirement, which was 3.2 * 5 * [fish weight (g)/1,000]0.8 daily for 56 days. Processing improved the nutritional profile of raw sesame seed meal in terms of its crude protein and antinutrient compositions. Growth performance of fish was similar (P > 0.05) in the control and dietary treatments. The group fed diet 3 exhibited significantly poorer feed conversion ratio (1.14), protein efficiency ratio (2.77) and economic conversion ratio (US$1.38/kg) relative to the group that received diet 5. Apparent digestibility coefficients for protein, lipid and energy in diet 3 were similar (P > 0.05) to those in diet 6 but significantly lower (P < 0.05) than those of the control and other dietary groups. The sesame seed meals processed with different methods did not significantly affect crude protein, crude lipid and gross energy compositions in the fish carcass. The study demonstrated that 71.2 g/kg of autoclaved and 164.3 g/kg of fermented sesame seed meal could be incorporated in the diet of Til-aqua NMT with cost benefit. PMID- 29767032 TI - Correction to 'Isospectrals of non-uniform Rayleigh beams with respect to their uniform counterparts'. AB - [This corrects the article DOI: 10.1098/rsos.171717.]. PMID- 29767033 TI - The effect of diet supplemented with vegetable oils and/or monensin on the vaccenic acid production in continuous culture fermenters. AB - Studies have shown that supplementing ruminant diets with vegetable oils modulated the rumen biohydrogenation and increased polyunsaturated fatty acid in their products. These positive values are often accompanied by a marginal loss of supplemented unsaturated fatty acids and rise in the concentrations of saturated fatty acids. This study were carried out mainly to investigate the effect of supplementing diets with sunflower oil, olive oil with or without monensin on the production and accumulation of vaccenic acid (VA) in continuous culture fermenters as a long term in vitro rumen simulation technique. Eight dual-flow continuous culture fermenters were used in an 8 replication experiment lasted 10 days each (first 7 days for adaptation and last 3 days for samples collection). Supplementing diets with plant oils and monensin in the present experiment increased VA and conjugated linoleic acids (P > 0.05) in ruminal cultures. The results suggest that supplementing diets with both olive oil and sunflower oil and monensin increased VA accumulation compared to plant oils supplemented alone without affecting the rumen dry matter and organic matter digestibility. PMID- 29767035 TI - Erratum: Impact of MRI on changing management of the cervical spine in blunt trauma patients with a 'negative' CT scan. AB - [This corrects the article DOI: 10.1136/tsaco-2016-000016.]. PMID- 29767034 TI - Supplementation of branched-chain amino acids in protein-restricted diets modulates the expression levels of amino acid transporters and energy metabolism associated regulators in the adipose tissue of growing pigs. AB - This experiment was conducted to investigate the effects of branched-chain amino acids (BCAA) supplemented in protein-restricted diets on the growth performance and the expression profile of amino acid transporters and energy metabolism related regulators in the white adipose tissue (WAT) of different regional depots including dorsal subcutaneous adipose (DSA) and abdominal subcutaneous adipose (ASA). A total of 24 crossbred barrows (7.40 +/- 0.70 kg) were randomly divided into 4 groups and were fed the following isocaloric diets for 33 days: 1) a recommended adequate protein diet (AP, 20% CP, as a positive control); 2) a low protein diet (LP, 17% CP); 3) the LP diet supplemented with BCAA (LP + B, 17% CP) to reach the same level of the AP diet group; 4) the LP diet supplemented with 2 times the amount of BCAA (LP + 2B, 17% CP). The daily gain and daily feed intake of the LP diet group were the lowest among all the treatments (P < 0.01). The feed conversion was improved markedly in the group of LP + B compared with the LP diet group (P < 0.05). No significant difference was noted for the serum biochemical parameter concentrations of glucose, triglyceride, nonesterified fatty acid and insulin among the groups (P > 0.05). Moreover, BCAA supplementation down-regulated the expression levels of amino acid transporters including L-type amino acid transporter 1 and sodium-coupled neutral amino acid transporter 2 in DSA, but up-regulated the expression level of L-type amino acid transporter 4 in ASA (P < 0.05). Meanwhile, the energy sensor AMP-activated protein kinase alpha was activated in the DSA of pigs fed LP diet and in the ASA of the pigs fed AP or LP + 2B diets (P < 0.05). The mRNA expression profile of the selected mitochondrial component and mitochondrial biogenesis associated regulators in DSA and ASA also responded differently to dietary BCAA supplementation. These results suggested that the growth performance of growing pigs fed protein restricted diets supplemented with BCAA could catch up to that of the pigs fed AP diets. The results also partly demonstrated that the regulation mechanisms of BCAA are different in the adipose tissues of different depots. PMID- 29767036 TI - Response to: Comment on "First-Line Helicobacter pylori Eradication with Vonoprazan, Clarithromycin, and Metronidazole in Patients Allergic to Penicillin". PMID- 29767038 TI - Enzymology properties of two different xylanases and their impacts on growth performance and intestinal microflora of weaned piglets. AB - The enzyme xylanase is more and more widely used in feed production, but different xylanase have different properties, mechanism and application effects. To provide a theoretical basis for choosing more suitable xylanase in feed production, we selected bacterial xylanase (BX), labeled enzyme A, and trichoderma xylanase (TX), labeled enzyme B, and studied the enzymology properties and application effects on growth performance and gut flora in weaned piglets. The results showed that the activity levels of both appear parabolic along with increasing pH or temperature, but the amplitude of enzyme activity changing curves and the pH/temperature of optimal activity level are different, where enzyme A has the optimal activity level at 50 degrees C with a pH value of 5.0. The optimal activity level of enzyme B was achieved at 70 degrees C with a pH around 6.0. Enzyme B suffered very little activity loss with moisture level at 16% and temperature from 80 degrees C to 90 degrees C. Enzyme A suffered a big drop in activity level when processed with high temperature from around 80 degrees C to 90 degrees C, and it was even completely inactivated at 90 degrees C. Enzyme A has very low activity level after being processed in acid environment, but enzyme B has minor changes in activity level with respect to changes in acid level, indicating significantly different enzymatic properties between the two different sources of xylanases. In feeding experiment, the control group, was fed the basal diet, and the BX group and TX group were fed basal diets supplemented with 0.01% bacterial and fungal xylanases, respectively. The results showed that ADG of the BX group and TX group increased by 3.25% (P > 0.05) and 8.22% (P < 0.05), respectively, and the feed conversion ratio decreased by 6.74% and 7.86% (P > 0.05), respectively compared with the control group; TX group had significantly higher (P < 0.05) ADG compared with BX group; BX group and TX group had significantly lower ileum Escherichia coli level than the control group, which were reduced by up to 12.98% (P < 0.05) and 11.68% (P < 0.05), respectively, but the ileal lactic acid bacteria levels were significantly increased by 16.21% (P < 0.01) and 27.02% (P < 0.01), respectively. There were no significant differences (P > 0.05) between BX group and TX group in terms of lactic acid bacteria E. coli level. We concluded that fungal xylanase (enzyme B) has better performances in improving weaned piglet growth and in increasing ileal lactic acid bacteria level compared with bacterial xylanase (enzyme A). PMID- 29767037 TI - Impact of mycotoxin on immune response and consequences for pig health. AB - Mycotoxins are fungal secondary metabolites detected in many agricultural commodities, especially cereals. Due to their high consumption of cereals, pigs are exposed to these toxins. In the European Union, regulations and/or recommendations exist in pig feed for aflatoxins, ochratoxin A, fumonisins, zearalenone, and trichothecenes, deoxynivalenol and T-2 toxin. These mycotoxins have different toxic effects, but they all target the immune system. They have immunostimulatory or immunosuppressive effects depending on the toxin, the concentration and the parameter investigated. The immune system is primarily responsible for defense against invading organisms. The consequences of the ingestion of mycotoxin-contaminated feed are an increased susceptibility to infectious diseases, a reactivation of chronic infection and a decreased vaccine efficacy. In this review we summarized the data available on the effect of mycotoxins on the immune system and the consequences for pig health. PMID- 29767039 TI - Effects of aflatoxins on growth performance and skeletal muscle of Cherry Valley meat male ducks. AB - This study aims to evaluate the effects of aflatoxins on growth performance and skeletal muscle of Cherry Valley meat male ducks as they grow and develop. One day-old healthy meat male ducks (n = 180) were randomly divided into 2 groups; there were 6 replicates in each group and 15 ducks in each replicate. The control group was fed a basic diet, and the experimental group was fed a mold-exposed cottonseed meal diet containing aflatoxins instead of normal cottonseed meal. The experimental period was 35 days, and divided into two stages of 1 to 14 days (early stage) and 15 to 35 days (late stage). During the experimental period, live weight, breast muscle weight and thigh muscle weight of meat male ducks were measured weekly. Results showed as follows: 1) aflatoxins contained in the mold exposed diet significantly reduced daily weight gain and feed intake, and increased feed-to-gain ratio of meat male ducks at different ages (P < 0.05); 2) the Gompertz equation (Wt = Wm exp {-exp [-B (t - t* )]}) could successfully fit the growth curve and growth and developmental patterns of skeletal muscles of Cherry Valley meat male ducks (R2 >= 0.97); 3) the relationship between chest muscle and live weight was the best described by a power regression and polynomial regression (R2 = 0.99); the relationship between live weight and thigh muscle weight was the best described by linear regression, polynomial regression, and power regression (R2 = 0.99); 4) aflatoxins in the mold-exposed diet significantly reduced live weight, breast muscle weight and thigh muscle weight of Cherry Valley meat male ducks at various ages; and 5) aflatoxins delayed the age at peak in growth of meat male ducks, and reduced weights at the peak for breast muscle, thigh muscle and whole body as well as the maximal daily weight gain. In summary, aflatoxins delayed growth of Cherry Valley meat male ducks and development of skeletal muscle. PMID- 29767040 TI - Effect of medium-chain triglycerides on growth performance, nutrient digestibility, plasma metabolites and antioxidant capacity in weanling pigs. AB - The aim of this study was to investigate the effect of medium-chain triglycerides (MCTs) on growth performance, nutrient digestibility, plasma metabolites and antioxidant capacity in weanling pigs. A total of 160 weanling (Duroc * Landrace * Yorkshire) pigs (age: 21 +/- 1 d; body weight: 7.50 +/- 0.28 kg) were randomly allotted to 4 treatments, receiving the following diets for 28 d: control diet [containing 3.5% soybean oil (SO)], MCT1 diet (containing 0.7% MCTs and 2.8% SO), MCT2 diet (containing 1.4% MCTs and 2.1% SO) and MCT3 diet (containing 2.1% MCTs and 1.4% SO). Dietary inclusion of MCTs improved the average daily gain and feed efficiency (FE) of pigs compared with the control during the first 2 weeks post weaning (P < 0.05). A similar positive effect was also observed for the overall FE in MCT2 group (P < 0.05). Compared with the control, apparent total tract digestibility (ATTD) of ether extract was improved by MCT2 and MCT3 treatment from day 12-14 post-weaning (P < 0.05). In addition, MCT2 treatment also exerted a beneficial effect on the ATTD of dry matter (P < 0.05). The increased total protein concentration and decreased urea nitrogen and malondialdehyde levels of plasma were observed in both MCT2 and MCT3 groups on day 14 post-weaning (P < 0.05). In conclusion, MCTs could improve growth performance, nutrients utilization, and antioxidant ability of weanling piglets. PMID- 29767042 TI - Effects of dietary arginine levels on growth performance, body composition, serum biochemical indices and resistance ability against ammonia-nitrogen stress in juvenile yellow catfish (Pelteobagrus fulvidraco). AB - This experiment was conducted to investigate the effects of dietary arginine levels on growth performance, body composition, serum biochemical indices and resistance ability against ammonia-nitrogen stress in juvenile yellow catfish (Pelteobagrus fulvidraco). Five isonitrogenous and isolipidic diets (42% protein and 9% lipid) were formulated to contain graded levels of arginine (2.44%, 2.64%, 2.81%, 3.01% and 3.23% of diet), by supplementing L-Arginine HCl. Seven hundred juvenile yellow catfish with an initial average body weight of 1.13 +/- 0.02 g were randomly divided into 5 groups with 4 replicates of 35 fish each and each group was fed one of the diets. After 56 d feeding, fish were exposed to 100 mg/L of ammonia-nitrogen for 72 h. The results showed that weight gain (WG) and specific growth rate (SGR) in 2.64% and 2.81% groups were significantly higher than those in 3.23% group (P < 0.05). The feed conversation ratio (FCR) in 2.64%, 2.81% and 3.01% groups was significantly decreased when compared with 3.23% group. The protein efficiency ratio (PER) in 2.64% group was significantly higher than that in 2.44% and 3.23% groups (P < 0.05). The condition factor (CF) of fish was significantly higher in 2.81% group than that in 2.44% group (P < 0.05). Dietary arginine levels had no significant effect on hepatosomatic index (HSI), viscerosomatic index (VSI), and whole-body dry matter, crude protein, crude lipid, ash contents, as well as serum total protein (TP), triglyceride (TG), glucose (GLU), urea nitrogen (UN) contents and aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities (P > 0.05). After the fish were challenged to ammonia-nitrogen for 72 h, their cumulative mortality rate in 2.81% group was significantly lower than that in 2.44% group (P < 0.05). The results suggested that dietary arginine level at 2.81% could optimize anti-ammonia nitrogen stress ability of juvenile yellow catfish and a level of 3.23% arginine seemed to depress the growth performance of fish and decreased their tolerance to the ammonia-nitrogen stress under current study. A quadratic regression analysis based on WG indicated that the optimal dietary arginine requirement of juvenile yellow catfish was estimated to be 2.74% of the diet (6.45% of dietary protein) under current culture conditions. PMID- 29767041 TI - The cytotoxicity and protective effects of Astragalus membranaceus extracts and butylated hydroxyanisole on hydroxyl radical-induced apoptosis in fish erythrocytes. AB - Erythrocytes play an essential role in transporting O2 and CO2 for respiration in fish. However, erythrocytes continuously suffer from reactive oxygen species (ROS) -induced oxidative stress and apoptosis. Thus, it is essential to expand our knowledge of how to protect erythrocytes against ROS-induced oxidative stress and apoptosis in fish. In this study, we explored the cytotoxicity and the effects of butylated hydroxyanisole (BHA), ethyl ether extracts, ethyl acetate extracts, acetone extracts (AE), ethanol extracts, and aqueous extracts of Astragalus membranaceus (EAm) on hydroxyl radical (*OH)-induced apoptosis in carp erythrocytes. The rat hepatocytes and carp erythrocytes were incubated with different concentrations of BHA or EAm(0.125 to 1 mg/mL). The toxicity in rat hepatocytes and carp erythrocytes was then measured using a 3-(4, 5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and a haemolysis assay, respectively. The carp erythrocytes were treated with BHA or EAm in the presence of 40 MUmol/L FeSO4 and 20 MUmol/L H2O2 at 37 degrees C, except for the control group. Oxidative stress and apoptosis parameters in the carp erythrocytes were then evaluated using the commercial kit. The results indicated that at high concentrations, BHA and EAm could induce toxicity in rat hepatocytes and fish erythrocytes. However, BHA was more toxic than EAm at the same concentrations. Moreover, the toxicity order of BHA and EAm in the fish erythrocytes approximately agreed with that for the rat hepatocytes. Butylated hydroxyanisole and EAm suppressed the *OH-induced phosphatidylserine exposure and DNA fragmentation (the biomarkers of apoptosis) by decreasing the generation of ROS, inhibiting the oxidation of cellular components, and restoring the activities of antioxidants in carp erythrocytes. Of all of the examined EAm, the AE showed the strongest effects. The effects of AE on superoxide anion, H2O2, met haemoglobin and reduced glutathione levels, as well as glutathione reductase activity and apoptosis were equivalent to or stronger than those of BHA. These results revealed that the AE of Astragalus membranaceus could be used as a potential natural antioxidant or apoptosis inhibitor in fish erythrocytes. PMID- 29767043 TI - Study of Bacillus subtilis on growth performance, nutrition metabolism and intestinal microflora of 1 to 42 d broiler chickens. AB - To study the influence of different levels of Bacillus subtilis on growth performance, nutrition metabolism and intestinal microflora of 1 to 42 d Arbor Acres (AA) broilers, a total of 800 one-day-old healthy broilers were randomly divided into 5 groups with 4 replicates per group and 40 broilers per replicate. Broilers were fed a basic diet (group 1) which acted as the control group, and 4 other groups (2 to 5) were fed the basal diet with B. subtilis added at concentrations of 100, 150, 200 and 250 mg/kg, respectively for 42 days. The results showed as follow: the average daily gain (ADG) of group 4 was significantly higher than (P < 0.05) that of group 1, and the average daily feed intake (ADFI) of group 5 was the highest but the differences between groups were not significant (P > 0.05). The feed to gain ratio (F/G) of all the experimental groups was lower than that of the control and the difference was significant in group 4 (P < 0.05). In addition, supplementation of B. subtilis increased the apparent metabolism of crude protein (P > 0.05), crude fat (P > 0.05), dry matter (P > 0.05) and organic matter (P < 0.05). B. subtilis decreased the Escherichia coli and Salmonella populations in the cecum. This shows that adding B. subtilis to the broiler diet can improve the growth performance, increase feed efficiency, regulate serum index and reduce harmful bacteria in the intestinal tract. Based on our study, it could be recommended that addition of B. subtilis at 200 mg/kg could improve the growth performance of broilers. PMID- 29767044 TI - Optimizing bio-physical conditions and pre-treatment options for breaking lignin barrier of maize stover feed using white rot fungi. AB - The greatest limitation to utilization of maize stover by ruminants as a feed is the high concentration of lignin, which limits fibre digestibility. However, ruminants can effectively utilize maize stover if its nutritive value is improved using white rot fungal species. This study was designed to determine optimal bio physical conditions for mycelial growth and select the most ideal fungal species and pre-treatment options for improving nutritive value of maize stover. Four popular edible Pleurotus fungal species (viz. Pleurotus florida, Pleurotus ostreatus, Pleurotus sajor caju and Pleurotus pulmonarius) were subjected to varying temperatures, pH levels, hydrogen peroxide (H2O2) concentration and illumination to establish the extent of mycelial growth rate. Inclusion of H2O2 was used to determine optimal levels for preservation and prevention of contamination from other indigenous microbiota. Effects of pre-treatment options on chemical composition and nutritive value of maize stover were also examined. Mycelial growth rate of Pleurotus species on potato dextrose agar (PDA) varied (P < 0.05) with temperature, pH level and H2O2 concentration following a quadratic trend. Optimal temperature, pH and H2O2 concentration for mycelial growth on PDA were 25 degrees C, 5 and 0.01 mL/L, respectively. Under the different bio physical conditions, P. sajor caju had the highest mycelia density and growth rate. Chemical composition of solid-state fermented maize stover differed (P < 0.05) among the Pleurotus species. Maize stover fermented with P. sajor caju had the highest crude protein (CP) of 86.6 g/kg DM, in-vitro dry matter digestibility (IVDMD) of 731 g/kg DM, in-vitro organic matter digestibility (IVOMD) of 670.4 g/kg DM and metabolizable energy (ME) of 10.0 MJ/kg DM but with the lowest lignin (sa) of 50 g/kg DM. At 25 degrees C, P. sajor caju had the highest mycelial growth rate on PDA and highest lignin (sa) breakdown in the maize stover substrate. It was, therefore, selected as the most ideal fungal species for improving nutritive value of maize stover. Pre-treatment of maize stover with Lactobacillus plantarum and molasses under anaerobic condition for 7 days before inoculation with P. sajor caju resulted into a substrate with the highest (P < 0.05) CP (96.6 g/kg DM), IVDMD (752.3 g/kg DM), IVOMD (687.2 g/kg DM) and ME (10.2 MJ/kg DM). However, neutral detergent fiber exclusive of residual ash (NDFom) and lignin (sa) fractions decreased (P < 0.05) as a result of subjecting maize stover to pre-treatment with L. plantarum and molasses prior to fermentation with P. sajor caju. Therefore, pre-treatment of maize stover with L. plantarum and molasses for 7 days prior to fermentation with P. sajor caju for 14 days in darkness at 25 degrees C offered the greatest potential for breaking the lignin barrier. PMID- 29767045 TI - Reproductive stage associated changes in plasma fatty acid profile and proinflammatory cytokine expression in rat mammary glands. AB - Mastitis is a common disease for mammals all around the world. Figuring out why mastitis mainly occurs around parturition may be helpful for dealing with the disease. Lipolytic activity and oxidative stress take place around parturition, which may leads to alteration in fatty acids profile and proinflammatory cytokine expression. Thus, the aim of the present study was to further our understanding about the high incidence of mastitis around parturition by comparison of plasma fatty acid profile and mammary inflammation indicators at different reproductive stages. A total of 47 female rats were included in the present study. After mating, all the pregnant and non-pregnant rats began to receive the same experimental diet. Blood samples were collected at day 1 and 14 of gestation as well as day 3 postpartum. Mammary samples were collected at day 14 of gestation and day 3 postpartum from pregnant and non-pregnant rats. The results showed that rats at d 3 postpartum had greater (P < 0.05) plasma concentrations of non esterified fatty acids (NEFA), arachidonic acid (ARA) and docosahexaenoic acid (DHA) as well as ARA: eicosapentaenoic acid (EPA) ratio than those at d 14 of gestation. The mRNA abundances of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-8 and xanthine oxidoreductase (XOR) in mammary of the pregnant rats were greater (P < 0.05) than those in age-matched non-pregnant rats. Rats at d 3 postpartum had higher (P < 0.05) protein expression levels of IL-1beta and TNF-alpha as well as meloperoxidase (MPO) activity and polymorphonuclear neutrophils (PMN) prevalence than those at d 1 of gestation. The rats at d 3 postpartum also had greater (P < 0.05) IL-1beta and MPO activity than those at d 14 of gestation. The results indicated that elevated mammary expression of proinflammatory cytokines and XOR as well as altered fatty acid profile around parturition might facilitate the recruitment of neutrophils into mammary glands. PMID- 29767046 TI - Effects of mulberry leaf flavonoid and resveratrol on methane emission and nutrient digestion in sheep. AB - As a new type of methane control agent, natural plant extract has been widely studied in recent years, but in vivo studies are few. This study was to investigate the effects of the dietary supplementation of 2 different polyphenols on the methane (CH4) emission and digestion metabolism in sheep. Ten healthy crossbred sheep (Dorper ? * small-tailed Han ?; BW 60.0 +/- 1.73 kg) were used in a change-over design. The sheep were fed the following 3 diets in the present study: the basal diet (CON) with no supplementation; the basal diet supplemented with 2 g mulberry leaf flavonoid (MLF) per day per sheep; the basal diet supplemented with 0.25 g resveratrol (RES) per day per sheep. Both MLF and RES reduced CH4 emission scaled to metabolic weight per kilogram of DMI and CO2 output scaled to metabolic weight, but the effect of RES was significant (P < 0.05). Both MLF and RES significantly improved apparent digestibility of DM, OM, NDF, ADF, and nitrogen, but the effect of RES was significant (P < 0.05). Both MLF and RES significantly improved ME (P < 0.05) and reduced energy losses in CH4 emission (P > 0.05). In conclusion, MLF and RES can improve the digestibility of nutrients, the utilization of nutrients and energy, and reduce CH4 emission, but they are not conducive to nitrogen retention. PMID- 29767047 TI - New insights into the role of spermine in enhancing the antioxidant capacity of rat spleen and liver under oxidative stress. AB - Oxidative stress can damage cellular antioxidant defense and reduce livestock production efficiency. Spermine is a ubiquitous cellular component that plays important roles in stabilizing nucleic acids, modulating cell growth and differentiation, and regulating ion channel activities. Spermine has the potential to alleviate the effects of oxidative stress. However, to date no information is available about the effect of spermine administration on antioxidant property of the liver and spleen in any mammalian in vivo system. This study aims to investigate the protective effect of spermine on rat liver and spleen under oxidative stress. Rats received intragastric administration of either 0.4 MUmol/g body weight of spermine or saline once a day for 3 days. The rats in each treatment were then injected with either diquat or sterile saline at 12 mg/kg body weight. Liver and spleen samples were collected 48 h after the last spermine ingestion. Results showed that regardless of diquat treatment, spermine administration significantly reduced the malondialdehyde (MDA) content by 23.78% in the liver and by 5.75% in the spleen, respectively (P < 0.05). Spermine administration also enhanced the catalase (CAT) activity, anti-hydroxyl radical (AHR) capacity and glutathione (GSH) content by 38.68%, 15.53% and 1.32% in the spleen, respectively (P < 0.05). There were interactions between spermine administration and diquat injection about anti-superoxide anion (ASA), AHR capacity, CAT activity, GSH content, and total antioxidant capacity (T-AOC) in the liver and about ASA capacity and T-AOC in the spleen of weaned rats (P < 0.05). Compared with the control group, spermine administration significantly increased the AHR capacity, CAT activity, GSH content, and T-AOC by 40.23%, 31.15%, 30.25%, 35.37% in the liver, respectively (P < 0.05) and increased the T AOC by 8% in the spleen of weaned rats (P < 0.05). Compared with the diquat group, spermine + diquat group significantly increased ASA capacity by 15.63% in the liver and by 73.41% in the spleen of weaned rats, respectively (P < 0.05). Results demonstrate that spermine administration can increase the antioxidant capacity in the liver and spleen and can enhance the antioxidant status in the spleen and liver under oxidative stress. PMID- 29767049 TI - Effect of feeding broilers diets differing in susceptible phytate content. AB - Measurements of total phytate phosphorus content of diets may be deceptive as they do not indicate substrate availability for phytase; it may be that measurements of phytate susceptible to phytase effects are a more accurate measure of phosphorus (P) availability to the bird. To verify this hypothesis, an experiment was conducted to compare diets formulated to contain either high or low susceptible phytate, supplemented with either 0 or 500 FTU/kg phytase. Susceptible phytate was determined by exposing the feed samples to conditions that mimicked the average pH of the proximal gastrointestinal tract (pH 4.5) and the optimum temperature for phytase activity (37 degrees C) and then measuring phytate dissolved. Ross 308 birds (n = 240) were fed one of 4 dietary treatments in a 2 * 2 factorial design; 2 diets with high (8.54 g/kg, 57.90% of total phytate) or low (5.77 g/kg, 46.33% of total phytate) susceptible phytate, containing 0 or 500 FTU/kg phytase. Diets were fed to broilers (12 replicate pens of 5 birds per pen) from d 0 to 28 post hatch. Birds fed diets high in susceptible phytate had greater phytate hydrolysis in the gizzard (P < 0.001), jejunum (P < 0.001) and ileum (P < 0.001) and resulting greater body weight gain (BWG) (P = 0.015) and lower FCR (P = 0.003) than birds fed the low susceptible phytate diets, irrespective of phytase presence. Birds fed the high susceptible diets also had greater P solubility in the gizzard and Ca and P solubility in the jejunum and ileum (P < 0.05) and resulting greater tibia and femur Ca and P (P < 0.05) content than those fed the low susceptible diets. All the susceptible phytate was fully degraded in the tract in the absence of added phytase, suggesting the assay used in this study was able to successfully estimate the amount of total dietary phytate that was susceptible to the effects of phytase when used at standard levels. No interactions were observed between susceptible phytate and phytase on phytate hydrolysis. Hydrolysis of phytate was greater (P < 0.05) in the gizzard of birds fed the diets supplemented with phytase, regardless of the concentration of susceptible phytate in the diet. Phytase supplementation resulted in improved BWG (P < 0.001) and FCR (P = 0.001), increased P solubility (P < 0.001) in the gizzard, Ca and P solubility (P < 0.001) in the jejunum and ileum and Ca and P concentration (P < 0.001) and strength (P < 0.001) in the tibia and femur. Pepsin activity was higher in birds fed the diets supplemented with phytase (P < 0.001) and was greater (P = 0.031) in birds fed the high susceptible phytate diets compared with the low susceptible phytate diets. Findings from this study suggest that there may be a measure more meaningful to animal nutritionists than measurements of total phytate. PMID- 29767048 TI - Effects of raw material extrusion and steam conditioning on feed pellet quality and nutrient digestibility of growing meat rabbits. AB - This study was conducted to investigate the effects of raw material extrusion and steam conditioning on feed pellet quality and nutrient digestibility of growing meat rabbits, in order to determine appropriate rabbit feed processing methods and processing parameters. In Exp. 1, an orthogonal design was adopted. Barrel temperature, material moisture content and feed rate were selected as test factors, and acid detergent fiber (ADF) content was selected as an evaluation index to research the optimum extrusion parameters. In Exp. 2, a two-factor design was adopted. Four kinds of rabbit feeds were processed and raw material extrusion adopted optimum extrusion parameters of Exp. 1. A total of 40 healthy and 42-day-old rabbits with similar weight were used in a randomized design, which consisted of 4 groups and 10 replicates in each group (1 rabbits in each replicate). The adaptation period lasted for 7 d, and the digestion trial lasted for 4 d. The results showed as follows: 1) ADF was significantly affected by barrel temperature (P < 0.05); the optimum extrusion parameters were barrel temperature 125 degrees C, moisture content 16% and feed rate 9 Hz. 2) Raw material extrusion and steam conditioning both significantly decreased powder percentage, pulverization ratio and protein solubility (P < 0.05), significantly improved hardness and starch gelatinization degree of rabbit feed (P < 0.05). They both had significant interaction effects on the processing quality of rabbit feed (P < 0.05). 3) Extrusion significantly improved the apparent digestibility of dry matter and total energy (P < 0.05). Extrusion and steam conditioning both significantly improved the apparent digestibility of crude fiber (CF), ADF and NDF (P < 0.05), but they had no interaction effects on the apparent digestibility of rabbit feed. Thus, using extrusion and steam conditioning technology at the same time in the weaning rabbits feed processing can improve the pellet quality and nutrient apparent digestibility of rabbit feed. PMID- 29767050 TI - Effects of octacosanol extracted from rice bran on blood hormone levels and gene expressions of glucose transporter protein-4 and adenosine monophosphate protein kinase in weaning piglets. AB - The object of this study was to explore the regulatory mechanism of octacosanol to the body of animals and the effects of octacosanol on blood hormone levels and gene expressions of glucose transporter protein (GLUT-4) and adenosine monophosphate protein kinase (AMPK) in liver and muscle tissue of weaning piglets. A total of 105 crossbred piglets ([Yorkshire * Landrace] * Duroc) with an initial BW of 5.70 +/- 1.41 kg (21 d of age) were used in a 6-wk trial to evaluate the effects of octacosanol and tiamulin supplementation on contents of triiodothyronine (T3), thyroxine (T4), growth hormone (GH), glucagon (GU) and adrenaline (AD) in blood and gene expressions of GLUT-4 and AMPK in liver and muscle. Piglets were randomly distributed into 3 dietary treatments on the basis of BW and sex. Each treatment had 7 replicate pens with 5 piglets per pen. Treatments were as followed: control group, tiamulin group and octacosanol group. The results showed that compared with control group and tiamulin group, octacosanol greatly promoted the secretion of T3, GH, GU and AD (P < 0.01) and significantly up-regulated the gene expressions of GLUT-4 and AMPK in muscle and liver tissues (P < 0.05). There was no significant difference between the control group and tiamulin group in T3, T4, GH, GU or AD (P > 0.05). Results of the present study has confirmed that octacosanol affects energy metabolism of body by regulating secretion of blood hormones and related gene expression in tissue of weaning piglets, which can reduce stress response and has an impact on performance. PMID- 29767051 TI - Effects of dietary methionine supplementation on growth performance of cubs, nutrient digestibility, nitrogen metabolism and serum biochemical indicators of female blue foxes (Alopex lagopus). AB - The objective of the present study was to investigate the effects of methionine (Met) supplementation on growth performance of cubs, nutrient digestibility, nitrogen metabolism and serum biochemical parameters of female blue foxes. One hundred primiparous female blue foxes that were similar in breeding date, pedigree, age, and weight were selected for the trial. The foxes were randomly assigned to four groups (n = 25 each group) and fed diets supplemented with Met at 2 (Met2), 4 (Met4), 6 (Met6) and 8 g/kg (Met8), respectively, for 40 days. Our data showed that body weights at 20 and 40 d were significantly higher in the Met4 group than in the Met2 group (P < 0.05). The Met4 group also had the highest apparent digestibility of dry matter and crude protein compared with either the Met2, Met6, or Met8 group (P < 0.05). The serum Met and isoleucine (Ile) concentrations were significantly higher in the Met4 group than in the Met6 or Met8 group (P < 0.05). In summary, these data indicate that supplementary Met improves growth performance of cubs likely due to increased crude protein and dry matter and increased nitrogen retention of female blue foxes. The optimal amount of Met supplementation is 10 g/kg basal diet. PMID- 29767053 TI - Effects of wet feeding and early feed restriction on blood parameters and growth performance of broiler chickens. AB - The aim of the study was to investigate the effects of early feed restriction (FR) with wet feeding on size of small intestine, blood lipids and performance parameters in broilers from d 1 to 42. A total of 160 one-day-old male broiler chickens were randomly allocated to 4 treatments with 4 pens per treatment and 10 chickens per pen, in a fully randomized 2 * 2 factorial arrangement, two feeding arrangement; providing feed ad libitum (Full Fed) or FR by 50% between days 6 to 12, and feed in either wet or dry form (wet form, 1.2 g water per 1 g dry feed). Body weight and feed intake of broiler chickens were determined at d 0, 21, and 42, and feed conversion ratio (FCR) was calculated. At d 42, two birds per replicate were euthanised for determination of carcass weight, organ weight and length, and also for blood parameters, which included high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol and triglycerides (TG). The broilers fed wet form irrespective of FR throughout had superior body weight gain and carcass weight compared with birds fed dry diets at d 22 and 42 (P < 0.05). The wet form with FR significantly showed lower FCR compared with the wet form and ad libitum at d 1 to 21 (P < 0.05). The broilers fed wet form had significantly increased HDL, LDL, and total cholesterol and decreased TG (P < 0.05). In conclusion, wet form can improve performance growth and blood parameters, and the FR birds were able to attain normal market body weight at d 42, which suggests that growth compensation occurred. PMID- 29767052 TI - Comparative ileal amino acid digestibility of distillers' grains for growing pigs. AB - The objective of the experiment reported here was to investigate and compare the amino acid (AA) digestibility of distillers' dried grains (DDG), distillers' dried grains with solubles (DDGS), high protein distillers' dried grains (HP DDG), and high protein distillers' dried grains with solubles (HP-DDGS) in growing pigs. Five semi-purified diets consisting of DDG, DDGS, HP-DDG, HP-DDGS, and nitrogen-free diet (NFD) were fed to pigs fitted with simple T-cannula for 5 observations per diet. Endogenous losses of AA at the terminal ileum of pigs that received the NFD were used to calculate standardized ileal digestibility (SID) of AA from apparent ileal digestibility (AID) of AA. The AID of Lys in DDGS was lower (P < 0.05) than that in DDG, which was also lower (P < 0.05) than that in HP-DDG. There were no differences in AID of Met among DDG, DDGS and HP-DDGS, but was greater (P < 0.05) in HP-DDG than in DDG or DDGS. The AID of Thr in HP-DDG was greater (P < 0.05) than that in DDGS but not different from that in DDG or HP DDGS. The branched-chain AA Ile and Leu had greater (P < 0.05) AID in HP-DDG than in DDG, DDGS or HP-DDGS, and there was no difference among DDG, DDGS, and HP DDGS. The AID of Trp in DDG and DDGS or HP-DDG and HP-DDGS were not different, but the AID of Trp in HP-DDGS was greater (P < 0.05) than that of DDGS. The greatest SID of the indispensable AA was in HP-DDG. Except for Arg and Lys in which DDG had greater (P < 0.05) digestibility, there was no difference between DDG and DDGS in the SID of the indispensable AA. The SID of Lys in DDG was greater (P < 0.05) than that of DDGS but there was no difference between that of DDG and HP-DDGS. Only His, Ile, and Met had lower (P < 0.05) SID in HP-DDGS than HP-DDG within the indispensable AA. The SID of Ala, Asp, Cys, Glu, Gly, Ser and Tyr were lower (P < 0.05) in DDGS than in HP-DDG. There SID of dispensable AA in DDG was not different from that of HP-DDGS. The current study provided apparent and standardized ileal amino acids digestibility values for traditional and high protein corn distillers' dried grains coproducts for use in formulating swine diets. Amino acid digestibility was generally higher in HP-DDG than in other tested co-products of the dry grind processing of corn for ethanol. PMID- 29767054 TI - Effects of a two-meal daily feeding pattern with varied crude protein levels on growth performance and antioxidant indexes in pigs. AB - The present study aimed to evaluate the effects of daily feeding pattern on growth performance, blood biochemistry, and antioxidant indexes in pigs. One hundred and eighty female Duroc * Landrace * Yorkshire (DLY) pigs with similar body weight (11.00 +/- 0.12 kg) were randomly assigned to 3 groups: the control group (fed 17.01% CP diet, twice daily); high-low group (H-L group, fed 18.33% CP diet in the morning, followed by 15.70% CP diet in the afternoon); and low-high group (L-H group, fed 15.70% CP diet in the morning, followed by 18.33% CP diet in the afternoon) (n = 6). Comparable amounts of their respective diets were given at 05:30 and 15:00 throughout the experimental periods to make all the treatments consumed the same type of food and the same amount of calories on a daily basis. On day 30, one pig was randomly selected per litter for blood samples. Compared with the control group, ADG in the H-L and L-H groups increased by 8.11% and 16.23%, but not significant (P > 0.05); and blood urea nitrogen (BUN) in the H-L and L-H groups decreased by 26.76% and 41.04% (P < 0.05), respectively. The H-L group feeding pattern could significantly improve levels of serum superoxide dismutase (SOD), when compared with the control group. These findings suggest that the two-meal daily feeding pattern with varied levels of CP affects serum levels of BUN and SOD. These changes could effectively silightly improve growth performance and antioxidant capacity in pigs without incurring increased feeding costs. PMID- 29767055 TI - The use of Lactobacillus as an alternative of antibiotic growth promoters in pigs: A review. AB - Antibiotics, often supplemented in feed, used as a growth promoter, may cause their residual effect in animal produce and also trigger antibiotic resistance in bacteria, which is of serious concern among swine farming entrepreneurs. As an alternative, supplementing probiotics gained interest in recent years. Lactobacillus being the most commonly used probiotic agent improves growth performance, feed conversion efficiency, nutrient utilization, intestinal microbiota, gut health and regulates immune system in pigs. The characteristics of Lactobacillus spp. and their probiotic effects in swine production are reviewed here under. PMID- 29767056 TI - Performance and ruminal parameters of fattening Moghani lambs fed recycled poultry bedding. AB - This study investigated the effects of recycled poultry bedding (RPB) on performance and protozoa population, microbial enzyme activity and microbial protein synthesis (MPS) in rumen contents of fattening lambs. Thirty-six male Moghani lambs (31.4 +/- 3.2 kg body weight) were fed iso-energetic and iso nitrogenous diets containing 0, 70, 140 or 210 g/kg dry matter (DM) RPB in a balanced randomized design (9 lambs per treatment). Results showed that final body weight, DM intake, average daily gain and feed conversion ratio were unchanged (P > 0.05) by RPB inclusion. Total protozoa population and sub-family of Entoniniinae and Diplodiniiae were linearly decreased by RPB (L, P < 0.05). For rumen fibrolytic enzymes including carboxymethyl-cellulase, microcrystalline cellulase and filter paper degrading activity, the extra cellular, cellular and total (extra cellular plus cellular fraction) activity were similar (P > 0.05) by feeding the experimental diets. Inclusion of RPB in the diet linearly decreased extra cellular and total alpha-amylase activity (L, P < 0.05), while cellular activity was unchanged (P > 0.05). The extra cellular activity of proteases tended to increase (L, P = 0.07) and their total and cellular activity increased (P > 0.05) in lambs fed RPB. Incorporation of RPB into the diet had no effect (L, P > 0.05) on urinary purine derivative excretion and MPS. In conclusion, inclusion of RPB up to 210 g/kg DM had no negative impact on performance, ruminal fibrolytic enzyme activity and MPS, while it increased rumen protease activity and decreased protozoa population in fattening Moghani lambs. PMID- 29767057 TI - Xylanase, protease and superdosing phytase interactions in broiler performance, carcass yield and digesta transit time. AB - The interaction of xylanase, protease and superdosing (1,500 FTU/kg) phytase in a 2 * 2 * 2 factorial arrangement was studied in broilers fed sorghum-based diets. A total of 2,800 one-day-old unsexed Ross 308 chicks were housed in 56 pens with 50 birds per pen, with or without inclusion of xylanase, protease and phytase, totaling 8 treatments and 7 replicates per treatment. Body weight (BW) and feed intake (FI) were measured at 21 and 42 days of age, and mortality corrected feed conversion ratio (FCR) was calculated for each period and cumulatively. Tibia ash and carcass yield were determined in 2 birds per replicate at 21 and 42 days of age, respectively. Digesta transit time was determined at 21, 28, 35 and 42 days of age using 5 birds per replicate. Results showed that superdosing phytase increased BW and FI at 42 days of age (P < 0.05) and xylanase improved FCR (P < 0.05). Xylanase and phytase also positively influenced carcass yield and breast weight, respectively. Overall, inclusion of superdosing phytase increased transit time when included in a diet containing xylanase, and no change with protease inclusion. In conclusion, the beneficial effects of xylanase, protease and superdosing phytase in broiler performance were not additive. This limitation is likely not related to the lack of efficacy of any one of the individual enzymes but to a limitation of the bird to respond additively to successive additions of enzymes. PMID- 29767058 TI - Identification of differential metabolites in liquid diet fermented with Bacillus subtilis using gas chromatography time of flight mass spectrometry. AB - Growth and health responses of pigs fed fermented liquid diet are not always consistent and causes for this issue are still not very clear. Metabolites produced at different fermentation time points should be one of the most important contributors. However, currently no literatures about differential metabolites of fermented liquid diet are reported. The aim of this experiment was to explore the difference of metabolites in a fermented liquid diet between different fermentation time intervals. A total of eighteen samples that collected from Bacillus subtilis fermented liquid diet on days 7, 21 and 35 respectively were used for the identification of metabolites by gas chromatography time of flight mass spectrometry (GC-TOF-MS). Fifteen differential metabolites including melibiose, sortitol, ribose, cellobiose, maltotriose, sorbose, isomaltose, maltose, fructose, d-glycerol-1-phosphate, 4-aminobutyric acid, beta-alanine, tyrosine, pyruvic acid and pantothenic acid were identified between 7-d samples and 21-d samples. The relative level of melibiose, ribose, maltotriose, d glycerol-1-phosphate, tyrosine and pyruvic acid in samples collected on day 21 was significantly higher than that in samples collected on day 7 (P < 0.01), respectively. Eight differential metabolites including ribose, sorbose, galactinol, cellobiose, pyruvic acid, galactonic acid, pantothenic acid and guanosine were found between 21-d samples and 35-d samples. Samples collected on day 35 had a higher relative level of ribose than that in samples collected on day 21 (P < 0.01). In conclusion, many differential metabolites which have important effects on the growth and health of pigs are identified and findings contribute to explain the difference in feeding response of fermented liquid diet. PMID- 29767059 TI - Growth rate, body composition, digestive enzymes and transaminase activities, and plasma ammonia concentration of different weight Jian carp (Cyprinus carpio var. Jian). AB - The present study investigated the effect of body weight on body composition, digestive and absorptive capacity, transaminase activities in hepatopancreas and muscle, and plasma ammonia concentration of Jian carp (Cyprinus carpio var. Jian). A total of 750 Jian carps (18.0 +/- 0.2 g) were randomly distributed into five groups with three replicates and fed the same diet for 56 days. Tissue and plasma samples were collected on days 14, 28, 42, and 56. The results were used to develop a mathematical model for specific growth rate, body moisture and fat content, aspartate transaminase activity and alanine aminotransferase activity in hepatopancreas and muscle, plasma ammonia concentration, and trypsin, chymotrypsin, lipase, and amylase activities in hepatopancreas and intestine, activities of creatine kinase, Na+/K+-ATPase, alkaline phosphatase, and gamma glutamyl transpeptidase in intestine in Jian carp. There were linear relationships between natural logarithms of above indexes and body weight. The body moisture and fat content, digestive and absorptive enzymes activities, and transaminase activities showed negative allometry against body weight of Jian carp which were partial reasons to explain fish growth rate decreasing. PMID- 29767061 TI - Biochemical and histopathological changes in sheep fed different detoxified karanj (Pongamia glabra) seed cake as partial protein supplements. AB - The study investigated the long-term effect of feeding processed solvent extracted karanj (Pongamia glabra) cake (SKC) on gross pathology and histopathological changes in some vital organs, and on the activities of serum enzymes in Jalauni lambs. Twenty-four male lambs were divided into 4 groups and allotted randomly to a soybean meal (SBM) based control (CON) and 3 treatment groups receiving concentrate mixtures, containing water washed (WW), 2.5% lime (LM) and 0.4% binder (BN) treated SKC replacing 50% nitrogen of SBM to meet the protein requirements. Blood was collected after 150 days from all the lambs and serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were assayed. All lambs were sacrificed after 196 days, and vital organs screened for gross pathological lesions. The representative tissues of liver, intestine, parathyroid gland, testis, and epididymis were sampled, preserved in 10% formalin and processed to examine histopathological changes by staining with haematoxylin and eosin (HE). The serum enzyme activities of AST and ALT were similar in the treatments, but the activity of LDH was higher (P < 0.01) in processed SKC-fed groups than the control. The weight and size of the liver were decreased in BN group, while those of testes were decreased in both LM and BN groups. The histological sections of the testes and epididymis of lambs from LM group showed hypoplastic seminiferous tubules and empty ductules, respectively. The histological sections of the parathyroid gland in the same diet revealed smaller and non-secretory chief cells. The small intestine of lambs from BN group showed infiltration of mononuclear cells (MNC) in lamina propria with mild fibroplasia in intervillous areas. The histological section of liver from this group showed MNC infiltration in portal areas. The inclusion of water washed SKC in the concentrate mixture of lambs did not show gross pathological and histological alterations in the tissues in the vital organs; however, the activity of LDH was significantly (P = 0.001) elevated in processed SKC-fed groups than the control. Thus, feeding of water washed SKC in the concentrate at 225 g/kg for a longer period do not cause any adverse effect in lambs. This is supported by normal activities of serum enzymes and intact histological features in the tissues of liver, intestine, parathyroid gland and testis. PMID- 29767062 TI - Evaluation of kefir as a potential probiotic on growth performance, serum biochemistry and immune responses in broiler chicks. AB - This experiment was conducted to evaluate the effect of milk or molasses kefir as a probiotic on growth performance, carcass traits, serum biochemistry and humoral immune responses in broiler chickens. A total of 192 one-d-old as hatched broiler chicks (Ross 308) were randomly allotted to 4 treatments, each with 4 replicate pens of 12 chicks. The following treatments were applied: 1) a basal diet (C) and normal drinking water, 2) 2% milk kefir in drinking water, 3) 2% molasses kefir in drinking water, and 4) the diet C supplemented with commercial probiotic. At d 42, eight birds per treatment were killed for determination of carcass traits. Broilers at 28 days of age were bled for measuring antibody titers against Newcastle disease virus (NDV) and avian influenza virus (AIV), at 30 days of age for antibody titers against sheep red blood cell (SRBC), and at 42 days of age for biochemical analysis. Supplementing 2% milk kefir increased body weight of broilers at 28 and 42 days of age (P < 0.05). Supplementing 2% molasses kefir improved feed conversation ratio (FCR) of broilers during growth period (P < 0.05), but FCR of broilers in other periods was not affected. Daily feed intake, internal organ weights, and carcass traits were not influenced by the treatments except for small intestine and ceca length. Small intestinal length significantly decreased in broilers supplemented with milk and molasses kefir (P < 0.05). Molasses kefir supplementation significantly (P < 0.05) increased antibody titer against SRBC at 31 days of age but other immune related parameters were not statistically different among treatments. Biochemical parameters including serum protein, albumin, and triglyceride concentrations were not statistically (P > 0.05) influenced. Broilers supplemented with molasses kefir, had a significantly lower concentration of serum total cholesterol, low density lipoprotein cholesterol and elevated high density lipoprotein cholesterol at 42 days of age (P < 0.05). In conclusion, the results indicated that inclusion of 2% milk kefir in drinking water would improve growth performance of broiler chickens. PMID- 29767060 TI - Effects of catechins on litter size, reproductive performance and antioxidative status in gestating sows. AB - This study was conducted to investigate the effects of catechins on reproductive performance, antioxidative capacity and immune function of gestating sows. A total of 60 cross-bred (Landrace * Large White) multiparious sows were blocked by body weight, parity and backfact and randomly allocated to 1 of 5 treatments: 0, 100, 200, 300, or 400 mg/kg catechins. Dietary treatments were imposed from mating to d 40 of gestation of sows. At farrowing, litter total born, born alive, dead, and normal-(healthy piglets, >=0.85 kg) and low-birth weight piglets (<0.85 kg) were recorded. Within 3.00 +/- 0.50 days after farrowing litter size was standardized to 8.00 +/- 1.50 piglets within treatment. The piglets were weighed at birth (d 1) and weaning (d 28). Sows serum samples were obtained from blood samples collected on d 40 of gestation for analyses of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), hydrogen peroxide (H2O2), nitric oxide synthetase (NOS) and nitrogen monoxide (NO). Our results showed that supplementation of catechins at levels of 200 or 300 mg/kg led to improvements in litter born alive (P < 0.01) and piglet born healthy (P < 0.01) and a decrease in stillborn (P < 0.05) at farrowing when compared with the control. In comparison with the control, catechins at any supplemental levels all enhanced the serum SOD (P < 0.05) and CAT (P < 0.01) activities of sows at farrowing but no obvious differences in the serum GSH-Px and NOS activities were observed in this trial (P > 0.05). Sows received 200 mg catechin per kg diets showed a reduction (P < 0.05) of the serum MDA level at farrowing compared with all other treatments. Sows received all the levels of catechin showed a reduction (P < 0.05) of serum H2O2 level compared with sows received the control diet on both d 40 of gestation and farrowing. Our results demonstrated that the catechins may be a potential antioxidant to increase the reproductive performance and antioxidative capacity of sows when it was added into diets during the early gestation. PMID- 29767063 TI - Effects of bamboo vinegar powder on growth performance and mRNA expression levels of interleukin-10, interleukin-22, and interleukin-25 in immune organs of weaned piglets. AB - The aim of this study was to explore the effects of bamboo vinegar powder on growth performance, diarrhea situation and mRNA expression levels of cytokines i.e., interleukin-10 (IL-10), interleukin-22 (IL-22), and interleukin-25 (IL-25) in immune organs of weaned piglets, and to accumulate theoretical data for the application of bamboo vinegar powder in weaned piglet production. Forty-five crossbred (Duroc * Landrace * Yorkshire, all male) weaned piglets with similar body weight (6.74 +/- 0.17 kg) at 31 days of age were randomly assigned to 5 treatments with 3 replicates per treatment and 3 piglets in each replicate. The five treatments were as follows: CON (a basal diet), ANT (the basal diet + 0.12% antibiotics), BV1 (the basal diet + 0.1% bamboo vinegar powder), BV5 (the basal diet + 0.5% bamboo vinegar powder), BV10 (the basal diet + 1.0% bamboo vinegar powder). This experiment lasted 35 days. The growth performance and diarrhea situation were recorded. The relative mRNA expression levels of IL-10, IL-22 and IL-25 in liver, spleen, duodenum and mesenteric lymph nodes were detected by real time PCR. Feed: gain of BV5 was significantly lower than that of CON (P < 0.05). In comparison with CON, diarrhea rate and diarrhea index of BV1 and BV5 all tended to decrease (P < 0.1). Compared with CON, mRNA expression level of IL-10 in liver of ANT tended to be lower (P < 0.1) and these of BV1, BV5 and BV10 were significantly reduced (P < 0.05). The mRNA expression levels of IL-10 in duodenum of ANT, BV1, BV5 and BV10 were all lower than those of CON, of which BV10 had significantly decreased IL-10 mRNA expression in duodenum (P < 0.05). The mRNA expression levels of IL-22 in duodenum of ANT, BV1, BV5 and BV10 all tended to be inhibited compared with CON (P < 0.1). With the increase of bamboo vinegar powder dosage, mRNA expression levels of IL-25 in spleen and mesenteric lymph nodes of BV1, BV5 and BV10 tended to be up-regulated. Overall, bamboo vinegar powder could improve growth performance, and regulate mRNA expression levels of IL-10, IL-22 and IL-25 in immune organs of weaned piglets. The dosage at 0.5% showed optimum effects. PMID- 29767064 TI - Amino acid sensing in the gut and its mediation in gut-brain signal transduction. AB - Animal gastrointestinal tract is not only a digestive organ, but also a nutrient sensing organ which detects luminal nutrient and thus can regulate food intake. There are many amino acid sensing receptors and transporters in the gut. Amino acids sensing by these receptors and transporters can stimulate the intestinal endocrine cells to release a variety of gut hormones. These hormones trigger a series of physiological effects via the nerve system. This review summarized the recent advance on the amino acid sensing receptors and transporters in the gastrointestinal tract, the gut hormones released from the intestinal endocrine cells and the hormones-induced signal transduction between the gut and brain. A better understanding of these processes may help to gain further insight into the specific role of amino acids in digestion and provide guidelines in developing strategy for the better use of amino acids in the diet. PMID- 29767065 TI - A mathematical model to describe the diurnal pattern of enteric methane emissions from non-lactating dairy cows post-feeding. AB - Enteric methane emission is not only a source of energy loss in ruminants, but also a potent contributor to greenhouse gas production. To identify the nature and timing of interventions to reduce methane emissions requires knowledge of temporal kinetics of methane emissions during animal husbandry. Accordingly, a mathematical model was developed to investigate the pattern of enteric methane emissions after feeding in dairy cows. The model facilitated estimation of total enteric methane emissions (V, g) produced by the residual substrate (V1, g) and newly ingested feed (V2, g). The model was fitted to the 10 h methane emission patterns after morning feeding of 16 non-lactating dairy cows with various body weights (BW), and the obtained parameters were used to predict the kinetics of 24 h methane emission for each animal. The rate of methane emission (g/h) reached a maximum within 1 to 2 h after feeding, followed by a gradual post-prandial decline to a basal value before the next feeding. The model satisfactorily fitted curves for each cow according to the criterion of goodness-of-fit, and provided biological descriptions for fluctuations in methane emissions based on basal V1 and feeding V2 in response to the changes in BW and dry matter intake (DMI) of different dairy cows. The basal V1 and feeding V2 are probably maintained by slow and readily-degradable substrates, respectively. The former contributed at least 0.6 of methane production. In summary, the model provides a means to separate basal V1 and feeding V2 within V, and can be used to predict 24 h emission from a single feeding period. PMID- 29767066 TI - Effects of different levels of urea supplementation on nutrient intake and growth performance in growing camels fed roughage based complete pellet diets. AB - The utilization of urea in camels has beneficial and negative effects. The aims of this study were to investigate the effects of different levels of urea supplementation on nutrients intake, digestibility, growth performance, feed efficiency and economics in growing camels fed roughage based complete pellet diets. In the present study, eighteen growing camels with an average live body weight of 306.17 +/- 2.05 kg were randomly assigned in three treatments: T1 = roughage complete pellet diet without urea, T2 = T1 plus 1% urea, and T3 = T1 plus 2% urea. The results showed that the urea supplementation significantly affected average daily feed and nutrient intake of dry matter (DM), organic matter (OM), crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) (P < 0.05). On the contrary, the average daily intake of nitrogen free extract (NFE) and water were not influenced by increasing urea supplementation (P > 0.05). Similarly, digestion coefficient of DM, CP, ether extract (EE), crude fiber (CF) and ADF was influenced by increasing urea level (P < 0.05), while the digestion coefficient of OM, NFE and NDF was not affected by increasing urea level (P > 0.05). The intake of digestive nutrients was similar among all treatment groups. Total body live weight gain and average daily gain were significantly higher in urea supplemented groups (P < 0.05) than in the control group. The supplementation of urea at 1% in low quality roughage complete pellet diets significantly improved (P < 0.05) the feed efficiency. In conclusion, these results indicated that the incorporation of urea at 1% in roughage based complete pellet diets could positively improve nutrients intake, digestibility, growth performance and feed conversion efficiency of growing camels. PMID- 29767067 TI - Cassava: Nutrient composition and nutritive value in poultry diets. AB - Insufficient supply, high prices and competition with the human food and biofuel industries means there is a continuous demand for alternative energy sources for poultry. As a result, cassava is becoming an increasingly important ingredient in poultry diets, largely due to its high availability. Efficient use of cassava products has been shown to reduce feed costs of poultry production. The utilisation of cassava is, however, limited by a number of factors, including its high fibre and low energy content and the presence of anti-nutritional factors, primarily hydrocyanic acid (HCN). With correct processing the inclusion level of cassava in poultry diets could be increased. Extensive research has been conducted on cassava products for poultry, but there is still a lack of consistency amongst the measured nutritive values for cassava and its products, hence variation exists in results from poultry studies. This paper reviews the nutrient composition of cassava products and its value as an alternative energy source in poultry diets. PMID- 29767068 TI - Effects of aqua agar as water replacement for posthatch chicks during transportation on residual yolk-sac and growth performance of young broiler chickens. AB - Water is one of the most essential nutrients for the maintenance of chicks' function, and delayed access to feed and water post hatch has been reported to dehydrate chicks. Aqua agar (AA) was formulated to contain more than 95% water and an experiment was conducted to evaluate the effects of AA as water replacement for posthatch chicks during transportation. During the simulated transport, chicks were held for 24 h with (AA group) or without (NO-AA group) aqua agar in chick boxes. During the holding period, chicks in the AA group lost less body weight, compared with the NO-AA group. However, the weight of residual yolk tended to be lower in the AA-treated birds. There were no significant differences in the weight of gizzard, proventriculus, and liver, nor in the weights and lengths of the duodenum, jejunum and ileum. A higher body weight was also observed in the AA group at 7 days of age. At 21 days of age, weight gain and feed intake were higher (P < 0.05) in the AA group, when compared to that of the NO-AA group. No significant differences were observed in the feed conversion rate (FCR) between the two groups. In conclusion, the data suggests that the use of AA as a water replacement could reduce the negative impact of water deficiency in posthatch period during transportation, resulting in greatly improved growth performance of young broilers at 21 days of age. PMID- 29767069 TI - Comparisons of blood biochemical parameters, digestive enzyme activities and volatile fatty acid profile between Meishan and Yorkshire piglets. AB - This study was conducted to compare physiological characteristics between Meishan and Yorkshire piglets in their early lives. Six healthy purebred Meishan sows and Yorkshire sows with close farrowing dates were used in this research. The piglets sucked their respective sow's milk for 14 days, then they were slaughtered to collect samples of blood, pancreas, contents of stomach, jejunum, cecum, colon as well as feces for analysis of blood biochemical parameters, digestive enzymes, and volatile fatty acid (VFA). The results showed that Yorkshire piglets had higher concentrations of high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) (P < 0.05). Gastric lipase activity was higher in Meishan piglets but Yorkshire piglets had higher lactase activity (P < 0.05). The total VFA together with acetate and propionate in cecum and colon were higher in Meishan piglets than in Yorkshire piglets (P < 0.05), but acetate in jejunum and ratio of acetate to propionate in colon were lower in Meishan piglets than in Yorkshire piglets (P < 0.05). In conclusion, in early suckling period, significant differences exist in host metabolism and intestinal microbial metabolism between Meishan and Yorkshire piglets. PMID- 29767070 TI - Effects of spermine supplementation on the morphology, digestive enzyme activities, and antioxidant capacity of intestine in weaning rats. AB - The main objective of this study was to investigate the effects of different doses of spermine and its extended supplementation on the morphology, digestive enzyme activities, and intestinal antioxidant capacity in weaning rats. Nineteen day-old male rats received intragastric spermine at doses of 0.2 and 0.4 MUmol/g BW for 3 or 7 d, whereas control rats received similar doses of saline. The results are as follows: 1) In the jejunum, the seven-day supplementation with both doses of spermine significantly increased crypt depth (P < 0.05) compared with the control group; the supplementation extension of the high spermine dose increased villus height and crypt depth (P < 0.05); in the ileum, the low spermine dose significantly increased villus height and crypt depth compared with the control group for 7 days (P < 0.05). 2) The 3-day supplementation with high spermine dose increased alkaline phosphatase activity in the jejunum (P < 0.05). 3) In the jejunum, the anti-hydroxyl radical (AHR), total superoxide dismutase (T SOD), catalase (CAT), and total antioxidant capacity (T-AOC) activities were increased (P < 0.05); however, the malondialdehyde (MDA) content was reduced (P < 0.05) in groups supplemented with the high spermine dose relative to those in the control groups after 3 and 7 d; moreover, the anti-superoxide anion (ASA) and glutathione (GSH) contents increased with the high spermine dose that lasted for 3 days (P < 0.05). Furthermore, the T-SOD and CAT activities (after 3 and 7 d), ASA (after 3 d), and AHR (after 7 d) increased with the high spermine dose compared with those of the low spermine dose (P < 0.05). Extending the supplementation duration (7 d) of the high spermine dose decreased the MDA content and ASA and T-AOC activities (P < 0.05). These results suggested that spermine supplementation can modulate gut development and enhance the antioxidant status of the jejunum in weaning rats, and a dosage of 0.4 MUmol spermine/g BW had better effects than the dosage of 0.2 MUmol spermine/g BW on accelerating gut development and increasing antioxidant capacity. PMID- 29767071 TI - Milk fatty acids profiles and milk production from dairy cows fed different forage quality diets. AB - Thirty lactating Holstein cows were used to investigate the effects of different forages quality on milk fatty acids (FA) profiles and production. The cows were assigned to 3 dietary treatments (n = 10 per treatment) in a randomized block design with 3 repeated measures. They were fed the experimental diets for 90 d with 3 days of collection of samples for analysis at about 27 d intervals (samples were collected on days 28, 29, 30, 58, 59, 60, 88, 89 and 90). The treatments were (DM basis): 1) mixed forages diet (MF) consisting of 3.7% Chinese wild rye, 26.7% corn silage and 23.4% alfalfa hay; 2) corn stalk diet 1 (CS1) where corn stalk was used to formulate a similar chemical nutrient level to MF; 3) corn stalk diet 2 (CS2) which used corn stalk to formulate a similar forage level to MF for the diet. Dry matter intake and BW were similar between treatments, but daily milk yield, milk fat and protein yield decreased (P < 0.05) in CS1 and CS2 compared with MF, with CS2 being the lowest (P < 0.05). In total FA of milk, the compositions of C18:1c9, C18:3 and unsaturated FA increased (P < 0.05) in CS1 and CS2 compared with MF, and C18:0 and trans-C18:1 were trended to increase (P < 0.10), but C4:0-C16:0 were decreased (P < 0.05). Compared with cows fed CS2, cows receiving CS1 increased the compositions of C4:0 to C12:0 and C18:2 (P < 0.05). The results suggests feeding corn stalk could produce a greater proportion of unsaturated fatty acid (UFA) in milk fat without resulting in milk fat depression (MFD) in mid lactation cows, but simply increasing the ratio of concentrate in low forages diets is not an effective way to increase milk fat synthesis and milk production. PMID- 29767072 TI - Isolation and identification of sinapine-degrading bacteria from the intestinal tract of laying hens. AB - This study was aimed to isolate sinapine-degrading bacteria from the intestinal tract of laying hens and to identify the predominant bacteria. Thirty-week old healthy laying hens were killed, and the chyme in the digestive tract was inoculated into modified Czapek medium containing sinapin and cultivated at 37 degrees C for 10 days. The optical density (OD) values of the bacterial solutions at different cultivating times were detected by a spectrophotometric method. The predominant strains were identified by 16S rRNA gene analysis. We extracted the extracellular products of the predominant strains to determine the total protein using the Coomassie brilliant blue method, and to determine the activities of some extracellular enzymes using the agar plate diffusion method. Nine strains were isolated from the lower intestinal tract of laying hens. Among the 9 strains, 5 were from the ileum, 2 were from the ceca and 2 were from the jejunum. We could not isolate any strains from the upper intestinal tract, such as the stomach and duodenum. Eight of those 9 isolated strains were gram negative and one was gram positive. Strains YD-1 and YD-2 were better than other strains in their abilities to degrade sinapine. Strains YD-1 and YD-2 were identified as Escherichia coli and Klebsiella spp., respectively, by the 16S rRNA sequence analysis. The total protein level of the extracellular products was 1.213 g/L for YD-1 and 1.990 g/L for YD-2. Both extracellular products of YD-1 and YD-2 had the activities of protease, amylase and urease. This study confirmed that the primary site of sinapine degradation is in the lower intestinal tract of laying hens. The sinapine-degrading strains are mainly gram negative. Strains YD-1 and YD-2 are predominant in degrading sinapine and they belong to E. coli and Klebsiella spp., respectively. Both extracellular products of YD-1 and YD-2 contain protease, amylase and urease. Strain YD-2 is better than strain YD-1 in its ability to degrade sinapine. PMID- 29767074 TI - Occurrence of Clostridium perfringens contamination in poultry feed ingredients: Isolation, identification and its antibiotic sensitivity pattern. AB - This work has been undertaken to study the occurrence of Clostridium perfringens contamination in the poultry feed ingredients and find out its in-vitro antibiotic sensitivity pattern to various antimicrobial drugs. Two hundred and ninety-eight poultry feed ingredient samples received at Poultry Disease Diagnosis and Surveillance Laboratory, Namakkal, Tamil Nadu in South India were screened for the presence of C. perfringens. The organisms were isolated in Perfringens agar under anaerobic condition and subjected to standard biochemical tests for confirmation. In vitro antibiogram assay has been carried out to determine the sensitivity pattern of the isolates to various antimicrobial drugs. One hundred and one isolates of C. perfringens were obtained from a total of 298 poultry feed ingredient samples. Overall positivity of 33.89% could be made from the poultry feed ingredients. Highest level of C. perfringens contamination was detected in fish meal followed by bone meal, meat and bone meal and dry fish. Antibiogram assay indicated that the organisms are highly sensitive to gentamicin (100%), chlortetracycline (96.67%), gatifloxacin (93.33%), ciprofloxacin (86.67%), ofloxacin (86.67%) and lincomycin (86.67%). All the isolates were resistant to penicillin-G. Feed ingredients rich in animal proteins are the major source of C. perfringens contamination. PMID- 29767073 TI - Magnolol additive as a replacer of antibiotic enhances the growth performance of Linwu ducks. AB - Magnolol rich in Magnolia officinalis is a bioactive polyphenolic compound. The aim of this study was to examine the effects of magnolol additive (MA) on growth performance, expression levels of antioxidant-related genes, and intestinal mucosal morphology of Linwu ducks aged from 49 to 70 days, comparing with that of an antibiotic additive (colistin sulfate [CS]). A total of 275, 49-day-old ducks were assigned to 5 groups with 5 cages of 11 ducks each and fed diets supplemented with 0, 100, 200 and 300 mg of MA/kg and 300 mg of CS/kg for 3 weeks, respectively. The results showed that the average daily body weight gain (ADG) was increased significantly in MA-fed groups (200 and 300 mg/kg), compared with the basal diet (BD) group (P < 0.05). The mRNA levels of superoxide dismutase-1 (SOD1), manganese superoxide dismutase-2 (MnSOD2) and catalase (CAT) were also increased significantly in MA groups (P < 0.05). In addition, hematoxylin and eosin staining revealed that Linwu ducks fed the diets with MA had more intact intestinal mucosa than those fed the BD and CS diets. In addition, ileal villus height, ileal villus height/crypt depth ratio (V/C) and duodenal V/C were also improved significantly (P < 0.05). Taken together, these data demonstrated that MA is an effective feed additive to enhance the growth performance of the Linwu ducks by improving the antioxidant and intestinal mucosal status, suggesting that MA will be a potential additive to replace antibiotic (CS). PMID- 29767075 TI - Ovine hippocampal mRNA expression in offspring from dams supplemented with fishmeal and stress challenged in late pregnancy with endotoxin. AB - Previous research has shown that adulthood disease can be attributed to stress events that occur during gestation. The objective of the present study was to determine whether maternal stress during late pregnancy, using a bacterial endotoxemia model, causes changes in hippocampal mRNA expression of candidate genes related to hypothalamic-pituitary-adrenal axis (HPAA) regulation in sheep. This study also sought to investigate whether maternal diets supplemented with fishmeal (FM) rich in omega-3 polyunsaturated fatty acids (PUFAs) offer protection to the fetus when subjected to maternal endotoxin stress. Using RT qPCR, relative mRNA expression was assessed in both fetal lambs and 6-month-old lambs from dams supplemented with soybean meal (SM) or FM and challenged with either endotoxin or saline. From this it was found that fetal mineralocorticoid receptor (MR) gene expression had a tendency to be altered during endotoxin challenge, however, in the 6-month-old offspring, MR and glucocorticoid receptor (GR) gene expression were differently altered across treatment groups. These results suggest that gene regulation within the hippocampus is altered into adulthood by maternal endotoxin stress and that dietary supplementation affects outcome. PMID- 29767076 TI - Effects of dietary alfalfa flavonoids extraction on growth performance, organ development and blood biochemical indexes of Yangzhou geese aged from 28 to 70 days. AB - This experiment was conducted to study the effects of dietary alfalfa flavonoids extraction supplemental level on growth performance, organ development and blood biochemical indexes of Yangzhou geese at the age of 28 to 70 days. Two hundred and forty 21-day-old healthy male geese with similar body weight were randomly distributed into 4 groups with 6 replicates per group and 10 geese per replicate. Geese in the control group were fed a basal diet and the others in the experimental groups (groups 1, 2, and 3) were fed experimental diets supplemented with 150, 300 and 450 mg/kg alfalfa flavonoids extraction (the concentration of it was 81%), respectively. The experiment had 7 days for pre-test and 42 days for formal test. The results showed that the final body weight and average daily intake of group 2 were significantly higher than those of other groups (P < 0.05). The average daily gain of group 2 was significantly higher than that in the control group and group 1 (P < 0.05). There was no significant difference in feed-to-gain ratio between each group (P > 0.05). Pre-slaughter live weight, carcass weight, slaughter rate, semi-eviscerated weight, semi-eviscerated rate, eviscerated weight, eviscerated rate, leg muscle weight and leg muscle rate had no significant difference between each group (P > 0.05). The breast muscle weight and ratio of each test group were significantly higher than those in the control group (P < 0.05) and the group 2 was the best. The abdominal fat weight and ratio in the group 1 were significantly higher than those in the control group and group 3 (P < 0.05) and the tibia weight in the group 2 was significantly higher than that in the control group and group 1 (P < 0.05); There were no significant differences in heart weight, liver weight and the gland stomach weight among all groups (P > 0.05). Spleen weight in test groups was significantly higher than that in the control group (P < 0.05). The bursa weight and muscular stomach weight in the group 2 were significantly higher than those in the control group and group 1 (P < 0.05). In serum, total cholesterol, triglycerides, low-density lipoprotein and urea nitrogen in the group 2 were significantly lower comparing with those in the control group (P < 0.05). High-density lipoprotein in the group 2 was significantly higher than that in other groups (P < 0.05). There were no significant differences in total serum protein, albumin, globulin and albumin/globulin among all groups (P > 0.05). Alanine aminotransferase and aspartate transaminase (AST) in groups 2 and 3 were higher than those in the group 1 and control group but not obvious (P > 0.05) and alkaline phosphatase (ALP) in groups 1 and 2 was higher than that in the control group and group 3 (P > 0.05). It is concluded that alfalfa flavonoids extraction added in dietary feed improve the growth performance, organ development and blood biochemical indexes of Yangzhou geese. It is concluded that 300 mg/kg supplemental level of the dietary alfalfa flavonoids extraction is optimal in this experiment. PMID- 29767077 TI - Strategies and challenges to increase the precision in feeding zinc to monogastric livestock. AB - Practical diets for monogastric livestock must be supplemented with zinc (Zn) due to their high contents of antagonistic substances like phytates. Current feeding recommendations include quite generous safety margins because of uncertainties regarding the gross Zn requirements under varying rearing conditions. Furthermore, the use of pharmacological Zn doses to stabilise animal performance and wellbeing is widespread. Taken together, modern diets for pigs and poultry contain considerably more Zn than necessary to meet animal requirements, which is associated with concerns related to the environment as well as animal and consumer safety. Therefore, European authorities most recently reduced the allowed upper limits for Zn in complete feed. To maintain animal productivity and wellbeing while reducing the Zn load in complete feed, all measures that stabilize feed Zn bioavailability must be applied. Most importantly, reliable information on the gross Zn requirement under practical conditions must be provided, considering the bioavailability of native or supplemented feed Zn, antagonisms with dietary factors as well as the physiological status of the animal. PMID- 29767078 TI - Review on biological degradation of mycotoxins. AB - The worldwide contamination of feeds and foods with mycotoxins is a significant problem. Mycotoxins pose huge health threat to animals and humans. As well, mycotoxins bring enormous economic losses in food industry and animal husbandry annually. Thus, strategies to eliminate or inactivate mycotoxins in food and feed are urgently needed. Traditional physical and chemical methods have some limitations such as limited efficacy, safety issues, losses in the nutritional value and the palatability of feeds, as well as the expensive equipment required to implement these techniques. Biological degradation of mycotoxins has shown promise because it works under mild, environmentally friendly conditions. Aflatoxin (AF), zearalenone (ZEA) and deoxynivalenol (DON) are considered the most economically important mycotoxins in terms of their high prevalence and significant negative effects on animal performance. Therefore, this review will comprehensively describe the biological degradation of AF, ZEA and DON by microorganisms (including fungi and bacteria) and specific enzymes isolated from microbial systems that can convert mycotoxins with varied efficiency to non- or less toxic products. Finally, some strategies and advices on existing difficulties of biodegradation research are also briefly proposed in this paper. PMID- 29767079 TI - Gluconeogenesis during starvation and refeeding phase is affected by previous dietary carbohydrates levels and a glucose stimuli during early life in Siberian sturgeon (Acipenser baerii). AB - Gluconeogenesis responses was assessed during a short starvation period and subsequent refeeding in Siberian sturgeon (Acipenser baerii) previously fed different dietary carbohydrates levels and experienced to a glucose stimuli during early life. The sturgeon larvae were previously fed either a high glucose diet (G) or a low glucose diet (F) from the first feeding to yolk absorption (8 to 12 d post-hatching [dph]). Each group of fish was sub-divided into 2 treatments at 13 dph and was fed either a high-carbohydrate diet (H) or a low carbohydrate diet (L) until 20 wk. In the current study, the fish in 4 groups (GL, FL, GH and FH) were experienced to starvation for 21 d following by re feeding of their corresponding diets for 21 d. Fish were sampled at postprandial 6 and 24 h before starvation (P6h and P24h), starvation 7, 14 and 21 d (S7, S14 and S21) and 1, 7, 14 and 21 d during refeeding (R1, R7, R14 and R21). Plasma samples during refeeding were taken at P6h at each time point. Glycaemia levels, liver and muscle glycogen contents, activities and mRNA levels of hepatic gluconeogenic enzymes were examined. We found that both dietary carbohydrate levels and early glucose stimuli significantly affected the metabolic responses to starvation and refeeding in Siberian sturgeon (P < 0.05). During prolonged starvation, Siberian sturgeon firstly mobilized the liver glycogen and then improved gluconeogenesis when the dietary carbohydrates were abundant, whereas preserved the liver glycogen stores at a stable level and more effectively promoted gluconeogenesis when the dietary carbohydrates are absent to maintain glucose homoeostasis. During refeeding, as most teleostean, Siberian sturgeon failed controlling the activities and mRNA levels of phosphoenolpyruvate carboxykinase cytosolic forms (PEPCK-C), fructose-1,6-bisphosphatase (FBPase), but particularly controlled phosphoenolpyruvate carboxykinase mitochondrial forms (PEPCK-M) activities and mRNA expression of glucose-6-phosphatase (G6Pase, except in GL group). Siberian sturgeon has a full compensatory ability on growth, but this ability would be obstructed by early glucose stimuli when refeeding the low carbohydrate diet after S21. PMID- 29767080 TI - Optimal sulfur amino acid to lysine ratio for post weaning piglets reared under clean or unclean sanitary conditions. AB - Two 14-day experiments, each with 90 (Duroc * [Yorkshire * Landrace]; 7.3 +/- 0.6 kg) piglets, were conducted to determine the optimum sulfur amino acid (SAA) to lysine (Lys) ratio (SAA:Lys) for piglets when reared under clean or unclean sanitary conditions using performance and non-performance response criteria. Piglets were randomly assigned to the following dietary treatments. The basal diet contained 1.18% standardized ileal digestible (SID) Lys, and the SAA:Lys was 52%. In diets 2 to 5, the basal diet was supplemented with 4 graded levels of dl Met to make SAA:Lys of 56%, 60%, 64% and 68%. In Exp. 1, piglets were housed in disinfected clean room. In Exp. 2, piglets were housed in a room previously occupied by other pigs and was not disinfected. On the last day, blood was collected to measure plasma urea nitrogen (PUN) and one pig per pen was euthanized to collect jejunal tissue to measure villus height (VH), crypt depth (CD), and VH:CD. In Exp. 1, increasing SAA:Lys linearly and quadratically increased VH and VH:CD (P < 0.05). In Exp. 2, increasing SAA:Lys linearly increased (P < 0.05) VH and VH:CD and linearly and quadratically decreased PUN (P < 0.05). Estimated PUN and VH-based optimum SAA:Lys requirements for clean and unclean sanitary condition were 60%, 63% and 66%, respectively. PMID- 29767081 TI - Effect of dietary protein sources and storage temperatures on egg internal quality of stored shell eggs. AB - This study was conducted to evaluate the effects of various protein sources (soybean meal, SBM; cottonseed protein, CSP; double-zero rapeseed meal, DRM) on the internal quality (Haugh unit, yolk index, albumen pH, yolk hardness and yolk springiness) of eggs when stored at either 4 or 28 degrees C for 28 d. A total of 288 laying hens (32 wk of age) were randomly allotted to 6 treatment groups (4 replicates per treatment) and fed diets containing SBM, CSP, or DRM individually or in combination with equal crude protein content (SBM-CSP, SBM-DRM, and CSP DRM) as the protein ingredient(s). A 6 * 2 factorial arrangement was employed with dietary types and storage temperatures (4 and 28 degrees C) as the main effects. After 12 wk of diet feeding, a total of 216 eggs was collected for egg internal quality determination. The results showed as follows: 1) lower egg quality was observed in the DRM group compared with the other groups when stored at 4 and 28 degrees C for 28 d (P < 0.05), while there was no difference in egg internal quality among the other groups. 2) The CSP diet resulted in higher yolk hardness compared with the other diets when eggs were stored at 4 degrees C for 28 d (P < 0.05). Lower Haugh unit was observed in the DRM and SBM-DRM groups compared with the other groups when eggs were stored for 28 d at 4 degrees C (P < 0.05). 3) Yolk breakage occurred in the DRM group and eggs could not be analyzed for egg internal quality when stored at 28 degrees C for 28 d. The overall results indicated that CSP or DRM as the sole dietary protein source for laying hens may adversely affect the internal quality of stored eggs as compared with the SBM diet, and half replacement of CSP combined with SBM may maintain similar egg quality to SBM diet alone for eggs stored under refrigerated conditions. PMID- 29767082 TI - Effects of dynamic segmentation of nutrient supply on growth performance and intestinal development of broilers. AB - This experiment was to investigate the effects of dynamic segmentation of interval nutrient supply phase feeding on the growth performance, carcass characteristics, immune organs indexes and intestinal morphology of broilers. A total of 320 one-day-old broilers were randomly assigned into 4 feeding treatments, which included 4 interval nutrient supply phases as follows. Treatment A: a nutrient supply standard was used for every 14 d. Treatment B: a nutrient supply standard was used for every 7 d. Treatment C: a nutrient supply standard was used for every 3.5 d except that one nutrient supply standard was used for d 1 to 7. Treatment D: a nutrient supply standard was used for every 3.5 d including d 1 to 7. Each treatment was represented by 8 replicates with 10 broilers per replicate. The trial lasted for 42 days. Throughout the 42 d trial period, treatment A showed significantly higher average daily gain than treatments B and C (P < 0.05). The feed:gain ratio of treatment A was significantly lower than those of treatments C and D (P < 0.05). On d 28 and 42, body weight of broilers in treatment A was much higher than those of treatments B and C (P < 0.05). The slaughter rate of treatment A was significantly higher than that of treatment B (P < 0.05). Eviscerated percentage of treatment A was significantly higher than those of treatment B and D (P < 0.05). There were no significant differences among 4 treatments in immune organs indexes (P > 0.05). The crypt depth of duodenum was significantly greater in treatments A and B than in treatment C on day 42 (P < 0.05). Meanwhile, the ratio of villus height to crypt depth (V:C ratio) of treatment D was significantly higher than that of treatment A (P < 0.05). No significant differences were found between treatments C and D in growth performance, carcass performance, immune organs indexes and intestinal structure (P > 0.05). In conclusion, this study revealed that the growth and carcass performance of broilers is the best for 14 days segmentation phase feeding, and 3.5 days segmentation interval phase feeding can promote small intestinal development of broilers. Dynamic segmentation of dietary supply fails to affect the immune function of broilers. PMID- 29767084 TI - The influence of meat-and-bone meal and exogenous phytase on growth performance, bone mineralisation and digestibility coefficients of protein (N), amino acids and starch in broiler chickens. AB - The objective of this study was to examine the influence of meat-and-bone meal (MBM) and phytase inclusion on growth performance, bone mineralisation and apparent digestibility coefficients of nutrients in broiler chickens offered wheat-based diets. The feeding study comprised 7 dietary treatments: positive control (PC, 9.0% Ca and 4.5% available phosphorous [AvP] in starter, 7.0% Ca and 3.5% AvP in finisher); negative control (NC, 7.2% Ca and 3.0% AvP in starter, 5.2% Ca and 2.0% AvP in finisher) diets incorporating a 3 * 2 factorial array of 3 MBM inclusions (0, 60, 120 g/kg) and 2 levels of phytase supplementation (0 and 1,000 FYT/kg). Each treatment was allocated to 6 replicated pens with 30 birds per pen in an environmentally-controlled deep litter facility. A total of 1,260 one-day-old male Ross 308 chicks were offered starter diets from 1 to 14 days post-hatch and finisher diets from 15 to 36 days post-hatch. There were significant (P < 0.05) interactions between MBM inclusions and phytase supplementation on weight gain and feed intake in starter diets. Phytase significantly increased weight gain in diets without MBM and did not influence weight gain in diets with 60 and 120 g/kg MBM. Collectively, increasing MBM inclusion significantly reduced weight gain in starter diets (P < 0.0001). There were dietary interactions (P < 0.01) on toe ash where phytase significantly improved toe ash in diet without MBM and did not influence toe ash in the other two groups of negative control diets. There were no dietary treatment interactions on apparent ileal digestibility coefficients of starch and protein except that diets without MBM had significantly (P < 0.01) lower ileal starch digestibility and diets with 120 g/kg MBM had significantly (P < 0.0001) lower ileal protein digestibility. No dietary influence on ileal fat digestibility was observed. There were dietary interactions on ileal digestibilities of isoleucine, valine and glycine. Phytase significantly increased glycine digestibility in diets with 60 and 120 g/kg MBM but not in diets without MBM. Including 120 g/kg MBM significantly (P < 0.01) depressed apparent digestibility coefficients of 13 ex 16 amino acids in the distal ileum. This study demonstrated the negative impacts of MBM on amino acid digestibility and growth performance. Also, responses to phytase were more pronounced in diets without MBM, which may have been due to their relatively lower available P and higher phytate concentrations in comparison to diets containing MBM. PMID- 29767083 TI - Nano zinc, an alternative to conventional zinc as animal feed supplement: A review. AB - The uniqueness of Zn is that, it is the second most abundant trace element in the animal body but can't be stored in the body, thus regular dietary intake is required. Zinc oxide (ZnO) nanoparticles (NP) particles are being extensively used in paints, skin lotions pigments, food, electronics appliances, biological and pharmaceutical applications and many more. Zinc oxide nanoparticles are the specially prepared mineral salt having particle size of 1 to 100 nm. It promotes growth can act as antibacterial agent, modulates the immunity and reproduction of the animals. Both in lower and higher doses of specifications it has exhibited a variety of effects on animal performances. Apart from being highly bio-available, reports have already pointed out the growth promoting, antibacterial, immuno modulatory and many more effects of nano zinc (nZn). These can be used at lower doses and can provide better result than the conventional Zn sources and indirectly prevents environmental contamination also. The toxicological studies provide mixed results in animal models. Studies been undertaken in diversified animal species and encouraging effects have been reported with nZn supplementation. However, there is a need to optimize the dose and duration of ZnO NP supplementation for human and livestock, depending on its biological effects. Actual bioavailability of ZnO NP in livestock is still to be worked out. In this review we have attempted to summarize, conclude the beneficial effects of nZnO and its possible usage as mineral supplement to different categories of human and livestock. PMID- 29767085 TI - Nitrogen fractionation of certain conventional- and lesser-known by-products for ruminants. AB - Dietary proteins for ruminants are fractionated according to solubility, degradability and digestibility. In the present experiment, 11 vegetable protein meals and cakes used in ruminant nutrition were included with a main focus on determining various nitrogen (N) fractions in vitro. Total N (N * 6.25) content varied from 22.98% (mahua cake) to 65.16% (maize gluten meal), respectively. Guar meal korma contained the lowest and rice gluten meal had the highest acid detergent insoluble nitrogen (ADIN; N * 6.25). Borate-phosphate insoluble N (BIN, N * 6.25) and Streptomyces griseus protease insoluble N (PIN; N * 6.25) were higher (P < 0.01) in maize gluten meal than in other feeds, whereas groundnut cake and sunflower cake had lower (P < 0.01) BIN, and PIN, respectively. Available N, calculated with the assumption that ADIN is indigestible, was maximum in guar meal korma and minimum in rice gluten meal. Furthermore, rapid and slowly degradable N (N * 6.25) was found to be higher (P < 0.01) in groundnut cake and coconut cake, respectively. Intestinal digestion of rumen undegradable protein, expressed as percent of PIN, was maximum in guar meal korma and minimum in rice gluten meal. It was concluded that vegetable protein meals differed considerably in N fractions, and therefore, a selective inclusion of particular ingredient is needed to achieve desired level of N fractions to aid precision N rationing for an improved production performance of ruminants. PMID- 29767086 TI - Effects of the ratio of unsaturated fatty acid to saturated fatty acid on the growth performance, carcass and meat quality of finishing pigs. AB - The effects on finishing pigs (80-100 kg BW) fed diets supplemented with oil sources containing different ratios of unsaturated to saturated fatty acids (UFA:SFA ratio) were evaluated in 15 barrows and 15 gilts (Duroc * Large White * Landrace). Three experimental diets were evaluated using a randomized complete block design, with broken rice, soybean meal and rice bran as the main feedstuffs in the control diet. Diets 2 and 3 consisted of the control diet supplemented with 3% oil, with UFA:SFA ratios of 2.5:1 and 5:1, respectively. Overall, there was no significant difference (P > 0.05) found in the average daily gain (ADG) of the pigs fed the treatment diets; however, the pigs fed the control diet and diet 3 had better (P < 0.05) feed conversion ratios (FCR) than the pigs fed diet 2. The pigs fed diets 2 and 3, which were supplemented with oil at UFA:SFA ratios of 2.5:1 and 5:1, had greater (P < 0.05) average daily feed intakes (ADFI) than the pigs in the control group. Additionally, it was found that the gender of the pigs had an effect (P < 0.05) on the FCR. Interaction effects between the experimental diets and the gender of the pigs (P < 0.05) were found in the ADFI and FCR. There were no significance differences (P > 0.05) among the treatment groups with regard to the carcass quality of the pigs; however, it was found that the gilts had greater (P < 0.01) loin eye areas than the barrows fed diets 2 and 3 and the loin eye area of pig fed diet 2 was the largest (P < 0.05). In the case of the meat quality parameters, it was clearly found that the pigs fed the control diet had a greater (P < 0.05) lightness (L*) in the meat colour, and the lowest cooking loss was found in the pigs fed the diet supplemented with fat containing the UFA:SFA ratio of 5:1. Overall, the dietary treatment did not significantly affect the drip loss, thawing loss and shear force of the pork. In conclusion, the supplementation of oil with UFA:SFA ratios of 2.5:1 and 5:1 has the potential to improve pork quality. PMID- 29767087 TI - Exploring polyamines: Functions in embryo/fetal development. AB - Polyamines such as putrescine, spermidine, spermine and agmatine are aliphatic polycationic compounds present in all living cells, and are derived from amino acids, intestinal bacteria, exfoliated enterocytes and supported from diet. Polyamines as the key compounds play essential role in cell proliferation, growth and differentiation. They also exert significant effects on embryonic development, implantation, embryonic diapause, placentation, angiogensis and fetal development. This review paper summarizes the functions of polyamines and embryo/fetus development and its regulatory mechanism which should help to provide some evidences for clinic. PMID- 29767088 TI - Interactive effect of dietary vitamin E and inorganic mercury on growth performance and bioaccumulation of mercury in juvenile olive flounder, Paralichthys olivaceus treated with mercuric chloride. AB - A 6-week feeding trial was carried out to evaluate the effects of dietary vitamin E (dl-alpha-tocopheryl acetate, TA) on growth and mercury (Hg) accumulation in juvenile olive flounder (Paralichthys olivaceus) treated with mercuric chloride (HgCl2). Vitamin E and HgCl2 were added to the semi-purified basal diet. Six semi purified diets in a 2 * 3 factorial design were formulated to contain 2 levels of Hg (0 or 20 mg HgCl2/kg diet) and 3 levels of vitamin E (0, 100, or 200 mg TA/kg diet). Experimental fish (n = 360, 9.99 +/- 0.15 g) were randomly allocated into 30-L tanks at a density of 20 fish per tank with 3 replicates in each treatment and were fed twice a day. At the end of the feeding trial, dietary Hg depressed the growth performances in terms of weight gain (WG), specific growth rate (SGR), feed efficiency (FE) and protein efficiency ratio (PER) in fish, while fish fed the diets supplemented with vitamin E showed significant growth improvement in both presence and absence of HgCl2 in the diets (P < 0.05). Survival rate was not affected in fish fed the experimental diets. Whole body compositions of fish such as lipid and moisture contents were influenced by dietary vitamin E supplementation. Total Hg contents of muscle, liver and kidney tissues were significantly reduced in fish fed diets supplemented with vitamin E (P < 0.05), while the two-way ANOVA showed that increasing Hg concentration has resulted in a reduction in vitamin E. Whole body fatty acids of fish like eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) contents were decreased by dietary Hg. However, supplementation of dietary vitamin E improved the alpha-linolenic acid (ALA) and EPA contents in fish. Our results suggest that dietary supplementation of vitamin E has potential effects on growth improvement and ameliorating inorganic Hg bioaccumulation in juvenile olive flounder. PMID- 29767090 TI - Combined effects of chitosan and microencapsulated Enterococcus faecalis CG1.0007 probiotic supplementation on performance and diarrhea incidences in enterotoxigenic Escherichia coli K88+ challenged piglets. AB - The aim of this study was to investigate the combined effects of chitosan oligosaccharide (COS) and a microencapsulated Enterococcus faecalis CG1.0007 probiotic (PRO) on growth performance and diarrhea incidences in enterotoxigenic Escherichia coli (ETEC) K88+ challenged piglets in a 14-d study. Thirty piglets, 7.19 +/- 0.52 kg initial BW weaned at 21 +/- 1 d, were allotted to 5 treatment groups (n = 6) consisting of a corn-soybean meal diet with no additive (negative control, NC), NC + 0.25% chlortetracycline (positive control, PC), NC + 400 mg/kg COS (COS), NC + 100 mg/kg PRO (PRO) and NC + a combination of COS and PRO (CPRO). Pigs were individually housed in cages, acclimated to treatments for a 7-d period and had ad libitum access to feed and water throughout the study. On d 8, pigs were weighed, blood samples were collected, and then orally challenged with 6 mL (1 * 1011 cfu/mL) of freshly grown ETEC inoculum. During post-challenge period, blood was sampled at 24 and 48 h to determine plasma urea nitrogen (PUN), and diarrhea incidences and fecal consistency scores were recorded from d 9 to 12. On d 14, all pigs were weighed and then euthanized to obtain intestinal tissue samples for histomorphometric measurements. Growth performance responses were similar among treatments during the pre- and post-challenge periods. There were no significant differences in PUN content, incidences of diarrhea, and fecal consistency scores among treatments. The intestinal histomorphology results did not differ significantly among treatments except for PC with increased (P = 0.0001) villus:crypt ratio compared with the NC. Under the conditions of the present study, it can be concluded that supplementation of piglet diets with 400 mg/kg COS, 100 mg/kg microencapsulated PRO or their combination did not significantly improve piglet growth performance both during the pre- and post ETEC K88+ oral inoculation. Also, there were no significant reduction of incidences and severity of diarrhea after challenge compared with the control group. PMID- 29767089 TI - Using probiotics to improve swine gut health and nutrient utilization. AB - To maintain a healthy gut is definitely key for a pig to digest and absorb dietary nutrients efficiently. A balanced microbiota (i.e., a healthy micro ecosystem) is an indispensable constituent of a healthy gut. Probiotics, the live microorganisms which, when administered in adequate amounts, confer good health benefits onto the host, are a category of feed additives that can be used to replenish the gut microbial population while recuperating the host immune system. Besides their antitoxin and diarrhea reduction effects, dietary supplementation of probiotics can improve gut health, nutrient digestibilities and, therefore, benefit nutrient utilization and growth performance of pigs. Current knowledge in the literature pertinent to the beneficial effects of utilizing various probiotics for swine production has been comprehensively reviewed, and the safety and the risk issues related to probiotic usage have also been discussed in this paper. Considering that the foremost cost in a swine operation is feed cost, feed efficiency holds a very special, if not the paramount, significance in commercial swine production. Globally, the swine industry along with other animal industries is moving towards restricting and eventually a total ban on the usage of antibiotic growth promoters. Therefore, selection of an ideal alternative to the in-feed antibiotics to compensate for the lost benefits due to the ban on the antibiotic usage is urgently needed to support the industry for profitable and sustainable swine production. As is understood, a decision on this selection is not easy to make. Thus, this review paper aims to provide some much needed up-to date knowledge and comprehensive references for swine nutritionists and producers to refer to before making prudent decisions and for scientists and researchers to develop better commercial products. PMID- 29767092 TI - Effects of dietary supplementation of Artemisia argyi aqueous extract on antioxidant indexes of small intestine in broilers. AB - The present study was conducted to investigate the effect of Artemisia argyi aqueous extract (AAE) on antioxidant indexes in the small intestine. A total of 192 Arbor Acre broiler chickens (one-day-old) were randomly divided into 4 treatments with 6 replicates of 8 chickens. These 4 diets were formulated by adding 0, 500, 1,000 and 2,000 mg/kg AAE to the basal diet. The results showed as follows: 1) compared with the control, the total antioxidant capacity (T-AOC) in ileum for the 2,000 mg/kg treatment group was significantly increased at 21 days of age (P < 0.05); the T-AOC levels in jejunum and ileum were significantly increased in broilers supplemented with 500 mg/kg AAE at 42 days of age (P < 0.05), and the T-AOC levels in jejunum and ileum were significantly improved in 1,000 mg/kg treatment group (P < 0.01). 2) At 21 days of age, supplementation of 500 mg/kg AAE significantly increased the catalase (CAT) activity of small intestine, and the glutathione peroxidase (GSH-Px) activity of jejunum was improved (P < 0.01), meanwhile, the GSH-Px activity of duodenum and the total superoxide dismutase (T-SOD) activity of duodenum and jejunum were significantly higher than those of the control group (P < 0.05); supplementation of 1,000 mg/kg AAE significantly increased the CAT activity of duodenum and ileum and the GSH-Px activity of duodenum and jejunum (P < 0.05), and the ileum GSH-Px activity was significantly increased (P < 0.01); supplementation of 2,000 mg/kg AAE significantly increased the CAT activity of duodenum and ileum (P < 0.05). At 42 days of age, supplementation of 500 mg/kg AAE significantly increased the GSH-Px activity of ileum and the T-SOD activity of duodenum (P < 0.05), meanwhile, the T SOD activity of jejunum was significantly increased (P < 0.01); supplementation of 1,000 mg/kg AAE significantly increased the CAT activity of jejunum and the T SOD activity of ileum (P < 0.01), and the GSH-Px activity of jejunum was significantly increased (P < 0.05); supplementation of 2,000 mg/kg AAE significantly increased the T-SOD activity of ileum (P < 0.05), but significantly decreased the CAT activity of ileum and the GSH-Px activity of jejunum (P < 0.05). 3) The malondialdehyde (MDA) levels of 3 AAE supplementation groups were significantly decreased at 21 and 42 days of age (P < 0.05). The results suggested that dietary supplementation with AAE could improve the antioxidative capacity of small intestine in broilers. PMID- 29767091 TI - Nutritional modulation of health, egg quality and environmental pollution of the layers. AB - World egg production and consumption have been increasing for the past decades. Traditional strategies in poultry nutrition have made vital contributions to this great growth in quantity. However, current global issues should be considered in modern egg production such as growing populations and food security, food safety and quality, limited resources and environmental problems. The development of knowledge of poultry nutrition and modern biotechnology provides novel nutritional approaches to closely fit the requirement of pullets and laying hens, which will consequently decrease the nutrition excretion and maintain the lower cost of feed. Nutrition has also been widely accepted as a strategy to influence health and diseases of laying hens. The maintenance of good health is an important prerequisite for improving productivity and egg quality. In addition, there are many measures and strategies for minimizing the incidence of egg defects and providing a choice of lifestyle to enhance human health. This paper reviews current research progress on developing innovative technologies and strategies to maximize animal health and performance, improve the quality of egg products and minimize pollution caused by poultry production. PMID- 29767093 TI - Leucine increases mucin 2 and occludin production in LS174T cells partially via PI3K-Akt-mTOR pathway. AB - Mucin 2 and occludin play a crucial role in preserving the intestinal mucosal integrity. However, the role for leucine mediating intestinal mucin 2 and occludin expression has little been investigated. The current study was conducted to test the hypothesis that leucine treatment could increase mucin 2 and occludin levels in LS174T cells. The LS174T cells were incubated in the Dulbecco's Modified Eagle Medium (DMEM) supplementing 0, 0.5 and 5 mmol/L L-leucine for the various durations. Two hours after the leucine treatment, the inhibitor of mammalian target of rapamycin (mTOR) and protein kinase B (Akt) phosphorylation in LS174T cells were significantly increased (P < 0.05), and the mucin 2 and occludin levels were also significantly enhanced (P < 0.05). However, the pretreatment of 10 nmol/L rapamycin, which was an mTOR inhibitor, or 1 MUmol/L wortmanin, which was an inhibitor of phosphatidylinositol 3-kinase (PI3K), completely inhibited leucine-induced mTOR or Akt phosphorylation (P < 0.05), and significantly reduced leucine-stimulated mucin 2 and occludin levels (P < 0.05). These results suggest that leucine treatment promotes the mucin 2 and occludin levels in LS174T cells partially through the PI3K-Akt-mTOR signaling pathway. PMID- 29767096 TI - The effects of Lippia javanica dietary inclusion on growth performance, carcass characteristics and fatty acid profiles of broiler chickens. AB - This study was conducted to determine the effect of inclusion of fever tea (Lippia javanica) leaf meal in broiler diets on growth performance, carcass characteristics and fatty acid (FA) profiles over a 42-day feeding period. One hundred and eighty, one-day-old, broiler chicks were randomly allocated to the following four treatments: 1) negative control (commercial broiler diet only [Negcontrol]); 2) positive control (commercial broiler diet + prophylactic antibiotics [Poscontrol]); 3) commercial broiler diet without prophylactic antibiotics + 5 g of L. javanica per kg of feed (Ljav5) and 4) commercial broiler diet without prophylactic antibiotics + 12 g of L. javanica per kg of feed (Ljav12). Body weights (BW) and feed intake (FI) were recorded weekly and used to calculate feed conversion ratio (FCR) and average daily weight gain (ADG). At the end of the trial (day 42), all chickens were slaughtered at a local commercial abattoir for assessment of carcass characteristics and FA profiles of meat. The broilers fed L. javanica had significantly (P < 0.05) lower FI compared with the other two groups. However, the broilers in the Poscontrol and Ljav5 treatment groups had higher (P < 0.05) ADG, lower FCR and higher slaughter weights. L. javanica inclusion had no effect on the breast weight, thigh weight, carcass weight, and dressing percentage of the broilers. Most of the n-3 FA were not affected by diets except for the docosapentaenoic, which was found to be higher (P < 0.05) in the Ljav12 treatment group and the lowest in the Negcontrol. The broilers in the Negcontrol and Poscontrol groups had higher (P < 0.05) total saturated fatty acids (SFA). On the contrary, the L. javanica fed broilers had higher (P < 0.05) total polyunsaturated fatty acids (PUFA), total n-3 FA and PUFA:SFA ratio and also had significantly lower n-6:n-3 ratios compared with the other two treatment groups. No differences were observed with regards to total monounsaturated fatty acids (MUFA) and total n-6 FA. Overall, the findings from the study showed that inclusion of L. javanica in broiler diets at 5 g/kg feed has positive influences on growth performance, carcass characteristics and FA profiles of broiler meat. PMID- 29767094 TI - Effect of dietary incorporation of n-3 polyunsaturated fatty acids rich oil sources on fatty acid profile, keeping quality and sensory attributes of broiler chicken meat. AB - The present study was undertaken to investigate the effect of dietary replacement of commonly used vegetable oil (sunflower oil, SFO) with n-3 polyunsaturated fatty acids (PUFA) rich oil sources on broiler chicken performance, carcass yield, meat fatty acid composition, keeping quality and sensory attributes of meat. In the current experiment, 300 day-old Krishibro broiler chicks were randomly distributed to 5 dietary groups (50 replicates with 6 chicks in each) prepared by replacing SFO (2% and 3% of diet during starter and finisher periods, respectively) with n-3 PUFA rich soybean oil (SO), mustard oil (MO), linseed oil (LO) or fish oil (FO) on weight basis. Variation in oil sources had no influence (P > 0.05) on performance and carcass yield. Supplementation of MO, LO or FO significantly (P < 0.01) increased the n-3 PUFA, lowered the n-6 PUFA deposition and n-6:n-3 ratio in breast and thigh without affecting the organoleptic characters (appearance, flavour, juiciness, tenderness and overall acceptability) of meat. However, thiobarbituric acid reacting substances concentration in meat was increased (P < 0.01) with LO and FO supplementation compared with SFO. It is concluded that, dietary incorporation of MO, LO or FO at 2% and 3% levels during starter and finisher phase can enrich broiler chicken meat with n-3 PUFA without affecting the bird's performance and sensory characters of meat. PMID- 29767097 TI - Effects of derived meals from juncea (Brassica juncea), yellow and black seeded canola (Brassica napus) and multicarbohydrase enzymes supplementation on apparent metabolizable energy in broiler chickens. AB - Two experiments were conducted to determine the nitrogen-corrected apparent metabolizable energy (AMEn) of differently processed meals from Juncea (Brassica juncea), yellow and black seeded canola (Brassica napus), with or without supplementation of multi-carbohydrase enzymes (Enz) in diets for broiler chickens. The first experiment was a 3 * 2 * 2 factorial arrangement with the main factors being seed type (yellow [Yellow] or black [B1] canola seeds and Juncea seeds), processed at two temperatures (high temperature desolventized toasted [HTDT] at 95 degrees C or low temperature desolventized-toasted [LTDT] at 57 degrees C), with or without Enz. In Exp. 1, a total of 384 one-day-old male broiler chicks were randomly assigned to 64 battery cages, with 6 birds/cage. The second experiment was a 2 * 2 * 2 factorial arrangement with the main factors being seed type (Yellow or black [B2]), seed source (Scott, Saskatchewan or Truro, Nova Scotia) and Enz (with or without) supplementation. A total of 264 one day-old male broiler chicks were randomly assigned to 44 battery cages, with 6 birds per cage. In Exp. 1 and 2, all birds were fed a common starter diet from 1 to 14 days of age. From d 15 to 21, the birds were fed one of the test treatments, a basal grower diet or the basal grower diet replaced with 30% test ingredient with celite (0.8%) added as an inert marker. Excreta was collected on d 20 and 21. In Exp. 1, there were no interactions (P > 0.05) among seed type, processing temperature and Enz. Processing temperature and dietary Enz did not affect (P > 0.05) AMEn of different canola meals. The AMEn of prepress solvent extracted canola and juncea meals (PSEM) from Yellow (11.2 MJ/kg) was higher (P < 0.05) than B1 (10.2 MJ/kg) and Juncea (10.2 MJ/kg). In Exp. 2, there were no interactions (P > 0.05) among seed color, location and Enz. Supplementation of dietary Enz did not affect (P > 0.05) AMEn of different cold press canola meals. The AMEn of cold press canola meals (CPM) from Yellow (14.7 MJ/kg) was higher (P < 0.05) compared with B2 (12.2 MJ/kg). In conclusion, among the different processing methods of oil extraction, meals derived from yellow seeded canola had higher AMEn than B seeded canola and Juncea. PMID- 29767095 TI - Arginine, N-carbamylglutamate, and glutamine exert protective effects against oxidative stress in rat intestine. AB - The objective of the current study is to evaluate the effects of dietary supplementation with arginine (ARG), N-carbamylglutamate (NCG), and glutamine (GLN) on rat intestinal morphology and antioxidant status under oxidative stress. Rats were fed for 30 d with one of the following iso-nitrogenous diets: basal diet (BD), BD plus 1% ARG, BD plus 0.1% NCG, and BD plus 1% GLN. On day 28, half of the rats fed BD were intraperitoneally injected with 12 mg/kg body weight of diquat (DT; i.e., the DT group) and the other half was intraperitoneally injected with sterile solution (i.e., the control group). The other diet groups were intraperitoneally injected with 12 mg/kg body weight of DT (i.e., DT + 1% GLN [DT + GLN], DT + 1% ARG [DT + ARG], and DT + 0.1% NCG [DT + NCG]). Rat jejunum samples obtained at 48 h after DT injection were analyzed. Results showed that DT significantly decreased catalase (CAT) activity and glutathione (GSH) content by 58.25% and 56.57%, respectively, and elevated malondialdehyde (MDA) content and crypt depth (CD) by 19.39% and 22.13%, respectively, in the jejunum (P < 0.05, relative to the control group). Compared with the DT group, the DT + GLN group exhibited significantly improved villus height (VH), villus width (VW), villus surface area (VSA), CD and total antioxidant capacity (T-AOC) activity (P < 0.05); the DT + ARG group exhibited significantly increased the ratio of VH to CD (H:D) and T-AOC activity (P < 0.05); the DT + GLN, DT + ARG and DT + NCG groups exhibited significantly enhanced CAT activity and GSH content as well as decreased MDA content (P < 0.05). Moreover, VH, VW, VSA, CD and GSH content in the DT + GLN group were higher whereas MDA content was lower compared with the corresponding values observed in both the DT + ARG and the DT + NCG groups (P < 0.05). The H:D ratio in the DT + ARG group significantly increased compared with that in the DT + NCG and DT + GLN groups (P < 0.05). Collectively, this study suggested that dietary supplementation with 1% GLN, 0.1% NCG, and 1% ARG was effective in enhancing the antioxidant status and maintaining the morphological structure of rat jejunum under oxidative stress; of these supplements, 1% GLN exerted the greatest effects on mitigating oxidative stress. PMID- 29767098 TI - Evaluation of the effect of different wheats and xylanase supplementation on performance, nutrient and energy utilisation in broiler chicks. AB - The aim of this study was to evaluate the performance, nutrient utilisation and energy metabolism of broiler chicks fed 8 different wheat samples, supplemented or not with xylanase. Seven-hundred sixty eight male broilers (1-day-old) were distributed to 16 experimental treatments (6 replicates per treatment). The treatments were in a factorial arrangement with 8 different wheats and 2 levels of xylanase (0 or 16,000 BXU/kg). The predicted apparent metabolisable energy (AME) of the wheat samples ranged from 13.0 to 13.9 MJ/kg and all diets were formulated to contain the same amount of wheat. Body weight gain (BWG) and feed intake (FI) were measured at 21 d, as was jejunal digesta viscosity, and feed conversion ratio (FCR) calculated. On day 24, one representative bird per pen was selected to calculate whole body energetics. At 21 d, 3 chicks per replicate were randomly allocated to metabolism cages for energy and nutrient utilisation determinations, and were continued on the experimental diets until 24-d-old. No interactions were observed for any performance response variables, ileal nutrient utilisation or digesta viscosity. Xylanase improved BWG and reduced FCR and digesta viscosity (P < 0.05). Wheat influenced dry matter (DM) utilisation and xylanase increased ileal digestible energy (P = 0.04). Xylanase also improved (P < 0.05) DM and nitrogen retention. Apparent metabolisable energy and AME corrected for nitrogen (AMEn) were subject to an interaction whereby wheats 2 and 6, which returned the lowest AME and AMEn values, responded to xylanase supplementation and the remainder did not. Net energy for production and the efficiency of energy use for production were not influenced by xylanase, but were affected by wheat (P < 0.05). Despite the significant differences between wheats with regards to their nutrient utilisation and energy metabolism in birds, xylanase removed this variance and resulted in more homogeneous performance. PMID- 29767099 TI - Growth performance, nutrient digestibility, antioxidant capacity, blood biochemical biomarkers and cytokines expression in broiler chickens fed different phytogenic levels. AB - The effects of inclusion levels of a phytogenic feed additive (PFA), characterized by menthol anethol and eugenol, on broiler growth performance, nutrient digestibility, biochemical biomarkers and total antioxidant capacity (TAC) of plasma and meat, as well as on the relative expression of selected cytokines, were studied in a 42-d experiment. A total of 225 one-day-old male Cobb broiler chickens were assigned into 3 treatments, with 5 replicates of 15 chickens each. Chickens were fed maize-soybean meal basal diets following a 3 phase (i.e., starter, grower and finisher) feeding program. Depending on PFA inclusion level, treatments were: no PFA (PFA-0), PFA at 100 mg/kg (PFA-100) and PFA at 150 mg/kg (PFA-150). Feed and water were available ad libitum. Feed conversion ratio (FCR) during finisher phase was improved quadratically (P < 0.05) with increasing PFA level. Overall, increasing PFA level increased body weight gain (BWG) in a linear (P < 0.05) and quadratic (P < 0.05) manner with treatments PFA-100 and PFA-150 being greater (P < 0.05) compared with PFA-0. Total tract apparent digestibility of dry matter increased linearly (P < 0.05) and quadratically (P < 0.05) with increasing PFA level. The apparent metabolizable energy corrected for nitrogen (AMEn) also increased linearly (P < 0.05). Increasing PFA level resulted in a linear (P < 0.05) increase in blood plasma TAC. Expression of pro-inflammatory cytokine interleukin -18 (IL-18) was reduced linearly (P < 0.05) in spleen with increasing PFA level. In conclusion, PFA inclusion at 100 mg/kg diet positively influenced performance, whereas PFA inclusion at 150 mg/kg resulted in a stronger improvement in AMEn and plasma TAC. Finally, PFA inclusion resulted in a pattern of reduced pro-inflammatory biomarker IL-18 at spleen. Overall, this study provides evidence for the beneficial role of PFA as a natural growth and health promoter in broiler chickens that needs to be further confirmed in field studies. PMID- 29767101 TI - Effects of moisture content or particle size on the in situ degradability of maize silage and alfalfa haylage in lactating dairy cows. AB - A study using four Holstein cows with ruminal cannulas was conducted to evaluate the degradability of different moisture content or particle size of maize silage and alfalfa haylage. The maize silage (MS; 20-mm length) and alfalfa haylage (AH; 40-mm length) samples were wet (wet maize silage, MSW; wet alfalfa haylage, AHW), dried (dried maize silage, MSD; dried alfalfa haylage, AHD), or ground to pass through a 2.5-mm screen (dried ground maize silage, MSG; dried ground alfalfa haylage, AHG). Samples were incubated in the rumen for 2, 6, 12, 24, 36, 48, and 72 h. Cows were fed ad libitum and allowed free access to water. High moisture content treatment of MSW expressed a lower rinsing NDF and ADF degradability at 2 h (P < 0.05) compared with dried samples (MSD and MSG). Different moisture content and particle size had a significant impact (P < 0.05) on the NDF degradability at 72 h, ADF degradability at 36, 48, and 72 h, and ruminally degradable ADF. All of the highest values were observed in small particle size and low moisture content AHG treatment. Based on this study, sample processing, such as drying and grinding, should be considered when evaluating nutritive values of forages. PMID- 29767100 TI - Antioxidant systems in chick embryo development. Part 1. Vitamin E, carotenoids and selenium. AB - Chick viability is known to be an important factor determining profitability of the poultry industry. Chick embryo tissues contain a high proportion of highly polyunsaturated fatty acids in the lipid fraction and therefore need antioxidant defence. The antioxidant system of the developing embryo and newly hatched chick includes the antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase), water-soluble antioxidants (ascorbic acid, taurine, carnitine, glutathione, etc.), fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q) as well as selenium (Se). In fact, the high levels of endogenous antioxidants within the egg and embryonic tissues can clearly serve as a major adaptive mechanism for the protection of the tissue during the oxidative stress experienced at hatching. It has been shown that among different nutrients in the maternal diet which could significantly affect chick embryo development and their viability in the early posthatch life, natural antioxidants have been suggested to play a central role. Our data indicate that increased supplementation of the maternal diet can substantially increase concentrations of vitamin E, carotenoids (especially canthaxanthin) and Se in developing chick tissues and significantly decrease susceptibility to lipid peroxidation being effective nutritional tools to deal with various commercial stresses in poultry production. PMID- 29767102 TI - Methodological aspects of determining phosphorus digestibility in swine: A review. AB - The role of phosphorus (P) in swine nutrition has been taken on new significance in recent years. Methods to determine the available phosphorus (AP) content of swine feeds include relative bioavailability (RBV), apparent total tract digestibility (ATTD), standardized total tract digestibility (STTD), and true total tract digestibility (TTTD). The RBV of P is determined by measuring bone ash or bone P, whereas the ATTD of P is determined by calculating the difference between P intake and P excretion in feces. Recent research has shown that the use of ATTD of P underestimates the AP due to the existence of endogenous P in feces and digesta. The STTD can be calculated from ATTD by taking basal endogenous phosphorus losses (EPL) into consideration. The basal EPL in pigs can be measured by feeding a P-free diet. Values for STTD of P are believed to be additive in mixed diets but not for ATTD of P. The regression method is a common approach to determine total EPL and TTTD of P, which measures the linear relationship between fecal P excretion and the dietary intake of total P. In addition, in vitro methods such as the bionic enzymatic method are being increasingly utilized because they can be done quickly and simply. Several dietary factors such as P and Ca concentrations, phytate, Ca to P ratio and vitamin D may affect AP. This review summarizes the evolution of methods to measure AP and factors that can affect AP, which may provide information to formulate swine diet more accurately. Moreover, the knowledge about AP may help to reduce the P waste in swine production and thus decrease its impact on the environment. PMID- 29767103 TI - Comparative methane estimation from cattle based on total CO2 production using different techniques. AB - The objective of this study was to compare the precision of CH4 estimates using calculated CO2 (HP) by the CO2 method (CO2T) and measured CO2 in the respiration chamber (CO2R). The CO2R and CO2T study was conducted as a 3 * 3 Latin square design where 3 Dexter heifers were allocated to metabolic cages for 3 periods. Each period consisted of 2 weeks of adaptation followed by 1 week of measurement with the CO2R and CO2T. The average body weight of the heifer was 226 +/- 11 kg (means +/- SD). They were fed a total mixed ration, twice daily, with 1 of 3 supplements: wheat (W), molasses (M), or molasses mixed with sodium bicarbonate (Mbic). The dry mater intake (DMI; kg/day) was significantly greater (P < 0.001) in the metabolic cage compared with that in the respiration chamber. The daily CH4 (L/day) emission was strongly correlated (r = 0.78) between CO2T and CO2R. The daily CH4 (L/kg DMI) emission by the CO2T was in the same magnitude as by the CO2R. The measured CO2 (L/day) production in the respiration chamber was not different (P = 0.39) from the calculated CO2 production using the CO2T. This result concludes a reasonable accuracy and precision of CH4 estimation by the CO2T compared with the CO2R. PMID- 29767104 TI - Effects of purified zearalenone on selected immunological measurements of blood in post-weaning gilts. AB - Zearalenone (ZEA), an estrogenic mycotoxin, is produced mainly by Fusarium fungi. Previous studies have indicated that acute ZEA exposure induced various damages in different species; however, its transparent hematotoxicity in female piglets at dietary levels of 1.1 to 3.2 mg/kg has not been shown. The present study was conducted to investigate the effects of dietary ZEA (1.1-3.2 mg/kg) on hematology, T lymphocyte subset, immunoglobulin, antibody titer, lymphocyte proliferation rate (LPR), and interleukin-2 (IL-2) in peripheral blood of post weaning gilts. A total of 20 female piglets (Landrace * Yorkshire * Duroc), weaned at 42 d with an average body weight of 10.36 +/- 1.21 kg were used in the study. Female piglets were kept in a temperature controlled room, divided into four treatments, and fed a diet based on corn-soybean meal-fishmeal-whey, with an addition of 0, 1.1, 2.0, or 3.2 mg/kg purified ZEA for 18 d ad libitum. Feed intake and refusal were measured daily and individual pigs were weighed weekly. Blood and serum samples were collected for selected immunological measurements. Female piglets fed different levels of dietary ZEA grew similarly with no difference in feed intake. Hematological values including leukocytes, platelets, lymphocytes, hematocrit, and mean corpuscular hemoglobin (MCH) decreased linearly (P < 0.05) as dietary ZEA increased. Female piglets fed diets containing 2.0 mg/kg ZEA or greater showed significantly decreased CD4+CD8+, CD4+, and CD4+/CD8+ in comparison to the control (P < 0.05), whereas CD8+ was significantly increased (P = 0.026) in the gilts which were fed the diet containing 3.2 mg/kg ZEA. Serum immunoglobulin G (IgG) and the antibody titer on d 18 were reduced linearly as dietary ZEA levels increased (P < 0.001). Linear decrease in LPR was observed (P < 0.05). Female piglets fed diets containing 2.0 mg/kg ZEA or more showed significantly decreased IL-2 in comparison to the control (P < 0.05). The results suggested that dietary ZEA at the levels of 1.1 to 3.2 mg/kg can induce different degrees of hematotoxicity and negatively affect immune function in female piglets. PMID- 29767105 TI - Techniques for evaluating digestibility of energy, amino acids, phosphorus, and calcium in feed ingredients for pigs. AB - Sound feed formulation is dependent upon precise evaluation of energy and nutrients values in feed ingredients. Hence the methodology to determine the digestibility of energy and nutrients in feedstuffs should be chosen carefully before conducting experiments. The direct and difference procedures are widely used to determine the digestibility of energy and nutrients in feedstuffs. The direct procedure is normally considered when the test feedstuff can be formulated as the sole source of the component of interest in the test diet. However, in some cases where test ingredients can only be formulated to replace a portion of the basal diet to provide the component of interest, the difference procedure can be applied to get equally robust values. Based on components of interest, ileal digesta or feces can be collected, and different sample collection processes can be used. For example, for amino acids (AA), to avoid the interference of fermentation in the hind gut, ileal digesta samples are collected to determine the ileal digestibility and simple T-cannula and index method are commonly used techniques for AA digestibility analysis. For energy, phosphorus, and calcium, normally fecal samples will be collected to determine the total tract digestibility, and therefore the total collection method is recommended to obtain more accurate estimates. Concerns with the use of apparent digestibility values include different estimated values from different inclusion level and non additivity in mixtures of feed ingredients. These concerns can be overcome by using standardized digestibility, or true digestibility, by correcting endogenous losses of components from apparent digestibility values. In this review, methodologies used to determine energy and nutrients digestibility in pigs are discussed. It is suggested that the methodology should be carefully selected based on the component of interest, feed ingredients, and available experimental facilities. PMID- 29767107 TI - Effects of purified zearalenone on selected immunological and histopathologic measurements of spleen in post-weanling gilts. AB - The present study was aimed at investigating the adverse effects of dietary zearalenone (ZEA) on the lymphocyte proliferation rate (LPR), interleukin-2 (IL 2), mRNA expressions of pro-inflammatory cytokines, and histopathologic changes of spleen in post-weanling gilts. A total of 20 crossbred piglets (Yorkshire * Landrace * Duroc) with an initial BW of 10.36 +/- 1.21 kg (21 d of age) were used in the study. Piglets were fed a basal diet with an addition of 0, 1.1, 2.0, or 3.2 mg/kg purified ZEA for 18 d ad libitum. The results showed that LPR and IL-2 production of spleen decreased linearly (P < 0.05) as dietary ZEA increased. Splenic mRNA expressions of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) were linearly up-regulated (P < 0.05) as dietary ZEA increased. On the contrary, linear down-regulation (P < 0.05) of mRNA expression of interferon-gamma (IFN gamma) was observed as dietary ZEA increased. Swelling splenocyte in 1.1 mg/kg ZEA treatments, atrophy of white pulp and swelling of red pulp in 2.0 and 3.2 mg/kg ZEA treatments were observed. The cytoplasmic edema in 1.1 mg/kg ZEA treatments, significant chromatin deformation in 2.0 mg/kg ZEA treatment and phagocytosis in 3.2 mg/kg ZEA treatment were observed. Results suggested that dietary ZEA at 1.1 to 3.2 mg/kg can induce splenic damages and negatively affect immune function of spleen in post-weanling gilts. PMID- 29767108 TI - Optimizing protein and lipid levels in practical diet for juvenile northern snakehead fish (Channa argus). AB - A 3 * 3 factorial feeding trial was conducted to evaluate the production response of juvenile northern snakehead fish (Channa argus). Nine diets containing 3 protein levels (45%, 48% and 51%) and 3 lipid levels (9%, 12% and 15%) were formulated and fed to triplicate groups of juvenile northern snakehead (15.78 +/- 0.09 g/fish) for 8 weeks. The formulated diets were named as P45L9, P45L12, P45L15, P48L9, P48L12, P48L15, P51L9, P51L12 and P51L15 (P-Protein, L-Lipid), respectively. Fish fed diets with the lowest protein and lipid combination (P45L9) had the lowest growth performance. Weight gains (WG) of fish fed the 4 diets P48L12, P48L15, P51L9, and P51L12 were not significantly different (P > 0.05), but significantly higher (P < 0.05) than those of fish fed the other diets. Fish fed diets P48L12 and P48L15 had significantly lower (P < 0.05) feed conversion ratios (FCR) than the rest of the treatments. Protein retentions (PR) among fish fed the diets P45L12, P45L15, P48L12, P48L15, P51L9, and P51L12 were similar and significantly higher (P < 0.05) than those of fish fed the remaining diets. Protein sparing effect was observed in the treatments when fish was fed diets containing 45% or 48% dietary protein levels with dietary lipid increased from 9% to 12%. Fish fed diets with 9% lipid tended to have lower viscerosomatic index (VSI), hepatosomatic index (HSI), and whole-body lipid. Increasing dietary protein level significantly increased (P < 0.05) liver moisture and lipid while dietary lipid level increased liver lipid. Intestinal lipase activity increased significantly (P < 0.05) with increasing dietary lipid and protein levels while intestinal alpha-amylase and protease activities were not significantly influenced (P > 0.05) by dietary treatments. Based on these results, the diet containing 48% protein with either 12% or 15% lipid is the optimal for supporting growth and feed utilization of juvenile northern snakehead under the current testing conditions. PMID- 29767109 TI - Nutrient density of prestarter diets from 1 to 10 days of age affects intestinal morphometry, enzyme activity, serum indices and performance of broiler chickens. AB - A total of 480 day-old Cobb 500 broilers were used to investigate the effects of different levels of digestible amino acids (DAA; 100%, 107% and 114% of Cobb recommendations) and ME (3,000 or 2,900 kcal/kg) of prestarter diet on mixed sex broilers performance, enzyme activity, small intestine morphology, and serum metabolites. Broilers were randomly allotted to 6 treatments, where each treatment applied to 4 pens with 20 birds in each. The birds were subjected to their respective treatment diets from 1 to 10 days of age. This was followed by feeding common starter and finisher diets for the last 29 days. The enzyme activity of the pancreas was measured at 10 days of age. Morphometric indexes of jejunum were measured at 10 days of age and the end of the feeding period. Our results showed that the body weight (BW) increased as the DAA density of the prestarter diet increased from 100% to 114% over the first 10 days and the entire period of the study. Birds fed 114% DAA presented a better feed conversion ratio on day 10 (P < 0.05). At day 39, carcass weight and breast yield increased as the DAA levels increased from 100% to 114% (P < 0.05). The whole intestine length, small intestine length, and weights of the pancreas were lower in birds fed 100% DAA-diets at 10 days of age (P < 0.05). Increasing the dietary DAA and ME did not affect serum amylase, lipase, and protease concentrations and pancreatic amylase and lipase activity (P > 0.05); however, the activity of pancreatic protease increased as the DAA level increased from 100% to 114% (P < 0.05). The villus width and villus surface area (VSA) increased as the DAA level increased from 100% to 114% on day 10 (P < 0.05). At 10 days of age, crypt depth was the lowest in the birds fed plenty DAA prestarter diets (P < 0.05). It was found that dietary treatments at 39 days of age did not affect intestinal morphology. The results of the present work indicate that DAA level of 114% of Cobb recommendations and energy level of 2,900 kcal/kg diet may be recommended for starting broiler chicks. PMID- 29767106 TI - Epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals. AB - It is well known that phenotype of animals may be modified by the nutritional modulations through epigenetic mechanisms. As a key and central component of epigenetic network, DNA methylation is labile in response to nutritional influences. Alterations in DNA methylation profiles can lead to changes in gene expression, resulting in diverse phenotypes with the potential for decreased growth and health. Here, I reviewed the biological process of DNA methylation that results in the addition of methyl groups to DNA; the possible ways including methyl donors, DNA methyltransferase (DNMT) activity and other cofactors, the critical periods including prenatal, postnatal and dietary transition periods, and tissue specific of epigenetic modulation of DNA methylation by nutrition and its mechanisms in animals. PMID- 29767112 TI - Correction: Which patients presenting with arthralgia eventually develop rheumatoid arthritis? AB - [This corrects the article DOI: 10.1136/rmdopen-2017-000479.]. PMID- 29767110 TI - Effects of feeding whole linseed on ruminal fatty acid composition and microbial population in goats. AB - The objective of the present study was to evaluate the effect of feeding different levels of whole linseed, as a source of n-3 polyunsaturated fatty acids (PUFA), on ruminal fatty acid composition and microbial population in the goat. Twenty-four crossbred Boer goats were assigned to 3 dietary treatments: L0 (control), L10 and L20 containing 0, 10%, or 20% whole linseed, respectively. The ruminal pH and concentration of total volatile fatty acids (VFA) were not affected by dietary treatments. The feeding of L10 and L20 diets produced higher (P < 0.05) molar proportions of acetate and lower (P < 0.05) molar proportions of butyrate and valerate than the L0 diet. Molar proportions of myristic acid (C14:0) and palmitic acid (C16:0) were lower (P < 0.05) in the rumen of goats offered L10 and L20 diets than the control diet. However, stearic acid (C18:0), vaccenic acid (C18:1 trans-11), conjugated linoleic acid (CLA, C18:2 trans-10, cis-12) and alpha-lenolenic acid (C18:3 n-3) were higher (P < 0.05) in the rumen of goats fed L10 and L20 than L0. Both inclusion levels of linseed in the diet (L10 and L20) reduced the ruminal total bacteria, methanogens, and protozoa compared with L0 (P < 0.05). The effect of the dietary treatments on cellulolytic bacteria, varied between the individual species. Both inclusion levels of linseed resulted in a significant decrease (P < 0.05) in the population of Fibrobacter succinogenes, and Rumunococus flavefaciens compared with L0, with no significant difference between the groups fed linseed diets. The population of Rumunococus albus was not affected by the different dietary treatments. It was concluded that inclusion of whole linseed in the diet of goats could increase the concentration of PUFA in the rumen, and decrease the population of F. succinogenes, R. flavefaciens, methanogens and protozoa in rumen liquid of goats. PMID- 29767111 TI - Effect of exogenous fibrolytic enzymes on performance and blood profile in early and mid-lactation Holstein cows. AB - The supplementation of exogenous fibrolytic enzymes (EFE) to dairy cows diets could be a strategy to improve fiber degradation in the rumen which is especially important for the early lactating cows characterized by a high milk energy output and an insufficient energy intake. The objective of this study was to examine the effects of a fibrolytic enzyme product (Roxazyme G2 Liquid, 3.8 and 3.9 mL/kg total mixed ration [TMR] DM) supplemented to a TMR on production performance and blood parameters of dairy cows during early (trial 1) and mid-lactation (trail 2). In addition, rumination activity was measured in trial 2. The nutrient digestibility of the experimental TMR was obtained by using wethers. In the digestibility trial, EFE was supplemented at a rate of 4.4 mL/kg Roxazyme G2 Liquid TMR-DM. The TMR contained 60% forage and 40% concentrate (DM basis). Twenty eight 50 +/- 16 days in milk (DIM) and twenty six 136 +/- 26 DIM Holstein cows were used in two 8-wk completely randomized trails, stratified by parity and milk yield level. One milliliter of the enzyme product contained primarily cellulase and xylanase activities (8,000 units endo-1,4-beta glucanase, 18,000 units endo-1,3(4)-beta glucanase and 26,000 units 1,4-beta xylanase). No differences in digestibility of DM, OM, CP, NDF and ADF were observed (P > 0.05) between the control and the EFE supplemented TMR. Addition of EFE to the TMR fed to early (trial 1) and mid-lactation cows (trial 2) did not affect daily dry matter intake (DMI), milk yield, 4% fat-corrected milk, energy-corrected milk (ECM), concentration of milk fat, protein, fat-protein-quotients, somatic cell score, energy balance, and gross feed efficiency of early and mid-lactation cows (P > 0.05). Mid-lactation cows (trial 2) fed with TMR enzyme showed a tendency of a slightly higher ECM yield (P = 0.09). The tested blood parameters were not affected by treatment in trials 1 and 2 (P > 0.05). Exogenous fibrolytic enzymes supplementation did not alter daily time spent ruminating in trial 2 (P = 0.44). In conclusion, under the conditions of this study, no positive effects of enzyme supplementation on dairy performance and health status of dairy cows during early and mid-lactation were observed. PMID- 29767114 TI - Effects of physical form of diet on nutrient digestibility, rumen fermentation, rumination, growth performance and protozoa population of finishing lambs. AB - This study was conducted to compare effects of 3 physical forms of feed including mash (diet 1), pellet (diet 2) and complete feed block (CFB; diet 3) on digestion, fermentation and performance of lambs. Twenty-one lambs with an initial average body weight of 26 +/- 2.5 kg and 6 +/- 1.5 months of age were assigned through a completely randomized design to 3 treatments and 7 replicates. The experimental treatments had the same formulation. The results of present experiment showed that CFB significantly increased feed intake and nutrient digestibility (P < 0.05). There was no significant difference among the diets for rumen fluid pH, blood glucose, concentration of volatile fatty acids (P > 0.05), except acetic acid (P < 0.05). The rumen ammonia nitrogen (NH3-N), mixed rumen protozoa population (RPP), Entodiniums spp., Epidiniums spp., blood urea nitrogen (BUN) concentration, rumination time adjusted for dry matter (DM), neutral detergent fiber (NDF), acid detergent fiber (ADF) intake, and total body weight gain of lambs in CFB diet were the highest among all diets (P < 0.05). Feed conversion ratio at days 31 to 45 and whole experimental period were better in CFB than in other diets (P < 0.05). Overall, according to the findings of the present study, among 3 physical forms of the diets, CFB had the best efficiency due to improvement of nutrient digestibility, rumen fermentation and performance of lambs. Therefore, the CFB diet offers the best result in lambs compared with mash and pellet diets. PMID- 29767113 TI - Vitamin D3 increased intestinal Na/Pi-IIb and CYP27B1 mRNA level in rats fed low phosphorus diets. AB - The objective of the study was to determine the role of vitamin D3 (VD3) in regulating adaptation and mechanism of rats to low-phosphorus (P) diets. Rats were assigned to 4 diets containing 0.2%, 0.4%, 0.6%, or 0.8% P consisting of 5 replicate cages with 6 rats per replicate cage and fed for 7 days. Four rats from each replicate cage were treated with ethane-1-hydroxy-1,1-diphosphonicacid, tetrasodium salt (EHDP) and 2 rats remained untreated. Twelve hours prior to preparation on d 7, two of the EHDP-treated rats received an intraperitoneal injection of VD3 [1,25-(OH)2D3] at 600 ng per kg body weight, while two rats did not receive the injection. Rats that did not receive VD3 injection had decreased (P < 0.001) P absorption, but injection of VD3 resulted in increased (P < 0.001) absorption. The effect of VD3 injection was greater (P < 0.001) for rats fed 0.2% P diet than rats fed 0.8% P diet in ileum. Sodium dependent phosphate cotransporter type IIb (Na/Pi-II b) and 25-hydroxyvitamin D 1-alpha hydroxylase (CYP27B1) mRNA level showed the same trend with P absorption. Serum concentration of VD3 and 1alpha-hydroxylase activity in rats fed 0.2% P diet were lower than those fed 0.8% P diet. The injection of VD3 increased (P < 0.001) serum concentration of VD3 and 1alpha-hydroxylase activity. Thus, VD3 increased Na/Pi IIb and CYP27B1 mRNA level and improved serum concentration of VD3 and 1alpha hydroxylase activity in rats fed low-P diets. PMID- 29767115 TI - Dietary supplementation of Lonicera macranthoides leaf powder improves amino acid profiles in serum and longissimus thoracis muscle of growing-finishing pigs. AB - A 60-days feeding trial was conducted to determine the effect of dietary supplementation of Lonicera macranthoides leaf (LML) on growth performance, meat quality, and free amino acid profiles in growing-finishing pigs. L. macranthoides leaves were harvested, air-dried and milled to powder. A total of 288 crossbred barrows (Large White * Landrace) with an average initial BW of 54.0 +/- 3.4 kg were randomly allocated to 3 treatment groups and fed either a basal diet or a diet supplemented with 0.5% or 1.0% LML powder. Results showed that diet supplemented with LML powder did not affect average daily feed intake (ADFI) and feed: gain ratio (P > 0.05) in growing-finishing pigs. Moreover, diet supplemented with LML powder showed no significant effects on carcass traits (P > 0.05) including dressing percentage, backfat thickness and loin muscle area, and meat quality traits (P > 0.05) including meat color, intramuscular fat and cooking loss. However, diet supplemented with LML powder significantly improved free amino acid profiles in serum and longissimus thoracis muscle in growing finishing pigs. Most importantly, dietary LML powder increased total free amino acids content (P < 0.001) and essential free amino acid content (P < 0.001) in longissimus thoracis muscle. These results indicate that LML has the potential to improve the nutritional value of meat through improving free amino acid profiles. PMID- 29767116 TI - Effects of ammonia exposure on carcass traits and fatty acid composition of broiler meat. AB - We aimed to study the effects of ammonia on carcass traits, organ indices and fatty acid composition of broilers. Four hundred 21-d-old male Arbor Acres broilers with initial weight 563.52 +/- 2.82 g were randomly allotted to 1 of 4 groups treated with ammonia at <3 mg/kg (control), 25 +/- 3, 50 +/- 3, and 75 +/- 3 mg/kg concentrations. Each group consisted of 4 replicates of 25 birds. Broilers from 21 to 42 d were reared on the net floor in the respiration metabolism chambers where similar environmental conditions were maintained. At 32 and 42 d of age, carcass traits and organ indices were determined for 4 birds per pen. At 42 d of age, fatty acid composition in the breast and thigh muscle of broilers was measured. Results showed as follows: 1) At 32 d, the dressing percentage of broilers exposed to 25 and 75 mg/kg ammonia were lower than those in the control group (P < 0.05); eviscerated yield percentage of broilers in the 25 mg/kg ammonia group was also lower (P < 0.05). At 42 d, the dressing percentage of broilers in the ammonia treatments and the thigh muscle percentage of broilers in the 50 and 75 mg/kg ammonia groups were lower (P < 0.05) than those in the control. Breast muscle percentage of broilers exposed to 25 and 50 mg/kg ammonia and eviscerated yield percentage exposed to 50 mg/kg ammonia were lower than those in the control (P < 0.05). 2) The kidney index of broilers (d 32) exposed to ammonia was greater (P < 0.05) than that of the control. At 42 d, hepatic index of broilers exposed to ammonia was increased (P < 0.05), and spleen index was decreased (P < 0.05). 3) At 42 d, stearic (C18:0) and saturated fatty acids (SFA) in the thigh muscle of broilers were higher, while the unsaturated fatty acid:saturated fatty acid (U:F) ratio and unsaturated fatty acid (UFA) were lower in the 50 mg/kg ammonia treatment than in the control group (P < 0.05). In conclusion, ammonia over 25 mg/kg could decline carcass traits and immune organ indices and increase the kidney and hepatic indices. Further, exposure to 50 mg/kg ammonia could also decrease breast and thigh muscle yield percentage while increasing SFA content and decreasing UFA content in the thigh muscle of broilers. PMID- 29767117 TI - Growth performance and hematology of Djallonke rams fed haulms of four varieties of groundnut (Arachis hypogaea L.). AB - The study was conducted to assess the chemical composition of the haulms of 4 dual-purpose groundnut (Arachis hypogaea L.) varieties and their effects on the growth and hematology of Djallonke rams. The groundnut varieties were ICGV 97049 (Obolo), ICGX SM 87057 (Yenyawoso), RMP 12 (Azivivi) and Manipinta. Rams (live weight 15.0 +/- 3.0 kg) were randomly assigned to 4 sole groundnut haulm meal (GHM) treatments, with 4 rams each in an individual pen per treatment (total n = 16 rams). Samples of the groundnut haulms were milled and analyzed for crude protein (CP), neutral detergent fiber (NDF) and acid detergent fiber (ADF). The CP concentration was higher (P < 0.05) in Azivivi, Manipinta and Yenyawoso than in Obolo. The highest (P < 0.05) NDF and ADF fractions were obtained in Obolo. Whilst no significant difference was reported in total and daily dry matter (DM) intake among the varieties, CP, NDF and ADF intake all differed between Obolo and other varieties. The apparent nutrient digestibility did not differ (P > 0.05) when the Djallonke rams were fed the haulms. However, significant differences were observed in final live weight and average daily live weight gain. Rams fed the Yenyawoso variety had higher (P < 0.05) final live weight and average daily live weight gain compared with those fed Obolo and Azivivi varieties. Consumption of any of the 4 varieties of groundnut haulms by Djallonke rams did not have any harmful effect on their red and white blood cell numbers and hemoglobin concentration. The study revealed that the different varieties of groundnut haulms differ in nutrient composition and also affect the growth performance of the rams. The Yenyawoso variety may be used as a sole diet for fattening Djallonke rams. PMID- 29767118 TI - The potential of rapid visco-analysis starch pasting profiles to gauge the quality of sorghum as a feed grain for chicken-meat production. AB - Thirteen extensively characterised grain sorghum varieties were evaluated in a series of 7 broiler bioassays. The efficiency of energy utilisation of broiler chickens offered sorghum-based diets is problematic and the bulk of dietary energy is derived from sorghum starch. For this reason, rapid visco-analysis (RVA) starch pasting profiles were determined as they may have the potential to assess the quality of sorghum as a feed grain for chicken-meat production. In review, it was found that concentrations of kafirin and total phenolic compounds were negatively correlated with peak and holding RVA viscosities to significant extents across 13 sorghums. In a meta-analysis of 5 broiler bioassays it was found that peak, holding, breakdown and final RVA viscosities were positively correlated with ME:GE ratios and peak and breakdown RVA viscosities with apparent metabolizable energy corrected for nitrogen (AMEn) to significant extents. In a sixth study involving 10 sorghum-based diets peak, holding and breakdown RVA viscosities were positively correlated with ME:GE ratios and AMEn. Therefore, it emerged that RVA starch pasting profiles do hold promise as a relatively rapid means to assess sorghum quality as a feed grain for chicken-meat production. This potential appears to be linked to quantities of kafirin and total phenolic compounds present in sorghum and it would seem that both factors depress RVA starch viscosities in vitro and, in turn, also depress energy utilisation in birds offered sorghum-based diets. Given that other feed grains do not contain kafirin and possess considerably lower concentrations of phenolic compounds, their RVA starch pasting profiles may not be equally indicative. PMID- 29767119 TI - Recent advances in sturgeon nutrition. AB - Sturgeons are fish species of biological and economical importance, and most of them are endangered, vulnerable or rare because of their large size, late sexual maturity, long period between spawning, and longevity. These unique biological characteristics make them highly susceptible to overfishing, degradation of habitat and spawning ground, and contamination of water and sediments by pollutants. The objective of the current review is not to exhaustively include all studies on sturgeon nutrient requirements and utilizations conducted under laboratory conditions, but to critique some studies and update previous reviews. The goal is to provide a basis for recommendations for future research so that these important fish species can be managed and produced sustainably. Energy, protein, lipid carbohydrate, vitamin, and mineral requirements and utilizations were reviewed or critiqued. Future studies to develop suitable chemically defined diets to support good growth of sturgeon are urgently needed. Furthermore, future experiments should be designed systematically with more consideration on within and among studies and within and among different species of sturgeon. Finally, future experiments should be designed with a systematic approach with multiple doses (inputs) and multiple responses (outputs) at several levels of hierarchical organization in a biological system using traditional biochemical and modern molecular techniques and computer modeling with proper experimental design and methodology. This approach will provide a more realistic and holistic understanding of the mechanisms of nutrient requirements and utilizations, which will help us better manage wild sturgeon stocks and produce sturgeon more efficiently and sustainably under aquaculture conditions. PMID- 29767120 TI - Impacts of low level aflatoxin in feed and the use of modified yeast cell wall extract on growth and health of nursery pigs. AB - This study was to investigate the effect of corn naturally contaminated with aflatoxins (AF) under the regulatory level on the growth performance and health of nursery pigs, and the efficiency of yeast cell wall based feed additive (YC) mainly composed of beta-glucans and mannan oligosaccharide (MOS) (Integral A+, Alltech, Lexington, KY) in prevention of mycotoxicosis. Pigs (60 barrows and 60 gilts at 6.02 +/- 0.83 kg BW) were randomly allotted to 4 treatments in a randomized complete block design based on a 2 * 2 factorial arrangement with 10 pens (5 barrow and 5 gilt pens) per treatment and 3 pigs per pen. Pigs were fed experimental diets for 5 wk. First factor was AF (0 or 20 ug/kg in feed) and the second factor was YC (0 or 2 g/kg in feed). Feed intake and body weight were measured weekly, and blood samples were used to measure blood cell counts, immunoglobulin G (IgG), tumor necrosis factor-a (TNF-a), oxidative damage status, and serological evaluation related to liver health. Aflatoxin decreased (P < 0.05) the number of platelet count (247.4 to 193.5 * 103/uL), and it also tended to increase the level of albumin (P = 0.055, 3.46 to 3.63 g/dL), albumin:globulin ratio (P = 0.050, 2.09 to 2.37), and Ca (P = 0.080, 10.79 to 10.97 mg/dL). Yeast cell wall based feed additive increased (P < 0.05) ADG (493 to 524 g/d), and ADFI (796 to 846 g/d) of pigs whereas G:F was not affected, and it also tended to increase (P = 0.055) albumin level (3.46 to 3.63 g/dL). Interactions (P < 0.05) on hemoglobin, hematocrit, and platelet count indicated that YC further increased their levels when pigs were eating AF contaminated feed. Interactions (P < 0.05) on urea nitrogen and blood urea N to creatinine ratio indicated that YC further decreased their levels when feed were contaminated with AF. In conclusion, low level of 20 ug AF/kg under the regulatory level had minor effects on hematology without affecting growth performance, however the supplementation of 2 g/kg YC as a source of beta-glucans and MOS in feed can improve feed intake and therefore the growth of pigs. PMID- 29767121 TI - Comparative efficacy of a phytogenic feed additive and an antibiotic growth promoter on production performance, caecal microbial population and humoral immune response of broiler chickens inoculated with enteric pathogens. AB - The aim of this work was to compare the efficacy of a commercially available phytogenic feed additive (PFA) and an antibiotic growth promoter, which was bacitracin methylene disalicylate (BMD), on performance, nutrient retention, caecal colonization of bacteria and humoral immune responses against Newcastle disease in broiler chickens challenged orally with Salmonella enteritidis and Escherichia coli. One-day-old male Cobb 400 broiler chicks (n = 120) were fed with 1) a negative control (NC) diet, which is the basal diet without any added growth promoter, 2) a positive control (PC) diet, the basal diet supplemented with BMD, 500 mg/kg and 3) a diet supplemented with PFA (150 mg/kg) for 39 days and the birds were inoculated with S. enteritidis and E. coli on d 28. Supplementation of PFA improved body weight, feed conversion ratio, retention of N and crude fiber, increased fecal moisture content and decreased digesta transit time as compared with the NC and PC groups (P < 0.01). Both the PC and the PFA was found to be equally effective in controlling the surge in numbers of Salmonella and E. coli following oral inoculation of these bacteria as compared with the NC group (P < 0.05) at 24 h past inoculation. Caecal content analysis on d 39 indicated lower numbers of Salmonella, E. coli and Clostridium in the PC and PFA groups as compared with the NC group (P < 0.05). The number of Lactobacillus in the PFA group was higher than those in the NC and PC groups (P < 0.05). Humoral immune response, measured as hemagglutination inhibition titer against Newcastle disease, was better in the PC and PFA groups compared with the NC group (P < 0.05) at d 21 but the difference did not last till d 39. The heterophil to lymphocyte ratio was narrower (P < 0.001) and alkaline phosphatase activity was higher (P < 0.01) in the PFA group as compared with the NC and PC groups on d 39. It was concluded that the PFA, which is animal, environment and consumer friendly, may be used as an effective replacement for common in-feed antibiotics like BMD to enhance broiler performance especially when the birds are exposed to heavy infections on fields. PMID- 29767123 TI - Influence of feeding crimped kernel maize silage on the course of subclinical necrotic enteritis in a broiler disease model. AB - This experiment was carried out with 375 male broilers (Ross 308) from days 1 to 28 to evaluate the influence of crimped kernel maize silage (CKMS) on the manifestation of subclinical necrotic enteritis, microbiota counts, organic acid production and relative weights of gastrointestinal segments. A necrotic enteritis disease model was applied. Birds were allocated into 3 different dietary treatments: a maize-based feed (MBF, control diet), and 2 diets supplemented with 15% (CKMS15) or 30% (CKMS30) of crimped ensiled kernel maize. The disease model involved a 10-time overdose of an attenuated live vaccine against coccidiosis given orally on day 17, followed by oral inoculation of Clostridium perfringens Type A (S48, 108 to 109 bacteria/bird) twice daily on days 18, 19, 20 and 21. Scoring of intestinal lesions was performed on days 22, 23, 25 and 28. Ileal and caecal digesta samples were collected for the quantification of selected bacterial groups and organic acids. The results showed that there was no effect of dietary treatments on small intestinal lesion scores (P > 0.05). Lesions scores peaked on days 23 and 25 and decreased again on day 28 (P = 0.001). No effect of age on microbiota counts was observed, but feeding of CKMS30 reduced the number of coliforms in ileal contents (P = 0.01). Dietary treatments did not affect organic acid concentrations in ileum and caeca, but there was an effect of age; butyric acid was higher on days 22, 23 and 25 than on day 28 (P = 0.04). Acetic acid and propionic acid concentrations in caeca were the highest on days 22 and 28 but the lowest on days 23 and 25. Relative gizzard and caeca weights were increased, and relative ileum weights were decreased when birds were fed CKMS30 (P < 0.05). In conclusion, the inclusion of CKMS in broiler diets had no effects on the course of necrotic enteritis but had potential benefits in terms of inhibition of potentially harmful microorganisms. PMID- 29767122 TI - Select nutrients and their effects on conceptus development in mammals. AB - The dialogue between the mammalian conceptus (embryo/fetus and associated membranes) involves signaling for pregnancy recognition and maintenance of pregnancy during the critical peri-implantation period of pregnancy when the stage is set for implantation and placentation that precedes fetal development. Uterine epithelial cells secrete and/or transport a wide range of molecules, including nutrients, collectively referred to as histotroph that are transported into the fetal-placental vascular system to support growth and development of the conceptus. The availability of uterine-derived histotroph has long-term consequences for the health and well-being of the fetus and the prevention of adult onset of metabolic diseases. Histotroph includes numerous amino acids, but arginine plays a particularly important role as a source of nitric oxide and polyamines required for fetal-placental development in rodents, swine and humans through mechanisms that remain to be fully elucidated. Mechanisms whereby arginine regulates expression of genes via the mechanistic target of rapamycin cell signaling pathways critical to conceptus development, implantation and placentation are discussed in detail in this review. PMID- 29767124 TI - An early feeding regime and a high-density amino acid diet on growth performance of broilers under subclinical necrotic enteritis challenge. AB - Broilers that have early access to feed have been shown to have enhanced immune system and gut development and heightened resilience against necrotic enteritis (NE). This study examined the effect of early feeding a high amino acid density diet on performance of broilers under a sub-clinical NE challenge model. Ross 308 broilers (n = 576) were assigned to a 2 * 2 * 2 factorial design with 2 feeding regimes (feed access either within 6 h post-hatch or after 48 h post-hatch), 2 diets (control diet or the control diet with an additional 10% digestible amino acids [HAA]) and either presence or absence of NE challenge. Oral administrations of Eimeria species (d 9) and a field strain of Clostridium perfringens (d 14) were used to induce NE. Broiler performance was analysed at d 13, 23, 30 and 35. Intestinal lesion score and bacterial count were analysed on d 16. The NE challenge reduced overall bird performance and induced severe intestinal lesions, without causing notable mortality. At d 23 bird weight was significantly lower (P < 0.001) in the challenged birds compared with the unchallenged birds, but by d 30 the challenged birds had recovered and challenge no longer had an impact on bird performance. Birds fed the HAA diet had greater body weight by d 35 and heightened Lactobacillus content in the ileum at d 16 (P < 0.05). Birds that were fed the HAA diet after a period of fasting performed better in terms of feed conversion ratio (FCR) under challenge. The findings from this study suggest there are beneficial effects of feeding high amino acid diets to birds in response to external stresses, such as post-hatch fasting and subclinical NE. PMID- 29767125 TI - Fermented soybean meal improves the growth performance, nutrient digestibility, and microbial flora in piglets. AB - In order to increase nutritive values of soybean meal (SBM), 3 species of microbes were used to ferment SBM. Through a 3 * 3 orthogonal design and parameter measurements of soybean peptide and anti-nutritional factor contents in the fermented soybean meal (FSBM), it was estimated that the best microbial proportion of Bacillus subtilis, Hansenula anomala and Lactobacillus casei was 2:1:2 for SBM fermentation (P < 0.05). The further piglet feeding experiment showed that 10% FSBM substitute for SBM had no significant effect on growth performance of suckling piglets (d 7-28) (P > 0.05). However, newly-weaned piglets (d 28-38) fed 10% FSBM and different levels of plasma protein obtained higher average daily gain (ADG) and feed conversion ratio (FCR), compared with those without FSBM but with 6% plasma protein (P < 0.05). Piglets (d 38-68) fed diets supplemented with FSBM and soybean protein concentrate (SBPC) at 3.75% and 7.5% respectively increased nutrient digestibility, fecal enzyme activity and lactic acid bacteria counts, and decreased fecal Escherichia coli counts (P < 0.05), compared with the control. These data indicated that FSBM had positive effects on nutrient digestibility and fecal microflora for piglets. PMID- 29767126 TI - Effects of flavonoids from Allium mongolicum Regel on growth performance and growth-related hormones in meat sheep. AB - This study was conducted to investigate the effects of different doses of flavonoids from Allium mongolicum Regel on the production performance and neuroendocrine hormones in meat sheep and to determine the optimum dosage of Allium mongolicum Regel flavonoids to add to the basal diet of dry lot-feeding meat sheep. Sixty meat sheep (initial body weight = 39.9 +/- 3.2 kg; 6-month-old) were randomly assigned to 4 groups (15 sheep per group). The sheep in the control group were fed a basal diet, and the 3 experimental groups were fed the basal diet supplemented with flavonoids at 11, 22 and 33 mg/kg. Blood samples were collected via the jugular vein at d 0, 15, 30, 45, and 60 to determine the neuroendocrine hormone levels. The fasting weight of the sheep was measured during the experimental period, and feed offered and refusals were recorded daily. The basal diet supplemented with flavonoids from 11 to 33 mg/kg significantly increased the daily weight gain and average daily feed intake (P < 0.05) and significantly decreased the feed conversion ratio (P < 0.05), but there were no differences among the supplementation groups (P > 0.05). Starting on d 30, the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in the sera of the sheep in the supplementation groups increased significantly (P < 0.05), and the increases occurred in a time-dependent manner. Compared with control group, after d 30, the serum corticosterone (CORT) levels were reduced in the sheep that consumed the basal diet supplemented with 22 mg/kg flavonoids (P < 0.05), but among the other experimental groups, there was a non-significant effect (P > 0.05). The serum adrenocorticotropic hormone (ACTH) levels were increased by the supplementation of flavonoids, but compared with the control group, the effect was not significant. The basal diet supplemented with flavonoids at levels from 11 to 33 mg/kg had a significant effect on the production performance and neuroendocrine hormone levels of meat sheep, and the effect occurred in a time-dependent manner. The effect was especially obvious after 30 d of feeding. PMID- 29767128 TI - Accuracy of two optical chlorophyll meters in predicting chemical composition and in vitro ruminal organic matter degradability of Brachiaria hybrid, Megathyrsus maximus, and Paspalum atratum. AB - The objective of this study was to determine the accuracy and reliability of 2 optical chlorophyll meters: FieldScout CM 1,000 NDVI and Yara N-Tester, in predicting neutral detergent fibre (NDF), acid detergent fibre (ADF), acid detergent lignin (ADL), acid detergent insoluble nitrogen (ADIN) and in vitro ruminal organic matter degradability (IVOMD) of 3 tropical grasses. Optical chlorophyll measurements were taken at 3 stages (4, 8 and 12 weeks) of regrowth in Brachiaria hybrid, and Megathyrsus maximus and at 6 and 12 weeks of regrowth in Paspalum atratum (cv. Ubon). Optical chlorophyll measurements showed the highest correlation (r = 0.57 to 0.85) with NDF concentration. The FieldScout CM 1,000 NDVI was better than the Yara N-Tester in predicting NDF (R2 = 0.70) and ADF (R2 = 0.79) concentrations in Brachiaria hybrid and NDF (R2 = 0.79) in M. maximus. Similarly, FieldScout CM 1,000 NDVI produced better estimates of 24 h IVOMD (IVOMD24h) in Brachiaria hybrid (R2 = 0.81) and IVOMD48h in Brachiaria hybrid (R2 = 0.65) and M. maximus (R2 = 0.75). However, these prediction models had relatively low concordance correlation coefficients, i.e., CCC >0.90, but random errors were the main source of bias. It was, therefore, concluded that both optical chlorophyll meters were poor and unreliable predictors of ADIN and ADL concentrations. Overall, the FieldScout CM 1,000 NDVI shows potential to produce useful estimates of IVOMD24h and ADF in Brachiaria hybrid and IVOMD48h and NDF concentrations in M. maximus. PMID- 29767129 TI - Development of growth rate, body lipid, moisture, and energy models for white sturgeon (Acipenser transmontanus) fed at various feeding rates. AB - The objectives were to develop and evaluate: 1) growth rate models, 2) body lipid, moisture, and energy models for white sturgeon fed at various feeding rates (FR; % body weight [BW] per day) and then evaluate responses at proportions of optimum feeding rate (OFR) across increasing BW (g). For objective 1, 19 datasets from the literature containing initial BW, FR and specific growth rate (SGR; % BW increase per day) were used. For objective 2, 12 datasets from the literature (11 from objective 1) containing SGR, FR, final BW, body lipid (%), protein (%), ash (%), moisture (%), and energy (kJ/g) were used. The average rearing temperatures was 19.2 +/- 1.5 degrees C (mean +/- SD). The average nutrient compositions and gross energy of the diets were 45.7 +/- 4.3% protein, 14.8 +/- 3.2% lipid, and 20.4 +/- 1.3 kJ/g, respectively. The logistic model was used for objectives 1 and 2 to develop a statistical relationship between SGR and FR, then an iterative technique was used to estimate OFR for each dataset. For objective 2, the statistical relationship between body lipid, energy, and moisture and FR was established. Using the OFR estimate, SGR, body lipid, energy and moisture were computed at various FR as a proportion of OFR. Finally, a nonparametric fitting procedure was used to establish relationships between SGR, body lipid, energy and moisture (responses) compared with BW (predictor) at various proportions of OFR. This allows visualization of the effect of under- or over-feeding on the various responses. When examining the differences between OFR at 100% and various proportions of OFR, SGR differences decrease and moisture differences increase as BW increases. Lipid and energy differences decrease as BW increases. To our knowledge, these are the first description of changes in nutrient compositions when white sturgeon are fed at various FR. Because physiological and behavioral properties that are unique to sturgeon, results from this study are specific to sturgeon under the conditions of this study and cannot be compared directly with salmonids even if some of the results are similar. This research provides insight to designing future nutritional studies in sturgeon. PMID- 29767127 TI - Phosphorus utilization response of pigs and broiler chickens to diets supplemented with antimicrobials and phytase. AB - Three experiments were conducted to evaluate the phosphorus (P) utilization responses of pigs and broiler chickens to dietary supplementation with antimicrobials and phytase and to determine if P digestibility response to phytase is affected by supplementation with antimicrobials. Experiment 1 used 4 diets (a basal negative control formulated to contain 0.41% total P and 0.71% calcium [Ca] without added antimicrobials, basal negative control with added carbadox, basal negative control with added tylosin, or basal negative control with added virginiamycin) and six 18-kg barrows in individual metabolism crates per diet. There was no effect of antimicrobials on P and Ca digestibility or retention. Carbadox supplementation increased (P < 0.05) digestibility and retention of gross energy (GE) and supplementation with tylosin increased (P < 0.05) N retention relative to the basal negative control diet. Experiment 2 used eight 19-kg barrows in individual metabolism crates per treatment and 9 dietary treatments arranged in a 3 * 3 factorial of antimicrobials (none, tylosin, or virginiamycin) and phytase (0, 500, or 1,500 FTU/kg). Phytase addition to the diets linearly increased (P < 0.05) apparent total tract digestibility or retention of P, Ca, nitrogen (N) and GE. Supplementation with antimicrobials did not affect apparent total tract digestibility or retention of P, Ca, N or GE. There were linear effects (P < 0.01) of phytase on Ca utilization in diets that were not supplemented with antimicrobials but only tendencies (P < 0.10) in diets supplemented with tylosin or virginiamycin. Phytase linearly improved (P < 0.05) N utilization in diets supplemented with tylosin or virginiamycin but not in diets without added antimicrobials. Experiment 3 was a broiler chicken experiment with the same experimental design as Exp. 2 but feeding 8 birds per cage and 10 replicate cages per diet. Antimicrobial supplementation improved (P < 0.05) feed efficiency and adding tylosin improved (P < 0.05) tibia ash but did not affect nutrient utilization. Dietary phytase improved (P < 0.01) growth performance, tibia ash and apparent ileal digestibility and retention of P regardless of antimicrobial supplementation. Overall, phytase supplementation improved growth performance and nutrient digestibility and retention, regardless of supplementation of diets with antimicrobials. Supplementation of diets with antimicrobials did not affect P digestibility or retention because of a lack of interaction between antimicrobials and phytase, there was no evidence that P digestibility response to phytase is affected by supplementation with antimicrobials. PMID- 29767130 TI - Effect of different levels of corn steep liquor addition on fermentation characteristics and aerobic stability of fresh rice straw silage. AB - The object of this study was to determine the proper mixing ratio of fresh rice straw to corn steep liquor (CSL) to obtain a high protein content silage feed. The following experimental silages were generated: the control (C1), composed of fresh rice straw without CSL additive, mixed with CSL in the ratios of 4:1 (C4), 3:1 (C3) and 2:1 (C2). Lactic acid bacteria (LAB) inoculant was applied at the rate of 50 mL/kg (fresh basis) of forage to achieve a final application rate of 1 * 106 cfu/g of fresh matter (FM). Duplicate silos for each treatment were opened after 0, 3, 7, 10, 20, 30, 45 and 60 d for microbiological and chemical analysis. The results showed that the addition of CSL significantly increased crude protein (CP) contents, and decreased neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents of treatments after 60 d of ensiling (P < 0.05). The lactic acid contents in C4 and C3 were significantly higher than that in C1 (P < 0.05). In summary, mixing fresh rice straw with CSL at addition levels of 4:1 (C4) and 3:1 (C3) can improve the fermentation quality and nutrient composition of fresh rice straw silage. However, a large proportion of CSL (C3) had a negative impact on the aerobic stability of fresh rice straw. PMID- 29767132 TI - Performance, litter quality and gaseous odour emissions of broilers fed phytase supplemented diets. AB - The effect of graded levels of phytase on performance, bone characteristics, excreta/litter quality and odorant emissions was examined using 720 Ross 308 male d-old broilers. A 2 * 4 factorial arrangement of treatments was employed with 6 replicates of 15 birds per pen. Factors were: diets-positive and negative control (PC, NC); phytase - 0, 500, 1,000, 1,500 FTU/kg. The PC was formulated to meet the 2014 Ross 308 nutrient specifications, whereas the NC was formulated with lower Ca (-1.4 g/kg), available P (-1.5 g/kg), Na (-0.3 g/kg), dLys (-0.2 g/kg) and MEn (-0.28 MJ/kg) equivalent to nutrient matrix values for 500 FTU/kg phytase in the starter, grower and finisher periods (i.e., downspec diet). On d 24, phytase decreased FCR by 1.6, 4.3 and 4.6 points at inclusion levels of 500, 1,000 and 1,500 FTU/kg, respectively (P < 0.01) across all diets. Phytase by diet interactions on BW gain were observed on d 24 and 35 (P < 0.01). The effect of phytase was much more pronounced in the NC diet as compared with the PC diet. On d 24, phytase increased BW gain by 37, 55 and 68 g in the PC and 127, 233 and 173 g in the NC at 500, 1,000 and 1,500 FTU/kg, respectively. Diet by phytase interactions were also observed for tibia ash, litter quality and water to feed intake ratio (P < 0.01) with higher phytase effect in NC as compared with PC. Neither diet nor phytase impacted excreta moisture content on d 18 or 21 (P > 0.05). Solid phase micro-extraction gas chromatography-mass spectrometry (SPME-GC MS) analysis of gaseous emissions on d 39 indicated no difference in the emission of alcohols, aldehydes, ketones, volatile fatty acids and phenols between treatments (P > 0.05). The results indicate that phytase has greater benefits when formulated using nutrient matrix values as compared with adding it over the top in an already nutrient sufficient diet. The later method would be expected to increase feed costs without concomitant performance benefits. PMID- 29767131 TI - Effect of chicken egg anti-F4 antibodies on performance and diarrhea incidences in enterotoxigenic Escherichia coli K88+-challenged piglets. AB - The aim was to evaluate the effects of dietary supplementation of spay-dried whole egg containing anti-F4 antibodies (SDWE) against recombinantly produced F4 antigens in enterotoxigenic Escherichia coli K88+ (ETEC)-challenged piglets. Twenty-seven 21-d-old and individually housed piglets were randomly allotted to 3 treatments consisting of a wheat-soybean meal basal diet containing either 0 (control egg powder; CEP), 0.1% (SDWE1) or 0.4% (SDWE2) SDWE. After a 7-d adaptation period, blood samples were collected from all pigs, and pigs were weighed and orally challenged with an ETEC inoculum. Blood was sampled at 24 and 48 h post-challenge, and diarrhea incidences and scores were recorded. On d 14, all pigs were weighed and then euthanized to obtain intestinal tissue samples for histomorphology measurement. During the pre-challenge period, pigs fed the SDWE showed a linear improvement (P < 0.05) in average daily gain (ADG) and gain to feed ratio (G:F), but there were no differences among treatments in growth performance during the post-challenge period. Diarrhea incidences and scores, fecal shedding of ETEC, plasma urea nitrogen content and intestinal histomorphology were similar among treatments. The results show that 0.4% SDWE supported greater piglet performance before challenge although such benefits were not evident during the post-challenge period at either 0.1% or 0.4% supplementation. PMID- 29767134 TI - Reducing agent and exogenous protease additions, individually and in combination, to wheat- and sorghum-based diets interactively influence parameters of nutrient utilisation and digestive dynamics in broiler chickens. AB - The objective of the study was to investigate the possibility that tandem inclusions of a reducing agent and a protease may advantage chicken-meat production and to ascertain if the established benefits of including sodium metabisulphite in sorghum-based diets extend to wheat-based diets. The study comprised a 2 * 2 * 2 factorial array of treatments in which either nutritionally iso-nitrogenous and iso-energetic wheat- or sorghum-based diets, without and with sodium metabisulphite (2.75 g/kg), without and with protease (1,000 units/kg) were offered to broiler chickens from 7 to 28 days post-hatch. The effects of dietary treatments on growth performance, nutrient utilisation, protein (N) and starch digestibility coefficients and digestive dynamics were determined. A preliminary investigation into the effects of two treatments on concentrations of free amino acids and glucose in the portal circulation was conducted. There was significant feed grain by sodium metabisulphite interactions (P = 0.03 to 0.005) for parameters of nutrient utilisation (AME, ME:GE ratios, N retention, AMEn). For example, sodium metabisulphite inclusions in sorghum-based diets enhanced AME by 0.18 MJ (12.47 versus 12.29 MJ/kg) but depressed AME by 0.43 MJ (11.88 versus 12.31 MJ/kg) in wheat-based diets. There was a linear relationship between starch:protein disappearance rate ratios in the distal ileum with weight gain (r = -0.484; P = 0.0012) indicating that condensed ratios (or absorption of more protein relative to starch) advantaged growth performance. Concentrations of free amino acids in the portal circulation or the post-enteral availability of certain amino acids, including the branched-chain amino acids, methionine, phenylalanine and threonine, were significantly correlated to FCR. For example, threonine concentrations were negatively correlated to FCR (r = -0.773; P = 0.005). Finally, tandem inclusions of sodium metabisulphite and protease in sorghum-based diets may hold merit but it appears that the established 'energy sparing' effects of sodium metabisulphite inclusions in sorghum-based diets are not duplicated in wheat-based diets. PMID- 29767135 TI - Impacts of energy feeds and supplemental protease on growth performance, nutrient digestibility, and gut health of pigs from 18 to 45 kg body weight. AB - A total of 144 pigs with 18.4 +/- 2.3 kg initial body weight (BW) at 6 wk of age were used in a 40-d trial to evaluate effects of protease (300,000 U/kg feed, BioResource International Inc., Durham, NC, USA) on growth performance, apparent ileal digestibility (AID) of nutrients, and gut health of pigs fed diets with sorghum. Pigs were randomly allotted to 4 treatments (12 pens per treatment, 3 pigs per pen) in a 2 * 2 factorial arrangement (corn or sorghum basal diets, and 0 or 0.05% protease as 2 factors) with sex and initial BW as blocks. Experimental period had phase 1 (d 1 to 21) and phase 2 (d 22 to 40). About 65% (phase 1) and 72% (phase 2) of cereal grains were used in corn or sorghum based diets. Both grains were ground to 400 MUm. Body weight and feed intake were recorded weekly. On d 35, serum was collected to quantify tumor necrosis factor-alpha (TNF-alpha) and malondialdehyde (MDA). Titanium dioxide (0.3%) was added as an indigestible marker for an additional 4 d feeding. On d 40, 32 pigs (8 pigs per treatment) were euthanized to collect digesta from jejunum and ileum (for viscosity and AID), tissues (for morphology) and mucosa samples (for TNF-alpha and MDA) from duodenum, jejunum, and ileum. Replacing corn with sorghum in the diet increased (P < 0.05) overall average daily gain (from 756 to 787 g/day) and average daily feed intake (from 1,374 to 1,473 g/day), reduced (P < 0.05) overall gain:feed ratio (from 0.553 to 0.537), and did not affect AID. Pigs fed diets with sorghum had lower (P < 0.05) MDA content in serum (from 14.61 to 6.48 MUmol/L) and jejunum (from 1.42 to 0.91 MUmol/g protein), and reduced (P < 0.05) villus height (from 492 to 396 MUm) and crypt depth (from 310 to 257 MUm) in jejunum. Dietary protease improved (P < 0.05) AID of crude protein (from 81.8% to 86.0%), decreased MDA level (from 1.20 to 0.98 MUmol/g protein) in duodenum, and increased (P < 0.05) the ratio of villus height to crypt depth (from 1.08 to 1.21) in duodenum. Overall, use of sorghum fully replacing corn in diets could benefit pigs with enhanced growth and feed intake potentially by reducing oxidative stress, whereas feed efficiency was compromised. Supplementation of protease improved protein digestion and maintained gut health, irrespective of sorghum or corn based diets. PMID- 29767133 TI - Intestinal challenge with enterotoxigenic Escherichia coli in pigs, and nutritional intervention to prevent postweaning diarrhea. AB - Gut health of nursery pigs immediately after weaning is tightly associated with their growth performance and economic values. Postweaning diarrhea (PWD) is one of the major concerns related to gut health of nursery pigs which often is caused by infections of enterotoxigenic Escherichia coli (ETEC), mainly including F4 (K88)+ and F18+E. coli. The main virulence factors of ETEC are adhesins (fimbriae or pili) and enterotoxins. The common types of fimbriae on ETEC from PWD pigs are F18+ and F4+. Typically, PWD in pigs is associated with both F18+ and F4+ ETEC infections whereas pre-weaning diarrhea in pigs is associated with F4+ ETEC infection. Enterotoxins including heat-labile enterotoxins (LT) and heat-stable peptide toxins (ST) are associated with causing diarrhea in pigs. At least 109 to 1010 ETEC are required to induce diarrhea in nursery pigs typically lasting 1 to 5 days after ETEC infection. Antibiotics used to be the most effective way to prevent PWD, however, with the increased bacterial resistance to antibiotics, alternatives to the use of antibiotics are urgently needed to prevent PWD. Immunopropylaxis and nutritional intervention of antimicrobial minerals (such as zinc oxide and copper sulfate), organic acids, functional feedstuffs (such as blood plasma and egg yolk antibodies), direct fed microbials, phytobiotics, and bacteriophage can potentially prevent PWD associated with ETEC. Some other feed additives such as nucleotides, feed enzymes, prebiotic oligosaccharides, and clay minerals can enhance intestinal health and thus indirectly help with preventing PWD. Numerous papers show that nutritional intervention using selected feed additives can effectively prevent PWD. PMID- 29767136 TI - Novel probiotics: Their effects on growth performance, gut development, microbial community and activity of broiler chickens. AB - A total of 294 one-day-old Cobb broiler chickens were used to investigate the effects of four Lactobacillus strains on gut microbial profile and production performance. The six dietary treatments, each with 7 replicates were: 1) basal diet (negative control), 2) one of four strains of Lactobacillus (tentatively identified as Lactobacillus johnsonii, Lactobacillus crispatus, Lactobacillus salivarius and an unidentified Lactobacillus sp.) and 3) basal diet with added zinc-bacitracin (ZnB, 50 mg/kg). Results showed that the addition of probiotic Lactobacillus spp. to the feed did not significantly improve weight gain, feed intake and feed conversion rate (FCR) of broiler chickens raised in cages during the 6-week experimental period, but tended to increase the number of total anaerobic bacteria in the ileum and caeca, and the number of lactic acid bacteria and lactobacilli in the caeca; and to significantly increase the small intestinal weight (jejunum and ileum). Furthermore, all 4 probiotics tended to reduce the number of Enterobacteria in the ileum, compared with the control treatments. The probiotics did not affect the pH and the concentrations of short chain fatty acids (SCFA) and lactic acid in both the ileum and caeca. PMID- 29767137 TI - Use of Lactobacillus johnsonii in broilers challenged with Salmonella sofia. AB - The effects of Lactobacillus johnsonii (L. johnsonii) on gut microflora, bird performance and intestinal development were assessed using 288 one-day-old Cobb broilers challenged with Salmonella sofia (S. sofia). The experiment was a 3 * 2 factorial design which consisted of three treatments, a negative control (NC) with no additives, a positive control (PC) containing antimicrobials (zinc bacitracin, 50 mg/kg) and a probiotic group (Pro), and with the two factors being unchallenged or challenged with S. sofia. A probiotic preparation of L. johnsonii (109 cfu/chick) was administered to chicks individually by oral gavage on days 1, 3, 7 and 12. Chicks were individually challenged with S. sofia (107 cfu/chick) by oral gavage on d 2, 8 and 13. Results showed that the challenge itself markedly reduced (P < 0.05) bird performance and feed intake. And, transient clinical symptoms of the infection with S. sofia were observed from the second time they were challenged with S. sofia in the negative challenge groups. The novel probiotic candidate L. johnsonii reduced the number of S. sofia and Clostridium perfringens in the gut environment, and improved the birds' colonization resistance to S. sofia. PMID- 29767138 TI - Effects of essential oils on performance, egg quality, nutrient digestibility and yolk fatty acid profile in laying hens. AB - The study was conducted to investigate the effect of essential oils on performance, egg quality, nutrient digestibility and yolk fatty acid profile in laying hens. A total of 960 Lohmann laying hens aged 53 weeks were enrolled, under 4 different treatment diets supplemented with 0, 50, 100 and 150 mg/kg essential oils (Enviva EO, Dupont Nutrition Biosciences ApS, Denmark), respectively. Each treatment was replicated 8 times with 30 birds each. Birds were fed dietary treatment diets for 12 weeks (54 to 65 weeks). For data recording and analysis, a 12-week period was divided into 3 periods of 4 weeks' duration each: period 1 (54 to 57 weeks), period 2 (58 to 61 weeks), and period 3 (62 to 65 weeks). For the diet supplemented with Enviva EO, hen-day egg production and the feed conversion ratio (FCR) were significantly improved (P < 0.05) at weeks 58 to 61, and the eggshell thickness was significantly increased (P < 0.05) at week 65. However, egg production, egg weight, feed intake, FCR and other egg quality parameters (albumen height, Haugh unit, egg yolk color and eggshell strength) were not affected by the dietary treatment. In addition, compared with the control diet, protein digestibility in the 100 mg/kg Enviva EO treatment group was significantly increased (P < 0.05), and fat digestibility in the 100 and 150 mg/kg Enviva EO treatment groups was significantly decreased (P < 0.05), but Enviva EO had no effect on energy apparent digestibility. Saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) gradually decreased and polyunsaturated fatty acid (PUFA) increased with Enviva EO supplementation, but the difference was not significant. The data suggested that the supplementation of essential oils (Enviva EO) in laying hen diet did not show a significant positive effect on performance and yolk fatty acid composition but it tended to increase eggshell thickness and protein digestibility, especially at the dose of 50 mg/kg. PMID- 29767140 TI - Sheep numbers required for dry matter digestibility evaluations when fed fresh perennial ryegrass or forage rape. AB - Research trials with fresh forages often require accurate and precise measurement of digestibility and variation in digestion between individuals, and the duration of measurement periods needs to be established to ensure reliable data are obtained. The variation is likely to be greater when freshly harvested feeds are given, such as perennial ryegrass (Lolium perenne L.) and forage rape (Brassica napus L.), because the nutrient composition changes over time and in response to weather conditions. Daily feed intake and faeces output data from a digestibility trial with these forages were used to calculate the effects of differing lengths of the measurement period and differing numbers of sheep, on the precision of digestibility, with a view towards development of a protocol. Sixteen lambs aged 8 months and weighing 33 kg at the commencement of the trial were fed either perennial ryegrass or forage rape (8/treatment group) over 2 periods with 35 d between measurements. They had been acclimatised to the diets, having grazed them for 42 d prior to 11 days of indoor measurements. The sheep numbers required for a digestibility trial with different combinations of acclimatisation and measurement period lengths were subsequently calculated for 3 levels of imposed precision upon the estimate of mean dry matter (DM) digestibility. It is recommended that if the standard error of the mean for digestibility is equal to or higher than 5 g/kg DM, and if sheep are already used to a fresh perennial ryegrass or forage rape diet, then a minimum of 6 animals are needed and 4 acclimatisation days being fed individually in metabolic crates followed by 7 days of measurement. PMID- 29767139 TI - Effects of dietary yeast nucleotides on growth, non-specific immunity, intestine growth and intestinal microbiota of juvenile hybrid tilapia Oreochromis niloticus ? * Oreochromis aureus ?. AB - This study investigated the effect of dietary supplementation of yeast nucleotides on the growth, non-specific immunity, intestine growth and intestinal microbiota of juvenile hybrid tilapia. Tilapia (initial average weight of 8.02 g) was fed test diets supplemented with a yeast-originated nucleotide mixture (0, 0.15, 0.30, 0.60, and 1.20 g/100 g diet) for 8 weeks. Fish fed the diet with 0.60% nucleotide had significantly higher weight gain than the control group (P < 0.05). Feed efficiency was improved in the fish fed 0.60 and 1.20% nucleotide compared with that in the control group. The optimal doses of nucleotides supplementation for growth and feed efficiency of fish were determined as 0.63 and 0.81%, respectively. Intestinal growth was improved in the 0.30 and 0.60% groups, as indicated by significant increase in intestine length. The fish fed 0.60 and 1.20% nucleotide showed higher super oxide dismutase (SOD) activity and lower malondialdehyde (MDA) level in the liver than the control fish, indicating enhancement of the anti-oxidant status. Serum lysozyme activity was significantly increased in the 0.15 and 0.3% nucleotide supplementation groups, suggesting an enhancement effect on the non-specific immune response. Lastly, dietary nucleotides supplementation exerted moderate influence on the intestinal microbiota of hybrid tilapia. A reduction in the cumulative abundance of putative butyrate-producing species was observed in the intestinal microbiota of fish fed diets with 0.60% nucleotide compared with the control, implying an interaction between dietary nucleotides and butyrate production. Briefly, dietary supplementation with 0.60% nucleotide improve the growth performance, immune activity and intestine growth in tilapia. PMID- 29767143 TI - Okara as a protein supplement affects feed intake and milk composition of ewes and growth performance of lambs. AB - Evaluating the feeding value of wet okara as a protein supplement for lactating ewes with twin lambs was the objective. A 4 * 4 Latin square replicated 2* (4 sheep, 4 treatments, 4 periods per square; 2 squares) was conducted to examine the influence of concentrate mix (okara or not) and type of forage (silage or hay) on ewe milk composition and growth of their lactating lambs. Treatment periods were 14 days (7 days adaptation and 7 days collection). Ewes (55 to 74.8 kg BW) were fed 1 of 4 diets: wheat middling and corn concentrate with mixed grass hay (TSH), okara and corn with mixed grass hay (OSH), soybean and wheat middlings with hay crop silage (TSS), and okara and corn with hay crop silage (OSS). Ewes fed hay diets had lower forage dry matter intakes than ewes fed silage. Intake of okara supplement was higher (P < 0.05) with OSH (3.64 kg/d) than with OSS (1.70 kg/d). There was no difference in supplement intake between TSH and TSS. There were no differences among diets for lamb daily gains or in ewe milk compositions among the diets. Okara is an effective source of protein for lactating ewes and their twin lambs. PMID- 29767142 TI - Corrigendum: Design and Preliminary Feasibility Study of a Soft Robotic Glove for Hand Function Assistance in Stroke Survivors. AB - [This corrects the article on p. 547 in vol. 11, PMID: 29062267.]. PMID- 29767141 TI - Weaning stress and gastrointestinal barrier development: Implications for lifelong gut health in pigs. AB - The gastrointestinal (GI) barrier serves a critical role in survival and overall health of animals and humans. Several layers of barrier defense mechanisms are provided by the epithelial, immune and enteric nervous systems. Together they act in concert to control normal gut functions (e.g., digestion, absorption, secretion, immunity, etc.) whereas at the same time provide a barrier from the hostile conditions in the luminal environment. Breakdown of these critical GI functions is a central pathophysiological mechanism in the most serious GI disorders in pigs. This review will focus on the development and functional properties of the GI barrier in pigs and how common early life production stressors, such as weaning, can alter immediate and long-term barrier function and disease susceptibility. Specific stress-related pathophysiological mechanisms responsible for driving GI barrier dysfunction induced by weaning and the implications to animal health and performance will be discussed. PMID- 29767144 TI - Growth performance of nursery and grower-finisher pigs fed diets supplemented with benzoic acid. AB - Two experiments were conducted to investigate the efficacy of benzoic acid on the growth performance of nursery and grower-finisher pigs. A randomized complete block design was used in both experiments with the initial body weight as the blocking factor. There were 3 treatments corresponding to 3 dietary levels of benzoic acid: 0, 0.3%, and 0.5%. In experiment 1, a total of 144 PIC L1050 barrows (initial body weight 7.1 +/- 0.6 kg) were used with each treatment replicated 8 times. In experiment 2, a total of 288 PIC L1050 barrows (initial body weight 36.1 +/- 3.6 kg) were used with each treatment replicated 16 times. There were 6 barrows in each replicate pen for both experiments. Experiments 1 and 2 lasted 28 and 70 days, respectively. In experiment 1, average daily gain (ADG) of all growth phases increased linearly (P < 0.05) with increasing supplementation of benzoic acid, which led to a linear improvement in average body weight on d 28 (P < 0.05). There was also an improvement in feed conversion ratio (FCR) of d 0 to 14 (linear effect: P < 0.05) and in average daily feed intake (ADFI) of d 14 to 28 and d 0 to 28 (linear effect: P < 0.01). In experiment 2, ADG during d 0 to 35 and d 35 to 70 and average body weight on d 35 improved linearly (P < 0.05) with increasing supplementation of benzoic acid. Average daily gain of d 0 to 70 and average body weight on d 70 increased significantly in a both linear and quadratic manner. There was a linear improvement in FCR in all growth phases (P < 0.05). In conclusion, the dietary inclusion of benzoic acid at the supplementation levels of 0.3% and 0.5% significantly improved the growth performance of nursery and grower-finisher pigs in the current study; the nursery pigs responded to the dietary supplementation of benzoic acid up to 0.5% linearly while the grower-finisher pigs achieved the optimal ADG at the calculated supplementation level of 0.36%. PMID- 29767145 TI - An increase in corn resistant starch decreases protein fermentation and modulates gut microbiota during in vitro cultivation of pig large intestinal inocula. AB - High-protein diet could cause an increase in protein fermentation in the large intestine, leading to an increased production of potentially detrimental metabolites. We hypothesized that an increase in corn resistant starch content may attenuate the protein fermentation. The aim of this study was to evaluate the effect of resistant starch on protein fermentation by inocula from large intestine of pigs using in vitro cultivation. Fermentation patterns were analyzed during a 24-h incubation of cecal and colonic digesta with varying corn resistant starch contents, using casein protein as sole nitrogen source. The results showed that the concentration of short-chain fatty acids (SCFA) and cumulative gas production were significantly increased (P < 0.05), while ammonia-nitrogen (NH3 N) and branched-chain fatty acids (BCFA), which indicated protein fermentation, decreased when the corn resistant starch levels increased (P < 0.05). The copies of total bacteria, Bifidobacterium and Lactobacillus were significantly increased with the increased corn resistant starch levels after incubation (P < 0.05). The copies of the Bifidobacterium and Lactobacillus in cecum were significantly higher than those in colon (P < 0.05). We conclude that the addition of corn resistant starch weakens the protein fermentation by influencing microbial population and reducing protein fermentation in the cecum and colon in vitro. PMID- 29767146 TI - Environmental responsibilities of livestock feeding using trace mineral supplements. AB - Trace elements are essential dietary components for livestock species. However, they also exhibit a strong toxic potential. Therefore, their fluxes through the animal organism are tightly regulated by a complex molecular machinery that controls the rate of absorption from the gut lumen as well as the amount of excretion via faeces, urine and products (e.g., milk) in order to maintain an internal equilibrium. When supplemented in doses above the gross requirement trace elements accumulate in urine and faeces and, hence, manure. Thereby, trace element emissions represent a potential threat to the environment. This fact is of particular importance in regard to the widely distributed feeding practice of pharmacological zinc and copper doses for the purpose of performance enhancement. Adverse environmental effects have been described, like impairment of plant production, accumulation in edible animal products and the water supply chain as well as the correlation between increased trace element loads and antimicrobial resistance. In the light of discussions about reducing the allowed upper limits for trace element loads in feed and manure from livestock production in the European Union excessive dosing needs to be critically reconsidered. Moreover, the precision in trace element feeding has to be increased in order to avoid unnecessary supplementation and, thereby, heavy metal emissions from livestock production. PMID- 29767147 TI - Homeostatic responses to amino acid insufficiency. AB - This article provides a brief overview describing how two key signaling pathways, namely the integrated stress response and the mammalian target of rapamycin complex 1, work together to facilitate cellular adaptation to dietary amino acid insufficiency. A deeper understanding of these mechanisms is leading to identification of novel targets which aid in disease treatments, improve stress recovery and increase health span through slowed aging and enhanced metabolic fitness. PMID- 29767148 TI - Effect of dietary supplementation with sugar cane extract on meat quality and oxidative stability in finishing pigs. AB - The aim of the present study was to investigate the effect of dietary supplementation with sugar cane extract (SCE) on meat quality and oxidative stability of Longissimus dorsi muscle in finishing pigs. Eighteen barrows (Duroc * Landrace * Jiaxing Black), with an average initial body weight of 62.1 +/- 5.0 kg, were randomly allotted to 1 of 3 diets with 6 replicates per treatment for 42 days. The diets comprised a normal diet and the normal diets supplemented with 5 and 25 g/kg SCE. The results showed that SCE supplementation did not affect final body weight of finishing pigs. Dietary SCE supplementation significantly increased (P < 0.05) Longissimus dorsi muscle pH24 h, and tended to reduce (P < 0.1) and significantly decreased (P < 0.05) shear force, drip loss, myofiber cross sectional area and lactate dehydrogenase activity at 5 and 25 g/kg, respectively. Meanwhile, dietary SCE treatments significantly decreased (P < 0.05) malonaldehyde content and total superoxide dismutase activity in Longissimus dorsi muscle, and tended to reduce (P < 0.1) malonaldehyde content in serum. Altogether, these data indicate that SCE is an effective feed additive to improve pork meat quality, and the underlying mechanism may be partly due to the improved oxidative stability induced by dietary SCE supplementation. PMID- 29767149 TI - The role of supplemental glycine in establishing a subclinical necrotic enteritis challenge model in broiler chickens. AB - Subclinical necrotic enteritis (NE) is an economically important disease in the broiler industry. With the move towards removal of antibiotics from feeds, solutions to control subclinical NE are desperately being sought. Dietary glycine has been shown to promote proliferation of Clostridium perfringens (Cp) and may thus be useful to include in a NE challenge model. A study was conducted to evaluate the effect of increased dietary glycine levels on subclinical NE. A 2 * 2 * 2 factorial arrangement of treatments was carried out using day-old male Ross 308 chicks (n = 624) allocated to 48 floor pens with 8 treatments of 6 replicates with 11 birds per treatment. Factors were: Cp challenge (C- or C+), Eimeria spp. challenge (E- or E+), and dietary glycine in the grower diet (0 or 10 g/kg). Birds had higher FCR when challenged with Eimeria (P < 0.01) or Cp (P < 0.05) on d 24 or Cp on d 35 but FCR was lower when fed glycine on d 24 (P < 0.01). Supplementation of glycine reduced feed intake on d 24 and increased weight gain on d 35 (P < 0.05). A Cp * Eimeria * glycine interaction (P < 0.05) showed a higher jejunal lesion scores in birds challenged with a combination of Cp and glycine compared with those with Eimeria and glycine or the unchallenged birds. Lesion score interactions between Cp and glycine (P < 0.05) in the ileum and Cp and Eimeria in the duodenum (P < 0.05) and ileum (P < 0.05) illustrated higher lesion scores in birds challenged with Cp without Eimeria or glycine compared to those not challenged with Cp. This study suggests that using glycine can partially replace Eimeria in a subclinical NE challenge model in promoting the intestinal lesions but not impairing chicken performance. PMID- 29767150 TI - Effect of storage time on the characteristics of corn and efficiency of its utilization in broiler chickens. AB - Corn is one of the staple food and feed ingredients in China, therefore its storage is of particular importance. Corn is typically stored for 2 or more years in national barns before it is sold as a food or feed ingredient. However, the effects of stored corn in national barns on the animal performance and nutrient utilization have not been investigated thus far. This study attempted to determine the effects of storage time on the chemical and physical characteristics of corn and its nutritional value, broiler growth performance, and meat quality. Corn grains used in the present study were stored for 4 different periods, from 2 to 5 yr, under the same conditions in a building at the Beijing National Grain Storage Facility. A total of 240 birds in Exp. 1 and 90 birds in Exp. 2 were used to compare the effects of storage time on the utilization of nutrients of corn, the performance, and meat quality of broilers. The content of starch, crude protein, amino acids, fatty acids, and test weight generally decreased with increasing storage time. Corn stored for over 4 yr showed decreased catalase (CAT) and peroxidase (POD) activities and increased fat acidity. Body weight gain (BWG) and European production index (EPI) of broilers from 0 to 3 wk tended to decrease linearly with storage time (0.05 < P < 0.10), and the BWG and EPI of broilers from 4 to 6 wk decreased quadratically (P < 0.05), whereas feed conversion ratio (FCR) increased with storage time (P < 0.05). The FCR, performance, and EPI of broilers positively correlated with CAT activity (P < 0.05), and negatively correlated with fat acidity (P < 0.05). Drip loss of breast muscle increased linearly with corn storage time (P < 0.001); however, pH decreased linearly with corn storage time. Drip loss had a strong negative correlation with POD (P < 0.05). There were no significant differences of the storage length on metabolizable energy (ME), digestibility of crude protein, and starch (P > 0.05). The digestibility of histidine and arginine, and C18:2 and C18:3 changed quadratically with storage time (P < 0.05). Collectively, the results suggest that the use of corn stored for 4 yr in animal feed decreased the performance and meat quality of broilers. Fat acidity, CAT, and POD activities can be used as indexes for evaluating the storage quality of corn. PMID- 29767151 TI - Meta-analysis of calorimeter data to establish relationships between methane and carbon dioxide emissions or oxygen consumption for dairy cattle. AB - Recent developments suggest the use of other gases such as carbon dioxide (CO2) to estimate methane (CH4) emissions from livestock, yet little information is available on the relationship between these two gases for a wide range of animals. A large respiration calorimeter dataset with dairy cattle (n = 987 from 30 experiments) was used to investigate relationships between CH4 and CO2 production and oxygen (O2) consumption and to assess whether the predictive power of these relationships could be improved by taking into account some dietary variables, including forage proportion, fibre and metabolisable energy concentrations. The animals were of various physiological states (young n = 60, dry cows n = 116 and lactating cows n = 811) and breeds (Holstein-Friesian cows n = 876, Jersey * Holstein-Friesian n = 47, Norwegian n = 50 and Norwegian * Holstein-Friesian n = 14). The animals were offered forage as a sole diet or a mixture of forage and concentrate (forage proportion ranging from 10 to 100%, dry matter basis). Data were analysed using a series of mixed models. There was a strong positive linear relationship between CH4 and CO2, and observations within an experiment were very predictable (adjusted R2 = 0.93). There was no effect of breed on the relationship between CH4 and CO2. Using O2 instead of CO2 to predict CH4 production also provided a very good fit to the observed empirical data, but the relationship was weaker (adjusted R2 = 0.86). The inclusion of dietary variables to the observed CO2 emissions, in particular forage proportion and fibre concentration, provided a marginal improvement to the prediction of CH4. The observed variability in the CH4:CO2 ratio could only marginally be explained by animal physiological state (lactating vs. dry cows and young cattle) and dietary variables, and thus most likely reflected individual animal differences. The CH4:CO2 ratio can therefore be particularly useful to identify low CH4 producing cows. These findings indicate that CO2 production data can be used to accurately predict CH4 emissions to generate large scale data for management and genetic evaluations for the dairy industry. PMID- 29767152 TI - Rumen liquor from slaughtered cattle as inoculum for feed evaluation. AB - Use of nonlinear mathematical models has been majorly based on in vitro gas production (GP) data generated when substrates are incubated with rumen liquor from fistulated steers. However, existing evidence suggests that rumen liquor from slaughtered cattle of unknown dietary history also generates quantifiable in vitro GP data. Fitting and description of GP data obtained from 4 diets incubated with rumen liquor from slaughtered cattle was evaluated using single-pool exponential model with discrete lag time (EXPL), logistic (LOG), Groot's (GRTS) and Gompertz (GOMP) models. Diets were formulated by varying proportions of Rhodes grass (Chloris gayana) hay and a concentrate mixed on dry matter basis to be: 1,000 g/kg Rhodes grass hay (RGH) and 0 of the concentrate (D1), 900 g/kg RGH and 100 g/kg concentrate (D2), 800 g/kg RGH and 200 g/kg concentrate (D3), 700 g/kg RGH and 300 g/kg concentrate (D4). Dietary kinetics for the models were determined by measuring GP at 2, 4, 8, 10, 18, 24, 36, 48, 72, 96 and 120 h. Model comparison was based on derived GP kinetics, graphical analysis of observed versus predicted GP profiles plus residual distribution and goodness-of-fit from analysis of root mean square error (RMSE), adjusted coefficient of determination (Adj-R2) and Akaike's information criterion (AIC). Asymptotic GP, half-life and fractional rate of GP differed (P < 0.001) among the 4 models. The RMSE, Adj-R2 and AIC ranged from 1.555 to 4.429, 0.906 to 0.984 and 2.452 to 15.874, respectively, for all diets compared across the 4 models. Based on the goodness of-fit statistical criterion, GP profiles of D1 were more appropriately fitted and described by GRTS and GOMP than the EXPL and LOG models. The GRTS model had the lowest AIC value for D2 (2.452). Although GRTS model had the most homogenous residual dispersion for the 4 diets, all the 4 models exhibited a sigmoidal behavior. Therefore, rumen liquor from slaughtered cattle of unknown dietary history can be used to derive nutritionally important feed parameters, but choice of the most appropriate model should be made based on fitting criteria and dietary substrates incubated. PMID- 29767154 TI - Husbandry practices and gut health outcomes in weaned piglets: A review. AB - The immediate post-weaning period is one of the most stressful phases in a pig's life, and during this period, piglets are usually exposed to environmental, social and psychological stressors which have direct or indirect effects on gut health and overall growth performance. In this review, the impact of husbandry practices on gut health outcomes and performance of piglets is discussed. Husbandry practices in the swine barn generally include nutrition and management practices, maintenance of hygienic standards and disease prevention protocols, and animal welfare considerations. Poor husbandry practices could result in reduced feed intake, stress and disease conditions, and consequently affect gut health and performance in weaned piglets. Reduced feed intake is a major risk factor for impaired gut structure and function and therefore a key goal is to maximize feed intake in newly weaned piglets. In weaned piglets, crowding stress could reduce pig performance, favor the proliferation of pathogenic bacteria resulting in diarrhea, stimulate immune responses and interfere with beneficial microbial activities in the gut. Sanitation conditions in the swine barn plays an important role for optimal piglet performance, because unclean conditions reduced growth performance, shifted nutrient requirements to support the immune system and negatively affected the gut morphology in weaned piglets. Appropriate biosecurity measures need to be designed to prevent disease entry and spread within a swine operation, which in turn helps to keep all pigs and piglets healthy. Collectively, husbandry practices relating to feeding and nutrition, animal welfare, biosecurity and disease prevention are important determinants of gut health and piglet performance. Thus, it is suggested that adopting high husbandry practices is a critical piece in strategies aimed at raising pigs without the use of in-feed antibiotics. PMID- 29767153 TI - Effect of phytase superdosing, myo-inositol and available phosphorus concentrations on performance and bone mineralisation in broilers. AB - A total of 2,376 one-day-old Ross broiler chickens were used to investigate the effect of myo-inositol (MYO) and phytase supplementation on performance and bone mineralization variables in broilers fed diets formulated to have varying concentrations of available phosphorus (P). The trial was designed as a 2 * 2 * 3 factorial; with and without phytase superdosing (0 or 1,500 FTU/kg), MYO (0 or 3 g/kg), and dietary P (low, moderate or high). At 21 d, dietary phytase and MYO had no consistent benefit on bone mineralization variables. Bone ash reduced by 4.7% from the medium to low P diet (P < 0.01), with no effect of phytase supplementation. Superdosing improved bone P content by 6% in birds fed the low P diet, signifying an interaction between dietary P concentrations and phytase (P < 0.05). Dietary MYO addition resulted in a numerical reduction in bone ash and a significant reduction in bone strength (P < 0.05). At 42 d, the beneficial effect of phytase superdosing on feed intake and body weight gain was evident in the low P diet. Superdosing reduced feed conversion rate (FCR) at all P levels (P < 0.05), although this effect was more pronounced on the low P diet, suggesting that sufficient P being released from the phytase itself to re-phosphorylate MYO and hence improve FCR. The significant improvement in FCR was greater with superdosing than with MYO alone, and the combination led to no further improvement in FCR compared with superdosing alone, signifying a phytase and MYO interaction (P < 0.05). From these results, it can be estimated that MYO is providing around 30% to 35% of the total response to superdosing. PMID- 29767155 TI - Responses of milk production of dairy cows to jugular infusions of a mixture of essential amino acids with or without exclusion leucine or arginine. AB - The purpose of this study was to determine effects of jugular infusion of either balanced or imbalanced amino acid mixture on milk production and composition in dairy cows. Eight mid-lactation Holstein cows were randomly assigned to 5-d continuous jugular infusions of saline (CTL), essential amino acid (EAA) mixture prepared on the profile of casein (CSN, 160 g/d), EAA mixture excluding leucine (Leu) (-Leu, 163 g/d) or EAA mixture excluding arginine (Arg) (-Arg, 158 g/d) in a duplicated 4 * 4 Latin square design with 4 infusion periods separated by a 7-d interval period. The basal diet was formulated with corn grain, soybean meal, cottonseed meal, corn silage, alfalfa hay and Chinese wildrye grass hay according to NRC (2001) and supplied 1.6 Mcal net energy for lactation (NEL) and 94.4 g metabolizable protein (MP) per kg dry matter (DM) to meet requirements for lactation. The results showed that the dry matter intake (DMI) and normal physiological status were not affected by amino acid mixture infusions. Compared with CTL treatment, the CSN treatment increased milk yield (14.9%, P < 0.001), milk lactose yield (14.5%, P = 0.001), milk fat yield (16.6%, P = 0.01), milk protein yield (18.2%, P < 0.001) and the contents of alphaS1-casein (alphaS1-CN, 11.8%, P = 0.007), beta-casein (beta-CN, 4.2%, P = 0.035) and kappa-casein (kappa CN, 8.5%, P = 0.003). However, the -Leu and -Arg treatments had lower milk yield (6.3%, P = 0.058 and 5.7%, P = 0.073, respectively), milk protein yield (8.8%, P = 0.010 and 8.2%, P = 0.011, respectively) and the contents of alphaS1-CN (7.3%, P = 0.057 and 8.4%, P = 0.026, respectively), beta-CN (4.2%, P = 0.033 and 3.8%, P = 0.048, respectively) and kappa-CN (5.8%, P = 0.023 and 7.6%, P = 0.003, respectively) than those of the CSN treatment. Milk lactose yield (5.9%, P = 0.076) tended to decrease when Leu was removed from amino acid mixture infusate. In conclusion, the supply of casein profile can increase milk production in dairy cows, but a deficiency of Leu or Arg had negative effects on milk yield and milk protein yield. PMID- 29767156 TI - Dietary sources and their effects on animal production and environmental sustainability. AB - Animal agriculture has been an important component in the integrated farming systems in developing countries. It serves in a paramount diversified role in producing animal protein food, draft power, farm manure as well as ensuring social status-quo and enriching livelihood. Ruminants are importantly contributable to the well-being and the livelihood of the global population. Ruminant production systems can vary from subsistence to intensive type of farming depending on locality, resource availability, infrastructure accessibility, food demand and market potentials. The growing demand for sustainable animal production is compelling to researchers exploring the potential approaches to reduce greenhouse gases (GHG) emissions from livestock. Global warming has been an issue of concern and importance for all especially those engaged in animal agriculture. Methane (CH4) is one of the major GHG accounted for at least 14% of the total GHG with a global warming potential 25 fold of carbon dioxide and a 12-year atmospheric lifetime. Agricultural sector has a contribution of 50 to 60% methane emission and ruminants are the major source of methane contribution (15 to 33%). Methane emission by enteric fermentation of ruminants represents a loss of energy intake (5 to 15% of total) and is produced by methanogens (archae) as a result of fermentation end-products. Ruminants' digestive fermentation results in fermentation end-products of volatile fatty acids (VFA), microbial protein and methane production in the rumen. Rumen microorganisms including bacteria, protozoa and fungal zoospores are closely associated with the rumen fermentation efficiency. Besides using feed formulation and feeding management, local feed resources have been used as alternative feed additives for manipulation of rumen ecology with promising results for replacement in ruminant feeding. Those potential feed additive practices are as follows: 1) the use of plant extracts or plants containing secondary compounds (e.g., condensed tannins and saponins) such as mangosteen peel powder, rain tree pod; 2) plants rich in minerals, e.g., banana flower powder; and 3) plant essential oils, e.g., garlic, eucalyptus leaf powder, etc. Implementation of the -feed-system using cash crop and leguminous shrubs or fodder trees are of promising results. PMID- 29767157 TI - Dietary glutamine, glutamic acid and nucleotide supplementation accelerate carbon turnover (delta13C) on stomach of weaned piglets. AB - The use of stable isotope analysis as a tool for characterization of carbon turnover (delta13C) in piglet's tissues by tracing its feeding system has drawn attention. Thus, this study aimed at evaluating the influence of dietary glutamine, glutamic acid and nucleotides supplementation on carbon turnover in fundic-stomach region of weaned piglets at an average age of 21 days. The diets consisted of additive-free diet - control (C); 1% glutamine (G); 1% glutamic acid (GA) and 1% nucleotides (Nu). At weaning day (day 0: baseline), 3 piglets were slaughtered to quantify the delta13C of stomach. The remaining 120 piglets were blocked by weight and sex, randomly assigned to pens with 3 piglets slaughtered per treatment at days 1, 2, 4, 5, 7, 9, 13, 20, 27 and 49 after weaning in order to verify the fundic-stomach isotopic composition by treatments. Samples were analyzed in terms of 13C/12C ratio by mass spectrometry and converted to relative isotopic enrichment values (delta13C 0/00) used to plot the first order exponential curves over time using OriginPro 8.0 software. The inclusion of glutamine, glutamate and nucleotides in piglet's diets has accelerated the carbon turnover in stomach during the post-weaning period, demonstrating also that glutamate has guaranteed fastest 13C incorporation rate on fundic-stomach region and pH-lowering. Besides that, stable isotopes technique (delta13C) has proved to be an important methodology to determine the time-scales at which piglets shift among diets with different isotopic values, characterizing the trophic effects of additives and the phenotypic flexibility of stomach. PMID- 29767158 TI - Glutamine and glutamate: Nonessential or essential amino acids? AB - Glutamine and glutamate are not considered essential amino acids but they play important roles in maintaining growth and health in both neonates and adults. Although glutamine and glutamate are highly abundant in most feedstuffs there is increasing evidence that they may be limiting during pregnancy, lactation and neonatal growth, particularly when relatively low protein diets are fed. Supplementation of diets with glutamine, glutamate or both at 0.5 to 1.0% to both suckling and recently weaned piglets improves intestinal and immune function and results in better growth. In addition such supplementation to the sow prevents some of the loss of lean body mass during lactation, and increases milk glutamine content. However, a number of important questions related to physiological condition, species under study and the form and amount of the supplements need to be addressed before the full benefits of glutamine and glutamate supplementation in domestic animal production can be realized. PMID- 29767159 TI - Niacin alters the ruminal microbial composition of cattle under high-concentrate condition. AB - To understand the effects of niacin on the ruminal microbial ecology of cattle under high-concentrate diet condition, Illumina MiSeq sequencing technology was used. Three cattle with rumen cannula were used in a 3 * 3 Latin-square design trial. Three diets were fed to these cattle during 3 periods for 3 days, respectively: high-forage diet (HF; forage-to-concentrate ratio = 80:20), high concentrate diet (HC; forage-to-concentrate ratio = 20:80), and HC supplemented with 800 mg/kg niacin (HCN). Ruminal pH was measured before feeding and every 2 h after initiating feeding. Ruminal fluid was sampled at the end of each period for microbial DNA extraction. Overall, our findings revealed that subacute ruminal acidosis (SARA) was induced and the alpha-diversity of ruminal bacterial community decreased in the cattle of HC group. Adding niacin in HC could relieve the symptoms of SARA in the cattle but the ruminal pH value and the Shannon index of ruminal bacterial community of HCN group were still lower than those of HF group. Whatever the diet was, the ruminal bacterial community of cattle was dominated by Bacteroidetes, Firmicutes and Proteobacteria. High-concentrate diet significantly increased the abundance of Prevotella, and decreased the abundance of Paraprevotella, Sporobacter, Ruminococcus and Treponema than HF. Compared with HC, HCN had a trend to decrease the percentage of Prevotella, and to increase the abundance of Succiniclasticum, Acetivibrio and Treponema. Increasing concentrate ratio could decrease ruminal pH value, and change the ruminal microbial composition. Adding niacin in HC could increase the ruminal pH value, alter the ruminal microbial composition. PMID- 29767160 TI - Effects of yeast cell wall on growth performance, immune responses and intestinal short chain fatty acid concentrations of broilers in an experimental necrotic enteritis model. AB - Subclinical necrotic enteritis (NE) causes devastating economic losses in the broiler chicken industry, especially in birds raised free of in-feed antibiotics. Prebiotics are potential alternatives to in-feed antibiotics. Yeast cell wall extract (YCW) derived from Saccharomyces cerevisiae is a prebiotic with known immune modulating effects. This study examined the effects of YCW and antibiotics (AB) during subclinical NE on broiler growth performance, intestinal lesions, humoral immune response and gut microflora metabolites. The study employed a 2 * 3 factorial arrangement of treatments. Factors were: NE challenge (yes or no) and feed additive (control, AB, or YCW). Each treatment was replicated in 8 floor pens with 15 birds per pen. Challenged birds had higher feed conversion ratio (FCR) than unchallenged birds on d 35 (P < 0.05). Dietary inclusion of AB decreased FCR regardless of challenge (P < 0.05) on d 24 and 35. Inclusion of YCW reduced serum interleukin-1 (IL-1) concentration in NE challenged birds (P < 0.01) and increased immunoglobulin (Ig) G (P < 0.05) and Ig M (P < 0.05) levels compared to other dietary treatments regardless of challenge. Yeast cell wall extract increased formic acid concentration in cecal contents during challenge and increased butyric acid concentration in unchallenged birds on d 16. This study indicates YCW suppressed inflammatory response, promoted generation of immunoglobulin and increased short chain fatty acid production suggesting potential benefits to bird health. PMID- 29767163 TI - Response of primiparous and multiparous buffaloes to yeast culture supplementation during early and mid-lactation. AB - Strains of live Saccharomyces cerevisiae yeast have exhibited probiotic effects in ruminants. This study investigated the effects of the dietary yeast supplement, S. cerevisiae (Yea-Sacc1026), on primiparous (PP) and multiparous (MP) Egyptian buffaloes in early to mid-lactation. Lactating buffaloes were fed either a basal total mixed ration (TMR, control; 4 PP and 8 MP) or the basal TMR plus 10 g Yea-Sacc1026 per buffalo cow per day (yeast; 4 PP and 8 MP). The feeds were given from 15 days prepartum to 180 days postpartum. Feed intake, body weight, and milk yields (MY) were recorded, and milk and blood samples were collected for analyses. Feces were collected from days 45 to 47 during early lactation and from days 90 to 92 during mid-lactation to determine apparent digestibility of dry matter (DM), organic matter (OM), crude protein (CP) and crude fiber (CF). Energy corrected milk yield (ECM), feed conversion, and energy and nitrogen conversion efficiency were calculated. Yeast treated MP buffaloes consumed more DM (P <= 0.041) and CP than the untreated control group. Apparent digestibility of DM and OM were significantly greater at mid-lactation for treated versus control group (P = 0.001). Crude fiber digestibility was greater in MP than in PP buffaloes (P = 0.049), and yeast supplemented MP cows had a greater CF digestibility than control MP buffaloes at mid-lactation (P = 0.010). Total blood lipids decreased after yeast supplementation (P = 0.029). Milk yields, ECM, fat and protein yields increased for yeast treated MP buffaloes (P <= 0.039). The study concluded that the response to yeast supplementation in buffalo cows is parity dependent. Multiparous buffaloes respond to yeast supplementation with an increased DM intake and CF digestibility without significant weight gains, allowing a greater ECM yield with less fat mobilization. Supplementing buffaloes with yeast culture may increase milk production in early lactation and results in a more persistent milk production during mid-lactation. Feed conversion and energy and nitrogen conversion efficiency may be increased with the use of yeast supplementation in Egyptian buffaloes. PMID- 29767162 TI - Dietary energy intake affects fetal survival and development during early and middle pregnancy in Large White and Meishan gilts. AB - This experiment was designed to determine the effects of variations in dietary energy intake on reproductive performance and gene expression of luteal and endometrium tissues in Large White (LW) and Meishan (MS) gilts during early and middle pregnancy. After insemination, 32 LW gilts were assigned to high and low (HEL and LEL, 14.23 and 12.56 MJ DE/kg, respectively) diet treatment groups, while 32 MS gilts were allocated to HEM and LEM (12.56 and 10.88 MJ DE/kg) groups. Gilts were slaughtered on days 35, 55 and 90 of gestation. The fetal survival and luteal progesterone (P4) concentration in the HEL group were higher on day 35 but lower on day 90 of gestation compared with the LEL group (P < 0.05) for LW gilts. However, fetal survival and luteal P4 concentration on day 35 of gestation were greater (P < 0.05) in the LEM group than in the HEM group for MS gilts, but no significant difference in mid-gestation was showed. The fetal weights of both breeds were higher for the high energy diets compared with the respective control group on day 90 of gestation (P < 0.05). In addition, the mRNA levels of P4 synthesis-related proteins had correlated with luteal P4 concentration in both breeds. Further, endometrial levels of uteroferrin (ACP5), retinol-binding protein 4 (RBP4) and secreted phosphoprotein 1 (SPP1) mRNA were upregulated in the HEL group on day 35 of gestation but ACP5 and SPP1 were downregulated on day 55 of gestation compared with the LEL group (P < 0.05) for LW gilts. In MS gilts, diet only affected the expression of SPP1 (P < 0.05). Our results revealed the differential sensitivity of LW and MS breeds to variations in dietary energy intake. For LW gilts, the HEL group improved fetal survival on day 35 but a sustained high energy diet decreased fetal survival on day 90 of gestation. The differences in dietary energy intake did not influence fetal survival on day 90 of gestation but the higher energy diet did increase fetal weight in the MS breed compared with the lower energy intake diet. These results may be due to differential luteal secretion activity and endometrium gene expression in these two breeds. PMID- 29767164 TI - The profiles of mitochondrial respiration and glycolysis using extracellular flux analysis in porcine enterocyte IPEC-J2. AB - The porcine intestinal mucosa require large amounts of energy for nutrient processing and cellular functions and is vulnerable to injury by weaning stress involving bioenergetics failure. The mitochondrial bioenergetic measurement in porcine enterocytes have not been defined. The present study was to establish a method to measure mitochondrial respiratory function and profile mitochondrial function of IPEC-J2 using cell mito stress test and glycolysis stress test assay by XF24 extracellular flux analyzer. The optimal seeding density and concentrations of the injection compounds were determined to be 40,000 cells/well as well as 0.5 uM oligomycin, 1 uM carbonyl cyanide p-trifluoromethoxy phenylhydrazone (FCCP) and 1 uM rotenone & antimycin A, respectively. The profiles of mitochondrial respiration and glycolysis confirmed that porcine enterocyte preferentially derived much more energy from glutamine than glucose. These results will provide a basis for further study of mitochondrial function and bioenergetics of the porcine small intestine. PMID- 29767165 TI - Dose-response effects of in-feed antibiotics on growth performance and nutrient utilization in weaned pigs fed diets supplemented with yeast-based nucleotides. AB - Dietary nucleotides are bioactive compounds with the potential to mitigate weaning-associated challenges in piglets. An experiment was conducted to determine the interaction effect of antimicrobial growth promoters (AGP) and a nucleotide-rich yeast extract (NRYE) on growth performance and apparent total tract digestibility (ATTD) of dry matter (DM), crude protein (CP) and gross energy (GE), and to establish whether NRYE supplementation may completely or partially replace AGP in diets for weaned pigs. In phase 1 and 2, corn, wheat, canola meal and soybean meal based diets, which were formulated to contain 0.0 or 0.1% NRYE with 0, 25, 50, 75 or 100% of the recommended AGP dosage, were fed to 108 twenty-one day old piglets (initial body weight 7.11 +/- 0.9 kg; mean +/- SD) from d 1 to 14 and 15 to 28, respectively. Overall, increasing AGP level in NRYE supplemented diets linearly decreased average daily gain (ADG) (P = 0.002) and gain-to-feed ratio (G:F) (P = 0.007); and quadratically decreased ATTD of DM (P = 0.001), CP (P = 0.003) and G:F (P = 0.017) during phase 2. Compared with control and pigs fed NRYE with 100% of recommended AGP dosage, pigs fed 0.1% NRYE without AGP had greater (P < 0.05) ADG and G:F in phase 2 and overall. In conclusion, supplementing 0.1% NRYE improved growth performance of pigs but this beneficial effect was reduced by increasing dietary AGP dosage. PMID- 29767161 TI - Feed supplementation with arginine and zinc on antioxidant status and inflammatory response in challenged weanling piglets. AB - Although supplementing the diet with zinc oxide and arginine is known to improve growth in weanling piglets, the mechanism of action is not well understood. We measured the antioxidant status and inflammatory response in 48 weanling castrated male piglets fed diets supplemented with or without zinc oxide (2,500 mg Zn oxide per kg) and arginine (1%) starting at the age of 20 days. The animals were injected with lipopolysaccharide (100 MUg/kg) on day 5. Half of them received another injection on day 12. Blood samples were taken just before and 6, 24 and 48 h after injection and the mucosa lining the ileum was recovered following euthanizing on days 7 and 14. Zinc supplementation increased reduced and total glutathione (GSH) (reduced and total) during days 5 to 7 and arginine decreased oxidized GSH measured on days 5 and 12 and the ratio of total antioxidant capacity to total oxidative status during days 12 to 14. Zinc decreased plasma malondialdehyde measured on days 5 and 12 and serum haptoglobin measured on day 12 and increased both metallothionein-1 expression and total antioxidant capacity measured in the ileal mucosa on day 14. Tumour necrosis factor alpha concentration decreased from days 5 to 12 (all effects were significant at P < 0.05). This study shows that the zinc supplement reduced lipid oxidation and lipopolysaccharide-induced inflammation during the post-weaning period, while the arginine supplementation had only a limited effect. PMID- 29767166 TI - Performance of broiler chickens offered nutritionally-equivalent diets based on two red grain sorghums with quantified kafirin concentrations as intact pellets or re-ground mash following steam-pelleting at 65 or 97 degrees C conditioning temperatures. AB - The Liverpool Plains is a fertile agricultural region in New South Wales, Australia. Two sorghums from the 2009 Liverpool Plains harvest, sorghums #3 and #5, were extensively characterised which included concentrations of kafirin and phenolic compounds plus rapid visco-analysis (RVA) starch pasting profiles. Diets based on these two sorghums were formulated to be iso-nitrogenous and iso energetic and were offered to male Ross 308 broiler chicks from 7 to 28 days post -hatch as either intact pellets or reground mash following steam-pelleting at conditioning temperatures of either 65 or 97 degrees C. Thus the feeding study consisted of a 2 * 2 * 2 factorial array of dietary treatments: two sorghum varieties, two feed forms and two conditioning temperatures. Each of the eight treatments was replicated six times with six birds per replicate cage. Assessed parameters included growth performance, nutrient utilisation, apparent starch and protein (N) digestibility coefficients and disappearance rates from the distal jejunum and distal ileum. Intact pellets supported higher (P < 0.001) feed intakes and weight gains by 9.83 and 9.08%, respectively, than reground mash diets. Feed conversion ratios of broilers offered diets steam-conditioned at 97 degrees C were 2.46% inferior (P < 0.001) in comparison to 65 degrees C diets and both apparent metabolizable energy (AME) and N-corrected AME (AMEn) were compromised. Broilers offered sorghum #3-based diets significantly (P < 0.001) outperformed their sorghum #5 counterparts in terms of weight gain by 3.75% (1,334 versus 1,223 g/bird), FCR by 4.81% (1.524 versus 1.601), AME by 1.06 MJ (13.61 versus 12.55 MJ/kg), ME:GE ratio (ME:GE) by 4.81% (0.806 versus 0.769) and AMEn by 1.03 MJ (12.38 versus 11.35 MJ/kg). The inferiority of sorghum #5 appeared to be associated with higher concentrations of kafirin (61.5 versus 50.7 g/kg) and conjugated phenolic acids, including ferulic acid (31.1 versus 25.6 ug/g). There were no significant differences in jejunal and ileal starch and protein (N) digestibility coefficients between the two sorghums. However, starch to protein (N) disappearance rate ratios from the distal jejunum were significantly (P < 0.001) correlated with ME:GE and AME. The multiple linear regression equations indicated that energy utilisation was enhanced by coupling rapidly digestible protein with slowly digestible starch, which suggests that bilateral bioavailability of starch and protein is pivotal to efficient energy utilisation. PMID- 29767167 TI - Pattern of non-starch polysaccharide digestion along the gut of the pig: Contribution to available energy. AB - We investigated the pattern of non-starch polysaccharide (NSP) digestion along the gut of pigs fed two different wheats, which were offered with or without xylanase supplementation. The two wheats used were pre-characterised before the experiment on the basis of low and normal feed intake of young pigs. Wheat type significantly influenced feed intake and growth rate in the first 7 days, however, by day 14 the only significant effect of wheat type was on growth rate. Xylanase supplementation increased the growth performance of pigs fed the poor quality wheat to a level similar to those fed the normal wheat. It also increased the daily gain of pigs fed the normal wheat. Wheat type had no significant effect on the digestibility of dry matter (DM), energy, free sugars or the different fractions of NSP in the duodenum, ileum or in the faeces. The duodenal gross energy digestibility values for the low and high performance diets were -27.4 and -47.5%, respectively, and xylanase supplementation significantly increased the digestibility of energy back to positive levels. Dry matter digestibility values followed a similar pattern. In the duodenum, xylanase increased (P < 0.05) the digestibility values of both soluble and insoluble NSP, whereas in the ileum, xylanase had a significant effect only on the digestibility of the soluble NSP fraction. Xylanase did not affect free sugar digestibility. The reduction in soluble NSP level coincided with a marked reduction in the amount of fucose, a prominent component of mucosal polysaccharides. This suggests that soluble NSP substantially increase endogenous losses. The absence of differences in the digestibility of the measured NSP between the two wheat samples suggests that the structures of the NSP, rather than just their amount and solubility, are important for the anti-nutritional properties of NSP in pig diets. PMID- 29767168 TI - Delivery routes for probiotics: Effects on broiler performance, intestinal morphology and gut microflora. AB - Four delivery routes, via, feed, water, litter and oral gavage, were examined for their efficacy in delivering a novel probiotic of poultry origin, Lactobacillus johnsonii, to broilers. Seven treatments of 6 replicates each were allocated using 336 one-day-old Cobb broiler chicks. The treatments consisted of a basal diet with the probiotic candidate, L. johnsonii, added to the feed, and three treatments with L. johnsonii added to the drinking water, sprayed on the litter, or gavaged orally. In addition, a positive control treatment received the basal diet supplemented with zinc-bacitracin (ZnB, 50 mg/kg). The probiotic strain of L. johnsonii was detected in the ileum of the chicks for all four delivery routes. However, the addition of L. johnsonii as a probiotic candidate did not improve body weight gain, feed intake and feed conversion ratio of broiler chickens raised on litter during the 5-week experimental period regardless of the route of administration. The probiotic treatments, regardless of the routes of delivery, affected (P < 0.05) the pH of the caecal digesta and tended (P = 0.06) to affect the pH of the ileal digesta on d 7, but the effect disappeared as the birds grew older. All probiotic treatments reduced the number of Enterobacteria in the caeca on d 21, and tended (P < 0.054) to reduce it in the ileum and caeca on d 7 and in the ileum on d 21 compared with the controls. The probiotic also tended to increase the number of lactic acid bacteria and lactobacilli in the ileum and caeca on d 7, but this trend was not evident on d 21. The trend appeared most pronounced when the probiotic was delivered orally or via litter. The probiotic also decreased (P < 0.05) the population of Clostridium perfringens rapidly from an early age to d 21 in the caeca, leading to a 3-fold decrease in the number of C. perfringens between d 7 and 21. It also showed that the probiotic treatment presented the lowest number of C. perfringens in the caeca. Delivery of the probiotic through feed, water and litter increased (P < 0.01) the weight of the pancreas on d 21, but the probiotic did not affect other morphometric parameters of the gut. Furthermore, the probiotic did not affect the pH and the concentrations of short chain fatty acids and lactic acid in either the ileum or caeca. PMID- 29767169 TI - Effects of feed form and feed particle size on growth performance, carcass characteristics and digestive tract development of broilers. AB - This study was conducted to evaluate the effects of feed form (mash and crumble pellet) and feed particle size (fine, medium and coarse) on growth performance, carcass characteristics and digestive tract development of broilers. A total of 1,152 one day-old Ross 308 mixed-sex broilers were used in a factorial arrangement (2 * 3) based on a completely randomized design with six replicates of 32 birds each. Higher average daily gain (ADG) and average daily feed intake (ADFI) were observed (P < 0.01) for birds fed the crumble-pellet diets (CPD) than for those fed the mash diets (MD) during starter, grower and the entire experiment period. From d 1 to 40, birds fed CPD had a higher (P < 0.01) body weight (BW) than those fed MD. Birds fed CPD had a lower (P < 0.01) feed:gain ratio (F:G) during the starter phase than those fed MD. Medium or coarse particle size increased (P < 0.01) ADG and ADFI during the starter phase, but birds fed fine particle size diets had lower (P < 0.01) F:G during the grower phase. In MD, medium and coarse particle sizes resulted in higher (P < 0.05) BW, ADG and ADFI than fine particle size during the whole experiment. In CPD, particle size had no significant effect on growth performance, as indicated by a feed form * particle size interaction (P < 0.05). At 41 days of age, ten birds per treatment were randomly selected and killed for slaughter yields and digestive tract characteristics determination. It was shown that particle size and feed form alone had no significant effect on slaughter yields, so changes was the feed form * particle size interaction. The relative empty weight of the gizzard was greater (P < 0.01) and the relative length of the ileum was longer (P < 0.05) in birds fed MD than in those fed CPD. Overall, CPD improved growth performance during the entire period of the study with effects being less evident during the finisher phase than during the starter and grower phases, and the effect of feed particle size varied depending on feed form. PMID- 29767170 TI - Sustainable livestock production: Low emission farm - The innovative combination of nutrient, emission and waste management with special emphasis on Chinese pig production. AB - Global livestock production is going to be more and more sophisticated in order to improve efficiency needed to supply the rising demand for animal protein of a growing, more urban and affluent population. To cope with the rising public importance of sustainability is a big challenge for all animal farmers and more industrialized operations especially. Confined animal farming operations (CAFO) are seen very critical by many consumers with regard to their sustainability performance, however, the need to improve the sustainability performance especially in the ecological and social dimension exists at both ends of the intensity, i.e., also for the small holder and family owned animal farming models. As in livestock operations, feed and manure contribute the majority to the three most critical environmental impact categories global warming potential (GWP), acidification (AP) and eutrophication potential (EP) any effort for improvement should start there. Intelligent combination of nutrient-, emission- and waste management in an integrated low emission farm (LEF) concept not only significantly reduces the environmental footprint in the ecological dimension of sustainability, but by producing renewable energy (heat, electricity, biomethane) with animal manure as major feedstock in an anaerobic digester also the economic dimension can be improved. Model calculations using new software show the ecological improvement potential of low protein diets using more supplemented amino acids for the Chinese pig production. The ecological impact of producing biogas or upgraded biomethane, of further treatment of the digestate and producing defined fertilizers is discussed. Finally, the LEF concept allows the integration of an insect protein plant module which offers additional ecological and economical sustainability improvement potential in the future. Active stakeholder communication about implementation steps of LEF examples improves also the social aspect of sustainability. PMID- 29767171 TI - Effects of protein sources and levels in antibiotic-free diets on diarrhea, intestinal morphology, and expression of tight junctions in weaned piglets. AB - This study examined effects of dietary protein sources and levels on intestinal health of 21 to 35 d-old weaned piglets fed antibiotics-free diets. A total of 150 weaned piglets (21 d of age) were allotted to 5 dietary treatment groups. Diets were formulated, based on corn-soybean meal, with different protein sources (fish meal and soy protein concentrate) to provide different dietary CP levels. Piglets within 5 dietary treatments were fed diets as follows, respectively: 1) control diet of 17% CP (control); 2) 19% CP diets formulated with more soy protein concentrate (SPC19); 3) fish meal (FM19); 4) 23.7% CP diets formulated with more soy protein concentrate (SPC23); 5) fish meal (FM23). The results showed that piglets from control group had higher ADG and lower incidence of diarrhea compared with those of other groups (P < 0.05). The incidence of diarrhea of piglets in FM19 group was lower than those from SPC23 group and FM23 group (P < 0.05). With the higher CP levels, villous height and villous height to crypt depth ratio of piglets in the duodenum and jejunum were decreased (P < 0.05), but crypt depth was increased (P < 0.05). Comparing control group and other groups, we found the expression of inflammatory cytokines interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) were increased (P < 0.05) in the jejunum and colon of piglets, as did cystic fibrosis transmembrane conductance regulators (CFTR) in the distal colon. The relative transcript abundance of Zonula occludens-1 (ZO-1) in the jejunum, and occludin in the jejunum and ileum of piglets fed 23.7% CP diets were reduced compared with those fed control diet (P < 0.05). In conclusion, the 17% CP diet without in-feed antibiotics helped improve growth performance and relief of diarrhea of 21 to 35 d-old weaned piglets. Dietary CP level, rather than its source (either fish meal or soy protein concentrate), has more significant impacts on the growth performance and intestinal health of 21 to 35 d-old weaned piglets when fed antibiotics-free diets. PMID- 29767172 TI - Post-weaning and whole-of-life performance of pigs is determined by live weight at weaning and the complexity of the diet fed after weaning. AB - The production performance and financial outcomes associated with weaner diet complexity for pigs of different weight classes at weaning were examined in this experiment. A total of 720 weaner pigs (360 entire males and 360 females) were selected at weaning (27 +/- 3 d) and allocated to pens of 10 based on individual weaning weight (light weaning weight: pigs below 6.5 kg; medium weaning weight: 6.5 to 8 kg; heavy weaning weight: above 8.5 kg). Pens were then allocated in a 3 * 2 * 2 factorial arrangement of treatments with the respective factors being weaning weight (heavy, medium and light; H, M and L, respectively), weaner diet complexity (high complexity/cost, HC; low complexity/cost, LC), and gender (male and female). Common diets were fed to both treatment groups during the final 4 weeks of the weaner period (a period of 39 days). In the first 6 d after weaning, pigs offered the HC diets gained weight faster and used feed more efficiently than those offered the LC diets (P = 0.031). Pigs fed a HC diet after weaning tended to be heavier at the sale live weight of 123 d of age compared with pigs fed the LC diet (P = 0.056). There were no other main effects of the feeding program on growth performance through to slaughter. Weaning weight had a profound influence on lifetime growth performance and weight at 123 d of age, with H pigs at weaning increasing their weight advantage over the M and L pigs (101.3, 97.1, 89.6 kg respectively, P < 0.001). Cost-benefit analyses suggested there was a minimal benefit in terms of cost per unit live weight gain over lifetime when pigs were offered a HC feeding program to L, with a lower feed cost/kg gain. The results from this investigation confirm the impact of weaning weight on lifetime growth performance, and suggest that a HC feeding program should be focused on L weaner pigs (i.e., weaning weight less than 6.5 kg at 27 d of age) in order to maximise financial returns. PMID- 29767173 TI - Autophagy and tight junction proteins in the intestine and intestinal diseases. AB - The intestinal epithelium (IE) forms an indispensible barrier and interface between the intestinal interstitium and the luminal environment. The IE regulates water, ion and nutrient transport while providing a barrier against toxins, pathogens (bacteria, fungi and virus) and antigens. The apical intercellular tight junctions (TJ) are responsible for the paracellular barrier function and regulate trans-epithelial flux of ions and solutes between adjacent cells. Increased intestinal permeability caused by defects in the IE TJ barrier is considered an important pathogenic factor for the development of intestinal inflammation, diarrhea and malnutrition in humans and animals. In fact, defects in the IE TJ barrier allow increased antigenic penetration, resulting in an amplified inflammatory response in inflammatory bowel disease (IBD), necrotizing enterocolitis and ischemia-reperfusion injury. Conversely, the beneficial enhancement of the intestinal TJ barrier has been shown to resolve intestinal inflammation and apoptosis in both animal models of IBD and human IBD. Autophagy (self-eating mechanism) is an intracellular lysosome-dependent degradation and recycling pathway essential for cell survival and homeostasis. Dysregulated autophagy has been shown to be directly associated with many pathological processes, including IBD. Importantly, the crosstalk between IE TJ and autophagy has been revealed recently. We showed that autophagy enhanced IE TJ barrier function by increasing transepithelial resistance and reducing the paracellular permeability of small solutes and ions, which is, in part, by targeting claudin 2, a cation-selective, pore-forming, transmembrane TJ protein, for lysosome (autophagy)-mediated degradation. Interestingly, previous studies have shown that the inflamed intestinal mucosa in patients with active IBD has increased claudin 2 expression. In addition, inflammatory cytokines (for example, tumor necrosis factor-alpha, interleukin-6, interleukin-13, and interleukin-17) whose levels are increased in IBD patients cause an increase in claudin-2 expression and a claudin 2-dependent increase in TJ permeability. Thus, the role of claudin-2 in intestinal pathological processes has been attributed, in part, to the increase of intestinal TJ permeability. Claudin-2 represents a new therapeutic target in treating IBD, diarrhea and malnutrition in animals and humans. PMID- 29767175 TI - Phase separation in mixed polymer brushes on nanoparticle surfaces enables the generation of anisotropic nanoarchitectures. AB - The preparation of nanoparticles and their targeted connection with other functional units is one key challenge in developing nanoscale devices. Herein, we report an experimental strategy toward the development of anisotropic nanoparticle architectures. Our approach is based on phase separation of binary mixed polymer brushes on gold nanoparticle surfaces leading to Janus-type structures, as revealed by scanning transmission electron microscopy and electron energy-loss spectroscopy and, additionally, corroborated by computer simulation. We show that such structures can be used for the site-selective functionalization with additional nanosized entities. PMID- 29767182 TI - Morphology control of anatase TiO2 for well-defined surface chemistry. AB - A specific allotrope of titanium dioxide (anatase) was synthesized both with a standard thermodynamic morphology ({101}-anatase) and with a highly anisotropic morphology ({001}-anatase) dominated by the {001} facet (81%). The surface chemistry of both samples after dehydroxylation was studied by 1H NMR and FT-IR. The influence of surface fluorides on the surface chemistry was also studied by 1H NMR, FT-IR and DFT. Full attribution of the IR spectra of anatase with dominant {001} facets could be provided based on experimental data and further confirmed by DFT. Our results showed that chemisorbed H2O molecules are still present on anatase after dehydroxylation at 350 degrees C, and that the type of surface hydroxyls present on the {001} facet is dependent on the presence of fluorides. They also provided general insight into the nature of the surface species on both fluorinated and fluorine-free anatase. The use of vanadium oxychloride (VOCl3) allowed the determination of the accessibility of the various OH groups spectroscopically observed. PMID- 29767186 TI - Mechanical characterization and modeling of sponge-reinforced hydrogel composites under compression. AB - Load-bearing applications of hydrogels call for materials with excellent mechanical properties. Despite the considerable progress in developing tough hydrogels, there is still a requirement to prepare high-performance hydrogels using simple strategies. In this paper, a sponge-reinforced hydrogel composite is synthesized by combining poly(acrylamide) (PAAm) hydrogel and polyurethane (PU) sponge. Uniaxial compressive testing of the hydrogel composites reveals that both the compressive modulus and the strength of the hydrogel composites are much higher than those of the PAAm hydrogel or sponge. In order to predict the compressive modulus of the hydrogel composite, we develop a theoretical model that is validated by experiments and numerical simulations. The present work may guide the design and manufacture of hydrogel-based composite materials, especially for biomaterial scaffolds and soft transducers. PMID- 29767187 TI - Separately enhanced dual emissions of the amphiphilic derivative of 2-(2' hydroxylphenyl) benzothiazole by supramolecular complexation. AB - Here, we report separately enhanced dual emissions of the amphiphilic derivative of 2-(2'-hydroxyphenyl)benzothiazole (denoted as HBT-11) by supramolecular complexation with cyclodextrins (CDs). When dispersed in water, HBT-11 shows two relatively weak emission bands, which can be assigned to the emissions of enol- and keto-forms, the two tautomers, owing to excited-state intramolecular proton transfers. Upon the addition of alpha-CD and beta-CD, the keto- and enol emissions, respectively, are separately enhanced; the enhancement effect is due to the formation of HBT-11/alpha-CD and HBT-11/beta-CD complexes through multiple hydrogen bonding and host-guest interactions, respectively. It is worth to note that the keto-emission caused by the complex of HBT-11/alpha-CD has a much shorter wavelength compared with that of the aggregates formed by pure HBT-11. To the best of our knowledge, this is the first time that a study on keto-emission of the isolated HBT chromophore has been reported. PMID- 29767188 TI - Hunting mermaids in real space: known knowns, known unknowns and unknown unknowns. AB - We review efforts to realise so-called mermaid (or short-ranged attraction/long ranged repulsion) interactions in 3d real space. The repulsive and attractive contributions to these interactions in charged colloids and colloid-polymer mixtures, may be accurately realised, by comparing particle-resolved studies with colloids to computer simulation. However, when we review work where these interactions have been combined, despite early indications of behaviour consistent with predictions, closer analysis reveals that in the non-aqueous systems used for particle-resolved studies, the idea of summing the attractive and repulsive components leads to wild deviations with experiment. We suggest that the origin lies in the weak ion dissociation in these systems with low dielectric constant solvents. Ultimately this leads even to non-centro-symmetric interactions and a new level of complexity in these systems. PMID- 29767189 TI - Covalent layer-by-layer films: chemistry, design, and multidisciplinary applications. AB - Covalent layer-by-layer (LbL) assembly is a powerful method used to construct functional ultrathin films that enables nanoscopic structural precision, componential diversity, and flexible design. Compared with conventional LbL films built using multiple noncovalent interactions, LbL films prepared using covalent crosslinking offer the following distinctive characteristics: (i) enhanced film endurance or rigidity; (ii) improved componential diversity when uncharged species or small molecules are stably built into the films by forming covalent bonds; and (iii) increased structural diversity when covalent crosslinking is employed in componential, spacial, or temporal (labile bonds) selective manners. In this review, we document the chemical methods used to build covalent LbL films as well as the film properties and applications achievable using various film design strategies. We expect to translate the achievement in the discipline of chemistry (film-building methods) into readily available techniques for materials engineers and thus provide diverse functional material design protocols to address the energy, biomedical, and environmental challenges faced by the entire scientific community. PMID- 29767174 TI - Novel and disruptive biological strategies for resolving gut health challenges in monogastric food animal production. AB - Use of feed antibiotics as growth promoters for control of pathogens associated with monogastric food animal morbidity and mortality has contributed to the development of antimicrobial resistance, which has now become a threat to public health on a global scale. Presently, a number of alternative feed additives have been developed and are divided into two major categories, including 1) the ones that are supposed to directly and indirectly control pathogenic bacterial proliferation; and 2) the other ones that are intended to up-regulate host gut mucosal trophic growth, whole body growth performance and active immunity. A thorough review of literature reports reveal that efficacy responses of current alternative feed additives in replacing feed antibiotics to improve performances and gut health are generally inconsistent dependent upon experimental conditions. Current alternative feed additives typically have no direct detoxification effects on endotoxin lipopolysaccharides (LPS) and this is likely the major reason that their effects are limited. It is now understood that pathogenic bacteria mediate their negative effects largely through LPS interactions with toll-like receptor 4, causing immune responses and infectious diseases. Therefore, disruptive biological strategies and a novel and new generation of feed additives need to be developed to replace feed antibiotic growth promoters and to directly and effectively detoxify the endotoxin LPS and improve gut health and performance in monogastric food animals. PMID- 29767190 TI - Aggregation kinetics of the Abeta1-40 peptide monitored by NMR. AB - The aggregation of Abeta1-40 was monitored by solution NMR, which showed a trend complementary to the one observed by ThT-fluorescence. The NMR data support a kinetic model where Abeta1-40 initially aggregates with the reversible formation of oligomeric species, which then irreversibly convert into fibrils. PMID- 29767192 TI - Ultra-low voltage triggered release of an anti-cancer drug from polypyrrole nanoparticles. AB - We have synthesized polypyrrole nanoparticles using three different oxidizing agents (hydrogen peroxide, chloroauric acid and ferric chloride) and shown that films assembled from these nanoparticles have significantly different drug release profiles. When ferric chloride is used as the oxidizing agent, it is possible to release drugs at voltages as low as -0.05 V, almost an order of magnitude lower than typically used voltages. These ultra-low voltage responsive nanoparticles widen the window of operation of conducting polymers and enable delivery of redox active drugs. As an example, we have shown pulsed release of the chemotherapeutic methotrexate at voltages as low as -0.075 V, demonstrating the potential application of these nanoparticles in cancer treatment. We have also verified the anti-tumor efficacy of the released drug using PC12 cell cultures. PMID- 29767193 TI - Floating catalyst CVD synthesis of single walled carbon nanotubes from ethylene for high performance transparent electrodes. AB - We have developed the floating catalyst chemical vapor deposition (FCCVD) synthesis of single walled carbon nanotubes (SWCNTs) using C2H4 hydrocarbon as a carbon source and iron nanoparticles as the catalyst in an environmentally friendly and economical process. For the first time, ethylene was used as the only carbon source in FCCVD with N2 as the main carrier gas. No sulphur and less than 15% H2 in a N2 carrier gas were used. By varying the ferrocene concentration, the diameter of the SWCNTs was tuned in the range of 1.3-1.5 nm with the optimized control of ferrocene concentration. The process produced SWCNTs with an average length of 13 MUm and with a low level of bundling, that is a high proportion (28%) of individual tubes. The electron diffraction (ED) pattern indicated a random chirality distribution of the tubes between armchair and zigzag structures. The ED analysis also revealed that 35-38% of tubes are metallic. As a result of having long SWCNTs with a low level of bundling and a high fraction of metallic tubes, we produced a highly conductive transparent film with a sheet resistance of 51 Ohm per sq. for 90% transmission at 550 nm after HNO3 treatment, this being one of the lowest sheet resistance values reported for SWCNT thin films. PMID- 29767194 TI - QM/MM simulations identify the determinants of catalytic activity differences between type II dehydroquinase enzymes. AB - Type II dehydroquinase enzymes (DHQ2), recognized targets for antibiotic drug discovery, show significantly different activities dependent on the species: DHQ2 from Mycobacterium tuberculosis (MtDHQ2) and Helicobacter pylori (HpDHQ2) show a 50-fold difference in catalytic efficiency. Revealing the determinants of this activity difference is important for our understanding of biological catalysis and further offers the potential to contribute to tailoring specificity in drug design. Molecular dynamics simulations using a quantum mechanics/molecular mechanics potential, with correlated ab initio single point corrections, identify and quantify the subtle determinants of the experimentally observed difference in efficiency. The rate-determining step involves the formation of an enolate intermediate: more efficient stabilization of the enolate and transition state of the key step in MtDHQ2, mainly by the essential residues Tyr24 and Arg19, makes it more efficient than HpDHQ2. Further, a water molecule, which is absent in MtDHQ2 but involved in generation of the catalytic Tyr22 tyrosinate in HpDHQ2, was found to destabilize both the transition state and the enolate intermediate. The quantification of the contribution of key residues and water molecules in the rate-determining step of the mechanism also leads to improved understanding of higher potencies and specificity of known inhibitors, which should aid ongoing inhibitor design. PMID- 29767197 TI - AIE-active boron complexes based on benzothiazole-hydrazone chelates. AB - A new family of aggregation-induced emission (AIE)-active monoboron and bisboron complexes based on benzothiazole-hydrazone chelates was synthesized. These complexes showed very weak fluorescence in fluid solution due to active intramolecular rotation and were emissive in high-viscosity solvents or in the aggregation state. Single crystal X-ray diffraction analyses and theoretical calculations were carried out to explain AIE behavior. The large Stokes shifts (3590-7400 cm-1) and relatively highly efficient solid-state emission make these complexes valuable AIE luminophores for further potential applications. PMID- 29767196 TI - Strategies for directing cells into building functional hearts and parts. AB - The increasing population of patients with heart disease and the limited availability of organs for transplantation have encouraged multiple strategies to fabricate healthy implantable cardiac tissues. One of the main challenges in cardiac tissue engineering is to direct cell behaviors to form functional three dimensional (3D) biomimetic constructs. This article provides a brief review on various cell sources used in cardiac tissue engineering and highlights the effect of scaffold-based signals such as topographical and biochemical cues and stiffness. Then, conventional and novel micro-engineered bioreactors for the development of functional cardiac tissues will be explained. Bioreactor-based signals including mechanical and electrical cues to control cardiac cell behavior will also be elaborated in detail. Finally, the application of computational fluid dynamics to design suitable bioreactors will be discussed. This review presents the current state-of-the-art, emerging directions and future trends that critically appraise the concepts involved in various approaches to direct cells for building functional hearts and heart parts. PMID- 29767198 TI - Opposite mechanoluminescence behavior of two isomers with different linkage positions. AB - Two isomers of mm-TPE(PI)2 and pp-TPE(PI)2, constructed by the two same aromatic blocks of tetraphenylethene and phenanthro[9,10-d]imidazole, exhibit totally different mechanoluminescence, as a result of the ignorable different linkage positions on the tetraphenylethene moiety. Detailed analysis and theoretical calculations demonstrate the structure-packing-property relationship of organic mechanoluminescent luminogens, with the emphasis on the important role of molecular packing in the solid state. PMID- 29767199 TI - Facile synthesis of 2,3-benzodiazepines using one-pot two-step phosphate-assisted acylation-hydrazine cyclization reactions. AB - Here, we report new methodology for synthesizing 2,3-benzodiazepines and their analogues by means of phosphate-assisted acylation reaction of 1-arylpropan-2 ones with a carboxylic acid followed by hydrazine cyclization in a one-pot two step manner. An unprotected amino group is tolerated in this reaction. This method provides a direct access to 2,3-benzodiazepines containing aromatic 7,8 dimethoxy and 1-p-aminophenyl groups, which are generally considered important for bioactivity. The presence of 3,4-dimethoxy or 3-methoxy substitution on the benzene ring of the 1-arylpropan-2-one is important for high regioselectivity in the acylation reaction. PMID- 29767201 TI - Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow. AB - We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput. PMID- 29767200 TI - NMR analyses on N-hydroxymethylated nucleobases - implications for formaldehyde toxicity and nucleic acid demethylases. AB - Formaldehyde is produced in cells by enzyme-catalysed demethylation reactions, including those occurring on N-methylated nucleic acids. Formaldehyde reacts with nucleobases to form N-hydroxymethylated adducts that may contribute to its toxicity/carcinogenicity when added exogenously, but the chemistry of these reactions has been incompletely defined. We report NMR studies on the reactions of formaldehyde with canonical/modified nucleobases. The results reveal that hydroxymethyl hemiaminals on endocyclic nitrogens, as observed with thymidine and uridine monophosphates, are faster to form than equivalent hemiaminals on exocyclic nitrogens; however, the exocyclic adducts, as formed with adenine, guanine and cytosine, are more stable in solution. Nucleic acid demethylase (FTO) catalysed hydroxylation of (6-methyl)adenosine results in (6 hydroxymethyl)adenosine as the major observed product; by contrast no evidence for a stable 3-hydroxymethyl adduct was accrued with FTO-catalysed oxidation of (3-methyl)thymidine. Collectively, our results imply N-hydroxymethyled adducts of nucleic acid bases, formed either by reactions with formaldehyde or via demethylase catalysis, have substantially different stabilities, with some being sufficiently stable to have functional roles in disease or the regulation of nucleic acid/nucleobase activity. PMID- 29767202 TI - Achieving deep-red-to-near-infrared emissions in Sn-doped Cu-In-S/ZnS quantum dots for red-enhanced white LEDs and near-infrared LEDs. AB - Semiconductor quantum dots (QDs) are promising luminescent materials for use in lighting, display and bio-imaging, and the color tuning is a necessity for such applications. In this work, we report tunable colors and deep-red or near infrared (NIR) emissions in Cu-In-S and Cu-In-S/ZnS QDs by incorporating Sn. These QDs (with a size of 5 nm) with varying Sn concentrations and/or Cu/In ratios were synthesized by a non-injection method, and characterized by a variety of analytical techniques (i.e., XRD, TEM, XPS, absorption, photoluminescence, decay time, etc.). The Cu-Sn-In-S and Cu-Sn-In-S/ZnS QDs with Cu/In = 1/2 show the emission maximum in the ranges of 701-894 nm and 628-785 nm, respectively. The red-shift in emission is ascribed to the decrease of the band gap with the Sn doping. The highest quantum yield of 75% is achieved in Cu-Sn-In-S/ZnS with 0.1 mmol Sn and Cu/In = 1/2. Both the white and NIR LEDs were fabricated by using Cu Sn-In-S/ZnS QDs and a 365 nm LED chip. The white LED exhibits superhigh color rendering indices of Ra = 97.2 and R9 = 91 and a warm color temperature of 2700 K. And the NIR LED shows an interesting broadband near-infrared emission centered at 741 nm, allowing for applications in optical communication, sensing and medical devices. PMID- 29767203 TI - Asymmetric synthesis of alpha-trifluoromethoxy ketones with a tetrasubstituted alpha-stereogenic centre via the palladium-catalyzed decarboxylative allylic alkylation of allyl enol carbonates. AB - The palladium-catalyzed asymmetric decarboxylative allylic alkylation of trifluoromethoxy allyl enol carbonates afforded enantioenriched alpha trifluoromethoxy allyl ketones that feature a tetrasubstituted alpha-stereogenic center in excellent yield and high enantioselectivity. The method was further extended to the asymmetric synthesis of alpha-difluoromethoxy and alpha-methoxy allyl ketones, which proceeded under similar catalytic conditions. PMID- 29767205 TI - Homoleptic uranium and lanthanide phosphinodiboranates. AB - Here we report a new class of homoleptic f-element borohydride complexes called phosphinodiboranates. Treating UI3(1,4-dioxane)1.5, NdI3, or ErI3, with three equiv. of K(H3BPtBu2BH3) in Et2O yielded M2(H3BPtBu2BH3)6, where M = U, Nd, and Er. All three complexes form solid-state dimers, but exist as mixtures of monomers and dimers in solution. PMID- 29767206 TI - 3D nanostructured N-doped TiO2 photocatalysts with enhanced visible absorption. AB - Considering the environmental issues, it is essential to develop highly efficient and recyclable photocatalysts in purification systems. Conventional TiO2 nanoparticles have strong intrinsic oxidizing power and high surface area, but are difficult to collect after use and rarely absorb visible light, resulting in low photocatalytic efficiency under sunlight. Here we develop a new type of highly efficient and recyclable photocatalyst made of a three-dimensional (3D) nanostructured N-doped TiO2 monolith with enhanced visible light absorption. To prepare the sample, an ultrathin TiN layer (~10 nm) was conformally coated using atomic layer deposition (ALD) on 3D nanostructured TiO2. Subsequent thermal annealing at low temperature (550 degrees C) converted TiN to anatase phase N doped TiO2. The resulting 3D N-doped TiO2 showed ~33% enhanced photocatalytic performance compared to pure 3D TiO2 of equivalent thickness under sunlight due to the reduced bandgap, from 3.2 eV to 2.75 eV through N-doping. The 3D N-doped TiO2 monolith could be easily collected and reused at least 5 times without any degradation in photocatalytic performance. PMID- 29767207 TI - Electrochemical polymerization of pyrene and aniline exclusively inside the pores of activated carbon for high-performance asymmetric electrochemical capacitors. AB - An asymmetric polymer capacitor was prepared from pyrene (PY), aniline (ANI), and commercially available activated carbon (AC) through a solvent-free preparation. PY and ANI were adsorbed into the AC host material in the gas phase and electrochemically polymerized exclusively inside the AC pores in an aqueous H2SO4 electrolyte (1 M). No volumetric expansion of the AC particles occurred upon the adsorption of monomers and their subsequent polymerizations; thus, the volumetric capacitance was enhanced by the inclusion of pseudocapacitive polypyrene (PPY) and polyaniline (PANI). The PPY and PANI structures formed inside the AC pores are very thin and have a large contact area with the conductive carbon surfaces. Therefore, the charge transfer distance between the polymers and the carbon surfaces was drastically shortened, significantly reducing the charge transfer resistance; i.e., high power density. The maximum volumetric capacitances for the PPY- and PANI-hybridized AC reached 314 and 299 F cm-3, respectively. Moreover, the strong adhesion derived from their large contact areas and adsorption capability of AC endow these materials with long cycle lifetimes. The PPY- and PANI-hybridized AC have different redox potentials and can be assembled into an asymmetric capacitor. The volumetric capacitance obtained for the asymmetric capacitor further surpassed that of the symmetric capacitor consisting of pristine AC, with high power density and long cycle lifetimes. PMID- 29767208 TI - Insights into the thermal phase transition behavior of a gemini dicationic polyelectrolyte in aqueous solution. AB - The thermal-induced phase transition behavior of a LCST-type poly(ionic liquid) (PIL) aqueous solution with gemini-cationic structure, poly[(1,8-octanediyl bis(tri-n-butylphosphonium)4-styrene sulfonate)] (P[SS-P2]), was investigated in this paper. Based on the calorimetric measurements, a unique dependence of transition points on concentration was found in P[SS-P2] aqueous solution compared to its mono-cationic PIL and [SS-P2] aqueous solution. Optical microscopy showed that globular microscopic droplets were formed during the phase transition, suggesting that gemini dications and the possible dynamic ionic bonds may facilitate the liquid-liquid phase separation (LLPS) in P[SS-P2] aqueous solution. Temperature-variable 1H NMR and FT-IR investigations manifested that the dehydration of anionic chains instead of the dehydration of dications served as the driving force of the phase separation in the P[SS-P2] aqueous solution, implying that the polymerized anions tended to aggregate together first and lay in the core with dications distributed around the globules at the end of the transition process. Notably, considering that the SO3 groups in the gemini cationic system tended to be distributed around the surface of collapsed anionic main chains rather than be wrapped into the aggregates, it is supposed that dynamic ionic bonding between dication and anionic backbones was distributed in the periphery of the globules and acted as the "cross-linkers", which enhanced the stability of regular droplets after the phase transition in P[SS-P2] aqueous solution. PMID- 29767210 TI - Low-threshold lasing from colloidal CdSe/CdSeTe core/alloyed-crown type-II heteronanoplatelets. AB - Colloidal type-II heterostructures are believed to be a promising solution processed gain medium given their spatially separated electrons and holes for the suppression of Auger recombination and their wider emission tuning range from the visible to near-infrared region. Amplified spontaneous emission (ASE) was achieved from colloidal type-II core/shell nanocrystals several years ago. However, due to the limited charge-transfer (CT) interfacial states and minimal overlap of electron and hole wave functions, the ASE threshold has still been very high. Herein, we achieved ASE through type-II recombination at a lower threshold using CdSe/CdSeTe core/alloyed-crown nanoplatelets. Random lasing was also demonstrated in the film of these nanoplatelets under sub-ns laser-pumping. Through a detailed carrier dynamics investigation using femtosecond transient absorption, steady state, and time-resolved photoluminescence (PL) spectroscopies, we confirmed the type-II band alignment, and found that compared with normal CdSe/CdTe core/crown nanoplatelets (where no ASE/lasing was observed), CdSe/CdSeTe core/alloyed-crown nanoplatelets had a much higher PL quantum yield (75% vs. 31%), a ~5-fold larger density of type-II charge-transfer states, a faster carrier transfer to interfaces (0.32 ps vs. 0.61 ps) and a slower Auger recombination lifetime (360 ps vs. 160 ps). Compared with CdSe/CdTe nanoplatelets, their counterparts with an alloyed crown boast a promoted charge transfer process, higher luminescence quantum yield, and smaller Auger rate, which results in their excellent application potential in solution-processed lasers and light-emitting devices. PMID- 29767209 TI - Chemically non-perturbing SERS detection of a catalytic reaction with black silicon. AB - All-dielectric resonant micro- and nano-structures made of high-index dielectrics have recently emerged as a promising surface-enhanced Raman scattering (SERS) platform which can complement or potentially replace the metal-based counterparts in routine sensing measurements. These unique structures combine the highly tunable optical response and high field enhancement with the non-invasiveness, i.e. chemically non-perturbing the analyte, simple chemical modification and recyclability. Meanwhile, commercially competitive fabrication technologies for mass production of such structures are still missing. Here, we attest a chemically inert black silicon (b-Si) substrate consisting of randomly-arranged spiky Mie resonators for a true non-invasive (chemically non-perturbing) SERS identification of the molecular fingerprints at low concentrations. Based on the comparative in situ SERS tracking of the para-aminothiophenol (PATP)-to-4,4' dimercaptoazobenzene (DMAB) catalytic conversion on the bare and metal-coated b Si, we justify the applicability of the metal-free b-Si for ultra-sensitive non invasive SERS detection at a concentration level as low as 10-6 M. We performed supporting finite-difference time-domain (FDTD) calculations to reveal the electromagnetic enhancement provided by an isolated spiky Si resonator in the visible spectral range. Additional comparative SERS studies of the PATP-to-DMAB conversion performed with a chemically active bare black copper oxide (b-CuO) substrate as well as SERS detection of the slow daylight-driven PATP-to-DMAB catalytic conversion in the aqueous methanol solution loaded with colloidal silver nanoparticles (Ag NPs) confirm the non-invasive SERS performance of the all-dielectric crystalline b-Si substrate. A proposed SERS substrate can be fabricated using the easy-to-implement scalable technology of plasma etching amenable on substrate areas over 10 * 10 cm2 making such inexpensive all dielectric substrates promising for routine SERS applications, where the non invasiveness is of high importance. PMID- 29767211 TI - At the Vatican, Physicians Debate Euthanasia and Assisted Suicide. PMID- 29767212 TI - Commentary on "At the Vatican, Physicians Debate Euthanasia and Assisted Suicide". PMID- 29767213 TI - Teaching Medical Educators How to Teach Communication Skills: More than a Decade of Experience. AB - OBJECTIVES: Although opportunities exist for medical educators to gain additional training in teaching, literature that describes how to teach educators to teach communication skills to trainees is limited. The authors developed and evaluated a faculty development course that uses didactics, demonstration, drills, and role play in a small-group format. METHODS: The course has been offered through the Institute for Clinical Research Education at the University of Pittsburgh for almost 15 years. Course effectiveness was evaluated with a survey of 62 clinicians who completed the course between 2003 and 2012. RESULTS: The response rate was 85%. A total of 98% would recommend the course to a colleague and 98% indicated the course was effective at developing teaching techniques. Their use of standardized patients, teaching in small groups, and role-play increased as a result of participation in the course. A total of 70% went on to formally teach communication skills at various medical education levels. CONCLUSIONS: This structured course effectively taught participants how to teach patient-doctor communication in both classroom and clinical settings. The majority put these techniques to use in formal settings. This course also provided educators with the skills necessary to meet the growing needs of training programs charged with teaching the next generation of providers to effectively communicate with patients. The description presented can serve as a framework for faculty development in teaching communication. PMID- 29767214 TI - Commentary on "Teaching Medical Educators How to Teach Communication Skills: More than a Decade of Experience". PMID- 29767215 TI - And Now, Please Sign on the Dotted Line: Teaching Residents About Professional Life After Residency. AB - OBJECTIVES: Despite possible long-term repercussions, few training programs teach their residents about the business of medicine. In particular, certain contractual issues can adversely affect a young physician's career mobility. METHODS: We designed a business-of-medicine curriculum and used a survey to determine whether the curriculum satisfied attendees' perceived knowledge gaps about the topics covered in the course, which included four key contractual matters: physician employment contracts (including restrictive covenants), malpractice insurance, job search, and interviewing skills. We used a postsurvey in 2015 and added a presurvey for the course in 2016. The same content was delivered in a 1-hour conference to internal medicine residents attending a regular noon conference series in 2015 and a regional academic meeting in 2016. Survey data are presented in terms of descriptive statistics. We used chi2 tests for comparisons of pre- and post-Likert scale survey data. RESULTS: Of 108 residents, 50 returned the surveys for an overall response rate of 46% across the 2 years of the course. Overwhelmingly, residents found the conference to be beneficial to the understanding of the four key contractual matters, with each topic having a statistically significant difference in perceived knowledge between the pre- and postconference questionnaires (P < 0.001). The majority of the residents indicated that they wanted to learn more about business-of-medicine topics, in particular financial challenges (76%) and job opportunities (68%). CONCLUSIONS: Our results confirm that our curriculum is effective in increasing the residents' perceived understanding of restrictive covenants, malpractice insurance, negotiating skills, and job search. Our results also demonstrate that residents have a desire to learn more about job searches; negotiating skills; and contractual issues, including restrictive covenants and malpractice insurance. PMID- 29767216 TI - Commentary on "And Now, Please Sign on the Dotted Line: Teaching Residents About Professional Life After Residency". PMID- 29767217 TI - Assessing Mentorship Experiences of Faculty at a Military Academic Center: Challenge and Opportunity. AB - OBJECTIVES: Mentor relationships are a key component of professional development within academic medicine. To date, there are no investigations into the prevalence and effects of mentor relationships within military academic medicine. This quality improvement initiative aimed to establish the prevalence and effects of mentorship, including whether sex differences exist among faculty at a military academic center, the San Antonio Uniformed Services Health Education Consortium, and identify opportunities to improve faculty development efforts for mentorship to benefit faculty at this institution. METHODS: A 17-item survey was developed using an iterative process. Using the SurveyMonkey platform, the survey was distributed to each faculty member within the 33 Accreditation Council for Graduate Medical Education-accredited programs. RESULTS: A total of 104 responses (26%) were received from 393 total faculty members, including 48 Air Force, 45 Army, 3 Navy, and 8 Contractor/Government Service respondents. Thirty-four respondents were women (33%) and 70 were men (67%). Only 42% of faculty reported currently having a mentor. Thirty-nine respondents (38%; 44% men and 27% women) received formal mentorship at their first staff physician position after residency training. Mentorship helped respondents the most in the areas of clinical skills, understanding departmental/institutional culture, professionalism/officership, academic promotion/advancement, and clarification of priorities/goals. When asked whether more effective mentorship would affect their own decision to remain on active-duty military service, 14% responded "yes" and 28% responded "possibly." CONCLUSIONS: Increased mentorship has the potential to positively affect career development in military academic military medicine. Results from this study affirm previous reports that effective mentorship potentially represents a powerful tool for faculty retention. Future study should include other military medical academic centers to assess the generalizability of these results across US military medicine. PMID- 29767218 TI - Management of Emotionally Challenging Responses of Hospitalized Patients with Cancer. AB - Cancer is the second leading cause of death in the United States, and the majority of hospital admissions of patients with cancer occur because of uncontrolled, urgent symptoms. In addition to complex physical presentations, these patients often manifest a number of complex emotional and psychological responses resulting in a unique set of healthcare needs and expectations. Inpatient generalists or hospitalists frequently serve as the primary providers of medical care for these patients. Formal training for nononcologists on effective communication strategies in managing patients with cancer in a hospital setting may not fully prepare generalists for challenging patient encounters, however. This review assists generalists in approaching emotionally charged encounters when caring for patients with cancer on the wards. We explore patient factors that negatively affect successful communication, some of which can be addressed through a multidisciplinary approach. In addition, we present a checklist of preventive strategies in addressing emotionally charged patient responses and offer a number of preventive and restorative management approaches for dealing with such encounters. We provide a practical framework for recognition and management of the psychosocial and emotional challenges in the care of hospitalized patients with cancer. PMID- 29767219 TI - Alabama Children's Body Mass Index, Nutritional Attitudes, and Food Consumption: An Exploratory Analysis. AB - OBJECTIVES: This study had three aims: assess the extent to which middle school children in southern Alabama were classified as overweight or obese; determine the magnitude of the relation between children's attitudes toward healthy eating and their actual dietary choices; and examine the role of race, sex, and ZIP codes on children's eating attitudes and behaviors. METHODS: Registered dietitians took height and weight measurements of middle school children in southern Alabama to establish body mass index (BMI). Children were given a Likert type survey with multiple-choice items to assess the study's objectives. Descriptive statistics were generated, and structural equation modeling was used to examine potential moderating effects on the associations between a latent variable of healthy eating attitudes and a latent variable of healthy eating behaviors across race and ethnicity. A series of analyses of variance was used to determine any significant differences in the children's attitudes across schools. The chi2 tests were used to examine potential race differences in BMI. RESULTS: A total of 630 children participated in the study. Their average age was 12 years. More than half (53%) of the children were girls, and more than half (61%) were White. Approximately one-third (29%) identified as Black/African America. A large proportion of children across the sample (42.3%) were classified as overweight or obese. The multigroup structural equation modeling yielded a significant direct path between healthy attitudes and healthy eating behaviors. Healthy eating attitudes strongly predicted intentions toward healthy eating behaviors for children classified as normal weight and for those children classified as overweight or obese. Children's BMI classifications did not differ significantly across schools, race, or sex. CONCLUSIONS: A large percentage of children in south Alabama were classified as overweight or obese, conditions that are preventable. Moreover, evidence suggests a lack of nutritious food in their diets. Children overall endorsed healthy eating attitudes, and those attitudes were strongly related to healthy food choices; however, their level of healthy food consumption was not related to their BMI classification. Although children in this study were from three schools and represented a variety of racial, sex, and socioeconomic systems, there were more similarities than differences in their healthy eating attitudes or behavior. These similarities highlight the need for research to examine other factors, such as southern culture, as a potential contributor to childhood obesity. PMID- 29767220 TI - Patients' Perceptions of Bedside Rounding. AB - OBJECTIVES: Concerns regarding lack of privacy, poor patient understanding, and physician discomfort have led to a decline in rounding at the bedside. Our project explored patient perceptions of the implementation and value of bedside rounding. METHODS: This mixed-methods study used semi-structured qualitative interviews and a five-item Likert survey, which included questions about patients' experiences with rounds, their comfort level with the rounding process, and their understanding of care after rounds. Interviews were analyzed using the constant comparative method and conducted until thematic saturation occurred. RESULTS: Patients described positive attributes of bedside rounds: meeting the medical team, helping teach the medical team, and understanding more about their illness. Although patients enjoyed undivided attention from physicians, distractions included too many participants in rounds, confusion about roles, and unclear expectations about the goal of rounds. Although physicians sought to use patient-centered language, 53% of patients stated that medical jargon was still used. Male patients reported a statistically significant improvement in their understanding about the plan for the day and borderline significance regarding knowing who was responsible for their care as compared with female patients. CONCLUSIONS: Well-conducted, patient-centered bedside rounds greatly enhance patient-physician rapport and foster patient understanding and satisfaction. PMID- 29767221 TI - Minimal Use of Opioids for Pain Relief in an Internal Medicine Department. AB - OBJECTIVES: The objective of the study was to determine if pain control was adequate despite our policy of limited opioid use. METHODS: In this observational cohort study, we reviewed 300 consecutive patient charts from an internal medicine department. We extracted demographic data, as well as the patients' primary diagnosis, pain on admission, daily pain evaluations (numerical rating score [NRS]), and treatment. Significant pain was defined as a score of >=3 on the NRS. We determined the incidence of pain and pain control and reviewed the charts of those with an NRS >=3 for >=3 days to determine the need for opioid therapy. RESULTS: Of 1692 total hospitalization days in the 300 consecutive patients with a median age of 80 years (1st-3rd quartiles, 65-87 years) there were 204 days with complaints of pain (12.1%) and 149 days (8.8%) with reports of pain of >=3 on the NRS. Overall, 28.3% (85 of 300) of the patients had significant pain during their hospitalization. Most of the pain, however, (80.0%, 68 of 85) was short-term (1-2 days) whether or not the patient received pain medication. Pain relief treatment in the hospital included opioids in 17 (5.7%, 95% confidence interval [CI] 3.5-8.9) and dipyrone in 36 (12%, 95% CI 8.8-16) of the 300 patients. Pain control was adequate in the seven patients with prolonged pain who did not receive opioids. There were only two patients discharged with prescriptions for opioids (0.7%, 95% CI 0.2-2.6). CONCLUSIONS: Significant pain is common in patients hospitalized in an internal medicine department, but the pain is mostly short term and pain control is adequate despite the restricted use of opioid therapy during hospitalization. PMID- 29767222 TI - Mortality in Asthma-Chronic Obstructive Pulmonary Disease Overlap in the United States. AB - OBJECTIVES: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is recognized increasingly as a distinct clinical entity and is associated with higher comorbidities compared with patients with asthma and COPD alone. Little is known about the leading causes of death related to ACO in the US general population, however. Our aim was to define the causes of mortality among patients with ACO compared with asthma and COPD in the US population. METHODS: We examined questions using the National Health and Nutrition Examination Survey III database linked to the National Death Index. The data from 4434 participants were stratified into 4 groups, those with asthma, COPD, ACO, and those without any obstructive lung disease. We examined baseline demographics and used multivariate logistic regression to model the impact of demographics, smoking, and self reported, physician-diagnosed lung disease on mortality generating odds ratios (ORs) and confidence intervals (CIs). RESULTS: Among 4434 participants, 120 (2.7%), 340 (7.6%), and 126 (2.8%) participants self-reported diagnoses of asthma, COPD, and ACO syndrome, respectively. Patients with COPD were older (69.7 +/- 10.9 years) than other groups. Cardiovascular disease, malignancy, and chronic lower respiratory disease were frequent causes of death. The mortality rates for cardiovascular disease and malignancy were not significantly different among respiratory disease categories. Deaths resulting from chronic respiratory disease were higher in the ACO group (OR 4.9, 95% CI 2.5-9.4) and the COPD group (OR 2.9, 95% CI 1.5-5.4) when compared with those without obstructive lung disease (P < 0.0001). CONCLUSIONS: Although cardiovascular- and malignancy related deaths are common, a higher proportion of mortality in ACO and COPD is attributed to chronic lung disease. PMID- 29767223 TI - Evaluation of Renal Function Estimation Formulas Specific to Dynamic Renal Function for Drug Dosing in Critically Ill Patients. AB - OBJECTIVES: The study compared estimated creatinine clearance (eCrCl) between the Cockcroft-Gault (CG) equation and the Jelliffe, Chiou, and Brater equations designed for estimation in dynamic renal function and resulting antimicrobial dosing concordance of five antimicrobials (cefepime, meropenem, piperacillin/tazobactam, vancomycin, and fluconazole) commonly used in the intensive care unit (ICU). METHODS: Electronic medical records were used to identify the target patient population. Analysis of variance tests with repeated measures were performed to compare eCrCl. Bowker's tests of symmetry were applied to compare the dosing regimen discordance between CG and candidate equations. RESULTS: From January 1, 2008 through December 31, 2012, we identified 387 patients with acute kidney injury (AKI), among whom 62% (n = 240) were older adults (65 years and older) and 46% (n = 178) were obese (body mass index >=30). In the declining phase of renal function, eCrCl means were different between the CG and Brater equations (32.0 vs 26.1 mL/min, P < 0.001). The dosing regimen discordance rates (CG vs candidate equations) in declining renal function varied from 19.3% to 25% and were statistically significant for cefepime and meropenem (P < 0.001) based on Food and Drug Administration recommendations for dose adjustment. In the improving phase, eCrCl means were different (P < 0.001) between CG (43.0 mL/min) and candidate formulas (Brater 47.9, Chiou 31.7, and Jelliffe 55.3 mL/min). The dosing regimen discordance rates (CG vs candidate equations) in the improving phase varied from 8.3% to 39% and were statistically significant for all 5 antimicrobials (P < 0.001). CONCLUSIONS: Differences in eCrCl between CG and candidate formulas were observed in surgical ICU patients with acute kidney injury. Discordant dosing recommendations may affect antimicrobial regimens in ICU patients with dynamic renal function. PMID- 29767225 TI - Effect of balance training on falls in patients with osteoporosis: A systematic review and meta-analysis. AB - BACKGROUND: Balance training may be beneficial for patients with osteoporosis, although current results are inconclusive. The aim of this systematic review and meta-analysis was to explore the effect of balance training on falls in patients with osteoporosis. METHODS: PubMed, Embase, Web of Science, EBSCO, and Cochrane Library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of balance training vs usual activities on falls in patients with osteoporosis were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. The primary outcome was fall frequency. This meta-analysis was performed using the fixed- or random-effect model when appropriate. RESULTS: Six RCTs were included in the systematic review and 3 in the meta-analyses. Compared with control groups, a balance training intervention was found to significantly reduce the frequency of falls (risk ratio = 0.63; 95% confidence interval (95% CI) 0.42 0.95; p = 0.03) in patients with osteoporosis, but demonstrated no remarkable influence on the results of the Berg Balance Scale (mean difference -3.66; 95% CI -12.04-4.72; p = 0.39) and Timed Up and Go test (mean difference -1.79; 95% CI 6.05-2.47; p = 0.41). CONCLUSION: Balance training may significantly reduce the frequency of falls in patients with osteoporosis. PMID- 29767224 TI - Innovative Technique for Endoscopic Placement of Sengstaken-Blakemore Tube. AB - OBJECTIVES: The Sengstaken-Blakemore (SB) tube is used in cases of uncontrolled variceal bleeding. Because of the complexity of the procedure and the lack of visualization, various techniques have been described to avoid blind placement. We report an innovative and simple technique for placement of the SB tube under direct endoscopic visualization. METHODS: A grasp-and-place technique for endoscopic placement of SB tubes is described and a retrospective cohort study chart review of endoscopies done for variceal bleeding in our medical center is reported. All patients with uncontrolled variceal bleeding who required placement of an SB tube from July 1, 2013 through December 31, 2015 were included. The primary outcome analyses were technical success of tube placement and achievement of hemostasis. RESULTS: Of 143 endoscopies done for variceal bleeding, 10 were managed with SB tubes placed endoscopically after initial endoscopic therapy was unsuccessful. Successful placement of the tube was achieved in all of the patients. Hemostasis was achieved in 9 of the 10 patients. CONCLUSIONS: We propose a new grasp-and-place technique for endoscopic placement of SB tubes. Review of our experience shows that massive variceal bleeding can be managed effectively with this technique. PMID- 29767226 TI - Evaluation of the wear-and-tear scale for therapeutic footwear, results of a generalizability study. AB - OBJECTIVE: Therapeutic footwear is often prescribed at considerable cost. Foot care specialists normally assess the wear-and-tear of therapeutic footwear in order to monitor the adequacy of the prescribed footwear and to gain an indicator of its use. We developed a simple, rapid, easily applicable indicator of wear-and tear of therapeutic footwear: the wear-and-tear scale. The aim of this study was to investigate the intra- and inter-rater reliability of the wear-and-tear scale. METHODS: A test set of 100 therapeutic shoes was assembled; 24 raters (6 inexperienced and 6 experienced physiatrists, and 6 inexperienced and 6 experienced orthopaedic shoe technicians) rated the degree of wear-and-tear of the shoes on the scale (range 0-100) twice on 1 day with a 4-h interval (short term) and twice over a 4-week interval (long-term). Generalizability theory was applied for the analysis. RESULTS: Short-term, long-term and overall intra-rater reliability was excellent (coefficients 0.99, 0.99 and 0.98; standard error of measurement (SEM) 2.6, 2.9 and 3.9; smallest detectable changes (SDC) 7.3, 8.0 and 10.8, respectively). Inter-rater reliability between professions, experience and inexperienced raters, and overall was excellent (coefficients 0.97, 0.98 and 0.93; SEM 4.9, 4.5, and 8.1; SDC 13.7, 12.4 and 22.5, respectively). CONCLUSION: The wear-and-tear scale has excellent intra-rater, inter-rater, and overall reliability. PMID- 29767227 TI - Effect of a balance-training programme on postural balance, aerobic capacity and frequency of falls in women with osteoporosis: A randomized controlled trial. AB - OBJECTIVE: To investigate the effect of a 12-month complex balance-training programme on static and dynamic postural balance, aerobic capacity and frequency of falls in women with established osteoporosis. DESIGN: Randomized controlled trial in which the intervention group was assigned a 12-month exercise programme (3 times a week for 30 min) and the control group had no intervention. SUBJECTS: A total of 100 osteoporotic women with at least one previous fracture. METHODS: Performance-based Timed Up and Go (TUG), Berg Balance Scale (BBS) and stabilometric platform tests were used to evaluate balance. Aerobic capacity was measured by bicycle ergometry. Frequency of falls was assessed using a falls diary. RESULTS: After 1 year, there was a statistically significant difference between the improvement achieved in the intervention and control groups on the performance-based TUG, BBS and stabilometric platform tests (p < 0.05). Mean metabolic equivalent (MET) value decreased in the intervention group, from 4.91 to 3.82 (a significant difference from the change achieved in the control group; p = 0.05). Relative risk of falls was 0.534 at 1 year (p = 0.17). CONCLUSION: The 12-month balance-training programme significantly improved postural balance and increased aerobic capacity in women with established osteoporosis. PMID- 29767228 TI - Whiplash injury results in sustained impairments of cervical muscle function: A one-year prospective, controlled study. AB - OBJECTIVE: To investigate the temporal development of neck muscle function following whiplash injuries. DESIGN: A 1-year prospective, controlled observational study. SUBJECTS: A total of 141 individuals exposed to whiplash injury due to rear-end vehicle collisions and 40 age- and sex-matched controls with acute ankle distortion. METHODS: Neck muscle strength and endurance during cervical flexion and extension were measured at 1 week, 1 month, 3 months, 6 months and 1 year after injury. RESULTS: Notable reductions (23-30%) of neck strength in both directions were seen for whiplash-exposed subjects at all time points, compared with controls. Also, extensor endurance was reduced at 1 week, 1 month, 3 months, 6 months* and 1 year* (*non-significant). Within the whiplash group, non-recovered individuals (individuals who had not returned to pre-injury work capacity at one year) displayed ~50% reductions in cervical strength in both directions at all time points, compared with recovered whiplash individuals. CONCLUSION: Cervical muscular functioning is impaired for at least one year after whiplash injury, well beyond the time course of recovery of neck mobility and pain sensations. In whiplash-exposed individuals, non-recovery is associated with considerable muscular weakness. There is a need for increased clinical focus on early neck function after whiplash injury. PMID- 29767229 TI - Usability of World Health Organization Disability Assessment Schedule in chronic traumatic brain injury. AB - OBJECTIVES: To investigate functioning measured with the 12-item World Health Organization Disability Assessment Schedule (WHODAS 2.0) in patients with mild, moderate and severe traumatic brain injury, and to compare patients' experiences with assessments made by their significant others and by consultant neurologists. METHODS: A total of 112 consecutive patients with traumatic brain injury (29 mild, 43 moderate, 40 severe) and their significant others completed a 12-item WHODAS 2.0 survey. A neurologist assessed functioning with the International Classification of Functioning, Disability and Health minimal generic set. RESULTS: The total patient and proxy WHODAS 2.0 sum score was rated as severe, and impairments in household tasks, learning, community life, emotional functions, concentrating, dealing with strangers, maintaining friendships, and working ability as around moderate in all 3 severity groups. In standing, walking, washing, and dressing oneself the reported impairments increased from mild in mild traumatic brain injury to moderate in severe traumatic brain injury. A neurologist rated the overall functioning, working ability, and motor activities most impaired in severe traumatic brain injury, while there were no between-group differences in energy and drive functions and emotional functions. CONCLUSION: Patients with chronic traumatic brain injury perceive a diversity of significant difficulties in activities and participation irrespective of the severity of the injury. We recommend assessing disability in traumatic brain injury with the short and understandable WHODAS 2.0 scale, when planning client oriented services. PMID- 29767230 TI - Competing endogenous RNA regulatory network in papillary thyroid carcinoma. AB - The present study aimed to screen all types of RNAs involved in the development of papillary thyroid carcinoma (PTC). RNA-sequencing data of PTC and normal samples were used for screening differentially expressed (DE) microRNAs (DE miRNAs), long non-coding RNAs (DE-lncRNAs) and genes (DEGs). Subsequently, lncRNA miRNA, miRNA-gene (that is, miRNA-mRNA) and gene-gene interaction pairs were extracted and used to construct regulatory networks. Feature genes in the miRNA mRNA network were identified by topological analysis and recursive feature elimination analysis. A support vector machine (SVM) classifier was built using 15 feature genes, and its classification effect was validated using two microarray data sets that were downloaded from the Gene Expression Omnibus (GEO) database. In addition, Gene Ontology function and Kyoto Encyclopedia Genes and Genomes pathway enrichment analyses were conducted for genes identified in the ceRNA network. A total of 506 samples, including 447 tumor samples and 59 normal samples, were obtained from The Cancer Genome Atlas (TCGA); 16 DE-lncRNAs, 917 DEGs and 30 DE-miRNAs were screened. The miRNA-mRNA regulatory network comprised 353 nodes and 577 interactions. From these data, 15 feature genes with high predictive precision (>95%) were extracted from the network and were used to form an SVM classifier with an accuracy of 96.05% (486/506) for PTC samples downloaded from TCGA, and accuracies of 96.81 and 98.46% for GEO downloaded data sets. The ceRNA regulatory network comprised 596 lines (or interactions) and 365 nodes. Genes in the ceRNA network were significantly enriched in 'neuron development', 'differentiation', 'neuroactive ligand-receptor interaction', 'metabolism of xenobiotics by cytochrome P450', 'drug metabolism' and 'cytokine-cytokine receptor interaction' pathways. Hox transcript antisense RNA, miRNA-206 and kallikrein-related peptidase 10 were nodes in the ceRNA regulatory network of the selected feature gene, and they may serve import roles in the development of PTC. PMID- 29767232 TI - Free-floating cancer cells in lymph node sinuses of hilar lymph node-positive patients with non-small cell lung cancer. AB - Previous studies demonstrated that free-floating cancer cells (FFCCs) in the lymph node sinuses were of prognostic significance for colorectal and gastric cancer. The present study investigated the clinical significance of detecting FFCCs using Fast Red staining for cytokeratin in stage I/II non-small cell lung cancer (NSCLC) patients and hilar lymph node positive NSCLC patients who underwent curative resection. Between 2002 and 2011, a total of 164 patients (including 22 hilar lymph node positive patients) were investigated. Resected lymph nodes were stained for cytokeratin using an anti-cytokeratin antibody. In order to achieve a clear distinction from coal dust, an anti-cytokeratin antibody was labeled with a secondary antibody conjugated with alkaline phosphatase, which was detected by a reaction with Fast Red/naphthol that produced a red color. Patients were considered to be positive for FFCCs (FFCCs+) if one or more than one free-floating cytokeratin-positive cell was detected in the lymph node sinuses, which could not be detected by hematoxylin and eosin staining. Among all 164 patients, a significant difference was observed in 5-year relapse-free survival (5Y-RFS) rates, with 76.9 and 33.3% being achieved by FFCCs- and FFCCs+ patients, respectively (P<0.001). Similarly, the 5-year overall survival (5Y-OS) rate was significantly lower in FFCCs+ patients, with 86.6% being achieved by FFCCs- and 65.8% by FFCCs+ patients, respectively (P=0.014). Among 22 hilar lymph node-positive patients, a significant difference was also observed in 5Y-RFS, with 53.8 and 0.0% being achieved by FFCCs- and FFCCs+ patients, respectively (P=0.006). The 5Y-OS tended to be lower in FFCCs+ patients, with 69.2 and 53.3% being achieved by FFCCs- and FFCCs+ patients, respectively (P=0.463). The findings of the present study suggested the presence of FFCCs in stage I/II NSCLC patients was associated with a poor prognosis. In addition, FFCCs in hilar lymph node-positive patients may potential be a useful marker in foreseeing the recurrence of cancer. PMID- 29767231 TI - Bidirectional modulation of insulin action by reactive oxygen species in 3T3-L1 adipocytes. AB - Reactive oxygen species (ROS) serve an important role in glucose-lipid metabolic regulation. In the present study, the results demonstrated that there was bidirectional regulation of insulin action in 3T3-L1 adipocytes treated with ROS. Transient and acute ROS exposure improved insulin-induced metabolic effects in 3T3-L1 adipocytes. Hydrogen peroxide (H2O2), as a stable and diffusible ROS, diffused into adipocytes and altered intracellular redox homeostasis, resulting in oxidation and inactivation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Inactivation of PTEN enhanced the activation of insulin induced protein kinase B (AKT), leading to increased glucose transporter 4 (GLUT4) redistribution and glucose uptake in 3T3-L1 adipocytes. However, chronic ROS treatment induced insulin resistance in 3T3-L1 adipocytes. It was also revealed that insulin-induced AKT activation, GLUT4 translocation to cell membrane and glucose uptake were significantly inhibited in chronic ROS-treated 3T3-L1 adipocytes. Taken together, the present study provided further demonstration that transient ROS treatment improved insulin sensitivity; however, chronic ROS exposure induced insulin resistance in 3T3-L1 adipocytes. PMID- 29767233 TI - Potential role of cyclin F mRNA expression in the survival of skin melanoma patients: Comprehensive analysis of the pathways altered due to cyclin F upregulation. AB - Cyclin F is a part of the Skp, Cullin, F-box containing ligase complex. The activity of cyclin F includes cell cycle control, centrosome duplication and response to DNA damage. The cyclin F expression pattern is very similar to cyclin A, but cyclin F is an orphan cyclin without its cyclin-dependent kinase partner. There is little evidence concerning the role of cyclin F in cancer. In the present study, for the first time, we present analysis from The Cancer Genome Atlas (TCGA) data in the context of expression of cyclin F mRNA in melanoma patients. Our original in silico analysis, not published elsewhere before, revealed that high expression of cyclin F in melanoma patients is associated with worse overall survival. Cyclin F and ribonucleotide reductase family member 2 (RRM2) compose a functional axis responsible for nucleotide metabolism. Impairment in this pathway may contribute to increased DNA damage repair and drug resistance. Additionally, we analyzed the expression of RRM2 mRNA and discovered that high expression of RRM2 is associated with worse overall survival. To shed more light on cyclin F overexpression in melanoma, we analyzed all protein data available in the TCGA melanoma dataset. It was found that in patients with upregulated cyclin F mRNA, we noted increased activity of pathways related to cell cycle and DNA damage repair. These data will support further in vitro and in vivo studies on the involvement of cyclin F in skin cutaneous melanoma. PMID- 29767235 TI - Inhibition of microRNA-16 protects mesenchymal stem cells against apoptosis. AB - Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been used in experimental research and clinical trials for heart function restoration and cardiomyocyte regeneration. However, due to a hostile microenvironment created by ischemia, hypoxia and pro-inflammatory factors, the survival rate of implanted BM MSCs remains low. Therefore, strategies that can promote BM-MSC survival and prevent apoptosis are required. Previous studies have reported that microRNA-16 (miR-16) can inhibit cell proliferation by targeting several proteins and signal pathway, not only by inducing apoptosis. In the present study, it was investigated whether inhibition of miR-16 reduced BM-MSC apoptosis in a model of ischemia. Flow cytometry analysis revealed that BM-MSCs underwent apoptosis in response to hypoxia/serum deprivation (SD). Additionally, in hypoxic/SD conditions, miR-16 expression increased and B-cell lymphoma (Bcl)-2 protein expression decreased in BM-MSCs. miR-16 did not affect Bcl-2 mRNA expression but downregulated Bcl-2 protein expression. miR-16 inhibitor transfection significantly increased Bcl-2 protein expression and the percentage of apoptotic BM-MSCs was reduced. The pro-apoptotic effects of miR-16 were partially elevated by knocking down of Bcl-2. Furthermore, it was demonstrated that miR-16 exerted its pro-apoptotic effects by activating the mitochondrial pathway of apoptosis via apoptotic protease activating factor-1/caspase-9/poly (ADP ribose) polymerase. Taken together, the results indicated that miR-16 downregulated Bcl-2 expression and promoted BM-MSC apoptosis, indicating that therapies targeting miR 16 may improve the effectiveness of BM-MSC transplantation therapy. PMID- 29767236 TI - Fenretinide inhibits the proliferation and migration of human liver cancer HepG2 cells by downregulating the activation of myosin light chain kinase through the p38-MAPK signaling pathway. AB - N-(4-hydroxyphenyl)retinamide (4-HPR or fenretinide), which is a synthetic analog of all-trans retinoic acid (ATRA), effectively inhibits the growth of several types of tumor cells; however, its molecular mechanism remains unclear. We found that 4-HPR altered the morphology of human liver cancer HepG2 cells and also inhibited their proliferation and suppressed the colony formation in a dose- and time-dependent manner. A wound healing assay revealed that 4-HPR significantly hindered HepG2 cell migration, and that this was accompanied by the phosphorylation of p38-MAPK (mitogen-activated protein kinase). Mechanistically, the MAPK-specific inhibitor SB203580 attenuated the inhibitory effects of 4-HPR on the migration of HepG2 cells. Moreover, we also observed that 4-HPR inhibited the activation and expression of myosin light chain kinase (MLCK) in HepG2 cells. Simultaneously, 4-HPR lowered the expression of F-actin and promoted the expression of E-cadherin. ML-7, a selective inhibitor of MLCK, significantly inhibited the migration of HepG2 cells while increasing the phosphorylation of p38-MAPK and the expression of E-cadherin, and decreasing the activation of MLCK and the expression of F-actin. In conclusion, 4-HPR inhibited the proliferation and migration of HepG2 cells, and p38-MAPK plays an important role in regulating these 4-HPR effects by reducing the activation of MLCK. The present study suggests that 4-HPR may be a potent antimetastatic agent. PMID- 29767234 TI - MicroRNA-125a-5p enhances the sensitivity of esophageal squamous cell carcinoma cells to cisplatin by suppressing the activation of the STAT3 signaling pathway. AB - Increasing evidence has demonstrated that microRNAs (miRNAs or miRs) play a variety of roles in tumor development, progression and chemosensitivity in a wide range of tumors. In this study, we found that miR-125a-5p exhibited a low expression in esophageal squamous cell carcinoma (ESCC) tissues and cells, and that its low expression was associated with higher tumor staging and shorter a survival time of patients with ESCC. Moreover, miR-125a-5p overexpression contributed to the suppression of cell proliferation, cell cycle arrest, cell apoptosis and a decrease in cell migratory and invasive abilities, whereas the downregulation of miR-125a-5p promoted cell proliferation, accelerated cell cycle progression, suppressed apoptosis and enhanced the migratory and invasive abilities of ESCC EC1 and TE1 cells, which may be tightly associated with the epithelial-mesenchymal transition (EMT) process in ESCC. Importantly, miR-125a-5p enhanced the cytotoxic effects of cisplatin on EC1 and TE1 cells, and co treatment with miR-125a-5p and cisplatin significantly induced cell apoptosis and reduced the cell migratory and invasive abilities of EC1 and TE1 cells, coupled with an increase in the E-cadherin level and a decrease in the N-cadherin and Vimentin levels. Most notably, signal transducer and activator of transcription-3 (STAT3) was found to be a direct target of miR-125a-5p in ESCC cells, and miR 125a-5p overexpression significantly reduced the protein levels of t-STAT3, p STAT3 and vascular endothelial growth factor (VEGF) in EC1 and TE1 cells. Furthermore, the combination of miR-125a-5p and cisplatin markedly inactivated the STAT3 signaling pathway; however, interleukin (IL)-6, a widely reported activator of the STAT3 signaling pathway, reversed the suppressive effects of miR 125a-5p/cisplatin in ESCC cells on the activation of the STAT3 signaling pathway. Of note, we found that IL-6 markedly reversed the altered cell phenotype mediated by the combination of miR-125a-5p and cisplatin in ESCC cells. These findings suggest that miR-125a-5p may play a pivotal role in the development and progression of ESCC, which may be achieved via the manipulation of the STAT3 signaling pathway. PMID- 29767237 TI - A novel anti-proliferative pentapeptide (ILYMP) isolated from Cyclina sinensis protein hydrolysate induces apoptosis of DU-145 prostate cancer cells. AB - Prostate cancer is the main causes of cancer associated mortality in men worldwide, cancer patients often suffer serious side effects when treated with chemotherapy or radiotherapy, therefore novel drugs are in high demand to treat prostate cancer. In the present study, a pentapeptide (Ile-Leu-Tyr-Met-Pro; ILYMP) with a molecular weight of 635.71 Da was isolated from the protein hydrolysate of Cyclina sinensis via ultrafiltration and chromatographic methods, and subsequently named Cyclina sinensis pentapeptide (CSP). The activity of CSP was first investigated in prostate cancer (PCa) DU-145 cells. CSP was demonstrated to significantly inhibit DU-145 cell proliferation at a half-maximal inhibitory concentration of 11.25 mM at a 72 h time interval. In addition, the results of acridine orange/ethidium bromide double staining, scanning electron microscopy and flow cytometry analyses suggested that CSP inhibited DU-145 cell proliferation via the induction of apoptosis. Following treatment with CSP, Bcl-2 associated X (Bax), cleaved caspase-3 and cleaved caspase-9 protein expression levels were enhanced in DU-145 cells; whereas B-cell lymphoma 2 expression was suppressed in DU-145 cells. In conclusion, to the best of the authors' knowledge, this is the first study to investigate the effects of an anti-proliferative peptide derived from Cyclina sinensis on DU-145 cells, and the results suggested that CSP may represent a therapeutic nutraceutical agent for the treatment of patients with PCa. PMID- 29767238 TI - Red mulberry fruit aqueous extract and silk proteins accelerate acute ethanol metabolism and promote the anti-oxidant enzyme systems in rats. AB - Red mulberry (Morus alba) fruit is rich in anthocyanins, and mulberry leaves are used by silk worms to make silk protein. We determined that the water and ethanol extract of mulberry fruit and silk amino acids accelerated ethanol degradation and suppressed temporal cognitive dysfunction in acute alcohol administered rats. The mechanism was explored in rats with acute oral administration of silk protein and mulberry fruit extracts. Rats were given 0.3 g of dextrin (control) and water extract (WMB) and ethanol extract of mulberry (EMB), silk protein hydrolysates (SKA), and a commercial product (positive-control) based on body weight. After 30 min, rats were administered 3 g ethanol/kg body weight and serum ethanol and acetaldehyde levels were measured. After 3 h movements were measured with a video tracking system and at 5 h cognitive function was measured by Y maze test. WMB contain much higher rutin, luteolin and quercetins than EMB. In SKA rats, serum alcohol concentrations slowly increased until 60 min, but were markedly elevated until 120 min. However, WMB rats exhibited rapidly increased serum alcohol levels until 60 min and showed the lowest peak of serum alcohol levels, indicating the highest degradation of alcohol. The patterns of serum acetaldehyde levels were similar to those of serum ethanol levels but WMB was more effective for reducing serum acetaldehyde levels than serum ethanol levels. WMB was most effective for increasing mRNA expression of alcohol dehydrogenase and acetaldehyde dehydrogenase. WMB and SKA decreased lipid peroxides by increasing activities of SOD and GSH-Px in the liver and they also reduced pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6. WMB and SKA exerted better anti oxidant effects than the positive-control. WMB containing higher flavonoids reduced pro-inflammatory cytokines better than SKA. In conclusions, both WMB and SKA might reduce acute alcohol-induced hangover and liver and brain damage by lowering serum alcohol and acetaldehyde levels. PMID- 29767239 TI - Time-dependent and independent effects of thyroid hormone administration following myocardial infarction in rats. AB - Cardiac function is reduced following myocardial infarction (MI) due to myocardial injury and alterations in the viable non-ischemic myocardium, a process known as cardiac remodeling. The current treatments available for patients with acute MI (AMI) reduce infarct size, preserve left ventricular (LV) function and improve survival; however, these treatments do not prevent remodeling, which can lead to heart failure. The aim of the present study was to investigate the effects of thyroid hormone (TH) treatment following MI in an in vivo rat model. A total of 199 rats were separated into 3 groups: Sham operated and 2 different coronary artery ligation (CAL) groups. Rats subjected to CAL were randomly divided into a further 2 groups 24 h following surgery. The first group received standard rat chow (designated the CAL group), while the second group received food containing 0.05% thyroid powder (designated the CALTH group). The mean daily intake of TH per rat was estimated at 3.0 ug T3 and 12 ug T4. Echocardiography was used to monitor the rats. Large-scale analysis confirmed the favorable effects of TH treatment following CAL on various parameters of cardiac function. TH treatment reduced LV dilation, and increased global and regional LV function. The development of cardiac hypertrophy was induced and, thus, wall stress was limited. Furthermore, TH treatment improved cardiac geometry, which manifested as an increased sphericity index. Myocardial function, as well as LV dilatation, following CAL and TH treatment was not closely associated with the extent of injury, indicating a novel therapeutic intervention that may alter the course of LV remodeling that typically leads to post-MI heart failure. Data modelling and regressions may be developed to enable the simulation of the pathophysiological processes that occur following MI, and to predict with accuracy the effects of novel or current treatments that act via the modulation of tissue injury, LV dilation, LV geometry and hypertrophy. PMID- 29767240 TI - Munc13-4 mediates human neutrophil elastase-induced airway mucin5AC hypersecretion by interacting with syntaxin2. AB - The overexpression and hypersecretion of mucus is a hallmark of chronic pulmonary inflammatory disease. Mucin5AC (MUC5AC) is a major component of airway gel forming mucin. Members of the Unc13 (Munc13) protein family act as important activators of granule exocytosis from various types of mammalian cells. The present study aimed to determine the role of Munc13 family proteins in MUC5AC secretion via an in vitro study with BEAS-2B and Calu-3 cell lines. Reverse transcription-quantitative polymerase chain reaction and western blotting indicated that stimulation of the cells with 100 nM human neutrophil elastase (hNE) for 1 h did not affect the expression of either unc13 homolog B (Munc13-2) or unc13 homolog D (Munc13-4), but immunofluorescence analysis demonstrated that hNE treatment was associated with the recruitment of Munc13-4 to the plasma membrane. Co-immunoprecipitation analysis indicated increased binding between Munc13-4 and syntaxin2 followingh NE stimulation; however, Munc13-2 formed a stable interaction with syntaxin2 with or without hNE stimulation. Subsequently, Munc13-2 and Munc13-4 expression levels were downregulated in BEAS-2B and Calu-3 cells using small interfering RNA (siRNA). ELISAs and immunofluorescence analysis were performed to assess MUC5AC secretion and intracellular retention, respectively. Munc13-2 siRNA transfection did not alter the expression levels of intracellular or secreted MUC5AC following hNE stimulation in either cell line; however, it increased the baseline intracellular levels of MUC5AC and decreased the amount of secreted MUC5AC. Conversely, Munc13-4 siRNA transfection increased the intracellular levels of MUC5AC and decreased the amount of secreted MUC5AC following hNE stimulation, but did not affect their baseline quantities. The results of the present study indicate that Munc13-2 may be an essential regulator of basal MUC5AC exocytosis, while Munc13-4 appears to be a Munc13 protein subtype that may to be sensitive to hNE stimulation during airway MUC5AC hypersecretion. PMID- 29767241 TI - Transcriptome sequencing analysis reveals the effect of combinative treatment with low-intensity pulsed ultrasound and magnesium ions on hFOB1.19 human osteoblast cells. AB - Biodegradable magnesium (Mg) materials are considered ideal as osteosynthesis implants. However, clinical application has proven complex. This is primarily associated with the issue of reducing the extent of implant degradation to a range acceptable for the human body, while simultaneously enhancing osteogenesis or osteoinduction. In the present study, a combination of Mg ions and low intensity pulsed ultrasound (LIPUS) treatment was applied in hFOB 1.19 human osteoblast cells as a potential strategy to resolve this issue. A total of 7,314 differentially expressed genes (DEGs) and 826 shared DEGs in hFOB1.19 osteoblast cells were identified by microarray analysis following treatment with Mg and/or LIPUS. Gene Ontology analysis demonstrated that among cells treated with a combination of Mg and LIPUS, DEGs were significantly enriched in various functional annotations, including 'wound healing', 'transforming growth factor beta receptor signaling pathway', 'transcription, DNA-templated', 'receptor complex', 'nucleus', 'SMAD protein complex', 'DNA binding', 'metal ion binding' and 'GTPase activator activity'. Notably, the transforming growth factor (TGF) beta, mitogen-activated protein kinase (MAPK) and tumor necrosis factor (TNF) signaling pathways were preferentially overrepresented in the Mg and LIPUS combination group, which was subsequently confirmed by reverse transcription quantitative polymerase chain reaction. Furthermore, genes involved in osteoblast mineralization promotion, including bone morphogenetic protein 6, noggin, bone morphogenetic protein receptor (BMPR)1A, BMPR2 and SMAD 5/8, were significantly upregulated following combination treatment compared with the control group. Genes involved in the promotion of migration, including c-Jun N-terminal kinase, doublecortin, paxillin and Jun proto-oncogene AP-1 transcription factor subunit, were also upregulated in the combination treatment group compared with the control group. The DEG data were supported by morphological observations of the osteoblasts using alizarin red S staining and wound healing assays, which indicated that Mg and LIPUS combinative treatment had a synergistic effect on osteoblast mineralization and migration. Additionally, the combined treatment significantly upregulated metal transporter genes associated with Mg entry, including ATPase Na+/K+-transporting subunit alpha1, cyclin and CBS domain divalent metal cation transport mediator 2, K+ voltage-gated channel subfamily J member 14, transient receptor potential cation channel (TRP) subfamily M member 7 and TRP subfamily V member 2. In summary, the findings of the present study revealed that combined stimulation with Mg and LIPUS may exhibit a synergistic effect on human osteoblast bone formation through the TGF-beta, MAPK and TNF signaling pathways, while also facilitating Mg influx. The present study demonstrated the potential of combinative LIPUS and Mg treatment as a novel therapeutic strategy for enhancing the osteoinduction, biocompatibility and biosafety of biodegradable Mg implants. PMID- 29767242 TI - In vivo antitumor activity of liposome-plasmid DNA encoding mutant survivin-T34A in cervical cancer. AB - The aim of the present study was to investigate the influence of liposome-plasmid encoding mutant survivin-T34A (PST34A) on tumor growth in cervical cancer in vivo. Liposome-plasmid DNA encoding mutant survivin-T34A was constructed and administered via an intraperitoneal injection in mice inoculated with cervical cancer cells. Following the establishment of the tumor model, the animals were randomly divided into four groups: i) The normal saline group (NS; 100 ul sterile saline once/3 days for 15 days); ii) the 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) control (100 ug DOTAP once/3 days for 15 days); iii) the plasmid PST34A (10 ug PST34A once/3 days for 15 days); and iv) the PST34A+DOTAP (10 ug PST34A+100 ug DOTAP once/3 days for 15 days). All treatments were administered via intraperitoneal injections. Tumor growth was evaluated following injection with liposome-plasmid DNA encoding mutant survivin-T34A. Apoptosis of cells in ascitic fluid was detected by flow cytometry. The expression of Ki67 and CD34 was detected by immunohistochemical staining. Administration of liposome-plasmid complexes encoding mutant survivin-T34A inhibited tumor growth, reduced the number of tumor nodules and the volume of ascitic fluid, and decreased abdomen circumference and tumor weight. The number of Ki67-positive cells was markedly reduced in the DOTAP+PST34A group compared with the remaining groups. Flow cytometry demonstrated that the number of cells in the sub-G1 phase (apoptosis) increased in the DOTAP+PST34A group compared with all other groups. In addition, tumors in the DOTAP+PST34A group exhibited lower microvessel density compared with all other groups. In the present study, liposome-plasmid DNA encoding mutant survivin-T34A could inhibit tumor growth of cervical cancer. This inhibition may be associated with an increase in the apoptosis rate of tumor cells and a reduction in angiogenesis. PMID- 29767243 TI - Inhibitory roles of miR-9 on papillary thyroid cancer through targeting BRAF. AB - MicroRNA-9 (miR-9) is reported to be underexpressed in papillary thyroid carcinoma (PTC) tissues; however, the molecular mechanisms underlying the implication of miR-9 in PTC have yet to be elucidated. The present study aimed to explore the potential roles of miR-9 in PTC. PTC tissue samples and paired non cancerous adjacent tissues were collected from 60 patients with PTC. The human TPC-1 thyroid gland papillary carcinoma cell line was used to investigate the molecular mechanisms underlying the roles of miR-9 in PTC. The levels of miR-9 and its downstream target gene BRAF were detected through reverse transcription quantitative polymerase chain reaction. MTT assay and flow cytometry were performed to evaluate cell viability and apoptosis, respectively. A mouse xenograft tumor model was established to observe the effects of miR-9 on thyroid gland tumorigenesis in vivo. The present study revealed that the expression of miR-9 was significantly reduced in PTC tissues compared with paired normal tissues. In addition, miR-9 upregulation suppressed the expression of BRAF in TPC 1 cells in vitro. Luciferase reporter assay demonstrated that BRAF may be a direct target gene of miR-9 in TPC-1 cells. In addition, following transfection with miR-9 mimics, the viability of TPC-1 cells was suppressed and their apoptosis was enhanced; conversely, transfection with miR-9 inhibitor exerted the opposite effects in vitro. miR-9 overexpression or downregulation also affected in vivo PTC tumorigenesis in athymic mice. The present findings suggested that miR-9 may suppress the viability of PTC cells and inhibit tumor growth through directly targeting the expression of BRAF in PTC. PMID- 29767245 TI - miR-142-5p regulates CD4+ T cells in human non-small cell lung cancer through PD L1 expression via the PTEN pathway. AB - The present study aimed to evaluate the function of microRNA (miR)-142-5p on cancer immunity to induce apoptosis in human non-small cell lung cancer (NSCLC) and its mechanism. miR-142-5p expression was upregulated, and CD4+ T cell levels were reduced in patients with NSCLC. Overexpression of miR-142-5p expression inhibited the cancer effects of CD4+ T cells on NSCLC cell lines, and downregulation of miR-142-5p increased the cancer effects of CD4+ T cells on NSCLC cell lines, compared with the control group. In addition, we found that overexpression of miR-142-5p suppressed PTEN protein expression and induced PI3K, p-Akt and PD-L1 protein expression in an in vitro model of NSCLC. Downregulation of miR-142-5p induced PTEN and PD-L1 protein expression and suppressed PI3K and p Akt and protein expression in an in vitro model of NSCLC. The suppression of PD L1 reduced the cancer effects of CD4+ T cells on NSCLC cell lines following miR 142-5p downregulation. The inhibition of PTEN also reduced the cancer effects of CD4+ T cells on NSCLC cell lines following miR-142-5p downregulation. Therefore, our study demonstrated that miR-142-5p regulated CD4+ T cells in human NSCLC through PD-L1 expression via the PTEN pathway. PMID- 29767244 TI - Propranolol induces hemangioma endothelial cell apoptosis via a p53-BAX mediated pathway. AB - The use of propranolol for the treatment of infantile hemangioma (IH) has been widely investigated in recent years. However, the underlying therapeutic mechanism of propranolol for the treatment of IH remains poorly understood. The aim of the present study was to investigate the expression of proteins regulated by cellular tumor antigen p53 (p53) in associated apoptosis pathways in IH endothelial cells (HemECs) treated with propranolol. Furthermore, the present study aimed to investigate the exact apoptotic pathway underlying the therapeutic effect of propranolol against IH. In the present study, HemECs were subcultured and investigated using an inverted phase contrast microscope, immunocytochemical staining and a scanning electron microscope (SEM). Experimental groups and blank control groups were prepared. All groups were subjected to drug treatment. A high p53 expression model of HemECs was successfully established via transfection, and a low p53 expression model of HemECs was established using pifithrin-alpha. The apoptosis rate of each group was determined using Annexin V-fluorescein isothiocyanate/propidium iodide double staining and flow cytometry. The expression levels of downstream proteins regulated by p53 [tumour necrosis factor receptor superfamily member 6 (FAS), p53-induced death domain-containing protein (PIDD), death receptor 5 (DR5), BH3-interacting domain death agonist (BID), apoptosis regulator BAX (BAX), p53 unregulated modulator of apoptosis (PUMA), phosphatidylinositol-glycan biosynthesis class S protein (PIGS), and insulin-like growth factor-binding protein 3 (IGF-BP3)] were revealed in the experimental and control groups via western blotting. Microscopic observation revealed the growth of an adherent monolayer of cells, which were closely packed and exhibited contact inhibition. Immunocytochemical staining demonstrated increased expression of clotting factor VIII. SEM analysis revealed presence of Weibel-Palade bodies. The results of the analyses verified that the cultured cells were HemECs. The staining of the samples resulted in a significantly increased rate of apoptosis in experimental groups compared with the blank control group. This result suggested that there is an association between p53 expression and the rate of apoptosis of propranolol-treated HemECs. The results of the western blot analysis demonstrated an upregulation of BAX expression and a downregulation of IGF-BP3 expression in the HemECs treated with propranolol. There were no significant differences in the expression levels of FAS, DR5, PIDD, BID, PUMA and PIGS between experimental and control groups. This result suggests that p53 has an important role in HemEC apoptosis. The results of the present study additionally suggest that the propranolol-induced HemEC apoptosis pathway is a mitochondrial apoptosis pathway and is regulated by p53-BAX signaling. PMID- 29767246 TI - DNAJC3 mutation in Thai familial type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2D) is a heterogeneous disease, with certain cases presenting an autosomal dominant type. The rare coding variants of disease causing genes in T2D remain mostly unclear. The present study aimed to identify the disease-causing gene conducting whole exome sequencing in a Thai T2D family with an autosomal dominant transmission of T2D with no evidence of mutations in known maturity-onset diabetes of the young (MODY) genes. Candidate variants were selected according to certain criteria of mutation prediction programs, followed by segregation analysis with diabetes in the family. The results demonstrated that, of the 68,817 variants obtained, 122 were considered as candidate variants subsequent to the filtering processes. Genotyping of these variants revealed that DnaJ homolog subfamily C member 3 (DNAJC3) p.H238N segregated with diabetes in the family. This mutation was also identified in another proband from the autosomal dominant T2D family without mutation in known MODY genes and was segregated with diabetes. This variant was also identified in 14/1,000 older onset T2D patients [minor allele frequency (MAF)=0.007], 2/500 non-diabetic controls (MAF=0.002) and 3 prediabetic individuals who were previously classified as non-diabetic controls. In silico mutagenesis and protein modeling of p.H238N revealed changes of the polar contacts across the tetratricopeptide repeat (TPR) motif and TPR subdomains, which may affect the protein tertiary structure. Furthermore, the expression of DNAJC3 H238N protein was 0.68+/-0.08 fold (P<0.05) lower when compared with that of the wild-type, possibly due to protein instability. Thus, DNAJC3 p.H238N is likely to be a variant causing diabetes. PMID- 29767247 TI - Comparison of the synergistic anticancer activity of AlPcS4 photodynamic therapy in combination with different low-dose chemotherapeutic agents on gastric cancer cells. AB - Limited cellular delivery and internalization efficiency of Al(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) induce poor penetration ability in cells and a slight photodynamic therapy (PDT) effect on gastric cancer. The combination treatment of AlPcS4/PDT with low-dose chemotherapeutic agents may provide a promising treatment strategy to increase the weak delivery efficiency of AlPcS4, reducing the dose of chemical agents without reducing efficacy, and improving apoptosis-inducing abilities, thereby increasing the antitumor effects and decreasing the noxious side effects on gastric cancer. We investigated and compared the synergistic antitumor growth effect on gastric cancer cells by combining AlPcS4/PDT treatment with different low-dose chemotherapeutic agents, namely, 5-fluorouracil (5-FU), doxorubicin (DOX), cisplatin (CDDP), mitomycin C (MMC), and vincristine (VCR). The inhibitory effect was increased in treatments that combined AlPcS4/PDT with all the aforementioned low-dose chemotherapeutic agents, to a different extent. An evident synergistic effect was obtained in the combination treatment of AlPcS4/PDT with low-dose 5 FU, DOX, and MMC by increasing AlPcS4 intracellular uptake ability, improving apoptosis-inducing abilities, and prolonging apoptosis-inducing time. The low dose chemotherapeutic agents prolonged the apoptosis-inducing period of AlPcS4/PDT, and AlPcS4/PDT quickly improved apoptosis-inducing abilities of chemotherapy even at low doses. Generally, the combination treatment of AlPcS4/PDT with low-dose chemotherapeutic agents had significant antitumor growth effects in addition to a low dark-cytotoxicity effect on gastric cancer, thereby representing an effective and feasible therapy method for gastric cancer. PMID- 29767248 TI - Combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib is effective in inhibiting the gastric cancer cells with ARID1A deficiency. AB - Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors. Herein, we evaluated the therapeutic role of the combined treatment of PI3K inhibitor BKM120 and PARP inhibitor olaparib on gastric cancer cells, and explored ARID1A as a predictive biomarker. The results demonstrated that combined treatment with PI3K and PARP inhibitors effectively inhibited proliferation detected by MTS and clonogenic assay, invasion and migration by Transwell assay, of gastric cancer cells with ARID1A deficiency. Mechanistically, dual blockade of PI3K and PARP in ARID1A-depleted gastric cancer cells significantly increased apoptosis detected by flow cytometry, and induced DNA damage by immunofluorescent staining. Taken together, these data suggest that the combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib may be a promising therapeutic regimen for the treatment of gastric cancer, and ARID1A deficiency could serve as a potential predictive therapeutic biomarker. PMID- 29767249 TI - TRIM27 functions as an oncogene by activating epithelial-mesenchymal transition and p-AKT in colorectal cancer. AB - Tripartite motif-containing 27 (TRIM27) belongs to the tripartite motif (TRIM) protein family and is involved in various malignant tumor processes. However, the function and mechanism of TRIM27 in colorectal cancer (CRC) remains to be elucidated. In the present study, the expression of TRIM27 was analyzed in CRC tissues and adjacent normal tissues by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. LoVo and HCT116 cell lines were then selected to further investigate the function of TRIM27 in the proliferation, invasion and metastasis of CRC in vitro and in vivo. Finally, the potential mechanism underlying the effects of TRIM27 in CRC was examined by western blotting. The results showed that TRIM27 was upregulated in CRC tissues, and the expression level of TRIM27 was significantly associated with tumor invasion, metastasis and prognosis. Following TRIM27 inhibition and overexpression in CRC cells, it was found that TRIM27 promoted cell proliferation, possibly via the inhibition of apoptosis and cell cycle regulation. TRIM27 also facilitated invasion and metastasis. Finally, it was observed that TRIM27 promoted epithelial-mesenchymal transition and activated phosphorylated AKT serine/threonine kinase in CRC cells. These results suggested that TRIM27 is an oncogenic protein in the progression of CRC, and may represent a novel target for CRC detection and therapy. PMID- 29767250 TI - Diosmetin suppresses human prostate cancer cell proliferation through the induction of apoptosis and cell cycle arrest. AB - Diosmetin, a plant flavonoid, has been shown to exert promising effects on prostate cancer cells as an anti-proliferative and anticancer agent. In this study, using western blot analysis for protein expression and flow cytometry for cell cycle analysis, we determined that the treatment of the LNCaP and PC-3 prostate cancer cells with diosmetin resulted in a marked decrease in cyclin D1, Cdk2 and Cdk4 expression levels (these proteins remain active in the G0-G1 phases of the cell cycle). These changes were accompanied by a decrease in c-Myc and Bcl 2 expression, and by an increase in Bax, p27Kip1 and FOXO3a protein expression, which suggests the potential modulatory effects of diosmetin on protein transcription. The treatment of prostate cancer cells with diosmetin set in motion an apoptotic machinery by inhibiting X-linked inhibitor of apoptosis (XIAP) and increasing cleaved PARP and cleaved caspase-3 expression levels. On the whole, the findings of this study provide an in-depth analysis of the molecular mechanisms responsible for the regulatory effects of diosmetin on key molecules that perturb the cell cycle to inhibit cell growth, and suggest that diosmetin may prove to be an effective anticancer agent for use in the treatment of prostate cancer in the future. PMID- 29767251 TI - Overexpression of PRDM13 inhibits glioma cells via Rho and GTP enzyme activation protein. AB - PR (PRDI-BFI and RIZ) domain containing (PRDM) proteins have been shown to be important in several types of human cancer. PRDM13, a member of the PRDM family, contains transcriptional regulators involved in modulating several cellular processes. However, the function of PRDM13 in glioma remains to be elucidated. The purpose of the present study was to evaluate the expression and effect of PRDM13 on glioma cells. It was found that the expression of PRDM13 was reduced in glioma cells, and the overexpression of PRDM13 significantly decreased the proliferation, migration and invasion of U87 glioma cells. Through validation of RNA-sequencing analysis, genes regulating cell proliferation and migration were classified from Gene Ontology sources. In addition, PRDM13 was shown to be associated with Rho protein and GTP enzyme activation protein. The over expression of PRDM13 upregulated deleted in liver cancer 1 (DLC1) to inhibit the proliferation and invasion of U87 cells. In conclusion, PRDM13 decreased the proliferation and invasion of U87 cells, and may be of potential value for glioma therapy. PMID- 29767253 TI - [Corrigendum] Inhibitory activity of apogossypol in human prostate cancer in vitro and in vivo. AB - An interested reader drew to the attention of the Editorial Board of Molecular Medicine Reports that certain data featured in the above paper had been published in 2014 in the same journal, in an article featuring several of the same authors [Zhang X, Hu X, Mu S, Zhan Y, An Q, Liu Z and Huang X: "Apogossypolone inhibits the proliferation of LNCaP cells in vitro and in vivo", Mol Med Rep 10: 1184 1194, 2014]. Specifically, data in Fig. 2A of the above paper (the Apogossypol, 15 umol/l data panel) had appeared in Fig. 3B, c in the 2014 paper. The authors responded to our original enquiry asking for an explanation concerning the data that had been shared between these papers, and confirmed that the inclusion of the same data in the two papers had occurred in error. Subsequently, they were able to identify the proper data for the affected figure of the above paper, and a corrected version of Fig. 2 is printed here. We apologize to the readership of the Journal for any inconvenience caused. [the original article was published in the Molecular Medicine Reports 11: 4142-4148, 2015; DOI: 10.3892/mmr.2015.3326]. PMID- 29767252 TI - Colony-stimulating factor-1 and colony-stimulating factor-1 receptor co expression is associated with disease progression in gastric cancer. AB - Colony-stimulating-factor-1 (CSF-1) is a hematopoietic growth factor that exerts its effects through the c-fms/CSF-1 receptor (CSF-1R). The CSF-1/CSF-1R axis is thought to be involved in the development of several types of cancer. This study aimed to clarify the clinical and biological significance of the CSF-1/CSF-1R axis in gastric cancer (GC). For this purpose, we evaluated CSF-1 and CSF-1R expression in GC tissues from 148 patients by RT-qPCR and immunohistochemistry. The biological roles of the CSF-1/CSF-1R axis were investigated by measuring the cell proliferation and migration, and anoikis resistance in a human GC cell line following treatment with recombinant human CSF-1 and/or CSF-1R inhibitor. The results revealed that an elevated expression of CSF-1 or CSF-1R significantly correlated with disease progression and with a poor overall survival (OS, P=0.037 and 0.016, respectively) and disease-free survival (DFS, P<0.001 and <0.001, respectively) of patients with GC. Furthermore, a high co-expression of CSF-1 and CSF-1R was an independent prognostic factor for OS (HR, 1.38; 95% CI, 1.02-1.88; P=0.038) and DFS (HR, 1.79; 95% CI, 1.21-2.67; P=0.004), and an independent risk factor for lymph node and peritoneal metastasis. Immunohistochemical analysis revealed an intense CSF-1/CSF-1R expression in the cytoplasm of cancer cells in primary GC tissues. CSF-1 or CSF-1R expression positively correlated with vascular endothelial growth factor A (VEGFA) or Fms related tyrosine kinase 1 (FLT1) expression in GC tissues. Treatment with recombinant human CSF-1 promoted proliferation, migration and anoikis resistance in a GC cell line. These effects were generally blocked by CSF-1R inhibition. On the whole, the findings of this study indicate that the CSF-1/CSF-1R axis may be a clinically useful prognostic and predictive biomarker for lymph node and peritoneal metastasis and a potential therapeutic target in GC. PMID- 29767254 TI - MicroRNA-433 reduces cell proliferation and invasion in non-small cell lung cancer via directly targeting E2F transcription factor 3. AB - MicroRNAs (miRNA/miRs) have been associated with the initiation and progression of non-small-cell lung cancer (NSCLC). Hence, a comprehensive understanding of the association between dysregulated miRNAs and NSCLC may contribute to the identification of novel therapeutic methods for patients with NSCLC. MiRNA-433 (miR-433) has been reported to be dysregulated in numerous types of human cancers; however, its expression pattern, biological roles and associated mechanisms in NSCLC require further investigation. The present study aimed to detect miR-433 expression and determine its roles and underlying molecular mechanisms in NSCLC. In the present study, reverse transcription-quantitative polymerase chain reaction revealed that miR-433 was significantly downregulated in NSCLC tissues and cell lines. This decreased miR-433 expression was strongly associated with the tumor node metastasis stage and lymph node metastasis of patients with NSCLC. Cell Counting kit-8 and cell invasion assays revealed that the resumption of miR-433 expression decreased the proliferation and invasion of NSCLC cells. Bioinformatics analysis predicted E2F transcription factor 3 (E2F3) as a potential target of miR-433. Luciferase reporter assay, RT-qPCR and western blot analysis further demonstrated that E2F3 was a direct target of miR-433 in NSCLC. E2F3 downregulation induced by small interfering RNA exhibited inhibitory effects similar to those of miR-433 overexpression in NSCLC cells, and the restored E2F3 expression counteracted the suppressive effects on NSCLC cells induced by miR-433 overexpression. Therefore, miR-433 may inhibit the progression of NSCLC, at least in part, by targeting E2F3. The present study indicated that miR-433 may be investigated as an innovative candidate target for the therapy of patients with this fatal disease. PMID- 29767256 TI - Umbilical cord-derived mesenchymal stem cells can inhibit the biological functions of melanoma A375 cells. AB - Tumor tropism is an important property of mesenchymal stem cells (MSCs) that has been used in tumor-targeting therapies. However, the effects of MSCs on tumors remain controversial. The aim of the present study was to investigate the effects of MSCs on A375 melanoma cells. Umbilical cord-derived mesenchymal stem cells (UCMSCs) were co-cultured with A375 cells. MTT and Transwell assays were used to assess cell proliferation and invasion, while flow cytometry was performed to detect the apoptosis and the cell cycle distribution of A375 cells. The expression levels of kinases were assayed by western blotting and fluorescence analysis was conducted to detect cytoskeletal rearrangement. The results clearly indicated that UCMSCs could inhibit the proliferation, induce apoptosis and suppress the invasion of A375 cells. Mechanistic studies revealed decreased expression of several kinases (AKT, STAT3 and mTOR) and UCMSCs were also found to promote cytoskeletal rearrangement in A375 cells. These results confirmed that UCMSCs exert antitumor effects on melanoma A375 cells. PMID- 29767255 TI - Bioinformatic analyses reveal the key pathways and genes in the CXCR4 mediated mesenchymal subtype of glioblastoma. AB - Glioblastoma multiforme (GBM) is one of the most lethal types of tumour, despite severe treatment methods. The Cancer Genome Atlas has categorised GBMs into proneural, neural, classical and mesenchymal subtypes; the mesenchymal subgroup has the worst prognosis. CXCR4 has been reported as selectively overexpressed in the mesenchymal subtype and positively associated with MES markers. However, to the best of our knowledge the underlying mechanisms regarding how CXCR4 may regulate mesenchymal GBM are still unknown. The present study aimed to investigate the critical pathways mediated by CXCR4 in mesenchymal GBM using bioinformatic analyses. The results suggested that CXCR4 is a predictor of poor prognosis and may serve as a biomarker of the mesenchymal subtype in patients with GBM. In addition, CXCR4 mediated the mitogen-activated protein kinase signaling pathway, which was identified specifically in patients with mesenchymal GBM. CXCR4 associated genes or pathways may be a 'basket trial' option for the management of melanoma, prostate cancer and mesenchymal GBM. PMID- 29767257 TI - BMP-6 protects retinal pigment epithelial cells from oxidative stress-induced injury by inhibiting the MAPK signaling pathways. AB - Worldwide, neovascular age-related macular degeneration (nAMD) is one of the most common causes of blindness in the elderly. In particular, degeneration of retinal pigment epithelial (RPE) cells represents the main pathological process in the development of nAMD, and oxidative stress serves a major role. The present study aimed to investigate the association between bone morphogenetic protein 6 (BMP-6) and nAMD. BMP-6 concentration was significantly reduced in patients with wet nAMD compared with in the control group. Furthermore, the present study investigated the protective effects of BMP-6 on RPE cells following oxidative stress-induced injury. Cell Counting Kit-8 assay and terminal deoxynucleotidyl transferase dUTP nick-end labeling staining demonstrated that BMP-6 increased RPE cell viability, which was decreased following treatment with hydrogen peroxide (H2O2), and reduced H2O2-induced apoptosis. In addition, western blotting revealed that BMP-6 reversed the decrease in pro-caspase-3 levels and the dysregulation of the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) balance caused by H2O2. In addition, alterations in c-Jun N-terminal protein kinase (JNK) and p38 mitogen activated protein kinase (MAPK) expression were examined, and pretreatment with BMP-6 was demonstrated to reduce H2O2-induced activation of JNK and p38 MAPK. Conversely, the effects of BMP-6 were attenuated by its inhibitor noggin. In conclusion, the present study demonstrated that BMP-6 may protect RPE cells from oxidative stress injury to a certain extent, which may be associated with alterations in the MAPK signaling pathway. However, the specific mechanism of action underlying this effect requires further investigation. Overall, the present study laid a foundation for exploring novel nAMD treatment methods. PMID- 29767259 TI - Silencing of miR-155 suppresses inflammatory responses in psoriasis through inflammasome NLRP3 regulation. AB - Psoriasis is a dermatosis with the major clinical symptoms of scale, erythema and itching, and it has a long disease course. In addition, it is easily recurrent and refractory, greatly affecting the physical and mental health of patients. In the present study, it was hypothesized that the function of miR-155 increases psoriasis-induced inflammation and that its expression may be dependent on inflammasome activation. miR-155 expression was examined by gene chip array and quantitative polymerase chain reaction analysis. miR-155 expression levels were significantly increased in an in vivo model of psoriasis compared with normal tissues, as was the expression of NLR family pyrin domain containing 3 (NLRP3). In vitro, using keratinocyte-induced HaCaT cells as a model for psoriasis, silencing of miR-155 was confirmed to significantly decrease inflammation and NLRP3/caspase-1 signaling. Activation of toll-like receptor 4 (TLR4) enhanced the miR-155-induced inflammatory response in the in vitro keratinocyte model. Treatment with a TLR4 inhibitor or an NLRP3 inhibitor reversed the miR-155 mediated inflammation in the same cell system. The present study demonstrated that miR-155 silencing suppressed psoriasis-associated inflammatory responses through inflammasome NLRP3 regulation. PMID- 29767261 TI - Inhibition of MEK/ERK/STAT3 signaling in oleuropein treatment inhibits myocardial ischemia/reperfusion. AB - Studies have shown that oleuropein has antifungal, anti-inflammatory, antiviral, antioxidant, anticancer and hypoglycemic functions. TTC solution staining was used to measure myocardial infarction size. A commercial kit was used to measure lactate dehydrogenase (LDH), creatinine kinase-MB (CK-MB), tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL 6, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and catalase levels. Western blot analysis was used to measure p53, p-MEK p-ERK and p-IkappaBalpha protein expression. The present study reports that the protective effect of oleuropein also prevents against myocardial ischemia/reperfusion (myocardial I/R). The aim of this retrospective study was to evaluate this protective effect of oleuropein and the mechanisms by which myocardial I/R is prevented. Oleuropein inhibited myocardial infarction size, CK-MB and LDH serum levels in a myocardial I/R rat model. Moreover, oleuropein also attenuated caspase-3 activity, and p53, phosphorylated (p)-mitogen-activated protein kinase kinase (MEK), p-extracellular signal-regulated protein kinase (ERK) and p-IkappaBalpha protein expression. TNF alpha, IL-1beta, IL-6 and MDA were decreased; SOD, GSH and catalase levels inhibited TNF-alpha, IL-1beta, IL-6 and MDA levels, and increased SOD, GSH and catalase levels in myocardial I/R rats treated with oleuropein. Rats orally administered the MEK inhibitor PD0325901, in addition to oleuropein, exhibited inhibited myocardial infarction size, CK-MB and LDH serum levels compared with rats treated with oleuropein only. Rats treated with MEK inhibitor also exhibited suppressed caspase-3 activity, p53, p-MEK p-ERK and p-IkappaBalpha protein expression, TNF-alpha, IL-1beta, IL-6, SOD, GSH, MDA and catalase levels, and induced p-signal transducer and activator of transcription 3 (STAT3) protein expression compared with rats treated with oleuropein only. Taken together, these results suggest that MEK/ERK/STAT3 signaling regulates the inhibition of myocardial I/R in rats treated with oleuropein. PMID- 29767258 TI - PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma. AB - Molecular mechanisms of programmed death-ligand 1 (PD-L1) mRNA expression and roles of apoptosis and biomarkers are poorly understood in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma patients. Thirty-three patients with recurrent postoperative EGFR-mutant lung adenocarcinoma (exon 19 deletion in 16, L858R in 15, G719C in 2 patients) treated with gefitinib were studied. PD-L1 mRNA expression of formalin-fixed paraffin-embedded paratumoral and intratumoral tissues was quantified by PCR. Correlations of PD-L1 mRNA expression with BIM, p53 upregulated modular of apoptosis (PUMA), human epidermal growth factor receptor 2 (HER2), mesenchymal-epithelial transition (MET), EGFR, and vascular endothelial growth factor A (VEGFA) were determined. Eleven of the 33 patients (33.3%) and 14/33 patients (42.4%) expressed intratumoral and paratumoral PD-L1 mRNA, respectively. Patients with intratumoral PD-L1 mRNA expression had significantly higher BIM and lower VEGFA expression compared with paratumoral PD L1 mRNA patients (P=0.049, P=0.009). PD-L1 mRNA expression was not associated with the expression of PUMA, HER2, EGFR and MET but was positively correlated with BIM expression (r=0.41, P=0.017) and inversely correlated with VEGFA expression (r=-0.33, P=0.043). Patients with intratumoral PD-L1 mRNA expression had significantly shorter median progression-free survival (PFS) after gefitinib therapy compared with no PD-L1 expression (255 vs. 732 days, respectively; P=0.032). Thus, PD-L1 mRNA expression in EGFR-mutant lung adenocarcinoma was associated with BIM and VEGFA mRNA expression and with shorter PFS after gefitinib therapy. PMID- 29767260 TI - RNAi-mediated downregulation of asparaginase-like protein 1 inhibits growth and promotes apoptosis of human cervical cancer line SiHa. AB - Asparaginase like 1 (ASRGL1) protein belongs to the N-terminal nucleophile group, cleaving the isoaspartyl-dipeptides and L-asparagine by adding water. It tends to be overexpressed in cancerous tumors including ovarian cancer and breast tumors. The present study assessed the potential ability of ASRGL1 as a molecular target in gene-based cervical cancer treatment. The protein expression level of ASRGL1 was determined in paraffin-embedded tumor specimen by immunohistochemistry. Additionally, in order to assess the activity of ASRGL1 during the process of cervical cancer cell multiplication, ASRGL1-short hairpin (sh) RNA-expressing lentivirus was established, which was used to infect SiHa cells. The Cellomics ArrayScan VT1 Reader identified the influence of downregulation on SiHa caused by RNA interference-intervened ASRGL1. Flow cytometric analysis was also performed to evaluate the influence. The cyclin dependent kinase (CDK2), cyclin A2, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) expression levels were assessed by western blot analysis. ASRGL1 was observed to be overexpressed in cervical cancer tissues when compared with the adjacent normal tissues. The knockdown of ASRGL1 in SiHa by ASRGL1-shRNA lentivirus infection significantly inhibited cell growth and enhanced cellular apoptosis; the cells were also captured during the S phase. The knockdown of ASRGL1 expression led to the increased expression of Bax and decreased expression of Bcl-2, CDK2 and cyclin A2. In conclusion, ASRGL1 was closely associated with growth and apoptosis in cervical cancer. Therefore, ASRGL1 may be a novel, potentially effective anti cervical cancer therapy. PMID- 29767262 TI - Transcutaneous carbon dioxide enhances the antitumor effect of radiotherapy on oral squamous cell carcinoma. AB - Radiotherapy (RT) is one of the main treatment modalities for oral squamous cell carcinoma (OSCC), however, radioresistance is a major impediment to its clinical success and poses as a concern that needs to be addressed. Tumor hypoxia is known to be significantly associated with radioresistance in various malignancies, hence, resolving the hypoxic state of a tumor may improve the antitumor effect of RT on OSCC. We have previously revealed that transcutaneous CO2 induced mitochondrial apoptosis and suppressed tumor growth in OSCC by resolving hypoxia. Considering the previous study, we hypothesized that transcutaneous CO2 may enhance the antitumor effect of RT on OSCC by improving intratumoral hypoxia, thereby overcoming radioresistance. In the present study, the combination of transcutaneous CO2 and RT significantly inhibited tumor growth compared with other treatments. This combination therapy also led to decreased expression of HIF-1alpha in parallel with increased expression of the cleaved forms of caspase 3-8-9 and PARP, which play essential roles in mitochondrial apoptosis. Additionally, the combination therapy increased the expression of ROS modulator 1 and subsequent mitochondrial ROS production, compared to RT alone. These results indicated that transcutaneous CO2 could potentially improve the antitumor effect of RT by decreasing the intratumoral hypoxia and increasing the mitochondrial apoptosis. Our findings indicated that CO2 therapy may be a novel adjuvant therapy in combination with RT for OSCC. PMID- 29767263 TI - Icariin promotes wound healing by enhancing the migration and proliferation of keratinocytes via the AKT and ERK signaling pathway. AB - Icariin is a traditional Chinese drug that has long been used to treat various diseases. In the present study, the effect of icariin was investigated on cutaneous wound healing. Using in vitro experiments, it was demonstrated that icariin significantly promoted the migration and proliferation of keratinocytes via the activation of AKT serine/threonine kinase 1 (AKT) and extracellular signal-regulated kinase (ERK). Inhibition of AKT or ERK reversed the effects of icariin on the proliferation and migration of keratinocytes. In addition, icariin inhibited the production of interleukin (IL)-6 and tumor necrosis factor (TNF) alpha and induced the production of IL-10. Finally, animal experiments demonstrated that icariin treatment accelerated the wound closure rate. The present findings revealed that icariin may be a promising drug to promote the migration and proliferation of keratinocytes, and to accelerate the healing of skin wounds, through its role in the upregulation of AKT and ERK signaling. PMID- 29767264 TI - Elemental diet inhibits pro-inflammatory cytokine production in keratinocytes through the suppression of NF-kappaB activation. AB - An elemental diet (ED) has been reported to reduce oral mucositis and dermatitis induced by chemotherapy. However, its molecular mechanism of action as an anti inflammatory agent is still unknown. The aim of the present study was to clarify whether ED confers its anti-inflammatory action via reduction of pro-inflammatory cytokine production in keratinocytes in vivo and in vitro. We evaluated the efficacy of ED in the treatment of 5-fluorouracil (5-FU)-induced dermatitis of nude mice, and examined the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6 using immunohistochemistry. Moreover, we assessed the expression and production of these pro-inflammatory cytokines by western blotting and ELISA assays, respectively, in immortalized human keratinocyte cell line, HaCaT. Furthermore, we investigated the effect of ED on a major inflammation-related factor, nuclear transcription factor-kappaB (NF-kappaB), since it controls many genes involved in the inflammation pathway. Our results indicated that ED reduced the expression of TNF-alpha, IL-1beta and IL-6. It also inhibited the nuclear transition of p65 NF kappaB, which is known to regulate inflammatory cytokine expression in keratinocytes suffering from 5-FU-induced dermatitis. In addition, ED reduced the production of TNF-alpha, IL-1beta and IL-6 in HaCaT cells. Moreover, ED attenuated 5-FU-induced transcriptional activation of NF-kappaB. These findings revealed that ED suppresses the expression of pro-inflammatory cytokines by suppressing NF-kappaB in keratinocytes, suggesting the potential usefulness of ED in the treatment of various inflammatory diseases of the dermal region. PMID- 29767266 TI - Inhibition of SOX4 induces melanoma cell apoptosis via downregulation of NF kappaB p65 signaling. AB - SOX4 (SRY Box 4) has attracted attention due to its important effects on cell growth, proliferation and apoptosis, among other cellular processes. However, the role of SOX4 in melanoma cell apoptosis remains unclear. In the present study, we investigated whether inhibition of SOX4 induces melanoma cell apoptosis, and explored the possible mechanism involving the NF-kappaB signaling pathway. SOX4 was knocked down using a lentivirus in melanoma A2058 and SK-MEL-5 cell lines. Cell proliferation was measured by MTT assay. Apoptosis was determined by flow cytometry. Western blotting was performed to detect the protein levels of SOX4, p65 and apoptosis-related proteins, such as PARP, Bcl-2, Bax and survivin. Quantitative real-time PCR (qRT-PCR) was used to examine the mRNA levels of SOX4 and p65. To determine whether SOX4 is able to bind to the promoter of p65, a CHIP PCR assay was performed. Our data demonstrated that SOX4 knockdown significantly induced apoptosis in melanoma cells, which was accompanied by increases in cleaved PARP and Bax, and decreases in Bcl-2 and survivin. The expression of p65 was also decreased in SOX4-knockdown melanoma cells. The CHIP-PCR assay indicated that SOX4 was able to bind to the promoter region of p65. We also observed that apoptosis in SOX4-knockdown and p65-overexpressing A2058 cells was much lower than that in SOX4-knockdown alone cells. This revealed that the overexpression of p65 partially reversed SOX4 downregulation-induced apoptosis. In conclusion, our results demonstrated that inhibition of SOX4 markedly induced melanoma cell apoptosis via downregulation of the NF-kappaB signaling pathway, which thus may be a novel approach for the treatment of melanoma. PMID- 29767265 TI - Knockdown of TNF-alpha alleviates acute lung injury in rats with intestinal ischemia and reperfusion injury by upregulating IL-10 expression. AB - Intestinal ischemia and reperfusion (II/R) injury often triggers severe injury in remote organs, with the lungs being considered the main target. Excessive elevation of proinflammatory cytokines is a major contributor in the occurrence and development of II/R-induced acute lung injury (ALI). Therefore, the present study aimed to investigate whether blocking tumor necrosis factor-alpha (TNF alpha) expression could protect the lungs from injury following II/R, and to explore the possible underlying mechanism involving interleukin-10 (IL-10). Briefly, II/R was induced in rats by 40 min occlusion of the superior mesenteric artery and celiac artery, followed by 8, 16 or 24 h of reperfusion. Subsequently, lentiviral vectors containing TNF-alpha short hairpin (sh)RNA were injected into the right lung tissues, in order to induce TNF-alpha knockdown. The severity of ALI was determined according to lung injury scores and lung edema (lung wet/dry weight ratio). The expression levels of TNF-alpha were analyzed by quantitative polymerase chain reaction (qPCR), western blotting and immunofluorescence (IF) staining. IL-10 expression, in response to TNF-alpha knockdown, was detected in lung tissues by qPCR and IF. The results detected marked inflammatory responses, and increased levels of lung wet/dry weight ratio and TNF-alpha expression, in the lungs of II/R rats. Conversely, treatment with TNF-alpha shRNA significantly alleviated the severity of ALI and upregulated the expression levels of IL-10 in lung tissues. These findings suggested that TNF-alpha RNA interference may exert a protective effect on II/R-induced ALI via the upregulation of IL-10. Therefore, TNF-alpha knockdown may be considered a potential strategy for the prevention or treatment of ALI induced by II/R in future clinical trials. PMID- 29767267 TI - HDAC inhibitors, trichostatin A and valproic acid, increase E-cadherin and vimentin expression but inhibit migration and invasion of cholangiocarcinoma cells. AB - The effects of histone deacetylase (HDAC) inhibitors on epithelial-mesenchymal transition (EMT) differ in various cancers. E-cadherin is a cell-to-cell adhesion protein, whereas accumulation of vimentin is related to the development of the spindle shape of the mesenchymal cell phenotype. We investigated the EMT phenotypes of human cholangiocellular carcinoma HuCC-T1, JCK and SNU-1079 cell lines. To this end, we measured the expression of E-cadherin or zonula occludens (ZO)-1 and vimentin, epithelial and mesenchymal cell markers, respectively, using real-time reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence microscopy following treatment with trichostatin A (TSA, 200 nM) or valproic acid (VPA, 0.5 mM) with or without gemcitabine (GEM, 50 nM) for 24 h. In addition, we performed cell morphology, migration, and invasion assays. HuCC-T1 cells changed from spindle- to rectangular-shaped after co-treatment with GEM and TSA or VPA. Furthermore, cells co-treated with GEM and TSA or VPA exhibited protein levels of E-cadherin or ZO-1 that were higher than those in cells treated with GEM alone, indicating stronger inhibition of EMT. However, vimentin expression was also increased. Confocal microscopy revealed enhanced expression of E-cadherin or ZO-1 and vimentin in all three cell lines. Migration and invasion were inhibited in HuCC-T1 cells co-treated with GEM and TSA or VPA, compared to those treated with GEM alone. In conclusion, co-treatment of cholangiocarcinoma cells with TSA or VPA and GEM suppressed EMT with tolerable cytotoxicity. However, the HDAC inhibitors augmented both E-cadherin and vimentin expression and their effects varied in different cholangiocarcinoma cell lines. Therefore, the clinical use of HDAC inhibitors in biliary cancer should be considered cautiously. PMID- 29767270 TI - No correlation between rotation of femoral components in the transverse plane and clinical outcome after total knee arthroplasty. AB - PURPOSE: It was hypothesized that malrotation of femoral component in total knee arthroplasty (TKA) will significantly impact clinical outcome. METHODS: Eighty eight consecutive patients with primary osteoarthritis of the knee were prospectively evaluated. They received a cemented posterior stabilized TKA (NexGen, Zimmer/Biomet(r) Inc., Warsaw, IN, USA). The femoral component was placed in 3 degrees of external rotation referenced to the posterior condylar line. Postoperatively, a CT scan was performed to evaluate rotation of femoral component in the transverse plane. SF-36, KSS, and WOMAC, as well as their range of motion was assessed prior to surgery, after 6 and 24 months. Data are presented as mean and standard deviation (SD), as well as range if applicable. Correlation analysis was performed between the placement of the femoral component in the transverse plane and the clinical outcome. RESULTS: Femoral component placement was on average 0.1 degrees [SD 2.5 degrees , range - 6.5 degrees to + 6.5 degrees ] referenced to the surgical transepicondylar line showing a wide range between the two landmarks after surgery. After 6 months, WOMAC category 'physical function' correlated significantly with femoral component rotation (r = - 0.28, p = 0.007). After 24 months, WOMAC categories 'physical function' and 'pain' correlated significantly with femoral rotation (r = - 0.41, p < 0.001; and r = - 0.33, p = 0.001). No significant correlations were found between femoral component rotation and range of motion (r = 0.04), WOMAC category "stiffness", KSS, as well as SF-36 questionnaires. These reported formally significant correlations were without any clinical relevance. DISCUSSION: The study showed that there is a significant patients specific femoral component placement in the transverse plane. Internal or external malrotation of the femoral component does not correlate automatically with poor knee function. The lack of correlation between femoral component position and clinical as well as functional outcome underlines complexity and significant individuality of each patient. The surgeon should be aware of the finding and attention should be paid during surgery when significant divergency is seen between the two landmarks. Soft tissue balancing might be very crucial in these specific patients, which needs to be studied in depth in the future. LEVEL OF EVIDENCE: II. PMID- 29767268 TI - CHAF1B knockdown blocks migration in a hepatocellular carcinoma model. AB - The roles and model of action of the chromatin assembly complex factor-1B (CHAF1B) gene in liver cancer have not been fully elucidated. The CHAF1B gene in human hepatocellular carcinoma cell line HUH-7 was knocked down using a lentivirus and the transfected cells were assayed for migration and invasion abilities and cell cycle arrest using the scratch wound healingand Transwell assays as well as flow cytometry, respectively. Cells transfected with an empty vector were used as the control. The expression of genes was profiled. Models were constructed using CHAF1B-knockdown cells and investigated for tumor growth and pathological changes. Our experiments revealed that the knockdown of the CHAF1 gene reduced the invasion and migration ability of HUH-7 cells. Gene expression profiling revealed that after knockdown, PSMB6, SLC30A7, SMC3, TWF2 and BLM genes had the most marked changes as compared with the control. Western blot and RT-PCR analyses revealed that following the knockdown of the CHAF1B gene, protein and mRNA levels of the PSMB6, SLC30A7 and SMC3 genes were significantly upregulated, while those of the BLM and TWF2 genes were significantly downregulated. In the HUH-7-knockdown cells, there were significantly fewer G0/G1 cells and more S1 cells as compared with the control (36.10 vs. 54.10% and 59.7 vs. 40.8%, respectively), while the number of G2/M cells was similar (4.20 vs. 5.10%). The volumes of the tumors were similar between those injected with the empty vector and control, but were significantly smaller in the knockdown models, suggesting that the knockdown of the CHAF1B gene inhibited tumor growth. H&E staining revealed that tumors were developed in mice in all groups. PMID- 29767269 TI - [IgG4-associated cholangitis - clinical presentation of an overlooked disease entity]. AB - IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease, which is an immune-mediated fibroinflammatory systemic disorder characterised by often elevated IgG4 serum levels and typical histopathological findings in affected tissues. IAC is frequently (>90%) accompanied by autoimmune pancreatitis type 1 (AIP), which is the pancreatic manifestation of immunoglobulin G4-related disease. In 80-85% of the cases patients with IAC are male, above 50 years of age and present with jaundice and weight loss. A remarkable percentage of patients with IAC has a history of long term exposure to solvents, oil products and other organic agents representing so called "blue-collar workers". Clinical features and imaging (i. e. strictures or mass-forming lesions in the biliary tract) may mimic other biliary diseases, such as primary or secondary sclerosing cholangitis and cholangiocarinoma. The HISORt criteria are used for diagnosing IAC and comprise histologic and imaging findings, serum IgG4, organ manifestation pattern and response to immunosuppressive therapy. Serum IgG4 levels are of diagnostic value when it is above 4 times the upper limit of normal. Determination of the blood IgG4/IgG mRNA ratio using quantitative polymerase chain reaction (qPCR) is an accurate diagnostic tool currently under clinical validation. The majority of patients show an excellent response to corticosteroid therapy. Symptom recurrence, however, is common making long-term treatment with low-dose prednisolone and/or azathioprine frequently necessary. PMID- 29767271 TI - Graft failure is more frequent after hamstring than patellar tendon autograft. AB - PURPOSE: The risk of graft failure after anterior cruciate ligament (ACL) reconstructions with hamstring or patellar tendon was evaluated in a French population of athletes. METHODS: Athletes who had undergone ACL autograft reconstruction and who received rehabilitation care at the European Center for Sports Rehabilitation (CERS; Capbreton, France) were screened for this prospective cohort study. Eligibility criteria included a simple hamstring autograft or patellar tendon autograft surgical technique. Patients were contacted by phone to participate in follow-up during the second year after surgery. The primary endpoint was the graft failure frequency, evaluated with a multivariate logistic model with adjustment for baseline patient characteristics. The secondary endpoint was time to graft failure, analyzed by an adjusted Cox model. RESULTS: A total of 2424 athletes were included after having a hamstring autograft (semitendinosus and gracilis) or a patellar tendon autograft between 2011 and 2014. Of the 988 athletes who responded to a follow-up phone call (40.7% response rate), 33 were excluded for new contralateral ACL rupture (3.3%), with 955 included for analysis (713 hamstring autografts; 242 patellar-tendon autografts). There were no significant differences between the baseline characteristics of the patients analyzed and the population which did not respond to the questionnaire. A significant difference in the frequency of graft failure was seen, 6.5% for hamstring autografts vs 2.1% for patellar-tendon autografts [adjusted odds ratio (OR) = 3.64, 95% CI (1.55; 10.67); p = 0.007]. Mean time to graft failure was 10.7 vs 17.4 months for hamstring and patellar-tendon autografts respectively [adjusted hazard ratio (HR) = 3.50, 95% CI (1.53; 10.11); p = 0.008]. Age less than 25 years significantly increased the frequency of graft failure [adjusted OR = 3.85 (1.89; 8.72); p < 0.001]. The rate of patients returning to competitive sport after the first graft was not significantly different for the two techniques: 70.8% for hamstring and 77.8% for patellar tendon [adjusted OR = 0.718; 95% CI (0.50; 1.02)]. CONCLUSIONS: Graft failure is significantly more frequent after hamstring than patellar tendon autografts in a French population, despite similar rates of return to competition. Athletes aged less than 25 years have a higher risk of failure than those aged >= 25 years. Our results are in accordance with recent Scandinavian studies. LEVEL OF EVIDENCE: II. PMID- 29767273 TI - Correction to: Expanding tryptophan-containing cyclodipeptide synthase spectrum by identification of nine members from Streptomyces strains. AB - The original version of this article contained mistake. After careful re examination of the LC-MS data, the products of CDPSs "WP_031028810" and "BAU83478" should be cFL instead of cPY. We apologize for any inconvenience that this may have caused. PMID- 29767274 TI - Retraction Note to: Diverging views of epigenesis: the Wolff-Blumenbach debate. AB - The author has retracted this article (Gambarotto 2017) as it contains sections that substantially overlap with the following publications (Roe 1981; Dupont 2007; Witt 2008). PMID- 29767272 TI - The ESSKA-AFAS international consensus statement on peroneal tendon pathologies. AB - INTRODUCTION: Peroneal tendon injuries are a significant cause of lateral ankle symptoms in the active population. Accurate diagnosis and prompt treatment is important for minimizing the risk of long-term sequelae associated with chronic peroneal tendinopathy. Although several studies have been published on diagnostic strategies and treatment outcomes, there is no consensus on the optimal management of peroneal tendon pathologies. PURPOSE: The purpose of this ESSKA AFAS consensus statement was to conduct an international and multidisciplinary agreed guideline on management of patients with peroneal tendon pathologies. METHODS: Using the Nominal Group Technique, a panel comprised of sixteen specialists spanning nine countries was convened by the ESSKA-AFAS board. In preparation for the meeting, relevant questions were identified and supported by a systematic literature search. During the meeting, the panel members gave presentations on each question, and the evidence supporting each subject was then vetted by open discussion. Statements were thereafter adjusted on the basis of the discussion and voted upon to determine consensus using a 0-10 range Likert scale. Agreement was confirmed when a mean score of at least 7.5 was reached. CONCLUSION: This ESSKA-AFAS consensus statement on the optimal management of peroneal tendon pathologies is the result of international and multidisciplinary agreement combined with a systematic review of the literature. LEVEL OF EVIDENCE: V. PMID- 29767275 TI - ALDH2 Protects Against Ischemic Stroke in Rats by Facilitating 4-HNE Clearance and AQP4 Down-Regulation. AB - Aldehyde dehydrogenase 2 (ALDH2) is a new therapeutic target in the central nervous system. However, the association between ALDH2 and brain edema following ischemic stroke (IS) remains unclear. The present study was investigated to whether active ALDH2 can attenuate brain edema by using a rat model of IS, with the aim of clarifying the underlying mechanisms involved. Rats were administered the ALDH2 agonist Alda-1, vehicle or the ALDH2 inhibitor cyanamide (CYA) 15 min prior to a 1.5 h middle cerebral artery occlusion (MCAO) surgery. The effects of ALDH2 were subsequently investigated 24 h after reperfusion by evaluating neurological function, infarct sizes, brain edema volumes, 4-hydroxy-2-nonenal (4 HNE) levels, and aquaporin 4 (AQP4) protein expression. The results demonstrated that increasing ALDH2 activity significantly improved neurological deficits, reduced infarct sizes, and attenuated brain edema after MCAO. Alda-1 administration led to decreased 4-HNE levels and inhibited AQP4 protein expression in the peri-infarct section of the brain. Whereas, CYA administration increased 4-HNE levels, AQP4 expression, and simultaneously aggravated brain edema following MCAO. In conclusion, increasing ALDH2 activity can improve brain edema, infarct volumes, and reduce neurological impairment in a rat IS model. The therapeutic benefits of ALDH2 are related to 4-HNE clearance and AQP4 down regulation. PMID- 29767277 TI - Microglial density determines the appearance of pathological neovascular tufts in oxygen-induced retinopathy. AB - The oxygen-induced retinopathy (OIR) animal model established in C57 mice and SD rats has been widely used in retinal neovascular disease studies, while Balb/c mice have not been used because Balb/c OIR mice lack neovascular tufts. One study found a substantial difference in the density of retinal microglia between C57 and Balb/c mice; however, no direct evidence could clarify whether the density of retinal microglia in Balb/c mice led to this difference. In our study, intraperitoneal injection of minocycline was used to inhibit the activation of microglia and intravitreal injection of clodronate liposomes was used to decrease the density of microglia in Balb/c OIR model mice. We found that with the decline in microglia induced by the two drugs, the avascular area in treated Balb/c OIR mice was higher than that in untreated Balb/c OIR mice; moreover, a small area of neovascular tufts appeared at P17. After checking the expression of Iba1, a microglial marker and GFAP, an astrocyte and Muller cell marker, we found that minocycline and clodronate could inhibit the activation of microglia or decrease the density of microglia, while they had no significant effect on astrocytes and Muller cells. Therefore, these data suggest that the density of microglia in the retina may determine the result of vasculopathy in OIR mice to some extent. In future studies, predicting the development of retinal neovascular diseases by detecting the density of microglia in living animals or human beings with newly developed instruments and methods may be useful. PMID- 29767278 TI - The hypothalamus and neuropsychiatric disorders: psychiatry meets microscopy. AB - The past decades have witnessed an explosion of knowledge on brain structural abnormalities in schizophrenia and depression. Focusing on the hypothalamus, we try to show how postmortem brain microscopy has contributed to our understanding of mental disease-related pathologic alterations of this brain region. Gross anatomical abnormalities (volume changes of the third ventricle, the hypothalamus, and its nuclei) and alterations at the cellular level (loss of neurons, increased or decreased expression of hypothalamic peptides such as oxytocin, vasopressin, corticotropin-releasing hormone, and other regulatory factors as well as of enzymes involved in neurotransmitter and neuropeptide metabolism) have been reported in schizophrenia and/or depression. While histologic research has mainly concentrated on neurons, little is currently known about the impact of non-neuronal cells for hypothalamus pathology in mental disorders. Their study would be a rewarding task for the future. PMID- 29767280 TI - Carnosine and Histidine Supplementation Blunt Lead-Induced Reproductive Toxicity through Antioxidative and Mitochondria-Dependent Mechanisms. AB - Lead (Pb)-induced reproductive toxicity is a well-characterized adverse effect associated with this heavy metal. It has been found that Pb exposure is associated with altered spermatogenesis, increased testicular degeneration, and pathological sperm alterations. On the other hand, it has been reported that Pb induced reproductive toxicity is associated with increased reactive oxygen species (ROS) formation and diminished antioxidant capacity in the reproductive system. Hence, administration of antioxidants as protective agents might be of value against Pb-induced reproductive toxicity. This study was designed to investigate whether carnosine (CAR) and histidine (HIS) supplementation would mitigate the Pb-induced reproductive toxicity in male rats. Animals received Pb (20 mg/kg/day, oral, 14 consecutive days) alone or in combination with CAR (250 and 500 mg/kg/day, oral, 14 consecutive days) or HIS (250 and 500 mg/kg/day, oral, 14 consecutive days). Pb toxicity was evident in the reproductive system by a significant increase in tissue markers of oxidative stress along with severe histopathological changes, seminal tubule damage, tubular desquamation, low spermatogenesis index, poor sperm parameters, and impaired sperm mitochondrial function. It was found that CAR and HIS supplementation blunted the Pb-induced oxidative stress and mitochondrial dysfunction in the rat reproductive system. Thereby, antioxidative and mitochondria-protective properties serve as primary mechanisms for CAR and HIS against Pb-induced reproductive toxicity. PMID- 29767282 TI - The Effect of Medical Marijuana Laws on Marijuana-Related Attitude and Perception Among US Adolescents and Young Adults. AB - Marijuana liberalization policies are gaining momentum in the USA, coupled with limited federal interference and growing dispensary industry. This evolving regulatory landscape underscores the importance of understanding the attitudinal/perceptual pathways from marijuana policy to marijuana use behavior, especially for adolescents and young adults. Our study uses the restricted-access National Survey on Drug Use and Health (NSDUH) 2004-2012 data and a difference-in differences design to compare the pre-policy, post-policy changes in marijuana related attitude/perception between adolescents and young adults from ten states that implemented medical marijuana laws during the study period and those from the remaining states. We examined four attitudinal/perception pathways that may play a role in adolescent and young adult marijuana use behavior, including (1) perceived availability of marijuana, (2) perceived acceptance of marijuana use, (3) perceived wrongfulness of recreational marijuana use, and (4) perceived harmfulness of marijuana use. We found that state implementation of medical marijuana laws between 2004 and 2012 was associated with a 4.72% point increase (95% CI 0.15, 9.28) in the probability that young adults perceived no/low health risk related to marijuana use. Medical marijuana law implementation is also associated with a 0.37% point decrease (95% CI - 0.72, - 0.03) in the probability that adolescents perceived parental acceptance of marijuana use. As more states permit medical marijuana use, marijuana-related attitude/perception need to be closely monitored, especially perceived harmfulness. The physical and psychological effects of marijuana use should be carefully investigated and clearly conveyed to the public. PMID- 29767281 TI - HIV Risk Among Displaced Adolescent Girls in Ethiopia: the Role of Gender Attitudes and Self-Esteem. AB - Adolescent girls in sub-Saharan Africa have been deemed one of the most critical populations to address in the campaign for an HIV-free generation. Experiences of intimate partner violence (IPV), harmful gender norms, diminished personal agency, and age-disparate sex have been identified as factors in the increasing rate of new infections among this population. Using baseline data from a cluster randomized controlled trial in three refugee camps in Benishangul-Gumuz Regional State in Ethiopia, our study quantitatively examined the associations between HIV risk factors, attitudes on gender inequality, IPV acceptability, and self-esteem for female adolescent refugees primarily from Sudan and South Sudan (n = 919). In multivariate models, adjusting for age and education, results showed girls who were more accepting of gender inequitable norms and IPV had greater odds of ever experiencing forced (OR 1.40, CI 1.15-1.70; OR 1.66, CI 1.42-1.94) or transactional sex (OR 1.28, CI 1.05-1.55; OR 1.59, CI 1.37-1.85) compared to girls who demonstrated less approval. Higher self-esteem was associated with increased odds of condom use (OR 1.13, CI 1.02-1.24) as well as decreased odds of adolescent marriage (OR 0.93, CI 0.90-0.95), age-disparate sex (OR 0.90, CI 0.86 0.94), and transactional sex (OR 0.96, CI 0.93-0.99). The findings suggest acceptance of inequitable gender norms (including those that perpetuate violence against women) and low self-esteem to be associated with common HIV risk factors among refugee adolescents living in Ethiopia. Greater attention towards the intersections of gender equality and self-valuation is needed when seeking to understand HIV risk among refugee adolescent girls in sub-Saharan Africa. PMID- 29767279 TI - Identification and validation of QTL for grain yield and plant water status under contrasting water treatments in fall-sown spring wheats. AB - KEY MESSAGE: Chromosome regions affecting grain yield, grain yield components and plant water status were identified and validated in fall-sown spring wheats grown under full and limited irrigation. Increases in wheat production are required to feed a growing human population. To understand the genetic basis of grain yield in fall-sown spring wheats, we performed a genome-wide association study (GWAS) including 262 photoperiod-insensitive spring wheat accessions grown under full and limited irrigation treatments. Analysis of molecular variance showed that 4.1% of the total variation in the panel was partitioned among accessions originally developed under fall-sowing or spring-sowing conditions, 11.7% among breeding programs within sowing times and 84.2% among accessions within breeding programs. We first identified QTL for grain yield, yield components and plant water status that were significant in at least three environments in the GWAS, and then selected those that were also significant in at least two environments in a panel of eight biparental mapping populations. We identified and validated 14 QTL for grain yield, 15 for number of spikelets per spike, one for kernel number per spike, 11 for kernel weight and 9 for water status, which were not associated with differences in plant height or heading date. We detected significant correlations among traits and colocated QTL that were consistent with those correlations. Among those, grain yield and plant water status were negatively correlated in all environments, and six QTL for these traits were colocated or tightly linked (< 1 cM). QTL identified and validated in this study provide useful information for the improvement of fall-sown spring wheats under full and limited irrigation. PMID- 29767283 TI - Correction to: Multi-institutional analysis of CT and MRI reports evaluating indeterminate renal masses: comparison to a national survey investigating desired report elements. AB - The original version of this article contained an error in author name. The co author's name was published as Ivan M. Pedrosa, instead it should be Ivan Pedrosa. The original article has been corrected. PMID- 29767284 TI - Diagnostic accuracy of MRI in assessing tumor regression and identifying complete response in patients with locally advanced rectal cancer after neoadjuvant treatment. AB - BACKGROUND: The diagnostic accuracy of Magnetic Resonance Imaging (MRI) in restaging locally advanced rectal cancers (LARC) after neoadjuvant chemo-radio therapy (NCRT) has been under recent scrutiny. There is limited data on the accuracy of MRI and its timing in assessing tumor regression grade (TRG) and in identifying patients with complete response (CR). NCRT seems to cause tissue inflammation and oedema which renders reading the scans difficult for radiologist. AIM: This study aims to assess the accuracy of MRI at different time intervals after NCRT in staging TRG and in identifying CR. Inter-observer agreement between 2 blinded radiologists will also be assessed. METHOD: In this retrospective analysis, all patients diagnosed with LARC between January 2003 and 2014, who underwent long-course NCRT, who had at least one post-treatment MRI scan, and who underwent surgery with available pathology results are included. Histopathology staging is considered the reference standard. Accuracy of MRI in T staging and in TRG staging is assessed using weighted kappa. Accuracy, sensitivity, and specificity in identifying CR are calculated from a 2 * 2 contingency table. Inter-observer agreement between two-staging blinded radiologists is calculated using weighted kappa. These are calculated at 2 different time intervals after completion of NCRT. RESULTS: 114 patients were identified who had a first post-treatment MRI scan at an average of 6.2 weeks after completion of NCRT. A subgroup of 68 patients had a second post-treatment MRI at an average of 10.4 weeks. Pathology results were available for 103 patients. By the second post-treatment scan, an additional 25% of patients experienced downstaging; accuracy in T staging increased from 43% to 57.4%; accuracy in TRG staging rose from 28.2% to 38.1%; accuracy in identifying CR rose from 83.4% to 84.1%. Inter-observer agreement in T staging rose from 0.1 for first post-treatment MRI to 0.206 for second post-treatment MRI. CONCLUSION: This study advocates that restaging should occur at 10 weeks rather than the standard 6 weeks. This results in higher complete response rates and higher concordance with pathological specimens. Our results also showed that it is easier for radiologists to stage the MRI scans, resulting in higher inter-rater agreements. PMID- 29767285 TI - Endoscopic submucosal injection: a novel technique facilitating dissection in transanal minimally invasive surgery (TAMIS). PMID- 29767286 TI - Pituitary surgery is becoming more common: does this reflect a change in tumor incidence, detection, or treatment pattern? PMID- 29767288 TI - Therapeutic Applications of Mesenchymal Stem Cells for Systemic Lupus Erythematosus. AB - Mesenchymal stem cells (MSCs) have been intensively studied and applied in regenerative medicine and tissue engineering. Recently, their immune modulation functions make them as attractive potential approaches for autoimmune disease treatment. Systemic lupus erythematosus (SLE) is one type of chronic autoimmune diseases with multi-organ damaged by the immune system. Although current available treatments are effective for some patients, others are refractory for these therapies. The immuno-modulatory and regenerative characteristics of MSCs make them as one promising candidate for treating SLE. Thus, we would discuss their immune modulation effects, pre-clinical and clinical applications, and the potentials for immune tolerance re-establishment in SLE here. PMID- 29767290 TI - Stem Cells in Alzheimer's Disease: Current Standing and Future Challenges. AB - To date, there is no definitive treatment for Alzheimer's disease (AD). The realm of stem cells is very promising in regenerative medicine, particularly for neurodegenerative diseases. Various types of stem cells have been used in preclinical/clinical trials for AD aiming the development of an elusive disease modifying therapy. Over the last decade, much knowledge has been gained in this field regarding types of cells, routes and timing of administration, and outcomes of stem cells-based strategies for AD. In this chapter, we will trace the state of art and the challenges facing the use of stem cells in AD. PMID- 29767287 TI - Screening for comorbid conditions in patients enrolled in the SODA registry: a 2 year observational analysis. AB - PURPOSE: This 2-year analysis assessed frequency of comorbidities and comorbidity screening in the Somatuline(r) (lanreotide, LAN) Depot for Acromegaly (SODA) registry. METHODS: Patient data collected included pituitary hormone deficiencies, sleep studies, echocardiograms, gallbladder sonographies, colonoscopies, and glycated hemoglobin (HbA1c) levels. Insulin-like growth factor 1 (IGF-1) and growth hormone levels in patients with (DM) and without (non-DM) diabetes mellitus were analyzed. RESULTS: There were 241 patients enrolled. Pituitary hormone deficiencies were reported more frequently at enrollment in male (56.9%) vs female patients (32.0%; p < 0.001). TSH deficiency was the most common endocrine deficiency (69.8%), followed by gonadotropin deficiency (62.3%). Screening tests reported at enrollment: sleep studies in 29.9% (79.2% had sleep apnea), echocardiogram in 46.1% (46.8% abnormal), gallbladder sonography in 18.7% (17.8% had gallstones), and colonoscopy in 48.1% (35.3% had polyps). Follow-up studies were reported less frequently at 1 and 2 years. HbA1c data were reported in 30.8% and 41.2% after 1 and 2 years. HbA1c levels were similar at 1 and 2 years of LAN therapy among DM and non-DM patients with available data. Fewer DM vs non-DM patients achieved IGF-1 below upper limit of normal at Month 24 (58.3% vs 80.6%; p = 0.033). CONCLUSIONS: Fewer than half of patients in SODA had screening results reported at enrollment for sleep apnea, cardiomyopathy, and colon polyps. Gallbladder imaging was reported in a minority of patients. Lower IGF-1 control rates were observed in DM vs non-DM patients at Month 24. These data suggest a need for better monitoring of comorbidities in US acromegaly patients. PMID- 29767289 TI - Regenerative Medicine Applications of Mesenchymal Stem Cells. AB - A major research challenge is to develop therapeutics that assist with healing damaged tissues and organs because the human body has limited ability to restore the majority of these tissues and organs to their original state. Tissue engineering (TE) and regenerative medicine (RM) promises to offer efficient therapeutic biological strategies that use mesenchymal stem cells (MSCs). MSCs possess the capability for self-renewal, multilineage differentiation, and immunomodulatory properties that make them attractive for clinical applications. They have been extensively investigated in numerous preclinical and clinical settings in an attempt to overcome their challenges and promote tissue regeneration and repair. This review explores the exciting opportunities afforded by MSCs, their desirable properties as cellular therapeutics in RM, and implicates their potential use in clinical practice. Here, we attempt to identify challenges and issues that determine the clinical efficacy of MSCs as treatment for skeletal and non-skeletal tissues. PMID- 29767291 TI - Bioengineered Scaffolds for Stem Cell Applications in Tissue Engineering and Regenerative Medicine. AB - Stem cell-based therapies, harnessing the ability of stem cells to regenerate damaged or diseased tissues, are under wide-ranging consideration for regenerative medicine applications. However, limitations concerning poor cell persistence and engraftment upon cell transplantation still remain. During the recent years, several types of biomaterials have been investigated to control the fate of the transplanted stem cells, aiming to increase their therapeutic efficiency. In the present chapter we focus on the general properties of some of these biomaterials, which include polymers, ceramics, and nano-biomaterials. In the first part of the chapter, a brief explanation about stem cell biology, sources, and their microenvironment is provided. The second part of the chapter presents some of the most recent studies investigating different types of biomaterials and approaches that aim to mimic the stem cell microenvironment for a more precise control of the stem cell fate. PMID- 29767292 TI - Short-Axis Diastolic Ventricular Area Ratio as a New Index in Screening Patients with Repaired Tetralogy of Fallot. AB - Right ventricular (RV) end-diastolic volume measured by cardiovascular magnetic resonance imaging (CMR) is a criterion for pulmonary valve replacement in patients with tetralogy of Fallot (TOF). We sought to determine if the ratio of echocardiographic, short-axis RV-to-left ventricular (LV) end-diastolic areas (EDA) could be used to predict RV volume on CMR. We retrospectively reviewed the echocardiograms of all patients with repaired TOF who underwent CMR at our institution from 2011 to 2015 and also had an echocardiogram within 6 months of the CMR. The short-axis RV and LV EDAs were measured and the ratio of the two was calculated. Results were compared with CMR RV end-diastolic volume index (RVEDVi) and RV:LV end-diastolic volume ratio. The sensitivity and specificity values predicting RV volumes > 150 ml/m2 were calculated. Fifty-eight studies met inclusion criteria. There were 47 studies with RVEDVi < 150 ml/m2 and 11 with RVEDVi > 150 ml/m2. RV:LV EDA and CMR RV:LV end-diastolic volume ratio correlated strongly (r = 0.76, p < 0.0001). An RV:LV EDA >= 1.57 had a 90% sensitivity to predict RVEDVi > 150 ml/m2 (area under the curve = 0.74, 95% CI 1.5-27.9; p = 0.012). An RV:LV EDA >= 1.88 had an 81% specificity to detect RV volume index > 150 ml/m2. Short-axis RV:LV EDA correlates well with an increased RVEDVi as measured by CMR. This new and simple measure can be used to predict optimal timing for CMR in anticipation of pulmonary valve replacement in repaired TOF. PMID- 29767293 TI - Left Ventricular Ejection Fraction and Fractional Shortening are Useful for the Prediction of the Therapeutic Response to Metoprolol in Children with Vasovagal Syncope. AB - The objective of this manuscript was to explore if left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) could predict the efficacy of metoprolol therapy on vasovagal syncope (VVS) in children. Forty nine children, including 30 with VVS and 19 gender- and age-matched healthy controls, were included in the study. Metoprolol was prescribed to the VVS subjects. The clinical data were obtained during follow-up at 2 and 6 months. The results showed that LVEF and LVFS of responders were significantly higher than those of non-responders both at the 2-month follow-up (LVEF: 72.5 +/- 3.2% vs. 64.6 +/- 3.4%; LVFS: 40.9 +/- 2.3% vs. 34.9 +/- 2.9%), and at the 6-month follow up (LVEF: 72.8 +/- 2.8% vs. 65.5 +/- 4.6%; LVFS: 41.1 +/- 1.9% vs. 35.8 +/- 3.6%). The receiver operating characteristic curve (ROC) analysis demonstrated that 70.5% as a cutoff value of baseline LVEF yielded a sensitivity of 80% and a specificity of 100% in predicting the therapeutic effectiveness of metoprolol at 2 months. For baseline LVFS, 38.5% as a cutoff value yielded a sensitivity of 90% and a specificity of 90%. At the 6-month follow-up, the ROC analysis demonstrated that 70.5% as a cutoff value of baseline LVEF yielded a sensitivity of 81.3% and a specificity of 88.9% in the prediction of metoprolol efficacy. For baseline LVFS, 37.5% as a cutoff value yielded a sensitivity of 93.8% and a specificity of 66.7%. In conclusion, baseline LVEF and LVFS might be useful predictors of the efficacy of beta-blocker therapy on VVS in children. PMID- 29767294 TI - Multiband and Broadband Absorption Enhancement of Monolayer Graphene at Optical Frequencies from Multiple Magnetic Dipole Resonances in Metamaterials. AB - It is well known that a suspended monolayer graphene has a weak light absorption efficiency of about 2.3% at normal incidence, which is disadvantageous to some applications in optoelectronic devices. In this work, we will numerically study multiband and broadband absorption enhancement of monolayer graphene over the whole visible spectrum, due to multiple magnetic dipole resonances in metamaterials. The unit cell of the metamaterials is composed of a graphene monolayer sandwiched between four Ag nanodisks with different diameters and a SiO2 spacer on an Ag substrate. The near-field plasmon hybridizations between individual Ag nanodisks and the Ag substrate form four independent magnetic dipole modes, which result into multiband absorption enhancement of monolayer graphene at optical frequencies. When the resonance wavelengths of the magnetic dipole modes are tuned to approach one another by changing the diameters of the Ag nanodisks, a broadband absorption enhancement can be achieved. The position of the absorption band in monolayer graphene can be also controlled by varying the thickness of the SiO2 spacer or the distance between the Ag nanodisks. Our designed graphene light absorber may find some potential applications in optoelectronic devices, such as photodetectors. PMID- 29767296 TI - Evaluating the antimicrobial, apoptotic, and cancer cell gene delivery properties of protein-capped gold nanoparticles synthesized from the edible mycorrhizal fungus Tricholoma crassum. AB - Biosynthesis of gold nanoparticles of distinct geometric shapes with highly functional protein coats without additional capping steps is rarely reported. This study describes green synthesis of protein-coated gold nanoparticles for the first time from the edible, mycorrhizal fungus Tricholoma crassum (Berk.) Sacc. The nanoparticles were of the size range 5-25 nm and of different shapes. Spectroscopic analysis showed red shift of the absorption maxima with longer reaction period during production and blue shift with increase in pH. These were characterized with spectroscopy, SEM, TEM, AFM, XRD, and DLS. The particle size could be altered by changing synthesis parameters. These had potent antimicrobial activity against bacteria, fungi, and multi-drug-resistant pathogenic bacteria. These also had inhibitory effect on the growth kinetics of bacteria and germination of fungal spores. These showed apoptotic properties on eukaryotic cells when tested with comet assays. Moreover, the particles are capped with a natural 40 kDa protein which was utilized as attachment sites for genes to be delivered into sarcoma cancer cells. The present work also attempted at optimizing safe dosage of these nanoparticles using hemolysis assays, for application in therapy. Large-scale production of the nanoparticles in fermentors and other possible applications of the particles have been discussed. PMID- 29767295 TI - Violation of expectations about movement and goal achievement leads to Sense of Agency reduction. AB - The control of one's own movements and of their impact on the external world generates a feeling of control referred to as Sense of Agency (SoA). SoA is experienced when actions match predictions and is reduced by unpredicted events. The present study investigated the contribution of monitoring two fundamental components of action-movement execution and goal achievement-that have been most often explored separately in previous research. We have devised a new paradigm in which participants performed goal-directed actions while viewing an avatar's hand in a mixed-reality scenario. The hand performed either the same action or a different one, simultaneously or after various delays. Movement of the virtual finger and goal attainment were manipulated, so that they could match or conflict with the participants' expectations. We collected judgments of correspondence (an explicit index of SoA that overcomes the tendency to over-attribute actions to oneself) by asking participants if the observed action was synchronous or not with their action. In keeping with previous studies, we found that monitoring both movement execution and goal attainment is relevant for SoA. Moreover, we expanded previous findings by showing that movement information may be a more constant source of SoA modulation than goal information. Indeed, an incongruent movement impaired SoA irrespective of delay duration, while a missed goal did so only when delays were short. Our novel paradigm allowed us to simultaneously manipulate multiple action features, a characteristic that makes it suitable for investigating the contribution of different sub-components of action in modulating SoA in healthy and clinical populations. PMID- 29767297 TI - Magnetic resonance assessment of fetal lung maturity: comparison between signal intensity and volume measurement. AB - PURPOSE: We evaluated the associations between gestational age (GA) and lung-to liver signal intensity ratio (LLSIR) and fetal lung volume (FLV) using magnetic resonance imaging (MRI). Moreover, we evaluated the reproducibility of these measurements. MATERIALS AND METHODS: LLSIR and FLV were measured using single shot fast spin-echo MRI in 88 consecutive fetuses. The Spearman test was used to assess the relationships between (1) LLSIR and GA, and (2) FLV and GA in 81 fetuses without lung abnormalities. Intra- and inter-observer reliabilities were assessed using intra-class correlation coefficients (ICCs). RESULTS: Overall, GA and LLSIR were significantly correlated (r = 0.62, p < 0.001). However, GA and LLSIR were only significantly correlated during the third trimester (before third trimester: r = 0.39, p = 0.08; during third trimester: r = 0.46, p < 0.001). Overall, GA and FLV were significantly correlated (r = 0.72, p < 0.001). FLV was significantly correlated with GA before (r = 0.86, p < 0.001) and during the third trimester (r = 0.47, p < 0.001). All ICCs were above 0.90. CONCLUSIONS: LLSIR and FLV are useful for the assessment of fetal lung maturity and are highly reproducible. Before the third trimester, FLV is more suitable than LLSIR for the evaluation of fetal lung maturity. PMID- 29767298 TI - [Complications and side effects of conservative treatment of rhinological diseases]. AB - BACKGROUND: The spectrum of rhinological diseases is wide, as is that of their drug-based treatment. Only 1272 compounds coded R01 (nasal preparations) are listed in the ATC group (Anatomical Therapeutic Chemical Classification). Conservative therapy of rhinological diseases additionally includes systemic (often oral) application of corticosteroids, antibiotics and immunomodulators. OBJECTIVE: The aim of this paper is to outline possible complications of medication (subdivided into classes of ingredients) commonly used to treat rhinological diseases in hospitals. Useful therapeutic and preventive measures will be presented. MATERIALS AND METHODS: Based on the expert information in the current pharmacological drug index (ATC) for the R01 group as well as literature research in the PubMed, Cochrane Library and MEDLINE databases, medication used for the treatment of rhinological diseases was analysed in terms of side effects and their frequency. RESULTS: Common side effects of intranasally applied medication are local irritations, burning, dryness and epistaxis. Orally or intravenously applied rhinological medication can affect the organs and lead to side effects such as cardiac dysrhythmia or alterations of the blood count. It is recommended that the therapeutic be selected on an individual basis and that the patient be thoroughly informed about possible side effects. CONCLUSION: Particularly when treating children or pregnant or breastfeeding women, the indications of all nasal preparations should be checked carefully. The huge variety of rhinologicals enables an optimal individual selection on the basis of consideration of known side effects. PMID- 29767300 TI - Development and evaluation of a rapid recombinase polymerase amplification assay for the detection of human enterovirus 71. AB - Enterovirus 71 (EV71) is one of the most common pathogens of hand, foot, and mouth disease (HFMD). A rapid reverse transcription recombinase polymerase amplification (RT-RPA) assay was established to detect EV71 subgenotype C4 (EV71 C4). The 95% detection limit of the RT-RPA was 3.767 log10 genomic copies (LGC)/reaction. The specificity was 100%. In a clinical sample evaluation, this approach demonstrated sufficient clinical performance when compared with a commercial RT-qPCR diagnostic kit. Thus, the RT-RPA assay may be a promising alternative for the detection of EV71-C4. PMID- 29767299 TI - Assessing the efficacy of a live vaccine against avian encephalomyelitis virus. AB - Avian encephalomyelitis virus (AEV) causes typical neurological symptoms in young chicks and a transient drop in egg production and hatchability in adult laying birds, resulting in huge economic losses in the poultry industry. An effective way to control and prevent this disease is vaccination of the flocks. Here, we assessed the efficacy of the live vaccine candidate strain GDt29 against avian encephalomyelitis virus. The GDt29 strain has low virulence, was confirmed safe, and showed no signs of pathogenicity. High titers of AEV-specific antibodies were detected in GDt29-vaccinated hens (S/P > 3.0) and their progeny (S/P > 2.0). Moreover, the eggs of GDt29-vaccinated hens with high levels of maternal antibodies were hatched successfully regardless of challenge with a heterologous AEV strain, and the GDt29 attenuated vaccine showed higher protective efficacy against AEV than the commercial vaccine. Furthermore, contact-exposed chicks bred with GDt29-vaccinated birds generated high titers against AE virus (S/P > 2.8). Collectively, our studies are proof of the principle that GDt29 might be an ideal vaccine candidate to prevent AEV infection, and they highlight the utility of using a live vaccine against AEV. PMID- 29767301 TI - Capillary electrophoresis-tandem mass spectrometry for multiclass analysis of polar marine toxins. AB - Polar marine toxins are more challenging to analyze by mass spectrometry-based methods than lipophilic marine toxins, which are now routinely measured in shellfish by multiclass reversed-phase liquid chromatography-tandem mass spectrometry (MS/MS) methods. Capillary electrophoresis (CE)-MS/MS is a technique that is well suited for the analysis of polar marine toxins, and has the potential of providing very high resolution separation. Here, we present a CE MS/MS method developed, with use of a custom-built interface, for the sensitive multiclass analysis of paralytic shellfish toxins, tetrodotoxins, and domoic acid in seafood. A novel, highly acidic background electrolyte (5 M formic acid) was designed to maximize protonation of analytes and to allow a high degree of sample stacking to improve the limits of detection. The method was applied to a wide range of regulated and less common toxin analogues, and exhibited a high degree of selectivity between toxin isomers and matrix interference. The limits of detection in mussel tissue were 0.0052 mg/kg for tetrodotoxins, 0.160 mg/kg for domoic acid, and between 0.0018 and 0.120 mg/kg for paralytic shellfish toxins, all of which showed good linearity. Minimal ionization suppression was observed when the response from neat and mussel-matrix-matched standards was corrected with multiple internal standards. Analysis of shellfish matrix reference materials and spiked samples demonstrated good accuracy and precision. Finally, the method was transferred to a commercial CE-MS/MS system to demonstrate its widespread applicability for use in both R & D and routine regulatory settings. The approach of using a highly acidic background electrolyte is of broad interest, and can be considered generally applicable to simultaneous analysis of other classes of small, polar molecules with differing pKa values. Graphical abstract ?. PMID- 29767302 TI - Amyloid causes intermittent network disruptions in cognitively intact older subjects. AB - Recent findings in AD models but also human patients suggest that amyloid can cause intermittent neuronal hyperactivity. The overall goal of this study was to use dynamic fMRI analysis combined with graph analysis to a) characterize the graph analytical signature of two types of intermittent hyperactivity (spike-like (spike) and hypersynchronus-like (synchron)) in simulated data and b) to attempt to identify one of these signatures in task-free fMRIs of cognitively intact subjects (CN) with or without increased brain amyloid. The toolbox simtb was used to generate 33 data sets with 2 short spike events, 33 with 2 synchron and 33 baseline data sets. A combination of sliding windows, hierarchical cluster analysis and graph analysis was used to characterize the spike and the synchron signature. Florbetapir-F18 PET and task-free 3 T fMRI was acquired in 49 CN (age = 70.7 +/- 6.4). Processing the real data with the same approach as the simulated data identified phases whose graph analytical signature resembled that of the synchron signature in the simulated data. The duration of these phases was positively correlated with amyloid load (r = 0.42, p < 0.05) and negatively with memory performance (r = -0.43, p < 0.05). In conclusion, amyloid positivity is associated with intermittent hyperactivity that is caused by short phases of hypersynchronous activity. The negative association with memory performance suggests that these disturbances have the potential to interfere with cognitive processes and could lead to cognitive impairment if they become more frequent or more severe with increasing amyloid deposition. PMID- 29767303 TI - The neural signatures of egocentric bias in normative decision-making. AB - Bargaining parties often disagree on what fair is, due to the reason that people are prone to believe that what favors oneself is fair, i.e., an egocentric bias. In this study, we investigated the neural signatures underlying egocentric bias in fairness decision-making, conjoining an adapted ultimatum game (UG) with event related fMRI and functional connectivity. Participants earned monetary rewards with a partner in a production stage, wherein their contributions to the earnings were manipulated. Afterwards, the joint earnings were randomly divided, and the distribution was presented simultaneously with contribution information to participants, who accepted/rejected distributions of earnings as the same manner in standard UG. We identified an egocentric bias in fairness decisions, such that participants frequently rejected self-contributed disadvantageous outcomes, but much less so in response to other-contributed advantageous outcomes, although both involved mismatch between contribution and payoff. This bias was underpinned by regions involved in representing fairness norms, including the anterior insula and dorsal anterior cingulate cortex (dACC). Furthermore, the thalamus activity was predictive of the bias, such that the level of egocentric bias decreased as a function of the activation level of the thalamus. Finally, our functional connectivity findings indicated that the thalamus worked together with insula and dACC to modulate behavioral egocentric bias in fairness-related decisions. Our findings uncover the neural basis underlying the modulation of egocentric bias in normative decision-making, and highlight the role of neural circuits associated with norm enforcement in this phenomenon. PMID- 29767304 TI - Development and Characterization of Sr-Containing Glass-Ceramic Composites Based on Biogenic Hydroxyapatite. AB - Composite materials based on hydroxyapatite are widely used for bone tissue engineering. There is evidence of a positive effect of the presence of strontium in osteoplastic materials in the case of a Ca/Sr certain ratio. To examine the effect of the addition of Sr2+, a study was made by introducing it into the material composition based on biogenic hydroxyapatite and sodium borosilicate glass (50/50% wt.). The strontium was introduced into the composition in an amount of 1% wt. Composite materials were obtained at final sintering temperatures of 780 degrees C and a sintering time of 1 h. The effect of additions of glass phase and strontium affect changes in the crystal lattice of biogenic hydroxyapatite was investigated with the help of X-ray phase analysis, IR spectroscopy. Also the behavior of composites in vitro in physiological solution was studied. PMID- 29767305 TI - Modulation of Morphology and Optical Property of Multi-Metallic PdAuAg and PdAg Alloy Nanostructures. AB - In this work, the evolution of PdAg and PdAuAg alloy nanostructures is demonstrated on sapphire (0001) via the solid-state dewetting of multi-metallic thin films. Various surface configurations, size, and arrangements of bi- and tri metallic alloy nanostructures are fabricated as a function of annealing temperature, annealing duration, film thickness, and deposition arrangements such as bi-layers (Pd/Ag), tri-layers (Pd/Au/Ag), and multi-layers (Pd/Au/Ag * 5). Specifically, the tri-layers film shows the gradual evolution of over-grown NPs, voids, wiggly nanostructures, and isolated PdAuAg alloy nanoparticles (NPs) along with the increased annealing temperature. In contrast, the multi-layers film with same thickness show the enhanced dewetting rate, which results in the formation of voids at relatively lower temperature, wider spacing, and structural regularity of alloy NPs at higher temperature. The dewetting enhancement is attributed to the increased number of interfaces and reduced individual layer thickness, which aid the inter-diffusion process at the initial stage. In addition, the time evolution of the Pd150 nm/Ag80 nm bi-layer films at constant temperature show the wiggly-connected and isolated PdAg alloy NPs. The overall evolution of alloy NPs is discussed based on the solid-state dewetting mechanism in conjunction with the diffusion, inter-diffusion, alloying, sublimation, Rayleigh instability, and surface energy minimization. Depending upon their surface morphologies, the bi- and tri-metallic alloy nanostructures exhibit the dynamic reflectance spectra, which show the formation of dipolar (above 700 nm) and quadrupolar resonance peaks (~ 380 nm) and wide dips in the visible region as correlated to the localized surface plasmon resonance (LSPR) effect. An absorption dip is readily shifted from ~ 510 to ~ 475 nm along with the decreased average size of alloy nanostructures. PMID- 29767306 TI - Correction to: Results of nimotuzumab and vinorelbine, radiation and re irradiation for diffuse pontine glioma in childhood. AB - The therapeutic experience reported in the paper was conceived after the use of nimotuzumab and radiotherapy (BSCPED-05 international multicentric trial, EUDRACT 2005-003100-11) in 2009 when we decided to explore the activity of the same combination plus vinorelbine (see the paper for the rationale). PMID- 29767308 TI - Differentiating pseudoprogression from true progression: analysis of radiographic, biologic, and clinical clues in GBM. AB - INTRODUCTION: Pseudoprogression (PsP) is a diagnostic dilemma in glioblastoma (GBM) after chemoradiotherapy (CRT). Magnetic resonance imaging (MRI) features may fail to distinguish PsP from early true progression (eTP), however clinical findings may aid in their distinction. METHODS: Sixty-seven patients received CRT for GBM between 2003 and 2016, and had pre- and post-treatment imaging suitable for retrospective evaluation using RANO criteria. Patients with signs of progression within the first 12-weeks post-radiation (P-12) were selected. Lesions that improved or stabilized were defined as PsP, and lesions that progressed were defined as eTP. RESULTS: The median follow up for all patients was 17.6 months. Signs of progression developed in 35/67 (52.2%) patients within P-12. Of these, 20/35 (57.1%) were subsequently defined as eTP and 15/35 (42.9%) as PsP. MRI demonstrated increased contrast enhancement in 84.2% of eTP and 100% of PsP, and elevated CBV in 73.7% for eTP and 93.3% for PsP. A decrease in FLAIR was not seen in eTP patients, but was seen in 26.7% PsP patients. Patients with eTP were significantly more likely to require increased steroid doses or suffer clinical decline than PsP patients (OR 4.89, 95% CI 1.003-19.27; p = 0.046). KPS declined in 25% with eTP and none of the PsP patients. CONCLUSIONS: MRI imaging did not differentiate eTP from PsP, however, KPS decline or need for increased steroids was significantly more common in eTP versus PsP. Investigation and standardization of clinical assessments in response criteria may help address the diagnostic dilemma of pseudoprogression after frontline treatment for GBM. PMID- 29767309 TI - The reactivity of Fe/Ni colloid stabilized by carboxymethylcellulose (CMC-Fe/Ni) toward chloroform. AB - The use of stabilizers can prevent the reactivity loss of nanoparticles due to aggregation. In this study, carboxymethylcellulose (CMC) was selected as the stabilizer to synthesize a highly stable CMC-stabilized Fe/Ni colloid (CMC-Fe/Ni) via pre-aggregation stabilization. The reactivity of CMC-Fe/Ni was evaluated via the reaction of chloroform (CF) degradation. The effect of background solution which composition was affected by the preparation of Fe/Ni (Fe/Ni precursors, NaBH4 dosage) and the addition of solute (common ions, sulfur compounds) on the reactivity of CMC-Fe/Ni was also investigated. Additionally, the dried CMC-Fe/Ni was used for characterization in terms of scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The experimental results indicated that CMC stabilization greatly improved the reactivity of Fe/Ni bimetal and CF (10 mg/L) could be completely degraded by CMC-Fe/Ni (0.1 g/L) within 45 min. The use of different Fe/Ni precursors resulting in the variations of background solution seemed to have no obvious influence on the reactivity of CMC-Fe/Ni, whereas the dosage of NaBH4 in background solution showed a negative correlation with the reactivity of CMC-Fe/Ni. Besides, the individual addition of external solutes into background solution all had an adverse effect on the reactivity of CMC Fe/Ni, of which the poisoning effect of sulfides (Na2S, Na2S2O4) was significant than common ions and sulfite. PMID- 29767310 TI - The removal of silver nanoparticle by titanium tetrachloride and modified sodium alginate composite coagulants: floc properties, membrane fouling, and floc recycle. AB - In this study, a modified sodium alginate (MSA) composited with TiCl4 was used to treat the synthetic Ag nanoparticles (AgNPs) water in coagulation-ultrafiltration process. The floc properties and membrane fouling of TiCl4 and MSA composite coagulants (TiCl4 + MSA) were investigated by a laser diffraction instrument and ultrafiltration fouling model. The recycle of the AgNP-containing flocs was evaluated by XRD and photocatalytic experiments. The results showed that TiCl4 + MSA could achieve better coagulation performance than TiCl4 alone with AgNP and DOC removal up to 97 and 59% at the optimum condition (pH = 5 and dosage = 12 mg TiCl4/L). TiCl4 + MSA produced larger and looser flocs than TiCl4 and TiCl4 + SA composite coagulant (TiCl4 + SA), which was benefit for the inhibition of subsequence membrane fouling. The strongly attached external fouling resistance (Ref-s) and the reversible internal fouling resistance (Rif-r) of TiCl4 + MSA were only 43 and 39.2% of those achieved by TiCl4 at the optimal coagulation condition. Besides, the adopted AgCl-TiO2 could be recycled from AgNP-containing flocs. And MSA could promote the form of TiO2 anatase. It gives us a possible way for silver nanoparticle recycle. PMID- 29767312 TI - [Fast-track protocols in esophageal surgery - what is possible?] PMID- 29767311 TI - Developing a non-point source P loss indicator in R and its parameter uncertainty assessment using GLUE: a case study in northern China. AB - Uncertainty analysis is an important prerequisite for model application. However, the existing phosphorus (P) loss indexes or indicators were rarely evaluated. This study applied generalized likelihood uncertainty estimation (GLUE) method to assess the uncertainty of parameters and modeling outputs of a non-point source (NPS) P indicator constructed in R language. And the influences of subjective choices of likelihood formulation and acceptability threshold of GLUE on model outputs were also detected. The results indicated the following. (1) Parameters RegR2, RegSDR2, PlossDP fer , PlossDP man , DPDR, and DPR were highly sensitive to overall TP simulation and their value ranges could be reduced by GLUE. (2) Nash efficiency likelihood (L1) seemed to present better ability in accentuating high likelihood value simulations than the exponential function (L2) did. (3) The combined likelihood integrating the criteria of multiple outputs acted better than single likelihood in model uncertainty assessment in terms of reducing the uncertainty band widths and assuring the fitting goodness of whole model outputs. (4) A value of 0.55 appeared to be a modest choice of threshold value to balance the interests between high modeling efficiency and high bracketing efficiency. Results of this study could provide (1) an option to conduct NPS modeling under one single computer platform, (2) important references to the parameter setting for NPS model development in similar regions, (3) useful suggestions for the application of GLUE method in studies with different emphases according to research interests, and (4) important insights into the watershed P management in similar regions. PMID- 29767307 TI - Virus vector-mediated genetic modification of brain tumor stromal cells after intravenous delivery. AB - The malignant primary brain tumor, glioblastoma (GBM) is generally incurable. New approaches are desperately needed. Adeno-associated virus (AAV) vector-mediated delivery of anti-tumor transgenes is a promising strategy, however direct injection leads to focal transgene spread in tumor and rapid tumor division dilutes out the extra-chromosomal AAV genome, limiting duration of transgene expression. Intravenous (IV) injection gives widespread distribution of AAV in normal brain, however poor transgene expression in tumor, and high expression in non-target cells which may lead to ineffective therapy and high toxicity, respectively. Delivery of transgenes encoding secreted, anti-tumor proteins to tumor stromal cells may provide a more stable and localized reservoir of therapy as they are more differentiated than fast-dividing tumor cells. Reactive astrocytes and tumor-associated macrophage/microglia (TAMs) are stromal cells that comprise a large portion of the tumor mass and are associated with tumorigenesis. In mouse models of GBM, we used IV delivery of exosome-associated AAV vectors driving green fluorescent protein expression by specific promoters (NF-kappaB-responsive promoter and a truncated glial fibrillary acidic protein promoter), to obtain targeted transduction of TAMs and reactive astrocytes, respectively, while avoiding transgene expression in the periphery. We used our approach to express the potent, yet toxic anti-tumor cytokine, interferon beta, in tumor stroma of a mouse model of GBM, and achieved a modest, yet significant enhancement in survival compared to controls. Noninvasive genetic modification of tumor microenvironment represents a promising approach for therapy against cancers. Additionally, the vectors described here may facilitate basic research in the study of tumor stromal cells in situ. PMID- 29767313 TI - [Reddish node on the scalp of a young man]. PMID- 29767315 TI - Current state of surgical training using cadavers in Japan compared with Western countries. AB - Surgical skill training using cadavers is important for surgeons to gain an understanding of anatomical approaches. However, the laws and guidelines stipulating surgical technique training using corpses differ in each country. We discuss the new guidelines and the current situation in Japan in comparison with that in Western Europe and the United States. PMID- 29767314 TI - Minimally invasive reduction and percutaneous posterior fixation of one-level traumatic thoraco-lumbar and lumbar spine fractures. AB - INTRODUCTION: Although open procedures are the gold standard, the alternative approach of minimal invasive reduction using percutaneous screws for thoracic and lumbar spine fractures is under discussion. Aim of this study was to investigate the results of reduction and the accuracy of screw placement in minimally invasive percutaneous posterior instrumentation for these fractures. MATERIALS AND METHODS: One hundred and twenty-seven patients with thoraco-lumbar and lumbar burst fractures and minimal invasive dorsal instrumentation were analyzed retrospectively in terms of the accuracy of pedicle screw placement and results of fracture reduction. RESULTS: In total, 542 screws were placed. Thirty-four (6.3%) screws of 22 patients (17.3%) were misplaced, but misplacement was minimal, replacement of any screw position due to instability was not necessary, and no new neurological deficit occurred. In thoraco-lumbar fractures (82/64.5%), reduction succeeded from 2.5 +/- 6 degrees kyphosis to 5.6 +/- 5.7 degrees lordosis (p < 0.001) and in lumbar spine fractures from 6.9 degrees +/- 10.3 degrees lordosis to 14.5 degrees +/- 8.8 degrees lordosis (p < 0.001). CONCLUSION: Minimal invasive percutaneous dorsal instrumentation of burst fractures of the thoraco-lumbar and lumbar spine provides adequate reduction and reliable regular screw placement. LEVEL OF EVIDENCE: Level IV (retrospective series). PMID- 29767316 TI - [CEUS-diagnosis of solid renal tumors]. AB - CLINICAL ISSUE: Renal lesions are detected earlier, often as a result of ultrasound examinations. However, the imaging-based differential diagnosis of different tumour entities remains challenging STANDARD RADIOLOGICAL METHODS: All renal tumours >1 cm should be evaluated for malignancy by computed tomography (CT) or magnetic resonance imaging (MRI). If an angiomyolipoma diagnosis cannot be established with imaging, further diagnostics are appropriate or if malignant progression is suspected, then multidisciplinary discussion for TNM-staging based uro-oncologic therapy is usual. METHODICAL INNOVATIONS: Contrast-enhanced ultrasound (CEUS) gives clear information about the microperfusion of renal tumours. PERFORMANCE: CEUS is helpful for the differentiation of renal cysts and especially papillary renal cell carcinomas. Moreover, CEUS advances renal tumour detection compared to B-mode and Doppler ultrasound per se. Cortical pseudolesions may be confidently ruled out using CEUS. ACHIEVEMENTS: Clear differentiation of benign and malignant renal lesions >1 cm remains challenging, and only in rare cases is it possible with CEUS alone. Nevertheless CEUS is, in combination with other ultrasound techniques, eminently suitable for diagnosing focal pyelonephritis, renal abscesses and suspected renal lymphoma and supports the planning of ultrasound-assisted tumour biopsies. PRACTICAL RECOMMENDATIONS: Combining different imaging techniques is essential to accurately diagnose renal tumors. These imaging results (including the ultrasound/CEUS clips) should be viewed by the multidisciplinary cancer tumour board to facilitate individual treatment concepts for each patient. PMID- 29767317 TI - Successful Sequential Treatment with Itraconazole and ALA-PDT for Cutaneous Granuloma by Candida albicans: A Case Report and Literature Review. AB - Photodynamic therapy (PDT) is a process that combines a photosensitizing drug and light and promotes phototoxic responses in target cells, mainly via oxidative damage. Antifungal photodynamic therapy has been successfully employed against Candida species, dermatophytes, and deep mycoses. We present a case of a cutaneous granuloma caused by C. albicans treated with 5-aminolevulinic acid (ALA)-PDT. A 64-year-old man presented with two plaques on his right hand and wrist for 2 years. The diagnosis was made based on histopathology, mycology, and molecular identification of paraffin-embedded tissues. The patient was treated with itraconazole for 1 month and two sessions of ALA-PDT. After 2 months of follow-up, the patient was cured and has not experienced any recurrence to date. ALA-PDT was well tolerated in this patient with little pain. In general, application of PDT in mycoses is safe and effective in most cases. ALA-PDT is a good choice for inactivation of C. albicans. PMID- 29767318 TI - Strategies for Effective Discontinuation of Proton Pump Inhibitors. AB - PURPOSE OF REVIEW: Proton pump inhibitors (PPIs) are effective for many conditions but are often overprescribed. Recent concerns about long-term risks have made patients re-evaluate their need to take PPIs chronically, though these population-based studies have methodological weaknesses. The goal of this review is to provide evidenced-based strategies for discontinuation of PPI therapy. RECENT FINDINGS: Given that some patients experience rebound symptoms when abruptly stopping continuous PPI therapy due to its effect on hypergastrinemia, strategies focus on avoiding rebound. Tapering the PPI and then initiating a "step-down" approach with the use of alternative medications may be effective. "On-demand therapy" provides patients with the option to take intermittent PPI courses, reducing overall use and cost while preserving patient satisfaction. It is important for providers to consider ambulatory pH or pH/impedance testing to rule out diagnoses that may require alternative medications like neuromodulators. A number of studies reviewed here can provide guidance in counseling patients on PPI discontinuation. It is important for the provider to obtain a baseline needs assessment for PPI therapy and to elucidate predictors of difficulty in discontinuation prior to initiating a strategy. PMID- 29767321 TI - Arterial pressure targets in patients with septic shock and prior hypertension: should we throw SEPSISPAM findings out with the bathwater? PMID- 29767320 TI - Post-hepatectomy liver failure after major hepatic surgery: not only size matters. AB - OBJECTIVES: To compare the value of functional future liver remnant (functFLR) to established clinical and imaging variables in prediction of post-hepatectomy liver failure (PHLF) after major liver resection. METHODS: This retrospective, cross-sectional study included 62 patients, who underwent gadoxetic acid enhanced MRI and MDCT within 10 weeks prior to resection of >= 4 liver segments. Future liver remnant (FLR) was measured in MDCT using semi-automatic software. Relative liver enhancement for each FLR segment was calculated as the ratio of signal intensity of parenchyma before and 20 min after i.v. administration of gadoxetic acid and given as mean (remnantRLE). Established variables included indocyanine green clearance, FLR, proportion of FLR, weight-adapted FLR and remnantRLE. functFLR was calculated as FLR multiplied by remnantRLE and divided by patient's weight. The association of measured variables and PHLF was tested with univariate and multivariate logistic regression analysis and receiver operator characteristics (ROC) curves compared with the DeLong method. RESULTS: Sixteen patients (25.8%) experienced PHLF. Univariate logistic regression identified FLR (p = 0.015), proportion of FLR (p = 0.004), weight-adapted FLR (p = 0.003), remnantRLE (p = 0.002) and functFLR (p = 0.002) to be significantly related to the probability of PHLF. In multivariate logistic regression analysis, a decreased functFLR was independently associated with the probability of PHLF (0.561; p = 0.002). Comparing ROC curves, functFLR showed a significantly higher area under the curve (0.904; p < 0.001) than established variables. CONCLUSIONS: functFLR seems to be superior to established variables in prediction of PHLF after major liver resection. KEY POINTS: * functFLR is a parameter combining volumetric and functional imaging information, derived from MDCT and gadoxetic acid enhanced MRI. * In comparison to other established methods, functFLR is superior in prediction of post-hepatectomy liver failure. * functFLR could help to improve patient selection prior major hepatic surgery. PMID- 29767319 TI - Endoscopic vs. microscopic transsphenoidal surgery for Cushing's disease: a systematic review and meta-analysis. AB - PURPOSE: Systematic review and meta-analysis comparing endoscopic and microscopic transsphenoidal surgery for Cushing's disease regarding surgical outcomes (remission, recurrence, and mortality) and complication rates. To stratify the results by tumor size. METHODS: Nine electronic databases were searched in February 2017 to identify potentially relevant articles. Cohort studies assessing surgical outcomes or complication rates after endoscopic or microscopic transsphenoidal surgery for Cushing's disease were eligible. Pooled proportions were reported including 95% confidence intervals. RESULTS: We included 97 articles with 6695 patients in total (5711 microscopically and 984 endoscopically operated). Overall, remission was achieved in 5177 patients (80%), with no clear difference between both techniques. Recurrence was around 10% and short term mortality < 0.5% for both techniques. Cerebrospinal fluid leak occurred more often in endoscopic surgery (12.9 vs. 4.0%), whereas transient diabetes insipidus occurred less often (11.3 vs. 21.7%). For microadenomas, results were comparable between both techniques. For macroadenomas, the percentage of patients in remission was higher after endoscopic surgery (76.3 vs. 59.9%), and the percentage recurrence lower after endoscopic surgery (1.5 vs. 17.0%). CONCLUSIONS: Endoscopic surgery for patients with Cushing's disease reaches comparable results for microadenomas, and probably better results for macroadenomas than microscopic surgery. This is present despite the presumed learning curve of the newer endoscopic technique, although confounding cannot be excluded. Based on this study, endoscopic surgery may thus be considered the current standard of care. Microscopic surgery can be used based on neurosurgeon's preference. Endocrinologists and neurosurgeons in pituitary centers performing the microscopic technique should at least consider referring Cushing's disease patients with a macroadenoma. PMID- 29767324 TI - An Empiric Risk Score to Guide PrEP Targeting Among MSM in Coastal Kenya. AB - Men who have sex with men (MSM), who have heterogeneous HIV-acquisition risks are not specifically targeted in Kenyan pre-exposure prophylaxis (PrEP) guidelines. We used data from an open cohort, which followed 753 initially HIV-negative MSM participants for more than 1378.5 person-years, to develop an empiric risk score for targeting PrEP delivery. Independent predictors of incident HIV-1 infection in this cohort were an age of 18-24 years, having only male sex partners, having receptive anal intercourse, having any unprotected sex, and having group sex. Poisson model coefficients were used to assign a numeric score to each statistically significant predictor. A risk score of >= 1 corresponded to an HIV 1 incidence of >= 2.2 [95% confidence interval (CI) 1.2-4.1] and identified 81.3% of the cohort participants as being at high risk for HIV-1 acquisition. The area under the receiver operating characteristic curve was 0.76 (95% CI 0.71-0.80). This empiric risk score may help Kenyan health care providers to assess HIV-1 acquisition risk and encourage PrEP uptake by high-risk MSM. PMID- 29767327 TI - Follow-up after curative treatment of localised renal cell carcinoma. AB - PURPOSE: Patients with localised renal cell carcinoma (RCC) receiving curative surgery, either radical or partial nephrectomy, have been shown in contemporary studies to develop recurrence within 5 years in 20-30% of case. Therefore, post operative follow-up (FU) imaging plays a crucial role in detecting recurrent or metastatic disease. A number of prognostic scores have been developed to predict risk of recurrence. This review summarises the current knowledge on established FU protocols and their limitations. METHODS: A non-systematic literature search was conducted using Medline. Furthermore, major guidelines [European Association of Urology (EAU), American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN)] were reviewed and assessed. RESULTS: The EAU, AUA and NCCN post-operative follow-up guidelines differ in the frequency and type of imaging modalities recommended. The optimal duration of follow-up remains to be elucidated as does the impact of follow-up protocols on patient outcomes and quality of life. Established follow-up protocols do not take non-RCC-related factors, such as patient age and performance status into account. However, in the future individualised duration of FU based on competing risks of cancer recurrence and non-RCC death may be optimised, maximising resources and patient quality of life. CONCLUSION: There is a clear need to establish evidence-based follow-up protocols and to assess the impact of follow-up protocols on individual patients and society. PMID- 29767326 TI - Fluorescence-supported lymphography and extended pelvic lymph node dissection in robot-assisted radical prostatectomy: a prospective, randomized trial. AB - PURPOSE: To demonstrate the benefits of fluorescence-supported extended pelvic lymph node dissection (ePLND) compared to regular ePLND in robot-assisted radical prostatectomy. METHODS: 120 patients with intermediate- or high-risk prostate cancer were prospectively randomized (1:1): in the intervention group, indocyanine green (ICG) was injected transrectally into the prostate before docking of the robot. In both groups, ePLND was performed including additional dissection of fluorescent lymph nodes (LN) in the ICG group. RESULTS: After drop out of two patients, 59 patients were allocated to the control (A) and intervention group (B) with a median PSA of 8,6 ng/ml. Median console time was 159 (A) vs. 168 (B) min (p = 0.20) with a longer time for ICG-ePLND: 43 (A) vs. 55 min (B) (p = 0.001). 2609 LN were found with significantly more LN after ICG supported ePLND with a median of 25 vs. 17 LN in A (p < 0.001). Nodal metastases were detected in 6 patients in A (25 cancerous LN) vs. 9 patients in B (62 positive LN) (p = 0.40). In seven of nine patients, ICG-ePLND identified at least one cancer-positive LN (sensitivity 78%), 27 of 62 cancerous LN were fluorescent. Symptomatic lymphocele occurred in one patient in a and in three patients in b (p = 0.62). After a median follow-up of 22.9 months, PSA levels were similar. CONCLUSIONS: While ICG-ePLND seems to be beneficial for a better understanding of the lymphatic drainage and a more meticulous diagnostic approach, the sensitivity is not sufficient to recommend stand-alone ICG lymph node dissection. PMID- 29767322 TI - Management of cardiogenic shock complicating myocardial infarction. AB - Up to 10% of acute coronary syndromes are complicated by cardiogenic shock (CS) with contemporary mortality rates of 40-50%. The extent of ischemic myocardium has a profound impact on the initial, in-hospital, and post-discharge management and prognosis in this patient population. Individualized patient risk assessment plays an important role in determining appropriate revascularization, drug treatment with inotropes and vasopressors, mechanical circulatory support, intensive care support of other organ systems, hospital level of care triage, and allocation of clinical resources. This review will outline the underlying causes and diagnostic criteria, pathophysiology, and treatment of CS complicating acute coronary syndromes with a focus on (a) potential therapeutic issues from the perspective an interventional cardiologist, an emergency physician, and an intensive care physician, (b) the type of revascularization, and PMID- 29767325 TI - Associations with Unprotected Sexual Behavior Among HIV-Infected Drinkers in Western Kenya. AB - Approximately 71% of HIV-infected individuals live in sub-Saharan Africa. Alcohol use increases unprotected sex, which can lead to HIV transmission. Little research examines risky sex among HIV-infected individuals in East Africa who are not sex workers. The study purpose was to examine associations with unprotected sex in a high-risk sample of 507 HIV-infected sexually active drinkers in western Kenya. They were enrolled in a trial to reduce alcohol use. Past-month baseline alcohol use and sexual behavior were assessed using the Timeline Followback. A zero-inflated negative binomial model examined associations with occurrence and frequency of unprotected sex. Results showed heavy drinking days were significantly associated with unprotected sex occurrence across gender, and with unprotected sex frequency among women. Among women, transactional sex, alcohol related sexual expectations, condom use self-efficacy, drinking-and-protected-sex days and age were associated with unprotected sex occurrence while alcohol related sexual expectations, depressive symptoms and condom use self-efficacy were associated with unprotected sex frequency. Among men, alcohol-related sexual expectations, condom use self-efficacy, and age were associated with unprotected sex occurrence, while drinking-and-protected-sex days were associated with unprotected sex occurrence and frequency. Findings suggest robust relationships between heavy drinking and unprotected sex. Further research is needed elucidating the temporal relationships between drinking and unprotected sex in this population. PMID- 29767328 TI - A placebo-controlled efficacy study of the intravesical immunomodulators TMX-101 and TMX-202 in an orthotopic bladder cancer rat model. AB - PURPOSE: TMX-101 and TMX-202 are formulations of toll-like receptor 7 (TLR-7) agonists, under investigation for the treatment of urothelial carcinoma. Our goal was to evaluate the efficacy of intravesical instillations of TMX-101 or TMX-202 in an orthotopic bladder cancer rat model. METHODS: Four groups of 14 rats received an instillation with isogenic AY-27 tumor cells on day 0, starting tumor development. On day 2 and 5, the rats were treated with an intravesical instillation of TMX-101 0.1%, TMX-202 0.38%, vehicle solution or NaCl. On day 12 the rats were sacrificed and the bladders were evaluated histopathologically. RESULTS: No signs of toxicity were seen. The number of tumor-positive rats was 11 of 14 (79%) in the vehicle control group and in the NaCl control group, versus 9 of 14 (64%) in the TMX-101-treated group, and 8 of 14 (57%) in the TMX-20-treated group. The difference between tumor-bearing rats in the treated and control groups was not significant (p = 0.12). Bladder weight was significantly lower for TMX-202-treated rats compared to vehicle (p = 0.005). CONCLUSIONS: TMX-101 and TMX-202 are TLR-7 agonists with antitumor activity. Treatment with TMX-101 and TMX-202 resulted in less tumor-bearing rats compared to vehicle or saline control groups, although not statistically significant. In this aggressive bladder cancer model, a lower number of tumor-positive rats after treatment with TLR-7 agonists indicates activity for the treatment of non-muscle invasive bladder cancer. PMID- 29767330 TI - Comparison of procedural success between two radial sheaths : Comparison of the 6 Fr Glidesheath Slender to 6-Fr standard sheath. AB - BACKGROUND: The most common cause of procedural failure in cardiac catheterization using the transradial approach is radial artery spasm. The aim of this study was to compare the procedural success rate of the 6-Fr Glidesheath Slender with the 6-Fr standard sheath in transradial coronary angiography and intervention. METHODS: Patients who underwent percutaneous coronary angiography via the transradial approach through placement of a 6-Fr Glidesheath Slender or a 6-Fr standard sheath for primary radial access were prospectively enrolled in the study. RESULTS: The study included 200 cases: 76 patients undergoing percutaneous coronary angiography with the Glidesheath Slender and 124 patients with the standard sheath. Failed procedures were recorded for 19 patients (9.5%), defined as inability to complete the procedure via the primary access. There was no difference in the percentage of failed cases between the Glidesheath Slender and standard sheath groups (10.5% vs. 8.9%, OR = 1.21, p = 0.8). More cases of spasm were observed in the Glidesheath Slender group compared with the standard sheath group, which was not statistically significant (7.9% vs. 5.7%, OR = 1.43, p = 0.56). Smoking, hyperlipidemia, and age influenced the procedural outcome in the Glidesheath Slender group, while body mass index, sex, and smoking impacted the procedural outcome in the standard sheath group. CONCLUSION: There is no difference in procedural success rates, as defined by the ability to complete the procedure via primary radial access, between the 6-Fr Glidesheath Slender and the 6-Fr standard sheath. Our study suggests that the patient characteristics that elevate the risk of procedural failure for Glidesheath Slender may differ from those for the standard sheath. PMID- 29767329 TI - Validity of the EQ-5D-5L and reference norms for the Spanish population. AB - BACKGROUND AND OBJECTIVE: The EuroQol 5 dimensions 5 levels (EQ-5D-5L) is the new version of EQ-5D, developed to improve its discriminatory capacity. This study aims to evaluate the construct validity of the Spanish version and provide index and dimension population-based reference norms for the new EQ-5D-5L. METHODS: Data were obtained from the 2011/2012 Spanish National Health Survey, with a representative sample (n = 20,587) of non-institutionalized Spanish adults (>= 18 years). The EQ-5D-5L index was calculated by using the Spanish value set. Construct validity was evaluated by comparing known groups with estimators obtained through regression models, adjusted by age and gender. Sampling weights were applied to restore the representativeness of the sample and to calculate the norms stratified by gender and age groups. We calculated the percentages and standard errors of dimensions, and the deciles, percentiles 5 and 95, means, and 95% confidence intervals of the health index. RESULTS: All the hypotheses established a priori for known groups were confirmed (P < 0.001). The EQ-5D-5L index indicated worse health in groups with lower education level (from 0.94 to 0.87), higher number of chronic conditions (0.96-0.79), probable psychiatric disorder (0.94 vs 0.80), strong limitations (0.96-0.46), higher number of days of restriction (0.93-0.64) or confinement to bed (0.92-0.49), and hospitalized in the previous 12 months (0.92 vs 0.81). CONCLUSIONS: The EQ-5D-5L is a valid instrument to measure perceived health in the Spanish-speaking population. The representative population-based norms provided here will help improve the interpretation of results obtained with the new EQ-5D-5L. PMID- 29767323 TI - Prevalence and risk factors related to haloperidol use for delirium in adult intensive care patients: the multinational AID-ICU inception cohort study. AB - PURPOSE: We assessed the prevalence and variables associated with haloperidol use for delirium in ICU patients and explored any associations of haloperidol use with 90-day mortality. METHODS: All acutely admitted, adult ICU patients were screened during a 2-week inception period. We followed the patient throughout their ICU stay and assessed 90-day mortality. We assessed patients and their variables in the first 24 and 72 h in ICU and studied their association together with that of ICU characteristics with haloperidol use. RESULTS: We included 1260 patients from 99 ICUs in 13 countries. Delirium occurred in 314/1260 patients [25% (95% confidence interval 23-27)] of whom 145 received haloperidol [46% (41 52)]. Other interventions for delirium were benzodiazepines in 36% (31-42), dexmedetomidine in 21% (17-26), quetiapine in 19% (14-23) and olanzapine in 9% (6 12) of the patients with delirium. In the first 24 h in the ICU, all subtypes of delirium [hyperactive, adjusted odds ratio (aOR) 29.7 (12.9-74.5); mixed 10.0 (5.0-20.2); hypoactive 3.0 (1.2-6.7)] and circulatory support 2.7 (1.7-4.3) were associated with haloperidol use. At 72 h after ICU admission, circulatory support remained associated with subsequent use of haloperidol, aOR 2.6 (1.1-6.9). Haloperidol use within 0-24 h and within 0-72 h of ICU admission was not associated with 90-day mortality [aOR 1.2 (0.5-2.5); p = 0.66] and [aOR 1.9 (1.0 3.9); p = 0.07], respectively. CONCLUSIONS: In our study, haloperidol was the main pharmacological agent used for delirium in adult patients regardless of delirium subtype. Benzodiazepines, other anti-psychotics and dexmedetomidine were other frequently used agents. Haloperidol use was not statistically significantly associated with increased 90-day mortality. PMID- 29767331 TI - Nonomuraea insulae sp. nov., isolated from forest soil. AB - Strain H2R21T, a novel actinobacterium, isolated from a forest soil sample collected from Heybeliada, Istanbul, Turkey, and a polyphasic approach was used for characterisation of the strain. Chemotaxonomic and morphological characterisation of strain H2R21T indicated that it belongs to the genus Nonomuraea. 16S rRNA gene sequence similarity showed that the strain is closely related to Nonomuraea purpurea 1SM4-01T (99.1%) and Nonomuraea solani CGMCC 4.7037T (98.4%). DNA-DNA relatedness values were found to be lower than 70% between the isolate and its phylogenetic neighbours N. purpurea 1SM4-01T, N. solani CGMCC 4.7037T and Nonomuraea rhizophila YIM 67092T. The whole cell hydrolysates of strain H2R21T were found to contain meso-diaminopimelic acid as the diagnostic diamino acid and glucose, madurose, mannose and ribose as the cell sugars. The polar lipids were identified as phosphatidylglycerol, diphosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine, hydroxy-phosphatidylethanolamine, dihydroxy-phosphatidylethanolamine, phosphatidylinositol, glycophosphatidylinositol, two glycophospholipids and two unidentified lipids. The predominant menaquinones were identified as MK-9(H4) and MK-9(H6). The major fatty acids were found to be iso-C16:0, iso-C16:0 2OH and C17:0 10-methyl. On the basis of DNA-DNA relatedness data and some phenotypic characteristics, it is evident that strain H2R21T can be distinguished from the closely related species in the genus Nonomuraea. Thus, it is concluded that strain H2R21T represents a novel species of the genus Nonomuraea, for which the name Nonomuraea insulae sp. nov. is proposed. The type strain is H2R21T (= DSM 102915T = CGMCC 4.7338T = KCTC 39769T). PMID- 29767333 TI - Laparoscopic adhesiolysis: not for all patients, not for all surgeons, not in all centres. AB - ASBO is a common cause of emergency surgery and the use of laparoscopy for the treatment of these patients is still under debate and conflicting results have been published, in particular regarding the high risk of iatrogenic bowel injury. In fact, although over the last few years there has been an increasing enthusiasm in the surgical community about the advantages and potential better outcomes of laparoscopic management of adhesive small bowel obstruction (ASBO), recently published studies have introduced a significant word of caution. From 2011 in our centre, we have started to systematically approach ASBO in carefully selected patients with a step-by-step standardized laparoscopic procedure, developed and performed by a single operator experienced in emergency laparoscopy, collecting data in a prospective database. Inclusion criteria were: stable patients (without diffuse peritonitis and/or septic shock with suspicion of bowel perforation), CT scan findings consistent with a clear transition point and therefore suspected to have a single obstructing adhesive band. Patients with diffuse SB distension in the absence of a well-defined transition point and suspected to have diffuse matted adhesions (based on their surgical history and radiological findings) should be initially managed conservatively, including gastrografin challenge. Up to date, 83 patients were enrolled in the study. The rate of iatrogenic full thickness bowel injury was 4/83 (4.8%); two of these cases were managed with simple repair and the other two required bowel resection and anastomosis. Conversion to open was performed in 3/4 of these cases, whereas in one a repair of the full-thickness injury was completed laparoscopically. All the iatrogenic injuries were detected intraoperatively and none of the reoperations that occurred in this series were due to missed bowel injuries. At 30 days follow-up, none reported incisional hernias or SSI or death. With the described accurate selection of patients, the use of such standardized step-by-step technique and in the presence of dedicated operating surgeons with advanced emergency surgery laparoscopic expertise, such procedure can be safe and feasible with multiple advantages in terms of morbidity and LOS. A careful preoperative selection of those patients who might be best candidates for laparoscopic adhesiolysis is needed. The level of laparoscopic expertise can also be highly variable, and not having advanced surgical expertise in the specific subspecialty of emergency laparoscopy, ultimately resulting in performing standardized procedures with proper careful and safe step-by-step technique, is highly recommended. PMID- 29767334 TI - Are phloem-derived amino acids the origin of the elevated malate concentration in the xylem sap following mineral N starvation in soybean? AB - MAIN CONCLUSION: A substantial increase in malate in the xylem sap of soybean subjected to mineral N starvation originates mainly from aspartate, a prominent amino acid of the phloem. A substantial increase in xylem malate was found when non-nodulated soybean plants were transferred to a N-free medium. Nodulated plants growing in the absence of mineral N and, therefore, dependent on symbiotic N2 fixation also contained elevated concentrations of malate in the xylem sap. When either nitrate or ammonium was supplied, malate concentrations in the xylem sap were low, both for nodulated and non-nodulated plants. Evidence was obtained that the elevated malate concentration of the xylem was derived from amino acids supplied by the phloem. Aspartate was a prominent component of the phloem sap amino acids and, therefore, a potential source of malate. Supplying the roots of intact plants with 13C-aspartate revealed that malate of the xylem sap was readily labelled under N starvation. A hypothetical scheme is proposed whereby aspartate supplied by the phloem is metabolised in the roots and the products of this metabolism cycled back to the shoot. Under N starvation, aspartate metabolism is diverted from asparagine synthesis to supply N for the synthesis of other amino acids via transaminase activity. The by-product of aspartate transaminase activity, oxaloacetate, is transformed to malate and its export accounts for much of the elevated concentration of malate found in the xylem sap. This mechanism represents a new additional role for malate during mineral N starvation of soybean, beyond that of charge balance. PMID- 29767336 TI - [Contribution of natural spaces to human health and wellbeing]. AB - Natural spaces and especially urban green and blue spaces have been recognised for a long time as spaces with great potential for protecting and promoting human health and well-being. They may affect human physical, mental and social health and well-being in various ways. On one hand, this comes to pass through reduction and moderation of potential environmental health risks (e. g. noise, particulate matter, heat), psycho-physiological effects of nature experience, as well as physical effects of exposure to natural compounds and elements. On the other hand, natural spaces can affect health and well-being indirectly e. g. through motivation of health promoting behaviour (e. g. more physical activity) and through use as outdoor meeting spaces, by decreasing aggression, and through the resulting positive effects on social well-being. Yet, some potential adverse health effects of nature and landscapes have been reported, too (e. g. insecurity or fear in confusing or unmaintained natural spaces, potential rivalry in usage, allergies or skin irritations due to natural elements, risk of communicable diseases from vectors). Against the background of positive effects of natural spaces, creating, restoring and enhancing urban green and blue spaces are often claimed in terms of sustainable and integrated urban development. But which associations and impacts exist between natural spaces and health? What are the resulting demands when integrating natural spaces for a health-promoting implementation practice? This overview article provides some answers to these questions. PMID- 29767337 TI - [The difference between errors and failures]. PMID- 29767335 TI - Regulation of enzyme activities in carnivorous pitcher plants of the genus Nepenthes. AB - MAIN CONCLUSION: Nepenthes regulates enzyme activities by sensing stimuli from the insect prey. Protein is the best inductor mimicking the presence of an insect prey. Carnivorous plants of the genus Nepenthes have evolved passive pitcher traps for prey capture. In this study, we investigated the ability of chemical signals from a prey (chitin, protein, and ammonium) to induce transcription and synthesis of digestive enzymes in Nepenthes * Mixta. We used real-time PCR and specific antibodies generated against the aspartic proteases nepenthesins, and type III and type IV chitinases to investigate the induction of digestive enzyme synthesis in response to different chemical stimuli from the prey. Transcription of nepenthesins was strongly induced by ammonium, protein and live prey; chitin induced transcription only very slightly. This is in accordance with the amount of released enzyme and proteolytic activity in the digestive fluid. Although transcription of type III chitinase was induced by all investigated stimuli, a significant accumulation of the enzyme in the digestive fluid was found mainly after protein and live prey addition. Protein and live prey were also the best inducers for accumulation of type IV chitinase in the digestive fluid. Although ammonium strongly induced transcription of all investigated genes probably through membrane depolarization, strong acidification of the digestive fluid affected stability and abundance of both chitinases in the digestive fluid. The study showed that the proteins are universal inductors of enzyme activities in carnivorous pitcher plants best mimicking the presence of insect prey. This is not surprising, because proteins are a much valuable source of nitrogen, superior to chitin. Extensive vesicular activity was observed in prey-activated glands. PMID- 29767338 TI - [Beginners' operations and medical specialist standards : Avoidance of criminal liability and civil liability]. AB - BACKGROUND: In all phases, patients are entitled to receive medical treatment according to medical specialist standards. This does not mean that patients necessarily have to be treated by a medical specialist. Operations performed by "beginners", e. g. assistant physicians, are permitted. However, there are increased liability risks, both for the specialist and the assistant physician. Furthermore, there are risks of criminal responsibility for causing bodily harm by negligence or negligent manslaughter. OBJECTIVES AND METHODS: This article portrays the requirements of civil liability and criminal responsibility concerning beginners' operations on the basis of cases and judgments of the Federal Court and the Higher Regional Courts in Germany. Additionally, the reception of the jurisprudence by the relevant legal literature will be discussed. RESULTS: Jurisprudence and legal literature categorize breaches of duty of care. Assistant physicians can be subject to contributory negligence liabilities, while specialists can bear liabilities for negligent selection, organization or supervision. Responsible specialist and assistant physicians can protect themselves (and the patient) and avoid legal risks by only performing operations adequate to their educational level or by delegating operations to beginners and ensuring intervention by a specialist by supervision of the operation which is suitable to the assistant physician's level of education. PMID- 29767339 TI - Simultaneous decolorization and deproteinization of alpha,omega-dodecanedioic acid fermentation broth by integrated ultrafiltration and adsorption treatments. AB - alpha,omega-Dicarboxylic acids (DC) are versatile chemical intermediates with different chain length. For biosynthesis of DC, to obtain the highly pure product via crystallization, it is required to remove pigments and proteins in fermentation broth. However, a trade-off between decolorization/deproteinization ratio and DC recovery during the purification process was found, which impeded DC production by fermentation. When ultrafiltration (UF) was applied to treat alpha,omega-dodecanedioic acid (DC12) broth, 93.4% of DC12 recovery, 80.5% of decolorization ratio and 61.7% of deproteinization ratio were achieved by a PES 3 membrane. However, the membrane technology could not effectively retain the pigments or proteins with low molecular weight when a high DC12 permeation was required. Meanwhile, the selected activated charcoal or macroporous resins were not good adsorbents for the present system. Furthermore, an integrated process for decolorization and deproteinization was developed. After filtration with PES3 membrane, an activated charcoal was used to remove the small proteins and pigments in the UF permeate. As a result, 91.4% of DC12 recovery, 94.7% of decolorization ratio and 84.8% of deproteinization ratio were obtained by such two-stage strategy. These results would serve as a valuable guide for process design and practical operation in subsequent industrial application. PMID- 29767340 TI - Speculation as to why the Frequency of Eosinophilic Esophagitis Is Increasing. AB - PURPOSE OF REVIEW: The frequency of eosinophilic esophagitis (EoE), an immune/antigen-mediated disorder first described in 1993, has been increasing rapidly. The purpose of this review is to consider hypotheses proposed to explain this increase and to speculate on their validity. RECENT FINDINGS: The hygiene hypothesis attributes the rise of EoE to modern hygienic conditions resulting in fewer childhood infections with microbes that might have protected against allergy development. Microbial dysbiosis, a change in the microbiome's composition and diversity caused by a modern affluent lifestyle, also might contribute to allergic conditions. Environmental factors including modern chemicals contaminating crops, livestock treated with hormones and antibiotics, food additives and processing changes, and pollutants in the air and water conceivably might predispose to EoE. One intriguing hypothesis attributes increasing EoE to increasing use of acid-suppressive medications like proton pump inhibitors, which might prevent peptic digestion of food allergens, increase gastric permeability, and alter the microbiome to favor food allergy development. In a recent pediatric case-control study, use of acid suppressants in infancy was by far the single strongest risk factor identified for later development of EoE. It remains unclear which, if any, of the above factors underlies the rising frequency of EoE. These factors need not be mutually exclusive, and the cause of EoE may well be multifactorial. PMID- 29767342 TI - Characterization of xanthine dehydrogenase and aldehyde oxidase of Marsupenaeus japonicus and their response to microbial pathogen. AB - Reactive oxygen species (ROS) play key roles in many physiological processes. In particular, the sterilization mechanism of bacteria using ROS in macrophages is a very important function for biological defense. Xanthine dehydrogenase (XDH) and aldehyde oxidase (AOX), members of the molybdo-flavoenzyme subfamily, are known to generate ROS. Although these enzymes occur in many vertebrates, some insects, and plants, little research has been conducted on XDHs and AOXs in crustaceans. Here, we cloned the entire cDNA sequences of XDH (MjXDH: 4328 bp) and AOX (MjAOX: 4425 bp) from Marsupenaeus japonicus (kuruma shrimp) using reverse transcriptase polymerase chain reaction (RT-PCR) and random amplification of cDNA ends (RACE). Quantitative real-time RT-PCR transcriptional analysis revealed that MjXDH mRNA is highly expressed in heart and stomach tissues, whereas MjAOX mRNA is highly expressed in the lymphoid organ and intestinal tissues. Furthermore, expression of MjAOX was determined to be up-regulated in the lymphoid organ in response to Vibrio penaeicida at 48 and 72 h after injection; in contrast, hydrogen peroxide (H2O2) concentrations increased significantly at 6, 12, 48, and 72 h after injection with white spot syndrome virus (WSSV) and at 72 h after injection with V. penaeicida. To the best of our knowledge, this study is the first to have identified and cloned XDH and AOX from a crustacean species. PMID- 29767341 TI - [Spondyloarthritis]. AB - Spondyloarthritis (SpA) describes the group of inflammatory diseases characterized by inflammation within axial joints and/or peripheral arthritis, enthesitis, and dactylitis. Disease development is strongly determined by genes and particularly associated with the presence of HLA-B27. Transgenic expression in animal models leads to induction of a SpA-like disease, suggesting a direct effect of HLA-B27 on disease development. Genome-wide association studies in SpA patients have identified further associations between polymorphisms in genes with an immune function, in particular in genes controlling the interleukin (IL)-23/IL 17 signaling pathway. The efficacy of IL-17 inhibitors in SpA patients underscores the impact of this pathway in this disease. Microscopic gut inflammation or chronic inflammatory bowel disease is found in the majority of patients with SpA, suggesting a pathogenic impact of commensal microbiota. In histopathologic examinations of axial manifestations, replacement of the subchondral bone marrow by granulation tissue with bone destructive and reparative properties is found. The mechanisms governing how genetic predisposition and gut inflammation promote inflammatory reactions at sites of mechanical stress is a matter of current research. PMID- 29767343 TI - Effect of artificial redox mediators on the photoinduced oxygen reduction by photosystem I complexes. AB - The peculiarities of interaction of cyanobacterial photosystem I with redox mediators 2,6-dichlorophenolindophenol (DCPIP) and N,N,N',N'-tetramethyl-p phenylenediamine (TMPD) were investigated. The higher donor efficiency of the reduced DCPIP form was demonstrated. The oxidized form of DCPIP was shown to be an efficient electron acceptor for terminal iron-sulfur cluster of photosystem I. Likewise methyl viologen, after one-electron reduction, DCPIP transfers an electron to the molecular oxygen. These results were discussed in terms of influence of these interactions on photosystem I reactions with the molecular oxygen and natural electron acceptors. PMID- 29767332 TI - Recent development in antihyperalgesic effect of phytochemicals: anti inflammatory and neuro-modulatory actions. AB - INTRODUCTION: Pain is an unpleasant sensation triggered by noxious stimulation. It is one of the most prevalent conditions, limiting productivity and diminishing quality of life. Non steroidal anti inflammatory drugs (NSAIDs) are widely used as pain relievers in present day practice as pain is mostly initiated due to inflammation. However, due to potentially serious side effects, long term use of these antihyperalgesic drugs raises concern. Therefore there is a demand to search novel medicines with least side effects. Herbal products have been used for centuries to reduce pain and inflammation, and phytochemicals are known to cause fewer side effects. However, identification of active phytochemicals of herbal medicines and clear understanding of the molecular mechanism of their action is needed for clinical acceptance. MATERIALS AND METHODS: In this review, we have briefly discussed the cellular and molecular changes during hyperalgesia via inflammatory mediators and neuro-modulatory action involved therein. The review includes 54 recently reported phytochemicals with antihyperalgesic action, as per the literature available with PubMed, Google Scholar and Scopus. CONCLUSION: Compounds of high interest as potential antihyperalgesic agents are: curcumin, resveratrol, capsaicin, quercetin, eugenol, naringenin and epigallocatechin gallate (EGCG). Current knowledge about molecular targets of pain and their regulation by these phytochemicals is elaborated and the scope of further research is discussed. PMID- 29767344 TI - In memory of Achim Trebst (1929-2017): a pioneer of photosynthesis research. AB - The life and work of Achim Trebst (1929-2017) was dedicated to photosynthesis, involving a wide span of seminal contributions which cumulated in more than five decades of active research: Major topics include the separation of light and dark phases in photosynthesis, the elucidation of photosynthesis by the use of inhibitors, the identification of the three-dimensional structure of photosystem II and its degradation, and an explanation of singlet oxygen formation. For this tribute, which has been initiated by Govindjee, twenty-two personal tributes by former coworkers, scientific friends, and his family have been compiled and combined with an introduction tracing the different stages of Achim Trebst's scientific life. PMID- 29767346 TI - Biomechanical properties of suprapectoral biceps tenodesis: double knotless screw fixation is superior to single knotless screw fixation. AB - INTRODUCTION: The purpose of this study is to biomechanically evaluate a new technique of double knotless screw fixation for suprapectoral biceps tenodesis and compare the results with that of the single knotless screw fixation as well as the interference screw fixation. METHODS: 24 fresh-frozen human cadaveric shoulders with a mean age of 68.3 +/- 9 years were studied. The specimens were randomly divided into three experimental biceps tenodesis groups (n = 8): single knotless screw, double knotless screw and interference screw. Each tenodesis specimen was mounted on a mechanical testing machine, preloaded for 2 min at 5 N, tested with cyclic loading from 5 to 70 N for 500 load cycles and subjected to an axial load to failure test (1 mm/s). The ultimate failure load, stiffness, cyclic displacement and mode of failure were evaluated. RESULTS: The interference screw fixation had the highest ultimate failure load (215.8 +/- 43.1 N) and stiffness (25.7 +/- 5.2 N/mm) which were significantly higher than the corresponding results for the single and double knotless screw groups (P = 0.0029). The double knotless screw group had the second highest ultimate failure load (162.8 +/- 13.8 N) and stiffness (15.1 +/- 4.1 N/mm) which were significantly higher than the corresponding results for the single knotless screw technique (P = 0.0002). The most common mode of failure was suture slippage for both the double (7/8) and single knotless screw (6/8) groups while biceps tendon tearing occurred most often for the interference screw group (6/8). CONCLUSION: In this biomechanical study, the double knotless screw fixation was found to have a significantly greater ultimate failure load and stiffness than the single knotless screw fixation but lower values than the interference screw fixation. PMID- 29767345 TI - Metastatic Breast Cancer Collateral Damage Project (MBCCD): Scale development and preliminary results of the Survey of Health, Impact, Needs, and Experiences (SHINE). AB - PURPOSE: Until recently, people with metastatic breast cancer (MBC) had a very poor prognosis. New treatment approaches have prolonged the time that people with MBC live, but their quality of life has received less attention. Consequently, the needs and concerns across financial, vocational, psychological, social, and physical domains in MBC patients are poorly understood-particularly regarding the collateral damage or longer-term, life-altering impacts of MBC and its treatments. This study's aims were to characterize MBC-related collateral damage, identify groups most likely to experience collateral damage, and examine its associations with psychological health, illness management, and health behaviors. METHODS: Participants (N = 515) with MBC were recruited from Dr. Susan Love Research Foundation's Army of Women(r) and other advocacy organizations. Participants completed questionnaires of MBC-related collateral damage, depressive symptoms, anxiety, self-efficacy for managing oncologic treatments and physical symptoms, sleep, and physical activity. RESULTS: Eight domains of MBC related collateral damage, as well as MBC-related benefit finding, were reliably characterized. Concerns about mortality/uncertainty were most prominent. Participants also endorsed high levels of benefit finding. Participants younger than 50 years, with limited financial resources, or with children under 18 at home reported the most collateral damage. Collateral damage was associated significantly with compromised psychological health, lower illness management efficacy, and poorer health behaviors, beyond sociodemographic and medical characteristics. CONCLUSIONS: Subgroups of MBC patients report long-term, life altering consequences of MBC and its treatments, which relate to important health outcomes. Clinical implications and recommendations are discussed. PMID- 29767349 TI - [Primary ophthalmological diagnosis of Treponema pallidum infection: A case series]. AB - This report is on five patients (four men and one woman) between the age of 24 and 66 years old who presented with unclear visual impairment in our clinic between 2009 and 2016 for co-evaluation. The clinical picture included intermediate uveitis, chorioretinitis, panuveitis and bilateral spontaneous cystoid macular edema. None of the patients reported systemic or dermatological symptoms. In all five patients, serological testing revealed a Treponema pallidum infection as the reason for ocular inflammation. The ophthalmologist was therefore the first to discover a syphilitic infection. After initiation of appropriate antibiotic therapy, there was improvement in all five patients and an increase in visual acuity. PMID- 29767348 TI - [Dynamic Scheimpflug Analyzer (Corvis ST) for measurement of corneal biomechanical parameters : A praxis-related overview]. AB - BACKGROUND: Topographic and tomographic parameters alone are often not sufficient for early detection of corneal changes. Pathological alterations in the microstructure of the cornea occur before changes in topography and tomography can be detected. Biomechanical parameters show a strong correlation with microscopic structural changes. OBJECTIVE: The aim of the study was to gain information about the microscopic structure and consistency of the cornea by measuring biomechanical parameters. MATERIALS AND METHODS: The deformation behavior of the cornea was analyzed with the Dynamic Scheimpflug Analyzer (Corvis ST; OCULUS, Wetzlar, Germany). Deformation parameters and biomechanical indices were derived from the deformation response of the cornea. RESULTS: Deformation parameters and indices in keratoconus patients differ significantly from healthy subjects. Alterations of the cornea can be detected before topographic and tomographic changes occur. The repeatability and reproducibility of relevant deformation parameters is good to very good. In glaucoma patients a modified deformation behavior of the cornea can be observed, which might be related to structural changes. CONCLUSION: The Corvis ST allows a reliable characterization of the tissue structure and consistency of the cornea. PMID- 29767347 TI - Enhanced Plasmonic Biosensors of Hybrid Gold Nanoparticle-Graphene Oxide-Based Label-Free Immunoassay. AB - In this study, we propose a modified gold nanoparticle-graphene oxide sheet (AuNP GO) nanocomposite to detect two different interactions between proteins and hybrid nanocomposites for use in biomedical applications. GO sheets have high bioaffinity, which facilitates the attachment of biomolecules to carboxyl groups and has led to its use in the development of sensing mechanisms. When GO sheets are decorated with AuNPs, they introduce localized surface plasmon resonance (LSPR) in the resonance energy transfer of spectral changes. Our results suggest a promising future for AuNP-GO-based label-free immunoassays to detect disease biomarkers and rapidly diagnose infectious diseases. The results showed the detection of antiBSA in 10 ng/ml of hCG non-specific interfering protein with dynamic responses ranging from 1.45 nM to 145 fM, and a LOD of 145 fM. Considering the wide range of potential applications of GO sheets as a host material for a variety of nanoparticles, the approach developed here may be beneficial for the future integration of nanoparticles with GO nanosheets for blood sensing. The excellent anti-interference characteristics allow for the use of the biosensor in clinical analysis and point-of-care testing (POCT) diagnostics of rapid immunoassay products, and it may also be a potential tool for the measurement of biomarkers in human serum. PMID- 29767350 TI - Inverse relationship between changes of maximal aerobic capacity and changes in walking economy after weight loss. AB - PURPOSE: The aims of this study were to: (1) determine the relationships between maximum oxygen uptake ([Formula: see text]O2max) and walking economy during non graded and graded walking among overweight women and (2) examine potential differences in [Formula: see text]O2max and walking economy before and after weight loss. METHODS: One-hundred and twenty-four premenopausal women with a body mass index (BMI) between 27 and 30 kg/m2 were randomly assigned to one of three groups: (a) diet only; (b) diet and aerobic exercise training; and (c) diet and resistance exercise training. All were furnished with standard, very-low calorie diet to reduce BMI to < 25 kg/m2. [Formula: see text]O2max was measured using a modified-Bruce protocol while walking economy (1-net [Formula: see text]O2) was obtained during fixed-speed (4.8 k.h-1), steady-state treadmill walking at 0% grade and 2.5% grade. Assessments were conducted before and after achieving target BMI. RESULTS: Prior to weight loss, [Formula: see text]O2max was inversely related (P < 0.05) with non-graded and graded walking economy (r = - 0.28 to - 0.35). Similar results were also observed following weight loss (r = - 0.22 to - 0.28). Additionally, we also detected a significant inverse relationship (P < 0.05) between the changes (?, after weight loss) in ?[Formula: see text]O2max, adjusted for fat-free mass, with non-graded and graded ?walking economy (r = - 0.37 to - 0.41). CONCLUSIONS: Our results demonstrate [Formula: see text]O2max and walking economy are inversely related (cross-sectional) before and after weight loss. Importantly though, ?[Formula: see text]O2max and ?walking economy were also found to be inversely related, suggesting a strong synchrony between maximal aerobic capacity and metabolic cost of exercise. PMID- 29767352 TI - Multifocal motor neuropathy following treatment with adalimumab for ulcerative colitis. PMID- 29767351 TI - Evaluating the methods used for measuring cerebral blood flow at rest and during exercise in humans. AB - The first accounts of measuring cerebral blood flow (CBF) in humans were made by Angelo Mosso in ~1880, who recorded brain pulsations in patients with skull defects. In 1890, Charles Roy and Charles Sherrington determined in animals that brain pulsations-assessed via a similar method used by Mosso-were altered during a variety of stimuli including sensory nerve stimulation, asphyxia, and pharmacological interventions. Between 1880 and 1944, measurements for CBF were typically relied on skull abnormalities in humans. Thereafter, Kety and Schmidt introduced a new methodological approach in 1945 that involved nitrous oxide dilution combined with serial arterial and jugular venous blood sampling. Less than a decade later (1950's), several research groups employed the Kety-Schmidt technique to assess the effects of exercise on global CBF and metabolism; these studies demonstrated an uncoupling of CBF and metabolism during exercise, which was contrary to early hypotheses. However, there were several limitations to this technique related to low temporal resolution and the inability to measure regional CBF. These limitations were overcome in the 1960's when transcranial Doppler ultrasound (TCD) was developed as a method to measure beat-by-beat cerebral blood velocity. Between 1990 and 2010, TCD further progressed our understanding of CBF regulation and allowed for insight into other mechanistic factors, independent of local metabolism, involved in regulating CBF during exercise. Recently, it was discovered that TCD may not be accurate under several physiological conditions. Other measures of indexing CBF such as Duplex ultrasound and magnetic resonance imaging, although not without some limitations, may be more applicable for future investigations. PMID- 29767355 TI - Overview of Gene Expression Analysis: Transcriptomics. AB - Currently, the study of the transcriptome is widely used to interpret the functional elements of the genome and molecular constituents of cells and tissues in an effort to unravel biological pathways associated with development and disease. The advent of technologies is now enabling the study of such comprehensive transcriptional characterization of mRNA, miRNA, lncRNA, and small RNA in a robust and successful manner. Transcriptomic strategies are gaining momentum across diverse areas of biological, plant sciences, medical, clinical, and pharmaceutical research for biomarker discovery, and disease diagnosis and prognosis. PMID- 29767354 TI - Proprioceptive muscle tendon stimulation reduces symptoms in primary orthostatic tremor. AB - INTRODUCTION: Primary orthostatic tremor (OT) is characterized by high-frequency lower limb muscle contractions and a disabling sense of unsteadiness while standing. To date, therapeutic options for OT are limited. Here, we examined the effects of proprioceptive leg muscle stimulation via muscle tendon vibration (MTV) on tremor and balance control in patients with primary OT. METHODS: Tremor in nine patients with primary OT was examined during four conditions: standing (1), standing with MTV on the bilateral soleus muscles (2), lying (3), and lying with MTV (4). Tremor characteristics were assessed by frequency domain analysis of surface EMG recordings from four leg muscles. Body sway was analyzed using posturographic recordings. RESULTS: During standing, all patients showed a coherent high-frequency tremor in leg muscles and body sway that was absent during lying (p < 0.001). MTV during standing did not reset tremor frequency, but resulted in a decreased tremor intensity (p < 0.001; mean reduction: 32.5 +/- 7.1%) and body sway (p = 0.032; mean reduction: 37.2 +/- 6.8%). MTV did not affect muscle activity during lying. Four patients further reported a noticeable relief from unsteadiness during stimulation. CONCLUSION: Proprioceptive stimulation did not reset tremor frequency consistent with the presumed central origin of OT. However, continuous MTV influenced the emergence of OT symptoms resulting in reduced tremor intensity, improved posture, and a relief from unsteadiness in half of the examined patients. These findings indicate that MTV either directly interferes with the peripheral manifestation of the central oscillatory pattern or prevents proprioceptive afferent feedback from becoming extensively synchronized at the tremor frequency. PMID- 29767356 TI - RNA-Seq and Expression Arrays: Selection Guidelines for Genome-Wide Expression Profiling. AB - The development of genome-wide gene expression profiling technologies over the past two decades has produced great opportunity for researchers to explore the transcriptome and to better understand biological systems and their perturbation. In this chapter we provide an overview of microarray and massively parallel sequencing technologies and their application to gene expression analysis. We discuss factors that impact expression data generation and analysis that which should be considered in the application of these technology platforms. We further present the results of a simple illustration study to highlight performance similarities and differences in expression profiling of protein-coding mRNAs with each platform. Based on technical and analytical differences between the two platforms, reports in the literature comparing arrays and RNA-Seq for gene expression, and our own example study and experience, we provide recommendations for platform selection for gene expression studies. PMID- 29767353 TI - Influences of temporal lobe epilepsy and temporal lobe resection on olfaction. AB - Although temporal lobe epilepsy (TLE) and resection (TLR) impact olfactory eloquent brain structures, their influences on olfaction remain enigmatic. We sought to more definitively assess the influences of TLE and TLR on olfaction using three well-validated olfactory tests and measuring the tests' associations with the volume of numerous temporal lobe brain structures. The University of Pennsylvania Smell Identification Test and an odor detection threshold test were administered to 71 TLE patients and 71 age- and sex-matched controls; 69 TLE patients and controls received an odor discrimination/memory test. Fifty-seven patients and 57 controls were tested on odor identification and threshold before and after TLR; 27 patients and 27 controls were similarly tested for odor detection/discrimination. Scores were compared using analysis of variance and correlated with pre- and post-operative volumes of the target brain structures. TLE was associated with bilateral deficits in all test measures. TLR further decreased function on the side ipsilateral to resection. The hippocampus and other structures were smaller on the focus side of the TLE subjects. Although post-operative volumetric decreases were evident in most measured brain structures, modest contralateral volumetric increases were observed in some cases. No meaningful correlations were evident pre- or post-operatively between the olfactory test scores and the structural volumes. In conclusion, we demonstrate that smell dysfunction is clearly a key element of both TLE and TLR, impacting odor identification, detection, and discrimination/memory. Whether our novel finding of significant post-operative increases in the volume of brain structures contralateral to the resection side reflects plasticity and compensatory processes requires further study. PMID- 29767359 TI - Simultaneous, Multiplexed Detection of RNA and Protein on the NanoString(r) nCounter(r) Platform. AB - The NanoString nCounter Analysis System uses a digital fluorescent barcode technology that allows for direct multiplexed measurement of gene expression (mRNA), DNA, and protein. The technology uses molecular barcodes and single molecule imaging to detect and count unique mRNA and protein targets in a single reaction. nCounter-based detection is enzyme-free (no amplification of mRNA is required), fully automated, and allows simultaneous detection of up to 770 mRNA and 30 protein targets from multiple sample types. Target counting is fully digital with quantitative data output. Here we describe preparation of solid tumor lysate samples for use in the nCounter Analysis System. PMID- 29767357 TI - A Guide for Designing and Analyzing RNA-Seq Data. AB - The identity of a cell or an organism is at least in part defined by its gene expression and therefore analyzing gene expression remains one of the most frequently performed experimental techniques in molecular biology. The development of the RNA-Sequencing (RNA-Seq) method allows an unprecedented opportunity to analyze expression of protein-coding, noncoding RNA and also de novo transcript assembly of a new species or organism. However, the planning and design of RNA-Seq experiments has important implications for addressing the desired biological question and maximizing the value of the data obtained. In addition, RNA-Seq generates a huge volume of data and accurate analysis of this data involves several different steps and choices of tools. This can be challenging and overwhelming, especially for bench scientists. In this chapter, we describe an entire workflow for performing RNA-Seq experiments. We describe critical aspects of wet lab experiments such as RNA isolation, library preparation and the initial design of an experiment. Further, we provide a step by-step description of the bioinformatics workflow for different steps involved in RNA-Seq data analysis. This includes power calculations, setting up a computational environment, acquisition and processing of publicly available data if desired, quality control measures, preprocessing steps for the raw data, differential expression analysis, and data visualization. We particularly mention important considerations for each step to provide a guide for designing and analyzing RNA-Seq data. PMID- 29767358 TI - SureSelectXT RNA Direct: A Technique for Expression Analysis Through Sequencing of Target-Enriched FFPE Total RNA. AB - Gene expression profiling of samples from biobanks requires a method that can be used with intact as well as partially degraded RNA. High throughput applications can benefit from reducing the number of processing steps including eliminating the poly(A) selection and ribosomal depletion steps. When performing targeted capture, we have found that we can eliminate the upfront poly(A) selection/ribosomal depletion steps that cause bias in standard mRNA-Seq workflows. This target enrichment solution allows for whole transcriptome or customized content to characterize differential gene expression patterns (especially for mid/low level transcripts). Protocol modifications to the Agilent Strand-Specific RNA Library Prep kit resulted in a new workflow called "RNA Direct" that generates RNA-Seq data with minimal ribosomal contamination and good sequencing coverage. Using RNA isolated from a set of matched samples including fresh frozen (FF) or formalin-fixed, paraffin-embedded (FFPE) from tumor/normal tissues we generated high-quality data using a protocol that does not require upfront ribosomal depletion or poly(A) selection. Using SureSelectXT RNA Direct protocol (RNA Direct) workflow, we found transcripts to be upregulated or downregulated to similar degrees with similar confidence levels in both the FF and FFPE samples, demonstrating the utility for meaningful gene expression studies with biobank samples of variable quality. PMID- 29767360 TI - Transcript Profiling Using Long-Read Sequencing Technologies. AB - RNA sequencing using next-generation sequencing (NGS, RNA-Seq) technologies is currently the standard approach for gene expression profiling, particularly for large-scale high-throughput studies. NGS technologies comprise short-read RNA-Seq (dominated by Illumina) and long-read RNA-Seq technologies provided by Pacific Bioscience (PacBio) and Oxford Nanopore Technologies (ONT). Although short-read sequencing technologies are the most widely used, long-read technologies are increasingly becoming the standard approach for de novo transcriptome assembly and isoform expression quantification due to the complex nature of the transcriptome which consists of variable lengths of transcripts and multiple alternatively spliced isoforms for most genes. In this chapter, we describe experimental procedures for library preparation, sequencing, and associated data analysis approaches for PacBio and ONT with a major focus on full length cDNA synthesis, de novo transcriptome assembly, and isoform quantification. PMID- 29767361 TI - Making and Sequencing Heavily Multiplexed, High-Throughput 16S Ribosomal RNA Gene Amplicon Libraries Using a Flexible, Two-Stage PCR Protocol. AB - Deep sequencing of polymerase chain reaction (PCR)-amplified small subunit (16S or 18S) ribosomal RNA (rRNA) genes fragments is commonly employed to characterize the composition and structure of microbial communities. Preparing genomic DNA for sequencing of such gene fragments on Illumina sequencers can be performed in a straightforward, two-stage PCR method, described herein. The protocol described allows for up to 384 samples to be sequenced simultaneously, and provides great flexibility in choice of primers. PMID- 29767362 TI - MicroRNA Expression Analysis: Next-Generation Sequencing. AB - MicroRNAs are a class of small noncoding RNAs that function as regulators involving in many biological processes. The evaluation of miRNAs and their targets has been aided by miRNA expression profiling studies including multiplex PCR, microarrays, and recent next-generation sequencing tools. Next-generation sequencing has enabled us to profile thousands of genes in a single experiment and overcome the background signal and cross-hybridization issues of microarrays. Next-generation sequencing also allows for the simultaneous confirmation of known miRNAs and discovery of new miRNAs, and significantly reduces costs while providing billions of nucleotide information within a single experiment. Here we describe a detailed procedure of generation of miRNA library for next-generation sequencing to increase the efficiency of adapter ligation and finally construct a more specific cDNA library for sequencing and analyses for miRNA expression profiling. PMID- 29767364 TI - Single-Cell mRNA-Seq Using the Fluidigm C1 System and Integrated Fluidics Circuits. AB - Single-cell mRNA-seq is a valuable tool to dissect expression profiles and to understand the regulatory network of genes. Microfluidics is well suited for single-cell analysis owing both to the small volume of the reaction chambers and easiness of automation. Here we describe the workflow of single-cell mRNA-seq using C1 IFC, which can isolate and process up to 96 cells. Both on-chip procedure (lysis, reverse transcription, and preamplification PCR) and off-chip sequencing library preparation protocols are described. The workflow generates full-length mRNA information, which is more valuable compared to 3' end counting method for many applications. PMID- 29767363 TI - Identification of Transcriptional Regulators That Bind to Long Noncoding RNAs by RNA Pull-Down and RNA Immunoprecipitation. AB - Long noncoding RNAs (lncRNAs) are RNA transcripts that are at least 200 nucleotides long and lack coding potential, and they have been demonstrated to be involved in a wide range of biological processes. Many lncRNAs, especially those enriched in nucleus, have been found to regulate gene expression at transcriptional level. Regulation of gene transcription by lncRNAs are mainly mediated by transcriptional regulators (TRs) which interact with lncRNAs. LncRNAs can either enhance or suppress TR's activity, which depends on different mechanism and cellular context. RNA pull-down assay followed by RNA immunoprecipitation is a powerful tool to identify and confirm the specific interaction between TRs and lncRNAs. In this chapter, we illustrate how to perform RNA pull-down and RNA immunoprecipitation to identify TRs that interact with lncRNAs using frozen liver tissues. PMID- 29767365 TI - Current and Future Methods for mRNA Analysis: A Drive Toward Single Molecule Sequencing. AB - The transcriptome encompasses a range of species including messenger RNA, and other noncoding RNA such as rRNA, tRNA, and short and long noncoding RNAs. Due to the huge role played by mRNA in development and disease, several methods have been developed to sequence and characterize mRNA, with RNA sequencing (RNA-Seq) emerging as the current method of choice particularly for large high-throughput studies. Short-read RNA-Seq which involves sequencing of short cDNA fragments and computationally assembling them to reconstruct the transcriptome, or aligning them to a reference is the most widely used approach. However, due to inherent limitations of this approach in de novo transcriptome assembly and isoform quantification, long-read RNA-Seq approaches, which also happen to be single molecule sequencing approaches, are increasingly becoming the standard for de novo transcriptome assembly and isoform quantification. In this chapter, we review the technical aspects of the current methods of RNA-Seq, both short and long-read approaches, and data analysis methods available. We discuss recent advances in single-cell RNA-Seq and direct RNA-Seq approaches, which perhaps will dominate the future of RNA-Seq. PMID- 29767366 TI - Expression Profiling of Differentially Regulated Genes in Fanconi Anemia. AB - Gene expression analysis mainly helps to study gene quantification methods by using various downstream detection approaches like imaging, amplification, probe hybridization, or sequencing. With respect to DNA, which is less static, mRNA levels vary over time, between cell types under divergent conditions. Gene expression analysis is principally focused on determination of mRNA levels transcribed from DNA. DNA microarrays are one of the robust and powerful tools to detect changes in multiple transcripts in larger cohorts in parallel. The basic principle of DNA microarray hybridization is complementary base pairing of single stranded nucleic-acid sequences. On a microarray platform (also called a chip), known sequences called targets are attached at fixed locations (spots) to a solid surface such as glass using robotic spotting. Since a large number of samples (variables) are used in a typical hybridization experiment, which often leads to impreciseness for example, target mRNA transcribed from the same source should be identical every time. In such cases, developing an optimized protocol for microarray platform to study the expression profiling of differentially regulated genes is a challenging task. Thus genome-wide expression array analysis yields data about candidate genes that may be involved in disease acquisition progression, and helps in better understanding the pathophysiology of the disease. In this chapter we describe in detail the microarray technique, a well accepted method for understanding the development and progression of Fanconi anemia (FA), a genetic disorder which is characterized by progressive bone marrow failure and a predisposition to cancer. PMID- 29767368 TI - Differential Gene Expression Analysis of Plants. AB - Since the next-generation sequencing (NGS) systems were invented and introduced to life science research about a decade ago, the NGS technology has extensively utilized in wide range of genomic, transcriptomic, and evolutionary studies. Compared with other eukaryotic species, the application of NGS technology in plant research reveals some challenges in sample preparation and data analysis due to some structural and physiological characteristics and genome complexity nature in plants. Hence, despite of the standard sample preparation and data process protocols widely used in high throughput transcriptomic analysis, we also describe the modified hot borate RNA extraction protocol specific for high quality and quantity plant total RNA isolation, and some comments and suggestions to achieve better assessments in the validation of RNA and library quality and data analysis. PMID- 29767369 TI - High Throughput Sequencing-Based Approaches for Gene Expression Analysis. AB - Next-generation sequencing has emerged as the method of choice to answer fundamental questions in biology. The massively parallel sequencing technology for RNA-Seq analysis enables better understanding of gene expression patterns in model and nonmodel organisms. Sequencing per se has reached the stage of commodity level while analyzing and interpreting huge amount of data has been a significant challenge. This chapter is aimed at discussing the complexities involved in sequencing and analysis, and tries to simplify sequencing based gene expression analysis. Biologists and experimental scientists were kept in mind while discussing the methods and analysis workflow. PMID- 29767370 TI - Network Analysis of Gene Expression. AB - Studies have pointed out that the expression of genes are highly regulated, which result in a cascade of distinct patterns of coexpression forming a network. Identifying and understanding such patterns is crucial in deciphering molecular mechanisms that underlie the pathophysiology of diseases. With the advance of high throughput assay of messenger RNA (mRNA) and high performance computing, reconstructing such network from molecular data such as gene expression is now possible. This chapter discusses an overview of methods of constructing such networks, practical considerations, and an example. PMID- 29767367 TI - A Review of Transcriptome Analysis in Pulmonary Vascular Diseases. AB - Transcriptome analysis is a powerful tool in the study of pulmonary vascular disease and pulmonary hypertension. Pulmonary hypertension is a disease process that consists of several unique pathologies sharing a common clinical definition, that of elevated pressure within the pulmonary circulation. As such, it has become increasingly important to identify both similarities and differences among the different classes of pulmonary hypertension. Transcriptome analysis has been an invaluable tool both in the basic science research on animal models as well as clinical research among the various different groups of pulmonary hypertension. This work has identified new potential candidate genes, implicated numerous biochemical and molecular pathways in diseased onset and progression, developed gene signatures to appropriately classify types of pulmonary hypertension and severity of illness, and identified novel gene mutations leading to hereditary forms of the disease. PMID- 29767372 TI - Bayesian Network to Infer Drug-Induced Apoptosis Circuits from Connectivity Map Data. AB - The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. As most targeted anticancer therapeutics aim to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using Connectivity MAP microarray-based gene expression data, we applied a Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular pathway. We focused on 13 apoptotic genes that showed significant differential expression across all drug-perturbed samples to reconstruct the apoptosis network. In our predicted subnetwork, 9 out of 15 high-confidence interactions were validated in literature, and our inferred network captured two major cell death pathways by identifying BCL2L11 and PMAIP1 as key interacting players for the intrinsic apoptosis pathway, and TAXBP1 and TNFAIP3 for the extrinsic apoptosis pathway. Our inferred apoptosis network also suggested the role of BCL2L11 and TNFAIP3 as "gateway" genes in the drug-induced intrinsic and extrinsic apoptosis pathways. PMID- 29767371 TI - Analysis of ChIP-Seq and RNA-Seq Data with BioWardrobe. AB - The massive amount of information produced by ChIP-Seq, RNA-Seq, and other next generation sequencing-based methods requires computational data analysis. However, biologists performing these experiments often lack training in bioinformatics. BioWardrobe aims to bridge this gap by providing a convenient user interface and by automating routine data-processing steps. This protocol details the use of BioWardrobe for identifying and visualizing ChIP-Seq peaks, calculating RPKMs, performing differential binding or gene expression analysis, and creating plots and heat maps. We specifically describe how to use BioWardrobe's quality control measures for troubleshooting NGS-based experiments. PMID- 29767373 TI - Parkinson's disease and risk of hip fracture: systematic review and meta analysis. AB - The relationship between Parkinson's disease (PD) and risk of hip fracture yielded inconsistent results. Therefore, we conducted the present systematic review and meta-analysis of published observational studies to assess the association between PD and risk of hip fracture. PubMed, ISI, EMBASE, and Cochrane databases were searched systematically to identify studies assessing the relationship between PD and the risk of hip fracture up to July 01, 2017. In addition, to find related articles, the reference section of retrieved articles was checked. Random-effects model was used for calculation of pooled hazard ratio (HR) and 95% confidence intervals (CI). Thirteen independent studies containing 564,947 participants were included in the meta-analysis. The overall results of included studies showed PD to be associated with the risk of hip fracture (HRoverall = 3.13, 95% CI 2.53-3.87) in women 3.11 (2.51-3.86) and men 2.60 (2.19 3.09). Our meta-analysis showed the direct association between PD and the risk of hip fracture in both men and women. However, due to the limitations of this study, further well-designed studies are required to confirm our findings. PMID- 29767374 TI - The effect of CA1 dopaminergic system on amnesia induced by harmane in mice. AB - In the present study, the effects of bilateral injections of dopaminergic drugs into the hippocampal CA1 regions (intra-CA1) on harmane-induced amnesia were examined in mice. We used a single-trial step-down inhibitory avoidance task for the assessment of memory acquisition in adult male mice. Our data indicated that pre-training intra-peritoneal (i.p.) administration of harmane (12 mg/kg) impaired memory acquisition. Moreover, intra-CA1 administration of dopamine D1 receptor agonist, SKF38393 (0.25 ug/mouse), dopamine D1 receptor antagonist, SCH23390 (0.25 ug/mouse), dopamine D2 receptor agonist, quinpirole (0.125 and 0.25 ug/mouse) and dopamine D2 receptor antagonist, sulpiride (0.2 and 0.4 ug/mouse) decreased the learning of a single-trial inhibitory avoidance task. Furthermore, pre-training intra-CA1 injection of sub-threshold doses of SKF38393 (0.0625 ug/mouse) or sulpiride (0.1 ug/mouse) increased pre-training harmane (4 and 8 mg/kg, i.p.)-induced amnesia. On the other hand, pre-training intra-CA1 injection of a sub-threshold dose of SCH23390 (0.0625 ug/mouse) reversed amnesia induced by an effective dose of harmane (12 mg/kg; i.p.). In addition, Pre training intra-CA1 injection of quinpirole (0.0625 ug/mouse) had no effect on memory impairment induced by harmane. These findings indicate the involvement of CA1 dopaminergic system on harmane-induced impairment of memory acquisition. PMID- 29767375 TI - Strategies to Guide the Return of Genomic Research Findings: An Australian Perspective. AB - In Australia, along with many other countries, limited guidance or other support strategies are currently available to researchers, institutional research ethics committees, and others responsible for making decisions about whether to return genomic findings with potential value to participants or their blood relatives. This lack of guidance results in onerous decision-making burdens-traversing technical, interpretative, and ethical dimensions-as well as uncertainty and inconsistencies for research participants. This article draws on a recent targeted consultation conducted by the Australian National Health and Medical Research Council to put forward strategies for supporting return of finding decision-making. In particular, we propose a pyramid of decision-making support: decision-making guidelines, technical and interpretative assistance, and ethical assistance for intractable "tough" cases. Each step of the pyramid involves an increasing level of regulatory involvement and applies to a smaller subsection of genomic research findings. Implementation of such strategies would facilitate a growing evidence base for return of finding decisions, thereby easing the financial, time, and moral burdens currently placed on researchers and other relevant decision-makers while also improving the quality of such decisions and, consequently, participant outcomes. PMID- 29767376 TI - Evaluating the Effectiveness of an Autism-Specific Workplace Tool for Employers: A Randomised Controlled Trial. AB - : A randomised controlled trial evaluated the effectiveness of the Integrated Employment Success Tool (IESTTM) in improving employers' self-efficacy in modifying the workplace for individuals on the autism spectrum. Employers (N = 84) were randomised to the IESTTM or support as usual groups. Measurements of self-efficacy, knowledge and attitudes towards disability in the workplace were obtained at baseline and post-test. Results revealed a significant improvement in self-efficacy within the IESTTM group between baseline and post-test (p = 0.016). At post-test, there were no significant differences between groups in relation to self-efficacy in implementing autism-specific workplace modifications and employer attitudes towards disability in the workplace. Given the lack of significant outcomes, further research is needed to determine the effectiveness of the IESTTM for employers. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry #ACTRN12614000771651, registered 21/7/2014. Trial URL https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366699 . PMID- 29767377 TI - The effect of omitted covariates in marginal and partially conditional recurrent event analyses. AB - There have been many advances in statistical methodology for the analysis of recurrent event data in recent years. Multiplicative semiparametric rate-based models are widely used in clinical trials, as are more general partially conditional rate-based models involving event-based stratification. The partially conditional model provides protection against extra-Poisson variation as well as event-dependent censoring, but conditioning on outcomes post-randomization can induce confounding and compromise causal inference. The purpose of this article is to examine the consequences of model misspecification in semiparametric marginal and partially conditional rate-based analysis through omission of prognostic variables. We do so using estimating function theory and empirical studies. PMID- 29767378 TI - Dying to communicate: apoptotic functions of Eph/Ephrin proteins. AB - The Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors constitute the largest family of receptor tyrosine kinases and interact with a group of ligands called Ephrins. An essential feature of the Eph receptors and Ephrin ligands is that both are membrane-bound and, upon cell-cell interaction, initiate a bidirectional signaling involving both the receptor (forward signaling) and the ligand (reverse signaling). They regulate a large set of pleiotropic functions in virtually every tissue and physiological system. In vitro as well as in vivo data support a role for Eph and Ephrin molecules in cellular processes such as proliferation, cell-cell attraction and repulsion, motility and sorting. An increasing amount of evidence supports a role for these molecules in apoptosis and, although this function in cell death has been barely examined, the available information warrants a global consideration, to identify unmet needs and potential research avenues. Here we propose a comprehensive analysis of the data available regarding the importance of Ephs and Ephrins in cell death mechanisms throughout a large array of physiological systems. PMID- 29767379 TI - Individual cognitive change after DBS-surgery in Parkinson's disease patients using Reliable Change Index Methodology. AB - Long-term therapy of Parkinson's disease (PD) with levodopa (L-DOPA) is associated with a high risk of developing motor fluctuations and dyskinesia. Deep brain stimulation (DBS) in PD patients of the subthalamic nucleus can improve these motor complications. Although the positive effect on motor symptoms has been proven, postoperative cognitive decline has been documented. To tackle the impact of PD-DBS on cognition, 18 DBS patients were compared to 25 best medically treated Parkinson's patients, 24 Mild Cognitive Impairment (MCI) patients and 12 healthy controls using the Neuropsychological Test Battery Vienna-long (NTBV long) for cognitive outcome 12 months after first examination. Reliable change index methodology was used. Overall, there was cognitive change in individual patients, but the change was very heterogeneous with gains and losses. Further research is needed to identify the mechanisms that lead to improvement or deterioration of cognitive functions in individual cases. PMID- 29767380 TI - Analysis of an Attractor Neural Network's Response to Conflicting External Inputs. AB - The theory of attractor neural networks has been influential in our understanding of the neural processes underlying spatial, declarative, and episodic memory. Many theoretical studies focus on the inherent properties of an attractor, such as its structure and capacity. Relatively little is known about how an attractor neural network responds to external inputs, which often carry conflicting information about a stimulus. In this paper we analyze the behavior of an attractor neural network driven by two conflicting external inputs. Our focus is on analyzing the emergent properties of the megamap model, a quasi-continuous attractor network in which place cells are flexibly recombined to represent a large spatial environment. In this model, the system shows a sharp transition from the winner-take-all mode, which is characteristic of standard continuous attractor neural networks, to a combinatorial mode in which the equilibrium activity pattern combines embedded attractor states in response to conflicting external inputs. We derive a numerical test for determining the operational mode of the system a priori. We then derive a linear transformation from the full megamap model with thousands of neurons to a reduced 2-unit model that has similar qualitative behavior. Our analysis of the reduced model and explicit expressions relating the parameters of the reduced model to the megamap elucidate the conditions under which the combinatorial mode emerges and the dynamics in each mode given the relative strength of the attractor network and the relative strength of the two conflicting inputs. Although we focus on a particular attractor network model, we describe a set of conditions under which our analysis can be applied to more general attractor neural networks. PMID- 29767381 TI - Novel FGFR2-INA fusion identified in two low-grade mixed neuronal-glial tumors drives oncogenesis via MAPK and PI3K/mTOR pathway activation. PMID- 29767383 TI - 67th Annual Scientific Sessions of the American College of Cardiology: 10-12 March 2018; Orlando, FL, USA. PMID- 29767382 TI - Direct pulp capping in primary molars using a resin-modified Portland cement based material (TheraCal) compared to MTA with 12-month follow-up: a randomised clinical trial. AB - AIM: This study was to compare the success of resin-modified Portland cement based material (TheraCal) with MTA in direct pulp capping (DPC) of primary molars. METHODS: Symmetrical bilateral primary molars (92) from 46 healthy subjects aged 5-7 years were included in this split-mouth randomised clinical trial. DPC for small non-contaminated pulp exposures using either TheraCal or MTA were randomly performed in symmetrical molars. Thereafter, teeth were restored with amalgam. Clinical and radiographic evaluations were performed at 6 and 12 month follow-ups. Data were analysed using Chi square test at a significance level of 0.05. RESULTS: At the final follow-up session 74 teeth were available. After 12 months, the overall success rates for MTA and TheraCal were 94.5 and 91.8%, respectively. The difference between outcomes of the two groups was not statistically significant (P > 0.05). CONCLUSION: Within the limitations of the current study, radiographic and clinical findings revealed that TheraCal exhibited a comparable outcome to MTA in DPC of primary molars after 12 months. PMID- 29767385 TI - Author's reply: "How much do plastic surgeons add to the closure of myelomeningoceles?" PMID- 29767386 TI - An unusual calf lesion in an immunocompromised patient. PMID- 29767384 TI - Understanding Physical Activity through Interactions Between the Built Environment and Social Cognition: A Systematic Review. AB - BACKGROUND: Few people in most developed nations engage in regular physical activity (PA), despite its well-established health benefits. Socioecological models highlight the potential interaction of multiple factors from policy and the built environment to individual social cognition in explaining PA. OBJECTIVE: The purpose of this review was to appraise this interaction tenet of the socioecological model between the built environment and social cognition to predict PA. METHODS: Eligible studies had to have been published in peer-reviewed journals in the English language, and included any tests of interaction between social cognition and the built environment with PA. Literature searches, concluded in October 2017, used five common databases. Findings were grouped by type of PA outcomes (leisure, transportation, total PA and total moderate vigorous PA [MVPA]), then grouped by the type of interactions between social cognitive and built environment constructs. RESULTS: The initial search yielded 308 hits, which was reduced to 22 independent studies of primarily high- to medium-quality after screening for eligibility criteria. The interaction tenet of the socioecological model was not supported for overall MVPA and total PA. By contrast, while there was heterogeneity of findings for leisure-time PA, environmental accessibility/convenience interacted with intention, and environmental aesthetics interacted with affective judgments, to predict leisure time PA. Interactions between the built environment and social cognition in PA for transport are limited, with current results failing to support an effect. CONCLUSIONS: The results provide some support for interactive aspects of the built environment and social cognition in leisure-time PA, and thus highlight potential areas for integrated intervention of individual and environmental change. PMID- 29767388 TI - Concise Commentary: The Benefits of Recycling-How Autophagy Regulation Affects Acute Pancreatitis. PMID- 29767389 TI - High Expression of ABL2 Suppresses Apoptosis in Gastric Cancer. AB - BACKGROUND: Diseases associated with Abelson-related gene (also called ABL2) include leukemia; furthermore, previous researches have studied the expressions and functions of ABL2 in different types of malignancies and found that it plays an important role in almost all kinds of cancers. AIMS: Nevertheless, the mechanism of ABL2 in gastric cancer (GC) remains vague. METHODS: In the present study, the level of ABL2 in human GC tissues was detected by immunohistochemistry. Also, the GC cell lines MGC-803 and BGC-823 were selected to stably knock down and overexpress the level of ABL2 by corresponding lentiviral vectors. Puromycin was used to maintain the stable low expression of ABL2 MGC-803 cells compared with control cells; what is more, the high expression of ABL2 BGC-823 cells was also obtained. Based on it, we detected the proteins associated with apoptosis, such as Bcl-2 family and caspase family by western blotting. RESULTS: The most appropriate concentration of puromycin to kill GC cells is 1 ug/mL; then, we obtained the corresponding stable cell lines. Furthermore, we found that high level of ABL2 in BGC-823 cells increased the expression of Bcl-XL, total PARP, and caspase3, while decreased the level of cleaved caspase3 and cleaved caspase9. Consistent results are received in MGC-803 cells. In addition, ABL2 overexpression led to the protein related with Ras/Erk and PI3K/AKT signaling pathway increased; also, we found that the major proteins play a significant role in it. CONCLUSION: All the data showed that high expression of ABL2 suppresses apoptosis through Ras/Erk and PI3K/AKT signaling pathway in GC cell lines. PMID- 29767387 TI - No Medication for My Child! A Naturalistic Study on the Treatment Preferences for and Effects of Cogmed Working Memory Training Versus Psychostimulant Medication in Clinically Referred Youth with ADHD. AB - In this naturalistic clinical study, we explored the applicability and clinical effectiveness of Cogmed WMT, pharmacotherapy, and their combination for clinically referred children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Ninety youth with ADHD (ages 6-16 years) and their parents were offered the possibility to choose one of the three interventions. The motives for choosing various interventions were quite different. Medication was chosen because this treatment was expected to be most effective, but also because the Cogmed WMT program was regarded as too taxing. The choice for Cogmed WMT was mainly negatively motivated: participants tended to be strongly against the use of medication, found it a too rigorous step, or feared side effects and addiction problems. The choice for the combination treatment was strongly positively motivated: parents and youth indicated that they wanted to receive the best possible intervention and part of them also had high expectations of Cogmed WMT. In terms of clinical effectiveness, pharmacotherapy with stimulant medication and the combination treatment produced larger reductions in ADHD symptomatology than Cogmed WMT. Further, results indicated that Cogmed WMT selectively enhanced working memory performance. Finally, after conducting Cogmed WMT, youths and parents were more 'open' to accept pharmacotherapy as intervention, probably because the training increased greater insight in and awareness of the problematic features of ADHD. PMID- 29767391 TI - Self-Expanding Metallic Biliary Stents: Time to Suit Up? PMID- 29767390 TI - Safety and Efficacy of Endoscopic Retrograde Cholangiopancreatography for Choledocholithiasis in Long-Term Dialysis: A Propensity Score Analysis. AB - BACKGROUND AND AIM: Previous studies evaluating the safety of endoscopic retrograde cholangiopancreatography (ERCP) in patients with end-stage renal disease (ESRD) undergoing hemodialysis reported an increased risk of post procedural bleeding. We investigated the safety and efficacy of ERCP for the treatment of choledocholithiasis in patients with ESRD undergoing long-term dialysis. METHODS: A total of 3466 patients who underwent ERCP due to choledocholithiasis between January 2000 and Feb 2018 were reviewed and analyzed retrospectively. Patients were divided into dialysis and non-dialysis group, and propensity score matching was used to minimize selection bias. RESULTS: Patients of dialysis group (n = 39) and non-dialysis group (n = 78) were compared after propensity score matching. Among 39 patients of dialysis group, hemodialysis was used in 28 (71.8%) patients for renal replacement therapy, while 11 (28.2%) patients received peritoneal dialysis. The median duration of dialysis was 8 years (range 1-24 years). Overall success rate of ERCP was not different between two groups. The overall prevalence of post-procedural complications in dialysis group and non-dialysis group was 28.2 and 15.4%, respectively (p = 0.100). Post procedural bleeding occurred more frequently in dialysis group than non-dialysis group (23.1 vs 5.1%, p = 0.004). All procedure-related bleeding episodes were successfully controlled using endoscopic management. Prevalence of post-ERCP pancreatitis, infection, and perforation were not significantly different between two groups (p > 0.05). CONCLUSIONS: Overall success rate of complete ductal clearance was not different between dialysis and non-dialysis groups. The risk of post-procedural bleeding seems to be increased in patients with ESRD undergoing long-term dialysis. PMID- 29767392 TI - A Novel Rabbit Model for Benign Biliary Stricture Formation and the Effects of Medication Infusions on Stricture Formation. AB - BACKGROUND: Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS. METHOD: A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy. Biliary infusions with Rapamycin, Pirfenidone and Fasudil were performed daily during the 4 weeks following the surgery. The wall thickness and luminal area of the bile duct were assessed. RESULTS: All rabbits formed BBS after surgery. The mortality rate was 13% (8/60) and tube withdrawal rate was 4% (2/48). The thickness of the bile duct wall was significantly reduced; whereas the luminal area of the bile duct was dramatically enlarged in the Rapamycin or the Pirfenidone treated group, compared to the saline treated group. Furthermore, the local treatment significantly decreased the levels of proliferation makers, including PCNA, Collagen I and fibrogenic mediators, including ACTA2 and TGF beta. CONCLUSION: We have established a novel animal model for BBS formation. We have further demonstrated that biliary infusion with Rapamycin or Pirfenidone limits the biliary strictures through inhibiting the proliferation of the bile duct wall in this model. This may represent a new avenue for preventing biliary restenosis. PMID- 29767393 TI - Small-Bowel Capsule Endoscopy in Clinical Practice: Has Anything Changed Over 13 Years? AB - BACKGROUND: In Lombardia, one of the 20 Italian administrative Regions, small bowel capsule endoscopy (SBCE) was introduced in 2001. In January 2011, the Regional Health Authorities established a reimbursement for outpatient SBCE. AIM: To prospectively record data on SBCE between 2011-2013 and compare them to similar data retrospectively collected from the same geographical area (covering the period 2001-2008) and published in 2008. METHODS: Consecutive SBCEs performed between January 2011 and December 2013 in Lombardia were prospectively collected. RESULTS: In 3 years, 3142 SBCEs were collected; the diagnostic yield (DY) and the overall complication rate were 48.4 and 0.9%, respectively. The main indication was suspected small-bowel bleeding (76.6% of patients); complete small-bowel inspection was achieved in 2796 (89.0%) patients. SBCE was performed as an outpatient procedure in 1945 patients (61.9%). A significant increase in the rate of patients undergoing SBCE for suspected small-bowel bleeding was observed from 2001-2008 to 2011-2013 (67.3 vs. 76.1%; p < 0.001). There was an increase in the number of complete small-bowel examinations (81.2 vs. 89.0%; p < 0.001) and of outpatient SBCEs (6.7 vs. 61.9%; p < 0.001). Conversely, both the retention rate (2.1 vs. 0.8%; p < 0.001) and the rate of patients undergoing SBCE for Crohn's disease (11.5 vs. 5.5%; p < 0.001) decreased significantly. The overall DY remained stable (50.6 vs. 48.4%; p = 0.089). CONCLUSION: Our study shows that, over 13 years, the SBCE safety profile and completion rate significantly improved over time; a change in the spectrum of clinical indications was also observed. PMID- 29767394 TI - Prognostic factors and scoring model of hematological malignancies patients with bloodstream infections. AB - PURPOSE: Patients with hematological malignancies (HMs) are at a higher risk for bloodstream infections (BSIs), which pose significant burden on morbidity and mortality. Better risk stratification helps in medical decision making, increasing efficiency and reducing economic burden. The aim of this study was to develop and validate a reliable prediction model which can be used to identify HM patients at higher risk for BSIs. METHODS: We conducted a retrospective cohort study in three university-affiliated hospitals in Hunan Province, China, from January 2010 to April 2015. A total of 521 HMs patients with BSIs were finally included in this study and were divided into the derivation set and validation set. Survivors and non-survivors were compared to identify the predictors of 30 day mortality. RESULTS: The multivariate analysis yielded the following significant mortality-related risk factors: age > 60 years (95% CI 1.047-5.474), relapsed or uncontrolled malignancy (95% CI 2.043-14.029), Pitt bacteremia score > 3 (95% CI 1.614-6.35), prolonged neutropenia (95% CI 1.181-5.824), use of vasopressors (95% CI 3.009-12.210), acute respiratory failure (95% CI 3.061 14.911), fungemia (95% CI 1.334-12.121), inadequate antibiotic treatment (95% CI 1.682-7.591), albumin < 30 g/L (95% CI 1.030-3.446), TBil > 34.2 umol/L (95% CI 1.109-5.438). In both derivation and validation sets, our model showed reliable prediction value with areas under the receiver operating curve of 0.876 and 0.873. CONCLUSIONS: The risk factors in this study have the ability to identify patients with HMs and BSIs at high risk for mortality. Our model provides an excellent foundation for predicting 30-day morality in HM patients suffering from BSI and helps target high-risk patients for management decision making. PMID- 29767397 TI - The potential role of spherocrystals in the detoxification of essential trace metals following exposure to Cu and Zn in the fighting conch Strombus (Lobatus) pugilis. AB - Crypt cells-one of the three cell types composing Strombidae digestive tubules are characterized by the presence of numerous metal-containing phosphate granules termed spherocrystals. We explored the bioaccumulation and detoxification of metals in Strombidae by exposing wild fighting conch Strombus pugilis for 9 days to waterborne CuSO4 and ZnSO4. The total amount of Cu and Zn was determined in the digestive gland and in the rest of the body by Inductively Coupled Plasma (ICP) analyses. The digestive gland spherocrystal metal content was investigated based on the semi-quantitative energy dispersive X-ray (EDX) elemental analysis. ICP analyses of unexposed individuals revealed that 87.0 +/- 5.9% of the Zn is contained in the digestive gland, where its concentration is 36 times higher than in the rest of the body. Regarding Cu, 25.8 +/- 16.4% of the metal was located in the digestive gland of the control individuals, increasing to 61.5 +/- 16.4% in exposed individuals. Both Cu and Zn concentrations in the digestive gland increased after exposures, pointing to a potential role of this organ in the detoxification of these metals. EDX analysis of spherocrystals revealed the presence of Ca, Cl, Fe, K, Mg, P, and Zn in unexposed individuals. No difference was found in the relative proportion of Zn in spherocrystals of exposed versus control individuals. Contrastingly, copper was never detected in the spherocrystals from controls and Zn-exposed individuals, but the relative proportion of Cu in spherocrystals of Cu-exposed individuals varied from 0.3 to 5.7%. Our results show the direct role of spherocrystals in Cu detoxification. PMID- 29767395 TI - Behavioral Therapy Approaches for the Management of Low Back Pain: An Up-To-Date Systematic Review. AB - Low back pain is one of the most common causes for seeking medical treatment and it is estimated that one in two people will experience low back pain at some point during their lifetimes. Management of low back pain includes pharmacological and non-pharmacological approaches. Non-pharmaceutical treatments include interventions such as acupuncture, spinal manipulation, and psychotherapy. The latter is especially important as patients who suffer from low back pain often have impaired quality of life and also suffer from depression. Depressive symptoms can appear because back pain limits patients' ability to work and engage in their usual social activities. The aim of this systematic review was to overview the behavioral approaches that can be used in the management of patients with low back pain. Approaches such as electromyography (EMG) biofeedback, cognitive behavioral therapy, and mindfulness-based stress reduction are discussed as non-pharmacological options in the management of low back pain. PMID- 29767396 TI - Are lactoferrin receptors in Gram-negative bacteria viable vaccine targets? AB - A number of important Gram-negative pathogens that reside exclusively in the upper respiratory or genitourinary tract of their mammalian host rely on surface receptors that specifically bind host transferrin and lactoferrin as a source of iron for growth. The transferrin receptors have been targeted for vaccine development due to their critical role in acquiring iron during invasive infection and for survival on the mucosal surface. In this study, we focus on the lactoferrin receptors, determining their prevalence in pathogenic bacteria and comparing their prevalence in commensal Neisseria to other surface antigens targeted for vaccines; addressing the issue of a reservoir for vaccine escape and impact of vaccination on the microbiome. Since the selective release of the surface lipoprotein lactoferrin binding protein B by the NalP protease in Neisseria meningitidis argues against its utility as a vaccine target, we evaluated the release of outer membrane vesicles, and transferrin and lactoferrin binding in N. meningitidis and Moraxella catarrhalis. The results indicate that the presence of NalP reduces the binding of transferrin and lactoferrin by cells and native outer membrane vesicles, suggesting that NalP may impact all lipoprotein targets, thus this should not exclude lactoferrin binding protein B as a target. PMID- 29767398 TI - Bioinformatic analysis of the metal response element and zinc-dependent gene regulation via the metal response element-binding transcription factor 1 in Caco 2 cells. AB - The purpose of this study was to determine the correlation between the position or number of metal regulatory elements (MREs) near gene transcriptional or translational start sites, and the strength of metal response element-binding transcription factor 1 (MTF-1) regulation. A secondary analysis was performed in silico on published results measuring the effects of Zn and MTF-1 on transcriptional regulation of genes (n = 120) in the Caco-2 cell line. MRE sequence variations throughout the human genome were sorted using a position weight matrix. Three null hypotheses (H0) were tested: (1) there is no correlation between the number of MREs and MTF-1 transcriptional strength, (2) there is no correlation between the distance of the MRE upstream from the transcriptional start site (TSS) and MTF-1 transcriptional strength, and (3) there is no correlation between the distance of the MRE downstream from the translational start site (TrSS) and MTF-1 transcriptional strength. Spearman correlation was used to test for significance (p < 0.05). From our results we rejected the first H0; we observed a significant correlation between the total number of MRE sequences - 7Kbp upstream from the TSS, within the 5' untranslated region, and + 1Kbp downstream from the TrSS, versus the strength of MTF-1 regulation (r = 0.202; p = 0.027). The second and third H0 were accepted. These results expand our understanding of the role of the MRE in Zn-dependent gene regulation. The data indicate that Zn influences the transcriptional control of gene expression beyond maintaining intracellular Zn homeostasis. PMID- 29767399 TI - A decreased soluble Klotho level with normal eGFR, FGF23, serum phosphate, and FEP in an ADPKD patient with enlarged kidneys due to multiple cysts. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder. ADPKD is characterized clinically by the presence of multiple bilateral renal cysts that lead to chronic renal failure. The cysts evolve from renal tubular epithelial cells that express the Klotho gene. Notably, Klotho acts as a co-receptor for fibroblast growth factor 23 (FGF23); in this context, it induces phosphaturia and maintains serum phosphate at a normal level. Many reports have shown that decreases in the soluble Klotho level and increases in the FGF23 level are associated with glomerular filtration rate (GFR) decline, but a recent study observed these changes in patient with normal eGFR. It remains unclear whether the decrease in the Klotho level precedes the increase in FGF23. Here, we present an ADPKD patient with enlarged kidneys due to multiple cysts who had a decreased soluble Klotho level but a normal eGFR and a normal FGF23 level. The patient's serum phosphate level was normal, as was the fractional excretion of phosphate (FEP). This appears to be the first reported case to show a decreased soluble Klotho level plus normal eGFR, FGF23, and FEP. These results suggest that Klotho decreases before FGF23 increases and further suggest that Klotho is not required to maintain normal serum phosphate levels in ADPKD if the FEP and serum phosphate levels are normal. PMID- 29767402 TI - Connecting Refugees to Medical Homes Through Multi-Sector Collaboration. AB - As increasing numbers of refugees have resettled globally, an interdisciplinary group of stakeholders in Forsyth, North Carolina, recognized obstacles preventing coordinated medical care, which inspired the development of our Refugee Health Collaborative. This study assessed the Collaborative's impact on access to coordinated care within patient-centered medical homes (PCMH). A Collaborative developed novel algorithm guided the process by which refugees establish care in PCMHs. All refugees who established medical care in the two primary health systems in our county (n = 285) were included. Logistic non-linear mixed models were used to estimate the differences between three time frames: pre-algorithm, algorithm implementation and refinement, and ongoing algorithm implementation. After algorithm implementation, there has been a significant decrease in the time required to establish care in PCMHs, increased provider acknowledgment of refugee status, and decreased emergency department (ED) visits. Multi-disciplinary, organized collaboration can facilitate enhanced access to care for refugee families at the population level. PMID- 29767403 TI - Predicting the Influence of Situational and Immigration Stress on Latino Day Laborers' Workplace Injuries: An Exploratory Structural Equation Model. AB - Latino day laborers are a socially and economically marginalized immigrant population with a high risk of occupational injury. These workers confront multiple social, psychological, and environmental hardships that increase their risk for adverse health outcomes. How these stressors interact and influence work related injuries in this population remains unclear. We conducted an exploratory study with 327 Latino day laborers who completed a community survey. We developed a structural equation model, using cross-sectional data to explore the relationships among socioeconomic status, situational and immigration stress, depression, work risk exposure, and occupational injury. The model revealed a statistically significant mediated effect from situational stress to injury through work risk exposure as well as a significant mediated effect from immigration stress through depression to injury. These initial findings suggest that situational and immigration-related stress have a detrimental impact on Latino day laborers' mental health and workplace safety and, ultimately, increase their risk of occupational injury. PMID- 29767400 TI - Volumetric image interpretation in radiology: scroll behavior and cognitive processes. AB - The interpretation of medical images is a primary task for radiologists. Besides two-dimensional (2D) images, current imaging technologies allow for volumetric display of medical images. Whereas current radiology practice increasingly uses volumetric images, the majority of studies on medical image interpretation is conducted on 2D images. The current study aimed to gain deeper insight into the volumetric image interpretation process by examining this process in twenty radiology trainees who all completed four volumetric image cases. Two types of data were obtained concerning scroll behaviors and think-aloud data. Types of scroll behavior concerned oscillations, half runs, full runs, image manipulations, and interruptions. Think-aloud data were coded by a framework of knowledge and skills in radiology including three cognitive processes: perception, analysis, and synthesis. Relating scroll behavior to cognitive processes showed that oscillations and half runs coincided more often with analysis and synthesis than full runs, whereas full runs coincided more often with perception than oscillations and half runs. Interruptions were characterized by synthesis and image manipulations by perception. In addition, we investigated relations between cognitive processes and found an overall bottom-up way of reasoning with dynamic interactions between cognitive processes, especially between perception and analysis. In sum, our results highlight the dynamic interactions between these processes and the grounding of cognitive processes in scroll behavior. It suggests, that the types of scroll behavior are relevant to describe how radiologists interact with and manipulate volumetric images. PMID- 29767404 TI - Carrier Cells for Delivery of Oncolytic Measles Virus into Tumors: Determinants of Efficient Loading. AB - Oncolytic measles virus (OMV) is a promising antitumor agent. However, the presence of anti-measles neutralizing antibodies (NAbs) against the hemagglutinin (H) protein of OMV is a major barrier to the therapeutic application of OMV in clinical practice. In order to overcome this challenge, specific types of cells have been used as carriers for OMV. Differential loading strategies appear to result in different therapeutic outcomes; despite this, only few studies have reported practical ex vivo loading strategies required for effective treatment. To this end, we systematically evaluated the antitumor efficacy of OMV using different loading strategies; this involved varying the in vitro loading duration and loading dose of OMV. We found that improved oncolysis of carrier cells was achieved by a prolonged loading duration in the absence of NAbs. However, the enhanced oncolytic effect was abrogated in the presence of NAbs. Further, we found that the expression of H protein on the surface of carrier cells was predominantly determined by the loading duration rather than the loading dose. Finally, we showed that NAbs blocked viral transfer by targeting H protein prior to the occurrence of cell-to-cell interactions. Our results provide comprehensive information on the determinants of an effective loading strategy for carrier cell based virotherapy; these results may be useful for guiding the application of OMV as an antitumor agent in clinical practice. PMID- 29767405 TI - Sevuparin blocks sickle blood cell adhesion and sickle-leucocyte rolling on immobilized L-selectin in a dose dependent manner. PMID- 29767401 TI - From Theory to Application: A Description of Transnationalism in Culturally Appropriate HIV Interventions of Outreach, Access, and Retention Among Latino/a Populations. AB - Interventions aiming to improve access to and retention in HIV care are optimized when they are tailored to clients' needs. This paper describes an initiative of interventions implemented by ten demonstration sites using a transnational framework to tailor services for Mexicans and Puerto Ricans living with HIV. Transnationalism describes how immigrants (and their children) exist in their "receiving" place (e.g., continental U.S.) while simultaneously maintaining connections to their country or place of origin (e.g., Mexico). We describe interventions in terms of the strategies used, the theory informing design and the tailoring, and the integration of transnationalism. We argue how applying the transnational framework may improve the quality and effectiveness of services in response to the initiative's overall goal, which is to produce innovative, robust, evidence-informed strategies that go beyond traditional tailoring approaches for HIV interventions with Latino/as populations. PMID- 29767406 TI - Dehydrated hereditary stomatocytosis causing fetal hydrops and perinatal ascites. PMID- 29767407 TI - The difficult business of assessing new therapies for smouldering multiple myeloma. PMID- 29767408 TI - Fanconi anaemia presenting as acute myeloid leukaemia and myelodysplastic syndrome in adulthood: a family report on co-occurring FANCC and CHEK2 mutations. PMID- 29767409 TI - The use of serum free light chain dimerization patterns assist in the diagnosis of AL amyloidosis. AB - The discrimination between benign and malignant forms of plasma cell dyscrasia (PCD) is often difficult. Free light chain monomer-dimer pattern analysis (FLC MDPA) may assist in solving this dilemma and distinguish between AL amyloidosis and benign PCD. Serum samples of patients with AL amyloidosis and benign PCD were analysed in a blinded manner. Quantitative Western blotting was performed to estimate dimerization and clonality indices, and thereby determine the source of the tested samples, as derived either from benign or malignant PCD. The findings obtained by the FLC-MDPA were compared with the actual diagnosis. Of 37 samples from patients with active AL amyloidosis, 34 (91.9%) fulfilled dimerization criteria for diagnosis of AL amyloidosis. Of the 45 samples from patients with benign PCD, 10 (21.2%) tested falsely positive or gave an inconclusive result. Thus, the sensitivity of the analysis was 92.5% with a remarkable negative predictive value of 91.9%. In addition, of 20 patients who were in complete or very good partial remission, only one tested positive. By multivariate analysis, FLC-MDPA was the best independent marker predicting AL amyloidosis (odds ratio of 84). The FLC-MDPA offers a highly effective tool in the diagnostic assessment of patients with PCD. PMID- 29767410 TI - Combination targeted therapy in chronic lymphocytic leukaemia - can pre-clinical studies translate to the clinic? PMID- 29767411 TI - MEK1/2 inhibition by binimetinib is effective as a single agent and potentiates the actions of Venetoclax and ABT-737 under conditions that mimic the chronic lymphocytic leukaemia (CLL) tumour microenvironment. AB - The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti-IgM antibody or stroma-derived factor-1alpha (SDF-1alpha) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co-cultured with CD40 ligand (CD40L)-expressing fibroblasts to the BH3-mimetics ABT-737 and Venetoclax (ABT 199) via a mechanism involving down-regulation of Mcl-1 (MCL1) activity and Bim (BCL2L11) and Bcl-xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment-derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment. PMID- 29767412 TI - METHODOLOGICAL CONSIDERATIONS FOR HOME-VISITING RESEARCH IN TRIBAL COMMUNITIES. AB - Drawing on previous studies and the collective experience of conducting rigorous evaluations as part of the Tribal Maternal, Infant, and Early Childhood Home Visiting grants, we outline methodological considerations that will inform future research in tribal communities, particularly in the area of home visiting. The methodological issues we discuss are study design choices, measurement and data collection, and including community members in all aspects of the research. PMID- 29767413 TI - The statistical joys-and added complications-of twin studies. PMID- 29767414 TI - Variation in reproduction of the smallest-bodied primate radiation, the mouse lemurs (Microcebus spp.): A synopsis. AB - Reproduction is a fundamental trait in the life history of any species and contributes to species diversity and evolution. Here, we aim to review the barely known variation in reproductive patterns of the smallest-bodied primate radiation, the Malagasy mouse lemurs, focusing on twelve species of four phylogenetic clades. We present a new reproductive field dataset collected between May and November 1996-2016 for nine species (Microcebus murinus, M. myoxinus, M. ravelobensis, M. bongolavensis, M. danfossi, M. sambiranensis, M. margothmarshae, M. mamiratra, and M. lehilahytsara) and add published field information on three additional species. In the majority of species, the estrus of females was recorded in the period of long days (day length longer than 12 hr), whereas male testes size increased about one to three months prior to this. Reproductive schedules varied considerably between the four clades. Sympatric species-pairs of different clades differed in the timing of female and male reproduction, suggesting strong phylogenetic constraints. Populations of the same species in a different ecological setting varied in the onset of reproduction, suggesting substantial environmental plasticity. Warm temperatures and rainfall throughout the year may allow for less expressed reproductive seasonality. Our results suggest that an interplay between phylogenetic relatedness, ambient temperature (as a proxy for thermo regulatory constraints), and rainfall (as a proxy for food availability), may best explain this variation. Findings further point to a more complex control of mouse lemur reproduction than previously described and illuminate phylogenetic constraints and adaptive potentials in behavioral reaction norms of a species-rich primate radiation. PMID- 29767415 TI - Micellized Tris(bipyridine)ruthenium Catalysts Affording Preparative Amounts of Hydrated Electrons with a Green Light-Emitting Diode. AB - We have explored alkyl substitution of the ligands as a means to improve the performance of the title complexes in photoredox catalytic systems that produce synthetically useable amounts of hydrated electrons through photon pooling. Despite generating a super-reductant, these electron sources only consume the bioavailable ascorbate and are driven by a green light-emitting diode (LED). The substitutions influence the catalyst activity through the interplay of the quenching parameters, the recombination rate of the reduced catalyst OER and the ascorbyl radical across the micelle-water interface, and the quantum yield of OER photoionization. Laser flash photolysis yields comprehensive information on all these processes and allows quantitative predictions of the activity observed in LED kinetics, but the latter method provides the only access to the catalyst stability under illumination on the timescale of the syntheses. The homoleptic complex with dimethylbipyridine ligands emerges as the optimum that combines an activity twice as high with an undiminished stability in relation to the parent compound. With this complex, we have effected dehalogenations of alkyl and aryl chlorides and fluorides, hydrogenations of carbon-carbon double bonds, and self- as well as cross-coupling reactions. All the substrates employed are impervious to ordinary photoredox catalysts but present no problems to the hydrated electron as a super-reductant. A particularly attractive application is selective deuteration with high isotopic purity, which is achieved simply by using heavy water as the solvent. PMID- 29767416 TI - Utility of electrical velocimetry-based noninvasive stroke volume variation in predicting fluid responsiveness under different ventilation modes in anaesthetized dogs. AB - We evaluated the utility of noninvasive stroke volume variation (SVV) as a functional haemodynamic predictor for fluid responsiveness under different ventilation modes [assist control (A/C), synchronized intermittent mandatory ventilation (SIMV), and continuous positive airway pressure (CPAP)] in 45 anaesthetized dogs, using an electrical velocimetry device. Receiver operating curve analysis confirmed the best predictive value during SVVA/C (12.5% of cut off value; 75% sensitivity and 86% specificity) followed by SVVSIMV (13.5% of cut off value; 75% sensitivity and 75% specificity), while no statistically significance detected during SVVCPAP (P > .05). These data suggest that SVV is useful for the prediction of fluid responsiveness in laboratory dogs during A/C and SIMV, while its reliability during CPAP is poor. This article is protected by copyright. All rights reserved. PMID- 29767418 TI - Dermatoscopic chaos of border-abruptness led to diagnosis of a minute melanoma. PMID- 29767417 TI - Do concordances of social support and relationship quality predict psychological distress and well-being of cancer patients and caregivers? AB - This study examined concordances of cancer patients' received and caregivers' provided support and dyadic relationship quality, and their predictive utility in prospective psychological distress and well-being. A total of 83 Chinese cancer patient-caregiver dyads were recruited in two government-funded hospitals in Hong Kong. Participants reported received (patient)/provided (caregiver) emotional and instrumental support and dyadic relationship quality within 6 months after diagnosis (T1), and anxiety and depressive symptoms, positive affect and life satisfaction at both T1 and 6-month follow-up (T2). We hypothesised that concordances at T1 would predict lower psychological distress and higher psychological well-being among both patients and caregivers at T2. Concordances were indicated by Gwet's AC2 scores (possible range = -1.00 to 1.00) and as follows: emotional support: M = 0.92, SD = 0.12, range = 0.25-1.00; instrumental support: M = 0.92, SD = 0.16, range = 0.08-1.00; and relationship quality: M = 0.63, SD = 0.27, range = -0.31 to 1.00. Hierarchical multiple regressions revealed that T1 concordances of perceived emotional and instrumental support and dyadic relationship quality positively predicted T2 anxiety symptoms [F(9, 74) = 6.725, ?R2 = .031, p < .001)] and state positive affect [F(9, 74) = 3.436, ?R2 = .042, p = .001)], whereas inversely predicted T2 depressive symptoms [F(9, 74) = 4.189, ?R2 = .042, p < .01)]. Significant associations were found only among caregivers, but not patients. PMID- 29767420 TI - Ocular coherence tomography-measured changes over time in anterior chamber angle and diurnal intraocular pressure after laser iridotomy: IMPACT study. AB - IMPORTANCE: The change in the anatomical dimensions over time and the effect on diurnal intraocular pressure (DIOP) following laser peripheral iridotomy is poorly understood. BACKGROUND: To evaluate change over time in anterior chamber angle anatomy following laser peripheral iridotomy (LPI) in patients with primary angle closure compared to control eyes. Additionally, the effect of LPI on DIOP fluctuation was investigated. DESIGN: Longitudinal, prospective, double randomized research study. PARTICIPANTS: Adults with suspected angle closure or angle closure diagnosis referred to hospital services in the United Kingdom. METHODS: Thirty-nine patients newly diagnosed with bilateral primary angle closure/suspects (PAC/PACS) received LPI to one eye and changes in angle morphology were measured over eight sections with swept source AS-OCT. The other eye acted as control with intraocular pressure (IOP) measured hourly. MAIN OUTCOME MEASURES: Angle opening distance (AOD), trabecular-iris angle (TIA), angle recess area (ARA), and trabecular-iris space area (TISA) at 500 and 750 MUm from scleral spur. RESULTS: There was an increase in all angle parameters following LPI, which was maintained for 6 months (e.g. inferotemporal segment AOD500 0.041 mm (P = 0.008) at 1 week and 0.039 mm (P = 0.003) at 6 months) following LPI. Greatest effect at 6 months post-LPI was observed opposite the iridotomy site in the inferior/inferotemporal sections (AOD500 0.039 mm, P = 0.003 and AOD750 0.075 mm, P = 0.002). There were no statistically significant differences for the overall DIOP fluctuation values in the treated group at 6 months post-LPI compared to baseline. CONCLUSIONS AND RELEVANCE: LPI widened all angle sections with maximum effect observed in the site opposite the iridotomy. Angle changes were maintained up to 6 months after LPI treatment without any statistically significant change in DIOP fluctuation. PMID- 29767419 TI - Association between expression of MMP-7 and MMP-9 and pelvic lymph node and para aortic lymph node metastasis in early cervical cancer. AB - AIMS: To investigate the association of matrix metalloproteinase (MMP)-7 and MMP 9 with pelvic lymph node and para-aortic lymph node metastasis in early cervical cancer. METHODS: A total of 137 patients with early cervical cancer (Stage Ia2 IIa2) were recruited from the Department of Gynecology and Obstetrics, Tumor Hospital of Liaoning Province from January 2009 to May 2014. We evaluated the expression of MMP-7 and MMP-9 by immunohistochemistry and their association with the clinicopathological parameters such as pelvic, common iliac and para-aortic lymph node metastasis. Spearman correlation was performed to analyze the correlation between MMP-7 and MMP-9 in cervical cancer. Finally, the areas under the receiver operating characteristic curve (ROC) of MMP-7 and MMP-9 in pelvic lymph node metastasis were assessed. RESULTS: MMP-7 expression was significantly higher in patients with adenocarcinomas and adenosquamous carcinomas (P = 0.014), vascular cancer embolus (P = 0.041), pelvic lymph node metastasis (P = 0.000) and a higher level of Ki-67 (P = 0.000). MMP-9 expression was significantly associated with vascular cancer embolus (P = 0.003), depth of stromal invasion (P = 0.001), pelvic lymph node metastasis (P = 0.003), common iliac lymph node metastasis (P = 0.001) and para-aortic lymph nodes metastasis (P = 0.004). Coexpression of MMP-7 and MMP-9 was significantly associated with vascular cancer embolus (P < 0.001), higher expression of Ki-67 (P < 0.001) and pelvic lymph node metastasis (P < 0.001). Spearman correlation analysis indicated a positive correlation between MMP-7 and MMP-9 (r = 0.263, P = 0.002). Areas under the ROC of MMP-7 and MMP-9 were 0.707 and 0.646, respectively. CONCLUSION: MMP-7 and MMP 9 expressions were associated with lymph node metastasis in patients with early cervical cancers, suggesting a positive correlation of MMP-7 and MMP-9 with invasive potential in early cervical cancers. PMID- 29767421 TI - Coumaraz-2-on-4-ylidene: Ambiphilic N-Heterocyclic Carbenes with a Tunable Electronic Structure. AB - Herein, a coumaraz-2-on-4-ylidene (1) as a new example of an ambiphilic N heterocyclic carbene, having electronic properties that can be fine-tuned, is reported. The N-carbamic and aryl groups on the carbene carbon center provide exceptionally high electrophilicity and nucleophilicity simultaneously to the carbene center, as evidenced by the 77 Se NMR chemical shifts of their selenoketone derivatives and the CO stretching strengths of their rhodium carbonyl complexes. Since the precursors of 1 could be synthesized from various functionalized Schiff bases in a practical and scalable manner, the electronic properties of 1 can be fine-tuned in a quantitative and predictable way by using the Hammett sigma constant of the functional groups on aryl ring. The facile electronic tuning capability of 1 may be applicable to eliciting novel properties in main-group and transition-metal chemistry. PMID- 29767422 TI - Reduction-Triggered Transformation of Disulfide-Containing Micelles at Chemically Tunable Rates. AB - A dilemma exists between the circulation stability and cargo release/mass diffusion at desired sites when designing delivery nanocarriers and in vivo nanoreactors. Reported herein are disulfide-crosslinked (DCL) micelles exhibiting reduction-triggered switching of crosslinking modules and synchronized hydrophobic-to-hydrophilic transition. Tumor cell targeted DCL micelles undergo cytoplasmic milieu triggered disulfide cleavage and self-immolative decaging reactions at chemically adjustable rates, generating primary amine moieties. Extensive amidation reactions with neighboring ester moieties then occur because of the high local concentration and suppression of the apparent amine pKa value within the hydrophobic cores, thus leading to the transformation of crosslinking modules and formation of tracelessly crosslinked (TCL) micelles, with hydrophilic cores, inside live cells. We further integrate this design principle with theranostic nanocarriers for selective intracellular drug transport guided by enhanced magnetic resonance (MR) imaging performance. PMID- 29767423 TI - Blood pressure measurement techniques: Assessing performance in outpatient settings of a tertiary-level hospital in Rwanda. AB - Cardiovascular diseases (CVD) are the leading cause of mortality globally. Hypertension is a known modifiable risk factor for CVD. Diagnosis and management of hypertension hinges upon accurate blood pressure (BP) measurement. In this study, we assessed performance to recommended guidelines for BP measurement in Rwanda. In 2017, a cross-sectional study investigating performance on 11 techniques recommended for BP measurement was undertaken across outpatient settings of 3 departments at the University Teaching Hospital of Kigali, Rwanda. Performance was checked by an inside observer. The study enrolled 164 patients. The overall mean performance on the 11 BP measurement techniques was 5.69 (+/ 1.02) out of the 11 possible points. There was no significant difference in performance across departments (P = .28). The findings suggest that performance on currently recommended guidelines for BP measurement is not optimal. Going forward, it is important to implement interventions that will enhance performance given that diagnosis and management of hypertension depend upon accurate BP measurement. PMID- 29767425 TI - Increased chewing reduces energy intake, but not postprandial glucose and insulin, in healthy weight and overweight young adults. AB - AIM: This randomised cross-over design study aimed to investigate different chewing activities between healthy weight and overweight individuals and to determine the effect of chewing on energy intake and postprandial plasma glucose and insulin concentrations. METHODS: Forty-one participants were classified into healthy weight and overweight groups according to body mass index (BMI). In Phase I, bite size (g/bite), bite rate (bites/minutes), chewing frequency (chews/minutes) and chews (chews/g food) were recorded after a sandwich breakfast. In Phase II, the mass of a sandwich consumed after 15 and 50 chews per bite (results of Phase I) was recorded. Postprandial plasma glucose and insulin were also examined at 0 (baseline), 30, 60, 90, 120 and 180 minutes. RESULTS: The results showed that the number of chews per bite was higher in lean participants as compared to overweight participants. Energy intake was highest in overweight participants who chewed 15 times per bite. Additionally, participants consumed less energy after 50 chews regardless of their BMI status. The results also demonstrated that 50 chews per bite insignificantly increased plasma insulin concentrations at every time point in both lean and obese subjects. Insulin concentrations were not significantly changed at each time point regardless of the number of chews. CONCLUSIONS: Overweight participants chewed less and ingested more calories. Chewing 50 times per bite could reduce caloric intake regardless of weight status, suggesting that slow eating via increased chewing may help to reduce energy intake during meals. However, chewing did not affect postprandial plasma glucose and insulin levels in healthy young adults. PMID- 29767424 TI - CULTURAL ADAPTATIONS OF EVIDENCE-BASED HOME-VISITATION MODELS IN TRIBAL COMMUNITIES. AB - The Tribal Maternal, Infant, and Early Childhood Home Visiting (Tribal MIECHV) Program provides federal grants to tribes, tribal consortia, tribal organizations, and urban Indian organizations to implement evidence-based home visiting services for American Indian and Alaska Native (AI/AN) families. To date, only one evidence-based home-visiting program has been developed for use in AI/AN communities. The purpose of this article is to describe the steps that four Tribal MIECHV Programs took to assess community needs, select a home-visiting model, and culturally adapt the model for use in AI/AN communities. In these four unique Tribal MIECHV Program settings, each program employed a rigorous needs assessment process and developed cultural modifications in accordance with community strengths and needs. Adaptations occurred in consultation with model developers, with consideration of the conceptual rationale for the program, while grounding new content in indigenous cultures. Research is needed to improve measurement of home-visiting outcomes in tribal and urban AI/AN settings, develop culturally grounded home-visiting interventions, and assess the effectiveness of home visiting in AI/AN communities. PMID- 29767426 TI - Uncommon Optical Properties and Silver-Responsive Turn-Off/On Luminescence in a PtII Heteroleptic Dithiolene Complex. AB - Complex [Pt(iPr2 pipdt)(Quinoxdt)] (iPr2 pipdt=1,4-diisopropyl-piperazine-2,3 dithione; Quinoxdt=[1,4]dithiino[2,3-b]quinoxaline-2,3-dithiolate) exhibits a remarkable green emission at 570 nm (room temperature), which is above the lowest excited state. The complex is characterized by negative solvatochromism as well as a high second-order polarizability. Addition of AgI ions induces 1) hypsochromic shift of the lowest frequencies and 2) reversible quenching of luminescence. The corresponding Ni and Pd complexes have also been prepared and investigated to assist interpretation of optical properties within the triad. Computational studies based on DFT and time-dependent DFT highlight the electronic properties of [Pt(iPr2 pipdt)(Quinoxdt)]. The preferential site of interaction between the Pt complex and incoming AgI is evidenced by the shape of the Fukui functions, pointing to the thiolic sulfur and platinum atoms as the most reactive sites towards a soft cation. Calculated optical properties are in agreement with experimental findings. This study sheds light on the structure property relationship for this class of compounds. PMID- 29767427 TI - Azacitidine in the 'real-world': an evaluation of 1101 higher-risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario, Canada. AB - The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher-risk disease treated with azacitidine (AZA) in the 'real-world' remains largely unknown. We evaluated 1101 consecutive higher-risk MDS patients (International Prognostic Scoring System intermediate-2/high) and low-blast count acute myeloid leukaemia (AML; 21-30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24.7% received AZA for seven consecutive days, 12.4% for six consecutive days and 62.9% by 5-2-2. Overall, median number of cycles was 6 (range 1-67) and 8 (range 6-14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11.6 months [95% confidence interval (CI) 10.7-12.4) for the entire cohort and 18.0 months (landmark analysis; 95% CI 16.6-19.1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0.87). In our large 'real-world' evaluation of AZA in higher-risk MDS/low-blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest 'real-world' evaluation of AZA in higher-risk MDS/low blast count AML. PMID- 29767429 TI - Spectral domain optical coherence tomography interpretation - Response to Blacklaws et al. PMID- 29767428 TI - Photonic crystal enhanced fluorescence immunoassay on diatom biosilica. AB - Fluorescence biosensing is one of the most established biosensing methods, particularly fluorescence spectroscopy and microscopy. These are two highly sensitive techniques but require high-grade electronics and optics to achieve the desired sensitivity. Efforts have been made to implement these methods using consumer grade electronics and simple optical setups for applications such as point-of-care diagnostics, but the sensitivity inherently suffers. Sensing substrates, capable of enhancing fluorescence are thus needed to achieve high sensitivity for such applications. In this paper, we demonstrate a photonic crystal-enhanced fluorescence immunoassay biosensor using diatom biosilica, which consists of silica frustules with sub-100 nm periodic pores. Utilizing the enhanced local optical field, the Purcell effect and increased surface area from the diatom photonic crystals, we create ultrasensitive immunoassay biosensors that can significantly enhance fluorescence spectroscopy as well as fluorescence imaging. Using standard antibody-antigen-labeled antibody immunoassay protocol, we experimentally achieved 100* and 10* better detection limit with fluorescence spectroscopy and fluorescence imaging respectively. The limit of detection of the mouse IgG goes down to 10-16 M (14 fg/mL) and 10-15 M (140 fg/mL) for the two respective detection modalities, virtually sensing a single mouse IgG molecule on each diatom frustule. The effectively enhanced fluorescence imaging in conjunction with the simple hot-spot counting analysis method used in this paper proves the great potential of diatom fluorescence immunoassay for point-of-care biosensing. PMID- 29767430 TI - Ultra-Narrow-Band Blue-Emitting Oxoberyllates AELi2 [Be4 O6 ]:Eu2+ (AE=Sr,Ba) Paving the Way to Efficient RGB pc-LEDs. AB - Highly efficient phosphor-converted light-emitting diodes (pc-LEDs) are popular in lighting and high-tech electronics applications. The main goals of present LED research are increasing light quality, preserving color point stability and reducing energy consumption. For those purposes excellent phosphors in all spectral regions are required. Here, we report on ultra-narrow band blue emitting oxoberyllates AELi2 [Be4 O6 ]:Eu2+ (AE=Sr,Ba) exhibiting a rigid covalent network isotypic to the nitridoalumosilicate BaLi2 [(Al2 Si2 )N6 ]:Eu2+ . The oxoberyllates' extremely small Stokes shift and unprecedented ultra-narrow band blue emission with fwhm ~25 nm (~1200 cm-1 ) at lambdaem =454-456 nm result from its rigid, highly condensed tetrahedra network. AELi2 [Be4 O6 ]:Eu2+ allows for using short-wavelength blue LEDs (lambdaem <440 nm) for efficient excitation of the ultra-narrow band blue phosphor, for application in violet pumped white RGB phosphor LEDs with improved color point stability, excellent color rendering, and high energy efficiency. PMID- 29767432 TI - Open sepulchers and closed boundaries? Biodistance analysis of cemetery structure and postmarital residence in the late prehispanic Andes. AB - OBJECTIVES: In the Late Intermediate Period Andes (AD 1100-1450), the proliferation of above-ground sepulchers reconfigured social boundaries within and between communities engaged in protracted conflict. However, the biosocial dimensions of these mortuary practices, and their implications for conflict and alliance formation, remain unexplored. This study examines patterns of phenotypic variation to: (1) evaluate if open sepulchers were organized on the basis of biological relatedness, and (2) explore if sex-specific phenotypic variability conforms to models of postmarital residence. MATERIALS AND METHODS: Cranial nonmetric traits were recorded in five skeletal samples from two cemeteries in the Colca Valley, Peru. Biological distances between burial groups were calculated using the Mean Measure of Divergence (MMD) statistic. Postmarital residence was explored by calculating and bootstrapping the ratio of male-to female mean pairwise differences (MPD) at the within-group level. RESULTS: The MMD analysis yields greater than expected between-group distances for burial groups with a minimum sample size of 20 individuals. In contrast, a prevailing pattern of sex-specific, within-group phenotypic variability is not apparent from the analysis of MPD. The use of 12 or 24 dichotomous traits produces similar results. DISCUSSION: Greater than expected biological distances suggest that above-ground mortuary practices reinforced biosocial boundaries between corporate household groups. Intracemetery heterogeneity persisted even as cranial vault modification, a correlate of social identity, became more homogenous, revealing how corporate group organization was negotiated at multiple scales. Sex-specific variation does not conform to traditional migration models. If migration occurred, it did not have a homogenizing effect on phenotypic variation. These results should be viewed with caution in light of the smaller sample sizes of sex specific groupings. PMID- 29767431 TI - Vocal repertoire of free-ranging adult golden snub-nosed monkeys (Rhinopithecus roxellana). AB - Vocal signaling represents a primary mode of communication for most nonhuman primates. A quantitative description of the vocal repertoire is a critical step in in-depth studies of the vocal communication of particular species, and provides the foundation for comparative studies to investigate the selective pressures in the evolution of vocal communication systems. The present study was the first attempt to establish the vocal repertoire of free-ranging adult golden snub-nosed monkeys (Rhinopithecus roxellana) based on quantitative methods. During 8 months in Shennongjia National Park, China, we digitally recorded the vocalizations of adult individuals from a provisioned, free-ranging group of R. roxellana across a variety of social-ecological contexts. We identified 18 call types, which were easily distinguishable by ear, visual inspection of spectrograms, and quantitative analysis of acoustic parameters measured from recording samples. We found a great sexual asymmetry in the vocal repertoire size (females produced many more call types than males), likely due to the sex differences in body size and social role. We found a variety of call types that occurred during various forms of agonistic and affiliative interactions at close range. We made inference about the functions of particular call types based on the contexts in which they were produced. Studies on the vocal communication in R. roxellana are particularly valuable since they provide a case about how nonhuman primates, inhabiting forest habitats and forming complex social systems, use their vocalizations to interact with their social and ecological environments. PMID- 29767433 TI - t(6;9)(p23;q34.1) acute myeloid leukaemia with cup-like blasts. PMID- 29767435 TI - APPROACHES TO THE EVALUATION OF CULTURAL ADAPTATIONS OF HOME VISITING IN TRIBAL COMMUNITIES. AB - The research that underlies evidence-based practices is often based on relatively homogenous study samples, thus limiting our ability to understand how the study findings apply in new situations as well as our understanding of what might need to be adapted. In a preliminary effort to address those gaps, the requirements for the Tribal Maternal Infant and Early Childhood Home Visiting Program (MIECHV) included the expectation that grantees design and implement rigorous evaluations to address local priorities and to help build the knowledge base regarding the use of evidence-based home-visiting programs in tribal communities. A priority that emerged across many Tribal MIECHV grantees was to determine the added benefit of the cultural adaptations that they were making to their home-visiting programs. While there is literature to describe recommended processes for making cultural adaptations to evidence-based programs themselves, there are very few guidelines for evaluating these adaptations. In this article, we review the varied evaluation approaches utilized by Tribal MIECHV grantees and provide three case examples of how evaluators and tribal communities worked together to articulate evaluation questions and choose appropriate and feasible evaluation designs. The lessons derived from these Tribal MIECHV evaluation experiences have implications for the role of the evaluator in diverse communities across the country evaluating home visiting and other evidence-based practices in settings characterized by unique cultural contexts. PMID- 29767434 TI - Regenerative surgical therapy for peri-implantitis using deproteinized bovine bone mineral with 10% collagen, enamel matrix derivative and Doxycycline-A prospective 3-year cohort study. AB - OBJECTIVES: There is limited evidence regarding the long-term efficacy of regenerative treatment for peri-implantitis. The aim of this study was to evaluate a combination therapy of deproteinized bovine bone mineral with 10% collagen (DBBMC), enamel matrix derivative (EMD) and Doxycycline in the regeneration of bone defects associated with peri-implantitis. METHODS: Thirty patients diagnosed with peri-implantitis (BoP/suppuration, probing depth greater than 4 mm, minimum radiographic bone loss of 20%, at least 2 years in function) were enrolled in the study. Clinical measurements included probing depths, recession, radiographic bone fill, gingival inflammation and bleeding on probing/suppuration. Following surgical access and debridement, the implant surfaces were decontaminated with 24% EDTA for 2 min, and the bone defects were filled with a combined mixture of DBBMC, EMD and Doxycycline powder. The defects were covered with connective tissue grafts where necessary. Clinical measurements were recorded after 12, 24 and 36 months. RESULTS: The mean probing depth and bone loss at the initial visit was 8.9 mm (+/-1.9) and 6.92 mm (+/-1.26), respectively. Both mean probing depth and bone loss reduced significantly from baseline to 3.55 mm (+/-0.50) and 2.85 mm (+/-0.73) at 12 months, 3.50 (+/-0.50) and 2.62 mm (+/-0.80) at 24 months and 3.50 mm (+/-0.50) and 2.60 mm (+/-0.73) at 36 months. 56.6% of the implants were considered successfully treated (according to Successful Treatment Outcome Criterion: PD < 5 mm, no further bone loss >10%, no BoP/suppuration, no recession >0.5 mm for anterior implants and >1.5 mm for posterior implants) after 36 months. CONCLUSION: Regenerative treatment of peri implantitis using a combined mixture of DBBMC, EMD and Doxycycline achieved promising results. The benefits of this protocol incorporating EMD should be tested in randomized clinical trials. PMID- 29767437 TI - A case of acitretin-induced haemorrhagic lesions in Darier disease. PMID- 29767436 TI - Police interactions and interventions with suspects flagged as experiencing mental health problems. AB - BACKGROUND: Interactions between individuals experiencing mental health (MH) problems and the police are complex, and effectiveness of innovative support and diversion models in England and Wales not yet fully evaluated. AIMS/HYPOTHESES: Our aims were to examine police interactions with suspects and to measure the immediate effectiveness of police/NHS MH interventions, including liaison and diversion and embedded staff in police contact and control rooms. We hypothesised that those with an MH flag would have significantly greater benefit from such interventions than those without in terms of how far they are taken down the criminal justice pathway and how long they spend in police custody. METHODS: We examined police interactions with suspects with and without flagged MH problems in relation to key outcome measures over a 15-month period, overall or when flagged by nurses alone. 'MH flagging' is defined as the presence of a marker on police systems, including both historical and current information, that alerts control room staff and response officers that the call may involve an individual/s with MH problems. Serial cross-sectional analysis of material from a database of individual cases integrating information from three police sources (N = 13,472) was used to test for associations between 'mental health flagging' and outcomes. RESULTS: Individuals with an MH flag have almost identical police dispatch response profiles to those without; they were arrested for and charged with similar offences. Those with an MH flag were significantly more likely to be charged with a criminal offence, less likely to receive a caution and spent longer periods in police custody than people under similar accusations but no MH flag. CONCLUSIONS: MH flagging appeared to disadvantage the people flagged, despite the presence of theoretically appropriate interventions. Further research is needed to understand this. It may be that indicating this form of vulnerability if the person is not judged to qualify for a MH service is discriminatory and may even account for excessive rates of mental disorder among prisoners. PMID- 29767440 TI - Successful treatment of systemic AA amyloidosis associated with underlying Hodgkin lymphoma. PMID- 29767438 TI - Serum SP70 is a sensitive predictor of chemotherapy response in patients with advanced nonsmall cell lung cancer. AB - SP70 is a novel tumor biomarker in patients with nonsmall cell lung cancer (NSCLC). However, its role as a marker for predicting the response to chemotherapy for patients with advanced NSCLC has not been investigated. A total of 152 patients were enrolled. Serum SP70, carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), and neuron-specific enolase (NSE) were detected before and after 2 cycles of chemotherapy. The correlation between serum tumor biomarker levels and chemotherapy responses and their association with epidermal growth factor receptor (EGFR) mutation status and progression-free survival (PFS) were analyzed. Serum SP70 levels were significantly decreased after chemotherapy in the partial remission (PR) group (P < .001) and increased in the progressive disease (PD) group (P < .001), but not significantly changed in the stable disease (SD) group (P = .114). Although similar changes were observed on CEA and CYFRA21-1 levels but not NSE, ROC analysis demonstrated that SP70 is superior to the others. Additionally, patients with EGFR mutation had higher serum SP70 levels and tissue SP70 expression than patients without EGFR mutation (P = .014 and P = .002, respectively). The median PFS of patients with decreased SP70 levels after chemotherapy was longer than that of patients with stable or increased serum SP70 level (24 months vs 12 months vs 2 months, P < .001), and the differences of all other 3 tumor markers were not obvious. Serum SP70 is a sensitive and real-time indicator of chemotherapeutic efficacy in patients with advanced NSCLC and related to PFS. PMID- 29767439 TI - LESSONS LEARNED AND NEXT STEPS FOR BUILDING KNOWLEDGE ABOUT TRIBAL MATERNAL, INFANT, AND EARLY CHILDHOOD HOME VISITING. AB - Authors in this Special Issue of the Infant Mental Health Journal shared the work of the first three cohorts of Tribal Maternal, Infant, and Early Childhood Home Visiting (MIECHV) grantees funded by the Administration for Children and Families. Since 2010, Tribal MIECHV grantees have served families and children prenatally to kindergarten entry in American Indian and Alaska Native (AI/AN) communities across the lower 48 United States and Alaska. Articles highlighted challenges and opportunities that arose as grantees adapted, enhanced, implemented, and evaluated their home-visiting models. This article summarizes nine lessons learned across the articles in this Special Issue. Lessons learned address the importance of strengths-based approaches, relationship-building, tribal community stakeholder involvement, capacity-building, alignment of resources and expectations, tribal values, adaptation to increase cultural and contextual attunement, indigenous ways of knowing, community voice, and sustainability. Next steps in Tribal MIECHV are discussed in light of these lessons learned. PMID- 29767442 TI - Hepatobiliary and Pancreatic: Intrahepatic cholangiocarcinoma with distant cutaneous metastases to the face. PMID- 29767443 TI - Is the Neonatal Tongue Screening Test a valid and reliable tool for detecting ankyloglossia in newborns? AB - BACKGROUND: Although there is a lack of strong evidence for the association between ankyloglossia in newborns and impaired breastfeeding, screening for ankyloglossia using the Neonatal Tongue Screening Test (NTST) is mandated by law in Brazilian maternities. AIM: To assess the reliability and validity of the NTST. DESIGN: cohort study; baseline sample comprised 268 mother-newborn dyads. At follow-up, 169 mothers were contacted by telephone. Interviews with the mothers for data collection were performed up to 48 h and at 1-3 months after childbirth. Trained and calibrated personnel performed the oral examinations of the newborns. Thirty newborns were examined for inter-reproducibility assessment. RESULTS: Of the 268 newborns included, 212 had a lingual frenulum that could be visually inspected and their NTST scores ranged from zero to nine (mean = 2.0, +/ 2.0). Interexaminer reproducibility was acceptable (Intraclass correlation coefficient = 0.77). Internal consistency of the NTST was poor (Cronbach's alpha = 0.28). Construct validity was investigated through the association between NTST scores and difficulties in breastfeeding at baseline and follow-up, and infants' weight gain at follow-up (mean age 32 +/- 6.7 days). No statistically significant associations were found. CONCLUSION: NTST is neither reliable nor valid for detecting ankyloglossia that may interfere with breastfeeding in newborns. PMID- 29767444 TI - MOF Scaffold for a High-Performance Mixed-Matrix Membrane. AB - A novel composite membrane consisting of an interconnected MOF scaffold coated with cross-linked poly(ethylene glycol) (PEG) has been developed. As a result of its unique structure, the membrane shows an exceptional 18-fold permeability enhancement as compared to pristine PEG membranes, without compromising the selectivity. This performance is unattainable with current mixed-matrix membranes (MMMs). Our optimized membrane has a permeability of 2700 Barrer with a CO2 /N2 selectivity of 35, which surpasses the latest Robeson upper bound. PMID- 29767441 TI - Hydrogen sulfide pathway and skeletal muscle: an introductory review. AB - The presence of the H2 S pathway in skeletal muscle (SKM) has recently been established. SKM expresses the three constitutive H2 S-generating enzymes in animals and humans, and it actively produces H2 S. The main, recognized molecular targets of H2 S, that is, potassium channels and PDEs, have been evaluated in SKM physiology in order to hypothesize a role for H2 S signalling. SKM dysfunctions, including muscular dystrophy and malignant hyperthermia, have also been evaluated as conditions in which the H2 S and transsulfuration pathways have been suggested to be involved. The intrinsic complexity of the molecular mechanisms involved in excitation-contraction (E-C) coupling together with the scarcity of preclinical models of SKM-related disorders have hampered any advances in the knowledge of SKM function. Here, we have addressed the role of the H2 S pathway in E-C coupling and the relative importance of cystathionine beta-synthase, cistathionine gamma-lyase and 3-mercaptopyruvate sulfurtransferase in SKM diseases. PMID- 29767445 TI - Comparison of de novo IgM and IgG anti-HLA DSAs between belatacept- and calcineurin-treated patients: An analysis of the BENEFIT and BENEFIT-EXT trial cohorts. AB - Preventing conversion of donor-specific anti-HLA antibodies (DSAs) from an IgM-to IgG could a way to prevent chronic rejection. We evaluated whether belatacept treated patients (belatacept less-intensive [LI] or more-intensive [MI] regimens) have a lower rate of conversion than do cyclosporine A (CsA)-treated patients. We included 330 HLA-mismatched patients from 2 phase 3 trials with either (a) complete donor/recipient HLA-A, -B, -DR, and -DQ loci typing or (b) incomplete HLA typing with IgG DSAs detected pretransplant or posttransplant. IgM and IgG DSAs were tested with single antigen beads at 0, 6, 12, 24, and 36 months posttransplant. The overall (preexisting or de novo) rates of IgM- and IgG positive DSAs were 29% and 34%, respectively. The pretransplant IgM and IgG DSA positive frequencies were similar between treatment groups. The IgG-positive dnDSA rate was significantly higher in the CsA-treated group (34%) compared with the belatacept-LI (8%) and belatacept-MI (11%) (P < .001) groups. In IgM-positive dnDSA patients, the IgG-positive dnDSA rate of conversion was 2.8 times higher in the CsA group than in the combined belatacept groups (P = .006). However, the observed association between belatacept treatment and more limited conversion of IgM-to-IgG dnDSAs was based on a limited number of patients and requires further validation. PMID- 29767447 TI - Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients. AB - Diffuse large B cell lymphoma (DLBCL) patients with early relapse or refractory disease have a very poor outcome. Immunochemotherapy resistance will probably, also in the era of targeted drugs, remain the major cause of treatment failure. We used proteomic mass spectrometry to analyse the global protein expression of micro-dissected formalin-fixed paraffin-embedded tumour tissues from 97 DLBCL patients: 44 with primary refractory disease or relapse within 1 year from diagnosis (REF/REL), and 53 who were progression-free more than 5 years after diagnosis (CURED). We identified 2127 proteins: 442 were found in all patients and 102 were differentially expressed. Sixty-five proteins were overexpressed in REF/REL patients, of which 46 were ribosomal proteins (RPs) compared with 2 of the 37 overexpressed proteins in CURED patients (P = 7.6 * 10-10 ). Twenty of 37 overexpressed proteins in CURED patients were associated with actin regulation, compared with 1 of 65 in REF/REL patients (P = 1.4 * 10-9 ). Immunohistochemical staining showed higher expression of RPS5 and RPL17 in REF/REL patients while MARCKS-like protein, belonging to the actin network, was more highly expressed in CURED patients. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings suggest new mechanisms behind immunochemotherapy resistance in DLBCL. PMID- 29767446 TI - Hydroxycarbamide adherence and cumulative dose associated with hospital readmission in sickle cell disease: a 6-year population-based cohort study. AB - Sickle cell disease (SCD) is a congenital haemoglobinopathy that causes frequent acute care/emergency room visits and hospital admissions for affected individuals. Evidence from population-based studies demonstrating the role of hydroxycarbamide (HC, also termed hydroxyurea) in reducing hospital readmission rates is limited. Our objective was to describe the use of HC and its association with acute care utilization and readmission rates using a large, nationally representative US health insurance claims database over a 6-year period between 2009 and 2014. We identified 20 721 SCD-related inpatient and acute care encounters. Patients had been exposed to HC within 6 months prior to admission in 4263 (21%) of SCD-related admission events. HC use was more common among children aged 10-17 years and young adults aged 18-29 years. HC was associated with lower 30-day all-cause readmission rates in adults treated with average daily doses >=1 g (odds ratio [OR], 0.72, 95% confidence interval [CI] 0.52-0.99) and doses of 0.5-1 g (OR, 0.73, 95% CI 0.57-0.93), compared to HC treatment with average daily doses of <0.5 g; adherence to HC with proportion of days covered of >=0.80 was also associated with significantly lower 30-day all-cause readmission risks (OR, 0.59, 95% CI 0.41-0.84). Optimal therapeutic dosing and adherence to HC treatment significantly reduces 30-day readmissions among patients with SCD. PMID- 29767448 TI - Development and validation of a fast and sensitive UHPLC-ESI-MS method for the simultaneous quantification of spironolactone and its metabolites in ocular tissues. AB - Glucocorticoids are a mainstay for the treatment of immune-mediated conditions and inflammatory diseases. However, their chronic use causes numerous side effects including delays in corneal and cutaneous wound healing. This is attributed to off-target agonism of the mineralocorticoid receptor, which can be reduced by co-administration of a mineralocorticoid receptor antagonist such as spironolactone. The aim of this study was to develop a fast, selective and sensitive UHPLC-ESI-MS method for the simultaneous quantification of spironolactone, its active metabolites (7alpha-thiomethylspironolactone and canrenone), the latter's water-soluble prodrug potassium canrenoate and the synthetic glucocorticoid, dexamethasone, in corneal samples (17alpha methyltestosterone served as an internal standard). A one-step extraction procedure using MeOH-H2 O (1:1) was validated and employed to recover the analytes from the corneal tissue. Extracts were centrifuged and the supernatant analyzed under isocratic conditions. Compounds were detected using selected ion recording mode. The method satisfied US Food and Drug Administration guidelines with respect to selectivity, precision and accuracy and displayed linearity from 5 to 1000 ng/mL for all of the analytes. The lower limit of quantitation of the method was 5 ng/mL, making it sufficiently sensitive for quantification of the analytes in samples from in vivo studies. PMID- 29767449 TI - Outcomes of intradetrusor onabotulinum toxin A injection in patients with Parkinson's disease. AB - OBJECTIVE: To assess the safety and efficacy of intradetrusor onabotulinum toxin A injections for the treatment of overactive bladder (OAB) in patients with Parkinson's disease (PD). METHODS: All PD patients who underwent intradetrusor injections of onabotulinum toxin A (BoNT-A) for storage symptoms between 2010 and 2017 were included in a retrospective study. A 100 U dose of BoNT-A (Botox(r), Allergan Irvine, CA) was used for the first injection in all patients. The primary endpoint was clinical success defined as any subjective improvement in OAB symptoms self-assessed by the patients 4 weeks after the injections. RESULTS: Out of 24 patients analyzed, 19 reported improvement of their OAB symptoms 4 weeks after the first injection (79.2%) with complete resolution of urgency urinary incontinence in seven patients (29.1%; P < 0.001). The average post-void residual (PVR) increased significantly after the first injection from 17.6 to 125.3 mL (P < 0.001). Three of the patients had to start clean intermittent catheterization (CIC) after the first injection (12.5%). Out of 49 injections in total, only five caused incomplete bladder emptying requiring the use of CIC (10.2%). Higher pre-injection PVR was significantly associated with both a lower chance of symptomatic improvement (P = 0.04) and a higher risk of incomplete bladder emptying with institution of CIC (P = 0.047). CONCLUSION: Intradetrusor injections of BoNT-A 100 U appeared as a safe and effective option in PD patients with OAB symptoms and a low PVR before the injection. Higher preoperative PVR was the strongest predictor of both treatment failure and postoperative urinary retention requiring CIC. PMID- 29767450 TI - Cost-effectiveness of alternative changes to a national blood collection service. AB - OBJECTIVES: To evaluate the cost-effectiveness of changing opening times, introducing a donor health report and reducing the minimum inter-donation interval for donors attending static centres. BACKGROUND: Evidence is required about the effect of changes to the blood collection service on costs and the frequency of donation. METHODS/MATERIALS: This study estimated the effect of changes to the blood collection service in England on the annual number of whole blood donations by current donors. We used donors' responses to a stated preference survey, donor registry data on donation frequency and deferral rates from the INTERVAL trial. Costs measured were those anticipated to differ between strategies. We reported the cost per additional unit of blood collected for each strategy versus current practice. Strategies with a cost per additional unit of whole blood less than L30 (an estimate of the current cost of collection) were judged likely to be cost-effective. RESULTS: In static donor centres, extending opening times to evenings and weekends provided an additional unit of whole blood at a cost of L23 and L29, respectively. Introducing a health report cost L130 per additional unit of blood collected. Although the strategy of reducing the minimum inter-donation interval had the lowest cost per additional unit of blood collected (L10), this increased the rate of deferrals due to low haemoglobin (Hb). CONCLUSION: The introduction of a donor health report is unlikely to provide a sufficient increase in donation frequency to justify the additional costs. A more cost-effective change is to extend opening hours for blood collection at static centres. PMID- 29767451 TI - Feline ureteral obstructions Part 1: medical management. AB - Feline ureteral obstructions are an increasingly recognised and challenging diagnostic and management problem. Many cats with ureteral obstructions are critically ill at the time of diagnosis, especially if there is dysfunction of the contralateral kidney. They may present with varying severities of acute kidney injury, electrolyte disturbances, and may have comorbidities such as heart disease that complicate perioperative and long-term management. Medical management, which may consist of rehydration and restoration of intravascular volume with intravenous fluid therapy, osmotic diuresis, ureteral muscle relaxation, and antimicrobials for infection, is important in feline ureteral obstruction patients. Despite medical management, many cats with ureteral obstructions will require decompression of the obstructed kidney to relieve pressure-nephropathy and restore urine flow. However, some cats may be too unstable for traditional medical management and require more emergent intervention to relieve the obstruction and address the life-threatening sequelae to acute kidney injury, such as hyperkalaemia and fluid overload. Both surgical and interventional methods to address ureteral obstructions have been described in veterinary medicine, though debate continues as to the ideal approach. PMID- 29767454 TI - Guideline for the management of mantle cell lymphoma. PMID- 29767453 TI - Optimizing Antimicrobial Peptide Dendrimers in Chemical Space. AB - We used nearest-neighbor searches in chemical space to improve the activity of the antimicrobial peptide dendrimer (AMPD) G3KL and identified dendrimer T7, which has an expanded activity range against Gram-negative pathogenic bacteria including Klebsiellae pneumoniae, increased serum stability, and promising activity in an in vivo infection model against a multidrug-resistant strain of Acinetobacter baumannii. Imaging, spectroscopic studies, and a structural model from molecular dynamics simulations suggest that T7 acts through membrane disruption. These experiments provide the first example of using virtual screening in the field of dendrimers and show that dendrimer size does not limit the activity of AMPDs. PMID- 29767452 TI - Adenoma of colorectal laterally spreading tumor nongranular type with biological phenotypic features similar to cancer. AB - BACKGROUND AND AIM: Colorectal laterally spreading tumors (LSTs) are morphologically subdivided into granular (LST-G) and nongranular (LST-NG) categories. We aimed to elucidate the differences in oncogenic characteristics between the two types. METHODS: Laterally spreading tumors resected by endoscopic submucosal dissection and surgery from March 2009 to May 2017 were examined for p53 positivity, Ki-67 labeling index (LI), microvessel density, degree of fibrosis, intensities of inducible nitric oxide synthase (iNOS) and nitrotyrosine (NT), and expression of acid mucins. We compared these factors between adenomas, noninvasive cancers, and invasive cancers, both LST-G and LST-NG. RESULTS: Ninety three LST-G (53 adenomas [LST-GA] and 40 cancers [LST-GC]) and 55 LST-NG (24 adenomas [LST-NGA] and 31 cancers [LST-NGC]) were evaluated. Although p53 positivity was lower in LST-GA than in LST-NGA (P < 0.001), there was no difference between LST-GC and LST-NGC. Ki-67 LI was higher in LST-NGA than in LST GA (P < 0.001) and higher in LST-NGC than in LST-GC of noninvasive cancers (P < 0.001). Microvessel density and degree of fibrosis were higher in LST-NGA than in LST-GA (P < 0.001), and intensities of iNOS and NT were also higher in LST-NGA than in LST-GA (P < 0.001). Expression of acid mucins was lower in LST-NGA than in LST-GA (P < 0.001). Although there were significant differences in p53 positivity, Ki-67 LI, microvessel density, degree of fibrosis, intensities of iNOS and NT, and expression of acid mucins between LST-GA and LST-NGA, these factors were only slightly different between LST-GC and LST-NGC of invasive cancers. CONCLUSIONS: Unlike LST-GA, LST-NGA possessed phenotypic features similar to cancer. PMID- 29767456 TI - Three-dimensional structures of bacteriophage neck subunits are shared in Podoviridae, Siphoviridae and Myoviridae. AB - Tailed bacteriophages (Caudovirales) are divided into three families: Myoviridae with long contractile tails, Siphoviridae with long noncontractile tails and Podoviridae with short noncontractile tails. All have an icosahedral head with a portal vertex connected to a neck structure followed by a tail. Bacteriophage Mu belongs to the Myoviridae family. Herein, the gp29 portal subunit and neck subunits gp35, gp36 and gp37 of the Mu phage were purified to elucidate their arrangement in the neck. Both gp29 and gp36 were monomeric in solution, like the corresponding subunits of Podoviridae P22 and Siphoviridae SPP1. X-ray crystal structure of gp36 showed structural similarity to neck subunits of Siphoviridae and Podoviridae. The gp36 structure has a characteristic aromatic hydrophobic core, and the structure of the ring form of the Mu phage connector deduced from the Siphoviridae and Podoviridae connector showed that this feature builds the contact surface between gp36 subunits. Structural comparison with the neck of Siphoviridae and Podoviridae also implies direct interaction between gp36 and gp29. Because gp35 and gp36 form a stable complex, we predict that the head portal ring (gp29), the connector complex (gp36 and gp35), the tail terminator (gp37) and the tube (gp40) are arranged in the Mu phage neck in this order. PMID- 29767455 TI - Ureterocalicostomy with lower pole nephrectomy in a renal transplant: A case report. AB - As the number of kidney transplants continues to rise, so does the number and complexities of surgical-related complications, which may be associated with increased morbidity and potentially graft loss. Ureteral stenosis, the most prevalent urological complication, may require diverse techniques for surgical correction depending on several recipient and graft abnormalities. Here we report the surgical and clinical outcomes of a 62-year-old man with a posttransplant pyeloureterostomy stricture successfully treated with ureterocalicostomy after a lower pole nephrectomy. Although the resection of renal parenchyma may prevent a stenosis recurrence, surgeons can be reluctant to use this strategy due to the possible negative impact on renal function. We highlight some key steps of the surgical technique to prevent unnecessary allograft lesion and present short-term outcomes, suggesting that this rarely described procedure is a safe and effective alternative treatment for kidney transplant recipients with pyeloureterostomy stenosis. PMID- 29767457 TI - Suicidal Behavior and Personality Traits Contribute to Disability in First episode Psychosis: A 1-Year Follow-up Study. AB - BACKGROUND: Disability encompasses impairments, activity limitations, and restrictions on participation. Improvement in functioning has therefore become a crucial outcome of treatment in psychosis. OBJECTIVE: The main aim of this study was to analyze the potential relationship between suicidal behavior after first episode of psychosis (FEP) and family disability. The second aim was to find out whether personality traits are associated with disability dimensions. METHOD: The study sample was composed of 65 FEP patients. The personal care, occupational, family, and social dimensions of disability were evaluated at 12 months after FEP. Bivariate and multivariate analyses were performed to explore any putative outcome factors associated with dimensions of disability. RESULTS: Personal care during the 1-year follow-up was significantly impaired in suicide attempters and significantly associated with sociopathic personality traits. A decline in occupational functioning was significantly associated with schizotypy traits. On the other hand, deterioration in family, social, and global functioning at 1 year after FEP was related to poor premorbid adjustment during late adolescence. CONCLUSIONS: Suicidal behavior prevention could improve psychosocial functioning, particularly personal care, in FEP. In addition, sociopathic and schizotypy personality traits as well as poor premorbid adjustment during late adolescence appear to be useful early markers of future disability. PMID- 29767458 TI - Overlapping but distinct roles for NOTCH receptors in human cardiovascular disease. AB - The NOTCH signalling pathway is an essential pathway, involved in many cellular processes, including cell fate decision, cell proliferation, and cell death and important in the development of most organs. Mutations in genes encoding components of the NOTCH signalling pathway lead to a spectrum of congenital disorders. Over the past decades, mutations in human NOTCH signalling genes have been identified in several diseases with cardiovascular involvement. NOTCH1 mutations have been described in bicuspid aortic valve disease, left-sided congenital heart disease, and Adams-Oliver syndrome. NOTCH2 mutations lead to the development of Alagille syndrome, while mutations in NOTCH3 cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. To date, mutations in NOTCH4 have not been associated with cardiovascular disease. This review focuses on the mutations described in NOTCH1, NOTCH2, and NOTCH3 and their associated cardiovascular phenotypes. PMID- 29767460 TI - Pyrimidine-based pyrazoles as cyclin-dependent kinase 2 inhibitors: Design, synthesis, and biological evaluation. AB - A series of new pyrimidine-pyrazole hybrid molecules were designed as inhibitors of cyclin-dependent kinase 2. Designed compounds were docked using Glide and the compounds showing good score values and encouraging interactions with the residues were selected for synthesis. They were then evaluated using CDK2 CyclinA2 enzyme inhibition by a luminescent ADP detection assay. We show that of the 26 compounds synthesized and evaluated, at least 5 compounds were found to be highly potent (IC50 < 20 nm); which can be further optimized to have selectivity over other kinase isoforms. PMID- 29767459 TI - Long-term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin-converting enzymes/angiotensin receptor blockers: results from AMETHYST-DN. AB - AIMS: Chronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium-free, non-absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer's long-term safety and efficacy in HF patients from AMETHYST-DN. METHODS AND RESULTS: Patients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0-5.5 mmol/L (mild) or >5.5-<6.0 mmol/L (moderate)], with or without HF (New York Heart Association Class I and II, by investigator judgement), on ACE I/ARB, were randomized to patiromer 8.4-33.6 g to start, divided twice daily. Overall, 105/304 (35%) patients had HF (75%, Class II). Mean (standard deviation) ejection fraction (EF) was 44.9% (8.2) (n = 81) in patients with HF; 26 had EF <=40%. In HF patients, mean serum potassium decreased by Day 3 through Week 52. At Week 4, estimated mean (95% confidence interval) change in serum potassium was -0.64 mmol/L (-0.72, -0.55) in mild and -0.97 mmol/L (-1.14, -0.80) in moderate HK (both P < 0.0001). Most HF patients with mild (>88%) and moderate (>=73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer-related adverse event was hypomagnesaemia (8.6%). CONCLUSIONS: In patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE-I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks. PMID- 29767461 TI - Sex differences but no evidence of quantitative honesty in the warning signals of six-spot burnet moths (Zygaena filipendulae L.). AB - The distinctive black and red wing pattern of six-spot burnet moths (Zygaena filipendulae, L.) is a classic example of aposematism, advertising their potent cyanide-based defences. While such warning signals provide a qualitatively honest signal of unprofitability, the evidence for quantitative honesty, whereby variation in visual traits could provide accurate estimates of individual toxicity, is more equivocal. Combining measures of cyanogenic glucoside content and wing color from the perspective of avian predators, we investigate the relationship between coloration and defences in Z. filipendulae, to test signal honesty both within and across populations. There were no significant relationships between mean cyanogenic glucoside concentration and metrics of wing coloration across populations in males, yet in females higher cyanogenic glucoside levels were associated with smaller and lighter red forewing markings. Trends within populations were similarly inconsistent with quantitative honesty, and persistent differences between the sexes were apparent: larger females, carrying a greater total cyanogenic glucoside load, displayed larger but less conspicuous markings than smaller males, according to several color metrics. The overall high aversiveness of cyanogenic glucosides and fluctuations in color and toxin levels during an individual's lifetime may contribute to these results, highlighting generally important reasons why signal honesty should not always be expected in aposematic species. PMID- 29767462 TI - Soluble Fiber Use in Pediatric Short Bowel Syndrome: A Survey on Prevailing Practices. AB - BACKGROUND: In pediatric short bowel syndrome (SBS), adding fiber to enteral feedings is 1 treatment method to manage increased stool output. However, there are no standardized recommendations on the use of fiber in this setting, including type, dosage, titration strategies, etc. OBJECTIVE: The aim of this study is to determine current prevailing practices on the use of fiber in the treatment of chronic high stool output in the pediatric SBS population. METHODS: An anonymous electronic survey with 13 questions was sent through health professional electronic mailing lists. The survey was completed by healthcare professionals including physicians (primary care, subspecialists, and surgeons), nurse practitioners, and registered dietitians. RESULTS: A total of 94 responses were received. The most common supplemental fiber used was pectin (62.8%). The 2 major factors considered when initiating fiber therapy were consistency of stool (74.5%) and volume of stool output (85.1%). The major factor that determined discontinuation of fiber was abdominal distention (67%). A majority of providers waited 2 weeks or less to see improvement following fiber initiation before discontinuing it. CONCLUSIONS: The goal of the survey was to gather more information with regard to fiber use in the management of SBS patients. The data collected can be used to provide future direction on determining best practices for fiber use in SBS patients. PMID- 29767464 TI - Platinum-resistant recurrent ovarian cancer with long survival on bevacizumab and gemcitabine. AB - Platinum-resistant recurrent ovarian cancer has a poor prognosis, but combined therapy with bevacizumab and anticancer agents may be useful. We report a patient with long-term disease control by the combination of bevacizumab and gemcitabine (BEV + GEM). The patient was a 77-year-old woman with high-grade Stage IIIC serous ovarian carcinoma. In 2012, a complete response (CR) was obtained by neoadjuvant and adjuvant chemotherapy using paclitaxel plus carboplatin and tumor debulking surgery. After recurrence in 2013, CR was achieved again with gemcitabine plus carboplatin. In 2014, recurrence was detected again, but CR was achieved by third-line combination therapy with gemcitabine, carboplatin and bevacizumab. In 2015, the third recurrence was found during bevacizumab maintenance therapy. Fourth-line treatment was initiated with BEV + GEM, which has maintained stable disease for 29 months. This is the first report about marked prolongation of survival by BEV + GEM in a patient with platinum-resistant recurrent ovarian cancer. PMID- 29767463 TI - Mechanical and Biological Properties of a Biodegradable Mg-Zn-Ca Porous Alloy. AB - OBJECTIVES: As promising alternative to current metallic biomaterials, the porous Mg scaffold with a 3-D open-pore framework has drawn much attention in recent years due to its suitable biodegradation, biocompatibility, and mechanical properties for human bones. This experiment's aim is to study the mechanical properties, biosafety, and osteogenesis of porous Mg-Zn alloy. METHODS: A porous Mg-2Zn-0.3Ca (wt%) alloy was successfully prepared by infiltration casting, and the size of NaCl particles was detected by a laser particle size analyzer. The microstructure of the Mg-2Zn-0.3Ca alloy was characterized by the stereoscopic microscope and Sirion Field emission scanning electron microscope. X-ray computerized tomography scanning (x-CT) was used to create the 3-D image. The degradation rate was measured using the mass loss method and the pH values were determined together. The engineering stress-strain curve, compressive modulus, and yield strength were tested next. The bone marrow stromal cells (BMSC) were cultured in vitro. The CCK-8 method was used to detect the proliferation of the BMSC. Alkaline phosphatase (ALP) and alizarin red staining were used to reflect the differentiation effects. After co-culturing, cell growth on the material's surface was observed by scanning electron microscope (SEM). The cell adhesion was tested by confocal microscopy. RESULTS: The obtained results showed that by using near-spherical NaCl filling particles, the porous Mg alloy formed complete open cell foam with a very uniform size of pores in the range of 500-600 MUm. Benefitting from the small size and uniform distribution of pores, the present porous alloy exhibited a very high porosity, up to 80%, and compressive yield strength up to 6.5 MPa. The degradation test showed that both the pH and the mass loss rate had similar change tendency, with a rapid rise in the early stage for 1 2 day's immersion and subsequently remaining smooth after 3 days. In vitro cytocompatibility trials demonstrated that in comparison with Ti, the porous alloy accelerated proliferation in 1, 3, 5, and 7 days (P < 0.001), and the osteogenic differentiation test showed that the ALP activity in the experimental group was significantly higher (P = 0.017) and has more osteogenesis nodules. Cell adhesion testing showed good osteoconductivity by more BMSC adhesion around the holes. The confocal microscopy results showed that cells in porous Mg-based alloy had better cytoskeletal morphology and were larger in number than in titanium. CONCLUSIONS: These results indicated that this porous Mg-based alloy fabricated by infiltration casting shows great mechanical properties and biocompatibilities, and it has potential as an ideal bone tissue engineering scaffold material for bone regeneration. PMID- 29767465 TI - Salt, inflammation, IL-17 and hypertension. AB - Traditionally, arterial hypertension and subsequent end-organ damage have been attributed to haemodynamic factors, but increasing evidence indicates that inflammation also contributes to the deleterious consequences of this disease. The immune system has evolved to prevent invasion of foreign microorganisms and to promote tissue healing after injury. However, this beneficial activity comes at a cost of collateral damage when the immune system overreacts to internal injury, such as prehypertension. Over the past few years, important findings have revolutionized hypertension research. Firstly, in 2007, a seminal paper showed that adaptive immunity is involved in the pathogenesis of hypertension. Secondly, salt storage in the skin and its consequences for cardiovascular physiology were discovered. Thirdly, after the discovery that salt promotes the differentiation of CD4+ T cells into TH 17 cells, it was demonstrated that salt directly changes several cells of the innate and adaptive immune system and aggravates autoimmune disease but may improve antimicrobial defence. Herein, we will review pathways of activation of immune cells by salt in hypertension as the framework for understanding the multiple roles of salt and immunity in arterial hypertension and autoimmune disease. PMID- 29767467 TI - Treatment of periorbital dark circles: Comparative study of carboxy therapy vs chemical peeling vs mesotherapy. AB - OBJECTIVE: Evaluation and comparison of the efficacy and safety of 3 different modalities of treatment for dark circles that function via different modes of action. METHODS: In total, 45 female patients with periorbital hyperpigmentation were randomly selected to participate from those attending the outpatient dermatology clinic of Al-Zahraa University Hospital within a 6-month period. Patients were divided into 3 groups, and the groups were subjected to different types of therapy: group A, carboxy therapy; group B, chemical peel; and group C, vitamin C mesotherapy. RESULTS: No statistically significant differences were detected in improvements in pigmentation or the degree of patient satisfaction between any of the groups. However, the mesotherapy group reported more of a burning sensation following treatment than the other 2 groups but also showed a significant improvement in pigmentation and patient satisfaction compared with the carboxy group. CONCLUSION: All 3 treatment modalities were effective in the reduction in periorbital pigmentation. However, mesotherapy showed a significant improvement in pigmentation and a higher level of patient satisfaction compared with the other types of treatment. PMID- 29767466 TI - Addressing transboundary conservation challenges through marine spatial prioritization. AB - The Adriatic and Ionian Region is an important area for both strategic maritime development and biodiversity conservation in the European Union (EU). However, given that both EU and non-EU countries border the sea, multiple legal and regulatory frameworks operate at different scales, which can hinder the coordinated long-term sustainable development of the region. Transboundary marine spatial planning can help overcome these challenges by building consensus on planning objectives and making the trade-offs between biodiversity conservation and its influence on economically important sectors more explicit. We address this challenge by developing and testing 4 spatial prioritization strategies with the decision-support tool Marxan, which meets targets for biodiversity conservation while minimizing impacts to users. We evaluated these strategies in terms of how priority areas shift under different scales of target setting (e.g., regional vs. country level). We also examined the trade-off between cost efficiency and how equally solutions represent countries and maritime industries (n = 14) operating in the region with the protection-equality metric. We found negligible differences in where priority conservation areas were located when we set targets for biodiversity at the regional versus country scale. Conversely, the prospective impacts on industries, when considered as costs to be minimized, were highly divergent across scenarios and biased the placement of protection toward industries located in isolation or where there were few other industries. We recommend underpinning future marine spatial planning efforts in the region through identification of areas of national significance, transboundary areas requiring cooperation between countries, and areas where impacts on maritime industries require careful consideration of the trade-off between biodiversity conservation and socioeconomic objectives. PMID- 29767469 TI - CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo. AB - Osteoporosis is a global public health problem that is increasing along with an aging population. A major determinant of osteoporosis is high bone turnover, which results from osteoclast activation. CD109 is a glycosylphosphatidylinositol anchored glycoprotein, a deficiency that leads to a psoriasis-like skin inflammation in mice. Although the expression of CD109 has been reported in mouse pre-osteoclast cells, its function in osteoclasts in vivo remains largely unknown. To investigate the physiological role of CD109 in bone metabolism, we analyzed bones from wild-type and CD109-deficient adult mice. Micro-computed tomography analysis of the femur (thigh bone) showed that bone volume was lower in CD109-deficient mice than in wild-type mice. Bone histomorphometric analysis showed not only a reduction in bone volume but also an increase in bone turnover in CD109-deficient mice as compared with wild-type mice. Additionally, we measured serum levels of several markers of bone turnover and found a significant increase in the N-terminal telopeptide of type I collagen, a bone resorption marker, as well as alkaline phosphatase, a bone formation marker, in CD109 deficient mice. These results indicate that CD109 deficiency induces a high turnover, osteoporosis-like phenotype, which suggests that CD109 plays a role in bone metabolism in vivo. PMID- 29767470 TI - Early increase of neutrophil-to-lymphocyte ratio predicts 30-day mortality in patients with spontaneous intracerebral hemorrhage. AB - AIMS: To examine whether early rise of neutrophil-to-lymphocyte ratio (NLR) after patient hospitalization correlates with 30-day mortality in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This retrospective study included all patients receiving treatment for spontaneous ICH between January 2015 and September 2016 at the Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences in Shanghai, China. NLR was determined at admission (T1), at 24-48 hours (T2) and 5-7 days (T3). NLR and clinicopathologic features were compared between those who survived for >30 days vs not. Multivariate regression was used to identify risk factors for 30-day mortality. RESULTS: A total of 275 subjects were included in the analysis: 235 survived for at least 30 days; the remaining 40 subjects died within 30 days. The patients who died within 30 days had higher ICH score, larger ICH volume, and lower GCS score (all P < 0.05). In comparison with the baseline (NLRT1 ), NLR at 24-48 hours (NLRT2 ) and 5-7 days (NLRT3 ) was significantly higher in patients who died within 30 days (P < 0.05), but not in patients surviving for >30 days. In the multivariate analysis, the 30-day mortality was associated with both NLRT2 (OR 1.112, 95%CI 1.032-1.199, P = 0.006) and NLRT3 (OR 1.163, 95%CI 1.067-1.268, P = 0.001). Spearman correlation analysis showed that both NLRT2 and NLRT3 correlated inversely with GCS score and positively with ICH score and ICH volume at the baseline. CONCLUSIONS: Early rise of NLR predicts 30-day mortality in patients with spontaneous ICH. PMID- 29767468 TI - Central adenosine A1 receptors inhibit cough via suppression of excitatory glutamatergic and tachykininergic neurotransmission. AB - BACKGROUND AND PURPOSE: The adenosine A1 receptor is reported to mediate several excitatory effects in the airways and has inhibitory effects in the CNS. In this study, we investigated the role of peripheral and central A1 receptors in regulating cough and airway obstruction. EXPERIMENTAL APPROACH: Drugs were administered to guinea pigs via inhalation or i.c.v. infusion. Following the administration of different drugs, cough was induced by exposing guinea pigs to aerosolized 0.4 M citric acid. An automated analyser recorded both cough and airway obstruction simultaneously using whole-body plethysmography. KEY RESULTS: The A1 receptor agonist, cyclopentyladenosine (CPA, administered by inhalation), dose-dependently inhibited cough and also inhibited airway obstruction. Similarly, CPA, administered i.c.v., inhibited both the citric acid-induced cough and airway obstruction; this was prevented by pretreatment with the A1 receptor antagonist DPCPX (i.c.v.). Treatment with DPCPX alone dose-dependently enhanced the citric acid-induced cough and airway obstruction. This effect was reversed following treatment with either the glutamate GluN1 receptor antagonist D-AP5 or the neurokinin NK1 receptor antagonist FK-888. CONCLUSIONS AND IMPLICATIONS: These findings suggest that activation of either peripheral or central adenosine A1 receptors inhibits citric acid-induced cough and airway obstruction. The data also suggest that tonic activation of central adenosine A1 receptors serves as a negative regulator of cough and airway obstruction, secondary to inhibition of excitatory glutamatergic and tachykininergic neurotransmission. PMID- 29767471 TI - Converting immunosuppression from an oral suspension to a granule formulation of tacrolimus in pediatric renal transplant recipients. AB - OS of tacrolimus prepared from tacrolimus powder is not licensed for children. A licensed GF for OS allows flexibility for body weight-based dose adjustments. This study aimed at exploring the efficacy of conversion from OS to the GF of tacrolimus in stable pediatric renal transplant recipients. Records of 25 pediatric renal transplant recipients aged under 18 years who were switched from an unlicensed tacrolimus OS to GF were reviewed. At day 0, 1 week, and 4-8 weeks post-conversion, there were no differences regarding daily tacrolimus dose (3.4 +/- 3 vs 3.5 +/- 2.9 vs 3.5 +/- 2.9 mg/day), trough tacrolimus levels (4.5 +/- 2.7 vs 4.2 +/- 2.7 vs 4.4 +/- 3.1 ng/mL), dose-normalized trough tacrolimus levels (1.7 +/- 1.1 vs 1.5 +/- 1.0 vs 1.7 +/- 1.3 ng/mL/mg), PCr (65.6 +/- 29.4 vs 67.9 +/- 30.4 vs 69.8 +/- 27.9 MUmol/L), and eGFR (73 +/- 24.9 vs 68.7 +/- 20.2 vs 65.5 +/- 18.2 mL/min/1.73 m2 ) (P > .05). GF dose adjustment was required in 52% of participants. Eighty-eight percent of patients had to return for repeat tacrolimus levels following dose modifications, generating 33 extra visits (>=2 extra visits for 1/3 of subjects). No rejection episodes occurred in the year after conversion. In conclusion, conversion from tacrolimus OS to GF in stable pediatric renal transplant recipients is safe and efficacious. However, close therapeutic drug monitoring in the immediate post-conversion period is necessary. PMID- 29767472 TI - The impact of real-world cardiovascular-related pharmacogenetic testing in an insured population. AB - BACKGROUND: Pharmacogenomics is intended to help clinicians provide the right drug to the right patient at an appropriate dose. However, limited evidence of clinical utility has slowed uptake of pharmacogenomic testing (PGT). OBJECTIVE: To evaluate the impact of real-world cardiovascular (CV)-related PGT on clinical outcomes, healthcare resource utilisation (HCRU) and cost in a large, heterogeneous population. METHODS: Individuals with Medicare Advantage Prescription Drug, Medicaid, or commercial coverage between 1/1/2011 and 9/30/2015 and >=1 atherosclerotic CV-related diagnosis were identified. Those with >=1 claim for CV-related PGT were included in the test group (index date = 1st PGT claim) and matched 1:2 to controls without PGT. Individuals aged <22 or >=90 years old on the index date, with <12 months continuous enrollment before and after the index date, or without an ASCVD-related diagnosis in the 12-month pre-index period were excluded. The primary outcome was occurrence of a major CV event during the 12-month post-index period. RESULTS: After adjustment, the PGT group was significantly more likely to experience ischaemic stroke, pulmonary embolism, deep vein thrombosis or a composite event compared with controls. Adjusting for baseline characteristics, HCRU was significantly higher for the test group across all measured outcomes except all-cause and ASCVD-related inpatient admissions. Median all-cause and ASCVD-related healthcare costs were significantly higher for the test group. CONCLUSIONS: Real world PGT in a large population did not improve outcomes. Tailoring medication therapy to each patient holds great promise for providing quality care but a deeper understanding of how widespread utilisation of PGT might impact objective health outcomes is needed. PMID- 29767475 TI - Iron-Catalyzed Vinylic C-H Alkylation with Alkyl Peroxides. AB - A variety of alkyl peresters and alkyl diacyl peroxides, which are readily accessible from carboxylic acids, are utilized as general primary, secondary, and tertiary alkylating reagents for iron-catalyzed vinylic C-H alkylation of vinyl arenes, dienes, and 1,3-enynes. This transformation affords olefinic products in up to 98 % yield with high E/Z values. A broad range of functionalities, including carboxyl, boronic acid, methoxy, ester, amino, and halides, are tolerated. This protocol provides a facile approach to some olefins that are difficult to access, and hence, offers an alternative to existing systems. The synthetic utility of this method is demonstrated by late-stage functionalization of selected natural-product derivatives. PMID- 29767473 TI - Prediction of Callus Subsidence in Distraction Osteogenesis Using Callus Formation Scoring System: Preliminary Study. AB - OBJECTIVE: To develop the scoring system which describes both quality and quantity of callus formation to predict the callus subsidence. METHODS: Forty seven bony segments with an average lengthening of 5.17 +/- 2.83 cm were included. The score was calculated based on the amount of callus classified in five patterns and the summation with the density of the callus classified in four patterns; the total score was 9. Bony subsidence >10% or >10 degrees angulation were considered significant. We analyzed all of the data to find the most appropriate score that would prevent callus subsidence <10% and prevented angulation of the regeneration bone <10 degrees. Data was analyzed by using the receiver operating characteristic (ROC) curve. An area under the curve of 0.9-1 indicated an excellent test, 0.8-0.9 indicated a good test, 0.7-0.8 indicated a fair test, 0.6-0.7 indicated a poor test, and 0.5-0.6 indicated a fail test. The appropriate score for Ilizarov removal was selected from the highest sensitivity and specificity. RESULTS: Twenty-two tibia segments and 25 femur segments were included. The mean of bone lengthening was 5.17 +/- 2.83 cm (range, 1.6-13.5 cm) and the mean of percentage lengthening was 16.58% +/- 10.03% (range, 4.63% 56.84%). The mean distraction period was 5 months. The average months of follow up for measurement of bony subsidence was 4.2 months. Mean subsidence was 21.06% (1.54%-57.44%). The mean of callus subsidence was 1.29 +/- 1.17 cm (range, 0.03 4.72 cm). There were 32 segments (68%) with callus subsidence greater than 10% and 15 segments (32%) with subsidence less than 10%. The callus subsidence ranged from 0.3 mm to 4.72 cm, with 68% of bony fragments having significant subsidence. Type 5 callus diameter was statistically significant (P < 0.0001) in preventing callus subsidence compared to the other types. Type 4 callus density was statistically significant in preventing callus subsidence compared to the other types (P < 0.0001). The ROC curve with area under the curve 0.961 and sensitivity 0.933 showed that a callus scoring system score >7.5 was effective in preventing significant callus subsidence. When using score 8 as a result from the ROC curve, 73.3% of bony fragment subsidence was <10% with sensitivity 93.3 and specificity 83.2. CONCLUSION: Callus diameter 81%-100% and callus density type 4 could prevent significant callus subsidence. Based on the results of the present study we suggest using callus score > 8 to determine the time of Ilizarov removal. PMID- 29767476 TI - Enhancing Hydrogen Generation Through Nanoconfinement of Sensitizers and Catalysts in a Homogeneous Supramolecular Organic Framework. AB - Enrichment of molecular photosensitizers and catalysts in a confined nanospace is conducive for photocatalytic reactions due to improved photoexcited electron transfer from photosensitizers to catalysts. Herein, the self-assembly of a highly stable 3D supramolecular organic framework from a rigid bipyridine-derived tetrahedral monomer and cucurbit[8]uril in water, and its efficient and simultaneous intake of both [Ru(bpy)3 ]2+ -based photosensitizers and various polyoxometalates, that can take place at very low loading, are reported. The enrichment substantially increases the apparent concentration of both photosensitizer and catalyst in the interior of the framework, which leads to a recyclable, homogeneous, visible light-driven photocatalytic system with 110-fold increase of the turnover number for the hydrogen evolution reaction. PMID- 29767474 TI - Mesenchymal stromal cells from Shwachman-Diamond syndrome patients fail to recreate a bone marrow niche in vivo and exhibit impaired angiogenesis. AB - Shwachman-Diamond syndrome (SDS) is a rare multi-organ recessive disease mainly characterised by pancreatic insufficiency, skeletal defects, short stature and bone marrow failure (BMF). As in many other BMF syndromes, SDS patients are predisposed to develop a number of haematopoietic malignancies, particularly myelodysplastic syndrome and acute myeloid leukaemia. However, the mechanism of cancer predisposition in SDS patients is only partially understood. In light of the emerging role of mesenchymal stromal cells (MSCs) in the regulation of bone marrow homeostasis, we assessed the ability of MSCs derived from SDS patients (SDS-MSCs) to recreate a functional bone marrow niche, taking advantage of a murine heterotopic MSC transplant model. We show that the ability of semi cartilaginous pellets (SCPs) derived from SDS-MSCs to generate complete heterotopic ossicles in vivo is severely impaired in comparison with HD-MSC derived SCPs. Specifically, after in vitro angiogenic stimuli, SDS-MSCs showed a defective ability to form correct networks, capillary tubes and vessels and displayed a marked decrease in VEGFA expression. Altogether, these findings unveil a novel mechanism of SDS-mediated haematopoietic dysfunction based on hampered ability of SDS-MSCs to support angiogenesis. Overall, MSCs could represent a new appealing therapeutic target to treat dysfunctional haematopoiesis in paediatric SDS patients. PMID- 29767477 TI - Effect of neurological monitoring in postoperative 5-15 days residual thyroidectomy after primary thyroid cancer surgery. AB - AIM: To explore the application of intraoperative neurological monitoring in residual thyroidectomy 5-15 days after thyroid cancer operation and the influence on postoperative serum thyroglobulin (Tg), recurrent laryngeal nerve and function of parathyroid glands. METHODS: Material of patients receiving thyroid surgery from January 2010 to December 2016 was retrospectively analyzed. Cases meeting with standards were enrolled for analysis and the patients were divided into neurological monitoring group and non-neurological monitoring group in line with the use of neurological monitoring during the operation. Recurrent laryngeal nerve-injured hoarseness, hypoparathyroidism and concentration of serum Tg before and after the surgery were collected and analyzed. RESULTS: Four-hundred and thirty-five patients met with standards, among which 227 from neurological monitoring group and 208 from non-neurological monitoring group. Temporary hoarseness rate of non-neurological monitoring group and neurological monitoring group was 8.67% and 2.2%. Permanent hoarseness rate of non-neurological monitoring group and neurological monitoring group was 1.92% and 0.44%. Temporary hypoparathyroidism rate of non-neurological monitoring group and neurological monitoring group was 18.75% and 7.48%. Permanent hypoparathyroidism rate of non neurological monitoring group and neurological monitoring group was 1.92% and 0.88%. Average Tg concentration 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 2.82 and 1.37 ng/mL, respectively. Rate of average Tg concentration less than 1 ng/mL 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 45.06% and 67.4%. CONCLUSION: Intraoperative neurological monitoring can be adopted in residual thyroidectomy in postoperative 5-15 days after primary thyroid cancer surgery, as to reduce incidence rate of recurrent laryngeal nerve injury and hypoparathyroidism and to enhance thorough removal of thyroid tissues and cancer tissues. PMID- 29767478 TI - The effect of Share 35 on biliary complications: An interrupted time series analysis. AB - The purpose of the Share 35 allocation policy was to improve liver transplant waitlist mortality, targeting high MELD waitlisted patients. However, policy changes may also have unintended consequences that must be balanced with the primary desired outcome. We performed an interrupted time series assessing the impact of Share 35 on biliary complications in a select national liver transplant population using the Vizient CDB/RM database. Liver transplants that occurred between October 2012 and September 2015 were included. There was a significant change in the incident-rate of biliary complications between Pre-Share 35 (n = 3018) and Post-Share 35 (n = 9984) cohorts over time (P = .023, r2 = .44). As a control, a subanalysis was performed throughout the same time period in Region 9 transplant centers, where a broad sharing agreement had previously been implemented. In the subanalysis, there was no change in the incident-rate of biliary complications between the two time periods. Length of stay and mean direct cost demonstrated a change after implementation of Share 35, although they did not meet statistical difference. While the target of improved waitlist mortality is of utmost importance for the equitable allocation of organs, unintended consequences of policy changes should be studied for a full assessment of a policy's impact. PMID- 29767480 TI - N-Heterocyclic Carbene-Catalyzed Annulation of Ylides with Ynals: Direct Access to alpha-Pyrones. AB - We herein report an N-Heterocyclic Carbene (NHC)-catalyzed annulation of ylides with ynals that provides an efficient protocol to make 4,6-disubstituted alpha pyrones. This method affords a variety of alpha-pyrones in good to high yields as well as broad substrate scope and good functional group tolerance. PMID- 29767479 TI - Nocturia is more bothersome than daytime LUTS: Results from an Observational, Real-life Practice Database including 8659 European and American LUTS patients. AB - PURPOSE: Lower urinary tract symptoms (LUTS) encompass several diagnoses, including overactive bladder (OAB) and benign prostatic hyperplasia (BPH). Nocturia is a standalone symptom, but also included in OAB and BPH. Current discussion addresses whether the overlap of the diagnoses is too broad, leading to misdiagnosis. This study explored the differences in level, causes and consequences for patients with a diagnosis of daytime LUTS compared with a diagnosis of nocturia, and discussed whether people are being treated for the symptoms that truly bother them the most. PATIENTS AND METHODS: Data were drawn from a survey of physicians and patients in France, Germany, Spain, UK and USA. Physicians filled out patient record forms (PRFs) for patients with LUTS diagnosis. The patients completed the patient self-completion form (PSC). Three PRO questionnaires were included; the OAB-q SF, NI-Diary and WPAI. Patients were grouped based on the diagnoses assigned to them by their physicians in a real life setting. RESULTS: Eight thousand seven hundred and thirty eight patients had a LUTS diagnosis and 5335 completed a PSC. Patients diagnosed with night-time symptoms were significantly more bothered by their LUTS than only daytime LUTS patients (all questionnaires P < .0001). Patients with nocturia reported being tired "always" or "usually" more often than patients with daytime problems only (P < .0001). Only 13% of patients with nocturia had an initial sleep period of more than 2-3 hours. CONCLUSION: In this population of real-life patients, those with a diagnosis of nocturia reported significantly higher impact on their quality of life than patients with a diagnosis of daytime LUTS only. The underlying causes of bother were related to sleep problems. It is essential that nocturia is understood, treated and monitored as a distinct problem from OAB and BPH, to ensure that patients are treated for their main symptom. PMID- 29767481 TI - Supporting care home staff to manage residents' care safely and avoid admissions. AB - The community matron care homes team (CHT) was set up in Sandwell, West Midlands in 2011 to support care home staff to manage residents' care safely and reduce unplanned and/or avoidable use of acute health services. The service was reviewed in 2015 and attention focused on care homes with the highest levels of hospital use and emergency 999 services. Working with these care home staff and health professionals, a training and education opportunity to aid staff to manage residents in crisis was sourced, organised and implemented. The outcome of this training was positive: it demonstrated a reduction in hospital attendances and admissions and an increase in the confidence and morale of care home staff. The community matron CHT won the Nursing Older People category of the RCNi Nurse Awards in May 2017. This award has resulted in the team's profile being raised, and the team being asked to participate in further initiatives to provide enhanced support for care homes. PMID- 29767483 TI - Glossotillomania as cause of Riga-Fede syndrome. PMID- 29767482 TI - Multicenter clinical trial on a permanent hair dye containing paratoluenediamine. AB - BACKGROUND: Adverse reactions to hair dyes are frequent and usually caused by sensitization to paraphenylenediamine (PPD). The aim of the study was to evaluate the tolerability of a PPD-free permanent hair dye (Shine On, BioNike, Milan, Italy) containing paratoluenediamine (PTD) in a group of subjects sensitized to PPD. METHODS: The trial, which carried out at four dermatology centers, included subjects sensitized to PPD that turned out negative to patch testing to PTD. The subjects underwent to an open test consisting in the application of two hair dye colors of the product under examination. Finally, subjects who were negative upon the open test were offered to undergo the usage test with the dye, with dermatological evaluations carried out 48 and 96 hours after product application. RESULTS: Sixty subjects were enrolled. They underwent the open test with two shades of dyes: "color 1 - black," the dye color with the highest concentration of color intermediates, and "color 7.3 - golden blonde," the dye color with the highest number of chemically different color intermediates. No reactions occurred with "color 7.3 - golden blonde," while 3 cases (3 out of 60) showed erythema and edema reactions to color 1. The hair dye usage test was negative for all the 21 subjects that were enrolled. CONCLUSIONS: The hair dye evaluated in this study (Shine On, BioNike) can be a valid alternative for subjects sensitized to PPD. PMID- 29767485 TI - Head lice in African children. PMID- 29767484 TI - Dermoscopy of solitary cutaneous reticulohistiocytoma. PMID- 29767486 TI - Mudi-chood in an Indian woman living in Italy. PMID- 29767487 TI - Melanoma in female patients: general features and focus on the impact of estro progestinic pills in prognostic factors. PMID- 29767488 TI - A lesion of the nipple in a previously mastectomized patient. PMID- 29767489 TI - Shiitake dermatosis in a Caucasian woman. PMID- 29767490 TI - Kaposi's sarcoma associated with localized bullous pemphigoid: two conflicting diseases. PMID- 29767491 TI - Dermatophytosis in a psoriatic patient treated with secukinumab: an underrated adverse effect? PMID- 29767492 TI - Solitary vulvar neurofibroma in a patient without neurofibromatosis. PMID- 29767493 TI - Melanoma and hemangioma: an atypical presentation. PMID- 29767494 TI - Genital bowenoid papulosis: the variegated dermoscopic features. PMID- 29767495 TI - Graphdiyne-Supported NiFe Layered Double Hydroxide Nanosheets as Functional Electrocatalysts for Oxygen Evolution. AB - Graphdiyne (GDY), a novel two-dimensional full-carbon material, has attracted lots of attention because of its high conjugated system comprising sp2 and sp hybridized carbons. The distinctive structure characteristics endow it unique electronic structure, uniform distributed pores and excellent chemical stability. A novel GDY-supported NiFe layered double hydroxide (LDH) composite was successfully prepared for the first time. By taking advantage of the increased surface active areas and improved conductivity, the designed hierarchical GDY@NiFe composite exhibits outstanding catalytic activity that only required a small overpotential about 260 mV to achieve the current density of 10 mA cm-2. The nanocomposite shows excellent durability in alkaline medium implying a superior OER electrocatalytic activity. It is anticipated that the as-prepared GDY@NiFe composite electrocatalyst provide new insights in designing graphdiyne supported electrocatalyst materials for oxygen evolution application. PMID- 29767496 TI - Extraordinary Thermoelectric Performance Realized in Hierarchically Structured AgSbSe2 with Ultralow Thermal Conductivity. AB - Thermoelectric conversion from low-grade heat to electricity is regarded as the highly reliable and environmentally friendly technology in energy-harvesting area. However, how to develop efficient thermoelectric materials using a simple fabrication method is still a critical challenge in thermoelectric community. Here, we first fabricate the high thermoelectric performance of Ca-doped AgSbSe2 with a hierarchical microstructure using a facile approach, namely, mechanical alloying (for only 30 min) and a quick hot-pressing method. The hierarchical microstructure, including point defects (atomic scale), dislocations, and nanoprecipitates (nanoscale) as well as grain boundaries (microscale), strongly scatters phonons with comparable sizes without deterioration of carrier mobility. Because of the higher carrier concentration of nanostructured AgSbSe2 than that of coarse-grain AgSbSe2, power factor can also be improved slightly after nanostructuring. Ca doping further optimizes the carrier concentration and creates the point-defect scattering of phonons, leading to the ultralow lattice thermal conductivity ~0.27 W m-1 K-1 at 673 K and thus largely improving the peak ZT up to 1.2. The high thermoelectric performance in combination with a facile fabrication method highlights AgSbSe2-based materials as robust thermoelectric candidates for energy harvesting. PMID- 29767497 TI - Highly Sensitive and Reusable Membraneless Field-Effect Transistor (FET)-Type Tungsten Diselenide (WSe2) Biosensors. AB - In recent years when the demand for high-performance biosensors has been aroused, a field-effect transistor (FET)-type biosensor (BioFET) has attracted great interest because of its high sensitivity, label-free detection, fast detection speed, and miniaturization. However, the insulating membrane in the conventional BioFET, which is essential in preventing the surface dangling bonds of typical semiconductors from nonspecific bindings, has limited the sensitivity of biosensors. Here, we present a highly sensitive and reusable membraneless BioFET based on a defect-free van der Waals material, tungsten diselenide (WSe2). We intentionally generated a few surface defects that serve as extra binding sites for the bioreceptor immobilization through weak oxygen plasma treatment, consequently magnifying the sensitivity values to 2.87 * 105 A/A for 10 mM glucose. The WSe2 BioFET also maintained its high sensitivity even after several cycles of rinsing and glucose application were repeated. PMID- 29767498 TI - Reagentless Detection of Low-Molecular-Weight Triamterene Using Self-Doped TiO2 Nanotubes. AB - TiO2 nanotube electrodes were self-doped by electrochemical cathodic polarization, potentially converting Ti4+ into Ti3+, and thereby increasing both the normalized conductance and capacitance of the electrodes. One-hundred (from 19.2 +/- 0.1 MUF cm-2 to 1.9 +/- 0.1 mF cm-2 for SD-TNT) and two-fold (from ~6.2 to ~14.4 mS cm-2) concomitant increases in capacitance and conductance, respectively, were achieved in self-doped TiO2 nanotubes; this was compared with the results for their undoped counterparts. The increases in the capacitance and conductance indicate that the Ti3+ states enhance the density of the electronic states; this is attributed to an existing relationship between the conductance and capacitance for nanoscale structures built on macroscopic electrodes. The ratio between the conductance and capacitance was used to detect and quantify, in a reagentless manner, the triamterene (TRT) diuretic by designing an appropriate doping level of TiO2 nanotubes. The sensitivity was improved when using immittance spectroscopy (Patil et al. Anal. Chem. 2015, 87, 944-950; Bedatty Fernandes et al. Anal. Chem. 2015, 87, 12137-12144) (2.4 * 106 % decade-1) compared to cyclic voltammetry (5.8 * 105 % decade-1). Furthermore, a higher linear range from 0.5 to 100 MUmol L-1 (5.0 to 100 MUmol L-1 for cyclic voltammetry measurements) and a lower limit-of-detection of approximately 0.2 MUmol L-1 were achieved by using immittance function methodology (better than the 4.1 MUmol L-1 obtained by using cyclic voltammetry). PMID- 29767500 TI - Enhanced Performance of Field-Effect Transistors Based on Black Phosphorus Channels Reduced by Galvanic Corrosion of Al Overlayers. AB - Two-dimensional (2D)-layered semiconducting materials with considerable band gaps are emerging as a new class of materials applicable to next-generation devices. Particularly, black phosphorus (BP) is considered to be very promising for next generation 2D electrical and optical devices because of its high carrier mobility of 200-1000 cm2 V-1 s-1 and large on/off ratio of 104 to 105 in field-effect transistors (FETs). However, its environmental instability in air requires fabrication processes in a glovebox filled with nitrogen or argon gas followed by encapsulation, passivation, and chemical functionalization of BP. Here, we report a new method for reduction of BP-channel devices fabricated without the use of a glovebox by galvanic corrosion of an Al overlayer. The reduction of BP induced by an anodic oxidation of Al overlayer is demonstrated through surface characterization of BP using atomic force microscopy, Raman spectroscopy, and X ray photoemission spectroscopy along with electrical measurement of a BP-channel FET. After the deposition of an Al overlayer, the FET device shows a significantly enhanced performance, including restoration of ambipolar transport, high carrier mobility of 220 cm2 V-1 s-1, low subthreshold swing of 0.73 V/decade, and low interface trap density of 7.8 * 1011 cm-2 eV-1. These improvements are attributed to both the reduction of the BP channel and the formation of an Al2O3 interfacial layer resulting in a high- k screening effect. Moreover, ambipolar behavior of our BP-channel FET device combined with charge trap behavior can be utilized for implementing reconfigurable memory and neuromorphic computing applications. Our study offers a simple device fabrication process for BP-channel FETs with high performance using galvanic oxidation of Al overlayers. PMID- 29767499 TI - Large Area alpha-Cu2S Particle-Stacked Nanorod Arrays by Laser Ablation in Liquid and Their Strong Structurally Enhanced and Stable Visible Photoelectric Performances. AB - A flexible route is developed for fabrication of large area alpha-Cu2S nanorod arrays (NRAs) on the basis of one-step laser ablation of a copper foil in CS2 liquid. It has been demonstrated that the obtained products are the high temperature phase alpha-Cu2S and consist of the nanorods vertically standing on the Cu foil, exhibiting the array. The nanorods were about 1 MUm in length and around 100 nm in thickness and built by stacking the nearly spherical and ?110? oriented nanoparticles (NPs) up. Such array can be peeled off from the foil and remain freestanding. Further, it has been found that the ablation duration, the laser power, and the foil surface state are crucial to the formation of the Cu2S NRA. The formation of such oriented NP-stacked Cu2S NRAs is attributed to the laser-induced generation of alpha-Cu2S NPs and the NPs' deposition/oriented connection growth on the surface-vulcanized copper foil. Importantly, the visible photocurrent response of the alpha-Cu2S NRAs is 8 times higher than that of the Cu2S NPs' film with the equivalent thickness and also larger than that of previously reported Cu2S, showing significantly enhanced photoelectric performances. As an application, such NRAs have exhibited markedly enhanced visible photocatalytic activity and highly stable recycling performances, compared with the alpha-Cu2S NPs. Further studies have revealed that the enhanced performances are attributed to the structurally enhanced light trapping effect of the NRAs as well as short and smooth carrier diffusion path in the oriented NP stacked nanorods. This work provides a new and simple method for fabrication of the large area Cu2S NRAs with high and stable photoelectric performances. PMID- 29767501 TI - Enhanced Antimicrobial Activity and Structural Transitions of a Nanofibrillated Cellulose-Nisin Biocomposite Suspension. AB - Resistance to antibiotics has posed a high demand for novel strategies to fight bacterial infections. Antimicrobial peptides (AMPs) are a promising alternative to conventional antibiotics. However, their poor solubility in water and sensitivity to degradation has limited their application. Here, we report the design of a smart, pH-responsive antimicrobial nanobiocomposite material based on the AMP nisin and 2,2,6,6-tetramethyl-1-piperidinyloxyl-oxidized nanofibrillated cellulose (TONFC). Morphological transformations of the nanoscale structure of nisin functionalized-TONFC fibrils were discovered at pH values between 5.8 and 8.0 using small-angle X-ray scattering. Complementary zeta potential measurements indicate that electrostatic attractions between the negatively charged TONFC surface and the positively charged nisin molecules are responsible for the integration of nisin. Modification of the pH level or increasing the ionic strength reduces the nisin binding capacity of TONFC. Biological evaluation studies using a bioluminescence-based reporter strain of Bacillus subtilis and a clinically relevant strain of Staphylococcus aureus indicated a significantly higher antimicrobial activity of the TONFC-nisin biocomposite compared to the pure nisin against both strains under physiological pH and ionic strength conditions. The in-depth characterization of this new class of antimicrobial biocomposite material based on nanocellulose and nisin may guide the rational design of sustainable antimicrobial materials. PMID- 29767502 TI - Low-Voltage Solution-Processed Hybrid Light-Emitting Transistors. AB - We report the development of low operating voltages in inorganic-organic hybrid light-emitting transistors (HLETs) based on a solution-processed ZrO x gate dielectric and a hybrid multilayer channel consisting of the heterojunction In2O3/ZnO and the organic polymer "Super Yellow" acting as n- and p channel/emissive layers, respectively. Resulting HLETs operate at the lowest voltages reported to-date (<10 V) and combine high electron mobility (22 cm2/(V s)) with appreciable current on/off ratios (~103) and an external quantum efficiency of 2 * 10-2% at 700 cd/m2. The charge injection, transport, and recombination mechanisms within this HLET architecture are discussed, and prospects for further performance enhancement are considered. PMID- 29767503 TI - Effect of Dispersants on Photochromic Behavior of Tungsten Oxide Nanoparticles in Methylcellulose. AB - Tungsten oxide-based photochromic films that change reversibly in air between colorless-transparent in the dark and dark blue under UV irradiation were prepared by using methylcellulose as a film matrix and various dispersants. Alpha hydroxyl acid such as glycolic acid (GA) or glyceric acid (GlyA) is the best dispersant because it can make the film transparent by adding a small quantity much less than that of 3-hydroxypropionic acid or ethylene glycol. Fourier transform infrared spectra and Raman spectra indicate that a strong interaction exists between WO3 and GA or GlyA. The coloration and bleaching processes of the prepared films were investigated to clarify the effect of the dispersants and the moisture contents. The bleaching rate remarkably decreased in the films containing GA or GlyA but accelerated by increasing the contact with O2. Measurements of electron-spin resonance reveals that GA and GlyA as dispersants stabilize the W5+ state. This paper shows that the coloring rate and the period for keeping the blue-colored state are tunable by changing the dispersants. The photochromic films containing alpha-hydroxyl acid as the dispersant have the potential for application as rewritable film on which information displayed with blue-colored state can be clearly readable for longer times compared with other dispersants. PMID- 29767504 TI - Motion-Based Immunological Detection of Zika Virus Using Pt-Nanomotors and a Cellphone. AB - Zika virus (ZIKV) infection is an emerging pandemic threat to humans that can be fatal in newborns. Advances in digital health systems and nanoparticles can facilitate the development of sensitive and portable detection technologies for timely management of emerging viral infections. Here we report a nanomotor-based bead-motion cellphone (NBC) system for the immunological detection of ZIKV. The presence of virus in a testing sample results in the accumulation of platinum (Pt)-nanomotors on the surface of beads, causing their motion in H2O2 solution. Then the virus concentration is detected in correlation with the change in beads motion. The developed NBC system was capable of detecting ZIKV in samples with virus concentrations as low as 1 particle/MUL. The NBC system allowed a highly specific detection of ZIKV in the presence of the closely related dengue virus and other neurotropic viruses, such as herpes simplex virus type 1 and human cytomegalovirus. The NBC platform technology has the potential to be used in the development of point-of-care diagnostics for pathogen detection and disease management in developed and developing countries. PMID- 29767507 TI - Palladium-Catalyzed alpha-Allylation of Secondary Nitroalkanes with Allylic Alcohols and Strategic Exploitation of Seebach's Reagent for the Total Synthesis of (+/-)-Adalinine. AB - A method is reported for the catalytic direct coupling of allylic alcohols and nitroalkanes. In the allylation process, the synergistic action of palladium complexes and titanium(IV) alkoxide facilitates the formation of nitronate and pi allylpalladium intermediate. In the cases of reluctant allylations, typically with sterically demanding nitroalkanes, we found the addition of substoichiometric amount of DBU greatly facilitates the desired transformation. We also accomplished a total synthesis of (+/-)-adalinine through a homoallyl nitroalkane derived from Seebach's reagent. PMID- 29767506 TI - Effect of the Substitution Pattern (Peripheral vs Non-Peripheral) on the Spectroscopic, Electrochemical, and Magnetic Properties of Octahexylsulfanyl Copper Phthalocyanines. AB - In order to investigate the substitution position effect on the spectroscopic, electrochemical, and magnetic properties of copper phthalocyanines, a detailed structure-property analysis has been performed by examining two copper phthalocyanines that are octasubstituted by hexylsulfanyl chains respectively in the peripheral (Cu-P) and non-peripheral (Cu-NP) positions. Cu-NP showed a marked near-IR maximum absorption compared to Cu-P and, accordingly, a smaller HOMO-LUMO energy gap, calculated via the electrochemical results and simulations in the gas phase, as well as for Cu-NP from its crystallographic data. An electron-spin resonance (ESR) technique is used to extract the g values from the powder spectra that are taken at room temperature. The g values were determined to be g? = 2.160 and g? = 2.045 for Cu-P and g? = 2.150 and g? = 2.050 for Cu-NP. These values indicate that the paramagnetic copper center in both phthalocyanines has axial symmetry with a planar anisotropy ( g? > g?). The ESR spectra in solution could be obtained only for Cu-P. Curie law is used to fit the experimental data of the magnetic susceptibility versus temperature graphs, and the Curie constant ( C) and diamagnetic/temperature-independent paramagnetic (alpha) contributions are deduced as 0.37598 (0.39576) cm3.K/mol and -23 * 10-5 (25 * 10-5) cm3/mol respectively for Cu-P and Cu-NP. The room temperature magnetic moment value (1.70 MUB) is close to the spin-only value (1.73 MUB) for the peripheral complex, showing that there is no orbital contribution to MUeff. In contrast, at room temperature, the value of the magnetic moment (1.77 MUB) is above the spin-only value, showing an orbital contribution to the magnetic moment. Cu-NP's room temperature magnetic moment value is larger than the value for Cu-P, demonstrating that the orbital contribution to the magnetic moment depends upon the substituent position. The magnitudes of the effective magnetic moment values also support that both Cu-P and Cu-NP complexes have square-planar coordination. This result is consistent with the determined g values. The spin densities were determined experimentally, and the results suggest that the positions of the substituents affect these values (0.469 for Cu-P and 0.490 for Cu-NP). PMID- 29767505 TI - Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells. AB - Antibody fragment (Fab')-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab' was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab'(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab' (or DBCO) to micelle (or azide). The resulting micelles exhibited ~40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab' conjugation. Flow cytometric analysis showed that three molecules of Fab' installed PIC micelles (3(Fab')-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab')-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab')-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab'-installed PIC micelles. These results demonstrate the potential of anti-TF Fab'-installed PIC micelles for active targeting of stroma rich pancreatic tumors. PMID- 29767508 TI - Comparison of Uranium(VI) and Thorium(IV) Silicates Synthesized via Mixed Fluxes Techniques. AB - Two uranium and two thorium silicates were obtained using high temperature mixed fluxes methods. K14(UO2)3Si10O30 crystallizes in the P21/ c space group and contains open-branched sechser (six) single silicate chains, whereas K2(UO2)Si2O6 crystallizes in the C2/ c space group and is built of unbranched achter (eight) silicate chains. The crystals of K14(UO2)3Si10O30 and K2(UO2)Si2O6 are related by increasing U/Si molar ratios, and both structures contain the same secondary building units (SBUs), [USi6] heptamers. The triangle diagram for all known A+ UO22+-SiO44- phases demonstrates the high polymerization level of silicate groups in the system, which was compared with the family of A+-UO22+-BO33-/BO45- compounds. For both thorium silicates, the transformation of K2ThSi2O7 to K2ThSi3O9 was found to be a factor of the reaction time. K2ThSi2O7 crystallizes in the C2/ c space group and belongs to the Na2SiVISi2O7 structure type. Its 3D framework consists of diorthosilicate Si2O7 group and ThO6 octahedra. Noncentrosymmetric K2ThSi3O9 crystallizes in the hexagonal P63 space group and adopts mineral wadeite-type structure based upon triorthosilicate Si3O9 rings and ThO6 octahedra. The coordination environment of thorium for all existing oxo anion compounds including B, Si/Ge, P/As, Cr/Mo/W, and S/Se/Te are summarized and analyzed. Additionally, spectroscopic properties of all novel materials have been studied. PMID- 29767509 TI - Proton Transfer Hydrogels: Versatility and Applications. AB - Proton transfer polymerization between thiol and epoxide groups is shown to be an adaptable and utilitarian method for the synthesis of hydrogels. For instance, the polymerization catalyst can be organic or inorganic, and the polymerization medium can be pure water, buffer solutions, or organic solvents. The gelation mechanism can be triggered at ambient conditions, at a physiological temperature of 37 degrees C, or through using light as an external stimulus. The ambient and photochemical methods both allow for nanoimprint lithography to produce freestanding patterned thick films. The required thiol- and epoxide-carrying precursors can be chosen from a long list of commercially available small molecular as well as polymeric materials. The water uptake, mechanical, and biodegradation properties of the gels can, therefore, be tuned through the choice of appropriate gelation precursors and polymerization conditions. Finally, the thio-ether groups of the cross-linked networks can be functionalized through a postgelation modification reaction to access sulfonium-based cationic structures. Such structural changes endow antibacterial properties to the networks. In their pristine form, however, the gels are biocompatible and nonadhesive, allowing cancer cells to grow in a cluster formation. PMID- 29767510 TI - Nonenzymatic Wearable Sensor for Electrochemical Analysis of Perspiration Glucose. AB - We report a nonenzymatic wearable sensor for electrochemical analysis of perspiration glucose. Multipotential steps are applied on a Au electrode, including a high negative pretreatment potential step for proton reduction which produces a localized alkaline condition, a moderate potential step for electrocatalytic oxidation of glucose under the alkaline condition, and a positive potential step to clean and reactivate the electrode surface for the next detection. Fluorocarbon-based materials were coated on the Au electrode for improving the selectivity and robustness of the sensor. A fully integrated wristband is developed for continuous real-time monitoring of perspiration glucose during physical activities, and uploading the test result to a smartphone app via Bluetooth. PMID- 29767511 TI - Low-Dose Arsenic Trioxide Modulates the Differentiation of Mouse Embryonic Stem Cells. AB - Arsenic (As) is a well-known environmental pollutant, while arsenic trioxide (ATO) has been proven to be an effective treatment for acute promyelocytic leukemia, however, the mechanism underlying its dual effects is not fully understood. Embryonic stem cells (ESCs) exhibit properties of stemness and serve as a popular model to investigate epigenetic modifiers including environmental pollutants. Herein, the effects of low-dose ATO on differentiation were evaluated in vitro using a mouse ESCs (mESCs) cell line, CGR8. Cells treated with 0.2-0.5 MUM ATO for 3-4 days had slight inhibition of proliferation with elevation of apoptosis, but obvious alterations of differentiation by morphological checking and alkaline phosphatase (AP) staining. Moreover, ATO exposure significantly decreased the mRNA expression of the stemness maintenance genes including Oct4, Nanog, and Rex-1 ( P < 0.01), whereas obviously increased some tissue-specific differentiation marker genes such as Gata4, Gata-6, AFP, and IHH. These alterations were consistent with the differentiation phenotype induced by retinoic acid (RA) and the expression patterns of distinct pluripotency markers such as SSEA-1 and Oct4. Furthermore, low-dose ATO led to a quantitative increase in Caspase 3 (CASP3) activation and subsequent cleavage of Nanog around 27 kDa, which corresponded with the mouse Nanog cleaved by CASP3 in a tube cleavage assay. Taken together, we suggest that low-dose ATO exposure will induce differentiation, other than apoptosis, of ESCs, such effects might be tuned partially by ATO-induced CASP3 activation and Nanog cleavage coupling with other differentiation related genes involved. The present findings provide a preliminary action mechanism of arsenic on the cell fate determination. PMID- 29767512 TI - Azide- and Dye-Conjugated Coelenterazine Analogues for a Multiplex Molecular Imaging Platform. AB - Native coelenterazine (nCTZ) is a common substrate to most marine luciferases and photoproteins. In this study, nine novel dye- and azide-conjugated CTZ analogues were synthesized by conjugating a series of fluorescent dyes or an azide group to the C-2 or C-6 position of the nCTZ backbone to obtain bulkiness-driven substrate specificity and potential chemiluminescence/bioluminescence resonance energy transfer (C/BRET). The investigation on the optical properties revealed that azide-conjugated CTZs emit greatly biased bioluminescence to ALucs and ca. 130 nm blue-shifted bioluminescence with RLuc8.6 in living animal cells or lysates. The corresponding kinetic study explains that azide-conjugated CTZ exerts higher catalytic efficiency than nCTZ. Nile red-conjugated CTZ completely showed red shifted CRET spectra and characteristic BRET spectra with artificial luciferase 16 (ALuc16). No or less spectral overlap occurs among [Furimazine-NanoLuc], [6-N3 CTZ-ALuc26], [6-pi-OH-CTZ-RLuc8.6], and [6-N3-CTZ-RLuc8.6] pairs, because of the substrate-driven luciferase specificity and color shifts, providing a crosstalk free multiplex bioassay platform. The unique bioluminescence system appends a new toolbox to bioassays and multiplex molecular imaging platforms. This study is the first example that systematically synthesized fluorescent dye-conjugated CTZs and applied them for a bioluminescence assay system. PMID- 29767513 TI - Structural Compromise between High Hardness and Crack Resistance in Aluminoborate Glasses. AB - Alkali aluminoborate glasses have recently been shown to exhibit a high threshold for indentation cracking compared to other bulk oxide glasses. However, to enable the use of these materials in engineering applications, there is a need to improve their hardness by tuning the chemical composition. In this study, we substitute alkaline earth for alkali network-modifying species at fixed aluminoborate base glass composition and correlate it with changes in the structure, mechanical properties, and densification behavior. We find that the increase in field strength (i.e., the charge-to-size ratio) achieved by substituting alkaline earth oxide from BaO to MgO manifests itself in a monotonic increase in several properties, such as atomic packing density, glass-transition temperature, densification ability, indentation hardness, and crack resistance. Although the use of alkaline earth oxides as modifier enables higher hardness values (increasing from 2.0 GPa for Cs to 5.8 GPa for Mg), their crack resistance is generally lower than that of the corresponding alkali aluminoborate glasses. We discuss the origin of this compromise between hardness and crack resistance in terms of the ability of the glass networks to undergo structural transformations and self-adapt under stress. We show that the extent of volume densification scales linearly with the number of pressure-induced coordination number changes of B and Al. PMID- 29767515 TI - Correction to "Exploiting Alkylquinone Tautomerization for the Total Synthesis of Calothrixin A and B". PMID- 29767514 TI - Solvent Polarity Predictably Tunes Spin Crossover T1/2 in Isomeric Iron(II) Pyrimidine Triazoles. AB - Two isomeric pyrimidine-based Rdpt-type triazole ligands were made: 4-(4 methylphenyl)-3-(2-pyrimidyl)-5-phenyl-4 H-1,2,4-triazole (L2pyrimidine) and 4-(4 methylphenyl)-3-(4-pyrimidyl)-5-phenyl-4 H-1,2,4-triazole (L4pyrimidine). When reacted with [FeII(pyridine)4(NCE)2], where E = S, Se, or BH3, two families of mononuclear iron(II) complexes are obtained, including six solvatomorphs, giving a total of 12 compounds: [FeII(L2pyrimidine)2(NCS)2] (1), [FeII(L2pyrimidine)2(NCSe)2] (2), 2.1.5H2O, [FeII(L2pyrimidine)2(NCBH3)2].2CHCl3 (3.2CHCl3), 3 and 3.2H2O, [FeII(L4pyrimidine)2(NCS)2] (4), 4.H2O, [FeII(L4pyrimidine)2(NCSe)2] (5), 5.2CH3OH, 5.1.5H2O, and [FeII(L4pyrimidine)2(NCBH3)2].2.5H2O (6.2.5H2O). Single-crystal X-ray diffraction reveals that the N6-coordinated iron(II) centers in 1, 2, 3.2CHCl3, 4, 5, and 5.2CH3OH have two bidentate triazole ligands equatorially bound and two axial NCE co-ligands trans-coordinated. All structures are high spin (HS) at 100 K, except 3.2CHCl3, which is low spin (LS). Solid-state magnetic measurements show that only 3.2CHCl3 ( T1/2 above 400 K) and 5.1.5H2O ( T1/2 = 110 K) undergo spin crossover (SCO); the others remain HS at 300-50 K. When 3.2CHCl3 is heated at 400 K it desorbs CHCl3 becoming 3, which remains HS at 400-50 K. UV-Vis studies in CH2Cl2, CHCl3, (CH3)2CO, CH3CN, and CH3NO2 solutions for the BH3 analogues 3 and 6 led to a 6:1 ratio of L npyrimidine/Fe(II) being employed for the solution studies. These revealed SCO activity in all five solvents, with T1/2 values for the 2-pyrimidine complex (247-396 K) that were consistently higher than for the 4 pyrimidine complex (216-367 K), regardless of solvent choice, consistent with the 2-pyrimidine ring providing a stronger ligand field than the 4-pyrimidine ring. Strong correlations of solvent polarity index with the T1/2 values in those solvents are observed for each complex, enabling predictable T1/2 tuning by up to 150 K. While this correlation is tantalizing, here it may also be reflecting solvent-dependent speciation-so future tests of this concept should employ more stable complexes. Differences between solid-state (ligand field; crystal packing; solvent content) and solution (ligand field; solvation; speciation) effects on SCO are highlighted. PMID- 29767516 TI - Specific N-Alkylation of Hydroxypyridines Achieved by a Catalyst- and Base-Free Reaction with Organohalides. AB - A specific N-alkylation of 2-hydroxypyridines is achieved by reacting with organohalides under catalyst- and base-free conditions. The observed HX facilitated conversion of pyridyl ether intermediates to 2-pyridone products may account for the success and specific N-alkylation of the reaction under the unexpectedly simple conditions. This new reaction may provide a useful alternative for the synthesis of 2-pyridones and analogous structures because of its >99% N-selectivity, relatively broad scopes of both substrates, and no mandatory use of catalysts and bases. PMID- 29767518 TI - Turn-on and Turn-off Fluorescent Probes for Carbon Monoxide Detection and Blood Carboxyhemoglobin Determination. AB - Water-soluble, carbazole-based two-photon excitable fluorescent probes MPVC-I ("turn-on") and MPVC-II ("turn-off") are rationally designed and synthesized for the selective monitoring of carbon monoxide (CO). Both probes can effectively measure carboxyhemoglobin (HbCO) in the blood of the animals exposed to a CO dose as low as 100 ppm for 10 min. The palladium catalyzed azidocarbonylation reaction was optimized to improve the sensing efficiency. PMID- 29767519 TI - Molecular Structure and Permeability at the Interface between Phase-Separated Membrane Domains. AB - Phase-separated membrane domains, also known as lipid rafts, are believed to play an important role in cell function. Although most rafts are sterol-enriched membrane regions, evidence suggests that living cells may also contain gel-like rafts. Interactions between gel and fluid domains have a large impact on membrane properties, as is the case with permeability. The membrane permeability may reach a peak at the main phase transition temperature, by far exceeding the values recorded at the fluid phase. It has been proposed that gel-fluid interfaces are leaky, but the effect has not yet been demonstrated at the molecular level. Here, we performed atomistic molecular dynamics simulations of phospholipid bilayers with coexisting gel-like and fluid domains. We found that the thickness mismatch between both phases, the membrane elasticity, and the lipid packing acted together to promote the formation of a thickness minimum at the gel-fluid interface. Free energy calculations showed that pore-mediated ionic permeation was strongly facilitated at the constriction region, whereas water permeation by simple diffusion was only marginally affected. Long-lived, peristaltic undulations were recorded at the bulk fluid phase near the main transition temperature. They gave rise to thickness minima that, although shallower than the interface constrictions, could also enhance permeability. Finally, we demonstrated that an interface constriction was also formed at the boundaries of regular, cholesterol-enriched lipid rafts. Our simulation results will hopefully contribute to a better understanding of biological processes such as transport, signaling, and cellular damage promoted by low temperature and dehydration. PMID- 29767517 TI - Formation of ZnO4 Tetrahedra and ZnO6 Octahedra in TeZnO3 Synthesized under High Pressure. AB - A new TeZnO3 phase was synthesized by high-pressure techniques. Different from the ambient-pressure orthorhombic phase composed of ZnO5 units, the current high pressure one crystallizes to a monoclinic structure with space group P21/ n. Moreover, both ZnO4 tetrahedral and ZnO6 octahedral polyhedra are found to occur in this new phase, providing a unique Zn-based material system that simultaneously possesses two distinct coordinated units. Because the outermost orbitals are fully occupied for both Zn2+ and Te4+, the compound exhibits diamagnetism and strong insulating behavior with a wide bandgap as large as 6.0 eV. Dielectric constant and specific heat measurements show a broad anomaly around 240 K. Low-temperature synchrotron X-ray diffraction reveals an isostructural phase transition at this temperature. PMID- 29767520 TI - Enhanced Oxidative and Adsorptive Removal of Diclofenac in Heterogeneous Fenton like Reaction with Sulfide Modified Nanoscale Zerovalent Iron. AB - Sulfidation of nanoscale zerovalent iron (nZVI) has shown some fundamental improvements on reactivity and selectivity toward pollutants in dissolved-oxygen (DO)-stimulated Fenton-like reaction systems (DO/S-nZVI system). However, the pristine microstructure of sulfide-modified nanoscale zerovalent iron (S-nZVI) remains uncovered. In addition, the relationship between pollutant removal and the oxidation of the S-nZVI is largely unknown. The present study confirms that sulfidation not only imparts sulfide and sulfate groups onto the surface of the nanoparticle (both on the oxide shell and on flake-like structures) but also introduces sulfur into the Fe(0) core region. Sulfidation greatly inhibits the four-electron transfer pathway between Fe(0) and oxygen but facilitates the electron transfer from Fe(0) to surface-bound Fe(III) and consecutive single electron transfer for the generation of H2O2 and hydroxyl radical. In the DO/S nZVI system, slight sulfidation (S/Fe molar ratio = 0.1) is able to nearly double the oxidative removal efficacy of diclofenac (DCF) (from 17.8 to 34.2%), whereas moderate degree of sulfidation (S/Fe molar ratio = 0.3) significantly enhances both oxidation and adsorption of DCF. Furthermore, on the basis of the oxidation model of S-nZVI, the DCF removal process can be divided into two steps, which are well modeled by parabolic and logarithmic law separately. This study bridges the knowledge gap between pollutant removal and the oxidation process of chemically modified iron-based nanomaterials. PMID- 29767521 TI - Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid Construction of Spiro NH Aziridines from Vinyl Azides. AB - A range of novel (poly)cyclic alkaloids incorporating an unprecedented 1,5 diazaspiro[2.4]heptane core that carry a spiro NH aziridine moiety and a 7-vinyl group are constructed from the thermal reaction of vinyl azides with tethered alkenes. Vinyl azides are converted to 2H-azirines in situ, which serve as enophiles for intramolecular imino-ene reactions with suitable alkenes. High stereoselectivity and specificity have been achieved for this novel intramolecular imino-ene reaction of azirines. PMID- 29767522 TI - Traceless Release of Alcohols Using Thiol-Sensitive Oxanorbornadiene Linkers. AB - A class of ester-amide oxanorbornadiene (EA-OND) molecules was developed to release alcohol cargos by succinimide formation upon addition of a thiol reagent. The resulting ring-closed adducts undergo further fragmentation by retro-Diels Alder reaction to release a furan moiety in a manner similar to oxanorbornadiene diesters. The rates of each of these fragmentation pathways in the same medium were found to be sensitive to the steric nature of the amide substituent. Alcohol release was much faster in protic solvents than in aprotic ones, suggesting that this system may be useful for rapid response to thiols in biological environments. Accordingly, the attachment and thiol-dependent release of cholesterol was characterized as an example of the manipulation of a drug-like cargo. PMID- 29767523 TI - Microscopic Insight into the Protein Denaturation Action of Urea and Its Methyl Derivatives. AB - We employ site-specific, linear and nonlinear infrared spectroscopic techniques as well as fluorescence spectroscopy and molecular dynamics simulations to investigate the binding interactions of urea and three of its derivatives, methylurea, 1,3-dimethylurea, and tetramethylurea, with protein aromatic and polar side chains. We find that (1) urea methylation leads to preferential interactions between the cosolvent molecules and aromatic side chains with an affinity that increases with the number of methyl groups; (2) interactions with tetramethylurea cause significant dehydration of aromatic side chains and the effect is most pronounced for tryptophan; and (3) while neither urea nor tetramethylurea shows preferential accumulation around a polar side chain, the number of hydrogen-bond donors around this side chain is significantly decreased in the presence of tetramethylurea. Taken together, our findings suggest that these urea derivatives, especially tetramethylurea, can effectively disrupt hydrophobic interactions in proteins. Additionally, tetramethylurea can promote intramolecular hydrogen-bond formation and hence induce alpha-helix folding in peptides, as observed. PMID- 29767524 TI - Resonant Grazing-Incidence Small-Angle X-ray Scattering at the Sulfur K-Edge for Material-Specific Investigation of Thin-Film Nanostructures. AB - Scattering techniques are a powerful tool for probing thin-film nanomorphologies but often require additional characterization by other methods. We applied the well-established grazing-incidence small-angle X-ray scattering (GISAXS) technique for a selection of energies around the absorption edge of sulfur to exploit the resonance effect (grazing incidence resonant tender X-ray scattering, GIR-TeXS) of the sulfur atoms within a poly(3-hexylthiophene-2,5-diyl):phenyl-C61 butyric acid methyl ester (P3HT:PC61BM) sample to gain information about the composition of the film morphology. With this approach, it is possible not only to identify structures within the investigated thin film but also to link them to a particular material combination. PMID- 29767525 TI - Distribution of Nanodiamond Inside the Nanomatrix in Natural Rubber. AB - The distribution of nanodiamond inside a nanomatrix, which is related to the mechanical and viscoelastic properties, is investigated for a natural rubber nanodiamond composite. The composite is prepared by reacting nanodiamond with deproteinized natural rubber (NR-ND) in the presence of a tert-butylhydroperoxide (TBHPO)/tetraethylenepentamine (TEPA) radical initiator at 30 degrees C in the latex stage and subsequent drying. The morphology of the composite is observed by three-dimensional transmission electron microscopy. NR-ND prepared with an initiator exhibits a nanomatrix structure, whereas NR-ND prepared without an initiator displays an island matrix structure. The nanomatrix is densely loaded with 15 nm or smaller-sized nanodiamond. Both the mechanical and viscoelastic properties of NR-ND depend upon the morphology. The stress at break and the plateau modulus are 12 MPa and 1.19 * 106 Pa, respectively, when NR-ND is prepared with a TBHPO/TEPA initiator and contains 25 w/w % nanodiamond, which are 4 and 8 times higher than those of deproteinized natural rubber, respectively. PMID- 29767526 TI - Role of Solute Attractive Forces in the Atomic-Scale Theory of Hydrophobic Effects. AB - The role that van der Waals (vdW) attractive forces play in the hydration and association of atomic hydrophobic solutes such as argon (Ar) in water is reanalyzed using the local molecular field (LMF) theory of those interactions. In this problem, solute vdW attractive forces can reduce or mask hydrophobic interactions as measured by contact peak heights of the ArAr correlation function compared to reference results for purely repulsive core solutes. Nevertheless, both systems exhibit a characteristic hydrophobic inverse temperature behavior in which hydrophobic association becomes stronger with increasing temperature through a moderate temperature range. The new theoretical approximation obtained here is remarkably simple and faithful to the statistical mechanical LMF assessment of the necessary force balance. Our results extend and significantly revise approximations made in a recent application of the LMF approach to this problem and, unexpectedly, support a theory of nearly 40 years ago. PMID- 29767527 TI - Tuning Solvated Electrons by Polar-Nonpolar Oxide Heterostructure. AB - Solvated electron states at the oxide/aqueous interface represent the lowest energy charge-transfer pathways, thereby playing an important role in photocatalysis and electronic device applications. However, their energies are usually higher than the conduction band minimum (CBM), which makes the solvated electrons difficult to utilize in charge-transfer processes. Thus it is essential to stabilize the energy of the solvated electron states. Taking LaAlO3/SrTiO3 (LAO/STO) oxide heterostructure with H2O-adsorbed monolayer as a prototypical system, we show using DFT and ab initio time-dependent nonadiabatic molecular dynamics simulation that the energy and dynamics of solvated electrons can be tuned by the electric field in the polar-nonpolar oxide heterostructure. In particular, for LAO/STO with p-type interface, the CBM is contributed by the solvated electron state when LAO is thicker than four unit cells. Furthermore, the solvated electron band minimum can be partially occupied when LAO is thicker than eight unit cells. We propose that the tunability of solvated electron states can be achieved on polar-nonpolar oxide heterostructure surfaces as well as on ferroelectric oxides, which is important for charge and proton transfer at oxide/aqueous interfaces. PMID- 29767528 TI - Correction to "Tin-Free Access to the ABC Core of the Calyciphylline A Alkaloids and Unexpected Formation of a D-Ring-Contracted Tetracyclic Core". PMID- 29767529 TI - Fractal Gold Nanoframework for Highly Stretchable Transparent Strain-Insensitive Conductors. AB - Percolation networks of one-dimensional (1D) building blocks (e.g., metallic nanowires or carbon nanotubes) represent the mainstream strategy to fabricate stretchable conductors. One of the inherent limitations is the control over junction resistance between 1D building blocks in natural and strained states of conductors. Herein, we report highly stretchable transparent strain-insensitive conductors using fractal gold (F-Au) nanoframework based on a one-pot templateless wet chemistry synthesis method. The monolayered F-Au nanoframework (~20 nm in thickness) can be obtained from the one-pot synthesis without any purification steps involved and can be transferred directly to arbitrary substrates like polyethylene terephthalate, food-wrap, polydimethylsiloxane (PDMS), and ecoflex. The F-Au thin film with no capping agents leads to a highly conductive thin film without any post-treatment and can be stretched up to 110% strain without significantly losing conductivity yet with the optical transparency of 70% at 550 nm. Remarkably, the F-Au thin film shows the strain insensitive behavior up to 20% stretching strain. This originates from the unique fractal nanomesh-like structure which can absorb external mechanical forces, thus maintaining electron pathways throughout the nanoframework. In addition, a semitransparent bilayered F-Au film on 100% prestrained PDMS could achieve to a high stretchability of 420% strain with negligible resistance changes under low level strains. PMID- 29767530 TI - Lanthanide-Based Porous Coordination Polymers: Syntheses, Slow Relaxation of Magnetization, and Magnetocaloric Effect. AB - Two lanthanide-containing structurally analogous porous coordination polymers (PCPs) have been isolated with the general molecular formula [Ln2(L1)2(H2O)4(ox)] n.4 nH2O (where L1 = fumarate, ox = oxalate; Ln = Dy (1), Gd (2)). Thermogravimetric analysis (TGA) and TG-MS measurements performed on 1 and 2 suggest that not only the solvated water molecules in the crystal lattice but also the four coordinated water molecules on the respective lanthanides in 1 and 2 are removed upon activation. Due to the removal of the waters, 1 and 2 lost their crystallinity and became amorphous, as confirmed by powder X-ray diffraction (PXRD). We propose the molecular formula [Ln2(L1)2(ox)] n for the amorphous phase of 1 and 2 (where Ln = Dy (1'), Gd (2')) on the basis of XANES, EXAFS, and other experimental investigations. Magnetization relaxation dynamics probed on 1 and 1' reveal two different relaxation processes with effective energy barriers of 53.5 and 7.0 cm-1 for 1 and 45.1 and 6.4 cm-1 for 1', which have been rationalized by detailed ab initio calculations. For the isotropic lanthanide complexes 2 and 2', magnetocaloric effect (MCE) efficiency was estimated through detailed magnetization measurements. We have estimated -Delta S m values of 52.48 and 41.62 J kg1- K-1 for 2' and 2, respectively, which are one of the largest values reported for an extended structure. In addition, a 26% increase in -Delta Sm value in 2' in comparison to 2 is achieved by simply removing the passively contributing (for MCE) solvated water molecule in the lattice and coordinated water molecules. PMID- 29767531 TI - Correction to Ultrathin Au-Alloy Nanowires at the Liquid-Liquid Interface. PMID- 29767532 TI - Reply: Response to Cookstove Trials and Tribulations: What Is Needed to Decrease the Burden of Household Air Pollution? PMID- 29767533 TI - Sirtuin-1 Controls Poly (I:C)-Dependent Matrix Metalloproteinase 9 Activation in Primary Human Nasal Epithelial Cells. AB - Matrix metalloproteinase (MMP)-9 is thought to be involved in the etiopathogenesis of chronic rhinosinusitis (CRS) with nasal polyps and cleaves collagen IV, causing hyperpermeability of the basement membrane within mucosal tissue. It is known that MMP-9 expression is negatively affected by sirtuin (SIRT)-1 in human monocytotic cells, retinal endothelial cells, and epithelial carcinoma cells. However, it is unknown which factors affect MMP-9 expression and activity in human nasal epithelial cells (HNECs). To examine factors affecting MMP-9 expression and activity in HNECs, HNECs were stimulated with Toll-like receptor (TLR) agonists, followed by quantitative PCR, immunofluorescence, and zymography to examine MMP-9 expression and activity. MMP-9 expression was evaluated in sinonasal tissue of control subjects without CRS, and patients with CRS without nasal polyps and those with CRS with nasal polyps, in relation to the expression of SIRT1 using a tissue microarray. The effect of SIRT1 stimulation/inhibition on MMP-9 expression in HNECs was also tested. TLR3 agonists increased MMP-9 mRNA expression (473 fold, P = 0.0198) and activity (20.4-fold, P < 0.05). SIRT1 activation or inhibition reciprocally affected MMP-9 expression in the presence of TLR3 agonists. MMP-9 and SIRT1 expression within the epithelial layer of sinonasal tissue was inversely correlated only in patients with CRS but not in control subjects. TLR3 agonists increased MMP-9 expression and activity in HNECs, and the effect was abolished in the presence of SIRT1 activation. SIRT1 and MMP-9 expression was inversely correlated in CRS tissue, supporting SIRT1 as a possible therapeutic target for nasal polyp formation. PMID- 29767534 TI - Sensitive Hg2+ Ion Detection Using Metal Enhanced Fluorescence of Novel Polyvinyl Pyrrolidone (PVP)-Templated Gold Nanoparticles. AB - In this study, we report a straightforward strategy for Hg2+ ion detection. Fluorescent Au nanoparticles (NPs) were one-pot synthesized using a polymer (polyvinyl pyrrolidone [PVP]) as both capping and fluorescence agent. The as synthesized PVP-Au NPs showed a remarkably rapid response selectively for Hg2+ ions compared to 14 other metal ions. The detection limit of Hg2+ was estimated at 100 nM. We discuss the emission and quenching mechanism of the PVP-Au NPs, the former being attributed to metal enhanced fluorescence and the latter being related to static quenching by Hg2+. The fluorescence of PVP-Au NPs offers an efficient and reliable strategy for Hg2+ ions detection. They therefore have a great potential for applications in health and environmental monitoring. PMID- 29767536 TI - Highlights from the British Society for Heart Failure 20th Annual Autumn Meeting: three decades of heart failure. AB - The 20th Annual Autumn Meeting of the British Society for Heart Failure took place on the 23-24 November 2017 at the Queen Elizabeth II Conference Centre, London, UK. Over 800 delegates were in attendance: a multidisciplinary league of professionals who treat patients with heart failure, including specialist nurses, trainees, cardiologists, geriatricians, pharmacists and general practitioners. The theme of the conference was 'three decades of heart failure' and celebrated the success of modern heart failure management. This report highlights the 'three decades' session, the clinical trials update, and the main discussion points from heart failure question time. PMID- 29767535 TI - Classical Least Squares-Assisted Mid-Infrared (MIR) Laser Spectroscopy Detection of High Explosives on Fabrics. AB - Mid-infrared (MIR) laser spectroscopy was used to detect the presence of residues of high explosives (HEs) on fabrics. The discrimination of the vibrational signals of HEs from a highly MIR-absorbing substrate was achieved by a simple and fast spectral evaluation without preparation of standards using the classical least squares (CLS) algorithm. Classical least squares focuses on minimizing the differences between the spectral features of the actual spectra acquired using MIR spectroscopy and the spectral features of calculated spectra modeled from linear combinations of the spectra of neat components: HEs, fabrics, and bias. Samples in several combinations of cotton fabrics/HEs were used to validate the methodology. Several experiments were performed focusing on binary, ternary, and quaternary mixtures of TNT, RDX, PETN, and fabrics. The parameters obtained from linear combinations of the calculated spectra were used to perform discrimination analyses and to determine the sensitivity and selectivity of HEs with respect to the substrates and to each other. However, discrimination analysis was not necessary to achieve successful detection of HEs on cotton fabric substrates. The RDX signals ( mRDX > 0.02 mg) on cotton were used to calculate the limit of detection (LOD). The signal-to-noise ratios (S/N) calculated from the spectra of cotton dosed with decreasing masses of RDX until S/N ~ 3 resulted in a LOD of 15 33 ug, depending on the vibrational band used. Linear fits generated by comparing the mass dosed RDX with the fraction predicted were also used to calculate the LOD based on the uncertainty of the blank and the slope. This procedure resulted in a LOD of 58 ug. Probably the most representative value of the method LOD was calculated using an interpolation of a threshold determined using the predicted average value for the blank plus 3.28 times the standard deviations ( p-value threshold) for low surface dosages of RDX (LOD = 40 ug). The contribution demonstrates that to achieve HE detection on fabrics using the proposed algorithm, i.e., determining the presence/absence of HEs on the substrates, the library must contain the spectra of HEs, substrates, and potential interferents or that these spectra be added to the models in the field. If the model does not contain the spectra of the fabric components, there is a high probability of finding false positives for clean samples (no HEs) and a low probability for failed detection in samples with HEs. More work will be required to demonstrate that these new approaches to HE detection work on real-world samples and when contaminating materials are present in the samples. PMID- 29767537 TI - Response to Cookstove Trials and Tribulations: What Is Needed to Decrease the Burden of Household Air Pollution? PMID- 29767538 TI - Is relational medicine the key to providing truly personalized high-tech modern medicine? PMID- 29767539 TI - 10 years of personalizing medicine: how the incorporation of genomic information is changing practice and policy. PMID- 29767540 TI - Clinical players and healthcare payers: aligning perspectives on the cost effectiveness of next-generation sequencing in oncology. PMID- 29767541 TI - Factors affecting the adoption and use of gene expression profiling by oncologists in clinical practice. AB - AIM: In this study, we evaluated the association between oncologists' perceptions of and attitudes toward one frequently used gene expression profiling assays, the Oncotype DX(r) and oncologists' intention to use this assay in making treatment recommendations for breast cancer patients. METHODS: A nationally representative sample of breast cancer oncologists was surveyed using an adapted technology acceptance model. RESULTS: The survey response rate was 44.1%. The test characteristics 'validity of the test' (p = 0.006) and 'use of Oncotype DX by fellow oncologists' (p = 0.0068) were significantly associated with use of the assay by oncologists. Oncologists' intention to use Oncotype DX increased consistently with their perceptions about its usefulness (beta = 0.222). Insurance status of the patients was also significantly associated with physicians' use of Oncotype DX (p = 0.008). CONCLUSION: We report a novel application of an adapted technology acceptance model to understand the adoption of gene expression profiling by oncologists who treat breast cancer patients in making treatment recommendations. PMID- 29767542 TI - Optimal left ventricular lead placement for cardiac resynchronization therapy in postmyocardial infarction patients. AB - AIM: To evaluate at a 12-month follow-up, the clinical and echocardiographic outcomes in postmyocardial infarction (MI) heart failure patients who underwent cardiac resynchronization therapy (CRT) device implantation. MATERIALS & METHODS: A total of 100 patients received a CRT device, and the study population was divided into three groups, according to the site of MI and left ventricular (LV) lead placed downstream of the ischemic area, as evaluated by echocardiography. RESULTS: At the end of the 12-month follow-up, we reported a general improvement of LV ejection fraction from 28 +/- 7% to 35 +/- 9% (p < 0.001) and a significant reverse remodeling: LV end-systolic volume changed from 147 +/- 54 to 125 +/- 63 (p = 0.001) with a 53% of echocardiographic responders. We also observed 67% of CRT responders in the group with optimal LV lead placement compared with 38% in the remaining population (p = 0.01). CONCLUSION: The optimal positioning of LV lead is a feasible method to improve the percentage of CRT responders in post-MI heart failure patients. PMID- 29767544 TI - The 'aerobic/resistance/inspiratory muscle training hypothesis in heart failure'. AB - Evidence from large multicentre exercise intervention trials in heart failure patients, investigating both moderate continuous aerobic training and high intensity interval training, indicates that the 'creme de la creme' exercise programme for this population remains to be found. The 'aerobic/resistance/inspiratory (ARIS) muscle training hypothesis in heart failure' is introduced, suggesting that combined ARIS muscle training may result in maximal exercise pathophysiological and functional benefits in heart failure patients. The hypothesis is based on the decoding of the 'skeletal muscle hypothesis in heart failure' and on revision of experimental evidence to date showing that exercise and functional intolerance in heart failure patients are associated not only with reduced muscle endurance, indication for aerobic training (AT), but also with reduced muscle strength and decreased inspiratory muscle function contributing to weakness, dyspnoea, fatigue and low aerobic capacity, forming the grounds for the addition of both resistance training (RT) and inspiratory muscle training (IMT) to AT. The hypothesis will be tested by comparing all potential exercise combinations, ARIS, AT/RT, AT/IMT, AT, evaluating both functional and cardiac indices in a large sample of heart failure patients of New York Heart Association class II-III and left ventricular ejection fraction <=35% ad hoc by the multicentre randomized clinical trial, Aerobic Resistance, InSpiratory Training OutcomeS in Heart Failure (ARISTOS-HF trial). PMID- 29767543 TI - Efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide in the treatment of HIV-1. AB - INTRODUCTION: HIV eradication is not feasible and lifelong treatment is warranted to manage HIV infection. In this scenario, the advent of single-tablet, once daily, fixed-dose co-formulations is important for reducing pill burden and maximize long-term drug adherence. Cobicistat-boosted darunavir along with emtricitabine and tenofovir alafenamide co-formulation (DRV/c/FTC/TAF or the trade name Symtuza(r)) is the first marketed protease inhibitor-based fixed-dose combination regimen for the treatment of HIV infection. It was approved in late 2017 by the European Medical Agency both for naive patients and treatment experienced patients with viral suppression. Areas covered: PubMed, ClinicalTrials.gov and presentations at scientific meetings were searched with the terms 'darunavir/cobicistat' and 'tenofovir alafenamide and emtricitabine' for clinical trials either conducted to date or ongoing as well as a review of abstracts from major HIV/AIDS and infectious diseases conferences from 2015 to up to date. Expert opinion: DRV/c/FTC/TAF is a novel unique antiretroviral drug co formulation that exhibits a convenient dosing, satisfactory safety profile, and high antiviral efficacy, even in patients harboring viruses with resistance to antivirals other than darunavir in the short-midterm. It represents the first fixed-dose combination therapy including a protease inhibitor given as one single pill once daily for drug-naive patients and as second-line antiretroviral therapy. PMID- 29767545 TI - Pharmacogenetics of novel oral anticoagulants: a review of identified gene variants & future perspectives. AB - Novel oral anticoagulants (NOACs) are becoming a therapy of choice in everyday clinical practice after almost 50 years during which warfarin and related coumarin derivatives were used as the main anticoagulants. Advantages of NOACs over standard anticoagulants include their predictable pharmacodynamics and pharmacokinetics, stable plasma concentrations and less drug-drug and food-drug interactions. However, pharmacogenetics has its place in administration of NOACs, as considerable interindividual variations have been detected. In this review, previous findings in pharmacogenetics of dabigatran, rivaroxaban, apixaban and edoxaban are summarized, along with recommendations for studying genes encoding metabolically important enzymes for four selected NOACs. Future directions include identification of clinically relevant SNPs, and change in optimum dosage for patients who are carriers of significant variants. PMID- 29767546 TI - Examining courses of sleep quality and sleepiness in full 2 weeks on/2 weeks off offshore day shift rotations. AB - To better understand sleep quality and sleepiness problems offshore, we examined courses of sleep quality and sleepiness in full 2-weeks on/2-weeks off offshore day shift rotations by comparing pre-offshore (1 week), offshore (2 weeks) and post-offshore (1 week) work periods. A longitudinal observational study was conducted among N=42 offshore workers. Sleep quality was measured subjectively with two daily questions and objectively with actigraphy, measuring: time in bed (TIB), total sleep time (TST), sleep latency (SL) and sleep efficiency percentage (SE%). Sleepiness was measured twice a day (morning and evening) with the Karolinska Sleepiness Scale. Changes in sleep and sleepiness parameters during the pre/post and offshore work periods were investigated using (generalized) linear mixed models. In the pre-offshore work period, courses of SE% significantly decreased (p=.038). During offshore work periods, the courses of evening sleepiness scores significantly increased (p<.001) and significantly decreased during post-offshore work periods (p=.004). During offshore work periods, TIB (p<.001) and TST (p<.001) were significantly shorter, SE% was significantly higher (p=.002), perceived sleep quality was significantly lower (p<.001) and level of rest after wake was significantly worse (p<.001) than during the pre- and post-offshore work periods. Morning sleepiness was significantly higher during offshore work periods (p=.015) and evening sleepiness was significantly higher in the post-offshore work period (p=.005) compared to the other periods. No significant changes in SL were observed. Courses of sleep quality and sleepiness parameters significantly changed during full 2-weeks on/2 weeks off offshore day shift rotation periods. These changes should be considered in offshore fatigue risk management programmes. PMID- 29767547 TI - Prehospital fibrinolysis followed by urgent percutaneous coronary intervention after ST-elevation myocardial infarction. PMID- 29767548 TI - Disruption of Chloroplast Function Through Downregulation of Phytoene Desaturase Enhances the Systemic Accumulation of an Aphid-Borne, Phloem-Restricted Virus. AB - Chloroplasts play a central role in pathogen defense in plants. However, most studies explaining the relationship between pathogens and chloroplasts have focused on pathogens that infect mesophyll cells. In contrast, the family Luteoviridae includes RNA viruses that replicate and traffic exclusively in the phloem. Recently, our lab has shown that Potato leafroll virus (PLRV), the type species in the genus Polerovirus, forms an extensive interaction network with chloroplast-localized proteins that is partially dependent on the PLRV capsid readthrough domain (RTD). In this study, we used virus-induced gene silencing to disrupt chloroplast function and assess the effects on PLRV accumulation in two host species. Silencing of phytoene desaturase (PDS), a key enzyme in carotenoid, chlorophyll, and gibberellic acid (GA) biosynthesis, resulted in a substantial increase in the systemic accumulation of PLRV. This increased accumulation was attenuated when plants were infected with a viral mutant that does not express the RTD. Application of GA partially suppressed the increase in virus accumulation in PDS-silenced plants, suggesting that GA signaling also plays a role in limiting PLRV infection. In addition, the fecundity of the aphid vector of PLRV was increased when fed on PDS-silenced plants relative to PLRV-infected plants. PMID- 29767549 TI - A Confounding Effect of Bacterial Titer in a Type III Delivery-Based Assay of Eukaryotic Effector Function. AB - This letter describes a newly discovered confounding effect of bacterial titer in a previously published type III delivery-based assay of the fungal effector BEC1019. The original publication (Whigham et al. 2015) has been retracted as a consequence of this discovery. Here, we tabulate the affected and unaffected figures and conclusions in the original publication and briefly reflect on potential pitfalls to bear in mind when designing experiments that use bacterial type III secretion to characterize eukaryotic effectors. PMID- 29767550 TI - Effectiveness of adjunct psychotherapy for cancer treatment: a review. AB - Psychotherapies were offered to alleviate psychological and physical symptoms; however, most psychological interventions were only delivered after cancer treatment. Newly diagnosed cancer patients experienced psychological distress while waiting for treatments. This review paper focused on randomized control trial studies, aimed to investigate the effectiveness of psychological intervention among newly diagnosed cancer patients. Eight randomized control trial papers were found in recent 10 year period through electronic database. A moderate to large effect size was detected on the outcomes, ranging from 0.43 to 0.89. This indicated that psychological-based prehabilitation with standard care yielded better outcomes than standard care alone. Psychological-based prehabilitation provides evidence in its effectiveness to reduce psychological distress, functional impairment, recurrence of cancer, numbers of immune reactivity and sleeping quality; however, inconsistent with longer survival result among cancer patients. In conclusion, psychological-based prehabilitation before cancer treatment is necessary for better treatment outcome, and future research is needed to investigate more directly the outcome. PMID- 29767551 TI - Moving beyond the genome with computer modeling. PMID- 29767553 TI - Mating System in the Brown Rot Pathogens Monilinia fructicola, M. laxa, and M. fructigena. AB - Monilinia fructicola, M. laxa, and M. fructigena are the most important pathogens responsible for brown rot disease of stone and pome fruits. Information on their mating system and sexual behavior is scant. A mating-type-specific PCR-based assay was developed and applied to 155 Monilinia isolates from 10 countries and 10 different host plants. We showed that single isolates carry only one of two opposite idiomorphs at the MAT1 locus consistent with a heterothallic mating system for all three species. MAT1-1 and MAT1-2 mating types were detected in similar proportions in samples of isolates of each species and hence there do not appear to be genetic obstacles to the occurrence of sexual reproduction in their populations. Inter simple sequence repeat markers suggested that asexual reproduction is prevalent, but that sexual recombination occurs in M. fructicola populations in Italy. The genetic architectures of the MAT1 loci of the three pathogens were analyzed. MAT1-1 and MAT1-2 idiomorphs are flanked upstream and downstream by the APN2 and SLA2 genes and resemble those of Botrytis cinerea and other heterothallic fungi in the family Sclerotiniaceae. Each idiomorph contains a specific couple of genes, MAT1-1-1 (with alpha-box domain) and MAT1-1-5 in MAT1 1, and MAT1-2-1 (with HMG-box domain) and MAT1-2-10 in MAT1-2. Small gene fragments (dMAT1-1-1 and dMAT1-2-1) from the opposite idiomorph were detected close to their flanking regions. Constitutive expression of the four MAT1 genes during vegetative growth was ascertained by transcriptomic analysis (RNA-Seq). Antisense transcription of the MAT1-1-1 and MAT1-2-1 genes and intergenic transcribed regions of the MAT1 locus were detected. These results represent new insights into the mating systems of these three economically-important pathogens which could contribute to improve the knowledge on their population biology. PMID- 29767554 TI - A New Resistance Gene in Combination with Rmg8 Confers Strong Resistance Against Triticum Isolates of Pyricularia oryzae in a Common Wheat Landrace. AB - The wheat blast fungus (Triticum pathotype of Pyricularia oryzae) first arose in Brazil in 1985 and has recently spread to Asia. Resistance genes against this new pathogen are very rare in common wheat populations. We screened 520 local landraces of common wheat collected worldwide with Br48, a Triticum isolate collected in Brazil, and found a highly resistant, unique accession, GR119. When F2 seedlings derived from a cross between GR119 and Chinese Spring (CS, susceptible control) were inoculated with Br48, resistant and susceptible seedlings segregated in a 15:1 ratio, suggesting that GR119 carries two resistance genes. When the F2 seedlings were inoculated with Br48DeltaA8 carrying a disrupted allele of AVR-Rmg8 (an avirulence gene corresponding to a previously reported resistance gene, Rmg8), however, the segregation fitted a 3:1 ratio. These results suggest that one of the two genes in GR119 was Rmg8. The other, new gene was tentatively designated as RmgGR119. GR119 was highly resistant to all Triticum isolates tested. Spikes of GR119 were highly resistant to Br48, moderately resistant to Br48DeltaA8 and a hybrid culture carrying avr-Rmg8 (nonfunctional allele), and highly resistant to its transformant carrying AVR Rmg8. The strong resistance of GR119 was attributed to the combined effects of Rmg8 and RmgGR119. PMID- 29767552 TI - RAVL1 Activates Brassinosteroids and Ethylene Signaling to Modulate Response to Sheath Blight Disease in Rice. AB - Rhizoctonia solani causes sheath blight disease in rice; however, the defense mechanism of rice plants against R. solani remains elusive. To analyze the roles of brassinosteroid (BR) and ethylene signaling on rice defense to R. solani, wild type (WT) rice and several mutants and overexpressing (OX) lines were inoculated with R. solani. Mutants d61-1 and d2 were less susceptible to sheath blight disease, bri1-D was more susceptible, and ravl1 and d61-1/EIL1 Ri5 were similarly susceptible compared with WT. The double mutant ravl1/d61-1 was phenotypically similar to the ravl1 mutant. Transcriptome analysis, chromatin immunoprecipitation assay, electrophoretic mobility shift assay, and transient assays indicted that RAVL1 might directly activate Ethylene insensitive 3-like 1 (EIL1), a master regulator of ethylene signaling. Mutants ers1 and d61-1/RAVL1 OX were resistant to sheath blight disease, whereas EIL1 RNAi mutants and RAVL1 OX were more susceptible than WT. BRI1 and D2 expression in EIL1 Ri5/RAVL1 OX and EIL1 expression in d61-1/RAVL1 OX indicated that RAVL1 activates BRI1/D2 and EIL1, respectively, independent of BR and ethylene signaling. Our analyses provide information on how BR and ethylene signaling regulate sheath blight disease and on the regulatory function of RAVL1 in rice sheath blight disease. PMID- 29767556 TI - Hydronephrosis is associated with elevated plasmin in urine in pediatric patients and rats and changes in NCC and gamma-ENaC abundance in rat kidney. AB - Obstruction of urine flow at the level of the pelvo-ureteric junction (UPJO) and subsequent development of hydronephrosis is one of the most common congenital renal malformations. UPJO is associated with development of salt-sensitive hypertension, which is set by the obstructed kidney, and with a stimulated renin angiotensin-aldosterone system (RAAS) in rodent models. This study aimed at investigating the hypothesis that 1) in pediatric patients with UPJO the RAAS is activated before surgical relief of the obstruction; 2) in rats with UPJO the RAAS activation is reflected by increased abundance of renal aldosterone stimulated Na transporters; and 3) the injured UPJO kidney allows aberrant filtration of plasminogen, leading to proteolytic activation of the epithelial Na channel gamma-subunit (gamma-ENaC). Hydronephrosis resulting from UPJO in pediatric patients and rats was associated with increased urinary plasminogen-to creatinine ratio. In pediatric patients, plasma renin, angiotensin II, urine and plasma aldosterone, and urine soluble prorenin receptor did not differ significantly before or after surgery, or compared with controls. Increased plasmin-to-plasminogen ratio was seen in UPJO rats. Intact gamma-ENaC abundance was not changed in UPJO kidney, whereas low-molecular cleavage product abundance increased. The Na-Cl cotransporter displayed significantly lower abundance in the UPJO kidney compared with the nonobstructed contralateral kidney. The Na-K-ATPase alpha-subunit was unaltered. Treatment with an angiotensin-converting enzyme inhibitor (8 days, captopril) significantly lowered blood pressure in UPJO rats. It is concluded that the RAAS contributes to hypertension following partial obstruction of urine flow at the pelvo-ureteric junction with potential contribution from proteolytic activation of ENaC. PMID- 29767555 TI - Protective effect of the BET protein inhibitor JQ1 in cisplatin-induced nephrotoxicity. AB - As a potent chemotherapy drug, cisplatin is also notorious for its side-effects including nephrotoxicity in kidneys, presenting a pressing need to identify renoprotective agents. Cisplatin nephrotoxicity involves epigenetic regulations, including changes in histone acetylation. Bromodomain and extraterminal (BET) proteins are "readers" of the epigenetic code of histone acetylation. Here, we investigated the potential renoprotective effects of JQ1, a small molecule inhibitor of BET proteins. We show that JQ1 significantly ameliorated cisplatin induced nephrotoxicity in mice as indicated by the measurements of kidney function, histopathology, and renal tubular apoptosis. JQ1 also partially prevented the body weight loss during cisplatin treatment in mice. Consistently, JQ1 inhibited cisplatin-induced apoptosis in renal proximal tubular cells. Mechanistically, JQ1 suppressed cisplatin-induced phosphorylation or activation of p53 and Chk2, key events in DNA damage response. JQ1 also attenuated cisplatin induced MAP kinase (p38, ERK1/2, and JNK) activation. In addition, JQ1 enhanced the expression of antioxidant genes including nuclear factor erythroid 2-related factor 2 and heme oxygenase-1, while diminishing the expression of the nitrosative protein inducible nitric oxide synthase. JQ1 did not suppress cisplatin-induced apoptosis in A549 nonsmall cell lung cancer cells and AGS gastric cancer cells. These results suggest that JQ1 may protect against cisplatin nephrotoxicity by suppressing DNA damage response, p53, MAP kinases, and oxidative/nitrosative stress pathways. PMID- 29767557 TI - Polycystin-1 dysfunction impairs electrolyte and water handling in a renal precystic mouse model for ADPKD. AB - The PKD1 gene encodes polycystin-1 (PC1), a mechanosensor triggering intracellular responses upon urinary flow sensing in kidney tubular cells. Mutations in PKD1 lead to autosomal dominant polycystic kidney disease (ADPKD). The involvement of PC1 in renal electrolyte handling remains unknown since renal electrolyte physiology in ADPKD patients has only been characterized in cystic ADPKD. We thus studied the renal electrolyte handling in inducible kidney specific Pkd1 knockout (iKsp- Pkd1-/-) mice manifesting a precystic phenotype. Serum and urinary electrolyte determinations indicated that iKsp- Pkd1-/- mice display reduced serum levels of magnesium (Mg2+), calcium (Ca2+), sodium (Na+), and phosphate (Pi) compared with control ( Pkd1+/+) mice and renal Mg2+, Ca2+, and Pi wasting. In agreement with these electrolyte disturbances, downregulation of key genes for electrolyte reabsorption in the thick ascending limb of Henle's loop (TA;, Cldn16, Kcnj1, and Slc12a1), distal convoluted tubule (DCT; Trpm6 and Slc12a3) and connecting tubule (CNT; Calb1, Slc8a1, and Atp2b4) was observed in kidneys of iKsp- Pkd1-/- mice compared with controls. Similarly, decreased renal gene expression of markers for TAL ( Umod) and DCT ( Pvalb) was observed in iKsp- Pkd1-/- mice. Conversely, mRNA expression levels in kidney of genes encoding solute and water transporters in the proximal tubule ( Abcg2 and Slc34a1) and collecting duct ( Aqp2, Scnn1a, and Scnn1b) remained comparable between control and iKsp- Pkd1-/- mice, although a water reabsorption defect was observed in iKsp Pkd1-/- mice. In conclusion, our data indicate that PC1 is involved in renal Mg2+, Ca2+, and water handling and its dysfunction, resulting in a systemic electrolyte imbalance characterized by low serum electrolyte concentrations. PMID- 29767558 TI - Molecular basis of the counteraction by calcium channel blockers of cyclosporine nephrotoxicity. AB - Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg.kg-1.day-1 ip), verapamil (2 mg.kg-1.day-1 ip), nifedipine (3 mg.kg-1.day 1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-beta1 expression), and inflammatory (NF-kappaB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA induced nephrotoxicity and predisposing biochemical and molecular machineries. PMID- 29767560 TI - Acknowledgment of Members of Health Education & Behavior's Review Panel. PMID- 29767561 TI - The New HE&B Editorial Team. PMID- 29767559 TI - G protein pathway suppressor 2 enhanced the renal large-conductance Ca2+ activated potassium channel expression via inhibiting ERK1/2 signaling pathway. AB - G protein pathway suppressor 2 (GPS2) is a multifunctional protein and transcriptional regulation factor that is involved in the G protein MAPK signaling pathway. It has been shown that the MAPK signaling pathway plays an important role in the regulation of renal large-conductance Ca2+-activated potassium (BK) channels. In this study, we investigated the effects of GPS2 on BK channel activity and protein expression. In human embryonic kidney (HEK) BK stably expressing cells transfected with either GPS2 or its vector control, a single-cell recording showed that GPS2 significantly increased BK channel activity ( NPo), increasing BK open probability ( Po), and channel number ( N) compared with the control. In Cos-7 cells and HEK 293 T cells, GPS2 overexpression significantly enhanced the total protein expression of BK in a dose-dependent manner. Knockdown of GPS2 expression significantly decreased BK protein expression, while increasing ERK1/2 phosphorylation. Knockdown of ERK1/2 expression reversed the GPS2 siRNA-mediated inhibition of BK protein expression in Cos-7 cells. Pretreatments of Cos-7 cells with either the lysosomal inhibitor bafilomycin A1 or the proteasomal inhibitor MG132 partially reversed the inhibitory effects of GPS2 siRNA on BK protein expression. In addition, feeding a high-potassium diet significantly increased both GPS2 and BK protein abundance in mice. These data suggest that GPS2 enhances BK channel activity and its protein expression by reducing ERK1/2 signaling-mediated degradation of the channel. PMID- 29767562 TI - Lawrence W. Green Paper of the Year Award. PMID- 29767565 TI - Medical management of deep ulcerative keratitis in cats: 13 cases. AB - Case series summary Described are 13 cats diagnosed with deep ulcerative keratitis and successfully managed medically without grafting procedures. Typical treatment involved frequent topical application of serum and antibiotics (usually a fluoroquinolone and a cephalosporin). Seven cats also received systemic antibiotics. Analgesia was achieved using various combinations of topical atropine and systemic buprenorphine, robenacoxib or corticosteroids. Six cats were hospitalized for a median (range) period of 2.5 (1-8) days, typically because of frequent medication administration. Median (range) follow-up time was 41.5 (9-103) days. Median (range) number of recheck examinations was 4 (2-6). Median (range) time to corneal re-epithelialization was 21 (9-103) days. Median (range) topical antibiotic course was 29.5 (16-103) days. Median (range) duration of Elizabethan collar use was 28 (13-73) days. At the time of writing, no further recheck examinations were recommended for 10 cats; median (range) time between initial to final examinations in these cats was 35 (20-103) days. All cats retained the affected globes and were apparently comfortable and visual at the latest recheck examination. Relevance and novel information These cases reveal that aggressive medical management is highly successful in select cats with deep ulcerative keratitis, and can result in a cosmetically acceptable, apparently comfortable and visual globe. However, therapy is intensive with frequent administration of multiple topical and sometimes systemic medications, and requires multiple veterinary visits over many weeks. Referral to a veterinary ophthalmologist for consideration of surgical stabilization is recommended, as not all cases may be amenable to the medical therapy described here. PMID- 29767564 TI - Interorgan Metabolic Crosstalk in Human Insulin Resistance. AB - Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue. PMID- 29767566 TI - External beam radiotherapy for the treatment of feline salivary gland carcinoma: six new cases and a review of the literature. AB - Case series summary Salivary gland carcinoma is uncommon in cats. We report the outcome of radiation therapy in six cases (four salivary gland adenocarcinomas, one tubulopapillary adenocarcinoma, one carcinoma). Five were treated after surgical excision of the primary tumour, but four had gross disease (primary or metastatic) at the time of starting radiotherapy. Exact progression-free interval from the start of radiotherapy in the two cats where this was known was 120 and 144 days, respectively. One cat was signed off at 766 days with no evidence of recurrence. Another cat was in remission at 202 days (when last seen by the referring practice) but subsequently developed recurrence (date uncertain). Survival time was known for three cats (55 days, 258 days and 570 days from initiation of radiotherapy, respectively). In two cases, locoregional progressive disease (PD) was confirmed, and the other presumed as the cause of death. Two cats, known to have developed PD, were alive at the time of writing (at 206 and 549 days, respectively). No cat died as a result of distant metastatic disease. Relevance and novel information There is a paucity of information on the treatment of salivary gland tumours. In humans, as in cats, there is no optimised standard of care for malignant tumours. It is accepted that, for surgical candidates (even with large tumours), surgery and radiotherapy is superior to radiotherapy alone. However, the benefits of postoperative radiotherapy compared with surgery alone are only clear in patients with high-risk tumours (ie, those with large and invasive primary tumours, close or incomplete margins, high histopathological grade, histological evidence of neural or vascular invasion, or positive lymph nodes). This population is analogous to the population reported here, and likely to most cats presented in practice. Thus, radiation therapy may help improve locoregional control and survival in cats. PMID- 29767567 TI - Impact of NTRK2, DRD2 and ACE polymorphisms on prolactin levels in antipsychotic treated patients with first-episode psychosis. AB - BACKGROUND: Hyperprolactinemia is a common side-effect of antipsychotics (APs), which may trigger serious secondary problems and compromise the adherence to treatment which is crucial for prognosis, especially in patients presenting with a first-episode of psychosis (FEP). AIMS: We evaluated, in some cases for the first time, the effect of polymorphisms in multiple candidate genes on serum prolactin (PRL) levels in an AP-treated FEP cohort recruited in the multicenter PEPs study (Phenotype - genotype and environmental interaction; Application of a predictive model in first psychotic episodes). METHODS: PRL concentration was measured in serum from 222 patients. A total of 167 polymorphisms were selected in 23 genes. Genetic association analysis was performed in the whole sample and also in homogenous subgroups of patients treated with APs with a high (N = 101) or low risk (N = 95) of increasing PRL release, which showed significant differences in their PRL levels. RESULTS: After Bonferroni correction, polymorphisms in NTRK2, DRD2 and ACE genes were associated with PRL concentration. CONCLUSION: Our results give more support to the impact of DRD2, but also of other genes related to dopamine availability such as ACE. Moreover, this study provides the first evidence for the involvement of NTRK2, which suggests that pathways other than the ones related to dopamine or serotonin may participate in the AP-related PRL levels. PMID- 29767569 TI - Teaching Tip: Development of Veterinary Anesthesia Simulations for Pre-Clinical Training: Design, Implementation, and Evaluation Based on Student Perspectives. AB - Anesthesia simulations have been used in pre-clinical medical training for decades to help learners gain confidence and expertise in an operating room environment without danger to a live patient. The authors describe a veterinary anesthesia simulation environment (VASE) with anesthesia scenarios developed to provide a re-creation of a veterinarian's task environment while performing anesthesia. The VASE uses advanced computer technology with simulator inputs provided from standard monitoring equipment in common use during veterinary anesthesia and a commercial canine training mannequin that allows intubation, ventilation, and venous access. The simulation outputs are determined by a script that outlines routine anesthesia scenarios and describes the consequences of students' hands-on actions and interventions during preestablished anesthetic tasks and critical incidents. Patients' monitored physiologic parameters may be changed according to predetermined learner events and students' interventions to provide immediate learner feedback and clinical realism. A total of 96 students from the pre-clinical anesthesia course participated in the simulations and the pre- and post-simulation surveys evaluating students' perspectives. Results of the surveys and comparisons of overall categorical cumulative responses in the pre- and post-simulation surveys indicated improvement in learners' perceived preparedness and confidence as a result of the simulated anesthesia experience, with significant improvement in the strongly agree, moderately agree, and agree categories (p<.05 at a 95% CI). These results suggest that anesthesia simulations in the VASE may complement traditional teaching methods through experiential learning and may help foster classroom-to-clinic transference of knowledge and skills without harm to an animal. PMID- 29767570 TI - On Teaching Biomedical Science to Undergraduates. PMID- 29767568 TI - The Relationship between Intuitive Action Choices and Moral Reasoning on Animal Ethics Issues in Students of Veterinary Medicine and Other Relevant Professions. AB - With growing understanding of animals' capabilities, and public and organizational pressures to improve animal welfare, moral action by veterinarians and other relevant professionals to address animal issues is increasingly important. Little is known about how their action choices relate to their moral reasoning on animal ethics issues. A moral judgment measure, the VetDIT, with three animal and three non-animal scenarios, was used to investigate the action choices of 619 students in five animal- and two non-animal-related professional programs in one Australian university, and how these related to their moral reasoning based on Personal Interest (PI), Maintaining Norms (MN), or Universal Principles (UP) schemas. Action choices showed significant relationships to PI, MN, and UP questions, and these varied across program groups. Having a previous degree or more experience with farm animals had a negative relationship, and experience with horses or companion animals a positive relationship, with intuitive action choices favoring life and bodily integrity of animals. This study helps to explain the complex relationship between intuitive moral action choices and moral reasoning on animal ethics issues. As a useful research and educational tool for understanding this relationship, the VetDIT can enhance ethical decision making. PMID- 29767572 TI - The Personal and Professional Experiences of Integrative Nurse Coach Certificate Program Graduates: A Pilot Study. PMID- 29767571 TI - Student Perceptions of Veterinary Anatomy Practical Classes: A Longitudinal Study. AB - Using cadaveric material to teach veterinary students poses many challenges. However, little research exists on the contribution of this traditional approach to student learning. This longitudinal study aimed to investigate student perceptions of cadaver-based anatomy classes in a vertically integrated veterinary curriculum at the University of Nottingham's School of Veterinary Medicine and Science. Likert-scale statements and free-text boxes were used in a questionnaire distributed to second-year veterinary students (response rate 59%, 61/103). The same questionnaire was subsequently distributed to the same cohort 2 years later, in the students' fourth year of study (response rate 68%, 67/98). Students agreed that cadaver-based activities aid their learning, and they particularly value opportunities to develop practical skills while learning anatomy. There are few changes in perception as undergraduates progress to clinical years of teaching. Students perceive anatomy to be important, and feel that their learning has prepared them for clinical placements. This study emphasizes the importance of using cadaveric materials effectively in anatomy teaching and, in particular, using clinical skills training to enhance the anatomy curriculum. PMID- 29767574 TI - Right ventricular stroke work correlates with outcomes in pediatric pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR). Optimizing treatment strategies and timing for transplant remains challenging. Thus, a quantitative measure to predict disease progression would be greatly beneficial in treatment planning. We devised a novel method to assess right ventricular (RV) stroke work (RVSW) as a potential biomarker of the failing heart that correlates with clinical worsening. Pediatric patients with idiopathic PAH or PAH secondary to congenital heart disease who had serial, temporally matched cardiac catheterization and magnetic resonance imaging (MRI) data were included. RV and PA hemodynamics were numerically determined by using a lumped parameter (circuit analogy) model to create pressure-volume (P-V) loops. The model was tuned using optimization techniques to match MRI and catheterization derived RV volumes and pressures for each time point. RVSW was calculated from the corresponding P-V loop and indexed by ejection fraction and body surface area (RVSWEF) to compare across patients. Seventeen patients (8 boys; median age = 9.4 years; age range = 4.4-16.3 years) were enrolled. Nine were clinically stable; the others had clinical worsening between the time of their initial matched studies and their most recent follow-up (mean time = 3.9 years; range = 1.1-8.0 years). RVSWEF and the ratio of pulmonary to systemic resistance (Rp:Rs) values were found to have more significant associations with clinical worsening within one, two, and five years following the measurements, when compared with PVR index (PVRI). A receiver operating characteristic analysis showed RVSWEF outperforms PVRI, Rp:Rs and ejection fraction for predicting clinical worsening. RVSWEF correlates with clinical worsening in pediatric PAH, shows promising results towards predicting adverse outcomes, and may serve as an indicator of future clinical worsening. PMID- 29767573 TI - Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension. AB - Interleukin-6 (IL-6) is a pleotropic cytokine that signals through the membrane bound IL-6 receptor (mIL-6R) to induce anti-inflammatory ("classic-signaling") responses. This cytokine also binds to the soluble IL-6R (sIL-6R) to promote inflammation ("trans-signaling"). mIL-6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL-6R into adjacent tissues to induce trans-signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports show that IL-6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL-6 knockout mice are protected from CH-induced pulmonary hypertension (PH). IL-6 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH-induced PH is associated with increased proliferation and migration of PASMCs to previously non-muscularized vessels of the lung. We tested the hypothesis that IL-6 trans-signaling contributes to CH-induced PH and arterial remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to normoxic control mice (630 mmHg), while sIL-6R levels were unchanged. Consistent with our hypothesis, mice that received the IL-6 trans-signaling-specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant portion of the mouse IgG1 antibody, showed attenuation of CH-induced increases in right ventricular systolic pressure, right ventricular and pulmonary arterial remodeling as compared to vehicle (saline)-treated control mice. In addition, PASMCs cultured in the presence of IL-6 and sIL-6R showed enhanced migration but not proliferation compared to those treated with IL-6 or sIL-6R alone or in the presence of sgp130Fc. These results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell migration and CH-induced PH. PMID- 29767577 TI - The relationship between inertial measurement unit-derived 'force signatures' and ground reaction forces during cricket pace bowling. AB - This study assessed the reliability and validity of segment measured accelerations in comparison to front foot contact (FFC) ground reaction force (GRF) during the delivery stride for cricket pace bowlers. Eleven recreational bowlers completed a 30-delivery bowling spell. Trunk- and tibia-mounted inertial measurement units (IMUs) were used to measure accelerations, converted to force, for comparisons to force plate GRF discrete measures. These measures included peak force, impulse and the continuous force-time curve in the vertical and braking (horizontal) planes. Reliability and validity was determined by intra class correlation coefficients (ICC), coefficient of variation (CV), Bland-Altman plots, paired sample t-tests, Pearson's correlation and one-dimensional (1D) statistical parametrical mapping (SPM). All ICC (0.90-0.98) and CV (4.23-7.41%) were acceptable, except for tibia-mounted IMU braking peak force (CV = 12.44%) and impulse (CV = 18.17%) and trunk vertical impulse (CV = 17.93%). Bland-Altman plots revealed wide limits of agreement between discrete IMU force signatures and force plate GRF. The 1D SPM outlined numerous significant (p < 0.01) differences between trunk- and tibia-located IMU-derived measures and force plate GRF traces in vertical and braking (horizontal) planes. The trunk- and tibia-mounted IMUs appeared to not represent the GRF experienced during pace bowling FFC when compared to a gold-standard force plate. PMID- 29767576 TI - Characteristics and survival data from Latvian pulmonary hypertension registry: comparison of prospective pulmonary hypertension registries in Europe. AB - Patient registries are a valuable tool in the research of rare conditions such as pulmonary hypertension (PH). We report comprehensive hemodynamic and survival data of 174 patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), included in the prospective Latvian PH registry over a period of > 9 years. In total, 130 adult PAH patients (75%) and 44 adult CTEPH patients (25%) were enrolled. The median follow-up period was 33 months for PAH and 18 months for CTEPH, P = 0.001. Latvian CTEPH patients had significantly higher plasma levels of B-type natriuretic peptide, higher pulmonary vascular resistance, and lower cardiac index than Latvian PAH patients. Calculated incidence of PAH and CTEPH in Latvia in 2016 was 13.7 and 5.1 cases per million inhabitants, calculated prevalence was 45.7 and 15.7 cases per million inhabitants, respectively. Survival rates at one, three, and five years for PAH patients was 88.0%, 73.3%, and 58.1%, and 83.8%, 59.0%, and 44.2% for CTEPH patients, respectively. We compared our study results with data from European adult PH registries. Latvian PAH patients had the fourth lowest and CTEPH patients the lowest one-year survival rate among European adult PH registries. As most PH registries in Europe are small, yet with equivalent patient inclusion criteria, it would be desirable to combine these registries to produce more reliable and high-quality study results. PMID- 29767578 TI - 'Death is difficult in any language': A qualitative study of palliative care professionals' experiences when providing end-of-life care to patients from culturally and linguistically diverse backgrounds. AB - BACKGROUND: Ethnic minority patients have unique challenges in accessing health services. These include language difficulties, unfamiliarity with the health system, lower rates of cancer screening and survival, higher rates of reported side effects from cancer treatment and poorer quality of life. Little is known about this patient group when transitioning to palliative care. AIM: To elicit the experiences of palliative care health professionals when providing care for patients from culturally and linguistically diverse backgrounds which differ from mainstream Australian language and culture. DESIGN: An emergent qualitative design, informed by theoretical and procedural direction from grounded theory research. SETTING/PARTICIPANTS: Four focus groups held with palliative care staff ( n = 28) in a single specialist palliative care service in Australia. RESULTS: The following themes emerged: (1) determining the rules of engagement around discussion of diagnosis and prognosis, (2) navigating the challenge of language to patient understanding, (3) understanding migration experiences to establish trust, (4) maintaining the balance between patient safety and comfort care, (5) providing a good death experience through accommodation of beliefs, and (6) navigating the important role of family members while privileging patient preferences. CONCLUSION: Underlying provider perceptions of caring for patients was that death is difficult in any language. Care was conceptualised as considering cultural and linguistic backgrounds within individualistic care. Understanding the migration experience and building trust were key elements of this individualised approach. Acknowledgement of the key role played by families in patient care and safety are strategies to minimise barriers and understand the concerns of this patient group. PMID- 29767575 TI - Dart to the target: an alternative bull's eye parametric display for European Society of Cardiology / European Respiratory Society goal-orientated risk reduction strategy in pulmonary arterial hypertension. AB - Despite the significant mortality and mobidity benefits being obtained with the targeted therapies in patients with pulmonary arterial hypertension (PAH), mid- to long-term survival of patients with this disease has remained unsatisfactory. For earlier and reliable risk stratification in PAH and tailoring the dynamic management strategies, various risk assessment models have been developed. Currently available risk reduction strategy recommended by the European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2015 Pulmonary Hypertension Guidelines has been utilized in three recent registries. In this review, we evaluated the risk prediction models and management algorithms in this setting and propose an alternative parametric display, a bull's eye, dart table scheme for ESC/ERS goal-orientated risk reduction strategy in patients with PAH. PMID- 29767579 TI - Healthcare use, costs and quality of life in patients with end-stage kidney disease receiving conservative management: results from a multi-centre observational study (PACKS). AB - BACKGROUND: Previous research has explored the cost of providing renal replacement therapies in patients with end-stage kidney disease and their quality of life. This is the first study to examine the healthcare costs of patients receiving conservative care without dialysis for end-stage kidney disease. This alternative to dialysis is an option for patients who prefer a supportive and palliative care approach. AIM: Descriptive cost and quality of life analyses alongside a UK-based multi-centre observational study in patients receiving conservative management for end-stage kidney disease. DESIGN: Health service use was recorded up to 12 months after making the decision to receive conservative management. Mean costs were calculated for each 3-month time period. The annual cost was calculated in two ways: by using only patients with complete cost data and by using all available data weighted by the number of patients at each time point. SETTING: In total, 42 patients who opted for conservative management over dialysis were recruited. RESULTS: Mean costs were L1622 (0-3 months), L1008 (3-6 months), L554 (6-9 months) and L2626 (9-12 months). Mean annual cost based on complete data ( n = 8) was L5511, and the weighted mean annual cost was L5620. CONCLUSION: The importance of this study is twofold. First, it provides substantive new information for health and social care planning of conservative management by demonstrating where demand exists for services, in both the United Kingdom and other countries with a comparable health service structure. Second, methodologically, it indicates that it is feasible to collect service use data directly from this patient population. PMID- 29767580 TI - Psychiatry is warming up to personalized medicine 2.0. PMID- 29767581 TI - Lethal hepatotoxicity following 5-fluorouracil/cisplatin chemotherapy: a relevant case report. AB - Some articles have reported severe toxicities induced by cisplatin/5-fluorouracil regimens, nevertheless, severe and lethal liver toxicity has not been previously reported. In this article, we report the case of a 72-year-old woman, who developed fulminant hepatitis, hypoglycemia and hypotension with atrial fibrillation not responding to treatment. After ruling out all other possible causes of hepatitis, the toxicity was more likely attributed to 5-fluorouracil. Genotyping was performed and the patient was found to be a homozygote carrier of the T variant of the MTHFR gene. The patient died two days later. Several factors, including genetic factors, could explain this severe toxicity. The present case discusses the importance of personalized medicine in oncology based on pharmacogenetic analysis of polymorphisms. PMID- 29767582 TI - Direct-to-consumer genetic testing: where and how does genetic counseling fit? AB - Direct-to-consumer genetic testing for disease ranges from well-validated diagnostic and predictive tests to 'research' results conferring increased risks. While being targeted at public curious about their health, they are also marketed for use in reproductive decision-making or management of disease. By virtue of being 'direct-to-consumer' much of this testing bypasses traditional healthcare systems. We argue that direct-to-consumer genetic testing companies should make genetic counseling available, pre- as well as post-test. While we do not advocate that mandatory genetic counseling should gate-keep access to direct-to-consumer genetic testing, if the testing process has the potential to cause psychological distress, then companies have a responsibility to provide support and should not rely on traditional healthcare systems to pick up the pieces. A video abstract is available for this article via this link . PMID- 29767583 TI - Toward health technology assessment of whole-genome sequencing diagnostic tests: challenges and solutions. AB - Whole-genome sequencing (WGS) is being applied within research settings across Europe to develop genomic WGS-based diagnostic tests. The focus of this perspective paper is to describe if, and how, current approaches of health technology assessment could be applied to WGS-based diagnostic tests. This perspective draws on the collective view from a trans-European multidisciplinary consortium of methodologists, clinicians and scientists. Specific challenges can be described by using the PICO (population, intervention, comparator, outcome) framework to inform health technology assessment. Practical solutions are suggested which require joined-up, multidisciplinary working across healthcare systems using existing expert networks so that emergent issues for the health technology assessment of WGS can be met in a timely fashion. PMID- 29767584 TI - Long noncoding RNAs in the pathogenesis of diabetic kidney disease: implications for novel therapeutic strategies. AB - Diabetic kidney disease is a progressive disorder that develops secondary to diabetes. Current strategies for the clinical management of the disease can delay its onset and prevent progression, yet a significant proportion of patients still develop renal failure. The need for more advanced pharmaceuticals is therefore critical for improved treatment strategies. Recent studies support a role for long noncoding RNAs (lncRNAs) in the pathogenesis of human disease. Here we review recent experimental results linking lncRNAs with diabetic kidney disease. A better understanding of the regulatory role that lncRNAs play in the development of diabetic kidney disease may lead to identification of novel targets for therapeutic intervention. PMID- 29767585 TI - Optimization of quality assurance to increase clinical utility and cost effectiveness of hereditary cancer testing. AB - AIM: To evaluate one laboratory's hereditary cancer testing clinical quality assurance (QA) process to minimize test-ordering errors. METHODS: The proportion of tests canceled/revised due to pre-analytic QA processes or provider consultation prior to test ordering were determined and the resulting health cost savings were estimated. RESULTS: Over 2000 genetic test orders were canceled/revised over a 1-year period due to the laboratory QA process, saving US$5,801,832 in healthcare costs. Consultation with healthcare providers prior to submitting genetic test requests resulted in 37 canceled/revised test orders in a 2-week period, which extrapolates to a savings of US$3,049,098 over 1 year. CONCLUSION: QA processes can contribute to the curtailment of healthcare costs through canceling or revising test orders. PMID- 29767587 TI - Avoidable drug-gene conflicts and polypharmacy interactions in patients participating in a personalized medicine program. AB - AIM: Determine the ability of a pharmacogenetic service, PRIMER, to identify drug gene (DGI) and drug-drug interactions (DDI) in patients across multiple conditions. PRIMER consists of patient selection criteria, a gene panel and actionable guidance for DGIs and DDIs. RESULTS: The average patient was prescribed 12 medications. PRIMER identified significant DGIs in 73% of patients tested, with 43% having more than one DGI. DDIs were found in 87% of patients. The most common actionable DGIs were for opioid, psychotropic and cardiovascular medications. CONCLUSION: The pairing of patient selection criteria, a multigene panel with evidence-based interpretation and review of DDIs maximizes the patients tested who have actionable benefit and alerts physicians to potentially critical adjustments needed for the patient's medication regimen. PMID- 29767588 TI - Could food act as personalized medicine for chronic disease? PMID- 29767589 TI - Efficient nonparametric confidence bands for receiver operating-characteristic curves. AB - Receiver operating-characteristic curve is a popular graphical method frequently used in order to study the diagnostic capacity of continuous (bio)markers. In spite of the existence of a huge number of papers devoted to both theoretical and practical aspects of this topic, the construction of confidence bands has had little impact in the specialized literature. As far as the authors know, in the CRAN there are only three R packages providing receiver operating-characteristic curve confidence regions: plotROC, pROC and fbroc. This work tries to fill this gap studying and proposing a new nonparametric method to build confidence bands for both the standard receiver operating-characteristic curve and its generalization for nonmonotone relationships. The behavior of the proposed procedure is studied via Monte Carlo simulations and the methodology is applied on two real-world biomedical problems. In addition, an R function to compute the proposed and some of the previously existing methodologies is provided as online supplementary material. PMID- 29767586 TI - The swinging pendulum of cancer immunotherapy personalization. AB - Cancer immunotherapy has long offered the promise of producing cancer treatments that are more effective and less toxic than traditional chemotherapy and radiotherapy. That potential has only begun to be realized in the last 5 years with the first US FDA-approved cancer vaccine (sipuleucel-T), checkpoint inhibitors and adoptive cell therapy. While these therapies have been remarkably more effective than previous cancer immunotherapeutics, they are often limited by their inherently personalized nature. Indeed, each patient's immune system and cancer are unique, limiting the scalability and generalizability of new approaches. However, emerging solutions may overcome these limitations, producing 'off-the-shelf' cancer immunotherapies that transform patient outcomes. PMID- 29767590 TI - Time-dependent efficacy of longitudinal biomarker for clinical endpoint. AB - Joint modelling of longitudinal biomarker and event-time processes has gained its popularity in recent years as they yield more accurate and precise estimates. Considering this modelling framework, a new methodology for evaluating the time dependent efficacy of a longitudinal biomarker for clinical endpoint is proposed in this article. In particular, the proposed model assesses how well longitudinally repeated measurements of a biomarker over various time periods (0,t) distinguish between individuals who developed the disease by time t and individuals who remain disease-free beyond time t. The receiver operating characteristic curve is used to provide the corresponding efficacy summaries at various t based on the association between longitudinal biomarker trajectory and risk of clinical endpoint prior to each time point. The model also allows detecting the time period over which a biomarker should be monitored for its best discriminatory value. The proposed approach is evaluated through simulation and illustrated on the motivating dataset from a prospective observational study of biomarkers to diagnose the onset of sepsis. PMID- 29767591 TI - Compositional data analysis in epidemiology. AB - Compositional data analysis refers to analyzing relative information, based on ratios between the variables in a data set. Data from epidemiology are usually treated as absolute information in an analysis. We outline the differences in both approaches for univariate and multivariate statistical analyses, using illustrative data sets from Austrian districts. Not only the results of the analyses can differ, but in particular the interpretation differs. It is demonstrated that the compositional data analysis approach leads to new and interesting insights. PMID- 29767592 TI - Sapientia: accelerating rare disease diagnosis and treatment. AB - Congenica (Cambridge, UK) is a world leading developer of genome-based discovery and diagnostic technologies. The UK company is a spin-out from the Wellcome Trust Sanger Institute (Cambridge, UK) and was founded by scientists and clinicians at the leading edge of genomic analysis. Congenica's SapientiaTM technology platform allows whole-genome sequence analysis to be easily interpreted and presented within a clinically actionable diagnostic report. It is based on pioneering research from Wellcome Trust Sanger Institute, National Health Service clinicians and regional genetic testing laboratories and validated by Genomics England Ltd (London, UK). Sapientia used for medical diagnosis in hospitals including Great Ormond Street Hospital (London, UK), Manchester Centre for Genomic Medicine (Manchester, UK), Birmingham Women's Hospital (Birmingham, UK) and for new drug development by pharmaceutical companies. This profile follows the journey from proof of concept to clinical diagnosis. PMID- 29767563 TI - Integrative Physiology of Pneumonia. AB - Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and inflammation is damaging. Intercellular and interorgan signaling networks coordinate these actions to fight infection and protect the tissue. Cells residing in the lung initiate and steer these responses, with additional immunity effectors recruited from the bloodstream. Responses of extrapulmonary tissues, including the liver, bone marrow, and others, are essential to resistance and resilience. Responses in the lung and extrapulmonary organs can also be counterproductive and drive acute and chronic comorbidities after respiratory infection. This review discusses cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lung injury, chronic pulmonary disease, and adverse extrapulmonary sequelae. Pneumonia should no longer be perceived as simply an acute infection of the lung. Pneumonia susceptibility reflects ongoing and poorly understood chronic conditions, and pneumonia results in diverse and often persistent deleterious consequences for multiple physiological systems. PMID- 29767593 TI - EthicsandGenetics: organizational profile. AB - EthicsandGenetics (Glasgow, Scotland) campaigns for openness and inclusion in bioscience policy. Recent developments in UK biosciences policy demonstrate the need for this, illustrated most vividly by the 100,000 Genome Project. PMID- 29767594 TI - Family health history: an essential starting point for personalized risk assessment and disease prevention. AB - Family health history (FHH) information is well established as a basis for assessing a patient's personal disease risk, but is underutilized for diagnosis and making medical recommendations. Epidemiological and genetic information have heightened the value of FHH to an individual's health. This has motivated the development of new FHH collection tools and strategies for family members, but will require greater awareness and knowledge by both patients and practitioners. FHH will be increasingly important as genomic data become a mainstay of medical diagnostics, since in many cases, a medically important FHH results from lineage specific genetic variants. The impact of complementary FHH and genomic information will drive the pursuit of personalized and precise targeting of treatments and interventions aimed at maintaining patient health. PMID- 29767595 TI - Gene polymorphism of CYP2C19*2, *3 and CYP3A4*1B and early stent thrombosis: case reports and literature review. AB - We present two clinical cases of acute and subacute coronary artery stent thrombosis in patients treated at the Department of Interventional Cardiology in Aktobe, Kazakhstan. Our results draw attention to the impact of CYP3A4*1B on the clinical effect of clopidogrel during dual antiplatelet therapy after PCI. The genotyping performed at the Laboratory of Molecular Cardiology of Institute of Cardiology of Lithuanian University of Health Sciences in Lithuania revealed that both patients were homozygous carriers of CYP3A4*1B*1B. They also were carriers of CYP2C19 loss-of-function *2 or *3 alleles (*1*2 and *1*3, respectively). PMID- 29767597 TI - Potential biomarker panels in overall breast cancer management: advancements by multilevel diagnostics. AB - Breast cancer (BC) prevalence has reached an epidemic scale with half a million deaths annually. Current deficits in BC management include predictive and preventive approaches, optimized screening programs, individualized patient profiling, highly sensitive detection technologies for more precise diagnostics and therapy monitoring, individualized prediction and effective treatment of BC metastatic disease. To advance BC management, paradigm shift from delayed to predictive, preventive and personalized medical services is essential. Corresponding step forwards requires innovative multilevel diagnostics procuring specific panels of validated biomarkers. Here, we discuss current instrumental advancements including genomics, proteomics, epigenetics, miRNA, metabolomics, circulating tumor cells and cancer stem cells with a focus on biomarker discovery and multilevel diagnostic panels. A list of the recommended biomarker candidates is provided. PMID- 29767596 TI - Challenges of implementing personalized (precision) medicine: a focus on diabetes. AB - The concept of personalized (precision) medicine (PM) emphasizes the scientific and technological innovations that enable the physician to tailor disease prediction, diagnosis and treatment to the individual patient, based on a personalized data-driven approach. The major challenge for the medical systems is to translate the molecular and genomic advances into clinical available means. Patients and healthcare providers, the pharmaceutical and diagnostic industries manifest a growing interest in PM. Multiple stakeholders need adaptation and re engineering for successful clinical implementation of PM. Drawing primarily from the field of 'diabetes', this article will summarize the main challenges to implementation of PM into current medical practice and some of the approaches currently being implemented to overcome these challenges. PMID- 29767598 TI - Time for paradigm change in management of hepatocellular carcinoma: is a personalized approach on the horizon? AB - Hepatocellular carcinoma (HCC) is the fifth most frequent cancer form but the second leading cause of all cancer-related deaths. There are several reasons for high mortality in the HCC cohort: lack of effective screening programs and consequently late diagnosis, multifactorial origin with cumulative risk factors, complex carcinogenesis, tumor heterogeneity, unpredictable impacts of individual microenvironment on tumor development and progression, and, as the consequence, frequently untargeted therapy and cancer resistance toward currently applied treatment approaches. The currently applied 'treat and wait' approach is inappropriate in the overall HCC management. Urgent need in paradigm change toward predictive, preventive and personalized medicine is discussed in this review article. Innovative strategies for an advanced predictive, preventive and personalized medicine approach in the overall HCC management benefiting the patient are presented. PMID- 29767599 TI - Systems Medicine: hype or revolution? AB - Research and innovation in healthcare can change existing practices aiming at constant improvement of diagnosis, treatment and prevention. As a new holistic approach Systems Medicine (SM) may revolutionize the healthcare system. This paper analyzes ethical and economic obstacles of SMs development from a niche innovation to a standard solution. We adapt a model of innovation theory to structure the barriers of adopting SM to become standard in the medical system. SM has the potential to change the medical system if barriers to this innovation can be overcome. The article discusses the potential of SM in becoming the future health paradigm considering these barriers and provides an overview of the current situation. PMID- 29767600 TI - The evolution of high complexity companion testing for targeted and immuno oncology. PMID- 29767601 TI - Parkinson's disease is ready for precision medicine. PMID- 29767602 TI - Excess stroke incidence in young Aboriginal people in South Australia: Pooled results from two population-based studies. AB - Background Retrospective data indicate increased stroke incidence in Aboriginal/Torres Strait Islander (Indigenous) Australians, possibly with poorer outcomes. We present the first prospective population-based stroke incidence study in Indigenous Australians. Methods We pooled data from ASCEND and SEARCH, two prospective "ideal" South Australian stroke incidence studies, ASCEND conducted in urban Northwestern Adelaide (2009-2010) and SEARCH in five South Australian rural centers (2009-2011). We calculated age-standardized incidence for Aboriginal and non-Aboriginal people. Results The study population comprised 261,403 inhabitants. Among 432 first-ever strokes, 13 were in Aboriginal people (median age 51 vs. 78 years for non-Aboriginal people, p < 0.001). Age standardized stroke incidence per 100,000 in Aboriginal patients (116, 95% CI: 95 137) was nearly two-fold that of non-Aboriginal patients (67, 95% CI: 51-84). Age stratified excess incidence in Aboriginal people was restricted to those aged < 55 years (incidence rate ratio (IRR) 3.5, 95% CI: 2-7), particularly for intracerebral hemorrhage (IRR: 16, 95% CI: 4-61). Conclusion The excess stroke incidence in Aboriginal South Australians appears substantial, especially in those aged <55 years. Further work is required to delineate and address disparities. PMID- 29767603 TI - Genomics ruins a genre. PMID- 29767604 TI - Encouraging physician adoption of genetic testing for precision medicine. PMID- 29767605 TI - Chromosomal microarray in prenatal diagnosis: case studies and clinical challenges. AB - Chromosomal microarray analysis (CMA) is a diagnostic tool used in the evaluation of pediatric patients with congenital anomalies or developmental and intellectual disability. In both the pediatric and prenatal patient population, CMA has been shown to have a higher detection rate of chromosomal abnormalities than conventional karyotype alone. Currently, the diagnostic yield of prenatal CMA is highest when applied to the evaluation of a fetus with multiple ultrasound anomalies. Challenges arise when CMA yields isolated findings not associated with a phenotype on ultrasound or variants of uncertain significance, which warrants evaluation of the risks, benefits, limitations and optimal incorporation of CMA into prenatal care. The clinical cases presented here will be used to illustrate these issues. PMID- 29767606 TI - Detecting rejection in cardiac transplantation: applications of genomic medicine. AB - The primary focus of care in heart transplant recipients is to prevent rejection. Checking serum levels of immunosuppressant drugs as well as performing biopsies to obtain tissue samples for histological analysis have been the mainstays of rejection surveillance. Novel applications of genomics have proven to be useful in adding a noninvasive alternative to the standard of care. In particular, the use of gene-expression profiling to detect upregulation of rejection-related genes, detection of donor-derived cell-free DNA as a marker of graft apoptosis and rejection, as well as mRNA and miRNA as intragraft and peripheral markers of rejection have come to the forefront of genomics as they relate to transplantation. This review focuses on the use of genomics in heart transplant recipients. PMID- 29767607 TI - Patient willingness to undergo efavirenz dose reduction based on pharmacogenetic testing. AB - AIM: Among HIV-infected adults receiving efavirenz fixed-dose combination tablets, genotyping could guide efavirenz dose reduction but would require more pills. METHODS: We assessed willingness to dose reduce among 129 patients at an HIV primary care clinic in the southeastern USA. RESULTS: When told that switching from one pill to two or three pills "might make you feel a little better", 47% expressed definite or possible willingness. This decreased to 9% if there was "a small chance it might not control your HIV as well". Clinical variables were not associated with willingness. CONCLUSION: Many patients receiving a fixed-dose combination tablet may be willing to take more pills in order to dose reduce, guided by genetic testing, but only if virologic control is not compromised. PMID- 29767608 TI - How does biobanking affect the patient-physician relationship? PMID- 29767609 TI - Psychological and behavioral effects of genetic risk testing for obesity: a systematic review. AB - BACKGROUND: Interest is growing in the use of genetic risk testing for lifestyle related chronic diseases, including obesity, to promote health behavior change. OBJECTIVE: A systematic review of the literature was conducted to determine the effects that genetic risk feedback for obesity may have on psychological and behavioral factors influencing weight. METHODS: The MEDLINE/PubMed online database was searched using predefined search terms. RESULTS: The studies revealed that risk feedback may increase motivation to improve health behaviors, especially among individuals at higher genetic risk. Overweight and obese individuals seemed to experience additional psychological benefits when provided an external explanation for their weight status. CONCLUSION: While the psychological benefits are promising, the clinical utility of genetic risk testing for obesity remains uncertain. PMID- 29767610 TI - Detecting novel genes for low-density lipoprotein cholesterol in European population using bioinformatics analysis. AB - AIM: The aim of this study was to identify related genes for low-density lipoprotein cholesterol and evaluate the functional relevance to provide evidences for prioritizing these genes. MATERIALS & METHODS: We performed a gene based association study in about 188,578 individuals. Furthermore, we performed bioinformatics analyses to support the identified genes. RESULTS: A total of 292 genes were found to be significant after Bonferroni correction (p < 2.3 * 10-6). Among these genes, 59 seemed to be associated with coronary artery disease (CAD). CONCLUSION: The evidence obtained from the analyses of this study signified the importance of many genes, for example, LDLR, ABCG5, ABCG8, APOB, HNF1A, PTPN11, APOA5 and MCM6, which were also associated with CAD. The findings might provide more insights into the genetic basis of lipid metabolism and CAD. PMID- 29767612 TI - Can we predict those at higher risk for migraine? PMID- 29767611 TI - Tandem repeats of TSER significantly influence the efficacy of 5-fluorouracil in the treatment of plantar warts. AB - AIM: To identify potential genetic risk markers associated with 5-fluorouracil (5 FU) treatment outcomes in plantar warts patients. METHODS: In this study, 126 plantar warts patients were treated with an intralesional mixture of 5-FU, lidocaine and epinephrine. Treatment outcomes were compared with DNA mutation analysis. RESULTS: More patients with TSER 3R/3R genotype failed 5-FU treatment than TSER 2R/3R+2R/2R (72.1 vs 43.8%; odds ratio: 3.32; 95% CI: 1.26-8.72; p = 0.013). In addition, the regression modeling identified patient age and TSER 3R allele as covariates of the risk of 5-FU treatment failure (p = 0.025). CONCLUSION: TSER 3R/3R of TYMS gene was found to be the major risk of treatment failure. This genetic marker provides a potential treatment stratification target to modulate 5-FU treatment in plantar wart patients. PMID- 29767613 TI - Clinical RNA sequencing in oncology: where are we? PMID- 29767614 TI - Differential attenuation of Marek's disease virus-induced tumours and late Marek's disease virus-induced immunosuppression. AB - Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and a variety of non-neoplastic syndromes in chickens. Furthermore, very virulent plus (vv+) MDVs induce a form of immunosuppression (late-MDV-IS) that might involve both neoplastic and non-neoplastic mechanisms. The objective of this study was to evaluate whether the attenuation of MDV-induced tumours and late-MDV-IS occurs simultaneously or can be dissociated. The immunosuppressive ability of three viruses derived from vv+ MDV strain 686 (wild-type 686, the somewhat attenuated molecular clone 686-BAC, and the nononcogenic molecular clone lacking the two copies of the oncogene meq 686-BACDeltaMEQ) was evaluated. Late-MDV-IS was evaluated indirectly by assessing the negative effect of MDV strains on the protection conferred by infectious laryngotracheitis (ILT) vaccines. Our results showed that the ability to induce late-MDV-IS was attenuated before the ability to induce tumours. Strain 686 induced both tumours and late-MDV-IS, 686-BAC induced tumours but did not induce late-MDV-IS and 686-BACDeltaMEQ did not induce either tumours or late-MDV-IS. Further comparison of strains 686 and 686-BAC revealed that strain 686 reduced the humoral immune responses to ILTV (1132 vs 2167) more severely, showed higher levels of meq transcripts (2.1E+09 vs 4.98E+8) and higher expression of MDV microRNAs (mdv1-miR-M4-5p and mdv1-miR-M2-3p) in the spleen, and further reduced the percentage of CD45+-MHC-I+splenocytes (13 vs32 %) compared to molecular clone 686-BAC. This study suggests that the immunosuppressive ability of MDV might follow a continuous spectrum and only the most virulent MDVs can overcome a certain threshold level and induce clinical MDV IS in the ILT model. PMID- 29767615 TI - Relevance of antifungal penetration in biofilm-associated resistance of Candida albicans and non-albicans Candida species. AB - The role of penetration limitation in Candida biofilm-associated antifungal resistance remains unclear. Most of the previous work has been done on Candida albicans, although non-albicans (NAC) species are also implicated in invasive candidiasis and the biofilm matrix has been shown to vary amongst different species. Only a few studies have evaluated clinical isolates. This study aimed to determine the relevance of penetration limitation in the antifungal resistance of biofilms formed by C. albicans and NAC clinical isolates, using an agar disk diffusion assay. The penetration of posaconazole and amphotericin B through the biofilms was significantly reduced. Fluconazole, voriconazole and caspofungin showed a superior penetration capacity in C. albicans, Candida tropicalis and Candida parapsilosis biofilms, but exhibited inter-species and strain/isolate variation. Candida krusei biofilms were the most resilient to antifungal permeation. All of the antifungal drugs failed to kill the biofilm cells, independent of penetration, suggesting that the other factors contribute markedly to the recalcitrance of the biofilms. PMID- 29767616 TI - Nalidixic acid surrogate test for susceptibility to ciprofloxacin in Salmonella. Revisiting the question. AB - We investigated the reliability of nalidixic acid (NA) susceptibility as a marker of ciprofloxacin susceptibility in Salmonella, analysing 302 stool isolates. NC53 of the MicroScan system was used for NA susceptibility tests and the E-test was used for ciprofloxacin susceptibility tests. Among the isolates, 178 (58.9 %) were serogroup B, 74 (24.5 %) were serogroup D, 27 (8.9 %) were serogroup C and 23 (7.6 %) were from other minor serogroups. Globally, susceptibility to NA correctly predicted the susceptibility of Salmonella to ciprofloxacin, with a sensitivity of 81.5 %, a specificity of 97.6 %, and positive and negative predictive values of 88 and 96 %, respectively. However, there were differences among the serogroups in terms of sensitivity (P<0.001) and positive predictive values (P=0.013). NA is a reliable marker for serogroup D, but not for serogroups B or C. According to these findings, NA susceptibility measured with the MicroScan system can be used as a marker of ciprofloxacin resistance in some serogroups in our setting. PMID- 29767617 TI - Mangrovicoccus ximenensis gen. nov., sp. nov., isolated from mangrove forest sediment. AB - A Gram-strain-negative, coccoid bacterium, lacking bacteriochlorophyll, designated strain T1lg56T, was isolated from a sediment sample collected from Ximen island mangrove forest, Zhejiang province, China. Cells were halotolerant, and catalase- and oxidase-positive. Growth was observed at 18-42 degrees C (optimum, 35 degrees C), at pH 6.0-9.5 (optimum, pH 6.5) and in the presence of 0-15 % (w/v) NaCl (optimum, 2-5 %). The major cellular fatty acids were C18 : 1omega7c and C16 : 0. The polar lipid profile of strain T1lg56T consisted of phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylmonomethylethanolamine, two unidentified phospholipids and five unidentified lipids. Ubiquinone-10 was the predominant respiratory quinone. The assimilation of the substrates in the API 20NE kit was positive in strain T1lg56T. The DNA G+C content of strain T1lg56T was 67.2 mol%. 16S rRNA gene sequence analysis indicated that strain T1lg56T was a member of family Rhodobacteraceae and was closely related to Poseidonocella pacifica KMM 9010T, with 95.7 % similarity to the type strain. Phylogenetic analysis showed that strain T1lg56T formed a separate evolutionary branch, and was parallel to other related genera of Rhodobacteraceae. Its phylogenetic distinctiveness and distinguishing phenotypic characteristics supported that strain T1lg56T represents a novel genus of the family Rhodobacteraceae, for which the name Mangrovicoccus ximenensis gen. nov., sp. nov. is proposed. The type strain is T1lg56T (=CCTCC AB 2016238T=KCTC 52623T). PMID- 29767618 TI - Hymenobacter pedocola sp. nov., a novel bacterium isolated from soil. AB - Strain S12-2-1T was isolated from a soil sample collected in the Gyeongsangnam-do province of the Republic of Korea. The isolate is a Gram-stain-negative, aerobic, short, rod-shaped bacterium, and its colonies are red to pink in colour. Analysis of the 16S rRNA gene identified strain S12-2-1T as a member of the genus Hymenobacter in the family Cytophagaceae, with high levels of 16S rRNA gene sequence similarity to Hymenobacter arizonensis OR362-8T (97.7 %), Hymenobacter sedentarius DG5BT (97.4 %) and Hymenobacter humi DG31AT (97.2 %). The isolate was positive for catalase and oxidase, but negative for acid production from glucose. The growth of strain S12-2-1T was supported at 4-30 degrees C, pH 7-10 and in the presence of 0-0.5 % NaCl. Strain S12-2-1T contained menaquinone-7 as the predominant respiratory quinone, sym-homospermidine as the major polyamine and iso-C15 : 0, anteiso-C15 : 0 and summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) as the major fatty acids. Phosphatidylethanolamine was the major polar lipid. The genomic DNA G+C content was 58.7 mol%. Phenotypic and chemotaxonomic data supported the assignment of the isolate to the genus Hymenobacter. However, strain S12-2-1T exhibited a relatively low level of DNA-DNA relatedness with H. humi (31.7 %), H. arizonensis (24.4 %) and H. sedentarius (21.3 %). Based on its phenotypic and genotypic properties, along with its phylogenetic distinctiveness, strain S12-2-1T should be considered a novel species in the genus Hymenobacter, for which the name Hymenobacter pedocola sp. nov. is proposed. The type strain is S12-2-1T (=KCTC 52730T=JCM 32198T). PMID- 29767619 TI - Metrics to assess injury prevention programs for young workers in high-risk occupations: a scoping review of the literature. AB - INTRODUCTION: Despite legal protections for young workers in Canada, youth aged 15-24 are at high risk of traumatic occupational injury. While many injury prevention initiatives targeting young workers exist, the challenge faced by youth advocates and employers is deciding what aspect(s) of prevention will be the most effective focus for their efforts. A review of the academic and grey literatures was undertaken to compile the metrics-both the indicators being evaluated and the methods of measurement-commonly used to assess injury prevention programs for young workers. Metrics are standards of measurement through which efficiency, performance, progress, or quality of a plan, process, or product can be assessed. METHODS: A PICO framework was used to develop search terms. Medline, PubMed, OVID, EMBASE, CCOHS, PsychINFO, CINAHL, NIOSHTIC, Google Scholar and the grey literature were searched for articles in English, published between 1975-2015. Two independent reviewers screened the resulting list and categorized the metrics in three domains of injury prevention: Education, Environment and Enforcement. RESULTS: Of 174 acquired articles meeting the inclusion criteria, 21 both described and assessed an intervention. Half were educational in nature (N=11). Commonly assessed metrics included: knowledge, perceptions, self-reported behaviours or intentions, hazardous exposures, injury claims, and injury counts. One study outlined a method for developing metrics to predict injury rates. CONCLUSION: Metrics specific to the evaluation of young worker injury prevention programs are needed, as current metrics are insufficient to predict reduced injuries following program implementation. One study, which the review brought to light, could be an appropriate model for future research to develop valid leading metrics specific to young workers, and then apply these metrics to injury prevention programs for youth. PMID- 29767621 TI - Commentary - The case for more comprehensive data on household food insecurity. PMID- 29767620 TI - Quantile regression analysis of language and interpregnancy interval in Quebec, Canada. AB - INTRODUCTION: Short and long interpregnancy intervals are associated with adverse perinatal outcomes such as miscarriage and preterm delivery, but cultural differences in interpregnancy intervals are understudied. Identifying cultural inequality in interpregnancy intervals is necessary to improve maternal-child outcomes. We assessed interpregnancy intervals for Anglophones and Francophones in Quebec. METHODS: We obtained birth records for all infants born in Quebec, 1989-2011. We identified 571 461 women with at least two births, and determined the interpregnancy interval. We defined short interpregnancy intervals (< 18 months) as the 20th percentile of the distribution, and long intervals (>= 60 months) as the 80th percentile. Using quantile regression, we evaluated the association of language with short and long intervals, adjusted for maternal characteristics. We assessed differences over time and by maternal age for disadvantaged groups defined as no high school diploma, rural residence, and material deprivation. RESULTS: In adjusted regression models, Anglophones who had no high school diploma had intervals that were 1.0 month (95% CI: -1.5 to -0.4) shorter than Francophones at the 20th percentile of the distribution, and 1.9 months (-0.5 to 4.3) longer at the 80th percentile. Results were similar for Anglophones in rural and materially deprived areas. The trends persisted over time, but were stronger for women < 30 years. There were no differences between advantaged Anglophones and Francophones. CONCLUSION: Disadvantaged Anglophones are more likely to have short and long interpregnancy intervals relative to Francophones in Quebec. Public health interventions to improve perinatal health should target suboptimal intervals among disadvantaged Anglophones. PMID- 29767623 TI - Release notice - The Health and Social Dimensions of Adult Skills in Canada. PMID- 29767622 TI - At-a-glance - Perceptions of caffeinated drinks among youth and young adults in Canada. AB - The current study assessed youth and young adults' perceptions and attitudes toward caffeine and energy drinks (EDs). An online survey was conducted with 2036 panelists aged 12-24, about caffeine and ED knowledge, caffeine perceptions, and perceptions of ED safety. Few respondents (2.1%) could state Health Canada's recommended limit for caffeine intake, although most participants (64.9%) correctly stated the maximum number of EDs that should be consumed per day. When shown four beverages, only 17.5% correctly identified the beverage with the most caffeine. Overall, young people generally have low levels of knowledge about caffeine amounts and intake from caffeinated beverages. PMID- 29767625 TI - Correction: Quantifying the contribution of Plasmodium falciparum malaria to febrile illness amongst African children. PMID- 29767627 TI - Comment on 'Invasive and noninvasive means of measuring intracranial pressure: a review'. PMID- 29767626 TI - Patterning the spine. AB - The patterning of the spine of a zebrafish is controlled by the notochord, a rod like structure that supports and instructs the developing embryo. PMID- 29767624 TI - The maternal brain in women with a history of early-life maltreatment: an imagination-based fMRI study of conflictual versus pleasant interactions with children. AB - BACKGROUND: Early-life maltreatment has severe consequences for the affected individual, and it has an impact on the next generation. To improve understanding of the intergenerational effects of abuse, we investigated the consequences of early-life maltreatment on maternal sensitivity and associated brain mechanisms during mother-child interactions. METHODS: In total, 47 mothers (22 with a history of physical and/or sexual childhood abuse and 25 without, all without current mental disorders) took part in a standardized real-life interaction with their 7- to 11-year-old child (not abused) and a subsequent functional imaging script-driven imagery task. RESULTS: Mothers with early-life maltreatment were less sensitive in real-life mother-child interactions, but while imagining conflictual interactions with their child, they showed increased activation in regions of the salience and emotion-processing network, such as the amygdala, insula and hippocampus. This activation pattern was in contrast to that of mothers without early-life maltreatment, who showed higher activations in those regions in response to pleasant mother-child interactions. Mothers with early life maltreatment also showed reduced functional connectivity between regions of the salience and the mentalizing networks. LIMITATIONS: Region-of-interest analyses, which were performed in addition to whole-brain analyses, were exploratory in nature, because they were not further controlled for multiple comparisons. CONCLUSIONS: Results suggest that for mothers with early-life maltreatment, conflictual interactions with their child may be more salient and behaviourally relevant than pleasant interactions, and that their salience network is poorly modulated by the brain regions involved in mentalizing processes. This activation pattern offers new insights into the mechanisms behind the intergenerational effects of maltreatment and into options for reducing these effects. PMID- 29767628 TI - Heart rate differences between symptomatic and asymptomatic Brugada syndrome patients at night. AB - OBJECTIVE: Ventricular arrhythmias in Brugada syndrome (BS) mainly occur at rest, especially during nighttime, suggesting that parasympathetic activity at night may play an important role in the arrhythmogenesis of the disease. This study examined and compared the autonomic function of symptomatic and asymptomatic BS patients overnight. APPROACH: We analyzed various heart rate variability (HRV) and heart rate complexity (HRC) markers in a clinical series including 87 BS patients, where 23 were symptomatic. MAIN RESULTS: Statistically significant differences were found in markers MIRR, SDNN, SDANN, [Formula: see text] and SampEn, suggesting that symptomatic patients may be related to lower heart rate variability and complexity values, as well as to greater circadian fluctuations overnight. SIGNIFICANCE: The results provide further evidence for the role of autonomic imbalance in the pathophysiology of BS, highlighting the relevance of nighttime analysis to the unmasking of significant ANS changes. Based on these outcomes, the role of HRV and HRC assessment at night could be a step forward towards the understanding of BS and the risk for the occurrence of symptoms in these patients, with a potential future impact on therapeutic strategies. PMID- 29767629 TI - Amplitude and phase modulation in microwave ring resonators by doped CVD graphene. AB - In this paper, we numerically and experimentally demonstrate how to modulate the amplitude and phase of a microwave ring resonator by means of few-layers chemical vapour deposition graphene. In particular, both numerical and experimental results show a modulation of about 10 dB and a 90 degrees-shift (quadrature phase shift) when the graphene sheet-resistance is varied. These findings prove once again that graphene could be efficiently exploited for the dynamically tuning and modulation of microwave devices fostering the realization of (i) innovative beam steering and beam-forming systems and (ii) graphene-based sensors. PMID- 29767631 TI - Finite-temperature stress calculations in atomic models using moments of position. AB - Continuum modeling of finite temperature mechanical behavior of atomic systems requires refined description of atomic motions. In this paper, we identify additional kinematical quantities that are relevant for a more accurate continuum description as the system is subjected to step-wise loading. The presented formalism avoids the necessity for atomic trajectory mapping with deformation, provides the definitions of the kinematic variables and their conjugates in real space, and simplifies local work conjugacy. The total work done on an atom under deformation is decomposed into the work corresponding to changing its equilibrium position and work corresponding to changing its second moment about equilibrium position. Correspondingly, we define two kinematic variables: a deformation gradient tensor and a vibration tensor, and derive their stress conjugates, termed here as static and vibration stresses, respectively. The proposed approach is validated using MD simulation in NVT ensembles for fcc aluminum subjected to uniaxial extension. The observed evolution of second moments in the MD simulation with macroscopic deformation is not directly related to the transformation of atomic trajectories through the deformation gradient using generator functions. However, it is noteworthy that deformation leads to a change in the second moment of the trajectories. Correspondingly, the vibration part of the Piola stress becomes particularly significant at high temperature and high tensile strain as the crystal approaches the softening limit. In contrast to the eigenvectors of the deformation gradient, the eigenvectors of the vibration tensor show strong spatial heterogeneity in the vicinity of softening. More importantly, the elliptic distribution of local atomic density transitions to a dumbbell shape, before significant non-affinity in equilibrium positions has occurred. PMID- 29767632 TI - Reply to Comment on 'Invasive and noninvasive means of measuring intracranial pressure: a review'. PMID- 29767630 TI - Characterization of cardiorespiratory phase synchronization and directionality in late premature and full term infants. AB - OBJECTIVE: Though the mutual influence of cardiovascular and respiratory rhythms in healthy newborns has been documented, its full characterization is still pending. In general, the activity of many physiological subsystems has a well expressed rhythmic character, and often an interdependency between physiological rhythms emerges early in development. Traditional methods of data analysis only address the quantification of the strength of subsystem interactions. In this work, we will investigate system interrelationships in terms of the possible presence of causal or directional interplays. APPROACH: In this paper, we propose a methodological application that quantifies phase coupling and its directionality in a population of newborn infants born between 35 and 40 weeks of gestational age (GA). The aim is to assess whether GA at birth significantly influences the development of phase synchronization and the directionality of the coupling between the cardiovascular and respiratory system activity. Several studies indicating irregular cardiorespiratory coupling as a leading cause of several pathologies underscore the need to investigate this phenomenon in this at risk population. MAIN RESULTS: Results from our investigation show a different directionality profile as a function of GA and sleep state. SIGNIFICANCE: These findings are a contribution to the understanding of higher risk for the documented negative outcomes in the late preterm population. Moreover, these parameters could provide a tool for the development of early markers of cardiorespiratory dysregulation in infants. PMID- 29767633 TI - Nanopatterning on calixarene thin films via low-energy field-emission scanning probe lithography. AB - Field-emitted, low-energy electrons from the conducting tip of an atomic force microscope were adopted for nanolithography on calixarene ultrathin films coated on silicon wafers. A structural evolution from protrusion to depression down to a 30 nm spatial resolution was reproducibly obtained by tuning the sample voltage and exposure current in the lithography process. Close analyses of the profiles showed that the nanostructures formed by a single exposure with a high current are almost identical to those created by cumulative exposure with a lower current but an equal number of injected electrons. Surface potential imaging by Kelvin probe force microscopy found a negatively charged region surrounding the groove structures once the structures were formed. We conclude that the mechanism related to the formation of a temporary negative state and molecule decomposition, rather than thermal ablation, is responsible for the low-energy field-emission electron lithography on a calixarene molecular resist. We hope that our elucidation of the underlying mechanism is helpful for molecular resist design and further improving the reproducibility and throughput of nanolithography. PMID- 29767634 TI - Measurement and estimation of human forced expiratory noise parameters using a microphone with a stethoscope head and a lapel microphone. AB - OBJECTIVE: The time signature of tracheal noise in the 200-2000 Hz frequency band recorded during a forced expiratory manoeuvre (FETa) is a promising tool for diagnosis of bronchial obstructions. FETa is typically registered using a microphone with a stethoscope head placed on the neck over the trachea (stethoscope sensor). We studied basic time and spectral parameters of forced expiratory tracheal noises with a microphone placed near the mouth (lapel microphone, outside the flow of exhaled air) and compared these with measurements via stethoscope sensor, with the aim of providing patient home monitoring via standard personal computer facilities. APPROACH: FETa, 200 Hz band pass times, and frequency responses of signals recorded simultaneously with both sensors were analysed in a sample of 24 healthy volunteers. MAIN RESULTS: Averaged real transfer function of signals from a stethoscope sensor and a lapel microphone in the frequency range 200-1800 Hz was characterized by a slope of -7.2 dB/octave. This is near the slope of -6 dB/octave predicted via theoretical models of both sensors. The lapel microphone and stethoscope sensor were not interchangeable regarding spectral characteristics of forced expiratory tracheal noises. However, FETa measurements in healthy volunteers via stethoscope sensor and lapel microphone showed no significant differences according to U-Mann-Whitney test for independent samples. SIGNIFICANCE: The ability to measure FETa successfully with a lapel microphone placed near the mouth was experimentally demonstrated in healthy volunteers. Additional studies are needed to verify whether FETa measured near the mouth is acceptable for monitoring pulmonary status in patients with asthma or chronic obstructive pulmonary disease. PMID- 29767635 TI - Detecting atrial fibrillation from short single lead ECGs using statistical and morphological features. AB - OBJECTIVE: Point of care ECG devices can improve the early detection of atrial fibrillation (AF). The efficiency of such devices depends on the capability of automatic AF detection against normal sinus rhythm and other arrhythmias from a short single lead ECG record in the presence of noise and artifacts. The objective of this study was to develop an algorithm that classifies a short single lead ECG record into 'Normal', 'AF', 'Other' and 'Noisy' classes, and identify the challenges in developing such algorithms and potential mitigation steps. APPROACH: Rule-based identification was used to detect lead inversion and records too noisy to be of immediate use. A set of statistical and morphological features describing the rhythm was then extracted, and support vector machine classifiers were used to classify records into three classes: 'Normal', 'AF' or 'Other'. The algorithm was trained and tested using 12 186 short single lead ECGs recorded on a point of care device made available via the Computing in Cardiology Challenge 2017. MAIN RESULTS: The algorithm achieved a sensitivity of 77.5%, a specificity of 97.9% and an accuracy of 96.1% in the detection of AF from a non AF rhythm in a five-fold cross validation. It achieved F1 measures of 89%, 78% and 67% for 'Normal', 'AF' and 'Other' classes, respectively, when evaluated with a hidden test set. The overall challenge score was 78%. SIGNIFICANCE: Most existing algorithms can distinguish the AF rhythm from the normal sinus rhythm when ECG recordings are clean and are obtained with multi-lead systems, while their ability to discriminate against other arrhythmias and noise remains largely unknown. This study proposes an algorithm that classifies a short single lead ECG record from point of care devices into 'Normal', 'AF', 'Other' and 'Noisy' classes and discusses computational approaches to mitigate any unique challenges such as lead inversion, low amplitude signals, noise and artifacts. PMID- 29767636 TI - The Surviving Sepsis Campaign Bundle: 2018 Update. PMID- 29767637 TI - HIV Risk Among Adolescent Girls and Young Women in Age-Disparate Partnerships: Evidence From KwaZulu-Natal, South Africa. AB - BACKGROUND: Evidence on the role of age-disparate partnerships in high HIV infection rates among young women in sub-Saharan Africa remains inconclusive. This study examined the HIV-infection risk associated with age-disparate partnerships among 15- to 24-year-old women in a hyperendemic setting in South Africa. METHODS: Face-to-face questionnaire, and laboratory HIV and viral load data were collected during 2014-2015 among a representative sample (15-49 years old) in KwaZulu-Natal. The association between age-disparate partnerships (age difference >=5 years) and HIV status among 15- to 24-year-old women (N = 1459) was assessed using multiple logistic regression analyses. Data from the male sample on all on-going partnerships (N = 1229) involving 15- to 24-year-old women were used to assess whether young women's age-disparate male partners were more likely to have a viral load >=1000 copies per milliliter, a marker of HIV infection risk. RESULTS: Women reporting an age disparity in any of their 3 most recent partnerships were more likely to test HIV positive compared to women with only age-similar partners [adjusted odds ratio (aOR): 1.58, 95% confidence interval (CI): 1.20 to 2.09, P < 0.01]. Among partnerships men reported with 15- to 24-year-old women, the age-disparate male partners were more likely to be HIV positive and have a viral load >=1000 copies per milliliter (aOR: 2.05, 95% CI: 1.30 to 3.24, P < 0.01) compared with age-similar partners. Results were similar for each category of age disparity: partners 5-9 years older (aOR: 2.01, 95% CI: 1.18 to 3.43, P = 0.010) and those >=10 years older (aOR: 2.17, 95% CI: 1.01 4.66, P = 0.048). CONCLUSIONS: Results indicate that age-disparate partnerships increase young women's HIV risk, although conclusive evidence was not ascertained. Interventions addressing risk from age-disparate sexual partnering, including expanding antiretroviral treatment among older partners, may help to reduce HIV incidence among young women. PMID- 29767640 TI - Burden of Exposure to Potential Interactions Between Antiretroviral and Non Antiretroviral Medications in a Population of HIV-Positive Patients Aged 50 Years or Older. AB - BACKGROUND: As HIV-infected patients aged 50 years or older are at increased risk of comorbidities and multidrug treatments, we examined their exposure to the potential drug-drug interactions (PDDIs) of antiretroviral (ARV) and other medications. METHODS: This cross-sectional study involved the patients aged 50 years or older receiving ARV and non-ARV medications at our clinic. PDDIs were identified using the University of Liverpool HIV Drug Interaction Checker. Logistic regression models were used to assess risk factors for PDDIs. The American Geriatrics Society Beers Criteria were used to identify potentially inappropriate medications (PIMs). RESULTS: A total of 395 (53.9%) of 744 patients showed >=1 PDDI: 47.4% >= 1 amber-PDDI (comedications requiring appropriate management) and 5.6% >= 1 red-PDDI (contraindicated comedications). A higher risk of PDDIs was associated with the use of >=5 medications (P < 0.001), of antiosteoporotics (P < 0.001), calcium channel blockers (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001), hypnotics/sedatives (P = 0.022), and anticoagulants (P = 0.006). A higher risk of red-PDDIs was associated with the use of antacids (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001) and antipsychotics (P = 0.023). The use of nucleoside reverse transcriptase inhibitor + nonnucleoside reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor rather than protease inhibitor-based regimens was associated with a reduced risk of PDDIs (P < 0.001). Overall, 119 (16.0%) patients were receiving PIMs (mainly hypnotics/sedatives) and 49 (41.2%) of them had PDDIs able to increase the blood levels of these medications. CONCLUSIONS: Older patients with HIV are highly exposed to PDDIs between ARVs and comedications. The knowledge of their complete medication regimens and the screening for PDDIs and PIMs is therefore crucial to prevent drug-related adverse outcomes in this population. PMID- 29767638 TI - Pre-exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Kidney Tubular Dysfunction in HIV-Uninfected Individuals. AB - BACKGROUND: Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is becoming increasingly adopted for HIV prevention. Tenofovir can cause proximal tubular damage and chronic kidney disease in HIV-infected persons, but little is known regarding its nephrotoxic potential among HIV-uninfected persons. In this study, we evaluated the effects of PrEP on urine levels of the following: alpha1-microglobulin (alpha1m), a marker of impaired tubular reabsorption; albuminuria, a measure of glomerular injury; and total proteinuria. SETTING: The Iniciativa Profilaxis Pre-Exposicion (iPrEx) study randomized HIV-seronegative men and transgender women who have sex with men to oral TDF/FTC or placebo. The iPrEx open-label extension (iPrEx-OLE) study enrolled former PrEP trial participants to receive open-label TDF/FTC. METHODS: A cross-sectional analysis compared urine biomarker levels by study arm in iPrEx (N = 100 treatment arm, N = 100 placebo arm). Then, urine biomarker levels were compared before and after PrEP initiation in 109 participants of iPrEx-OLE. RESULTS: In iPrEx, there were no significant differences in urine alpha1m, albuminuria, or proteinuria by treatment arm. In iPrEx-OLE, after 24 weeks on PrEP, urine alpha1m and proteinuria increased by 21% [95% confidence interval (CI): 10 to 33] and 18% (95% CI: 8 to 28), respectively. The prevalence of detectable alpha1m increased from 44% to 65% (P < 0.001) and estimated glomerular filtration rate declined by 4 mL/min/1.73 m (P < 0.001). There was no significant change in albuminuria (6%; 95% CI: -7% to 20%). CONCLUSION: PrEP with TDF/FTC was associated with a statistically significant rise in urine alpha1m and proteinuria after 6 months, suggesting that PrEP may result in subclinical tubule dysfunction. PMID- 29767641 TI - Willingness to Pay for HIV Self-Tests Among Women in Kenya: Implications for Subsidy and Pricing Policies. PMID- 29767642 TI - Regarding the 'Joint statement from the American College of Surgeons Committee on Trauma (ACS COT) and the American College of Emergency Physicians (ACEP) regarding the clinical use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA)'. PMID- 29767639 TI - Pharmacokinetics and Pharmacodynamics of Tenofovir Reduced-Glycerin 1% Gel in the Rectal and Vaginal Compartments in Women: A Cross-Compartmental Study With Directly Observed Dosing. AB - BACKGROUND: Evidence is lacking regarding whether vaginal pre-exposure prophylaxis with topical tenofovir (TFV) reduces the risk of rectal HIV acquisition. SETTING: Bronx, NY. METHODS: MTN-014 was a phase 1, cross-over, randomized sequence trial comparing the cross-compartment pharmacokinetics and pharmacodynamics of daily TFV reduced-glycerin 1% gel after 14 days each of rectal and vaginal application, with directly observed dosing and a 6-week washout period between phases. RESULTS: Fourteen HIV-uninfected women enrolled; 91% of doses were observed and 13 women completed all study procedures. TFV and TFV diphosphate (TFV-DP) were detected in most samples collected from the dosing compartment. After vaginal dosing, TFV was detected in 10/14 samples of rectal fluid (RF) (median 4.4 ng/sponge) and 1/13 rectal tissue samples (0.2 ng/mg); TFV DP was detected in 2/13 rectal tissue samples at 59.8 and 76.5 fmol/mg. After rectal dosing, TFV was detected in 9/14 samples of vaginal fluid (median 1.1 ng/swab) and in 6/14 vaginal tissue samples (median below limit of quantification); TFV-DP was detected in 3/14 vaginal tissue samples at 17.3, 87.6, and 77.1 fmol/mg. Neither cervicovaginal lavage fluid nor RF collected 24 hours after rectal or vaginal dosing resulted in a statistically significant suppression of viral replication. CONCLUSIONS: In this study of 14 days each of vaginal and rectal application of TFV reduced-glycerin 1% gel, we found only a small degree of cross-compartment distribution of TFV in RF and vaginal fluids and no pharmacodynamic activity in ex vivo testing. Although high TFV concentrations in the dosing compartment may be protective, low cross-compartment tissue concentrations are not likely to be protective. PMID- 29767643 TI - Response to letter to the editor from Dubose and colleagues regarding the Joint statement from the American College of Surgeons Committee on Trauma (ACS COT) and the American College of Emergency Physicians (ACEP) regarding the clinical use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). PMID- 29767645 TI - Authors' Response to Letter to the Editor by Allen et al regarding Joint statement from the American College of Surgeons Committee on Trauma (ACS COT) and the American College of Emergency Physicians (ACEP) regarding the clinical use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) by Brenner et al. PMID- 29767644 TI - Surgeon's guide to anticoagulant and antiplatelet medications part two: antiplatelet agents and perioperative management of long-term anticoagulation. AB - An increasing number of potent antiplatelet and anticoagulant medications are being used for the long-term management of cardiac, cerebrovascular, and peripheral vascular conditions. Management of these medications in the perioperative and peri-injury settings can be challenging for surgeons, mandating an understanding of these agents and the risks and benefits of various management strategies. In this two part review, agents commonly encountered by surgeons in the perioperative and peri-injury settings are discussed and management strategies for patients on long-term antiplatelet and anticoagulant therapy reviewed. In part one, we review warfarin and the new direct oral anticoagulants. In part two, we review antiplatelet agents and assessment of platelet function and the perioperative management of long-term anticoagulation and antiplatelet therapy. PMID- 29767646 TI - Letter to the editor regarding the joint statement from the American College of Surgeons' Committee on Trauma (ACS-COT) and the American College of Emergency Physicians (ACEP) regarding the clinical use of resuscitative endovascular balloon occlusion of the aorta (REBOA). PMID- 29767647 TI - A surgeon's guide to anticoagulant and antiplatelet medications part one: warfarin and new direct oral anticoagulant medications. AB - An increasing number of potent antiplatelet and anticoagulant medications are being used for the long-term management of cardiac, cerebrovascular, and peripheral vascular conditions. Management of these medications in the perioperative and peri-injury settings can be challenging for surgeons, mandating an understanding of these agents and the risks and benefits of various management strategies. In this two-part review, agents commonly encounter by surgeons in the perioperative and peri-injury settings are discussed and management strategies for patients on long-term antiplatelet and anticoagulant therapy reviewed. In part I, we review warfarin and the new direct oral anticoagulants. In part II, we review antiplatelet agents and assessment of platelet function and the perioperative management of long-term anticoagulant and antiplatelet therapy. PMID- 29767649 TI - Experimental Psychological Stress on Quantitative Sensory Testing Response in Patients with Temporomandibular Disorders. AB - AIMS: To assess the modulatory effects of experimental psychological stress on the somatosensory evaluation of myofascial temporomandibular disorder (TMD) patients. METHODS: A total of 20 women with myofascial TMD and 20 age-matched healthy women were assessed by means of a standardized battery of quantitative sensory testing. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT), wind-up ratio (WUR), and pressure pain threshold (PPT) were performed on the facial skin overlying the masseter muscle. The variables were measured in three sessions: before (baseline) and immediately after the Paced Auditory Serial Addition Task (PASAT) (stress) and then after a washout period of 20 to 30 minutes (poststress). Mixed analysis of variance (ANOVA) was applied to the data, and the significance level was set at P = .050. RESULTS: A significant main effect of the experimental session on all thermal tests was found (ANOVA: F > 4.10, P < .017), where detection tests presented an increase in thresholds in the poststress session compared to baseline (CDT, P = .012; WDT, P = .040) and pain thresholds were reduced in the stress (CPT, P < .001; HPT, P = .001) and poststress sessions (CPT, P = .005; HPT, P = .006) compared to baseline. In addition, a significant main effect of the study group on all mechanical tests (MPT, WUR, and PPT) was found (ANOVA: F > 4.65, P < .037), where TMD patients were more sensitive than healthy volunteers. CONCLUSION: Acute mental stress conditioning can modulate thermal sensitivity of the skin overlying the masseter in myofascial TMD patients and healthy volunteers. Therefore, psychological stress should be considered in order to perform an unbiased somatosensory assessment of TMD patients. PMID- 29767648 TI - Antinociception Induced by Copper Salt Revisited: Interaction with Ketamine in Formalin-Induced Intraplantar and Orofacial Pain in Mice. AB - AIMS: To evaluate in mice the antinociceptive effect of copper in spinal and trigeminal nociceptive pathways by using the intraplantar and orofacial formalin tests, respectively, and to examine whether this effect may interact synergistically with ketamine-induced antinociception. METHODS: Nociceptive behaviors (licking/biting of the formalin-injected limb and rubbing/scratching of the formalin-injected orofacial area) in male mice were evaluated during a 45 minute observation period post-formalin injection. Dose-response curves for intraperitoneal (ip) copper sulfate and ketamine allowed their combination in equi-effective doses, and their interaction was determined with isobolographic analysis. The results were examined with one-way analysis of variance followed by the Bonferroni post hoc test. Significance was accepted at an alpha level of .05. RESULTS: Irrespective of the region injected with formalin (upper lip or hindlimb), copper sulfate (0.3, 1.0, and 3.0 mg/kg) and ketamine (1.0, 3.0, and 10 mg/kg) dose-dependently decreased the nociceptive behaviors evoked by formalin injection. Isobolographic analysis showed a superadditive interaction between copper and ketamine at the spinal level, but this interaction was only additive at the trigeminal level. CONCLUSION: The results suggest that copper salts could be used to synergistically improve the efficacy of some commercial centrally acting analgesic agents, such as ketamine, while reducing the possibility of side effects. However, a synergistic effect probably should not be expected if treatment is for orofacial pain. PMID- 29767650 TI - Immediate Effect of Continuous Ultrasound vs Sham Ultrasound for Bilateral Masseter Myalgia: A Double-Blinded Trial. AB - AIMS: To investigate the local and segmental effects of therapeutic ultrasound at a dose of 0.4 w/cm2 with 100% duty cycle for 5 minutes compared to the effect of sham ultrasound on painful masticatory muscles. METHODS: A total of 20 adult female subjects with bilateral masseter myalgia diagnosed according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) were included. Each subject was randomized to either an active ultrasound group or a sham ultrasound group. The intervention was applied to each masseter muscle for 5 minutes. Measures included pre- and post-self-reported pain intensity recorded on a verbal rating scale (VRS), pressure pain thresholds for the masseter (PPT-M) and temporalis (PPT-T) muscles, and intraoral temperature for the masseter muscle. Preintervention score was subtracted from the postintervention score for all measures to calculate mean change in pain, and nonparametric Mann-Whitney test was used to compare the groups. Statistical significance was set at P < .05. RESULTS: Changes in VRS did not show a significant difference between groups (P > .05). There were significant increases in PPT-M and intraoral temperature in the ultrasound group compared to the sham group (P < .05). There was no significant difference in PPT-T (P > .05), suggesting no segmental effect. CONCLUSION: Therapeutic ultrasound produced an immediate increase in PPT-M and intraoral temperature compared to sham ultrasound in female subjects with bilateral masseter myalgia. PMID- 29767651 TI - Impaired Standing Balance in Individuals with Cervicogenic Headache and Migraine. AB - AIMS: To determine whether a difference in standing balance exists among individuals with cervicogenic headache, those with migraine, and asymptomatic controls. METHODS: A total of 24 participants with cervicogenic headache, 24 with migraine, and 24 asymptomatic controls of similar age, gender, and body mass index were included. Standing balance was assessed with a swaymeter under the conditions of eyes open and closed; on firm and soft surfaces; and in comfortable and narrow stances (for a total of eight testing conditions). Each condition was tested for 30 seconds. The outcome measures were sway area and displacement. Multivariate analysis of variance with Bonferroni post hoc test were used to analyze between-group differences in the postural sway variables. RESULTS: Both headache groups had significantly larger sway areas than the control group during comfortable stance with eyes open and with eyes closed on a soft surface (P < .05) and during narrow stance with eyes closed on firm and soft surfaces (P < .05). The overall results demonstrated significantly greater sway in the anterior posterior direction and less sway in the medial-lateral direction in selected tests in the cervicogenic headache group compared to the migraine group. CONCLUSION: Individuals with cervicogenic headache and those with migraine have impaired balance during standing, but possibly to a different extent and pattern. Assessment of balance in patients with cervicogenic headache and migraine should be considered in clinical practice. PMID- 29767653 TI - Planetary Health thematic web collection. PMID- 29767654 TI - Hydrosoluble Cu(i)-DAPTA complexes: synthesis, characterization, luminescence thermochromism and catalytic activity for microwave-assisted three-component azide-alkyne cycloaddition click reaction. AB - New hydrosoluble and air-stable Cu(i) halide compounds, viz. [CuX(DAPTA)3] (1) and (2), and [Cu(MU-X)(DAPTA)2]2 (3) and (4) (X = Br or I, in this order), have been prepared by reacting Cu(i) halide (i.e., bromide or iodide) with 3,7 diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) under mild conditions. They represent the first examples of Cu(i) halide complexes bearing the DAPTA ligand, which have been fully characterized by elemental analysis, IR, 1H, 13C{1H} and 31P{1H} NMR spectroscopies, ESI-MS+ and, for 4, also by single crystal X-ray diffraction (SCXRD) analyses. Complexes 1-4 are efficient catalysts for the one-pot microwave assisted three-component (terminal alkyne, organic halide and NaN3) Huisgen cycloaddition reaction in aqueous media to afford the corresponding disubstituted triazoles. The catalysis proceeds with a broad alkyne substrate scope and according to "click rules". Photophysical studies of compound 4 showed an unusual reversible thermochromic behaviour exhibiting a blue emission at 298 K due to the halide-to-ligand charge transfer (3XLCT) and a red emission at 77 K because of the {Cu2I2} unit. PMID- 29767652 TI - Peripheral Glial Cell Line-Derived Neurotrophic Factor Facilitates the Functional Recovery of Mechanical Nociception Following Inferior Alveolar Nerve Transection in Rats. AB - AIMS: To identify endogenous sources of glial cell line-derived neurotrophic factor (GDNF) at the injury site following inferior alveolar nerve transection (IANX) and to determine whether GDNF signaling promotes the recovery of orofacial pain sensation. METHODS: Nociceptive mechanical sensitivity of the facial skin was assessed following IANX (n = 10) or sham operation (n = 7). GDNF-positive cells were identified and the amount of GDNF measured in the injured region of IANX rats (n = 10) and in sham rats (n = 10). The number of trigeminal ganglion neurons with regenerated axons and the nociceptive mechanical sensitivity after continuous GDNF administration at the injury site were also assessed in IANX (n = 28) and sham (n = 12) rats. The effect of GDNF neutralization on nociceptive mechanical sensitivity at the injury site was evaluated using a neutralizing antibody (GFRalpha1 Nab) in four groups: IANX + phosphate-buffered saline (PBS) (n = 6); sham (n = 12); IANX + GDNF (n = 12); and IANX + GDNF + GFRalpha1 Nab (n = 12). Statistical analyses included one-way and two-way repeated measures analysis of variance followed by post hoc tests or unpaired t tests. The threshold for statistical significance was set at P < .05. RESULTS: Nociceptive mechanical sensitivity was lost over the 5 days following IANX and was recovered by day 13. GDNF was expressed in infiltrating inflammatory cells and had enhanced expression. GDNF administration enhanced axonal regeneration and recovery of nociceptive mechanical sensitivity. GDNF neutralization inhibited the recovery of nociceptive mechanical sensitivity after IANX. CONCLUSION: GDNF signaling at the injury site facilitates the functional recovery of mechanical nociception following IANX and is an attractive therapeutic target for the functional disturbance of pain sensation. PMID- 29767655 TI - Proteomic analysis of stachyose contribution to the growth of Lactobacillus acidophilus CICC22162. AB - Stachyose is a functional oligosaccharide, acting as a potential prebiotic for colonic fermentation. To understand the mechanism of how stachyose promotes the growth of probiotic bacterium, we analyzed the differences of the proteome of Lactobacillus acidophilus grown on stachyose or glucose. By a combination of two dimensional electrophoresis and mass spectrometry analysis, we observed 16 proteins differentially abundant under these two conditions and identified 9 protein spots. Six of these proteins were highly abundant when stachyose was used as the sole carbon source. They included the phosphotransferase system, the energy coupling factor (ECF) transporter and the mannose-6-phosphate isomerase, involved in the uptake and catabolism of stachyose in Lactobacillus acidophilus CICC22162. Supportively, these observations were validated by quantitative RT-PCR analysis and enzymatic activity determination. Positive correlation was found between the content of the proteins and their mRNA levels. Additionally, we explored the recognition mechanism for stachyose binding to the newly identified ECF transporter by MD simulations and free energy analysis. Taken together, these results provide new insights into the mechanism of stachyose in promoting the growth of probiotic bacterium. PMID- 29767656 TI - A multilayer assembly of two mixed-valence Mn16-containing polyanions and study of their electrocatalytic activities towards water oxidation. AB - Herein, two mixed-valence Mn16-containing polyanions, (Mn16) [MnIII10MnII6O6(OH)6(PO4)4(A-a-SiW9O34)4]28- (Mn16-Cs) and [MnIII4MnII12(OH)12(PO4)4(A-a-SiW9O34)4]28- (Mn16-Rb), were successfully fabricated on an indium tin oxide (ITO)-coated glass electrode and a glass carbon electrode (GCE) by a layer-by-layer assembly method. Moreover, four composite films, i.e. [PDDA/Mn16-Cs]n, [PDDA/Mn16-Rb]n, [Mn16-Cs/Rubpy]n, and [Mn16 Rb/Rubpy]n (PDDA: poly(diallyldimethylammonium chloride); Rubpy: tris(2,2' bipyridyl)ruthenium(ii) chloride; n = 1-10), were constructed for comparison and characterized by UV-visible spectroscopy, cyclic voltammetry (CV), and X-ray photoelectron spectroscopy (XPS). Their electrocatalytic activities towards water oxidation were studied under the same experimental conditions. The results of the controlled experiments indicate that (1) all the four films exhibit expected electrocatalytic activities towards water oxidation; (2) the electrocatalytic activity of Mn16-Cs is better than that of Mn16-Rb in solution and composite films; and (3) the electrocatalytic activities of the composite film [Mn16/Rubpy]n are better than those of the composite film [PDDA/Mn16]n. PMID- 29767657 TI - Structural and electrochemical studies of TiO2 complexes with (4,4'-((1E,1'E) (2,5-bis(octyloxy)-1,4-phenylene)bis(ethene-2,1-diyl))bis-(E)-N-(2,5 bis(octyloxy)benzylidene)) imine derivative bases towards organic devices. AB - Three (4,4'-((1E,1'E)-(2,5-bis(octyloxy)-1,4-phenylene)bis(ethene-2,1-diyl))bis (E)-N-(2,5-bis(octyloxy)benzylidene)) imine derivatives were synthesized via a condensation reaction with p-toluenesulfonic acid as a catalyst. The effects of the end groups and vinylene (-HC[double bond, length as m-dash]CH-) moieties on the structural, thermal, optical, electrochemical and photovoltaic properties of imines were investigated to check the influence of TiO2 on the imine properties. The thermal behavior of imines and their complexes with TiO2 was widely investigated using FT-IR, XRD, DSC and POM methods in order to determine the order type in the imine structure. All imines present the highest occupied molecular orbital (HOMO) levels of about -5.39 eV (SAI1 and SAI2) and -5.27 eV (SAI3) and the lowest unoccupied molecular orbital (LUMO) levels at about -3.17 eV. The difference of the end groups in the imines in each case did not affect redox properties. Generally, both oxidation and reduction are easier after TiO2 addition and it also changes the HOMO-LUMO levels of imines. Moreover, changes in the characteristic bands for imines in the region 1500-1700 cm-1 observed as a drastic decrease of intensity or even disappearance of bands in the imine : TiO2 mixture suggest the formation of a complex (C[double bond, length as m-dash]N) TiO2. Organic devices with the configuration of ITO/TiO2/SAIx (or SAIx : TiO2)/Au were fabricated and investigated in the presence and absence of visible light irradiation with an intensity of 93 mW cm-2. In all imines and complexes with TiO2, the generation of the photocurrent indicates their use as photodiodes and the best result was observed for SAI3 : TiO2 complexes. PMID- 29767663 TI - COX-2 gene expression and methylation profile in Sapajus apella as an experimental model for gastric adenocarcinoma. AB - Gastric cancer (GC) remains one of the main causes of cancer-related death worldwide. There are two distinct histological types of GC: diffuse and intestinal. The latter is characterized by the presence of pre-neoplastic lesions. One of the most frequently altered enzymes in intestinal GC is COX-2, an important lesion marker. This work aimed to study COX-2 methylation and expression in N-methyl-N-Nitrosurea (MNU)-induced intestinal GC in six Sapajus apella animals. The partial promoter sequence of S. apella COX-2 gene was obtained and used to identify transcription factors and cis-regulatory element binding sites. The COX-2 methylation pattern was assessed using Methylation Specific PCR (MSP), and expression was analyzed by immunohistochemistry (IHQ). A total of 20 samples were obtained. A 675 bp fragment of the S. apella COX-2 promoter region was obtained, and it was 99.2% and 68.2% similar to H. sapiens and S. boliviensis, respectively. Similar to humans, several transcription factors and cis-regulatory element binding sites were identified in the S. apella sequence. MSP revealed that all samples were methylated. However, IHQ results demonstrated positive COX-2 expression in all pre-neoplastic and tumoral samples. The results suggest that the analyzed fragment is not crucial in COX-2 regulation of GC in S. apella. PMID- 29767664 TI - Biochemical and molecular characterization of 3-Methylcrotonylglycinuria in an Italian asymptomatic girl. AB - 3-Methylcrotonylglycinuria is an organic aciduria resulting from deficiency of 3 methylcrotonyl-CoA carboxylase (3-MCC), a biotin-dependent mitochondrial enzym carboxylating 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA during leucine catabolism. Its deficiency, due to mutations on MCCC1 and MCCC2 genes, leads to accumulation of 3-methylcrotonyl-CoA metabolites in blood and/or urine, primarily 3-hydroxyisovaleryl-carnitine (C5-OH) in plasma and 3-methylcrotonyl-glycine (3 MCG) and 3-hydroxyisovaleric acid (3-HIVA) in the urine. The phenotype of 3-MCC deficiency is highly variable, ranging from severe neurological abnormalities and death in infancy to asymptomatic adults. Here we report the biochemical and molecular characterization of an Italian asymptomatic girl, positive for the newborn screening test. Molecular analysis showed two mutations in the MCCC2 gene, an already described missense mutation, c.691A > T (p.I231F), and a novel splicing mutation, c.1150-1G > A. We characterized the expression profile of the splice mutation by functional studies. PMID- 29767665 TI - Karyotype and genome size comparative analyses among six species of the oilseed bearing genus Jatropha (Euphorbiaceae). AB - Jatropha is an important genus of Euphorbiaceae, with species largely used for various purposes, including the manufacturing of soaps and pharmaceutical products and applications in the bioenergetic industry. Although there have been several studies focusing J. curcas in various aspects, the karyotype features of Jatropha species are poorly known. Therefore, we analyzed six Jatropha species through fluorochrome staining (CMA/DAPI), fluorescent in situ hybridization (FISH) with 5S and 45S rDNA probes and genome size estimation by flow cytometry. Our results revealed several chromosome markers by both CMA/DAPI and FISH for the analyzed species. Five Jatropha species (J. curcas, J. gossypiifolia, J. integerrima, J. multifida and J. podagrica) showed four CMA-positive (CMA+) bands associated with the 5S and 45S rDNA sites (one and two pairs, respectively). However, J. mollissima displayed six CMA+/DAPI- bands co-localized with both 5S and 45S rDNA, which showed a FISH superposition. A gradual variation in the genome sizes was observed (2C = 0.64 to 0.86 pg), although an association between evidenced heterochromatin and genome sizes was not found among species. Except for the unique banding pattern of J. mollissima and the pericentromeric heterochromatin of J. curcas and J. podagrica, our data evidenced relatively conserved karyotypes. PMID- 29767667 TI - Cytotaxonomic study of the Chilean endemic complex Alstroemeria magnifica Herb. (Alstroemeriaceae). AB - Alstroemeria L. (Alstroemeriaceae) represents one of the most diverse genera of vascular plants in Chile. It contains approximately 54 taxa, 40 of which are endemic. The "complex" Alstroemeria magnifica is endemic to Chile, and it comprises four varieties: A. magnifica var. magenta, A. magnifica var. magnifica, A. magnifica var. sierrae, and A. magnifica var. tofoensis. It is distributed from Coquimbo to the Valparaiso Region. We analyzed karyotypes of 10 populations along its natural distribution. All the populations presented an asymmetric karyotype, with 2n = 16 chromosomes but with three different karyotypic formulae. Alstroemeria magnifica var. magnifica and A. magnifica var. sierrae presented the same karyotypic fomula, and A. magnifica var. magenta, and A. magnifica var. tofoensis each had a different formula. The scatter plot among CVCL vs. MCA shows different groupings between populations of the four varieties. Based on the results, it is possible to consider raising Alstroemeria magnifica var. magenta to species level (A. magenta) and A. magnifica var. tofoensis to subspecies level (A. magnifica subsp. tofoensis); A. magnifica var. magnifica and A. magnifica var. sierrae should each remain as varieties. Nevertheless, these taxonomic changes should be considered tentative, as additional sources of evidence become available. PMID- 29767666 TI - The genome sequence of Dyella jiangningensis FCAV SCS01 from a lignocellulose decomposing microbial consortium metagenome reveals potential for biotechnological applications. AB - Cellulose and its associated polymers are structural components of the plant cell wall, constituting one of the major sources of carbon and energy in nature. The carbon cycle is dependent on cellulose- and lignin-decomposing microbial communities and their enzymatic systems acting as consortia. These microbial consortia are under constant exploration for their potential biotechnological use. Herein, we describe the characterization of the genome of Dyella jiangningensis FCAV SCS01, recovered from the metagenome of a lignocellulose degrading microbial consortium, which was isolated from a sugarcane crop soil under mechanical harvesting and covered by decomposing straw. The 4.7 Mbp genome encodes 4,194 proteins, including 36 glycoside hydrolases (GH), supporting the hypothesis that this bacterium may contribute to lignocellulose decomposition. Comparative analysis among fully sequenced Dyella species indicate that the genome synteny is not conserved, and that D. jiangningensis FCAV SCS01 carries 372 unique genes, including an alpha-glucosidase and maltodextrin glucosidase coding genes, and other potential biomass degradation related genes. Additional genomic features, such as prophage-like, genomic islands and putative new biosynthetic clusters were also uncovered. Overall, D. jiangningensis FCAV SCS01 represents the first South American Dyella genome sequenced and shows an exclusive feature among its genus, related to biomass degradation. PMID- 29767668 TI - Genetic variations in circadian rhythm genes and susceptibility for myocardial infarction. AB - Disruption of endogenous circadian rhythms has been shown to increase the risk of developing myocardial infarction (MI), suggesting that circadian genes might play a role in determining disease susceptibility. We conducted a case-control study on 200 patients hospitalized due to MI and 200 healthy controls, investigating the association between MI and single nucleotide polymorphisms (SNPs) in four circadian genes (ARNTL, CLOCK, CRY2, and PER2). The variants of all four genes were chosen based on their previously reported association with cardiovascular risk factors, which have a major influence on the occurrence of myocardial infarction. Statistically significant differences, assessed through Chi-square analysis, were found in genotype distribution between cases and controls of the PER2 gene rs35333999 (p=0.024) and the CRY2 gene rs2292912 (p=0.028); the corresponding unadjusted odds ratios, also significant, were respectively OR=0.49 (95% CI 0.26-0.91) and OR=0.32 (95% CI 0.11-0.89). Our data suggest that genetic variability in the CRY2 and PER2 genes might be associated with myocardial infarction. PMID- 29767669 TI - Identification of mutations in patients with acquired pure red cell aplasia. AB - Idiopathic acquired pure red cell aplasia (PRCA) is a rare, autoimmune-related disease. This study aimed to describe the previously unidentified DNA alterations associated with PRCA. Here, next generation sequencing using a panel containing 295 critical genes was applied to detect potentially pathogenic mutations in four patients with PRCA. A total of 529 mutations were identified and further classified into three categories, namely, uncertain (n = 25), likely benign (n = 20) and benign (n = 484) mutations, based on the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines and ClinVar database. The spatial proximity between two loci of the uncertain or benign mutations was evaluated using Hi-C datasets of KBM7 and K562 cell lines, respectively. Significant spatial proximity was observed in uncertain mutation pairs compared with benign mutation pairs. In addition, 17 variants were eventually identified after excluding those with mutant frequencies >0.001, including 7 newly identified variants. FANCF and LRP1B mutations existed twice in patients. FANCF and LRP1B mutations were likely to affect protein stability based on prediction analysis. Taken together, our data may provide valuable information about PRCA. FANCF and LRP1B mutations may be associated with acquired PRCA. PMID- 29767670 TI - Treatment of the myeloid/lymphoid neoplasm with FGFR1 rearrangement with FGFR1 inhibitor. PMID- 29767671 TI - Significance of an Increase in Diastolic Blood Pressure During a Stress Test in Terms of Comorbidities and Long-Term Total and CV Mortality. AB - BACKGROUND: A decrease in diastolic blood pressure (DBP) with exercise is considered normal, but the significance of an increase in DBP has not been validated. Our aim was to determine the relationship of DBP increasing on a stress test regarding comorbidities and mortality. METHODS: Our database was reviewed from 1993 to 2010 using the first stress test of a patient. Non Minnesota residence, baseline cardiovascular (CV) disease, rest DBP <60 or >100 mm Hg, and age <30 or >=80 were exclusion criteria. DBP response was classified: normal if peak DBP-rest DBP < 0, borderline 0-9, and abnormal >=10 mm Hg. Mortality was determined from Mayo Clinic records and Minnesota Death Index. Logistic regression was used to determine the relationship of DBP response to the presence of comorbidities. Cox regression was used to determine total and CV mortality risk by DBP response. All analyses were adjusted for age, sex, and resting DBP. RESULTS: Twenty thousand seven hundred sixty patients were included (51 +/- 11 years, female n = 7,314). Rest/peak averaged DBP 82 +/- 8/69 +/- 15 mm Hg in normal vs. 79 +/- 9/82 +/- 9 mm Hg in borderline vs. 76 +/- 9/92 +/- 11 mm Hg in abnormal DBP response. There were 1,582 deaths (8%) with 557 (3%) CV deaths over 12 +/- 5 years of follow-up. In patients with borderline and abnormal DBP response, odds ratios for obesity, hypertension, diabetes, and current smoking were significant, while hazard ratios for total and CV death were not significant compared with patients with normal DBP response. CONCLUSIONS: DBP response to exercise is significantly associated with important comorbidities at the time of the stress test but does not add to the prognostic yield of stress test. PMID- 29767672 TI - Blockade of TLR4 Within the Paraventricular Nucleus Attenuates Blood Pressure by Regulating ROS and Inflammatory Cytokines in Prehypertensive Rats. AB - BACKGROUND: Toll-like receptor 4 (TLR4) has been implicated in the progression of cardiovascular disease, including hypertension. However, the role of TLR4 in the development of prehypertension is uncertain. METHODS: Prehypertensive rats were treated with 8% salt for 12 weeks to induce prehypertension. These rats were then given either TAK-242 selective TLR4 blocker, or vehicle by bilateral micro injection to the paraventricular nucleus (PVN). Blood pressure (BP) and renal sympathetic nerve activity were recorded. PVN expression of TLR4, myeloid differentiation factor 88 (Myd88), nuclear factor-kappa B (NF-kappaB) p65, proinflammation cytokines (PICs), interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NADPH oxidase 4 (NOX4), Cu/Zn superoxide dismutase (SOD) level, tyrosine hydroxylase, and 67 kDa isoform of glutamate decarboxylase (GAD67) were tested to determine the influence of TLR4 blockade. RESULTS: TLR4 expression increased significantly in the PVN of high-salt groups with a corresponding increase in reactive oxygen species (ROS) and PICs. TLR4 blockade significantly reduced the signaling molecules downstream TLR4 and the expression of TNF-alpha, IL-6, IL-1beta, decreased ROS, NOX2, NOX4 level, increased Cu/Zn-SOD, re-balanced neurotransmitters, and regulated sympathetic nerve activity in the PVN of prehypertensive rats. CONCLUSIONS: Salt-induced prehypertension is partly due to the upregulation of TLR4 in PVN. Blockade of TLR4 in the brain reduced salt induced prehypertension response, possibly through downregulation of ROS and PICs expression, and the restorage of neurotransmitter balance in the PVN. PMID- 29767673 TI - Modeling the impact of folic acid fortification and supplementation on red blood cell folate concentrations and predicted neural tube defect risk in the United States: have we reached optimal prevention? AB - Background: The US CDC and the Institute of Medicine recommend that women capable of becoming pregnant consume >=400 ug synthetic folic acid/d to prevent neural tube defects (NTDs). The United States has 3 sources of folic acid: fortified enriched cereal grain products (ECGPs), fortified ready-to-eat (RTE) cereals, and dietary supplements. Objective: Our objectives were as follows: 1) to estimate the usual daily folic acid intake and distributions of red blood cell (RBC) folate concentrations among women consuming folic acid from different sources; 2) to assess the usual daily total folic acid intake associated with optimal RBC folate concentrations for NTD prevention; 3) to predict NTD prevalence; and 4) to estimate the number of preventable folate-sensitive NTDs. Design: NHANES data (2007-2012) for nonpregnant women of reproductive age (12-49 y) were used to estimate usual daily intakes of synthetic folic acid and natural food folate. We applied existing models of the relation between RBC folate concentrations and NTD risk to predict NTD prevalence. Results: Based on the distribution of overall RBC folate concentrations (4783 women), the predicted NTD prevalence was 7.3/10,000 live births [95% uncertainty interval (UI): 5.5-9.4/10,000 live births]. Women consuming folic acid from ECGPs as their only source had lower usual daily total folic acid intakes (median: 115 ug/d; IQR: 79-156 ug/d), lower RBC folate concentrations (median: 881 nmol/L; IQR: 704-1108 nmol/L), and higher predicted NTD prevalence (8.5/10,000 live births; 95% UI: 6.4-10.8/10,000 live births) compared with women consuming additional folic acid from diet or supplements. If women who currently consume folic acid from ECGPs only (48% of women) consumed additional folic acid sources, 345 (95% UI: 0-821) to 701 (95% UI: 242-1189) additional NTDs/y could be prevented. Conclusions: This analysis supports current recommendations and does not indicate any need for higher intakes of folic acid to achieve optimal NTD prevention. Ensuring 400 ug/d intake of folic acid prior to pregnancy has the potential to increase the number of babies born without an NTD. PMID- 29767674 TI - Optimal Blood Pressure in Elderly Hypertensive Subjects: A Korean National Health Insurance Service Health Examinee Cohort Study. AB - BACKGROUND: To describe the association between mean blood pressure (BP) and clinical outcomes and to investigate the optimal BP in elderly hypertensive subjects. METHODS: This study used the National Health Insurance Service health examinee cohort. Subjects aged >60 years with a new diagnosis of hypertension from 2003 to 2006 were selected. Patients with previous major cardiovascular events were excluded. The remaining 23,523 subjects were divided into three groups according to the average of the observed systolic BP (SBP) and diastolic BP (DBP): (i) average SBP <130 mm Hg (n = 6,893), 130-140 mm Hg (n = 8,676), and >=140 mm Hg (n = 7,954) or (ii) average DBP <80 mm Hg (n = 9,273), 80-90 mm Hg (n = 11,607), and >=90 mm Hg (n = 2,643). RESULTS: Compared with SBP >=140 mm Hg, SBP 130-140 mm Hg was associated with significantly lower rates of all-cause mortality (hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.62-0.76, P < 0.001) and cardiovascular mortality (HR = 0.61, 95% CI = 0.50-0.75, P < 0.001). However, SBP <130 mm Hg did not show further lowering of all-cause and cardiovascular mortality rates compared with SBP 130-140 mm Hg. DBP 80-90 mm Hg was also associated with lower risks of all-cause death (HR = 0.64, 95% CI = 0.57 0.72, P < 0.001) and cardiovascular death (HR = 0.51, 95% CI = 0.40-0.64, P < 0.001) compared with DBP >=90 mm Hg. There were no additional benefits with DBP <80 mm Hg for all-cause death and cardiovascular death. CONCLUSIONS: Mean BP of <140/90 mm Hg were associated with lowest all-cause and cardiovascular mortality without any further benefit with mean BP <130/80 mm Hg. PMID- 29767675 TI - A comparison of methods for adjusting biomarkers of iron, zinc, and selenium status for the effect of inflammation in an older population: a case for interleukin 6. AB - Background: Older people are at risk of micronutrient deficiencies, which can be under- or overestimated in the presence of inflammation. Several methods have been proposed to adjust for the effect of inflammation; however, to our knowledge, none have been investigated in older adults in whom chronic inflammation is common. Objective: We investigated the influence of various inflammation-adjustment methods on micronutrient biomarkers associated with anemia in older people living in aged-care facilities in New Zealand. Design: Blood samples were collected from 289 New Zealand aged-care residents aged >65 y. Serum ferritin, soluble transferrin receptor (sTfR), total body iron (TBI), plasma zinc, and selenium as well as the inflammatory markers high-sensitivity C reactive protein (CRP), alpha1-acid glycoprotein (AGP), and interleukin 6 (IL-6) were measured. Four adjustment methods were applied to micronutrient concentrations: 1) internal correction factors based on stages of inflammation defined by CRP and AGP, 2) external correction factors derived from the literature, 3) a regression correction model in which reference CRP and AGP were set to the maximum of the lowest decile, and 4) a regression correction model in which reference IL-6 was set to the maximum of the lowest decile. Results: Forty percent of participants had elevated concentrations of CRP, AGP, or both, and 37% of participants had higher than normal concentrations of IL-6. Adjusted geometric mean values for serum ferritin, sTfR, and TBI were significantly lower (P < 0.001), and plasma zinc and selenium were significantly higher (P < 0.001), than the unadjusted values regardless of the method applied. The greatest inflammation adjustment was observed with the regression correction that used IL-6. Subsequently, the prevalence of zinc and selenium deficiency decreased (-13% and 14%, respectively; P < 0.001), whereas iron deficiency remained unaffected. Conclusions: Adjustment for inflammation should be considered when evaluating micronutrient status in this aging population group; however, the approaches used require further investigation, particularly the influence of adjustment for IL-6. PMID- 29767676 TI - "Complete Streets" and Adult Bicyclist Fatalities: Applying G-Computation to Evaluate an Intervention That Affects the Size of a Population at Risk. AB - "Complete streets" policies require transportation engineers to make provisions for pedestrians, bicyclists, and mass transit users. These policies may make bicycling safer for individual cyclists while increasing the overall number of bicycle fatalities if more people cycle due to improved infrastructure. We merged county-level records of complete streets policies with Fatality Analysis Reporting System counts of cyclist fatalities occurring between January 2000 and December 2015. Because comprehensive county-level estimates of numbers of cyclists were not available, we used bicycle commuter estimates from the American Community Survey and the US Census as a proxy for the cycling population and limited analysis to 183 counties (accounting for over half of the US population) for which cycle commuting estimates were consistently nonzero. We used G computation to estimate the effect of complete streets policies on overall numbers of cyclist fatalities while also accounting for potential policy effects on the size of the cycling population. Over a period of 16 years, 5,254 cyclists died in these counties, representing 34 fatalities per 100,000 cyclist-years. We estimated that complete streets policies made cycling safer, averting 0.6 fatalities per 100,000 cyclist-years (95% confidence interval: -1.0, -0.3) by encouraging a 2.4% increase in cycling but producing only a 0.7% increase in cyclist fatalities. G-computation is a useful tool for understanding the impact of policy on risk and exposure. PMID- 29767677 TI - Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer. AB - Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of beta2 glycoprotein 1 (beta2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum beta2GP1 levels >=200 ug/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high beta2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673. PMID- 29767679 TI - Recurrent Cytogenetic Abnormalities in Intravascular Large B-Cell Lymphoma. AB - Objectives: Data characterizing the cytogenetic landscape of intravascular large B-cell lymphoma (ILBCL) are limited. Here, we developed a comprehensive karyotypic data set to identify recurrent cytogenetic abnormalities in ILBCL. Methods: Cases of ILBCL with complete cytogenetic analysis were identified from an institutional database and the literature. The combined data were systematically reviewed for the presence of recurrent abnormalities. Results: Four new cases were identified and combined with 25 karyotypes previously published in the literature. Karyotypes were uniformly complex with a median of 10 aberrations. In total, 72.4% had abnormalities involving chromosome 1, with 31.0% involving rearrangements of 1p13 or 1q21; 58.6% had abnormalities involving chromosome 6, which in almost all cases involved 6q; 34.5% had abnormalities involving chromosome 14, with 27.6% involving rearrangements of 14q32; and 55.2% had abnormalities of chromosome 18, with 37.9% harboring trisomy 18. Conclusions: Recurrent cytogenetic abnormalities involving chromosomes 1, 6q, and 18 are present in greater than 50% of ILBCL. PMID- 29767678 TI - Identification of Etiology-Specific Diarrhea Associated With Linear Growth Faltering in Bangladeshi Infants. AB - Childhood diarrhea in low-resource settings has been variably linked to linear growth shortfalls. However, the association between etiology-specific diarrhea and growth has not been comprehensively evaluated. We tested diarrheal stools collected from the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries study from 2011 to 2013 in Dhaka, Bangladesh, by quantitative polymerase chain reaction for a broad range of enteropathogens to characterize diarrhea etiology and examine the association between etiology-specific diarrhea and linear growth and systemic inflammation. Pathogen-specific burdens of diarrhea were determined using attributable fractions. Linear regression was used to examine associations of pathogen-specific diarrhea with length-for-age z scores (LAZ) and serum C-reactive protein. There was no relationship between all cause diarrhea and length at 12 months (change in 12-month LAZ per episode, 0.01, 95% confidence interval (CI): -0.06, 0.03). However, Cryptosporidium (change in 12-month LAZ per attributable episode, -0.23, 95% CI: -0.50, 0.03), Campylobacter jejuni/coli (change of -0.16, 95% CI: -0.32, -0.01), and Shigella/enteroinvasive Escherichia coli diarrhea (change of -0.12, 95% CI: 0.26, 0.03) were associated with linear growth deficits. Diarrhea attributable to C. jejuni/coli and Shigella/enteroinvasive E. coli were associated with elevated C-reactive protein. The association between diarrhea and linear growth appears to be pathogen-specific, reinforcing the need for pathogen-specific interventions. PMID- 29767680 TI - Propensity for adverse pregnancy outcomes in African-American women may be explained by low energy expenditure in early pregnancy. AB - Background: African-American (AA) women have poorer pregnancy outcomes, and studies in nonpregnant women suggest a different etiology of weight gain in AA compared with white women. We hypothesized that physiologic factors such as low energy expenditure and physical activity would be present in AA compared with white women in pregnancy. Objective: We aimed to identify physiologic risk factors for disordered energy balance in AA and white women early in pregnancy. Design: This was a cross-sectional study in 66 pregnant women with obesity, between 14 and 16 wk of gestation. Energy intake was calculated using the intake balance method. Energy expenditure was measured in free-living conditions [total daily energy expenditure (TDEE)] over 7 d with the use of doubly labelled water and during sleep [sleeping EE (SleepEE)] in a room calorimeter. Body composition was measured by air displacement plethysmography and physical activity by accelerometers. Markers of metabolic health were obtained from fasting blood and urine. Results: AA (n = 34) and white (n = 32) women were comparable in age (mean +/- SEM: 27.7 +/- 0.6 y), enrollment body mass index [mean +/- SEM (in kg/m2): 36.9 +/- 0.7], and body fat (mean +/- SEM: 45.0% +/- 0.6%). AA women had more fat free mass (P = 0.01) and tended to be more insulin-resistant (homeostasis model assessment of insulin resistance, P = 0.06). Energy intake was significantly lower in AA than in white women (2499 +/- 76 compared with 2769 +/- 58 kcal/d, P = 0.001), although absolute TDEE was comparable (AA: 2590 +/- 77 kcal/d; white: 2711 +/- 56 kcal/d; P = 0.21). After adjusting for body composition, TDEE was significantly lower in AA women (-231 +/- 74 kcal/d, P = 0.003), as was SleepEE ( 81 +/- 37 kcal/d, P = 0.03). Physical activity, substrate oxidation, and metabolic biomarkers (triiodothyronine and thyroxine concentrations, catecholamine excretion) were not significantly different between groups. Conclusions: Body mass-adjusted energy expenditure is significantly lower in AA than in white pregnant women. Energy intake recommendations for pregnancy do not consider this difference and may therefore overestimate energy requirements in AA women. This may lead to unintentional overeating and contribute to the disparity of excess gestational weight gain and postpartum weight retention that is more prevalent in AA women. This trial was registered at clinicaltrials.gov as NCT01954342. PMID- 29767682 TI - Best Care for Patients Achieved Through Multidisciplinary Stewardship. PMID- 29767681 TI - Medication Side Effects and Retention in HIV Treatment: A Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia. AB - Tenofovir is less toxic than other nucleoside reverse-transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of human immunodeficiency virus (HIV)-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir for first-line ART. We applied regression discontinuity in a prospective cohort study of 52,294 HIV-infected adults initiating first-line ART within 12 months (+/-12 months) of each guideline change. We compared outcomes in patients presenting just before and after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24 months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentages of patients initiating tenofovir in South Africa (risk difference (RD) = 81 percentage points, 95% confidence interval (CI): 73, 89) and Zambia (RD = 42 percentage points, 95% CI: 38, 45). With the guideline change, the percentage of single-drug substitutions decreased substantially in South Africa (RD = -15 percentage points, 95% CI: -18, -12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD = -1.8% (95% CI: -3.5, -0.1); complier relative risk = 0.74) but not in South Africa (RD = -0.9% (95% CI: -5.9, 4.1); complier relative risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts. PMID- 29767683 TI - Large Outbreak of Hepatitis C Virus Associated With Drug Diversion by a Healthcare Technician. AB - Background: In May 2012, the New Hampshire (NH) Division of Public Health Services (DPHS) was notified of 4 persons with newly diagnosed hepatitis C virus (HCV) infection at hospital X. Initial investigation suggested a common link to the hospital cardiac catheterization laboratory (CCL) because the infected persons included 3 CCL patients and a CCL technician. NH DPHS initiated an investigation to determine the source and control the outbreak. Methods: NH DPHS conducted site visits, case patient and employee interviews, medical record and medication use review, and employee and patient HCV testing using enzyme immunoassay for anti-HCV, reverse-transcription polymerase chain reaction for HCV RNA, nonstructural 5B (NS5B) and hypervariable region 1 (HVR1) sequencing, and quasispecies analysis. Results: HCV HVR1 analysis of the first 4 cases confirmed a common source of infection. HCV testing identified 32 of 1074 CCL patients infected with the outbreak strain, including 3 patients coinfected with >1 HCV strain. The epidemiologic investigation revealed evidence of drug diversion by the HCV-infected technician, evidenced by gaps in controlled medication control, higher fentanyl use during procedures for confirmed cases, and building card key access records documenting the presence of the technician during days when transmission occurred. The employee's status as a traveling technician led to a multistate investigation, which identified additional cases at prior employment sites. Conclusions: This is the largest laboratory-confirmed drug diversion associated HCV outbreak published to date. Recommendations to reduce drug diversion risk and to conduct outbreak investigations are provided. PMID- 29767685 TI - Smelling Anxiety Chemosignals Impairs Clinical Performance of Dental Students. AB - Despite the fact that human body odors can transfer anxiety-related signals, the impact of such signals in real-life situations is scant. In this study, the effects of anxiety chemosignals on the performance of dental students operating on simulation units, wearing T-shirts imbued with human sweat and masked with eugenol were tested. A total of 24 fourth-year dental students (17 F) donated their body odors in two sessions (Anxiety and Rest). Twenty-four normosmic, sex- and age-matched test subjects who were third-year dental students performed 3 dental procedures while smelling masked anxiety body odors, masked rest body odors, or masker alone. The intensity and pleasantness ratings showed that the test subjects could not report perceptual differences between the odor conditions. When exposed to masked anxiety body odors, the test subjects' dental performance was significantly worse than when they were exposed to masked rest body odors and masker alone, indicating that their performance was modulated by exposure to the emotional tone of the odor. These findings call for a careful evaluation of the anxiety-inducing effects of body odors in performance-related tasks and provide the first ecological evaluation of human anxiety chemosignal communication. PMID- 29767686 TI - Stratification of mouse vaginal epithelium. 1. Development of three-dimensional models in vitro with clonal cell lines. AB - The mouse vagina consists of stratified squamous epithelium and stroma and is regulated by ovarian hormones. Vaginal epithelial cells do not stratify, but rather form a monolayer and show an inconsistent responsiveness to ovarian hormones when cultured on plastic dish or matrix. To address the discrepancy between in vivo and in vitro observations, three-dimensional (3D) co-culture models are developed with clonal vaginal epithelial and stromal cell lines; stromal cells are embedded in collagen gel and epithelial cells are seeded on the gel. In the 3D models, epithelial cells express Transformation related protein 63 (Trp63) and begin to stratify when they are co-cultured with two out of three stromal cell lines, but not with the other stromal cell line. Stroma may consist of various types of cells with distinct functions. PMID- 29767684 TI - Ultrasensitive Human Immunodeficiency Virus Type 1 Viral Load as a Marker of Treatment Choice for Simplification Strategies. AB - Background: Using 3 randomized Protease inhibitor (PI) monotherapy studies: Kalesolo, Dream and Monoi, we performed a pooled-analysis. Our objective was to determine in PI monotherapy and standard tritherapy: 1) distribution of ultrasensitive viral load (USVL) at week 96 (W96); 2) factors associated with virological failure (VF) at W96 and 3) factors associated with USVL<1 copy at W96. Methods: VF was defined as 2 consecutive measurements of Human Immunodeficiency Virus Type 1 RNA viral load>50 copies/mL and analysed in Intention-To-Treat. A logistic model was used to investigate which variables were predictive of a VF and Fisher test to investigate differences in USVL at W96. Results: Among 609 patients, 73% were male with median age of 44.4 years (IQR 39.8-52.1), baseline CD4/CD8 ratio was 0.8 (IQR 0.6-1.10), baseline CD4 was 564.5/mm3 (IQR 422-707) and 59% presented a baseline USVL<1 copy/mL. At W96, the proportion of USVL<1 copy/mL was significantly different between PI monotherapy and standard tritherapy in pooled-analysis (65% versus 74%; p=0.04). Overall, baseline USVL<1copy/mL, tritherapy and to be a female were associated with USVL<1 copy/mL at W96 (p<0.0001, p=0.049 and p=0.006). In PI monotherapy receiving DRV/r was associated with USVL<1 copy/mL at W96 (p=0.003). Factors associated to virological succes at W96 were higher baseline CD4 (p=0.034) and baseline USVL<1 copy/mL (p=0.0005). Conclusion: Pooled-analysis of 3 PI monotherapy trials showed better efficacy of tritherapy in terms of USVL at W96. Furthermore regarding USVL at W96, to receive LPV/r seems to be more deleterious than DRV/r. Baseline USVL impacts VF at W96 more specifically in tritherapy arm. Clinical Trials Registration: NCT00421551, NCT00946595, and NCT00140751. PMID- 29767687 TI - Hormone-responsive genes in the SHH and WNT/beta-catenin signaling pathways influence urethral closure and phallus growth. AB - Environmental endocrine disruptors (EEDs) that affect androgen or estrogen activity may disrupt gene regulation during phallus development to cause hypospadias or a masculinized clitoris. We treated developing male tammar wallabies with estrogen and females with androgen from day 20-40 postpartum (pp) during the androgen imprinting window of sensitivity. Estrogen inhibited phallus elongation but had no effect on urethral closure and did not significantly depress testicular androgen synthesis. Androgen treatment in females did not promote phallus elongation but initiated urethral closure. Phalluses were collected for transcriptome sequencing at day 50 pp when they first become sexually dimorphic to examine changes in two signaling pathways, sonic hedgehog (SHH) and wingless-type MMTV integration site family (WNT)/beta-catenin. SHH mRNA and beta-catenin were predominantly expressed in the urethral epithelium in the tammar phallus, as in eutherian mammals. Estrogen treatment and castration of males induced an upregulation of SHH, while androgen treatment downregulated SHH. These effects appear to be direct since we detected putative estrogen receptor alpha (ERalpha) and androgen receptor (AR) binding sites near SHH. WNT5A, like SHH, was downregulated by androgen, while WNT4 was upregulated in female phalluses after androgen treatment. After estrogen treatment, WIF1 and WNT7A were both downregulated in male phalluses. After castration, WNT9A was upregulated. These results suggest that SHH and WNT pathways are regulated by both estrogen and androgen to direct the proliferation and elongation of the phallus during differentiation. Their response to exogenous hormones makes these genes potential targets of EEDs in the etiology of abnormal phallus development including hypospadias. PMID- 29767689 TI - Commentary on: Plastic Surgery Resident-Run Cosmetic Clinics: A Survey of Current Practices. PMID- 29767690 TI - Entorhinal Cortex Volume Is Associated With Dual-Task Gait Cost Among Older Adults With MCI: Results From the Gait and Brain Study. AB - Background: Low dual-task gait performance (the slowing of gait speed while performing a demanding cognitive task) is associated with low cognitive performance and an increased risk of progression to dementia in older adults with mild cognitive impairment. However, the reason for this remains unclear. This study aimed to examine the relationship between dual-task cost and regional brain volume, focusing on the hippocampus, parahippocampal gyrus, entorhinal cortex, and motor and lateral frontal cortices in older adults with mild cognitive impairment. Methods: Forty older adults with mild cognitive impairment from the "Gait and Brain Study" were included in this study. Gait velocity was measured during single-task (ie, walking alone) and dual-task (ie, counting backwards, subtracting serial sevens, and naming animals, in addition to walking) conditions, using an electronic walkway. Regional brain volumes were derived by automated segmentation, using 3T magnetic resonance imaging. Results: Partial rank correlation analyses demonstrated that a smaller volume of the left entorhinal cortex was associated with higher dual-task costs in counting backwards and subtracting serial sevens conditions. Subsequent logistic regression analyses demonstrated that a smaller volume of the left entorhinal cortex was independently associated with higher dual-task cost (slowing down >20% when performing cognitive task) in these two conditions. There were no other significant associations. Conclusions: Our results show that lower dual-task gait performance is associated with volume reduction in the entorhinal cortex. Cognitive and motor dysfunction in older adults with mild cognitive impairment may reflect a shared pathogenic mechanism, and dual-task-related gait changes might be a surrogate motor marker for Alzheimer's disease pathology. PMID- 29767688 TI - Safety and dose modification for patients receiving niraparib. AB - Background: Niraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methods: All analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade >=3 thrombocytopenia within 30 days after the first dose of niraparib and determine cut-off points for chosen variables. Results: Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade >=3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150 000/ul in effect received an average daily dose ~200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100 mg was consistent with that of patients who remained at the 300 mg starting dose. Conclusions: The analysis presented suggests that patients with baseline body weight of <77 kg or baseline platelets of <150 000/ul may benefit from a starting dose of 200 mg/day. ClinicalTrials.gov ID: NCT01847274. PMID- 29767691 TI - Thyroid hormones and female reproduction. AB - Thyroid hormones are vital for the proper functioning of the female reproductive system, since they modulate the metabolism and development of ovarian, uterine and placental tissues. Therefore, hypo- and hyperthyroidism may result in subfertility or infertility in both women and animals. Other well-documented sequelae of maternal thyroid dysfunctions include menstrual/estral irregularity, anovulation, abortion, preterm delivery, preeclampsia, intrauterine growth restriction, postpartum thyroiditis, and mental retardation in children. Several studies have been carried out involving prospective and retrospective studies of women with thyroid dysfunction, as well as in vivo and in vitro assays of hypo- and hyperthyroidism using experimental animal models and/or ovarian, uterine and placental cell culture. These studies have sought to elucidate the mechanisms by which thyroid hormones influence reproduction to better understand the physiology of the reproductive system and to provide better therapeutic tools for reproductive dysfunctions that originate from thyroid dysfunctions. Therefore, this review aims to summarize and update the available information related to the role of thyroid hormones in the morphophysiology of the ovary, uterus and placenta in women and animals and the effects of hypo- and hyperthyroidism on the female reproductive system. PMID- 29767692 TI - Erratum. PMID- 29767693 TI - Neoadjuvant score in locally advanced rectal cancer: integrating downstaging in risk assessment and looking for new valuable end points. PMID- 29767695 TI - Molybdenum. AB - Molybdenum, a trace element essential for micro-organisms, plants, and animals, was discovered in 1778 by a Swedish chemist named Karl Scheele. Initially mistaken for lead, molybdenum was named after the Greek work molybdos, meaning lead-like. In the 1930s, it was recognized that ingestion of forage with high amounts of molybdenum by cattle caused a debilitating condition. In the 1950s, the essentiality of molybdenum was established with the discovery of the first molybdenum-containing enzymes. In humans, only 4 enzymes requiring molybdenum have been identified to date: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime-reducing component (mARC). Sulfite oxidase, an enzyme found in mitochondria, catalyzes oxidation of sulfite to sulfate, the final step in oxidation of sulfur amino acids (cysteine and methionine). Xanthine oxidase converts hypoxanthine to xanthine, and further converts xanthine to uric acid, preventing hypoxanthine, formed from spontaneous deamination of adenine, from leading to DNA mutations if paired with cytosine in place of thymine. Aldehyde oxidase is abundant in the liver and is an important enzyme in phase 1 drug metabolism. Finally, mARC, discovered less than a decade ago, works in concert with cytochrome b5 type B and NAD(H) cytochrome b5 reductase to reduce a variety of N-hydroxylated substrates, although the physiologic significance is still unclear. In the case of each of the molybdenum enzymes, activity is catalyzed via a tricyclic cofactor composed of a pterin, a dithiolene, and a pyran ring, called molybdenum cofactor (MoCo) (1). PMID- 29767694 TI - Shorter Time to Pregnancy With Increasing Preconception Carotene Concentrations Among Women With 1-2 Previous Pregnancy Losses. AB - Although maternal nutrition may affect fecundity, associations between preconception micronutrient levels and time to pregnancy (TTP) have not been examined. We assessed the relationship between preconception fat-soluble micronutrient concentrations and TTP among women with 1-2 prior pregnancy losses. This was a prospective cohort study of 1,228 women set within the Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial (United States, 2007-2011), which assessed the association of preconception-initiated daily low-dose aspirin with reproductive outcomes. We measured preconception levels of zeaxanthin, cryptoxanthin, lycopene, alpha- and beta-carotene, and alpha- and gamma tocopherol in serum. We used discrete Cox regression models, accounting for left truncation and right-censoring, to calculate fecundability odds ratios and 95% confidence intervals. The models adjusted for age, body mass index, race, smoking, alcohol, physical activity, income, vitamin use, cholesterol, treatment arm, and study site. Serum alpha-carotene levels (per log unit (MUg/dL) increase, fecundability odds ratio (FOR) = 1.17, 95% confidence interval (CI): 1.00, 1.36) and serum alpha-carotene concentrations at or above the US average (2.92 MUg/dL) versus below the average (FOR = 1.21, 95% CI: 1.02, 1.44) were associated with shorter TTP. Compared with levels below the US average (187 MUg/dL), gamma tocopherol concentrations at or above the average were associated with longer TTP (FOR = 0.83, 95% CI: 0.69, 1.00). The potential for these nutrients to influence fecundability deserves further exploration. PMID- 29767696 TI - Clinical Outcomes Related to the Gastrointestinal Trophic Effects of Erythropoietin in Preterm Neonates: A Systematic Review and Meta-Analysis. AB - Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings. PMID- 29767697 TI - Perspective: Structure-Function Claims on Infant Formula. AB - In the context of a food product label, the term "claim" refers to information that attributes value to the product. The term extends to many different types of information, from product identity, descriptors of intended use, and identification of characteristic properties to the physiologic effects in the body of substances in the food, including the reduction of risk of disease. Food labeling, which includes claims, provides information that consumers want and use to improve their diets. Consumers prefer short statements on the front label claims to longer, more detailed information, including ingredients statements and a nutrition panel. Three types of claims are permitted in the United States. Nutrient content claims describe the level of the nutrient in the food relative to an established daily value, e.g., "Excellent source of choline," and are subject to composition limits for other nutrients, such as total fat, saturated fat, and cholesterol. Health claims describe the relation between a food substance and the risk of disease, e.g., "Adequate calcium and vitamin D throughout life, as part of a well-balanced diet, may reduce the risk of osteoporosis." They must undergo a premarket evaluation by the FDA to ensure that there is significant scientific agreement about the relation in question. The third type of claim, structure-function (SF) claims, has recently come under scrutiny, particularly regarding their use on infant formula. Such claims represent a food's effect on the structure or function of the body for maintenance of good health and nutrition. These claims must be truthful and not misleading, but are not subject to premarket approval before use. The purpose of this perspective is to describe the origins and unique niche of SF claims, and to comment on recent proposals to further regulate such claims on infant formula. PMID- 29767699 TI - Impact of Double-Fortified Salt with Iron and Iodine on Hemoglobin, Anemia, and Iron Deficiency Anemia: A Systematic Review and Meta-Analysis. AB - Double-fortified salt (DFS) containing iron and iodine has been proposed as a feasible and cost-effective alternative for iron fortification in low- and middle income countries (LMICs). We conducted a systematic review and meta-analysis from randomized and quasi-randomized controlled trials to 1) assess the effect of DFS on biomarkers of iron status and the risk of anemia and iron deficiency anemia (IDA) and 2) evaluate differential effects of DFS by study type (efficacy or effectiveness), population subgroups, iron formulation (ferrous sulfate, ferrous fumarate, and ferric pyrophosphate), iron concentration, duration of intervention, and study quality. A systematic search with the use of MEDLINE, EMBASE, Cochrane, Web of Science, and other sources identified 221 articles. Twelve efficacy and 2 effectiveness studies met prespecified inclusion criteria. All studies were conducted in LMICs: 10 in India, 2 in Morocco, and 1 each in Cote d'Ivoire and Ghana. In efficacy studies, DFS increased hemoglobin concentrations [standardized mean difference (SMD): 0.28; 95% CI: 0.11, 0.44; P < 0.001] and reduced the risk of anemia (RR: 0.59; 95% CI: 0.46, 0.77; P < 0.001) and IDA (RR 0.37; 95% CI: 0.25, 0.54; P < 0.001). In effectiveness studies, the effect size for hemoglobin was smaller but significant (SMD: 0.03; 95% CI: 0.01, 0.05; P < 0.01). Stratified analyses of efficacy studies by population subgroups indicated positive effects of DFS among women and school-age children. For the latter, DFS increased hemoglobin concentrations (SMD: 0.32; 95% CI: 0.03, 0.60; P < 0.05) and reduced the risk of anemia (SMD: 0.48; 95% CI: 0.34, 0.67; P < 0.001) and IDA (SMD: 0.37; 95% CI: 0.25, 0.54; P < 0.001). Hemoglobin concentrations, anemia prevalence and deworming at baseline, sample size, and study duration were not associated with effect sizes. The results indicate that DFS is efficacious in increasing hemoglobin concentrations and reducing the risk of anemia and IDA in LMIC populations. More effectiveness studies are needed. PMID- 29767700 TI - Effects of Iodized Salt and Iodine Supplements on Prenatal and Postnatal Growth: A Systematic Review. AB - Hypothyroidism due to iodine deficiency can impair physical development, most visibly in the marked stunting of myxedematous cretinism caused by severe in utero iodine deficiency. Whether iodine repletion improves growth in noncretinous children is uncertain. Therefore, the aim of our systematic review was to assess the effects of iodine fortification or supplementation on prenatal and postnatal growth outcomes in noncretinous children. Following Cochrane methods and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) reporting guidelines, we searched 10 databases including 2 Chinese databases (latest search February 2017). We included randomized and nonrandomized controlled trials (RCTs; non-RCTs), controlled before-after (CBA) studies, and interrupted time-series studies in pregnant women and children (<=18 y), which compared the effects of iodine (any form, dose, regimen) to placebo, noniodized salt, or no intervention on prenatal and postnatal growth outcomes. We calculated mean differences with 95% CIs, performed random-effects meta-analyses, and assessed the quality of evidence with the use of GRADE (Grading of Recommendations Assessment, Development and Evaluation). We included 18 studies (13 RCTs, 4 non-RCTs, 1 CBA) (n = 5729). Iodine supplementation of severely iodine-deficient pregnant women increased mean birthweight [mean difference (MD): 200 g; 95% CI: 183, 217 g; n = 635; 2 non-RCTs] compared to controls, but the quality of this evidence was assessed as very low. Iodine repletion across the other groups showed no effects on primary growth outcomes (quality of evidence mostly low and very low). Meta analyses showed a positive effect in moderate-to-mildly iodine-deficient schoolchildren on insulin-like growth factor-1 (MD: 38.48 ng/mL; 95% CI: 6.19, 70.76 ng/mL; n = 498; 2 RCTs, low-quality evidence) and insulin-like growth factor binding protein-3 (MD: 0.46 MUg/mL; 95% CI: 0.25, 0.66 MUg/mL; n = 498; 2 RCTs, low-quality evidence). In conclusion, we identified few well-designed trials examining the effects of iodine repletion on growth. We are uncertain whether prenatal iodine repletion increases infant growth. Postnatal iodine repletion may improve growth factors but has no clear effects on somatic growth. Our systematic review was registered with PROSPERO as CRD42014012940. PMID- 29767698 TI - Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease. AB - Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization. The composition and molecular organization of these membranes are crucial to the maintenance and function of mitochondria. In this review, we first present a general overview of mitochondrial membrane biochemistry and biophysics followed by the role of different dietary saturated and unsaturated fatty acids in modulating mitochondrial membrane structure-function. We focus extensively on long-chain n-3 (omega-3) polyunsaturated fatty acids and their underlying mechanisms of action. Finally, we discuss implications of understanding molecular mechanisms by which dietary n-3 fatty acids target mitochondrial structure function in metabolic diseases such as obesity, cardiac-ischemia reperfusion injury, obesity, type 2 diabetes, nonalcoholic fatty liver disease, and select cancers. PMID- 29767703 TI - Gender inequality and the gender gap in life expectancy in the European Union. AB - The gender gap in life expectancy (GGLE) varies substantially in EU 28 Member States. This paper addresses the question of whether gender inequality affects the GGLE as well as life expectancy (LE) in both genders. We conducted an ecological study and used the gender inequality index (GII) developed by the United Nations as well as the gender difference in LE in 2015. We found a correlation between GGLE and GII (r2=0.180) and between GII and LE of 0.418 (women) and 0.430 (men). Gender equality policies are still necessary and will have an effect on women's as well as men's health. PMID- 29767701 TI - Microbiome-Mediated Effects of the Mediterranean Diet on Inflammation. AB - The Mediterranean diet pattern is increasingly associated with improved metabolic health. Two mechanisms by which consuming a Mediterranean diet pattern may contribute to improved metabolic health are modulation of the gastrointestinal (GI) microbiota and reduction of metabolic endotoxemia. Metabolic endotoxemia, defined as a 2- to 3-fold increase in circulating levels of bacterial endotoxin, has been proposed as a cause of inflammation during metabolic dysfunction. As the largest source of endotoxins in the human body, the GI microbiota represents a crucial area for research on strategies for reducing endotoxemia. Diets high in saturated fat and low in fiber contribute to metabolic endotoxemia through several mechanisms, including changes in the GI microbiome and bacterial fermentation end products, intestinal physiology and barrier function, and enterohepatic circulation of bile acids. Thus, the Mediterranean diet pattern, rich in unsaturated fats and fiber, may be one dietary strategy to reduce metabolic endotoxemia. Preclinical studies have demonstrated the differential effects of dietary saturated and unsaturated fats on the microbiota and metabolic health, but human studies are lacking. The role of dietary fiber and the GI microbiome in metabolic endotoxemia is underinvestigated. Clinical research on the effects of different types of dietary fat and fiber on the GI microbiota and GI and systemic inflammation is necessary to determine efficacious dietary strategies for reducing metabolic endotoxemia, inflammation, and subsequent metabolic disease. PMID- 29767702 TI - Long reads: their purpose and place. AB - In recent years long-read technologies have moved from being a niche and specialist field to a point of relative maturity likely to feature frequently in the genomic landscape. Analogous to next generation sequencing, the cost of sequencing using long-read technologies has materially dropped whilst the instrument throughput continues to increase. Together these changes present the prospect of sequencing large numbers of individuals with the aim of fully characterizing genomes at high resolution. In this article, we will endeavour to present an introduction to long-read technologies showing: what long reads are; how they are distinct from short reads; why long reads are useful and how they are being used. We will highlight the recent developments in this field, and the applications and potential of these technologies in medical research, and clinical diagnostics and therapeutics. PMID- 29767705 TI - Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. AB - Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between alpha4beta7 and its ligand, mucosal addressin cellular adhesion molecule 1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by alphaEbeta7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti integrin therapeutics, including gut-selective antibodies against the beta7 integrin subunit [etrolizumab] and the alpha4beta7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-alpha4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules. PMID- 29767704 TI - Gene regulation in the 3D genome. AB - The spatial organization of the genome is essential for the precise control of gene expression. Recent advances in sequencing and imaging technologies allow us to explore the 3D genome and its relationship to gene regulation at an unprecedented scale. In this review, we provide an overview of lessons learned from studying the chromatin structure and their implications in communications between gene promoters and distal cis-regulatory elements, such as enhancers. We first review the current knowledge of general genome organization, followed by the importance of chromatin folding in gene regulation. Next, we proceed to a brief survey of the recently developed chromosome conformation capture technologies, as well as most widely adopted read-outs from such data. We then introduce two emerging models that offer explanations regarding how distal enhancers achieve transcriptional control of target genes in the 3D genome. Last, we discuss the promising prospects of leveraging knowledge in chromatin spatial organization for studying complex diseases and traits. PMID- 29767706 TI - Associations between vigorous physical activity and chronic diseases in older adults: a study in 13 European countries. AB - Background: This study aimed to assess cross-sectional and prospective relationships between vigorous physical activity (VPA) and the risk of major chronic diseases among European older adults. Methods: Participants were 37 524 older adults who responded to the fourth (in 2011) and fifth (in 2013) wave of the SHARE project, from 13 European countries. Participants answered interview questions about the presence of chronic conditions and VPA. The cross-sectional and prospective association between PA and the number of chronic diseases was assessed using logistic regression models. Results: Among men and women, the prevalence of chronic diseases was significantly lower among those who reported VPA once a week or more than once a week. For men, VPA once a week was prospectively related with lower odds of heart attack, chronic lung disease, Parkinson's disease and Alzheimer's disease. VPA more than once a week was prospectively related with lower odds of having all chronic diseases. Women who engaged in VPA once a week presented lower odds of having chronic diseases, except for hypertension, high blood cholesterol and cancer. For VPA more than once a week, cancer was the only disease not associated with physical activity. Conclusion: VPA is associated with reduced risk of chronic diseases in men and women. Even the practice of VPA once a week seems to be sufficient to reduce risks of chronic diseases. PMID- 29767707 TI - Preantral follicular atresia occurs mainly through autophagy, while antral follicles degenerate mostly through apoptosis. AB - There is a general agreement that granulosa cell apoptosis is the cause of antral follicle attrition. Less clear is whether this pathway is also activated in case of preantral follicle degeneration, as several reports mention that the incidence of granulosa cell apoptosis in preantral follicles is negligible. Our objective is therefore to determine which cell-death pathways are involved in preantral and antral follicular degeneration.Atretic preantal and antral follicles were investigated using immunohistochemistry and laser-capture microdissection followed by quantitative real-time reverse transcription polymerase chain reaction. Microtubule-associated light-chain protein 3 (LC3), sequestosome 1 (SQSTM1/P62), Beclin1, autophagy-related protein 7 (ATG7), and cleaved caspase 3 (cCASP3) were used as markers for autophagy and apoptosis, respectively. P62 immunostaining was far less intense in granulosa cells of atretic compared to healthy preantral follicles, while no difference in LC3 and BECLIN1 immunostaining intensity was observed. This difference in P62 immunostaining was not observed in atretic antral follicles. mRNA levels of LC3 and P62 were not different between healthy and atretic (pre)antral follicles. ATG7 immunostaining was observed in granulosa cells of preantral atretic follicles, not in granulosa cells of degenerating antral follicles. The number of cCASP3-positive cells was negligible in preantral atretic follicles, while numerous in atretic antral follicles. Taken together, we conclude that preantral and antral follicular atresia is the result of activation of different cell-death pathways as antral follicular degeneration is initiated by massive granulosa cell apoptosis, while preantral follicular atresia occurs mainly via enhanced granulosa cell autophagy. PMID- 29767708 TI - Resinosis Inhibits Monochamus spp. (Coleoptera: Cerambycidae) Colonization of Healthy Shortleaf Pines in Southeastern United States. AB - The genus Monochamus Dejean (Coleoptera: Cerambycidae) includes large, woodboring, longhorned beetles, which colonize pine trees in North America. Many authors have classified the genus as saprophagous, but one recent study reported successful colonization of standing jack pine trees (Pinus banksiana Lamb.) (Pinales: Pinaceae) following severe wind disturbance in Minnesota. We tested whether two Monochamus species native to the southeastern United States (M. titillator (Fabricius) and M. carolinensis (Olivier)) could successfully colonize healthy shortleaf pines (Pinus echinata Mill.) (Pinales: Pinaceae) in recently harvested stands without coincident abiotic or biotic stressors, such as lightning strikes or bark beetle attacks. We attached commercially available semiochemical lures, including monochamol, ethanol, and ipsenol, to healthy shortleaf pine trees and observed Monochamus spp. oviposition response. Egg development was monitored following oviposition by harvesting attacked trees and dissecting oviposition pits. High numbers of oviposition pits were observed on trees treated with lures containing the bark beetle pheromone ipsenol and pits were highly concentrated on the tree bole near lures. Although egg deposition occurred, pit dissection revealed large amounts of resin present in almost all dissected pits and that egg hatch and subsequent larval development were rare. Our results demonstrate that southeastern Monochamus spp. are unlikely to be primary pests of healthy shortleaf pines due to resinosis. To better understand the host finding behavior of these two Monochamus species, we also conducted trapping trials with several semiochemical combinations. Both species and sexes demonstrated similar attraction to compounds, and the most attractive lure combined host volatiles, pheromone, and sympatric insect kairomone. PMID- 29767710 TI - Relationship between dissolved organic matter quality and microbial community composition across polar glacial environments. AB - Vast expanses of Earth's surface are covered by ice, with microorganisms in these systems affecting local and global biogeochemical cycles. We examined microbial assemblages from habitats fed by glacial meltwater within the McMurdo Dry Valleys, Antarctica and on the west Greenland Ice Sheet (GrIS), evaluating potential physicochemical factors explaining trends in community structure. Microbial assemblages present in the different Antarctic dry valley habitats were dominated by Sphingobacteria andFlavobacteria, while Gammaproteobacteria and Sphingobacteria prevailed in west GrIS supraglacial environments. Microbial assemblages clustered by location (Canada Glacier, Cotton Glacier and west GrIS) and were separated by habitat type (i.e. ice, cryoconite holes, supraglacial lakes, sediment and stream water). Community dissimilarities were strongly correlated with dissolved organic matter (DOM) quality. Microbial meltwater assemblages were most closely associated with different protein-like components of the DOM pool. Microbes in environments with mineral particles (i.e. stream sediments and cryoconite holes) were linked to DOM containing more humic-like fluorescence. Our results demonstrate the establishment of distinct microbial communities within ephemeral glacial meltwater habitats, with DOM-microbe interactions playing an integral role in shaping communities on local and polar spatial scales. PMID- 29767709 TI - Double Hits in Schizophrenia. AB - The co-occurrence of a Copy Number Variant (CNV) and a functional variant on the other allele may be a relevant genetic mechanism in schizophrenia. We hypothesized that the cumulative burden of such double hits - in particular those composed of a deletion and a coding single nucleotide variation (SNV) - is increased in patients with schizophrenia.We combined CNV data with coding variants data in 795 patients with schizophrenia and 474 controls. To limit false CNV-detection, only CNVs called only by two algorithms we included. CNV-affected genes were subsequently examined for coding SNVs, which we termed "CNV-SNVs". Correcting for total queried sequence, we assessed the CNV-SNV-burden and the combined predicted deleterious effect. We estimated p-values by permutation of the phenotype.We detected 105 CNV-SNVs; 67 in duplicated and 38 in deleted genic sequence. While the difference in CNV-SNVs rates was not significant, the combined deleteriousness inferred by CNV-SNVs in deleted sequence was almost fourfold higher in cases compared to controls (nominal p = 0.009). This effect may be driven by a higher number of CNV-SNVs and/or by a higher degree of predicted deleteriousness of CNV-SNVs. No such effect was observed for duplications.We provide early evidence that deletions co-occurring with a functional variant may be relevant, albeit of modest impact, for the genetic etiology of schizophrenia. Large-scale consortium studies are required to validate our findings. Sequence-based analyses would provide the best resolution for detection of CNVs as well as coding variants genome-wide. PMID- 29767711 TI - CRISPR/Cas9/sgRNA-mediated targeted gene modification confirms the cause-effect relationship between gyrA mutation and quinolone resistance in Escherichia coli. AB - Quinolones are broad-spectrum antibiotics that have been used for decades in treating bacterial infections in humans and animals, and subsequently bacterial resistance to these agents has increased. While studies indicated the relationship between gyrA mutations and bacterial resistance to quinolones, CRISPR/Cas9 was used in this study to investigate causal role of gyrA mutation in the quinolone resistance. In this study, 818 clinical Escherichia coli isolates were analyzed for gyrA mutations and their resistance to quinolones. The CRISPR/Cas9 system was used to generate gyrA mutations in quinolone-susceptible E. coli ATCC 25922, and quinolone-resistant clinical E. coli. The antimicrobial resistance prevalence rate in E. coli against nalidixic acid, ciprofloxacin and enrofloxacin was 77.1% (631/818), 51.1% (418/818) and 49.8% (407/818), respectively. The gyrA mutations were identified in nucleotide positions 248, 255, 259, 260, 261, 273 and 300, and mutations at positions 248 and 259 resulting in amino acid changes at positions 83 and 87 were associated with quinolone resistance. Double-site amino acid mutations increase resistance to quinolones. The gyrA mutations causing changes at amino acids 83 and 87 reversed the features of quinolone resistance in ATCC and clinical strains, verifying the causal role of gyrA mutation in the quinolone resistance of E. coli. PMID- 29767712 TI - Limited influence of hospital wastewater on the microbiome and resistome of wastewater in a community sewerage system. AB - Effluents from wastewater treatment plants (WWTPs) have been proposed to act as point sources of antibiotic-resistant bacteria (ARB) and antimicrobial resistance genes (ARGs) in the environment. Hospital sewage may contribute to the spread of ARB and ARGs as it contains the feces and urine of hospitalized patients, who are more frequently colonized with multi-drug resistant bacteria than the general population. However, whether hospital sewage noticeably contributes to the quantity and diversity of ARGs in the general sewerage system has not yet been determined.Here, we employed culture-independent techniques, namely 16S rRNA gene sequencing and nanolitre-scale quantitative PCRs, to assess the role of hospital effluent as a point source of ARGs in the sewerage system, through comparing microbiota composition and levels of ARGs in hospital sewage with WWTP influent with and without hospital sewage.Compared to other sites, hospital sewage was richest in human-associated bacteria and contained the highest relative levels of ARGs. Yet, the relative abundance of ARGs was comparable in the influent of WWTPs with and without hospital sewage, suggesting that hospitals do not contribute importantly to the quantity and diversity of ARGs in the investigated sewerage system. PMID- 29767713 TI - Commentary on: Hypochlorous Acid Versus Povidone-Iodine Containing Irrigants: Which Antiseptic is More Effective for Breast Implant Pocket Irrigation? PMID- 29767714 TI - Comparing Postnatal Development of Gonadal Hormones and Associated Social Behaviors in Rats, Mice, and Humans. AB - Postnatal development includes dramatic changes in gonadal hormones and the many social behaviors they help regulate, both in rodents and humans. Parental care seeking is the most salient social interaction in neonates and infants, play and prosocial behaviors are commonly studied in juveniles, and the development of aggression and sexual behavior begins in peripubertal stages but continues through late adolescence into adulthood. Although parental behaviors are shown after reproductive success in adulthood, alloparenting behaviors are actually high in juveniles as well. These behaviors are sensitive to both early-life organizational effects of gonadal hormones and later-life activational regulation. However, changes in circulating gonadal hormones and the display of the previous behaviors over development differ between rats, mice, and humans. These endpoints are of interest to endocrinologist, toxicologists, and neuroscientists because of their relevance to mental health disorders and their vulnerability to effects of endocrine-disrupting chemical exposure. As such, the goal of this mini-review is to succinctly describe and relate the postnatal development of gonadal hormones and social behaviors to each other, over time, and across animal models. Ideally, this will help identify appropriate animal models and age ranges for continued study of both normative development and in contexts of environmental disruption. PMID- 29767715 TI - Stable isotope probing of hypoxic toluene degradation at the Siklos aquifer reveals prominent role of Rhodocyclaceae. AB - The availability of oxygen is often a limiting factor for the degradation of aromatic hydrocarbons in subsurface environments. However, while both aerobic and anaerobic degraders have been intensively studied, degradation betwixt, under micro- or hypoxic conditions has rarely been addressed. It is speculated that in environments with limited, but sustained oxygen supply, such as in the vicinity of groundwater monitoring wells, hypoxic degradation may take place. A large diversity of subfamily I.2.C extradiol dioxygenase genes has been previously detected in a BTEX-contaminated aquifer in Hungary. Older literature suggests that such catabolic potentials could be associated to hypoxic degradation. Bacterial communities dominated by members of the Rhodocyclaceae were found, but the majority of the detected C23O genotypes could not be affiliated to any known bacterial degrader lineages. To address this, a stable isotope probing (SIP) incubation of site sediments with 13C7-toluene was performed under microoxic conditions. A combination of 16S rRNA gene amplicon sequencing and T-RFLP fingerprinting of C23O genes from SIP gradient fractions revealed the central role of degraders within the Rhodocyclaceae in hypoxic toluene degradation. The main assimilators of 13C were identified as members of the genera Quatrionicoccus and Zoogloea, and a yet uncultured group of the Rhodocyclaceae. PMID- 29767717 TI - Introduction to the Hot Topics in Aesthetic Surgery Supplement. PMID- 29767716 TI - Soft Tissue Contraction in Body Contouring With Radiofrequency-Assisted Liposuction: A Treatment Gap Solution. AB - Radiofrequency-assisted liposuction is a relatively new concept in energy assisted body contouring techniques and has received instrument approval. This supplemental article reviews the clinical application of electromagnetic energy via the BodyTite (InMode Corporation, Toronto, Canada) device on soft tissues during suction lipectomy, its effect on soft tissue contraction, and its use in aesthetic body contouring in various clinical scenarios. PMID- 29767718 TI - Prediction of Treatment Outcomes for Neck Rejuvenation Utilizing a Unique Classification System of Treatment Approach Using a 1440-nm Side-Firing Laser. AB - Background: The appearance of a youthful neck is lost with age causing excessive skin laxity, a loss of subcutaneous fat, prominence of platysmal banding, and jowling. In view of the success obtained with laser treatment for neck rejuvenation, the authors have recently taken an algorithmic approach to developing a 7-category classification system of the aging conditions throughout the anatomic spectrum of three areas: skin, fat, and muscle. This system will correlate with specific treatment options. Objective: The objective of the study was to confirm the 7-category classification system and treatment approaches based on clinical outcome data for treatment of the mandibular and submandibular areas, specifically for skin tightening and laser lipolysis after a single 1440 nm laser treatment. Methods: Patients were treated with a single treatment of PrecisionTXTM 1440-nm wavelength laser on their necks. Baseline and posttreatment photographs were taken and evaluated by 3 blinded reviewers using the Cervicomental Angle Scale (CAS). Results: Subjects were rated grades II-III (2.9 +/- 0.8) on average at baseline and grades I-II (1.3 +/- 0.5) at follow-up. The average improvement was a mean score of 1.5 +/- 0.07. Patients, 23/25 (92%), showed at least a 1 score improvement. Conclusions: This study confirms a new minimally invasive treatment approach based on a unique classification system with no adverse events reported and high patient satisfaction. Level of Evidence 4: PMID- 29767719 TI - The ups and downs of S. aureus nasal carriage. AB - Staphylococcus aureus infections are a growing concern worldwide due to the increasing number of strains that exhibit antibiotic resistance. Recent studies have indicated that some percentage of people carry the bacteria in the nasal cavity and therefore are at a higher risk of subsequent, and more serious, infections in other parts of the body. However, individuals carrying the infection can be classified as only intermittent carriers versus persistent carriers, being able to eliminate the bacteria and later colonized again. Using a model of bacterial colonization of the anterior nares, we investigate oscillatory patterns related to intermittent carriage of S. aureus. Following several studies using global sensitivity analysis techniques, various insights into the model's behaviour were made including interacting effects of the bacteria's growth rate and movement in the mucus, suggesting parameter connections associated with biofilm-like behaviour. Here the bacterial growth rate and bacterial movement are explicitly connected, leading to expanded oscillatory behaviour in the model. We suggest possible implications that this oscillatory behaviour can have on the definition of intermittent carriage and discuss differences in the bacterial virulence dependent upon individual host health. Furthermore, we show that connecting the bacterial growth and movement also expands the region of the parameter space for which the bacteria are able to survive and persist. PMID- 29767720 TI - Functional analyses of rare genetic variants in complement component C9 identified in patients with age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a progressive disease of the central retina and the leading cause of irreversible vision loss in the western world. The involvement of abnormal complement activation in AMD has been suggested by association of variants in genes encoding complement proteins with disease development. A low-frequency variant (p.P167S) in the complement component C9 (C9) gene was recently shown to be highly associated with AMD, however its functional outcome remains largely unexplored. In this study, we reveal five novel rare genetic variants (p.M45L, p.F62S, p.G126R, p.T170I and p.A529T) in C9 in AMD patients, and evaluate their functional effects in vitro together with the previously identified (p.R118W and p.P167S) C9 variants.Our results demonstrate that the concentration of C9 is significantly elevated in patients' sera carrying the p.M45L, p.F62S, p.P167S and p.A529T variants compared to non-carrier controls. However, no difference can be observed in soluble terminal complement complex levels between the carrier and non-carrier groups. Comparing the polymerization of the C9 variants we reveal that the p.P167S mutant spontaneously aggregates, while the other mutant proteins (except for C9 p.A529T) fail to polymerize in the presence of zinc. Altered polymerization of the p.F62S and p.P167S proteins associated with decreased lysis of sheep erythrocytes and ARPE 19 cells by carriers' sera. Our data suggest that the analysed C9 variants affect only the secretion and polymerization of C9, without influencing its classical lytic activity. Future studies need to be performed to understand the implications of the altered polymerization of C9 in AMD pathology. PMID- 29767721 TI - BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes. AB - Birt-Hogg-Dube (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. The responsible gene FLCN is a tumor suppressor for kidney cancer which plays an important role in energy homeostasis through the regulation of mitochondrial oxidative metabolism. However, the process by which FLCN deficiency leads to renal tumorigenesis is unclear. In order to clarify molecular pathogenesis of BHD-associated kidney cancer, we conducted whole-exome sequencing analysis using next-generation sequencing technology as well as metabolite analysis using LC/MS and GC/MS. Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations (CNV) of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. In somatic variant analysis, very few variants were commonly observed in BHD associated kidney cancer; however, variants in chromatin remodeling genes were frequently observed in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis of BHD-associated kidney cancer revealed metabolic reprogramming towards upregulated redox regulation which may neutralize reactive oxygen species potentially produced from mitochondria with increased respiratory capacity under FLCN-deficiency. BHD-associated kidney cancer displays unique molecular characteristics which are completely different from sporadic kidney cancer, providing mechanistic insight into tumorigenesis under FLCN-deficiency as well as a foundation for development of novel therapeutics for kidney cancer. PMID- 29767724 TI - Fluctuations in populations of subsurface methane oxidizers in coordination with changes in electron acceptor availability. AB - The concentrations of electron donors and acceptors in the terrestrial subsurface biosphere fluctuate due to migration and mixing of subsurface fluids, but the mechanisms and rates at which microbial communities respond to these changes are largely unknown. Subsurface microbial communities exhibit long cellular turnover times and are often considered relatively static-generating just enough ATP for cellular maintenance. Here, we investigated how subsurface populations of CH4 oxidizers respond to changes in electron acceptor availability by monitoring the biological and geochemical composition in a 1339 m-below-land-surface (mbls) fluid-filled fracture over the course of both longer (2.5 year) and shorter (2 week) time scales. Using a combination of metagenomic, metatranscriptomic, and metaproteomic analyses, we observe that the CH4 oxidizers within the subsurface microbial community change in coordination with electron acceptor availability over time. We then validate these findings through a series of 13C-CH4 laboratory incubation experiments, highlighting a connection between composition of subsurface CH4 oxidizing communities and electron acceptor availability. PMID- 29767723 TI - ISCA1 Mutation In A Patient With Infantile-Onset Leukodystrophy Causes Defects In Mitochondrial [4Fe-4S] Proteins. AB - Multiple Mitochondrial Dysfunction Syndromes (MMDS) comprise a group of severe autosomal recessive diseases characterized by impaired respiration and lipoic acid metabolism, resulting in infantile-onset mitochondrial encephalopathy, non ketotic hyperglycinemia, myopathy, lactic acidosis and early death. Four different MMDS have been analyzed in detail according to the genes involved in the disease, MMDS1 (NFU1), MMDS2 (BOLA3), MMDS3 (IBA57), and MMDS4 (ISCA2). MMDS5 has recently been described in a clinical case report of patients carrying a mutation in ISCA1, but with no further functional analysis. ISCA1 encodes a mitochondrial protein essential for the assembly of [4Fe-4S] clusters in key metabolic and respiratory enzymes. Here, we describe a patient with a severe early onset leukodystrophy, multiple defects of respiratory complexes, and a severe impairment of lipoic acid synthesis. A homozygous missense mutation in ISCA1 (c.29T>G; p.V10G) identified by targeted MitoExome sequencing resulted in dramatic reduction of ISCA1 protein level. The mutation located in the uncleaved presequence severely affected both mitochondrial import and stability of ISCA1. Down-regulation of ISCA1 in HeLa cells by RNAi impaired the biogenesis of mitochondrial [4Fe-4S] proteins, yet could be complemented by expression of wild type ISCA1. In contrast, the ISCA1 p.V10G mutant protein only partially complemented the defects, closely resembling the biochemical phenotypes observed for ISCA1 patient fibroblasts. Collectively, our comprehensive clinical and biochemical investigations show that the ISCA1 p.V10G mutation functionally impaired mitochondrial [4Fe-4S] protein assembly and hence was causative for the observed clinical defects. PMID- 29767722 TI - Influence of bull age, ejaculate number, and season of collection on semen production and sperm motility parameters in Holstein Friesian bulls in a commercial artificial insemination centre. AB - In the current era of genomic selection, there is an increased demand to collect semen from genomically selected sires at a young age. The objective of this study was to assess the effect of bull age, ejaculate number, and season of collection on semen production (ejaculate volume, sperm concentration, and total sperm number; TSN) and sperm motility (prefreeze and post-thaw total and gross motility) parameters in Holstein Friesian bulls in a commercial artificial insemination (AI) center. The study involved the interrogation of a large dataset collected over a 4-yr period, (n = 8,983 ejaculates; n = 176 Holstein Friesian bulls aged between 9 mo and 8 yr). Bulls aged less than 1 yr had the poorest semen production and sperm motility values for all parameters assessed compared with bulls older than 1 yr (P < 0.01). First ejaculates had greater semen production and greater prefreeze motility values than second consecutive ejaculates (P < 0.01), but despite this, there was no difference in post-thaw motility. When subsequent ejaculates were collected from bulls aged less than 1 yr, semen production and sperm motility did not differ compared with mature bulls. Semen collected in winter was poorest in terms of sperm concentration and TSN, but best in terms of post-thaw motility (P < 0.01). In conclusion, second ejaculates can be collected, particularly from bulls aged less than 1 yr, without a significant decrease in post-thaw sperm motility, thus may be a useful strategy to increase semen availability from young genomically selected AI bulls in high demand. PMID- 29767725 TI - Advancing the health of women and newborns: predictors of patient satisfaction among women attending antenatal and maternity care in rural Rwanda. AB - Objective: Identify predictors of patient satisfaction with antenatal care (ANC) and maternity services in rural Rwanda. Design: Cross-sectional. Setting: Twenty six health facilities in Southern Kayonza (SK) and Kirehe districts. Participants: Sample of women >= 16 years old receiving antenatal and delivery care between November and December 2013. Intervention: Survey of patient satisfaction with antenatal and delivery care to inform quality improvement (QI) initiatives aimed at reducing neonatal mortality. Main Outcome Measure: Overall satisfaction with antenatal and delivery care (reported as excellent or very good). Results: In multivariate logistic regression analysis, high perceived quality [odds ratio (OR) = 3.03, 95% confidence intervals (CI): 1.565.88], respect [OR = 4.13, 95% CI: 2.16-7.89], and confidentiality [SK: OR = 7.50, 95% CI: 2.16-26.01], [Kirehe: OR = 1.54, 95% CI: 0.60-3.94] were associated with higher overall satisfaction with ANC, while having >=1 child compared to none [OR = 0.46, 95% CI: 0.25-0.84] was associated with lower satisfaction. For maternity services, <5 years of school versus >=5 years [OR = 0.13, 95% CI: 0.026-0.69] and higher cleanliness [OR = 19.23, 95% CI: 2.22-166.83], self-reported quality [OR = 10.52, 95% CI: 1.81-61.22], communication [OR = 8.78, 95%CI: 1.95-39.59], and confidentiality [OR = 8.66, 95% CI: 1.20-62.64] were all positively associated with high satisfaction. Higher comfort [OR: 0.050, 95% CI: 0.0034-0.71] and Kirehe vs. SK district [OR: 0.21, 95% CI: 0.042-1.01] were associated with lower satisfaction. Conclusions: Patient-centeredness (including interpersonal relationships), organizational factors, and location are important individual determinants of satisfaction for women seeking maternal care at study facilities. Understanding variation in these factors should inform QI efforts in maternal and newborn health programs. PMID- 29767726 TI - The role of ethics in data governance of large neuro-ICT projects. AB - Objective: We describe current practices of ethics-related data governance in large neuro-ICT projects, identify gaps in current practice, and put forward recommendations on how to collaborate ethically in complex regulatory and normative contexts. Methods: We undertake a survey of published principles of data governance of large neuro-ICT projects. This grounds an approach to a normative analysis of current data governance approaches. Results: Several ethical issues are well covered in the data governance policies of neuro-ICT projects, notably data protection and attribution of work. Projects use a set of similar policies to ensure users behave appropriately. However, many ethical issues are not covered at all. Implementation and enforcement of policies remain vague. Conclusions: The data governance policies we investigated indicate that the neuro-ICT research community is currently close-knit and that shared assumptions are reflected in infrastructural aspects. This explains why many ethical issues are not explicitly included in data governance policies at present. With neuro-ICT research growing in scale, scope, and international involvement, these shared assumptions should be made explicit and reflected in data governance. PMID- 29767727 TI - Effects of long-term intake of a yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 on mice. AB - The gut is an extremely complicated ecosystem where micro-organisms, nutrients and host cells interact vigorously. Although the function of the intestine and its barrier system weakens with age, some probiotics can potentially prevent age related intestinal dysfunction. Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131, which are the constituents of LB81 yogurt, are representative probiotics. However, it is unclear whether their long-term intake has a beneficial influence on systemic function. Here, we examined the gut microbiome, fecal metabolites and gene expression profiles of various organs in mice. Although age-related alterations were apparent in them, long-term LB81 yogurt intake led to an increased Bacteroidetes to Firmicutes ratio and elevated abundance of the bacterial family S24-7 (Bacteroidetes), which is known to be associated with butyrate and propanoate production. According to our fecal metabolite analysis to detect enrichment, long-term LB81 yogurt intake altered the intestinal metabolic pathways associated with propanoate and butanoate in the mice. Gene ontology analysis also revealed that long-term LB81 yogurt intake influenced many physiological functions related to the defense response. The profiles of various genes associated with antimicrobial peptides-, tight junctions-, adherens junctions- and mucus-associated intestinal barrier functions were also drastically altered in the LB81 yogurt-fed mice. Thus, long-term intake of LB81 yogurt has the potential to maintain systemic homeostasis, such as the gut barrier function, by controlling the intestinal microbiome and its metabolites. PMID- 29767728 TI - Andecaliximab [Anti-matrix Metalloproteinase-9] Induction Therapy for Ulcerative Colitis: A Randomised, Double-Blind, Placebo-Controlled, Phase 2/3 Study in Patients With Moderate to Severe Disease. AB - Background and Aims: Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. Methods: Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. Results: Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. Conclusions: Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported. PMID- 29767729 TI - A comparative study on the excretion of urinary metabolites in goats and sheep to evaluate spot sampling applied to protein nutrition trials. AB - The main objective of this study was to establish a protocol to validate urine spot samples to estimate N excretion and microbial synthesis in goat and sheep; and to study factors that affect daily creatinine and purine derivatives (PD) urinary excretion. Also a performance trial was carried out to compare goat and sheep slaughtered after different feedlot periods. Twelve Boer goats (20.6 kg +/- 3.4 initial BW) and 12 Dorper sheep (18.4 kg +/- 2.3 initial BW), all 4-mo-old, males, were used. Eight animals (4 goats and 4 sheep) were randomly allocated to be slaughtered at 28, 56, and 84 d in feedlot. The experiment was conducted in a completely randomized design in a 2 * 3 factorial scheme, in which the factors were both species and the 3 feedlot periods. Diet consisted of 50% sorghum silage and 50% concentrate on a DM basis. Nutrient intake was higher (P < 0.01) for sheep than goats. Apparent digestibility of nutrients was similar (P > 0.05) in both species. Sheep had greater (P < 0.01) ADG and final BW than goats. Fat deposition and fat:muscle ratio was higher (P < 0.01) in sheep carcasses. Sheep had higher N urinary (P = 0.02) excretion and N retention (g/d; P < 0.01) than goats. Urinary N excretion increased linearly (P < 0.01) in response to feedlot period. However, feedlot did not affect (P = 0.20) N retention, but linearly reduced the relationship between N retained and ingested (P = 0.04) or apparently digested (P < 0.01). Microbial efficiency (P > 0.05) did not differ between species. Creatinine excretion (C mg/d; P < 0.01) was higher in sheep than goats. Purine derivatives (Y) were related closely with OM intake (Y = 0.013+/-0.0007X; r2 = 94). A difference (P < 0.01) was found between the allometric model for creatinine excretion (Y) and muscle weight (X) for both species, and the following equations were obtained: Y = 89.04(+/-31.44)X0.9797(+/-0.16) for goats and Y = 109.8(+/-47.50)X0.8002(+/-0.20) for sheep. Creatinine concentration was greater during nocturnal than diurnal periods, with lower diurnal fluctuations. Sampling time did not affect (P = 0.27) the PD:C ratio. The urea (U):C ratio was higher (P < 0.01) in sheep than goats, and was also higher (P < 0.01) during diurnal than nocturnal sampling periods. Our results suggest that it is necessary to take 2 and 3 spot urine samples after feeding to estimate N compounds excretions in goats and sheep, respectively. PMID- 29767731 TI - Development and Reproduction of Neoseiulus californicus (Acari: Phytoseiidae) and Tetranychus urticae (Acari: Tetranychidae) Under Simulated Natural Temperature. AB - Although laboratory observations provide basic knowledge of the development and reproduction of predacious and phytophagous mites, little is known of their behavior under natural conditions. Using a closed system designed to simulate natural climate patterns, we investigated the development and reproduction of the predatory mite Neoseiulus californicus (McGregor) (Acari: Phytoseiidae) and the pest mite Tetranychus urticae Koch (Acari: Tetranychidae) at air temperatures typical of June to October at three latitudes (Aomori, Tottori, and Naha) in Japan. The peaks of development in both species showed similar trends at each location. The shortest developmental times for both species were observed during August in Aomori, from July to September in Tottori and during August and September in Naha. Development of T. urticae was not completed during October in Aomori due to the decreased air temperature. High reproduction (number of eggs produced during 5 d from the first oviposition) of N. californicus was attained at the conditions that shortened the developmental times (i.e., high-temperature months). T. urticae showed a reproduction trend similar to that of N. californicus except for the low number of eggs produced during August in Naha due to the high mortality of adult females and during October in Tottori due to diapause incidence. This information is in agreement with field observations and together might be useful for planning biological control programs for phytophagous mites and for successful establishment of predacious mites in new habitats. PMID- 29767730 TI - Physicochemical characteristics and sensory attributes of meat from heavy-weight Iberian and F1 Large White * Landrace pigs finished intensively or in free-range conditions. AB - Iberian (IB, n = 60) and crossbred Large White * Landrace (F1, n = 58) pigs were slaughtered at 160 kg, after finishing under intensive conditions or on pasture and acorns. The study was carried out as a factorial arrangement of treatments, and physicochemical properties and sensory attributes of meat were assessed in Longissimus thoracis samples. Physical characteristics included the assessment of drip loss, cooking loss, shear force, and color coordinates in meat samples processed at 2 and 9 d postmortem. The interactions of genetic group and finishing system were significant (P < 0.05) for cooking loss in meat aged for 9 d and for sensorial tenderness and global acceptability of meat, but none of the other physicochemical, color coordinates, and sensory variables analyzed showed a significant interaction. Genetic group was the main factor influencing the variables analyzed, with a major (P < 0.01) influence on all meat physicochemical characteristics and sensory attributes. Relative to F1 pigs, the IB produced meat with higher intramuscular fat content and marbling score, more appealing color coordinates, lower shear force, and higher sensorial tenderness. The finishing systems affected (P < 0.05) most physical characteristics, but not chemical composition of meat and their impact on sensory properties was small. The tenderness, juiciness, and global acceptability of meat were much higher in IB pigs, and flavor was also more desirable, but the difference was smaller. The differences in sensory properties between meats originating from the two genetic groups were largely explained by the higher fat deposition in IB pigs, such that a higher level of marbling was positively associated with all the sensory attributes evaluated. Ageing meat for up to 9 d postmortem benefited pork quality, improving meat tenderness, and color, particularly in crossbred pigs and those finished intensively. PMID- 29767732 TI - Dietary Intake of alpha-Linolenic Acid Is Not Appreciably Associated with Risk of Ischemic Stroke among Middle-Aged Danish Men and Women. AB - Background: Intake of the plant-derived omega-3 (n-3) fatty acid alpha-linolenic acid (ALA) may reduce the risk of ischemic stroke. Objective: We have investigated the associations between dietary intake of ALA and the risk of ischemic stroke and ischemic stroke subtypes. Methods: This was a follow-up study. A total of 57,053 participants aged 50-64 y were enrolled into the Danish Diet, Cancer and Health cohort between 1993 and 1997. Intake of ALA was assessed by a validated semiquantitative food frequency questionnaire. Potential incident cases of ischemic stroke were identified in the Danish National Patient Register, validated, and classified into subtypes based on assumed etiology. Statistical analyses were performed via Cox proportional hazard regression with adjustment for established ischemic stroke risk factors. Results: A total of 1859 ischemic stroke cases were identified during a median of 13.5 y of follow-up. In multivariable analyses using restricted cubic splines adjusting for traditional risk factors for ischemic stroke, we observed no clear associations between dietary intake of ALA and the risk of total ischemic stroke or any of its subtypes including ischemic stroke due to large artery atherosclerosis, ischemic stroke due to small-vessel occlusion, and ischemic stroke due to cardio-embolism. Conclusion: Dietary intake of ALA was neither consistently nor appreciably associated with the risk of ischemic stroke or ischemic stroke subtypes among middle-aged Danish men and women. This study was registered at clinicaltrials.gov as NCT03258983. PMID- 29767734 TI - Electrical Burns and Late Spontaneous Artery Ruptures: About Three Cases. AB - Electrical burns are responsible for arterial and venous thrombosis, as well as weakening of the arteries. Immediate or delayed arterial occlusions, secondary to the aggression of the intima, or aneurysms, secondary to the aggression of the media, sometimes lead to artery ruptures without any warning signs. Such ruptures may trigger a hemorrhagic shock whose period of onset is variable and unpredictable. We are presenting here three cases treated in our department for electrical burns, whose complications were marked by hemorrhagic shock, secondary to late artery ruptures, sometimes occurring several months following the event. These case reports required performance of emergency hemostasis in order to control sudden bleeding, with first approach being placement of a tourniquet at the base of the limb and/or a compression point. Through these cases, we thought it is crucial to closely monitor for a few weeks all patients who were victims of electrical injury, even more so if it was associated with a compartment syndrome of one or more limbs and high rhabdomyolysis, which seem to be predictive factors of late artery ruptures in our case reports. PMID- 29767733 TI - Risk and Timing of Tuberculosis Among Close Contacts of Persons with Infectious Tuberculosis. AB - Background: The risk and timing of tuberculosis among recently exposed close contacts of patients with infectious tuberculosis are not well established. Methods: We prospectively enrolled patients >=15 years of age with culture confirmed pulmonary tuberculosis and their close contacts at 9 health departments in the United States and Canada. Close contacts were screened and cross-matched with tuberculosis registries to identify those who developed tuberculosis. Results: Tuberculosis was diagnosed in 158 of 4490 contacts (4%) of 718 index patients with tuberculosis. Of tuberculosis cases among contacts, cumulative totals of 81 (51%), 119 (75%), 128 (81%), and 145 (92%) were diagnosed by 1, 3, 6, and 12 months, respectively, after the index patients' diagnosis. Tuberculosis rates among contacts were 2644, 115, 46, 69, and 25 cases per 100000 persons, respectively, in the 5 consecutive years after the index patients' diagnosis. Of the tuberculosis cases among contacts, 121 (77%) were identified by contact investigation and 37 (23%) by tuberculosis registry cross-match. Conclusions: Close contacts to infectious patients with tuberculosis had high rates of tuberculosis, with most disease diagnosed before or within 3 months after the index patient' diagnosis. Contact investigations need to be prompt to detect tuberculosis and maximize the opportunity to identify and treat latent infection, to prevent disease. PMID- 29767736 TI - Pollination of Granadilla (Passiflora ligularis) Benefits From Large Wild Insects. AB - The contribution of wild pollinators to food production has recently been assessed for many crops, although it remains unclear for several tropical crops. Granadilla (Passiflora ligularis Juss), a crop native to the tropical Andes, is one such crop where a gap exists regarding comprehensive knowledge about its pollination system. In a field experiment in the Colombian Andes, we 1) describe flower visitors in terms of visit quantity (visitation rate) and quality (touches of flower-reproductive structures), 2) assess the pollination system by comparing fruit set and fruit weight per flower in three pollination treatments: pollinator exclusion, open pollination, and supplementary pollination, and 3) evaluate pollination deficits (difference between open and supplementary pollination) in relation to pollinator density. We observed 12 bee species visiting granadilla flowers, with Apis mellifera Linnaeus being the most frequent species. However, large bees such as Xylocopa lachnea Moure and Epicharis rustica Olivier touched stigmata and anthers more often. Fruit set and fruit weight per flower were significantly lower in the pollinator exclusion treatment compared to open and supplementary pollination, while the latter treatments showed nonsignificant differences. Pollination deficit significantly decreased with the increasing density of large bees and wasps. Our results illustrate the high dependency of granadilla on wild pollinating insects and highlight the crucial role of large insects to granadilla production. This stresses the need to maintain or increase the density of large pollinators in granadilla production areas, which in turn will necessitate better knowledge on their ecological requirements to inform landscape planning and population-management programs. PMID- 29767735 TI - Untargeted Metabolomics Identifies Novel Potential Biomarkers of Habitual Food Intake in a Cross-Sectional Study of Postmenopausal Women. AB - Background: Recent studies suggest that untargeted metabolomics is a promising tool to identify novel biomarkers of individual foods. However, few large cross sectional studies with comprehensive data on habitual diet and circulating metabolites have been conducted. Objective: We aimed to identify potential food biomarkers and evaluate their predictive accuracy. Methods: We conducted a cross sectional analysis of consumption of 91 food groups or items, assessed by a 152 item food-frequency questionnaire, in relation to 1186 serum metabolites measured by mass spectrometry-based platforms from 1369 nonsmoking postmenopausal women (mean age = 68.3 y). Diet-metabolite associations were selected by Pearson's partial correlation analysis (P < 4.63 * 10-7, |r| > 0.2). The predictive accuracy of the selected food metabolites was evaluated from the area under the curve (AUC) calculated from receiver operating characteristic analysis conducted among women in the top and bottom quintiles of dietary intake. Results: We identified 379 diet-metabolite associations. Forty-two food groups or items were correlated with 199 serum metabolites. We replicated 63 metabolites as biomarkers of habitual food intake reported in previous cross-sectional studies. Among those not previously shown to be associated with habitual diet, several are biologically plausible and were reported in acute feeding studies including: banana and dopamine 3-O-sulfate (r = 0.34, AUC = 76%) and dopamine 4-O-sulfate (r = 0.33, AUC = 74%), garlic and alliin (r = 0.24, AUC = 69%), N-acetylalliin (r = 0.27, AUC = 70%), and S-allylcysteine (r = 0.23, AUC = 69). Two unannotated metabolites were the strongest predictors for dark fish (X-02269, r = 0.51, AUC = 94%) and coffee intake (X-21442, r = 0.62, AUC = 98%). Conclusion: In this comprehensive, cross-sectional analysis of habitual food intake and serum metabolites among postmenopausal women, we identified several potentially novel food biomarkers and replicated others. Our findings contribute to the limited literature on food-based biomarkers and highlight the significant and promising role that large cohort studies with archived blood samples could play in this field. This study was registered at clinicaltrials.gov as NCT03282812. PMID- 29767737 TI - Recent Issues in the Use of Signed Language Assessments for Diagnosis of Language Disorders in Signing Deaf and Hard of Hearing Children. AB - In recent years, normed signed language assessments have become a useful tool for researchers, practitioners, and advocates. Nevertheless, there are limitations in their application, particularly for the diagnosis of language disorders, and learning disabilities. Here, we discuss some of the available normed, signed language assessments and some of their limitations. We have also provided information related to practices that should lead to improvement in the quality of signed language assessments. PMID- 29767738 TI - Microsatellite Markers Transferability in Culex nigripalpus (Diptera: Culicidae). AB - Microsatellite loci specifically designed and optimized for secondary vectors and neglected species of mosquitoes are lacking. Cross-species transferability of microsatellite loci between close taxa has been used as a reliable option, being successfully done for Aedes taeniorhynchus Wiedemann (Diptera: Culicidae), Triatoma sordida Stal (Hemiptera: Reduviidae), and Aedes fluviatilis Lutz (Diptera: Culicidae). Nonetheless, prior to the utilization of transferred microsatellites, they must be assessed for their performance and reliability on the target species. Therefore, the goal of this study was to transfer and validate SSR primers previously developed for the Culex pipiens complex to Culex (Culex) nigripalpus Theobald (Diptera: Culicidae). Culex nigripalpus were collected in seven different locations throughout the city of Sao Paulo using CDC traps baited with dry ice between 2011 and 2013, yielding a total of 223 specimens. Six SSR primers were successfully transferred to Cx. nigripalpus yielding satisfactory results for allele richness, ranging from 5 to 12 alleles per locus. The expected heterozygosity values were higher than the observed heterozygosity (P < 0.05) for the loci CxqCTG10, CxqGT51, and Cxpq59. Linkage disequilibrium results were statistically significant only for the comparison between the loci CxqCA115 and CxqCTG10, and the estimation for the probability of null alleles was also low, ranging from 0 to 0.052. These results substantially validate the SSRs transference to Cx. nigripalpus as well as their subsequent use in microevolution studies comprising this species. PMID- 29767740 TI - Corrigendum to "Long-Term Empirical and Observational Evidence of Practical Helicoverpa zea Resistance to Cotton With Pyramided Bt Toxins". PMID- 29767741 TI - Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system. AB - The neural regulation of organs can be categorized as systemic or local. Whereas systemic regulation by the hypothalamus-pituitary-adrenal gland-mediated release of steroid hormones has been well studied, the mechanisms for local regulation have only recently emerged. Two types of local neural regulation are known, the gateway reflex and the inflammatory reflex. The gateway reflex describes a mechanism that converts regional neural stimulations into inflammatory outputs by changing the state of specific blood vessels. Molecularly, the enhancement of NF kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity in endothelial cells by neurotransmitters, such as noradrenaline and ATP, induces an enhanced production of pro-inflammatory mediators, including chemokines, which form immune cell gateways at specific vessels. Several types of gateway reflex have been identified, and each regulates distinct organs by creating gateways for autoreactive T cells that induce local inflammation. On the other hand, the inflammatory reflex elicits an anti-inflammatory response through vagal nerves. Here, we summarize recent works on these two local neuro-immune interactions, giving special focus to the gateway reflex. PMID- 29767739 TI - Efficacy, Immunogenicity, and Safety of a 9-Valent Human Papillomavirus Vaccine: Subgroup Analysis of Participants From Asian Countries. AB - Background: A 9-valent human papillomavirus-6/11/16/18/31/33/45/52/58 (9vHPV) vaccine extends coverage to 5 next most common oncogenic types (31/33/45/52/58) in cervical cancer versus quadrivalent HPV (qHPV) vaccine. We describe efficacy, immunogenicity, and safety in Asian participants (India, Hong Kong, South Korea, Japan, Taiwan, and Thailand) from 2 international studies: a randomized, double blinded, qHPV vaccine-controlled efficacy study (young women aged 16-26 years; NCT00543543; Study 001); and an immunogenicity study (girls and boys aged 9-15 years; NCT00943722; Study 002). Methods: Participants (N = 2519) were vaccinated at day 1 and months 2 and 6. Gynecological samples (Study 001 only) and serum were collected for HPV DNA and antibody assessments, respectively. Injection-site and systemic adverse events (AEs) were monitored. Data were analyzed by country and vaccination group. Results: 9vHPV vaccine prevented HPV-31/33/45/52/58 related persistent infection with 90.4%-100% efficacy across included countries. At month 7, >=97.9% of participants seroconverted for each HPV type. Injection site AEs occurred in 77.7%-83.1% and 81.9%-87.5% of qHPV and 9vHPV vaccine recipients in Study 001, respectively, and 62.4%-85.7% of girls/boys in Study 002; most were mild to moderate. Conclusions: The 9vHPV vaccine is efficacious, immunogenic, and well tolerated in Asian participants. Data support 9vHPV vaccination programs in Asia. Clinical Trials Registration: NCT00543543; NCT00943722. PMID- 29767742 TI - Bed management team with Kanban web-based application. AB - Objective: To measure the effectiveness of the bed management process that uses a web-based application with Kanban methodology to reduce hospitalization time of hospitalized patients. Design: Before-after study was performed. Setting: The study was conducted between July 2013 and July 2017, at the Unimed Regional Hospital of Fortaleza, which has 300 beds, of which 60 are in the intensive care unit (ICU). It is accredited by International Society for Quality in Healthcare. Population: Patients hospitalized in the referred period. Intervention: Bed management with an application that uses color logic to signal at which stage of high flow the patients meet, in which each patient is interpreted as a card of the classical Kanban theory. It has an automatic user signaling system for process movement, and a system for monitoring and analyzing discharge forecasts. Main Outcome Measures: Length of hospital stay, number of customer complaints related to bed availability. Results: After the intervention, the hospital's overall hospital stay time was reduced from 5.6 days to 4.9 days (P = 0.001). The units with the greatest reduction were the ICUs, with reduction from 6.0 days to 2.0 (P = 0.001). The relative percentage of complaints regarding bed availability in the hospital fell from 27% to 0%. Conclusion: We conclude that the use of an electronic tool based on Kanban methodology and accessed via the web by a bed management team is effective in reducing patients' hospital stay time. PMID- 29767743 TI - Premeal Low-Fat Yogurt Consumption Reduces Postprandial Inflammation and Markers of Endotoxin Exposure in Healthy Premenopausal Women in a Randomized Controlled Trial. AB - Background: Metabolic endotoxemia is associated with obesity and contributes to postprandial inflammation. Objective: We aimed to determine if low-fat yogurt consumption prevents postprandial inflammation and dysmetabolism in healthy women by inhibiting biomarkers of metabolic endotoxemia. Methods: Premenopausal women defined as obese and nonobese [body mass index (BMI, in kg/m2) 30-40 and 18.5-27, respectively, n = 120] were randomly assigned to consume 339 g of low-fat yogurt (YN, yogurt nonobese; YO, yogurt obese) or 324 g of soy pudding (CN, control nonobese; CO, control obese) for 9 wk (n = 30/group). The intervention foods each supplied 330 kcal with 3 g fat, 66 g carbohydrate, and 4-6 g protein. At weeks 0 and 9, participants ingested 226 g of yogurt or 216 g of soy pudding before a meal providing 56-60 g fat, 82 g carbohydrate, and 28-30 g protein. Plasma soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP), LPS activity, interleukin-6 (IL-6), glucose, triglyceride, and insulin were measured hourly for 4 h to assess differences in postprandial responses between groups by 2-factor ANOVA. Results: Premeal yogurt consumption prevented the postprandial decrease in sCD14 net incremental area under the curve (net iAUC) by 72% in obese individuals at week 0 (P = 0.0323). YN and YO had >=40% lower net iAUC of LBP-to-sCD14 ratio and plasma IL-6 concentration than CN and CO, respectively (P < 0.05). CO had postprandial hyperglycemia which was not evident in YO; in contrast YN had 57% less postprandial hypoglycemia than did CN (P-interaction = 0.0013). After 9 wk of yogurt consumption, DeltaAUC of LBP-to-sCD14 ratios of YO and YN were less than half of those of the control groups (P = 0.0093). Conclusion: Yogurt consumption improved postprandial metabolism and biomarkers of metabolic endotoxemia in healthy premenopausal women. Premeal yogurt consumption is a feasible strategy to inhibit postprandial dysmetabolism and thus may reduce cardiometabolic risk. This trial was registered at clinicaltrials.gov as NCT01686204. PMID- 29767744 TI - Genome-wide association reveals novel genomic loci controlling rice grain yield and its component traits under water-deficit stress during the reproductive stage. AB - A diversity panel comprising of 296 indica rice genotypes was phenotyped under non-stress and water-deficit stress conditions during the reproductive stage in the 2013 and 2014 dry seasons (DSs) at IRRI, Philippines. We investigated the genotypic variability for grain yield, yield components, and related traits, and conducted genome-wide association studies (GWAS) using high-density 45K single nucleotide polymorphisms. We detected 38 loci in 2013 and 64 loci in 2014 for non stress conditions and 69 loci in 2013 and 55 loci in 2014 for water-deficit stress. Desynchronized flowering time confounded grain yield and its components under water-deficit stress in the 2013 experiment. Statistically corrected grain yield and yield component values using days to flowering helped to detect 31 additional genetic loci for grain yield, its components, and the harvest index in 2013. There were few overlaps in the detected loci between years and treatments, and when compared with previous studies using the same panel, indicating the complexity of yield formation under stress. Nevertheless, our analyses provided important insights into the potential links between grain yield with seed set and assimilate partitioning. Our findings demonstrate the complex genetic architecture of yield formation and we propose exploring the genetic basis of less complex component traits as an alternative route for further yield enhancement. PMID- 29767746 TI - Mixing Mutation Location With Carcinogen Exposure: A Recipe for Tissue Specificity in BRCA2-Associated Cancers? PMID- 29767745 TI - Preconception Maternal Iodine Status Is Positively Associated with IQ but Not with Measures of Executive Function in Childhood. AB - Background: Adverse effects of severe maternal iodine deficiency in pregnancy on fetal brain development are well-established, but the effects of milder deficiency are uncertain. Most studies examine iodine status in pregnancy; less is known about iodine nutrition before conception. Objective: We examined relations between maternal preconception iodine status and offspring cognitive function, within a prospective mother-offspring cohort. Methods: Maternal iodine status was assessed through the use of the ratio of iodine:creatinine concentrations (I/Cr) in spot urine samples [median (IQR) period before conception 3.3 y (2.2-4.7 y)]. Childhood cognitive function was assessed at age 6 7 y. Full-scale IQ was assessed via the Wechsler Abbreviated Scale of Intelligence, and executive function through the use of tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses (n = 654 mother child dyads) were adjusted for potential confounders including maternal intelligence, education, and breastfeeding duration. Results: The median (IQR) urinary iodine concentration was 108.4 ug/L (62.2-167.8 ug/L) and the I/Cr ratio 114 ug/g (76-164 ug/g). The preconception I/Cr ratio was positively associated with child IQ, before and after adjustment for potential confounding influences [beta = 0.13 (95% CI: 0.04, 0.21)/SD, P = 0.003]. 8.9% of women had a preconception urinary I/Cr ratio <50 ug/g; compared with those with an I/Cr ratio >=150 ug/g, the IQ of their offspring was 0.49 (95% CI: 0.79, 0.18) SD lower. There were no associations with the executive function outcomes assessed via CANTAB, before or after adjustment for confounders. Conclusion: The positive association between iodine status before conception and child IQ provides some support for demonstrated links between low maternal iodine status in pregnancy and poorer cognitive function reported in other studies. However, given the negative effects on school performance previously observed in children born to iodine-deficient mothers, the lack of associations with measures of executive function in the present study was unexpected. Further data are needed to establish the public health importance of low preconception iodine status. PMID- 29767747 TI - The use of privacy-protected computer vision to measure the quality of healthcare worker hand hygiene. AB - Objectives: (i) To demonstrate the feasibility of automated, direct observation and collection of hand hygiene data, (ii) to develop computer visual methods capable of reporting compliance with moment 1 (the performance of hand hygiene before touching a patient) and (iii) to report the diagnostic accuracy of automated, direct observation of moment 1. Design: Observation of simulated hand hygiene encounters between a healthcare worker and a patient. Setting: Computer laboratory in a university. Participants: Healthy volunteers. Main outcome measures: Sensitivity and specificity of automatic detection of the first moment of hand hygiene. Methods: We captured video and depth images using a Kinect camera and developed computer visual methods to automatically detect the use of alcohol-based hand rub (ABHR), rubbing together of hands and subsequent contact of the patient by the healthcare worker using depth imagery. Results: We acquired images from 18 different simulated hand hygiene encounters where the healthcare worker complied with the first moment of hand hygiene, and 8 encounters where they did not. The diagnostic accuracy of determining that ABHR was dispensed and that the patient was touched was excellent (sensitivity 100%, specificity 100%). The diagnostic accuracy of determining that the hands were rubbed together after dispensing ABHR was good (sensitivity 83%, specificity 88%). Conclusions: We have demonstrated that it is possible to automate the direct observation of hand hygiene performance in a simulated clinical setting. We used cheap, widely available consumer technology and depth imagery which potentially increases clinical application and decreases privacy concerns. PMID- 29767748 TI - Glial Activation and Central Synapse Loss, but Not Motoneuron Degeneration, Are Prevented by the Sigma-1 Receptor Agonist PRE-084 in the Smn2B/- Mouse Model of Spinal Muscular Atrophy. AB - Spinal muscular atrophy (SMA) is characterized by the loss of alpha-motoneurons (MNs) with concomitant muscle denervation. MN excitability and vulnerability to disease are particularly regulated by cholinergic synaptic afferents (C-boutons), in which Sigma-1 receptor (Sig1R) is concentrated. Alterations in Sig1R have been associated with MN degeneration. Here, we investigated whether a chronic treatment with the Sig1R agonist PRE-084 was able to exert beneficial effects on SMA. We used a model of intermediate SMA, the Smn2B/- mouse, in which we performed a detailed characterization of the histopathological changes that occur throughout the disease. We report that Smn2B/- mice exhibited qualitative differences in major alterations found in mouse models of severe SMA: Smn2B/- animals showed more prominent MN degeneration, early motor axon alterations, marked changes in sensory neurons, and later MN deafferentation that correlated with conspicuous reactive gliosis and altered neuroinflammatory M1/M2 microglial balance. PRE-084 attenuated reactive gliosis, mitigated M1/M2 imbalance, and prevented MN deafferentation in Smn2B/- mice. These effects were also observed in a severe SMA model, the SMNDelta7 mouse. However, the prevention of gliosis and MN deafferentation promoted by PRE-084 were not accompanied by any improvements in clinical outcome or other major pathological changes found in SMA mice. PMID- 29767750 TI - Mosquitoes (Diptera: Culicidae) From the Northwestern Brazilian Amazon: Araca River. AB - The mosquito fauna (Diptera: Culicidae) from two remote localities along the Araca River, within the Municipality of Barcelos, towards the northern border of the Brazilian State of Amazonas, were sampled using CDC, Shannon, Malaise, and Suspended traps, along with net sweeping and immature collections. During June 2010, 111 collections yielded more than 23,500 mosquitoes distributed in 15 genera, representing 119 different species, together with eight morphospecies, which may represent undescribed new taxa. Among the species collected, there is one new distributional record for Brazil and nine new distributional records for the State of Amazonas. With the highest number of species, the genus Culex Linnaeus also had the largest number of individuals followed by Aedes Meigen with the second highest number of species. The most abundant species was Culex (Melanoconion) gnomatos Sallum, Hutchings & Ferreira followed by Culex (Melanoconion) portesi Senevet & Abonnenc, Culex (Culex) mollis Dyar & Knab, Aedes (Ochlerotatus) fulvus (Wiedemann), Culex (Melanoconion) pedroi Sirivanakarn & Belkin, Culex (Melanoconion) crybda Dyar, Aedes (Ochlerotatus) nubilus (Theobald), and Anopheles (Anopheles) peryassui Dyar & Knab. The epidemiological implications of mosquito species found are discussed and are compared with other mosquito inventories from the Amazon region. As the first standardized mosquito inventory of the Araca River, with the identification of 127 species level taxa, the number of mosquito species which have been collected along the northern tributaries of the middle Rio Negro Basin (i.e., Padauari and Araca Rivers) increased significantly. PMID- 29767751 TI - Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients. AB - Background: The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). Methods: We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. Results: Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. Conclusion: Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs. PMID- 29767749 TI - Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin. AB - Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress. PMID- 29767753 TI - Benzaldehyde Synergizes the Response of Female Xyleborinus saxesenii (Coleoptera: Curculionidae, Scolytinae) to Ethanol. AB - The ambrosia beetle, Xyleborinus saxesenii Ratzeburg (Coleoptera: Curculionidae, Scolytinae), infests physiologically stressed apple and peach trees in Korea. Dispersing females utilize the degradation product ethanol and host-related volatiles to locate and colonize new host trees. We examined the extent to which 12 chemicals emitted from fruit trees act synergistically with ethanol to attract X. saxesenii. The addition of benzaldehyde to ethanol significantly increased beetle attraction, although benzaldehyde was not attractive by itself. The addition of (-)-alpha-pinene, ethyl butyrate, ethyl isovalerate, (R)-(+) limonene, 3-methyl-1-butanol, ethyl tiglate, (+)-aromadendrene, vanillin, 2 butanol, styrene, or ethyl 3,3-dimethylacrylate to ethanol had no effect on beetle attraction. In a dose-response test, the addition of 5-50% benzaldehyde doses synergistically increased the number of beetle captures; however, trap catches did not increase as the benzaldehyde dosage increased. The synergistic influence of benzaldehyde on beetle response to ethanol was lower in early spring than in late summer to early fall, probably because synthetic benzaldehyde emissions from field lures were overwhelmed by background levels of natural benzaldehyde emitted from peach twigs in the flowering stage. PMID- 29767752 TI - Stunting at 24 Months Is Not Related to Incidence of Overweight through Young Adulthood in an Urban South African Birth Cohort. AB - Background: The role that childhood stunting plays in the development of overweight and obesity later in life is not well understood, particularly in adolescence and young adulthood, because most studies have only followed up through midchildhood. Objective: The objective of this study was to examine the relation between stunting and age-specific patterns of overweight and obesity incidence from early childhood to young adulthood in the context of a country in the process of the nutrition transition while these children were growing up. Methods: We analyzed data from 895 participants in the Birth-to-Twenty Plus Cohort (Bt20+), an urban South African birth cohort initiated in 1990. Anthropometric data were collected at multiple ages and participants were included if they provided height at age 24 mo and >=1 measure of body mass index [BMI; weight (kg)/height (m)2] in each of the following time periods: 4-8 y, 11 12 y, 13-15 y, 16-18 y, and 22-24 y. We defined stunting at age 24 mo as height for-age z score <2 and overweight as BMI z score (BMIZ) >1 in childhood (4-8 y) and adolescence (11-12 y, 13-15 y, and 16-18 y) and BMI >=25 in young adulthood (22-24 y). We compared BMI, BMIZ, and the prevalence of overweight by stunting status, stratified by sex. Results: Our sample was 93% black and 51% female. The prevalence of stunting at 24 mo was 26% in males and 19% in females. In young adulthood, the prevalence of overweight and obesity was 15.5% (men) and 47.5% (women). Among both males and females, neither mean BMI nor a combined measure of overweight and obesity in any subsequent period differed by stunting status at 24 mo (P >= 0.05). Conclusion: Stunting at 24 mo was not related to the risk of overweight or obesity in this cohort. Stunting may not be an important contributor to the increasing obesity rates in urban South Africa. PMID- 29767754 TI - Midluteal Progesterone: A Marker of Treatment Outcomes in Couples With Unexplained Infertility. AB - Context: Adequate luteal phase progesterone exposure is necessary to induce endometrial changes required for a successful pregnancy outcome. The relationship between low midluteal progesterone concentration and the outcome of live birth in ovarian stimulation with intrauterine insemination (OS-IUI) treatments is not defined. Objective: To determine the level of midluteal progesterone portending a low chance of live birth after OS-IUI in couples with unexplained infertility. Design and Setting: Secondary analyses of data from a prospective, randomized, multicenter clinical trial that determined pregnancy outcomes following OS-IUI with clomiphene citrate, letrozole, or gonadotropins for couples with unexplained infertility. Participants: Couples (n = 900) underwent 2376 OS-IUI cycles during the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. Main Outcome Measures: Live birth as it relates to midluteal progesterone level and thresholds below which no live births occur by treatment group. Results: Thresholds for non-live birth cycles were similar for clomiphene (14.4 ng/mL) and letrozole (13.1 ng/mL) yet were lower for gonadotropin (4.3 ng/mL) treatments. A midluteal progesterone level >10th percentile specific for each treatment group independently was associated with greater odds for a live birth in all OS-IUI cycles (adjusted OR: 2.17; 95% CI: 1.05, 4.48). Conclusions: During OS-IUI, a low midluteal progesterone level was associated with a low probability of live birth. Thresholds differed by medication, with the lowest threshold for gonadotropin. Several pathophysiologic mechanisms may account for low progesterone levels. Refinement of the predictive range associated with particular ovarian stimulation medications during treatment of unexplained infertility may improve accuracy. PMID- 29767757 TI - The contribution of organelles to plant intracellular Calcium signalling. AB - Calcium (Ca2+) is among the most important intracellular messengers in living organisms. Understanding of the players and dynamics of Ca2+ signalling pathways in plants may help to unravel the molecular basis of their exceptional flexibility to respond and to adapt to different stimuli. In the present review we focus on new tools that have recently revolutionized our view of organellar Ca2+ signalling as well as on the current knowledge regarding the pathways mediating Ca2+ fluxes across intracellular membranes. The contribution of organelles and cellular subcompartments to the orchestrated response via Ca2+ signalling within a cell is also discussed, underlining the fact that one of the greatest challenges in the field is the elucidation of how influx and efflux Ca2+ transporters/channels are regulated in a concerted manner to translate specific information into a Ca2+ signature. PMID- 29767756 TI - Influenza vaccination coverage among US children from 2004/2005 to 2015/2016. AB - Background: Quantify the influenza vaccine coverage is essential to identify emerging concerns and to immunization programs for targeting interventions. Methods: Data from National Health Interview Survey were used to estimate receipt of at least one dose of influenza vaccination among children 6 months to 17 years of age. Results: Influenza vaccination coverage increased from 16.70% during 2004/2005 to 49.43% during 2015/2016 (3.18% per year, P < 0.001); however, the coverage increased slightly after 2010/2011. Children at high risk of influenza complications had higher influenza vaccination coverage than non at-risk children. Boys and girls had similar coverage each year. While the coverage increased from 2004/2005 to 2015/2016 for all age groups, the coverage decreased with age each year (-0.64 to -1.58% per age group). There was a higher and rapid increase of coverage in Northeast than Midwest, South and West. American Indian or Alaskan Native and Asian showed higher coverage than other race groups (White, Black/African American, Multiple race). Multivariable analysis showed that high risk status and region had the greatest associations with levels of vaccine coverage. Conclusions: Although the influenza vaccination coverage among children had increased remarkably since 2004/2005, establishing more effective immunization programs are warranted to achieve the Healthy People 2020 target. PMID- 29767758 TI - Turgor maintenance by osmotic adjustment: 40 years of progress. AB - Osmotic adjustment (OA), the accumulation of solutes in higher plant cells in response to water deficits, was first reported more than four decades ago. Since then, variation in OA among genotypes/cultivars in response to drought has been reported in many crop plants, but its role in maintaining growth and yield in water-limited environments has been questioned. The role of OA in the physiological and agronomic adaptation to water stress of crops, the methods of reliably measuring the degree of OA among genotypes or species, the range of OA in many studies, and its impact on grain yield in water-limited environments are reviewed. The genetics of OA has received limited study, and the breeding and selection for high OA has only resulted in the release of one commercial cultivar of wheat as far as is known. The reasons for the limited interest in breeding for the OA trait are discussed. PMID- 29767755 TI - A protein phosphatase 2C, AP2C1, interacts with and negatively regulates the function of CIPK9 under potassium-deficient conditions in Arabidopsis. AB - Potassium (K+) is a major macronutrient required for plant growth. An adaptive mechanism to low-K+ conditions involves activation of the Ca2+ signaling network that consists of calcineurin B-like proteins (CBLs) and CBL-interacting kinases (CIPKs). The CBL-interacting protein kinase 9 (CIPK9) has previously been implicated in low-K+ responses in Arabidopsis thaliana. Here, we report a protein phosphatase 2C (PP2C), AP2C1, that interacts with CIPK9. Fluorescence resonance energy transfer (FRET), bimolecular fluorescence complementation (BiFC), and co localization analyses revealed that CIPK9 and AP2C1 interact in the cytoplasm. AP2C1 dephosphorylates the auto-phosphorylated form of CIPK9 in vitro, presenting a regulatory mechanism for CIPK9 function. Furthermore, genetic and molecular analyses revealed that ap2c1 null mutants (ap2c1-1 and ap2c1-2) are tolerant to low-K+ conditions, retain higher K+ content, and show higher expression of K+ deficiency related genes contrary to cipk9 mutants (cipk9-1 and cipk9-2). In contrast, transgenic plants overexpressing AP2C1 were sensitive to low-K+ conditions. Thus, this study shows that AP2C1 and CIPK9 interact to regulate K+ deficiency responses in Arabidopsis. CIPK9 functions as positive regulator whereas AP2C1 acts as a negative regulator of Arabidopsis root growth and seedling development under low-K+ conditions. PMID- 29767760 TI - Influence of the nutrition and health information presented on food labels on portion size consumed: a systematic review. AB - Context: In recent decades, portion sizes have increased significantly. Although previous research indicates that food labels impact on product choice and healthiness perception, their impact on portion sizes consumed is less clear. Objective: This systematic review examined whether food label information influenced portion size consumption. Data sources: A search of 7 major electronic databases for studies published from 1980 to April 2016 was conducted. Data extraction: Two reviewers independently screened 11 128 abstracts. Data were extracted from 32 articles (comprising 36 studies). Results: Based on the test food used, the overall effects were found to be: no effect, a positive effect, or a negative effect. Labels displaying energy content (n = 15 studies, 17 effects) and fat content information (n = 13 studies, 14 effects) were evaluated most commonly, with exercise equivalent labels evaluated least (n = 2 studies, 2 effects). Conclusions: Nutrition and health information presented on food labels has varying impacts on portion sizes consumed, from increased to decreased intake. Recommendations for future research include evaluating more recent food label types and achieving more consistent reporting standards. PMID- 29767759 TI - Comparing Auditory-Only and Audiovisual Word Learning for Children With Hearing Loss. AB - Although reducing visual input to emphasize auditory cues is a common practice in pediatric auditory (re)habilitation, the extant literature offers minimal empirical evidence for whether unisensory auditory-only (AO) or multisensory audiovisual (AV) input is more beneficial to children with hearing loss for developing spoken language skills. Using an adapted alternating treatments single case research design, we evaluated the effectiveness and efficiency of a receptive word learning intervention with and without access to visual speechreading cues. Four preschool children with prelingual hearing loss participated. Based on probes without visual cues, three participants demonstrated strong evidence for learning in the AO and AV conditions relative to a control (no-teaching) condition. No participants demonstrated a differential rate of learning between AO and AV conditions. Neither an inhibitory effect predicted by a unisensory theory nor a beneficial effect predicted by a multisensory theory for providing visual cues was identified. Clinical implications are discussed. PMID- 29767761 TI - Significance of HBV NAT Among HBs Antigen-Negative Blood Donors in Saudi Arabia. AB - Background: Bloodborne hepatitis B virus (HBV) transmission from asymptomatic donors with acute HBV infections who have undetectable surface antigen of HBV (HBsAg), or from donors with chronic infections in whom serological markers were not detected, could cause residual infections leading to relevant transfusion transmitted infections (RTTIs). HBV nucleic acid testing (NAT) can detect HBV DNA in the HBsAg-negative and total hepatitis B core antibody (anti-HBc)-negative window period of infection and in chronic cases. Objective: To assess the presence or absence of HBV DNA in blood donors with HBsAg negativity. Methods: We collected 3014 blood specimens from volunteer blood donors at the blood bank of King Khalid University Hospital in Riyadh, Saudia Arabia. Specimens from each donor were tested for HBsAg, anti-HBc, and hepatitis B surface antibody (anti HBs) by commercial immunoassays and for qualitative assessments of HBV-DNA by HBV NAT testing. Results: Of the 3014 donors, 7 (0.23%) tested positive for HBsAg and anti-HBc, 1 for HBsAg (0.03%) only, and of those 264 donors (8.8%) for anti-HBc. Of these last, 6.9% also tested positive for anti-HBs and 1.9% tested negative for anti-HBs. HBV-NAT testing was reactive in 75.0% of subjects who tested HBsAg positive, and nonreactive in 100% of subjects who tested anti-HBc positive/HBsAg negative (with or without anti-HBs). Among 2742 donors who tested seronegative, 1 specimen was determined to be reactive via HBV-NAT testing. Conclusions: The frequency of HBV DNA in blood donors who tested seronegative was low. This finding may indicate the significance of the HBV NAT technique in reducing the residual risk of transfusion-transmitted HBV infection. PMID- 29767762 TI - Surgical Outcomes Following Repeat Transsphenoidal Surgery for Nonfunctional Pituitary Adenomas: A Retrospective Comparative Study. AB - BACKGROUND: Endonasal transsphenoidal surgery (ETSS) remains the preferred treatment for recurrent or residual nonfunctional pituitary adenomas (NFPAs). However, surgical complications and outcomes with repeat ETSS are unclear. OBJECTIVE: To compare outcomes from primary and repeat ETSS in patients with NFPAs. METHODS: Retrospective review of ETSS for NFPAs at USC University Hospital and LAC + USC Medical Center between 2000 and 2015. Patients with >=3-mo follow up data were included. Patients were categorized as primary or repeat ETSS. Patient and tumor characteristics were compared preoperatively, and postoperative outcomes were analyzed. RESULTS: Two hundred sixty-eight patients (89%) met the inclusion criteria (primary ETSS = 211 and repeat ETSS = 57) with a mean follow up time of 38 mo (range 3-235 mo). Both groups had similar demographics, endocrine function, and tumor characteristics. Surgical complication rates were similar and no mortalities were observed. Repeat ETSS patients had a higher rate of new postoperative panhypopituitarism (primary ETSS: 0.5% vs repeat ETSS: 7.1%, P = .011), lower rates of gross total resection (GTR; primary ETSS: 59.2% vs repeat ETSS: 26.3%, P = .001), and greater rates of postoperative radiosurgery (36.8% vs 24.2%, P = .009). At 2-yr follow-up, progression-free survival on MRI was similar in both groups (primary ETSS: 97.9% vs repeat ETSS: 95.4%, log-rank test P = .807). CONCLUSION: At experienced tertiary pituitary centers, repeat ETSS for NFPAs was associated with a similar incidence of surgical complications as primary ETSS. However, repeat ETSS carried a higher rate for worsening endocrine dysfunction and a lower rate of GTR. PMID- 29767764 TI - Erratum: Visit the workplace? What's wrong with it? PMID- 29767763 TI - Commentary: Impact of Hospital and Health System Mergers and Acquisitions on the Practicing Neurosurgeon: Survey and Analysis from the Council of State Neurosurgical Societies Medical Director's Ad Hoc Representative Section. PMID- 29767765 TI - RADON EXHALATION FROM BUILDING MATERIALS USED IN YEMEN. AB - The present article seeks to determine the annual effective doses of 222Rn exposure, effective radium content and radon exhalation rates in some building materials from the local market of Ibb province, Yemen. A total of 33 samples of building materials were collected from the target area. The radon exhalation rate and effective radium content in these samples were measured using solid-state nuclear track detector, which has become an important tool in every investigation of the radon levels in the surrounding environment. Surface exhalation rate has been found to vary from 178.90 to 1267.6 mBq m-2 h-1, whereas mass exhalation rate has been found to vary from 5.51 to 33.25 mBq kg-1 h-1. All the values of effective radium content in all samples under test were found to be quite lower than the permissible value of 370 Bq kg-1 recommended by Organization for Economic Cooperation and Development. Annual effective doses have also been estimated. PMID- 29767766 TI - Cost Transparency in Neurosurgery: A Single-Institution Analysis of Patient Out of-Pocket Spending in 13 673 Consecutive Neurosurgery Cases. AB - BACKGROUND: Patient out-of-pocket (OOP) spending is an increasingly discussed topic; however, there is minimal data available on the patient financial burden of surgical procedures. OBJECTIVE: To analyze hospital and surgeon expected payment data and patient OOP spending in neurosurgery. METHODS: This is a retrospective cohort study of neurosurgical patients at a tertiary-referral center from 2013 to 2016. Expected payments, reflecting negotiated costs-of-care, as well as actual patient OOP payments for hospital care and surgeon professional fees were analyzed. A 4-tiered model of patient OOP cost sharing and a multivariate model of patient expected payments were created. RESULTS: A total of 13 673 consecutive neurosurgical cases were analyzed. Patient age, insurance type, case category, severity of illness, length of stay (LOS), and elective case status were significant predictors of increased expected payments (P < .05). Craniotomy ($53 397 +/- 811) and posterior spinal fusion ($48 329 +/- 864) were associated with the highest expected payments. In a model of patient OOP cost sharing, nearly all neurosurgical procedures exceeded yearly OOP maximums for Healthcare Marketplace plans. Mean patient payments for hospital care and surgeon professional fees were the highest for anterior/lateral spinal fusion cases for commercially insured patients ($1662 +/- 165). Mean expected payments and mean patient payments for commercially insured patients increased significantly from 2013 to 2016 (P < .05). CONCLUSION: Expected payments and patient OOP spending for commercially insured patients significantly increased from 2013 to 2016, representing increased healthcare costs and patient cost sharing in an evolving healthcare environment. Patients and providers can consider this information prior to surgery to better anticipate the individual financial burden for neurosurgical care. PMID- 29767767 TI - Waking Up on the Wrong Side of the Bed: The Effects of Stress Anticipation on Working Memory in Daily Life. AB - Objectives: The aim of this study was to examine the association between stress anticipated for the upcoming day and cognitive function later on that day, and how this relationship differed across age. Method: A diverse adult community sample (N = 240, age 25-65 years) completed ecological momentary assessment (EMA) reports for 2 weeks on a smartphone; each day they completed a morning survey upon waking, beeped surveys at five times during a day, and an end-of-day survey. Morning and end-of-day surveys included questions to measure stress anticipation, and each beeped survey included measures of stressful events, followed by a spatial working memory (WM) task. Results: Results from multilevel models indicated that stress anticipation reported upon waking, but not on the previous night, was associated with deficit in WM performance later that day; importantly, this effect was over and above the effect of EMA-reported stress. The detrimental effect of stress anticipation upon waking was invariant across age. Discussion: These findings suggest that anticipatory processes can produce harmful effects on cognitive functioning that are independent of everyday stress experiences. This may identify an important avenue to mitigate everyday cognitive lapses among older adults. PMID- 29767768 TI - Developing mHealth Applications for Older Adults with Pain: Seek Out the Stakeholders! PMID- 29767769 TI - Regulation of Chlorophagy during Photoinhibition and Senescence: Lessons from Mitophagy. AB - Light energy is essential for photosynthetic energy production and plant growth. Chloroplasts in green tissues convert energy from sunlight into chemical energy via the electron transport chain. When the level of light energy exceeds the capacity of the photosynthetic apparatus, chloroplasts undergo a process known as photoinhibition. Since photoinhibition leads to the overaccumulation of reactive oxygen species (ROS) and the spreading of cell death, plants have developed multiple systems to protect chloroplasts from strong light. Recent studies have shown that autophagy, a system that functions in eukaryotes for the intracellular degradation of cytoplasmic components, participates in the removal of damaged chloroplasts. Previous findings also demonstrated an important role for autophagy in chloroplast turnover during leaf senescence. In this review, we describe the turnover of whole chloroplasts, which occurs via a type of autophagy termed chlorophagy. We discuss a possible regulatory mechanism for the induction of chlorophagy based on current knowledge of photoinhibition, leaf senescence and mitophagy-the autophagic turnover of mitochondria in yeast and mammals. PMID- 29767770 TI - beta-1,6-linked Galactofuranose- rich peptidogalactomannan of Fusarium oxysporum is important in the activation of macrophage mechanisms and as a potential diagnostic antigen. AB - A peptidogalactomannan (PGM) from Fusarium oxysporum was structurally characterized by a combination of chemical and spectroscopic methods, including one and two-dimensional nuclear magnetic resonance (1D and 2D NMR). The galactomannan component consists of a main chain containing (1->6)-linked beta-D galactofuranose residues with side chains containing (1->2)-linked alpha-D-Glcp, (1->2)-linked -beta-D-Manp (1->2) and beta-D-Manp terminal nonreducing end units and differs from that of Aspergillus fumigatus and Cladosporium resinae that present a main chain containing (1->6)-linked alpha-D-Manp residues presenting beta-D-Galf as side chains of 3-4 units that are (1->5)-interlinked. The importance of the carbohydrate moiety of the F. oxysporum PGM was demonstrated. Periodate oxidation abolished much of the PGM antigenic activity. A strong decrease in reactivity was also observed with de-O-glycosylated PGM. In addition, de-O-glycosylated PGM was not able to inhibit F. oxysporum phagocytosis, suggesting that macrophages recognize and internalize F. oxysporum via PGM. F. oxysporum PGM triggered TNF-alpha release by macrophages. Chemical removal of O linked oligosaccharides from PGM led to a significant increase of TNF-alpha cytokine levels, suggesting that their removal could exposure another PGM motifs able to induce a higher secretion of TNF-alpha levels. Interestingly, F. oxysporum conidia, intact and de-O-linked PGM were not able to induce IL-10 cytokine release. The difference in patient serum reativity using a PGM from F. oxysporum characterized in the present study as compared with a PGM from C. resinae, that presents the same epitopes recognized by serum from patients with aspergillosis, could be considered a potential diagnostic antigen and should be tested with more sera. PMID- 29767771 TI - Do Sleep and Psychological Distress Mediate the Association Between Neighborhood Factors and Pain? AB - Objective: Pain affects millions of American adults. However, individuals from socioeconomically disadvantaged groups experience higher rates of pain, and individuals from racial/ethnic minorities report greater pain severity and pain related disability. Some studies find an association between neighborhood socioeconomic status and pain. The present study aimed to further understand the association between neighborhood disadvantage and pain, including the role of objective (e.g., crime rates) and subjective neighborhood characteristics (e.g., perceived safety, neighborhood satisfaction), and to examine sleep and psychological distress as potential mediators of these associations. Methods: The sample included 820 participants from two predominantly African American socioeconomically disadvantaged neighborhoods. Trained data collectors interviewed participants on a number of self-report measures, and objective neighborhood characteristics were obtained from city crime data and street segment audits. Results: Subjective characteristics, specifically perceived infrastructure and perceived safety, were associated with pain. Based on bootstrapped regression models, sleep efficiency and psychological distress were tested as mediators of the association between these neighborhood factors and pain. Results of mediation testing indicated that psychological distress served as a significant mediator. Though sleep efficiency was not a mediator, it had a significant independent association with pain. Conclusions: Understanding the contribution of sleep problems and psychological distress to pain among at-risk individuals living in disadvantaged neighborhoods is important to identifying ways that individual- and neighborhood-level interventions may be leveraged to reduce pain-related disparities. PMID- 29767772 TI - Illicit Cigarette Trade in Five South American Countries: A Gap Analysis for Argentina, Brazil, Chile, Colombia and Peru. AB - Introduction: Due to its nature, it is very hard to measure tobacco illicit trade in any product. In the case of Latin American countries, there is scant information on the magnitude and characteristics of this trade in the case of cigarettes. The goal of this article is to provide estimates on the evolution of the illicit cigarette trade in five South American countries: Argentina, Brazil, Chile, Colombia and Peru. Methods: Gap analysis estimates for cigarette tax evasion/avoidance (a comparison on the evolution of the difference between registered cigarette sales and measured population consumption) is developed for Argentina, Brazil, Chile, Colombia and Peru. Nationally representative surveys, conducted regularly, are used to measure population consumption. Confidence intervals constructed by bootstrapping sample estimates are generated in order to statistically evaluate the evolution of the gap. Results: Cigarette illicit trade has increased as a percentage of total sales in Brazil in recent years. In the case of Argentina, after a relative decrease between 2005 and 2009 it seems to have stabilized. There is no statistical evidence to argue that there has been an increase of cigarette illicit trade in Chile, Colombia and Peru, despite substantial price increases in Chile and tax increase in both Colombia and Peru. Conclusion: Using simple statistical methods, it is possible to assess the trend in tobacco illicit trend over time to better inform policy-makers. Getting reliable and regular population consumption surveys can also help to track tobacco illicit trade. Claims by tobacco industry of a positive association between price/tax changes and illicit trade are unsubstantiated. Implications: Evolution of cigarette illicit trade in five Latin American countries show different trajectories, not in line with tobacco industry estimates, which highlight the importance of producing solid, independent estimates. There are inexpensive methodologies that can provide estimates of the evolution of the relative importance of illicit trade and can be used to inform policy-makers. Claims by tobacco industry of a positive association between price/tax changes and illicit trade are unsubstantiated. PMID- 29767773 TI - Aneurysm Size is the Strongest Risk Factor for Intracranial Aneurysm Growth in the Eastern Finnish Population. AB - BACKGROUND: Saccular intracranial aneurysm (sIA) growth during follow-up is associated with high risk for subsequent rupture. Finnish patients have been suggested to have higher risk for subarachnoid hemorrhage, but follow-up studies of sIA growth in the Finnish population are scarce. OBJECTIVE: To identify the strongest risk factors for sIA growth in Eastern Finnish population by studying 205 patients with 350 unruptured sIAs with angiographic follow-up imaging. METHODS: In this population-based cohort study, we included unruptured sIA patients from the Kuopio University Hospital Intracranial Aneurysm Patient and Family database with at least 6 mo of angiographic follow-up after the diagnosis of sIAs. Angiograms were re-evaluated to detect aneurysms with growth of at least 1.0 mm. Cox regression analysis with patient- and aneurysm-related risk factors was used to calculate hazard ratios with 95% confidence intervals for growth. In addition, we tested the diagnostic value of previously introduced PHASES score for the prediction of sIA growth in Eastern Finnish population. RESULTS: Of the 350 unruptured aneurysms, 36 (10.3%) showed growth during median follow-up of 1.7 yr and total follow-up of 790 yr. In the multivariate Cox regression analysis, sIA size and location in the middle cerebral artery were significant risk factors for sIA growth. In receiver operator characteristic curves, both PHASES score and sIA size had relatively low areas under the curve. CONCLUSION: Our study indicates that aneurysm size is the strongest risk factor for aneurysm growth in Eastern Finnish population. Further studies are required to identify new risk factors for aneurysm growth. PMID- 29767774 TI - Common and rare variants genetic association analysis of cigarettes per day among ever smokers in COPD cases and controls. AB - Introduction: Cigarette smoking is a major environmental risk factor for many diseases, including chronic obstructive pulmonary disease (COPD). There are shared genetic influences on cigarette smoking and COPD. Genetic risk factors for cigarette smoking in cohorts enriched for COPD are largely unknown. Methods: We performed genome-wide association analyses for average cigarettes per day (CPD) across the COPDGene Non-Hispanic White (NHW) (n=6,659) and African American (AA) (n=3,260), GenKOLS (n=1,671), and ECLIPSE (n=1,942) cohorts. In addition, we performed exome array association analyses across the COPDGene NHW and AA cohorts. We considered analyses across the entire cohort and stratified by COPD case-control status. Results: We identified genome-wide significant associations for CPD on chromosome 15q25 across all cohorts (lowest p=1.78x10-15), except in the COPDGene AA cohort alone. Previously reported associations on chromosome 19 had suggestive and directionally consistent associations (RAB4 p=1.95x10-6; CYP2A7 p=7.50x10-5; CYP2B6 4.04x10-4). When we stratified by COPD case-control status, single nucleotide polymorphisms (SNPs) in chromosome 15q25 were nominally associated in both NHW COPD cases (Beta=0.11, p=5.58x10-4) and controls (Beta=0.12, p=3.86x10-5). For the gene-based exome array association analysis of rare variants, there were no exome-wide significant associations. For these previously replicated associations, the most significant results were among COPDGene NHW subjects for CYP2A7 (p=5.2x10-4). Conclusions: In a large genome wide association study of both common variants and a gene-based association of rare coding variants in ever smokers, we found genome-wide significant associations on chromosome 15q25 with CPD for common variants, but not for rare coding variants. These results were directionally consistent among COPD cases and controls. IMPLICATIONS: We examined both common and rare coding variants associated with CPD in a large population of heavy smokers with and without COPD of NHW and AA descent. We replicated genome-wide significant associations on chromosome 15q25 with CPD for common variants among NHW subjects, but not for rare variants. We demonstrated for the first time that common variants on chromosome 15q25 associated with CPD are similar among COPD cases and controls. Previously reported associations on chromosome 19 showed suggestive and directionally consistent associations among common variants (RAB4, CYP2A7, and CYP2B6) and for rare variants (CYP2A7) among COPDGene NHW subjects. While the genetic effect sizes for these SNPs on chromosome 15q25 are modest, we show that this creates a substantial smoking burden over the lifetime of a smoker. PMID- 29767775 TI - Tobacco industry denormalisation beliefs in Hong Kong adolescents. AB - Introduction: Tobacco industry denormalisation (TID) seeks to expose the industry's misconducts. Research on TID beliefs, meaning negative attitudes towards the tobacco industry (TI), may inform TID programmes, but was limited to western populations. We investigated TID beliefs and their association with smoking and sociodemographic characteristics in Hong Kong adolescents. Methods: In a school-based cross-sectional survey of 14214 students (mean age 15.0 years, 51.5% boys), TID beliefs were assessed by two questions: (i) whether the TI was respectable and (ii) whether the TI tried to get youth to smoke, each with 4 options from "definitely no" to "definitely yes". Smoking susceptibility and behaviours were also assessed. Sociodemographic characteristics included age, sex, perceived family affluence, highest parental education, numbers of co residing smokers, and school-level smoking prevalence. Results: Of all students, 77.6% considered the TI not respectable and 56.6% believed that the TI tried to get youth to smoke. Stronger TID beliefs were inversely associated with smoking susceptibility and behaviours. For example, students considering the TI definitely not respectable (vs definitely yes) were 56% (95% CI 45-66%), 49% (41 56%), and 53% (36-65%) less likely to be susceptible to smoking (among never smokers) and be ever and current smokers, respectively. Of all correlates examined, only younger age and having no co-residing smoker were associated with TID beliefs. Conclusions: Substantial proportions of Hong Kong adolescents did not hold TID beliefs, but those who did were less likely to smoke. Our results suggest that TID programmes may help reduce adolescent smoking. Implications: The TI's misconducts and responsibility for the tobacco epidemic were not well known by Hong Kong adolescents. TID beliefs in this population were inversely associated with smoking. These findings suggest that TID programmes in local adolescents may be of value. The investigation of TID beliefs' correlates found that socio-economic status and school-level smoking prevalence was not associated with TID beliefs. This suggests that local TID programmes targeting adolescents in general, e.g., mass media campaigns, may be more appropriate than those targeting particular schools or selected groups of adolescents. PMID- 29767777 TI - Prison staff and prisoner views on a prison smoking ban: evidence from the Tobacco in Prisons Study. AB - Introduction: In jurisdictions permitting prisoner smoking, rates are high (c75%), with smoking embedded in prison culture, leading to secondhand smoke exposures among staff and prisoners and challenges for smoking cessation. Momentum is building to ban smoking in prisons, but research on staff and prisoner views is lacking. We address this gap, providing evidence on staff and prisoner views throughout all Scottish prisons. Methods: Data were collected prior to announcement of a (November 2018) prison smoking ban throughout Scotland. Mixed methods were used: surveys of staff (online, N=1,271, ~27%) and prisoners (questionnaire, N=2,512, ~34%); 17 focus groups and two paired interviews with staff in 14 prisons. Results: Staff were more positive than prisoners about bans and increased smoking restrictions, although prisoner views were more favourable should e-cigarettes be permitted. Non-smokers were more positive than smokers. Whilst 74% staff and 22% prisoners agreed bans were a good idea, both groups acknowledged implementation and enforcement challenges. Staff views were influenced by beliefs about: acceptability of the policy in principle; and whether/how bans could be achieved. Although some voiced doubts about smoke free policies, staff likened a ban to other operational challenges. Staff raised concerns around needs for appropriate measures, resources and support, adequate lead-in time, and effective communication prior to a ban. Conclusion: We recommend that regular and open opportunities for dialogue within and between different stakeholder groups are created when preparing for prison smoking bans, and that specific measures to address staff and prisoner concerns are incorporated into plans to create and maintain smoke-free environments. Implications: To our knowledge, this study is the first to research staff and prisoner views across a whole prison system prior to implementation of smoke-free policies. The results highlight potential challenges and suggest measures which might help to maximise the success of bans. Our results are relevant for prison service managers responsible for the forthcoming introduction of a ban in Scottish prisons (November 2018) and for other prison systems and comparable institutions planning smoke-free initiatives. Given that prison smoking bans may be contentious, we recommend creating regular and open opportunities for dialogue between stakeholders when preparing for and maintaining smoke-free environments. PMID- 29767778 TI - 'Pseudonymisation at source' undermines accuracy of record linkage. PMID- 29767776 TI - ScGAI is a key regulator of culm development in sugarcane. AB - Sugarcane contributes more than 70% of sugar production and is the second largest feedstock for ethanol production globally. Since sugar accumulates in sugarcane culms, culm biomass and sucrose content are the most commercially important traits. Despite extensive breeding, progress in both cane yield and sugar content remains very slow in most countries. We hypothesize that manipulating the genetic elements controlling culm growth will alter source-sink regulation and help break down the yield barriers. In this study, we investigate the role of sugarcane ScGAI, an ortholog of SLR1/D8/RHT1/GAI, on culm development and source-sink regulation through a combination of molecular techniques and transgenic strategies. We show that ScGAI is a key molecular regulator of culm growth and development. Changing ScGAI activity created substantial culm growth and carbon allocation changes for structural molecules and storage. ScGAI regulates spatio temporal growth of sugarcane culm and leaf by interacting with ScPIF3/PIF4 and ethylene signaling elements ScEIN3/ScEIL1, and its action appears to be regulated by SUMOylation in leaf but not in the culm. Collectively, the remarkable culm growth variation observed suggests that ScGAI could be used as an effective molecular breeding target for breaking the slow yield gain in sugarcane. PMID- 29767779 TI - Survival Outcomes After Intracranial Hemorrhage in Liver Disease. AB - BACKGROUND: Survival outcomes for patients with liver disease who suffer an intracranial hemorrhage (ICH) have not been thoroughly investigated. OBJECTIVE: To understand survival outcomes for 3 groups: (1) patients with an admission diagnosis of liver disease (end-stage liver disease [ESLD] or non-ESLD) who developed an ICH in the hospital, (2) patients with ESLD who undergo either operative vs nonoperative management, and (3) patients with ESLD on the liver transplant waitlist who developed an ICH in the hospital. METHODS: We retrospectively reviewed hospital charts from March 2006 through February 2017 of patients with liver disease and an ICH evaluated by the neurosurgery service at a single academic medical center. The primary outcome was survival. RESULTS: We included a total of 53 patients in this study. The overall survival for patients with an admission diagnosis of liver disease who developed an ICH (n = 29, 55%) in the hospital was 22%. Of those patients with an admission diagnosis of liver disease, 27 patients also had ESLD. Kaplan-Meier analysis found no significant difference in survival for ESLD patients (n = 33, 62%) according to operative status. There were 11 ESLD patients on the liver transplant waitlist. The overall survival for patients with ESLD on the liver transplant waitlist who suffered an in-hospital ICH (n = 7, 13%) was 14%. CONCLUSION: ICH in the setting of liver disease carries a grave prognosis. Also, a survival advantage for surgical hematoma evacuation in ESLD patients is not clear. PMID- 29767780 TI - Medical phycology 2017. AB - In 2014, ISHAM formed a new working group: "Medical Phycology: Protothecosis and Chlorellosis." The purpose of this working group is to help facilitate collaboration and communication among people interested in the pathogenic algae, to share ideas and work together. Here we present reports on recent work we have done in five areas. 1. The history of medical phycology as a branch of science. 2. Aspects of the genetics of Prototheca. 3. Aspects of the proteins of Prototheca. 4. Human infections caused by Prototheca. 5. Dairy cow mastitis caused by Prototheca. PMID- 29767782 TI - Fact Finders for Patient Safety: Are Gadolinium-Based Contrast Media Safe Alternatives to Iodinated Contrast Agents for the Safe Performance of Spinal Injection Procedures? PMID- 29767783 TI - Timing of radiotherapy in newly diagnosed glioblastoma: no need to rush? PMID- 29767781 TI - Featured Article: Adolescent Condom Use and Connectivity in the Social-Planful Brain. AB - Objective: To reduce rates of sexually transmitted infections (STIs) and unwanted pregnancy among adolescents, it is critical to investigate brain connectivity that may underlie adolescents' sexual health decision-making in the context of intercourse. This study explored relationships between adolescent condom use frequency and the brain's resting-state functional connectivity, to identify differential patterns of social-affective processing among sexually active youth. Methods: In this study, N = 143 sexually active adolescents (68.5% male, Mage = 16.2 years, SD = 1.06) completed magnetic resonance imaging and reported past 3 month frequency of condom use. Resting-state connectivity, seeded on a social region of the brain, the temporoparietal junction (TPJ), was assessed to determine its correspondence with protected sex (condom use). Results: Condom use was associated with positive connectivity between the left TPJ and bilateral inferior frontal gyrus (IFG). This relationship was observed in adolescent males only; no connectivity differences were observed with adolescent females. Conclusions: This study reflects functional synchrony between nodes of the "social brain," including the TPJ, and a region of planfulness and control, the IFG. The relationship between these regions suggests that adolescents who have more coordinated systems of communication between these critical components of the brain are more likely to be successful in planning and engaging in safer sexual decision-making; for young males, this differentiated more frequent from less frequent condom use. In turn, interventions designed to reduce STIs/human immunodeficiency virus may benefit from targeting social-planfulness dimensions to help youth implement safer sex behaviors. PMID- 29767784 TI - Imaging features of typical usual interstitial pneumonia (UIP). PMID- 29767785 TI - Adding Power to Systems Science in Rehabilitation. PMID- 29767786 TI - Functional connectivity of the human amygdala in health and in depression. AB - To analyse the functioning of the amygdala in depression, we performed the first voxel-level resting state functional-connectivity neuroimaging analysis of depression of voxels in the amygdala with all other voxels in the brain, with 336 patients with major depressive disorder and 350 controls. Amygdala voxels had decreased functional connectivity (FC) with the orbitofrontal cortex, temporal lobe areas, including the temporal pole, inferior temporal gyrus and the parahippocampal gyrus. The reductions in the strengths of the FC of the amygdala voxels with the medial orbitofrontal cortex and temporal lobe voxels were correlated with increases in the Beck Depression Inventory score and in the duration of illness measures of depression. Parcellation analysis in 350 healthy controls based on voxel-level FC showed that the basal division of the amygdala has high FC with medial orbitofrontal cortex areas, and the dorsolateral amygdala has strong FC with the lateral orbitofrontal cortex and related ventral parts of the inferior frontal gyrus. In depression, the basal amygdala division had especially reduced FC with the medial orbitofrontal cortex, which is involved in reward; and the dorsolateral amygdala subdivision had relatively reduced FC with the lateral orbitofrontal cortex, which is involved in non-reward. PMID- 29767787 TI - Sleep-disordered breathing in C57BL/6J mice with diet-induced obesity. AB - Obesity leads to sleep-disordered breathing (SDB) manifested by recurrent upper airway obstructions termed obstructive sleep apnea (OSA) and carbon dioxide retention due to hypoventilation. The objective of this work was to characterize breathing during sleep in C57BL6/J mice with diet-induced obesity (DIO). Arterial blood gas was measured in nine obese and nine lean mice during wakefulness. Nine male mice with DIO and six lean male C57BL/6J mice were head mounted with electroencephalogram (EEG) and electromyogram (EMG) electrodes. Sleep recordings were performed in the whole body plethysmography chamber; upper airway obstruction was characterized by the presence of inspiratory flow limitation in which airflow plateaus with increases in inspiratory effort. Obese mice showed significantly lower pH and higher partial pressure of arterial CO2 (PaCO2) in arterial blood gas compared to lean mice, 7.35 +/- 0.04 versus 7.46 +/- 0.06 (p < 0.001) and 38 +/- 8 mm Hg versus 30 +/- 5 mm Hg (p < 0.001). Obese mice had similar levels of minute ventilation to lean mice during sleep and wakefulness, despite higher body weight and temperature, indicating an increase in the metabolic rate and hypoventilation. Obese mice also showed baseline hypoxemia with decreased mean oxyhemoglobin saturation across sleep/wake states. Obese mice had a higher prevalence of flow-limited breathing compared to lean mice during sleep. However, the oxygen desaturation index in lean and obese mice did not differ. We conclude that DIO in mice leads to hypoventilation. Obesity also increases the frequency of inspiratory limited breaths, but it does not translate into progression of OSA. PMID- 29767788 TI - Acute Maneb Exposure Significantly Alters Both Glycolysis and Mitochondrial Function in Neuroblastoma Cells. AB - The pesticides paraquat (PQ) and maneb (MB) have been described as environmental risk factors for Parkinson's disease (PD), with mechanisms associated with mitochondrial dysfunction and reactive oxygen species generation. A combined exposure of PQ and MB in murine models and neuroblastoma cells has been utilized to further advance understanding of the PD phenotype. MB acts as a redox modulator through alkylation of protein thiols and has been previously characterized to inhibit complex III of the electron transport chain and uncouple the mitochondrial proton gradient. The purpose of this study was to analyze ATP linked respiration and glycolysis in human neuroblastoma cells utilizing the Seahorse extracellular flux platform. Employing an acute, subtoxic exposure of MB, this investigation revealed a MB-mediated decrease in mitochondrial oxygen consumption at baseline and maximal respiration, with inhibition of ATP synthesis and coupling efficiency. Additionally, MB-treated cells showed an increase in nonmitochondrial respiration and proton leak. Further investigation into mitochondrial fuel flex revealed an elimination of fuel flexibility across all 3 major substrates, with a decrease in pyruvate capacity as well as glutamine dependency. Analyses of glycolytic function showed a substantial decrease in glycolytic acidification caused by lactic acid export. This inhibition of glycolytic parameters was also observed after titrating the MB dose as low as 6 MUM, and appears to be dependent on the dithiocarbamate functional group, with manganese possibly potentiating the effect. Further studies into cellular ATP and NAD levels revealed a drastic decrease in cells treated with MB. In summary, MB significantly impacted both aerobic and anaerobic energy production; therefore, further characterization of MB's effect on cellular energetics may provide insight into the specificity of PD to dopaminergic neurons. PMID- 29767789 TI - Effects of tannic acid extract on performance and intestinal health of broiler chickens following coccidiosis vaccination and/or a mixed-species Eimeria challenge. AB - Two experiments were conducted to investigate the effects of tannic acid extract (TAE) formulations on the performance and intestinal health of male Cobb * Cobb 500 broilers exposed to coccidiosis. In the first experiment, 320 broiler chicks were randomly assigned to 5 treatments with 8 replicates. Treatments included non medicated, uninfected (NC); non-medicated, infected (PC); salinomycin (SAL, 66 mg/kg); tannic acid (TA, 0.5 g/kg) and TAE (TAE, 0.5 g/kg). On d 14, all groups (except NC) were orally inoculated with Eimeria acervulina, E. maxima and E. tenella oocysts. Intestinal lesion scores, fecal oocyst counts (OPG) and performance were evaluated on d 20. The PC had greater lesions and higher FCR than infected, supplemented groups. Only TAE reduced OPG compared to PC (P < 0.05). In the second experiment, 3,000 broiler chicks were vaccinated on day of hatch with live coccidial oocysts, then randomly assigned to 5 treatments with 15 replicates. Treatments included non-medicated (CNT); salinomycin (SAL, 66 mg/kg); robenidine (ROB, 33 mg/kg); TAE (0.5 g/kg) and TAE with Bacillus coagulans (TAE+BC, 0.5 g/kg). On d 29, a subset of pens (n = 20) were challenged with a mixed Eimeria spp. oral inoculum; performance, lesions and OPG were evaluated on d 35. An immune challenge was created in half the pens by issuing broilers feed without supplementation materials during the challenge. For the non-challenged pens (n = 55), performance was measured up to d 49. Performance of non challenged, vaccinated-CNT birds was improved with all treatments at d 21 and d 49. Among the challenged birds, withdrawal of SAL or ROB resulted in FCR similar to the challenged CNT group (P > 0.05), whereas withdrawal of TAE or TAE+BC maintained improved FCR compared to challenged-CNT birds (P < 0.05). These findings indicate supplementation of TAE and TAE+BC with coccidiosis vaccination can be considered as a potential alternative strategy to address coccidiosis in broiler chickens. PMID- 29767790 TI - Identification and Functional Characterization of a Maize Phosphate Transporter Induced by Mycorrhiza Formation. AB - Phosphorus (P) is an essential macronutrient for plant life, although it is frequently not readily available to crops. Arbuscular mycorrhiza fungi (AMF) can improve plant P levels by inducing the expression of some phosphate (Pi) transporters. Symbiotic Pi uptake by Pi transporters is crucial for AMF colonization and arbuscule dynamics. However, the functions of mycorrhiza inducible maize Pi transporters are largely unclear. We focused on the interaction between the Pi concentration and AMF colonization in maize, and detecting the induction of a Pi transporter. We investigated AMF colonization and arbuscular development in maize under high and low Pi environments. Low Pi increased AMF colonization and promoted arbuscular development. Further measurement of P concentration showed that AMF significantly improved the maize P status under low Pi conditions. Here, we identified the Pi transporter gene, ZmPt9, which was induced by mycorrhiza formation. In addition, ZmPt9 overexpressing roots were difficult to colonize by AMF. Pi response analysis showed that ZmPt9 complements a yeast mutant defective in Pi transporter activity and improves the P concentration in rice. Together, these data indicated that ZmPt9 is a mycorrhiza-inducible Pi transporter gene involved in Pi uptake. PMID- 29767791 TI - Noninvasive Vagal Nerve Stimulation in Chronic Migraine with Medication Overuse Headache. PMID- 29767793 TI - Inhalation of House Dust and Ozone Alters Systemic Levels of Endothelial Progenitor Cells, Oxidative Stress, and Inflammation in Elderly Subjects. AB - Ambient air pollution including ozone and especially particulate matter represents important causes of cardiovascular disease. However, there is limited knowledge on indoor air dust with respect to this risk and the potential interactions between dust and ozone. Here, we exposed 23 healthy elderly subjects for 5.5 h, to either clean air, house dust at 275 ug/m3 (diameter < 2.5 um), ozone at 100 ppb or combined house dust and ozone in a double-blinded randomized cross-over study. The combined house dust and ozone exposure was associated with a 48% (95% CI 24%-65%) decrease as compared with the clean air exposure, in CD34+KDR+ late endothelial progenitor cells (EPCs) per leukocyte in the blood shortly after exposure, whereas none of the single exposures resulted in a significant effect. The combined exposure also increased reactive oxygen species production capacity in granulocytes and monocytes as well as an up-regulation of interleukin-8 mRNA levels in leukocytes. Ozone alone reduced the gene expression of tumor necrosis factor and C-C motif chemokine ligand 2, while dust alone showed no effects. The combined exposure to house dust and ozone also reduced levels of oxidized purines in DNA consistent with concomitant up-regulation of mRNA of the repair enzyme 8-oxoguanine DNA glycosylase. The reduction in late EPCs can be an indicator of cardiovascular risk caused by the combination of pulmonary oxidative stress induced by ozone and the inflammatory potential of the house dust. These data were corroborated with in vitro findings from exposed human macrophages and endothelial cells. PMID- 29767795 TI - Quality measurement in physician-staffed emergency medical services: a systematic literature review. AB - Purpose: Quality measurement of physician-staffed emergency medical services (P EMS) is necessary to improve service quality. Knowledge and consensus on this topic are scarce, making quality measurement of P-EMS a high-priority research area. The aim of this review was to identify, describe and evaluate studies of quality measurement in P-EMS. Data sources: The databases of MEDLINE and Embase were searched initially, followed by a search for included article citations in Scopus. Study selection: The study eligibility criteria were: (1) articles describing the use of one quality indicator (QI) or more in P-EMS, (2) original manuscripts, (3) articles published from 1 January 1968 until 5 October 2016. The literature search identified 4699 records. 4543 were excluded after reviewing title and abstract. An additional 129 were excluded based on a full-text review. The remaining 27 papers were included in the analysis. Methodological quality was assessed using an adapted critical appraisal tool. Data extraction: The description of used QIs and methods of quality measurement was extracted. Variables describing the involved P-EMSs were extracted as well. Results of data synthesis: In the included papers, a common understanding of which QIs to use in P-EMS did not exist. Fifteen papers used only a single QI. The most widely used QIs were 'Adherence to medical protocols', 'Provision of advanced interventions', 'Response time' and 'Adverse events'. Conclusion: The review demonstrated a lack of shared understanding of which QIs to use in P-EMS. Moreover, papers using only one QI dominated the literature, thus increasing the risk of a narrow perspective in quality measurement. Future quality measurement in P-EMS should rely on a set of consensus-based QIs, ensuring a comprehensive approach to quality measurement. PMID- 29767792 TI - How face blurring affects body language processing of static gestures in women and men. AB - The role of facial coding in body language comprehension was investigated by event-related potential recordings in 31 participants viewing 800 photographs of gestures (iconic, deictic and emblematic), which could be congruent or incongruent with their caption. Facial information was obscured by blurring in half of the stimuli. The task consisted of evaluating picture/caption congruence. Quicker response times were observed in women than in men to congruent stimuli, and a cost for incongruent vs congruent stimuli was found only in men. Face obscuration did not affect accuracy in women as reflected by omission percentages, nor reduced their cognitive potentials, thus suggesting a better comprehension of face deprived pantomimes. N170 response (modulated by congruity and face presence) peaked later in men than in women. Late positivity was much larger for congruent stimuli in the female brain, regardless of face blurring. Face presence specifically activated the right superior temporal and fusiform gyri, cingulate cortex and insula, according to source reconstruction. These regions have been reported to be insufficiently activated in face-avoiding individuals with social deficits. Overall, the results corroborate the hypothesis that females might be more resistant to the lack of facial information or better at understanding body language in face-deprived social information. PMID- 29767794 TI - Effects of supplementing organic microminerals and methionine during the rearing phase of replacement gilts on lameness, growth, and body composition. AB - Lameness is a primary reason for culling and mortality within a sow herd. This study evaluated the impact of feeding organic trace minerals and methionine (Met) to growing gilts (134 d) on lameness, performance, body composition and claw health (to first parity), productivity (to second parity), and reproductive performance through 2 parities. Young gilts (28.8 +/- 8.8 kg of body weight [BW], n = 360) were BW blocked (10 gilts/pen) and randomly allotted to 1 of 4 dietary treatments: control (CON, basal diet); CON plus organic minerals (MIN, at 10, 20, and 50 mg/kg of Cu, Mn, and Zn, respectively; Aplomotec Plus, Tecnologia & Vitaminas, S.L, Alforja, Spain); additional Met (MET, at 102% Met: Lys); and MET plus MIN (MM). Feed was provided ad libitum. Lameness, BW, and body composition were measured 7 times during rearing, at gilt service, day 109 of gestation, and first weaning. Gilts fed the MM diet had lower average daily feed intake (5.1%) and final BW (2.1%) than CON gilts (P < 0.05), whereas MIN and MET were intermediate and not different from each other. Similarly, final backfat (BF) was greatest in CON (P < 0.05), whereas CON and MIN increased final loin depth compared with MM (P < 0.05) with MET not being different. During rearing, 7.7% of all gilts presented lameness, which appeared between 106.8 and 129.7 kg BW confidence interval. Gilts that had been or were lame had reduced BW and average daily gain compared with never lame gilts (P < 0.05). Lameness during rearing was highest (P < 0.01) in gilts fed CON diet (14.8%), with no differences amongst MIN (2.0%), MET (5.3%), or MM (6.5%). In the sow herd, 21% of sows showed lameness and 24% of those were associated with claw lesions. At weaning, gilts fed CON diet had highest (P < 0.01) prevalence of lameness (20.8%) with no differences amongst MIN (6.5%), MET (11.1%), or MM (7.6%). Over the first 2 parities, 27.3% of gilts were culled. On farm, lameness was associated with 0.7 more stillborn piglets (P < 0.10), 1 mm more BF loss in first lactation (P < 0.05), and increased weaning-to-estrus by 3 d (P < 0.05). In conclusion, lameness during rearing was decreased by supplementing organic trace minerals, methionine, and their combination, which also reduced lameness during lactation. PMID- 29767796 TI - Specificity in nitric oxide signalling. AB - Reactive nitrogen species (RNS) and their cognate redox signalling networks pervade almost all facets of plant growth, development, immunity, and environmental interactions. The emerging evidence implies that specificity in redox signalling is achieved by a multilayered molecular framework. This encompasses the production of redox cues in the locale of the given protein target and protein tertiary structures that convey the appropriate local chemical environment to support redox-based, post-translational modifications (PTMs). Nascent nitrosylases have also recently emerged that mediate the formation of redox-based PTMs. Reversal of these redox-based PTMs, rather than their formation, is also a major contributor of signalling specificity. In this context, the activities of S-nitrosoglutathione (GSNO) reductase and thioredoxin h5 (Trxh5) are a key feature. Redox signalling specificity is also conveyed by the unique chemistries of individual RNS which is overlaid on the structural constraints imposed by tertiary protein structure in gating access to given redox switches. Finally, the interactions between RNS and ROS (reactive oxygen species) can also indirectly establish signalling specificity through shaping the formation of appropriate redox cues. It is anticipated that some of these insights might function as primers to initiate their future translation into agricultural, horticultural, and industrial biological applications. PMID- 29767797 TI - Hydraulic processes in roots and the rhizosphere pertinent to increasing yield of water-limited grain crops: a critical review. AB - HIGHLIGHT: A review of the role of roots in extracting water from the soil with regard to amount and timing leading to maximal grain yield, and of the various mechanisms underlying this. PMID- 29767799 TI - THE CONSISTENCY OF EXPOSURE INDICATOR VALUES IN DIGITAL RADIOGRAPHY SYSTEMS. AB - After years of establishment of computed radiography (CR) and digital radiography (DR), manufacturers have introduced exposure indicator/index (EI) as a feedback mechanism for patient dose. However, EI consistency is uncertain for CR. Most manufacturers recommended EI values in a range of numbers for all examination, instead of giving the exact range for a specific body part, raising a concern of inappropriate exposure given to the patient in clinical practice. The aims of this study were to investigate the EI consistency in DR systems produced in constant exposure parameters and clinical condition, and to determine the interaction between the anatomical part and EI. A phantom study of skull, chest, abdomen and hand was carried out and four systems were used for comparison-Fuji CR, Carestream CR, Siemens DR and Carestream DR. For each projection, the phantom positioning and exposure parameters were set according to the standard clinical practice. All exposure parameters and clinical conditions were kept constant. Twenty (20) exposures were taken for each projection and the EI was recorded. Findings showed that EI is not consistent in DR systems despite constant exposure parameters and clinical condition except in Siemens DR, through skull examination. Statistical analysis showed a significant interaction between anatomical parts and EI values (P < 0.05). EI alone was proven to be less reliable to provide technologist a correct feedback on exposure level. The interaction between anatomical parts and EI values intensifies the need for an anatomical-specific EI values set by all manufacturers for accurate feedback on the exposure parameters used and the detector entrance dose. PMID- 29767798 TI - Genome-wide association of yield traits in a nested association mapping population of barley reveals new gene diversity for future breeding. AB - To explore wild barley as a source of useful alleles for yield improvement in breeding, we have carried out a genome-wide association scan using the nested association mapping population HEB-25, which contains 25 diverse exotic barley genomes superimposed on an ~70% genetic background of cultivated barley. A total of 1420 HEB-25 lines were trialled for nine yield-related grain traits for 2 years in Germany and Scotland, with varying N fertilizer application. The phenotypic data were related to genotype scores for 5398 gene-based single nucleotide polymorphism (SNP) markers. A total of 96 quantitative trait locus (QTL) regions were identified across all measured traits, the majority of which co-localize with known major genes controlling flowering time (Ppd-H2, HvCEN, HvGI, VRN-H1, and VRN-H3) and spike morphology (VRS3, VRS1, VRS4, and INT-C) in barley. Fourteen QTL hotspots, with at least three traits coinciding, were also identified, several of which co-localize with barley orthologues of genes controlling grain dimensions in rice. Most of the allele effects are specific to geographical location and/or exotic parental genotype. This study shows the existence of beneficial alleles for yield-related traits in exotic barley germplasm and provides candidate alleles for future improvement of these traits by the breeder. PMID- 29767800 TI - Copper requirements of broiler breeder hens. AB - One-hundred-twenty Cobb 500 hens, 20 wk of age, were randomly allocated into individual cages with the objective of estimating Cu requirements. After being fed a Cu deficient diet for 4 wk, hens were fed diets with graded increments of supplemental Cu (0.0; 3.5; 7.0; 10.5; 14; and 17.5 ppm) from Cu sulfate (CuSO4 5H2O), totaling 2.67; 5.82; 9.38; 12.92; 16.83; and 20.19 ppm analyzed Cu in feeds for 20 weeks. Estimations of Cu requirements were done using exponential asymptotic (EA), broken line quadratic (BLQ), and quadratic polynomial (QP) models. Obtained Cu requirements for hen d egg production and total settable eggs per hen were 6.2, 7.3, and 12.9 ppm and 8.1, 9.0, and 13.4 ppm, respectively, using EA, BLQ, and QP models. The QP model was the only one having a fit for total eggs per hen with 13.1 ppm Cu as a requirement. Hemoglobin, hematocrit, and serum Cu from hens had requirements estimated as 13.9, 11.3, and 18.5, ppm; 14.6, 13.0, and 19.0 ppm; and 16.2, 14.6, and 14.2 ppm, respectively, for EA, BLQ, and QP models. Hatching chick hemoglobin was not affected by dietary Cu, whereas requirements estimated for hatching chick hematocrit and body weight and length were 10.2, 12.3, and 13.3 ppm using EA, BLQ, and QP models; and 6.8 and 7.1 ppm, and 12.9 and 13.9 ppm Cu using EA and BLQ models, respectively. Maximum responses for egg weight, yolk Cu content, and eggshell membrane thickness were 14.9, 12.7, and 15.1 ppm; 15.0, 16.3, and 15.7 ppm; and 7.3, 7.8, and 14.0 ppm Cu, respectively, for EA, BLQ, and QP models. Yolk and albumen percentage were adjusted only with the QP model and had requirements estimated at 11.0 ppm and 11.3 ppm, respectively, whereas eggshell mammillary layer was maximized with 10.6, 10.1, and 14.4 ppm Cu using EA, BLQ, and QP models, respectively. The average of all Cu requirement estimates obtained in the present study was 12.5 ppm Cu. PMID- 29767803 TI - Current Funding Opportunities. PMID- 29767801 TI - Reliability of In Vitro Methods Used to Measure Intrinsic Clearance of Hydrophobic Organic Chemicals by Rainbow Trout: Results of an International Ring Trial. AB - In vitro assays are widely employed to obtain intrinsic clearance estimates used in toxicokinetic modeling efforts. However, the reliability of these methods is seldom reported. Here we describe the results of an international ring trial designed to evaluate two in vitro assays used to measure intrinsic clearance in rainbow trout. An important application of these assays is to predict the effect of biotransformation on chemical bioaccumulation. Six laboratories performed substrate depletion experiments with cyclohexyl salicylate, fenthion, 4-n nonylphenol, deltamethrin, methoxychlor, and pyrene using cryopreserved hepatocytes and liver S9 fractions from trout. Variability within and among laboratories was characterized as the percent coefficient of variation (CV) in measured in vitro intrinsic clearance rates (CLIN VITRO, INT; ml/h/mg protein or 106 cells) for each chemical and test system. Mean intralaboratory CVs for each test chemical averaged 18.9% for hepatocytes and 14.1% for S9 fractions, whereas interlaboratory CVs (all chemicals and all tests) averaged 30.1% for hepatocytes and 22.4% for S9 fractions. When CLIN VITRO, INT values were extrapolated to in vivo intrinsic clearance estimates (CLIN VIVO, INT; l/d/kg fish), both assays yielded similar levels of activity (<4-fold difference for all chemicals). Hepatic clearance rates (CLH; l/d/kg fish) calculated using data from both assays exhibited even better agreement. These findings show that both assays are highly reliable and suggest that either may be used to inform chemical bioaccumulation assessments for fish. This study highlights several issues related to the demonstration of assay reliability and may provide a template for evaluating other in vitro biotransformation assays. PMID- 29767804 TI - Enhancing Recovery After Sepsis. PMID- 29767805 TI - Is Social Support Always Related to Stress Reduction in Nursing Home Residents? A Study in Leisure Contexts. AB - The current study examined the main and interaction effects of leisure self determination and two leisure social support types (emotional and instrumental) on stress in nursing home residents. A total of 139 nursing home residents (mean age = 79.4 years) in Taichung City, Taiwan, were recruited. Data were collected using face-to-face surveys, which included measures of leisure self determination, leisure emotional support, leisure instrumental support, and stress. Data were analyzed using a hierarchical regression analysis. Results indicated that leisure self-determination and leisure emotional support were significantly and negatively correlated with stress, whereas leisure instrumental support was not. Moreover, higher levels of leisure instrumental support decreased the relationship between leisure self-determination and stress reduction. Therefore, enhancing levels of leisure self-determination and leisure emotional support appears to be an effective means of reducing stress in nursing home residents. However, providing excessive leisure instrumental support to nursing home residents should be avoided. [Res Gerontol Nurs. 2018; 11(4):174 180.]. PMID- 29767802 TI - Sitting Together And Reaching To Play (START-Play): Protocol for a Multisite Randomized Controlled Efficacy Trial on Intervention for Infants With Neuromotor Disorders. AB - Background: There is limited research examining the efficacy of early physical therapy on infants with neuromotor dysfunction. In addition, most early motor interventions have not been directly linked to learning, despite the clear association between motor activity and cognition during infancy. Objective: The aim of this project is to evaluate the efficacy of Sitting Together And Reaching To Play (START-Play), an intervention designed to target sitting, reaching, and motor-based problem solving to advance global development in infants with motor delays or neuromotor dysfunction. Design: This study is a longitudinal multisite randomized controlled trial. Infants in the START-Play group are compared to infants receiving usual care in early intervention (EI). Setting: The research takes place in homes in Pennsylvania, Delaware, Washington, and Virginia. Participants: There will be 140 infants with neuromotor dysfunction participating, beginning between 7 to 16 months of age. Infants will have motor delays and emerging sitting skill. Intervention: START-Play provides individualized twice-weekly home intervention for 12 weeks with families to enhance cognition through sitting, reaching, and problem-solving activities for infants. Ten interventionists provide the intervention, with each child assigned 1 therapist. Measurements: The primary outcome measure is the Bayley III Scales of Infant Development. Secondary measures include change in the Early Problem Solving Indicator, change in the Gross Motor Function Measure, and change in the type and duration of toy contacts during reaching. Additional measures include sitting posture control and parent-child interaction. Limitations: Limitations include variability in usual EI care and the lack of blinding for interventionists and families. Conclusions: This study describes usual care in EI across 4 US regions and compares outcomes of the START-Play intervention to usual care. PMID- 29767806 TI - Telephone Support and Telemonitoring for Low-Income Older Adults. AB - The objective of the current pilot study was to determine whether nurse-led telephone counseling improves health behavior, self-care, and physiological indices for low-income older adults using a telemonitoring system. The control group (n = 15) was provided with weekly health education only, and the intervention group (n = 20) was given additional telephone support by nurses. At baseline and 8 weeks, data on health and self-care behaviors were collected using a self-reported questionnaire, and blood pressure and fasting blood glucose levels were assessed. Nurse-led telephone support had a medium effect on improving health behavior (Cohen's d = 0.58, 95% confidence interval [CI] [-0.10, 1.27]), reducing systolic blood pressure (Cohen's d = -0.61, 95% CI [-1.29, 0.08]), and improving self-care behavior for hypertension (Cohen's d = 1.16, 95% CI [0.05, 2.27]). Findings support that nurse-led telephone support may be effective for improvements in health behavior, systolic blood pressure, and hypertension self-care in disadvantaged older adults under remote monitoring. Further studies are needed to obtain a powered sample size and investigate the long-term effects of personalized elements surrounding telehealth in community based settings. [Res Gerontol Nurs. 2018; 11(4):198-206.]. PMID- 29767808 TI - Are New Technologies Being Introduced and Adopted Appropriately in Orthopedic Practice? PMID- 29767807 TI - Impact of Sociodemographic and Clinical Factors on Health-Related Quality of Life in Older Adults With Atrial Fibrillation. AB - Atrial fibrillation (AF) is more prevalent in older adults than other populations and affects health-related quality of life (HRQoL). However, few studies have investigated HRQoL and clinical factors in older adults with AF. The aim of the current cross-sectional study was to describe HRQoL using an AF-specific QoL instrument and identify factors influencing HRQoL in Korean older adults with AF. Data from 205 patients diagnosed with AF in a tertiary hospital were analyzed. Patients' mean age was 74.24 years and 43.9% of patients were female. The total HRQoL score was 49.6 of 100. The lowest score was in the physical dimension of HRQoL. Concern about lethal complications from AF was an essential concept related to QoL. In multiple linear regression, age and gender were significant predictors for the physical dimension of HRQoL. Gender and comorbidity were significant factors for the sexual activity dimension. Health care providers should help improve the HRQoL of older adults with AF by reducing physical burdens and concerns about health-related complications. [Res Gerontol Nurs. 2018; 11(4):207-215.]. PMID- 29767809 TI - Pediatric Anterior Cruciate Ligament Reconstruction. AB - The rate of anterior cruciate ligament (ACL) ruptures diagnosed among the pediatric and adolescent population is increasing. The rise in ACL injuries may be attributed to earlier sports specialization, year-round sports participation, increased awareness, and improved ability to diagnose the injury. Treatment options for pediatric or adolescent ACL injuries include nonoperative conservative treatment, ACL repair, or various techniques for ACL reconstruction. The best course of treatment for ACL rupture in young patients continues to be debated. Anterior cruciate ligament reconstruction with autograft is currently the gold standard and has been shown to be successful in restoring joint stability. This article reviews predisposing factors, common mechanisms, diagnostic procedures, and treatments for ACL rupture in adolescent patients, with a focus on using quadriceps patellar tendon autograft. [Orthopedics. 2018; 41(3):129-134.]. PMID- 29767810 TI - A novel remaining tendon preserving repair technique leads to improved outcomes in special rotator cuff tear patterns. AB - INTRODUCTION: The purpose of this study was to identify the tear pattern that could be anatomically repaired by preserving the remaining tendon on footprint and evaluate clinical outcomes of patients who underwent remaining tendon preserving cuff repair. MATERIALS AND METHODS: Of 523 patients with full thickness rotator cuff tears who underwent arthroscopic repair, 41 (7.8%) patients had repairable rotator cuff tear while preserving the remaining tendon. Among them, 31 patients were followed-up for more than 2 years, including 26 patients with posterior L-shaped tear and 5 patients with transtendinous tear patterns. Clinical outcomes were evaluated using ASES and Constant score, SANE score for patient satisfaction, and VAS for pain. MRI was taken for tendon integrity 6 months postoperatively. RESULTS: Of the 31 patients, 11 (35.5%) had previous injury history before rotator cuff tear, including 7 (26.9%) of the 26 patients with posterior L-shaped tear and 4 (80%) of the 5 patients with transtendinous tear. The average size of preoperative cuff tear was 17.8 +/- 6.8 mm in anterior-to-posterior direction and 15.2 +/- 5.1 mm in medial-to-lateral direction. ASES and Constant score, SANE score, and VAS for pain were significantly (p < 0.001) improved after remaining tendon preserving rotator cuff repair. Rotator cuff tendons of 22(84.6%) patients with posterior L-shaped tear and 4(80%) patients with transtendinous tear patterns were healed. CONCLUSION: Patients who underwent rotator cuff repair with preservation of the remaining tendon on the footprint obtained satisfactory functional outcomes. Rotator cuff tears in patients who had posterior L-shaped tear extending between supraspinatus and infraspinatus tendons or transtendinous tear pattern with substantial remaining tendon could be repaired using remaining tendon preserving repair technique. Anatomic reduction of torn cuff tendon without undue tension could be achieved using the remaining tendon preserving repair technique. PMID- 29767811 TI - Peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a rare and potentially life-threatening disease that occurs toward the end of pregnancy or in the months following delivery in previously heart-healthy women. The incidence varies widely depending on geographical region and ethnic background, with an estimated number of 1 in 1000-1500 pregnancies in Germany. The course of the disease ranges from mild forms with minor symptoms to severe forms with acute heart failure and cardiogenic shock. The understanding of the etiology of PPCM has evolved in recent years. An oxidative stress-mediated cleaved 16-kDa fragment of the nursing hormone prolactin is thought to damage endothelial cells and cardiomyocytes. Bromocriptine, a dopamine-receptor agonist, effectively blocks prolactin release from the pituitary gland. In addition to standard heart failure therapy, this disease-specific treatment reduces morbidity and mortality in PPCM patients. This review summarizes the current knowledge on PPCM and the disease-specific treatment options. PMID- 29767812 TI - Tolerance of subzero winter cold in kudzu (Pueraria montana var. lobata). AB - The use of species distribution as a climate proxy for ecological forecasting is thought to be acceptable for invasive species. Kudzu (Pueraria montana var. lobata) is an important invasive whose northern distribution appears to be limited by winter survival; however, kudzu's cold tolerance thresholds are uncertain. Here, we used biogeographic evidence to hypothesize that exposure to - 20 degrees C is lethal for kudzu and thus determines its northern distribution limit. We evaluated this hypothesis using survival tests and electrolyte leakage to determine relative conductivity, a measure of cell damage, on 14 populations from eastern North America. Relative conductivity above 36% was lethal. Temperatures causing this damage averaged - 19.6 degrees C for northern and - 14.4 degrees C for southern populations, indicating kudzu acclimates to winter cold. To assess this, we measured relative conductivity of above- and belowground stems, and roots collected throughout the winter at a kudzu population in southern Ontario, Canada. Consistent with acclimation, the cold tolerance threshold of aboveground stems at the coldest time of year was - 26 degrees C, while stems insulated from cold extremes survived to - 17 degrees C-colder than the survival limits indicated by kudzu's biogeographic distribution. While these results do not rule out alternative cold limitations, they indicate kudzu can survive winters north of its current distribution. For kudzu, biogeography is not a proxy for climatic tolerance and continued northward migration is possible. Efforts to limit its spread are therefore prudent. These results demonstrate that physiological constraints inform predictions of climate-related changes in species distribution and should be considered where possible. PMID- 29767813 TI - Older studies can underestimate prognosis of glioblastoma biomarker in meta analyses: a meta-epidemiological study for study-level effect in the current literature. AB - INTRODUCTION: There are many potential biomarkers in glioblastoma (GBM), and meta analyses represent the highest level of evidence when inferring their prognostic significance. It is possible however, that inherent design properties of the studies included in these meta-analyses may affect the pooled hazard ratio (HR) of the meta-analyses. This meta-epidemiological study aims to investigate the potential bias of three study-level properties in meta-analyses of GBM biomarkers currently published in the literature. METHODS: Seven electronic databases from inception to December 2017 were searched for meta-analyses evaluating different GBM biomarkers, which were screened against specific criteria. Study-level data were extracted from each meta-analysis, and analyzed using logistic regression to yield the ratio of HR (RHR) summary statistic. RESULTS: Nine meta-analyses investigating different GBM biomarkers were included. Of all the meta-analyses, the HRs of two studies were significantly underestimated by older studies; they investigated biomarkers IDH1 (RHR = 1.145; p = 0.017) and CD133 (RHR = 0.850; p = 0.013). Study-level size and design showed non-significant trends towards affecting the overall HR in all included meta-analyses. CONCLUSIONS: This meta epidemiological study demonstrated that study-level year can already significantly affect the pooled HR of GBM biomarkers reported by meta-analyses. It is possible that in the future, more study-level properties will exert significant effect. In terms of future GBM biomarker meta-analyses, special consideration of bias should be given to these study-level properties as potential sources of effect on the prognostic pooled HR. PMID- 29767814 TI - Inborn errors of coenzyme A metabolism and neurodegeneration. AB - Two inborn errors of coenzyme A (CoA) metabolism are responsible for distinct forms of neurodegeneration with brain iron accumulation (NBIA), a heterogeneous group of neurodegenerative diseases having as a common denominator iron accumulation mainly in the inner portion of globus pallidus. Pantothenate kinase associated neurodegeneration (PKAN), an autosomal recessive disorder with progressive impairment of movement, vision and cognition, is the most common form of NBIA and is caused by mutations in the pantothenate kinase 2 gene (PANK2), coding for a mitochondrial enzyme, which phosphorylates vitamin B5 in the first reaction of the CoA biosynthetic pathway. Another very rare but similar disorder, denominated CoPAN, is caused by mutations in coenzyme A synthase gene (COASY) coding for a bi-functional mitochondrial enzyme, which catalyzes the final steps of CoA biosynthesis. It still remains a mystery why dysfunctions in CoA synthesis lead to neurodegeneration and iron accumulation in specific brain regions, but it is now evident that CoA metabolism plays a crucial role in the normal functioning and metabolism of the nervous system. PMID- 29767815 TI - The Effect of Glatiramer Acetate on Retinal Nerve Fiber Layer Thickness in Patients with Relapsing-Remitting Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study. AB - BACKGROUND: Optical coherence tomography (OCT) is a technique that allows for the assessment of retinal nerve fiber layer thickness (RNFLT) and total macular volume (TMV), which reflect neuroaxonal integrity within the retina. As such it has been used in multiple sclerosis (MS) to study neurodegeneration. Glatiramer acetate (GA) is a widely used treatment for MS, which is suggested to have a possible neuroprotective role. OBJECTIVE: The aim of this study was to assess RFNLT and TMV changes in relapsing-remitting MS (RRMS) patients who started treatment with GA and were followed for a 24-month period. METHODS: A cohort of 60 RRMS patients and 40 healthy controls (HCs) were imaged with OCT at baseline and follow-up. All subjects also underwent clinical and neurological examination. Measurements were compared between the RRMS patients and HCs as well as between optic neuritis (ON)-affected and ON-unaffected eyes. RESULTS: At baseline, MS patients showed lower average RNFLT (p = 0.046) and TMV (p = 0.013) when compared with HCs. No significant differences in the evolution of OCT measures were detected over the follow-up between MS patients and HCs. MS patients with both affected and unaffected eyes showed significantly lower average RNFLT, temporal inferior RNFLT, and TMV at baseline, compared with HCs. No significant differences between ON-affected and ON-unaffected eyes in MS patients were detected over the follow-up, except for the nasal superior RNFLT (p = 0.019). CONCLUSIONS: This study suggests a beneficial role of GA on retinal axonal degeneration in MS, and further confirms the utility of OCT to monitor the neuroprotective effect of disease-modifying treatment. PMID- 29767816 TI - [Recurrence of carotodynia or TIPIC syndrome]. PMID- 29767819 TI - Is there a prospect for hybrid aortic arch surgery? AB - The surge of endovascular repair of aortic aneurysm in current modern aortic surgery practice has been the key for surgical management of elective cases of thoracic aortic aneurysms. This has paved way for the combined hybrid approach to be amongst the armamentarium for the management of aortic arch disease. The pivotal understanding of the aortic arch natural history coupled with device technology advancement allowed surgeons insight into delivery of hybrid surgery with acceptable morbidity and mortality results. This review article provides current insights into hybrid technique of aortic arch aneurysm repair and the evidences behind its applicability to arch surgery. It is aimed to highlight the challenges encountered for this innovative approach and correlate its challenges to those that are met by the conventional open aortic arch repair. PMID- 29767817 TI - [Motor neuron diseases : Clinical and genetic differential diagnostics]. AB - The causes of degenerative disease of the upper and lower motor neurons are incompletely understood. In this review the current concepts in the clinical and genetic differential diagnostics of motor neuron diseases are presented. Hereditary spastic paraplegia, primary lateral sclerosis, spinal muscular atrophy and amyotrophic lateral sclerosis are explained, structured according to the affection of the upper and/or lower motor neuron. The substantial variability in the presentation and course of motor neuron diseases as well as the lack of specific laboratory tests hinder an early diagnosis. The precise description of the clinical picture, thorough testing of possible differential diagnoses as well as monitoring of the clinical course are essential. Genetic analyses should be offered to patients with a positive family history. Early identification of clinical and genetic subentities of the individual motor neuron diseases is a prerequisite for future neuroprotective interventions. PMID- 29767818 TI - Adapting the Risk Environment Framework to Understand Substance Use, Gender-Based Violence, and HIV Risk Behaviors Among Female Sex Workers in Tanzania. AB - Female sex workers (FSWs) in sub-Saharan Africa are disproportionately affected by HIV and gender-based violence (GBV). Substance use overlaps with these co occurring epidemics to further increase FSWs' risk for negative health outcomes. We explored the relationship between substance use, GBV, and consistent condom use utilizing baseline data from a cohort of 496 FSWs in Tanzania. Results demonstrate high levels of alcohol use and GBV, and low levels of consistent condom use. Frequent intoxication during sex work was associated with increased odds of recent GBV (aOR 1.64, 95% CI 1.07, 2.49; p value 0.02) and reduced odds of consistent condom use with clients (aOR 0.58, 95% CI 0.37, 0.92; p-value 0.02). We adapt the risk environment framework to contextualize our findings in the social and structural context and to gain insight into intervention approaches to address the intersecting challenges of substance use, GBV, and HIV among FSWs in Tanzania and similar settings. PMID- 29767820 TI - [Role of visceral surgery in oligometastases of non-gastrointestinal tumors]. AB - BACKGROUND: Patients with oligometastatic disease can benefit from local treatment of the metastases. Under these premises the resection of liver metastases and visceral metastases of non-gastrointestinal tumors is performed increasingly more frequently in selected patients. The aim of this study was to evaluate the role of visceral oncological surgery in hepatic oligometastatic disease of non-gastrointestinal tumors according to the currently available literature. MATERIAL AND METHODS: A systematic search of MEDLINE and PubMed was carried out focusing on the topics of oligometastases, liver resection and metastectomy for breast cancer, renal cell carcinoma, malignant melanoma, ovarian cancer and non-small cell lung cancer. RESULTS: The evidence is limited to retrospective studies and case series. In selected patients after liver resection and multimodal therapy 5-year survival rates of 53% (breast cancer), 62% (renal cell carcinoma), 22% (malignant melanoma) and 50% (ovarian cancer) are described. For lung cancer (NSCLC) median survival was 12 month. Prognostic factors n were a disease free survival of >12 months, R0-resection, response to systemic therapy and extra hepatic/extra abdominal metastases. These could be selection criteria for liver resection. Recurrence liver resection, resection of the pancreas and cytoreductive surgery including multivisceral resection (ovarian cancer) could also improve survival. CONCLUSION: Regarding limited evidence patients with oligometastatic disease origin from non-gastrointestinal tumors could benefit from liver resection. Tumor biology and response to targeted individualized systemic therapy become more important in this scenario. PMID- 29767821 TI - Formative Research on Knowledge and Preferences for Stool-based Tests compared to Colonoscopy: What Patients and Providers Think. AB - The rates of colorectal cancer (CRC) screening in the U.S. remain below national targets, so many people at risk are not being screened. The objective of this qualitative research project was to assess patient and provider knowledge and preferences about CRC screening modalities and specifically the use of the fecal immunochemical test (FIT) as a first line screening choice. Nine focus groups were conducted with a medically underserved patient population and qualitative interviews were administered to their medical providers. Thematic analysis was used to synthesize key findings. Both providers and patients thought that the FIT would be a good option for CRC screening both as an individual choice and for an overall program approach. The test is less expensive and therefore more readily available for patients compared to colonoscopy. Overall, there was consensus that the FIT offers a reasonably priced, simple approach to CRC screening which has broad appeal to both providers and patients. Concerns identified by patients and providers included the possibility of false positives with the FIT which could be caused by test contamination or failing to perform the test properly. Patients also described feelings of disgust toward performing the FIT and difficulties in following the instructions. Study findings indicate provider and patient support for using the FIT for CRC screening at both the individual and system-wide levels of implementation. While barriers to the use of the FIT were listed, benefits of using the FIT were perceived as positive motivators to engage previously unscreened and uninsured or under-insured individuals in CRC screening. PMID- 29767822 TI - Sexual Activity and Cognitive Decline in Older Adults. AB - This prospective study tested whether sexual activity and emotional closeness during partnered sexual activity relate to cognitive decline (episodic memory performance) in older adulthood. In total, 6016 adults aged 50 and over (2672 men, 3344 women; M age = 66.0 +/- 8.8 years) completed an episodic memory task and self-report questions related to health, sexual activity, and emotional closeness. Two years later, participants again completed the episodic memory task. After controlling for demographic and health-related lifestyle factors, more frequent sexual activity and greater emotional closeness during partnered sexual activity were associated with better memory performance. The association between sexual activity and memory performance was stronger among older participants in the sample. Memory performance worsened over 2 years, but change in memory performance was unrelated to sexual activity or emotional closeness during partnered sexual activity. These findings build on experimental research that has found sexual activity enhances episodic memory in non-human animals. Further research using longer timeframes and alternative measures of cognitive decline is recommended. PMID- 29767823 TI - The validity of open-source data when assessing jail suicides. AB - BACKGROUND: The Bureau of Justice Statistics' Deaths in Custody Reporting Program is the primary source for jail suicide research, though the data is restricted from general dissemination. This study is the first to examine whether jail suicide data obtained from publicly available sources can help inform our understanding of this serious public health problem. METHODS: Of the 304 suicides that were reported through the DCRP in 2009, roughly 56 percent (N = 170) of those suicides were identified through the open-source search protocol. Each of the sources was assessed based on how much information was collected on the incident and the types of variables available. A descriptive analysis was then conducted on the variables that were present in both data sources. The four variables present in each data source were: (1) demographic characteristics of the victim, (2) the location of occurrence within the facility, (3) the location of occurrence by state, and (4) the size of the facility. RESULTS: Findings demonstrate that the prevalence and correlates of jail suicides are extremely similar in both open-source and official data. However, for almost every variable measured, open-source data captured as much information as official data did, if not more. Further, variables not found in official data were identified in the open-source database, thus allowing researchers to have a more nuanced understanding of the situational characteristics of the event. CONCLUSIONS: This research provides support for the argument in favor of including open-source data in jail suicide research as it illustrates how open-source data can be used to provide additional information not originally found in official data. In sum, this research is vital in terms of possible suicide prevention, which may be directly linked to being able to manipulate environmental factors. PMID- 29767825 TI - [Palliative sedation : Development and consensus of a German language documentation template]. AB - BACKGROUND: Palliative sedation (PS) serves as a therapeutic option in cases of otherwise intractable suffering. As the use of sedative and hypnotic medication in many diverse situations is a core competency of anesthesiology, anesthesiologists are confronted with questions of sedative therapy at the end of life in institutions for specialized palliative care, in intensive care units and intermediate care wards. In recent years a number of guidelines have been published internationally but so far no official guidelines exist in Germany. The most recognized document is the European Association for Palliative Care (EAPC) framework on PS. This project aims to develop a German language template for the preparation, application, documentation and evaluation of PS according to the current frameworks, especially the EAPC framework on PS. METHODS: A first draft of the template was generated by the project team using the EAPC framework and individual templates of various institutions, which had been collected during a previous project. Professionals (n = 136) from inpatient and outpatient specialist palliative and hospice care were invited to assess all items of the draft regarding "relevance", "wording" and "feasibility" in an online Delphi survey (Unipark(r), Questback, Cologne, Germany). After the second Delphi round an expert panel was asked to reflect the results and generate a final draft. Approval was granted if acceptance exceeded 75% of participants. RESULTS: The 3 rounds of the Delphi process were completed by 64, 46 and 41 participants, respectively. The Delphi process as well as the expert panel led to significant changes of the template. The indications for PS had to be clarified. The significance of documentation of vital parameters, such as oxygen saturation, blood pressure or respiratory rate during PS was intensively discussed. In many teams, predominantly hospice or outpatient palliative care teams, it seems to be difficult to measure these parameters or it is regarded as inappropriate in a palliative care setting. In contrast, the EAPC framework recommends monitoring of vital parameters in cases of intermittent or respite sedation. Finally, a solution was found to support documentation of additional data without the explicit mentioning of specific parameters. After the third Delphi round, all 16 items of the documentation template reached consensus with respect to relevance (82.9-100%), clarity of wording (80.5-100%), and feasibility in practice (78 100%). CONCLUSION: This article provides an empirically based, multiprofessional consented documentation template for PS. Core elements of the documentation of PS are the indications and the decision process towards PS. During the treatment, at least the level of sedation and the symptom burden have to be recorded. The documentation of vital signs during PS remains a highly disputed topic. The presented data suggest that especially in outpatient settings and in hospices measuring and documentation of vital parameters is uncommon and therefore is often regarded as not feasible. This template can help to support the medically and ethically sound use of PS and facilitate research. The template can be accessed at http://www.palliativmedizin.uk-erlangen.de/forschung/downloads/ . PMID- 29767826 TI - Accidental or intentional exposure to potentially toxic medications, natural toxins and chemicals during pregnancy: analysis of data from Tox Info Suisse. AB - OBJECTIVE: Affected women and health professionals are still often unsure about how to react to exposures to potentially harmful agents during pregnancy. We wanted to find out which agents worry both pregnant women and professionals, under what circumstances the exposures take place, how they are currently dealt with and how serious they are. METHODS: Making use of the archives of Tox Info Suisse, the foundation that provides poisons information in Switzerland both for members of the general public and for healthcare professionals, we set up an analysis of exposures to possibly harmful agents during pregnancy. Queries during pregnancy between 1995 and 2015 were analysed. Demographic information, exposure and agent characteristics as well as - in a subgroup of cases - the corresponding treatments were considered in the present descriptive, retrospective analysis. RESULTS: Over the 21-year period, 2871 exposures during pregnancy were identified. The majority of the calls were made by members of the general public (2035, 70.9%; most often by the affected women themselves), followed by physicians (733, 25.5%). General public queries were mostly due to exposures connected with household chemicals (675/2035, 33.2%); those of physicians were most often due to medications (415/733, 56.6%). The majority of agent exposures occurred accidentally at home, at work, outdoors or at various other places (2297/2871, 80.0%). Less frequently, the exposures were intentional and had a suicidal, abusive, criminal or other character (471/2871, 16.4%). Of the 2871 calls, 905 cases with symptoms were recorded. Of the 1268 symptoms, 820 were mild (64.7%), 144 moderate (11.3%), 24 severe (1.9%, including 12 abortions) and 280 were not further specified (22.1%). In 1867 cases (65%), a total of 2331 measures were recommended by Tox Info Suisse, 1961 thereof to be carried out immediately. The two most common immediate measures were exposure interruption (412/1961, 21.0%) and forwarding to another institution (345/1961, 17.6%). In 70 cases, physicians' follow-up reports could be analysed; paracetamol was the agent most frequently involved (15 cases), followed by mefenamic acid (9) and the household product sodium hypochlorite (9). CONCLUSIONS: Tox Info Suisse recorded an average of 137 cases of agent exposure during pregnancy per year, mostly due to accidents with household products. Suicidal intentions played a role in a considerable number of exposures. Measures are needed to prevent accidental exposure of pregnant women to toxic substances and to support them in this exceptional life period. PMID- 29767827 TI - Directing citizens to create advance directives. AB - This article describes the Swiss law on advance directives that was passed at the beginning of 2013 and led to more certainty about the legally binding character of such directives. However, for various reasons the drafting of advance directives is not yet widespread in Switzerland, and many resources might be put to better use if this became a common practice. A recent proposal by members of a political party to make the discussion, although not the actual drafting, of advance directives mandatory was rejected by the Swiss Federal Parliament, and the proposal was written off after having been pending for 2 years. We consider that the rejection of this proposal was not justified and that discussion of advance directives should become mandatory, so that individuals can fully assume their role as responsible citizens taking proactive decisions. The decision not to draft advance directives should be a deliberate one, marking a shift from the current "opt-in" approach to an "opt-out" scenario. PMID- 29767824 TI - Variability in Verbal and Nonverbal Communication in Infants at Risk for Autism Spectrum Disorder: Predictors and Outcomes. AB - Early communication impairment is among the most-reported first concerns in parents of young children with autism spectrum disorder (ASD). Using a parent report questionnaire, we derived trajectory groups for early language and gesture acquisition in siblings at high risk for ASD and in children at low risk, during their first 2 years of life. Developmental skills at 6 months were associated with trajectory group membership representing growth in receptive language and gestures. Behavioral symptoms also predicted gesture development. All communication measures were strongly related to clinical and developmental outcomes. Trajectory groups further indicated slowest language/gesture acquisition in infants with later ASD diagnoses, in particular when associated with language delay. Overall, our results confirm considerable variability in communication development in high-risk infants. PMID- 29767828 TI - A digitally facilitated citizen-science driven approach accelerates participant recruitment and increases study population diversity. AB - QUESTION UNDER STUDY: Our aim was to assess whether a novel approach of digitally facilitated, citizen-science research, as followed by the Swiss Multiple Sclerosis Registry (Swiss MS Registry), leads to accelerated participant recruitment and more diverse study populations compared with traditional research studies where participants are mostly recruited in study centres without the use of digital technology. METHODS: The Swiss MS Registry is a prospective, longitudinal, observational study covering all Switzerland. Participants actively contribute to the Swiss MS Registry, from defining research questions to providing data (online or on a paper form) and co-authoring papers. We compared the recruitment dynamics over the first 18 months with the a priori defined recruitment goals and assessed whether a priori defined groups were enrolled who are likely to be missed by traditional research studies. RESULTS: The goal to recruit 400 participants in the first year was reached after only 20 days, and by the end of 18 months 1700 participants had enrolled in the Swiss MS Registry, vastly exceeding expectations. Of the a priori defined groups with potential underrepresentation in other studies, 645 participants (46.5%) received care at a private neurology practice, 167 participants (12%) did not report any use of healthcare services in the past 12 months, 32 (2.3%) participants lived in rural mountainous areas, and 20 (2.0% of the 1041 for whom this information was available) lived in a long-term care facility. Having both online and paper options increased diversity of the study population in terms of geographic origin and type and severity of disease, as well as use of health care services. In particular, paper enrolees tended to be older, more frequently affected by progressive MS types and more likely to have accessed healthcare services in the past 12 months. CONCLUSION: Academic and industry-driven medical research faces substantial challenges in terms of patient involvement, recruitment, relevance and generalisability. Digital studies and stakeholder engagement may have enormous potential for medical research. But many digital studies are based on limited participant information and/or informed consent and unclear data ownership, and are subject to selection bias, confounding and information bias. The Swiss MS Registry serves as an example of a digitally enhanced, citizen science study that leverages the advantages of both traditional medical research, with its established research methods, and novel societal and technological developments, while mitigating their ethical and legal disadvantages and risks. PMID- 29767829 TI - Homeopathy in the Age of Antimicrobial Resistance: Is It a Viable Treatment for Upper Respiratory Tract Infections? AB - BACKGROUND: Acute upper respiratory tract infections (URTIs) and their complications are the most frequent cause of antibiotic prescribing in primary care. With multi-resistant organisms proliferating, appropriate alternative treatments to these conditions are urgently required. Homeopathy presents one solution; however, there are many methods of homeopathic prescribing. This review of the literature considers firstly whether homeopathy offers a viable alternative therapeutic solution for acute URTIs and their complications, and secondly how such homeopathic intervention might take place. METHOD: Critical review of post 1994 clinical studies featuring homeopathic treatment of acute URTIs and their complications. Study design, treatment intervention, cohort group, measurement and outcome were considered. Discussion focused on the extent to which homeopathy is used to treat URTIs, rate of improvement and tolerability of the treatment, complications of URTIs, prophylactic and long-term effects, and the use of combination versus single homeopathic remedies. RESULTS: Multiple peer reviewed studies were found in which homeopathy had been used to treat URTIs and associated symptoms (cough, pharyngitis, tonsillitis, otitis media, acute sinusitis, etc.). Nine randomised controlled trials (RCTs) and 8 observational/cohort studies were analysed, 7 of which were paediatric studies. Seven RCTs used combination remedies with multiple constituents. Results for homeopathy treatment were positive overall, with faster resolution, reduced use of antibiotics and possible prophylactic and longer-term benefits. CONCLUSIONS: Variations in size, location, cohort and outcome measures make comparisons and generalisations concerning homeopathic clinical trials for URTIs problematic. Nevertheless, study findings suggest at least equivalence between homeopathy and conventional treatment for uncomplicated URTI cases, with fewer adverse events and potentially broader therapeutic outcomes. The use of non-individualised homeopathic compounds tailored for the paediatric population merits further investigation, including through cohort studies. In the light of antimicrobial resistance, homeopathy offers alternative strategies for minor infections and possible prevention of recurring URTIs. PMID- 29767830 TI - Effect of Homeopathic Dilutions of Cuprum Arsenicosum on the Electrical Properties of Poly(Vinylidene Fluoride-Co-Hexafluoropropylene). AB - BACKGROUND: We report the effects of nanoparticles in homeopathic preparations of copper salts on the electrical properties of polymer film. Previous work showed that the incorporation of metal-derived homeopathic medicines increases the dielectric constant and alternating current (AC) conductivity of an electroactive polymer film that is commonly used as a capacitor in the electronic industry.We report here the effect of dilution of one homeopathic medicine, Cuprum arsenicosum (CuAs), at 200C potency on the electrical properties of the polymer film of poly(vinylidene fluoride-co-hexafluoropropylene). METHODS: CuAs 200c was incorporated in the film by the solution casting method. The electrical characteristics were measured at different frequencies using an inductance, capacitance, and resistance meter. Fourier transform infrared spectroscopy (FTIR) was performed to detect phase change in the polymer film due to the incorporation of CuAs. Morphology and particle size were studied using field emission scanning electron microscopy (FESEM) and energy dispersive X-ray (EDX) spectroscopy. RESULTS: At 10 kHz frequency, both dielectric constant and AC conductivity increased approximately 18 times for the polymer film when incorporated with 2 mL CuAs at 200C potency. FTIR indicated the increase in conducting phase, while FESEM and EDX confirmed the presence of spherical CuAs particles. CONCLUSION: The incorporation of CuAs in the electroactive polymer film enhances the conductivity and dielectric constant. We conclude that these changes arise from the change in phase of the polymer film, and because of the presence of two different metals that affects the interfacial polarization. PMID- 29767831 TI - Heterogeneity in skin manifestations of spotted fever group rickettsial infection in Australia. PMID- 29767832 TI - Cancer survivors exhibit a different relationship between muscle strength and health-related quality of life/fatigue compared to healthy subjects. AB - We investigated the difference in relationship between muscle strength and quality of life (QOL)/fatigue in long-term cancer survivors and healthy subjects. Thirty-six cancer survivors and 29 healthy subjects were assessed for body composition and bone status at the calcaneus using the Osteo Sono Assessment Index. Muscle strength was evaluated via handgrip and knee extensor strength. Health-related QOL was assessed using the Medical Outcome Study 36-item Short Form Health Survey. Fatigue was measured using the brief fatigue inventory. Cancer survivors exhibited lower QOL scores in the physical functioning, physical role function, bodily pain and general health domains (p < .05). Grip and knee extension muscle strength in cancer survivors was positively correlated with the physical function and bodily pain of QOL (p < .05). The usual fatigue subscale score was only significantly higher in cancer survivors than in healthy subjects (p < .05). However, there were no correlations between muscle strength and fatigue in cancer survivors. Our results showed that muscle strength was an important factor for improving QOL in cancer survivors. We believe that the findings of this study will be relevant in the context of planning rehabilitation for cancer survivors. PMID- 29767833 TI - Post-operative care of interventional therapy for 40 liver cancer patients with obstructive jaundice. AB - The care of 40 patients with primary liver cancer with obstructive jaundice treated with liver puncture bile drainage or biliary stent implantation was reported. Treated with the interventional therapy, patients were observed closely to identify symptoms of hepatic encephalopathy and pain; diet care was well performed. Bile drainage tube and skin acre were performed carefully. Liver function, bilirubin and other biochemical indicators were monitored; occurrence of bleeding, acute pancreatitis, biliary tract infection, leakage of ascites around drainage tube and other complication were observed with good discharge instruction. After this operation, three rounds of liver had poor function, and hepatic encephalopathy and death occurred during hospitalisation. Seven patients had bloody bile drainage fluid after operation; eight had increased blood amylase; nine had biliary infection and four had leakage of ascites around the drainage tube. After positive treatment and care, the situation was improved with varied degrees of jaundice increase. PMID- 29767834 TI - Nutrition care of cancer patients-A survey among physicians and nurses. AB - In order to quantify gaps in the provision of medical nutrition care in Germany and pinpoint specific areas of need, we collected data from patients, nurses and physicians. The results from the patient survey were published separately. A total of 506 participants from 69 certified centers answered the questions developed in cooperation with representatives from different professional groups (physicians, nurses and dietitians). Only about a third of participants reported that their institution provides structured pathways to nutritional counseling. 70.1% of those physicians reported that there was a specialist in nutrition available at their center while only 55.8% of nurses agreed. Only a quarter (24.2% and 26.9%) of physicians and nurses reported that their institution provided continuation of nutrition care after dismissal. A gap exists between need and consistent delivery of nutrition care services. Structured nutrition care pathways provided by legally certified nutrition professionals pathways are lacking. Cancer organizations may support this process by requiring documented nutrition care pathways and provision of services on a need based system into guidelines and certification criteria. PMID- 29767835 TI - Strategic leadership will be essential for dietitian eHealth readiness: A qualitative study exploring dietitian perspectives of eHealth readiness. AB - AIM: To explore dietitians' perspectives on the eHealth readiness of Australian dietitians, and to identify strategies to improve eHealth readiness of the profession. METHODS: Dietitians who met the criteria for nutrition informatics experts participated in semi-structured interviews between June 2016 and March 2017. The interviews were recorded and transcribed verbatim. Thematic analysis using coding was undertaken until consensus was reached by the researchers regarding key themes, topics and exemplar quotes. RESULTS: Interviews with 10 nutrition informatics experts revealed 25 discussion topics grouped into four main themes: benefits of eHealth for dietitians; risks of dietitians not being involved in eHealth; dietitians are not ready for eHealth; and strategies to improve eHealth readiness. The strategies identified for improving eHealth readiness included: collaboration and representation, education, offering of incentives and mentoring, as well as development of a national strategy, organisational leaders, nutrition informatics champions and a supportive environment. CONCLUSIONS: These findings suggest that dietitians may not be ready for eHealth. Strategic leadership and the actioning of other identified strategies will be imperative to preparing dietitians for eHealth to ensure the profession can practice effectively in the digital age, optimise nutrition care and support research for eHealth. If dietitians do not engage in eHealth, others may take their place, or dietitians may be forced to use eHealth in ways that are not the most effective for practice or maximising patient outcomes. PMID- 29767836 TI - How do we manage iron deficiency after blood donation? AB - Blood donors and the RBCs and other components they willingly provide are essential in the delivery of healthcare in all parts of the world. Nearly 70% of donated blood comes from repeat or committed donors. The amount of iron removed in the 10 min or so it takes to withdraw a unit of blood (500 ml, plus 25 ml for testing) requires over 24 weeks to replace on a "standard" diet, i.e., without added iron in the form of supplements The cumulative effect of repeat blood donations without adequate iron replacement or a longer wait between donations results in iron deficiency (ID) in many donors, low haemoglobin deferral (~8% of donation attempts), and frank anaemia in some. Moreover, ID can be associated with side effects that can impact a blood donor's health, such as fatigue, cognitive changes and other neuromuscular symptoms. In an effort to better identify and prevent ID, blood collection agencies are recommending various strategies, including changes in the donation interval, donation frequency, testing of iron status and iron supplementation. In this review, we present the evidence basis for these strategies and suggest our own approaches to improving iron balance in blood donors. PMID- 29767837 TI - Romiplostim for the management of perioperative thrombocytopenia. AB - Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single-centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty-seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47 * 109 /l (9-120 * 109 /l) at romiplostim initiation to 164 * 109 /l (28-603 * 109 /l) at the time of surgery (P < 0.0001). A dose of 3 MUg/kg per week for 2 doses increased the platelet count to >100 * 109 /l in 79% of patients within 14 days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population. PMID- 29767838 TI - Trichoscopy helps to predict the time point of clinical cure of tinea capitis. PMID- 29767839 TI - JAK2 V617F-positive acute myeloid leukaemia (AML): a comparison between de novo AML and secondary AML transformed from an underlying myeloproliferative neoplasm. A study from the Bone Marrow Pathology Group. AB - The JAK2 V617F mutation is characteristic of most Philadelphia chromosome negative myeloproliferative neoplasms (MPNs) and occurs rarely in de novo acute myeloid leukaemia (AML). We sought to characterize AMLs that harbour this mutation and distinguish those that arise de novo (AML-DN) from those that reflect transformation of an underlying MPN (AML-MPN). Forty-five patients with JAK2 V617F-mutated AML were identified; 15 were AML-DN and 30 were AML-MPN. AML MPN cases were more likely to have splenomegaly (P = 0.02), MPN-like megakaryocytes and higher mean JAK2 V617F VAF at diagnosis (P = 0.04). Mutations involving TET2 were exclusively identified in AML-DN patients. Mutations of genes affecting DNA methylation were more common in AML-DN (P < 0.01). A complex karyotype was more frequent in AML-MPN cases than in AML-DN (P < 0.01), with AML DN more likely to display a normal karyotype (P = 0.02). Bone marrow histology after recovery from induction chemotherapy in AML-DN cases revealed no morphological evidence of any previously occult MPNs, while this was evident in most of the AML-MPN specimens (P < 0.01). These findings in this largest study of JAK2 V617F-mutated AMLs indicate that AML-DN is distinct from AML-MPN. PMID- 29767840 TI - Ethnicity, migration status and dental caries experience among adults in East London. AB - OBJECTIVE: To assess the interrelationship between ethnicity, migration status and dental caries experience among adults in East London. METHODS: We analysed data from 1910 adults (16-65 years) representing 9 ethnic groups, who took part in a community-based health survey in East London. Participants completed a supervised questionnaire and were clinically examined by trained dentists. Dental caries was assessed with the number of decayed, missing and filled teeth (DMFT). The association of ethnicity, nativity status and migration history with DMFT was assessed in negative binomial regression models controlling for demographic, socioeconomic and behavioural factors. RESULTS: White migrants had greater DMFT than UK-born adults, whereas every Asian and Black migrant group had lower DMFT than adults of the same ethnic group born in the UK (albeit significant only for Black Caribbean and Asian Others). Among foreign-born adults, age at arrival (Rate Ratio: 1.03; 95% Confidence Interval: 1.01-1.05) and length of residence (1.04; 95% CI: 1.02-1.06) were positively associated with DMFT. A significant interaction between both factors was also found, with more pronounced differences between older and younger migrants at longer stay in the UK for White Others, Black Caribbean and Asian Others. CONCLUSION: Large inequalities in caries experience were found between foreign- and UK-born adults, with considerable variation across ethnic groups. Looking beyond cultural explanations, in favour of social and environmental factors, may help to explain those inequalities. PMID- 29767841 TI - Lignin composition is related to xylem embolism resistance and leaf life span in trees in a tropical semiarid climate. AB - Wood properties influence the leaf life span (LL) of tree crowns. As lignin is an important component of wood and the water transport system, we investigated its relationship with embolism resistance and the LL of several tree species in a seasonally dry tropical ecosystem. We determined total lignin and the monomer contents of guaiacyl (G) and syringyl (S) and related them to wood traits and xylem vulnerability to embolism (Psi50 ) for the most common species of the Brazilian semiarid, locally known as Caatinga. Leaf life span was negatively related to Psi50 and positively related to S : G, which was negatively related to Psi50 . This means that greater S : G increases LL by reducing Psi50 . Lignin content was not correlated with any variable. We found two apparently unrelated axes of drought resistance. One axis, associated with lignin monomeric composition, increases LL in the dry season as a result of lower xylem embolism vulnerability. The other, associated with wood density and stem water content, helps leafless trees to withstand drought and allows them to resprout at the end of the dry season. The monomeric composition of lignin (S : G) is therefore an important functional wood attribute affecting several key functional aspects of tropical tree species in a semiarid climate. PMID- 29767842 TI - More than just CO2 -recycling: corticular photosynthesis as a mechanism to reduce the risk of an energy crisis induced by low oxygen. AB - Reassimilation of internal CO2 via corticular photosynthesis (PScort ) has an important effect on the carbon economy of trees. However, little is known about its role as a source of O2 supply to the stem parenchyma and its implications in consumption and movement of O2 within trees. PScort of young Populus nigra (black poplar) trees was investigated by combining optical micro-optode measurements with monitoring of stem chlorophyll fluorescence. During times of zero sap flow in spring, stem oxygen concentrations (cO2 ) exhibited large temporal changes. In the sapwood, over 80% of diurnal changes in cO2 could be explained by respiration rates (Rd(mod) ). In the cortex, photosynthetic oxygen release during the day altered this relationship. With daytime illumination, oxygen levels in the cortex steadily increased from subambient and even exhibited a diel period of superoxia of up to 110% (% air sat.). By contrast, in the sapwood, cO2 never reached ambient levels; the diurnal oxygen deficit was up to 25% of air saturation. Our results confirm that PScort is not only a CO2 -recycling mechanism, it is also a mechanism to actively raise the cortical O2 concentration and counteract temporal/spatial hypoxia inside plant stems. PMID- 29767843 TI - How i treat primary haemophagocytic lymphohistiocytosis. AB - Primary haemophagocytic lymphohistiocytosis (HLH) diseases are a collection of inherited genetic disorders that cause the syndrome of HLH. Great advances have been made in the last 20 years with regard to the discovery of many of the genetic aetiologies of disease. Several advances have also been made on the clinical stage. Accurate screening diagnostics for primary HLH diseases that are superior to traditional Natural Killer cell function testing have been developed and are now available in many countries. There is now grounded clinical experience on which to base routine treatment decisions for patients with HLH. Newer approaches to allogeneic haematopoietic cell transplantation have increased overall patient survival. Despite these advances, however, there is still much work to be done to further improve patient care. This 'How I Treat' article will focus on summarizing current diagnostic, treatment and transplant strategies for patients with primary HLH diseases. PMID- 29767846 TI - Access to gynecologic oncology care and the network adequacy standard. PMID- 29767844 TI - Comorbidities associated with higher von Willebrand factor (VWF) levels may explain the age-related increase of VWF in von Willebrand disease. AB - Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the 'WiN" study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0.23 iu/ml, 95% confidence interval (CI): 0.11-0.35], diabetes mellitus (0.11 iu/ml, 95% CI: -0.02 to 0.23), cancer (0.14 iu/ml, 95% CI: 0.03-0.25) and thyroid dysfunction (0.14 iu/ml, 95% CI: 0.03-0.26) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF collagen binding capacity (VWF:CB), VWF activity as measured by the VWF monoclonal antibody assay (VWF:Ab) and factor VIII (FVIII) coagulant activity (FVIII:C). In type 1 VWD, age was associated with higher VWF:Ag (0.03 iu/ml; 95% CI: 0.01-0.04), VWF:CB (0.02 iu/ml; 95% CI: 0.00-0.04), VWF:Ab (0.04 iu/ml; 95% CI: 0.02-0.06) and FVIII:C (0.03 iu/ml; 95% CI: 0.01-0.06) per decade increase. After adjustment for relevant comorbidities, these associations were no longer significant. Despite the higher VWF and FVIII levels, type 1 VWD patients with comorbidities had more bleeding episodes, particularly during surgery. There was no association between comorbidities and VWF/FVIII levels or bleeding phenotype in type 2 VWD patients. In conclusion, comorbidities are associated with higher VWF and FVIII levels in type 1 VWD and may explain the age-related increase of VWF and FVIII levels. PMID- 29767847 TI - Access to quality gynecologic oncology care: A work in progress. PMID- 29767845 TI - Final results from a defibrotide treatment-IND study for patients with hepatic veno-occlusive disease/sinusoidal obstruction syndrome. AB - Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi-organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded-access treatment programme (T IND; NCT00628498). In the completed T-IND, the Kaplan-Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58.9% [95% confidence interval (CI), 55.7-61.9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (<=21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67.9% (95% CI, 63.8-71.6%) and 47.1% (95% CI, 42.3-51.8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T-IND study was similar to previous reports. PMID- 29767848 TI - Difficulty distinguishing essential thrombocythaemia from polycythaemia vera in children with JAK2 V617F-positive myeloproliferative neoplasms. PMID- 29767849 TI - Brodalumab-induced palmar pustular eruption and joint swelling accompanied by muscle pains in two cases of psoriasis. PMID- 29767850 TI - Forest aging, disturbance and the carbon cycle. AB - Contents Summary 1188 I. Introduction 1188 II. Forest aging and carbon storage 1189 III. Successional trends of NEP in northern deciduous forests 1190 IV. Mechanisms sustaining NEP in aging deciduous forests 1191 Acknowledgements 1192 References 1192 SUMMARY: Large areas of forestland in temperate North America, as well as in other parts of the world, are growing older and will soon transition into middle and then late successional stages exceeding 100 yr in age. These ecosystems have been important regional carbon sinks as they recovered from prior anthropogenic and natural disturbance, but their future sink strength, or annual rate of carbon storage, is in question. Ecosystem development theory predicts a steady decline in annual carbon storage as forests age, but newly available, direct measurements of forest net CO2 exchange challenge that prediction. In temperate deciduous forests, where moderate severity disturbance regimes now often prevail, there is little evidence for any marked decline in carbon storage rate during mid-succession. Rather, an increase in physical and biological complexity under these disturbance regimes may drive increases in resource-use efficiency and resource availability that help to maintain significant carbon storage in these forests well past the century mark. Conservation of aging deciduous forests may therefore sustain the terrestrial carbon sink, whilst providing other goods and services afforded by these biologically and structurally complex ecosystems. PMID- 29767852 TI - Membrane-tethered syntaxin-4 locally abrogates E-cadherin function and activates Smad signals, contributing to asymmetric mammary epithelial morphogenesis. AB - Spatial and temporal epithelial-mesenchymal transition (EMT) is a critical event for the generation of asymmetric epithelial architectures. We found that only restricted cell populations in the morphogenic mammary epithelia extrude syntaxin 4, a plasmalemmal t-SNARE protein, and that epithelial cell clusters with artificial heterogenic presentation of extracellular syntaxin-4 undergo asymmetric morphogenesis. A previous study revealed that inducible expression of cell surface syntaxin-4 causes EMT-like cell behaviors in the clonal mammary epithelial cells, where laminin-mediated signals were abolished so that cells readily succumb to initiate EMT. The present study added new mechanistic insight into syntaxin-4-driven EMT-like cell behaviors. Extracellular syntaxin-4 directly perturbs E-cadherin-mediated epithelial cell-cell adhesion and activates Smad signals. We found that the epithelial cells activated Smad2/3 upon induction of expression of extracellular syntaxin-4, leading to the upregulation of certain transcriptional targets of these TGF-beta signaling mediators. Intriguingly, however, mRNA expression of canonical EMT initiators, such as Snail and Slug, was unchanged. In addition, E-cadherin protein was steeply decreased, yet its transcriptional expression remained constant for a couple of days. We found that extracellular syntaxin-4 directly bound to E-cadherin and sequestered beta catenin from cell-cell contact sites, perturbing intercellular adhesive property. The functional ablation of E-cadherin by syntaxin-4 was further validated by L cells with stably expressing E-cadherin, in which cells shows intercellular adhesive property solely by E-cadherin. These results underline the role of local exportation of syntaxin-4 for onset of complex epithelial morphogenesis. PMID- 29767853 TI - Nicorandil-induced ulcerations: a 10-year observational study of all cases spontaneously reported to the French pharmacovigilance network. AB - Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23.0% of patients, revealed by a severe complication in 12.8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23.4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3.3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5.2 versus 14.0 months, P = 0.001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil. PMID- 29767851 TI - Risk factors for vitamin D deficiency in sickle cell disease. AB - Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0.001) and vitamin D supplementation (P < 0.001). 25-OHD levels were higher in SCD patients over 40 years of age compared to the general African-American population. Both lower 25-OHD levels and increased pain frequency were associated with increased expression of SLC6A5 encoding glycine transporter-2 (GlyT2), a protein involved in neuronal pain pathways. Lower 25-OHD levels were also associated with increased expression of CYP3A4, and with decreased expression of GC (also termed DBP) and VDR, three genes involved in vitamin D metabolism. We conclude that vitamin D supplementation should be an almost universal feature of the care of young adults with SCD, and that further research is warranted into genomic factors that regulate vitamin D metabolism in SCD. PMID- 29767855 TI - Corrigendum. PMID- 29767854 TI - Emerging Association Between Parathyroid Hormone and Anemia in Hemodialysis Patients. AB - Anemia is a common complication of chronic kidney disease (CKD). There are various causes of renal anemia such as decreased production of erythropoietin, resistance to erythropoietin, shortened survival of red blood cells, and bone marrow fibrosis. Secondary hyperparathyroidism (SHPT) is a less recognized, but potentially significant cause of renal anemia in CKD patients. Parathyroid hormone (PTH) has been regarded as a uremic toxin that has multiple adverse effects, and its elevated levels have been associated with renal anemia in hemodialysis patients. Moreover, recent clinical studies have shown that the treatment of SHPT using either vitamin D receptor activators, calcimimetics, or parathyroidectomy leads to improvement of anemia, supporting the role of PTH in renal anemia. Emerging data have also indicated the involvement of bone-derived fibroblast growth factor 23 in renal anemia. This review summarizes recent insights into the role of PTH in renal anemia and discusses the importance of treating SHPT in improving the control of renal anemia in hemodialysis patients. PMID- 29767856 TI - Combination therapy of cytotoxic t-lymphocyte-associated antigen 4 (ctla-4) and programmed death 1 (pd 1) blocker, check point inhibitors for treatment of patients with advanced and recurrent epithelial ovarian cancer. AB - The standard of care for patients with recurrent ovarian cancer is platinum-based combination chemotherapy for those who relapse more than six months after completing adjuvant therapy. The use of biological agents such as bevacizumab has increased progression- free survival (PFS), but has not shown a significant increase in overall survival (OS). Immunotherapy treatment modality is being ac- tively pursued for patients with ovarian cancer. The goal of immunotherapy is to generate a tumor specific, T cell response that decrease residual disease, and protects against future recurrence. Combination therapy of anti-PD-1 antibodies, and anti-CTLA-4 antibodies re- verses the TIL dysfunction and induces tumor regression in solid tumors, including ovarian cancer. When GM-CSF vaccine is added, it results in increased tumor rejection. PMID- 29767857 TI - Risk factors to develop multicentric lesions of the lower genital tract. AB - : Purpose ofinvestigation: To analyze which are the risk factors in developing multicentric lesions of lower genital tract. MATERIALS AND METHODS: A prospective study of 1,011 patients was conducted at the low genital tract pathology clinic of Sant Joan de Deu Hospital between 2003-2011. A complete assessment of cervix, vagina, and vulva was carried out including HPV-DNA testing, cytology study, colposcopy, and biopsy in case of atypical findings. The statistical analysis was done with SPSS v.19 software. Differences between groups were considered statistically significant atp < 0.05. RESULTS: Twenty-two patients presented multicentric lesions (2.2%). The average age was 43 years. Most of the lesions were bicentric affecting cervix and vagina and cervix and vulva. Only in two cases (9%) there were three sites of genital neoplasia. The authors found four cervical cancer, 17 high grade, and one low grade lesions of the cervix. Eighteen vaginal intraepithelial neoplasia (VAIN), six high grade, 14 low grade, and four vulvar intraepithelial neoplasia (VIN) were found. HPV infection, age > 35 years, multiparity, contraceptive method, immunodeficiency, and level of studies were significantly correlated with multicentric lesions. High percentage of affected margins were found. VIN cases were treated with surgical excision and in two cases microinvasion was found. VAIN III cases were treated with surgical excision or with laser and one case progressed to vaginal cancer. Recurrence after treatment was 27%. CONCLUSION: Age, multiparity, contraceptive method, immunodeficiency, and level of studies were significantly correlated with multicentric lesion. Multicentric lesions had an increased risk of recurrence and progression to cancer. PMID- 29767858 TI - Patterns of recurrence and outcomes in patients with luminal breast cancer: a retrospective study. AB - BACKGROUND: Patients with luminal breast cancer have better prognosis and survival rates compared to patients with non-luminal breast cancers, such as basal-like and HER-2 subtypes, owing to the added benefits of adjuvant endocrine therapy. However, local relapses and distant metastasis still frequently occur. In recent years, more studies on breast cancer relapse and metastasis have focused on non-luminal breast cancers despite there being more number of cases of luminal breast cancer. MATERIALS AND METHODS: In this study, the authors included 387 breast cancer patients with recurrence and metastasis who were treated in their hospital between January 2001 and June 2011, and divided them into luminal and non-luminal groups. The differences in clinical and pathological characteristics, survival rates, and prognostic features after follow-up treatment were retrospectively analyzed in the two groups. RESULTS: The authors found there was a higher proportion of local recurrence and single bone metastasis in luminal group than in the non-luminal group. The risk of recurrence and metastasis in the luminal group two to five years and after five years post operation continued to be stable, but the risk in the non-luminal group significantly decreased after two years. CONCLUSIONS: Luminal breast cancer patients with recurrence or/and metastasis had better prognosis after reasonable treatment. These results are of potential clinical relevance, especially for clinical prognosis monitoring and targeted therapy interventions in patients with luminal breast cancer. PMID- 29767859 TI - Can preoperative neutrophil to lymphocyte and platelet to lymphocyte ratios predict cervical stromal involvement in endometrioid endometrial adenocarcinoma? AB - PURPOSE: To evaluate the possible relationships between preoperative inflammatory markers [neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)] and cervical stromal involvement in endometrioid endometrial adenocarcinoma. MATERIALS AND METHODS: Charts and pathology results of 639 women who were operated on for endometrioid endometrial adenocarcinoma between 2000 and 2013 in the present clinic were retrospectively reviewed. Demographic, laboratory, and clinical parameters were evaluated. RESULTS: 118 women (18.4%) had cervical stromal involvement. Lymph node positivity was significantly more frequent in the cervical stromal involvement group (p < 0.001). A threshold value of 2.41 for NLR had a sensitivity of 62.7%, specificity of 60.1%, PPV of 61.1%, and NPV of 61.8% for the presence of cervical stromal involvement. In multivariate analysis, increased NLR had a significant predictive value for cervical stromal involvement (p = 0.006, OR = 2.03), although PLR remained non significant (p = 0.77, OR = 1.08). CONCLUSIONS: The preoperative NLR assessment is a significant predictor for cervical stromal involvement in endometrioid endometrial adenocarcinoma. PMID- 29767860 TI - The identification of patients at high risk for recurrent disease after treatment for early-stage cervical cancer. AB - OBJECTIVE: To investigate prognostic factors in patients with recurrent cervical cancer after treatment of early-stage disease in order to identify high-risk patients who might benefit from alternative treatment strategies. STUDY DESIGN: The authors retrospectively analyzed clinical and pathology data from 130 recurrent cervical cancer patients after surgical treatment for early-stage disease. Patients were compared with a recurrence-free control group matched for age, FIGO Stage, and adjuvant treatment. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors for recurrence and survival. RESULTS: Of 889 patients, 130 (14.6%) developed recurrent disease after primary treatment for early-stage cervical cancer. Local or loco-regional metastasis was observed in 45%, distant metastasis in 31%, and combined pelvic and distant metastasis in 24%. Median survival after recurrence was 12 months (range 1-107 months). Median five-year survival was 96% in the control group and 29% in the recurrence group. Tumor size >= 40 mm and lymph node metastasis were independent unfavorable prognostic factors for overall survival (OS) and disease free survival (DFS). The number of positive lymph nodes (>= one) and bilateral occurrence of pelvic lymph node metastasis were associated with adverse clinical outcome. CONCLUSIONS: Tumor size >= 40 mm and lymph node metastasis were independent unfavorable prognostic factors in surgically treated, early-stage cervical cancer patients. The combination of these factors was particularly associated with recurrence. Future trials should focus on the role of alternative adjuvant treatment strategies in patients at high risk of recurrent disease (e.g., by chemotherapy, immunotherapy or combinations thereof). PMID- 29767861 TI - Serum expression level of cytokine and chemokine correlates with progression of human ovarian cancer. AB - OBJECTIVE: This work was designed to determine the relationship between serum expression level of cytokines and chemokines and progression of human ovarian cancer, and to evaluate the utility and diagnostic value of target markers as risk indicators. MATERIALS AND METHODS: A set of candidate cytokines and chemokines (GM-CSF, IFN-gamma, GRO, IL-1beta, IL-2, IL-6, IL-8, MCP-1, TNF-a, VEGF, EGF, RANTES, CCL21/6Ckine, and SDF-1/CXCL12) were measured using Luminex liquid chip technique in healthy women (n=75) and in women with ovarian cancer (n=77). RESULTS: EGF, IL-6, MCP-1, 6Ckine, RANTES, and IL-10 were significantly overexpressed in the tumor group compared to those in normal controls, while IL-2 was reduced. The combined markers (EGF, MCP- 1, 6Ckine, IL-6, and TNF-alpha) achieved 91.1% sensitivity, 65.8% specificity, and 83.3% area under the ROC curve (AUC) in distinguishing serous ovarian cancer from health controls. CONCLUSION: This study suggested that serum expression level of cytokines and chemokines correlate with progression of human ovarian cancer. The association of EGF, MCP 1, 6Ckine, IL-6, and TNF-alpha may contribute to increase diagnosis rate of malignant ovarian tumors. PMID- 29767862 TI - Platinum-Gemcitabine-Avastin (PGA) for platinum-resistant/refractory ovarian cancer. AB - OBJECTIVES: Synergism between gemcitabine and platinum is known clinically. Bevacizumab in combination with single-agent chemotherapy has demonstrated significant clinical activity in platinum-resistant recurrent ovarian cancer in AURELIA study. However, the efficacy of platinum-gemcitabine-bevacizumab (PGA) has not been investigated in the platinum-resistant population. MATERIALS AND METHODS: A retrospective chart review was conducted in all patients with platinum resistant/refractory ovarian cancer treated with triplet combination therapy containing a platinum agent, gemcitabine, and bevacizumab between July 2011 and December 2013. RESULTS: In total, 13 patients met the selection criteria, including ten patients with resistant disease (10/13, 77%) and three patients with refractory disease (3/13, 23%). Most of the patients were heavily pre treated, having received over three lines of prior chemotherapy regimens on average (range 1-11). All patients had previously received taxane therapy; four patients received gemcitabine, seven patients failed combination regimens including bevacizumab, and three patients progressed on chemotherapy including both gemcitabine and bevacizumab. Ten patients responded biochemically to the therapy (defined by CA-125 declined by at least 50%). Of ten responders, one patient achieved CR for 24 months (8%), six patients achieved PR for 6.8 months (46%), three had stable disease for 6.7 months (23%), and three patients had PD (23%) by RECIST 1.1 criteria. The regimen was well-tolerated. One patient (8%) developed grade 3 neutropenia and neutropenic fever, requiring hospitalization, two patients developed grade 3 thrombocytopenia, two patients (15%) developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab, one patient (8%) experienced skin ulcer, and two patients developed thrombosis in internal jugular vein, requiring discontinuation of bevacizumab. CONCLUSIONS: Combination of PGA appears to be safe and very active against platinum resistant/refractory ovarian cancer and merits further evaluation prospectively. A randomized phase II study (NCTO 1936974) is currently under way to confirm this important finding. PMID- 29767863 TI - Influence of VEGF, COX-2, and MMP-9 expression on the molybdenum-targeted X-ray in breast cancer. AB - AIM: To investigate the correlation of the expression of vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and matrix metalloprotease-9 (MMP 9) in breast cancer tissues with molybdenum-targeted X-ray images. MATERIALS AND METHODS: Sixtynine patients with invasive ductal carcinoma of the breast confirmed by molybdenum-targeted mammography, surgical, and pathologic examinations were enrolled. The expression of VEGF, COX-2, and MMP-9 were detected by immunohistochemical staining (IHS) and the correlation of VEGF, COX 2, and MMP-9 expression and classification of breast cancer on molybdenum targeted X-ray was statistically analyzed. RESULTS: The expression of VEGF, COX 2, and MMIP-9 were significantly higher (p < 0.05) in spiculation group (n = 50), vascular abnormalities group (n = 21), and lymph node metastasis group (n = 29),than the other three groups, respectively. However, the expression of VEGF, COX-2, and MMP-9 had no significant differences (p > 0.05) between the group with (n = 30) and without (n = 39) calcification. CONCLUSION: Expression of VEGF, COX 2, and MMP-9 is highly correlated to the mammaographic appearance of spiculation, vascular abnormalities, and lymph node metastasis. However, the present results suggest that expression of VEGF, COX-2, and MMP-9 is either not or weakly correlated to mammographic appereance of calcification. PMID- 29767864 TI - Hysteroscopy combined dilatation and curettage, serum CA125 and CA19-9 play an important role in preserving fertility or endocrine function for early-stage endometrial cancer patients. AB - OBJECTIVE: The aim of the study was to evaluate the role of hysteroscopy combined dilatation and curettage (D&C), serum CA125 and CA19-9 in endometrial cancer (EC) patients who desire to preserve fertility or endocrine function. MATERIALS AND METHODS: This retrospective study included a total of 622 patients with EC between January 2006 and December 2014. The consistency of preoperative and postoperative histopathological findings were compared in patients who underwent D&C with or without hysteroscopy. The incidence of positive peritoneal cytology was also compared to assess the safety of hysteroscopy. Receiver operating characteristic (ROC) curve was used to evaluate the role of preoperative serum CA125 and CA19-9 in predicting extrauterine metastasis. RESULTS: In 151 patients who underwent hysteroscopy combined D&C, the consistency of pre- and postoperative pathology was higher than the remaining 447 patients who underwent classical D&C alone (83.44% vs. 74.94%,p < 0.05) and there was no significant difference in the incidence of positive peritoneal cytology between the two groups (2.64% vs. 2.73%, p > 0.05). ROC curve analysis results showed the CA125 serum level of 31.75 U/ml and CA19-9 serum level of 35.40 U/ml were the best cutoff to predict extrauterine metastasis in endometrial cancer, with 66.7% sensitivity, 83% specificity, and 61.9% sensitivity and 84.9% of specificity, respectively. CONCLUSIONS: Hysteroscopy combined D&C should be recommended for early-stage EC patients who desire to preserve fertility or endocrine function, and the preoperative serum levels of CA125 and CA19-9 were powerful in predicting tumor stage in these patients. PMID- 29767865 TI - The influence of biopsy in cervical high-grade squamous intraepithelial lesion, evaluated by HPV E6/E7 mRNA, Pap test, and conization results. AB - OBJECTIVE: To evaluate the influence of biopsy on cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: A study was conducted involving 124 women underwent colposcopy-guided biopsy. At the first appointment, the women answered the survey questionnaire, cervical samples were collected for Papanicolaou (Pap) testing and the HPV E6/E7 mRNA test. At the second appointment at three to four months after the first, samples were collected from 81 patients with indications for conization, Pap test, and HPV E6/E7 mRNA testing before they underwent the procedure. PCR was used to detect HPV mRNA. The percentage of negative results before and after the biopsy was evaluated. The agreement between the tests results was evaluated using Cohen's kappa. RESULTS: Sixty-two patients (76.4%) were between 21 and 40 years of age, 35 (43.2%) had four or more pregnancies, 41 (50.5%) had their sexual debut at 16 years of age or more, and 52 patients (64.2%) had undergone five or more Pap tests. The initial biopsy was negative for CIN2/3 in 14 (12.3%) patients; however, all patients were submitted to conization. Among those women with biopsy showing CIN2/3 (66 [81.5%]), 7.41% showed CIN1 and 14.81% were negative in the conization (kappa = 0.2052). The E6/E7 test performed before and after biopsy showed the best level of agreement by the kappa coefficient (0.7491) Conclusions: A higher percentage of negative results were observed in the histopathology, cytopathology, and E6/E7 after biopsy, suggesting that biopsy could affect the regression of CIN. PMID- 29767866 TI - HE4: really a novel biomarker for ovarian cancer?. AB - Ovarian cancer forms 4% of all cancers and approximately 23% of all gynecological cancers in women and is responsible for the 47% of deaths related to cancers of the genital tract of women. Tumor markers are the biochemical substances which can be detected in the presence of tumors. Generally they are either the products of tumoral tissues or secreted from the normal cells which are in the inter- action with tumoral ones. The present authors attempted to determine the efficacy of the tumor marker CA- 125 and HE4 to differentiate the malign cases from the benign adnexal masses. A total of 76 patients with the appropriate criteria were included in the study. They were divided into three groups; healthy control group (n=3 1), ones with benign masses (n=23), and ones with malign ovarian masses (n=22). In the study, when the cut-off values were accepted as 55I U/ml for CA 125 and 150 pM for HE4 in differentiation of benign and malign groups, the sensitivity was found as 59.09%, specificity 91.3%, PPV 86.67% and NPV 70% LR = +6.8. This combination gives one false positive result to every five positive cases which were detected as high. With the combination of CA-125 and HE4, the value of sensitivity was found decreased as expected, although the value of the specificity increased. PMID- 29767867 TI - Expressions of H2AX in cervical squamous carcinoma and their clinical significances. AB - OBJECTIVE: To evaluate the expression and clinical significance of H2AX in cervical squamous carcinoma. MATERIALS AND METHODS: The expression of H2AX in the cervical squamous carcinoma of 37 patients and in the normal cervical tissue of 15 patients was detected by immuneohistochemical method. Chi-square, correlation analysis, and Kaplan-Meier were utilized to analyze the data. RESULTS: The positive expression rate of H2AX in cervical squamous carcinoma was higher than that in normal cervical tissues (p = 0.016) . The expression of H2AX was negatively correlated with FIGO staging, vaginal invasion, and parametrial infiltration (p < 0.05). Survival analysis showed the expression intensity of H2AX had no significant effect on the prognosis. CONCLUSION: H2AX was an anticancer protein for cervical squamous carcinoma. PMID- 29767868 TI - Knowledge about cervical cancer, Pap test, and barriers to women's participation in screening in Belgrade, Serbia. AB - INTRODUCTION: Cervical cancer (CC) is a serious public health concern in Serbia, due to opportunistic screening still being in force, which led to twice higher than the average incidence rate of cervical cancer in Europe. Despite the fact that early detection and treatment services of CC are available at no additional cost, majority of women use inadequate screening services in Serbia. OBJECTIVE: This study aimed to examine the link between the knowledge about CC and Papanicolaou (Pap) test and perception of barriers to women's participation in CC screening. MATERIALS AND METHODS: The study included 300 women aged 21 to 69, with a place of residence in the city of Belgrade (Serbia), who were attending for their medical examination to the University Clinic of Gynecology and Obstetrics - "Narodni front", from June through December 2014. A survey instrument to collect data was an adapted questionnaire for the assessment of knowledge about and barriers to CC and Pap test. Patients were divided into three groups: a study group consisted of women attending irregularly (over three years), women who never participated in screening, and a control group that included women regularly participating in screening. RESULTS: Women regularly participating in screening (52.7%) had adequate knowledge about CC and Pap test, while women who irregularly (79.4%) or never participated (71.9%) did not have any adequate knowledge. There was a significant statistical difference between the CC and Pap test awareness in a group of respondents who regularly participated in comparison to respondents who irregularly or never participated in screening (x2= 27.772, p = 0.000). Regarding knowledge about human papillomavirus (HPV), 80% of women did not know that Pap test cannot be used for detection of HPV, as well as that abnormal Pap test result may be due to HPV (61.7%). Majority of women (93.7%) had poor knowledge about Pap test role in CC early detection and considered Pap test to be used to diagnose CC. The authors found a significant statistical correlation between participation of women in screening and barriers. Women who were irregular or never participated, had barriers such as: lack of time (F = 9.51; p = 0,000), difficult access to Healthcare facilities (F = 11.29; p = 0.000), lack of knowledge about the Pap test procedure (F = 21.27,p = 0.000), discomfort (F = 9.36; p = 0.000), and anxiety of Pap test results (F = 3.35; p = 0.036). Women who regularly participated did not have prejudice when choosing a gynecologist, unlike the other two groups that preferred a female gynecologist (F = 3.61; p = 0.028). CONCLUSION: This study showed that the level of knowledge about CC and Pap test in women is an important factor associated with regular participation in screening. It is necessary to take educational measures in order to raise awareness of women regarding risk factors, as well as to overcome fear and shame, with the ultimate aim to reduce frequency and mortality rate caused by CC in Serbia. PMID- 29767869 TI - Short-term curative effect and safety of bevacizumab combined with chemotherapy for treating recurrent and metastatic cervical cancer. AB - OBJECTIVE: To observe bevacizumab plus chemotherapy curative effect and safety for recurrent and metastatic cervical cancer. MATERIALS AND METHODS: Retrospective analysis of 30 recurrent and metastatic cervical cancer cases. The experimental group received beva- cizumab plus paclitaxel-, docetaxel-, and platinum-based chemotherapy. The control group received only chemotherapy. Curative effects were recorded after at least two treatment cycles; adverse reactions were recorded with every cycle. RESULTS: Experimental group patients were treated for an average 2.6 cycles. Compared to the control group, the experimental group effective rate (26.7%) was similar, disease control rate (73.7%) was significantly higher, and median survival time was three months longer. Bevacizumab-associated adverse reactions were bleeding, hypertension, and thrombosis/embolism; most were level 1 and 2 reactions. Adverse reactions in the two groups were not statistically different. CONCLUSIONS: The bevacizumab plus chemotherapy disease control rate for recurrent and metastatic cervical cancer is comparatively high, prolonging median survival; bevacizumab-associated adverse reactions are mild and tolerable. PMID- 29767870 TI - Surgical staging of low-risk Stage IA endometrioid endometrial cancers. AB - PURPOSE: Surgical staging in early endometrial cancer is not universally done and lymphadenectomy in early-stage disease is controversial. Aim of the present study was to evaluate surgical staging in patients with endometrioid histology, FIGO Stage IA endometrial cancer. MATERIALS AND METHODS: Eighty-seven patients with FIGO Stage IA, low-risk patients were included in the study. Staging surgery group included patients who had comprehensive surgical staging (hysterectomy, oophorectomy, and pelvic lymph node dissection with or without para-aortic lymph node dissection). Non-staging surgery group included patients who had hysterectomy, and bilateral oophorectomy with or without lymph node sampling. Two groups were compared for lymph node status, occult cervical involvement, other prognostic factors, and outcome were analyzed. RESULTS: In total 17.2% of patients were upstaged in final pathological examination; 12.9% in non-staging surgery group and 24.2% in staging surgery group. Upstaging was due to lymph node involvement (6%), cervical stromal invasion (13.7%), and myometrial invasion greater than 50% (1.1%). Median pelvic lymph node number was 23 and pelvic lymph node metastases was found in 3% of the patients. Median para-aortic lymph node number was 11.5 and there was one isolated para-aortic lymph node metastases (5.8%). CONCLUSION: Of the patients, 17.2% had stage migration. Until the issue is solved by future studies, surgical staging might be considered standard surgery for endometrial cancer. PMID- 29767871 TI - Expression and clinical significance of Ki-67, E-cadherin, and mesothelin in serous borderline ovarian tumor. AB - OBJECTIVE: This study aimed to investigate the expression of Ki-67, epithelial cadherin (E-cadherin), mesothelin, and their correlations with clinicopathological features of serous borderline ovarian tumors (SBOTs). MATERIALS AND METHODS: Immunohistochemistry was conducted to investigate the expression of a cellular proliferation-related factor (Ki-67) and metastasis related factors (E-cadherin and mesothelin) in 41 cases of SBOTs, 30 benign ovarian tumor tissues, and 30 malignant ovarian tumor tissues. RESULTS: The results showed that the expression rate of Ki-67 (46.3%) in SBOTs was higher than that in benign tumors (6.7%), but lower than that in ovarian carcinomas (80%). SBOTs significantly differed from benign ovarian tumors (p < 0.01) and carcinoma (p < 0.01). The positive expression rate of Ki-67 was significantly correlated with FIGO stage and peritoneal implantation of SBOTs (p < 0.01). The expression rate of E-cadherin was significantly lower in ovarian carcinomas (56.7%) than in SBOTs (80.5%) and benign ovarian tumors (90%; p < 0.05). The mesothelin expression in ovarian carcinomas and SBOTs significantly differed from that in benign ovarian tumors (p < 0.01). The positive expression rate of mesothelin was related to the serum CA125 level (p < 0.05). The expression of Ki-67 was positively correlated with the expression of E-cadherin and mesothelin in SBOTs. CONCLUSION: SBOTs generally behave in a benign manner. Ki-67, E-cadherin, and mesothelin may play an important role in the oncogenesis and progression of SBOT. Patients with Ki-67 and mesothelin overexpression and low E-cadherin expression should be followed up. PMID- 29767872 TI - Gestational trophoblastic disease in Campinas, Brazil and persistency predictors. AB - PURPOSE: To determine the prevalence of the gestational trophoblastic disease (GTD) and to evaluate the risk factors for persistence of the disease. MATERIALS AND METHODS: A retrospective study with 152 women diagnosed with GTD at University of Campinas from 2006 to 2013. Frequencies, average, and standard deviation were evaluated for each variable and an exact Fisher test was utilized to study persistent disease risk factors. RESULTS: The women were on average 25.81 +/- 8.02 years old. The most prevalent blood type was O positive (49.6%). The diagnosis of complete mole was found in 64.8%, followed by partial mole in 32%, and choriocarcinoma in 3%. Complete mole developed invasive mole in 12.3%, the same occurred with 7.5% of the partial moles. No significant association was found between age, number of gestations, race, BMI or blood type and persistent mole. CONCLUSION: The complete mole is the most fre- quent GTD, and is at high risk for developing malignant forms. PMID- 29767873 TI - Role of HAND2 gene and protein expression in endometrial carcinoma. AB - OBJECTIVES: To explore the relationship between HAND2 gene and protein expression and the development of endometrial carcinoma (EC). MATERIALS AND METHODS: The expression of HAND2 protein was detected by immunohistochemistry in 77 cases of EC paraffin block and their matched adjacent tissues. Western blot, real-time polymerase chain reaction (RT-PCR) were used to detect the expression of HAND2 protein and mRNA HAND2 expression in 34 cases of EC fresh tissue and paired adjacent tissues. RESULTS: The expression of HAND2 protein and the content of HAND2 mRNA in EC tissue were significantly lower than those in the non-tumorous tissue adjacent to EC. The positive expression rates of HAND2 protein in type I and type II EC were 19.67% and 50.00%, respectively. The expression of HAND2 protein in G1, G3, and G2 EC were 30.43%, 26.32%, 18.75%, respectively, with no statistically difference. The positive expression rates of HAND2 in the two groups of specimens with shallow and deep muscularis infiltrating were 40.63% and 15.56%, respectively. With the increase of EC FIGO stage, the positive expression rates of HAND2 protein decreased, and the difference was statistically significant (p <0.05). CONCLUSIONS: HAND2 mRNA and protein low expressed in EC tissues, which suggested the degree of endometrial malignancy. HAND2 may be helpful to the early diagnosis, treatment, and to evaluate the prognosis of endometrial cancer. PMID- 29767874 TI - 1,138 women with adnexal mass: pathologic findings according to age. AB - : Purpose ofinvestigation: Influence of the patients' age are not well established to predict the malignancy potential of adnexal masses. This study was conducted to evaluate the impact of women's age on both histopathology and malignancy potential of adnexal masses. MATERIALS AND METHODS: This is a retrospective chart review study. Patients who were operated for suspected adnexal masses were included in the study. Malignancy potentials of tumors were divided in benign and at least borderline in univariate and multivariate analyses. Univariate analyses and RR calculations were performed according to malignancy potential for age, serum cancer antigen-125 (CA-125) levels and menopause status. RESULTS: A total of 1,138 women were included for this study; median age was 39 (16-92) years. Patients > 50 years had 5.920 times higher risk (95% CI 4.091-8.566; p = 0.0001) of having at least borderline tumor compared the younger group. The risk of at least borderline pathology was calculated as 3.723 (95% CI 2.595-5.342;p = 0.0001) in patients with CA 125 >= 35 IU/ml compared to the others. In multivariate analyses, only >= 35 IU/ml CA 125 level and > 50 years age groups were defined as independent variables for having at least borderline tumor. (OR: 4.456, 95% CI 2.982-6.659, p = 0.0001 and OR: 3.134, 95% CI 1.435-6.843, p = 0.004, respectively). CONCLUSION: In this study; the age of > 50 years was detected as an independent factor for having at least borderline pathology for adnexal masses. The data from these results might be used as a differential diagnostic tool in a new combination for benign and malignant adnexal masses in future studies. PMID- 29767875 TI - Microarray gene expression profiling for identifying different responses to radiotherapy and chemoradiotherapy in patients with cervical cancer. AB - PURPOSE: Cervical cancer, which is treated by radiotherapy (RT) and chemoradiotherapy (CRT), has high morbidity and mortality in women. This study aimed to identify differences in gene response to CRT and RT. MATERIALS AND METHODS: GSE3578 was downloaded from Gene Expression Omnibus including specimens from 20 RT-treated patients and 19 CRT-treated patients. Differentially expressed genes (DEGs) were identified using siggenes package in R. Protein-protein interaction (PPI) network was visualized by cytoscape. MCODE and cytoscape was used separately to mine and construct modules in the PPI network. Transcription factor (TF)-DEG and miRNA-DEG pairs were predicted and then visualized by cytoscape. RESULTS: Total 22 upregulated and 181 downregulated genes were identified in CRT samples. Several functions were enriched for these DEGs. A module involving ZNF449 and ZNF673 was mined from the PPI network of downregulated genes. In the TF-DEG regulatory networks, downregulated GATA3 (which was modulated by SPI) was also a TF, as well as upregulated CDK6 was regulated by several TFs (e.g. GATA3). Hsa-miR-17, hsa-miR-34a, hsa-miR-124, hsa miR-I185-2-3p, hsa- 1185-1-3p, and hsa-let-7f-2-3p were identified as key miRNAs in the miRNA-DEG regulatory network. Conclu- sion: CRT might cure cervical cancer by acting on those molecules that were more sensitive to CRT than CT. PMID- 29767876 TI - Sternocleidomastoid muscle metastasis of breast cancer: case report. AB - The authors report a case of 84-year-old women, with dysphagia to liquids and solid foods, and with infiltration of right stemocleidomastoid muscle that compressed the upper third of the esophagus to the thoracic hull. The biopsy of sternocleidomastoid muscle permitted the diagnosis of metastatic breast cancer relapse after 22 years. PMID- 29767877 TI - Treosulfan for advanced breast cancer in a heavily pre-treated patient - a case report. AB - BACKGROUND: Treatment of metastatic breast cancer experienced significant improvement in the past decades by introduction of highly effective therapies, but survival still remains poor. Nonetheless, in some patients, long-term survival can be achieved by sequent endocrine and chemotherapy treatment, although toxicity and resistance eventually occur, until no further suitable and approved therapies remain. If further therapy is needed, therapist may be forced to consider treatients which are promising but not approved, such as the alkylating agent treosulfan, which is approved for the treatment of ovarian cancer only. Thus, relevant clinical data on its use in human breast cancer are lacking. CASE REPORT: The authors report the case of a 49-yeAr-old woman with heavily pre-treated, metastatic breast cancer, who experienced complete remission of pulmonary and soft tissue metastases while under treatment with treosulfan. Treatment was generally well-tolerated. CONCLUSION: Treosulfan might be an effective and well-tolerated treatment even in heavily pre-treated patients with metastatic breast cancer. PMID- 29767878 TI - Benign metastasizing leiomyoma of bone and lung in postmenopausal women: two rare case reports and review of the literature. AB - Benign metastasizing leiomyoma (BML) is a rare disease that mostly occurs in women of reproductive age. Patients usually have a history of uterine leiomyoma and/or myomectomy. Although lung is the most common site of metastasis, bone involvement is rarely occurred. Here the authors report two rare cases of BML with lung and bone metastasis in postmenopausal women that were successfully treated with surgery and anti-estrogen approach. PMID- 29767880 TI - A case of melanocytic cervical adenosquamous carcinoma complicated with Cushing's syndrome. AB - BACKGROUND: To date, cervical carcinoma complicated with Cushing's syndrome were all diagnosed as small cell carcinoma histo- logically, but not adenosquamous carcinoma. Here the authors present the diagnosis, management, and prognosis of a case of melanocytic cervical adenosquamous carcinoma complicated with Cushing's syndrome. CASE: A 28-year-old woman was admitted with the chief complaint of post coital bleeding for one month. Gynecological examination revealed a nodular yellowish-pigmented vegetation (6x5 cm) on the cervix. Laboratory findings proved the diagnosis of Cushing's syndrome. Histopathological diagnosis showed the adenosquamous carcinoma with melanoma differentiation. Immunohistochemical stainings for melanoma A and anti- adrenocorticotropic hormone (ACTH) were positive in the majority of the tumor cells, which indicated that this melanocytic cervical carcinoma lesion was the source of ectopic ACTH production resulting in Cushing's syndrome. CONCLUSION: This is a unique case of a rare type of cervical carcinoma. PMID- 29767879 TI - Surgical removal of an isolated femoral metastasis of uterine cervical squamous cell carcinoma: a case report and review of the literature. AB - A bone metastasis from uterine cervical cancer normally indicates short life expectancy. Resection of the lesion is therefore palliative. The authors consider herein whether surgical resection can promote disease control while improving quality of life. A 33-year-old woman -presenting FIGO Stage IB 1 uterine cervical squamous cell carcinoma underwent a radical hysterectomy and pelvic irradiation. Twenty-two-months later, a solitary femoral metastasis was detected. Given the pain, imminent bone fracture, the patient's relative youth, absence of other metastases, and complete control of the primary lesion, wide excision of the lesion, and reconstruction were performed. Sixteen months later, she was disease free and ambulatory using a cane. The findings of both the present case and the review showed that patients were disease-free for over one year after surgery, suggesting that resection may assist disease control as well as improve patients' quality of life. PMID- 29767881 TI - Abdominal radical trachelectomy (ART) performed during pregnancy: a case report. AB - PURPOSE OF INVESTIGATION: Cervical cancer is one of the most frequent malignant diseases diagnosed during pregnancy. Abdominal or vaginal radical trachelectomies are fertility-preserving alternatives to radical hysterectomy for young women with early-stage cervical cancer that can be performed during ongoing pregnancy. MATERIAL AND METHODS: The authors report a pregnancy complicated by cervical cancer treated by abdominal radical trachelectomy (ART) at 16-17 gestational weeks with preservation of the concurrent pregnancy. RESULTS: The pregnancy evolved normally and delivery occurred at 38-39 gestational weeks by elective caesarean section. CONCLUSIONS: Radical trachelectomy could be offered as an option for pregnant patients with early invasive cervical cancer. It may help women to avoid the triple losses of a desired pregnancy, fertility, and motherhood. PMID- 29767883 TI - Effective therapeutic strategy for massive retroperitoneal hematoma after conization: arterial embolization and pigtail catheter insertion. AB - The loop electrosurgical excision procedure (LEEP) is commonly used to remove cervical intraepithelial neoplasia (CIN) because of its safety profile and likelihood of fewer complications. The authors report a rare case of massive retroperitoneal bleeding combined with hypovolemic shock after LEEP conization. Vessel injury was detected by angiographic computed tomography (CT) and embolization of the uterine artery was successfully performed to achieve hemostasis by an intervention radiologist. A pigtail catheter was subsequently inserted for the drainage of the large retroperitoneal hematoma. The patient did not show any further hemorrhage and recovered safely from hypovolemic shock. Th present case demonstrates a successful multidisciplinary and minimal invasive approach to manage retroperitoneal bleeding with uterine artery embolization. Thus, it should be considered a potential treatment option for hemostasis. PMID- 29767882 TI - Tertiary cytoreduction for recurrent endometrial cancer. AB - This paper reviews the surgical approach experiences in endometrial cancer recurrence and presents for the first time data on the surgical management of endometrial cancer patients at the time of their second recurrence. Surgery could represent a pivotal role in selected cases of recurrent endometrial cancer, offering long-term complete remissions and a survival advantage. PMID- 29767884 TI - Squamous cell carcinoma arising from teratoma of the ovary: magnetic resonance, computed tomography, and pathological findings. AB - In the present case report, the authors investigated the clinicopathological characteristics of squamous cell carcinoma (SCC) arising from teratoma of the ovary and intended to report their clinical experience. Malignant transformation of ovarian teratoma is a quite rare condition with SCC observed to be the most common form of transformation. The present case was a 43-year-old female patient and her clinical presentation was abdominal pain, abdominal distension, and abdominal mass sensation. The patient underwent ultrasonography. After detection of a mass, magnetic resonance imaging (MRI) was performed. Surgery was performed on the patient and the pathological report revealed SCC arising from teratoma. The patient was evaluated retrospectively in terms of demographic characteristics, MRI, surgical findings, and prognosis. PMID- 29767885 TI - Robot-assisted laparoscopic adenomyomectomy of adenomyotic nodule implanted in the uterine endometrium manifesting as endometrial cancer: a case report and literature review. AB - Thickened uterine endometrium with abnormal uterine bleeding highly suggests endometrial hyperplasia or endometrial carcinoma. A case of 35-year-old nulliparous woman came to our department with endometrial mass manifesting as endometrial cancer. Transrectal ultrasonography and magnetic resonance imaging (MRI) showed an 8x6 cm multicystic, ill-defined mass compacted at the uterine endometrium, the anterior wall of the uterus, and 3x3 cm heterogenous mass at the left adnexa. The edometrial mass showed multiple septations with enhancement and low-signal intensity on T2-weighted images. After endometrial biopsy was done and simple hyperplasia without atypia was observed at the histopathologic finding, the patient underwent robot-assisted laparoscopy and diagnosed as adenomyoma at the frozen pathology. After adenomyomectomy, permanent pathologic analysis revealed the same result and she recovered without any complications and responded well to gonadotropin-releasing hormone (GnRH) agonist therapy. PMID- 29767886 TI - Ovarian gastrointestinal stromal tumor: does this diagnosis exist?. AB - Gastrointestinal stromal tumors (GISTs) are rare gastrointestinal (GI ) tract tumors. Those tumors rarely arise extra intestinally; within omentum, mesentery, and rarely uterus. The authors report a case of myxoid variant of GIST arising in the ovary with no evidence of a primary tumor in the GI tract. Surgeons as well as gynecologists should bear this possibility in mind when managing pelvic masses. PMID- 29767887 TI - Retroperitoneal leiomyosarcoma: a case report. AB - Retroperitoneal leiomyosarcoma is a relatively rare and aggressive tumor. Because of its rarity, it is difficult to arrive at a definite diagnosis preoperatively and to design an effective strategy. Here the authors report a case of peritoneal leiomyosarcoma in which diagnosis was difficult because the clinical course resembled that of ovarian cancer. A 77-year-old woman diagnosed with ovarian cancer underwent laparotomy. The excised tumor contained a necrotic polypoid mass that histologically displayed the features of leiomyosarcoma. The patient received adjuvant chemotherapy with a combination of gemcitabine and docetaxel but died two months after surgery owing to the aggressive behavior of the tumor. Because the preoperative diagnosis in this case was ovarian cancer, arriving at a treatment strategy assuming peritoneal leiomyosarcoma was difficult. If complete surgical resection of tumor is not performed, as in the present case, the prognosis can be extremely poor. PMID- 29767888 TI - Seminoma leading to detection of testicular feminization syndrome: a case report. AB - The authors here report a 54-year-old (gravida 0, para 0), who claimed to have had her menarche at age 13 and menopause at 52 years. Two months prior to presentation, the subject first noticed a hard but elastic fist-sized mass in the left inguinal region that gradually grew, causing pressure-related pain. Although the external genitalia appeared female, the vagina was short and blind-ending, and no uterus or ovaries were identified on transvaginal ultrasound. Chromosome banding results (G-band method) showed 46XY. Laparoscopy revealed no traces of a vestigial uterus or ovaries; thus, based on the appearance of the external genitalia, a diagnosis of testicular feminization syndrome was made. Pathological testing of the palpable mass led to a diagnosis of seminoma with Leydig cell hyperplasia. Thus, in this case, the development of a seminoma in an undescended testis led to the detection of testicular feminization syndrome. PMID- 29767889 TI - Non-diethylstilbestrol exposed vaginal adenocarcinoma in young patients associated with unilateral renal agenesis: two case reports and literature review. AB - BACKGROUND: Adenocarcinoma, accounts for up to 14% of all vaginal cancer. In young patients, common histological feature is clear cell adenocarcinoma (CCA) while mesonephric adenocarcinoma (MA) is very rare. The authors report two patients in their early twenties with unilateral renal agenesis and vaginal adenocarcinoma not exposed to diethylstilbestrol (DES). CASES: Two patients with vaginal adenocarcinoma were treated, with external beam radiotherapy of pelvis combined with brachytherapy to a radical dose. In 2000, 25-year-old female, was admitted for radiotherapy after incomplete excision of the tumor localized in left vaginal apex and fornix. Histopathology confirmed CCA and classified as clinical Stage II. CT revealed left renal agenesis.The patient is alive and disease-free 15 years after therapy. Vaginal, urethral stenosis, and hydronephrosis occurred and ureteral stent was inserted. In the second patient, 22-year-old, in 2004, after biopsy of bulky tumor of vagina and histology, revealed MA in Stage III and CT scan also confirmed right renal agenesis. Radiotherapy was followed by chemotherapy. After 11 years, patient is disease free with vaginal stenosis and incipient renal hydronephrosis. CONCLUSION: Radiotherapy is effective treatment in advance vaginal adenocarcinoma, however, with high morbidity. The authors advise rigorous gynecologic exams in young females with renal agenesis as there may be a risk of malignant changes in vagina. PMID- 29767890 TI - Intensity modulated radiotherapy and brachytherapy for a cervical cancer after renal transplantation. AB - Radiotherapy and surgery are important radical treatment options for cervical cancer, but the presence of a pelvic kidney complicates the situation. Fine radiation technique can help avoiding side effects. Radiation to the modified pelvis using intensity modulated radiotherapy (IMRT) followed by brachytherapy, while avoiding the renal allograft is technically feasible which ensures adequate target volume and reduces side effects. Here, the authors report a 45-year-old patient with invasive cervical cancer with a pelvic kidney who was treated by pelvic IMRT in combination with high-dose rate brachytherapy. There was no evidence of disease and with normal kidney function currently at 12 months. PMID- 29767891 TI - ? PMID- 29767892 TI - [Paraneoplastic syndromes : multiple aspects]. AB - Knowledge of paraneoplastic syndromes, and above all their diversity, is very important in terms of clinical application because they often forerun the oncologic diagnosis and thereby may be a tell-tale sign. Recognizing them could allow an early diagnosis at the beginning of the disease or at the relapse. The diversity of these syndromes is an additional problem and clinicians must be aware of this differential diagnosis. Conventional therapeutic management could be insufficient, and recognizing the diagnosis allows to adapt the therapeutic strategy. In this review, we will try to illustrate the diversity of the most frequent paraneoplastic syndromes, present their oncologic connections and their clinical features. PMID- 29767893 TI - [Hemolytic anemia in cancer]. AB - Hemolysis (from the Greek word: hemolysis: hema = blood + lysis = liberation) is a medical term that describes red blood cell's destruction by mechanisms of lysis of the membrane. An hemolytic anemia occurs when excessive destruction of red blood cells overwhelms bone marrow's capacity of regeneration. Although anemia is frequently associated with an oncologic disease, hemolytic anemia is rarely diagnosed in oncologic patients. Consequently, a massive hemolysis can be quickly deleterious and often fatal. An early diagnosis can improve survival and can be made with inexpensive tests. In this article, we present the different types of hemolytic anemia associated with oncologic diseases, their mechanism and the treatment propositions depending on the etiology. PMID- 29767894 TI - [Liquid biopsy, a new opportunity for personalized oncology]. AB - Knowledge about cancer biology is extending and has meaningful repercussions on patients' care. Therefore, there is a growing need to assess tumor biology not only at diagnosis, but also throughout the course of management. Tumor tissue biopsies are particularly useful, but are not convenient for repetitive analyses because of the need for invasive procedures. Advances in biotechnology allow currently getting more and more information from liquid biopsies, based on small amounts of tumor material released for instance into the peripheral blood. Already used in the treatment of non-small cell lung cancers, these new techniques represent more generally an important step forward for personalized oncology. PMID- 29767895 TI - [" Doctor, I am fasting during chemotherapy " : illusion or new clinical facts ?] AB - Fasting concomitantly with oncology treatments (chemotherapy mainly) induces a growing interest among patients following overmediatisation of recent discoveries. The goal of this article is to provide updated information about this approach. According to preclinical studies, fasting may be a way to increase the therapeutic index of major oncology treatments. However, clinical data is based on small exploratory studies only and the results of larger scale studies are not yet available. The approach of fasting during chemotherapy can and should neither be recommended nor implemented in standard care. However, further scientific and clinical investigation may contribute to a better understanding of the metabolic aspects of cancer. PMID- 29767896 TI - [High grade serous ovarian cancer 2018 : advances and controversies]. AB - The primary treatment of ovarian cancer consists in a complete surgical debulking followed by adjuvant chemotherapy combining platinum with taxanes. Despite this treatment, patient survival has remained stable over the last 20 years. Recently, advances in the sequence, regimens, and route of administration of treatment have enhanced effectiveness and reduced toxicity. Targeted anti-angiogenic therapy and recently PARP inhibitors are now complementing standard treatment and have improved patient progression-free survival. The development of immunotherapy, alone or in combination, brings new perspectives for the future treatment of ovarian cancer. PMID- 29767897 TI - [Oncology trajectories of elderly patients in a palliative situation : " The long and winding road "]. AB - This paper focuses on trajectories of elderly patients with metastatic cancer who experience several lines of systemic palliative cancer treatments. Based on photographs representing paths, the representations between patients and professional caregivers vary. Where the latter see wearisome treatments and spaces of negotiation, the patients wish to be seen as fighters, a figure that ought to be adopted to face cancer and its treatments, day after day, to meet medical and social expectations. PMID- 29767898 TI - ? PMID- 29767899 TI - ? PMID- 29767901 TI - ? PMID- 29767900 TI - ? PMID- 29767902 TI - ? PMID- 29767903 TI - ? PMID- 29767904 TI - ? PMID- 29767905 TI - Virtual Health Library in Nursing for Colombia: a New Scientific Communication Portal. PMID- 29767906 TI - Use of crack in pregnancy: repercussions for the newborn. AB - OBJECTIVES: To know the effects for the newborn of the use of crack in pregnancy. METHODS: This is a qualitative study conducted in a university hospital in southern Brazil, in the first half of 2014. Fifteen mothers crack users and five grandparents participated. The data were produced through semi-structured interviews and later submitted to content analysis. RESULTS: It was found that the use of crack in pregnancy leads to repercussions related to the health of the newborn and repercussions related to family restructuring. In relation to the newborn, prematurity, congenital malformation, hospitalization in an intensive care unit, use of care and feeding technologies through artificial milk formulas were mentioned. In the family context, it was evidenced the occurrence of abandonment of the child by the mother, causing the adoption of the newborn by relatives of the family nucleus or their institutionalization due to lack of family structure. CONCLUSIONS: It was found that the use of crack in pregnancy leads to repercussions related to the health of the newborn and repercussions related to family restructuring. In this sense, the recruitment of pregnant users of crack by health/nursing professionals and referral for high-risk prenatal care, as well as early identification of the peculiarities of the newborns of these women, and the development of actions that minimize the repercussions of crack are imperative. PMID- 29767907 TI - The teacher's body elements that influence the teaching-learning process of university nursing students. AB - OBJECTIVES: To identify the body elements of the teacher that influence the teaching-learning process and to analyze their effects on university nursing students. METHODS: Qualitative research with descriptive approach implemented through a dramatic play dynamics. In the second half of 2015, sixteen students from a private university center located in Rio de Janeiro (Brazil) participated in the study. The data processing was carried out by using Bardin's theoretical and analytical framework. RESULTS: Four decoding units were created. They verse about the teacher's positioning, body movements, eyes, facial expressions as well as the clothes used to teach nursing. CONCLUSIONS: The teacher's elements are capable of generating effects that influence the process of learning nursing. This leads us to believe that the body should continue to be an object of study and discussion in the higher education of nurses. PMID- 29767908 TI - Gender Differences in Body Mass Index, Body Weight Perception, weight satisfaction, disordered eating and Weight control strategies among Indian Medical and Nursing Undergraduates. AB - OBJECTIVES: To assess gender disparity in body weight perception, Body Mass Index (BMI), weight satisfaction and role of depression among undergraduate Medical and Nursing students. METHODS: A descriptive cross sectional descriptive study was conducted in conveniently selected medical (n=241) and nursing (n=213) students of Bangalore, South India. Data was collected using self-administered SCOFF questionnaires. RESULTS: Our findings revealed that men had a significantly higher BMI than women (t=5.403, p<0.001). More number of women compared to men, perceived themselves as over weight (74.8%) and not satisfied with their weight status (81.6%). More men than women scored positively for disordered eating behaviors on SCOFF (45.4% vs. 31.1%) and EAT scale (16.5% vs. 8.7%). While, 48.2% of the women practice binge eating, 41.2% of the men practice it (p<0.004); more men (47.4%) than women (25.4%) exercised for more than sixty minutes (p<0.001) to control their weight. CONCLUSIONS: Findings indicate small differences between the genders that have to be taken in consideration in planning interventional programs to prevent eating disorders in this population. PMID- 29767909 TI - Challenges of motherhood in the voice of primiparous mothers: initial difficulties. AB - OBJECTIVES: To identify the main difficulties first-time mothers experience in the postpartum period, during the first six months of the baby's life. METHODS: Level I qualitative, exploratory-descriptive study. The sample consisted of 11 first-time mothers of full-term healthy newborns. The data were collected through the "focus group" method. The mothers' discourse was subject to content analysis, categorizing the registry units. RESULTS: Three categories emerged from the data analyzed that indicate the mothers' main difficulties in this period: postpartum recovery; baby care; marital relationship. CONCLUSIONS: The results indicate that, although motherhood is an event marked by positive emotions, the difficulties that emerge in the mothers' daily life can interfere negatively in the quality of parenthood. In this scenario, the nurses play a determinant role in the enhancement of interventions that are sensitive to these needs and that, at the same time, favor these mothers and their families' empowerment, thus optimizing the children's development trajectories. PMID- 29767910 TI - Preparation for Motherhood during Pregnancy: a Concept Analysis. AB - OBJECTIVES: This work sought to identify the attributes of the concept of preparation for motherhood during pregnancy. METHODS: Concept analysis with the method by Walker and Avant, which conducted a literature review in databases and other sources. Inclusion criteria were defined and a database was created with the articles included for the analysis. The information was integrated, responding to the eight steps proposed in the method. RESULTS: The concept of preparation for motherhood during pregnancy is defined as an intermediate process of active and conscious participation defined by the cultural, social, and historical contexts, which favor lifestyle changes to optimize health and whose attributes are classified into physical and psychological preparation. CONCLUSIONS: The attributes identified contribute to understanding the preparation for motherhood during gestation as a multidimensional concept. These results could be used to design care actions to evaluate pregnant women and prescribe nursing care beyond purely biomedical issues. PMID- 29767911 TI - Analysis of the concept of powerlessness in individuals with stroke. AB - OBJECTIVES: To identify and analyze the concept of the powerlessness in individuals with stroke, according to the NANDA-I Taxonomy. METHODS: Concept analysis from online access of four databases using the descriptors: impotence; helplessness, learned; Stroke, depression in languages: Portuguese, English and Spanish. RESULTS: The critical attributes of the feeling of powerlessness are: fragility, helplessness, lack of control, and power to achieve the proposed results for recovery and adaptation. Eleven new antecedents were found. It is recommended to reformulate three antecedents present in the taxonomy. Fourteen consequent were found. It is suggested to amend three consequential from the review. CONCLUSIONS: With the analysis, a more complete concept of the powerlessness was elaborated allowing clarifying the critical attributes that, in turn, will help the rehabilitating nurse to recognize the signs and symptoms and to strengthen mechanisms of tolerance and resistance to stress. PMID- 29767912 TI - Gender differences in the perception of quality of life of patients with colorectal cancer. AB - OBJECTIVES: To identify the gender differences in assessing quality of life of patients undergoing chemotherapy treatment for colorectal cancer. METHODS: This is a cross-sectional investigation conducted with 144 patients (72 men and 72 women) undergoing chemotherapy treatment in a southeastern Brazilian hospital. Data were gathered trough a sociodemographic and clinical information form and the Health-related Quality of Life instrument from the European Organization for Research and Treatment of Cancer. RESULTS: Cognitive function leads to lower general quality of life, with higher effect in men when compared to women. Body image (p=0.023), abdominal pain (p=0.020) and dry mouth (p=0.001) produced lower quality of life in women. On other hand, men showed lower quality of life related to the following symptoms: fecal incontinency (p<0.001), sexual impotency (p=0.027) and sexual arousal (p<0.001). CONCLUSIONS: The illness symptoms and chemotherapy treatment effects that negatively impact on quality of life differ between men and women. Thus, healthcare needs to be focused on these specific factors that affect the quality of life according to the patient's gender. PMID- 29767913 TI - Development of coverage and its evaluation in the treatment of chronic wounds. AB - OBJECTIVES: To describe the development of the bacterial cellulose coating with anti-inflammatory Ibuprofen (BC/Ibu) and to evaluate the cicatrization process with its use in patients with chronic wounds of venous and diabetic etiology. METHODS: Longitudinal descriptive study. The cellulose membrane, cultivated with bacteria Gluconacetobacter xylinus and with incorporation of Ibuprofen, was used in the treatment of patients with chronic wounds in public health services in a Brazilian municipality. The ideal coverage characteristics were evaluated through physical, chemical and cell proliferation tests. RESULTS: The sample consisted of 14 patients (10 women and 4 men), 8 with venous ulcer, 5 with diabetic foot and one with mixed wound. There was reduction of area and pain in 9 lesions; total healing of 3 wounds; and debridement of the devitalized tissue in 5 wounds with increased area. The use of the membrane was important in the reduction of pain, exudation and ease in the accomplishment of the curative. CONCLUSIONS: BC/Ibu favored the cicatrization process of patients with chronic vasculogenic wounds. PMID- 29767914 TI - Impact of Applying a Learning Strategy to Improve the Sample Quality in Cervical Screening in Nursing Staff in Social Service. AB - OBJECTIVES: The study sought to assess the impact of applying a learning strategy to improve the quality of sample collection during cervical screening by students from the Nursing Degree Program doing social service. METHODS: This was a longitudinal, quasi-experimental study with the participation of 23 interns from the Nursing Degree Program at a public university from San Luis Potosi, Mexico. The work assessed knowledge of practical skills in taking cervical cytology tests and the quality of samples before and after applying a learning strategy that included 10 h of theoretical training and 22 h of practices on themes related to sample collection in cervical screening. RESULTS: A statistically significant difference was obtained in improved knowledge (t = -12.8 p<0.001) and practical skills (t = -8.86 p<0.001) after the intervention. The increased percentage of suitable samples from 30.43% to 82.60% was attributed to the application of the learning strategy in the pre- and post-intervention phases (p<0.001). CONCLUSIONS: Training is effective to improve knowledge and practical skills to collect samples in cervical screening, as well as the quality of the samples for their interpretation. PMID- 29767916 TI - In-depth Knowledge of the Role of the Clinical Mentor. AB - OBJECTIVES: This work sought to unveil the meaning expressed by clinical nurses by being mentors for students from the nursing internship level. METHODS: Phenomenological research. In-depth interviews were conducted with nine clinical nurses from a hospital in Santiago de Chile, who participate as mentors of nursing students in their last stage of university formation. RESULTS: Four comprehensive categories were obtained with their respective units of meaning by nursing: 1) vocation and gratification, 2) personal and professional challenge, 3) big responsibility, and 4) transmission of experience. CONCLUSIONS: Clinical mentorship is a relevant experience in the professional lives of nurses, which implies overcoming challenges, self-training, and delivering the best of oneself, for the purpose of training future professionals prepared to practice nursing integrally. PMID- 29767915 TI - Meaning of parenting as a teenager. AB - OBJECTIVES: Describe the meaning of parenting as a teenager. METHODS: Study of the qualitative approach with phenomenological approach in the fourth village of San Cristobal (Bogota, Colombia). The information was obtained by means of semi structed interviews, participant observation, photos, daily and focal groups field. The information analysis was performed using the phenomenological method of Amadeo Giorgi. RESULTS: The meaning of their parenthood in the adolescents revealed five units of sense: emotional ambivalence, paternity as a process of learning, changes in lifestyle, making a life project and support networks. CONCLUSIONS: Teenage fatherhood was interpreted by the participants as a positive change and assumed a patriarchal perspective. PMID- 29767918 TI - Strategy for nursing research in Sweden. PMID- 29767917 TI - Puerperae bonding with their children and labor experiences. AB - OBJECTIVES: To analyze the degree of bonding of puerperae with their babies, both in isolation and associated with experiences during and after labor. METHODS: A cross-sectional study carried out among 200 puerperae in Sao Jose do Rio Preto, Brazil. To evaluate the mother-child bond, we used the Mother-to-Infant Bonding Scale (MIBS). RESULTS: The mean age of puerperae was 26.4 years; most women were white (60.0%), were married (87.5%), and had an elementary education (51.5%). Most deliveries were cesarean (80.0% of cases); 68.0% of women had no pain during labor, and only 54% had skin-to-skin contact immediately after delivery. Type of labor and pain did not significantly change the maternal bond, and the lack of skin-to-skin contact negatively influenced the bond. CONCLUSIONS: Pueperae participants had a high degree of bonding with their babies that is mainly related to history of skin-to-skin contact. Nurses must promote strategies that encourage skin-to-skin contact between mother and newborn in the delivery room. PMID- 29767920 TI - Educational process in palliative care and the thought reform. AB - OBJECTIVES: To know the contributions of the educational process in Palliative Care during the undergraduate level for the professional action of nurses in the care of patients at the end of life. METHODS: This is a qualitative research, with discursive thematic analysis, based on Morin's theory of complexity. It was attended by seven newly-trained nurses and six nursing teachers from a Nursing Undergraduate Course. RESULTS: It has found disruptions and the development of new ways of thinking and caring for patients at the end of life, highlighting that these patients should be treated with therapies to mitigate their signs and symptoms until death, focusing on quality of life; moreover, their psychosocial and spiritual aspects should be appreciated. CONCLUSIONS: The educational process in palliative care seems to be essential for nurses, as a way of organizing and systematizing patient care. It becomes indispensable that nursing programs also provide the students with the development of the awareness of the complexity of the human being and its relationship with the multiple biopsychosocial and spiritual aspects. PMID- 29767919 TI - Care models for people with chronic diseases: integrative review. AB - OBJECTIVES: To identify the care models and the impact of the use of these in the care of people with chronic diseases reported in the literature in the years 2000 to 2014. METHODS: Integrative literature review in which the following guiding question was adopted: Which care models are used in the care of patients with chronic diseases and what impacts can be verified through their application? We consulted the bibliographic databases Virtual Health Library, LILACS, MEDLINE, Spanish Bibliographic Index of Health Sciences and the Database of Nursing. RESULTS: The sample consisted of 17 articles on the topic of interest. Three categories emerged from the analysis: health care costs, model-based care experience, and patient autonomy. The articles addressed self-management, case management and care model for people with chronic diseases. The major impacts on the use of the models were: a better relationship between the patient and the health professional, an increase in the autonomy of the person with chronic illness, and a reduction in personal and health care expenditure. CONCLUSIONS: The use of care models for people with chronic diseases presents benefits to the patient and to the health system. Nurses must actively participate in the application of these care models of people with this type of illness. PMID- 29767921 TI - Health-promoting lifestyle and assertiveness in university workers. AB - OBJECTIVES: The work sought to analyze the health-promoting lifestyle variables, assertiveness, and their relation to health condition in university workers. METHODS: This was a correlational study with the participation of 112 workers selected through census-type random sampling. To gather information, a form was used that included sociodemographic, anthropometric, and clinical data, in addition to the health-promoting lifestyle scale by Walker et al., and the Assertiveness Questionnaire by Lazarus and Folkman. RESULTS: Participants ranged between 24 and 72 years of age (mean = 45), 61.6% were women, 49.1% worked the day shift, and 59.8% worked as teaching staff. With respect to health problems diagnosed: 17.0% had high blood pressure, 4.5% type II diabetes mellitus, and 4.5% suffer both diseases; 46.4% were found with overweight condition and 23.9% with some degree of obesity. The general index of health-promoting lifestyle was of 39.2 points (medium level) and assertiveness of 74.5 points (high level). A positive and significant relationship was found between assertiveness and the general index of the health-promoting lifestyle (r = 0.22, p <0.05) and the dimensions of spiritual development (r = 0.35, p<0.01) and interpersonal relations (r = 0.29, p <0.01). Likewise, glucose level, one of the parameters of the health condition, was inversely related to the health-promoting lifestyle (r = -0.20, p <0.05) and to the dimensions of physical activity (r = -0.24, p <0.01) and stress management (r = -0.24, p <0.01). RESULTS: Participants ranged between 24 and 72 years of age (mean = 45), 61.6% were women, 49.1% worked the day shift, and 59.8% worked as teaching staff. With respect to health problems diagnosed: 17.0% had high blood pressure, 4.5% type II diabetes mellitus, and 4.5% suffer both diseases; 46.4% were found with overweight condition and 23.9% with some degree of obesity. The general index of health-promoting lifestyle was of 39.2 points (medium level) and assertiveness of 74.5 points (high level). A positive and significant relationship was found between assertiveness and the general index of the health-promoting lifestyle (r = 0.22, p <0.05) and the dimensions of spiritual development (r = 0.35, p<0.01) and interpersonal relations (r = 0.29, p <0.01). Likewise, glucose level, one of the parameters of the health condition, was inversely related to the health-promoting lifestyle (r = -0.20, p <0.05) and to the dimensions of physical activity (r = -0.24, p <0.01) and stress management (r = -0.24, p <0.01). CONCLUSIONS: The findings show the relationship between the health-promoting lifestyle and assertiveness in university workers studied, which justifies the design of educational interventions from nursing aimed at improving these aspects. PMID- 29767922 TI - Risk factors for developing cardiovascular disease in women. AB - OBJECTIVES: To evaluate the factors that predispose to the development of cardiovascular diseases in women who were attended at a Basic Health Unit in Londrina, Parana, Brazil. METHODS: The research was characterized as observational and quantitative. The population sample consisted of 60 women aged over 18 years, being chosen at random. For data collection, mHealth Data Collector (mHDC), a mobile device, was used with a questionnaire on daily habits, health status, and disease. Measurements were made of glucose and blood cholesterol, blood pressure and anthropometric measurements. Data collection took place in February 2014 to November 2014. RESULTS: Risk factors were overweight / obesity (63.8%) and sedentary lifestyle (65%), followed by family history of cardiovascular disease (43.3%), hypercholesterolemia (38.3%), and hypertension (13.3%). CONCLUSIONS: This population of women presented risk factors for the development of cardiovascular disease in all ages, being necessary the implementation of measures that stimulate changes in the daily habits and improve health conditions among women by the health team. PMID- 29767924 TI - Effect of an educational intervention based on the model of health beliefs in self-medication of Iranian mothers. AB - OBJECTIVES: This study sought to determine the effect of education based on the model of health beliefs in self-medication of women in Iran. METHODS: Quasi experimental study in a group of mothers (N = 90, 45 in the intervention group and 45 in the control group) users of health centers from the city of Fasa, province of Fars, southern Iran. Before and after the educational intervention (four training sessions in three months), a questionnaire was applied containing questions based on the model of health beliefs, on the components of knowledge, vulnerability, severity, benefits, and barriers perceived, and practices on self medication. RESULTS: Prior to the educational intervention, the level of knowledge, sensitivity, intensity, and benefits of self-medication were equal in both groups; however, after the educational intervention, it was observed that the intervention group improved in all components of evaluation and diminished barriers perceived and self-treatment practices. CONCLUSIONS: The educational intervention based on the model of health beliefs was effective in reducing self medication practices in the group of mothers. Hence, this type of training is recommended in health centers to diminish the frequency of this practice. PMID- 29767923 TI - Functional disability and morbidities among the elderly people, according to socio-demographic conditions and indicative of depression. AB - OBJECTIVES: To investigate the association of functional incapacity and the number of morbidities with sociodemographic, economic and health variables. METHODS: This is a household survey, quantitative and transversal approach, conducted with 1,693 elderly in Uberaba-MG in 2012. We used the Mini-Mental State Examination, Katz Scale, Lawton and Brody Scale; Geriatric Depression Scale abbreviated and semi-structured instrument for evaluation of demographic data, economic and morbidities. RESULTS: Functional incapacity in basic activities of daily living was associated with older age, a greater number of morbidities and presence of indicative of depression. Regarding the instrumental activities of daily living, functional incapacity was related to age, lower education and income, the greater number of morbidities and have indicative of depression. The largest number of comorbidities was associated with female sex, older age, lower income and indicative of depression. CONCLUSIONS: This study highlights the need for health actions directed to the oldest old, with less education and income, and indicative of depression to minimize the dependency on the performance of functional capacity and impact on morbidities. PMID- 29767925 TI - Development of a measurement index of critical thinking in professional formation. AB - OBJECTIVES: This research sought to construct and validate a measurement index of critical thinking (CT) in professional formation. METHODS: Transversal, quantitative, test validation-type study. After reviewing scientific production in CT, which permitted defining the concept and its conceptual domains, a 65-item scale was constructed of closed questions on the analysis of cases evaluating CT. The scale was subjected to expert evaluation to then be applied to 53 undergraduate students (35 from nursing and 18 from sociology) to evaluate validity and reliability. RESULTS: The 65-item scale has an explained variance of 61.3% and is comprised of five CT domains: inference, evaluation, argumentation, analysis, and interpretation. A Cronbach's alpha coefficient of 0.61 was obtained. CONCLUSIONS: The scale proposed to assess students' CT skills converges with concepts by known authors with the CT theory and is adequate for use as a CT measurement index in professional formation. PMID- 29767926 TI - Nursing diagnoses associated with the national policy for health promotion. AB - OBJECTIVES: To identify the relationships between nursing diagnoses proposed by NANDA-I taxonomy II and the priority themes (PT) of the National Policy for Health Promotion (PNPS in Portuguse). METHODS: An integrative literature review was carried out in the Scopus, Cinahl and SciELO databases, using the descriptors: health promotion, food habits, traffic accidents, drugs abuse, environment and public health. The search considered scientific articles published between 2000 and 2016. RESULTS: Twelve articles were selected to identify and explore nursing actions related to PT. It was identified that although the said taxonomy offers a Domain called Health promotion, there is a need to relate the diagnoses of other domains to include the health actions described in the aforementioned Policy. It was observed that there is an attention and concern of the nursing professionals to address topics such as the training of managers and the promotion of healthy eating. In relation to the priority themes promotion of safe mobility and sustainable development, no nursing diagnoses were identified due to the scarcity of diagnoses related to them in the mentioned taxonomy. CONCLUSIONS: Although the NANDA-I taxonomy presents a specific domain on health promotion, these are not sufficient to meet the needs of the priority themes proposed by PNPS. PMID- 29767927 TI - Medical and nursing students' attitudes toward mental illness: An Indian perspective. AB - OBJECTIVES: Compare the attitudes toward mental illness between medical and nursing undergraduate students from a university in India. METHODS: A cross sectional descriptive study was carried out among medical (n=154) and nursing undergraduate students (n=168) using Attitude Scale for Mental Illness (ASMI) questionnaire with six sub scales namely; Separatism, Stereotyping, Restrictiveness, Benevolence, Pessimistic prediction and Stigmatization. This was a 5-point Likert scale with 34 items to rate participants responses from totally disagree (1) to totally agree (5). The lower scores indicate positive attitudes toward persons with mental illness. RESULTS: Our findings revealed that 54.5% of medical students versus 64.8% of nursing students have positive attitudes toward mental illness. While medical students have better attitudes against separatism and stigmatization, nursing students have more positive attitudes in benevolence and against pessimism. CONCLUSIONS: An important proportion of medical and nursing students have negative attitudes toward mental illness. It is necessary to review and adapt the current curriculum to favor the positive attitude of future professionals toward people with these types of diseases. PMID- 29767928 TI - Menopause, the beginning of aging for Chilean women: A qualitative study. AB - OBJECTIVES: To develop the meaning of menopause of a group of post-menopausal women and their relationship with aging. METHODS: Qualitative descriptive study on 15 Chilean women that completed a taped face-to-face in depth interview that were interpreted according to Krippendorff. RESULTS: A qualitative content analysis revealed the presence of two themes: (a) Cessation of women's reproductive stage and (b) a life transition to aging. CONCLUSIONS: Women perceived their menopause as the beginning of aging focusing on the end of fertility and the social connotation that this new role implies. Feeling old 10 years before the customary beginning of old age is an important starting point to be incorporated in women's health education. PMID- 29767929 TI - Preparing for post-discharge care of premature infants: Experiences of parents. AB - OBJECTIVES: The study sought to describe the experiences of parents of premature children regarding discharge from the neonatal unit. METHODS: This was a qualitative study, in which 10 semi-structured interviews were conducted with parents of premature infants upon discharge from the neonatal unit. Data were analyzed following principles of grounded theory; open and axial coding was performed. RESULTS: The following categories emerged from the analysis of the information: feelings experienced upon discharge, and experience of the discharge as a process; the latter category clearly identified barriers and facilitators. The results highlight that the parents experience ambivalent feelings; joy is mixed with the fear of caring for a premature child at home. CONCLUSIONS: For parents, discharge of premature children from the neonatal unit is a complex process during which conflicting feelings are experienced. Nursing must develop strategies to involve parents early in the care of their children during the hospital stay. PMID- 29767931 TI - The gap remains: The challenge of translating research into policies for the health care of people and communities. PMID- 29767930 TI - Quality of life of women with pre-and post-operative breast cancer. AB - OBJECTIVES: The objective of this study was to evaluate the Quality of Life (QOL) at the pre and postoperative time of women with breast cancer submitted to surgery and to associate it with the socioeconomic class. METHODS: This is a longitudinal study, performed at Santa Rita de Cassia Hospital (HSRC), Vitoria - ES, Brazil. The EORTC QLQ instrument C-30 and the EORTC BR-23 were used to measure the QOL of the interviewees before and after breast surgery. RESULTS: A population composed of 87 women, 42.5% were 60 years old or more. The socioeconomic condition C was identified as predominant among the interviewees, covering 62% of the sample (n=54). Women's QOL in the preoperative period was better in the Physical Function dimensions for class C and D; and the Emotional was better for class B. There was improvement in QOL after surgery for Body Image in class C, and for Social Function in B. Evaluating all social classes, only the dimensions Cognitive Function and Future Perspectives improved in the postoperative period. CONCLUSIONS: The quality of life of women after breast surgery worsened in most of the studied dimensions, evidencing the need for an interdisciplinary work dedicated to the recovery and rehabilitation of these patients. PMID- 29767932 TI - Biosocial-academic profile and stress in first- and fourth-year nursing students. AB - OBJECTIVES: To compare the biosocial and academic profile and stress levels between first- and last-year nursing students from a public university in Sao Paulo. METHODS: This is an analytic and quantitative study. A biosocial and academic form and the instrument for Assessment of Stress in Nursing Students by Costa and Polak were applied to 83 students between February and March 2016. RESULTS: Insufficient income and extracurricular activities contribute to higher levels of stress in both groups of students assessed. Fourth-year students showed higher levels of general stress, particularly generated by the factors: performance of practical activities, professional communication, environment and professional training. Time management produces higher stress in first-year students. CONCLUSIONS: Fewbiosocial and academic features equally contribute for the stress levels in first- and last-year nursing students, but those in last year present higher stress than students who are starting the course. PMID- 29767933 TI - Profile of nursing diagnoses in people with hypertension and diabetes. AB - OBJECTIVES: To identify the profile of nursing diagnoses in people with hypertension and diabetes in primary health care. METHODS: A cross-sectional study involving 175 individuals followed up in eight primary health units of Minas Gerais, Brazil. Data collection was made through interview and physical examination, and diagnostic inference was made according with NANDA-I Taxonomy II. RESULTS: The average age of the users was 62.1 years and the female gender predominated (66.9%). A total of 26 diagnoses were identified, an average of 16 per client (standard deviation=3.9). The most frequent problem-focused diagnosis were: Ineffective Health Management (98.9%), Ineffective Peripheral Tissue Perfusion (78.3%), Sedentary lifestyle (74.3%), Obesity (54.3%) and Insomnia (51.4%). With respect to the defining characteristics and related factors, the average per person was 24 and 28, respectively. CONCLUSIONS: In this group of clients, the most frequent diagnoses were in the domain activity/rest. These diagnoses are the basis for planning nursing interventions and provide improved quality of life for these clients. PMID- 29767934 TI - Validity and Reliability of the Spanish Version of the Technological Competencyas Caring in Nursing Instrument. AB - OBJECTIVES: This work aimed to evaluate validity and reliability to measure the technological competency of Nursing in Colombia of the Spanish version of the Technological Competency as Caring in Nursing Instrument (TCCNI). METHODS: This was a test validation study, which evaluated linguistic, facial, content, and construct validity, besides, the instrument's reliability. RESULTS: The instrument reported face validity with Lawshe's index: clarity 0.86, precision 0.83, and comprehension 0.89. Agreement of Fleiss' kappa index was clarity 0.75, precision 0.72, and comprehension 0.81. Content validity was obtained with Lawshe's index: relevance of 0.9 and pertinence of 0.9. Agreement of experts with Fleiss' kappa index was relevance at 0.9 and pertinence at 0.9. For construct validity, 255 nurses participated. Factor analysis generated six factors (Knowing is Caring, Professional and Disciplinary Values of Nursing, Care and Ethics, Technological Competency, Healing and Human Care), which yielded a total accumulated variance of 54.2% and Cronbach's alphaof 0.88. CONCLUSIONS: The TCCNI Spanish version reported a consolidated validity, becoming a viable and reliable instrument to measure the technological competency of Nursing in Colombia. PMID- 29767935 TI - Meanings of 'Tuberculosis' in Rural Indigenous Communities from a Municipality in the Colombian Amazon. AB - OBJECTIVES: The purpose herein was to describe the meanings on tuberculosis (TB) in rural indigenous communities from a municipality in the Colombian Amazon. METHODS: This was an ethnographic study with theoretical reference of dialectical hermeneutics, which created focus groups, one for each rural community of Puerto Narino, for a total of 15 focus groups. The participants were community leaders and health referents. RESULTS: Seventy-nine subjects participated, mostly midwives, kurakas, traditional physicians, and shamans. The analysis yielded four categories: knowledge of TB, attitudes regarding TB, community practices of TB, and the intervention proposal on TB by the participants. It was found that community leaders recognize TB as a disease that can cause death, but which can be cured if timely care is secured. The study also identified the need to conjugate western medicine with traditional medicine. CONCLUSIONS: It is recognized that meanings may impact upon knowledge, attitudes, and practices that affect early detection and treatment of the disease. In addition, this work corroborates the need to strengthen and develop educational programs on tuberculosis supported by the real needs of the communities to enhance their knowledge, attitudes, and practices on the disease. PMID- 29767936 TI - Outcome assessment of patients classified through the Manchester Triage System in emergency units in Brazil and Portugal. AB - OBJECTIVES: The aim was to evaluate the outcomes of patients' treatment classified according to the Manchester Triage System (MTS) in two large hospitals. METHODS: Historical cohort study performed in two hospitals in different countries: one emergency unit of a hospital in Portugal, and another in Brazil. The studied population was composed of all patients attended and triaged by nurses in emergency services using the MTS, based on data obtained through the ALERT(r) software. The sample in this study was composed of 158 959 triages in Portugal and 155 121 in Brazil. RESULTS: The higher the priority attributed to the patient according to the MTS, the longer the hospital stay and risk of death. For both groups, the higher the risk classification of the patient, the greater the risk of death when compared to the group classified as "green". In Portugal, patients classified in the "red" category according to the MTS had 1 516-fold higher risk of death compared to those classified in the green category, and in Brazil, this risk was 1 177-fold higher. CONCLUSIONS: In both countries, the MTS proved to be a good predictor of length of hospital stay and death. PMID- 29767937 TI - Questionnaire to Measure the Participation of Nursing Professionals in Mentoring Students. AB - OBJECTIVES: The aim herein was to validate a questionnaire to measure the level of participation of clinical nursing professionals in the mentorship of nursing students during clinical practices. METHODS: Design and validation of a questionnaire. The psychometric properties of the tool were determined through four phases: 1- literature review; 2- evaluation of content validity; 3- pilot test, cognitive pretest and intra-observer reliability study; 4- construct validity study through an exploratory factor analysis of main components with varimax rotation in a sample of 249 nursing professionals from primary care and hospital care from different Spanish provinces. The internal consistency was studied with Cronbach's alpha coefficient. RESULTS: The global content validity was above 0.8. The final version of the questionnaire had 33 items, with a global intraclass correlation coefficient of 0.852 and Cronbach's alpha of 0.837. Factor analysis explained 55.4% of the total variance, with a solution of five factors that made up the dimensions: Implication, Motivation, Satisfaction, Obstacles, and Commitment. CONCLUSIONS: The questionnaire evaluated has adequate validity and reliability to permit determining the level of nurse participation in the mentorship of students. PMID- 29767938 TI - Overweight and Obesity Conditions: Prevalence and Associated Risk Factors in Nursing Students in a Public University in Medellin, Colombia. AB - OBJECTIVES: This work sought to identify the prevalence of overweight and obesity conditions and the associated factors in nursing students in a public university in Medellin, Colombia. METHODS: This was a descriptive cross-sectional study conducted in 2015. The study selected 171 participants through stratified random sampling. A structured questionnaire was applied and weight and height were taken to calculate the body mass index (BMI). RESULTS: The prevalence of overweight condition was 25.1% and obesity at 7.6%. Statistically significant association exists with family background of overweight or obesity conditions (OR = 6.65) and the perception of unhealthy feeding (OR = 3.01). No association was found with cases suggesting anxiety and depression and physical activity. CONCLUSIONS: A high prevalence was found of overweight and obesity conditions in the population studied, which is why it is recommended to develop self-care programs in university populations, principally in Nursing, given that as future professionals they will be co-responsible for health promotion in individuals and collectives. PMID- 29767939 TI - The possible meanings of care: self-care and care-for-the-other. AB - OBJECTIVES: To understand and to reflect about care based on the experiences of managers, professionals and users of maternal and child health services. METHODS: We developed an evaluative research with a qualitative approach in a Northeastern state of Brazil with extensive experience in the regionalization and implementation process of integrated health networks. Semi-structured interviews were carried out with 68 subjects and direct observation of the maternal and child health services. We adopted the theoretical reference framework of Gadamer's hermeneutics to analyze the narratives. RESULTS: Some units of meaning were present, such as: perception and knowledge about oneself; exercise of autonomy; weaknesses in the provision of resources for the materialization of self-care; and difficulties in accessing health services and care practices. We perceive that care is dynamic, comprises various subjective aspects with respect to the singularities of the subjects and is related to the possibility of generating both individual and collective transformation. CONCLUSIONS: Care is built based on a movement among the subjects and between them and the social and health services. Thus, when we intend to take care, we need to consider this instead of focusing care solely on the technical support of health professionals. PMID- 29767940 TI - Depressive symptoms of the elderly people and caregiver's burden in home care. AB - OBJECTIVES: To characterize the elderly population and their caregivers and to verify the association of depressive symptoms of the elderly and the caregiver's burden with the variables of interest. METHODS: A cross-sectional study with 80 elderly people and 78 caregivers in a Primary Health Service in southern Brazil. Retrospective collection conducted in a structured database based on the multidimensional evaluation tool applied to home care for the elderly participants and their caregivers. RESULTS: Most elderly participants were women (71.3%), with an average age of 82.1 years and 52.6% reported sadness or discouragement. Systemic arterial hypertension was the most frequent morbidity (68.8%). Most caregivers were women (85.7%), daughters of the elderly person (53.2%), mean age 57.8 years and 38.7% reported feeling the burden. The presence of depressive symptoms in the elderly was associated with Parkinson's disease (p=0.016) and to have a male caregiver (p=0.006). Caregiver's burden was associated with daily life activities such as bathing (p=0.021). CONCLUSIONS: There was evidence of differences in caregiver's gender in the presence of depressive symptoms and differences in the assistance in daily life activities for the caregiver's burden. PMID- 29767942 TI - The Meaning of Assuming Dependency at Home of a Person with Cardiovascular Surgery: the Vision of Informal Caregivers. AB - OBJECTIVES: Herein, the study sought to understand the significance for informal caregivers of assuming the dependency at home of an individual subjected to cardiovascular surgery. METHODS: This was a phenomenological interpretative study conducted with eight adult participants, home caregivers of individuals with cardiovascular surgery discharged from intensive care units to their homes. An in depth interview was used as technique to collect the information and the procedures proposed by Cohen, Kahn, and Steeves were used for analysis. RESULTS: Caregivers of individuals with cardiovascular surgery at home face situations that lead them to taking on the dependency of the person being cared. The significance participants granted to the experience was the lack of preparation to deal with it due to the unexpected way it emerged. This created a difficult situation, where feelings surfaced, like misgivings, fear, and stress during the time dedicated to caring. In some cases, the caregiver prolonged the dependency of caring for another. CONCLUSIONS: Undertaking the dependency of a person at home meant to caregivers coping with new situations without preparation. This dependency stirs feelings and sometimes limits participation by the person in their own care. PMID- 29767941 TI - Quality of information given to surgical patients with abdominal cancer. AB - OBJECTIVES: To evaluate the need for information in patients with abdominal neoplasms. METHODS: The sample consisted of 100 patients hospitalized in a surgical ward for patients with abdominal neoplasms at the National Institute of Cancer Jose de Alencar Gomes da Silva / INCA, in the period between June and December 2016. To collect the data, the Brazilian Portuguese version of the European Organization for Research and Treatment of Cancer (EORTC) information module questionnaire (QLQ-INFO25) was used. RESULTS: In general, for most items, the patients showed satisfaction with the amount of information received. The items referring to the disease, examinations, treatment and general information stand out, with an average score of more than 80%. For some items, however, there is dissatisfaction with the amount of information received, especially those related to the cause of the disease, aspects of out-of-hospital and home care, different places of care and aspects of self-help, with a satisfaction level of less than 40. CONCLUSIONS: Despite the high level of satisfaction with the information received, it was observed that almost all patients would like more information, which makes us recommend that, as part of the care, the information offered to these patients about the treatment and the evolutionary process of the disease should be enhanced. PMID- 29767943 TI - Attitudes toward Community - based training and internship of Nursing students and professors: a qualitative study. AB - OBJECTIVES: To explore the attitudes of nursing students and professors towards community-based training and internship in Fasa, Fars, Iran. METHODS: This qualitative study was conducted using the content analysis approach. Data from students and professors were collected through five focal groups and data from patients was collected by using field notes. Interviews were conducted with 17 students and three professors responsible for implementing the study plan; in addition, 800 patient-related field notes were analyzed. RESULTS: Community-based training and internship were identified as useful from the point of view of students, professors, and clients. Results were classified into two principal categories: "health preservation and promotion" and "promotion of students' skills". CONCLUSIONS: Attitudes toward the formation and community internship are favorable insofar as it is a highly beneficial experience for students, professors, and patients. PMID- 29767944 TI - Theranostic Niosomes for Efficient siRNA/MicroRNA Delivery and Activatable Near Infrared Fluorescent Tracking of Stem Cells. AB - RNA interference-mediated gene regulation in stem cells offers great potential in regenerative medicine. In this study, we developed a theranostic platform for efficient delivery of small RNAs [small interfering RNA (siRNA)/microRNA (miRNA)] to human mesenchymal stem cells (hMSCs) to promote differentiation, and meanwhile, to specifically label the transfected cells for the in vivo tracking purpose. We encapsulated indocyanine green (ICG) in a nonionic surfactant vesicle, termed "niosome", that is mainly composed of a nonionic surfactant sorbitan monooleate (Span 80) and a cationic lipid 1,2-dioleoyl-3 trimethylammonium-propane (DOTAP). This novel ICG-containing niosome system (iSPN) demonstrated highly efficient siRNA and miRNA delivery in hMSCs. Specific inhibition of miR-138, a negative regulator of osteoblast differentiation, was achieved by iSPN/miR-138, which significantly promoted osteogenesis of hMSCs. Furthermore, iSPN exhibited OFF/ON activatable fluorescence upon cellular internalization, resulting in efficient near-infrared labeling and the capability to dynamically monitor stem cells in mice. In addition, iSPN/siRNA achieved simultaneous long-term cell tracking and in vivo gene silencing after implantation in mice. These results indicate that our theranostic niosomes could represent a promising platform for future development of stem cell-based therapy. PMID- 29767945 TI - High-Temperature Corrosion Behavior of SiBCN Fibers for Aerospace Applications. AB - Amorphous SiBCN fibers possessing superior stability against oxidation have become a desirable candidate for high-temperature aerospace applications. Currently, investigations on the high-temperature corrosion behavior of these fibers for the application in high-heat engines are insufficient. Here, our polymer-derived SiBCN fibers were corroded at 1400 degrees C in air and simulated combustion environments. The fibers' structural evolution after corrosion in two different conditions and the potential mechanisms are investigated. It shows that the as-prepared SiBCN fibers mainly consist of amorphous networks of SiN3C, SiN4, B-N hexatomic rings, free carbon clusters, and BN2C units. High-resolution transmission electron microscopy cross-section observations combined with energy-dispersive spectrometry/electron energy-loss spectroscopy analysis exhibit a trilayer structure with no detectable cracks for fibers after corrosion, including the outermost SiO2 layer, the h-BN grain contained interlayer, and the uncorroded fiber core. A high percentage of water vapor contained in the simulated combustion environment triggers the formation of abundant alpha-cristobalite nanoparticles dispersing in the amorphous SiO2 phase, which are absent in fibers corroded in air. The formation of h-BN grains in the interlayer could be ascribed to the sacrificial effects of free carbon clusters, Si-C, and Si-N units reacting with oxygen diffusing inward, which protects h-BN grains formed by networks of B-N hexatomic rings in original SiBCN fibers. These results improve our understanding of the corrosion process of SiBCN fibers in a high-temperature oxygen- and water-rich atmosphere. PMID- 29767946 TI - Highly Stable Graphene-Based Nanocomposite (GO-PEI-Ag) with Broad-Spectrum, Long Term Antimicrobial Activity and Antibiofilm Effects. AB - Various silver nanoparticle (AgNP)-decorated graphene oxide (GO) nanocomposites (GO-Ag) have received increasing attention owing to their antimicrobial activity and biocompatibility; however, their aggregation in physiological solutions and the generally complex synthesis methods warrant improvement. This study aimed to synthesize a polyethyleneimine (PEI)-modified and AgNP-decorated GO nanocomposite (GO-PEI-Ag) through a facile approach through microwave irradiation without any extra reductants and surfactants; its antimicrobial activity was investigated on Gram-negative/-positive bacteria (including drug-resistant bacteria) and fungi. Compared with GO-Ag, GO-PEI-Ag acquired excellent stability in physiological solutions and electropositivity, showing substantially higher antimicrobial efficacy. Moreover, GO-PEI-Ag exhibited particularly excellent long-term effects, presenting no obvious decline in antimicrobial activity after 1 week storage in physiological saline and repeated use for three times and the lasting inhibition of bacterial growth in nutrient-rich culture medium. In contrast, GO-Ag exhibited a >60% decline in antimicrobial activity after storage. Importantly, GO-PEI-Ag effectively eliminated adhered bacteria, thereby preventing biofilm formation. The primary antimicrobial mechanisms of GO-PEI-Ag were evidenced as physical damage to the pathogen structure, causing cytoplasmic leakage. Hence, stable GO PEI-Ag with robust, long-term antimicrobial activity holds promise in combating public-health threats posed by drug-resistant bacteria and biofilms. PMID- 29767947 TI - Application of Calcium-Binding Motif of E-Cadherin for Electrochemical Detection of Pb(II). AB - We report, for the first time, the use of a 13-amino-acid peptide sequence derived from the calcium-binding site of E-cadherin in the fabrication of an electrochemical peptide-based (E-PB) Pb(II) sensor. The sensing mechanism is analogous to that of previously developed E-PB sensors. Binding of Pb(II) rigidifies the surface-immobilized and methylene blue (MB)-modified peptide probe, thereby limiting the accessibility of the tethered MB to the electrode surface. This change in probe flexibility results in a reduction in the MB current that is dependent on the target concentration. The sensor behaves as a "signal-off" sensor in alternating current voltammetry and cyclic voltammetry, but it can behave as a "signal-on" sensor in differential pulse voltammetry when a longer pulse width is employed. It is capable of specific detection of Pb(II) and is selective enough to be employed in realistically complex samples such as diluted tap water, saliva, and urine samples. The detection is fast; signal saturation can be achieved in <60 s. The sensor can also be fabricated on gold plated screen-printed carbon electrodes, electrode substrates that are ideal for cost-effective analysis of Pb(II) in real-world settings. PMID- 29767948 TI - Inorganic Surface Coating with Fast Wetting-Dewetting Transitions for Liquid Manipulations. AB - Liquid manipulation is a fundamental issue for microfluidics and miniaturized sensors. Fast wetting-state transitions by optical methods have proven being efficient for liquid manipulations by organic surface coatings, however rarely been achieved by using inorganic coatings. Here, we report a fast optical-induced wetting-state transition surface achieved by inorganic coating, enabling tens of second transitions for a wetting-dewetting cycle, shortened from an hour, as typically reported. Here, we demonstrate a gravity-driven microfluidic reactor and switch it to a mixer after a second-step exposure in a minimum of within 80 s of UV exposure. The fast wetting-dewetting transition surfaces enable the fast switchable or erasable smart surfaces for water collection, miniature chemical reaction, or sensing systems by using inorganic surface coatings. PMID- 29767949 TI - Topotactic Growth of Edge-Terminated MoS2 from MoO2 Nanocrystals. AB - Layered transition metal dichalcogenides have distinct physicochemical properties at their edge-terminations. The production of an abundant density of edge structures is, however, impeded by the excess surface energy of edges compared to basal planes and would benefit from insight into the atomic growth mechanisms. Here, we show that edge-terminated MoS2 nanostructures can form during sulfidation of MoO2 nanocrystals by using in situ transmission electron microscopy (TEM). Time-resolved TEM image series reveal that the MoO2 surface can sulfide by inward progression of MoO2(20-2):MoS2(002) interfaces resulting in upright-oriented and edge-exposing MoS2 sheets. This topotactic growth is rationalized in interplay with density functional theory calculations by successive O-S exchange and Mo sublattice restructuring steps. The analysis shows that e-MoS2 formation is energetically favorable at MoO2(110) surfaces and provides a necessary requirement for the propensity of a specific MoO2 surface termination to form edge-terminated MoS2. Thus, the present findings should benefit the rational development of transition metal dichalcogenide nanomaterials with abundant edge-terminations. PMID- 29767951 TI - Nanogel-Incorporated Injectable Hydrogel for Synergistic Therapy Based on Sequential Local Delivery of Combretastatin-A4 Phosphate (CA4P) and Doxorubicin (DOX). AB - Drug combination therapies employing dual-drug delivery systems offer an effective approach to reduce disadvantages of single-drug therapy, such as high dose and easy generation of drug resistance. Herein, a dual-drug delivery system based on nanogel-incorporated injectable hydrogel (NHG) was designed for sequential local delivery of combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) for antiangiogenesis and anticancer combination therapy. The injectable hydrogel was prepared for loading and quick release of hydrophilic drug CA4P, while the pH and redox stimuli-responsive nanohydrogels were incorporated into the injectable hydrogel by pH-responsive boronate ester bond for sustained long term DOX delivery. The dual-drug-loaded NHG system released CA4P and DOX sequentially and exhibited high inhibitory activities on the cancer cell proliferation in vitro. It displayed superior therapeutic efficacy in vivo with only one single injection. Immunohistochemistry analyses suggested a synergistic therapeutic effect through tumor vascular collapse caused by CA4P and tumor cell apoptosis induced by DOX. The combination therapy of antiangiogenic and cytotoxic drugs using NHG delivery system offers a promising approach for improved cancer therapeutic efficacy. The nanogel-embedded injectable hydrogel can be employed as a universal drug carrier for local dual-drug delivery with sequential release behaviors by simple injection. PMID- 29767950 TI - Different Benzodiazepines Bind with Distinct Binding Modes to GABAA Receptors. AB - Benzodiazepines are clinically relevant drugs that bind to GABAA neurotransmitter receptors at the alpha+/gamma2- interfaces and thereby enhance GABA-induced chloride ion flux leading to neuronal hyperpolarization. However, the structural basis of benzodiazepine interactions with their high-affinity site at GABAA receptors is controversially debated in the literature, and in silico studies led to discrepant binding mode hypotheses. In this study, computational docking of diazepam into alpha+/gamma2- homology models suggested that a chiral methyl group, which is known to promote preferred binding to alpha5-containing GABAA receptors (position 3 of the seven-membered diazepine ring), could possibly provide experimental evidence that supports or contradicts the proposed binding modes. Thus, we investigated three pairs of R and S isomers of structurally different chemotypes, namely, diazepam, imidazobenzodiazepine, and triazolam derivatives. We used radioligand displacement studies as well as two-electrode voltage clamp electrophysiology in alpha1beta3gamma2-, alpha2beta3gamma2-, alpha3beta3gamma2-, and alpha5beta3gamma2-containing GABAA receptors to determine the ligand binding and functional activity of the three chemotypes. Interestingly, both imidazobenzodiazepine isomers displayed comparable binding affinities, while for the other two chemotypes, a discrepancy in binding affinities of the different isomers was observed. Specifically, the R isomers displayed a loss of binding, whereas the S isomers remained active. These findings are in accordance with the results of our in silico studies suggesting the usage of a different binding mode of imidazobenzodiazepines compared to those of the other two tested chemotypes. Hence, we conclude that different chemically related benzodiazepine ligands interact via distinct binding modes rather than by using a common binding mode. PMID- 29767952 TI - Laser Cleavable Probes-Based Cell Surface Engineering for in Situ Sialoglycoconjugates Profiling by Laser Desorption/Ionization Mass Spectrometry. AB - Cell-surface sialoglycoconjugates (sialoglycoproteins and sialoglycolipids) play important roles in cell-cell interactions and related tumor metastasis process. Although there have been some analytical methods to evaluate the sialoglycoconjugates, an effective method providing both qualitative and quantitative information is still deficient. Here we establish an extraction free, sensitive, and high-throughput platform to realize in situ detection of the cell-surface sialoglycoconjugates on various cell lines, e.g., cancer and normal cells by laser desorption/ionization mass spectrometry (LDI MS). In this proposal, azide groups were introduced into the ends of cell-surface sialoglycoconjugates by the biorthogonal method, and then the sialoglycoconjugates were armed with a laser-cleavable probe (Tphsene) through click chemistry. We can easily get the probes signal under laser irradiation, which reflected the presence of cell-surface sialoglycoconjugates. Different cell lines were discriminated simultaneously, and the LDI relative quantification agreed with fluorescent results. Besides, a linear quantitation relationship in the range of 100 fmol to 100 pmol was obtained with a designed and synthesized internal standard (phTsane) added. A detection limit of 5 fmol was obtained with good reproducibility. Based on the quantitative and high-throughput ability, we conducted pharmacodynamics study of drug (tunicamycin) on cancer cells. In addition, we found the tag was safe from sweet-spot effect of matrix adding. The simultaneous detection of sialoglycoconjugates and metabolites was therefore achieved. We believe that this laser cleavable probes-based cell-surface engineering for sialoglycoconjugates platform means great significance to diagnosis, prognosis, and therapeutic purposes. Besides, this strategy can be applied to other glycoconjugates which is hard to detect and the related disease processes when more corresponding chemically modified sugar substrates and exact biorthogonal reactions are developed. PMID- 29767954 TI - Development of Molecularly Imprinted Polymers To Block Quorum Sensing and Inhibit Bacterial Biofilm Formation. AB - Bacterial biofilms are responsible for most clinical infections and show increased antimicrobial resistance. In this study, molecularly imprinted polymers (MIPs) were developed to specifically capture prototypical quorum sensing autoinducers [i.e., N-(3-oxododecanoyl)-l-homoserine lactone (3-oxo-C12AHL)], interrupt quorum sensing, and subsequently inhibit biofilm formation of Pseudomonas aeruginosa, an important human nosocomial pathogen. The synthesis of MIPs was optimized by considering the amount and type of the functional monomers itaconic acid (IA) and 2-hydroxyethyl methacrylate (HEMA). IA-based MIPs showed high adsorption affinity toward 3-oxo-C12AHL with an imprinting factor of 1.68. Compared to IA-based MIPs, the adsorption capacity of HEMA-based MIPs was improved fivefold. HEMA-based MIPs significantly reduced biofilm formation (by ~65%), whereas biofilm suppression by IA-based MIPs was neutralized because of increased bacterial attachment. The developed MIPs represent promising alternative biofilm intervention agents that can be applied to surfaces relevant to clinical settings and food processing equipment. PMID- 29767955 TI - Low-Cost, Efficient, and Durable H2 Production by Photoelectrochemical Water Splitting with CuGa3Se5 Photocathodes. AB - Photoelectrochemical (PEC) water splitting is an elegant method of converting sunlight and water into H2 fuel. To be commercially advantageous, PEC devices must become cheaper, more efficient, and much more durable. This work examines low-cost polycrystalline chalcopyrite films, which are successful as photovoltaic absorbers, for application as PEC absorbers. In particular, Cu-Ga-Se films with wide band gaps can be employed as top cell photocathodes in tandem devices as a realistic route to high efficiencies. In this report, we demonstrate that decreasing Cu/Ga composition from 0.66 to 0.31 in Cu-Ga-Se films increased the band gap from 1.67 to 1.86 eV and decreased saturated photocurrent density from 18 to 8 mA/cm2 as measured by chopped-light current-voltage (CLIV) measurements in a 0.5 M sulfuric acid electrolyte. Buffer and catalyst surface treatments were not applied to the Cu-Ga-Se films, and they exhibited promising stability, evidenced by unchanged CLIV after 9 months of storage in air. Finally, films with Cu/Ga = 0.36 (approximately stoichiometric CuGa3Se5) and 1.86 eV band gaps had exceptional durability and continuously split water for 17 days (~12 mA/cm2 at -1 V vs RHE). This is equivalent to ~17 200 C/cm2, which is a world record for any polycrystalline PEC absorber. These results indicate that CuGa3Se5 films are prime candidates for cheaply achieving efficient and durable PEC water splitting. PMID- 29767953 TI - Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists. AB - This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist. PMID- 29767957 TI - Magnetic Manipulation of Reversible Nanocaging Controls In Vivo Adhesion and Polarization of Macrophages. AB - Macrophages are key immune cells that perform various physiological functions, such as the maintenance of homeostasis, host defense, disease progression, and tissue regeneration. Macrophages adopt distinctly polarized phenotypes, such as pro-inflammatory M1 phenotype or anti-inflammatory (pro-healing) M2 phenotype, to execute disparate functions. The remotely controlled reversible uncaging of bioactive ligands, such as Arg-Gly-Asp (RGD) peptide, is an appealing approach for temporally regulating the adhesion and resultant polarization of macrophages on implants in vivo. Here, we utilize physical and reversible uncaging of RGD by a magnetic field that allows facile tissue penetration. We first conjugated a RGD bearing gold nanoparticle (GNP) to the substrate and then a magnetic nanocage (MNC) to the GNP via a flexible linker to form the heterodimeric nanostructure. We magnetically manipulated nanoscale displacement of MNC and thus its proximity to the GNP to reversibly uncage and cage RGD. The uncaging of RGD temporally promoted the adhesion and subsequent M2 polarization of macrophages while inhibiting their M1 polarization both in vitro and in vivo. The RGD uncaging mediated adhesion and M2 polarization of macrophages involved rho-associated protein kinase signaling. This study demonstrates physical and reversible uncaging of RGD to regulate the adhesion and polarization of host macrophages in vivo. This approach of magnetically regulating the heterodimer conformation for physical and reversible uncaging of RGD offers the promising potential to manipulate inflammatory or tissue-regenerative immune responses to the implants in vivo. PMID- 29767956 TI - Humidity-Independent Oxide Semiconductor Chemiresistors Using Terbium-Doped SnO2 Yolk-Shell Spheres for Real-Time Breath Analysis. AB - The chemiresistive sensing characteristics of metal oxide gas sensors depend closely on ambient humidity. Herein, we report that gas sensors using Tb-doped SnO2 yolk-shell spheres can be used for reliable acetone detection, regardless of the variations in humidity. Pure SnO2 and Tb-doped SnO2 yolk-shell spheres were prepared via ultrasonic spray pyrolysis and their chemiresistive sensing characteristics were studied. The sensor resistance and gas response of the pure SnO2 yolk-shell spheres significantly changed and deteriorated upon exposure to moisture. In stark contrast, the Tb-doped SnO2 yolk-shell spheres exhibited similar gas responses and sensor resistances in both dry and humid [relative humidity (RH) 80%] atmospheres. In addition, the Tb-doped SnO2 yolk-shell sensors showed a high gas response (resistance ratio) of 1.21 to the sub-ppm-levels (50 ppb) of acetone with low responses to the other interference gases. The effects of Tb oxide and the chemical interactions among the Tb oxide, SnO2, and water vapor on this humidity-independent gas sensing behavior of the Tb-doped SnO2 yolk shell sensors were investigated. This strategy can provide a new road to achieve highly sensitive, selective, and humidity-independent sensing of acetone, which will facilitate miniaturized and real-time exhaled breath analysis for diagnosing diabetes. PMID- 29767958 TI - Distinguishing between Deep Trapping Transients of Electrons and Holes in TiO2 Nanotube Arrays Using Planar Microwave Resonator Sensor. AB - A large signal direct current (DC) bias and a small signal microwave bias were simultaneously applied to TiO2 nanotube membranes mounted on a planar microwave resonator. The DC bias modulated the electron concentration in the TiO2 nanotubes and was varied between 0 and 120 V in this study. Transients immediately following the application and removal of DC bias were measured by monitoring the S-parameters of the resonator as a function of time. The DC bias stimulated Poole Frenkel-type trap-mediated electrical injection of excess carriers into TiO2 nanotubes, which resulted in a near-constant resonant frequency but a pronounced decrease in the microwave amplitude due to free electron absorption. When ultraviolet illumination and DC bias were both present and then stepwise removed, the resonant frequency shifted due to trapping-mediated change in the dielectric constant of the nanotube membranes. Characteristic lifetimes of 60-80, 300-800, and ~3000 s were present regardless of whether light or bias was applied and were also observed in the presence of a hole scavenger, which we attributed to oxygen adsorption and deep electron traps, whereas another characteristic lifetime >8000 s was only present when illumination was applied, and is attributed to the presence of hole traps. PMID- 29767959 TI - Stabilization of Immobilized Enzymes via the Chaperone-Like Activity of Mixed Lipid Bilayers. AB - Biomimetic lipid bilayers represent intriguing materials for enzyme immobilization, which is critical for many biotechnological applications. Here, through the creation of mixed lipid bilayers, the retention of immobilized enzyme structures and catalytic activity are dramatically enhanced. The enhancement in the retention of enzyme structures, which correlated with an increase in enzyme activity, is observed using dynamic single-molecule (SM) fluorescence methods. The results of SM analysis specifically show that lipid bilayers composed of mixtures of 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl- sn glycero-3-phospho-(1'- rac-glycerol) (DOPG) stabilize the folded state of nitroreductase (NfsB), increasing the rate of refolding relative to unfolding of enzyme molecules on the bilayer surface. Remarkably, for optimal compositions with 15-50% DOPG, over 95% of NfsB remains folded while the activity of the enzyme is increased as much as 2 times over that in solution. Within this range of DOPG, the strength of the interaction of folded and unfolded NfsB with the bilayer surface was also significantly altered, which was evident by the change in the diffusion of folded and unfolded NfsB in the bilayer. Ultimately, these findings provide direct evidence for the chaperone-like activity of mixed DOPG/DOPC lipid bilayers, which can be controlled by tuning the fraction of DOPG in the bilayer. PMID- 29767961 TI - Real-Time Monitoring of Tricarboxylic Acid Metabolites in Exhaled Breath. AB - The tricarboxylic acid (TCA) cycle is one of the most important metabolic pathway for cellular respiration in aerobic organisms. It provides and collects intermediates for many other interconnecting pathways and acts as a hub connecting metabolism of carbohydrates, fatty acids, and amino acids. Alteration in intracellular levels of its intermediates has been linked with a wide range of illnesses ranging from cancer to cellular necrosis or liver cirrhosis. Therefore, there exists an intrinsic interest in monitoring such metabolites. Our goal in this study was to evaluate whether, at least the most volatile metabolites of the TCA cycle, could be detected in breath in vivo and in real time. We used secondary electrospray ionization coupled with high-resolution mass spectrometry (SESI-HRMS) to conduct this targeted analysis. We enrolled six healthy individuals who provided full exhalations into the SESI-HRMS system at different times during 3 days. For the first time, we observed exhaled compounds that appertain to the TCA cycle: fumaric, succinic, malic, keto-glutaric, oxaloacetic, and aconitic acids. We found high intraindividual variability and a significant overall difference between morning and afternoon levels for malic acid, oxaloacetic acid, and aconitic acid, supporting previous studies suggesting circadian fluctuations of these metabolites in humans. This study provides first evidence that TCA cycle could conveniently be monitored in breath, opening new opportunities to study in vivo this important metabolic pathway. PMID- 29767960 TI - Comparison of Alicyclobacillus acidocaldarius o-Succinylbenzoate Synthase to Its Promiscuous N-Succinylamino Acid Racemase/ o-Succinylbenzoate Synthase Relatives. AB - Studying the evolution of catalytically promiscuous enzymes like those from the N succinylamino acid racemase/ o-succinylbenzoate synthase (NSAR/OSBS) subfamily can reveal mechanisms by which new functions evolve. Some enzymes in this subfamily have only OSBS activity, while others catalyze OSBS and NSAR reactions. We characterized several NSAR/OSBS subfamily enzymes as a step toward determining the structural basis for evolving NSAR activity. Three enzymes were promiscuous, like most other characterized NSAR/OSBS subfamily enzymes. However, Alicyclobacillus acidocaldarius OSBS (AaOSBS) efficiently catalyzes OSBS activity but lacks detectable NSAR activity. Competitive inhibition and molecular modeling show that AaOSBS binds N-succinylphenylglycine with moderate affinity in a site that overlaps its normal substrate. On the basis of possible steric conflicts identified by molecular modeling and sequence conservation within the NSAR/OSBS subfamily, we identified one mutation, Y299I, that increased NSAR activity from undetectable to 1.2 * 102 M-1 s-1 without affecting OSBS activity. This mutation does not appear to affect binding affinity but instead affects kcat, by reorienting the substrate or modifying conformational changes to allow both catalytic lysines to access the proton that is moved during the reaction. This is the first site known to affect reaction specificity in the NSAR/OSBS subfamily. However, this gain of activity was obliterated by a second mutation, M18F. Epistatic interference by M18F was unexpected because a phenylalanine at this position is important in another NSAR/OSBS enzyme. Together, modest NSAR activity of Y299I AaOSBS and epistasis between sites 18 and 299 indicate that additional sites influenced the evolution of NSAR reaction specificity in the NSAR/OSBS subfamily. PMID- 29767962 TI - Targeting Photoinduced DNA Destruction by Ru(II) Tetraazaphenanthrene in Live Cells by Signal Peptide. AB - Exploiting NF-kappaB transcription factor peptide conjugation, a Ru(II)-bis-tap complex (tap = 1,4,5,8-tetraazaphenanthrene) was targeted specifically to the nuclei of live HeLa and CHO cells for the first time. DNA binding of the complex within the nucleus of live cells was evident from gradual extinction of the metal complex luminescence after it had crossed the nuclear envelope, attributed to guanine quenching of the ruthenium emission via photoinduced electron transfer. Resonance Raman imaging confirmed that the complex remained in the nucleus after emission is extinguished. In the dark and under imaging conditions the cells remain viable, but efficient cellular destruction was induced with precise spatiotemporal control by applying higher irradiation intensities to selected cells. Solution studies indicate that the peptide conjugated complex associates strongly with calf thymus DNA ex-cellulo and gel electrophoresis confirmed that the peptide conjugate is capable of singlet oxygen independent photodamage to plasmid DNA. This indicates that the observed efficient cellular destruction likely operates via direct DNA oxidation by photoinduced electron transfer between guanine and the precision targeted Ru(II)-tap probe. The discrete targeting of polyazaaromatic complexes to the cell nucleus and confirmation that they are photocytotoxic after nuclear delivery is an important step toward their application in cellular phototherapy. PMID- 29767963 TI - Furfural to Furfuryl Alcohol: Computational Study of the Hydrogen Transfer on Lewis Acidic BEA Zeolites and Effects of Cation Exchange and Tetravalent Metal Substitution. AB - The hydrogen transfer of furfural to furfuryl alcohol with i-propanol as the hydrogen source over cation-exchanged Lewis acidic BEA zeolite has been investigated by means of density functional calculations. The reaction proceeds in three steps. First the O-H bond of i-propanol is broken to form a propoxide intermediate. After that, the furylmethoxy intermediate is formed via hydrogen transfer process, and finally furylmethoxy abstracts the proton to form the furfuryl alcohol product. The second step is rate-determining by requiring the highest activation energy (23.8 kcal/mol) if the reaction takes place on Li-Sn BEA zeolite. We find that the catalytic activity of various cation-exchanged Sn BEA zeolites is in the order Li-Sn-BEA > Na-Sn-BEA > K-Sn-BEA. The lower activation energy for Li-Sn-BEA compared to Na-Sn-BEA and K-Sn-BEA can be explained by the larger charge transfer from the carbonyl bond to the catalyst, leading to its activation and to the attraction of the hydrogen being transferred. The larger charge transfer in turn is due to the smaller gap between the energies of furfural HOMO and the zeolite LUMO in Li-Sn-BEA, compared to both Na-Sn-BEA and K-Sn-BEA. In a similar way, we also compare the catalytic activity of tetravalent metal centers (Sn, Zr, and Hf) substituted into BEA and find in the order Zr >= Hf > Sn, based on activation energies. Finally we investigate statistically which property of the reactants is a suitable descriptor for an approximative prediction of the reaction rate in order to be able to quickly screen promising catalytic materials for this reaction. PMID- 29767966 TI - Recent Advances and Perspectives on Nonadiabatic Mixed Quantum-Classical Dynamics. AB - Nonadiabatic mixed quantum-classical (NA-MQC) dynamics methods form a class of computational theoretical approaches in quantum chemistry tailored to investigate the time evolution of nonadiabatic phenomena in molecules and supramolecular assemblies. NA-MQC is characterized by a partition of the molecular system into two subsystems: one to be treated quantum mechanically (usually but not restricted to electrons) and another to be dealt with classically (nuclei). The two subsystems are connected through nonadiabatic couplings terms to enforce self consistency. A local approximation underlies the classical subsystem, implying that direct dynamics can be simulated, without needing precomputed potential energy surfaces. The NA-MQC split allows reducing computational costs, enabling the treatment of realistic molecular systems in diverse fields. Starting from the three most well-established methods-mean-field Ehrenfest, trajectory surface hopping, and multiple spawning-this review focuses on the NA-MQC dynamics methods and programs developed in the last 10 years. It stresses the relations between approaches and their domains of application. The electronic structure methods most commonly used together with NA-MQC dynamics are reviewed as well. The accuracy and precision of NA-MQC simulations are critically discussed, and general guidelines to choose an adequate method for each application are delivered. PMID- 29767964 TI - Synthetic Polymer Affinity Ligand for Bacillus thuringiensis ( Bt) Cry1Ab/Ac Protein: The Use of Biomimicry Based on the Bt Protein-Insect Receptor Binding Mechanism. AB - We report a novel strategy for creating abiotic Bacillus thuringiensis ( Bt) protein affinity ligands by biomimicry of the recognition process that takes place between Bt Cry1Ab/Ac proteins and insect receptor cadherin-like Bt-R1 proteins. Guided by this strategy, a library of synthetic polymer nanoparticles (NPs) was prepared and screened for binding to three epitopes 280FRGSAQGIEGS290, 368RRPFNIGINNQQ379 and 436FRSGFSNSSVSIIR449 located in loop alpha8, loop 2 and loop 3 of domain II of Bt Cry1Ab/Ac proteins. A negatively charged and hydrophilic nanoparticle (NP12) was found to have high affinity to one of the epitopes, 368RRPFNIGINNQQ379. This same NP also had specific binding ability to both Bt Cry1Ab and Bt Cry1Ac, proteins that share the same epitope, but very low affinity to Bt Cry2A, Bt Cry1C and Bt Cry1F closely related proteins that lack epitope homology. To locate possible NP- Bt Cry1Ab/Ac interaction sites, NP12 was used as a competitive inhibitor to block the binding of 865NITIHITDTNNK876, a specific recognition site in insect receptor Bt-R1, to 368RRPFNIGINNQQ379. The inhibition by NP12 reached as high as 84%, indicating that NP12 binds to Bt Cry1Ab/Ac proteins mainly via 368RRPFNIGINNQQ379. This epitope region was then utilized as a "target" or "bait" for the separation and concentration of Bt Cry1Ac protein from the extract of transgenic Bt cotton leaves by NP12. This strategy, based on the antigen-receptor recognition mechanism, can be extended to other biotoxins and pathogen proteins when designing biomimic alternatives to natural protein affinity ligands. PMID- 29767965 TI - Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus-Cell Interface. AB - To address the urgent need for new agents to reduce the global occurrence and spread of AIDS, we investigated the underlying hypothesis that antagonists of the HIV-1 envelope (Env) gp120 protein and the host-cell coreceptor (CoR) protein can be covalently joined into bifunctional synergistic combinations with improved antiviral capabilities. A synthetic protocol was established to covalently combine a CCR5 small-molecule antagonist and a gp120 peptide triazole antagonist to form the bifunctional chimera. Importantly, the chimeric inhibitor preserved the specific targeting properties of the two separate chimera components and, at the same time, exhibited low to subnanomolar potencies in inhibiting cell infection by different pseudoviruses, which were substantially greater than those of a noncovalent mixture of the individual components. The results demonstrate that targeting the virus-cell interface with a single molecule can result in improved potencies and also the introduction of new phenotypes to the chimeric inhibitor, such as the irreversible inactivation of HIV-1. PMID- 29767967 TI - Structure-Guided Modification of Heterocyclic Antagonists of the P2Y14 Receptor. AB - The P2Y14 receptor (P2Y14R) mediates inflammatory activity by activating neutrophil motility, but few classes of antagonists are known. We have explored the structure-activity relationship of a 3-(4-phenyl-1 H-1,2,3-triazol-1-yl)-5 (aryl)benzoic acid antagonist scaffold, assisted by docking and molecular dynamics (MD) simulation at a P2Y14R homology model. A computational pipeline using the High Throughput MD Python environment guided the analogue design. Selection of candidates was based upon ligand-protein shape and complementarity and the persistence of ligand-protein interactions over time. Predictions of a favorable substitution of a 5-phenyl group with thiophene and an insertion of a three-methylene spacer between the 5-aromatic and alkyl amino moieties were largely consistent with empirical results. The substitution of a key carboxylate group on the core phenyl ring with tetrazole or truncation of the 5-aryl group reduced affinity. The most potent antagonists, using a fluorescent assay, were a primary 3-aminopropyl congener 20 (MRS4458) and phenyl p-carboxamide 30 (MRS4478). PMID- 29767968 TI - Screw- Type Motion and Its Impact on Cooperativity in BaNa2Fe[VO4]2. AB - BaNa2Fe[VO4]2 contains a Jahn-Teller active ion (FeII, 3d6, high-spin) in an octahedral coordination. On the basis of a combination of temperature-dependent X ray diffraction and Mossbauer and Raman spectroscopies, we demonstrate the coupling of lattice dynamics with the electronic ground state of FeII. We identify three lattice modes combined to an effective canted screw- type motion that drives the structural transition around room temperature from the high temperature ( P3) via intermediate phases to the low-temperature phase ( C2/ c). The dynamics of the electronic ground state of Fe(II) are evident from Mossbauer data with signatures of a motion-narrowed doublet above 320 K, a gradual evolution of the 5Eg electronic state below 293 K, and finally the signature of the thermodynamically preferred orbitally nondegenerate ground state (5Ag) of Fe(II) below 100 K. The continuous nature of the transition is associated with the temperature-dependent phonon parameters derived from Raman spectroscopy, which point out the presence of strong electron-phonon coupling in this compound. We present a microscopic mechanism and evaluate the collective component leading to the structural phase transition. PMID- 29767969 TI - Single-Molecule Imaging Reveals Conformational Manipulation of Holliday Junction DNA by the Junction Processing Protein RuvA. AB - Interactions between DNA and motor proteins regulate nearly all biological functions of DNA such as gene expression, DNA replication and repair, and transcription. During the late stages of homologous recombination (HR), the Escherichia coli recombination machinery, RuvABC, resolves the four-way DNA motifs called Holliday junctions (HJs) that are formed during exchange of nucleotide sequences between two homologous duplex DNA. Although the formation of the RuvA-HJ complex is known to be the first critical step in the RuvABC pathway, the mechanism for the binding interaction between RuvA and HJ has remained elusive. Here, using single-molecule fluorescence resonance energy transfer (smFRET) and ensemble analyses, we show that RuvA stably binds to the HJ, halting its conformational dynamics. Our FRET experiments in different ionic environments created by Mg2+ and Na+ ions suggest that RuvA binds to the HJ via electrostatic interaction. Further, while recent studies have indicated that the HR process can be modulated for therapeutic applications by selective targeting of the HJ by chemotherapeutic drugs, we investigated the effect of drug-modified HJ on binding. Using cisplatin as a proof-of-concept drug, we show that RuvA binds to the cisplatin-modified HJ as efficiently as to the unmodified HJ, demonstrating that RuvA accommodates for the cisplatin-introduced charges and/or topological changes on the HJ. PMID- 29767970 TI - Reduction of Plutonium(VI) to (V) by Hydroxamate Compounds at Environmentally Relevant pH. AB - Natural organic matter is known to influence the mobility of plutonium (Pu) in the environment via complexation and reduction mechanisms. Hydroxamate siderophores have been specifically implicated due to their strong association with Pu. Hydroxamate siderophores can also break down into di and monohydroxamates and may influence the Pu oxidation state, and thereby its mobility. In this study we explored the reactions of Pu(VI) and Pu(V) with a monohydroxamate compound (acetohydroxamic acid, AHA) and a trihydroxamate siderophore desferrioxamine B (DFOB) at an environmentally relevant pH (5.5-8.2). Pu(VI) was instantaneously reduced to Pu(V) upon reaction with AHA. The presence of hydroxylamine was not observed at these pHs; however, AHA was consumed during the reaction. This suggests that the reduction of Pu(VI) to Pu(V) by AHA is facilitated by a direct one electron transfer. Importantly, further reduction to Pu(IV) or Pu(III) was not observed, even with excess AHA. We believe that further reduction of Pu(V) did not occur because Pu(V) does not form a strong complex with hydroxamate compounds at a circum-neutral pH. Experiments performed using desferrioxamine B (DFOB) yielded similar results. Broadly, this suggests that Pu(V) reduction to Pu(IV) in the presence of natural organic matter is not facilitated by hydroxamate functional groups and that other natural organic matter moieties likely play a more prominent role. PMID- 29767971 TI - Structural Characterization and Photochemical Properties of Mono- and Bimetallic Cu-Mabiq Complexes. AB - We present a series of monometallic ([Cu(Mabiq)OTf] (1) and [Cu(Mabiq)] (2)) and bimetallic copper-Mabiq complexes ([Cu2(Mabiq)(PPh3)2(OTf)2] (3) and [Cu2(Mabiq)(PPh3)2]PF6 (4)). The latter compounds contain an additional CuI center that binds in a tetrahedral fashion to the external bipyrimidine nitrogens of the macrocyclic ligand. Compounds 3 and 4 represent the first examples of bimetallic transition metal Mabiq complexes, stable both in solution and in the solid state. The structural and electronic properties of compounds 1-4 were analyzed by means of X-ray crystallography, cyclic voltammetry, and spectroscopic methods. One-electron reduced 2 and 4 consist of a CuII ion coordinated by a Mabiq ligand radical, [CuII(Mabiq*)]. Thus, both bimetallic compounds are mixed valent with respect to the copper oxidation states. Complexes 2 and 4 can be generated photochemically, upon irradiation of 1 or 3 with visible light in the presence of a sacrificial electron donor. PMID- 29767972 TI - Deconvoluting the Role of Charge in a Supramolecular Catalyst. AB - We have demonstrated that the microenvironment of a highly anionic supramolecular catalyst can mimic the active sites of enzymes and impart rate accelerations of a million-fold or more. However, these microenvironments can be challenging to study, especially in the context of understanding which specific features of the catalyst are responsible for its high performance. We report here the development of an experimental mechanistic probe consisting of two isostructural catalysts. When examined in parallel transformations, the behavior of these catalysts provides insight relevant to the importance of anionic host charge on reactivity. These two catalysts exhibit similar host-substrate interactions, but feature a significant difference in overall anionic charge (12- and 8-). Within these systems, we compare the effect of constrictive binding in a net neutral aza-Cope rearrangement. We then demonstrate how the magnitude of anionic host charge has an exceptional influence on the reaction rates for a Nazarov cyclization, evidenced by an impressive 680-fold change in reaction rate as a consequence of a 33% reduction in catalyst charge. PMID- 29767974 TI - In Vitro and In Vivo Demonstration of Human-Ovarian-Cancer Necrosis through a Water-Soluble and Near-Infrared-Absorbing Chlorin. AB - With the objective of developing efficient sensitizers for therapeutic applications, we synthesized a water-soluble 5,10,15,20-tetrakis(3,4 dihydroxyphenyl)chlorin (TDC) and investigated its in vitro and in vivo biological efficacy, comparing it with the commercially available sensitizers. TDC showed high water solubility (6-fold) when compared with that of Foscan and exhibited excellent triplet-excited-state (84%) and singlet-oxygen (80%) yields. In vitro photobiological investigations in human-ovarian-cancer cell lines SKOV-3 showed high photocytotoxicity, negligible dark toxicity, rapid cellular uptake, and specific localization of TDC in neoplastic cells as assessed by flow cytometric cell-cycle and propidium iodide staining analysis. The photodynamic effects of TDC include confirmed reactive-oxygen-species-induced mitochondrial damage leading to necrosis in SKOV-3 cell lines. The in vivo photodynamic activity in nude-mouse models demonstrated abrogation of tumor growth without any detectable pathology in the skin, liver, spleen, or kidney, thereby demonstrating TDC application as an efficient and safe photosensitizer. PMID- 29767975 TI - Cytotoxic Anthracycline Metabolites from a Recombinant Streptomyces. AB - The C7 (C9 or C10)- O-l-rhodosamine-bearing anthracycline antibiotic cytorhodins and their biosynthetic intermediates were recently isolated from Streptomyces sp. SCSIO 1666. Cosmid p17C4 from the Streptomyces lydicus genomic library, which harbors both the biosynthetic genes for l-rhodinose (or 2-deoxy-l-fucose) and its glycosyltransferase (encoded by slgG), was introduced into SCSIO 1666 to yield the recombinant strain Streptomyces sp. SCSIO 1666/17C4. Chemical investigations of this strain's secondary metabolic potential revealed the production of different anthracyclines featuring C7- O-l-rhodinose (or 2-deoxy-l-fucose) instead of the typically observed l-rhodosamine. Purification of the fermentation broth yielded 12 new anthracycline antibiotics including three new epsilon rhodomycinone derivatives, 1, 4, and 8, nine new beta-rhodomycinone derivatives, 2, 3, 5-7, and 9-12, and three known compounds, l-rhodinose-l-rhodinose-l rhodinoserhodomycinone (13), epsilon-rhodomycinone (14), and gamma-rhodomycinone (15). All compounds were characterized on the basis of detailed spectroscopic analyses and comparisons with previously reported data. These compounds exhibited cytotoxicity against a panel of human cancer cell lines. Significantly, compounds 4 and 13 displayed pronounced activity against HCT-116 as characterized by IC50 values of 0.3 and 0.2 MUM, respectively; these IC50 values are comparable to that of the positive control epirubicin. PMID- 29767973 TI - Discovery of Orally Bioavailable, Quinoline-Based Aldehyde Dehydrogenase 1A1 (ALDH1A1) Inhibitors with Potent Cellular Activity. AB - Aldehyde dehydrogenases (ALDHs) are responsible for the metabolism of aldehydes (exogenous and endogenous) and possess vital physiological and toxicological functions in areas such as CNS, inflammation, metabolic disorders, and cancers. Overexpression of certain ALDHs (e.g., ALDH1A1) is an important biomarker in cancers and cancer stem cells (CSCs) indicating the potential need for the identification and development of small molecule ALDH inhibitors. Herein, a newly designed series of quinoline-based analogs of ALDH1A1 inhibitors is described. Extensive medicinal chemistry optimization and biological characterization led to the identification of analogs with significantly improved enzymatic and cellular ALDH inhibition. Selected analogs, e.g., 86 (NCT-505) and 91 (NCT-506), demonstrated target engagement in a cellular thermal shift assay (CETSA), inhibited the formation of 3D spheroid cultures of OV-90 cancer cells, and potentiated the cytotoxicity of paclitaxel in SKOV-3-TR, a paclitaxel resistant ovarian cancer cell line. Lead compounds also exhibit high specificity over other ALDH isozymes and unrelated dehydrogenases. The in vitro ADME profiles and pharmacokinetic evaluation of selected analogs are also highlighted. PMID- 29767977 TI - Predicting Keto-Enol Equilibrium from Combining UV/Visible Absorption Spectroscopy with Quantum Chemical Calculations of Vibronic Structures for Many Excited States. A Case Study on Salicylideneanilines. AB - Salicylideneanilines are characterized by a tautomer equilibrium, between an enol and a keto form of different colors, at the origin of their remarkable thermochromic, solvatochromic, and photochromic properties. The enol form is usually the most stable but appropriate choice of substituents and conditions (solvent, crystal, host compound) can displace the equilibrium toward the keto form so that there is a need for fast prediction of the keto:enol abundance ratio. Here we demonstrate the reliability of a combined theoretical-experimental method, based on comparing simulated and measured UV/visible absorption spectra, to determine this keto/enol ratio. The calculations of the excitation energies, oscillator strengths, and vibronic structures of both enol and keto forms are performed for all excited states absorbing in the relevant (visible and near-UV) wavelength range at the time-dependent density functional theory level by accounting for solvent effects using the polarizable continuum model. This approach is illustrated for two salicylideneaniline derivatives, which are present, in solution, under the form of keto-enol mixtures. The results are compared to those of chemometric analysis as well as ab initio predictions of the reaction free enthalpies. PMID- 29767976 TI - Hopper Growth of Salt Crystals. AB - The growth of hopper crystals is observed for many substances, but the mechanism of their formation remains ill understood. Here we investigate their growth by performing evaporation experiments on small volumes of salt solutions. We show that sodium chloride crystals that grow very fast from a highly supersaturated solution form a peculiar form of hopper crystal consisting of a series of connected miniature versions of the original cubic crystal. The transition between cubic and such hopper growth happens at a well-defined supersaturation where the growth rate of the cubic crystal reaches a maximum (~6.5 +/- 1.8 MUm/s). Above this threshold, the growth rate varies as the third power of supersaturation, showing that a new mechanism, controlled by the maximum speed of surface integration of new molecules, induces the hopper growth of cubic crystals in cascade. PMID- 29767978 TI - Dynamics of Ionic Liquid-Assisted Refolding of Denatured Cytochrome c: A Study of Preferential Interactions toward Renaturation. AB - In vitro refolding of denatured protein and the influence of the alkyl chain on the refolding of a protein were tested using long chain imidazolium chloride salts, 1-methyl-3-octylimidazolium chloride [C8mim][Cl], and 1-decyl-3 methylimidazolium chloride [C10mim][Cl]. The horse heart cytochrome c (h-cyt c) was denatured by urea and guanidinium hydrochloride (GdnHCl), as well as by base induced denaturation at pH 13, to provide a broad overview of the overall refolding behavior. The variation in the alkyl chain of the ionic liquids (ILs) showed a profound effect on the refolding of denatured h-cyt c. The ligand induced refolding was correlated to understand the mechanism of the conformational stability of proteins in aqueous solutions of ILs. The results showed that the long chain ILs having the [C8mim]+ and [C10mim]+ cations promote the refolding of alkali-denatured h-cyt c. The IL having the [C10mim]+ cation efficiently refolded the alkali-denatured h-cyt c with the formation of the MG state, whereas the IL having the [C8mim]+ cation, which is known to be compatible for protein stability, shows slight refolding and forms a different transition state. The lifetime results show successful refolding of alkaline-denatured h-cyt c by both of the ILs, however, more refolding was observed in the case of [C10mim][Cl], and this was correlated with the fast and medium lifetimes (tau1 and tau2) obtained, which show an increase accompanied by an increase in secondary structure. The hydrophobic interactions plays an important role in the refolding of chemically and alkali-denatured h-cyt c by long chain imidazolium ILs. The formation of the MG state by [C10mim][Cl] was also confirmed, as some regular structure exists far below the CMC of IL. The overall results suggested that the [C10mim]+ cation bound to the unfolded h-cyt c triggers its refolding by electrostatic and hydrophobic interactions that stabilize the MG state. PMID- 29767980 TI - HNO3/HFIP: A Nitrating System for Arenes with Direct Observation of pi-Complex Intermediates. AB - This report describes an efficient nitrating system for the nitration of arenes at room temperature by using an equivalent of nitric acid in HFIP (1,1,1,3,3,3 hexafluoroisopropanol). The pi-complex intermediate of an arene with a nitronium ion stabilized by HFIP can be directly observed by UV-vis spectra and is supported by theoretical calculations. PMID- 29767979 TI - Ultracompliant Heterogeneous Copper-Tin Nanowire Arrays Making a Supersolder. AB - Due to the substantial increase in power density, thermal interface resistance that can constitute more than 50% of the total thermal resistance has generally become a bottleneck for thermal management in electronics. However, conventional thermal interface materials (TIMs) such as solder, epoxy, gel, and grease cannot fulfill the requirements of electronics for high-power and long-term operation. Here, we demonstrate a high-performance TIM consisting of a heterogeneous copper tin nanowire array, which we term "supersolder" to emulate the role of conventional solders in bonding various surfaces. The supersolder is ultracompliant with a shear modulus 2-3 orders of magnitude lower than traditional solders and can reduce the thermal resistance by two times as compared with the state-of-the-art TIMs. This supersolder also exhibits excellent long-term reliability with >1200 thermal cycles over a wide temperature range. By resolving this critical thermal bottleneck, the supersolder enables electronic systems, ranging from microelectronics and portable electronics to massive data centers, to operate at lower temperatures with higher power density and reliability. PMID- 29767981 TI - Optical Activity of Semiconductor Gammadions beyond Planar Chirality. AB - We present rigorous analysis of optical activity of chiral semiconductor gammadions whose chirality in three dimensions is caused by the nonuniformity of thickness in the transverse plane. It is shown that such gammadions not only distinguish between the two circular polarizations upon scattering and reflection of light, like all two-dimensional semiconductor nanostructures with planar chirality do, but also exhibit circular dichroism and circularly polarized luminescence. Chiral semiconductor gammadions whose charge carriers are mostly confined to the arms are found to feature both high dissymmetry of optical response and a constant-sign circular dichroism signal over a wide frequency range. It is also shown that the strength of the gammadion's chiroptical response is determined solely by two geometric factors: the variation range of the gammadion's thickness and the arms' curvature. Our seminal theoretical study is intended to lay the foundation for future applications of semiconductor gammadions in chiral nanophotonics and nanotechnology. PMID- 29767983 TI - Reductive Radical Cascades Triggered by Alkoxyl Radicals in the beta-Cyclodextrin Framework. AB - The generation and fate of 2I-VII,3I-VII,6II-VII-icosa- O-methyl-beta cyclomaltoheptaos-6I- O-yl radical under reductive conditions is described. Two radical cascade reactions are involved: the main one is triggered by a 1,8-HAT of the hydrogen at 5VIIC. The radical can reach the anomeric hydrogen at 1VC three sugar units ahead using a six-step sequence. The different hydrogen donor ability of the group 14 hydrides permits one to selectively stop the cascade at 5VIIC, 2VIC, and 4VIC to obtain beta-CD with a beta-l-Ido p unit, acyclic hepta-, and hexa-saccharide structures, respectively. PMID- 29767982 TI - DenTimol as A Dendrimeric Timolol Analogue for Glaucoma Therapy: Synthesis and Preliminary Efficacy and Safety Assessment. AB - In this work, we report the synthesis and characterization of DenTimol, a dendrimer-based polymeric timolol analog, as a glaucoma medication. A timolol precursor ( S)-4-[4-(oxiranylmethoxy)-1,2,5-thiadiazol-3-yl]morpholine (OTM) was reacted with the heterobifunctional amine polyethylene glycol acetic acid (amine PEG-acetic acid, Mn = 2000 g/mol) via a ring opening reaction of an epoxide by an amine to form the OTM-PEG conjugate. OTM-PEG was then coupled to an ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimer G3 to generate DenTimol using the N-(3-(dimethylamino)propyl)- N'-ethylcarbodiimide hydrochloride (EDC)/ N-hydroxysuccinimide (NHS) coupling reaction. MALDI mass spectrometry, 1H NMR spectroscopy, and HPLC were applied to characterize the intermediate and final products. Ex vivo corneal permeation of DenTimol was assessed using the Franz diffusion cell system mounted with freshly extracted rabbit cornea. The cytotoxicity of DenTimol was assessed using the WST-1 assay. Our results show that DenTimol is nontoxic up to an OTM equivalent concentration of 100 MUM. DenTimol is efficient at crossing the cornea. About 8% of the dendrimeric drug permeated through the cornea in 4 h. Its IOP-lowering effect was observed in normotensive adult Brown Norway male rats. Compared to the undosed eye, an IOP reduction by an average of 7.3 mmHg (~30% reduction from baseline) was observed in the eye topically treated with DenTimol (2 * 5 MUL, 0.5% w/v timolol equivalent) in less than 30 min. Daily dosing of DenTimol for a week did not cause any irritation or toxicity as confirmed by the histological examination of ocular tissues, including the cornea, ciliary body, and retina. PMID- 29767984 TI - Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery. AB - Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery. PMID- 29767985 TI - Imaging Nanometer Phase Coexistence at Defects During the Insulator-Metal Phase Transformation in VO2 Thin Films by Resonant Soft X-ray Holography. AB - We use resonant soft X-ray holography to image the insulator-metal phase transition in vanadium dioxide with element and polarization specificity and nanometer spatial resolution. We observe that nanoscale inhomogeneity in the film results in spatial-dependent transition pathways between the insulating and metallic states. Additional nanoscale phases form in the vicinity of defects which are not apparent in the initial or final states of the system, which would be missed in area-integrated X-ray absorption measurements. These intermediate phases are vital to understand the phase transition in VO2, and our results demonstrate how resonant imaging can be used to understand the electronic properties of phase-separated correlated materials obtained by X-ray absorption. PMID- 29767986 TI - Low-Frequency Current Fluctuations and Sliding of the Charge Density Waves in Two Dimensional Materials. AB - We investigated low-frequency noise in two-dimensional (2D) charge density wave (CDW) systems, 1 T-TaS2 thin films, as they were driven from the nearly commensurate (NC) to incommensurate (IC) CDW phases by voltage and temperature stimuli. This study revealed that noise in 1 T-TaS2 has two pronounced maxima at the bias voltages, which correspond to the onset of CDW sliding and the NC-to-IC phase transition. We observed unusual Lorentzian features and exceptionally strong noise dependence on electric bias and temperature, leading to the conclusion that electronic noise in 2D CDW systems has a unique physical origin different from known fundamental noise types. We argue that noise spectroscopy can serve as a useful tool for understanding electronic transport phenomena in 2D CDW materials characterized by coexistence of different phases and strong pinning. PMID- 29767987 TI - A Full-Visible-Spectrum Invisibility Cloak for Mesoscopic Metal Wires. AB - Structured metals can sustain a very large scattering cross-section that is induced by localized surface plasmons, which often has an adverse effect on their use as transparent electrodes in displays, touch screens, and smart windows due to an issue of low clarity. Here, we report a broadband optical cloaking strategy for the network of mesoscopic metal wires with submicrometer to micrometer diameters, which is exploited for manufacturing and application of high-clarity metal-wires-based transparent electrodes. We prepare electrospun Ag wires with 300-1800 nm in diameter and perform a facile surface oxidation process to form Ag/Ag2O core/shell heterogeneous structures. The absorptive Ag2O shell, together with the coating of a dielectric cover, leads to the cancellation of electric multipole moments in Ag wires, thereby drastically suppressing plasmon-mediated scattering over the full visible spectrum and rendering Ag wires to be invisible. Simultaneously with the effect of invisibility, the transmittance of Ag/Ag2O wires is significantly improved compared to bare Ag wires, despite the formation of an absorptive Ag2O shell. As an application example, we demonstrate that these invisible Ag wires serve as a high-clarity, high-transmittance, and high-speed defroster for automotive windshields. PMID- 29767988 TI - Experimentally Validated Structures of Supported Metal Nanoclusters on MoS2. AB - In nanometer clusters (NCs), each atom counts. It is the specific arrangement of these atoms that determines the unique size-dependent functionalities of the NCs and hence their applications. Here, we employ a self-consistent, combined theoretical and experimental approach to determine atom-by-atom the structures of supported Pt NCs on MoS2. The atomic structures are predicted using a genetic algorithm utilizing atomistic force fields and density functional theory, which are then validated using aberration-corrected scanning transmission electron microscopy. We find that relatively small clusters grow with (111) orientation such that Pt[110] is parallel to MoS2[100], which is different from predictions based on lattice-match for thin-film epitaxy. Other 4d and 5d transition metals show similar behavior. The underpinning of this growth mode is the tendency of the NCs to maximize the metal-sulfur interactions rather than to minimize lattice strain. PMID- 29767989 TI - Metal-Free C(sp3)-H Allylation via Aryl Carboxyl Radicals Enabled by Donor Acceptor Complex. AB - The first aryl carboxyl radical generation by the donor-acceptor complex with N acyloxyphthalimides and Hantzsch esters is reported. Regio- and chemoselective C(sp3)-H bond allylation is enabled by aryl carboxyl radicals with visible light irradiation under mild and metal-free conditions. PMID- 29767990 TI - Synthesis of Carbolines via Palladium/Carboxylic Acid Joint Catalysis. AB - The combination of a Pd(0) complex with benzoic acid converts propargylic tryptamines to the corresponding tetrahydro-beta-carbolines. The method uses unprotected indoles and affords the desired products with ample functional group tolerance. Detailed modeling studies reveal a close synergy between the organic and metal catalysts, which enables sequential alkyne isomerization, indole C-H activation, and eventual C-C reductive elimination to afford the target heterocycles. PMID- 29767991 TI - Metal-Free-Visible Light C-H Alkylation of Heteroaromatics via Hypervalent Iodine Promoted Decarboxylation. AB - A metal-free photoredox C-H alkylation of heteroaromatics from readily available carboxylic acids using an organic photocatalyst and hypervalent iodine reagents under blue LED light is reported. The developed methodology tolerates a broad range of functional groups and can be applied to the late-stage functionalization of drugs and drug-like molecules. The reaction mechanism was investigated with control experiments and photophysical experiments as well as DFT calculations. PMID- 29767992 TI - Gold(I)-Catalyzed Formal Intramolecular Dehydro-Diels-Alder Reaction of Ynamide ynes: Synthesis of Functionalized Benzo[ b]carbazoles. AB - A gold-catalyzed cycloisomerization of ynamide-ynes via a formal dehydro-Diels Alder reaction has been developed, providing an attractive route to diversely substituted benzo[ b]carbazoles. The reaction likely proceeds via regioselective attack of the pendant alkyne moiety to a keteniminium ion intermediate followed by benzannulation. The method offers several advantages such as high efficiency, mild reaction conditions, and wide functional group tolerance and serves as a highly useful complement to the thermal DDA reactions of ynamide-ynes. PMID- 29767993 TI - Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis ( M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant. PMID- 29767994 TI - Thermodynamics of Alkanethiol Self-Assembled Monolayer Assembly on Pd Surfaces. AB - We investigate the structure and binding energy of alkanethiolate self-assembled monolayers (SAMs) on Pd (111), Pd (100), and Pd (110) facets at different coverages. Dispersion-corrected density functional theory calculations are used to correlate the binding energy of alkanethiolates with alkyl chain length and coverage. The equilibrium coverage of thiolate layers strongly prefers 1/3 monolayer (ML) on the Pd (111) surface. The coverage of thiolates varies with chemical potential on Pd (100) and Pd (110), increasing from 1/3 to 1/2 ML on (100) and from 1/4 to 1/2 ML on (110) as the thiol chemical potential is increased. Higher coverages are driven by attractive dispersion interactions between the extended alkyl chains, such that transitions to higher coverages occur at lower thiol chemical potentials for longer chain thiolates. Stronger adsorption to the Pd (100) surface causes the equilibrium Wulff construction of Pd particles to take on a cubic shape upon saturation with thiols. The binding of H, O, and CO adsorbates is weakened as the thiolate coverage is increased, with saturation coverages causing unfavorable binding of O and CO on Pd (100) and weakened binding on other facets. Temperature-dependent CO diffuse reflectance infrared Fourier transform spectroscopy experiments are used to corroborate the weakened binding of CO in the presence of thiolate SAMs of varying surface density. Preliminary results of multiscale modeling efforts on the Pd-thiol system using a reactive force field, ReaxFF, are also discussed. PMID- 29767995 TI - Structure-Activity Relationships and Therapeutic Potentials of 5-HT7 Receptor Ligands: An Update. AB - Serotonin 5-HT7 receptor (5-HT7R) has been the subject of intense research efforts because of its presence in brain areas such as the hippocampus, hypothalamus, and cortex. Preclinical data link the 5-HT7R to a variety of central nervous system processes including the regulation of circadian rhythms, mood, cognition, pain processing, and mechanisms of addiction. 5-HT7R blockade has antidepressant effects and may ameliorate cognitive deficits associated with schizophrenia. 5-HT7R has been recently shown to modulate neuronal morphology, excitability, and plasticity, thus contributing to shape brain networks during development and to remodel neuronal wiring in the mature brain. Therefore, the activation of 5-HT7R has been proposed as a therapeutic approach for neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. This Perspective celebrates the silver jubilee of the discovery of 5-HT7R by providing a survey of recent studies on the medicinal chemistry of 5-HT7R ligands and on the neuropharmacology of 5-HT7R. PMID- 29767996 TI - Nanoscale Probing of Local Hydrogen Heterogeneity in Disordered Carbon Nitrides with Vibrational Electron Energy-Loss Spectroscopy. AB - In graphitic carbon nitrides, (photo)catalytic functionality is underpinned by the effect that residual hydrogen content, manifesting in amine (N-H x) defects, has on its optoelectronic properties. Therefore, a detailed understanding of the variation in the local structure of graphitic carbon nitrides is key for understanding structure-activity relationships. Here, we apply aloof-beam vibrational electron energy-loss spectroscopy in the scanning transmission electron microscope (STEM) to locally detect variations in hydrogen content in two different layered carbon nitrides with nanometer resolution. Through low dose rate TEM, we obtain atomically resolved images from crystalline and disordered carbon nitrides. By employing an aloof-beam configuration in a monochromated STEM, radiation damage can be dramatically reduced, yielding vibrational spectra from carbon nitrides to be assessed on 10's of nanometer length scales. We find that in disordered graphitic carbon nitrides the relative amine content can vary locally up to 27%. Cyano (C=N) defects originating from uncondensed precursor are also revealed by probing small volumes, which cannot be detected by infrared absorption or Raman scattering spectroscopies. The utility of this technique is realized for heterogeneous soft materials, such as disordered graphitic carbon nitrides, in which methods to probe catalytically active sites remain elusive. PMID- 29767997 TI - Dissecting the Conformational Dynamics-Modulated Enzyme Catalysis with Single Molecule FRET. AB - Conformational changes of enzyme proteins are often coupled with a catalytic reaction and modulate the enzyme activity. Single-molecule technology is a powerful tool to study the mechanism of enzyme catalysis in these complicated cases. However, the chemical reaction cycles and conformational changes could not be monitored simultaneously in a single-molecule detection experiment, resulting in some unresolved key kinetic parameters. Here, we describe a method to extract all of the kinetic parameters from comprehensive single-molecule FRET (smFRET) measurements and model analysis. On the basis of the smFRET, we calculated the undetectable parameters by solving the rate equations of the kinetic model with the input of the smFRET-measured conformational state populations and state transition rate constants. A case study of MalK2 ATPase demonstrates that this method could reveal the quantitative mechanism of the catalytic reaction of the enzyme as well as its coupled conformational dynamics. The strategy employed in this study could be widely applied to investigate the conformational fluctuation coupled catalysis of other enzymes. PMID- 29767998 TI - Rapid on-Chip Assembly of Niosomes: Batch versus Continuous Flow Reactors. AB - The large-scale continuous production of niosomes remains challenging. The inherent drawbacks of batch processes such as large particle polydispersity and reduced batch-to-batch reproducibility are here overcome by using commercially available microfluidic reactors. Compared to the traditional batch-based film hydration method, herein, we demonstrate that it is possible to carry out the homogeneous, large-scale (up to 120 mg/min) production of niosomes using two different synthesis techniques (the thin film hydration method and the emulsification technique). Niosomes particle size can be controlled depending on the need by varying the synthesis temperature. The high cytocompatibility of the resulting niosomes was also demonstrated in this work on three different somatic cell lines. For the first time, the structure of the niosome multilamellar shell was also elucidated using high-resolution transmission electron microscopy (HR STEM) as well as their colloidal stability over time (6 weeks) under different storage conditions. The morphology of cryo-protected or as-made niosomes was also evaluated by HR-STEM after freeze-drying. Finally, the dual ability of those synthetic, nonionic, surfactant-based vesicles to carry both hydrophilic and hydrophobic molecules was also here demonstrated by using laser scanning confocal microscopy. PMID- 29767999 TI - Operando Atomic Force Microscopy Reveals Mechanics of Structural Water Driven Battery-to-Pseudocapacitor Transition. AB - The presence of structural water in tungsten oxides leads to a transition in the energy storage mechanism from battery-type intercalation (limited by solid state diffusion) to pseudocapacitance (limited by surface kinetics). Here, we demonstrate that these electrochemical mechanisms are linked to the mechanical response of the materials during intercalation of protons and present a pathway to utilize the mechanical coupling for local studies of electrochemistry. Operando atomic force microscopy dilatometry is used to measure the deformation of redox-active energy storage materials and to link the local nanoscale deformation to the electrochemical redox process. This technique reveals that the local mechanical deformation of the hydrated tungsten oxide is smaller and more gradual than the anhydrous oxide and occurs without hysteresis during the intercalation and deintercalation processes. The ability of layered materials with confined structural water to minimize mechanical deformation likely contributes to their fast energy storage kinetics. PMID- 29768001 TI - Crystal Structures of the Mango-II RNA Aptamer Reveal Heterogeneous Fluorophore Binding and Guide Engineering of Variants with Improved Selectivity and Brightness. AB - Several RNA aptamers that bind small molecules and enhance their fluorescence have been successfully used to tag and track RNAs in vivo, but these genetically encodable tags have not yet achieved single-fluorophore resolution. Recently, Mango-II, an RNA that binds TO1-Biotin with ~1 nM affinity and enhances its fluorescence by >1500-fold, was isolated by fluorescence selection from the pool that yielded the original RNA Mango. We determined the crystal structures of Mango-II in complex with two fluorophores, TO1-Biotin and TO3-Biotin, and found that despite their high affinity, the ligands adopt multiple distinct conformations, indicative of a binding pocket with modest stereoselectivity. Mutational analysis of the binding site led to Mango-II(A22U), which retains high affinity for TO1-Biotin but now discriminates >5-fold against TO3-biotin. Moreover, fluorescence enhancement of TO1-Biotin increases by 18%, while that of TO3-Biotin decreases by 25%. Crystallographic, spectroscopic, and analogue studies show that the A22U mutation improves conformational homogeneity and shape complementarity of the fluorophore-RNA interface. Our work demonstrates that even after extensive functional selection, aptamer RNAs can be further improved through structure-guided engineering. PMID- 29768000 TI - Monolayer Molybdenum Disulfide Transistors with Single-Atom-Thick Gates. AB - Two-dimensional transition-metal dichalcogenides (TMDs) are unique candidates for the development of next-generation electronic devices. However, the large contact resistance between metal and the monolayer TMDs have significantly limited the devices' performance. Also, the integration of ultrathin high- k dielectric layers with TMDs remains difficult due to the lack of dangling bonds on the surface of TMDs. We present monolayer molybdenum disulfide field-effect transistors with bottom local gates consisting of monolayer graphene. The atomic level thickness and surface roughness of graphene facilitate the growth of high quality ultrathin HfO2 and suppress gate leakage. Strong displacement fields above 8 V/nm can be applied using a single graphene gate to electrostatically dope the MoS2, which reduces the contact resistances between Ni and monolayer MoS2 to 2.3 kOmega.MUm at low gate voltages. The devices exhibit excellent switching characteristics including a near-ideal subthreshold slope of 64 millivolts per decade, low threshold voltage (~0.5 V), high channel conductance (>100 MUS/MUm), and low hysteresis. Scaled devices with 50 and 14 nm channels as well as ultrathin (5 nm) gate dielectrics show effective immunity to short channel effects. The device fabricated on flexible polymeric substrate also exhibits high performance and has a fully transparent channel region that is desirable in optical-related studies and practical applications. PMID- 29768002 TI - Synergistic Enhancement of Enzyme Performance and Resilience via Orthogonal Peptide-Protein Chemistry Enabled Multilayer Construction. AB - Protein immobilization is critical to utilize their unique functions in diverse applications. Herein, we report that orthogonal peptide-protein chemistry enabled multilayer construction can facilitate the incorporation of various folded structural domains, including calmodulin in different states, affibody, and dihydrofolate reductase (DHFR). An extended conformation is found to be the most advantageous for steady film growth. The resulting protein thin films exhibit sensitive and selective responsive behaviors to biosignals, such as Ca2+, trifluoperazine, and nicotinamide adenine dinucleotide phosphate (NADPH), and fully maintain the catalytic activity of DHFR. The approach is applicable to different substrates such as hydrophobic gold and hydrophilic silica microparticles. The DHFR enzyme can be immobilized onto silica microparticles with tunable amounts. The multilayer setup exhibits a synergistic enhancement of DHFR activity with increasing numbers of bilayers and also makes the embedded DHFR more resilient to lyophilization. Therefore, this is a convenient and versatile method for protein immobilization with potential benefits of synergistic enhancement in enzyme performance and resilience. PMID- 29768003 TI - Catalyzed Atomic Layer Deposition of Silicon Oxide at Ultralow Temperature Using Alkylamine. AB - We report the catalyzed atomic layer deposition (ALD) of silicon oxide using Si2Cl6, H2O, and various alkylamines. The density functional theory (DFT) calculations using the periodic slab model of the SiO2 surface were performed for the selection of alternative Lewis base catalysts with high catalytic activities. During the first half-reaction, the catalysts with less steric hindrance such as pyridine would be more effective than bulky alkylamines despite lower nucleophilicity. On the other hand, during the second half-reaction, the catalysts with a high nucleophilicity such as triethylamine (Et3N) would be more efficient because the steric hindrance is less critical. The in situ process monitoring shows that the calculated atomic charge is a good indicator for expecting the catalyst activity in the ALD reaction. The use of Et3N in the second half-reaction was essential to improving the growth rate as well as the step coverage of the film because the Et3N-catalyzed process deposited a SiO2 film with a step coverage of 98% that is better than 93% of the pyridine catalyzed process. The adsorption of pyridine, ammonia (NH3), or trimethylamine (Me3N) salts was more favorable than that of Et3N, n-Pr3N, or iPr3N salts. Therefore, Et3N was expected to incorporate less amine salts in the film as compared to pyridine, and the compositional analyses confirmed that the concentrations of Cl and N by the Et3N-catalyzed process were significantly lower than those by the pyridine-catalyzed process. PMID- 29768004 TI - Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers. AB - At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the beta subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We perform multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3 MUs for each replica, 0.9 MUs for each octamer system, and 1.8 MUs total) of both octamers. We observe that a single GTP cap layer induces structural differences in neighboring PFs, finding that one PF possesses a gradual curvature, compared to the second PF which possesses a kinked conformation. This results in either curling or splaying between these PFs. We suggest that this is due to asymmetric strengths of longitudinal contacts between the two PFs. Furthermore, using NMA, we calculate mechanical properties of these octamer systems and find that octamer system with a single GTP cap layer possesses a lower flexural rigidity. PMID- 29768006 TI - Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor. AB - Efficient syntheses of 3,3-difluorooxindoles and 3-fluorooxindoles via fluorination of hydrazonoindolin-2-one with Selectfluor are reported. Under different solvent conditions, this method produced 3,3-difluorooxindoles and 3 fluorooxindoles selectively. The broad substrate scope and mild reaction conditions make this transformation a valuable method in drug discovery and development. PMID- 29768005 TI - A Versatile AuNP Synthetic Platform for Decoupled Control of Size and Surface Composition. AB - While a plethora of protocols exist for the synthesis of sub-10-nm gold nanoparticles (AuNPs), independent control over the size and surface composition remains restricted. This poses a particular challenge for systematic studies of AuNP structure-function relationships and the optimization of crucial design parameters. To this end, we report on a modular two-step approach based on the synthesis of AuNPs in oleylamine (OAm) followed by subsequent functionalization with thiol ligands and mixtures thereof. The synthesis of OAm-capped AuNPs enables fine-tuning of the core size in the range of 2-7 nm by varying the reaction temperature. The subsequent thiol-for-OAm ligand exchange allows a reliable generation of thiol-capped AuNPs with target surface functionality. The compatibility of this approach with a vast library of thiol ligands provides detailed control of the mixed ligand composition and solubility in a wide range of solvents ranging from water to hexane. This decoupled control over the AuNP core and ligand shell provides a powerful toolbox for the methodical screening of optimal design parameters and facile preparation of AuNPs with target properties. PMID- 29768007 TI - Sorting of Molecular Building Blocks from Solution to Surface. AB - We demonstrate that molecular gradients on an organic monolayer is formed by preferential binding of ruthenium complexes from solutions also containing equimolar amounts of isostructural osmium complexes. The monolayer consists of a nanometer-thick assembly of 1,3,5-tris(4-pyridylethenyl)benzene (TPEB) covalently attached to a silicon or metal-oxide surface. The molecular gradient of ruthenium and osmium complexes is orthogonal to the surface plane. This gradient propagates throughout the molecular assembly with thicknesses over 30 nm. Using other monolayers consisting of closely related organic molecules or metal complexes results in the formation of molecular assemblies having an homogeneous and equimolar distribution of ruthenium and osmium complexes. Spectroscopic and computational studies revealed that the geometry of the complexes and the electronic properties of their ligands are nearly identical. These subtle differences cause the isostructural osmium and ruthenium complexes to pack differently on modified surfaces as also demonstrated in crystals grown from solution. The different packing behavior, combined with the organic monolayer significantly contributes to the observed differences in chemical composition on the surface. PMID- 29768008 TI - Striking a Balance between Carbonate/Carbamate Linkage Bond- and Reduction Sensitive Disulfide Bond-Bearing Linker for Tailored Controlled Release: In Situ Covalent-Albumin-Binding Gemcitabine Prodrugs Promote Bioavailability and Tumor Accumulation. AB - To address the challenges of rapid enzyme inactivation, poor tumor targeting, and acquired drug resistance in gemcitabine (GEM) application, we report two groups of maleimide-functionalized GEM prodrugs conjugating covalently in situ with Cys 34 of blood-circulating albumin and then resulting in macromolecular prodrugs after intravenous administration. Tailored and accurate controlled release was achieved through different combinations of linkage bonds, relatively stable and labile (carbamate and carbonate, respectively), and linkers with or without insertion of a disulfide bond. Interestingly, we found that the overall advantages or disadvantages brought by a disulfide bond varied with the stability of the linkage bond. Finally, the carbonate linkage bond-bearing group, especially the one with a linker lacking a disulfide bond, stood out with remarkably increased bioavailability (21-fold greater than GEM) and efficient tumor free-GEM accumulation (8-fold of GEM), which consequently contributed to excellent in vivo antitumor efficacy. PMID- 29768009 TI - Use of Dual-Ligand Modification in Kupffer Cell-Targeted Liposomes To Examine the Contribution of Kupffer Cells to Accelerated Blood Clearance Phenomenon. AB - The "accelerated blood clearance (ABC) phenomenon" is known to be involved in the adaptive immune system. Regretfully, the relationship between the ABC phenomenon and innate immune system, especially with respect to Kupffer cells (KCs) has been largely unexplored. In this study, the contribution of KCs to ABC was examined using the 4-aminophenyl-alpha-d-mannopyranoside (APM) lipid derivative DSPE PEG2000-APM (DPM) and the 4-aminophenyl-beta-l-fucopyranoside (APF) lipid derivative DSPE-PEG2000-APF (DPF) as ligands for mannose/fucose receptors on KCs, which were synthesized and modified on the surface of liposomes. The results of cellular liposome uptake in vitro and biodistribution in vivo indicated that DPM and DPF comodified liposomes (MFPL5-5) present the strongest capability of KC targeting among all preparations tested. In rats pretreated with MFPL5-5 instead of PEGylated liposomes (PL), the ABC phenomenon was significantly enhanced and the distribution of liposomes in the liver was increased. Cellular uptake of the second injection of PL in vivo demonstrated that KCs was responsible for the uptake. Furthermore, compared to pretreatment with PL, the uptake of second injection of PL was more enhanced when pretreated with MFPL5-5. These findings suggest that KCs, which are considered traditional members of the innate immune system, play a crucial role in the ABC phenomenon and act as a supplement to the phenomenon. PMID- 29768010 TI - Highly Sensitive Electromechanical Piezoresistive Pressure Sensors Based on Large Area Layered PtSe2 Films. AB - Two-dimensional (2D) layered materials are ideal for micro- and nanoelectromechanical systems (MEMS/NEMS) due to their ultimate thinness. Platinum diselenide (PtSe2), an exciting and unexplored 2D transition metal dichalcogenide material, is particularly interesting because its low temperature growth process is scalable and compatible with silicon technology. Here, we report the potential of thin PtSe2 films as electromechanical piezoresistive sensors. All experiments have been conducted with semimetallic PtSe2 films grown by thermally assisted conversion of platinum at a complementary metal-oxide semiconductor (CMOS)-compatible temperature of 400 degrees C. We report high negative gauge factors of up to -85 obtained experimentally from PtSe2 strain gauges in a bending cantilever beam setup. Integrated NEMS piezoresistive pressure sensors with freestanding PMMA/PtSe2 membranes confirm the negative gauge factor and exhibit very high sensitivity, outperforming previously reported values by orders of magnitude. We employ density functional theory calculations to understand the origin of the measured negative gauge factor. Our results suggest PtSe2 as a very promising candidate for future NEMS applications, including integration into CMOS production lines. PMID- 29768012 TI - Asymmetric Two-Terminal Graphene Detector for Broadband Radiofrequency Heterodyne and Self-Mixing. AB - Graphene, a single atomic layer of covalently bonded carbon atoms, has been investigated intensively for optoelectronics and represents a promising candidate for high-speed electronics. Here, we present a microwave mixer constructed as an asymmetrically contacted two-terminal graphene device based on the thermoelectric effect. We report a 50 GHz (minimum) mixer bandwidth as well as 130 V/W (163 mA/W) extrinsic direct-detection responsivity. Anomalous second-harmonic generation due to self-mixing in our graphene detector is also observed. Careful investigation of the responsivity from four different approaches gives consistent results, confirming the exceptional performance of our zero-bias device operating at room temperature. The 50 GHz bandwidth indicates an extremely fast response time and our experimental results represent an encouraging advance toward practical graphene microwave devices with anticipated future applications extended through millimeter wave and terahertz frequencies. PMID- 29768011 TI - Detection of Sub-fM DNA with Target Recycling and Self-Assembly Amplification on Graphene Field-Effect Biosensors. AB - All-electronic DNA biosensors based on graphene field-effect transistors (GFETs) offer the prospect of simple and cost-effective diagnostics. For GFET sensors based on complementary probe DNA, the sensitivity is limited by the binding affinity of the target oligonucleotide, in the nM range for 20 mer targets. We report a ~20 000* improvement in sensitivity through the use of engineered hairpin probe DNA that allows for target recycling and hybridization chain reaction. This enables detection of 21 mer target DNA at sub-fM concentration and provides superior specificity against single-base mismatched oligomers. The work is based on a scalable fabrication process for biosensor arrays that is suitable for multiplexed detection. This approach overcomes the binding-affinity-dependent sensitivity of nucleic acid biosensors and offers a pathway toward multiplexed and label-free nucleic acid testing with high accuracy and selectivity. PMID- 29768013 TI - Synergistic Effects of Electrical Stimulation and Aligned Nanofibrous Microenvironment on Growth Behavior of Mesenchymal Stem Cells. AB - Incontrollable cellular growth behavior is a significant issue, which severely affects the functional tissue formation and cellular protein expression. Development of natural extracellular matrix (ECM) like biomaterials to present microenvironment cues for regulation of cell responses can effectively overcome this problem. The external simulation and topological characteristics as typical guiding cues are capable of providing diverse influences on cellular growth. Herein, we fabricated two-dimensional aligned conductive nanofibers (2D-ACNFs) by an electrospinning process and surface polymerization, and the obtained 2D-ACNFs provided the effects of both alignment and electrical stimulation (ES) on cellular response of human mesenchymal cells (hMSCs). The results of cellular responses implied that the obtained 2D-ACNFs could offer a synergistic effect of both ES and aligned nanopattern on hMSC growth behavior. The effects could not only promote hMSCs to contact each other and maintain cellular activity but also provide positive promotion to regulate cellular proliferation. Thus, we believe that the obtained 2D-ACNFs will have a broad application in the biomedical field, such as cell culture with ES, directional induction for cell growth, and damaged tissue repair, etc. PMID- 29768014 TI - Hybrid Mesoporous-Microporous Nanocarriers for Overcoming Multidrug Resistance by Sequential Drug Delivery. AB - Combination chemotherapy with a modulator and a chemotherapeutic drug has become one of the most promising strategies for the treatment of multidrug resistance (MDR) in cancer therapy. However, the development of nanocarriers with a high payload and sequential release of therapeutic agents poses a significant challenge. In this work, we report a type of hybrid nanocarriers prepared by polydopamine (PDA) mediated integration of the mesoporous MSN core and the microporous zeolite imidazolate frameworks-8 (ZIF-8) shell. The nanocarriers exploit storage capacities for drugs based on the high porosity and molecular sieving capabilities of ZIF-8 for sequential drug release. Particularly, large amounts of an anticancer drug (DOX, 607 MUg mg-1) and a MDR inhibitor curcumin (CUR, 778 MUg mg-1) were sequentially loaded in the mesoporous core via pi-pi stacking interactions mediated by PDA and in the microporous shell via the encapsulation during ZIF-8 growth. The sustained release of DOX was observed to follow earlier and faster release of CUR by acid-sensitive dissolution of the ZIF 8 shell. Furthermore, the nanoparticles showed good biocompatibility and effective cellular uptake in in vitro evaluations using drug-resistant MCF-7/ADR cancer cells. More importantly, the preferentially released CUR inhibited the drug efflux function of the membrane P-glycoprotein (P-gp), which subsequently facilitated the nuclear transportation of DOX released from the PDA-MSN core, and, in turn, the synergistic effects on killing MDR cancer cells. The hybrid mesoporous-microporous nanocarrier holds great promise for combination chemotherapy applications on the basis of sequential drug release. PMID- 29768015 TI - First-Principles Simulations of Liquid Water Using a Dielectric-Dependent Hybrid Functional. AB - We carried out first-principles simulations of liquid water under ambient conditions using a dielectric-dependent hybrid functional, where the fraction of exact exchange is set equal to the inverse of the high-frequency dielectric constant of the liquid. We found excellent agreement with experiment for the oxygen-oxygen partial correlation function at the experimental equilibrium density and 311 +/- 3 K. Other structural and dynamical properties, such as the diffusion coefficient, molecular dipole moments, and vibrational spectra, are also in good agreement with experiment. Our results, together with previous findings on electronic properties of the liquid with the same functional, show that the dielectric-dependent hybrid functional accurately describes both the structural and electronic properties of liquid water. PMID- 29768016 TI - Cisplatin Encapsulation Generates Morphologically Different Multicompartments in the Internal Nanostructures of Nonlamellar Liquid-Crystalline Self-Assemblies. AB - Cisplatin ( cis-diamminedichloroplatinum(II)) is among the most potent cytotoxic agents used in cancer chemotherapy. The encapsulation of cisplatin in lipid-based drug carriers has been challenging owing to its low solubility in both aqueous and lipid phases. Here, we investigated cisplatin encapsulation in nonlamellar liquid-crystalline (LC) nanodispersions formed from a ternary mixture of phytantriol (PHYT), vitamin E (Vit E), and an anionic phospholipid [either phosphatidylglycerol (DSPG) or phosphatidylserine (DPPS)]. We show an increase in cisplatin encapsulation efficiency (EE) in nanodispersions containing 1.5-4 wt % phospholipid. The EE was highest in DPPS-containing nanodispersions (53-98%) compared to DSPG-containing counterparts (25-40%) under similar experimental conditions. Through structural and morphological characterizations involving synchrotron small-angle X-ray scattering and cryogenic transmission electron microscopy, we further show that varying the phospholipid content of cisplatin free nanodispersions triggers an internal phase transition from a neat hexagonal (H2) phase to a biphasic phase (internal H2 phase coexisting with the lamellar (Lalpha) phase). However, cisplatin encapsulation in both DPPS- and DSPG containing nanodispersions generates the coexistence of morphologically different multicompartments in the internal nanostructures comprising vesicles as a core, enveloped by an inverted-type surface bicontinuous cubic Im3 m (primitive, QIIP) phase or H2 phase. We discuss the biophysical basis of these drug-induced morphological alterations and provide insights into the potential development of inverted-type LC nanodispersions for cisplatin delivery. PMID- 29768017 TI - The Signaling Network Resulting in Ventilator-induced Diaphragm Dysfunction. AB - Mechanical ventilation (MV) is a life-saving measure for those incapable of adequately ventilating or oxygenating without assistance. Unfortunately, even brief periods of MV result in diaphragm weakness (i.e., ventilator-induced diaphragm dysfunction [VIDD]) that may render it difficult to wean the ventilator. Prolonged MV is associated with cascading complications and is a strong risk factor for death. Thus, prevention of VIDD may have a dramatic impact on mortality rates. Here, we summarize the current understanding of the pathogenic events underlying VIDD. Numerous alterations have been proven important in both human and animal MV diaphragm. These include protein degradation via the ubiquitin proteasome system, autophagy, apoptosis, and calpain activity-all causing diaphragm muscle fiber atrophy, altered energy supply via compromised oxidative phosphorylation and upregulation of glycolysis, and also mitochondrial dysfunction and oxidative stress. Mitochondrial oxidative stress in fact appears to be a central factor in each of these events. Recent studies by our group and others indicate that mitochondrial function is modulated by several signaling molecules, including Smad3, signal transducer and activator of transcription 3, and FoxO. MV rapidly activates Smad3 and signal transducer and activator of transcription 3, which upregulate mitochondrial oxidative stress. Additional roles may be played by angiotensin II and leaky ryanodine receptors causing elevated calcium levels. We present, here, a hypothetical scaffold for understanding the molecular pathogenesis of VIDD, which links together these elements. These pathways harbor several drug targets that could soon move toward testing in clinical trials. We hope that this review will shape a short list of the most promising candidates. PMID- 29768018 TI - Psychostimulants: Influence on Body Mass Index and Height in a Pediatric Population with Attention-Deficit/Hyperactivity Disorder? AB - OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is often treated with psychostimulants. Psychostimulants' adverse effects on body mass index standard deviation score (BMI-sds) and height in children/adolescents with ADHD have been reported. However, literature is inconsistent, and it is unclear whether the observed effects are dosage- and/or BMI-dependent. Therefore, the aim of this retrospective observational study is to evaluate the influence of psychostimulants on BMI-sds and height-sds in a pediatric cohort with ADHD from an outpatient clinic, and to study the correlation between psychostimulant dosage and BMI-sds and height-sds change. METHOD: Participants <=18 years of age diagnosed with ADHD who started with psychostimulants (methylphenidate) were studied. Changes in BMI-sds and height-sds over an 18-month treatment period were assessed in subgroups according to baseline BMI-sds, gender, and age. Furthermore, correlations between BMI-sds, height-sds, and psychostimulant dose were studied. RESULTS: In total, 298 participants [median age 9.8 years, height sds 0.0, BMI-sds 0.5, psychostimulant dosage 0.5 (0.2-1.4) mg/kg/day] were analyzed, with an underweight, overweight, and obesity prevalence of 5%, 21%, and 7%, respectively. After 18 months of treatment a significant decline in BMI-sds ( 0.4) and height-sds (-0.2) was observed. These effects were consistent in all subgroups except for no change in BMI-sds in the underweight subgroup and no change in height-sds in the overweight subgroup. Medication dosage was weakly correlated with change in BMI-sds [r = -0.3 (-0.9 to +0.5); p < 0.01] and height sds [r = -0.2 (-0.4 to -0.1); p = 0.01]. CONCLUSION: After 18 months of psychostimulant treatment, a significant decline in BMI-sds and height-sds was observed. However, the correlation with psychostimulant dosage was weak, and the decline was not observed in all subgroups. Therefore, further studies on the etiology of BMI-change are warranted, particularly with regard to the ADHD symptoms. PMID- 29768019 TI - Does Anterior Cruciate Ligament Reconstruction Affect the Outcome of Osteochondral Allograft Transplantation? A Matched Cohort Study With a Mean Follow-up of 6 Years. AB - BACKGROUND: Few studies have evaluated the influence of anterior cruciate ligament (ACL) reconstruction on the outcome of cartilage repair. Hypothesis/Purpose: The purpose was to investigate the association between ACL reconstruction and functional outcomes after osteochondral allograft (OCA) transplantation. The hypothesis was that patients treated with OCA transplantation who had a history of ACL reconstruction would have inferior clinical outcomes and lower osteochondral graft survivorship when compared with a matched group of patients undergoing OCA transplantation without a history of ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: This study compared 31 knees that underwent OCA transplantation with a history of ACL reconstruction (OCA and ACL group) and 62 knees treated with isolated OCA transplantation (OCA group) that had an intact ACL. Groups were matched by age, diagnosis, year of surgery, and graft size. Minimum follow-up was 2 years. Frequency and type of reoperation were assessed. Clinical failure was defined as revision OCA transplantation or conversion to arthroplasty. Subjective outcome measures included International Knee Documentation Committee scores, Knee injury and Osteoarthritis Outcome Scores, and patient satisfaction. RESULTS: Clinical failure occurred in 3 of 31 knees (9.7%) in the OCA and ACL group and 6 of 62 knees (9.7%) in the OCA group ( P <= .999). Five- and 10-year survivorship of the OCA was 94.7% and 82.3% for the OCA and ACL group and 93.4% and 79.6% for OCA group, respectively ( P = .979). Mean follow-up was 6.2 +/- 3.3 years among all knees with grafts in situ. Changes from preoperative to latest follow-up visit (difference scores) on all subjective outcome measures were greater in the OCA group; however, none of the difference scores were statistically significant. Satisfaction with the results of OCA transplantation was reported in 78.3% of the OCA and ACL group and 71.7% of the OCA group ( P = .551). CONCLUSION: Treatment of cartilage lesions with OCA transplantation proved to be reliable and effective regardless of a history of ACL reconstruction as demonstrated by the improvements in outcome scores, long survivorship, and high satisfaction rates. History of ACL reconstruction did not influence outcome of OCA transplantation. PMID- 29768020 TI - Chemical diversity of the essential oils of twenty populations of Tanacetum polycephalum Sch. Bip. from Iran. AB - Chemical diversity of the essential oils of twenty wild populations of Tanacetum polycephalum Sch. Bip., was investigated. The aerial parts of T. polycephalum were collected at full flowering stage from West Azerbaijan Province of Iran, air dried; hydrodistilled to produce essential oils. The essential oils were analyzed by GC-FID and GC-MS. A total of forty compounds were identified accounting for 96.4-99.9% of the total oils. The most principal compounds were cis-thujone (0 82.3%), trans-thujone (0-79.8%), camphor (1.3-75.0%), 1,8-cineole (4.5-43.3%), borneol (1.0-36.2%) and bornyl acetate (0-26.8%). Hierarchical cluster analysis based on the percentages (>0.5%) of the essential oils components was carried out to determine the chemical diversity among the populations studied. The cluster analysis resulted in the identification of four main chemotypes namely: 'camphor + 1,8-cineole', 'mixed', 'cis-thujone' and 'trans-thujone'. PMID- 29768021 TI - Diminished heart rate complexity in adolescent girls: a sign of vulnerability to anxiety disorders? AB - BACKGROUND AND OBJECTIVES: Diminished heart rate variability has been found to be associated with high anxiety symptomatology. Since adolescence is the period of onset for many anxiety disorders, this study aimed to determine sex- and anxiety related differences in heart rate variability and complexity in adolescents. METHODS: We created four groups according to sex and anxiety symptomatology: high anxiety girls (n = 24) and boys (n = 25), and low-anxiety girls (n = 22) and boys (n = 24) and recorded their cardiac function while they performed regular school activities. A series of two-way (sex and anxiety) MANOVAs were performed on time domain variability, frequency domain variability, and non-linear complexity. RESULTS: We obtained no multivariate interaction effects between sex and anxiety, but highly anxious participants had lower heart rate variability than the low anxiety group. Regarding sex, girls showed lower heart rate variability and complexity than boys. CONCLUSIONS: The results suggest that adolescent girls have a less flexible cardiac system that could be a marker of the girls' vulnerability to developing anxiety disorders. PMID- 29768023 TI - Natural Killer Cell: Looks Like a Sniper but Is Part of the Team. PMID- 29768022 TI - A pharmaceutical industry perspective on transporter and CYP-mediated drug-drug interactions: kidney transporter biomarkers. PMID- 29768024 TI - Isofraxisecoside, a new coumarin-secoiridoid from the stem bark of Fraxinus xanthoxyloides. AB - A new coumarin-secoiridoid diglucoside, named Isofraxisecoside, was isolated from the stem bark of Fraxinus xanthoxyloides (G. Don) Wall. ex A. DC. along with nine known compounds. The structure of new compound has been determined on the basis of 1H, 13C, 2D NMR and HRMS methods. PMID- 29768026 TI - Return-to-Play and Performance Outcomes of Professional Athletes in North America After Hip Arthroscopy From 1999 to 2016. AB - BACKGROUND: The effect of hip arthroscopy on athletic performance compared with preinjury levels for professional athletes in different sports remains unknown. In addition, while return rates have been reported for professional baseball, football, and hockey players, return rates have not been reported for professional basketball players. HYPOTHESIS: Professional athletes in 4 major North American sports would be able to return to their sport and preoperative level of performance at a high rate after arthroscopic hip surgery. STUDY DESIGN: Descriptive epidemiology study. METHODS: Major League Baseball (MLB), National Basketball Association (NBA), National Football League (NFL), and National Hockey League (NHL) athletes who underwent hip arthroscopy were identified through a previously reported protocol based on public sources. Successful return to play (RTP) was defined as returning for at least 1 professional regular season game after surgery. Performance scores were calculated by use of previously established scoring systems. Each player served as his own control, with the season prior to surgery defined as baseline. To make comparisons across sports, the authors adjusted for expected season and career length differences between sports and calculated percentage changes in performance. RESULTS: The authors identified 227 procedures performed on 180 professional athletes between 1999 and 2016. Successful RTP was achieved in 84.6% (192/227) of the procedures. Compared with all other athletes, NBA athletes returned at a similar rate (85.7%, P >= .999). NFL offensive linemen returned at a significantly lower rate than all other athletes (61.1%, P = .010). NHL athletes returned at a significantly higher rate than all other athletes (91.8%, P = .048) and demonstrated significantly decreased performance during postoperative season 1 compared with baseline ( 35.1%, P = .002). Lead leg surgery for MLB athletes (batting stance for hitters, pitching stance for pitchers) resulted in a 12.7% reduction in hitter performance score ( P = .041), a 1.3% reduction in pitcher fastball velocity ( P = .004), and a 60.7% reduction in pitch count ( P = .007) one season after surgery compared with baseline. Players in nearly every sport demonstrated significant reductions in game participation after surgery. CONCLUSION: This study supports the hypothesis that hip arthroscopy in professional athletes is associated with excellent rates of return at the professional level. However, postoperative performance outcomes varied based on sport and position. PMID- 29768027 TI - Professional burnout and work stress among Israeli dental assistants. AB - Professional burnout and work-related stress are known problems that have been the subject of in-depth examination among dentists. Nevertheless, these issues have not been widely studied among dental assistants. The aims of this study were threefold: to confirm the structure of a Work Stress Inventory (WSI) for Dental Assistants which was originally developed for Jordanian dental assistants (factor analysis); to evaluate work stress and burnout among Israeli dental assistants and to discover the factors predicting Israeli assistants' burnout (regression analyses). The Maslach Burnout Inventory and the WSI were distributed by mail and in person. Varimax factor analysis revealed that the items which contribute to different aspects of work stress are similar among both Jordanian and Israeli populations. Among the 299 Israeli dental assistants who completed the questionnaires, the most stressful work-related factors were income, workload, and work hazards. Eighteen percent of the participants exhibited a high to very high level of burnout. Participants exhibited a moderate level of emotional exhaustion (EE), low level of depersonalization (DP), and high level of personal accomplishment (PA). Most WSI factors were found to correlate positively with EE and DP. Linear stepwise regression analyses revealed that the best predictor of EE was the dentist-assistant relationship, followed by workload, patient type, and salary. The best predictor of DP was patient suffering followed by dentist assistant relationship, years of professional experience, and work hazards. Professional stress and burnout among dental assistants are important factors that can possibly affect the wellbeing of both dental personnel and their patients. Further studies are necessary to better understand these factors in addition to the effects of personal relationships on burnout among dentists and their assistants. PMID- 29768028 TI - Application of in vitro CYP and transporter assays to predict clinical drug-drug interactions. PMID- 29768025 TI - The Postinjury Inflammatory State and the Bone Marrow Response to Anemia. AB - RATIONALE: The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse. OBJECTIVES: To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis. METHODS: A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8). MEASUREMENTS AND MAIN RESULTS: During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate). CONCLUSIONS: Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731). PMID- 29768029 TI - Fungal Spoilage in Food Processing. AB - Food processing, packaging, and formulation strategies are often specifically designed to inhibit or control microbial growth to prevent spoilage. Some of the most restrictive strategies rely solely or on combinations of pH reduction, preservatives, water activity limitation, control of oxygen tension, thermal processing, and hermetic packaging. In concert, these strategies are used to inactivate potential spoilage microorganisms or inhibit their growth. However, for select microbes that can overcome these controls, the lack of competition from additional background microbiota helps facilitate their propagation. PMID- 29768030 TI - Evaluation of Petrifilm Lactic Acid Bacteria Plates for Counting Lactic Acid Bacteria in Food. AB - Although lactic acid bacteria (LAB) are used widely as starter cultures in the production of fermented foods, they are also responsible for food decay and deterioration. The undesirable growth of LAB in food causes spoilage, discoloration, and slime formation. Because of these adverse effects, food companies test for the presence of LAB in production areas and processed foods and consistently monitor the behavior of these bacteria. The 3M Petrifilm LAB Count Plates have recently been launched as a time-saving and simple-to-use plate designed for detecting and quantifying LAB. This study compares the abilities of Petrifilm LAB Count Plates and the de Man Rogosa Sharpe (MRS) agar medium to determine the LAB count in a variety of foods and swab samples collected from a food production area. Bacterial strains isolated from Petrifilm LAB Count Plates were identified by 16S rDNA sequence analysis to confirm the specificity of these plates for LAB. The results showed no significant difference in bacterial counts measured by using Petrifilm LAB Count Plates and MRS medium. Furthermore, all colonies growing on Petrifilm LAB Count Plates were confirmed to be LAB, while yeast colonies also formed in MRS medium. Petrifilm LAB Count Plates eliminated the plate preparation and plate inoculation steps, and the cultures could be started as soon as a diluted food sample was available. Food companies are required to establish quality controls and perform tests to check the quality of food products; the use of Petrifilm LAB Count Plates can simplify this testing process for food companies. PMID- 29768031 TI - Phytochemical compounds and anti-corrosion activity of Veronica rosea. AB - The aim of this work is the phytochemical study of the butanolic extract of the aerial parts of Veronica rosea. Four compounds 1-4 have been isolated using different chromatographic methods. The structures of these compounds were determined by NMR spectral analysis and mass spectroscopy. The adsorption and anticorrosion effects of this extract were investigated towards the corrosion of copper in 1 M HNO3 aqueous by the weight loss technique and potentiodynamic polarization. The results showed that the butanolic extract is a good inhibitor and the inhibition efficiency increases with increasing of concentration of the inhibitor. The adsorption of this extract on the copper specimen surface was spontaneous and obeyed the Langmuir's adsorption isotherm. Large value of adsorption equilibrium Constant (Kads = 35 L g-1) was obtained. The polarization experiments confirmed the data obtained by gravimetric weight-loss. Tafel plot of polarization curves indicates that the extract acts as a mixed type inhibitor. PMID- 29768032 TI - Flavonoid subclasses and type 2 diabetes mellitus risk: a meta-analysis of prospective cohort studies. AB - Epidemiological studies have suggested controversial associations between flavonoid subclasses and type 2 diabetes mellitus (T2DM) risk. The aim of the present meta-analysis was to quantitatively estimate these associations with prospective cohort study. A systematic literature search in PubMed and Scopus databases was performed up to May 2018. Multivariate-adjust relative risks (RRs) with corresponding 95% confidence intervals (CIs) for the highest versus the lowest category were pooled by using a random-effects model. Using restricted cubic spline regression model, non-linear dose-response analysis was estimated. Nine independent prospective cohort studies with 172,058 participants and 16910 events were included. Dietary intakes of flavanols, flavonols, flavan-3-ols and isoflavones were inversely associated with T2DM risk, and the summary RRs were 0.86 (95%CI: 0.77, 0.97), 0.91 (95%CI: 0.85, 0.98), 0.90 (95%: 0.82, 0.99) and 0.91 (95%CI: 0.84, 0.98), respectively. Dose-response analysis showed that 135 mg/day increment of flavanols (95%CI: 0.92, 0.96; P for trend < 0.001), 50 mg/day increment of flavonols (95%CI: 0.88, 0.99, P for trend = 0.021), 68 mg/day increment of flavan-3-ols (95%CI: 0.92, 0.96, P for trend < 0.001), or 1.8 mg/day increment of isoflavones (95%CI: 0.92, 0.97, P for trend < 0.001) were associated with 6% reduction in T2DM risk. Non-significant association was observed with respect to flavanones and flavones. The present meta-analysis provides substantial evidence that dietary intakes of flavanols, flavonols, flavan-3-ols and isoflavones were inversely associated with T2DM risk, respectively. Higher dietary intakes of flavanol-, flavonol-, flavan-3-ol- and isoflavone-foods would have beneficial effects for protection against T2DM. PMID- 29768033 TI - Endogenous probes for human liver organic anion-transporting polypeptides: the intersection of bioanalytical and ADME science. PMID- 29768034 TI - Staphylococcus aureus Induces a Mucosal Type 2 Immune Response via Epithelial Cell-derived Cytokines. AB - RATIONALE: Chronic rhinosinusitis with nasal polyps is characterized by a T helper cell type 2-skewed upper airway inflammation. Mucosal Staphylococcus aureus colonization is found in the majority of patients with nasal polyps. S. aureus is known to induce type 2 cytokine release via enterotoxins. OBJECTIVES: To investigate the impact of non-enterotoxin-producing S. aureus on type 2 cytokine release. METHODS: TSLP (thymic stromal lymphopoietin), IL-33, and type 2 cytokines were assessed in a human mucosal tissue model upon S. aureus infection. MEASUREMENTS AND MAIN RESULTS: S. aureus exposure increased the expression of IL 33, TSLP, IL-5, and IL-13 in nasal polyp tissue, accompanied by elevated expression levels of TSLP and IL-33 receptors, predominantly on CD3+ T cells. S. aureus infection led to the release of TSLP, but not IL-33, IL-5, or IL-13, from healthy inferior turbinate tissue. In contrast, S. epidermidis did not induce any epithelial cell-derived cytokines in nasal polyp or healthy tissue. S. aureus infection also increased the release of IL-33 and TSLP in BEAS-2B epithelial cells, accompanied by activation of NF-kappaB (nuclear factor kappaB) pathways. Incubation with CU-CPT22, a specific Toll-like receptor 2 antagonist, significantly reduced the S. aureus-induced release of TSLP and IL-33, and the activity of the NF-kappaB signal in BEAS-2B cells. CONCLUSIONS: This study demonstrates for the first time that S. aureus can directly induce epithelial cell-derived cytokine release via binding to Toll-like receptor 2, and may thereby propagate type 2 cytokine expression in nasal polyp tissue. PMID- 29768035 TI - Microgravity-induced ocular changes are related to body weight. AB - On Earth, tissue weight generates compressive forces that press on body structures and act on the walls of vessels throughout the body. In microgravity, tissues no longer have weight, and tissue compressive forces are lost, suggesting that individuals who weigh more may show greater effects from microgravity exposure. One unique effect of long-duration microgravity exposure is spaceflight associated neuroocular syndrome (SANS), which can present with globe flattening, choroidal folds, optic disk edema, and a hyperopic visual shift. To determine whether weight or other anthropometric measures are related to ocular changes in space, we analyzed data from 45 individual long-duration astronauts (mean age 47, 36 male, 9 female, mean mission duration 165 days) who had pre- and postflight measures of disk edema, choroidal folds, and manifest ocular refraction. The mean preflight weights of astronauts who developed new choroidal folds [78.6 kg with no new folds vs. 88.6 kg with new folds ( F = 6.2, P = 0.02)] and disk edema [79.1 kg with no edema vs. 95 kg with edema ( F = 9.6, P = 0.003)] were significantly greater than those who did not. Chest and waist circumferences were also significantly greater in those who developed folds or edema. The odds of developing disk edema or new choroidal folds were 55% in the highest- and 9% in the lowest-weight quartile. In this cohort, no women developed disk edema or choroidal folds, although women also weighed significantly less than men [62.9 vs. 85.2 kg ( F = 53.2, P < 0.0001)]. Preflight body weight and anthropometric factors may predict microgravity-induced ocular changes. PMID- 29768037 TI - Naturally occurring furofuran lignans: structural diversity and biological activities. AB - Furofuran lignans containing the 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane skeleton, represent one of the major subclasses of the lignan family of natural products. Furofuran lignans feature a wide variety of structures due to different substituents at aryl groups and diverse configurations at furofuran ring. Moreover, they exhibit a wide range of significant biological activities, including antioxidant, anti-inflammatory, cytotoxic, and antimicrobial activities. This review summarizes source, phytochemistry, and biological activities of 137 natural furofuran lignans isolated from 53 species in 41 genera of 27 plant families for the last 20 years, which provides a comprehensive information for further research of these furofuran lignans as potential pharmaceutical agents. PMID- 29768036 TI - Greater reductions in fat preferences in CALHM1 than CD36 knockout mice. AB - Several studies indicate an important role of gustation in intake and preference for dietary fat. The present study compared fat preference deficits produced by deletion of CD36, a putative fatty acid taste receptor, and CALHM1, an ion channel responsible for release of the ATP neurotransmitter used by taste cells. Naive CD36 knockout (KO) mice displayed reduced preferences for soybean oil emulsions (Intralipid) at low concentrations (0.1-1%) compared with wild-type (WT) mice in 24 h/day two-bottle tests. CALHM1 KO mice displayed even greater Intralipid preference deficits compared with WT and CD36 KO mice. These findings indicate that there may be another taste receptor besides CD36 that contributes to fat detection and preference. After experience with concentrated fat (2.5-5%), CD36 KO and CALHM1 KO mice displayed normal preferences for 0.1-5% fat, although they still consumed less fat than WT mice. The experience-induced rescue of fat preferences in KO mice can be attributed to postoral fat conditioning. Short-term (3-min) two-bottle tests further documented the fat preference deficits in CALHM1 KO mice but also revealed residual preferences for concentrated fat (5-10%), which may be mediated by odor and/or texture cues. PMID- 29768039 TI - Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice. AB - Sonic hedgehog ( Shh) is crucial for organogenesis in the foregut. This study investigated the function of Shh at the late-gestational stage; during which, the esophagus continues to differentiate. We established cytokeratin 14 ( CK14) Cre;Shhfl/fl mice in which the down-regulation of Shh in the epithelium occurred at approximately the same time as esophageal muscle conversion. Hematoxylin and eosin and immunohistochemical staining, with antibodies against keratin 14, Shh, patched 1 (Ptch1), Gli1, proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alphaSMA), high-molecular-weight caldesmon (hCD), myogenin, paired box 7 (Pax7), beta3-tubulin, and protein gene product 9.5 (PGP9.5), was performed to detect specific tissue dysplasia. Organ culture was conducted in vitro, and total mRNA was extracted to determine the transcriptional dysregulation. The esophagus of CK14-Cre;Shhfl/fl mice developed into an independent tube with an obvious dilatation at postnatal d 0.5. The number of cell layers and the expression of PCNA were decreased in mutant mice, compared with those in wild type mice. The expression of hCD declined progressively in the middle, distal, and lower esophageal sphincter levels of the mutant esophagus from embryonic d 17.5, compared with the expression in wild-type littermates. Pax7 accumulation and myogenin reduction in mutant mice indicated that esophageal skeletal-myoblast progression was blocked. RNA sequencing analysis revealed a significant down regulation of genes involved in proliferation and muscular motivation in CK14 Cre;Shhfl/fl mice. Thus, loss of Shh at the late-gestational stage leads to megaesophagus with reduced proliferation and a muscle development disorder in mice.-Jia, X., Min, L., Zhu, S., Zhang, S., Huang, X. Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice. PMID- 29768038 TI - Use and Characteristics of Antipsychotic/Methylphenidate Combination Therapy in Children and Adolescents with a Diagnosis of Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) frequently have comorbidities that are potential indications for antipsychotics (APs). Some studies have suggested that the combined use of methylphenidate (MPH) and APs is increasing in this population group. Longitudinal analyses and in-depth investigations on the substance level are lacking. This study aimed to estimate the cumulative proportion of concomitant AP/MPH use in children and adolescents with ADHD over a follow-up of up to 9 years and to describe patient characteristics stratified by specific AP drug. METHODS: Based on claims data, concomitant AP/MPH use was identified among 67,595 children and adolescents with ADHD starting MPH treatment between 2005 and 2013. Characteristics and diagnoses-including those indicating appropriateness of AP use according to approved indications and/or guidelines-were examined at the time of first AP/MPH combination therapy. In addition, subsequent use of AP/MPH combination therapy was evaluated. RESULTS: The cumulative proportion of individuals with any AP/MPH combination therapy rose to over 6% within 9 years after initiating MPH. The most frequent APs first used in combination with MPH were risperidone (72%), pipamperone (15%), and tiapride (8%). Percentages of psychiatric hospitalization in the year preceding the first combination therapy with MPH were 33%, 43%, and 19%, respectively. The proportion of individuals with potentially appropriate use was high (>72%) in risperidone/MPH and tiapride/MPH and low (15%) in pipamperone/MPH combination users. Conduct disorders and tic disorders were frequent in users who were prescribed MPH with risperidone and tiapride, respectively. One-quarter of patients with AP/MPH combination therapy were one-time-only combination users. CONCLUSION: Our study suggests that a considerable proportion of children and adolescents with ADHD receive MPH in combination with APs and that this is a factor not only during the first years of MPH treatment. ADHD guidelines should specify algorithms concerning the use of AP medication. PMID- 29768041 TI - Getting Hit by Pitch in Professional Baseball: Analysis of Injury Patterns, Risk Factors, Concussions, and Days Missed for Batters. AB - BACKGROUND: Although batters are frequently hit by pitch (HBP) in baseball, the effect of HBP injuries remains undefined in the literature. PURPOSE: To determine the effect of HBP injuries in terms of time out of play, injury patterns resulting in the greatest time out of play, and the value of protective gear such as helmets and elbow pads. STUDY DESIGN: Descriptive laboratory study. METHODS: Based on the Major League Baseball (MLB) Health and Injury Tracking System, all injuries to batters HBP during the 2011-2015 MLB and Minor League Baseball (MiLB) seasons were identified and analyzed. Video analysis was performed on all HBP events from the 2015 MLB season. Multivariate stepwise regression analysis was utilized to determine the predictive capacity of multiple variables (velocity, pitch type, location, etc) on injury status and severity. RESULTS: A total of 2920 HBP injuries resulted in 24,624 days missed (DM) over the 5 seasons. MLB HBP injuries occurred at a rate of 1 per 2554 plate appearances (1 per 9780 pitches thrown). Mean DM per injury were 8.4 (11.7 for MLB vs 8.0 for MiLB, P < .001). Surgery was required for 3.1% of MLB injuries and 1.2% of MiLB injuries ( P = .005). The most common body regions injured were the hand/fingers (n = 638, 21.8%), head/face (n = 497, 17.0%), and elbow (n = 440, 15.7%), and there were 146 (5.0%) concussions. Injury rates and mean DM correlated with velocity in a near linear fashion. Players hit in the head/face (odds ratio, 28.7) or distal upper extremity (odds ratio, 6.4) were more likely to be injured than players HBP in other locations. Players with an unprotected elbow missed 1.7 more days (95% CI, -4.1 to 7.6) than those with an elbow protector ( P = .554) when injured after being HBP. CONCLUSION/CLINICAL RELEVANCE: Although HBP injuries occur infrequently in the course of normal play, they collectively represent a significant source of time out of play. The most common body regions injured include the hands/fingers and head/face, and batters hit in these locations are significantly more likely to be injured. After contusions, concussions were the most common injury diagnosis. PMID- 29768042 TI - Baseline knowledge of potential pet toxins among the US general public. AB - In 2014, the American Society for the Prevention of Cruelty to Animals Animal Poison Control Center fielded more than 167,000 cases of potential nonhuman animal toxicosis. Concomitantly, there remain limited free and reputable veterinary toxicology resources available for companion-animal (pet) caregivers (owners) seeking assistance and advice about potentially harmful exposures in animals. The objective of this study was to assess pet toxicant knowledge among a representative sample of Americans and gauge the need for additional toxicology resources. The study involved a survey designed to capture participants' ability to identify potential animal toxicants and what resource they would use if an accidental toxic ingestion occurred. Participants were able to correctly identify 52% of potential pet toxins. Women, older participants and participants from the South expressed more concern about each potential pet poison. Approximately half of participants indicated they would consult a veterinarian whereas most others indicated they would search the Internet for more information about pet toxicology. The findings suggest more veterinary poisoning education is needed for pet owners to be able to accurately distinguish potential pet toxicants from nontoxicants. PMID- 29768040 TI - Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells. AB - Saturated fatty acids (SFAs) have been shown to induce endoplasmic reticulum (ER) stress and chronic inflammatory responses, as well as alter sphingolipid metabolism. Disruptions in ER stress and sphingolipid metabolism have also been implicated in intestinal inflammation. Therefore, to elucidate the roles of SFAs in ER stress and inflammation in intestinal epithelial cells, we examined myristate (C14:0) and palmitate (C16:0). Myristate, but not palmitate, induced ER stress signaling, including activation of inositol-requiring enzyme 1 (IRE1) and X-box binding protein 1 (XBP1) signaling. Myristate significantly increased C14 ceramide levels, whereas palmitate increased several long-chain ceramides. To define the role of ceramide synthases (CerSs) in myristate-induced ER stress, we used the pharmacologic inhibitor, fumonisin B1 (FB1), and small interfering RNA (siRNA) for CerS5 and 6, the primary isoforms that are involved in C14-ceramide generation. FB1 and siRNA for CerS5 or 6 suppressed myristate-induced C14 ceramide generation and XBP1 splicing (XBP1s). Moreover, increased XBP1s induced the downstream expression of IL-6 in a CerS5/6-dependent manner. In addition, a myristate-enriched milk fat-based diet, but not a lard-based diet, increased C14 ceramide, XBP1s, and IL-6 expression in vivo. Taken together, our data suggest that myristate modulates ER stress and cytokine production in the intestinal epithelium via CerS5/6 and C14-ceramide generation.-Choi, S., Snider, J. M., Olakkengil, N., Lambert, J. M., Anderson, A. K., Ross-Evans, J. S., Cowart, L. A., Snider, A. J. Myristate-induced endoplasmic reticulum stress requires ceramide synthases 5/6 and generation of C14-ceramide in intestinal epithelial cells. PMID- 29768043 TI - Haptic Foot Pedal: Influence of Shoe Type, Age, and Gender on Subjective Pulse Perception. AB - OBJECTIVE: This study investigates the influence of shoe type (sneakers and safety boots), age, and gender on the perception of haptic pulse feedback provided by a prototype accelerator pedal in a running stationary vehicle. BACKGROUND: Haptic feedback can be a less distracting alternative to traditionally visual and auditory in-vehicle feedback. However, to be effective, the device delivering the haptic feedback needs to be in contact with the person. Factors such as shoe type vary naturally over the season and could render feedback that is perceived well in one situation, unnoticeable in another. In this study, we evaluate factors that can influence the subjective perception of haptic feedback in a stationary but running car: shoe type, age, and gender. METHOD: Thirty-six drivers within three age groups (<=39, 40-59, and >=60) took part. For each haptic feedback, participants rated intensity, urgency, and comfort via a questionnaire. RESULTS: The perception of the haptic feedback is significantly influenced by the interaction between the pulse's duration and force amplitude and the participant's age and gender but not shoe type. CONCLUSION: The results indicate that it is important to consider different age groups and gender in the evaluation of haptic feedback. Future research might also look into approaches to adapt haptic feedback to the individual driver's preferences. APPLICATION: Findings from this study can be applied to the design of an accelerator pedal in a car, for example, for a nonvisual in-vehicle warning, but also to plan user studies with a haptic pedal in general. PMID- 29768044 TI - CoCl2 induces apoptosis via a ROS-dependent pathway and Drp1-mediated mitochondria fission in periodontal ligament stem cells. AB - Oxygen deficiency is associated with various oral diseases, including chronic periodontitis, age-related alveolar bone loss, and mechanical stress-linked cell injury from orthodontic appliances. Nevertheless, our understanding of the impact of hypoxia on periodontal tissues and its biochemical mechanism is still rudimentary. The purpose of this research was to elucidate the effects of hypoxia on the apoptosis of human periodontal ligament stem cells (PDLSCs) in vitro and the underlying mechanism. Herein, we showed that cobalt chloride (CoCl2) triggered cell dysfunction in human PDLSCs in a concentration-dependent manner and resulted in cell apoptosis and oxidative stress overproduction and accumulation in PDLSCs. In addition, CoCl2 promoted mitochondrial fission in PDLSCs. Importantly, CoCl2 increased the expression of dynamin-related protein 1 (Drp1), the major regulator in mitochondrial fission, in PDLSCs. Mitochondrial division inhibitor-1, pharmacological inhibition of Drp1, not only inhibited mitochondrial fission but also protected against CoCl2-induced PDLSC dysfunction, as shown by increased mitochondrial membrane potential, increased ATP level, reduced reactive oxygen species (ROS) level, and decreased apoptosis. Furthermore, N-acety-l-cysteine, a pharmacological inhibitor of ROS, also abolished CoCl2-induced expression of Drp1 and protected against CoCl2-induced PDLSC dysfunction, as shown by restored mitochondrial membrane potential, ATP level, inhibited mitochondrial fission, and decreased apoptosis. Collectively, our data provide new insights into the role of the ROS-Drp1-dependent mitochondrial pathway in CoCl2-induced apoptosis in PDLSCs, indicating that ROS and Drp1 are promising therapeutic targets for the treatment of CoCl2-induced PDLSC dysfunction. PMID- 29768047 TI - Glucocorticoid-activated IRE1alpha/XBP-1s signaling: an autophagy-associated protective pathway against endotheliocyte damage. AB - Glucocorticoid-induced endothelial injury has been reported in several diseases. Although there are several theories, the exact mechanism underlying the role of glucocorticoids in this process remains unclear. Autophagy has been reported to occur as a response to different stimuli and can affect cell survival and function. In this study, we found that glucocorticoids induced apoptosis and endoplasmic reticulum (ER) stress in endotheliocytes. Furthermore, we discovered that glucocorticoids induced autophagy in these cells and the inositol requiring protein 1 (IRE1alpha)/X-box binding protein 1s (XBP-1s) axis, one of the downstream signaling pathways of ER stress, was associated with the glucocorticoid-induced autophagy. The autophagy partly protected endotheliocytes from glucocorticoid-induced apoptosis and inhibition of proliferation. In conclusion, glucocorticoid-induced endoplasmic reticulum stress activated the IRE1alpha/XBP-1s signaling and induced autophagy, which, in turn, played a protective role in endotheliocyte survival and proliferation, avoiding further cellular damage caused by glucocorticoids. PMID- 29768046 TI - Does partial titin degradation affect sarcomere length nonuniformities and force in active and passive myofibrils? AB - The aim of this study was to determine the role of titin in preventing the development of sarcomere length nonuniformities following activation and after active and passive stretch by determining the effect of partial titin degradation on sarcomere length nonuniformities and force in passive and active myofibrils. Selective partial titin degradation was performed using a low dose of trypsin. Myofibrils were set at a sarcomere length of 2.4 um and then passively stretched to sarcomere lengths of 3.4 and 4.4 um. In the active condition, myofibrils were set at a sarcomere length of 2.8 um, activated, and actively stretched by 1 um/sarcomere. The extent of sarcomere length nonuniformities was calculated for each sarcomere as the absolute difference between sarcomere length and the mean sarcomere length of the myofibril. Our main finding is that partial titin degradation does not increase sarcomere length nonuniformities after passive stretch and activation compared with when titin is intact but increases the extent of sarcomere length nonuniformities after active stretch. Furthermore, when titin was partially degraded, active and passive stresses were substantially reduced. These results suggest that titin plays a crucial role in actively stretched myofibrils and is likely involved in active and passive force production. PMID- 29768048 TI - Hypoxic stress upregulates Kir2.1 expression by a pathway including hypoxic inducible factor-1alpha and dynamin2 in brain capillary endothelial cells. AB - Brain capillary endothelial cells (BCECs) play a central role in maintenance of blood-brain barrier (BBB) function and, therefore, are essential for central nervous system homeostasis and integrity. Although brain ischemia damages BCECs and causes disruption of BBB, the related influence of hypoxia on BCECs is not well understood. Hypoxic stress can upregulate functional expression of specific K+ currents in endothelial cells, e.g., Kir2.1 channels without any alterations in the mRNA level, in t-BBEC117, a cell line derived from bovine BCECs. The hyperpolarization of membrane potential due to Kir2.1 channel upregulation significantly facilitates cell proliferation. In the present study, the mechanisms underlying the hypoxia-induced Kir2.1 upregulation was examined. We emphasize the involvement of dynamin2, a protein known to be involved in a number of surface expression pathways. Hypoxic culture upregulated dynamin2 expression in t-BBEC117 cells. The inhibition of dynamin2 by Dynasore canceled hypoxia induced upregulation of Kir2.1 currents by reducing surface expression. On the contrary, Kir2.1 currents and proteins in t-BBEC117 cultured under normoxia were increased by overexpression of dynamin2, but not by dominant-negative dynamin2. Molecular imaging based on bimolecular fluorescence complementation, double immunostaining, and coimmunoprecipitation assays revealed that dynamin2 can directly bind to the Kir2.1 channel. Moreover, hypoxic culture downregulated hypoxic-inducible factor-1alpha (HIF-1alpha) expression. Knockdown of HIF-1alpha increased dynamin2 expression in t-BBEC117 cells, in both normoxic and hypoxic culture conditions. In summary, our results demonstrated that hypoxia downregulates HIF-1alpha, increases dynamin2 expression, and facilitates Kir2.1 surface expression, resulting in hyperpolarization of membrane potential and subsequent increase in Ca2+ influx in BCECs. PMID- 29768045 TI - MFehi adipose tissue macrophages compensate for tissue iron perturbations in mice. AB - Resident adipose tissue macrophages (ATMs) play multiple roles to maintain tissue homeostasis, such as removing excess free fatty acids and regulation of the extracellular matrix. The phagocytic nature and oxidative resiliency of macrophages not only allows them to function as innate immune cells but also to respond to specific tissue needs, such as iron homeostasis. MFehi ATMs are a subtype of resident ATMs that we recently identified to have twice the intracellular iron content as other ATMs and elevated expression of iron-handling genes. Although studies have demonstrated that iron homeostasis is important for adipocyte health, little is known about how MFehi ATMs may respond to and influence adipose tissue iron availability. Two methodologies were used to address this question: dietary iron supplementation and intraperitoneal iron injection. Upon exposure to high dietary iron, MFehi ATMs accumulated excess iron, whereas the iron content of MFelo ATMs and adipocytes remained unchanged. In this model of chronic iron excess, MFehi ATMs exhibited increased expression of genes involved in iron storage. In the injection model, MFehi ATMs incorporated high levels of iron, and adipocytes were spared iron overload. This acute model of iron overload was associated with increased numbers of MFehi ATMs; 17% could be attributed to monocyte recruitment and 83% to MFelo ATM incorporation into the MFehi pool. The MFehi ATM population maintained its low inflammatory profile and iron-cycling expression profile. These studies expand the field's understanding of ATMs and confirm that they can respond as a tissue iron sink in models of iron overload. PMID- 29768050 TI - Getting up-to-date in the management of soft tissue sarcoma. AB - Surgery (+ radiation therapy in selected cases) is standard treatment for adult type localized soft tissue sarcoma (STS). Accumulating randomized clinical evidence also supports adjuvant chemotherapy as a treatment option, although this remains contentious. Doxorubicin (+/- ifosfamide) is the standard first-line systemic treatment for advanced STS; however, newer chemotherapeutic agents may improve outcomes achieved with single-agent doxorubicin. In a Phase II study, adding olaratumab to doxorubicin markedly improved overall survival. Agents for second- and further lines include trabectedin, which combines long-term tumor stabilization with good quality of life, and gemcitabine + docetaxel which can produce a marked clinical response although at the cost of high toxicity. Pazopanib, eribulin, aldoxorubicin and regorafenib are other options for use in advanced STS. PMID- 29768051 TI - The key role of pathology, surgery and radiotherapy in the initial management of soft tissue sarcoma. AB - Soft tissue sarcomas are a heterogeneous group of rare malignancies. The diagnostic gold standard is conventional histomorphology with integrated immunohistochemistry. Molecular genetic profiling has identified new subgroups of undifferentiated sarcomas involving genetic rearrangements with creation of fusion genes. Accurate classification of sarcomas is critical for appropriate clinical decision-making which should involve a multidisciplinary team. A preoperative biopsy is necessary to confirm a diagnosis. Strategy is discussed in the multidisciplinary board. Reconstructive surgery must be planned in advance taking into account possible surgical morbidity. In high-risk situations, neo adjuvant treatment could facilitate surgery in some cases, increase survival and provide indications of tumor biology. The decision is based on tumor subtype, grade and location, patient age and presence of comorbidities. PMID- 29768052 TI - Options for treating different soft tissue sarcoma subtypes. AB - Management of soft tissue sarcoma is increasingly subtype-dependent. Surgery is recommended for uterine leiomyosarcoma, with trabectedin being the preferred option for advanced disease when the treatment goal is long-term tumor stabilization. Liposarcoma subgroups are characterized by distinctive morphologies and genetics, different patterns of disease progression and clinical behavior, and variable responses to treatment. Genetic analysis of sarcomas has provided insights into pathogenesis with potential for developing new molecular targets. At the cytogenetic level, soft tissue sarcomas are categorized into specific, balanced translocations and those due to massive chromosomal rearrangements. For subtypes such as undifferentiated sarcomas, angiosarcomas, alveolar soft part sarcomas and clear cell sarcomas, evidence is especially limited, although it is known that these tumors display markedly different sensitivities to chemotherapeutic and targeted agents. PMID- 29768054 TI - Assessment and the Journal of Clinical Child and Adolescent Psychology's Evidence Base Updates Series: Evaluating the Tools for Gathering Evidence. AB - In 2014, Michael Southam-Gerow and Mitch Prinstein launched the Evidence Base Updates series. As invited contributors, authors of Evidence Base Updates articles offer the field an invaluable resource: regular evaluations of the latest data on tools for addressing the mental health needs of children and adolescents. Until now, authors of Evidence Base Updates articles have focused exclusively on evaluating treatment techniques. In this article, we outline how the Evidence Base Updates series will evolve to also include evaluations of assessment techniques. In our treatment-focused updates, contributors follow strict criteria when evaluating the evidence. Following these criteria allows authors of Evidence Base Updates articles to provide mental health professionals with clear "take-home messages" about the evidence underlying the treatments evaluated. Similarly, we outline the criteria that authors will follow when preparing Evidence Base Updates articles that evaluate assessments. We also highlight the formats of these articles, which will include evaluations of condition-focused measures (e.g., anxiety, conduct problems); transdiagnostic constructs (e.g., parenting, rumination); specific, widely used measures that cut across conditions; and updates on field-wide considerations regarding measurement (e.g., clinical utility, incremental validity). PMID- 29768053 TI - Quality of life and patients' expectations in soft tissue sarcoma. AB - Assessment of health-related quality of life (HRQoL) is essential for holistic care. Greater efforts are required to incorporate HRQoL measures into clinical trials and daily practice. Considerable HRQoL data are available for localized soft tissue sarcomas (STS), particularly in the orthopedic setting. In future, HRQoL is expected to become increasingly important in the evaluation of palliative therapy in advanced STS. A patient-centric approach is advocated for STS management. Greater awareness of STS by nonspecialist clinicians, and timely referral to specialized sarcoma reference centers, is crucial for patient welfare. The patient is central to shared decision-making during consultations and during case review in tumor boards. The management approach to STS should be collaborative, involving a multidisciplinary team, multiple centers and patient advocacy groups. PMID- 29768055 TI - Age-related effect of aerobic exercise training on antioxidant and oxidative markers in the liver challenged by doxorubicin in rats. AB - The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise + doxorubicin, and aerobic exercise + saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20 mg kg-1 while the aerobic exercise + saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers. PMID- 29768056 TI - Presentation and prognosis of liver disease in alpha-1 antitrypsin deficiency. PMID- 29768057 TI - Nocebo effects: more investigation is needed. PMID- 29768058 TI - Taishan Pinus massoniana Pollen Polysaccharides Enhance Immune Responses in Chickens Infected by Avian Leukosis Virus Subgroup B. AB - Immunosuppressive virus, which can cause suppressed immunity and vaccination failure, frequently occurs in chicken flocks and seriously destroys the poultry industry. Our previous studies have reported that Taishan Pinus massoniana pollen polysaccharide (TPPPS) possess immunomodulatory effects and improve the immune effects of vaccines. In this study, avian leukosis virus subgroup B (ALV-B) was chosen as immunosuppressive virus to artificially establish immunosuppressive models in chickens, and the immune modulatory ability of TPPPS on the immune response of chickens was evaluated. Four randomly assigned groups (Group I-IV) of these immunosuppressed chickens were administered with TPPPS at doses of 0, 100, 200, and 400 mg/kg (every kilogram chick), respectively. Group V was administered with saline as control. At seven day old, 10 chickens randomly selected from Group I-V were inoculated with the attenuated Newcastle disease (ND) vaccine. The results showed that during the monitoring period, TPPPS significantly enhanced weight of immune organs, peripheral lymphocyte proliferation, the percentage of CD4+ and the ratio of CD4+/CD8+, IL-2 and IFN-gamma production, and ALV-B antibody positive rate of chickens in a dose-dependent manner, with 400 mg/kg TPPPS being the most effective. In addition, the antibody titer against Newcastle disease virus (NDV) in Group IV with 400 mg/kg was significantly higher than those in other groups. We observed the stronger immunity in the TPPPS group, which indicates that TPPPS could be used as an immunoenhancer to relieve immunosuppression caused by ALV-B in the poultry industry. PMID- 29768060 TI - Seek and destroy: improving PK/PD profiles of anticancer agents with nanoparticles. AB - INTRODUCTION: The Pharmacokinetics/pharmacodynamics (PK/PD) relationships with cytotoxics are usually based on a steepening concentration-effect relationship; the greater the drug amount, the greater the effect. The Maximum Tolerated Dose paradigm, finding the balance between efficacy, while keeping toxicities at their manageable level, has been the rule of thumb for the last 50-years. Developing nanodrugs is an appealing strategy to help broaden this therapeutic window. The fact that efficacy and toxicity with cytotoxics are intricately linked is primarily due to the complete lack of specificity toward the tumor tissue during their distribution phase. Because nanoparticles are expected to better target tumor tissue while sparing healthy cells, accumulating large amounts of cytotoxics in tumors could be achieved in a safer way. Areas covered: This review aims at presenting how nanodrugs present unique features leading to reconsidering PK/PD relationships of anticancer agents. Expert commentary: The constant interplay between carrier PK, interactions with cancer cells, payload release, payload PK, target expression and target engagement, makes picturing the exact PK/PD relationships of nanodrugs particularly challenging. However, those improved PK/PD relationships now make the once contradictory higher efficacy and lower toxicities requirement an achievable goal in cancer patients. PMID- 29768062 TI - Pocket colposcope: could it improve attendance and increase access to cervical cancer screening programmes? PMID- 29768061 TI - Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma. AB - Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7 dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted. PMID- 29768063 TI - Overexpression of HOXC10 promotes glioblastoma cell progression to a poor prognosis via the PI3K/AKT signalling pathway. AB - OBJECTIVE: The HOX gene is expressed in neoplasias occurred in multiple tissues, such as the colon, lung and breast. However, the effects of the HOX gene on glioblastoma (GBM) remain poorly understood. We examined HOXC10 expression in GBM tissues and cells, analysed its effect on GBM prognosis, and finally assessed its possible underlying mechanisms in this study. METHODS: HOXC10 expression levels and its prognostic effects on GBM tissues were analysed based on The Cancer Genome Atlas (TCGA) and ONCOMINE database. Overall survival (OS) analysis was performed using the Kaplan-Meier method and log rank test. Then, the expression of HOXC10 was detected in four GBM cell lines using quantitative real-time reverse transcription-PCR (qRT-PCR). In addition, small interfering RNA (si-RNA) was utilised in the U87 cell line with the highest HOXC10 expression to facilitate subsequent in vitro cell experiment. Cell proliferation, migration and invasion were assessed using the Cell Counting Kit-8 (CCK-8) and colony formation assay, wound healing, Transwell assay, respectively in GBM U87 cell after HOXC10 knockdown. Key proteins related to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signalling pathway were measured by western blotting. RESULTS: HOXC10 expression was significantly increased in GBM tissues and cell lines, leading a poor OS in GBM patients. Knockdown of HOXC10 could inhibit the GBM U87 cells proliferation, migration and invasion, as well as decreased expression levels of key proteins in PI3K/AKT signalling pathway. CONCLUSION: HOXC10 was overexpressed in GBM tissues and cells, and associated with poor prognosis in GBM patients. Moreover, HOXC10 knockdown inhibited U87 cell proliferation, migration and invasion, which were potentially related to PI3K/AKT signalling pathway activation. Our findings revealed that HOXC10 represent a promising biological target for GBM treatment in the future. PMID- 29768064 TI - A look at treatment strategies for relapsed multiple myeloma. AB - INTRODUCTION: Multiple myeloma treatment considerably improved during the past decade, thanks to novel effective drugs, a better understanding of myeloma biology and clonal heterogeneity, and an improved management of toxicities. The choice of regimen at relapse is usually based on prior response, toxicities, age and comorbidities of relapsed patients. Areas covered: A review was performed of the most recent and effective therapeutic strategies for the relapsed myeloma setting, by documenting the latest clinical evidence from phase II and III clinical trials. Of note, new drugs, such as carfilzomib, ixazomib, pomalidomide, daratumumab and elotuzumab, alone or in combinations in doublet or triplet regimens, have greatly increased the treatment armamentarium against myeloma. Expert commentary: Impressive results have been obtained with new drugs in relapsed patients. Besides number of prior therapies and previous response, other factors play a crucial role in the selection of therapy. Re-challenge with previous drugs can be adopted if previous responses lasted at least 6 months and therapy had induced low toxicity. Patients' risk status can further help to appropriately select therapy at relapse, and clinical trials will allow physicians to use newer targeted therapies and immune-therapies, thus delaying palliative approaches to later relapse stages. PMID- 29768059 TI - Pentabromopseudilin: a myosin V inhibitor suppresses TGF-beta activity by recruiting the type II TGF-beta receptor to lysosomal degradation. AB - Pentabromopseudilin (PBrP) is a marine antibiotic isolated from the marine bacteria Pseudomonas bromoutilis and Alteromonas luteoviolaceus. PBrP exhibits antimicrobial, anti-tumour, and phytotoxic activities. In mammalian cells, PBrP is known to act as a reversible and allosteric inhibitor of myosin Va (MyoVa). In this study, we report that PBrP is a potent inhibitor of transforming growth factor-beta (TGF-beta) activity. PBrP inhibits TGF-beta-stimulated Smad2/3 phosphorylation, plasminogen activator inhibitor-1 (PAI-1) protein production and blocks TGF-beta-induced epithelial-mesenchymal transition in epithelial cells. PBrP inhibits TGF-beta signalling by reducing the cell-surface expression of type II TGF-beta receptor (TbetaRII) and promotes receptor degradation. Gene silencing approaches suggest that MyoVa plays a crucial role in PBrP-induced TbetaRII turnover and the subsequent reduction of TGF-beta signalling. Because, TGF-beta signalling is crucial in the regulation of diverse pathophysiological processes such as tissue fibrosis and cancer development, PBrP should be further explored for its therapeutic role in treating fibrotic diseases and cancer. PMID- 29768066 TI - Evaluation of long pulsed Nd-YAG laser in the treatment of onychomycosis. PMID- 29768065 TI - Fibroblast growth factor 21, adiposity, and macronutrient balance in a healthy, pregnant population with overweight and obesity. AB - AIM OF THE STUDY: The regulation and actions of fibroblast growth factor 21 (FGF21) are responsive to energy status and macronutrient balance, and investigations of FGF21 in normal pregnancy, which could be informative for FGF21 biology, are seldom. The goal of our study was to examine FGF21 levels in a contemporary healthy, pregnant population. METHODS: We phenotyped 43 women with overweight and obesity during pregnancy for weight, body composition, and fasting blood. Serum FGF21 was measured during the first and third trimesters. Placentas were collected at delivery. RESULTS: Maternal FGF21 concentrations were positively correlated with body mass index and adiposity, but not lean mass or glucose homeostasis. FGF21 concentrations significantly increased from the first to third trimester of pregnancy (0.105 vs. 0.256 ng/mL, p < 0.0001). Changes in FGF21 concentrations across pregnancy were not associated with changes in body weight or composition but inversely with the change in fasting glucose. FGF21 mRNA levels in placenta were very low and do not likely contribute to FGF21 in the maternal circulation. CONCLUSIONS: FGF21 increases throughout pregnancy in our healthy cohort with overweight and obesity, independent of the placenta, and does not appear to be sensing the changes in energy balance (reflected in the change in maternal energy stores), but changes in macronutrient status. Thus, we propose FGF21 may be a potential signal of maternal nutrient status in pregnancy. PMID- 29768067 TI - The development of fluorescence guided surgery for pancreatic cancer: from bench to clinic. AB - INTRODUCTION: Surgeons face major challenges in achieving curative R0 resection for pancreatic cancers. When the lesion is localized, they must appropriately visualize the tumor, determine appropriate resection margins, and ensure complete tumor clearance. Real-time surgical navigation using fluorescence-guidance has enhanced the ability of surgeons to see the tumor and has the potential to assist in achieving more oncologically complete resections. When there is metastatic disease, fluorescence enhancement can help detect these lesions and prevent unnecessary and futile surgeries. Areas covered: This article reviews different approaches for delivery of a fluorescence signal, their pre-clinical and clinical developments for fluorescence guided surgery, the advantages/challenges of each, and their potential for advancements in the future. Expert commentary: A variety of molecular imaging techniques are available for delivering tumor-specific fluorescence signals. Significant advancements have been made in the past 10 years due to the large body of literature on targeted therapies and this has translated into rapid developments of tumor-specific probes. PMID- 29768068 TI - Population-level study links short-wavelength nighttime illumination with breast cancer incidence in a major metropolitan area. AB - Several population-level studies revealed a positive association between breast cancer (BC) incidence and artificial light at night (ALAN) exposure. However, the effect of short-wavelength illumination, implicated by laboratory research and small-scale cohort studies as the main driving force behind BC-ALAN association, has not been supported by any population-level study carried out to date. We investigated a possible link between BC and ALAN of different subspectra using a multi-spectral year-2011 satellite image, taken from the International Space Station, and superimposing it with year-2013 BC incidence data available for the Great Haifa Metropolitan Area in Israel. The analysis was performed using both ordinary least square (OLS) and spatial dependency models, controlling for socioeconomic and locational attributes of the study area. The study revealed strong associations between BC and blue and green light subspectra (B = 0.336 +/- 0.001 and B = 0.335 +/- 0.002, respectively; p < 0.01), compared to a somewhat weaker effect for the red subspectrum (B = 0.056 +/- 0.001; p < 0.01). However, spatial dependency models, controlling for spatial autocorrelation of regression residuals, confirmed only a positive association between BC incidence and short wavelength (blue) ALAN subspectrum (z = 2.462, p < 0.05) while reporting insignificant associations between BC and either green (z = 1.425, p > 0.1) or red (z = -0.604, p > 0.1) subspectra. The obtained result is in line with the results of laboratory- and small-scale cohort studies linking short-wavelength nighttime illumination with circadian disruption and melatonin suppression. The detected effect of blue lights on BC incidence may help to develop informed illumination policies aimed at minimizing the adverse health effects of ALAN exposure on human health. PMID- 29768069 TI - Analyzing Trend for U.S. Immigrants' e-Health Engagement from 2008 to 2013. AB - Our study examines the trend of U.S. immigrants' engagement in various e-health activities and how immigrants' use of e-health technologies is associated with their cultural characteristics over years. Aggregating three national representative samples of U.S. immigrants from the Health Information National Trends Survey (HINTS) conducted between 2008 and 2013, our results from trend analyses and logistic regressions revealed that the U.S. immigrants exhibited an increasing trend on two types of e-health engagement: tracking personal health information online and communicating with a doctor online. But we did not find any significant change in the other two e-health activities throughout these years: the percentage of immigrants who sought a health provider online remained moderate (about 37%), whereas the percentage of immigrants who joined an online support group kept low (about 5%). Furthermore, immigrants of different race/ethnicity or length of residence in the United States showed different trends of e-health engagement. Asian immigrants and immigrants with 13-34 years of residence were more proactive to engage in various e-health activities. Our study informs the practice aiming to enhance U.S. immigrants' Internet use for better health-related outcomes. PMID- 29768070 TI - Web-Based Intervention to Reduce Substance Abuse and Depression: A Three Arm Randomized Trial in Mexico. AB - BACKGROUND: Web-based cognitive-behavioral interventions to reduce substance use can be a useful low-cost treatment for a large number of people, and an attractive option in countries where a greater availability of treatment is needed. OBJECTIVE: To evaluate the feasibility and initial effectiveness of a web based cognitive-behavioral intervention for the reduction of substance use and depression compared with treatment as usual, with and without a printed self-help manual. METHOD: Individuals seeking outpatient treatment for substance use were randomly assigned to one of the following: (1) the web-based Help Program for Drug Abuse and Depression (n = 23); (2) an in-person session with an addiction therapist and use of the Alcohol, Smoking, and Substance Involvement Screening Test Self-Help Strategies guide, followed by treatment as usual (n = 25), or (3) treatment ordinarily offered in the participating treatment centers (n = 26). The study took place in 2013-2014 (trial registration: ISRCTN25429892), and participants completed baseline, posttreatment, and 1-month follow-up evaluation interviews. RESULTS: Treatment retention and data availability were comparable in all three conditions. A reduction was observed from baseline to follow-up in average days of use [F(1,28) = 29.70, p < 0.001], severity of use [F(2,28) = 143.66, p < 0.001], and depressive symptomatology [F = (4)16.40, p < 0.001], independent of the type of treatment provided. CONCLUSIONS: The findings suggest that the web-based intervention to reduce substance abuse is feasible, although it is not more effective than other intervention modalities; its effectiveness must be evaluated in a larger sample. Attrition was a main limitation; future studies must improve retention and assess cost-effectiveness. PMID- 29768071 TI - Student mental health: some answers and more questions. PMID- 29768072 TI - An Integrated, Developmental Four-Year Medical School Curriculum in Palliative Care: A Longitudinal Content Evaluation Based on National Competency Standards. AB - BACKGROUND: While palliative care (PC) competencies for medical school graduates have been defined, the lack of established curriculum models and assessment tools hampers curricular evaluation. OBJECTIVE: To describe the scope and content of the University of Rochester's longitudinal, integrated four-year PC curriculum after 17 years of implementation, review student evaluative responses, and compare the curriculum to national competency standards. DESIGN AND SETTING: Combining and reorganizing a published PC curriculum assessment tool and a list of medical school PC competencies, we created a novel nine-topic framework to assess the content coverage of our curriculum. We queried our electronic medical school curriculum database and surveyed course and clerkship directors, as well as PC, pain, ethics, and humanities faculty, to locate where and when PC topics are taught and to collate student responses to these experiences. RESULTS: We present a comprehensive list of PC curricular activities over a four-year medical school experience. The curriculum covers all nine PC topics longitudinally in multiple formats. Five in-depth activities cover multiple PC topics in a format that integrates biological, psychological, and social dimensions; these activities have survived and evolved over 17 years in our setting. A majority of year 3 University of Rochester students feel "well" or "extremely well" trained in PC. CONCLUSIONS: Our four-year PC curriculum provides robust and developmentally appropriate training that addresses all nine evidence-based core topics for PC education. Medical student feedback and their Association of American Medical Colleges (AAMC) survey responses suggest that they find their PC learning experiences rewarding. This curriculum could serve as a model for other schools. PMID- 29768073 TI - An open-label non-randomized prospective pilot study of the efficacy of Q switched Nd-YAG laser in management of facial lichen planus pigmentosus. AB - Lichen planus pigmentosus (LPP) is a cosmetically disfiguring condition. Many treatment options are available which are effective in halting the progression of the disease. The treatment of persistent pigmentation is still a challenge. We describe the use of Q-switched Nd-YAG laser in 13 patients with stable LPP using a standard protocol. Most of our patients showed complete to near-complete resolution of pigment without much complications. PMID- 29768074 TI - Cancer Treatment and End-of-Life Care. AB - AIM: To study to what extent tumor-specific treatment (chemo- or radiotherapy) was given during the last 30 days in life and to examine how many of the patients were referred to a specialized palliative care unit (PCU), at a low-resource governmental hospital in India. PATIENTS AND METHODS: Medical records of adult cancer patients deceased between April 1 and May 31 in 2016, and pediatric cancer patients deceased between April 1 and September 30 in 2016 were collected. Data regarding gender, age at admission, cancer diagnosis, tumor-specific treatment received, referral to the PCU, and date of death, were sampled. RESULTS: A total of 96 patients (52 adults and 44 pediatric patients) were included in the study. In the last 30 days of life, tumor-specific treatment was given to 39 adult patients and 38 pediatric patients. During the last week in life, 26 adult and 25 pediatric patients, respectively, received tumor-specific treatment. Twenty-six adult and 25 pediatric patients, respectively, were referred to the PCU. End-of life (EoL) tumor therapy was given to a lesser extent among referred patients. CONCLUSIONS: Eighty percent of the patients were given tumor-specific treatment near EoL. Half of the patients had been referred for specialized palliative care (SPC). PMID- 29768075 TI - Evaluating mice lacking serum carboxylesterase as a behavioral model for nerve agent intoxication. AB - Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure. No expression differences were detected between Es1 KO and WT mice in more than 34 000 mouse genes tested. There was a significant difference between Es1 KO and WT mice in MLD values, as the MLD for GD-exposed WT mice was significantly higher than the MLD for GD-exposed Es1 KO mice. Behavioral assessments of Es1 KO and WT mice included an open field test, a zero maze, a Barnes maze, and a sucrose preference test (SPT). While sex differences were observed in various measures of these tests, overall, Es1 KO mice behaved similarly to WT mice. The two genotypes also showed virtually identical neuropathological changes following GD exposure. Es1 KO mice appear to have an enhanced susceptibility to GD toxicity while retaining all other behavioral and physiological responses to this nerve agent, making the Es1 KO mouse a more human-like model for nerve agent research. PMID- 29768076 TI - Depressive Symptoms and Quality of Life Among Adolescent and Young Adult Cancer Survivors: Impact of Gender and Latino Culture. AB - Ethnic and sex variations in depressive symptoms and quality of life (QOL) among adolescent and young adult (AYA) childhood cancer survivors were explored among a sample of Latino and non-Latino childhood cancer survivors (CCSs) (n = 194) treated at hospitals in Los Angeles County. Latinos scored higher in depressive symptoms and lower in QOL when compared with non-Latinos. Males had higher depressive symptoms. Among Latinos, higher levels of acculturation were associated with depression and a poorer QOL, and we found that more acculturated Latino males were more likely to have meaningful levels of depression than less acculturated males or females. Interventions addressing depressive symptoms may be most needed for Hispanic male CCSs. PMID- 29768077 TI - Strategy to Address Private Location Cardiac Arrest: A Public Safety Survey. AB - OBJECTIVE: Most cardiac arrests occur in the private setting where response is often delayed and outcomes are poor. We surveyed public safety personnel to determine if they would volunteer to respond into private locations and/or be equipped with a personal automated external defibrillator (AED) as part of a vetted responder program that would use smart geospatial technology. METHODS: We conducted an anonymized survey among personnel from fire-based emergency medical services (EMS) and search and rescue organizations from Washington State. The goal of the survey was to evaluate whether there was interest among cardiopulmonary resuscitation (CPR)-trained, public safety personnel to respond with or without an AED to private-residence cardiac arrest outside of working hours using a smartphone platform. We used a 5-point Likert scale to assess responses. RESULTS: Overall the response rate was 73.7% (527/715). Two-thirds of respondents were between the ages of 30-59 with a similar proportion certified as a firefighter-emergency medical technician (EMT). Most were male (80%). As a vetted volunteer responder, the majority would "almost always" or "often" respond to private (79.7%) or public locations (85.2%) outside of work hours. The majority (54.1%) would store the AED in their vehicle while 38% would plan to keep the AED on their person. A total of 83% were "definitely' or "probably interested" in participating in the program. CONCLUSION: The results of this survey indicate that public safety personnel are willing to respond to suspected cardiac arrest during off-hours using geospatial smart technology to private locations with or without an AED. PMID- 29768078 TI - Wet-wrap therapy with halometasone cream for severe adult atopic dermatitis. AB - BACKGROUND: Currently there is no cure for severe atopic dermatitis (AD). Wet wrap therapy (WWT) has also been used to treat pediatric AD and shown a satisfactory effectiveness, but clinical evidence supporting the use of WWT on severe adult AD is still insufficient. METHODS: Twelve patients (eight men and four women) with severe AD (SCORing Atopic Dermatitis [SCORAD] score >= 50) treated between January 2015 and September 2017 in our hospital were included. The patients underwent WWT (daily dose: 15 g halometasone cream+100g Vaseline ointment) twice daily for 2 h/session for 7 days. SCORAD, visual analog scale (VAS) for pruritus, investigator's global assessment (IGA), dermatology life quality index (DLQI) scores and serum cortisol levels were determined before and after the WWT. RESULTS: The patients (mean age: 58.9 +/- 18.9 years; range: 27-85 years) had a median disease duration of 27.5 months. After the WWT, the average scores of SCORAD (28.79 +/- 5.16 vs. 68.59 +/- 8.61, 95%CI: 35.18-44.42), VAS (2.75 +/- 0.62 vs. 7.5 +/- 1.17, 95%CI: 4.14-5.36), IGA (1.83 +/- 0.39 vs. 4.08 +/- 0.51, 95%CI: 1.96-2.54), and DQLI score (8.33 +/- 1.83 vs. 13.83 +/- 2.79, 95%CI: 4.16-6.84) reduced significantly compared with the scores before the WWT (All P < 0.001). However, serum cortisol levels were not affected significantly by the WWT. Four patients complained of tolerable wet dressing-associated discomforts, which was resolved after the wet dressing was removed when the WWT was completed. For the 85-year-old man, serum cortisol levels were lower than the normal value after the WWT (3.67 MUg/dL) but restored to the normal levels (13.44 MUg/dL) 2 weeks after the WWT was ended. No other adverse events occurred. CONCLUSION: WWT can relieve pruritus, reduce skin lesions, and improve quality of life in adult patients with severe AD. Thus, WWT may be effective and safe for severe adult AD. Trial registration No. is ChiCTR1800014909 ( http://www.chictr.org.cn/index.aspx ). PMID- 29768080 TI - Effects of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. AB - 1. This study investigates the influence of quercetin on the pharmacokinetics of losartan and its metabolite EXP3174 in rats. 2. The pharmacokinetic profiles of losartan and EXP3174 of orally administered losartan (10 mg/kg) with or without pretreatment with quercetin (20 mg/kg/day for 7 days) were investigated. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. 3. The results showed that when the rats were pretreated with quercetin, the Cmax (2.16 +/- 0.40 vs. 1.33 +/- 0.21 mg/L) and the AUC(0-t) (13.89 +/- 1.22 vs. 7.34 +/- 0.75 mg.h/L) of losartan increased significantly (p < .05), and while the Cmax (0.76 +/- 0.09 vs. 1.14 +/- 0.18 mg/L) of EXP3174 decreased significantly compared to the control (p < .05). The t1/2 of losartan was prolonged from 3.27 +/- 0.45 h to 4.74 +/- 0.51 h (p < .05). The results also indicated that quercetin could increase losartan absorption rate by inhibiting the activity of P gp and decrease its metabolic stability by inhibiting the activity of CYP450 enzyme. 4. These results indicated that the herb-drug interaction between quercetin and losartan might occur when they are co-administered in rats, quercetin could increase the systemic exposure of losartan and decrease the plasma concentration of EXP3174, possibly by inhibiting the activity of P-gp or CYP450 enzyme. PMID- 29768079 TI - The Spectrum of Surgical Remediation of Transoral Incisionless Fundoplication Related Failures. AB - AIM: To evaluate outcomes of surgical remediation for symptomatic or anatomic failure after a transoral incisionless fundoplication (TIF). METHODS: This retrospective study was performed on 11 patients who underwent a remedial operation following TIF failure between June 2011 and September 2016 at the Mayo Clinic in Florida for persistent foregut symptoms. Upper gastrointestinal workup characterized 1 patient as having normal post-TIF anatomy and 10 as having anatomic failure. Ambulatory pH testing was performed in 7 patients and was abnormal in all. All patients underwent a laparoscopic takedown of the prior endoscopic fundoplication and removal of all accessible polypropylene T fasteners. RESULTS: All patients had esophageal salvage and have not required a reoperation. Anatomical findings included hiatal hernia (7), esophageal diverticulum (2), hiatal mesh erosion of esophagus (1), long-segment esophageal stricture (1), and normal anatomy (1). Remedial operations included laparoscopic explant of fasteners in all patients with conversion to fundoplication (7), resection/imbrication of esophageal diverticulum (2), Heller myotomy (1), and mesh explant and complex esophageal repair (1). Mean operative time was 177 minutes and median length of stay 3 days (range 2-13 days). At mean follow-up of 10.7 months (range 1-42 months), 7 patients had persistent complaints. Esophagogastroduodenoscopy was repeated in these 7 patients and was normal (n = 3), mild stenosis requiring dilation (n = 2), Los Angeles grade B esophagitis (n = 1), and Barrett's esophagus (n = 1). CONCLUSION: Anatomic distortion of the distal esophagus after TIF can be significant, making subsequent operations complex. After remedial surgery, few patients will continue to have troublesome symptoms such as dysphagia. PMID- 29768082 TI - Mary Jane Hogue (1883-1962): A pioneer in human brain tissue culture. AB - The ability to maintain human brain explants in tissue culture was a critical step in the use of these cells for the study of central nervous system disorders. Ross G. Harrison (1870-1959) was the first to successfully maintain frog medullary tissue in culture in 1907, but it took another 38 years before successful culture of human brain tissue was accomplished. One of the pioneers in this achievement was Mary Jane Hogue (1883-1962). Hogue was born into a Quaker family in 1883 in West Chester, Pennsylvania, and received her undergraduate degree from Goucher College in Baltimore, Maryland. Research with the developmental biologist Theodor Boveri (1862-1915) in Wurzburg, Germany, resulted in her Ph.D. (1909). Hogue transitioned from studying protozoa to the culture of human brain tissue in the 1940s and 1950s, when she was one of the first to culture cells from human fetal, infant, and adult brain explants. We review Hogue's pioneering contributions to the study of human brain cells in culture, her putative identification of progenitor neuroblast and/or glioblast cells, and her use of the cultures to study the cytopathogenic effects of poliovirus. We also put Hogue's work in perspective by discussing how other women pioneers in tissue culture influenced Hogue and her research. PMID- 29768081 TI - Unremarkable impact of Oatp inhibition on the liver concentration of fluvastatin, lovastatin and pitavastatin in wild-type and Oatp1a/1b knockout mouse. AB - 1. Oatp inhibitors have been shown to significantly increase the plasma exposure of statins. However, understanding alterations of liver concentration is also important. While modeling has simulated liver concentration changes, availability of experimental data is limited, especially when concerning drug-drug interactions (DDI). The objective of this work was to determine blood and liver concentrations of fluvastatin, lovastatin and pitavastatin, when blocking uptake transporters. 2. In wild-type mouse, rifampin pre-treatment decreased the unbound liver-to-plasma ratio (Kp,uu) of fluvastatin by 4.2-fold to 2.2, lovastatin by 4.9-fold to 0.81 and pitavastatin by 10-fold to 0.21. Changes in Kp,uu were driven by increases in systemic exposures as liver concentrations were not greatly altered. 3. In Oatp1a/1b knockout mouse (KO), rifampin exerted no additional effect on fluvastatin and lovastatin. Contrarily, rifampin further decreased pitavastatin Kp,uu by 3.4-fold, suggesting that the KO is inadequate to completely block liver uptake of pitavastatin as there are additional rifampin sensitive uptake mechanism(s) not captured in the KO model. 4. This work provides experimental data showing that the plasma compartment is more sensitive to Oatp modulation than the liver compartment, even for rifampin-mediated DDI. Consistent with previous simulations, inhibiting or targeting Oatps may change Kp,uu, but exhibit only a minimal effect on absolute liver concentrations. PMID- 29768083 TI - Sebo-pharmacokinetics: a proposed percutaneous sebum egression method. AB - BACKGROUND/AIMS: The sebaceous gland is widely believed a critical factor in the pathogenesis of acne vulgaris. Although extensive studies document the ability of oral and topical treatments to improve acne, little is known about the quantification and mechanism of drug delivery via the sebaceous gland. A percutaneous egression method presents a way to study how drugs reaching the bloodstream can enter the skin. METHODS: A literature search was performed across databases (PubMed, Embase, and Google Scholar) and the University of California, San Francisco (UCSF) textbook library with relevant search terms. RESULTS: This search failed to reveal data on sebo-pharmacokinetics (PK); however, many articles center on pharmacodynamics (PD) - i.e. functional improvement instigated by oral or topical treatments. Experiments on humans and hamsters - representative sebaceous gland models - demonstrate indirect PD measures of sebaceous gland function. DISCUSSION: Here, we summarize the current available data on drug delivery via the sebaceous gland and suggest a practical method to directly document sebo-PK in man and animal. PMID- 29768084 TI - Effect of Phototherapy on Masseter and Anterior Temporal Muscles Before Induction of Fatigue: A Randomized, Sham-Controlled, Blind Clinical Trial. AB - OBJECTIVE: This is a randomized, sham-controlled, blind clinical trial that aimed to evaluate the effect of phototherapy on bite force, mandibular range of motion, sensitivity to palpation, and fatigue in the masseter and anterior temporal muscles of young patients when administered before the induction of fatigue. MATERIALS AND METHODS: Fifty-two healthy volunteers aged 18-23 years were randomly allocated to a laser group and sham group. Both groups were submitted to a clinical evaluation to record mandibular range of motion, bite force, muscle sensitivity to palpation, and muscle fatigue. The laser group was then submitted to phototherapy (780 nm, 25 J/cm2, 50 mW, 20 sec, and 1 J per point) on three points of the masseter and one point of the anterior temporal muscle on each side. The sham group was submitted to the same procedure, but with the device switched off. The volunteers were then instructed to chew two pieces of gum (one on each side) for 6 min, with the pace set by a metronome calibrated to 80 bpm, followed by the reevaluation of all variables. The results were submitted to t test and Wilcoxon test. A significance level of 5% (p < 0.05) was considered in all analyses. RESULTS: No statistically significant intergroup or intragroup differences were found for the variables analyzed. CONCLUSIONS: With the proposed protocol, phototherapy administered before the induction of fatigue did not lead to any changes in bite force and mandibular range of motion, indicating that further studies are needed with different phototherapy dosimetric parameters. PMID- 29768087 TI - Corrigendum. PMID- 29768086 TI - Visual associations to retrieve episodic memory across healthy elderly, mild cognitive impairment, and patients with Alzheimer's disease. AB - Episodic memory tests need to determine the degree to which patients with moderate to severe memory deficits can still benefit from retrieval support. Especially in the case of Alzheimer's disease (AD), this may support health care to be more closely aligned with patients' memory capacities. We investigated whether the different measures of episodic memory of the Visual Association Test Extended (VAT-E) can provide a more detailed and informative assessment on memory disturbances across a broad range of cognitive decline, from normal to severe impairment as seen in AD, by examining differences in floor effects. The VAT-E consists of 24 pairs of black-and-white line drawings. In a within-group design, we compared score distributions of VAT-E subtests in healthy elderly controls, mild cognitive impairment (MCI), and AD (n = 144), as well as in relation to global cognitive impairment. Paired associate recall showed a floor effect in 41% of MCI patients and 62% of AD patients. Free recall showed a floor effect in 73% of MCI patients and 84% of AD patients. Multiple-choice cued recognition did not show a floor effect in either of the patient groups. We conclude that the VAT-E covers a broad range of episodic memory decline in patients. As expected, paired associate recall was of intermediate difficulty, free recall was most difficult, and multiple-choice cued recognition was least difficult for patients. These varying levels of difficulty enable a more accurate determination of the level of retrieval support that can still benefit patients across a broad range of cognitive decline. PMID- 29768088 TI - Foot and ankle joint movements of dancers and non-dancers: a comparative study. AB - Ballerinas use their ankle joints more extremely and sustain injuries on the ankle joint more frequently than non-dancers. Therefore, the ankle movement of dancers is important and should be studied to prevent injuries. Measuring ankle joint range of motion (ROM) using radiographs could demonstrate the contribution to motion of each joint. The aim of this study was to analyse and compare ankle joint movements and the ratio of each joint's contribution during movement between dancers and non-dancers, using radiographic images. Dancers have lower dorsiflexion (26.7 +/- 6.2 degrees ), higher plantarflexion (74.3 +/- 7.1 degrees ) and higher total (101.1 +/- 10.8 degrees ) ROMs than non-dancers (33.9 +/- 7.0 degrees , 57.2 +/- 6.8 degrees and 91.1 +/- 9.3 degrees , respectively) (p < 0.05). Although the ROMs were different between the two groups, the ratios of each joint movement were similar between these two groups, in all movements. Regarding total movement, the movement ratio of the talocrural joint was almost 70% and other joints accounted for almost 30% of the movement role in both dancers and non-dancers. Therefore, the differences in ROM between dancers and non-dancers were not a result of a specific joint movement but of all the relevant joints' collaborative movement. PMID- 29768089 TI - Commentary on: "Effects of Regular Physical Activity on the Cognitive Performance of Type 2 Diabetic Patients: A Systematic Review" by Podolski et al. (Metab Syndr Relat Disord 2017;15:481-493). AB - Type 2 diabetes mellitus (T2DM) imparts an increased risk for cognitive decline, specifically executive function, which is important to maintain for diabetes self management. There is evidence to suggest that exercise improves cognition in healthy older adults; however, the literature in adults with T2DM is lacking. This commentary is in complement to Podolski et al.'s systematic review evaluating the effects of physical activity on cognitive function in adults with T2DM. We have included eight additional studies and further highlight their conclusions on the heterogeneity of the literature thus far. Three current issues with the literature are as follows: (1) variability in interventions (e.g., aerobic, resistance, lifestyle, and yoga), (2) variability in cognitive outcome measures, and (3) lack of detailed description of the population studied, for example, baseline glycated hemoglobin (A1C) values. Overall, making it difficult to compare these studies and draw final conclusions. Thus, the efficacy for exercise to improve cognition in adults with T2DM is not yet well understood. Potential ways to mitigate these limitations could be for future studies that (1) use robust methodology whenever possible, that is, randomized controlled trials, (2) to follow current guideline-derived exercise recommendations for adults with T2DM, and (3) utilize cognitive outcome measures that are consistent across studies. The hope is that these consistencies in turn will help to determine the efficacy of exercise on cognitive function in adults with T2DM and therefore, allow national organizations to develop recommendations and guidelines for healthcare practitioners to follow. PMID- 29768090 TI - Kinematic differences in upper limb joints between flat and topspin forehand drives in competitive male tennis players. AB - The topspin tennis forehand drive has become a feature of modern game; yet, as compared to the serve, there has been little research analysing its kinematics. This is surprising given that there is considerably more variation in the execution of the topspin forehand. Our study is the first to examine the amplitude of upper limb joint rotations that produce topspin in the forehand drives of 14 male competitive tennis players using video-based motion analysis. Humerothoracic abduction (-)/adduction (+), extension (-) /flexion (+), and external (-)/internal (+) rotation, elbow extension (-) /flexion (+) and forearm supination (-)/pronation (+), wrist extension (-)/flexion (+) and ulnar ( )/radial (-) deviation were computed. Our findings revealed that the generation of topspin demanded more humeral extension and forearm pronation but less humeral internal rotation angular displacement during the forwardswing. The follow through phase of the topspin shot was characterised by greater humeral internal rotation and forearm pronation, and reduced humeral horizontal adduction when compared to the flat shot. This study provides practitioners with a better understanding of the upper limb kinematics associated with the topspin tennis forehand drive production to help guide skill acquisition interventions and physical training. PMID- 29768091 TI - Effect of 830 nm Diode Laser Irradiation of Root Canal on Bond Strength of Metal and Fiber Post. AB - OBJECTIVE AND BACKGROUND: The correct selections of the cementing agent, the endodontic post material and placement protocol are critical to provide an increased longevity of the teeth that went through endodontic treatment. The irradiation with diode laser before post cementation, can promote an antimicrobial effect. However, there is a lack of information about the effect of 830 nm diode laser on the post bond strength. This study analyzed the effect of dentin root canal irradiation with high-intensity diode laser, at 830 nm, operating in continuous or pulsed mode, on the retention of metal or fiber posts, cemented with self-etching resinous composite (Panavia F) and zinc phosphate cement (ZnPO4). MATERIALS AND METHODS: Human roots were irradiated with diode laser (continuous and pulsed mode). The fiber posts were luted with Panavia F and the metal posts with Panavia F or ZnPO4 cement. Specimens were sectioned into three sections (cervical, middle, and apical). The bond strength was measured by a push-out mechanical analysis. For the statistical analysis, a three-way ANOVA test was applied following a Tukey's pairwise comparison with a significance level of p = 0.05. RESULTS: The irradiated groups presented higher bond strength compared with nonirradiated group (p < 0.05), and the cervical and middle thirds presented higher on bond strength than the apical. The association of metal post and Panavia F presented higher bond strength when irradiated on continuous mode (p < 0.05). Fiber post and Panavia F presented higher bond strength associated to pulsed mode. The mode seems not to make a significant difference. CONCLUSIONS: These results corroborate the importance of the post bond to dentin and root canal debris removal to increase the tooth longevity. It was shown that the dentin to post bond strength were enhanced by the diode laser irradiation either on continuous or pulsed modes. PMID- 29768092 TI - Are only infants held more often on the left? If so, why? Testing the attention emotion hypothesis with an infant, a vase, and two chimeric tests, one "emotional," one not. AB - Most adults, especially women, hold infants and dolls but not books or packages on the left side. One reason may be that attention is more often leftward in response to infants, unlike emotionally neutral objects like books and packages. Women's stronger bias may reflect greater responsiveness to infants. Previously, we tested the attention hypothesis by comparing women's side-of-hold of a doll, book, and package with direction-of-attention on the Chimeric Faces Test (CFT) [Harris, L. J., Cardenas, R. A., Spradlin, Jr., M. P., & Almerigi, J. B. (2010). Why are infants held on the left? A test of the attention hypothesis with a doll, a book, and a bag. Laterality: Asymmetries of Body, Brain and Cognition, 15(5), 548-571. doi:10.1080/13576500903064018]. Only the doll was held more often to the left, and only for the doll were side-of-hold and CFT scores related, with left holders showing a stronger left-attention bias than right-holders. In the current study, we tested men and women with a doll and the CFT along with a vase as a neutral object and a "non-emotional" chimeric test. Again, only the doll was held more often to the left, but now, although both chimeric tests showed left attention biases, scores were unrelated to side-of-hold. Nor were there sex differences. The results support left-hold selectivity but not the attention hypothesis, with or without the element of emotion. They also raise questions about the contribution of sex-of-holder. We conclude with suggestions for addressing these issues. PMID- 29768093 TI - Alterations in kinematics and muscle activation patterns with the addition of a kipping action during a pull-up activity. AB - Recently, addition of a gymnastics glide kip to a standard pull-up (SPU) has resulted in the kipping pull-up (KPU). Changes in muscle activation and kinematics were evaluated with eleven athletes performing sets of 5 SPU and 5 KPU. Surface electromyography of upper body and lower body muscles was recorded along with movement kinematics obtained via markers and motion tracking software. Most kinematic variables were significantly higher in the KPU including (KPU minus SPU deg): Max hip angle (48.8 degrees +/- 6.8 degrees , p < 0.001) and max knee angle (56.5 degrees +/- 11.3 degrees , p < 0.001). The recruitment of core and lower body muscles was significantly higher in the KPU (% MVIC increase): rectus abdominis (28.7 +/- 4.7%, p < 0.001), external oblique (21.8 +/- 4.1%, p < 0.001), iliopsoas (26.1 +/- 5.5%, p = 0.001) and tensor fasciae latae (13.5 +/- 2.3%, p < 0.001). Correspondingly, the biceps brachii had lower activation in the KPU (% MVIC decrease): (26.7 +/- 0.6%, p = 0.006). Depending on the athlete's goal, they may elect to perform an SPU for higher upper body muscle activation; or the KPU for more full-body activation with the potential to perform more repetitions through reduced upper body fatigue. PMID- 29768094 TI - Lower limb stiffness testing in athletic performance: a critical review. AB - Stiffness describes the resistance of a body to deformation. In regard to athletic performance, a stiffer leg-spring would be expected to augment performance by increasing utilisation of elastic energy. Two-dimensional spring mass and torsional spring models can be applied to model whole-body (vertical and/or leg stiffness) and joint stiffness. Various tasks have been used to characterise stiffness, including hopping, gait, jumping, sledge ergometry and change of direction tasks. Appropriate levels of reliability have been reported in most tasks, although they vary between investigations. Vertical stiffness has demonstrated the strongest reliability across tasks and may be more sensitive to changes in high-velocity running performance than leg stiffness. Joint stiffness demonstrates the weakest reliability, with ankle stiffness more reliable than knee stiffness. Determination of stiffness has typically necessitated force plate analyses; however, validated field-based equations permit determination of whole body stiffness without force plates. Vertical, leg and joint stiffness measures have all demonstrated relationships with performance measures. Greater stiffness is typically demonstrated with increasing intensity (i.e., running velocity or hopping frequency). Greater stiffness is observed in athletes regularly subjecting the limb to high ground reaction forces (i.e., sprinters). Careful consideration should be given to the most appropriate assessment of stiffness on a team/individual basis. PMID- 29768095 TI - TEST-retest reliability of kinetic variables measured on campus board in sport climbers. AB - Sport climbers frequently use campus board (CB) to improve their upper limb strength under similar conditions of high-difficulty sport climbing routes. The objective of this study was to assess the test-retest reliability of peak force and impulse measured using a CB instrumented with two load cells on starting holds. The same evaluator examined 22 climbers on two days with 48 h between the assessments. The participants performed five concentric lunges (CL) and five lunges with stretch-shortening cycle with 1 min intervals between repetitions and 10 min between exercises. All variables were associated with significant intraclass correlation coefficient (ICC) values (p = 0.001), and none variable showed systematic errors (p > 0.05). Peak force ICC was higher than 0.88, and the standard error of measurement (SEM%) was less than 5%. Impulse ICC for the CL was greater than 0.90, and the SEM% was less than 14%. We conclude that the kinetic variables measured using the CB were reliable. The ability of the hands to maintain contact with the holds (peak force) and the abilities of the arms and shoulders vertically move the centre of mass (impulse) should be taken into account by coaches on CB training prescription as well for further research. PMID- 29768096 TI - Lower extremity muscle function of front row rugby union scrummaging. AB - A rugby scrum's front row must act uniformly to transfer maximal horizontal force and improve performance. This study investigated the muscle activation patterns of lower extremity muscles in front row forwards during live and machine scrums at professional and amateur levels. Electromyography was collected bilaterally on vastus lateralis, rectus femoris and gastrocnemius muscles of 75 male rugby prop players during live and machine scrums. ANOVAs compared muscle reaction time, rate of change in muscle amplitude and muscle amplitude between groups and conditions. Cross-correlation analysis explored muscle synchronicity. There were significantly greater rates of change in each muscle amplitude in professional players than amateur players. Additionally, there was significantly quicker muscle reaction time in all muscles, and greater amplitude in vastus lateralis and gastrocnemius, during the live scrum vs. machine condition. The professional props produced more synchronised muscle activation than amateur players and all players produced more synchronised muscle activation against the scrum machine vs. live scrummage. The results indicate a higher skill proficiency and muscle synchronicity in professional players. While scrum machine training is ideally suited for functional muscle strengthening during practice, to truly simulate the requirements of the scrum, training should incorporate the live situation as much as possible. PMID- 29768098 TI - Surface-enhanced Raman spectroscopic analysis of N6-benzylaminopurine residue quantity in sprouts with gold nanoparticles. AB - A rapid and quantitative method for the determination of N6-Benzylademine (N6-BA) was established through the application of surface-enhanced Raman spectroscopy (SERS). The Raman peak intensities of N6-BA at 1002 cm-1 positively correlated to N6-BA concentrations in sprout extracts. The R2 reached 0.99, and RSDs calculated below 10% at the concentration range of 0.1 ~5MUg mL-1. The average recoveries were 80.0% ~ 98.2% for blank samples intentionally contaminated at differing levels of 0.04, 0.4, and 1 MUg g-1. The whole procedure, including sample preparation and SERS detection, did not exceed 30 min for a set of 6 samples. This study indicates that SERS is a promising technique for rapid tracing analysis and on-site testing of N6-BA. PMID- 29768097 TI - A new method for assessment of the sludge disintegration degree with the use of differential centrifugal sedimentation. AB - A novel method for assessing the disintegration degree (DD) of waste activated sludge (WAS) with the use of differential centrifugal sedimentation method (DCS) was shown herein. The method was validated for a WAS sample at four levels of disintegration in the range of 14.4-82.6% corresponding to the median particle size range of 8.5-1.6 um. From the several sludge disintegration methods used (i.e. microwave, alkalization, ultrasounds and peroxydisulfate activated by ultrasounds), the activated peroxydisulfate disintegration resulted in the greatest DD 83% and the smallest median particle size of WAS. Particle size distribution of pretreated sludge, measured by DCS, was in a negative correlation with the DD, determined from soluble chemical oxygen demand (SCOD; determination coefficient of 0.995). Based on the obtained results, it may be concluded that the DCS analysis can approximate the WAS disintegration degree. PMID- 29768100 TI - Corrigendum. PMID- 29768099 TI - mcr-1 Gene Has No Effect on Colistin Resistance When It Coexists with Inactivated mgrB Gene in Klebsiella pneumoniae. AB - The inactivated mgrB gene and the mcr-1 gene are important mechanisms of colistin resistance in Klebsiella pneumoniae and they are threats to the clinical use of colistin. In this study, mcr-1 gene was cloned into K. pneumoniae strains (XH209 and KP10) and their derived strains (XH209 M and KP10 M), which showed high-level resistance to colistin. The acquisition of the mcr-1 gene led to colistin resistance in XH209 and KP10, but the addition of mcr-1 gene did not cause change of colistin minimum inhibitory concentrations in the XH209 M and KP10 M. In addition, the impact of mcr-1 gene on growth rate showed strain specific in K. pneumoniae. In conclusion, the mcr-1 gene does not cause the same level of colistin resistance as the inactivated mgrB gene in K. pneumoniae. The mcr-1 gene has no effect on colisitin resistance when it coexists with inactivated mgrB gene in K. pneumoniae. PMID- 29768101 TI - Expression of concern. PMID- 29768102 TI - Identification of Dengue and Chikungunya Cases Among Suspected Cases of Yellow Fever in the Democratic Republic of the Congo. AB - For more than 95% of acute febrile jaundice cases identified through surveillance for yellow fever, a reemerging arthropod-borne viral disease, no etiological exploration is ever done. The aim of this study was to test for other arthropod borne viruses that can induce the same symptoms in patients enrolled in the yellow fever surveillance in the Democratic Republic of the Congo (DRC). Of 652 patients included in the surveillance of yellow fever in DRC from January 2003 to January 2012, 453 patients that tested negative for yellow fever virus (YFV) immunoglobulin M (IgM) antibodies were selected for the study. Real-time polymerase chain reaction was performed for the detection of dengue, West Nile, Chikungunya, O'nyong-nyong, Rift Valley fever, Zika, and YFV. The average age of patients was 22.1 years. We reported 16 cases (3.5%; confidence interval [CI]: 0.8-5.2) of dengue (serotypes 1 and 2) and 2 cases (0.4%; CI: 0.0-1.0) of Chikungunya. Three patients were co-infected with the two serotypes of dengue virus. Three cases of dengue were found in early July 2010 from the city of Titule (Oriental province) during a laboratory-confirmed outbreak of yellow fever, suggesting simultaneous circulation of dengue and yellow fever viruses. This study showed that dengue and Chikungunya viruses are potential causes of acute febrile jaundice in the DRC and highlights the need to consider dengue and Chikungunya diagnosis in the integrated disease surveillance and response program in the DRC. A prospective study is necessary to establish the epidemiology of these diseases. PMID- 29768104 TI - Knowledge, beliefs, attitudes, and behaviors regarding sickle cell disease: Implications for prevention. AB - Sickle cell disease (SCD) is a widespread inherited blood disorder, which leaves lasting effects on the health, social functioning, and finances of individuals, families, communities, and health care systems. A nonexperimental, cross sectional research design was used to assess 415 college students' knowledge about SCD. Data was obtained through an online survey derived from a modified version of the SCD Knowledge Assessment Tool. The majority of participants (79%) reported previous SCD knowledge; however, 21% of the participants reported no previous SCD knowledge. Results support the need for improved education and awareness for at risk groups. The lack of SCD knowledge among African Americans shows a need for improved, nongendered specific education, awareness, and screening efforts geared toward at-risk populations. PMID- 29768103 TI - Efficacy of Recombinase Polymerase Amplification to Diagnose Trypanosoma cruzi Infection in Dogs with Cardiac Alterations from an Endemic Area of Mexico. AB - Chagas disease is a lingering Public Health problem in Latin America with ~5.7 million people infected with Trypanosoma cruzi. Transmission is still taking place in most countries of the Americas, including the United States. Dogs are frequently infected with T. cruzi and its high infection prevalence is associated with increased risk of Chagas disease in humans. The city of Merida in the Yucatan peninsula is endemic for Chagas disease and canines are frequently infected with T. cruzi. The objective of this study was to evaluate the performance of a qualitative point of care (POC) molecular test (RPA-LF, recombinase polymerase amplification-lateral flow) developed in our laboratory for identifying infected dogs. We used retrospective samples of dogs that came for consultation because of cardiac alterations and proved to be infected with T. cruzi as determined by enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative PCR (qPCR). The analytical sensitivity indicated that RPA-LF amplified T. cruzi DNA in samples containing almost equal to one to two parasites per reaction. Serial twofold dilutions of T. cruzi epimastigotes showed that the test had 95% (19/20) repeatability at concentrations of two parasites per reaction. The test showed no cross reactivity with human DNA or other protozoan parasites (Trypanosoma rangeli, Leishmania spp., and Plasmodium spp.). RPA-LF had the capacity to amplify all discrete typing units (DTUs I-VI) of T. cruzi that circulate in domestic or extradomestic environments. The RPA-LF had 93.2% (95% confidence interval 87.2-98.1) sensitivity and excellent agreement with qPCR used as gold standard (Cohen's Kappa test = 0.963). ELISA was positive in 96.6% (85/88) of dogs, which together with the molecular tests confirmed the frequent contact with infected triatomine bugs in the city of Merida. These preliminary results on the diagnostic efficacy of the RPA-LF deserve further large-scale field testing of this POC test for T. cruzi infection in endemic areas. PMID- 29768106 TI - Effect of oral baclofen on spasticity poststroke: responders versus non responders. AB - Objective To assess quantitatively the efficacy of oral baclofen for spasticity poststroke. Methods The participants were 29 persons poststroke with increased resistance to passive ankle dorsiflexion and ankle clonus on clinical assessment. Baclofen was administered at 20 mg/day for 1 week. The ankle joint was passively dorsiflexed at either 5 degrees /s (slow stretch) or 90 degrees /s (fast stretch) by a custom-built device. The ankle joint angle and resistive torque were measured during the ramp-and-hold stretch, with gastrocnemius electromyogram. The main outcome measures were the numbers of ankle clonus during hold, and the torques at 10 degrees of ankle dorsiflexion in slow stretch (T-slow) and fast stretch (T-fast). Moreover, the velocity-dependent torque (DeltaT = T-fast - T slow) was compared between before and after oral baclofen. Results The numbers of ankle clonus, T-slow, T-fast, and DeltaT for all participants did not exhibit significant differences between before and after baclofen administration. However, reduction in the number of ankle clonus of five or more was accompanied with a reduction in DeltaT (4.0 +/- 1.8 Nm) in three participants (the responders). Conclusion Although the responder rate was low, some participants responded to oral baclofen. Thus, a short-term trial of oral baclofen, and quantitative and electrophysiological assessments of muscle tone and ankle clonus are recommended. PMID- 29768105 TI - Identification of a Recurrent LMO7-BRAF Fusion in Papillary Thyroid Carcinoma. AB - BACKGROUND: The BRAFV600E mutation is the most common driver in papillary thyroid carcinoma (PTC) tumors. In recent years, gene fusions have also been recognized as important drivers of cancer in PTC. Previous studies have suggested that thyroid tumors with fusion genes frequently display an aggressive course. These observations prompted further exploration of gene fusions in PTC tumors. The aim was to search for previously unrecognized gene fusions using thyroid tissue samples from PTC patients. METHODS: Gene fusions were analyzed in RNA sequencing data obtained from 12 PTC tumors and paired unaffected thyroid tissue samples. Candidate fusions were further filtered and validated using reverse transcriptase polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization. An Ohio cohort of 148 PTC tumor samples was screened for a LMO7 BRAF fusion and the BRAFV600E mutation. Functional assays were performed to assess the LMO7-BRAF fusion. RESULTS: Two coding fusions (CCDC6-RET and LMO7 BRAF) were found in one tumor sample each. The novel LMO7-BRAF fusion was validated by reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization. The LMO7-BRAF fusion was a recurrent somatic alteration with a frequency of 2.0% (3/148) in PTC tumors, while the BRAFV600E point mutation was found in 63.5% (94/148) of tumors. Enforced expression of LMO7-BRAF fusion protein stimulated endogenous ERK1/2 phosphorylation and promoted anchorage independent cell growth to an extent similar to BRAFV600E. CONCLUSIONS: A novel fusion gene, LMO7-BRAF, was identified in PTC tumors. The results indicate that the LMO7-BRAF fusion behaves as an oncogenic alteration. This observation expands the spectrum of fusion genes involving kinases in thyroid cancer. PMID- 29768108 TI - Gender differences in the effect of social resources and social status on the retirement satisfaction and health of retirees. AB - This study explores the effect of positive and negative social support, social reciprocity, and subjective social status on the retirement satisfaction and health of retirees and gender differences therein. Using cross-sectional data from the 2010 and 2012 waves of the Health and Retirement Study (HRS), we found that social support seems to matter more for the retirement satisfaction and health of women, while social reciprocity matters more for the health of men and subjective social status for the retirement satisfaction of men. Implications for the development of social programs and policies over the life course are discussed. PMID- 29768107 TI - Does expanding fiscal space lead to improved funding of the health sector in developing countries?: lessons from Kenya, Lagos State (Nigeria) and South Africa. AB - BACKGROUND: The global focus on promoting Universal Health Coverage has drawn attention to the need to increase public domestic funding for health care in low- and middle-income countries. OBJECTIVES: This article examines whether increased tax revenue in the three territories of Kenya, Lagos State (Nigeria) and South Africa was accompanied by improved resource allocation to their public health sectors, and explores the reasons underlying the observed trends. METHODS: Three case studies were conducted by different research teams using a common mixed methods approach. Quantitative data were extracted from official government financial reports and used to describe trends in general tax revenue, total government expenditure and government spending on the health sector and other sectors in the first decade of this century. Twenty-seven key informant interviews with officials in Ministries of Health and Finance were used to explore the contextual factors, actors and processes accounting for the observed trends. A thematic content analysis allowed this qualitative information to be compared and contrasted between territories. FINDINGS: Increased tax revenue led to absolute increases in public health spending in all three territories, but not necessarily in real per capita terms. However, in each of the territories, the percentage of the government budget allocated to health declined for much of the period under review. Factors contributing to this trend include: inter-sectoral competition in priority setting; the extent of fiscal federalism; the Ministry of Finance's perception of the health sector's absorptive capacity; weak investment cases made by the Ministry of Health; and weak parliamentary and civil society involvement. CONCLUSION: Despite dramatic improvements in tax revenue collection, fiscal space for health in the three territories did not improve. Ministries of Health must strengthen their ability to motivate for larger allocations from government revenue through demonstrating improved performance and the relative benefits of health investments. PMID- 29768109 TI - Effects of Phytosterol Supplementation on Serum Levels of Lipid Profiles, Liver Enzymes, Inflammatory Markers, Adiponectin, and Leptin in Patients Affected by Nonalcoholic Fatty Liver Disease: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. AB - OBJECTIVE: Considering the high prevalence of nonalcoholic fatty liver disease and based on the evidence about the role of dietary cholesterol in liver inflammation, and also with regard to the effect of phytosterols on the metabolism of cholesterol, we aimed at exploring the therapeutic potential of phytosterol supplementation against nonalcoholic fatty liver disease. METHOD: Thirty-eight patients with nonalcoholic fatty liver disease were randomly divided into two groups: The phytosterol group (n = 19) received a 1.6-g phytosterol supplement daily and the control group (n = 19) received 1.6 g starch daily as placebo for an 8-week period. Blood samples of all patients were taken at baseline (week 0) and at the end of the study (week 8) for measurement of lipid profiles, liver enzymes, inflammatory markers, adiponectin, and leptin. RESULTS: Phytosterol supplementation significantly improved the levels of low-density lipoprotein cholesterol, aspartate aminotransferase, alanine aminotransferase, and tumor necrosis factor alpha compared to the placebo group. On the other hand, there were no significant differences between the two groups in total cholesterol, triglycerides, high-density lipoprotein cholesterol, very-low density lipoprotein cholesterol, ratios of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and total cholesterol/high density lipoprotein cholesterol, gamma-glutamyl transferase, interleukin 6, high sensitivity C-reactive protein, adiponectin, and leptin. CONCLUSIONS: The present study suggested that daily consumption of 1.6 g phytosterols efficiently lowers low-density lipoprotein cholesterol, aspartate aminotransferase, alanine aminotransferase, and tumor necrosis factor alpha in patients with nonalcoholic fatty liver disease. PMID- 29768110 TI - Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update Summary. PMID- 29768111 TI - Effect of right lateral position with head elevation on tracheal aspirate pepsin in ventilated preterm neonates: randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of right lateral positioning in comparison with supine positioning on tracheal aspirate pepsin levels as a marker of aspiration of gastric contents in ventilated preterm neonates. STUDY DESIGN: This randomized controlled trial was conducted on 60 ventilated preterm neonates <35 weeks; 30 neonates were nursed in right lateral position for 6 hours while the other 30 neonates were nursed in supine position for 6 hours. Tracheal aspirate sample was obtained from each neonate in both the groups just after the end of 6 hours and pepsin level was measured. RESULTS: Neonates in right lateral position group had significantly lower tracheal pepsin level than neonates in supine position group (6 ng/ml) interquartile range [IQR] (3-20) versus 15 ng/ml [IQR] (5.5-90) (p = .024). There is positive correlation between tracheal aspirate pepsin level and fraction of inspired oxygen (FiO2) needed during the intervention (r = 0.383, p = .040). There is no correlation between tracheal pepsin level and gestational age, birth weight, or duration of mechanical ventilation and other ventilatory settings. CONCLUSION: Nursing ventilated premature infants in right lateral position is associated with decreased aspiration of gastric contents. PMID- 29768112 TI - "Marvin, the Paranoid Android": The Case of an Alpha-PVP User in the Expanding Galaxy of NPS. AB - Alpha-PVP can be defined as a novel psychoactive substance (NPS)-more specifically, a novel synthetic cathinone with unpredictable stimulant effects in humans. "Marvin" arrived at a Dual Diagnosis Unit at Parco dei Tigli, Italy. He underwent a 30-day rehabilitation program to overcome his problematic Alpha-PVP use as a psychonaut. We conducted an online search to understand the properties of Alpha-PVP and its presence in scientific literature, reviewing official reports and the online drug market (e.g., fora, webpages). In the Dual Diagnosis Unit, Marvin completed the 30-day rehabilitation program that included assessments and group and individual cognitive behavioral therapy. Alpha-PVP is a synthetic cathinone with stimulant properties, available in the online market but with unpredictable effects in humans. The present case reports an important risk of psychosis in a psychonaut patient who arrived and declared its intense use before admission to our Unit. This article describes the psychopathological effects of the novel compound Alpha-PVP in a psychonaut patient. Patients attending clinics that have used Alpha-PVP pose a new challenge for traditional services of mental health and addiction. PMID- 29768113 TI - Choosing When to Be Born. PMID- 29768114 TI - Differences in Contraceptive Discontinuation Among Black and White Women: Evidence from the Contraceptive CHOICE Project. AB - OBJECTIVE: We sought to evaluate whether differences in rates of contraceptive discontinuation exist among black and white women receiving contraceptive counseling and no-cost contraception among users of long-acting reversible contraceptive (LARC; intrauterine devices or subdermal implant) and non-LARC (oral contraceptive pills, contraceptive vaginal ring, patch, or injection) methods. MATERIALS AND METHODS: We analyzed data from a prospective cohort study of 7546 non-Hispanic black and white women who participated in the Contraceptive CHOICE Project. Among women who initiated their method within 12 weeks of enrollment, discontinuation was defined as any break in use longer than 1 month. Using Cox proportional hazards regression analysis, we estimated discontinuation stratified by use of LARC methods. RESULTS: There were no statistically significant differences in contraceptive discontinuation between black and white women at 12, 24, or 36 months among both LARC [12-month adjusted hazard ratio (HRadj-12M) 1.01 (95% confidence interval or 95% CI 0.86-1.18); HRadj-24M 1.10 (95% CI 0.97-1.24); and HRadj-36M 1.10 (95% CI 0.98-1.23)] and non-LARC users [HRadj-12M 1.08 (95% CI 0.92, 1.26); HRadj-24M 1.07 (95% CI 0.94, 1.23); and HRadj-36M 1.08 (95% CI 0.95, 1.23)] adjusting for confounders. Secondary analyses found no significant differences in discontinuation of LARC and non-LARC methods among black and white women at highest risk of pregnancy or those receiving public assistance at baseline. CONCLUSIONS: At 12, 24, and 36 months there were no differences in contraceptive discontinuation of both LARC methods and non-LARC methods when comparing white and black women. PMID- 29768116 TI - Endogenous Endophthalmitis. PMID- 29768115 TI - Three-Dimensional Printing of Vitrification Loop Prototypes for Aquatic Species. AB - Vitrification is a method of cryopreservation that freezes samples rapidly, while forming an amorphous solid ("glass"), typically in small (MUL) volumes. The goal of this project was to create, by three-dimensional (3D) printing, open vitrification devices based on an elliptical loop that could be efficiently used and stored. Vitrification efforts can benefit from the application of 3D printing, and to begin integration of this technology, we addressed four main variables: thermoplastic filament type, loop length, loop height, and method of loading. Our objectives were to: (1) design vitrification loops with varied dimensions; (2) print prototype loops for testing; (3) evaluate loading methods for the devices; and (4) classify vitrification responses to multiple device configurations. The various configurations were designed digitally using 3D CAD (Computer Aided Design) software, and prototype devices were produced with MakerBot(r) 3D printers. The thermoplastic filaments used to produce devices were acrylonitrile butadiene styrene (ABS) and polylactic acid (PLA). Vitrification devices were characterized by the film volumes formed with different methods of loading (pipetting or submersion). Frozen films were classified to determine vitrification quality: zero (opaque, or abundant crystalline ice formation); one (translucent, or partial vitrification), or two (transparent, or substantial vitrification, glass). A published vitrification solution was used to conduct experiments. Loading by pipetting formed frozen films more reliably than by submersion, but submersion yielded fewer filling problems and was more rapid. The loop designs that yielded the highest levels of vitrification enabled rapid transfer of heat, and most often were characterized as being longer and consisting of fewer layers (height). 3D printing can assist standardization of vitrification methods and research, yet can also provide the ability to quickly design and fabricate custom devices when needed. PMID- 29768117 TI - Experiences and Expectations of Bereavement Contact among Caregivers of Patients with Advanced Cancer. AB - BACKGROUND: Contact with bereaved caregivers is not standard practice among cancer physicians, and little is known about its impact on caregivers. OBJECTIVE: Our aim was to describe the experiences and opinions of caregivers regarding bereavement contact from healthcare providers (HCP). DESIGN: Semistructured qualitative interviews were conducted with 61 bereaved caregivers. SUBJECTS: Bereaved caregivers of advanced cancer patients who had completed a randomized controlled trial of an early palliative care intervention were approached one to five years after the patient's death. Caregivers completed qualitative interviews from April 2012 to March 2015 after completion of quantitative measures. APPROACH: In semistructured interviews, bereaved caregivers were asked to describe the contact they received from HCP after the patient's death and their opinions about bereavement contact. We used thematic analysis informed by grounded theory to code and analyze the data. RESULTS: Of 60 caregivers included in the study, 30 (50%) received bereavement contact. There were no thematic differences between trial arms. The themes "contact reflects caring," "contact offers support," and "contact facilitates closure" were prominent among those who were contacted. "Contact is a courtesy," "contact is not always necessary," and "caregiver-initiated contact" were most evident among those who were not contacted. Overall, contact was appreciated by those who received it; for those who did not, reactions included rationalization, ambivalence, and regret. No negative consequences of contact were reported. CONCLUSIONS: Bereavement contact is well received and may be missed if not provided. These data support integration of bereavement contact into routine supportive care for caregivers. PMID- 29768118 TI - Final Overall Survival Analysis From a Study Comparing First-Line Crizotinib Versus Chemotherapy in ALK-Mutation-Positive Non-Small-Cell Lung Cancer. AB - Purpose The phase III PROFILE 1014 trial compared crizotinib with chemotherapy as first-line treatment in patients with anaplastic lymphoma kinase (ALK) -positive advanced nonsquamous non-small-cell lung cancer. Here, we report the final overall survival (OS) results. Patients and Methods Patients were randomly assigned to receive oral crizotinib 250 mg twice daily (n = 172) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration-time curve of 5 to 6 mg.mL/min) every 3 weeks for a maximum of six cycles (n = 171). Crossover to crizotinib was permitted after disease progression. OS was analyzed using a stratified log-rank test and a prespecified rank-preserving structural failure time model to account for crossover. Results Median follow-up duration for OS was approximately 46 months for both arms. In the chemotherapy arm, 144 patients (84.2%) received crizotinib in subsequent lines. Hazard ratio for OS was 0.760 (95% CI, 0.548 to 1.053; two-sided P = .0978). Median OS was not reached (NR) with crizotinib (95% CI, 45.8 months to NR) and 47.5 months with chemotherapy (95% CI, 32.2 months to NR). Survival probability at 4 years was 56.6% (95% CI, 48.3% to 64.1%) with crizotinib and 49.1% (95% CI, 40.5% to 57.1%) with chemotherapy. After crossover adjustment, there was an improvement in OS that favored crizotinib (hazard ratio, 0.346; 95% bootstrap CI, 0.081 to 0.718). The longest OS was observed in crizotinib-treated patients who received a subsequent ALK tyrosine kinase inhibitor. No new safety signals were identified. Conclusion The final analysis of the PROFILE 1014 study provides a new benchmark for OS in patients with ALK-rearranged non-small-cell lung cancer and highlights the benefit of crizotinib for prolonging survival in this patient population. PMID- 29768119 TI - Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials. AB - Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (>= 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in). PMID- 29768120 TI - Three dimensionally printed pearl powder/poly-caprolactone composite scaffolds for bone regeneration. AB - Pearl has great potential as a natural biomaterial for bone tissue engineering, but it suffers from low porosity, difficulty in molding, and poor anti-buckling property. In this study, we used the 3-D printing technique to fabricate original pearl powder and PCL composite scaffolds with different concentrations of pearl powder. The four groups of scaffolds were termed PCL, 30% Pearl/PCL, 50% Pearl/PCL and 80% Pearl/PCL scaffolds according to the proportion of pearl powder. The samples were systematically investigated by scanning electron microscopy (SEM), wide-angle XRD, liquid substitution, Zwick static materials testing, and energy dispersive X-ray analysis. Biological characterization included SEM, fluorescent staining using calcein-AM, cell counting kit-8 assay, alkaline phosphatase and qRT-PCR analysis. The results show that the pore size and the pore morphology of the scaffolds are closely controlled via 3-D printing. This is very beneficial for tissue growth and nutrition transmission. The regular and uniform square macropore structure ensured that the pearl powder/PCL scaffolds had favorable mechanical strength. As the concentration of pearl powder in the scaffolds increase, the compressive strength and apatite formation increase as well as cell adhesion, proliferation, and osteogenic differentiation. These results show that pearl powder/PCL scaffolds fit the requirements of bone tissue engineering. The structures as well as physicochemical and biological properties of pearl powder/PCL composite scaffolds are positively associated with pearl powder concentrations. PMID- 29768121 TI - A biomechanical comparison of initial sprint acceleration performance and technique in an elite athlete with cerebral palsy and able-bodied sprinters. AB - Cerebral palsy is known to generally limit range of motion and force producing capability during movement. It also limits sprint performance, but the exact mechanisms underpinning this are not well known. One elite male T36 multiple Paralympic sprint medallist (T36) and 16 well-trained able-bodied (AB) sprinters each performed 5-6 maximal sprints from starting blocks. Whole-body kinematics (250 Hz) in the block phase and first two steps, and synchronised external forces (1,000 Hz) in the first stance phase after block exit were combined to quantify lower limb joint kinetics. Sprint performance (normalised average horizontal external power in the first stance after block exit) was lower in T36 compared to AB. T36 had lower extensor range of motion and peak extensor angular velocity at all lower limb joints in the first stance after block exit. Positive work produced at the knee and hip joints in the first stance was lower in T36 than AB, and the ratio of positive:negative ankle work produced was lower in T36 than AB. These novel results directly demonstrate the manner in which cerebral palsy limits performance in a competition-specific sprint acceleration movement, thereby improving understanding of the factors that may limit performance in elite sprinters with cerebral palsy. PMID- 29768122 TI - Long-Term Trait Consistency in Mice Selected for Swim-Induced High Aerobic Capacity. AB - The majority of studies show that metabolic rates are usually repeatable at the individual level, although their repeatabilities tend to decline with time and to be strongly affected by physiological changes. Changes in individual repeatabilities may therefore affect putative differences between experimental groups or populations. This problem is particularly relevant to artificial selection experiments that apply the selection protocol at early life stages, running the risk of a poor correlation of the trait with itself throughout the life cycle of individuals. Moreover, significant physiological changes (e.g., induced by reproduction) may affect traits under selection and therefore their postreproductive differentiation between selected lines. Here, using a unique animal model-mice from four lines selected for [Formula: see text] during swimming in 25 degrees C water and four random-bred control (reference) lines-we analyzed the long-term consistency of aerobic capacity as well as postswim hypothermia in primiparous and nonreproducing females at 12, 25, and 29 wk of age. Our results show that significant between-line type divergence in [Formula: see text] and hypothermia persists over time and is only weakly affected by past reproduction. Furthermore, both traits are also repeatable within lines at the individual level. More generally, our results suggest that past reproduction events are unlikely to significantly affect between-population and between individual differences in [Formula: see text] and related traits. PMID- 29768124 TI - The Importance of Being Honest: Correlating Self-Report Accuracy and Network Centrality with Academic Performance. AB - This study investigates the correlation of self-report accuracy with academic performance. The sample was composed of 289 undergraduate students (96 senior and 193 junior) enrolled in two engineering classes. Age ranged between 22 and 24 years, with a slight over representation of male students (53%). Academic performance was calculated based on students' final grades in each class. The tendency to report inaccurate information was measured at the end of the Raven Progressive Matrices Test, by asking students to report their exact finishing times. We controlled for gender, age, personality traits, intelligence, and past academic performance. We also included measures of centrality in their friendship, advice and trust networks. Correlation and multiple regression analyses results indicate that lower achieving students were significantly less accurate in self-reporting data. We also found that being more central in the advice network was correlated with higher performance (r = .20, p < .001). The results are aligned with existing literature emphasizing the individual and relational factors associated with academic performance and, pending future studies, may be utilized to include a new metric of self-report accuracy that is not dependent on academic records. PMID- 29768126 TI - Porcine Reproductive and Respiratory Syndrome Virus and Porcine Circovirus 2 in Albania. PMID- 29768125 TI - Investigating the usefulness of trauma-focused cognitive behavioral therapy in adolescent residential care. AB - OBJECTIVE: This study investigated the usefulness of the trauma intervention, trauma-focused cognitive behavioral therapy (TF-CBT), for adolescents in residential treatment. METHOD: The study employed a secondary analysis of 132 adolescent trauma cases collected from youth while in a residential treatment facility in Mississippi. RESULTS: Analysis indicated that clients showed significant decreases in posttraumatic stress disorder (PTSD) severity scores after receiving TF-CBT in residential care. PTSD severity scores were significantly higher for the residential care sample as compared to the National Child Traumatic Stress Network's average baseline score. Females reported significantly higher PTSD and substance use scores than males. PTSD baseline scores, substance use scores, and gender contributed significantly to the prediction of PTSD outcomes post intervention. CONCLUSION: Implications, based on study findings, to enhance services for traumatized youth in residential care were explored and discussed. PMID- 29768127 TI - An Evaluation of Removal Trapping to Control Rodents Inside Homes in a Plague Endemic Region of Rural Northwestern Uganda. AB - Rodents pose a significant threat to human health, particularly in rural subsistence farming communities in Africa, where rodents threaten food security and serve as reservoirs of human pathogens, including the agents of plague, leptospirosis, murine typhus, rat-bite fever, Lassa fever, salmonellosis, and campylobacteriosis. Our study focused on the plague-endemic West Nile region of Uganda, where a majority of residents live in Uganda government-defined poverty, rely on subsistence farming for a living, and frequently experience incursions of rodents into their homes. In this study, we show that rodent removal was achieved in a median of 6 days of intensive lethal trapping with multiple trap types (range: 0-16 days). However, rodent abundance in 68.9% of homesteads returned to pretreatment levels within a median of 8 weeks (range 1-24 weeks), and at least a single rodent was captured in all homesteads by a median of 2 weeks (range 1-16 weeks) after removal efforts were terminated. Results were similar between homesteads that practiced rodent control whether or not their neighbors implemented similar strategies. Overall, intensive lethal trapping inside homes appears to be effective at reducing rodent abundance, but control was short lived after trapping ceased. PMID- 29768130 TI - Super Pill is Less Effective than an Ordinary Mint in Altering Subjective Psychological Feeling States within a Few Minutes. AB - Expectations shape human behavior. Initial drug use might be associated with information-based expectations. In this study, we presumed that changes in affect and perceived physical wellbeing will be stronger after receiving an active placebo (Tic Tac mint; n = 40), than a pure placebo (inert pill; n = 40) given as a mood-enhancing "super pill." After baseline measures, participants completed a treatment-expectancy scale, ingested the mint/super pill, and attended to the effects over 3-minutes. Subsequently, they completed again the psychological tests. Expectancy scores were positive and did not differ between the groups. The pure placebo group increased in physical wellbeing but less than the active placebo group, which also showed an increase in positive affect. Negative affect decreased in both groups. The Tic Tac produced greater affective changes than the pure placebo. Since these are new findings on the ultra-short placebo effects on affect, the results might have relevance for drug-use studies. PMID- 29768128 TI - The Importance of Emotional Intelligence and Cognitive Style in Institutionalized Older Adults' Quality of Life. AB - Despite previous evidence showing a positive relationship between emotional intelligence (EI) and quality of life (QoL), associating older adults' emotional processing with several health indicators, few studies have explored both the IE and the a mechanisms through which they affect QoL. This cross-sectional study analyzes the mediator role of optimistic and pessimistic cognitive styles in the relationship between perceived EI (PEI) and QoL in 115 institutionalized older adults from Southern Spain. Regression analyses showed, after controlling for cognitive style, that PEI predicted a significant percentage of variance in: Health (beta = .25, p < .01), Functional abilities (beta = .20, p < .05), Activity and leisure (beta = .17, p < .05) and Life satisfaction (beta = .21, p < .05). Additionally, multiple mediation analysis revealed that cognitive style partially mediated the relationship between PEI and Health, Activity and leisure and Life satisfaction. Thus, PEI could promote personal but not external or environmental QoL aspects, highlighting the importance of developing emotional skills for healthy aging. PMID- 29768129 TI - The Impact of Face Skin Tone vs. Face Symmetry on Perceived Facial Attractiveness. AB - The purpose of this study was to assess and compare the relative contribution of skin tone and symmetry on judgment of attractiveness regarding female faces. Two hundred and fifteen Mozambican adults were presented with a set of faces, and instructed to rate their degree of attractiveness along a continuous scale. Chi square, factorial weight analyses and ANOVA were used to analyze the data. Face skin tone had a significant impact on the participants' attractiveness judgment of target faces. However, the target face skin tone contribution to the participants' attractiveness judgment (5% of the total variance) was much weaker than the contribution of the target face symmetry (85% of the total variance). These results imply that skin bleaching, common among Black people across sub Saharan African countries, is not only dangerous to the health of those who practice it, but it is unlikely to make them appear much more attractive. PMID- 29768132 TI - Post-Operative Infections among Patients Undergoing Radical Cystectomy at a Tertiary Center. AB - BACKGROUND: Post-operative infection after radical cystectomy is a common complication. It is essential to identify modifiable risk factors that can predict post-operative infection to reduce the incidence of infection after radical cystectomy. We investigated the incidence of post-operative infection, associated pathogens, and risk factors for post-operative infection after radical cystectomy. PATIENTS AND METHODS: Patients who underwent radical cystectomy for bladder cancer in a single urologic department from 2014 to 2016 were included. Age, gender, length of stay, body mass index (BMI), diabetes mellitus, hypertension, pre-operative estimated glomerular filtration rate, hydronephrosis, smoking status, neoadjuvant chemotherapy, pathologic tumor stage, pathologic nodal stage, types of urinary diversion, laparoscopic approach, operative time, and receipt of peri-operative blood transfusion were assessed to determine the association of these factors with the risk of infection within 30 days of radical cystectomy. Risk factors were assessed for correlation with any kind of infection and separately for urinary tract infection (UTI), blood infection/septic shock (BI), and surgical site infection (SSI). Pathogens were identified in all cases of infection. RESULTS: A total of 134 patients were included in the analysis. Post-operative infection was diagnosed in 10.45%. Urinary tract infection, BI, and SSI were diagnosed in 3.73%, 4.48%, and 7.46%, respectively. Co-infections and mixed infection were diagnosed in 50% of patients with infection. Enterococcus was the most common pathogen. On multivariable analysis, age, BMI >=30 kg/m2, and laparoscopic approach were associated with the risk of infection; odds ratios (ORs) were 1.27 (95% confidence interval [CI] 1.01-1.59), 13.07 (1.39 122.88), and 0.07 (0.01-0.78), respectively. CONCLUSION: One-tenth of patients undergoing radical cystectomy developed an infection within 30 days of surgery. Fifty percent of patients had co-infection with UTI, SSI, and/or BI and 50% of infections were polymicrobial. Increased BMI is the strongest factor associated independently with all types of infection. Therefore, obese patients should be encouraged to lose weight pre-operatively. PMID- 29768133 TI - Data source mapping: an essential step for health inequality monitoring. AB - The task of health inequality monitoring is not possible without the availability of appropriate and high-quality data at various levels. Data source mapping - a process by which data sources are systematically enlisted, their properties detailed and each source appraised for the purposes of monitoring - is an essential initial step for health inequality monitoring. We outline a simple process along with a template for data source mapping and its application in Indonesia, concluding with the lessons learned from this process, in terms of both challenges as well as the opportunities and advantages arising from the use of equity-related data from the Indonesian health information system. PMID- 29768134 TI - mTOR signalling: jack-of-all-trades. AB - The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that senses and integrates environmental information into cellular regulation and homeostasis. Accumulating evidence has suggested a master role of mTOR signalling in many fundamental aspects of cell biology and organismal development. mTOR deregulation is implicated in a broad range of pathological conditions, including diabetes, cancer, neurodegenerative diseases, myopathies, inflammatory, infectious, and autoimmune conditions. Here, we review recent advances in our knowledge of mTOR signalling in mammalian physiology. We also discuss the impact of mTOR alteration in human diseases and how targeting mTOR function can treat human diseases. PMID- 29768131 TI - A New Scoring System to Predict Blood Stream Infections in Patients with Complicated Intra-Abdominal Infections: Experience from a Tertiary Referral Hospital in China. AB - BACKGROUND: This purpose of this study was to investigate the effects of blood stream infections (BSIs) on the prognosis of patients with complicated intra abdominal infections (IAIs) and to make predictions based on patients' characteristics on admission. PATIENTS AND METHODS: One hundred eighty-seven patients with complicated IAI in 2014 and 2015 were included in our retrospective analysis, except for those diagnosed with central line-associated blood stream infections (CLABSIs). Patients with BSIs were compared with patients without BSIs. Multivariable logistic regression was applied to identify factors associated with BSIs and also the subtypes of BSIs. The predictive score systems were established further. RESULTS: Seventy-four patients (39.6%) with complicated IAIs developed BSIs after admission. Four factors evaluated on admission were associated independently with BSIs including alanine aminotransferase (ALT) >=66 U/L (two scores), insensitivity to initial empirical antibiotic agents (IIEA; three scores), Sepsis-Related Organ Failure Assessment (SOFA) score of two or more (three scores), and generalized peritonitis (four scores). A total score of five or more was regarded as the critical value in the combined test to predict BSIs, with a sensitivity of 0.78 and a specificity of 0.73. Blood stream infections were further divided as secondary BSIs and non-secondary BSIs. The risk factors of secondary BSIs included IIEA (three scores), SOFA score of two or more (five scores), and generalized peritonitis (eight scores), where a total score of nine or more was regarded as the critical value in the combined test, with a sensitivity of 0.68 and a specificity of 0.87, whereas the risk factors of non-secondary BSIs included IIEA (three scores), SOFA score of two or more (three scores) and procalcitonin (PCT) >=0.43 mcg/L (three scores), where a total score of six or more was regarded as the critical value in the combined test, with a sensitivity of 0.75 and a specificity of 0.70. Moreover, BSIs were linked with the worse clinical outcomes in organ functions, hospitalization costs, and mortality. CONCLUSIONS: Our new scoring methods may have potential advantages on the early prediction and recognition of BSIs in patients with complicated IAIs. PMID- 29768135 TI - Seeing the Light: The Roles of Red- and Blue-Light Sensing in Plant Microbes. AB - Plants collect, concentrate, and conduct light throughout their tissues, thus enhancing light availability to their resident microbes. This review explores the role of photosensing in the biology of plant-associated bacteria and fungi, including the molecular mechanisms of red-light sensing by phytochromes and blue light sensing by LOV (light-oxygen-voltage) domain proteins in these microbes. Bacteriophytochromes function as major drivers of the bacterial transcriptome and mediate light-regulated suppression of virulence, motility, and conjugation in some phytopathogens and light-regulated induction of the photosynthetic apparatus in a stem-nodulating symbiont. Bacterial LOV proteins also influence light mediated changes in both symbiotic and pathogenic phenotypes. Although red-light sensing by fungal phytopathogens is poorly understood, fungal LOV proteins contribute to blue-light regulation of traits, including asexual development and virulence. Collectively, these studies highlight that plant microbes have evolved to exploit light cues and that light sensing is often coupled with sensing other environmental signals. PMID- 29768136 TI - The Genome Biology of Effector Gene Evolution in Filamentous Plant Pathogens. AB - Filamentous pathogens, including fungi and oomycetes, pose major threats to global food security. Crop pathogens cause damage by secreting effectors that manipulate the host to the pathogen's advantage. Genes encoding such effectors are among the most rapidly evolving genes in pathogen genomes. Here, we review how the major characteristics of the emergence, function, and regulation of effector genes are tightly linked to the genomic compartments where these genes are located in pathogen genomes. The presence of repetitive elements in these compartments is associated with elevated rates of point mutations and sequence rearrangements with a major impact on effector diversification. The expression of many effectors converges on an epigenetic control mediated by the presence of repetitive elements. Population genomics analyses showed that rapidly evolving pathogens show high rates of turnover at effector loci and display a mosaic in effector presence-absence polymorphism among strains. We conclude that effective pathogen containment strategies require a thorough understanding of the effector genome biology and the pathogen's potential for rapid adaptation. PMID- 29768137 TI - Organic Amendments, Beneficial Microbes, and Soil Microbiota: Toward a Unified Framework for Disease Suppression. AB - Organic amendments (OAs) and soilborne biocontrol agents or beneficial microbes (BMs) have been extensively studied and applied worldwide in most agriculturally important plant species. However, poor integration of research and technical approaches has limited the development of effective disease management practices based on the combination of these two bio-based strategies. Insights into the importance of the plant-associated microbiome for crop productivity, which can be modified or modulated by introducing OAs and/or BMs, are providing novel opportunities to achieve the goal of long-term disease control. This review discusses novel ways of functionally characterizing OAs and how they may be used to promote the effect of added biocontrol agents and/or beneficial soil microbiota to support natural suppressiveness of plant pathogens. PMID- 29768138 TI - Knockdown of the prolyl isomerase Pin1 inhibits Hep-2 cell growth, migration, and invasion by targeting the beta-catenin signaling pathway. AB - There is increasing evidence indicating that peptidylprolyl cis/trans isomerase, NIMA-interacting 1 (Pin1) plays a decisive role in a variety of cancers. Nevertheless, its function in laryngeal squamous cell carcinoma (LSCC) has not been elaborated. The aim of this study is to determine the role of Pin1 in LSCC. Here, we established stably transfected Hep-2 cells with low expression of Pin1. Intriguingly, cell proliferation, migration, and invasion was significantly inhibited in Pin1-silenced Hep-2 cells. Similarly, knockdown of Pin1 induced apoptosis of Hep-2 cells, as evidenced by increased expression of cleaved-caspase 3, cleaved-PARP, and bax, and decreased expression of bcl2. We also demonstrated that silencing of Pin1 down-regulated beta-catenin and cyclin D1 expression. Inversely, over-expression of beta-catenin reversed the inhibiting effect of Pin1 silencing on Hep-2 cells. Moreover, we proved that knockdown of Pin1 inhibited tumorigenesis of Hep-2 cells in vivo. Taken together, we demonstrate that silencing of Pin1 effectively suppresses the growth of Hep-2 cells through beta catenin, indicating that Pin1 possess the potential to serve as a therapeutic target for the treatment of LSCC. PMID- 29768140 TI - Addressing Generic-Drug Market Failures - The Case for Establishing a Nonprofit Manufacturer. PMID- 29768141 TI - The Drug-Intoxication Epidemic and Solid-Organ Transplantation. PMID- 29768142 TI - HIV Population Surveys - Bringing Precision to the Global Response. PMID- 29768139 TI - Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. AB - BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label canakinumab. RESULTS: At week 16, significantly more patients receiving canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .). PMID- 29768143 TI - Trametinib in Histiocytic Sarcoma with an Activating MAP2K1 (MEK1) Mutation. PMID- 29768144 TI - Leadership Development in Medicine. PMID- 29768145 TI - Case 15-2018: An 83-Year-Old Woman with Nausea, Vomiting, and Confusion. PMID- 29768146 TI - On-Demand versus Maintenance Inhaled Treatment in Mild Asthma. PMID- 29768148 TI - Initial Treatment of Hypertension. PMID- 29768147 TI - As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. AB - BACKGROUND: Patients with mild asthma often rely on inhaled short-acting beta2 agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk. METHODS: We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide-formoterol (200 MUg of budesonide and 6 MUg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 MUg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide-formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire-5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment). RESULTS: A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide-formoterol group (66 MUg) than in the budesonide maintenance group (267 MUg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy. CONCLUSIONS: In patients with mild asthma, budesonide-formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group. (Funded by AstraZeneca; SYGMA 2 ClinicalTrials.gov number, NCT02224157 .). PMID- 29768150 TI - Balanced Crystalloids versus Saline in Critically Ill Adults. PMID- 29768151 TI - Raindrop Skull. PMID- 29768149 TI - Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma. AB - BACKGROUND: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting beta2-agonist may be an alternative to conventional treatment strategies. METHODS: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide formoterol (200 MUg of budesonide and 6 MUg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 MUg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as needed terbutaline with regard to electronically recorded weeks with well controlled asthma. RESULTS: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 MUg) was 17% of the dose in the budesonide maintenance group (340 MUg). CONCLUSIONS: In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy. (Funded by AstraZeneca; SYGMA 1 ClinicalTrials.gov number, NCT02149199 .). PMID- 29768153 TI - Improving the Supply and Quality of Deceased-Donor Organs for Transplantation. PMID- 29768152 TI - Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome. AB - BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS: In this double-blind, placebo controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .). PMID- 29768154 TI - Tuberculous Pericarditis. PMID- 29768155 TI - Rapid Progression of Adult T-Cell Leukemia-Lymphoma after PD-1 Inhibitor Therapy. PMID- 29768156 TI - [Impaired kidney function in patients with atrial fibrillation: practical aspects]. AB - The article focuses on practical aspects of managing patients with a frequently observed combination of atrial fibrillation (AF) and chronic kidney disease (CKD). Based on the authors" own data taken as an example, incidence of different CKD stages in CKD patients was compared with international reports. EchoCG changes were shown to be related with CKD severity. Antithrombotic prevention administered to such patients in the settings of real practice was compared with the existing guidelines. PMID- 29768157 TI - [Major predictors of stent thrombosis in patients with acute coronary syndrome following transcutaneous coronary intervention who received different double antiplatelet therapy]. AB - The review analyzes the reports addressing from different standpoints the issue of stent thrombosis and its major predictors in patients with acute coronary syndrome following transcutaneous coronary interventions. The review focuses on comparative efficacy and safety of ticagrelor and clopidogrel and the effect of double antiplatelet therapy on stent thrombosis. The issue of patients' compliance with double antiplatelet therapy is also discussed. Such comprehensive evaluation is warranted since despite all efforts for expanding both technical and therapeutic possibilities, the issue of stent thrombosis remains relevant. PMID- 29768158 TI - [Issues of antithrombotic therapy in ACS patients with atrial fibrillation]. AB - The review analyzed current ideas on prevalence and clinical significance of atrial fibrillation following acute coronary syndrome; described modern approaches to administration of antithrombotic therapy; and addressed available clinical studies on the treatment with warfarin and new oral anticoagulants as a part of combination antithrombotic therapy in patients with atrial fibrillation and acute coronary syndrome. PMID- 29768159 TI - [Hypertrophic cardiomyopathy and ischemic heart disease: the problem of pathology combination]. AB - Hypertrophic cardiomyopathy (HCM) is a disease with left ventricular hypertrophy caused by mutations in the genes of myocardial contractile proteins, whose frequency is about 0.5 %. Due to the high incidence of anginal pain and marked changes in ECG with HCM, the problem of diagnosing the combination of HCM and coronary artery disease (CAD) presents a rather difficult task for the clinician. The complexity of this diagnosis is due to the ability of standard methods of instrumental examination (ECG, a test with physical activity, stress tests in conjunction with visualization of the myocardium) to detect myocardial ischemia in both SAD and HCM. In such cases, the coronary angiography, or multispiral computed tomography of coronary arteries (in patients with low SAD risk) remains the gold standard for detecting atherosclerotic lesions of the coronary arteries. The possibility of combining HCM and SAD in patients of older age groups raises the question of the features of the course of diseases and the prognosis of such patients. PMID- 29768160 TI - [Selection of antiplatelet therapy for patients with stable angina]. AB - Acetylsalicylic acid (ASA) has a 120-years long history. First ASA was used as an antipyretic and anesthetic medicine, nowadays it is widely prescribed to patients with coronary arteries disease as antithrombotic cure for prevention of major adverse clinical events (MACE). Though there are a lot of trials about usage of ASA for first and secondary MACE prevention still there are unmet clinical needs dosage choice, the therapy length, diagnostic and management of ASA resistance, and also the prophylaxis of gastro-enteric hemorrhages. PMID- 29768161 TI - [Practical aspects of anticoagulant therapy in patients with atrial fibrillation and arterial hypertension]. AB - Atrial fibrillation (AF) represents the most frequent sustained cardiac arrhythmia, the prevalence of AF is 1-2 % in the general population and up to 6 % for population over 80 years. Arterial hypertension (AH) is the commonest background comorbidity in patients with AF. Patients with AF have 3-6-fold increased risk of ischemic stroke in comparison to that in general population, additionally the presence of AH leads an 2-3-fold increase in risk of subsequent stroke. Current clinical guidelines recommend long-time anticoagulant treatment for prevention of stroke and thromboembolic complications in majority of patients with confirmed AF. Not only does uncontrolled high blood pressure contribute to developing new-onset AF or AF progression but also can increase a bleeding risk related to oral anticoagulants. Patients with AF and concomitant AH resulting in target organ damage need for more favorable safety profile of oral anticoagulants. Instruction label dabigatran treatment in two doses can individualize approach to choice of long-term anticoagulation with lower risk of major bleeding in AF patients. PMID- 29768162 TI - [Structural and functional changes of blood vessels in women in early postmenopause, the possibility of correction of the revealed violations]. AB - AIM: To evaluate severity and pattern of structural and functional changes of vascular wall in early postmenopausal women receiving chronic treatment with a low-dose combination of 17beta-estradiol (E2) 1 mg and drospirenone 2 mg (DRSP). Evaluation of structural and functional arterial remodeling might be important for assessment of cardiovascular risk in postmenopausal women. MATERIALS AND METHODS: The study included 162 early postmenopausal women with postmenopausal syndrome. The women were divided into two groups. The main group consisted of 84 patients receiving the postmenopausal hormonal therapy (PMHT) with E2 1 mg / DRSP 2 mg (Angeliq, Bayer) and the control group included 78 women not receiving PMHT. The follow-up duration was 5.2 years. 24-h blood pressure monitoring with evaluation of arterial stiffness (RWTT, AIx, ASI, AASI, (dP/dt) max) was performed. Endothelium-dependent dilation of the brachial artery was measured using the reactive hyperemia test. Aortic pulse wave velocity (aPWV) and common carotid intima-media thickness (ccIMT) were measured ultrasonically. RESULTS: At baseline, increased aPWV was observed in 15 (21.4 %) women of the main group and 19 (24.3 %) women of the control group (r=0.4). At the end of study, increased aPWV was observed in both groups but the increase was more pronounced in the control group. Increased pulse blood pressure (PBP) was observed in 27 (32.1 %) patients of the main group and 26 (33.3 %) patients of the control group (r=0.87). At the end of study, PBP decreased from 47.2+/-7.2 to 45.3+/-6.9 mm Hg (r. PMID- 29768163 TI - Tissue Damage Signaling Is a Prerequisite for Protective Neutrophil Recruitment to Microbial Infection in Zebrafish. AB - Tissue damage and infection are deemed likewise triggers of innate immune responses. But whereas neutrophil responses to microbes are generally protective, neutrophil recruitment into damaged tissues without infection is deleterious. Why neutrophils respond to tissue damage and not just to microbes is unknown. Is it a flaw of the innate immune system that persists because evolution did not select against it, or does it provide a selective advantage? Here we dissect the contribution of tissue damage signaling to antimicrobial immune responses in a live vertebrate. By intravital imaging of zebrafish larvae, a powerful model for innate immunity, we show that prevention of tissue damage signaling upon microbial ear infection abrogates leukocyte chemotaxis and reduces animal survival, at least in part, through suppression of cytosolic phospholipase A2 (cPla2), which integrates tissue damage- and microbe-derived cues. Thus, microbial cues are insufficient, and damage signaling is essential for antimicrobial neutrophil responses in zebrafish. PMID- 29768165 TI - Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency. PMID- 29768167 TI - When the Gut Gets Tough, the Enterocytes Get Going. AB - It is assumed that collateral damage from the immune system drives intestinal epithelial cell (IEC) expulsion during enteric infections. In this issue of Immunity, Zhai et al. (2018) describe how Drosophila's canonical immune deficiency (Imd) pathway programs IEC delamination in the gut. PMID- 29768164 TI - Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells. AB - Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns. An exhaustion severity metric was developed and integrated with high-dimensional phenotypes to define Tex cell clusters that were present in healthy subjects, common across chronic infection and cancer or enriched in either disease, linked to disease severity, and changed with HIV therapy. Combinatorial patterns of immunotherapy targets on different Tex cell clusters were also defined. This approach and associated datasets present a resource for investigating human Tex cell biology, with implications for immune monitoring and immunomodulation in chronic infections, autoimmunity, and cancer. PMID- 29768166 TI - Conditional Gene-Targeting in Mice: Problems and Solutions. PMID- 29768168 TI - A Worm's Gut Feelings: Neuronal Muscarinic and Epithelial Canonical Wnt Pathways Promote Antimicrobial Defense. AB - Molecular mechanisms connecting the gut-brain axis to immunity remain elusive. In this issue of Immunity, Labed et al. (2018) demonstrate that two evolutionarily conserved signaling mechanisms, the neuronal muscarinic and the epithelial Wnt pathways, together induce antimicrobial peptide expression that protects Caenorhabditis elegans against intestinal infection. PMID- 29768169 TI - TREMendous 2 Be Social. AB - TREM2 is known for its role in microglial phagocytosis and in neurodegenerative diseases. In this issue of Immunity, Filipello et al. (2018) show that microglial TREM2 is required for synaptic pruning in early development. TREM2-deficient mice show altered social behavior in adulthood, linking TREM2 to neurodevelopmental disease. PMID- 29768171 TI - Getting DAMP(s) Wets the Whistle for Neutrophil Recruitment. AB - Neutrophil recruitment in response to pathogen invasion is mediated through "self" tissue damage signals (DAMPs) and pathogen associated signals (PAMPs). In this issue of Immunity, Huang and Niethammer, (2018) demonstrate that DAMP signaling is a prerequisite for neutrophil recruitment. PMID- 29768170 TI - A Little Fiber Goes a Long Way. AB - In this issue of Immunity, Trompette et al. (2018) show that dietary fiber and short chain fatty acids reduce influenza A virus-associated immunopathology by enhancing CD8+ T cell effector function and by promoting the differentiation of alternatively activated macrophages. PMID- 29768172 TI - Trained Microglia Trigger Memory Loss. AB - Innate immune training is a recently described mechanism that allows innate cells to recollect a previous inflammatory episode. In a recent issue of Nature, Wendeln et al. (2018) show that peripheral inflammation can alter long-term microglia function, influencing neuropathology later in life. PMID- 29768173 TI - Peek-Peak-Pique: Repeating Motifs of Subtle Variance Are Targets for Potent Malaria Antibodies. AB - Biomedical interventions to curb malaria-causing Plasmodium falciparum (Pf) infections are critically needed. Two studies in Nature Medicine,Kisalu et al. (2018) and Tan et al. (2018), report the isolation of potent human antibodies that target a new epitope on Pf sporozoites and mediate effective parasite inhibition in pre-clinical models. PMID- 29768174 TI - HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. AB - HIV-1 vaccine development has been stymied by an inability to induce broadly reactive neutralizing antibodies to the envelope (Env) trimer, the sole viral antigen on the virion surface. Antibodies isolated from HIV-1-infected donors, however, have been shown to recognize all major exposed regions of the prefusion closed Env trimer, and an emerging understanding of the immunological and structural characteristics of these antibodies and the epitopes they recognize is enabling new approaches to vaccine design. Antibody lineage-based design creates immunogens that activate the naive ancestor-B cell of a target antibody lineage and that mature intermediate-B cells toward effective neutralization, with proof of principle achieved with select HIV-1-neutralizing antibody lineages in human gene knock-in mouse models. Epitope-based vaccine design involves the engineering of sites of Env vulnerability as defined by the recognition of broadly neutralizing antibodies, with cross-reactive neutralizing antibodies elicited in animal models. Both epitope-based and antibody lineage-based HIV-1 vaccine approaches are being readied for human clinical trials. PMID- 29768176 TI - The Chaperone UNC93B1 Regulates Toll-like Receptor Stability Independently of Endosomal TLR Transport. AB - Unc-93 homolog B1 (UNC93B1) is a key regulator of nucleic acid (NA)-sensing Toll like receptors (TLRs). Loss of NA-sensing TLR responses in UNC93B1-deficient patients facilitates Herpes simplex virus type 1 (HSV-1) encephalitis. UNC93B1 is thought to guide NA-sensing TLRs from the endoplasmic reticulum (ER) to their respective endosomal signaling compartments and to guide the flagellin receptor TLR5 to the cell surface, raising the question of how UNC93B1 mediates differential TLR trafficking. Here, we report that UNC93B1 regulates a step upstream of the differential TLR trafficking process. We discovered that UNC93B1 deficiency resulted in near-complete loss of TLR3 and TLR7 proteins in primary splenic mouse dendritic cells and macrophages, showing that UNC93B1 is critical for maintaining TLR expression. Notably, expression of an ER-retained UNC93B1 version was sufficient to stabilize TLRs and largely restore endosomal TLR trafficking and activity. These data are critical for an understanding of how UNC93B1 can regulate the function of a broad subset of TLRs. PMID- 29768177 TI - Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells. AB - Infections are thought to trigger CD8+ cytotoxic T lymphocyte (CTL) responses during autoimmunity. However, the transcriptional programs governing the tissue destructive potential of CTLs remain poorly defined. In a model of central nervous system (CNS) inflammation, we found that infection with lymphocytic choriomeningitis virus (LCMV), but not Listeria monocytogenes (Lm), drove autoimmunity. The DNA-binding factor TOX was induced in CTLs during LCMV infection and was essential for their encephalitogenic properties, and its expression was inhibited by interleukin-12 during Lm infection. TOX repressed the activity of several transcription factors (including Id2, TCF-1, and Notch) that are known to drive CTL differentiation. TOX also reduced immune checkpoint sensitivity by restraining the expression of the inhibitory checkpoint receptor CD244 on the surface of CTLs, leading to increased CTL-mediated damage in the CNS. Our results identify TOX as a transcriptional regulator of tissue destructive CTLs in autoimmunity, offering a potential mechanistic link to microbial triggers. PMID- 29768180 TI - Dietary Fiber Confers Protection against Flu by Shaping Ly6c- Patrolling Monocyte Hematopoiesis and CD8+ T Cell Metabolism. AB - Dietary fiber protects against chronic inflammatory diseases by dampening immune responses through short-chain fatty acids (SCFAs). Here we examined the effect of dietary fiber in viral infection, where the anti-inflammatory properties of SCFAs in principle could prevent protective immunity. Instead, we found that fermentable dietary fiber increased survival of influenza-infected mice through two complementary mechanisms. High-fiber diet (HFD)-fed mice exhibited altered bone marrow hematopoiesis, characterized by enhanced generation of Ly6c- patrolling monocytes, which led to increased numbers of alternatively activated macrophages with a limited capacity to produce the chemokine CXCL1 in the airways. Blunted CXCL1 production reduced neutrophil recruitment to the airways, thus limiting tissue immunopathology during infection. In parallel, diet-derived SCFAs boosted CD8+ T cell effector function by enhancing cellular metabolism. Hence, dietary fermentable fiber and SCFAs set an immune equilibrium, balancing innate and adaptive immunity so as to promote the resolution of influenza infection while preventing immune-associated pathology. PMID- 29768178 TI - Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies. AB - Natural killer cells (NKs) are abundant in the human decidua, regulating trophoblast invasion and angiogenesis. Several diseases of poor placental development are associated with first pregnancies, so we thus looked to characterize differences in decidual NKs (dNKs) in first versus repeated pregnancies. We discovered a population found in repeated pregnancies, which has a unique transcriptome and epigenetic signature, and is characterized by high expression of the receptors NKG2C and LILRB1. We named these cells Pregnancy Trained decidual NK cells (PTdNKs). PTdNKs have open chromatin around the enhancers of IFNG and VEGFA. Activation of PTdNKs led to increased production and secretion of IFN-gamma and VEGFalpha, with the latter supporting vascular sprouting and tumor growth. The precursors of PTdNKs seem to be found in the endometrium. Because repeated pregnancies are associated with improved placentation, we propose that PTdNKs, which are present primarily in repeated pregnancies, might be involved in proper placentation. PMID- 29768181 TI - Description of hot debriefings after in-hospital cardiac arrests in an international pediatric quality improvement collaborative. AB - BACKGROUND: The American Heart Association recommends debriefing after attempted resuscitation from in-hospital cardiac arrest (IHCA) to improve resuscitation quality and outcomes. This is the first published study detailing the utilization, process and content of hot debriefings after pediatric IHCA. METHODS: Using prospective data from the Pediatric Resuscitation Quality Collaborative (pediRES-Q), we analyzed data from 227 arrests occurring between February 1, 2016, and August 31, 2017. Hot debriefings, defined as occurring within minutes to hours of IHCA, were evaluated using a modified Team Emergency Assessment Measure framework for qualitative content analysis of debriefing comments. RESULTS: Hot debriefings were performed following 108 of 227 IHCAs (47%). The median interval to debriefing was 130 min (Interquartile range [IQR] 45, 270). Median debriefing duration was 15 min (IQR 10, 20). Physicians facilitated 95% of debriefings, with a median of 9 participants (IQR 7, 11). After multivariate analysis, accounting for hospital site, debriefing frequency was not associated with patient age, gender, race, illness category or unit type. The most frequent positive (plus) comments involved cooperation/coordination (60%), communication (47%) and clinical standards (41%). The most frequent negative (delta) comments involved equipment (46%), cooperation/coordination (45%), and clinical standards (36%). CONCLUSION: Approximately half of pediatric IHCAs were followed by hot debriefings. Hot debriefings were multi-disciplinary, timely, and often addressed issues of team cooperation/coordination, communication, clinical standards, and equipment. Additional studies are warranted to identify barriers to hot debriefings and to evaluate the impact of these debriefings on patient outcomes. PMID- 29768179 TI - Intestinal Epithelial Wnt Signaling Mediates Acetylcholine-Triggered Host Defense against Infection. AB - Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system. Infection-induced acetylcholine release from neurons stimulated muscarinic signaling in the epithelium, driving downstream induction of Wnt expression in the same tissue. Wnt induction activated the epithelial canonical Wnt pathway, resulting in the expression of C-type lectin and lysozyme genes that enhanced host defense. Furthermore, the muscarinic and Wnt pathways are linked by conserved transcription factors. These results reveal a tight connection between the nervous system and the intestinal epithelium, with important implications for host defense, immune homeostasis, and cancer. PMID- 29768182 TI - Enhanced production and immunological characterization of recombinant West Nile virus envelope domain III protein. AB - West Nile virus (WNV) is an emerging mosquito-borne virus which is responsible for severe and fatal encephalitis in humans and for which there is no licensed vaccine or therapeutic available to prevent infection. The envelope domain III protein (EDIII) of WNV was over-expressed in Escherichia coli and purified using a two-step chromatography process which included immobilized metal affinity chromatography and ion exchange chromatography. E. coli cells were grown in a bioreactor to high density using batch and fed-batch cultivation. Wet biomass obtained after batch and fed-batch cultivation processes was 11.2 g and 84 g/L of culture respectively. Protein yield after affinity purification was 5.76 mg and 5.81 mg/g wet cell weight after batch and fed-batch processes respectively. The purified WNV EDIII elicited specific antibodies in rabbits, confirming its immunogenicity. Moreover, the antibodies were able to neutralize WNV in vitro. These results established that the refolded and purified WNV EDIII could be a potential vaccine candidate. PMID- 29768184 TI - Effectiveness of depression interventions for people living with HIV in Sub Saharan Africa: A systematic review & meta-analysis of psychological & immunological outcomes. AB - This meta-analytic review evaluated the effectiveness of depression interventions on the psychological and immunological outcomes of people living with HIV in sub Saharan Africa. 14 studies, yielding 932 participants were eligible. A random effects models indicated that depression interventions were followed by large reductions in depression scores (effect size = 1.86, 95% CI = 1.71, 2.01, p < 0.01). No significant effect on immune outcome was observed, however there was a trend toward immune improvement of medium effect size (effect size on CD4 count and/or viral suppression = 0.57, 95% CI = -0.06, 1.20, p = 0.08). Pharmacological interventions appeared to have a significantly larger improvement in depression scores than psychological interventions. The greatest improvement in immune status was demonstrated in psychological treatments which incorporated a component to enhance HIV medication adherence, however these results did not reach significance. Small sample sizes and highly heterogeneous analysis necessitate caution in interpretation. The results of this meta-analysis should thus be treated as preliminary evidence and used to encourage further studies of immunopsychiatry in HIV in sub-Saharan Africa. PMID- 29768175 TI - Targeting the Latent Reservoir for HIV-1. AB - Antiretroviral therapy can effectively block HIV-1 replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to a cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will most likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, a cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here could pave the way. PMID- 29768185 TI - A simple, inexpensive method for subcortical stereotactic targeting in nonhuman primates. AB - BACKGROUND: Many current neuroscience studies in large animal models have focused on recordings from cortical structures. While sufficient for analyzing sensorimotor systems, many processes are modulated by subcortical nuclei. Large animal models, such as nonhuman primates (NHP), provide an optimal model for studying these circuits, but the ability to target subcortical structures has been hampered by lack of a straightforward approach to targeting. NEW METHOD: Here we present a method of subcortical targeting in NHP that uses MRI-compatible titanium screws as fiducials. The in vivo study used a cellular marker for histologic confirmation of accuracy. RESULTS: Histologic results are presented showing a cellular stem cell marker within targeted structures, with mean errors +/- standard deviations (SD) of 1.40 +/- 1.19 mm in the X-axis and 0.9 +/- 0.97 mm in the Z-axis. The Y-axis errors +/- SD ranged from 1.5 +/- 0.43 to 4.2 +/- 1.72 mm. COMPARISON WITH EXISTING METHODS: This method is easy and inexpensive, and requires no fabrication of equipment, keeping in mind the goal of optimizing a technique for implantation or injection into multiple interconnected areas. CONCLUSION: This procedure will enable primate researchers to target deep, subcortical structures more precisely in animals of varying ages and weights. PMID- 29768183 TI - NDRG1 disruption alleviates cisplatin/sodium glycididazole-induced DNA damage response and apoptosis in ERCC1-defective lung cancer cells. AB - BACKGROUND: Resistance to platinum-based chemotherapy becomes a major obstacle in lung cancer treatment. Compensatory activation of nucleotide excision repair (NER) pathway is the major mechanism accounting for cisplatin-resistance. We aimed at identifying additional regulators in NER-mediated chemoresistance in a hypoxic setting induced by sodium glycididazole (CMNa)-sensitized cisplatin chemotherapy of non-small cell lung cancer (NSCLC). METHODS: We performed an RNA sequencing (RNA-Seq) analysis to identify the genes whose expression had been differentially regulated in NER-deficient cells that had been treated by cisplatin/CMNa. DNA damage, apoptosis, and correlational analysis between the differentially expressed gene and drug sensitivity were determined by Western blots, flow cytometry and Oncomine expression analysis. RESULTS: The stress response gene, NDRG1 (N-Myc downstream-regulated gene 1), was among the differentially expressed genes in NER-deficient cells upon treatment of cisplatin/CMNa. Downregulation of NDRG1 by ERCC1 (excision repair cross complementing 1) could be a prevalent mechanism for drug resistance. Furthermore, lower NDRG1 level is observed in human lung cancer cells showing chemotherapeutic drug resistance compared with the drug-sensitive cells. CONCLUSION: NDRG1 is an important modulator linking DNA damage response and hypoxia-related cellular stress response during the development of drug resistance to cisplatin/CMNa in lung cancer. Targeting both NDRG1 and ERCC1 may be a viable strategy for overcoming drug resistance in cancer therapy, and has significant clinical implications. PMID- 29768186 TI - Predicted reach consequences drive time course of tactile suppression. AB - Sensitivity to touch is reduced during movement; this tactile suppression is likely the result of a mechanism that suppresses self-generated movement consequences. We sought to determine whether tactile suppression is modulated by naturally evoked changes in movement speed driven by task precision demands (Exp.1), and by changes in predicted movement consequences (Exp.2). We measured suppression by comparing detection thresholds for a vibration applied to the finger during reach and at rest. In Experiment 1 we varied reach target size to create a speed-accuracy tradeoff, where participants decelerated more to smaller targets to accurately hit them. We theorized that the reduction in late-reach speed associated with higher precision demands might lead to a reduction in late reach suppression, consistent with the literature showing a positive relationship between speed and suppression. Contrary to our hypothesis, we found suppression increased towards the end of the reach in all conditions, despite a significant decrease in reaching speed. We postulated this might be a de-emphasizing of the predicted tactile feedback associated with tapping the target. To test this, in Experiment 2 we paired a vibration consequence with a target of a certain colour. We found an increase in late-reach suppression for this target compared to a target of another colour with no associated consequence. Our results indicate that tactile suppression is temporally sensitive and increases as predicted consequences become more likely. We propose the positive correlation between movement speed and suppression previously reported may be driven by the predicted somatosensory consequences associated with increased movement speed. PMID- 29768188 TI - Micropatterned biodegradable polyesters clicked with CQAASIKVAV promote cell alignment, directional migration, and neurite outgrowth. AB - : The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) in terms of cellular spatial arrangement and directional migration as well as neurite orientation for bridging the proximal and distal stumps of the injured peripheral nervous system. In this study, stripe micropatterns having ridges/grooves of width 20/20 and 20/40 MUm were fabricated on the surface of maleimide-functionalized biodegradable poly(ester carbonate) (P(LLA-MTMC)) films by the polydimethylsiloxane mold-pressing method, respectively. The laminin-derived CQAASIKVAV peptides end-capped with an SH group were then grafted by the thiol-ene click reaction under mild conditions to obtain micropatterned and peptide-grafted films. SCs cultured on these films, especially on the 20/40-MUm film, displayed faster and aligned adhesion as well as a larger number of elongated cells with a higher length-to-width (L/W) ratio along the stripe direction than those on the flat-pep film. The migration rate of SCs was significantly enhanced in parallel to the stripe direction with a large net displacement. The micropatterned and peptide-grafted films, especially the 20/40 MUm film, could promote SC proliferation and nerve growth factor (NGF) secretion in a manner similar to that of the peptide-grafted planar film. Moreover, the neurites of rat pheochromocytoma 12 (PC12) cells sprouted along the ridges with a longer average length on the micropatterned and peptide-grafted films. The synergistic effect of physical patterns and biological cues was evaluated by considering the results of cell adhesion force; immunofluorescence staining of vinculin; fluorescence staining of F-actin and the nucleus; as well as gene expression of neural cadherin (NCAD), neurocan (NCAN), and myelin protein zero (P0). STATEMENT OF SIGNIFICANCE: The interplay of microstructures and biological cues is critical to regulate the behaviors of Schwann cells (SCs) and nerve cells, and thereby the regeneration of peripheral nerve system. In this study, the combined micropatterning and CQAASIKVAV grafting endowed the modified P(LLA MTMC) films with both contact guidance and bioactive chemical cues to enhance cell proliferation, directional alignment and migration, longer net displacement and larger NGF secretion, and stronger neurite outgrowth of SCs and PC12 cells. Hence, the integration of physical micropatterns and bioactive molecules is an effective way to obtain featured biomaterials for the regeneration of nerves and other types of tissues. PMID- 29768189 TI - Neural responses to perturbations in visual and auditory metronomes during sensorimotor synchronization. AB - Tapping in synchrony to an isochronous rhythm involves several key functions of the sensorimotor system including timing, prediction and error correction. While auditory sensorimotor synchronization (SMS) has been well studied, much less is known about mechanisms involved in visual SMS. By comparing error correction in auditory and visual SMS, it can be determined if the neural mechanisms for detection and correction of synchronization errors are generalized or domain specific. To study this problem, we measured EEG while subjects tapped in synchrony to separate visual and auditory metronomes that both contained small temporal perturbations to induce errors. The metronomes had inter-onset intervals of 600 ms and the perturbations where of 4 kinds: +/- 66 ms to induce period corrections, and +/- 16 ms to induce phase corrections. We hypothesize that given the less precise nature of visual SMS, error correction to perturbed visual flashing rhythms will be more gradual than with the equivalent auditory perturbations. Additionally, we expect this more gradual error correction will be reflected in the visual evoked potentials. Our findings indicate that the visual system is only capable of more gradual phase corrections to even the larger induced errors. This is opposed to the swifter period correction of the auditory system to large induced errors. EEG data found the peak N1 auditory evoked potential is modulated by the size and direction of an induced error in line with previous research, while the P1 visual evoked potential was only effected by the large late-coming perturbations resulting in reduced peak latency. Looking at the error response EEG data, an Error Related Negativity (ERN) and related Error Positivity (pE) was found only in the auditory + 66 condition, while no ERN or pE were found in any of the visual perturbation conditions. In addition to the ERPs, we performed a dipole source localization and clustering analysis indicating that the anterior cingulate was active in the error detection of the perturbed stimulus for both auditory and visual conditions in addition to being involved in producing the ERN and pE induced by the auditory + 66 perturbation. Taken together, these results confirm that the visual system is less developed for synchronizing and error correction with flashing rhythms by its more gradual error correction. The reduced latency of the P1 to the visual + 66 suggests that the visual system can detect these errors, but that detection does not translate into any meaningful improvement in error correction. This indicates that the visual system is not as tightly coupled to the motor system as the auditory system is for SMS, suggesting the mechanisms of SMS are not completely domain general. PMID- 29768187 TI - Activation of kappa opioid receptors in the dorsal raphe have sex dependent effects on social behavior in California mice. AB - Kappa opioid receptor activation has been linked to stress and anxiety behavior, thus leading to kappa antagonists being popularized in research as potential anxiolytics. However, while these findings may hold true in standard models, the neuromodulatory effects of social defeat may change the behavioral outcome of kappa opioid receptor activation. Previous research has shown that social defeat can lead to hyperactivity of serotonergic neurons in the dorsal raphe nucleus, and that inhibition of this increase blocks the social deficits caused by defeat. Kappa opioid receptor activation in the dorsal raphe nucleus works to decrease serotonergic activity. We injected the kappa opioid receptor U50,488 directly into the dorsal raphe nucleus of male and female, defeat and control adult California mice. Here we show evidence that U50,488 induces anxiety behavior in control male California mice, but helps relieve it in defeated males. Consistent with previous literature, we find little effect in females adding evidence that there are marked and important sex differences in the kappa opioid system. PMID- 29768190 TI - A Bayesian model comparison approach to test the specificity of visual integration impairment in schizophrenia or psychosis. AB - Impaired visual integration is well documented in schizophrenia and related to functional outcomes. However, it is unclear if this deficit is specific to schizophrenia, or characteristic of psychosis more broadly. To address this question, this study used a Bayesian model comparison approach to examine the evidence of three grouping models of visual integration performance in 116 individuals with schizophrenia (SZ), schizoaffective disorder (SA), bipolar disorder (BD) with or without a history of prominent psychosis (BDP+ and BDP-, respectively), or no psychiatric diagnosis (healthy controls; HC). We compared: (1) Psychosis Model (psychosis, non-psychosis), where the psychosis group included SZ, SA, and BDP+, and the non-psychosis group included BDP- and HC; (2) Schizophrenia Model (SZ, non-SZ); and (3) DSM Model (SZ, SA, BD, HC). The relationship between visual integration and general cognition was also explored. The Psychosis Model showed the strongest evidence, and visual integration was associated with general cognition in participants with psychosis. The results were consistent with the Research Domain Criteria (RDoC) framework, indicating that visual integration impairment is characteristic of psychosis and not specific to SZ or DSM categories, and may share similar disease pathways with observed neurocognitive deficits in psychotic disorders. PMID- 29768191 TI - Loss of a Negative Regulator of mTORC1 Induces Aerobic Glycolysis and Altered Fiber Composition in Skeletal Muscle. AB - The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance. Furthermore, loss of NPRL2 induces aerobic glycolysis and suppresses glucose entry into the TCA cycle. Such chronic activation of mTORC1 leads to compensatory increases in anaplerotic pathways to replenish TCA intermediates that are consumed for biosynthetic purposes. These phenotypes reveal a fundamental role for the GATOR1 complex in the homeostatic regulation of mitochondrial functions (biosynthesis versus ATP) to mediate carbohydrate utilization in muscle. PMID- 29768192 TI - Nuclear Export Inhibition Enhances HLH-30/TFEB Activity, Autophagy, and Lifespan. AB - Transcriptional modulation of the process of autophagy involves the transcription factor HLH-30/TFEB. In order to systematically determine the regulatory network of HLH-30/TFEB, we performed a genome-wide RNAi screen in C. elegans and found that silencing the nuclear export protein XPO-1/XPO1 enhances autophagy by significantly enriching HLH-30 in the nucleus, which is accompanied by proteostatic benefits and improved longevity. Lifespan extension via xpo-1 silencing requires HLH-30 and autophagy, overlapping mechanistically with several established longevity models. Selective XPO1 inhibitors recapitulated the effect on autophagy and lifespan observed by silencing xpo-1 and protected ALS-afflicted flies from neurodegeneration. XPO1 inhibition in HeLa cells enhanced TFEB nuclear localization, autophagy, and lysosome biogenesis without affecting mTOR activity, revealing a conserved regulatory mechanism for HLH-30/TFEB. Altogether, our study demonstrates that altering the nuclear export of HLH-30/TFEB can regulate autophagy and establishes the rationale of targeting XPO1 to stimulate autophagy in order to prevent neurodegeneration. PMID- 29768195 TI - Reprogramming of Chromatin Accessibility in Somatic Cell Nuclear Transfer Is DNA Replication Independent. AB - Mammalian oocytes have the ability to reset the transcriptional program of differentiated somatic cells into that of totipotent embryos through somatic cell nuclear transfer (SCNT). However, the mechanisms underlying SCNT-mediated reprogramming are largely unknown. To understand the mechanisms governing chromatin reprogramming during SCNT, we profiled DNase I hypersensitive sites (DHSs) in donor cumulus cells and one-cell stage SCNT embryos. To our surprise, the chromatin accessibility landscape of the donor cells is drastically changed to recapitulate that of the in vitro fertilization (IVF)-derived zygotes within 12 hr. Interestingly, this DHS reprogramming takes place even in the presence of a DNA replication inhibitor, suggesting that SCNT-mediated DHS reprogramming is independent of DNA replication. Thus, this study not only reveals the rapid and drastic nature of the changes in chromatin accessibility through SCNT but also establishes a DNA replication-independent model for studying cellular reprogramming. PMID- 29768196 TI - Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance. AB - Elevated circulating fatty acids (FAs) contribute to obesity-associated metabolic complications, but the mechanisms by which insulin suppresses lipolysis are poorly understood. We show that alpha/beta-hydrolase domain-containing 15 (ABHD15) is required for the anti-lipolytic action of insulin in white adipose tissue (WAT). Neither insulin nor glucose treatments can suppress FA mobilization in global and conditional Abhd15-knockout (KO) mice. Accordingly, insulin signaling is impaired in Abhd15-KO adipocytes, as indicated by reduced AKT phosphorylation, glucose uptake, and de novo lipogenesis. In vitro data reveal that ABHD15 associates with and stabilizes phosphodiesterase 3B (PDE3B). Accordingly, PDE3B expression is decreased in the WAT of Abhd15-KO mice, mechanistically explaining increased protein kinase A (PKA) activity, hormone sensitive lipase (HSL) phosphorylation, and undiminished FA release upon insulin signaling. Ultimately, Abhd15-KO mice develop insulin resistance. Notably, ABHD15 expression is decreased in humans with obesity and diabetes compared to humans with obesity and normal glucose tolerance, identifying ABHD15 as a potential therapeutic target to mitigate insulin resistance. PMID- 29768193 TI - GSK3beta Regulates Brain Energy Metabolism. AB - GSK3beta is a serine threonine kinase implicated in the progression of Alzheimer's disease. Although the role of GSK3beta in growth and pathology has been extensively studied, little is known about the metabolic consequences of GSK3beta manipulation, particularly in the brain. Here, we show that GSK3beta regulates mitochondrial energy metabolism in human H4 neuroglioma cells and rat PC12-derived neuronal cells and that inhibition of GSK3beta in mice in vivo alters metabolism in the hippocampus in a region-specific manner. We demonstrate that GSK3beta inhibition increases mitochondrial respiration and membrane potential and alters NAD(P)H metabolism. These metabolic effects are associated with increased PGC-1alpha protein stabilization, enhanced nuclear localization, and increased transcriptional co-activation. In mice treated with the GSK3beta inhibitor lithium carbonate, changes in hippocampal energy metabolism are linked to increased PGC-1alpha. These data highlight a metabolic role for brain GSK3beta and suggest that the GSK3beta/PGC-1alpha axis may be important in neuronal metabolic integrity. PMID- 29768194 TI - Extracellular Forms of Abeta and Tau from iPSC Models of Alzheimer's Disease Disrupt Synaptic Plasticity. AB - The early stages of Alzheimer's disease are associated with synaptic dysfunction prior to overt loss of neurons. To identify extracellular molecules that impair synaptic plasticity in the brain, we studied the secretomes of human iPSC-derived neuronal models of Alzheimer's disease. When introduced into the rat brain, secretomes from human neurons with either a presenilin-1 mutation, amyloid precursor protein duplication, or trisomy of chromosome 21 all strongly inhibit hippocampal long-term potentiation. Synaptic dysfunction caused by presenilin-1 mutant and amyloid precusor protein duplication secretomes is mediated by Abeta peptides, whereas trisomy of chromosome 21 (trisomy 21) neuronal secretomes induce dysfunction through extracellular tau. In all cases, synaptotoxicity is relieved by antibody blockade of cellular prion protein. These data indicate that human models of Alzheimer's disease generate distinct proteins that converge at the level of cellular prion protein to induce synaptic dysfunction in vivo. PMID- 29768198 TI - Myocardin-Related Transcription Factor A Promotes Recruitment of ITGA5+ Profibrotic Progenitors during Obesity-Induced Adipose Tissue Fibrosis. AB - Adipose tissue fibrosis is associated with inflammation and insulin resistance in human obesity. In particular, visceral fat fibrosis is correlated with hyperlipidemia and ectopic fat accumulation. Myocardin-related transcription factor A (MRTFA) is an important coactivator that mediates the transcription of extracellular matrix and other fibrogenic genes. Here, we examine the role of MRTFA in the development of adipose tissue fibrosis and identify a signaling pathway that regulates the fate of vascular progenitors. We demonstrate that obesity induces the formation of Sca1-, Sma+, ITGA5+ fibrogenic progenitor cells (FPCs) in adipose tissue. MRTFA deficiency in mice shifts the fate of perivascular progenitors from FPCs to adipocyte precursor cells and protects against chronic obesity-induced fibrosis and accompanying metabolic dysfunction, without a shift in energy expenditure. Our findings highlight the ITGA5-MRTFA pathway as a potential target to ameliorate obesity-associated metabolic disease. PMID- 29768199 TI - The Autism-Related Protein CHD8 Cooperates with C/EBPbeta to Regulate Adipogenesis. AB - The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein beta (C/EBPbeta) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPalpha and peroxisome-proliferator-activated receptor gamma (PPARgamma), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPbeta regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue. PMID- 29768200 TI - Sensory Afferents Use Different Coding Strategies for Heat and Cold. AB - Primary afferents transduce environmental stimuli into electrical activity that is transmitted centrally to be decoded into corresponding sensations. However, it remains unknown how afferent populations encode different somatosensory inputs. To address this, we performed two-photon Ca2+ imaging from thousands of dorsal root ganglion (DRG) neurons in anesthetized mice while applying mechanical and thermal stimuli to hind paws. We found that approximately half of all neurons are polymodal and that heat and cold are encoded very differently. As temperature increases, more heating-sensitive neurons are activated, and most individual neurons respond more strongly, consistent with graded coding at population and single-neuron levels, respectively. In contrast, most cooling-sensitive neurons respond in an ungraded fashion, inconsistent with graded coding and suggesting combinatorial coding, based on which neurons are co-activated. Although individual neurons may respond to multiple stimuli, our results show that different stimuli activate distinct combinations of diversely tuned neurons, enabling rich population-level coding. PMID- 29768197 TI - Induction of Nitric-Oxide Metabolism in Enterocytes Alleviates Colitis and Inflammation-Associated Colon Cancer. AB - Nitric oxide (NO) plays an established role in numerous physiological and pathological processes, but the specific cellular sources of NO in disease pathogenesis remain unclear, preventing the implementation of NO-related therapy. Argininosuccinate lyase (ASL) is the only enzyme able to produce arginine, the substrate for NO generation by nitric oxide synthase (NOS) isoforms. Here, we generated cell-specific conditional ASL knockout mice in combination with genetic and chemical colitis models. We demonstrate that NO derived from enterocytes alleviates colitis by decreasing macrophage infiltration and tissue damage, whereas immune cell-derived NO is associated with macrophage activation, resulting in increased severity of inflammation. We find that induction of endogenous NO production by enterocytes with supplements that upregulate ASL expression and complement its substrates results in improved epithelial integrity and alleviation of colitis and of inflammation-associated colon cancer. PMID- 29768201 TI - Activation of EphB2 Forward Signaling Enhances Memory Consolidation. AB - EphB2 is involved in enhancing synaptic transmission and gene expression. To explore the roles of EphB2 in memory formation and enhancement, we used a photoactivatable EphB2 (optoEphB2) to activate EphB2 forward signaling in pyramidal neurons in lateral amygdala (LA). Photoactivation of optoEphB2 during fear conditioning, but not minutes afterward, enhanced long-term, but not short term, auditory fear conditioning. Photoactivation of optoEphB2 during fear conditioning led to activation of the cAMP/Ca2+ responsive element binding (CREB) protein. Application of light to a kinase-dead optoEphB2 in LA did not lead to enhancement of long-term fear conditioning memory or to activation of CREB. Long term, but not short-term, auditory fear conditioning memory was impaired in mice lacking EphB2 forward signaling (EphB2lacZ/lacZ). Activation of optoEphB2 in LA of EphB2lacZ/lacZ mice enhanced long-term fear conditioning memory. The present findings show that the level of EphB2 forward signaling activity during learning determines the strength of long-term memory consolidation. PMID- 29768202 TI - Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering. AB - The endoplasmic reticulum (ER) is a complex network of sheets and tubules that is continuously remodeled. The relevance of this membrane dynamics is underscored by the fact that mutations in atlastins (ATLs), the ER fusion proteins in mammals, cause neurodegeneration. How defects in this process disrupt neuronal homeostasis is unclear. Using electron microscopy (EM) volume reconstruction of transfected cells, neurons, and patient fibroblasts, we show that hereditary sensory and autonomic neuropathy (HSAN)-causing ATL3 mutants promote aberrant ER tethering hallmarked by bundles of laterally attached ER tubules. In vitro, these mutants cause excessive liposome tethering, recapitulating the results in cells. Moreover, ATL3 variants retain their dimerization-dependent GTPase activity but are unable to promote membrane fusion, suggesting a defect in an intermediate step of the ATL3 functional cycle. Our data show that the effects of ATL3 mutations on ER network organization go beyond a loss of fusion and shed light on neuropathies caused by atlastin defects. PMID- 29768204 TI - An Amphipathic Helix Directs Cellular Membrane Curvature Sensing and Function of the BAR Domain Protein PICK1. AB - BAR domains are dimeric protein modules that sense, induce, and stabilize lipid membrane curvature. Here, we show that membrane curvature sensing (MCS) directs cellular localization and function of the BAR domain protein PICK1. In PICK1, and the homologous proteins ICA69 and arfaptin2, we identify an amphipathic helix N terminal to the BAR domain that mediates MCS. Mutational disruption of the helix in PICK1 impaired MCS without affecting membrane binding per se. In insulin producing INS-1E cells, super-resolution microscopy revealed that disruption of the helix selectively compromised PICK1 density on insulin granules of high curvature during their maturation. This was accompanied by reduced hormone storage in the INS-1E cells. In Drosophila, disruption of the helix compromised growth regulation. By demonstrating size-dependent binding on insulin granules, our finding highlights the function of MCS for BAR domain proteins in a biological context distinct from their function, e.g., at the plasma membrane during endocytosis. PMID- 29768203 TI - Unconventional Secretion Mediates the Trans-cellular Spreading of Tau. AB - The progressive deposition of misfolded hyperphosphorylated tau is a pathological hallmark of tauopathies, including Alzheimer's disease. However, the underlying molecular mechanisms governing the intercellular spreading of tau species remain elusive. Here, we show that full-length soluble tau is unconventionally secreted by direct translocation across the plasma membrane. Increased secretion is favored by tau hyperphosphorylation, which provokes microtubule detachment and increases the availability of free protein inside cells. Using a series of binding assays, we show that free tau interacts with components enriched at the inner leaflet of the plasma membrane, finally leading to its translocation across the plasma membrane mediated by sulfated proteoglycans. We provide further evidence that secreted soluble tau species spread trans-cellularly and are sufficient for the induction of intracellular tau aggregation in adjacent cells. Our study demonstrates the mechanistic details of tau secretion and provides insights into the initiation and progression of tau pathology. PMID- 29768205 TI - C. elegans Blastomeres Clear the Corpse of the Second Polar Body by LC3 Associated Phagocytosis. AB - To understand how undifferentiated pluripotent cells cope with cell corpses, we examined the clearance of polar bodies born during female meiosis. We found that polar bodies lose membrane integrity and expose phosphatidylserine in Caenorhabditis elegans. Polar body signaling recruits engulfment receptors to the plasma membrane of embryonic blastomeres using the PI3K VPS-34, RAB-5 GTPase and the sorting nexin SNX-6. The second polar body is then phagocytosed using receptor-mediated engulfment pathways dependent on the Rac1 ortholog CED-10 but undergoes non-apoptotic programmed cell death independent of engulfment. RAB-7 GTPase is required for lysosome recruitment to the polar body phagosome, while LC3 lipidation is required for degradation of the corpse membrane after lysosome fusion. The polar body phagolysosome vesiculates in an mTOR- and ARL-8-dependent manner, which assists its timely degradation. Thus, we established a genetic model to study clearance by LC3-associated phagocytosis and reveal insights into the mechanisms of phagosome maturation and degradation. PMID- 29768206 TI - Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis. AB - The effector B cell lymphoma-2 (BCL-2) protein BCL-2 ovarian killer (BOK) induces mitochondrial outer membrane permeabilization (MOMP) to initiate apoptosis upon inhibition of the proteasome. How BOK mediates MOMP is mechanistically unknown. The NMR structure of the BCL-2 core of human BOK reveals a conserved architecture with an atypical hydrophobic groove that undergoes conformational exchange. Remarkably, the BCL-2 core of BOK spontaneously associates with purified mitochondria to release cytochrome c in MOMP assays. Alanine substitution of a unique glycine in helix alpha1 stabilizes BOK, as shown by thermal shift and urea denaturation analyses, and significantly inhibits MOMP, liposome permeabilization, and cell death. Activated BID does not activate WT BOK or the stabilized alanine mutant to promote cell death. We propose that BOK-mediated membrane permeabilization is governed in part by its unique metastability of the hydrophobic groove and helix alpha1 and not through activation by BH3 ligands. PMID- 29768207 TI - Defective Replication Stress Response Is Inherently Linked to the Cancer Stem Cell Phenotype. AB - Extensive spontaneous DNA damage from oncogene-induced replication stress is ubiquitous in precancerous lesions. While this damage induces differentiation, senescence, or apoptosis in normal cells, defects in DNA replication stress response (RSR) allow cells to continue proliferating, ultimately leading to early tumorigenesis. Using systems-level approaches, we developed a replication stress response defect gene signature that predicted risk of cancer development from hyperplastic lesions. Intriguingly, we found that replication stress response defects rewire non-malignant cells into a cancer stem cell (CSC)-like state, and analysis of CSCs indicated that they inherently harbor replication stress response defects. High-throughput drug screening to elucidate molecules required for survival of replication stress response defective cells identified a dependence on MEK/ERK signaling. Inhibition of this signaling cascade restored oncogene-induced senescence through a p53-independent MDM2/p21 axis. Moreover, MEK/ERK inhibition also depleted CSC populations. Together, these findings provide insights into the role of replication stress response defects in CSCs and an actionable pathway for therapeutic targeting. PMID- 29768208 TI - The CST Complex Mediates End Protection at Double-Strand Breaks and Promotes PARP Inhibitor Sensitivity in BRCA1-Deficient Cells. AB - Selective elimination of BRCA1-deficient cells by inhibitors of poly(ADP-ribose) polymerase (PARP) is a prime example of the concept of synthetic lethality in cancer therapy. This interaction is counteracted by the restoration of BRCA1 independent homologous recombination through loss of factors such as 53BP1, RIF1, and REV7/MAD2L2, which inhibit end resection of DNA double-strand breaks (DSBs). To identify additional factors involved in this process, we performed CRISPR/SpCas9-based loss-of-function screens and selected for factors that confer PARP inhibitor (PARPi) resistance in BRCA1-deficient cells. Loss of members of the CTC1-STN1-TEN1 (CST) complex were found to cause PARPi resistance in BRCA1 deficient cells in vitro and in vivo. We show that CTC1 depletion results in the restoration of end resection and that the CST complex may act downstream of 53BP1/RIF1. These data suggest that, in addition to its role in protecting telomeres, the CST complex also contributes to protecting DSBs from end resection. PMID- 29768209 TI - Influenza Virus Mounts a Two-Pronged Attack on Host RNA Polymerase II Transcription. AB - Influenza virus intimately associates with host RNA polymerase II (Pol II) and mRNA processing machinery. Here, we use mammalian native elongating transcript sequencing (mNET-seq) to examine Pol II behavior during viral infection. We show that influenza virus executes a two-pronged attack on host transcription. First, viral infection causes decreased Pol II gene occupancy downstream of transcription start sites. Second, virus-induced cellular stress leads to a catastrophic failure of Pol II termination at poly(A) sites, with transcription often continuing for tens of kilobases. Defective Pol II termination occurs independently of the ability of the viral NS1 protein to interfere with host mRNA processing. Instead, this termination defect is a common effect of diverse cellular stresses and underlies the production of previously reported downstream of-gene transcripts (DoGs). Our work has implications for understanding not only host-virus interactions but also fundamental aspects of mammalian transcription. PMID- 29768210 TI - Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. AB - Chimeric antigen receptor (CAR) T cell therapy has proven clinically beneficial against B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, suboptimal clinical outcomes have been associated with decreased expansion and persistence of adoptively transferred CAR T cells, antigen-negative relapses, and impairment by an immunosuppressive tumor microenvironment. Improvements in CAR T cell design are required to enhance clinical efficacy, as well as broaden the applicability of this technology. Here, we demonstrate that interleukin-18 (IL 18)-secreting CAR T cells exhibit enhanced in vivo expansion and persistence and significantly increase long-term survival in syngeneic mouse models of both hematological and solid malignancies. In addition, we demonstrate that IL-18 secreting CAR T cells are capable of modulating the tumor microenvironment, as well as enhancing an effective endogenous anti-tumor immune response. IL-18 secreting CAR T cells represent a promising strategy to enhance the clinical outcomes of adoptive T cell therapy. PMID- 29768211 TI - Long-Term Persistence of Exhausted CD8 T Cells in Chronic Infection Is Regulated by MicroRNA-155. AB - Persistent viral infections and tumors drive development of exhausted T (TEX) cells. In these settings, TEX cells establish an important host-pathogen or host tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells. However, rather than strictly antagonizing exhaustion, miR-155 promoted a terminal TEX cell subset. Transcriptional profiling identified coordinated control of cell signaling and transcription factor pathways, including the key AP-1 family member Fosl2. Overexpression of Fosl2 reversed the miR-155 effects, identifying a link between miR-155 and the AP-1 transcriptional program in regulating TEX cells. Thus, we identify a mechanism of miR-155 regulation of TEX cells and a key role for Fosl2 in T cell exhaustion. PMID- 29768212 TI - mTOR Senses Environmental Cues to Shape the Fibroblast-like Synoviocyte Response to Inflammation. AB - Accumulating evidence suggests that metabolic master regulators, including mTOR, regulate adaptive and innate immune responses. Resident mesenchymal tissue components are increasingly recognized as key effector cells in inflammation. Whether mTOR also controls the inflammatory response in fibroblasts is insufficiently studied. Here, we show that TNF signaling co-opts the mTOR pathway to shift synovial fibroblast (FLS) inflammation toward an IFN response. mTOR pathway activation is associated with decreased NF-kappaB-mediated gene expression (e.g., PTGS2, IL-6, and IL-8) but increased STAT1-dependent gene expression (e.g., CXCL11 and TNFSF13B). We further demonstrate how metabolic inputs, such as amino acids, impinge on TNF-mTORC1 signaling to differentially regulate pro-inflammatory signaling circuits. Our results define a critical role for mTOR in the regulation of the pro-inflammatory response in FLSs and unfold its pathogenic involvement in TNF-driven diseases, such as rheumatoid arthritis (RA). PMID- 29768213 TI - miRNAs that Induce Human Cardiomyocyte Proliferation Converge on the Hippo Pathway. AB - Understanding the mechanisms that control human cardiomyocyte proliferation might be applicable to regenerative medicine. We screened a whole genome collection of human miRNAs, identifying 96 to be capable of increasing proliferation (DNA synthesis and cytokinesis) of human iPSC-derived cardiomyocytes. Chemical screening and computational approaches indicated that most of these miRNAs (67) target different components of the Hippo pathway and that their activity depends on the nuclear translocation of the Hippo transcriptional effector YAP. 53 of the 67 miRNAs are present in human iPSC cardiomyocytes, yet anti-miRNA screening revealed that none are individually essential for basal proliferation of hiPSC cardiomyocytes despite the importance of YAP for proliferation. We propose a model in which multiple endogenous miRNAs redundantly suppress Hippo signaling to sustain the cell cycle of immature cardiomyocytes. PMID- 29768214 TI - Noise in the Vertebrate Segmentation Clock Is Boosted by Time Delays but Tamed by Notch Signaling. AB - Taming cell-to-cell variability in gene expression is critical for precise pattern formation during embryonic development. To investigate the source and buffering mechanism of expression variability, we studied a biological clock, the vertebrate segmentation clock, controlling the precise spatiotemporal patterning of the vertebral column. By counting single transcripts of segmentation clock genes in zebrafish, we show that clock genes have low RNA amplitudes and expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling. We further show that expression noise surprisingly increases from the posterior progenitor zone to the anterior segmentation and differentiation zone. Our computational model reproduces the spatial noise profile by incorporating spatially increasing time delays in gene expression. Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators. PMID- 29768215 TI - Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1. AB - The splicing factor SRSF1 promotes nonsense-mediated mRNA decay (NMD), a quality control mechanism that degrades mRNAs with premature termination codons (PTCs). Here we show that transcript-bound SRSF1 increases the binding of NMD factor UPF1 to mRNAs while in, or associated with, the nucleus, bypassing UPF2 recruitment and promoting NMD. SRSF1 promotes NMD when positioned downstream of a PTC, which resembles the mode of action of exon junction complex (EJC) and NMD factors. Moreover, splicing and/or EJC deposition increase the effect of SRSF1 on NMD. Lastly, SRSF1 enhances NMD of PTC-containing endogenous transcripts that result from various events. Our findings reveal an alternative mechanism for UPF1 recruitment, uncovering an additional connection between splicing and NMD. SRSF1's role in the mRNA's journey from splicing to decay has broad implications for gene expression regulation and genetic diseases. PMID- 29768217 TI - Integrative Characterization of the R6/2 Mouse Model of Huntington's Disease Reveals Dysfunctional Astrocyte Metabolism. AB - Huntington's disease is a fatal neurodegenerative disease, where dysfunction and loss of striatal and cortical neurons are central to the pathogenesis of the disease. Here, we integrated quantitative studies to investigate the underlying mechanisms behind HD pathology in a systems-wide manner. To this end, we used state-of-the-art mass spectrometry to establish a spatial brain proteome from late-stage R6/2 mice and compared this with wild-type littermates. We observed altered expression of proteins in pathways related to energy metabolism, synapse function, and neurotransmitter homeostasis. To support these findings, metabolic 13C labeling studies confirmed a compromised astrocytic metabolism and regulation of glutamate-GABA-glutamine cycling, resulting in impaired release of glutamine and GABA synthesis. In recent years, increasing attention has been focused on the role of astrocytes in HD, and our data support that therapeutic strategies to improve astrocytic glutamine homeostasis may help ameliorate symptoms in HD. PMID- 29768216 TI - The RNA Exosome Adaptor ZFC3H1 Functionally Competes with Nuclear Export Activity to Retain Target Transcripts. AB - Mammalian genomes are promiscuously transcribed, yielding protein-coding and non coding products. Many transcripts are short lived due to their nuclear degradation by the ribonucleolytic RNA exosome. Here, we show that abolished nuclear exosome function causes the formation of distinct nuclear foci, containing polyadenylated (pA+) RNA secluded from nucleocytoplasmic export. We asked whether exosome co-factors could serve such nuclear retention. Co localization studies revealed the enrichment of pA+ RNA foci with "pA-tail exosome targeting (PAXT) connection" components MTR4, ZFC3H1, and PABPN1 but no overlap with known nuclear structures such as Cajal bodies, speckles, paraspeckles, or nucleoli. Interestingly, ZFC3H1 is required for foci formation, and in its absence, selected pA+ RNAs, including coding and non-coding transcripts, are exported to the cytoplasm in a process dependent on the mRNA export factor AlyREF. Our results establish ZFC3H1 as a central nuclear pA+ RNA retention factor, counteracting nuclear export activity. PMID- 29768219 TI - Efficacy of green nanoparticles against cancerous and normal cell lines: a systematic review and meta-analysis. AB - This study aimed to perform a systematic review and meta-analysis of papers discussing the efficacy of microbial synthesised metallic nanoparticles (MNPs) against cancerous and normal cell lines by exploiting Bayesian generalised linear (BGL) model. Data was systematically collected from published papers via Cochrane library, Web of Science, PubMed, Science Direct, ProQuest, Scopus, and Embase. Impressively, most of the studies were carried out on HeLa and A549 cancer cell lines. Specifically, a hefty 65.67% of studies employed bacteria to biofabricate MNPs. Significantly, BGL meta-analysis represented highly valuable information. Hence, based on adjusted analysis, the MNPs with the size of 25-50 nm were found to be far less cytotoxic than the MNPs with the size of <=25 nm (OR = 0.233, P ? 0.05) against either cancerous or normal cell lines. Interestingly, it was found that the odds of cytotoxicity in cancerous cell lines were practically nine times more than normal cell lines, representing the substantially more cytotoxicity of MNPs in cancerous cell lines (OR = 9.004, P ? 0.001). Green MNPs mentioned here may be developed as novel anti-cancer agents, which could lead to a revolution in the treatment of cancer. PMID- 29768220 TI - Metallic nanoparticle synthesised by biological route: safer candidate for diverse applications. AB - Biological synthesis of nanoparticles (NPs) involves greater prospect; however, a detailed review is required for ecofriendly, faster and stable NP formulation in large scale for different commercial applications. The present article highlighted recent updates on biological route of single and bimetallic NP synthesis wherein the chemical reducing agents are eliminated and biological entities are utilised to convert metal ions to NPs. Application of the biological reducing agents ranging from bacteria to fungi and even natural plant extracts have emerged as eco-friendly and cost-effective routes for the synthesis of metal nanomaterials. Potential applications of such NPs, a wide range of analytical techniques used for characterisation and factors influencing the synthesis of NPs are focused. Further, elucidation of the mechanisms associated with the NP formation using microorganisms, as well as plant-based materials are analysed which would be helpful for wide range of readers in the field of NP research for future selection and commercial implementation. PMID- 29768218 TI - MicroRNA-1247 inhibits lipopolysaccharides-induced acute pneumonia in A549 cells via targeting CC chemokine ligand 16. AB - OBJECTIVE: This study aimed to explore the potential roles and mechanism of miR 1247 in lipopolysaccharides (LPS)-induced acute pneumonia. MATERIALS AND METHODS: The miR-1247 expression in acute stage patients with infantile pneumonia was detected. To establish the cell model of acute pneumonia, A549 cells were treated with 1 mg/mL lipopolysaccharides (LPS). The effects of miR-1247 dysregulation on the cell viability, apoptosis, inflammation and autophagy of LPS-induced A549 cells were investigated. Moreover, the functional targets of miR-1247 were identified and the regulatory relationships between miR-1247 and JNK or NF-kappaB pathways were explored. RESULTS: The miR-1247 was lowly expressed in acute phage patients with infantile pneumonia. In addition, LPS treatment significantly inhibited A549cell viability, induced apoptosis, promoted the production of cytokines and decreased autophagy, thus causing A549 cell injury. Moreover, miR 1247 was decreased expression after LPS treatment, and overexpression of miR-1247 alleviated LPS-induced A549 cell injury. Furthermore, CC chemokine ligand (CCL) 16 was a functional target gene of miR-1247. Knockdown of CCL16 alleviated LPS induced cell injury, and the combination of miR-1247 inhibition and CCL16 knockdown reversed the effects of CCL16 knockdown alone on LPS-induced A549 cell injury. Besides, inhibition of miR-1247 activated JNK and NF-kappaB pathways, while knockdown of CCL16 inhibited the activation of these pathways. CONCLUSIONS: Our data reveals that miR-1247 is lowly expressed in acute stage patients with infantile pneumonia. Overexpression of miR-1247 may alleviate LPS-induced A549 cell injury through targeting CCL16. JNK and NF-kappaB pathways may be key mechanisms to regulate the role of miR-1247 in LPS-induced lung injury. PMID- 29768222 TI - Green synthesis of silver nanoparticles using flower extract of Malva sylvestris and investigation of their antibacterial activity. AB - High-quality colloidal silver nanoparticles (AgNP) were synthesised via a green approach by using hydroalcoholic extracts of Malva sylvestris. Silver nitrate was used as a substrate ion while the plant extract successfully played the role of reducing and stabilising agents. The synthesised nanoparticles were carefully characterised by using transmission electron microscopy, atomic-force microscopy, energy dispersive X-ray spectroscopy, Fourier transform infrared spectroscopy and UV-vis spectroscopy. The maximum absorption wavelengths of the colloidal solutions synthesised using 70 and 96% ethanol and 100% methanol, as extraction solvents, were 430, 485 and 504 nm, respectively. Interestingly, the size distribution of nanoparticles depended on the used solvent. The best particle size distribution belonged to the nanoparticles synthesised by 70% ethanol extract, which was 20-40 nm. The antibacterial activity of the synthesised nanoparticles was studied on Escherichia coli, Staphylococcus aureus and Streptococcus pyogenes using disk diffusion, minimum inhibitory concentrations and minimum bactericidal concentrations assays. The best antibacterial activity obtained for the AgNPs produced by using 96% ethanolic extract. PMID- 29768223 TI - Nano-biosensor based on reduced graphene oxide and gold nanoparticles, for detection of phenylketonuria-associated DNA mutation. AB - Phenylketonuria (PKU)-associated DNA mutation in newborn children can be harmful to his health and early detection is the best way to inhibit consequences. A novel electrochemical nano-biosensor was developed for PKU detection, based on signal amplification using nanomaterials, e.g. gold nanoparticles (AuNPs) decorated on the reduced graphene oxide sheet on the screen-printed carbon electrode. The fabrication steps were checked by field emission scanning electron microscope imaging as well as cyclic voltammetry analysis. The specific alkanethiol single-stranded DNA probes were attached by self-assembly methodology on the AuNPs surface and Oracet blue was used as an intercalating electrochemical label. The results showed the detection limit of 21.3 fM and the dynamic range of 80-1200 fM. Moreover, the selectivity results represented a great specificity of the nano-biosensor for its specific target DNA oligo versus other non-specific sequences. The real sample simulation was performed successfully with almost no difference than a synthetic buffer solution environment. PMID- 29768221 TI - Optimised synthesis of ZnO-nano-fertiliser through green chemistry: boosted growth dynamics of economically important L. esculentum. AB - Mounting-up economic losses to annual crops yield due to micronutrient deficiency, fertiliser inefficiency and increasing microbial invasions (e.g. Xanthomonas cempestri attack on tomatoes) are needed to be solved via nano biotechnology. So keeping this in view, the authors' current study presents the new horizon in the field of nano-fertiliser with highly nutritive and preservative effect of green fabricated zinc oxide-nanostructures (ZnO-NSs) during Lycopersicum esculentum (tomato) growth dynamics. ZnO-NS prepared via green chemistry possesses highly homogenous crystalline structures well characterised through ultraviolet and visible spectroscopy, Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscope. The ZnO-NS average size was found as small as 18 nm having a crystallite size of 5 nm. L. esculentum were grown in different concentrations of ZnO-NS to examine the different morphological parameters includes time of seed germination, germination percentage, the number of plant leaves, the height of the plant, average number of branches, days count for flowering and fruiting time period along with fruit quantity. Promising results clearly predict that bio-fabricated ZnO-NS at optimum concentration resulted as growth booster and dramatically triggered the plant yield. PMID- 29768224 TI - Encapsulation of the reductase component of p-hydroxyphenylacetate hydroxylase in poly(lactide-co-glycolide) nanoparticles by three different emulsification techniques. AB - p-Hydroxyphenylacetate 3-hydroxylase component 1 (C1) is a useful enzyme for generating reduced flavin and NAD+ intermediates. In this study, poly(lactide-co glycolide) (PLGA) nanoparticles (NPs) were used to encapsulate the C1 (PLGA-C1 NPs). Enzymatic activity, stability, and reusability of PLGA-C1 NPs prepared using three different methods [oil in water (o/w), water in oil in water (w/o/w), and solid in oil in water (s/o/w)] were compared. The s/o/w provided the optimal conditions for encapsulation of C1(PLGA-C1,s NPs), giving the highest enzyme activity, stability, and reusability. The s/o/w method improves enzyme activity ~11 and 9-fold compared to w/o/w (PLGA-C1,w NPs) and o/w (PLGA-C1,o NPs). In addition, s/o/w prepared PLGA-C1,s NPs could be reused 14 times with nearly 50% activity remaining, a much higher reusability compared to PLGA-C1,o NPs and PLGA C1,w NPs. These nanovesicles were successfully utilised to generate reduced flavin mononucleotide (FMN) and supply this cofactor to a hydroxylase enzyme that has application for synthesising anti-inflammatory compounds. Therefore, this recycling biocatalyst prepared using the s/o/w method is effective and has the potential for use in combination with other enzymes that require reduced FMN. Application of PLGA-C1,s NPs may be possible in additional biocatalytic processes for chemical or biochemical production. PMID- 29768225 TI - Optimisation of preparation conditions for Ti nanowires and suitability as an antibacterial material. AB - Ultrafine titanium dioxide (TiO2) nanowires were synthesised using a hydrothermal method with different volumes of ethylene glycol (EG) and annealing temperatures. It shows that sodium titanate nanowires synthesised using 5 and 10 ml EG, which annealed at 400 degrees C produced TiO2 nanowires that correspond to a photochemically active phase, which is anatase. The influences of annealing temperatures (400-600 degrees C) on the morphological arrangement of TiO2 nanowires were evident in the field emission scanning electron microscopy. The annealing temperature of 500 degrees C led to agglomeration, which formed a mixture of TiO2 nanoparticles and nanowires. High thermal stability of TiO2 nanowires revealed by thermogravimetric analysis and Fourier transform infrared spectroscopy spectrum showed the presence of the Ti-O-Ti vibrations as evidenced due to TiO2 lattices. An antibacterial study using TiO2 nanowires toward Escherichia coli and Klebsiella pneumoniae showed large zones of inhibition that indicated susceptibility of the microbe toward TiO2. Growth kinetic analysis shows that addition of TiO2 has reduced optical density (OD) suggesting an inhibition of the growth of bacteria. These results indicate TiO2 nanowires can be effectively used as an antimicrobial agent against gram-bacteria. The TiO2 nanowires could be exploited in the medical, packaging and detergent formulation industries and wastewater treatment. PMID- 29768226 TI - Comparison of the effects of three kinds of IgYs, (normal, nanoliposomal and nanoparticle conjugated), which are produced against the small domains of DR5 protein on cancer cells. AB - Cancer treatment with several kinds of drugs, especially targets the apoptotic pathways nowadays. TNF-related apoptosis-inducing ligand (TRAIL) as one of the important members of death receptors, significantly trigger induction of apoptosis in cancer cells. Three conserved domains of Death receptor (DR5) protein extracellular domain, which are fortified cysteine, were chosen and chemically synthesised. Hens were immunised with nano-liposomal peptides, and as a result the purified Immunoglobulin (IgYs) remarkably killed the cancerous MCF7 cells. The flow cytometric assay, confirmed the apoptotic death. Among several kinds of carriers that were used in this research, the nano-liposomal and nanoparticle conjugated, both were acceptable choices for drug delivery. Furthermore, the IgY against DR5's small peptides with such carriers successfully reached the target and significantly killed the cancer cells via apoptosis. PMID- 29768227 TI - Dual application of Shewanella oneidensis MR-1 in green biosynthesis of Pd nanoparticles supported on TiO2 nanotubes and assisted photocatalytic degradation of methylene blue. AB - Biosynthesised nanocomposites have attracted growing interests attributed to their 'green' synthesis nature in recent years. Shewanella oneidensis MR-1, a dissimilatory metal-reducing bacterium, was used to reduce palladium (II) nitrate to palladium (0) nanoparticles (Pd NPs) under anaerobic conditions, resulting in the in situ formation of Pd NPs immobilised on TiO2 nanotubes (TNTs) (Pd/TNTs nanocomposites). The Pd/TNTs nanocomposites were characterised by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, energy dispersive X-ray, and electron spin resonance, respectively. The results indicated that Pd NPs are successfully grown on the TNTs without aggregation. Photocatalytic degradation of methylene blue (MB) by Pd/TNTs nanocomposites under simulated sunlight was also investigated. Pd/TNTs nanocomposites had photocatalytic efficiency superior to that of single TiO2 nanomaterials. The photocatalytic activity of Pd/TNTs nanocomposites can be enhanced by S. oneidensis MR-1. The results showed that after only 10 min, the degradation ratio of MB reached 98.7% by Pd/TNTs nanocomposites when simultaneously assisted with S. oneidensis MR-1. PMID- 29768228 TI - Facile synthesis by a covalent binding reaction for pH-responsive drug release of carboxylated chitosan coated hollow mesoporous silica nanoparticles. AB - In this study, a promising drug nano-carrier system consisting of mono-dispersed and pH sensitive carboxylated chitosan-hollow mesoporous silica nanoparticles (Ccs-HMSNs) suitable for the treatment of malignant cells was synthesised and investigated. At neutral pH, the Ccs molecules are orderly aggregated state, which could effectively hinder the release of loaded drug molecules. However, in slightly acidic environment, Ccs chains are heavily and flexibly entangled in gel state, which would enhance the subsequent controlled release of the loaded drug. Using doxorubicin hydrochloride (DOX*HCl) as the drug model, their results demonstrated that the system had an excellent loading efficiency (64.74 MUg/mg Ccs-HMSNs) and exhibited a pH-sensitive release behaviour. Furthermore, confocal laser scanning microscopy revealed that the Ccs-HMSNs nanocomposite could effectively deliver and release DOX*HCl to the nucleus of HeLa cells, thereby inducing apoptosis. In addition, MTT assay also confirmed that DOX*HCl loaded Ccs HMSNs (DOX*HCl@Ccs-HMSNs) exhibited a good anticancer effect on HeLa cells with a time-dependent manner. Finally, haemolysis experiment showed Ccs-HMSNs had no haemolytic activity at all the tested concentrations (5-320 MUg/mL). Thus, this biocompatible and effective nano-carrier system will have potential applications in controllable drug delivery and cancer therapy. PMID- 29768229 TI - Cross-linking gold nanoparticles aggregation method based on localised surface plasmon resonance for quantitative detection of miR-155. AB - MiR-155 plays a critical role in the formation of cancers and other diseases. In this study, the authors aimed to design and fabricate a biosensor based on cross linking gold nanoparticles (AuNPs) aggregation for the detection and quantification of miR-155. Also, they intended to compare this method with SYBR Green real-time polymerase chain reaction (PCR). Primers for real-time PCR, and two thiolated capture probes for biosensor, complementary with miR-155, were designed. Citrate capped AuNPs (18.7 +/- 3.6 nm) were synthesised and thiolated capture probes immobilised to AuNPs. The various concentrations of synthetic miR 155 were measured by this biosensor and real-time PCR method. Colorimetric changes were studied, and the calibration curves were plotted. Results showed the detection limit of 10 nM for the fabricated biosensor and real-time PCR. Also, eye detection using colour showed the weaker detection limit (1 uM), for this biosensor. MiR-133b as the non-complementary target could not cause a change in both colour and UV-visible spectrum. The increase in hydrodynamic diameter and negative zeta potential of AuNPs after the addition of probes verified the biosensor accurately fabricated. This fabricated biosensor could detect miR-155 simpler and faster than previous methods. PMID- 29768231 TI - Enhanced stability of L-asparaginase by its bioconjugation to poly(styrene-co maleic acid) and Ecoflex nanoparticles. AB - Acute lymphoblastic leukemia (ALL) is the white blood cell cancer in children. L asparaginase (L-ASNase) is one of the first drugs used in ALL treatment. Anti tumor activity of L-ASNase is not specific and indicates limited stability in different biological environments, in addition to its quick clearance from blood. The purpose of the present study was to achieve a new L-ASNase polymer bioconjugate to improve pharmacokinetic, increase half-life and stability of the enzyme. The conjugations were achieved by the cross-linking agent of 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC) which activates the carboxylic acid groups of polymeric nanoparticles to create amide bond. EDC conjugated the L ASNase to two biodegradable polymers including; Ecoflex(r) and poly (styrene-co maleic acid) (PSMA) nanoparticles. To achieve optimal L-ASNase nanoparticles the amounts of each polymer and the crosslinker were optimized and the nanoparticles were characterized according to their particle size, zeta potential and percent of conjugation of the enzyme. The results showed that conjugated enzyme had more stability against pH changes and proteolysis. It had lower Km value (indicating more affinity to the substrate) and greater half-life in plasma and phosphate buffered saline, in comparison to native enzyme. Generally, the conjugated enzyme to PSMA nanoparticles showed greater results than Ecoflex(r) nanoparticles. PMID- 29768230 TI - Screening the UV-blocking and antimicrobial properties of herbal nanoparticles prepared from Aloe vera leaves for textile applications. AB - Nanomaterials play a vital role in textile industries due to their unique properties and applications. There is an increase in the use of nanoscale phyto products in textiles to control the bacterial infection in fabrics. Here, natural herbal nanoparticles of different sizes were prepared from shade-dried Aloe vera plant leaves using ball milling technique without any additives. The amorphous herbal A. vera nanoparticles possess an average particle size of 40 +/- 2 nm and UV-absorption maximum at 269 nm. A. vera nanopowders-chitosan nanocomposites were prepared and coated on cotton fabrics using pad-dry cure method. The evaluation of antibacterial activity against Escherichia coli (22.05 +/- 0.06 mm) and Staphylococcus aureus (27.17 +/- 0.02 mm), UV-protection properties (UV protection factor = 57.2 +/- 0.1), and superhydrophobic nature (155 +/- 3 degrees ) of the prepared herbal nanoparticles and their composites were analysed by disc diffusion, UV-visible spectral analysis, and contact angle analysis. Understanding the functional properties of herbal nanoparticles, coated particles on fabrics highlights their potential applications in protective clothing with better antimicrobial properties, hydrophobicity, and UV-protection properties. This study of using A. vera herbal nanoparticles in textiles significantly enhances the fabric performance to develop protective textile fabrics in defence and biomedical fields. PMID- 29768232 TI - Enhanced wound healing activity of Ag-ZnO composite NPs in Wistar Albino rats. AB - In the present study, silver (Ag) and Ag-zinc oxide (ZnO) composite nanoparticles (NPs) were synthesised and studied their wound-healing efficacy on rat model. Ultraviolet-visible spectroscopy of AgNPs displayed an intense surface plasmon (SP) resonance absorption at 450 nm. After the addition of aqueous Zn acetate solution, SP resonance band has shown at 413.2 nm indicating a distinct blue shift of about 37 nm. X-ray diffraction analysis Ag-ZnO composite NPs displayed existence of two mixed sets of diffraction peaks, i.e. both Ag and ZnO, whereas AgNPs exhibited face-centred cubic structures of metallic Ag. Scanning electron microscope (EM) and transmission EM analyses of Ag-ZnO composite NPs revealed the morphology to be monodispersed hexagonal and quasi-hexagonal NPs with distribution of particle size of 20-40 nm. Furthermore, the authors investigated the wound-healing properties of Ag-ZnO composite NPs in an animal model and found that rapid healing within 10 days when compared with pure AgNPs and standard drug dermazin. PMID- 29768233 TI - Biogenic gold nanoparticles for reduction of 4-nitrophenol to 4-aminophenol: an eco-friendly bioremediation. AB - The present study investigated the synthesis of gold nanoparticles (AuNPs) using mangrove plant extract from Avicennia marina as bioreductant for eco-friendly bioremediation of 4-nitrophenol (4-NP). The AuNPs synthesised were confirmed by UV spectrum, transmission electron microscopy (TEM), X-ray diffraction, Fourier transmission infrared spectroscopy (FTIR), dynamic light scattering (DLS), and zeta potential. The AuNPs were found to be spherical in shape with size ranging from 4 to 13 nm, as evident by TEM and DLS. Further, the AuNPs were encapsulated with sodium alginate in the form of gold nano beads and used as heterogeneous catalyst and degrading agent to reduce 4-NP. This reduction in 4-NP into 4 aminophenol was confirmed by UV and FTIR. The aqueous solution of 4-NP peaked its absorbance at 320 nm, and shifted to 400 nm, with an intense yellow colour, appeared due to formation of 4-nitrophenolate ion. After the addition of AuNps, the 4-NP solution became colourless and peaked at 400 nm and reduced to 290 nm corresponding to the formation of 4-aminophenol. Hence, the present work suggested the AuNPs as the potent, eco-friendly bionanocomposite catalyst for bioremediation of 4-NP. PMID- 29768234 TI - Improved experimental time of ultra-large bioassays using a parallelised microfluidic biochip architecture/scheduling. AB - Digital microfluidic is an emerging technology to reduce the cost and time of experiments and improve the flexibility, automate-ability and correctness of biochemical assays. In many of applications such as drug discovery and DNA profiling, a large number of bio-operations (e.g. the chemical operations used in biology applications) must be done. In these applications, parallelising the operations will be critical in accuracy and cost of the process and digital microfluidic biochips can be considered as a reasonable platform. In this study, a new microfluidic architecture and the corresponding CAD flow is introduced to parallelise the assays on this platform. The authors implemented the proposed architecture and evaluated it using the large real bioassays. The authors' simulations show that the degree-of-parallelism and speed of bioassays are increased more than 4* and the improvements will be better for larger assays. This contribution can open new horizons in drug testing, biology experiments and medical diagnosis operations that contain iterative, time-consuming and labour experiments. PMID- 29768235 TI - Green synthesis of silver nanoparticles with the Arial part of Dorema ammoniacum D. extract by antimicrobial analysis. AB - Silver nanoparticles (SNPs) were synthesised by using the Arial part extract of Dorema ammoniacum D. and characterised by employing UV-visible spectroscopy, Fourier transform infrared spectroscopy and X-ray diffraction techniques. Transmission electron microscopy and field emission scanning electron microscopy were applied to investigate the morphological structure of the bio-synthesised SNPs. The antimicrobial activity of SNPs was studied against Gram positive (Bacillus cereus and Staphylococcus aureus) and Gram-negative (Escherichia coli and Salmonella typhimurium) bacteria by employing the disk diffusion agar process. An extremely antimicrobial effect was observed for SNPs. Utilising D. ammoniacum D. as a mediator for the synthesis of SNPs helped to save time and cost. PMID- 29768237 TI - Preparation and characterisation of CNF/MWCNT carbon aerogel as efficient adsorbents. AB - In recent years, carbon aerogels have attracted much attention in basic research and as potential applications in many fields. Herein, the authors report a novel approach using bamboo powder as raw material to fabricate cellulose nanofibers (CNFs)/multi-walled carbon nanotubes (MWCNTs) carbon aerogels by a simple dipping and carbonisation process. The developed material exhibits many exciting properties including low density (0.056 g cm-3), high porosity (95%), efficient capability for separation of oily droplets from water, and high adsorption capacity for a variety of oils and organic solvents by up to 110 times its own weight. Furthermore, the CNF/MWCNT carbon aerogels (CMCA) can be recycled many times by distillation and combustion, satisfying the requirements of practical oil-water separation. Taken together with its economical, environmentally benign manufacturing process, sustainability of the precursor and versatility of material, the CMCA developed in this study will be a promising candidate for addressing the problems arising from the spills of oily compounds. PMID- 29768236 TI - Rapid synthesis of Bi2O3 nano-needles via 'green route' and evaluation of its anti-fungal activity. AB - Here, the authors report a rapid, simple, and eco-friendly process for synthesis of Bi2O3 nano-needles. Dioscorea alata tuber extract was used as both reducing and capping agent for the first time. These nanoparticles were characterised by X ray diffraction, field emission scanning electron microscope, and Fourier transform infrared (FTIR) spectrometry, the nano-structured Bi2O3 needles have an average diameter of 158 nm with the lengths in the range of 1-3 MUm. CLSI M27-A2 standard was followed for evaluation of anti-fungal activity. Bi2O3 nano-needles show remarkable activity against Candida albicans. It exhibits four time greater activity than bulk Bi2O3 powder and two time greater activity than itraconazole, which makes it a potent anti-fungal drug. PMID- 29768238 TI - One pot green fabrication of metallic silver nanoscale materials using Crescentia cujete L. and assessment of their bactericidal activity. AB - In this study, the leaf extract of an important medicinal plant Crescentia cujete L. (CC) was employed as a green reducing agent to synthesise highly-stable C. cujete silver nanoparticles (CCAgNPs). The reduction of Ag+ to Ag0 nanoparticles was initially observed by a colour change which generates an intense surface plasmon resonance peak at 417 nm using a UV-Vis spectrophotometer. Various optimisation factors such as temperature, pH, time and the stoichiometric proportion of the reaction mixture were performed, which influence the size, dispersity and synthesis rate of CCAgNPs. In addition, surface chemistry of synthesised CCAgNPs through Fourier transform infrared spectroscopy reveals the reducing/stabilising agent present in the aqueous extract of C. cujete and synthesised CCAgNPs. Transmission electron microscopy analysis features the spherical shape of CCAgNPs with an average size of 39.74 nm. Furthermore, an X ray diffraction study confirms that the synthesised CCAgNPs were face-centred cubic crystalline in nature. The CCAgNPs display tremendous bactericidal activity against human pathogens Bacillus subtilis, Staphylococcus epidermidis, Rhodococcus rhodochrous, Salmonella typhi, Mycobacterium smegmatis, Shigella flexneri and Vibrio cholerae via penetrating into the bacterial cell membrane and causing failure of an internal chain reaction. PMID- 29768239 TI - Antibacterial and catalytic activity of biogenic gold nanoparticles synthesised by Trichoderma harzianum. AB - This study reveals the antibacterial and catalytic activity of biogenic gold nanoparicles (AuNPs) synthesised by biomass of Trichoderma harzianum. The antibacterial activity of AuNPs was analysed by the means of growth curve, well diffusion and colony forming unit (CFU) count methods. The minimum inhibitory concentration of AuNPs was 20 ug/ml. AuNPs at 60 ug/ml show effective antibacterial activity as optical absorption was insignificant. The well diffusion and CFU methods were also applied to analyse the effect of various concentration of AuNPs. Further, the catalytic activity of AuNPs was analysed against methylene blue (MB) as a model pollutant in water. MB was degraded 39% in 30 min in the presence of AuNPs and sodium borohydrate and the rate constant (k) was found to be 0.2 * 10-3 s-1. This shows that the biogenic AuNP is an effective candidate for antibacterial and catalytic degradation of toxic pollutants. PMID- 29768240 TI - Green synthesis and characterisation of silver nanoparticles and their effects on antimicrobial efficacy and biochemical profiling in Citrus reticulata. AB - The synthesis of nanoparticles by utilising plant extract has revolutionised the field of nanotechnology. In the present study, AgNPs were synthesised by utilising the leaves of Moringa oleifera as reducing and stabilising agent. UV visible spectroscopy showed characteristic surface plasmon band in the range of 413-420 nm. Scanning electron microscopy (SEM) elucidated rectangular segments fused together. X-ray diffraction (XRD) analysis confirmed the crystalline nature of AgNPs and presence of metallic silver ions was confirmed by energy dispersive X-ray (EDX). The different concentrations (10, 20, 30 and 40 ppm) of AgNPs were exogenously applied on Citrus reticulata to record the disease incidence at different day intervals. The disease intensity was progressively increased in all the applied treatments with the passage of time. The 30 ppm concentration of AgNPs was found to be most suitable concentration for creating the resistance against brown spot disease. Moreover, the effects of AgNPs were also assessed for biochemical profiling in C. reticulata. The enhanced production of endogenous enzymes and non-enzymatic components was observed in response to 30 ppm concentration of AgNPs. The present work highlighted that green synthesised AgNPs can be as used as biological control of citrus diseases and the enhanced production of secondary metabolites antioxidants. PMID- 29768241 TI - Effects of Fe/SDS and Au nanoparticles on P. aeruginosa bacterial growth and biosurfactant production. AB - The aim of this study was to evaluate the effects of iron (Fe)/SDS and gold (Au) nanoparticles on growth and biosurfactant production of Pseudomonas aeruginosa PBCC5. The concentrations of the nanoparticles used were 1, 500 and 1000 mg/l. In this research, the surface tension of biosurfactant, dry weight of biosurfactant and biomass, emulsification indexes (E24) were measured and transmission electron microscopy analysis was used to monitor the nanoparticles. The test results showed that the effect of nanoparticles on the bacterial growth and biosurfactant production varied corresponding to the type and concentration of nanoparticles. Fe/SDS nanoparticles showed no bacterial toxicity when the concentration of nanoparticles was 1 mg/ml and increased the growth and biosurfactant production, 23.21 and 20.73%, respectively. While at higher concentrations (500, 1000 mg/l), the nanoparticles suppressed bacterial growth as well as biosurfactant production. Similarly, Au nanoparticles had no bacterial toxicity and also increased bacterial growth and biosurfactant production. The surface tensions of all samples decreased from 72 of distiled water to 32-35 mN/m. PMID- 29768243 TI - Corrigendum: Synthesis of extracellular gold nanoparticles using Cupriavidus metallidurans CH34 cells. PMID- 29768242 TI - Antibacterial, anticancer and antioxidant potential of silver nanoparticles engineered using Trigonella foenum-graecum seed extract. AB - In this study, the authors report a simple and eco-friendly method for the synthesis of silver nanoparticles (AgNPs) using Trigonella foenum-graecum (TFG) seed extract. They explored several parameters dictating the biosynthesis of TFG AgNPs such as reaction time, temperature, concentration of AgNO3, and TFG extract amount. Physicochemical characterisation of TFG-AgNPs was done on dynamic light scattering (DLS), field emission electron microscopy, energy dispersive X-ray spectroscopy, X-ray diffraction and Fourier transform infrared spectroscopy. The size determination studies using DLS revealed of TFG-AgNPs size between 95 and 110 nm. The antibacterial activity was studied against Escherichia coli, Proteus vulgaris, Pseudomonas aeruginosa and Staphylococcus aureus. The biosynthesised TFG-AgNPs showed remarkable anticancer efficacy against skin cancer cell line, A431 and also exhibited significant antioxidant efficacy. PMID- 29768244 TI - Harmonization activities of Noklus - a quality improvement organization for point of-care laboratory examinations. AB - Noklus is a non-profit quality improvement organization that focuses to improve all elements in the total testing process. The aim is to ensure that all medical laboratory examinations are ordered, performed and interpreted correctly and in accordance with the patients' needs for investigation, treatment and follow-up. For 25 years, Noklus has focused on point-of-care (POC) testing in primary healthcare laboratories and has more than 3100 voluntary participants. The Noklus quality system uses different tools to obtain harmonization and improvement: (1) external quality assessment for the pre-examination, examination and postexamination phase to monitor the harmonization process and to identify areas that need improvement and harmonization, (2) manufacturer-independent evaluations of the analytical quality and user-friendliness of POC instruments and (3) close interactions and follow-up of the participants through site visits, courses, training and guidance. Noklus also recommends which tests that should be performed in the different facilities like general practitioner offices, nursing homes, home care, etc. About 400 courses with more than 6000 delegates are organized annually. In 2017, more than 21,000 e-learning programs were completed. PMID- 29768246 TI - The Theranos saga and the consequences. PMID- 29768248 TI - Bisphenol A decreases the spontaneous contractions of rat uterus in vitro through a nitrergic mechanism. AB - BACKGROUND: Bisphenol A (BPA), a chemical used in the manufacture of plastics, has toxic effects on various systems of the human body including the reproductive system. BPA possesses estrogenic activity and is implicated in altering oogenesis, ovulation, and fertility. In addition to ovulatory changes, uterine contractility is an important factor for fertility. However, the effects of BPA on myometrial contractions are not known. Therefore, we examined the effect of BPA on rat uterine contractions. METHODS: The uterus was isolated from adult rats showing estrous phase, and spontaneous in vitro contractions were recorded (35+/ 1 degrees C). The effect of cumulative concentrations of BPA was determined. Further, the involvement of nitric oxide (NO) and guanylyl cyclase (GC) for the BPA-induced changes on uterine contractility was evaluated using the NO synthase inhibitor (L-NAME) or GC inhibitor (methylene blue). RESULTS: BPA decreased the amplitude and frequency of spontaneous uterine contractions in a concentration dependent manner. A decrease of 50% occurred at 1 and 3 MUM for amplitude and frequency, respectively. L-NAME (N-omega-nitro-l-arginine methyl ester) blocked the BPA-induced decrease in amplitude at all concentrations but antagonized the frequency only at the maximum concentration (10 MUM). Methylene blue (a GC inhibitor) did not block the BPA-induced responses but for the frequency at 10 MUM of BPA. CONCLUSIONS: The results indicate that BPA decreased the amplitude and frequency of spontaneous uterine contractions by involving the nitrergic mechanism; however, the GC mechanism is not involved in the depression. PMID- 29768245 TI - Exploring the potential of mucin 13 (MUC13) as a biomarker for carcinomas and other diseases. AB - BACKGROUND: Mucin 13 (MUC13) is a cell surface glycoprotein aberrantly expressed in a variety of epithelial carcinomas. Thus far, the role of MUC13 in various diseases remains elusive. To the best of our knowledge, this is the first study to examine the potential of MUC13 as a serum biomarker in a variety of carcinomas and other conditions. METHODS: We developed a recombinant MUC13 protein, mouse monoclonal antibodies and enzyme immunoassay (ELISA) for MUC13. We used this assay to measure MUC13 levels in the supernatants of cancer cell lines and a large cohort of serum samples from healthy and diseased individuals. RESULTS: MUC13 is secreted from cancer cell lines, with highest levels found in ovarian cancer cell lines. MUC13 levels in human sera were significantly increased in patients with renal failure and 20%-30% of patients with ovarian, liver, lung and other cancers. MUC13 was also elevated in 70% of patients with active cutaneous melanoma, but not uveal melanoma. Furthermore, we identified significant MUC13 elevations in the serum of patients with vasculitis (ANCA-positive) autoantibodies, but not in those with inflammatory bowel disease. CONCLUSIONS: Serum MUC13 is frequently elevated not only in a variety of malignant cases but also in some benign pathologies, thus appearing to be a non-specific disease biomarker. Nonetheless, serum MUC13 is clearly highly elevated in some carcinoma patients, and its relationship with tumor progression in this context warrant further research. Future studies that examine the correlation between serum MUC13 levels to stage of cancer could elucidate prognostic potential. PMID- 29768247 TI - Oocyte-triggering day progesterone levels and endometrial appearance in normoresponders undergoing IVF/ICSI cycles: a hypothesis and a study protocol. AB - In this report, we propose a study protocol capable of improving IVF outcomes in subfertile women with expected normal ovarian response. This proposal derives from conflicting published data and observations in our daily practice, concerning the negative impact of progesterone (P4) elevation at the day of oocyte triggering on pregnancy outcomes. Our hypothesis points to the combination of two previous "suspects" of reduced success after assisted reproduction techniques (ART) - the endometrium ultrasonographic parameters and P4 elevation at the day of oocyte triggering on their impact on pregnancy outcomes. Up-to-the minute data show that, there is a different impact of elevated P4 in fresh, frozen and donor cycles, whereas there are plenty of reports pointing to a different endometrial gene expression on different P4 measurements. Gaps in the literature are linked with a variation of the measurements of P4, its cycle-to cycle reproducibility, the different cut-off levels used, the impact of various protocols of ovarian stimulation and the limitations of systematic reviews originating from the initial studies. Our hypothesis states that the combination of P4 values and endometrial ultrasound parameters at the day of oocyte triggering can affect clinical pregnancy rates in normal responders undergoing ART. PMID- 29768249 TI - Detection of cytomegalovirus in saliva from infants undergoing sepsis evaluation in the neonatal intensive care unit: the VIRIoN-C study. AB - OBJECTIVE: To determine the frequency of detection of cytomegalovirus (CMV) among infants evaluated for late-onset sepsis in the neonatal intensive care unit (NICU). STUDY DESIGN: This study was a prospective cohort study. RESULTS: During the 13-month study, 84 infants underwent 116 sepsis evaluations, and CMV DNA was detected in saliva in three (4%) infants (median: gestational age 28 weeks, birth weight 950 g), representing 5% (n=6) of all sepsis evaluations. One infant had CMV DNA detected in saliva in all four sepsis evaluations. Two infants had acquired CMV infection, while the timing of CMV acquisition could not be determined in one infant. Two of the three infants had concomitant Gram-negative bacteremia and urinary tract infections (UTIs), two developed severe bronchopulmonary dysplasia (BPD) and none died. CONCLUSIONS: Detection of CMV DNA in saliva occurred in 4% of infants and 5% of sepsis evaluations. Persistence of CMV DNA shedding in saliva made attribution of clinical illness difficult to ascertain. PMID- 29768250 TI - Metabolic regulation of synaptic activity. AB - Brain tissue is bioenergetically expensive. In humans, it composes approximately 2% of body weight and accounts for approximately 20% of calorie consumption. The brain consumes energy mostly for ion and neurotransmitter transport, a process that occurs primarily in synapses. Therefore, synapses are expensive for any living creature who has brain. In many brain diseases, synapses are damaged earlier than neurons start dying. Synapses may be considered as vulnerable sites on a neuron. Ischemic stroke, an acute disturbance of blood flow in the brain, is an example of a metabolic disease that affects synapses. The associated excessive glutamate release, called excitotoxicity, is involved in neuronal death in brain ischemia. Another example of a metabolic disease is hypoglycemia, a complication of diabetes mellitus, which leads to neuronal death and brain dysfunction. However, synapse function can be corrected with "bioenergetic medicine". In this review, a ketogenic diet is discussed as a curative option. In support of a ketogenic diet, whereby carbohydrates are replaced for fats in daily meals, epileptic seizures can be terminated. In this review, we discuss possible metabolic sensors in synapses. These may include molecules that perceive changes in composition of extracellular space, for instance, ketone body and lactate receptors, or molecules reacting to changes in cytosol, for instance, KATP channels or AMP kinase. Inhibition of endocytosis is believed to be a universal synaptic mechanism of adaptation to metabolic changes. PMID- 29768251 TI - Balo's concentric sclerosis: an update and comprehensive literature review. AB - Balo's concentric sclerosis (BCS) is considered a variant of multiple sclerosis characterized by concentric lamella of alternating demyelinated and partially myelinated tissues. It is a rare and a relatively acute condition. Attacks may proceed rapidly over weeks or months, typically without remission, like Marburg's variant, resulting in death or severe disability. However, the majority of cases have a more benign, self-limiting course with spontaneous remission. Magnetic resonance imaging is a primary imaging modality in the diagnosis of BCS. Treatment with intense immunosuppression may be indicated in patients with more aggressive form. New reports reveal more evidence regarding the pathophysiology and treatment strategies. PMID- 29768252 TI - Chemical composition and antifungal activity of essential oils from four Asteraceae plants grown in Egypt. AB - The objective of the present paper was the assessment of the chemical composition of the essential oils from four Asteraceae species with a considerable food, medicinal, and agricultural value, collected in Egypt, together with their in vitro inhibitory activity against molds and yeasts. The essential oil of Launaea cornuta flowers was also evaluated for the first time, but because of its very low yield (<0.01%), no antifungal test was performed. PMID- 29768253 TI - Effect of yeast extract addition to a mineral salts medium containing hydrolyzed plant xylan on fungal pullulan production. AB - The ability of the fungus Aureobasidium pullulans ATCC 42023 to produce pullulan from yeast extract-supplemented xylan hydrolysates of the prairie grass prairie cordgrass was examined relative to polysaccharide and cell biomass production, yield, and pullulan content of the polysaccharide. A pullulan concentration of 11.2 g L-1 and yield of 0.79 g g-1 was produced by ATCC 42023 when grown for 168 h at 30 degrees C on the phosphate-buffered hydrolysate supplemented with yeast extract. The highest biomass level being 8.8 g L-1 was produced by ATCC 42023 after 168 h on a yeast extract-supplemented, hydrolysate-containing complete medium lacking sodium chloride. The highest pullulan content of the polysaccharide produced by ATCC 42023 after 168 h on the hydrolysate medium supplemented with yeast extract and ammonium sulfate was 70%. The findings indicate that a polysaccharide with a high pullulan content can be produced at a relatively high yield by the fungus grown on a yeast extract-supplemented xylan hydrolysate, suggesting that pullulan could be produced using a biomass-based process. PMID- 29768254 TI - Neuroprotection Against Hypoxic/Ischemic Injury: delta-Opioid Receptors and BDNF TrkB Pathway. AB - The delta-opioid receptor (DOR) is one of three classic opioid receptors in the opioid system. It was traditionally thought to be primarily involved in modulating the transmission of messages along pain signaling pathway. Although there were scattered studies on its other neural functions, inconsistent results and contradicting conclusions were found in past literatures, especially in terms of DOR's role in a hypoxic/ischemic brain. Taking inspiration from the finding that the turtle brain exhibits a higher DOR density and greater tolerance to hypoxic/ischemic insult than the mammalian brain, we clarified DOR's specific role in the brain against hypoxic/ischemic injury and reconciled previous controversies in this aspect. Our serial studies have strongly demonstrated that DOR is a unique neuroprotector against hypoxic/ischemic injury in the brain, which has been well confirmed in current research. Moreover, mechanistic studies have shown that during acute phases of hypoxic/ischemic stress, DOR protects the neurons mainly by the stabilization of ionic homeostasis, inhibition of excitatory transmitter release, and attenuation of disrupted neuronal transmission. During prolonged hypoxia/ischemia, however, DOR neuroprotection involves a variety of signaling pathways. More recently, our data suggest that DOR may display its neuroprotective role via the BDNF-TrkB pathway. This review concisely summarizes the progress in this field. PMID- 29768255 TI - Asiatic Acid (AA) Sensitizes Multidrug-Resistant Human Lung Adenocarcinoma A549/DDP Cells to Cisplatin (DDP) via Downregulation of P-Glycoprotein (MDR1) and Its Targets. AB - BACKGROUND/AIMS: P-glycoprotein (P-gp, i.e., MDR1) is associated with the phenotype of multidrug resistance (MDR) and causes chemotherapy failure in the management of cancers. Searching for effective MDR modulators and combining them with anticancer drugs is a promising strategy against MDR. Asiatic acid (AA), a natural triterpene isolated from the plant Centella asiatica, may have an antitumor activity. The present study assessed the reversing effect of AA on MDR and possible molecular mechanisms of AA action in MDR1-overexpressing cisplatin (DDP)-resistant lung cancer cells, A549/DDP. METHODS: Human lung adenocarcinoma A549/DDP cells were either exposed to different concentrations of AA or treated with DDP, and their viability was measured by the MTT assay. A Rhodamine 123 efflux assay, immunofluorescent staining, ATPase assay, reverse-transcription PCR (RT-PCR), and western blot analysis were conducted to elucidate the mechanisms of action of AA on MDR. RESULTS: Our results showed that AA significantly enhanced the cytotoxicity of DDP toward A549/DDP cells but not its parental A549 cells. Furthermore, AA strongly inhibited P-gp expression by blocking MDR1 gene transcription and increased the intracellular accumulation of the P-gp substrate Rhodamine 123 in A549/DDP cells. Nuclear factor (NF)-kB (p65) activity, IkB degradation, and NF-kB/p65 nuclear translocation were markedly inhibited by pretreatment with AA. Additionally, AA inhibited the MAPK-ERK pathway, as indicated by decreased phosphorylation of ERK1 and -2, AKT, p38, and JNK, thus resulting in reduced activity of the Y-box binding protein 1 (YB1) via blockage of its nuclear translocation. CONCLUSIONS: AA reversed P-gp-mediated MDR by inhibition of P-gp expression. This effect was likely related to downregulation of YB1, and this effect was mediated by the NF-kB and MAPK-ERK pathways. AA may be useful as an MDR reversal agent for combination therapy in clinical trials. PMID- 29768256 TI - Overexpression of PCK1 Gene Antagonizes Hepatocellular Carcinoma Through the Activation of Gluconeogenesis and Suppression of Glycolysis Pathways. AB - BACKGROUND/AIMS: Gluconeogenesis, a reverse process of glycolysis, is suppressed in neoplastic livers. Cytoplasmic phosphoenolpyruvate carboxykinase (PEPCK C/PCK1, encoded by PCK1) is a step limiting enzyme of gluconeogenesis. The induced expression of the factor is reported to initiate gluconeogenesis process and antagonize hepatocellular carcinoma (HCC). In the current study, the effect of the modulation of PCK1 expression on HCC was assessed. METHODS: The levels of PCK1 in clinical HCC tissues and different HCC cell lines were investigated with real time quantitative PCR, immunochemistry, and western blotting. Thereafter, the expression of PCK1 gene was induced in two HCC cell lines and the effect of the overexpression on proliferation and migration potentials of HCC cells was detected with CCK-8 assay, flow cytometry, TUNEL staining, and transwell assay. The activities of glycolysis and gluconeogenesis pathways in PCK1-overexpressed HCC cell lines were detected with specific kits to underlie the mechanism by which PCK1 exerted its function. The results of the in vitro experiments were validated with HCC xenograft rat models. RESULTS: The expression levels of PCK1 were suppressed in HCC samples and in cells derived from HCC tissues. According to the results of the in vitro assays, the overexpression of PCK1 decreased viability, induced apoptosis, and inhibited migration in both HCC cell lines. The effect was associated with the suppressed glycolysis and the induced gluconeogenesis pathways, represented by the enhanced production of glucose and the limited production of pyruvic acid, lactate, citrate, and malate. The results of the in vitro assays were confirmed in rat models in that the growth rate of solid HCC tumors was reduced in mice transplanted with PCK1-overexpressed HCC cells. CONCLUSION: Findings outlined in the current study demonstrated that activating gluconeogenesis process via PCK1 overexpression was a potential treating strategy against HCC. PMID- 29768257 TI - Systemic Immune-Inflammation Index (SII) is Useful to Predict Survival Outcomes in Patients After Liver Transplantation for Hepatocellular Carcinoma within Hangzhou Criteria. AB - BACKGROUND: There is growing evidence that the systemic immune-inflammation index (SII), a novel prognostic biomarker based on peripheral lymphocyte, neutrophil, and platelet counts, is associated with poor prognosis for several tumors. However, the prognostic value of SII in patients with hepatocellular carcinoma (HCC) who undergo liver transplantation (LT) remains unclear. The aim of this study was to determine the correlation between SII and prognosis in these patients. METHODS: This retrospective study involved 150 patients with HCC who underwent LT within the Hangzhou criteria. The optimal cut-off value was determined by receiver-operating characteristic (ROC) curve analysis to stratify the patients into those with a high SII and those with low SII. The Kaplan-Meier method and the Cox proportional hazards model were used to evaluate the prognostic value of SII. Finally, we calculated the area under the ROC curve to compare the prognostic power of SII, platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR). RESULTS: Patients were divided into high SII (>= 226) and low SII (< 226) groups. Five-year overall survival (OS) was lower in the high SII group than in the low SII group (56.1% vs. 82.4%, p = 0.002). SII >= 226 * 109/L, maximum tumor size> 5 cm, microvascular invasion, and poor differentiation were independent prognostic factors for OS. However, SII did not predict 5-year recurrence-free survival (high vs. low SII: 64.1% vs. 78.4%, p = 0.073). The area under the ROC curve was greater for SII than for PLR, NLR, and MLR. CONCLUSIONS: Preoperative SII may be a powerful prognostic biomarker in patients with HCC who undergo LT within the Hangzhou criteria. SII is superior to PLR, NLR, and MLR for prediction of OS in these patients. PMID- 29768258 TI - Multiple Actions of Rotenone, an Inhibitor of Mitochondrial Respiratory Chain, on Ionic Currents and Miniature End-Plate Potential in Mouse Hippocampal (mHippoE 14) Neurons. AB - BACKGROUND/AIMS: Rotenone (Rot) is known to suppress the activity of complex I in the mitochondrial chain reaction; however, whether this compound has effects on ion currents in neurons remains largely unexplored. METHODS: With the aid of patch-clamp technology and simulation modeling, the effects of Rot on membrane ion currents present in mHippoE-14 cells were investigated. RESULTS: Addition of Rot produced an inhibitory action on the peak amplitude of INa with an IC50 value of 39.3 uM; however, neither activation nor inactivation kinetics of INa was changed during cell exposure to this compound. Addition of Rot produced little or no modifications in the steady-state inactivation curve of INa. Rot increased the amplitude of Ca2+-activated Cl- current in response to membrane depolarization with an EC50 value of 35.4 uM; further addition of niflumic acid reversed Rot mediated stimulation of this current. Moreover, when these cells were exposed to 10 uM Rot, a specific population of ATP-sensitive K+ channels with a single channel conductance of 18.1 pS was measured, despite its inability to alter single-channel conductance. Under current clamp condition, the frequency of miniature end-plate potentials in mHippoE-14 cells was significantly raised in the presence of Rot (10 uM) with no changes in their amplitude and time course of rise and decay. In simulated model of hippocampal neurons incorporated with chemical autaptic connection, increased autaptic strength to mimic the action of Rot was noted to change the bursting pattern with emergence of subthreshold potentials. CONCLUSIONS: The Rot effects presented herein might exert a significant action on functional activities of hippocampal neurons occurring in vivo. PMID- 29768259 TI - Precise Intradermal Injection of Nanofat-Derived Stromal Cells Combined with Platelet-Rich Fibrin Improves the Efficacy of Facial Skin Rejuvenation. AB - BACKGROUND/AIMS: The rejuvenation properties of nanofat grafting have been described in recent years. However, it is not clear whether the clinical efficacy of the procedure is attributable to stem cells or linked to other components of adipose tissue. In this study we isolated nanofat-derived stem cells (NFSCs) to observe their biological characteristics and evaluate the efficacy of precise intradermal injection of nanofat combined with platelet-rich fibrin (PRF) in patients undergoing facial rejuvenation treatment. METHODS: Third-passage NFSCs were isolated and cultured using a mechanical emulsification method and their surface CD markers were analyzed by flow cytometry. The adipogenic and osteogenic nature and chondrogenic differentiation capacity of NFSCs were determined using Oil Red O staining, alizarin red staining, and Alcian blue staining, respectively. Paracrine function of NFSCs was evaluated by enzyme-linked immunosorbent assay (ELISA) at 1, 3, 7, 14, and 28 days after establishing the culture. Then, the effects of PRF on NFSC proliferation were assessed in vitro. Finally, we compared the outcome in 103 patients with facial skin aging who underwent both nanofat and intradermal PRF injection (treatment group) and 128 patients who underwent hyaluronic acid (HA) injection treatment (control group). Outcomes in the two groups were compared by assessing pictures taken at the same angle before and after treatment, postoperative recovery, incidence of local absorption and cysts, and skin quality before treatment, and at 1, 12, 24 months after treatment using the VISIA Skin Image Analyzer and a SOFT5.5 skin test instrument. RESULTS: NFSCs expressed CD29, CD44, CD49d, CD73, CD90, and CD105, but did not express CD34, CD45, and CD106. NFSCs also differentiated into adipocytes, osteoblasts, and chondrocytes under appropriate induction conditions. NFSCs released large amounts of growth factors such as VEGF, bFGF, EGF, and others, and growth factor levels increased in a time-dependent manner. At the same time, PRF enhanced proliferation of NFSCs in vitro in a dose-dependent manner, and the growth curves under different concentrations of PRF all showed plateaus 6d after seeding. Facial skin texture was improved to a greater extent after combined injection of nanofat and PRF than after control injection of HA. The nanofat-PRF group had a higher satisfaction rate. Neither treatment caused any complications such as infection, anaphylaxis, or paresthesia during long-term follow-up. CONCLUSION: NFSCs demonstrate excellent multipotential differentiation and paracrine function, and PRF promotes proliferation of NFSCs during the early stage after seeding. Both nanofat-PRF and HA injection improve facial skin status without serious complications, but the former was associated with greater patient satisfaction, implying that nanofat-PRF injection is a safe, highly effective, and long-lasting method for skin rejuvenation. PMID- 29768260 TI - Carboplatin Dosing Accuracy by Estimation of Glomerular Filtration versus Creatinuria in Cancer Patients. AB - BACKGROUND: The glomerular filtration rate (GFR) is essential for calculating the dose and the monitoring of carboplatin. Although GFR measurement (mGFR) by external markers is ideal, in most cases these are not employed; the most used method is GFR estimation (eGFR) by formulae, hence the need to identify the formula with the best performance. METHODS: Patients admitted between 2011 and 2017 and diagnosed with ovarian, endometrial, lung, esophageal, or testicular cancer were assessed retrospectively. The accuracy of the carboplatin dose calculated by creatinine concordance and by the Cockroft-Gault (CG), CKD-EPI, MDRD, Wright, and Jelliffe formulae was assessed using the intraclass correlation coefficient. RESULTS: Fifty-six medical histories were analyzed. The best accuracy was observed between the Wright formula (i.e., 0.71) and the dose calculated based on the 24-h creatinine clearance. Stratification by CKD was made in depurations < 60 mL/min, where the Jelliffe value was excellent (i.e., 0.75). In depurations >=60 mL/min, CKD-EPI was the best formula, with an accuracy of 0.65. CG was the formula with the worst performance in calculating the dose and glomerular filtration, losing its usefulness with very low filtrations. CONCLUSIONS: GFR formulae and calculation of the carboplatin dose have good accuracy with the GFR obtained based on the 24-h creatinine clearance, with the Wright formula being the one with best performance and CG the one with worst performance. PMID- 29768261 TI - N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-kappaB Pathway. AB - BACKGROUND/AIMS: Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. METHODS: Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated beta-galactosidase (SA-beta-Gal) activity was measured by SA-beta-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer's instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-kappaB expression was also analyzed by Western blotting to evaluate NF-kappaB pathway activity. RESULTS: High glucose significantly decreased N-CDH expression, increased ROS generation and NF-kappaB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-beta-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-kappaB pathway under the high glucose condition. CONCLUSION: High glucose decreases N CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-kappaB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP degeneration. PMID- 29768262 TI - MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer. AB - BACKGROUND/AIMS: MicroRNAs regulate a wide range of biological processes of non small cell lung cancer (NSCLC). Although miR-598 has been reported to act as a suppressor in osteosarcoma and colorectal cancer, the physiological function of miR-598 in NSCLC remains unknown. In this study, the role of miR-598 in NSCLC was investigated. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to estimate the expression of miR-598 and Derlin-1 (DERL1) in both NSCLC tissues and cell lines. Immunohistochemistry (IHC) analyzed the association between the miR-598 expression and epithelial-mesenchymal transition (EMT) hallmark genes (E-cadherin, Vimentin) by staining the tumors representative of the high- and low-expression groups. The effect of miR-598 and DERL1 on invasion and migration was determined in vitro using transwell and wound-healing assays. The molecular mechanism underlying the relevance between miR-598 and DERL1 was elucidated by luciferase assay and Western blot. Western blot assessed the expression levels of EMT hallmark genes in cell lines. Xenograft tumor formation assay was conducted as an in vivo experiment. RESULTS: In this study, a relatively low level of miR-598 and high DERL1 expressions were found in NSCLC specimens and cell lines. IHC results established a positive correlation between the miR-598 expression and E-cadherin and a negative with Vimentin. DERL1 was verified as a direct target of miR-598 by luciferase assay. In vitro, the over expression of miR-598 negatively regulated DERL1 and EMT for the suppression of invasion and migration. In vivo, the over-expression of miR-598 could inhibit tumor cell metastasis in NSCLC. CONCLUSIONS: These findings for the first time revealed that miR-598, as a tumor suppressor, negatively regulate DERL1 and EMT to suppress the invasion and migration in NSCLC, thereby putatively serving as a novel therapeutic target for NSCLC clinical treatment. PMID- 29768263 TI - Fibrinopeptide A Induces Expression of C-Reactive Protein via the ROS-ERK1/2/ P38 NF-kappaB Signal Pathway in Vascular Smooth Muscle Cells. AB - BACKGROUND/AIMS: Atherosclerosis is a chronic inflammatory disease in the artery walls. Fibrinopeptide A (FPA) is a biomarker of the activation of coagulation system, and a high concentration of FPA in blood occurs in patients with ischemic heart disease etc. However, there exist few studies on the pathological effects of FPA in cardiovascular system. Therefore, the present study examined the effect of FPA on CRP expression in VSMCs and the molecular mechanisms. METHODS: mRNA and protein expression was identified by quantitative real-time PCR and Western blot, respectively. Reactive oxygen species (ROS) and the immunofluorescence staining were observed by a fluorescence microscope. Plasma FPA and CRP level was determined by ELISA. RESULTS: FPA induced the expressions of CRP, IL-1beta and IL 6 in VSMCs, and anti-IL-1beta and anti-IL-6 neutralizing antibodies partially reduced FPA-induced CRP expression in VSMCs. The subchronic administration of FPA to rats increased FPA level in plasma and CRP expression in the aortic artery walls. The further studies showed that FPA promoted superoxide anion generation in VSMCs. Antioxidant NAC antagonized FPA-stimulated superoxide anion generation and inhibited FPA-induced CRP expression in VSMCs. FPA activated ERK1/2 and p38 phosphorylation, and PD98059 and SB203580 reduced FPA-induced CRP expression. Moreover, NAC inhibited the activation of ERK1/2 and p38. In addition, FPA enhanced NF-kappaB level in the nuclei of VSMCs, and PDTC reduced FPA-induced expression of CRP. CONCLUSIONS: FPA induces CRP expression in VSMCs via ROS ERK1/2/p38-NF-kappaB signal pathway. This finding for the first time provides an experimental evidence for pro-inflammatory effect of FPA. PMID- 29768264 TI - Opportunities and Challenges in Global Perinatal Research. AB - BACKGROUND: The global plight of stillbirths and neonatal mortality is concentrated in low- and middle-income countries. The ambitious targets introduced by the World Health Organization in the Every Newborn Action Plan demand a commitment to research that promotes equitable perinatal outcomes. OBJECTIVES: The aim of this review was to understand the opportunities for global perinatal research and the accompanying challenges. METHODS: We conducted a literature search to identify research prioritization exercises from 2014 to 2018 pertaining to global perinatal health. The top 50 questions with the highest research prioritization scores were extracted and analyzed. RESULTS: The greatest priorities centered on community-based, implementation research targeting major causes of stillbirth and neonatal mortality in low-resource settings. The priorities are saddled with prerequisite conditions, design obstacles, and ethical considerations that require attention. CONCLUSIONS: While the challenges are undeniable, the need to make the perinatal period healthier for babies worldwide has never been clearer. PMID- 29768265 TI - Disease Burden, Psychological Well-Being and Attitudes regarding the Set of Emergency Medication in Adults with Insect Venom Allergy. AB - BACKGROUND: Insect venom allergy is common and greatly impairs patients' quality of life. Additionally, low compliance with carrying emergency medication is reported. The aim of our study was to analyze the disease burden, levels of anxiety and depression, and to evaluate attitudes towards the set of emergency medication in affected patients. METHODS: Between April 2016 and January 2017, patients >=18 years visiting our department because of an insect venom allergy were asked to complete a paper-based questionnaire. The questionnaire assessed willingness to pay (WTP), the Hospital Anxiety and Depression Scale (HADS), subjective anxiety levels, willingness to carry the set of emergency medication, self-assurance in using it, compliance with carrying it, and reasons for not always carrying it. RESULTS: 55 patients (81.8% wasp allergy) were included. On average, WTP for a complete cure was EUR 1,727 (median: 500). Using the HADS, 14.5% showed definite anxiety disorders while 5.5% had significant depression disorders. Most patients stated to carry the emergency medication "always" (25.5%) or "almost always" (47.3%). "Forgetfulness" (36.4%) was reported as the main reason for not always carrying the medication, followed by "too big" (18.2%). CONCLUSIONS: In our patient cohort, insect venom allergy was associated with a moderate disease burden and a good compliance with carrying the emergency medication. However, several of our participants demonstrated borderline or significant anxiety and/or depression disorders. In this regard, this study highlights the necessity to regularly ask the patient about the psychological well-being to identify patients needing psychological support. PMID- 29768266 TI - Subfoveal Choroidal Thickness in Eyes with Neovascular Age-Related Macular Degeneration Treated with Anti-Vascular Endothelial Growth Factor Agents. AB - PURPOSE: We aimed to assess the subfoveal choroidal thickness (SFChT) and the effect of treatment with anti-vascular endothelial growth factor (anti-VEGF) agents on the SFChT in age-related macular degeneration (AMD) subtypes. METHODS: We enrolled 128 eyes of 107 patients with neovascular AMD (60 women; 47 men; mean age, 73.6 +/- 8.9 years), and prospectively evaluated the best-corrected visual acuity (BCVA) and SFChT at baseline and at 3, 6, and 12 months after treatment with anti-VEGF agents. Patients were assigned to the typical AMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP) subgroups. RESULTS: In total, 85 (66.4%), 31 (24.2%), and 12 (9.4%) eyes were assigned to the typical AMD, PCV, and RAP subgroups, respectively. The baseline mean BCVA was 0.75 +/- 0.26, 0.72 +/- 0.21, and 0.77 +/- 0.24 logMAR in the typical AMD, PCV, and RAP subgroups, respectively (p = 0.774). The mean baseline SFChT was 203.20 +/- 35.80, 271.80 +/- 24.50, and 182.93 +/- 31.31 um, respectively (p < 0.001). Mean SFChT significantly decreased from baseline to 3, 6, and 12 months after treatment. The RAP subtype presented a significantly higher decrease in SFChT compared to the other subtypes (p = 0.01). The percentage reduction in SFChT was not significantly correlated with the number of injections (r = -0.02; p = 0.823). No association was observed between baseline SFChT and final visual acuity at 12 months (r = 0.0; p = 0.586). CONCLUSIONS: SFChT was greatest in eyes with PCV and least in eyes with RAP. The reduction in SFChT after treatment was greater in the RAP cases. The decrease in SFChT after 12 months of anti-VEGF treatment was not associated with the number of injections and there was no correlation between the baseline SFChT and visual acuity in all AMD subtypes. PMID- 29768268 TI - Antifungal Innate Immunity: A Perspective from the Last 10 Years. AB - Fungal pathogens can rarely cause diseases in immunocompetent individuals. However, commensal and normally nonpathogenic environmental fungi can cause life threatening infections in immunocompromised individuals. Over the last few decades, there has been a huge increase in the incidence of invasive opportunistic fungal infections along with a worrying increase in antifungal drug resistance. As a consequence, research focused on understanding the molecular and cellular basis of antifungal immunity has expanded tremendously in the last few years. This review will provide an overview of the most exciting recent advances in innate antifungal immunity, discoveries that are helping to pave the way for the development of new strategies that are desperately needed to combat these devastating diseases. PMID- 29768267 TI - Type 2 Diabetes Promotes Cell Centrosome Amplification via AKT-ROS-Dependent Signalling of ROCK1 and 14-3-3sigma. AB - BACKGROUND/AIMS: Type 2 diabetes is associated with oxidative stress and DNA damage which can cause centrosome amplification. Thus, the study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. METHODS: Centrosome numbers in human peripheral blood mononuclear blood cells (PBMC) from healthy subjects and patients with type 2 diabetes were compared to access the association between type 2 diabetes and centrosome amplification. Colon cancer cells were used to investigate the molecular mechanisms underlying the centrosome amplification triggered by high glucose, insulin and palmitic acid. Western blot analysis was used to quantify the level of protein and protein phosphorylation. Immunofluorescent staining was performed to detect centrosomes. ROS was quantified using flow cytometry technique. Transcriptpmic profiling was performed using Illumina HiSeqTM500 platform. RESULTS: We found that centrosome amplification was increased PBMC from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3sigma. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3sigma was the molecular pathway underlying the centrosome amplification in vitro triggered by high glucose, insulin and palmitic acid. Moreover, the key in vitro molecular signalling events activated by high glucose, insulin and palmitic acid were verified in PBMC from the patients with type 2 diabetes. CONCLUSION: Our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3sigma is the underlying molecular mechanism. PMID- 29768269 TI - Long-Term Results of Combination Treatment with Single-Dose Ranibizumab plus Photodynamic Therapy for Retinal Angiomatous Proliferation. AB - PURPOSE: To present functional and anatomic outcomes of combination therapy with ranibizumab and photodynamic therapy (PDT) in a series of retinal angiomatous proliferation (RAP) cases. METHODS: A total of 17 eyes of 17 patients with RAP were included. Thirteen eyes were treatment naive and 4 were already on ranibizumab monotherapy. Combined treatment with single-dose ranibizumab and PDT was performed on all treatment-naive cases. Follow-up was performed every month for 6-38 months, using optical coherence tomography and indocyanine green angiography when necessary. RESULTS: Overall, 6 out of 7 treatment-naive cases with stage I or II disease manifested complete angiographic resolution of the hot spot with a single injection of ranibizumab plus PDT. In stage III disease, 7 out of 10 eyes showed persistent leakage immediately after the combined treatment. The rate of hot spot occlusion was found to correlate with the stage of disease (p = 0.05). There was a significant improvement in posttreatment BCVA for all patients regardless of disease stage (p = 0.02), which was more evident in the earlier stages. Improvement was also greater for treatment-naive patients (p = 0.03). The posttreatment improvement in BCVA was strongly correlated with hot spot occlusion (p < 0.001). CONCLUSIONS: Single-dose modified anti-VEGF treatment in combination with PDT may provide long-term regression at the initial stages of RAP. PMID- 29768270 TI - Associations of Current Wheeze and Body Mass Index with Perennial and Seasonal Allergic Rhinitis in Young Adults. AB - BACKGROUND: The coexistence of asthma and allergic rhinitis (AR) and its distinct association with obesity have been reported. However, few studies have differentiated the two types of AR, i.e., perennial (PAR) and seasonal AR (SAR), with regard to their associations with asthma and obesity. The aim of this study was to evaluate the coexistence of current wheeze and two types of AR and the impact of body mass index (BMI) on these two conditions in Japanese young adults. METHODS: First-year students from Hokkaido University were enrolled into this study from 2011 to 2016. A questionnaire survey including the prevalence of current wheeze, PAR, and SAR every year for 11,917 nonsmoking young adults was conducted. The difference in the impact of current wheeze and BMI on these two types of AR was separately evaluated. RESULTS: Although both PAR and SAR were significantly associated with current wheeze, the impact of these two AR types on current wheeze was different (OR for PAR = 2.46 vs. OR for SAR = 1.29). When we classified all of the subjects into 4 groups with or/and without the two types of AR, the prevalence of current wheeze was significantly higher in subjects with PAR than in those without PAR (p < 0.001). However, the prevalence of current wheeze did not differ between subjects with or without SAR. Multinomial regression analyses showed that the association of wheeze with PAR and/or SAR was stronger compared to that of wheeze with SAR without PAR. The prevalence of PAR was not associated with BMI. Contrarily, a low BMI was significantly associated with a high SAR prevalence (p < 0.05). CONCLUSION: Comparisons between PAR and SAR showed that the conditions are differentially associated with current wheeze and BMI. PMID- 29768271 TI - Direct Potentiation of Capsaicin Current by Histamine and Its Effect by Suplatast on Rat Trigeminal Ganglia Neurons. AB - In this study, we investigated the effect of histamine on capsaicin-induced current and its influence by suplatast in rat trigeminal ganglia neurons using a patch-clamp technique. We found that histamine directly potentiated capsaicin induced currents in rat sensory neurons, and suplatast had little effect on this potentiation. Since it has been known that suplatast suppresses histamine release from mast cells, it is possible that suplatast inhibits the activation of nociceptive fibers in the pathological condition via prevention of histamine induced potentiation of the transient receptor potential vanilloid 1 receptor mediated currents. PMID- 29768272 TI - Modulation of Gamma Band Activity and Late Positive Potential in Patients with Chronic Depression after Psychodynamic Psychotherapy. PMID- 29768273 TI - Subcaudate Tractotomy White Matter Anatomy and Variability: A Diffusion Tensor Imaging Study. AB - BACKGROUND: Subcaudate tractotomy is a functional ablative procedure performed for treatment-resistant psychiatric disease, targeting the white matter tracts ventral to the head of the caudate nucleus. The white matter anatomy of this region has extensive interindividual variability, and this is thought to impact upon the treatment response to ablative and deep brain stimulation procedures. OBJECTIVE: We aim to assess in detail the white matter tract anatomy and topographic variability underlying subcaudate tractotomy. METHODS: 74 non depressed adult volunteers underwent MRI including diffusion tensor imaging. Individualized regions of interest were formed in both hemispheres using native non-normalized data to simulate a subcaudate tractotomy. Tractography and analysis were performed and the exact tract locations measured including mean distances and standard deviations to assess variability. RESULTS: The cingulum bundle, uncinate fasciculus, corticostriatal fibres, and corticothalamic fibres were consistently demonstrated. The location of the cingulum bundle was consistent across subjects, but there was extensive interindividual variability in the topographic location of the other tracts. CONCLUSION: We have demonstrated a detailed analysis of the white matter tracts and their anatomical variability underlying subcaudate tractotomy. This has significant implications for neurosurgical targeting. PMID- 29768274 TI - Reliability of a New Symptom Score in a Titrated Quantitative Conjunctival Provocation Test Supported by an Objective Photodocumentation. AB - BACKGROUND: Allergen provocation tests are useful methods for proving the clinical relevance of an allergen-specific sensitization. Among these methods, the conjunctival provocation test (CPT) represents an easy-to-use tool. However, its readout parameters have not yet been internationally standardized or validated. Photodocumentation has been shown as a good option for objectifying a CPT reaction, supporting the local investigator assessment. Based on test-retest reliability of the score and an objective digital photoanalysis of the conjunctival redness, this study aimed to prove the reproducibility of a new CPT scoring system for use in clinical trials (ClinicalTrials.gov identifier: NCT02690740). METHODS: A titrated quantitative CPT was conducted outside of the pollen season in a final cohort of 23 adult patients with birch or grass pollen induced allergic rhinoconjunctivitis. Conjunctival symptoms were analyzed using a standardized symptom score. Conjunctival redness was also evaluated by an external observer and correlated with a digital photoanalysis using MATLAB software. RESULTS: A test-retest correlation of 0.6 (p < 0.01) was found for the symptom score results. Likewise, a correlation of 0.65 (p < 0.01) was observed in the digital photoanalysis. The total symptom score showed a decrease in the mean value of 0.48 score points in the retest. CONCLUSIONS: This study reveals both a valuable test-retest correlation of the proposed score as well as a good correlation of eye redness with the (objective) photodocumentation. Based on our results, we can recommend the use of this scoring system as a valuable clinical protocol for future clinical trials. PMID- 29768275 TI - Predictive Factors for the Long-Term Deterioration of Pulmonary Function in Interstitial Lung Disease Associated with Anti-Aminoacyl-tRNA Synthetase Antibodies. AB - BACKGROUND: Little has been reported on long-term pulmonary function trends among patients with interstitial lung disease associated with anti-aminoacyl-tRNA synthetase antibodies (ARS-ILD). OBJECTIVES: To clarify the factors predictive of progression in ARS-ILD based on patients' initial clinical and radiological features. METHODS: The clinical courses of 88 patients with > 1 year of follow-up data on pulmonary function tests (PFTs) were retrospectively analyzed. Disease behavior was categorized into three groups: (1) improved or (2) worsened (defined as increases or decreases, respectively, of > 10% in forced vital capacity and > 15% in %diffusing capacity of lung carbon monoxide) or (3) stable based on PFT changes compared between 1-year results as the initial data and results at 3 years to assess the long-term course. RESULTS: In the initial course of 75 patients with ARS-ILD who received anti-inflammatory therapy within 6 months after diagnosis, 48 patients (64.0%) improved and 6 patients (8.0%) worsened. The radiological patterns in the patients with ARS-ILD included nonspecific interstitial pneumonia (NSIP) in 46.7% and NSIP with organizing pneumonia overlap in 52.0% of the cases. One-third of the initially improved patients who worsened over the long-term course were assigned to the unstable group. By multivariate logistic analysis, middle lobe traction bronchiectasis was a significant predictive factor for the patients in the unstable group. CONCLUSIONS: Most patients with ARS-ILD receiving anti-inflammatory therapy had improved or remained stable in the first year. However, over the long-term course, some patients worsened despite their initial improvement. Even though the extent of the disease is limited, middle lobe traction bronchiectasis in ARS-ILD may be a useful predictor of poor long-term disease behavior. PMID- 29768276 TI - Mindfulness-Based Attention Training Improves Cognitive and Affective Processes in Daily Life in Remitted Patients with Recurrent Depression: A Randomized Controlled Trial. PMID- 29768277 TI - The Brief Sexual Symptom Checklist as a Screening Tool for Sex-Related Problems in the Primary Care Setting: Focus on Erectile Dysfunction. AB - PURPOSE: To assess the performance of the Brief Sexual Symptom Checklist for men (BSSC-M) questionnaire in General Practitioner's (GP) consults in Spain. METHODS: Multicenter, cross-sectional study conducted in Spain among men >=50 years, visiting a GP for any reason, and being able to answer self-administered questionnaires. Patients receiving medicines for erectile dysfunction (ED) and those with poor functional status were excluded. Sexual satisfaction was assessed by the BSSC-M, ED by the Sexual Health Inventory for Men (SHIM), and quality of life (QoL) using a 5-point Likert scale. RESULTS: In all, 770 men met all the selection criteria and 556 patients (72.2%) reported sexually related problems, ED being the most frequent (n = 427; 55.5%). The SHIM score decreased progressively with the number of causes of sexual dissatisfaction. Prevalence of ED (SHIM <=21) was greater in patients who referred problems with erection in the BSSC-M questionnaire (76 vs. 14%; p < 0.001). Multivariate analysis for ED prediction revealed that sexual dissatisfaction, QoL (average or low/very low), and the presence of 3 or more comorbidities significantly influenced the chances of having ED. CONCLUSIONS: Our results encourage the use of the BSSC-M for identifying suspicion of ED and other sexual problems in patients > 50 who visit their GP for a routine follow-up. PMID- 29768278 TI - Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer's Disease. AB - BACKGROUND: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer's disease (LOAD) have been reported. OBJECTIVE: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. METHODS: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. RESULTS: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (<=514.8 pg/mL, OR 3.54, 95% CI 1.05-11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30-14.06) compared to the 3rd tertile (>=659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. CONCLUSION: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct. PMID- 29768279 TI - Congenital Pyriform Sinus Fistula: Management of an Extra-Delayed and Atypical Case. AB - Clinical presentations of pyriform sinus fistulas vary, and this sometimes leads to a delay in diagnosis and treatment. Recently, we experienced a case of recurrent cervical abscesses occurring after thyroidectomy in an adult affected by a bifidus pyriform sinus fistula. The diagnostic dilemma was related to the timing of events, with a single episode of acute suppurative thyroiditis having occurred 16 years before the onset of the more recent clinical scenario. An endoscopic approach allowed effective management of this clinical case. PMID- 29768281 TI - Ultrasound Cyclo-Plasty in Patients with Glaucoma: 1-Year Results from a Multicentre Prospective Study. AB - PURPOSE: The aim of this study was to evaluate the safety and efficacy of ultrasound cyclo-plasty (UCP) for reducing intraocular pressure (IOP) in patients with glaucoma. METHODS: This is a multicentre prospective study conducted in 3 Italian glaucoma centres. UCP was performed by EyeOP1, which delivers ultrasound beams using 6 piezoelectric transducers activated for 4/6 s (first generation) or 8 s (second generation). Primary outcomes were the mean IOP reduction and the rates of success after 1 year. Secondary outcomes were the mean IOP reduction at each follow-up, and the reduction of the number of hypotensive medications. RESULTS: In total, 49 eyes from 47 patients were treated. One year postoperatively, the mean IOP had decreased from 27.7 +/- 9.2 to 19.8 +/- 6.9 mm Hg (p < 0.001), and the mean number of hypotensive drops and tablets had decreased from 3.2 and 0.5 to 2.3 and 0.2, respectively (p < 0.05). Postoperative IOP reduction was significantly related to preoperative IOP (r2 = 0.5034; p < 0.0001). Second-generation probes determined a significantly higher IOP reduction (p < 0.05). Qualified success was achieved in 25 eyes (51.1%) and complete success in 21 (42.9%), while failure was recorded in 12 (24.5%). CONCLUSIONS: UCP is safe and effective for reducing IOP. The procedure determines a greater IOP reduction in patients with higher preoperative IOP. Second-generation probes improve outcomes without detrimental effects on safety. PMID- 29768280 TI - Phase I/II Trial of Chemotherapy with Docetaxel, Cisplatin, and S-1 for Unresectable Advanced Squamous Cell Carcinoma of the Esophagus. AB - Our previous trial with a docetaxel, cisplatin, and 5-fluorouracil (DCF) regimen showed high response rates in metastatic squamous cell carcinoma of the esophagus (SCCE). The observed increased toxicity of the DCF regimen, however, was clinically harmful. S-1, an oral anticancer drug, has been approved as a combination therapy for SCCE, and alternate-day regimen with S-1 has shown lower levels of toxicity. This prospective single-center phase I/II trial examines the efficacy and toxicity of a combination of docetaxel, cisplatin, and an alternate day regimen of S-1 (modified DCS) for patients with metastatic SCCE. We use a two stage design. Phase I is undertaken to determine the maximum tolerated dose and the recommended dose. The phase I trial adopts a three-patient cohort with escalating dose study design. In the phase II trial, the primary endpoint is the assessment of the overall response rate (Response Evaluation Criteria in Solid Tumors 1.1). The secondary endpoints are the evaluation of drug-related toxicity (National Cancer Institute Common Toxicity Criteria 4.0), overall survival, and progression-free survival. Fifty patients with metastatic SCCE participate in the phase II section. This study protocol is the first to test the effects of the modified DCS regimen for metastatic SCCE. PMID- 29768282 TI - Baseline Thromboelastogram as a Predictor of Left Ventricular Assist Device Thrombosis. AB - Left ventricular assist device (LVAD) pump thrombosis occurs in up to 8.4% of patients within 3-months postimplantation. Thromboelastography (TEG) could be used to signal hypercoagulability at LVAD implantation to predict patients at high risk for thrombosis. We sought to evaluate whether TEG maximum amplitude (MA) hypercoagulability (MA >=69 mm) at the time of LVAD implantation predicts pump thrombosis. A single center, retrospective, nested case-control study was conducted using patients from January 1, 2005, to March 31, 2015. Each pump thrombosis case was matched to two control subjects based on age +/- 5 years, sex, and duration of follow-up. A multivariable logistic regression analysis was performed on the matched sets; the odds ratio with 95% confidence interval (CI) was calculated to estimate the relative risk. Thirty-seven age- and sex-matched case-control sets were included for a total of 111 study participants. TEG-MA hypercoagulability occurred in 10.8% of the case group versus 6.8% of controls. There was no association between TEG-MA hypercoagulability and device thrombosis (odds ratio 1.71, 95% confidence interval 0.42-7.05, p = 0.46). Utilization of baseline TEG-MA hypercoagulability to detect individuals at risk for LVAD thrombosis is a novel concept. This study found no significant association between TEG-MA and LVAD thrombosis. PMID- 29768283 TI - Cerebral Oxygenation as a Monitoring Parameter for Mortality During Venoarterial Extracorporeal Membrane Oxygenation. AB - There are no recommended guidelines for monitoring parameters during venoarterial extracorporeal membrane oxygenation (VA-ECMO). We evaluated whether regional cerebral oxygen saturation (rScO2) could be a monitoring parameter for mortality during VA-ECMO. We retrospectively searched our database for adult patients who underwent VA-ECMO between April 2015 and October 2016 and identified 21 patients with rScO2 data. Their baseline and clinical characteristics during the first 7 days (vital signs, arterial blood gas results, ECMO variables, rScO2, Swan-Ganz catheter parameters, transthoracic echocardiography parameters, and outcomes) were collected and evaluated for associations with 28 day mortality. The survivor group (12 patients, 57.1%) had higher rScO2 values and lower lactate levels, compared with the nonsurvivor group (nine cases, 42.9%) during the first 7 days. The areas under the receiver operating characteristics curves were 0.87 for right rScO2 (p < 0.001) and 0.86 for left rScO2 (p < 0.001). The optimal cutoff values for right and left rScO2 were 58% (sensitivity: 78.7%, specificity: 83.3%) and 57% (sensitivity: 80.0%, specificity: 70.8%), respectively. Kaplan-Meier analysis revealed that the risks of 28 day mortality were higher among patients with a right rScO2 of <58% and a left rScO2 of <57%, compared with patients with a right rScO2 of >=58% and a left rScO2 of >=57% (both, p < 0.001). We suggest that rScO2 may be used as a monitoring parameter for 28 day mortality among patients undergoing VA-ECMO. PMID- 29768284 TI - Predictive value of excision repair cross-complementing group 2 gene Lys751Gln and Asp312Asn polymorphisms in melanoma risk. AB - Epidemiological studies have assessed the association between excision repair cross-complementing group 2 (ERCC2) Lys751Gln and Asp312Asn polymorphisms and melanoma risk with conflicting results. Relevant articles were searched from PubMed, Embase, and Web of Science with a time limit of 3 September 2016. Pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the association. We performed this meta-analysis with 12 studies including 6157 cases and 8873 controls for Lys751Gln and nine studies including 5037 cases and 7542 controls for Asp312Asn polymorphism. Overall, no significant associations were found under all the models for Lys751Gln polymorphism, and significant associations were found for Asp312Asn polymorphism for AA versus GG (OR=1.12, 95% CI=1.00-1.26) and for the recessive model (OR=1.11, 95% CI=1.00 1.24). In the stratification analyses by source of control: for Lys751Gln polymorphism, significant associations were found for CC versus AA (OR=1.19, 95% CI=1.04-1.36) and the recessive model (OR=1.15, 95% CI=1.02-1.30); for Asp312Asn polymorphism, significant associations were found for AA versus GG (OR=1.31, 95% CI=1.11-1.53) and the recessive model (OR=1.29, 95% CI=1.11-1.50). This meta analysis suggested that both the Lys751Gln and Asp312Asn polymorphisms were risk factors for melanoma risk in population-based subgroup. PMID- 29768285 TI - Obstetrics and Gynecology Ultrasound. PMID- 29768286 TI - Comparison Between Ultrasonography and Galactography in Detecting Lesions in Patients With Pathologic Nipple Discharge. AB - PURPOSE: This study aimed to compare the diagnostic performance of breast ultrasonography (US) with that of galactography in the detection of lesions in patients with pathologic nipple discharge. METHODS: We included 46 cases from 39 patients (all women; mean age, 44.0 years; range, 22-68 years) who had pathologic nipple discharge and underwent US and galactography between March 2004 and December 2012. Two radiologists retrospectively reviewed and compared the detectability of lesions on US and galactography images. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of US and galactography, and the area under the curve was compared between the 2 imaging modalities. RESULTS: A total of 35 cases were pathologically diagnosed. Out of 11 cases that completed a follow-up, none developed malignancies during the follow-up period (mean: 63.5 months; range: 34.8-125.7 months). The sensitivity, specificity, and positive and negative predictive values of US with respect to detectability of lesions were 75%, 42.9%, 11.1%, and 94.7%, respectively, and those of galactography were 100%, 38.1%, 13.3%, and 100%, respectively. CONCLUSIONS: Galactography is more sensitive than US in the detection of lesions in patients with pathologic nipple discharge. PMID- 29768287 TI - Ultrasound, Computed Tomography, and Magnetic Resonance Imaging in a Patient With Medullary Cystic Kidney Disease. AB - Among the renal cystic diseases that result in end-stage renal disease, an important hereditary cause is medullary cystic kidney disease, which affects adults in an autosomal dominant pattern. It is characterized by progressive renal failure, tubulointerstitial fibrosis, and formation of small cysts in the renal medulla and corticomedullary junction. While the appearance of medullary/corticomedullary cysts may not be pathognomonic for medullary cystic kidney disease, encountering a patient with renal failure and medullary/corticomedullary cysts should prompt further investigation, given the implication of having the disease. Genetic testing can be used to identify potential renal donors as well as identify affected individuals in order to control risk factors for chronic renal disease that may mitigate the progression of the disease process. The treatment of choice is renal transplantation. PMID- 29768288 TI - Caffeine Sodium Benzoate for Electroconvulsive Therapy Augmentation. AB - OBJECTIVES: Because of an ongoing manufacturer shortage of injectable caffeine sodium benzoate (CSB), patients at our health system were given CSB compounded in house to increase seizure response during electroconvulsive therapy (ECT). Therefore, we aimed to evaluate its effectiveness and safety as an ECT augmentation agent. METHODS: Medical records of patients who received compounded CSB at Virginia Commonwealth University Health System were reviewed to identify adults receiving it as part of an index ECT treatment course between June 2012 and December 2016. The primary outcome was change in electroencephalogram seizure duration from pre-caffeine session to initial caffeine session. Data were also collected on demographics, motor seizure duration, maximum heart rate, mean arterial pressure, and concurrent medication use for these sessions and the last caffeine session. RESULTS: Seven-one patients were included in the study, predominantly white females with a mean age of 58.6 years. The most common indication for ECT was major depressive disorder resistant to pharmacotherapy (71.8%), followed by catatonia associated with another mental disorder (19.7%). Electroencephalogram seizure duration increased by 24.1 seconds on average with first CSB use (P < 0.0001), allowing 24 more patients overall to achieve goal of at least 30 seconds (P < 0.0001). No clinically significant changes in maximum heart rate or mean arterial pressure were observed, nor did any patients require an abortive agent for prolonged seizure. Five patients (7%) discontinued CSB prematurely: 4 related to adverse effects and 1 secondary to ineffectiveness. CONCLUSIONS: We confirm results of prior studies of the utility of CSB and add that compounded CSB is effective for ECT augmentation, maintaining effectiveness throughout the index course with minimal safety concerns. PMID- 29768289 TI - Electroconvulsive Therapy-Related Anxiety: Treat or Threat? PMID- 29768290 TI - Intense aerobic exercise lowers blood pressure in individuals with metabolic syndrome taking antihypertensive medicine. AB - OBJECTIVE: There is a growing tendency for physicians to prescribe exercise in accordance with the 'exercise is medicine' global health initiative. However, the exercise-pharmacologic interactions for controlling blood pressure are not well described. Our purpose was to study whether angiotensin II receptor type 1 blocker (ARB) antihypertensive medicine enhances the blood pressure-lowering effects of intense exercise. PARTICIPANTS AND METHODS: Fifteen hypertensive individuals with metabolic syndrome chronically medicated with ARB underwent two exercise trials in a blind randomized order. One trial was conducted after taking their habitual dose of ARB (ARB MED trial) and another after 48 h of placebo medicine (i.e. dextrose; PLAC trial). RESULTS: After placebo medication, brachial systolic blood pressure increased by 5.5 mmHg [P=0.009; effect size (ES)=0.476] and diastolic by 2.5 mmHg (P=0.030; ES=0.373). Exercise reduced systolic and diastolic blood pressures to the same extent in ARB MED and PLAC trials (7 and 8 mmHg, respectively, for systolic and 5 and 4 mmHg, respectively, for diastolic, all P<0.05). Pulsatile measures of arterial stiffness did not reveal an interaction effect between exercise and medication. However, postocclusion reactive hyperemia increased after exercise only in the ARB MED trial (361+/-169 to 449+/-240% from baseline; P=0.033; ES=0.429). CONCLUSION: ARBs and a bout of intense exercise each have an independent effect on lowering blood pressure in hypertensive individuals, and these effects are additive. PMID- 29768292 TI - Impact of Peripheral Venous Catheter Placement With Vein Visualization Device Support on Success Rate and Pain Levels in Pediatric Patients Aged 0 to 3 Years. AB - BACKGROUND: Pediatric nurses should be able to use techniques that increase the success rate or shorten the procedural duration of peripheral intravenous catheterization (PIVC). OBJECTIVES: This study was performed to define the effect of the infrared vein visualization device support on the success of PIVC in pediatric patients aged 0 to 3 years. Success was determined based on the number of attempts per patient, the duration of the procedure, the success rate of first attempts, and the pain levels of the children. METHODS: The study was a randomized, controlled experimental study on 54 children aged 0 to 3 years. RESULTS: Peripheral intravenous catheterization in the study group was performed with fewer attempts (study group: 1.44 +/- 0.85 [median, 1]; control group: 2.41 +/- 1.99 [median, 2]; P = 0.016) and in a shorter period (study group: 44.37 +/- 32.22 [median, 40 seconds]; control group: 168.89 +/- 171.54 [median, 112 seconds; P = 0.001), and the first attempt success rate in the study group (74.1%) was higher than in the control group (40.7%; P = 0.028). Also, the pain level of the children in the study group was significantly lower than that in the control group (P < 0.05). CONCLUSIONS: In conclusion, PIVC supported by the infrared vein visualization device reduces the number of attempts per patient, reduces the duration of the procedure, and increases the success rate of first attempts, and there is procedural pain; therefore, vein visualization improves the success of PIVC. PMID- 29768291 TI - Quality of the Triage of Children With Anaphylaxis at the Emergency Department. AB - OBJECTIVE: Early recognition of symptoms is essential in anaphylaxis management. The Canadian Paediatric Emergency Triage and Acuity Scale prioritizes anaphylaxis to level I or II (resuscitation or emergency). We analyzed the accuracy of pediatric anaphylaxis triage. METHODS: This was a retrospective review of the triage charts (adaptation of the Canadian Paediatric Emergency Triage and Acuity Scale) of 137 children attended for anaphylaxis at our pediatric emergency department. Per triages' accuracy, charts were divided into TR1 (levels I-II) and TR2 (levels III-V), comparing demographics, initial triage level given by initial assessment (Paediatric Assessment Triangle), vital signs, observations recorded by the staff, and waiting times for physician. RESULTS: Forty-six (33.3%) were triaged correctly (TR1 group), and 91 (66.7%) were not. Median ages were similar (TR1: 5 years [interquartile range, 13.1 years] vs TR2: 4.5 years [interquartile range, 14.5 years]; P = 0.837). Initial triage level 5 was given by Paediatric Assessment Triangle to 69.5% of TR1 and 83% of TR2 cases (P = 0.001; likelihood ratio for TR2: 1.985 [95% confidence interval, 1.11-3.49]). Vital signs were normal in 71.7% of TR1 and 94.5% of TR2 patients (P < 0.001; likelihood ratio for TR2: 2.602 [95% confidence interval, 1.22-5.52]). Symptoms suggestive of anaphylaxis (mention of 2 different organs) were recorded in 45.6% of TR1 and 48.3% of TR2 charts (P = 0.08). Median waiting times were 3 minutes (interquartile range, 26 minutes) and 11 minutes (interquartile range, 111 minutes) for TR1 and TR2, respectively (P = 0.001). CONCLUSIONS: Current triage, based on severity perception, missed most of the cases. Anaphylaxis-defining symptoms were overlooked. Inaccurate triage delayed medical attention. Improving measures, such as emphasizing symptom recognition and defining anaphylaxis risk discriminators, is mandatory to improve their identification. PMID- 29768293 TI - Seasonality of Common Pediatric Infectious Diseases. AB - BACKGROUND/OBJECTIVE: Traditional sources cite seasonal patterns for common infectious diseases, often based on microbiologic data, but little is known about cyclical trends in clinically diagnosed infectious conditions in the emergency department (ED). We leveraged the publicly available Nationwide Emergency Department Sample database to measure the seasonality of the most common pediatric infectious diseases diagnosed in US EDs. METHODS: We searched the Nationwide Emergency Department Sample database to identify infectious diagnoses comprising at least 1% of all diagnosis codes ascribed to patients 21 years and younger in US EDs from 2009 to 2013. We used Fourier regression to examine seasonal trends in disease and calculated the peak-to-nadir ratio for each infectious condition. RESULTS: Over 20% of pediatric visits during the study period were for infectious conditions. Upper respiratory infection, otitis media, gastroenteritis, urinary tract infection/pyelonephritis, cellulitis/abscess, and pneumonia showed a seasonal pattern that matched trends found in prior regional or microbiologic-based studies. The strongest seasonal trend as measured by goodness of model fit was found in pneumonia (peak-to-nadir incidence ratio of 2.7), followed by otitis media (2.0), cellulitis/abscess (2.0), gastroenteritis (1.6), upper respiratory infection (3.2), and urinary tract infection/pyelonephritis (1.4). Pharyngitis did not show a strong seasonal trend. CONCLUSIONS: Many of the most common pediatric infectious diseases diagnosed in US EDs exhibited seasonal patterns. Large administrative databases can be used to track seasonal disease patterns, with the advantage that they reflect clinician diagnosis beyond microbiologic confirmation. This methodology could aid in resource planning, infection control, and public health educational initiatives. PMID- 29768294 TI - A Pilot Study to Reduce Computed Tomography Utilization for Pediatric Mild Head Injury in the Emergency Department Using a Clinical Decision Support Tool and a Structured Parent Discussion Tool. AB - INTRODUCTION: The American College of Emergency Physicians embarked on the "Choosing Wisely" campaign to avoid computed tomographic (CT) scans in patients with minor head injury who are at low risk based on validated decision rules. We hypothesized that a Pediatric Mild Head Injury Care Path could be developed and implemented to reduce inappropriate CT utilization with support of a clinical decision support tool (CDST) and a structured parent discussion tool. METHODS: A quality improvement project was initiated for 9 weeks to reduce inappropriate CT utilization through 5 interventions: (1) engagement of leadership, (2) provider education, (3) incorporation of a parent discussion tool to guide discussion during the emergency department (ED) visit between the parent and the provider, (4) CDST embedded in the electronic medical record, and (5) importation of data into the note to drive compliance. Patients prospectively were enrolled when providers at a pediatric and a freestanding ED entered data into the CDST for decision making. Rate of care path utilization and head CT reduction was determined for all patients with minor head injury based on International Classification of Diseases, Ninth Revision codes. Targets for care path utilization and head CT reduction were established a priori. Results were compared with baseline data collected from 2013. RESULTS: The CDST was used in 176 (77.5%) of 227 eligible patients. Twelve patients were excluded based on a priori criteria. Adherence to recommendations occurred in 162 (99%) of 164 patients. Head CT utilization was reduced from 62.7% to 22% (odds ratio, 0.17; 95% confidence interval, 0.12-0.24) where CDST was used by the provider. There were no missed traumatic brain injuries in our study group. CONCLUSION: A Pediatric Mild Head Injury Care Path can be implemented in a pediatric and freestanding ED, resulting in reduced head CT utilization and high levels of adherence to CDST recommendations. PMID- 29768295 TI - Requirement for Head Magnetic Resonance Imaging in Children Who Present to the Emergency Department With Acute Nontraumatic Visual Disturbance. AB - OBJECTIVES: This study aimed to investigate the clinical features and head magnetic resonance imaging (MRI) findings in children who presented to the emergency department with acute nontraumatic visual disturbance and to study related clinical factors for discovering positive lesions on head MRI. METHODS: We performed a retrospective study of 1-month to 15-year-old children who underwent head MRI as an evaluation for acute nontraumatic visual disturbance as a chief complaint in our pediatric emergency department between March 2010 and March 2015. The symptoms of visual disturbance were blurred vision, diplopia, loss of vision, and visual hallucination. Head MRI findings were considered positive when lesions could explain the symptoms. RESULTS: We identified 39 patients (25 with blurred vision, 9 with diplopia, 3 with loss of vision, and 2 with visual hallucination) with a mean age of 8.35 +/- 4.06 years. Positive head MRI findings were identified in 13 patients (33.3%). Brain tumors were most common (53.8%), followed by optic nerve inflammations (23.1%), congenital brain lesions (15.4%), and hypertensive encephalopathy (7.7%). Compared with the negative head MRI group, the positive head MRI group showed significantly less transient visual disturbance (duration <1 hour to complete recovery) (P = 0.001), more limited eye movement (P = 0.003), and more pupillary abnormalities (P = 0.030). CONCLUSIONS: We suggest performing urgent head MRI in children with acute nontraumatic visual disturbance if the symptoms last longer than 1 hour without complete recovery and are accompanied by limited eye movement or pupillary abnormality. PMID- 29768296 TI - Pediatric Diabetic Ketoacidosis With Hypotensive Shock and Rash-An Unusual Presentation. AB - We describe a previously healthy adolescent boy who presented with respiratory distress, hypotensive shock, and a diffuse erythematous rash. The final diagnosis was diabetic ketoacidosis. Caregivers should be alert to this unusual combination of symptoms in the emergency department setting in order to improve the recognition and management of children with new-onset diabetes. PMID- 29768297 TI - Pediatric Esophageal Foreign Body: Possible Role for Digital Tomosynthesis. AB - OBJECTIVES: Foreign body (FB) ingestion is a common reason for emergency department visits, affecting more than 80,000 children in the United States annually. Whereas most ingested FBs are coins or other radiopaque objects, some are radiolucent FBs such as food. Digital tomosynthesis (DTS) is a radiographic technique that produces cross-sectional images with in-plane resolution similar to that of traditional radiographs. Our pilot study evaluated the sensitivity and specificity of DTS to detect FB in comparison to esophagram and clinical impression. METHODS: This was a retrospective review on patients aged 0 to 18 years with suspected esophageal FB who received an esophagram with DTS at our institution between January 2014 and June 2016. Digital tomosynthesis images were analyzed by 3 readers for identification of FB impaction and compared with esophagram and discharge diagnosis. This study was approved by our local institutional review board. RESULTS: A total of 17 patients underwent an esophagography with DTS for suspected esophageal FB, of which 9 (53%) were suspected of having an FB on esophagram. Compared with esophagram, DTS had a sensitivity of 44%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 62%. Compared with clinical impression, DTS had a sensitivity of 33%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 38%. CONCLUSIONS: This pilot study showed that chest DTS has a very high positive predictive value, compared with esophagram and clinical impression, in detecting radiolucent esophageal FBs in children. Chest DTS is a promising modality for ruling in the presence of a radiolucent esophageal FB. PMID- 29768298 TI - Orbital Cellulitis-When Computed Tomography Imaging Is Falsely Reassuring. AB - An 8-year-old male presented to the pediatric emergency department with subjective fever, blurry vision, and left eye pain. On physical examination, there was mild left lower lid erythema and a subtle left eye elevation deficit. Computed tomography demonstrated preseptal soft tissue swelling without orbital involvement; however, there was varying amounts of paranasal sinus opacification. Despite the negative scan, a diagnosis of orbital cellulitis associated with sinusitis was made and treatment with intravenous antibiotics was initiated. A magnetic resonance imaging performed subsequently revealed orbital fat stranding and inferior rectus enlargement and enhancement near the orbital apex, indicating the presence of orbital cellulitis. This case demonstrates the utility of magnetic resonance imaging when initial computed tomography imaging is negative in patients with concern for orbital cellulitis. PMID- 29768299 TI - Early variation of quick sequential organ failure assessment score to predict in hospital mortality in emergency department patients with suspected infection. AB - BACKGROUND: The quick sequential organ failure assessment (qSOFA) score showed good prognostic performance in patients with suspicion of infection in the emergency department (ED). However, previous studies only assessed the performance of individual values of qSOFA during the ED stay. As this score may vary over short timeframes, the optimal time of measurement, and the prognostic value of its variation are unclear. The objective of the present study was to prospectively assess the prognostic value of the change in qSOFA over the first 3 h (DeltaqSOFA=qSOFA at 3 h-qSOFA at inclusion). PATIENTS AND METHODS: This is an international prospective cohort study conducted in 17 EDs in France, Belgium, and Spain. From November 2016 to March 2017, patients with a suspected infection and a qSOFA score of 2 or higher were included and followed up until death or hospital discharge. qSOFA was measured at inclusion, 1 h and 3 h. Primary end point was in-hospital mortality, truncated at 28 days. RESULTS: Of 534 recruited patients, 512 were included in the analysis. The qSOFA was improved at 3 h (DeltaqSOFA<0) in 287 (55%) patients. Overall in-hospital mortality was 27%: 44% when DeltaqSOFA greater than 0, 36% when DeltaqSOFA=0, and 18% when DeltaqSOFA less than 0. A positive DeltaqSOFA was independently associated with reduced in hospital mortality (adjusted hazard ratio of 0.48, 95% confidence interval: 0.34 0.68). After modeling qSOFA kinetics in the first 3 h, there was a significant difference in adjusted slopes between patients who died and those who survived (0.15, 95% confidence interval: 0.09-0.22, P<0.001). CONCLUSION: In patients with suspected infection presenting to the ED with a qSOFA of 2 or higher, the early change in qSOFA is a strong independent predictor of mortality. PMID- 29768300 TI - The hemodynamic response to constant dobutamine infusion: the effect of ADRB1 389 polymorphism and sex. AB - OBJECTIVES: Prolonged activation of the beta-1 adrenergic receptor (ADRB1) is associated with receptor desensitization. This process has been suggested to have important pathophysiological and clinical implications in conditions such as congestive heart failure. The contribution of genetic factors to this process is a patient of ongoing research. We have previously shown that the ADRB1 389 polymorphism affects the response to incremental dose infusion of the ADRB agonist dobutamine. The aim of the current study was to determine whether the ADRB1 389 polymorphism affects the hemodynamic response to constant dose infusion of dobutamine in healthy patients. PATIENTS AND METHODS: Healthy patients were recruited according to their ADRB1 49 and 389 genotypes [15 Arg389Arg, 10 Gly389Arg, and 10 Gly389Gly patients (all Ser49Ser), 21 men and 14 women]. Following a standardized protocol of dose increase, 6 mcg/kg/min dobutamine was infused over 2 h. Heart rate (HR), blood pressure (BP), and active plasma renin (PR) were measured. Standardized exercise (1 min) was performed at three time points during infusion. RESULTS: In all patients, resting systolic BP was significantly decreased during infusion [144.4+/-11.5 vs. 140.3+/-12.2 mmHg (mean+/-SD), P=0.007]. There was no change in HR, and PR following 120 min of dobutamine infusion. ADRB1 389 genotypes were not associated with HR, systolic BP, and PR changes during dobutamine infusion (all P>0.05, repeated measures analysis of variance). Sex was associated with response to dobutamine. Among women, but not in men, resting HR significantly increased, and diastolic blood pressure (DBP) significantly decreased during dobutamine infusion [HR: 76.0+/-7.3 to 86.3+/-17.5 beats per minute (P=0.023), and DBP 78.5+/-8.49 mmHg to 72.36+/ 6.16 (P=0.041) (repeated measures analysis of variance)]. CONCLUSION: In healthy patients, the ADRB1 389 genotype was not associated with hemodynamic changes during constant dobutamine infusion. In women, but not in men, HR significantly increased and DBP decreased during 2 h of infusion. PMID- 29768302 TI - Pharmacogenomics in Papua New Guineans: unique profiles and implications for enhancing drug efficacy while improving drug safety. AB - Papua New Guinea (PNG) can be roughly divided into highland, coastal and island peoples with significant mitochondrial DNA differentiation reflecting early and recent distinct migrations from Africa and East Asia, respectively. Infectious diseases such as tuberculosis, malaria and HIV severely impact on the health of its peoples for which drug therapy is the major treatment and pharmacogenetics has clinical relevance for many of these drugs. Although there is generally little information about known single nucleotide polymorphisms in the population, in some instances, their frequencies have been shown to be higher than anywhere worldwide. For example, CYP2B6*6 is over 50%, and CYP2C19*2 and *3 are over 40 and 25%, respectively. Conversely, CYP2A6*9, 2B6*2, *3, *4 and *18, and 2C8*3 appear to be much lower than in Whites. CYP2D6 known variants are unclear, and for phase II enzymes, only UGT2B7 and UGT1A9 data are available, with variant frequencies either slightly lower than or similar to Whites. Although almost all PNG people tested are rapid acetylators, but which variant(s) define this phenotype is not known. For HLA-B*13:01, HLA-B*35:05 and HLA-C*04:01, the frequencies show some regioselectivity, but the clinical implications with respect to adverse drug reactions are not known. There are minimal phenotype data for the CYPs and nothing is known about drug transporter or receptor genetics. Determination of genetic variants that are rare in Whites or Asians but common in PNG people is a topic of both scientific and clinical importance, and further research needs to be carried out. Optimizing the safety and efficacy of infectious disease drug therapy through pharmacogenetic studies that have translation potential is a priority. PMID- 29768303 TI - Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females: Erratum. PMID- 29768305 TI - Recently introduced definition of "nociplastic pain" by the International Association for the Study of Pain needs better formulation. PMID- 29768301 TI - Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab. AB - Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. A total of 920 women from B-40 were analyzed, and 237 patients achieved a pCR. GWAS with three phenotypes (pCR, disease-free survival, overall survival) revealed no single nucleotide polymorphisms (SNPs) that were genome wide significant (i.e. P<=5E-08) signals; P values for top SNPs were 2.04E-07, 5.61E-08, and 5.63E-08, respectively, and these SNPs were not significant in the GeparQuinto data. An ad-hoc GWAS was performed in the patients randomized to bevacizumab (457 patients with 128 pCR) who showed signals on chromosome 6, located within a gene, CDKAL1, that approached, but did not reach, genome-wide significance (top SNP rs7453577, P=2.97E-07). However, this finding was significant when tested in the GeparQuinto data set (P=0.04). In conclusion, we identified no SNPs significantly associated with NAC. The observation, in a hypothesis-generating GWAS, of an SNP in CDKAL1 associated with pCR in the bevacizumab arm of both B-40 and GeparQuinto requires further validation and study. PMID- 29768306 TI - Reply. PMID- 29768304 TI - Pain after surgery. PMID- 29768307 TI - Tired of pain or painfully tired? A reciprocal relationship between chronic pain and fatigue. PMID- 29768308 TI - Reply. PMID- 29768309 TI - The Impact of a Change in the Price of VA Health Care on Utilization of VA and Medicare Services. AB - INTRODUCTION: The passage of the Veterans Access, Choice, and Accountability Act of 2014 has expanded the non-Veteran Affairs (VA) care options for eligible US Veterans. In order for these new arrangements to provide the best care possible for Veterans, it is important to understand the relationship between VA and non VA care options. The purpose of this study was to use another recent VA policy change, one that increased the reimbursement rate that eligible Veterans receive for travel for health care to VA, to understand the use of VA and Medicare services among Medicare-enrolled Veterans. METHODS: We used a difference-in difference technique to compare inpatient and outpatient utilization and cost in VA and Medicare between Veterans who were eligible for travel reimbursement and those who were not eligible following 2 increases in the travel reimbursement rate. We used generalized estimating equation models and 2-part models when cost outcomes were rare. RESULTS: Our cohort consisted of 110,007 Medicare-enrolled Veterans, including 25,076 under 65 and 84,931 over 65 years old. Following the travel reimbursement rate increases, the number of VA outpatient encounters increased for Veterans in our cohort regardless of age group or whether living in an urban or rural area. The number of non-VA outpatient encounters decreased significantly for Veterans in both age groups living in rural areas following these policy changes. CONCLUSIONS: Our estimates suggest that VA outpatient care may be a substitute for Medicare outpatient care for Medicare-enrolled Veterans living in rural areas. These results are important because they indicate how Veteran health care utilization might be affected by future policy changes designed to increase access to VA services. They also indicate the ripple effects that may occur in other health systems due to changes in the VA system. PMID- 29768310 TI - Examining Women Veteran's Experiences, Perceptions, and Challenges With the Veterans Choice Program. AB - BACKGROUND: The Veterans Choice Program (VCP) was launched in 2014 to address the growing concerns about the timeliness and quality of Veterans Health Administration (VHA) care. Given that many sex-specific health services, such as mammography and maternity care, are not routinely provided in all VHA facilities, women Veterans may disproportionately rely on VCP care. Understanding the provision and coordination of VCP care is crucial in order to ensure that care is not fragmented across the 2 health care systems. OBJECTIVES: The main objective of this study was to understand women Veterans' experiences, perceptions, and challenges with VCP care. DESIGN: This study was a semistructured interview with 148 women at 13 VHA facilities nationwide. RESULTS: Four major themes emerged: (1) eligibility information for the VCP was limited and confusing; (2) women experienced difficulty scheduling VCP appointments; (3) VCP care results were not shared with women Veterans or their VHA providers in a timely manner; and (4) concerns with unpaid VCP bills were common. CONCLUSIONS: Our study highlights challenges women experienced with VCP care, and the need for improved care coordination. An ideal care coordination system would be the one in which all Veterans' non-Veteran Affairs care, including scheduling, follow-up, communication with community providers, coordination of services, and transition back to Veteran Affairs care is ensured. PMID- 29768311 TI - Impact of Provider Participation in ACO Programs on Preventive Care Services, Patient Experiences, and Health Care Expenditures in US Adults Aged 18-64. AB - BACKGROUND: Little is known about the impact of accountable care organization (ACO) on US adults aged 18-64. OBJECTIVES: To examine whether having a usual source of care (USC) provider participating in an ACO affects receipt of preventive care services, patient experiences, and health care expenditures among nonelderly Americans. RESEARCH DESIGN: A cross-sectional analysis of the 2015 Medical Organizations Survey linked with the Medical Expenditure Panel Survey. SUBJECTS: Survey respondents aged 18-64 with an identified USC and continuous health insurance coverage during 2015. MEASURES: Preventative care services (routine checkup, flu vaccination, and cancer screening), patient experiences with health care (access to care, interaction quality with providers, and global satisfaction), and health care expenditures (total and out-of-pocket expenditures) for respondents with USC by ACO and non-ACO provider groups. RESULTS: Among 1563, nonelderly Americans having a USC, we found that nearly 62.7% [95% confidence interval (CI), 58.6%-66.7%; representing 15,722,208 Americans] were cared for by ACO providers. Our analysis showed no significant differences in preventive care services or patient experiences between ACO and non-ACO groups. Adjusted mean total health expenditures were slightly higher for the ACO than non-ACO group [$7016 (95% CI, $4949-$9914) vs. $6796 (95% CI, $4724 $9892)]; however, this difference was not statistically significant (P=0.250). CONCLUSIONS: Our findings suggest that having a USC provider participating in an ACO is not associated with preventive care services use, patient experiences, or health care expenditures among a nonelderly population. PMID- 29768313 TI - The Incidence of Myocardial Injury after Loading Doses of Clopidogrel versus Prasugrel in the Candidates for Percutaneous Coronary Intervention: A Randomized Controlled Trial. AB - INTRODUCTION: Prevention of myocardial injury is an essential issue in percutaneous coronary intervention (PCI). We compared the incidence of myocardial injury after loading doses of clopidogrel versus prasugrel in the candidates for PCI. METHODS: In this randomized-controlled clinical trial, we enrolled 88 stable angina patients, candidate for PCI. Patients received either prasugrel (60 mg orally) (n = 42) or clopidogrel (600 mg orally) (n = 46). Serum levels of creatine phosphokinase muscle-brain type, cardiac troponin I, and high sensitive C-reactive protein were measured at baseline and 6 and 12 hours postprocedural. Primary endpoint was periprocedural myocardial infarction (MI), defined as elevation of cTn values (>5 times) in patients with normal baseline values or a rise of cTn values >20% if the baseline values are elevated. RESULTS: Based on the levels of cTnI 6 hours after PCI, 1 patient (2.4%) had MI in the prasugrel group, whereas 4 patients (8.7%) had MI in the clopidogrel group. After 12 hours, 4 patients (9.5%) had MI in the prasugrel group versus 5 patients (10.9%) in the clopidogrel arm. There was no significant difference between the groups regarding the changes in cardiac specific enzyme levels. However, serum levels of cTnI were significantly lower in patients with myocardial injury in the prasugrel arm (P < 0.001). CONCLUSIONS: Prasugrel is an effective antiplatelet drug in preventing periprocedural MI. PMID- 29768314 TI - Medication Administration Delays in Non-ST Elevation Myocardial Infarction: Analysis of 1002 Patients Admitted to an Academic Medical Center. AB - Our goal was to assess adherence to American College of Cardiology/American Heart Association guideline-based medical therapy in patients admitted with type I non ST elevation myocardial infarction (NSTEMI) and to determine factors associated with medication administration delay. We performed a retrospective analysis using data from the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry. Baseline patient demographics, 12-lead electrocardiogram (ECG) findings, laboratory values, medications administered and the time they were administered, and in-hospital clinical outcomes were collected. Global Registry of Acute Coronary Events risk scores were calculated for all patients. We included 1002 patients admitted from the emergency department with a type I NSTEMI. A total of 802 (80%) patients received appropriate initial therapy consisting of therapeutic anticoagulation with heparin and dual antiplatelet therapy. Of the 200 (20%) patients who did not receive therapy, documentation in the chart regarding possible contraindications for administration of the medications was missing in up to half. Female sex, older age, a normal initial ECG, and prolonged time spent in the emergency department were predictors of significant delay in receiving guideline-based medications, while an elevated initial troponin was a predictor of faster medication administration. Global Registry of Acute Coronary Events risk scores had no association with the timing of medication administration. In conclusion, 20% of NSTEMI patients did not receive American College of Cardiology/American Heart Association guideline-based medical therapy. Delay in medication administration was significant for women, older individuals, and patients who did not have ischemic findings on the initial ECG. PMID- 29768312 TI - Advances in the Treatment of Stable Coronary Artery Disease and Peripheral Artery Disease. PMID- 29768315 TI - Angiography-guided Multivessel Percutaneous Coronary Intervention Versus Ischemia guided Percutaneous Coronary Intervention Versus Medical Therapy in the Management of Significant Disease in Non-Infarct-related Arteries in ST-Elevation Myocardial Infarction Patients With Multivessel Coronary Disease. AB - BACKGROUND: In ST-elevation myocardial infarction (STEMI) patients with multivessel (MV) disease, after primary percutaneous coronary intervention (PCI), emerging evidence suggests that significant disease in non-infarct-related coronary arteries (IRAs) should be routinely stented. Whether this procedure should be guided by angiography alone or ischemia testing is unclear. METHODS: All STEMI patients treated with primary PCI between January 1, 2005, and December 31, 2012, at a tertiary cardiology center were reviewed retrospectively. Inclusion criterion is patients with at least 70% stenosis in non-IRAs. There were 3 treatment groups: (1) angiography-guided MV-PCI, (2) ischemia-guided PCI, and (3) medical therapy. Primary endpoint is all-cause mortality, and secondary end point is major adverse cardiovascular events (MACE), including death, acute coronary syndrome, revascularization, or stent thrombosis. Event-free survivals were compared using multivariate Cox proportional-hazards analysis. A propensity score-adjusted analysis was performed. RESULTS: Four hundred forty-seven STEMI patients had >70% stenosis in non-IRAs. For all-cause mortality, the 3 strategies did not differ. For MACE, ischemia-guided PCI was associated with the lowest MACE rate, followed by angiography-guided PCI and medical therapy, which was associated with the highest MACE rate, driven by death and myocardial infarction. Hazard ratios (HRs) for MACE: angiography-guided MV-PCI versus ischemia-guided MV PCI: HR = 2.23 [95% confidence interval (CI), 1.11-4.48; P = 0.023]; medical therapy versus angiography-guided MV-PCI: HR = 1.58 (95% CI, 0.99-2.63; P = 0.062); medical therapy versus ischemia-guided MV-PCI: HR = 1.72 (95% CI, 1.08 2.74; P = 0.022). Propensity score-adjusted analysis yielded similar results. CONCLUSIONS: After primary PCI, complete revascularization in STEMI multivessel disease is associated with lower MACE rates than medical therapy. However, ischemia-testing-guided rather than angiography-guided revascularization was associated with the lowest MACE. This study provides preliminary data and hypotheses for future randomized controlled studies. PMID- 29768316 TI - Evaluation of Compliance with a Weight-based Nurse-driven Heparin Nomogram in a Tertiary Academic Medical Center. AB - BACKGROUND: Recently, our institution adopted a weight-based nurse-driven heparin titration protocol that relies on nurses ordering laboratories, adjusting doses, and initiating boluses. Numerous institutions have implemented similar protocols with reported success. METHODS: A single-center retrospective analysis was conducted at the Brigham and Women's Hospital in Boston, Massachusetts that included all patients who were initiated on the weight-based nurse-driven heparin nomogram during a 30-day period. Nomogram compliance was defined as the rate of correct titrations per nomogram encounter and further separated into laboratory, titration, or dosing compliance. Spearman's coefficient was utilized to determine the correlation between noncompliance and percentage of activated partial thromboplastin time (aPTT) values in range. RESULTS: Overall, 211 patients were evaluated for inclusion, of which 95 patients were determined to meet criteria for evaluation. The total nomogram compliance rate was 84.6% +/- 10.5%. Laboratory, titration, and dosing compliances were 77.6% +/- 19.2%, 87.2% +/- 14.5%, and 91.8% +/- 10.6%, respectively. The percent of aPTT values in therapeutic range was 39.6% +/- 24.6%. A moderate negative correlation between the percentage of aPTT values in range and the nomogram error rate was observed (r = -0.452, P < 0.001). This relationship was found to be driven by the rate of dosing error, which showed the strongest correlation with percentage of aPTT values out of range (r = -0.465, P = 0.001). CONCLUSIONS: Implementation of a nurse-driven heparin titration nomogram relies on compliance with the prescribed protocol. Dosing compliance had the lowest error rate, whereas dosing noncompliance had the strongest impact on percentage of aPTT values in range. PMID- 29768317 TI - HEART Failure? Episodes of Missed Major Cardiac Events When Applying the HEART Pathway to an Observation Unit Population. AB - OBJECTIVE: The HEART Pathway risk prediction tool (HEART score plus serial troponin measures at 0 and 3 hours post-presentation) is used to identify low risk patients with chest pain who may qualify for safe, early discharge. We calculated the percentage of patients in our observation unit that qualified as low risk using HEART Pathway, as well as their associated outcomes. METHODS: We retrospectively reviewed charts on 966 consecutive patients admitted to our observation unit for chest pain (January 2015 to February 2016); HEART Pathway scores were retrospectively calculated and serial cardiac troponin values logged. The primary outcome was 42-day major adverse cardiac events (MACE), including acute myocardial infarction, urgent revascularization, and all-cause death. RESULTS: The patients' mean age was 59, 42% were male, 46% white, and 68 (7.7%) had MACE. HEART Pathway defined 384 patients as low risk (39.8%) and eligible for early discharge. Applying HEART Pathway would have missed 1.2% of patients with MACE; however, all adverse cardiac events occurred in patients with a HEART Pathway score of 3 (4 of 193, 2.1%) and none in those with a HEART Pathway score <=2 (0 of 134). CONCLUSIONS: While the HEART Pathway identifies a pooled population at low risk for MACE, risk is not homogenous within this population. Patients with a score of 3 may have higher risk of 42-day MACE that may be unacceptable to some providers, while scores <=2 saw no events. Caution is advised for those with HEART Pathway score of 3 until more data is available to accurately estimate risk. PMID- 29768318 TI - Angiographic Characteristics of ST-Elevation Myocardial Infarction Patients With Infarct-related Coronary Artery Ectasia Undergoing Primary Percutaneous Coronary Intervention. AB - Coronary ectasia accounts for 0.3%-4.9% of patients undergoing coronary angiography. We conducted the present study to evaluate the angiographic characteristics of ST-elevation myocardial infarction (STEMI) patients with infarct-related coronary artery ectasia (IRAE) undergoing primary percutaneous coronary intervention. We evaluated 667 STEMI patients who were divided into 2 groups of IRAE (n = 81) and non-IRAE (n = 568). Preprocedural thrombolysis in myocardial infarction (TIMI) flow grade, postprocedural TIMI flow grade, thrombus burden grade, and TIMI frame count were then evaluated. In adjusted analysis, fewer patients with IRAE had open (TIMI flow grade II or III) infarct-related arteries before the primary percutaneous coronary intervention (7.4% vs. 27.5%; odds ratio: 4.522; 95% confidence interval, 1.924-10.628; P = 0.001). Meanwhile, postprocedural TIMI flow grade 3 was less common in these patients (49.4% vs. 68.4%; odds ratio: 2.239; 95% confidence interval, 1.392-3.599; P = 0.001). High thrombus burden was more frequent in the patients with IRAE, with an odds ratio of 1.938 in the adjusted analysis. The corrected TIMI frame count was also significantly higher in the IRAE patients than in those without. Our STEMI patients with IRAE had impaired perfusion. Moreover, this group of patients more frequently had high thrombus burden. These patients might be at increased risk of unsuccessful revascularization probably due to distal embolization and no-reflow phenomenon, which could impact their short- and long-term outcomes. Because coronary ectasia is a known risk factor for acute coronary syndrome, it is beneficial that these patients be deemed high risk and kept under close monitoring. PMID- 29768319 TI - Contrast-Enhanced Stress Echocardiography and Myocardial Perfusion Imaging in Patients Hospitalized With Chest Pain: A Randomized Study. AB - Ultrasound contrast-enhanced stress echocardiography improves endocardial visualization, but diagnostic test rates versus stress myocardial perfusion imaging (MPI) have not been studied. A prospective randomized trial was performed between April 2012 and October 2014 at a single-center, safety net hospital. Hospitalized patients referred for noninvasive stress imaging were randomized 1:1 to stress echocardiography or stress MPI. The primary outcome was diagnostic test rate defined as interpretable images and achievement of >85% of age-predicted maximal heart rate (for dobutamine and exercise). Rates were assessed among those completing testing and then based solely on image interpretability. Charges and length of stay were secondary outcomes. A total of 240 patients were randomized, and 229 completed testing. Diagnostic test rates were similar for stress echocardiography versus MPI {89.4% [95% confidence interval (CI), 82.2-94.4] vs. 94.8% [95% CI, 89.1-98.1], P = 0.13} and did not differ with multivariable adjustment. Modalities requiring a diagnostic heart rate criteria were more frequently ordered with stress echocardiography (100% vs. 26%; P < 0.001). Therefore, an imaging-based analysis without the 12 individuals who failed to achieve target heart rate (n = 217) was evaluated with diagnostic test rates of 100% versus 94.8% (95% CI, 89.1%-98.1%; P = 0.03) for stress echocardiography and MPI, respectively. Median length of stay did not differ. Median (interquartile range) test-related charges were lower with stress echocardiography: $2,424 ($2400-$2508) versus $3619 ($3584-$3728), P < 0.0001. Overall, tests were positive for ischemia in 8% of patients. In conclusion, contrast-enhanced stress echocardiography provides comparable diagnostic test rates to MPI with lower associated charges. PMID- 29768320 TI - Monocyte Chemoattractant Protein-1 as a Predictor of Coronary Atherosclerosis in Patients Receiving Coronary Angiography. AB - BACKGROUND: Animal studies suggest that monocyte chemoattractant protein-1 (MCP 1) is a promising biomarker for coronary artery atherosclerosis (CAA), but human studies have been inconclusive. OBJECTIVE: To determine potential relationships between plasma MCP-1 and CAA in patients with acute chest pain. METHODS: A secondary analysis of 150 patients enrolled in emergency department chest pain risk stratification clinical investigations was conducted. Participants with stored blood and known coronary phenotypes (determined by coronary angiography) were selected using stratified randomization such that 50 patients were included into 3 groups: (1) no angiographic evidence of CAA, (2) nonobstructive CAA, and (3) obstructive CAA (stenosis >= 70%). Plasma MCP-1 levels were determined by enzyme-linked immunosorbent assay. The association between MCP-1 and obstructive CAA or any CAA was modeled using logistic regression. Variables in the unreduced model included age, sex, race, prior diagnosis of CAA or acute coronary syndrome, hyperlipidemia, hypertension, diabetes, smoking, and cardiac troponin I measurement. RESULTS: Among the 150 participants, 65.3% (98/150) had invasive coronary angiography and 34.7% (52/150) had coronary computed tomographic angiography. Myocardial infarction occurred in 27.3% (41/150) and coronary revascularization occurred in 26% (39/150) of the participants. Each 10 pg/mL increase in MCP-1 measurement was associated with an odds ratio of 1.12 (95% confidence interval, 1.06-1.19) for obstructive CAA. MCP-1 remained a significant predictor of obstructive CAA and any CAA after adjustment for age, sex, race, traditional cardiac risk factors, and cardiac troponin I. CONCLUSIONS: MCP-1 is independently associated with CAA among emergency department patients with chest pain. PMID- 29768321 TI - Anesthetic management of cesarean delivery for a parturient with Wilson's disease: A case report. AB - RATIONALE: Wilson's disease (WD), or hepatolenticular degeneration, is an autosomal recessive disorder with a prevalence of 1:50,000 to 1:100,000 live births. PATIENT CONCERNS: A 26-year-old primipara with WD was admitted to our hospital, due to awaiting delivery. Her main symptoms were slightly higher total bile acid (TBA) and bilateral depressed edema of lower limbs. DIAGNOSIS: She was at 38 weeks and 4 days of gestation with a 15-year history of WD, controlled with penicillamine in the past and replaced by zinc preparations from three months before pregnancy. OUTCOMES: General anesthesia was successfully administered for a female with WD undergoing cesarean delivery. LESSON: General anesthesia can be administered in an asymptomatic primigravida with WD. Appropriate anesthetics choice can effectively minimize the rates of complications and sequelae. PMID- 29768322 TI - Lung cancer screening CT-based coronary artery calcification in predicting cardiovascular events: A systematic review and meta-analysis. AB - BACKGROUND: Coronary artery calcificition (CAC) is a well-established predictor of cardiovascular events (CVEs). We aimed to evaluate whether lung cancer screening computed tomography (CT)-based CAC score has a good cost-effectiveness for predicting CVEs in heavy smokers. METHODS: A literature search was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. Pubmed, EMBASE, and Cochrane library databases were systematically searched for relevant studies that investigated the association between lung cancer screening CT-based CAC and CVEs up to December 31, 2017. We selected fixed-effect model for analysis of data heterogeneity. Statistical analyses were performed by using Review Manager Version 5.3 for Windows. RESULTS: Four randomized controlled trials with 5504 participants were included. Our results demonstrated that CVEs were significantly associated with the presence of CAC (relative risk [RR] 2.85, 95% confidence interval [CI] 2.02-4.02, P < .00001). Moreover, higher CAC score (defined as CAC score >400 or >1000) was associated with a significant increased CVE count (RR 3.47, 95% CI 2.65-4.53, P < .00001). However, the prevalence of CVEs was not different between male and female groups (RR 2.46, 95% CI 0.44-13.66, P = .30). CONCLUSION: CAC Agatston score evaluated by lung cancer screening CT had potential in predicting the likelihood of CVEs in the early stage without sexual difference. Thus, it may guide clinicians to intervene those heavy smokers with increased risk of CVEs earlier by CAC score through lung cancer screening CT. PMID- 29768323 TI - Efficacy and risks of anticoagulation for cerebral venous thrombosis. AB - BACKGROUND AND PURPOSE: Cerebral venous thrombosis (CVT) is a rare but life threatening disease. Timely and proper treatments are the keys in saving patients' life and preventing from permanent neurological deficits. We performed this network meta-analysis to evaluate the role of anticoagulation in CVT, especially for the patients accompanied with hemorrhagic stroke. METHODS: PubMed, Embase, Web of Science, Cochrane Database, and Chinese Biomedical (CBM) databases were searched comprehensively to select eligible articles (up to 30 June 2017). Network meta-analysis was performed based on classical frequency statistics. RESULTS: Around 14 studies comprising 1135 cases were included. Overall analysis showed that low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) were more effective (LMWH vs placebo: OR 4.76, 95%CI: 2.56-8.33; UFH vs placebo: OR 4.12, 95%CI: 2.17-8.33), and safe (LMWH vs placebo: OR 0.22, 95%CI: 0.069 0.65; UFH vs placebo: OR 0.28, 95%CI: 0.058-0.99) than placebo in the management of CVT. Besides, LMWH showed more advantages than UFH; As for the patients accompanied with hemorrhagic stroke, LMWH and UFH were also better than placebo (efficacy: LMWH vs placebo: OR 20, 95%CI: 5.56-100; UFH vs placebo: OR 12.5, 95%CI: 3.7-33.3; safety: LMWH vs placebo: OR 0.18, 95%CI: 0.04-0.77; UFH vs placebo: OR 0.16, 95%CI: 0.04-0.6) in the management of CVT. In addition, LMWH was more effective than UFH for the patients accompanied with hemorrhagic stroke. CONCLUSION: Anticoagulant treatment with heparin is safe and beneficial for patients with CVT, even for those accompanied with hemorrhagic stroke. Besides, LMWH is better than UFH in the management of CVT. PMID- 29768324 TI - Intravenous glucocorticoid for pain control after spinal fusion: A meta-analysis of randomized controlled trials. AB - OBJECTIVE: Postoperative pain was a common symptom after spinal surgery. This meta-analysis aimed to assess whether intravenous glucocorticoids has a beneficial role in reducing pain in patients following spinal fusion. METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Google databases, from inception to March 2, 2018. Randomized controlled trials (RCTs) that comparing intravenous glucocorticoids with control treatment for spinal fusion were included. A meta analysis was performed to generate pooled risk ratio (RR) and weighted mean difference with corresponding 95% confidence interval (CI) for discontinuous outcomes (the occurrence of nausea and infection) and continuous outcomes (visual analog scale [VAS] at 12, 24, and 48 h; total morphine consumption; and the length of hospital stay), respectively. RESULTS: Eight clinical trials involving 918 patients (glucocorticoid group = 449, control group = 469) were finally included in this meta-analysis. Compared with control, intravenous glucocorticoids had significantly reduced VAS at 12, 24, and 48 hours with statistically significance (P < .05). Intravenous glucocorticoids can decrease the occurrence of nausea (RR = 0.42, 95% CI 0.29-0.62, P = .000; I = 0.0%) and the length of hospital stay. No difference was noticed in the occurrence of infection between glucocorticoids intravenous and control (P > .05). CONCLUSION: Existing evidence indicated that intravenous glucocorticoids have a beneficial role in decreasing early pain and the occurrence of nausea after spinal fusion surgery. In consideration of the limitation in current meta-analysis, more high quality RCTs were needed to identify the optimal dose of glucocorticoids in spinal fusion patients. PMID- 29768325 TI - Is nucleate cell count and neutrophil to lymphocyte ratio related to patients with audiographically distinct sudden sensorineural hearing loss? AB - The aim of this study was to investigate the possible relationships between sudden sensorineural hearing loss (SSNHL) patients with distinct audiographic data and nucleate cell count and neutrophil to lymphocyte ratio (NLR).SSNHL patients differed in audiographic curves were included, 40 with low-frequency SSNHL (LF-SSNHL), 33 with high-frequency SSNHL (HF-SSNHL), 36 with all-frequency SSNHL (AF-SSNHL), 34 with total-deafness SSNHL (TD-SSNHL), and 31 age- and sex matched healthy controls. Peripheral venous blood samples were collected and nucleate cell such as white blood cell (WBC), neutrophil and lymphocyte, and NLR were measured. Each group was divided into recovery and unrecovery subgroup according to hearing levels after 1-month therapy, and then compared the difference of the count of WBC, neutrophil and lymphocyte, and NLR between the 2 subgroups.The WBC count of the HF-SSNHL, AF-SSNHL, and TD-SSNHL group was significantly higher than that of the control group (P = .024, P = .003, P = .008, respectively), not for LF-SSNHL group (P = .248). WBC count between LF SSNHL and AF-SSNHL group was significantly different (P = .045). The neutrophil count of the HF-SSNHL, AF-SSNHL, and TD-SSNHL group was significantly higher than that of the control group (P = .002, P = .000, P = .000, respectively), not for LF-SSNHL group (P = .069). Neutrophil count of LF-SSNHL was significantly lower than that of AF-SSNHL and TD-SSNHL groups (P = .014, P = .013). The lymphocyte count of AF-SSNHL and TD-SSNHL group was significantly lower than that of the control group (P = .027, P = .003), not for LF-SSNHL and HF-SSNHL group (P = .119, P = .054). NLR of HF-SSNHL, AF-SSNHL, and TD-SSNHL group was significantly higher than that of the control group (P = .001, P = .000, P = .000, respectively), not for LF-SSNHL group (P = .070). NLR of LF-SSNHL was significantly lower than that of AF-SSNHL and TD-SSNHL group (P = .041, P = .005). In HF-SSNHL patients, lymphocyte count of unrecovery subgroup was significantly lower, while NLR of the unrecovery subgroup were significantly higher than those of recovery subgroup (P = .017, P = .015).The count of WBC, neutrophil, lymphocyte, and NLR may be related to SSNHL, but they were unreliable at predicting SSNHL characterized by differences in audiometric curves. Higher NLR and lower lymphocyte count maybe used to evaluate prognosis of HF-SSNHL patients. PMID- 29768326 TI - Chronic constipation: A review of literature. AB - BACKGROUND: Chronic constipation is described as a common complication determined by difficult and/or rare passage of stool or both. The difference in definition of constipation has led to a wide range of reported prevalence (i.e., between 1% and 80%). Various factors are involved in the pathogenesis of the disease, including type of diet, genetic predisposition, colonic motility, absorption, social economic status, daily behaviors, and biological and pharmaceutical factors. Diagnostic and therapeutic options play a key role in the treatment of chronic constipation. There are still debates about the timing of these diagnostic and therapeutic algorithms. METHODS: A systematic and comprehensive search will be performed using MEDLINE, PubMed, EMBASE, AMED, the Cochrane Library and Google Scholar. Better understanding of the pathophysiology of chronic constipation and efficacy of pharmacological agent can help physicians for treating and managing symptoms.In this study, some of the old and new therapies in the treatment of chronic constipation have been studied based on the controlled studies and strong evidence. We are trying to address some of the controversial issues to manage the disease and to provide appropriate diagnostic options in an efficient and cost-effective way. RESULTS: The results of this systematic review will be published in a peer-reviewed journal. CONCLUSION: To our knowledge, our study will provide an overall estimate of chronic constipation to assess controversial issues, available diagnostic and therapeutic strategies of chronic constipation. ETHICS AND DISSEMINATION: Ethical approval and informed consent are not required, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. PMID- 29768327 TI - Survival benefit of neoadjuvant chemotherapy for resectable breast cancer: A meta analysis. AB - BACKGROUND: Neoadjuvant chemotherapy (NAC) increases breast conservation rates in patients with resectable breast cancer at the associated cost of higher locoregional recurrence rates; however, the magnitude of the survival benefits of NAC for these patients remains undefined. Therefore, we aimed to clarify the survival benefit of NAC versus postoperative chemotherapy by conducting an updated meta-analysis of randomized clinical trials (RCTs). METHODS: The authors searched the Cochrane Library, PubMed, Embase, Web of Science, Chinese biomedical literature database, and Chinese Scientific Journals full-text database from their inception to December 2016. The authors identified relevant RCTs that compared NAC with postoperative chemotherapy in the treatment of operable breast cancer. The main endpoints were overall survival (OS) and recurrence-free survival (RFS). RESULTS: A total of 21 citations representing 16 unique studies were eligible. There were 787 deaths among 2794 patients assigned to NAC groups and 816 deaths among 2799 patients assigned to adjuvant chemotherapy groups. A meta-analysis of data indicated that there was no significant benefit in terms of OS ([hazard ratio [HR] = 1.03, 95% confidence interval [CI]: 0.94-1.13, P = .51) and RFS (HR = 1.01, 95% CI: 0.93-1.10, P = .80) between the NAC and postoperative chemotherapy groups. The pooled HR estimate for OS was not influenced by NAC cycles, the total number of chemotherapy cycles, administration of tamoxifen, administration of adjuvant chemotherapy, or type of NAC regimen. Subgroup analysis showed that the pooled HR estimate for RFS was influenced by anthracycline-containing regimens. Patients with a pathological complete response had superior survival outcomes compared with patients who had residual disease. CONCLUSION: The survival benefits for patients with operable breast cancer who received either NAC or adjuvant chemotherapy based on anthracycline regimens were comparable. PMID- 29768328 TI - Efficacy and safety of etomidate-midazolam for screening colonoscopy in the elderly: A prospective double-blinded randomized controlled study. AB - BACKGROUND AND AIMS: Recent studies have shown that etomidate is associated with fewer serious adverse events than propofol and has a noninferior sedative effect. We investigated whether etomidate-midazolam is associated with fewer cardiopulmonary adverse events and has noninferior efficacy compared to propofol midazolam for screening colonoscopy in the elderly. METHODS: A prospective, single-center, double-blinded, randomized controlled trial was performed. Patients aged over 65 years who were scheduled to undergo screening colonoscopy were randomized to receive either etomidate or propofol based on midazolam. The primary outcome was all cardiopulmonary adverse events. The secondary outcomes were vital sign fluctuation (VSF), adverse events disturbing the procedure, and sedation-related outcomes. RESULTS: The incidence of cardiopulmonary adverse events was higher in the propofol group (72.6%) than in the etomidate group (54.8%) (P = .040). VSF was detected in 17 (27.4%) and 31 (50.0%) patients in the etomidate and propofol groups, respectively (P = .010). The incidence rate of adverse events disturbing the procedure was significantly higher in the etomidate group (25.8%) than in the propofol group (8.1%) (P = .008). Moreover, the incidence rate of myoclonus was significantly higher in the etomidate group (16.1%) than in the propofol group (1.6%) (P = .004). There was no statistical significance between the 2 groups with respect to sedation times and sedation related outcomes including patients' and endoscopist's satisfaction. In the multivariate analysis, the etomidate group had significantly low odds ratio (OR) associated with VSF (OR: 0.407, confidence interval: 0.179-0.926, P = .032). CONCLUSIONS: We recommend using etomidate-midazolam in patients with high ASA score or vulnerable to risk factors; propofol-midazolam may be used as a guideline in patients with low ASA score. PMID- 29768329 TI - Retrospective analysis of culture-negative versus culture-positive postoperative spinal infections. AB - Retrospective analysis.This study aimed to investigate the characteristics, clinical features, and outcomes of culture-negative (CN) and culture-positive (CP) postoperative spinal infections (PSIs).Causative organism cultures and the use of adequate antibiotics are essential for treating postoperative spinal wound infections. However, managing infected surgical sites with negative wound culture results is a common clinical problem. Although the outcomes of microbiologically confirmed PSIs have been well studied, the outcomes and clinical characteristics of CN PSIs have not been previously published.Between January 1995 and December 2014, 69 patients diagnosed with PSIs were enrolled. Enrolled patients were classified into 2 groups: CN (28 patients) and CP (41 patients). Baseline data, clinical manifestations, specific treatments, and treatment outcomes were compared with the groups.The overall rate of CN PSI was 40.6% (28/69). Baseline data and clinical manifestations were similar between the 2 groups. There were no significant differences in the duration of parenteral antibiotic use between the CN and CP groups. Revision surgery was required less often for the CN group (64.3%) than for the CP group (87.8%) (P = .020). Revision surgeries were repeated 0.82 times/case in the CN group and 1.34 times/case in the CP group (P = .014). Treatment outcomes, such as poor radiologic findings, need for additional anterior surgery, extension of fusion to adjacent segment surgery, and total length of hospital stay, were not different between groups.Revision surgery was performed less often for the CN group than for the CP group. From the perspective of revision surgery, CN PSIs have better prognosis than CP PSIs. However, clinical presentations and radiologic prognoses were not different between the two groups. We suggest that CN PSIs may be treated in the same way as CP PSIs. PMID- 29768331 TI - The value of 18F-FDG PET/CT in patient with neurofibromatosis type 1: A case report and literature review. AB - RATIONALE: Neurofibromatosis type one (NF1) is characterized by cutaneous and nervous lesions, and the tendency to form plexiform neurofibromas (PNFs). PNFs may undergo malignant transformation into a malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs often carry an significant morbidity and mortality. PATIENT CONCERNS: A 17-year-old man with gradually increased multiple subcutaneous soft lesions. He also presented with numerous lentigines and multiple cafe-au-lait macules on his body. DIAGNOSES: These were collagen neurofibroma, which were definitively diagnosed by pathology. NF1 was eventually diagnosed. INTERVENTIONS: These lesions were abnormal uptake of radiotracer, when he underwent positron emission tomography (PET) with fluorine-18 fluorodeoxyglucose (FDG) scanning. Standard uptake value (SUV) and other parameters can help to distinguish benign and malignant lesions in patient with NF1. He was underwent serials F-FDG PET/CT examinations to followed up, in order to monitor these lesions malignant transformation. OUTCOMES: So far, these subcutaneous soft lesions were not malignant transformation. LESSONS: F-FDG PET/CT is being increasingly used as an imaging modality to discover the systemic lesions and to discriminate between benign and malignant plexiform neurofibromas. PMID- 29768330 TI - Risk factors for osteoporosis in liver cirrhosis patients measured by transient elastography. AB - Osteoporosis or osteopenia is a common complication in patients with cirrhosis, but little is known about the risk factors for the occurrence of osteoporosis.Patients with liver cirrhosis due to chronic virus infection and alcoholic abuse were enrolled. Bone mineral density (BMD) was determined using dual-energy x-ray absorptiometry (DXA). Osteoporosis was diagnosed according to WHO criteria. The severity of liver stiffness was measured by Fibroscan. Demographic data, such as age, gender, weight, height, and body mass index (BMI), were collected. Logistic regression analysis was used to recognize the risk factors of osteoporosis in patients with cirrhosis.A total of 446 patients were included in this study: 217 had liver cirrhosis (male, 74.2%; mean age, 57.2 +/- 10.27) and 229 were matched controls (male, 69%, mean age, 56.69 +/- 9.37). Osteoporosis was found in 44 patients (44/217, 20.3%). The spine and hip BMD in cirrhotic patients were significantly lower than that in controls. When the cirrhotic and control subjects were stratified by age, gender, and BMI, the significant difference was also observed in women patients, patients older than 60, and patients with BMI < 18. Multivariate analysis showed that the older age [odds ratio (OR) = 1.78, P = .046], lower BMI (OR = 0.63, P = .049), greater fibroscan score (OR = 1.15, P = .009), and liver cirrhosis induced by alcohol liver disease (OR = 3.42, P < .001) were independently associated with osteoporosis in cirrhotic patients.Osteoporosis occurred in about one-fifth of patients with liver cirrhosis, which was associated with age, BMI, Fibroscan score, and alcohol liver disease related liver cirrhosis. PMID- 29768334 TI - A case report of B lymphoblastic lymphoma with brain metastases: Clinical and pathological significance of head trauma misdiagnosis. AB - INTRODUCTION: B lymphoblastic lymphoma (B-LBL) is a rare type of lymphoma that originates from precursor lymphocytes. B-BLB in adults with brain metastases is extremely rare as the disease mainly affects children and adults. Therefore, such a seldom-seen case can easily trigger a dispute regarding clinical diagnosis and treatment.This paper reports the case of a 22-year-old man hospitalized for a head injury that resulted from a physical altercation. Upon admission to the hospital, the patient was diagnosed with a diffuse axonal injury (DAI). Accordingly, the patient receiving follow-up treatments, but died 30 days later. After a systematic necropsy, immunohistochemical staining, radiological consultation, and a complete review of the clinical dates, we defined the case as a brain metastasis of B lymphoblastic lymphoma. Imaging results of the intracranial lymphoma were nearly indistinguishable from DAI during the acute phase, which led to misdiagnosis and incorrect treatment for B-LBL. CONCLUSION: We present this case to broaden the scope of pathologic and clinical diagnosis for intracranial tumors and to inform physicians, general neurologists, and even medical examiners with an added degree of differential awareness in dealing with the clinical materials before further diacrisis and disposal. PMID- 29768332 TI - Short-term effects of customized arch support insoles on symptomatic flexible flatfoot in children: A randomized controlled trial. AB - BACKGROUND: Limited evidence is available regarding the effects of insoles on pediatric flexible flatfoot because of the heterogeneity and low methodological quality of previous studies. The purpose of this prospective trial is to examine the short-term effects of customized arch support insoles on symptomatic flexible flatfoot in children by using the International Classification of Functioning, randomized controlled Disability, and Health (ICF) framework. METHODS: This study was conducted in a rehabilitation outpatient clinic of a teaching hospital. Fifty two children with symptomatic flexible flatfoot were included. The children in the treatment group wore customized arch support insoles for 12 weeks, whereas those in the control group did not wear the insoles. Both clinical and radiographic measurements, including the navicular drop, foot posture index, Beighton hypermobility score, talonavicular coverage angle, calcaneal inclination angle, and calcaneal-first metatarsal angle, were used for diagnosing flexible flatfoot. Physical activity (10-m normal and fast walking, stair ascent, stair descent, and chair rising), physical function, and psychometric properties (Pediatric Outcome Data Collection Instrument and Pediatric Quality of Life Inventory) were evaluated at the baseline and 12 weeks after the intervention. RESULTS: Compared with the control group, the treatment group exhibited significant improvement in pain/comfort (P = .048), physical health (P = .035), stair ascent time (P = .015), upper extremity and physical function (P = .016), and transfer and basic mobility (P = .042) during the intervention period. CONCLUSION: Children with flexible flatfoot who wore customized arch support insoles for 12 weeks exhibited significantly improved pain/comfort, physical health, stair ascent time, upper extremity and physical function, and transfer and basic mobility. These variables belong to the domains of body functions and structures and activity and participation in the ICF framework. However, because the groups were not comparable, additional studies with larger sample sizes should be conducted. PMID- 29768333 TI - Association between VEGF genetic variants and diabetic foot ulcer in Chinese Han population: A case-control study. AB - The aim of this study was to investigate the association of vascular endothelial growth factor (VEGF) gene polymorphisms with diabetic foot ulcer (DFU) susceptibility in a Chinese Han population.Around 88 type 2 diabetes mellitus (T2DM) patients without DFU and 97 T2DM patients with DFU were enrolled in this study. A total of 103 age and gender matched healthy individuals were recruited as healthy control. VEGF gene polymorphisms rs699947 and rs13207351 were analyzed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Odds ratio (OR) with 95% confidence interval (CI) was calculated to assess the association between VEGF gene polymorphisms and DFU risk.The frequency of AA and AC genotypes of rs699947 were lower in DFU patients than that in healthy controls (P = .020, P = .031), suggesting that AC and AA genotypes were negatively associated with DFU risk originating from healthy individuals (OR = 0.496, 95%CI = 0.274-0.899; OR = 0.130, 95%CI = 0.015-1.112). Significantly decreased trend of rs699947 A allele was observed in DFU patients when compared to the controls (P = .004), suggesting A allele was distinctly correlated with decreased DFU risk (OR = 0.490, 95%CI = 0.298-0.804). But no significant differences were detected in rs13207351 genotype and allele distributions between patients and control groups (P > .05).Individuals carrying VEGF rs699947 A allele show low susceptibility to DFU in the Chinese Han population. PMID- 29768335 TI - IgG4-related disease of pulmonary artery causing pulmonary hypertension. AB - IgG4-related disease (IgG4-RD) is recognized as an immune-mediated condition with pathology features of lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis, accompanied with or without elevated serum IgG4 concentrations. However, few of pulmonary artery IgG4-RD causing pulmonary hypertension (PH) was reported.The medical records of 3 patients with pulmonary artery IgG4-RD inducing PH were analyzed retrospectively.Imaging findings demonstrated that the lesions of 3 patients located in pulmonary artery, which were initially diagnosed as pulmonary thrombus or malignant tumor. Computed tomography pulmonary angiography (CTPA), ultrasonic cardiogram, and positron emission tomography/computed tomography (PET/CT) didn't support the diagnosis of pulmonary thrombus or malignant tumor. Right heart catheterization (RHC) showed definite PH. Biopsy by right heart catheterization in 2 patients or pneumonectomy in 1 patient confirmed the diagnosis as IgG4-RD. Treated with glucocorticoids and cyclophosphamide or rituximab, 2 patients' IgG4 concentrations declined sharply and the lesions shrunk gradually. Another patient treated with glucocorticoids died of heart failure.IgG4-RD involved pulmonary artery causing PH was rare. A high index of awareness of this disease is required for early diagnosis and treatment. PET/CT might be a valuable approach to distinguish pulmonary artery IgG4-RD from pulmonary thrombus and malignant tumor. PMID- 29768336 TI - Primary diffuse large B-cell lymphoma in the maxilla: A case report. AB - RATIONALE: Lymphomas are the second most common non-epithelial malignant tumors in the oral and maxillofacial region. Non-Hodgkin's lymphoma (NHL) develops at extranodal sites, and cases involving the maxilla account for less than 1% of all NHLs. We describe a case of diffuse large B-cell lymphoma (DLBCL) in the maxilla, and highlight the clinical signs, symptoms, differential diagnosis, and appropriate treatment of DLBCL in the oral cavity and maxillofacial region. PATIENT CONCERNS: A 67-year-old woman was admitted to our surgical department with pain and swelling in her right upper posterior teeth for about six months. She was previously misdiagnosed with periodontal disease and had a history of tooth extraction. DIAGNOSES: Computed tomography (CT) scan revealed extensive osteolysis in the right posterior part of the maxilla with enhanced neoplasm. A solid mass was found upon incisional biopsy, and immunohistochemistry confirmed the diagnosis of DLBCL. INTERVENTIONS: The patient was treated with six courses of rituximab, cyclophosphamide, pirarubicin, vincristine, and prednisolone (R CHOP), followed by external irradiation treatment. OUTCOMES: The treatment was well tolerated, and the patient is presently alive after two years of follow-up. LESSONS: Non-specific symptoms, such as unclear primary dental pain and unresolved periapical swelling, can make an accurate diagnosis of DLBCL difficult, which frequently lead to delayed diagnosis. A CT or cone beam computed tomography (CBCT) scan of the maxilla and immunohistochemical staining of the biopsy specimen is recommended. Combination therapy including radiotherapy and chemotherapy is the optimal treatment for NHL. PMID- 29768337 TI - Variation in origin of the long head of the biceps brachii tendon in a cadaver: A case report. AB - INTRODUCTION: In general, the long head of the biceps brachii (LHB) tendon arises from the supraglenoid tubercle in the shoulder joint, and it has an important stabilizing mechanism for the humeral head in the shoulder joint. This case demonstrates that even if the LHB tendon can be palpated outside of the shoulder joint, it may disappear in the intertubercular sulcus (IS) and in the glenohumeral (GH) joint because of abnormal articulation. PATIENT CONCERNS: This case involved the cadaver of an 82-year-old Japanese man (number 1936, cause of death: hepatocellular tumor), who was selected from the bodies used for gross anatomy practice at the Tokai University School of Medicine in 2017. INTERVENTION: We removed the fat and skin around the shoulder joint for observational purposes and carefully examined the gross anatomy of the structures. DIAGNOSIS: We suspected that the long head of the biceps brachii tendon arose from the lesser tubercle (LT) in the cadaver. In our case, it was found that the upper part of the subscapularis (SSC) tendon was torn first, and the succeeding degenerative changes and rupture of the LHB tendon were intra articular. OUTCOMES: The long head of the biceps brachii tendon was found to be ruptured in the GH joint, and scar tissue developed between the distal stump of the tendon and the articular capsule, resulting in fusion with the LT. CONCLUSIONS: This case necessitates confirmation that the LHB tendon is present in the IS and in the GH joint to treat cases wherein failure of the dynamic stabilizing mechanism for the humeral head occurs. PMID- 29768338 TI - Botulinum toxin injection to improve functional independence and to alleviate parenting stress in a child with advanced pantothenate kinase-associated neurodegeneration: A case report and literature review. AB - RATIONALE: Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disease. Progressive motor symptoms such as dystonia and spasticity begin in childhood and relentlessly become incapacitating later in life. Treatments including anticholinergics and iron chelation are usually ineffective. Botulinum toxin type A (BoNT-A) is effective for adult patients with dystonia or spasticity. PATIENT CONCERNS: We reported a 10-year-old female patient with advanced PKAN, manifesting as generalized dystonia and spasticity. DIAGNOSIS: The patient was diagnosed with PKAN by a pediatric neurologist. INTERVENTIONS: The patient received BoNT-A injection. OUTCOMES: The effect was obvious at four weeks after the injection, with an improvement of 25% in Barry Albright Dystonia Scale and 4% in Functional Independence Measure for Children score. Furthermore, there was a 3.8% reduction in Parenting Stress Index Short Form score and 8.3% improvement in Pain and Impact of Disability domain in the score of Cerebral Palsy Quality of Life for Children. LESSONS: BoNT-A injection was effective to improve functional independence and to alleviate stress of caregivers in the patient with advanced PKAN. PMID- 29768339 TI - Foreign body aspiration as a cause of cryptogenic hemoptysis in a child: A case report. AB - RATIONALE: Hemoptysis is rare but potentially life-threatening condition in children. The most common cause of pediatric hemoptysis is lower respiratory tract infections. Sometimes foreign body aspiration may result in hemoptysis too. PATIENT CONCERNS: A 4-year old girl suffered from recurrent cryptogenic hemoptysis for almost 2 years. DIAGNOSES: The wheatear was finally found to be the underlying cause. INTERVENTIONS: The girl received multiple bronchoscopy. OUTCOMES: The girl's symptoms improved rapidly and remained well without relapse of hemoptysis. LESSONS: This case indicates that foreign body aspiration should be considered in any child with recurrent cryptogenic hemoptysis and persistent focal lung injury. Multiple bronchoscopy is rational in order to find out the underlying reasons. PMID- 29768340 TI - The patient general satisfaction of mandibular single-implant overdentures and conventional complete dentures: Study protocol for a randomized crossover trial. AB - BACKGROUND: Mandibular overdentures retained by a single implant placed in the midline of edentulous mandible have been reported to be more comfortable and function better than complete dentures. Although single-implant overdentures are still more costly than conventional complete dentures, there are a few studies which investigated whether mandibular single-implant overdentures are superior to complete dentures when patient general satisfaction is compared. The aim of this study is to assess patient general satisfaction with mandibular single-implant overdentures and complete dentures. METHODS: This study is a randomized crossover trial to compare mandibular single-implant overdentures and complete dentures in edentulous individuals. Participant recruitment is ongoing at the time of this submission. Twenty-two participants will be recruited. New mandibular complete dentures will be fabricated. A single implant will be placed in the midline of the edentulous mandible. The mucosal surface of the complete denture around the implant will be relieved for 3 months. The participants will then be randomly allocated into 2 groups according to the order of the interventions; group 1 will receive single-implant overdentures first and will wear them for 2 months, followed by complete dentures for 2 months. Group 2 will receive the same treatments in a reverse order. After experiencing the 2 interventions, the participants will choose one of the mandibular prostheses, and yearly follow-up visits are planned for 5 years. The primary outcome of this trial is patient ratings of general satisfaction on 100 mm visual analog scales. Assessments of the prostheses and oral health-related quality of life will also be recorded as patient-reported outcomes. The secondary outcomes are cost and time for treatment. Masticatory efficiency and cognitive capacity will also be recorded. Furthermore, qualitative research will be performed to investigate the factors associated with success of these mandibular denture types. Clinical outcomes, such as implant survival rate, marginal bone loss, and prosthodontic complications, will also be recorded. DISCUSSION: The results of this randomized crossover trial will clarify whether mandibular single implants and overdentures for edentulous individuals provide better patient general satisfaction when compared to conventional complete dentures. TRIAL REGISTRATION: This clinical trial was registered at the University Hospital Medical Information Network (UMIN) Center (UMIN000017883). PMID- 29768342 TI - Mucosa-associated lymphoid tissue lymphoma of the trachea associated with idiopathic pulmonary fibrosis: A case report and literature review. AB - RATIONALE: Mucosa-associated lymphoid tissue (MALT) lymphoma of the trachea is a rare disease that has been shown to be associated with chronic antigenic stimulation. There have been few reports of MALT lymphoma of the trachea in association with idiopathic pulmonary fibrosis (IPF). PATIENT CONCERNS: A 73-year old patient visited with a 2-year history of dyspnea on exertion and productive cough, which had worsened 1 month ago. DIAGNOSES: MALT lymphoma of the trachea associated with IPF. INTERVENTIONS: After taking into consideration the age, poor performance status, and comorbidities of the patient and the extent of disease, we utilized an observational approach as a treatment strategy. OUTCOMES: The patient is well without any evidence of progression for 12 months since the initial diagnosis. LESSONS: We present a case of MALT lymphoma of the trachea associated with IPF. A common predisposing factor may exist for tracheal MALT lymphoma and IPF. As there are no randomized clinical trials focusing on tracheal MALT lymphoma, individualized treatment decision is important, and in some cases, simply monitoring the patient might be the most appropriate approach. PMID- 29768341 TI - The plethysmographic variability index does not predict fluid responsiveness estimated by esophageal Doppler during kidney transplantation: A controlled study. AB - Research is ongoing to find a noninvasive method of monitoring, which can predict fluid responsiveness in patients undergoing kidney transplantation.To compare the responses to fluid challenges with the Pleth Variability Index, a noninvasive dynamic index derived from plethysmographic variability (Radical 7 pulse oximeter; Masimo Corporation, Irvine, CA), and the esophageal Doppler, the criterion standard.Observational study.University hospital; study from May 2011 and May 2012.Forty-eight patients with end-renal function were included and 44 analyzed. Patients with cardiac failure were not eligible.Fluid challenges were administered during maintenance of general anesthesia but before skin incision and repeated if the patient was deemed to be a "responder" (increase in stroke volume >=10%).The primary endpoint was to assess if the Pleth Variability Index is an accurate predictor of fluid responsiveness.Among 76 fluid challenges, 38 were considered as positive (increase in stroke volume measured by Doppler >=10%). Pleth Variability Index was similar at baseline between responders and nonresponder patients. Fluid challenges were associated with a significant decrease in Pleth Variability Index in overall cases (12 [8-14] vs 10 [6-17], P = .050), but it was not able to discriminate between responders (12 [8-15] vs 10 [5 15], P = .650) and nonresponders (11 [6-16] vs 8 [5-14], P = .047). The area under the Receiver Operating Characteristic curve for Pleth Variability Index was 0.49 (0.36-0.62).Pleth Variability Index is not an accurate predictor of fluid responsiveness during kidney transplantation. PMID- 29768344 TI - Synchronous adrenocortical carcinoma and ovarian malignant mixed germ cell tumor: A case report and literature review. AB - RATIONALE: Adrenocortical carcinoma (ACC) is an endocrine malignancy with poor prognosis, which commonly arises in a sporadic manner, but may also become a part of a familial syndrome. ACC rarely arises simultaneously with other malignant tumors. PATIENT CONCERNS: We report a case of a 29-year-old woman with ACC synchronously followed by an ovarian malignant mixed germ cell tumor. We describe the clinical, histopathological, and immunohistochemical findings and review the English literatures. So far, as we know, the patient presented here is the first case with synchronous malignant tumors of the adrenal gland and ovary. DIAGNOSES: She was diagnosed with ovarian malignant mixed germ cell tumor with admixture of dysgerminoma and yolk sac tumor after ACC. INTERVENTIONS: The left adrenal tumor was resected laparoscopically on April 28, 2017. A total laparoscopic hysterectomy with unilateral (right) adnexectomy was performed on November 11, 2017. OUTCOMES: Up to now, illness condition has not progressed. Patient is free of disease at 3 months of follow-up. LESSONS: This is the first report in English literature about coexistence of ACC with ovarian malignant mixed germ cell tumor and the sixteenth case that presents a synchronous tumor associated with a sporadic ACC. This case reminds us that a comprehensive examination of patients with ACC is necessary to identify a possible synchronous tumor. PMID- 29768345 TI - Atypical symptoms in patients with cervical spondylosis: Comparison of the treatment effect of different surgical approaches. AB - To compare the effectiveness of total disk replacement (TDR), anterior cervical discectomy and fusion (ACDF), and laminoplasty on atypical symptoms of cervical spondylosis.Patients with confirmed diagnosis of cervical spondylosis and reported atypical symptoms such as blurred vision, headache, nausea, palpitation, tinnitus, vertigo, hypomnesia, and abdominal discomfort were retrospectively included in the present study. They were treated with TDR, ACDF, or laminoplasty depending on the etiology and patient preference. Severity of the atypical symptoms before the surgery and at the end of 2-year follow-up was recorded and the degree of severity alleviation was compared between different surgical approaches.A total number of 336 patients who were treated in our institute from February 2002 to March 2011 were included in the final analysis. Atypical symptoms were significantly alleviated in most patients after surgical intervention. No significant differences were found regarding the change of severity of those symptoms among patients in different surgery groups.TDR, ACDF, and laminoplasty can equally alleviate the severity of atypical symptoms in patients with cervical spondylosis. This indicates that the neural network in the posterior longitudinal ligament may not be the cause of atypical symptoms in patients with cervical spondylosis. PMID- 29768343 TI - Potential common factors associated with predisposition to common cold in middle aged and elderly Japanese: A community-based cross-sectional study. AB - People worldwide frequently catch a common cold, which occasionally develops into secondary severe conditions such as pneumonia. However, it is unclear whether predisposition to the common cold is associated with the individual's characteristics including age, body weight, lifestyles, diets, and intestinal functions, besides exposure to a responsible pathogen. We addressed this issue epidemiologically considering many relevant clinical factors.We reviewed data from a cross-sectional study consisting of 39,524 apparently healthy Japanese aged 40 to 79 years (26,975 men and 12,549 women) who underwent a checkup in 2007. Self-reported predisposition to common cold (SPCC) and relevant clinical conditions and parameters were considered.We observed no significant difference in most clinical parameters including age, body mass index (BMI), glycated hemoglobin (HbA1c), and prevalence of men and current smokers between subjects with and without SPCC. In univariate analysis, circulating white blood cell (WBC) count and serum alanine-aminotransferase (ALT) were significantly higher in subjects with SPCC than in those without, whereas serum high-density lipoprotein cholesterol (HDL-C) and duration of sleep were lower. In logistic regression analysis after full adjustment for relevant confounding factors, BMI categories except BMI of >=27.0 kg/m were significantly associated with SPCC compared with BMI of 23.0 to 24.9 kg/m. Short duration of sleep (<=5 hours), occasional alcohol drinking, and no-exercise were significantly associated with SPCC compared with 7 hours sleep duration, no-drinking alcohol, and low frequent exercise (twice per month), respectively. All gastrointestinal disorders (gastric complaints, constipation, and diarrhea) were independently associated with SPCC. Imbalanced diet and taking a snack were also associated with SPCC in a degree dependent manner. Furthermore, WBC count, serum ALT, and HDL-C (as continuous variables) were associated with SPCC (HDL-C was inversely), whereas no significant association was observed between SPCC and age, smoking, HbA1c, and pharmacotherapy for diabetes, hypertension, and dyslipidemia.Our results demonstrated that multifactorial conditions and parameters might be simultaneously associated with the predisposition to common cold. Prospective studies including detailed common cold questionnaire and measurements are needed to confirm currently suspected causative and protective factors. PMID- 29768346 TI - Abnormally high expression of POLD1, MCM2, and PLK4 promotes relapse of acute lymphoblastic leukemia. AB - This study aimed to explore the underlying mechanism of relapsed acute lymphoblastic leukemia (ALL).Datasets of GSE28460 and GSE18497 were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between diagnostic and relapsed ALL samples were identified using Limma package in R, and a Venn diagram was drawn. Next, functional enrichment analyses of co-regulated DEGs were performed. Based on the String database, protein-protein interaction network and module analyses were also conducted. Moreover, transcription factors and miRNAs targeting co-regulated DEGs were predicted using the WebGestalt online tool.A total of 71 co-regulated DEGs were identified, including 56 co-upregulated genes and 15 co-downregulated genes. Functional enrichment analyses showed that upregulated DEGs were significantly enriched in the cell cycle, and DNA replication, and repair related pathways. POLD1, MCM2, and PLK4 were hub proteins in both protein-protein interaction network and module, and might be potential targets of E2F. Additionally, POLD1 and MCM2 were found to be regulated by miR 520H via E2F1.High expression of POLD1, MCM2, and PLK4 might play positive roles in the recurrence of ALL, and could serve as potential therapeutic targets for the treatment of relapsed ALL. PMID- 29768347 TI - A retrospective study of alendronate for the treatment of ankylosing spondylitis. AB - This retrospective study assessed the effect of alendronate for treating patients with ankylosing spondylitis (AS).Eighty-six patients with AS were included in this retrospective study, and were divided into 2 groups. Forty-six patients in the intervention group received alendronate plus vitamin D (400 mg/day) and calcium (500 mg/day), while 40 patients in the control group received vitamin D and calcium only, the same dose as the intervention group. The primary outcome included bone densitometry. The secondary outcomes consisted of quality of life, measured by Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, disease activity, measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional status, measured by Bath Ankylosing Spondylitis Functional Index (BASFI), as well as the adverse events (AEs).At the end of 6 month treatment, patients in the intervention group were not superior to the patients in the control group in bone densitometry (hip, P = .47; lumbar, P = .53), quality of life (P = .32), disease activity (P = .39), and functional status (P = .41). Moreover, no significant differences in AEs were found between 2 groups.The results of the present study showed that alendronate can neither be used to treat bone loss, nor to enhance the quality of life, disease activity, and functional status. PMID- 29768348 TI - A new strategy for enteral nutrition using a deflection flexible visual gastric tube: A randomized crossover manikin trial. AB - BACKGROUND: Enteral nutrition via gastric tube insertion is a routine clinical practice for critically ill patients, although complications due to blind manipulation are occasionally reported. METHODS: An 8.4Fr deflection flexible ureteroscope was delivered into a 15Fr conventional gastric tube to create a gastric visual guidance system. Twenty inexperienced physicians were randomly assigned to perform 5 repeated orogastric tube placements in a manikin using both the conventional method and the deflection visual gastric tube, for a total of 10 procedures per physician. Placement time, procedure-related complications, and participants' experience with both methods were recorded. RESULTS: Under real time guidance, the visual gastric tube successfully reached the stomach. The procedure provided additional information on the anatomy of the esophagus and stomach. Placement time was significantly less in the visual group than in the conventional group (39.39 +/- 2.11 seconds vs 49.82 +/- 3.11 seconds; P < .001). Procedure-related complications were not observed in the visual group; however, the gastric tube was misplaced into the airway in 19 out of 100 cases (19%) in the conventional group. Furthermore, 17 out of 20 participants (85%) preferred the visual gastric tube guide over the standard method. CONCLUSIONS: Results of this manikin model demonstrate that it is feasible to use the deflection flexible visual gastric tube to create a route for enteral nutrition and that such a procedure decreases placement time and procedure-related complications compared to the conventional procedure. These findings may point to a new strategy for gastric tube insertion in the future. PMID- 29768349 TI - Comparison of multiple interventions for older adults with Alzheimer disease or mild cognitive impairment: A PRISMA-compliant network meta-analysis. AB - BACKGROUND: The increasing prevalence of Alzheimer disease (AD) emphasizes the need for effective treatments. Both pharmacological therapies such as nutrition therapy (NT) and nonpharmacologic therapies including traditional treatment or personalized treatment (e.g., physical exercise, music therapy, computerized cognitive training) have been approved for the treatment of AD or mild cognitive impairment (MCI) in numerous areas. METHODS: The aim of this study was to compare 4 types of interventions, physical exercise (PE), music therapy (MT), computerized cognitive training (CCT), and NT, in older adults with mild to moderate AD or MCI and identify the most effective intervention for their cognitive function. We used a system of search strategies to identify relevant studies and include randomized controlled trials (RCTs), placebo-controlled trials evaluating the efficacy and safety of 4 interventions in patients with AD or MCI. We updated the relevant studies which were published before March 2017 as a full-text article. Using Bayesian network meta-analysis (NMA), we ranked cognitive ability based objectively on Mini-Mental State Examination (MMSE), and assessed neuropsychiatric symptoms based on Neuropsychiatric Inventory (NPI). Pairwise and network meta-analyses were sequentially performed for efficacy and safety of intervention compared to control group through RCTs included. RESULTS: We included 17 RCTs. Fifteen trials (n = 1747) were pooled for cognition and no obvious heterogeneity was found (I = 21.7%, P = .212) in NMA, the mean difference (MD) of PE (MD = 2.1, confidence interval [CI]: 0.44-3.8) revealed that PE was significantly efficacious in the treatment group in terms of MMSE. Five trials (n = 660) assessed neuropsychiatric symptoms with an obvious heterogeneity (I = 61.6%, P = .034), the MD of CCT (MD = -7.7, CI: -14 to -2.4), revealing that CCT was significantly efficacious in NPI. CONCLUSIONS: As the first NMA comparing different interventions for AD and MCI, our study suggests that PE and CCT might have a significant improvement in cognition and neuropsychiatric symptoms respectively. Moreover, nonpharmacological therapies might be better than pharmacological therapies. PMID- 29768350 TI - Docetaxel, oxaliplatin, 5FU, and trastuzumab as first-line therapy in patients with human epidermal receptor 2-positive advanced gastric or gastroesophageal junction cancer: Preliminary results of a phase II study. AB - The aim of this study is to report first preliminary results of patients enrolled in a phase II study that will investigate the activity and safety of docetaxel, oxaliplatin, and 5-fluorouracil (DOF) in combination with trastuzumab in human epidermal receptor-2 (HER-2) positive patients with advanced gastric or gastroesophageal junction (GEJ) cancer.Treatment consisted of docetaxel 70 mg/m combined with oxaliplatin 130 mg/m on day 1, and continuous infusion 5 fluorouracil mg/m days 1-5 plus trastuzumab at the standard dose on day 1, every 3 weeks for a maximum of 8 cycles.Fifteen patients were enrolled. The overall response rate was 60%. The median progression-free survival was 9.2 months (95% confidence interval [CI], 4.4-10.1 months) and the median overall survival was 19.4 months (95% CI, 8.9-21.1 months). Grade 3 neutropenia was observed in 3 patients (20%).The DOF plus trastuzumab seems active in HER-2 positive advanced gastric or GEJ cancer, final results of the phase II study are awaited. PMID- 29768351 TI - The CDK4/6 inhibitor in HR-positive advanced breast cancer: A systematic review and meta-analysis. AB - BACKGROUND: Recently, several high-quality clinical randomized controlled trials (RCTs) have identified that cyclin-dependent kinases (CDKs) 4/6 inhibitors obtained a great safety and efficacy, which can be consequently applied as a combination therapy with letrozole or fulvestrant for women who had advanced breast cancer and progressed while receiving endocrine therapy. In this systemic review, we performed a meta-analysis to explore whether CDK4/6 inhibitors had a significantly benefit to treating hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2 negative (HER2-negative) advanced breast cancer. METHODS: The data for meta-analysis were collected from MEDLINE, EMBASE, and Cochrane Library from January 1980 to December 2017, and eventually 3182 patients from 6 RCTs were included. RESULTS: The result showed the CDK4/6 inhibitor group had a longer progression-free survival (PFS) (hazard ratio = 0.51; 95% confidence interval [CI], 0.46-0.57, P < .00001), a better objective response (risk rate = 1.53; 95% CI, 1.35-1.74, P < .00001), as well as a better clinical benefit response (risk rate = 1.29; 95% CI, 1.13-1.47, P = .0001). Besides, subgroup analyses of PFS according to stratification factors and other baseline characteristics confirmed a great performance of CDK4/6 inhibitors across the all subgroups. And sensitive analysis showed that all outcomes were stable except Finn 2014 trail. CONCLUSION: CDK4/6 inhibitors can significantly prolong the PFS and improve the objective response and clinical benefit response among the patients with HR-positive/ HER2-negative advanced breast cancer. PMID- 29768352 TI - Effectiveness of Trevo stent retriever in acute ischemic stroke: Comparison with Solitaire stent. AB - Recently, mechanical thrombectomy with stent retriever has achieved faster and higher rates of recanalization for intracranial major vessel occlusion. However, comparative studies of the most widely used Solitaire and Trevo stents have been rarely published.The authors retrospectively reviewed a total of 200 patients who performed mechanical thrombectomy at our center during 4 years and divided patients into 2 groups: mechanical thrombectomy with Solitaire stent (Group 1: Solitaire) and mechanical thrombectomy with Trevo stent (Group 2: Trevo). All patients underwent a clinical assessment with National Institutes of Health Stroke Scale (NIHSS) score and underwent modified Rankin Scale (mRS) score. Radiologic results were evaluated using thrombolysis in cerebral infarction (TICI) score and number of stent passes. In addition, multiple time intervals were analyzed.There was no statistically significant difference in clinical outcome between the 2 groups. Trevo group revealed the shorter procedure time, less number of stent passage, and more one pass cases than Solitaire group with statistically significance (P = .009, P = .014, P = .030). In addition, Trevo group achieved higher successful recanalization (TICI 2b or 3) rate (89.7%) with statically significant than group1 (82.3%) (P = .018). In multivariate logistic regression analysis, the use of Trevo stent was a predictive for successful recanalization. (odds ratio 1.40, 95% confidence interval 1.250-1.550, P = .028).Our study suggests that the Trevo stent allows higher recanalization rate through the less number of stent passages and shorter procedure time than the Solitaire stent. More randomized control trials are needed to determine which stents are more effective. PMID- 29768353 TI - Correlation of increased Th17/Treg cell ratio with endoplasmic reticulum stress in chronic kidney disease. AB - To investigate the relationship between the regulatory immune network and endoplasmic reticulum stress (ERS) in patients with different stages of chronic kidney disease (CKD).A total of 91 patients diagnosed with CKD were divided into different groups according to the stage of disease and treatment with hemodialysis (HD) or peritoneal dialysis (PD). Routine blood and biochemical tests were performed in patients in the different CKD groups and in healthy controls (n = 20). The frequencies of T helper type 17 (Th17) and regulatory T (Treg) cells in the overall T cell population were measured by flow cytometric analysis. Levels of Th17 cell (IL-17) and Treg cell (IL-10) cytokines and the ERS markers CCAAT-enhancer-binding protein homologous protein (CHOP) and glucose regulated protein 78 (GRP78) were measured by enzyme-linked immunosorbent assay in serum samples collected from controls and patients. Correlations between each parameter and serum creatinine were analyzed by Spearman rank correlation and regression test.CKD stage showed a positive correlation with serum creatinine level, and increased and decreased percentages of Th17 and Treg cells, respectively, reflected in an increased Th17/Treg cell ratio. Consistent with this, CKD stage was positively correlated with serum concentrations of IL-17 and negatively correlated with serum IL-10 levels. Moreover, serum levels of CHOP and GRP78 increased with advancing CKD stage. These correlations were most pronounced in patients in the CKD5 group, who also had the poorest response to HD and PD treatment, compared with CKD5 patients in the nondialysis group. Correlation analysis showed that serum levels of CHOP and GRP78 were independently and positively correlated with the ratio of Th17/Treg cells.We have found that an increased Th17/Treg cell ratio and increased serum levels of ERS markers correlate with the progression of CKD. Our results indicate that the interplay between regulation of the immune network and management of ERS is closely associated with the pathogenesis of CKD. Although HD and PD treatment manage chronic kidney conditions and prevent further deterioration of renal function, they have limited effects on improving the immune disorder and relieving ERS. Our study suggests a potential new direction for development of therapeutic strategies in CKD. PMID- 29768354 TI - Feasibility and effectiveness of electrochemical dermal conductance measurement for the screening of diabetic neuropathy in primary care. DECODING Study (Dermal Electrochemical Conductance in Diabetic Neuropathy). Rationale and design. AB - Diabetes mellitus is the leading cause of polyneuropathy in the Western world. Diabetic neuropathy is a frequent complication of diabetes and may have great clinical transcendence due to pain and possible ulceration of the lower extremities. It is also a relevant cause of morbidity and mortality in patients with diabetes. Although the cause of polyneuropathy in patients with diabetes is only partially known, it has been associated with chronic hyperglycemia suggesting the possible etiopathogenic implication of advanced glycosylation end products. The strategy of choice in the medical management of diabetic neuropathy is early detection since glycaemic control and the use of certain drugs may prevent or slow the development of this disease. Diabetic neuropathy most often presents with a dysfunction of unmyelinated C-fibers, manifested as an alteration of the sweat reflex of the eccrine glands. This dysfunction can now be demonstrated using a newly developed technology which measures dermal electrochemical conductivity. This noninvasive test is easy and cost-effective. The aim of the present study is to evaluate the feasibility and effectiveness of dermal electrochemical conductance measurement (quantitative expression of the sudomotor reflex) as a screening test for the diagnosis of diabetic neuropathy in patients in primary care. PMID- 29768355 TI - Infantile medulloepithelioma in the lateral ventricle and cerebellopontine angle: Two case reports. AB - RATIONALE: Intracranial medulloepitheliomas are extremely rare and highly malignant. Intraventricular medulloepitheliomas are even rarely reported, and little is known about the clinical features. PATIENT CONCERNS: In this article, we report two cases of intracranial medulloepitheliomas. In the first patient, a one-month old boy, the tumor was located in in right lateral ventricle, which was the first report of such location of this disease; in the second patient, an eleven-month old girl, the tumor was in right cerebellopontine angle. DIAGNOSES: Both patients were diagnosed as medulloepithelioma by pathologists. INTERVENTIONS: Both patients underwent craniotomy to resect the lesion totally. OUTCOMES: The boy underwent chemotherapy after operation and was alive 3 months after operation. The girl died 6 months after operation, despite aggressive adjuvant chemotherapy. LESSONS: Surgical resection is safe and effective to prolong patient survival. However, despite aggressive adjuvant therapy, prognosis of medulloepithelioma remains poor, and further study is needed to improve treatment of this rare disease. PMID- 29768356 TI - Late distant recurrence of breast carcinoma and metastasis to the main bronchus and choroid: A case report. AB - RATIONALE: Metastases of breast carcinoma to the main bronchus and choroid are rare, but have been reported in relevant literature. Late distant recurrence of breast carcinoma after more than 20 years is extremely rare. Herein, we report a 57-year-old woman with late distant recurrence and metastasis to the main bronchus and choroid almost 28 years after surgery. PATIENT CONCERNS: At the age of 29, the patient underwent chemotherapy and endocrine treatment after a right side mastectomy to remove breast carcinoma. The patient was hospitalized for a cough with blood-tinged sputum, dysphagia, and blurred vision in the left eye at the age of 57. DIAGNOSES: On evaluation, laboratory findings detected the elevated serum tumor markers of CA12-5, CA15-3, NSE, and Cyfra21-1. The imaging showed left lung metastase, multiple lymph node metastases, and small suspected metastases in the both sides of parietal lobes. Fundus fluorescein angiography showed choroidal occupying lesion of the left side which indicates secondary metastasis and retinal detachment. Combined with the pathological finding via fiberoptic bronchoscopic biopsy, the patient was clinically diagnosed with a late distant recurrence of breast carcinoma. INTERVENTIONS: The patient received oral endocrine therapy of letrozole, but she refused chemotherapy, radiotherapy and other topical treatments. OUTCOMES: At the 3-month follow-up visit, the multiple lesions of the left lung and lymph nodes had partially regressed, and the lesion of right parietal lobe had disappeared. The patient's clinical symptoms, such as blood-tinged sputum and dysphagia, had significantly improved. LESSONS: We have described this case and reviewed the relevant literature concerning late distant recurrence of breast carcinoma. Importantly, this case indicates that patients with HR positive breast carcinoma are more likely to develop late distant recurrence and clinicians should not ignore the follow-up examinations even more than 20 years after the surgery. PMID- 29768357 TI - Dysembryoplastic neuroepithelial tumor-like pilocytic astrocytoma: A case report. AB - RATIONALE: Pilocytic astrocytoma (PA) typically shows biphasic pattern with a mixture of loose microcystic and compact regions, in which it is not uncommon to see heterogeneous morphology. However, there has not been reported in the literatures of the PA type that shows similarity to dysembryoplastic neuroepithelial tumor (DNT) in both histological morphology and immunophenotype. PATIENT CONCERNS: The present study described a case of PA affecting the right temporal-occipital lobe in a 22-year-old male patient. Morphologically, it composed of totally distinctive microcystic pattern. The classical biphasic pattern of PA was not observed. Immunohistochemically, neuronal marker NeuN was expressed in tumor cells scattered in the background which simulated its expression morphology in DNT. However, KIAA1549-BRAF fusion gene was identified by fluorescence in situ hybridization (FISH), supporting for the diagnosis of PA. DIAGNOSES: DNT-like PA (WHO grade I). INTERVENTIONS: The tumor was totally removed via a right temporal-occipital craniotomy. OUTCOMES: The patient is free of local recurrence and dissemination eleven months after surgical resection of the lesion. LESSONS: We herein report a rare case of DNT-like PA. For diagnosis, KIAA1549-BRAF fusion gene should be detected under similar situation. PMID- 29768358 TI - Spastic paraparesis caused by X-linked adrenoleukodystrophy mimicking vacuolar myelopathy in a human immunodeficiency virus patient: A case report. AB - RATIONALE: Vacuolar myelopathy is one of most common cause of spastic paresis in patients with human immunodeficiency virus (HIV) infection. However, X-linked adrenoleukodystrophy (X-ALD), which is a metabolic disorder caused by impairment of peroxisomal beta-oxidation of very-long-chain fatty acids (VLCFA), also manifests as various neurological deteriorations including adult onset spastic paraparesis. To the best of our knowledge, there has been no report of newly developed spastic paresis due to X-ALD in a patient with HIV infection. PATIENT CONCERNS: A 30-year-old male had presented with progressive spastic paraparesis for 1 year. DIAGNOSIS: X-ALD. INTERVENTION: Brain and spine magnetic resonance imaging (MRI), VLCFA, and genetic test. OUTCOMES: His spinal MRI mimicked vacuolar myelopathy, but he was finally diagnosed with X-ALD using the VLCFA and genetic test. LESSONS: Although rare, isolated spastic paraparesis can occur in HIV patients; additional tests such as VLCFA can be useful for the differential diagnosis. More data are needed to understand the pathological mechanisms underlying the two diseases. PMID- 29768359 TI - Case report of gastric distension due to superior mesenteric artery syndrome mimicking hollow viscus perforation: Considerations in critical care ultrasound. AB - RATIONALE: Critical care ultrasound identifies the signs of free intraperitoneal air and echogenic free fluid always indicates hollow viscus perforation (HVP) and needs immediate surgical interventions. However, in rare cases, these classic signs may also mislead proper clinical decisions. We report perforated viscus associated large peritoneal effusion with initial critical care ultrasound findings, whereas computed tomography (CT) examination confirmed a giant stomach due to superior mesenteric artery syndrome (SMAS). PATIENT CONCERNS: A 70-year old man was admitted to our emergency department with a complaint of recurrent vomiting with coffee ground emesis for 15 hours and worsen with hypotension for 6 hours. During gastric tube placement, the sudden cardiac arrest occurred. With 22 minutes resuscitation, sinus rhythm was restored. DIAGNOSES: Quick ultrasound screen showed large echogenic fluid distributed in the whole abdomen. Diagnostic paracentesis collected "unclotted blood" and combined with a past history of duodenal ulcer, HVP was highly suspected. However, surgical intervention was not performed immediately as unstable vital signs and unfavorable coma states. After adequate resuscitation in intensive care unit, the patient was transferred to perform enhanced CT. Surprisingly, there was no evidence of HVP. Instead, CT showed a giant stomach possibly explained by SMAS. INTERVENTIONS: Continuous gastric decompression was performed and 3100 mL coffee ground content was drainage within 24 hours of admission. OUTCOMES: Abdominal distension was significantly relieved with improved vital signs. However, as the poor neurological outcome, family members abandon further treatment, and the patient died. LESSONS: SMAS is a rare disorder, characterized by small bowel obstruction and severe gastric distension. Nasogastric tube insertion should be aware to protect airway against aspiration. Caution should be utilized to avoid over interpretation of ultrasonography findings on this condition. PMID- 29768360 TI - Clinical efficacy of xenon versus propofol: A systematic review and meta analysis. AB - BACKGROUND: Interest in the anesthetic use of xenon, a noble gas, has waxed and waned for decades, and the clinical effects of xenon are still debated. We performed a meta-analysis to compare the clinical efficacy of xenon with that of propofol. METHODS: Electronic searches were performed through December 2017 using various databases, including PubMed, Embase, and the Cochrane Library. We identified thirteen trials that included a total of 817 patients. RESULTS: Patients treated with xenon had a lower bispectral index (BIS) (weighted mean difference (WMD): -6.26, 95% confidence interval (CI): -11.33 to -1.18, P = .02), a higher mean arterial blood pressure (MAP) (WMD: 7.00, 95% CI: 2.32-11.68, P = .003) and a lower heart rate (HR) (WMD: -9.45, 95% CI: -12.28 to -6.63, P < 0.00001) than propofol-treated patients. However, there were no significant differences between the 2 treatment groups in the effects of nondepolarizing muscular relaxants, the duration spent in the postanesthesia care unit (PACU) (WMD: -0.94, 95% CI: -8.79-6.91, P = .81), or the incidence of perioperative complications [assessed using the outcomes of postoperative nausea and vomiting (PONV) (relative risk (RR): 2.01, 95% CI: 0.79-5.11, P = .14), hypotension (RR: 0.62, 95% CI: 0.27 to 1.40, P = .25), hypertension (RR: 1.27, 95% CI: 0.73-2.21, P = .39) and bradycardia (RR: 1.00, 95% CI: 0.36-2.74, P = 1.00)]. CONCLUSION: In this meta-analysis of randomized controlled trials, we found that xenon treatment resulted in a higher MAP, a lower HR, and a smaller BIS index than treatment with propofol. PMID- 29768361 TI - A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A case report. AB - RATIONALE: We report a case of Spastic paraplegia 8 (SPG8) with a novel mutation of KIAA0196 gene. PATIENTS CONCERNS: A 12-year-old boy presented as ankle sprained, lower limb stiffness, abnormal gait since he was 5 years old. DIAGNOSES: The next generation sequence showed a novel c.1128delG (p.L376fs) mutation in KIAA0196 gene, the electromyography showed the pyramidal tract conduction dysfunction and deep sensory conduction abnormalities of lower limbs without motor neuron damage. The diagnose was SPG8. INTERVENTIONS: Patient was gaven Baclofen treatment (30 mg/day, orally). OUTCOMES: At one year follow up, his symptoms didn't improved. LESSONS: We describe a novel KIAA0196 c.1128del.G (p.L376fs) mutation in a Chinese patient with SPG8. To our knowledge, it's the first frame delete mutation causing shift mutation of KIAA0196 gene, resulting in the earliest onset of SPG8 in the world. Gene sequencing is a powerful diagnostic tool to identify a causal mutation in genetically heterogeneous HSP. PMID- 29768362 TI - Intraductal papilloma arising from the accessory parotid gland: A case report and literature review. AB - RATIONALE: Intraductal papillomas of the accessory parotid glands are extremely rare benign tumors that are most commonly derived from minor salivary glands and are easily misdiagnosed as other diseases. Studying these lesions by pathology and immunohistochemistry can raise awareness of the disease, reduce the rate of misdiagnosis, and provide more precise treatments. PATIENT CONCERNS: A 35-year old man first presented to our hospital with a 6-month history of a painless mass on his left parotid gland. DIAGNOSES: The patient was diagnosed with intraductal papilloma of the accessory parotid gland by pathology and immunohistochemistry. INTERVENTIONS: The mass was completely resected. OUTCOMES: After 2 years of postoperative follow-up, the patient recovered well without recurrence. LESSONS: Intraductal papilloma of the accessory parotid gland is very rare, and can easily be misdiagnosed as sialadenoma papilliferum, inverted ductal papilloma, or papillary cystadenoma, among others. It is necessary to analyze its pathology and immunohistochemistry in comparison with other diseases. Early excision and long term follow-up are necessary to provide optimal treatment and to better understand the pathological processes of intraductal papilloma. PMID- 29768364 TI - Comparative effectiveness of fragility fracture integrated rehabilitation management for elderly individuals after hip fracture surgery: A study protocol for a multicenter randomized controlled trial. AB - INTRODUCTION: Although it is essential to provide comprehensive rehabilitation after hip fracture to restore the patient to preoperative physical functioning, feasibility issues remain. Here, we describe a protocol for a randomized controlled trial (RCT) to evaluate the effectiveness of fragility fracture integrated rehabilitation management (FIRM) for elderly individuals after hip fracture surgery. We also examine the feasibility of applying FIRM in a chronic care hospital or community-based setting. METHODS AND ANALYSIS: Elderly patients will be randomly assigned to either the FIRM, conventional, or control group for a 2-week intervention period following hip fracture surgery. The primary outcome of this study is Koval walking ability. All functional outcomes will be measured 1 and 3 weeks, 3, 6, and 12 months after the surgical intervention. Researchers will be blind to group allocation, and participants will be blind to outcome. A sample size of 282 participants will be necessary to demonstrate the effect of the FIRM program. After the RCT has been conducted in 3 core hospitals, FIRM will be applied in 6 community-based local hospitals to investigate the feasibility of the program. The data will be analyzed using the intention-to-treat principle. TRIAL REGISTRATION NUMBER: NCT03430193. PMID- 29768363 TI - Ex vivo resection and intestinal autotransplantation for a large mesenteric desmoid tumor secondary to familial adenomatous polyposis: A case report and literature review. AB - RATIONALE: The mesenteric desmoid tumor requires special attention and the most demanding treatment. PATIENT CONCERNS: Here we present a rare case of a large mesenteric desmoid tumor secondary to familial adenomatous polyposis (FAP) in a 34-year-old man accepted the ex vivo resection, and intestinal autotransplantation. DIAGNOSES: A 34-year-old man was referred to our department with a 6-year history of intermittent hematochezia without any other discomfort after undergoing partial colectomy in February 2013, and 5 endoscopic mucosal resections of colon polyps between May 2012 and July 2015 due to pathological diagnosis of FAP. A computed tomography scan showed a huge abdominal mass with indistinct boundary at the root of the mesentery. The adjacent organs were pushed and most of the superior mesenteric artery branches were infiltrated. INTERVENTIONS: An en bloc resection (R0 resection), and an ex vivo resection followed by intestinal autotransplantation was performed. OUTCOMES: The patient was discharged from the hospital on the 25th day after the operation, and was regularly followed up after surgery with abdominal ultrasonography and laboratory biochemical tests every month, and serial CT scans every 3 months which showed no evidence of tumor recurrence, thrombus, intestinal obstruction or abdominal infection so far. LESSONS: An ex vivo resection and intestinal autotransplantation appear feasible for cases with pathological lesions involving the vessels at the root of mesentry, and represents an attractive alternative for the management of mesenteric desmoid tumors. PMID- 29768365 TI - Recurrent juvenile fibroadenoma of the breast in an adolescent: A case report. AB - RATIONALE: Most breast masses are benign and are rare in adolescent girls. The most frequent tumor is fibroadenoma. Juvenile fibroadenoma is a rare variant of fibroadenoma and is characterized by rapidly enlarging, painless, and unilateral masses occurring at ages between 10 and 18 years. PATIENT CONCERNS: A 17-year-old girl who first presented to a hospital due to a left breast tumor. DIAGNOSES: Juvenile fibroadenoma of the left breast. INTERVENTIONS: She underwent fibroadenoma excision, but she complained of a mass that presented in her left breast 3 months after surgery. After 2 years of observation, the mass became tender and enlarged. We conducted a wide excision of the tumor. Recurrent juvenile fibroadenoma with hypercellular fibromyxoid stroma of the breast was noted. OUTCOMES: The patient is in good general condition without tumor relapses during the 4 months of follow-up. LESSONS: Recurrent fibroadenomas, particularly those of a large size with a rapid growth rate, in the same breast suggest a high possibility of transformation. We recommend wide tumor resection. PMID- 29768366 TI - Case report: A rare case of focal myositis presenting as Sartorius muscle contracture: A case report and review of literature. AB - RATIONALE: Focal myositis (FM) is a very rare myopathy of unknown etiology characterized by focal enlargement within one single skeletal muscle. In particular, it occurs only involving the Sartorius muscle has never been reported. PATIENT CONCERNS: A 25-year-old man was admitted to the hospital with progressive restricted left hip joint extension, left thigh discomfort and gait disturbance for 6 years. DIAGNOSES: Combining clinical manifestations with results of radiological and pathological examinations, it was consistent with the diagnosis of FM INTERVENTIONS:: The patient received a surgery under general anesthesia to release the contracted Sartorius tendon. OUTCOMES: The range of motion of the patient's left hip and ipsilateral knee has significantly improved as well as the discomfort of his left thigh relieved obviously after the surgery. LESSONS: This case report is the first to report FM presenting as sartorius muscle contracture and the surgery is an alternative therapy for these patients. PMID- 29768368 TI - Meta-analysis of computed tomography angiography versus magnetic resonance angiography for intracranial aneurysm. AB - BACKGROUND: Whether the diagnosis value of computed tomography angiography (CTA) for intracranial aneurysm is in accordance with magnetic resonance angiography (MRA) remains inconclusive. This meta-analysis aims to synthesize relevant studies to compare the diagnostic efficacies of the 2 methods. METHODS: Potentially relevant studies were selected through PubMed, Embase, Wanfang, Chongqing VIP, and China National Knowledge Infrastructure databases by using the core terms "computer tomography angiography" (CTA) and "magnetic resonance angiography" (MRA) and "intracranial aneurysm*" in the titles, abstracts, and keywords of the articles. Quality Assessment for Diagnostic Accuracy Studies (QUADAS-2) was utilized to evaluate the quality. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) were count. Summary receiver operating characteristic curves (SROC) and area under the curve (AUC) were used to summarize the overall diagnostic performance. Statistical analyses were performed by Stata version 12.0 and MetaDisc 1.4 software. RESULTS: Ten articles were identified in this current paper. For CTA, the pooled estimates of diagnostic parameters for intracranial aneurysm were as follows: sensitivity, 0.84 (95%CI = 0.81-0.86); specificity, 0.85 (95%CI = 0.79-0.89); PLR, 4.09 (95%CI = 2.45-6.81); NLR, 0.18 (95%CI = 0.11 0.28); DOR, 23.74 (95%CI = 10.49-53.74); AUC, 0.90, respectively. For MRA, the pooled estimates of diagnostic parameters for intracranial aneurysm were as follows: sensitivity, 0.80 (95%CI = 0.77-0.83); specificity, 0.87 (95%CI = 0.82 0.91); PLR, 3.61 (95%CI = 1.72-7.55); NLR; 0.27 (95%CI = 0.21-0.35); DOR, 16.77 (95%CI = 7.38-38.11); AUC, 0.87, respectively. No significant difference was found the AUC value between CTA and MRA for intracranial aneurysm (Z = 0.828, P > .05). CONCLUSION: This comprehensive meta-analysis demonstrated that the diagnosis value of CTA was in accordance with MRA for intracranial aneurysm. However, considering the limitation of sample size, the results should be treated with caution. PMID- 29768369 TI - Pembrolizumab-induced acute thrombosis: A case report. AB - RATIONALE: Acute thrombosis has not been reported in the literature so far in lung cancer patients as an immune-related adverse event (irAE) associated with PD 1 pathway inhibitors. PATIENTS CONCERNS: Here, we for the first time present two NSCLC (non-small cell lung cancer) patients suffering from acute thrombosis as a pembrolizumab-induced irAE. Immediate treatment with continuous heparin infusion improved their symptoms and enabled them to continue pembrolizumab administration. METHODS: Ethical approval was given by the ethics committee of Osaka International Cancer Institute and the informed consents were given by the patients. DIAGNOSIS: Serum D-dimer level testing, venous ultrasonography, enhanced computed tomography (CT). INTERVENTIONS: Continuous heparin infusion, direct oral anticoagulants (DOAC). OUTCOMES: Immediate continuous heparin infusion improved their symptoms and continuing pembrolizumab with direct oral anticoagulant successfully induced tumor shrinkage. LESSONS: Reinvigoration of exhausted T cells by pembrolizumab induced systemic inflammation possibly resulting in development of thrombosis. Although acute thrombosis is a rare irAE, it may lead to cessation of treatment and can be lethal. PMID- 29768367 TI - The phenotypic heterogeneity of patients with Marfan-related disorders and their variant spectrums. AB - Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are the connective tissue disorders characterized by aortic root aneurysm and/or dissection and various additional features. We evaluated the correlation of these mutations with the phenotypes and determined the clinical applicability of the revised Ghent criteria.The mutation spectrum and phenotypic heterogeneities of the 83 and 5 Korean patients with suspected MFS and LDS were investigated as a retrospective manner. In patients with suspected MFS patients, genetic testing was conducted in half of 44 patients who met the revised Ghent criteria clinically and half of 39 patients who did not meet these criteria.Fibrillin1 gene (FBN1) variants were detected in all the 22 patients (100%) who met the revised Ghent criteria and in 14 patients (77.8%) who did not meet the revised Ghent criteria (P = .0205). Patients with mutations in exons 24-32 were diagnosed at a younger age than those with mutations in other exons. Ectopia lentis was more common in patients with missense mutations than in patients with other mutations. Aortic diameter was greater in patients with missense mutations in cysteine residues than in patients with missense mutations in noncysteine residues. Five LDS patients had either TGFBR1 or TGFBR2 variants, of which 1 patient identified TGFBR1 variant uncertain significance.The revised Ghent criteria had very high clinical applicability for detecting FBN1 variants in patients with MFS and might help in selecting patients with suspected MFS for genetic testing. PMID- 29768370 TI - A case report of neurological complications owing to lately diagnosed hyperargininemia emphasizing the role of national neonatal screening policies in the kingdom of Bahrain. AB - INTRODUCTION: Arginine is an essential amino acid that plays an important role in various body functions including cell division, wound healing, removal of ammonia, immune function, and release of hormones. Hyperargininemia, an autosomal recessive genetic disorder, is considered one of the least common urea cycle disorders. It rarely presents in the neonatal period but rather appears in children at the age between 2 and 4 years. CASE PRESENTATION: Herein, we demonstrate a case of a 14-year-old female who presented to the neurology clinic with several neurological complications, which were found to be a consequence of high levels of arginine discovered after performing a metabolic screening test. The hyperargininemia was because of a point mutation of A1 gene on 6q23 resulting in deficiency in arginase enzyme. The complications of this lately diagnosed case of hyperargininemia would have been avoided if a newborn screen were done as a part of a national program. CONCLUSION: This study presented certain neurological complications in a 14-year-old female who was lately diagnosed with hyperargininemia. Out case report strongly emphasizes the importance of establishing a national neonatal screening policy to ensure early detection of inherited metabolic disorders, in particular those which can be easily treated, in the Kingdom of Bahrain. PMID- 29768371 TI - Complex regional pain syndrome type II after cervical transforaminal epidural injection: A case report. AB - RATIONALE: We report a case of a 61-year-old patient who developed complex regional pain syndrome (CRPS) type II after a cervical transforaminal epidural steroid injection (CTESI). PATIENT CONCERNS: The patient developed sudden-onset severe pain and swelling of his upper right limb after a cervical transforaminal epidural injection. DIAGNOSES: On physical examination, the patient's symptoms and signs corresponded to the Budapest criteria for CRPS. Cervical magnetic resonance imaging and laboratory tests were performed to rule out other causes. An electrodiagnostic study revealed right C6/7 radiculopathies. A three-phase bone scan showed increased uptake in the right wrist in all phases. Thus, he was diagnosed with CRPS type II due to a cervical nerve root injury caused by the transforaminal epidural injection. INTERVENTIONS: He received oral methylprednisolone and gabapentin, and underwent physical therapy for 9 days. OUTCOMES: The pain and swelling of his right upper limb disappeared and he returned to his previous functional activities. LESSONS: CRPS type II due to cervical root injury is rare but can develop during CTESI. Early comprehensive physical therapy and oral medications might result in good outcomes. PMID- 29768372 TI - Technologies for participatory medicine and health promotion in the elderly population. AB - INTRODUCTION: The progressive aging of the population is a socio-demographic phenomenon experienced by most countries in the world in recent decades, especially in Japan and in many European Union countries. During this process, so called "geriatric syndromes" frequently occur. The focus of this study is the quality of life of the elderly in relation to these 3 factors: risk of falls, urinary incontinence, and insomnia. OBJECTIVE: The main purpose is to determine the impact of a multifactorial intervention program implemented with institutionalized elderly people. The program is focused on the treatment of the aforementioned factors. METHODS AND ANALYSIS: The study will be carried out with elderly people living in three residences for the elderly in A Coruna Province (Galicia, Spain).It is a prospective and longitudinal study, with a temporary series design of a "quasi-experimental" type that evaluates the effect of an intervention in 1 given population by doing assessments pre- and post intervention, but there is no comparison with a control group.The intervention will be based on a multifactorial program, including the following phases: the use of wearable devices (wearable fitness trackers to register physical activity and sleep), the use of an App on a Tablet to record the participants' occupations and activities, counseling about performance in activities of daily living, the implementation of a physical activity program, and the treatment of the pelvic floor (according to each research line). The Quality of Life (QoL) will be assessed before and after the intervention, with the use of the questionnaire EuroQol-5D-5L. Data analysis will be applied with all registered variables through a quantitative perspective. ETHICS AND DISSEMINATION: The protocol has been approved by the host institution's ethics committee (Research Ethics Committee of Galicia) under the number 2017/106. Results will be disseminated via peer-reviewed journal articles and conferences. This clinical trial is registered at ClinicalTrials.gov identifier: NCT03504813. PMID- 29768373 TI - Acute myelitis of children with positive anti-GM1 antibody: Case series and literature review. AB - RATIONALE: To explore the clinical features, treatment, and prognosis of acute myelitis (AM) of children with positive blood anti- ganglioside (GM1) antibodies. PATIENT CONCERNS: Two cases of AM of children with positive anti-GM1 antibody were retrospectively collected and followed up for 6 months. Two cases had positive helicobacter pylori IgG antibody, and Case 2 also had positive mycoplasma IgM antibody. DIAGNOSES: Two cases had typical symptoms of myelitis, abnormal spinal magnetic resonance imaging (MRI), and positive serum anti-GM1 IgM. INTERVENTIONS: They were treated with steroid, immunoglobulin and rehabilitation. OUTCOMES: Symptoms of AM were relieved after treatment. After 6 months of follow-up, case 1 was fully recovered and case 2 was partially recovered. Summarizing previous reports in literature and our 2 cases, AM with positive anti-GM1 antibody can be induced by multiple pathogen infections. About 35.7% were fully recovered, 42.9% had mild sequelae, and 21.4% had severe sequelae. LESSONS: Post-infection immune injury plays an important role in the pathogenesis of AM with positive anti-GM1 antibody. H pylori and Mycoplasma pneumoniae infection may also induce AM with positive anti-GM1 antibody. Screening and treatment of pathogens were required and only 21.4% patients had severe sequelae after treatment. PMID- 29768375 TI - Total spondylectomy of recurrent giant cell tumors in the cervical spine: Two case reports and review of literature. AB - RATIONALE: Spinal Giant Cell Tumors (SGCTs) are rare, aggressive, and benign tumors. Their presence in the cervical spine is even more exceptional. There are few reports of cervical GCT in the literature, especially recurrent cases. The treatment are challenging to clinically because radical resection is extremely difficult. PATIENT CONCERNS: In this study, we present the cases of a 25-year-old man and a 41-year-old woman who suffered from recurrent cervical GCT. INTERVENTIONS: They underwent extensive total spondylectomy of C3-5 and C2-4, respectively, by a combined anterior and posterior approach. OUTCOMES: Both patients had a satisfactory prognosis after 2 years followe-up, and extensive total spondylectomy provided good disease-free survival rates. Extensive total spondylectomy of cervical recurrent giant cell tumor was successfully achieved combined anterior and posterior approach. LESSONS: This surgical technique can be an effective option for this pathological condition, which is difficult to manage using other conventional treatment options including repeated curettage and radiotherapy. However, there are insufficient data on long-term subjective outcomes in this type of patient, and larger series studies are needed to determine the efficacy of this approach, especially compared with piecemeal resection techniques. PMID- 29768374 TI - Treatment of multiple refractory ankle ulcerations in thromboangiitis obliterans: A case report. AB - RATIONALE: Thromboangiitis obliterans (TAOs, or Buerger's disease) present as a non-atherosclerotic segmental occlusive vasculitis within medium- and small-sized blood vessels. TAO frequently occurs in young adults and is associated with cigarette smoking. At present, there are no accurately defined treatments for TAO. PATIENT CONCERNS: A 34-year-old Asian woman with a 20-year history of heavy cigarette smoking and recurrent, small, and self-limited lower limb ulcerations since adolescence, presented with persisting unhealed ulcerations on both ankles for 6 months. Her wound healing response was poor following the 2-month administration of colchicine, prednisolone, hydroxychloroquine, and mycophenolic acid. DIAGNOSIS: The patient was diagnosed with TAO with hyperimmunoglobulin E and refractory ulcerations on her ankles. INTERVENTIONS: The patient received monthly omalizumab (300 mg) and previous medications for 2 months and shifted to omalizumab and colchicine without mycophenolic acid and hydroxychloroquine because of onychomadesis, which was considered to be a possible adverse drug reaction. OUTCOMES: The wounds healed almost completely. The administration of omalizumab and colchicine will be continued until they the wounds are fully healed. LESSONS: Mycophenolic acid has a limited function in TAO treatment, especially in cases of refractory skin ulcerations. Omalizumab can be a valuable treatment option for patients with TAO and hyperimmunoglobulin E. PMID- 29768376 TI - Rare case of squamous cell carcinoma arising in a recurrent ovarian mature cystic teratoma of a young woman: A case report and review of the literature. AB - RATIONALE: Malignant transformations of ovarian mature cystic teratomas (MCTs) occur rarely, especially in young women. Although it is extremely difficult to diagnose them, serum tumor marker level testing in combination with the use of imaging techniques may be useful in preoperative diagnosis. PATIENT CONCERNS: We present the case of a 31-year-old Chinese woman with the malignant transformation of an ovarian MCT. The patient had a history of oophorocystectomy due to an MCT of the right ovary 6 years prior and a gemellary pregnancy owing to in vitro fertilization and embryo transfer. Her serum CA19-9 levels were persistently mildly elevated after the first surgery. DIAGNOSES: She was diagnosed with ovarian squamous carcinoma, arising from an MCT (International Federation of Gynecology and Obstetrics stage IA). INTERVENTIONS: A right salpingo-oophorectomy and omentectomy were performed and the patient underwent chemotherapy. OUTCOMES: The patient was disease-free at the 6-month follow-up. LESSONS: The malignant transformation of MCTs usually occurs in postmenopausal women with poor prognoses; it is very rarely observed in young women. Although the early detection and complete surgical resection of the tumor are crucial to survival, preoperative diagnosis of this malignancy is difficult. This case reiterates the fact that malignant transformation of MCTs can occur at any age. Rapid tumor growth along with persistently elevated tumor marker levels may be indicative of the malignant transformation of MCTs. PMID- 29768378 TI - Cerebral infarction as initial presentation in stress cardiomyopathy: Case report and literature review. AB - RATIONALE: The typical symptoms of stress cardiomyopathy include sudden-onset chest pain and breathlessness or collapse as well as classical symptoms of cardiovascular disease; however, rare reports have described nervous system symptoms as the initial manifestation. Here, we report the case of a young man who presented with a large cerebral infarction as the main clinical symptom of stress cardiomyopathy to increase recognition of the disease. PATIENT CONCERNS: A 28-year-old man was admitted to our hospital for sudden-onset weakness of the right limbs and unconsciousness for 1 day. Ten days prior, he began consuming copious amounts of alcohol (500 mL/day) secondary to reactive depression. DIAGNOSES: Imaging revealed a left internal carotid artery occlusion as assessed by carotid artery ultrasonography. Brain magnetic resonance imaging/magnetic resonance angiography showed new large left cerebral infarction complicated by a reperfusion injury. Moreover, cardiac ultrasonography showed decreased motion of the left ventricular apex, a 3.7 cm mural thrombus in the ventricular apex. The results of coronary and renal artery angiography did not reveal any significant epicardial coronary disease with thrombolysis in the myocardial infarction grade 3 in any of the coronary arteries. INTERVENTIONS: The patient was administered antiplatelet, anticoagulation, antihypertension, antibiotic, and neurotrophic therapies. OUTCOMES: The symptoms of cerebral infarction improved significantly after 12 days of admission. Cardiac ultrasonography showed that the wall movement of the left ventricular apex had recovered fully and the mural thrombus resolved completely. LESSONS: Patients with stress cardiomyopathy exhibit various clinical manifestations and characteristics. On the basis of our in-depth understanding of stress cardiomyopathy, clinicians should diagnose early and develop reasonable and effective therapies to prevent the harmful effects of related complications. PMID- 29768379 TI - Usefulness of polydeoxyribonucleotide as an alternative to corticosteroids in patients with lateral epicondyitis: A case series. AB - RATIONALE: Local corticosteroid injections are commonly used as an easy, cost effective treatment for patients with lateral epicondylitis (LE). Despite their strong anti-inflammatory effect, repeated injections of corticosteroids are not recommended in LE because they can aggravate tearing of the tendons. PATIENT CONCERNS: A 65-year-old (Case1) man and a 59-year-old (Case2) man had a 2-month history of right lateral elbow pain exacerbation. DIAGNOSES: Lateral epicondylitis with hypervascularity of the common extensor tendon. INTERVENTION: After informed consent was provided, ultrasound (US)-guided polydeoxyribonucleotide (PDRN) injections were made into on the common extensor tendons of both patients. OUTCOMES: After 2 weeks from PDRN injection, both patients reported significant pain relief. The US 2 weeks after the PDRN injection showed that the hypervascularity of the common extensor tendon in both patients had been completely cured, although there was no significant change in the findings of tendinosis. LESSONS: PDRN may be useful for patients with LE because there were no negative effects on tendon cells and tissues in previous in vitro and in vivo studies, despite its anti-inflammatory effects. PMID- 29768377 TI - Occurrence of metachronous multiple primary cancers occurred in different parts of the stomach with 2 pathologic features: A case report. AB - RATIONALE: With the increasing survival rate of gastric cancer, more multiple primary cancers (MPC) have been reported. However, few cases involve metachronous multiple primary cancers which both occurred in the stomach. PATIENT CONCERNS: An 83-year-old Chinese male had been diagnosed with gastric cardia cancer and underwent proximal gastrectomy. The pathological result was gastric adenocarcinoma. 13 years later the patient's gastroscope result deteriorated. The biopsy of the antrum revealed dysplasia with doubtful focal cancerization. DIAGNOSES: Metachronous multiple primary cancers in the stomach. INTERVENTIONS: Endoscopic submucosal dissection (ESD) was performed. The pathological result showed an intra-mucosal signet-ring carcinoma. OUTCOMES: After treatment, the patient is alive with good condition until now. LESSONS: This is an unusual case of MPC with different pathological features in different parts of the same organ in an interval of more than ten years and undergoing different operations. PMID- 29768380 TI - Tradeoff between noise reduction and inartificial visualization in a model-based iterative reconstruction algorithm on coronary computed tomography angiography. AB - We aimed to evaluate the image quality performance of coronary CT angiography (CTA) under the different settings of forward-projected model-based iterative reconstruction solutions (FIRST).Thirty patients undergoing coronary CTA were included. Each image was reconstructed using filtered back projection (FBP), adaptive iterative dose reduction 3D (AIDR-3D), and 2 model-based iterative reconstructions including FIRST-body and FIRST-cardiac sharp (CS). CT number and noise were measured in the coronary vessels and plaque. Subjective image-quality scores were obtained for noise and structure visibility.In the objective image analysis, FIRST-body produced the significantly highest contrast-to-noise ratio. Regarding subjective image quality, FIRST-CS had the highest score for structure visibility, although the image noise score was inferior to that of FIRST-body.In conclusion, FIRST provides significant improvements in objective and subjective image quality compared with FBP and AIDR-3D. FIRST-body effectively reduces image noise, but the structure visibility with FIRST-CS was superior to FIRST-body. PMID- 29768381 TI - Tuberculous pleurisy mimicking Mycoplasma pneumoniae infection in a previously healthy young adult: A case report. AB - RATONALE: Sometimes, pleural effusion accompanying an acute Mycoplasma pneumoniae infection or tuberculous pleurisy has similar analysis results. We report a case of tuberculous pleurisy which was initially diagnosed as acute M pneumoniae infection, which is of special interest because anti-Mycoplasma antibody results were positive, which served as a red herring. PATIENT CONCERNS: A 20-year-old woman visited the outpatient emergency romm of our hospital for chief complaints of high fever, dry cough, and pleuralgia persiting for 2 days. Since anti mycoplasma antibody test results were positive, we treated acute M pneumoniae infection and drained her pleural effusion. The condition tended to improve, but on day 16 postadmission, the acid-fast bacterial culture of the pleural effusion was positive for Mycobacterium tuberculosis. DIAGNOSES: Tuberculous pleurisy. INTERVENTIONS: After the diagnosis, the patient received antituberculous drugs. OUTCOMES: She completed treatment with no noticeable adverse events, and the right pleural effusion disappered and diffuse right pleural thickening improved. LESSONS: Exudative pleural effusion with lymphocyte dominance and a high adenosine deaminase level in M pneumoniae infection have been reported. Even though the condition suggests acute M pneumoniae infection, clinicians should be aware that tuberculous pleurisy and M pneumoniae infection can share similar clinical features, and should understand the usefulness and limitations of the anit-Mycoplasma antibody test. PMID- 29768382 TI - Transbronchial drainage using endobronchial ultrasonography with guide sheath for lung abscess: A case report. AB - RATIONALE: Lung abscess was previously treated surgically, but is now mainly treated with antibiotics and ideally with direct drainage, although postural drainage canalso be used. PATIENT CONCERNS: A chest abnormal shadow was detected in an 82-year-old man and he was referred to our department in November 2017. On chest computed tomography (CT), a low-density mass shadow was present in the left S8 segment. Lung abscess and lung cancer were considered as differential diagnoses, and treatment with sulbactam sodium/ampicillin sodium (SBT/ABPC) was first initiated for lung abscess. The etiologic agent could not be identified by sputum examination, and the abscess shadow remained. DIAGNOSES: Lung abscess. INTERVENTIONS: Endobronchial ultrasonography with a guide sheath (EBUS-GS)-guided bronchoscopy was performed on hospital day 21 to diagnose the lesion, identify the etiologic agent if the lesion was a lung abscess, and attempt drainage. Vacuum aspiration performed in the guide sheath after the probe was placed within the lesion produced 4-5 ml of gray turbid pus, and the abscess was judged to have been drained. OUTCOMES: A subsequent pathological examination did not detect malignant cells. Klebsiella pneumoniae, Prevotella spp. was identified as the etiologic agent in bacteriological tests. Antibiotics were changed based on sensitivity test results, and drainage was similarly performed on hospital day 28. The shadow gradually improved and disappeared. Therefore, this procedure and treatment led to identification of the etiologic agent and helped with cure of the disease. LESSONS: Based on the basic principle of treatment for abscess using as much drainage as possible, EBUS-GS-guided transbronchial drainage may be considered to be a "new procedure" for lung abscess. PMID- 29768383 TI - Treatable massive pericardial effusion and hypertrophic cardiomyopathy in an infant with a novel homozygous ACADVL mutation: A case report. AB - RATIONALE: Infantile-onset hypertrophic cardiomyopathy (HCMP) should be considered a largely genetic condition, although its onset is most often triggered by infection. Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive inborn error of mitochondrial fatty acid beta oxidation that often causes severe cardiomyopathy and/or sudden death during the neonatal period. PATIENT CONCERNS: Herein, we report an infant with VLCAD deficiency who presented with severe cardiac manifestations, including massive pericardial effusion and HCMP. The subject's older sister died of unknown causes at three days of age; however, the subject exhibited a normal tandem mass spectrometry profile during the neonatal period. DIAGNOSES: During her later cardiac presentation, the subject's C-14 and C-18 levels became elevated, and she was determined, via the conducted molecular analysis, to harbor a novel homozygous frameshift mutation (c.103_112dup) in ACADVL. INTERVENTIONS: After VLCAD deficiency diagnosis, the subject was treated with the administration of a medium chain triglyceride formula and fluid therapy. OUTCOMES: The subject's cardiac status was markedly improved by the dietary intervention and fluid therapy. LESSONS: This report highlights that genetic mutations should be investigated as possible causes of infantile-onset HCMP, and that early diagnosis and intervention can prevent mortality for patients with VLCAD deficiency. PMID- 29768384 TI - Therapeutic experience of severe and recurrent secondary hyperparathyroidism in a patient on hemodialysis for 18 years: A case report. AB - INTRODUCTION: For patients with refractory secondary hyperparathyroidism (SHPT), parathyroidectomy (PTX) has received increasing attention. However, evidence based medicine shows that there is still controversy regarding surgical methods, efficacy, and safety. We retrospectively analyzed the process of diagnosis and treatment in one patient with severe SHPT and long-term chronic renal failure (CRF), so as to further improve the therapeutic effect. CASE PRESENTATION: A 61 year-old female with SHPT and CRF manifested as no urine for 18 years, underwent PTX 4 times since September 2010, with satisfactory final recovery. The first operation involved resection of 3 parathyroid glands in the normal position; the second operation involved removal of an ectopic parathyroid gland, combined with parathyroid gland autotransplantation; the third operation was performed to resect suspected recurrent parathyroid gland; the fourth operation involved partial excision of the autotransplanted parathyroid glands. CONCLUSION: Accurate preoperative localized diagnosis and optimal surgical approach play key roles in the prevention and treatment of SHPT; postoperative recurrence of SHPT caused by ectopic or autotransplanted parathyroid gland should receive more attention. PMID- 29768386 TI - Are left ventricular ejection fraction and left atrial diameter related to atrial fibrillation recurrence after catheter ablation?: A meta-analysis. AB - Atrial fibrillation (AF), the most common form of arrhythmia, is associated with the prevalence of many common cardiovascular and cerebrovascular diseases. Catheter ablation is considered the first-line therapy for AF; however, AF recurrence is very common after catheter ablation. Studies have been performed to analyze the factors associated with AF recurrence, but none have reached a consistent conclusion on whether left ventricular ejection fraction (LVEF) and left atrial diameter (LA diameter) affect AF recurrence after catheter ablation.The databases PubMed, Embase, and the Cochrane Library were used to search for relevant studies up to September 2017. RevMan 5.3.5 software provided by the Cochrane Collaboration Network was used to conduct this meta analysis.Thirteen studies involving 2825 patients were included in this meta analysis. Overall, the results revealed that elevated LA diameter values were significantly associated with AF recurrence in patients after catheter ablation (MD = 2.19, 95% CI: 1.63-2.75, P < .001), while baseline LVEF levels were not significantly positively associated with AF recurrence in patients after catheter ablation (MD = -0.91, 95% CI: -1.18 to 1.67, P = .14).Overall, elevated LA diameter may be associated with AF recurrence after catheter ablation; however, there was no direct relationship between LVEF values and AF recurrence after catheter ablation when baseline LVEF values are normal or mildly decreased. Besides, because of publication bias, further studies should be performed to explore the mechanisms underlying AF recurrence. PMID- 29768389 TI - Analysis of preoperative blood platelet parameters in terms of diversity of epithelial ovarian cancer: Erratum. PMID- 29768385 TI - Low PG I/II ratio as a marker of atrophic gastritis: Association with nutritional and metabolic status in healthy people. AB - A low pepsinogen (PG) I/II ratio can be used to detect atrophic gastritis (AG). Recent research has found that the PG I/II ratio is associated with several nutritional and metabolic disorders. The aim of this study is to investigate the relationship between the PG I/II ratio and biochemical markers in a Chinese population.In total, 1896 participants in a gastric cancer screening program underwent a health screening test that included assessment of serum pepsinogens. Subjects with PG I/II < 3.0 were considered as having atrophic gastritis. Associations between the PG I/II ratio and biochemical markers reflecting glucose and lipid metabolism, liver, kidney and thyroid functions were evaluated using SPSS software version 20.The prevalence of atrophic gastritis was 5.3% and increased with age but did not differ between sexes. Albumin, ferritin, and total and direct bilirubin were significantly lower in patients with AG than in those without AG, whereas age, total bile acid, and amylase were significantly higher. Albumin, ferritin, and triglyceride correlated positively with the PG I/II ratio, while age, total bile acid, blood urea nitrogen, amylase, aspartate aminotransferase, creatine kinase, and lactate dehydrogenase correlated inversely with the PG I/II ratio. Logistic regression analysis demonstrated that age, total bile acid, total protein, and ferritin correlated independently with AG.Low PG I/II ratio is not only a marker of atrophic gastritis but also an indicator of nutritional and metabolic status. Special attention should be paid to the metabolism of iron, protein, and bile acid in patients with a low PG I/II ratio. PMID- 29768388 TI - A rational-emotive stress management intervention for reducing job burnout and dysfunctional distress among special education teachers: An effect study: Erratum. PMID- 29768390 TI - Marital status and survival in patients with rectal cancer: A population-based STROBE cohort study: Erratum. PMID- 29768391 TI - Prevention of late-life dementia: what works and what does not. AB - Advances in the treatment and prevention of disease have contributed to an aging global population. Subsequently, there is an increasing prevalence of age-related conditions, such as dementia. There are currently no disease-modifying therapies commercially available, and there is a growing emphasis on strategies to prevent dementia. We have reviewed the relevant literature pertaining to dementia risk and putative prevention factors. We present our findings by summarizing the pertinent items that may play a role in prevention and conclude our recommendations at this time. PMID- 29768387 TI - Optimal reconstruction methods after distal gastrectomy for gastric cancer: A systematic review and network meta-analysis. AB - BACKGROUND: The choice of anastomosis methods including Billroth I, Billroth II, and Roux-en-Y after a distal gastrectomy is still controversial. The conventional meta-analyses assessing 2 alternative treatments were not powered to compare differences in clinical outcomes. To guide treatment decisions in patients with gastric cancer (GC) after distal gastrectomy, we did a systematic review and network meta-analysis to identify the best reconstruction method. METHODS: We systematically searched PubMed, EMBASE, the Cochrane Library for randomized controlled trials comparing the outcomes of Billroth I, Billroth II, or Roux-en-Y reconstruction after distal subtotal gastrectomy for patients with GC, then we performed a direct meta-analysis and Bayesian network meta-analysis to pooled odds ratios (OR) or weighted mean differences (WMD) with 95% credible intervals (CrI) with random effects model. The node-splitting method was used to assess the inconsistency. We estimated the potential ranking probability of treatments by calculating the surface under the cumulative ranking curve for each intervention. RESULTS: Nine studies involving 1161 patient were included in the network meta analysis. Statistical significance was reached for the comparisons of Roux-en-Y versus Billroth I reconstruction (WMD 37, 95% Crl: 22-51) and Billroth II versus Billroth I reconstruction (WMD 25, 95% Crl: 5.8-43) for operation time; and Roux en-Y versus Billroth I reconstruction (WMD 26, 95% Crl: 2.1-68) for intraoperative blood loss; and Roux-en-Y versus Billroth I reconstruction (OR 3.4, 95% Crl: 1.1-13) for delayed gastric emptying. Roux-en-Y reconstruction was superior to Billroth I and Billroth II reconstruction in terms of frequency of bile reflux (OR 0.095, 95% Crl: 0.010-0.63; OR 0.064, 95% Crl: 0.0037-0.84, respectively) and the incidence of remnant gastritis (OR 0.33, 95% Crl: 0.16 0.58; OR 0.40, 95% Crl: 0.17-0.92, respectively). CONCLUSION: Roux-en-Y reconstruction is superior to Billroth I and Billroth II reconstruction in terms of preventing bile reflux and remnant gastritis, Billroth I and Billroth II anastomosis could be considered as the substitute in consideration of technical simplicity. As for postoperative morbidity and the advantage of physiological food passage, Billroth I method is the choice. PMID- 29768392 TI - Corneal complication of anticancer chemotherapeutic drug. PMID- 29768393 TI - An unexpected diagnosis in a patient with 2 left atrial pathological masses found by echocardiography. PMID- 29768394 TI - Stroke risk reduction after left atrial appendage occlusion in elderly patients with atrial fibrillation: long-term results. PMID- 29768395 TI - Measurement of apixaban concentrations in real-world clinical and laboratory settings: the first Polish experience. PMID- 29768396 TI - Acute cardiovascular responses elicited by consumption of beer in healthy people. PMID- 29768399 TI - Social and environmental exposures-the bidirectional learning between health policy and practice. PMID- 29768398 TI - Urinary metabolites of volatile organic compounds of infants in the neonatal intensive care unit. AB - BackgroundPreterm infants (PTI) in the NICU are often placed in incubators that may increase their exposure to volatile organic chemicals (VOCs). To determine whether PTI in incubators have higher urinary concentrations of VOC metabolites compared with infants in cribs.MethodsUrine from 40 PTI in incubators and 40 infants in cribs was collected and analyzed for 28 urinary VOC biomarkers. Differences in metabolite concentrations between the two groups were compared.ResultsTwenty two of the VOC metabolites were detected in at least one urine sample. All urine samples tested had measurable levels of six VOC metabolites. Biomarkers for acrolein, acrylonitrile, carbon disulfide, cyanide, N dimethylformamide, ethylbenzene, ethylene oxide, propylene oxide, styrene, toluene/benzyl alcohol, vinyl chloride, and xylene were higher in the incubator group. The geometric means of five VOC metabolites were 2-fold higher than those reported for NHANES children 6-11 years of age in one or both of the groups with benzyl mercapturic acid being 7-fold and 12-fold greater than NHANES in the crib and incubator group, respectively.ConclusionAll infants were exposed to VOCs. PTI in incubators have a different VOC exposure profile compared with infants in cribs. The health implications associated with these exposures require further study. PMID- 29768397 TI - Lipopolysaccharide Exposure Alleviates Asthma in Mice by Regulating Th1/Th2 and Treg/Th17 Balance. AB - BACKGROUND It is generally believed that endotoxin exposure exacerbates risk of developing asthmatic symptoms. However, recent studies have indicated that prior bacterial exposure may prevent future symptoms of asthma. Here, we evaluated the influence of pre-exposure to different concentrations of lipopolysaccharide (LPS) to subsequent ovalbumin (OVA) allergen sensitization and challenge. MATERIAL AND METHODS Four-week-old Balb/c mice were treated intranasally with varying concentrations of LPS (1 ug, 10 ug, and 100 ug) or sterile PBS for 10 days, then 2 weeks later they were exposed to OVA. Both the molecular and functional airway responses to OVA administration were assessed following prior exposure to different doses of LPS or controls. Additionally, the Th1/Th2 and Treg/Th17 balance was measured. RESULTS Airway responsiveness and immune cell recruitment in the bronchoalveolar lavage (BALF) were decreased in animals exposed to a low dose of LPS (1 ug) treatment compared with the asthma group. Moderate-dose (10 ug) and high-dose (100 ug) LPS administration showed no differences from controls. Further, low-dose LPS (1 ug) exposure was associated with increased Th1 cytokines, T-bet, Treg cytokine (IL-10, TGF-beta), and Foxp3 expression, but decreased Th2 cytokines (IL-4,5,13), GATA3, Th17, and ROR-gt expression compared with the asthma group. Finally, higher numbers of CD4+CD25+Foxp3+Treg cells, and CD4+INF-gamma+T cells, and lower CD4+IL-4+T cells and CD4+IL-17+T cells were observed in the low-dose LPS-treated groups compared to controls. CONCLUSIONS Our findings suggest that prior exposure to low doses of LPS may protect from OVA induced airway hyperresponsiveness (AHR) and histopathologic changes through regulation of the Th1/Th2 and Treg/Th17 balance. PMID- 29768400 TI - Do plants have a segregated germline? AB - For the last 100 years, it has been uncontroversial to state that the plant germline is set aside late in development, but there is surprisingly little evidence to support this view. In contrast, much evolutionary theory and several recent empirical studies seem to suggest the opposite-that the germlines of some and perhaps most plants may be set aside early in development. But is this really the case? How much does it matter? How can we reconcile the new evidence with existing knowledge of plant development? And is there a way to reliably establish the timing of germline segregation in both model and nonmodel plants? Answering these questions is vital to understanding one of the most fundamental aspects of plant development and evolution. PMID- 29768401 TI - Near real-time forecasting for cholera decision making in Haiti after Hurricane Matthew. AB - Computational models of cholera transmission can provide objective insights into the course of an ongoing epidemic and aid decision making on allocation of health care resources. However, models are typically designed, calibrated and interpreted post-hoc. Here, we report the efforts of a team from academia, field research and humanitarian organizations to model in near real-time the Haitian cholera outbreak after Hurricane Matthew in October 2016, to assess risk and to quantitatively estimate the efficacy of a then ongoing vaccination campaign. A rainfall-driven, spatially-explicit meta-community model of cholera transmission was coupled to a data assimilation scheme for computing short-term projections of the epidemic in near real-time. The model was used to forecast cholera incidence for the months after the passage of the hurricane (October-December 2016) and to predict the impact of a planned oral cholera vaccination campaign. Our first projection, from October 29 to December 31, predicted the highest incidence in the departments of Grande Anse and Sud, accounting for about 45% of the total cases in Haiti. The projection included a second peak in cholera incidence in early December largely driven by heavy rainfall forecasts, confirming the urgency for rapid intervention. A second projection (from November 12 to December 31) used updated rainfall forecasts to estimate that 835 cases would be averted by vaccinations in Grande Anse (90% Prediction Interval [PI] 476-1284) and 995 in Sud (90% PI 508-2043). The experience gained by this modeling effort shows that state-of-the-art computational modeling and data-assimilation methods can produce informative near real-time projections of cholera incidence. Collaboration among modelers and field epidemiologists is indispensable to gain fast access to field data and to translate model results into operational recommendations for emergency management during an outbreak. Future efforts should thus draw together multi-disciplinary teams to ensure model outputs are appropriately based, interpreted and communicated. PMID- 29768403 TI - High-dimensional single-cell phenotyping reveals extensive haploinsufficiency. AB - Haploinsufficiency, a dominant phenotype caused by a heterozygous loss-of function mutation, has been rarely observed. However, high-dimensional single cell phenotyping of yeast morphological characteristics revealed haploinsufficiency phenotypes for more than half of 1,112 essential genes under optimal growth conditions. Additionally, 40% of the essential genes with no obvious phenotype under optimal growth conditions displayed haploinsufficiency under severe growth conditions. Haploinsufficiency was detected more frequently in essential genes than in nonessential genes. Similar haploinsufficiency phenotypes were observed mostly in mutants with heterozygous deletion of functionally related genes, suggesting that haploinsufficiency phenotypes were caused by functional defects of the genes. A global view of the gene network was presented based on the similarities of the haploinsufficiency phenotypes. Our dataset contains rich information regarding essential gene functions, providing evidence that single-cell phenotyping is a powerful approach, even in the heterozygous condition, for analyzing complex biological systems. PMID- 29768402 TI - Condensin I protects meiotic cohesin from WAPL-1 mediated removal. AB - Condensin complexes are key determinants of higher-order chromatin structure and are required for mitotic and meiotic chromosome compaction and segregation. We identified a new role for condensin in the maintenance of sister chromatid cohesion during C. elegans meiosis. Using conventional and stimulated emission depletion (STED) microscopy we show that levels of chromosomally-bound cohesin were significantly reduced in dpy-28 mutants, which lack a subunit of condensin I. SYP-1, a component of the synaptonemal complex central region, was also diminished, but no decrease in the axial element protein HTP-3 was observed. Surprisingly, the two key meiotic cohesin complexes of C. elegans were both depleted from meiotic chromosomes following the loss of condensin I, and disrupting condensin I in cohesin mutants increased the frequency of detached sister chromatids. During mitosis and meiosis in many organisms, establishment of cohesion is antagonized by cohesin removal by Wapl, and we found that condensin I binds to C. elegans WAPL-1 and counteracts WAPL-1-dependent cohesin removal. Our data suggest that condensin I opposes WAPL-1 to promote stable binding of cohesin to meiotic chromosomes, thereby ensuring linkages between sister chromatids in early meiosis. PMID- 29768405 TI - Pathology and causes of death in stranded humpback whales (Megaptera novaeangliae) from Brazil. AB - This study describes the pathologic findings of 24 humpback whales (Megaptera novaeangliae) found stranded along the Brazilian coast from 2004 to 2016. Eighteen (75%) animals evaluated were found stranded alive. From these, 13 died naturally on shore and five were euthanized. Six died at sea and were washed ashore. Of the 24, 19 (79.2%) were calves, four (16.7%) were juveniles, and one (4.2%) was an adult. The most probable cause of stranding and/or death (CSD) was determined in 23/24 (95.8%) individuals. In calves, CSD included neonatal respiratory distress (13/19; 68.4%), infectious disease (septicemia, omphaloarteritis and urachocystitis; 3/19; 15.8%), trauma of unknown origin (2/19; 10.5%), and vehicular trauma (vessel strike; 1/19; 5.3%). In juveniles and adult individuals, CSD was: emaciation (2/5; 40%), sunlight-thermal burn shock (1/5; 20%); and discospondylitis (1/5; 20%). In one juvenile, the CSD was undetermined (1/5; 20%). This study integrates novel findings and published case reports to delineate the pathology of a South-western Atlantic population of humpback whales. This foundation will aid in the assessment of the population health and establish a baseline for development of conservation policies. PMID- 29768404 TI - Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis. AB - Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissue-specific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation but tightly associated with elongating axons of its partner MNs. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool. Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets, including the CM-innervating pool. We identify mesenchyme derived connective tissue (CT) as a cell type in which Fat1 activity is required for the non-cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types. PMID- 29768406 TI - Silencing of RpATG6 impaired the yolk accumulation and the biogenesis of the yolk organelles in the insect vector R. prolixus. AB - In oviparous animals, the egg yolk is synthesized by the mother in a major metabolic challenge, where the different yolk components are secreted to the hemolymph and delivered to the oocytes mostly by endocytosis. The yolk macromolecules are then stored in a wide range of endocytic-originated vesicles which are collectively referred to as yolk organelles and occupy most of the mature oocytes cytoplasm. After fertilization, the contents of these organelles are degraded in a regulated manner to supply the embryo cells with fundamental molecules for de novo synthesis. Yolk accumulation and its regulated degradation are therefore crucial for successful development, however, most of the molecular mechanisms involved in the biogenesis, sorting and degradation of targeted yolk organelles are still poorly understood. ATG6 is part of two PI3P-kinase complexes that can regulate the recruitment of the endocytic or the autophagy machineries. Here, we investigate the role of RpATG6 in the endocytosis of the yolk macromolecules and in the biogenesis of the yolk organelles in the insect vector Rhodnius prolixus. We found that vitellogenic females express high levels of RpATG6 in the ovaries, when compared to the levels detected in the midgut and fat body. RNAi silencing of RpATG6 resulted in yolk proteins accumulated in the vitellogenic hemolymph, as a consequence of poor uptake by the oocytes. Accordingly, the silenced oocytes are unviable, white (contrasting to the control pink oocytes), smaller (62% of the control oocyte volume) and accumulate only 40% of the yolk proteins, 80% of the TAG and 50% of the polymer polyphosphate quantified in control oocytes. The cortex of silenced oocytes present atypical smaller vesicles indicating that the yolk organelles were not properly formed and/or sorted, which was supported by the lack of endocytic vesicles near the plasma membrane of silenced oocytes as seen by TEM. Altogether, we found that RpATG6 is central for the mechanisms of yolk accumulation, emerging as an important target for further investigations on oogenesis and, therefore, reproduction of this vector. PMID- 29768407 TI - The Health-e Babies App for antenatal education: Feasibility for socially disadvantaged women. AB - BACKGROUND: The use of mobile technology such as phone applications (apps) has been proposed as an efficient means of providing health and clinical information in a variety of healthcare settings. We developed the Health-e Babies app as an Android smart phone application for pregnant women attending a tertiary hospital in a low socio-economic community, with the objective of providing health information about early pregnancy that would increase maternal confidence and reduce anxiety. Based on our earlier research, this form of health communication was viewed as a preferred source of information for women of reproductive age. However, the pilot study had a poor participation rate with 76% (n = 94) not completing the study requirements. These initial findings raised some very important issues in relation to the difficulties of engaging women with a pregnancy app. This paper analyses the characteristics of the participants who did not complete the study requirements in an attempt to identify potential barriers associated with the implementation of a pregnancy app. METHODS: This retrospective review of quantitative and qualitative data collected at the commencement of the Health-e Babies App trial, related to the participant's communication technology use, confidence in knowing where to seek help and mental health status, maternal-fetal attachment and parenting confidence. Engagement and use of the Health-e Babies App was measured by the completion of a questionnaire about the app and downloaded data from participant's phones. Mental health status, confidence and self-efficacy were measured by questionnaires. RESULTS: All women were similar in terms of age, race, marital status and level of education. Of the 94 women (76%) who did not complete the trial, they were significantly more anxious as indicated by State Trait Anxiety Inventory (p = 0.001 Student T-test) and more likely to be unemployed (50% vs 31%, p = 0.012 Student T-Test). CONCLUSION: This study provides important information about the challenges associated with the implementation of a pregnancy app in a socially disadvantaged community. The data suggests that factors including social and mental health issues, financial constraints and technological ability can affect women's engagement with a mobile phone app. PMID- 29768409 TI - Willingness to pay for health insurance in the informal sector of Sierra Leone. AB - PURPOSE: The objective of this project is to study the willingness to pay (WTP) for health insurance (HI) of individuals working in the informal sector in Sierra Leone, using a purposely-designed survey of a representative sample of this sector. METHODS: We elicit the WTP using the Double-Bounded Dichotomous Choice with Follow Up method. We also examine the factors that are positively and negatively associated with the likelihood of the respondents to answer affirmatively to joining a HI scheme and to paying three different possible premiums, to join the HI scheme. We additionally analyze the individual and household characteristics associated with the maximum amount the household is willing to pay to join the HI scheme. RESULTS: The results indicate that the average WTP for the HI is 20,237.16 SLL (3.6 USD) per adult but it ranges from about 14,000 SLL (2.5 USD) to about 35,000 SLL (6.2 USD) depending on region, occupation, household and respondent characteristics. The analysis of the maximum WTP indicates that living outside the Western region and working in farming instead of petty trade are associated with a decrease in the maximum premium respondents are WTP for the HI scheme. Instead, the maximum WTP is positively associated to being a driver or a biker; having secondary or tertiary education (as opposed to not having any); the number of pregnant women in the household; having a TV; and, having paid for the last medical requirement. CONCLUSIONS: In summary, the various analyses show that a premium for the HI package could be set at approximately 20,000 SLL (3.54 USD) but also that establishing a single premium for all individuals in the informal sector could be risky. The efficient functioning of a HI scheme relies on covering as much of the population as possible, in order to spread risks and make the scheme viable. The impact of the various population characteristics raises the issue of how to rate premiums. In other words, setting a premium that may be too high for a big proportion of the population could mean losing many potential enrollees and might have viability consequences for the operation of the scheme. PMID- 29768410 TI - Correction: U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line. AB - [This corrects the article DOI: 10.1371/journal.pgen.1000832.]. PMID- 29768408 TI - A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. AB - Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-gamma, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders. PMID- 29768413 TI - Wild boar mapping using population-density statistics: From polygons to high resolution raster maps. AB - The wild boar is an important crop raider as well as a reservoir and agent of spread of swine diseases. Due to increasing densities and expanding ranges worldwide, the related economic losses in livestock and agricultural sectors are significant and on the rise. Its management and control would strongly benefit from accurate and detailed spatial information on species distribution and abundance, which are often available only for small areas. Data are commonly available at aggregated administrative units with little or no information about the distribution of the species within the unit. In this paper, a four-step geostatistical downscaling approach is presented and used to disaggregate wild boar population density statistics from administrative units of different shape and size (polygons) to 5 km resolution raster maps by incorporating auxiliary fine scale environmental variables. 1) First a stratification method was used to define homogeneous bioclimatic regions for the analysis; 2) Under a geostatistical framework, the wild boar densities at administrative units, i.e. subnational areas, were decomposed into trend and residual components for each bioclimatic region. Quantitative relationships between wild boar data and environmental variables were estimated through multiple regression and used to derive trend components at 5 km spatial resolution. Next, the residual components (i.e., the differences between the trend components and the original wild boar data at administrative units) were downscaled at 5 km resolution using area-to point kriging. The trend and residual components obtained at 5 km resolution were finally added to generate fine scale wild boar estimates for each bioclimatic region. 3) These maps were then mosaicked to produce a final output map of predicted wild boar densities across most of Eurasia. 4) Model accuracy was assessed at each different step using input as well as independent data. We discuss advantages and limits of the method and its potential application in animal health. PMID- 29768411 TI - Cytoskeleton structure and total methylation of mouse cardiac and lung tissue during space flight. AB - The purpose of this work was to evaluate the protein and mRNA expression levels of multiple cytoskeletal proteins in the cardiac and lung tissue of mice that were euthanized onboard the United States Orbital Segment of the International Space Station 37 days after the start of the SpaceX-4 mission (September 2014, USA). The results showed no changes in the cytoskeletal protein content in the cardiac and lung tissue of the mice, but there were significant changes in the mRNA expression levels of the associated genes, which may be due to an increase in total genome methylation. The mRNA expression levels of DNA methylases, the cytosine demethylases Tet1 and Tet3, histone acetylase and histone deacetylase did not change, and the mRNA expression level of cytosine demethylase Tet2 was significantly decreased. PMID- 29768412 TI - Adverse events following single dose treatment of lymphatic filariasis: Observations from a review of the literature. AB - BACKGROUND: WHO's Global Programme to Eliminate Lymphatic Filariasis (LF) uses mass drug administration (MDA) of anthelmintic medications to interrupt LF transmission in endemic areas. Recently, a single dose combination of ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB) was shown to be markedly more effective than the standard two-drug regimens (DEC or IVM, plus ALB) for achieving long-term clearance of microfilaremia. OBJECTIVE AND METHODS: To provide context for the results of a large-scale, international safety trial of MDA using triple drug therapy, we searched Ovid Medline for studies published from 1985-2017 that reported adverse events (AEs) following treatment of LF with IVM, DEC, ALB, or any combination of these medications. Studies that reported AE rates by treatment group were included. FINDINGS: We reviewed 162 published manuscripts, 55 of which met inclusion criteria. Among these, 34 were clinic or hospital-based clinical trials, and 21 were community-based studies. Reported AE rates varied widely. The median AE rate following DEC or IVM treatment was greater than 60% among microfilaremic participants and less than 10% in persons without microfilaremia. The most common AEs reported were fever, headache, myalgia or arthralgia, fatigue, and malaise. INTERPRETATION: Mild to moderate systemic AEs related to death of microfilariae are common following LF treatment. Post-treatment AEs are transient and rarely severe or serious. Comparison of AE rates from different community studies is difficult due to inconsistent AE reporting, varied infection rates, and varied intensity of follow-up. A more uniform approach for assessing and reporting AEs in LF community treatment studies would be helpful. PMID- 29768414 TI - Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. AB - BACKGROUND: Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures. PATIENTS AND METHODS: In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded. RESULTS: Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy. CONCLUSION: Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique. PMID- 29768415 TI - Automated and real-time segmentation of suspicious breast masses using convolutional neural network. AB - In this work, a computer-aided tool for detection was developed to segment breast masses from clinical ultrasound (US) scans. The underlying Multi U-net algorithm is based on convolutional neural networks. Under the Mayo Clinic Institutional Review Board protocol, a prospective study of the automatic segmentation of suspicious breast masses was performed. The cohort consisted of 258 female patients who were clinically identified with suspicious breast masses and underwent clinical US scan and breast biopsy. The computer-aided detection tool effectively segmented the breast masses, achieving a mean Dice coefficient of 0.82, a true positive fraction (TPF) of 0.84, and a false positive fraction (FPF) of 0.01. By avoiding positioning of an initial seed, the algorithm is able to segment images in real time (13-55 ms per image), and can have potential clinical applications. The algorithm is at par with a conventional seeded algorithm, which had a mean Dice coefficient of 0.84 and performs significantly better (P< 0.0001) than the original U-net algorithm. PMID- 29768416 TI - Poverty dynamics, poverty thresholds and mortality: An age-stage Markovian model. AB - Recent studies have examined the risk of poverty throughout the life course, but few have considered how transitioning in and out of poverty shape the dynamic heterogeneity and mortality disparities of a cohort at each age. Here we use state-by-age modeling to capture individual heterogeneity in crossing one of three different poverty thresholds (defined as 1*, 2* or 3* the "official" poverty threshold) at each age. We examine age-specific state structure, the remaining life expectancy, its variance, and cohort simulations for those above and below each threshold. Survival and transitioning probabilities are statistically estimated by regression analyses of data from the Health and Retirement Survey RAND data-set, and the National Longitudinal Survey of Youth. Using the results of these regression analyses, we parameterize discrete state, discrete age matrix models. We found that individuals above all three thresholds have higher annual survival than those in poverty, especially for mid-ages to about age 80. The advantage is greatest when we classify individuals based on 1* the "official" poverty threshold. The greatest discrepancy in average remaining life expectancy and its variance between those above and in poverty occurs at mid ages for all three thresholds. And fewer individuals are in poverty between ages 40-60 for all three thresholds. Our findings are consistent with results based on other data sets, but also suggest that dynamic heterogeneity in poverty and the transience of the poverty state is associated with income-related mortality disparities (less transience, especially of those above poverty, more disparities). This paper applies the approach of age-by-stage matrix models to human demography and individual poverty dynamics. In so doing we extend the literature on individual poverty dynamics across the life course. PMID- 29768417 TI - What are the implications for practice that arise from studies of medication taking? A systematic review of qualitative research. AB - BACKGROUND: Despite several decades of evidence supporting the benefits of taking medications in various diseases and healthcare settings, a significant proportion of prescribed treatments are not taken. This review sought to synthesise qualitative research exploring experiences of medication taking around the world, and to determine whether there were consistent messages arising from these studies. METHODS AND FINDINGS: 5 databases (MEDLINE, PsycINFO, EMBASE, SCOPUS, CINAHL) were systematically searched to identify published research papers using qualitative methodologies, which explored medication-taking experiences in patients, citizens, carers, relatives and clinicians. Data were extracted independently by at least two clinician reviewers. Implications for practice from individual papers were charted and coded using thematic content analysis. These were then cross-tabulated with research paper categories to explore emergent patterns with particular implications for practice. 192 papers from 34 different countries were included in the review. Implications for practice fitted into 11 categories: increase family involvement, increase clinician involvement, promote personalised management, address practical barriers, provide ongoing support, promote self-management, adopt a patient-centred approach, improve patient education, address system barriers, increase access to non-prescribing clinicians and improve clinician training. These implications for practice were generally evenly spread across research paper categories. CONCLUSIONS: Implications for practice from the published qualitative literature exploring medication-taking are notably consistent across research methods, disease categories and geographical settings. More recent clinical trials of interventions to improve adherence have started to draw on these findings by focussing on improving clinical interactions and involving patients in healthcare decisions. Promoting patient education and self-management have been widely advocated, and improvements at a system level have been frequently cited in studies from developing countries and those relating to communicable diseases. Regardless of the setting, clinicians and policymakers around the world can focus efforts to improve medication-taking by considering a number of consistently emerging findings. PMID- 29768418 TI - OBGYN screening for environmental exposures: A call for action. AB - BACKGROUND: Prenatal exposures have known adverse effects on maternal and neonatal outcomes. Professional societies recommend routine screening for environmental, occupational, and dietary exposures to reduce exposures and their associated sequelae. OBJECTIVE: Our objective was to determine the frequency of environmental exposure screening by obstetricians and gynecologists (OBGYNs) at initial patient visits. STUDY DESIGN: Practicing OBGYNs were approached at the University of Colorado and by social media. The survey instrument queried demographics, environmental literacy, and screening practices. Statistical analysis was performed using Chi-square and two-sample t-test. RESULTS: We received 312 online survey responses (response rate of 12%). Responding OBGYNs were predominantly female (96%), board-certified (78%), generalists (65%) with a mean age of 37.1 years. Fewer than half of physicians screened for the following factors: occupational exposures, environmental chemicals, air pollution, pesticide use, personal care products, household cleaners, water source, use of plastics for food storage, and lead and mercury exposure. Eighty five percent of respondents reported that they did not feel comfortable obtaining an environmental history and 58% respondents reported that they performed no regular screening of environmental exposures. A higher frequency of screening was associated with > 4 years of practice (p = 0.001), and having read the environmental committee opinion (p = <0.001). CONCLUSION: The majority of OBGYNs did not incorporate screening for known environmental exposures into routine practice. Reading the environmental committee opinions was strongly and significantly associated with a higher rate of screening. Improving physician comfort in counseling patients may enhance screening for exposures that affect reproductive health. PMID- 29768421 TI - Theoretical analysis and design of hydro-hammer with a jet actuator: An engineering application to improve the penetration rate of directional well drilling in hard rock formations. AB - Rapid horizontal directional well drilling in hard or fractured formations requires efficient drilling technology. The penetration rate of conventional hard rock drilling technology in horizontal directional well excavations is relatively low, resulting in multiple overgrinding of drill cuttings in bottom boreholes. Conventional drilling techniques with reamer or diamond drill bit face difficulties due to the long construction periods, low penetration rates, and high engineering costs in the directional well drilling of hard rock. To improve the impact energy and penetration rate of directional well drilling in hard formations, a new drilling system with a percussive and rotary drilling technology has been proposed, and a hydro-hammer with a jet actuator has also been theoretically designed on the basis of the impulse hydro-turbine pressure model. In addition, the performance parameters of the hydro-hammer with a jet actuator have been numerically and experimentally analyzed, and the influence of impact stroke and pumped flow rate on the motion velocity and impact energy of the hydro-hammer has been obtained. Moreover, the designed hydro-hammer with a jet actuator has been applied to hard rock drilling in a trenchless drilling program. The motion velocity of the hydro-hammer ranges from 1.2 m/s to 3.19 m/s with diverse flow rates and impact strokes, and the motion frequency ranges from 10 Hz to 22 Hz. Moreover, the maximum impact energy of the hydro-hammer is 407 J, and the pumped flow rate is 2.3 m3/min. Thus, the average penetration rate of the optimized hydro-hammer improves by over 30% compared to conventional directional drilling in hard rock formations. PMID- 29768420 TI - Molecular phylogeny of Planaltina Bohlke (Characidae: Stevardiinae) and comments on the definition and geographic distribution of the genus, with description of a new species. AB - A molecular phylogeny of Planaltina, including the three previously described species and an undescribed species, is presented. The monophyly of the genus, included in Diapomini, is strongly supported. Its sister group, the remaining Diapomini, includes only species without modified caudal-fin squamation in the present analysis (species of Diapoma with caudal organs were not sampled). Creagrutus is sister to Planaltina plus remaining Diapomini instead of Planaltina being sister to Creagrutus plus Diapomini, as a previous analysis had suggested. Species of Planaltina form two clades: P. britskii plus the new species, with low support (< 50%); and P. myersi plus P. glandipedis, with higher support. Planaltina is rediagnosed from all Characidae based on the morphology of the caudal organ, the absence of a humeral spot and the presence of a complete lateral line. Comments on the caudal-fin squamation of Diapoma and Lepidocharax burnsi, on the type-series of L. burnsi and on the geographic distribution of Planaltina and Lepidocharax species are provided. Finally, a formal description of the aforementioned new species and a novel identification key to Planaltina are presented. PMID- 29768419 TI - A secreted Heat shock protein 90 of Trichomonas vaginalis. AB - Trichomonas vaginalis is a causative agent of Trichomoniasis, a leading non-viral sexually transmitted disease worldwide. In the current study, we show Heat shock protein 90 is essential for its growth. Upon genomic analysis of the parasite, it was found to possess seven ORFs which could potentially encode Hsp90 isoforms. We identified a cytosolic Hsp90 homolog, four homologs which can align to truncated cytosolic Hsp90 gene products along with two Grp94 homologs (ER isoform of Hsp90). However, both Grp94 orthologs lacked an ER retention motif. In cancer cells, it is very well established that Hsp90 is secreted and regulates key clients involved in metastases, migration, and invasion. Since Trichomonas Grp94 lacks ER retention motif, we examined the possibility of its secretion. By using cell biology and biochemical approaches we show that the Grp94 isoform of Hsp90 is secreted by the parasite by the classical ER-Golgi pathway. This is the first report of a genome encoded secreted Hsp90 in a clinically important parasitic protozoan. PMID- 29768422 TI - An endangered new species of seasonal killifish of the genus Austrolebias (Cyprinodontiformes: Aplocheiloidei) from the Bermejo river basin in the Western Chacoan Region. AB - Austrolebias wichi, new species, is herein described from seasonal ponds of the Bermejo river basin in the Western Chacoan district in northwestern Argentina. This species was found in a single pond, a paleochannel of the Bermejo River, which is seriously disturbed by soybean plantations surrounding it. Despite intensive sampling in the area, this species was only registered in this pond where it was relatively scarce. Therefore, we consider this species as critically endangered. This species is the sister species of A. patriciae in our phylogenetic analyses and is similar, in a general external aspect, to A. varzeae and A. carvalhoi. It can be distinguished among the species of Austrolebias by its unique color pattern in males. Additionally, from A. varzeae by presenting a supraorbital band equal or longer than the infraorbital band (vs. shorter) and from A. patriciae by the convex dorsal profile of head (vs. concave). Further diagnostic characters and additional comments on its ecology and reproduction are provided. PMID- 29768423 TI - Projecting shifts in thermal habitat for 686 species on the North American continental shelf. AB - Recent shifts in the geographic distribution of marine species have been linked to shifts in preferred thermal habitats. These shifts in distribution have already posed challenges for living marine resource management, and there is a strong need for projections of how species might be impacted by future changes in ocean temperatures during the 21st century. We modeled thermal habitat for 686 marine species in the Atlantic and Pacific oceans using long-term ecological survey data from the North American continental shelves. These habitat models were coupled to output from sixteen general circulation models that were run under high (RCP 8.5) and low (RCP 2.6) future greenhouse gas emission scenarios over the 21st century to produce 32 possible future outcomes for each species. The models generally agreed on the magnitude and direction of future shifts for some species (448 or 429 under RCP 8.5 and RCP 2.6, respectively), but strongly disagreed for other species (116 or 120 respectively). This allowed us to identify species with more or less robust predictions. Future shifts in species distributions were generally poleward and followed the coastline, but also varied among regions and species. Species from the U.S. and Canadian west coast including the Gulf of Alaska had the highest projected magnitude shifts in distribution, and many species shifted more than 1000 km under the high greenhouse gas emissions scenario. Following a strong mitigation scenario consistent with the Paris Agreement would likely produce substantially smaller shifts and less disruption to marine management efforts. Our projections offer an important tool for identifying species, fisheries, and management efforts that are particularly vulnerable to climate change impacts. PMID- 29768424 TI - Deterred but not preferred: Predation by native whelk Reishia clavigera on invasive bivalves. AB - This study tested the potential bio-control role of the common native predatory whelk Reishia clavigera on the invasive bivalves Xenostrobus securis and Mytilopsis sallei and the native Brachidontes variabilis in Hong Kong. Predation experiments were conducted in the laboratory under salinity levels of 220/00 and 320/00, as well as under field conditions. The results indicate that the invasive bivalves are more vulnerable to predation than the native bivalve in environments with high salinity, whereas environments with moderately low salinity (220/00) may reduce predation. Because R. clavigera did not show clear prey preference, the low survival of the invasive species might be due to a lack of effective anti predatory defenses under experimental conditions. These findings could explain the high abundance of the invasive bivalves in disturbed environments in Hong Kong where predation appears to be lower. PMID- 29768425 TI - Defining health standards through economic optimisation: The example of colostrum management in beef and dairy production. AB - There is extensive literature addressing acceptable practices of colostrum distribution to new-born calves; however, no economic analyses are available concerning the profitability of this practice. Moreover, the health standards associated with colostrum management have been defined through the observation of reference farms without explicit reference to economic assessments. The objective of the current study was to evaluate the profitability of farm colostrum management and to define the optimal economic situations for given livestock systems and farm situations. The herd-level net value was calculated using the value of calf products, the cost of passive transfer failure and the cost of prevention. This value was determined for various beef and dairy scenarios and the various time periods spent managing colostrum. The maximal net values defined the optimal economic situations and enabled the determination of the optimal times for colostrum management and respective health standards (i.e., the prevalence of disorders at optimum). The results showed that the optimal time farmers should spend on colostrum management is approximately 15 min per calf. Furthermore, farmers should err on the side of spending too much time (> 15 min) on colostrum management rather than not enough, unless the cost of labour is high. This is all the more true that potential long term consequences of passive transfer failure on milk yields were not accounted for here due to scarcity of data, leading to consider this time threshold (15 min) as a minimal recommendation. This potential underestimation may arise from the greater nutrient content and bioactive compounds identified in colostrum although the passive immune transfer is here defined through immunoglobulins only. The present results show that for small farms that cannot hire colostrum managers, this work can be performed by the farmer after subcontracting other tasks. Moreover, the method proposed here-the definition of health standards through economic optimisation-is a promising approach to analysing health conventions in the cattle industry. PMID- 29768427 TI - Differential effects of TNF-alpha and IL-1beta on the control of metal metabolism and cadmium-induced cell death in chronic inflammation. AB - OBJECTIVE: Interleukin-1-beta (IL-1beta) and tumour necrosis factor-alpha (TNF alpha) are both monocyte-derived cytokines. Both cytokines have been previously described to exert a role in rheumatoid arthritis (RA) pathogenesis synergizing with other pro-inflammatory mediators, such as interleukin-17 (IL-17) on target cells, for the perpetuation of the inflammatory response (e.g. IL-6 production). In the context of experimental RA, Cd addition has an anti-proliferative and anti inflammatory effect when associated to IL-17/TNF-alpha stimulation, due to its accumulation in synoviocytes. The aim of this work was to evaluate if IL-1beta interaction with IL-17 also contributes to metal-import mechanisms and its effects on cell viability and inflammation. METHODS: IL-17 and IL-1beta were added to synoviocyte cultures with or without exogenous Cd addition (0.1 ppm, 0.89 MUM). IL-6 production, Cd import kinetics, gene expression of ZIP-8 importer and metallothioneins (MTs) and cell viability were evaluated by ELISA, inductively-coupled mass spectrometry (ICP-MS), q-RT-PCR and viability assays (neutral red and annexin V) respectively. RESULTS: IL-17 and IL-1beta acted in synergy on synoviocytes to induce IL-6 production similarly to the IL-17/TNF alpha combination. Metal import was lower with IL17/ IL-1beta in comparison to IL 17/TNF-alpha exposed-synoviocytes, as the expression of ZIP-8 and MT-1F was less induced. Monocyte and PBMCs exposure to Cd resulted in a reduced production of IL 1beta and an increased production of TNF-alpha and this result was confirmed in co-cultures of synoviocytes and PBMCs. The IL-17/IL-1beta combination with Cd slightly reduced cell viability in comparison to the IL-17/TNF-alpha combination and resulted in a strong induction of IL-6 production. CONCLUSION: IL-17/TNF alpha combination but not IL-17/IL-1beta combination mainly drives the accumulation of Cd in synoviocytes and its effects on cell viability and inflammation. PMID- 29768426 TI - The Ryerson Audio-Visual Database of Emotional Speech and Song (RAVDESS): A dynamic, multimodal set of facial and vocal expressions in North American English. AB - The RAVDESS is a validated multimodal database of emotional speech and song. The database is gender balanced consisting of 24 professional actors, vocalizing lexically-matched statements in a neutral North American accent. Speech includes calm, happy, sad, angry, fearful, surprise, and disgust expressions, and song contains calm, happy, sad, angry, and fearful emotions. Each expression is produced at two levels of emotional intensity, with an additional neutral expression. All conditions are available in face-and-voice, face-only, and voice only formats. The set of 7356 recordings were each rated 10 times on emotional validity, intensity, and genuineness. Ratings were provided by 247 individuals who were characteristic of untrained research participants from North America. A further set of 72 participants provided test-retest data. High levels of emotional validity and test-retest intrarater reliability were reported. Corrected accuracy and composite "goodness" measures are presented to assist researchers in the selection of stimuli. All recordings are made freely available under a Creative Commons license and can be downloaded at https://doi.org/10.5281/zenodo.1188976. PMID- 29768428 TI - Socio-environmental factors and diarrheal diseases in under five-year old children in the state of Tocantins, Brazil. AB - BACKGROUND: Diarrhea is a waterborne disease that affects children, especially those under 5 years of age. The objective of this study was to identify the spatial patterns of distribution of diarrheal disease in under 5-year-old children in the State of Tocantins, Brazil, from 2008 to 2013. METHODS: Geoprocessing tools were used to carry out an epidemiological study, to prepare thematic maps in the TerraView 4.2.2 software based on secondary data. General indicators of the disease, presence of spatial dependence through the Global Moran's Index (I) and the Spatial Association Index (LISA) were described. RESULTS: There were 3,015 cases of under 5-year-old children hospitalized for diarrhea, with an average annual rate (AAR) of 4.10/1,000 inhabitants (inhab.). Among the main characteristics were: increasing rates in under 1-year-old children (6.16 to 9.66/1,000 inhabitants); children aged 1 to 4 full years (63%); males (55%); 8 deaths of under one-year-old children (75%); county of Araguaina (67%); incidence in the county of Nazare (63.97/1,000 inhab.); prevalence and incidence in the Araguaina microregion (45%, AAR 9.38/1,000 inhab.). The presence of a cluster with spatial autocorrelation was found in the Araguaina microregion, which was statistically significant (I = 0.11, p-value < 0.03), with priority of intervention (Moran Map). CONCLUSIONS: There was an increase in the number of hospitalizations for diarrhea in under 5-year-old children in the state of Tocantins. The spatial analysis identified clusters of priority areas for measures of maintenance and control of diarrheal diseases. PMID- 29768429 TI - Virtual reality method to analyze visual recognition in mice. AB - Behavioral tests have been extensively used to measure the visual function of mice. To determine how precisely mice perceive certain visual cues, it is necessary to have a quantifiable measurement of their behavioral responses. Recently, virtual reality tests have been utilized for a variety of purposes, from analyzing hippocampal cell functionality to identifying visual acuity. Despite the widespread use of these tests, the training requirement for the recognition of a variety of different visual targets, and the performance of the behavioral tests has not been thoroughly characterized. We have developed a virtual reality behavior testing approach that can essay a variety of different aspects of visual perception, including color/luminance and motion detection. When tested for the ability to detect a color/luminance target or a moving target, mice were able to discern the designated target after 9 days of continuous training. However, the quality of their performance is significantly affected by the complexity of the visual target, and their ability to navigate on a spherical treadmill. Importantly, mice retained memory of their visual recognition for at least three weeks after the end of their behavioral training. PMID- 29768430 TI - A qualitative study of implementation and adaptations to Progressive Tinnitus Management (PTM) delivery. AB - BACKGROUND: Tinnitus is a common condition, especially prevalent among military Veterans. Progressive Tinnitus Management (PTM) is an interdisciplinary, structured, stepped-care approach to providing clinical services, including teaching coping skills, to people bothered by tinnitus. PTM has been shown to be effective at reducing functional distress, but implementation of the intervention outside of a research setting has not been studied, even though dissemination is underway within the Veterans Health Administration (VHA) system in the United States. This study was designed to address a gap in knowledge of PTM clinical implementation to date, with a focus on factors facilitating or hindering implementation in VHA audiology and mental health clinic contexts, and whether implementing sites had developed intervention adaptations. METHODS: Qualitative interviews were conducted with 21 audiology and mental health clinicians and service chiefs across a regional service network. Interviews were transcribed and coded using a hybrid inductive-deductive analytic approach guided by existing implementation research frameworks and then iteratively developed for emergent themes. RESULTS: PTM prioritization was rare overall, with providers across disciplines challenged by lack of capacity for implementation, but with differences by discipline in challenges to prioritization. Where PTM was prioritized and delivered, this was facilitated by perception of unique value, provider's own experience of tinnitus, observation/experience with PTM delivery, intervention fit with provider's skills, and an environment with supportive leadership and adaptive reserve. PTM was frequently adapted to local contexts to address delivery challenges and diversify patient options. Adaptations included shifting from group to individual formats, reducing or combining sessions, and employing novel therapeutic approaches. CONCLUSIONS: Existing adaptations highlight the need to better understand mechanisms underlying PTM's effectiveness, and research on the impact of adaptations on patient outcomes is an important next step. Prioritization of PTM is a key barrier to the scale up and spread of this evidence-based intervention. Developing clinician champions may facilitate dissemination, especially if accompanied by signals of systemic prioritization. Novel approaches exposing clinicians and administrators to PTM may identify and develop clinical champions. Acknowledging the potential for PTM adaptations may make delivery more feasible in the context of existing system constraints and priorities. PMID- 29768431 TI - Loss of HtrA1 serine protease induces synthetic modulation of aortic vascular smooth muscle cells. AB - Homozygous mutations of human HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HtrA1-/ mice were examined for arterial abnormalities. Although their cerebral arteries were normal, the thoracic aorta was affected in HtrA1-/- mice. The number of vascular smooth muscle cells (VSMCs) in the aorta was increased in HtrA1-/- mice of 40 weeks or younger, but decreased thereafter. The cross-sectional area of the aorta was increased in HtrA1-/- mice of 40 weeks or older. Aortic VSMCs isolated from HtrA1-/- mice rapidly proliferated and migrated, produced high MMP9 activity, and were prone to oxidative stress-induced cell death. HtrA1-/- VSMCs expressed less smooth muscle alpha-actin, and more vimentin and osteopontin, and responded to PDGF-BB more strongly than wild type VSMCs, indicating that HtrA1-/- VSMCs were in the synthetic phenotype. The elastic lamina was disrupted, and collagens were decreased in the aortic media. Calponin in the media was decreased, whereas vimentin and osteopontin were increased, suggesting a synthetic shift of VSMCs in vivo. Loss of HtrA1 therefore skews VSMCs toward the synthetic phenotype, induces MMP9 expression, and expedites cell death. We propose that the synthetic modulation is the primary event that leads to the vascular abnormalities caused by HtrA1 deficiency. PMID- 29768432 TI - The ecology of the Drosophila-yeast mutualism in wineries. AB - The fruit fly, Drosophila melanogaster, is preferentially found on fermenting fruits. The yeasts that dominate the microbial communities of these substrates are the primary food source for developing D. melanogaster larvae, and adult flies manifest a strong olfactory system-mediated attraction for the volatile compounds produced by these yeasts during fermentation. Although most work on this interaction has focused on the standard laboratory yeast Saccharomyces cerevisiae, a wide variety of other yeasts naturally ferment fallen fruit. Here we address the open question of whether D. melanogaster preferentially associates with distinct yeasts in different, closely-related environments. We characterized the spatial and temporal dynamics of Drosophila-associated fungi in Northern California wineries that use organic grapes and natural fermentation using high throughput, short-amplicon sequencing. We found that there is nonrandom structure in the fungal communities that are vectored by flies both between and within vineyards. Within wineries, the fungal communities associated with flies in cellars, fermentation tanks, and pomace piles are distinguished by varying abundances of a small number of yeast species. To investigate the origins of this structure, we assayed Drosophila attraction to, oviposition on, larval development in, and longevity when consuming the yeasts that distinguish vineyard microhabitats from each other. We found that wild fly lines did not respond differentially to the yeast species that distinguish winery habitats in habitat specific manner. Instead, this subset of yeast shares traits that make them attractive to and ensure their close association with Drosophila. PMID- 29768433 TI - The long-term outcomes of epilepsy surgery. AB - OBJECTIVE: Despite modern anti-epileptic drug treatment, approximately 30% of epilepsies remain medically refractory and for these patients, epilepsy surgery may be a treatment option. There have been numerous studies demonstrating good outcome of epilepsy surgery in the short to median term however, there are a limited number of studies looking at the long-term outcomes. The aim of this study was to ascertain the long-term outcome of resective epilepsy surgery in a large neurosurgery hospital in the U.K. METHODS: This a retrospective analysis of prospectively collected data. We used the 2001 International League Against Epilepsy (ILAE) classification system to classify seizure freedom and Kaplan Meier survival analysis to estimate the probability of seizure freedom. RESULTS: We included 284 patients who underwent epilepsy surgery (178 anterior temporal lobe resections, 37 selective amygdalohippocampectomies, 33 temporal lesionectomies, 36 extratemporal lesionectomies), and had a prospective median follow-up of 5 years (range 1-27). Kaplan-Meier estimates showed that 47% (95% CI 40-58) remained seizure free (apart from simple partial seizures) at 5 years and 38% (95% CI 31-45) at 10 years after surgery. 74% (95% CI 69-80) had a greater than 50% seizure reduction at 5 years and 70% (95% CI 64-77) at 10 years. Patients who had an amygdalohippocampectomy were more likely to have seizure recurrence than patients who had an anterior temporal lobe resection (p = 0.006) and temporal lesionectomy (p = 0.029). There was no significant difference between extra temporal and temporal lesionectomies. Hippocampal sclerosis was associated with a good outcome but declined in relative frequency over the years. CONCLUSION: The vast majority of patients who were not seizure free experienced at least a substantial and long-lasting reduction in seizure frequency. A positive long-term outcome after epilepsy surgery is possible for many patients and especially those with hippocampal sclerosis or those who had anterior temporal lobe resections. PMID- 29768434 TI - Plasma membrane insertion of KCa2.3 (SK3) is dependent upon the SNARE proteins, syntaxin-4 and SNAP23. AB - We previously demonstrated endocytosis of KCa2.3 is caveolin-1-, dynamin II- and Rab5-dependent. KCa2.3 then enters Rab35/EPI64C- and RME-1-containing recycling endosomes and is returned to the plasma membrane (PM). Herein, we report on the mechanism by which KCa2.3 is inserted into the PM during recycling and following exit from the Golgi. We demonstrate KCa2.3 colocalizes with SNAP-23 and Syntaxin 4 in the PM of HEK and endothelial cells by confocal immunofluorescence microscopy. We further show KCa2.3 can be co-immunoprecipitated with SNAP-23 and Syntaxin-4. Overexpression of either Syntaxin-4 or SNAP-23 increased PM expression of KCa2.3, whereas shRNA-mediated knockdown of these SNARE proteins significantly decreased PM KCa2.3 expression, as assessed by cell surface biotinylation. Whole-cell patch clamp studies confirmed knockdown of SNAP-23 significantly decreased the apamin sensitive, KCa2.3 current. Using standard biotinylation/stripping methods, we demonstrate shRNA mediated knockdown of SNAP 23 inhibits recycling of KCa2.3 following endocytosis, whereas scrambled shRNA had no effect. Finally, using biotin ligase acceptor peptide (BLAP)-tagged KCa2.3, coupled with ER-resident biotin ligase (BirA), channels could be biotinylated in the ER after which we evaluated their rate of insertion into the PM following Golgi exit. We demonstrate knockdown of SNAP-23 significantly slows the rate of Golgi to PM delivery of KCa2.3. The inhibition of both recycling and PM delivery of newly synthesized KCa2.3 channels likely accounts for the decreased PM expression observed following knockdown of these SNARE proteins. In total, our results suggest insertion of KCa2.3 into the PM depends upon the SNARE proteins, Syntaxin-4 and SNAP-23. PMID- 29768435 TI - Tuna labels matter in Europe: Mislabelling rates in different tuna products. AB - Tuna fisheries and processing represent economic activities of paramount importance around the world. Most of these products are traded for human consumption and in general are highly demanded commodities. However, not all tuna products achieve the same market price, some consumers are willing to pay a huge amount of money for certain species (i.e. Japanese market for Bluefin tuna) while other species are rather affordable (i.e. Skipjack tuna), therefore mislabelling has been observed frequently. We collected and analysed 545 tuna samples in six European countries, including fresh, frozen and canned products, and we have investigated whether or not these products were correctly labelled under European and national legislations. We found an overall mislabelling rate of 6.79%; in particular, 6.70% of the fresh and frozen tuna products and 7.84% of canned tuna were mislabelled, and only in the case of fresh and frozen tuna samples significant differences among countries were found. Mislabelling rates for Atlantic Bluefin tuna labelled products were very high, ranging from 50 up to 100%. In general, mislabelling was higher when specific names were included in the labels. The "tuna" umbrella term is a very popular one with consumers, but also one that remains vulnerable to ambiguity, hampering efforts towards market transparency and with potential negative consequences to the adequate management of tuna species stocks. PMID- 29768436 TI - The effectiveness of various computer-based interventions for patients with chronic pain or functional somatic syndromes: A systematic review and meta analysis. AB - Computer-based interventions target improvement of physical and emotional functioning in patients with chronic pain and functional somatic syndromes. However, it is unclear to what extent which interventions work and for whom. This systematic review and meta-analysis (registered at PROSPERO, 2016: CRD42016050839) assesses efficacy relative to passive and active control conditions, and explores patient and intervention factors. Controlled studies were identified from MEDLINE, EMBASE, PsychInfo, Web of Science, and Cochrane Library. Pooled standardized mean differences by comparison type, and somatic symptom, health-related quality of life, functional interference, catastrophizing, and depression outcomes were calculated at post-treatment and at 6 or more months follow-up. Risk of bias was assessed. Sub-group analyses were performed by patient and intervention characteristics when heterogeneous outcomes were observed. Maximally, 30 out of 46 eligible studies and 3,387 participants were included per meta-analysis. Mostly, internet-based cognitive behavioral therapies were identified. Significantly higher patient reported outcomes were found in comparisons with passive control groups (standardized mean differences ranged between -.41 and -.18), but not in comparisons with active control groups (SMD = -.26 - -.14). For some outcomes, significant heterogeneity related to patient and intervention characteristics. To conclude, there is a minority of good quality evidence for small positive average effects of computer-based (cognitive) behavior change interventions, similar to traditional modes. These effects may be sustainable. Indications were found as of which interventions work better or more consistently across outcomes for which patients. Future process analyses are recommended in the aim of better understanding individual chances of clinically relevant outcomes. PMID- 29768438 TI - Survival in patients on hemodialysis: Effect of gender according to body mass index and creatinine. AB - BACKGROUND: The association of a higher body mass index (BMI) with better survival is a well-known "obesity paradox" in patients on hemodialysis (HD). However, men and women have different body compositions, which could impact the effect of BMI on mortality. We investigated the effect of gender on the obesity mortality relationship in Korean patients on HD. METHODS: This study included 2,833 maintenance patients on HD from a multicenter prospective cohort study in Korea (NCT00931970). The relationship between categorized BMI and gender-specific mortality was evaluated by an adjusted Cox proportional hazard model with restricted cubic spline analyses and the Competing risk analysis. We also investigated the effect of changes in BMI over 12 months and serum creatinine level on survival in male and female patients on HD. RESULTS: The mean BMI was 22.6 +/- 3.3 kg/m2 and the mean follow up duration was 24.2 +/- 3.4 months. The patients with the highest quintile of BMI (>=25.1 kg/m2) showed lower mortality (subdistributional hazard ratio [SHR] = 0.63, 95% confidence interval [CI] = 0.43 0.93, P = 0.019) compared with those with the reference BMI quintile. When analyzed by gender, male patients with a BMI over 25.1 kg/m2 had lower mortality risk (HR = 0.43, 95% CI = 0.25-0.75, P = 0.003); however, no significant difference was found in female patients. Increased BMI after 12 months and high serum creatinine were associated with better survival only in male patients on HD. CONCLUSIONS: BMI could be used as a risk factor for mortality in male patients on HD. However, the mortality of female patients on HD was not related with baseline and follow-up BMI. This suggests that BMI is a good surrogate marker of lean body composition, especially in male patients on HD. PMID- 29768437 TI - Oral health status in historic population: Macroscopic and metagenomic evidence. AB - Recent developments in High-Throughput DNA sequencing (HTS) technologies and ancient DNA (aDNA) research have opened access to the characterization of the microbial communities within past populations. Most studies have, however, relied on the analysis of dental calculus as one particular material type particularly prone to the molecular preservation of ancient microbial biofilms and potential of entire teeth for microbial characterization, both of healthy communities and pathogens in ancient individuals, remains overlooked. In this study, we used shotgun sequencing to characterize the bacterial composition from historical subjects showing macroscopic evidence of oral pathologies. We first carried out a macroscopic analysis aimed at identifying carious or periodontal diseases in subjects belonging to a French rural population of the 18th century AD. We next examined radiographically six subjects showing specific, characteristic dental pathologies and applied HTS shotgun sequencing to characterize the microbial communities present in and on the dental material. The presence of Streptococcus mutans and also Rothia dentocariosa, Actinomyces viscosus, Porphyromonas gingivalis, Tannerella forsythia, Pseudoramibacter alactolyticus, Olsenella uli and Parvimonas micra was confirmed through the presence of typical signatures of post-mortem DNA damage at an average depth-of-coverage ranging from 0.5 to 7X, with a minimum of 35% (from 35 to 93%) of the positions in the genome covered at least once. Each sampled tooth showed a specific bacterial signature associated with carious or periodontal pathologies. This work demonstrates that from a healthy independent tooth, without visible macroscopic pathology, we can identify a signature of specific pathogens and deduce the oral health status of an individual. PMID- 29768439 TI - Earliest evidence for equid bit wear in the ancient Near East: The "ass" from Early Bronze Age Tell es-Safi/Gath, Israel. AB - Analysis of a sacrificed and interred domestic donkey from an Early Bronze Age (EB) IIIB (c. 2800-2600 BCE) domestic residential neighborhood at Tell es Safi/Gath, Israel, indicate the presence of bit wear on the Lower Premolar 2 (LPM2). This is the earliest evidence for the use of a bit among early domestic equids, and in particular donkeys, in the Near East. The mesial enamel surfaces on both the right and left LPM2 of the particular donkey in question are slightly worn in a fashion that suggests that a dental bit (metal, bone, wood, etc.) was used to control the animal. Given the secure chronological context of the burial (beneath the floor of an EB IIIB house), it is suggested that this animal provides the earliest evidence for the use of a bit on an early domestic equid from the Near East. PMID- 29768441 TI - Factors influencing patients' satisfaction at different levels of health facilities in Bangladesh: Results from patient exit interviews. AB - There is a paucity in current literature about the level of patients' satisfaction and factors influencing it in Bangladesh health system. We aimed to measure the level of patients' satisfaction across different types and levels of healthcare facilities and to determine which factors influence this satisfaction level. A patient exit interview was carried out among 2207 patients attending selected health facilities in two administrative divisions of Bangladesh, namely Rajshahi and Sylhet. Information on healthcare experience and satisfaction with received care was collected through an electronic structured questionnaire. Information about 'overall satisfaction with healthcare' was collected on a 10 point scale and then dichotomized based on the median-split. Binomial logistic regressions, both simple and multivariable, were conducted to identify which factors contribute significantly to patients' satisfaction. We found that 63.2% of the participants were satisfied with the healthcare service they received. Patients attending the private facilities had the highest level of satisfaction (i.e. 73%) and patients attending the primary care facilities had the lowest level of satisfaction (i.e. 52%). Factors like convenient opening hours, asking related questions to the providers, facility cleanliness and privacy settings were significantly associated with patients' satisfaction. Being satisfied with facility cleanliness (multivariable OR 4.30; 95% CI: 3.29-5.62) and privacy settings (multivariable OR 1.68; 95% CI: 1.28-2.21) were the strongest predictors of patients' satisfaction. In conclusion, a significant portion of the patients in Bangladesh are not satisfied with their received care. Patients' satisfaction can be increased by focusing on improving facility cleanliness, privacy settings and providers' interpersonal skills. PMID- 29768440 TI - Transcriptome analysis reveals a stress response of Shewanella oneidensis deprived of background levels of ionizing radiation. AB - Natural ionizing background radiation has exerted a constant pressure on organisms since the first forms of life appeared on Earth, so that cells have developed molecular mechanisms to avoid or repair damages caused directly by radiation or indirectly by radiation-induced reactive oxygen species (ROS). In the present study, we investigated the transcriptional effect of depriving Shewanella oneidensis cultures of background levels of radiation by growing the cells in a mine 655 m underground, thus reducing the dose rate from 72.1 to 0.9 nGy h-1 from control to treatment, respectively. RNASeq transcriptome analysis showed the differential expression of 4.6 and 7.6% of the S. oneidensis genome during early- and late-exponential phases of growth, respectively. The greatest change observed in the treatment was the downregulation of ribosomal proteins (21% of all annotated ribosomal protein genes during early- and 14% during late exponential) and tRNA genes (14% of all annotated tRNA genes in early exponential), indicating a marked decrease in protein translation. Other significant changes were the upregulation of membrane transporters, implying an increase in the traffic of substrates across the cell membrane, as well as the up and downregulation of genes related to respiration, which could be interpreted as a response to insufficient oxidants in the cells. In other reports, there is evidence in multiple species that some ROS not just lead to oxidative stress, but act as signaling molecules to control cellular metabolism at the transcriptional level. Consistent with these reports, several genes involved in the metabolism of carbon and biosynthesis of amino acids were also regulated, lending support to the idea of a wide metabolic response. Our results indicate that S. oneidensis is sensitive to the withdrawal of background levels of ionizing radiation and suggest that a transcriptional response is required to maintain homeostasis and retain normal growth. PMID- 29768442 TI - Genetic variation in the CLOCK gene is associated with idiopathic recurrent spontaneous abortion. AB - Physiological studies in animals and human support an important role of circadian system in reproduction. The aim of this study was to investigate the potential association of CLOCK gene polymorphisms with idiopathic recurrent spontaneous abortion (IRSA). We performed a case-control study. The study group consisted of 268 women with a history of three or more idiopathic recurrent spontaneous abortions and 284 women with at least two live births and no history of pathologic pregnancies all from Slovenia and Serbia. Two SNPs in the CLOCK gene were chosen and genotyped. The results showed a statistically significant difference in genotype distribution between the two groups in the CLOCK gene for rs6850524 and rs11932595. Our analysis showed that G allele under dominant model (GG+GC/CC) for rs6850524 (p = 2?10-4, OR = 2.28, 95%CI = 1.46-3.56) as well as G allele under dominant model (GA+AA/AA) for rs11932595 (p = 0.04, OR = 1.47, 95%CI = 1.01-2.04) might be risk factors against IRSA. Our data suggest that genetic variability in the CLOCK gene is associated with IRSA warranting further confirmation and mechanistic investigations. PMID- 29768443 TI - Use of existing hydrographic infrastructure to forecast the environmental spawning conditions for Eastern Baltic cod. AB - The semi-enclosed nature and estuarine characteristics, together with its strongly alternating bathymetry, make the Baltic Sea prone to much stronger interannual variations in the abiotic environment, than other spawning habitats of Atlantic cod (Gadus morhua). Processes determining salinity and oxygen conditions in the basins are influenced both by long term gradual climate change, e.g. global warming, but also by short-term meteorological variations and events. Specifically one main factor influencing cod spawning conditions, the advection of highly saline and well-oxygenated water masses from the North Sea, is observed in irregular frequencies and causes strong interannual variations in stock productivity. This study investigates the possibility to use the available hydrographic process knowledge to predict the annual spawning conditions for Eastern Baltic cod in its most important spawning ground, the Bornholm Basin, only by salinity measurements from a specific location in the western Baltic. Such a prediction could serve as an environmental early warning indicator to inform stock assessment and management. Here we used a hydrodynamic model to hindcast hydrographic property fields for the last 40+ years. High and significant correlations were found for months early in the year between the 33m salinity level in the Arkona Basin and the oxygen-dependent cod spawning environment in the Bornholm Basin. Direct prediction of the Eastern Baltic cod egg survival in the Bornholm Basin based on salinity values in the Arkona Basin at the 33 m depth level is shown to be possible for eggs spawned by mid-age and young females, which currently predominate the stock structure. We recommend to routinely perform short-term predictions of the Eastern Baltic cod spawning environment, in order to generate environmental information highly relevant for stock dynamics. Our statistical approach offers the opportunity to make best use of permanently existing infrastructure in the western Baltic to timely provide scientific knowledge on the spawning conditions of Eastern Baltic cod. Furthermore it could be a tool to assist ecosystem-based fisheries management with a cost-effective implementation by including the short term predictions as a simple indicator in the annual assessments. PMID- 29768445 TI - Nogo receptor 1 is expressed by nearly all retinal ganglion cells. AB - A variety of conditions ranging from glaucoma to blunt force trauma lead to optic nerve atrophy. Identifying signaling pathways for stimulating axon growth in the optic nerve may lead to treatments for these pathologies. Inhibiting signaling by the nogo-66 receptor 1 (NgR1) promotes the re-extension of axons following a crush injury to the optic nerve, and while NgR1 mRNA and protein expression are observed in the retinal ganglion cell (RGC) layer and inner nuclear layer, which retinal cell types express NgR1 remains unknown. Here we determine the expression pattern of NgR1 in the mouse retina by co-labeling neurons with characterized markers of specific retinal neurons together with antibodies specific for NgR1 or Green Fluorescent Protein expressed under control of the ngr1 promoter. We demonstrate that more than 99% of RGCs express NgR1. Thus, inhibiting NgR1 function may ubiquitously promote the regeneration of axons by RGCs. These results provide additional support for the therapeutic potential of NgR1 signaling in reversing optic nerve atrophy. PMID- 29768444 TI - Ensemble methods for stochastic networks with special reference to the biological clock of Neurospora crassa. AB - A major challenge in systems biology is to infer the parameters of regulatory networks that operate in a noisy environment, such as in a single cell. In a stochastic regime it is hard to distinguish noise from the real signal and to infer the noise contribution to the dynamical behavior. When the genetic network displays oscillatory dynamics, it is even harder to infer the parameters that produce the oscillations. To address this issue we introduce a new estimation method built on a combination of stochastic simulations, mass action kinetics and ensemble network simulations in which we match the average periodogram and phase of the model to that of the data. The method is relatively fast (compared to Metropolis-Hastings Monte Carlo Methods), easy to parallelize, applicable to large oscillatory networks and large (~2000 cells) single cell expression data sets, and it quantifies the noise impact on the observed dynamics. Standard errors of estimated rate coefficients are typically two orders of magnitude smaller than the mean from single cell experiments with on the order of ~1000 cells. We also provide a method to assess the goodness of fit of the stochastic network using the Hilbert phase of single cells. An analysis of phase departures from the null model with no communication between cells is consistent with a hypothesis of Stochastic Resonance describing single cell oscillators. Stochastic Resonance provides a physical mechanism whereby intracellular noise plays a positive role in establishing oscillatory behavior, but may require model parameters, such as rate coefficients, that differ substantially from those extracted at the macroscopic level from measurements on populations of millions of communicating, synchronized cells. PMID- 29768446 TI - Inhibitory effect of K+ ions and influence of other ions and osmolality on the spermatozoa motility of European burbot (Lota lota L.). AB - BACKGROUND: In fish with external fertilization, two main start-up mechanisms of the path that blocks or activates the spermatozoan motility apparatus are known. The main factor managing the path is osmolality or potassium ion. In burbot from the European and North American population, contradictory findings regarding the factors influencing the onset of spermatozoa motility were reported. The objective of the current study was to determine the effect of potassium and osmolality on the spermatozoa activation of European burbot, Lota lota (Actinopterygii, Gadiformes, Lotidae). Moreover, the influence of pH, as well as sodium ion concentrations on spermatozoa motility was investigated. Seven parameters characterising motility were traced by means of computer-assisted sperm analysis (CASA). PRINCIPAL FINDINGS: The spermatozoa of European burbot are K+ ion-sensitive. A 6-mM KCl solution significantly decreased motility, and above 12-mM (50 mOsm kg-1) totally ceased spermatozoa movement. Sucrose and Na+ solutions inhibited spermatozoa movement only at concentrations > 450-480 mOsm kg 1. Greater differences in the percentage of motile sperm between individuals were noted in solutions containing high concentrations of chemicals triggering sperm motility. The optimum osmolality for spermatozoa motility is in the range of 100 200 mOsm kg-1. The burbot spermatozoa were motile over a wide range of pH values with the best activation at pH 9. CONCLUSION: It was demonstrated that the spermatozoa of European burbot are inhibited by K+ ions similarly as in North American burbot. Other electrolyte and non-electrolyte solutions inhibit spermatozoa movement only if their osmolality is greater than that of the physiological osmolality of seminal plasma. The data provided on basic knowledge of burbot spermatozoa allow to ensure appropriate conditions during artificial reproduction and scientific research. PMID- 29768447 TI - The role of social relationships in the link between olfactory dysfunction and mortality. AB - Recent work suggests that olfactory dysfunction is a strong predictor of five year mortality in older adults. Based on past work showing: 1) that olfactory dysfunction impairs social functioning and 2) that social ties are linked with mortality, the current work explored whether impairments in social life mediated the relationship between olfactory dysfunction and mortality. Additionally, based on work showing gender differences in the social consequences of olfactory dysfunction, gender was assessed as a potential moderator of this association. Social network size mediated the olfactory-mortality link for females. To probe what feature of social networks was driving this effect, we investigated two subcomponents of social life: emotional closeness (e.g., perceived social support, loneliness) and physical closeness (e.g., physical contact, in-person socializing with others). Physical closeness significantly mediated the olfactory mortality link for females, even after controlling for social network size. Emotional closeness did not mediate this link. Possible mechanisms underlying this relationship are discussed. PMID- 29768448 TI - Urinary shedding of pathogenic Leptospira in stray dogs and cats, Algiers: A prospective study. AB - BACKGROUND: Leptospirosis is an important worldwide zoonosis. This disease is caused by pathogenic species of the genus Leptospira which are maintained in the environment via chronic renal infection of carrier animals which can be asymptomatic excretors of the organisms in their urines and become a source of infection for humans and other hosts. The prevalence of animal leptospirosis in Algiers, Algeria, is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Real-time PCR and standard PCR and sequencing were used to detect pathogenic Leptospira organisms in the urines of stray dogs and cats in Algiers. In the presence of appropriate controls, none of the 107 cat urine samples were positive while 5/104 (4.8%) canine urine samples (asymptomatic mixed-breed dogs, three females and two males) were positive in two real-time PCR assays targeting the rrs and hsp genes. The positivity of these samples was confirmed by partial PCR-sequencing of the rpoB gene which yielded 100% sequence similarity with Leptospira interrogans reference sequence. In this study, L. interrogans prevalence was significantly higher in dogs aged < one year (16.46% - 29.41%) than in adults (0%) (P value = 0.0001) and then in the overall dog population (2.68% - 4.8%) (P = 0.0007). CONCLUSIONS/SIGNIFICANCE: These results suggest that dogs are maintenance hosts for zoonotic leptospirosis in Algiers, Algeria. To face this situation, effective canine vaccination strategies and raising public health awareness are mandatory. Further investigations incorporating a larger sample in more localities will be undertaken to document the epidemiology of urban animal leptospirosis in Algeria at large. PMID- 29768450 TI - A VVWBO-BVO-based GM (1,1) and its parameter optimization by GRA-IGSA integration algorithm for annual power load forecasting. AB - Annual power load forecasting is not only the premise of formulating reasonable macro power planning, but also an important guarantee for the safety and economic operation of power system. In view of the characteristics of annual power load forecasting, the grey model of GM (1,1) are widely applied. Introducing buffer operator into GM (1,1) to pre-process the historical annual power load data is an approach to improve the forecasting accuracy. To solve the problem of nonadjustable action intensity of traditional weakening buffer operator, variable weight weakening buffer operator (VWWBO) and background value optimization (BVO) are used to dynamically pre-process the historical annual power load data and a VWWBO-BVO-based GM (1,1) is proposed. To find the optimal value of variable weight buffer coefficient and background value weight generating coefficient of the proposed model, grey relational analysis (GRA) and improved gravitational search algorithm (IGSA) are integrated and a GRA-IGSA integration algorithm is constructed aiming to maximize the grey relativity between simulating value sequence and actual value sequence. By the adjustable action intensity of buffer operator, the proposed model optimized by GRA-IGSA integration algorithm can obtain a better forecasting accuracy which is demonstrated by the case studies and can provide an optimized solution for annual power load forecasting. PMID- 29768449 TI - Children with type 1 diabetes who experienced a honeymoon phase had significantly lower LDL cholesterol 5 years after diagnosis. AB - IMPORTANCE: Landmark studies showed that partial clinical remission in new-onset type 1 diabetes is associated with reduced prevalence of long-term complications, but early clinical indicators of this favorable outcome are poorly characterized. AIM: To determine if there were any differences in lipid parameters, especially LDL-cholesterol, between remitters and non-remitters 4 to 5 years after the diagnosis of type 1 diabetes after controlling for hemoglobin A1c, body mass index, and pubertal status. SUBJECTS AND METHODS: A longitudinal retrospective cohort study of 123 subjects of mean age 11.9 +/- 2.9 years, [male 11.7 +/- 2.9 years, (n = 55); female 12.0 +/- 2.9 years, (n = 68), p = 0.60] with type 1 diabetes of 4-5 years duration. Anthropometric and biochemical data were collected at the 4th or 5th year after diagnosis in line with the American Diabetes Association recommendation to initiate screening for complications in children either at the beginning of puberty or 4-5 years after diagnosis. Puberty was defined by Tanner stages II-V. Partial clinical remission was defined by the gold-standard insulin-dose adjusted hemoglobin A1c (IDAA1c) of <=9. RESULTS: There were 44 (35.8%) remitters (age 13.0 +/- 2.5y; male 52.3%). Both the total cholesterol and LDL-cholesterol were significantly lower in remitters compared to non-remitters: LDL-C: 78.8 +/- 28.7 mg/dL vs. 91.6 +/- 26.5 mg/dL, p = 0.023; and total cholesterol: 151.5 +/- 32.6 mg/dL vs. 167.0 +/- 29.6 mg/dL, p = 0.015. Other lipid fractions were similar between the groups. There were no differences between the groups for glycemic control, body mass index z score, thyroid function, celiac disease occurrence, or vitamin D status. A greater number of remitters were in puberty compared to non-remitters (86.4% vs. 60.8%, p = 0.006). LDL-C concentration was similar in prepubertal remitters vs. non-remitters (p = 0.93), but was significantly lower in remitters in puberty compared to non remitters in puberty (p = 0.018) after adjusting for age and duration of diabetes. CONCLUSIONS: Children with type 1 diabetes who underwent a honeymoon phase had significantly lower LDL cholesterol 5 years after diagnosis. This early divergence in lipidemia may explain the dichotomy in the prevalence of long-term complication in type 1 diabetes between remitters and non-remitters. It also offers a pathway for targeted lipid monitoring in type 1 diabetes, by establishing non-remission as a non-modifiable risk factor for vascular complication in type 1 diabetes. PMID- 29768451 TI - Intravitreal ocriplasmin for the treatment of vitreomacular traction and macular hole- A study of efficacy and safety based on NICE guidance. AB - PURPOSE: To evaluate the real world clinical outcomes of intravitreal ocriplasmin in patients with vitreomacular traction (VMT) with and without full thickness macular holes (FTMH) treated according to NICE guidance. METHODS: Retrospective observational case series of 25 patients treated with a single intravitreal ocriplasmin injection between December 2013 and December 2015. Best corrected visual acuity and optical coherence tomography exams were performed to determine visual outcomes and anatomical VMT release and FTMH closure over time. Two patient groups were identified: ocular macular co-morbidity (OCM) and no OCM (nOCM), with follow-up at 4, 12, and 24 weeks. RESULTS: Twenty-five patients were identified that included 19 patients with VMT, and 6 patients with VMT plus FTMH. In the nOCM group of 22 patients, the release rate of VMT was 44%, 63%, and 69% at 4, 12 and 24 weeks respectively. In the "real-world" OCM group of 25 patients, the VMT release rate was 37%, 53%, and 58% at the same time-points. In both groups, the FTMH closure rate was 33%, 50%, and 67% at 4, 12, and 24 weeks. At mean follow-up of 30 weeks in the VMT group with nOCM, the mean LogMAR VA improved significantly from 0.44 to 0.28 (p = 0.0068, paired t-test). Three were no serious adverse events. CONCLUSIONS: This study reports improved efficacy of intravitreal ocriplasmin for both VMT and FTMH, and is more favourable in patients with no ocular co-morbidity. We highlight the importance of careful patient selection and structured standard of care pathways to identify patients who will benefit from the positive visual and anatomical effects of intravitreal ocriplasmin. PMID- 29768452 TI - Tyrosine nitration of cytosolic peroxidase is probably triggered as a long distance signaling response in sunflower seedling cotyledons subjected to salt stress. AB - Present work focuses on tissue and concentration-dependent effect of nitric oxide (NO) on the modulation of cytosolic peroxidase (POD; EC 1.11.1.7) activity in 2 day old etiolated sunflower (Helianthus annuus L.) seedlings. Exogenously supplied NO (in the form of sodium nitroprusside [SNP] or diethylenetriamine NONOate [DETA]; 125 to 500 MUM) results in noteworthy enhancement in seedling growth in a concentration dependent manner irrespective of salt-stress and differentially affects POD activity in 2-day old seedling cotyledons. Elevated NO availability leads to an increase in the specific activity of POD in a concentration-dependent manner within 48 hrs as a rapid signaling response. Purification of POD protein using immunoprecipitation technique has shown that cotyledons derived from salt stressed seedlings exhibit a higher extent of tyrosine nitration of POD as compared to the control seedlings. Out of the four tyrosine residues found in the amino acid sequence of POD, the one at position 100 has been predicted to undergo nitration. Thus, a probable NO-POD crosstalk is evident in sunflower seedling cotyledons accompanying salt stress. PMID- 29768453 TI - Spatiotemporal characteristics of elderly population's traffic accidents in Seoul using space-time cube and space-time kernel density estimation. AB - The purpose of this study is to analyze how the spatiotemporal characteristics of traffic accidents involving the elderly population in Seoul are changing by time period. We applied kernel density estimation and hotspot analyses to analyze the spatial characteristics of elderly people's traffic accidents, and the space-time cube, emerging hotspot, and space-time kernel density estimation analyses to analyze the spatiotemporal characteristics. In addition, we analyzed elderly people's traffic accidents by dividing cases into those in which the drivers were elderly people and those in which elderly people were victims of traffic accidents, and used the traffic accidents data in Seoul for 2013 for analysis. The main findings were as follows: (1) the hotspots for elderly people's traffic accidents differed according to whether they were drivers or victims. (2) The hourly analysis showed that the hotspots for elderly drivers' traffic accidents are in specific areas north of the Han River during the period from morning to afternoon, whereas the hotspots for elderly victims are distributed over a wide area from daytime to evening. (3) Monthly analysis showed that the hotspots are weak during winter and summer, whereas they are strong in the hiking and climbing areas in Seoul during spring and fall. Further, elderly victims' hotspots are more sporadic than elderly drivers' hotspots. (4) The analysis for the entire period of 2013 indicates that traffic accidents involving elderly people are increasing in specific areas on the north side of the Han River. We expect the results of this study to aid in reducing the number of traffic accidents involving elderly people in the future. PMID- 29768454 TI - fiReproxies: A computational model providing insight into heat-affected archaeological lithic assemblages. AB - Evidence for fire use becomes increasingly sparse the further back in time one looks. This is especially true for Palaeolithic assemblages. Primary evidence of fire use in the form of hearth features tends to give way to clusters or sparse scatters of more durable heated stone fragments. In the absence of intact fireplaces, these thermally altered lithic remains have been used as a proxy for discerning relative degrees of fire use between archaeological layers and deposits. While previous experimental studies have demonstrated the physical effects of heat on stony artefacts, the mechanisms influencing the proportion of fire proxy evidence within archaeological layers remain understudied. This fundamental study is the first to apply a computer-based model (fiReproxies) in an attempt to simulate and quantify the complex interplay of factors that ultimately determine when and in what proportions lithic artefacts are heated by (anthropogenic) fires. As an illustrative example, we apply our model to two hypothetical archaeological layers that reflect glacial and interglacial conditions during the late Middle Palaeolithic within a generic simulated cave site to demonstrate how different environmental, behavioural and depositional factors like site surface area, sedimentation rate, occupation frequency, and fire size and intensity can, independently or together, significantly influence the visibility of archaeological fire signals. PMID- 29768455 TI - Ready for change: Oscillatory mechanisms of proactive motor control. AB - Proactive motor control is a preparatory mechanism facilitating upcoming action inhibition or adaptation. Previous studies investigating proactive motor control mostly focused on response inhibition, as in the classical go-nogo or stop-signal tasks. However, everyday life rarely calls for the complete suppression of actions without subsequent behavioral adjustment. Therefore, we conducted a modified cued go-nogo-change task, in which cues indicated whether participants might have to change to an alternative action or inhibit the response to an upcoming target. Based on the dual-mechanisms of control framework and using electroencephalography (EEG), we investigated the role of the sensorimotor cortex and of prefrontal regions in preparing to change and cancel motor responses. We focused on mu and beta power over sensorimotor cortex ipsi- and contralateral to an automatic motor response and on prefrontal beta power. Over ipsilateral sensorimotor cortex, mu and beta power was relatively decreased when anticipating to change or inhibit the automatic motor behavior. Moreover, alpha phase coupling between ipsilateral motor cortex and prefrontal areas decreased when preparing to change, suggesting a decoupling of sensorimotor regions from prefrontal control. When the standard motor action actually had to be changed, prefrontal beta power increased, reflecting enhanced cognitive control. Our data highlight the role of the ipsilateral motor cortex in preparing to inhibit and change upcoming motor actions. Here, especially mu power and phase coupling seem to be critical to guide upcoming behavior. PMID- 29768456 TI - The hidden costs: Identification of indirect costs associated with acute gastrointestinal illness in an Inuit community. AB - BACKGROUND: Acute gastrointestinal illness (AGI) incidence and per-capita healthcare expenditures are higher in some Inuit communities as compared to elsewhere in Canada. Consequently, there is a demand for strategies that will reduce the individual-level costs of AGI; this will require a comprehensive understanding of the economic costs of AGI. However, given Inuit communities' unique cultural, economic, and geographic contexts, there is a knowledge gap regarding the context-specific indirect costs of AGI borne by Inuit community members. This study aimed to identify the major indirect costs of AGI, and explore factors associated with these indirect costs, in the Inuit community of Rigolet, Canada, in order to develop a case-based context-specific study framework that can be used to evaluate these costs. METHODS: A mixed methods study design and community-based methods were used. Qualitative in-depth, group, and case interviews were analyzed using thematic analysis to identify and describe indirect costs of AGI specific to Rigolet. Data from two quantitative cross-sectional retrospective surveys were analyzed using univariable regression models to examine potential associations between predictor variables and the indirect costs. RESULTS/SIGNIFICANCE: The most notable indirect costs of AGI that should be incorporated into cost-of-illness evaluations were the tangible costs related to missing paid employment and subsistence activities, as well as the intangible costs associated with missing community and cultural events. Seasonal cost variations should also be considered. This study was intended to inform cost of-illness studies conducted in Rigolet and other similar research settings. These results contribute to a better understanding of the economic impacts of AGI on Rigolet residents, which could be used to help identify priority areas and resource allocation for public health policies and programs. PMID- 29768457 TI - Choice of time horizon critical in estimating costs and effects of changes to HIV programmes. AB - BACKGROUND: Uganda changed its antiretroviral therapy guidelines in 2014, increasing the CD4 threshold for antiretroviral therapy initiation from 350 cells/MUl to 500 cells/MUl. We investigate what effect this change in policy is likely to have on HIV incidence, morbidity, and programme costs, and estimate the cost-effectiveness of the change over different time horizons. METHODS: We used a complex individual-based model of HIV transmission and antiretroviral therapy scale-up in Uganda. 100 model fits were generated by fitting the model to 51 demographic, sexual behaviour, and epidemiological calibration targets, varying 96 input parameters, using history matching with model emulation. An additional 19 cost and disability weight parameters were varied during the analysis of the model results. For each model fit, the model was run to 2030, with and without the change in threshold to 500 cells/MUl. RESULTS: The change in threshold led to a 9.7% (90% plausible range: 4.3%-15.0%) reduction in incidence in 2030, and averted 278,944 (118,452-502,790) DALYs, at a total cost of $28M (-$142M to +$195M). The cost per disability adjusted life year (DALY) averted fell over time, from $3238 (-$125 to +$29,969) in 2014 to $100 (-$499 to +$785) in 2030. The change in threshold was cost-effective (cost <3*Uganda's per capita GDP per DALY averted) by 2018, and highly cost-effective (cost